PMID- 24044449 TI - A reply. PMID- 24044450 TI - The analgesic efficacy and safety of neuraxial magnesium sulphate. PMID- 24044451 TI - Magnesium sulphate and postoperative pain. PMID- 24044452 TI - Checking the secondary oxygen supply. PMID- 24044453 TI - A reply. PMID- 24044454 TI - Preservative-free bicarbonate for epidural top-up. PMID- 24044455 TI - Closing the door on fire. PMID- 24044459 TI - Effects of gaseous sulphuric acid on diesel exhaust nanoparticle formation and characteristics. AB - Diesel exhaust gaseous sulphuric acid (GSA) concentrations and particle size distributions, concentrations, and volatility were studied at four driving conditions with a heavy duty diesel engine equipped with oxidative exhaust after treatment. Low sulfur fuel and lubricant oil were used in the study. The concentration of the exhaust GSA was observed to vary depending on the engine driving history and load. The GSA affected the volatile particle fraction at high engine loads; higher GSA mole fraction was followed by an increase in volatile nucleation particle concentration and size as well as increase of size of particles possessing nonvolatile core. The GSA did not affect the number of nonvolatile particles. At low and medium loads, the exhaust GSA concentration was low and any GSA driven changes in particle population were not observed. Results show that during the exhaust cooling and dilution processes, besides critical in volatile nucleation particle formation, GSA can change the characteristics of all nucleation mode particles. Results show the dual nature of the nucleation mode particles so that the nucleation mode can include simultaneously volatile and nonvolatile particles, and fulfill the previous results for the nucleation mode formation, especially related to the role of GSA in formation processes. PMID- 24044460 TI - BMP4 is involved in the chemoresistance of myeloid leukemia cells through regulating autophagy-apoptosis balance. AB - This study showed that silencing BMP4 expression significantly activated caspase 2, 3, and 9, while decreasing Matrigel colony formation in Cytarabine (Ara-C) treated leukemia HL-60 cells. In contrast, Ara-C significantly upregulated Atg5 and Beclin-1 expression, the ratio of LC3-II/LC3-I, and CDK1 and cyclin B1 expression in leukemia cells expressing BMP4. BafA significantly sensitized the apoptotic effect of Ara-C in leukemia cells. Injection of Ara-C significantly inhibited tumor growth in mice inoculated with leukemia cells with BMP4 silenced. In conclusion, BMP4 plays a crucial role in the chemoresistance of leukemia cells through the activation of autophagy and subsequent inhibition of apoptosis. PMID- 24044461 TI - Nanocrystalline hydroxyapatite-based material already contributes to implant stability after 3 months: a clinical and radiologic 3-year follow-up investigation. AB - The present study reports on a 3-year clinical and radiologic follow-up investigation of dental implants placed 3 and 6 months after sinus augmentation in 14 patients. Augmentation was performed with a synthetic bone substitute material composed of nanocrystalline hydroxyapatite. The aim of the study was to determine how the integration period of the bone substitute material, that is, 3 months or 6 months, influences implant integration within the patient's upper jaw. Therefore, the following clinical and radiologic parameters were investigated: implant being in situ; Periotest value; and presence of peri implant osteolysis, bleeding on probing, plaque, and soft tissue recession around the implants. At the follow-up investigation 3 years after placement, 23 of 24 implants were in situ and suitable for prosthetic rehabilitation. No implants in either study group were mobile or showed peri-implant osteolysis. Only a few implants showed plaque or soft tissue variations. Within its limits, the present study showed comparable clinical performance of dental implants placed 3 months after sinus floor augmentation to implants placed 6 months after augmentation. The results of all investigated parameters were in accordance with results found in the literature. It can be concluded that augmentation with the applied synthetic bone substitute material already forms a sufficient implantation bed 3 months after augmentation, which enables long-term, stable, implant-retained restoration. These findings might contribute to a reduced healing time after augmentation, which would be favorable for patients and clinicians. PMID- 24044462 TI - Proteogenomic definition of biomarkers for the large Roseobacter clade and application for a quick screening of new environmental isolates. AB - Whole-cell, matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF) mass spectrometry has become a routine and reliable method for microbial characterization due to its simplicity, low cost, and high reproducibility. The identification of microbial isolates relies on the spectral resemblance of low molecular-weight proteins to already-existing isolates within the databases. This is a gold standard for clinicians who have a finite number of well-defined pathogenic strains but represents a problem for environmental microbiologists with an overwhelming number of organisms to be defined. Here we set a milestone for implementing whole-cell MALDI-TOF mass spectrometry to identify isolates from the biosphere. To make this technique accessible for environmental studies, we propose to (i) define biomarkers that will always show up with an intense m/z signal in the MALDI-TOF spectra and (ii) create a database with all the possible m/z values that these biomarkers can generate to screen new isolates. We tested our method with the relevant marine Roseobacter lineage. The use of shotgun nanoLC-MS/MS proteomics on the small proteome fraction of nine Roseobacter strains and the proteogenomic toolbox helped us to identify potential biomarkers in terms of protein abundance and low variability among strains. We show that the DNA binding protein, HU, and the ribosomal proteins, L29 and L30, are the most robust biomarkers within the Roseobacter clade. The molecular weights of these three biomarkers, as for other conserved homologous proteins, vary due to sequence variation above the genus level. Therefore, we calculated the m/z values expected for each one of the known Roseobacter genera and tested our strategy during an extensive screening of natural marine isolates obtained from coastal waters of the Western Mediterranean Sea. The use of this technique versus standard sequencing methods is discussed. PMID- 24044463 TI - Human papillomavirus G-quadruplexes. AB - Infection with human papillomaviruses (HPVs) is one of the most common sexually transmitted infections and can lead to development of head and neck, skin, and anogenital cancer, including cervical cancer, which represents one of the world's most significant health problems. In this study, we analyze G-rich regions in all known HPV genomes in order to evaluate their potential to fold into G-quadruplex structure. Interestingly, G-rich loci fulfilling the criteria for G-quadruplex formation were found in only 8 types of HPV. Nevertheless, viral G-quadruplexes in 7 sequences derived directly from HPVs are confirmed here for the first time. G-rich regions with the capacity to form G-quadruplexes are located in the LCR, L2, E1, and E4 regions of the HPV genome; therefore we assume that regulation processes in viruses could be affected by G-quadruplex formation. Our results represent a starting point for the design of specific ligands with viral G quadruplex motifs and suggest novel methods for the control of viral replication and transcription. PMID- 24044465 TI - The role of community in public health. PMID- 24044464 TI - Assessing the relative timeliness of Ontario's syndromic surveillance systems for early detection of the 2009 influenza H1N1 pandemic waves. AB - OBJECTIVES: Building on previous research noting variations in the operation and perceived utility of syndromic surveillance systems in Ontario, the timeliness of these different syndromic systems for detecting the onset of both 2009 H1N1 pandemic (A(H1N1)pdm09) waves relative to laboratory testing data was assessed using a standardized analytic algorithm. METHODS: Syndromic data, specifically local emergency department (ED) visit and school absenteeism data, as well as provincial Telehealth (telephone helpline) and antiviral prescription data, were analyzed retrospectively for the period April 1, 2009 to January 31, 2010. The C2 MEDIUM aberration detection method from the US Centers for Disease Control and Prevention's EARS software was used to detect increases above expected in syndromic data, and compared to laboratory alerts, defined as notice of confirmed A(H1N1)pdm09 cases over two consecutive days, to assess relative timeliness. RESULTS: In Wave 1, provincial-level alerts were detected for antiviral prescriptions and Telehealth respiratory calls before the laboratory alert. In Wave 2, Telehealth respiratory calls similarly alerted in advance of the laboratory, while local alerts from ED visit, antiviral prescription and school absenteeism data varied in timing relative to the laboratory alerts. Alerts from syndromic data were also observed to coincide with external factors such as media releases. CONCLUSIONS: Alerts from syndromic surveillance systems may be influenced by external factors and variation in system operations. Further understanding of both the impact of external factors on surveillance data and standardizing protocols for defining alerts is needed before the use of syndromic surveillance systems can be optimized. PMID- 24044466 TI - The contribution of socio-economic position to the excesses of violence and intimate partner violence among aboriginal versus non-Aboriginal Women in Canada. AB - OBJECTIVE: To examine the contribution of socio-economic position (SEP) in explaining the excess of any abuse and intimate partner violence (IPV) among Aboriginal versus non-Aboriginal women in Canada. This comparison has not been studied before. METHODS: We conducted logistic regression analysis, using nationwide data from a weighted sample of 57,318 Canadian-born mothers of singletons who participated in the Canadian Maternity Experiences Survey 2006-7. RESULTS: The unadjusted odds of any abuse and IPV were almost four times higher among Aboriginal compared to non-Aboriginal mothers; OR 3.91 (95% CI 3.12-4.89) and OR 3.78 (2.87-4.97), respectively. Adjustment for SEP reduced the unadjusted OR of any abuse and IPV by almost 40%. However, even with this adjustment, the odds of any abuse and IPV for Aboriginal mothers remained twice that of non Aboriginal mothers; OR 2.34 (1.82-2.99) and OR 2.19 (1.60-3.00), respectively. CONCLUSIONS: SEP is a predominant contributor to the excess of abuse against Aboriginal vs. non-Aboriginal women in Canada. Reducing violence against Aboriginal women can be achieved mostly by improving their SEP, and simultaneously be informed by social processes and services that can mitigate abuse. The fact that SEP did not fully explain the excess of abuse among the Aboriginal women might lend support to "colonization or postcolonial theories," and related contextual factors such as differences in community social resources (e.g., social capital) and services. The effect of these factors on the excess of abuse warrants future research. PMID- 24044467 TI - Disparities in receipt of screening tests for cancer, diabetes and high cholesterol in Ontario, Canada: a population-based study using area-based methods. AB - OBJECTIVES: Few have compared socio-economic disparities in screening tests for cancer with recommended tests for other chronic diseases. We examined whether receipt of testing for colorectal, cervical and breast cancer, as well as diabetes and high cholesterol, differs by neighbourhood-level socio-economic and recent immigrant status. METHODS: We conducted a population-based retrospective cohort study of patients identified as screen-eligible in 2009 living in Ontario, Canada. Postal codes were used to assign residents to a dissemination area (DA). Using Canadian census data, DAs were stratified by income quintile and proportion of recent immigrants. Prevalence of screening for cancer (colorectal, cervical, breast), diabetes, and high cholesterol, using administrative data, and prevalence ratios (least/most advantaged) were calculated. RESULTS: The cohort comprised 7,652,592 people. Receipt of screening for colorectal cancer (women 61.6%; men 55.1%) and breast cancer (59.9%) were the lowest and diabetes (women 72.9%; men 61.4%) and high cholesterol (women 82.4%; men 70.3%) were the highest. We found disparities in the receipt of all tests, with the lowest uptake and largest disparities for cancer screening among those living in both low-income and high-immigration DAs: colorectal - women 48.6%; RR 0.77; 95% CI (0.74-0.79) and men 40.6%; RR 0.71 (0.68-0.74); cervical - 52.0%; RR 0.80 (0.78-0.81) and breast - 45.7%; RR 0.74 (0.72-0.77). CONCLUSION: People living in low-income and high-immigration DAs had the lowest screening participation for all tests, although disparities were highest for cancer. An organized integrated chronic disease screening strategy leveraging the higher diabetes and high cholesterol screening participation may increase screening for cancer and other chronic diseases in never- and underscreened populations. PMID- 24044468 TI - Prevalence of vitamin D insufficiency and associated factors among Canadian Cree: a cross-sectional study. AB - OBJECTIVES: Aboriginal peoples affected by a nutrition transition and living at high latitudes are among the ethnic groups most at risk of vitamin D deficiency. The objectives of this study were to determine the prevalence of meeting predefined cut-off concentrations of vitamin D and to examine associated factors among James Bay Cree aged >= 15 years. METHODS: A cross-sectional study was conducted between the months of May and September from 2005 to 2009. Serum 25 hydroxyvitamin D (25(OH)D) concentrations were determined by radioimmunoassay. Anthropometrics were measured and additional information on socio-demographic characteristics, lifestyle and dietary habits was obtained using questionnaires. A logistic regression model predicting vitamin D insufficiency (<50 nmol/L) included known covariates. RESULTS: Data were obtained from 944 Cree (406 men (43%); mean age 37.4 years), with an effective participation rate of 49% among women and 41% among men. Mean serum 25(OH)D concentrations (nmol/L) by gender were 52.9 (95% CI 51.4-54.5) in men and 47.5 (95% CI 46.2-48.9) in women, and by age group were 46.0 (95% CI 44.9-48.9) in those 15-39 years and 59.6 (95% CI 57.9 61.4) in those >= 40 years of age. Overall, 5.8%, 42.6%, 40.0%, and 11.7% of the participants had 25(OH)D concentrations <30, 30-49.9, 50-74.9 and >= 75 nmol/L, respectively. Female gender, obesity, younger age, spring, low fish and milk intake, and low vigorous physical activity predicted vitamin D insufficiency (all p<0.05). CONCLUSION: The vitamin D status in Eastern James Bay Cree is suboptimal with nearly half of the population having insufficient concentrations for optimum bone health. PMID- 24044469 TI - Predictors of obesity among Metis children: socio-economic, behavioural and cultural factors. AB - OBJECTIVES: To examine the socio-economic, behavioural and Metis-specific factors that predict obesity among Metis children aged 6 to 14 years. Socio-economic factors included household structure and income, parental education and food insecurity. Cultural factors included knowledge of an Aboriginal language, participation in cultural activities, time spent with Elders and parental residential school attendance. METHODS: The 2006 Aboriginal Peoples Survey, Children and Youth component collected data about Metis children, including child height and weight, reported by the person most knowledgeable about the child (PMK). Multivariate binary logistic regression was used to predict obesity, defined using IOTF BMI cut-offs. After testing for interactions, models were stratified by age (6-10, 11-14) and gender. RESULTS: An estimated 18.5% of Metis boys and 14.4% of girls were obese. The effects of socio-economic factors and region varied across age and gender groups, although living in a lone-parent family and rural residence had consistent effects. Many effects of cultural variables were unexpected. Although PMK residential schooling was positively associated with obesity generally, the effects were negative among older girls. As expected, children participating in frequent physical activity generally had lower risk, independent of other factors. CONCLUSIONS: Although socio-economic factors are related to risk of obesity among Metis children, the effects may not be the same across age groups and for boys and girls. There is some evidence of independent effects of Metis-specific cultural factors, including parental residential schooling, on the risk of child obesity, but further investigation and better data are needed to understand these relationships. PMID- 24044470 TI - Examining the capacities of municipal governments to reduce health inequities: a survey of municipal actors' perceptions in Metro Vancouver. AB - OBJECTIVES: Canada is an increasingly urban nation, with considerable health inequities (HI) within its urban centres. While Canadian municipalities have a range of policy and planning levers that could reduce the burden of HI, little is known about how municipal employees perceive the capacities of municipal governments to address HI within their jurisdictions. This study sought to capture these perceptions through a survey of politicians and senior-level staff working in Metro Vancouver municipalities. METHODS: The survey was administered by mail to 637 politicians and senior-level staff from 17 municipal governments in Metro Vancouver. The survey captured respondents' perceptions on the responsibilities of, opportunities for, and constraints on, municipal-level action to address HI, as well as respondents' input on existing municipal policies and programs that could reduce HI in their jurisdictions. RESULTS: Respondents perceived senior governments to bear greater responsibility for reducing HI than municipalities. Investing in "parks & recreation facilities" was considered the most promising policy lever for addressing HI, while "insufficient federal and provincial funding" was perceived to be the greatest constraint on municipal action. "Affordable housing" and "recreational programs" were the most commonly identified existing strategies to address HI in the municipalities sampled. CONCLUSIONS: Our findings revealed concerns about inter-governmental downloading of responsibilities, and behaviour-based assumptions of disease etiology. To advance an urban health equity agenda, more work is needed to engage and educate municipal actors from a range of departments on the social determinants of health inequities. PMID- 24044471 TI - Should we enhance the commonly used deprivation index for a regional context? AB - BACKGROUND/OBJECTIVES: Versions of deprivation indices have been increasingly used to monitor patterns and magnitudes of inequality in health. For policy makers, it is of interest to assess whether they need to construct regionally tailored indices, or whether the existing indices perform sufficiently in detecting inequalities in their respective jurisdiction. Few studies have explored the benefits of constructing a more tailored index for a regional context. METHODS: The study examined, in linear regression models, the proportion of variance (adjusted R2) explained in age-standardized cardiovascular disease (CVD) incidence rate ratios by an index emulating a now-widely-used multiple deprivation index created in Quebec (INSPQI), and a newly created index for Nova Scotia with additional census variables. The magnitudes of inequality were compared by the differences between mean incidences of most and least deprived groups. RESULTS: The newly created deprivation index did not explain as well as the INSPQI-like index the community-level variability in CVD incidences. The gap in mean CVD incidences between the most and least deprived groups was somewhat narrower with the new index, indicating that the new index is not necessarily more sensitive to the inequality attributed to community social disadvantages. CONCLUSIONS: Complicating the indices may not necessarily be of benefit when used for surveillance of population health inequalities. For public health practitioners and decision makers who need to make quick decisions in provisions of services and programs, a generic, well-established deprivation index such as INSPQI can serve well in a regional context. PMID- 24044473 TI - Diet quality and feelings of worry, sadness or unhappiness in Canadian children. AB - OBJECTIVE: To examine the association between diet quality and feelings of worry, sadness or unhappiness in Canadian children. METHODS: Responses to the Harvard Food Frequency Questionnaire of 6,528 grade 5 students were used to calculate a composite score of diet quality, and its components: variety, adequacy, moderation and balance. Responses to the question on "feelings of worry, sadness or unhappiness" from the EuroQoL 5 Dimension questions for Youth (EQ-5D-Y), a validated Health Related Quality of Life questionnaire, constitute the outcome of interest. Multilevel logistic regression methods were used to examine the association between diet quality and feelings of worry, sadness or unhappiness. All analyses were adjusted for gender, household income, parental education, energy intake, weight status, physical activity level, geographic area and year of data collection. RESULTS: Diet quality was inversely associated with children's feelings of worried, sad or unhappy (Odds ratio (95% confidence interval): 0.90 (0.85-0.97)). Dietary variety and dietary adequacy were also statistically significantly associated with lower odds of feeling worried, sad or unhappy. When the results were stratified by gender, the effect of diet on feeling worried, sad or unhappy was more pronounced in girls than boys. CONCLUSION: These findings suggest that diet quality plays a role in feelings of worry, sadness or unhappiness and complement other studies that have suggested the link between diet and mental health. We recommend consideration of diet quality in public health strategies that aim to reduce the burden of poor mental health in children and youth. PMID- 24044472 TI - Decreased prevalence of overweight and obesity in the newfoundland and labrador preschool population. AB - OBJECTIVE: This study was conducted to determine the prevalence of overweight and obesity in preschool-aged (42-66 months) children in Newfoundland and Labrador in 2009/10. Second, 2009/10 rates were compared to those reported for 2001/02 and 1988/89 to ascertain whether the previous rising trend had continued, stabilized or decreased while public health prevention and intervention efforts increased. METHODS: Heights and weights of children measured in clinics in 2009/10, 2001/02 and 1988/89 were sampled, representing 29%, 77% and 45% of provincial births in 2005, 1997 and 1984, respectively. Body mass indices were calculated and classified as overweight, obese or neither, using World Health Organization (WHO) growth charts. ANOVA and regression procedures were used to compare cohorts. RESULTS: Combined overweight and obesity was significantly lower in 2009/10 (35.7%) than in 2001/02 (38.9%), (OR 0.87, 95% CI 0.76-0.99). Considered separately, both overweight and obesity rates stabilized. Boys were 1.4 times more likely to be overweight or obese than girls in all samples. In 2009/10, combined overweight and obesity was higher in rural areas (OR 1.67, 95% CI 1.28 2.18). In three of four public health jurisdictions, prevalence in 2009/10 remained significantly higher than 20 years earlier. In one region, rates returned to 1988/89 levels. CONCLUSION: Progress has been made in stabilizing, even reversing, overweight and obesity in the Newfoundland and Labrador preschool population, however, prevalence rates remain high. Surveillance and intervention efforts must continue. Given the jurisdictional and regional differences found, further research should compare ecological contexts and thus attempt to isolate and identify important contributing factors and effective interventions. PMID- 24044474 TI - The corporate determinants of health: how big business affects our health, and the need for government action! AB - Corporations have a great effect on the health of Canadians.Good companies create jobs, sell valued products at market value, pay a living wage, empower employees, have progressive human resource policies (parental, mental health leaves, workplace wellness programs, day care), and pay their appropriate corporate taxes. They embrace corporate social responsibility and some have a triple bottom line - people, planet and profits. More good corporations are needed.But others are selling products that are damaging to health and the environment, at prices that do not account for these damaging effects and often target consumers that are ill-informed and susceptible (e.g., children). These include businesses involving tobacco, alcohol, drugs, junk foods and beverages, resource extraction, arms production and the electronic media.Governments have a responsibility to take action when the market mechanism fails in this way.A priority for action is the food and beverage sector. The overconsumption of sugar, fat and salt is causing a rising prevalence of all the major chronic diseases, rising health care costs and declining population health and productivity. Urgent government action is required: taxation, advertising and sales restrictions, and a salt reduction program. PMID- 24044475 TI - Diabetes care and mental illness: the social organization of food in a residential care facility. AB - OBJECTIVE: To explore the social organization of food provision and dietary intake in seriously mentally ill people with diabetes who reside in a for-profit group home. METHODS: Institutional ethnography was used to explore diabetes related care practices among 26 women in a rural residential care facility in southern Ontario. Semi-structured, in-depth interviews were conducted with residents with diabetes, care providers, field workers, and health professionals. Observations and document analysis were also used to understand the lack of congruence between diabetes guidelines and the possibilities for diabetes management within the confines of group home care. RESULTS: Although it was mandated in group home guidelines that "Health Canada's Eating Well with Canada's Food Guide" (2007) be followed, menus were planned within the context of a limited food budget of approximately $1.91 per day per resident. Group home policies regulated systems of safety, reporting, and financial accountability, but not health promotion. Inspections carried out by the Public Health Department focused primarily on food safety during handling, preparation, and storage, and compliance to regulations regarding environmental cleanliness and infection control. CONCLUSION: Resource rationing found in group home care exacerbates illness in an already marginalized group. Financial support is required to enable provision of healthy food choices, including dairy products, fresh fruits, and vegetables. Additional support is required for care of co-morbid conditions such as diabetes for associated food costs and education to improve outcomes. Group home policies must take into consideration health threats to this population and give primacy to health promotion and illness prevention. PMID- 24044476 TI - Challenges to the surveillance of meningococcal disease in an era of declining incidence in montreal, Quebec. AB - OBJECTIVES: Though rare in Montreal, meningococcal disease continues to cause serious morbidity and mortality. In an era of declining incidence, our objective was to evaluate the sensitivity and the timeliness of case reporting and the capacity to statistically detect disease clusters. METHODS: We used the public health department's reportable disease database (RDD) to calculate the timeliness of reporting by physicians and laboratories for the period 1995 to 2008. The sensitivity of case reporting was evaluated through capture-recapture estimation using the RDD and the hospitalization discharge database (MED-ECHO). To evaluate the detection of cases clustered by time and proximity, we applied scan statistics to the RDD with cases coded by time and geographic location for the period 1992 to 2008. RESULTS: While the system sensitivity was judged to be high at 94%, physicians reported only 54% of cases. A total of 92.3% of cases were notified by physicians or laboratories within seven days, meaning that in theory, 13 cases were not notified in time to conduct thorough contact tracing and offer chemoprophylaxis to close contacts. In high-incidence years, scan statistics detected two statistically-significant clusters one to two weeks earlier than traditional detection through the manual monitoring of cumulative cases. CONCLUSIONS: To improve system performance, we recommended increasing the emphasis of laboratory reporting, reinforcing early reporting by physicians and if incidence increases, using scan statistics to identify clusters that can add to a public health practitioner's initial "hunch" of an emerging outbreak. PMID- 24044477 TI - The power and pitfalls of HIV phylogenetics in public health. AB - Phylogenetics is the application of comparative studies of genetic sequences in order to infer evolutionary relationships among organisms. This tool can be used as a form of molecular epidemiology to enhance traditional population-level communicable disease surveillance. Phylogenetic study has resulted in new paradigms being created in the field of communicable diseases and this commentary aims to provide the reader with an explanation of how phylogenetics can be used in tracking infectious diseases. Special emphasis will be placed upon the application of phylogenetics as a tool to help elucidate HIV transmission patterns and the limitations to these methods when applied to forensic analysis. Understanding infectious disease epidemiology in order to prevent new transmissions is the sine qua non of public health. However, with increasing epidemiological resolution, there may be an associated potential loss of privacy to the individual. It is within this context that we aim to promote the discussion on how to use phylogenetics to achieve important public health goals, while at the same time protecting the rights of the individual. PMID- 24044478 TI - Breastfeeding difficulties and exclusivity among late preterm and term infants: results from the all our babies study. AB - OBJECTIVE: To compare breastfeeding difficulties attributable to the baby and mother/milk and exclusive breastfeeding between a group of late preterm (LP) infants and term infants. METHODS: We utilized data from a prospective community based cohort (n=2977) in Calgary, Alberta, and performed bivariate and multivariable analyses to identify demographic, obstetric, maternal and infant health indicators that were independently associated with term status and breastfeeding outcomes. RESULTS: Multivariable analyses found that LP status was an independent risk factor for breastfeeding difficulties attributable to the baby (OR 1.72, 95% CI 1.24-2.38), but not for difficulties due to mother/milk (defined as not producing enough milk or having flat or inverted nipples). Among women who were breastfeeding at hospital discharge, mothers of LP infants were less likely to report exclusive breastfeeding at 4 months (OR 0.67, 95% CI 0.46 0.97), after controlling for household income level, mode of delivery and postpartum maternal physical health. CONCLUSIONS: Mothers of LP infants need increased support to establish successful breastfeeding outcomes and to ensure that these infants receive the full benefits of breast milk. PMID- 24044479 TI - Active ciliated surfaces expel model swimmers. AB - Continually moving cilia on the surface of marine organisms provide a natural defense against biofouling. To probe the physical mechanisms underlying this antifouling behavior, we integrate the lattice Boltzmann and immersed boundary methods and undertake the first computational studies of the interactions between actuated, biomimetic cilia and a model swimmer. We find that swimmers are effectively "knocked away" from the ciliated surface through a combination of steric repulsion and locally fluctuating flows. In addition, the net flow generated by the collective motion of the entire ciliary array was important for significantly reducing the times spent by relatively slow swimmers near the surface. The results reveal that active ciliated layers can offer a means to resist a wide range of species with a single surface. PMID- 24044481 TI - Nanoreactors for simultaneous remote thermal activation and optical monitoring of chemical reactions. AB - We report herein the design of plasmonic hollow nanoreactors capable of concentrating light at the nanometer scale for the simultaneous performance and optical monitoring of thermally activated reactions. These reactors feature the encapsulation of plasmonic nanoparticles on the inner walls of a mesoporous silica capsule. A Diels-Alder cycloaddition reaction was carried out in the inner cavities of these nanoreactors to evidence their efficacy. Thus, it is demonstrated that reactions can be accomplished in a confined volume without alteration of the temperature of the bulk solvent while allowing real-time monitoring of the reaction progress. PMID- 24044482 TI - Interdisciplinary strategy to train graduate students in English communication for international academic conferences. PMID- 24044485 TI - New and emerging treatments for osteoarthritis management: will the dream come true with personalized medicine? AB - INTRODUCTION: Osteoarthritis (OA) is a dynamic process involving the main tissues of the joint for which a global approach should be considered. No disease modifying OA drug (DMOAD) has yet been approved. New therapeutic strategies are needed that would be cost effective by reducing the need for pharmacological interventions and surgical management while targeting specific pathways leading to OA. The treatment landscape of OA is about to change based on new agents having shown some structural effects and emerging therapies with DMOAD effects. AREAS COVERED: In this review based on a Medline (via PubMed) search, promising new and emerging therapies with a potential structural effect (DMOAD) will be discussed including growth factors, platelet-rich plasma, autologous stem cells, bone remodeling modulators, cytokine inhibition, gene therapy, and RNA interference. EXPERT OPINION: DMOAD development should focus on targeting some phenotypes of OA patients evidenced with sensitive techniques such as magnetic resonance imaging, as a single treatment will unlikely be appropriate for all OA patients. This will allow the development of DMOADs based on personalized medicine. An exciting new era in DMOAD development is within reach, provided future clinical trials are sufficiently powered, systematically designed, use the appropriate evaluation tools, and target the appropriate categories of OA patients. PMID- 24044484 TI - Mastocytosis: update on pharmacotherapy and future directions. AB - INTRODUCTION: Mastocytosis is a disorder characterized by abnormal mast cell (MC) accumulation in skin and internal organs such as bone marrow. The disease follows a benign course in most patients with cutaneous and indolent systemic mastocytosis (SM); however, advanced variants associated with decreased life expectancy also exist. Pharmacotherapy of mastocytosis is aimed at the control of symptoms caused by MC mediator release, treatment of comorbidities and cytoreductive therapies in advanced variants. AREAS COVERED: This article will cover the general treatment principles of anti-MC mediator and cytoreductive therapies of mastocytosis. The literature discussed was retrieved with PubMed using the search terms 'treatment of mastocytosis,' 'mastocytosis antimediator therapy' and looking for important cross-references. EXPERT OPINION: Pharmacotherapy of mastocytosis should be individualized for each patient considering the category of disease, reduction of risk of anaphylaxis, constitutional symptoms and comorbidities including osteoporosis. Cytoreductive therapies are generally reserved for patients with aggressive mastocytosis (ASM), MC leukemia (MCL) and MC sarcoma (MCS); however, some patients with indolent disease and recurrent anaphylactic episodes not responsive to antimediator therapies may also be considered for cytoreduction on a case-by-case basis. PMID- 24044487 TI - The changing landscape of scholarly publishing: will radiation research survive? AB - As a society published journal, Radiation Research has been a successful and enduring project of the Radiation Research Society (RRS). In 59 years of publication, the journal has produced 732 issues and 10,712 articles. As a nonprofit organization, RRS, like most societies, has used revenues from subscriptions to support, in part, the life of the organization (meetings, conferences and grants to new scholars). The model for scientific publishing, however, continues to evolve. Radiation Research has weathered the rise of electronic publishing, consolidation in the commercial publishing industry, the aggregation of library subscriptions and library subscription cuts. Recent years have seen dramatic changes in how scholarly publishing is financed and new funder and institution policies will accelerate these changes. The growth of open access to journal articles reflects the information habits of readers and facilitates the dissemination of new knowledge. The Radiation Research Society, however, will need to account for and adapt to changes in the publishing market if it intends to support the communication of peer reviewed scholarship in the future. PMID- 24044483 TI - Is pain reporting to health care professionals age-related? A cross sectional multicenter study in a hospital setting. AB - BACKGROUND: Failure to report pain by older patients is usually considered a major obstacle to receive adequate pain management. OBJECTIVES: To compare the frequency of reporting pain to health care professionals (HCPs) among older (>= 65 yrs) and younger adults (< 65 yrs) and to evaluate whether age and setting of care influence pain reporting to HCPs. RESULTS: Overall, 3285 patients (54.7 >= 65 yrs) were interviewed. Despite analgesic therapy, 2821 patients had pain. Among these, 1178 patients (41.8%) had severe pain. The frequency of patients not reporting pain to HCPs is significantly lower among older vs. younger adults (18.1 vs. 23.6%; p < 0.001). Multiple multilevel logistic regression, however, shows that nonreporting pain is not age-related, but is associated with: nonmalignant pain (OR = 1.53; 95% CI: 1.00 - 2.35; p = 0.05), a short hospitalization (OR = 1.58; 95% CI: 1.20 - 2.07; p = 0.001), admission to a hospital without a 'pain-free hospital' project (OR = 2.00; 95% CI: 1.18 - 3.39; p = 0.011). CONCLUSIONS: The results suggest that failure to report pain does not appear to be associated with the age of the patient in itself, but with type of pain and clinical context. Both patients and physicians should be encouraged to actively address pain management. Further research is needed. PMID- 24044488 TI - Rubus coreanus Miquel inhibits acetylcholinesterase activity and prevents cognitive impairment in a mouse model of dementia. AB - To find acetylcholinesterase (AChE) inhibitors for the prevention of neurological disorders, such as Alzheimer's disease, ethanol extracts of promising traditional edible Korean plants were tested. Among them, Rubus coreanus Miquel extract exhibited the most significant AChE inhibitory activity. The effect of R. coreanus extract on trimethyltin-induced memory impairment in mice was investigated using Y-maze and passive avoidance tests. Our results showed that administration of R. coreanus extract significantly improved alternation behavior and step-through latency. In addition, R. coreanus extract was sequentially fractionated, and the purified constituent was determined to be 3,4,5 trihydroxybenzoic acid. PMID- 24044489 TI - Saikosaponin a and saikosaponin d inhibit proliferation and migratory activity of rat HSC-T6 cells. AB - The proliferation and migration of hepatic stellate cells (HSCs) profoundly impact the pathogenesis of liver inflammation and fibrogenesis. As a perennial herb native to China, Bupleurum falcatum is administered for its anti inflammatory, antipyretic, and antihepatotoxic effects. Saikosaponin a (SSa) and Saikosaponin d (SSd) are the major active components of triterpene saponins in Bupleurum falcatum. This study analyzes how SSa and SSd affect rat HSC-T6 cell line proliferation and migration. Experimental results indicate that, in addition to suppressing HSC-T6 proliferation, wound healing activity and cell migration in a time- and dose-dependent manner, SSa and SSd significantly induce apoptosis. Additionally, SSa and SSd decreased the expressions of extracellular matrix regulated kinase 1/2 (ERK1/2), platelet-derived growth factor receptor 1 (PDGFR1), and subsequently transforming growth factor-beta1 receptor (TGF beta1R), alpha-smooth muscle actin, TGF-beta1 and connective tissue growth factor. They also decreased phosphorylation of p38 (p-p38) and ERK1/2 (p-ERK1/2) of HSC-T6. Furthermore, both SSa and SSd can block PDGF-BB and TGF-beta1-induced cell proliferation and migration of HSC-T6. These results suggest that SSa and SSd may inhibit proliferation and activation of HSC-T6, and the modulated mechanisms warrant further study. PMID- 24044490 TI - Effects of Telfairia occidentalis (fluted pumpkin; Cucurbitaceae) in mouse models of convulsion, muscle relaxation, and depression. AB - Telfairia occidentalis (Cucurbitaceae) is a leafy vegetable used in soup and folk medicine in southern Nigeria. Ethnobotanical survey revealed that preparations of the plant are used in the treatment of central nervous system-related disorders including convulsion. This study was conducted to investigate the effect of the hydroethanolic leaf extract of T. occidentalis in mouse models of convulsion, muscle relaxation, and depression. The strychnine and isoniazid convulsion, traction and climbing muscle relaxation, and forced swim and tail suspension depression tests were used in this study. The extract was administered orally (p.o.) at dose range of 25-800 mg/kg while distilled water (10 mL/kg p.o.) served as negative control. Diazepam (5 mg/kg p.o.) was used as positive control in the convulsion and muscle relaxation models while imipramine (64 mg/kg p.o.) served the same purpose in the depression tests. T. occidentalis significantly increased the onset (P<.001) and reduced the duration of convulsion (P<.05, .01) in the strychnine test and increased the time to death (P<.05, .01, .001) in the isoniazid model. The extract insignificantly increased the reaction time in the traction test while it significantly increased the time in the climbing test (P<.001). In the forced swim and tail suspension models, T. occidentalis significantly (P<.001) and dose-dependently increased the duration of immobility. The results obtained in this study suggest that the hydroethanolic leaf extract of T. occidentalis possesses anticonvulsant and muscle relaxant properties, thus justifying its folkloric use. PMID- 24044491 TI - Olive leaf extracts are a natural source of advanced glycation end product inhibitors. AB - Advanced glycation end products (AGEs), which are readily formed and accumulated with sustained hyperglycemia, contribute to the development of diabetic complications. As a consequence, inhibition of AGE formation constitutes an attractive therapeutic/preventive target. In the current study, we explored the phytochemical composition and the in vitro effect of two different olive leaf extracts (an aqueous and a methanolic) on AGE formation. The methanolic olive leaf extract inhibited fluorescent AGE formation in a bovine serum albumin (BSA) ribose system, whereas the aqueous extract had no effect in both BSA-fructose and BSA-ribose systems. The phytochemical profile was investigated with liquid chromatography-ultraviolet-visible (UV-Vis) diode array coupled to electrospray ionization multistage mass spectrometry (LC/DAD/ESI-MS(n)). Quantification of the major phenolic compounds was performed with high performance liquid chromatography with UV-Vis diode array detection and nuclear magnetic resonance spectroscopy. Among the major phenolic components (luteolin, hydroxytyrosol, luteolin-4'-O-beta-D-glucopyranoside, luteolin-7-O-beta-D-glucopyranoside, and oleuropein), luteolin and luteolin-4'-O-beta-D-glucopyranoside were assigned as potent inhibitors of AGE formation. The extraction procedure greatly affects the composition and therefore the anti-glycation potential of olive leaves. PMID- 24044492 TI - Grape seed extract effects in brain after hypobaric hypoxia. AB - Hypoxia induces a wide range of deleterious effects at the cellular level due to an increased production of reactive oxygen species (ROS). Polyphenols from grape seeds, which are potent antioxidants might protect the brain against oxidative stress produced by hypobaric hypoxia. The brain effects of three doses of grape seed extract intraperitoneally (i.p.) administered in rats after exposure to hypobaric hypoxia corresponding to 5500 m altitude were investigated. Some oxygen and nitrogen reactive species, inflammatory cytokine (IL-6) and molecules involved in angiogenesis (vascular endothelial growth factor [VEGF], matrix metalloproteinase 2 [MMP2], and tissue inhibitors of metalloproteinase 1 [TIMP1]) were determined. Forty-two rats were divided in seven groups: group 1, control; groups 2, 3, and 4 were exposed to hypobaric hypoxia for 24 h in a hypobaric chamber; groups 5, 6, and 7 were exposed to hypobaric hypoxia for 5 days. After returning to normal atmospheric pressure, rats from groups 2 and 5 were sacrificed without other treatment. Animals from groups 3 and 6 were i.p treated with carboxymethyl cellulose (CMC) vehicle and those from groups 4 and 7 were i.p. treated with grape seed extract (GSE) (50 mg gallic acid equivalents/kg body weight in 0.5 mL CMC suspension/animal). The treatment was applied at 2, 24, and 72 h from returning to normoxia. Hypobaric hypoxia produced increased brain levels of ROS, nitric oxide (NO), IL-6, and VEGF after both time intervals (P<.05). The MMP2 concentration was significantly increased in groups treated only with vehicle, whereas TIMP1 was slightly changed. GSE produced a significant reduction of ROS and NO levels proving its antioxidant capacity. It also decreased IL-6 and MMP2 concentrations to values similar to controls. The VEGF concentration was also significantly reduced. These effects are indicative for anti-inflammatory and antiangiogenic properties of GSE. PMID- 24044493 TI - Renoprotective effect of Coccinia indica fruits and leaves in experimentally induced diabetic rats. AB - Diabetic nephropathy is one of the secondary complications of diabetes mellitus that is marked by changes in extracellular matrix components leading to end-stage renal failure. Diet plays an important role in managing diabetes. In the present study, the effect of Coccinia indica consumption on diabetes-mediated kidney damage was determined. Both control and diabetic rats were fed with AIN-76 diet supplemented with C. indica fruits and leaves individually at 10% and 5%, respectively, for a period of 2 months. Various parameters, such as fasting blood glucose, urine sugar, albumin excretion, kidney index, and glomerular filtration rate, were ameliorated to various extents by the supplementation of C. indica in the diet. Additionally, diabetic rats fed with diet supplemented with C. indica fruits or leaves showed improvement in glucose tolerance compared to control diabetic rats. They also exhibited beneficial effects on key antioxidant enzymes of the kidney. Furthermore, an increase in laminin and fibronectin as a result of diabetes was alleviated in C. indica-fed rats. These results indicate that the consumption of C. indica is beneficial in partially containing diabetes-mediated deleterious effects on the kidney. PMID- 24044494 TI - Wound healing activity of the fruit skin of Punica granatum. AB - The skin of the fruit and the bark of Punica granatum are used as a traditional remedy against diarrhea, dysentery, and intestinal parasites. The fruit skin extract of P. granatum was tested for its wound healing activity in rats using an excision wound model. The animals were divided into three groups of six each. The experimental group of animals was topically treated with P. granatum at a dose of 100 mg/kg every day for 15 days, while the controls and standard group animals were treated with petroleum jelly and mupirocin ointment, respectively. Phytochemical analysis of the extract revealed the presence of saponins, triterpenes, tannins, alkaloids, flavonoids, and cardiac glycosides. Extract treated animals exhibited 95% reduction in the wound area when compared with controls (84%), which was statistically significant (P<.01). The extract-treated wounds were found to epithelize faster compared with controls. The hydroxyproline content of extract-treated animals was significantly higher than controls (P<.05). The fruit skin extract did not show any antimicrobial activity against the microrganisms tested. P. granatum promotes significant wound healing in rats and further evaluation of this activity in humans is suggested. PMID- 24044495 TI - Impact of dietary fiber fermentation from cereal grains on metabolite production by the fecal microbiota from normal weight and obese individuals. AB - Gut bacteria may influence obesity through the metabolites produced by dietary fiber fermentation (mainly, short-chain fatty acids [SCFA]). Five cereal grain samples (wheat, rye, maize [corn], rice, and oats) were subjected to in vitro digestion and fermentation using fecal samples from 10 obese and nine normal weight people. No significant differences in total SCFA production between the normal weight and obese groups were observed [279 (12) vs. 280 (12), mean (standard error), respectively; P=.935]. However, the obese microbiota resulted in elevated propionate production compared with that of normal weight [24.8(2.2) vs. 17.8(1.9), respectively; P=.008]. Rye appeared to be particularly beneficial among grain samples due to the lowest propionate production and highest butyrate production during fermentation. These data suggest that the dietary fibers from cereal grains affect bacterial metabolism differently in obese and normal weight classes and that certain grains may be particularly beneficial for promoting gut health in obese states. PMID- 24044496 TI - Ovarian stem cells: absence of evidence is not evidence of absence. AB - BACKGROUND: Lei and Spradling in a recent study published in PNAS failed to detect 'germline cysts' by elegant studies using lineage tracing approach and thus concluded that adult mouse ovaries lack stem cells. They proposed that primordial follicle pool generated during fetal life is sufficient to sustain oogenesis and that there is no renewal of oocytes during adult life. Contrary to their results, we have reported presence of very small pluripotent, embryonic like stem cells (VSELs), their immediate descendants (OGSCs) and germ cell 'cysts' or 'nests' (formed by rapid cell division and incomplete cytokinesis) in surface epithelial cell smears of adult sheep, monkey and human ovaries. METHODS: In the present study, ovaries were collected from adult mouse (treated with 5 IU pregnant mare serum gonadotropin, PMSG) and sheep (from slaughter house) and testis from mouse treated with busulphan (25 mg/Kg). Ovarian surface epithelial (OSE) cells and testicular smears were studied for the presence of cysts. Sheep OSE smears were also used to show cytoplasmic continuity amongst the cyst cells studied by immunolocalization and confocal microscopy of stem cells specific markers OCT-4 and SSEA-4. RESULTS: Cysts were observed and confocal microscopy imaging confirmed cytoplasmic continuity amongst the cells comprising the cysts. CONCLUSIONS: Cysts represent self-renewal and clonal expansion of stem cells with incomplete cytokinesis and are a hallmark feature of stem cells. We suggest the use of PMSG stimulated mouse ovaries and use of more primitive markers like OCT-4 or STELLA rather than MVH for lineage tracing studies to conclusively show presence of stem cells by lineage-tracing studies. PMID- 24044497 TI - Beak and skull shapes of human commensal and non-commensal house sparrows Passer domesticus. AB - BACKGROUND: The granivorous house sparrow Passer domesticus is thought to have developed its commensal relationship with humans with the rise of agriculture in the Middle East some 10,000 years ago, and to have expanded with the spread of agriculture in Eurasia during the last few thousand years. One subspecies, P. d. bactrianus, residing in Central Asia, has apparently maintained the ancestral ecology, however. This subspecies is not associated with human settlements; it is migratory and lives in natural grass- and wetland habitats feeding on wild grass seeds. It is well documented that the agricultural revolution was associated with an increase in grain size and changes in seed structure in cultivated cereals, the preferred food source of commensal house sparrow. Accordingly, we hypothesize that correlated changes may have occurred in beak and skull morphology as adaptive responses to the change in diet. Here, we test this hypothesis by comparing the skull shapes of 101 house sparrows from Iran, belonging to five different subspecies, including the non-commensal P. d. bactrianus, using geometric morphometrics. RESULTS: The various commensal house sparrow subspecies share subtle but consistent skeletal features that differ significantly from those of the non-commensal P. d. bactrianus. Although there is a marked overall size allometry in the data set, the shape difference between the ecologically differentiated sparrows cannot be explained by differences in size alone. Relative to the size allometry commensal house sparrows exhibit a skull shape consistent with accelerated development (heterochrony), resulting in a more robust facial cranium and a larger, more pointed beak. CONCLUSION: The difference in skull shape and robustness of the beak between commensal and non-commensal house sparrows is consistent with adaptations to process the larger and rachis encapsulated seeds of domesticated cereals among human associated populations. PMID- 24044498 TI - Tufted angioma (Angioblastoma) of eyelid in adults-report of two cases. AB - Tufted angioma, first recognized in Japanese literature as "Angioblastoma of Nagakawa", is a rare benign vascular tumour with a variable clinical presentation. It commonly manifests as a macule, papule or nodule in infancy or childhood in the region of the upper trunk and neck. Here in we report two cases of this rare progressive angioma as lesions of the eyelid in adults. Tufted angioma has a classical "cannon ball" like appearance of vascular tufts on histopathology. Immunohistochemical staining with actin highlights the spindly stromal cells surrounding the capillaries. Complete physical examination and haematological work up is recommended in patients with tufted angioma to exclude rare association of port wine stain and Kasabach-Merritt syndrome with this rare entity. To the best of our knowledge, our cases illustrate the first case report of tufted angioma presenting as an eyelid lesion. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1230909536950947. PMID- 24044499 TI - Barriers to successful implementation of care in home haemodialysis (BASIC HHD):1. Study design, methods and rationale. AB - BACKGROUND: Ten years on from the National Institute of Health and Clinical Excellence' technology appraisal guideline on haemodialysis in 2002; the clinical community is yet to rise to the challenge of providing home haemodialysis (HHD) to 10-15% of the dialysis cohort. The renal registry report, suggests underutilization of a treatment type that has had a lot of research interest and several publications worldwide on its apparent benefit for both physical and mental health of patients. An understanding of the drivers to introducing and sustaining the modality, from organizational, economic, clinical and patient perspectives is fundamental to realizing the full benefits of the therapy with the potential to provide evidence base for effective care models. Through the BASIC-HHD study, we seek to understand the clinical, patient and carer related psychosocial, economic and organisational determinants of successful uptake and maintenance of home haemodialysis and thereby, engage all major stakeholders in the process. DESIGN AND METHODS: We have adopted an integrated mixed methodology (convergent, parallel design) for this study. The study arms include a. patient; b. organization; c. carer and d. economic evaluation. The three patient study cohorts (n = 500) include pre-dialysis patients (200), hospital haemodialysis (200) and home haemodialysis patients (100) from geographically distinct NHS sites, across the country and with variable prevalence of home haemodialysis. The pre-dialysis patients will also be prospectively followed up for a period of 12 months from study entry to understand their journey to renal replacement therapy and subsequently, before and after studies will be carried out for a select few who do commence dialysis in the study period. The process will entail quantitative methods and ethnographic interviews of all groups in the study. Data collection will involve clinical and biomarkers, psychosocial quantitative assessments and neuropsychometric tests in patients. Organizational attitudes and dialysis unit practices will be studied together with perceptions of healthcare providers on provision of home HD. Economic evaluation of home and hospital haemodialysis practices will also be undertaken and we will apply scenario ("what ... if") analysis using system dynamics modeling to investigate the impact of different policy choices and financial models on dialysis technology adoption, care pathways and costs. Less attention is often given to the patient's carers who provide informal support, often of a complex nature to patients afflicted by chronic ailments such as end stage kidney disease. Engaging the carers is fundamental to realizing the full benefits of a complex, home-based intervention and a qualitative study of the carers will be undertaken to elicit their fears, concerns and perception of home HD before and after patient's commencement of the treatment. The data sets will be analysed independently and the findings will be mixed at the stage of interpretation to form a coherent message that will be informing practice in the future. DISCUSSION: The BASIC-HHD study is designed to assemble pivotal information on dialysis modality choice and uptake, investigating users, care-givers and care delivery processes and study their variation in a multi-layered analytical approach within a single health care system. The study results would define modality specific service and patient pathway redesign. STUDY REGISTRATION: This study has been reviewed and approved by the Greater Manchester West Health Research Authority National Research Ethics Service (NRES) The study is on the NIHR (CLRN) portfolio. PMID- 24044500 TI - Synthesis and structure-activity relationship studies of novel dihydropyridones as androgen receptor modulators. AB - A library of 3-hydroxy-2,3-dihydropyridones was synthesized, and their activities as antiandrogens were tested in the human prostate cancer cell line LNCaP. Structure-activity relationship (SAR) studies resulted in the identification of a potent compound whose activity is comparable to that of MDV3100. Homology modeling and molecular mechanics were used to build a structural model of the androgen receptor-ligand binding domain and to investigate the structural basis of the antagonism. The model is qualitatively consistent with the observed SAR. Moreover, the enrichment plot shows that screening with the model performs significantly better than random screening. Therefore, the model probably represents a realistic conformation of the antagonist form and can be utilized for structure-based design of novel antiandrogens. PMID- 24044501 TI - The value of stress perfusion cardiovascular magnetic resonance imaging for patients referred from the adult congenital heart disease clinic: 5-year experience at the Toronto General Hospital. AB - BACKGROUND: Vasodilator stress perfusion cardiovascular magnetic resonance imaging is a clinically useful tool for detection of clinically significant myocardial ischaemia in adults. We report our 5-year retrospective experience with perfusion cardiovascular magnetic resonance in a large, quarternary adult congenital heart disease centre. METHODS: We reviewed all cases of perfusion cardiovascular magnetic resonance in patients referred from the adult congenital heart disease service. Dipyridamole stress perfusion cardiovascular magnetic resonance was undertaken on commercially available 1.5 and 3 T cardiovascular magnetic resonance scanners. Late gadolinium enhancement imaging was performed 8 10 minutes after completion of the rest perfusion sequence. Navigator whole-heart coronary magnetic resonance angiography was also performed where feasible. RESULTS of stress cardiovascular magnetic resonance were correlated with complementary imaging studies, surgery, and clinical outcomes. RESULTS: Over 5 years, we performed 34 stress perfusion cardiovascular magnetic resonance examinations (11 positive). In all, 84% of patients had further investigations for ischaemia in addition to cardiovascular magnetic resonance. Within a subgroup of 19 patients who had definitive alternative assessment of their coronary arteries, stress perfusion cardiovascular magnetic resonance demonstrated a sensitivity of 82% and specificity of 100%. Of the 34 studies, two were false negatives, in which the aetiology of ischaemia was extrinsic arterial compression rather than intrinsic coronary luminal narrowing. Coronary abnormalities were identified in 71% of cases who had coronary magnetic resonance angiography. CONCLUSION: Stress perfusion cardiovascular magnetic resonance is a useful and accurate tool for investigation of myocardial ischaemia in an adult congenital heart disease population with suspected non-atherosclerotic coronary abnormalities. PMID- 24044502 TI - Elevated depressive symptoms in metabolic syndrome in a general population of Japanese men: a cross-sectional study. AB - BACKGROUND: Uncertainty still surrounds the association between metabolic syndrome (MetS) and depression. We aimed to evaluate the association between MetS and elevated depressive symptoms in a general Japanese population. METHODS: This is a cross-sectional survey of 3,113 community-dwelling individuals aged 40 years or over. MetS was defined according to the joint interim statement. MetS was diagnosed when a subject had three or more of the following components: 1) central obesity (waist circumference >= 90 cm for men, >= 80 cm in for women); 2) elevated blood pressure (>= 130/85 mmHg or current use of antihypertensive medication); 3) hypertriglyceridemia (>= 1.7 mmol/L); 4) low HDL cholesterol (< 1.0 mmol/L for men, < 1.3 mmol/L for women); and 5) elevated fasting plasma glucose (>= 5.55 mmol/L or current use of antidiabetic medication). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The age- and multivariable-adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated using a logistic regression model. RESULTS: Elevated depressive symptoms were observed in 4.3% of male and 6.3% of female participants. In men, the age-adjusted prevalence of elevated depressive symptoms was significantly higher in subjects with MetS than in those without (7.1% versus 3.6%, p = 0.04). The prevalence of elevated depressive symptoms rose progressively as the number of MetS components increased (3.5%, 3.6%, 5.8%, and 9.2% in male subjects with 0-1, 2, 3, and >= 4 components, respectively; p = 0.02 for trend). This association remained significant even after adjustment for age, marital status, history of cardiovascular disease, smoking habit, alcohol intake, and regular exercise. In women, on the other hand, there was no clear association between MetS and depressive symptoms. CONCLUSIONS: MetS was associated with elevated depressive symptoms in a general population of Japanese men. PMID- 24044503 TI - Inkjet-printed paper-based colorimetric sensor array for the discrimination of volatile primary amines. AB - This paper describes a colorimetric sensor array for the discrimination of volatile amines. Analyte discrimination is achieved by combining two functional elements: (1) a "chemical class-selective" single chromogenic sensing dye with selectivity for amines in general, encapsulated into (2) polymer nanoparticles with different polarities. The resulting array has the ability to distinguish one closely related amine from another, relying on a polarity-based approach. In order to achieve reproducible, cost efficient, and flexible sensor array fabrication with the potential for mass production, inkjet-printing technology combined with standard copy paper as a sensor substrate is applied. Printing of 6 types of inks, which are prepared by mixing two dye encapsulating nanoparticles of different polarity in different mixture ratios, results in a colorimetric sensor array with a polarity gradient. Seven primary amines with increasing alkyl chain lengths have been selected to demonstrate the performance of the sensor array. The RGB color differences (DeltaR, DeltaG, DeltaB) of the sensor array spots before and after gas exposure were analyzed by principal component analysis (PCA) and agglomerative hierarchical clustering (AHC) analysis. Under the selected measurement conditions, results of PCA and AHC analysis indicated high discrimination ability with high reproducibility of the sensor array down to amine concentrations of 50 ppm. The discrimination ability was maintained at relative humidities between 10% and 80%. Furthermore, the sensor array showed no significant response to common volatile organic compounds, confirming the high selectivity toward amines. This is, to the best of our knowledge, the first report of a colorimetric sensor array with selectivity for a specific chemical class of analytes and the ability to discriminate compounds of the same class, which is obtained by simply mixing two types of single dye-encapsulating polymer nanoparticles. PMID- 24044504 TI - Effects of water molecules on tribological behavior and property measurements in nano-indentation processes - a numerical analysis. AB - Nano/micro-manufacturing under wet condition is an important consideration for various tool-based processes such as indentation, scratching, and machining. The existence of liquids adds complexity to the system, changes the tool/work interfacial condition, and affects material behaviors. For indentation, it may also affect material property measurements. However, little effort has been made to study this challenging issue at nano- or atomistic scale. In this study, we tackle this challenge by investigating nano-indentation processes submerged in water using the molecular dynamics (MD) simulation approach. Compared with dry indentation in which no water molecules are present, the existence of water molecules causes the increase of indentation force in initial penetration, but the decrease of indentation force in full penetration. It also reduces the sticking phenomenon between the work and tool atoms during indenter retraction, such that the indentation geometry can be better retained. Meanwhile, nano indentation under wet condition exhibits the indentation size effect, while dry nano-indentation exhibits the reverse indentation size effect. The existence of water leads to higher computed hardness values at low indentation loads and a smaller value of Young's modulus. In addition, the friction along the tool/work interface is significantly reduced under wet indentation. PMID- 24044506 TI - Case investigation and reactive case detection for malaria elimination in northern Senegal. AB - BACKGROUND: Given progress in malaria control in recent years, many control programmes in sub-Saharan Africa will soon be required to strengthen systems for surveillance in order to further drive transmission to zero. Yet few practical experiences are available to guide control programmes in designing surveillance system components in low transmission, pre-elimination, and elimination phases. METHODS: A malaria case investigation programme was piloted for 12 weeks in 2012 in Richard Toll district of northern Senegal. Malaria infections (N = 110) were identified through facility-based passive case detection and investigated within three days. Rapid diagnostic tests (RDT) and a brief questionnaire were administered to 5,520 individuals living within the index case compound or within five neighbouring compounds. RESULTS: In comparison with family and neighbours, index cases were more likely to be male, age 15-49, and to report travel within the past 15 days that entailed an overnight stay. Twenty-three (0.4%) of family/neighbours were RDT-positive. Potential risk factors for infection among family and neighbours were examined, including: sex, age, occupation, travel history, bed net usage, and residence (index vs neighbouring compound). Adjusting for all factors, relative risk (RR) of infection was associated with residence in the index case household (RR = 3.18, p < 0.05) and recent travel, including travel to Dakar (RR = 19.93, p < 0.001), travel within the region (RR = 9.57, p < 0.01), and to other regions in Senegal (RR = 94.30, p < 0.001). Recent fever among RDT-positive family/neighbours was uncommon (30%). Modifications to testing criteria were examined to optimize the efficiency of secondary case investigations in this population. Limiting blood testing to residents of the index case compound and neighbours with recent travel or fever would have identified 20/23 (87%) of the infections through testing 1,173 individuals. Information on the remaining three infections suggests that additional screening for boarding school attendees may facilitate identification of all cases. CONCLUSIONS: The primary risk factor for malaria infection in the low transmission district of Richard Toll is travel. Additional intervention and monitoring strategies to target travellers at risk of malaria infection are needed in this region. Optimizing case investigation with specific targeted testing and treatment of at-risk family and neighbours strengthens the systems needed for continued progress towards malaria elimination in northern Senegal. PMID- 24044505 TI - An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models. AB - INTRODUCTION: The human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase (RTK) oncogene is an attractive therapeutic target for the treatment of HER2-addicted tumors. Although lapatinib, an FDA-approved small molecule HER2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), represents a significant therapeutic advancement in the treatment of HER2+ breast cancers, responses to lapatinib have not been durable. Consequently, elucidation of mechanisms of acquired therapeutic resistance to HER directed therapies is of critical importance. METHODS: Using a functional protein pathway activation mapping strategy, along with targeted genomic knockdowns applied to a series of isogenic-matched pairs of lapatinib-sensitive and resistant cell lines, we now report an unexpected mechanism of acquired resistance to lapatinib and similar TKIs. RESULTS: The signaling analysis revealed that whereas HER2 was appropriately inhibited in lapatinib-resistant cells, EGFR tyrosine phosphorylation was incompletely inhibited. Using a targeted molecular knockdown approach to interrogate the causal molecular underpinnings of EGFR-persistent activation, we found that lapatinib-resistant cells were no longer oncogene addicted to HER2-HER3-PI3K signaling, as seen in the parental lapatinib-sensitive cell lines, but instead were dependent on a heregulin (HRG) driven HER3-EGFR-PI3K-PDK1 signaling axis. Two FDA-approved EGFR TKIs could not overcome HRG-HER3-mediated activation of EGFR, or reverse lapatinib resistance. The ability to overcome EGFR-mediated acquired therapeutic resistance to lapatinib was demonstrated through molecular knockdown of EGFR and treatment with the irreversible pan-HER TKI neratinib, which blocked HRG-dependent phosphorylation of HER3 and EGFR, resulting in apoptosis of resistant cells. In addition, whereas HRG reversed lapatinib-mediated antitumor effects in parental HER2+ breast cancer cells, neratinib was comparatively resistant to the effects of HRG in parental cells. Finally, we showed that HRG expression is an independent negative predictor of clinical outcome in HER2+ breast cancers, providing potential clinical relevance to our findings. CONCLUSIONS: Molecular analysis of acquired therapeutic resistance to lapatinib identified a new resistance mechanism based on incomplete and "leaky" inhibition of EGFR by lapatinib. The selective pressure applied by incomplete inhibition of the EGFR drug target resulted in selection of ligand-driven feedback that sustained EGFR activation in the face of constant exposure to the drug. Inadequate target inhibition driven by a ligand-mediated autocrine feedback loop may represent a broader mechanism of therapeutic resistance to HER TKIs and suggests adopting a different strategy for selecting more effective TKIs to advance into the clinic. PMID- 24044507 TI - Nanotubes from chalcogenide misfit compounds: Sn-S and Nb-Pb-S. AB - Carbon fullerenes and nanotubes revolutionized understandingof the reactivity of nanoscale compounds. Subsequently, our group and others discovered analogous inorganic compounds with hollow, closed nanostructures. Such inorganic nanostructures offer many applications, particularly in the energy and electronics industries. One way to create inorganic nanostructures is via misfit layer-ed compounds (MLC), which are stacks of alternating two-dimensional molecular slabs, typically held together via weak van der Waals forces. They contain "misfits" in their a-b plane structures that can make them unstable, leading to collapse of the slabs into tubular nanostructures. For example, metal chalcogenide MLCs of the general formula (MX)1+y/TX2 (M = Sn, Pb, Bi, Sb, and other rare earths; T = Sn, Ti, V, Cr, Nb, Ta, etc.; X = S or Se) consist of a superstructure of alternating layers where the MX unit belongs to a (distorted NaCl) orthorhombic symmetry group (O), the TX2 layer possesses trigonal (T) or octahedral symmetry, and the two layers are held together via both van der Waals and polar forces. A misfit in the a axis or both a and b axes of the two sublattices may lead to the formation of nanostructures as the lattices relax via scrolling. Previous research has also shown that the abundance of atoms with dangling bonds in the rims makes nanoparticles of compounds with layered structure unstable in the planar form, and they tend to fold into hollow closed structures such as nanotubes. This Account shows that combining these two triggers, misfits and dangling bond annihilation in the slab rims, leads to new kinds of nanotubes from MLCs. In particular, we report the structure of two new types of nanotubes from misfits, namely, the SnS/SnS2 and PbS/NbS2 series. To decipher the complex structures of these nanotubes, we use a range of methods: high-resolution transmission electron microscopy (HRTEM), energy-dispersive X-ray spectroscopy (EDS), selected area electron diffraction (SAED) analyses, scanning electron microscopy (SEM), and Cs-corrected scanning transmission electron microscopy (STEM) in the high-angle annular dark-field mode (HAADF). In both new types, the lattice mismatch between the two alternating sublayers dictates the relative layer-stacking order and leads to a variety of chiral tubular structures. In particular, the incommensuration (a type of misfit) of the SnS2/SnS system in both the (in plane) a and b directions leads to a variety of relative in-plane orientation and stacking orders along the common c-axis. Thus the SnS/SnS2 nanotubes form superstructures with the sequence O-T and O-T-T, and mixtures thereof. We also report nanotubes of the misfit layered compound (PbS)1.14NbS2, and of NbS2 intercalated with Pb atoms, with the chemical formula PbNbS2. Thus, the possibility to use two kinds of folding mechanisms jointly offers a new apparatus for the synthesis of unique 1-D nanostructures of great complexity and a potentially large diversity of physicochemical properties. PMID- 24044508 TI - Two-dimensional modeling of volatile organic compounds adsorption onto beaded activated carbon. AB - A two-dimensional heterogeneous computational fluid dynamics model was developed and validated to study the mass, heat, and momentum transport in a fixed-bed cylindrical adsorber during the adsorption of volatile organic compounds (VOCs) from a gas stream onto a fixed bed of beaded activated carbon (BAC). Experimental validation tests revealed that the model predicted the breakthrough curves for the studied VOCs (acetone, benzene, toluene, and 1,2,4-trimethylbenzene) as well as the pressure drop and temperature during benzene adsorption with a mean relative absolute error of 2.6, 11.8, and 0.8%, respectively. Effects of varying adsorption process variables such as carrier gas temperature, superficial velocity, VOC loading, particle size, and channelling were investigated. The results obtained from this study are encouraging because they show that the model was able to accurately simulate the transport processes in an adsorber and can potentially be used for enhancing absorber design and operation. PMID- 24044509 TI - Impact of left anterior line on left atrial appendage contractility in patients who underwent catheter ablation for chronic atrial fibrillation. AB - BACKGROUND: Left anterior line (LAL) has been used as a substitute for mitral isthmus line for catheter ablation of chronic atrial fibrillation (AF). However, it results in left anterolateral conduction delay and might affect left atrial (LA) contractility. We aimed to investigate whether LAL decreases LA appendage function. METHODS: This study included 46 patients (30 men, mean age 58 +/- 9 years, group 1) with persistent AF who underwent catheter ablation including LAL. Thirty patients with paroxysmal AF who received no additional LA ablation were compared as control group (21 males, mean age 56 +/- 8 years, group 2). Transthoracic and transesophageal echocardiography with Doppler tissue imaging was performed in sinus rhythm before and after the ablation. We compared the following variables: (1) E/A ratio of the mitral flow velocity, (2) ratio of early mitral inflow and mitral septal annulus velocity (E/Em), (3) peak velocity of appendage outflow (ApVmax), and (4) time delay from QRS onset to appendage outflow (TDqa). RESULTS: LA diameter was significantly reduced after ablation in both groups. In group 1, parameters for diastolic function (E/A ratio, 1.7 +/- 0.5 vs 2.0 +/- 0.6, P = 0.197; E/Em, 11.7 +/- 4.8 vs 11.6 +/- 5.1, P = 0.883) and appendage flow (ApVmax, 55.2 +/- 19.9 cm/s vs 50.3 +/- 19.3 cm/s, P = 0.203; TDqa, -77.3 +/- 30.1 ms vs -66.1 +/- 60.8 ms, P = 0.265) did not change significantly after ablation. Changes of ApVmax and TDqa after ablation were not significantly different between two groups (P = 0.409 and P = 0.195, respectively). CONCLUSIONS: LAL ablation did not aggravate mitral flow pattern or change appendage outflow. LAL could be used without concern over worsening LA diastolic and appendage function. PMID- 24044510 TI - Reappraisal inventiveness: the ability to create different reappraisals of critical situations. AB - In this article, we propose a new ability approach to reappraisal that focuses on individual differences in the ability to spontaneously generate different reappraisals for critical situations. Adopting concepts from the realms of creativity and divergent thinking, we developed the Reappraisal Inventiveness Test (RIT) to measure a person's fluency and flexibility in inventing as many categorically different reappraisals for an anger-eliciting situation as possible within a limited period of time. The results of two studies in which we examined the psychometric characteristics of the RIT provided evidence that the RIT produces reliable test scores. The construct validity of the RIT was confirmed by positive associations of reappraisal inventiveness with openness to experience and tests that measure divergent thinking. Moreover, RIT performance proved to be unrelated to the self-reported habitual use of reappraisal, indicating differences between ability tests and self-report measures. RIT performance was not significantly related to Neuroticism or to trait anger. In our view, this points to the notion that effective emotion regulation is a function of both the ability and the motivation to act upon one's ability to generate reappraisals for critical situations. PMID- 24044511 TI - MicroRNA hsa-miR-125a-3p activates p53 and induces apoptosis in lung cancer cells. AB - The mature microRNA hsa-miR-125a-3p is derived from the 3' end of pre-miR-125a. Here, we reported that hsa-miR-125a-3p suppressed proliferation and induced apoptosis in A549 cells. In addition, wild-type p53 mRNA and protein expression was increased by hsa-miR-125a-3p over-expression. Moreover, blocking wild-type p53 attenuated the effect of hsa-miR-125a-3p on apoptosis but could not restore completely. In p53-deficient cell line H1299, hsa-miR-125a-3p still induced apoptosis. Taken together, these data suggest that hsa-miR-125a-3p induces apoptosis not only via the p53 pathway in human lung cancer cells. These results provide new insight into the roles of the miR-125a family in lung cancer. PMID- 24044512 TI - Innovative intercalated degrees at a modern medical school in the United Kingdom. PMID- 24044513 TI - ESEM study of the humidity-induced swelling of clay film. AB - We measured the humidity-induced swelling of thin self-standing films of montmorillonite clay by a combination of environmental scanning electron microscopy (ESEM) and digital image correlation (DIC). The films were about 40 MUm thick. They were prepared by depositing and evaporating a suspension of clay and peeling off the highly oriented deposits. The rationale for creating such original samples was to obtain mesoscopic samples that could be used to bridge experimentally the gap between the scale of the clay layer and the engineering scale of a macroscopic clay sample. Several montmorillonite samples were used: the reference clay Swy-2, the same clay homoionized with sodium or calcium ions, and a sodium-exchanged Cloisite. The edges of the clay films were observed by ESEM at various relative humidity values between 14% and 95%. The ESEM images were then analyzed by DIC to measure the swelling or the shrinkage of the films. We also measured the adsorption/desorption isotherms by weighing the film samples in a humidity-controlled environment. In order to analyze our results, we compared our swelling/shrinkage and adsorption/desorption data with previously published data on the interlayer spacing obtained by X-ray diffraction and with numerical estimates of the interlayer water obtained by molecular dynamics simulation. The swelling and the hysteresis of this swelling were found to be comparable for the overall macroscopic films and for the interlayer space. The same correspondence between film and interlayer space was observed for the amount of adsorbed water. This suggests that, in the range of relative humidities values explored, the films behave like freely swelling oriented stacks of clay layers, without any significant contribution from the mesoporosity. The relevance of this result for the behavior of clayey sedimentary rocks and the differences with the behavior of nonoriented samples (powders or compacted powders) are briefly discussed. PMID- 24044514 TI - LAPS-FSH: a new and effective long-acting follicle-stimulating hormone analogue for the treatment of infertility. AB - Although several long-acting follicle-stimulating hormone (FSH) therapies have been developed to enhance the ovarian response, a disadvantage of FSH therapy is its relatively short half-life, which requires women to receive one to two injections per day for almost 2 weeks. In the present study, we developed a novel FSH analogue by conjugating recombinant human FSH (rhFSH) and the constant region of the human immunoglobulin G4 fragment via non-peptidyl linkers. The efficacy of the FSH analogue was evaluated in vitro by cAMP level assessments, pharmacokinetic studies and a determination of ovarian weight and by comparing these findings with the results from other FSH analogues. In addition, the total number of antral and Graafian follicles was determined after 7 days of treatment with control, 6ugkg(-1) follitropin beta, 6, 12 or 42ugkg(-1) corifollitropin alpha or 3, 6 or 12ugkg(-1) long acting protein/peptide discovery-follicle stimulating hormone (LAPS-FSH). As a result, the animals treated with 12ugkg(-1) LAPS-FSH produced additional and larger healthy follicles. These data demonstrate that LAPS-FSH promotes growth and inhibits atresia of the ovarian follicle compared with other available drugs, suggesting that our new drug enhances the efficacy and duration of treatment. It is expected that our new FSH analogue will result in a higher chance of pregnancy in patients who are unresponsive to other drugs. PMID- 24044515 TI - Calorie restriction down-regulates expression of the iron regulatory hormone hepcidin in normal and D-galactose-induced aging mouse brain. AB - It has been shown that iron progressively accumulates in the brain with age. Calorie restriction (CR) may allay many of the adverse effects of aging on the brain, yet the underlying mechanisms, in particular in relation to brain iron metabolism, remain unclear. This study aimed to investigate the role of CR in the regulation of cerebral cellular iron homeostasis. C57BL/6 mice were randomly divided into four groups of eight. The control group was fed a conventional diet ad libitum; the CR group received 70% of the calories of the control mouse intake per day; the D-galactose (D-gal) group received subcutaneous injection of D-gal at a dose of 100 mg/kg once daily to produce mouse model of aging; the D-gal plus CR group received both of the two interventions for 14 weeks. The Morris water maze (MWM) was employed to test the cognitive performance of all animals, and the expression of iron regulatory genes, ferroportin and hepcidin, in the cortex and hippocampus were detected by quantitative real-time PCR. Compared to the controls, the D-gal group mice showed significant spatial reference memory deficits in the MWM test, whereas the D-gal-CR group mice exhibited almost normal cognitive function, indicating that CR protects against D-gal-induced learning and memory impairment. Hepcidin mRNA expression was increased in the D-gal group, decreased in the CR group, and was basically unchanged in the D-gal-CR group. There was no statistical difference in the transmembrane iron exporter ferroportin expression between control and any of the experimental groups. The results suggest that the anti-aging effects of CR might partially lie in its capacity to reduce or avoid age-related iron accumulation in the brain through down-regulating expression of brain hepcidin--the key negative regulator for intracellular iron efflux--and that facilitating the balance of brain iron metabolism may be a promising anti-aging measure. PMID- 24044516 TI - Enhanced levels of double-strand DNA break repair proteins protect ovarian cancer cells against genotoxic stress-induced apoptosis. AB - BACKGROUND: Earlier, proteomic profiling of a Serous Ovarian Carcinoma (SeOvCa) progression model in our lab had identified significantly enriched expression of three double-strand break (DSB) -repair proteins viz. RAD50, NPM1, and XRCC5 in transformed cells over pre-transformed, non-tumorigenic cells. Analysis of the functional relevance of enhanced levels of these proteins was explored in transformed ovarian cancer cells. METHODS: Expression profiling, validation and quantitation of the DSB-repair proteins at the transcriptional and protein levels were carried out. Further analyses included identification of their localization, distribution and modulation on exposure to Estradiol (E2) and cisplatin. Effects on silencing of each of these under conditions of genomic-stress were studied with respect to apoptosis, alterations in nuclear morphology and DNA fragmentation; besides profiling known mitotic and spindle check-point markers in DSB-repair. RESULTS: We identified that levels of these DSB-repair proteins were elevated not only in our model, but generally in cancer and are specifically triggered in response to genotoxic stress. Silencing of their expression led to aberrant DSB repair and consequently, p53/p21 mediated apoptosis. Further compromised functionality generated genomic instability. CONCLUSIONS: Present study elucidates a functional relevance of NPM1, RAD50 and XRCC5 DSB-repair proteins towards ensuring survival and evasion of apoptosis during ovarian transformation, emphasizing their contribution and association with disease progression in high-grade SeOvCa. PMID- 24044517 TI - Thyroglobulin in the washout fluid of lymph-node biopsy: what is its role in the follow-up of differentiated thyroid carcinoma? AB - BACKGROUND: The clinical evaluation of enlarged local lymph nodes (LNs) is difficult at the beginning and throughout the follow-up of differentiated thyroid carcinoma (DTC). Although the examination of samples collected from LNs by fine needle aspiration biopsy cytology (FNAB-C) is extremely specific for the diagnosis of metastases, its sensitivity is low, especially in paucicellular samples. SUMMARY: The measurement of thyroglobulin (Tg) in the fine-needle aspiration biopsy (FNAB) washout fluid (FNAB-Tg) increases the diagnostic performance of cytology to up to 100% sensitivity and specificity. However, the application of FNAB-Tg is currently hindered by the absence of methodological standardization, a lack of definite cutoff points, and the ongoing debate regarding its accuracy in nonthyroidectomized patients, those with elevated serum Tg, and those with circulating anti-Tg antibodies. CONCLUSION: FNAB-Tg improves the diagnostic performance of FNAB-C in LN metastases, even when the latter is unable to diagnose the metastases. For that reason, FNAB-Tg should be included in the monitoring of DTC. PMID- 24044518 TI - Left ventricular strain and strain rates are decreased in children with normal fractional shortening after exposure to anthracycline chemotherapy. AB - BACKGROUND: Anthracycline chemotherapeutic agents carry the well-recognised risk of cardiotoxicity. Previous methods to evaluate cardiac function are useful, but have significant limitations. We sought to determine the left ventricular strain and strain rate of paediatric cancer patients with normal fractional shortening treated with anthracyclines using the latest ultrasound feature-tracking technology. PATIENTS AND METHODS: Echocardiograms on cancer patients before anthracycline exposure and following completion of treatment were retrospectively analysed using Velocity Vector Imaging software in the circumferential and longitudinal planes. The same analysis was performed on matched controls. Only patients with a fractional shortening >=28% were included. RESULTS: In all, 71 patients were identified with an age at diagnosis of 10.5 +/- 4.7 years. The time from diagnosis to follow-up was 3.9 +/- 4.0 years and the cumulative anthracycline dose was 356 +/- 106 mg/m2. Following anthracycline exposure, paediatric cancer patients had a higher heart rate and a lower longitudinal strain, longitudinal diastolic strain rate, circumferential strain, and circumferential systolic and diastolic strain rate when compared with controls. Diastolic strain rate showed the greatest percent difference following anthracycline exposure versus controls. CONCLUSION: Despite having a normal fractional shortening, children exposed to anthracyclines have subclinical derangement of their left ventricular deformation as measured by decreases in strain and strain rate in both the circumferential and longitudinal axis. In particular, there was a profound decrease in diastolic strain rate following anthracycline exposure compared with controls. Whether the decline of strain or strain rate can predict future risk of developing cardiomyopathy requires further investigation. PMID- 24044519 TI - Biogeography, phylogeny, and morphological evolution of central Texas cave and spring salamanders. AB - BACKGROUND: Subterranean faunal radiations can result in complex patterns of morphological divergence involving both convergent or parallel phenotypic evolution and cryptic species diversity. Salamanders of the genus Eurycea in central Texas provide a particularly challenging example with respect to phylogeny reconstruction, biogeography and taxonomy. These predominantly aquatic species inhabit karst limestone aquifers and spring outflows, and exhibit a wide range of morphological and genetic variation. We extensively sampled spring and cave populations of six Eurycea species within this group (eastern Blepsimolge clade), to reconstruct their phylogenetic and biogeographic history using mtDNA and examine patterns and origins of cave- and surface-associated morphological variation. RESULTS: Genetic divergence is generally low, and many populations share ancestral haplotypes and/or show evidence of introgression. This pattern likely indicates a recent radiation coupled with a complex history of intermittent connections within the aquatic karst system. Cave populations that exhibit the most extreme troglobitic morphologies show no or very low divergence from surface populations and are geographically interspersed among them, suggesting multiple instances of rapid, parallel phenotypic evolution. Morphological variation is diffuse among cave populations; this is in contrast to surface populations, which form a tight cluster in morphospace. Unexpectedly, our analyses reveal two distinct and previously unrecognized morphological groups encompassing multiple species that are not correlated with spring or cave habitat, phylogeny or geography, and may be due to developmental plasticity. CONCLUSIONS: The evolutionary history of this group of spring- and cave-dwelling salamanders reflects patterns of intermittent isolation and gene flow influenced by complex hydrogeologic dynamics that are characteristic of karst regions. Shallow genetic divergences among several species, evidence of genetic exchange, and nested relationships across morphologically disparate cave and spring forms suggests that cave invasion was recent and many troglobitic morphologies arose independently. These patterns are consistent with an adaptive-shift hypothesis of divergence, which has been proposed to explain diversification in other karst fauna. While cave and surface forms often do not appear to be genetically isolated, morphological diversity within and among populations may be maintained by developmental plasticity, selection, or a combination thereof. PMID- 24044520 TI - Factor structure and validation of the Attentional Control Scale. AB - The Attentional Control Scale (ACS; Derryberry & Reed, 2002) has been used to assess executive control over attention in numerous studies, but no published data have examined the factor structure of the English version. The current studies addressed this need and tested the predictive and convergent validity of the ACS subscales. In Study 1, exploratory factor analysis yielded a two-factor model with Focusing and Shifting subscales. In Study 2, confirmatory factor analysis supported this model and suggested superior fit compared to the factor structure of the Icelandic version (Olafsson et al., 2011). Study 3 examined correlations between the ACS subscales and measures of working memory, anxiety, and cognitive control. Study 4 examined correlations between the subscales and reaction times on a mixed-antisaccade task, revealing positive correlations for antisaccade performance and prosaccade latency with Focusing scores and between switch trial performance and Shifting scores. Additionally, the findings partially supported unique relationships between Focusing and trait anxiety and between Shifting and depression that have been noted in recent research. Although the results generally support the validity of the ACS, additional research using performance-based tasks is needed. PMID- 24044521 TI - A simple approach of three-isocenter IMRT planning for craniospinal irradiation. AB - PURPOSE: To develop a new IMRT technique to simplify the process and improve efficiency in radiotherapy treatment planning for craniospinal irradiation (CSI) treatment. METHODS: Image data of 9 patients who received CSI treatment in 2012 were used, the prescription was 36Gy in 20 fractions. Two treatment plans were created for each patient, one was with the new technique called three-isocenter overlap-junction (TIOJ) IMRT and the other was with the three-isocenter jagged junction (TIJJ) IMRT technique. The comparative study was conducted using the parameters of heterogeneity index (HI), conformity index (CI), and doses to the organs at risk (OARs). RESULTS: Comparing the TIOJ IMRT plans with the TIJJ IMRT plans, the average homogeneity index is 0.071 +/- 0.003 and 0.077 +/- 0.002, respectively, and the averaged conformity number is 0.80 +/- 0.012 and 0.80 +/- 0.009, respectively. There are no significant differences (p > 0.05). Both plans provide satisfactory sparing for the OARs. CONCLUSIONS: The TIOJ IMRT technique for CSI treatment planning can create similar plans as with the TIJJ IMRT technique, but the new technique greatly simplifies the steps required to manually set field widths and boundaries and improved efficiency. PMID- 24044522 TI - Pnicogen bonded complexes of PO2X (X = F, Cl) with nitrogen bases. AB - An ab initio MP2/aug'-cc-pVTZ study has been carried out on complexes formed between PO2X (X = F and Cl) as the Lewis acids and a series of nitrogen bases ZN, including NH3, H2C?NH, NH2F, NP, NCH, NCF, NF3, and N2. Binding energies of these complexes vary from -10 to -150 kJ/mol, and P-N distances from 1.88 to 2.72 A. Complexes ZN:PO2F have stronger P(...)N bonds and shorter P-N distances than the corresponding complexes ZN:PO2Cl. Charge transfer from the N lone pair through the pi-hole to the P-X and P-O sigma* orbitals leads to stabilization of these complexes, although charge-transfer energies can be evaluated only for complexes with binding energies less than -71 kJ/mol. Complexation of PO2X with the strongest bases leads to P...N bonds with a significant degree of covalency, and P-N distances that approach the P-N distances in the molecules PO2NC and PO2NH2. In these complexes, the PO2X molecules distort from planarity. Changes in (31)P absolute chemical shieldings upon complexation do not correlate with changes in charges on P, although they do correlate with the binding energies of the complexes. EOM-CCSD spin-spin coupling constants (1p)J(P-N) are dominated by the Fermi-contact term, which is an excellent approximation to total J. (1p)J(P-N) values are small at long distances, increase as the distance decreases, but then decrease at short P-N distances. At the shortest distances, values of (1p)J(P-N) approach (1)J(P-N) for the molecules PO2NC and PO2NH2. PMID- 24044523 TI - Quantifying the burden of disease due to premature mortality in Hong Kong using standard expected years of life lost. AB - BACKGROUND: To complement available information on mortality in a population Standard Expected Years of Life Lost (SEYLL), an indicator of premature mortality, is increasingly used to calculate the mortality-associated disease burden. SEYLL consider the age at death and therefore allow a more accurate view on mortality patterns as compared to routinely used measures (e.g. death counts). This study provides a comprehensive assessment of disease and injury SEYLL for Hong Kong in 2010. METHODS: To estimate the SEYLL, life-expectancy at birth was set according to the 2004 Global Burden of Disease study at 82.5 and 80 years for females and males, respectively. Cause of death data for 2010 were corrected for misclassification of cardiovascular and cancer causes. In addition to the baseline estimates, scenario analyses were performed using alternative assumptions on life-expectancy (Hong Kong standard life-expectancy), time discounting and age-weighting. To estimate a trend of premature mortality a time series analysis from 2001 to 2010 was conducted. RESULTS: In 2010 524,706.5 years were lost due to premature death in Hong Kong with 58.3% of the SEYLL attributable to male deaths. The three overall leading single causes of SEYLL were "trachea, bronchus and lung cancers", "ischaemic heart disease" and "lower respiratory infections" together accounting for about 29% of the overall SEYLL. Further, self-inflicted injuries (5.6%; ranked 5) and liver cancer (4.9%; ranked 7) were identified as important causes not adequately captured by classical mortality measures. Scenario analyses highlighted that by using a 3% time discount rate and non-uniform age-weights the SEYLL dropped by 51.6%. Using Hong Kong's standard life-expectancy values resulted in an overall increase of SEYLL by 10.8% as compared to the baseline SEYLL. Time-series analysis indicates an overall increase of SEYLL by 6.4%. In particular, group I (communicable, maternal, perinatal and nutritional) conditions showed highest increases with SEYLL-rates per 100,000 in 2010 being 1.4 times higher than 2001. CONCLUSIONS: The study stresses the mortality impact of diseases and injuries that occur in earlier stages of life and thus presents the SEYLL measure as a more sensitive indicator compared to classical mortality indicators. SEYLL provide useful additional information and supplement available death statistics. PMID- 24044524 TI - Perinatal mortality following assisted reproductive technology treatment in Australia and New Zealand, a public health approach for international reporting of perinatal mortality. AB - BACKGROUND: There is a need to have uniformed reporting of perinatal mortality for births following assisted reproductive technology (ART) treatment to enable international comparison and benchmarking of ART practice. METHODS: The Australian and New Zealand Assisted Reproduction Database was used in this study. Births of >= 20 weeks gestation and/or >= 400 grams of birth weight following embryos transfer cycles in Australia and New Zealand during the period 2004 to 2008 were included. Differences in the mortality rates by different perinatal periods from a gestational age cutoff of >= 20, >= 22, >= 24, or >= 28 weeks (wks) to a neonatal period cutoff of either < 7 or < 28 days after birth were assessed. Crude and specific (number of embryos transferred and plurality) rates of perinatal mortality were calculated for selected gestational and neonatal periods. RESULTS: When the perinatal period is defined as >= 20 wks gestation to < 28 days after birth, the perinatal mortality rate (PMR) was 16.1 per 1000 births (n = 630). A progressive contraction of the gestational age groups resulted in marked reductions in the PMR for deaths at < 28 days (22 wks 11.0; 24 wks 7.7; 28 wks 5.6); and similarly for deaths at < 7 days (20 wks 15.6, 22 wks 10.5; 24 wks 7.3; 28 wks 5.3). In contrast, a contraction of the perinatal period from < 28 to < 7 days after birth only marginally reduced the PMR from 16.2 to 15.6 per 1000 births which was consistent across all gestational ages.The PMR for single embryo transfer (SET) births (>= 20 weeks gestation to < 7 days post birth) was significantly lower (12.8 per 1000 SET births) compared to double embryo transfer (DET) births (PMR 18.3 per 1000 DET births; p < 0.001, Fisher's Exact Test). Similarly, the PMR for SET births (>= 22 weeks gestation to < 7 days post-birth) was significantly lower (8.8 per 1000 SET births, p < 0.001, Fisher's Exact Test) when compared to DET births (12.2 per 1000 DET births). The highest PMR (50.5 per 1000 SET births, 95% CI 36.5-64.5) was for twins following SET births (>= 20 weeks gestation to < 7 days post-birth) compared to twins following DET (23.9 per 1000 DET births, 95% CI 20.8-27.1). CONCLUSION: Reporting of perinatal mortality of ART births is an essential component of quality ART practice. This should include measures that monitor the impact on perinatal mortality of multiple embryo transfer. We recommend that reporting of perinatal deaths following ART treatment, should be stratified for three gestation-specific perinatal periods of >= 20, >= 22 and >= 28 completed weeks to < 7 days post birth; and include plurality specific rates by SET and DET. This would provide a valuable international evidence-base of PMR for use in evaluating ART policy, practice and new research. PMID- 24044525 TI - The non-coding snRNA 7SK controls transcriptional termination, poising, and bidirectionality in embryonic stem cells. AB - BACKGROUND: Pluripotency is characterized by a unique transcriptional state, in which lineage-specification genes are poised for transcription upon exposure to appropriate stimuli, via a bivalency mechanism involving the simultaneous presence of activating and repressive methylation marks at promoter-associated histones. Recent evidence suggests that other mechanisms, such as RNA polymerase II pausing, might be operational in this process, but their regulation remains poorly understood. RESULTS: Here we identify the non-coding snRNA 7SK as a multifaceted regulator of transcription in embryonic stem cells. We find that 7SK represses a specific cohort of transcriptionally poised genes with bivalent or activating chromatin marks in these cells, suggesting a novel poising mechanism independent of Polycomb activity. Genome-wide analysis shows that 7SK also prevents transcription downstream of polyadenylation sites at several active genes, indicating that 7SK is required for normal transcriptional termination or control of 3'-UTR length. In addition, 7SK suppresses divergent upstream antisense transcription at more than 2,600 loci, including many that encode divergent long non-coding RNAs, a finding that implicates the 7SK snRNA in the control of transcriptional bidirectionality. CONCLUSIONS: Our study indicates that a single non-coding RNA, the snRNA 7SK, is a gatekeeper of transcriptional termination and bidirectional transcription in embryonic stem cells and mediates transcriptional poising through a mechanism independent of chromatin bivalency. PMID- 24044526 TI - Identification of protein biomarkers associated with cardiac ischemia by a proteomic approach. AB - Angina is chest pain induced by ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries. People that suffer from average to severe cases of angina have an increased percentage of death before the age of 55, usually around 60%. Therefore, prevention of major complications, optimizing diagnosis, prognosis and therapeutics are of primary importance. The main objective of this study was to uncover biomarkers by comparing serum protein profiles of patients suffering from stable or unstable angina and controls. We identified by non-targeted proteomic approach and confirmed by the means of independent techniques, the differential expression of several proteins indicating significantly increased vascular inflammation response, disturbance in the lipid metabolism and in atherogenic plaques stability. PMID- 24044527 TI - CuO hollow nanosphere-catalyzed cross-coupling of aryl iodides with thiols. AB - New functionalized CuO hollow nanospheres on acetylene black (CuO/AB) and on charcoal (CuO/C) have been found to be effective catalysts for C-S bond formation under microwave irradiation. CuO catalysts showed high catalytic activity with a wide variety of substituents which include electron-rich and electron-poor aryl iodides with thiophenols by the addition of two equivalents of K2CO3 as base in the absence of ligands. PMID- 24044528 TI - Quantifying protein-ligand interactions by direct electrospray ionization-MS analysis: evidence of nonuniform response factors induced by high molecular weight molecules and complexes. AB - The deleterious effects of high molecular weight (MW) solute (polymers and noncovalent assemblies) on protein-ligand (PL) affinity measurements carried out using the direct electrospray ionization mass spectrometry (ESI-MS) assay are described. The presence of high MW solute, that do not interact with the protein (P) or ligand (L) of interest, is shown to result in a decrease in the abundance (Ab) ratio (R) of ligand-bound to free protein ions (i.e., Ab(PL)/Ab(P)) measured for protein-carbohydrate complexes. This effect, which can reduce the apparent association constant by more than 60%, is found to be more pronounced as the differences in the surface properties of P and PL become more significant. It is proposed that the decrease in R reflects a reduction in the number of available surface sites in the ESI droplets upon introduction of large solute and increased competition between P and the more hydrophilic PL for these sites. That a similar decrease in R is observed upon introduction of surfactants to solution provides qualitative support for this hypothesis. PMID- 24044529 TI - Self-assembly of rodlike virus to superlattices. AB - Rodlike tobacco mosaic virus (TMV) has been found to assemble into superlattices in aqueous solution using the polymer methylcellulose to induce depletion and free volume entropy-based attractive forces. Both transmission electron microscopy and small-angle X-ray scattering show that the superlattices form in both semidilute and concentrated regimes of polymer, where the free volume entropy and the depletion interaction are the dominant driving force, respectively. The superlattices are NaCl and temperature responsive. The rigidity of the rodlike nanoparticles also plays an important role for the formation of superlattices through the free volume entropy mechanism. Compared to the rigid TMV particle, flexible bacteriophage M13 particles are only responsive to the depletion force and thus only assemble in highly concentrated polymer solution, where depletion interaction is dominant. PMID- 24044530 TI - Cytostatic versus cytocidal profiling of quinoline drug combinations via modified fixed-ratio isobologram analysis. AB - BACKGROUND: Drug combination therapy is the frontline of malaria treatment. There is an ever-accelerating need for new, efficacious combination therapies active against drug resistant malaria. Proven drugs already in the treatment pipeline, such as the quinolines, are important components of current combination therapy and also present an attractive test bank for rapid development of new concepts. METHODS: The efficacy of several drug combinations versus chloroquine-sensitive and chloroquine-resistant strains was measured using both cytostatic and cytocidal potency assays. CONCLUSIONS: These screens identify quinoline and non quinoline pairs that exhibit synergy, additivity, or antagonism using the fixed ratio isobologram method and find tafenoquine - methylene blue combination to be the most synergistic. Also, interestingly, for selected pairs, additivity, synergy, or antagonism defined by quantifying IC50 (cytostatic potency) does not necessarily predict similar behaviour when potency is defined by LD50 (cytocidal potency). These data further support an evolving new model for quinoline anti malarials, wherein haem and haemozoin are the principle target for cytostatic activity, but may not be the only target relevant for cytocidal activity. PMID- 24044531 TI - Synthesis, radiofluorination, and in vivo evaluation of novel fluorinated and iodinated radiotracers for PET imaging and targeted radionuclide therapy of melanoma. AB - Our project deals with a multimodal approach using a single fluorinated and iodinated melanin-targeting structure and offering both imaging (positron emission tomography (PET)/fluorine-18) and treatment (targeted radionuclide therapy/iodine-131) of melanoma. Six 6-iodoquinoxaline-2-carboxamide derivatives with various side chains bearing fluorine were synthesized and radiofluorinated, and their in vivo biodistribution was studied by PET imaging in B16Bl6 primary melanoma-bearing mice. Among this series, [(18)F]8 emerged as the most promising compound. [(18)F]8 was obtained by a fully automated radiosynthesis process within 57 min with an overall radiochemical yield of 21%, decay-corrected. PET imaging of [(18)F]8 demonstrated very encouraging results as early as 1 h postinjection with high tumor uptake (14.33% +/- 2.11% ID/g), high contrast (11.04 +/- 2.87 tumor-to-muscle ratio), and favorable clearance properties. These results, associated with the previously reported pharmacokinetic properties and dosimetry of 8, make it a potential agent for both PET imaging and targeted radionuclide therapy of melanoma. PMID- 24044532 TI - Factors associated with severe effects following acute glufosinate poisoning. AB - CONTEXT: In acute glufosinate poisoning, sudden respiratory arrest and convulsion can occur after a latent period of 4-60 h. There is still no factor that accurately predicts the occurrence of these symptoms. OBJECTIVE: To elucidate the predictors of severe effects following acute glufosinate poisoning. MATERIALS AND METHODS: This study is a retrospective observational case series. The subjects were 16 patients who had acute glufosinate poisoning. They were divided into a group with respiratory arrest or convulsion during hospitalization (severe group) and a group without (non-severe group). The following characteristics (or predictors) were compared between the groups: age, sex, calculated amount of glufosinate (volume of ingested poison (glufosinate-containing herbicide) * glufosinate concentration of the product), time duration from poison ingestion to arrival at our hospital, use of gastric lavage, use of whole bowel irrigation, Glasgow Coma Scale, laboratory parameters, PaO2/FiO2 ratio (P/F ratio), shock index, and presence or absence of systemic inflammatory response syndrome (SIRS) on arrival. RESULTS: The P/F ratio was significantly lower in the severe group than in the non-severe group (median, 287.5 vs. 409.0; P = 0.049). The receiver operating characteristic (ROC) curve was plotted for the predictor of increasing severity based on the P/F ratio. The area under the curve was 0.714, and the optimal cutoff point for increasing severity was 374.0. The sensitivity was 75.0%, specificity of 71.4%, and accuracy of 75.0%. The shock index was significantly higher (median, 0.52 vs. 0.41; P = 0.031). Significantly more patients had SIRS in the severe group than in the non-severe group (P = 0.015). Logistic regression analysis was performed with a backward elimination procedure. SIRS was selected as the independent predictor of increasing severity (odds ratio, 29.810; 95% confidence interval, 1.011-878.952; P = 0.049). DISCUSSION AND CONCLUSION: Severe effects following acute glufosinate poisoning were associated with two positive SIRS criteria. A low P/F ratio may be useful for predicting the occurrence of respiratory complications. PMID- 24044533 TI - Difficulty creating an anticholinergic rat model with atropine. PMID- 24044534 TI - Microbial metabolomic fingerprinting in urine after regular dealcoholized red wine consumption in humans. AB - The regular consumption of dealcoholized red wine (DRW) has demonstrated benefits in cardiovascular risk factors. The analysis of phenolic metabolites formed in the organism, especially those that could come from microbiota metabolism, would help to understand these benefits. The aim of this study was to determine the widest urinary metabolomic fingerprinting of phenolics and microbial-derived phenolic acids (n = 61) after regular intake of DRW in men at high cardiovascular risk by UPLC-MS/MS using a targeted approach. Up to 49 metabolites, including phase II and microbial phenolic metabolites, increased after DRW consumption compared to baseline (P < 0.05). The highest percentage of increase was found for microbial metabolites from anthocyanin degradation such as syringic, p-coumaric, gallic acids and pyrogallol and from flavan-3-ols degradation such as hydroxyphenylvalerolactones and (epi)catechins. These findings provide the most complete metabolic fingerprinting after wine consumption, amplifying the spectrum of microbial derived metabolites and their potential bioactivity related with health benefits. PMID- 24044535 TI - [Why do we not have screening for aortic aneurysm in Denmark?]. PMID- 24044536 TI - [Screening for abdominal aortic aneurysms has a positive clinical effect]. AB - In Denmark 2-3% of men aged 65 years or more die from abdominal aortic aneurysms (AAA). The lethality of ruptured AAA is 75%, while the risk of preventive surgery is 2-3%. Ultrasonographic screening for AAA is fast, safe and reliable. Randomized trials show that screening halves the mortality from AAA, and reduces total mortality by 2%. The latest health economic study concludes that it is highly cost-effective to screen 65-year-old Danish men, as a quality-adjusted life year can be gained for about 5,100 DKK (555 GBP). This is less than one tenth of the recently approved Danish colorectal cancer-screening programme. PMID- 24044537 TI - [No conclusive evidence for replacing conventional laparoscopic cholecystectomy with newer operating techniques]. AB - Single-insicion laparoscopic surgery (SILS) and natural orifice transluminal endoscopic surgery (NOTES) represent the latest development in minimally invasive surgery and are used in a wide variety of operations, e.g. cholecystectomies. The proposed benefits are less surgical trauma, reduced post-operative pain, smaller risk of infection and hence a shortened hospital stay compared with conventional laparoscopy. So far, no randomised study has uniformly shown clear advantages of SILS or NOTES that could justify an implementation of these techniques as acceptable alternatives to conventional laparoscopy. PMID- 24044538 TI - [Large venous malformations increase the risk of thromboembolic complications]. AB - Venous malformations (VM) represent vascular developmental errors. They are low flow lesions composed of ectatic vessels that histologically and morphologically are similar to veins. Episodic thromboses commonly occur in VM. Moreover, pulmonary emboli, sudden death and chronic thromboembolic pulmonary hypertension have been described in children and adults with extensive VM. This article discusses the management and treatment of patients with extensive VM. PMID- 24044539 TI - [Fatal Klippel-Trenaunay syndrome in a child with pulmonary embolism]. AB - Klippel-Trenaunay syndrome is characterized by the venous varicosities, ipsilateral cutaneous capillary malformations, and bony/soft-tissue overgrowth. Potential complications such as hypercoagulability, thrombosis and pulmonary embolism have been casuistically reported. Here, we describe a child with Klippel Trenaunay syndrome complicated by a pulmonary embolism leading to sudden death. PMID- 24044540 TI - [Doctors in training for general practice profit from being employed in both orthopaedic and general surgery wards]. AB - In the statement of aims of the education for general practice in Denmark competences in orthopaedic as well as in internal general surgery are specified by the Danish Health and Medicines Authority. In the period 2008-2010 there were three different types of employment for the assessment of competences in surgery. We found that doctors in training who had been employed in both orthopaedic and general surgery wards to a greater extent felt confident about their required competences in orthopaedic surgery. A majority of the 27 doctors participating in this survey felt that this kind of employment would be the best way to ensure the achievement of surgical competences. PMID- 24044541 TI - [Abdominal pseudocyst as a complication of ventriculoperitoneal shunt]. AB - The abdominal pseudocyst is an unfrequent complication in patients with ventriculoperitoneal shunts. Although many cases have been reported in children, it is rare in adult patients. However, a 47-year-old man with congenital hydrocephalus who had been treated with ventriculoperitoneal shunt since the age of three months, was admitted to hospital due to abdominal pain. He was eventually diagnosed radiologically as having an abdominal pseudocyst. Despite this complication being rare, especially in adults, it should be highly suspected whenever an abdominal cyst co-occurs with a ventriculoperitoneal shunt. PMID- 24044542 TI - [Visceral leishmaniasis in two children after vacation in Southern Europe]. AB - Pancytopenia, fever and splenomegaly are frequent causes for referrals to paediatric haematology departments, on the suspicion of acute leukaemia. We report two cases of Danish children with the tropical disease visceral leishmaniasis (VL) contracted on short vacations in Southern Europe. One of the patients developed secondary haemophagocytic lymphohistocytosis (HLH). Both children were successfully treated with liposomal amphotericin B. In Denmark, VL is a rare but important differential diagnosis to acute leukaemia and HLH, and should be ruled out after journeys to endemic areas, including Southern Europe. PMID- 24044543 TI - [Videocapsule endoscopy used for diagnosis of Henoch-Schonlein purpura with gastrointestinal complications]. AB - Henoch-Schonlein purpura (HSP) is primarily a childhood disease and is less common in adults where the incidence varies from 3.4 to 14.3 cases per million. We describe a case of adult HSP and discuss the role of videocapsule endoscopy, which is a non-invasive and safe method to evaluate the typical mucosa changes in especially small bowel. Medical doctors should be aware of HSP in adults and pay attention to the fact that in an unusual presentation with gastrointestinal manifestation videocapsule endoscopy may play a safe diagnostic role. PMID- 24044544 TI - A short commentary on the review by Weller and Kuchta: the DNA helicase-primase complex as a target for herpes virus infection. PMID- 24044545 TI - Pregnane X receptor polymorphisms associated with human diseases. AB - INTRODUCTION: Pregnane X receptor (PXR) belongs to the nuclear hormone receptor superfamily and is mostly expressed in liver and intestine. PXR is activated by a wide range of compounds, including drugs, and regulates the transcription of numerous metabolic enzymes implicated in cellular response to xenobiotics. Genetic variation in the PXR gene may influence a wide range of physiologic pathways and have widespread effects on the pharmacokinetics of many drugs. In addition, PXR polymorphisms have been associated with both benign and malignant disease states, in terms of disease risk and severity, gene expression and drug clearance. AREAS COVERED: The aim of the present review is to assess the significance of PXR polymorphisms in human diseases and their putative therapeutic perspectives. To this end, all the existing English literature concerning PXR polymorphisms in relation to disease risk and severity, as well as treatment response, is summarized and presented. EXPERT OPINION: The importance of PXR polymorphisms lies both in their prognostic value and their exploitation for improved individualized therapeutic approaches. PXR polymorphisms could be implicated in selective drug targeting leading to PXR modulation. Nevertheless, additional studies are required to fully understand their potential. PMID- 24044547 TI - Is mTOR inhibition a systemic treatment for tuberous sclerosis? AB - Tuberous sclerosis complex (TSC) is a genetic multisystem disorder characterized by the development of hamartomas in several organs. Mutations in the TSC1 and TSC2 tumor suppressor genes determin overactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for TSC patients. Everolimus has been recently approved as a pharmacotherapy option for TSC patients with subependymal giant-cell astrocytomas (SEGAs) or renal angiomyolipomas (AMLs). However, clinical evidence suggests that this treatment can benefit other TSC-associated disease manifestations, such as skin manifestations, pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas, and epilepsy. Therefore, the positive effects that mTOR inhibition have on a wide variety of TSC disease manifestations make this a potential systemic treatment option for this genetic multifaceted disorder. PMID- 24044548 TI - Combining neural networks and ANFIS classifiers for supervised examining of electrocardiogram beats. AB - Abstract In this paper, the supervised classification of the electrocardiogram (ECG) beats based on the fusion of several intelligent learning machines is described. For classification of ECG heartbeats, first, the QRS complexes are delineated by an efficient algorithm so as to identify the fiducial and J locations of each complex. For each delineated QRS complex, a feature vector is established based on the geometrical properties of the complex waveform and its associated discrete-wavelet transform. Next, three different multi-layer perceptron back-propagation (MLP-BP) networks are trained with different topologies and intrinsic parameters. Afterwards, the outputs of MLP-BPs are used as the new feature space elements for training three adaptive fuzzy network inference systems (ANFIS) in order to increase the final accuracy. At the end, the outputs of ANFIS classifiers are voted based on majority for each input sample. The method was applied to seven arrhythmias (Normal, LBBB, RBBB, PVC, APB, VE, VF) which belong to the MIT-BIH Arrhythmia Database and the average accuracy value Acc=98.28% was achieved for the beat-level. Also, the proposed method was assessed to five arrhythmias (Normal, LBBB, RBBB, PVC, APB) according to validation standards of the American Heart Association (AHA) at record (subject) level and the average accuracy value Acc=73.39% was achieved. To evaluate performance quality of the new proposed hybrid learning machine, the obtained results were compared with similar peer-reviewed studies in this area. PMID- 24044549 TI - Fine root branch orders contribute differentially to uptake, allocation, and return of potentially toxic metals. AB - Growing evidence has revealed high heterogeneity of fine root networks in both structure and function, with different root orders corporately maintaining trees' physiological activities. However, little information is available on how fine root heterogeneity of trees responds to environmental stresses. We examined concentrations of seven potentially toxic metals (Cr, Ni, Cu, Zn, As, Cd, and Pb) within fine root networks and their correlations with root morphological and macro-elemental traits in six Chinese subtropical trees. The contributions of different orders of roots to fine-root metal storage and return were also estimated. Results showed no consistent pattern for the correlation among different metal concentration against root traits. Unlike root metal concentration that generally decreased with root order, root metal storage was commonly lowest in middle root orders. Root senescence was at least comparable to leaf senescence contributing to metal removal. Although the first-order roots constituted 7.2-22.3% of total fine root biomass, they disproportionately contributed to most of metal return fluxes via root senescence. The two distinct root functional modules contributed differentially to metal uptake, allocation, and return, with defensive (lower-order) roots effectively stabilizing and removing toxic metals and bulk buffering (higher-order) roots possessing a persistent but diluted metal pool. Our results suggest a strong association of physiological functions of metal detoxification and metal homeostasis with the structural heterogeneity in fine root architecture. PMID- 24044550 TI - Initial use of endothelial progenitor cells capturing stents in paediatric congenital heart disease. AB - INTRODUCTION: Stenosis, mediated by neointimal hyperplasia and thrombosis, is a major limiting factor in successful stent implantation. The introduction of a stent, coated in its endoluminal surface by antihuman CD34 antibodies with endothelial progenitor cell-capturing properties, opens the possibility of promoting a rapid and normal functioning coverage by endothelium and thus avoids both an excessive cell proliferation within stent and the need for long-term dual antiplatelet therapy. These stents, developed for adult coronary artery disease, have not yet been implanted in children or in those with congenital heart disease. OBJECTIVE AND METHODS: In this paper, we describe the implantation of Genous(r) stents in three children with cyanotic congenital heart disease and obstructed systemic-to-pulmonary shunts. We describe the use of this stent and address its potential feasibility in paediatric congenital heart disease. RESULTS: To maintain the patency of two modified Blalock-Taussig shunts and one ductus arteriosus, four Genous(r) stents were implanted in three infants with cyanotic heart disease. All procedures were immediately successful, with resolution of stenosis and improvement in transcutaneous oxygen saturation from 66% +/- 3.6% to 92% +/- 2.6%. In the follow-up, one stent had no occlusion; however, the remaining two had partial occlusion after 5 and 5.5 months, which were successfully managed with balloon dilatation preceding elective definitive surgical correction. CONCLUSION: In our preliminary experience, we demonstrated that Genous(r) stent implantation was feasible in infants with complex congenital heart disease. Additional studies with larger samples and longer follow-up are required to confirm the potential benefits of this technology in this clinical setting. PMID- 24044552 TI - Enhanced interoceptive awareness during anticipation of public speaking is associated with fear of negative evaluation. AB - Interoceptive awareness (IA)--the ability to detect internal body signals--has been linked to various aspects of emotional processing. However, it has been examined mostly as a trait variable, with few studies also investigating state dependent fluctuations in IA. Based on the known positive correlation between IA and emotional reactivity, negative affectivity, and trait anxiety, the current study examined whether IA, as indexed by heartbeat detection accuracy, would change during an anxiety-provoking situation. Participants in the experimental condition, in which they anticipated giving a speech in front of a small audience, displayed significant IA increases from baseline to anticipation. Enhancement in IA was positively correlated with fear of negative evaluation. Implications of the results are discussed in relation to the role of trait and state IA in emotional experience. PMID- 24044553 TI - DRIFTS studies on the role of surface water in stabilizing catechol-iron(III) complexes at the gas/solid interface. AB - Surface water plays a crucial role in facilitating or inhibiting surface reactions in atmospheric aerosols. However, little is known about the role of surface water in the complexation of organic acid molecules to transition metals in multicomponent aerosol systems. We report herein results from real time DRIFTS experiments that show in situ complexation of catechol to Fe(III) under humid conditions. Catechol was schosen as a simple model for humic-like substances (HULIS) in aerosols and aged polyaromatic hydrocarbons (PAH). It was also detected in secondary organic aerosols (SOA) formed from the reaction of hydroxyl radicals with benzene. Given the importance of the iron content in aerosols and its biogeochemistry, our studies were conducted using FeCl3. For comparison, these surface-sensitive studies were complemented with bulk aqueous ATR-FTIR, UV vis, and HPLC measurements for structural, quantitative, and qualitative information about complexes in the bulk, and potential degradation products in the dark. Under dry conditions, DRIFTS spectra show that gas phase catechol adsorbs molecularly and is fully protonated on samples containing FeCl3 with no evidence of complexation to Fe(III). Upon increasing the relative humidity to a value below the deliquescence of FeCl3, surface water facilitates ionic mobility resulting in the formation of monodentate catechol-Fe complexes. These complexes are stable at the gas/solid interface and do not undergo any further degradation in the dark as shown from bulk UV-vis and HPLC experiments. The implications of our studies on understanding interfacial and condensed phase chemistry relevant to multicomponent aerosols, water thin films on buildings, and ocean surfaces containing transition metals are discussed. PMID- 24044554 TI - Probing the ArcA regulon under aerobic/ROS conditions in Salmonella enterica serovar Typhimurium. AB - BACKGROUND: Hydrogen peroxide (H2O2) is a reactive oxygen species (ROS), which is part of the oxidative burst encountered upon internalization of Salmonella enterica serovar Typhimurium (S. Typhimurium) by phagocytic cells. It has previously been established that, the ArcAB two-component system plays a critical role in ROS resistance, but the genes regulated by the system remained undetermined to date. We therefore investigated the ArcA regulon in aerobically growing S. Typhimurium before and after exposure to H2O2 by querying gene expression and other physiological changes in wild type and DeltaarcA strains. RESULTS: In the DeltaarcA strain, expression of 292 genes showed direct or indirect regulation by ArcA in response to H2O2, of which 141were also regulated in aerobiosis, but in the opposite direction. Gene set enrichment analysis (GSEA) of the expression data from WT and DeltaarcA strains, revealed that, in response to H2O2 challenge in aerobically grown cells, ArcA down regulated multiple PEP PTS and ABC transporters, while up regulating genes involved in glutathione and glycerolipid metabolism and nucleotide transport. Further biochemical analysis guided by GSEA results showed that deletion of arcA during aerobic growth lead to increased reactive oxygen species (ROS) production which was concomitant with an increased NADH/NAD+ ratio. In absence of ArcA under aerobic conditions, H2O2 exposure resulted in lower levels of glutathione reductase activity, leading to a decreased GSH (reduced glutathione)/GSSG (oxidized glutathione) ratio. CONCLUSION: The ArcA regulon was defined in 2 conditions, aerobic growth and the combination of peroxide treatment and aerobic growth in S. Typhimurium. ArcA coordinates a response that involves multiple aspects of the carbon flux through central metabolism, which ultimately modulates the reducing potential of the cell. PMID- 24044555 TI - The Nedd4-binding protein 3 (N4BP3) is crucial for axonal and dendritic branching in developing neurons. AB - BACKGROUND: Circuit formation in the nervous system essentially relies on the proper development of neurons and their processes. In this context, the ubiquitin ligase Nedd4 is a crucial modulator of axonal and dendritic branching. RESULTS: Herein we characterize the Nedd4-binding protein 3 (N4BP3), a Fezzin family member, during nerve cell development. In developing rat primary hippocampal neurons, endogenous N4BP3 localizes to neuronal processes, including axons and dendrites. Transient in vitro knockdown of N4BP3 in hippocampal cultures during neuritogenesis results in impaired branching of axons and dendrites. In line with these findings, in vivo knockdown of n4bp3 in Xenopus laevis embryos results in severe alteration of cranial nerve branching. CONCLUSIONS: We introduce N4BP3 as a novel molecular element for the correct branching of neurites in developing neurons and propose a central role for an N4BP3-Nedd4 complex in neurite branching and circuit formation. PMID- 24044556 TI - Intraoperative parathyroid hormone assay during focused parathyroidectomy: the importance of 20 minutes measurement. AB - BACKGROUND: Parathyroid hormone (PTH) monitoring during the surgical procedure can confirm the removal of all hyperfunctioning parathyroid tissue, as the half life of PTH is approximately 5 min. The commonly applied Irvin criterion is reported to correctly predict post-operative calcium levels in 96-98% of patients. However, the PTH baseline reference concentration is markedly influenced by surgical manipulations during preparation of the affected glands, interindividual variability of the PTH half-life and modifications in the physiological state of the patient during surgery. The aim of this study was to evaluate the possible impact of the measurement of intraoperative PTH 20 minutes after surgery. METHODS: Between 2003 and 2012, 188 patients underwent a focused parathyroidectomy associated to rapid intraoperative PTH assay monitoring. Blood samples were collected: 1) at pre-incision time, 2) at 10 min after gland excision and 3) at 20 min after excision, if a sufficient reduction of PTH value was not observed. On the bases of the Irvin criterion, an intra-operative PTH drop>50% from the highest either pre-incision or pre-excision level after parathyroid excision was considered a surgical success. RESULTS: A >50% decrease of PTH after gland excision compared to the highest pre-excision value occurred in 156/188 patients (83%) within 10 min and in further 12/188 after 20 minutes (6.4%). In the remaining 20 patients (10.6%) values of PTH remained substantially unchanged or decreased less than 50% and for this reason bilateral neck exploration was performed. An additional pathologic parathyroid was removed in 9 cases, a third in one. In the other 10 cases further neck exploration by a standard cervical approach was negative and in four of these persistent postoperative hypercalcemia was demonstrated. The overall operative success was 97.3%. Intraoperative PTH monitoring was accurate in predicting operative success or failure in 96.3% of patients. CONCLUSIONS: The 20 minutes PTH measurement appears very useful, avoiding unnecessary bilateral exploration and the related risk of complications with only a slight increase of the duration of surgery and of the costs. PTH values decreasing appeared to be influenced by surgical manipulations during minimally invasive parathyroidectomy. PMID- 24044557 TI - Beyond BRCA1/2: polygenic, 'polyfunctional' molecular circuitry model to predict breast cancer risk. PMID- 24044558 TI - Pteridine detection in urine: the future of cancer diagnostics? PMID- 24044561 TI - Analysis of the 2010-2012 results of the multicenter external proficiency study for 25-hydroxyvitamin D. AB - BACKGROUND: Results collected from the 2010-2012 cycles of the 'Immunocheck' external quality assessment scheme for 25-hydroxyvitamin D, conducted by QualiMedLab CNR (Italy) and ProBioQual (France; 250 among Italian and French laboratories) are presented in this article. METHODS: Details of how QualiMedLab operates can be found in QualiMedLab website. RESULTS: Interlaboratory imprecision was 19 (2010), 15 (2011) and 13% (2012). The LIAISON((r)) analyzer (DiaSorin, Italy) was the most utilized, followed by Roche (UK), ImmunoDiagnostic Systems methods (UK), ARCHITECT (Abbott, IL, USA), radioimmunoassay (DiaSorin) and others. The within-method variability between laboratories (percentage coefficient of variation) were 15, 12.7 versus 9.8% for LIAISON, 27.8, 16.5 versus 11.7% for Roche, 15, 12 versus 17% for ImmunoDiagnostic Systems and 17.4, 18.6 versus 17.5% for radioimmunoassay in the 2010, 2011 versus 2012 cycles, and 15 versus 8.9% for ARCHITECT in the 2011 versus 2012, respectively. CONCLUSION: Significant differences in specific samples and discrepancies between laboratories and methods still exist, making the actuation of appropriate external quality assessment schemes mandatory. PMID- 24044562 TI - Salivary biomarker analysis complementing regular clinical examination. AB - AIM: Tools for the diagnosis and evaluation of the severity and prognosis of periodontitis are currently insufficient. The aim of the current study was to find an array of salivary biomarkers that would be both sensitive and specific enough to be used as a complement to regular clinical examination. Furthermore, we investigated salivary markers of successful periodontal treatment to elucidate the underlying mechanism of disease. PATIENTS & METHODS: Saliva was collected from periodontitis patients during illness and following successful disease termination. Parameters measured included sodium, potassium, chloride, calcium, phosphate, magnesium, total protein, Alb, LDH, amylase, IL-1alpha, uric acid and carbonyls. RESULTS: Seven of the parameters analyzed were significantly altered when the disease is active and may be considered biomarkers. CONCLUSION: Salivary composition reflects disease severity and response to therapy, suggesting the efficacy of saliva monitoring for periodontal disease status and care. PMID- 24044563 TI - Associations between total serum GGT activity and metabolic risk: MESA. AB - AIM: To evaluate associations between total serum GGT activity, metabolic risk factors and prevalent metabolic disease in MESA. PATIENTS & METHODS: Continuous associations between GGT and fasting blood glucose (FBG), fasting insulin, HbA1c and Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR) were evaluated in the entire MESA cohort and in metabolic disease subgroups using linear regression models incrementally adjusted for age, gender, site, race, lifestyle, traditional risk factors and medications. Cross-sectional odds of prevalent impaired FBG, metabolic syndrome and Type 2 diabetes were calculated for GGT quintiles in the entire cohort and in subgroups defined by age (< or >=65 years) and ethnicity. RESULTS: In multivariable models, significant associations were present between GGT activity and FBG, fasting insulin, HbA1c and HOMA-IR, with the interaction between GGT and BMI affecting the association between GGT and HOMA-IR as well as the association between BMI and HOMA-IR (p < 0.0001). Adjusted odds ratios (95% CIs) of prevalent impaired FBG, metabolic syndrome and Type 2 diabetes for quintile 5 versus 1 in the entire cohort were 2.4 (1.7-3.5), 3.3 (2.5-4.5) and 2.8 (1.8-4.4), respectively (p < 0.0001). GGT associations weakened with age. The significance of linear trends for increased prevalent metabolic disease by increasing GGT quintile varied by ethnicity. CONCLUSION: GGT is strongly associated with both cardiovascular and metabolic risk factors, including prevalent metabolic disease, in the MESA cohort. PMID- 24044564 TI - A-FABP and its association with atherogenic risk profile and insulin resistance in young overweight and obese women. AB - AIM: We evaluated the association of A-FABP with proatherogenic risk profile and insulin resistance (IR) in young, nondiabetic, overweight/obese women. MATERIALS & METHODS: Serum A-FABP, high-sensitivity CRP, adiponectin, glucose, insulin, lipids and apolipoproteins were measured in 104 women (aged 20-45 years; BMI >=25 kg/m(2)) and age-matched healthy controls (n = 76; BMI <25 kg/m(2)). All patients underwent blood pressure and anthropometric measurements. RESULTS: A-FABP concentration was related to IR, and anthropometric and atherogenic indices. A FABP was an independent predictor of triglyceride:high-density lipoprotein cholesterol, explaining 42% of its variation in overweight/obese women. At a cutoff level of 16 ng/ml, A-FABP discriminated between controls and overweight/obese (area under curve = 0.96) with high sensitivity and specificity. A-FABP predicted atherogenic risk, with an odds ratio of 11.2 (95% CI: 3.7-34.2), 7.1 (1.9-27.2) and 6.7 (2.6-17.2) for having elevated triglyceride:high-density lipoprotein cholesterol, apoB and CRP, respectively, and IR with an odds ratio 5.6 (1.8-17.2). CONCLUSION: A-FABP seems to be a valuable predictor of atherogenic risk profile; if elevated it contributes to cardiovascular disease beyond its effect on IR. PMID- 24044565 TI - Association of adipokines with obesity in children and adolescents. AB - BACKGROUND: Childhood obesity is a global epidemic and is associated with a higher risk of chronic diseases such as hypertension, diabetes mellitus and other metabolic disorders. Several adipokines including resistin, visfatin, leptin and adiponectin are synthesized and secreted by adipocytes, which play an important role in obesity. PATIENTS & METHODS: A total of 90 subjects (60 controls and 30 obese) between the ages of 5 and 18 years were selected. Serum visfatin, TNF alpha, resistin, insulin and adiponectin were measured using ELISA and insulin resistance was calculated by the Homeostasis Model of Assessment-Insulin Resistance. RESULTS: Mean +/- standard deviation Homeostasis Model of Assessment Insulin Resistance, serum TNF-alpha and visfatin levels were significantly higher in obese subjects (3.99 +/- 0.94, 12.99 +/- 3.42, 10.89 +/- 2.72, respectively) compared with the control group (1.60 +/- 0.34, 7.22 +/- 2.22 and 4.97 +/- 1.57, respectively). Mean +/- standard deviation serum adiponectin levels were significantly lower in obese children (5.95 +/- 1.02) compared with controls (9.07 +/- 1.25). Binary logistic regression shows that adiponectin and visfatin are associated with obesity. CONCLUSION: Circulating levels of adipokines vary in obesity and adiponectin and visfatin are associated with obesity. PMID- 24044566 TI - Serum adiponectin, leptin, resistin and RBP4 levels in obese and metabolic syndrome children with nonalcoholic fatty liver disease. AB - AIM: To investigate the relationship of adiponectin, leptin, resistin and RBP4 levels in obese and metabolic syndrome children with nonalcoholic fatty liver disease (NAFLD). PATIENTS & METHODS: Group I consisted of 63 obese children with liver steatosis, group II consisted of 12 obese children with elevated serum ALT activity from group I, and group III included 85 obese children without liver steatosis. RESULTS: Leptin levels were higher in the NAFLD children than in the control group. Serum RBP4 levels in obese children with NAFLD were higher than those in obese children without NAFLD and controls. Adiponectin and resistin levels were negatively correlated and RBP4 levels positively correlated with ALT activity and ultrasonographic grading. CONCLUSION: These data suggest that adiponectin, resistin and RBP4 may have a role in the pathogenesis of NAFLD in obese children. Adiponectin, leptin, resistin and RBP4 may be suitable markers for predicting metabolic syndrome and NAFLD. PMID- 24044567 TI - Cathepsin D as an indicator of clinical outcome in early breast carcinoma during the first 3 years of follow-up. AB - AIM: The aim of this study was to evaluate clinical usefulness of cathepsin D status in early breast cancer during the first 3 years of follow-up. PATIENTS & METHODS: The study included 226 patients with histologically verified, primary operable invasive early breast carcinomas. Concentrations of estrogen receptor (ER) and progesterone receptor (PR) in breast tumor cytosols were measured by use of the classical biochemical method. The concentration of three cathepsin D forms (52-, 48- and 34-kDa proteins) was determined by a radioimmunoassay RESULTS: On the basis of differences in cathepsin D levels either within an ER(-)/PR(-) phenotype or between this and either ER(+)/PR(+) or ER(+)/PR(-) phenotypes, a concentration of 39 pmol/mg was determined as the cutoff value for distinguishing estrogen-regulated cathepsin D expression. Estrogen-regulated cathepsin D expression was recognized as a high-risk biomarker for low-risk (histological grade I) breast cancer patients and as a low-risk biomarker for high-risk patients (pN(+) pT2,3). CONCLUSION: Determination of cathepsin D status in breast cancer might identify patients at different risk for relapse and might facilitate the selection of more or less aggressive adjuvant therapy for early breast cancer patients during the first 3 years of follow-up. PMID- 24044568 TI - Defining the seriousness of proliferative vitreoretinopathy by aspiration of cytokines from the anterior chamber. AB - AIM: Proliferative vitreoretinopathy is the major cause of retinal detachment surgery failure. Our prospective cohort study of 27 eyes aimed to determine intraocular levels of growth factors and cytokines in patients with retinal detachment with various degrees of severity of proliferative vitreoretinopathy using multiplex xMAP((r)) Technology. PATIENTS & METHODS: The concentrations of 12 proangiogenic, antiangiogenic, inflammatory and neurotrophic factors were measured from 0.05-ml samples of intraocular fluid using multiplex xMAP Technology. The results were compared with levels of various factors, which were measured in samples from the control group of 31 eyes prior to senile cataract surgery. RESULTS: The concentration of the MCP-1 cytokine was found to be higher in eyes with retinal detachment compared with the control group. The concentration of VEGF was found to be higher in eyes with retinal detachment complicated with proliferative vitreoretinopathy compared with the uncomplicated retinal detachment group and the control group. CONCLUSION: MCP-1 and VEGF may participate in pathogenesis of retinal detachment and proliferative vitreoretinopathy. Biomarkers in disease detection and management have become important tools in modern clinical medicine, and their application to retinal disease should be no exception. PMID- 24044569 TI - Exosomes: the future of biomarkers in medicine. AB - Exosomes are nanovesicles secreted into the extracellular environment upon internal vesicle fusion with the plasma membrane. The molecular content of exosomes is a fingerprint of the releasing cell type and of its status. For this reason, and because they are released in easily accessible body fluids such as blood and urine, they represent a precious biomedical tool. A growing body of evidence suggests that exosomes may be used as biomarkers for the diagnosis and prognosis of malignant tumors. This article focuses on the exploitation of exosomes as diagnostic tools for human tumors and discusses possible applications of the same strategies to other pathologies, such as neurodegenerative diseases. PMID- 24044570 TI - Urinary biomarkers of bladder cancer: an update and future perspectives. AB - Bladder cancer is one of the most prevalent cancers worldwide. Early detection of bladder tumors is critical for improved patient outcomes. The standard method for detection and surveillance of bladder tumors is cystoscopy with urinary cytology. Limitations of cystoscopy and urinary cytology have brought to light the need for more robust diagnostic assays. Ideally, such assays would be applicable to noninvasively obtained, voided urine, and be designed not only for diagnosis, but also for monitoring disease recurrence and response to therapy. Consequently, the development of a noninvasive urine-based assay would be of tremendous benefit to both patients and healthcare systems. This article reports some of the more prominent urine-based biomarkers reported in the literature. In addition, some new technologies that have been used to identify novel urinary biomarkers are highlighted. PMID- 24044571 TI - Biomarkers in childhood non-Hodgkin's lymphomas. AB - Pediatric non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of malignancies with distinct clinical, pathological, immunological and genetic characteristics. More than 90% of pediatric NHLs belong to one of three major histological subtypes: mature B-cell neoplasms, lymphoblastic lymphomas and anaplastic large-cell lymphomas. The recognition that different subtypes require different treatment regimens resulted in therapeutic strategies leading to over 80% of patients being cured. On the other hand, patients with resistant or relapsed disease have a poor prognosis. Prognostic biomarkers have not yet been identified for all pediatric NHLs and, although some are very important for diagnosis and prognosis, others may be of questionable value. Discovery of new biomarkers suitable for clinical application may aid the diagnosis and classification of lymphomas, which should, in turn, lead to better patient stratification. Consequent development of new treatment and follow-up approaches should lead to more efficient and less toxic treatment in children with NHL. PMID- 24044572 TI - Cell surface membrane proteins as personalized biomarkers: where we stand and where we are headed. AB - Personalized medicine requires the development of a wide array of biomarker diagnostic assays, reflecting individual variations and thus allowing tailored therapeutic interventions. Membrane proteins comprise approximately 30% of total human proteins; they play a key role in various physiological functions and pathological conditions, although, currently, only a limited number of membrane proteins are applied as biomarkers. In many normal tissues, cell surface membrane proteins are not easily accessible for diagnostic sampling, and tumor-derived membrane preparations - while serving as potential tumor biomarkers - may not reflect physiological protein expression. In addition to post-translational modifications, which may include glycosylation, phosphorylation and lipid modifications, the trafficking of membrane proteins is also regulated. Moreover, a tight cellular quality control monitors membrane protein maturation, and continuous removal and reinsertion, involving special signaling systems, occurs in many cases. However, cell surface membrane proteins already serve as valuable prognostic and predicative biomarkers, for example, in hematological and immunological diseases, by the determination of the cluster of differentiation markers. In this review, we demonstrate the relevance of cell surface membrane biomarkers in various diseases and call attention to the potential application of red blood cell (erythrocyte) membrane proteins in this regard. Surprisingly, red blood cells express hundreds of membrane proteins, which seem to reflect a general genetic and regulatory background, and may serve as relatively stable and easily accessible personalized membrane biomarkers. Quantitative membrane protein detection in red blood cells by flow cytometry may bring a breakthrough in this regard. PMID- 24044574 TI - The periodic focusing ion funnel: theory, design, and experimental characterization by high-resolution ion mobility-mass spectrometry. AB - Simulation-based development and experimental characterization of a DC-only ion funnel is described herein. Radial ion confinement is achieved via periodic focusing whereby a collisionally dampened effective potential is generated in the inertial frame of an ion traversing the device with appreciable velocity. The new device, termed a periodic focusing ion funnel (PF IF), provides an efficient alternative to the rf ion funnel providing high ion transmission with fewer electrodes, simplified electrical circuitry, and reduced power supply requirements. The utility of the PF IF for structural ion mobility-mass spectrometry (IM-MS) studies is demonstrated using model peptide ions (bradykinin, gramicidin S, and trpzip 1). PMID- 24044575 TI - Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization. AB - BACKGROUND: Tumor-associated macrophages (TAM) play an important role in tumor microenvironment. Particularly, M2 macrophages contribute to tumor progression, depending on the expression of NF-kappaB. Tumor-derived exosomes can modulate tumor microenvironment by transferring miRNAs to immune cells. Epigallocatechin gallate (EGCG) has well known anti-tumor effects; however, no data are available on the influence of EGCG on communication with cancer cells and TAM. METHODS: Murine breast cancer cell lines, 4T1, was used for in vivo and ex vivo studies. Exosome was extracted from EGCG-treated 4T1 cells, and the change of miRNAs was screened using microarray. Tumor cells or TAM isolated from murine tumor graft were incubated with exosomes derived from EGCG-treated and/or miR-16 inhibitor transfected 4T1 cells. Chemokines for monocytes (CSF-1 and CCL-2), cytokines both with high (IL-6 and TGF-beta) and low (TNF-alpha) expression in M2 macrophages, and molecules in NF-kappaB pathway (IKKalpha and Ikappa-B) were evaluated by RT qPCR or western blot. RESULTS: EGCG suppressed tumor growth in murine breast cancer model, which was associated with decreased TAM and M2 macrophage infiltration. Expression of chemokine for monocytes (CSF-1 and CCL-2) were low in tumor cells from EGCG-treated mice, and cytokines of TAM was skewed from M2- into M1-like phenotype by EGCG as evidenced by decreased IL-6 and TGF-beta and increased TNF-alpha. Ex vivo incubation of isolated tumor cells with EGCG inhibited the CSF-1 and CCL-2 expression. Ex vivo incubation of TAM with exosomes from EGCG-treated 4T1 cells led to IKKalpha suppression and concomitant I-kappaB accumulation; increase of IL-6 and TGF-beta; and, decrease of TNF-alpha. EGCG up regulated miR-16 in 4T1 cells and in the exosomes. Treatment of tumor cells or TAM with exosomes derived from EGCG-treated and miR-16-knock-downed 4T1 cells restored the above effects on chemokines, cytokines, and NF-kappaB pathway elicited by EGCG-treated exosomes. CONCLUSIONS: Our data demonstrate that EGCG up regulates miR-16 in tumor cells, which can be transferred to TAM via exosomes and inhibits TAM infiltration and M2 polarization. We suggest a novel mechanism by which EGCG exerts anti-tumor activity via regulation of TAM in tumor microenvironment. PMID- 24044576 TI - Layer-by-layer assembly of thick, Cu(2+)-chelating films. AB - Layer-by-layer adsorption of protonated poly(allylamine) (PAH) and deprotonated poly(N,N-dicarboxymethylallylamine) (PDCMAA) yields thick films with a high density of iminodiacetic acid (IDA) ligands that bind metal ions. When film deposition occurs at pH 3.0, PAH/PDCMAA bilayer thicknesses reach 200 nm, and Cu(2+) binding capacities are ~2.5 mmol per cm(3) of film. (PAH/PDCMAA)10 films deposited at pH 3.0 are 4-8-fold thicker than films formed at pH 5.0, 7.0, or 9.0, presumably because of the low charge density on PDCMAA chains at pH 3.0. However, with normalization to film thickness, all films bind similar amounts of Cu(2+) from pH 4.1 solutions of CuSO4. In micrometer-thick films, equilibration of binding sites with Cu(2+) requires ~4 h due to a low Cu(2+) diffusion coefficient (~2.6 * 10(-12) cm(2)/s). Sorption isotherms determined at several temperatures show that Cu(2+) binding is endothermic with a positive entropy (binding constants increase with increasing temperature), presumably because metal-ion complexation involves displacement of both a proton from IDA and water molecules from Cu(2+). (PAH/PDCMAA)10 films retain their binding capacity over four absorption/elution cycles and may prove useful in metal-ion scavenging, catalysis, and protein binding. PMID- 24044577 TI - Parguerene and precarriebowmide, two classes of lipopeptides from the marine cyanobacterium Moorea producens. AB - Two new marine cyanobacterial natural products, parguerene (1) and precarriebowmide (2), were isolated from a collection of Moorea producens obtained from La Parguera, Puerto Rico. The planar structures of both were deduced by 2D NMR spectroscopy and mass spectrometry. Parguerene is a modified acyl amide with some structural similarity to the bacterial metabolite stipiamide (3), whereas precarriebowmide is a lipopeptide and represents a minor modification compared to two other known metabolites, carriebowmide (4) and carriebowmide sulfone (5). The identification of 2 led to an investigation into whether carriebowmide and carriebowmide sulfone were true secondary metabolites or isolation artifacts. PMID- 24044578 TI - Articular cartilage degeneration in the contralateral non-surgical temporomandibular joint in mice with a unilateral partial discectomy. AB - OBJECTIVE: The objective was to characterize the contralateral non-surgical temporomandibular joint (TMJ) in mice that had an opposing osteoarthrosis(OA) like joint induced by unilateral partial discectomy. METHODS: TMJs on one side in mice were subjected to partial discectomy. Both surgical and contralateral non surgical TMJs were collected at 4, 8, 12 and 16 weeks post-surgery for histological examination. The morphology of the articular cartilage of the condyle was evaluated using a scoring system. RESULTS: A progression of articular cartilage degeneration was seen in the TMJs following unilateral partial discectomy, including increased proteoglycan staining in the extracellular matrix at 4 weeks, the appearance of chondrocyte clusters at 8 weeks, reduced proteoglycan staining and fibrillation at 12 weeks and the loss of articular cartilage at 16 weeks. In the contralateral non-surgical TMJs, increased proteoglycan staining occurred in the articular cartilage of the condyle at 8 weeks and continued to age. CONCLUSION: The result indicated that OA-like changes in one TMJ by partial discectomy could initiate early-onset articular cartilage degeneration in the contralateral non-surgical TMJ in mice. PMID- 24044580 TI - Lack of an association between interleukin-6 -174G/C polymorphism and circulating interleukin-6 levels in normal population: a meta-analysis. AB - Interleukin-6 (IL-6) signaling may play a causal role in the development of coronary heart disease. However, the relationship between IL-6 genotypes and plasma levels of IL-6 appears to be complex. To help clarify the inconsistent findings, we conducted a meta-analysis of the published genetic association studies of the -174 G/C polymorphisms in the IL-6 gene and the circulating IL-6 levels in a normal population. In this meta-analysis, no significant association of IL-6 -174G/C polymorphism and circulating IL-6 levels in a normal population was observed. However, when compared among GG, GC, and CC genotypes, heterogeneity existed among the studies. Sensitivity analysis revealed that, the independent study by Shen et al. influenced the heterogeneity in the homozygous and heterozygous comparison. Although Shen et al.'s study was excluded, no significant association was observed between IL-6 -174G/C polymorphism and circulating IL-6 levels in a normal population [homozygous comparison (GG vs. CC): the pooled standard mean difference (SMD) was -0.01, 95% confidence interval (CI): -0.1-0.08; heterozygous comparison (GC vs. GG or CC): the pooled SMD (GG vs. GC) was -0.05, 95%CI: -0.11-0.01, and the pooled SMD (CC vs. GC) was 0.03, 95%CI: -0.03-0.1]. Under the dominant model, the pooled SMD was -0.05, 95%CI: 0.11-0.01). The meta-analysis provides evidence that the -174G/C polymorphism in the IL-6 gene is not significantly associated with circulating IL-6 levels in a normal population. PMID- 24044579 TI - Age-dependent effect of high-fructose and high-fat diets on lipid metabolism and lipid accumulation in liver and kidney of rats. AB - BACKGROUND: The metabolic syndrome (MS) is characterized by variable coexistence of metabolic and pathophysiological alterations which are important risk factors for developing of type II diabetes and/or cardiovascular diseases. Increased of MS patients in worldwide has stimulated the development of experimental models. However, it is still challenging to find an dietetic model that most closely approximates human MS and, in addition, is not yet fully established the effect of different diets of MS in lipid metabolism in rats of different ages. The aim of this study was to evaluate the effect of different diets of MS in lipid metabolism and ectopic fat deposition and define the most appropriate diet for inducing the characteristic disturbances of the human MS in rats of different ages. METHODS: Young (4 weeks old) and adult rats (12 weeks old) were given a high-fat (FAT) or high-fructose diet (FRU) for 13 weeks and biochemical, physiological, histological and biometric parameters were evaluated. RESULTS: In young rats, the FAT diet induced increased mean blood pressure (MAP) and heart rate (HR), body weight after 6 to 10 weeks, and in the 13th week, increased the liver, mesenteric, retroperitoneal and epididymal fat weights, fasting glucose, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and reduced HDL cholesterol; and also induced non-alcoholic fatty liver disease (NAFLD) and renal inflammatory infiltrates. In adult rats, the FRU diet induced transient elevations of MAP and HR in the 6th week, and, at 13 weeks, increased fasting glucose, triglycerides, total cholesterol, AST and ALT; increased liver, kidneys and retroperitoneal fat weights; and induced macrovesicular and microvesicular NAFLD, the presence of fat cells in the kidney, glomerular sclerosis, and liver and kidney inflammation. Additionally, the FAT and FRU diets induced, respectively, increases in liver glycogen in adults and young rats. CONCLUSIONS: Our data show that FRU diet in adult rats causes biggest change on metabolism of serum lipids and lipid accumulation in liver and kidney, while the FAT diet in young rats induces elevation of MAP and HR and higher increased visceral lipid stores, constituting the best nutritional interventions to induce MS in rats. PMID- 24044581 TI - Changes in cortical excitability and blood lactate after a fatiguing hand-grip exercise. AB - Excitability of primary hand motor cortex (PHMC), evaluated with transcranial magnetic stimulation by using the "1 mV resting motor threshold" method, and capillary blood lactate were measured at the end, as well as 5 and 10 min after a fatiguing hand-grip exercise. The relation between blood lactate and the amplitudes of motor-evoked potentials showed a significant direct proportionality. Blood lactate seems to exert a protective role on PHMC against fatigue reduction during extremely intensive isometric exercises. PMID- 24044582 TI - Sociodemographic predictors of multiple non-communicable disease risk factors among older adults in South Africa. AB - BACKGROUND AND OBJECTIVE: Unhealthy lifestyle behaviours are important risk factors of morbidity and mortality. This study aimed to explore the sociodemographic predictors of multiple non-communicable disease (NCD) risk factors experienced by elderly South Africans. METHODS: We conducted a national population-based cross-sectional survey with a sample of 3,840 individuals aged 50 years or above in South Africa in 2008. The outcome variable was the co existence of multiple NCD risk factors (tobacco use, alcohol, physical inactivity, fruit and vegetable intake, overweight or obesity, and hypertension) in each individual. The exposure variables were sociodemographic characteristics, namely, age, gender, education, wealth status, population group, marital status, and residence. Multivariate linear regression was used to assess the association between sociodemographic variables and multiple NCD risk factors. RESULTS: The mean number of NCD risk factors among all participants was three (95% confidence interval: 2.81-3.10). Multivariate linear regression analysis revealed that being female, being in the age group of 60-69 years, and being from the Coloured and Black African race were associated with a higher number of NCD risk factors. Marital status, educational level, wealth, and residence were not significantly associated with the number of NCD risk factors experienced. CONCLUSIONS: The co existence of multiple lifestyle NCD risk factors among the elderly is a public health concern. Comprehensive health-promotion interventions addressing the co existence of multiple NCD risk factors tailored for specific sociodemographic groups are needed. PMID- 24044583 TI - Performing masculinity, influencing health: a qualitative mixed-methods study of young Spanish men. AB - BACKGROUND: The literature shows how gender mandates contribute to differences in exposure and vulnerability to certain health risk factors. This paper presents the results of a study developed in the south of Spain, where research aimed at understanding men from a gender perspective is still limited. OBJECTIVE: The aim of this paper is to explore the lay perceptions and meanings ascribed to the idea of masculinity, identifying ways in which gender displays are related to health. DESIGN: The study is based on a mixed-methods data collection strategy typical of qualitative research. We performed a qualitative content analysis focused on manifest and latent content. RESULTS: Our analysis showed that the relationship between masculinity and health was mainly defined with regard to behavioural explanations with an evident performative meaning. With regard to issues such as driving, the use of recreational drugs, aggressive behaviour, sexuality, and body image, important connections were established between manhood acts and health outcomes. Different ways of understanding and performing the male identity also emerged from the results. The findings revealed the implications of these aspects in the processes of change in the identity codes of men and women. CONCLUSIONS: The study provides insights into how the category 'man' is highly dependent on collective practices and performative acts. Consideration of how males perform manhood acts might be required in guidance on the development of programmes and policies aimed at addressing gender inequalities in health in a particular local context. PMID- 24044584 TI - A potential target for organophosphate insecticides leading to spermatotoxicity. AB - Organophosphate (OP) insecticides as an anticholinesterase also act on the diverse serine hydrolase targets, thereby revealing secondary or unexpected toxic effects including male reproductive toxicity. The present investigation detects a possible target molecule(s) for OP-induced spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) from a chemical standpoint. The activity based protein profiling (ABPP) approach with a phosphonofluoridate fluorescent probe pinpointed the molecular target for fenitrothion (FNT, a major OP insecticide) oxon (bioactive metabolite of FNT) in the mouse testicular membrane proteome, i.e., FNT oxon phosphorylates the fatty acid amide hydrolase (FAAH), which plays pivotal roles in spermatogenesis and sperm motility acquirement. Subsequently, mice were treated orally with vehicle or FNT for 10 days, and FAAH activity in testis or epididymis cauda was markedly reduced by the subacute exposure. ABPP analysis revealed that FAAH was selectively inhibited among the FNT-treated testicular membrane proteome. Accordingly, FAAH is a potential target for OP-elicited spermatotoxicity. PMID- 24044585 TI - Enhanced fasting and post-prandial plasma bile acid responses after Roux-en-Y gastric bypass surgery. AB - OBJECTIVE: Exogenous bile acid (BA) administration is associated with beneficial metabolic effects very similar to those seen after Roux-en-Y gastric bypass (RYGB) surgery. Re-routing of bile into a biliopancreatic limb with simultaneous exclusion of food occurs after RYGB, with subsequent increased fasting plasma BAs. The study assessed fasting and post-prandial plasma BA response before and 15 months after RYGB. MATERIAL AND METHODS: The prospective study recruited 63 obese individuals (43 females), aged 43 (36-56) [median (IQR)] years. Blood samples were collected before and every 30 min for 120 min after a standard 400 kcal meal. Fasting and post-prandial plasma BAs, glucagons like peptide-1 (GLP 1), -tyrosine (PYY), fasting C-reactive protein (CRP), glucose and insulin were measured and homeostasis model assessment-insulin resistance (HOMA-IR) was calculated. RESULTS: Following RYGB, body mass index, CRP, fasting glucose and HOMA-IR decreased; 43.7 (39.3-49.2) kg/m(2) to 29.2 (25.1-35.0) kg/m(2), 7.9 (4.1 11.9) mg/L to 0.4 (0.2-1.0) mg/L, 5.5 (5.0-6.0) mmol/L to 4.6 (4.3-4.9) mmol/L and 5.9 (3.5-9.2) to 1.7 (1.1-2.2), respectively, all P < 0.001. Fasting total BAs, GLP-1 and PYY increased after RYGB; 1.69 (0.70-2.56) umol/L to 2.43 (1.23 3.82) umol/L (P = 0.02), 6.8 (1.5-15.3) pmol/L to 17.1 (12.6-23.9) pmol/L (P < 0.001) and 4.0 (1.0-7.1) pmol/L to 15.2 (10.0-28.3) pmol/L (P < 0.001), respectively. The area under the curve for post-prandial total BAs, total glycine conjugated BAs, GLP-1 and PYY were greater after RYGB; 486 (312-732) umol/L/min versus 1012 (684-1921) umol/L/min, 315 (221-466) umol/L/min versus 686 (424-877) umol/L/min, 3679 (3162-4537) pmol/L/min versus 5347 (4727-5781) pmol/L/min and 1887 (1423-2092) pmol/L/min versus 3296 (2534-3834) pmol/L/min, respectively, all P < 0.0001. CONCLUSION: Weight loss following RYGB is associated with an increase in post-prandial plasma BA response due to larger amounts of glycine-conjugated BAs. This suggests up regulation of BA production and conjugation after RYGB. PMID- 24044586 TI - Analysis of heart rate variability signal during meditation using deterministic chaotic quantifiers. AB - This study investigated the level of chaos and the existence of fractal patterns in the heart rate variability (HRV) signal prior to meditation and during meditation using two quantifiers adapted from non-linear dynamics and deterministic chaos theory: (1) component central tendency measures (CCTMs) and (2) Higuchi fractal dimension (HFD). CCTM quantifies degree of variability/chaos in the specified quadrant of the second-order difference plot for HRV time series, while HFD quantifies dimensional complexity of the HRV series. Both the quantifiers yielded excellent results in discriminating the different psychophysiological states. The study found (1) significantly higher first quadrant CCTM values and (2) significantly lower HFD values during meditation state compared to pre-meditation state. Both of these can be attributed to the respiratory-modulated oscillations shifting to the lower frequency region by parasympathetic tone during meditation. It is thought that these quantifiers are most promising in providing new insight into the evolution of complexity of underlying dynamics in different physiological states. PMID- 24044587 TI - Experimental investigation of the stent-artery interaction. AB - It is well acknowledged that stent implantation causes abnormal stretch and strains on the arterial wall, which contribute to the formation and progression of restenosis. However, the experimental characterization of the strain field on the stented vessel is scant. In this work, the balloon-expandable stent implantation inside an artery analogue was captured through two high-speed CCD cameras. The surface strain maps on the stented tube were quantified with a 3-D digital image correlation technique. The strain history at one specific reference point illustrated three stenting phases, including balloon inflation, pressurization and deflation. The surface strain distributions along one axial path were obtained at various time points to demonstrate the stent-vessel interactions. The radial wall thickness reduction history was used to evaluate the pressure-diameter relationship for the balloon. Results indicated that the expansion process of the balloon was significantly altered by the external loadings from both the stent and artery analogue. In addition, the repeatability of the stenting experiments was demonstrated through two tests with a change of 5% in the stent-induced maximum first principal strain. Moreover, a computational model of the stenting procedure was developed to recapture the stenting experiments. Comparison between experiments and simulation showed a difference of 7.17% in the first principal strain averaged over the high strain area. This indicated the validation of the computational framework, which can be used to investigate the strain or stress field throughout the computational domain, a feature that is not affected by experimental techniques. PMID- 24044590 TI - Imerslund-Grasbeck syndrome in a 25-month-old Italian girl caused by a homozygous mutation in AMN. AB - Imerslund-Grasbeck syndrome is a rare autosomal recessive disorder, characterized by vitamin B12 deficiency due to selective malabsorption of the vitamin and usually results in megaloblastic anemia appearing in childhood. It is responsive to parenteral vitamin B12 therapy.The estimated prevalence (calculated based on Scandinavian data) is less than 6:1,000,000. However, many cases may be misdiagnosed.When there is reasonable evidence to suspect that a patient suffers from IGS, a new and straightforward approach to diagnosis is mutational analysis of the appropriate genes. We report for the first time the case of a girl of Italian ancestry with IGS genetically confirmed by the detection of a homozygous missense mutation in the AMN gene (c.208-2 A > G). PMID- 24044591 TI - Synthesis and characterization of polyvinylpyrrolidone coated cerium oxide nanoparticles. AB - There is a pressing need for the development of standard and reference nanomaterials for environmental nanoscience and nanotoxicology. To that aim, suspensions of polyvinylpyrrolidone (PVP)-coated ceria nanoparticles (NPs) were produced. Four differently sized monodispersed samples were produced by using different PVP chain lengths. The chemical and physical properties of these NPs were characterized as prepared and in different ecotoxicology exposure media. Dynamic light scattering analysis showed that the samples were monodispersed, with an unchanged size when suspended in the different media over a 72 h period. Electron microscopy confirmed this and revealed that the larger (ca. 20 nm) particles were aggregates composed of the smaller individual particles (4-5 nm). Electron energy loss spectroscopy (EELS) showed that the smallest and largest samples were composed almost entirely of cerium(III) oxide, with only small amounts of cerium(IV) present in the largest sample. Dissolved cerium concentrations in media were low and constant, showing that the NPs did not dissolve over time. The simple synthesis of the these NPs and their physical and chemical stability in different environmental conditions make them potentially suitable for use as reference materials for (eco)toxicology and surface water environmental studies. PMID- 24044592 TI - Mitral valve lipomatous hamartoma: a rare entity. AB - Lipomatous hamartoma of cardiac valves is a very rare entity, with only three reported cases in children. We describe the case of a 9-year-old girl with a mass in the mitral valve, which was detected in an echocardiogram performed for heart murmur investigation. At surgery, a white round-shaped tumour was removed and histopathological examination revealed a lipomatous hamartoma. PMID- 24044593 TI - Photolysis of CF3CH2CHO in the presence of O2 at 248 and 266 nm: quantum yields, products, and mechanism. AB - Three different detection techniques, coupled to pulsed laser photolysis (PLP), have been employed to determine the quantum yields of CF3CH2CHO at 248 and 266 nm: CF3CH2CHO + hnu -> CF3CH2 + HCO (R1a), CF3CH2CHO + hnu -> CF3CH3 + CO (R1b), and CF3CH2CHO + hnu -> CF3CH2O + H (R1c). (a) In the presence of air, Fourier transform infrared (FTIR) spectroscopy was employed at a total pressure of 760 Torr to monitor and quantify the loss of CF3CH2CHO at both wavelengths as well as the build-up of formed products (CO, CF3CH3, CF3CHO, and CF3CH2OH) after various laser pulses. Cyclohexane was added as OH-scavenger in most experiments. CF3CH3 was observed and quantified at both wavelengths, confirming that channel R1b is occurring. Small amounts of HCOOH and COF2 were also detected. (b) Time-resolved cw-cavity ring down spectroscopy (cw-CRDS) at 40 Torr He coupled to photolysis at 248 nm was employed for the detection of HO2 radicals. Varying the O2 concentration allows distinguishing the origin of the HO2 radicals from either R1a or R1c. OH radicals were simultaneously detected by laser-induced fluorescence. (c) Time-resolved tunable diode laser absorption spectroscopy (TDLAS) at 30 Torr N2 coupled to photolysis at 266 nm was employed for the determination of the quantum yields of CO. By varying the O2 concentration, a distinction can be achieved between the yields of prompt CO R1b or decomposition of highly excited CF3CH2CO from R1c and HCO radicals R1a. Channel R1a has been identified as the major reaction path. The overall quantum yield, Philambda(CF3CH2CHO), at 248 nm was found as Phi248nm = (0.76 +/- 0.14) and (0.73 +/- 0.20) from cw-CRDS and FTIR experiments, respectively. At 266 nm, the overall quantum yield was found as Phi266nm = (0.55 +/- 0.10) and (0.47 +/- 0.10) from TDLAS and FTIR experiments, respectively. PMID- 24044594 TI - Warmth of familiarity and chill of error: affective consequences of recognition decisions. AB - The present research aimed to assess the effect of recognition decision on subsequent affective evaluations of recognised and non-recognised objects. Consistent with the proposed account of post-decisional preferences, results showed that the effect of recognition on preferences depends upon objective familiarity. If stimuli are recognised, liking ratings are positively associated with exposure frequency; if stimuli are not recognised, this link is either absent (Experiment 1) or negative (Experiments 2 and 3). This interaction between familiarity and recognition exists even when recognition accuracy is at chance level and the "mere exposure" effect is absent. Finally, data obtained from repeated measurements of preferences and using manipulations of task order confirm that recognition decisions have a causal influence on preferences. The findings suggest that affective evaluation can provide fine-grained access to the efficacy of cognitive processing even in simple cognitive tasks. PMID- 24044595 TI - Defining recovery in adult bulimia nervosa. AB - To examine how different definitions of recovery lead to varying rates of recovery, maintenance of recovery, and relapse in bulimia nervosa (BN), end-of treatment (EOT) and follow-up data were obtained from 96 adults with BN. Combining behavioral, physical, and psychological criteria led to recovery rates between 15.5% and 34.4% at EOT, though relapse was approximately 50%. Combining these criteria and requiring abstinence from binge eating and purging when defining recovery may lead to lower recovery rates than those found in previous studies; however, a strength of this definition is that individuals who meet this criteria have no remaining disordered behaviors or symptoms. PMID- 24044596 TI - Parents' experiences of having and caring for a child with an eating disorder. AB - Eating disorders (ED) are serious conditions that affect both patients and their families. Little is known about the influence of these disorders on family life in a Swedish population and the ways that affected families actually attempt to cope. The aim of this study was to specifically investigate parental experiences of having and caring for a child with ED. A qualitative approach was used and rich narratives were obtained from interviews with 10 parents. Results promote insights into lived experiences concerning social disruption, emotional impact, and coping strategies related to ED. This knowledge can be utilized to further develop programs to help affected families. PMID- 24044597 TI - The use of pro-ana blogs for online social support. AB - The aim of this research was to document the content on pro-ana blogs and to uncover how the unique socio-technical features of blogs (interactivity, self disclosure, masspersonal communication) facilitate social support among members. A final sample of 48 pro-ana blogs provided 624 individual units for coding. Results indicate that prevalent forms of social support were emotional support, esteem support, and informational support. A new category, reciprocal self disclosure, was also revealed to be quite frequent. Blogs are spaces where social support is sought and communicated among members of the pro-ana network. Interpretation of blog communication and implications for treatment and research are discussed. PMID- 24044598 TI - Race, ethnicity, and eating disorder recognition by peers. AB - We investigated racial/ethnic stereotyping in the recognition and referral of eating disorders with 663 university students. We explored responses to problem and eating disorder recognition and health care referrals after subjects read a vignette concerning a patient of a different race/ethnic background presenting with eating disorders. A series of three 4 * 3 ANOVAs revealed significant main effects for eating disorders across all three outcome variables. There were no significant main effects across the four different race/ethnicity conditions and no significant race by condition interactions. Lack of general eating disorder recognition and health care referrals by student participants were found. [Supplemental files are available for this article. Go to the publishers's online edition of Eating Disorders for the following free supplemental resource: online appendix containing vignettes 1-3, as described in the "Methods" section]. PMID- 24044599 TI - Muscle dysmorphia: methodological issues, implications for research. AB - Muscle dysmorphia is a male-dominated, body image-related psychological condition. Despite continued investigation, contention surrounds the nosological status of this disorder. The aim of this article was to review the literature on muscle dysmorphia to provide a qualitative account of methodological issues that may inhibit our understanding. Key areas relating to non-standardized participant groups, measuring instruments, and terminology were identified as potentially inhibiting symptom coherence and diagnostic reliability. New measuring instruments validated with clinical samples and carefully described participant groups, standardized terminology, and a greater emphasis on prospective longitudinal research with specific sub groups of the weight training community would be of interest to the field. PMID- 24044603 TI - Stories I tell my patients: Togglers and Dimmers. PMID- 24044605 TI - The splice site variant rs11078928 may be associated with a genotype-dependent alteration in expression of GSDMB transcripts. AB - BACKGROUND: Many genetic variants have been associated with susceptibility to complex traits by genome wide association studies (GWAS), but for most, causal genes and mechanisms of action have yet to be elucidated. Using bioinformatics, we identified index and proxy variants associated with autoimmune disease susceptibility, with the potential to affect splicing of candidate genes. PCR and sequence analysis of whole blood RNA samples from population controls was then carried out for the 8 most promising variants to determine the effect of genetic variation on splicing of target genes. RESULTS: We identified 31 splice site SNPs with the potential to affect splicing, and prioritised 8 to determine the effect of genotype on candidate gene splicing. We identified that variants rs11078928 and rs2014886 were associated with altered splicing of the GSDMB and TSFM genes respectively. rs11078928, present in the asthma and autoimmune disease susceptibility locus on chromosome 17q12-21, was associated with the production of a novel Delta exon5-8 transcript of the GSDMB gene, and a separate decrease in the percentage of transcripts with inclusion of exon 6, whereas the multiple sclerosis susceptibility variant rs2014886, was associated with an alternative TFSM transcript encompassing a short cryptic exon within intron 2. CONCLUSIONS: Our findings demonstrate the utility of a bioinformatic approach in identification and prioritisation of genetic variants effecting splicing of their host genes, and suggest that rs11078928 and rs2014886 may affect the splicing of the GSDMB and TSFM genes respectively. PMID- 24044606 TI - Regional consensus opinion for the management of Beta thalassemia major in the Arabian Gulf area. AB - Thalassemia syndrome has diverse clinical presentations and a global spread that has far exceeded the classical Mediterranean basin where the mutations arose. The mutations that give rise to either alpha or beta thalassemia are numerous, resulting in a wide spectrum of clinical severity ranging from carrier state to life-threatening, inherited hemolytic anemia that requires regular blood transfusion. Beta thalassemia major constitutes a remarkable challenge to health care providers. The complications arising due to the anemia, transfusional iron overload, as well as other therapy-related complications add to the complexity of this condition. To produce this consensus opinion manuscript, a PubMed search was performed to gather evidence-based original articles, review articles, as well as published work reflecting the experience of physicians and scientists in the Arabian Gulf region in an effort to standardize the management protocol. PMID- 24044608 TI - HIV infection and drugs of abuse: role of acute phase proteins. AB - BACKGROUND: HIV infection and drugs of abuse such as methamphetamine (METH), cocaine, and alcohol use have been identified as risk factors for triggering inflammation. Acute phase proteins such as C-reactive protein (CRP) and serum amyloid A (SAA) are the biomarkers of inflammation. Hence, the interactive effect of drugs of abuse with acute phase proteins in HIV-positive subjects was investigated. METHODS: Plasma samples were utilized from 75 subjects with METH use, cocaine use, alcohol use, and HIV-positive alone and HIV-positive METH, cocaine, and alcohol users, and age-matched control subjects. The plasma CRP and SAA levels were measured by ELISA and western blot respectively and the CD4 counts were also measured. RESULTS: Observed results indicated that the CRP and SAA levels in HIV-positive subjects who are METH, cocaine and alcohol users were significantly higher when compared with either drugs of abuse or HIV-positive alone. The CD4 counts were also dramatically reduced in HIV-positive with drugs of abuse subjects compared with only HIV-positive subjects. CONCLUSIONS: These results suggest that, in HIV-positive subjects, drugs of abuse increase the levels of CRP and SAA, which may impact on the HIV infection and disease progression. PMID- 24044607 TI - Molecular dynamics simulations on the Tre1 G protein-coupled receptor: exploring the role of the arginine of the NRY motif in Tre1 structure. AB - BACKGROUND: The arginine of the D/E/NRY motif in Rhodopsin family G protein coupled receptors (GPCRs) is conserved in 96% of these proteins. In some GPCRs, this arginine in transmembrane 3 can form a salt bridge with an aspartic acid or glutamic acid in transmembrane 6. The Drosophila melanogaster GPCR Trapped in endoderm-1 (Tre1) is required for normal primordial germ cell migration. In a mutant form of the protein, Tre1sctt, eight amino acids RYILIACH are missing, resulting in a severe disruption of primordial germ cell development. The impact of the loss of these amino acids on Tre1 structure is unknown. Since the missing amino acids in Tre1sctt include the arginine that is part of the D/E/NRY motif in Tre1, molecular dynamics simulations were performed to explore the hypothesis that these amino acids are involved in salt bridge formation and help maintain Tre1 structure. RESULTS: Structural predictions of wild type Tre1 (Tre1+) and Tre1sctt were subjected to over 250 ns of molecular dynamics simulations. The ability of the model systems to form a salt bridge between the arginine of the D/E/NRY motif and an aspartic acid residue in transmembrane 6 was analyzed. The results indicate that a stable salt bridge can form in the Tre1+ systems and a weak salt bridge or no salt bridge, using an alternative arginine, is likely in the Tre1sctt systems. CONCLUSIONS: The weak salt bridge or lack of a salt bridge in the Tre1sctt systems could be one possible explanation for the disrupted function of Tre1sctt in primordial germ cell migration. These results provide a framework for studying the importance of the arginine of the D/E/NRY motif in the structure and function of other GPCRs that are involved in cell migration, such as CXCR4 in the mouse, zebrafish, and chicken. PMID- 24044609 TI - Continuous real time breath gas monitoring in the clinical environment by proton transfer-reaction-time-of-flight-mass spectrometry. AB - Analysis of volatile organic compounds (VOCs) in breath holds great promise for noninvasive diagnostic applications. However, concentrations of VOCs in breath may change quickly, and actual and previous uptakes of exogenous substances, especially in the clinical environment, represent crucial issues. We therefore adapted proton-transfer-reaction-time-of-flight-mass spectrometry for real time breath analysis in the clinical environment. For reasons of medical safety, a 6 m long heated silcosteel transfer line connected to a sterile mouth piece was used for breath sampling from spontaneously breathing volunteers and mechanically ventilated patients. A time resolution of 200 ms was applied. Breath from mechanically ventilated patients was analyzed immediately after cardiac surgery. Breath from 32 members of staff was analyzed in the post anesthetic care unit (PACU). In parallel, room air was measured continuously over 7 days. Detection limits for breath-resolved real time measurements were in the high pptV/low ppbV range. Assignment of signals to alveolar or inspiratory phases was done automatically by a matlab-based algorithm. Quickly and abruptly occurring changes of patients' clinical status could be monitored in terms of breath-to-breath variations of VOC (e.g. isoprene) concentrations. In the PACU, room air concentrations mirrored occupancy. Exhaled concentrations of sevoflurane strongly depended on background concentrations in all participants. In combination with an optimized inlet system, the high time and mass resolution of PTR-ToF-MS provides optimal conditions to trace quick changes of breath VOC profiles and to assess effects from the clinical environment. PMID- 24044610 TI - Vitamin K series: current status and future prospects. AB - The Vitamin K series, particularly menaquinone, have been attracting research attention, due to the potential in reducing both osteoporosis and cardiovascular diseases. This review provides an overview of the types of vitamin K and their health benefits. This is followed by a critical review of the various biotechnological approaches used in the production of menaquinone, including solid and liquid state fermentations, extraction and recovery. The currently available market information is summarized and future growth prospects are discussed. Recommendations are also given for areas of future research in order to improve the production process for menaquinone and reduce costs. PMID- 24044612 TI - Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development. AB - Acid-reducing agents (ARAs) are the most commonly prescribed medications in North America and Western Europe. There are currently no data describing the prevalence of their use among cancer patients. However, this is a paramount question due to the potential for significant drug-drug interactions (DDIs) between ARAs, most commonly proton pump inhibitors (PPIs), and orally administered cancer therapeutics that display pH-dependent solubility, which may lead to decreased drug absorption and decreased therapeutic benefit. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility, but there are currently no data describing the potential for this ARA DDI liability among targeted agents currently in clinical development. The objectives of this study were to (1) determine the prevalence of ARA use among different cancer populations and (2) investigate the prevalence of orally administered cancer therapeutics currently in development that may be liable for an ARA-DDI. To address the question of ARA use among cancer patients, a retrospective cross-sectional analysis was performed using two large healthcare databases: Thomson Reuters MarketScan (N = 1,776,443) and the U.S. Department of Veterans Affairs (VA, N = 1,171,833). Among all cancer patients, the total prevalence proportion of ARA use (no. of cancer patients receiving an ARA/total no. of cancer patients) was 20% and 33% for the MarketScan and VA databases, respectively. PPIs were the most commonly prescribed agent, comprising 79% and 65% of all cancer patients receiving a prescription for an ARA (no. of cancer patients receiving a PPI /no. of cancer patients receiving an ARA) for the MarketScan and VA databases, respectively. To estimate the ARA-DDI liability of orally administered molecular targeted cancer therapeutics currently in development, two publicly available databases, (1) Kinase SARfari and (2) canSAR, were examined. For those orally administered clinical candidates that had available structures, the pKa's and corresponding relative solubilities were calculated for a normal fasting pH of 1.2 and an "ARA-hypochlorhydric" pH of 4. Taking calculated pKa's and relative solubilities into consideration, clinical candidates were classified based on their risk for an ARA-DDI. More than one quarter (28%) of the molecules investigated are at high risk for an ARA-DDI, and of those high risk molecules, nearly three-quarters (73%) are being clinically evaluated for at least one of five cancer types with the highest prevalence of ARA use (gastrointestinal, pancreatic, lung, glioblastoma multiforme, gastrointestinal stromal tumor (GIST)). These data strongly suggest that with the clinical development of ARA-DDI-susceptible cancer therapeutics will come continued challenges for drug-development scientists, oncologists, and regulatory agencies in ensuring that patients achieve safe and efficacious exposures of their cancer therapeutics and thus optimal patient outcomes. PMID- 24044611 TI - Prognostic impact of tumor infiltrating CD8+ T cells in association with cell proliferation in ovarian cancer patients--a study of the OVCAD consortium. AB - BACKGROUND: Epithelial ovarian cancer is one of the most lethal gynecologic malignancies. Clinicopathological factors do not permit precise prognosis and cannot provide guidance to specific treatments. In this study we assessed tumor infiltrating CD8+ T cells in association with Ki67 proliferation index and evaluated their prognostic impact in EOC samples. METHODS: CD8+ cells and Ki67 proliferation index were immunohistochemically determined on tissue microarrays including 203 primary epithelial ovarian tumors. Additionally, CD8 gene expression was assessed with RT-qPCR. Correlations were analyzed using Pearson's correlation coefficients, ANOVA or T-test, or Fischer's exact tests. Prognostic impact was evaluated using the Kaplan-Meier method and Cox regression model. RESULTS: The density of CD8+ infiltrating lymphocytes did not correlate with tumor cell proliferation. Epithelial ovarian cancer patients with no Ki67+ cells in the tumor had a more than three times higher risk to die compared to the population with Ki67+ cells in the tumor (Hazard ratio (HR) = 3.34, 95%CI 1.59 7.04). High CD8+ cell infiltration was associated with improved overall survival (HR = 0.82, 95%CI 0.73-0.92). CONCLUSIONS: The density of tumor infiltrating lymphocytes is independent of tumor cell proliferation. Ovarian cancer patients with Ki67- tumors showed a significantly reduced overall survival, presumably due to no or poor response to platinum-based chemotherapy. Moreover, the association of high densities of tumor infiltrating cytotoxic T lymphocytes with a better overall survival was confirmed. PMID- 24044613 TI - Design of microencapsulated carbon nanotube-based microspheres and its application in colon targeted drug delivery. AB - The present study aims to prepare and evaluate carbon nanotubes (CNTs)-based colon-specific microspheres using irinotecan as a model of drug. The synthesis of CNTs-based microspheres including attachment of folate-chitosan conjugate and irinotecan to CNTs via non-covalent interaction, followed by microencapsulation with Eudragit S-100 by an oil-in-oil solvent evaporation technique. The obtained samples were characterized in case of surface morphology, drug loading efficiency and particle size. In vitro drug release behavior was studied in different pH medium and the obtained data were subjected to kinetic equations. It was found that the Eudragit-coated microparticles were spherical with smooth surface, and the particle size varied with the core/coat ratio. In vitro drug release shows that the irinotecan released in a slow and sustained fashion from the CNTs-based carriers without coating with Eudragit. No drug release was observed from Eudragit-coated microspheres when the medium pH below 7, while when the pH reached 7.4, the coating layer of Eudragit began to dissolve and a controlled release of irinotecan was observed. The cell viability test indicates that the drug free FA-CS decorated CNTs had no influence on the cell proliferation rates of HT-29 cells, while the irinotecan-loaded CNTs drug system proved to be the most cytotoxic. PMID- 24044614 TI - Inhibition of Orobanche crenata seed germination and radicle growth by allelochemicals identified in cereals. AB - Orobanche crenata is a parasitic weed that causes severe yield losses in important grain and forage legume crops. Cereals have been reported to inhibit O. crenata parasitism when grown intercropped with susceptible legumes, but the responsible metabolites have not been identified. A number of metabolites have been reported in cereals that have allelopathic properties against weeds, pests, and pathogens. We tested the effect of several allelochemicals identified in cereals on O. crenata seed germination and radicle development. We found that 2 benzoxazolinone, its derivative 6-chloroacetyl-2-benzoxazolinone, and scopoletin significantly inhibited O. crenata seed germination. Benzoxazolinones, l tryptophan, and coumalic acid caused the stronger inhibition of radicle growth. Also, other metabolites reduced radicle length, this inhibition being dose dependent. Only scopoletin caused cell necrotic-like darkening in the young radicles. Prospects for their application to parasitic weed management are discussed. PMID- 24044615 TI - High CDC20 expression is associated with poor prognosis in oral squamous cell carcinoma. AB - OBJECTIVES: Human Cell Division Cycle 20 (CDC20) homolog is a crucial target of the spindle assembly checkpoint. It is an activator of the Anaphase-Promoting Complex/Cyclosome (APC/C) which promotes anaphase onset and mitotic exit through the ubiquitination of securin and cyclin B1. Overexpression of CDC20 was previously reported in oral squamous cell carcinoma (OSCC). Here, we propose to explore the clinicopathological significance of CDC20 overexpression and its potential use as a prognostic marker in OSCC. METHODS: Using tissue microarray technology, we analyzed CDC20 expression in 65 primary OSCC tissues by immunohistochemistry. Statistical analysis was performed to evaluate the clinicopathological and prognostic significance of CDC20 expression in OSCC. RESULTS: Of the 65 cases of patients with OSCC studied, 37 (56.9%) showed high CDC20 protein expression. No clinicopathological features were correlated with CDC20 expression. Importantly, in univariable analysis, OSCC patients with higher CDC20 protein expression showed significantly shorter cancer-specific survival rate (P = 0.018). Multivariable analysis identified high CDC20 expression as an independent prognostic factor (P = 0.032). CONCLUSION: High CDC20 expression is associated with poor prognosis in OSCC and may be used to identify high-risk OSCC patients and may serve as a therapeutic target. PMID- 24044616 TI - Comment on "Modeling nitrous oxide production during biological nitrogen removal via nitrification and denitrification: extensions to the general asm models". PMID- 24044617 TI - Responsiveness to change for the Brazilian Scale of Oral Health Outcomes for 5 year-old children (SOHO-5). AB - BACKGROUND: The responsiveness of oral health-related quality of life (OHRQoL) instruments has become relevant, given the increasing tendency to use OHRQoL measures as outcomes in clinical trials and evaluations studies. The purpose of this study was to assess the responsiveness of the Brazilian Scale of Oral Health Outcomes for 5-year-old children (SOHO-5) to dental treatment. METHODS: One hundred and fifty-four children and their parents completed the child self- and parental' reports of the SOHO-5 prior to treatment and 7 to 14 days after the completion of treatment. The post-treatment questionnaire also included a global transition judgment that assessed subject's perceptions of change in their oral health following treatment. Change scores were calculated by subtracting post treatment SOHO-5 scores from pre-treatment scores. Longitudinal construct validity was assessed by using one-way analysis of variance to examine the association between change scores and the global transition judgments. Measures of responsiveness included standardized effect sizes (ES) and standardized response mean (SRM). RESULTS: The improvement of children's oral health after treatment are reflected in mean pre- and post-treatment SOHO-5 scores that declined from 2.67 to 0.61 (p<0.001) for the child-self reports, and 4.04 to 0.71 (p<0.001) for the parental reports. Mean change scores showed a gradient in the expected direction across categories of the global transition judgment, and there were significant differences in the pre- and post-treatment scores of those who reported improving a little (p<0.05) and those who reported improving a lot (p<0.001). For both versions, the ES and SRM based on change scores mean for total scores and for categories of global transitions judgments were moderate to large. CONCLUSIONS: The Brazilian SOHO-5 is responsive to change and can be used as an outcome indicator in future clinical trials. Both the parental and the child versions presented satisfactory results. PMID- 24044618 TI - Improvement of metabolic parameters in healthy older adult men following a fasting calorie restriction intervention. AB - OBJECTIVE: Calorie restriction and intermittent fasting are two dietary interventions that can improve aging. Religious fasting also suggested having similar benefit; however, such studies are still scarce. Thus, this study aimed to determine the effect of fasting calorie restriction (FCR) on metabolic parameters and DNA damage among healthy older adult men. METHODS: A randomized controlled study was done on men, aged 50-70 years in Klang Valley, Malaysia. Subjects were divided into two groups; FCR (reduction of 300-500 kcal/d combined with 2 days/week of Muslim Sunnah Fasting) and control. Assessment was ascertained at three time point; baseline, weeks 6 and 12. Blood samples were analyzed for lipid profile, DNA damage and malondialdehyde (MDA). RESULTS: The FCR group reduced their energy intake for approximately 18% upon completion of the study. A significant interaction effect was found in body weight, body mass index, fat percentage, fat mass, blood pressure, total cholesterol, low-density lipoprotein cholesterol and the ratio of total cholesterol/high-density lipoprotein cholesterol (p < 0.05). A significant improvement (p < 0.001) in total DNA rejoining cells and MDA (p < 0.05) was also observed in the FCR group. CONCLUSION: FCR improved metabolic parameters and DNA damage in healthy older adult men. Therefore, there is a need to further examine the mechanism of FCR. PMID- 24044619 TI - Formation of iridium(IV) oxide (IrOX) films by electroflocculation. AB - Films of iridium(IV) oxide nanoparticles (IrOX NPs) become deposited on electrodes from nanoparticle solutions when potentials sufficient to initiate water oxidation are applied. Evidence is given that the film-forming mechanism is nanoparticle precipitation. Following an induction period during which a significant amount of charge is passed, the NPs begin to deposit as islands. It appears that the proton release that accompanies nanoparticle oxidation triggers the nanoparticle electroflocculation and subsequent precipitation. Flocculation from nanoparticle solutions can also be induced by the addition of a chemical oxidant (Ce(IV)). The film formation is followed by cyclic voltammetry (CV), rotated ring disk voltammetry (RRDE), and electrochemical quartz crystal microbalance (eQCM) measurements, supplemented with AFM and SEM microscopies. PMID- 24044620 TI - The anti-inflammatory effects of therapies for ocular allergy. AB - PURPOSE: In this review, we aim to summarize the currently available compounds targeting the different components of the inflammatory cascade triggered by an ocular allergic reaction, from mast cells to eosinophils and lymphocytes, with a special focus on specific signs and symptoms that are related to them. METHODS: The article gives a review of topical therapies utilized to treat the various forms of allergic conjunctivitis, starting from the first drugs developed in the 1980s up to the new compounds that are currently being developed. These include antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory agents, and topical immunosuppressants. RESULTS: The treatment options that have been developed for allergic conjunctivitis in the past 30 years are the result of a better understanding of the pathogenic mechanisms involved in the initiation and perpetuation of the ocular allergic reaction, which is guiding us toward a more specific treatment approach. CONCLUSIONS: Several reports and literature reviews have demonstrated that a better knowledge of the immunopathogenesis of the different types of ocular allergy has improved the treatment choice resulting in better clinical outcomes for ocular allergy sufferers. Specifically, the development of novel compounds targeting specific cells and/or cytokines involved in the ocular immune reaction provided safer and more tolerated drugs for both mild-to-moderate and severe forms of allergic conjunctivitis. The correlation of clinical responses to drugs with what we understand about the molecular mechanisms involved could possibly prove useful for developing more standardized treatments in the near future. PMID- 24044623 TI - Ab initio calculation of molecular aggregation effects: a Coumarin-343 case study. AB - We present time-dependent density functional theory (TDDFT) calculations for single and dimerized Coumarin-343 molecules to investigate the quantum mechanical effects of chromophore aggregation in extended systems designed to function as a new generation of sensors and light-harvesting devices. Using the single chromophore results, we describe the construction of effective Hamiltonians to predict the excitonic properties of aggregate systems. We compare the electronic coupling properties predicted by such effective Hamiltonians to those obtained from TDDFT calculations of dimers and to the coupling predicted by the transition density cube (TDC) method. We determine the accuracy of the dipole-dipole approximation and TDC with respect to the separation distance and orientation of the dimers. In particular, we investigate the effects of including Coulomb coupling terms ignored in the typical tight-binding effective Hamiltonian. We also examine effects of orbital relaxation which cannot be captured by either of these models. PMID- 24044622 TI - Nijmegen breakage syndrome and chronic polyarthritis. AB - We report on pediatric patient with Nijmegen breakage syndrome (NBS), a rare DNA repair disorder characterized by microcephaly, immunodeficiency and predisposition to malignant lymphomas, who developed juvenile idiopathic arthritis (JIA)-like polyarthritis. In patients with primary immunodeficiencies (PID), septic arthritis due to pyogenic bacteria or mycoplasmal arthritis are the most common osteoarticular manifestations. In certain PID, chronic, non infectious arthritis resembling rheumatoid arthritis may occur. In our patient microbiologic cultures of synovial fluid including Mycoplasma spp. were negative. At first, because of suspected mycoplasmal arthritis we used macrolides and doxycycline combined with hydroxychloroquine but without therapeutic response. However, the use of rituximab led to remission of her polyarthritis lasting for 9 months. Autoimmune features were rarely reported in NBS. An occurrence of JIA like, chronic polyarthritis in NBS, a DNA repair disorder characterized by decreased tolerance of immunosuppressive drugs such as methotrexate and a high natural risk for lymphomas, makes therapeutic approach even more complex. PMID- 24044624 TI - Validity and reliability of the EQ-5D-3LTM among a paediatric injury population. AB - BACKGROUND: Injuries are a leading cause of death and disabilities for children and youth globally. Measuring the health related quality of life of injured children and youth can help gain understanding of the impact of injuries on this population; however, psychometric evaluation of health related quality of life tools among this population is lacking. The purpose of this study was to determine the construct validity of the EQ-5D-3LTM for use among a population of injured young people and to examine the reliability of different modes of administration including paper and pencil, online and telephone. METHODS: In total, 345 participants (aged 0 - 16) were recruited from a paediatric hospital in a large urban centre in British Columbia, Canada. To capture a variety of injury types and severity, patients were recruited from in-patient units and the emergency department. Data were collected at the time of recruitment and at one month post injury. RESULTS: Repeated measures analysis (rANOVA) showed that EQ-5D 3LTM scores were different before and after injury and significant between group differences (Visual Analog Scale: F = 4.61, p = 0.011; Descriptive Scale: F = 29.58, p < 0.001), within group differences (Visual Analog Scale: F = 60.02, p < 0.001; Descriptive Scale: F = 92.37, p < 0.001), and interaction between variables (Visual Analog Scale: F = 10.89, p < 0.001; Descriptive Scale: F = 19.25, p < 0.001) were detected, indicating its suitability for assessment of post-injury health related quality of life. Bland-Altman plots confirmed that few differences existed between modes of administration. CONCLUSION: The EQ-5D-3LTM is an appropriate instrument for collecting health related quality of life data among injured children and can be administered via paper-pencil, online or by telephone. PMID- 24044625 TI - Hepatitis A vaccination and immunological parameters in HIV-infected patients. AB - Vaccination against hepatitis A is an important intervention to prevent disease in HIV-patients. There are insufficient data on the association of the response to hepatitis A vaccine with immunological parameters, including subpopulations of T-cells. We studied HIV-infected adults with CD4 T-cells>200 cells/mm(3) who received two doses of hepatitis A vaccine (Havrix or Vaqta). The counts of CD3, CD4, CD8, CD4+T-cells, NK, NK CD8+, NK CD8 - cells, and HIV RNA were measured at the time of first dose administration and one month after the end of the vaccination period. The geometric mean titer of antibodies to hepatitis A virus (anti-HAV) and factors affecting response were evaluated. 113 patients (50 antiretroviral treatment-naive and 63 treatment-experienced) were enrolled in the study. There was no change in the immunological parameters and in the HIV-RNA post-vaccination, except for a decrease in CD8 and in double positive CD4+CD8+t cell count. The immune response and geometric mean titer of anti-HAV were similar among treated and naive patients (78% vs. 76% and 237 mIU/mL vs. 158 mIU/mL). Vaccine response was achieved in 71% of patients with CD4=200-499 cells/mm(3) compared with 80% of participants with CD4 >=500 cells/mm(3) (p>0.05). Logistic regression revealed that immunological cells tested do not affect response differently in treatment-naive vs. experienced patients. The only factor affecting response is the CD4 T-cell count at vaccination (OR 1.320; 95% CI 1.052 1.656; p=0.016). Patients with CD4 T-cell count >=500 cells/mm(3) were 4.3 times more likely to respond to the vaccine than patients with CD4 T-cell count 200-499 cells/mm(3) (p=0.005). In conclusion, successful vaccination is associated with CD4 T-cells. The count of other immune cells or the administration of antiretroviral therapy does not predict response to hepatitis A vaccine in HIV patient with baseline CD4 T-cell>200 cells/mm(3). PMID- 24044626 TI - The dynamics of complex formation between amylose brushes on gold and fatty acids by QCM-D. AB - Amylose brushes were synthesized by enzymatic polymerization with glucose-1 phosphate as monomer and rabbit muscle phosphorylase b as catalyst on gold covered surfaces of a quartz crystal microbalance. Fourier transform infrared (FT IR) spectra confirmed the presence of the characteristic absorption peaks of amylose between 3100 cm(-1) and 3500 cm(-1). The thickness of the amylose brushes measured by Spectroscopic Ellipsometry--can be tailored from 4 to 20 nm, depending on the reaction time. The contour length of the stretched amylose chains on gold surfaces has been evaluated by single molecule force spectroscopy, and a total chain length of about 20 nm for 16.2 nm thick amylose brushes was estimated. X-ray photoelectron spectroscopy (XPS) was employed to characterize the amylose brushes before and after the adsorption of fatty acids. The dynamics of inclusion complex formation between amylose brushes and two fatty acids (octanoic acid and myristic acid) with different chain length was investigated as a function of time using a quartz crystal microbalance with dissipation monitoring (QCM-D) immersed in the liquid phase. QCM-D signals including the frequency and dissipation shifts elucidated the effects of the fatty acid concentration, the solvent types, the chain length of the fatty acids and the thickness of the amylose brushes on the dynamics of fatty acid molecule adsorption on the amylose brush-modified sensor surfaces. PMID- 24044627 TI - Comparison of point-of-care versus laboratory-based CD4 cell enumeration in HIV positive pregnant women. AB - INTRODUCTION: Early initiation of antiretroviral therapy (ART) in eligible pregnant women is a key intervention for prevention of mother-to-child transmission (PMTCT) of HIV. However, in many settings in sub-Saharan Africa where ART-eligibility is determined by CD4 cell counts, limited access to laboratories presents a significant barrier to rapid ART initiation. Point-of care (POC) CD4 cell count testing has been suggested as one approach to overcome this challenge, but there are few data on the agreement between POC CD4 cell enumeration and standard laboratory-based testing. METHODS: Working in a large antenatal clinic in Cape Town, South Africa, we compared POC CD4 cell enumeration (using the Alere Pima(TM) Analyzer) to laboratory-based flow cytometry in consecutive HIV-positive pregnant women. Bland-Altman methods were used to compare the two methods, including analyses by subgroups of participant gestational age. RESULTS: Among the 521 women participating, the median gestational age was 23 weeks, and the median CD4 cell count according to POC and laboratory-based methods was 388 and 402 cells/uL, respectively. On average, the Pima POC test underestimated CD4 cell count relative to flow cytometry: the mean difference (laboratory test minus Pima POC) was 22.7 cells/uL (95% CI, 16.1 to 29.2), and the limits of agreement were -129.2 to 174.6 cells/uL. When analysed by gestational age categories, there was a trend towards increasing differences between laboratory and POC testing with increasing gestational age; in women more than 36 weeks' gestation, the mean difference was 45.0 cells/uL (p=0.04). DISCUSSION: These data suggest reasonable overall agreement between Pima POC CD4 testing and laboratory-based flow cytometry among HIV-positive pregnant women. The finding for decreasing agreement with increasing gestational age requires further investigation, as does the operational role of POC CD4 testing to increase access to ART within PMTCT programmes. PMID- 24044628 TI - Neonatal small intestinal zygomyocosis misdiagnosed as intussusception in a two day-old child with a review of the literature. AB - Neonatal mucormycosis is caused by fungi belonging to the class Zygomycetes. Clinically, it mimics necrotizing enterocolitis. We describe a case of 2-day-old baby who presented with abdominal distension and vomiting. A clinical diagnosis of intussusception was suspected. An exploratory laprotomy revealed gangrenous bowel wall and no intussusception or any gas-filled vesicles. Histological examination of the gangrenous segment showed transmural ischemic necrosis with fungal hyphae of zygomycosis. The baby is doing well postoperatively at a follow up of 3 months. Hence, a high degree of clinical suspicion is important in neonates not responding to usual therapy or antibiotics. PMID- 24044629 TI - Placental mesenchymal dysplasia with hepatic mesenchymal hamartoma: a case report and literature review. AB - Placental mesenchymal dysplasia (PMD) is characterized by placentomegaly and grapelike vesicles resembling a partial molar pregnancy and in most cases, a phenotypically normal fetus. Hepatic mesenchymal hamartoma (HMH) is a benign hamartomatous proliferation of mesenchymal liver tissue. PMD has been associated with HMH. Although rare, in combination, it is known to carry a poorer prognosis than in fetuses without structural abnormalities. There are only a few reported cases of PMD and associated HMH with varying management strategies and outcomes, precluding ascertainment of the most appropriate treatment plan. We present a case of PMD with associated cystic HMH resulting in fetal death. We also reviewed the published literature on this issue and explored possible management strategies to prevent adverse fetal and neonatal outcomes. PMID- 24044630 TI - Niemann-Pick type C1 patient-specific induced pluripotent stem cells display disease specific hallmarks. AB - BACKGROUND: Niemann-Pick type C1 disease (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene. In this lysosomal storage disorder the intracellular transport and sequestration of several lipids like cholesterol is severely impaired, resulting in an accumulation of lipids in late endosomes and lysosomes. The neurological manifestation of the disease is caused by dysfunction and cell death in the central nervous system. Several animal models were used to analyze the impaired pathways. However, the underlying pathogenic mechanisms are still not completely understood and the genetic variability in humans cannot be reflected in these models. Therefore, a human model using patient-specific induced pluripotent stem cells provides a promising approach. METHODS: We reprogrammed human fibroblasts from a NPC1 patient and a healthy control by retroviral transduction with Oct4, Klf4, Sox2 and c-Myc. The obtained human induced pluripotent stem cells (hiPSCs) were characterized by immunocytochemical analyses. Neural progenitor cells were generated and patch clamp recordings were performed for a functional analysis of derived neuronal cells. Filipin stainings and the Amplex Red assay were used to demonstrate and quantify cholesterol accumulation. RESULTS: The hiPSCs expressed different stem cell markers, e.g. Nanog, Tra-1-81 and SSEA4. Using the embryoid body assay, the cells were differentiated in cells of all three germ layers and induced teratoma in immunodeficient mice, demonstrating their pluripotency. In addition, neural progenitor cells were derived and differentiated into functional neuronal cells. Patch clamp recordings revealed voltage dependent channels, spontaneous action potentials and postsynaptic currents. The accumulation of cholesterol in different tissues is the main hallmark of NPC1. In this study we found an accumulation of cholesterol in fibroblasts of a NPC1 patient, derived hiPSCs, and neural progenitor cells, but not in cells derived from fibroblasts of a healthy individual. These findings were quantified by the Amplex Red assay, demonstrating a significantly elevated cholesterol level in cells derived from fibroblasts of a NPC1 patient. CONCLUSIONS: We generated a neuronal model based on induced pluripotent stem cells derived from patient fibroblasts, providing a human in vitro model to study the pathogenic mechanisms of NPC1 disease. PMID- 24044631 TI - Public awareness and attitudes toward palliative care in Northern Ireland. AB - BACKGROUND: The World Health Organisation recognises palliative care as a global public health issue and this is reflected at strategic level. Despite this, palliative care may not be universally welcomed. Surveys over the last decade have suggested that the general public have a lack of knowledge and negative perceptions towards palliative care. A detailed and comprehensive understanding of public views is needed in order to target education and policy campaigns and to manage future needs, expectations and resourcing of end of life care. The aim of this study was to establish the current levels of awareness and attitudes towards palliative care among the general public in Northern Ireland. METHODS: A community-based cross-sectional survey with a population of 3,557 individuals aged over 17 years was performed. Information was collected using a structured questionnaire consisting of 17 items. Open questions were subject to content analysis; closed questions were subject to descriptive statistics with inferential testing as appropriate. RESULTS: A total of 600 responses were obtained (response rate 17%). Responses indicated limited knowledge about palliative care. Female gender and previous experience influenced awareness in a positive direction. Respondents who worked in healthcare themselves or who had a close relative or friend who had used a palliative care service were more aware of palliative care and the availability of different palliative care services. Findings reveal the preferred place of care was the family home. The main barriers to raising awareness were fear, lack of interaction with health services and perception of lack of resources. A number of strategies to enhance awareness, access and community involvement in palliative care were suggested. CONCLUSIONS: Public awareness of the concept of palliative care and of service availability remains insufficient for widespread effective and appropriate palliative care to be accepted as the norm. In particular, those without previous family-related experiences lack awareness. This has implications for palliative care service provision and policy. An increased awareness of palliative care is needed, in order to improve knowledge of and access to services when required, empower individuals, involve communities and ultimately to realise the objectives contained within international strategies for palliative and end-of-life care. PMID- 24044632 TI - Chronic pain in children after cardiac surgery via sternotomy. AB - INTRODUCTION: Chronic pain is common after sternotomy in adults with reported prevalence rates of 20-50%. So far, no studies have examined whether children develop chronic pain after sternotomy. MATERIAL AND METHODS: Postal questionnaires were sent to 171 children 10-60 months after undergoing cardiac surgery via sternotomy at the age of 0-12 years. The children were asked to recall the intensity and duration of their post-operative pain, if necessary with the help from their parents, and to describe the intensity and character of any present pain. Another group of 13 children underwent quantitative sensory testing of the scar area 3 months after sternotomy. RESULTS: A total of 121 children, median (range) age 7.7 (4.2-16.9) years, answered the questionnaire. Their age at the time of surgery was median (range) 3.8 (0-12.9) years, and the follow-up period was median (range) 4 (0.8-5.1) years. In all, 26 children (21%) reported present pain and/or pain within the last week located in the scar area; in 12 (46%) out of the 26 children, the intensity was >=4 on a numeric rating scale (0 10). Quantitative sensory testing of the scar area revealed sensory abnormalities -pinprick hyperalgesia and brush and cold allodynia--in 10 out of 13 children. CONCLUSION: Chronic pain after cardiac surgery via sternotomy in children is a problem that should not be neglected. The pain is likely to have a neuropathic component as suggested by the sensory abnormalities demonstrated by quantitative sensory testing. PMID- 24044633 TI - Real time observation of X-ray-induced surface modification using simultaneous XANES and XEOL-XANES. AB - In experiments preliminary to the design of an X-ray-excited optical luminescence (XEOL)-based chemical mapping tool we have used X-ray micro (4.5 * 5.2 MUm) and macro (1 * 6 mm) beams with similar total fluxes to assess the effects of a high flux density beam of X-rays at energies close to an absorption edge on inorganic surfaces in air. The near surface composition of corroded cupreous alloys was analyzed using parallel X-ray and optical photoemission channels to collect X-ray absorption near-edge structure (XANES) data at the Cu K edge. The X-ray fluorescence channel is characteristic of the composition averages over several micrometers into the surface, whereas the optical channel is surface specific to about 200 nm. While the X-ray fluorescence data were mostly insensitive to the X ray dose, the XEOL-XANES data from the microbeam showed significant dose dependent changes to the superficial region, including surface cleaning, changes in the oxidation state of the copper, and destruction of surface compounds responsible for pre-edge fluorescence or phosphorescence in the visible. In one case, there was evidence that the lead phase in a bronze had melted. Conversely, data from the macrobeam were stable over several hours. Apart from localized heating effects, the microbeam damage is probably associated with the O3 loading of the surface and increased reaction rate with atmospheric water vapor. PMID- 24044634 TI - Using solvents with different molecular sizes to investigate the structure of Antheraea pernyi silk. AB - The interaction between silk and polar solvents of different molecular size can be an important tool for understanding the structural features of natural silk; in particular, the disordered regions associated with the key property of mechanical toughness. In this work, we investigate the transitions induced in the tensile performance and structure of as-reeled Antheraea pernyi silks from different silkworms by a range of solvents that can only soften the protein chains in the amorphous regions. The results indicate that polar solvents with different molecular sizes affect the silk to different degrees, and silks with slightly different structures display significantly different tensile performance in the same solvent. The solvent molecular size is quantitatively correlated with the accessible volume in the amorphous regions before and after the yield point, which suggests that the volume accessible to the solvent molecules decreases as the solvent radius increases. Moreover, silks with more ordered structure (less free volume) in the amorphous regions are less sensitive to solvents than those with more disordered structures. However, silks with higher free volume have higher toughness due to the greater strain to failure. PMID- 24044635 TI - High flux thin film nanocomposite membranes based on metal-organic frameworks for organic solvent nanofiltration. AB - Thin-film nanocomposite membranes containing a range of 50-150 nm metal-organic framework (MOF) nanoparticles [ZIF-8, MIL-53(Al), NH2-MIL-53(Al) and MIL-101(Cr)] in a polyamide (PA) thin film layer were synthesized via in situ interfacial polymerization on top of cross-linked polyimide porous supports. MOF nanoparticles were homogeneously dispersed in the organic phase containing trimesoyl chloride prior to the interfacial reaction, and their subsequent presence in the PA layer formed was inferred by a combination of contact angle measurements, FT-IR spectroscopy, SEM, EDX, XPS, and TEM. Membrane performance in organic solvent nanofiltration was evaluated on the basis of methanol (MeOH) and tetrahydrofuran (THF) permeances and rejection of styrene oligomers (PS). The effect of different post-treatments and MOF loadings on the membrane performance was also investigated. MeOH and THF permeance increased when MOFs were embedded into the PA layer, whereas the rejection remained higher than 90% (molecular weight cutoff of less than 232 and 295 g.mol(-1) for MeOH and THF, respectively) in all membranes. Moreover, permeance enhancement increased with increasing pore size and porosity of the MOF used as filler. The incorporation of nanosized MIL 101(Cr), with the largest pore size of 3.4 nm, led to an exceptional increase in permeance, from 1.5 to 3.9 and from 1.7 to 11.1 L.m(-2).h(-1).bar(-1) for MeOH/PS and THF/PS, respectively. PMID- 24044636 TI - Reply to comment on "Modeling nitrous oxide production during biological nitrogen removal via nitrification and denitrification: extensions to the general asm models". PMID- 24044637 TI - Symptoms, CA125 and HE4 for the preoperative prediction of ovarian malignancy in Brazilian women with ovarian masses. AB - BACKGROUND: This manuscript evaluates whether specific symptoms, a symptom index (SI), CA125 and HE4 can help identify women with malignant tumors in the group of women with adnexal masses previously diagnosed with ultrasound. METHODS: This was a cross-sectional study with data collection between January 2010 and January 2012. We invited 176 women with adnexal masses of suspected ovarian origin, attending the hospital of the Department of Obstetrics and Gynecology of the Unicamp School of Medicine. A control group of 150 healthy women was also enrolled. Symptoms were assessed with a questionnaire tested previously. Women with adnexal masses were interviewed before surgery to avoid recall bias. The Ward Agglomerative Method was used to define symptom clusters. Serum measurements of CA125 and HE4 were made. The Risk of Ovarian Malignancy Algorithm (ROMA) was calculated using standard formulae. RESULTS: Sixty women had ovarian cancer and 116 benign ovarian tumors. Six symptom clusters were formed and three specific symptoms (back pain, leg swelling and able to feel abdominal mass) did not agglomerate. A symptom index (SI) using clusters abdomen, pain and eating was formed. The sensitivity of the SI in discriminating women with malignant from those with benign ovarian tumors was 78.3%, with a specificity of 60.3%. Positive SI was more frequent in women with malignant than in women with benign tumors (OR 5.5; 95% CI 2.7 to 11.3). Elevated CA125 (OR 11.8; 95% CI 5.6 to 24.6) or HE4 (OR 7.6; 95% CI 3.7 to 15.6) or positive ROMA (OR 9.5; 95% CI 4.4 to 20.3) were found in women with malignant tumors compared with women with benign tumors. The AUC ROC for CA125 was not different from that for HE4 or ROMA. The best specificity and negative predictive values were obtained using CA125 in women with negative SI. CONCLUSION: Women diagnosed with an adnexal mass could benefit from a short enquiry about presence, frequency and onset of six symptoms, and CA125 measurements. Primary care physicians can be thereby assisted in deciding as to whether or not reference the woman to often busy, congested specialized oncology centers. PMID- 24044638 TI - Effect of P-glycoprotein on the rat intestinal permeability and metabolism of the BDDCS class 1 drug verapamil. AB - The Biopharmaceutics Drug Disposition Classification System (BDDCS) predicts intestinal transporter effects to be clinically insignificant following oral dosing for highly soluble and highly permeable/metabolized drugs (class 1 drugs). We investigated the effect of inhibiting P-glycoprotein (P-gp) on the in vitro rat intestinal permeability (Papp) and metabolism of the class 1 drug verapamil. Jejunal segments from Sprague-Dawley rats fasted overnight were mounted in Ussing chambers filled with 10 mL of Krebs-Ringer buffer (KRB). For P-gp inhibition studies, GG918 0.5 MUM was added to the KRB solution. The experiment started by the addition of verapamil (1 or 10 MUM) to either apical or basolateral sides. Samples from verapamil donor and receiver compartments were collected at 30 s and 0.166, 0.5, 1, 1.83 and 3 h after the start of the experiment. Analysis of verapamil and its major metabolite, norverapamil, in the samples and intracellularly at 3 h was performed by HPLC. The same experiment was repeated with norverapamil 10 MUM (verapamil metabolite), digoxin 100 nM (positive control for P-gp activity) and atorvastatin 1 and 10 MUM (example of a class 2 drug). For 1 MUM verapamil, efflux ratio (B to A Papp/A to B Papp) was 4.6 and markedly decreased by GG918 (efflux ratio = 1.1). For 10 MUM verapamil efflux ratio was 4.1 (control) vs 1.8 (GG918), comparable to the change seen for digoxin 100 nM with an efflux ratio of 3.6 (control) vs 1.6 (with GG918) and atorvastatin (efflux ratio of 5.2 and 3.0 for atorvastatin 1.0 and 10 MUM, respectively, changed to 1.0 and 0.65 with GG918). The changes observed in the norverapamil 10 MUM experiment were also significant, where efflux ratio decreased from 13.5 (control) to 1.5 (GG918). The extraction ratio (ER) of 10 MUM verapamil to norverapamil decreased from 0.41 after an apical dose to 0.21 after a basolateral dose, but was unaffected by the incubation with GG918. The results suggest that P gp inhibition has an effect on class 1 drug verapamil and class 2 drug atorvastatin Papp in the rat intestine. Moreover, a stronger P-gp effect on the Papp of the more polar norverapamil metabolite was observed. Papp changes caused by the P-gp inhibitor GG918 do not affect the extent of verapamil metabolism. PMID- 24044639 TI - Policy lessons from physicians' strikes. AB - Drawing upon the literature on physicians' strikes from other OECD countries, the experience with physician strikes in Israel is put into comparative perspective. There are both structural and ideological factors that help to explain why there have been more strikes in Israel relative to other countries. At the same time, the dynamics of the strike and divisions within the medical profession in Israel, may be contributing to policy drift. This is a commentary on http://www.ijhpr.org/content/2/1/33. PMID- 24044640 TI - The influence of domestic living arrangement and neighborhood identity on mental health among urban Chinese elders. AB - OBJECTIVES: The primary purposes of the present study were (1) to assess the living arrangements among urban Chinese elders, (2) to examine the relationship between household living arrangement and elders' mental health, and (3) to investigate how individuals' neighborhood identity affects their mental health. METHOD: The random sample was collected in 2011, including 939 respondents aged 60 and above who lived in the Jing'an district of Shanghai, China. The study examined well-being and depression of elders. The domestic living arrangements were assessed by a single item with five options: 'With whom are you living together?' The neighborhood identity was measured by four items: the sense of belonging, the sense of pride, volunteer work, and monetary donation for the neighborhood. RESULTS: Urban Chinese elders' living arrangement had transited from a traditional intergenerational co-residence pattern to a more self independent style. However, living with children was positively associated with elders' mental health after controlling for demographic variables. Although the neighborhood identity had no interaction with living arrangement, it also contributed to elders' mental health. CONCLUSION: The study highlighted the importance of living with children and spouse, the sense of belonging, volunteer work, and the feelings of pride on elders' mental health. Results of the current study suggested implications for both government and non-governmental organizations to design family-based support for eldercare and improve neighborhood identity for elders. PMID- 24044641 TI - Exercise reduces activation of microglia isolated from hippocampus and brain of aged mice. AB - BACKGROUND: Aging is associated with low-grade neuroinflammation that includes basal increases in proinflammatory cytokines and expression of inflammatory markers on microglia. Exercise can reduce neuroinflammation following infection in aged animals, but whether exercise modulates basal changes in microglia activation is unknown. Therefore, we evaluated changes in basal microglia activation in cells isolated from the hippocampus and remaining brain following running-wheel access. METHODS: Adult (4 months) and aged (22 months) male and female BALB/c mice were housed with or without running wheels for 10 weeks. Microglia were isolated from the hippocampus or remaining brain. Flow cytometry was used to determine microglia (CD11b+ and CD45(low)) that co-labeled with CD86, CD206, and MHC II. RESULTS: Aged mice showed a greater proportion of CD86 and MHC II positive microglia. In aged females, access to a running wheel decreased proportion of CD86+ and MHC II+ microglia in the hippocampus whereas aged males in the running group showed a decrease in the proportion of CD86+ microglia in the brain and an increase in the proportion of MHC II+ microglia in hippocampus and brain. CONCLUSION: Overall, these data indicate that running-wheel access modulates microglia activation, but these effects vary by age, sex, and brain region. PMID- 24044643 TI - Early stages of Ti-O cluster growth on carbon nanotubes by ab initio calculations. AB - Ti-O combined with carbon nanotubes are excelled candidates for many technological applications. The early stages of growth comprise octahedral (Oh) anatase or rutile nanoparticles depending on the tetrahedral (Th) precursors. However, the underline mechanisms are still unknown. Here, we present results of a systematic study of Th or Oh clusters on (4,0) and (8,0). We found that although the Th may exist in several conformations, with well localized electronic states, the Oh is unstable. We found that due to charge localization and the emergence of C dangling bonds at the Fermi level, Th could be considered as more active compared to Oh that adopts the tube's C(2p)-C(2p) pi-like features. In addition, when parallel to the tubes and along the zigzag chiral direction, the linear rutile-like trimers on zigzag (8,0), armchair (5,5), and (3,0)@(12,0) multiwall were clearly found to be energetically favored, while when vertically aligned, equi-probable rutile or spinal anatase-like growth is expected. At the Fermi level, the charge is localized at the Ti-O trimer, when on (5,5) and (3,0)@(12,0) cases, rendering Ti-O active. These results could enlighten the early stages of Ti-O growth on SWCNT providing useful information in the field of nanoelectronics and nanotechnology. PMID- 24044642 TI - Genome-wide analysis of small RNAs reveals eight fiber elongation-related and 257 novel microRNAs in elongating cotton fiber cells. AB - BACKGROUND: MicroRNAs (miRNAs) and other types of small regulatory RNAs play critical roles in the regulation of gene expression at the post-transcriptional level in plants. Cotton is one of the most economically important crops, but little is known about the roles of miRNAs during cotton fiber elongation. RESULTS: Here, we combined high-throughput sequencing with computational analysis to identify small RNAs (sRNAs) related to cotton fiber elongation in Gossypium hirsutum L. (G. hirsutum). The sequence analysis confirmed the expression of 79 known miRNA families in elongating fiber cells and identified 257 novel miRNAs, primarily derived from corresponding specific loci in the Gossypium raimondii Ulbr. (G. raimondii) genome. Furthermore, a comparison of the miRNAomes revealed that 46 miRNA families were differentially expressed throughout the elongation period. Importantly, the predicted and experimentally validated targets of eight miRNAs were associated with fiber elongation, with obvious functional relationships with calcium and auxin signal transduction, fatty acid metabolism, anthocyanin synthesis and the xylem tissue differentiation. Moreover, one tasiRNA was also identified, and its target, ARF4, was experimentally validated in vivo. CONCLUSION: This study not only facilitated the discovery of 257 novel low abundance miRNAs in elongating cotton fiber cells but also revealed a potential regulatory network of nine sRNAs important for fiber elongation. The identification and characterization of miRNAs in elongating cotton fiber cells might promote the further study of fiber miRNA regulation mechanisms and provide insight into the importance of miRNAs in cotton. PMID- 24044644 TI - Development, in vitro and in vivo characterization of Eudragit RL 100 nanoparticles for improved ocular bioavailability of acetazolamide. AB - Glaucoma is characterized by increased intra ocular pressure (IOP) which results in blindness if left untreated. Acetazolamide (ACZ) is used to treat glaucoma since long back. Since it is a Class IV drug [According to Biopharmaceutics Classification System (BCS)], so its topical delivery results in poor ocular bioavailability. Objective of the present study is to increase the topical ocular bioavailability and to sustain the release of drug for longer time. ACZ-loaded Eudragit(r) RL 100 nanoparticle suspension (ACZ-E-NPs) was prepared by the nanoprecipitation method. Ratio of organic to aqueous phase and composition of organic phase were altered to get the best formulation. Formulations prepared with acetone and methanol as organic phase were smallest in size. EE was in the range of 57.8% to 68.5%. According to drug release study almost all the formulations released 80% of drug in 8 h duration. The kinetics of drug release showed that the drug release pattern followed Higuchi's model (highest R2 values) and further it was fitted to the Korsemeyer-Peppas model, which showed the release was as per Fickian diffusion. IOP lowering effects of plain drug solution and ACZ-E-NPs were compared in adult male albino rabbits with a Riester Tonometer. The data revealed that the ACZ-E-NPs lower the IOP for longer time and of higher magnitude also. The difference was significant (p<0.001). Short-term stability study showed that none of the formulations was having remarked difference in their physicochemical properties after 6 months of storage at various temperatures. PMID- 24044645 TI - PEGylated non-ionic surfactant vesicles as drug delivery systems for Gambogenic acid. AB - Gambogenic acid (GNA), a popular Chinese traditional medicine, has its limitations of coming into use due to its low aqueous solubility and poor bioavailability. In this study, therefore, the PEGylated non-ionic surfactant vesicles drug delivery systems were prepared from biocompatible non-ionic surfactant of Span60, cholesterol and dicetyl phosphate (DCP) by the improved ethanol injection method, and were modified with a polyethylene glycol monostearate15 (PEG15-SA). PEG15-SA, as a biocompatible, non-toxic and non immunogenic hydrophilic segment, was grafted onto the surface of colloidal niosomes carries to reduce the uptake by the reticuloendothelial system (RES), prolonging the circulation time and attaining higher entrapment efficiency. To our knowledge, this work is the first to report that PEG15-SA was applied to coating of niosomes for encapsulation of GNA. The optimized PEG-GNA-NISVs (P-GNA NISVs) were characterized in terms of mean vesicles size, polydispersity index (PDI), Zeta potential and entrapment efficiency of the P-GNA-NISVs. The results showed that the mean diameter, PDI, Zeta potential, and the entrapment efficiency of the P-GNA-NISVs were 70.1 nm, 0.166, -44.3 mV and 87.74%, respectively. Furthermore, the release studies of GNA from PEGylated niosomes in vitro and the pharmacokinetics in vivo exhibited a prolonged release profile as studied over 24 h. In conclusion, the result suggests that P-GNA-NISVs prepared in this way not only have higher encapsulation capacity, more colloidal stability but also offer an approach that the PEGylated niosomes is a promising carrier for anticancer GNA. PMID- 24044646 TI - Ultrasound well below the intensity threshold of cavitation can promote efficient uptake of small drug model molecules in fibroblast cells. AB - Ultrasound (US) induced enhancement of plasma membrane permeability is a hugely promising tool for delivering exogenous vectors at the specific biological site in a safe and efficient way. In this respect, here we report effects of membrane permeability alteration on fibroblast-like cells undergoing very low-intensity of US. The change in permeability was pointed out in terms of high uptake efficiency of the fluoroprobe calcein, thus resembling internalization of small cell impermeable model drugs, as measured by fluorescence microscopy and flow cytometry. Fluorescence evidences moreover suggests that the higher the time of exposure, the larger will be the size of molecules can be internalized. The uptake events were related to the cell viability and also with structural changes occurring at membrane level as revealed by infrared spectroscopy and preliminary membrane fluidity and atomic force microscopy (AFM) investigation. Thus, the question of whether the uptake of cell-impermeable molecules is consistent with the presence of disruptions on the cell membrane (sonopore formation) has been addressed. In this framework, our findings may constitute experimental evidence in support of sub-cavitation sonoporation models recently proposed, and they may also provide some hints towards the actual working condition of medical US dealing with the optimum risk to benefit therapeutic ratio. PMID- 24044647 TI - Guanidinylated 3-gluconamidopropyl methacrylamide-s-3-aminopropyl methacrylamide copolymer as siRNA carriers for inhibiting human telomerase reverse transcriptase expression. AB - In this report, a series of well-defined glucose- and guanidine-based cationic copolymers as gene carriers were developed to inhibit human telomerase reverse transcriptase (hTERT) gene expression. First of all, guandinylated 3 gluconamidopropyl methacrylamide-s-3-aminopropyl methacrylamide copolymers (guanidinylated GAPMA-s-APMA, abbreviated as GGA) were prepared via aqueous reversible addition--fragmentation chain transfer polymerization (RAFT). Then, three target hTERT siRNA TERT-1, TERT-2 and TERT-3 were designed and combined with GGA copolymers to form siRNA/GGA polyplexes. The polyplexes were examined by dynamic light scattering and agarose gel electrophoresis. The results indicated that GGA copolymers can condense siRNA effectively to form particles with the diameter from 157 nm to 411 nm and zeta potential values in the range from +3.7 to +15.8 mV at various charge ratios (N/P). The MTT assay data of siRNA/GGA polyplexes on human hepatocellular liver carcinoma cells (HepG2) indicated that GGA copolymer had better cell viabilities than polyethylenimine (PEI). Furthermore, the transfection of siRNA/GGA polyplexes was detected by real-time quantitative PCR (RT-qPCR) in HepG2. It was found that siRNA/GGA polyplexes could effectively silence hTERT mRNA expression in serum-free media (p<0.01). In the presence of serum, the hTERT mRNA expression in HepG2 cells have significant difference (p<0.01) between siRNA/GGA3 polyplexes and blank. The results showed that the GAPMA component can reduce the aggregation of protein in serum media. Therefore, the enhancement of transfection may be attributed to the combination of guadino groups and glucose component. And, the guandinylated 3 gluconamidopropyl methacrylamide-s-3-aminopropyl methacrylamide copolymers might be promise in gene delivery. PMID- 24044648 TI - Nanoparticles laden in situ gel of levofloxacin for enhanced ocular retention. AB - Availability of proper concentration of medicament on to the corneal surface is a challenging task. Many novel formulations, i.e. hydrogels, nanoparticles, ocuserts, etc. had been tested to improve ocular bioavailability, out of which our group found, in situ gel and polymeric nanoparticle are the most interesting approach to achieve ocular retention. We found that in situ gel stay only for 12 h and poly(lactic-co-glycolic acid (PLGA) nanoparticles are non mucoadhesive in nature so we try to combine both these formulations and termed it as "Nanoparticle laden in situ gel". Here we prepare nanoparticle laden in situ gel containing levofloxacin encapsulated PLGA nanoparticle, incorporated in chitosan in situ gel and evaluated its ocular retention by gamma scintigraphy in rabbits. The observations of acquired gamma camera images showed good retention over the entire precorneal area. From static and dynamic gamma scintigraphy evaluation, we can be interpret that developed nanoparticle laden in situ gel formulation cleared at a very slow rate and remained at corneal surface for longer duration than marketed formulation, in situ gel and nanosuspension alone. PMID- 24044649 TI - Technology and active agency of older adults living in service house environment. AB - PURPOSE: The purpose of the study was to explore whether or not the assistive and safety technology that is currently used in service house environment supports the active agency of the elderly residents. METHOD: Twelve purposively chosen elderly residents were interviewed. The data were analyzed by theory-driven content analysis using the modalities of the agency-model as a theoretical frame. RESULTS: The technological devices and systems partially support the active agency of the residents. Deterioration of their functioning seems to limit the use of devices as well as complicate their learning on how to use these systems. The respondents had only few insights of the possibilities that this technology could offer to them in their daily life and they were not expecting their functioning to improve in the future. The homeliness and intimacy of the environment was highly appreciated. CONCLUSIONS: Although the attitude towards technology was, in general, reserved, technology was seen as one possibility to support active agency. The current technologies seem to be designed from the needs of the organization and not from the needs of the residents. In the future, more emphasis needs to be put on designing individualized devices in cooperation with the users. Implications for Rehabilitation To support independence, autonomy and active agency of the older adults, the technological solutions must be based on perceived needs of the individual and the design should be adaptable to the functional limitations one has. Nursing staff's knowledge about assistive devices and technologies need to be updated on regular bases in order to be able to recommend appropriate devices for the elderly. Taking into account the fact that many older adults have mild to moderate memory problems as well as difficulties with vision and hearing, more attention needs to be paid to didactics, i.e. how the introduction and guidance of the use of new technologies, assistive devices or safety systems is best done with them. PMID- 24044650 TI - A bilateral rehabilitation system for the lower limbs. AB - PURPOSE: Bilateral and unilateral training equipment for the upper limbs facilitates rehabilitation after stroke. In this work, we tested the first device designed for bilateral training of the lower limbs. METHOD: Characteristics and usage of the novel MedExercise(r) ST device were evaluated by four healthy volunteers. A pedometer and temperature sensor were attached to the device and used to measure cadence and intensity of training, respectively. The heart rates of participants were recorded with a fingertip pulse oximeter. Thirty elderly patients assessed usability of the device and completed the survey. RESULTS: It was shown that the device could be operated in sitting and recumbent positions. The resistance levels and range of joint motion were individually adjustable for each leg, allowing both bilateral and unilateral training. When pedals were linked together, one leg could help moving the other leg. Recording of training intensities allowed leg fitness testing, personalized exercise prescription and analysis of self-controlled training. A usability survey demonstrated positive perception of elderly patients towards the device. CONCLUSIONS: This training system has a range of useful features, which can facilitate rehabilitation of the lower limbs via early leg mobilization and self-controlled training. Implications for Rehabilitation Bilateral and unilateral training devices are widely used to improve the effectiveness of upper limb rehabilitation, but there is no analogous equipment available for the lower limbs. Here, we show that the MedExercise(r) ST training system allows independent exercise of each leg in bilateral and unilateral modes, and objective recording of training activities. Elderly patients attending the exercise rehabilitation clinic demonstrated a positive perception towards usability of this equipment. The results of this study suggest suitability of the system for optimization of lower limb rehabilitation, including early leg mobilisation and self-controlled training. PMID- 24044652 TI - Triboelectric nanogenerator for harvesting wind energy and as self-powered wind vector sensor system. AB - We report a triboelectric nanogenerator (TENG) that plays dual roles as a sustainable power source by harvesting wind energy and as a self-powered wind vector sensor system for wind speed and direction detection. By utilizing the wind-induced resonance vibration of a fluorinated ethylene-propylene film between two aluminum foils, the integrated TENGs with dimensions of 2.5 cm * 2.5 cm * 22 cm deliver an output voltage up to 100 V, an output current of 1.6 MUA, and a corresponding output power of 0.16 mW under an external load of 100 MOmega, which can be used to directly light up tens of commercial light-emitting diodes. Furthermore, a self-powered wind vector sensor system has been developed based on the rationally designed TENGs, which is capable of detecting the wind direction and speed with a sensitivity of 0.09 MUA/(m/s). This work greatly expands the applicability of TENGs as power sources for self-sustained electronics and also self-powered sensor systems for ambient wind detection. PMID- 24044653 TI - Niphargus-Thiothrix associations may be widespread in sulphidic groundwater ecosystems: evidence from southeastern Romania. AB - Niphargus is a speciose amphipod genus found in groundwater habitats across Europe. Three Niphargus species living in the sulphidic Frasassi caves in Italy harbour sulphur-oxidizing Thiothrix bacterial ectosymbionts. These three species are distantly related, implying that the ability to form ectosymbioses with Thiothrix may be common among Niphargus. Therefore, Niphargus-Thiothrix associations may also be found in sulphidic aquifers other than Frasassi. In this study, we examined this possibility by analysing niphargids of the genera Niphargus and Pontoniphargus collected from the partly sulphidic aquifers of the Southern Dobrogea region of Romania, which are accessible through springs, wells and Movile Cave. Molecular and morphological analyses revealed seven niphargid species in this region. Five of these species occurred occasionally or exclusively in sulphidic locations, whereas the remaining two were restricted to nonsulphidic areas. Thiothrix were detected by PCR on all seven Dobrogean niphargid species and observed using microscopy to be predominantly attached to their hosts' appendages. 16S rRNA gene sequences of the Thiothrix epibionts fell into two main clades, one of which (herein named T4) occurred solely on niphargids collected in sulphidic locations. The other Thiothrix clade was present on niphargids from both sulphidic and nonsulphidic areas and indistinguishable from the T3 ectosymbiont clade previously identified on Frasassi-dwelling Niphargus. Although niphargids from Frasassi and Southern Dobrogea are not closely related, the patterns of their association with Thiothrix are remarkably alike. The finding of similar Niphargus-Thiothrix associations in aquifers located 1200 km apart suggests that they may be widespread in European groundwater ecosystems. PMID- 24044654 TI - The spinning task: a new protocol to easily assess motor coordination and resistance in zebrafish. AB - The increasing use of adult zebrafish in behavioral studies has created the need for new and improved protocols. Our investigation sought to evaluate the swimming behavior of zebrafish against a water current using the newly developed Spinning Task. Zebrafish were individually placed in a beaker containing a spinning magnetic stirrer and their latency to be swept into the whirlpool was recorded. We characterized that larger fish (>4 cm) and lower rpm decreased the swimming time in the Spinning Task. There was also a dose-related reduction in swimming after acute treatment with haloperidol, valproic acid, clonazepam, and ethanol, which alter coordination. Importantly, at doses that reduced swimming time in the Spinning Task, these drugs influenced absolute turn angle (ethanol increased and the other drugs decreased), but had no effect of distance travelled in a regular water tank. These results suggest that the Spinning Task is a useful protocol to add information to the assessment of zebrafish motor behavior. PMID- 24044656 TI - Endoscopic findings of the stomach in pleasure horses in Poland. AB - BACKGROUND: This study was performed to determine the prevalence of ulcers in the gastric squamous and glandular mucosa in Polish pleasure horses. STUDY DESIGN: Medical records from gastroscopic examinations of 108 pleasure horses of different breeds were reviewed. The study population consisted of two groups; group I (n = 48) with horses that expressed mild clinical signs of gastric ulcer syndrome (EGUS) including poor appetite, slight weight loss or poor body condition, and group II (n = 60) with horses that had no signs of gastrointestinal problems. The age range was 4-10 years, including 5 males, 34 castrated males (geldings) and 69 mares. The prevalence, distribution and severity of gastric ulcers were recorded. Lesions involving the squamous mucosa and the glandular mucosa of the antrum and pylorus were graded and compared between groups. RESULTS: Significant difference was found in the presence and severity of gastric ulcers between the two groups of horses. The overall prevalence of gastric ulcers in the first group of horses (n = 48) was 59% while in the group of clinically healthy horses (n = 60) the prevalence of gastric lesion was 40% (P = 0.004). Almost 19% of horses from group I had between 6-10 lesions (EGUS score III) and nearly 19% had either >10 localized lesions or very large diffuse lesions (EGUS number score IV). The number of ulcerations in affected horses were significantly lower in group II compared to group I (P = 0.016) as 10% of horses had 6-10 lesions (EGUS number score III) and nearly 14% had either >10 localized lesions or very large diffuse lesions (EGUS number score IV). Gastroscopy revealed that nearly 32% of horses from the second group had an ulceration EGUS score >= II. DISCUSSION AND CONCLUSIONS: This study confirms that gastric ulcerations can be prevalent in apparently clinically normal pleasure horses and a complete gastroscopic examination including the examination of the pylorus is advisable to evaluate this syndrome. PMID- 24044655 TI - Catechin prevents the calcium oxalate monohydrate induced renal calcium crystallization in NRK-52E cells and the ethylene glycol induced renal stone formation in rat. AB - BACKGROUND: Reactive oxygen species play important roles in renal calcium crystallization. In this study, we examined the effects of catechin, which have been shown to have antioxidant properties on the renal calcium crystallization. METHODS: In the vitro experiment, the changes of the mitochondrial membrane potential, expression of superoxide dismutase (SOD), 4-hydroxynonenal (4-HNE), cytochrome c, and cleaved caspase 3 were measured to show the effects of catechin treatment on the NRK-52E cells induced by calcium oxalate monohydrate (COM). In the vivo study, Sprague-Dawley rats were administered 1% ethylene glycol (EG) to generate a rat kidney stone model and then treated with catechin (2.5 and 10 mg/kg/day) for 14 days. The urine and serum variables were dected on 7 and 14 days after EG administration. The expression of cytochrome c, cleaved caspase 3, SOD, osteopontin (OPN), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8 OHdG) in kidney were measured. Furthermore, the mitochondrial microstructure in the kidney was also examined by transmission electron microscopy. RESULTS: Catechin treatment could prevent the changes in mitochondrial membrane potential and expression of SOD, 4-HNE, cytochrome c, and cleaved caspase 3 in NRK-52E cells induced by the COM. For the in vivo experiments, the EG administration induced renal calcium crystallization was also prevented by the catechin. The expression of SOD, OPN, MDA, OPN and 8-OHdG, were increased after EG administration and this increase was diminished by catechin. Moreover, catechin also prevented EG induced mitochondrial collapse in rat. CONCLUSIONS: Catechin has preventive effects on renal calcium crystallization both in vivo and in vitro, and provide a potential therapeutic treatment for this disease. PMID- 24044657 TI - Left hemitruncus with normal right-sided pressures in an adult. AB - Hemitruncus is a rare congenital heart disease. Anomalous origin of the left pulmonary artery is not only rare but also pathogenetically different from anomalous origin of the right pulmonary artery from the ascending aorta. In most cases in isolated hemitrucus pressures in the right ventricle and the normally originating pulmonary artery are systemic or suprasystemic. We present a rare case of anomalous origin of the left pulmonary artery from the ascending aorta diagnosed in an adult with normal pressures in the right ventricle and normally originating pulmonary artery. To the best of our knowledge, this unique haemodynamics has never been reported in the literature. PMID- 24044658 TI - Epistemological pluralism and scientific development. PMID- 24044659 TI - Epistemological pluralism and scientific development: an argument against authoritative nosologies. AB - The author examines the influence of authoritative nosological systems--those developed by an authoritative body or organization (e.g., the DSM, ICD, RDoC)--on the development of scientific theory and research. Although there has been extensive discussion of how such systems should be organized, and of the historical role of such systems, little focus has been placed on whether these systems impede or facilitate scientific progress. The author reviews the nature and role of constructs in scientific theory and the role of authoritative taxonomy in science. He presents an argument that, although authoritative classification systems clearly have value for nonscientific purposes, or for specific scientific purposes, the systems themselves, at least as they have been constructed thus far, likely impede scientific development by constraining competitive discourse. Implications and recommendations are discussed. PMID- 24044660 TI - Science should drive the bus of clinical description; but how does "science take the wheel"?: a commentary on Markon. PMID- 24044661 TI - Nosology is usually wrong, but is a test bed for science: a commentary on Markon. AB - Kristian Markon (2013) is generally right in his diagnostic assessment but less so in his solutions. Nosology gets in the way of science when it becomes authoritative, as it often prevents science from proceeding in the systematic way that it would do otherwise, but the solution is not to abandon formal nosologies. Rather, we should endeavor to stop them from becoming authoritative, by overcoming nosological practice when it stands in the way of science. By considering the different functions of nosology and science, it is possible to get a compromise. PMID- 24044662 TI - Abandoning official psychiatric nosologies: a cure that may be worse than the disease: a commentary on Markon. PMID- 24044663 TI - The tower of Babel: a commentary on Markon. PMID- 24044664 TI - Personality disorders as maladaptive, extreme variants of normal personality: borderline personality disorder and neuroticism in a substance using sample. AB - Although the current diagnostic manual conceptualizes personality disorders (PDs) as categorical entities, an alternative perspective is that PDs represent maladaptive extreme versions of the same traits that describe normal personality. Existing evidence indicates that normal personality traits, such as those assessed by the five-factor model (FFM), share a common structure and obtain reasonably predictable correlations with the PDs. However, very little research has investigated whether PDs are more extreme than normal personality traits. Utilizing item-response theory analyses, the authors of the current study extend previous research to demonstrate that the diagnostic criterion for borderline personality disorder and FFM neuroticism could be fit along a single latent dimension. Furthermore, the authors' findings indicate that the borderline criteria assessed the shared latent trait at a level that was more extreme (d = 1.11) than FFM neuroticism. This finding provides further evidence for dimensional understanding of personality pathology and suggests that a trait model in DSM-5 should span normal and abnormal personality functioning, but focus on the extremes of these common traits. PMID- 24044665 TI - Chemical wave propagation preserved on an inhibitory field in the ruthenium catalyzed Belousov-Zhabotinsky reaction. AB - The propagation of a chemical wave on an inhibitory field, which was wedged between two excitable fields, was investigated for the photosensitive Belousov Zhabotinsky (BZ) reaction. With an increase in the width of the inhibitory field between the excitable fields (W), the chemical wave divided into two waves at W = Walpha. The divided chemical waves then coalesced at W = Wbeta with a decrease in W. Walpha was larger than Wbeta, i.e., hysteresis on the width of the inhibitory field was observed between the division and coalescence of the chemical wave. The experimental results were qualitatively reproduced by a numerical calculation based on a three-variable Oregonator model modified for the photosensitive BZ reaction. These results suggest that the chemical wave may be preserved on the inhibitory field due to an activator supplied from a chemical wave on the excitable field. PMID- 24044666 TI - After the storm. PMID- 24044667 TI - Combined NMR analysis of huge residual dipolar couplings and pseudocontact shifts in terbium(III)-phthalocyaninato single molecule magnets. AB - Several small paramagnetic complexes combine large hyperfine NMR shifts with large magnetic anisotropies. The latter are a prerequisite for single molecule magnet (SMM) behavior. We choose the SMM tris(octabutoxyphthalocyaninato) diterbium (1) for a high resolution NMR study where we combined for the first time a comprehensive (1)H and (13)C chemical shift analysis of a SMM with the evaluation of large residual dipolar couplings (RDCs). The latter are a consequence of partial alignment of SMM 1 in the strong magnetic field of the NMR spectrometer. To the best of our knowledge RDCs in SMMs have never been reported before. We measured RDCs between -78 and +99 Hz for the (13)C-(1)H vectors of CH bonds and up to -109 Hz for (1)H-(1)H vectors of geminal hydrogen atoms (magnetic field of 14.09 T, temperature 295 K). Considerable negative Fermi contact shifts (up to -60 ppm) were determined for (13)C atoms at the phthalocyaninato core. Paramagnetic (13)C NMR shifts of the butoxy chains as well as all (1)H NMR chemical shifts are a result of pseudocontact shifts (pcs), and therefore it is easily possible to determine the positions of the respective nuclei in solution. Measurements of CH and HH vectors by RDC analysis are in accordance with the geometry as determined by the pseudocontact shifts, but in addition to that, RDCs give information about internal mobility. The axial component of the magnetic susceptibility tensor has been determined independently by pcs and by RDC. PMID- 24044668 TI - Surfactant-promoted reactions of Cl2 and Br2 with Br- in glycerol. AB - Gas-liquid scattering experiments are used to explore reactions of gaseous Cl2 and Br2 with a 0.03 M solution of the surfactant tetrahexylammonium bromide (THABr) dissolved in glycerol. At thermal collision energies, 79 +/- 2% of incident Cl2 molecules react with Br(-) to form Cl2Br(-) in the interfacial region. This reaction probability is three times greater than the reactivity of Cl2 with 3 M NaBr-glycerol, even though the interfacial Br(-) concentrations are similar in each solution. We attribute the high 79% uptake to the presence of surface THA(+) ions that stabilize the Cl2Br(-) intermediate as it is formed in the charged, hydrophobic pocket created by the hexyl chains. Cl2Br(-) generates the single exchange product BrCl in a 1% yield close to the surface, while the remaining 99% desorbs as the double exchange product Br2 over >0.1 s after diffusing deeply into the bulk. When NaCl is added to the surfactant solution in a 20:1 Cl(-)/Br(-) ratio, the Cl2 reaction probability drops from 79% to 46 +/- 1%, indicating that Cl(-) in the interfacial region only partially blocks reaction with Br(-). In parallel, we observe that gaseous Br2 molecules dissolve in 0.03 M THABr for 10(4) times longer than in 3 M NaBr. We attribute this change to formation of stabilizing interfacial and bulk-phase THA(+)Br3(-) ion pairs, in analogy with the capture of Cl2 and formation of THA(+)Cl2Br(-) pairs. The THA(+) ion appears to be a powerful interfacial catalyst for promoting reaction of Cl2 and Br2 with Br(-) and for ferrying the resultant ions into solution. PMID- 24044669 TI - Application of pattern recognition tools for classifying acute coronary syndrome: an integrated medical modeling. AB - OBJECTIVE: The classification of Acute Coronary Syndrome (ACS), using artificial intelligence (AI), has recently drawn the attention of the medical researchers. Using this approach, patients with myocardial infarction can be differentiated from those with unstable angina. The present study aims to develop an integrated model, based on the feature selection and classification, for the automatic classification of ACS. METHODS: A dataset containing medical records of 809 patients suspected to suffer from ACS was used. For each subject, 266 clinical factors were collected. At first, a feature selection was performed based on interviews with 20 cardiologists; thereby 40 seminal features for classifying ACS were selected. Next, a feature selection algorithm was also applied to detect a subset of the features with the best classification accuracy. As a result, the feature numbers considerably reduced to only seven. Lastly, based on the seven selected features, eight various common pattern recognition tools for classification of ACS were used. RESULTS: The performance of the aforementioned classifiers was compared based on their accuracy computed from their confusion matrices. Among these methods, the multi-layer perceptron showed the best performance with the 83.2% accuracy. CONCLUSION: The results reveal that an integrated AI-based feature selection and classification approach is an effective method for the early and accurate classification of ACS and ultimately a timely diagnosis and treatment of this disease. PMID- 24044670 TI - Real-time observation of the destruction of hydration shells under electrochemical force. AB - Major alteration or even destruction of the hydration shell around interacting molecules and ions in solution is an important process that determines how hydrated substances interact. Therefore, the direct observation of structural changes in hydration shells around solutes in close contact with other solutes or surfaces is important for understanding chemical processes that take place in solution. In the work described in this paper, time-resolved IR absorption measurements were performed to study the interaction of hydrated Na(+) or tetrapropylammonium cation (Pr4N(+)) with a hydrophobic CO-covered Pt surface; the adsorption force between cations and the surface was controlled by using an electrochemical system. We found that the hydrophobic hydration shell of Pr4N(+) is initially stabilized on the hydrophobic surface, but application of a strong force to the cation approaching CO destroys the water layers between them. This process is rather slow, taking a few hundred milliseconds. Hydrophilic Na(+) behaves quite differently from Pr4N(+) due to the different structure of its hydration shell. These experimental results are supported by molecular dynamics simulations. PMID- 24044671 TI - Toward a research agenda on gendered violence in sub-Saharan Africa. PMID- 24044672 TI - The road to patient experience of care measurement: lessons from the United States. AB - Patient-centered care has become an increasing priority in the United States and plays a prominent role in recent healthcare reforms. One way the country has managed to advance patient-centered care is through establishment of a family of national patient experience surveys (the Consumer Assessment of Healthcare Providers and Systems Plans (CAHPS). CAHPS is publicly reported for several types of providers and was recently tied to hospital reimbursement. This is part of a trend over the last two decades that has shifted provider-patient relationships from a traditional paternal approach to customer service and then to clinical partnership. The health care system in Israel, however, is still struggling to overcome barriers to change in this area. While community based biannual patient experience surveys are conducted by the Myers-JDC-Brookdale Institute, there is no comprehensive national approach to measuring the patient experience across a broad range of settings. Only recently did the Israeli Ministry of Health take its first steps to include patient experience as a dimension of health care quality.In its current position, Israel should learn from the U.S. experience with policies promoting patient-centered care, and specifically the impact on clinical services of measuring the patient experience. Looking at what has happened in the United States, we suggest three main lessons. First, there is a need for a set of national patient experience surveys that would be publicly reported and eventually tied to provider reimbursement. Secondly, the national survey tools should be customized to the unique characteristics of Israeli society and draw from recent research on patient-centeredness to include new and important domains such as patient activation and shared decision-making. Finally, newer technological approaches should be explored with the aim of increasing response rates and the timeliness and usefulness of the surveys. PMID- 24044673 TI - A prospective study of high dose sedation for rapid tranquilisation of acute behavioural disturbance in an acute mental health unit. AB - BACKGROUND: Acute behavioural disturbance (ABD) is a common problem in psychiatry and both physical restraint and involuntary parenteral sedation are often required to control patients. Although guidelines are available, clinical practice is often guided by experience and there is little agreement on which drugs should be first-line treatment for rapid tranquilisation. This study aimed to investigate sedation for ABD in an acute mental healthcare unit, including the effectiveness and safety of high dose sedation. METHODS: A prospective study of parenteral sedation for ABD in mental health patients was conducted from July 2010 to June 2011. Drug administration (type, dose, additional doses), time to sedation, vital signs and adverse effects were recorded. High dose parenteral sedation was defined as greater than the equivalent of 10 mg midazolam, droperidol or haloperidol (alone or in combination), compared to patients receiving 10 mg or less (normal dose). Effective sedation was defined as a fall in the sedation assessment tool score by two or a score of zero or less. Outcomes included frequency of adverse drug effects, time to sedation/tranquilisation and use of additional sedation. RESULTS: Parenteral sedation was given in 171 cases. A single drug was given in 96 (56%), including droperidol (74), midazolam (19) and haloperidol (3). Effective sedation occurred in 157 patients (92%), and the median time to sedation was 20 min (Range: 5 to 100 min). The median time to sedation for 93 patients receiving high dose sedation was 20 min (5-90 min) compared to 20 min (5-100 min; p = 0.92) for 78 patients receiving normal dose sedation. Adverse effects occurred in 16 patients (9%); hypotension (14), oxygen desaturation (1), hypotension and oxygen desaturation (1). There were more adverse effects in the high dose sedation group compared to the normal dose group [11/93 (12%) vs. 5/78 (6%); p = 0.3]. Additional sedation was given in 9 of 171 patients (5%), seven in the high dose and two in the normal dose groups. CONCLUSIONS: Large initial doses of sedative drugs were used for ABD in just over half of cases and additional sedation was uncommon. High dose sedation did not result in more rapid or effective sedation but was associated with more adverse effects. PMID- 24044674 TI - General synthesis of discrete mesoporous carbon microspheres through a confined self-assembly process in inverse opals. AB - A general confined coassembly process has been demonstrated to produce discrete uniform mesoporous carbon microspheres with 0.8-1 MUm particle size using 3-D ordered macroporous silica as the template. The obtained mesoporous carbon microspheres (MC-MSs) have uniform and discrete spherical morphology, variable symmetry (hexagonal p6mm or cubic Im3m) of mesostructures, high specific surface areas (500-1100 m(2)/g), large pore volumes (0.6-2.0 cm(3)/g), and highly accessible large mesopores (7-10.3 nm). The particle size of the carbon microspheres can be easily tuned by simply using templates with different macropore sizes. It was found that the smaller MC-MSs (330 nm) with higher surface-to-volume ratio tend to shape into an integral monolithic MC-MS matrix and larger MC-MSs (>800 nm) with lower surface-to-volume ratio to discrete spherical morphology. This feature is attributed to the difference in shrinkage behavior of mesoporous carbon spheres confined in the macropores caused by the interaction between the silica wall and carbon microspheres. Adsorption experiments indicate that the cobalt-based nanoparticle-incorporated mesoporous carbon microspheres exhibit excellent size selectivity for protein adsorption in a complex solution and good magnetic separability for easy recycling. PMID- 24044675 TI - Use of combined scanning electrochemical and fluorescence microscopy for detection of reactive oxygen species in prostate cancer cells. AB - Release of ROS from prostate cancer (PC3) cells was studied using scanning electrochemical microscopy (SECM) and fluorescence microscopy. One-directional lateral scan SECM was used as a rapid and reproducible tool for simultaneous mapping of cell topography and reactive oxygen species (ROS) release. Fluorescence microscopy was used in tandem to monitor the tip position, in addition to providing information on intracellular ROS content via the use of ROS reactive fluorescent dyes. A unique tip current (iT) vs lateral distance profile was observed when the tip potential (ET) was set at -0.65 V. This profile reflects the combined effects of topographical change and ROS release at the PC3 cell surfaces. Differentiation between topographical-related and ROS-induced current change was achieved by comparing the scans collected at -0.65 and -0.85 V. The effects of other parameters such as tip to cell distance, solvent oxygen content, and scan direction on the profile of the scan were systematically evaluated. Cells treated with tert-butyl hydroperoxide, a known ROS stimulus, were also evaluated using the lateral scanning approach. Overall, the SECM results correlate well with the fluorescence results. The extracellular ROS level detected at the SECM tip was found to be similar to the intracellular ROS level monitored using fluorescence microscopy. While the concentration of each contributing ROS species has not been determined and is thus part of the future study, here we have successfully demonstrated the use of a simple two-potential lateral scan approach for analysis of ROS released by living cells under real physiological conditions. PMID- 24044676 TI - Alveolar macrophages of GM-CSF knockout mice exhibit mixed M1 and M2 phenotypes. AB - BACKGROUND: Activin A is a pleiotrophic regulatory cytokine, the ablation of which is neonatal lethal. Healthy human alveolar macrophages (AMs) constitutively express activin A, but AMs of patients with pulmonary alveolar proteinosis (PAP) are deficient in activin A. PAP is an autoimmune lung disease characterized by neutralizing autoantibodies to Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF). Activin A can be stimulated, however, by GM-CSF treatment of AMs in vitro. To further explore pulmonary activin A regulation, we examined AMs in bronchoalveolar lavage (BAL) from wild-type C57BL/6 compared to GM-CSF knockout mice which exhibit a PAP-like histopathology. Both human PAP and mouse GM-CSF knockout AMs are deficient in the transcription factor, peroxisome proliferator activated receptor gamma (PPARgamma). RESULTS: In sharp contrast to human PAP, activin A mRNA was elevated in mouse GM-CSF knockout AMs, and activin A protein was increased in BAL fluid. Investigation of potential causative factors for activin A upregulation revealed intrinsic overexpression of IFNgamma, a potent inducer of the M1 macrophage phenotype, in GM-CSF knockout BAL cells. IFNgamma mRNA was not elevated in PAP BAL cells. In vitro studies confirmed that IFNgamma stimulated activin A in wild-type AMs while antibody to IFNgamma reduced activin A in GM-CSF knockout AMs. Both IFNgamma and Activin A were also reduced in GM-CSF knockout mice in vivo after intratracheal instillation of lentivirus-PPARgamma compared to control lentivirus vector. Examination of other M1 markers in GM-CSF knockout mice indicated intrinsic elevation of the IFNgamma-regulated gene, inducible Nitrogen Oxide Synthetase (iNOS), CCL5, and interleukin (IL)-6 compared to wild-type. The M2 markers, IL-10 and CCL2 were also intrinsically elevated. CONCLUSIONS: Data point to IFNgamma as the primary upregulator of activin A in GM CSF knockout mice which in addition, exhibit a unique mix of M1-M2 macrophage phenotypes. PMID- 24044677 TI - Analysis of pulmonary surfactant in rat lungs after intratracheal instillation of short and long multi-walled carbon nanotubes. AB - Multi-walled carbon nanotubes (MWCNTs) are interesting new materials, but there is some concern about their harmfulness due to their fibrous nature. To determine the difference in the biological effects of MWCMTs by fiber length, we prepared two MWCNT samples from one bulk sample. One consisted of cut up short fibers (Short; average length=0.94 um) and the other was just dispersed (Long; average length=3.4 um). The samples were administered to male Wistar rats by intratracheal instillation at doses of 0.2 mg and 1 mg/animal (Short) and 0.2 mg and 0.6 mg/animal (Long). The animals were sacrificed at time points from 3 d to 12 months after administration. Bronchoalveolar lavage fluid (BALF) was taken from the lungs and pathological specimens were prepared. The concentrations of phospholipids, total protein and surfactant protein D (SP-D) in the pulmonary surfactant of the BALF were determined, the surface tension of BALF was measured, and the inflammation score was determined by the point-counting method to assess pulmonary tissue inflammation. The present study suggests that inflammatory response in the lung was slightly higher for long MWCNTs than for short MWCNTs when compared at the same mass dose. The correlation between pulmonary surfactant components and BALF surface tension was also evaluated. The Spearman's rank correlation coefficients obtained for the phospholipid, total protein and SP-D concentrations were -0.068 (p=0.605), -0.360 (p=0.005) and -0.673 (p=0.000), respectively. Surface tension, measured by a simple method, should be reflected in the change of a surfactant protein, such as SP-D. PMID- 24044678 TI - Toxicological effects of PM0.25-2.0 particles collected from a photocopy center in three human cell lines. AB - Printing devices such as photocopiers and printers emit predominantly nanoparticles, which may aggregate with time to form PM0.25-2.0 particles. To date, there are no reports on cytotoxic or genotoxic effects of PM0.25-2.0 particles emitted from photocopiers. To investigate the ability of PM0.25-2 fraction emitted from photocopiers, induce pro-inflammatory cytokines, DNA damage and apoptosis in different human-derived cell lines. Three cell types, i.e. a THP 1 line, primary human nasal and small airway epithelial cells, were used. The airborne PM0.25-2.0 size fraction collected from a photocopy center was characterized for its physicochemical and morphological properties, dispersed in culture media and cells were treated with 30, 100 or 300 ug/ml doses. Levels of 13 cytokines and chemokines in the culture medium harvested at 6 and 24 h of treatment were measured using Luminex cytokine kits. In cells harvested at the same timepoints, DNA damage in cells was studied by a Comet assay, and apoptosis was measured by cytofluorimetry using an Annexin V staining kit. The results indicate that in THP-1 cells, several cytokines (IL-6, IL-8, TNFalpha and IL 1beta) were significantly elevated. Only IL-8 was significantly elevated in the primary nasal and small airway cells. Cells exposed to PM0.25-2.0 underwent apoptosis in a dose-dependent manner, but no significant differences were found in the extent of DNA damage at either timepoint. Airborne PM0.25-2.0 collected at one photocopier center was capable of inducing several pro-inflammatory cytokines and apoptosis, but no genotoxicity, in all cell lines suggesting a role for PM0.25-2.0 in our previously documented airway inflammation in human volunteers. Further toxicological evaluations of these particles across different toner manufacturers are warranted. PMID- 24044679 TI - The effect of Asian sand dust-activated respiratory epithelial cells on activation and migration of eosinophils. AB - CONTEST: Asian sand dust (ASD) contains various chemical and microbiological materials. ASD aggravate the inflammatory response of respiratory epithelial cells and symptoms of asthma. OBJECTIVE: To evaluate the inflammatory effects of ASD on the activation of bronchial epithelial cells and the effect on the activation and migration of eosinophils. MATERIALS AND METHODS: BEAS-2B cells were exposed to three forms of ASD: particles less than 10 MUm in diameter (PM), dried sand dust (SD) and sand dust collected from the Gobi Desert (GB). Activation of the epithelial cells was determined using interleukin-6 (IL-6), IL 8, granulocyte macrophage colony-stimulating factor (GM-CSF), regulated on activation normal T expressed and secreted (RANTES), and eotaxin. Eosinophil migration was induced with bronchial epithelial cell conditioned medium. Eosinophils were stimulated with the ASDs and production of superoxide and eosinophil cationic protein was measured. RESULTS: PM and SD enhanced the production of IL-6, IL-8 and RANTES. However, only IL-6 production was significantly increased with GB. Conditioned medium stimulated PM and SD enhanced the migration of eosinophils. PM and SD strongly activated eosinophils. DISCUSSION AND CONCLUSIONS: ASD, which contains smaller particles and air pollutants, might exacerbate the inflammatory process of bronchial tissue and asthmatic symptoms with the production of inflammatory mediators and tissue eosinophilia. PMID- 24044680 TI - Age influence on hypersensitivity pneumonitis induced in mice by exposure to Pantoea agglomerans. AB - Hypersensitivity pneumonitis (HP) represents the immunologically mediated lung disease induced by repeated inhalations of a wide variety of certain finely dispersed organic antigens. In susceptible subjects, these inhalations provoke a hypersensitivity reaction characterized by intense inflammation of the terminal bronchioles, the interstitium and the alveolar tree. The inflammation often organizes into granulomas and may progress to pulmonary fibrosis. Our previous work indicated that cell extract of gram-negative bacteria Pantoea agglomerans (SE-PA) causes, in young C57BL/6J mice, pulmonary changes that are very similar to the clinical manifestations of HP in men. The purpose of presented studies was to describe the response of mice immune system while exposed to SE-PA. Particular attention was paid to examine the age influence on SE-PA induced inflammation and fibrosis in lung tissue. We used 3- and 18-month-old C57BL/6J mice. Lung samples were collected from untreated mice and animals exposed to harmful agent for 7 and 28 days. HP development was monitored by histological and biochemical evaluation. Using ELISA tests, we examined concentration of pro- and anti-inflammatory cytokines in lung homogenates. Our study demonstrated again that SE-PA provokes in mice changes typical for the clinical picture of HP, and that successive stages of disease (acute, subacute and chronic) might be obtained by modulation of time exposure. Furthermore, we found that animals' age at the time of sensitization influences the nature of observed changes (cytokine expression pattern) and the final outcome (reaction intensity and scale of fibrosis). PMID- 24044681 TI - Comment on incidence of cancer in Iranian sulfur mustard (SM) exposed veterans. PMID- 24044682 TI - Endolytic, pH-responsive HPMA-b-(L-Glu) copolymers synthesized via sequential aqueous RAFT and ring-opening polymerizations. AB - A facile synthetic pathway for preparing block copolymers with pH-responsive L glutamic acid segments for membrane disruption is reported. Aqueous reversible addition-fragmentation chain transfer (aRAFT) polymerization was first used to prepare biocompatible, nonimmunogenic poly[N-(2-hydroxypropyl)methacrylamide]. This macro chain transfer agent (CTA) was then converted into a macroinitiator via simultaneous aminolysis and thiol-ene Michael addition using the primary amine substituted N-(3-aminopropyl)methacrylamide. This macroinitiator was subsequently utilized in the ring-opening polymerization of the N carboxyanhydride monomer of gamma-benzyl-L-glutamate. After deprotection, the pH dependent coil-to-helix transformations of the resulting HPMA-b-(L-Glu) copolymers were monitored via circular dichroism spectroscopy. HPMA segments confer water solubility and biocompatibility while the L-glutamic acid repeats provide reversible coil-to-helix transitions at endosomal pH values (~5-6). The endolytic properties of these novel [HPMA-b-(L-Glu)] copolymers and their potential as modular components in drug carrier constructs was demonstrated utilizing red blood cell hemolysis and fluorescein release from POPC vesicles. PMID- 24044683 TI - Microneedle integrated transdermal patch for fast onset and sustained delivery of lidocaine. AB - Lidocaine as an analgesic is of particular interest in both acute and chronic pain conditions and is used via injections or transdermal patches. While injections are associated with problems such as patient incompliance, topical administration of lidocaine using patches is less efficient due to variability of drug absorption among individuals, slower drug permeation through the skin, and hence a resultant undesirable delay in analgesic effects. To address this clinical problem, we developed a microneedle integrated transdermal patch (MITP), using a photolithography based process, in which microneedles create micrometer sized channels in the skin to deliver lidocaine rapidly, while the reservoir patch holding the bulk of the drug enables higher drug loading and carries on to release the drug for prolonged periods. We demonstrated a new approach of drug delivery using microneedles, where drugs diffuse out of microneedles through the porous channels left by dissolving drug particles. MITP was shown to be able to encapsulate up to 70 mg of lidocaine. In vitro permeation through rat skin demonstrated that MITP delivered a significantly higher amount of lidocaine than a commercial patch and with a faster onset of drug permeation. PMID- 24044684 TI - Neglected synovial osteochondromatosis of the elbow: a rare case. AB - BACKGROUND: Synovial osteochondromatosis is a benign metaplastic proliferative disorder of the synovium characterised by the formation of multiple cartilaginous nodules in the synovium, many of which detach and become loose bodies. The disease is characteristically monoarticular, most commonly involving the knee. A site in the elbow was first reported in 1918 by Henderson, but any joint may be involved. Very few cases of synovial osteochondromatosis of the elbow have been reported in the literature. The presenting symptoms are usually diffuse discomfort in the affected joint and decreased range of motion with an accompanying gritty or locking sensation. The treatment of choice is excision of the synovium and removal of the loose bodies. CASE PRESENTATION: We report a rare neglected case covering a 32-year period of a locally aggressive synovial osteochondromatosis of the elbow in a 47-year-old man. Clinical examination revealed a significant increase in size of the left elbow compared to the contralateral one. The simple radiographs and the computed tomography showed multiple rounded, calcified bodies widespread throughout the elbow joint. At surgery we removed and counted a total of 312 loose bodies, varying in size from a few millimeters to 3 cm. The evaluation at 6 months postoperatively showed marked reduction in the volume of the elbow, improvement of extension and flexion and an increase of the Mayo elbow performance score from 50 points before surgery to 80 points at 6 months postoperative. CONCLUSION: Synovial osteochondromatosis is an uncommon condition characterized by the formation of multiple nodules of hyaline cartilage within the sub-synovial connective tissue. The differential diagnosis includes chronic articular infection, osteoarthritis, pigmented villonodular synovitis, mono-articular inflammatory arthritis and periarticular neoplasms like synovial sarcoma. The treatment of choice is excision of the synovium and removal of the loose bodies. The prognosis is good, but recurrences may occur if the removal is incomplete. PMID- 24044685 TI - Measuring participation outcomes following life-saving medical interventions: the Role Checklist Version 2: Quality of Performance. AB - PURPOSE: To establish the Role Checklist Version 2: Quality of Performance as a measure of past, present and desired future role incumbency, role value and self perception of the quality of role performance for 10 roles consistent with the ICF Participation Domains. METHODS: Discuss the literature on the measurement of participation; present a conceptually based case for similarities in content between the RC V2: QP; and illustrate through a case example its efficacy as a balanced measure of performance. RESULTS: Despite different origins, the ICF domain areas: Chapters 6-9 correspond to the roles included in the RC V2: QP. The measure is shown sensitive to change in quality of performance through insider self-report serving in the case provided, as an early indicator of deterioration in physical status. CONCLUSION: A balanced measure of the insider and outsider perspective of participation, the case of one liver transplant recipient illustrates how the RC V2: QP serves to reflect participation outcomes thus, adding an available measure of the ICF construct of participation. Implications for Rehabilitation The Role Checklist Version 2: Quality of Performance is consistent with the ICF performance qualifier of participation. The insider view of participation is strengthened in this Second version of the Role Checklist. The Role Checklist Version 2: Quality of Performance provides a general measure of participation that can be used across populations. PMID- 24044686 TI - Instituting systems-based practice and practice-based learning and improvement: a curriculum of inquiry. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) requires that training programs integrate system-based practice (SBP) and practice-based learning and improvement (PBLI) into internal medicine residency curricula. CONTEXT AND SETTING: We instituted a seminar series and year-long mentored curriculum designed to engage internal medicine residents in these competencies. METHODS: Residents participate in a seminar series that includes assigned reading and structured discussion with faculty who assist in the development of quality improvement or research projects. Residents pursue projects over the remainder of the year. Monthly works in progress meetings, protected time for inquiry, and continued faculty mentorship guide the residents in their project development. Trainees present their work at hospital-wide grand rounds at the end of the academic year. We performed a survey of residents to assess their self-reported knowledge, attitudes and skills in SBP and PBLI. In addition, blinded faculty scored projects for appropriateness, impact, and feasibility. OUTCOMES: We measured resident self-reported knowledge, attitudes, and skills at the end of the academic year. We found evidence that participants improved their understanding of the context in which they were practicing, and that their ability to engage in quality improvement projects increased. Blinded faculty reviewers favorably ranked the projects' feasibility, impact, and appropriateness. The 'Curriculum of Inquiry' generated 11 quality improvement and research projects during the study period. Barriers to the ongoing work include a limited supply of mentors and delays due to Institutional Review Board approval. Hospital leadership recognizes the importance of the curriculum, and our accreditation manager now cites our ongoing work. CONCLUSIONS: A structured residency-based curriculum facilitates resident demonstration of SBP and practice based learning and improvement. Residents gain knowledge and skills though this enterprise and hospitals gain access to trainees who help to solve ongoing problems and meet accreditation requirements. PMID- 24044687 TI - A Lactobacillus casei Shirota probiotic drink reduces antibiotic-associated diarrhoea in patients with spinal cord injuries: a randomised controlled trial. AB - Certain probiotics may prevent the development of antibiotic-associated diarrhoea (AAD) and Clostridium difficile-associated diarrhoea (CDAD), but their effectiveness depends on both strain and dose. There are few data on nutritional interventions to control AAD/CDAD in the spinal cord injury (SCI) population. The present study aimed to assess (1) the efficacy of consuming a commercially produced probiotic containing at least 6.5 * 109 live Lactobacillus casei Shirota (LcS) in reducing the incidence of AAD/CDAD, and (2) whether undernutrition and proton pump inhibitors (PPI) are risk factors for AAD/CDAD. A total of 164 SCI patients (50.1 (sd 17.8) years) with a requirement for antibiotics (median 21 d, range 5-366) were randomly allocated to receive LcS (n 76) or no probiotic (n 82). LcS was given once daily for the duration of the antibiotic course and continued for 7 days thereafter. Nutritional risk was assessed by the Spinal Nutrition Screening Tool. The LcS group had a significantly lower incidence of AAD (17.1 v. 54.9%, P< 0.001). At baseline, 65% of patients were at undernutrition risk. Undernutrition (64.1 v. 33.3%, P< 0.01) and the use of PPI (38.4 v. 12.1 %, P= 0.022) were found to be associated with AAD. However, no significant difference was observed in nutrient intake between the groups. The multivariate logistic regression analysis identified poor appetite ( < 1/2 meals eaten) (OR 5.04, 95% CI 1.28, 19.84) and no probiotic (OR 8.46, 95% CI 3.22, 22.20) as the independent risk factors for AAD. The present study indicated that LcS could reduce the incidence of AAD in hospitalised SCI patients. A randomised, placebo-controlled study is needed to confirm this apparent therapeutic success in order to translate into improved clinical outcomes. PMID- 24044688 TI - Anthropogenic activities have contributed moderately to increased inputs of organic materials in marginal seas off China. AB - Sediment has been recognized as a gigantic sink of organic materials and therefore can record temporal input trends. To examine the impact of anthropogenic activities on the marginal seas off China, sediment cores were collected from the Yellow Sea, the inner shelf of the East China Sea (ECS), and the South China Sea (SCS) to investigate the sources and spatial and temporal variations of organic materials, i.e., total organic carbon (TOC) and aliphatic hydrocarbons. The concentration ranges of TOC were 0.5-1.29, 0.63-0.83, and 0.33 0.85%, while those of Sigman-C14-35 (sum of n-alkanes with carbon numbers of 14 35) were 0.08-1.5, 0.13-1.97, and 0.35-0.96 MUg/g dry weight in sediment cores from the Yellow Sea, ECS inner shelf, and the SCS, respectively. Terrestrial higher plants were an important source of aliphatic hydrocarbons in marine sediments off China. The spatial distribution of Sigman-C14-35 concentrations and source diagnostic ratios suggested a greater load of terrestrial organic materials in the Yellow Sea than in the ECS and SCS. Temporally, TOC and Sigman C14-35 concentrations increased with time and peaked at either the surface or immediate subsurface layers. This increase was probably reflective of elevated inputs of organic materials to marginal seas off China in recent years, and attributed partly to the impacts of intensified anthropogenic activities in mainland China. Source diagnostics also suggested that aliphatic hydrocarbons were mainly derived from biogenic sources, with a minority in surface sediment layers from petroleum sources, consistent with the above-mentioned postulation. PMID- 24044689 TI - Proteomic analysis profile of engineered articular cartilage with chondrogenic differentiated adipose tissue-derived stem cells loaded polyglycolic acid mesh for weight-bearing area defect repair. AB - The present study was designed to investigate the possibility of full-thickness defects repair in porcine articular cartilage (AC) weight-bearing area using chondrogenic differentiated autologous adipose-derived stem cells (ASCs) with a follow-up of 3 and 6 months, which is successive to our previous study on nonweight-bearing area. The isolated ASCs were seeded onto the phosphoglycerate/polylactic acid (PGA/PLA) with chondrogenic induction in vitro for 2 weeks as the experimental group prior to implantation in porcine AC defects (8 mm in diameter, deep to subchondral bone), with PGA/PLA only as control. With follow-up time being 3 and 6 months, both neo-cartilages of postimplantation integrated well with the neighboring normal cartilage and subchondral bone histologically in experimental group, whereas only fibrous tissue in control group. Immunohistochemical and toluidine blue staining confirmed similar distribution of COL II and glycosaminoglycan in the regenerated cartilage to the native one. A vivid remolding process with repair time was also witnessed in the neo-cartilage as the compressive modulus significantly increased from 70% of the normal cartilage at 3 months to nearly 90% at 6 months, which is similar to our former research. Nevertheless, differences of the regenerated cartilages still could be detected from the native one. Meanwhile, the exact mechanism involved in chondrogenic differentiation from ASCs seeded on PGA/PLA is still unknown. Therefore, proteome is resorted leading to 43 proteins differentially identified from 20 chosen two-dimensional spots, which do help us further our research on some committed factors. In conclusion, the comparison via proteome provided a thorough understanding of mechanisms implicating ASC differentiation toward chondrocytes, which is further substantiated by the present study as a perfect supplement to the former one in nonweight-bearing area. PMID- 24044690 TI - De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies. AB - BACKGROUND: Currently, diagnosis of affected individuals with rare genetic disorders can be lengthy and costly, resulting in a diagnostic odyssey and in many patients a definitive molecular diagnosis is never achieved despite extensive clinical investigation. The recent advent and use of genomic medicine has resulted in a paradigm shift in the clinical molecular genetics of rare diseases and has provided insight into the causes of numerous rare genetic conditions. In particular, whole exome and genome sequencing of families has been particularly useful in discovering de novo germline mutations as the cause of both rare diseases and complex disorders. CASE PRESENTATION: We present a six year old, nonverbal African American female with microcephaly, autism, global developmental delay, and metopic craniosynostosis. Exome sequencing of the patient and her two parents revealed a heterozygous two base pair de novo deletion, c.1897_1898delCA, p.Gln633ValfsX13 in ASXL3, predicted to result in a frameshift at codon 633 with substitution of a valine for a glutamine and introduction of a premature stop codon. CONCLUSIONS: We provide additional evidence that, truncating and frameshifting mutations in the ASXL3 gene are the cause of a newly recognized disorder characterized by severe global developmental delay, short stature, microcephaly, and craniofacial anomalies. Furthermore, we expand the knowledge about disease causing mutations and the genotype-phenotype relationships in ASXL3 and provide evidence that rare, nonsynonymous, damaging mutations are not associated with developmental delay or microcephaly. PMID- 24044691 TI - Trans-chalcone and quercetin down-regulate fatty acid synthase gene expression and reduce ergosterol content in the human pathogenic dermatophyte Trichophyton rubrum. AB - BACKGROUND: Fatty acid synthase (FAS) is a promising antifungal target due to its marked structural differences between fungal and mammalian cells. The aim of this study was to evaluate the antifungal activity of flavonoids described in the scientific literature as FAS inhibitors (quercetin, trans-chalcone, ellagic acid, luteolin, galangin, and genistein) against the dermatophyte Trichophyton rubrum and their effects on fatty acid and ergosterol synthesis. METHODS: The antifungal activity of the natural products was tested by the microdilution assay for determination of the minimum inhibitory concentration (MIC). The effect of the compounds on the cell membrane was evaluated using a protoplast regeneration assay. Ergosterol content was quantified by spectrophotometry. Inhibition of FAS by flavonoids was evaluated by an enzymatic assay to determine IC50 values. Quantitative RT-PCR was used to measure transcription levels of the FAS1 and ERG6 genes involved in fatty acid and ergosterol biosynthesis, respectively, during exposure of T. rubrum to the flavonoids tested. RESULTS: The flavonoids quercetin and trans-chalcone were effective against T. rubrum, with MICs of 125 and 7.5 MUg/mL for the wild-type strain (MYA3108) and of 63 and 1.9 MUg/mL for the ABC transporter mutant strain (DeltaTruMDR2), respectively. The MICs of the fluconazole and cerulenin controls were 63 and 125 MUg/mL for the wild-type strain and 30 and 15 MUg/mL for the mutant strain, respectively. Quercetin and trans-chalcone also reduced ergosterol content in the two strains, indicating that interference with fatty acid and ergosterol synthesis caused cell membrane disruption. The MIC of quercetin reduced the number of regenerated protoplasts by 30.26% (wild-type strain) and by 91.66% (mutant strain). Half the MIC (0.5 MIC) of quercetin did not reduce the number of regenerated wild-type fungal colonies, but caused a 36.19% reduction in the number of mutant strain protoplasts. In contrast, the MIC and 0.5 MIC of trans-chalcone and cerulenin drastically reduced protoplast regeneration in the two strains. The FAS1 gene was repressed in the presence of MICs of quercetin, trans-chalcone, fluconazole and cerulenin. The ERG6 gene was induced in the presence of MICs of fluconazole and cerulenin and was repressed in the presence of MICs of trans-chalcone and quercetin. Trans chalcone and quercetin inhibited the enzymatic activity of FAS, with IC50 values of 68.23 and 17.1 MUg/mL, respectively. CONCLUSION: Trans-chalcone and quercetin showed antifungal activity against T. rubrum, reducing ergosterol levels and modulating the expression of FAS1 and ERG6. PMID- 24044692 TI - Differential contributions of executive and episodic memory functions to problem solving in younger and older adults. AB - The relationship of higher order problem solving to basic neuropsychological processes likely depends on the type of problems to be solved. Well-defined problems (e.g., completing a series of errands) may rely primarily on executive functions. Conversely, ill-defined problems (e.g., navigating socially awkward situations) may, in addition, rely on medial temporal lobe (MTL) mediated episodic memory processes. Healthy young (N = 18; M = 19; SD = 1.3) and old (N = 18; M = 73; SD = 5.0) adults completed a battery of neuropsychological tests of executive and episodic memory function, and experimental tests of problem solving. Correlation analyses and age group comparisons demonstrated differential contributions of executive and autobiographical episodic memory function to well defined and ill-defined problem solving and evidence for an episodic simulation mechanism underlying ill-defined problem solving efficacy. Findings are consistent with the emerging idea that MTL-mediated episodic simulation processes support the effective solution of ill-defined problems, over and above the contribution of frontally mediated executive functions. Implications for the development of intervention strategies that target preservation of functional independence in older adults are discussed. PMID- 24044693 TI - Rotational spectrum and structure of cyclohexene oxide and the argon-cyclohexene oxide van der Waals complex. AB - The rotational spectra of cyclohexene oxide and its van der Waals complex with argon have been observed with a Balle-Flygare type pulsed jet Fourier transform microwave spectrometer in the 6 to 20 GHz region. This work improves the existing rotational and quartic centrifugal distortion constants of cyclohexene oxide, its six singly substituted (13)C, and the (18)O isotopologue. In addition, the (17)O isotopologue was observed in natural abundance. The quadrupole coupling constants for the (17)O isotopologue are chi(aa) = 8.855(5), chi(bb) = -4.560(4), and chi(cc) = -4.296(4) MHz. The argon-(12)C6H10(16)O complex has rotational constants of A = 2146.4825(2), B = 908.64292(8), and C = 859.00320(8) MHz. Additionally, the six unique singly substituted (13)C isotopologues of the argon complex are reported here. The position of the argon that is consistent with the parent and six (13)C complex rotational constants is above the ring on the side opposite the epoxide. PMID- 24044694 TI - Pharmaceutical application of frog skin on full-thickness skin wound healing in mice. AB - CONTEXT: It has been proved that fresh frog skin is efficient in the wound healing process. OBJECTIVE: The purpose of study is to introduce a formulation of frog skin powder for evaluation of wound repair where fresh frog skin is not available. MATERIALS AND METHODS: Rana ridibunda (Ranidae) skins were lyophilized, and a powder was prepared. The powder (0.0005 g) was then mixed with ointment (0.0065 g) for treating each wound. Formulation was used on full thickness wounds on mice (FO group) and compared to positive and negative controls. In order to study the wound healing process, wound contraction, inflammation, number of fibroblast cells, neovascularization and collagen density were evaluated on days 2, 4 and 6 following the injury. Moreover, CFU measurement was performed for the evaluation of wound contamination. RESULTS: Acceleration in wound contraction in the FO group compared to control groups was significant (p < 0.001) on days 4 and 6. Results showed that FO treatment considerably decreased inflammatory cells during the study. On day 4, FO treatment was significantly effective in increasing the number of fibroblast cells and collagen density (p < 0.01 and p < 0.05, respectively). On day 6 the number of fibroblast cells (p < 0.001), collagen density (p < 0.05) and neovascularization (p < 0.05), were higher in the FO group than the control groups. Results of CFU measurement demonstrated significant reduction of wound contamination in FO treated wounds on days 2 (p < 0.05) and 4 (p < 0.01). DISCUSSION AND CONCLUSION: Our findings indicated that the pharmaceutical form of frog skin used in this study has considerable healing and antibacterial effects on wounds. PMID- 24044695 TI - Experiments optimized for magic angle spinning and oriented sample solid-state NMR of proteins. AB - Structure determination by solid-state NMR of proteins is rapidly advancing as a result of recent developments of samples, experimental methods, and calculations. There are a number of different solid-state NMR approaches that utilize stationary samples, aligned samples, or magic angle spinning of unoriented "powder" samples, and depending on the sample and the experimental method they can emphasize the measurement of distances or angles, ideally both, as sources of structural constraints. Multidimensional correlation spectroscopy of low-gamma nuclei such as (15)N and (13)C is an important step for making resonance assignments and measurements of angular restraints in membrane proteins. However, the efficiency of coherence transfer predominantly depends upon the strength of the dipole-dipole interaction, and this can vary from site to site and between sample alignments, for example, during the mixing of (13)C and (15)N magnetization in stationary aligned and in magic angle spinning samples. Here, we demonstrate that the efficiency of polarization transfer can be improved by using adiabatic demagnetization and remagnetization techniques on stationary aligned samples, and proton assisted insensitive nuclei cross-polarization in magic angle sample spinning samples. The adiabatic cross-polarization technique provides an alternative mechanism for spin-diffusion experiments correlating (15)N/(15)N and (15)N/(13)C chemical shifts over large distances. Improved efficiency in cross polarization with 40-100% sensitivity enhancements is observed in proteins and single crystals, respectively. We describe solid-state NMR experimental techniques that are optimal for membrane proteins in liquid crystalline phospholipid bilayers under physiological conditions. The techniques are illustrated with data from single crystals both of peptides and of membrane proteins in phospholipid bilayers. PMID- 24044696 TI - Water networks contribute to enthalpy/entropy compensation in protein-ligand binding. AB - The mechanism (or mechanisms) of enthalpy-entropy (H/S) compensation in protein ligand binding remains controversial, and there are still no predictive models (theoretical or experimental) in which hypotheses of ligand binding can be readily tested. Here we describe a particularly well-defined system of protein and ligands--human carbonic anhydrase (HCA) and a series of benzothiazole sulfonamide ligands with different patterns of fluorination--that we use to define enthalpy/entropy (H/S) compensation in this system thermodynamically and structurally. The binding affinities of these ligands (with the exception of one ligand, in which the deviation is understood) to HCA are, despite differences in fluorination pattern, indistinguishable; they nonetheless reflect significant and compensating changes in enthalpy and entropy of binding. Analysis reveals that differences in the structure and thermodynamic properties of the waters surrounding the bound ligands are an important contributor to the observed H/S compensation. These results support the hypothesis that the molecules of water filling the active site of a protein, and surrounding the ligand, are as important as the contact interactions between the protein and the ligand for biomolecular recognition, and in determining the thermodynamics of binding. PMID- 24044697 TI - A teachable moment for providers and patients alike: contraceptive counseling when prescribing medications with teratogenic potential. PMID- 24044698 TI - Biodiversity into your hands - A call for a virtual global natural history 'metacollection'. AB - BACKGROUND: Many scientific disciplines rely on correct taxon delineations and identifications. So does a great part of the general public as well as decision makers. Researchers, students and enthusiastic amateurs often feel frustrated because information about species remains scattered, difficult to access, or difficult to decipher. Together, this affects almost anyone who wishes to identify species or verify identifications. Many remedies have been proposed, but we argue that the role of natural history collections remains insufficiently appreciated. We suggest using state-of-the-art mass imaging technology and to join forces to create a global natural history metacollection on the internet, providing access to the morphology of tens of millions of specimens and making them available for automated digital image analysis. DISCUSSION: Robotic high resolution imaging technology and fast (high performance) computer-based image stitching make it now feasible to digitize entire collection drawers typically used for arthropod collections, or trays or containers used for other objects. Resolutions of 500 megapixels and much higher are already utilized to capture the contents of 40x50 cm collection drawers, providing amazing detail of specimens. Flanked by metadata entry, this helps to create access to tens of thousands of specimens in days. By setting priorities and combining the holdings of the most comprehensive collections for certain taxa, drawer digitizing offers the unique opportunity to create a global, virtual metacollection.The taxonomic and geographic coverage of such a collection could never be achieved by a single institution or individual. We argue that by joining forces, many new impulses will emerge for systematic biology, related fields and understanding of biodiversity in general.Digitizing drawers containing unidentified, little curated specimens is a contribution towards the beginning of a new era of online curation. It also will help taxonomists and curators to discover and process the millions of "gems" of undescribed species hidden in museum accessions. SUMMARY: Our proposal suggests creating virtual, high-resolution image resources that will, for the first time in history, provide access for expert scientists as well as students and the general public to the enormous wealth of the world's natural history collections. We foresee that this will contribute to a better understanding, appreciation and increased use of biodiversity resources and the natural history collections serving this cause. PMID- 24044699 TI - The level of leisure time physical activity is associated with work ability-a cross sectional and prospective study of health care workers. AB - BACKGROUND: With increasing age, physical capacity decreases, while the need and time for recovery increases. At the same time, the demands of work usually do not change with age. In the near future, an aging and physically changing workforce risks reduced work ability. Therefore, the impact of different factors, such as physical activity, on work ability is of interest. Thus, the aim of this study was to evaluate the association between physical activity and work ability using both cross sectional and prospective analyses. METHODS: This study was based on an extensive questionnaire survey. The number of participants included in the analysis at baseline in 2004 was 2.783, of whom 2.597 were also included in the follow-up in 2006. The primary outcome measure was the Work Ability Index (WAI), and the level of physical activity was measured using a single-item question. In the cross-sectional analysis we calculated the level of physical activity and the prevalence of poor or moderate work ability as reported by the participants. In the prospective analysis we calculated different levels of physical activity and the prevalence of positive changes in WAI-category from baseline to follow-up. In both the cross sectional and the prospective analyses the prevalence ratio was calculated using Generalized Linear Models. RESULTS: The cross-sectional analysis showed that with an increased level of physical activity, the reporting of poor or moderate work ability decreased. In the prospective analysis, participants reporting a higher level of physical activity were more likely to have made an improvement in WAI from 2004 to 2006. CONCLUSIONS: The level of physical activity seems to be related to work ability. Assessment of physical activity may also be useful as a predictive tool, potentially making it possible to prevent poor work ability and improve future work ability. For employers, the main implications of this study are the importance of promoting and facilitating the employees' engagement in physical activity, and the importance of the employees' maintaining a physically active lifestyle. PMID- 24044700 TI - Electrooxidation of alcohols catalyzed by amino alcohol ligated ruthenium complexes. AB - Ruthenium transfer hydrogenation catalysts physisorbed onto edge-plane graphite electrodes are active electrocatalysts for the oxidation of alcohols. Electrooxidation of CH3OH (1.23 M) in a buffered aqueous solution at pH 11.5 with [(eta(6)-p-cymene)(eta(2)-N,O-(1R,2S)-cis-1-amino-2-indanol)]Ru(II)Cl (2) on edge plane graphite exhibits an onset current at 560 mV vs NHE. Koutecky-Levich analysis at 750 mV reveals a four-electron oxidation of methanol with a rate of 1.35 M(-1) s(-1). Mechanistic investigations by (1)H NMR, cyclic voltammetry, and desorption electrospray ionization mass spectrometry indicate that the electroxidation of methanol to generate formate is mediated by surface-supported Ru-oxo complexes. PMID- 24044701 TI - Deletion of the HAMP domains from the histidine kinase CaNik1p of Candida albicans or treatment with fungicides activates the MAP kinase Hog1p in S. cerevisiae transformants. AB - BACKGROUND: Microorganisms use two-component signal transduction (TCST) systems to regulate the response of the organism to changes of environmental conditions. Such systems are absent from mammalian cells and are thus of interest as drug targets. Fungal TCST systems are usually composed of a hybrid histidine kinase, comprising the histidine kinase (HisKA) domain and a receiver domain, a histidine phosphotransfer protein and a response regulator. Among the 11 groups of fungal histidine kinases, group III histidine kinases are of particular relevance as they are essential for the activity of different groups of fungicides. A characteristic feature is the N-terminal amino acid repeat domain comprising multiple HAMP domains, of which the function is still largely unknown. In Candida albicans, a fungal human pathogen, three histidine kinases were identified, of which CaNik1p is a group III histidine kinase. Heterologous expression of this protein in Sacchromyces cerevisiae conferred susceptibility to different fungicides. Fungicide activity was associated with phosphorylation of the mitogen activated protein kinase Hog1p. RESULTS: We have constructed mutated versions of CaNik1p, from which either all HAMP domains were deleted (CaNik1pDeltaHAMP) or in which the histidine kinase or the receiver domains were not-functional. Expression of CaNIK1DeltaHAMP in S. cerevisiae led to severe growth inhibition. Normal growth could be restored by either replacing the phosphate-accepting histidine residue in CaNik1pDeltaHAMP or by expressing CaNIK1DeltaHAMP in S. cerevisiae mutants, in which single genes encoding several components of the HOG pathway were deleted. Expression of proteins with non-functional histidine kinase or receiver domains resulted in complete loss of susceptibility to antifungals, such as fludioxonil. Conditions leading to growth inhibition of transformants also led to phosphorylation of the MAP kinase Hog1p. CONCLUSION: Our results show that functional histidine kinase and receiver domains of CaNik1p were essential for antifungal susceptibility and for activation of the Hog1p. Moreover, for the first time we show that deletion of all HAMP domains from CaNik1p led to activation of Hog1p without an external stimulus. This phenotype was similar to the effects obtained upon treatment with fungicides, as in both cases growth inhibition correlated with Hog1p activation and was dependent on the functionality of the conserved phosphate-accepting histidine residue. PMID- 24044702 TI - Expanding the use of patient reports about patient-centered care. AB - In an informative article on the assessment of patient care experiences, Zimlichman, Rozenblum, and Millenson describe the evolving use of surveys that elicit patient reports about medical care experiences in Israel, a trend that parallels developments in the U.S. This commentary summarizes some of experiences in the U.S. that might inform the development of more consistent and extensive strategies for assessing and promoting patient-centered care in Israel.More comprehensive patient experience surveys, the results of which would be publicly available, as Zimlichman and colleagues advocate, would facilitate quality improvements, especially if users are provided with support for the use and interpretation of the data. Developing more efficient survey methods will facilitate the broader use of such surveys, although it is important to use methods that yield results that are as representative of the target population as possible and to account for survey mode effects when data are reported. Although the surveys need to be appropriate for the Israeli context, the use of standard questions used in other countries would facilitate comparisons that could help to identify best practices that can be adopted in different settings. Those who work on assessing patient-centered care in the U.S. look forward to learning from the work of their Israeli colleagues.This is a commentary on http://www.ijhpr.org/content/2/1/35/. PMID- 24044703 TI - Five recent expert recommendations on the treatment of childhood and adolescent obesity: toward an emerging consensus--a stepped care approach. AB - BACKGROUND: Various organizations published five sets of expert recommendations recently: 2007 Healthcare Organizations' Four Stage Model; 2006 Canadian Clinical Practice Guidelines; 2008 The Endocrine Society Recommendations; 2009 Seven Step Model; and 2010 US Preventive Task Force Recommendations. METHODS: We compared the recommendations' approaches and conclusions pertaining to four treatments (self-help groups, outpatient cognitive-behavior therapy [CBT], immersion CBT, and surgery). RESULTS: All of the expert committees supported using intensive dietary, physical activity, and cognitive-behavioral counseling; two of the five groups discouraged reliance on educational interventions alone, and two of the groups explicitly promoted a stepped-care approach. CONCLUSIONS: Greatest benefits may accrue by encouraging healthcare providers and parents to view medical management and education as foundations to change, but to pursue increasingly intensive viable options until overweight and obese children make clinically significant progress toward improved health and happiness. PMID- 24044704 TI - Combination therapy for macular edema secondary to retinal vein occlusion. PMID- 24044705 TI - Electronic health records: future business applications: part 1 in a two-part series. PMID- 24044706 TI - A new paradigm for incorporating the joint statement screening guidelines for retinopathy of prematurity into clinical practice: outcomes from a quaternary referral program. AB - BACKGROUND AND OBJECTIVE: This study examines patient experience at a quaternary referral pediatric clinic with a retinopathy of prematurity (ROP) screening program that monitors infants at least on a weekly basis for any stage of ROP. PATIENTS AND METHODS: Admission records of 399 prematurely born patients treated at the Byers Eye Institute outpatient ROP clinic were retrospectively reviewed. Patients were categorized according to ROP status and whether they completed, canceled, or failed to show up for scheduled examinations. Demographic information was collected from medical records. RESULTS: Of 1,823 scheduled ROP related visits, 327 (17.9%) resulted in cancellations and 90 (4.9%) in no-shows, with 238 missed visits due to caregiver-related and 149 due to caregiver unrelated reasons. Of 399 total patients, 142 (35.6%) canceled or failed to show up for at least one appointment because of caregiver-related reasons. CONCLUSION: More than one-third of patients with ROP canceled or missed appointments. The true risk of delay is difficult to assess because all patients requiring treatment received it prior to discharge from the hospital. To achieve maximal compliance with joint statement guidelines on ROP screening, patients should be scheduled for examination earlier than recommended. PMID- 24044707 TI - Association between systemic anticoagulation and rate of intraocular hemorrhage following intravitreal anti-VEGF therapy for age-related macular degeneration. AB - BACKGROUND AND OBJECTIVE: To investigate the association between systemic anticoagulant medication usage at the time of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection with post-injection intraocular hemorrhage among patients with age-related macular degeneration (AMD). PATIENTS AND METHODS: Retrospective, consecutive case series of all patients treated with anti-VEGF injection for neovascular AMD at the Penn State Hershey Eye Center between 2004 and 2010: 1,710 anti-VEGF injections performed in 228 eyes of 191 patients. Each injection was analyzed according to whether the patient was taking systemic anticoagulant medication at the time of injection. RESULTS: Intraocular hemorrhage occurred after intravitreal anti-VEGF injection in four eyes (0.25%). Vitreous hemorrhage occurred in three patients taking systemic anticoagulation. Subretinal hemorrhage occurred in one patient not on anticoagulant therapy. In a bivariate analysis, the odds of intraocular hemorrhage are 1.9 times higher for injections performed in patients on systemic anticoagulation versus those not on systemic anticoagulation; this difference is not statistically significant. CONCLUSION: The rate of intraocular hemorrhage after intravitreal injection of anti-VEGF therapy among patients with AMD is low, and there is no significant difference between patients taking systemic anticoagulant medications at the time of injection and patients not on anticoagulation. PMID- 24044708 TI - Ocular hypertension and intraocular pressure asymmetry after intravitreal injection of anti-vascular endothelial growth factor agents. AB - BACKGROUND AND OBJECTIVE: To evaluate elevated intraocular pressure (IOP) after intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors and contribute toward the recognition and understanding of its mechanisms, pattern, and treatment. PATIENTS AND METHODS: Retrospective case series of VEGF inhibitor injections at two academic centers (Stanford University and Mayo Clinic) over 4 years. Cases were evaluated for IOP elevation (>= 24 mm Hg) or asymmetry (>= 3 mm Hg IOP difference between eyes on three visits). RESULTS: Twenty-one eyes were identified with pathologically elevated IOP after treatment. Most had delayed-onset (average: 15 months after treatment, after 10 injections) elevation. IOP-lowering therapy was required in 81%. More consecutive visits with IOP asymmetry occurred in patients developing ocular hypertension (11.1% pre diagnosis vs 66.7% post-diagnosis; OR = 9.00, P = .003). CONCLUSION: Elevated IOP may occur after ranibizumab or bevacizumab injections, often exhibiting a delayed and perhaps cumulative effect. The authors found significant bilateral IOP asymmetry in patients developing unilateral glaucoma after VEGF-inhibitor injections, a potential early indicator or proxy for pathologic IOP elevation. PMID- 24044709 TI - Micropulse diode laser treatment for chronic central serous chorioretinopathy: a randomized pilot trial. AB - BACKGROUND AND OBJECTIVE: To evaluate 810-nm subthreshold diode micropulse (SDM) laser in patients with chronic central serous chorioretinopathy (CSC). PATIENTS AND METHODS: Prospective, randomized, double-blind, sham-controlled pilot trial. Patients were randomized to SDM laser treatment (group 1) or sham procedure (group 2). Primary outcome measure was change in best corrected visual acuity (BCVA); secondary outcome was central macular thickness after 3 months. Laser treatment was performed along the detached area. At the 3-month visit, all patients were evaluated for re-treatment if they met re-treatment criteria. RESULTS: Fifteen patients were included in this study: five patients in the sham group and 10 in the treatment group. At 3 months, BCVA was significantly enhanced in the treatment group (P = .006) compared with the sham group (P = .498). All patients from the sham group needed treatment after 3 months. An improvement in central macular thickness and leakage on fluorescein angiography was noted in all treated patients (in both groups). CONCLUSION: In this limited-size, short-term exploratory study, SDM laser was effective in treating chronic CSC. There was no evidence of retinal damage induced by treatment. PMID- 24044710 TI - Hemorrhagic age-related macular degeneration managed with vitrectomy, subretinal injection of tissue plasminogen activator, gas tamponade, and upright positioning. AB - BACKGROUND AND OBJECTIVE: To investigate the outcomes of vitrectomy, subretinal tissue plasminogen (tPA) injection, gas tamponade, and upright positioning in patients with hemorrhagic neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: Retrospective, noncomparative case series. Records of patients who were diagnosed with submacular hemorrhage secondary to neovascular AMD and underwent treatment with the combined method between 2004 and 2010 were reviewed. The main outcome measure was the difference between preoperative and post-operative best corrected visual acuity (BCVA). RESULTS: In 10 eyes of 10 patients, mean preoperative and postoperative BCVA values were 1.75 and 1.23 logMAR, respectively (P = .011), after a mean follow-up time of 38.7 +/- 26.5 months (range: 10 to 71 months). Eight of 10 patients (80%) gained at least three lines. CONCLUSION: In patients with hemorrhagic neovascular AMD, treatment with vitrectomy, subretinal tPA injection, gas tamponade, and upright positioning was associated with better visual outcomes than those reported for patients with untreated disease. PMID- 24044711 TI - Amniotic membrane corneal buffering during plaque radiation therapy for anterior uveal melanoma. AB - BACKGROUND AND OBJECTIVE: To report results after amniotic membrane-protected epicorneal plaque brachytherapy for anterior uveal melanoma. PATIENTS AND METHODS: Sixty-three patients were treated with epicorneal radioactive plaques for 5 to 7 days. To prevent corneal damage, eye irritation, and reduce pain, 0.1 mm-thick fresh-frozen amniotic membrane grafts were interposed between the plaque and the cornea during brachytherapy. All amniotic membranes were removed at the end of brachytherapy. Patients were questioned about subjective comfort during treatment and observed for clinical outcomes. RESULTS: Only 4.8% of patients reported pain during brachytherapy. Short-term brachytherapy-related corneal complications including mild keratopathy, corneal epithelial defect, and edema were noted in 41.3% of patients. All corneal complications resolved within 2 weeks. No patients developed corneal melting or opacity during a mean follow-up of 28 months. Local tumor control was achieved in 95.2%. CONCLUSION: Amniotic membrane-buffered epicorneal plaque therapy provided comfort and excellent local tumor control. PMID- 24044712 TI - Novel retrobulbar anesthesia technique through the sub-Tenon's space using a sharp needle in a blunt cannula. AB - BACKGROUND AND OBJECTIVE: The authors developed a new technique for retrobulbar anesthesia and compared it with the conventional transcutaneous method in 223 eyes undergoing vitrectomy. PATIENTS AND METHODS: In the new technique, a 24-mm long 19-gauge curved cannula with a 27-gauge straight needle with an oval tip was inserted into the sub-Tenon's space, and then the oval-tipped needle was replaced with a 50-mm-long 25-gauge curved needle. Anesthetic was then injected into the muscle cone from the syringe. The authors compared 118 eyes undergoing vitrectomy with the new technique and 105 eyes undergoing the procedure with conventional anesthesia. RESULTS: The pain scores were 0.1 +/- 0.32 for the new technique and 1.57 +/- 0.73 for the conventional technique (P < .001). Additional anesthetic required was 0.1 +/- 0.33 mL using the new technique and 0.3 +/- 0.68 mL using the conventional method (P = .03). CONCLUSION: This novel approach to retrobulbar anesthesia using a guarded cannula is safe and effective, causing less pain than the conventional technique. PMID- 24044713 TI - Suction-based grasping tool for removal of regular- and irregular-shaped intraocular foreign bodies. AB - BACKGROUND AND OBJECTIVE: To describe a suction-based grasping tool for the surgical removal of irregular-shaped and nonferromagnetic intraocular foreign bodies. MATERIALS AND METHODS: A surgical tool with suction capabilities, consisting of a stainless steel shaft with a plastic handle and a customizable and interchangeable suction tip, was designed in order to better engage and manipulate irregular-shaped in-traocular foreign bodies of various sizes and physical properties. The maximal suction force and surgical capabilities were assessed in the laboratory and on a cadaveric eye vitrectomy model. RESULTS: The suction force of the water-tight seal between the intraocular foreign body and the suction tip was estimated to be approximately 40 MN. During an open-sky vitrectomy in a porcine model, the device was successful in engaging and firmly securing foreign bodies of different sizes and shapes. CONCLUSION: The suction based grasping tool enables removal of irregular-shaped and nonferromagnetic foreign bodies. PMID- 24044714 TI - Intra-arterial chemotherapy for group C retinoblastoma with adjacent high-flow infantile hemangioma. AB - Intra-arterial chemotherapy for retinoblastoma is an emerging technique that is being adopted at various centers worldwide. The authors report the first case of an infantile hemangioma that shunted flow during intra-arterial chemotherapy in a 4-month-old girl who presented with macular group C retinoblastoma. Excellent tumor response was noted despite only a fraction of the dose entering the central retinal artery. Further studies to examine intra-arterial chemotherapy's pharmacokinetics and dose-response relations are warranted in order to minimize the necessary exposure to chemotherapy. PMID- 24044715 TI - Acute exudative polymorphous vitelliform maculopathy in a patient with Lyme disease. AB - Acute exudative polymorphous vitelli-form maculopathy (AEPVM) is a rare condition of unclear etiology that has been seen in association with respiratory and viral infections. It has also been reported as a paraneoplastic phenomenon in older individuals. The authors report the first case of AEPVM associated with Lyme disease with over 3.5 years of follow-up. Multimodality serial imaging suggested the lesions began as multiple serous detachments followed by accumulation of photoreceptor outer segments in the subretinal space that gradually resolved over time and gave rise to the characteristic fundus findings at various stages. PMID- 24044716 TI - Spontaneous improvement of macular traction retinal detachment associated with myopic macular schisis. AB - High myopia can be associated with a range of pathologic changes within the macula that are now easily appreciated with optical coherence tomography. In the setting of high myopia and a macular traction retinal detachment, the expectation is for progressive worsening over time, and surgical intervention is often undertaken early. The authors present a case of spontaneous improvement of myopic macular detachment, which illustrates the potential value of an initial period of observation in this clinical setting. PMID- 24044717 TI - Spontaneous anatomical and visual improvement in myopic macular retinoschisis. AB - Myopic macular retinoschisis is a source of visual impairment in patients with high myopia. Many patients present with progressive visual loss or increasing distortion. Some eyes progress to macular hole or foveal retinal detachment, causing further vision loss. The mechanisms for development of myopic macular retinoschisis have been postulated to be from tractional forces exerted on the inner retina, either anteriorly from a shortened internal limiting membrane and the retinal vessels or posteriorly from staphylomatous changes. Surgical intervention is often indicated for patients with declining visual function. The authors report a case of myopic macular retinoschisis that spontaneously improved without surgical intervention. PMID- 24044718 TI - The use of pars plana vitrectomy in the treatment of a serous retinal detachment secondary to lupus choroidopathy. AB - This report describes the use of pars plana vitrectomy (PPV) in the management of a patient with a serous retinal detachment (SRD) secondary to lupus choroidopathy. Surgery was performed after anti-inflammatory treatments and laser photocoagulation failed to resolve the condition. The patient's vision improved, and the subretinal fluid has not reaccumulated at 5 years postoperatively. The high viscosity of the subretinal fluid observed during the procedure may account for the persistence of the SRD despite control of inflammation. PPV surgery can be considered as a treatment option for patients with lupus-related SRD when anti inflammatory medications are not successful and the subretinal fluid does not reabsorb independently. PMID- 24044719 TI - Reversal of paracentral occlusive retinopathy in a case of sickle cell disease using exchange transfusion. AB - Paracentral occlusive retinopathy is an uncommon manifestation of sickle cell disease. If macular ischemia is not reversed, permanent vision loss can result. The authors report the successful use of exchange transfusion to treat unilateral paracentral occlusive retinopathy secondary to sickle cell disease in a 23-year old man with hemoglobin SS disease. Initial presentation demonstrated arteriolar occlusion, perivenous hemorrhages, vessel tortuosity, and areas of retinal ischemia. Visual acuity was count fingers, and the patient noted a paracentral scotoma. Following transfusion, there was restoration of arteriolar flow as documented with fluorescein angiogram, and visual acuity returned to 20/20. PMID- 24044720 TI - Epiretinal macular edema associated with thick epiretinal membranes. AB - High-resolution imaging with spectral-domain optical coherence tomography has identified an unusual group of epiretinal membranes (ERMs) in the presence of lamellar macular holes. These ERMs are unusually thick. The authors present the case of a patient with age-related macular degeneration who developed edema within a thickened ERM in both eyes after cataract surgery. The edema resolved with anti-vascular endothelial growth factor (VEGF) therapy. The authors propose that the VEGF-responsive fluid within these thick ERMs arose from fibrovascular tissue derived from the retina. Further studies with histopathology will be required to determine whether neovascular tissue is present in all cases of thickened ERMs with epiretinal edema. PMID- 24044721 TI - Eight questions with Dr. Puliafito. PMID- 24044722 TI - Carcinoma ex pleomorphic adenoma of the upper lip: a case of an unusual malignant component of squamous cell carcinoma. AB - BACKGROUND: Squamous cell carcinoma (SCC) as the malignant component of carcinoma ex pleomorphic adenoma (CXPA) occurring in upper lip is rare. CASE REPORT: A 55 year-old male patient presented with an asymptomatic mass of the upper lip that had noticed 8 years previously. The mass was clinically suspected to be a benign salivary gland tumor based on palpation and magnetic resonance imaging findings. A needle biopsy was then carried out, and the pathological diagnosis was pleomorphic adenoma. The tumor was removed under general anesthesia. Histopathological examination revealed well-demarcated tumor tissues showing typical histologic features of pleomorphic adenoma. However, SCC tissue with several mitotic figures was found in the central area of the tumor tissue. The tumor was finally diagnosed as CXPA. There was no evidence of recurrence or metastasis 6 years postoperatively. CONCLUSION: This is the first report of CXPA of the upper lip with an unusual malignant component of SCC. PMID- 24044723 TI - Regioselective synthesis of 1,2-dihydroquinolines by a solvent-free MgBr2 catalyzed multicomponent reaction. AB - A highly efficient and regioselective synthesis of 1,2-dihydroquinolines via a multicomponent reaction between an aniline and two ketones is described. This reaction was catalyzed by magnesium bromide and carried out under solvent-free conditions. When the reaction was performed by using 3-substituted anilines and nonsymmetrically substituted ketones, principally a single product was found among the four expected regioisomers. A variety of anilines and ketones, including cyclic ketones, were evaluated providing a series of 1,2 dihydroquinolines with diverse substitution patterns. A study of the mechanism is discussed. There is evidence of the in situ formation of the imine as a result of the reaction between the aniline and one of the ketones, before annulation to the heterocyclic ring. PMID- 24044725 TI - Inter- and intraspecific interactions in two mealybug predators Spalgis epius and Cryptolaemus montrouzieri in the presence and absence of prey. AB - Spalgis epius and Cryptolaemus montrouzieri are the two potential predators of different species of mealybugs. However, the mode of their interactions is not known to use these predators together in the field. Hence, we investigated on the possible interactions i.e., cannibalism, intraguild predation (IGP) and competition between the predators in the presence and absence of prey Planococcus citri. In the presence of prey, no cannibalism and predation were observed in both S. epius and C. montrouzieri larvae. A pair of S. epius larvae consumed significantly more number of mealybugs than one S. epius/C. montrouzieri larva or a pair of C. montrouzieri larvae. The predation of S. epius larva by C. montrouzieri larva was significantly more than the predation of C. montrouzieri by S. epius. Conspecific and interspecific egg predation was absent both in S. epius and C. montrouzieri. Cannibalism in C. montrouzieri was more than that in S. epius. The study indicated that C. montrouzieri larvae can be used as an additive along with voracious S. epius larvae under abundant prey population. IGP was asymmetric between the two predators in the absence of prey. Both S. epius and C. montrouzieri larvae can maintain a stable coexistence when prey is abundantly available, however, in the complete absence of prey C. montrouzieri may dominate the guild. This study provides an insight into the possible complex inter- and intraspecific predatory phenomena in the field to use these two predators in the biological control of mealybugs. PMID- 24044724 TI - Effects of HO-/MeO-PBDEs on androgen receptor: in vitro investigation and helix 12-involved MD simulation. AB - Hydroxylated and methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) have received increasing attention for their potential endocrine disrupting activities and widely environmental distribution. However, little information is available for the anti-androgenic activities, and the molecular mechanism of interactions with androgen receptor (AR) is not fully understood. In the present study, cell line assay and computational simulation were integrated to systematically explore the molecular mechanism of interactions between chemicals and AR. The metabolites with similar molecular structures exhibited different anti-androgenic activity while none of them showed androgenic activity. According to the multisystem molecular dynamics simulation, minute differences in the structure of ligands induced dramatic different conformational transition of AR-ligand binding domain (LBD). The Helix12 (H12) component of active ligands occupied AR-LBD could become stable, but this component continued to fluctuate in inactive ligands occupied AR LBD. Settling time and reposition of H12 obtained in dynamics process are important factors governing anti-androgenic activities. The related settling times were characteristic of anti-androgenic potencies of the tested chemicals. Overall, in our study, the stable reposition of H12 is characterized as a computational mark for identifying AR antagonists from PBDE metabolites, or even other various environmental pollutants. PMID- 24044726 TI - Similar hyaline-like cartilage repair of osteochondral defects in rabbits using isotropic and anisotropic collagen scaffolds. AB - Lesions in knee joint articular cartilage (AC) have limited repair capacity. Many clinically available treatments induce a fibrous-like cartilage repair instead of hyaline cartilage. To induce hyaline cartilage repair, we hypothesized that type I collagen scaffolds with fibers aligned perpendicular to the AC surface would result in qualitatively better tissue repair due to a guided cellular influx from the subchondral bone. By specific freezing protocols, type I collagen scaffolds with isotropic and anisotropic fiber architectures were produced. Rabbits were operated on bilaterally and two full thickness defects were created in each knee joint. The defects were filled with (1) an isotropic scaffold, (2) an anisotropic scaffold with pores parallel to the cartilage surface, and (3) an anisotropic scaffold with pores perpendicular to the cartilage surface. Empty defects served as controls. After 4 (n=13) and 12 (n=13) weeks, regeneration was scored qualitatively and quantitatively using histological analysis and a modified O'Driscoll score. After 4 weeks, all defects were completely filled with partially differentiated hyaline cartilage tissue. No differences in O'Driscoll scores were measured between empty defects and scaffold types. After 12 weeks, all treatments led to hyaline cartilage repair visualized by increased glycosaminoglycan staining. Total scores were significantly increased for parallel anisotropic and empty defects over time (p<0.05). The results indicate that collagen scaffolds allow the formation of hyaline-like cartilage repair. Fiber architecture had no effect on cartilage repair. PMID- 24044727 TI - Qualities of an effective teacher: what do medical teachers think? AB - BACKGROUND: Effective teaching in medicine is essential to produce good quality doctors. A number of studies have attempted to identify the characteristics of an effective teacher. However, most of literature regarding an effective medical teacher includes student ratings or expert opinions. Furthermore, interdisciplinary studies for the same are even fewer. We did a cross-sectional study of the characteristics of effective teachers from their own perspective across medicine and dentistry disciplines. METHODS: A questionnaire comprising of 24 statements relating to perceived qualities of effective teachers was prepared and used. The study population included the faculty of medicine and dentistry at the institution. Respondents were asked to mark their response to each statement based on a 5-point Likert scale ranging from strongly disagree to strongly agree. These statements were grouped these into four main subgroups, viz. Class room behaviour/instructional delivery, interaction with students, personal qualities and professional development, and analysed with respect to discipline, cultural background, gender and teaching experience using SPSS v 13.0. For bivariate analysis, t-test and one way ANOVA were used. Multiple linear regression for multivariate analysis was used to control confounding variables. RESULTS: The top three desirable qualities of an effective teacher in our study were knowledge of subject, enthusiasm and communication skills. Faculty with longer teaching experienced ranked classroom behaviour/instructional delivery higher than their less experienced counterparts. There was no difference of perspectives based on cultural background, gender or discipline (medicine and dentistry). CONCLUSION: This study found that the faculty perspectives were similar, regardless of the discipline, gender and cultural background. Furthermore, on review of literature similar findings are seen in studies done in allied medical and non-medical fields. These findings support common teacher training programs for the teachers of all disciplines, rather than having separate training programs exclusively for medical teachers. Logistically, this would make it much easier to arrange such programs in universities or colleges with different faculties or disciplines. PMID- 24044729 TI - Prospective memory in Parkinson's disease: a meta-analysis. AB - Prospective memory (PM) refers to the ability to remember to carry out an intended action in the future and it is pervasive in our daily living. A failure to execute an intended action (e.g., take medication) at the appropriate juncture in future (e.g., after dinner) can negatively affect our daily functioning and at times, may have devastating effects (e.g., forgetting to turn off the gas stove before leaving the house). Patients with Parkinson's disease (PD) exhibit widespread cognitive deficits including deficits in PM. The present study provides a meta-analytic review of PM in PD. Results across nine studies indicated time and event-based PM to be similarly impaired in PD, with time-based PM compromised to a slightly larger extent (Hedges' g = -0.71) as compared to event-based PM (Hedges' g = -0.55). The impairment in PM is more likely due to failure in self-initiated retrieval of intention to be executed, rather than forgetting the content of the intention itself. Furthermore, factors such as intervening task complexity and the mediating role of other executive functions have also been proposed to be responsible for impaired PM in PD. PMID- 24044728 TI - Triallelic relationships between the serotonin transporter polymorphism and cognition among healthy older adults. AB - The biallelic serotonin transporter polymorphism (5-hydroxytryptamine transporter linked polymorphic region (5-HTTLPR)) is a common genetic sequence associated with serotonin transporter (5-hydroxytryptamine transporter (5-HTT)) expression, which is further modulated by a triallelic single-nucleotide polymorphism (rs25531). Recent studies using the biallelic 5-HTTLPR have identified a beneficial role of low 5-HTT expression on cognitive performance, although no studies have examined the impact of the triallelic 5-HTTLPR/rs25531 marker on cognitive performance among healthy older adults. In the present study, we addressed this issue in 84 healthy older adults genotyped for biallelic and triallelic variants of 5-HTT. Groups were created based on low, medium and high levels of expression, as indicated by the triallelic marker. Results indicated that individuals with low 5-HTT expression performed significantly better on a test of memory compared with individuals with medium 5-HTT expression. This suggests that possession of low-expressing genetic variants of 5-HTT is modestly associated with enhanced cognitive performance among healthy older adults. PMID- 24044730 TI - Risk of retained placenta in women previously delivered by caesarean section: a population-based cohort study. AB - OBJECTIVE: To evaluate whether women with a caesarean section at their first delivery have an increased risk of retained placenta at their second delivery. DESIGN: Population-based cohort study. SETTING: Sweden. POPULATION: All women with their first and second singleton deliveries in Sweden during the years 1994 2006 (n = 258,608). Women with caesarean section or placental abruption in their second pregnancy were not included in the study population. METHODS: The risk of retained placenta at second delivery was estimated for women with a first delivery by caesarean section (n = 19,458), using women with a first vaginal delivery as reference (n = 239,150). Risks were calculated as odds ratios by unconditional logistic regression analysis with 95% confidence intervals (95%) after adjustments for maternal, delivery, and infant characteristics. MAIN OUTCOME MEASURES: Retained placenta with normal (<=1000 ml) and heavy (>1000 ml) bleeding. RESULTS: The overall rate of retained placenta was 2.07%. In women with a previous caesarean section and in women with previous vaginal delivery, the corresponding rates were 3.44% and 1.96%, respectively. Compared with women with a previous vaginal delivery, women with a previous caesarean section had an increased risk of retained placenta (adjusted OR 1.45; 95% CI 1.32-1.59), and the association was more pronounced for retained placenta with heavy bleeding (adjusted OR 1.61; 95% CI 1.44-1.79). CONCLUSIONS: Our report shows an increased risk for retained placenta in women previously delivered by caesarean section, a finding that should be considered in discussions of mode of delivery. PMID- 24044731 TI - Inhibitors of alpha-glucosidase and alpha-amylase from Cyperus rotundus. AB - CONTEXT: A methanol extract of Cyperus rotundus L. (Cyperaceae) rhizomes showed inhibitory activity against alpha-glucosidase and alpha-amylase, two enzymes involve in carbohydrate digestion. OBJECTIVE: Identification of compounds from C. rotundus rhizomes responsible for the inhibition of alpha-glucosidase and alpha amylase. MATERIALS AND METHODS: Compounds were identified by a phytochemical investigation using combined chromatographic and spectroscopic methods. alpha glucosidase and alpha-amylase inhibitory activities were evaluated by in vitro enzyme inhibition assays. RESULTS: A new (2RS,3SR)-3,4',5,6,7,8 hexahydroxyflavane (1), together with three known stilbene dimers cassigarol E (2), scirpusin A (3) and B (4) were isolated. Compound 2 inhibited both alpha glucosidase and alpha-amylase activities while the flavane 1 only showed effect on alpha-amylase, and compounds 3 and 4 were active on alpha-glucosidase. All four compounds showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity. DISCUSSION: The inhibitory activities against alpha-amylase and alpha glucosidase of the C. rotundus rhizomes were reported for the first time. Stilbene dimers are considered as potent inhibitors of alpha-glucosidase and promising antihyperglycemic agents. CONCLUSION: The isolated compounds may contribute to the antidiabetic property of C. rotundus. PMID- 24044732 TI - Intramolecular charge transfer and solvation dynamics of thiolate-protected Au20(SR)16 clusters studied by ultrafast measurement. AB - It is accepted that the monolayer ligand shell in monolayer-protected gold nanoclusters (MPCs) plays an important role in stabilizing the metal core structure. Previous reports have shown that the core and shell do not interact chemically, and very few studies investigating the intramolecular charge transfer (ICT) between the core and ligand shell in clusters have been reported. The underlying excited state relaxation mechanisms about the influence of solvents, the optically excited vibration, and the roles of the core and shell in charge transfer remain unknown to a large extent. Here we report a femtosecond transient absorption study of a Au20(SR)16 (R = CH2CH2Ph) cluster in toluene and tetrahydrofuran. The ICT from the outside shell to the inside core upon excitation in Au20(SR)16 is identified. The observed solvation-dependent oscillations in different solvents further confirm the photoinduced ICT formation in Au20(SR)16. The results provide a fundamental understanding of the structure property relationships about the solvation-dependent core-shell interaction in Au MPCs. PMID- 24044733 TI - Expansion and internal friction in unfolded protein chain. AB - Similarities in global properties of homopolymers and unfolded proteins provide approaches to mechanistic description of protein folding. Here, hydrodynamic properties and relaxation rates of the unfolded state of carbonmonoxide-liganded cytochrome c (cyt-CO) have been measured using nuclear magnetic resonance and laser photolysis methods. Hydrodynamic radius of the unfolded chain gradually increases as the solvent turns increasingly better, consistent with theory. Curiously, however, the rate of intrachain contact formation also increases with an increasing denaturant concentration, which, by Szabo, Schulten, and Schulten theory for the rate of intramolecular contact formation in a Gaussian polymer, indicates growing intramolecular diffusion. It is argued that diminishing nonbonded atom interactions with increasing denaturant reduces internal friction and, thus, increases the rate of polypeptide relaxation. Qualitative scaling of the extent of unfolding with nonbonded repulsions allows for description of internal friction by a phenomenological model. The degree of nonbonded atom interactions largely determines the extent of internal friction. PMID- 24044734 TI - Intimate binding mechanism and structure of trigonal nickel(I) monocarbonyl adducts in ZSM-5 zeolite-spectroscopic continuous wave EPR, HYSCORE, and IR studies refined with DFT quantification of disentangled electron and spin density redistributions along sigma and pi channels. AB - Interaction of tetracoordinated nickel(I) centers generated inside the channels of ZSM-5 zeolite with carbon monoxide ((12,13)CO, pCO < 1 Torr) led to the formation of T-shaped, top-on monocarbonyl adducts with a unique trigonal nickel core, supported by two oxygen donor ligands. The mechanism of the formation of the {Ni(I)-CO}ZSM-5 species was accounted for by a quantitative molecular orbital correlation diagram of CO ligation. Detailed electronic and magnetic structure of this adduct was obtained from comprehensive DFT calculations, validated by quantitative reproduction of its continuous wave electron paramagnetic resonance (CW-EPR), hyperfine sublevel correlation (HYSCORE), and IR fingerprints, using relativistic Pauli and ZORA-SOMF/B3LYP methods. Molecular analysis of the stretching frequency, nuCO = 2109 cm(-1), g and A((13)C) tensors (g(xx) = 2.018, g(yy) = 2.380, g(zz) = 2.436, A(xx) = +1.0 +/- 0.3 MHz, A(yy) = -3.6 +/- 0.9 MHz, A(zz) = -1.6 +/- 0.3 MHz) and Q((27)Al) parameters (e(2)Qq/h = -13 MHz and eta = 0.8) supported by quantum chemical modeling revealed that the Ni-CO bond results from the pi overlap between the low-laying pi(2p) CO states with the 3d(xz) and 3d(yz) orbitals, with a small sigma contribution due to the overlap of sigma(2p+2s) orbital and a protruding lobe of the in-plane 3d(xz) orbital. Two types of orbital channels (associated with the sigma and pi overlap) of the electron and spin density flows within the {Ni(I)-CO} unit were identified. A bathochromic shift of the nuCO stretching vibration was accounted for by resolving quantitatively the separate contributions due to the sigma donation and pi back-donation, whereas the (13)C hyperfine coupling was rationalized by incongruent alpha and beta spin flows via the sigma and pi channels. As a result the very nature of the carbon-metal bond in the Ni(I)-CO adduct and the molecular backbone of the corresponding spectroscopic parameters were revealed with unprecedented accuracy. PMID- 24044735 TI - Shape alloys of nanorods and nanospheres from self-assembly. AB - Mixtures of anisotropic nanocrystals promise a great diversity of superlattices and phase behaviors beyond those of single-component systems. However, obtaining a colloidal shape alloy in which two different shapes are thermodynamically coassembled into a crystalline superlattice has remained a challenge. Here we present a joint experimental-computational investigation of two geometrically ubiquitous nanocrystalline building blocks-nanorods and nanospheres-that overcome their natural entropic tendency toward macroscopic phase separation and coassemble into three intriguing phases over centimeter scales, including an AB2 type binary superlattice. Monte Carlo simulations reveal that, although this shape alloy is entropically stable at high packing fraction, demixing is favored at experimental densities. Simulations with short-ranged attractive interactions demonstrate that the alloy is stabilized by interactions induced by ligand stabilizers and/or depletion effects. An asymmetry in the relative interaction strength between rods and spheres improves the robustness of the self-assembly process. PMID- 24044736 TI - Is ecological speciation a major trend in aphids? Insights from a molecular phylogeny of the conifer-feeding genus Cinara. AB - INTRODUCTION: In the past decade ecological speciation has been recognized as having an important role in the diversification of plant-feeding insects. Aphids are host-specialised phytophagous insects that mate on their host plants and, as such, they are prone to experience reproductive isolation linked with host plant association that could ultimately lead to species formation. The generality of such a scenario remains to be tested through macroevolutionary studies. To explore the prevalence of host-driven speciation in the diversification of the aphid genus Cinara and to investigate alternative modes of speciation, we reconstructed a phylogeny of this genus based on mitochondrial, nuclear and Buchnera aphidicola DNA sequence fragments and applied a DNA-based method of species delimitation. Using a recent software (PhyloType), we explored evolutionary transitions in host-plant genera, feeding sites and geographic distributions in the diversification of Cinara and investigated how transitions in these characters have accompanied speciation events. RESULTS: The diversification of Cinara has been constrained by host fidelity to conifer genera sometimes followed by sequential colonization onto different host species and by feeding-site specialisation. Nevertheless, our analyses suggest that, at the most, only half of the speciation events were accompanied by ecological niche shifts. The contribution of geographical isolation in the speciation process is clearly apparent in the occurrence of species from two continents in the same clades in relatively terminal positions in our phylogeny. Furthermore, in agreement with predictions from scenarios in which geographic isolation accounts for speciation events, geographic overlap between species increased significantly with time elapsed since their separation. CONCLUSIONS: The history of Cinara offers a different perspective on the mode of speciation of aphids than that provided by classic models such as the pea aphid. In this genus of aphids, the role of climate and landscape history has probably been as important as host plant specialisation in having shaped present-day diversity. PMID- 24044737 TI - The odd man out in Sub-Saharan Africa: understanding the tobacco use prevalence in Madagascar. AB - BACKGROUND: The tobacco industry has globalized and tobacco use continues to increase in low- and middle-income countries. Yet, the data and research to inform policy initiatives for addressing this phenomenon is sparse. This study aims to estimate the prevalence of adult tobacco use in 17 Sub-Saharan Africa (SSA) countries, and to identify key factors associated with adult tobacco consumption choices (smoked, smokeless tobacco and dual use) in Madagascar. METHODS: We used Demographic Health Survey for estimating tobacco use prevalence among adults in SSA. A multinomial logistic regression model was used to identify key determinants of adult tobacco consumption choices in Madagascar. RESULTS: While differences in tobacco use exist in SSA, Madagascar has exceptionally higher prevalence rates (48.9% of males; 10.3% of females). The regression analyses showed complexity of tobacco use in Madagascar and identified age, education, wealth, employment, marriage, religion and place of residence as factors significantly associated with the choice of tobacco use among males, while age, wealth, and employment were significantly associated with that of females. The effects, however, differ across the three choices of tobacco use compared to non-use. CONCLUSIONS: Tobacco use in Madagascar was higher than the other 16 SSA countries. Although the government continues to enact policies to address the problem, there is a need for effective implementation and enforcement. There is also the need for health education to modify social norms and denormalize tobacco use. PMID- 24044739 TI - A two-dimensional polymer from the anthracene dimer and triptycene motifs. AB - A two-dimensional polymer (2DP) based on the dimerization of anthraceno groups arranged in a triptycene motif is reported. A photoinduced polymerization is performed in the crystalline state and gives a lamellar 2DP via a crystal-to crystal (but not single-crystal to single-crystal) transformation. Solvent induced exfoliation provides monolayer sheets of the 2DP. The 2DP is considered to be a tiling, a mathematical approach that facilitates structural elucidation. PMID- 24044740 TI - Female physicians: trends and likely impacts on healthcare in Israel. AB - BACKGROUND: Female physicians have become an increasing proportion of the medical workforce in Israel. This study investigates this trend and discusses its likely impact on the quantity and quality of medical care available. METHOD: Data on licensed physicians and new licenses issued to physicians were taken from a Ministry of Health database, and analyzed by gender, age, academic origin (Israeli graduates, immigrants, Israeli-born who studied abroad), and specialty for the years 1999-2011.Data on employed physicians, their population group, and work hours were taken from the Central Bureau of Statistics (CBS) annual Labour Force Survey for the years 2009-2011. RESULTS: The proportion of women amongst physicians aged under 65 rose from 38% in 1999 to 42% in 2011, and was even higher for younger physicians. The highest proportion of females is found amongst new immigrant physicians who studied abroad. The corresponding proportion has been rising steadily amongst Israeli-educated physicians, and is lowest amongst Israeli-born physicians who studied abroad.Similarly, among newly licensed physicians, the proportion of females has traditionally been highest among immigrants who studied abroad and lowest among Israeli-born graduates who studied abroad. Among newly-licensed physicians who studied in Israel, the proportion of females has historically been intermediate between the other two groups, but it has recently risen to 54% and now parallels the proportion of females among immigrants who studied abroad. In recent years, the mix of academic origins among newly licensed physicians has changed dramatically, with important implications for the proportion of women among newly licensed physicians.The highest percentage of females was found in family medicine followed by oncology, pediatrics and psychiatry. The greatest increase over the years in this percentage was for gynecology and internal medicine.Female physicians worked shorter hours than males, particularly at younger ages. The proportion of females among employed Arab physicians is much lower than among Jewish physicians. CONCLUSIONS: The proportion of female physicians has been steadily rising, although in recent years the increase has leveled off. This has been due, in part, to the decline in the flow of immigrant physicians and the increase in the number of Israelis studying abroad. Future developments in medical education options and immigration will determine whether their proportion will continue rising. Planning for future medical personnel must take these results into consideration. PMID- 24044741 TI - Surface glycosaminoglycans mediate adherence between HeLa cells and Lactobacillus salivarius Lv72. AB - BACKGROUND: The adhesion of lactobacilli to the vaginal surface is of paramount importance to develop their probiotic functions. For this reason, the role of HeLa cell surface proteoglycans in the attachment of Lactobacillus salivarius Lv72, a mutualistic strain of vaginal origin, was investigated. RESULTS: Incubation of cultures with a variety of glycosaminoglycans (chondroitin sulfate A and C, heparin and heparan sulfate) resulted in marked binding interference. However, no single glycosaminoglycan was able to completely abolish cell binding, the sum of all having an additive effect that suggests cooperation between them and recognition of specific adhesins on the bacterial surface. In contrast, chondroitin sulfate B enhanced cell to cell attachment, showing the relevance of the stereochemistry of the uronic acid and the sulfation pattern on binding. Elimination of the HeLa surface glycosaminoglycans with lyases also resulted in severe adherence impairment. Advantage was taken of the Lactobacillus glycosaminoglycans interaction to identify an adhesin from the bacterial surface. This protein, identify as a soluble binding protein of an ABC transporter system (OppA) by MALDI-TOF/(MS), was overproduced in Escherichia coli, purified and shown to interfere with L. salivarius Lv72 adhesion to HeLa cells. CONCLUSIONS: These data suggest that glycosaminoglycans play a fundamental role in attachment of mutualistic bacteria to the epithelium that lines the cavities where the normal microbiota thrives, OppA being a bacterial adhesin involved in the process. PMID- 24044742 TI - Detection and source tracking of Escherichia coli, harboring intimin and Shiga toxin genes, isolated from the Little Bighorn River, Montana. AB - The Little Bighorn River flows through the Crow Indian Reservation in Montana. In 2008, Escherichia coli concentrations as high as 7179 MPN/100 ml were detected in the river at the Crow Agency Water Treatment Plant intake site. During 2008, 2009, and 2012, 10 different serotypes of E. coli, including O157:H7, harboring both intimin and Shiga toxin genes were isolated from a popular swim site of the Little Bighorn River in Crow Agency. As part of a microbial source tracking study, E. coli strains were isolated from river samples as well as from manure collected from a large cattle feeding operation in the upper Little Bighorn River watershed; 23% of 167 isolates of E. coli obtained from the manure tested positive for the intimin gene. Among these manure isolates, 19 were identified as O156:H8, matching the serotype of an isolate collected from a river sampling site close to the cattle feeding area. PMID- 24044743 TI - Target of rapamycin signaling regulates high mobility group protein association to chromatin, which functions to suppress necrotic cell death. AB - BACKGROUND: The target of rapamycin complex 1 (TORC1) is an evolutionarily conserved signal transduction pathway activated by environmental nutrients that regulates gene transcription to control cell growth and proliferation. How TORC1 modulates chromatin structure to control gene expression, however, is largely unknown. Because TORC1 is a major transducer of environmental information, defining this process has critical implications for both understanding environmental effects on epigenetic processes and the role of aberrant TORC1 signaling in many diseases, including cancer, diabetes, and cardiovascular disease. RESULTS: To elucidate the role of TORC1 signaling in chromatin regulation, we screened a budding yeast histone H3 and H4 mutant library using the selective TORC1 inhibitor rapamycin to identify histone residues functionally connected to TORC1. Intriguingly, we identified histone H3 lysine 37 (H3K37) as a residue that is essential during periods of limited TORC1 activity. An H3K37A mutation resulted in cell death by necrosis when TORC1 signaling was simultaneously impaired. The induction of necrosis was linked to alterations in high mobility group (HMG) protein binding to chromatin. Furthermore, the necrotic phenotype could be recapitulated in wild-type cells by deregulating the model HMG proteins, Hmo1 or Ixr1, thus implicating a direct role for HMG protein deregulation as a stimulus for inducing necrosis. CONCLUSIONS: This study identifies histone H3 and H4 residues functionally required for TORC1-dependent cell growth and proliferation that are also candidate epigenetic pathways regulated by TORC1 signaling. It also demonstrates a novel role for H3K37 and TORC1 in regulating the binding of select HMG proteins to chromatin and that HMG protein deregulation can initiate a necrotic cell death response. Overall, the results from this study suggest a possible model by which chromatin anchors HMG proteins during periods of limited TORC1 signaling, such as that which occurs during conditions of nutrient stress, to suppress necrotic cell death. PMID- 24044745 TI - Evidence-based medicine: the salad is only as good as the ingredients. PMID- 24044744 TI - Embryonic diapause in humans: time to consider? AB - BACKGROUND: When a competent blastocyst stage embryo finds itself in an unreceptive uterus, it delays development. In around one hundred species representing various orders, this delay is known to be reversible, but this phenomenon - termed embryonic diapause (ED) - is not considered a general characteristic of all mammals. PRESENTATION OF THE HYPOTHESIS: Recently, however, we demonstrated that a non-diapausing species, the sheep, is capable of ED, suggesting the hypothesis that this is in fact an ancestral trait common to all mammals, including humans. TESTING THE HYPOTHESIS: In spite of the obvious difficulties in testing this idea, we propose a combination of indirect observations on human fertility patients, and direct study of the embryos of non human primates. IMPLICATIONS OF THE HYPOTHESIS: Support for our hypothesis would require revision of obstetric interventions routinely performed when a human pregnancy extends beyond the due date. PMID- 24044746 TI - GLIMPSE: a rapid decision framework for energy and environmental policy. AB - Over the coming decades, new energy production technologies and the policies that oversee them will affect human health, the vitality of our ecosystems, and the stability of the global climate. The GLIMPSE decision model framework provides insights about the implications of technology and policy decisions on these outcomes. Using GLIMPSE, decision makers can identify alternative techno-policy futures, examining their air quality, health, and short- and long-term climate impacts. Ultimately, GLIMPSE will support the identification of cost-effective strategies for simultaneously achieving performance goals for these metrics. Here, we demonstrate the utility of GLIMPSE by analyzing several future energy scenarios under existing air quality regulations and potential CO2 emission reduction policies. We find opportunities for substantial cobenefits in setting both climate change mitigation and health-benefit based air quality improvement targets. Though current policies which prioritize public health protection increase near-term warming, establishing policies that also reduce greenhouse gas emissions may offset warming in the near-term and lead to significant reductions in long-term warming. PMID- 24044748 TI - Noncontiguous atom matching structural similarity function. AB - Measuring similarity between molecules is a fundamental problem in cheminformatics. Given that similar molecules tend to have similar physical, chemical, and biological properties, the notion of molecular similarity plays an important role in the exploration of molecular data sets, query-retrieval in molecular databases, and in structure-property/activity modeling. Various methods to define structural similarity between molecules are available in the literature, but so far none has been used with consistent and reliable results for all situations. We propose a new similarity method based on atom alignment for the analysis of structural similarity between molecules. This method is based on the comparison of the bonding profiles of atoms on comparable molecules, including features that are seldom found in other structural or graph matching approaches like chirality or double bond stereoisomerism. The similarity measure is then defined on the annotated molecular graph, based on an iterative directed graph similarity procedure and optimal atom alignment between atoms using a pairwise matching algorithm. With the proposed approach the similarities detected are more intuitively understood because similar atoms in the molecules are explicitly shown. This noncontiguous atom matching structural similarity method (NAMS) was tested and compared with one of the most widely used similarity methods (fingerprint-based similarity) using three difficult data sets with different characteristics. Despite having a higher computational cost, the method performed well being able to distinguish either different or very similar hydrocarbons that were indistinguishable using a fingerprint-based approach. NAMS also verified the similarity principle using a data set of structurally similar steroids with differences in the binding affinity to the corticosteroid binding globulin receptor by showing that pairs of steroids with a high degree of similarity (>80%) tend to have smaller differences in the absolute value of binding activity. Using a highly diverse set of compounds with information about the monoamine oxidase inhibition level, the method was also able to recover a significantly higher average fraction of active compounds when the seed is active for different cutoff threshold values of similarity. Particularly, for the cutoff threshold values of 86%, 93%, and 96.5%, NAMS was able to recover a fraction of actives of 0.57, 0.63, and 0.83, respectively, while the fingerprint-based approach was able to recover a fraction of actives of 0.41, 0.40, and 0.39, respectively. NAMS is made available freely for the whole community in a simple Web based tool as well as the Python source code at http://nams.lasige.di.fc.ul.pt/. PMID- 24044749 TI - Effect of field edges on dispersal and distribution of colonizing stink bugs across farmscapes of the southeast USA. AB - Stink bugs (Heteroptera: Pentatomidae), including Nezara viridula (L.), Euschistus servus (Say), and Chinavia hilaris (Say), are economic pests in farmscapes where they move within and between closely associated crop and non crop habitats. Thus, field edges in these farmscapes include not only crop-to crop interfaces but also those edges adjoining non-crop habitats. We examined the influence of field edges on colonization of stink bugs in southeastern USA farmscapes composed of typical combinations of corn, peanut, and cotton. For E. servus and N. viridula, egg-to-adult development and presence of both sexes on all crops indicated that the crops served as reproductive plants. Adult C. hilaris were rarely found on corn and on crops associated with it, and they were present mainly in cotton in peanut-cotton farmscapes. Mature crop height was significantly higher for corn than for cotton and significantly higher for cotton over peanut, and an edge effect in dispersal of stink bugs into a crop was detected up to 4.6, 8.2, and 14.6 m from the crop-to-crop interface in corn, cotton, and peanut, respectively. These results suggest that stink bug dispersal into a crop decreases as crop height increases. The first stink bug-infested crop at the crop-to-crop interface was the most significant contributor of colonizing stink bugs to an adjacent crop. An edge effect in dispersal of stink bug adults was detected in corn next to non-woodlands and woodlands and in cotton adjacent to woodlands. Edge effects were never detected in side edges of peanut. Overall, our results indicate that both plant height and host plant suitability can influence edge-mediated dispersal of stink bugs at field edges. PMID- 24044750 TI - Measuring safety culture in Dutch primary care: psychometric characteristics of the SCOPE-PC questionnaire. AB - BACKGROUND: Patient safety has been a priority in primary healthcare in the last years. The prevailing culture is seen as an important condition for patient safety in practice and several tools to measure patient safety culture have therefore been developed. Although Dutch primary care consists of different professions, such as general practice, dental care, dietetics, physiotherapy and midwifery, a safety culture questionnaire was only available for general practices. The purpose of this study was to modify and validate this existing questionnaire to a generic questionnaire for all professions in Dutch primary care. METHODS: A validated Dutch questionnaire for general practices was modified to make it usable for all Dutch primary care professions. Subsequently, this questionnaire was administered to a random sample of 2400 practices from eleven primary care professions. The instrument's factor structure, reliability and validity were examined using confirmatory and explorative factor analyses. RESULTS: 921 questionnaires were returned. Of these, 615 were eligible for factor analysis. The resulting SCOPE-PC questionnaire consisted of seven dimensions: 'open communication and learning from errors', 'handover and teamwork', 'adequate procedures and working conditions', 'patient safety management', 'support and fellowship', 'intention to report events' and 'organisational learning' with a total of 41 items. All dimensions had good reliability with Cronbach's alphas ranging from 0.70-0.90, and the questionnaire had a good construct validity. CONCLUSIONS: The SCOPE-PC questionnaire has sound psychometric characteristics for use by the different professions in Dutch primary care to gain insight in their safety culture. PMID- 24044752 TI - Mechanistic origin of chemo- and regioselectivity of nickel-catalyzed [3 + 2 + 2] cyclization reaction. AB - A density functional theory (DFT) study was performed to elucidate the mechanism of the Ni-catalyzed [3 + 2 + 2] cyclization reaction of cyclopropylideneacetate with two alkynes. A systematic search showed that the nature of the alkynes determines the choice between two reaction pathways and hence the regioselectivity. Strongly electron-deficient acetylenes preferentially afford 2,5-disubstituted products via nickelacyclopentadienes generated by [2 + 2] cocyclization, whereas normal alkynes afford 3,4- or 3,5-products via an unprecedented pathway involving a [3 + 2] nickelacycle intermediate. PMID- 24044751 TI - Structure and barrier properties of human embryonic stem cell-derived retinal pigment epithelial cells are affected by extracellular matrix protein coating. AB - Extracellular matrix (ECM) interactions play a vital role in cell morphology, migration, proliferation, and differentiation of cells. We investigated the role of ECM proteins on the structure and function of human embryonic stem cell derived retinal pigment epithelial (hESC-RPE) cells during their differentiation and maturation from hESCs into RPE cells in adherent differentiation cultures on several human ECM proteins found in native human Bruch's membrane, namely, collagen I, collagen IV, laminin, fibronectin, and vitronectin, as well as on commercial substrates of xeno-free CELLstartTM and MatrigelTM. Cell pigmentation, expression of RPE-specific proteins, fine structure, as well as the production of basal lamina by hESC-RPE on different protein coatings were evaluated after 140 days of differentiation. The integrity of hESC-RPE epithelium and barrier properties on different coatings were investigated by measuring transepithelial resistance. All coatings supported the differentiation of hESC-RPE cells as demonstrated by early onset of cell pigmentation and further maturation to RPE monolayers after enrichment. Mature RPE phenotype was verified by RPE-specific gene and protein expression, correct epithelial polarization, and phagocytic activity. Significant differences were found in the degree of RPE cell pigmentation and tightness of epithelial barrier between different coatings. Further, the thickness of self-assembled basal lamina and secretion of the key ECM proteins found in the basement membrane of the native RPE varied between hESC RPE cultured on compared protein coatings. In conclusion, this study shows that the cell culture substrate has a major effect on the structure and basal lamina production during the differentiation and maturation of hESC-RPE potentially influencing the success of cell integrations and survival after cell transplantation. PMID- 24044753 TI - The effect of the binding of ZnO nanoparticle on the structure and stability of alpha-lactalbumin: a comparative study. AB - Nanoparticles (NPs), when exposed to biofluids, become coated with proteins. As the protein is adsorbed on the surface, the extent of adsorption and the consequent effect on protein conformation and activity depend on the chemical nature, shape, and size of the nanoparticle. We have carried out a detailed study on the interaction of alpha-lactalbumin (a protein which forms the regulatory subunit of lactose synthase) with zinc oxide nanoparticles. The NPs were prepared by the sol-gel route and characterized by transmission electron microscopy, X-ray diffraction, UV-visible, and photoluminescence spectroscopy. ZnO particles were found to have a size of 4-7 nm with hexagonal structure. The interaction of protein with NP was examined using a combination of spectroscopic and computational methods. The binding was studied by ITC (isothermal calorimetry), and the result revealed that the complexation is mostly entropy driven and involves hydrophobic interaction. There is alteration in secondary structures in protein on binding ZnO nanoparticle, as revealed by circular dichroism (CD) and Fourier transform infrared spectroscopy (FITR). Finally, a comparison of structure, function, and stability of the alpha-lactalbumin-NP complex has been made by binding ZnO to other model proteins to get a better insight into the process of protein nanoparticle interaction. The present study thus provides useful insights into issues such as protein-nanoparticle recognition. PMID- 24044754 TI - Contextual analysis of immunological response through whole-organ fluorescent imaging. AB - BACKGROUND: As fluorescent microscopy has developed, significant insights have been gained into the establishment of immune response within secondary lymphoid organs, particularly in draining lymph nodes. While established techniques such as confocal imaging and intravital multi-photon microscopy have proven invaluable, they provide limited insight into the architectural and structural context in which these responses occur. To interrogate the role of the lymph node environment in immune response effectively, a new set of imaging tools taking into account broader architectural context must be implemented into emerging immunological questions. METHODS AND RESULTS: Using two different methods of whole-organ imaging, optical clearing and three-dimensional reconstruction of serially sectioned lymph nodes, fluorescent representations of whole lymph nodes can be acquired at cellular resolution. Using freely available post-processing tools, images of unlimited size and depth can be assembled into cohesive, contextual snapshots of immunological response. Through the implementation of robust iterative analysis techniques, these highly complex three-dimensional images can be objectified into sortable object data sets. These data can then be used to interrogate complex questions at the cellular level within the broader context of lymph node biology. CONCLUSIONS: By combining existing imaging technology with complex methods of sample preparation and capture, we have developed efficient systems for contextualizing immunological phenomena within lymphatic architecture. In combination with robust approaches to image analysis, these advances provide a path to integrating scientific understanding of basic lymphatic biology into the complex nature of immunological response. PMID- 24044755 TI - Insights into the pathogenesis of disease in human lymphatic filariasis. AB - Although two thirds of the 120 million people infected with lymph-dwelling filarial parasites have subclinical infections, ~40 million have lymphedema and/or other pathologic manifestations including hydroceles (and other forms of urogenital disease), episodic adenolymphangitis, lymphedema, and (in its most severe form) elephantiasis. Adult filarial worms reside in the lymphatics and lymph nodes and induce lymphatic dilatation. Progressive lymphatic damage and pathology results primarily from the host inflammatory response to the parasites but also perhaps from the host inflammatory response to the parasite's Wolbachia endosymbiont and as a consequence of superimposed bacterial or fungal infections. This review will attempt to shed light on disease pathogenesis in lymphatic filariasis. PMID- 24044756 TI - An immunological fingerprint differentiates muscular lymphatics from arteries and veins. AB - The principal function of the lymphatic system is to transport lymph from the interstitium to the nodes and then from the nodes to the blood. In doing so lymphatics play important roles in fluid homeostasis, macromolecular/antigen transport and immune cell trafficking. To better understand the genes that contribute to their unique physiology, we compared the transcriptional profile of muscular lymphatics (prenodal mesenteric microlymphatics and large, postnodal thoracic duct) to axillary and mesenteric arteries and veins isolated from rats. Clustering of the differentially expressed genes demonstrated that the lymph versus blood vessel differences were more profound than between blood vessels, particularly the microvessels. Gene ontology functional category analysis indicated that microlymphatics were enriched in antigen processing/presentation, IgE receptor signaling, catabolic processes, translation and ribosome; while they were diminished in oxygen transport, regulation of cell proliferation, glycolysis and inhibition of adenylate cyclase activity by G-proteins. We evaluated the differentially expressed microarray genes/products by qPCR and/or immunofluorescence. Immunofluorescence documented that multiple MHC class II antigen presentation proteins were highly expressed by an antigen-presenting cell (APC) type found resident within the lymphatic wall. These APCs also expressed CD86, a co-stimulatory protein necessary for T-cell activation. We evaluated the distribution and phenotype of APCs within the pre and postnodal lymphatic network. This study documents a novel population of APCs resident within the walls of muscular, prenodal lymphatics that indicates novel roles in antigen sampling and immune responses. In conclusion, these prenodal lymphatics exhibit a unique profile that distinguishes them from blood vessels and highlights the role of the lymphatic system as an immunovascular system linking the parenchymal interstitium, lymph nodes and the blood. PMID- 24044757 TI - Dendritic cell interactions with lymphatic endothelium. AB - Afferent lymphatic vessels fulfill essential immune functions by transporting leukocytes and lymph-borne antigen to draining lymph nodes (dLNs). An important cell type migrating through lymphatic vessels are dendritic cells (DCs). DCs reside in peripheral tissues like the skin, where they take up antigen and transport it via the lymphatic vascular network to dLNs for subsequent presentation to T cells. As such, DCs play a key role in the induction of adaptive immune responses during infection and vaccination, but also for the maintenance of tolerance. Although the migratory pattern of DCs has been known for long time, interactions between DCs and lymphatic vessels are only now starting to be unraveled at the cellular level. In particular, new tools for visualizing lymphatic vessels in combination with time-lapse microscopy have recently generated valuable insights into the process of DC migration to dLNs. In this review we summarize and discuss current approaches for visualizing DCs and lymphatic vessels in tissues for imaging applications. Furthermore, we review the current state of knowledge about DC migration towards, into and within lymphatic vessels, particularly focusing on the cellular interactions that take place between DCs and the lymphatic endothelium. PMID- 24044758 TI - Lymphatic vessel function in head and neck inflammation. AB - BACKGROUND: Serious infections of the head and neck cause lymphedema that can lead to airway compromise and oropharyngeal obstruction. Lymphangiogenesis occurs in the head and neck during infection and after immunization. The goal of this project was to develop tools to image lymphatic vessels in living animals and to be able to isolate individual lymphatic endothelial cells in order to quantify changes in single cells caused by inflammation. METHODS: The ProxTom transgenic red-fluorescent reporter mouse was developed specifically for the purpose of imaging lymphatic vessels in vivo. Prox1 is a transcription factor that is necessary for lymphangiogenesis in development and for the maintenance of lymphatics in adulthood. Mice were immunized and their lymphatic vessels in lymph nodes were imaged in vivo. Individual lymphatic endothelial cells were isolated by means of their fluorescence. RESULTS: The ProxTom transgene has the red fluorescent reporter td-Tomato under the control of Prox1 regulatory elements. tdTomato was faithfully expressed in lymphatic vessels coincident with endogenous Prox1 expression. We show lymphangiogenesis in vivo after immunization and demonstrate a method for the isolation of lymphatic endothelial cells by their tdTomato red-fluorescence. CONCLUSIONS: The faithful expression of the red fluorescent reporter in the lymphatic vessels of ProxTom means that these mice have proven utility for in vivo study of lymphatic vessels in the immune response. ProxTom has been made available for distribution from the Jackson Laboratory: http://jaxmice.jax.org/strain/018128.html . PMID- 24044760 TI - Intrapartum management of trial of labour after caesarean delivery: evidence and experience. AB - Few studies have focused specifically on the intrapartum management of patients following a prior caesarean delivery. Contemporary assessments and recommendations on attempting vaginal birth after caesarean delivery (VBAC) vary. The actual conduct of labour and delivery of the infant in an uncomplicated trial of labour after caesarean (TOLAC) is similar to the management of a patient without a previous caesarean. Intrapartum management of TOLAC differs primarily in the need for caution with induction of labour in women with an unfavourable cervix, the avoidance of overstimulation with oxytocin augmentation, and surveillance for prompt recognition of the rare case of uterine rupture. PMID- 24044761 TI - History, background, concepts and current use of comedication and polypharmacy in psychiatry. AB - Based on a careful literature search a review is presented of the history, background, concepts and current use of comedication and polypharmacy in psychiatry. The pros and cons of comedication and polypharmacy are presented, as well as their apparent increase in recent times. Possible reasons for the increase of comedication/polypharmacy are described. Both the potential advantages as well as the potential risks are discussed. The one sided view that all comedication/polypharmacy is nothing but problematic is questioned. Comedication/polypharmacy seems to be, among others, the current answer to the well-known limited efficacy and effectiveness of current monotherapy treatment strategies. PMID- 24044762 TI - Red-hair-inspired chromogenic system based on a proton-switched dehydrogenative free-radical coupling. AB - In the presence of micromolar peroxides or biometals (Fe(III), Cu(II), V(V) salts), and following a strong acid input, the stable 3-phenyl-2H-1,4 benzothiazine is efficiently converted to a green-blue Delta(2,2')-bi(2H-1,4 benzothiazine) chromophore via dehydrogenative coupling of a 1,4-benzothiazinyl radical. The new system is of potential practical interest for colorimetric peroxide and redox biometal detection. PMID- 24044763 TI - HPLC method with fluorescence detection for the determination of ligustilide in rat plasma and its pharmacokinetics. AB - CONTEXT: Few methods have been reported for the quantification of ligustilide (LIG) in biosamples: the pretreatment of the biological samples were laborious and time-consuming. OBJECTIVE: A high-performance liquid chromatographic method with fluorescence detection (HPLC-FLD) for the determination of LIG in rat plasma was developed and validated. Pharmacokinetics and bioavailability of LIG were determined by systematic investigation in Sprague-Dawley rats. MATERIALS AND METHODS: LIG was isolated from the volatile oil of Radix Angelica sinensis and further purified by silica gel column chromatography. Podophyllotoxin was used as an internal standard. The analytes were detected by using fluorescence detection at an excitation and emission wavelength of 290 and 395 nm during 0-4 min, and 336 and 453 nm during 4-14 min, respectively. LIG pharmacokinetics was studied in rats after oral and intravenous administration of 12.5, 25 and 50 mg/kg doses. RESULTS: Two calibration curves (Y = 133.49 X - 14.27 (r = 0.9995), Y = 145.61 X + 13.76 (r = 0.9996)) were constructed in the range of 2.44-10,000 ng/mL for LIG with a lower limit of quantitation of 2.44 ng/mL. Both intra-day and inter-day precision were less than 6%. Accuracy ranged from 88.93 to 99.52%. The recovery ranged from 89.07 to 99.71%. The absolute bioavailability values were 71.36, 68.26 and 75.44% for oral doses of 12.5, 25 and 50 mg/kg, respectively. CONCLUSION: The present HPLC-FLD method was rapid, sensitive and reliable. LIG was absorbed and eliminated rapidly in rat. PMID- 24044765 TI - Two distinct types of the inhibition of vasculogenesis by different species of charged particles. AB - BACKGROUND: Charged particle radiation is known to be more biologically effective than photon radiation. One example of this is the inhibition of the formation of human blood vessels. This effect is an important factor influencing human health and is relevant to space travel as well as to cancer radiotherapy. We have previously shown that ion particles with a high energy deposition, or linear energy transfer (LET) are more than four times more effective at disrupting mature vessel tissue models than particles with a lower LET. For vasculogenesis however, the relative biological effectiveness between particles is the same. This unexpected result prompted us to investigate whether the inhibition of vasculogenesis was occurring by distinct mechanisms. METHODS: Using 3-Dimensional human vessel models, we developed assays that determine at what stage angiogenesis is inhibited. Vessel morphology, the presence of motile tip structures, and changes in the matrix architecture were assessed. To confirm that the mechanisms are distinct, stimulation of Protein Kinase C (PKC) with phorbol ester (PMA) was employed to selectively restore vessel formation in cultures where early motile tip activity was inhibited. RESULTS: Endothelial cells in 3-D culture exposed to low LET protons failed to make connections with other cells but eventually developed a central lumen. Conversely, cells exposed to high LET Fe charged particles extended cellular processes and made connections to other cells but did not develop a central lumen. The microtubule and actin cytoskeletons indicated that motility at the extending tips of endothelial cells is inhibited by low LET but not high LET particles. Actin-rich protrusive structures that contain bundled microtubules showed a 65% decrease when exposed to low LET particles but not high LET particles, with commensurate changes in the matrix architecture. Stimulation of PKC with PMA restored tip motility and capillary formation in low but not high LET particle treated cultures. CONCLUSION: Low LET charged particles inhibit the early stages of vasculogenesis when tip cells have motile protrusive structures and are creating pioneer guidance tunnels through the matrix. High LET charged particles do not affect the early stages of vasculogenesis but they do affect the later stages when the endothelial cells migrate to form tubes. PMID- 24044764 TI - Detailed statistical analysis plan for the target temperature management after out-of-hospital cardiac arrest trial. AB - BACKGROUND: Animal experimental studies and previous randomized trials suggest an improvement in mortality and neurological function with temperature regulation to hypothermia after cardiac arrest. According to a systematic review, previous trials were small, had a risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management (TTM) strategy is not known. To prevent outcome reporting bias, selective reporting and data-driven results, we present the a priori defined detailed statistical analysis plan as an update to the previously published outline of the design and rationale for the TTM trial. METHODS: The TTM trial is an investigator-initiated, multicenter, international, randomized, parallel group, and assessor-blinded clinical trial of temperature management in 950 adult unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients are randomized to a TTM of either 33 degrees C or 36 degrees C after return of spontaneous circulation. The primary outcome is all-cause mortality at maximal follow-up (until end of the trial and a minimum of 180 days). The main secondary outcomes are the composite outcome of all-cause mortality and poor neurological function (Cerebral Performance Category (CPC) 3 and 4, and modified Rankin Scale (mRS) 4 and 5) at hospital discharge and at 180 days; and assessment of safety and harm: bleeding, infections, electrolyte and metabolic disorders, seizures, cardiac arrhythmia, and renal replacement therapy. CONCLUSION: The TTM trial investigates potential benefit and harm of two target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01020916. PMID- 24044766 TI - Increasing condom use and declining STI prevalence in high-risk MSM and TGs: evaluation of a large-scale prevention program in Tamil Nadu, India. AB - BACKGROUND: This paper presents an evaluation of Avahan, a large scale HIV prevention program that was implemented using peer-mediated strategies, condom distribution and sexually transmitted infection (STI) clinical services among high-risk men who have sex with men (HR-MSM) and male to female transgender persons (TGs) in six high-prevalence state of Tamil Nadu, in southern India. METHODS: Two rounds of large scale cross-sectional bio-behavioural surveys among HR-MSM and TGs and routine program monitoring data were used to assess changes in program coverage, condom use and prevalence of STIs (including HIV) and their association to program exposure. RESULTS: The Avahan program for HR-MSM and TGs in Tamil Nadu was significantly scaled up and contacts by peer educators reached 77 percent of the estimated denominator by the end of the program's fourth year. Exposure to the program increased between the two rounds of surveys for both HR MSM (from 66 percent to 90 percent; AOR = 4.6; p < 0.001) and TGs (from 74.5 percent to 83 percent; AOR = 1.82; p < 0.06). There was an increase in consistent condom use by HR-MSM with their regular male partners (from 33 percent to 46 percent; AOR = 1.9; p < 0.01). Last time condom use with paying male partners (up from 81 percent to 94 percent; AOR = 3.6; p < 0.001) also showed an increase. Among TGs, the increase in condom use with casual male partners (18 percent to 52 percent; AOR = 1.8; p < 0.27) was not significant, and last time condom use declined significantly with paying male partners (93 percent to 80 percent; AOR = 0.32; p < 0.015). Syphilis declined significantly among both HR-MSM (14.3 percent to 6.8 percent; AOR = 0.37; p < 0.001) and TGs (16.6 percent to 4.2 percent; AOR = 0.34; p < 0.012), while change in HIV prevalence was not found to be significant for HR-MSM (9.7 percent to 10.9 percent) and TGs (12 percent to 9.8 percent). For both groups, change in condom use with commercial and non commercial partners was found to be strongly linked with exposure to the Avahan program. CONCLUSION: The Avahan program for HR-MSM and TGs in Tamil Nadu achieved a high coverage, resulting in improved condom use by HR-MSM with their regular and commercial male partners. Declining STI prevalence and stable HIV prevalence reflect the positive effects of the prevention strategy. Outcomes from the program logic model indiacte the effectiveness of the program for HR-MSM and TGs in Tamil Nadu. PMID- 24044767 TI - Integration of promoters, inverted repeat sequences and proteomic data into a model for high silencing efficiency of coeliac disease related gliadins in bread wheat. AB - BACKGROUND: Wheat gluten has unique nutritional and technological characteristics, but is also a major trigger of allergies and intolerances. One of the most severe diseases caused by gluten is coeliac disease. The peptides produced in the digestive tract by the incomplete digestion of gluten proteins trigger the disease. The majority of the epitopes responsible reside in the gliadin fraction of gluten. The location of the multiple gliadin genes in blocks has to date complicated their elimination by classical breeding techniques or by the use of biotechnological tools.As an approach to silence multiple gliadin genes we have produced 38 transgenic lines of bread wheat containing combinations of two endosperm-specific promoters and three different inverted repeat sequences to silence three fractions of gliadins by RNA interference. RESULTS: The effects of the RNA interference constructs on the content of the gluten proteins, total protein and starch, thousand seed weights and SDSS quality tests of flour were analyzed in these transgenic lines in two consecutive years. The characteristics of the inverted repeat sequences were the main factor that determined the efficiency of silencing. The promoter used had less influence on silencing, although a synergy in silencing efficiency was observed when the two promoters were used simultaneously. Genotype and the environment also influenced silencing efficiency. CONCLUSIONS: We conclude that to obtain wheat lines with an optimum reduction of toxic gluten epitopes one needs to take into account the factors of inverted repeat sequences design, promoter choice and also the wheat background used. PMID- 24044768 TI - Comparison of the transperitoneal and retroperitoneal approach in robot-assisted partial nephrectomy in an initial case series in Japan. AB - PURPOSE: To compare the results from the transperitoneal and retroperitoneal approaches in our initial case series of robot-assisted partial nephrectomy (RAPN) in terms of surgical time, renal artery clamping time, postoperative renal function, adverse events, and surgical margin status. PATIENTS AND METHODS: The initial 26 consecutive RAPNs performed for solid renal tumors in our hospital were categorized by the approach used, transperitoneal or retroperitoneal, and compared for body mass index, tumor size, R.E.N.A.L. nephrometry score, PADUA score, tumor location, surgical time, renal artery clamping time, renal function change after surgery, operative blood loss, surgical margin status, and adverse events (AEs). RESULTS: The median tumor size was 25 mm (range 15-50). A transperitoneal approach was used in 16 patients and a retroperitoneal approach was used in 10 patients. There was no significant difference in renal tumor and patient characteristics between the two groups except tumor location (anterior tumor was significantly more in the transperitoneal approach and posterior tumor was significantly more in retroperitoneal approach (P=0.0144 and P=0.0100, respectively)). Operative time (239 +/- 63.0 minutes in the transperitoneal group vs. 193 +/- 40.6 minutes in the retroperitoneal group), warm ischemic time (24.3 +/- 9.07 minutes in the transperitoneal group vs. 24.7 +/- 8.35 minutes in the retroperitoneal group) and AEs (1/16 in the transperitoneal group vs. 1/10 in the retroperitoneal group; both cases were Clavien-Dindo grade I) did not show any significant difference between the two approaches (P=0.0792, 0.5485, and 0.7270, respectively). CONCLUSIONS: The retroperitoneal approach in RAPN appears to be a safe and technically feasible minimally invasive option for nephron-sparing surgery, based on our initial case series, and showed equivalent outcomes to those of the transperitoneal approach even though it was an initial robotic renal surgery series. Future studies, including a larger number of cases, are planned to draw more definitive conclusions. PMID- 24044769 TI - Prevalence and determinants of SHS exposure in public and private areas after the 2010 smoke-free legislation in Greece. AB - The objective of the present survey was to assess the extent and socio-economic determinants of population exposure to secondhand smoke (SHS) in Greece in 2011. The national household survey Hellas Health IV was conducted in October 2011. SHS exposure was based on self-reported exposure within home, workplace and public places. Thirty-three per cent of the respondents reported living in a smoke-free home. Smokers (p < 0.001) and single individuals (p < 0.017) were less likely to prohibit smoking at home. SHS exposure at work, in restaurants and in bars/clubs/cafes was frequently mentioned by 41.6, 84.2 and 90.5%, respectively. SHS exposure in a bar/club/cafe was noted more among single individuals (p = 0.004) and those aged 18-34 years (p = 0.007). Inhabitants of rural areas were more likely to report someone smoking indoors in all the above venues. Public health education and effective enforcement of the nationwide smoke-free legislation are imperative. PMID- 24044770 TI - Emergency department management of vaginal bleeding in the nonpregnant patient. AB - Abnormal uterine bleeding is the most common reason women seek gynecologic care, and many of these women present to an emergency department for evaluation. It is essential that emergency clinicians have a thorough understanding of the underlying physiology of the menstrual cycle to appropriately manage a nonpregnant woman with abnormal bleeding. Evidence to guide the management of nonpregnant patients with abnormal bleeding is limited, and recommendations are based mostly on expert opinion. This issue reviews common causes of abnormal bleeding, including anovulatory, ovulatory, and structural causes in both stable and unstable patients. The approach to abnormal bleeding in the prepubertal girl is also discussed. Emergency clinicians are encouraged to initiate treatment to temporize an acute bleeding episode until timely follow-up with a gynecologist can be obtained. PMID- 24044771 TI - Lipid exchange and flip-flop in solid supported bilayers. AB - Inter- and intrabilayer transfer of phospholipid molecules was investigated by neutron reflectometry. The structure of solid supported lipid bilayers exposed to a solution of isotopically labeled vesicles was monitored as a function of temperature, time, and vesicle concentration. Lipid interbilayer exchange was shown to be the time limiting process, while lipid intrabilayer movement, the so called flip-flop, was too fast to be visualized within the experimental acquisition time. The exchange process was characterized by an Arrhenius-like behavior and the activation energy of the process was concentration-independent. The results are discussed and compared extensively with the literature available on the topic. PMID- 24044772 TI - Specific and non-specific protein association in solution: computation of solvent effects and prediction of first-encounter modes for efficient configurational bias Monte Carlo simulations. AB - Weak and ultraweak protein-protein association play a role in molecular recognition and can drive spontaneous self-assembly and aggregation. Such interactions are difficult to detect experimentally, and are a challenge to the force field and sampling technique. A method is proposed to identify low population protein-protein binding modes in aqueous solution. The method is designed to identify preferential first-encounter complexes from which the final complex(es) at equilibrium evolve. A continuum model is used to represent the effects of the solvent, which accounts for short- and long-range effects of water exclusion and for liquid-structure forces at protein/liquid interfaces. These effects control the behavior of proteins in close proximity and are optimized on the basis of binding enthalpy data and simulations. An algorithm is described to construct a biasing function for self-adaptive configurational-bias Monte Carlo of a set of interacting proteins. The function allows mixing large and local changes in the spatial distribution of proteins, thereby enhancing sampling of relevant microstates. The method is applied to three binary systems. Generalization to multiprotein complexes is discussed. PMID- 24044773 TI - Macrocyclic drugs and clinical candidates: what can medicinal chemists learn from their properties? AB - Macrocycles are ideal in efforts to tackle "difficult" targets, but our understanding of what makes them cell permeable and orally bioavailable is limited. Analysis of approximately 100 macrocyclic drugs and clinical candidates revealed that macrocycles are predominantly used for infectious disease and in oncology and that most belong to the macrolide or cyclic peptide class. A significant number (N = 34) of these macrocycles are administered orally, revealing that oral bioavailability can be obtained at molecular weights up to and above 1 kDa and polar surface areas ranging toward 250 A(2). Moreover, insight from a group of "de novo designed" oral macrocycles in clinical studies and understanding of how cyclosporin A and model cyclic hexapeptides cross cell membranes may unlock wider opportunities in drug discovery. However, the number of oral macrocycles is still low and it remains to be seen if they are outliers or if macrocycles will open up novel oral druggable space. PMID- 24044774 TI - Assessing the implementation of performance management of health care workers in Uganda. AB - BACKGROUND: The performance management concept is relatively new to the Ugandan health sector. Uganda has been implementing health sector reforms for nearly two decades. The reforms included the introduction of the results-oriented management in the public sector and the decentralisation of the management of health care workers from central to local governments. This study examined the implementation of performance management of health care workers in order to propose strategies for improvement. METHODS: The study was a descriptive survey carried out in the Kumi, Mbale, Sironko and Tororo districts and utilising mixed research methodology. A self-administered questionnaire was used to collect quantitative data from the health care workers. A semi-structured interview guide was used to collect qualitative data from the health service managers. The sample for the quantitative method was selected using stratified random sampling. Purposive sampling was used to select health service managers. Quantitative data were analysed using Statistical Package for Social Sciences (version 18.0). Qualitative data were categorised according to the themes and analysed manually. RESULTS: The findings show that to some extent performance management is implemented in the health sector; however, there were loopholes in its implementation. There were inadequacies in setting performance targets and performance management planning was hardly done. Although many health care workers had job descriptions, the performance indicators and standards were not clearly defined and known to all workers and managers. Additionally the schedules for performance assessments were not always adhered to. There were limited prospects for career progression, inadequate performance feedback and poor rewarding mechanisms. CONCLUSIONS: Performance management of health care workers is inadequately done in the districts. Performance management is a key component of attempts to improve health sector outcomes. As a result of this study, suggestions to enhance health sector performance management in the districts have been put forward. The authors are optimistic that if these suggestions are implemented, the performance of health care workers is likely to improve. PMID- 24044775 TI - The diagnostic value of brain-fatty acid binding protein in traumatic brain injury. PMID- 24044777 TI - Chemical bond characterization of a mixed-valence tri-cobalt complex, Co3(MU admtrz)4(MU-OH)2(CN)6.2H2O. AB - Charge density study of a mixed-valence tri-cobalt compound, Co3(MU-admtrz)4(MU OH)2(CN)6.2H2O (1) (admtrz = 3,5-dimethyl-4-amino-1,2,4-triazole), is investigated based on high resolution X-ray diffraction data and density functional theory (DFT) calculations. The molecular structure of this compound contains three cobalt atoms in a linear fashion, where two terminal ones are Co(III) at a low-spin (LS) state and a central one is Co(II) at a high-spin (HS) state with a total spin quantum number, S(total), of 3/2. It is centrosymmetric with the center of inversion located at the central Co atom (Co2). The Co2 ion is linked with each terminal cobalt (Co1) ion through two MU-admtrz ligands and a MU OH ligand in a CoN4O2 coordination, where the Co1 is bonded additionally to three CN ligands with CoN2OC3 coordination. The combined experimental and theoretical charge density study identifies the different characters of two types of cobalt ions; more pronounced charge concentration and depletion features in the valence shell charge concentration (VSCC) are found in the Co(III) ion than in the Co(II) ion, and d-orbital populations also show the difference. According to topological properties associated with the bond critical point (BCP), the Co1-C(N) bond is the strongest among all the Co-ligand bonds in this compound; the Co-O is stronger than Co-N bond. Again Co1-O is stronger than Co2-O, so as the Co1-N being stronger than Co2-N bond. The electronic configuration of each type of Co atom is further characterized through magnetic measurement, Co-specific X-ray absorption near edge spectroscopy (XANES), and X-ray emission spectra (XES). PMID- 24044776 TI - Toward 3D biomimetic models to understand the behavior of glioblastoma multiforme cells. AB - Glioblastoma multiforme (GBM) tumors are one of the most deadly forms of human cancer and despite improved treatments, median survival time for the majority of patients is a dismal 12-15 months. A hallmark of these aggressive tumors is their unique ability to diffusively infiltrate normal brain tissue. To understand this behavior and successfully target the mechanisms underlying tumor progression, it is crucial to develop robust experimental ex vivo disease models. This review discusses current two-dimensional (2D) experimental models, as well as animal based models used to examine GBM cell migration, including their advantages and disadvantages. Recent attempts to develop three-dimensional (3D) tissue engineering-inspired models and their utility in unraveling the role of microenvironment on tumor cell behaviors are also highlighted. Further, the use of 3D models to bridge the gap between 2D and animal models is explored. Finally, the broad utility of such models in the context of brain cancer research is examined. PMID- 24044778 TI - Reaction pathways for oxygen evolution promoted by cobalt catalyst. AB - The in-depth understanding of the molecular mechanisms regulating the water oxidation catalysis is of key relevance for the rationalization and the design of efficient oxygen evolution catalysts based on earth-abundant transition metals. Performing ab initio DFT+U molecular dynamics calculations of cluster models in explicit water solution, we provide insight into the pathways for oxygen evolution of a cobalt-based catalyst (CoCat). The fast motion of protons at the CoCat/water interface and the occurrence of cubane-like Co-oxo units at the catalyst boundaries are the keys to unlock the fast formation of O-O bonds. Along the resulting pathways, we identified the formation of Co(IV)-oxyl species as the driving ingredient for the activation of the catalytic mechanism, followed by their geminal coupling with O atoms coordinated by the same Co. Concurrent nucleophilic attack of water molecules coming directly from the water solution is discouraged by high activation barriers. The achieved results suggest also interesting similarities between the CoCat and the Mn4Ca-oxo oxygen evolving complex of photosystem II. PMID- 24044780 TI - Bariatric surgery reduces risk factors for development of type 2 diabetes mellitus in morbidly obese, nondiabetic patients. AB - BACKGROUND: Patients with morbid obesity have a high risk of developing type 2 diabetes mellitus (T2DM). Important risk factors include body mass index (BMI), waist circumference, and insulin resistance. In this prospective study, we investigated if preoperative lifestyle changes followed by bariatric surgery could reduce these risk factors. METHODS: Forty nondiabetic obese patients aged 27-57 years participated. Baseline BMI was 36.1-65.6 kg/m(2). Fasting glucose, C peptide, and glycated hemoglobin (HbA1c) were measured at baseline and 1 year after surgery. The patients underwent lifestyle changes for a period of 3 months prior to bariatric surgery and were followed for 1 year after surgery. The correlations between risk factors and weight reduction were assessed by a Pearson test. RESULTS: Lifestyle changes resulted in a mean weight reduction of 14.3 kg. One year after bariatric surgery, the patients had a mean reduction in BMI of 17.6. Mean waist circumference was reduced from 136.5 cm to 100.7 cm. At baseline, all 40 patients had a waist circumference >100 cm; 1 year after surgery 18 of 40 patients did. At baseline, 11 out of 40 had insulin resistance (as defined by a homeostasis model score >3.99), whereas 1 year after surgery none of the patients did. There was a statistically significant correlation between change in waist circumference and change in insulin resistance (P<0.02), and between HbA1c and weight loss (P<0.002). CONCLUSIONS: Our study shows that, in morbidly obese individuals, lifestyle changes followed by bariatric surgery led to a significant weight loss and a reduction in risk factors for development of T2DM. PMID- 24044779 TI - Are morphological criteria sufficient for the identification of circulating tumor cells in renal cancer? AB - BACKGROUND: Single circulating tumor cells (CTCs) or circulating tumor microemboli (CTMs) are potential biomarkers of renal cell cancer (RCC), however studies of CTCs/CTMs in RCC are limited. In this pilot study we aimed to evaluate a novel blood filtration technique suited for cytomorphological classification, immunocytochemical and molecular characterization of filtered, so called circulating non-hematologic cells (CNHCs) - putative CTCs/CTMs - in patients with RCC. METHODS: Blood of 40 patients with renal tumors was subjected to ScreenCell filtration. CNHCs were classified according to cytomorphological criteria. Immunocytochemical analysis was performed with antibodies against CD45, CD31 and carbonic anhydrase IX (CAIX, a RCC marker). DNA of selected CNHCs and respective primary tumors was analysed by array-CGH. RESULTS: CNHC-clusters with malignant or uncertain malignant cytomorphological features - putative CTMs - were negative for CD45, positive for CD31, while only 6% were CAIX positive. Array-CGH revealed that 83% of malignant and uncertain malignant cells did represent with a balanced genome whereas 17% presented genomic DNA imbalances which did not match the aberrations of the primary tumors. Putative single CTCs were negative for CD45, 33% were positive for CD31 and 56% were positive for CAIX. CONCLUSIONS: The majority of CNHC-clusters, putative CTMs, retrieved by ScreenCell filtration may be of endothelial origin. Morphological criteria seem to be insufficient to distinguish malignant from non-malignant cells in renal cancer. PMID- 24044781 TI - Potential prescription drug misuse in assisted living. AB - Prescription drug misuse among older adults includes inappropriate and harmful use of these drugs. In this study, prescription drug misuse in assisted living settings as reported by direct care workers (DCWs) was examined. Data came from DCWs in 45 assisted living settings located in Pennsylvania. A total of 944 DCWs completed a questionnaire on their opinions of prescription drug misuse. DCWs believed most assisted living residents take prescription medications. In addition, 10% of DCWs observed or had evidence that residents used unnecessarily high doses, 30% were preoccupied with the cost of prescription drugs, and 26% had problems understanding the complexity of their drug treatment regimen. Prescription drug misuse may be a problem of importance in assisted living settings. Assisted living has experienced rapid growth in capacity, yet the ability of these settings and their residents to manage prescription drugs may not have kept pace with this growth. PMID- 24044782 TI - Achieving a balance. PMID- 24044783 TI - The in vivo evaluation of anti-angiogenic effects of Hypericum essential oils using the chorioallantoic membrane assay. AB - CONTEXT: Hypericum species including Hypericum confertum Choisy, H. hircinum L., H. hyssopifolium Chaix. subsp. elongatum (Ledeb.) Woron var. microcalycinum (Boiss. & Heldr.) Boiss. and H. perforatum L. (Clusiaceae) are used as medicinal plants in Turkey. OBJECTIVE: The anti-angiogenic evaluation of Hypericum essential oils using the chick embryo chorioallantoic membrane (CAM) assay are performed with this study for the first time. MATERIALS AND METHODS: The anti angiogenic activity of Hypericum essential oils (0.5-5.0 mg/ml) was evaluated in vivo using the CAM assay, compared to standard anti-angiogenic substances at the same concentrations, in trice replicated independent assays. GC and GC-MS analyses were carried out simultaneously to identify the chemical compositions of the Hypericum essential oils. RESULTS: The CAM treated with H. perforatum essential oil showed anti-angiogenic effect (score 0.6 +/- 0.3) at 50 ug/pellet concentration, whereas other tested Hypericum essential oils showed no effect compared to the standards (e.g. suramin score 0.5 +/- 0.2). Furthermore, the tested oils showed neither membrane toxicity nor irritation at the tested concentrations. The major compound of the essential oil of H. confertum was identified as germacrene D (30.2%). The major compound of the essential oils of the H. hircinum. H. hyssopifolium subsp. elongatum var. microcalycinum and H. perforatum was identified as alpha-pinene (88.3, 57.8, 33.3%), respectively. DISCUSSION AND CONCLUSION: Hypericum species and in particular H. perforatum essential oil may have important effect toward wound healing and various inflammations. The data obtained in this experiment suggest further investigations on various cancers due to its anti-angiogenic effects observed. PMID- 24044784 TI - Quick staining technique for myeloperoxidase using potassium iodide and oxidized pyronine B. AB - Myeloperoxidase (MPO) staining has been important for the cytomorphological diagnosis and classification of leukemia. A novel staining method for MPO and its clinical application are presented in the report. Pyronine B (PyB), serving as a chromogenic reagent, was pre-oxidized to obtain stable oxidized Pyronine B solution. The MPO working solution for oxidized pyronine B method consisted of phosphate buffer solution, potassium iodide (KI) solution, and oxidized Pyronine B solution. The positive products of the oxidized Pyronine B method of MPO staining were vibrant red particles located in cytoplasm and the nucleus was stained bluish green. Bone marrow smears from 229 patients with acute leukemia or with grossly normal bone marrow were stained by both oxidized Pyronine B method and the conventional Washburn benzidine staining and a comparison revealed no significant difference in the positive detection rate between the two techniques. The new method eliminates the influence of the varying amount of H2O2 on MPO staining. With this method, the reagents were more stable and the staining procedure was simple and time-saving. This MPO staining technique is a better alternative than the conventional benzidine-based methods. PMID- 24044785 TI - Seasonal variation of platelets in a cohort of Italian blood donors: a preliminary report. AB - BACKGROUND: Since available data are not univocal, the aim of this study was to explore the existence of a seasonal variation in platelet count. METHODS: The study was based on the database of the Italian Association of Blood Volunteers (AVIS), section of Ferrara, Italy, 2001-2010. Hematological data (170,238 exams referring to 16,422 donors) were categorized into seasonal and monthly intervals, and conventional and chronobiological analyses were applied. RESULTS: Platelets and plateletcrit were significantly higher in winter-autumn, with a main peak in December-February (average +3.4% and +4.6%, respectively, P <0.001 for both). CONCLUSIONS: Although seasonal variations have been reported for several acute cardiovascular diseases, it is extremely unlikely that such a slight increase in platelet count in winter alone may be considered as a risk factor. PMID- 24044786 TI - An evidence-based approach to the evaluation and treatment of low back pain in the emergency department. AB - Low back pain is the most common musculoskeletal complaint that results in a visit to the emergency department, and it is 1 of the top 5 most common complaints in emergency medicine. Estimates of annual healthcare expenditures for low back pain in the United States exceed $90 billion annually, not even taking lost productivity and business costs into account. This review explores an evidence-based rationale for the evaluation of the patient with low back pain, and it provides guidance on risk stratification pertaining to laboratory assessment and radiologic imaging in the emergency department. Published guidelines from the American College of Physicians and American Pain Society are reviewed, with emphasis on best evidence for pharmacologic treatments, self-care interventions, and more invasive procedures and surgery in management of low back pain. Utilizing effective and proven strategies will avoid medical errors, provide better care for patients, and help manage healthcare resources and costs. PMID- 24044787 TI - Spectroscopic and kinetic investigation of the reactions of peroxyacetic acid with Burkholderia pseudomallei catalase-peroxidase, KatG. AB - Catalase-peroxidases or KatGs can utilize organic peroxyacids and peroxides instead of hydrogen peroxide to generate the high-valent ferryl-oxo intermediates involved in the catalase and peroxidase reactions. In the absence of peroxidatic one-electron donors, the ferryl intermediates generated with a low excess (10 fold) of peroxyacetic acid (PAA) slowly decay to the ferric resting state after several minutes, a reaction that is demonstrated in this work by both stopped flow UV-vis absorption measurements and EPR spectroscopic characterization of Burkholderia pseudomallei KatG (BpKatG). EPR spectroscopy showed that the [Fe(IV)?O Trp330(*+)], [Fe(IV)?O Trp139(*)], and [Fe(IV)?O Trp153(*)] intermediates of the peroxidase-like cycle of BpKatG ( Colin, J. Wiseman, B. Switala, J. Loewen, P. C. Ivancich, A. ( 2009 ) J. Am. Chem. Soc. 131 , 8557 - 8563 ), formed with a low excess of PAA at low temperature, are also generated with a high excess (1000-fold) of PAA at room temperature. However, under high excess conditions, there is a rapid conversion to a persistent [Fe(IV)?O] intermediate. Analysis of tryptic peptides of BpKatG by mass spectrometry before and after treatment with PAA showed that specific tryptophan (including W330, W139, and W153), methionine (including Met264 of the M-Y-W adduct), and cysteine residues are either modified with one, two, or three oxygen atoms or could not be identified in the spectrum because of other undetermined modifications. It was concluded that these oxidized residues were the source of electrons used to reduce the excess of PAA to acetic acid and return the enzyme to the ferric state. Treatment of BpKatG with PAA also caused a loss of catalase activity towards certain substrates, consistent with oxidative disruption of the M-Y-W adduct, and a loss of peroxidase activity, consistent with accumulation of the [Fe(IV)?O] intermediate and the oxidative modification of the W330, W139, and W153. PAA, but not H2O2 or tert-butyl hydroperoxide, also caused subunit cross linking. PMID- 24044788 TI - A qualitative case study of child protection issues in the Indian construction industry: investigating the security, health, and interrelated rights of migrant families. AB - BACKGROUND: Many of India's estimated 40 million migrant workers in the construction industry migrate with their children. Though India is undergoing rapid economic growth, numerous child protection issues remain. Migrant workers and their children face serious threats to their health, safety, and well-being. We examined risk and protective factors influencing the basic rights and protections of children and families living and working at a construction site outside Delhi. METHODS: Using case study methods and a rights-based model of child protection, the SAFE model, we triangulated data from in-depth interviews with stakeholders on and near the site (including employees, middlemen, and managers); 14 participants, interviews with child protection and corporate policy experts in greater Delhi (8 participants), and focus group discussions (FGD) with workers (4 FGDs, 25 members) and their children (2 FGDs, 9 members). RESULTS: Analyses illuminated complex and interrelated stressors characterizing the health and well-being of migrant workers and their children in urban settings. These included limited access to healthcare, few educational opportunities, piecemeal wages, and unsafe or unsanitary living and working conditions. Analyses also identified both protective and potentially dangerous survival strategies, such as child labor, undertaken by migrant families in the face of these challenges. CONCLUSIONS: By exploring the risks faced by migrant workers and their children in the urban construction industry in India, we illustrate the alarming implications for their health, safety, livelihoods, and development. Our findings, illuminated through the SAFE model, call attention to the need for enhanced systems of corporate and government accountability as well as the implementation of holistic child-focused and child-friendly policies and programs in order to ensure the rights and protection of this hyper-mobile, and often invisible, population. PMID- 24044789 TI - An in silico comparison between margin-based and probabilistic target-planning approaches in head and neck cancer patients. AB - BACKGROUND AND PURPOSE: To apply target probabilistic planning (TPP) approach to intensity modulated radiotherapy (IMRT) plans for head and neck cancer (HNC) patients. MATERIAL AND METHODS: Twenty plans of HNC patients were re-planned replacing the simultaneous integrated boost IMRT optimization objectives for minimum dose on the boost target and the elective volumes with research probabilistic objectives: the latter allow for explicit handling of systematic and random geometric uncertainties, enabling confidence level based probabilistic treatment planning. Monte-Carlo evaluations of geometrical errors were performed, with endpoints D98%, D2% and Dmean, calculated at a confidence level of 90%. The dose distribution was expanded outside the patient to prevent large bilateral elective treatment volumes ending up in air for probabilistic shifts. RESULTS: TPP resulted in more regular isodoses and in reduced dose, on average, to organs at risk (OAR), up to more than 6Gy, while maintaining target coverage and keeping the maximum dose to limiting structures within requirements. In particular, when the surrounding OARs overlap with the planning target volume (PTV) but not with the clinical target volume (CTV), better results were achieved. CONCLUSION: The TPP approach was evaluated in HNC patients, and proven to be an efficient tool for managing uncertainties. PMID- 24044790 TI - Hypoxia imaging with [18F]HX4 PET in NSCLC patients: defining optimal imaging parameters. AB - BACKGROUND AND PURPOSE: [(18)F]HX4 is a promising hypoxia PET-tracer. Uptake, spatio-temporal stability and optimal acquisition parameters for [(18)F]HX4 PET imaging were evaluated in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: [(18)F]HX4 PET/CT images of 15 NSCLC patients were acquired 2h and 4h after injection (p.i.). Maximum standardized-uptake-value (SUV(max)), tumor-to blood-ratio (TBR(max)), hypoxic fraction (HF) and contrast-to-noise-ratio (CNR) were determined for all lesions. To evaluate spatio-temporal stability, DICE similarity and Pearson correlation coefficients were calculated. Optimal acquisition-duration was assessed by comparing 30, 20, 10 and 5 min acquisitions. RESULTS: Considerable uptake (TBR >1.4) was observed in 18/25 target lesions. TBR(max) increased significantly from 2 h (1.6 +/- 0.3) to 4 h p.i. (2.0 +/- 0.6). Uptake patterns at 2 h and 4 h p.i. showed a strong correlation (R=0.77 +/- 0.10) with a DICE similarity coefficient of 0.69 +/- 0.08 for the 30% highest uptake volume. Reducing acquisition-time resulted in significant changes in SUV(max) and CNR. TBR(max) and HF were only affected for scan-times of 5 min. CONCLUSIONS: The majority of NSCLC lesions showed considerable [(18)F]HX4 uptake. The heterogeneous uptake pattern was stable between 2 h and 4 h p.i. [(18)F]HX4 PET imaging at 4 h p.i. is superior to 2 h p.i. to reach highest contrast. Acquisition time may be reduced to 10 min without significant effects on TBR(max) and HF. PMID- 24044791 TI - Dose-response of critical structures in the posterior eye segment to hypofractioned stereotactic photon radiotherapy of choroidal melanoma. AB - PURPOSE: To identify modifying factors and dose-/volume-response relationships for the retina and optic nerve related to highly conformal hypofractionated radiotherapy. PATIENTS AND METHODS: Seventy-three patients undergoing hypofractionated stereotactic photon radiotherapy of choroidal melanoma were included in this retrospective study. The volumes of the optic nerve receiving doses of more than 7.5 or 12 Gy, respectively, were defined. Optic nerve circumference included in the 30%, 40%, 50%, or 80% isodose (ON%) and retina included in 30% or 40% were determined as quantal effects. Univariate and multivariate analyses were performed for clinical variables as well as probit analysis to define EDx (doses where a positive response is expected in x% of the cases). RESULTS: Median follow-up was 90.0 (interquartile range 69.0-98.0) months. Fifty-two (71%) and 49 (67%) patients developed radiation retinopathy and optic neuropathy (any grade). Age, length of follow-up and diabetes were significant parameters regarding retinopathy. Optic neuropathy was significantly influenced by age, length of follow-up, and ON30. The probability of optic neuropathy (any grade and grade >= 2) significantly increases with the dose (p ranges from 0.0126 to 0.0211). CONCLUSION: Treatment planning should aim at minimizing encompassing isodoses particularly in the low dose region, without compromising PTV coverage. PMID- 24044792 TI - Motion-specific internal target volumes for FDG-avid mediastinal and hilar lymph nodes. AB - BACKGROUND AND PURPOSE: To quantify the benefit of motion-specific internal target volumes for FDG-avid mediastinal and hilar lymph nodes generated using 4D PET, vs. conventional internal target volumes generated using non-respiratory gated PET and 4D-CT scans. MATERIALS AND METHODS: Five patients with FDG-avid tumors metastatic to 11 hilar or mediastinal lymph nodes were imaged with respiratory-correlated FDG-PET (4D-PET) and 4D-CT. FDG-avid nodes were contoured by a radiation oncologist in two ways. Standard-of-care volumes were contoured using conventional un-gated PET, 4D-CT, and breath-hold CT. A second, motion specific, set of volumes were contoured using 4D-PET.Contours based on 4D-PET corresponded directly to an internal target volume (ITV(4D)), whereas contours based on un-gated PET were expanded by a series of exploratory isotropic margins (from 5 to 13 mm) based on literature recommendations on lymph node motion to form internal target volumes (ITV(3D)). RESULTS: A 13 mm expansion of the un gated PET nodal volume was needed to cover the ITV(4D) for 10 of 11 nodes studied. The ITV(3D) based on a 13 mm expansion included on average 45 cm(3) of tissue that was not included in the ITV(4D). CONCLUSIONS: Motion-specific lymph node internal target volumes generated from 4D-PET imaging could be used to improve accuracy and/or reduce normal-tissue irradiation compared to the standard of-care un-gated PET based internal target volumes. PMID- 24044793 TI - Endorectal balloons in the post prostatectomy setting: do gains in stability lead to more predictable dosimetry? AB - PURPOSE: To perform a comparative study assessing potential benefits of endorectal-balloons (ERB) in post-prostatectomy patients. METHOD AND MATERIALS: Ten retrospective post-prostatectomy patients treated without ERB and ten prospective patients treated with the ERB in situ were recruited. All patients received IMRT and IGRT using kilovoltage cone-beam computed tomography (kVCBCT). kVCBCT datasets were registered to the planning dataset, recontoured and the original plan recalculated on the kVCBCTs to recreate anatomical conditions during treatment. The imaging, structure and dose data were imported into in house software for the assessment of geometric variation and cumulative equivalent uniform dose (EUD) in the two groups. RESULTS: The difference in location (DeltaCOV) for the bladder between planning and each CBCT was similar for each group. The range of mean DeltaCOV for the rectum was 0.15-0.58 cm and 0.15-0.59 cm for the non-ERB and ERB groups. For superior-CTV and inferior-CTV the difference between planned and delivered D95% (mean +/- SD) for the non-ERB group was 2.1 +/- 6.0 Gy and -0.04 +/- 0.20 Gy. While for the ERB group the difference in D95% was 8.7 +/- 12.6 Gy and 0.003 +/- 0.104 Gy. CONCLUSIONS: The use of ERBs in the post-prostatectomy setting did improve geometric reproducibility of the target and surrounding normal tissues, however no improvement in dosimetric stability was observed for the margins employed. PMID- 24044794 TI - Cardiac comorbidity is an independent risk factor for radiation-induced lung toxicity in lung cancer patients. AB - PURPOSE: To test the hypothesis that cardiac comorbidity before the start of radiotherapy (RT) is associated with an increased risk of radiation-induced lung toxicity (RILT) in lung cancer patients. MATERIAL AND METHODS: A retrospective analysis was performed of a prospective cohort of 259 patients with locoregional lung cancer treated with definitive radio(chemo)therapy between 2007 and 2011 (ClinicalTrials.gov Identifiers: NCT00572325 and NCT00573040). We defined RILT as dyspnea CTCv.3.0 grade >=2 within 6 months after RT, and cardiac comorbidity as a recorded treatment of a cardiac pathology at a cardiology department. Univariate and multivariate analyses, as well as external validation, were performed. The model-performance measure was the area under the receiver operating characteristic curve (AUC). RESULTS: Prior to RT, 75/259 (28.9%) patients had cardiac comorbidity, 44% of whom (33/75) developed RILT. The odds ratio of developing RILT for patients with cardiac comorbidity was 2.58 (p<0.01). The cross-validated AUC of a model with cardiac comorbidity, tumor location, forced expiratory volume in 1s, sequential chemotherapy and pretreatment dyspnea score was 0.72 (p<0.001) on the training set, and 0.67 (p<0.001) on the validation set. CONCLUSION: Cardiac comorbidity is an important risk factor for developing RILT after definite radio(chemo)therapy of lung cancer patients. PMID- 24044795 TI - Characterization of tumor heterogeneity using dynamic contrast enhanced CT and FDG-PET in non-small cell lung cancer. AB - PURPOSE: Dynamic contrast-enhanced CT (DCE-CT) quantifies vasculature properties of tumors, whereas static FDG-PET/CT defines metabolic activity. Both imaging modalities are capable of showing intra-tumor heterogeneity. We investigated differences in vasculature properties within primary non-small cell lung cancer (NSCLC) tumors measured by DCE-CT and metabolic activity from FDG-PET/CT. METHODS: Thirty three NSCLC patients were analyzed prior to treatment. FDG-PET/CT and DCE-CT were co-registered. The tumor was delineated and metabolic activity was segmented on the FDG-PET/CT in two regions: low (<50% maximum SUV) and high (>=50% maximum SUV) metabolic uptake. Blood flow, blood volume and permeability were calculated using a maximum slope, deconvolution algorithm and a Patlak model. Correlations were assessed between perfusion parameters for the regions of interest. RESULTS: DCE-CT provided additional information on vasculature and tumor heterogeneity that was not correlated to metabolic tumor activity. There was no significant difference between low and high metabolic active regions for any of the DCE-CT parameters. Furthermore, only moderate correlations between maximum SUV and DCE-CT parameters were observed. CONCLUSIONS: No direct correlation was observed between FDG-uptake and parameters extracted from DCE-CT. DCE-CT may provide complementary information to the characterization of primary NSCLC tumors over FDG-PET/CT imaging. PMID- 24044796 TI - Radiation-induced carotid artery atherosclerosis. AB - PURPOSE: Carotid arteries frequently receive significant doses of radiation as collateral structures in the treatment of malignant diseases. Vascular injury following treatment may result in carotid artery stenosis (CAS) and increased risk of stroke and transient ischaemic attack (TIA). This systematic review examines the effect of radiotherapy (RT) on the carotid arteries, looking at the incidence of stroke in patients receiving neck radiotherapy. In addition, we consider possible surrogate endpoints such as CAS and carotid intima-medial thickness (CIMT) and summarise the evidence for radiation-induced carotid atherosclerosis. MATERIALS AND METHODS: From 853 references, 34 articles met the criteria for inclusion in this systematic review. These papers described 9 studies investigating the incidence of stroke/TIA in irradiated patients, 11 looking at CAS, and 14 examining CIMT. RESULTS: The majority of studies utilised suboptimally-matched controls for each endpoint. The relative risk of stroke in irradiated patients ranged from 1.12 in patients with breast cancer to 5.6 in patients treated for head and neck cancer. The prevalence of CAS was increased by 16-55%, with the more modest increase seen in a study using matched controls. CIMT was increased in irradiated carotid arteries by 18-40%. Only two matched control studies demonstrated a significant increase in CIMT of 36% and 22% (p=0.003 and <0.001, respectively). Early prospective data demonstrated a significant increase in CIMT in irradiated arteries at 1 and 2 years after RT (p<0.001 and <0.01, respectively). CONCLUSIONS: The incidence of stroke was significantly increased in patients receiving RT to the neck. There was a consistent difference in CAS and CIMT between irradiated and unirradiated carotid arteries. Future studies should optimise control groups. PMID- 24044797 TI - Malignant salivary gland tumours: can fast neutron therapy results point the way to carbon ion therapy? AB - BACKGROUND AND PURPOSE: To evaluate the outcome of malignant salivary gland tumours treated with neutron therapy to assess the potential for other high linear energy transfer (LET) beams. MATERIALS AND METHODS: Neutrons at iThemba LABS are produced by the reaction of 66MeV protons on a beryllium target. A median dose 20.4Gy, in 12 fractions in 4weeks or 15 fractions in 5weeks, was given to 335 patients with 176 irresectable, 104 macroscopically residual and 55 unresected tumours. RESULTS: Locoregional control was 60.6% at 5years and 39.1% at 10years and DSS was 66.8% and 53.7% at 5 and 10years respectively. In the univariate analysis T4, >4cm, high grade, squamous carcinoma, unresected and irresectable tumours, and positive nodes were significantly worse for LRC. In the multivariate analysis tumours >6cm, squamous carcinoma, irresectable tumours and nodes were significantly worse for LRC. Tumours >6cm, high grade, squamous carcinoma and nodes were significantly worse for DSS. Neither LRC nor DSS was influenced by age, sex, site, dose, fractionation or for initial or recurrent disease. CONCLUSIONS: Neutron therapy appears to be the treatment of choice for macroscopically incompletely excised and irresectable salivary gland tumours with improved survival rates. Further improvement may be achieved with other high LET modalities with a superior dose profile, such as carbon ions. PMID- 24044799 TI - Phase III trial of low-level laser therapy to prevent oral mucositis in head and neck cancer patients treated with concurrent chemoradiation. AB - BACKGROUND: Oral mucositis (OM) is a complication of chemoradiotherapy treatment of head and neck squamous cell carcinoma (HNSCC) patients with no effective therapy. This study was designed to assess the efficacy of preventive low-level laser therapy (LLLT) in reducing the incidence of grade 3-4 OM. MATERIAL AND METHODS: From June 2007 to December 2010, 94 HNSCC patients entered a prospective, randomized, double-blind, placebo-controlled phase III trial. Chemoradiotherapy consisted of conventional radiotherapy plus concurrent cisplatin every 3weeks. A diode InGaAlP (660nm-100mW-1J-4J/cm(2)) was used. OM evaluation was performed by WHO and OMAS scales and quality of life by EORTC questionnaires (QLQ). RESULTS: A six-fold decrease in the incidence of grades 3-4 OM was detected in the LLLT group compared to the placebo; (6.4% versus 40.5%). LLLT impacted the incidence of grades 3-4 OM to a relative risk ratio of 0.158 (CI 95% 0.050-0.498). After treatment QLQ-C30 showed, differences favoring LLLT in physical, emotional functioning, fatigue, and pain; while the QLQ-H&N35 showed improvements in LLLT arm for pain, swallowing, and trouble with social eating. CONCLUSION: Preventive LLLT in HNSCC patients receiving chemoradiotherapy is an effective tool for reducing the incidence of grade 3-4 OM. Efficacy data were corroborated by improvements seen in quality of life. PMID- 24044798 TI - Effect of local therapy on locoregional recurrence in postmenopausal women with breast cancer in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. AB - BACKGROUND AND PURPOSE: The TEAM trial investigated the efficacy and safety of adjuvant endocrine therapy consisting of either exemestane or the sequence of tamoxifen followed by exemestane in postmenopausal hormone-sensitive breast cancer. The present analyses explored the association between locoregional therapy and recurrence (LRR) in this population. MATERIAL AND METHODS: Between 2001 and 2006, 9779 patients were randomized. Local treatment was breast conserving surgery plus radiotherapy (BCS+RT), mastectomy without radiotherapy (MST-only), or mastectomy plus radiotherapy (MST+RT). Patients with unknown data on surgery, radiotherapy, tumor or nodal stage (n=199), and patients treated by lumpectomy without radiotherapy (n=349) were excluded. RESULTS: After a median follow-up of 5.2 years, 270 LRRs occurred (2.9%) among 9231 patients. The 5-years actuarial incidence of LRR was 4.2% (95% CI 3.3-4.9%) for MST-only, 3.4% (95% CI 2.4-4.2%) for MST+RT and 1.9% (95% CI 1.5-2.3%) for BCS+RT. After adjustment for prognostic factors, the hazard ratio (HR, reference BCS+RT) for LRR remained significantly higher for MST-only (HR 1.53; 95% CI 1.10-2.11), not for MST+RT (HR 0.78; 95% CI 0.50-1.22). CONCLUSION: This explorative analysis showed a higher LRR risk after MST-only than after BCS+RT, even after adjustment for prognostic factors. As this effect was not seen for MST+RT versus BCS+RT, it might be explained by the beneficial effects of radiation treatment. PMID- 24044800 TI - Hypofractionated stereotactic photon radiotherapy of posteriorly located choroidal melanoma with five fractions at ten Gy--clinical results after six years of experience. AB - PURPOSE: To evaluate long-term safety and efficacy of hypofractionated stereotactic photon radiotherapy with 5 five fractions at 10 Gy each in patients with centrally located choroidal melanoma. MATERIALS AND METHODS: Ninety-one patients with centrally located choroidal melanoma were treated stereotactically at a linear accelerator with 6 MV photon beams with 5 fractions at 10 Gy each. Examinations were performed at baseline and every 3 months in the first 2 years, then every 6 months until 5 years and yearly thereafter. Median follow-up was 37.8 months (IQR 19.2-49.9). They included visual acuity assessment, routine ophthalmological examinations with fundoscopy, echography for measurement of tumor dimensions, medical examinations and, if necessary, fluorescein angiography. RESULTS: Initial tumor base diameters, height and volume were 11.20mm (IQR 9.10-13.70), 9.80 mm (IQR 7.80-11.70), 4.53 mm (IQR 3.33-6.43) and 253.8mm(3) (IQR 127.5-477.0). Local tumor control and eye retention rates were 97.7% and 86.4% after 5 years, respectively. Eight patients developed metastatic disease and 3 of them died due to metastatic disease during the follow-up period. Median visual acuity decreased from 0.67 initially to 0.05 at the last individual follow-up (p<0.001). The most common toxicities (any grade) were radiation retinopathy (n=39), optic neuropathy (n=32), radiogenic cataract (n=21), neovascular glaucoma (n=15) and dry eye syndrome (n=10). The 5 year probabilities to remain free of these side effects (any grade) were 26.0%, 45.4%, 55.4%, 72.6% and 80.5%, respectively. The most important prognostic factors for toxicities were the largest tumor base diameter, tumor height and tumor distance to the optic disk. CONCLUSION: Hypofractionated stereotactic photon radiotherapy with a total dose of 50 Gy delivered in 5 fractions is a highly effective treatment option in patients with centrally located choroidal melanoma and has a moderate toxicity profile. PMID- 24044801 TI - Palliative pelvic radiotherapy of symptomatic incurable prostate cancer - a systematic review. AB - BACKGROUND AND PURPOSE: Patients with prostate cancer (PC) and a symptomatic pelvic tumor may be treated with palliative pelvic radiotherapy for symptom relief or to delay symptom progression. Radiotherapy dose and fractionation regimens vary. We aimed to provide an overview of the literature and to evaluate palliative pelvic radiotherapy of PC focusing on symptomatic effect, quality of life (QOL), and toxicity, and to determine the optimal radiotherapy schedule. MATERIAL AND METHODS: Systematic literature searches of Medline, Embase and Cochrane databases were performed through 2011. Studies reporting symptom and QOL responses were eligible. RESULTS: Nine studies were included, all retrospective chart reviews. There were large variations in radiotherapy dose and fractionation. Overall symptom response rate was 75% and positive responses were reported for hemorrhage (73%), pain (80%), bladder outlet obstruction (63%), rectal symptoms (78%) and ureteric obstruction (62%). Toxicity results were not evaluable. CONCLUSIONS: Despite limitations in the review process and the included studies, we conclude that pelvic radiotherapy for symptomatic PC appears to provide effective palliation of a variety of symptoms. There is currently no valid documentation regarding onset or duration of palliation. No recommendations can be provided regarding target dose or fractionation schedule in this context. PMID- 24044802 TI - Outcome of a phase II prospective study on partial breast irradiation with interstitial multi-catheter high-dose-rate brachytherapy. AB - BACKGROUND AND PURPOSE: Partial breast irradiation (PBI) is an alternative to whole-breast irradiation after breast-conserving surgery in selected patients. Until the results of randomized phase III studies are available, phase II studies inform about PBI. We report the 5 year results of a phase II prospective study with PBI using interstitial multi-catheter high-dose-rate brachytherapy (ClinicalTrials.gov Identifier: NCT00499057). METHODS: Hundred patients received PBI (4 Gy, twice a day for 4 days, until 32 Gy). Inclusion criteria were: age >= 40years, infiltrating carcinoma without lobular histology, ductal in situ carcinoma, tumor size <= 2.5 cm, negative surgical margins and axillary lymph nodes. RESULTS: At a median follow-up of 60 months late toxicity occurred in 25 patients; the 5-year probability of freedom from late toxicity was 72.6% (95% CI: 63.7-81.7). Tamoxifen was the only significant risk factor for late toxicity. Cosmetic results, judged by physicians and patients, were good/excellent in 98 patients. Three local relapses (1 true, 2 elsewhere) and 1 regional relapse occurred. The 5-year probability of local or regional relapse-free survival was 97.7% (95% CI: 91.1-99.4) and 99.0% (95% CI: 92.9-99.8), respectively. CONCLUSION: PBI with interstitial multi-catheter brachytherapy is associated with low relapse and late toxicity rates. PMID- 24044803 TI - Hypofractionated whole breast irradiation for patients with large breasts: a randomized trial comparing prone and supine positions. AB - BACKGROUND AND PURPOSE: Comparison of acute toxicity of whole-breast irradiation (WBI) in prone and supine positions. MATERIALS AND METHODS: This non-blinded, randomized, prospective, mono-centric trial was undertaken between December 29, 2010, and December 12, 2012. One hundred patients with large breasts were randomized between supine multi beam (MB) and prone tangential field (TF) intensity modulated radiotherapy (IMRT). Dose-volume parameters were assessed for the breast, heart, left anterior descending coronary artery (LAD), ipsilateral lung and contralateral breast. The primary endpoint was acute moist skin desquamation. Secondary endpoints were dermatitis, edema, pruritus and pain. RESULTS: Prone treatment resulted in: improved dose coverage (p<0.001); better homogeneity (p<0.001); less volumes of over-dosage (p=0.001); reduced acute skin desquamation (p<0.001); a 3-fold decrease of moist desquamation p=0.04 (chi square), p=0.07 (Fisher's exact test)); lower incidence of dermatitis (p<0.001), edema (p=0.005), pruritus (p=0.06) and pain (p=0.06); 2- to 4-fold reduction of grades 2-3 toxicity; lower ipsilateral lung (p<0.001) and mean LAD (p=0.007) dose; lower, though statistically non-significant heart and maximum LAD. CONCLUSIONS: This study provides level I evidence for replacing the supine standard treatment by prone IMRT for whole-breast irradiation in patients with large breasts. A confirmatory trial in a multi-institutional setting is warranted. PMID- 24044804 TI - Left-sided breast cancer radiotherapy with and without breath-hold: does IMRT reduce the cardiac dose even further? AB - PURPOSE: In radiotherapy for left-sided breast cancer, Active Breathing Control enables a decrease of cardiac and Left Anterior Descending (LAD) coronary artery dose. We compared 3D-Conformal (3D-CRT) to Intensity Modulated Radiotherapy (IMRT) treatment plans based on free-breathing (FB) and breath-hold (BH). We investigated whether IMRT enables an additional decrease of cardiac dose in radiotherapy plans with and without BH. METHODS AND MATERIALS: Twenty patients referred for whole breast irradiation were included. The whole breast, heart and LAD-region were contoured. Four treatment plans were generated: FB_3D-CRT; FB_IMRT; BH_3D-CRT; BH_IMRT. Several doses were obtained from Dose Volume Histograms and compared. Results were compared statistically using the Wilcoxin Signed Rank Test. For heart and LAD-region, a significant dose reduction was found in BH (p<0.01). For both BH and FB, a significant dose reduction was found using IMRT (p<0.01). By using IMRT an average reduction of 5% was noted in the LAD-region for the volume receiving 20Gy. In 5 cases, the LAD-region remained situated in the vicinity of the radiation portals even in BH. Nevertheless, with IMRT the LAD dose was reduced in these cases. CONCLUSION: IMRT results in a significant additional decrease of dose in the heart and LAD-region in both breath-hold and free-breathing. PMID- 24044805 TI - Prognostic significance of visible cardiophrenic angle lymph nodes in the presence of peritoneal metastases from colorectal cancers. AB - BACKGROUND: Visible cardiophrenic angle lymph nodes (CPALN) (enlarged or not), detected on CT scan are correlated with the presence of peritoneal metastases (PM), and contribute to the diagnosis of PM in colorectal cancer patients. OBJECTIVE: To study whether visible CPALN exert a prognostic impact on survival after complete cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CCRS + HIPEC) treating PM. PATIENTS AND METHODS: From 1999 to 2010, 114 patients with colorectal cancer and PM were treated with CCRS + HIPEC. CPALN were depicted in 64% of cases. The impact of visible CPALN on survival was investigated retrospectively. RESULTS: The mean peritoneal cancer index (PCI) score was 9.2, 21% of the patients had presented with associated liver metastases, and 71% of the women with ovarian metastases. Median follow-up was 3.9 years. Visible CPALN had no impact on OS nor on DFS, unlike the PCI score which was unequivocably the most potent prognostic factor in the multivariate analysis. CONCLUSION: Although some arguments might suggest that CPALN are malignant, paradoxically, we found that visible CPALN did not exert a positive nor a negative impact on survival after CCRS + HIPEC. SYNOPSIS: Visible cardiophrenic angle lymph nodes (CPALN) on CT-scan are strongly associated with the presence of peritoneal metastases. But this study demonstrates that the presence of CPALN has no prognostic impact after optimal cytoreductive surgery plus HIPEC. PMID- 24044806 TI - No difference between lowest and highest volume hospitals in outcome after colorectal cancer surgery in the southern Netherlands. AB - AIM: To investigate the quality of surgical colorectal cancer (CRC) care in the southern Netherlands by evaluating differences between the five hospitals with the lowest volume and the five hospitals with the highest volume. METHODS: Patients who underwent resection for primary CRC diagnosed between 2008 and 2011 in southern Netherlands were included (n = 5655). The five hospitals performing <130 resections/year were classified 'low volume'; the five hospitals performing >= 130 resections/year 'high volume'. Differences in surgical approach, circumferential resection margins (CRM), anastomotic leakage and 30-day mortality between hospital volumes were analysed using Chi(2) tests. Expected proportions anastomotic leakage and 30-day mortality were calculated using multivariable logistic regression. Crude 3-year survival was calculated using Kaplan-Meier curves. Cox regression was used to discriminate independent risk factors for death. RESULTS: 23% of patients with locally advanced rectal cancer (LARC) diagnosed in a low volume centre was referred to a high volume centre. Patients with colon cancer underwent less laparoscopic surgery and less urgent surgery in low compared to high volume hospitals (10% versus 32%, p < 0.0001, and 8% versus 11%, p = 0.003, respectively). For rectal cancer, rates of abdominoperineal resections versus low anterior resections, and CRM were not associated with hospital volume. Anastomotic leakage, 30-day mortality, and survival did not differ between hospital volumes. CONCLUSION: In southern Netherlands, low volume hospitals deliver similar high quality surgical CRC care as high volume hospitals in terms of CRM, anastomotic leakage and survival, also after adjustment for casemix. However, this excludes LARC since a substantial proportion was referred to high volume hospitals. PMID- 24044807 TI - Inconsistency in the items included in tools used in general health research and physical therapy to evaluate the methodological quality of randomized controlled trials: a descriptive analysis. AB - BACKGROUND: Assessing the risk of bias of randomized controlled trials (RCTs) is crucial to understand how biases affect treatment effect estimates. A number of tools have been developed to evaluate risk of bias of RCTs; however, it is unknown how these tools compare to each other in the items included. The main objective of this study was to describe which individual items are included in RCT quality tools used in general health and physical therapy (PT) research, and how these items compare to those of the Cochrane Risk of Bias (RoB) tool. METHODS: We used comprehensive literature searches and a systematic approach to identify tools that evaluated the methodological quality or risk of bias of RCTs in general health and PT research. We extracted individual items from all quality tools. We calculated the frequency of quality items used across tools and compared them to those in the RoB tool. Comparisons were made between general health and PT quality tools using Chi-squared tests. RESULTS: In addition to the RoB tool, 26 quality tools were identified, with 19 being used in general health and seven in PT research. The total number of quality items included in general health research tools was 130, compared with 48 items across PT tools and seven items in the RoB tool. The most frequently included items in general health research tools (14/19, 74%) were inclusion and exclusion criteria, and appropriate statistical analysis. In contrast, the most frequent items included in PT tools (86%, 6/7) were: baseline comparability, blinding of investigator/assessor, and use of intention-to-treat analysis. Key items of the RoB tool (sequence generation and allocation concealment) were included in 71% (5/7) of PT tools, and 63% (12/19) and 37% (7/19) of general health research tools, respectively. CONCLUSIONS: There is extensive item variation across tools that evaluate the risk of bias of RCTs in health research. Results call for an in depth analysis of items that should be used to assess risk of bias of RCTs. Further empirical evidence on the use of individual items and the psychometric properties of risk of bias tools is needed. PMID- 24044808 TI - Thermodynamically stable emulsions using Janus dumbbells as colloid surfactants. AB - One of the most important properties of emulsions is their stability. Most emulsions stabilized with molecular surfactants tend to lose their stability over time via different mechanisms. Although the stability of emulsions stabilized with homogeneous particles have been shown to be superior to that of surfactant stabilized emulsions, these Pickering emulsions nevertheless are only kinetically stable and thus can undergo destabilization. Janus particles that have two opposite wetting surfaces have shown promise in imparting emulsions with long term stability because of their strong attachment to the oil-water interface. In this theoretical study, we consider thermodynamics of emulsion stabilization using amphiphilic Janus dumbbells, which are nonspherical particles made of two partially fused spherical particles of opposite wettability. These amphiphilic dumbbells are attractive candidates as colloid surfactants for emulsion stabilization because highly uniform Janus dumbbells can be synthesized in large quantities; thus, their application in emulsion stabilization can become practical. Our theoretical calculation demonstrates that Janus dumbbells can indeed generate thermodynamically stable Pickering emulsions. In addition, we also find that there exists a total oil-water interfacial area that results in the lowest energy state in the system, which occurs when Janus dumbbells available in the system are completely consumed to fully cover the droplet interfaces. We show that the geometry of dumbbells as well as the composition of the emulsion mixtures has significant influences on the average size of dumbbell stabilized emulsions. We also investigate the effect of asymmetry of Janus dumbbells on the average droplet radius. Our results clearly show that amphiphilic Janus dumbbells provide unique opportunities in stabilizing emulsions for various applications. PMID- 24044809 TI - The legacy of nursing through the troubles. PMID- 24044810 TI - Revalidation could depend on the quality of employers' appraisals. PMID- 24044811 TI - Nightingale, Seacole and Cavell to be included on curriculum. PMID- 24044813 TI - Volunteer inspector urges others to step up and help. PMID- 24044812 TI - Whistleblower hopes her 'culture change' post will be emulated. PMID- 24044814 TI - 'Use every chance to promote health'. PMID- 24044815 TI - Pressure ulcer and falls figures show trust performance. PMID- 24044816 TI - Royal Navy seeks intrepid nurses for pirate missions off African coast. PMID- 24044818 TI - Guidance on how to keep patients' sensitive data safe. PMID- 24044819 TI - New care model cuts conflict. PMID- 24044820 TI - Fast action by nurses essential to prevent deaths from sepsis. PMID- 24044821 TI - Prescribers urged to resist patients' pleas for antibiotics. PMID- 24044822 TI - Political notebook. PMID- 24044823 TI - Skills academy will help HCAs to access better training courses. PMID- 24044825 TI - One-off L500 million not enough to solve A&E crisis, RCN warns. PMID- 24044826 TI - 'Two tough' sister shows no fear of jabs. PMID- 24044827 TI - Patients and employers given a say on whether nurses are fit to practise. AB - Revalidation of the UK's nursing and midwifery workforce drew a step closer last week when the Nursing and Midwifery Council approved a model to be rolled out by the end of 2015. PMID- 24044833 TI - Self-harm. PMID- 24044834 TI - Nurses join debate on splitting the UK. AB - Scotland's referendum on whether to become independent is only a year away. The likely effects of independence on the health service and the lives of health professionals are still unclear, with supporters arguing it is a 'natural' move that would boost the health system and opponents warning of risks to funding an increased isolation. PMID- 24044835 TI - Care knew no sides during the troubles. AB - The patient was a member of the security forces who had been brought in with injuries to his head, abdomen and legs. PMID- 24044858 TI - Measuring airway inflammation using the fraction of exhaled nitric oxide. AB - Although asthma is a common respiratory condition, there is no standardised definition of the type, severity or frequency of symptoms, nor of the findings on investigation. Therefore, it is not possible to make evidence-based recommendations on how to diagnose patients with asthma. This article describes the use of the fraction of exhaled nitric oxide (FeNO) as a biomarker of airway inflammation, thereby assisting diagnosis of asthma in clinical practice. FeNO can also be used to monitor adherence to inhaled corticosteroid therapy. PMID- 24044859 TI - Implications for carers of terminally ill patients dying at home. AB - Most terminally ill patients will express a wish to die at home. To achieve this, patients must rely on the support of family carers, who may experience emotional and health difficulties in providing such care, both before and after the death. Healthcare professionals can help to relieve the burden on family carers, and there is guidance available to direct GPs and other community healthcare professionals on providing good anticipatory palliative care for patients, and support for carers. This will increase the likelihood that patients at the end of life will achieve a 'good death', and family members will have a positive experience of care giving. PMID- 24044860 TI - Pressure ulcer prevention in the community setting. AB - Pressure ulcers are associated with reduced quality of life, affecting individuals physically, socially and emotionally. The financial cost to the NHS of preventing and treating such ulcers is substantial. Although largely preventable, pressure ulcers are still common. The Department of Health is committed to eliminating all avoidable pressure ulcers in NHS-provided care. This article explores methods of preventing pressure ulcers, with particular focus on risk assessment, skin inspection, pressure-relieving measures, nutrition and hydration, and patient and carer education. PMID- 24044861 TI - Staff appraisal. AB - As a nurse and supervisor of an acute surgical ward, I found the CPD article interesting because it identified ways to monitor staff performance continually. The approach to staff appraisal described was suitable for addressing poor performance and acknowledging good performance among nurses. PMID- 24044862 TI - Grow your own success. AB - Each person's career is an individual journey. The decisions you have made since you were young about what to study, which job to go into and how you perform your role are highly idiosyncratic. PMID- 24044864 TI - An ideal role for the right nurse. AB - What was once often seen as a backwater for nurses, the perception of occupational health is starting to change. PMID- 24044865 TI - Shifting the focus from disease. AB - Rhiannon Beaumont-Wood was appointed the first ever director of nursing for Public Health Wales in April. She hopes the role will raise the profile of nurses and midwives, highlighting their contribution to improving health outcomes for the people of Wales. PMID- 24044866 TI - Student life - learning opportunity of a lifetime. AB - The Cavell Nurses' Trust supports nurses, midwives and healthcare assistants. Its student awards are intended to demonstrate students' commitment to caring and compassion in their community. In 2013, five exceptional nursing and midwifery students were awarded scholarships. PMID- 24044868 TI - Evaluation and management of bradydysrhythmias in the emergency department. AB - Bradydysrhythmias represent a collection of cardiac conduction abnormalities that span the spectrum of emergency presentations, from relatively benign conditions to conditions that represent serious, life-threatening emergencies. This review presents the electrocardiographic findings seen in common bradydysrhythmias and emphasizes prompt recognition of these patterns. Underlying etiologies that may accompany these conduction abnormalities are discussed, including bradydysrhythmias that are reflex mediated (including trauma induced) and those with metabolic, environmental, infectious, and toxicologic causes. Evidence regarding the management of bradydysrhythmias in the emergency department is limited; however, there are data to guide the approach to the unstable bradycardic patient. When decreased end-organ perfusion is present, the use of atropine, beta agonists, and transcutaneous or transvenous pacing may be required. PMID- 24044869 TI - Effective sugar nucleotide regeneration for the large-scale enzymatic synthesis of Globo H and SSEA4. AB - We report here the development of chemoenzymatic methods for the large-scale synthesis of cancer-associated antigens globopentaose (Gb5), fucosyl-Gb5 (Globo H), and sialyl-Gb5 (SSEA4) by using overexpressed glycosyltransferases coupled with effective regeneration of sugar nucleotides, including UDP-Gal, UDP-GalNAc, GDP-Fuc, and CMP-Neu5Ac. The enzymes used in the synthesis were first identified from different species through comparative studies and then overexpressed in E. coli and isolated for synthesis. These methods provide multigram quantities of products in high yield with only two or three purification steps and are suitable for the evaluation and development of cancer vaccines and therapeutics. PMID- 24044867 TI - Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. AB - Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson's disease and HIV-1 associated neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concentration levels. We report here URMC-099 (1) an orally bioavailable (F = 41%), potent (IC50 = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. The compound inhibits LPS-induced TNFalpha release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat injected brains of mice. Compound 1 likely functions in HAND preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). We compare the kinase specificity and BBB penetration of 1 with CEP-1347 (2). Compound 1 is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development. PMID- 24044870 TI - Unknown risk: co-exposure to lead and other heavy metals among children living in small-scale mining communities in Zamfara State, Nigeria. AB - The lead poisoning crisis in Zamfara State, Northern Nigeria has been called the worst such case in modern history and it presents unique challenges for risk assessment and management of co-exposure to multiple heavy metals. More than 400 children have died in Zamfara as a result of ongoing lead intoxication since early in 2010. A review of the common toxic endpoints of the major heavy metals advances analysis of co-exposures and their common pathologies. Environmental contamination in Bagega village, examined by X-ray fluorescence of soils, includes lead, mercury, cadmium, arsenic and manganese. Co-exposure risk is explored by scoring common toxic endpoints and hazard indices to calculate a common pathology hazard risk ranking of Pb > As > Hg >> Cd > Mn. Zamfara presents an extreme picture of both lead and multiple heavy metal mortality and morbidity, but similar situations have become increasingly prevalent worldwide. PMID- 24044872 TI - Multisector prostate dosimetric quality: analysis of a large community database. AB - PURPOSE: To evaluate multi-institutional prostate brachytherapy dosimetric quality using multisector analysis. METHODS AND MATERIALS: In the database, 4547 patients underwent brachytherapy (3094 for (125)I, 1437 for (103)Pd, and 16 for (131)Cs). The original prostate postimplant dosimetry was reported using the maximum dose covering 90% of the prostate volume (D90) and the percentage of the prostate volume covered by the prescription dose (V100). Retrospectively, the dosimetry of all implants was recalculated after segmenting the prostate into 12 sectors (anterior, left and right lateral and posterior, about the center of gravity, and subdivided lengthwise into three-base, midgland, and apex). The dosimetric quality of each sector and combinations of sectors was compared across radionuclides. RESULTS: For each radionuclide, there was no significant difference between monotherapy and boost in terms of V100 or D90. When classified as excellent (V100 >= 90%), standard (V100 >= 80%), or minimal (V100 < 80%), 33.0%, 4.6%, and 10.5% of all base, midgland, and apical sectors, respectively, were of minimal quality. Specifically, 59.2% of the anterior base and 30.3% of the posterior base sectors were minimal. At the anterior midgland and apex, 22% and 19% of sectors were minimal. Excellent quality was observed in more than 90% of lateral and posterior midgland sectors and in >70% of lateral and posterior sectors. When stratified by (103)Pd vs. (125)I, sector analysis did not result in clinically significant dosimetric differences. CONCLUSIONS: Coverage of base sectors was inferior to midgland and apical sectors, and coverage of anterior sectors was notably inferior to lateral and posterior sectors. Further critique of brachytherapy planning and intraoperative technique is necessary for brachytherapists to minimize these dosimetric differences. PMID- 24044871 TI - Modulation of respiratory dendritic cells during Klebsiella pneumonia infection. AB - BACKGROUND: Klebsiella pneumoniae is a leading cause of severe hospital-acquired respiratory tract infections and death but little is known regarding the modulation of respiratory dendritic cell (DC) subsets. Plasmacytoid DC (pDC) are specialized type 1 interferon producing cells and considered to be classical mediators of antiviral immunity. METHOD: By using multiparameter flow cytometry analysis we have analysed the modulation of respiratory DC subsets after intratracheal Klebsiella pneumonia infection. RESULTS: Data indicate that pDCs and MoDC were markedly elevated in the post acute pneumonia phase when compared to mock-infected controls. Analysis of draining mediastinal lymph nodes revealed a rapid increase of activated CD103+ DC, CD11b+ DC and MoDC within 48 h post infection. Lung pDC identification during bacterial pneumonia was confirmed by extended phenotyping for 120G8, mPDCA-1 and Siglec-H expression and by demonstration of high Interferon-alpha producing capacity after cell sorting. Cytokine expression analysis of ex vivo-sorted respiratory DC subpopulations from infected animals revealed elevated Interferon-alpha in pDC, elevated IFN-gamma, IL-4 and IL-13 in CD103+ DC and IL-19 and IL-12p35 in CD11b+ DC subsets in comparison to CD11c+ MHC-class IIlow cells indicating distinct functional roles. Antigen-specific naive CD4+ T cell stimulatory capacity of purified respiratory DC subsets was analysed in a model system with purified ovalbumin T cell receptor transgenic naive CD4+ responder T cells and respiratory DC subsets, pulsed with ovalbumin and matured with Klebsiella pneumoniae lysate. CD103+ DC and CD11b+ DC subsets represented the most potent naive CD4+ T helper cell activators. CONCLUSION: These results provide novel insight into the activation of respiratory DC subsets during Klebsiella pneumonia infection. The detection of increased respiratory pDC numbers in bacterial pneumonia may indicate possible novel pDC functions with respect to lung repair and regeneration. PMID- 24044873 TI - Synthesis and antimicrobial activity of polyhalobenzonitrile quinazolin-4(3H)-one derivatives. AB - A novel series of polyhalobenzonitrile quinazolin-4(3H)-one derivatives were synthesized and characterized by NMR, IR, MS, and HRMS spectra. All of the newly prepared compounds were screened for antimicrobial activities against four strains of bacteria (Gram-positive bacterial: Staphylococcus aureus and Bacillus cereus; Gram-negative bacterial: Escherichia coli and Pseudomonas aeruginosa) and one strain of fungi (Candida albicans). Among the synthesized compounds, 5 (dimethylamino)-8-(2,4,5-trichloro-isophthalonitrile) quinazolin-4(3H)-one (7k) exhibited significant activity towards Gram-positive bacterial, Gram-negative bacterial, and the fungi strains. The MIC (0.8-3.3MUg/mL) and MBC (2.6-7.8MUg/mL) for this compound were close to those of nofloxacin, chlorothalonil, and fluconazole, making it the most potent antimicrobial agents in the series. PMID- 24044874 TI - 4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor. AB - This letter describes the mechanism behind the protective effect of 4 phenylbutyric acid (4-PBA) against endoplasmic reticulum (ER) stress-induced neuronal cell death using three simple 4-(p-substituted phenyl) butyric acids (4 PBA derivatives). Their relative human histone deacetylase (HDAC) inhibitory activities were consistent with a structural model of their binding to HDAC7, and their ability to suppress neuronal cell death and activity of chemical chaperone in vitro. These data suggest that 4-PBA protects against neuronal cell death mediated by the chemical chaperone activity rather than by inhibition of histone deacetylase. PMID- 24044875 TI - Synthesis, characterization and in vitro biological evaluation of some novel 1,3,5-triazine-Schiff base conjugates as potential antimycobacterial agents. AB - A series of some novel 1,3,5-triazine-Schiff base conjugates (1-32) have been synthesized and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv using Alamar Blue assay and the activity expressed as the minimum inhibitory concentration (MIC) in MUg/mL. Compounds 4 (4 Methoxy-6-methyl-N-(3,4,5-trimethoxybenzylidene)-1,3,5-triazin-2-amine), 11 (4 Methoxy-6-methyl-N-(2-hydroxy-3-bromo-5-chloro-benzylidene)-1,3,5-triazin-2 amine) and 24 (4-Methoxy-6-methyl-N-(1-(2,5-dihydroxyphenyl)ethylidene)-1,3,5 triazin-2-amine) exhibited a significant activity at 3.125, 6.25 and 6.25MUg/mL, respectively, when compared with the antitubercular drugs such as ethambutol (3.125MUg/mL), pyrazinamide (6.25MUg/mL) and streptomycin (6.25MUg/mL) and it could be a potential starting point to develop new lead compounds in the fight against Mycobacterium tuberculosis H37Rv. PMID- 24044876 TI - Continuous and batch cultures of Escherichia coli KJ134 for succinic acid fermentation: metabolic flux distributions and production characteristics. AB - BACKGROUND: Succinic acid (SA) has become a prominent biobased platform chemical with global production quantities increasing annually. Numerous genetically modified E. coli strains have been developed with the main aim of increasing the SA yield of the organic carbon source. In this study, a promising SA-producing strain, E. coli KJ134 [Biotechnol. Bioeng. 101:881-893, 2008], from the Department of Microbiology and Cell Science of the University of Florida was evaluated under continuous and batch conditions using D-glucose and CO2 in a mineral salt medium. Production characteristics entailing growth and maintenance rates, growth termination points and metabolic flux distributions under growth and non-growth conditions were determined. RESULTS: The culture remained stable for weeks under continuous conditions. Under growth conditions the redox requirements of the reductive tricarboxylic acid (TCA) cycle was solely balanced by acetic acid (AcA) production via the pyruvate dehydrogenase route resulting in a molar ratio of SA:AcA of two. A maximum growth rate of 0.22 h(-1) was obtained, while complete growth inhibition occurred at a SA concentration of 18 g L(-1). Batch culture revealed that high-yield succinate production (via oxidative TCA or glyoxylate redox balancing) occurred under non-growth conditions where a SA:AcA molar ratio of up to five was attained, with a final SA yield of 0.94 g g(-1). Growth termination of the batch culture was in agreement with that of the continuous culture. The maximum maintenance production rate of SA under batch conditions was found to be 0.6 g g(-1) h(-1). This is twice the maintenance rate observed in the continuous runs. CONCLUSIONS: The study revealed that the metabolic flux of E. coli KJ134 differs significantly for growth and non-growth conditions, with non-growth conditions resulting in higher SA:AcA ratios and SA yields. Bioreaction characteristics entailing growth and maintenance rates, as well as growth termination markers will guide future fermentor designs and improvements. PMID- 24044877 TI - Cobalt catalysis in the gas phase: experimental characterization of cobalt(I) complexes as intermediates in regioselective Diels-Alder reactions. AB - In situ-formed cobalt(I) complexes are proposed to act as efficient catalysts in regioselective Diels-Alder reactions of unactivated substrates such as 1,3-dienes and alkynes. We report the first experimental evidence for the in situ reduction of CoBr2(dppe) [dppe = 1,2-bis(diphenylphosphino)ethane] by Zn/ZnI2 to [Co(I)(dppe)](+) by means of electrospray MS(n) experiments. Additionally, the reactivities of Co(II) and Co(I) dppe complexes toward the Diels-Alder substrates isoprene and phenylacetylene were probed in gas-phase ion/molecule reactions (IMRs). Isoprene and phenylacetylene were introduced into the mass spectrometer via the buffer gas flow of a linear ion trap. The IMR experiments revealed a significantly higher substrate affinity of [Co(I)(dppe)](+) compared with [Co(II)Br(dppe)](+). Furthermore, the central intermediate of the solution-phase cobalt-catalyzed Diels-Alder reaction, [Co(I)(dppe)(isoprene)(phenylacetylene)](+), could be generated via IMR and examined in the gas phase. Collision activation of this complex ion delivered evidence for the gas-phase reaction of isoprene with phenylacetylene in the coordination sphere of the cobalt ion. The experimental findings are consistent with the results of quantum-chemical calculations on all of the observed Co(I) dppe complex ions. The results constitute strong analytical evidence for the formation and importance of different cobalt(I) species in regioselective Diels Alder reactions of unactivated substrates and identify [Co(I)(dppe)](+) as the active Diels-Alder catalyst. PMID- 24044878 TI - Spatial sensitivity, responsivity, and surround suppression of LGN cell responses in the macaque. AB - Responses of cells in the lateral geniculate nucleus (LGN) of the macaque monkey have been measured for different sizes of chromatic and achromatic stimuli, with relative luminance spanning a range of 3-6 log units. Homogeneous illuminated test fields, centered on the receptive field, were used. Responses to these stimuli deviated from what is expected for the grating stimuli used to study the contrast-sensitive mechanisms in the visual pathway. For test fields smaller than the center of the receptive field, both the excitatory and the inhibitory cone opponent components were present in the response, and the sensitivity to both components increased with the same factor when the test field increased in size (area summation). For test field areas extending into the suppressive surround of the extraclassical receptive field, the excitatory and the inhibitory cone opponents were both suppressed, again by the same factor. This suppression of the cell's responsiveness, as a function of test spot area, was described by a logarithmic function, and the spatial sensitivity of attenuation could therefore be described by a power function of radius. The logarithmic suppression was clear for parvocellular and koniocellular cells but was more prominent for magnocellular cells. The surround field suppression was also found for the prepotential inputs to LGN cells, indicating a retinal origin. The difference of Gaussian (DOG) model has been used successfully to describe the cells' contrast behavior for grating stimuli. However, this model fails to describe the constant excitatory/inhibitory response balance needed to obtain color (hue) stability for light stimuli of different sizes but with the same Commission Internationale de l'Eclairage (CIE) chromaticity and luminance factor. Neither the constant responsiveness found in the center of the receptive field nor the suppressive response in the surround can be described by the DOG model. PMID- 24044879 TI - Tuning transverse anisotropy in Co(III)-Co(II)-Co(III) mixed-valence complex toward slow magnetic relaxation. AB - Two cobalt mixed-valence complexes with different substituents have been prepared and structurally characterized by single-crystal X-ray diffraction to alter slow magnetic relaxation by tailoring the transverse anisotropy. The trinuclear complexes [(L(1))4Co3(H2O)2](NO3)4.CH3OH.5H2O (1-NO3) and [(L(2))4Co3(H2O)2](NO3)4.6H2O (2-NO3) feature a distorted octahedral Co(II) strongly hindered in a trinuclear Co(III)-Co(II)-Co(III) mixed-valence array. Detailed magnetic studies of 1-NO3 and 2-NO3 have been conducted using direct- and alternating-current magnetic susceptibility data. In accordance with variable field magnetic susceptibility data at low temperatures, high-field electron paramagnetic resonance (HF-EPR) spectroscopy reveals the presence of an easy plane anisotropy (D > 0) with a significant transverse component, E, in complexes 1-NO3 and 2-NO3. These findings indicate that the onset of the variation of distortion within complex 2-NO3 leads to a suppression of quantum tunneling of the magnetization within the easy plane, resulting in magnetic bistability and slow relaxation behavior. Consequently, the anisotropy energy scale associated with the relaxation barrier, 5.46 cm(-1) (tauo = 1.03 * 10(-5) s), is determined by the transverse E term. The results demonstrate that slow magnetic relaxation can be switched through optimization of the transverse anisotropy associated with magnetic ions that possess easy-plane anisotropy. PMID- 24044880 TI - Social support and smoking abstinence among incarcerated adults in the United States: a longitudinal study. AB - BACKGROUND: In the United States, tobacco use among prisoners is nearly three times that of the general population. While many American prisons and jails are now tobacco-free, nearly all inmates return to smoking as soon as they are released back into the community. METHODS: To better understand the role that personal relationships may play in enabling return to smoking, we enrolled former smokers who were inmates in a tobacco-free prison. Baseline assessments were conducted six weeks prior to inmates' scheduled release and included measures of smoking prior to incarceration, motivation, confidence and plans for remaining quit after release. We also assessed global social support (ISEL) and a measure of social support specific to quitting smoking (SSQ). Smoking status was assessed three weeks after prison release and included 7-day point-prevalence abstinence validated by urine cotinine, days to first cigarette and smoking rate. RESULTS: A diverse sample comprised of 35% women, 20% Hispanic, and 29% racial minorities (average age 35.5 years) provided baseline data (n = 247). Over 90% of participants provided follow up data at 3-weeks post-release. Prior to incarceration participants had smoked an average of 21.5 (SD = 11.7) cigarettes per day. Only 29.2% had definite plans to remain smoking-abstinent after release. Approximately half of all participants reported that "most" or "all" of their family (42.2%) and friends (68%) smoked, and 58.8% reported their spouse or romantic partner smoked.SSQ scores were not significantly predictive of smoking outcomes at three weeks, however, social support from family and friends were each significantly and positively correlated with motivation, confidence, and plans for remaining abstinent (all p values <0.05). These smoking-related attitudinal variables were significantly predictive of smoking outcomes (all p values <0.01). General social support (ISEL) was not associated with smoking related attitudinal variables or smoking outcomes. CONCLUSIONS: Inmates of smoke free prisons have a head-start on being smoke-free for life. They have been abstinent well past the duration of nicotine withdrawal and have great financial incentive not to begin smoking again. However, this advantage may be offset by a lack of non-smoking role models among their family and friends, and perceived lack of support for remaining smoke-free. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01684995. PMID- 24044881 TI - Management of persistent diplopia after surgical repair of orbital fractures. PMID- 24044882 TI - Molecular targeting of Akt by thymoquinone promotes G(1) arrest through translation inhibition of cyclin D1 and induces apoptosis in breast cancer cells. AB - AIM: Thymoquinone (TQ), the predominant bioactive constituent of black seed oil (Nigella Sativa), has been shown to possess antineoplastic activity against multifarious tumors. However, the meticulous mechanism of TQ on Akt mediated survival pathway is still unrevealed in breast cancer. Here, we investigated TQ's mechanism of action against PI3K/Akt signaling and its downstream targets by modulating proteins translational machinery, leading to apoptosis in cancer cells. MAIN METHODS: MDA-MB-468 and T-47D cells were treated with TQ and evaluated for its anticancer activity through phase distribution and western blot. Modulatory effects of TQ on Akt were affirmed through kinase and drug potential studies. KEY FINDINGS: Studies revealed G1 phase arrest till 24h incubation with TQ while extended exposure showed phase shift to subG1 indicating apoptosis, supported by suppression of cyclin D1, cyclin E and cyclin dependent kinase inhibitor p27 expression. Immunoblot and membrane potential studies revealed mitochondrial impairment behind apoptotic process with upregulation of Bax, cytoplasmic cytochrome c and procaspase-3, PARP cleavage along with Bcl-2, Bcl-xL and survivin downregulation. Moreover, we construed the rationale behind mitochondrial dysfunction by examining the phosphorylation status of PDK1, PTEN, Akt, c-raf, GSK-3beta and Bad in TQ treated cells, thus ratifying the involvement of Akt in apoptosis. Further, the consequential effect of Akt inhibition by TQ is proven by translational repression through deregulated phosphorylation of 4E-BP1, eIF4E, S6R and p70S6K. SIGNIFICANCE: Our observations for the first time may provide a new insight for the development of novel therapies for Akt overexpressed breast cancer by TQ. PMID- 24044883 TI - Peripheral B-cell activation and exhaustion markers in patients with ankylosing spondylitis. AB - AIMS: Ankylosing spondylitis (AS) is an autoimmune disease and is associated with abnormal B cell function. However, the roles of different B cell subsets are less clear. This study aimed to examine the frequency of different subsets of B cells in AS patients following standard therapies. MAIN METHODS: Eighteen newly diagnosed AS patients and 10 healthy controls (HC) were recruited in this study. The expression of CD27, CD38, CD86, CD95 and IgD on CD19(+) B cells was examined by flow cytometry. The disease activity was scored according to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Serum levels of C reactive protein (CRP), rheumatoid factor (RF), IgG, IgA and IgM, and the erythrocyte sedimentation rate (ESR) were measured. KEY FINDINGS: The frequency of CD27(+) B cells was decreased in AS patients compared with HC (p=0.018), while CD86(+) and CD27(-)CD95(+) B cell subsets increased in AS patients (p<0.001). Meanwhile, the frequencies of CD38(+) and CD95(+) B cell positively correlated with BASDAI (r=0.6505, p=0.0035; r=0.6854, p=0.0017, respectively), while CD38( )CD86(+) B cell negatively correlated with BASDAI (r=-0.7329, p<0.001). We also found that CD27(-) and CD95(+) B cell negatively correlated with RF levels (r= 0.5141, p=0.0290; r=-0.4944, p=0.0370, respectively), while CD27(+) B cell positively correlated with IgG levels (p=0.0148, r=0.5640). Moreover, CD86(+) and CD27(-)CD95(+) B cell subsets increased following treatment with Meloxicam and Etanercept for one month (p<0.001; p<0.001). SIGNIFICANCE: These findings suggest that CD27(-)CD95(+)CD19(+) and CD86(+)CD19(+) B cells may be reasonable cellular targets for the therapeutic intervention of AS. PMID- 24044884 TI - TBK1-targeted suppression of TRIF-dependent signaling pathway of Toll-like receptors by helenalin. AB - AIMS: The purpose of this study was to evaluate the therapeutic potential of the helenalin in Toll-like receptor (TLR) signaling pathways. MAIN METHODS: RAW264.7 cells were transfected with a NF-kappaB, IFNbeta PRDIII-I, or IP-10 luciferase plasmid and then luciferase enzyme activities were determined by luciferase assay. The expression of iNOS, COX-2, and IP-10 and phosphorylation of IRF3 were determined by Western blotting. The levels of IP-10 were determined with culture medium by using IP-10 ELISA kit. TBK1 kinase activity was determined by MBP assay kit. KEY FINDINGS: Helenalin inhibited transcription factor NF-kappaB and IRF3 activation, which was induced by TLR agonists as well as its target genes, such as COX-2, iNOS, and IP-10. Helenalin attenuated ligand-independent activation of NF-kappaB induced by MyD88, IKKbeta, and p65, and IRF3 induced by TRIF, TBK1, or IRF3. Furthermore, helenalin inhibited TBK1 kinase activity in vitro. SIGNIFICANCE: TLRs are primary sensors that detect a wide variety of microbial components and play an important role in the induction of innate immune. To evaluate the therapeutic potential of helenalin, we examined its effect on signal transduction via the TLR signaling pathways. Our results suggest that beneficial effects of helenalin on chronic inflammatory diseases are mediated through modulation of TLR signaling pathways by targeting TBK1. PMID- 24044885 TI - Quercetin glucosides promote ischemia-induced angiogenesis, but do not promote tumor growth. AB - AIMS: Dietary flavonoid intake shows a significant inverse association with mortality from coronary heart disease, incidence of myocardial infarction and stroke. Quercetin is one of the most common flavonoids in our diet and has several favorable biological activities. Quercetin glucosides, which are enzymatically trans-glycosylated isoquercitrin, have high water-solubility and bioavailability compared with quercetin. Here, we investigated the effects of quercetin glucosides on collateral development in a murine hindlimb ischemia model. MAIN METHODS: We induced hindlimb ischemia in 24- to 32-week-old male C3H/HeJ mice by resecting the right femoral artery. Then, 0.5% carboxymethyl cellulose (control) or quercetin glucosides (100mg/kg/day) were administered daily by gavage. Blood flow was monitored weekly by laser Doppler imaging. KEY FINDINGS: Recovery of blood flow to the ischemic leg was significantly enhanced by quercetin glucosides (blood flow ratio at 4 weeks: control, 0.57 +/- 0.11; quercetin glucosides, 0.95 +/- 0.10, p<0.05). Furthermore, anti-CD31 immunostaining revealed that quercetin glucosides increased capillary density in the ischemic muscle (control, 200 +/- 24/mm(2); quercetin glucosides, 364 +/- 41/mm(2), p<0.01). Quercetin glucosides did not promote tumor growth. The beneficial effect of quercetin glucosides was abrogated in eNOS-deficient mice. SIGNIFICANCE: These results suggest that quercetin glucosides may have therapeutic potential to promote angiogenesis in ischemic tissue. PMID- 24044886 TI - A diterpenoid compound, excisanin A, inhibits the invasive behavior of breast cancer cells by modulating the integrin beta1/FAK/PI3K/AKT/beta-catenin signaling. AB - AIM: Excisanin A, a diterpenoid compound purified from Isodon macrocalyxin D, has anti-cancer properties with little toxicity. In this study, the anti-invasive effects of excisanin A on breast cancer cells and its molecular mechanism of action were investigated. MAIN METHODS: MTT, wound healing, transwell chamber and cell adhesion assays were utilized to investigate the effects of excisanin A on MDA-MB-231 and SKBR3 cells. Western blotting, real-time PCR, RNA interference and luciferase reporter assays were employed to determine the molecular mechanism of action of excisanin A. KEY FINDINGS: Treating MDA-MB-231 and SKBR3 cells with 10 40MUM excisanin A significantly inhibited cell migration and invasion and suppressed the mRNA and protein levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in a dose-dependent manner. Excisanin A efficiently abolished integrin beta1 expression and reduced the phosphorylation of the downstream kinases focal adhesion kinase (FAK) and Src. Excisanin A inhibited the phosphorylation of phosphoinositide 3-kinase (PI3K), AKT and glycogen synthase kinase 3 beta (GSK3beta) and down-regulated beta-catenin expression and the luciferase activity of the transcription factor LEF-1. Moreover, treating breast cancer cells with siRNA targeting integrin beta1 inhibited cell invasion and migration. SIGNIFICANCE: These results demonstrated that excisanin A inhibited invasion by suppressing MMP-2 and MMP-9 expression; the integrin beta1/FAK/PI3K/AKT/beta-catenin signaling pathway was involved in this process. Therefore, excisanin A might be a potential anti-metastatic chemotherapeutic agent for the treatment of breast cancer. PMID- 24044887 TI - Characterization of fragmented 3-phosphoinsitide-dependent protein kinase-1 (PDK1) by phosphosite-specific antibodies. AB - AIMS: The 3-phosphoinositide-dependent protein kinase-1 (PDK1) activates a number of protein kinases of the AGC subfamily, including protein kinase B and ribosomal S6 protein kinase by phosphorylating these kinases at the activation-loop. PDK1 activity is regulated by auto-phosphorylation and is further increased by stimulation of cells. PDK1 has been shown to have several phosphorylation sites including 5 serine and 3 tyrosine residues. However, Ser241 and Tyr373/376 are only involved in the regulation of PDK1 activity. MAIN METHODS: In this study, we found the putative fragments of PDK1 by using anti-Myc and anti-PDK1 antibodies. Furthermore, the existence of four different sizes of PDK1 were confirmed with other phosphosite specific antibodies. KEY FINDINGS: Taken together, the catalytic domain of PDK1 (42 kDa and 37 kDa) is separately existed in the cells and might be important for the regulation of subset of PDK1 substrate. Because the crystal structural studies suggested that PIF-pocket is located at the catalytic domain and plays a critical role on substrate recognition. SIGNIFICANCE: These suggested importance and roles of this fragment are needed to be determined. Further study on these fragments of PDK1 will provide new insight on the regulatory mechanism of PDK1 in patho-physiological condition. PMID- 24044888 TI - Combined TIM-3 blockade and CD137 activation affords the long-term protection in a murine model of ovarian cancer. AB - BACKGROUND: T-cell immunoglobulin and mucin domain 3 (TIM-3) is known as a negative immune regulator and emerging data have implicated TIM-3 a pivotal role in suppressing antitumor immunity. The co-stimulatory receptor CD137 is transiently upregulated on T-cells following activation and increases their proliferation and survival when engaged. Although antagonistic anti-TIM-3 or agonistic anti-CD137 antibodies can promote the rejection of several murine tumors, some poorly immunogenic tumors were refractory to this treatment. In this study, we sought to evaluate whether combined TIM-3 blockade and CD137 activation would significantly improve the immunotherapy in the murine ID8 ovarian cancer model. METHODS: Mice with established ID8 tumor were intraperitoneally injected with single or combined anti-TIM-3/CD137 monoclonal antibody (mAb); mice survival was recorded, the composition and gene expression of tumor-infiltrating immune cells in these mice was analyzed by flow cytometry and quantitative RT-PCR respectively, and the function of CD8+ cells was evaluated by ELISA and cytotoxicity assay. RESULTS: Either anti-TIM-3 or CD137 mAb alone, although effective in 3 days established tumor, was unable to prevent tumor progression in mice bearing 10 days established tumor, however, combined anti-TIM-3/CD137 mAb significantly inhibited the growth of these tumors with 60% of mice tumor free 90 days after tumor inoculation. Therapeutic efficacy was associated with a systemic immune response with memory and antigen specificity, required CD4+ cells and CD8+ cells. The 2 mAb combination increased CD4+ and CD8+ cells and decreased immunosuppressive CD4+FoxP3+ regulatory T (Treg) cells and CD11b+Gr-1+ myeloid suppressor cells (MDSC) at tumor sites, giving rise to significantly elevated ratios of CD4+ and CD8+ cells to Treg and MDSC; This is consistent with biasing local immune response towards an immunostimulatory Th1 type and is further supported by quantitative RT-PCR data showing the increased Th1-associated genes by anti-TIM-3/CD137 treatment. The increased CD8+ T cells produced high level of IFN-gamma upon tumor antigen stimulation and displayed antigen-specific cytotoxic activity. CONCLUSIONS: To our knowledge, this is the first report investigating the effects of anti-TIM-3/CD137 combined mAb in a murine ovarian cancer model, and our results may aid the design of future trials for ovarian cancer immunotherapy. PMID- 24044889 TI - Peroxiredoxin-5 targeted to the mitochondrial intermembrane space attenuates hypoxia-induced reactive oxygen species signalling. AB - The ability to adapt to acute and chronic hypoxia is critical for cellular survival. Two established functional responses to hypoxia include the regulation of gene transcription by HIF (hypoxia-inducible factor), and the constriction of pulmonary arteries in response to alveolar hypoxia. The mechanism of O2 sensing in these responses is not established, but some studies implicate hypoxia-induced mitochondrial ROS (reactive oxygen species) signalling. To further test this hypothesis, we expressed PRDX5 (peroxiredoxin-5), a H2O2 scavenger, in the IMS (mitochondrial intermembrane space), reasoning that the scavenging of ROS in that compartment should abrogate cellular responses triggered by the release of mitochondrial oxidants to the cytosol. Using adenoviral expression of IMS-PRDX5 (IMS-targeted PRDX5) in PASMCs (pulmonary artery smooth muscle cells) we show that IMS-PRDX5 inhibits hypoxia-induced oxidant signalling in the IMS and cytosol. It also inhibits HIF-1alpha stabilization and HIF activity in a dose dependent manner without disrupting cellular oxygen consumption. IMS-PRDX5 expression also attenuates the increase in cytosolic [Ca(2+)] in PASMCs during hypoxia. These results extend previous work by demonstrating the importance of IMS-derived ROS signalling in both the HIF and lung vascular responses to hypoxia. PMID- 24044890 TI - Mechanism of protein decarbonylation. AB - Ligand/receptor stimulation of cells promotes protein carbonylation that is followed by the decarbonylation process, which might involve thiol-dependent reduction (C.M. Wong et al., Circ. Res. 102:301-318; 2008). This study further investigated the properties of this protein decarbonylation mechanism. We found that the thiol-mediated reduction of protein carbonyls is dependent on heat labile biologic components. Cysteine and glutathione were efficient substrates for decarbonylation. Thiols decreased the protein carbonyl content, as detected by 2,4-dinitrophenylhydrazine, but not the levels of malondialdehyde or 4 hydroxynonenal protein adducts. Mass spectrometry identified proteins that undergo thiol-dependent decarbonylation, which include peroxiredoxins. Peroxiredoxin-2 and -6 were carbonylated and subsequently decarbonylated in response to the ligand/receptor stimulation of cells. siRNA knockdown of glutaredoxin inhibited the decarbonylation of peroxiredoxin. These results strengthen the concept that thiol-dependent decarbonylation defines the kinetics of protein carbonylation signaling. PMID- 24044891 TI - VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity. AB - VE-cadherin is a component of endothelial cell-to-cell adherens junctions, and it has a key role in the maintenance of vascular integrity. During embryo development, VE-cadherin is required for the organization of a stable vascular system, and in the adult it controls vascular permeability and inhibits unrestrained vascular growth. The mechanisms of action of VE-cadherin are complex and include reshaping and organization of the endothelial cell cytoskeleton and modulation of gene transcription. Here we review some of the most important pathways through which VE-cadherin modulates vascular homeostasis and discuss the emerging concepts in the overall biological role of this protein. PMID- 24044892 TI - Autoregulatory feedback controls sequential action of cis-regulatory modules at the brinker locus. AB - cis-regulatory modules (CRMs) act sequentially to regulate temporal expression of genes, but how the switch from one to the next is accomplished is not well understood. To provide insight, here we investigate the cis-regulatory system controlling brinker (brk) expression in the Drosophila embryo. Two distally located CRMs support expression at different times, while a promoter-proximal element (PPE) is required to support their action. In the absence of Brk protein itself or upon mutagenesis of Brk binding sites within the PPE, the late-acting CRM, specifically, is delayed. This block to late-acting CRM function appears to be removed when the early-acting CRM is also deleted. These results demonstrate that autoregulatory feedback is necessary for the early-acting CRM to disengage from the promoter so that the late-acting CRM may act. Autoregulation may be a commonly used mechanism to control sequential CRM action necessary for dynamic gene expression throughout the course of development. PMID- 24044894 TI - The evolution and diversity of a low complexity vaccine candidate, merozoite surface protein 9 (MSP-9), in Plasmodium vivax and closely related species. AB - The merozoite surface protein-9 (MSP-9) has been considered a target for an anti malarial vaccine since it is one of many proteins involved in the erythrocyte invasion, a critical step in the parasite life cycle. Orthologs encoding this antigen have been found in all known species of Plasmodium parasitic to primates. In order to characterize and investigate the extent and maintenance of MSP-9 genetic diversity, we analyzed DNA sequences of the following malaria parasite species: Plasmodium falciparum, Plasmodium reichenowi, Plasmodium chabaudi, Plasmodium yoelii, Plasmodium berghei, Plasmodium coatneyi, Plasmodium gonderi, Plasmodium knowlesi, Plasmodium inui, Plasmodium simiovale, Plasmodium fieldi, Plasmodium cynomolgi and Plasmodium vivax and evaluated the signature of natural selection in all MSP-9 orthologs. Our findings suggest that the gene encoding MSP 9 is under purifying selection in P. vivax and closely related species. We further explored how selection affected different regions of MSP-9 by comparing the polymorphisms in P. vivax and P. falciparum, and found contrasting patterns between these two species that suggest differences in functional constraints. This observation implies that the MSP-9 orthologs in human parasites may interact differently with the host immune response. Thus, studies carried out in one species cannot be directly translated into the other. PMID- 24044893 TI - Repositioning forelimb superficialis muscles: tendon attachment and muscle activity enable active relocation of functional myofibers. AB - The muscles that govern hand motion are composed of extrinsic muscles that reside within the forearm and intrinsic muscles that reside within the hand. We find that the extrinsic muscles of the flexor digitorum superficialis (FDS) first differentiate as intrinsic muscles within the hand and then relocate as myofibers to their final position in the arm. This remarkable translocation of differentiated myofibers across a joint is dependent on muscle contraction and muscle-tendon attachment. Interestingly, the intrinsic flexor digitorum brevis (FDB) muscles of the foot are identical to the FDS in tendon pattern and delayed developmental timing but undergo limited muscle translocation, providing strong support for evolutionary homology between the FDS and FDB muscles. We propose that the intrinsic FDB pattern represents the original tetrapod limb and that translocation of the muscles to form the FDS is a mammalian evolutionary addition. PMID- 24044895 TI - Selective cytotoxicity, inhibition of cell cycle progression, and induction of apoptosis in human breast cancer cells by sesquiterpenoids from Inula lineariifolia Turcz. AB - Four new sesquiterpenoid dimers (lineariifolianoids E-H, 1-4), five new sesquiterpenoids (5-9), and seven known sesquiterpenoids (10-16) were isolated from the aerial parts of Inula lineariifolia Turcz. Their structures were determined by spectroscopic data analysis and X-ray diffraction studies. The compounds were then evaluated for their in vitro cytotoxicity against two human breast cancer cell lines (MCF-7 and MDA-MB-231) and one normal breast cell line (MCF-10A). Lineariifolianoid E (1) showed IC50 values of 1.56 MUM and 2.75 MUM against MCF-7 and MDA-MB-231, respectively. However, lineariifolianoid E demonstrated low toxicity to MCF-10A cells, which indicated a selective cytotoxicity for tumor cells. Further studies also presented that lineariifolianoid E had significant, dose-dependent effects on cell cycle progression and apoptosis in breast cancer cells. PMID- 24044896 TI - Etomidate evokes synaptic vesicle exocytosis without increasing miniature endplate potentials frequency at the mice neuromuscular junction. AB - Etomidate is an intravenous anesthetic used during anesthesia induction. This agent induces spontaneous movements, especially myoclonus after its administration suggesting a putative primary effect at the central nervous system or the periphery. Therefore, the aim of this study was to investigate the presynaptic and postsynaptic effects of etomidate at the mouse neuromuscular junction (NMJ). Diaphragm nerve muscle preparations were isolated and stained with the styryl dye FM1-43, a fluorescent tool that tracks synaptic vesicles exo endocytosis that are key steps for neurotransmission. We observed that etomidate induced synaptic vesicle exocytosis in a dose-dependent fashion, an effect that was independent of voltage-gated Na(+) channels. By contrast, etomidate-evoked exocytosis was dependent on extracellular Ca(2+) because its effect was abolished in Ca(2+)-free medium and also inhibited by omega-Agatoxin IVA (30 and 200nM) suggesting the participation of P/Q-subtype Ca(2+) channels. Interestingly, even though etomidate induced synaptic vesicle exocytosis, we did not observe any significant difference in the frequency and amplitude of miniature end-plate potentials (MEPPs) in the presence of the anesthetic. We therefore investigated whether etomidate could act on nicotinic acetylcholine receptors labeled with alpha-bungarotoxin-Alexa 594 and we observed less fluorescence in preparations exposed to the anesthetic. In conclusion, our results suggest that etomidate exerts a presynaptic effect at the NMJ inducing synaptic vesicle exocytosis, likely through the activation of P-subtype voltage gated Ca(2+) channels without interfering with MEPPs frequency. The present data contribute to a better understanding about the effect of etomidate at the neuromuscular synapse and may help to explain some clinical effects of this agent. PMID- 24044897 TI - Cytosolic phospholipase A2alpha upregulation mediates apoptotic neuronal death induced by aggregated amyloid-beta peptide1-42. AB - Increased cytosolic phospholipase A2alpha (cPLA2alpha) immunoreactivity and transcript were observed in Alzheimer's disease (AD) brain associated with amyloid deposits. Thus, the present study examined whether cPLA2alpha upregulation participate in cortical neuron damage induced by aggregated Abeta1 42 and determined its role in the signaling events leading to damage, using an antisense technology. Exposure of primary cortical neurons to 1MUM aggregated Abeta1-42 for 24h induced up-regulation and activation of cPLA2alpha and apoptotic cell death of about 30% as detected by: cell count, MTT reduction, caspases-3 and -8 activation, DAPI and TUNEL staining, that were prevented by inhibition of cPLA2alpha up-regulation and activity in the presence of antisense against cPLA2alpha (AS). cPLA2alpha was rapidly activated upon addition of aggregated Abeta1-42, as determined by its phosphorylated form on serine 505, and this activity was dependent on NADPH oxidase activity. NOX2- and NOX4-NADPH oxidase upregulation at 24h of aggregated Abeta1-42 exposure was not affected by the presence of AS, but superoxide production was reduced, probably due to NOX2 inhibition. cPLA2alpha upregulation led to activation of neutral sphingomyelinase (N-SMase) as its activity was inhibited in the presence of AS, and could be restored by addition of arachidonic acid. Addition of ceramide analog induced caspase-8 activation leading to caspase-3 activation and apoptotic neuronal death. In conclusion, our results suggest that cPLA2alpha activity plays a crucial role in the signaling cascade leading to apoptotic neuronal death by aggregated Abeta1-42 probably via activation of N-SMase, ceramide production and caspases-3 and -8. PMID- 24044898 TI - Accumulation of altered aspartyl residues in erythrocyte membrane proteins from patients with sporadic amyotrophic lateral sclerosis. AB - Spontaneous protein deamidation of labile asparagines (Asn), generating abnormal l-isoaspartyl residues (IsoAsp), is associated with cell aging and enhanced by an oxidative microenvironment. The presence of isopeptide bonds impairs protein structure/function. To minimize the damage, IsoAsp can be "repaired" by the protein l-isoaspartyl/d-aspartyl O-methyltransferase (PIMT) and S adenosylmethionine (AdoMet) is the methyl donor of this reaction. PIMT is a repair enzyme that initiates the conversion of l-isoAsp (or d-Asp) residues to l Asp residues. Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease principally affecting motor neurons. The condition of oxidative stress reported in familial and sporadic forms of ALS prompted us to investigate Asn deamidation in ALS tissue. Erythrocytes (RBCs) were selected as a model system since they are unable to replace damaged proteins and protein methylesterification is virtually the only AdoMet-consuming reaction operating in these cells. Our data show that, in vitro assay, abnormal IsoAsp residues were significantly higher in ALS patients erythrocyte membrane proteins with an increased methyl accepting capability relative to controls (p<0.05). Moreover, we observed a reduction in AdoMet levels, while AdoHcy concentration was comparable to that detected in the control, resulting in a lower [AdoMet]/[AdoHcy] ratio. Then, the accumulation of altered aspartyl residues in ALS patients is probably related to a reduced efficiency of the S-adenosylmethionine (AdoMet)-dependent repair system causing increased protein instability at Asn sites. The increase of abnormal residues represents a new protein alteration that may be present not only in red blood cells but also in other cell types of patients suffering from ALS. PMID- 24044899 TI - Ammonia-induced Na,K-ATPase/ouabain-mediated EGF receptor transactivation, MAPK/ERK and PI3K/AKT signaling and ROS formation cause astrocyte swelling. AB - Ammonia toxicity is clinically important and biologically poorly understood. We reported previously that 3mM ammonia chloride (ammonia), a relevant concentration for hepatic encephalopathy studies, increases production of endogenous ouabain and activity of Na,K-ATPase in astrocytes. In addition, ammonia-induced upregulation of gene expression of alpha2 isoform of Na,K-ATPase in astrocytes could be inhibited by AG1478, an inhibitor of the EGF receptor (EGFR), and by PP1, an inhibitor of Src, but not by GM6001, an inhibitor of metalloproteinase and shedding of growth factor, suggesting the involvement of endogenous ouabain induced EGF receptor transactivation. In the present cell culture study, we investigated ammonia effects on phosphorylation of EGF receptor and its intracellular signal pathway towards MAPK/ERK1/2 and PI3K/AKT; interaction between EGF receptor, alpha1, and alpha2 isoforms of Na,K-ATPase, Src, ERK1/2, AKT and caveolin-1; and relevance of these signal pathways for ammonia-induced cell swelling, leading to brain edema, an often fatal complication of ammonia toxicity. We found that (i) ammonia increases EGF receptor phosphorylation at EGFR(845) and EGFR(1068); (ii) ammonia-induced ERK1/2 and AKT phosphorylation depends on the activity of EGF receptor and Src, but not on metalloproteinase; (iii) AKT phosphorylation occurs upstream of ERK1/2 phosphorylation; (iv) ammonia stimulates association between the alpha1 Na,K-ATPase isoform, Src, EGF receptor, ERK1/2, AKT and caveolin-1; (v) ammonia-induced ROS production might occur later than EGFR transactivation; (vi) both ammonia induced ERK phosphorylation and ROS production can be abolished by canrenone, an inhibitor of ouabain, and (vii) ammonia-induced cell swelling depends on signaling via the Na,K ATPase/ouabain/Src/EGF receptor/PI3K-AKT/ERK1/2, but in response to 3mM ammonia it does not appear until after 12h. Based on literature data it is suggested that the delayed appearance of the ammonia-induced swelling at this concentration reflects required ouabain-induced oxidative damage of the ion and water cotransporter NKCC1. This information may provide new therapeutic targets for treatment of hyperammonic brain disorders. PMID- 24044900 TI - Ecologically relevant UV-B dose combined with high PAR intensity distinctly affect plant growth and accumulation of secondary metabolites in leaves of Centella asiatica L. Urban. AB - We investigated the effects of environmentally relevant dose of ultraviolet (UV) B and photosynthetic active radiation (PAR) on saponin accumulation in leaves on the example of Centella asiatica L. Urban. For this purpose, plants were exposed to one of four light regimes i.e., two PAR intensities with or without UV-B radiation. The experiment was conducted in technically complex sun simulators under almost natural irradiance and climatic conditions. As observed, UV-B radiation increased herb and leaf production as well as the content of epidermal flavonols, which was monitored by non-destructive fluorescence measurements. Specific fluorescence indices also indicate an increase in the content of anthocyanins under high PAR; this increase was likewise observed for the saponin concentrations. In contrast, UV-B radiation had no distinct effects on saponin and sapogenin concentrations. Our findings suggest that besides flavonoids, also saponins were accumulated under high PAR protecting the plant from oxidative damage. Furthermore, glycosylation of sapogenins seems to be important either for the protective function and/or for compartmentalization of the compounds. Moreover, our study revealed that younger leaves contain higher amounts of saponins, while in older leaves the sapogenins were the most abundant constituents. Concluding, our results proof that ambient dose of UV-B and high PAR intensity distinctly affect the accumulation of flavonoids and saponins, enabling the plant tissue to adapt to the light conditions. PMID- 24044902 TI - Drinking games as a venue for sexual competition. AB - Based on sexual selection theory, we hypothesized that sex differences in mating effort and social competitiveness-and subsequent sex differences in sexual and competitive motivations for participating in drinking games-are responsible for the well-documented sex differences in college students' drinking game behaviors. Participants in a cross-sectional study were 351 women and 336 men aged 17 to 26. In a mediation model, we tested sex differences in mating effort, social competitiveness, sexual and competitive motivations for participating in drinking games, drinking game behaviors, and alcohol-related problems. Men participated in drinking games more frequently, consumed more alcohol while participating in drinking games, and experienced more problems associated with drinking. These sex differences appeared to be partially mediated by mating effort, social competitiveness, and sexual and competitive motivations for participating in drinking games. Drinking games are a major venue in which college students engage in heavy episodic drinking, which is a risk factor for college students' behavioral and health problems. Thus, the functional perspective we used to analyze them here may help to inform public health and university interventions and enable better identification of at-risk students. PMID- 24044901 TI - YB-1 dependent oncolytic adenovirus efficiently inhibits tumor growth of glioma cancer stem like cells. AB - BACKGROUND: The brain cancer stem cell (CSC) model describes a small subset of glioma cells as being responsible for tumor initiation, conferring therapy resistance and tumor recurrence. In brain CSC, the PI3-K/AKT and the RAS/mitogen activated protein kinase (MAPK) pathways are found to be activated. In consequence, the human transcription factor YB-1, knowing to be responsible for the emergence of drug resistance and driving adenoviral replication, is phosphorylated and activated. With this knowledge, YB-1 was established in the past as a biomarker for disease progression and prognosis. This study determines the expression of YB-1 in glioblastoma (GBM) specimen in vivo and in brain CSC lines. In addition, the capacity of Ad-Delo3-RGD, an YB-1 dependent oncolytic adenovirus, to eradicate CSC was evaluated both in vitro and in vivo. METHODS: YB 1 expression was investigated by immunoblot and immuno-histochemistry. In vitro, viral replication as well as the capacity of Ad-Delo3-RGD to replicate in and, in consequence, to kill CSC was determined by real-time PCR and clonogenic dilution assays. In vivo, Ad-Delo3-RGD-mediated tumor growth inhibition was evaluated in an orthotopic mouse GBM model. Safety and specificity of Ad-Delo3-RGD were investigated in immortalized human astrocytes and by siRNA-mediated downregulation of YB-1. RESULTS: YB-1 is highly expressed in brain CSC lines and in GBM specimen. Efficient viral replication in and virus-mediated lysis of CSC was observed in vitro. Experiments addressing safety aspects of Ad-Delo3-RGD showed that (i) virus production in human astrocytes was significantly reduced compared to wild type adenovirus (Ad-WT) and (ii) knockdown of YB-1 significantly reduced virus replication. Mice harboring othotopic GBM developed from a temozolomide (TMZ)-resistant GBM derived CSC line which was intratumorally injected with Ad-Delo3-RGD survived significantly longer than mice receiving PBS injections or TMZ treatment. CONCLUSION: The results of this study supported YB-1 based virotherapy as an attractive therapeutic strategy for GBM treatment which will be exploited further in multimodal treatment concepts. PMID- 24044903 TI - The role of vitamin D in metabolic disturbances in polycystic ovary syndrome: a systematic review. AB - CONTEXT: Metabolic disturbances, in particular, insulin resistance (IR) and dyslipidemia, are common in women suffering from polycystic ovary syndrome (PCOS). Evidence is accumulating that vitamin D status may contribute to the development of metabolic disturbances in PCOS. OBJECTIVE: The aim of this study was to carry out a systematic review addressing the association between vitamin D status, vitamin D receptor polymorphisms, and/or polymorphisms related to vitamin D metabolism and metabolic disturbances in women with PCOS. DESIGN AND METHODS: A systematic search of electronic databases was carried out up to January 2013 for observational studies and clinical trials in women suffering from PCOS with outcome measures that were related to vitamin D status. We conducted univariate and multivariate regression analyses of the weighted means to gain insights into the association between vitamin D, BMI, and IR based on existing literature. RESULTS: We found 29 eligible trials with inconsistency in their results. One well-designed randomized controlled trial has been carried out until now. Univariate regression analyses of the weighted means revealed vitamin D to be a significant and independent predictor of IR in both PCOS and control women. The significance disappeared after adjustment for BMI in PCOS women. CONCLUSIONS: Current evidence suggests an inverse association between vitamin D status and metabolic disturbances in PCOS. Owing to the heterogeneity of the studies, it is hard to draw a definite conclusion. The causal relationship between vitamin D status and metabolic disturbances in PCOS remains to be determined in well designed placebo-controlled randomized clinical trials. PMID- 24044904 TI - National surveys of radiofrequency field strengths from radio base stations in Africa. AB - The authors analysed almost 260 000 measurement points from surveys of radiofrequency (RF) field strengths near radio base stations in seven African countries over two time frames from 2001 to 2003 and 2006 to 2012. The results of the national surveys were compared, chronological trends investigated and potential exposures compared by technology and with frequency modulation (FM) radio. The key findings from thes data are that irrespective of country, the year and mobile technology, RF fields at a ground level were only a small fraction of the international human RF exposure recommendations. Importantly, there has been no significant increase in typical measured levels since the introduction of 3G services. The mean levels in these African countries are similar to the reported levels for countries of Asia, Europe and North America using similar mobile technologies. The median level for the FM services in South Africa was comparable to the individual but generally lower than the combined mobile services. PMID- 24044905 TI - Effects of nicotine on the testicular toxicity of streptozotocin-induced diabetic rat: intervention of enalapril. AB - The aim of the present study is to investigate whether nicotine augmented the testicular toxicity and angiotensin converting enzyme inhibitor, enalapril, can ameliorate the effects in diabetic rat. Male Sprague Dawley rats were randomized into five groups: control, nicotine, diabetic, Diab + Nico, and Diab + Nico + Enal. Animals were made diabetic by single injection of streptozotocin (55 mg/kg/intraperitoneally). Nicotine dissolved in drinking water at a concentration of 100 ug/ml was given ad libitum and enalapril was given orally at a dose of 10 mg/kg/day for four consecutive weeks. After 4 weeks of treatment, animals were killed and biochemical parameters glucose, glycosylated hemoglobin, cotinine, and the testosterone levels were measured. Testicular toxicity was evaluated using sperm count, sperm comet assay, histology, and immunohistochemical staining of 8 oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and the proinflammatory markers (nuclear factor kappa B (NF-kappaB), cyclooxygenase (COX-2), and tissue necrotic factor alpha (TNF-alpha)) evaluated by western blotting. Results showed that nicotine did not alter the blood glucose and glycosylated hemoglobin level, significantly decreased the sperm count and increased the sperm DNA damage. These changes were accompanied by significant increases in the 8-oxo-dG, NF-kappaB, COX 2, and TNF-alpha expression. Furthermore, the intervention of enalapril in nicotine-treated diabetic rat attenuated the testicular damage and restored sperm count, sperm DNA damage, as well as reduced the expression of NF-kappaB, COX-2, and TNF-alpha. These findings clearly suggest that nicotine not only augmented the testicular toxicity in the diabetic rat but also increases the risk of germ cell toxicity effects that were attenuated by enalapril treatment. PMID- 24044906 TI - Factors associated with meniscal tears and chondral lesions in patients undergoing anterior cruciate ligament reconstruction: a prospective study. AB - BACKGROUND: Increased time from anterior cruciate ligament (ACL) injury to surgery is known to be associated with increased medial meniscal tears. Few studies have examined the predictors of meniscal tears and chondral lesions, including instability episodes. PURPOSE: To examine the predictors of meniscal tears and chondral injuries in patients undergoing ACL reconstruction. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Data were collected prospectively from 541 patients undergoing ACL reconstruction. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals for predictors of meniscal tears, tear management, and chondral injuries. Predictors included age, sex, body mass index (25-29.99 and >=30 vs <=24.99 kg/m(2)), mechanism (contact vs noncontact) and type (high-impact sports [basketball, football, soccer, and skiing] and other sports vs not sports related) of injury, interval from injury to surgery (<=6 vs >6 weeks and <=12 vs >12 weeks), and instability episodes (vs none). RESULTS: A total of 211 lateral meniscal tears (35.3% untreated, 48.3% meniscectomized, 16.4% repaired), 197 medial meniscal tears (25% untreated, 52% meniscectomized, 23% repaired), and 82 chondral injuries occurred. Age predicted chondral injuries. Male sex predicted more lateral meniscal tears overall, untreated lateral tears, and lateral meniscectomies as well as predicting medial meniscal tears overall and medial meniscectomies. Obesity predicted more chondral injuries. Sports-related injuries predicted fewer medial meniscal tears overall and medial meniscectomies. Injuries <=6 weeks from surgery predicted more lateral meniscal repairs but fewer medial meniscectomies. Injuries <=12 weeks from surgery predicted more chondral injuries. More instability episodes predicted medial meniscal tears overall, untreated medial tears, medial meniscectomies, and medial repairs. CONCLUSION: Male sex predicted lateral meniscal tears and management. Male sex, sports, injuries <=6 weeks from surgery, and preoperative episodes of instability predicted medial meniscal tears and management. Age predicted chondral injuries. This was one of the first studies to examine the number of instability episodes as a predictor of an intra-articular injury. PMID- 24044907 TI - Overestimation of nuclear matrix protein 22 in concentrated urine. AB - OBJECTIVE: To confirm the hypothesis that nuclear matrix protein 22 (NMP22) is overestimated in concentrated urine, we compared the NMP22 values measured at different dietary states. METHODS: We retrospectively reviewed 531 healthy subjects who had had abnormal urinary NMP22 values >= 10 U/mL at the first test and underwent a second NMP22 test within 2 weeks. The first NMP22 test was performed after overnight fasting, and the second was performed with no dietary restrictions. We compared the NMP22 values between the 2 measurements and investigated the relationship between the NMP22 value and urine specific gravity. RESULTS: At the second test, 504 subjects (94.9%) had a normal NMP22 value of <10 U/mL and only 27 subjects (5.1%) persistently had an abnormal NMP22 value of >= 10 U/mL. Both NMP22 and urine specific gravity at the first test were significantly higher than at the second test (P <.0001). Subjects with an abnormal NMP22 value tended to have a more concentrated urine with a greater urine specific gravity than did the subjects with a normal NMP22 value. This difference was significant in the subgroup undergoing bowel preparation for colonoscopy (P <.001). CONCLUSION: NMP22 will be overestimated in concentrated urine after overnight fasting. When interpreting the NMP22 value, we should consider the overestimation of NMP22 in concentrated urine. PMID- 24044909 TI - Editorial comment. PMID- 24044910 TI - Retroperitoneoscopic living donor nephrectomy: short learning curve and our original hybrid technique. AB - OBJECTIVE: To evaluate the effect of the learning curve for the hybrid technique of retroperitoneoscopic living donor nephrectomy (RDN) on donor and recipient outcomes. METHODS: We retrospectively reviewed 120 consecutive patients who underwent RDN, performed by a laparoscopic surgeon, at Sendai Shakaihoken Hospital between May 2005 and September 2011. A new hybrid technique, in which 2 laparoscopic ports were inserted through a hand-port device and all the procedures except mobilization and taping of ureter and extracting kidney were performed with nonhand-assisted technique, was used. These 120 patients were classified into 4 groups (groups 1-4) of 30 patients each on the basis of the order in which they were operated on by the surgeon. RESULTS: Baseline data including donors' age, gender, and body mass index did not differ among the groups. The time required for graft extraction and overall operative time were significantly longer in group 1 than in the other 3 groups. However, warm ischemia time, blood loss, length of postoperative hospital stay, and graft function did not differ among the groups. CONCLUSION: These results indicate that the hybrid technique of RDN could be performed by surgeons with acceptable outcomes, in donors and recipients, even during the early stages of practicing RDN. Although the time required for graft extraction and overall operative time were much longer during the learning phase, the learning curve was short and improved rapidly after performing only 30 procedures. PMID- 24044911 TI - Obesity is associated with larger prostate volume but not with worse urinary symptoms: analysis of a large multiethnic cohort. AB - OBJECTIVE: To evaluate the associations between body mass index (BMI) and prostate volume (PV) and lower urinary tract symptoms in a multiethnic cohort. METHODS: A cohort of men without prostate cancer seen at our institution was assembled, excluding those with previous transurethral resection of the prostate. Height and weight were measured to compute BMI, PV was measured by transrectal ultrasound, and the International Prostate Symptom Score (IPSS) questionnaire was administered. After stratified bivariate analyses, multiple linear regression and ordinal logistic regression models were used to assess the independent effect of BMI on PV and IPSS, respectively. RESULTS: The cohort included 1613 patients, and mean BMI was 27.1 kg/m(2). Patients with a BMI of <25.0, 25.0-29.9, and 30.0-34.9 had a median PV of 44.0 mL, 48.0 mL, and 52.0 mL, respectively. The African ethnicity subgroup generally had larger median PVs than European and Asian subgroups and had the largest differences in median PV between normal and obese men. There were no significant differences in IPSS or usage of benign prostatic hyperplasia medications between BMI categories. In multivariable analyses, higher BMI was associated with larger PV (P <.001) but not IPSS (P = .91). On the basis of our model, given a PV of 40 mL, 50 mL, and 60 mL, each 5 kg/m(2) increase in BMI was associated with a 2.19 mL, 2.74 mL, and 3.29 mL increase in PV, respectively. Body weight (P <.001) but not height (P = .13) was associated with PV. CONCLUSION: Higher BMI is associated with larger PV but not worse lower urinary tract symptoms (measured using IPSS). Usage rate of alpha blockers or 5 alpha reductase inhibitors was not significantly different between BMI categories. PMID- 24044912 TI - Does simultaneous inversion during extracorporeal shock wave lithotripsy improve stone clearance: a long-term, prospective, single-blind, randomized controlled study. AB - OBJECTIVE: To determine the efficacy of a combination of simultaneous shock wave lithotripsy (SWL), hydration with controlled inversion therapy compared with SWL with hydration alone in patients with lower pole calyx stones. METHODS: Patients with lower pole stones (4-20 mm) were randomized to SWL or SWL with simultaneous inversion therapy (30 degrees head down Trendelenburg position). Standardized shock waves were given to all patients stratified according to stone size. Subsequent standardized shock waves were given to patients with stone fragments determined by plain abdominal radiography and ultrasound by 2 radiologists blinded to treatment at day 1, weeks 2, 4, 12, 24, and at 1 year. The primary endpoint is stone-free rate (SFR) at week 12. RESULTS: A total of 140 patients were recruited into the study. Patients were comparable with respect to age, sex, race, and stone parameters at baseline. The overall SFR at week 12 was 72% (n = 49 of 68) in patients with SWL and 76% (n = 54 of 71) in SWL with simultaneous inversion at the end of study (P = .591). There was a trend for SFR to improve over time with >80% of patients being stone-free after 1 year in both groups. No significant adverse effects were noted in both groups of patients. CONCLUSION: Although not statistically significant, SWL with simultaneous inversion is a valuable adjunct in assisting the passage of lower pole renal stones with a SFR of 76%. In clinical practice, this also translates to a 1.28 times improvement in SFR with no or minimal additional costs. PMID- 24044913 TI - Calculating the number of shock waves, expulsion time, and optimum stone parameters based on noncontrast computerized tomography characteristics. AB - OBJECTIVE: To define the parameters that accompanied a successful extracorporeal shock wave lithotripsy (ESWL), namely the number of shock waves (SWs), expulsion time (ET), mean stone density (MSD), and the skin-to-stone distance (SSD). METHODS: A total of 368 patients diagnosed with renal calculi using noncontrast computerized tomography had their MSD, diameter, and SSD recorded. All patients were treated using a Siemens lithotripter. ESWL success meant a stone-free status or presence of residual fragments <3 mm, ET was the time in days for the successful clearance of stone fragments. Correlation was performed between the stone characteristics, number of SWs, and ET. Two multiple regression analysis models defined the number of SWs and ET. Two receiver operating characteristic curves plotted the best MSD cutoff value and optimum SSD for a successful ESWL. RESULTS: Three hundred one patients were ESWL successes. A significant positive correlation was elicited between number of SWs and stone diameter, density and SSD; between ET and stone diameter and density. Multiple regressions concluded 2 equations: Number of SWs = 265.108 + 5.103 x1 + 22.39 x2 + 10.931 x3 ET (days) = 10.85 + 0.031 x1 + 2.11 x2 x1 = stone density (Hounsfield unit [HUs]), x2 = stone diameter (mm), and x3 = SSD (mm). Receiver operating characteristic curves demonstrated a cutoff value of <= 934 HUs with 94.4% sensitivity and 66.7% specificity and P = .0211. The SSD curve showed that a distance <= 99 mm was 85.7% sensitive, 87.5% specific, P <.0001. CONCLUSION: Stone disintegration is not recommended if MSD is >934 HUs and SSD >99 mm. The required number of SWs and the expected ET can be anticipated. PMID- 24044914 TI - Leukemoid reaction: a rare paraneoplastic syndrome in bladder cancer associated with a grave prognosis. PMID- 24044915 TI - Editorial comment. PMID- 24044917 TI - Late presentation of ectopic dysplastic kidney and Mullerian duct anomaly. PMID- 24044918 TI - Cytology as an alternative to frozen section at the time of nephron-sparing surgery to evaluate surgical margin status. AB - OBJECTIVE: To evaluate quick-staining cytology as an alternative method to intraoperative frozen sectioning after nephron-sparing nephrectomy. MATERIALS AND METHODS: Eighty-two partial nephrectomies were performed with intraoperative quick-staining cytology and frozen section evaluation. The results of both were compared with permanent histology as the gold standard. RESULTS: After partial nephrectomy, permanent histologic surgical margins were positive in 8 of 82 (9.7%), cytology in 10 of 82 (12%), and frozen sectioning in 4 of 82 (5%). In comparison with permanent histologic examination, sensitivity of the cytologic examination was 87.5%, positive predictive value 70%, specificity 95.9%, and negative predictive value 98.6%. Kappa values (kappa) revealed a good level of agreement between intraoperative cytology and final histologic examination (kappa = 0.751; P <.0001). In comparison with permanent histology, sensitivity of frozen sections was 50%, specificity 100%, positive predictive value 100%, and negative predictive value 95%. Of the 8 cases with positive margin on permanent histologic examination, 7 were cytologically positive and only 4 positive on frozen sectioning. Two patients had a local recurrence on follow-up, of which both were correctly identified on quick-staining cytology. The quick-staining cytologic evaluations were completed in <4 minutes. CONCLUSION: Quick-staining cytology is rapid, highly sensitive, and specific to evaluate intraoperative surgical margins at partial nephrectomy. It reduces diagnostic time, could be used as alternative to intraoperative frozen section, and warrants further investigation. PMID- 24044919 TI - A new assay for fast, reliable CRIM status determination in infantile-onset Pompe disease. AB - Pompe disease is caused by a deficiency of acid alpha-glucosidase (GAA; EC, 3.2.1.20), and the infantile-onset form is rapidly fatal if left untreated. However, recombinant human GAA (rhGAA) enzyme replacement therapy (ERT) extends survival for infantile Pompe patients. Although cross-reactive immunologic material (CRIM)-negative patients, who lack detectable endogenous GAA, mount an immune response to rhGAA that renders the therapy ineffective, timely induction of immune tolerance in these patients may improve clinical outcomes. Previously, CRIM status has been determined by Western blot analysis in cultured skin fibroblasts, a process that can take a few weeks. We present a blood-based CRIM assay that can yield results within 48 to 72 h. Results from this assay have been confirmed by GAA Western blot analysis in fibroblasts or by GAA sequencing in a small number of Pompe disease patients. Rapid classification of CRIM status will assist in identifying the most effective treatment course and minimizing treatment delays in patients with infantile-onset Pompe disease. PMID- 24044920 TI - Phosphorylation of serine 323 of ASB2alpha is pivotal for the targeting of filamin A to degradation. AB - ASB proteins are the specificity subunits of cullin5-RING E3 ubiquitin ligases (CRL5) that play roles in ubiquitin-mediated protein degradation. However, how their activity is regulated remains poorly understood. Here, we unravel a novel mechanism of regulation of a CRL5 through phosphorylation of its specificity subunit ASB2alpha. Indeed, using mass spectrometry, we showed for the first time that ASB2alpha is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2alpha is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. Mutation of ASB2alpha Ser-323 to Ala had no effect on intrinsic E3 ubiquitin ligase activity of ASB2alpha but abolished the ability of ASB2alpha to induce degradation of FLNa. In contrast, the ASB2alpha Ser-323 to Asp phosphomimetic mutant induced acute degradation of FLNa. Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2alpha-mediated FLNa degradation. We further showed that the subcellular localization of ASB2alpha to actin-rich structures is dependent on ASB2alpha Ser 323 phosphorylation and propose that the interaction with FLNa depends on the electrostatic potential redistribution induced by the Ser-323 phosphate group. Taken together, these data unravel an important mechanism by which ASB2alpha mediated FLNa degradation can be regulated. PMID- 24044921 TI - Regulation of epithelial to mesenchymal transition by bone morphogenetic proteins. AB - Epithelial to mesenchymal transition (EMT) is a process in which fully differentiated epithelial cells lose many of their epithelial characteristics and adopt features typical of mesenchymal cells, thus allowing cells to become migratory and invasive. EMT is a critical process in development and its role in cancer and fibrosis is becoming increasingly recognised. It is also becoming apparent that EMT is not just restricted to embryonic development and disease in adults, but in fact may be an important process for the maintenance and regeneration of adult tissue architecture. While transforming growth factor-beta (TGF-beta) is considered a prototypic inducer of EMT, relatively little is known about other signalling molecules that regulate EMT. Bone morphogenic proteins (BMPs) are members of the TGF-beta superfamily and 20 different human BMPs have been identified. Originally named for their effects on bone, these proteins are now considered to be key morphogenetic signals that orchestrate tissue architecture throughout the body. BMP2, -4 and -7 are the best studied to date. There are disparate reports of the roles of BMPs in EMT during development, cancer and fibrosis. Here, we present an overview of this literature as well as the emerging role of EMT in tissue regeneration and the involvement of BMPs in regulating this process. PMID- 24044922 TI - Bcl-3, induced by Tax and HTLV-1, inhibits NF-kappaB activation and promotes autophagy. AB - The human T cell leukemia virus type 1 (HTLV-1) is a complex human retrovirus that causes an aggressive leukemia known as adult T cell leukemia (ATL). The HTLV 1-encoded oncoprotein Tax induces persistent activation of the nuclear factor kappaB (NF-kappaB) pathway, which is perceived as the primary cause of ATL. Bcl 3, a member of the NF-kappaB inhibitor (IkappaB) family, is highly expressed in many HTLV-1-infected T cell lines and ATL cells. However, the role of Bcl-3 in Tax-induced NF-kappaB activation has not been fully elucidated. Here, we show that Tax induces Bcl-3 expression, which in turn negatively regulates the Tax induced NF-kappaB activation. Interestingly, both Bcl-3 up-regulation and NF kappaB inhibition promote the autophagy process in HTLV-1-infected cells. Consistent with this, over-expression of Bcl-3 also results in enhancement of rapamycin-, pifithrin-alpha- or starvation-induced autophagy in control cells. Together, these data demonstrate that Bcl-3 acts as a negative regulator of NF kappaB activation and promotes autophagy in HTLV-1-infected cells. PMID- 24044923 TI - Mechanical characterization of living and dead undifferentiated human adipose derived stem cells by using atomic force microscopy. AB - In this article, to map the mechanical properties of undifferentiated human adipose-derived stem cells, local mechanical characterization is carried out on the adipose-derived stem cells. In addition, to distinguish the living and dead human adipose-derived stem cells, mechanical characterization is also implemented on both living and dead adipose-derived stem cells. In this study, Young's modulus of the cell membrane is used for representing the mechanical properties of cells. To obtain Young's modulus of cell membrane, the force-spectroscopy mode of atomic force microscopy is employed to measure the atomic force microscopy tip indentation depth and force on the cells. Then, Young's modulus is obtained through fitting these experimental data to the Hertzian contact mechanics model. The global Young's moduli of living and dead undifferentiated adipose-derived stem cells are about 1.27 and 18.61 kPa, respectively. This displays obvious gap of Young's modulus between the living and dead undifferentiated adipose-derived stem cells. Finally, comparison of the local Young's modulus shows deviation of the local Young's modulus for either living or dead undifferentiated adipose derived stem cells, and the root-mean-square errors of the global Young's modulus of living and dead undifferentiated adipose-derived stem cells are about 0.48 and 5.05 kPa, respectively. PMID- 24044924 TI - Foreword. Qualitative and quantitative applied research and evaluation. PMID- 24044925 TI - A cultural lens to understanding daily experiences with type 2 diabetes self management among clinic patients in M'bour, Senegal. AB - Diabetes is a steadily increasing threat in Sub-Saharan Africa (SSA). Factors such as urbanization, obesity, physical inactivity, and inadequate access to healthcare are believed to contribute to the increasing burden of diabetes. Interventions that optimize diabetes self-management are critically important since obtaining diabetes medications is challenging due to cost constraints and availability. Culture is a significant factor in shaping health behaviors such as diabetes self-management, where individual health behaviors operate in confluence with family, community, and social structures. This study examined experiences with diabetes self-management among clinic patients residing in M'bour, Senegal, using the PEN3 model as a cultural framework. Results indicate that financial challenges related to accessing medical care and adhering to the prescribed diabetic diet were the main barriers to diabetes management. Family dynamics serve as both supportive and inhibiting forces that influence the aforementioned barriers. PMID- 24044926 TI - Predicting Mexican youths' intention to engage in risky behaviors: applying moral norms to the theory of planned behavior. AB - This study explored if moral norms as applied to the theory of planned behavior (TPB) account for additional variance in predicting intention to consume alcohol, smoke cigarettes, and engage in sexual activity among youth at a high school in Mexico. Additionally, it investigated if moral norms provide a moderating influence on the constructs of the theory: attitude, subjective norm, and perceived behavioral control for prediction of risky behavior intention. Multiple regression analyses identified predictive power of constructs; interactions of moral norms with the theory constructs were studied. Moral norms only significantly predicted sexual activity. Significant interactions were found between moral norms and the theory constructs for the three behaviors. Interventions aimed at preventing risky conduct among youth would benefit from strategies targeting beliefs in the moral order, especially because of its interaction with the other theoretical mechanisms. PMID- 24044927 TI - Condom access in San Antonio, Texas: the "three A's" and HIV/STI incidence. AB - Condoms are highly effective at reducing STI transmission. Access is a critical precursor to use. This socio-ecologic study operationalizes the concept of condom access by defining it in terms of availability, affordability, and affect, and explores the relationship between these and STI incidence. Three pairs of zip codes, each with similar demographics but different Chlamydia and HIV incidence rates, were identified. Supermarkets, convenience stores, and pharmacies (N = 102) were evaluated for the three A's. Nonparametric methods were used to compare the moderate-Chlamydia areas to the high-incidence areas. High-Chlamydia areas were significantly less likely to have 12-packs available compared to moderate Chlamydia areas. Prices averaged over $1 per condom and did not vary by incidence. High-incidence areas were significantly less likely to allow patrons to select condoms unassisted. High-HIV areas placed more positively-connoted items near condoms. Improving these factors may improve condom acquisition and in turn reduce STI and HIV incidence rates. PMID- 24044928 TI - Healthcare-seeking behavior among the Chakma ethnic group in Bangladesh: can accessibility and cultural beliefs shape healthcare utilization? AB - Existing studies lack qualitative information on the perceived reasons for ethnic minority groups' healthcare choices, attitudes toward healthcare services, and common practices based on traditional cultural belief systems in Bangladesh. This study noted the important influence of culture and beliefs with regard to availing healthcare services. Informal sector providers such as para professionals and traditional healers take the lead in rendering physically, financially, and culturally accessible healthcare services in the context of under-utilization of public healthcare facilities. Salient factors determining the choice of therapy were the perceived causes of illness and physical and financial access to the health services. These drivers of health seeking behavior in an increasingly pluralistic healthcare system need to be taken into account to strengthen the current healthcare delivery system and to design specific health education and healthcare promotion programs for the poor, hard-to-reach, and under-served ethnic minority. PMID- 24044929 TI - Exercise program-induced mood improvement and improved eating in severely obese adults. AB - BACKGROUND: Using a practical setting, this study aimed to test exercise and nutrition interventions' effects on negative mood, self-regulation, and self efficacy to control eating; and to assess the ability of mood change to predict changes in eating behavior, while accounting for changes in self-regulation and self-efficacy. METHODS: Severely obese adults participated in a cognitive behavioral exercise support treatment paired with either nutrition education (n = 140) or cognitive-behavioral methods applied to improved eating (n = 146). They were assessed on measures of overall negative mood, self-regulatory skill usage, self-efficacy to control eating when negative moods are present, and fruit and vegetable consumption at baseline and Week 26. RESULTS: Significant improvements in each psychosocial variable and fruit and vegetable intake were found. Improved mood significantly predicted fruit and vegetable consumption change, R2 = 0.12, P < 0.001. Entry of changes in self-regulation and self-efficacy into the multiple regression equation significantly strengthened the variance explained, R2 = 0.18, P < 0.001. DISCUSSION: Findings suggest that exercise-induced improvements in mood improve eating behaviors, with increases in self-regulation and self efficacy adding to this effect. PMID- 24044931 TI - Global South is key to accelerating human development in sub-Saharan Africa. PMID- 24044930 TI - Barriers to family planning and contraception uptake in sub-Saharan Africa: a systematic review. AB - This review assessed barriers to uptake of family planning and contraceptive services among women in sub-Saharan Africa. Included were studies: (1) published in the English; (2) between the years January 2010 and July 2012; (3) that measure barriers to family planning/contraceptive methods; and (4) that use any quantitative or qualitative study design. Eleven studies fitting the inclusion criteria were reviewed. The major barriers found to prevent uptake of services included cultural and societal pressure on women, socioeconomic status, financial barriers, and regional barriers associated with lack of access to services. Due to the diversity of the populations in sub-Saharan Africa, it is clear that a one size-fits-all approach will not be efficacious; rather, a strategy that takes into account cultural and societal norms for the population of interest is better. PMID- 24044934 TI - Preliminary investigation of the impact of anticentromere antibody on oocyte maturation and embryo cleavage. AB - OBJECTIVE: To explore whether anticentromere antibody (ACA) is the most significant antibody among antinuclear antibodies (ANA), which adversely affect oocyte maturation, embryo cleavage, and pregnancy outcome in women undergoing an intracytoplasmic sperm injection program. DESIGN: Retrospective, nested case control study. SETTING: Center for reproductive medicine, university hospital. PATIENT(S): A total of 187 women receiving the first intracytoplasmic sperm injection cycle were enrolled in this study, including 20 women with positive ACA and ANA (ACA[+]/ANA[+] group), 51 women with negative ACA and positive ANA(ACA[ ]/ANA[+] group), and 116 patients with negative ACA and ANA (ACA[-]/ANA[-] group). Patients in the three groups were age-matched. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Percentages of germinal vesicle, metaphase I, and metaphase II oocytes, embryo cleavage rate, number of high-quality embryos, and rates of pregnancy and implantation. RESULT(S): The metaphase I oocyte percentage was markedly higher and the metaphase II oocyte percentage and the normal cleavage rate were significantly lower in the ACA[+]/ANA[+] group as compared with the ACA[-]/ANA[+] group. Furthermore, statistically significant differences were found in rates of pregnancy and implantation among the three groups. However, no significant difference was found between any two groups owing to the small sample size, except for a significantly lower implantation rate being found in the ACA[+]/ANA[+] group when compared with the ACA[-]/ANA[-] group. CONCLUSION(S): Our data suggest that ACA may be the essential marker for defective oocytes or embryos in infertile women with any type of ANA. PMID- 24044935 TI - Finasteride and male infertility: a case for prospective collaborative research databases? PMID- 24044936 TI - Synthesis of conformationally constrained gamma-D-glutamyl-meso-diaminopimelic acid derivatives as ligands of nucleotide-binding oligomerization domain protein 1 (Nod1). AB - Nod1, an important member of the pattern recognition receptor family, remains a virtually unexploited target. Harnessing its innate immune stimulatory properties still remains an unfulfilled goal of medicinal chemistry. Nucleotide-binding oligomerization domain protein 1 (Nod1) agonists have been shown to boost the inflammatory responses against pathogenic microbes and could thus constitute a new class of broad spectrum antimicrobial agents. To gain additional insight into the structure/activity relationships of Nod1 agonistic compounds, a series of novel, conformationally constrained gamma-D-glutamyl-meso-diaminopimelic acid (iE DAP) analogs have been designed and synthesized. Ramos-Blue cells expressing Nod1 were used to screen and validate our compounds for their Nod1-agonist activity. Their immunomodulatory properties were subsequently determined in vitro, by evaluating their capacity to induce pro-inflammatory cytokine and chemokine production from human peripheral blood mononuclear cells (PBMC), by themselves and in synergy with lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand. The synthesized iE-DAP analogs were shown to possess immuno-enhancing properties as a result of their potent and specific Nod1-agonistic effect. The activity of the compound exhibiting the greatest capacity to induce pro inflammatory cytokine release from PBMC surpassed that of lauroyl-gamma-D glutamyl-meso-diaminopimelic acid (C12-iE-DAP). PMID- 24044937 TI - Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group. AB - Osteoarthritis is a disabling disease characterized by the articular cartilage breakdown. Aggrecanases are potential therapeutic targets for the treatment of this pathology. At the starting point of this project, an acylthiosemicarbazide was discovered to inhibit aggrecanase-2. The acylthiosemicarbazide Zn binding group is also a convenient linker for library synthesis. A focused library of 920 analogs was thus prepared and screened to establish structure-activity relationships. The modification of the acylthiosemicarbazide was also explored. This strategy combining library design and discrete compounds synthesis yielded inhibitor 35, that is highly selective for aggrecanases over a panel of metalloproteases and inhibits the degradation of native fully glycosylated aggrecan. A docking study generated binding conformations explaining the structure-activity relationships. PMID- 24044938 TI - Synthesis and in vitro/in vivo antibacterial activity of oxazolidinones having thiocarbamate at C-5 on the A-ring and an amide- or urea-substituted [1,2,5]triazepane or [1,2,5]oxadiazepane as the C-ring. AB - Oxazolidinones bearing a seven-membered [1,2,5]triazepane or [1,2,5]oxadiazepane heterocycle substituted with an amide or urea functionality as the C-ring and having a [1,2,3]triazole, a thiocarbamate, an isoxazole-3-ylamino, or a thioacetamide C-5 side chain unit on the A-ring instead of the typical acetamide were synthesized and their in vitro antibacterial activities towards various pathogens were evaluated. Several derivatives exhibited potent in vitro antibacterial activity toward not only Gram-positive, but also Gram-negative and linezolid-resistant pathogens. The in vivo therapeutic effects of amide 11a and ureas 16e, 17a were 2- to 3-fold greater than that of linezolid in a systemic mouse infection model treated by intravenous administration. Furthermore, compounds 11a and 17a showed lower monoamine oxidase (MAO)-inhibitory activity than our previously reported potent oxazolidinone antibacterials 3a and 3b. PMID- 24044939 TI - The impact of primary Sjogren's syndrome on pregnancy outcome: our series and review of the literature. AB - OBJECTIVE: Firstly, to investigate the pregnancy outcome of women with primary Sjogren's Syndrome (pSS) in a case-control study; secondly, to perform a review of the literature in order to clarify if the pregnancy outcome is affected by pSS and influenced by the disease clinical onset. METHOD OF STUDY: Thirty-four pregnancies with pSS and 136 controls were retrospectively collected. RESULTS: Six pregnancies occurred before the pSS diagnosis and 28 after the pSS diagnosis. Two cases were complicated by intrauterine atrio-ventricular block. A statistically significant increase of the rate of spontaneous abortions, preterm deliveries and cesarean section was found in pSS pregnancies. The mean neonatal birth weight and the mean neonatal birth weight percentile were significantly lower in the offspring of women with pSS in comparison to controls. Similar pregnancy outcome was observed in women with pSS diagnosis before and after the index pregnancy. CONCLUSIONS: Women with pSS experienced complicated pregnancies more frequently than controls, regardless of the onset of the symptoms, showing that the immunological disturbance is present throughout the reproductive life. PMID- 24044940 TI - Influenza and pneumococcal vaccinations of patients with systemic lupus erythematosus: current views upon safety and immunogenicity. AB - Systemic lupus erythematosus (SLE) is a chronic immune-mediated inflammatory multisystem disease. The onset of viral and bacterial infections may favor the exacerbation of the disease, amplify autoimmune processes and contribute to mortality and morbidity. The prevention of influenza and Streptococcus pneumoniae infections with vaccination should receive particular attention in SLE patients considering their elevated incidence, their high attack rate in epidemic periods, their potentially severe complications as well as the immunocompromised state of the host. The use of non-adjuvanted vaccine preparations should be preferred in order to avoid the onset of the "Autoimmune (auto-inflammatory) Syndrome Induced by Adjuvants" or "ASIA". In this review, we report that influenza and pneumococcal vaccinations in SLE patients are: 1) recommended to reduce the risk of development of these infections; 2) strongly suggested in elderly subjects and in those receiving high dose immunosuppressive treatments; 3) efficacious, even if specific immune responses may be lower than in the general population, as generally the humoral response fulfills the criteria for vaccine immunogenicity; and 4) safe in inactive disease although may favor a transient increase in autoantibody levels and rarely disease flares. PMID- 24044941 TI - The circling mutant Pcdh15roda is a new mouse model for hearing loss. AB - Mouse mutagenesis is a key tool for studying gene function and several mutant alleles have been described and constitute mouse models for human hereditary diseases. Genetic hearing loss represents over 50% of all hearing loss cases in children and, due to the heterogeneity of the disorder, there is still a demand for the isolation and characterization of new genes and alleles. Here we report phenotypic and molecular characterization of a new mouse model for hereditary hearing loss. The mutant rodador, isolated by Massironi and colleagues in 2006, presents an autosomal recessive disorder characterized by deafness and balance dysfunction associated with abnormal stereocilia in the inner ear. The mutation was mapped to mouse chromosome 10, and characterization of the gene Pcdh15 revealed an AT-to-GC transition in intron 23 of mutant animals. The alteration led to the switch of a dinucleotide ApA for ApG, creating a novel intronic acceptor splice site, which leads to incorporation of eight intronic bases into the processed mRNA and alteration of the downstream reading frame. In silico analysis indicated that the mutated protein is truncated and lacks two cadherin domains, and the transmembrane and cytoplasmic domains. Real Time PCR analyses revealed a significantly reduced Pcdh15 mRNA level in the brain of mutant mice, which might be due to the mechanism of non-sense mediated decay. In man, mutations in the orthologue PCDH15 cause non-syndromic deafness and Usher Syndrome Type 1F, a genetic disorder characterized by hearing loss and retinitis pigmentosa. Rodador mouse constitutes a new model for studying deafness in these conditions and may help in the comprehension of the pathogeneses of the disease, as well as of the mechanisms involved in the morphogenesis and function of inner ear stereocilia. This is a new ENU-induced allele and the first isolated in a BALB/c background. PMID- 24044943 TI - Effect of environmental variables and stand structure on ecosystem respiration components in a Mediterranean beech forest. AB - The temporal variability of ecosystem respiration (RECO) has been reported to have important effects on the temporal variability of net ecosystem exchange, the net amount of carbon exchanged between an ecosystem and the atmosphere. However, our understanding of ecosystem respiration is rather limited compared with photosynthesis or gross primary productivity, particularly in Mediterranean montane ecosystems. In order to investigate how environmental variables and forest structure (tree classes) affect different respiration components and RECO in a Mediterranean beech forest, we measured soil, stem and leaf CO2 efflux rates with dynamic chambers and RECO by the eddy-covariance technique over 1 year (2007 2008). Ecosystem respiration showed marked seasonal variation, with the highest rates in spring and autumn and the lowest in summer. We found that the soil respiration (SR) was mainly controlled by soil water content below a threshold value of 0.2 m(3) m(-3), above which the soil temperature explained temporal variation in SR. Stem CO2 effluxes were influenced by air temperature and difference between tree classes with higher rates measured in dominant trees than in co-dominant ones. Leaf respiration (LR) varied significantly between the two canopy layers considered. Non-structural carbohydrates were a very good predictor of LR variability. We used these measurements to scale up respiration components to ecosystem respiration for the whole canopy and obtained cumulative amounts of carbon losses over the year. Based on the up-scaled chamber measurements, the relative contributions of soil, stem and leaves to the total annual CO2 efflux were: 56, 8 and 36%, respectively. These results confirm that SR is the main contributor of ecosystem respiration and provided an insight on the driving factors of respiration in Mediterranean montane beech forests. PMID- 24044942 TI - Apparent mtDNA sequence heterogeneity in single human blood CD34+ cells is markedly affected by storage and transport. AB - Single CD34(+) cells from adult human peripheral blood show mtDNA sequence heterogeneity. In this study, we compared mtDNA sequence variation in single CD34(+) cells from peripheral blood (PB) mononuclear cells (MNCs) from the same donors but under different conditions of storage and transport: group I, MNCs from heparinized PB that inadvertently required six days to be transported to the testing laboratory; group II, MNCs which were isolated from PB within a day of phlebotomy and frozen prior to transportation and storage. We observed more cell death for MNCs of group I than group II. Concordantly, group I CD34(+) cells had a very low potential for hematopoietic colony formation in vitro compared with group II cells. CD34(+) cells of group II showed an unexpectedly higher level of mtDNA sequence heterogeneity than was present in group I cells. These observations suggest that reduced mtDNA sequence heterogeneity in single CD34(+) cells of group I was likely due to elimination of cells harboring mutations. CD34(+) cells that survive stress ex vivo may be more enriched in quiescent primitive hematopoietic stem cells, with fewer mtDNA mutations than are present in committed progenitors. Technically, attention is required to conditions of preparation of human blood samples for single cell mtDNA analysis. PMID- 24044944 TI - The sub-chronic toxicity in rats of isoparaffinic solvents. AB - Results from a 13-week inhalation study in rats on a C10-C12 isoparaffinic solvent are compared to the results of repeated inhalation and oral toxicity studies of four other isoparaffinic hydrocarbon solvents. Statistically significant findings which were consistent across all studies included: nephropathy and small but significant changes in hematological parameters in male rats and liver enlargement in both male and female rats. The male rat kidney changes were due to an alpha 2u globulin process and not relevant for human health or risk assessment. The liver enlargement without pathologic changes or elevations in liver enzyme markers was considered to be an adaptive response. The reason for the reductions in hematological parameters that were observed in males only is not clear, but it is suggested that these were either due to normal variation or a secondary consequence of the nephropathy. The overall No Observed Adverse Effect Concentration (NOAEC) was the highest concentration tested in the study, >10,000 mg/m(3). Because of the overall pattern of response, this solvent is considered to be representative of low aromatic C9-C14 aliphatic solvents in general. The data are useful for risk assessment and other purposes including the development of occupational exposure recommendations. PMID- 24044945 TI - The role of a Schiff base scaffold, N-(2-hydroxy acetophenone) glycinate-in overcoming multidrug resistance in cancer. AB - Drug resistance is a problem that hinders the numerous successes of chemotherapeutic intervention of cancer and continues to be a major obstacle for cures. Till date, several attempts have been made to develop suitable multidrug resistance (MDR) reversing agents. But, throughout the clinical development of MDR reversing agents, patients repeatedly suffer from toxicities. So far, some anticancer activity of Schiff bases which are the condensation products of carbonyl compounds and primary amines and their metal complexes has been described. But, overcoming multidrug resistance, by the use of such small molecules still remain unexplored. Under this backdrop, in search of less toxic and more effective MDR reversing agents our laboratory has developed the different metal chelates of Schiff base N-(2-hydroxy acetophenone)glycinate (NG) which is structurally similar to azatyrosine [L-beta-(5-hydroxy-2-pyridyl) alanine] that inhibits tumor formation by deactivating the c-Raf-1 kinase and c Ha-ras signalling pathway. A decade-long research proposes possible strategies to overcome MDR by exploiting the chemical nature of such metal chelates. In this review we have catalogued the success of metal chelates of NG to overcome MDR in cancer. The review depict that the problem of MDR can be circumvent by synchronized activation of immunogenic cell death pathways that utilize the components of a host's immune system to kill cancer cells in combination with other conventional strategies. The current wealth of preclinical information promises better understanding of the cellular processes underlying MDR reversing activity of metal derivatives of NG and thus exposes several cellular targets for rational designing of new generation of Schiff base metal chelates as MDR reversing agents. PMID- 24044946 TI - Guillain-Barre/CIDP-like neuropathy in two parkinsonian patients following intestinal levodopa/carbidopa treatment. PMID- 24044947 TI - Parkinson's disease and history of outdoor occupation. AB - BACKGROUND: Human and animal studies, albeit not fully consistent, suggest that vitamin D may reduce risk of Parkinson's disease (PD). Ultraviolet radiation converts vitamin D precursor to the active form. This study examined the hypothesis that working outdoors is associated with a decreased risk of PD. METHODS: PD cases were enrolled from Group Health Cooperative, a health maintenance organization in the Puget Sound region in western Washington State, and the University of Washington Neurology Clinic in Seattle. Participants included 447 non-Hispanic Caucasian newly diagnosed PD cases diagnosed between 1992 and 2008 and 578 unrelated neurologically normal controls enrolled in Group Health Cooperative, frequency matched by race/ethnicity, age and gender. Subjects' amount of outdoor work was estimated from self-reported occupational histories. Jobs were categorized by degree of time spent working outdoors. A ten year lag interval was included to account for disease latency. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression, with adjustment for age, gender, and smoking. RESULTS: Outdoor work was inversely associated with risk of PD (outdoor only compared to indoor only): OR = 0.74, 95% CI 0.44-1.25. However, there was no trend in relation to portion of the workday spent laboring outdoors and PD risk. CONCLUSION: Occupational sunlight exposure and other correlates of outdoor work is not likely to have a substantial role in the etiology of PD. PMID- 24044948 TI - Rejuvenation of human cardiac progenitor cells with Pim-1 kinase. AB - RATIONALE: Myocardial function is enhanced by adoptive transfer of human cardiac progenitor cells (hCPCs) into a pathologically challenged heart. However, advanced age, comorbidities, and myocardial injury in patients with heart failure constrain the proliferation, survival, and regenerative capacity of hCPCs. Rejuvenation of senescent hCPCs will improve the outcome of regenerative therapy for a substantial patient population possessing functionally impaired stem cells. OBJECTIVE: Reverse phenotypic and functional senescence of hCPCs by ex vivo modification with Pim-1. METHODS AND RESULTS: C-kit-positive hCPCs were isolated from heart biopsy samples of patients undergoing left ventricular assist device implantation. Growth kinetics, telomere lengths, and expression of cell cycle regulators showed significant variation between hCPC isolated from multiple patients. Telomere length was significantly decreased in hCPC with slow-growth kinetics concomitant with decreased proliferation and upregulation of senescent markers compared with hCPC with fast-growth kinetics. Desirable youthful characteristics were conferred on hCPCs by genetic modification using Pim-1 kinase, including increases in proliferation, telomere length, survival, and decreased expression of senescence markers. CONCLUSIONS: Senescence characteristics of hCPCs are ameliorated by Pim-1 kinase resulting in rejuvenation of phenotypic and functional properties. hCPCs show improved cellular properties resulting from Pim-1 modification, but benefits were more pronounced in hCPC with slow-growth kinetics relative to hCPC with fast-growth kinetics. With the majority of patients with heart failure presenting advanced age, infirmity, and impaired regenerative capacity, the use of Pim-1 modification should be incorporated into cell-based therapeutic approaches to broaden inclusion criteria and address limitations associated with the senescent phenotype of aged hCPC. PMID- 24044949 TI - MicroRNA-223 antagonizes angiogenesis by targeting beta1 integrin and preventing growth factor signaling in endothelial cells. AB - RATIONALE: Endothelial cells in situ are largely quiescent, and their isolation and culture are associated with the switch to a proliferative phenotype. OBJECTIVE: To identify antiangiogenic microRNAs expressed by native endothelial cells that are altered after isolation and culture, as well as the protein targets that regulate responses to growth factors. METHODS AND RESULTS: Profiling studies revealed that miR-223 was highly expressed in freshly isolated human, murine, and porcine endothelial cells, but those levels decreased in culture. In primary cultures of endothelial cells, vascular endothelial cell growth factor and basic fibroblast growth factor further decreased miR-223 expression. The overexpression of precursor-miR-223 did not affect basal endothelial cell proliferation but abrogated vascular endothelial cell growth factor-induced and basic fibroblast growth factor-induced proliferation, as well as migration and sprouting. Inhibition of miR-223 in vivo using specific antagomirs potentiated postnatal retinal angiogenesis in wild-type mice, whereas recovery of perfusion after femoral artery ligation and endothelial sprouting from aortic rings from adult miR-223(-/y) animals were enhanced. MiR-223 overexpression had no effect on the growth factor-induced activation of ERK1/2 but inhibited the vascular endothelial cell growth factor-induced and basic fibroblast growth factor-induced phosphorylation of their receptors and activation of Akt. beta1 integrin was identified as a target of miR-223 and its downregulation reproduced the defects in growth factor receptor phosphorylation and Akt signaling seen after miR-223 overexpression. Reintroduction of beta1 integrin into miR-223-ovexpressing cells was sufficient to rescue growth factor signaling and angiogenesis. CONCLUSIONS: These results indicate that miR-223 is an antiangiogenic microRNA that prevents endothelial cell proliferation at least partly by targeting beta1 integrin. PMID- 24044951 TI - Three-dimensional reconstruction of cardiac sarcoplasmic reticulum reveals a continuous network linking transverse-tubules: this organization is perturbed in heart failure. AB - RATIONALE: The organization of the transverse-tubular (t-t) system and relationship to the sarcoplasmic reticulum (SR) underpins cardiac excitation contraction coupling. The architecture of the SR, and relationship with the t-ts, is not well characterized at the whole-cell level. Furthermore, little is known regarding changes to SR ultrastructure in heart failure. OBJECTIVE: The aim of this study was to unravel interspecies differences and commonalities between the relationship of SR and t-t networks within cardiac myocytes, as well as the modifications that occur in heart failure, using a novel high-resolution 3 dimensional (3D) imaging technique. METHODS AND RESULTS: Using serial block face imaging coupled with scanning electron microscopy and image analysis, we have generated 3D reconstructions of whole cardiomyocytes from sheep and rat left ventricle, revealing that the SR forms a continuous network linking t-ts throughout the cell in both species. In sheep, but not rat, the SR has an intimate relationship with the sarcolemma forming junctional domains. 3D reconstructions also reveal details of the sheep t-t system. Using a model of tachypacing-induced heart failure, we show that there are populations of swollen and collapsed t-ts, patches of SR tangling, and disorder with rearrangement of the mitochondria. CONCLUSIONS: We provide the first high-resolution 3D structure of the SR network showing that it forms a cell-wide communication pipeline facilitating Ca(2+) diffusion, buffering, and synchronicity. The distribution of the SR within the cell is related to interspecies differences in excitation contraction coupling, and we report the first detailed analysis of SR remodeling as a result of heart failure. PMID- 24044950 TI - Gli3 regulation of myogenesis is necessary for ischemia-induced angiogenesis. AB - RATIONALE: A better understanding of the mechanism underlying skeletal muscle repair is required to develop therapies that promote tissue regeneration in adults. Hedgehog signaling has been shown previously to be involved in myogenesis and angiogenesis: 2 crucial processes for muscle development and regeneration. OBJECTIVE: The objective of this study was to identify the role of the hedgehog transcription factor Gli3 in the cross-talk between angiogenesis and myogenesis in adults. METHODS AND RESULTS: Using conditional knockout mice, we found that Gli3 deficiency in endothelial cells did not affect ischemic muscle repair, whereas in myocytes, Gli3 deficiency resulted in severely delayed ischemia induced myogenesis. Moreover, angiogenesis was also significantly impaired in HSA Cre(ERT2); Gli3(Flox/Flox) mice, demonstrating that impaired myogenesis indirectly affects ischemia-induced angiogenesis. The role of Gli3 in myocytes was then further investigated. We found that Gli3 promotes myoblast differentiation through myogenic factor 5 regulation. In addition, we found that Gli3 regulates several proangiogenic factors, including thymidine phosphorylase and angiopoietin-1 both in vitro and in vivo, which indirectly promote endothelial cell proliferation and arteriole formation. In addition, we found that Gli3 is upregulated in proliferating myoblasts by the cell cycle-associated transcription factor E2F1. CONCLUSIONS: This study shows for the first time that Gli3-regulated postnatal myogenesis is necessary for muscle repair-associated angiogenesis. Most importantly, it implies that myogenesis drives angiogenesis in the setting of skeletal muscle repair and identifies Gli3 as a potential target for regenerative medicine. PMID- 24044952 TI - Cancer risks from CT radiation: is there a dose threshold? PMID- 24044953 TI - A dowel exercise tool to improve finger range of motion. AB - A new clinical and home dowel exercise tool to reduce joint stiffness of the fingers is introduced, along with the fabrication and the exercises that are used with it. Patients may utilize it to improve their finger joint range of motion, and facilitate tendon glide by isolating the targeted stiff joints of the fingers. PMID- 24044954 TI - The use of joint mobilization to improve clinical outcomes in hand therapy: a systematic review of the literature. AB - STUDY DESIGN: Systematic review. INTRODUCTION: Joint mobilizations are used as an intervention for improving range of motion, decreasing pain and ultimately improving function in patients with a wide variety of upper extremity diagnoses. However, there are only a limited number of studies describing this treatment for conditions affecting the elbow, wrist, and hand. Furthermore, it is unclear as to the most effective joint mobilization technique utilized and the most beneficial functional outcomes gained. PURPOSE: Examine the current evidence describing joint mobilizations for treatment of conditions of the elbow, wrist and hand, and offer informative practical clinical guidance. METHODS: Twenty-two studies dated between 1980 and 2011 were included in the systematic review for analysis. RESULTS: The current evidence provides moderate support for the inclusion of joint mobilizations in the treatment of lateral epicondylalgia (LE). In particular, mobilization with movement as described by Mulligan is supported with evidence from nine randomized clinical trials as an effective technique for the treatment of pain. Other described techniques include those known as Kaltenborn, Cyriax physical therapy, and Maitland, but the evidence for these techniques is limited. There is also limited evidence for the joint mobilizations in the treatment of wrist and hand conditions. CONCLUSIONS: The current literature offers limited support for joint mobilizations of the wrist and hand, and moderate support for joint mobilizations of the elbow for LE. There is moderate support for mobilization with movement. . PMID- 24044955 TI - Predictive role of prenasal thickness and nasal bone for Down syndrome in the second trimester. AB - OBJECTIVE: To assess the efficacy of prenasal thickness (PNT) and nasal bone (NB) for prediction of Down syndrome (DS) fetuses in the second trimester ultrasound examination. STUDY DESIGN: PNT was measured from stored two-dimensional fetal profile images taken at 15-23 weeks in 242 fetuses with normal karyotype (Group 1) and 24 fetuses with DS (Group 2). It was measured as the shortest distance from the anterior edge of the lowest part of the frontal bone to the skin. The efficacy of PNT, NB, PNT/NB and biparietal diameter (BPD)/NB was evaluated for prediction of DS. RESULTS: PNT values increased with gestational age in normal fetuses. PNT measurement was >=95th percentile in 54.2% (13/24) of the DS cases and 2.9% of the normal cases. Receiver operator curve analysis showed that PNT/NB ratio had the best area under the curve with a detection rate of 80% for a false positive rate of 5% at a cut-off value of 0.76. CONCLUSIONS: PNT is increased in fetuses with DS as compared to normal fetuses. PNT/NB>=0.76 in the second trimester is a better predictor of DS than the use of PNT or NB alone. PMID- 24044959 TI - Upregulation of tumor suppressor WWOX promotes immune response in glioma. AB - Previous studies demonstrate that human glioma cells could evade the host's immune surveillance system, result in aggressive proliferation. WWOX, a tumor suppressor gene affected in multiple cancers, induces tumor apoptosis and suppresses growth in vitro and in vivo. However, the effect of WWOX expression in glioma cells to immune cells is still unknown. In the present study, we transduced WWOX into human glioma cell line U251, and cocultured with Jurkat T cells together. We demonstrated that upregulation of WWOX could increase proliferation of Jurkat T cells and decrease the FasL and TGF-beta expression of U251 cells, result in inhibiting apoptosis of Jurkat T cells. Therefore, our results suggested that loss of WWOX expression not only resulted in glioma carcinogenesis, but also suppressed immune cell attack by inducing Fas/FasL mediated apoptotic signaling. PMID- 24044960 TI - Constitutive expression of ligand for natural killer cell NKp44 receptor (NKp44L) by normal human articular chondrocytes. AB - Normal chondrocytes display susceptibility to lysis by natural killer (NK) cells and this phenomenon may play a role in some inflammatory cartilage disorders. The mechanisms of chondrocyte recognition and killing by NK cells remain unclear. Using flow cytometry and immunohistochemical staining we found that normal human articular chondrocytes constitutively express a ligand for NKp44, one of stimulatory NK cell receptors involved in recognition and killing of target cells. Expression of NKp44 ligand by normal articular chondrocytes is not involved in their killing by unstimulated NK cells; however, it is responsible for anti-chondrocyte cytotoxicity mediated by long-term activated NK cells. Thus, expression of NKp44 ligand may play a role in chondrocyte destruction in course of chronic inflammatory cartilage disorders. PMID- 24044961 TI - Reverse signaling from LIGHT promotes pro-inflammatory responses in the human monocytic leukemia cell line, THP-1. AB - LIGHT is a type II transmembrane protein belonging to the TNF superfamily which is involved in co-stimulation of T cells or apoptosis in tumors. In this study, the possibility of LIGHT-mediated reverse signaling was tested in the human monocytic leukemia cell line, THP-1. For stimulation of LIGHT, cells were stimulated with specific monoclonal antibody and changes in macrophage-related functions such as phagocytosis, adhesion, migration, cytokine secretion, and production of pro-inflammatory mediators were tested. Triggering of LIGHT induced production of pro-inflammatory mediators such as interleukin (IL)-8 and matrix metalloproteinase (MMP)-9 while suppressing the phagocytic activity. Utilization of signaling inhibitors and Western blot demonstrated that LIGHT activated ERK MAPK and PI3K and the major inflammatory transcription factor NF-kappaB. These data indicate that LIGHT-mediated signaling could modulate the macrophage activities and that successful regulation of its activity could be beneficial to the treatment of chronic inflammatory conditions where macrophages play an important role. PMID- 24044962 TI - Correlation between Th17 cells and tumor microenvironment. AB - Since their identification in 2005, T helper (TH)17 cells have been proposed to play important roles in several human diseases, including various autoimmune conditions, inflammations, allergy, and tumors. Focusing on human studies, we review the current understanding of molecular interactions (IL-1beta, IL-6, IL 23, IL-21 and TGF-beta), the signaling pathway (STAT3->RORgammat) and the migration (induced by CCR6/CCL20) that contribute to Th17 differentiation and function in tumor microenvironment. Furthermore, we also make a synthesis of contradictory conclusions as to the roles that these cells are playing in the process of tumourigenesis in order to provide guidance of Th17-targeted therapy in tumors. PMID- 24044964 TI - CD14 tobacco gene-environment interaction in atopic children. AB - Studying gene-environment interactions may elucidate the complex origins of atopic diseases. The aim of this study was to evaluate the association of CD14 polymorphisms and atopy in Egyptian children and to study whether atopy is influenced by CD14 interaction with tobacco smoke exposure. CD14 -159 C/T and CD14 -550 C/T were genotyped in 500 asthmaic children, 150 allergic rhinitis children and 150 controls. We found that CD14 -159T allele, CD14 -550T allele and CD14 -159T/-550T haplotype were significantly associated with atopic asthma and allergic rhinitis groups. CD14 -159 TT and CD14 -550 TT genotypes associated with elevated IgE levels in children exposed to tobacco smoke. The TT genotype of CD14 -159 C/T and CD14 -550 C/T was associated with higher serum levels of sCD14. The present study indicated that CD14 gene polymorphisms may contribute to susceptibility to atopy in Egyptian children and influenced with tobacco smoke exposure. PMID- 24044963 TI - Human T cells upregulate CD69 after coculture with xenogeneic genetically modified pig mesenchymal stromal cells. AB - Mesenchymal stromal cells (MSC) obtained from alpha1,3-galactosyltransferase gene knock-out pigs transgenic for the human complement-regulatory protein CD46 (GTKO/CD46 pMSC) suppress in vitro human anti-pig cellular responses as efficiently as allogeneic human MSC. We investigated the immunoregulatory effects of GTKO/CD46 pMSC on human CD4(+) and CD8(+) T cell proliferation in response to pig aortic endothelial cells (pAEC). pMSC efficiently suppressed T cell proliferation, which was associated with downregulation of granzyme B expression. No induction of CD4(+)CD25(+)Foxp3(hi) regulatory T cells or T cell apoptosis was documented. In correlation with T cell proliferation, CD25 expression was upregulated on T cells in response to pAEC but not to pMSC. In contrast, CD69 expression was upregulated on T cells in response to both pMSC and pAEC, which was associated with a significant increase in the phosphorylation of STAT5. GTKO/CD46 pMSC possibly regulate human T cell responses through modulation of CD69 expression and STAT5 signaling. PMID- 24044965 TI - TLR4-mediated anti-atherosclerosis mechanisms of angiotensin-converting enzyme inhibitor--fosinopril. AB - Recently, angiotensin-converting enzyme inhibitor (ACEI) has gained increasing attention for its anti-atherosclerosis activity, but the underlying mechanism is unknown. In our study, we used rabbits fed with high-fat forage, as an atherosclerosis model to investigate the effect of fosinopril, which is an ACEI. Animals which received both high-fat forage and fosinopril, were maintained as the drug-treated group. Ultrasonography and Sudan III staining were used to determine the process of atherosclerosis. The expression of TLR4 and activity NF kappaB were determined using western blot, RT-PCR and ELISA. The results showed that the atherosclerotic plaque was visible at sixteen weeks. More importantly, the atherosclerotic plaque was significantly decreased after fosinopril treatment. In the atherosclerosis model, the levels of TLR4 and NF-kappaB were increased, but this increased expression was inhibited in the fosinopril treated group. Our results demonstrated that TLR4 could be used as a potential biomarker for atherosclerosis and ACEI has the potential to be a new anti-atherosclerotic drug. PMID- 24044966 TI - Computation in the rabbit aorta of a new metric - the transverse wall shear stress - to quantify the multidirectional character of disturbed blood flow. AB - Spatial variation of the haemodynamic stresses acting on the arterial wall is commonly assumed to explain the focal development of atherosclerosis. Disturbed flow in particular is thought to play a key role. However, widely-used metrics developed to quantify its extent are unable to distinguish between uniaxial and multidirectional flows. We analysed pulsatile flow fields obtained in idealised and anatomically-realistic arterial geometries using computational fluid dynamics techniques, and in particular investigated the multidirectionality of the flow fields, capturing this aspect of near-wall blood flow with a new metric - the transverse wall shear stress (transWSS) - calculated as the time-average of wall shear stress components perpendicular to the mean flow direction. In the idealised branching geometry, multidirectional flow was observed downstream of the branch ostium, a region of flow stagnation, and to the sides of the ostium. The distribution of the transWSS was different from the pattern of traditional haemodynamic metrics and more dependent on the velocity waveform imposed at the branch outlet. In rabbit aortas, transWSS patterns were again different from patterns of traditional metrics. The near-branch pattern varied between intercostal ostia, as is the case for lesion distribution; for some branches there were striking resemblances to the age-dependent patterns of disease seen in rabbit and human aortas. The new metric may lead to improved understanding of atherogenesis. PMID- 24044967 TI - Multiple-quantum spin counting in magic-angle-spinning NMR via low-power symmetry based dipolar recoupling. AB - By using a symmetry-based R2(8)(1)R2(8)(-1) double-quantum (2Q) dipolar recoupling sequence, we demonstrate high-order multiple-quantum coherence (MQC) excitation at fast magic-angle spinning (MAS) frequencies up to 34 kHz. This scheme combines several attractive features, such as a relatively high dipolar scaling factor, good compensation to rf-errors, isotropic and anisotropic chemical shifts, as well as an ultra-low radio-frequency (rf) power requirement. The latter translates into nutation frequencies below 30 kHz for MAS rates up to 60 kHz, thereby permitting rf application for very long excitation periods without risk of damaging the NMR probehead or sample, while the compensation to chemical shifts improves as the MAS rate increases. (31)P MQC spin counting is demonstrated on powders of calcium hydroxyapatite (Ca5(PO4)3OH) and anhydrous sodium diphosphate (Na4P2O7), from which all even coherence orders up to 30 and 14 were detected, respectively, over the respective MAS ranges of 15-24 kHz and 20-34 kHz. The amplitude distributions among the (31)P MQC orders depend on the precise nutation frequency during recoupling, despite that the highest detected order was relatively insensitive to this parameter. An observed gradual transition from a Gaussian to exponential functionality of the MQC amplitude profile is discussed in relation to the prevailing approach to derive spin cluster sizes by fitting the MQC amplitude-distribution to a Gaussian decay, where minor systematic deviations between the model and experimental data are frequently reported. PMID- 24044968 TI - The relation of maternal fluid balance to offspring passive immunity. AB - The objectives were to measure changes in fluid balance of mares at parturition and relate those changes to the foals' acquisition of passive immunity. Twelve Thoroughbred mares and their foals were observed for suckling behavior for the first 12h post-partum. The mare's water intake, packed cell volume, plasma protein concentration, and plasma osmolality were measured pre- and post-partum. The foals' immunoglobulin concentrations were measured at birth and 24h later. The median increase from pre- to post-foaling in mares' packed cell volume was 4.0% (interquartile range=0.3-6.8). The median increases in plasma protein and plasma osmolality after foaling were 0.9 (0.5-1.4)g/dL and 2.5 (0.8-6.0) milliosm/kg, respectively. Median daily water intake was 13.8 (7.6-20.8)L before and 42.1 (26.2-61.4)L 24h after foaling. The foals' IgG at 24h was significantly correlated with their dam's water intake in the 12h following parturition (r=0.66, P=0.039). The median duration of suckling during the first 4h of the foals' lives was 20 (5-85)min and 85 (42-220)min during the first 12h. The median number of suckling bouts was 34 (11-71) during the first 12h after birth. PMID- 24044969 TI - MART-10, a novel vitamin D analog, inhibits head and neck squamous carcinoma cells growth through cell cycle arrest at G0/G1 with upregulation of p21 and p27 and downregulation of telomerase. AB - For the head and neck squamous cell carcinoma (HNSCC), surgery in combination with radiation therapy is the current standard treatment. However, the complex anatomy and important functions over the head and neck region often make HNSCC patients with severe comorbidities. Even after aggressive treatment, the 5year survival for HNSCC patients is only around 61%. Thus, new therapeutic regimens against HNSCC are urgently needed. 1alpha,25-Dihydroxyvitamin D3 [1alpha,25(OH)2D3] is a potent anti-tumor agent in a variety of pre-clinical studies, but its clinical application is impeded by hypercalcemic side effect. A new class of less-calcemic 1alpha,25(OH)2D3 analog, MART-10 (19-nor-2alpha-(3 hydroxypropyl)- 1alpha,25-Dihydroxyvitamin D3), has been shown to be much more potent than 1alpha,25(OH)2D3 in inhibiting cancer cell growth in vitro and in vivo without inducing hypercalcemia. In this study, we compared the antiproliferative activity of MART-10 with 1alpha,25(OH)2D3 and the mechanism responsible for the inhibition in FaDu and SCC-25 squamous carcinoma cells. Our results demonstrate that MART-10 is more potent than 1alpha,25(OH)2D3 in suppressing FaDu and SCC-25 cell growth through greater cell cycle arrest at G0/G1, accompanied by a greater downregulation of ki-67 expression and upregulation of p21 and p27. We also showed that telomerase expression in SCC-25 was suppressed to a greater extent by MART-10 than by 1alpha,25(OH)2D3. Thus, given the previously-proven in vivo antitumor effect and safety of MART-10 and bleak background of HNSCC, based on our current result, we concluded that MART-10 has a potential as a chemo-preventive and - therapeutic agent to treat HNSCC. PMID- 24044970 TI - Spatio-temporal gait analysis in children with cerebral palsy using, foot-worn inertial sensors. AB - A child's natural gait pattern may be affected by the gait laboratory environment. Wearable devices using body-worn sensors have been developed for gait analysis. The purpose of this study was to validate and explore the use of foot-worn inertial sensors for the measurement of selected spatio-temporal parameters, based on the 3D foot trajectory, in independently walking children with cerebral palsy (CP). We performed a case control study with 14 children with CP aged 6-15 years old and 15 age-matched controls. Accuracy and precision of the foot-worn device were measured using an optical motion capture system as the reference system. Mean accuracy +/- precision for both groups was 3.4 +/- 4.6 cm for stride length, 4.3 +/- 4.2 cm/s for speed and 0.5 +/- 2.9 degrees for strike angle. Longer stance and shorter swing phases with an increase in double support were observed in children with CP (p=0.001). Stride length, speed and peak angular velocity during swing were decreased in paretic limbs, with significant differences in strike and lift-off angles. Children with cerebral palsy showed significantly higher inter-stride variability (measured by their coefficient of variation) for speed, stride length, swing and stance. During turning trajectories speed and stride length decreased significantly (p<0.01) for both groups, whereas stance increased significantly (p<0.01) in CP children only. Foot worn inertial sensors allowed us to analyze gait spatiotemporal data outside a laboratory environment with good accuracy and precision and congruent results with what is known of gait variations during linear walking in children with CP. PMID- 24044971 TI - Prevalence and risk factors for iron-deficiency anemia in very-low-birth-weight preterm infants at 1 year of corrected age. AB - OBJECTIVE: To determine the prevalence of iron-deficiency anemia and iron deficiency at 1 year of corrected age (CA) in preterm very-low-birth-weight infants, and to identify risk factors for iron-deficiency anemia. METHODS: A cohort of infants with birth weight <1500 g and gestational age <34 weeks on iron prophylaxis were followed up to 12 months' CA. Anemia diagnosis was based on hemoglobin <11 g/dl. Iron deficiency was defined by ferritin levels <10 MUg/l, transferrin saturation <10% and mean corpuscular volume <80 fl. Neonatal data and feeding at 6 and 12 months' CA (breastfeeding and/or cow's milk or infant formula); hospitalizations during the first year and weight, head circumference, body mass index and length at 12 months' CA were analyzed. RESULTS: Prevalence of anemia in 310 participants was 26.5% [95% confidence interval (CI) 21.8-31.6%] and of iron deficiency was 48% (95% CI 39.0-56.9%). Increased consumption of cow's milk at 6 months [relative risk (RR) 1.687; 95% CI 1.146-2.483], lower maternal age (RR 0.953; 95% CI 0.923-0.983), high number of pregnancies (RR 1.256; 95% CI 1.122-1.406) and being born small for gestational age (RR 1.578; 95% CI 1.068-2.331) were independently associated with anemia after adjustments. CONCLUSIONS: Prevalence of anemia is high at 1 year of CA. Dietary and environmental education strategies may help prevent anemia after discharge. PMID- 24044972 TI - Single point incremental forming of a facial implant. AB - BACKGROUND: The investigation draws from the fundamentals of the mechanical behaviour of titanium grade 2 to the design and fabrication of facial implants by means of single point incremental forming. OBJECTIVES: To provide knowledge on the capabilities and limitations of a new manufacturing technology to fabricate low-cost, patient-specific medical implants. STUDY DESIGN: Rapid fabrication of a simplified model of a facial implant. METHODS: Circle grid analysis and its graphical representation in the fracture forming limit diagram combined with finite element modelling are utilized to identify the failure limits and to assist the overall design of the facial implants. RESULTS: Fabrication of facial implants without and with failure by cracking due to excessive thinning of the sheet from where the implant is to be cut. CONCLUSIONS: Identification of the major operative parameters that influence fabrication of sound facial implants by means of single point incremental forming. CLINICAL RELEVANCE: Reduce the gap between production engineers and the medical community by presenting a state-of the-art manufacturing technology to produce low-cost, patient-specific medical implants. PMID- 24044973 TI - The influence of light administration on interpersonal behavior and affect in people with mild to moderate seasonality. AB - Bright light is used to treat winter depression and may also have positive effects on mood in some healthy individuals. However, there is little information on how bright light treatment influences social behavior. We performed a cross over study in winter comparing the effects of morning bright light administration with placebo (exposure to negative ions) on mood and social behavior in 38 healthy people with mild to moderate seasonality. Each treatment was given for 21days with a washout period of 14days between treatments. An event-contingent recording assessment was used to measure mood, and social behavior along two axes, agreeable-quarrelsome and dominant-submissive, during each 21-day treatment period. During treatments, participants wore a combined light-sensor and accelerometer to test this method for adherence to light treatment self administered at home. Data were analyzed using multilevel modeling. Bright light improved mood but increased quarrelsome behavior and decreased submissiveness. Data from the light monitor and accelerometer suggested that 21% of the participants did not adhere to bright light treatment; when this group was analyzed separately, there was no change in quarrelsomeness or mood. However, results for individuals who followed the procedure were similar to those reported for the whole sample. PMID- 24044974 TI - Multifunctional aspects of allopregnanolone in stress and related disorders. AB - Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) is a major cholesterol derived neurosteroid in the central nervous system and is synthesized from progesterone by steroidogenic enzymes, 5alpha-reductase (the rate-limiting enzyme) and 3alpha-hydroxysteroid dehydrogenase. The pathophysiological role of allopregnanolone in neuropsychiatric disorders has been highlighted in several investigations. The changes in neuroactive steroid levels are detected in stress and stress-related disorders including anxiety, panic and depression. The changes in allopregnanolone in response to acute stressor tend to restore the homeostasis by dampening the hyper-activated HPA axis. However, long standing stressors leading to development of neuropsychiatric disorders including depression and anxiety are associated with decrease in the allopregnanolone levels. GABAA receptor complex has been considered as the primary target of allopregnanolone and majority of its inhibitory actions are mediated through GABA potentiation or direct activation of GABA currents. The role of progesterone receptors in producing the late actions of allopregnanolone particularly in lordosis facilitation has also been described. Moreover, recent studies have also described the involvement of other multiple targets including brain-derived neurotrophic factor (BDNF), glutamate, dopamine, opioids, oxytocin, and calcium channels. The present review discusses the various aspects of allopregnanolone in stress and stress-related disorders including anxiety, depression and panic. PMID- 24044975 TI - First human cases of Leishmania (Viannia) naiffi infection in Ecuador and identification of its suspected vector species. AB - Epidemiological surveillance of leishmaniasis was conducted in a northern Amazonian region of Ecuador, in which cutaneous leishmaniasis cases were recently reported. Sand flies were captured in the military training camp, and the natural infection of sand flies by Leishmania species was examined. Out of 334 female sand flies dissected, the natural infection by flagellates was microscopically detected in 3.9% of Lutzomyia yuilli yuilli and 3.7% of Lutzomyia tortura, and the parasite species were identified as Endotrypanum and Leishmania (Viannia) naiffi, respectively. After the sand fly surveillance, specimens from cutaneous leishmaniasis (CL) patients considered to have acquired the infection in the training camp area were obtained, and the infected parasite species were identified as L. (V.) naiffi. The present study reported first cases of CL caused by L. (V.) naiffi infection in Ecuador. In addition, a high ratio of infection of Lu. tortura by L. (V.) naiffi in the same area strongly suggested that Lu. tortura is responsible for the transmission of L. (V.) naiffi in this area. PMID- 24044976 TI - Architecture of vagal motor units controlling striated muscle of esophagus: peripheral elements patterning peristalsis? AB - Little is known about the architecture of the vagal motor units that control esophageal striated muscle, in spite of the fact that these units are necessary, and responsible, for peristalsis. The present experiment was designed to characterize the motor neuron projection fields and terminal arbors forming esophageal motor units. Nucleus ambiguus compact formation neurons of the rat were labeled by bilateral intracranial injections of the anterograde tracer dextran biotin. After tracer transport, thoracic and abdominal esophagi were removed and prepared as whole mounts of muscle wall without mucosa or submucosa. Labeled terminal arbors of individual vagal motor neurons (n=78) in the esophageal wall were inventoried, digitized and analyzed morphometrically. The size of individual vagal motor units innervating striated muscle, throughout thoracic and abdominal esophagus, averaged 52 endplates per motor neuron, a value indicative of fine motor control. A majority (77%) of the motor terminal arbors also issued one or more collateral branches that contacted neurons, including nitric oxide synthase-positive neurons, of local myenteric ganglia. Individual motor neuron terminal arbors co-innervated, or supplied endplates in tandem to, both longitudinal and circular muscle fibers in roughly similar proportions (i.e., two endplates to longitudinal for every three endplates to circular fibers). Both the observation that vagal motor unit collaterals project to myenteric ganglia and the fact that individual motor units co-innervate longitudinal and circular muscle layers are consistent with the hypothesis that elements contributing to peristaltic programming inhere, or are "hardwired," in the peripheral architecture of esophageal motor units. PMID- 24044977 TI - Myocardial deformation analysis in contrast echocardiography: first results using two-dimensional cardiac performance analysis. AB - BACKGROUND: Contrast echocardiography (CE) provides closer agreement with magnetic resonance imaging (MRI) for left ventricular (LV) volumes and ejection fraction (EF) than noncontrast echocardiography. However, the feasibility and role of myocardial deformation analysis on contrast echocardiographic images have not been well established. The aim of this study was to assess the feasibility of deformation analysis on CE using a new software tool that provides simultaneous measurements for LV volumes and EF. METHODS: Data from 52 patients who were recruited for the Alberta Heart Failure Etiology and Analysis Research Team Study (34 men; mean age, 64 +/- 9 years) and underwent CE and MRI were considered. Contrast bolus injections were administered for optimal endocardial definition. Offline LV volume analysis was performed by standard manual tracing. A single frame was traced manually for two-dimensional (2D) cardiac performance analysis (CPA), which automatically calculated LV volumes, EF, and global longitudinal strain (GLS). Volumes obtained with 2D CPA were compared with those measured with standard CE and MRI. GLS from noncontrast echocardiographic recordings was also calculated with 2D CPA and compared with CE-derived and MRI-derived GLS. RESULTS: Tracing of contrast echocardiographic images with 2D CPA was possible in 49 out of 52 patients, and measurements correlated well with standard CE and MRI (EF: r = 0.93, P < .001, and r = 0.85, P < .001, respectively). Mean GLS from noncontrast echocardiographic and contrast echocardiographic recordings was -13.4 +/- 5.8 and -15.3 +/- 4.64, respectively (P = .056), and the latter correlated well with MRI-derived GLS (r = 0.78 vs 0.81, respectively). CONCLUSIONS: Simultaneous volumetric and deformation analysis on contrast echocardiographic recordings is feasible and reproducible. While volumes and EF obtained with the new software compare well with those obtained from standard CE and MRI, GLS from CE shows a good correlation with strain measured with MRI. PMID- 24044978 TI - Left ventricular noncompaction in patients with bicuspid aortic valve. AB - BACKGROUND: Left ventricular noncompaction (LVNC) is commonly associated with complex congenital anomalies. The association of LVNC with less complex but more frequent anomalies, such as bicuspid aortic valve (BAV), is not well described in the literature. The aims of this study were to (1) determine the incidence of association of LVNC with the most common congenital anomaly, BAV, in an echocardiographic database and (2) describe clinical and imaging characteristics of these patients. METHODS: An echocardiography database was retrospectively interrogated to identify 109 patients who fulfilled the echocardiographic criteria for BAV from July 1, 2011, to March 31, 2013. Echocardiograms were carefully evaluated to identify patients with concomitant LVNC. RESULTS: Twelve patients (11.0%) with BAV fulfilled the criteria for LVNC. The mean age at diagnosis was 33 +/- 16.9 years; nine of 12 were men. Eight patients (66.7%) had symptoms during initial presentation. The most common BAV morphology was fusion of the right and left coronary cusps. Nine patients had mild or moderate aortic valve dysfunction (aortic regurgitation and/or stenosis), and eight had associated aortopathy. LVNC was located at the apex in all patients except one. Mean systolic global longitudinal strain was -16.9 +/- 2.7%. CONCLUSIONS: In this series of patients, concomitant BAV and LVNC were observed in 11% of a BAV population. Further studies are needed to understand the genetic and pathophysiologic basis of this association. PMID- 24044979 TI - Do the sites of metastases provide additional information regarding prognosis and biology in renal cell carcinoma? PMID- 24044980 TI - Denaturing reversed phase liquid chromatographic separation of non-coding ribonucleic acids on macro-porous polystyrene-divinylbenzene resins. AB - The ability of denaturing ion-paired reversed phase LC to separate RNA was assessed using macro-porous polystyrene-divinylbenzene resins as the stationary phase. Using the three stationary phases with different pore size and a mobile phase containing phosphate, we separated RNAs of 20-8000 nucleotides with extremely high sensitivity, e.g., 50pg for an RNA 20 nucleotides in length, S/N=5. The method was used to separate non-coding RNAs obtained from biological sources and is suited for use with direct MS-based chemical characterization. PMID- 24044981 TI - Allopregnanolone as regenerative therapeutic for Alzheimer's disease: translational development and clinical promise. AB - Herein, we review a translational development plan to advance allopregnanolone to the clinic as a regenerative therapeutic for neurodegenerative diseases, in particular Alzheimer's. Allopregnanolone, an endogenous neurosteroid that declines with age and neurodegenerative disease, was exogenously administered and assessed for safety and efficacy to promote neuro-regeneration, cognitive function and reduction of Alzheimer's pathology. Allopregnanolone-induced neurogenesis correlated with restoration of learning and memory function in a mouse model of Alzheimer's disease and was comparably efficacious in aged normal mice. Critical to success was a dosing and treatment regimen that was consistent with the temporal requirements of systems biology of regeneration in brain. A treatment regimen that adhered to regenerative requirements of brain was also efficacious in reducing Alzheimer's pathology. With an optimized dosing and treatment regimen, chronic allopregnanolone administration promoted neurogenesis, oligodendrogenesis, reduced neuroinflammation and beta-amyloid burden while increasing markers of white matter generation and cholesterol homeostasis. Allopregnanolone meets three of the four drug-like physicochemical properties described by Lipinski's rule that predict the success rate of drugs in development for clinical trials. Pharmacokinetic and pharmacodynamic outcomes, securing GMP material, development of clinically translatable formulations and acquiring regulatory approval are discussed. Investigation of allopregnanolone as a regenerative therapeutic has provided key insights into mechanistic targets for neurogenesis and disease modification, dosing requirements, optimal treatment regimen, route of administration and the appropriate formulation necessary to advance to proof of concept clinical studies to determine efficacy of allopregnanolone as a regenerative and disease modifying therapeutic for Alzheimer's disease. PMID- 24044982 TI - Trade-off between learning and exploitation: the Pareto-optimal versus evolutionarily stable learning schedule in cumulative cultural evolution. AB - Inheritance of culture is achieved by social learning and improvement is achieved by individual learning. To realize cumulative cultural evolution, social and individual learning should be performed in this order in one's life. However, it is not clear whether such a learning schedule can evolve by the maximization of individual fitness. Here we study optimal allocation of lifetime to learning and exploitation in a two-stage life history model under a constant environment. We show that the learning schedule by which high cultural level is achieved through cumulative cultural evolution is unlikely to evolve as a result of the maximization of individual fitness, if there exists a trade-off between the time spent in learning and the time spent in exploiting the knowledge that has been learned in earlier stages of one's life. Collapse of a fully developed culture is predicted by a game-theoretical analysis where individuals behave selfishly, e.g., less learning and more exploiting. The present study suggests that such factors as group selection, the ability of learning-while-working ("on the job training"), or environmental fluctuation might be important in the realization of rapid and cumulative cultural evolution that is observed in humans. PMID- 24044983 TI - Coevolution of intelligence, behavioral repertoire, and lifespan. AB - Across many taxa, intriguing positive correlations exist between intelligence (measured by proxy as encephalization), behavioral repertoire size, and lifespan. Here we argue, through a simple theoretical model, that such correlations arise from selection pressures for efficient learning of behavior sequences. We define intelligence operationally as the ability to disregard unrewarding behavior sequences, without trying them out, in the search for rewarding sequences. We show that increasing a species' behavioral repertoire increases the number of rewarding behavior sequences that can be performed, but also the time required to learn such sequences. This trade-off results in an optimal repertoire size that decreases rapidly with increasing sequence length. Behavioral repertoire size can be increased by increasing intelligence or lengthening the lifespan, giving rise to the observed correlations between these traits. PMID- 24044984 TI - The local enhancement conundrum: in search of the adaptive value of a social learning mechanism. AB - Social learning mechanisms are widely thought to vary in their degree of complexity as well as in their prevalence in the natural world. While learning the properties of a stimulus that generalize to similar stimuli at other locations (stimulus enhancement) prima facie appears more useful to an animal than learning about a specific stimulus at a specific location (local enhancement), empirical evidence suggests that the latter is much more widespread in nature. Simulating populations engaged in a producer-scrounger game, we sought to deploy mathematical models to identify the adaptive benefits of reliance on local enhancement and/or stimulus enhancement, and the alternative conditions favoring their evolution. Surprisingly, we found that while stimulus enhancement readily evolves, local enhancement is advantageous only under highly restricted conditions: when generalization of information was made unreliable or when error in social learning was high. Our results generate a conundrum over how seemingly conflicting empirical and theoretical findings can be reconciled. Perhaps the prevalence of local enhancement in nature is due to stimulus enhancement costs independent of the learning task itself (e.g. predation risk), perhaps natural habitats are often characterized by unreliable yet highly rewarding payoffs, or perhaps local enhancement occurs less frequently, and stimulus enhancement more frequently, than widely believed. PMID- 24044985 TI - High rate capability of hydrogen annealed iron oxide-single walled carbon nanotube hybrid films for lithium-ion batteries. AB - A facile and effective hydrogen annealing method has been demonstrated to synthesize iron oxide/SWNT hybrid films involving the thermal reduction of rhombohedral Fe2O3 to cubic Fe3O4 through the phase transformation while maintaining the morphological integrity of the films. The poor rate capability and cyclic stability of the original alpha-Fe2O3/SWNT hybrid films have been significantly improved by H2 annealing. The prepared iron oxide/SWNT hybrid films have a high capacity of 786 mA h g(-1) at a high current density of 4 A g(-1) with a prolonged lifetime. The enhancement of the electrochemical performance is attributed to the presence of highly conductive Fe3O4, accelerated charge transfer kinetics, and the increased Li+ diffusivity confirmed by electrochemical impedance spectra and galvanostatic intermittent titration. PMID- 24044986 TI - Dose-dependent metabolic disposition of hydroxytyrosol and formation of mercapturates in rats. AB - Hydroxytyrosol (HT), one of the major polyphenols present in olive oil, is known to possess a high antioxidant capacity. The aim of the present study was to investigate dose dependent (0, 1, 10 and 100 mg/kg) alterations in the metabolism of HT in rats since it has been reported that metabolites may contribute to biological effects. Special attention was paid to the activation of the semiquinone-quinone oxidative cycle and the formation of adducts with potential deleterious effects. Thus, we developed a novel analytical methodology to monitor the in vivo formation of the HT mercapturate, N-acetyl-5-S-cysteinyl hydroxytyrosol in urine samples. Biomarkers of hepatic and renal toxicity were evaluated within the dose range tested. Following HT administration, dose dependent effects were observed for the recovery of all the metabolites studied. At the lowest dose of 1 mg/kg, the glucuronidation pathway was the most relevant (25-30%), with lower recoveries for sulfation (14%), while at the highest dose of 100 mg/kg, sulfation was the most prevalent (75%). In addition, we report for the first time the formation of the mercapturate conjugate of HT in a dose-dependent manner. The biochemical data did not reveal significant toxic effects of HT at any of the doses studied. An increase in the GSH/GSSG ratio at the highest dose was observed indicating that the products of HT autoxidation are counteracted by glutathione, resulting in their detoxification. These results indicate that the metabolic disposition of HT is highly dependent on the dose ingested. PMID- 24044987 TI - Synthesis and characterization of heterotrinuclear bis(MU2-chlorido)dicopper (II) mono zinc(II) complexes derived from succinoyldihydrazones. AB - Three new zinc (II)-copper (II) heterometallic trinuclear complexes of the composition [ZnCu2(L(n))(MU2-Cl)2(H2O)6]?2H2O (H4L(n)=H4L(1), H4L(2), H4L(3)) have been synthesized from substituted succinoyldihydrazones (H4L(n)) in methanol medium. The composition of the complexes has been established on the basis of data obtained from analytical, mass spectral studies and molecular weight determinations in DMSO. The structure of the ligand H4L(2) has been established by X-ray crystallography. The structure of the complexes has been discussed in the light of molar conductance, magnetic moment, electronic, EPR, IR and FT-IR spectral studies. The molar conductance values for the complexes fall in the region 1.2-1.7 ohm(-1) cm(2) mol(-1) in DMSO solution indicating that all of these are non-electrolyte. The magnetic moment values suggest weak M-M interaction in the structural unit of the complexes. The dihydrazone ligand is present in enol form in all of the complexes. Copper centre has tetragonally distorted octahedral stereochemistry. The EPR parameters of the complexes indicate that the copper centre has doublet state as the ground state. The electron transfer reactions of the complexes have been investigated by cyclic voltammetry. PMID- 24044988 TI - Structure and spectral properties of L-histidinium dipicrate dihydrate. AB - Non-linear optical active L-histidinium dipicrate dihydrate (LHDD) single crystals were grown by slow evaporation method. The Fourier transform FT-IR, FT Raman, (1)H and (13)C NMR spectra of the crystal have been recorded and analysed. The spectral analyses confirm the formation of the compound and the stoichiometry. The geometry and spectral characteristics were examined using the density functional theory (DFT) method, B3LYP with 6-31G(d,p) basis set. The first-order hyperpolarisability, energies of frontier molecular orbitals and the Mulliken population analysis were also calculated. The HOMO-LUMO energy gap value 2.73 eV indicates the charge transfer from picrate to histidinium through the hydrogen bond. The second-order NLO properties of the molecule are studied by Kurtz-Perry powder technique. SHG efficiency of the compound is nearly 2.5 times greater than KDP. Theoretical calculations indicate hyperpolarisability of LHDD is 39 times greater than urea. The results show that the title molecule can be used for opto-electronic applications. PMID- 24044989 TI - Spectroscopic and DFT study of solvent effects on the electronic absorption spectra of sulfamethoxazole in neat and binary solvent mixtures. AB - The solvatochromic behavior of sulfamethoxazole (SMX) was investigated using UV vis spectroscopy and DFT methods in neat and binary solvent mixtures. The spectral shifts of this solute were correlated with the Kamlet and Taft parameters (alpha, beta and pi(*)). Multiple lineal regression analysis indicates that both specific hydrogen-bond interaction and non specific dipolar interaction play an important role in the position of the absorption maxima in neat solvents. The simulated absorption spectra using TD-DFT methods were in good agreement with the experimental ones. Binary mixtures consist of cyclohexane (Cy)-ethanol (EtOH), acetonitrile (ACN)-dimethylsulfoxide (DMSO), ACN-dimethylformamide (DMF), and aqueous mixtures containing as co-solvents DMSO, ACN, EtOH and MeOH. Index of preferential solvation was calculated as a function of solvent composition and non-ideal characteristics are observed in all binary mixtures. In ACN-DMSO and ACN-DMF mixtures, the results show that the solvents with higher polarity and hydrogen bond donor ability interact preferentially with the solute. In binary mixtures containing water, the SMX molecules are solvated by the organic co solvent (DMSO or EtOH) over the whole composition range. Synergistic effect is observed in the case of ACN-H2O and MeOH-H2O, indicating that at certain concentrations solvents interact to form association complexes, which should be more polar than the individual solvents of the mixture. PMID- 24044990 TI - A systematic investigation on biological activities of a novel double zwitterionic Schiff base Cu(II) complex. AB - Double zwitterionic amino acid Schiff base, o-vanillylidene-L-histidine (OVHIS) and its copper complex (CuOVHIS) have been synthesized and characterized. CuOVHIS has distorted octahedral geometry, and OVHIS coordinates the copper ion in a tetradentate manner (N2O2). The pKa of OVHIS in aqueous solution was studied by potentiometric and spectrophotometric methods. DNA binding behavior of the compounds was investigated using spectrophotometric, cyclic voltammetric, and viscosity methods. The efficacy of DNA cleaving nature was tested on pUC19 DNA. The in vitro biological activity was tested against various micro organisms. The effect of CuOVHIS on the surface feature of Escherichia coli was analyzed by SEM. DPPH assay studies revealed that CuOVHIS has higher antioxidant activity. OVHIS inhibits proliferation of HCT117 cells with half maximal inhibition (IC50) of 71.15+/-0.67. Chelation of OVHIS with Cu(II) ion enhances the inhibition of proliferation action (IC50=53.14+/-0.67). PMID- 24044991 TI - A vinblastine fluorescent probe for pregnane X receptor in a time-resolved fluorescence resonance energy transfer assay. AB - The pregnane X receptor (PXR) regulates the metabolism and excretion of xenobiotics and endobiotics by regulating the expression of drug-metabolizing enzymes and transporters. The unique structure of PXR allows the binding of many drugs and drug leads to it, possibly causing undesired drug-drug interactions. Therefore, it is crucial to evaluate whether lead compounds bind to PXR. Fluorescence-based assays are preferred because of their sensitivity and nonradioactive nature. One fluorescent PXR probe is currently commercially available; however, because its chemical structure is not publicly disclosed, it is not optimal for studying ligand-PXR interactions. Here we report the characterization of BODIPY FL-vinblastine, generated by labeling vinblastine with the fluorophore 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY FL), as a high-affinity ligand for human PXR with a Kd value of 673 nM. We provide evidence that BODIPY FL-vinblastine is a unique chemical entity different from either vinblastine or the fluorophore BODIPY FL in its function as a high affinity human PXR ligand. We describe a BODIPY FL-vinblastine-based human PXR time-resolved fluorescence resonance energy transfer assay, which was used to successfully test a panel of human PXR ligands. The BODIPY FL-vinblastine-based biochemical assay is suitable for high-throughput screening to evaluate whether lead compounds bind to PXR. PMID- 24044992 TI - Microscopy basics and the study of actin-actin-binding protein interactions. AB - Actin is a multifunctional eukaryotic protein with a globular monomer form that polymerizes into a thin, linear microfilament in cells. Through interactions with various actin-binding proteins (ABPs), actin plays an active role in many cellular processes, such as cell motility and structure. Microscopy techniques are powerful tools for determining the role and mechanism of actin-ABP interactions in these processes. In this article, we describe the basic concepts of fluorescent speckle microscopy, total internal reflection fluorescence microscopy, atomic force microscopy, and cryoelectron microscopy and review recent studies that utilize these techniques to visualize the binding of actin with ABPs. PMID- 24044993 TI - The independent roles of mechanical, structural and adhesion characteristics of 3D hydrogels on the regulation of cancer invasion and dissemination. AB - Metastasis begins with the escape, or dissemination, of cancer cells from the primary tumor. We recently demonstrated that tumors preferentially disseminate into collagen I and not into basement membrane protein gels (Matrigel). In this study, we used synthetic polymer systems to define material properties that could induce dissemination into Matrigel. We first specifically varied rigidity by varying the crosslinking density of poly(ethylene glycol) (PEG) networks within Matrigel scaffolds. Increased microenvironmental rigidity limited epithelial growth but did not promote dissemination. We next incorporated adhesive signals into the PEG network using peptide-conjugated cyclodextrin (alpha-CDYRGDS) rings. The alpha-CDYRGDS rings threaded along the PEG polymers, enabling independent control of matrix mechanics, adhesive peptide composition, and adhesive density. Adhesive PEG networks induced dissemination of normal and malignant mammary epithelial cells at intermediate values of adhesion and rigidity. Our data reveal that microenvironmental signals can induce dissemination of normal and malignant epithelial cells without requiring the fibrillar structure of collagen I or containing collagen I-specific adhesion sequences. Finally, the nanobiomaterials and assays developed in this study are generally useful both in 3D culture of primary mammalian tissues and in the systematic evaluation of the specific role of mechanical and adhesive inputs on 3D tumor growth, invasion, and dissemination. PMID- 24044994 TI - A polyvalent aptamer system for targeted drug delivery. AB - Poor efficacy and off-target systemic toxicity are major problems associated with current chemotherapeutic approaches to treat cancer. We developed a new form of polyvalent therapeutics that is composed of multiple aptamer units synthesized by rolling circle amplification and physically intercalated chemotherapy agents (termed as "Poly-Aptamer-Drug"). Using a leukemia cell-binding aptamer and doxorubicin as a model system, we have successfully constructed Poly-Aptamer-Drug systems and demonstrated that the Poly-Aptamer-Drug is significantly more effective than its monovalent counterpart in targeting and killing leukemia cells due to enhanced binding affinity (~ 40 fold greater) and cell internalization via multivalent effects. We anticipate that our Poly-Aptamer-Drug approach will yield new classes of tunable therapeutics that can be utilized to effectively target and treat cancers while minimizing the side effects of chemotherapy. PMID- 24044995 TI - The osteogenic response of mesenchymal stem cells to an injectable PLGA bone regeneration system. AB - The enrichment of substrates/surfaces with selected functional groups, methyl ( CH3), allyl amine (-NH2), allyl alcohol (-OH) and acrylic acid (-COOH), can be used to trigger mesenchymal stem (MSC) cell differentiation into specified lineages, minimising the need for exogenous biological supplementation. We present the successful translation of this research phenomenon to an injectable two phase injectable PLGA system, utilising plasma techniques, for the repair of bone defects. Modified microspheres were characterised using water contact angel (WCA), X-ray Photon Spectroscopy (XPS) and scanning electron microscopy (SEM). When cultured in contact with MSCs in vitro, the ability of the modified particles, within the 2 phase system, to induce differentiation was characterised using quantitative assays for cell viability and histological analysis for key markers of differentiation throughout the entirety of the three dimensional scaffold. Biological analysis proved that selected modified microspheres have the ability to induce MSC osteogenic (-NH2 modified scaffolds) and chondrogenic (-OH modified scaffolds) differentiation throughout the entirety of the formed scaffold. Therefore optimised plasma modification of microspheres is an effective tool for the production of injectable systems for the repair of bone and cartilage defects. PMID- 24044996 TI - NIR photothermal therapy using polyaniline nanoparticles. AB - Developing a biocompatible and efficient photothermal coupling agent with appropriate size is a prerequisite for the development of near-infrared (NIR) light-induced photothermal therapy (PTT). In the present study, polyaniline nanoparticles (PANPs) with a size of 48.5 +/- 1.5 nm were fabricated and exhibited excellent dispersibility in water by a hydrothermal method and further surface functionalization by capping with F127. The developed F127-modified PANPs (F-PANPs) had a high molar extinction coefficient of 8.95 * 10(8) m(-1) cm(-1), and high NIR photothermal conversion efficiency of 48.5%. Furthermore, combined with NIR irradiation at 808 nm and injection of F-PANP samples, in vivo photothermal ablation of tumor with excellent treatment efficacy was achieved. In vitro transmission electron microscopy (TEM) images of cells, methyl thiazolyl tetrazolium (MTT) assay, histology, and hematology studies revealed that the F PANPs exhibit low toxicity to living systems. Therefore, F-PANPs could be used as PTT agents for ablating cancer, and the concept of developing polyaniline-based nanoparticles can serve as a platform technology for the next generation of in vivo PTT agents. PMID- 24044997 TI - RhBMP-2-loaded calcium silicate/calcium phosphate cement scaffold with hierarchically porous structure for enhanced bone tissue regeneration. AB - Calcium phosphate cement scaffold (CPC) has been widely used as bone graft substitutes, but undesirable osteoinductivity and slow degradability greatly hamper their clinic application. To address these problems, a recombinant human bone morphogenetic protein-2 (rhBMP-2)-loaded calcium silicate/calcium phosphate cement scaffold (CSPC) with hierarchical pores was developed in this study. The CSPC scaffold with both interconnected macropores on the order of 200-500 MUm and micropores of 2-5 MUm was synthesized from CPC and calcium silicate (CS) by a NaCl particulate-leaching method. In vitro cell culture with C2C12 model cells, in vivo ectopic bone formation and rabbit femur cavity defect repair were performed to evaluate the osteogeneic capacity of the CSPC/rhBMP-2 scaffold. CPC, CSPC and CPC/rhBMP-2 scaffolds were parallelly investigated for comparison. The results demonstrated that the hierarchical macro/microporous structure, whether in presence of CS or rhBMP-2, highly favored the adhesion of C2C12 cells and bone in-growth into the CPC-based scaffolds. But, in comparison to the CPC-based scaffolds with CS or rhBMP-2 alone, the CSPC/rhBMP-2 scaffold strongly promoted osteogenic differentiation in vitro and osteogenetic efficacy in vivo. Further studies demonstrated that Si ions derived from CSPC contributed mainly to maintain the conformation of rhBMP-2 and thus stimulate the synergistic action of CS and rhBMP-2 in osteogenic differentiation and osteoinductivity. Additionally, the incorporation of CS was also beneficial for the dissolution of the scaffold. Those results suggest that the CSPC has superior properties for incorporation of rhBMP-2 and our developed CSPC/rhBMP-2 scaffold have great potential for future use in bone tissue regeneration. PMID- 24044999 TI - Early circulating biomarker detection using a wearable microprojection array skin patch. AB - Microprojection array (MPA) skin patches selectively capture circulating biomarkers from the dermal layers of the skin, avoiding the need to extract, handle or process blood. Here we investigate the effect of improving biomarker capture in vivo on MPA detection of a model biomarker (antigen-specific-IgG raised in response to Fluvax vaccine) in a murine model. First, we investigate targeting MPA penetration to biomarker rich regions of the skin by varying MPA penetration depth. We observed a 4-fold increase in biomarker capture from predominantly epidermal to deep dermal penetration (27 +/- 9 MUm-153 +/- 30 MUm penetration range). We then study the kinetics of biomarker capture by varying the contact time with skin from rapid application (less than 20 min) to long term application (up to 24 h) with a wearable MPA patch. We observed MPAs reproducibly captured detectable amounts of our model biomarker after 10 min application and a greater than 6-fold increase in capture was observed up to 6 h application. Combining the effect of penetration depth and application time we obtained comparable early detection (after vaccination) of our model biomarker as a standard enzyme-linked immunosorbent assay (ELISA). We expect that integration of these devices with existing detection technologies has potential advantages in rapid diagnostic tests, particularly in cases where laboratory-based sample collection and processing is not available. PMID- 24044998 TI - Enhancement of tenogenic differentiation of human adipose stem cells by tendon derived extracellular matrix. AB - Mesenchymal stem cells (MSCs) have gained increasing research interest for their potential in improving healing and regeneration of injured tendon tissues. Developing functional three-dimensional (3D) scaffolds to promote MSC proliferation and differentiation is a critical requirement in tendon tissue engineering. Tendon extracellular matrix has been shown to maintain the tenogenic potential of tendon stem cells and stimulate tenogenesis of human adipose stem cells (hASCs) in 2D culture. This study aims at characterizing the biological composition of urea-extracted fraction of tendon ECM (tECM) and its tenogenic effect on hASCs cultured in a 3D collagen scaffold under uniaxial tension. The tECM obtained was cell-free and rich in ECM proteins. hASCs seeded in tECM supplemented scaffold exhibited significantly increased proliferation and tenogenic differentiation. The presence of tECM also greatly suppressed the osteogenic differentiation of hASCs triggered by uniaxial tension. In addition, tECM-supplemented constructs displayed enhanced mechanical strength, accompanied by reduced expression and activity of MMPs in the seeded hASCs, indicating a regulatory activity of tECM in cell-mediated scaffold remodeling. These findings support the utility of tECM in creating bio-functional scaffolds for tendon tissue engineering. PMID- 24045000 TI - Plasma homocysteine levels in HIV-infected men with and without lipodystrophy. AB - OBJECTIVE: Lipodystrophy syndrome is an unexpected clinical manifestation in patients infected with HIV and might be a clinical marker of increased risk for cardiovascular diseases (CVDs). Because hyperhomocysteinemia has been associated with CVD, the goal of the present study was to investigate homocysteine (Hcy) levels and their association with the factors of lipodystrophy syndrome in men with HIV. METHODS: Hcy metabolism-related molecules were determined in 13 men infected with HIV with lipodystrophy (HIV+LIP), 10 men with HIV without lipodystrophy (HIV), and 10 healthy controls (C). RESULTS: Significant (P < 0.05) increased Hcy plasma levels were found in HIV (20.5%) and in HIV+LIP (35.2%) compared with the control group. Plasma levels of vitamin B12 (HIV, 26.5%; HIV+LIP, 28.8%) and folate (HIV, 39.1% and HIV+LIP, 49.4%) were significantly (P < 0.05) lower in the two groups of HIV patients compared with control. HIV+LIP men presented raised plasma total sulfur-containing amino acids (20.1%) and lower total plasma thiol (11.3%) than controls. The same was not observed in the HIV group. Spearman's correlation test revealed significant (P < 0.05) association between plasma Hcy and duration of highly active antiretroviral therapy (HAART) and plasma insulin, as well as plasma adiponectin levels. CONCLUSION: Our results demonstrated that HIV+LIP men were more susceptible to disturbances in Hcy metabolism compared with men infected with HIV without lipodystrophy characteristics. Duration of HAART treatment, elevated plasma insulin, and low levels of adiponectin seem to be relevant for the appearance of these Hcy metabolic disorders. PMID- 24045001 TI - Stick to the script: the effect of witnessing multiple actors on children's imitation. AB - What kinds of cues increase imitative fidelity in early childhood? The effects of multiple models and verbal framing were examined in preschool children (N = 259, 3-6-year-olds). Each participant was presented with one of eight possible combinations of type of modeling and verbal frame. The type of modeling involved: (i) a single model offering two demonstrations, (ii) two successive models each offering a single demonstration, (iii) two synchronous models each offering two demonstrations, or (iv) two synchronous models each offering a single demonstration. The verbal frame preceding the demonstrations emphasized either the instrumental outcome of the actions or their conventionality. Imitative fidelity was highest for the synchronous models (types iii and iv) and lowest for the single model (type i). Imitative fidelity was also higher for the convention oriented than the outcome-oriented frame and higher for older than younger children. Children also provided more conventional explanations for their actions after viewing the synchronous models and after the convention-oriented framing. The results indicate that children's imitative fidelity depends on the number of actors and the way the actions are framed. PMID- 24045003 TI - Open Access in biomedical sciences: what the current turning point means more specifically to Oral Oncology contributors and readers. PMID- 24045002 TI - Ways of looking ahead: hierarchical planning in language production. AB - It is generally assumed that language production proceeds incrementally, with chunks of linguistic structure planned ahead of speech. Extensive research has examined the scope of language production and suggests that the size of planned chunks varies across contexts (Ferreira & Swets, 2002; Wagner & Jescheniak, 2010). By contrast, relatively little is known about the structure of advance planning, specifically whether planning proceeds incrementally according to the surface structure of the utterance, or whether speakers plan according to the hierarchical relationships between utterance elements. In two experiments, we examine the structure and scope of lexical planning in language production using a picture description task. Analyses of speech onset times and word durations show that speakers engage in hierarchical planning such that structurally dependent lexical items are planned together and that hierarchical planning occurs for both direct and indirect dependencies. PMID- 24045004 TI - Effect of copper on in vivo fate of BDE-209 in pumpkin. AB - A 60-day growth chamber experiments were performed to investigate the effect of Cu stress on the uptake, translocation and metabolism of decabromodiphenyl ether (BDE-209) by pumpkin. A total of nine debrominated metabolites (de-PBDEs), two hydroxylated PBDEs (OH-PBDEs) and one methoxylated PBDEs (MeO-PBDEs) were detected in the tested plants. Concentrations of the total debrominated, hydroxylated or methoxylated metabolites generally followed the order of roots>stems>leaves, and de-PBDEs>OH-PBDEs>MeO-PBDEs. These results indicate that metabolism occurred preferentially in roots than in stems and leaves. The addition of moderate dosage of Cu (50mg/kg) resulted in increment in OH-PBDE concentrations in plant tissues, whereas higher concentrations of Cu could inhibit uptake and metabolism of BDE-209. No in vivo mineralization of BDE-209 was detected in the plants. These results provide valuable information about the behavior of BDE-209 in plant tissues under heavy metal exposure. PMID- 24045005 TI - Effects of a Web-based tailored intervention to reduce alcohol consumption in adults: randomized controlled trial. AB - BACKGROUND: Web-based tailored interventions provide users with information that is adapted to their individual characteristics and needs. Randomized controlled trials assessing the effects of tailored alcohol self-help programs among adults are scarce. Furthermore, it is a challenge to develop programs that can hold respondents' attention in online interventions. OBJECTIVE: To assess whether a 3 session, Web-based tailored intervention is effective in reducing alcohol intake in high-risk adult drinkers and to compare 2 computer-tailoring feedback strategies (alternating vs summative) on behavioral change, dropout, and appreciation of the program. METHODS: A single-blind randomized controlled trial was conducted with an experimental group and a control group (N=448) in Germany in 2010-2011. Follow-up took place after 6 months. Drinking behavior, health status, motivational determinants, and demographics were assessed among participants recruited via an online access panel. The experimental group was divided into 2 subgroups. In the alternating condition (n=132), the tailored feedback was split into a series of messages discussing individual topics offered while the respondent was filling out the program. Participants in the summative condition (n=181) received all advice at once after having answered all questions. The actual texts were identical for both conditions. The control group (n=135) only filled in 3 questionnaires. To identify intervention effects, logistic and linear regression analyses were conducted among complete cases (n=197) and after using multiple imputation. RESULTS: Among the complete cases (response rate: 197/448, 44.0%) who did not comply with the German national guideline for low-risk drinking at baseline, 21.1% of respondents in the experimental group complied after 6 months compared with 5.8% in the control group (effect size=0.42; OR 2.65, 95% CI 1.14-6.16, P=.02). The experimental group decreased by 3.9 drinks per week compared to 0.4 drinks per week in the control group, but this did not reach statistical significance (effect size=0.26; beta=-0.12, 95% CI -7.96 to 0.03, P=.05). Intention-to-treat analyses also indicated no statistically significant effect. Separate analyses of the 2 experimental subgroups showed no differences in intervention effects. The dropout rate during the first visit to the intervention website was significantly lower in the alternating condition than in the summative condition (OR 0.23, 95% CI 0.08-0.60, P=.003). Program appreciation was comparable for the 2 experimental groups. CONCLUSIONS: Complete case analyses revealed that Web-based tailored feedback can be an effective way to reduce alcohol intake among adults. However, this effect was not confirmed when applying multiple imputations. There was no indication that one of the tailoring strategies was more effective in lowering alcohol intake. Nevertheless, the lower attrition rates we found during the first visit suggest that the version of the intervention with alternating questions and advice may be preferred. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 91623132; http://www.controlled trials.com/ISRCTN91623132 (Archived by WebCite at http://www.webcitation.org/6J4QdhXeG). PMID- 24045006 TI - Synthesis and anti-tumor activity of carbohydrate analogues of the tetrahydrofuran containing acetogenins. AB - The tetrahydrofuran (THF) containing annonaceous acetogenins (AAs) are attractive candidates for drug development because of their potent cytotoxicity against a wide range of tumors and their relatively simple and robust structures. Replacement of the THF segment with a sugar residue may deliver analogues with improved tumor selectivity and pharmacokinetics and are therefore attractive for drug development. As a first test to the feasibility of such structures, a set of such monosaccharide analogues was synthesized and assayed against four human tumor cell lines, cervical (HeLa), breast (MDA-MB231), T-cell leukemia (Jurkat) and prostate (PC-3). Certain analogues showed low micromolar activity that was comparable to a structurally similar, naturally occurring mono-THF acetogenin. A preliminary examination of the structure-activity profile of these carbohydrate analogues suggests that they have a similar mechanism of action as their THF congeners. PMID- 24045007 TI - Biodistribution of vaccines comprised of hydrophobically-modified poly(gamma glutamic acid) nanoparticles and antigen proteins using fluorescence imaging. AB - Fluorophores-modified nanoparticles comprised of poly(gamma-glutamic acid) phenylalanine (gamma-PGA-Phe-633) and ovalbumin (OVA-750) termed NPs-633/OVA-750 were prepared to assess their biodistribution using an in vivo fluorescence imager. Dynamic light scattering measurements indicated that NPs-633/OVA-750 were about 200nm in diameter. The release of encapsulated OVA from NPs-633 in PBS was negligible (~10%) for a week. When subcutaneously injected, the localization period of OVA-750-encapsulated into NPs-633 at the site of injection (SOI) was much longer than that of free OVA-750, but was shorter as compared to a mixture with aluminum hydroxide. The NPs-633 disappeared at the SOI and major organs within 1month after administration. Moreover, intravenously and intraperitoneally administered NPs-633 were mainly observed at the liver, and there was more rapid clearance from all organs as compared with non-biodegradable NPs. These fast clearance and degradation characteristics of gamma-PGA-Phe NPs will be important not only for avoiding undesired adverse effects, but also for inducing a strong vaccine effect. PMID- 24045008 TI - New derivatives of salicylamides: Preparation and antimicrobial activity against various bacterial species. AB - Three series of salicylanilides, esters of N-phenylsalicylamides and 2-hydroxy-N [1-(2-hydroxyphenylamino)-1-oxoalkan-2-yl]benzamides, in total thirty target compounds were synthesized and characterized. The compounds were evaluated against seven bacterial and three mycobacterial strains. The antimicrobial activities of some compounds were comparable or higher than the standards ampicillin, ciprofloxacin or isoniazid. Derivatives 3f demonstrated high biological activity against Staphylococcus aureus (?0.03MUmol/L), Mycobacterium marinum (?0.40MUmol/L) and Mycobacterium kansasii (1.58MUmol/L), 3g shows activity against Clostridium perfringens (?0.03MUmol/L) and Bacillus cereus (0.09MUmol/L), 3h against Pasteurella multocida (?0.03MUmol/L) and M. kansasii (?0.43MUmol/L), 3i against methicillin-resistant S. aureus and B. cereus (?0.03MUmol/L). The structure-activity relationships are discussed for all the compounds. PMID- 24045009 TI - Prevalence and associated factors of intention to participate in HIV voluntary counseling and testing for the first time among men who have sex with men in Hong Kong, China. AB - OBJECTIVE: We investigated the prevalence and associated factors of men who have sex with men (MSM) and had never participated in Human Immunodeficiency Virus (HIV) voluntary counseling and testing (VCT) but intended to do so in the next six months. METHOD: An anonymous cross-sectional survey interviewed 577 MSM in Hong Kong, China, face-to-face or through an electronic questionnaire. RESULTS: We identified 245 MSM who had never participated in VCT (never-testers), among whom 12.7% intended to do so in the next six months. Factors associated positively with high behavioral intention were: 1) perceived necessity to participate in HIV test regularly (multivariate odds ratios (ORm)=4.54, 95% confidence interval (CI): 1.30-15.83), 2) perception that >20% of the local MSM had participated in VCT (ORm=17.86, 95% CI: 1.89-169.08) and 3) perceived higher chance to have sex with people living with HIV (PLWH) in the next six months (ORm=2.92, 95% CI: 1.08-7.93). Negatively associated factors were: local residency (ORm=0.06, 95% CI: 0.01-0.34) and perceived higher chance of having unprotected anal intercourse (UAI) in the next six months (ORm=0.27, 95% CI: 0.09 0.84). In addition, no interaction term between the independent variable and UAI status was found to be statistically significant. CONCLUSION: Many sampled never testers had low intention to take up VCT and were in the pre-contemplation stage of the Transtheoretical Model. Stage-matched promotions are warranted. PMID- 24045010 TI - Fetal programming of sexual development and reproductive function. AB - The recent growth of interest in developmental programming of physiological systems has generally focused on the cardiovascular system (especially hypertension) and predisposition to metabolic dysfunction (mainly obesity and diabetes). However, it is now clear that the full range of altered offspring phenotypes includes impaired reproductive function. In rats, sheep and nonhuman primates, reproductive capacity is altered by challenges experienced during critical periods of development. This review will examine available experimental evidence across commonly studied experimental species for developmental programming of female and male reproductive function throughout an individual's life-course. It is necessary to consider events that occur during fetal development, early neonatal life and prior to and during puberty, during active reproductive life and aging as reproductive performance declines. PMID- 24045011 TI - The effect of the adaptor protein Isd11 on the quaternary structure of the eukaryotic cysteine desulphurase Nfs1. AB - Small inorganic assemblies of alternating ferrous/ferric iron and sulphide ions, so-called iron-sulphur (Fe-S) clusters, are possibly nature's most ancient prosthetic groups. One of the early actors in Fe-S cluster biosynthesis is a protein complex composed of a cysteine desulphurase, Nfs1, and its functional binding partner, Isd11. Although the essential function of Nfs1.Isd11 in the liberation of elemental sulphur from free cysteine is well established, little is known about its structure. Here, we provide evidence that shows Isd11 has a profound effect on the oligomeric state of Nfs1. PMID- 24045012 TI - Malignant transformation of colonic epithelial cells by a colon-derived long noncoding RNA. AB - Recent progress has been made in the identification of protein-coding genes and miRNAs that are expressed in and alter the behavior of colonic epithelia. However, the role of long non-coding RNAs (lncRNAs) in colonic homeostasis is just beginning to be explored. By gene expression profiling of post-mitotic, differentiated tops and proliferative, progenitor-compartment bottoms of microdissected adult mouse colonic crypts, we identified several lncRNAs more highly expressed in crypt bottoms. One identified lncRNA, designated non-coding Nras functional RNA (ncNRFR), resides within the Nras locus but appears to be independent of the Nras coding transcript. Stable overexpression of ncNRFR in non transformed, conditionally immortalized mouse colonocytes results in malignant transformation, as determined by growth in soft agar and formation of highly invasive tumors in nude mice. Moreover, ncNRFR appears to inhibit the function of the tumor suppressor let-7. These results suggest precise regulation of ncNRFR is necessary for proper cell growth in the colonic crypt, and its misregulation results in neoplastic transformation. PMID- 24045013 TI - A novel prophylactic effect of furosemide treatment on autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). AB - The transgenic rat strain S284L-TG harbors the S284L mutant of the neuronal nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4), which is responsible for human autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). S284L-TG rats have epileptic seizure phenotypes during slow-wave sleep, similar to those in NFLE. We previously demonstrated that gamma-aminobutyric acid (GABA)ergic action of these rats was suppressed before the onset of ADNFLE seizures, and that glutamate release in the epileptic focus lesion was increased at the onset of epilepsy. Here, mRNA analysis revealed that Cl(-)-accumulating Na K-2Cl cotransporter 1 (NKCC1) levels were increased and Cl(-)-extruding K-Cl cotransporter 1 and 2 (KCC1 and KCC2) levels were decreased at the onset of ADNFLE seizures in S284L-TG rat frontal cortexes, which perturbed the GABAergic inhibitory system. The reversal potentials (EGABA) of GABAA receptor-mediated currents in cortical layer V pyramidal neurons of S284L-TG rats also changed their polarity from hyperpolarization to depolarization, and S284L-TG miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs), significantly increased in both amplitude and frequency. Administration of 25mg/kg/day furosemide before, but not after, the onset of interictal discharges prevented idiopathic epileptic activity, reversed the depolarizing shift of EGABA and increased mEPSC amplitude to normal levels. These data indicate that early treatment with an agent that normalizes pathogenesis has a prophylactic effect on epilepsy. We propose a strategy for prophylactic medication against idiopathic epilepsy through the suppression of epileptogenesis and/or ictogenesis. PMID- 24045014 TI - Eating epilepsy: phenotype, MRI, SPECT and video-EEG observations. AB - BACKGROUND: Eating epilepsy is one of the rare forms of reflex epilepsy precipitated by eating. Previous studies have demonstrated lesions due to variable aetiology involving the temporolimbic and suprasylvian regions. OBJECTIVE: To study anatomical correlates of reflex eating epilepsy using multimodality investigations (MR imaging, video-EEG and SPECT). METHODOLOGY: Six patients (M:F=3:3; mean age: 20.7+/-4.9 years) with eating epilepsy were subjected to MRI of brain, video-EEG studies and SPECT scan. These were correlated with phenotypic presentations. RESULTS: Among the five patients with ictal recording of eating epilepsy during video-EEG, semiology was characterized by behavioural arrest followed by either flexion or extension of trunk and neck and two patients had speech arrest and four had salivation from angle of mouth. Another patient had EEG changes during "thought about eating". Four patients had perisylvian frontal lobe lesions and one had high frontal lesion on MRI. Ictal EEG (n=6) showed ictal rhythmic slowing/fast activity in parieto-temporal (n=2) or fronto-temporal (n=4) regions with subsequent secondary generalization in three. Ictal and interictal SPECT imaging showed changes in frontal lobe (n=1), anterior temporal lobe (n=1), and parieto-insular region (n=1) suggesting it to be seizure onset zone. Three of four patients with structural lesions in MRI had concordant ictal EEG and ictal SPECT changes. CONCLUSION: Lesions near the perisylvian region might play a major role in eating epilepsy. PMID- 24045015 TI - Prepotency in action: does children's knowledge of an artifact affect their ability to inhibit acting on it? AB - Prepotent actions are actions that are strongly triggered by the environment and so tend to be carried out unless intentionally avoided. Understanding what makes an action prepotent is central to an understanding of inhibitory control. The current study investigated actions made on artifacts because in artifact-dense cultures much everyday behavior is focused on them. A total of 80 3-year-olds were tested on a Go/No-go task that required children to make an action on go trials and to withhold it on no-go trials. These actions were made on artifacts with which the actions were either associated (e.g., drawing with a crayon) or unassociated (e.g., drawing with a hammer). Failure to avoid the go action on no go trials was taken as evidence that the action was prepotent. Results suggested that an action did not need to be associated with an artifact in order for it to be prepotent (so drawing with a hammer could be prepotent). However, associated actions were sometimes produced even when children had been instructed to make an unassociated action. Children sometimes drew with a crayon when told to hammer with it, but they never hammered when told to draw. PMID- 24045016 TI - Phase II trial of customized first line chemotherapy according to ERCC1 and RRM1 SNPs in patients with advanced non-small-cell lung cancer. AB - OBJECTIVES: Customized chemotherapy has several advantages: patients are more likely to be treated with the most effective agents and can be spared the toxicity of ineffective drugs. Based on the literature, excision repair cross complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) genes represent predictive biomarkers of response to platinum compound and gemcitabine, in NSCLC. MATERIALS AND METHODS: We had planned a phase II trial (Simon design) to evaluate combination chemotherapy according to single nucleotide polymorphisms (SNPs) of ERCC1 (118T/C and 8092C/A) and RRM1 (-37C/A and -524T/C) in naive patients affected by advanced NSCLC. ERCC1 and RRM1 SNPs assessment was performed in peripheral blood lymphocytes (PBLs). Combination chemotherapy was selected based on ERCC1 and RRM1 SNPs: we assume that patients with one or two C alleles at position 118 and with one or two A alleles at position 8092 in ERCC1 gene would correspond to Cisplatin non-responder and than with two A alleles at -37 and two C alleles at -524 in RRM1 gene to gemcitabine non-responder. Four schedules were provided: cisplatin+gemcitabine, cisplatin+docetaxel, gemcitabine+docetaxel; docetaxel+vinorelbine. Primary endpoint was overall response (ORR) in the intention-to-treat population. RESULTS: 42 patients were enrolled from January 2010 to November 2011; 40 patients received at least 1 cycle of chemotherapy; median age was 66 years (range: 47-72); 36(90%) had stage IV, 4(10%) IIIB; 23(58%) had adenocarcinoma, 14(35%) squamous carcinoma. Twenty five (62%) patients received treatment A, 3(8%) treatment B, 11(28%) treatment C, 1(23%) treatment D. ORR was 55%, analysis in squamous patients subgroups showed 71.4% ORR. The median follow-up was 19.7 months, PFS was 23 weeks (95% CI = 15 26) and OS was 40.4 weeks (95% CI = 32-55). Treatment was well tolerated. CONCLUSION: We observed an increase of ORR in NSCLC patients when they were treated with chemotherapy according to ERCC1 and RRM1 SNPs status. PMID- 24045018 TI - Endoplasmic reticulum-localized transcription factors and mitochondrial retrograde regulation. PMID- 24045017 TI - A membrane-bound NAC transcription factor, ANAC017, mediates mitochondrial retrograde signaling in Arabidopsis. AB - Plants require daily coordinated regulation of energy metabolism for optimal growth and survival and therefore need to integrate cellular responses with both mitochondrial and plastid retrograde signaling. Using a forward genetic screen to characterize regulators of alternative oxidase1a (rao) mutants, we identified RAO2/Arabidopsis NAC domain-containing protein17 (ANAC017) as a direct positive regulator of AOX1a. RAO2/ANAC017 is targeted to connections and junctions in the endoplasmic reticulum (ER) and F-actin via a C-terminal transmembrane (TM) domain. A consensus rhomboid protease cleavage site is present in ANAC017 just prior to the predicted TM domain. Furthermore, addition of the rhomboid protease inhibitor N-p-Tosyl-l-Phe chloromethyl abolishes the induction of AOX1a upon antimycin A treatment. Simultaneous fluorescent tagging of ANAC017 with N terminal red fluorescent protein (RFP) and C-terminal green fluorescent protein (GFP) revealed that the N-terminal RFP domain migrated into the nucleus, while the C-terminal GFP tag remained in the ER. Genome-wide analysis of the transcriptional network regulated by RAO2/ANAC017 under stress treatment revealed that RAO2/ANAC017 function was necessary for >85% of the changes observed as a primary response to cytosolic hydrogen peroxide (H2O2), but only ~33% of transcriptional changes observed in response to antimycin A treatment. Plants with mutated rao2/anac017 were more stress sensitive, whereas a gain-of-function mutation resulted in plants that had lower cellular levels of H2O2 under untreated conditions. PMID- 24045019 TI - The membrane-bound NAC transcription factor ANAC013 functions in mitochondrial retrograde regulation of the oxidative stress response in Arabidopsis. AB - Upon disturbance of their function by stress, mitochondria can signal to the nucleus to steer the expression of responsive genes. This mitochondria-to-nucleus communication is often referred to as mitochondrial retrograde regulation (MRR). Although reactive oxygen species and calcium are likely candidate signaling molecules for MRR, the protein signaling components in plants remain largely unknown. Through meta-analysis of transcriptome data, we detected a set of genes that are common and robust targets of MRR and used them as a bait to identify its transcriptional regulators. In the upstream regions of these mitochondrial dysfunction stimulon (MDS) genes, we found a cis-regulatory element, the mitochondrial dysfunction motif (MDM), which is necessary and sufficient for gene expression under various mitochondrial perturbation conditions. Yeast one-hybrid analysis and electrophoretic mobility shift assays revealed that the transmembrane domain-containing no apical meristem/Arabidopsis transcription activation factor/cup-shaped cotyledon transcription factors (ANAC013, ANAC016, ANAC017, ANAC053, and ANAC078) bound to the MDM cis-regulatory element. We demonstrate that ANAC013 mediates MRR-induced expression of the MDS genes by direct interaction with the MDM cis-regulatory element and triggers increased oxidative stress tolerance. In conclusion, we characterized ANAC013 as a regulator of MRR upon stress in Arabidopsis thaliana. PMID- 24045020 TI - The ubiquitin receptor DA1 interacts with the E3 ubiquitin ligase DA2 to regulate seed and organ size in Arabidopsis. AB - Seed size in higher plants is determined by the coordinated growth of the embryo, endosperm, and maternal tissue. Several factors that act maternally to regulate seed size have been identified, such as auxin response factor2, apetala2, KLUH, and DA1, but the genetic and molecular mechanisms of these factors in seed size control are almost totally unknown. We previously demonstrated that the ubiquitin receptor DA1 acts synergistically with the E3 ubiquitin ligase enhancer1 OF DA1 (EOD1)/big brother to regulate the final size of seeds in Arabidopsis thaliana. Here, we describe another RING-type protein with E3 ubiquitin ligase activity, encoded by DA2, which regulates seed size by restricting cell proliferation in the maternal integuments of developing seeds. The da2-1 mutant forms large seeds, while overexpression of DA2 decreases seed size of wild-type plants. Overexpression of rice (Oryza sativa) grain width and weight2, a homolog of DA2, restricts seed growth in Arabidopsis. Genetic analyses show that DA2 functions synergistically with DA1 to regulate seed size, but does so independently of EOD1. Further results reveal that DA2 interacts physically with DA1 in vitro and in vivo. Therefore, our findings define the genetic and molecular mechanisms of three ubiquitin-related proteins DA1, DA2, and EOD1 in seed size control and indicate that they are promising targets for crop improvement. PMID- 24045021 TI - A kinetic analysis of the auxin transcriptome reveals cell wall remodeling proteins that modulate lateral root development in Arabidopsis. AB - To identify gene products that participate in auxin-dependent lateral root formation, a high temporal resolution, genome-wide transcript abundance analysis was performed with auxin-treated Arabidopsis thaliana roots. Data analysis identified 1246 transcripts that were consistently regulated by indole-3-acetic acid (IAA), partitioning into 60 clusters with distinct response kinetics. We identified rapidly induced clusters containing auxin-response functional annotations and clusters exhibiting delayed induction linked to cell division temporally correlated with lateral root induction. Several clusters were enriched with genes encoding proteins involved in cell wall modification, opening the possibility for understanding mechanistic details of cell structural changes that result in root formation following auxin treatment. Mutants with insertions in 72 genes annotated with a cell wall remodeling function were examined for alterations in IAA-regulated root growth and development. This reverse-genetic screen yielded eight mutants with root phenotypes. Detailed characterization of seedlings with mutations in cellulase3/glycosylhydrolase9b3 and leucine rich extensin2, genes not normally linked to auxin response, revealed defects in the early and late stages of lateral root development, respectively. The genes identified here using kinetic insight into expression changes lay the foundation for mechanistic understanding of auxin-mediated cell wall remodeling as an essential feature of lateral root development. PMID- 24045024 TI - Template-free synthesis of a porous organic-inorganic hybrid tin(IV) phosphonate and its high catalytic activity for esterification of free fatty acids. AB - Here we have synthesized an organic-inorganic hybrid mesoporous tin phosphonate monolith (MLSnP-1) with crystalline pore walls by a template-free sol-gel route. N2 sorption analysis shows Brunauer-Emmett-Teller (BET) surface area of 347 m2 g( 1). Wide-angle powder X-ray diffraction (PXRD) pattern shows few broad diffraction peaks indicating crystalline pore wall of the material. High resolution transmission electron microscopic (HR TEM) image further reveals the crystal fringes on the pore wall. Framework bonding and local environment around phosphorus and carbon were examined by Fourier transform infrared (FT IR) spectroscopy and solid-state MAS NMR spectroscopy. The material exhibits remarkable catalytic activity for esterification of long chain fatty acids under mild reaction conditions at room temperature. PMID- 24045022 TI - Expression quantitative trait locus mapping across water availability environments reveals contrasting associations with genomic features in Arabidopsis. AB - The regulation of gene expression is crucial for an organism's development and response to stress, and an understanding of the evolution of gene expression is of fundamental importance to basic and applied biology. To improve this understanding, we conducted expression quantitative trait locus (eQTL) mapping in the Tsu-1 (Tsushima, Japan) * Kas-1 (Kashmir, India) recombinant inbred line population of Arabidopsis thaliana across soil drying treatments. We then used genome resequencing data to evaluate whether genomic features (promoter polymorphism, recombination rate, gene length, and gene density) are associated with genes responding to the environment (E) or with genes with genetic variation (G) in gene expression in the form of eQTLs. We identified thousands of genes that responded to soil drying and hundreds of main-effect eQTLs. However, we identified very few statistically significant eQTLs that interacted with the soil drying treatment (GxE eQTL). Analysis of genome resequencing data revealed associations of several genomic features with G and E genes. In general, E genes had lower promoter diversity and local recombination rates. By contrast, genes with eQTLs (G) had significantly greater promoter diversity and were located in genomic regions with higher recombination. These results suggest that genomic architecture may play an important a role in the evolution of gene expression. PMID- 24045023 TI - The cytosolic nucleoprotein of the plant-infecting bunyavirus tomato spotted wilt recruits endoplasmic reticulum-resident proteins to endoplasmic reticulum export sites. AB - In contrast with animal-infecting viruses, few known plant viruses contain a lipid envelope, and the processes leading to their membrane envelopment remain largely unknown. Plant viruses with lipid envelopes include viruses of the Bunyaviridae, which obtain their envelope from the Golgi complex. The envelopment process is predominantly dictated by two viral glycoproteins (Gn and Gc) and the viral nucleoprotein (N). During maturation of the plant-infecting bunyavirus Tomato spotted wilt, Gc localizes at endoplasmic reticulum (ER) membranes and becomes ER export competent only upon coexpression with Gn. In the presence of cytosolic N, Gc remains arrested in the ER but changes its distribution from reticular into punctate spots. Here, we show that these areas correspond to ER export sites (ERESs), distinct ER domains where glycoprotein cargo concentrates prior to coat protein II vesicle-mediated transport to the Golgi. Gc concentration at ERES is mediated by an interaction between its cytoplasmic tail (CT) and N. Interestingly, an ER-resident calnexin provided with Gc-CT was similarly recruited to ERES when coexpressed with N. Furthermore, disruption of actin filaments caused the appearance of a larger amount of smaller ERES loaded with N-Gc complexes, suggesting that glycoprotein cargo concentration acts as a trigger for de novo synthesis of ERES. PMID- 24045025 TI - In vitro characterization of Fluorescence by Unbound Excitation from Luminescence: broadening the scope of energy transfer. AB - Energy transfer mechanisms represent the basis for an array of valuable tools to infer interactions in vitro and in vivo, enhance detection or resolve interspecies distances such as with resonance. Based upon our own previously published studies and new results shown here we present a novel framework describing for the first time a model giving a view of the biophysical relationship between Fluorescence by Unbound Excitation from Luminescence (FUEL), a conventional radiative excitation-emission process, and bioluminescence resonance energy transfer. We show here that in homogeneous solutions and in fluorophore-targeted bacteria, FUEL is the dominant mechanism responsible for the production of red-shifted photons. The minor resonance contribution was ascertained by comparing the intensity of the experimental signal to its theoretical resonance counterpart. Distinctive features of the in vitro FUEL signal include a macroscopic depth dependency, a lack of enhancement upon targeting at a constant fluorophore concentration cf and a non-square dependency on cf. Significantly, FUEL is an important, so far overlooked, component of all resonance phenomena which should guide the design of appropriate controls when elucidating interactions. Last, our results highlight the potential for FUEL as a means to enhance in vivo and in vitro detection through complex media while alleviating the need for targeting. PMID- 24045026 TI - Autonomic dysfunction as a possible cause of residual dizziness after successful treatment in benign paroxysmal positional vertigo. AB - OBJECTIVE: To investigate whether residual dizziness after successful treatment in patients with benign paroxysmal positional vertigo (BPPV) was associated with autonomic dysfunction. METHODS: Fifty-eight consecutive patients with BPPV who had successful canal repositioning procedures (CRPs) and showed no nystagmus or positional vertigo at the next follow-up visit were enrolled and divided into two groups with and without residual dizziness. We performed a standardized autonomic function test. RESULTS: Of the 58 patients, 25 (43%) complained of residual dizziness after successful CRPs, in which postural lightheadedness when righting from sitting, or short-lasting nonspecific dizziness that occurred during head movement or walking were common complaints. Orthostatic hypotension (OH) occurred in 11 patients (19%). Incidence of OH was significantly higher in patients with residual dizziness at the next follow-up than those without residual dizziness (40% and 3%, p=0.000). Compared to patients without residual dizziness, patients with residual dizziness had larger falls in systolic BP during the valsalva maneuver and head-up tilt test. However, cardiovagal parasympathetic function was not different between the patients with and without residual dizziness. CONCLUSION: In BPPV, residual dizziness after successful treatment may be associated with sympathoneural autonomic dysfunction. SIGNIFICANCE: This investigation could be useful in understanding the mechanism of residual dizziness in patients with BPPV. PMID- 24045027 TI - DNMT3A mutations in AML: a new prognostic factor? PMID- 24045028 TI - "It's effective therapy, stupid!". PMID- 24045029 TI - The effect of rumination on craving across the continuum of drinking behaviour. AB - BACKGROUND: Rumination is an abstract, persistent, and repetitive thinking style that can be adopted to control negative affect. Recent studies have suggested the role of rumination as direct or indirect cognitive predictor of craving experience in alcohol-related problems. AIMS: The goal of this study was to explore the effect of rumination induction on craving across the continuum of drinking behaviour. METHODS: Participants of three groups of alcohol-dependent drinkers (N=26), problem drinkers (N=26) and social drinkers (N=29) were randomly allocated to two thinking manipulation tasks: distraction versus rumination. Craving was measured before and after manipulation and after a resting phase. RESULTS: Findings showed that rumination had a significant effect on increasing craving in alcohol-dependent drinkers, relative to distraction, but not in problem and social drinkers. This effect was independent of baseline depression and rumination and was maintained across the resting phase. CONCLUSIONS: Rumination showed a direct causal impact on craving that is specific for a population of alcohol-dependent drinkers. PMID- 24045030 TI - Days of heroin use predict poor self-reported health in hospitalized heroin users. AB - This study examined associations between substance use behaviors and self reported health among hospitalized heroin users. Of the 112 participants, 53 (47%) reported good or better health. In multivariable logistic regression models, each day of heroin use in the last month was associated with an 8% lower odds of reporting health as good or better (OR=.92; 95% CI 0.87, 0.97, p<.05). Cocaine, cannabis, cigarettes, alcohol use, unintentional overdose, nor injection drug use was associated with health status. PMID- 24045031 TI - Alcohol and sexual risk: an event-level analysis in commercial sex setting. AB - OBJECTIVE: To assess the episodic relationship between alcohol and sexual risk in multiple-client occasions among female sex workers (FSWs). METHODS: Data on alcohol use and sexual episodes with clients from the past two days were collected among FSWs in Guangxi, China (N=336 for yesterday, and N=299 for the day before yesterday). Logistic regression using generalized estimating equations with robust variance estimation was used to assess the alcohol-sexual risk relationship, controlling for contextual variables salient in the setting of commercial sex. RESULTS: Alcohol use among FSWs was associated with a higher likelihood of unprotected sex with clients during both days. This relationship was modified by the number of clients received within a day. Additionally, having a larger number of drinks was associated with higher odds of unprotected sex, but the association was not consistent across the two days. CONCLUSION: Findings from the study support an association between alcohol use and sexual risk among FSWs. The design of alcohol and sexual risk reduction intervention among FSWs in China may take advantage of the interaction between contextual factors and alcohol use on sexual risk. PMID- 24045032 TI - Spanish language proficiency among providers and Latino clients' engagement in substance abuse treatment. AB - Quality of care, such as provision of services in Spanish, is a common factor believed to improve treatment engagement among Spanish-speaking Latinos in health care. However, there is little evidence that Spanish language proficiency among providers increases treatment access and retention in publicly funded substance abuse treatment. We analyzed client and program data collected in 2010-2011 from publicly funded treatment programs in Los Angeles County, California. An analytic sample of 1903 Latino clients nested within 40 treatment programs located in minority communities was analyzed using multilevel negative binomial regressions on days to initiate and spent in treatment. As hypothesized, Spanish language proficiency was negatively associated with client wait time and positively associated with retention in treatment, after controlling for individual and program characteristics. The path analysis models showed that Spanish language proficiency played a mediating role between professional accreditation and client wait time and retention. These preliminary findings provide an evidentiary base for the role of providers' Spanish language proficiency and Latino engagement in treatment for a population at high risk of treatment dropout. Implications related to health care reform legislation, which seeks to enhance linguistically competent care, are discussed. PMID- 24045033 TI - The ultrastructure of shelled and unshelled cashew nuts. AB - Cashew nuts have many attributes, including sensory, nutritional and health appeal, which contribute to their worldwide acceptance. We demonstrate details of the microstructure of shelled and unshelled cashew kernels with regard to pericarp and cotyledon organization. This study also provides evidence of the colonization of these kernels by filamentous fungi. Nuts were examined by scanning electron and confocal scanning laser microscopy. Staining with acridine orange was performed. A tight lignified palisade layer adjacent to the exocarp surface explains the hardness of the shell's pericarp. The mesocarp contains large secretory cavities that confer a spongy property to this tissue. Papillose cells, which are responsible for secreting CNSL (cashew nutshell liquid), were observed to cover the inner wall of these cavities. Lipid components are readily released from the parenchyma and appear as oil droplets. The outer surface of the shelled samples exhibited a dense Aspergillus infestation. PMID- 24045034 TI - Cardiovascular benefits of phlebotomy: relationship to changes in hemorheological variables. AB - Renewed interest in the age-old concept of "bloodletting", a therapeutic approach practiced until as recently as the 19th century, has been stimulated by the knowledge that blood loss, such as following regular donation, is associated with significant reductions in key hemorheological variables, including whole blood viscosity (WBV), plasma viscosity, hematocrit and fibrinogen. An elevated WBV appears to be both a strong predictor of cardiovascular disease and an important factor in the development of atherosclerosis. Elevated WBV through wall shear stress is the most direct physiological parameter that influences the rupture and erosion of vulnerable plaques. In addition to WBV reduction, phlebotomy may reduce an individual's cardiovascular risk through reductions in excessive iron, oxidative stress and inflammation. Reflecting these findings, blood donation in males has shown significant drops in the incidence of cardiovascular events, as well as in procedures such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting. Collectively, the available data on the benefits of therapeutic phlebotomy point to the importance of monitoring WBV as part of a cardiovascular risk factor, along with other risk-modifying measures, whenever an increased cardiovascular risk is detected. The development of a scanning capillary tube viscometer allows the measurement of WBV in a clinical setting, which can prove to be valuable in providing an early warning sign of an increased risk of cardiovascular disease. PMID- 24045035 TI - Caseous calcification of mitral annulus. PMID- 24045036 TI - Acupuncture referrals in rural primary healthcare: a survey of general practitioners in rural and regional New South Wales, Australia. AB - BACKGROUND: Acupuncture services form a significant part of the Australian healthcare setting, with national registration of acupuncture practitioners, public subsidies for acupuncture services and high use of acupuncture by the Australian public. Despite these circumstances, there has been little exploration of the interface between acupuncture providers and conventional primary healthcare practitioners in rural and regional Australia. METHODS: A 27-item questionnaire was sent by post in the second half of 2010 to all 1486 general practitioners (GPs) currently practising in rural and regional Divisions of General Practice in New South Wales, Australia to explore their practices and attitudes to a variety of complementary and alternative medicine (CAM) practices. Their responses on other therapies have been published previously; this report covers acupuncture. RESULTS: A total of 585 GPs completed the questionnaire; 49 were returned as 'no longer at this address', resulting in an adjusted response rate of 40.7%. Two-thirds of GPs (68.3%) referred patients to an acupuncturist at least a few times per year, while only 8.4% stated that they would not refer patients to an acupuncturist under any circumstances. GPs being older (OR=6.08), GPs being women (OR=2.94), GPs practising in a rural rather than remote area (OR=6.25), GPs having higher levels of self-reported knowledge of acupuncture (OR=5.54), the use of complementary medicine (CAM) by a GP for their personal health (OR=2.37), previous prescription of CAM to other patients (OR=2.99), lack of other treatment options (OR=4.31) and GPs using CAM practitioners as the major source of their CAM information (OR=3.05) were all predictive of increased referral to acupuncture among rural GPs. CONCLUSIONS: There is a significant interface between acupuncture and Australian rural and regional general practice, with generally high levels of support for acupuncture. PMID- 24045037 TI - Individualizing recurrence risks for severe mental illness: epidemiologic and molecular genetic approaches. PMID- 24045038 TI - Using treatment response to subtype schizophrenia: proposal for a new paradigm in classification. PMID- 24045039 TI - Antitumor enhancement by adoptive transfer of tumor antigen primed, inactivated MHC-haploidentical lymphocytes. AB - The present study investigated the antitumor effects by adoptive transfer of tumor antigen primed, inactivated MHC-haploidentical lymphocytes in TC-1 lung cancer mouse model. Our studies revealed that the inactivated MHC-haploidentical effecter cells display the antitumor activity in vitro and target the tumor in vivo. After adoptive transferring these effecter cells, the Th1 cytokines such as IL-2 and IFN-gamma are elevated in the serum; the recipient tumor-specific cytotoxic T-cells and natural killer cells are activated; tumor specific memory T cells are induced; tumor growth is inhibited and mouse survival is prolonged. The results indicate that MHC-haploidentical lymphocytes provide both effecter cells which can target the tumor cells through the identical MHC molecules and an adjuvant effects through the unmatched allogeneic MHC molecules which induces endogenous innate and adaptive antitumor immune responses. PMID- 24045040 TI - Oxidized extracellular DNA as a stress signal that may modify response to anticancer therapy. AB - An increase in the levels of oxidation is a universal feature of genomic DNA of irradiated or aged or even malignant cells. In case of apoptotic death of stressed cells, oxidized DNA can be released in circulation (cfDNA). According to the results of the studies performed in vitro by our group and other researchers, the oxidized cfDNA serves as a biomarker for a stress and a stress signal that is transmitted from the "stressed" area i.e. irradiated cells or cells with deficient anti-oxidant defenses to distant (bystander) cells. In recipient cells, oxidized DNA stimulates biosynthesis of ROS that is followed up by an increase in the number of single strand and double strand breaks (SSBs and DSBs), and activation of DNA Damage Response (DDR) pathway. Effects of oxidized DNA are considered similar to that of irradiation. It seems that downstream effects of irradiation, in part, depend on the release of oxidized DNA fragments that mediate the effects in distant cells. The responses of normal and tumor cell to oxidized DNA may differ. It seems that tumor cells are more sensitive to oxidized DNA-dependent DNA damage, while developing pronounced adaptive response. This may suggest that in chemotherapy or irradiation-treated human body, the release of oxidized DNA from dying cancer cells may give a boost to remaining malignant cells by augmenting their survival and stress resistance. Further studies of the effects of oxidized DNA in both in vitro and in vivo systems are warranted. PMID- 24045041 TI - Direct and bystander radiation effects: a biophysical model and clinical perspectives. AB - In planning treatment for each new patient, radiation oncologists pay attention to the aspects that they control. Thus their attention is usually focused on volume and dose. The dilemma for the physician is how to protract the treatment in a way that maximizes control of the tumor and minimizes normal tissue injury. The initial radiation-induced damage to DNA may be a biological indicator of the quantity of energy transferred to the DNA. However, until now the biophysical models proposed cannot explain either the early or the late adverse effects of radiation, and a more general theory appears to be required. The bystander component of tumor cell death after radiotherapy measured in many experimental works highlights the importance of confirming these observations in a clinical situation. PMID- 24045043 TI - Development, validation and evaluation of added diagnostic value of a q(RT)-PCR for the detection of genotype A strains of small ruminant lentiviruses. AB - Small ruminant lentiviruses (SRLV) infect sheep and goats. Diagnosis of SRLV infection mostly relies on serological testing but more recently, also PCR is regarded as a useful complementary tool in SRLV diagnosis. The goal of this study was to develop and validate a quantitative PCR capable to detect a broad range of SRLV strains from genotype A, including strains circulating in Belgium. The developed q(RT)-PCR targets a region of the gag gene and showed to be highly sensitive and specific with a limit of detection of 6 DNA and 40 RNA copies/reaction respectively. SRLV sequences could be detected in lung samples and leukocytes pellets. The q(RT)-PCR identified SRLV positive animals in Belgian sheep flocks, but also SRLV isolates and samples from Scotland, The Netherlands, Spain, Portugal, UK, Iceland, Finland and USA were found positive. Samples known to contain 'CAEV like' SRLV from France and Spain were not identified as positive. Combined serological and PCR analysis of a limited number (n=35) of Belgian sheep underlined the usefulness of the described PCR as a complementary diagnostic tool since 3 seronegative animals were found positive by the PCR. In conclusion, the validated q(RT)-PCR shows excellent analytical characteristics and is capable to detect SRLV strains belonging to genotype A from various countries. PMID- 24045042 TI - The GLI1 splice variant TGLI1 promotes glioblastoma angiogenesis and growth. AB - We investigated truncated glioma-associated oncogene homolog 1 (TGLI1) that behaves as gain-of-function GLI1 and promotes tumor cell migration and invasion. Herein, we report that TGLI1 had a higher propensity than GLI1 to enhance glioblastoma angiogenesis and growth, both in vivo and in vitro. TGLI1 has gained the ability to enhance expression of pro-angiogenic heparanase. In patient glioblastomas, TGLI1 levels are correlated with heparanase expression. Together, we report that TGLI1 is a novel mediator of glioblastoma angiogenesis and that heparanase is a novel transcriptional target of TGLI1, shedding new light on the molecular pathways that support tumor angiogenesis and aggressive growth. PMID- 24045044 TI - Temporal differences in out-of-hospital cardiac arrest incidence and survival. AB - BACKGROUND: Understanding temporal differences in the incidence and outcomes of out-of-hospital cardiac arrest (OHCA) has important implications for developing preventative strategies and optimizing systems for OHCA care. METHODS AND RESULTS: We studied 18 588 OHCAs of presumed cardiac origin in patients aged >=18 years who received resuscitative efforts by emergency medical services (EMS) and were enrolled in the Cardiac Arrest Registry to Enhance Survival (CARES) from October 1, 2005, to December 31, 2010. We evaluated temporal variability in OHCA incidence and survival to hospital discharge. There was significant variability in the frequency of OHCA by hour of the day (P<0.001), day of the week (P<0.001), and month of the year (P<0.001), with the highest incidence occurring during the daytime, from Friday to Monday, in December. Survival to hospital discharge was lowest for OHCA that occurred overnight (from 11:01 pm to 7 am; 7.1%) versus daytime (7:01 am to 3 pm; 10.8%) or evening (3:01 pm to 11 pm; 11.3%; P<0.001) and during the winter (8.8%) versus spring (11.1%), summer (11.0%), or fall (10.0%; P<0.001). There was no difference in survival to hospital discharge between OHCAs that occurred on weekends and weekdays (9.5% versus 10.4%, P=0.06). After multivariable adjustment for age, sex, race, witness status, layperson resuscitation, first monitored cardiac rhythm, and emergency medical services response time, compared with daytime and spring, survival to hospital discharge remained lowest for OHCA that occurred overnight (odds ratio, 0.81; 95% confidence interval, 0.70-0.95; P=0.008) and during the winter (odds ratio, 0.81; 95% confidence interval, 0.70-0.94; P=0.006), respectively. CONCLUSIONS: There is significant temporal variability in the incidence of and survival after OHCA. The relative contribution of patient pathophysiology, likelihood of the OHCA being observed, and prehospital and hospital-based resuscitative factors deserves further exploration. PMID- 24045045 TI - Moving from political declaration to action on reducing the global burden of cardiovascular diseases: a statement from the global cardiovascular disease taskforce. PMID- 24045047 TI - Increased concentrations of plasma growth arrest-specific 6 and its soluble tyrosine kinase receptor sAxl in Taiwanese women with pelvic inflammatory disease. AB - BACKGROUNDS: To investigate the concentrations of plasma growth arrest-specific protein 6 (Gas6) and its soluble tyrosine kinase receptor sAxl in women with pelvic inflammatory disease (PID) and their association with clinical outcomes of PID. METHODS: Blood specimens were consecutively collected from the 64 patients with PID before and after treatment and 70 healthy women in university hospital. Concentrations of plasma Gas6 and sAxl were detected using enzyme-linked immunosorbent assay. RESULTS: The concentration of plasma Gas6 and sAxl was significantly increased in the patients with PID compared to the healthy controls, and then reduced significantly after treatment. Gas6 was significantly correlated with sAxl. When we selected 7.5 and 15.2 ng/ml as the cutoff concentration of plasma Gas6 and sAxl to detect PID respectively, the sensitivities of Gas6 and sAxl were 76.6% and 75.0%. When Gas6 and sAxl were combined, the sensitivity rose to 92.2%. They were not related to the incidences of tuboovarian abscesses and surgery, which were, however, significantly associated with length of hospital stay. CONCLUSIONS: Novel application of Gas6 or sAxl in combination had a high sensitivity to detect PID and is important in order to prevent severe sequelae. PMID- 24045046 TI - Alloantibody and complement promote T cell-mediated cardiac allograft vasculopathy through noncanonical nuclear factor-kappaB signaling in endothelial cells. AB - BACKGROUND: Cardiac allograft vasculopathy is the major cause of late allograft loss after heart transplantation. Cardiac allograft vasculopathy lesions contain alloreactive T cells that secrete interferon-gamma, a vasculopathic cytokine, and occur more frequently in patients with donor-specific antibody. Pathological interactions between these immune effectors, representing cellular and humoral immunity, respectively, remain largely unexplored. METHODS AND RESULTS: We used human panel reactive antibody to form membrane attack complexes on allogeneic endothelial cells in vitro and in vivo. Rather than inducing cytolysis, membrane attack complexes upregulated inflammatory genes, enhancing the capacity of endothelial cells to recruit and activate allogeneic interferon-gamma--producing CD4(+) T cells in a manner dependent on the activation of noncanonical nuclear factor-kappaB signaling. Noncanonical nuclear factor-kappaB signaling was detected in situ within endothelial cells both in renal biopsies from transplantation patients with chronic antibody-mediated rejection and in panel reactive antibody--treated human coronary artery xenografts in immunodeficient mice. On retransplantation into immunodeficient hosts engrafted with human T cells, panel-reactive antibody--treated grafts recruited more interferon-gamma- producing T cells and enhanced cardiac allograft vasculopathy lesion formation. CONCLUSIONS: Alloantibody and complement deposition on graft endothelial cells activates noncanonical nuclear factor-kappaB signaling, initiating a proinflammatory gene program that enhances alloreactive T cell activation and development of cardiac allograft vasculopathy. Noncanonical nuclear factor-kappaB signaling in endothelial cells, observed in human allograft specimens and implicated in lesion pathogenesis, may represent a target for new pharmacotherapies to halt the progression of cardiac allograft vasculopathy. PMID- 24045048 TI - Infectious complication of Blunt head injury. PMID- 24045049 TI - Capillary refill time is a predictor of short-term mortality for adult patients admitted to a medical department: an observational cohort study. AB - BACKGROUND: Capillary refill time (CRT) has been advocated as a tool for rapid assessment of circulatory status. The correlation between neither CRT and mortality nor CRT and markers of circulatory status has been assessed. We performed a prospective observational cohort study to assess the relationship between CRT (using two existing definitions and as a continuous variable) and short-term mortality. METHODS: We included all acutely admitted adult patients to a medical admission unit. We measured CRT, blood pressure, pulse, temperature and peripheral oxygen saturation. We presented the data descriptively. Difference between continuous data was analysed using Wilcoxon Rank Sum Test and categorical data using chi(2) test. The primary endpoint was 1-day all-cause mortality. RESULTS: 3046 patients were enrolled and CRT was measured on 1935. In univariate analyses, we found increasing all-cause 1-day mortality with all definitions of CRT. Performing multivariable analysis, controlling for age, sex, mean blood pressure, pulse, temperature and peripheral oxygen saturation, we found increasing CRT as a continuous variable and according to the Schriger and Baraff definition to be associated with increased mortality. Both the Trauma score and Schriger and Baraff definitions had high negative predictive values. The calculations on the Schriger and Baraff definition were based on limited power. CONCLUSIONS: We found a significant association between CRT measured as a continuous variable and short-term mortality. Using the definition of Schriger and Baraff also seems appropriate, but this is based on calculations of limited power. PMID- 24045050 TI - How do emergency physicians make discharge decisions? AB - BACKGROUND: One of the most important decisions that emergency department (ED) physicians make is patient disposition (admission vs discharge). OBJECTIVES: To determine how ED physicians perceive their discharge decisions for high-acuity patients and the impact on adverse events (adverse outcomes associated with healthcare management). METHODS: We conducted a real-time survey of staff ED physicians discharging consecutive patients from high-acuity areas of a tertiary care ED. We asked open-ended questions about rationale for discharge decisions and use of clinical judgement versus evidence. We searched for 30-day flagged outcomes (deaths, unscheduled admissions, ED or clinic visits). Three trained blinded ED physicians independently reviewed these for adverse events and preventability. We resolved disagreements by consensus. We used descriptive statistics and 95% CIs. RESULTS: We interviewed 88.9% (32/36) of possible ED physicians for 366 discharge decisions. Respondents were mostly male (71.9%) and experienced (53.1% >10 years). ED physicians stated they used clinical judgement in 87.6% of decisions and evidence in 12.4%. There were 69 flagged outcomes (18.8%) and 10 adverse events (2.7%, 95% CI 1.1 to 4.5%). All adverse events were preventable (1 death, 4 admissions, 5 return ED visits). No significant associations occurred between decision-making rationale and adverse events. CONCLUSIONS: Experienced ED physicians most often relied on clinical acumen rather than evidence-based guidelines when discharging patients from ED high acuity areas. Neither approach was associated with adverse events. In order to improve the safety of discharge decisions, further research should focus on decision support solutions and feedback interventions. PMID- 24045052 TI - Avian influenza remains a challenge to China in the post-SARS era. PMID- 24045053 TI - Clostridium difficile infection: how safe are the household contacts? PMID- 24045051 TI - Altered phospholipid metabolism in schizophrenia: a phosphorus 31 nuclear magnetic resonance spectroscopy study. AB - Phospholipid (PL) metabolism is investigated by in vivo 31P magnetic resonance spectroscopy (MRS). Inconsistent alterations of phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) have been described in schizophrenia, which might be overcome by specific editing techniques. The selective refocused insensitive nuclei-enhanced polarization transfer (RINEPT) technique was applied in a cross-sectional study involving 11 schizophrenia spectrum disorder patients (SZP) on stable antipsychotic monotherapy and 15 matched control subjects. Metabolite signals were found to be modulated by cerebrospinal fluid (CSF) content and gray matter/brain matter ratio. Corrected metabolite concentrations of PC, GPC and PE differed between patients and controls in both subcortical and cortical regions, whereas antipsychotic medication exerted only small effects. Significant correlations were found between the severity of clinical symptoms and the assessed signals. In particular, psychotic symptoms correlated with PC levels in the cerebral cortex, depression with PC levels in the cerebellum and executive functioning with GPC in the insular and temporal cortices. In conclusion, after controlling for age and tissue composition, this investigation revealed alterations of metabolite levels in SZP and correlations with clinical properties. RINEPT 31P MRS should also be applied to at-risk-mental-state patients as well as drug-naive and chronically treated schizophrenic patients in order to enhance the understanding of longitudinal alterations of PL metabolism in schizophrenia. PMID- 24045054 TI - High-performance supercapacitor electrodes based on graphene achieved by thermal treatment with the aid of nitric acid. AB - In this work, graphene materials have been prepared via thermal treatment of graphene oxides with the aid of intercalated nitric acid. The nitric acid not only favors the expansion of graphene but also facilitates the generation of pores into graphene. The specific surface area of such graphene frameworks is as high as 463 m(2)/g, and the pore volume reaches up to 2.23 cm(3)/g. When tested as supercapacitor electrodes, the graphene frameworks delivered an extremely high specific capacitance of ~370 F/g while simultaneously maintained an excellent energy density of 12.9 Wh/kg and power delivery of 250 W/kg in aqueous electrolyte. These performances are much better than those of the control samples prepared without the aid of nitric acid. The porous structure and large specific surface area are believed to have contributed to the high performances. PMID- 24045055 TI - Process development and production of cGMP grade Melan-A for cancer vaccine clinical trials. AB - Melan-A is a cancer testis antigen commonly found in melanoma, and has been shown to stimulate the body's immune response against cancerous cells. We have developed and executed a process utilizing current good manufacturing practices (cGMP) to produce the 6 times-His tagged protein in C41DE3 Escherichia coli for use in Phase I clinical trials. Approximately 11 g of purified Melan-A were produced from a 20 L fed-batch fermentation. Purification was achieved through a three column process utilizing immobilized metal affinity, anion exchange, and cation exchange chromatography with a buffer system optimized for low-solubility, high LPS binding capacity proteins. The host cell proteins, residual DNA, and endotoxin concentration were well below limits for a prescribed dose with a final purity level of 91%. PMID- 24045056 TI - Seasonal dynamics of Schistosoma japonicum infection in buffaloes in the Poyang Lake region and suggestions on local treatment schemes. AB - Schistosomiasis japonica remains a major public health problem and the Poyang Lake region in Jiangxi province is one of the worst affected endemic areas. Buffaloes play a major role in the transmission of Schistosoma japonicum to humans. The aim of the present study was to increase understanding of the epidemic characteristics of schistosomiasis japonica in water buffaloes in the Poyang Lake region, after achieving the national mid-term goal, and to provide a basis for further interventions. The baseline prevalence in two villages in the Poyang Lake region in May 2010 was compared with respect to usage, sex and age in the total study population. Seasonal dynamics from May 2010 to May 2011 were observed in a natural village in the studied area. The baseline prevalence of infection in both villages (Caohui and Gaozhou) was 4.94% in May 2010. The prevalence in buffalo younger than 12 months was 12.82% in Caohui and 15.11% in Gaozhou, which was significantly higher than that found in those aged 13-24 months and older than 24 months. Of the 28 infected buffaloes, 82.14% (23) were younger than 12 months. The flow of seasonal dynamics showed that S. japonicum infection buffaloes were found from May to July and from November to January of the following year. This survey suggested that it is necessary to conduct two mass treatments (especially for young animals) in late March or early April and November, with an additional treatment of positive animals in July or June. PMID- 24045058 TI - Socioeconomic forces and the problem of counting in understanding child abuse and neglect: commentary on "The great recession and the risk for child maltreatment". PMID- 24045057 TI - The Great Recession and the risk for child maltreatment. AB - This study draws on the Fragile Families and Child Wellbeing Study (N=2,032), a birth cohort study of families with children from 20 U.S. cities. Interviews occurred between August 2007, and February 2010, when the children were approximately 9 years old. Macro-economic indicators of the Great Recession such as the Consumer Sentiment Index and unemployment and home foreclosure rates were matched to the data to estimate the links between different measures of the Great Recession and high frequency maternal spanking. We find that the large decline in consumer confidence during the Great Recession, as measured by the Consumer Sentiment Index, was associated with worse parenting behavior. In particular, lower levels of consumer confidence were associated with increased levels of high frequency spanking, a parenting behavior that is associated with greater likelihood of being contacted by child protective services. PMID- 24045059 TI - Comparison of accuracy of aortic root annulus assessment with cardiac magnetic resonance versus echocardiography and multidetector computed tomography in patients referred for transcatheter aortic valve implantation. AB - The evaluation of the aortic root in patients referred for transcatheter aortic valve implantation is crucial. The aim of the present study was to compare the accuracy of cardiac magnetic resonance (CMR) evaluation of the aortic annulus (AoA) with transthoracic and transesophageal echocardiography and multidetector computed tomography (MDCT) in patients referred for transcatheter aortic valve implantation. In 50 patients, maximum diameter, minimum diameter and AoA, length of the left coronary, right coronary, and noncoronary aortic leaflets, degree (grades 1 to 4) of aortic leaflet calcification, and distance between AoA and coronary artery ostia were assessed. AoA maximum diameter, minimum diameter, and area by CMR were 26.4 +/- 2.8 mm, 20.6 +/- 2.3 mm, 449.8 +/- 86.2 mm(2), respectively. The length of left coronary, right coronary, and noncoronary leaflets by CMR were 13.9 +/- 2.2, 13.3 +/- 2.1, and 13.4 +/- 1.8 mm, respectively, whereas the score of aortic leaflet calcifications was 2.9 +/- 0.8. Finally, the distances between AoA and left main and right coronary artery ostia were 16.1 +/- 2.8 and 16.1 +/- 4.4 mm, respectively. Regarding AoA area, transthoracic and transesophageal echocardiography showed an underestimation (p <0.01), with a moderate agreement (r: 0.5 and 0.6, respectively, p <0.01) compared with CMR. No differences and excellent correlation were observed between CMR and MDCT for all parameters (r: 0.9, p <0.01), except for aortic leaflet calcifications that were underestimated by CMR. In conclusion, aortic root assessment with CMR including AoA size, aortic leaflet length, and coronary artery ostia height is accurate compared with MDCT. CMR may be a valid imaging alternative in patients unsuitable for MDCT. PMID- 24045060 TI - Sleep disturbances in a clinical forensic psychiatric population. AB - OBJECTIVE: Poor sleep is known to cause detrimental effects on the course of diverse psychiatric disorders and is a putative risk factor for hostility and aggression. Thus, sleep may be crucial in forensic psychiatric practice. However, little is known about the prevalence of sleep disturbances in these complex psychiatric patients. METHODS: In this study we investigated the presence of sleep disorders and subjective sleep quality using the Sleep Diagnosis List (SDL), the Pittsburgh Sleep Quality Index (PSQI), interviews addressing the causes of sleep complaints, and file information on sleep medications in 110 patients admitted to a forensic psychiatric hospital. RESULTS: Almost 30% of the participants suffered from one or more sleep disorders, especially insomnia. An even larger proportion of the participants (49.1%) experienced poor sleep quality. Interestingly, patients with an antisocial personality disorder or traits were particularly dissatisfied with their sleep. The most common causes of sleep problems were suboptimal sleep hygiene, stress or ruminating, negative sleep conditioning, and side effects of psychotropic medication. Of the poor sleepers, 40.7% received a hypnotic drug. CONCLUSION: Despite intensive clinical treatment, sleep problems are experienced by a large number of forensic psychiatric patients. It would be worthwhile to examine the effects of pharmacological and non-pharmacological sleep interventions on both psychiatric symptoms and reactive aggressive behavior in forensic patients. PMID- 24045062 TI - Influence of lipid type on water and fat mobility in fermented sausages studied by low-field NMR. AB - The effects of diacylglycerols (DAG), pork back fat and sunflower oil on water and fat mobility in fermented sausages were studied with (1)H NMR relaxometry. The added fat affected the physicochemical parameters weight loss, water activity, moisture content and moisture content on a defatted-dry-matter basis of reduced-fat non-acid fermented sausages. The weight losses were the lowest in sausages prepared with DAG and sunflower oil, which resulted in higher water activity compared to sausages prepared with back fat. The relaxation times related to fat mobility differed between fat types and increased in the order: control200 repeats) result in transcriptional silencing of the FMR1 gene and deficiency/absence of the FMR1 protein (FMRP). Carriers with a premutation allele (55-200 CGG repeats) are often associated with mildly reduced levels of FMRP and/or elevated levels of FMR1 mRNA, and are associated with the risk of developing a neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). While impairments in numerical processing have been well documented in FXS, recent behavioral research suggests that premutation carriers also present with subtle but significant impairments in numerical processing. Using fMRI, the current study examined whether asymptomatic adults with the premutation would show aberrant neural correlates of magnitude estimation processing in the fronto parietal area. Using a magnitude estimation task, we demonstrated that activity in the intraparietal sulcus and inferior frontal gyrus, associated with magnitude estimation processing, was significantly attenuated in premutation carriers compared to their neurotypical counterparts despite their comparable behavioral performance. Further, multiple regression analysis using CGG repeat size and FMR1 mRNA indicated that increased CGG repeat size is a primary factor for the decreased fronto-parietal activity, suggesting that reduced FMRP, rather than a toxic gain-of-function effect from elevated mRNA, contributes to altered neural activity of magnitude estimation processing in premutation carriers. In conclusion, we provide the first evidence on the aberrant neural correlates of magnitude estimation processing in premutation carriers accounted for by their FMR1 gene expression. PMID- 24045063 TI - Pre-treatment with silymarin reduces brain myeloperoxidase activity and inflammatory cytokines in 6-OHDA hemi-parkinsonian rats. AB - Most chronic neurodegenerative diseases such as Parkinson's disease (PD) are accompanied by neuroinflammation which is associated with glial cells activation and production of different inflammatory cytokines. In the present study we evaluated the anti-cataleptic effect of silymarin pre-treatment in 6 hydroxydopamine (6-OHDA)-lesioned rats, striatum myeloperoxidase (MPO) activity and cerebrospinal fluid (CSF) levels of inflammatory cytokines. Male Wistar rats were pre-treated with intraperitoneal (i.p.) injections of silymarin (100, 200 and 300mg/kg) for 5 consecutive days. Then, catalepsy was induced by unilateral infusion of 6-OHDA (8MUg/2MUl/rat) into the central region of the SNc. The anti cataleptic effect of silymarin was assessed by the bar test 3-weeks after neurotoxin injection. Striatal myeloperoxidase activity and CSF levels of TNF alpha and IL-6 were assessed at the end of behavioral experiments. Our data demonstrated that silymarin pre-treatment decreased catalepsy. The most anti cataleptic effect was observed at the dose of 300mg/kg of silymarin (p<0.001). There was a significant (p<0.001) increase in MPO activity of 6-OHDA-lesioned rats whereas; in silymarin (in all 3 doses, i.p. for 5 days) pre-treated hemi parkinsonian rats' MPO activity was decreased markedly (p<0.001). Furthermore the CSF levels of TNF-alpha and IL-6 were decreased (p<0.001) in silymarin (100, 200 and 300mg/kg) pre-treated rats up to the range of normal non-parkinsonian animals. From these results, it may be concluded that pre-treatment with silymarin attenuates 6-OHDA-induced catalepsy by decreasing striatal MPO activity and restores CSF concentration of inflammatory cytokines, TNF-alpha and IL-6 to the levels of normal non-parkinsonian rats. PMID- 24045064 TI - The decline in rat hippocampal theta activity during response inhibition for the compound stimulus of negative patterning and simultaneous feature-negative tasks. AB - In experiment 1 of this study, we compared hippocampal theta activity between negative patterning and simple discrimination tasks. Our results demonstrated a transient decline in theta activity during response inhibition for a compound stimulus in the negative patterning task. In experiment 2 of this study, we compared hippocampal theta activity among simultaneous feature-negative, compound stimulus discrimination, and simple discrimination tasks in order to determine the cause of the decline in hippocampal theta activity during negative patterning tasks. Our results revealed that the decline in hippocampal theta activity occurred during the response inhibition for a compound stimulus in the simultaneous feature-negative task but not during the compound stimulus discrimination or simple discrimination tasks. Thus, we conclude that the transient decline in hippocampal theta activity is related to the inhibition in response to a compound stimulus that has an element that overlaps with a single stimulus. PMID- 24045065 TI - Atypical antipsychotic olanzapine reversed deficit on prepulse inhibition of the acoustic startle reflex produced by microinjection of dizocilpine (MK-801) into the inferior colliculus in rats. AB - Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. PPI is the normal reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus (pulse). MK-801 is an NMDA receptor-antagonist known to produce hyperactivity, deficits in prepulse inhibition and social withdrawal, behaviors which correlate well with some of the positive, cognitive and negative symptoms of schizophrenia. The inferior colliculus (IC) is a critical part of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. Thus, the purpose of the present study was to elucidate the role of glutamatergic transmission in the IC on the expression of acoustic PPI. For that we investigated whether NMDA receptor stimulation or blockade would affect this response. Unilateral microinjections of NMDA (30 nmol/0.5 MUL) into the IC did not alter PPI while microinjections of MK-801 (30 nmol/0.5 MUL) into this structure disrupted PPI. We also examined the ability of the atypical antipsychotic olanzapine (5.0mg/kg; i.p.) to reverse the disruption of pre-pulse inhibition produced by unilateral microinjections of MK-801 into the IC of rats. Pretreatment with olanzapine blocked MK-801-induced disruption of PPI. Altogether, these results suggest that glutamate-mediated mechanisms of the IC are involved in the expression of PPI in rodents and that this response is sensitive to atypical antipsychotic olanzapine. PMID- 24045066 TI - Amphipathic polymer-mediated uptake of trehalose for dimethyl sulfoxide-free human cell cryopreservation. AB - For stem cell therapy to become a routine reality, one of the major challenges to overcome is their storage and transportation. Currently this is achieved by cryopreserving cells utilising the cryoprotectant dimethyl sulfoxide (Me2SO). Me2SO is toxic to cells, leads to loss of cell functionality, and can produce severe side effects in patients. Potentially, cells could be frozen using the cryoprotectant trehalose if it could be delivered into the cells at a sufficient concentration. The novel amphipathic membrane permeabilising agent PP-50 has previously been shown to enhance trehalose uptake by erythrocytes, resulting in increased cryosurvival. Here, this work was extended to the nucleated human cell line SAOS-2. Using the optimum PP-50 concentration and media osmolarity, cell viability post-thaw was 60 +/- 2%. In addition, the number of metabolically active cells 24h post-thaw, normalised to that before freezing, was found to be between 103 +/- 4% and 91 +/- 5%. This was found to be comparable to cells frozen using Me2SO. Although reduced (by 22 +/- 2%, p=0.09), the doubling time was found not to be statistically different to the non-frozen control. This was in contrast to cells frozen using Me2SO, where the doubling time was significantly reduced (by 41 +/- 4%, p=0.004). PP-50 mediated trehalose delivery into cells could represent an alternative cryopreservation protocol, suitable for research and therapeutic applications. PMID- 24045067 TI - Season of ejaculate collection influences the freezability of boar spermatozoa. AB - The aim of this retrospective study was to evaluate whether the season of ejaculate collection influences the freezability of porcine sperm. A total of 434 ejaculates were collected from boars of six different breeds over three years (2008-2011) and throughout the four seasons of the year identified in the northern hemisphere (winter, spring, summer and autumn). The ejaculates were cryopreserved using a standard 0.5 mL straw freezing protocol. Sperm quality was assessed before (fresh semen samples kept 24h at 17 degrees C) and after freezing and thawing (at 30 and 150 min post-thawing in semen samples kept in a water bath at 37 degrees C), according to the percentages of total motility, as assessed by the CASA system, and viability, as assessed by flow cytometry after staining with SYBR-14, PI and PE-PNA. The data, in percentages, on sperm motility and viability after freezing and thawing were obtained at each evaluation time (recovered) and were normalized to the values before freezing (normalized). The season of ejaculate collection influenced (P<0.01) sperm quality before freezing and after thawing (recovered and normalized), irrespective of the breed of boar. Sperm quality was lower in summer, both in terms of motility and viability, and in autumn, in terms of motility, than in winter and spring. Seasonality in the normalized data indicates that the season of ejaculate collection influences sperm freezability, regardless of the season's influence on sperm quality before freezing. Consequently, the spermatozoa from ejaculates collected during summer and, to a lesser extent, also in autumn, are more sensitive to cryopreservation than those from ejaculates collected during winter and spring. PMID- 24045068 TI - Nickel oxide grafted andic soil for efficient cesium removal from aqueous solution: adsorption behavior and mechanisms. AB - An andic soil, akadama clay, was modified with nickel oxide and tested for its potential application in the removal of cesium from aqueous solution. Scanning electron microscope (SEM), energy dispersive X-ray spectroscopy (EDS), and powder X-ray diffraction (XRD) results revealed the nickel oxide was successfully grafted into akadama clay. N2 adsorption-desorption isotherms indicated the surface area decreased remarkably after modification while the portion of mesopores increased greatly. Thermogravimetric-differential thermal analysis (TG DTA) showed the modified akadama clay had better thermostability than the pristine akadama clay. Decreases in cation exchange capacity (CEC) and zeta potential were also detected after the modification. Adsorption kinetic and isotherm studies indicated the adsorption of Cs+ on the modified akadama clay was a monolayer adsorption process. Adsorption capacity was greatly enhanced for the modified akadama clay probably due to the increase in negative surface charge caused by the modification. The adsorption of Cs+ on the modified akadama clay was dominated by an electrostatic adsorption process. Results of this work are of great significance for the application of akadama clay as a promising adsorbent material for cesium removal from aqueous solutions. PMID- 24045069 TI - Autoimmune hemolytic anemia occurred in burn patient: a case report. PMID- 24045070 TI - Enhancing the clinical utility of the burn specific health scale-brief: not just for major burns. AB - INTRODUCTION: Like many other Western burn services, the proportion of major to minor burns managed at Royal Perth Hospital (RPH) is in the order of 1:10. The Burn Specific Health Scale-Brief (BSHS-B) is an established measure of recovery after major burn, however its performance and validity in a population with a high volume of minor burns is uncertain. Utilizing the tool across burns of all sizes would be useful in service wide clinical practice. AIM: This study was designed to examine the reliability and validity of the BSHS-B across a sample of mostly minor burn patients. METHOD: BSHS-B scores of patients, obtained between January 2006 and February 2013 and stored on a secure hospital database were collated and analyzed Cronbach's alpha, factor analysis, logistic regression and longitudinal regression were used to examine reliability and validity of the BSHS B. RESULTS: Data from 927 burn patients (2031 surveys) with a mean % total burn surface area (TBSA) of 6.7 (SD 10.0) were available for analysis. The BSHS-B demonstrated excellent reliability with a Cronbach's alpha of 0.95. First and second order factor analyses reduced the 40 item scale to four domains: Work; Affect and Relations; Physical Function; Skin Involvement, as per the established construct. TBSA, length of stay and burn surgery all predicted burn specific health in the first three months of injury (p<0.001, p<0.001, p=0.03). BSHS-B whole scale and domain scores showed significant improvement over 24 months from burn (p<0.001). DISCUSSION: The results from this study show that the structure and performance of the BSHS-B in a burn population consisting of 90% minor burns is consistent with that demonstrated in major burns. CONCLUSION: The BSHS-B can be employed to track and predict recovery after burns of all sizes to assist the provision of targeted burn care. PMID- 24045071 TI - Microsurgery and limb salvage after electrical burn injury. PMID- 24045072 TI - Aquacel((r)) Ag dressing versus ActicoatTM dressing in partial thickness burns: a prospective, randomized, controlled study in 100 patients. Part 1: burn wound healing. AB - INTRODUCTION: Studies comparing contemporary silver dressings in burns are scarce. METHODS: In a prospective, randomized, controlled study, counting 50 patients/research group, we compared two frequently used silver dressings, ActicoatTM and Aquacel((r)) Ag, in the management of partial thickness burns with a predicted healing time between 7 and 21 days as assessed by laser Doppler imaging between 48 and 72h after burn. Variables investigated were related to baseline research group characteristics, wound healing, bacteriology, economics, nurse, and patient experience. RESULTS: Both research groups were comparably composed taking into account gender, age and burn characteristics. Similar results were obtained as to healing time and bacterial control with both silver dressings. A statistically significant difference in favor of the Aquacel((r)) Ag dressing was found for average ease of use (p<0.001), average ease of application (p=0.001), patient pain (p<0.001), patient comfort with the dressing (p=0.017), silver staining (p<0.001), and cost effectiveness (p<0.001). CONCLUSION: Both silver dressings resulted in comparable healing times and bacterial control but the Aquacel((r)) Ag dressing significantly increased comfort for patients as well as nurses and was significantly more cost-effective than the ActicoatTM dressing for the given indication. PMID- 24045073 TI - Transposition of great arteries with aortopulmonary window: our surgical experience. AB - BACKGROUND: Transposition of the great arteries with aortopulmonary window is a rare congenital cardiac anomaly. An arterial switch operation with repair of the aortopulmonary window is the preferred operation in this subset. As the tissue between the great arteries is missing, it is considered to be a complex operation. The purpose of this study is to present our experience of a simple yet highly effective surgical technique for the management of this rare complex cardiac defect. METHODS: We detail our experience of the surgery of this complex defect in 4 patients. Standard technique of an arterial switch operation with minor modification in excision of branch pulmonary arteries is all that is needed in approaching this complex subset. The moiety of tissue resulting from the absence of an aortopulmonary window was naturally covered by the proximal and distal neo-aortic flap tissue. The operative technique used in the 4 cases and their presentations are detailed in the text. RESULTS: Four patients of ages 28 days, 35 days, 40 days, and 6 months were successfully operated. One patient expired on postoperative day 21. In this case, advanced age of presentation, severe pulmonary artery hypertension, and sepsis possibly caused the death. The remaining 3 patients are off medication now and are being regularly followed up. CONCLUSIONS: In our experience early diagnosis and an arterial switch operation have been crucial in getting a favorable outcome in planning of this complex congenital heart disease. PMID- 24045074 TI - Effects of phentolamine infusion during selective cerebral perfusion in neonatal piglets. AB - BACKGROUND: An optimal selective cerebral perfusion protocol in pediatric cardiac surgery is unknown. Phentolamine is frequently used in pediatric cardiopulmonary bypass. We sought to determine the effects of continuous phentolamine infusion during selective cerebral perfusion. METHODS: Twenty-seven neonatal piglets (3.38 +/- 0.32 kg) were randomly assigned to 3 groups; sham (n = 7, anesthesia alone, no surgery or bypass), control (n = 10, saline infusion), or experimental (n = 10, phentolamine infusion 0.1 mg/kg per hour). Animals underwent 90 minutes of selective cerebral perfusion. Cerebral vascular resistance index (CVRI) and metabolic rate of oxygen (CMRO2) were determined every 15 minutes. Standardized sections of hippocampus, basal ganglia, and neo-cortex were obtained. Tissue samples were stained for caspase-3 and analyzed for positive apoptotic cell count. Data were analyzed with repeated measures and one-way analysis of variance. RESULTS: The CVRI tended to increase over time in the control group and decrease over time in the experimental group, but difference was not statically significant (0.46 +/- 0.24 vs 0.39 +/- 0.10 mm Hg * min * kg(2/3)/mL, p = 0.15). Mean CMRO2 was higher in the control group compared with the experimental group (0.90 +/- 0.27 vs 0.59 +/- 0.12 mLO2/min * kg(2/3), p = 0.005) and decreased over time in both groups. The percentage of caspase-3 positive cells was significantly different among regions (hippocampus = 16.9 +/- 8.8; basal ganglia = 14.6 +/- 7.5; neocortex = 10.8 +/- 6.3; p < 0.0001) but not significantly different among sham (11.8% +/- 2.68%), control (14.4% +/- 2.24%), and experimental (15.5% +/- 2.24%) groups. CONCLUSIONS: A continuous infusion of phentolamine during selective cerebral perfusion significantly decreases CMRO2 and tends to decrease CVRI when compared with control. At the dose studied and at the time of tissue sampling, phentolamine does not appear to decrease apoptosis during or early after selective cerebral perfusion. PMID- 24045075 TI - Deep hypothermic circulatory arrest effectively preserves neurocognitive function. AB - BACKGROUND: Few (conflicting) studies have quantitatively assessed neurocognitive effects of deep hypothermic circulatory arrest (DHCA). We assess neurocognitive function quantitatively before and after DHCA in comparison with non-DHCA patients. METHODS: Sixty-two aortic surgical patients underwent a battery of neuropsychometric tests, both preoperative and postoperative, evaluating multiple aspects of memory, processing speed, executive function, and global cognition. Thirty-three patients did not require DHCA, and 29 underwent DHCA as the sole means of cerebral protection. Neurocognitive deficit was defined as greater than 20% decline in 2 or more cognitive areas. Preoperative and postoperative test scores, as well as incidence of neurocognitive deficit, were compared within each group, and between the non-DHCA and DHCA groups. RESULTS: There were no significant differences in the postoperative versus preoperative scores in any cognitive area tested between DHCA and non-DHCA groups. There was also no difference between the 2 groups in incidence of neurocognitive deficit; 13 non DHCA, 11 DHCA (p = 1.00). In addition, there was no correlation between time under DHCA and incidence of neurocognitive deficit. Within both groups, there was a decline in memory in the areas of acquisition, retention, and delayed recall. Within the DHCA group, recognition was also affected. CONCLUSIONS: While cardiac surgery had some effects on memory, overall neurocognitive function was well preserved and not different between DHCA and non-DHCA patients. Time under DHCA up to 40 minutes was also found to be safe neurocognitively. This study provides strong evidence that straight DHCA effectively preserves neurocognitive function. PMID- 24045076 TI - Connectivity patterns of pallidal DBS electrodes in focal dystonia: a diffusion tensor tractography study. AB - Deep brain stimulation (DBS) of the internal pallidal segment (GPi: globus pallidus internus) is gold standard treatment for medically intractable dystonia, but detailed knowledge of mechanisms of action is still not available. There is evidence that stimulation of ventral and dorsal GPi produces opposite motor effects. The aim of this study was to analyse connectivity profiles of ventral and dorsal GPi. Probabilistic tractography was initiated from DBS electrode contacts in 8 patients with focal dystonia and connectivity patterns compared. We found a considerable difference in anterior-posterior distribution of fibres along the mesial cortical sensorimotor areas between the ventral and dorsal GPi connectivity. This finding of distinct GPi connectivity profiles further confirms the clinical evidence that the ventral and dorsal GPi belong to different functional and anatomic motor subsystems. Their involvement could play an important role in promoting clinical DBS effects in dystonia. PMID- 24045077 TI - Inter-modality relationship constrained multi-modality multi-task feature selection for Alzheimer's Disease and mild cognitive impairment identification. AB - Previous studies have demonstrated that the use of integrated information from multi-modalities could significantly improve diagnosis of Alzheimer's Disease (AD). However, feature selection, which is one of the most important steps in classification, is typically performed separately for each modality, which ignores the potentially strong inter-modality relationship within each subject. Recent emergence of multi-task learning approach makes the joint feature selection from different modalities possible. However, joint feature selection may unfortunately overlook different yet complementary information conveyed by different modalities. We propose a novel multi-task feature selection method to preserve the complementary inter-modality information. Specifically, we treat feature selection from each modality as a separate task and further impose a constraint for preserving the inter-modality relationship, besides separately enforcing the sparseness of the selected features from each modality. After feature selection, a multi-kernel support vector machine (SVM) is further used to integrate the selected features from each modality for classification. Our method is evaluated using the baseline PET and MRI images of subjects obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our method achieves a good performance, with an accuracy of 94.37% and an area under the ROC curve (AUC) of 0.9724 for AD identification, and also an accuracy of 78.80% and an AUC of 0.8284 for mild cognitive impairment (MCI) identification. Moreover, the proposed method achieves an accuracy of 67.83% and an AUC of 0.6957 for separating between MCI converters and MCI non-converters (to AD). These performances demonstrate the superiority of the proposed method over the state-of the-art classification methods. PMID- 24045078 TI - Feedback of the amygdala globally modulates visual response of primary visual cortex in the cat. AB - The amygdala is an important center for emotional behavior, and it influences other cortical regions. Long feedback projections from the amygdala to the primary visual cortex were recently reported in the cat and monkey, two animal models for vision research. However, the detailed functional roles of these extensive projections still remain largely unknown. In this study, intrinsic signal optical imaging was used to investigate the visually driven responses of the primary visual cortex of cats as focal drugs were injected into the basal nucleus of the amygdala. Both the visually evoked global signals and differential signals in the functional maps of the primary visual cortex were enhanced or reduced by glutamate-induced activation or GABA-induced deactivation of neurons in the amygdala, respectively. This modulation was found to be non-selective, consistent with the gain control mechanism-both the preferred orientation and its mapped orientation tuning width remained unchanged. The single unit recordings showed similar results supporting the above observations. These results suggest that the distal feedback signals of the amygdala enhance the primary sensory information processing in a non-selective, gain-control fashion. This provides direct neurophysiological evidence and insight for previous studies on emotional cue related psychological studies. PMID- 24045079 TI - Activation during the Trail Making Test measured with functional near-infrared spectroscopy in healthy elderly subjects. AB - Cognitive decline is very common in age and particularly in subjects with neurodegenerative conditions. Besides memory and language, executive functions are very often affected in elderly and patients with Alzheimer's disease or Parkinson's disease. However, the neural alterations associated with these executive deficits are still not fully understood. Therefore, we measured cortical activation using functional near-infrared spectroscopy (fNIRS) in 16 healthy elderly subjects (50-75 years) performing the Trail Making Test (TMT), a widely used neuropsychological instrument measuring executive function. In line with previous studies focusing on younger subjects, the results showed frontal activation during the TMT A and the TMT B in the dorsolateral prefrontal cortex, the frontopolar area and also Broca's area. Furthermore, significant activation in the left motor, somatosensory cortices and somatosensory association cortices was demonstrated. Additionally, after a median split the differences between younger (<58 years) and older (>58 years) subjects were analyzed with the older subjects showing a less focused prefrontal activation. Altogether, fNIRS was found to be suitable to detect cortical activation in elderly subjects during performance of the TMT as well as aging-related differences in prefrontal activation topography. These neural correlates of executive functions should be further investigated as a potential prodromal neural marker of executive deficits and neurodegenerative processes. PMID- 24045080 TI - Temporal changes of ulcerative plaques in the aortic arch in recurrent stroke patients. AB - BACKGROUND: Ulcerative aortic plaques (UAPs) are considered a major source of brain embolism. However, whether UAPs contribute to a specific stroke mechanism remains unknown. METHODS: Three consecutive patients with recurrent embolic stroke underwent repeated transesophageal echocardiography (TEE) examinations after their initial and recurrent strokes. RESULTS: All 3 patients had UAPs. Between TEEs, different morphologies of UAPs were found in cases 1 and 2, and case 3 maintained advanced UAPs with no significant morphological alteration. Case 3 underwent repeated contrast-enhanced computed tomographic examinations after each stroke event, which showed newly developed, uneven, ulcerative plaques in the aortic arch after recurrent stroke. CONCLUSIONS: Repeated TEE showed dynamic changes of UAPs in recurrent stroke patients and supported the diagnosis of aortogenic brain embolism. PMID- 24045081 TI - Early menopause and the risk of silent brain infarction in community-dwelling elderly subjects: the Sefuri brain MRI study. AB - Our previous study showed that the male predominance of silent brain infarction (SBI) was largely because of higher prevalence of alcohol habit and smoking in men than in women. In the present study, we further conducted an analysis of brain magnetic resonance imaging findings to examine whether early menopause contributes to SBI in community-dwelling subjects. Women were queried as to the age and cause of menopause, the total number of children, and the age at giving birth to her last child. Among 306 female subjects aged 60 years or older, univariate analysis showed that early menopause (total or natural) was significantly associated with SBI but age at natural menopause, number of children, and age at the last parity were not. In the total of 715 subjects (283 men and 432 women with a mean age of 67.2 years), the forward stepwise method of logistic analysis revealed that natural early menopause (odds ratio [OR] 4.28, 95% confidence interval [CI] 1.07-17.11), in addition to age, hypertension, alcohol intake, and smoking, was a significant factor concerning SBI. Also in the subgroup of female subjects aged 60 years or older, natural early menopause was a significant factor concerning SBI (OR 4.35, 95% CI 1.05-18.08) adjusted for covariates. Although the prevalence of natural early menopause was low (3.3% of 306 female subjects), natural menopause before the age of 40 years may be a risk for SBI or small-vessel disease of the brain. PMID- 24045082 TI - Utility of early post-treatment single-photon emission computed tomography imaging to predict outcome in stroke patients treated with intravenous tissue plasminogen activator. AB - It is important to predict the outcome of tissue plasminogen activator (tPA) treated patients early after the treatment for considering the post-tPA treatment option. We assessed cerebral blood flow (CBF) of tPA-treated patients with single photon emission computed tomography (SPECT) 1 hour after tPA infusion to predict the patient outcome. Technetium-99m-hexamethylpropyleneamine oxime SPECT was performed in 35 consecutive tPA-treated patients. Asymmetry index, a contralateral-to-ipsilateral ratio of CBF, was calculated to analyze CBF quantitatively. Hypoperfusion or hyperperfusion was defined as a decrease of 25% or more or a increase of 25% or more in asymmetry index, respectively. Of all 35 patients, 23 had only hypoperfusion, 8 had both hypoperfusion and hyperperfusion, 2 had only hyperperfusion, and 2 had no perfusion abnormality. When evaluating the association between hypoperfusion and outcome, hypoperfusion volumes were significantly correlated with the modified Rankin Scale at 3 months (r = .634, P < .001). Hyperperfusion was observed in 10 patients (28.6%) and they showed a marked National Institutes of Health Stroke Scale score improvement in the first 24-hour period, which were significantly greater than those of 25 patients without hyperperfusion (P = .033). Eight patients (22.9%) with intracerebral hemorrhage (ICH) were all asymptomatic. Most ICHs were located in hypoperfusion areas, and no ICH was related to hyperperfusion. The results of the present study demonstrated that hypoperfusion volume was associated with poor outcome, whereas the presence of hyperperfusion seemed to be predictive of symptom improvement but not of development of ICH. Taken together, early post-treatment SPECT imaging seems to be a useful biomarker of outcome in tPA-treated patients. PMID- 24045083 TI - A rare cause of embolic stroke in hereditary hemorrhagic telangiectasia. AB - A 57-year-old male patient with hereditary hemorrhagic telangiectasia presented with an acute right middle cerebral artery ischemic stroke. Investigations revealed a right middle cerebral artery M2 occlusion, hypoxemia, and a large pulmonary arteriovenous malformation and right lower limb deep venous thrombosis. Closure of the pulmonary arteriovenous malformation was successfully performed with an Amplatzer device. Catheter closure of pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia is a recognized treatment modality to prevent recurrent ischemic stroke and other embolic and hemorrhagic complications. PMID- 24045084 TI - Intracerebral hemorrhage with hypothyroidism. AB - BACKGROUND: Hypothyroidism is associated with increased ischemic stroke risk but paradoxically results in more favorable outcomes once a stroke occurs. Whether a similar pattern emerges in patients with primary intracerebral hemorrhage (ICH) is unknown. METHODS: A retrospective analysis of a prospective stroke center database was performed to analyze the clinical presentation and outcomes of hypothyroid patients with spontaneous ICH. Patients were classified into groups with no history of thyroid disease (n=491) versus those with hypothyroidism (n=72). Hypothyroid patients were further classified into patients receiving thyroid replacement on admission or those without replacement. The Glasgow Coma Scale, ICH score, and the National Institutes of Health Stroke Scale (NIHSS) were used to assess the initial severity. Outcome was assessed by admission to discharge change in the NIHSS and modified Barthel Index (mBI), in-hospital mortality, discharge disposition and mortality, and the mBI at 3 and 12 months. RESULTS: There were 563 patients in the analysis. Seventy-two patients had a history of hypothyroidism, and of these, 63% received thyroid hormone replacement. Patients receiving replacement had significantly lower NIHSS at presentation (median 4 [IQR 1, 11]) compared with either the control group (median 8 [IQR 3, 16]) or hypothyroid patients without replacement (median 9 [IQR 3.8, 15.5]; P=.004). There was no difference in in-hospital and 3-month mortality or functional outcomes at 3 and 12 months among the groups. CONCLUSIONS: This study suggests that the history of hypothyroidism does not affect clinical severity or outcome after ICH. PMID- 24045085 TI - Effect of middle cerebral artery territory ischemic stroke on QT interval. AB - BACKGROUND: Prolonged QT interval associates with increased risk for sudden cardiac death after acute ischemic stroke. However, pathophysiology of prolonged QT interval after stroke is poorly elucidated. In this study, we investigated whether QT interval dynamics is different in patients with right and left middle cerebral artery (MCA) territory stroke. METHOD: Electrocardiogram (ECG) intervals were compared between baseline (retrieved retrospectively from medical records) and admission (acquired at the acute hospital admission) in 33 patients (65 +/- 9.5 years) with right or left MCA territory ischemic stroke. Head computed tomography (CT), cardiac ultrasound, and cardiac CT scans were undertaken. RESULTS: Stroke was located in the right MCA territory in 21 (64%) and in the left MCA territory in 12 (36%) patients. Patients with right and left MCA stroke were similar with respect to time interval between baseline and admission ECG recordings, positive history of heart disease, and left ventricular dimensions. Increase in heart rate-corrected QT interval (QTc) from baseline to admission was demonstrated to occur more often in patients with right (16 of 21; 76%) than in patients with left (3 of 12; 25%; P < .01) MCA stroke. DeltaQTc between baseline and admission was significantly longer in patients with right (23 +/- 23 milliseconds) than in patients with left (-11 +/- 19 milliseconds; P < .0001) MCA stroke. Percent DeltaQTc between baseline and admission was longer in patients with right (5.5% +/- 5.5%) than in patients with left (-2.6% +/- 4.7%; P < .001) MCA stroke. CONCLUSIONS: Right MCA ischemic stroke results in prolongation of QT interval. Findings indicate cerebral asymmetry in brain-heart interaction during acute ischemic stroke. PMID- 24045087 TI - The Cochrane Collaboration and geriatric medicine. PMID- 24045086 TI - Probiotic supplementation reduces the duration and incidence of infections but not severity in elite rugby union players. AB - OBJECTIVES: The attenuation of the number and severity of infections is of importance to athletes. Probiotics use has increased over recent years with beneficial effects believed to include improvements in immune function. Research has focused on their effectiveness for reducing the number, duration and severity of infections amongst endurance athletes. At present no research has been undertaken with team sport athletes. This randomised controlled trial aimed to determine the effectiveness of probiotics on the number, duration and severity of infections amongst elite union rugby players. DESIGN: Randomised control trial with two arms; placebo and probiotic. METHODS: Thirty elite rugby union players were allocated in random order to receive a probiotics supplement or a placebo for four weeks each. Supplements were consumed on a daily basis. There was a four week washout period between treatments. Participants completed a daily diary to identify and rate the severity of any infectious symptoms. RESULTS: During the probiotic treatment 14/30 participants never experienced a single upper respiratory tract illness (URTI) or gastrointestinal (GI) episode, compared to 6/30 on the placebo supplementation (p=0.033). The mean+/-standard deviation for the number of days of illness tended to be higher for the placebo, (5.8+/-6.6 days) than probiotic (3.4+/-4.6 days), (p=0.054). There was no significant difference in the severity of the symptoms between the two treatment groups (p=0.110). CONCLUSIONS: These positive effects of probiotic supplements provide evidence for the beneficial effects of daily supplementation with these probiotic strains in highly trained rugby union players. PMID- 24045088 TI - Glycine receptor and myelin oligodendrocyte glycoprotein antibodies in Turkish patients with neuromyelitis optica. AB - BACKGROUND: Seronegative NMO is highly prevalent in non-Western countries implying the presence of as yet unknown antibodies (Ab). We investigated potential novel Ab in aquaporin-4 Ab (AQP-4-Ab) positive and negative NMO patients. METHODS: Sera of 20 NMO patients were examined for AQP-4, myelin oligodendrocyte glycoprotein (MOG) and glycine receptor (GlyR) Ab by cell-based assays. RESULTS: AQP-4-Ab was identified in 10 NMO patients, MOG-Ab was detected only in one AQP-4-Ab positive patient and GlyR-Ab was detected in two AQP-4-Ab negative patients. GlyR-Ab positive patients displayed simultaneous optic neuritis and transverse myelitis attacks and relatively low disability, whereas MOG and AQP-4-Ab double positive patient had a significantly increased disability. CONCLUSION: This study showed for the first time the presence of GlyR Ab in Turkish NMO patients. In contrast with previous reports, MOG Ab does not appear to be a distinctive marker for Turkish AQP-4-Ab negative NMO patients. PMID- 24045089 TI - Structural and functional characterization of simvastatin-induced myotoxicity in different skeletal muscles. AB - BACKGROUND: Statins are the most commonly used drugs for the treatment of hypercholesterolemia. Their most frequent side effect is myotoxicity. To date, it remains unclear whether statins preferentially induce myotoxicity in fast- or in slow-twitch muscles. Therefore, we investigated these effects on fast- (extensor digitorum longus; EDL), slow- (soleus; SOL), and mixed-twitch muscles (diaphragm; DIA) in rats by comparing their contractile and molecular structural properties. METHODS: Simvastatin-induced functional changes were determined by muscle contraction measurements, and drug-induced molecular changes were investigated using Fourier transform infrared (FTIR) and attenuated total reflectance (ATR) FTIR spectroscopy. RESULTS: With simvastatin administration (30 days, 50mg/kg), a depression in the force-frequency curves in all muscles was observed, indicating the impairment of muscle contractility; however, the EDL and DIA muscles were affected more severely than the SOL muscle. Spectroscopic findings also showed a decrease in protein, glycogen, nucleic acid, lipid content and an increase in lipid order and lipid dynamics in the simvastatin-treated muscles. The lipid order and dynamics directly affect membrane thickness. Therefore, the kinetics and functions of membrane ion channels were also affected, contributing to the statin-induced impairment of muscle contractility. Furthermore, a reduction in alpha-helix and beta-sheet and an increase in random coil, aggregated and antiparallel beta-sheet were observed, indicating the protein denaturation. Spectral studies showed that the extent of molecular structural alterations in the muscles following simvastatin administration was in the order EDL>DIA>SOL. CONCLUSIONS: Simvastatin-induced structural and functional alterations are more profound in the fast-twitch than in the slow-twitch muscles. GENERAL SIGNIFICANCE: Myotoxic effects of simvastatin are primarily observed in the fast twitch muscles. PMID- 24045091 TI - Is folate involved in the pathogenesis of inflammatory bowel disease? AB - The inflammatory bowel diseases, Crohn's and ulcerative colitis, are common and a significant cause of morbidity. They were rare before the 1930's but the incidence has been increasing in both developed and developing countries. We have recently reported that the incidence in Nova Scotia, the area with one of the highest reported burden globally, is decreasing since 1997. We postulate that this decrease may be due to the addition of folate to cereals. This was mandated in 1998 but the process of fortification began in 1997. There is circumstantial evidence from epidemiology studies that a diet deficient in folate may have contributed to the global rise in these diseases. This hypothesis, if proven to be correct, has important implications for the prevention and treatment of these diseases. PMID- 24045090 TI - Demographic changes and trends in risk behaviours, HIV and other sexually transmitted infections among female sex workers in Bangalore, India involved in a focused HIV preventive intervention. AB - The primary objectives of this study were to assess the changing demographic characteristics of female sex workers (FSWs) in the urban Bangalore district, India, and trends in programme coverage, HIV/sexually transmitted infection prevalence rates and condom use. Cross-sectional, integrated behavioural and biological assessments of FSWs were conducted in 2006, 2009 and 2011. Univariate and multivariate analyses were used to describe trends over time. The results indicate the mean age of initiation into sex work has increased (26.9 years in 2006 vs 27.6 years in 2011, p<0.01), a higher proportion of FSWs reported being in 'stable' relationships in 2011 (70.2% vs 43.2% in 2006, p<0.01) and having conducted sex work outside the district in the past 6 months (10.0% in 2011 vs 16.0% in 2006 p=0.01). There was an increase in the proportion of FSWs using cellphones to solicit clients (4.4% in 2006 vs 57.5% in 2011, p<0.01) and their homes for sex work (61.4% in 2006 vs 77.8% in 2011, p<0.01). Reactive syphilis prevalence declined (12.6% in 2006 to 4% in 2011, p=0.02), as did high-titre syphilis prevalence (9.5% in 2006 to 2.5% in 2011, p=0.01). HIV prevalence declined but not significantly (12.7% in 2006 and 9.3% in 2011, p=0.39). Condom use remained above 90% increasing significantly among repeat (paying) clients (66.6% in 2006 to 93.6% in 2011, p<0.01). However, condom use remained low with non-paying partners when compared with occasional paying partners (17.6% vs 97.2% in 2011, p<0.01). Given the changing dynamics in the FSW population at multiple levels, there is a need to develop and customise strategies to meet local needs. PMID- 24045092 TI - CPEB4 is a candidate biomarker for defining metastatic cancers and directing personalized therapies. AB - Identification of prognostic markers of metastatic disease and targets for treatment is critical for the management of cancer patients. Cytoplasmic polyadenylation element binding protein 4 (CPEB4) associates with specific sequences in mRNA 3' untranslated regions and promote translation by inducing cytoplasmic polyadenylation. Aberrant expression of CPEB4 correlates with certain types of cancer, indicating that CPEB4 might play critical roles in the control of cancer proliferation and metastasis. Here we demonstrate that (A) CPEB4 is selectively overexpressed in invasive or metastatic cancers and has the potential to be used for defining cancer subtypes. (B) CPEB4 might promote invasion and metastasis by exerting its effect on TGF-beta signaling pathway. (C) By generating a CPEB4 regulated gene-drug network, we show that CPEB4 is a candidate biomarker that could be beneficial for directing therapies. Taken together, our results indicate that CPEB4 is a candidate biomarker for defining metastatic cancers and directing personalized therapies. PMID- 24045093 TI - The site of the optical image in the eye. AB - Based on good empirical evidence it is generally said that the layer of the retina containing the rod and cone cells is the site where the optical image of the external world falls, and whence the neural signal is transmitted to the brain. The historical path to this idea is traced from the ancient Greeks, through Kepler to modern times. The newer hypothesis suggests that the retinal pigment epithelial (RPE) layer behind the rods and cones may be the actual photoreceptive apparatus. It is supported by clinical pictures, such as retinal detachment and Vitamin A deficiency, and the physical law of Grotthuss and Draper, together with further evidence from recent advances in molecular biology dealing with G protein-coupled receptors, that received the Nobel Prize in 2012. PMID- 24045094 TI - Restoration of endogenous substance P is associated with inhibition of apoptosis of retinal cells in diabetic rats. AB - This study was designed to investigate the alterations of substance P (SP) and its correlation with apoptosis of the retinal neurons in diabetic rats. The study was carried out with diabetic rats induced by streptozotocin. Changes of SP and its mRNA were examined using enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction. The effect of restoration of SP level by capsaicin (20mg/kg, s.c.) on the apoptosis of the retinal cells was studied. The apoptosis was evaluated by change of ratio of the apoptotic cells and caspase-3 activity in the retina. It was found that increase in apoptosis of retinal cells, by 3.5 fold of control, was accompanied by reduction of SP, by 28% in protein and 32% in the mRNA in the retina at 10 weeks of induction of diabetes, compared to the controls. Capsaicin significantly elevated endogenous SP, by 29% in the mRNA and 17% in protein in the retina, with marked inhibition of the apoptosis and the activity of caspase-3 in the diabetic rats. Induction of diabetes leads to the increase of cell apoptosis and the decrease of SP in the retina. The reduction of the endogenous SP and the increase of the cell apoptosis in the retina of the diabetic rats were reversed by pretreatment with capsaicin. Restoration of SP in the retina may be a novel option for prevention of the retinal injury during development of diabetes. PMID- 24045095 TI - Dysregulation of the epigenome in triple-negative breast cancers: basal-like and claudin-low breast cancers express aberrant DNA hypermethylation. AB - A subset of human breast cancer cell lines exhibits aberrant DNA hypermethylation that is characterized by hyperactivity of the DNA methyltransferase enzymes, overexpression of DNMT3b, and concurrent methylation-dependent silencing of numerous epigenetic biomarker genes. The objective of this study was to determine if this aberrant DNA hypermethylation (i) is found in primary breast cancers, (ii) is associated with specific breast cancer molecular subtypes, and (iii) influences patient outcomes. Analysis of epigenetic biomarker genes (CDH1, CEACAM6, CST6, ESR1, GNA11, MUC1, MYB, SCNN1A, and TFF3) identified a gene expression signature characterized by reduced expression levels or loss of expression among a cohort of primary breast cancers. The breast cancers that express this gene expression signature are enriched for triple-negative subtypes basal-like and claudin-low breast cancers. Methylation analysis of primary breast cancers showed extensive promoter hypermethylation of epigenetic biomarker genes among triple-negative breast cancers, compared to other breast cancer subclasses where promoter hypermethylation events were less frequent. Furthermore, triple-negative breast cancers either did not express or expressed significantly reduced levels of protein corresponding to methylation-sensitive biomarker gene products. Together, these findings suggest strongly that loss of epigenetic biomarker gene expression is frequently associated with gene promoter hypermethylation events. We propose that aberrant DNA hypermethylation is a common characteristic of triple-negative breast cancers and may represent a fundamental biological property of basal-like and claudin-low breast cancers. Kaplan-Meier analysis of relapse-free survival revealed a survival disadvantage for patients with breast cancers that exhibit aberrant DNA hypermethylation. Identification of this distinguishing trait among triple-negative breast cancers forms the basis for development of new rational therapies that target the epigenome in patients with basal-like and claudin-low breast cancers. PMID- 24045096 TI - Depressive symptoms in adolescence: a poor indicator of increases in body mass index. AB - PURPOSE: The purpose of this study was to examine the association between depressive symptoms and subsequent body mass index (BMI) z scores among early-to mid adolescents, extending previous research by using objectively measured weight and height data. METHODS: Latent growth curve analysis was used to examine whether growth parameters of zBMI could be predicted by depressive symptoms (n = 2,051 adolescents, 48.5% female, at baseline; 1,465 with data at all three time points). Specifically, we tested whether depressive symptoms were associated with the initial assessment of BMI (intercept) as well as with changes in BMI over time (slope). Analyses were performed for the total group, and separately for boys and girls. RESULTS: Depressive symptoms were not associated with the slope of zBMI. In girls, but not boys, depressive symptoms were positively associated with the intercept of zBMI. CONCLUSIONS: Findings suggest that although depressive symptoms among females are associated with a higher zBMI, they do not predict excessive weight gain during early-to-mid adolescence. PMID- 24045097 TI - Comments on "probabilistic mercury multimedia exposure assessment in small children and risk assessment". PMID- 24045098 TI - Influence of affective states on comprehension and hazard perception of warning pictorials. AB - The purpose of the present study was to examine the effect of positive and negative affective states on comprehension and hazard perception of warning pictorials. The International Affective Picture System (IAPS) was used to manipulate the affective states of sixty male undergraduate and graduate student participants. We used sixteen standard industrial warning pictorials, which were representative of a variety of industries, to assess changes in comprehension and hazard perception. Participants in the positive affect condition perceived greater hazards from the warning signs than those in the neutral affect condition or the negative affect condition. Post-hoc analyses confirmed this finding. We discuss implications for warning pictorials and future research. PMID- 24045099 TI - Fish oil-supplementation from 9 to 12 months of age affects infant attention in a free-play test and is related to change in blood pressure. AB - INTRODUCTION: This intervention examined whether fish-oil-supplementation in late infancy modifies free-play test scores and if this is related to blood pressure (BP) and mean RR interval. PATIENTS AND METHODS: 83 Danish 9-month-old infants were randomized to +/-fish oil (FO) (3.4+/-1.1mL/d) for 3months and 61 of these completed the free-play-test before and after the intervention. RESULTS: Most of the free-play scores changed during the intervention, but the intervention affected only the number of looks away from the toy, which was increased in +FO and decreased in -FO (p=0.037). The increased numbers of looks away were associated with an increase in erythrocyte eicosapentaenoic acid (r=0.401, p=0.017, n=35) and were also associated with a decrease in systolic-BP (r=-0.511, p<0.001, n=52). CONCLUSIONS: The results indicate that n-3 fatty acid intake also in late infancy can influence brain development and that the cognitive and cardiovascular effects may be related. PMID- 24045100 TI - Dietary cholesterol increases ventricular volume and narrows cerebrovascular diameter in a rabbit model of Alzheimer's disease. AB - Using structural magnetic resonance imaging in a clinical scanner at 3.0T, we describe results showing that following 12weeks on a diet of 2% cholesterol, rabbits experience a significant increase in the volume of the third ventricle compared to rabbits on a diet of 0% cholesterol. Using time-of-flight magnetic resonance angiography, we find cholesterol-fed rabbits also experience a decrease in the diameter of a number of cerebral blood vessels including the basilar, posterior communicating, and internal carotid arteries. Taken together, these data confirm that, despite the inability of dietary cholesterol to cross the blood-brain barrier, it does significantly enlarge ventricular volume and decrease cerebrovascular diameter in the rabbit - effects that are also seen in patients with Alzheimer's disease. PMID- 24045101 TI - Chemosensory signals and their receptors in the olfactory neural system. AB - Chemical communication is widely used among various organisms to obtain essential information from their environment required for life. Although a large variety of molecules have been shown to act as chemical cues, the molecular and neural basis underlying the behaviors elicited by these molecules has been revealed for only a limited number of molecules. Here, we review the current knowledge regarding the signaling molecules whose flow from receptor to specific behavior has been characterized. Discussing the molecules utilized by mice, insects, and the worm, we focus on how each organism has optimized its reception system to suit its living style. We also highlight how the production of these signaling molecules is regulated, an area in which considerable progress has been recently made. PMID- 24045102 TI - Plasma-polyplumbagin-modified microfiber probes: a functional material approach to monitoring vascular access line contamination. AB - Atmospheric plasma treated carbon fiber filaments (10 micrometer) were used as the base substrate in the design of a probe intended for use within intravascular access devices. The microfiber probe was further functionalized with a polyplumbagin layer through which the line pH could be determined voltammetrically and therein provide the potential for obtaining diagnostic information relating to bacterial colonization of the line. The redox processes attributed to the immobilized polymer are characterized and a methodology developed to enable the acquisition of a redox signal that is selective and sensitive to pH. The applicability of the composite probe was demonstrated through examining the direct response in whole blood. PMID- 24045103 TI - A multilocus molecular phylogeny of combtooth blennies (Percomorpha: Blennioidei: Blenniidae): multiple invasions of intertidal habitats. AB - The combtooth blennies (f. Blenniidae) is a diverse family of primarily marine fishes with approximately 387 species that inhabit subtidal, intertidal, supralittoral habitats in tropical and warm temperate regions throughout the world. The Blenniidae has typically been divided into six groups based on morphological characters: Blenniini, Nemophini, Omobranchini, Phenablenniini, Parablenniini, and Salariini. There is, however, considerable debate over the validity of these groups and their relationships. Since little is known about the relationships in this group, other aspects of their evolutionary history, such as habitat evolution and remain unexplored. Herein, we use Bayesian and maximum likelihood analyses of four nuclear loci (ENC1, myh6, ptr, and tbr1) from 102 species, representing 41 genera, to resolve the phylogeny of the Blenniidae, determine the validity of the previously recognized groupings, and explore the evolution of habitat association using ancestral state reconstruction. Bayesian and maximum likelihood analyses of the resulting 3100bp of DNA sequence produced nearly identical topologies, and identified many well-supported clades. Of these clades, Nemophini was the only traditionally recognized group strongly supported as monophyletic. This highly resolved and thoroughly sampled blenniid phylogeny provides strong evidence that the traditional rank-based classification does not adequately delimit monophyletic groups with the Blenniidae. This phylogeny redefines the taxonomy of the group and supports the use of 13 unranked clades for the classification of blenniids. Ancestral state reconstructions identified four independent invasions of intertidal habitats within the Blenniidae, and subsequent invasions into supralittoral and freshwater habitats from these groups. The independent invasions of intertidal habitats are likely to have played an important role in the evolutionary history of blennies. PMID- 24045104 TI - Measuring physiotherapy intervention in high performance sport. PMID- 24045105 TI - Computer-assisted orthognathic surgery: waferless maxillary positioning, versatility, and accuracy of an image-guided visualisation display. AB - There may well be a shift towards 3-dimensional orthognathic surgery when virtual surgical planning can be applied clinically. We present a computer-assisted protocol that uses surgical navigation supplemented by an interactive image guided visualisation display (IGVD) to transfer virtual maxillary planning precisely. The aim of this study was to analyse its accuracy and versatility in vivo. The protocol consists of maxillofacial imaging, diagnosis, planning of virtual treatment, and intraoperative surgical transfer using an IGV display. The advantage of the interactive IGV display is that the virtually planned maxilla and its real position can be completely superimposed during operation through a video graphics array (VGA) camera, thereby augmenting the surgeon's 3-dimensional perception. Sixteen adult class III patients were treated with by bimaxillary osteotomy. Seven hard tissue variables were chosen to compare (DeltaT1-T0) the virtual maxillary planning (T0) with the postoperative result (T1) using 3 dimensional cephalometry. Clinically acceptable precision for the surgical planning transfer of the maxilla (<0.35 mm) was seen in the anteroposterior and mediolateral angles, and in relation to the skull base (<0.35 degrees ), and marginal precision was seen in the orthogonal dimension (<0.64 mm). An interactive IGV display complemented surgical navigation, augmented virtual and real-time reality, and provided a precise technique of waferless stereotactic maxillary positioning, which may offer an alternative approach to the use of arbitrary splints and 2-dimensional orthognathic planning. PMID- 24045106 TI - Hard palate-repair technique and facial growth in patients with cleft lip and palate: a systematic review. AB - The vomer flap technique for repair of the hard palate is assumed to improve maxillary growth because it causes less scarring in growth-sensitive areas of the palate. The aim of this systematic review was to investigate the effect of techniques using the vomer flap compared with the palatal flap on facial growth in patients with cleft lip and palate. All papers published before 21 July 2012 were sought in the databases PubMed and MEDLINE. Search terms included "facial growth", "cleft lip and palate", "palatal repair technique", and "vomer flap". Additional studies were identified by hand searching the reference lists of the papers retrieved from the electronic search. Two independent reviewers assessed the eligibility of studies for inclusion, extracted the data, and assessed the quality of the methods. Six studies met the selection criteria. Outcomes assessed in 4 studies were dentofacial morphology after vomer or palatal flap, maxillary dental arch in 1 study, and dental arch relations in 2 studies. The quality of the methods used in 3 studies was poor. Contradictory results and a lack of high quality and long-term outcomes of reviewed studies provided no conclusive scientific evidence about whether the vomer flap technique has more or less of an adverse effect on maxillary growth than the palatal flap. Further well-designed, well-controlled, and long-term studies particularly of the vomer flap (2-stage) and palatal flap (von Langenbeck or two-flap, 1-stage) are needed. PMID- 24045107 TI - The human immunodeficiency virus type 1 Vpr protein upregulates PVR via activation of the ATR-mediated DNA damage response pathway. AB - Viral infection may induce the cell-surface expression of PVR (CD155) that, upon recognition by its cognate activating DNAM-1 receptor present on cytotoxic lymphocytes, may promote antiviral immune responses. Here we show that expression of the human immunodeficiency virus type 1 (HIV-1) Vpr protein in Jurkat T cells increases cell-surface and total PVR levels. Analysis of mutated Vpr variants indicated that Vpr uses the same protein surfaces, and hence probably the same mechanisms, to upregulate PVR and arrest the cell cycle in the G2 phase. Moreover, we found that PVR upregulation by Vpr relied on the ability of the protein to activate the ATR kinase that triggers the DNA damage response pathway and G2 arrest. Finally, we showed that Vpr contributes to PVR up-modulation in HIV-infected CD4(+) T lymphocytes and inhibits the PVR downregulating activity of the viral Nef protein. PMID- 24045108 TI - Molecular identification of a novel gammaherpesvirus in the endangered Darwin's fox (Lycalopex fulvipes). AB - We report the detection and characterization of a novel gammaherpesvirus in the critically endangered Darwin's fox (Lycalopex fulvipes; syn. Pseudalopex fulvipes) on Chiloe Island, Chile. Out of 28 analysed blood samples stored in alcohol, four were positive for this herpesvirus using a previously described pan herpesvirus PCR assay targeting the herpesvirus DNA polymerase. Positive samples were subsequently characterized by means of a PCR targeting a 500 bp fragment of the glycoprotein B of the gammaherpesviruses. This novel herpesvirus was most closely related to other gammaherpesviruses from terrestrial carnivores, and is tentatively named Darwin's fox gammaherpesvirus. No apparent lesions were observed in the surveyed foxes. This is the first report of a gammaherpesvirus infecting a canid worldwide, and also of one infecting a carnivore from South America. PMID- 24045109 TI - Role of the line probe assay INNO-LiPA HBV DR and ultradeep pyrosequencing in detecting resistance mutations to nucleoside/nucleotide analogues in viral samples isolated from chronic hepatitis B patients. AB - Despite the effectiveness of nucleoside/nucleotide analogues in the treatment of chronic hepatitis B (CHB), their long-term administration is associated with the emergence of resistant hepatitis B virus (HBV) mutants. In this study, mutations resulting in antiviral resistance in HBV DNA samples isolated from 23 CHB patients (nine treatment naive and 14 treated previously) were studied using a line probe assay (INNO-LiPA HBV DR; Innogenetics) and ultradeep pyrosequencing (UDPS) methods. Whilst the INNO-LiPA HBV DR showed no resistance mutations in HBV DNA samples from treatment-naive patients, mutations mediating lamivudine resistance were detected in three samples by UDPS. Among patients who were treated previously, 19 mutations were detected in eight samples using the INNO LiPA HBV DR and 29 mutations were detected in 12 samples using UDPS. All mutations detected by the INNO-LiPA HBV DR were also detected by UDPS. There were no mutations that could be detected by INNO-LiPA HBV DR but not by UDPS. A total of ten mutations were detected by UDPS but not by INNO-LiPA HBV DR, and the mean frequency of these mutations was 14.7 %. It was concluded that, although INNO LiPA HBV DR is a sensitive and practical method commonly used for the detection of resistance mutations in HBV infection, UDPS may significantly increase the detection rate of genotypic resistance in HBV at an early stage. PMID- 24045110 TI - Perturbation of biogenesis and targeting of Epstein-Barr virus-encoded miR-BART3 microRNA by adenosine-to-inosine editing. AB - Epstein-Barr virus (EBV) encodes at least 44 mature microRNAs (miRNAs), some of which are abundantly expressed in nasopharyngeal carcinoma cells. EBV-encoded miR BART6 miRNA is known to undergo adenosine-to-inosine (A-to-I) RNA editing, which impacts on processing and function. Whether additional EBV miRNAs might be A-to-I edited remains to be determined. In this study, we have reported on A-to-I editing of EBV miR-BART3. The A-to-I editing enzyme was expressed abundantly in EBV-infected epithelial carcinoma cells. pri-miR-BART3 was found to be edited at four sites in these cells and in nasopharyngeal carcinoma samples. Whereas editing of the second site located within the seed region prevented the targeting of DICE1 mRNA, editing of the third site effectively crippled the biogenesis of mature miR-BART3. Thus, A-to-I editing perturbs biogenesis and targeting of miR BART3 and may contribute to its differential expression and function in EBV infected epithelial cells. PMID- 24045111 TI - Nucleo-cytoplasmic shuttling of VPg encoded by Wheat yellow mosaic virus requires association with the coat protein. AB - VPg (virus protein, genome-linked) is a multifunctional protein that plays important roles in viral multiplication in the cytoplasm. However, a number of VPgs encoded by plant viruses target the nucleus and this appears to be biologically significant. These VPgs may therefore be translocated between nuclear and cytoplasmic compartments during virus infection, but such nucleo cytoplasmic transport has not been demonstrated. We report that VPg encoded by Wheat yellow mosaic virus (WYMV, genus Bymovirus, family Potyviridae) accumulated in both the nucleus and cytoplasm of infected cells, but localized exclusively in the nucleus when expressed alone in plants. Computational analyses predicted the presence of a nuclear localization signal (NLS) and a nuclear export signal (NES) in WYMV VPg. Mutational analyses showed that both the N-terminal and the NLS domains of VPg contribute to the efficiency of nuclear targeting. In vitro and in planta assays indicated that VPg interacts with WYMV coat protein (CP) and proteinase 1 (P1) proteins. Observation of VPg fused to a fluorescent protein and subcellular fractionation experiments showed that VPg was translocated to the cytoplasm when co-expressed with CP, but not with P1. Mutations in the NES domain or treatment with leptomycin B prevented VPg translocation to the cytoplasm when co-expressed with CP. Our results suggest that association with CP facilitates the nuclear export of VPg during WYMV infection. PMID- 24045112 TI - Presence of subclinical infection in gene-targeted human prion protein transgenic mice exposed to atypical bovine spongiform encephalopathy. AB - The transmission of bovine spongiform encephalopathy (BSE) to humans, leading to variant Creutzfeldt-Jakob disease has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health. Until recently, TSE disease in cattle was thought to be caused by a single agent strain, BSE, also known as classical BSE, or BSE-C. However, due to the initiation of a large-scale surveillance programme throughout Europe, two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H have since been discovered. To model the risk to human health, we previously inoculated these two forms of atypical BSE (BASE and BSE-H) into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP) (HuTg) but were unable to detect any signs of TSE pathology in these mice. However, despite the absence of TSE pathology, upon subpassage of some BASE challenged HuTg mice, a TSE was observed in recipient gene-targeted bovine PrP Tg (Bov6) mice but not in HuTg mice. Disease transmission from apparently healthy individuals indicates the presence of subclinical BASE infection in mice expressing human PrP that cannot be identified by current diagnostic methods. However, due to the lack of transmission to HuTg mice on subpassage, the efficiency of mouse-to-mouse transmission of BASE appears to be low when mice express human rather than bovine PrP. PMID- 24045113 TI - foxl2 and foxl3 are two ancient paralogs that remain fully functional in teleosts. AB - FOXL2 is a forkhead transcription factor involved in mammalian development and regulation of reproduction. Two foxl2 paralogs, foxl2a and foxl2b, have been described in various teleost species and were considered as fish-specific duplicates. Here, we report the isolation and characterization of foxl2a (foxl2) and foxl2b (foxl3) in European sea bass (Dicentrarchus labrax), together with the identification of these two genes in non-teleost genomes. Phylogenetic and synteny analyses indicate that these paralogs originated from an ancient genome duplication event that happened long before the teleost specific duplication. While foxl2/foxl2a has been maintained in most vertebrate lineages, foxl2b, which we propose to rename as foxl3, was repeatedly lost in tetrapods. Gonadal expression patterns of the sea bass genes point to a strong sexual dimorphism, and the mRNA levels of foxl2 in ovary and foxl3 in testis vary significantly during the reproductive cycle. When overexpressed in cultured ovarian follicular cells, foxl2 and foxl3 produced functional transcription factors able to control the expression of reproduction-related genes. Taken together, these data suggest that Foxl2 may play a conserved role in ovarian maturation, while Foxl3 could be involved in testis physiology. PMID- 24045114 TI - Fatigue-induced motor cortex excitability changes in subjects with spinal cord injury. AB - To further investigate the mechanisms of exercise-induced cortical plasticity after spinal cord injury (SCI), the cortical silent period (CoSP) evoked by transcranial magnetic stimulation (TMS) during a fatiguing muscle contraction was evaluated in 5 patients with incomplete cervical SCI and in 5 healthy subjects. The physiological lengthening of CoSP end latency during fatigue was not observed in the SCI patients. This reduced intracortical inhibition, probably secondary to decreased activity of the GABAergic inhibitory interneurons that modulate the corticomotoneuronal output, could represent a 'positive' neuroplastic response in an attempt to compensate for the loss of corticospinal axons. The investigation of motor cortex excitability during fatiguing exercise may shed light on the role of exercise therapy in promoting brain reorganization and functional recovery in humans. PMID- 24045115 TI - Human decidual macrophages suppress IFN-gamma production by T cells through costimulatory B7-H1:PD-1 signaling in early pregnancy. AB - In human pregnancy, CD14+ decidual macrophages (DMs) are the dominant professional antigen-presenting cells in the decidua, comprising 20-30% of the local leukocyte population. Although the relevance of DMs to feto-maternal immune tolerance has been described, the molecular mechanisms underlying these functions have not been fully elucidated. B7-H1, a costimulatory ligand in the B7 family, negatively modulates T cell activity by binding to its corresponding receptor, PD 1. The present study aimed to investigate the functional significance of costimulatory interactions between DMs and T cells, with a particular focus on B7 H1:PD-1 signaling. An analysis of the expression profile of B7 ligands on human DMs revealed that B7-H1 was present on DMs isolated from early but not term pregnancies. B7-H1 was not expressed on the peripheral monocytes (PMs) of pregnant women. In response to IFN-gamma, B7-H1 expression was induced on PMs and was enhanced on DMs, suggesting that this cytokine might be a key factor in the control of B7-H1 expression in the decidua. The majority of decidual T cells were noted to exhibit robust expression of PD-1, whereas the expression was limited to a small subpopulation of circulating T cells. Functional assays demonstrated that DMs are able to suppress T cell IFN-gamma production via B7-H1:PD-1 interactions. This suppressive property was not observed for PMs, which lack B7-H1. B7-H1 on DMs may function as a key regulator of local IFN-gamma production and thereby contribute to the development of appropriate maternal immune responses to the fetus in early pregnancy. PMID- 24045116 TI - Anticataleptic effects of 5-HT(1B) receptors in the globus pallidus. AB - The globus pallidus occupies an important position in the indirect pathway of the basal ganglia. Being a monoamine neurotransmitter, 5-HT is involved in mediating many physiological functions and pathophysiological processes in several movement disorders. Morphological studies have revealed that the globus pallidus receives serotonergic innervation arising from the raphe nuclei, mainly the dorsal raphe nucleus. A high level of 5-HT and 5-HT(1B) receptors were detected in the globus pallidus. In the present study, bilateral microinjection of 5-HT or 5-HT(1B) receptor agonist, CP-93129, into the globus pallidus significantly alleviated the symptoms of rigidity caused by haloperidol. To further elucidate 5-HT(1B) receptor-induced anticatalepsy, in vivo extracellular recordings were performed to examine the effects of 5-HT(1B) receptor activation on the firing activity of the globus pallidus neurons under the presence of haloperidol. Micro-pressure ejection of 5-HT or CP-93129 increased the spontaneous firing rate of the pallidal neurons. Furthermore, by using immunohistochemistry, positive staining of 5-HT(1B) receptor was observed in the globus pallidus neurons. Taken together, the present findings provide evidence that activation of 5-HT(1B) receptor may exert anticataleptic effects by increasing the activity of pallidal neurons. PMID- 24045117 TI - Nitrogen dioxide and allergic sensitization in the 2005-2006 National Health and Nutrition Examination Survey. AB - BACKGROUND: Allergic sensitization is a risk factor for asthma and allergic diseases. The relationship between ambient air pollution and allergic sensitization is unclear. OBJECTIVE: To investigate the relationship between ambient air pollution and allergic sensitization in a nationally representative sample of the US population. METHODS: We linked annual average concentrations of nitrogen dioxide (NO2), particulate matter <=10 MUm (PM10), particulate matter <=2.5 MUm (PM2.5), and summer concentrations of ozone (O3), to allergen-specific immunoglobulin E (IgE) data for participants in the 2005-2006 National Health and Nutrition Examination Survey (NHANES). In addition to the monitor-based air pollution estimates, we used the Community Multiscale Air Quality (CMAQ) model to increase the representation of rural participants in our sample. Logistic regression with population-based sampling weights was used to calculate adjusted prevalence odds ratios per 10 ppb increase in O3 and NO2, per 10 MUg/m(3) increase in PM10, and per 5 MUg/m(3) increase in PM2.5 adjusting for race, gender, age, socioeconomic status, smoking, and urban/rural status. RESULTS: Using CMAQ data, increased levels of NO2 were associated with positive IgE to any (OR 1.15, 95% CI 1.04, 1.27), inhalant (OR 1.17, 95% CI 1.02, 1.33), and indoor (OR 1.16, 95% CI 1.03, 1.31) allergens. Higher PM2.5 levels were associated with positivity to indoor allergen-specific IgE (OR 1.24, 95% CI 1.13, 1.36). Effect estimates were similar using monitored data. CONCLUSIONS: Increased ambient NO2 was consistently associated with increased prevalence of allergic sensitization. PMID- 24045118 TI - Assessment of asthma control: the SERENA study. AB - BACKGROUND: Several studies suggest that many asthmatic subjects have uncontrolled asthma. The control of asthma is now considered the major goal of therapy. OBJECTIVES: to ascertain the level of asthma control, by Asthma Control Test (ACT), in "real-life" clinical practice and the potential risk factors for uncontrolled disease in patients treated with inhaled corticosteroids (ICS) and long-acting beta-adrenergic agonists (LABA). METHODS: SERENA is a multi-centre, cross-sectional, 6-month observational, non-interventional study carried out in 16 Pulmonary Units in Italy. Asthmatic outpatients aged over 18, undergoing treatment with ICS at medium-high daily doses associated with LABA, were enrolled. The patients were divided in 3 subgroups according to the level of asthma control by ACT score (25:controlled; 20-24:partly controlled; <20: uncontrolled). RESULTS: Out of a total of 548 patients, 396 met the inclusion criteria. Only 9.1% of patients had asthma controlled, while partly controlled and uncontrolled asthma accounted for 39.6% and 51.3% respectively. The mean age was 54.5 +/- 15.8 and the mean duration of asthma was 16.1 +/- 14.1 years. There were more females than males (63% vs 37%) and females had highest prevalence of uncontrolled asthma (63.1%). The mean values of FEV1% predicted were lower in the uncontrolled group (p < 0.001). The percentage of patients with at least 1 exacerbation, unscheduled visit and/or admissions was lower in controlled (22.2%, 8.3%, 8.3%) than in partly controlled (50%, 38.6%, 9.2%) and uncontrolled (83.2%, 66.2%, 27.8%) groups (p < 0.0001). The multivariate ordinal logistic regression analysis identified female sex, FEV1 and exacerbations as the strongest independent factors associated with the uncontrolled disease. CONCLUSION: This study highlights the importance in clinical practice of a periodic assessment by a validated asthma control instrument and exacerbations/health care contacts during previous year. Clinicians should be aware that a significant proportion of patients can have uncontrolled asthma, despite regular pharmacological treatment. PMID- 24045119 TI - Association of geographical factors with administration of tissue plasminogen activator for acute ischemic stroke. AB - BACKGROUND: Intravenous tissue plasminogen activator (tPA) is an effective treatment for acute ischemic stroke if administered within a few hours of stroke onset. Because of this time restriction, tPA administration remains infrequent. Ambulance use is an effective strategy for increasing tPA administration but may be influenced by geographical factors. The objectives of this study are to investigate the relationship between tPA administration and ambulance use and to examine how patient travel distance and population density affect tPA utilization. METHODS AND RESULTS: We analyzed administrative claims data from 114,194 acute ischemic stroke cases admitted to 603 hospitals between July 2010 and March 2012. Mixed-effects logistic regression models of patients nested within hospitals with a random intercept were generated to analyze possible predictive factors (including patient characteristics, ambulance use, and driving time from home to hospital) of tPA administration for different population density categories to investigate differences in these factors in various regional backgrounds. Approximately 5.1% (5797/114,194) of patients received tPA. The composition of baseline characteristics varied among the population density categories, but adjustment for covariates resulted in all factors having similar associations with tPA administration in every category. The administration of tPA was associated with patient age and severity of stroke symptoms, but driving time showed no association. Ambulance use was significantly associated with tPA administration even after adjustment for covariates. CONCLUSION: The association between ambulance use and tPA administration suggests the importance of calling an ambulance for suspected stroke. Promoting ambulance use for acute ischemic stroke patients may increase tPA use. PMID- 24045120 TI - Randomized trial of conventional transseptal needle versus radiofrequency energy needle puncture for left atrial access (the TRAVERSE-LA study). AB - BACKGROUND: Transseptal puncture is a critical step in achieving left atrial (LA) access for a variety of cardiac procedures. Although the mechanical Brockenbrough needle has historically been used for this procedure, a needle employing radiofrequency (RF) energy has more recently been approved for clinical use. We sought to investigate the comparative effectiveness of an RF versus conventional needle for transseptal LA access. METHODS AND RESULTS: In this prospective, single-blinded, controlled trial, 72 patients were randomized in a 1:1 fashion to an RF versus conventional (BRK-1) transseptal needle. In an intention-to-treat analysis, the primary outcome was time required for transseptal LA access. Secondary outcomes included failure of the assigned needle, visible plastic dilator shavings from needle introduction, and any procedural complication. The median transseptal puncture time was 68% shorter using the RF needle compared with the conventional needle (2.3 minutes [interquartile range {IQR}, 1.7 to 3.8 minutes] versus 7.3 minutes [IQR, 2.7 to 14.1 minutes], P = 0.005). Failure to achieve transseptal LA access with the assigned needle was less common using the RF versus conventional needle (0/36 [0%] versus 10/36 [27.8%], P < 0.001). Plastic shavings were grossly visible after needle advancement through the dilator and sheath in 0 (0%) RF needle cases and 12 (33.3%) conventional needle cases (P < 0.001). There were no differences in procedural complications (1/36 [2.8%] versus 1/36 [2.8%]). CONCLUSIONS: Use of an RF needle resulted in shorter time to transseptal LA access, less failure in achieving transseptal LA access, and fewer visible plastic shavings. PMID- 24045121 TI - Testicular outcome following laparoscopic second stage Fowler-Stephens orchidopexy. AB - OBJECTIVE: To assess outcome after laparoscopic second-stage Fowler-Stephens orchidopexy (L2(nd)FSO). PATIENTS AND METHODS: Retrospective review of 94 children (aged 0.75-16 years, median 2.75 years), who underwent L2(nd)FSO for 113 intra-abdominal testes between January 2000 and May 2009: 75 unilateral, 19 bilateral (11 synchronous; 8 metachronous). Follow-up (range 3 months-10.9 years, median 2.1 years) was available for 88 children (102 testes: 71 unilateral, 31 bilateral). RESULTS: Testicular atrophy occurred in 9 out of 102 (8.8%), including 8 out of 71 (11.3%) unilateral and 1 out of 31 (3.2%) bilateral intra abdominal testes (multivariate analysis: p = 0.59). Testicular ascent ensued in 9 out of 102 (8.8%), comprising four (5.6%) unilateral and five (16.1%) bilateral testicles (multivariate analysis: p = 0.11). Of the 18 bilateral testes brought to the scrotum synchronously none atrophied and four (22.2%) ascended, compared to one (7.7%) atrophy and one (7.7%) ascent among the 13 testes brought to the scrotum on separate occasions (Fisher exact test: p = 0.42 and p = 0.37, respectively). Mobilization of the testis through the conjoint tendon tended towards less ascent (multivariate analysis p = 0.08) but similar atrophy (p = 0.56) compared to mobilization through the deep-ring/inguinal canal. Logistical regression analysis identified no other patient or surgical factors influencing outcome. CONCLUSIONS: This is the largest series of L2(nd)FSO to date. A successful outcome is recorded in 85 out of 102 (83.3%) testicles. Atrophy occurred in 8.8% and ascent in 8.8%. PMID- 24045122 TI - Characterization and regulation of Bacillus thuringiensis Cry toxin binding aminopeptidases N (APNs) from non-gut visceral tissues, Malpighian tubule and salivary gland: Comparison with midgut-specific APN in the moth Achaea janata. AB - Bacillus thuringiensis (Bt) crystal proteins (Cry) bind to aminopeptidase N (APN) receptors on insect midgut membrane leading to pore formation and subsequent death. However, evolution of insect resistance to Bt toxins threatens their long term application. Therefore, search for new targets which could function as Cry toxin receptors is an immediate mandate. In the present study, two full-length APN cDNAs were cloned from Malpighian tubule and salivary gland tissues of the moth, Achaea janata. Both these APNs showed 99% and 32% sequence homology with fat body and midgut APNs respectively. Tissue distribution analysis revealed the presence of two different APN isoforms, one predominant in non-gut visceral tissues while the other exclusively expressed in the midgut. Immunofluorescence and western blot analyses showed cross-reactivity in Malpighian tubule and salivary gland when probed with anti-fat body APN antiserum. These results clearly indicated the presence of non-gut (AjAPN1) and gut-specific (AjAPN4) isoforms in this moth. The expression of both the isoforms steadily increased during the larval development. Hormonal studies indicated regulation of the APN genes by the morphogenetic hormones, 20-hydroxyecdyone and juvenile hormone. Further, in vitro ligand-blotting studies demonstrated binding of Cry toxins to APNs in Malpighian tubule and salivary gland indicating their potential as alternate targets. PMID- 24045123 TI - Biodegradation of crude oil by Pseudomonas aeruginosa and Escherichia fergusonii isolated from the Goan coast. AB - Petroleum hydrocarbons are major pollutants of the marine environment. Bioremediation is a promising approach for treating such contaminated environments. The present study aims at isolating naturally occurring bacteria from the coast of Goa, India and to study their hydrocarbonoclastic capacity. Pseudomonas aeruginosa and Escherichia fergusonii were isolated from a crude oil contaminated sediment sample using diesel oil as the sole carbon source. The capability of the enriched culture to degrade crude oil was estimated using microcosm studies under saline conditions. Based on GC-MS analysis, the culture was found to degrade n-alkanes at a higher rate compared to polyaromatic hydrocarbons. It was also found that the culture degraded alkylated polyaromatic hydrocarbons much less than unalkylated ones. Alkanes ranging from C12 to C33 were highly degraded compared to n-C34. This study shows bioremediation of crude oil in saline (3% NaCl) conditions by naturally existing bacteria isolated from the marine environment. PMID- 24045124 TI - Assessing the impact of fishing in shallow rocky reefs: a multivariate approach to ecosystem management. AB - In this paper we develop a tool to assess the impact of fishing on ecosystem functioning in shallow rocky reefs. The relationships between biological parameters (fishes, sea urchins, seaweeds), and fishing activities (fish traps, boats, land-based fishing, spearfishing) were tested in La Palma island (Canary Islands). Data from fishing activities and biological parameters were analyzed using principal component analyses. We produced two models using the first component of these analyses. This component was interpreted as a new variable that described the fishing pressure and the conservation status at each studied site. Subsequently the scores on the first axis were mapped using universal kriging methods and the models obtained were extrapolated across the whole island to display the expected fishing pressure and conservation status more widely. The fishing pressure and conservation status models were spatially related; zones where fishing pressure was high coincided with zones in the unhealthiest ecological state. PMID- 24045125 TI - pH and ion strength modulated ionic species loading in mesoporous silica nanoparticles. AB - Mesoporous silica nanoparticles (MSN) have emerged as appealing host materials to accommodate guest molecules for biomedical applications, and recently various methods have been developed to modulate the loading of guest molecules in the silica matrix. Herein, it was demonstrated that pH and ion strength showed great influence on the loading of charged species into the nanoparticles, taking MCM-41 as a host MSN model and methylviologen (MV(2+)) and 1,5-naphthalene disulfonate (NDS(2-)) as typical charged ionic guest molecules. As the pH increased from 3.0 to 8.0, the loading amount of MV(2+) increased gradually, while on the contrary, it decreased gradually for NDS(2-), for the solution pH changed the electrostatic interaction between the silica matrix and the ionic guest molecules. Additionally, the adding of NaCl reduced the electrostatic interaction, which resulted in a decreasing of the electrostatic rejection and electrostatic accumulation for the molecules carrying the same and the opposite charge to the particle respectively. Thus, pH and ion strength can be employed as simple approaches to modulate the loading of charged molecules and permselectivity in MSN. This work has a definite guidance function for molecule loading, transport modulation, controlled release as well as sensors based on MSN. PMID- 24045127 TI - Molecular immune response of the American lobster (Homarus americanus) to the White Spot Syndrome Virus. AB - The adult American lobster (Homarus americanus) is susceptible to few naturally occurring pathogens, and no viral pathogen is known to exist. Despite this, relatively little is known about the H. americanus immune system and nothing is known about its potential viral immune response. Hundreds of rural communities in Atlantic Canada rely on the lobster fishery for their economic sustainability and could be devastated by large-scale pathogen-mediated mortality events. The White Spot Syndrome Virus is the most economically devastating viral pathogen to global shrimp aquaculture production and has been proposed to be capable of infecting all decapod crustaceans including the European Lobster. An in vivo WSSV injection challenge was conducted in H. americanus and WSSV was found to be capable of infecting and replicating within lobsters held at 20 degrees C. The in vivo WSSV challenge also generated the first viral disease model of H. americanus and allowed for the high-throughput examination of transcriptomic changes that occur during viral infection. Microarray analysis found 136 differentially expressed genes and the expression of a subset of these genes was verified using RT-qPCR. Anti-lipopolysaccharide isoforms and acute phase serum amyloid protein A expression did not change during WSSV infection, contrary to previous findings during bacterial and parasitic infection of H. americanus. This, along with the differential gene expression of thioredoxin and trypsin isoforms, provides compelling evidence that H. americanus is capable of mounting an immune response specific to infection by different pathogen classes. PMID- 24045126 TI - Obstructive sleep apnea as a risk factor after shoulder arthroplasty. AB - BACKGROUND: Obstructive sleep apnea (OSA) has been identified as an important risk factor in perioperative orthopaedic surgery outcomes despite limited evidence. Screening systems are being instituted in increasing frequency to prevent morbidity and mortality. Our objective was to determine if patients with OSA have a higher likelihood of postoperative in-hospital complications, length of stay, or increased costs after shoulder arthroplasty. METHODS: We utilized the Nationwide Inpatient Sample (NIS) to analyze 22988 patients undergoing TSA or hemiarthroplasty. Of these patients, 1983 (5.9%) were diagnosed with OSA. Multivariate analysis with logistic regression modeling was used to compare patients with and without OSA for various outcomes. RESULTS: Patients with obstructive sleep apnea had overall similar in-hospital mortality and complications including PE compared with those without OSA. OSA was not associated with increased postoperative charges ($39,741 in patients with OSA vs. $39,334 in those without OSA) and resulted in a shorter length of stay (mean, 2.61 vs. 2.91 days; P < .0001). CONCLUSION: This study does not support OSA as a significant risk factor for in-hospital morbidity and mortality following shoulder arthroplasty. Our results suggest that a diagnosis of OSA does not increase perioperative morbidity and mortality including perioperative complications. Given the results of this study, further research is warranted to attempt to keep patient screening costs down while optimizing outcomes. PMID- 24045128 TI - Molecular phylogenetic and positive selection analysis of Japanese encephalitis virus strains isolated from pigs in China. AB - Japanese encephalitis virus (JEV) is one of the most important virus which causes encephalitis. This disease is most prevalent in the south, southeast and the east region of Asia. In this study, two JEV strains, named JEV/SW/GD/01/2009 and JEV/SW/GZ/09/2004, were isolated from aborted fetuses and seminal fluid of pigs in China. To determine the characteristic of these virus isolates, the virulence of two newly JEV isolates was investigated, the result evidenced that the JEV/SW/GD/01/2009 did not kill mice, while the JEV/SW/GZ/09/2004 displayed neurovirulence with 0.925log10 p.f.u./LD50. Additionally, the full genome sequences of JEV were determined and compared with other known JEV strains. Results demonstrated that the genome of two JEV isolates was 10,976 nucleotides (nt) in length. As compared to the Chinese vaccine strain SA14-14-2, the JEV/SW/GD/01/2009 and the JEV/SW/GZ/09/2004 showed 99.7% and 97.5% identity at the nucleotide level, 99.6% and 96.7% identity at the amino acid level, respectively. Phylogenetic analysis, based on the full-length genome revealed that two JEV isolates were all clustered into genotype III compared to the reference strains. Furthermore, selection analyses revealed that dominant selective pressure acting on the JEV genome was purifying selection. Four sites under positive selection were identified: codon 521 (amino acid E-227), 2296 (amino acid NS4b-24), 3048 (amino acid NS5-521) and 3055 (amino acid NS5-528). Amino acid E-227 was proved to be related to neurovirulence. Taken together, the molecular epidemiology and functional of positively selected amino acid sites of two newly JEV isolates were fully understood, which might be helpful to predict possible changes in virulence. PMID- 24045129 TI - Short term outcome of term newborns with unexpected umbilical cord arterial pH between 7.000 and 7.100. AB - BACKGROUND: The relationship between cord arterial pH (CA-pH) > 7.000 and the neonatal outcome is not clear. AIMS: To evaluate if asymptomatic infants born with unexpected cord arterial pH (CA-pH) between 7.000 and 7.100 develop clinical, biochemical, and instrumental signs of hypoxic cerebral, renal, and heart failure more frequently than symptomatic infants. STUDY DESIGN: Term infants with CA-pH of 7.000-7.100 and appropriate birth weight were prospectively and consecutively enrolled and classified as asymptomatic, when they had no resuscitation, early respiratory distress or early abnormal neurologic signs, and symptomatic infants. Clinical, biochemical, and instrumental signs of hypoxic cerebral, renal, and heart failure were evaluated in the two groups. RESULTS: A total of 53 infants were enrolled. Twenty-eight (53%) were asymptomatic. CA-pH was similar in both the groups, while the cTnI serum concentration in the first day of life and the occurrence of poor feeding were higher in the symptomatic than in asymptomatic infants. An arterial lactate level of >= 4.1 mmol/l measured in the first hour of life was an independent risk factor for the development of a symptomatic course. CONCLUSIONS: In our population the majority of infants born with a CA-pH between 7.000 and 7.100 were asymptomatic and would not have needed immediate admission to the neonatal care unit. Symptomatic infants showed a higher occurrence of subclinical heart injury and poor feeding. PMID- 24045130 TI - Nutrition and growth in infants born preterm from birth to adulthood. AB - Prevention of extra-uterine growth retardation is of extreme importance, as the achievement of adequate growth has been associated with a favorable neurodevelopmental outcome through childhood. In addition, as disturbances in growth that take place early in life may affect adult health, a full understanding of the growth trajectory of very-low-birth-weight infants is also advisable. This review will focus attention on the nutritional strategies proposed during hospital admission and after discharge in order to limit extra uterine growth retardation in preterm infants. The dynamic changes that characterize growth of infants born preterm from birth up to adulthood will also be addressed. PMID- 24045131 TI - Cytokines in umbilical cord blood and the impact of labor events in low-risk term pregnancies. AB - BACKGROUND: Inflammatory mechanisms involved in the onset and progression of labor at term may affect the fetal compartment impacting neonatal outcomes. STUDY DESIGN: Umbilical cord blood collected from umbilical cords after delivery of the fetus and again after delivery of the placenta in low-risk non-laboring and laboring patients was analyzed for blood gases/pH and multiple cytokines. RESULTS: Umbilical cord levels of IL-6, IL-8 and IL-10 were increased 6, 2 and 1.5 fold, respectively, in laboring patients without placental inflammation, and for IL-6 and IL-8 a further 12 and 6 fold, respectively, in laboring patients showing histologic chorioamnionitis, but with no evident effect of nuchal cord with FHR decelerations, fetal acidemia, nor of labor duration. For laboring patients, umbilical vein levels of IL-10 and MIP-1alpha were increased compared to arterial levels indicating net flux from the placenta, while umbilical artery levels of IL-6 and IL-8 were increased compared to venous levels indicating net flux from fetal sources. Placental cord levels of IL-6, IL-10, MIP-1alpha and MIP 1beta were also increased compared to respective umbilical cord levels, confirming placental release of these cytokines into cord blood after delivery of the fetus. CONCLUSION: Labor in low-risk patients at term will result in increased cytokines in umbilical cord blood and moreso when associated with histologic chorioamnionitis with the potential to impact neonatal outcomes. IL-6 and IL-8 as the primary cytokines increased in cord blood may act synergistically in promoting the inflammatory response with labor, and are likely released from both placental and fetal tissues contributing to widespread distribution through the fetal circulation. PMID- 24045132 TI - Preterm birth, respiratory failure and BPD: which neonatal management? AB - Preterm birth is a significant problem in the world regarding perinatal mortality and morbidity in the long term, especially bronchopulmonary dysplasia (BPD). Premature delivery is often associated to failure in transition to create an early functional residual capacity (FRC), since many preterm babies need frequently respiratory support. The first and most effective preventive measure to reduce the incidence of BPD is represented by the attempt to avoid preterm birth. Whenever this fails, the prevention of every known risk factors for BPD should start in the delivery room and should be maintained in the NICU through the use of tailored management of high-risk infants. PMID- 24045133 TI - Genetic and phytochemical analysis of the in vitro regenerated Pilosocereus robinii by ISSR, SDS-PAGE and HPLC. AB - Pilosocereus robinii is a rare species which is experiencing sudden population collapse. Identifying and developing effective conservation and management strategies to halt the forestall extinction of this species is crucial. The present study was conducted to assess the best conditions for in vitro propagation of this plant in regard to its morphogenic, genetic as well as the chemical potentials. A successful in vitro propagation system of P. robinii has been developed. MS hormone-free medium induced the best root morphogenic potential. The plants were acclimatized in the greenhouse at 100% survival rate. Besides, the somaclonal variations between the in vitro raised plants were analyzed using PCR-ISSR markers and SDS-PAGE protein, where the regenerated explants on MS medium supplemented with TDZ were the highest in inducing new specific marker bands. Sh6 ISSR primer showed the highest polymorphism value, 81.8% with 33 total amplified fragments, while Sh3 ISSR primer showed the lowest value with polymorphic percentage of 14.3%. Furthermore, SDS-PAGE protein analysis showed no variation in protein pattern of the studied treatments. On the other side, HPLC analysis of the in vitro plantlets extracts has shown that 2iP based treatments were the highest in organic acids accumulation, while the phenolic constituents' accumulation was found to reach its peak in the BA based treatments. PMID- 24045134 TI - Treatment - mother-infant relationship psychotherapy. AB - In this chapter, we briefly describe several modes of parent-infant psychotherapy, an efficient way of treating parent-infant relationship disorders. We then focus on treatment for postnatally depressed mothers. Perinatal depression defines an episode of major or minor depression occurring during pregnancy or the first 12 months after birth. Attachment-based parent-infant interventions are particularly helpful in the context of maternal perinatal depression, as postpartum depression has a special link with unresolved trauma and losses in the mother's childhood. The goal of treatment is to improve the mother's mood but also to prevent or reduce the effects of postpartum depression on the child. Infants of perinatally depressed mothers are at risk for a large array of negative outcomes, including attachment insecurity (particularly disorganised attachment), social-skills deficits, cognitive difficulties, behaviour problems, and later psychopathology. The 'ghosts in the nursery' concept refers to the painful or disturbed early childhood experiences coming from the mother's past, which haunt the present mother-infant relationship. By addressing the mother's unresolved attachment conflicts (in her relationship to her own parents), it is believed that the development of a more adaptive parenting and a more secure and less disorganised attachment between the mother and her infant is facilitated. Changes in parent- infant interaction are not dependent on the port of entry (e.g. child's behaviour, parent's representation or parent-infant relationship). The perspective of attachment is key to install a therapeutic alliance with parents. PMID- 24045136 TI - Nanocontainer-based corrosion sensing coating. AB - The present paper reports on the development of new sensing active coating on the basis of nanocontainers containing pH-indicating agent. The coating is able to detect active corrosion processes on different metallic substrates. The corrosion detection functionality based on the local colour change in active cathodic zones results from the interaction of hydroxide ions with phenolphthalein encapsulated in mesoporous nanocontainers which function as sensing nanoreactors. The mesoporous silica nanocontainers are synthesized and loaded with pH indicator phenolphthalein in a one-stage process. The resulting system is mesoporous, which together with bulkiness of the indicator molecules limits their leaching. At the same time, penetration of water molecules and ions inside the container is still possible, allowing encapsulated phenolphthalein to be sensitive to the pH in the surrounding environment and outperforming systems when an indicator is directly dispersed in the coating layer.The performed tests demonstrate the pH sensitivity of the developed nanocontainers being dispersed in aqueous solutions. The corrosion sensing functionality of the protective coatings with nanocontainers are proven for aluminium- and magnesium-based metallic substrates. As a result, the developed nanocontainers show high potential to be used in a new generation of active protective coatings with corrosion-sensing coatings. PMID- 24045135 TI - Scientific considerations for evaluating cancer bioassays conducted by the Ramazzini Institute. AB - BACKGROUND: The Ramazzini Institute (RI) has completed nearly 400 cancer bioassays on > 200 compounds. The European Food Safety Authority (EFSA) and others have suggested that study design and protocol differences between the RI and other laboratories by may contribute to controversy regarding cancer hazard findings, principally findings on lymphoma/leukemia diagnoses. OBJECTIVE: We aimed to evaluate RI study design, protocol differences, and accuracy of tumor diagnoses for their impact on carcinogenic hazard characterization. METHODS: We analyzed the findings from a recent Pathology Working Group (PWG) review of RI procedures and tumor diagnoses, evaluated consistency of RI and other laboratory findings for chemicals identified by the RI as positive for lymphoma/leukemia, and examined evidence for a number of other issues raised regarding RI bioassays. The RI cancer bioassay design and protocols were evaluated in the context of relevant risk assessment guidance from international authorities. DISCUSSION: Although the PWG identified close agreement with RI diagnoses for most tumor types, it did not find close agreement for lymphoma/leukemia of the respiratory tract or for neoplasms of the inner ear and cranium. Here we discuss a) the implications of the PWG findings, particularly lymphoma diagnostic issues; b) differences between RI studies and those from other laboratories that are relevant to evaluating RI cancer bioassays; and c) future work that may help resolve some concerns. CONCLUSIONS: We concluded that a) issues related to respiratory tract infections have complicated diagnoses at that site (i.e., lymphoma/leukemia), as well as for neoplasms of the inner ear and cranium, and b) there is consistency and value in RI studies for identification of other chemical related neoplasia. PMID- 24045137 TI - Nonsuicidal self-injury disorder: clinician and expert ratings. AB - Nonsuicidal self-injury (NSSI) is a growing clinical and public health problem that affects individuals from all age groups, most prominently young adults. NSSI involves numerous methods and functions. NSSI has long been associated with borderline personality disorder (BPD), and in fact, it is only referenced among the diagnostic criteria of BPD in the DSM-IV-TR. However, recent studies have provided strong evidence that NSSI occurs outside of BPD. For these reasons, a diagnosis of nonsuicidal self-injury is included in DSM-5 Section-III as a condition that requires further study. The primary purpose of the present study was to identify whether the proposed DSM-5 NSSI criteria adequately reflect the symptoms of a prototypic individual who engages in self-injury. Clinicians in private practice and expert NSSI researchers (n=119) were asked to describe their familiarity and agreement with the proposed DSM-5 NSSI criteria, as well as the degree to which each proposed criterion is a prototypic symptom. Overall, most participants reported that the proposed DSM-5 criteria for NSSI accurately captured the behavior of the prototypic self-injurer. The results of this study provide incremental support for the proposed DSM-5 NSSI diagnostic criteria. PMID- 24045138 TI - Firearm injuries and children: a policy statement of the American Pediatric Surgical Association. PMID- 24045139 TI - A safe technique for radical antegrade modular pancreatosplenectomy with venous resection for pancreatic cancer. PMID- 24045140 TI - Outcomes of synthetic mesh in contaminated ventral hernia repairs. AB - BACKGROUND: Given the questionable long-term durability of biologic meshes, additional prosthetic options for ventral hernia repairs (VHR) in contaminated fields are necessary. Recent evidence suggests improved bacterial resistance of reduced-weight, large-pore synthetics, giving a potential mesh alternative for repair of contaminated hernias. We aimed to evaluate the clinical outcomes of 2 institutions' experience implanting lightweight polypropylene synthetic mesh in clean-contaminated and contaminated fields. STUDY DESIGN: Open VHRs performed with polypropylene mesh in the retro-rectus position in clean-contaminated and contaminated fields were evaluated. Primary outcomes parameters included surgical site infection, surgical site occurrence, mesh removal, and hernia recurrence. RESULTS: One hundred patients (50 male, 50 female) with a mean age of 60 +/- 13 years and a mean body mass index (calculated as kg/m(2)) of 32 +/- 9.3 met inclusion criteria. There were 42 clean-contaminated and 58 contaminated cases. The incidence of surgical site occurrence was 26.2% in clean-contaminated cases and 34% in contaminated cases. The 30-day surgical site infection rate was 7.1% for clean-contaminated cases and 19.0% for contaminated cases. There were a total of 7 recurrences with a mean follow-up of 10.8 +/- 9.9 months (range 1 to 63 months). Mesh removal was required in 4 patients: 2 due to early anastomotic leaks, 1 due to stomal disruption and retraction in a morbidly obese patient, and 1 from a long-term enterocutaneous fistula. CONCLUSIONS: Although perhaps not yet considered standard of care in the United States, we have demonstrated favorable infection, recurrence, and mesh removal rates associated with the use of synthetic mesh in contaminated VHR. PMID- 24045141 TI - Safety of outpatient laparoscopic cholecystectomy in the elderly: analysis of 15,248 patients using the NSQIP database. AB - BACKGROUND: Studies have shown that laparoscopic cholecystectomy (LC) in an ambulatory setting is a safe alternative to the traditional overnight hospital stay. However, there are limited data on the morbidity and mortality of outpatient LC in elderly patients. We evaluated the safety of ambulatory LC in the elderly and identified risk factors that predict inpatient admission. STUDY DESIGN: A retrospective analysis was performed using the American College of Surgeon's NSQIP database between 2007 and 2010. The database was searched for patients older than 65 years of age who underwent elective LC at all participating hospitals in the United States. Data from 15,248 patients were collected and we compared patients who underwent ambulatory procedures with those patients who were admitted for an inpatient stay. RESULTS: Seven thousand four hundred and ninety-nine (48.9%) patients were ambulatory and 7,799 (51.1%) were nonambulatory. Postoperative complications included mortality (0.2% vs 1.5%; p < 0.001), stroke (0.1% vs 0.3%; p < 0.001), myocardial infarction (0.1% vs 0.6%; p < 0.001), pulmonary embolism (0.1% vs 0.3%; p = 0.005), and sepsis (0.2% vs 0.7%; p < 0.001) for ambulatory and nonambulatory cases, respectively. We identified significant independent predictors of inpatient admission and mortality, including congestive heart failure, American Society of Anesthesiologists class 4, bleeding disorder, and renal failure requiring dialysis. CONCLUSIONS: We believe ambulatory LCs are safe in elderly patients as demonstrated by low complication rates. We identified multiple risk factors that might warrant inpatient hospital admission. PMID- 24045142 TI - Choice of intravenous antibiotic prophylaxis for colorectal surgery does matter. AB - BACKGROUND: The Surgical Care Improvement Program endorses mandatory compliance with approved intravenous prophylactic antibiotics; however, oral antibiotics are optional. We hypothesized that surgical site infection (SSI) rates may vary depending on the choice of antibiotic prophylaxis. STUDY DESIGN: A retrospective cohort study of elective colorectal procedures using Veterans Affairs Surgical Quality Improvement Program (VASQIP) and SSI outcomes data was linked to the Office of Informatics and Analytics (OIA) and Pharmacy Benefits Management (PBM) antibiotic data from 2005 to 2009. Surgical site infection rates by type of IV antibiotic agent alone (IV) or in combination with oral antibiotic (IV + OA) were determined. Generalized estimating equations were used to examine the association between type of antibiotic prophylaxis and SSI for the entire cohort and stratified by use of oral antibiotics. RESULTS: After 5,750 elective colorectal procedures, 709 SSIs (12.3%) developed within 30 days. Oral antibiotic + IV (n = 2,426) had a lower SSI rate than IV alone (n = 3,324) (6.3% vs 16.7%, p < 0.0001). There was a significant difference in the SSI rate based on type of preoperative IV antibiotic given (p <= 0.0001). Generalized estimating equations adjusting for significant covariates of age, body mass index, procedure work relative value units, and operation duration demonstrated an independent protective effect of oral antibiotics (odds ratio [OR] 0.37, 95% CI 0.29 to 0.46), as well as increased rates of SSI associated with ampicillin/sulbactam (OR 2.21, 95% CI 1.37 to 3.56) and second generation cephalosporins (cefoxitin, OR 2.50, 95% CI 1.83 to 3.42; cefotetan, OR 2.70, 95% CI 1.72 to 4.22) when compared with first generation cephalosporin/metronidazole. CONCLUSIONS: The choice of IV antibiotic was related to the SSI rate; however, oral antibiotics were associated with reduced SSI rate for every antibiotic class. PMID- 24045143 TI - Nodal status, number of lymph nodes examined, and lymph node ratio: what defines prognosis after resection of colon adenocarcinoma? AB - BACKGROUND: Lymph node ratio (LNR) has been proposed as an optimal staging variable for colorectal cancer. However, the interactive effect of total number of lymph nodes examined (TNLE) and the number of metastatic lymph nodes (NMLN) on survival has not been well characterized. STUDY DESIGN: Patients operated on for colon cancer between 1998 and 2007 were identified from the Surveillance, Epidemiology, and End Results database (n = 154,208) and randomly divided into development (75%) and validation (25%) datasets. The association of the TNLE and NMLN on survival was assessed using the Cox proportional hazards model with terms for interaction and nonlinearity with restricted cubic spline functions. Findings were confirmed in the validation dataset. RESULTS: Both TNLE and NMLN were nonlinearly associated with survival. Patients with no lymph node metastasis had a decrease in the risk of death for each lymph node examined up to approximately 25 lymph nodes, while the effect of TNLE was negligible after approximately 10 negative lymph nodes (NNLN) in those with lymph node metastasis. The hazard ratio varied considerably according to the TNLE for a given LNR when LNR >= 0.5, ranging from 2.88 to 7.16 in those with an LNR = 1. The independent effects of NMLN and NNLN on survival were summarized in a model-based score, the N score. When patients in the validation set were categorized according to the N stage, the LNR, and the N score, only the N score was unaffected by differences in the TNLE. CONCLUSIONS: The effect of the TNLE on survival does not have a unique, strong threshold (ie, 12 lymph nodes). The combined effect of NMLN and TNLE is complex and is not appropriately represented by the LNR. The N score may be an alternative to the N stage for prognostication of patients with colon cancer because it accounts for differences in nodal samples. PMID- 24045145 TI - Health discourse and within-group stigma in professional BDSM. AB - This article directly deals with health and stigma within practices of erotic labor. Scant previous literature has focused on erotic laborers' perceptions of stigma and the ways in which regimes of stigmatization operate within their particular social worlds. I use the commercial BDSM (Bondage, Discipline, Sadism, Masochism) "dungeon" as a strategic research site to investigate these workers' conceptions and management of their own stigma, and I find that discourses about stigma are inextricably entwined with concerns about health and wellbeing. Data are derived from ethnographic fieldwork with professional dominatrices ("pro dommes") who work in New York City and San Francisco as well as in-depth interviews conducted between September 2007 and April 2008. Counter to stereotypes of erotic laborers as violent or as vectors of disease, BDSM workers are in fact not only concerned about safety but professionally invested in it, reinforcing it through an identity politics of hierarchies of erotic labor. There are multiple implications of this work for public perception and policy implications that could only be brought to light through the ethnographic method. PMID- 24045144 TI - Cystic neoplasms of the liver: biliary cystadenoma and cystadenocarcinoma. PMID- 24045146 TI - Beijing ambient particle exposure accelerates atherosclerosis in ApoE knockout mice. AB - BACKGROUND: Air pollution is associated with significant adverse health effects including increased cardiovascular morbidity and mortality. However research on the cardiovascular effect of "real-world" exposure to ambient particulate matter (PM) in susceptible animal model is very limited. In this study, we aimed to investigate the association between Beijing ambient particle exposure and the atherosclerosis development in the apolipoprotein E knockout mice (ApoE(-/-) mice). METHODS: Two parallel exposure chambers were used for whole body exposure among ApoE knockout mice. One of the chambers was supplied with untreated ambient air (PM group) and the other chamber was treated with ambient air filtered by high-efficiency particulate air (HEPA) filter (FA group). Twenty mice were divided into two groups and exposed to ambient PM (n=10 for PM group) or filtered air (n=10 for FA group) for two months from January 18th to March 18th, 2010. During the exposure, the mass concentrations of PM2.5 and PM10 in the two chambers were continuously monitored. Additionally, a receptor source apportionment model of chemical mass balance using 19 organic tracers was applied to determine the contributions of sources on the PM2.5 in terms of natural gas, diesel vehicle, gasoline vehicle, coal burning, vegetable debris, biomass burning and cooking. At the end of the two-month exposure, biomarkers of oxidative stress, inflammation and lipid metabolism in bronchoalveolar lavage fluid (BAL) and blood samples were determined and the plaque area on the aortic endothelium was quantified. RESULTS: In the experiment, the concentrations of PM10 and PM2.5 in PM chamber were 99.45MUg/m(3) and 61.0MUg/m(3) respectively, while PM2.5 in FA chamber was 17.6MUg/m(3). Source apportionment analysis by organic tracers showed that gasoline vehicle (39.9%) and coal burning (24.3%) emission were the two major sources contributing to the mass concentration of PM2.5 in Beijing. Among the ApoE knockout mice, the PM group were significantly higher than the FA group in terms of serum total cholesterol, low-density lipoprotein, tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein as well as TNF-alpha and interleukin-6 in BAL. Also the total antioxidant capacity and oxidized low density lipoprotein were significantly different between the two groups. In addition, pathological analysis of aortic arch reveals that the plaques area in the PM group increased significantly compared to the FA group. CONCLUSIONS: Our results demonstrated that ambient PM exposure could induce considerable oxidative stress and systemic inflammation in ApoE knockout mice and contribute to the progression of atherosclerosis. PMID- 24045147 TI - Mixed monolayers of DOPC and palmitic acid at the liquid-air interface. AB - The interactions between 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and palmitic acid (PA) in mixed monolayers were investigated through surface pressure measurements, fluorescence microscopy (FM) and atomic force microscopy (AFM). The miscibility of two components and the interactions between DOPC and PA in the mixed monolayers were accessed by analyzing surface pressure (pi)-area (A) isotherms. It was found that there were both positive deviations for excess molecular area and excess Gibbs energy, which suggests the interaction is repulsive in all case and the strongest repulsive occurs at XPA=0.5 ratio. The FM and AFM images showed that there were discernible phase separations at selected surface pressures. The increase of surface pressure and the phenomenon that the PA-enriched domains have been connected to form much larger platforms are in agreement with the thermodynamic results. PMID- 24045149 TI - Controversy on the role of FoxP3+ regulatory T cells in fibrogenesis in chronic hepatitis C virus infections. PMID- 24045148 TI - Characterization of a human and murine mPGES-1 inhibitor and comparison to mPGES 1 genetic deletion in mouse models of inflammation. AB - Microsomal prostaglandin E synthase-1 (mPGES-1) inhibition has been suggested as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. We characterized a selective inhibitor of mPGES-1 activity (compound III) and studied its impact on the prostanoid profile in various models of inflammation. Compound III is a benzoimidazole, which has a submicromolar IC50 in both human and rat recombinant mPGES-1. In cellular assays, it reduced PGE2 production in A549 cells, mouse macrophages and blood, causing a shunt to the prostacyclin pathway in the former two systems. Lastly, we assayed compound III in the air pouch model to verify its impact on the prostanoid profile and compare it to the profile obtained in mPGES-1 k.o. mice. As opposed to mPGES-1 genetic deletion, which attenuated PGE2 production and caused a shunt to the thromboxane pathway, mPGES-1 inhibition with compound III reduced PGE2 production and tended to decrease the levels of other prostanoids. PMID- 24045150 TI - Met as a therapeutic target in HCC: facts and hopes. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its burden is expected to increase further in the next years. In spite of the advances of classical therapies, such as surgery, transplantation, use of radiofrequency and transarterial embolization, the prognosis of this neoplasm has not considerably improved over the past few years. The advent of targeted therapies and the approval of the systemic treatment of advanced HCC with the kinase inhibitor sorafenib have provided some hope for the future. Even if the molecular mechanisms responsible for the onset and progression of HCC are still largely unknown, new therapeutic targets have recently come to the spotlight. One of these targets is the tyrosine kinase receptor for the Hepatocyte Growth Factor, encoded by the MET gene, known to promote tumor growth and metastasis in many human organs. In this review we will summarize the contrasting results obtained in vitro (in HCC cell lines) and in animal experimental models and we will also try to analyze the reasons for the opposite findings, suggesting that the HGF/MET axis can have either a promoting or a suppressive role in the development of HCC. We will also reconsider the evidence of activation of this pathway in human HCCs and discuss the results of the clinical trials performed with MET inhibitors. The final purpose is to better clarify which can be the role of MET as a therapeutic target in HCC. PMID- 24045152 TI - Brd4 shields chromatin from ATM kinase signaling storms. AB - Upon activation, ataxia telangiectasia mutated (ATM) kinase rapidly phosphorylates hundreds of proteins, setting off chaotic signaling storms from areas of damaged chromatin. Recent work by Kaidi and Jackson and Floyd et al. advance our knowledge of the mechanisms that initiate or limit ATM kinase signaling storms at chromatin. PMID- 24045151 TI - A phase II study of cixutumumab (IMC-A12, NSC742460) in advanced hepatocellular carcinoma. AB - BACKGROUND & AIMS: IGF-IR is implicated in hepatic carcinogenesis. This and preliminary evidence of biological activity of anti-IGF-1R monoclonal antibody cixutumumab in phase I trials prompted this phase II study. METHODS: Patients with advanced HCC, Child-Pugh A-B8, received cixutumumab 6mg/kg weekly, in a Simon two-stage design study, with the primary endpoints being 4-month PFS and RECIST-defined response rate. Tissue and circulating markers plus different HCC scoring systems were evaluated for correlation with PFS and OS. RESULTS: As a result of pre-specified futility criteria, only stage 1 was accrued: N=24: median age 67.5 years (range 49-83), KPS 80% (70-90%), 20 males (83%), 9 stage III (37%)/15 stage IV (63%), 18 Child-Pugh A (75%), 11 HBV (46%)/10 HCV (42%)/11 alcoholic cirrhosis (46%)/2 NASH (8%), 11 (46%) diabetic. Median number of doses: 7 (range 1-140). Grade 3/4 toxicities >10% included: diabetes, elevated liver function tests, hyponatremia, and lymphopenia. Four-month PFS was 30% (95% CI 13 48), and there were no objective responses. Median overall survival was 8 months (95% CI 5.8-14). IGF-R1 staining did not correlate with outcome. Elevated IGFBP-1 correlated with improved PFS (1.2 [95% CI 1-1.4]; p 0.009) and OS (1.2 [95% CI 1.1-1.4]; p 0.003). CONCLUSIONS: Cixutumumab monotherapy did not have clinically meaningful activity in this unselected HCC population. Grade 3-4 hyperglycemia occurred in 46% of patients. Elevated IGFBP-1 correlated with improved PFS and OS. PMID- 24045153 TI - A cancer-associated mutation in atypical protein kinase Ciota occurs in a substrate-specific recruitment motif. AB - Atypical protein kinase Ciota (PKCiota) has roles in cell growth, cellular polarity, and migration, and its abundance is frequently increased in cancer. We identified a protein interaction surface containing a dibasic motif (RIPR) that bound a distinct subset of PKCiota substrates including lethal giant larvae 2 (LLGL2) and myosin X, but not other substrates such as Par3. Further characterization demonstrated that Arg471 in this motif was important for binding to LLGL2, whereas Arg474 was critical for interaction with myosin X, indicating that multiple complexes could be formed through this motif. A somatic mutation of the dibasic motif (R471C) was the most frequent mutation of PKCiota in human cancer, and the intact dibasic motif was required for normal polarized epithelial morphogenesis in three-dimensional cysts. Thus, the R471C substitution is a change-of-function mutation acting at this substrate-specific recruitment site to selectively disrupt the polarizing activity of PKCiota. PMID- 24045155 TI - Main individual and product characteristics influencing in-mouth flavour release during eating masticated food products with different textures: mechanistic modelling and experimental validation. AB - A mechanistic model predicting flavour release during oral processing of masticated foods was developed. The description of main physiological steps (product mastication and swallowing) and physical mechanisms (mass transfer, product breakdown and dissolution) occurring while eating allowed satisfactory simulation of in vivo release profiles of ethyl propanoate and 2-nonanone, measured by Atmospheric Pressure Chemical Ionization Mass Spectrometry on ten representative subjects during the consumption of four cheeses with different textures. Model sensitivity analysis showed that the main parameters affecting release intensity were the product dissolution rate in the mouth, the mass transfer coefficient in the bolus, the air-bolus contact area in the mouth and the respiratory frequency. Parameters furthermore affecting release dynamics were the mastication phase duration, the velopharynx opening and the rate of saliva incorporation into the bolus. Specific retention of 2-nonanone on mucosa was assumed to explain aroma release kinetics and confirmed when gaseous samples were consumed. PMID- 24045154 TI - The transcription factor CREB enhances interleukin-17A production and inflammation in a mouse model of atherosclerosis. AB - The enzyme 15-lipoxygenase (15-LO) plays a role in atherogenesis (also known as atherosclerosis), but the underlying mechanisms are unclear. We found that 15(S) hydroxyeicosatetraenoic acid [15(S)-HETE], the major 15-LO-dependent metabolite of arachidonic acid, stimulated the production of reactive oxygen species (ROS) by monocytes through the xanthine oxidase-mediated activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. ROS production led to the Syk-, Pyk2-, and mitogen-activated protein kinase (MAPK)-dependent production of the proinflammatory cytokine interleukin-17A (IL-17A) in a manner that required the transcription factor CREB (cyclic adenosine monophosphate response element binding protein). In addition, this pathway was required for the 15(S)-HETE dependent migration and adhesion of monocytes to endothelial cells. Consistent with these observations, we found that peritoneal macrophages from apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (a mouse model of atherosclerosis) exhibited increased xanthine oxidase and NADPH oxidase activities; ROS production; phosphorylation of Syk, Pyk2, MAPK, and CREB; and IL-17A production compared to those from similarly fed ApoE-/-:12/15-LO-/- mice. These events correlated with increased lipid deposits and numbers of monocytes and macrophages in the aortic arches of ApoE-/- mice, which resulted in atherosclerotic plaque formation. Together, these observations suggest that 15(S)-HETE exacerbates atherogenesis by enhancing CREB-dependent IL-17A production and inflammation. PMID- 24045156 TI - Cardiovascular dysfunction in symptomatic primary hyperparathyroidism and its reversal after curative parathyroidectomy: results of a prospective case control study. AB - BACKGROUND: Cardiovascular mortality in primary hyperparathyroidism (PHPT) is attributed to myocardial and endothelial dysfunction. In this prospective, case control study we assessed cardiovascular dysfunction in patients with symptomatic PHPT and its reversal after successful parathyroidectomy. METHODS: Fifty-six patients with symptomatic PHPT underwent two-dimensional echocardiography, tissue Doppler (diastolic function assessment), serum N-terminal pro-brain natriuretic peptide (s-NTproBNP, a myocardial damage marker), and endothelial- and smooth muscle-dependent vasodilatory response (vascular dysfunction) studies before, 3, and 6 months after parathyroidectomy; 25 age-matched controls were studied similarly. RESULTS: Patients had greater left ventricular mass (192 +/- 70 vs. 149 +/- 44 g; P = .006), interventricular septal thickness (10.8 +/- 2.5 vs. 9.0 +/- 1.6 mm; P = .001), posterior wall thickness (9.9 +/- 2.0 vs. 8.6 +/- 2.2 mm; P = .004), and diastolic dysfunction (lower E/A trans-mitral flow velocity ratio [1.0 +/- 0.4 vs. 1.3 +/- 0.4; P = .01). Patients had greater s-NTproBNP (4,625 +/ 1,130 vs. 58 +/- 49 pg/mL; P = .002) and lower endothelial-mediated vasodilation (9.3 +/- 8.6 vs. 11.7 +/- 6.3%; P = .03) and smooth muscle-mediated vasodilation (20.1 +/- 17.9 vs. 23.8 +/- 11.2%; P = .01). Improvements in left ventricular mass, systolic and diastolic function, and smooth muscle-mediated vasodilation were noted from 3 to 6 months after parathyroidectomy. Endothelial-mediated vasodilation did not improve significantly. S-NTproBNP levels mirrored echocardiographic changes with a substantial, sustained decrease. Results were similar in hypertensive and normotensive patients. CONCLUSION: Symptomatic PHPT patients have substantial cardiac and vascular dysfunction, which improve by 6 months after parathyroidectomy. Objective cardiovascular evaluation may improve outcomes in symptomatic PHPT patients. PMID- 24045157 TI - Use of prophylactic antibiotics following tube thoracostomy for blunt chest trauma in the prevention of empyema and pneumonia. PMID- 24045158 TI - Extent, consequences and economic burden of road traffic crashes in Iran. AB - BACKGROUND: Road Traffic Injuries (RTIs) as a result of road traffic crashes (RTCs) rank as the leading cause of death, disability and property loss worldwide, especially in low and middle-income countries. This study aims to analyze the costs of RTCs in Iran. METHODS: A standard human capital approach was used to estimate the costs. Costs included medical, administrative and funeral costs, property damage, production lost and intangible costs. Data about the number of deaths and injuries resulting from RTIs between 20 March 2009 and 20 March 2010 was obtained from two national databases designed at the Center for Disaster Management and Medical Emergencies (CDMME) and the Legal Medicine Organization (LMO), respectively. The severity and medical costs of injuries were identified by reviewing 400 medical records that were selected randomly from patients who were admitted to two large trauma centers in Shariati and Sina hospitals in Tehran province. Moreover, information about production lost, property damage, rehabilitation cost, intangible costs and administration costs were collected by review of current evidence and consulting with expert opinion. RESULTS: In total 806,922 RTIs and 22,974 deaths resulted from the RTCs in the study period. The total cost of RTCs was about 72,465 billion Rials (7.2 billion US Dollars), which amounts to 2.19% of Iran's Gross Domestic Production (GDP). Direct costs were 3,516 billion Rials (around 48.6 % of the total costs), following by 24,785 billion Rials (around 34.2 % of the total costs) for production lost and 12,513 billion Rials (around 17.2 % of the total costs) for intangible costs. CONCLUSIONS: This study indicated that the burden of both RTCs and RTIs in Iran is substantial. Moreover, RTCs have significant economic consequences and are a large drain on healthcare resources. PMID- 24045159 TI - Ossification in an extra-intradural spinal meningioma-pathologic and surgical vistas. AB - BACKGROUND CONTEXT: Intradural and intratumorous ossification in spinal meningiomas are rare compared to their cranial counterparts. Extradural extension of the spinal meningioma is not uncommon. To the best of our knowledge, the ossification in an extra-intradural spinal meningioma is not yet reported in the literature. PURPOSE: The authors report a rare case of an extra-intradural spinal meningioma with ossification and calcification. The review of literature including the surgical challenges and the histologic variations as well as histogenesis of the ossified spinal meningioma is discussed. STUDY DESIGN: Case report and review of the literature. METHODS: A 61-year-old woman presented with complaints of numbness and weakness for 3 years, and gait disturbances for 6 months. Magnetic resonance imaging revealed a mass compressing the spinal cord at the T4 level. RESULTS: Complete resection of the tumor was achieved with coagulation and partial resection of the dura. Histopathological examination demonstrated a psammomatous spinal meningioma with intratumorous and intradural mature lamellar bone formation, complete with marrow and hematopoietic cells. The patient is asymptomatic at 3-year postoperative follow-up. CONCLUSIONS: Despite adherence of the ossified mass to the dura, arachnoid, and spinal cord, complete atraumatic resection of the mass was possible with favorable surgical outcome. In addition to calcification as a likely forerunner of ossification in the psammomatous subtype of meningioma, metaplastic differentiation of neoplastic cells to osseous and hematopoietic component might play a crucial role. PMID- 24045160 TI - Epithelioid hemangioma of the spine: a case series of six patients and review of the literature. AB - BACKGROUND CONTEXT: Epithelioid hemangioma (EH) of bone is a benign vascular tumor that can be locally aggressive. It rarely arises in the spine, and the optimum management of EH of the vertebrae is not well delineated. PURPOSE: The report describes our experience treating six patients with EH of the spine in an effort to document the treatment of the rare spinal presentation. STUDY DESIGN: This study is designed as a retrospective cohort study. PATIENT SAMPLE: A continuous series of patients with the diagnosis of EH of the spine who presented at our institution. OUTCOME MEASURES: The clinical and radiographic follow-up of the patient population is documented. METHODS: The Bone Sarcoma Registry at our institution was used to obtain a list of all patients diagnosed with EH of the spine. Medical records, radiographs, and pathology reports were retrospectively reviewed in all cases. Only biopsy-proven cases were included. RESULTS: The six patients included five men and one woman who ranged in age from 20 to 58 years (with an average age of 40 years). The follow-up available for all six patients ranged from 6 to 115 (average 46.8) months. All patients presented with lytic vertebral body lesions. Five patients presented with pain secondary to their tumor, and the tumor in the sixth patient was found incidentally during the workup for a herniated disc. Three patients required surgical management for instability secondary to the destructive nature of their tumors, and two other patients required emergent decompression secondary to spinal cord compression by the tumor. The sixth patient was treated expectantly after biopsy confirmation. Three patients received postoperative radiation therapy as gross tumor remained after surgery. Three patients had gross total resections and did not receive postoperative radiation. Preoperative embolization was used in four patients. One patient continued to have back pain after surgery and radiation and another continued to have ataxia after surgery and radiation. No tumor locally recurred or progressed. CONCLUSIONS: Our data suggest that EH of the spine can be locally aggressive and lead to instability and cord compression. Surgery is required in such instances; however, observation should be considered in patients without instability or cord compression. PMID- 24045161 TI - Myopericytoma of the thoracic spine: a case report and review of literature. AB - BACKGROUND CONTEXT: Myopericytoma is a recently proposed term to describe a group of tumors originating from perivascular myoid cells. The tumor is most commonly located in the subcutaneous tissues and dermis of the extremities. Myopericytoma involving the skeletal system is a very rare entity, with only two such cases previously reported in literature. PURPOSE: To present only the third reported case of myopericytoma of the spine along with a review of literature. STUDY DESIGN: Case report with and review of literature. METHODS: We report the case of a 50-year-old woman who presented with pain in the back with gradual onset of paraparesis. Magnetic resonance imaging showed ill-defined signal changes in the body and posterior elements of the vertebrae with epidural soft tissue mass encasing the spinal cord. RESULTS: The patient underwent excision of the lesion with spinal fusion followed by a short course of radiotherapy. The patient recovered functional power after surgery, and at 32-month follow-up, there is no radiological evidence of recurrence of the lesion. CONCLUSIONS: Myopericytoma should be considered in the differential diagnosis of lytic lesions of the spine. Surgery is curative; however, a short course of chemotherapy or radiotherapy may be required to prevent recurrent disease in case of incomplete tumor excision. PMID- 24045162 TI - Environment and Health - Bridging South, North, East and West. Basel, Switzerland 19-23 August 2013. AB - EHP is pleased to present the abstracts from the 2013 conference Environment and Health-Bridging South, North, East and West, held 19-23 August 2013 in Basel, Switzerland, and hosted by the Swiss Tropical and Public Health Institute. The conference was a joint meeting of the International Society for Environmental Epidemiology (ISEE), the International Society of Exposure Science (ISES), and the International Society of Indoor Air Quality and Climate (ISIAQ). More than 1,700 participants from all continents and over 70 countries attended. The abstracts are searchable by abstract number, author name, and any word that appears anywhere in the abstract. Use the Filtered Search option to narrow search results by author-assigned keyword. Suggested citation: Abstracts of the 2013 Conference of the International Society of Environmental Epidemiology (ISEE), the International Society of Exposure Science (ISES), and the International Society of Indoor Air Quality and Climate (ISIAQ), August 19-23, 2013, Basel, Switzerland. 2013. Environ Health Perspect. Read how the organizers reduced the environmental footprint of the conference in "The Vision of a Green(er) Scientific Conference," an editorial in the August issue of EHP by Nino Kunzli and Martin Roosli, conference chairs, and Martina S. Ragettli, chair of the local organizing committee "green club." For more information on the conference, be sure to check out the press release and photos from the Swiss Tropical and Public Health Institute. PMID- 24045164 TI - Hybrid Ag@TiO2 core-shell nanostructures with highly enhanced photocatalytic performance. AB - A new synthetic approach has been developed to prepare silver@titanium dioxide (Ag@TiO2) core-shell nanostructures with controllable size, shape, crystal phase and function at ambient conditions (e.g. in water, <=100 degrees C). This approach shows a few unique features, including short reaction time (a few minutes) for forming core-shell nanostructures, no requirement of high temperature calcinations for generating TiO2 (e.g. at ~100 degrees C in our case), tunable TiO2 shell thickness, high yield and good reproducibility. The experimental results show that the Ag@TiO2 core-shell nanostructures exhibit excellent photocatalytic activity compared to the commercial TiO2 (P25) and Ag doped TiO2 nanocomposite in the degradation of organic dye molecules (e.g. methyl orange) with ultraviolet (UV) irradiation. This could be attributed to the large surface area of TiO2 nanoparticles for maximum harvesting of UV light, mixed anatase and rutile crystalline phases in the TiO2 shell and the effective charge separation between Ag and TiO2 that can reduce the possible recombination of electron-hole (e(-)-h(+)) pairs within TiO2 generated under UV radiation. To further understand the charge separation situation within Ag-TiO2 composites, theoretical simulation (e.g. density functional theory, DFT) was employed in this study. The DFT simulation results indicate that for the Ag@TiO2 core-shell nanostructures, photo-generated electrons transfer readily from the external TiO2 layer to the internal Ag layer with heavy accumulation compared to those doping Ag on TiO2 surfaces, which may reduce the recombination of e(-)-h(+) pairs and thus enhance the photocatalytic efficiency. The findings may open a new strategy to synthesize TiO2-based photocatalysts with highly enhanced efficiency for environmental remediation applications. PMID- 24045163 TI - Genome-wide evidence for speciation with gene flow in Heliconius butterflies. AB - Most speciation events probably occur gradually, without complete and immediate reproductive isolation, but the full extent of gene flow between diverging species has rarely been characterized on a genome-wide scale. Documenting the extent and timing of admixture between diverging species can clarify the role of geographic isolation in speciation. Here we use new methodology to quantify admixture at different stages of divergence in Heliconius butterflies, based on whole-genome sequences of 31 individuals. Comparisons between sympatric and allopatric populations of H. melpomene, H. cydno, and H. timareta revealed a genome-wide trend of increased shared variation in sympatry, indicative of pervasive interspecific gene flow. Up to 40% of 100-kb genomic windows clustered by geography rather than by species, demonstrating that a very substantial fraction of the genome has been shared between sympatric species. Analyses of genetic variation shared over different time intervals suggested that admixture between these species has continued since early in speciation. Alleles shared between species during recent time intervals displayed higher levels of linkage disequilibrium than those shared over longer time intervals, suggesting that this admixture took place at multiple points during divergence and is probably ongoing. The signal of admixture was significantly reduced around loci controlling divergent wing patterns, as well as throughout the Z chromosome, consistent with strong selection for Mullerian mimicry and with known Z-linked hybrid incompatibility. Overall these results show that species divergence can occur in the face of persistent and genome-wide admixture over long periods of time. PMID- 24045165 TI - Cladribine interferes with IL-1beta synaptic effects in experimental multiple sclerosis. AB - Alterations of glutamate-mediated synaptic transmission occur in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Here we investigated whether intracerebroventricular (Icv) administration of cladribine has effects on EAE. Icv infusion of cladribine reduced the clinical deficits of EAE mice and reversed EAE-induced enhancement of excitatory postsynaptic current (sEPSC) frequency, a neurophysiological measure of glutamatergic synaptopathy associated with central inflammation. Cladribine failed to interfere with EAE-induced microglial and astroglial activation, but blocked EAE synaptic alterations by interfering with interleukin-1beta effects. Cladribine possesses neuroprotective properties in experimental MS that are independent of its peripheral immunosuppressant action. PMID- 24045166 TI - Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. AB - We characterized GBM patients' tumor and systemic immune contexture with aim to reveal the mechanisms of immunological escape, their impact on patient outcome, and identify targets for immunotherapy. Increased CD3(+) T-cell infiltration was associated with prolonged survival independent of age, MGMT promoter methylation and post-operative treatment that implies potential for immunotherapy for GBM. Several mechanisms of escape were identified: within the tumor microenvironment: induced CD8(+)CD28(-)Foxp3(+) Tregs that may tolerize antigen presenting cells, elevated CD73 and CD39 ectonucleotidases that suppress T-cell function, and at the systemic level: elevated IL-10 levels in serum, diminished helper T-cell counts, and upregulated inhibitory CTLA-4. PMID- 24045167 TI - Management of spinal tuberculosis: a systematic review and meta-analysis. AB - OBJECTIVE: A systematic review and meta-analysis of randomized controlled trials (RCTs) studying the clinical benefit of chemotherapy with surgical intervention over chemotherapy alone for the treatment of spinal tuberculosis. METHODS: Relevant RCTs were identified by computerized database searches. Trial eligibility and methodological quality were assessed and data were extracted and analysed using odds ratios with 95% confidence intervals. The primary outcome measure was kyphosis angle. RESULTS: The literature search identified two RCTs conducted in the 1970s and 1980s and a Cochrane Database Systematic Review published in 2006. There were no significant between-group differences in kyphosis angle, bony fusion, bone loss or development of neurological deficit. CONCLUSIONS: There is no obvious statistically significant clinical precedence to suggest that routine surgery will improve the prognosis of patients with spinal tuberculosis. PMID- 24045168 TI - Relationship between epicardial adipose tissue volume measured using coronary computed tomography angiography and atherosclerotic plaque characteristics in patients with severe coronary artery stenosis. AB - AIM: To investigate the relationship between epicardial adipose tissue (EAT) volume and coronary plaque composition. METHODS: EAT volume (measured using coronary computed tomography angiography) and coronary plaque characteristics were assessed on a per-segment basis (modified 15-segment American College of Cardiology/American Heart Association classification) in patients with severe coronary artery stenosis. Coronary plaques were classified into four types: 1, calcified plaques; 2, mixed plaques (calcification dominant); 3, mixed plaques (non-calcification dominant); and 4, non-calcified plaques. The gold standard for luminal stenosis was conventional coronary angiography. RESULTS: In 365 patients (mean age 58.7 +/- 8.0 years), EAT volume was 169.85 +/- 29.94 ml. There were no significant between-group differences in patient characteristics. Statistically significant differences in EAT volume between non-calcified and calcified plaque groups were observed. EAT volume showed a positive correlation with total cholesterol and low-density-lipoprotein cholesterol, and a very weak correlation with age, triglyceride, body mass index and high-density-lipoprotein cholesterol. CONCLUSION: EAT volume was higher in the presence of non-calcified and mixed plaques in patients with >=50% severe coronary artery stenosis. PMID- 24045169 TI - High efficiency chlorine removal from polyvinyl chloride (PVC) pyrolysis with a gas-liquid fluidized bed reactor. AB - In this research a gas-liquid fluidized bed reactor was developed for removing chlorine (Cl) from polyvinyl chloride (PVC) to favor its pyrolysis treatment. In order to efficiently remove Cl within a limited time before extensive generation of hydrocarbon products, the gas-liquid fluidized bed reactor was running at 280 320 degrees C, where hot N2 was used as fluidizing gas to fluidize the molten polymer, letting the molten polymer contact well with N2 to release Cl in form of HCl. Experimental results showed that dechlorination efficiency is mainly temperature dependent and 300 degrees C is a proper reaction temperature for efficient dechlorination within a limited time duration and for prevention of extensive pyrolysis; under this temperature 99.5% of Cl removal efficiency can be obtained within reaction time around 1 min after melting is completed as the flow rate of N2 gas was set around 0.47-0.85 Nm(3) kg(-1) for the molten PVC. Larger N2 flow rate and additives in PVC would enhance HCl release but did not change the final dechlorination efficiency; and excessive N2 flow rate should be avoided for prevention of polymer entrainment. HCl is emitted from PVC granules or scraps at the mean time they started to melt and the melting stage should be taken into consideration when design the gas-liquid fluidized bed reactor for dechlorination. PMID- 24045170 TI - ICT reuse in socio-economic enterprises. AB - In Europe, socio-economic enterprises such as charities, voluntary organisations and not-for-profit companies are involved in the repair, refurbishment and reuse of various products. This paper characterises and analyses the operations of socio-economic enterprises that are involved in the reuse of Information and Communication Technology (ICT) equipment. Using findings from a survey, the paper specifically analyses the reuse activities of socio-economic enterprises in the U.K. from which Europe-wide conclusions are drawn. The amount of ICT products handled by the reuse organisations is quantified and potential barriers and opportunities to their operations are analysed. By-products from reuse activities are discussed and recommendations to improve reuse activities are provided. The most common ICT products dealt with by socio-economic enterprises are computers and related equipment. In the U.K. in 2010, an estimated 143,750 appliances were reused. However, due to limitations in data, it is difficult to compare this number to the amount of new appliances that entered the U.K. market or the amount of waste electrical and electronic equipment generated in the same period. Difficulties in marketing products and numerous legislative requirements are the most common barriers to reuse operations. Despite various constraints, it is clear that organisations involved in reuse of ICT could contribute significantly to resource efficiency and a circular economy. It is suggested that clustering of their operations into "reuse parks" would enhance both their profile and their products. Reuse parks would also improve consumer confidence in and subsequently sales of the products. Further, it is advocated that industrial networking opportunities for the exchange of by-products resulting from the organisations' activities should be investigated. The findings make two significant contributions to the current literature. One, they provide a detailed insight into the reuse operations of socio-economic enterprises. Previously unavailable data has been presented and analysed. Secondly, new evidence about the by products/materials resulting from socio-economic enterprises' reuse activities has been obtained. These contributions add substantially to our understanding of the important role of reuse organisations. PMID- 24045171 TI - A cumulative energy demand indicator (CED), life cycle based, for industrial waste management decision making. AB - Life cycle thinking is a good approach to be used for environmental decision support, although the complexity of the Life Cycle Assessment (LCA) studies sometimes prevents their wide use. The purpose of this paper is to show how LCA methodology can be simplified to be more useful for certain applications. In order to improve waste management in Catalonia (Spain), a Cumulative Energy Demand indicator (LCA-based) has been used to obtain four mathematical models to help the government in the decision of preventing or allowing a specific waste from going out of the borders. The conceptual equations and all the subsequent developments and assumptions made to obtain the simplified models are presented. One of the four models is discussed in detail, presenting the final simplified equation to be subsequently used by the government in decision making. The resulting model has been found to be scientifically robust, simple to implement and, above all, fulfilling its purpose: the limitation of waste transport out of Catalonia unless the waste recovery operations are significantly better and justify this transport. PMID- 24045172 TI - Evaluation of a classification method for biodegradable solid wastes using anaerobic degradation parameters. AB - We studied the biochemical and anaerobic degradation characteristics of 29 types of materials to evaluate the effects of a physical composition classification method for degradable solid waste on the computation of anaerobic degradation parameters, including the methane yield potential (L0), anaerobic decay rate (k), and carbon sequestration factor (CSF). Biochemical methane potential tests were conducted to determine the anaerobic degradation parameters of each material. The results indicated that the anaerobic degradation parameters of nut waste were quite different from those of other food waste and nut waste was classified separately. Paper was subdivided into two categories according to its lignin content: degradable paper with lignin content of <0.05 g g VS(-1), and refractory paper with lignin content >0.15 g g VS(-1). The L0, k, and CSF parameters of leaves, a type of garden waste, were similar to those of grass. This classification method for degradable solid waste may provide a theoretical basis that facilitates the more accurate calculation of anaerobic degradation parameters. PMID- 24045173 TI - Performance of a biogas upgrading process based on alkali absorption with regeneration using air pollution control residues. AB - This work analyzes the performance of an innovative biogas upgrading method, Alkali absorption with Regeneration (AwR) that employs industrial residues and allows to permanently store the separated CO2. This process consists in a first stage in which CO2 is removed from the biogas by means of chemical absorption with KOH or NaOH solutions followed by a second stage in which the spent absorption solution is contacted with waste incineration Air Pollution Control (APC) residues. The latter reaction leads to the regeneration of the alkali reagent in the solution and to the precipitation of calcium carbonate and hence allows to reuse the regenerated solution in the absorption process and to permanently store the separated CO2 in solid form. In addition, the final solid product is characterized by an improved environmental behavior compared to the untreated residues. In this paper the results obtained by AwR tests carried out in purposely designed demonstrative units installed in a landfill site are presented and discussed with the aim of verifying the feasibility of this process at pilot-scale and of identifying the conditions that allow to achieve all of the goals targeted by the proposed treatment. Specifically, the CO2 removal efficiency achieved in the absorption stage, the yield of alkali regeneration and CO2 uptake resulting for the regeneration stage, as well as the leaching behavior of the solid product are analyzed as a function of the type and concentration of the alkali reagent employed for the absorption reaction. PMID- 24045174 TI - Urine screening for patients with developmental disabilities detected a patient with creatine transporter deficiency due to a novel missense mutation in SLC6A8. AB - Creatine transporter deficiency (CTD) is an example of X-linked intellectual disability syndromes, caused by mutations in SLC6A8 on Xq28. Although this is the second most frequent genetic cause of intellectual disabilities in Europe or America after Fragile X syndrome, information on the morbidity of this disease is limited in Japan. Using the HPLC screening method we have established recently, we examined samples of urine of 105 patients (73 males and 32 females) with developmental disabilities at our medical center. And we have found a family with three ID boys with a novel missense mutation in SLC6A8. This is the second report of a Japanese family case of CTD. A systematic diagnostic system of this syndrome should be established in Japan to enable us to estimate its frequency and treatment. PMID- 24045175 TI - Acute toxicity, biochemical and haematological study of Aframomum melegueta seed oil in male Wistar albino rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aframomum melegueta is a popular medicinal plant in Nigeria believed to have many agents acting in different ways to bring about human health benefits. This study aimed to determine the acute toxicity, identify some phytochemicals known to be present in this plant and the possible effects on lipid profile, haematological indices and biomarker of prostate and cardiac dysfunction. MATERIALS AND METHODS: Twenty four Wistar rats (284-326 g) were used in four groups of six animals. Group 1 (control) received normal saline; groups 2, 3 and 4, received intraperitoneal injection of 27.39, 54.77 and 82.16 mg/kg body weight of the extract respectively for 7 days. Haematological and biochemical parameters were measured. RESULTS: Alkaloids, flavonoids, saponins, tannins, cardiac glycosides, terpenoids and steroids were identified in this plant extract. The LD50 was 273.86 mg/kg body weight. Prostate Specific Antigen (PSA) decreased significantly in group 2. Testosterone increased significantly in all the test groups compared to the control. Cardiac troponin I (0 ng/dl) was recorded for the test groups while the control had 1.69 +/- 0.12 ng/dl. Lipid profile results showed increase in HDL and decrease in total cholesterol and LDL cholesterol. Haemoglobin (Hb) and Red Blood Cells count (RBC) decreased significantly in group 4. White Blood Cells count (WBC), Mean Cell Volume (MCV), Mean Cell Haemoglobin (MCH) and Mean Cell Haemoglobin Concentration (MCHC) did not change significantly. CONCLUSION: Aframomum melegueta seed oil has the potential of ameliorating benign prostatic hyperplasia (BPH) and cardiac dysfunction as indicated by testosterone, PSA, lipid profile and troponin I levels. The LD50 of 273.86 mg/kg body weight is indicative of mild toxicity. The lower than normal Hb, RBC confirms the possibility of toxicity. PMID- 24045176 TI - Assessment of pyrrolizidine alkaloid-induced toxicity in an in vitro screening model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pyrrolizidine alkaloids (PAs) are a group of heterocyclic phytotoxins present in a wide range of plants. The consumption of PA containing medicinal herbs or PA-contaminated foodstuffs has long been reported to cause human hepatotoxicity. However, the degrees of hepatotoxicity of different PAs are unknown, which makes it difficult to determine a universal threshold of toxic dose of individual PAs for safe regulation of PA-containing natural products. The aim of the present study is to develop a simple and convenient in vitro model to assess the hepatotoxicity of different PAs. MATERIAL AND METHODS: Six common cytotoxicity assays were used to evaluate the hepatotoxicity of different PAs in human hepatocellular carcinoma HepG2 cells. RESULTS: The combination of MTT and bromodeoxyuridine incorporation (BrdU) assays demonstrated to be a suitable method to evaluate the toxic potencies of various PAs in HepG2 cells, and the results indicated that otonecine-type PA (clivorine: IC20=0.013 +/- 0.004 mM (MTT), 0.066 +/- 0.031 mM (BrdU)) exhibited significantly higher cytotoxic and anti-proliferative effects than retronecine-type PA (retrorsine: IC20=0.27 +/- 0.07 mM (MTT), 0.19 +/- 0.03 mM (BrdU)). While as expected, the known less toxic platyphylline-type PA (platyphylline: IC20=0.85 +/ 0.11 mM (MTT), 1.01 +/- 0.40 mM (BrdU)) exhibited significantly less toxicity. The different cytotoxic and anti-proliferative potencies of various PAs in the same retronecine-type could also be discriminated by using the combined MTT and BrdU assays. In addition, the developed assays were further utilized to test alkaloid extract of Gynura segetum, a senecionine and seneciphylline-containing herb, the overall cytotoxicity of two PAs in the extract was comparable to that of these two PAs tested individually. CONCLUSION: Using the developed in vitro model, the cytotoxicity of different PAs and the extract of a PA-containing herb were investigated in parallel in one system, and their different hepatotoxic potencies were determined and directly compared for the first time. The results suggested that the developed model has a great potential to be applied for the quick screening of the toxicity of PAs and PA-containing natural products. PMID- 24045177 TI - Safed musli (Chlorophytum borivilianum): a review of its botany, ethnopharmacology and phytochemistry. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Safed musli (Chlorophytum borivilianum) is an eminent medicinal plant of India and considered as a 'white gold' or 'divya aushad' in Indian systems of medicine. In Ayurveda, Chlorophytum borivilianum belongs to the group of "Vajikaran Rasayana" corroborated to its rejuvenating, aphrodisiac, natural sex tonic properties and effective in alleviating sexual disorders. It is largely used as ethnic medicine by local healers of indigenous communities of India. MATERIALS AND METHODS: A thorough bibliographic investigation was carried out by analyzing worldwide accepted scientific data base (Pub Med, SciFinder, Scopus and Web of Science), thesis, recognized books, non impact and non indexed journals. RESULTS: Traditionally, Chlorophytum borivilianum is well known for treating male impotency in India. The multi therapeutic and nutritional importance of Chlorophytum borivilianum is attributed to the rich source of phytochemicals particularly saponins. Recently, Chlorophytum borivilianum has gained a well established domestic (Indian) and international market for being the herbal alternative of "Viagra" without any side effects. Under the trade name 'Nai Chetna', the state government of Gujarat, India, has launched a novel potency drug from Chlorophytum borivilianum. Modern pharmacological studies of Chlorophytum borivilianum have demonstrated a wide range of pharmacological activities, most importantly aphrodisiac, immunomodulatory and anticancer activities. CONCLUSION: The increased commercial exploitation of Chlorophytum borivilianum and low productivity of this endangered plant has raised the concern over its conservation. It has been envisaged that efforts should be made to standardize, encourage and popularize the cultivation of Chlorophytum borivilianum as a commercial crop. The analysis of previous pharmacological investigations suggested lack of substantial scientific evidences in various studies and do not stand the test of critical assessment. Due to high economic value, Chlorophytum borivilianum has also encountered a problem of adulteration with closely resembling medicinally inferior species. The studies available on toxicity, safety and quality of Chlorophytum borivilianum are inadequate for providing information on commercial utilization. Thus, the present review summarizes comprehensive information on Chlorophytum borivilianum and possible scope for future research to fill the existing lacunae on its different aspects of the study. PMID- 24045178 TI - AACR Cancer Progress Report 2013. PMID- 24045179 TI - Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. AB - PURPOSE: Neuroblastoma is a pediatric cancer that continues to exact significant morbidity and mortality. Recently, a number of cell-cycle proteins, particularly those within the Cyclin D/CDK4/CDK6/RB network, have been shown to exert oncogenic roles in neuroblastoma, suggesting that their therapeutic exploitation might improve patient outcomes. EXPERIMENTAL PROCEDURES: We evaluated the effect of dual CDK4/CDK6 inhibition on neuroblastoma viability using LEE011 (Novartis Oncology), a highly specific CDK4/6 inhibitor. RESULTS: Treatment with LEE011 significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis at nanomolar concentrations (mean IC50 = 307 +/- 68 nmol/L in sensitive lines). LEE011 caused cell-cycle arrest and cellular senescence that was attributed to dose-dependent decreases in phosphorylated RB and FOXM1, respectively. In addition, responsiveness of neuroblastoma xenografts to LEE011 translated to the in vivo setting in that there was a direct correlation of in vitro IC50 values with degree of subcutaneous xenograft growth delay. Although our data indicate that neuroblastomas sensitive to LEE011 were more likely to contain genomic amplification of MYCN (P = 0.01), the identification of additional clinically accessible biomarkers is of high importance. CONCLUSIONS: Taken together, our data show that LEE011 is active in a large subset of neuroblastoma cell line and xenograft models, and supports the clinical development of this CDK4/6 inhibitor as a therapy for patients with this disease. Clin Cancer Res; 19(22); 6173-82. (c)2013 AACR. PMID- 24045180 TI - Overcoming IGF1R/IR resistance through inhibition of MEK signaling in colorectal cancer models. AB - PURPOSE: Results from clinical trials involving resistance to molecularly targeted therapies have revealed the importance of rational single-agent and combination treatment strategies. In this study, we tested the efficacy of a type 1 insulin-like growth factor receptor (IGF1R)/insulin receptor (IR) tyrosine kinase inhibitor, OSI-906, in combination with a mitogen-activated protein (MAP) ERK kinase (MEK) 1/2 inhibitor based on evidence that the MAP kinase pathway was upregulated in colorectal cancer cell lines that were resistant to OSI-906. EXPERIMENTAL DESIGN: The antiproliferative effects of OSI-906 and the MEK 1/2 inhibitor U0126 were analyzed both as single agents and in combination in 13 colorectal cancer cell lines in vitro. Apoptosis, downstream effector proteins, and cell cycle were also assessed. In addition, the efficacy of OSI-906 combined with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) was evaluated in vivo using human colorectal cancer xenograft models. RESULTS: The combination of OSI-906 and U0126 resulted in synergistic effects in 11 of 13 colorectal cancer cell lines tested. This synergy was variably associated with apoptosis or cell cycle arrest in addition to molecular effects on prosurvival pathways. The synergy was also reflected in the in vivo xenograft studies following treatment with the combination of OSI-906 and selumetinib. CONCLUSIONS: Results from this study demonstrate synergistic antiproliferative effects in response to the combination of OSI-906 with an MEK 1/2 inhibitor in colorectal cancer cell line models both in vitro and in vivo, which supports the rational combination of OSI 906 with an MEK inhibitor in patients with colorectal cancer. Clin Cancer Res; 19(22); 6219-29. (c)2013 AACR. PMID- 24045181 TI - CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. AB - PURPOSE: Upregulation of CD137 (4-1BB) on recently activated CD8(+) T cells has been used to identify rare viral or tumor antigen-specific T cells from peripheral blood. Here, we evaluated the immunobiology of CD137 in human cancer and the utility of a CD137-positive separation methodology for the identification and enrichment of fresh tumor-reactive tumor-infiltrating lymphocytes (TIL) or tumor-associated lymphocytes (TAL) from ascites for use in adoptive immunotherapy. EXPERIMENTAL DESIGN: TILs from resected ovarian cancer or melanoma were measured for surface CD137 expression directly or after overnight incubation in the presence of tumor cells and homeostatic cytokines. CD137(pos) TILs were sorted and evaluated for antitumor activity in vitro and in vivo. RESULTS: Fresh ovarian TILs and TALs naturally expressed higher levels of CD137 than circulating T cells. An HLA-dependent increase in CD137 expression was observed following incubation of fresh enzyme-digested tumor or ascites in IL-7 and IL-15 cytokines, but not IL-2. Enriched CD137(pos) TILs, but not PD-1(pos) or PD-1(neg) CD137(neg) cells, possessed autologous tumor reactivity in vitro and in vivo. In melanoma studies, all MART-1-specific CD8(+) TILs upregulated CD137 expression after incubation with HLA-matched, MART-expressing cancer cells and antigen-specific effector function was restricted to the CD137(pos) subset in vitro. CD137(pos) TILs also mediated superior antitumor effects in vivo, compared with CD137(neg) TILs. CONCLUSIONS: Our findings reveal a role for the TNFR-family member CD137 in the immunobiology of human cancer where it is preferentially expressed on tumor reactive subset of TILs, thus rationalizing its agonistic engagement in vivo and its use in TIL selection for adoptive immunotherapy trials. PMID- 24045182 TI - A phase I study of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) in patients with gastrointestinal stromal tumors or soft-tissue sarcomas. AB - PURPOSE: Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRalpha) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). EXPERIMENTAL DESIGN: IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. RESULTS: Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m(2) twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST. CONCLUSIONS: In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy. PMID- 24045183 TI - Hypoxic activation of the PERK/eIF2alpha arm of the unfolded protein response promotes metastasis through induction of LAMP3. AB - PURPOSE: Conditions of poor oxygenation (hypoxia) are present in many human tumors, including cervix cancer, and are associated with increased risk of metastasis and poor prognosis. Hypoxia is a potent activator of the PERK/eIF2alpha signaling pathway, a component of the unfolded protein response (UPR) and an important mediator of hypoxia tolerance and tumor growth. Here, the importance of this pathway in the metastasis of human cervix carcinoma was investigated. EXPERIMENTAL DESIGN: Amplification and expression of LAMP3, a UPR metastasis-associated gene, was examined using FISH and immunofluorescence in a cohort of human cervix tumors from patients who had received oxygen needle electrode tumor oxygenation measurements. To evaluate the importance of this pathway in metastasis in vivo, we constructed a series of inducible cell lines to interfere with PERK signaling during hypoxia and used these in an orthotopic cervix cancer model of hypoxia-driven metastasis. RESULTS: We show that LAMP3 expression in human cervix tumors is augmented both by gene copy number alterations and by hypoxia. Induced disruption of PERK signaling in established orthotopic xenografts resulted in complete inhibition of hypoxia-induced metastasis to the lymph nodes. This is due, in part, to a direct influence of the UPR pathway on hypoxia tolerance. However, we also find that LAMP3 is a key mediator of hypoxia-driven nodal metastasis, through its ability to promote metastatic properties including cell migration. CONCLUSION: These data suggest that the association between hypoxia, metastasis, and poor prognosis is due, in part, to hypoxic activation of the UPR and expression of LAMP3. Clin Cancer Res; 19(22); 6126-37. (c)2013 AACR. PMID- 24045184 TI - Molecular imaging of death receptor 5 occupancy and saturation kinetics in vivo by humanized monoclonal antibody CS-1008. AB - PURPOSE: CS-1008 (tigatuzumab; phase I/II), an antihuman death receptor 5 (DR5) agonist, induces apoptosis and has cytotoxic activity against human cancer cell lines. This study reports on the preclinical validation of (111)In-labeled anti DR5 humanized antibody CS-1008 as a diagnostic tool to study the DR5 occupancy in patients with cancer and establish dose ranges for receptor saturation kinetics in vivo. EXPERIMENTAL DESIGN: CS-1008 was radiolabeled and characterized for DR5 binding and labeling efficiency on TRAIL-sensitive DR5-positive colorectal cancer cells (COLO 205 and WiDr). Pharmacokinetic and biodistribution studies were conducted in BALB/c nu/nu mice bearing COLO 205, WiDr, or DR5-negative CT26 colon tumors. Planar gamma camera imaging and computerized tomography (CT) images were obtained to study receptor occupancy in vivo. RESULTS: Scatchard analysis showed high and specific binding affinity (Kd, 1.05 +/- 0.12 nmol/L) of (111)In-labeled CS-1008. (111)In-labeled CS-1008 was specifically taken up in mice bearing COLO 205 and WiDr tumors with prolonged tumor retention (26.25 +/- 2.85%ID/g vs. 12.20 +/- 2.24 at 168 hours post injection; n = 5, SD), and uptake correlated both with DR5 expression on tumor cells and antitumor activity. DR5 saturation was shown in vivo via both biodistribution studies and planar gamma camera imaging/CT imaging of (111)In-labeled CS-1008. Saturation of DR5 corresponded to maximal in vivo antitumor efficacy. CONCLUSIONS: Imaging of DR5 receptor occupancy in vivo correlates with tumor concentration and in vivo efficacy, and is a novel molecular imaging technique that can be used to determine receptor occupancy and effective dose levels of DR5 agonist antibodies in the clinic. PMID- 24045185 TI - Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer. AB - PURPOSE: Amplification of MYC is one of the most common genetic alterations in lung cancer, contributing to a myriad of phenotypes associated with growth, invasion, and drug resistance. Murine genetics has established both the centrality of somatic alterations of Kras in lung cancer, as well as the dependency of mutant Kras tumors on MYC function. Unfortunately, drug-like small molecule inhibitors of KRAS and MYC have yet to be realized. The recent discovery, in hematologic malignancies, that bromodomain and extra-terminal (BET) bromodomain inhibition impairs MYC expression and MYC transcriptional function established the rationale of targeting KRAS-driven non-small cell lung cancer (NSCLC) with BET inhibition. EXPERIMENTAL DESIGN: We performed functional assays to evaluate the effects of JQ1 in genetically defined NSCLC cell lines harboring KRAS and/or LKB1 mutations. Furthermore, we evaluated JQ1 in transgenic mouse lung cancer models expressing mutant kras or concurrent mutant kras and lkb1. Effects of bromodomain inhibition on transcriptional pathways were explored and validated by expression analysis. RESULTS: Although JQ1 is broadly active in NSCLC cells, activity of JQ1 in mutant KRAS NSCLC is abrogated by concurrent alteration or genetic knockdown of LKB1. In sensitive NSCLC models, JQ1 treatment results in the coordinate downregulation of the MYC-dependent transcriptional program. We found that JQ1 treatment produces significant tumor regression in mutant kras mice. As predicted, tumors from mutant kras and lkb1 mice did not respond to JQ1. CONCLUSION: Bromodomain inhibition comprises a promising therapeutic strategy for KRAS-mutant NSCLC with wild-type LKB1, via inhibition of MYC function. Clinical studies of BET bromodomain inhibitors in aggressive NSCLC will be actively pursued. Clin Cancer Res; 19(22); 6183-92. (c)2013 AACR. PMID- 24045186 TI - Assessment of the shape of the inferior alveolar canal as a marker for increased risk of injury to the inferior alveolar nerve at third molar surgery: a prospective study. AB - PURPOSE: Morphologic evaluation of computed tomographic images is an important assessment tool before surgical removal of the lower third molar (LM3). The aim of this study was to ascertain whether the shape of the inferior alveolar canal (IAC) is a reliable predictor for inferior alveolar nerve (IAN) injury during M3 surgery. MATERIALS AND METHODS: This prospective study assessed samples with a high risk of IAN injury during M3 surgery based on orthopantomographic examination. The predictor variables were demographic factors (patient's age and gender), anatomic factors (angulation of the tooth), and radiographic factors (cortication status, buccolingual position, shape of the IAC, number of roots, and root shape). The outcome variable was IAN injury. The relation between predictor and outcome variables was analyzed using the Fisher exact test and a logistic regression model. RESULTS: One hundred sixty-nine LM3s (115 patients) were analyzed. IAN injury was observed in 12 of 115 patients and 13 of 169 LM3s (7.7%). All 13 cases with IAN injury exhibited absence of cortication. A dumb bell-shaped IAC was considered a useful predictor for IAN injury (sensitivity, 69.2%; specificity, 84.6%). In cases with absence of cortication, logistic regression analysis indicated that a dumb-bell-shaped IAC was closely related to IAN injury (P = .005). CONCLUSION: The cortication status and shape of the IAC are reliable predictors for IAN injury at M3 surgery. Cases exhibiting absence of cortication and a dumb-bell-shaped IAC should be recognized as presenting a high risk of IAN injury at M3 surgery. PMID- 24045187 TI - Management of bilateral mandibular angle fractures with combined rigid and nonrigid fixation. AB - PURPOSE: There is very limited evaluation of the management of fractures of the bilateral mandibular angles. The purpose of this study was to determine the incidence, etiology, and outcomes of bilateral mandibular angle fractures treated with the transoral application of rigid fixation on one side and nonrigid fixation on the other. PATIENTS AND METHODS: Patients 18 years of age or older with isolated, noncomminuted fractures through the right and left mandibular angles and treated solely with 2.0-mm miniplates through intraoral incisions (and trocar) were collected from 2 sources. Patients treated at Allegheny General Hospital (Pittsburgh, PA) were prospectively collected from August 1, 2006 through December 31, 2012. Patients treated at Parkland Memorial Hospital (Dallas, TX) and University Hospital in San Antonio (San Antonio, TX) from January 1, 1992 through December 31, 2012 were retrospectively added to the sample. Data collected included age, gender, race, cause of fracture, presence or absence of mandibular third molars, occlusal relation documented at last visit, and occurrence and management of complications. Standard descriptive statistics were used and the relation between initial displacement and adequacy of reduction was evaluated with the Fisher exact test. RESULTS: Of 1,565 patients with 2,195 mandibular fractures, 33 (2.1%) presented with bilateral mandibular angle fractures. The average age of the cohort was 25.2 +/- 1.8 years (range, 18 to 48 yr). The mechanisms of injury were assaults (30 of 33, 90.9%), motor vehicle collisions (2 of 33, 6%), and a fall (1 of 33, 3%). Twenty-seven patients (81.8%) had at least 1 mandibular third molar at the time of injury. Three patients (9.1%) had minor postoperative wound problems, with 1 incident (3.0%) of malocclusion. There was no statistically significant relation between the initial displacement and the adequacy of reduction. CONCLUSIONS: Bilateral mandibular angle fractures are a rare traumatic event that may be successfully treated with transoral rigid and nonrigid fixation with 2.0-mm miniplates. PMID- 24045188 TI - Treatment of cT1N0M0 tongue cancer: outcome and prognostic parameters. AB - PURPOSE: The objective of the present study was to summarize the treatment and outcomes of cT1N0M0 tongue cancer for which the management is less defined. MATERIALS AND METHODS: A total of 65 consecutive cases of cT1 tongue cancer were retrospectively reviewed. The Fisher exact, chi(2), and Wilcoxon tests were used to statistically analyze the data. RESULTS: The tumor depth had a significant relation to the presence of neck metastasis (P < .05). A 3-mm cutoff point provided better predictive value, with a sensitivity of 92.9% and specificity of 43.1%. The biopsy depth combined with palpation was accurate in determining the tumor depth preoperatively in 87.7%. On multivariate analysis, only the tumor site (ventral tongue) and the presence of erythroleukoplakia had any significant relation to disease-free survival (P = .010). CONCLUSIONS: Elective neck dissection should be considered for patients with cT1N0 oral tongue squamous carcinoma with a biopsy depth of 3 mm or greater. The biopsy depth, combined with the clinical examination findings, is a useful method to help determine the tumor depth preoperatively. PMID- 24045189 TI - Orthognathic model surgery with LEGO key-spacer. AB - A new technique of model surgery using LEGO plates as key-spacers is described. This technique requires less time to set up compared with the conventional plaster model method. It also retains the preoperative setup with the same set of models. Movement of the segments can be measured and examined in detail with LEGO key-spacers. PMID- 24045190 TI - Intraosseous pseudocarcinomatous hyperplasia associated with chronic osteomyelitis of the mandible: report of two cases. AB - Pseudocarcinomatous hyperplasia (PH) is a marked proliferation of benign squamous epithelium lacking cytologic atypia and pleomorphism in response to chronic stimuli, such as inflammation, infection, irradiation, or an underlying neoplastic reaction. Intraosseous PH is a rare complication of chronic osteomyelitis and mimics squamous cell carcinoma and other squamous neoplasms. This report describes 2 cases of intraosseous PH arising in the mandible. PMID- 24045191 TI - A simple method to treat asymmetric expansions in three-segment surgically assisted rapid maxillary expansion. AB - Surgically assisted rapid maxillary expansion (SARME) is a well-documented and established procedure indicated to treat maxillary transverse deficiencies in the adult patient. Currently, the most popular SARME technique consists of performing a Le Fort I osteotomy without downfracture and a midline osteotomy that splits the maxilla into 2 halves between the central incisors. It is supposed that the 2 halves expand equally during the activation phase. However, after completion of the osteotomies, the expander is supported by only mobile segments; thus, if 1 side remains more resistant than the other, the less resistant side expands more than the other, resulting in asymmetric expansion of the maxilla. When this complication occurs in SARME, an open revision surgery is necessary to remove bone interferences that prevent bone movement on the resistant segment or to create resistance on the other half. An alternative SARME technique consists of performing an osteotomy above the maxillary apical roots, similar to the Le Fort I osteotomy, and bilateral transalveolar osteotomies between the lateral incisors and canines, dividing the maxilla into 3 segments: a central fixed segment containing the incisors and 2 lateral segments that are expanded. Some advantages of 3-segment SARME have been described, such as a less esthetic compromise resulting from the midline diastema, less midline dental papilla compromise, preservation of the nasopalatine bundle, and greater acceptance of the procedure. This article describes another advantage of 3-segment SARME: the possibility to treat asymmetric expansions of the maxilla with an easy and conservative technique. PMID- 24045192 TI - Oral syphilis: a series of 5 cases. AB - Syphilis is an infectious, usually sexually transmitted, disease caused by Treponema pallidum, subspecies pallidum. Because of the increasing prevalence in Europe during the past few years, dentists could be confronted with patients with oral manifestations of syphilis. Because oral lesions are highly contagious, it is vital to make the correct diagnosis quickly to initiate the proper therapy and to interrupt the chain of infection. We present the cases of 5 patients with syphilis-related oral lesions. These cases are representative because of their clinical presentation, age, and gender distribution and the diagnostic approach. The aim of the present report is to emphasize the importance of the dentist knowing and identifying syphilis in different stages to diagnose the disease and institute treatment at an early stage. PMID- 24045193 TI - Adsorption of proteins involved in hydrolysis of lignocellulose on lignins and hemicelluloses. AB - Protein adsorption onto eight lignocellulosic substances (six lignin preparations and two hemicelluloses) was investigated at pH 4.8 and at two different temperatures (4 degrees C and 45 degrees C). The kinetics of the adsorption of cellulase, xylanase, and beta-glucosidase were determined by enzyme activity measurements. The maximum adsorption capacities, the affinity constants and the binding strengths varied widely and were typically higher for the lignins than for the carbohydrates. As indicated by BET and gel permeation chromatography, different substances had widely different surface area, pore size, weight average molecular weight, and polydispersity index, but these properties were difficult to relate to protein binding. In most cases, an increase in temperature from 4 degrees C to 45 degrees C and a low content of carboxylic acid groups, as indicated by Fourier-Transform Infra-Red (FTIR) spectroscopy, resulted in increased protein adsorption capacity, which suggests that hydrophobic interactions play an important role. PMID- 24045194 TI - Synergistic effects of pretreatment and blending on fungi mediated biodegradation of polypropylenes. AB - Environmental issues raise concern on restrict the use of nondegradable polymers and encourage the development of degradable once. This study is carried out was to understand the rate of biodegradation of untreated and pretreated (100 degrees C or UV for 10 days) polypropylene (PP), pro-oxidant blended (MI-PP) and starch blended polypropylenes (ST-PP) with two different fungal strains, Phanerochaete chrysosporium NCIM 1170 (F1) and Engyodontium album MTP091 (F2). About 18.8% and 9.42% gravimetric weight loss and 79% and 57% TGA weight loss (at 400 degrees C) were observed with UV pretreated MI-PP in 1 year with F2 and F1 strains respectively. The amount of lacasse produced by the organism and biomass attached on the polymer surface are correlated with TGA weight loss (0.6-0.93). The formation of extractable oxygenated compounds and unoxidized low-molecular weight hydrocarbons are high in pretreated and blended samples. These results indicate blending and pretreatment strategy leads to an optimal waste-disposal strategy. PMID- 24045195 TI - The influence of sorbitol on the production of cellulases and xylanases in an airlift bioreactor. AB - The production of cellulases and xylanases by Penicillium echinulatum in an airlift bioreactor was evaluated. In batch production, we tested media with isolated or associated cellulose and sorbitol. In fed-batch production, we tested cellulose addition at two different times, 30 h and 48 h. Higher liquid circulation velocities in the downcomer were observed in sorbitol 10 g L(-1) medium. In batch production, higher FPA (filter paper activity) and endoglucanase activities were obtained with cellulose (7.5 g L(-1)) and sorbitol (2.5 g L(-1)), 1.0 U mL(-1) (120 h) and 6.4 U m L(-1) (100 h), respectively. For xylanases, the best production condition was cellulose 10 g L(-1), which achieved 5.5 U mL(-1) in 64 h. The fed-batch process was favorable for obtaining xylanases, but not for FPA and endoglucanases, suggesting that in the case of cellulases, the inducer must be added early in the process. PMID- 24045196 TI - Fumaric acid production in Saccharomyces cerevisiae by simultaneous use of oxidative and reductive routes. AB - In this study, the simultaneous use of reductive and oxidative routes to produce fumaric acid was explored. The strain FMME003 (Saccharomyces cerevisiae CEN.PK2 1CDeltaTHI2) exhibited capability to accumulate pyruvate and was used for fumaric acid production. The fum1 mutant FMME004 could produce fumaric acid via oxidative route, but the introduction of reductive route derived from Rhizopus oryzae NRRL 1526 led to lower fumaric acid production. Analysis of the key factors associated with fumaric acid production revealed that pyruvate carboxylase had a low degree of control over the carbon flow to malic acid. The fumaric acid titer was improved dramatically when the heterologous gene RoPYC was overexpressed and 32 MUg/L of biotin was added. Furthermore, under the optimal carbon/nitrogen ratio, the engineered strain FMME004-6 could produce up to 5.64 +/- 0.16 g/L of fumaric acid. These results demonstrated that the proposed fermentative method is efficient for fumaric acid production. PMID- 24045197 TI - Hydrolysis of ozone pretreated energy grasses for optimal fermentable sugar production. AB - Ozonated energy grass varieties were enzymatically hydrolyzed to establish process parameters for maximum fermentable sugar production. Conditions for ozonolysis were selected on the basis of maximum delignification and glucan retention after pretreatment. To study the effect of lignin degradation products generated during ozonolysis on cellulolytic enzymes, hydrolysis was carried out for washed and unwashed pretreated solids. Washing the solids significantly (p<0.05) enhanced glucan conversion from 34.3% to 100% while delivering glucose yields of 146.2-431.9 mg/g biomass. Highest fermentable sugars were produced when grasses were ozonated for maximum delignification and washed solids were hydrolyzed using 0.1g/g Cellic(r) CTec2. In a comparative study on alkaline pretreatment with 1% NaOH for 60 min, Saccharum arundinaceum exhibited the highest glucan conversion with maximum sugar production of 467.9 mg/g. Although ozonolysis is an effective and environmentally friendly technique for cellulosic sugar production, process optimization is needed to ascertain economic feasibility of the process. PMID- 24045198 TI - Effect of pretreatment on saccharification of sugarcane bagasse by complex and simple enzyme mixtures. AB - Saccharification of sugarcane bagasse pretreated at the pilot-scale with different processes (in combination with steam-explosion) was evaluated. Maximum glucan conversion with Celluclast 1.5L (15-25FPU/g glucan) was in the following order: glycerol/HCl>HCl>H2SO4>NaOH, with the glycerol system achieving ~ 100% conversion. Surprisingly, the NaOH substrate achieved optimum saccharification with only 8 FPU/g glucan. Glucan conversions (3.6-6%) obtained with mixtures of endo-1,4-beta-glucanase (EG) and beta-glucosidase (betaG) for the NaOH substrate were 2-6 times that of acid substrates. However, glucan conversions (15-60%) obtained with mixtures of cellobiohydrolase (CBH I) and betaG on acidified glycerol substrate were 10-30% higher than those obtained for NaOH and acid substrates. The susceptibility of the substrates to enzymatic saccharification was explained by their physical and chemical attributes. Acidified glycerol pretreatment offers the opportunity to simplify the complexity of enzyme mixtures required for saccharification of lignocellulosics. PMID- 24045199 TI - Characteristics of heterotrophic/biofilm-electrode autotrophic denitrification for nitrate removal from groundwater. AB - A heterotrophic/biofilm-electrode autotrophic denitrification reactor (HAD-BER) was developed to improve denitrification efficiency and reduce the consumption of organic carbon source. Maximum nitrate removal efficiency of 99.9% was gained under the optimum current density of 200 mA/m(2). The number of heterotrophic denitrification bacteria (HDB) 2.0 * 10(5) and hydrogen autotrophic denitrification bacteria (ADB) 2.0 * 10(3) in per milliliter biofilm solution were observed by the most probable number (MPN) culture, demonstrating that HDB and ADB coexist in the HAD-BER. The inorganic carbon source for autotrophic denitrification was supplied by the dissolved carbon dioxide (CO2) evolved from the heterotrophic denitrification process, indicating that there was synergistic interaction between the HDB and ADB, i.e., the organic carbon source used for denitrification could be decreased in the HAD-BER. Therefore, the developed HAD BER would be a promising approach for nitrate removal from groundwater. PMID- 24045200 TI - Enhanced methane production from rice straw co-digested with anaerobic sludge from pulp and paper mill treatment process. AB - Rice straw is a widely available lignocellulosic waste with potential for energy recovery through anaerobic digestion. Lignin slows the hydrolysis phase, resulting in low methane recovery and long digestion periods. Although pretreatment is effective, it often requires high energy inputs or chemicals that are not feasible for farm-scale systems. This study investigates a unique co digestion strategy to improve methane yields and reduce digestion times for farm scale systems. By adding both piggery wastewater and paper mill sludge, specific methane yields in laboratory-scale digesters reached the theoretical value for rice straw (i.e. 330LNCH4/kgVS) over the 92-day period. Accelerated hydrolysis of the straw was directly related to the quantity of sludge added. The most stable digester, with sufficient buffering capacity and nutrients, contained equal parts of straw, wastewater and sludge. This approach is feasible for farm-scale applications since it requires no additional energy inputs or changes to existing infrastructure for dry systems. PMID- 24045201 TI - Biological removal of nitrate and ammonium under aerobic atmosphere by Paracoccus versutus LYM. AB - The bacterium isolated from sea sludge Paracoccus versutus LYM was characterized with the ability of aerobic denitrification. Strain LYM performs perfect activity in aerobically converting over 95% NO3(-)-N (approximate 400mg L(-1)) to gaseous products via nitrite with maximum reduction rate 33 mg NO3(-)-N L(-1) h(-1). Besides characteristic of aerobic denitrification, strain LYM was confirmed in terms of the ability to be heterotrophic nitrification and aerobic denitrification (HNAD) with few accumulations of intermediates. After the nitrogen balance and enzyme assays, the putative nitrogen pathway of HNAD could be NH4(+) -> NH2OH -> NO2(-)-> NO3(-), then NO3(-) was denitrified to gaseous products via nitrite. N2 was sole denitrification product without any detection of N2O by gas chromatography. Strain LYM could also simultaneously remove ammonium and additional nitrate. Meanwhile, the accumulated nitrite had inhibitory effect on ammonium reduction rate. PMID- 24045202 TI - The effects of aerobic/anoxic period sequence on aerobic granulation and COD/N treatment efficiency. AB - The effects of period sequence (anoxic-aerobic and aerobic-anoxic) on aerobic granulation from suspended seed sludge, and COD, N removal efficiencies were investigated in two sequencing batch reactors. More stable granules with greater sizes (1.8-3.5mm) were developed in R1 (anoxic-aerobic sequence). Yet, no significant difference was observed between the reactors in terms of removal efficiencies. Under optimum operational conditions, 92-95% COD, 89-90% TAN and 38 46% total nitrogen removal efficiencies were achieved. The anoxic-aerobic period sequence (R1) resulted in almost complete denitrification during anoxic periods while aerobic-anoxic sequence (R2) led to nitrate accumulation due to limited carbon source and further granule disintegration. NH3-N concentration of 15-28 mg/L was found to inhibit COD removal up to 30%. This study also revealed the inhibitory sulfide production during anoxic periods. Sulfate concentration of 52.6-70.2mg/L was found to promote sulfate reduction and sulfide generation (0.24 0.62 mg/L) which, together with free-ammonia, inhibited TAN oxidation by 10-50%. PMID- 24045203 TI - Pilot-scale data provide enhanced estimates of the life cycle energy and emissions profile of algae biofuels produced via hydrothermal liquefaction. AB - Life cycle assessment (LCA) has been used widely to estimate the environmental implications of deploying algae-to-energy systems even though no full-scale facilities have yet to be built. Here, data from a pilot-scale facility using hydrothermal liquefaction (HTL) is used to estimate the life cycle profiles at full scale. Three scenarios (lab-, pilot-, and full-scale) were defined to understand how development in the industry could impact its life cycle burdens. HTL-derived algae fuels were found to have lower greenhouse gas (GHG) emissions than petroleum fuels. Algae-derived gasoline had significantly lower GHG emissions than corn ethanol. Most algae-based fuels have an energy return on investment between 1 and 3, which is lower than petroleum biofuels. Sensitivity analyses reveal several areas in which improvements by algae bioenergy companies (e.g., biocrude yields, nutrient recycle) and by supporting industries (e.g., CO2 supply chains) could reduce the burdens of the industry. PMID- 24045204 TI - Effect of organic matter strength on anammox for modified greenhouse turtle breeding wastewater treatment. AB - Anaerobic ammonium-N removal from modified greenhouse turtle breeding wastewater with different chemical oxygen demand (COD) strengths (194.0-577.8 mg L(-1)) at relatively fixed C/N ratios (~ 2) was investigated using a lab-scale up-flow anaerobic sludge blanket (UASB) anammox reactor. During the entire experiment, the total nitrogen (TN) removal efficiency was about 85% or higher, while the average COD removal efficiency was around 56.5 +/- 7.9%. Based on the nitrogen and carbon balance, the nitrogen removal contribution was 79.6 +/- 4.2% for anammox, 12.7 +/- 3.0% for denitrification+denitritation and 7.7 +/- 4.9% for other mechanisms. Denaturing gradient gel electrophoresis (DGGE) analyses revealed that Planctomycete, Proteobacteria and Chloroflexi bacteria were coexisted in the reactor. Anammox was always dominant when the reactor was fed with different COD concentrations, which indicated the stability of the anammox process with the coexistence of the denitrification process in treating greenhouse turtle breeding wastewater. PMID- 24045205 TI - Recycling cellulases for cellulosic ethanol production at industrial relevant conditions: potential and temperature dependency at high solid processes. AB - Different versions of two commercial cellulases were tested for their recyclability of enzymatic activity at high dry matter processes (12% or 25% DM). Recyclability was assessed by measuring remaining enzyme activity in fermentation broth and the ability of enzymes to hydrolyse fresh, pretreated wheat straw. Industrial conditions were used to study the impact of hydrolysis temperature (40 or 50 degrees C) and residence time on recyclability. Enzyme recycling at 12% DM indicated that hydrolysis at 50 degrees C, though ideal for ethanol yield, should be kept short or carried out at lower temperature to preserve enzymatic activity. Best results for enzyme recycling at 25% DM was 59% and 41% of original enzyme load for a Celluclast:Novozyme188 mixture and a modern cellulase preparation, respectively. However, issues with stability of enzymes and their strong adsorption to residual solids still pose a challenge for applicable methods in enzyme recycling. PMID- 24045206 TI - TET enzymatic oxidation of 5-methylcytosine, 5-hydroxymethylcytosine and 5 formylcytosine. AB - 5-Methylcytosine and methylated histones have been considered for a long time as stable epigenetic marks of chromatin involved in gene regulation. This concept has been recently revisited with the detection of large amounts of 5 hydroxymethylcytosine, now considered as the sixth DNA base, in mouse embryonic stem cells, Purkinje neurons and brain tissues. The dioxygenases that belong to the ten eleven translocation (TET) oxygenase family have been shown to initiate the formation of this methyl oxidation product of 5-methylcytosine that is also generated although far less efficiently by radical reactions involving hydroxyl radical and one-electron oxidants. It was found as additional striking data that iterative TET-mediated oxidation of 5-hydroxymethylcytosine gives rise to 5 formylcytosine and 5-carboxylcytosine. This survey focuses on chemical and biochemical aspects of the enzymatic oxidation reactions of 5-methylcytosine that are likely to be involved in active demethylation pathways through the implication of enzymatic deamination of 5-methylcytosine oxidation products and/or several base excision repair enzymes. The high biological relevance of the latter modified bases explains why major efforts have been devoted to the design of a broad range of assays aimed at measuring globally or at the single base resolution, 5-hydroxymethylcytosine and the two other oxidation products in the DNA of cells and tissues. Another critical issue that is addressed in this review article deals with the assessment of the possible role of 5-methylcytosine oxidation products, when present in elevated amounts in cellular DNA, in terms of mutagenesis and interference with key cellular enzymes including DNA and RNA polymerases. PMID- 24045207 TI - Effect of exercise on food consumption and appetite sensations in subjects with diabetes. AB - AIM: Evaluate appetite sensations following 60-min moderate intensity exercise and to predict energy intake in adults with diabetes. METHODS: Visual analogue scales measured appetite sensations before and after a fixed test meal. Fasting appetite sensations, 1h post-prandial area under the curve (AUC) and the satiety quotient predicted energy intake. Two measures of energy intake were recorded: (1) following an ad libitum test lunch and (2) a 3-day self-report dietary record. Appetite sensations were assessed in a control condition (rest, C) and when two exercise sessions were performed: one associated with a free (F) blood glucose decrease and one with limited blood glucose decreases i.e. maintained (M) above 4 mmol/l by dextrose infusion. RESULTS: 16 generally well-controlled (HbA1c: 7.0 +/- 0.6%) subjects (12 with type 1 diabetes, 4 with type 2 diabetes) ate 1020 +/- 519, 1170 +/- 282 and 1020 +/- 304 kcal (NS between conditions nor diabetes type) during the buffet meal following the C, F and M conditions, respectively. Exercise induced a mean blood glucose decrease of 3.7 +/- 0.6 and 3.1 +/- 0.6 mmol/l for the F and M conditions, respectively. The greater the blood glucose decrease, the greater the appetite sensations of hunger and prospective food consumption measured fasting and before the test meal (all p<0.05) in the whole group. One-hour post-prandial AUC for hunger and desire to eat represented the strongest predictors of ad libitum test lunch energy intake (p<0.05), especially in type 1 diabetes. CONCLUSIONS: These results suggest that appetite sensations are predictors of spontaneous energy intake in both diabetes type. Moderate intensity exercise for 60 min induced a positive effect by lowering blood glucose which was associated with appetite sensations. These results support the glucostatic theory of food intake control which protects against exercised-induced blood glucose declines. PMID- 24045208 TI - Eating behaviour patterns and BMI in Portuguese higher education students. AB - Our aim was to determine prototypical patterns of eating behaviour among Portuguese higher education students, and to relate these patterns with BMI. Data from 280 higher education students (63.2% females) aged between 18 and 27 years were analysed. Several eating behaviour dimensions (emotional and external eating, flexible and rigid restraint, binge eating, and eating self-efficacy) were assessed, and eating styles were derived through cluster analysis. BMI for current, desired and maximum self-reported weights and the differences between desired and current BMI and between maximum and current BMI were calculated. Women scored higher in emotional eating and restraint, whereas men showed higher eating self-efficacy. Men had higher current, desired and maximum BMI. Cluster analysis showed three eating styles in both male and female subsamples: "Overeating", "High self-efficacy" and "High restraint". High self-efficacy women showed lower BMI values than the others, and restrictive women had higher lost BMI. High self-efficacy men showed lower desired BMI than overeaters, and lower maximum and lost BMI than highly restrictive ones. Restrictive women and men differ on important eating behaviour features, which may be the cause of differences in the associations with BMI. Eating self-efficacy seems to be a central variable influencing the relationships between other eating behaviour dimensions and BMI. PMID- 24045209 TI - The lateral neostriatum is necessary for compensatory ingestive behaviour after intravascular dehydration in female rats. AB - Aberrant striatal function results in an array of physiological symptoms, including impaired consummatory and regulatory behaviours, which can lead to weight loss and dehydration. It was hypothesised, therefore, that cell loss in the neostriatum may contribute to altered fluid intake by regulating physiological signals related to dehydration status. To test this theory, rats with lesions of the lateral neostriatum and sham controls underwent a series of physiological challenges, including the experimental induction of intracellular and intravascular dehydration. No baseline differences in prandial or non prandial drinking were observed, nor were differences in locomotor activity evident between groups. Furthermore, intracellular dehydration increased water intake in lesion rats in a manner comparable to sham rats. Interestingly, a specific impairment was evident in lesion rats after subcutaneous injection of poly-ethylene glycol was used to induce intravascular dehydration, such that lesion rats failed to adapt their water intake to this physiological change. The results suggest that the striatal lesions resulted in regulatory dysfunction by impairing motivational control over compensatory ingestive behaviour after intravascular hydration, while the physiological signals related to dehydration remain intact. Loss of these cells in neurodegenerative disorders, such Huntington's disease, may contribute to regulatory changes evident in the course of the disease. PMID- 24045211 TI - Compassion and contamination. Cultural differences in vegetarianism. AB - A growing body of research has shown that Western vegetarians report more concern for animal welfare and environmental sustainability, and endorse more liberal values than do Western omnivores. However, despite the prevalence of Indian vegetarianism, its psychological associations and underpinnings remain largely unexamined. In Study 1, we find that Euro-American vegetarians are more concerned than omnivores with the impact of their daily food choices on the environment and animal welfare, show more concern for general animal welfare, and endorse universalistic values more, yet among Indian participants, these differences are not significant. In Study 2, we show that Indian vegetarians more strongly endorse the belief that eating meat is polluting, and show a heightened concern for the conservative ethics of Purity, Authority, and Ingroup relative to their omnivorous peers, whereas these differences are largely absent among Euro Canadians and Euro-Americans. PMID- 24045210 TI - Complementary feeding and "donner les bases du gout" (providing the foundation of taste). A qualitative approach to understand weaning practices, attitudes and experiences by French mothers. AB - Complementary feeding (CF) practices vary within and across cultures but have been investigated only to a very limited extent. It is however important to understand CF practices and how they differ, as CF sets the foundation for children's later food choices. The present study was set out to examine practices, attitudes and experiences of CF including the introduction of vegetables amongst French mothers (n=18, 25-39 years). Thematic analysis of transcribed focus groups and interviews revealed the perceived importance of the weaning period, as a critical milestone for infants' development but with a sense of "now or never" for introducing new tastes including vegetables. Flavour exposure and taste discovery during weaning were identified as the beginning of a "taste journey", in which educating the palate with a variety of different foods was considered important for children's later eating habits. Weaning was described as emotional and complex, a transition period in which the baby makes progress away from milk towards the family diet and which goes beyond mere nutrition. Advice was sought from official sources, but adapted to the needs of infants. In agreement with earlier observations of French adults, pleasure and taste development were considered of primary importance. In particular, French mothers believed complementary feeding lay the foundations of taste early in life. PMID- 24045212 TI - Adenovirus-associated health risks for recreational activities in a multi-use coastal watershed based on site-specific quantitative microbial risk assessment. AB - We used site-specific quantitative microbial risk assessment (QMRA) to assess the probability of adenovirus illness for three groups of swimmers: adults with primary contact, children with primary contact, and secondary contact regardless of age. Human enteroviruses and adenoviruses were monitored by qPCR in a multi use watershed and Adenovirus type 40/41 was detected in 11% of 73 samples, ranging from 147 to 4117 genomes per liter. Enterovirus was detected only once (32 genomes per liter). Seven of eight virus detections occurred when E. coli concentrations were below the single sample maximum water quality criterion for contact recreation, and five of eight virus detections occurred when fecal coliforms were below the corresponding criterion. We employed dose-harmonization to convert viral genome measurements to TCID50 values needed for dose-response curves. The three scenarios considered different amounts of water ingestion and Monte Carlo simulation was used to account for the variability associated with the doses. The mean illness risk in children based on adenovirus measurements obtained over 11 months was estimated to be 3.5%, which is below the 3.6% risk considered tolerable by the current United States EPA recreational criteria for gastrointestinal illnesses (GI). The mean risks of GI illness for adults and secondary contact were 1.9% and 1.0%, respectively. These risks changed appreciably when different distributions were fitted to the data as determined by Monte Carlo simulations. In general, risk was at a maximum for the log-logistic distribution and lowest for the hockey stick distribution in all three selected scenarios. Also, under default assumptions, the risk was lowered considerably when assuming that only a small proportion of Adenovirus 40/41 (3%) was as infectious as Adenovirus type 4, compared to the assumption that all genomes were Adenovirus 4. In conclusion, site-specific QMRA on water-borne adenoviruses in this watershed provided a similar level of protection against public health risks as would be obtained by enumeration of fecal indicator bacteria under the new U.S. EPA guidelines. PMID- 24045213 TI - Operating aerobic wastewater treatment at very short sludge ages enables treatment and energy recovery through anaerobic sludge digestion. AB - Conventional abattoir wastewater treatment processes for carbon and nutrient removal are typically designed and operated with a long sludge retention time (SRT) of 10-20 days, with a relatively high energy demand and physical footprint. The process also generates a considerable amount of waste activated sludge that is not easily degradable due to the long SRT. In this study, an innovative high rate sequencing batch reactor (SBR) based wastewater treatment process with short SRT and hydraulic retention time (HRT) is developed and characterised. The high rate SBR process was shown to be most effective with SRT of 2-3 days and HRT of 0.5-1 day, achieving >80% reduction in chemical oxygen demand (COD) and phosphorus and approximately 55% nitrogen removal. A majority of carbon removal (70-80%) was achieved by biomass assimilation and/or accumulation, rather than oxidation. Anaerobic degradability of the sludge generated in the high-rate SBR process was strongly linked to SRT, with measured degradability extent being 85% (2 days SRT), 73% (3 days), and 63% (4 days), but it was not influenced by digestion temperature. However, the rate of degradation for 3 and 4 days SRT sludge was increased by 45% at thermophilic conditions compared to mesophilic conditions. Overall, the treatment process provides a very compact and energy efficient treatment option for highly degradable wastewaters such as meat and food processing, with a substantial space reduction by using smaller reactors and a considerable net energy output through the reduced aerobic oxidation and concurrent increased methane production potential through the efficient sludge digestion. PMID- 24045214 TI - Enhancing Raman signals with an interferometrically controlled AFM tip. AB - We demonstrate the upgrade of a commercial confocal Raman microscope into a tip enhanced Raman microscope/spectroscopy system (TERS) by integrating an interferometrically controlled atomic force microscope into the base of an existing upright microscope to provide near-field detection and thus signal enhancement. The feasibility of the system is demonstrated by measuring the Raman near-field enhancement on thin PEDOT:PSS films and on carbon nanotubes within a device geometry. An enhancement factor of 2-3 and of 5-6 is observed, respectively. Moreover, on a nanotube device we show local conductivity measurement and its correlation to Raman and topography recordings. Upgrading an existing upright confocal Raman microscope in the demonstrated way is significantly cheaper than purchasing a complete commercial TERS system. PMID- 24045215 TI - Mutational analysis of the GALT gene in Filipino patients. AB - Classic galactosemia is an inherited metabolic disorder due to mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. This study describes the results of the GALT gene analysis of four unrelated Filipino patients with Classic Galactosemia. DNA extracted from dried blood spots and peripheral blood of the patients, age one month to two and a half years, underwent PCR amplification with subsequent bidirectional sequencing of all eleven exons with their flanking intronic regions following standard protocols. Clinical data of these patients were reviewed. The patients presented with jaundice, hepatomegaly, diarrhea, vomiting, poor feeding and seizures during their neonatal period. They were diagnosed with elevated blood galactose and galactose-1-phosphate and absent GALT activity. Four missense mutations were found wherein two were previously reported (p.V168L and p.A345D) and two were novel (p.L116P and p.M178R). The most frequent mutation in our cohort is p.V168L. This study suggests that GALT mutations are ethnic-specific and that galactosemia is a heterogeneous disorder at the molecular level. The importance of early detection, immediate and proper medical management and genetic counseling of the patients and their families cannot be overemphasized. PMID- 24045216 TI - Constitutive activation of Rac1 in pancreatic beta cells facilitates F-actin depolymerization but exerts no influence on the increase of pancreatic beta cell mass and facilitation of insulin secretion. AB - Insulin secretion from pancreatic beta cells has an important role in the onset of type 2 diabetes. Insulin secretion from pancreatic beta cells is regulated by pancreatic beta cell mass and their insulin secretory function. By using pancreatic beta cell-specific Rac1-knockout mice, we recently showed that Rac1 deletion, even with no reduction in pancreatic beta cell mass, inhibits F-actin depolymerization, which causes insulin secretion to decline. However, the effect of Rac1 deficiency on the growth and apoptosis of pancreatic beta cells was not clarified. Further, the effect of constitutive Rac1 activation on the secretion of insulin from pancreatic beta cells has not been studied. Here, we used pancreatic islets isolated from pancreatic beta cell-specific Rac1-knockout mice to evaluate the growth and apoptosis of pancreatic beta cells. We found that Rac1 deficiency does not influence the growth or apoptosis of pancreatic beta cells. Further, when a constitutively activated form of Rac1 (G12V) is expressed, F actin depolymerization was increased in the pancreatic beta cell lines, which had no effect on pancreatic beta cell growth or glucose-stimulated insulin secretion. These findings indicate that excessive Rac1 expression or activation in pancreatic beta cells facilitates F-actin depolymerization, but has no effect on insulin secretion. PMID- 24045217 TI - Myocardial impairment detected by late gadolinium enhancement in hypertrophic cardiomyopathy: comparison with 99mTc-MIBI/tetrofosmin and 123I-BMIPP SPECT. AB - PURPOSE: Myocardial fibrosis is considered to be an important factor in myocardial dysfunction and sudden cardiac death in hypertrophic cardiomyopathy (HCM). The purpose of this study was to compare myocardial fibrosis detected by late gadolinium enhancement (LGE) on cardiac MRI with myocardial perfusion and fatty acid metabolism assessed by single photon emission computed tomography in HCM. MATERIALS AND METHODS: We retrospectively evaluated 20 consecutive HCM patients (female, 7; mean age, 53.4 years) who underwent LGE, technetium-99m methoxyisobutylisonitrile/tetrofosmin (99mTc-MIBI/tetrofosmin), and iodine-123 beta-methyl-iodophenylpentadecanoic acid (123I-BMIPP) imaging. We calculated the myocardium-to-lumen signal ratio (M/L) for LGE in 17 segments based on the American Heart Association statement. Scoring of 99mTc-MIBI/tetrofosmin (PI) and 123I-BMIPP (BM) was performed for each segment using a 5-point scale (0, normal; 4, highly decreased). RESULTS: Nineteen of 20 patients (95%) and 153 of 340 segments (45%) showed LGE. M/Ls were 0.42+/-0.16, 0.55+/-0.17, and 0.65+/-0.24 in PI0/BM0, PI0/BM1-4 and PI1-4/BM1-4, respectively. All M/Ls were significantly higher than that of a normal control (0.34+/-0.14) (p<0.001). CONCLUSIONS: Myocardial fibrosis in HCM can occur despite normal perfusion and fatty acid metabolism, and is more strongly associated with disorders of fatty acid metabolism than with perfusion abnormalities. M/L may be a useful indicator of disease severity. PMID- 24045218 TI - Designated smoking areas in streets where outdoor smoking is banned. AB - Although Japan has been a signatory to the Framework Convention on Tobacco Control since 2004, progress in translating the recommendations into national policy has been limited. Globally, outdoor smoking bans cover outdoor dining areas, beaches, public parks, schools, etc. In Japan, most of existing outdoor smoking bans allow designated smoking areas (DSAs) in the no-smoking zones, thus limiting protection from second-hand smoke (SHS). We examined the impact of DSAs on air quality in the areas of Kobe City where such ordinance is in force. Air quality measurements were conducted near two DSAs in August 2012 by using personal aerosol monitors. Three measurements were performed, each for 15 minutes, by four investigators: a line-up measurement, a vertical and horizontal measurement, and a circle measurement. In the line-up measurement, over 150 ug/m3 of PM2.5 was detected by the monitor four metres from the ashtray, gradually reducing as the distance increased. In the vertical and horizontal measurement, 80-110 ug/m3 of PM2.5 was detected at 4, 11, 18 and 25 metres. In the circle measurement, similar concentrations of PM2.5 were detected at all testing points (mean concentration 94 ug/m3). The study indicates that DSAs are sources of SHS in zones where a street smoking ban is in force, since SHS spreads widely, both vertically and horizontally. Street smoking bans that permit DSAs strongly limit protection from SHS and should be eliminated if protection against SHS is to be effective where such bans are in force. PMID- 24045219 TI - [Poor prognostic value of weight change during chemotherapy in non-metastatic breast cancer patients: causes, mechanisms involved and preventive strategies]. AB - Numerous studies have demonstrated that a significant change in weight during chemotherapy treatment was a factor of poor prognosis in early breast cancer women. However, the causes and mechanisms involved in this phenomenon are not fully known. This review summarizes current knowledge about the causes of energy imbalance during chemotherapy treatment and the mechanisms that have been proposed as responsible for the increased risk of relapse and death in this population. Current preventive strategies focus on physical activity programs but also on the use of metformin during and after chemotherapy. PMID- 24045220 TI - Applicability of agricultural waste and by-products for adsorptive removal of heavy metals from wastewater. AB - This critical review discusses the potential use of agricultural waste based biosorbents (AWBs) for sequestering heavy metals in terms of their adsorption capacities, binding mechanisms, operating factors and pretreatment methods. The literature survey indicates that AWBs have shown equal or even greater adsorption capacities compared to conventional adsorbents. Thanks to modern molecular biotechnologies, the roles of functional groups in biosorption process are better understood. Of process factors, pH appears to be the most influential. In most cases, chemical pretreatments bring about an obvious improvement in metal uptake capacity. However, there are still several gaps, which require further investigation, such as (i) searching for novel, multi-function AWBs, (ii) developing cost-effective modification methods and (iii) assessing AWBs under multi-metal and real wastewater systems. Once these challenges are settled, the replacement of traditional adsorbents by AWBs in decontaminating heavy metals from wastewater can be expected in the future. PMID- 24045221 TI - Evolution of novel biomarkers for detection of prostate cancer. PMID- 24045222 TI - Radiation cystitis with pseudocarcinomatous urothelial hyperplasia. PMID- 24045225 TI - Mindful attention and awareness mediate the association between age and negative affect. AB - OBJECTIVES: Later life is often accompanied by experiences of loss and bereavement in several life domains. In spite of this, older adults experience less negative affect than their younger counterparts. Several explanations for this paradoxical finding have been put forward, but the mechanisms underlying the association between age and negative affect remain largely unclear. In the present study, we propose that mindfulness may be an important mediator of this association. METHOD: A cross-sectional sample of 507 participants (age range 18 85 years) was used to investigate this question. Participants completed a range of self-report questionnaires on demographic variables, mindfulness, affect, quality of life (QoL), and personality. In our mediation analysis, we used an advanced statistical technique called G-estimation to control for the impact of confounding variables such as personality dimensions and QoL. RESULTS: Our findings indicate that the age-related decrease in negative affect is mediated by mindfulness. The results remain significant when we control for QoL and personality. DISCUSSION: These findings imply that mindfulness skills may be an important link between age and negative affect. Implications of these findings for the understanding of the well-being paradox are discussed. PMID- 24045224 TI - Emetine dihydrochloride: a novel therapy for bladder cancer. AB - PURPOSE: Current cisplatin based therapies for stage IV bladder cancer show 4% to 20% 5-year survival, underscoring the need to develop novel therapies for these patients. In the 1970s the natural alkaloid emetine dihydrochloride demonstrated modest anticancer efficacy as a single agent in clinical trials but this was not pursued. Groups recently reported that emetine induced apoptosis in leukemia cell lines, which was enhanced by cisplatin. We determined the antiproliferative effects of emetine with and without cisplatin in bladder cancer cells. MATERIALS AND METHODS: Human bladder cancer cell lines and normal human urothelial cell cultures were treated with emetine and/or cisplatin. We measured cell proliferation and evaluated synergy using the Chou-Talalay method. The combination index was calculated. Cell cycle analysis was done and caspase activation was evaluated to assess growth arrest and apoptosis. RESULTS: Emetine and cisplatin individually inhibited bladder cancer cell proliferation. When combined, emetine and cisplatin acted synergistically to inhibit tumor cell proliferation with combination index values reflecting moderate to strong synergy. Normal urothelial cells were relatively resistant to this treatment. Emetine alone and combined with cisplatin appeared to primarily induce tumor cell growth arrest and not apoptosis. CONCLUSIONS: To our knowledge this study demonstrates for the first time that emetine has in vitro antiproliferative activity against bladder cancer cell lines at nanomolar concentrations but little effect on normal urothelial cells. Moreover, emetine and cisplatin worked synergistically to inhibit tumor cell proliferation. Results suggest that combined emetine and cisplatin based chemotherapy may benefit patients with bladder cancer. PMID- 24045226 TI - n-3 fatty acids: functional differences between food intake, oral supplementation and drug treatments. AB - n-3 polyunsaturated fatty acids (n-3 PUFAs) are essential for mammalian cells that are not able to synthesise de novo their precursor, alpha-linolenic acid, and may only partially convert it to eicosapentaenoic acid (EPA) and to a very small extent to docosahexaenoic acid (DHA). For this reason, nutritional guidelines for cardiovascular prevention recommend regular fish consumption (approximately two portions per week) in order to increase the intake of the n-3 PUFAs EPA and DHA, mainly referring to fatty fish, living in cold waters, usually very rich in these fatty acids. However, the indication to consume fish regularly is unlikely to be sufficient to ensure that patients with documented coronary heart diseases receive the daily amount of EPA+DHA (ca. 1g) necessary for effective secondary prevention of the disease. This has prompted the development of pharmaceutical formulations both for dietary supplementation and for therapeutic administration, based on several dietary sources, containing greatly variable amounts of EPA and DHA, often with different availabilities. Critical knowledge of these characteristics allows the selection of the best approach in order to optimise the n-3 PUFA supply in various individuals. PMID- 24045227 TI - Soft and hard tissues healing at immediate transmucosal implants placed into molar extraction sites with collagen membrane uncovered: a 12-month prospective study. AB - PURPOSE: To assess soft and hard tissues healing at immediate transmucosal implants placed into maxillary molar region with collagen membranes uncovered. MATERIALS AND METHODS: Twenty subjects received 20 immediate transmucosal implants placed in maxillary molar extraction sockets. Periimplant marginal defects were treated according to the principles of guided bone regeneration by means of deproteinized bovine bone mineral particles in conjunction with collagen membrane. Flaps were repositioned and sutured, allowing nonsubmerged, transmucosal soft tissues healing. The collagen membranes adapted around implant neck were uncovered. RESULTS: No implants were lost during the 1-year observation period yielding a survival rate of 100%. No postsurgical wound healing complications were observed. No degranulation of grafting material was reported. CONCLUSIONS: The results of this 12-month prospective study showed that the exposure of collagen membrane at time of the flap suturing does not represent a limitation for the soft and hard tissues healing at immediate transmucosal implants placed into maxillary molar extraction sites. PMID- 24045228 TI - Accumulation of brachycerine, an antioxidant glucosidic indole alkaloid, is induced by abscisic acid, heavy metal, and osmotic stress in leaves of Psychotria brachyceras. AB - Psychotria brachyceras Muell. Arg. produces the antioxidant monoterpene indole alkaloid (MIA) brachycerine, which, besides retaining a glucose residue, has its terpenoid moiety derived not from secologanin, but probably from epiloganin, representing a new subclass of MIAs. In this work we showed that osmotic stress agents, such as sodium chloride, sorbitol and polyethylene glycol (PEG), induced brachycerine accumulation in leaf disks of P. brachyceras. Other oxidative stress inducers, such as exposure to aluminum and silver, also increased brachycerine content. Abscisic acid (ABA) treatment was shown to increase brachycerine yield, suggesting its involvement in brachycerine induction during osmotic stress. Ascorbate peroxidase activity was induced in PEG-treated leaf disks, whereas superoxide dismutase (SOD) activity remained unaltered. Assays with specific inhibitors of the cytosolic mevalonate (MVA) and plastidic 2-C-methyl-D erythritol 4-phosphate (MEP) pathways showed that the terpenoid moiety of brachycerine derived predominantly from the MEP pathway. These results suggest a potential involvement of brachycerine in plant defense against osmotic/oxidative stress damage, possibly contributing to detoxification of hydroxyl radical and superoxide anion as a SOD-like molecule. PMID- 24045229 TI - Distinct function of the head region of human pancreas in the pathogenesis of diabetes. AB - The large size of the human pancreas challenges unbiased quantitative analyses that require a practical stereological approach. While many histological studies of the pancreas in the past lacked regional information, we have shown marked heterogeneity within an individual, where islet distribution/density is relatively low in the head and gradually increases through the body toward the tail region by>2-fold. Studies focusing on the tail region may be prone to overestimation of beta-cell/islet mass when normalizing measured values per person by using pancreas weight or volume. In this article, beyond technical issues, we discuss the pathophysiological importance of studying the head region of the human pancreas regarding its unique characteristics in early development, and the anatomical disposition that may lead to a preferential loss of beta-cells in patients with type 2 diabetes and the development of pancreatic cancer. PMID- 24045230 TI - Optimized and enhanced DNA plasmid vector based in vivo construction of a neutralizing anti-HIV-1 envelope glycoprotein Fab. AB - Monoclonal antibody preparations have demonstrated considerable clinical utility in the treatment of specific malignancies, as well as inflammatory and infectious diseases. Antibodies are conventionally delivered by passive administration, typically requiring costly large-scale laboratory development and production. Additional limitations include the necessity for repeat administrations, and the length of in vivo potency. Therefore, the development of methods to generate therapeutic antibodies and antibody like molecules in vivo, distinct from an active antigen-based immunization strategy, would have considerable clinical utility. In fact, adeno-associated viral (AAV) vector mediated delivery of immunoglobulin genes with subsequent generation of functional antibodies has recently been developed. As well, anon-viral vector mediated nucleic acid based delivery technology could permit the generation of therapeutic/prophylactic antibodies in vivo, obviating potential safety issues associated with viral vector based gene delivery. This delivery strategy has limitations as well, mainly due to very low in vivo production and expression of protein from the delivered gene. In the study reported here we have constructed an "enhanced and optimized" DNA plasmid technology to generate immunoglobulin heavy and light chains (i.e., Fab fragments) from an established neutralizing anti-HIV envelope glycoprotein monoclonal antibody (VRC01). This "enhanced" DNA (E-DNA) plasmid technology includes codon/RNA optimization, leader sequence utilization, as well as targeted potentiation of delivery and expression of the Fab immunoglobulin genes through use of "adaptive" in vivo electroporation. The results demonstrate that delivery by this method of a single administration of the optimized Fab expressing constructs resulted in generation of Fab molecules in mouse sera possessing high antigen specific binding and HIV neutralization activity for at least 7 d after injection, against diverse HIV isolates. Importantly, this delivery strategy resulted in a rapid increase (i.e., in as little as 48 h) in Fab levels when compared with protein-based immunization. The active generation of functional Fab molecules in vivo has important conceptual and practical advantages over conventional ex vivo generation, purification and passive delivery of biologically active antibodies. Further study of this technique for the rapid generation and delivery of immunoglobulin and immunoglobulin like molecules is highly relevant and timely. PMID- 24045231 TI - Conducting properties of nearly depleted ZnO nanowire UV sensors fabricated by dielectrophoresis. AB - ZnO nanowires (NWs) with different radii (rNW) have been aligned between pre patterned electrodes using dielectrophoresis (DEP) for the fabrication of high gain UV sensors. The DEP conditions (voltage amplitude and frequency) and electrode material, geometry and size were optimized to enhance the efficiency during the DEP process. To understand the alignment mechanism of the ZnO NWs, the dielectrophoretic force (FDEP) was analyzed as a function of the DEP conditions and NW dimensions. These studies showed that the DEP alignment process tends to trap NWs with a smaller radius. The effects of NW size on device performance were analyzed by means of I-V measurements in darkness and under illumination (200 nm < lambda < 600 nm). In darkness, the NW resistance increases as rNW decreases due to the reduction of the conduction volume, until saturation is reached for rNW < 65 nm. On the other hand, the NW spectral photoresponse shows high values around 10(8) A W(-1) (measured at 5 V and lambda < 370 nm) and follows a linear trend as a function of the NW cross section. In addition, the cut-off wavelength depends on rNW, presenting a clear blue-shift for NWs with a lower radius (rNW < 50 nm). Transient photoresponse studies show that NWs with lower radii have longer rise times and shorter decay times mainly due to surface trapping effects. Regardless of NW size, passivation of the surface using a dielectric capping layer of SiO2 reduces the dynamic range of the photoresponse due to a strong increase of the dark current. PMID- 24045234 TI - Production of graphene by reduction using a magnesiothermic reaction. AB - We have, for the first time, employed a magnesiothermic reaction to convert microwave-irradiated graphite oxide to pure graphene. The magnesiothermic reaction increases the carbon to oxygen atomic ratio from 22.2 to 165.7 and maintains a high surface area. The new strategy demonstrates an efficient method for obtaining highly pure graphene materials. PMID- 24045233 TI - Development of a cysteine-deprived and C-terminally truncated GLP-1 receptor. AB - The glucagon-like peptide-1 receptor (GLP-1R) belongs to family B of the G protein coupled receptors (GPCRs), and has become a promising target for the treatment of type 2 diabetes. Here we describe the development and characterization of a fully functional cysteine-deprived and C-terminally truncated GLP-1R. Single cysteines were initially substituted with alanine, and functionally redundant cysteines were subsequently changed simultaneously. Our results indicate that Cys(174), Cys(226), Cys(296) and Cys(403) are important for the GLP-1-mediated response, whereas Cys(236), Cys(329), Cys(341), Cys(347), Cys(438), Cys(458) and Cys(462) are not. Extensive deletions were made in the C terminal tail of GLP-1R in order to determine the limit for truncation. As for other family B GPCRs, we observed a direct correlation between the length of the C-terminal tail and specific binding of (125)I-GLP-1, indicating that the membrane proximal part of the C-terminal is involved in receptor expression at the cell surface. The results show that seven cysteines and more than half of the C-terminal tail can be removed from GLP-1R without compromising GLP-1 binding or function. PMID- 24045232 TI - Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. AB - Lgr5 marks adult stem cells in multiple adult organs and is a receptor for the Wnt-agonistic R-spondins (RSPOs). Intestinal, stomach and liver Lgr5(+) stem cells grow in 3D cultures to form ever-expanding organoids, which resemble the tissues of origin. Wnt signalling is inactive and Lgr5 is not expressed under physiological conditions in the adult pancreas. However, we now report that the Wnt pathway is robustly activated upon injury by partial duct ligation (PDL), concomitant with the appearance of Lgr5 expression in regenerating pancreatic ducts. In vitro, duct fragments from mouse pancreas initiate Lgr5 expression in RSPO1-based cultures, and develop into budding cyst-like structures (organoids) that expand five-fold weekly for >40 weeks. Single isolated duct cells can also be cultured into pancreatic organoids, containing Lgr5 stem/progenitor cells that can be clonally expanded. Clonal pancreas organoids can be induced to differentiate into duct as well as endocrine cells upon transplantation, thus proving their bi-potentiality. PMID- 24045235 TI - Value of perfusion computed tomography in acute ischemic stroke: diagnosis of infarct core and penumbra. AB - PURPOSE: This study aimed to perform an evaluation of 4 perfusion computed tomographic (PCT) parameters (relative cerebral blood flow, cerebral blood volume, mean transit time [MTT], and delay time [DT]) in a series of patients with acute ischemic stroke to find optimal parameters to predict infarct core and penumbra. METHODS: Twenty-six patients with symptoms suggesting stroke less than 7 hours from onset were enrolled in this study. They all underwent admission and 24-hour PCT and a 24-hour diffusion-weighted imaging. Perfusion computed tomographic maps were assessed for relative reduced cerebral blood flow and cerebral blood volume and increased MTT and DT. Receiver operating characteristic curve analysis was performed to locate the optimal threshold for each parameter, using diffusion-weighted imaging as the gold standard. RESULTS: The PCT parameter that most accurately describes the penumbra is the relative MTT of 150% or greater (area under the curve, 0.827; 95% confidence interval, 0.826-0.827), whereas the parameter that most accurately describes the infarct core is the relative DT of + 2.0 seconds or greater (area under the curve, 0.879; 95% confidence interval, 0.878-0.879). CONCLUSIONS: The optimal parameters to define the infarct core and the penumbra are relative DT (>=+ 2.0 seconds) and relative MTT (>= 150%). PMID- 24045236 TI - Anatomic olfactory structural abnormalities in congenital smell loss: magnetic resonance imaging evaluation of olfactory bulb, groove, sulcal, and hippocampal morphology. AB - BACKGROUND AND PURPOSE: There are 2 groups of patients with congenital smell loss: group 1 (12% of the total), in which patients exhibit a familial smell loss in conjunction with severe anatomical, somatic, neurological, and metabolic abnormalities such as hypogonadotropic hypogonadism; and a larger group, group 2 (88% of the total), in which patients possess a similar degree of smell loss but without somatic, neurological, or anatomical abnormalities or hypogonadism. Both groups are characterized by similar olfactory dysfunction, and both have been reported to have absent or decreased olfactory bulbs and grooves, which indicates some overlap in olfactory pathophysiology and anatomy. The purpose of this study was to evaluate patients with congenital smell loss, primarily among group 2 patients, comparing brain magnetic resonance imaging (MRI) results in patients with types of hyposmia. METHODS: Forty group 2 patients were studied by measurements of taste (gustometry) and smell (olfactometry) function and by use of MRI in which measurements of olfactory bulbs, olfactory sulcus depth, olfactory grooves, and hippocampal anatomy were performed. Anatomical results were compared with similar studies in group 1 patients and in 22 control subjects with normal sensory function. RESULTS: Olfactometry was abnormal in all patients with no patient reporting ever having normal olfaction. No patient had a familial history of smell loss. On MRI, all exhibited at least 1 abnormality in olfactory system anatomy, including absence or decreased size of at least 1 olfactory bulb, decreased depth of an olfactory sulcus, and abnormalities involving hippocampal anatomy with hippocampal malrotations. One patient had bilateral bulb duplication. Normal subjects with normal smell and taste function exhibited some but very few or significant neuroanatomical changes on MRI. CONCLUSIONS: Although both groups have similar abnormalities of smell function, group 2 patients demonstrate anatomical anomalies in olfactory structures that are neither as common nor as severe as in group 1 patients. Group 2 patients can have a wide range of olfactory anatomical abnormalities. PMID- 24045237 TI - Solitary fibrous tumors of the central nervous system: clinical features and imaging findings in 22 patients. AB - INTRODUCTION: Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm originating in the central nervous system (CNS), with imaging features currently not well known. The purposes were to describe and characterize clinical features and imaging findings of CNS SFT. METHODS: We retrospectively reviewed computed tomographic (CT; n = 10) and magnetic resonance (MR) images (n = 18) of 22 patients with SFT (13 males and 9 females; mean, 47.6 years) with associated clinical records. RESULTS: Each lesion was found as a solitary, well-defined mass, ranging in size from 12 to 70 mm (mean, 38 mm). The tumor shape was roundlike in 16 cases (72.7%) and irregular in 6 cases (27.2%). The cerebellopontine angle zone was the most affected area (n = 6). On precontrast CT scans, 10 cases showed predominantly hyperattenuation (n = 9) and isoattenuation (n = 1). No lesion contained calcification, and 2 cases showed bone invasions. All 18 tumors examined by MR imaging showed homogeneous hypointensive (n = 5) or isointensive (n = 7) signal intensity and heterogeneous mixed isointense and hypointense signal intensity (n = 6) on T1-weighted images, whereas most tumors were predominantly isointense (n = 13) and hypointense (n = 4) to the cortex on T2-weighted images; on postcontrast CT and MR images, enhancement was marked homogeneous (n = 10) or heterogeneous (n = 12). Fourteen tumors had thickening of the meninges adjacent to the tumor. CONCLUSIONS: Although SFT is a rare neoplasm in the CNS, it should be considered in the differential diagnosis. The most affected area is the cerebellopontine angle zone. Solitary fibrous tumor tends to have some imaging features, such as high attenuation on CT, isointense to hypointense signal intensity on MR images, and marked enhancement. PMID- 24045238 TI - Differentiation of benign and malignant neck pathologies: preliminary experience using spectral computed tomography. AB - PURPOSE: The objective of this study was to evaluate spectral Hounsfield unit (HU) curves and effective Z (atomic number) generated on dual-energy gemstone spectral imaging computed tomography (CT) in the differentiation of benign and malignant neck pathologic findings. METHODS: This was a retrospective review of 38 patients who underwent neck CT on a gemstone spectral imaging dual-energy CT (Lightspeed CT750 HD 64-slice CT scanner; GE Medical Systems, Milwaukee, Wis) from November 2009 to June 2012 with identifiable masses. One board-certified radiologist placed regions of interest within the mass (19 benign, 19 malignant) and in paraspinal muscles (PSMs) to create 2 spectral HU curves in each patient. The curve parameters compared between the benign and malignant groups included range (conceptually, the difference between the highest and lowest HU), asymptote, decay, and the differences and ratios (of lesion to PSM) of each of these 3 parameters. A logistic regression model was built with these parameters and effective Z. RESULTS: The difference in ranges (between lesion and PSM) was the best predictor of malignancy, with a threshold of 75 or greater demonstrating 95% sensitivity, 89% specificity, and 91.8% area under the curve (AUC). Adding other spectral HU parameters and effective Z to the model did not substantially increase the AUC (93.3%, difference between the 2 models not statistically significant, P > 0.25). The effective Z showed a 79.9% AUC with 68% sensitivity and 68% specificity at an 8.80 cutoff. CONCLUSIONS: The spectral HU curve is promising for differentiating benign and malignant neck pathologic findings, with the difference in range between the lesion and PSM showing the best predictive value. PMID- 24045239 TI - Early assessment of induction chemotherapy response of nasopharyngeal carcinoma by pretreatment diffusion-weighted magnetic resonance imaging. AB - OBJECTIVES: This study aimed to evaluate the feasibility of pretreatment diffusion-weighted imaging in predicting response after induction chemotherapy (IC) in nasopharyngeal carcinoma (NPC). METHODS: Fifty-four patients with stage III and IV NPC underwent MRI examination at baseline, after 2 cycles of chemotherapy, and at the end of chemoradiotherapy. Apparent diffusion coefficient (ADC) values were compared between effective and ineffective subjects after IC. RESULTS: Mean ADC in effective groups was significantly (P < 0.05) higher than that in the ineffective group. Average and minimum ADCs demonstrated higher sensitivity than maximum ADC for predicting IC response, with 68.4%, 71.1%, and 50.0%, respectively, at an equivalent 68.7% specificity. We observed negative correlations between pretreatment ADC and tumor regression after chemotherapy (gamma = - 0.425, P = 0.001) and after chemoradiotherapy (gamma = - 0.418, P = 0.003). CONCLUSIONS: Pretreatment ADC was a valuable biomarker for predicting IC response of NPC. Noninvasive diffusion-weighted imaging provides additional indicator in guiding optical therapeutic options for patients with NPC. PMID- 24045240 TI - Characteristics of cervical computed tomography findings in kawasaki disease: a single-center experience. AB - PURPOSE: The objective of this study was to characterize cervical computed tomography (CT) findings in Kawasaki disease (KD) patients that may facilitate early diagnosis. METHODS: We retrospectively reviewed cervical CT images of 78 children with cervical lymphadenopathy to analyze the distribution and morphology of lymphadenopathy and other soft-tissue findings. RESULTS: Twenty-eight patients were diagnosed with KD. Fifty had other diseases (non-KD). Retropharyngeal edema was observed in 82% (23/28) of KD and 30% (15/50) of non-KD (P < 0.01) cases. Retropharyngeal lymphadenopathy was observed in 89% (25/28) of KD and 48% (24/50) of non-KD (P < 0.01) cases. Levels III and IV lymphadenopathy was found in only 1 KD case, whereas levels III and IV lymphadenopathy was found in 58% (29/50) (P < 0.01) and 36% (18/50) (P < 0.01) of non-KD cases, respectively. CONCLUSIONS: Retropharyngeal lymphadenopathy and retropharyngeal edema are relatively common features of KD on CT. Given the potentially serious complications of KD, this diagnosis is an important consideration in a young child presenting with these imaging findings. PMID- 24045241 TI - The vallecular line: an objective measure in evaluating the base of the tongue and vallecular cancers for transoral robotic surgery. AB - OBJECTIVE: We hypothesized that the degree of the exophytic nature of the base of the tongue and vallecular cancers (BOTs) impacts the feasibility of transoral resection. The growth pattern of these cancers can be measured by the vallecular line (VL), which is the distance between the hyoid bone and the vallecular tip. MATERIALS AND METHODS: The normal VL was measured by 3 radiologists on 50 magnetic resonance imaging scans. The VL was then measured on magnetic resonance imaging scans of patients with BOT cancers. RESULTS: The mean VL was 8.2 mm (6.4 10 mm) in the healthy patients. The mean VL of the patients with predominantly exophytic BOT cancer was 22.7 mm (20.6-24.8 mm). Postoperative images of these patients demonstrate minimal loss of the native tongue after transoral resection. CONCLUSIONS: The VL is a valuable objective measurement of the exophytic nature of BOT cancers. Predominantly exophytic BOT cancers are deemed more amenable for successful and functional transoral surgical resection. PMID- 24045242 TI - Natalizumab (tysabri)-associated progressive multifocal leukoencephalopathy: insights from perfusion magnetic resonance imaging. AB - A case of natalizumab-associated progressive multifocal leukoencephalopathy in a 38-year-old woman is presented showing characteristics on magnetic resonance imaging (MRI) with high signal on T2-weighted images and patchy contrast enhancement. After 5 days of plasma exchange therapy, contrast enhancement decreased, but the abnormality on T2-weighted images increased. Perfusion MRI at this time demonstrated significantly increased blood flow to the lesion. Thirteen days after initiation of treatment, perfusion MR returned to normal in advance of significant anatomical changes on conventional MRIs. This case suggests that MR perfusion imaging may be helpful in monitoring the treatment of patients with natalizumab-associated progressive multifocal leukoencephalopathy. PMID- 24045243 TI - Alexander disease: a novel mutation in the glial fibrillary acidic protein gene with initial uncommon clinical and magnetic resonance imaging findings. AB - Alexander disease (AxD) is a rare neurodegenerative disorder related to mutations in the glial fibrillary acidic protein gene. We report the case of a child with disease onset at the age of 3 months and a novel mutation in the glial fibrillary acidic protein gene. Peculiar aspects were initially atypical clinical and magnetic resonance imaging (MRI) findings, which became typical during follow-up. The child was born after an uneventful pregnancy, presented initially only as a failure to thrive. The first MRI examination demonstrated obstructive hydrocephalus and cerebral white matter abnormalities (which were more prominent posteriorly). During follow-up, her clinical picture became typical of AxD with macrocephaly and neurodevelopmental delay. Sequential MRI examinations showed frontal white matter involvement, together with exuberant forniceal lesions and areas of contrast enhancement. PMID- 24045244 TI - Correlation of coronary atherosclerosis and subclinical plaque phenotype of carotid artery: a 320-row multidetector computed tomographic angiography study. AB - OBJECTIVE: This study aimed to evaluate the correlation between coronary atherosclerosis and the phenotype of subclinical carotid artery plaque using 320 row computed tomography via an original single-injection protocol. METHODS: A total of 122 patients with suspected coronary artery disease but free of transient ischemic attack and stroke underwent computed tomographic angiography of carotid and coronary artery simultaneously. The mean attenuation was measured at each artery. The plaques in either carotid or coronary were classified into noncalcified, calcified, and mixed. Coronary plaque was evaluated with plaque score. Logistic regression analysis was used to determine the predictive value of coronary plaque score to the phenotype of carotid plaque. The prevalence of each phenotype of carotid plaque in different coronary stenosis groups was also analyzed. RESULTS: The mean (SD) attenuation of carotid and coronary artery was 456.3 (81.7) Hounsfield units (HU), 466.0 (85.5) HU, 446.5 (84.1) HU, and 476.4 (90.0) HU, respectively. There was a significant correlation between the noncalcified coronary plaque score and noncalcified plaque in carotid artery (odds ratio [OR], 2.9; P < 0.05). The coronary calcified plaque scores were significantly correlated with carotid mixed (OR, 1.8; P < 0.05) and calcified plaque (OR, 2.0; P < 0.05). The noncalcified plaque of carotid artery was more frequent (72.5% vs 67%) in the nonsignificant coronary stenosis group. CONCLUSIONS: The subclinical carotid plaque phenotypes are significantly associated with coronary plaque score and defined grade of stenosis in patients with suspected coronary artery disease. Our tailored computed tomographic angiography protocol may have a positive impact on secondary prevention. PMID- 24045245 TI - The effect of the virtual monochromatic spectral imaging for the metallic artifact and the pulmonary nodule detection. AB - OBJECTIVES: This study aimed to evaluate whether dual-energy computed tomography can reduce metal artifacts and improve detection of pulmonary nodules. METHODS: Twelve simulated nodules were randomly placed inside a chest phantom with a pacemaker. Then, dual-energy computed tomography was performed, and 5 virtual monochromatic images at 40, 50, 65, 100, and 140 keV were reconstructed with 5- and 0.625-mm slice thicknesses. Two independent observers assessed the metal artifact (3-point scale from 1, none, to 3, severe) and detection of the nodule (5-point scale from 1, definitely absent, to 5, definitely present). Statistical analysis was performed with a P value of less than 0.01 (0.05/5). RESULTS: With both slice thicknesses, the metallic artifact increased at 40 or 50 keV and decreased at 100 or 140 keV relative to that at 65 keV (P < 0.01). The nodule detection score was not significantly different between each kiloelectron volt level with the 0.625-mm slice thickness; however, the score was significantly worse at 40 keV compared to 65 keV (P < 0.01) with the 5-mm slice thickness. CONCLUSIONS: High monochromatic energy images can reduce metal artifacts without a change in nodule detection score. Low monochromatic energy images increase metal artifacts and worsen nodule detection in thick slices. PMID- 24045246 TI - Computed tomography angiography for suspected pulmonary embolism: comparison of 2 adaptive statistical iterative reconstruction blends to filtered back-projection alone. AB - OBJECTIVE: The objective of this study was to analyze pulmonary computed tomography angiography image quality and pulmonary embolism (PE) depiction comparing 2 blends of adaptive statistical iterative reconstruction (ASIR) to filtered back-projection alone. METHODS: Seventy-nine consecutive patients (49 women, 30 men; 52 +/- 18 years) underwent pulmonary computed tomography angiography (120 kVp, 100-600 mA) reconstructed with filtered back-projection alone (ASIR0), 30% ASIR (ASIR30), and 50% ASIR (ASIR50) for this institutional review board-approved study. Two radiologists independently assessed PE depiction and vascular characterization, which was correlated with body mass index. RESULTS: Twelve patients (15%) had PE. No difference in PE depiction (P = 0.536), pulmonary arterial attenuation (P = 0.22-0.99), or subjective vascular characterization score (P = 0.58-.016) was observed for either blend. ASIR30 and ASIR50 achieved higher signal-to-noise ratio (P = 0.001-0.003). Body mass index inversely correlated with vascular characterization scores (P < 0.001). CONCLUSIONS: ASIR0, ASIR30, and ASIR50 accurately depict PE using the imaging parameters described. ASIR30 and ASIR50 improve objective image quality without altering subjective vascular characterization scores particularly when body mass index was less than 30 kg/m. PMID- 24045247 TI - Improving the image quality in computed tomographic pulmonary angiography with dual-energy subtraction: a new application of spectral computed tomography. AB - OBJECTIVES: The objectives of this study were to assess quantitative and subjective image quality in computed tomographic pulmonary angiography using dual energy subtraction methods compared with those of the monochromatic images using optimal contrast-to-noise ratios and those of the routine polychromatic images and to select the best dual-energy subtraction method. MATERIALS AND METHODS: A total of 1 routine polychromatic image, 3 sets of dual-energy subtraction images (DESIs), and 2 sets of monochromatic images with different optimal contrast-to noise ratios from 30 patients were obtained. The signal intensity and noise were measured; signal-to-noise ratio and contrast-to-noise ratio (CNR) were calculated. The global subjective image quality was subjectively assessed. RESULTS: The DESI 3 got the highest CNR and the DESI 1 got the second highest CNR. The DESI 1 got the highest global subjective image quality score. The 3 subtraction image sets got the highest score in visualization of the pulmonary artery branches. CONCLUSIONS: Computed tomographic pulmonary angiography with dual-energy subtraction technique is feasible. The DESI 1 afforded the best balance between the quantitative analysis and the subjective evaluation. PMID- 24045248 TI - Caudocranial scan direction and patient-specific injection protocols optimize ECG gated and non-gated thoracic CTA. AB - OBJECTIVES: Caudocranial scan direction and contrast injection timing based on measured patient vessel dynamics can significantly improve artery opacification and reduce contrast dose in the assessment of acute aortic syndrome using gated and non-gated thoracic CTA. This study aimed to investigate enhancement of the thoracic aorta using caudocranial scan direction and a patient-specific contrast regimen. METHODS: Electrocardiogram-gated (n = 120) and non-gated (n = 200) thoracic computed tomography angiography was performed on patients with nontraumatic acute aortic syndrome. Patients were assigned to one of 2 acquisition/contrast regimens, namely, regimen A, craniocaudal scan direction with 120 mL contrast, and regimen B, caudocranial scan direction using a patient specific contrast formula. Opacity of 9 arterial and venous segments was measured, arteriovenous contrast ratio calculated, and values compared using Mann Whitney U statistics. Receiver operating characteristic analyses and visual grading characteristic assessed diagnostic efficacy and clinical image quality. Interobserver variations were investigated using kappa methods. RESULTS: Regimen B when compared to A, for both scanning/contrast techniques, demonstrated higher opacification in the aorta (P < 0.01) and lower opacification in the venous system (P < 0.0001). For protocol B, arteriovenous contrast ratio was significantly increased (P < 0.0001) and mean contrast volume reduced (P < 0.05) during gated [94 (10 mL)] and non-gated [78 (5 mL)] thoracic computed tomography angiography compared to A. Receiver operating characteristic analysis Az scores and interobserver agreement were significantly higher with regimen B than A (P < 0.05). CONCLUSIONS: Caudocranial scan direction and injection timing based on patient-specific vessel dynamics can optimize artery opacification and diagnostic efficacy while reducing contrast volumes. PMID- 24045249 TI - Gadofosveset-enhanced magnetic resonance angiography of the thoracic vasculature in the equilibrium phase: feasibility and impact of dose. AB - OBJECTIVE: The objectives of this study were to evaluate the feasibility of gadofosveset-enhanced magnetic resonance angiography (MRA) of the thoracic vasculature in the equilibrium phase and to determine the impact of gadofosveset dose on imaging quality. METHODS: Thirty healthy volunteers were randomized to receive a dose of 0.03, 0.02, or 0.01 mmol/kg of gadofosveset for MRA at 3 T in the equilibrium phase. Two radiologists assessed the central veins, the pulmonary arteries, and the thoracic aorta. Quantitative assessments were also performed. RESULTS: At 0.03 and 0.02 mmol/kg, all vessel segments were rated as adequate. At a dose of 0.01 mmol/kg, less than 10% of vascular segments were collectively rated as inadequate. The signal-to-noise ratio and contrast-to-noise ratio were significantly lower in all segments at 0.01 mmol/kg compared with higher doses. CONCLUSIONS: Gadofosveset-enhanced MRA of the thoracic vessels in the equilibrium phase in healthy volunteers resulted in adequate vessel visualization, even when dose reduction was performed.This trial was registered with clinicaltrials.gov, identifier NCT01431300. PMID- 24045250 TI - Effect of lower tube voltage on the reproducibility of right-to-left ventricular diameter ratio measurements on computed tomographic pulmonary angiography images. AB - OBJECTIVE: This study aimed to evaluate the interobserver variability of right-to left ventricular (RV/LV) diameter ratios on computed tomographic pulmonary angiographies at reduced tube potential. METHODS: Consecutive computed tomographic pulmonary angiographies performed at 80 kVp for subjects weighing less than 80 kg (n = 40) and 100 kVp for those weighing 80 kg or greater (n = 40) were selected as the low peak kilovoltage cohort, with age- and sex-matched studies performed at 120 kVp forming the controls (n = 40 each). The interobserver variability in RV/LV diameter ratio on axial and 4-chamber images was evaluated. RESULTS: Interobserver correlation was excellent at both reduced tube voltages (correlation coefficients, 0.81-0.91; P < 0.001). Bland-Altman plots indicated higher variability at lower peak kilovoltage, confirmed only for axial measurements by multivariate regression adjusting for body weight and ventricular ratio (beta coefficient = 0.04 and 0.03, P = 0.049 and 0.022, for 80 kVp and 100 kVp, respectively). CONCLUSIONS: Lower tube voltage did not affect the reproducibility of RV/LV diameter ratio on 4-chamber images; for axial measurements, the increase in variability was 3% to 4% of the average ventricular ratio. PMID- 24045251 TI - Severity of systemic calcified atherosclerosis is associated with airflow limitation and emphysema. AB - OBJECTIVE: We investigated the association between systemic calcified atherosclerosis and airflow limitation. METHODS: A prospective cohort of 134 patients with chronic obstructive pulmonary disease (male:female = 124:10; mean age, 65.4 years) and 101 smokers without airflow limitation (male:female = 87:14; mean age, 51.8 y) were assessed by computed tomography, pulmonary function test, and blood sampling. We measured the extent of calcification in the major thoracic arteries (thoracic aorta, coronary arteries, aortic/mitral valvular annuli, and proximal neck vessels) as indicators of systemic calcified atherosclerosis. RESULTS: After adjustment for age and smoking, total calcium score correlated with volume fraction of emphysematous lung (r = 0.19, P = 0.005) and diffusing capacity (r = - 0.15, P = 0.028). Multivariate logistic regression showed significant associations between total calcium score and forced expiratory volume at 1 second/forced vital capacity (P = 0.016) and between coronary calcium score and forced expiratory volume at 1 second/forced vital capacity (P = 0.016; P = 0.004) and diffusing capacity (P = 0.041), independent of age, body mass index, and smoking amount. CONCLUSIONS: The amount of calcification was associated with the extent of emphysema on computed tomography and airflow limitation. PMID- 24045252 TI - Diabetes with preserved renal function is an independent risk factor for renal function deterioration after coronary computed tomography angiography. AB - OBJECTIVES: Diabetes mellitus (DM) and high fasting glucose levels are reportedly risk factors for contrast-induced nephropathy after invasive coronary angiography in patients with renal dysfunction. Cystatin C (CyC) is a sensitive marker for detecting early impairment of renal function. Using CyC, we investigated whether DM would be a risk for worsening renal function after coronary computed tomography angiography (CCTA) in patients with preserved renal function. METHODS: Two hundred twenty-eight patients scheduled for CCTA were enrolled. The serum CyC at preprocedure and 1 day after procedure, urinary microalbumin at preprocedure, and oral fluid volume for 24 hours after procedure were measured. The percentage changes in CyC from preprocedure to 1 day after procedure (%CyC) were also calculated. RESULTS: Ninety-eight patients had DM. The %CyC and urinary microalbumin were significantly greater in DM patients than in non-DM patients. The percentage of patients showing a %CyC of 10% or greater was significantly greater in DM patients than in non-DM patients (27% vs 8%, P < 0.01). Using multivariate regression analysis, oral fluid volume and urinary microalbumin were independent predictors for a %CyC of 10% or greater in DM patients (beta = - 0.428 [P < 0.0001] and beta = 0.464 [P < 0.0001], respectively). CONCLUSIONS: Diabetes mellitus is a risk factor for worsening changes in renal function after CCTA, even in patients with preserved renal function. In particular, elevated microalbuminuria and low oral fluid intake are high-risk factors for renal functional deterioration. PMID- 24045253 TI - Reduction of thoracic aorta motion artifact with high-pitch 128-slice dual-source computed tomographic angiography: a historical control study. AB - OBJECTIVES: Electrocardiogram-gated imaging combined with multi-detector row computed tomography (MDCT) has reduced cardiac motion artifacts, but it was not practical in the emergency setting. The purpose of this study was to evaluate the ability of a high-pitch, 128-slice dual-source CT (DSCT) scanner to reduce motion artifacts in patients admitted to the emergency room. METHODS: This study comprised 100 patients suspected of having thoracic aorta lesions. We examined 47 patients with the 128-slice DSCT scanner (DSCT group), and 53 patients were examined with a 64-slice MDCT scanner (MDCT group). Six anatomic areas in the thoracic aorta were evaluated. RESULTS: Computed tomography images in the DSCT group were distinct, and significant differences were observed in images of all areas between the 2 groups except for the descending aorta. CONCLUSIONS: The high pitch DSCT scanner can reduce motion artifacts of the thoracic aorta and enable radiological diagnosis even in patients with tachycardia and without breath hold. PMID- 24045254 TI - Chest computed tomography features predictive of elevated B-type natriuretic peptide independent of renal function: diagnostic implications for evaluation of congestive heart failure. AB - OBJECTIVE: B-type natriuretic peptide (BNP), commonly evaluated in patients suspected of congestive heart failure, is also elevated in patients with renal insufficiency. The objective of our study was to identify chest computed tomography features that correlate with BNP levels independent of renal function. MATERIALS AND METHODS: A total of 162 (of which 76 had normal BNP and 86 had elevated BNP) patients with chest computed tomography and serum BNP levels measured within 24 hours were evaluated for the presence of ground-glass opacities, interlobular septal thickening, mediastinal lymphadenopathy, mosaic perfusion, peribronchovascular thickening, pericardial effusion, and pleural effusion. Both univariate and multivariate analysis were used to correlate these features with the serum BNP. Multiple logistic regression was used to identify statistically significant correlates of BNP controlling for the glomerular filtration rate. RESULTS: Ground-glass opacity, interlobular septal thickening, pericardial effusion, and left- and right-sided pleural effusion were statistically significant predictors of elevated BNP on separate logistic regression incorporating the glomerular filtration rate. After multiple logistic regression, interlobular septal thickening (odds ratio, 5.69) and pleural effusion (odds ratio, 3.88) remained significant predictors of BNP independent of the glomerular filtration rate. CONCLUSIONS: Interlobular septal thickening and pleural effusion appear to be independent predictors of BNP, and this may be useful in the evaluation of patients for congestive heart failure in the setting of renal insufficiency. PMID- 24045255 TI - Dose reduction of 69% for computed tomography pulmonary angiography: reduced z axis computed tomography pulmonary angiography retains accuracy in those younger than 40 years. AB - OBJECTIVE: We sought to determine whether reduced scan range (z axis) computed tomography pulmonary angiography (CTPA) technique in 18- to 40-year age group can accurately detect pulmonary embolism (PE) and other important conditions and to quantify the resulting dose reduction. METHODS: We retrospectively identified 200 patients in the age group of 18 to 40 years who underwent CTPA over a period of 3 years. These included 86 patients with PEs and 114 randomly selected patients negative for PE (control subjects). The scans were modified by reducing the scan coverage by eliminating images above the aortic arch and below the base of the heart. Two blinded experienced radiologists rescored them for PE and incidental and pertinent non-PE findings. Discrepancies between these and the original report were assessed by a third experienced radiologist. Separately, a departmental quality-control project was conducted in 15 patients to assess the dose length product along the z axis across the 3 zones of thorax. RESULTS: Pulmonary embolism was diagnosed in all 86 patients. No pertinent additional findings were missed. Only 7 incidental findings were missed (eg, benign thyroid nodules [n = 4], benign adrenal adenoma [n = 1], gallstones [n = 1], and hepatic hemangioma [n = 1]). None affected clinical outcome or management. Dose length product was reduced by a mean of 69% (60%-79%). CONCLUSIONS: Reduced z-axis CTPA for PE is definitely feasible in 18- to 40-year age group. There is a significant radiation reduction (69%) and hence should be considered in selected subgroups of patients. PMID- 24045256 TI - A macroquantification approach for region-of-interest assessment in emission tomography. AB - In this article, we propose a quantification methodology for estimating the statistical parameters of the activity inside regions of interest (ROIs). Macroquantification implies a rearrangement of the emission projection data into macroprojections and a redefinition of the system matrix based either on an image reconstruction involving iterative ROI-wise regularization or on an ROI uniformity assumption. The technique allows a very fast computation of the ROI activities and covariance matrix in the least squares sense using a low dimensional model of the tomographic problem. The macroquantification approach is evaluated through Monte Carlo simulations using a numerical thorax phantom, without taking into account the measurement artifacts and assuming a perfect a priori ROI definition. Various tumor ROI configurations and count rates are considered to reflect clinical situations. The results show that our technique yields low-bias ROI estimations that turn out to be more accurate than classical estimates relying on pixel summation. Macroquantification also provides an approximation for the ROI variance that describes the effective variance obtained through the simulations fairly well. The technique is then validated using single photon emission computed tomography (SPECT) data from a physical phantom composed of cylinders filled with different Tc concentrations for the task of ROI comparison. Here again, the study shows excellent agreement between the measured and predicted values of the ROI variance resulting in efficient estimations of ROI ratios and highly accurate ROI comparisons. In its simplest formulation, macroquantification has a short computation time, making it an ideal technique for quantitative ROI assessment that is compatible with a wide range of routine clinical applications. PMID- 24045258 TI - Dynamic computed tomography of locally advanced pancreatic cancer: effect of low tube voltage and a hybrid iterative reconstruction algorithm on image quality. AB - OBJECTIVE: The objective of this study was to evaluate the effect of a low-tube voltage technique and hybrid iterative reconstruction (HIR) on image quality at dynamic computed tomography (CT) of the pancreas. METHODS: The study included 18 consecutive patients (10 women, 8 men; mean age, 68.5 +/- 9.5 years) with locally advanced pancreatic cancer who received chemotherapy and had stable disease during the 100- and 120-kV CT studies. The 120-kV images were reconstructed using filtered back projection, and the 100-kV images were postprocessed using filtered back projection and HIR. Scans obtained during 3 pancreatic phases were subjected to quantitative and qualitative analysis. RESULTS: The mean effective dose was significantly lower under the 100- than the 120-kV protocols (29.2 +/- 3.6 vs 52.1 +/- 5.1 mSv; P < 0.01). The mean contrast-to-noise ratio of the pancreatic cancer and the visual scores were significantly higher under 100 kV with HIR than those under the other 2 protocols (P < 0.01). CONCLUSIONS: Use of low tube voltage and HIR can provide significantly improved image quality at pancreatic dynamic CT. PMID- 24045257 TI - Extrinsic wrist ligaments: prevalence of injury by magnetic resonance imaging and association with intrinsic ligament tears. AB - OBJECTIVE: The objective of this study was to determine the prevalence of extrinsic wrist ligament injury by magnetic resonance imaging and its association with intrinsic ligament tears. METHODS: We reviewed conventional magnetic resonance images performed over a 5-year period from adult patients in the setting of wrist trauma. Two musculoskeletal radiologists examined the integrity of wrist ligaments and presence of bone abnormalities. RESULTS: In a cohort of 75 subjects, extrinsic ligament injury was present in 75%, with radiolunotriquetral being most frequently affected (45%). Intrinsic ligament injury was present in 60%. Almost half of subjects had combined intrinsic and extrinsic ligament injury. Bone abnormalities were seen in 69%. The rate of extrinsic injury was higher in subjects with bone injury (P = 0.008). CONCLUSIONS: There is high prevalence of extrinsic ligament injury in the setting of wrist trauma, especially in the presence of bone abnormalities, with combined injury of intrinsic and extrinsic ligaments in about half of cases. PMID- 24045259 TI - Morphologic classification of congenital short pancreas on multidetector computed tomography. AB - OBJECTIVE: The objective of this study was to assess the imaging characteristics and classify congenital short pancreas on the basis of morphologic features on multidetector computed tomography (MDCT) and to determine the associated diseases and congenital anomalies of each type. METHODS: We conducted a retrospective search from 2006 to 2012 using the keywords "short pancreas," "agenesis or hypoplasia of the dorsal pancreas," or "hypoplasia of the ventral pancreas." Clinical data and images were analyzed; finally, 24 patients with congenital short pancreas were included in this study. Imaging features of the 3 types of congenital short pancreas and their associated anomalies on MDCT were evaluated. RESULTS: Congenital short pancreas was classified into type 1 (agenesis or hypoplasia of the dorsal pancreas): no congenital anomaly but presence of diabetes mellitus (45%); type 2 (agenesis or hypoplasia of the pancreatic uncinate process): intestinal malrotation (100%); and type 3 (combined hypoplasia or agenesis of the uncinate process and dorsal pancreas): a spectrum of various congenital anomalies, including abdominal heterotaxy and abnormal spleen (100%). CONCLUSIONS: Recognizing the spectrum of agenesis or hypoplasia of the pancreas and morphologic classification of congenital short pancreas on MDCT may help radiologists detect and understand disease associated with congenital short pancreas. PMID- 24045260 TI - Prevalence and etiology of focal liver opacification in patients with superior vena cava obstruction. AB - OBJECTIVE: This study aimed to assess the prevalence and etiologies of focal liver opacification (FLO) in the setting of superior vena cava (SVC) obstruction. METHODS: An archival search using key words to identify patients with SVC obstruction or severe narrowing and who had computed tomographic scans with intravenous contrast was performed at our institution. RESULTS: Thirty-one patients were included. Focal liver opacification was identified in 9 (29%). The most common direct causes of FLO and SVC obstruction were benign. CONCLUSIONS: Focal liver opacification caused by SVC obstruction is relatively common. Focal liver opacification is more commonly associated with benign causes of obstruction such as end-stage renal disease. Identifying FLO is important not only as an indirect sign of SVC obstruction but also must be distinguished from avidly enhancing liver masses. This study also reflects the overall recent increase in benign causes of SVC obstruction. PMID- 24045261 TI - The usefulness of computed tomographic colonography for evaluation of deep infiltrating endometriosis: comparison with magnetic resonance imaging. AB - OBJECTIVE: We wanted to assess the diagnostic value and morphologic feature of deep infiltrating endometriosis (DIE), involving rectosigmoid colon, with computed tomography (CT) colonography in comparison with magnetic resonance (MR). METHODS: Fifty patients with DIE, who had undergone CT colonography and MR imaging (MRI) before surgery, were enrolled. Among these 50 patients who underwent laparoscopic surgery with DIE, 37 patients were diagnosed as rectosigmoid involvement of endometriosis (presence of rectal outer wall involvement, endometrial implantation in the rectouterine space, and complete obliteration of cul-de-sac with histologic confirmation). Image findings at CT colonography and MRI were reviewed by 2 radiologists to determine whether there are radiologic features that can help predict rectosigmoid endometriosis. Computed tomography images were analyzed for the luminal alteration of rectosigmoid colon, mural thickening, and mass formation in the rectosigmoid colon, whereas MR images were analyzed for the mass formation in the rectosigmoid colon, fat plane obliteration, between rectum and uterus or vagina, retroversion of uterus, retraction of uterus toward the colon, and detection of endometrial spot in rectovaginal or rectouterine space. Statistical analysis was performed with Pearson chi and receiver operating characteristic curve. RESULTS: With CT colonography, the luminal alteration of rectosigmoid colon was detected with sensitivity of 96.0% and specificity of 48.0% (P < 0.001) in the overall rectosigmoid endometriosis and with sensitivity of 84.0% and specificity of 80.0% (P = 0.005) in the case of DIE with cul-de-sac obliteration. With MR, the sensitivity and specificity for detection of endometriosis of rectosigmoid or rectouterine space were 94.4% and 37.5% (P = 0.013), respectively. Other variables had no statistical significance. The diagnostic accuracy of CT colonography is higher than that of MRI (area under the curve, 0.786 vs 0.691; P < 0.001), for the overall rectosigmoid endometriosis. In the evaluation of complete cul-de-sac obliteration, morphologic change of rectosigmoid colon is identified more accurately with CT colonography than that of MRI (area under the curve, 0.821 vs 0.686; P < 0.001). CONCLUSIONS: Both CT colonography and MRI are highly sensitive to the detection of rectosigmoid endometriosis, but lack specificity. However, the depiction rate of morphologic change in rectosigmoid colon is greater with CT colonography than that of MRI, in the case of cul-de-sac obliteration. The luminal alteration significantly correlates with morphologic change in rectosigmoid endometriosis. PMID- 24045262 TI - Factors affecting 18F-FDG uptake by metastatic lymph nodes in gastric cancer. AB - OBJECTIVE: We assessed factors affecting fluorine F 18 fluorodeoxyglucose (F-FDG) uptake of metastatic lymph nodes (LNs) in advanced gastric cancer (AGC) due to low F-FDG uptake of metastatic LNs in gastric cancer. METHODS: Retrospective analyses were performed on 31 patients with AGCs who underwent preoperative F-FDG positron emission tomography (PET) and subsequent gastrectomy. Metastatic LNs were compared with primary tumors (on a one-to-one basis) with respect to maximum standardized uptake values, glucose transporter type 1 (GLUT-1) expression, proliferation indices (using Ki-67), microvessel density, and lymphatic vessel density. RESULTS: Maximum standardized uptake values of metastatic LNs were significantly correlated with % GLUT-1 expression (rho = 0.80, P < 0.0001) and Ki 67 labeling index (rho = 0.57, P = 0.001) in LNs. These uptake values were also significantly correlated with SUVs (rho = 0.54; P = 0.002), % GLUT-1 expression (rho = 0.71, P < 0.0001), and Ki-67 labeling index (rho = 0.43, P = 0.019) in primary tumors. In multiple regression analysis, only % GLUT-1 expression in primary tumors and metastatic LNs were significant factors in predicting maximum standardized uptake value of metastatic LNs. CONCLUSIONS: In AGCs, GLUT-1 expression and Ki-67 labeling index are important factors in predicting F-FDG uptake by metastatic LNs. PMID- 24045263 TI - Serendipity in the diagnosis of pheochromocytoma. AB - OBJECTIVES: Pheochromocytomas are increasingly being discovered incidentally on imaging studies performed without clinical suspicion of the existence of an adrenal lesion. We aimed to determine the rate of diagnosis of adrenal pheochromocytoma as an incidental finding during a recent 7-year period. METHODS: We obtained the Department of Pathology database to study all the patients at our institution with newly diagnosed pheochromocytomas in the 7-year period from 2005 to 2011 to determine the clinical presentation and the means of diagnosis. RESULTS: In 40 (70.2%) of the 57 patients, an adrenal pheochromocytoma was detected in an imaging study performed without suspicion of an adrenal lesion. There were 13 chest computed tomography studies-8 to evaluate for possible pulmonary emboli. Other indications included abdominal pain or discomfort (n = 8), trauma (n = 3), abnormal liver function tests (n = 3), suspect renal artery stenosis (n = 3), hematuria (n = 2), colitis (n = 2), and 4 miscellaneous indications. DISCUSSION: Our study documents that the commonest current means of initial detection of pheochromocytoma is by serendipitous discovery. In 16 of our 40 patients with serendipitously discovered pheochromocytomas, there were no clinical symptoms of pheochromocytoma; these were true incidentalomas. More than two thirds of the new cases of pheochromocytoma were detected by serendipity (found during studies not performed to evaluate for pheochromocytoma), approximately one third were true incidentalomas (pheochromocytomas in patients without symptoms). CONCLUSIONS: In a 7-year period at a single institution, 40 patients, 70% of new cases of surgically proven pheochromocytoma, were initially detected by serendipity. Sixteen patients, 40% of those incidentally discovered represented true examples of "incidentalomas." PMID- 24045264 TI - Institutional experience with solid pseudopapillary neoplasms: focus on computed tomography, magnetic resonance imaging, conventional ultrasound, endoscopic ultrasound, and predictors of aggressive histology. AB - OBJECTIVE: Solid pseudopapillary neoplasms (SPNs) are low-grade malignancies with an excellent prognosis, albeit with the potential for metastatic disease. This study details our institution's experience with the diagnosis and treatment of SPN, including clinical presentation, multimodality imaging findings, and potential predictors of aggressive tumor behavior. MATERIALS AND METHODS: The institutional pathology database was searched through for all cases of SPN since 1988, yielding 51 patients. The electronic medical record was searched for clinical and demographic information regarding these patients, including age, sex, presenting symptoms, type of surgery, postoperative length of stay, tumor markers, and postsurgical follow-up. All available imaging data were reviewed, including those of 30 patients who underwent multidetector computed tomography, those of 9 patients who underwent magnetic resonance imaging (MRI), those of 3 patients who underwent conventional ultrasound, and those of 11 patients who underwent endoscopic ultrasound. RESULTS: A total of 84% of patients were females, with a mean age of only 33 years. Prognosis was excellent, with a mean follow-up of 3 years without recurrence. Only 1 of the 51 patients developed metastatic disease to the liver 8 years after the surgery. On computed tomography, lesions tended to be large (5.3 cm), well circumscribed (29/30), round/oval (20/30), and encapsulated (23/30). The lesions often demonstrated calcification (14/30) and typically resulted in no biliary or pancreatic ductal dilatation. The lesions ranged from completely cystic to completely solid. On MRI, the lesions often demonstrated a T2 hypointense or enhancing capsule (6/9) and demonstrated internal blood products (5/9). The lesions tended to be devoid of vascularity on conventional ultrasound. Ten patients were found to have "aggressive" histology at presentation (T3 tumor, nodal involvement, perineural invasion, or vascular invasion). No demographic, clinical, or multidetector computed tomographic imaging features were found to correlate with aggressive histology. CONCLUSIONS: Certain imaging features (eg, well-circumscribed mass with calcification, peripheral capsule, internal blood products, and lack of biliary/pancreatic ductal obstruction) on computed tomography and MRI are highly suggestive of the diagnosis of SPN, particularly when visualized in young female patients. However, it is not possible to predict aggressive histology on the basis of imaging findings, clinical presentation, or patient demographic features. PMID- 24045265 TI - Diagnostic role of computed tomographic enterography differentiating crohn disease from intestinal tuberculosis. AB - OBJECTIVES: The aim of the present study was to evaluate the diagnostic role of computed tomographic enterography (CTE) in distinguishing Crohn disease (CD) from intestinal tuberculosis (ITB). MATERIALS AND METHODS: From January 2006 to August 2011, a total of 81 consecutive patients (64 patients with CD and 17 patients with ITB) who received CTE on the initial workup were included. In CTE, degree of bowel involvement (number and length), mural change (mural hyperenhancement, stratification, wall thickening, and distribution), adjacent mesenteric change (comb sign, fibrofatty proliferation, fistula, abscess, and lymphadenopathy), and peritoneal change (peritoneal thickening and ascites) were assessed. RESULTS: Segmental involvement, comb sign, fibrofatty changes, moderate wall thickening, and asymmetric distribution were significantly more common in the patients with CD than those with ITB. A positive comb sign was the most suggestive finding of CD (sensitivity, 74.1%; specificity, 90.9%). CONCLUSIONS: A positive comb sign is the most suggestive finding that differentiates CD from ITB. PMID- 24045266 TI - Renal lymphoma: MR appearance with diffusion-weighted imaging. AB - Imaging of renal lymphoma on magnetic resonance imaging and diffusion-weighted imaging is not well documented in the literature. We present a case of renal lymphoma in a 61-year-old patient with computed tomography and magnetic resonance imaging correlation. The lymphomatous lesions demonstrate mild enhancement and restricted diffusion. Differential considerations for hypoenhancing masses include papillary or chromophobe renal cell carcinoma, lymphoma, urothelial tumor, or metastasis, all of which have different management pathways. Apparent diffusion coefficient values can be obtained using diffusion-weighted imaging, and may be useful in identifying focal renal lesions, especially on noncontrast imaging. Apparent diffusion coefficient values may be helpful in differentiating between some of these lesions, although more investigation is needed. PMID- 24045268 TI - Subicular activation preceding hippocampal ripples in vitro. AB - Sharp wave-ripple complexes (SW-Rs), a transient form of high-frequency field oscillations observed in the hippocampus, are thought to mediate memory consolidation. They are initiated mainly in hippocampal CA3 area and propagate to the entorhinal cortex through the subiculum; however, little is known about how SW-Rs are initiated and propagate. Here, we used functional multineuronal calcium imaging to monitor SW-R-relevant neuronal activity from the subiculum at single cell resolution. An unexpected finding was that a subset of subicular neurons was activated immediately before hippocampal SW-Rs. The SW-R-preceding activity was not abolished by surgical lesion of the CA1-to-subiculum projection, and thus, it probably arose from entorhinal inputs. Therefore, SW-Rs are likely to be triggered by entorhinal-to-CA3/CA1 inputs. Moreover, the subiculum is not merely a passive intermediate region that SW-Rs pass through, but rather, it seems to contribute to an active modification of neural information related to SW-Rs. PMID- 24045267 TI - The cone-dominant retina and the inner ear of zebrafish express the ortholog of CLRN1, the causative gene of human Usher syndrome type 3A. AB - Clarin-1 (CLRN1) is the causative gene in Usher syndrome type 3A, an autosomal recessive disorder characterized by progressive vision and hearing loss. CLRN1 encodes Clarin-1, a glycoprotein with homology to the tetraspanin family of proteins. Previous cell culture studies suggest that Clarin-1 localizes to the plasma membrane and interacts with the cytoskeleton. Mouse models demonstrate a role for the protein in mechanosensory hair bundle integrity, but the function of Clarin-1 in hearing remains unclear. Even less is known of its role in vision, because the Clrn1 knockout mouse does not exhibit a retinal phenotype and expression studies in murine retinas have provided conflicting results. Here, we describe cloning and expression analysis of the zebrafish clrn1 gene, and report protein localization of Clarin-1 in auditory and visual cells from embryonic through adult stages. We detect clrn1 transcripts as early as 24h post fertilization, and expression is maintained through adulthood. In situ hybridization experiments show clrn1 transcripts enriched in mechanosensory hair cells and supporting cells of the inner ear and lateral line organ, photoreceptors, and cells of the inner retina. In mechanosensory hair cells, Clarin-1 is polarized to the apical cell body and the synapses. In the retina, Clarin-1 localizes to lateral cell contacts between photoreceptors and is associated with the outer limiting membrane and subapical processes emanating from Muller glial cells. We also find Clarin-1 protein in the outer plexiform, inner nuclear and ganglion cell layers of the retina. Given the importance of Clarin-1 function in the human retina, it is imperative to find an animal model with a comparable requirement. Our data provide a foundation for exploring the role of Clarin-1 in retinal cell function and survival in a diurnal, cone dominant species. PMID- 24045269 TI - Higher order harmonic detection for exploring nonlinear interactions with nanoscale resolution. AB - Nonlinear dynamics underpin a vast array of physical phenomena ranging from interfacial motion to jamming transitions. In many cases, insight into the nonlinear behavior can be gleaned through exploration of higher order harmonics. Here, a method using band excitation scanning probe microscopy (SPM) to investigate higher order harmonics of the electromechanical response, with nanometer scale spatial resolution is presented. The technique is demonstrated by probing the first three harmonics of strain for a Pb(Zr(1-x)Ti(x))O3 (PZT) ferroelectric capacitor. It is shown that the second order harmonic response is correlated with the first harmonic response, whereas the third harmonic is not. Additionally, measurements of the second harmonic reveal significant deviations from Rayleigh-type models in the form of a much more complicated field dependence than is observed in the spatially averaged data. These results illustrate the versatility of n(th) order harmonic SPM detection methods in exploring nonlinear phenomena in nanoscale materials. PMID- 24045270 TI - Photonic polarization gears for ultra-sensitive angular measurements. AB - Quantum metrology bears a great promise in enhancing measurement precision, but is unlikely to become practical in the near future. Its concepts can nevertheless inspire classical or hybrid methods of immediate value. Here we demonstrate NOON like photonic states of m quanta of angular momentum up to m=100, in a setup that acts as a 'photonic gear', converting, for each photon, a mechanical rotation of an angle theta into an amplified rotation of the optical polarization by mtheta, corresponding to a 'super-resolving' Malus' law. We show that this effect leads to single-photon angular measurements with the same precision of polarization only quantum strategies with m photons, but robust to photon losses. Moreover, we combine the gear effect with the quantum enhancement due to entanglement, thus exploiting the advantages of both approaches. The high 'gear ratio' m boosts the current state of the art of optical non-contact angular measurements by almost two orders of magnitude. PMID- 24045271 TI - CoCEST: cobalt(II) amide-appended paraCEST MRI contrast agents. AB - The first examples of air-stable Co(II) paraCEST MRI contrast agents are reported. Amide NH protons on the complexes give rise to CEST peaks that are shifted up to 112 ppm from the bulk water resonance. One complex has multiple CEST peaks that may be useful for ratiometric mapping of pH. PMID- 24045272 TI - Impact of occult hepatitis B virus infection or hepatitis B virus DNA integration on efficacy of chronic hepatitis C treatment with peginterferon and ribavirin: where are we? PMID- 24045273 TI - Split dosing bowel preparation: patients' willingness and lack of interference with travel. PMID- 24045274 TI - In vitro analysis of gastric phytobezoar dissolubility by coca-cola, coca-cola zero, cellulase, and papain. PMID- 24045275 TI - Unexplained common bile duct dilatation with normal serum liver enzymes: diagnostic yield of endoscopic ultrasound and follow-up of this condition. AB - BACKGROUND: There is scant literature about common bile duct (CBD) dilatation with normal liver function tests (LFTs). AIMS: The aims of this study were to assess the diagnostic yield of endoscopic ultrasound (EUS) in patients with CBD dilatation, normal LFTs, and prior inconclusive imaging tests, and to assess the natural history of these subjects. METHODS: We retrospectively reviewed our EUS database for patients referred for evaluation of CBD dilatation, normal LFTs, and prior inconclusive imaging. We excluded patients with a prior endoscopic retrograde cholangiopancreatography or a history of biliary obstruction, pancreatitis, or jaundice. Follow-up data were retrieved from medical records or by calling the general practitioners, referring specialists, patients, or their closest relatives. RESULTS: A total of 57 patients were enrolled. The mean CBD diameter was 12.5+/-3.6 mm. The majority of patients (50.8%) were asymptomatic. Abnormal EUS findings were recorded in 12 (21%) subjects: 6 patients had a periampullary diverticulum, 2 had ampullary adenoma, 2 had signs of chronic pancreatitis, 1 had a cancer of the pancreatic head, and 1 had a 7 mm CBD stone. Neither age, sex, prior cholecystectomy, clinical presentation, CBD diameter, nor a dilated main pancreatic duct were predictors of abnormal EUS findings. None of the patients complained of biliary symptoms or showed abnormal LFTs on long-term follow-up. CONCLUSIONS: CBD dilatation with normal liver chemistry is not always a benign condition. Even when prior imaging tests are negative, EUS may allow to diagnose conditions overlooked by standard diagnostic imaging. PMID- 24045276 TI - Trends in epidemiology, treatment, and survival of hepatocellular carcinoma patients between 1998 and 2009: an analysis of 1066 cases of a German HCC Registry. AB - GOALS: The aim of this study was to analyze clinical presentation, course of disease, and management of patients with hepatocellular carcinoma (HCC) in a German referral center between 1998 and 2009. BACKGROUND: HCC is a rare tumor in Germany, but its incidence has increased over the last 30 years. New therapies such as chemoembolization with drug-eluting beads, selective internal radiotherapy, and sorafenib were introduced recently; however, the impact on clinical management and overall survival (OS) is unclear. STUDY: In this retrospective analysis, 1066 patients with HCC, separated into two 6-year periods (n=385; 1998 to 2003 and n=681; 2004 to 2009) were evaluated. RESULTS: The number of patients presenting each year (64 vs. 114 per year), with an age over 80 years or with nonalcoholic steatohepatitis increased significantly between periods. The main risk factors were alcoholic liver disease in 51.7%, chronic hepatitis C virus in 28.2%, and chronic hepatitis B virus in 13.4% of patients with liver cirrhosis and HCC. Patients presented with more advanced tumor stages and with worse liver function in period 2. The majority (61.6%) of patients received local treatment over a spectrum of Barcelona Clinic Liver-Cancer (BCLC) stages, whereas systemic therapy was offered to a minority (8.8%) and limited to BCLC stage C patients only. OS decreased in BCLC stage A and D and improved in BCLC stage B and C and decreased for all patients from 16.5 to 15.3 months between periods. CONCLUSIONS: No improvement of OS was observed when comparing time periods, partly because of the more advanced stage of HCC and because of the increasing age in the second time period. Improved and new therapeutic options and the intensification of surveillance programs are likely to increase survival of HCC patients in the future. PMID- 24045277 TI - Endoscopic and histologic abnormalities of gastrointestinal tract in patients with hereditary hemochromatosis. AB - BACKGROUND: Patients with iron overload frequently complained of upper gastrointestinal (GI) symptoms. This study aimed to systemically evaluate the association between hereditary hemochromatosis (HH) and gut inflammation. PATIENTS AND METHODS: HH patients were identified using the ICD-9 codes. Inclusion criteria were patients with primary HH who had esophagogastroduodenoscopy (EGD) and/or colonoscopy with GI biopsies (N=39). Patients undergoing EGD with duodenal biopsy for the indication of "rule out celiac disease" were included in the control group (N=40). GI biopsy specimens were rereviewed and scored. RESULTS: Of the 39 patients with genetically confirmed primary HH in the study group, 28 (71.8%) had liver biopsy and 25 (89.3%) of them showed iron deposition. Twenty-five patients (64.1%) had EGD and 23 (59.0%) had colonoscopy. Histologic inflammation was identified in the esophagus in 2 patients (8.0%), stomach in 11 (44.0%), duodenum in 2 (8.7%), and colon in 3 (13.0%). Duodenal biopsy specimen was available for rereview in 16 patients (41.0%). Patient demographics were comparable between the 16 cases in the study group and the 40 cases in the control group. On histology, the frequency of intraepithelial lymphocytosis of small intestine was 25.5% in the HH cases versus 2.5% in controls (P=0.020). HH patients also had a greater proportion of intraepithelial neutrophil infiltration (31.2% vs. 2.5%, P=0.006) and lamina propria lymphocyte infiltration (31.2% vs. 0%, P=0.001) than controls. CONCLUSIONS: GI inflammation was common in HH patients, which from the different perspective, supports the notion that iron overload may lead to GI inflammation. PMID- 24045278 TI - Otolaryngeal GERD symptoms and Barrett esophagus: implications for cancer prevention. PMID- 24045279 TI - Viral breakthrough is associated with resistance using direct acting agents in patients treated for chronic hepatitis C infection. AB - BACKGROUND: Despite improved virologic response with the addition of direct acting agents to peginterferon and ribavirin treatment in chronic hepatitis C virus (HCV) genotype 1 infection, a subset of patients experience viral breakthrough while on therapy. Defining viral breakthrough and patient characteristics is important for ongoing and future HCV treatment. METHODS: Thirty-four patients treated with telaprevir between June 2011 and July 2012 were retrospectively evaluated for presence of viral breakthrough. Baseline patient characteristics, time to viral breakthrough, and HCV resistance patterns were determined. RESULTS: Viral breakthrough was seen in 26.5% of patients treated. Eight of 9 patients experienced breakthrough in the peginterferon and ribavirin only phase of treatment with mean (+/-SD) time to breakthrough of 21.3 (+/-6.4) weeks. Viral breakthrough was more frequently seen in patients with genotype 1a, advanced liver fibrosis, and prior null treatment response. A majority of patients had presence of resistant mutations upon testing. CONCLUSIONS: A significant proportion of patients experience viral breakthrough after completion of the direct acting agent portion of triple therapy. More frequent virologic assessments during the peginterferon and ribavirin treatment phase may be necessary to reduce cost and adverse effects of treatment. PMID- 24045280 TI - Role of hepatitis B surface antigen (HBsAg) in identifying true inactive HBsAg carriers infected with genotype C hepatitis B virus. AB - BACKGROUND: Inactive and active phases of hepatitis B e antigen-negative chronic hepatitis B virus (HBV) infection are diagnosed by serum HBV DNA levels, with cutoff at 2000 IU/mL. However, it is difficult to distinguish inactive carriers at a single time point because HBV DNA levels can transiently decrease to <2000 IU/mL even in noninactive carriers. GOALS: We aimed to establish the role of serum hepatitis B surface antigen (HBsAg) in identifying "true inactive carriers" among treatment-naive genotype C HBV-infected patients with low viremia. STUDY: A total of 133 hepatitis B e antigen-negative carriers with serum HBV DNA levels of <2000 IU/mL and normal alanine aminotransferase levels were enrolled and followed up for >12 months. RESULTS: Forty patients (30.1%) were classified as noninactive carriers (HBV DNA >=2000 IU/mL and/or alanine aminotransferase >40 IU/L) during 12 months from enrollment. No baseline serum HBV DNA levels could identify true inactive carriers with 100% specificity, whereas baseline serum HBsAg levels (50 IU/mL) identified true inactive carriers with 100% specificity and 29% detection rate. Detection rate increased when different cutoff levels were applied to different age groups according to median age (46 y). It was comparable in both younger and older groups (37.2% vs. 38%) even when HBsAg cutoff level was increased in the former (400 vs. 50 IU/mL). Furthermore, none reversed to noninactive phase during long-term follow-up when these cutoff levels were applied. CONCLUSIONS: Baseline serum HBsAg levels at a single time point can identify persistently true inactive carriers, with different cutoff levels according to age. PMID- 24045281 TI - The potential of transabdominal 3D color doppler ultrasonography for diagnosis of gastric varices. AB - GOALS/BACKGROUND: To examine the potential of transabdominal 3-dimensional (3D) color Doppler ultrasonography (3D-US) as a noninvasive tool to characterize gastric varices. STUDY: This was a prospective study in which endoscopy was performed on 107 patients with chronic liver disease. Among these patients, 70 (42 males, 28 females) had gastric varices (46 fundal varices, 24 cardia varices; 30 small, 28 medium, and 12 large), and the 37 patients (25 males, 12 females) without gastric varices served as controls. The 3D-US data and endoscopic findings were compared with respect to grade, location, and similarity of varices. RESULTS: The sensitivity and specificity of the 3D-US technique to detect gastric varices were 88.6% (62/70) and 100% (37/37), respectively. Although all fundal varices appeared adjacent to the posterior gastric wall, cardia varices were detected separately from the wall with a mean distance of 21.2 mm. The vascular volumes (mL) were 0.84+/-0.71 in small varices, 5.52+/-3.81 in medium varices, and 10.9+/-6.3 in large varices, with significant differences between different grades. The best cutoff value to detect medium-grade/large grade gastric varices was 2.0 mL, with 83.3% sensitivity and 95.8% specificity. Seventy-nine percent (55/70) of patients showed partial resemblance or better between the 3D images and the endoscopic findings with good interreviewer agreement. CONCLUSIONS: 3D-US can quantitatively characterize gastric varices noninvasively in terms of grade, location, and appearance. This approach has the potential to improve objectivity and reduce invasiveness in the management of gastric varices. PMID- 24045282 TI - Systemic cytotoxic chemotherapy of patients with advanced hepatocellular carcinoma in the era of sorafenib nonavailability. AB - GOALS: The goal of the study was to compare the efficacy and safety of sorafenib with those of systemic cytotoxic chemotherapy. BACKGROUND: Sorafenib treatment has shown to improve the survival in patients with advanced hepatocellular carcinoma (HCC) when compared with placebo. However, whether sorafenib controls advanced-stage HCC better than systemic cytotoxic chemotherapy has not been elucidated. STUDY: We retrospectively reviewed the medical records of 220 patients with measurable advanced HCC who had not received systemic treatment previously between January 2007 and April 2012. Among these patients, 78 had been treated with sorafenib. Another 14 patients who were treated with a 4-weekly regimen of adriamycin, cisplatin, and capecitabine were included as the historical control group for comparison. The median overall survival, the progression-free survival, response rates, and safety profiles were evaluated. RESULTS: Baseline characteristics were similar between the treatment groups. The median overall survival was 7.2 months [95% confidence interval (CI), 5.6-8.8] in the sorafenib group and 11.2 months (95% CI, 8.1-14.2) in the cytotoxic chemotherapy group (P=0.10). The median progression-free survival was 3.2 months (95% CI, 2.2-4.3) in the sorafenib group and 5.9 months (95% CI, 3.6-8.2) in the cytotoxic chemotherapy group (P=0.07). The deterioration of liver function and neutropenia were the most frequent serious adverse events in the sorafenib and the systemic chemotherapy group. CONCLUSIONS: Although a direct head-to-head comparison could not be done, there were some patients who showed a good response to systemic cytotoxic chemotherapy. Further assessment is necessary to study the role of chemotherapy in patients who are intolerant or intractable to sorafenib. PMID- 24045283 TI - High-sensitivity C-reactive protein level is an independent predictor of poor prognosis in cirrhotic patients with spontaneous bacterial peritonitis. AB - BACKGROUND/AIMS: The production of high-sensitivity C-reactive protein (hs-CRP) may be affected by hepatic function, and the clinical importance of hs-CRP in patients with liver cirrhosis is still not clear. The aim of this study was to evaluate the clinical implications of hs-CRP in cirrhotic patients with spontaneous bacterial peritonitis (SBP). METHODS: We retrospectively investigated 336 consecutive patients treated for SBP from 2007 to 2012. The relationship between serum hs-CRP and the result of the treatment was assessed. RESULTS: A response to antibiotics was observed in 182 patients (54.2%), and 126 patients (37.5%) died of SBP. The initial hs-CRP (odds ratio=1.061, P=0.016), coexistent hepatocellular carcinoma, and Child-Pugh (CP) score were independent prognostic factors for high in-hospital mortality. Serum hs-CRP level was also an independent predictor of lower antibiotic response rate (odds ratio=0.916, P<0.001). However, hs-CRP was negatively correlated with the CP score (r=-0.199, P<0.001) and Model for End-Stage Liver Disease score (r=-0.182, P=0.001). CONCLUSIONS: This study found that serum hs-CRP level is related to a lower response rate to antibiotics, a higher mortality rate in patients with SBP. The hs-CRP level was negatively correlated with the CP and Model for End-Stage Liver Disease scores, which suggests that the prognostic function of hs-CRP was not a surrogate for hepatic dysfunction. PMID- 24045284 TI - Evaluation of the aspartate aminotransferase/platelet ratio index and enhanced liver fibrosis tests to detect significant fibrosis due to chronic hepatitis C. AB - BACKGROUND: The assessment of liver fibrosis in chronic hepatitis C patients is important for prognosis and making decisions regarding antiviral treatment. Although liver biopsy is considered the reference standard for assessing hepatic fibrosis in patients with chronic hepatitis C, it is invasive and associated with sampling and interobserver variability. Serum fibrosis markers have been utilized as surrogates for a liver biopsy. METHODS: We completed a prospective study of 191 patients in which blood draws and liver biopsies were performed on the same visit. Using liver biopsies the sensitivity, specificity, and negative and positive predictive values for both aspartate aminotransferase/platelet ratio index (APRI) and enhanced liver fibrosis (ELF) were determined. The patients were divided into training and validation patient sets to develop and validate a clinically useful algorithm for differentiating mild and significant fibrosis. RESULTS: The area under the ROC curve for the APRI and ELF tests for the training set was 0.865 and 0.880, respectively. The clinical sensitivity in separating mild (F0-F1) from significant fibrosis (F2-F4) was 80% and 86.0% with a clinical specificity of 86.7% and 77.8%, respectively. For the validation sets the area under the ROC curve for the APRI and ELF tests was, 0.855 and 0.780, respectively. The clinical sensitivity of the APRI and ELF tests in separating mild (F0-F1) from significant (F2-F4) fibrosis for the validation set was 90.0% and 70.0% with a clinical specificity of 73.3% and 86.7%, respectively. There were no differences between the APRI and ELF tests in distinguishing mild from significant fibrosis for either the training or validation sets (P=0.61 and 0.20, respectively). Using APRI as the primary test followed by ELF for patients in the intermediate zone, would have decreased the number of liver biopsies needed by 40% for the validation set. Overall, use of our algorithm would have decreased the number of patients who needed a liver biopsy from 95 to 24-a 74.7% reduction. CONCLUSIONS: This study has shown that the APRI and ELF tests are equally accurate in distinguishing mild from significant liver fibrosis, and combining them into a validated algorithm improves their performance in distinguishing mild from significant fibrosis. PMID- 24045285 TI - Abatacept: a new treatment option for refractory adult autoimmune enteropathy. AB - Autoimmune enteropathy (AIE) is a rare disease that has been observed in both children and adults. It typically manifests with symptoms of diarrhea, requiring long-term immunosuppression. Endoscopically, the duodenum typically exhibits villous blunting with partial or complete villous blunting, deep crypt lymphocytosis, increased apoptotic bodies, and minimal intraepithelial lymphocytosis on histologic analysis. The pathophysiology of AIE likely involves a hyperactive immune state in the setting of a T-cell regulatory defect, resulting in destruction of the enterocyte. We report a case of a 49-year-old woman who presented with refractory diarrhea, diagnosed as AIE. After failing multiple conventional therapies, she demonstrated clinical and histologic response to abatacept, a selective modulator of T-cell activation. We aim to increase awareness of this rare inflammatory disorder and new treatment options for this debilitating condition. PMID- 24045286 TI - Text messaging for sexual communication and safety among African American young adults. AB - African American young adults are at high risk of HIV infection during their lifetimes, and the male condom remains the best method of prevention. Efforts to increase condom use should address the barrier of condom negotiation. We conducted a thematic analysis of qualitative, semistructured interviews with African American young adults to examine their use of text messaging for requesting human immunodeficiency virus (HIV) or sexually transmitted infection (STI) testing and condom use within the larger context of general sexual communication using text messages. Text messaging gave participants a level of comfort and disinhibition to discuss sexual topics and negotiate sexual safety. Benefits of text messages included ease of communication, privacy, and increased ability to express condom desires. Difficulties reflected the potential relationship implications of suggesting HIV/STI testing and condom use. Condom negotiation strategies using text messages also mirrored those found to be used in face-to-face communication. PMID- 24045287 TI - Synthesis, structure, and reactivity of tris(amidate) mono(amido) and tetrakis(amidate) complexes of group 4 transition metals. AB - The syntheses of a series of tris(amidate) mono(amido) titanium and zirconium complexes are reported. The binding motif of the amidate ligand has been determined to depend on the size of the metal centre for these sterically demanding N,O-chelating ligands; the larger zirconium metal centre supports three kappa(2)-(N,O) bound amidate ligands while the titanium analogue has one ligand bound in a kappa(1)-(O) fashion to alleviate steric strain. Reactivity studies indicate that, despite high steric crowding about the tris(amidate) mono(amido) zirconium metal centre, transamination of the reactive dimethylamido ligand can be achieved using aniline. This complex is also an active precatalyst for intramolecular alkene hydroamination, in which protonolysis of one amidate ligand in the presence of excess amine is observed as an initiation step prior to catalytic turnover. Eight-coordinate homoleptic kappa(2)-amidate complexes of zirconium and hafnium have also been prepared. PMID- 24045288 TI - Influence of SiO2 on the structure-controlled synthesis and magnetic properties of prismatic MnO2 nanorods. AB - Silicon dioxide-doped tetragonal MnO2 single crystalline prismatic nanorods have been successfully synthesized through a facile hydrothermal route at a temperature of 250 degrees C with a reaction time as quick as 5 h. The synthesized MnO2 prismatic nanorods were characterized by x-ray diffraction, field emission scanning electron microscopy, energy dispersive x-ray analysis, transmission electron microscopy, high resolution transmission electron microscopy with selected area electron diffraction and Raman spectroscopy. Experimental results show that single crystalline tetragonal MnO2 nanorods have been successfully synthesized at all doping concentrations and that nanorods with a prismatic surface morphology have been obtained at 20 mass% of SiO2. The diameter of as-prepared MnO2 nanorods increases from 125 to 250 nm on increasing the dopant concentration. X-ray photoelectron spectroscopy analysis confirms the presence of valence Si (2p) of SiO2 in the as-prepared MnO2 nanostructures. The intensity of Raman modes clearly increases with increasing doping concentration, indicating an improvement in the structural aspects of the MnO2 nanorods. The magnetic properties of the products have been evaluated using a vibrating sample magnetometer, revealing that the as-prepared MnO2 nanorods exhibit weak ferromagnetic behavior at room temperature. The Neel temperature of the as obtained products is calculated as 97 K. On the basis of the structural information, a growth mechanism is proposed for the formation of prismatic-like 1D MnO2 nanorods. PMID- 24045289 TI - Room temperature rubbing for few-layer two-dimensional thin flakes directly on flexible polymer substrates. AB - The functional layers of few-layer two-dimensional (2-D) thin flakes on flexible polymers for stretchable applications have attracted much interest. However, most fabrication methods are "indirect" processes that require transfer steps. Moreover, previously reported "transfer-free" methods are only suitable for graphene and not for other few-layer 2-D thin flakes. Here, a friction based room temperature rubbing method is proposed for fabricating different types of few layer 2-D thin flakes (graphene, hexagonal boron nitride (h-BN), molybdenum disulphide (MoS2), and tungsten disulphide (WS2)) on flexible polymer substrates. Commercial 2-D raw materials (graphite, h-BN, MoS2, and WS2) that contain thousands of atom layers were used. After several minutes, different types of few layer 2-D thin flakes were fabricated directly on the flexible polymer substrates by rubbing procedures at room temperature and without any transfer step. These few-layer 2-D thin flakes strongly adhere to the flexible polymer substrates. This strong adhesion is beneficial for future applications. PMID- 24045290 TI - Single-crystalline, wormlike hematite photoanodes for efficient solar water splitting. AB - A hematite photoanode showing a stable, record-breaking performance of 4.32 mA/cm2 photoelectrochemical water oxidation current at 1.23 V vs. RHE under simulated 1-sun (100 mW/cm2) irradiation is reported. This photocurrent corresponds to ca. 34% of the maximum theoretical limit expected for hematite with a band gap of 2.1 V. The photoanode produced stoichiometric hydrogen and oxygen gases in amounts close to the expected values from the photocurrent. The hematitle has a unique single-crystalline "wormlike" morphology produced by in situ two-step annealing at 550 degrees C and 800 degrees C of beta-FeOOH nanorods grown directly on a transparent conducting oxide glass via an all-solution method. In addition, it is modified by platinum doping to improve the charge transfer characteristics of hematite and an oxygen-evolving co-catalyst on the surface. PMID- 24045291 TI - Living on a volcano's edge: genetic isolation of an extremophile terrestrial metazoan. AB - Communities of organisms inhabiting extreme terrestrial environments provide a unique opportunity to study evolutionary forces that drive population structure and genetic diversity under the combined challenges posed by multiple geogenic stressors. High abundance of an invasive pantropical earthworm (and the absence of indigenous lumbricid species) in the Furnas geothermal field (Sao Miguel Island, Azores) indicates its remarkable tolerance to high soil temperature, exceptionally high carbon dioxide and low oxygen levels, and elevated metal bioavailability, conditions which are lethal for the majority of terrestrial metazoans. Mitochondrial and nuclear markers were used to analyze the relationship between populations living inside and outside the geothermal field. Results showed that Pontoscolex corethrurus (Annelida, Oligochaeta, Glossoscolecidae) to be a genetically heterogeneous complex within the Sao Miguel landscape and is probably differentiated into cryptic species. The population exposed to the hostile soil conditions within the volcanic caldera possesses the lowest within-population mitochondrial diversity but an unexpectedly high degree of nuclear variability with several loci evidencing positive selection, parameters indicative of a genetically unique population only distantly related to conspecifics living outside the caldera. In conclusion, P. corethrurus inhabiting active volcanic soil is a discrete extremophile population that has evolved by tolerating a mixture of non-anthropogenic chemical and physical stressors. PMID- 24045293 TI - Theoretical study on low-lying states of Ga2X (X = P, As) with coupled-cluster approaches. AB - Low-lying states of Ga2P and Ga2As are investigated with the equation-of-motion coupled-cluster approach for ionized states at the singles and doubles level (EOMIP-CCSD) as well as at the CCSDT-3 level together with CCSD, CCSD(T), and DFT. Except for the asymmetric stretching b2 mode of the (2)B2 and (2)A1 states, all these approaches provide structures, frequencies and adiabatic electron affinities that are in reasonable agreement with each other. According to our results, the lowest-energy state of these two molecules is the (2)A' state of C(s) symmetry and the (2)B2 state is the ground electronic state with C(2v) symmetry. As for the b2 mode, CCSD and CCSD(T) afford real frequencies for the (2)B2 state, while EOM approaches and DFT with most exchange-correlation functionals give rise to imaginary frequencies. The (2)B2 and (2)A1 states couple with each other due to distortion along b2 mode through the pseudo-Jahn-Teller effect. Analysis on results shows that EOM approaches afford reasonable b2 frequencies for the two states and DFT approaches, except for BP86 and PBE, provide qualitatively correct b2 frequencies for the (2)B2 state. In addition, a potential matrix is introduced to describe the vibronic coupling between the (2)B2 and (2)A1 states and parameters in the matrix are fitted to the adiabatic potential curves from EOMIP-CCSD results. PMID- 24045292 TI - Comparing the intersex genetic correlation for fitness across novel environments in the fruit fly, Drosophila serrata. AB - Sexually antagonistic genetic variation can pose limits to the independent evolution and adaptation of the sexes. The extent of sexually antagonistic variation is reflected in the intersex genetic correlation for fitness (rw(FM)). Previous estimates of this correlation have been mostly limited to populations in environments to which they are already well adapted, making it difficult to gauge the importance of sexually antagonistic genetic variance during the early stages of adaptation, such as that occurring following abrupt environmental change or upon the colonization of new habitat. Here we assayed male and female lifetime fitness in a population of Drosophila serrata in four novel laboratory environments. We found that rw(FM) varied significantly across environments, with point estimates ranging from positive to negative values of considerable magnitude. We also found that the variability among estimates was because, at least in part, of significant differences among environments in the genetic variances of both male and female fitness, with no evidence of any significant changes in the intersex covariance itself, although standard errors of these estimates were large. Our results illustrate the unpredictable nature of rw(FM) in novel environments and suggest that, although sexually antagonistic genetic variance can be pronounced in some novel environments, it may have little effect in constraining the early stages of adaptation in others. PMID- 24045294 TI - The mode of action of anticancer gold-based drugs: a structural perspective. AB - The interactions between a few representative gold-based drugs and hen egg white lysozyme were studied by X-ray crystallography. High resolution crystal structures solved for three metallodrug-protein adducts provide valuable insight into the molecular mechanism of these promising metal compounds and the inherent protein metalation processes. PMID- 24045300 TI - Making sense of serotype-specific pneumococcal antibody measurements. PMID- 24045301 TI - The performances of the Cockcroft-Gault, modification of diet in renal disease study and chronic kidney disease epidemiology collaboration equations in predicting gentamicin clearance. AB - BACKGROUND: It is unclear which renal function equation, employing an isotope dilution mass spectrometry (IDMS)-aligned creatinine assay, best predicts gentamicin clearance. METHODS: The performances of the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD) Study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations for predicting gentamicin clearances were assessed retrospectively in 240 patients treated with gentamicin during 2011-2012, when the local creatinine assay was IDMS-aligned. Comparisons were based on the percentage within 30% of gentamicin clearance (P 30) and the root-mean-square error (RMSE) of each equation. Gentamicin clearance was calculated from plasma concentrations using a one-compartment model. RESULTS: The Cockcroft-Gault equation and the CKD-EPI equation corrected for individual body surface area (BSA) were associated with the highest P 30 (69% and 67%, respectively) and lowest RMSE (39 and 36 mL/min, respectively) in the 240 patients. Correction for individual BSA improved the performances of the MDRD Study and CKD-EPI equations in patients with body mass indices <18.5 or >=30 kg/m(2). The equations systematically underestimated gentamicin clearance as gentamicin clearance increased, with performance being inferior with gentamicin clearance >=90 versus <90 mL/min. CONCLUSIONS: The CKD-EPI equation corrected for individual BSA, and the Cockcroft-Gault equation, provided the best estimates of gentamicin clearance. The CKD-EPI and MDRD Study equations should be corrected for individual BSA at the extremes of body size, if used for guiding gentamicin therapy. The performances of the equations were inferior in patients with higher values of gentamicin clearance. PMID- 24045302 TI - Establishing trimester-specific maternal thyroid function reference intervals. AB - BACKGROUND: Thyroid disorders are common in women of childbearing age and are associated with adverse pregnancy outcomes. Physiological changes in pregnancy and the lack of pregnancy-specific reference ranges make managing thyroid disorders in pregnancy challenging. Our aim was to establish trimester-specific thyroid function reference intervals throughout pregnancy, and to examine the prevalence of thyroid autoimmunity in otherwise euthyroid women. METHOD: This was a prospective, cross-sectional study of thyroid function tests (TFTs) in pregnant women attending a large, tertiary referral maternity hospital. Patients with known thyroid disorders, autoimmune disease, recurrent miscarriage, hyperemesis gravidarum and pre-eclampsia were excluded. TFTs were analysed in the CUH biochemistry laboratory using Roche Modular E170 electrochemiluminescent immunoassay. Trimester-specific reference ranges (2.5th, 50th and 97.5th centiles) were calculated. RESULTS: Three-hundred-and-fifty-one women were included into the analysis. Median maternal age was 30. Thyroid-stimulating hormone concentrations showed slightly increasing median centile throughout gestation. Free thyroxine (T4) and T3 decreased throughout gestation. Table 1 demonstrates the calculated percentiles according to gestational weeks. CONCLUSION: We established pregnancy-specific thyroid function reference intervals for our pregnant population, for use in clinical practice. PMID- 24045303 TI - Pseudohyperkalaemia in leukaemic patients: the effect of test tube type and form of transport to the laboratory. AB - BACKGROUND: The present study was aimed at determining the effect of the tube type used for primary sample collection and the manner of transport prior to assessment (either manual or by pneumatic tube) on the degree of pseudohyperkalaemia in leukaemic patients. METHODS: Blood from six leukaemic patients was collected into seven primary sample tubes (Monovette(r), Sarstedt): sample A, heparinized blood gas syringe (potassium reference value); sample B, plasma Li-heparin without separator gel; sample C, plasma Li-heparin with separator gel; and sample D, serum with separator gel. The primary sample tubes designated B, C and D were transported to the laboratory manually. Duplicates of the same sample tubes, B(PT), C(PT) and D(PT), were sent to the laboratory by pneumatic tube. RESULTS: In patients with chronic lymphocytic leukaemia (CLL), there was no increase in the concentration of potassium in samples B, C and D when compared to the reference value. Transport of the samples by pneumatic tube led to a pronounced increase in potassium concentration in samples B(PT) and C(PT), whereas there was no increase in sample D(PT) when compared to the reference value. In the patient with chronic myeloid leukaemia (CML), an increase in potassium concentration occurred in sample D and in samples B(PT), C(PT) and D(PT). A similar finding was observed in the patient with acute lymphocytic leukaemia (ALL), furthermore with an extremely high concentration of potassium in samples C and C(PT). CONCLUSIONS: Manual transport of non-coagulable blood (plasma Li-heparin without separator gel) to the laboratory results in the least possible artificial increase in potassium concentration in the sample. PMID- 24045304 TI - Vaccine providers' perspectives on impact, challenges, and response during the California 2010 pertussis outbreak. AB - INTRODUCTION: California has experienced its worst outbreak of pertussis in 50 y. In preparing for such outbreaks of pertussis, vaccine providers in the state play a key role in educating patients about the public health implications of vaccination, explaining the benefits to immunization, and facilitating patients' receipt of recommended immunizations. METHODS: We conducted a survey of 800 California vaccine providers to investigate provider level response to recent pertussis outbreaks and regulation by provider type and geography. RESULTS: Sixty nine percent (533/777) of vaccine providers within the state of California responded to the survey. Fifty-three percent (278/527) of vaccine providers indicated that it was part of standard care at their practice or pharmacy location to ask adult patients about pertussis vaccine (Table 1) and this varied across practice types (P<0.0001). Fifty-seven percent of providers (270/476) indicated that the information they received from the state about pertussis during the 2010 California pertussis outbreak was very useful or useful, while 52% of providers indicated this information was neutral, not useful, not at all useful. Vaccine administration, patient groups seen, and challenges varied by provider type however meaningful differences among subpopulations to which the vaccine was administered were found between provider types (P<0.001, Table 2). CONCLUSION: The 2010 pertussis outbreak in California challenged vaccine providers in a way that changed the preparation, promotion, and planning for future outbreaks and emergency situations. Adaptability to the new state law and increased awareness of pertussis in the physician community were important in the number of patients receiving the vaccine. Also, forming partnerships with schools and health agencies were important in facilitating and promoting wide spread vaccination. PMID- 24045306 TI - A visible-light-induced overall water-splitting photocatalyst: conduction-band controlled silver tantalate. AB - Visible-light-induced water splitting was achieved by increasing the visible light sensitivity of AgTaO3, by the introduction of Nb, generating AgTa1-xNbxO3. After grafting NiO onto AgTa0.7Nb0.3O3, simultaneous, catalytic liberation of H2 and O2 at a molar ratio of ~2 : 1 was achieved from pure water under only visible light irradiation. PMID- 24045305 TI - Increasing functional modularity with residence time in the co-distribution of native and introduced vascular plants. AB - Species gain membership of regional assemblages by passing through multiple ecological and environmental filters. To capture the potential trajectory of structural changes in regional meta-communities driven by biological invasions, one can categorize species pools into assemblages of different residence times. Older assemblages, having passed through more environmental filters, should become more functionally ordered and structured. Here we calculate the level of compartmentalization (modularity) for three different-aged assemblages (neophytes, introduced after 1500 AD; archaeophytes, introduced before 1500 AD, and natives), including 2,054 species of vascular plants in 302 reserves in central Europe. Older assemblages are more compartmentalized than younger ones, with species composition, phylogenetic structure and habitat characteristics of the modules becoming increasingly distinctive. This sheds light on two mechanisms of how alien species are functionally incorporated into regional species pools: the settling-down hypothesis of diminishing stochasticity with residence time, and the niche-mosaic hypothesis of inlaid neutral modules in regional meta communities. PMID- 24045307 TI - Ultrafast branching in the excited state of coumarin and umbelliferone. AB - In the present work we have explored the ultrafast relaxation network of coumarin and umbelliferone (7-hydroxy-coumarin) using time-resolved femtosecond spectroscopy and quantum chemical calculations. Despite the importance of the photophysical properties of coumarin derivatives for applications in biomedicine, the low fluorescence quantum yield of coumarin itself has not been fully understood so far. On the basis of our combined experimental and theoretical results we suggest a model for the ultrafast decay after photoexcitation incorporating two parallel radiationless relaxation pathways: one within the initially excited state via ring opening and the other one by transition into a dark state along the carbonyl stretching mode. The fluorescence quantum yield is determined by the position of the branching point relative to the Franck-Condon region which is strongly influenced by interactions with the environment and the substitution pattern. This model is finally capable of giving a comprehensive account of the striking differences observed in the photophysical behavior of coumarin as opposed to umbelliferone. PMID- 24045308 TI - Reinforcing Ag nanoparticle thin films with very long Ag nanowires. AB - We employed very long nanowires mixed into nanoparticle thin films to improve their weak crack resistance for flexible electronics. We also measured the dependence of the failure strain and resistivity of the Ag nanowire-reinforced Ag nanoparticle thin films on the wt% and sintering condition of nanowires by means of resistance measurements under tension in an in situ tensile tester. Very long nanowires of over 90 MUm suppressed thin film cracking by bridging cracks in both the transverse and longitudinal directions and also reduced the electrical resistivity under tension. Moreover, diffusion and growth of nanowires induced by the thermal annealing process was observed, resulting in a highly increased failure strain. Due to the use of the same materials, effective diffusion was facilitated, thus inducing strong bonds between nanoparticles and nanowires. PMID- 24045309 TI - Reading between the COPD audits: have current GOLD standards lost their lustre? PMID- 24045310 TI - Pneumococcal disease in New Zealand and prevailing inequalities, the tip of the lower respiratory infection iceberg. PMID- 24045311 TI - A disease deadlier than war. PMID- 24045312 TI - Audit of acute exacerbations of chronic obstructive pulmonary disease at Waitemata District Health Board, New Zealand. AB - AIM: To examine management and outcome of patients admitted to Waitemata District Health Board (WDHB) with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and determine performance according to evidence-based guidelines. METHODS: Retrospective chart review of all patients admitted to WDHB hospitals with primary diagnosis of AECOPD during May and October 2010. 195 admissions (156 patients) were audited. RESULTS: Patients comprised 72 females and 84 males; mean age 73.1 years. 96% were ever-smokers. 10% of patients had BMI <18 kg/m2 and 40% of these received no dietician input. Spirometry was recorded in 72% within the previous 5 years. Chest X-ray was performed in 96% in the first 24 hours and 33% had arterial blood gas (ABG) performed. Twenty-three patients (29%) had acute respiratory acidosis. Continuous positive airways pressure (CPAP) was used in 11 but none received non-invasive ventilation (NIV). Systemic corticosteroids and antibiotics were prescribed to 87% and 84% respectively. Ten percent of patients were referred for pulmonary rehabilitation (PR). Overall 90 day mortality was 6.7% with 3.1% inpatient mortality. Mean length of stay was 5 days. 90-day re-admission rate was 44%. CONCLUSION: Areas of good adherence to best practice guidelines. Room for improvement in use of NIV, ABG and spirometry measurement, and PR referral. PMID- 24045313 TI - Impact of pneumococcal vaccine on hospital admission with lower respiratory infection in children resident in South Auckland, New Zealand. AB - AIM: To assess the change in admission rates for all Lower Respiratory Infection (LRI) including pneumonia for children resident in Counties Manukau District Health Board (CMDHB) with the introduction of the Pneumococcal Conjugate Vaccine 7 valent (PCV7) in June 2008. METHOD: National Minimum dataset ICD10 coded LRI admissions to any NZ hospital August 2001-July 2011 for children <2 year resident in CMDHB were analysed using Poisson regression, omitting 1 August 2008 to 31 July 2009, the first-year post vaccine introduction. RESULTS: Pneumonia but not bronchiolitis admissions have been declining since 2001. Pneumonia admissions decreased significantly after PCV7 introduction (incidence risk ratio (IRR) (95% CI) 1.51 (1.08-1.77), additional to the gradual decline since 2001. There was significant decline for Pacific children post PCV7 introduction IRR 1.70(1.39, 2.07) but not for Maori children, IRR 1.05 (0.78-1.40). Maori and Pacific children are at increased risk of admission with LRI compared to European children (relative risk (RR) (95%CI) 4.6 (4.3-5.0) and 5.0(3.7-5.3) respectively) as are those living in Decile 9, 10 compared with those from other deciles, RR 1.43 (1.36-1.50). CONCLUSION: The introduction of PCV7 is associated with reduced admissions for pneumonia in young children yet there has been less impact for Maori in CMDHB. PMID- 24045314 TI - Severe impact of the 1918-19 pandemic influenza in a national military force. AB - The impact of pandemic influenza on the New Zealand Expeditionary Force (NZEF) in 1918-19 has never been studied using modern epidemiological methods. Therefore we analysed mortality and descriptive data from various sources for these military personnel. An estimated 930 NZEF personnel deaths from pandemic influenza occurred in 1918-19, making it the main cause of disease deaths, and representing 5.1% of all NZEF deaths from World War One (WW1). The epidemic curve was much more drawn out in the Northern Hemisphere compared with the Southern Hemisphere. Mortality rates varied markedly by setting (e.g. in military camps, by country and by hemisphere). Significantly higher mortality rates were found amongst NZEF personnel: aged 30-34 years, those of Maori ethnicity, those with a rural background, and those who left New Zealand for Europe in 1918. In conclusion, this work documents the heavy mortality burden from pandemic influenza amongst this national military force and highlights the large variations in mortality rates through host and environmental factors. PMID- 24045316 TI - Assessing the value for money of pharmaceuticals in New Zealand--PHARMAC's approach to cost-utility analysis. AB - Cost-utility analysis (CUA) is a form of economic analysis that has been used by PHARMAC for nearly 20 years. It is also used by many health funding and assessment agencies internationally. So what is CUA and why is it so important? This article describes the process involved in undertaking CUA, including critical appraisal of clinical evidence; transforming the evidence to estimate quality-adjusted life years (QALYs); estimating costs; and how this information is combined to obtain an output that can be used to inform decision-making. The article also describes how PHARMAC uses CUA to prioritise pharmaceuticals for funding in New Zealand. PMID- 24045315 TI - Awareness and perceived effectiveness of smoking cessation treatments and services among New Zealand parents resident in highly deprived suburbs. AB - AIM: To describe the awareness and perceived effectiveness of smoking cessation treatments and services among a population of mainly Maori and Pacific parents in South Auckland, New Zealand. METHOD: Parents of pre-adolescent children from 4 schools were surveyed from 2007-2009 using a self-complete questionnaire. Awareness and perceived effectiveness of cessation treatments and services were analysed by smoking status, ethnicity, gender and age. Relative risks were calculated using log-binomial regression to establish differences between smokers and non-smokers. RESULTS: Awareness of Quitline, nicotine gum, and nicotine patch was higher among smokers (94%, 91%, 90%) than non-smokers (87%, 73%, 64%). Low percentages of smokers reported cessation interventions as effective (only 41% for Quitline--the intervention perceived effective by most). Awareness of varenicline, bupropion and nortriptyline was the lowest among both smokers and non-smokers (<31%). CONCLUSION: Poor awareness and low perceived efficacy of smoking cessation treatments and services among priority groups are barriers to accelerating the reduction of smoking prevalence in New Zealand. PMID- 24045317 TI - Negative pressure dressing around the airway. AB - BACKGROUND: Negative pressure wound therapy (NPWT) is an effective modality in most areas of the body and is associated with more rapid healing. However the use of negative pressure remains a challenge in managing complex wounds of the head and neck region. METHODS AND RESULTS: We present the case of a patient with a laryngectomy stoma and an adjacent defect. This was successfully closed in ten days using a novel dressing system comprising Aekin cohesive circular dressings, a Shiley cuffed non-fenestrated size 6.0 tracheostomy tube, and a NPWT device. CONCLUSIONS: Until now NPWT dressings in the head and neck region have been limited by wounds that develop around a laryngectomy stoma or tracheostomy site. We have described the successful use of a negative pressure dressing around the airway owing to the combined use of a tracheosotomy tube and the appropriate dressing. PMID- 24045318 TI - An unusual cause of pleural effusion. PMID- 24045319 TI - Medical image. A puzzling lady with persistent wheeze and pulmonary nodules: diffuse idiopathic pulmonary neuro-endocrine cell hyperplasia (DIPNECH). PMID- 24045320 TI - Medical image. An unexpected finding in a patient with cough: anterior mediastinal mass. PMID- 24045321 TI - Debate over tobacco and film ratings should be evidence-based. PMID- 24045322 TI - The 'moral flabbiness' of compulsory apologies. PMID- 24045323 TI - Critical influences on the rate of intramolecular vibrational redistribution: a comparative study of toluene, toluene-d3 and p-fluorotoluene. AB - The intramolecular vibrational redistribution (IVR) dynamics following the excitation of a mode in the first electronically excited states of toluene, toluene-d3 and p-fluorotoluene that has predominantly C-CH3 stretching character and an internal energy of ~1200 cm(-1) have been compared using picosecond time resolved photoelectron imaging spectroscopy as a probe. Temporal changes in the intensities of spectral features in each molecule have enabled IVR lifetimes of 12, 15 and 50 ps, respectively, to be determined. Our measurements show that doorway states are critical in mediating the IVR dynamics in toluene and toluene d3, and we deduce that these doorway states, which are assigned in the course of this work, are also instrumental in reducing the IVR lifetimes of these molecules relative to p-fluorotoluene. PMID- 24045324 TI - Synthesis and characterization of ruthenium polypyridyl complexes with hydroxypyridine derivatives: effect of protonation and ethylation at the pyridyl nitrogen. AB - A new series of ruthenium polypyridyl complexes with a hydroxypyridine ligand were prepared, and their properties were investigated spectroscopically and electrochemically. Particular focus is paid to the effects of protonation deprotonation and ethylation of the hydroxypyridine ligand, which affects the NMR, electronic spectroscopy, and electrochemistry of the complex. The changes to the UV-vis spectrum were used to determine a pka of 10.5 for the hydroxypyridine nitrogen. In the NMR, protonation of the hydroxypyridine ligand of the complex causes changes in the chemical shifts of the protons on both the hydroxypyridine and bipyridine rings, indicating some degree of electronic communication between these ligands. In addition, it is found that deprotonation of the hydroxypyridine ligand strongly affects the redox potential of the ruthenium metal center, shifting it more negative by 0.4 V. While the electrochemistry of the protonated complex contains irreversible electrochemical events, both deprotonation and subsequent ethylation of the hydroxypyridine ligand result in reversible electrochemistry for all events within the solvent window. For the ethylated complex, we search for a ligand to ligand charge transfer band, corresponding to electron transfer between bipyridine ligands in the mixed valence state. Despite the potential for electronic coupling between ligands through the metal center, we were unable to find any spectroscopic evidence of such electronic coupling. PMID- 24045326 TI - 2013 Award recipients--Reid R. Heffner, Jr., MD and Dawna D. Armstrong, MD. PMID- 24045328 TI - New approach for earthquake/tsunami monitoring using dense GPS networks. AB - In recent times increasing numbers of high-rate GPS stations have been installed around the world and set-up to provide data in real-time. These networks provide a great opportunity to quickly capture surface displacements, which makes them important as potential constituents of earthquake/tsunami monitoring and warning systems. The appropriate GPS real-time data analysis with sufficient accuracy for this purpose is a main focus of the current GPS research. In this paper we propose an augmented point positioning method for GPS based hazard monitoring, which can achieve fast or even instantaneous precise positioning without relying on data of a specific reference station. The proposed method overcomes the limitations of the currently mostly used GPS processing approaches of relative positioning and global precise point positioning. The advantages of the proposed approach are demonstrated by using GPS data, which was recorded during the 2011 Tohoku-Oki earthquake in Japan. PMID- 24045327 TI - Incidence rates of dementia, Alzheimer disease, and vascular dementia in the Japanese American population in Seattle, WA: the Kame Project. AB - There are few studies on the incidence of dementia in representative minority populations in the United States; however, no population-based study has been conducted on Japanese American women. We identified 3045 individuals aged 65+ with at least 1 parent of Japanese descent living in King County, WA in the period 1992 to 1994, of whom 1836 were dementia-free and were examined every 2 years (1994 to 2001) to identify incident cases of all dementias, Alzheimer disease (AD), vascular dementia (VaD), and other dementias. Cox regression was used to examine associations with age, sex, years of education, and apolipoprotein (APOE)-epsilon4. Among 173 incident cases of dementia, the overall rate was 14.4/1000/y, with rates being slightly higher among women (15.9/1000) than men (12.5/1000). Rates roughly doubled every 5 years for dementia and AD; the age trend for VaD and other dementias was less consistent. Sex was not significantly related to incidence of dementia or its subtypes in adjusted models. There was a trend for an inverse association with increasing years of education. APOE-epsilon4 was a strong risk factor for all dementias [hazard ratio (HR)=2.89; 95% confidence interval (CI), 1.88-4.46], AD (HR=3.27; 95% CI, 2.03 5.28), and VaD (HR=3.33; 95% CI, 1.34-8.27). This study is the first to report population-based incidence rates for both Japanese American men and women. PMID- 24045329 TI - New bhimamycins from Streptomyces sp. AK 671. AB - From the wild-type strain Steptomyces sp. AK 671, three nitrogen-containing octaketides were isolated, bhimamycins F, H and I, besides the known azaanthraquinone utahmycin A and polyketide shunt products SEK 4, SEK 4b, mutactin, dehydromutactin and EM18. The structures were characterized by MS and NMR experiments. The hitherto unknown absolute configuration of the two enantiomers of EM18 was determined by online-CD spectroscopy and quantum-chemical CD calculations. Bhimamycins H and I show weak antibacterial activities, whereas the enzyme phosphodiesterase 4 is strongly inhibited by bhimamycins H and I, which has never been reported for nitrogen-containing octaketides. In addition, bhimamycin H inhibits the enzyme glycogen synthase kinase-3beta. PMID- 24045330 TI - Antibiotic resistance and biofilm formation ability among coagulase-negative staphylococci in healthy individuals from Portugal. PMID- 24045332 TI - Optimizing insulin pump therapy: a quality improvement project. AB - PURPOSE: The purpose of the study was to assess insulin pump use and provide ongoing education. METHODS: A quality improvement project using a pump assessment questionnaire was implemented at an endocrinology office in the southeastern United States. The questionnaire was designed to evaluate all aspects of insulin pump therapy, including pump operations, infusion set failure, management of acute complications, and usage of advanced device features. Eighty-nine patients (80% with type 1 diabetes and 20% with type 2 diabetes) completed the questionnaire at the endocrinology practice. A certified diabetes educator reviewed the questions with each patient, identifying deficiencies and training opportunities. RESULTS: The most common areas of deficiency identified after implementation of the assessment form included the following: expired or no basal insulin prescription in the event of pump failure or removal, no mupirocin (Bactroban(r), GlaxoSmithKline, Research Triangle Park, North Carolina) prescription for suspected site infections, lack of insulin syringe if pump stopped working, failure to check urine ketones, no antiemetic prescription for sick day intervention, using manual bolus instead of bolus calculator, and lack of in-date glucagon kit. CONCLUSIONS: Use of a pump assessment questionnaire allows for focused discussion concerning patient behaviors related to pump operations, troubleshooting, and self-management. Incorporating use of a pump assessment questionnaire into routine practice may result in improved patient education and avoidance of adverse events specific to insulin pump therapy. PMID- 24045331 TI - A validated tool to predict colorectal neoplasia and inform screening choice for asymptomatic subjects. AB - OBJECTIVE: We aim to develop and validate a clinical scoring system to predict the risks of colorectal neoplasia to better inform screening participants and facilitate their screening test choice. DESIGN: We recruited 5220 Chinese asymptomatic screening participants who underwent colonoscopy in Hong Kong during 2008-2012. From random sampling of 2000 participants, independent risk factors were evaluated for colorectal neoplasia, defined as adenoma, advanced neoplasia, colorectal cancer or any combination thereof using binary regression analysis. The ORs for significant risk factors were used to develop a scoring system ranging from 0 to 6: 0-2 'average risk' (AR) and 3-6 'high risk' (HR). The other 3220 screening participants prospectively enrolled between 2008 and 2012 for screening colonoscopy formed an independent validation cohort. The performance of the scoring system for predicting colorectal neoplasia was evaluated. RESULTS: The prevalence of colorectal neoplasia in the derivation and validation cohorts was 31.4% and 30.8%, respectively. Using the scoring system developed, 78.9% and 21.1% in the validation cohort were classified as AR and HR, respectively. The prevalence of colorectal neoplasia in the AR and HR groups was 27.1% and 44.6%, respectively. The subjects in the HR group had 1.65-fold (95% CI 1.49 to 1.83) increased prevalence of colorectal neoplasia than the AR group. CONCLUSIONS: The scoring system based on age, gender, smoking, family history, Body Mass Index and self-reported diabetes is useful in predicting the risk of colorectal neoplasia. PMID- 24045333 TI - Analysis of behavior risk factor surveillance system data to assess the health of Hispanics with diabetes in US-Mexico border communities. AB - PURPOSE: The purpose of this study is to describe and compare personal characteristics, health care access and utilization, and self-management behaviors of Hispanic American adults diagnosed with diabetes who reside in 3 US Mexico border counties in Arizona, New Mexico, and Texas. This study also examines the status of this population in attaining Healthy People (HP) 2020 diabetes target goals. METHODS: Data were extracted from the 2005-2009 Selected Metropolitan/Micropolitan Area Risk Trends (SMART): Behavioral Risk Factor Surveillance System (BRFSS) to analyze behavioral and health system factors associated with diabetes management among Hispanic American adults who reside in the border counties (N = 600). Data were analyzed using descriptive statistics and compared using chi-square and one-way analysis of variance. RESULTS: There were significant differences in health care access and utilization and in 1 self management behavior (daily feet checks) across the counties. The majority of participants (83.4%) had a care provider, however the HP 2020 diabetes target goals for A1C monitoring or foot exams conducted by a care provider were not met. Participants in all counties met the target goal for dilated eye exams. CONCLUSIONS: Improvement of diabetes management among this population should focus on border health system barriers to attaining HP 2020 diabetes target goals. PMID- 24045334 TI - Fast and selective recognizes polysaccharide by surface molecularly imprinted film coated onto aldehyde-modified magnetic nanoparticles. AB - In this work, a starch imprinted magnetic nanoparticles composite material has been successfully synthesized. This molecular imprinted material has promising practical utility in capturing polysaccharides for pharmacology applications. First, we synthesized Fe3O4 nanoparticles by coprecipitation, followed by the modification of tetraethyl orthosilicate (TEOS) and functional amino group and aldehyde group, respectively. Then we used functionalized Fe3O4@SiO2 as the magnetic cores, starch as the template, 3-aminophenylboronic acid (APBA) as the functional monomer and ammonium persulphate (APS) as the initiator. Magnetic molecularly imprinted nanoparticles (MMIPs) were synthesized by surface-imprinted polymerization under airtight tubes at room temperature for 24 h. MMIPs were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA), X-ray diffraction (XRD) and vibrating sample magnetometer (VSM) analysis. This showed a high saturation magnetization value (5.59 emu g(-1)) easily reached under an external magnetic field. The binding experiments were shown to have relatively high adsorption capacity (15.45 mg g( 1)) and selective recognition ability over structurally related compounds. Therefore, MMIPs provide a sensitive and selective approach and offer the potential to become a new key for polysaccharide separation and purification. PMID- 24045335 TI - Improvements in an in vivo neutron activation analysis (NAA) method for the measurement of fluorine in human bone. AB - We previously published a method for the in vivo measurement of bone fluoride using neutron activation analysis (NAA) and demonstrated the utility of the technique in a pilot study of environmentally exposed people. The method involved activation of the hand in an irradiation cavity at the McMaster University Accelerator Laboratory and acquisition of the resultant gamma-ray signals in a '4pi' NaI(Tl) detector array of nine detectors. In this paper we describe a series of improvements to the method. This was investigated via measurement of hand simulating phantoms doped with varying levels of fluorine and fixed amounts of sodium, chlorine and calcium. Four improvements to the technique were tested since our first publication. The previously published detection limit for phantom measurements using this system was 0.66 mg F/g Ca. The accelerator irradiation and detection facilities were relocated to a new section of the laboratory and one more detector was added to the detection system. This was found to reduce the detection limit (possibly because of better detection shielding and additional detector) to 0.59 mg F/g Ca, a factor of 1.12. A new set of phantoms was developed and in this work we show that they improved the minimum detectable limit for fluoride in phantoms irradiated using neutrons produced by 2.15 MeV protons on lithium by a factor of 1.55. We compared the detection limits previously obtained using a summed signal from the nine detectors with the detection limit obtained by acquiring the spectra in anticoincidence mode for reduction of the disturbing signal from chlorine in bone. This was found to improve the ratio of the detection of fluorine to chlorine (an interfering signal) by a factor of 2.8 and the resultant minimum detection limit was found to be reduced by a factor of 1.2. We studied the effects of changing the timing of gamma-ray acquisition. Our previously published data used a series of three 10 s acquisitions followed by a 300 s count. Changing the acquisition to a series of six 5 s acquisitions was found to further improve the detection limit by a factor of 1.4. We also present data showing that if the neutron dose is delivered to the phantom in a shorter time period, i.e. the dose rate is increased and irradiation shortened then the detection limit can be reduced by a further factor of 1.35.The overall improvement in detection limit by employing all of these changes was found to be a factor of 3.9. The technique now has an in phantom detection limit of 0.17 mg F/g Ca compared to a previous detection limit of 0.66 mg F/g Ca. The system can now be tested on human volunteers to see if individuals with diagnosed fluorosis can be distinguished from the general Canadian population using this technique. PMID- 24045337 TI - Activation of liver X receptor suppresses the production of the IL-12 family of cytokines by blocking nuclear translocation of NF-kappaBp50. AB - There is now convincing evidence that liver X receptor (LXR) is an important modulator of the inflammatory response; however, its mechanism of action remains unclear. This study aimed to examine the effect of LXR on the IL-12 family of cytokines and examined the mechanism by which LXR exerted this effect. We first demonstrated that activation of murine-derived dendritic cells (DC) with a specific agonist to LXR enhanced expression of LXR following activation with LPS, suggesting a role in inflammation. Furthermore, we showed LXR expression to be increased in vivo in dextrane sulphate sodium-induced colitis. LXR activation also suppressed production of IL-12p40, IL-12p70, IL-27 and IL-23 in murine derived DC following stimulation with LPS, and specifically targeted the p35, p40 and EBI3 subunits of the IL-12 cytokine family, which are under the control of the NF-kappaB subunit p50 (NF-kappaBp50). Finally, we demonstrated that LXR can associate with NF-kappaBp50 in DC and that LXR activation prevents translocation of the p50 subunit into the nucleus. In summary, our study indicates that LXR can specifically suppress the IL-12 family of cytokines though its association with NF-kappaBp50 and highlights its potential as a therapeutic target for chronic inflammatory diseases. PMID- 24045338 TI - Innate immune pathways in afferent lymph following vaccination with poly(I:C) containing liposomes. AB - Many modern vaccines use defined adjuvants to stimulate the innate immune system and shape the adaptive immune response. The exact nature of these innate signals and whether immune differentiation can originate within the periphery is not known. Here we used an ovine lymphatic cannulation model to characterise the cellular and transcriptomic profile of the afferent lymph following injection of a liposomal vaccine formulation incorporating diphtheria toxoid and the innate stimulator poly(I:C) over a 78-h period. The response to this vaccine featured an early activation of broad pro-inflammatory pathways (e.g. TLR signalling and inflammasome pathways) and the transient recruitment of granulocytes into the lymph. At 24 h a more monocytic cellular profile arose coinciding with a transition to a specific antiviral response characterised by the up-regulation of genes associated with the receptors typical for the viral mimic, poly(I:C) (e.g. TLR3, RIG-I and MDA5). At the latest time points the up-regulation of IL-17A and IL-17F suggested that Th17 cells may participate in the earliest adaptive response to this vaccine. These data provide the most comprehensive picture of the cellular and molecular mechanisms that link the periphery to the draining lymph node following vaccination, and indicate that the immune response is capable of specialising within the periphery. PMID- 24045336 TI - Mouse nasal epithelial innate immune responses to Pseudomonas aeruginosa quorum sensing molecules require taste signaling components. AB - We previously observed that the human bitter taste receptor T2R38 is an important component of upper respiratory innate defense because it detects acyl homoserine lactone (AHL) quorum-sensing molecules secreted by Gram-negative bacteria. T2R38 activation in human sinonasal epithelial cells stimulates calcium and NO signals that increase mucociliary clearance, the major physical respiratory defense against inhaled pathogens. While mice do not have a clear T2R38 ortholog, they do have bitter taste receptors capable of responding to T2R38 agonists, suggesting that T2R-mediated innate immune mechanisms may be conserved in mice. We examined whether AHLs activate calcium and NO signaling in mouse nasal epithelial cells, and utilized pharmacology, as well as cells from knockout mice lacking important components of canonical taste signal transduction pathways, to determine if AHL stimulated responses require taste signaling molecules. We found that AHLs stimulate calcium-dependent NO production that increases mucociliary clearance and thus likely serves an innate immune role against Gram-negative bacteria. These responses require PLCbeta2 and TRPM5 taste signaling components, but not alpha-gustducin. These data suggest the mouse may be a useful model for further studies of T2R-mediated innate immunity. PMID- 24045339 TI - IFNL3 mediates interaction between innate immune cells: Implications for hepatitis C virus pathogenesis. AB - Common IFN lambda 3 (IFNL3) variants have been demonstrated to affect spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. The functional basis of these genetic variants has yet to be determined. Data examining the effect of IFNL3, specifically, in innate immune cells is lacking. Here, we determined the expression of IFNL3 and its receptor IFNLR1 in blood immune cell subsets and in HCV-infected livers. Next we assessed their sensitivity to IFNL3. All participants were genotyped for the IFNL3 SNPs rs8099917 and rs12979860. Importantly, unstimulated blood immune cells express significantly higher levels of IFNL3 than HCV liver biopsies. Plasmacytoid dendritic cells (pDCs) are the predominant producers of IFNLR1, especially in response to IFN-alpha. PBMCs, monocytes and pDCs all respond to IFNL3 based on MxA up-regulation. No differences in IFNL3 expression levels between rs8099917 or rs12979860 genotypes were detected. This is the first study to show peripheral blood pDCs to be the main producers of IFNL3, especially compared with HCV infected livers. This makes innate immune cells the key players in determining the functional significance of INFL3 polymorphisms in patients with HCV. PMID- 24045340 TI - Signaling mechanism for Aspergillus fumigatus tolerance in corneal fibroblasts induced by LPS pretreatment. AB - TLRs, particularly TLR2 and TLR4, play primary roles in inflammatory responses triggered by Aspergillus fumigatus and lead to the activation of signaling pathways that initiate host defense responses. We previously demonstrated that LPS, a ligand of TLR4, can induce tolerance of A. fumigatus hyphae in telomerase immortalized human stroma fibroblasts (THSFs). In the present study we investigated the role of TLR4, TLR2 and their downstream signaling pathways in this activity. The THSFs were pretreated with low-dose LPS and then exposed to A. fumigatus hyphae. It was demonstrated that enhanced expression of TLR4, but not of TLR2, was associated with LPS pretreatment. Inhibition of TLR4 with monoclonal Ab prevented reduction of pro-inflammatory cytokine secretion in LPS-pretreated THSFs. Pretreatment of THSFs with low-dose LPS caused an impaired response of the MyD88-dependent classical and MAPK signaling pathway upon subsequent A. fumigatus challenge, while expression of signaling molecules in the MyD88-independent Toll IL-1 receptor domain-containing adaptor inducing IFN-beta pathway was increased in THSFs pretreated with LPS. These results indicated that TLR4 mediates attenuated cytokine production induced by LPS pretreatment, and regulation of MyD88-dependent and MyD88-independent pathways may contribute to the development of A. fumigatus hyphae tolerance in LPS-pretreated THSFs. PMID- 24045341 TI - Biomarkers of periodontitis and inflammation in ischemic stroke: A case-control study. AB - Periodontitis is a common infectious disease associated with increased risk for ischemic stroke though presently unclear mechanisms. In a case-control study, we investigated salivary levels of four periodontal pathogens, as well as systemic and local inflammatory markers. The population comprised 98 patients with acute ischemic stroke (mean +/- SD, 68.2 +/- 9.7 yrs; 45.9% women) and 100 healthy controls (69.1 +/- 5.2 yrs; 47.0% women). Patients were more often edentulous and had fewer teeth than controls (13.8 +/- 10.8 versus 16.6 +/- 10.1). After adjusting for stroke risk factors and number of teeth, controls had higher saliva matrix metalloproteinase-8 (MMP-8), myeloperoxidase (MPO), IL-1beta, Aggregatibacter actinomycetemcomitans, and serum LPS activity levels. Patients had higher serum MMP-8 and MPO, and they were more often qPCR-positive for A. actinomycetemcomitans (37.9% versus 19.0%) and for >=3 periodontopathic species combined (50.0% versus 33.0%). We conclude that controls more often had evidence of current periodontal infection with higher periodontal pathogen amount, endotoxemia, local inflammation and tissue destruction. Stroke patients more often had evidence of end-stage periodontitis with edentulism and missing teeth. They were more often carriers of several periodontopathic pathogens in saliva, especially A. actinomycetemcomitans. Additionally, inflammatory burden may contribute to high systemic inflammation associated with elevated stroke susceptibility. PMID- 24045342 TI - Larger mammals have longer faces because of size-related constraints on skull form. AB - Facial length is one of the best known examples of heterochrony. Changes in the timing of facial growth have been invoked as a mechanism for the origin of our short human face from our long-faced extinct relatives. Such heterochronic changes arguably permit great evolutionary flexibility, allowing the mammalian face to be remodelled simply by modifying postnatal growth. Here we present new data that show that this mechanism is significantly constrained by adult size. Small mammals are more brachycephalic (short faced) than large ones, despite the putative independence between adult size and facial length. This pattern holds across four phenotypic lineages: antelopes, fruit bats, tree squirrels and mongooses. Despite the apparent flexibility of facial heterochrony, growth of the face is linked to absolute size and introduces what seems to be a loose but clade wide mammalian constraint on head shape. PMID- 24045343 TI - Retinal vascular abnormalities in neovascular age-related macular degeneration. AB - PURPOSE: To determine the prevalence of retinal vascular abnormalities (RVA) in neovascular age-related macular degeneration (AMD). METHODS: A post hoc subanalysis of images acquired during a Phase III randomized controlled trial was undertaken, selecting images from participants with untreated, neovascular AMD in at least one eye. Protocol mandated fundus photographs and fluorescein angiograms were acquired at baseline and Year 2, from 107 sham-treated study eyes with neovascular AMD and 107 untreated fellow eyes. Images were reanalyzed by an independent reading center for the presence of RVA, defined as at least one of the following: microaneurysms, vessel staining or leakage, dilated or tortuous vessels, intraretinal hemorrhage, vessel sheathing or narrowing, capillary nonperfusion, or capillary infarcts. RESULTS: The baseline prevalence of RVA in the sham-treated study eyes was 14.4% (15 of 104 gradable images) versus 8.3% (5 of 60) in the fellow eyes with dry AMD. The baseline prevalence of individual RVAs in study eyes was: microaneurysms (6.7%), vessel staining or leakage (6.7%), dilated or tortuous vessels (4.8%), intraretinal hemorrhage (4.8%), vessel sheathing or narrowing (2.9%), capillary nonperfusion (0%), and capillary infarcts (0%). Results were similar at 24 months. CONCLUSION: Compared with several studies that relied solely on fundus photographs, this study included fluorescein angiography and found a higher prevalence of RVAs occurring in eyes with neovascular AMD. PMID- 24045345 TI - Baseline blood work before initiation of chemotherapy: what is safe in the real world? AB - INTRODUCTION: This is an observational study of patterns of practice of the timing of baseline blood work (BBW) before chemotherapy initiation. The primary objective was to evaluate the incidence of significant changes in laboratory values within 6 weeks before therapy. METHODS: All consecutive patients receiving chemotherapy within a 6-month period were analyzed retrospectively. Time interval between date of chemotherapy initiation and nearest blood work was calculated. Data from patients with one or more sets of values within 6 weeks were used to evaluate dosing changes. Changes in laboratory values collected closest to the date of chemotherapy and values collected before that but within 6 weeks were graded according to the National Cancer Institute's Common Toxicity Criteria. A change of >=1 grade was considered clinically meaningful. RESULTS: Five hundred ninety-two patients were included. Median interval between BBW and initiation of chemotherapy was 4 days. Three hundred thirty-five patients had two or more sets of laboratory tests within the 6-week period, 33% of patients had a meaningful change in one or more values. The majority of changes occurred in hemoglobin (22%), ALT (14%), WBC (11%) and AST(10%), yet only 66% of patients had liver function tests as part of the BBW. CONCLUSIONS: Adherence to the institutional recommendation of BBW within 6 weeks was high. Baseline laboratory tests performed within 7 days of chemotherapy initiation would have detected nearly all significant changes; therefore, we suggest that this interval be tested in future randomized trials. PMID- 24045346 TI - Maori health. What next? PMID- 24045347 TI - Deserving of more: framing of Maori inequities in cardiovascular care remains a challenge. PMID- 24045348 TI - Maori have worse outcomes after coronary artery bypass grafting than Europeans in New Zealand. AB - AIMS: Disparities for Maori exist in New Zealand for cardiovascular risk factors, events and access to revascularisation. We compared characteristics and outcomes of coronary artery bypass grafting (CABG) between Maori and Europeans in New Zealand. METHODS: Patients undergoing isolated CABG at Auckland City Hospital from July 2010-June 2012 were retrospectively analysed. RESULTS: Of 818 patients, 82 were Maori and 444 were Europeans. Maori were younger (60.0 vs 67.9 years, p<0.001), had higher NZ deprivation index (8.5 vs 5.0, p<0.001), body mass index (32.6 vs 28.8 kg/m2, p<0.001), higher prevalence of heart failure (11.0% vs 2.3%, p<0.001), diabetes (43.9% vs 24.1%, p<0.001), smoking (39.0% vs 13.1%, p<0.001), dialysis (4.9% vs 0.9%, p=0.023), lower ejection fraction (p=0.001), lower additive EuroSCORE 1 (4.1 vs 4.8, p=0.041) and longer cardiopulmonary bypass time (100 vs 89 minutes p<0.001). Maori ethnicity was independently associated with 30 day mortality, odds ratio (OR) 6.35, 95% confidence interval 1.01-39.9, p=0.046; and surgical morbidity OR 2.05, 1.04-4.04, p=0.040. Maori had a trend for higher mortality at 1.4 plus or minus 0.6 years (hazards ratio 2.91, 0.92-9.20, p=0.069), 1-year mortality 6.3% vs 1.5%. CONCLUSION: Despite being younger, Maori undergoing CABG had more comorbidities and socioeconomic deprivation. Maori had higher mortality and complication rates. Maori should have earlier access to CABG. PMID- 24045349 TI - Are there differences between Maori and non-Maori patients undergoing primary total hip and knee arthroplasty surgery in New Zealand? A registry-based cohort study. AB - AIM: It has been well demonstrated that Maori have the poorest health status of any ethnic group in New Zealand. The aim of this study was to determine whether there are any differences between Maori and non-Maori patients in the severity of their arthritis preoperatively and in their postoperative functional outcomes following primary total hip and knee arthroplasty surgery. Secondary objectives were to compare general and mental health scores and to determine whether the intervention rate for Maori arthroplasty patients is appropriate. METHOD: We compared preoperative and postoperative (1 and 5 year) Oxford and WOMAC scores, general health (SF-12 PH) and mental health (SF-12 MH) scores in all public patients who underwent primary total hip and knee arthroplasty surgery in our region between 2005 and 2009. RESULTS: Maori patients are younger at the time of surgery, have higher ASA scores and worse preoperative function. They also have worse postoperative outcomes and smaller overall improvements following surgery when comparing their preoperative with postoperative scores. In terms of general health, Maori and non-Maori had similar SF-12 PH scores but worse SF-12 MH scores both pre- and postoperatively. CONCLUSION: Maori patients are younger, have worse general and mental health and worse preoperative function compared with non-Maori patients. Both absolute and differential scores show that Maori patients also have worse postoperative outcomes compared with non-Maori patients. These differences are likely clinically significant and ongoing education and effort is required in order to achieve earlier intervention rates and improve postoperative outcomes for Maori patients. PMID- 24045350 TI - Cross-sectional study on prevalence, causes and avoidable causes of visual impairment in Maori children. AB - AIMS: To provide information and comparison pertaining to visual impairment of Maori children with other children in New Zealand in particular: prevalence of blindness, causes of visual impairment, and avoidable causes of visual impairment. METHODS: Retrospective data collection utilising the WHO/PBL eye examination record for children with blindness and low vision at Blind and Low Vision Education Network New Zealand (BLENNZ), Homai. Individuals not of Maori ethnicity or over the age of 16 were excluded from the study. RESULTS: 106 blind and 64 low-vision Maori children were studied. The main cause of blindness in Maori children is cortical visual impairment. Twenty-eight percent of causes of blindness in this population are potentially avoidable with non-accidental injury as the main cause. CONCLUSION: The prevalence of blindness and low vision in children amounts to 0.05% and 0.03%, respectively. The prevalence and causes of childhood blindness are comparable to the other ethnic groups in New Zealand. The main difference lies in avoidable causes of blindness, which appeared to be much higher in the Maori population. The leading cause of avoidable blindness in Maori children is caused by non-accidental injuries. PMID- 24045351 TI - Injury severity and 3-month outcomes among Maori: results from a New Zealand prospective cohort study. AB - AIMS: To examine the prevalence of health and social outcomes pre- and 3 months post-injury, and the association between New Injury Severity Scores (NISS) and 3 month outcomes, for the Maori cohort of the Prospective Outcomes of Injury Study. METHODS: New Zealand residents were recruited from the Accident Compensation Corporation's entitlement claims register and participants interviewed at 3 months post-injury. Those who reported Maori ethnicity (n=566) were included in the Maori cohort. RESULTS: States indicative of favourable health were less prevalent among the cohort post-injury than pre-injury for all measures examined. Approximately half the cohort were experiencing difficulties walking 3 months after their injury, over two-thirds a level of pain or discomfort, and more than half a level of psychological distress. The prevalence of disability was 49%. The prevalence of some adverse outcomes increased with increasing NISS but a high level of problems were still experienced by those classified as having a 'minor' injury. Nonetheless, a majority of the cohort were satisfied with life and they considered themselves to be of good to excellent overall health. CONCLUSIONS: Findings emphasise the importance of injury prevention and appropriate post injury care to reduce the burden experienced by Maori due to injury. PMID- 24045352 TI - New Zealand guidelines for the diagnosis of acute rheumatic fever: small increase in the incidence of definite cases compared to the American Heart Association Jones criteria. AB - AIM: The aim of the study was to compare utilisation of the New Zealand guidelines for the diagnosis of acute rheumatic fever (ARF) compared to the American Heart Association Jones criteria in a cohort of children METHOD: Retrospective review of 79 consecutive hospital diagnosed cases of ARF referred for secondary penicillin prophylaxis. The 2006 New Zealand guidelines for ARF were applied to the cohort and the diagnostic classification compared to classification using the American Heart Association 1992 Jones criteria. Cases were defined as definite, probable, possible or not ARF. The New Zealand guidelines use subclinical (echocardiographic) carditis as a major criterion of ARF. Monoarthritis, if associated with anti-inflammatory medicine usage likely preventing polyarthritis, is also accepted as a major criterion. RESULTS: Sixty six cases were considered to be possible, probable or definite first episode of occurrence ARF. Utilisation of the New Zealand guidelines resulted in 16% (CL 7 29%) more cases defined as definite ARF than using American Heart Association 1992 Jones criteria (59/66 cases vs 51/66 cases). Polyathritis was the most frequent presenting symptom. Of those classified as definite ARF, 11% had monoarthritis with anti-inflammatory usage. Clinical carditis was present in 55% and subclinical carditis in 30%. The utilisation of subclinical carditis as a major criterion influenced the diagnosis to become definite ARF in 8% of the cohort only, as the remainder had polyarthritis or Sydenham's chorea as a major criterion. CONCLUSION: Utilisation of New Zealand guidelines for the diagnosis of ARF result in a modest increase (16%) in cases classified as definite ARF compared to the 1992 Jones criteria. PMID- 24045353 TI - Health consequences of tobacco use for Maori--cessation essential for reducing inequalities in health. AB - AIM: Tobacco use remains the largest preventable cause of death and disease in New Zealand. The aim of this paper was to identify all known health consequences of smoking, including exposure to other people's smoke, focusing on Maori. METHOD: A review of the scientific literature, 'grey' literature, and, Government health data and reports. RESULTS: Smoking has been causally linked with cardiovascular disease (CVD), many cancers, and several respiratory diseases, and, rates are higher for Maori than non-Maori. There are many consequences for smokers loved ones, including, pregnancy and birth complications, SUDI, and increased respiratory infections, cancers and CVD for children and adults. Maori have higher rates of still-birth and SUDI. CONCLUSION: This paper summarises all health consequences, to the smoker and their family. Supporting smoking cessation among Maori, particularly women and parents, may be one of the quickest pathways to health improvements for Maori. PMID- 24045354 TI - Improving health, safety and energy efficiency in New Zealand through measuring and applying basic housing standards. AB - Substandard housing is a problem in New Zealand. Historically there has been little recognition of the important aspects of housing quality that affect people's health and safety. In this viewpoint article we outline the importance of assessing these factors as an essential step to improving the health and safety of New Zealanders and household energy efficiency. A practical risk assessment tool adapted to New Zealand conditions, the Healthy Housing Index (HHI), measures the physical characteristics of houses that affect the health and safety of the occupants. This instrument is also the only tool that has been validated against health and safety outcomes and reported in the international peer-reviewed literature. The HHI provides a framework on which a housing warrant of fitness (WOF) can be based. The HHI inspection takes about one hour to conduct and is performed by a trained building inspector. To maximise the effectiveness of this housing quality assessment we envisage the output having two parts. The first would be a pass/fail WOF assessment showing whether or not the house meets basic health, safety and energy efficiency standards. The second component would rate each main assessment area (health, safety and energy efficiency), potentially on a five-point scale. This WOF system would establish a good minimum standard for rental accommodation as well encouraging improved housing performance over time. In this article we argue that the HHI is an important, validated, housing assessment tool that will improve housing quality, leading to better health of the occupants, reduced home injuries, and greater energy efficiency. If required, this tool could be extended to also cover resilience to natural hazards, broader aspects of sustainability, and the suitability of the dwelling for occupants with particular needs. PMID- 24045355 TI - SUDI prevention: a review of Maori safe sleep innovations for infants. AB - Recent research and policy around sudden unexpected death in infancy (SUDI) have emphasised the place of safe sleeping practices within SUDI prevention strategies. Maori SUDI prevention workers have focussed on innovations around the safe sleep environment for some time now, as they have grappled with difficult to change and disproportionately high Maori SUDI rates. The wahakura (a flax bassinet modelled on a traditional Maori infant sleeping item) was developed in 2006 aiming to mitigate some of the risks of bedsharing with vulnerable infants, in particular infants exposed to maternal smoking in pregnancy. Early wahakura projects in Gisborne and Hawke's Bay showed high acceptability, effectiveness as an infant health promotion vehicle but difficulty maintaining a low/no cost supply for vulnerable families. The Hawke's Bay project revealed two pathways forward: the need for robust research to ensure the safety of the wahakura and the exploration of financially viable and more readily available alternatives. Work on both pathways is currently in progress around the country, signalling New Zealand's ongoing contribution to SUDI prevention and its potential contribution to knowledge and practices applicable to indigenous and other marginalised communities worldwide. PMID- 24045356 TI - Shellfish-acquired Vibrio cholerae cellulitis and sepsis from a vulnerable leg. AB - The following case concerns a soft tissue Vibrio cholerae (V. cholerae) infection in a fisherman who cut his foot while retrieving his fishing dinghy. It is rare for V. cholerae to cause extraintestinal infection. This V. cholera was identified as a non-toxigenic organism. The patient was successfully treated with medical therapy at Waikato Hospital (Hamilton, New Zealand) and discharged home after 10 days. PMID- 24045357 TI - Drug-induced subacute cutaneous lupus erythematosus due to treatment with interferon beta-1a. AB - Drug-induced subacute cutaneous lupus is a very rare adverse reaction to medications. This case report describes onset of this condition caused by Interferon beta-1a, which has been rarely reported previously. PMID- 24045358 TI - Medical image. Raccoon eyes in amyloidosis. PMID- 24045359 TI - Medical image. Mediastinal enlargement: superior vena cava (SVC). PMID- 24045360 TI - Coke's anti-obesity campaign: a FIZZ or not? PMID- 24045361 TI - Revoke PM10 regulations. PMID- 24045362 TI - Additional evidence for concern about the quality of public toilets in New Zealand. PMID- 24045363 TI - Sb2Se3 under pressure. AB - Selected members of the A2B3 (A = Sb, Bi; B = Se, Te) family are topological insulators. The Sb2Se3 compound does not exhibit any topological properties at ambient conditions; a recent high-pressure study, however, indicated that pressure transforms Sb2Se3 from a band insulator into a topological insulator above ~2 GPa; in addition, three structural transitions were proposed to occur up to 25 GPa. Partly motivated by these results, we have performed x-ray diffraction and Raman spectroscopy investigations on Sb2Se3 under pressure up to 65 GPa. We have identified only one reversible structural transition: the initial Pnma structure transforms into a disordered cubic bcc alloy above 51 GPa. On the other hand, our high-pressure Raman study did not reproduce the previous results; we attribute the discrepancies to the effects of the different pressure transmitting media used in the high-pressure experiments. We discuss the structural behavior of Sb2Se3 within the A2B3 (A = Sb, Bi; B = Se, Te) series. PMID- 24045364 TI - Relevance of infection with human papillomavirus: the role of the p53 tumor suppressor protein and E6/E7 zinc finger proteins (Review). AB - Human papillomaviruses (HPV) are small circular, double-stranded DNA viruses infecting epithelial tissues. HPV types can be classified both as high-risk or low-risk. Of the more than 120 different identified types of HPV, the majority are involved in infections of the genital tract, cancer of the cervix, vulva, vagina and penis, and of non-anogenital localizations, such as the head and neck areas. From the point of view of the infection, human papillomaviruses have developed several molecular mechanisms to enable infected cells to suppress apoptosis. This review provides a comprehensive and critical summary of the current literature that focuses on cervical carcinoma and cancer of the head and neck caused by HPV. In particular, we discuss HPV virology, the molecular mechanisms of carcinogenesis, the role of the tumor suppressor protein p53 and the E6/E7 zinc finger proteins. Classification of HPV according to diagnosis is also described. PMID- 24045365 TI - Digitoxin sensitizes glioma cells to TRAIL-mediated apoptosis by upregulation of death receptor 5 and downregulation of survivin. AB - Glioblastoma multiforme is the most lethal and aggressive astrocytoma among primary brain tumors in adults. However, most glioblastoma cells have been reported to be resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Here, we have shown that digitoxin (DT), a clinically approved cardiac glycoside for heart failure, can induce TRAIL mediated apoptosis of glioblastoma cells. DT in noncytotoxic doses (20 nmol/l) can increase TRAIL-induced apoptosis in TRAIL-resistant U87MG glioblastoma cells. Treatment with DT led to apoptosis and a robust reduction in the levels of the antiapoptotic protein survivin by inducing its proteasomal degradation; however, it did not affect the levels of many other apoptosis regulators. Moreover, silencing survivin with small interfering RNAs sensitized glioma cells to TRAIL induced apoptosis, underscoring the functional role of survivin depletion in the TRAIL-sensitizing actions of DT. We demonstrate that inactivation of survivin and death receptor 5 expression by DT is sufficient to restore TRAIL sensitivity in resistant glioma cells. Our results suggest that combining DT with TRAIL treatments may be useful in the treatment of TRAIL-resistant glioma cells. PMID- 24045366 TI - Novel guanide-substituted compounds bind to CXCR4 and inhibit breast cancer metastasis. AB - CXCR4 has been shown to be overexpressed on breast cancer cells including the human MDA-MB-231 cell line. Cancer cells overexpressing the CXCR4 receptor are capable of undergoing metastasis to organs expressing high levels of CXCL12. We have synthesized numerous guanide, biguanide, phenylguanide, and naphthylguanide compounds that bind to CXCR4 at the CXCL12-binding site and thus should prevent CXCR4-facilitated cancer metastasis. The novel compounds presented here were tested for CXCR4 affinity, toxicity, receptor activation, and for their ability to prevent breast cancer metastases. Three of the compounds bound to CXCR4 at IC50 values of 0.06-0.2 MUmol/l, with no associated cell toxicity or receptor activation at these concentrations. These high CXCR4 affinity compounds also showed inhibition of in-vitro wound migration. They were then tested in an in vivo mouse breast cancer lung colony model. All of these compounds showed reductions in the number of MDA-MB-231 lung metastases compared with mock-treated control mice without evidence of cardiac, liver, or kidney toxicity in treated mice. PMID- 24045367 TI - Evaluation of the molecular mechanisms of a palladium(II) saccharinate complex with terpyridine as an anticancer agent. AB - Metal-based compounds represent promising anticancer therapeutic agents. In this study, the mechanism of action of a novel metal-based drug, a palladium(II) (Pd) complex ([PdCl(terpy)](sac).2H2O, terpy=2,2':6',2''-terpyridine and sac=saccharinate), was elucidated. The tested compound induced cytotoxicity in nine different human cancer cell lines that originated from various organs, suggesting a broad spectrum of activity. The IC50 values were significantly higher for noncancerous cells when compared with cancer cells. We found that cells treated with the Pd(II) complex exhibited increased caspase 3/7 activities and condensed/fragmented nuclei, as demonstrated by nuclear staining and DNA laddering. Morphological features, such as cellular shrinkage and blebbing, were also observed, indicating that apoptosis was the primary mechanism of cell death. Pd(II) treatment induced DNA double-stranded breaks both in vitro and in vivo, potentially accounting for the source of stress in these cells. Although caspase 3/7 activities were elevated after Pd(II) treatment, silencing or using inhibitors of caspase 3 did not block apoptosis. Other molecules that could potentially play a role in Pd(II)-induced apoptosis, such as p53 and Bax, were also tested using silencing technology. However, none of these proteins were essential for cell death, indicating either that these molecules do not participate in Pd(II)-induced apoptosis or that other pathways were activated in their absence. Hence, this new molecule might represent a promising anticancer agent that exhibits cytotoxicity in p53-mutant, Bax-mutant, and/or caspase 3 mutant cancer cells. PMID- 24045368 TI - The development of a validated checklist for femoral venous catheterization: preliminary results. AB - Femoral venous catheterization is a common, invasive procedure, which may lead to serious complications. Validated checklists are central to teaching and assessing procedural skills and may result in improved health care quality. The results of the first step of the validation of a femoral venous catheterization checklist are described. A comprehensive literature review of articles published on femoral venous catheterization did not yield a checklist validated by the Delphi method. A modified Delphi technique, involving a panel of 8 interdisciplinary, interinstitutional experts, was used to develop a femoral venous catheterization checklist. The internal consistency coefficient using Cronbach alpha was .99. Developing a 29-item checklist for teaching and assessing femoral venous catheterization is the first step in the validation process. For this checklist to become further validated, it should be implemented and studied in the simulation and clinical environments. PMID- 24045369 TI - Using NSQIP to investigate SCIP deficiencies in surgical patients with a high risk of developing hospital-associated urinary tract infections. AB - The study objectives were to identify risk factors for surgical patients who develop postoperative urinary tract infections (UTIs) and to characterize urethral catheter practices at the study hospital. Patients from the 2006-2010 institutional National Surgical Quality Improvement Program database were evaluated. Patients with UTIs within 30 postoperative days (n = 116) were compared to patients without UTIs (n = 8685) using multivariable logistic regression. A nested case-control study evaluated the effects of catheter practices on postoperative UTI using conditional logistic regression. Independent predictors of UTI were sex, age, inpatient stay, functional status, renal failure, preoperative transfusion, and preoperative hospital stay. Compared with controls, patients with UTI more often maintained catheters for >2 postoperative days (66% vs 43%, P < .001) and had longer mean catheter duration (11.6 vs 5.1 days, P < .001). Study findings led to institutional recommendations to reduce catheter-associated UTIs. Quality improvement initiatives can increase awareness of performance enhancement opportunities and encourage collaborative, interdisciplinary improvement through shared objectives. PMID- 24045370 TI - Deforming water droplets with a superhydrophobic silica coating. AB - The surface liquidity of a water droplet is eliminated by rubbing hydrophobic particles onto the droplet surface using a sol-gel silica coating with extremely weak binding force, which results in solid-like deformability of a liquid drop. PMID- 24045371 TI - Dengue--old disease, new challenges in an ageing population. PMID- 24045372 TI - The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and Singapore. PMID- 24045373 TI - Prevalence and control of hypercholesterolaemia as defined by NCEP-ATPIII guidelines and predictors of LDL-C goal attainment in a multi-ethnic Asian population. AB - INTRODUCTION: Few studies in Asia have assessed the burden of hypercholesterolaemia based on the global cardiovascular risk assessment. This study determines the burden of hypercholesterolaemia in an Asian population based on the National Cholesterol Education Program-Adult Treatment Panel III (NCEP ATPIII) guidelines, and examines predictors of low-density lipoprotein cholesterol (LDL-C) goal attainment. MATERIALS AND METHODS: Five thousand and eighty-three Chinese, Malays and Asian-Indians living in Singapore were assigned to coronary heart disease (CHD)-risk category based on the NCEP-ATPIII guidelines. Awareness, treatment and control of hypercholesterolaemia based on risk- specific LDL-C goal were determined, including the use of lipid-lowering therapy (LLT). Cox-regression models were used to identify predictors of LDL-C above goal among those who were aware and unaware of hypercholesterolaemia. RESULTS: One thousand five hundred and sixty-eight (30.8%) participants were aware of hypercholesterolaemia and 877 (17.3%) were newly diagnosed (unaware). For those who were aware, 39.3% participants received LLT. Among those with 2 risk factors, only 59.7% attained LDL-C goal. The majority of them were taking statin monotherapy, and the median dose of statins was similar across all CHD risk categories. Among participants with 2 risk factors and not receiving LLT, 34.1% would require LLT. Malays or Asian-Indians, higher CHD risk category, increasing body mass index (BMI), current smoking and lower education status were associated with higher risk of LDL-C above goal. Being on LLT reduced the risk of having LDL-C above goal. CONCLUSION: The burden of hypercholesterolaemia is high in this multi-ethnic population especially those in the higher CHD risk categories, and might be partly contributed by inadequate titration of statins therapy. Raising awareness of hypercholesterolaemia, appropriate LLT initiation and titration, weight management and smoking cessation may improve LDL-C goal attainment in this population. PMID- 24045374 TI - Clinical outcomes of below knee amputations in diabetic foot patients. AB - INTRODUCTION: This study aims to evaluate the predictive factors affecting the clinical outcome of Below Knee Amputations (BKA) performed in diabetic foot patients admitted to National University Hospital (NUH) Multi-Disciplinary Diabetic Foot Team. MATERIALS AND METHODS: This is a prospective cohort study of 151 patients admitted to the Department of Orthopaedic Surgery, NUH, for Diabetic Foot Problems (DFP) from January 2006 to January 2010. All had undergone BKA performed by NUH Multi-Disciplinary Diabetic Foot Team. Statistical analyses (univariate and multivariate analysis with logistic regression) were carried out using SPSS version 18.0, for factors such as demographic data, diabetic duration and control, clinical findings and investigations, indications for surgery, preoperative investigations and evaluation, microbiological cultures, and these were compared to the clinical outcome of the patient. A good clinical outcome is defined as one not requiring proximal re-amputation and whose stump healed well within 6 months. The ability to ambulate with successful use of a prosthesis after 1 year was documented. Statistical significance was set at P <0.050. RESULTS: Mean age of study population was 55.2 years with a male to female ratio of about 3:2. Mean follow up duration was 36 months. Of BKAs, 73.5% gave a good outcome. Univariate analysis showed that smoking, previous limb surgery secondary to diabetes, high Total White Count (TW), Erythrocyte Sedimentation Rate (ESR), C Reactive Protein (CRP), Urea, Creatinine (Cr), Neutrophils, absence of posterior tibial and popliteal pulses, low Ankle Brachial Index (ABI) and Toe Brachial Index (TBI) were associated with poor clinical outcome. Multivariate analysis showed that high CRP, ESR, Neutrophils, absence of popliteal pulse and low ABI were associated with poor clinical outcome. Of patients, 50.3% attained mobility with prosthesis after 1 year. Mortality rate was 21.2% within 6 months of operation, with sepsis being the most significant cause of death. CONCLUSION: Success rate of BKA was 73.5%, with mortality rate being 21.2% within 6 months. In this cohort, 50.3% were able to attain eventual mobility with prosthesis after 1 year. Sepsis was the most significant cause of death. Markers of infection such as high CRP, ESR, neutrophils; and indicators of poor vascularity such as absence of popliteal pulse and low ABI were significantly associated with poor clinical outcome. PMID- 24045375 TI - The use of parenteral nutrition in an acute care hospital. AB - INTRODUCTION: Parenteral nutrition (PN) is an important supportive therapy. However, it is expensive and associated with significant complications. Our aim is to describe the patients given PN in 2006, to compare with the 2001 cohort and determine if PN had been prescribed for the appropriate indications. MATERIALS AND METHODS: A retrospective cohort study of adult patients receiving PN between January and December 2006 was undertaken in a single institution. Appropriateness of indications for PN was based on the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) guidelines 2002. RESULTS: One hundred and eighty two patients received 194 courses (102 males, 92 females) of PN. Median age was 62 years (range, 16 to 100). Eighty-two percent were surgical patients and 18% were medical patients. Median PN duration was 9 days (range, 2 to 115). Common indications were surgeons' anticipation of non-functioning gut postoperatively [47 (24.2%) courses], postoperative complications [33 (17.0%) courses] and postoperative ileus [31 (16.1%) courses]. Indications for PN met A.S.P.E.N. guidelines in 93.3% of cases compared to 78.3% in 2001. In 1.5% of cases, we were unable to determine if the indications met the guidelines. Ten courses did not meet the guidelines; 3 had PN for <7 days preoperatively, 6 had PN because the managing team thought the patients were critically ill and 1 was given PN for refusal to eat because of depression. CONCLUSION: Since 2001, there has been an increase in the proportion of PN given for appropriate indications. However, physician education with respect to the benefit of PN for preoperative and critically ill patients with functioning guts needs reinforcing. PMID- 24045376 TI - Predictors of sustained six months quitting success: efforts of smoking cessation in low intensity smoke-free workplaces. AB - INTRODUCTION: This study aims to identify the predictors of a 6-month quitting success among employees involved in workplace smoking cessation with low intensity smoke-free policy. MATERIALS AND METHODS: A multicentre prospective cohort study was conducted among employees from 2 different public universities in Malaysia. Interventions include at least 2 sessions of behavioural therapy combined with free nicotine replacement therapy (NRT) for 8 weeks. Participants were followed up for 6 months. Independent variables assessed were on sociodemographic and environmental tobacco smoke. Their quit status were determined at 1 week, 3 months and 6 months. RESULTS: One hundred and eighty- five smokers volunteered to participate. Among the participants, 15% and 13% sustained quit at 3 months and 6 months respectively. Multivariate analysis revealed that at 6 months, attending all 3 behavioural sessions predicted success. None of the environmental tobacco exposure variables were predictive of sustained cessation. CONCLUSION: Individual predictors of success in intra workplace smoking cessation programmes do not differ from the conventional clinic based smoking cessation. Furthermore, environmental tobacco exposure in low intensity smoke-free workplaces has limited influence on smokers who succeeded in maintaining 6 months quitting. PMID- 24045377 TI - Why we do caesars: a comparison of the trends in caesarean section delivery over a decade. AB - INTRODUCTION: In the United Kingdom, caesarean section (CS) rates have increased from 9% of deliveries in 1980 to 21% in 2001. A similar increase in CS rates has been seen in many developed countries. This is beyond the World Health Organisation's (WHO's) recommended level of 15%. This is a worrying trend as the risks of placenta previa, placenta accreta, hysterectomies, bladder and bowel injuries are increased with subsequent CS. We aim to ascertain the commonest indications for CS in a tertiary hospital and make recommendations to decrease future CS rates. MATERIALS AND METHODS: This retrospective analysis compares the 5 most common indications for CS in 1999 and 2009. CS rates in the 2 study periods are tabulated and analysed as well. RESULTS: In the first study period between January and December 1999, there were 2048 deliveries of which 365 were via CS. In the second study period of a decade later from January to December 2009, there were 1572 deliveries of which 531 were via CS. This gives an increase in CS rate from 17.8% in 1999 to 34% in 2009. The main indications for CS in 1999 were: cephalopelvic disproportion (18.6%), breech (14.2%), non-reassuring fetal status (11.8%), 1 previous CS (11.2%) and pregnancy-induced hypertension/pre eclampsia/eclampsia (6.6%). The main indications for CS in 2009 were: 1 previous CS (18.1%), non-reassuring fetal status (12.2%), cephalopelvic disproportion (10.5%), 2 or more previous CS (7.9%) and breech (7.7%). CONCLUSION: There is a significant increase in CS rates over the last decade with an increased percentage of CS done because of a previous CS. This is associated with increased risk of complications as well. Recommendations are suggested with the view to decrease future CS rates. PMID- 24045378 TI - Exclusive breastfeeding: all merits and no peril? PMID- 24045379 TI - Infantile psoas abscess. PMID- 24045380 TI - Giant basal cell carcinoma of the face: role of radiotherapy. PMID- 24045381 TI - A woman with erythematous plaques. PMID- 24045382 TI - Upper lateral neck swelling: rare but important differential diagnosis. PMID- 24045384 TI - The role of inflammation in cancer and systemic lupus erythematosus. PMID- 24045385 TI - The role of neutrophyl lymphocyte count ratio as an inflammatory marker in systemic lupus erythematosus. AB - AIM: to evaluate neutrophyl lymphocyte count ratio (NLCR) as an inflammatory marker in systemic lupus erythematosus (SLE). METHODS: this was a cross sectional study involving 21 SLE patients with mild and moderate disease activity according to Mex SLEDAI score and 30 normal subjects. White blood cells counts were examined with Sysmex XE-5000. The absolute neutrophyl count and absolute lymphocyte count were tabulated and compared between SLE and normal subjects using unpaired t-test. The comparison of NLCR between SLE and normal subject was calculated using Mann-Whitney test. This study was conducted in the Department of Internal Medicine Hasan Sadikin Hospital from November 2011 until January 2012. RESULTS: there was no significant difference in absolute neutrophyl count between SLE and normal subjects (4158+1517 vs 4031+1218 /mm3, p=0.74). The absolute lymphocyte count was significantly lower in SLE than normal subjects (1721+600 vs 2397+587/mm3, p=0.000). NLCR was significantly higher in SLE than normal subjects (2.52 (1.01-10.92) vs 1.65 (0.77-4.59), p=0.007). There was no significant difference in NLCR between SLE with mild and moderate activity (2.59 (1.01-10.92) vs 2.01 (1.38-3.98), p= 0.412). Based on ROC curve, with AUC 0.727, cut off NLCR value >1.93 had 70% sensitivity and 67% specificity in differentiating between SLE and normal subjects. CONCLUSION: NLCR could be used as simple inflammatory parameter in SLE. PMID- 24045386 TI - Factors influencing bone mineral density in ARV-naive patients at Sanglah Hospital, Bali. AB - AIM: to evaluate factors which influence bone mineral density in ARV-naive patients in Sanglah Hospital, Bali. METHODS: a cross-sectional BMD measured by dual X-ray absorptiometry at the lumbar spine (LS) and femoral neck (FN) in 73 ARV-naive HIV-infected patients in out patient clinic of Sanglah Hospital, consecutively, from January to June 2012. Inclusion criteria are ARV-naive HIV infected patients age 13-50 year old. The relationship among factors influence BMD, CD4 level, HIV RNA, HIV stage (WHO) analysed with Anova and Spearman's correlation test. RESULTS: this study involved 49 males and 24 females. Mean age was 33.08+/-8.29. Mean CD4 was 144.71+/-143.40 cell/mmc with the lowest CD4 is 1. Mean viral load (VL) was 272.330+/-282.990 copies/ml, the lowest VL 400 copies/ml, and the highest 750 000 copies/ml. Low BMD found in 32/73 (43.8%). Osteopenia and osteoporosis were diagnosed in 26/73 (35.6%) and 6/73 (8.2%). 13 (40.6%) of the low BMD cases occurred on the age group 21-30 year. Significant correlation found between low BMD with HIV stage (r=0.337; p<0.001). CONCLUSION: patients with higher HIV stage have higher risk of low BMD in ARV-naive patient. Further study is needed to evaluate correlation of low BMD with its risk factors. PMID- 24045387 TI - Transcatheter closure of atrial septal defects in adolescents and adults: technique and difficulties. AB - AIM: to evaluate the results of transcatheter closure of atrial septal defect (ASD) in adolescents and adult. METHODS: a case series of patients undergoing transcatheter closure of ASD in RS Cipto Mangunkusumo, Jakarta during 2002 -2013. Transesophageal echocardiography, hemodynamic study, and angiography were performed before the procedure. Oxygen test was done if PA pressure was more than 2/3 of aortic pressure, followed by an occlusion test if no response observed to determine whether the device could be released. RESULTS: we enrolled 54 patients, of whom 26% were adolescents and 3% were males. Median body weight was 49 (26-75) kg and ASD size was 21 (9.4-39.6) mm. The procedure was done under general anesthesia in 26% of patients. Oxygen test was applied in 11% patients and occlusion test in 2% of patient. Transcatheter closure of ASD was successful in all patients using common technique (31%), right pulmonary vein-assisted (65%), left pulmonary assisted (2%), and cutting long sheath (2%). There was neither residual ASD nor complications observed. Mean fluoroscopy and procedure time were 29 (SD 18) and 109 (SD 36) minutes, respectively. Median hospital stay was 1 (1 3) day. CONCLUSION: transcatheter closure of ASD in adolescents and adults is safe and effective. PMID- 24045388 TI - Expression of NF-kB and COX2 in colorectal cancer among native Indonesians: the role of inflammation in colorectal carcinogenesis. AB - AIM: to evaluate the expression of NF-kB and COX2 in native Indonesians with sporadic colorectal cancer (CRC). METHODS: we conducted a matched-pair case control study by acquiring both CRC and tumor-adjacent normal tissues from the same subjects. CRC patients who underwent surgery at Cipto Mangunkusumo Hospital, Jakarta, or Hasan Sadikin Hospital, Bandung, were enrolled in the study. The specimens were immunohistologically stained with antibody directed against p65 (RelA) to assess NF-kB expression and against human COX2 protein to assess COX2 expression. RESULTS: sixty-seven specimens consisting of both CRC and tumor adjacent normal tissues were analyzed. COX2 expression was positive in 39 CRC tissues (58.2%), but in only 19 tumor-adjacent normal tissues (28.4%; p=0.0002). NF-kB expression was positive in 47 CRC tissues (70.1%), but in only 27 tumor adjacent normal tissues (40.3%; p<0.0001). CONCLUSION: inflammation plays a role in the carcinogenesis of sporadic CRC in native Indonesians. This support potential use of nonsteroidal anti-inflammatory drugs as chemopreventive agents for CRC. PMID- 24045389 TI - Safety and effectiveness of candesartan and candesartan/HCT fixed dose combination in patients with hypertension. AB - AIM: to assess the safety and effectiveness of candesartan and candesartan/HCT fixed-dose combination (FDC) in patients with hypertension in daily clinical practice. METHODS: an open observational study with a 12-week period of treatment. Candesartan tablets of 4 mg, 8 mg, or 16 mg, or candesartan/HCT FDC tablets (16/12.5 mg) were prescribed to adult hypertensive subjects, both treatment-naive patients and previously treated but uncontrolled patients, depending on the physicians' discretion based on his/her judgment on the clinical condition. RESULTS: from a total of 112 treatment-naive patients and 381 previously treated patients eligible for safety analysis, there were only 3 patients with adverse events, and 2 of which were considered possibly related to candesartan (0.41%) and there were no serious adverse events. Both patients were previously treated patients, one patient experienced nausea and the other patient experienced paresthesia. Candesartan and candesartan/HCT were effective in lowering systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline at weeks 4, 8, and 12, in both groups, with 26-27 mm Hg decreases in SBP at week 12 and a trend toward a larger reduction in treatment-naive patients than in previously treated patients, although not statistically significant. However, in terms of patients achieving a BP of <140/90 mm Hg between groups were significantly superior in treatment-naive patients than in previously treated patients at week 8 (56% vs 40%; p=0.003) and week 12 (69% vs 53%; p=0.004). Candesartan and candesartan/HCT were also effective for patients with long standing (>4 years) uncontrolled hypertension with previous antihypertensive therapy, which was most commonly calcium channel blockers (became controlled in >50% of all uncontrolled patients). CONCLUSION: results of this open observational study showed that candesartan and candesartan/HCT were well tolerated and effective in both treatment-naive patients and uncontrolled hypertensive patients with previous antihypertensive treatment. PMID- 24045390 TI - Do methicillin resistant staphylococcus (MRSA) carrier patients influence MRSA infection more than MRSA-carrier medical officers and MRSA-carrier family? AB - AIM: to determine the rate of MRSA-carrier among patients, family members and health care providers, and the association between MRSA-carrier family members and health care providers on MRSA infection patient after orthopaedic surgery. METHODS: this is a cross-sectional analytical study. Samples were taken consecutively during December 2010 to December 2011, consisting of postoperative patients infected with MRSA, attending family members, and the medical officers with history of contact with the patient. Swab culture were taken from nasal and axilla of all subjects. The incidence of MRSA infection, and MRSA-carrier on the patient, family members and medical officers were presented descriptively, while their association with MRSA infection was statistically tested using Fischer exact test. RESULTS: during the study period, there were 759 surgeries, with 4 (0.5%) patients were identified to have MRSA infection. Of these four cases, 48 subjects were enrolled. The rate of MRSA-carrier among patients, family and health care providers were 50%, 25% and 0% respectively. There were no significant association between MRSA and the rates of MRSA-carrier on the family member or health care providers. CONCLUSION: the incidence of MRSA infection, MRSA-carrier patient, MRSA-carrier health care providers, and family member carrier were 0.5%, 50%, 0%, and 25% respectively. No significant association found between MRSA-carrier on the family member or health care providers and MRSA infection patient. There were no MRSA infection found on the health care provider. PMID- 24045391 TI - A tool to assess knowledge, attitude and behavior of Indonesian health care workers regarding infection control. AB - AIM: to investigate knowledge, attitude and behaviour toward infection control in two teaching hospitals on the island of Java by means of a questionnaire and to evaluate the use of the questionnaire as a tool. METHODS: we investigated knowledge, attitude and behaviour toward infection control in two teaching hospitals on the island of Java by means of a questionnaire to identify problem areas, barriers and facilitators. The target was to include at least 50% of all health care workers (physicians, nurses, assistant nurses and infection control nurses) in each hospital, department and profession. Differences between demographic variables and scores for individual questions and groups of questions were compared using the chi-square statistic and analysis of variance and Spearman's rho was used to test for correlations between knowledge, attitude, self-reported behaviour and perceived obstacles. RESULTS: more than half of the health care workers of the participating departments completed the questionnaire. Of the 1036 respondents (44% nurses, 37% physicians and 19% assistant nurses), 34% were vaccinated against hepatitis B, 77% had experienced needle stick accidents and 93% had been instructed about infection control. The mean of the correct answers to the knowledge questions was 44%; of the answers to the attitude questions 67% were in agreement with the correct attitude; obstacles to compliance with infection control guidelines were perceived in 30% of the questions and the mean self-reported compliance was 63%. Safe handling of sharps, hand hygiene and the use of personal protective equipment were identified as the most important aspects for interventions. Significant positive correlations were found between knowledge, attitude, self-reported behaviour and perceived obstacles. CONCLUSION: the questionnaire in conjunction with site visits and interviews was a valuable strategy to identify trouble spots in the hospitals and to determine barriers to facilitators of change that should be taken into account when planning interventions. Successful interventions should cover hospital management, the infection control team, as well as the health care workers on the wards. PMID- 24045392 TI - Obstructive jaundice due to pancreatic metastasis from non-small cell lung cancer. AB - We report a 67-year-old female patient, recently diagnosed to have non-small cell lung cancer (NSCLC). On first PET (positron emission tomography) examination in October 2009, no distant metastasis. Four months later, second PET examination was done, detecting pancreatic foci in the uncinate process and in the tail of the pancreas measuring 22 mm which were more likely to be metastatic rather than primary origin. The patient underwent chemotherapy and radiotherapy. After 1 month of follow up, jaundice was noticed. Laboratory exams and MRCP showed obstructive jaundice. ERCP was performed with biliary stenting for palliative treatment. Symptomatic metastatic lesions of the pancreas from carcinoma of the lung are extremely rare. Typically, the patients remain asymptomatic until their disease reaches a fairly advanced stage, and therapeutic options are then limited to palliative measures. PMID- 24045393 TI - An HIV positive man with single erythema skin lesion: a case report of neglected tropical disease. AB - Skin lesion is common in person living with HIV. We reported a 42 years old HIV positive man with single erythema skin lesion on the right foot. Clinical examination, anamnesis and laboratory examination revealed that it was cutaneous larva migrant due to parasitic infection. The cutaneous larva migrant due to hookworms is one of neglected tropical disease that might occur in adult with immunocompromised. This neglected disease is discussed rarely and might not be found in developed country, but it is still a common disease in the tropical region. Patient was treated successfully with albendazole, cetirizine, chlorethyl spray and betamethasone cream. PMID- 24045394 TI - Transdermal bio-identical progesterone cream as hormonal treatment for osteoarthritis. AB - Osteoarthritis (OA) is a condition found worldwide, is strongly associated with aging and is the most common type of arthritis. Because of its effect on ambulation and mobility, it has significant functional impact and is associated with considerable medical costs. Because of the aging of the society and the obesity epidemic, the burden of OA can be expected to increase over the next 20 years. Although OA has been regarded primarily as a non-inflammatory arthropathy, symptoms of local inflammation and synovitis are present in many patients and have been observed and even in the absence of classical inflammation, which is characterized by infiltration of neutrophils and macrophages into joint tissue, elevated levels of inflammatory cytokines have been measured in OA synovial fluid. Although the cartilage lesion is present at sites remote from synovium, the fibroblast- and macrophage-like synovial cells, as well as the chondrocytes itself, are potential sources of cytokines that could induce chondrocytes to synthesize and secrete cartilage-degrading proteases, cytokines, and other inflammatory mediators. The bio-identical progesterone shows its anti inflammatory effects in OA by suppressing gene expressions in the production of inflammatory cytokines through the negative interaction between nuclear transcription factor and the progesterone receptor and/or the progesterone induced increase of nuclear transcription factor inhibition in the nucleus. The bio-identical progesterone may indirectly regulate bone remodeling and may also play a role in the development and maintenance of cartilage. This review will discuss about transdermal bio-identical progesterone cream as suggested hormonal treatment of OA, based on its pathogenic process. PMID- 24045395 TI - Pleomorphic adenoma with unusual cytological findings in aspiration: a diagnostic pitfall in aspiration cytology. PMID- 24045396 TI - Evidence-based case report: acute diabetic complication risks of Ramadan fasting in type 2 diabetics. AB - AIM: to investigate causal relationship between Ramadan fasting and acute diabetic complications in adult controlled type 2 diabetics. METHODS: a Pubmed's Clinical Queries and Embase search was conducted and resulted in 2 useful articles: 1 systematic review and 1 cohort study to be critically appraised. RESULTS: the incidence of acute diabetic complications is higher during Ramadan, with the relative risk for adult type 2 diabetics who fast during Ramadan is 1.36 and number needed to harm 50. CONCLUSION: Ramadan fasting was related with acute diabetic complications in adult controlled type 2 diabetics, but the risk was only slightly higher. It is acceptable for type 2 diabetics to fast during Ramadan. PMID- 24045397 TI - Potential clinical application of novel cardiac biomarkers for acute myocardial infarction. AB - Coronary heart disease is the leading cause of cardiac related death worldwide. Therefore, early and accurate diagnosis of acute coronary syndrome is required to determine the next clinical step. The current gold standard for cardiac markers, troponin and CK-MB have their downside. The delayed increase of detectable circulating level of these markers contribute to delayed diagnosis and therapy. Novel biomarkers that rise earlier, has a good diagnosis accuracy and has additional prognostic information, are highly needed. There are some potential emerging novel biomarkers for acute myocardial infarction. High sensitivity troponin have a greater sensitivity and accuracy for detection and early exclusion of myocardial infarction, as compared to troponin. B-natriuretic peptide (BNP and NT-pro BNP) provide prognostic information in regards of mortality. Myeloperoxidase identify subjects with increased risk of cardiac events in the absence of myocardial necrosis. Dual marker strategy combining copeptin with troponin T is more accurate assay to diagnose acute myocardial infarction. The level of Growth Differentiation Factor-15 is correlated with the risk of death or myocardial infarction in the next 6 months. While, Heart-Fatty Acid Binding Protein assay is an earlier marker for myocardial necrosis and provide valuable prognostic information and can further stratify patients' risk. Novel cardiac biomarkers provide a faster exclusion of acute myocardial infarction, yet with very good accuracy. However unlike their predecessors, the clinical use of these novel cardiac biomarkers are not only limited to establishing the diagnosis of myocardial infarction. Novel cardiac biomarkers possess additional potential use, some of which are to determine patients' prognosis and to further stratify patients' risk that would determine the next step of therapy. PMID- 24045398 TI - Resting mechanomyographic amplitude for the erector spinae and trapezius muscles following resistance exercise in a healthy population. AB - Musculoskeletal disorders are some of the most commonly occurring chronic conditions affecting the US population, with the most self-reported and diagnosed disorder being low back pain. Low back pain is often due to suboptimal back muscle function, at least in part, as a result of muscle inactivity and disuse. Resistance exercise has been shown to be successful in the treatment of low back pain. The purpose of the present investigation was to examine resting mechanomyographic (MMG) amplitude for the erector spinae and trapezius muscles prior to and following resistance exercise. Twenty healthy, college-aged men were measured for resting MMG amplitude levels prior to, and following a resistance training workout. The workout consisted of three sets of ten repetitions on the conventional deadlift, bent-over row, and lat pulldown exercises, with 1 min of rest between all sets and exercises. The results showed that there were approximate 10% and 15% decreases in normalized MMG amplitude after exercise for the erector spinae and trapezius muscles, respectively. These findings demonstrate a relaxation effect in the back muscles after exercise that could potentially be helpful in alleviating low back pain. PMID- 24045399 TI - Augmenting collateral blood flow during ischemic stroke via transient aortic occlusion. AB - Collateral circulation provides an alternative route for blood flow to reach ischemic tissue during a stroke. Blood flow through the cerebral collaterals is a critical predictor of clinical prognosis after stroke and response to recanalization, but data on collateral dynamics and collateral therapeutics are lacking. Here, we investigate the efficacy of a novel approach to collateral blood flow augmentation to increase collateral circulation by optically recording blood flow in leptomeningeal collaterals in a clinically relevant model of ischemic stroke. Using high-resolution laser speckle contrast imaging (LSCI) during thromboembolic middle cerebral artery occlusion (MCAo), we demonstrate that transiently diverting blood flow from peripheral circulation towards the brain via intra-aortic catheter and balloon induces persistent increases in blood flow through anastomoses between the anterior and middle cerebral arteries. Increased collateral flow restores blood flow in the distal middle cerebral artery segments to baseline levels during aortic occlusion and persists for over 1 hour after removal of the aortic balloon. Given the importance of collateral circulation in predicting stroke outcome and response to treatment, and the potential of collateral flow augmentation as an adjuvant or stand-alone therapy for acute ischemic stroke, this data provide support for further development and translation of collateral therapeutics including transient aortic occlusion. PMID- 24045400 TI - Cerebral arterial bolus arrival time is prolonged in multiple sclerosis and associated with disability. AB - Alterations in the overall cerebral hemodynamics have been reported in multiple sclerosis (MS); however, their cause and significance is unknown. While potential venous causes have been examined, arterial causes have not. In this study, a multiple delay time arterial spin labeling magnetic resonance imaging sequence at 3T was used to quantify the arterial hemodynamic parameter bolus arrival time (BAT) and cerebral blood flow (CBF) in normal-appearing white matter (NAWM) and deep gray matter in 33 controls and 35 patients with relapsing-remitting MS. Bolus arrival time was prolonged in MS in NAWM (1.0+/-0.2 versus 0.9+/-0.2 seconds, P=0.031) and deep gray matter (0.90+/-0.18 versus 0.80+/-0.14 seconds, P=0.001) and CBF was increased in NAWM (14+/-4 versus 10+/-2 mL/100 g/min, P=0.001). Prolonged BAT in NAWM (P=0.042) and deep gray matter (P=0.01) were associated with higher expanded disability status score. This study demonstrates alteration in cerebral arterial hemodynamics in MS. One possible cause may be widespread inflammation. Bolus arrival time was longer in patients with greater disability independent of atrophy and T2 lesion load, suggesting alterations in cerebral arterial hemodynamics may be a marker of clinically relevant pathology. PMID- 24045401 TI - Rapid and reversible enhancement of blood-brain barrier permeability using lysophosphatidic acid. AB - The present study characterizes the effects of lysophosphatidic acid (LPA) on blood-brain barrier (BBB) permeability focusing specifically on the time of onset, duration, and magnitude of LPA-induced changes in cerebrovascular permeability in the mouse using both magnetic resonance imaging (MRI) and near infrared fluorescence imaging (NIFR). Furthermore, potential application of LPA for enhanced drug delivery to the brain was also examined by measuring the brain accumulation of radiolabeled methotrexate. Exposure of primary cultured brain microvessel endothelial cells (BMECs) to LPA produced concentration-dependent increases in permeability that were completely abolished by clostridium toxin B. Administration of LPA disrupted BBB integrity and enhanced the permeability of small molecular weight marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRdye800cwPEG, and the P-glycoprotein efflux transporter probe, Rhodamine 800 (R800). The increase in BBB permeability occurred within 3 minutes after LPA injection and barrier integrity was restored within 20 minutes. A decreased response to LPA on large macromolecule BBB permeability was observed after repeated administration. The administration of LPA also resulted in 20-fold enhancement of radiolabeled methotrexate in the brain. These studies indicate that administration of LPA in combination with therapeutic agents may increase drug delivery to the brain. PMID- 24045402 TI - Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier. AB - Intravenous immunoglobulin (IVIg) is currently evaluated in clinical trials for the treatment of various disorders of the central nervous system. To assess its capacity to reach central therapeutic targets, the brain bioavailability of IVIg must be determined. We thus quantified the passage of IVIg through the blood brain barrier (BBB) of C57Bl/6 mice using complementary quantitative and qualitative methodologies. As determined by enzyme-linked immunosorbent assay, a small proportion of systemically injected IVIg was detected in the brain of mice (0.009+/-0.001% of injected dose in the cortex) whereas immunostaining revealed localization mainly within microvessels and less frequently in neurons. Pharmacokinetic analyses evidenced a low elimination rate constant (0.0053 per hour) in the cortex, consistent with accumulation within cerebral tissue. In situ cerebral perfusion experiments revealed that a fraction of IVIg crossed the BBB without causing leakage. A dose-dependent decrease of brain uptake was consistent with a saturable blood-to-brain transport mechanism. Finally, brain uptake of IVIg after a subchronic treatment was similar in the 3xTg-AD mouse model of Alzheimer disease compared with nontransgenic controls. In summary, our results provide evidence of BBB passage and bioavailability of IVIg into the brain in the absence of BBB leakage and in sufficient concentration to interact with the therapeutic targets. PMID- 24045403 TI - Blood pressure reduction does not reduce perihematoma oxygenation: a CT perfusion study. AB - Blood pressure (BP) reduction after intracerebral hemorrhage (ICH) is controversial, because of concerns that this may cause critical reductions in perihematoma perfusion and thereby precipitate tissue damage. We tested the hypothesis that BP reduction reduces perihematoma tissue oxygenation.Acute ICH patients were randomized to a systolic BP target of <150 or <180 mm Hg. Patients underwent CT perfusion (CTP) imaging 2 hours after randomization. Maps of cerebral blood flow (CBF), maximum oxygen extraction fraction (OEF(max)), and the resulting maximum cerebral metabolic rate of oxygen (CMRO2(max)) permitted by local hemodynamics, were calculated from raw CTP data.Sixty-five patients (median (interquartile range) age 70 (20)) were imaged at a median (interquartile range) time from onset to CTP of 9.8 (13.6) hours. Mean OEF(max) was elevated in the perihematoma region (0.44+/-0.12) relative to contralateral tissue (0.36+/-0.11; P<0.001). Perihematoma CMRO2(max) (3.40+/-1.67 mL/100 g per minute) was slightly lower relative to contralateral tissue (3.63+/-1.66 mL/100 g per minute; P=0.025). Despite a significant difference in systolic BP between the aggressive (140.5+/-18.7 mm Hg) and conservative (163.0+/-10.6 mm Hg; P<0.001) treatment groups, perihematoma CBF was unaffected (37.2+/-11.9 versus 35.8+/-9.6 mL/100 g per minute; P=0.307). Similarly, aggressive BP treatment did not affect perihematoma OEF(max) (0.43+/-0.12 versus 0.45+/-0.11; P=0.232) or CMRO2(max) (3.16+/-1.66 versus 3.68+/-1.85 mL/100 g per minute; P=0.857). Blood pressure reduction does not affect perihematoma oxygen delivery. These data support the safety of early aggressive BP treatment in ICH. PMID- 24045405 TI - Ordered bilayer ruthenium-platinum core-shell nanoparticles as carbon monoxide tolerant fuel cell catalysts. AB - Fabricating subnanometre-thick core-shell nanocatalysts is effective for obtaining high surface area of an active metal with tunable properties. The key to fully realize the potential of this approach is a reliable synthesis method to produce atomically ordered core-shell nanoparticles. Here we report new insights on eliminating lattice defects in core-shell syntheses and opportunities opened for achieving superior catalytic performance. Ordered structural transition from ruthenium hcp to platinum fcc stacking sequence at the core-shell interface is achieved via a green synthesis method, and is verified by X-ray diffraction and electron microscopic techniques coupled with density functional theory calculations. The single crystalline Ru cores with well-defined Pt bilayer shells resolve the dilemma in using a dissolution-prone metal, such as ruthenium, for alleviating the deactivating effect of carbon monoxide, opening the door for commercialization of low-temperature fuel cells that can use inexpensive reformates (H2 with CO impurity) as the fuel. PMID- 24045406 TI - Spin-orbit coupling and electron correlation at various coupled-cluster levels for closed-shell diatomic molecules. AB - In this work, equilibrium bond lengths and harmonic frequencies of some closed shell diatomic heavy-element compounds are calculated at a series of coupled cluster (CC) levels including CCS, CC2, CCSD and CCSD(T) with spin-orbit coupling (SOC) included in post-Hartree-Fock (HF) step. The purpose of this work is to demonstrate the performance of CC2 for heavy element compounds and to investigate the separability between SOC and electron correlation at different correlation levels. According to our calculations, CC2 results agree well with MP2 results for these molecules except for SnO, Sb2, PbO and Bi2 and the bond lengths of SnO and PbO with CC2 are overestimated by about 0.25 A compared to when using other approaches. Furthermore, SOC effects on electron correlation are significant for Bi2 and At2 at CCSD(T) level, while this is the case only for Bi2 at CCSD level. For 5th-row element compounds, SOC effects on bond lengths and harmonic frequencies at different levels agree well with each other except for Sb2. On the other hand, SOC effects at CCSD level are in good agreement with those at CCSD(T) level for the investigated 6th-row element compounds except for At2, whereas SOC effects at low correlation levels will be different from those at CCSD(T) level to some extent. PMID- 24045404 TI - Progesterone attenuates hemorrhagic transformation after delayed tPA treatment in an experimental model of stroke in rats: involvement of the VEGF-MMP pathway. AB - Tissue plasminogen activator (tPA) is the only FDA-approved treatment for acute stroke, but its use remains limited. Progesterone (PROG) has shown neuroprotection in ischemia, but before clinical testing, we must determine how it affects hemorrhagic transformation in tPA-treated ischemic rats. Male Sprague Dawley rats underwent middle cerebral artery occlusion with reperfusion at 4.5 hours and tPA treatment at 4.5 hours, or PROG treatment intraperitoneally at 2 hours followed by subcutaneous injection at 6 hours post occlusion. Rats were killed at 24 hours and brains evaluated for cerebral hemorrhage, swelling, blood brain barrier (BBB) permeability, and levels of matrix metalloproteinase-9 (MMP 9), vascular endothelial growth factor level (VEGF), and tight junction (TJ) proteins. We also evaluated PROG's efficacy in preventing tPA-induced impairment of transendothelial electrical resistance (TEER) and TJ proteins under hypoxia/reoxygenation in the endothelial cells. Delayed tPA treatment induced significant hemorrhagic conversion and brain swelling. Treatment with PROG plus tPA ameliorated hemorrhage, hemispheric swelling, BBB permeability, MMP-9 induction, and VEGF levels compared with controls. Progesterone treatment significantly prevented tPA-induced decrease in TEER and expression of occludin and claudin-5, and attenuated VEGF levels in culture media subjected to hypoxia. The study concluded that PROG may extend the time window for tPA administration in ischemic stroke and reduce hemorrhagic conversion. PMID- 24045408 TI - The effect of unit-based simulation on nurses' identification of deteriorating patients. AB - Patients are admitted to healthcare organizations with multiple, complex conditions that can lead to acute deterioration events. It is imperative that nurses are adequately trained to recognize and respond appropriately to these events to ensure positive patient outcomes. The purpose of this pilot research study was to examine the effects of a unit-based, high-fidelity simulation initiative on cardiovascular step-down unit registered nurses' identification and management of deteriorating patients. PMID- 24045407 TI - The social construction of violence among Northern Plains tribal members with antisocial personality disorder and alcohol use disorder. AB - Whereas recent reports from national studies have presented extremely high rates for many personality disorders in American Indian communities, persistent concerns about the meaning of these symptoms have left many troubled by these reports. American Indians as a group are known to suffer disproportionately from a number of violent experiences, but the dynamics of this violence have received little attention. This paper examines perspectives on violence in the lives of 15 northern plains tribal members who met criteria for antisocial personality disorder and comorbid alcohol use disorder. It explores how study participants constructed and understood their own violent encounters, as well as the motivations they described (characterized here as reputation, leveling, retaliation, catharsis, and self-defense). Violence was gendered in this study, with men generally presenting as perpetrators and women as victims. Men often described themselves as ready participants in a violent world, while women were quite clear that aggression for them was often simply required as they tried to defend themselves from male violence. While this analysis does not replace clinical analyses of violence in antisocial personality disorder, it does reveal an underlying cultural logic that may play a role in shaping the recourse to violence for that minority of individuals for whom it appears to be the obvious choice. PMID- 24045409 TI - Hydrophilic interaction chromatography coupled matrix assisted laser desorption/ionization mass spectrometry for molecular analysis of organic compounds in medicines, tea, and coffee. AB - Natural occurring organic compounds from food, natural organic matter, as well as metabolic products have received intense attention in current chemical and biological studies. Examination of unknown compounds in complex sample matrices is hampered by the limited choices for data readout and molecular elucidation. Herein, we report a generic method of hydrophilic interaction chromatography (HILIC) coupled with matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS) for the rapid characterization of ingredients in pharmaceutical compounds, tea, and coffee. The analytes were first fractionated using a cationic HILIC column prior to MALDI-MS analyses. It was found that the retention times of a compound arising from different samples were consistent under the same conditions. Accordingly, molecules can be readily characterized by both the mass and chromatographic retention time. The retention behaviors of acidic and basic compounds on the cationic HILIC column were found to be significantly influenced by the pH of mobile phases, whereas neutral compounds depicted a constant retention time at different pH. The general HILIC-MALDI-MS method is feasible for fast screening of naturally occurring organic compounds. A series of homologs can be determined if they have the same retention behavior. Their structural features can be elucidated by considering their mass differences and hydrophilic properties as determined by HILIC chromatogram. PMID- 24045410 TI - 'They will tell me if there is a problem': limited discussion between health professionals, older adults and their caregivers on falls prevention during and after hospitalization. AB - The objectives of this study were to describe the sources of falls prevention information provided to older adults during and after hospitalization, identify and explore reasons why discussion about falls prevention may not take place. Six participant groups were interviewed using semi-structured interviews or focus groups: (i) older patients (n = 16); (ii) caregivers (n = 8); (iii) allied health and nursing professionals (n = 33); (iv) doctors from acute wards (n = 8); (v) doctors from subacute wards (n = 10) and (vi) general practitioners (n = 9). Participants were recruited from three Australian hospitals that provided acute and subacute in-patient services to the older adults. General practitioners were recruited from the community of Melbourne. Findings showed provision of falls prevention information was dependent on setting of the ward and which health professionals the older adult encountered during and after hospitalization. Medical practitioners were reactive in providing information, whereas older adults and their caregivers were passive in seeking falls prevention information. Several barriers in information provision and information seeking were identified. There is great potential to improve the consistency of falls prevention information provision to older adults during hospitalization and in preparation for discharge to assist with prevention of falls in this high risk period. PMID- 24045411 TI - Changes in community readiness among key school stakeholders after Ready for Recess. AB - School community readiness (CR) for health promotion efforts may be critical to the effectiveness of school-based interventions aimed at promoting youth physical activity and reducing childhood obesity. The purpose of this study was to: (i) identify key informants who scored highest on school CR at baseline and (ii) determine the effects of Ready for Recess on changes in CR among school key informants from baseline to post-intervention. Key informants (N = 98) across 17 schools participated in CR interviews. Interview questions focused on school CR for physical activity and childhood obesity efforts across six dimensions. At baseline, principals scored higher than teachers in overall readiness and knowledge of the issue and higher than recess staff and nurses in leadership. Leadership readiness decreased across key informants at post-intervention and principals demonstrated greater decreases when compared with recess staff. Baseline disparities between principals and other key informants suggest principals may have overestimated the readiness of staff implementing the intervention. Declines among principals indicate that they may not have been prepared to deliver adequate support to successfully implement the intervention. These results illuminate the importance of assessing/improving school readiness prior to interventions. The CR model may provide an opportunity to improve school based physical activity interventions. PMID- 24045412 TI - Polymorphisms of CDKN1A gene and risk of retinoblastoma. AB - Retinoblastoma (RB) is a malignant neoplasia that occurs mostly in children under 5 years. Recently, CDKN1A gene has been shown to be up-regulated in a context of loss of function of pRb. This gene encodes the p21 protein, which is the bona fide effector of p53. We hypothesized whether two putatively functional single nucleotide polymorphisms (SNPs) of CDKN1A (rs1801270 C>A and rs1059234 C>T) may influence the risk and/or survival of RB patients. We genotyped both SNPs in 141 RB patients and 120 unrelated healthy individuals. Statistical analyses consisted of chi-square (chi(2)), odds ratio (OR) and survival curves by Kaplan-Meier method. We found that patients who carry the genotype CA for rs1801270 and CT for rs1059234 were associated to an increased risk of RB [OR = 2.5, 95% confidence interval (CI) = 1.38-4.53], whereas patients with CC for both polymorphisms were associated to a lower risk of developing RB (OR = 0.43, 95% CI = 0.25-0.74). On the other hand, Kaplan-Meier curves did not show statistically significant differences in survival among the studied polymorphisms. We conclude that the minor alleles of rs1801270 and rs1059234 polymorphisms may act as risk factors for the development of RB in our sample. SUMMARY: The minor alleles of polymorphisms rs1801270 C>A and rs1059234 C>T in CDKN1A (p21) gene may act as risk factors for the development of RB; however, they do not seem to influence overall survival. PMID- 24045413 TI - Connexin-43 regulates p38-mediated cell migration and invasion induced selectively in tumour cells by low doses of gamma-radiation in an ERK-1/2 independent manner. AB - Radiotherapy exposes certain regions of solid tumours to low sublethal doses of gamma-radiation that may cause secondary malignancies. Therefore, evaluating low dose-gamma-radiation-induced alterations in tumorigenic potential and understanding their mechanisms could help in improving radiotherapy outcome. Limited studies have indicated connexin (Cx) up-regulation by low doses, whereas Cxs are independently shown to alter cell migration in unirradiated cells. We investigated low-dose-gamma-radiation-induced alterations in Cx43 expression and cell proliferation/migration/invasion in various tumour cell lines, along with the putative molecular pathways such as p38 and extracellular signal-regulated kinase-1/2 (ERK-1/2)-mitogen-activated protein kinases (MAPKs). Interestingly, a narrow range of low doses (10-20 cGy) enhanced Cx43 expression and also selectively induced glioma cell migration without altering cell proliferation, accompanied by sustained activation of p38 and up-regulation of p21(waf1/cip1), whereas the lowest (5 cGy) dose induced cell proliferation coupled with enhanced p-ERK1/2, proliferating cell nuclear antigen and p-H3 levels without inducing cell migration. Most importantly, low-dose-gamma-radiation-induced cell migration and p38 activation was strongly inhibited by knocking down Cx43 expression, thereby demonstrating latter's upstream role, whereas the knock-down had no effect on ERK-1/2 or cell proliferation. Silencing Cx43 caused near-complete inhibition of radiation-induced cell migration/invasion in all tumour cell lines (U87, BMG-1, A549 and HeLa), whereas no cell migration/invasiveness was induced in the gamma-irradiated primary VH10 or transformed AA8 fibroblasts. Our study demonstrates for the first time that low-dose gamma-radiation induces p38-MAPK mediated cell migration selectively in tumour cells. Further, this effect is regulated by Cx43, which could thus be an important mediator in radiation-induced secondary malignancies and/or metastasis. PMID- 24045414 TI - Role of JNK and NF-kappaB pathways in Porphyromonas gingivalis LPS-induced vascular cell adhesion molecule-1 expression in human aortic endothelial cells. AB - An increasing number of studies have shown a correlation between Porphyromonas gingivalis (P. gingivalis) infection and atherosclerosis. A recent study demonstrated that the expression of vascular cell adhesion molecule-1 (VCAM-1) was induced by P. gingivalis lipopolysaccharide (LPS) in human aortic endothelial cells (HAECs). The activation of p38 mitogen-activated protein kinase (p38 MAPK) was at least partially involved in this process. Those results suggested the potential involvement of P. gingivalis LPS in the pathogenesis of atherosclerosis. However, the mechanism involved in P. gingivalis LPS-induced VCAM-1 production has not yet been elucidated. The present study examined the role of the c-Jun N-terminal kinase (JNK) and nuclear factor-kappaB (NF-kappaB) cell signaling pathways in P. gingivalis LPS-induced VCAM-1 expression in HAECs. Western blotting was used to investigate the activation of JNK and NF-kappaB pathways in HAECs exposed to P. gingivalis LPS. Following this, specific pharmacological inhibitors were introduced and the protein production of VCAM-1 was studied. The results showed that the JNK and NF-kappaB pathways in HAECs were capable of being activated by P. gingivalis LPS. The inhibition of NF-kappaB by SN50 significantly attenuated P. gingivalis LPS-induced VCAM-1 expression, while the inhibition of JNK by SP600125 enhanced VCAM-1 expression in P. gingivalis LPS treated HAECs. Therefore, the results indicated that NF-kappaB was essential for the P. gingivalis LPS-induced VCAM-1 expression in HAECs and that JNK may be a suppressor of VCAM-1 expression in HAECs. PMID- 24045415 TI - Characterisation of phosphate coacervates for potential biomedical applications. AB - In this study, amorphous (Na2O)x(CaO)0.50- x(P2O5)0.50.yH2O (where x = ~0.15 and y = ~3) samples were prepared by a coacervate method. Thermal analysis showed that two types of water molecules were present in the coacervate structures: one type loosely bound and the other part of the phosphate structure. Structural studies using Fourier transform infrared spectroscopy (FTIR) and X-ray total diffraction revealed the samples to have very similar structures to melt-quenched glasses of comparable composition. Furthermore, no significant structural differences were observed between samples prepared using calcium nitrate as the calcium source or those prepared from calcium chloride. A sample containing ~1 mol% Ag2O was prepared to test the hypothesis that calcium phosphate coacervate materials could be used as delivery agents for antibacterial ions. This sample exhibited significant antibacterial activity against the bacterium Psuedomonas aeruginosa. FTIR data revealed the silver-doped sample to be structurally akin to the analogous silver-free sample. PMID- 24045416 TI - Diversity of individual mobility patterns and emergence of aggregated scaling laws. AB - Uncovering human mobility patterns is of fundamental importance to the understanding of epidemic spreading, urban transportation and other socioeconomic dynamics embodying spatiality and human travel. According to the direct travel diaries of volunteers, we show the absence of scaling properties in the displacement distribution at the individual level,while the aggregated displacement distribution follows a power law with an exponential cutoff. Given the constraint on total travelling cost, this aggregated scaling law can be analytically predicted by the mixture nature of human travel under the principle of maximum entropy. A direct corollary of such theory is that the displacement distribution of a single mode of transportation should follow an exponential law, which also gets supportive evidences in known data. We thus conclude that the travelling cost shapes the displacement distribution at the aggregated level. PMID- 24045417 TI - What's new in Shock? October 2013. PMID- 24045419 TI - Use of animal models for the study of human disease-a shock society debate. PMID- 24045418 TI - Intestinal barrier disruption as a cause of mortality in combined radiation and burn injury. AB - Nuclear disaster associated with combined radiation injury (CRI) and trauma or burns results in higher mortality than component injuries. Early death is caused by sequelae of gastrointestinal (GI) leakiness such as bacterial translocation and shock. We developed a murine model to characterize GI injury after CRI and determine the extent of barrier disruption. Animals received radiation (5.5 Gy) alone or with 15% total body surface area (TBSA) scald burn and were euthanized at 24, 48, and 72 h. Mesenteric lymph node homogenate was plated on tryptic soy agar to assess for bacterial translocation. Tight junction protein, occludin, was characterized by Western blot and immunofluorescence. Intestinal histology was evaluated, and apoptosis was quantified using histone-associated DNA fragmentation enzyme-linked immunosorbent assay and Western blot for caspase-3 and caspase-8. At 72 h, a 100-fold increase in bacterial growth after CRI was observed. Occludin colocalization was reduced by radiation exposure, with largest differences in CRI at 24 and 48 h. Histopathology exhibited increased apoptosis in radiation alone and CRI animals at 24 and 48 h (P < 0.05). Further evidence of apoptotic activity in CRI was seen at 48 h, with 3-fold increases in enzyme linked immunosorbent assay detection relative to all groups and caspase-8 activity relative to radiation alone and sham (P < 0.05). Prolonged epithelial apoptosis and disruption of tight junctions likely contribute to gut leakiness after CRI. Subsequent bacterial translocation to mesenteric lymph node potentially leads to sepsis and death and could serve as a target for mitigating agents to improve survival from CRI. PMID- 24045420 TI - Electrophile induced branching cascade: a powerful approach to access various molecular scaffolds and their exploration as novel anti-mycobacterial agents. AB - Herein we report on the Electrophile Induced Branching Cascade (EIBC), a new technique to produce a variety of biologically important molecular scaffolds. Some compounds exhibit excellent activities against Mycobacterium smegmatis. PMID- 24045421 TI - Impact of nicotine metabolism on nicotine's pharmacological effects and behavioral responses: insights from a Cyp2a(4/5)bgs-null mouse. AB - Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgs-null] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed >90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgs-null and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgs-null mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans. PMID- 24045422 TI - Relationship between plasma l-lysine concentrations and levels of HIV-1 RNA. PMID- 24045423 TI - Catecholamines influence myocardial 123I MIBG uptake in neuroblastoma patients. AB - AIM: Cardiac 123I metaiodobenzylguanidine (MIBG) imaging can be influenced by several factors. We evaluated the relationship between catecholamine measurements and cardiac 123I MIBG uptake in neuroblastoma patients. PATIENTS, METHODS: 30 neuroblastoma patients were retrospectively assessed on cardiac 123I MIBG uptake and urinary catecholamine dopamine and metabolites, homovanillic acid (HVA) and vanillylmandelic acid (VMA). Cardiac 123I MIBG uptake was quantified by heart-to mediastinum (H/M) ratios, which were calculated into standard deviation scores (SDS) using age-specific reference values. RESULTS: In 17 (57%) and 12 patients (40%) H/M ratio measurements were below -1.0 and -2.0 SDS at diagnosis. A significant inverse correlation between the average of urine metabolites HVA and VMA, and H/M ratio SDS was observed (r -.39, p = 0.04). Furthermore, there was a significant correlation between the urinary catecholamine metabolite HVA and H/M ratio SDS (r -.40, p=0.04). CONCLUSION: Routine calculation of H/M ratios in 123I MIBG scintigrams of neuroblastoma patients is not helpful because it will not identify cardiac ventricular dysfunction in this patient category. A low H/M ratio on 123I MIBG scintigraphy is explained by increased cathecholamine levels secreted by neuroblastoma tumours. PMID- 24045424 TI - Climate change and influenza: the likelihood of early and severe influenza seasons following warmer than average winters. AB - The 2012-13 influenza season had an unusually early and severe start in the US, succeeding the record mild 2011-12 influenza season, which occurred during the fourth warmest winter on record. Our analysis of climate and past US influenza epidemic seasons between 1997-98 to present indicates that warm winters tend to be followed by severe epidemics with early onset, and that these patterns are seen for both influenza A and B. We posit that fewer people are infected with influenza during warm winters, thereby leaving an unnaturally large fraction of susceptible individuals in the population going into the next season, which can lead to early and severe epidemics. In the event of continued global warming, warm winters such as that of 2011-12 are expected to occur more frequently. Our results thus suggest that expedited manufacture and distribution of influenza vaccines after mild winters has the potential to mitigate the severity of future influenza epidemics. PMID- 24045425 TI - Number of distal limb and brachial pressure measurements required when diagnosing peripheral arterial disease by laser Doppler flowmetry. AB - We examine the reliability of single and repeated blood pressure measurements at ankle, toe, and arm levels for the diagnosis of peripheral arterial disease (PAD) by laser Doppler flowmetry. Segmental pressures were measured in 200 patients with known or suspected PAD. Segmental indices were calculated using (1) one measurement [M-1], two measurements [M-2], or by a predefined reproducibility criterion (RC) as well as (2) by using one brachial blood-pressure (BBP-one) or correspondent to each segmental pressure (BBP-all) as reference. The agreement in diagnosis of PAD by Cohen's Kappa was kappa = 0.930 when comparing RC to M-1, and kappa = 0.977 when comparing RC to M-2. The same comparison showed excellent relative reliability for segmental indices (all intra-class correlation coefficients (ICC) >= 0.980). Diagnostic classification agreement for BBP-all versus BBP-one were kappa = 0.831 for RC, kappa = 0.804 for M-1, and kappa = 0.847 for M-2. The relative reliability analysis showed excellent correlation in segmental indices (all ICC >= 0.957). The study shows minimal difference in segmental indices and diagnostic classification when comparing calculations based on the listed strategies. However, the study indicated that it is important to measure BBPs correspondent to each segmental pressure. PMID- 24045426 TI - Testing for effects of different stimuli on neuronal firing relative to background activity. AB - OBJECTIVE: Statistical testing for effects of stimuli on the responses of large populations of recorded neurons is a key technique for analyzing data generated using multi-channel recording systems. Combining statistical tests for differences of the responses to different stimuli and tests for changes from background firing, while appealing as apparently focusing analysis on neurons which react to the stimuli, can lead to significant overestimates of the magnitudes of the effects of stimulation or even erroneous identification of responses as being statistically significant. APPROACH: As this type of combination is common in the neurophysiological literature, we derive a non parametric hypothesis test for changes of responses to different types of stimuli relative to background firing. MAIN RESULTS: This test can be used to avoid improperly combining two statistical tests. We also model the overestimation of effects of stimulus type that can be observed in typical single-unit recordings when applying two statistical tests sequentially. SIGNIFICANCE: Over-estimation of the fraction of neurons with a response can range up to 1800% in plausible recording scenarios. The method of testing derived here avoids this type of error. PMID- 24045427 TI - Quantifying traffic exposure. AB - Living near traffic adversely affects health outcomes. Traffic exposure metrics include distance to high-traffic roads, traffic volume on nearby roads, traffic within buffer distances, measured pollutant concentrations, land-use regression estimates of pollution concentrations, and others. We used Geographic Information System software to explore a new approach using traffic count data and a kernel density calculation to generate a traffic density surface with a resolution of 50 m. The density value in each cell reflects all the traffic on all the roads within the distance specified in the kernel density algorithm. The effect of a given roadway on the raster cell value depends on the amount of traffic on the road segment, its distance from the raster cell, and the form of the algorithm. We used a Gaussian algorithm in which traffic influence became insignificant beyond 300 m. This metric integrates the deleterious effects of traffic rather than focusing on one pollutant. The density surface can be used to impute exposure at any point, and it can be used to quantify integrated exposure along a global positioning system route. The traffic density calculation compares favorably with other metrics for assessing traffic exposure and can be used in a variety of applications. PMID- 24045428 TI - Satellite-based PM concentrations and their application to COPD in Cleveland, OH. AB - A hybrid approach is proposed to estimate exposure to fine particulate matter (PM(2.5)) at a given location and time. This approach builds on satellite-based aerosol optical depth (AOD), air pollution data from sparsely distributed Environmental Protection Agency (EPA) sites and local time-space Kriging, an optimal interpolation technique. Given the daily global coverage of AOD data, we can develop daily estimate of air quality at any given location and time. This can assure unprecedented spatial coverage, needed for air quality surveillance and management and epidemiological studies. In this paper, we developed an empirical relationship between the 2 km AOD and PM(2.5) data from EPA sites. Extrapolating this relationship to the study domain resulted in 2.3 million predictions of PM(2.5) between 2000 and 2009 in Cleveland Metropolitan Statistical Area (MSA). We have developed local time-space Kriging to compute exposure at a given location and time using the predicted PM(2.5). Daily estimates of PM(2.5) were developed for Cleveland MSA between 2000 and 2009 at 2.5 km spatial resolution; 1.7 million (~79.8%) of 2.13 million predictions required for multiyear and geographic domain were robust. In the epidemiological application of the hybrid approach, admissions for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) was examined with respect to time space lagged PM(2.5) exposure. Our analysis suggests that the risk of AECOPD increases 2.3% with a unit increase in PM(2.5) exposure within 9 days and 0.05 degrees (~5 km) distance lags. In the aggregated analysis, the exposed groups (who experienced exposure to PM(2.5) >15.4 MUg/m(3)) were 54% more likely to be admitted for AECOPD than the reference group. The hybrid approach offers greater spatiotemporal coverage and reliable characterization of ambient concentration than conventional in situ monitoring-based approaches. Thus, this approach can potentially reduce exposure misclassification errors in the conventional air pollution epidemiology studies. PMID- 24045429 TI - Epidemiologic study of residential proximity to transmission lines and childhood cancer in California: description of design, epidemiologic methods and study population. AB - We conducted a large epidemiologic case-control study in California to examine the association between childhood cancer risk and distance from the home address at birth to the nearest high-voltage overhead transmission line as a replication of the study of Draper et al. in the United Kingdom. We present a detailed description of the study design, methods of case ascertainment, control selection, exposure assessment and data analysis plan. A total of 5788 childhood leukemia cases and 3308 childhood central nervous system cancer cases (included for comparison) and matched controls were available for analysis. Birth and diagnosis addresses of cases and birth addresses of controls were geocoded. Distance from the home to nearby overhead transmission lines was ascertained on the basis of the electric power companies' geographic information system (GIS) databases, additional Google Earth aerial evaluation and site visits to selected residences. We evaluated distances to power lines up to 2000 m and included consideration of lower voltages (60-69 kV). Distance measures based on GIS and Google Earth evaluation showed close agreement (Pearson correlation >0.99). Our three-tiered approach to exposure assessment allowed us to achieve high specificity, which is crucial for studies of rare diseases with low exposure prevalence. PMID- 24045431 TI - Characterization of amplification patterns and target genes on the short arm of chromosome 7 in early-stage lung adenocarcinoma. AB - Chromosomal alterations are a predominant genomic force contributing to the development of lung adenocarcinoma (ADC). High density genomic arrays were conducted to identify critical genetic landmarks that may be important mediators in the formation or progression of early-stage ADC. In this study, the most noteworthy and consistent observation was a copy number gain on the short arm of chromosome 7, which was detected in 85.7% (12/14) of cases. Notably, three distinct regions of amplification were identified between the 7p22.3 and q11.2 regions in 28.6% (4/14) of cases; at a size of 4.1 Mbp (7p22.3-p21.1), 2.6 Mbp (7p15.2-p14.1) and 1.5 Mbp (7p12.3-p11.2). Variations of the 7p11.2 locus that encodes EGFR are known to be oncogenic. Furthermore, potential target genes were identified that were previously not assumed to be involved in the pathogenesis of ADC, including CALM1P2 (7p11.2), HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXA10, HOXA11 and HOXA13 (7p15.2) and LOC442586, LOC442589, LOC442282, FAM20C and LOC442651 (7p22.3). The present study determined critical regions on the 7p arm of chromosome 7, which were implicated in ADC. The pattern of rearrangements on the 7p arm may be a consequence of the high density of potential targets and the identified genes at the 7p regions may aid in the development of therapeutic targets for ADC. PMID- 24045432 TI - 'Switch-off' biosensing for chymotrypsin-catalyzed reaction by SPR-SERS spectroscopy. AB - We describe a novel 'switch-off' biosensing strategy for the detection of chymotrypsin based on surface plasmon resonance (SPR) and surface-enhanced Raman scattering (SERS) spectroscopy. This approach analyzes the fingerprint spectrum of the chymotrypsin-catalyzed substrate. The lowest probed concentration is 0.4 nM for chymotrypsin. PMID- 24045430 TI - Non-Darwinian dynamics in therapy-induced cancer drug resistance. AB - The development of drug resistance, the prime cause of failure in cancer therapy, is commonly explained by the selection of resistant mutant cancer cells. However, dynamic non-genetic heterogeneity of clonal cell populations continuously produces metastable phenotypic variants (persisters), some of which represent stem-like states that confer resistance. Even without genetic mutations, Darwinian selection can expand these resistant variants, which would explain the invariably rapid emergence of stem-like resistant cells. Here, by using quantitative measurements and modelling, we show that appearance of multidrug resistance in HL60 leukemic cells following treatment with vincristine is not explained by Darwinian selection but by Lamarckian induction. Single-cell longitudinal monitoring confirms the induction of multidrug resistance in individual cells. Associated transcriptome changes indicate a lasting stress response consistent with a drug-induced switch between high-dimensional cancer attractors. Resistance induction correlates with Wnt pathway upregulation and is suppressed by beta-catenin knockdown, revealing a new opportunity for early therapeutic intervention against the development of drug resistance. PMID- 24045433 TI - Is medial pin use safe for treating pediatric supracondylar humerus fractures? AB - OBJECTIVES: We present a group of pediatric supracondylar humerus fractures in whom a medial pin was inserted, in addition to lateral-entry pins, and compared it with a group that was treated with lateral-only entry pins. We evaluated differences in the rate of complications related to the insertion of the medial pin. DESIGN: Prospective nonrandomized. SETTING: Level II academic center. METHODS: The data on 291 pediatric was analyzed. Patients in group 1 (n = 47) were treated with a combination of 2 lateral-entry pins and 1 medial-entry pin, whereas patients in group 2 (n = 244) were treated with lateral-only entry pins alone. Information related to the injury and surgical procedure was prospectively collected. The length of surgery, amount of pin separation at the fracture site, presence of neurological complications, pin tract infection, loss of fixation, final carrying angle, and range of motion were recorded. RESULTS: Fracture severity was similar in both groups (P = 0.6). Medial column comminution was identified preoperatively in all fractures in group 1 and in 10% of fractures in group 2. Length of surgery was a mean of 21 minutes longer for patients in group 1 (P < 0.00001). There were no iatrogenic nerve injuries, vascular complications, or compartment syndromes in either group. The use of a medial-entry pin significantly increased the amount of pin separation at the fracture site (P < 0.00001). The percentage of satisfactory results was similar in both groups (P = 0.6). CONCLUSIONS: The results of this study suggest that the use of a medial entry pin for the treatment of pediatric supracondylar humerus fractures is safe, if an adequate technique is followed. Although insertion of medial pins leads to longer surgeries, it does not seem to result in higher incidence of complications. PMID- 24045434 TI - Biomechanical evaluation of syndesmotic screw position: a finite-element analysis. AB - OBJECTIVES: To evaluate the stresses in syndesmotic screws and widening of syndesmosis under loading after placement of the screws at different levels from the ankle joint line and to determine the optimal level. METHODS: From a set of computed tomographic data of an ankle, a 3-dimensional finite-element model was reconstructed. Six fixation configurations of the syndesmosis with placement of 3.5 or 4.5 mm single tricortical screws at 20-45 mm from the tibiotalar joint were performed on this model. Physiological loads approximating those during both midstance and heel-off states of stance phase of normal walking were applied to evaluate the stress in the screw and widening of the syndesmosis. RESULTS: Among the 6 fixation configurations, the lowest von Mises stress was found in the screws placed 30-40 mm above the joint line (373.31-380.17 MPa for 3.5 mm cortical screw and 284.06-327.31 MPa for 4.5 mm cortical screw in midstance phases), whereas the least syndesmosis widening was determined when the screw was placed 30 mm above the tibial plafond (0.005 mm) for 3.5 mm cortical screw and 20, 25, and 30 mm above the tibial plafond (0.004 mm for each, respectively) for 4.5 mm cortical screw during midstance phases. CONCLUSIONS: This study showed that syndesmosis fixation at the level of 30-40 mm above the tibiotalar joint has advantages with regard to stress in screws in comparison with the other evaluated levels. PMID- 24045435 TI - Potential predictive ability of the orthopaedic trauma association open fracture classification. AB - OBJECTIVE: Is the OTA open fracture classification (OTA-OFC) potentially predictive of early amputation and specific clinical treatments? DESIGN: Retrospective chart review of prospectively collected data. SETTING: Level I trauma center, Seattle, WA. PATIENTS/PARTICIPANTS: Three hundred fifty-six patients with open fractures of the femur, tibia, malleoli, humerus, radius/ulna, pelvis, acetabulum, foot, or clavicle. INTERVENTION: No intervention. MAIN OUTCOME MEASUREMENTS: Vacuum-assisted closure placement, 3+ irrigation and debridements, antibiotic bead placement, and early amputation. RESULTS: The OTA OFC is related to the type of treatment used to treat an open fracture. The model demonstrated that the strongest potential predictor of vacuum-assisted closure use is the severity of the skin injury; multiple debridements (>= 2) is best predicted by the severity of the skin injury and muscle injury; bone loss was the strongest potential predictor of antibiotic bead placement; and the strongest predictors of early amputation are skin injury, contamination, and arterial injury. CONCLUSIONS: Exploratory analysis of these data demonstrates that variations in muscle damage, skin injury, bone loss, arterial injury, and contamination sustained in an open fracture are related to different treatments in the total study population and for anatomical regions. The information provided by this study demonstrates that the OTA-OFC may have predictive abilities relative to how an open fracture is treated. LEVEL OF EVIDENCE: Prognostic level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 24045437 TI - Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties. AB - The epithelial-mesenchymal transition (EMT) imparts metastatic competence on otherwise non-metastatic cancer cells through decreased inter-cellular adhesions, increased migratory capacity, stem cell properties and anoikis and chemotherapy resistance. In this study, we profiled changes in microRNA expression during EMT in conjunction with changes in DNA methylation at microRNA promoters to discover essential mediators of EMT-imparted stemness properties. MicroRNA-203 (miR-203) expression is repressed following EMT induced by multiple different stimuli and in established claudin-low cell lines as well as the CD44hi/CD24lo stem cell enriched fraction. Expression of miR-203 in mesenchymal cells compromises migratory and invasive capacity in vitro, and tumor initiation and metastasis in vivo. Unexpectedly, miR-203 expression affects the sphere-forming capacity of neighboring cells by indirectly enhancing expression of DKK1, a secreted inhibitor of Wnt signaling and stemness resulting in suppression of beta-catenin protein levels. Our data suggest that restoring miR-203 expression levels may inhibit metastasis and combat deregulated Wnt signaling. PMID- 24045438 TI - Randomized double-blinded prospective trial of fibrin sealant spray versus mechanical stapling in laparoscopic total extraperitoneal hernioplasty. AB - OBJECTIVE: The aim of the current study was to compare the clinical outcomes of mesh fixation with fibrin sealant (FS) spray or mechanical stapling (MS) in laparoscopic total extraperitoneal hernioplasty (TEP). BACKGROUND: The most appropriate method of mesh fixation is uncertain. METHODS: Between June 2007 and June 2011, consecutive patients with primary reducible unilateral inguinal hernia who underwent day-case laparoscopic TEP were recruited. Outcome parameters included the incidence of acute and chronic pain, recurrence rates, morbidity rates, analgesic requirements, quality-of-life (QOL) scores, and direct cost. RESULTS: During the study period, 130 patients were included in the study. Patients in the MS group had significantly worse pain scores on the day after operation (P = 0.006). Analgesic requirements were similar between the 2 groups (P = 0.558). At 6 months, no significant differences in the incidence of chronic pain were observed (at rest, after coughing or cycling). The incidence of seroma formation was similar between the 2 groups (P = 0.64), and no recurrences were observed at 1 year. No differences in the QOL scores were detected. The direct cost of the entire hospitalization in the FS group was less expensive (P < 0.001). CONCLUSIONS: FS and MS are both effective methods of providing mesh fixation. FS was associated with reduced acute pain but not chronic pain. The rates of seroma formation were similar. However, the use of FS for mesh fixation was less expensive. [corrected]. PMID- 24045439 TI - Distinct pathways regulated by RET and estrogen receptor in luminal breast cancer demonstrate the biological basis for combination therapy. AB - OBJECTIVE: We investigated directed therapy based on TFAP2C-regulated pathways to inform new therapeutic approaches for treatment of luminal breast cancer. BACKGROUND: TFAP2C regulates the expression of genes characterizing the luminal phenotype including ESR1 and RET, but pathway cross talk and potential for distinct elements have not been characterized. METHODS: Activation of extracellular signal-regulated kinases (ERK) and AKT was assessed using phosphorylation-specific Western blot. Cell proliferation was measured with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] after siRNA (small interfering RNA) gene knockdown or drug treatment. Cell cycle, Ki-67, and cleaved caspase 3 were measured by fluorescence-activated cell sorting. Tumorigenesis was assessed in mice xenografts. RESULTS: Knockdown of TFAP2C or RET inhibited GDNF (glial cell line-derived neurotrophic factor)-mediated activation of ERK and AKT in MCF-7 cells. Similarly, sunitinib, a small-molecule inhibitor of RET, blocked GDNF-mediated activation of ERK and AKT. Inhibition of RET either by gene knockdown or by treatment with sunitinib or vandetanib reduced RET-dependent growth of luminal breast cancer cells. Interestingly, knockdown of TFAP2C, which controls both ER (estrogen receptor) and RET, demonstrated a greater effect on cell growth than either RET or ER alone. Parallel experiments using treatment with tamoxifen and sunitinib confirmed the increased effectiveness of dual inhibition of the ER and RET pathways in regulating cell growth. Whereas targeting the ER pathway altered cell proliferation, as measured by Ki-67 and S phase, anti-RET primarily increased apoptosis, as demonstrated by cleaved caspase 3 and increased TUNEL (terminal deoxyneucleotidyl transferase dUTP nick end labeling) expression in xenografts. CONCLUSIONS: ER and RET primarily function through distinct pathways regulating proliferation and cell survival, respectively. The findings inform a therapeutic approach based on combination therapy with antiestrogen and anti-RET in luminal breast cancer. PMID- 24045440 TI - Treatment and outcome of patients suffering from perineal/perianal rhabdomyosarcoma: results from the CWS trials--retrospective clinical study. AB - OBJECTIVE: To analyze the clinical course, treatment, complications, outcome, and quality of life (QOL) in patients with perineal/perianal rhabdomyosarcoma (PRMS) treated within the CWS-86, -91, -96, and -2002P trials. BACKGROUND: Although multiple international study trials exist for the treatment of rhabdomyosarcoma, only very limited information is given on treatment, outcome, and QOL in PRMS. METHODS: A total of 35 patients suffering from PRMS were treated with neoadjuvant chemotherapy. Local therapy with radiation and/or surgery was performed, followed by adjuvant chemotherapy. Functional long-term follow-up was evaluated by a gastrointestinal/QOL survey. RESULTS: Thirty-two patients were evaluated (exclusion n = 3). Eight patients had embryonal histology, and 24 patients had alveolar histology. The median age was 108 months (median follow-up: 5.8 years). The 5-year overall survival was 47% (95% confidence interval: 29-64). Sixteen IRS (Intergroup Rhabdomyosarcoma Study) III and IV patients had locoregional lymph node involvement at diagnosis. Seven patients were treated with chemotherapy/surgery alone [5-year event-free survival (EFS): 85.7%]. Eleven patients received only radiochemotherapy (5-year EFS: 27.3%). Combined radiochemotherapy/surgery was used in 12 patients (5-year EFS: 63.6%). Two patients were treated only with chemotherapy and they died. Patients with embryonal histology had a significantly better 5-year EFS (87.5%) than patients with alveolar histology (39.1%; P = 0.013). Some patients reported symptoms of fecal incontinence. The median Wexner fecal incontinence score was 9 (possible range: 0-20), and the median QOL score was 90.5 (applicable range: 0-144). CONCLUSIONS: The outcome of these patients remains unsatisfactory. Prognostic factors for a favorable outcome are tumor size of smaller than 5 cm, negative locoregional lymph nodes, age less than 10 years, low IRS group, and embryonal histology. Fecal incontinence seems to be a problem. PMID- 24045441 TI - Laparoscopic sleeve gastrectomy in 108 obese children and adolescents ages 5 to 21 years by Alqahtani AR, Antonisamy B, Alamri H, Elahmedi M, Zimmerman VA. PMID- 24045442 TI - Robotic versus laparoscopic hepatectomy: a matched comparison. AB - OBJECTIVE: To perform a matched comparison of surgical and postsurgical outcomes between our robotic and laparoscopic hepatic resection experience. BACKGROUND: The application of robotic technology and technique to liver surgery has grown. Robotic methods may have the potential to overcome certain laparoscopic disadvantages, but few studies have drawn a matched comparison of outcomes between robotic and laparoscopic liver resections. METHODS: Demographics, intraoperative variables, and postoperative outcomes among patients undergoing robotic (n = 57) and laparoscopic (n = 114) hepatic resections between November 2007 and December 2011 were reviewed. A 1:2 matched analysis was performed by individually matching patients in the robotic cohort to patients in the laparoscopic cohort based on demographics, comorbidities, performance status, and extent of liver resection. RESULTS: Matched patients undergoing robotic and laparoscopic liver resections displayed no significant differences in operative and postoperative outcomes as measured by blood loss, transfusion rate, R0 negative margin rate, postoperative peak bilirubin, postoperative intensive care unit admission rate, length of stay, and 90-day mortality. Patients undergoing robotic liver surgery had significantly longer operative times (median: 253 vs 199 minutes) and overall room times (median: 342 vs 262 minutes) compared with their laparoscopic counterparts. However, the robotic approach allowed for an increased percentage of major hepatectomies to be performed in a purely minimally invasive fashion (81% vs 7.1%, P < 0.05). CONCLUSIONS: This is the largest series comparing robotic to laparoscopic liver resections. Robotic and laparoscopic liver resection display similar safety and feasibility for hepatectomies. Although a greater proportion of robotic cases were completed in a totally minimally invasive manner, there were no significant benefits over laparoscopic techniques in operative outcomes. PMID- 24045443 TI - The HARM score: a novel, easy measure to evaluate quality and outcomes in colorectal surgery. AB - OBJECTIVE: To develop a measurement tool based on HospitAl stay, Readmission, and Mortality rates (HARM) score, which is easily calculated from routine administrative data. Secondary goals were to validate the HARM score on a national inpatient sample. BACKGROUND: Concerns about patient safety, quality, and health care costs have increased demand for outcome measurement. Performance metrics such as Surgical Care Improvement Project and National Surgical Quality Improvement Program have been described, but they require significant personnel and expenses to maintain. METHODS: A national inpatient database was reviewed for all colectomy discharges from 2010 to 2011. Cases were stratified into emergent and elective. For each discharge, a 1 to 10 score was calculated on the basis of length of stay, vital status, and 30-day readmissions. The HARM score was correlated to the complication rate to test validity, and bootstrapping was used to test reliability. RESULTS: A total of 81,622 colectomy discharges were evaluated: 44% emergent and 56% elective. The mean HARM score was 3.04 (SD = 0.57) for emergent and 2.64 (SD = 0.65) for elective cases. For hospitals with a HARM score of less than 2, 2 to 3, 3 to 4, and 4+, the mean complication rates were 30.3%, 41.9%, 49.3%, and 56.6% (emergent) and 15.2%, 18.2%, 24.0%, and 35.6% (elective), respectively. Pearson correlation coefficients for the mean score and the complication rate were 0.45 (P < 0.01) for elective and emergent cases. Bootstrapping correlation demonstrated reliability for emergent and elective cases. CONCLUSIONS: The HARM score is easy, reliable, and valid for assessing quality in colorectal surgery. It may provide a low-cost solution for comparative quality assessment in surgery focused on true outlier performance rather than process or clinical outcome metrics alone. PMID- 24045444 TI - Glove and gown effects on intraoperative bacterial contamination. AB - OBJECTIVE: Experiments were performed to determine the risk of bacterial contamination associated with changing outer gloves and using disposable spunlace paper versus reusable cloth gowns. BACKGROUND: Despite decades of research, there remains a lack of consensus regarding certain aspects of optimal aseptic technique including outer glove exchange while double-gloving and surgical gown type selection. METHODS: In an initial glove study, 102 surgical team members were randomized to exchange or retain outer gloves 1 hour into clean orthopedic procedures; cultures were obtained 15 minutes later from the palm of the surgeon's dominant gloved hand and from the surgical gown sleeve. Surgical gown type selection was recorded. A laboratory strike-through study investigating bacterial transmission through cloth and paper gowns was performed with coagulase negative staphylococci. In a follow-up glove study, 251 surgical team members, all wearing paper gowns, were randomized as in the first glove study. RESULTS: Glove study 1 revealed 4-fold higher levels of baseline bacterial contamination (31% vs 7%) on the sleeve of surgical team members wearing cloth gowns than those using paper gowns [odds ratio (95% confidence interval): 4.64 (1.72-12.53); P = 0.0016]. The bacterial strike-through study revealed that 26 of 27 cloth gowns allowed bacterial transmission through the material compared with 0 of 27 paper gowns (P < 0.001). In glove study 2, surgeons retaining outer gloves 1 hour into the case had a subsequent positive glove contamination rate of 23% compared with 13% among surgeons exchanging their original outer glove [odds ratio (95% confidence interval): 1.97 (1.02-3.80); P = 0.0419]. CONCLUSIONS: Paper gowns demonstrated less bacterial transmission in the laboratory and lower rates of contamination in the operating room. Disposable paper gowns are recommended for all surgical cases, especially those involving implants, because of the heightened risk of infection. Outer glove exchange just before handling implant materials is also recommended to minimize intraoperative contamination. PMID- 24045445 TI - Anastomotic leak increases distant recurrence and long-term mortality after curative resection for colonic cancer: a nationwide cohort study. AB - OBJECTIVE: To investigate the impact of anastomotic leak (AL) on disease recurrence and long-term mortality in patients alive 120 days after curative resection for colonic cancer. BACKGROUND: There is no solid data as to whether AL after colonic cancer surgery increases the risk of disease recurrence. METHODS: This was a nationwide cohort study of 9333 patients, prospectively registered in the database of the Danish Colorectal Cancer Group and merged with data from the Danish Pathology Registry and the National Patient Registry. Multivariable Cox regression analysis was used to adjust for confounding. RESULTS: The incidence of AL was 6.4%, 744 patients died within 120 days. Of the remaining 8589 patients, 861 (10.0%) developed local recurrence with no association to AL [adjusted hazard ratio (HR) = 0.78; 95% confidence interval (CI): 0.55-1.12; P = 0.184]. Distant recurrence developed in 1281 (14.9%) patients and more frequently after AL (adjusted HR = 1.42; 95% CI: 1.13-1.78; P = 0.003). AL was also associated with increased long-term mortality (adjusted HR = 1.20; 95% CI: 1.01-1.44; P = 0.042). In 2841 patients with stage III cancer, AL was associated with both decreased likelihood of receiving adjuvant chemotherapy (adjusted HR = 0.58; 95% CI: 0.45 0.74; P < 0.001) and a delay to initial administration (16 days; 95% CI: 12-20 days; P < 0.001). CONCLUSIONS: AL was significantly associated with increased rates of distant recurrence and long-term all-cause mortality. Cancelled or delayed administration of adjuvant chemotherapy may partly account for these findings. PMID- 24045446 TI - The European Surgical Association: from birth to adulthood. PMID- 24045447 TI - Annals of Surgery and the European Surgical Association. PMID- 24045448 TI - Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival. AB - OBJECTIVES: We analyzed the impact of chemotherapy-related liver injuries (CALI), pathological tumor regression grade (TRG), and micrometastases on long-term prognosis in patients undergoing liver resection for colorectal metastases after preoperative chemotherapy. BACKGROUND: CALI worsen the short-term outcomes of liver resection, but their impact on long-term prognosis is unknown. Recently, a prognostic role of TRG has been suggested. Micrometastases (microscopic vascular or biliary invasion) are reduced by preoperative chemotherapy, but their impact on survival is unclear. METHODS: Patients undergoing liver resection for colorectal metastases between 1998 and 2011 and treated with oxaliplatin and/or irinotecan-based preoperative chemotherapy were eligible for the study. Patients with operative mortality or incomplete resection (R2) were excluded. All specimens were reviewed to assess CALI, TRG, and micrometastases. RESULTS: A total of 323 patients were included. Grade 2-3 sinusoidal obstruction syndrome (SOS) was present in 124 patients (38.4%), grade 2-3 steatosis in 73 (22.6%), and steatohepatitis in 30 (9.3%). Among all patients, 22.9% had TRG 1-2 (major response), whereas 55.7% had TRG 4-5 (no response). Microvascular invasion was detected in 37.8% of patients and microscopic biliary infiltration in 5.6%.The higher the SOS grade the lower the pathological response: TRG 1-2 occurred in 16.9% of patients with grade 2-3 SOS versus 26.6% of patients with grade 0-1 SOS (P = 0.032).After a median follow-up of 36.9 months, 5-year survival was 38.6%. CALI did not negatively impact survival. Multivariate analysis showed that grade 2-3 steatosis was associated with better survival than grade 0-1 steatosis (5 year survival rate of 52.5% vs 35.2%, P = 0.002). TRG better than the percentage of viable cells stratified patient prognosis: 5-year survival rate of 60.4% in TRG 1-2, 40.2% in TRG 3, and 29.8% in TRG 4-5 (P = 0.0001). Microscopic vascular and biliary invasion negatively impacted outcome (5-year survival rate of 23.3% vs 45.7% if absent, P = 0.017; 0% vs 42.3%, P = 0.032, respectively). CONCLUSIONS: TRG was confirmed to be a crucial prognostic determinant. CALI do not negatively impact long-term prognosis, but the tumor response is reduced in patients with grade 2-3 SOS. Steatosis was found to have a protective effect on survival. Micrometastases significantly impacted prognosis assessment. PMID- 24045449 TI - Outpatient endovascular aortic aneurysm repair: experience in 100 consecutive patients. AB - OBJECTIVES: To present the safety, feasibility, costs, and patient satisfaction of outpatient endovascular aneurysm repair (EVAR). BACKGROUND: Our experience in more than 1000 patients indicated that in technically uncomplicated EVAR procedures, the only need for hospitalization was for access vessel complications (bleeding or occlusion) requiring secondary procedures. These complications could always be identified within the first 3 hours after EVAR. METHODS: Two-center retrospective analysis of prospectively gathered data on 100 consecutive elective outpatient EVAR cases (Outpt EVAR). Inclusion criteria for Outpt EVAR were as follows: asymptomatic clinical state, informed consent, travel time to the hospital if readmission was required of less than 60 minutes, adult observer assistance for the first 24 hours, and a technically uncomplicated EVAR procedure. EVAR was mostly performed under local anesthesia and with percutaneous access. Patients were discharged home after 4 to 6 hours of observation and checked the next morning and on the fifth postoperative day in the outpatient clinic. RESULTS: From 104 patients selected, 4 (3.8%) preferred primary hospitalization and were excluded from further analysis. Four patients (4%) with access vessel complications required additional procedures and had to be hospitalized overnight. The 30-day readmission rate was 4% (4), all due to access vessel stenosis (2) or false aneurysm (2). There was no 30-day mortality. From the 96 outpatients who completed Outpt EVAR, 93 (97%) would undergo Outpt EVAR again and would recommend it to others. Cost comparison showed in 42 matched contemporary patients treated with just a standard stent graft that costs were significantly lower in 21 Outpt EVAR patients than in 21 inpatient EVAR. CONCLUSIONS: Elective Outpt EVAR can be performed safely, provided certain criteria are fulfilled and specific precautions are taken. In this series, Outpt EVAR morbidity was minimal, especially delirium common in elderly patients recovering from inpatient vascular surgery and nosocomial infections did not occur. Finally, patient satisfaction was high and costs were less than with standard inpatient EVAR. PMID- 24045450 TI - Classification of pathologic response to neoadjuvant therapy in esophageal and junctional cancer: assessment of existing measures and proposal of a novel 3 point standard. AB - OBJECTIVE: To assess existing measures of pathologic response to neoadjuvant therapy in esophageal and junctional cancer, and to recommend an optimum classification. BACKGROUND: Multimodal therapy is increasingly the standard of care for locally advanced esophageal cancer. Numerous measures of pathologic response have been studied; however, no international standardization exists and no measure is incorporated into the current American Joint Committee on Cancer staging system. METHODS: A total of 393 consecutive patients completing multimodal therapy were studied, all with prospectively recorded Mandard tumor regression grades (TRG). Seven other published methods of response were compared, and a novel 3-point TRG [TRG 1 (complete); TRG 2/3 (partial); TRG 4/5 (none/minimal)] was tested. Clinical and pathologic evidence of nodal regression was assessed in a consecutive subset of 200 comprehensively staged patients. RESULTS: All models had similar discriminatory and stratification power, and they predicted survival (P < 0.0001) on univariate analysis. Conversely, only the 3 point TRG (P = 0.042) along with ypN (P < 0.001) and ypT stage (P < 0.001) independently predicted survival. The median survival for TRG 1 was 71 months compared with 30 and 17 months for TRG 2/3 and TRG 4/5, respectively (P < 0.0001). Apparent complete nodal response (cN1 to ypN0) was seen in 64% of the TRG 1 group, 30% of the TRG 2/3 group, and 5% of the TRG 4/5 group (P < 0.0001). CONCLUSIONS: No existing response measure independently predicts outcome. A complete response (TRG 1) defines a unique cohort after neoadjuvant therapy, associated closely with nodal response, and overall survival. This classification merits consideration for standardization of treatment response, and for inclusion in staging nomenclature. PMID- 24045451 TI - Measured versus estimated total liver volume to preoperatively assess the adequacy of the future liver remnant: which method should we use? AB - OBJECTIVES: To determine which method of liver volumetry is more accurate in predicting a safe resection. BACKGROUND: Before major or extended hepatectomy, assessment of the future liver remnant (FLR) is crucial to reduce the risk of postoperative hepatic insufficiency. The FLR volume is usually expressed as the ratio of FLR to nontumorous total liver volume (TLV), which can be measured directly by computed tomography (mTLV) or estimated (eTLV) on the basis of correlation existing with the body surface area. To date, these 2 methods have never been compared. METHODS: All consecutive, noncirrhotic patients who underwent resection of 3 or more liver segments between April 2000 and April 2012 and for whom (i) preoperative computed tomographic scans and (ii) body surface area were available entered the study. The mTLV (calculated as TLV - tumor volume) was compared with the eTLV (calculated as -794.41 + 1267.28 * body surface area) using volumetric data (cm) and clinical outcome measures (specifically, hepatic insufficiency and 90-day mortality). Definition of hepatic insufficiency was peak postoperative serum total bilirubin level of more than 7 mg/dL or, in jaundiced patients, an increasing bilirubin level on day 5 or thereafter. RESULTS: Two-hundred forty-three patients who had undergone major (n = 135) or extended (n = 108) hepatectomies met the inclusion criteria. Twenty eight patients (11.5%) developed hepatic insufficiency, whereas 7 patients (2.9%) died postoperatively. Compared with the eTLV, the mTLV underestimated the liver volume in 60.1% of the patients (P < 0.01). Forty-seven and 73 patients had an inadequate FLR based on mTLV and eTLV, respectively. Portal vein occlusion (PVO) was used in 44 patients. In patients (n = 162) in whom both methods did not evidence the need for PVO, postoperative hepatic insufficiency and mortality were 4.9% and 0.6%, respectively. Conversely, in patients (n = 27) in whom the eTLV but not the mTLV evidenced the need for PVO, and thus PVO was not performed, hepatic insufficiency (22.2%; P = 0.001) and mortality (3.7%; P = ns) were higher. CONCLUSIONS: The use of eTLV identifies a subset of patients (~11%) in whom liver volumetry with the mTLV underestimates the risk of hepatic insufficiency. PMID- 24045452 TI - Posthepatectomy portal vein pressure predicts liver failure and mortality after major liver resection on noncirrhotic liver. AB - OBJECTIVES: To evaluate the predictive value of portal vein pressure (PVP) after major liver resection for posthepatectomy liver failure (PLF) and 90-day mortality in patients without cirrhosis. BACKGROUND: As elevated PVP is associated with liver failure after living donor liver transplantation, we hypothesized that the outcome after major hepatectomy may be influenced by posthepatectomy PVP. PATIENTS AND METHODS: All patients without severe fibrosis or cirrhosis who underwent a major liver resection (>=3 segments) with an intraoperative measurement of PVP at the end of the procedure were included. Outcome was analyzed regarding 3 most widely used definitions of PLF: "50-50" criteria, peak of serum bilirubin greater than 120 MUmol/L, and grade C PLF proposed by the International Study Group of Liver Surgery (ISGLS). Receiver operating characteristic curves and logistic regression model were used to determine the optimal cutoff of PVP and independent risk factors of PLF. RESULTS: The study population consisted of 277 patients. Posthepatectomy PVP was gradually correlated with the PLF risk. Probability for PLF was nil when PVP was 10 mm Hg or less, ranges from 13% to 16%, depending on PLF definitions, when PVP was 20 mm Hg, and from 24% to 33% when PVP was 30 mm Hg. The optimal value of posthepatectomy PVP to predict PLF was 22 mm Hg when considering the "50-50" criteria and grade C PLF (proposed by the International Study Group of Liver Surgery). A value of 21 mm Hg best predicted PLF defined by peak of serum bilirubin greater than 120 MUmol/L and 90-day mortality. At multivariate analysis, posthepatectomy PVP remained an independent predictor of PLF as well as the extent of resection, intraoperative transfusion, and the presence of diabetes. The 90-day mortality was associated with PVP greater than 21 mm Hg, older than 70 years, and intraoperative transfusion. CONCLUSIONS: Posthepatectomy PVP is an independent predictive factor of PLF and of 90-day mortality after major liver resection in patients without cirrhosis. Intraoperative modulation of PVP would be advisable when PVP exceeds 20 mm Hg. PMID- 24045453 TI - Gastric emptying as a prognostic factor for long-term results of total laparoscopic fundoplication for weakly acidic or mixed reflux. AB - OBJECTIVES: To evaluate the long-term effect of laparoscopic total fundoplication (LTF) on symptoms and reflux control in patients with combined (acidic and weakly acidic) (CR) or weakly acidic reflux (WAR), according to the gastric emptying (GE) rate. BACKGROUND: After LTF, 12% to 15% of patients experience persistent reflux symptoms and 20% and 25% develop gas-related symptoms. Both WAR and inability to belch have been suggestive of these symptoms. METHODS: Consecutive patients with CR and WAR selected for LTF were included in a prospective clinical study. Gastroesophageal function was assessed by clinical validated questionnaires, upper endoscopy, esophageal manometry, and 24-hour impedance-pH monitoring before and 12 and 60 months after LTF. Gastric scintigraphy was preoperatively performed in all patients to evaluate GE. This trial is registered with ClinicalTrials.gov (no. NCT01741441). RESULTS: Between June 2002 and June 2007, a total of 188 patients with CR and WAR underwent LTF; 172 (91.5%) completed the 5-year protocol. Among them, 42 (24.4%) had preoperative mild/moderate delayed GE (DGE). Quality of life at 12 and 60 months improved in patients with normal GE (Gastroesophageal Reflux Disease Health-Related Quality of Life score 18.2/2.5, P < 0.001; Health-Related Quality of Life score from 52.1 to 68.3, P < 0.001) but not in DGE patients. Manometric values of "gastroesophageal junction" significantly increased at 12 and 60 months in all patients with normal GE, whereas the values returned to the baseline at 60 months in 66.7% of DGE patients. Acidic and liquid reflux episodes significantly reduced in both groups, whereas a significant reduction of WAR and mixed (gas + liquid) reflux episodes occurred only in patients with normal GE (P < 0.001). CONCLUSIONS: DGE affects long-term results of LTF in CR and WAR patients. PMID- 24045454 TI - Distance learning improves attainment of professional milestones in the early years of surgical training. AB - OBJECTIVES: To assess the impact of a surgical sciences e-learning programme in supporting the academic development of surgical trainees during their preparation for professional examination. BACKGROUND: In 2007, a 3-year online part-time Master of Surgical Sciences (MSc) degree programme was launched, utilizing an innovative platform with virtual case scenarios based on common surgical conditions addressed by the curriculum relating to the Membership Examination of the Royal Colleges of Surgeons (MRCS). Multiple-choice questions with feedback and discussion boards facilitated by expert clinical tutors provided formative assessment. Summative assessment comprised written examination at the end of each of the first 2 years (equivalent to MRCS level), culminating in submission of a research dissertation in year 3 toward an MSc. METHODS: Students' age, gender, and level at entry to the programme were documented. Anonymized student feedback from 2008 to 2012 was examined using online questionnaires, and performance in the MSc programme was compared to MRCS examination outcomes for students who had consented to release of their results. RESULTS: A total of 517 surgical trainees from 40 countries were recruited over the 6-year period, and 116 MSc students have graduated to date. Of 368 students, 279 (76%) were foundation doctors (interns) and had not commenced formal surgical training on enrolling in the MSc programme. However, level at entry did not influence performance (P > 0.05 across all 3 years). Average pass rates since the programme launched, for those students completing all of the required assessments, were 84% +/- 11% in year 1, 85% +/- 10% in year 2, and 88% +/- 7% in year 3 of the MSc programme. MSc students had significantly higher MRCS pass rates than nonenrolled trainees (67% vs 51%, P < 0.01, n = 352). There was a significant correlation between MRCS examination performance and overall performance in the MSc (R = 58%; P < 0.01, n = 37). Of 248 respondents, 202 (81%) considered that the MSc would improve their chances of gaining a surgical training post, and 224 (90%) would recommend the programme to their peers. CONCLUSIONS: The online MSc programme supports academic development of trainees in the early years of surgical training, is well received by students, and is associated with improved success in their professional examination. PMID- 24045455 TI - Pulmonary post-transplant lymphoproliferative disorder with a CT halo sign. AB - BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) comprises a spectrum of clinically relevant lymphatic diseases that occur in patients after transplantation. The PTLD-related mortality is high and the clinical picture and location of the lesions are very variable. For these reasons, the diagnosis of PTLD is difficult and new diagnostic tools are sought. CASE REPORT: A 31-year-old woman, 17 years after kidney transplantation, presented with recurrent upper respiratory tract infections, fever, and weakness and was diagnosed with pulmonary PTLD. Computed tomography appearance was not typical for lymphoma and demonstrated multiple bilateral pulmonary nodules and masses with a halo sign. Initial differential diagnosis included invasive pulmonary aspergillosis and acute Wegener granulomatosis. Since cultures from bronchoalveolar lavage and anti neutrophil cytoplasmic antibodies were negative, videothoracoscopy with lung biopsy was performed. Pathology analysis revealed diffuse large T-cell lymphoma with histopathologic features of infiltrative growth along the lung interstitium, vessel invasion, and hemorrhagic necrosis possibly explaining the presence of a halo sign. CONCLUSIONS: We suggest PTLD should always be suspected in a transplant recipient presenting with the CT halo sign. Moreover, the correlation of this radiological phenomenon with the patient's clinical presentation and severe pathologic findings allows us to conclude that the thoracic halo sign in PTLD may reflect a worse prognosis. PMID- 24045456 TI - High speed versus pulsed images for micro-particle image velocimetry: a direct comparison of red blood cells versus fluorescing tracers as tracking particles. AB - High speed photography in micro-particle image velocimetry (MUPIV) using red blood cells as tracer particles and the use of fluorescing tracer particles (in conjunction with pulsed images) are directly compared by using both methods simultaneously. Measurements are taken on the same blood sample in the same microchip using both methods. This work directly and statistically compares the two methods of MUPIV measurement in a controlled in vitro environment for the first time in literature. The pulsed method using fluorescing tracer particles is found to decrease the depth of correlation as expected, and to better represent the shape of the velocity profile. Two methods of velocity characterization are used (single and double parameter) and the pulsed images provide better shape representation in both cases. PMID- 24045462 TI - Self-assembly of diphenylalanine peptides into microtubes with "turn on" fluorescence using an aggregation-induced emission molecule. AB - The self-assembly of diphenylalanine peptides (l-Phe-l-Phe) into microtubes with "turn on" bright yellow green fluorescence was described, which was achieved using an aggregation-induced emission (AIE) molecule of 9,10-bis[4-(3 sulfonatopropoxyl)-styryl] anthracene (BSPSA) sodium. PMID- 24045464 TI - Gold nanoparticle catalysis of the cis-trans isomerization of azobenzene. AB - Ablated, "pseudo-naked" gold nanoparticles (AuNPs) catalyze the cis-trans isomerization of substituted azobenzenes. para-Substitution was found to affect the rate of isomerization, suggesting the participation of AuNP-mediated electron transfer in the isomerization mechanism. PMID- 24045463 TI - A peptide probe for targeted brown adipose tissue imaging. AB - The presence of brown adipose tissue responsible for thermogenic energy dissipation has been revealed in adult humans and has high clinical importance. Owing to limitations of current methods for brown adipose tissue detection, analysing the abundance and localization of brown adipose tissue in the body has remained challenging. Here we screen a combinatorial peptide library in mice and characterize a peptide (with the sequence CPATAERPC) that selectively binds to the vascular endothelium of brown adipose tissue, but not of intraperitoneal white adipose tissue. We show that in addition to brown adipose tissue, this peptide probe also recognizes the vasculature of brown adipose tissue-like depots of subcutaneous white adipose tissue. Our results indicate that the CPATAERPC peptide localizes to brown adipose tissue even in the absence of sympathetic nervous system stimulation. Finally, we demonstrate that this probe can be used to identify brown adipose tissue depots in mice by whole-body near-infrared fluorescence imaging. PMID- 24045465 TI - Potato fiber as a dietary fiber source in dog foods. AB - Potato fiber (PF), a coproduct of potato starch manufacture, was evaluated as a potential novel fiber source in dog food. Potato fiber contained 55% total dietary fiber, 29% starch, 4% crude protein, and 2% acid-hydrolyzed fat. The PF substrate was evaluated for chemical composition, in vitro digestion and fermentation characteristics, and in vivo responses. For the in vitro hydrolytic enzymatic digestion and fermentation experiment, raw and cooked PF substrates were first subjected to hydrolytic-enzymatic digestion to determine OM disappearance and then fermented using dog fecal inoculum. Fermentation characteristics were then measured at 0, 3, 6, 9, and 12 h. For the in vivo experiment, 10 female mixed-breed dogs (6.13+/-0.17 yr; 22+/-2.1 kg) were provided 5 diets with graded concentrations (0%, 1.5%, 3%, 4.5%, or 6%) of PF in a replicated 5*5 Latin square design. Dogs were acclimated to the test diet for 10 d, followed by 4 d of total fecal collection. Fresh fecal samples were collected to measure fecal pH and fermentation end products. In vitro digestion revealed that raw and cooked PF were 32.3% and 27.9% digested enzymatically, whereas in vitro fermentation showed that PF was fermentable through 9 h. Raw PF had greater (P<0.05) acetate, propionate, and total short-chain fatty acid (SCFA) concentrations at the 12-h time point compared with cooked PF. The in vivo experiment showed no differences in apparent total tract DM, OM, CP, acid hydrolyzed fat, or energy digestibility of diets containing graded concentrations of PF. However, total dietary fiber digestibility exhibited a linear increase (P<0.01) with increasing PF concentrations in the diet. Overall, linear increases (P<0.01) were observed for all individual and total SCFA, with a concomitant linear decrease (P<0.01) in fecal pH with increasing dietary PF. Fecal protein catabolite concentrations were low or undetectable, with the exception of spermidine, which exhibited a linear increase with increasing concentrations of PF. These findings indicated that inclusion of PF elicited favorable fermentation characteristics without negatively affecting nutrient digestibility or stool characteristics, indicating that PF could be a functional dietary fiber source in dog foods. PMID- 24045467 TI - Behavior and handling of physically and immunologically castrated market pigs on farm and going to market. AB - Physical castration is a common management practice on commercial swine farms in the United States to reduce the incidence of boar taint and aggressive behavior. One alternative to physical castration (PC) is to immunologically castrate (IC) male pigs by blocking the gonadotropin-releasing factor (GnRF), thereby reducing levels of LH, FSH, testosterone, and androstenone. The objectives of this study were to evaluate the effects of IC on pig behavior, human-pig interactions, and handling during and after transport. Pigs were given the first immunization at wk 7 of the grower-finisher period, and second immunizations were given at wk 11, 13, or 14 of the grower-finisher period. Behaviors of PC and IC barrows were sampled at 3 time points after entering finishing at 9 wk of age: 7 wk before first injection, 16 wk (after immunization was complete) into finishing, and 1 d before marketing (16 to 19 wk into finishing). Handling during loading and unloading of trailers going to market was also quantified. Before the first injection, intact males showed increased aggression (P=0.014) and mounting (P=0.048), whereas PC barrows spent more (P=0.003) time feeding than intact males. There were treatment*time interactions for lying (P=0.018), aggression (P<0.001), and standing (P=0.009) behaviors. Few differences were observed in pig human interactions between PC and IC barrows, with IC and PC approaching people in the same amount of time, but IC barrows were more (P<0.001) aggressive in chewing and rubbing on the test person's pant leg and boots. When handling and loading for processing in the home barn, PC barrows were more (P<0.05) vocal than IC barrows. Fewer dead and down pigs were observed among IC (0%) compared with PC barrows (1.17%). Immunological castration may result in similar or improved animal welfare compared to the stress of physical castration without pain relief. PMID- 24045466 TI - Dietary plant extracts alleviate diarrhea and alter immune responses of weaned pigs experimentally infected with a pathogenic Escherichia coli. AB - A study was conducted to evaluate the effects of 3 different plant extracts on diarrhea, immune response, intestinal morphology, and growth performance of weaned pigs experimentally infected with a pathogenic F-18 Escherichia coli (E. coli). Sixty-four weaned pigs (6.3+/-0.2 kg BW, and 21 d old) were housed in individual pens in disease containment chambers for 15 d: 4 d before and 11 d after the first inoculation (d 0). Treatments were in a 2*4 factorial arrangement: with or without an F-18 E. coli challenge (toxins: heat-labile toxin, heat-stable toxin b, and Shiga-like toxin 2; 10(10) cfu/3 mL oral dose; daily for 3 d from d 0) and 4 diets [a nursery basal diet (CON) or 10 ppm of capsicum oleoresin, garlic botanical, or turmeric oleoresin]. The growth performance was measured on d 0 to 5, 5 to 11, and 0 to 11. Diarrhea score (1, normal, to 5, watery diarrhea) was recorded for each pig daily. Frequency of diarrhea was the percentage of pig days with a diarrhea score of 3 or greater. Blood was collected on d 0, 5, and 11 to measure total and differential white blood cell counts and serum tumor necrosis factor (TNF)-alpha, IL-10, transforming growth factor (TGF)-beta, C-reactive protein, and haptoglobin. On d 5 and 11, half of the pigs were euthanized to measure villi height and crypt depth of the small intestine and macrophage and neutrophil number in the ileum. The E. coli infection increased (P<0.05) diarrhea score, frequency of diarrhea, white blood cell counts, serum TNF-alpha and haptoglobin, and ileal macrophages and neutrophils but reduced (P<0.05) villi height and the ratio of villi height to crypt depth of the small intestine on d 5. In the challenged group, feeding plant extracts reduced (P<0.05) average diarrhea score from d 0 to 2 and d 6 to 11 and frequency of diarrhea and decreased (P<0.05) TNF-alpha and haptoglobin on d 5, white blood cell counts and neutrophils on d 11, and ileal macrophages and neutrophils on d 5. Feeding plant extracts increased (P<0.05) ileal villi height on d 5 but did not affect growth performance compared with the CON. In the sham group, feeding plant extract also reduced (P<0.05) diarrhea score, frequency of diarrhea, and ileal macrophages compared with the CON. In conclusion, the 3 plant extracts tested reduced diarrhea and inflammation caused by E. coli infection, which may be beneficial to pig health. PMID- 24045468 TI - The valence of the long-lasting emotional experiences with various handlers modulates discrimination and generalization of individual humans in sheep. AB - Between-farm variation in animal reactions to humans can reflect different management styles and behavioral tendencies among farmers. Animals are well known to discriminate among humans, but less clear is the key issue of whether they more or less easily generalize their experience from specific humans to others depending on management style. Here, we chose 2 contrasted management styles by known handlers: "gentle" management, that is, long-lasting exposure to positive human interactions (with limited negative interactions), and "aversive" management including long-lasting exposure to various negative human interactions (with only food delivery considered a positive interaction) and aversive events. Over a period of 19 wk, 15 female lambs were exposed to the gentle management treatment ("gently treated" group) and another 15 lambs ("aversively treated" group) were exposed to the aversive management treatment. To facilitate discrimination by animals, experimenters wore white clothes for aversive events and green clothes for farming handling (positive handling and feeding for the gently treated group and only feeding for the aversively treated group). Sheep perception of the human was assessed after the management period by submitting lambs from each group to 2 standardized tests: 1) the presence of a stationary human (familiar human in white vs. familiar human in green vs. unknown human) and 2) the presence of a moving human (familiar human in white vs. familiar human in green vs. unknown human). As expected, during the stationary human test, aversively treated lambs spent less time in the human zone (P<0.0001), showed greater latency to approach the human (P=0.05), and had fewer contacts with the human (P=0.05) than gently treated lambs. During the moving human test, aversively treated lambs also showed a greater escape distance from humans than gently treated lambs (P<0.0001). Aversively treated lambs showed the same fear responses towards familiar and unknown humans and tended to generalize their aversive experiences with one handler to all humans. In contrast, gently treated lambs seemed to discriminate familiar humans from unfamiliar humans. Different management styles could modulate farm generalization to humans in farm animals. PMID- 24045470 TI - Special topics--Mitigation of methane and nitrous oxide emissions from animal operations: III. A review of animal management mitigation options. AB - The goal of this review was to analyze published data on animal management practices that mitigate enteric methane (CH4) and nitrous oxide (N2O) emissions from animal operations. Increasing animal productivity can be a very effective strategy for reducing greenhouse gas (GHG) emissions per unit of livestock product. Improving the genetic potential of animals through planned cross breeding or selection within breeds and achieving this genetic potential through proper nutrition and improvements in reproductive efficiency, animal health, and reproductive lifespan are effective approaches for improving animal productivity and reducing GHG emission intensity. In subsistence production systems, reduction of herd size would increase feed availability and productivity of individual animals and the total herd, thus lowering CH4 emission intensity. In these systems, improving the nutritive value of low-quality feeds for ruminant diets can have a considerable benefit on herd productivity while keeping the herd CH4 output constant or even decreasing it. Residual feed intake may be a tool for screening animals that are low CH4 emitters, but there is currently insufficient evidence that low residual feed intake animals have a lower CH4 yield per unit of feed intake or animal product. Reducing age at slaughter of finished cattle and the number of days that animals are on feed in the feedlot can significantly reduce GHG emissions in beef and other meat animal production systems. Improved animal health and reduced mortality and morbidity are expected to increase herd productivity and reduce GHG emission intensity in all livestock production systems. Pursuing a suite of intensive and extensive reproductive management technologies provides a significant opportunity to reduce GHG emissions. Recommended approaches will differ by region and species but should target increasing conception rates in dairy, beef, and buffalo, increasing fecundity in swine and small ruminants, and reducing embryo wastage in all species. Interactions among individual components of livestock production systems are complex but must be considered when recommending GHG mitigation practices. PMID- 24045471 TI - Effectiveness of a nonpenetrating captive bolt for euthanasia of piglets less than 3 d of age. AB - The objective of this study was to determine the effectiveness of a nonpenetrating captive bolt (NPCB), the Zephyr-Euthanasia (Zephyr-E), for euthanasia of neonatal piglets<72 h of age using signs of insensibility and death, as well as postmortem assessment of traumatic brain injury (TBI). The Zephyr-E was used by 10 stock people to euthanize 100 low viability neonatal piglets from 3 commercial farrowing units and 1 research farm. Brainstem reflexes, convulsions, and heartbeat were used to assess insensibility, time of brain death, and cardiac arrest after Zephyr-E application. Hemorrhage severity and skull fracture displacement (FD) were quantified from computed tomography scans (n=10), macroscopic scoring was used to assess brain hemorrhage and skull fracture (SK) severity (n=100), and microscopic scoring was used to assess subdural (SDH) and parenchymal (PH) hemorrhage within specific brain regions that are responsible for consciousness and vital function (n=10). All 100 piglets were rendered immediately insensible without return to sensibility. On average, clonic convulsions (CC) ceased in 101 s (+/-7.4 SE), brain death was achieved in 229 s (+/-9.18 SE), and cardiac arrest occurred in 420 s (+/-13.57 SE). Time of cardiac arrest differed significantly among stock people when either body weight (BW: P=0.0053) or body mass index (BMI: P=0.0059) was used as a covariate. The BMI was inversely related to the duration of CC (P=0.0227). Moderate to severe hemorrhage severity was reported in 9 of 10 piglets. There was no relationship between FD and BW (P=0.8408) or BMI (P=0.6439). Macroscopic analyses indicated moderate to severe hemorrhage and SK in all piglets. No differences were found among brain sections for SDH (P=0.2302); PH was greater in the cerebral cortex than in the midbrain and brainstem (P=0.0328). The Zephyr-E NPCB reliably caused immediate, sustained insensibility followed by death in neonatal piglets. Postmortem assessment confirmed that application of the Zephyr-E caused widespread, irreversible brain damage. PMID- 24045472 TI - Technical note: Use of a simplified equation for estimating glomerular filtration rate in beef cattle. AB - This study was performed to clarify whether a formula (Holstein equation) based on a single blood sample and the isotonic, nonionic, iodine contrast medium iodixanol in Holstein dairy cows can apply to the estimation of glomerular filtration rate (GFR) for beef cattle. To verify the application of iodixanol in beef cattle, instead of the standard tracer inulin, both agents were coadministered as a bolus intravenous injection to identical animals at doses of 10 mg of I/kg of BW and 30 mg/kg. Blood was collected 30, 60, 90, and 120 min after the injection, and the GFR was determined by the conventional multisample strategies. The GFR values from iodixanol were well consistent with those from inulin, and no effects of BW, age, or parity on GFR estimates were noted. However, the GFR in cattle weighing less than 300 kg, aged<1 yr old, largely fluctuated, presumably due to the rapid ruminal growth and dynamic changes in renal function at young adult ages. Using clinically healthy cattle and those with renal failure, the GFR values estimated from the Holstein equation were in good agreement with those by the multisample method using iodixanol (r=0.89, P=0.01). The results indicate that the simplified Holstein equation using iodixanol can be used for estimating the GFR of beef cattle in the same dose regimen as Holstein dairy cows, and provides a practical and ethical alternative. PMID- 24045473 TI - Effects of increasing levels of corn dried distillers grains with solubles and monensin on intake, digestion, and ruminal fermentation in beef heifers fed high barley grain diets. AB - The objective of this study was to determine whether increasing corn-based dried distillers grains with solubles (DDGS) in high-barley grain diets reduces the merit of using higher levels of monensin by assessing intake, digestibility, and ruminal pH and fermentation in feedlot heifers. Five ruminally and duodenally cannulated Angus heifers (average BW of 599+/-36 kg) were used in a 5*5 Latin square with a 2*2+1 factorial arrangement. Treatments were control (CON, 10% barley silage, 90% barley-based concentrate, and 28 mg monensin/kg DM) and diets substituting 20% (LDG) or 40% (HDG) DDGS for barley grain with 28 mg (ML) or 48 mg (MH) monensin/kg diet DM: 1) CONML, 2) LDGML, 3) HDGML, 4) LDGMH, and 5) HDGMH. Contrasts compared LDG vs. HDG, ML vs. MH, interactions between DDGS and monensin, and the effect of increasing DDGS in the diet. Increasing DDGS quadratically (P<0.01) increased DMI. There was no interaction for DMI between the dietary inclusion rate of DDGS and the dose of monensin; however, DMI was reduced (P<0.05) for heifers fed MH vs. ML. Ruminal digestibility of OM, NDF, and starch linearly decreased (P<0.01), but intestinal digestibility linearly increased (P<0.01) with increasing DDGS, resulting in no differences in total tract digestibility. Ruminal digestibility of OM was greater (P<0.04) in heifers fed MH than ML; however, the total tract digestibility of OM was not affected. Intake of N, flows of total N, nonammonia N, and dietary N were linearly (P<0.02) increased, and the efficiency of ruminal microbial synthesis linearly (P<0.04) improved with increasing DDGS. Increasing DDGS inclusion linearly decreased (P<0.04) the acetate to propionate ratio. Inclusion of MH decreased (P<0.04) acetate and increased (P<0.05) NH3-N compared to ML, but high monensin did not affect mean ruminal pH, the duration of pH<5.8, 5.5, 5.2, or the area below the curve at pH 5.8, 5.5, and 5.2, indicating that there was no evidence that it modulated ruminal pH. These results suggest that feeding monensin at 48 vs. 28 mg/kg diet DM altered nutrient availability and site of feed digestion, likely as a result of reduced DMI and increased ruminal digestion of DM. High levels of monensin may reduce the risk of acidosis through a reduction in DMI, but in the present study this was not evident in differences in the ruminal pH profiles between heifers fed ML and MH diets. PMID- 24045474 TI - Effect of dietary levan fructan supplementation on growth performance, meat quality, relative organ weight, cecal microflora, and excreta noxious gas emission in broilers. AB - A total of 720 1-d-old male Ross broilers (BW of 48.0+/-0.3 g) were used to evaluate the effects of dietary levan fructan supplementation on growth performance, meat quality, relative organ weight, cecal microflora, and excreta noxious gas emission in broilers. This experiment lasted 31 d. Broilers were randomly allotted to 1 of 3 dietary treatments: 1) CON, basal diet, 2) CON+0.25% fructan (FC1), and 3) CON+0.50% fructan (FC2). Each treatment contained 16 pens with 15 chicks per pen. Broilers on levan fructan supplementation treatments (FC1+FC2) had a lower (P=0.005 for d 15 to 31) ADFI and greater (P=0.005 for d 15 to 31 and P=0.022 for d 1 to 31) G:F than those on the CON. A decreased (P=0.031) relative spleen weight was observed with levan fructan supplementation treatments compared with the CON. Cecal E. coli and C. perfringens concentrations in levan fructan treatments were decreased, while cecal Lactobacillus, as well as Bifidobacteria, concentrations in levan fructan treatments were increased compared with the CON. However, excreta NH3 concentrations were decreased (P=0.013) in levan fructan treatments compared with the CON. In conclusion, fructan supplementation improved later stage growth performance, increased cecal Lactobacillus and Bifidobacteria concentrations, and decreased cecal E. coli and C. perfringens concentrations, as well as excreta NH3 concentrations, in broilers. PMID- 24045475 TI - The effect of breed and individual heterosis on the feed efficiency, performance, and carcass characteristics of feedlot steers. AB - This study was conducted to evaluate maternal breed effects, direct breed effects, and individual heterosis on subsequent steer performance, carcass, and feed efficiency traits. This was a consecutive 2-yr trial using 158 steers. The same dam breeds, Angus (AN) and purebred Simmental (SM), were used both years. Also, the same AN and SM sires (n=11) were used both years. Steers were AN, SM, or AN*SM breed composition. Steers were managed similarly before weaning and early weaned at 56+/-9 d of age. Steers were then randomly allotted to pens and fed a common finishing ration. Contrasts were written to evaluate direct and maternal breed effects and individual heterosis in the PROC MIXED procedure of SAS (SAS Inst. Inc., Cary, NC) using dam breed, sire breed, and year as fixed effects. Simmental direct breed effect resulted in a 26 kg heavier initial BW (P<0.05) and a 46 kg heavier final BW (P<0.05). Simmental maternal breed effect increased initial BW by 43.5 kg (P<0.05). Dry matter intake was not impacted by direct breed effects, maternal breed effects, or individual heterosis. Individual heterosis did improve G:F 3.4% (P<0.05) and residual BW gain 0.048 kg/d (P<0.05). Residual intake and BW gain tended (P=0.07) to improve as a result of individual heterosis. Residual feed intake (RFI) was impacted by direct breed effect with SM cattle having a more desirable RFI (P=0.05). Angus direct breed effect increased backfat (P<0.05) and improved marbling score by 126 units (P<0.05). Simmental direct breed effect increased LM area (P<0.05), had the highest HCW at 410 kg (P<0.05), and had the most desirable yield grade at 2.74 (P<0.05). Individual heterosis improved marbling score (P=0.05). Maternal breed effect increased HCW (P<0.05) as a result of the SM dam. Direct breed effects were present for performance, feed efficiency measures, and carcass traits. Overall, heterosis impacted feedlot performance, carcass characteristics, and feed efficiency, which impacts beef production. PMID- 24045476 TI - True digestible phosphorus requirement for twenty- to forty-kilogram pigs. AB - The objective of this study was to determine the true digestible P requirements of 20- to 40-kg pigs by the broken-line regression analysis of growth performance using 6 levels of true total-tract digestible P. In Exp. 1, 24 barrows (initial BW=25.2+/-1.0 kg) were used to determine the true total-tract digestibility (TTTD) of P in monocalcium phosphate using the regression method. The dietary treatments included a corn-soybean meal-based diet (2.96 g total P/kg) and 3 additional dietary treatments with incremental addition of 0.50 g P/kg through monocalcium phosphate. Limestone (37.2% Ca) was added to maintain a constant Ca to P ratio of 1.25 to 1 across all diets. A 5-d adjustment period preceded a 5-d total collection of feces. Ferric oxide was used as a marker to time the initiation and termination of fecal collection. In Exp. 2, 108 barrows and gilts (initial BW=20.1+/-1.2 kg) were used in a 3-wk growth performance trial. Monocalcium phosphate was added to a corn-soybean meal-based diet to set up 6 levels of TTTD-based digestible P, ranging from 1.31 to 4.64 g/kg of diet with increments of 0.67 g/kg digestible P. Limestone was added to maintain a constant Ca level across all diets. The results of Exp.1 showed that dietary P intake, fecal P output, digested P, and apparent total-tract digestibility of P increased linearly (P<0.05) with the increasing supplementation of monocalcium phosphate. Regressing daily digested P against daily P intake resulted in TTTD of 84.3% for P in monocalcium phosphate. In Exp. 2, ADG, ADFI, and G:F increased both linearly (P<0.01) and quadratically (P<0.05) with increasing P level in wk 1 and 3 and for the overall 3-wk duration. In wk 2, both linear and quadratic effects of P level were observed for ADG and ADFI (P<0.05) whereas the G:F only showed linear improvement (P<0.01). The true digestible P requirement, defined as the breakpoint using the overall 3-wk G:F as the response variable, was estimated to be 3.03, 2.98, and 3.08 g/kg of diet for pigs of mixed sex, barrows, and gilts, respectively. Using ADG, the corresponding estimates of P requirement were 3.09, 3.08, and 3.10 g/kg of diet. In conclusion, the mean true digestible P requirement of pigs from 20 to 40 kg BW was determined to be 3.06 g/kg of diet using the average of the estimates for barrows and gilts based on ADG. PMID- 24045477 TI - Evaluation of response to bovine viral diarrhea virus type 2 vaccination and timing of weaning on yearling ultrasound body composition, performance, and carcass quality traits in Angus calves. AB - There are concerns about antagonisms between immunity and animal productivity in livestock production. The objective of this study was to evaluate the effect of antibody levels through a response to vaccination protocol, weaning timing, and their interaction on performance and carcass quality traits in Angus beef cattle. Final antibody level and response to vaccination were based on neutralizing serum antibodies against bovine viral diarrhea virus type 2 (BVDV2). Calves were followed through development and the feedlot phase, with collection of yearling ultrasound (n=957), preharvest (n=762), and carcass (n=673) data. In this study, 48% of the animals were observed to have positively responded to the vaccine, as evidenced by higher final antibody levels compared to prevaccination antibody levels. Increased final antibody levels were significantly (P<0.05) associated with increased yearling weight and increased subcutaneous fat over the rump. An interaction between final antibody level and weaning time also was associated (P<0.05) with Warner-Bratzler shear force (WBSF) and meat pH, with a favorable, negative relationship between final antibody and WBSF in calves weaned at initial vaccination. Overall antibody response by wean time interaction had a significant (P<0.05) association with ADG and meat pH, with calves weaned at initial vaccination having a favorable, positive relationship between overall antibody response and ADG. Under both the final antibody and overall antibody response models, animals weaned at initial vaccination had significantly (P<0.05) lower intramuscular fat at yearling time and conversely higher harvest weight than animals weaned at the booster vaccination. When antibody response was grouped (none, low, high), a significant interaction (P<0.05) between antibody response group and weaning time was identified for ADG, harvest weight, and HCW. Animals weaned at the initial vaccination in the high antibody response group had the advantage for ADG, harvest weight, and HCW compared to animals in the high response group that were weaned at booster vaccination. Linear increases in antibody response generally did not have negative effects on performance or carcass quality traits in finished cattle (P>0.05). Therefore, producers should not be concerned about decreased production or quality attributes as a result of developing a robust antibody response to vaccination for BVDV2 in beef cattle. PMID- 24045478 TI - Effects of domestication and growth hormone transgenesis on mRNA profiles in rainbow trout (Oncorhynchus mykiss). AB - Growth rate can be genetically modified in many vertebrates by domestication and selection and more recently by transgenesis overexpressing growth factor genes [e.g., growth hormone (GH)]. Although the phenotypic end consequence is similar, it is currently not clear whether the same modifications to physiological pathways are occurring in both genetic processes or to what extent they may interact when combined. To investigate these questions, microarray analysis has been used to assess levels of mRNA in liver of wild-type and growth-modified strains of rainbow trout (Oncorhynchus mykiss). This species has been used as a model because nondomesticated wild strains are available as comparators to assess genetic and physiological changes that have arisen both from domestication and from GH transgenesis. The analysis examined pure wild-type and pure domesticated strains as well as 2 different GH transgenes (with markedly different growth effects) both in pure wild and in wild * domesticated hybrid backgrounds. Liver mRNA showed highly concordant changes (Pearson correlations; r>0.828; P<0.001) in levels in domesticated and GH transgenic fish, relative to wild-type, for both up and downregulated genes. Furthermore, among domesticated, transgenic, and their hybrid genotypes, a strong correlation (P<0.001) was found between growth rate and the number of genes affected (r=0.761 for downregulated mRNA and r=0.942 for upregulated mRNA) or between growth rate and mRNA levels relative to wild-type (r=0.931 for downregulated mRNA and r=0.928 for upregulated mRNA). One GH transgenic strain was found to affect growth and mRNA levels similar to domestication whereas effects of the other GH transgenic strain were much stronger. For both GH transgenes, a hybrid domesticated*wild background influenced growth rate and mRNA levels to only a small extent relative to the transgenes in a pure wild-type genetic background. Functional analysis found that genes involved in immune function, carbohydrate metabolism, detoxification, transcription regulation, growth regulation, and lipid metabolism were affected in common by domestication and GH transgenesis. The common responses of mRNAs in domesticated and GH transgenic strains is consistent with the GH pathway or its downstream effects being upregulated in domesticated animals during their modification from wild-type growth rates. PMID- 24045479 TI - Effect of insoluble-low fermentable fiber from corn-ethanol distillation origin on energy, fiber, and amino acid digestibility, hindgut degradability of fiber, and growth performance of pigs. AB - Extensive use of corn coproducts in swine diets increases the concentration of dietary fiber, raising concerns on energy and nutrient digestibility and, ultimately, pig performance. A digestion trial was conducted to determine the effect of increasing levels of insoluble-low fermentable fiber from corn in the diet, using corn bran with solubles (CBS) from the corn-ethanol distillation industry, on digestibility of energy, fiber, and AA, and hindgut fermentation of fiber in diets fed to growing pigs. Fifteen growing pigs (BW=28.7 kg) arranged in a 3-period incomplete block design and fitted with a T-cannula in the distal ileum were provided 5 diets (n=9) containing either a corn-casein basal or the basal diet with 10, 20, 30, or 40% CBS. Fecal and ileal digesta samples were collected. Two subsequent 28-d growth trials determined the effects of increasing dietary fiber from CBS in 2 sets of 7 diets formulated either with declining (growing phase: 2,387 to 2,133 kcal NE/kg; finishing phase: 2,499 to 2,209 kcal NE/kg) or constant dietary NE (growing phase~2,390 kcal NE/kg; finishing phase~2,500 kcal NE/kg) on growth performance and apparent total tract digestibility (ATTD) of energy in 70 growing (BW=48.9 kg; n=10 per diet) and 70 finishing (BW=102.0 kg; n=10) pigs. Results indicated that increasing fiber from corn lowered (P<0.01) the apparent ileal digestibility of all indispensable amino acids except Arg, GE, DM, and CP but not NDF or total dietary fiber (TDF). Increased fiber from corn also reduced ATTD of GE, DM, CP, NDF, and TDF (P<0.01). Increasing fiber with declining diet NE lowered BW, ADG, and G:F (P<0.05) in growing and in finishing pigs. When NE was held constant, as fiber increased, BW and ADG were unaffected in growing and finishing pigs, and G:F was unaffected in finishing pigs but improved in growing pigs (P<0.05) with increasing dietary fiber. In both growing and finishing pigs, ADFI was unaffected by the increased fiber from corn, regardless of the NE content of diets. In conclusion, the dietary level of insoluble-low fermentable dietary fiber from corn origin decreased the digestibility of dietary AA, and the ability of the growing pig to ferment corn dietary fiber. In spite of the reduction in digestibility of energy and nutrients with insoluble-low fermentable fiber level from corn, growth performance was not impaired when the energy supply is adequately balanced in the diet using the NE system. PMID- 24045480 TI - Response of the hypothalamic-pituitary-adrenal axis to stimulation tests before and after exercise training in old and young Standardbred mares. AB - This study tested the hypotheses that age-induced alteration in cortisol, ACTH, and glucose concentrations are due to differences in the response of the hypothalamic-pituitary-adrenal axis and that exercise training would attenuate these differences. Six old (22.0+/-0.7 yr; mean+/-SE) and 6 young (7.3+/-0.6 yr) unfit Standardbred mares ran 3 graded exercise tests (GXT): before (GXT1), after 8 wk of training (GXT2), and at study end at 15 wk (GXT3). Mares trained 3 d/wk at 60% maximum heart rate. Each mare underwent 5 endocrine stimulation tests pre- and posttraining: 1) control (CON), 2) adrenocorticotropin hormone (ACTHtest), 3) combined dexamethasone suppression/ACTH (DEX/ACTH), 4) dexamethasone suppression (DEX), and 5) combined DEX/corticotropin releasing factor (DEX/CRF). For CON, there was no difference in plasma cortisol between age groups pretraining (P=0.19), but young mares had a 102% higher mean (P=0.02) plasma cortisol concentration than old mares posttraining. The pretraining ACTHtest showed young mares had a 72% higher (P=0.05) overall plasma cortisol concentration compared to old. There was no overall age difference in cortisol in the posttraining ACTHtest, but old mares still had lower cortisol concentrations at 30 min during the test, suggesting decreased adrenal response to ACTH stimulation. There was no difference in cortisol response between old and young mares in DEX, DEX/ACTH, or DEX/CRF tests. Young mares had higher (P=0.02) overall plasma cortisol concentration posttraining in response to DEX/ACTH, but old mares showed no change. In CON and DEX/CRF, there were no age differences in plasma ACTH concentration, pre- or posttraining. Pretraining, there was no age difference in glucose response to DEX, but posttraining old mares had a 4% (P=0.04) lower overall plasma glucose concentration compared to young. Posttraining, old mares had lower mean plasma glucose concentrations during DEX compared to pretraining (P=0.02), but there was no change pre- vs. posttraining in young mares (P=0.19). Old and young mares had lower plasma glucose concentrations posttraining during DEX/ACTH (P<0.001 and P=0.05, respectively) and DEX/CRF (P<0.001 and P=0.003, respectively) compared to pretraining. Both the pituitary and adrenal glands experience a decline in function with age although the exact mechanisms behind such changes remain unknown. Exercise training facilitates the counteraction of these deficits. PMID- 24045481 TI - Effect of nutrition on plasma lipid profile and mRNA levels of ovarian genes involved in steroid hormone synthesis in Hu sheep during luteal phase. AB - Ovarian steroid hormones regulate follicular growth and atresia. This study aims to determine whether key ovarian sterol-regulatory genes are differentially expressed in Hu sheep under different short-term nutritional regimens. Estrus was synchronized using intravaginal progestagen sponges. The ewes were assigned randomly to 3 groups. On d 6 to 12 of their estrous cycle, the control (CON) group received a maintenance diet (1.0*M), the supplemented (SUP) group received 1.5*M, and the restricted (R) group received 0.5*M. On d 7 to 12, blood samples were taken. The sheep were slaughtered at the end of the treatment, and their organs and ovaries were collected. The plasma concentrations of urea (P<0.01), total cholesterol (P<0.01), low-density lipoprotein cholesterol (P<0.01), NEFA (P<0.01), FSH (P<0.05), and estradiol (P<0.05) increased with decreasing dietary intake, whereas plasma triglyceride (P<0.01) and triiodothyronine (T3) concentrations decreased (P<0.05). The ewes in the R group had higher spleen weight and percentage of spleen to BW and lower liver and small intestine weights and percentage of liver/stomach to BW than the SUP group ewes (P<0.05). Nutritional restriction decreased the cytochrome p450 (CYP17A1) and estrogen receptor 1 (ESR1) mRNA expression (P<0.05) and increased the cytochrome p450 aromatase (CYP19A1) mRNA expression (P<0.05) in follicles>2.5 mm. Follicle size affected the mRNA expression of very low density lipoprotein receptor (VLDLR), estrogen receptor 2 (ESR2), FSH receptor (FSHR), CYP17A1, and CYP19A1 (P<0.05). In conclusion, we suggest that a potential mechanism by which short-term negative energy balance inhibits follicular growth may involve responses to disrupted reproductive hormone concentrations and influenced the intrafollicular expression of CYP17A1, CYP19A1, and ESR1. This result may be due to increased plasma urea and lipid concentrations. PMID- 24045482 TI - Effects of supplemental canola meal and various types of distillers grains on ruminal degradability, duodenal flow, and intestinal digestibility of protein and amino acids in backgrounded heifers. AB - The objective of this study was to compare the diets with and without supplemental protein or protein sources on ruminal degradability, duodenal flows, and intestinal digestibility of protein and AA in growing heifers; supplemental protein included canola meal (CM) or dried distillers grains with solubles (DDGS) that varied in grain source and milling process. Five ruminally and duodenally cannulated Angus heifers (initial BW, 386 kg+/-20 kg) were assigned to a 5*5 Latin square with 21-d experimental periods. The diets consisted of 60% barley silage and 40% barley grain-based concentrate (DM basis) varying in protein source: CON (no protein supplement), CM, wheat DDGS (wDDGS), corn DDGS (cDDGS), or fractionated corn DDGS (fDDGS) plus urea N. Dietary CP concentrations were 11.9, 14.4, 14.4, 14.3, and 14.3% (DM basis), respectively, for CON-, CM-, wDDGS , cDDGS-, and fDDGS-based diets. Intake of DM was less (P<0.02) for heifers fed CON than those fed protein-supplemented diets (PSD), which did not differ. Intake of N followed the same pattern as DMI with less (P<0.01) N intake by heifers fed CON than those fed PSD. Flows of OM, NDF, and starch to duodenum, and their digestibility in the rumen and in the total digestive tract did not differ among treatments. Flows of nonammonia N (NAN) and microbial N to the duodenum were greater (P<0.05) for heifers fed PSD than those fed CON. Furthermore, heifers fed fDDGS had greater (P<0.05) duodenal flow of NAN than those fed CM or cDDGS. Ruminal degradability of protein did not differ among diets, whereas digestibility of protein in the intestine was greater (P<0.04) for fDDGS than CON. Overall, flows of essential AA, nonessential AA, and total AA were greatest (P<0.05) for wDDGS and fDDGS, intermediate for CM and cDDGS, and least (P<0.01) for CON diets. Ruminal total VFA concentration was greater for wDDGS (P<0.01) and fDDGS (P<0.05) than CON and cDDGS with no differences in molar proportion of individual VFA. Ruminal NH3 N was greater for CM (P<0.01) and wDDGS (P<0.02) than CON, which was not different from cDDGS and fDDGS diets. These results indicate that wDDGS and fDDGS supplemented backgrounding diets delivered greater amounts of protein and AA at the small intestine compared to CM and cDDGS diets when formulated to be isonitrogenous. Supplemental protein increased the supply of protein and AA at the small intestine of cattle fed backgrounding diets comprised of barley silage and barley grain. PMID- 24045483 TI - Evaluation of dietary fructan supplementation on growth performance, nutrient digestibility, meat quality, fecal microbial flora, and fecal noxious gas emission in finishing pigs. AB - This study was conducted to determine the effect of dietary fructan supplementation on growth performance, nutrient digestibility, meat quality, fecal microbial flora, and fecal noxious gas emission in finishing pigs. A total of 96 finishing pigs [(Yorkshire*Landrace)*Duroc] with an average BW of 73.1+/ 2.5 kg were used in a 6-wk study. Pigs were randomly allotted to 1 of 3 dietary treatments: 1) CON, basal diet, 2) CON+1% fructan (FC1), and 3) CON+2% fructan (FC2) with 8 replicate pens per treatment and 2 barrows and 2 gilts per pen. During the overall study, pigs fed the fructan supplementation diets had a greater (P<0.05) ADG, G:F, the apparent total tract digestibility (ATTD) of DM and GE than pigs fed the CON diet. The levels of fructan supplementation did not affect growth performance and ATTD of DM, N, and GE. Fecal E. coli concentrations in the fructan treatments were lower (P<0.001), while fecal Lactobacillus concentrations in the fructan treatments were greater (P<0.001) compared with the CON treatment. Fecal ammonia and hydrogen sulfide emissions were lower (P<0.05) in d 3, 5, and 7 in the fructan treatments, and total mercaptans emission was lower (P<0.05) on d 3 and 5 compared with the CON treatment. In conclusion, fructan supplementation improved growth performance and ATTD of DM and GE, improved the fecal microbial balance, and inhibited the fecal E. coli. Furthermore, fructan may decrease fecal noxious gas emissions by finishing pigs. PMID- 24045484 TI - Selection of SNP from 50K and 777K arrays to predict breed of origin in cattle. AB - Reliable breed assignment can be performed with SNP. Currently, high density SNP chips are available with large numbers of SNP from which the most informative SNP can be selected for breed assignment. Several methods have been published to select the most informative SNP to distinguish among breeds. In this study, we evaluated Delta, Wright's FST, and Weir and Cockerham's FST, and extended these methods by adding a rule to avoid selection of sets of SNP in high linkage disequilibrium (LD) providing the same information. The SNP that had a r2 value>0.3 with any of the SNP already selected were discarded. The different selection methods were evaluated for both the 50K SNP and 777K Bovine BeadChip. Animals from 4 cattle breeds (989 Holstein Friesian, 97 Groningen White headed, 137 Meuse-Rhine-Yssel, and 64 Dutch Friesian) were genotyped. After editing 30,447 and 452,525 SNP were available for the 50K and 777K SNP chip, respectively. All selection methods showed that only a small set of SNP is needed to differentiate among the 4 Dutch cattle breeds, whereas comparison of the selection methods showed only small differences. In general, the 777K performed marginally better than the 50K BeadChip, especially at higher confidence thresholds. The rule to avoid selection of SNP in high LD reduced the required number of SNP to achieve correct breed assignment. The Global Weir and Cockerham's FST performed marginally better than other selection methods. There was little overlap in the SNP selected from the 2 BeadChips, whereas the number of SNP selected was about the same. PMID- 24045485 TI - Impacts of a limit-feeding procedure on variation and accuracy of cattle weights. AB - Cattle weights can be highly variable and are influenced by many factors, including time of weighing, ambient temperature, feed intake, and cattle handling. A protocol of limit feeding has been in use since the 1980s that was designed to reduce variation in gut fill due to differences in intakes. Cattle are penned and fed a 50% hay, 50% wet corn gluten feed or grain diet (DM basis) at an estimated 2% of BW for at least 5 d, after which weights are taken on 2 consecutive d and averaged for a limit-fed BW (LFW). For this analysis, full-fed weights (FFW) also were taken before the limit-feeding period while cattle had ad libitum intakes. Data from 18 experiments were used to analyze differences within 2-d LFW and between LFW and FFW. For 10 of the 18 experiments, FFW also were measured on 2 consecutive d. Cattle included in this summary were grazing cornstalks, smooth bromegrass pasture, Bermuda grass pasture, fescue pasture, native range, or in a dry lot on a 70% forage diet. The largest differences between FFW and LFW for individual cattle were -39 to +44 kg over all 18 experiments. Differences between 2 consecutive d of LFW were -23 to +24 kg for all 18 experiments. Differences between 2 d of FFW were -14 to +34 kg in the 10 experiments measuring FFW on 2 consecutive d. There was not a clear relationship between FFW and LFW; each weighing scenario had unique environmental conditions that led to different relationships. Differences in both beginning and ending BW were compounded when calculating ADG. Average daily gain was calculated for 15 of the experiments on the basis of either LFW or FFW. Differences between LFW and FFW ADG were -0.29 to +0.31 kg/d. The maximum ADG based on FFW was 1.62 kg/d. This large ADG, on a forage based diet, was likely due to changes in gut fill rather than tissue gain. These data suggest that handling cattle in a similar manner when weighing is more important than limiting intakes to decrease variance between weights. However, limiting intake before collection of beginning and ending BW better estimates empty body weight of cattle, allowing for a more accurate determination of actual body tissue weight gain. Measuring weights accurately becomes especially crucial when evaluating multiple components within a system (e.g., cornstalks to pasture to feedlot). Feeding a standard diet between these components of the system minimizes differences in gut fill due to treatment and allows for a more accurate determination of each component's contribution to the total system. PMID- 24045486 TI - Effects of levan-type fructan supplementation on growth performance, digestibility, blood profile, fecal microbiota, and immune responses after lipopolysaccharide challenge in growing pigs. AB - In Exp. 1, 80 growing pigs (27.1+/-0.7 kg) were used in a 42-d experiment to evaluate the effect of levan-type fructan on growth performance, digestibility, blood profile, and fecal microbiota. Pigs were randomly allocated to 1 of 4 treatments, according to initial BW and gender, with 5 replicate pens per treatment and 2 barrows and 2 gilts per pen. Treatments were corn-soybean meal based diets supplemented with 0%, 0.05%, 0.10%, or 0.20% levan-type fructan. Average daily gain and G:F increased (quadratic, P<0.05), as dietary levan-type fructan increased from 0 to 0.2%. Similarly, the apparent total tract digestibility of N and GE increased (quadratic, P<0.05), as dietary supplementation of levan-type fructan increased. Dietary levan-type fructan supplementation increased fecal Lactobacillus counts linearly (P<0.05). In Exp. 2, 20 individually housed barrows (26.2+/-0.6 kg) were used to evaluate immune responses after an Escherichia coli lipopolysaccharide (LPS) challenge. Pigs were fed corn-soybean meal-based diets supplemented with 0% or 0.10% levan-type fructan for 42 d. At d 42, 5 pigs from each treatment were injected with E. coli LPS (0.01% of BW) and the other 5 pigs with sterile saline solution, resulting in a 2*2 factorial arrangement of treatments. Blood was taken 0, 2, 4, 6, and 8 h after challenge. Challenge with LPS decreased blood lymphocyte percentage and had an interactive effect with levan-type fructan inclusion at 4, 6, and 8 h (P<0.01). Levan-type fructan supplementation increased (P<0.05) white blood cells at 6 and 8 h, and increased (P<0.05) lymphocyte percentage at 8 h after the challenge. Lipopolysaccharide injection increased (P<0.05) rectal temperature at 2 and 4 h, and had an interactive effect (P<0.05) with levan-type fructan supplementation at 4 h after the challenge. At 2, 4, 6, and 8 h, serum cortisol, tumor necrosis factor-alpha, and IL-6 concentration increased (P<0.05) by LPS challenge, and there was an interactive effect between LPS challenge and the inclusion of levan-type fructan (P<0.05). Dietary levan-type fructan supplementation decreased serum cortisol concentration at 8 h, tumor necrosis factor-alpha concentration at 4, 6, and 8 h, and IL-6 concentration at 6 and 8 h after the challenge (P<0.05). In conclusion, dietary supplementation with 0.10% levan-type fructan can improve growth performance, digestibility, and fecal Lactobacillus counts, and has a beneficial effect on the immune response during an inflammatory challenge in growing pigs. PMID- 24045487 TI - Effects of flunixin meglumine administration on physiological and performance responses of transported feeder cattle. AB - The objective was to evaluate the effects of flunixin meglumine administration on physiological and performance responses of transported cattle during feedlot receiving. Forty-five Angus * Hereford steers were ranked by BW on d 0 and assigned to 1 of 3 treatments: 1) transport for 1,280 km in a commercial livestock trailer and administration of flunixin meglumine (1.1 mg/kg BW; intravenous) at loading (d 0) and unloading (d 1; FM), 2) transport for 1,280 km in a commercial livestock trailer and administration of 0.9% saline (0.022 mL/kg BW; intravenous) at loading (d 0) and unloading (d 1; TRANS), or 3) no transport and administration of 0.9% saline (0.022 mL/kg BW; intravenous) concurrently with loading (d 0) and unloading (d 1) of FM and TRANS cohorts (CON). Upon arrival and processing for treatment administration on d 1, steers within each treatment were ranked by BW and assigned to 15 feedlot pens (5 pens/treatment, 3 steers/pen). Full BW was recorded before (d -1 and 0) treatment application and at the end of experiment (d 28 and 29) for ADG calculation. Total DMI was evaluated daily from d 1 to 28. Blood samples were collected on d 0 (before treatment administration), 1 (after unloading but before treatment administration), 4, 7, 10, 14, 21, and 28. Body weight shrink from d 0 to 1 was less (P<0.01) in CON vs. FM and TRANS but similar (P=0.94) between TRANS and FM. Mean ADG was greater (P<=0.04) in CON vs. FM and TRANS but similar (P=0.69) between TRANS and FM. No treatment effects were detected on DMI, but CON had greater G:F vs. TRANS (P=0.08) and FM (P=0.02), whereas G:F was similar (P=0.68) between TRANS and FM. Mean plasma cortisol concentrations tended (P<=0.09) to be greater in TRANS vs. FM and CON but was similar (P=0.87) between CON and FM. Plasma NEFA concentrations were greater (P<=0.02) for TRANS and FM vs. CON on d 1 and greater (P<=0.04) for FM vs. TRANS and CON on d 4. Plasma ceruloplasmin concentrations were greater (P<=0.03) for TRANS vs. CON on d 1, 4, and 7, greater (P<=0.05) for TRANS vs. FM on d 4 and 7, and greater (P<=0.04) for FM vs. CON on d 1 and 4. Plasma haptoglobin concentrations were greater (P<0.01) for TRANS vs. CON and FM on d 1 and 4 and greater (P<=0.05) for FM vs. CON on d 1 and 4. In conclusion, flunixin meglumine reduced the cortisol and acute-phase protein responses elicited by road transport but did not improve receiving performance of feeder cattle. PMID- 24045488 TI - Accounting for early rearing density effects on growth in the genetic evaluation of rainbow trout, Oncorhynchus mykiss. AB - In fish breeding, full-sib families are often kept in separate tanks until individuals are large enough to be tagged and pooled. This practice induces substantial environmental variation common to full sibs (VFS) in BW. We used multigeneration data on rainbow trout to investigate how variation among families in early rearing density affects BW at different ages and environments (fresh water and sea), and whether variance parameters and ranking of breeding candidates change when density is either excluded or included as a regression term in a multitrait animal model. Increasing density displayed a consistent negative relationship with full-sib tank-mean BW at the end of fry-stage when family sizes were equalized (r2 of linear regressions 11 to 31%). In 4 out of 6 year classes, the significant negative association between density and BW also remained through the family-tank period until tagging at 6 mo of age (r2=3 to 19%). In some year classes, early density had a carry-over effect on later BW means, reaching up to the age of >2 yr (after the second and third growing season). Yet, the association was generally weaker at later ages and varied from nonexistent to both significantly negative and positive (r2=0 to 6%). For each BW, the inclusion of early density in genetic model primarily captured the variance that was otherwise attributable to VFS. The reduction of VFS was most pronounced in tagging BW (21% difference between the models), where common environmental effects were moderately high (c2=0.18 in the model without density). For later BW traits, the difference in VFS was 6 to 8% (c2=0.04 to 0.05). The changes in genetic, residual, and phenotypic variances were generally small in the model, including density. Similarly, only a slight change in the heritability estimate of any BW was found (differences of h2 0.2 to 1.3% between models). Correlations between EBV obtained by the 2 models were highly positive in each BW trait (r range 0.94 to 1.00), indicating that ranking of the breeding candidates remained consistent, regardless of whether density was accounted for or not. Our findings highlight the importance of equalizing family sizes to decrease VFS in rainbow trout growth. If selection is practiced for EBV of BW recorded at an age of >2 yr, and equalization is done early enough, the effects induced by different initial density can be sufficiently corrected for by the common full-sib effect in models used for genetic evaluation. PMID- 24045489 TI - Influence of altitude on vitamin D and bone metabolism of lactating sheep and goats. AB - This study investigated the influence of alpine grazing on vitamin D (vitD) and bone metabolism in sheep and goats. Two groups of five adult lactating East Friesian milk sheep and Saanen dairy goats were kept on pastures at 2,000 to 2,600 m a.s.l. (SA: sheep alpine; GA: goats alpine) and 400 m a.s.l. (SL: sheep lowland; GL: goats lowland). The animals were milked twice daily and the milk yield was measured. Blood, milk, skin, and forage samples were collected and the left metatarsi were measured with peripheral quantitative computed tomography. The relative humidity and air temperature were recorded and the ultraviolet B (UVB) radiation was measured with a solar meter at both research stations. In addition, animals from the alpine group were equipped with a global positioning system receiver. The UVB radiation was higher at the alpine station (P<0.05) compared to the lowland station. In contrast, both the relative humidity and the air temperature were higher at the lowland station (P<0.04). The group GA produced more milk than GL (P<0.043). No differences in milk production between SA and SL were detected. Only minor differences between the alpine and lowland species groups were found in the total 25-hydroxyvitamin D (25(OH)D) and 1,25 dihydroxyvitamin D serum concentration and in the 25(OH)D milk concentration. 25 hydroxyvitamin D2 concentration in serum was higher in sheep compared to goats and the 25(OH)D3 concentration in serum increased in all four groups but was higher in the alpine groups during the experiment. In addition, no differences in 7-dehydrocholesterol (7-DHC) concentrations in the skin at high altitude and lowland groups were detectable. However the 7-DHC concentrations in the skin of sheep were less than a tenth of the concentrations in the skin of goats and were nearly not detectable. In both groups SA and SL bone strength index increased during the trial (P=0.043). Bone strength index was lower in GA compared to GL at wk 12 (P=0.047). Mean serum Ca concentrations were higher and P concentrations were lower in the alpine groups than in the lowland groups (P=0.047). In both groups SA and GA the distance travelled increased during the trial. In conclusion, no effect of altitude on vitD status, vitD milk concentration and bone strength could be detected. Both sheep and goats are able to produce vitD in the skin, but sheep depend more on vitD intake with feedstuff, whereas goats rely more on cutaneous vitD production. PMID- 24045490 TI - Phosphorus digestibility and concentration of digestible and metabolizable energy in corn, corn coproducts, and bakery meal fed to growing pigs. AB - Two experiments were conducted to determine the standardized total tract digestibility (STTD) of P and the concentration of DE and ME in corn, hominy feed, bakery meal, distillers dried grains with solubles (DDGS), corn gluten meal, corn gluten feed, and corn germ meal fed to growing pigs. In Exp. 1, 84 barrows (initial BW: 13.7+/-2.3 kg) were placed in metabolism cages and allotted to 14 diets with 6 replicate pigs per diet in a randomized complete block design. Seven diets were formulated to contain corn, hominy feed, bakery meal, DDGS, corn gluten meal, corn gluten feed, or corn germ meal as the sole source of P. Seven additional diets were similar to the initial 7 diets with the exception that 600 units of microbial phytase was included in each diet. The STTD of P was greater (P<0.05) in DDGS, corn gluten meal, and corn gluten feed than in corn, hominy feed, bakery meal, and corn germ meal, and the STTD of P was also greater (P<0.05) in bakery meal than in corn and hominy feed. Addition of phytase increased (P<0.05) the STTD of P in corn, hominy feed, bakery meal, and corn germ meal but not in corn gluten meal, corn gluten feed, or DDGS. In Exp. 2, 56 barrows (initial BW: 14.6+/-2.2 kg) were placed in metabolism cages and allotted to 7 diets with 8 replicate pigs per diet in a randomized complete block design. A corn-based diet consisting of 97.5% corn and vitamins and minerals was formulated. Four additional diets were formulated by mixing corn and DDGS, corn gluten feed, corn gluten meal, or corn germ meal, and 2 diets were based on hominy feed or bakery meal. The concentration of ME was 3,891, 3,675, 3,655, 3,694, 4,400, 3,169, and 3,150 kcal/kg DM in corn, hominy feed, bakery meal, DDGS, corn gluten meal, corn gluten feed, and corn germ meal, respectively. The ME (DM basis) in corn was greater (P<0.05) than in hominy feed, bakery meal, corn gluten feed, and corn germ meal, but less (P<0.05) than in corn gluten meal, and the ME in hominy feed, bakery meal, and DDGS was greater (P<0.05) than in corn gluten feed and corn germ meal. In conclusion, DDGS, corn gluten meal, and corn gluten feed have a greater STTD of P than corn, hominy feed, bakery meal, and corn germ meal, but phytase can be included in diets containing corn, hominy feed, bakery meal, and corn germ meal to improve P digestibility. The ME in corn gluten meal is greater than in bakery meal, corn, and other corn coproducts. PMID- 24045491 TI - In vitro studies on intestinal peptide transport in horses. AB - Published data on the physiology of nutrient transport across the equine intestine are limited, and the existence and relevance of peptide transporters are still unknown in the horse. In the present study, the equine intestinal peptide transport was investigated by Ussing chamber experiments using the radioisotope tracer technique and by uptake studies into brush border membrane vesicles (BBMV). Jejunal mucosae of 16 healthy adult horses were used. Tissue samples were mounted in Ussing chambers, and electrophysiological parameters as well as unidirectional flux rates of the radiolabelled dipeptide glycylglutamine (Gly-Gln) were determined. The short-circuit current (Isc) response to the luminal addition of Gly-Gln was significantly greater compared to the Isc response to glycylsarcosine (Gly-Sar) addition (P<0.01). Positive net flux rates were determined indicating absorption of the dipeptide. The addition of Gly-Sar reduced the flux rates significantly (P<0.01), suggesting that both peptides compete for the same transport system. The flux rates were not affected by changes in luminal pH value. Uptake studies into BBMV demonstrated an uphill transport in both the absence and the presence of an inwardly directed H+ gradient with the H+-mediated uphill transport being significantly greater than the transport under equilibrium conditions (P<0.001). A Na+-gradient did not cause an uphill transport. The Gly-Gln uptakes displayed Michaelis-Menten kinetics with the Km value for the H+-dependent Gly-Gln uptake being significantly different from the Km value for the Gly-Gln uptake under equilibrium conditions (P<0.05). In conclusion, the study demonstrated for the first time that dipeptides are transcellularly transported across the equine small intestine. The results indicate the presence of at least 2 transport systems for peptide absorption in the horse: 1 secondary active H+-mediated cotransport and 1 that is capable of an uphill transport energized by a mechanism other than a H+ or a Na+-gradient. PMID- 24045492 TI - Genetic evaluation of days to harvest in crossbred lambs. AB - Days to harvest (DTH) is the number of days a lamb is fed before reaching a target level of fatness. Although economically relevant, this trait has not been thoroughly evaluated in sheep. Most lambs harvested in the United Kingdom are crossbreds sired by purebred terminal sires, with Charollais, Suffolk, and Texel most commonly used. Sires from these breeds were selected on an index designed to increase lean growth while constraining fat. The purpose of this research was to 1) evaluate the effects of index selection in terminal sires on DTH and 2) evaluate the feasibility of incorporating DTH into genetic evaluation programs. Charollais, Suffolk, and Texel sheep had participated in sire referencing schemes where genetic links among flocks were established by sharing rams. Rams with high or low index scores were chosen from these schemes and mated to crossbred ewes at 3 farms in the United Kingdom. Lambs were harvested at a target 11% subcutaneous fat. Records on DTH from 6,350 lambs were analyzed in 2 ways: 1) as time to harvest fitting a survival model and 2) as a normally distributed variable in a bivariate analysis with weight at harvest. The survival analysis was stratified by rearing type (single or twin). In both approaches, sires were fitted using a multivariate normal distribution with a relationship matrix. Regardless of model fitted, sire index did not affect DTH (P>0.10). However, Texel-sired lambs reached harvest faster (P<0.01) than either Charollais- or Suffolk-sired lambs although DTH in those 2 breed types did not differ (P>0.1). Ewe lambs reached harvest faster than wethers (P<0.01). Lambs from older ewes were harvested faster (P<0.001). The heritability of DTH was 0.21 from the survival model and 0.20 from the bivariate model. Rank correlation of sire EBV between methods was 0.9, suggesting strong agreement. The use of high or low index sires did not extend DTH in lambs harvested at a target fatness. Importantly, there is no antagonism between improving carcass merit and extending the grazing season. Furthermore, DTH is moderately heritable. If economically justified within a breeding program, it could be reduced through genetic selection. PMID- 24045493 TI - Special topics--Mitigation of methane and nitrous oxide emissions from animal operations: II. A review of manure management mitigation options. AB - This review analyzes published data on manure management practices used to mitigate methane (CH4) and nitrous oxide (N2O) emissions from animal operations. Reducing excreted nitrogen (N) and degradable organic carbon (C) by diet manipulation to improve the balance of nutrient inputs with production is an effective practice to reduce CH4 and N2O emissions. Most CH4 is produced during manure storage; therefore, reducing storage time, lowering manure temperature by storing it outside during colder seasons, and capturing and combusting the CH4 produced during storage are effective practices to reduce CH4 emission. Anaerobic digestion with combustion of the gas produced is effective in reducing CH4 emission and organic C content of manure; this increases readily available C and N for microbial processes creating little CH4 and increased N2O emissions following land application. Nitrous oxide emission occurs following land application as a byproduct of nitrification and dentrification processes in the soil, but these processes may also occur in compost, biofilter materials, and permeable storage covers. These microbial processes depend on temperature, moisture content, availability of easily degradable organic C, and oxidation status of the environment, which make N2O emissions and mitigation results highly variable. Managing the fate of ammoniacal N is essential to the success of N2O and CH4 mitigation because ammonia is an important component in the cycling of N through manure, soil, crops, and animal feeds. Manure application techniques such as subsurface injection reduce ammonia and CH4 emissions but can result in increased N2O emissions. Injection works well when combined with anaerobic digestion and solids separation by improving infiltration. Additives such as urease and nitrification inhibitors that inhibit microbial processes have mixed results but are generally effective in controlling N2O emission from intensive grazing systems. Matching plant nutrient requirements with manure fertilization, managing grazing intensity, and using cover crops are effective practices to increase plant N uptake and reduce N2O emissions. Due to system interactions, mitigation practices that reduce emissions in one stage of the manure management process may increase emissions elsewhere, so mitigation practices must be evaluated at the whole farm level. PMID- 24045494 TI - Comparison of a genetic group and unknown paternity models for growth traits in Nellore cattle. AB - The aim of the present study was to compare a model assuming unknown paternity and a model using genetic grouping to indicate the most adequate statistical procedure for the estimation of breeding values for animals with uncertain paternity. After data consistency, 62,212 Nellore animals, offspring of 581 bulls and 27,743 cows, were used in the analyses. The pedigree file contained 75,088 animals, including 22,810 (30.18%) offspring of multiple sires and 12,876 animals belonging to the base population with unknown parents. Three different approaches were adopted to deal with uncertain paternity of multiple-sire (MS) offspring. In the model of unknown paternity, the MS groups were ignored, and the sires of MS offspring were considered to be unknown and to belong to a single base population. In the genetic group approach, 2 definitions were used. In the first definition (GGa), "phantom parents" for animals with uncertain paternity were attributed, defining the genetic group as the MS group. In the other approach, GGb, phantom parents for animals with uncertain paternity were also attributed; however, MS offspring were clustered in genetic groups according to their year of birth, every 3 yr, on the basis of the average of male generation interval. Univariate analyses were performed under the Bayesian approach via Markov chain Monte Carlo methods. Models were compared by deviance information criteria and the conditional predictive ordinate. According to the choice criteria results, the genetic group model defined by the generation interval of males was more appropriate for predicting the genetic merit of animals with uncertain paternity. Therefore, the use of this model is recommended for the prediction of genetic merit and classification of offspring of multiple sires. PMID- 24045495 TI - The effect of a split feeding regimen and breed on body temperature of hair sheep ewes in the tropics. AB - Lactating St. Croix White and Dorper*St. Croix White ewes were used to evaluate the effect of breed and feeding a split ration on body temperature during the cool (March-April) and warm (July-August) seasons in the U.S. Virgin Islands. Within each season ewes were assigned to treatments (n=8/treatment) based on breed, age, and number of lambs. Treatments consisted of individually feeding ewes daily 0.9 kg concentrate (16.4% CP and 68% TDN) in the morning (AM) or afternoon (PM), 0.45 kg in the morning and afternoon (AM-PM), or no feed (Control) for 56 d beginning on d 7 (lambing=d 0). Ewes were fitted with intravaginal temperature data loggers, set to record vaginal temperature (VT) at 5-min intervals, for 48 h in wk 2 (d 8-14), 5 (d 29-35), and 8 (d 50-56) postpartum. Repeated measures analysis of VT was conducted using a model including treatment, season, and breed as fixed effects. There was no effect of season so data were pooled across season. The interaction of breed with treatment or season was not significant so breed comparisons were made using data pooled across treatments and season. The mean temperature, relative humidity, and temperature-humidity index during the cool and warm seasons were 25.8 degrees C, 85.9%, and 76.1 and 28.3 degrees C, 86.7%, and 80.6, respectively. There was no effect of season or the breed*treatment*season interaction on VT (P>0.10) so all data were pooled across season and breed for analysis of the treatment effect. During wk 2 there was no difference (P>0.10) in VT among treatment groups. During wk 5 the AM-PM ewes had higher (P<0.01) VT than AM, PM, or Control ewes. During wk 8 the AM-PM and PM ewes had higher VT (P<0.01) than either the AM or Control ewes. To evaluate breed effect, data were pooled across treatments and seasons and analyzed using breed as the single main effect. Dorper*St. Croix White ewes had higher (P<0.0001) VT than St. Croix White ewes. The results show that body temperature of ewes can be influenced by time of feeding and breed. The local breed of sheep, St. Croix White, had a lower body temperature than Dorper*St. Croix White sheep. Ewes that were fed in the afternoon for an extended time during the postpartum period developed elevated body temperatures, which could make them more susceptible to heat stress. PMID- 24045496 TI - The effects of a step-up ractopamine feeding program on growth performance and low-sodium ham characteristics of purebred Berkshire pigs. AB - Objectives were to test the effect of a low-sodium curing solution on processing characteristics of hams from purebred Berkshire pigs that were fed a step-up ractopamine HCl (RAC) feeding program or a negative control diet. Sixty pairs (n=120) of hams were selected from two blocks of purebred Berkshire pigs (n=200) that were fed either a control diet or 7.4 mg of ractopamine/kg of diet for 14 d followed by 10.0 mg of ractopamine/kg of diet for the last 14 d before slaughter. Three-piece, section-formed hams were cured with a standard (1.98% NaCl; REG) curing solution or a low-sodium with KCl replacement (0.67% NaCl and 1.29% KCl; LOW) curing solution. Pigs fed RAC had 3.18% greater BW, 11.90% greater ADG, and 10.34% greater G:F compared with control pigs. No differences (P>=0.07) were detected for the effect of diet, curing solution, or the interaction between diet and curing solution for ham weights, pump uptake, or cook yield [(cooked weight/green weight) 100]. Break strength (an indication of protein interaction and bind strength; 5.97 vs. 6.99 kg) and protein fat-free values (24.58 vs. 25.98%) were less (P<=0.05) in hams cured with LOW curing solution compared with hams cured with REG curing solution. Lightness (L*) and yellowness (b*) values were greater (P<=0.03), while redness (a*) values were less (P<0.01) in hams cured with LOW curing solution compared with hams cured with REG curing solution. A trained sensory panel detected less (P=0.03) flavor intensity in hams cured with LOW curing solution compared with hams cured with REG curing solution. Yet, no differences (P>=0.55) were detected between hams cured with LOW or REG curing solution for saltiness. Overall acceptability of hams cured with LOW curing solution tended to be less (P=0.09) compared with hams cured with REG curing solution; however, the magnitude of this difference was 0.34 on a 1 to 9 scale. Hams cured with LOW curing solution made hams paler and contain less intense flavor compared with hams cured with REG curing solution, but this was a justifiable way to lower sodium content by 64% units (1.44 vs. 4.04% Na) without detrimental processing or sensory effects. PMID- 24045497 TI - Special topics--Mitigation of methane and nitrous oxide emissions from animal operations: I. A review of enteric methane mitigation options. AB - The goal of this review was to analyze published data related to mitigation of enteric methane (CH4) emissions from ruminant animals to document the most effective and sustainable strategies. Increasing forage digestibility and digestible forage intake was one of the major recommended CH4 mitigation practices. Although responses vary, CH4 emissions can be reduced when corn silage replaces grass silage in the diet. Feeding legume silages could also lower CH4 emissions compared to grass silage due to their lower fiber concentration. Dietary lipids can be effective in reducing CH4 emissions, but their applicability will depend on effects on feed intake, fiber digestibility, production, and milk composition. Inclusion of concentrate feeds in the diet of ruminants will likely decrease CH4 emission intensity (Ei; CH4 per unit animal product), particularly when inclusion is above 40% of dietary dry matter and rumen function is not impaired. Supplementation of diets containing medium to poor quality forages with small amounts of concentrate feed will typically decrease CH4 Ei. Nitrates show promise as CH4 mitigation agents, but more studies are needed to fully understand their impact on whole-farm greenhouse gas emissions, animal productivity, and animal health. Through their effect on feed efficiency and rumen stoichiometry, ionophores are likely to have a moderate CH4 mitigating effect in ruminants fed high-grain or mixed grain-forage diets. Tannins may also reduce CH4 emissions although in some situations intake and milk production may be compromised. Some direct-fed microbials, such as yeast-based products, might have a moderate CH4-mitigating effect through increasing animal productivity and feed efficiency, but the effect is likely to be inconsistent. Vaccines against rumen archaea may offer mitigation opportunities in the future although the extent of CH4 reduction is likely to be small and adaptation by ruminal microbes and persistence of the effect is unknown. Overall, improving forage quality and the overall efficiency of dietary nutrient use is an effective way of decreasing CH4 Ei. Several feed supplements have a potential to reduce CH4 emission from ruminants although their long-term effect has not been well established and some are toxic or may not be economically feasible. PMID- 24045498 TI - VTD consolidation, without bisphosphonates, reduces bone resorption and is associated with a very low incidence of skeletal-related events in myeloma patients post ASCT. AB - We prospectively evaluated the effect of bortezomib, thalidomide and dexamethasone (VTD) consolidation on bone metabolism of 42 myeloma patients who underwent an autologous stem cell transplantation (ASCT). VTD started on day 100 post ASCT; patients received four cycles of VTD (first block), were followed without treatment for 100 days and then received another four VTD cycles (second block). During this 12-month period, bisphosphonates were not administered. Best response included stringent complete remission (sCR) in 15 (35.7%) patients, complete response (CR) in 13 (30.9%), vgPR in 7 (16.6%), PR in 4 (9.5%), while 3 (7.1%) patients developed a progressive disease (PD). Importantly, 33.3% and 47.6% of patients improved their status of response after the first and second VTD block, respectively. VTD consolidation resulted in a significant reduction of circulating C-terminal cross-linking telopeptide of collagen type I (CTX), soluble receptor activator of the nuclear factor-kappa B ligand (sRANKL) and osteocalcin (OC), whereas bone-specific alkaline phosphatase (bALP) remained stable compared with pre-VTD values. During the study period, only one patient with a PD developed a skeletal-related event (that is, radiation to bone). The median time to progression (TTP) after ASCT was 34 months and the median time of next treatment was 40 months. We conclude that VTD consolidation post ASCT reduces bone resorption and is associated with a very low incidence of skeletal related events (SREs) despite the absence of bisphosphonates; the later do not appear to be necessary in this context. PMID- 24045499 TI - DNA methylation of membrane-bound tyrosine phosphatase genes in acute lymphoblastic leukaemia. AB - Aberrant DNA promoter methylation with associated gene silencing is a common epigenetic abnormality in acute lymphoblastic leukaemia (ALL) and is associated with poor survival. We have identified a family of transmembrane tyrosine phosphatase proteins as targets of hypermethylation in ALL and high-grade B cell lymphoma and demonstrated that this abnormal methylation correlates with transcript expression. PTPRG was methylated in 63% of ALL samples, PTPRK in 47%, PTPRM in 64% and PTPRO in 54% of cases, with most ALL samples containing methylation at multiple phosphatase loci. PTPRK promoter methylation was associated with a decreased overall survival in the cohort. Restoration of PTPRK transcript levels in leukaemia cells, where phosphatase transcript was silenced, reduced cell proliferation, inhibited colony formation and increased sensitivity to cytotoxic chemotherapy. These biological changes were associated with a reduction in levels of phosphorylated Erk1/2, Akt, STAT3 and STAT5 suggesting functional phosphatase activity after transcript re-expression. Methylation of the phosphatase promoters was reversible with decitabine and a histone deacetylase inhibitor, suggesting that PTPRK-mediated cell signalling pathways may be targeted with epigenetic therapies in lymphoid malignancy. PMID- 24045502 TI - Intra-articular loose body caused by avascular necrosis of the femoral head in children. AB - In children, avascular necrosis of the femoral head occurs easily because of the difference in the domination of blood flow compared with that in adults. Here we report a rare case of a 12-year-old girl who sustained a femoral neck fracture. The femoral head collapsed after open reduction and internal fixation. The hip developed into subluxation because of the gradually enlarged loose body in association with avascular necrosis. These results might be explained by the fact that blood circulation from the ligamentum teres temporarily increases during the ages of 8-12 years. PMID- 24045500 TI - Bone marrow angiogenesis in myeloma and its precursor disease: a prospective clinical trial. PMID- 24045501 TI - Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. AB - We hypothesized that specific molecular mutations are important biomarkers for response to DNA methyltransferase inhibitors (DNMT inhibitors) and may have prognostic value in patients with myelodysplastic syndromes (MDS). Mutational analysis was performed in 92 patients with MDS and related disorders who received 5-azacytidine (n=55), decitabine (n=26) or both (n=11). Mutational status was correlated with overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) by univariate and multivariate analysis. Risk stratification models were created. TET2, DNMT3A, IDH1/IDH2, ASXL1, CBL, RAS and SF3B1 mutations were found in 18, 9, 8, 26, 3, 2 and 13% of patients, respectively. In multivariate analysis, TET2(MUT) and/or DNMT3A(MUT) (P=0.03), platelets > or = 100 * 10(9)/l (P=0.007) and WBC<3.0 * 10(9)/l (P=0.03) were independent predictors of better response. TET2(MUT) and/or DNMT3A(MUT) (P=0.04) status was also independently prognostic for improved PFS, as were good or intermediate cytogenetic risk (P<0.0001), age<60 (P=0.0001), treatment with both 5-azacytidine and decitabine (P=0.02) and hemoglobin > or = 10 g/dl (P=0.01). Better OS was associated with ASXL1(WT) (P=0.008) and SF3B1(MUT) (P=0.01), and, similar to PFS, cytogenetic risk (P=0.0002), age (P=0.02) and hemoglobin (P=0.04). These data support the role of molecular mutations as predictive biomarkers for response and survival in MDS patients treated with DNMT inhibitors. PMID- 24045503 TI - The pediatric knee: current concepts in sports medicine. AB - As the popularity and intensity of children's athletics have increased, so has the risk for knee injuries. Fractures of the tibial eminence may be treated operatively or nonoperatively depending on fracture classification, but arthrofibrosis is a potentially significant complication. Anterior cruciate ligament rupture presents treatment challenges as regards the optimal timing and method of reconstruction. A number of novel reconstructive techniques have been developed to minimize risks to the physes in this population. Recent studies have focused on the prognosis, surgical indications, and operative techniques for osteochondritis dissecans in children. A number of authors have also sought to better-define the optimal diagnostic testing and management of patellar dislocation. In this review, we provide an update on current concepts for tibial eminence fractures, anterior cruciate ligament injuries, osteochondritis dissecans of the knee, and patellar dislocation in young athletes. PMID- 24045504 TI - Hidden Markov model and support vector machine based decoding of finger movements using electrocorticography. AB - OBJECTIVE: Support vector machines (SVM) have developed into a gold standard for accurate classification in brain-computer interfaces (BCI). The choice of the most appropriate classifier for a particular application depends on several characteristics in addition to decoding accuracy. Here we investigate the implementation of hidden Markov models (HMM) for online BCIs and discuss strategies to improve their performance. APPROACH: We compare the SVM, serving as a reference, and HMMs for classifying discrete finger movements obtained from electrocorticograms of four subjects performing a finger tapping experiment. The classifier decisions are based on a subset of low-frequency time domain and high gamma oscillation features. MAIN RESULTS: We show that decoding optimization between the two approaches is due to the way features are extracted and selected and less dependent on the classifier. An additional gain in HMM performance of up to 6% was obtained by introducing model constraints. Comparable accuracies of up to 90% were achieved with both SVM and HMM with the high gamma cortical response providing the most important decoding information for both techniques. SIGNIFICANCE: We discuss technical HMM characteristics and adaptations in the context of the presented data as well as for general BCI applications. Our findings suggest that HMMs and their characteristics are promising for efficient online BCIs. PMID- 24045506 TI - Histone H3 lysine methylation in cognition and intellectual disability disorders. AB - Recent research indicates that epigenetic mechanisms and, in particular, the post translational modification (PTM) of histones may contribute to memory encoding and storage. Among the dozens of possible histone PTMs, the methylation/demethylation of lysines in the N-terminal tail of histone H3 exhibits particularly strong links with cognitive abilities. First, the persistence and tight association with distinct transcriptional states of the gene make these modifications particularly suitable for being part of the molecular underpinnings of memory storage. Second, correlative evidence indicates that the methylation/demethylation of lysines in histone H3 is actively regulated during memory processes. Third, several enzymes regulating these PTMs are associated with intellectual disability disorders. We review here these three lines of evidence and discuss the potential role of epigenetic mechanisms centered on the methylation of lysine residues on histone H3 in neuroplasticity and neurodevelopmental disorders associated with intellectual disability. PMID- 24045507 TI - Immunological evaluation of a novel Mycobacterium tuberculosis antigen, Rv3117, absent in Mycobacterium bovis BCG. AB - Tuberculosis (TB) remains a global infectious disease. To investigate the value of a novel Mycobacterium tuberculosis (M. tuberculosis) region of difference 5 (RD5)-encoded antigen, Rv3117, in the development of effective immuno-diagnostics and vaccines against TB, the immune responses to the antigen were examined in human subjects, as well as in C57BL/6 mice. The results showed that Rv3117 was able to evoke specific humoral and cellular immune responses. Consistent with the results from the RD1-encoded antigens, culture filtrate protein 10 kDa (CFP-10) and early secreted antigenic target 6 kDa (ESAT-6), the immunoglobulin G (IgG), IgM and IgA antibody responses to Rv3117 were able to statistically distinguish between the 65 patients with active pulmonary TB and the 59 healthy controls (P<0.01, respectively). In addition, higher levels of Rv3117-specific interferon gamma (IFN-gamma) were observed in immunized C57BL/6 mice than in the negative control mice (P<0.05). Furthermore, high titers of total IgG, IgG1 and IgG2a antibodies were present in the sera from immunized mice, even six weeks subsequent to the immunization. In conclusion, the present results suggested that Rv3117 may be used as a candidate for the development of TB immunodiagnostics and vaccine design. PMID- 24045509 TI - [Toward the overcoming of controversies about adjuvant chemotherapy in patients radically resected for NSCLC stage IA]. AB - The Author remarks the dispute about the adjuvant chemotherapy in patients with completely resected NSCLC stage IA. The tendency to overcoming all these disputes on the basis of relevant data published in the pneumological literature, is taking shape. The most active role in this field of research is played by the pathologists as well as by thoracic surgeons in the interdisciplinary perspective concerning the new changed "scenario" after the 7th Edition 2009 of TNM Staging System. PMID- 24045510 TI - Protective effects of regular physical activity on human vascular system. AB - Regular physical activity exerts a comprehensive beneficial effect on the human vascular system. The benefits provided by physical activity are both direct and indirect. Direct protective actions of aerobic exercise are identifiable on vascular structures and functions, since regular physical activity guarantees the integrity of the endothelial function, promotes the decrease of oxidative stress and prompts the development of new muscular capillaries. Moreover, moderate aerobic effort has positive effects on fibrinolysis, blood viscosity and vascular tone. Indirect benefits include the pleiotropic actions of physical activity on cardiovascular risk factors, in particular hypercholesterolemia, hypertension, diabetes mellitus and obesity. In a primary and secondary prevention perspective, moderate physical activity reduces in a significant way the risk of appearance of ischemic heart disease and the mortality of already established ischemic heart disease. In conclusion, health operators ought to remind their patients to "Stay physically active" in order to "Stay really fit and healthy". PMID- 24045505 TI - The impact of sleep loss on hippocampal function. AB - Hippocampal cellular and molecular processes critical for memory consolidation are affected by the amount and quality of sleep attained. Questions remain with regard to how sleep enhances memory, what parameters of sleep after learning are optimal for memory consolidation, and what underlying hippocampal molecular players are targeted by sleep deprivation to impair memory consolidation and plasticity. In this review, we address these topics with a focus on the detrimental effects of post-learning sleep deprivation on memory consolidation. Obtaining adequate sleep is challenging in a society that values "work around the clock." Therefore, the development of interventions to combat the negative cognitive effects of sleep deprivation is key. However, there are a limited number of therapeutics that are able to enhance cognition in the face of insufficient sleep. The identification of molecular pathways implicated in the deleterious effects of sleep deprivation on memory could potentially yield new targets for the development of more effective drugs. PMID- 24045508 TI - Antihyperalgesia by alpha2-GABAA receptors occurs via a genuine spinal action and does not involve supraspinal sites. AB - Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABAA receptors (GABAARs) containing alpha2 subunits (alpha2-GABAARs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal alpha2-GABAARs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABAAR-mutated mice, which either lack alpha2-GABAARs specifically from the spinal cord, or, which express only benzodiazepine-insensitive alpha2-GABAARs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all alpha2-GABAARs were benzodiazepine insensitive. The major (alpha2-dependent) component of GABAAR-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal alpha2-GABAARs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target alpha2-GABAARs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions. PMID- 24045511 TI - Topography and morphological anatomy of nutrient foramina in human metacarpal bones and their clinical implications. AB - PURPOSE: To study the morphological and topographic anatomy of nutrient foramina and to determine the foraminal index of metacarpal bones. MATERIALS AND METHODS: The study consisted of 438 unpaired, human metacarpal bones of unknown age and sex. Nutrient foramina in each of the bones were grossly identified in relation to their number and location. The foraminal index was calculated by applying the Hughes formula. A digital vernier caliper was used to perform the measurements. RESULTS: Among our specimens, 93.1% of metacarpals had single foramen, 2% had double foramina, 0.3% of the bones had triple foramina and in 4.6% of cases the foramen was absent. The mean foraminal indexes of the 1st, 2nd, 3rd, 4th and 5th metacarpal were 60.1, 53, 43.1, 43.7 and 45.9 respectively. CONCLUSION: It was observed that the morphology and topography of nutrient foramina vary among different metacarpals. In 1st and 2nd metacarpals, foramina were more common at the medial surface and in other metacarpals, mostly seen on the lateral surface. The knowledge about these foramina is important in certain surgical procedures to preserve the circulation. This data is important to the plastic surgeon for microvascular bone transfer surgeries. PMID- 24045512 TI - Helicobacter pylori: molecular detection of vacA gene and vacuolating activity in human gastric adenocarcinoma cells. AB - BACKGROUND AND AIMS: Helicobacter pylori strains secrete a vacuolating cytotoxin (VacA), plays an important role for the development of peptic ulcer disease and gastro-duodenal diseases. vacA gene is responsible to regulate the activity of the vacuolating cytotoxin. The objective of this study was molecular detection of vacA gene and observes the vacuolating activity on human gastric adenocarcinoma (AGS) cells. MATERIALS AND METHODS: H. pylori vacA gene was determined by polymerase chain reaction. Vacuolation activity of VacA toxin in broth culture filtrates was assessed in AGS cells and quantified by neutral uptake assay. Different concentration dosages of VacA and incubation time were used in the measurement of the vacuolating activity on AGS cells. RESULTS: The results showed that VacA toxin could stimulate vacuolating activity on AGS cells with minimum concentration 1.0 MUg/ml from both of s1m1 and s1m2 alleles (vacA gene). The toxin produced optimal reaction at 5.0 MUg/ml with significant differences observed between the alleles. The results also showed that both alleles commenced the vacuolating activity at the minimum of 3 hr incubation time, and the activity showed in time-dependent manner. CONCLUSION: Optimal concentration of VacA toxin (s1m1 allele) causes more interaction with AGS cell producing more vacuolating activities. Time-dependent vaculation of both alleles might allow H. pylori for persistent infection without rapid destruction of gastric cells might promote gastro-duodenal diseases. The study provided us better understanding of the pathogenesis of the diseases associated with H. pylori infection which is an emerging problem in developing countries. PMID- 24045513 TI - Effect of curcumin on aortic changes in ovariectomized rats fed with repeatedly heated soy oil: a preliminary electron microscopic study. AB - BACKGROUND AND AIMS: Consumption of repeatedly heated soy oil has been linked with incidence of atherosclerosis particularly in oestrogen deficient states. In the present study, effect of curcumin extract on the prevention of atherosclerosis was evaluated. MATERIALS AND METHODS: Forty eight female Spraque Dawley rats (weighing 200-250 gm) were divided into eight groups. All groups were fed with 2% cholesterol diet. The sham control groups consisted of vitamin E free RBD Olein (IV62) that acted as vehicle, and curcumin treated groups without undergoing ovariectomy. The other six groups were subjected to ovariectomy and later treated with vehicle-only, curcumin-only, once heated soy oil (1HSO) with vehicle, 1HSO with curcumin, five times heated soy oil (5HSO) with vehicle and 5HSO with curcumin. Curcumin was administered orally at a dose of 50 mg/kg which was commenced two weeks following ovariectomy. Following four months, the rats were sacrificed and serial sections of arch of aorta were harvested and processed for electron microscopic studies (EM). RESULTS: EM studies showed thickened tunica intima, fenestration of internal elastic lamina and migration of smooth muscle cells from tunica media to tunica intima in the ovariectomized control, 1HSO and 5HSO treated groups, with the latter being most prominent. There were no significant ultra structural changes in the curcumin-treated groups compared to the non-treated groups. CONCLUSION: Oral administration of curcumin at a dose of 50 mg/ kg body weight did not show any changes in the aorta of the ovariectomized rats fed with 2% cholesterol and heated soy oil. PMID- 24045514 TI - Seroprevalence of IgG anti-Toxocara canis antibodies and anti-Fasciola sp. antibodies in patients with urticaria. AB - AIMS: Chronic urticaria (CU) is defined by recurrent episodes occurring at least twice a week for 6 weeks and generally characterized by the rapid appearance of wheals and/or angioedema and may be associated with parasitic infections. We aimed to investigate the seroprevalance of Toxocara canis and Fasciola species in patients with CU. MATERIALS AND METHODS: We included 55 patients (in age 16-55) with urticaria admitted in study. As a control group we recruited 30 healthy volunteers they had no history of urticaria, rhinitis, asthma, atopic eczema/dermatitis syndrome (AEDS), or other relevant diseases. IgG antibodies to Toxocara canis and Fasciola species were investigated by ELISA method. RESULTS: In a total of 55 patients (mean age: 31.85 +/- 8.92), 8 patients (14.5%) were positive for IgG antibodies to Toxocara canis. Among seropositive patients (mean age: 38.62 +/- 12.46) 6 patients were female. No patient was positive for Fasciola by ELISA. Six of Toxocara canis seropositive cases were frequently visited or lived in rural areas and had contact with pets. CONCLUSIONS: Patients with urticaria, should be tested for Toxocara canis and treated with anthelminthic drugs in endemics areas for toxocariasis. PMID- 24045515 TI - Bilateral emphysematous pyelitis: a rare encounter in urology. AB - Gas-forming infection of the kidneys can affect either the parenchyma or the collecting system. They are known as emphysematous pyelonephritis (EPN) and emphysematous pyelitis (EP) respectively. Bilateral EPN is a fairly established entity and numerous articles about this condition have been published. However, much less is known about bilateral EP. We report a rare case of bilateral EP and a literature review of this disease. A 66-year-old woman with long-standing bilateral staghorn calculi presented with bilateral EP and severe sepsis. She was treated with antibiotics and bilateral double-J stents to drain the upper urinary tracts. She recovered after 1 month of intensive care and medical therapy. Percutaneous nephrolithotomy (PCNL) had been scheduled to treat her staghorn calculi. A literature search on MEDLINE and Google Scholar with the terms "bilateral emphysematous pyelitis" only found 1 case report in English and another 2 reports in the Korean language that discussed bilateral EP. The collective experience of these few cases, including the present case, suggests that bilateral EP runs a more benign course than bilateral EPN. It should be diagnosed as soon as possible with computed tomography (CT) scans of the renal system. Current evidence shows that can be treated successfully with timely antibiotics. Drainage of the collecting system either percutaneously or with placement of double-J stents might facilitate recovery. PMID- 24045516 TI - Persistent Mullerian Duct Syndrome: an interesting case report. AB - Transverse testicular ectopia is an uncommon disorder of testicular ectopia. Nearly thirty percent of the cases is associated with Persistent mullerian duct syndrome which is characterized by karyotypically normal males with retained mullerian derivatives. Understanding the natural process of the condition and the association with malignant potential will allow for a better understanding of the optimal surgical approach. This is a case report of young male presented a left sided inguinal hernia in which the sac contained both testes and uterus. The literature review of the syndrome will be discussed. PMID- 24045517 TI - Incomplete discoid lateral meniscus: a case report. AB - The variations of lateral meniscus include pathologic entities which vary in size, shape and attachment. In this manuscript, we report a case of discoid lateral meniscus which was observed in an embalmed fetal cadaver. It was an incomplete variety of the discoid meniscus and observed on the right side knee. The clinical implication of this discoid meniscus has been emphasized along with the review of literature. The morphological and embryologic details of the discoid lateral menisci are discussed. PMID- 24045519 TI - Optimal wrist position for long and short axis ultrasound guided radial artery cannulation. AB - BACKGROUND: The radial artery is the most common site for arterial cannulation. Procedures for improving radial artery cannulation have involved direct visualization of the vessel with ultrasonography (US). The aim of this study evaluate the short axis and long axis radial artery measurements at 0o, 45o, 60o wrist joint angle and find out the optimal wrist joint angle for long and short axis US guided radial artery cannulation. MATERIALS AND METHODS: This study was approved by the Institutional Ethical Committee and the study was performed in accordance with the ethical principles for human investigations, as outlined by the Second Declaration of Helsinki. One hundred fifty-two (90 men and 62 women, 18-48 years of age, mean age: 32.9 +/- 6.1) healthy volunteers were recruited. The radial artery distance between skin and height, width, area in short axis and radial artery distance between skin and height was measured in long axis at 0o, 45o, 60o wrist joint angle were measured. Results. Short axis radial artery distance between skin, width, height, area and long axis radial artery distance between skin, height were statistically significantly different among 0o, 45o, 60o (p< 0.05; for all comparisons). Short axis width was statistically significantly increased at 45o compared to at 0o (p< 0.001;). Short axis radial artery distance between skin and height at 45o were statistically significantly decreased than at 0o (p< 0.001; for all comparisons) and long axis skin distance and height at 45o were also statistically significantly decreased than at 0o (p< 0.001; for both comparisons). Short axis radial artery skin distance and area at 60o is statistically significantly decreased than at 45o (p< 0.001; for both comparisons) and also long axis height of radial artery at 60o is statistically significantly decreased than at 45o (p< 0.001;). CONCLUSIONS: Angle increment up to 45o might help clinicians for radial artery cannulation in short axis plane whereas this angle increment maneuver decreased the arterial height in long axis which might be a potential disadvantage for cannulation. PMID- 24045518 TI - [Carpal tunnel syndrome and steel industry]. AB - OBJECTIVES: The carpal tunnel syndrome (CTS) is a common working pathology. The CTS diagnosis is not so easy because neurophysiological investigations are necessary. The purpose of this study is to evaluate the working risks and the presence of CTS signs using a focused anamnestic and clinical procedure. MATERIALS AND METHODS: We evaluated the working risks of CTS in a population of 65 male workers of a steel industry (average age 25.1 and seniority 2.82), performing 5 different tasks. The Borg Scale was used to evaluate the subjective muscle effort. Diurnal paresthesia (V1FG), nocturnal paresthesia (V1FN), hypersensitivity (V1IS), hypostenia (V1IT) were considered. RESULTS: We identified three main working risks repetitiveness of single actions, static and prolonged posture of the truck, muscle effort. 21.5% of the workers showed at least one of the three symptoms;13.8% showed one or more symptoms; the clinical objectivity was observed in 18.5%. A relation between V1FG, V1FN, clinical objective linked to the workers age of the task 1 (p =0.035) is showed. CONCLUSIONS: To prevent CTS, the use of the Borg Scale associated with identification of the risks and with the anamenstic-clinical investigation is useful to discriminate people at risk of CTS. PMID- 24045520 TI - Efficacy and safety of pneumatic trabeculoplasty versus timolol added to latanoprost in primary open angle glaucoma. AB - BACKGROUND: To compare the safety and short-term additive hypotensive effect of pneumatic trabeculoplasty (PNT) versus timolol among patients receiving topical latanoprost for primary open angle glaucoma (POAG). PATIENTS AND METHODS: This study prospectively evaluated 30 eyes of 30 patients with POAG receiving latanoprost monotherapy. We randomly assigned 15 eyes to PNT plus latanoprost (Group A), and 15 eyes to latanoprost/timolol fixed combination therapy (Group B). PNT treatment was performed at days 0, 7, and 90. Follow-up visits occurred at day 1, week 1, and months 1 and 3. RESULTS: Compared to baseline values, both treatments significantly lowered IOP (p <= 0.001).The mean IOP for Group A was 21.13 +/- 1.6 mmHg at baseline and 18.7 +/- 1.5 mmHg at three months (p <= 0.001). For Group B, mean IOP was 20.8 +/- 1.9 mmHg at baseline and 18.9 +/- 0.8 mmHg at three months (p <= 0.001). Transient conjunctival hyperaemia, the only adverse effect occurring after PNT, was observed in all patients in Group A. CONCLUSION: The additive IOP-lowering effect of PNT was similar to timolol in patients with POAG receiving latanoprost. PMID- 24045521 TI - [Duration of untreated psychosis and cognitive deficits in a cohort of chronic psychotic patients]. AB - AIMS: Outcome of psychotic disorders, particularly schizophrenia and related disorders, seems to be associated, among a number of other factors, to the latency of treatment of irst episode (duration of untreated psychosis, DUP); indeed, outcome seems to be worse in subjects with a longer DUP. However, few studies addressed the topic of long term outcome and DUP as regard to cognitive functioning, though the latter plays a crucial role in explaining a significant proportion of disability both in non-affective and affective psychoses. The study aims to analyze relationships between DUP and cognitive functioning in a sample of chronic psychotic patients. MATERIALS AND METHODS: We considered a unselected sample constituted by 82 chronic outpatients, 49 males (59,8%) e 33 females (40,2%), age range 20-74 yrs (mean age 46,59; s.d. 10,68 yrs); these patients were affected by schizofrenia (n=41, 50%), Bipolar Disorder type I, with psychotic mood congruent or uncongruent features (n=18, 22%,) and Schizoaffettive Disorder (n=23, 28%) according to DSMIVTR, with diagnosis confirmed by means of SCID-I. Patients underwent WAIS-R in order to evaluate cognitive functioning. RESULTS: A longer DUP (more than 3 months between onset of first clinically evident psychotic symptoms and first antipsychotic treatment) was associated with significantly lower scores in 9 out of 11 subtests of WAIS, weighted total score, IQ-verbal score, IQ-performance score and IQ-total score. A significant relationship between a longer DUP and lower cognitive performances was confirmed among schizophrenic and schizoaffective patients, although limited to some subtests. CONCLUSIONS: The study provides new evidence for a positive association between longer DUP and worse neurocognitive functioning, even in the long term. PMID- 24045522 TI - [Investigation on a group of autistic children: risk factors and medical social considerations]. AB - AIMS: The aim of this work is to study the association between autism in a group of autistic children and risk factors for specific familiar diseases and developmental disease in the early years of life, through a medical social investigation. MATERIALS AND METHODS: For this study, we have submitted an anamnestic questionnaire to 29 autistic children and their families in a South Italy region (Basilicata), collecting data about children and their parents. RESULTS: The results show that many children have a family history of autoimmune diseases (psoriasis, rheumatoid arthritis, celiac disease, Takayasu's arteritis), allergies and food intolerances, suggesting a putative involvement of the immune system in autism etiopathogenesis. Analyzing residences areas of patients, Potenza and Matera, with their environmental factors (radioactive waste repositories, incinerators, intensive farming), we demonstrate that the particular territorial characteristics don't affect autism. CONCLUSIONS: Autistic disorder is a spectrum of neurologic disorders complex both in etiopathogenesis and healthcare. So we aim to continue the study already undertaken on cytokines of autistic subjects serum and to extend it through biomolecular approaches assessing the presence of specific genetic polymorphisms in order to identify the physiopathogenetic mechanisms underlying the disease and to evaluate the predictive risk with the aim to improve care interventions. PMID- 24045523 TI - Treatment of neck pain with type A botulinum toxin evaluated by Neck Pain Questionnaire (NPQ). AB - AIMS: To investigate the effects of a treatment with botulinum toxin in patients suffering of cervical pain can be defined as a painful condition of the upper region of the spinal column affecting neck and shoulders. It is one of the most frequent complaints and estimates suggest it affects 7 out of 10 people, with varying degrees of intensity. Although there is a number of causes, most often muscular contraction is involved as a probable consequence of a variety of irritative phenomena. MATERIALS AND METHODS: In our study 26 patients suffering from cervical pain were treated (21 women and 5 men, mean age 60.8 years, range 37-88). Three scales were used to evaluate pain: the Visual Analogue Scale (VAS), the Verbal Scale (VS) and the Neck ad Pain Questionnaire (NPQ). Scoring on all three of these scales was carried out at time 0 (T0) prior to treatment and at time 1 (T1) after 4 months. Patients were treated with 500 MU of Type A Dysport Toxin (Ipsen SpA), made up with 2.5 ml of sodium chloride solution at 0.9%, giving 20 units of toxin in 1 ml. An average of 180 units of toxin were administered to each patient, equivalent to 0.9 ml per point/unit (range 40- 360 units). Patients were given from 1 to 4 units at each session with an average of 2 units. The most common muscles injected were splenius cervicis, the sternocleidomastioid, trapetius, paravertebral and levator scapulae. of patients with cervical pain treated with botulinum toxin were as follows: the mean score on the Visual analogue scale (VAS) at T0 was 6.31, while at T1 it fell to 2.65, i.e. a decrease of 3.66 scores, equivalent to 58%. On the verbal scale (VS), the mean score at T0 was 2, which dropped to 0.8 at T1, a decrease of 1.2 scores, equivalent to 60%. By the Neck Pain Questionnaire (NPQ) the mean T0 score was 12.76, a figure which fell to 7.62 at T1, a drop of 5.14 points, equivalent to 40.28%. The statistical analysis shows that between T0 and T1 the decrease in the VAS, VA and NPQ scores was highly significant (p< 0.01). CONCLUSIONS: The administration of botulinum toxin appears to be a useful therapy for the treatment of muscular-skeletal pain. Technically, the therapeutic use and efficacy of botulinum toxin principally consists in the practical possibility of delivering the toxin principally remains in the target structures. If performed by qualified personnel, the treatment with botulinum toxin can be carried out in day surgery and it appears to be safe, with few risks and a minimum of side effects. To conclude, the main goals in the treatment of muscular-skeletal pain with botulinum toxin are in the breaking of the vicious circle of contraction pain -contraction, in stopping the pain from becoming chronic and achieving a valid alternative therapy. PMID- 24045524 TI - Organ donation and pre-emptive kidney transplantation: ethical issues. AB - There is considerable evidence that pre-emptive transplants have several clinical advantages. However, pre-emptive transplants raise a number of ethical issues. Pre-emptive transplants from living donors offer distinctly greater benefits than those from deceased donors and some pre-emptive transplantation programmes actively encourage living organ donations. Moreover, the offer of a pre-emptive transplant to a patient who is not yet on dialysis unquestionably penalises patients already on dialysis who may have been on the waiting list for a long time. Therefore preemptive transplants give rise to conflicts between justice and utility. Several factors should be considered: health conditions, clinical urgency, probability of imminent worsening of a patient's clinical condition, the future chances of finding a matching organ, and others. From the various values at stake, ethical issues are analysed in search of an acceptable synthesis. PMID- 24045525 TI - Experimentation in organ transplants compared with clinical trials: ethical problems. AB - The origins of new techniques in transplant surgery vary widely. Frequently, new procedures are the result of small step-by-step departures from protocols already established in clinical practice; or they may be the result of radical innovation. Whatever their origin, experimental techniques in transplant surgery do not follow the route of randomised clinical trials; nor are they subject to the same procedures of review by an ethics committee. The present paper discusses some of the ethical implications of this situation. PMID- 24045526 TI - Male tuberculous mastitis: a rare entity. AB - A 28-year old male presented to our clinic complaining of a recent onset of a painful right breast lump with redness and nipple discharge. Fine-needle aspiration biopsy revealed caseating granulomas, with a culture positive for Mycobacterium tuberculosis. He was found to have a positive PPD, but no other site of pulmonary or extra-pulmonary tuberculosis was identified. Treatment with anti-tuberculous drugs lead to complete clinical resolution of the breast lesion. The breast is a rare site of extra-pulmonary tuberculosis (TB), comprising only 0.1% of all cases. TB is re-emerging in the Western world with the increasing prevalence of immunosuppressive disorders. Increasing immigration rates and widespread travel are further contributing to TB globalization. With the re emergence of TB, atypical forms are appearing, with an increase in the proportion of extra-pulmonary disease and a widening of the age range at presentation. Tuberculous mastitis(TM) is found mostly in young, multiparous women. Male TM is extremely rare, and accounts for only 4% of all cases. This strikingly lower incidence in males points towards a significant role of parity, pregnancy and lactation as likely predisposing factors. Although a rare disease, TM is an important differential diagnosis for breast cancer. A high index of suspicion is the cornerstone for diagnosis. Awareness of this condition is important not only for dermatologists, but for surgeons, radiologists and pathologists, as well. Clinicians are encouraged to provide a careful assessment of the breasts, an important organ also in men. PMID- 24045527 TI - [Medical terminology and lay users. A quali-quantitative survey of a group of young motivated graduates]. AB - AIMS: Medical terms occupy growing spaces in dictionaries and the media daily propose a great number of medical words. Nevertheless scientific data regarding the actual degree of comprehension of medical terminology on the part of lay users are scanty. Aim of this study was the evaluation, in a group of young motivated graduates, of the degree of understanding of a set of medical terms normally adopted by physicians in specialistic language, and also used when speaking with patients. PARTICIPANTS AND METHODS: Nine medical terms used by physicians in daily practice were selected ("aphasia", "edema", "erythema", "fibrillation", "fibroma", "jaundice", "paraplegia", "polypus", "sclerosis") and they were administered in paper form to eighteen young graduates, non-health operators who were asked to furnish one definition for each of the terms. A subsequent structured oral discussion integrated the recorded written findings. RESULTS: Erythema and fibrillation were the most well-known and understood terms. Among the selected medical terms, the more difficult ones to understand were sclerosis and jaundice. Interesting features emerged from the characterization of the site attributed to some of the investigated terms, in particular edema was mainly perceived as the pulmonary one, fibroma was more often interpreted as a benign tumor localized in the uterus and polypus was more frequently associated with its collocation in the nose. CONCLUSIONS: The participants involved in this quali-quantitative survey demonstrated a general good knowledge and comprehension of the medical terms proposed. Some limits in knowledge documented in this group, however, indicate that the use of medical terminology needs more clarification within the doctor-patient context. Such clarification appears even more mandatory in subjects with low scholastic-education levels. PMID- 24045528 TI - [Randomized controlled trial on the promotion of healthy lifestyles among adolescents in the orthodontic setting: study protocol]. AB - Many studies have shown that the bad lifestyles are the major factors thought to influence susceptibility to many diseases in our society and often these habits during the adolescence begin. The aim of the study was to evaluate the health promotion intervention effect in an orthodontic adolescent sample, in particular: deterring adolescents from smoking; discourage the use and abuse of alcoholic beverages; encourage the adherence to the Mediterranean style diet. A blinded randomized controlled trial will be performed. The participants will be adolescents aged 10 to 14 years that will receive a medical examination in the Complex Unit of Orthodontics. The sample will be followed for three years. The collected evidence would be a scientific support for decisions in public health, in order to increase the health of the young generations. PMID- 24045529 TI - HCV-related autoimmune disorders in HCV chronic infection. AB - Patients with hepatitis C virus (HCV) chronic infection may develop a great number of extrahepatic manifestations. Among these latter, mixed cryoglobulinemia (MC) represents the prototype of HCV-associated autoimmune-lymphoproliferative disorders. Other rheumatological manifestations of HCV chronic infection are Siogren syndrome, arthritis and CREST syndrome. Thyroid autoimmune disorders are among the most frequent manifestations of HCV chronic infections and are clinically relevant because of the association with thyroid dysfunctions and hypothyroidism. Autoimmune cytopenia is also reported in association with HCV infection. This paper reviews the association of HCV chronic infection with the above mentioned pathologies, and their immunopathogenesis. PMID- 24045530 TI - Program of home telemonitoring in patients with cystic fibrosis over a period of 2 years: a contribution to the rationalization of care. AB - OBJECTIVES: In present study we tested the possible presence of a saving for Italian National Health Service (INHS) when using telemonitoring in the follow-up at home of patients with Cystic Fibrosis (CF), in the aim to assess the possible role of Telemedicine in rationalization of hospital admissions. MATERIALS AND METHODS: We performed an economic analysis of the costs incurred by the INHS for patients with CF followed at home by telemonitoring, recalled to hospital under suspicion or diagnosis of acute pulmonary recurrence. RESULTS: We calculated, for 19 patients retrieved in the period of the study, a total saving compared to traditional home care of ? 132.144,91 in 24 months, corresponding to ? 3.303,62/year/patient. CONCLUSIONS: The presence of an economic advantage for the INHS is confirmed once again, although not significant. The data from this study are encouraging regarding the possible role of telemedicine in the organization of homecare of CF patients. PMID- 24045531 TI - [Genetics and epigenetics of schizophrenia]. AB - Schizophrenia is a severe psychiatric disorder with an estimate prevalence of 0.3 0.7%. Studies on family aggregation showed a higher incidence of disease among family members of affected people. This observation lead to formulate the hypothesis that schizophrenia could be inheritable, but twin studies have shown a concordance of disease between monozygotic twins only of 50%, indicating the concomitant role of environmental factors in the pathogenesis of schizophrenia. Researches in molecular biology field have allowed the identification of genes that confer susceptibility to schizophrenia on chromosomes 1, 2, 3, 5, 6, 8, 10, 11, 13, 14, 20 and 22. Epigenetic modifications of gene expression, that not involve the primary DNA sequence, may also predispose to schizophrenia, in particular the methylation of genes involved in neurotransmission (RELN, GAD1, MARLIN-1, and NR3B GRIA2, VGLUT1 and 2, 5HT2a, COMT and BDNF), the histone modifications and the action of non-coding RNAs. This review deals with the results of a bibliographic retrieval on PubMed, carried out, using the key words: schizophrenia, genetics, epigenetics. From the epitomized results it can be derived that schizophrenia seems to be a multifactorial disease. Environmental factors, that can cause epigenetic modifications, are important in its pathogenesis, acting on a biological inheritable vulnerability. PMID- 24045532 TI - The multifaceted and complex hypermobility syndrome (a.k.a. Ehlers-Danlos Syndrome Hypermobility Type): evaluation and management through a rehabilitative approach. AB - Joint hypermobility syndrome (JHS) is a hereditary disorder of connective tissue recently considered the one and the same as the Ehlers-Danlos Syndrome Hypermobility Type (EDS-HT). The JHS/EDS-HT is mainly characterized by joint hypermobility, chronic pain and a variable skin involvement. Clinical manifestations expressed by patients are multiple and varied. The rehabilitative approach may play a fundamental role in the understanding and management of symptoms and clinical manifestation. Aim of this study is to make a literature revision of all the aspects of this not so rare disease. PMID- 24045533 TI - Mixed cryoglobulinemia and thyroid autoimmune disorders. AB - In patients with hepatitis C virus-associated mixed cryoglobulinemia (MC+HCV) the following thyroid disorders are significantly more frequent than in HCV not infected controls: 1) high levels of serum anti-thyroperoxidase autoantibody (AbTPO), 2) high levels of serum AbTPO and/or anti-thyroglobulin (AbTg) autoantibody; 3) humoral and ultrasonographical signs of thyroid autoimmunity (35%); 4) prevalence of subclinical hypothyroidism (11%). Also, the prevalence of papillary thyroid cancer has been found higher in MC+HCV patients than in controls, in particular in patients with autoimmune thyroiditis. These results suggest a careful monitoring of thyroid function in these patients. PMID- 24045534 TI - The current status of lymph node dissection in the treatment of papillary thyroid cancer. A literature review. AB - AIM: Cervical lymph node micrometastases are observed in up to 90% of papillary thyroid cancers (PTC), showing that lymph nodal involvement is very common. Nevertheless, during the last years, the role of lymph node dissection in the treatment of PTC has been controversial and, at present, the best indications to the routine or therapeutic neck dissection remain subject of research. In order to better analyze the current role of lymph node dissection in the surgical treatment of PTC, an analysis of the most recent literature data was performed. STUDY DESIGN: By using as keywords lymph node dissection, selective, lateral or central lymph node dissection, modified radical neck dissection, prophylactic or therapeutic lymph node dissection, papillary thyroid cancer, a Pub Med data base research was carried out. The most recent guidelines of different referral endocrine societies, inhering neck dissection for PTC, were also evaluated. RESULTS: The role of neck dissection in PTC management remains controversial regarding routine or therapeutic indications, surgical extension, and its impact on local recurrence and long term survival. Due to inhomogeneous literature data, the current status of node dissection is still subject of research. CONCLUSIONS: There is agreement between endocrine and neck surgeons about the extension of therapeutic lymph node dissection in N+ PTC patients , and also in the prophylactic treatment of N0 "high risk" patients. Considering a recent trend toward routine central lymphadenectomy avoiding radioactive treatment, prospective randomized trials are needed to evaluate the benefits of different approaches. PMID- 24045535 TI - Remembering the father of chronobiology and chronomics: Franz Halberg, MD (5 July 1919 - 9 June 2013). PMID- 24045536 TI - Commemoration Erhard Haus, M.D., Ph.D. PMID- 24045537 TI - Stability of lower limb minimal perceptible difference in floor height during hopping stretch-shortening cycles. AB - This study aimed to investigate a novel proprioceptive test, the minimal perceptible difference (MPD) test, that assessed participants' ability to perceive floor height changes whilst hopping. Sixteen healthy volunteers performed multiple trials of five hops on a custom built sleigh apparatus that permitted a floor height change (range 3 -48 mm) or no change, as dictated by a structured searching algorithm. Minimum detected surface height change was recorded for eight different hopping conditions (factors-technique: alternate/bilateral hopping; side: dominant/non-dominant; direction of change: up/down) over two separate testing occasions. Within day and between day reliability were assessed using intraclass correlation coefficient (ICC) and 95% confidence intervals. The only factor which significantly influenced the sensitivity of subjects to detect changes in floor height was the hopping technique (bilateral or alternate). The mean MPD was significantly lower (p < 0.0001) for the bilateral hopping technique (MPDmean = 15.7 mm) when compared to the alternate hopping technique (MPDmean = 26.6 mm). All bilateral hopping techniques yielded moderate to high ICC for within (0.60-0.79) and between day (0.67-0.88) reliability. The results suggest that the bilateral hopping MPD assessment is a reliable, functional assessment of proprioception sensitivity during repeated stretch-shortening cycles that may better reflect human gait than established static assessment. Increased sensitivity to detection during bilateral hopping may reflect strategy dependent utility of proprioceptive information. PMID- 24045538 TI - Thoracoscopic confirmation of correct seating of minimaly-invasive rapid deployment aortic bioprosthesis. AB - There is a growing interest in minimally invasive access for aortic valve surgery. The upper hemi-sternotomy provides good aortic valve exposure, with numerous possible advantages. Nevertheless, some surgeons remain skeptical about limited access surgery because it is technically more demanding. Sutureless and rapid-deployment bioprostheses could alleviate these concerns by improving ease of implantation. We herein describe the use of video-assisted visualization to verify the position of the balloon-expandable frame during rapid aortic valve deployment. Sutureless and rapid-deployment bioprostheses improve implantation and make it easy to increase minimally invasive access for aortic valve surgery. PMID- 24045539 TI - Creep rupture as a non-homogeneous Poissonian process. AB - Creep rupture of heterogeneous materials occurring under constant sub-critical external loads is responsible for the collapse of engineering constructions and for natural catastrophes. Acoustic monitoring of crackling bursts provides microscopic insight into the failure process. Based on a fiber bundle model, we show that the accelerating bursting activity when approaching failure can be described by the Omori law. For long range load redistribution the time series of bursts proved to be a non-homogeneous Poissonian process with power law distributed burst sizes and waiting times. We demonstrate that limitations of experiments such as finite detection threshold and time resolution have striking effects on the characteristic exponents, which have to be taken into account when comparing model calculations with experiments. Recording events solely within the Omori time to failure the size distribution of bursts has a crossover to a lower exponent which is promising for forecasting the imminent catastrophic failure. PMID- 24045540 TI - Guidelines for radical reactions: some thirty years on. AB - In this viewpoint article we reflect on the state of play of organic free radical chemistry before the contributions of Beckwith et al. to our understanding of the factors that control intramolecular homolytic addition chemistry, and the rapid rise in the use of this chemistry once the impact of the "guidelines for radical reactions" became fully appreciated. PMID- 24045541 TI - From cytomorphology to molecular pathology: maximizing the value of cytology of lymphoproliferative disorders and soft tissue tumors. AB - OBJECTIVES: The field of cytopathology has been rapidly advancing in the era of molecular pathology and personalized medicine. On-site cytologic evaluation for adequacy and triaging specimens for small core biopsy or fine-needle aspiration (FNA) are often required. Cytopathologists face the challenge of how to best triage small specimens for diagnosis, molecular testing, and personalized treatment. Owing to its minimally invasive nature, FNA alone or combined with core biopsy for lymphoproliferative disorders and soft tissue tumors has gained popularity. METHODS: Literature review and author's institutional experience are used for this review article. This article will focus mainly on lymphoproliferative disorders and soft tissue tumors. RESULTS: Evaluation combining cytomorphology, immunohistochemistry, and/or molecular pathology is often needed to accurately diagnose and classify lymphomas and soft tissue tumors. Many molecular tests have been performed on cytologic specimens, such as tests for BRAF and RET in thyroid FNA. CONCLUSIONS: Molecular pathology has been widely integrated into conventional cytopathology for diagnosing lymphoproliferative disorders and soft tissue tumors, and the diagnostic value of FNA on those tumors has increased significantly. Cytology will play a more important role in the era of personalized medicine. PMID- 24045542 TI - Syndecan-1 overexpression is associated with nonluminal subtypes and poor prognosis in advanced breast cancer. AB - OBJECTIVES: Syndecan-1 expression is decreased in diverse tumor types but remains controversial in breast carcinomas. The goal of the study was to examine syndecan 1 expression in breast carcinoma and its prognostic significance. METHODS: The epithelial expression of syndecan-1 was examined in tissue microarrays constructed from 62 consecutive breast carcinoma cases diagnosed between 1997 and 2004 with distant organ metastasis and 10 consecutive control cases (breast carcinoma with no distant metastasis after at least 8 years of follow-up). The prognostic significance of syndecan-1 was estimated by utilizing a Cox proportional hazards regression model. RESULTS: Among tumors with distant metastasis, syndecan-1 expression was significantly associated with a higher histologic grade and inversely related to hormonal receptor status. The HER2 subtype and triple-negative carcinomas exhibited markedly higher syndecan-1 levels than those of luminal subtypes, while the latter remained significantly higher than nonmetastatic control cases. Furthermore, high syndecan-1 expression had a negative impact on both overall and disease-free survival rates. CONCLUSIONS: These findings suggest that syndecan-1 may regulate breast cancer cell behavior and thus deserves further investigation to ascertain its potential as a therapeutic target, especially in metastatic, triple-negative carcinomas. PMID- 24045543 TI - Transiently increased variation between a Point-of-Care and laboratory INR method after a long period of correlation: a case study demonstrating the need for ongoing correlation of POC with the central laboratory. AB - OBJECTIVES: To perform long-term comparison between laboratory Stago and Point-of Care (POC) i-STAT methods for determining the international normalized ratio (INR). METHODS: This was a multicenter method comparison of patient INR results and factors related to performance variance. RESULTS: For 5 years, the assays demonstrated close patient correlation within and above the 3.5 INR therapeutic range cutoff (bias, 0.23 INR units). Patient results above 3.5 INR were bimodal, with 60% demonstrating an i-STAT INR bias of less than 0.5. Several patient conditions were associated with the presence of a higher i-STAT bias. In year 6, a broader range i-STAT bias developed, increasing to 0.73 INR units. The increased bias persisted for 3 years, then returned to initial levels following i STAT adjustments. The substantial increase in i-STAT bias after a long period of stability was partly corrected by renewed correlation to the international reference preparation. Additional assay drift is discussed in relation to thromboplastin reagents and other testing variables. CONCLUSIONS: This study emphasizes the need for continual laboratory correlation with POC devices and caution in using published comparisons. PMID- 24045544 TI - Interobserver concordance in implementing the 2010 ASCO/CAP recommendations for reporting ER in breast carcinomas: a demonstration of the difficulties of consistently reporting low levels of ER expression by manual quantification. AB - OBJECTIVES: Endocrine therapy reduces recurrence risk by 30% to 50% in estrogen receptor (ER)-positive breast cancer. The ER-positive threshold recommended by the American Society of Clinical Oncology/College of American Pathologists is 1% based on studies using the ER-6F11 antibody. ER-SP1 antibody has a higher sensitivity and is more widely used. METHODS: We report interobserver concordance manually measuring ER in 264 breast cancers using ER-SP1 and 1D5 and 2 scoring methods (H-score and Allred score). RESULTS: With both antibodies, 3% to 4% of cases have a low level of ER expression (1%-10%), more than previously reported (<1%). We find a high level of paired observer concordance with both antibodies and scoring methods (kappa = 0.892-0.943) with no significant difference with method of scoring. Despite excellent concordance, positive/negative discordance was almost 5% among 3 observers using either antibody, an underappreciated clinically significant rate. CONCLUSIONS: Discordance overwhelmingly reflected differing opinions recording the proportion of tumor cells positive with low levels of expression (<10% staining; 12/13 cases). PMID- 24045545 TI - New fluorescent method (PLT-F) on Sysmex XN2000 hematology analyzer achieved higher accuracy in low platelet counting. AB - OBJECTIVES: In thrombocytopenia, high accuracy and precision of low platelet count is essential for appropriate decisions. The recently introduced Sysmex XN2000 analyzer (Sysmex, Kobe, Japan) offers 3 methods for platelet counting: impedance (PLT-I), optical (PLT-O), and a new fluorescence method (PLT-F). The precision of the PLT-F method in blood samples with platelet counts less than 50 * 10(3)/MUL (50 * 10(9)/L) was investigated and compared with the ICSH CD61 ImmunoPLT reference method. For comparison, PLT-I and PLT-O were determined on the Sysmex XN2000 and Sysmex XE2100 analyzer. METHODS: Blood samples with platelet counts less than 50 * 10(3)/MUL (50 * 10(9)/L) (n = 37) were analyzed on the Sysmex XN2000 and XE2100 analyzers. The CD61-ImmunoPLT method was performed on a Beckman Coulter FC-500 flow cytometer (Miami, FL). RESULTS: At a platelet count of 20 * 10(3)/MUL (20 * 10(9)/L), reproducibility for PLT-I, PLT-O, and PLT F on the XN2000 demonstrated coefficients of variation of 9.3%, 8.5%, and 3.0%, respectively. Correlation between PLT-O on the XN2000 and XE2100 yielded an r value of more than 0.977. Linear regression analysis between the PLT-F and CD61 ImmunoPLT methods resulted in a PLT-F of 0.71*CD61 - 0.8 (r = 0.988). Linear regression between PLT-F and PLT-O on the XN2000 resulted in a PLT-F of 1.05*PLT O - 2 (r = 0.975), and using the transfusion threshold of 20 * 10(9)/L platelets resulted in a PLT-F of 0.90*PLT-O - 0.4 (r = 0.956). CONCLUSIONS: The new PLT-F method demonstrated excellent results for reproducibility in samples with platelet counts less than 50 * 10(9)/L. PLT-F could be helpful in making better decisions for platelet transfusions. PMID- 24045546 TI - Growth pattern, an important pathologic prognostic parameter for clear cell renal cell carcinoma. AB - OBJECTIVES: To assess the validity of growth pattern as a unique prognostic parameter for clear cell renal cell carcinoma (ccRCC). METHODS: In total, 561 patients with pathologic tumor stage 1 (pT1), pT2, and pT3a ccRCC without preoperative metastasis were evaluated. Clinicopathologic parameters, including pathologic tumor stage, Fuhrman grade, tumor necrosis, lymphovascular invasion, and growth pattern, were analyzed to predict disease-free survival (DFS) and cancer-specific survival (CSS). RESULTS: Growth patterns were defined as follows: expansive included tumors with well-circumscribed margins without normal renal tissue in the tumor, and infiltrative involved tumors with ill-circumscribed margins or normal renal tissue in the tumors. In multivariate analysis, Fuhrman grade, tumor necrosis, and growth pattern were useful predictors of DFS, whereas Fuhrman grade and growth pattern were useful predictors of CSS, although only 30 cases showed the infiltrative pattern. CONCLUSIONS: Growth pattern can be considered a new prognostic parameter for ccRCC. PMID- 24045547 TI - Small-dense LDL cholesterol/large-buoyant LDL cholesterol ratio as an excellent marker for indicating lipodystrophy in HIV-infected patients. AB - OBJECTIVES: To examine whether the lipid parameters are predicting factors for human immunodeficiency virus (HIV)-associated lipodystrophy. METHODS: Whole-body fat compositions of HIV-positive patients receiving stavudine-containing antiretroviral regimens (n = 79) were determined. Lipodystrophy was defined as a ratio of trunk fat mass/lower limb fat mass greater than 2.28. Blood samples were analyzed for total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), small-dense LDL-C (sdLDL-C), apoAI, apoB, lipoprotein(a), and CD4 cell counts. Large-buoyant LDL-C (lbLDL-C) was calculated (LDL-C minus sdLDL-C). RESULTS: Twenty-six patients were classified as having lipodystrophy. The mean values of triglycerides, HDL-C, sdLDL-C, apoB, TC/HDL-C, apolipoprotein (apo) B/apoAI, and sdLDL-C/lbLDL-C showed significant differences between patients with and without lipodystrophy (P < .02). Using logistic regression analysis, sdLDL-C/lbLDL-C was identified as a significant predictor of lipodystrophy (P < .001). At a ratio of 0.554, the odds ratio was 17.8 with a likelihood ratio of 5.5. CONCLUSIONS: The sdLDL-C/lbLDL-C ratio is an excellent marker for indicating lipodystrophy in HIV infected patients. PMID- 24045548 TI - Value of additional level sections in the evaluation of lymph nodes for endometrial carcinoma staging. AB - OBJECTIVES: To evaluate the value of deeper sections for conventional (non sentinel) lymph node dissections in high-risk endometrial carcinoma (EC). METHODS: We conducted a retrospective review of all ECs with high-grade or serous histology, more than 50% myometrial invasion or International Federation of Gynecology and Obstetrics (FIGO) pathologic stage greater than 2, and conventional complete pelvic lymph node dissections. No sentinel lymph node (SLN) biopsies were performed. Nodes were originally processed entirely in 3-mm slices, with residual fatty tissue submitted separately. When lymph nodes were negative on original H&E sections, paraffin blocks were sectioned to produce 1 additional H&E slide at approximately 0.8 mm deep. With positive nodes, we examined the relationship between micrometastases, staging parameters, and recurrence. RESULTS: Fifty-one high-risk cases were identified, with a median of 15 pelvic lymph nodes per case. Fifteen (29%) cases contained positive nodes. Review of the original slides and additional sections of all blocks from the remaining 36 cases failed to reveal metastases. Statistically significant associations were found between node status and depth of myometrial invasion, lymphovascular invasion, and FIGO stage. We found no significant relationship between lymph node status and serous histology. CONCLUSIONS: Our results suggest that enhanced detection of metastasis by SLN biopsies may be related to targeted lymph node selection rather than additional histologic sectioning. PMID- 24045549 TI - IgM multiple myeloma: pathologic evaluation of a rare entity. AB - OBJECTIVES: To delineate the pathology of immunoglobulin M-producing multiple myeloma (IgM MM). METHODS: Clinicopathologic data were reviewed for 15 cases meeting World Health Organization criteria for MM and having a serum IgM paraprotein. Immunohistochemistry was performed on diagnostic bone marrow specimens for common B-cell and plasma cell markers. RESULTS: Of the 15 IgM MM bone marrows reviewed, 6 (40%) had lymphoplasmacytoid cytology, and 12 (80%) expressed CD19, CD20, and/or CD45. Cyclin D1 expression was common (11 cases, 73%) and usually associated with t(11;14). No cases expressed CD5 or had an associated CD5-positive B-cell population. CD117 was positive in 20% of cases. CONCLUSIONS: The frequent B-cell-associated antigen expression by IgM MM distinguishes it from other MM types, causing significant pathologic overlap with lymphoplasmacytic lymphoma (LPL). However, IgM MM is usually distinguished from LPL by aberrant cyclin D1 expression or t(11;14). Therefore, assessing for these abnormalities is recommended when evaluating bone marrow involvement by IgM associated lymphoplasmacytoid disorders. PMID- 24045550 TI - Hidden mastocytosis in acute myeloid leukemia with t(8;21)(q22;q22). AB - OBJECTIVES: To assess the frequency of systemic mastocytosis (SM) in a large series of acute myeloid leukemia (AML) with t(8;21)(q22;q22). METHODS: We retrospectively characterized 40 bone marrow aspirate smears and biopsy specimens from patients with AML with t(8;21) for the presence of SM. Cases were assessed for mast cell morphology and immunohistochemistry, as well as KIT exon 8 and 17 mutational assessment by reverse transcription polymerase chain reaction. RESULTS: Four patients met criteria for SM, 1 met criteria for myelomastocytic leukemia, and 8 demonstrated the benign finding of mast cell hyperplasia. CONCLUSIONS: We recommend examining all cases of AML with t(8;21) for the presence of SM via morphology, immunophenotyping, and KIT mutational analysis studies. PMID- 24045551 TI - CD200 flow cytometric assessment and semiquantitative immunohistochemical staining distinguishes hairy cell leukemia from hairy cell leukemia-variant and other B-cell lymphoproliferative disorders. AB - OBJECTIVES: To evaluate CD200 expression in B-cell proliferative disorders. METHODS: We analyzed 180 recent specimens of B-cell neoplasms for CD200 expression by flow cytometric immunophenotypic analysis, which is better able to assess relative intensity of staining than immunohistochemical staining. RESULTS: We found that hairy cell leukemia exhibits a high level of staining for CD200 in comparison to other B-cell lymphoproliferative disorders, including hairy cell leukemia-variant (HCL-V), marginal zone lymphoma, and lymphoplasmacytic lymphoma. We confirmed this observation by semiquantitative immunohistochemical staining. CONCLUSIONS: Assessment of the CD200 expression level is helpful to distinguish HCL from HCL-V and other B-cell lymphoproliferative disorders and in the differential diagnosis of B-cell neoplasms in general. PMID- 24045552 TI - CD90 is a diagnostic marker to differentiate between malignant pleural mesothelioma and lung carcinoma with immunohistochemistry. AB - OBJECTIVES: To pathologically distinguish mesothelioma from lung carcinoma, particularly adenocarcinoma. METHODS: We conducted immunohistochemical analyses on clinical specimens, including 26 cases of mesothelioma, 28 cases of lung adenocarcinoma, and 33 cases of lung squamous cell carcinoma. RESULTS: We found that CD90 expression was useful in making a differential diagnosis between epithelioid mesothelioma and lung adenocarcinoma, whereas sarcomatoid mesothelioma and lung carcinoma specimens, irrespective of the histologic types, were negative in general. The sensitivity and specificity of CD90 expression in epithelioid mesothelioma and lung adenocarcinoma were comparable to those of well established markers used for the differential diagnosis. CONCLUSIONS: These data collectively indicate that CD90 is a novel diagnostic marker that contributes to a diagnosis of epithelioid mesothelioma. PMID- 24045553 TI - Analytical variability among methods for the measurement of 25-hydroxyvitamin D: still adding to the noise. AB - OBJECTIVES: To compare total 25-hydroxyvitamin D [25(OH) D] results measured by 3 direct immunoassays, including the previous version of the DiaSorin Liaison2 assay and the current versions of the Siemens Centaur2 and the Abbott Architect assays, with results measured in serum extracts by liquid chromatography/tandem mass spectrometry (LC/MS) and radioimmunoassay (RIA). METHODS: Our study sample consisted of 163 consecutive clinical specimens submitted to our laboratory for 25(OH)D testing. RESULTS: Regression and bias analyses of the data revealed that results measured by the 3 direct immunoassay methods had high degrees of random variability and bias relative to the results determined by LC/MS and RIA. The relative biases between results measured by the direct assays and the comparison methods exceeded a recommended criterion for the total allowable error of a 25(OH)D test in as many as 48% of our clinical specimens. Of the subjects in our study sample, 33, 37, 30, 45, and 71 were classified as vitamin D deficient based on results determined by LC/MS, RIA, Liaison2, Architect, and Centaur2, respectively. CONCLUSIONS: Intermethod variability in 25(OH)D assays continues to limit our progress toward the establishment of reference values for 25(OH)D in health and our efforts to gain a better understanding of the role of vitamin D insufficiency as a risk factor for disease. PMID- 24045554 TI - Distinguishing score 0 from score 1+ in HER2 immunohistochemistry-negative breast cancer: clinical and pathobiological relevance. AB - OBJECTIVES: To investigate the clinical and pathobiological significance of distinguishing score 0 and score 1+ within the group of immunohistochemistry (IHC)-negative invasive breast cancers. METHODS: We studied HER2 status using both IHC and fluorescence in situ hybridization (FISH) in 150 consecutive breast tumors submitted to our laboratory after a negative IHC result in local testing centers. RESULTS: We were able to discern a group of score 0 tumors that had a lower HER2 copy number than the group consisting of score 1+ tumors. In contrast with the group of score 1+ tumors, HER2 FISH was consistently negative for both copy number-based and ratio-based tumors without equivocal results. CONCLUSIONS: In a setting with stringent quality assurance, score 0 and score 1+ tumors emerge as distinct and clinically important subgroups within the HER2 IHC-negative population. PMID- 24045555 TI - Performance and reproducibility of gynecologic cytology interpretation using the FocalPoint system: results of the RODEO Study Team. AB - OBJECTIVES: To assess whether automated screening in the cytologic examination of Papanicolaou smear slides results in smaller margins of error than manual screening. METHODS: We compared cytotechnologists' performance and reproducibility of manual and automated screening of 10,165 consecutive cervical cytology slides examined at Barretos Cancer Hospital using the FocalPoint system. RESULTS: In total, 83% of atypical squamous cells of undetermined significance and greater were classified as quintiles 1 and 2; no high-grade squamous intraepithelial lesions and greater were observed in quintile 5. No statistically significant differences were found between manual and automated screening, using cervical biopsy specimens as the gold standard. CONCLUSIONS: FocalPoint safely screened high-grade lesions, which can be valuable for high-workload routines. PMID- 24045556 TI - Novel spot tests for detecting the presence of zinc sulfate in urine, a newly introduced urinary adulterant to invalidate drugs of abuse testing. AB - OBJECTIVES: To find a suitable method for detecting zinc sulfate in adulterated urine. METHODS: Two rapid spot tests to detect the presence of zinc sulfate in urine were developed. RESULTS: Addition of 3 to 4 drops of 1N sodium hydroxide solution to approximately 1 mL of urine containing zinc sulfate led to the formation of a white precipitate, which was soluble in excess sodium hydroxide. In the second spot test, addition of 3 to 4 drops of 1% sodium chromate solution to 1 mL of urine containing zinc sulfate followed by the addition of 4 to 5 drops of 1N sodium hydroxide led to formation of a yellow precipitate (zinc chromate). Detection limit of these visual spot tests was 10 mg/mL of zinc sulfate in urine. Twenty drug-free urine specimens and urine containing high amounts of sugar or reducing substances were tested with no false-positive spot test results observed. However, if lead is present in high amounts in urine, it may cause false-positive spot test results. When aliquots of urine controls for drugs of abuse testing were supplemented with different amounts of zinc sulfate, false negative drug test results were observed except for amphetamine. Zinc sulfate also falsely reduced measured urine alcohol level in urine. CONCLUSIONS: Zinc sulfate can invalidate urine drug and alcohol testing but can be detected using the novel spot tests developed. PMID- 24045557 TI - Software-automated counting of Ki-67 proliferation index correlates with pathologic grade and disease progression of follicular lymphomas. AB - OBJECTIVES: To examine the accuracy of software-assisted measurement of the Ki-67 proliferation index (PI) and its correlation with the grade and clinical progression of follicular lymphoma (FL). METHODS: High-power field equivalents were extracted from H&E- and Ki-67-immunostained slides of FL, and a nuclear quantitation algorithm was used to calculate a PI. Representative fields were manually counted for validation with close agreement. RESULTS: The PI was significantly higher in World Health Organization grade 3 FL than grade 1 to 2 FL. Disease progression, as defined by subsequent treatment with radiation or cytotoxic chemotherapy, was also significantly associated with elevated PI but not pathologic grade. CONCLUSIONS: These data show that software-automated quantitation of Ki-67 can provide both a useful adjunct to pathologic grade in FL and improved prognostic information for patients. PMID- 24045558 TI - HER2 testing of multifocal invasive breast carcinoma: how many blocks are enough? AB - OBJECTIVES: To determine the diagnostic yield of testing multiple blocks for HER2 in cases of multifocal breast carcinoma. METHODS: We identified 246 consecutive cases of multifocal invasive breast carcinoma in which HER2 was tested on more than 1 tumor focus. We performed an audit of all cases with respect to tumor size, grade, and histologic type. RESULTS: HER2 status was concordant between multiple foci in 230 (93.5%) of 246 cases, with the largest focus having the most positive HER2 result in 242 (98.4%) of 246 cases. We did not find a single case in which a smaller focus demonstrated a more positive HER2 status unless this focus was either higher grade or different histologically. CONCLUSIONS: Our findings support the evaluation of HER2 on the largest focus, with additional testing on smaller foci having a different histologic type or higher grade. PMID- 24045560 TI - No benefit to intraoperative assessment of breast margins? PMID- 24045564 TI - 2013 "heads-up": Medicare news you should use. PMID- 24045565 TI - Urinary bladder matrix for the treatment of recalcitrant nonhealing radiation wounds. AB - Chronic wounds in previously radiated tissue are challenging to treat. In this article, the authors describe 3 such wounds that failed to heal despite multiple treatments with traditional wound healing methods. Treatment with porcine urinary bladder matrix, an extracellular matrix material, was initiated to facilitate epithelialization and promote wound healing. MatriStem powder (ACell, Inc, Columbia, Maryland), MatriStem (ACell, Inc) sheet, and DuoDerm (ConvaTec, Skillman, New Jersey) were applied biweekly and resulted in complete wound closure within 3 weeks of initial application for all 3 cases. All wounds remained closed 9 months following treatment, suggesting a role for urinary bladder matrix in the management of chronic wounds in the setting of irradiated tissue. PMID- 24045566 TI - International Skin Tear Advisory Panel: a tool kit to aid in the prevention, assessment, and treatment of skin tears using a Simplified Classification System (c). AB - PURPOSE: To enhance the learner's competence with knowledge regarding utilization of a tool kit to aid in the prevention, assessment, and treatment of skin tears. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to:1. Demonstrate knowledge of skin tear prevention and classification as presented in the International Skin Tear Advisory Panel's tool kit.2. Apply information from the skin tear tool kit to patient care scenarios. ABSTRACT: The International Skin Tear Advisory Panel has created a tool kit for the prevention, identification, and treatment of skin tears. The tool kit is based on extensive literature reviews, international input from healthcare professionals, and on expert opinion. It has undergone a modified Delphi process. PMID- 24045568 TI - Processes + workflows drive documentation compliance. PMID- 24045569 TI - The effect of posterior hypothalamus region deep brain stimulation on sleep. AB - BACKGROUND: Early observations by von Economo showed that the posterior part of the hypothalamus (PH) plays a prominent role in sleep-wake regulation. The PH is a candidate area involved in cluster headaches and other trigeminal autonomic cephalalgias (TACs) and is targeted for deep brain stimulation (DBS). CASE REPORTS: Sleep studies in two men, 69- and 39-years-old, with pre-existing sleep disorders, before and after PH-DBS for pharamacoresistant cluster headache and SUNCT syndrome showed that PH-DBS led to a dramatic alteration of the patients' sleep patterns. This coincided with an improvement of the predominantly diurnal TACs, suggesting a PH-DBS-induced change in sleep patterns. Hypnograms after DBS demonstrated disrupted sleep and a prolonged period of wakefulness after midnight in both patients, which was reproduced the second night. CONCLUSIONS: PH-DBS, a promising treatment for severe refractory TACs, affects sleep quality and pre existing sleep disorders. This needs to be considered when treating patients with PH-DBS. PMID- 24045570 TI - Central scotoma and 'muddled thinking' as migraine aura. PMID- 24045571 TI - Sturge-Weber syndrome with late onset hemiplegic migraine-like attacks and progressive unilateral cerebral atrophy. AB - BACKGROUND: Sturge-Weber syndrome (SWS) is an uncommon etiology of hemiplegic migraine-like (HM-like) attacks, associated with epilepsy and mental retardation. CASE: We report the case of a 40-year-old woman with SWS who has been suffering from HM-like episodes since she was 24, with no history of seizure or mental retardation. Susceptibility weighted imaging (SWI)-MRI and CT scans have shown bilateral calcifications of the choroidal plexuses, a developmental venous anomaly with dilated transmedullary veins and a left parieto-occipital leptomeningeal angioma. (18)F-Fluorodeoxyglucose (FDG)-PET/CT revealed a diffuse left-hemisphere hypometabolism. The comparison between the MRI performed at the age of 24 and the one performed at the age of 40 highlighted a progressive unilateral fronto-temporo-parietal atrophy. Surprisingly, even now, cognitive functions of this patient are relatively preserved. Lamotrigine permitted an improvement of HM-like attacks. DISCUSSION: Explanations for this minimally symptomatic form of SWS may be the absence of seizure, the importance of her deep venous drainage, the absence of cortical calcification and white matter impairment in the affected hemisphere, and, paradoxically, the severely asymmetric cortical metabolism. Furthermore, this case reinforces the hypothesis that alteration of cerebral hemodynamics could precipitate the cortical spreading depression giving rise to migraine with aura. CONCLUSION: We propose to consider SWS as a cause of apparently isolated hemiplegic migraine and lamotrigine as a preventive medication in HM-like attacks. PMID- 24045572 TI - Comment on "Central scotoma and 'muddled thinking' as migraine aura" by Daroff. PMID- 24045573 TI - Chronic post-traumatic headache after mild head injury: a descriptive study. AB - BACKGROUND: The aetiology behind chronic post-traumatic headache (CPTH) after mild head injury is unclear and management is complicated. In order to optimize treatment strategies we aimed to characterize a CPTH population. METHODS: Ninety patients with CPTH and 45 patients with chronic primary headaches were enrolled from the Danish Headache Center. All patients were interviewed about demographic and headache data. They completed the Harvard Trauma Questionnaire (HTQ), Rivermead Post Concussion Symptoms Questionnaire, SF-36 and a headache diary. RESULTS: The CPTH group experienced more cognitive ( P < 0.001) and somatic symptoms ( P = 0.048) and rated their self-perceived health as more affected in terms of physical function ( P = 0.036), physical role function ( P = 0.012) and social function ( P = 0.012) than the control group. Surprisingly, 31% of the CPTH group had a score equal to or above the cut-off score for having post traumatic stress disorder (PTSD) according to the HTQ. In terms of demographics and headache, the groups were comparable except the CPTH group were more often without affiliation to the labour market ( P < 0.001). CONCLUSIONS: The loss of work capacity and high levels of disability for the CPTH patients suggests directions for further research into what important factors are embedded in the patients' PTSD symptoms and might explain their prolonged illness. PMID- 24045574 TI - Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury. AB - Mononuclear phagocyte recognition of apoptotic cells triggering suppressive cytokine signaling is a key event in inflammation resolution from injury. Mice deficient in thrombospondin (TSP)-1 (thbs1-/-), an extracellular matrix glycoprotein that bridges cell-cell interactions, are prone to lipopolysaccharide induced lung injury and show defective macrophage interleukin (IL)-10 production during the resolution phase of inflammation. Reconstitution of IL-10 rescues thbs1-/- mice from persistent neutrophilic lung inflammation and injury and thbs1 /- alveolar macrophages show defective IL-10 production following intratracheal instillation of apoptotic neutrophils despite intact efferocytosis. Following co culture with apoptotic neutrophils, thbs1-/- macrophages show a selective defect in IL-10 production, whereas prostaglandin E2 and transforming growth factor beta 1 responses remain intact. Full macrophage IL-10 responses require the engagement of TSP-1 structural repeat 2 domain and the macrophage scavenger receptor CD36 LIMP-II Emp sequence homology (CLESH) domain in vitro. Although TSP-1 is not essential for macrophage engulfment of apoptotic neutrophils in vivo, TSP-1 aids in the curtailment of inflammatory responses during the resolution phase of injury in the lungs by providing a means by which apoptotic cells are recognized and trigger optimal IL-10 production by macrophages. PMID- 24045575 TI - Limited expression of APRIL and its receptors prior to intestinal IgA plasma cell development during human infancy. AB - The absence of immunoglobulin A (IgA) in the intestinal tract renders young infants highly susceptible to enteric infections. However, mediators of initial IgA induction in this population are undefined. We determined the temporal acquisition of plasma cells by isotype and expression of T cell-independent (TI) and -dependent (TD) IgA class switch factors in the human intestinal tract during early infancy. We found that IgA plasma cells were largely absent in the infant intestine until after 1 month of age, approaching adult densities later in infancy than both IgM and IgG. The restricted development of IgA plasma cells in the first month was accompanied by reduced expression of the TI factor a proliferation-inducing ligand (APRIL) and its receptors TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) and B cell maturation antigen (BCMA) within isolated lymphoid follicles (ILFs). Moreover, both APRIL and BCMA expression strongly correlated with increasing IgA plasma cell densities over time. Conversely, TD mediators (CD40 ligand (CD40L) and CD40) were expressed within ILFs before 1 month and were not associated with IgA plasma cell generation. In addition, preterm infants had lower densities of IgA plasma cells and reduced APRIL expression compared with full-term infants. Thus, blunted TI responses may contribute to the delayed induction of intestinal IgA during early human infancy. PMID- 24045576 TI - Tumor necrosis factor-related apoptosis-inducing ligand translates neonatal respiratory infection into chronic lung disease. AB - Respiratory infections in early life can lead to chronic respiratory disease. Chlamydia infections are common causes of respiratory disease, particularly pneumonia in neonates, and are linked to permanent reductions in pulmonary function and the induction of asthma. However, the immune responses that protect against early-life infection and the mechanisms that lead to chronic lung disease are incompletely understood. Here we identify novel roles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in promoting Chlamydia respiratory infection-induced pathology in early life, and subsequent chronic lung disease. By infecting TRAIL-deficient neonatal mice and using neutralizing antibodies against this factor and its receptors in wild-type mice, we demonstrate that TRAIL is critical in promoting infection-induced histopathology, inflammation, and mucus hypersecretion, as well as subsequent alveolar enlargement and impaired lung function. This suggests that therapeutic agents that target TRAIL or its receptors may be effective treatments for early-life respiratory infections and associated chronic lung disease. PMID- 24045578 TI - An ultrasensitive aptameric sensor for proteins based on hyperbranched rolling circle amplification. AB - A novel fluorescent aptameric sensor for thrombin has been developed by combination of the high amplification efficiency of HRCA and the specific function of aptameric recognition. PMID- 24045577 TI - Lyn activity protects mice from DSS colitis and regulates the production of IL-22 from innate lymphoid cells. AB - Intestinal homeostasis requires a complex balance of interactions between diverse resident microbial communities, the intestinal epithelium, and the underlying immune system. We show that the Lyn tyrosine kinase, a critical regulator of immune cell function and pattern-recognition receptor (PRR) responses, has a key role in controlling gastrointestinal inflammation. Lyn-/- mice were highly susceptible to dextran sulfate sodium (DSS)-induced colitis, whereas Lyn gain-of function (Lyn(up)) mice exhibited attenuated colitis during acute and chronic models of disease. Lyn(up) mice were hypersensitive to lipopolysaccharide (LPS), driving enhanced production of cytokines and factors associated with intestinal barrier function, including interleukin (IL)-22. Oral administration of LPS was sufficient to protect antibiotic-treated Lyn(up) but not wild-type mice from DSS, highlighting how Lyn-dependent changes in the nature/magnitude of PRR responses can impact intestinal health. Furthermore, protection from DSS-induced colitis and increased IL-22 production in response to LPS did not depend on the adaptive immune system, with increased innate lymphoid cell-derived IL-22 correlating with Lyn activity in dendritic cells. These data reveal a key role for Lyn in the regulation of innate immune responses and control of intestinal inflammation. PMID- 24045580 TI - Cell-based fuzzy metrics enhance high-content screening (HCS) assay robustness. AB - High-content screening (HCS) allows the exploration of complex cellular phenotypes by automated microscopy and is increasingly being adopted for small interfering RNA genomic screening and phenotypic drug discovery. We introduce a series of cell-based evaluation metrics that have been implemented and validated in a mono-parametric HCS for regulators of the membrane trafficking protein caveolin 1 (CAV1) and have also proved useful for the development of a multiparametric phenotypic HCS for regulators of cytoskeletal reorganization. Imaging metrics evaluate imaging quality such as staining and focus, whereas cell biology metrics are fuzzy logic-based evaluators describing complex biological parameters such as sparseness, confluency, and spreading. The evaluation metrics were implemented in a data-mining pipeline, which first filters out cells that do not pass a quality criterion based on imaging metrics and then uses cell biology metrics to stratify cell samples to allow further analysis of homogeneous cell populations. Use of these metrics significantly improved the robustness of the monoparametric assay tested, as revealed by an increase in Z' factor, Kolmogorov Smirnov distance, and strict standard mean difference. Cell biology evaluation metrics were also implemented in a novel supervised learning classification method that combines them with phenotypic features in a statistical model that exceeded conventional classification methods, thus improving multiparametric phenotypic assay sensitivity. PMID- 24045579 TI - Holographic display system for restoration of sight to the blind. AB - OBJECTIVE: We present a holographic near-the-eye display system enabling optical approaches for sight restoration to the blind, such as photovoltaic retinal prosthesis, optogenetic and other photoactivation techniques. We compare it with conventional liquid crystal displays (LCD) or digital light processing (DLP) based displays in terms of image quality, field of view, optical efficiency and safety. APPROACH: We detail the optical configuration of the holographic display system and its characterization using a phase-only spatial light modulator. MAIN RESULTS: We describe approaches to controlling the zero diffraction order and speckle related issues in holographic display systems and assess the image quality of such systems. We show that holographic techniques offer significant advantages in terms of peak irradiance and power efficiency, and enable designs that are inherently safer than LCD or DLP-based systems. We demonstrate the performance of our holographic display system in the assessment of cortical response to alternating gratings projected onto the retinas of rats. SIGNIFICANCE: We address the issues associated with the design of high brightness, near-the-eye display systems and propose solutions to the efficiency and safety challenges with an optical design which could be miniaturized and mounted onto goggles. PMID- 24045581 TI - High-content screening of natural products reveals novel nuclear export inhibitors. AB - Natural products are considered an extremely valuable source for the discovery of new drugs against diverse pathologies. As yet, we have only explored a fraction of the diversity of bioactive compounds, and opportunities for discovering new natural products leading to new drugs are huge. In the present study, U2nesRELOC, a previously established cell-based imaging assay, was employed to screen a collection of extracts of microbial origin for nuclear export inhibition activity. The fluorescent signal of untreated U2nesRELOC cells localizes predominantly to the cytoplasm. Upon treatment with the nuclear export inhibitor leptomycin B, the fluorescent-tagged reporter proteins appear as speckles in the nucleus. A proprietary collection of extracts from fungi, actinomycetes, and unicellular bacteria that covers an uncommonly broad chemical space was used to interrogate this nuclear export assay system. A two-step image-based analysis allowed us to identify 12 extracts with biological activities that are not associated with previously known active metabolites. The fractionation and structural elucidation of active compounds revealed several chemical structures with nuclear export inhibition activity. Here we show that substrates of the nuclear export receptor CRM1, such as Rev, FOXO3a and NF-kappaB, accumulate in the nucleus in the presence of the fungal metabolite MDN-0105 with an IC50 value of 3.4 uM. Many important processes in tumor formation and progression, as well as in many viral infections, critically depend on the nucleocytoplasmic trafficking of proteins and RNA molecules. Therefore, the disruption of nuclear export is emerging as a novel therapeutic approach with enormous clinical potential. Our work highlights the potential of applying high-throughput phenotypic imaging on natural product extracts to identify novel nuclear export inhibitors. PMID- 24045582 TI - Comparison of methods for image-based profiling of cellular morphological responses to small-molecule treatment. AB - Quantitative microscopy has proven a versatile and powerful phenotypic screening technique. Recently, image-based profiling has shown promise as a means for broadly characterizing molecules' effects on cells in several drug-discovery applications, including target-agnostic screening and predicting a compound's mechanism of action (MOA). Several profiling methods have been proposed, but little is known about their comparative performance, impeding the wider adoption and further development of image-based profiling. We compared these methods by applying them to a widely applicable assay of cultured cells and measuring the ability of each method to predict the MOA of a compendium of drugs. A very simple method that is based on population means performed as well as methods designed to take advantage of the measurements of individual cells. This is surprising because many treatments induced a heterogeneous phenotypic response across the cell population in each sample. Another simple method, which performs factor analysis on the cellular measurements before averaging them, provided substantial improvement and was able to predict MOA correctly for 94% of the treatments in our ground-truth set. To facilitate the ready application and future development of image-based phenotypic profiling methods, we provide our complete ground-truth and test data sets, as well as open-source implementations of the various methods in a common software framework. PMID- 24045583 TI - Benchmarking of multivariate similarity measures for high-content screening fingerprints in phenotypic drug discovery. AB - High-content screening (HCS) is a powerful tool for drug discovery being capable of measuring cellular responses to chemical disturbance in a high-throughput manner. HCS provides an image-based readout of cellular phenotypes, including features such as shape, intensity, or texture in a highly multiplexed and quantitative manner. The corresponding feature vectors can be used to characterize phenotypes and are thus defined as HCS fingerprints. Systematic analyses of HCS fingerprints allow for objective computational comparisons of cellular responses. Such comparisons therefore facilitate the detection of different compounds with different phenotypic outcomes from high-throughput HCS campaigns. Feature selection methods and similarity measures, as a basis for phenotype identification and clustering, are critical for the quality of such computational analyses. We systematically evaluated 16 different similarity measures in combination with linear and nonlinear feature selection methods for their potential to capture biologically relevant image features. Nonlinear correlation-based similarity measures such as Kendall's tau and Spearman's rho perform well in most evaluation scenarios, outperforming other frequently used metrics (such as the Euclidian distance). We also present four novel modifications of the connectivity map similarity that surpass the original version, in our experiments. This study provides a basis for generic phenotypic analysis in future HCS campaigns. PMID- 24045584 TI - Characterization of Pt-doped SnO2 catalyst for a high-performance micro gas sensor. AB - The atomic scale structure and its dependence on Pt concentration of a Pt-doped SnO2 (Pt-SnO2) thin film produced by a sputter-deposition method was investigated, which showed high-performance as a methane gas sensor. Extended X ray absorption fine structure (EXAFS) and X-ray diffraction (XRD) analyses showed that Pt-SnO2 has a rutile structure similar to SnO2 crystals at less than 10 at% Pt where the Pt ion was located at the Sn position in the rutile structure. There was no evidence that Pt metal clusters were formed in the Pt-SnO2 films. The Pt SnO2 structure became amorphous at greater than 11 at% Pt. We found a good correlation between the methane activity and local structure of Pt. PMID- 24045585 TI - An integrated quantitative proteomics and systems biology approach to explore synaptic protein profile changes during morphine exposure. AB - Morphine is a classic analgesic for the treatment of chronic pain. However, its repeated use is known to produce tolerance, physical dependence, and addiction; these properties limit its long-term therapeutic use and this has led to a quest for therapeutics without these unwanted side effects. Understanding the molecular changes in response to long-term use of morphine is likely to aid in the development of novel therapeutics for the treatment of pain. Studies examining the effects of chronic morphine administration have reported alterations in gene expression, synapse morphology, and synaptic transmission implying changes in synaptic protein profile. To fully understand the changes in protein profiles, proteomic techniques have been used. Studies using two-dimensional gel electrophoresis of various brain regions combined with mass spectrometry have found alterations in the levels of a number of proteins. However, neither the changes in brain regions relevant to morphine effects nor changes in the abundance of synaptic proteins have been clearly delineated. Recent studies employing subcellular fractionation to isolate the striatal synapse, combined with quantitative proteomics and graph theory-inspired network analyses, have begun to quantify morphine-regulated changes in synaptic proteins and facilitate the generation of networks that could serve as targets for the development of novel therapeutics for the treatment of chronic pain. Thus, an integrated quantitative proteomics and systems biology approach can be useful to identify novel targets for the treatment of pain and other disorders of the brain. PMID- 24045587 TI - Safety and efficacy of instrumented convex growth arrest in treatment of congenital scoliosis. AB - BACKGROUND: Anterior and posterior convex hemiepiphysiodesis is a widely used surgical alternative in the treatment of congenital scoliosis. This procedure has the disadvantage of the need for both anterior and posterior approaches. Furthermore, outcomes may be unpredictable. Posterior convex growth arrest (CGA) with pedicle screws at each segment on the convex side may obviate the need for anterior surgery and provides more predictable outcomes. This study retrospectively evaluates the safety and efficacy of instrumented posterior CGA in congenital scoliosis. METHODS: Patients who had posterior CGA with convex pedicle screw instrumentation for congenital scoliosis were evaluated retrospectively. Thirteen patients (6 male, 7 female) were included in the study. Preoperative, early postoperative, and last follow-up standing posteroanterior and lateral x-rays were evaluated. Cobb angles were recorded for the instrumented segment (main curve). Global thoracic kyphosis was measured between T2 and T12 on sagittal plane. These values were compared preoperatively, postoperatively, and at last follow-up. The T1-S1 vertical height and the height between the concave side pedicles of the upper and lower end vertebra of the main curve was also determined and recorded as the concave height. RESULTS: The average follow-up was 56.1+/-10 months (range, 36 to 74 mo) and the average age of the patients at the time of operation was 64.5+/-30.1 months (range, 15 to 108 mo). All patients were Risser zero at the time of surgery. The average curve magnitude was 49+/-10.9 degrees (range, 34 to 68 degrees) preoperatively, 38.3+/-9.7 degrees (range, 28 to 58 degrees) early postoperatively, and 33.5+/-12.4 degrees (16 to 52 degrees) at last follow-up. There was a significant difference between the preoperative and early postoperative main curve Cobb angle measurements (P=0.001). The average concave height was 94.2+/-20.2 mm in the early postoperative period and 104.7+/ 21.7 mm at last follow-up (P=0.003). The average T1-S1 height was 292.1+/-67.1 mm in the early postoperative period and 363.9+/-94.5 mm at last follow-up (P=0.005). There was at least >=5 degrees improvement in 9 of the 12 patients in the follow-up period after the index procedure. In 3 patients, the curve did not change and the correction was maintained. Curve progression was observed in 1 patient due to a technical error. There were no wound infections or instrumentation failures during follow-up. CONCLUSIONS: Instrumented CGA can safely be used in long sweeping curves of immature spines. Using this technique; thoracotomy, anterior procedure, and 2-stage surgery can be avoided. Moreover, it guarantees some degree of correction in all patients because of the instrumentation effect, eliminating the unpredictable nature of classic CGA. LEVEL OF EVIDENCE: Therapeutic level IV study. PMID- 24045586 TI - Meclizine enhancement of sensorimotor gating in healthy male subjects with high startle responses and low prepulse inhibition. AB - Histamine H1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H1 effects on sensorimotor gating to human studies. The effects of the histamine H1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli. PMID- 24045588 TI - Central polydactyly of the foot: surgical management with plantar and dorsal advancement flaps. AB - BACKGROUND: Central polydactyly is the least common form of foot polydactyly, and the intercalary location of the duplicated ray makes the surgical exposure, excision, and closure more complex. For these reasons there is little consensus concerning the optimal technique for surgical management. METHODS: A retrospective case series of 22 patients with 27 feet with central polydactyly, treated surgically by the dorsal and plantar advancement flap technique, was performed. Change in width of the forefoot was measured from radiographs by the metatarsal gap ratio. Functional outcomes were assessed by the Foot and Ankle Ability Measure. RESULTS: Signficant narrowing of the forefoot, as measured radiographically by the metatarsal gap ratio, was achieved after surgery (P<0.0001). This radiographic narrowing was maintained with growth after a mean follow-up of 8 years (P=0.0001). In 7 of the unilateral cases, the mean forefoot radiographic width of the affected side, after surgical resection and reconstruction of the central polydactyly, was 2% greater than the contralateral, uninvolved side. Persistent clinical widening of the forefoot after surgery was reported in the majority (82%) of cases. The Foot and Ankle Ability Measure results showed near-normal functional outcomes in itemized activities of daily living, itemized sports, and overall function categories. The few reports of less than normal foot function were related to shoe wear issues and incisional scarring that was painful or cosmetically unappealing. CONCLUSIONS: The radiographic and functional outcomes after surgical management of central polydactyly with the dorsal and plantar advancement flap technique are excellent. The technique successfully narrows the forefoot on radiographs, and this narrowing is maintained with growth over time. However, families should be advised that persistent perceived widening of the forefoot relative to normal is common, despite successful radiographic narrowing after surgery. LEVEL OF EVIDENCE: IV. PMID- 24045589 TI - Is there still a place for cast wedging in pediatric forearm fractures? AB - BACKGROUND: Forearm fractures are common skeletal injuries in childhood and can usually be treated nonoperatively with closed reduction and casting. Trends toward increasing operative treatment of these fractures have emerged. We aim to demonstrate the safety and efficacy of cast wedging for treatment of pediatric forearm fractures. METHODS: We performed a prospective chart review of patients with forearm fractures, including distal radius (DR) fractures, treated with cast wedging at a single large pediatric hospital from June 2011 to September 2012. Inclusion criteria specified open distal radial physis, closed injury, loss of acceptable reduction, and availability of clinical and radiographic data from injury to cast removal. Exclusion criteria included pathologic fractures, neurovascular injury, fracture dislocations, open fractures, and closed DR physis. Reductions were performed and patients followed according to standard protocol at our institution, including placement into long-arm casts, initial follow-up visit within 5 to 10 days postinjury, and weekly visits for 2 weeks thereafter. If alignment were deemed unacceptable within 3 weeks of injury, cast wedging was utilized. Radiographic measurements of alignment included both radius and ulna on the injury film, postreduction, prewedge, postwedge, and final films. Radiographic technique was standardized, with repeatability testing demonstrating a precision of +/-2 degrees. RESULTS: Over 15 months, our hospital treated 2124 forearm or DR fractures with closed reduction and casting. There were 60 fractures treated either with percutaneous fixation (36) or open treatment (24). A total of 79 forearm or DR fractures were treated with cast wedging secondary to loss of reduction, of which 70 patients had complete clinical and radiographic data. Average age was 8.4 years (range, 3 to 14 y), with 25 females and 45 males. Significant improvement in angulation for both-bone forearm fracture from prewedge to final films was seen in 69 children, with no major complications. One patient failed wedging and required surgical reduction and fixation. CONCLUSIONS: Cast wedging is a simple, safe, noninvasive, and effective method for treatment of excessive angulation in pediatric forearm fractures. LEVEL OF EVIDENCE: Level IV. PMID- 24045590 TI - Effects of clinical isolates of Streptococcus pneumoniae on THP-1 human monocytic cells. AB - Twenty-three clinical Streptococcus pneumoniae (SP) strains were isolated from blood and sputum specimens from the Second Affiliated Hospital of Wenzhou Medical College in 2009. These strains and the ATCC 49619 standard strain were cultured and suspended in normal saline (at a turbidity of 1.0 McFarland). The production of interleukin (IL)-8, intracellular adhesion molecule-1 (ICAM-1) and IL-10 in THP-1 cells following stimulation with the SP suspension was analyzed by an enzyme-linked immunosorbent assay. The concentrations of IL-8, ICAM-1 and IL-10 from the THP-1 monocytes were greater than those of the blank control following stimulation with the SP suspension. No significant difference was identified in the levels of IL-8, ICAM-1 and IL-10 secretion between THP-1 monocytes stimulated by blood-borne SP (bb-SP) and sputum-borne SP (sb-SP). PMID- 24045591 TI - Prophylactic erythromycin in acute upper gastrointestinal bleeding: moving forward in improving endoscopic efficacy. PMID- 24045593 TI - Administration of erythromycin before endoscopy in upper gastrointestinal bleeding: a meta-analysis of randomized controlled trials. AB - BACKGROUND/AIM: Erythromycin infusion before endoscopy in upper gastrointestinal bleeding (UGIB) has been hypothesized to aid in visualization and reduce the need for second-look endoscopy; however, the results have been controversial. To evaluate further, we performed a meta-analysis comparing the efficacy of erythromycin infusion before endoscopy in acute UGIB. METHODS: Multiple databases were searched (March 2013). Only randomized controlled trials were included in the analysis. A meta-analysis for the effect of erythromycin or no erythromycin before endoscopy in UGIB were analyzed by calculating pooled estimates of primary (visualization of gastric mucosa and need for second endoscopy) and secondary (units of blood transfused, length of hospital stay, duration of the procedure) outcomes. Statistical analysis was performed using RevMan 5.1 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration). RESULTS: Six studies (N = 558) met the inclusion criteria. Erythromycin infusion before endoscopy in UGIB demonstrated a statistically significant improvement in visualization of the gastric mucosa [odds ratio (OR) 3.43; 95% confidence interval (CI): 1.81 to 6.50, P < 0.01] compared with no erythromycin. In addition, erythromycin infusion before endoscopy resulted in a statistically significant decrease in the need for a second endoscopy (OR 0.47; 95% CI: 0.26 to 0.83, P = 0.01), units of blood transfused (WMD - 0.41; 95% CI: -0.82 to -0.01, P = 0.04), and the duration of hospital stay (WMD - 1.51; 95% CI: -2.45 to -0.56, P < 0.01). CONCLUSIONS: Erythromycin infusion before endoscopy in patients with UGIB significantly improves visualization of gastric mucosa while decreasing the need for a second endoscopy, units of blood transfused, and duration of hospital stay. PMID- 24045592 TI - State-of-the-art management of acute bleeding peptic ulcer disease. AB - The management of patients with non variceal upper gastrointestinal bleeding has evolved, as have its causes and prognosis, over the past 20 years. The addition of high-quality data coupled to the publication of authoritative national and international guidelines have helped define current-day standards of care. This review highlights the relevant clinical evidence and consensus recommendations that will hopefully result in promoting the effective dissemination and knowledge translation of important information in the management of patients afflicted with this common entity. PMID- 24045594 TI - Comparison of the virulence markers of Helicobacter pylori and their associated diseases in patients from Pakistan and Afghanistan. AB - BACKGROUND/AIM: Helicobacter pylori is a Gram-negative bacteria, which is associated with development of gastroduodenal diseases. The prevalence of H. pylori and the virulence markers cytotoxin-associated gene A and E (cagA, cagE) and vacuolating-associated cytotoxin gene (vacA) alleles varies in different parts of the world. H. pylori virulence markers cagA, cagE, and vacA alleles in local and Afghan nationals with H. pylori-associated gastroduodenal diseases were studied. PATIENTS AND METHODS: Two hundred and ten patients with upper gastrointestinal symptoms and positive for H. pylori by the urease test and histology were included. One hundred and nineteen were local nationals and 91 were Afghans. The cagA, cagE, and vacA allelic status was determined by polymerase chain reaction. RESULTS: The nonulcer dyspepsia (NUD) was common in the Afghan patients (P = 0.025). In Afghan H. pylori strains, cagA was positive in 14 (82%) with gastric carcinoma (GC) compared with 29 (45%) with NUD (P = 0.006), whereas cagE was positive in 11 (65%) with GC and 4 (67%) with duodenal ulcer (DU) compared with 12 (18%) with NUD (P < 0.001 and 0.021, respectively). The vacA s1a/b1was positive in 10 (59%) of GC compared with 20 (31%) in NUD (P = 0.033). In Pakistani strains, cagE was positive in 12 (60%) with GC, 7 (58%) with GU, 12 (60%) with DU compared with 11 (16%) with NUD (P < 0.001, 0.004, and < 0.001, respectively). In Pakistani strains, cagA/s1a/m1 was 39 (33%) compared with Afghans in 17 (19%) (P = 0.022). Moderate to severe mucosal inflammation was present in 51 (43%) Pakistani patients compared with 26 (28%) (P = 0.033) in Afghans. It was also associated with grade 1 lymphoid aggregate development in Pakistani patients 67 (56%) compared with 36 (40%) (P = 0.016) in Afghans. CONCLUSION: Distribution of H. pylori virulence marker cagE with DU was similar in Afghan and Pakistan H. pylori strains. Chronic active inflammation was significantly associated with Pakistani H. pylori strains. PMID- 24045595 TI - Appropriateness and diagnostic yield of upper gastrointestinal endoscopy in an open-access endoscopy system. AB - BACKGROUND/AIM: Open access endoscopy (OAE) decreases the waiting time for patients and clinical burden to gastroenterologist; however, the appropriateness of referrals for endoscopy and thus the diagnostic yield of these endoscopies has become an important issue. The aim of this study was to determine the appropriateness of upper gastrointestinal (GI) endoscopy requests in an OAE system. PATIENTS AND METHODS: A retrospective chart review of all consecutive patients who underwent an upper gastroscopy in the year 2008 was performed and was defined as appropriate or inappropriate according to the American Society for Gastrointestinal Endoscopy (ASGE) guidelines. Endoscopic findings were recorded and classified as positive or negative. Referrals were categorized as being from a gastroenterologist, internist, surgeon, primary care physicians or others, and on an inpatient or out-patient basis. RESULTS: A total of 505 consecutive patients were included. The mean age was 45.3 (standard deviation 18.1), 259 (51%) of them were males. 31% of the referrals were thought to be inappropriate. Referrals from primary care physicians were inappropriate in 47% of patients while only 19.5% of gastroenterologists referrals were considered inappropriate. Nearly, 37.8% of the out-patient referrals were inappropriate compared to only 7.8% for inpatients. Abnormal findings were found in 78.5% and 78% of patients referred by gastroenterologists and surgeons respectively while in those referred by primary care physicians it was (49.7%). Inpatients referred for endoscopy had abnormal findings in (81.7%) while in out-patients it was (66.6%). The most common appropriate indications in order of frequency were "upper abdominal distress that persisted despite an appropriate trial of therapy "(78.9%),''persistent vomiting of unknown cause "(19.2%), upper GI bleeding or unexplained iron deficiency anemia (7.6%). The sensitivity and specificity of the ASGE guidelines in our study population was 70.3% and 35% respectively. CONCLUSION: A large proportion of patients referred for endoscopy through our open-access endoscopy unit are considered inappropriate, with significant differences among specialties. These results suggest that if proper education of practitioners was implemented, a better utilization would be expected. PMID- 24045597 TI - Factors associated with development of complications after endoscopic foreign body removal. AB - BACKGROUND/AIMS: We analyzed the clinical characteristics of patients who underwent endoscopic foreign body removal and the risk factors of complications. PATIENTS AND METHODS: The medical records of 415 patients treated from January 2000 to August 2011 for suspected foreign bodies were retrospectively reviewed. Patient characteristics, endoscopic findings, clinical outcomes, and risk factors of complications were analyzed. RESULTS: Foreign bodies were detected endoscopically in 315 patients. Fish bone fragment (36.9%) and coins (15.3%) were the most common type of foreign bodies in adults and children, respectively. Complications associated with endoscopic procedure occurred in 26 patients (8.3%); 20 of the patients were treated conservatively and the other six patients underwent surgical treatment. Perforation (14%) was the most common complication. By univariate and multivariate analysis, the risk factors associated with complication after endoscopic foreign body removal were long duration from ingestion to endoscopy ( P = 0.009) and existence of initial mucosal injury ( P = 0.018). CONCLUSIONS: Most foreign bodies were successfully removed by endoscopy without complication, but long duration from ingestion to endoscopy and mucosal injury were risk factors of complications of endoscopic foreign body removal. Patients with these risk factors could require more careful treatment. PMID- 24045596 TI - Increased duration of dual pegylated interferon and ribavirin therapy for genotype 1 hepatitis C post-liver transplantation increases sustained virologic response: a retrospective review. AB - BACKGROUND/AIM: In patients with advanced post-transplant hepatitis C virus (HCV) recurrence, antiviral treatment (AVT) with interferon and ribavirin is indicated to prevent graft failure. The aim of this study was to determine and report Canadian data with respect to the safety, efficacy, and spontaneous virologic response (SVR) predictors of AVT among transplanted patients with HCV recurrence. PATIENTS AND METHODS: A retrospective chart review was performed on patients transplanted in London, Ontario and Edmonton, Alberta from 2002 to 2012 who were treated for HCV. Demographic, medical, and treatment information was collected and analyzed. RESULTS: A total of 85 patients with HCV received pegylated interferon with ribavirin post-liver transplantation and 28 of the 65 patients (43%) with genotype 1 achieved SVR. Of the patients having genotype 1 HCV who achieved SVR, there was a significantly lower stage of fibrosis (1.37 +/- 0.88 vs. 1.89 +/- 0.96; P = 0.03), increased ribavirin dose (total daily dose 1057 +/- 230 vs. 856 +/- 399 mg; P = 0.02), increased rapid virologic response (RVR) (6/27 vs. 0/31; P = 0.05), increased early virologic response (EVR) (28/28 vs. 18/35; P = 0.006), and longer duration of therapy (54.7 +/- 13.4 weeks vs. 40.2 +/- 18.7; P = 0.001). A logistic regression model using gender, age, RVR, EVR, anemia, duration of therapy, viral load, years' post-transplant, and type of organ (donation after cardiac death vs. donation after brain death) significantly predicted SVR (P < 0.001), with duration of therapy having a significant odds ratio of 1.078 (P = 0.007). CONCLUSIONS: This study identified factors that predict SVR in HCV-positive patients who received dual therapy post transplantation. Extending therapy from 48 weeks to 72 weeks of dual therapy is associated with increased SVR rates. Future studies examining the role of extended therapy are needed to confirm these findings, since the current study is a retrospective one. PMID- 24045598 TI - Propafenone hepatotoxicity: report of a new case and review of the literature. AB - Propafenone is a class Ic antiarrhythmic drug. It is a beta-adrenergic blocker that causes bradycardia and bronchospasm. It is metabolized primarily in the liver. Its bioavailability and plasma concentration differ among patients under long-term therapy. They are genetically determined by the hepatic cytochrome P 450 2D6. Hepatic toxicity is highly uncommon. To date, only eight patients were reported in the reviewed world literature. In this article, one new case will be reported emphasizing the importance of medication history taking in patients presenting with new-onset liver enzymes abnormalities. PMID- 24045599 TI - Widespread nodules and adhesions in abdomen. PMID- 24045600 TI - Clinical use of capsule endoscopy in a patient with cardiac pacemaker. PMID- 24045601 TI - Helicobacter pylori in the era of probiotics: a controversial application. PMID- 24045602 TI - The Ideas Lab Concept, Assembling the Tree of Life, and AVAToL. AB - In August 2011, a week-long NSF-sponsored workshop focusing on the Tree of Life (ToL) took place in Lake Placid, New York. This workshop, called AVAToL (Assembling Visualizing, and Analyzing the Tree of Life), was the first application of NSF's Ideas Lab concept to systematics. In this article we outline the history and motivation for the Ideas Lab approach and its application to the ToL, explain the nuts and bolts of the Ideas Lab process and look to the potential contributions of AVAToL funded projects to help enable the future of ToL and more broadly, comparative biological research. PMID- 24045603 TI - Attention-deficit/hyperactivity disorder and comorbid subsyndromal depression: what is the impact of methylphenidate on mood? AB - BACKGROUND: Youths with attention-deficit/hyperactivity disorder (ADHD) may develop demoralization or depressive or dysthymic symptoms related to chronic social, familial, and academic difficulties that are associated with their ADHD and are at higher risk for developing mood disorders. We assessed the effectiveness of methylphenidate (MPH) on both ADHD and mood symptoms in children and adolescents diagnosed with ADHD and coexistent subsyndromal depression (SSD). METHODS: A group of ADHD patients with SSD (n = 47), aged 8 to 18 years, received 12 weeks of MPH treatment. The severity of depressive and ADHD symptoms was assessed using the Child Depression Rating Scale (CDRS) and the Attention Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS), respectively. RESULTS: A highly significant decrease in both ADHD-RS and CDRS scores was obtained in the total group (N = 47) after MPH treatment (P = 0.0001 and P = 0.0001, respectively). A significant positive correlation was found between the changes in the CDRS total scores and the ADHD-RS (r = 0.34, N = 47, P = 0.018). However, no such correlation was found in a subgroup (N = 8) of patients with "possible depression" (baseline CDRS score, 65-74; r = 0.026, P = 0.95). CONCLUSIONS: Methylphenidate treatment is effective for both ADHD and SSD symptoms. It seems that ADHD symptoms are less responsive to MPH in patients with relatively high CDRS scores (possible depression) and that those patients may be candidates for selective serotonin reuptake inhibitor treatment as a supplement for MPH. Further, larger, placebo-controlled, double-blind studies are needed to examine the impact of MPH or d-amphetamine on patients with ADHD/SSD and ADHD/major depressive disorder. PMID- 24045604 TI - Acute treatment of trigeminal neuralgia with onabotulinum toxin A. AB - A double-blind, randomized, placebo-controlled study of patients with essential trigeminal neuralgia and treatment with a single injection of onabotulinum toxin A (BTX) was carried out. The efficacy, safety, and tolerability of either 1 mL 0.9% saline plus 50 U of BTX or only 1 mL of 0.9% saline injected subcutaneously in the affected area were evaluated. Cases with involvement of the third branch of the trigeminal nerve also received intramuscularly either 10 U of BTX or matching placebo in the masseter muscle, ipsilateral to the pain location. Pain was assessed with the visual analog scale (VAS). Twenty subjects were administered BTX, and 16 subjects received placebo. Two months after the intervention, a trend to statistical significance was observed for the VAS mean values in subjects treated with BTX and those who received placebo (VAS 4.9 vs 6.63, t test, P = 0.07). Three months after the injection, significant differences were observed in the average VAS score for subjects treated with BTX and those treated with placebo (VAS 4.75 vs 6.94, respectively; t test, P = 0.01). Onabotulinum toxin A was well tolerated and seems to be a safe and useful therapy for patients with essential trigeminal neuralgia. PMID- 24045605 TI - Effectiveness and tolerability of switching to aripiprazole from risperidone in subjects with autism spectrum disorders: a prospective open-label study. AB - BACKGROUND: Subjects with autism spectrum disorders (ASDs) often exhibit behavioral symptoms such as aggressiveness and irritability. The purpose of this study was to examine the efficacy and the tolerability of aripiprazole switched from risperidone in children and adolescents with ASD. METHODS: This prospective, 12-week, open-label study included 9 male subjects with ASD (age range, 9-22 years; mean +/- SD age, 14.8 +/- 4.0 years) followed up for 12 weeks after switching to aripiprazole from risperidone. The primary outcome measures were the Clinical Global Impression-Improvement scales and the irritability subscale of the Aberrant Behavior Checklist. RESULTS: The mean +/- SD maintenance dosages of risperidone and aripiprazole were 0.6 +/- 0.4 mg/d and 4.8 +/- 4.0 mg/d, respectively. The mean +/- SD scores of the irritability subscale of the Aberrant Behavior Checklist before switching to aripiprazole (baseline) and 12 weeks after switching to aripiprazole (end point) were 14.8 +/- 7.6 and 13.1 +/- 8.0, respectively. The mean +/- SD Clinical Global Impression-Improvement score, a comparison from baseline to end point, was 2.4 +/- 0.7. Mild somnolence was observed only in 1 subject. No significant changes in vital signs, weight, electrocardiogram, or laboratory measures occurred during switching to aripiprazole. Serum prolactin levels decreased significantly from 17.3 +/- 9.4 ng/mL (baseline) to 2.3 +/- 1.7 ng/mL (end point). CONCLUSIONS: The results show that aripiprazole might be generally well tolerated and might constitute an alternative treatment of subjects with ASD who experience poor efficacy or tolerability issues with risperidone treatment. Additional long-term controlled studies are needed to evaluate the efficacy and the safety of switching to aripiprazole from other antipsychotics in subjects with ASD. PMID- 24045606 TI - Augmentation of aripiprazole for depressed patients with an inadequate response to antidepressant treatment: a 6-week prospective, open-label, multicenter study. AB - OBJECTIVES: Nonresponse or a partial response to 1 or more antidepressants is a common and significant problem in clinical practice. Adjunctive therapy with atypical antipsychotics is considered as 1 of the next treatment options for such inadequate responses. The present trial evaluated the efficacy and the safety of aripiprazole as an augmentation to ongoing antidepressant monotherapy for patients with major depressive disorder (MDD) who have previously exhibited an inadequate clinical response. METHODS: This was a 6-week prospective, multicenter, open-label study with flexibly dosed adjunctive aripiprazole. The 86 participants with MDD showed inadequate responses to more than 8 weeks of standard antidepressant treatment. The primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale total score from baseline to the end point (week 6). RESULTS: The mean daily dose of aripiprazole at the end point was 6.9 mg. The Montgomery-Asberg Depression Rating Scale total score was significantly decreased with adjunctive aripiprazole during the study period (by 14.0 points, P = 0.000). At the end point, the response rate was 52.3% and the remission rate was 39.8%. Adjunctive aripiprazole produced a significant response and remission from week 1 through the end point. The study completion rate was 73.9%, and adverse events included sedation (n = 11), akathisia (n = 9), headache (n = 6), tremor (n = 6), and increased appetite (n = 5). Of the discontinuations, only 5.7% were due to adverse events. CONCLUSIONS: Adjunctive aripiprazole in patients with MDD who had previously exhibited an inadequate response to standard antidepressant therapy was efficacious and well tolerated. A low daily dose of aripiprazole would be more acceptable in the clinical setting. PMID- 24045607 TI - Low doses of rotigotine in patients with antipsychotic-induced parkinsonism. AB - OBJECTIVES: The aim of this study was to evaluate in a group of patients with psychosis the effect of the dopamine agonist rotigotine on neuroleptic-induced extrapyramidal symptoms (EPSs), a set of movement disorders such as pseudoparkinsonism, dyskinesias, akinesia, and akathisia that occur as result of taking drugs that block dopamine receptors. METHODS: Twenty patients with psychosis with EPSs were clinically evaluated before and after the administration of rotigotine. The drug was started at a dosage of 2 mg daily and gradually increased until the best clinical benefit was achieved (mean +/- SD, dosage, 3.2 +/- 1.8 mg; range, 2-8 mg). The neurological status was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) total and UPDRS section III, the Simpson-Angus Scale, and the Barnes Akathisia Rating Scale. The Positive and Negative Syndrome Scale and the Hamilton Depression Rating Scale were used to appraise possible modifications of the psychiatric conditions. RESULTS: Compared with baseline, there was a significant improvement in the UPDRS total, the UPDRS section III, the Simpson-Angus Scale (P < 0.0001), and the Barnes Akathisia Rating Scale (P < 0.05), without changes in the Positive and Negative Syndrome Scale and the Hamilton Depression Rating Scale (P < 0.05). All patients tolerated rotigotine well, except 1 who dropped out of the trial because of the recurrence of his psychotic symptoms. CONCLUSIONS: The results of this observational study suggest that low doses of rotigotine are well tolerated in patients with psychosis and are effective in neuroleptic-induced EPSs. PMID- 24045608 TI - Safety of perioperative treatment with intravenous amantadine in patients with Parkinson disease. AB - OBJECTIVES: Surgery in patients with Parkinson disease is associated with a high rate of complications largely because of difficulties in maintaining the antiparkinsonian treatment regimen perioperatively. The aim of the study was to investigate the safety and efficacy of intravenous administration of amantadine on parkinsonian features during and after surgery. METHODS: The study group included 6 patients being treated for Parkinson disease who were referred for surgery at a tertiary medical center. After providing written informed consent, participants received intravenous amantadine sulfate 200 mg after induction of anesthesia and 24 hours later. The regular antiparkinsonian regimen was stopped immediately before surgery and restarted after surgery. Patients underwent a neurological evaluation with the Unified Parkinson Disease Rating Scale at 3 time points: preoperatively, 24 to 72 hours postoperatively, and 1 month postoperatively, and the scores were compared. RESULTS: The mean Unified Parkinson Disease Rating Scale score improved from 24.8 (SD, 10.8) at baseline to 21.3 (SD, 11.1) at 24 to 72 hours postoperatively (P = 0.04); the value at 1 month (in the 5 patients assessed) was 22.5 (SD, 15.5) (P = 0.27). No adverse effects of amantadine or postoperative complications were recorded. All patients were discharged home as planned. CONCLUSIONS: Amantadine improves the parkinsonian symptoms after surgery, which may be beneficial in preventing complications. It appears to have a high safety profile in this setting. Larger, randomized, and blinded studies are warranted to corroborate these preliminary results and evaluate long-term outcome. PMID- 24045609 TI - Impulse control disorder in a patient on long-term treatment with bromocriptine for a macroprolactinoma. AB - Impulse control disorders (ICDs) constitute socially disruptive behaviors such as pathological gambling, impulsive eating, compulsive shopping, and hypersexuality. These conditions are well recognized in patients on dopamine agonist (DA) therapy for Parkinson disease. Dopamine agonists are widely used as first-line agents in the treatment of prolactinomas, but ICDs in this group of patients are relatively rare, perhaps because of lower therapeutic doses used. A review of the literature yielded only a few cases of ICDs in patients on DA treatment for prolactinomas. These symptoms are perhaps underreported because of lack of awareness among patients and health care professionals. Impulse control disorders are recognized psychiatric disorders that have significant psychological and social implications, and patients need to be counselled about this rare possibility when embarking on prolonged DA therapy. We describe a young patient with severe, socially disruptive impulsivity manifesting with pathological gambling who had been on long-term bromocriptine therapy for a macroprolactinoma. PMID- 24045610 TI - Visual hallucinations during duloxetine treatment in a patient with major depressive disorder. AB - Duloxetine is a serotonin-noradrenaline reuptake inhibitor that is effective in the treatment of major depressive disorder (MDD) and chronic pain. The safety of duloxetine has been shown by many previous studies. We report a patient who experienced visual hallucinations after taking duloxetine. The patient experienced insomnia and chronic somatic pain. He began taking duloxetine after a diagnosis of MDD and developed visual hallucinations after the duloxetine dose was increased. The hallucinations disappeared after the duloxetine dose was decreased and then stopped; the dose of quetiapine was increased as an alternative. The specific cause of the duloxetine-induced hallucinations is unclear. In addition to other prescription medications and possible interactions with duloxetine, increasing dopamine by blocking noradrenaline transporters or serotonergic neurotransmission function may contribute to the occurrence of hallucinations. PMID- 24045611 TI - Zolpidem-induced compulsive evening eating behavior. AB - Zolpidem is associated with an amnestic sleep-related eating disorder, but not with compulsive eating behaviors. A 57-year-old woman receiving zolpidem for insomnia showed compulsive evening eating behavior under a wakeful state. Her compulsive evening eating behavior disappeared when zolpidem treatment was halted. Here, we report her case. PMID- 24045612 TI - Repeated erythromycin/codeine-induced psychotic mania. AB - BACKGROUND: Mania is generally associated with bipolar disorder; however, it can be iatrogenic. For instance, antibiotics and corticosteroids can cause manic symptoms. CASE REPORT: Here, we present a case of a young man who had symptoms of psychotic mania after administration of erythromycin and acetaminophen with codeine on 2 separate occasions, with rapid resolution of each episode. CONCLUSIONS: Adverse events of psychotic mania have been rarely reported with erythromycin and acetaminophen with codeine, despite these being commonly prescribed medications. Clinicians should be aware that these drugs may be an iatrogenic cause of psychiatric disturbances and that these adverse events are more likely to occur during their concomitant use. PMID- 24045613 TI - 5-Methyldeoxycytidine enhances the substrate activity of DNA polymerase. AB - Here, we first demonstrated that 5-MedCTP could be incorporated into the synthetic DNA template by the exonuclease deficient Klenow fragment with a much higher efficiency than dCTP and 5-hydroxymethyl-dCTP. Further, we first conducted a comparable study of primer extension reaction using templates containing deoxycytidine (dC) or 5-methyldeoxycytidine (5-mdC) for incorporating different triphosphates. Based on our findings, 5-methyldeoxycytidine could enhance the substrate activity of the Klenow fragment (exo-) and this feature could potentially be used in DNA methylation analysis. PMID- 24045614 TI - Music cognition as mental time travel. AB - As we experience a temporal flux of events our expectations of future events change. Such expectations seem to be central to our perception of affect in music, but we have little understanding of how expectations change as recent information is integrated. When music establishes a pitch centre (tonality), we rapidly learn to anticipate its continuation. What happens when anticipations are challenged by new events? Here we show that providing a melodic challenge to an established tonality leads to progressive changes in the impact of the features of the stimulus on listeners' expectations. The results demonstrate that retrospective analysis of recent events can establish new patterns of expectation that converge towards probabilistic interpretations of the temporal stream. These studies point to wider applications of understanding the impact of information flow on future prediction and its behavioural utility. PMID- 24045615 TI - Frequent and sex-biased deletion of SLX4IP by illegitimate V(D)J-mediated recombination in childhood acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) accounts for ~25% of pediatric malignancies. Of interest, the incidence of ALL is observed ~20% higher in males relative to females. The mechanism behind the phenomenon of sex-specific differences is presently not understood. Employing genome-wide genetic aberration screening in 19 ALL samples, one of the most recurrent lesions identified was monoallelic deletion of the 5' region of SLX4IP. We characterized this deletion by conventional molecular genetic techniques and analyzed its interrelationships with biological and clinical characteristics using specimens and data from 993 pediatric patients enrolled into trial AIEOP-BFM ALL 2000. Deletion of SLX4IP was detected in ~30% of patients. Breakpoints within SLX4IP were defined to recurrent positions and revealed junctions with typical characteristics of illegitimate V(D)J-mediated recombination. In initial and validation analyses, SLX4IP deletions were significantly associated with male gender and ETV6/RUNX1 rearranged ALL (both overall P < 0.0001). For mechanistic validation, a second recurrent deletion affecting TAL1 and caused by the same molecular mechanism was analyzed in 1149 T-cell ALL patients. Validating a differential role by sex of illegitimate V(D)J-mediated recombination at the TAL1 locus, 128 out of 1149 T cell ALL samples bore a deletion and males were significantly more often affected (P = 0.002). The repeatedly detected association of SLX4IP deletion with male sex and the extension of the sex bias to deletion of the TAL1 locus suggest that differential illegitimate V(D)J-mediated recombination events at specific loci may contribute to the consistent observation of higher incidence rates of childhood ALL in boys compared with girls. PMID- 24045617 TI - Patterned neuronal networks using nanodiamonds and the effect of varying nanodiamond properties on neuronal adhesion and outgrowth. AB - OBJECTIVE: Detonation nanodiamond monolayer coatings are exceptionally biocompatible substrates for in vitro cell culture. However, the ability of nanodiamond coatings of different origin, size, surface chemistry and morphology to promote neuronal adhesion, and the ability to pattern neurons with nanodiamonds have yet to be investigated. APPROACH: Various nanodiamond coatings of different type are investigated for their ability to promote neuronal adhesion with respect to surface coating parameters and neurite extension. Nanodiamond tracks are patterned using photolithography and reactive ion etching. MAIN RESULTS: Universal promotion of neuronal adhesion is observed on all coatings tested and analysis shows surface roughness to not be a sufficient metric to describe biocompatibility, but instead nanoparticle size and curvature shows a significant correlation with neurite extension. Furthermore, neuronal patterning is achieved with high contrast using patterned nanodiamond coatings down to at least 10 um. SIGNIFICANCE: The results of nanoparticle size and curvature being influential upon neuronal adhesion has great implications towards biomaterial design, and the ability to pattern neurons using nanodiamond tracks shows great promise for applications both in vitro and in vivo. PMID- 24045616 TI - Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms. AB - Genome-wide significant associations with cigarettes per day (CPD) and risk for lung cancer and chronic obstructive pulmonary disease (COPD) were previously reported in a region of 19q13, including CYP2A6 (nicotine metabolism enzyme) and EGLN2 (hypoxia response). The associated single nucleotide polymorphisms (SNPs) were assumed to be proxies for functional variation in CYP2A6. Here, we demonstrate that when CYP2A6 and EGLN2 genotypes are analyzed together, the key EGLN2 variant, rs3733829, is not associated with nicotine metabolism independent of CYP2A6, but is nevertheless independently associated with CPD, and with breath carbon monoxide (CO), a phenotype associated with cigarette consumption and relevant to hypoxia. SNPs in EGLN2 are also associated with nicotine dependence and with smoking efficiency (CO/CPD). These results indicate a previously unappreciated novel mechanism behind genome-wide significant associations with cigarette consumption and disease risk unrelated to nicotine metabolism. PMID- 24045618 TI - Molecular imaging of hypoxia. PMID- 24045619 TI - Relevance of hypoxia in radiation oncology: pathophysiology, tumor biology and implications for treatment. AB - Tumors are characterized by an inefficient and disorganized vasculature which leads to tumor regions that are transiently or chronically undersupplied with oxygen (hypoxia) and nutrients (e.g., glucose). These adverse conditions are linked to treatment resistant and metastasizing disease with poor prognosis. Radiation sensitivity is dramatically lowered in hypoxic, yet viable and clonogenic, cells since oxygen is involved in the fixation of radiation-induced DNA damage (radiobiological hypoxia), and loco-regional tumor control is adversely affected in patients with hypoxic tumors. Hypoxia also leads to reduced sensitivity towards chemotherapeutics since drug delivery is reduced in hypoperfused hypoxic areas and hypoxic cells are quiescent, making drugs that target dividing cells ineffective. Fortunately, clinical attractive imaging and gene-expression based technologies that allows pre- and during treatment assessment of tumor hypoxia are now available. These technologies may identify patients suitable for established or emerging hypoxia-targeting treatments and, equally important; they allow us to monitor the efficacy of such intervention and may thus pave the way for effective individualized treatment. In the current review, we address 1) the causes and consequences of tumor hypoxia, 2) technologies that allow assessment of tumor hypoxia in individual patients and 3) current status of hypoxia-targeting treatments. PMID- 24045620 TI - Methodological aspects on hypoxia PET acquisition and image processing. AB - Tumor hypoxia is one of the main factors compromising the effectiveness of radiotherapy. As a consequence, non-invasive hypoxia imaging with positron emission tomography (PET) is very promising with regard to its potential to provide a functional basis for patient stratification or therapy modification. This review article aims at providing a comprehensive overview of different methodologies for hypoxia PET image acquisition protocols as well as data processing and analysis as used in recent studies and clinical trials. Furthermore, different physical and also technical aspects that may induce ambiguities and limitations into hypoxia PET image acquisition and interpretation are discussed in the context of this article. In the future, dedicated hypoxia PET image acquisition protocols and methodologies for processing, analysis and interpretation of hypoxia PET data are necessary to allow for comparison of hypoxia PET image data acquired in different study centers and enable for the definition of multicenter trials on hypoxia PET imaging and hypoxia-based treatment interventions. PMID- 24045621 TI - Hypoxia and tumor metabolism in radiation oncology: targets visualized by positron emission tomography. AB - Due to the amazing leap of technology in radiation oncology in the past few years, cancer treatment will become more individualized. Molecular imaging with PET contributed to this with its many tracers available, each of them visualizing a specific feature of a tumor and its microenvironment revealing the biological characteristics of cancer. Hypoxia is of interest as hypoxic tumor cells are associated with lower disease control because of an increased resistance to cytotoxic treatment. This is especially the case for radiotherapy. Treatment adaptations overcoming the negative effect of hypoxia have shown promising results. Several hypoxia tracers are available of which [18F]FMISO is studied most extensively, however other tracers are studied as well and the search for highly specific and reproducible PET tracers is still ongoing. Wide experience has been gained with the use of [18F]FDG PET as it is used on a routine basis for diagnosing and staging of cancer. Although not a specific marker for hypoxia, increased metabolic rate reflects increased proliferation and glycolysis indicating increased treatment resistance. Molecular imaging by means of PET creates an opportunity to provide personalized care, with optimal disease control, minimal toxicity and best cost-effectiveness. PMID- 24045622 TI - Imaging hypoxia in tumours with advanced MRI. AB - Tumour hypoxia results in biological alterations that leads to a more aggressive disease phenotype and is associated with resistance to treatment. In this review, we discuss current magnetic resonance imaging techniques, which can be applied to evaluate tumour hypoxia, highlighting the principles of each technique, their pre clinical and clinical deployment, as well as their strengths and limitations. The potential to combine these techniques, and also with other imaging modalities (e.g., PET imaging) using a multiparametric approach, may further improve our understanding of the complex interaction of vascular supply, oxygen diffusion and tissue metabolism in pathogenesis of tumour hypoxia; and its reversal with treatment. PMID- 24045623 TI - Implementation of hypoxia PET imaging in radiation therapy planning. AB - Hypoxia has historically been relevant to radiation oncology as it relates to radioresistance, poor response to therapy and unfavorable patient's outcome in many solid tumors. In that regard, the recent advances in imaging, computation and radiation delivery techniques have been offering new perspectives to prescribe and deliver radiation dose in accordance with the spatial distribution of hypoxia mapped with molecular or functional imaging modalities, i.e., the so called dose painting (DP). At first glance, the concept of dose painting appears promising and let foresee likely improvement in tumor local control at an acceptable clinical cost. However, adapting radiotherapy planning and delivery according to hypoxia imaging implicitly assumes: 1) that the imaging variable actually correlates with a local biological property associated with individual therapy outcome; 2) that the spatial distribution of the imaging parameter can be adequately converted into dose; and 3) that an irradiation device can actually deliver such a heterogeneous dose in fractionated RT treatments. In that regard, many uncertainties and difficulties remain at each step of the DP process, mainly related to the limitations of the current imaging techniques and the treatment fractionation. This paper will thus review the state of the art of DP with a specific focus on hypoxia, going from cancer biology to adaptive dose delivery. It will address the technological challenges and the clinical validation, which are both essential to translate an intuitively appealing concept into a clinically meaningful practice. PMID- 24045624 TI - Targeted therapies and hypoxia imaging. AB - Hypoxia-specific cytotoxins have long exhibited considerable promise for treating hypoxic tumors, however recent negative results in large scale clinical trials have highlighted the importance of selecting patients who are most likely to respond using hypoxia imaging methods. This review looks at the available hypoxia specific cytotoxins and describes how existing hypoxia imaging methods can be best used to predict which tumors will respond. It then surveys prior studies which combine hypoxia-selective cytotoxin treatment with hypoxia imaging, and finally concludes with a discussion of what lessons can be learnt from previous experiences in order to improve the use of these cytotoxic agents in future clinical evaluations. PMID- 24045625 TI - Evaluation of the contribution of the dynamic phase of lymphoscintigraphy to the detection of sentinel lymph node in breast cancer. AB - AIM: The aim of this study was to evaluate the contribution of an early dynamic phase (DP) of the lymphoscintigraphy (LS) to the detection of the sentinel lymph node (SLN) in breast cancer. METHODS: This prospective study included 164 breast lesions in 161 consecutive patients (160 women, mean age 57.5 years). Patients with tumor >5 cm, multicentric, palpable nodes, axillary involvement, previous surgery, lymphadenectomy, radio or chemotherapy were not included. All patients underwent preoperative LS before surgery. DP immediately after injection of [99mTc]Nanocolloid followed by early and delayed planar images (EPI and DPI) were acquired. RESULTS: SLN was detected in 162/164 lesions (98.8%). In 115 (71%) DP showed no lymph node uptake and the SLN was identified only by EPI and DPI. A focal uptake by at least one lymph node was observed in DP in the remaining 47 lesions (29%). Although in 30/74 lesions DP did not provide additional information to EPI and DPI, nevertheless in 17 cases (10.5%) DP was essential to identify correctly the SLN. CONCLUSION: We concluded that DP, by allowing a better interpretation of the lymphatic drainage pattern, provides unique information to distinguish the correct SLN from other lymph nodes and is recommended as the first part of LS. PMID- 24045626 TI - Trends in emergency hospital admissions of children: observations from Scotland. PMID- 24045627 TI - At the interface between organic radicals and TiO2(110) single crystals: electronic structure and paramagnetic character. AB - We find that in a paramagnetic pyrene derivative of the nitronyl nitroxide radical deposited on rutile TiO2(110) single crystals the molecules keep/lose their paramagnetic character depending on the local substrate hydroxylation. The first molecular layer may act as a "buffer" on which intact organic magnets are grown. PMID- 24045632 TI - The Effect of Rest Interval Length on Repetition Consistency and Perceived Exertion During Near Maximal Loaded Bench Press Sets. AB - The purpose of this study was to compare different rest intervals between sets on repetition consistency and ratings of perceived exertion (RPE) during consecutive bench press sets with an absolute 3RM (3 repetition maximum) load. Sixteen trained men (23.75 +/- 4.21 years; 74.63 +/- 5.36 kg; 175 +/- 4.64 cm; bench press relative strength: 1.44 +/- 0.19 kg/kg of body mass) attended 4 randomly ordered sessions during which 5 consecutive sets of the bench press were performed with an absolute 3RM load and 1, 2, 3, or 5 minutes of rest interval between sets. The results indicated that significantly greater bench press repetitions were completed with 2, 3, and 5 minutes vs. 1-minute rest between sets (p <= 0.05); no significant differences were noted between the 2, 3, and 5 minutes rest conditions. For the 1-minute rest condition, performance reductions (relative to the first set) were observed commencing with the second set; whereas for the other conditions (2, 3, and 5 minutes rest), performance reductions were not evident until the third and fourth sets. The RPE values before each of the successive sets were significantly greater, commencing with the second set for the 1-minute vs. the 3 and 5 minutes rest conditions. Significant increases were also evident in RPE immediately after each set between the 1 and 5 minutes rest conditions from the second through fifth sets. These findings indicate that when utilizing an absolute 3RM load for the bench press, practitioners may prescribe a time-efficient minimum of 2 minutes rest between sets without significant impairments in repetition performance. However, lower perceived exertion levels may necessitate prescription of a minimum of 3 minutes rest between sets. PMID- 24045634 TI - Methods comparison: assessing agreement of physiological parameters obtained from exercise on two different cycle ergometers. AB - The purpose of this study was to determine the agreement of physiological parameters measured during exercise testing on 2 devices at established power outputs (POs). Ten trained male cyclists were recruited. The devices used for comparison were the Lode stationary bicycle ergometer (SBE) (Lode Excalibur) and the PowerTap Pro+ (BPT) (Saris Cycling Group) mobile ergometer. The physiological parameters recorded at established PO (50, 100, 150, 200, 250 W) were heart rate (HR), oxygen consumption ((Equation is included in full-text article.)), pulmonary ventilation (VE), blood lactate, and ratings of perceived exertion (RPE). Subjects were randomized once to the SBE and 3 times to a bicycle equipped with a BPT. After 15 minutes of unloaded pedaling, the trial began with 5 minutes of cycling at 50 W. Intensity increased by 50 W every 5 minutes up to 250 W. Physiological measures were recorded at each PO. Bland-Altman plots were constructed including computation of the ratio of half the range of limits of agreement and the mean of the pairwise means along with bivariate regression calculations for analysis of the linear association between device measurements. Moderate to good agreement was found for HR with agreement improving as PO increased. Comparisons of (Equation is included in full-text article.)found agreement increased as the PO increased. VE, RPE, and lactate did not consistently provide similar measures across trials. The level of agreement between HR and (Equation is included in full-text article.)when comparing the SBE and BPT suggests that the PowerTap Pro+ is a sufficient tool for estimating PO and associated physiological parameters in the field. PMID- 24045635 TI - Echinacea purpurea supplementation does not enhance VO2max in distance runners. AB - Oral supplementation of Echinacea purpurea (ECH) has been reported to increase levels of serum erythropoietin and as a result improve endurance performance in untrained subjects. The purpose of this study was to determine if ECH supplementation alters maximal oxygen uptake (VO2max) in trained endurance runners. Using a double-blind design, 16 trained endurance runners (9 ECH and 7 placebo [PLA]) supplemented with either 8,000 mg.d(-1) of ECH or wheat flour (PLA) for 6 weeks. Maximal aerobic treadmill tests and blood samples were measured before and after supplementation to determine VO2max, hematocrit (Hct), and hemoglobin (Hb). VO2max, Hct, and Hb did not differ between the ECH and PLA groups before or after supplementation. Furthermore, supplementation of ECH failed to improve VO2max (67.37 +/- 4.62 vs. 67.23 +/- 5.82 ml.kg(-1).min(-1)), Hct (43.57 +/- 2.38 vs. 42.85 +/- 1.46%), or Hb (14.93 +/- 1.27 vs. 15.55 +/- 0.80 g.dL(-1)) from baseline measurements. Echinacea purpurea supplementation of 8,000 mg.d(-1) for 6 weeks failed to increase VO2max, Hct, or Hb in trained endurance runners and thus does not seem to influence physiological variables that affect distance running performance. PMID- 24045636 TI - Prolongation of rat renal allograft survival by CD4+CD25- T cells induced by recipient dendritic cells transfected with IKK2dn. AB - Previous studies have demonstrated that recipient-derived immature dendritic cells transfected by recombinant adenovirus-mediated IKK2dn (Adv-IKK2dn) and loaded with donor splenocyte lysate generate CD4+CD25- T cells (Adv-IKK2dn CD4+CD25- T cells). These cells may inhibit T cell responses in vitro. In the present study, Lewis (LW) rats were administered with an intravenous injection of naive CD4+ T cells, empty adenovirus (Adv-0)-dendritic cell-generated CD4+CD25- T cells (Adv-0-CD4+CD25- T cells), Adv-IKK2dn-CD4+CD25- T cells or an equal volume of normal saline, seven days prior to transplantation. The potency and the mechanism of action of Adv-IKK2dn-CD4+CD25- T cells was analyzed, as well as an investigation of their tolerogenic properties in vivo. Administration of Adv IKK2dn-CD4+CD25- T cells in vivo to LW rats was observed to markedly prolong the survival of a kidney allograft from Brown Norway rats. Furthermore, the Adv IKK2dn-CD4+CD25- T cell-treated group exhibited significantly reduced levels of interleukin (Il)-2 and interferon-gamma production and increased Il-10 and transforming growth factor-beta (TGF-beta) secretion. The serum creatinine levels remained at low levels in the Adv-IKK2dn-CD4+CD25- T cell-treated group. Their ability to induce allogeneic T cell proliferation was markedly reduced compared with the other groups. These observations indicated that Adv-IKK2dn-CD4+CD25- T cells induce prolongation of kidney allograft survival in vivo, which is hypothesized to be due to the high expression levels of Il-10 and TGF-beta. PMID- 24045638 TI - Reference electrode assembly and its use in the study of fluorohydrogenate ionic liquid silicon electrochemistry. AB - Silicon electrochemistry in fluorohydrogenate ionic liquids is partly hampered owing to the incapability of producing an accurate and reproducible potential measurement due to a lack of appropriate reference electrodes. This research work describes a simple assembly of a stable external reference electrode enabling accurate studies of silicon electrochemistry in fluorohydrogenate ionic liquids. The electrode configuration is based on the ferrocene/ferrocenium (Fc|Fc(+)) couple dissolved in the EMIm(HF)(2.3)F (1-ethyl-3-methyl-imidazolium fluorohydrogenate)/Carbopol 941 gel. A stable potential of 2.5 wt% Carbopol-based electrode was measured versus a calomel reference electrode at 250 +/- 3 mV. By utilizing the constructed electrode, an intensive electrochemical investigation on n-type silicon in EMIm(HF)(2.3)F was conducted. Flat-band and open circuit potentials were measured, along with Si-air half- and full-cell electrochemical measurements. A suggested mechanism for the n-type Si dissolution process in the EMIm(HF)(2.3)F electrolyte, without illumination, is discussed as well. PMID- 24045637 TI - Protein synthesis rate is the predominant regulator of protein expression during differentiation. AB - External perturbations, by forcing cells to adapt to a new environment, often elicit large-scale changes in gene expression resulting in an altered proteome that improves the cell's fitness in the new conditions. Steady-state levels of a proteome depend on transcription, the levels of transcripts, translation and protein degradation but system-level contribution that each of these processes make to the final protein expression change has yet to be explored. We therefore applied a systems biology approach to characterize the regulation of protein expression during cellular differentiation using quantitative proteomics. As a general rule, it seems that protein expression during cellular differentiation is largely controlled by changes in the relative synthesis rate, whereas the relative degradation rate of the majority of proteins stays constant. In these data, we also observe that the proteins in defined sub-structures of larger protein complexes tend to have highly correlated synthesis and degradation rates but that this does not necessarily extend to the holo-complex. Finally, we provide strong evidence that the generally poor correlation observed between transcript and protein levels can fully be explained once the protein synthesis and degradation rates are taken into account. PMID- 24045640 TI - Perturbation of cytochrome c maturation reveals adaptability of the respiratory chain in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis depends on aerobic respiration for growth and utilizes an aa3-type cytochrome c oxidase for terminal electron transfer. Cytochrome c maturation in bacteria requires covalent attachment of heme to apocytochrome c, which occurs outside the cytoplasmic membrane. We demonstrate that in M. tuberculosis the thioredoxin-like protein Rv3673c, which we named CcsX, is required for heme insertion in cytochrome c. Inactivation of CcsX resulted in loss of c-type heme absorbance, impaired growth and virulence of M. tuberculosis, and induced cytochrome bd oxidase. This suggests that the bioenergetically less efficient bd oxidase can compensate for deficient cytochrome c oxidase activity, highlighting the flexibility of the M. tuberculosis respiratory chain. A spontaneous mutation in the active site of vitamin K epoxide reductase (VKOR) suppressed phenotypes of the CcsX mutant and abrogated the activity of the disulfide bond-dependent alkaline phosphatase, which shows that VKOR is the major disulfide bond catalyzing protein in the periplasm of M. tuberculosis. IMPORTANCE: Mycobacterium tuberculosis requires oxygen for growth; however, the biogenesis of respiratory chain components in mycobacteria has not been explored. Here, we identified a periplasmic thioredoxin, CcsX, necessary for heme insertion into cytochrome c. We investigated the consequences of disrupting cytochrome c maturation (CCM) for growth and survival of M. tuberculosis in vitro and for its pathogenesis. Appearance of a second-site suppressor mutation in the periplasmic disulfide bond catalyzing protein VKOR indicates the strong selective pressure for a functional cytochrome c oxidase. The observation that M. tuberculosis is able to partially compensate for defective CCM by upregulation of the cytochrome bd oxidase exposes a functional role of this alternative terminal oxidase under normal aerobic conditions and during pathogenesis. This suggests that targeting both oxidases simultaneously might be required to effectively disrupt respiration in M. tuberculosis. PMID- 24045639 TI - The IL-33/ST2 axis is associated with human visceral leishmaniasis and suppresses Th1 responses in the livers of BALB/c mice infected with Leishmania donovani. AB - During visceral leishmaniasis, the control of hepatic parasite burden is mainly due to granuloma assembly in a microenvironment consisting of both Th1 and Th2 components. Using enzyme-linked immunosorbent assay (ELISA) dosages, quantitative PCR (qPCR), immunohistochemistry, and flow cytometry, we studied the role of interleukin-33 (IL-33), a recently described cytokine signaling through the ST2 receptor, during visceral leishmaniasis. We showed that a higher level of IL-33 was detected in the serum of patients with visceral leishmaniasis than in that from healthy donors and demonstrated the presence of IL-33(+) cells in a liver biopsy specimen from a patient. Similarly, in BALB/c mice experimentally infected with L. donovani, a higher level of IL-33 was detected in the serum, as well as the presence of IL-33(+) cells and ST2(+) cells in the mouse liver. In ST2(-/-) BALB/c mice, better control of the hepatic parasite burden and reduced hepatomegaly were observed. This was associated with strong induction of Th1 cytokines (gamma interferon [IFN-gamma] and IL-12) compared to the level in wild type (WT) mice and better recruitment of myeloid cells associated with strongly induced chemokines (CCL2 and CXCL2) and receptors (CCR2 and CXCR2). Conversely, BALB/c mice treated twice weekly with recombinant IL-33 showed a dramatically reduced induction of Th1 cytokines and delayed inhibition of monocyte and neutrophil recruitment in the liver, which was associated with reduced KC/CXCL1 and CXCR2 expression. Taken together, our results suggest that IL-33 could be a new deleterious regulator of the hepatic immune response against Leishmania donovani, via the repression of the Th1 response and myeloid cell recruitment. IMPORTANCE: Visceral leishmaniasis is a life-threatening systemic disease due to the Leishmania protozoa L. infantum and L. donovani and is ranked by the World Health Organization as the second most important protozoan parasitic disease after malaria for its grave morbidity, high mortality, and global distribution. Leishmania parasites subvert the host's immune response to propagate to target organs, including the spleen, the bone marrow, and the liver. Control of hepatic parasite burdens depends on a delicate and poorly understood Th1/Th2 immune balance. To better understand this complex immune response, new cytokines are interesting targets for research studies. IL-33 is a newly described cytokine usually associated with Th2 response and involved in different diseases, including infectious diseases and hepatitis. Our results suggest that IL-33 could be a new factor of susceptibility and a potential prognostic marker during visceral leishmaniasis. PMID- 24045641 TI - Ecological patterns of nifH genes in four terrestrial climatic zones explored with targeted metagenomics using FrameBot, a new informatics tool. AB - Biological nitrogen fixation is an important component of sustainable soil fertility and a key component of the nitrogen cycle. We used targeted metagenomics to study the nitrogen fixation-capable terrestrial bacterial community by targeting the gene for nitrogenase reductase (nifH). We obtained 1.1 million nifH 454 amplicon sequences from 222 soil samples collected from 4 National Ecological Observatory Network (NEON) sites in Alaska, Hawaii, Utah, and Florida. To accurately detect and correct frameshifts caused by indel sequencing errors, we developed FrameBot, a tool for frameshift correction and nearest neighbor classification, and compared its accuracy to that of two other rapid frameshift correction tools. We found FrameBot was, in general, more accurate as long as a reference protein sequence with 80% or greater identity to a query was available, as was the case for virtually all nifH reads for the 4 NEON sites. Frameshifts were present in 12.7% of the reads. Those nifH sequences related to the Proteobacteria phylum were most abundant, followed by those for Cyanobacteria in the Alaska and Utah sites. Predominant genera with nifH sequences similar to reads included Azospirillum, Bradyrhizobium, and Rhizobium, the latter two without obvious plant hosts at the sites. Surprisingly, 80% of the sequences had greater than 95% amino acid identity to known nifH gene sequences. These samples were grouped by site and correlated with soil environmental factors, especially drainage, light intensity, mean annual temperature, and mean annual precipitation. FrameBot was tested successfully on three ecofunctional genes but should be applicable to any. IMPORTANCE: High-throughput phylogenetic analysis of microbial communities using rRNA-targeted sequencing is now commonplace; however, such data often allow little inference with respect to either the presence or the diversity of genes involved in most important ecological processes. To study the gene pool for these processes, it is more straightforward to assess the genes directly responsible for the ecological function (ecofunctional genes). However, analyzing these genes involves technical challenges beyond those seen for rRNA. In particular, frameshift errors cause garbled downstream protein translations. Our FrameBot tool described here both corrects frameshift errors in query reads and determines their closest matching protein sequences in a set of reference sequences. We validated this new tool with sequences from defined communities and demonstrated the tool's utility on nifH gene fragments sequenced from soils in well-characterized and major terrestrial ecosystem types. PMID- 24045642 TI - Canine distemper virus (CDV) in another big cat: should CDV be renamed carnivore distemper virus? AB - One of the greatest threats to the conservation of wild cat populations may be dogs or, at least, one of their viruses. Canine distemper virus (CDV), a single stranded RNA virus in the Paramyxoviridae family and genus Morbillivirus, infects and causes disease in a variety of species, not just canids. An outbreak of CDV in wild lions in the Serengeti, Tanzania, in 1994 was a wake-up call for conservationists, as it demonstrated that an infectious disease could swiftly impact a previously healthy felid population. To understand how this virus causes disease in noncanid hosts, researchers have focused on specific mutations in the binding site of the CDV hemagglutinin gene. Now, Seimon et al. provide information on CDV in its latest feline victim, the endangered wild Amur tiger (Panthera tigris altaica) [T. A. Seimon et al., mBio 4(4):e00410-13, 2013, doi:10.1128/mBio.00410-13]. Their findings of CDV strains infecting tigers, in combination with recent information from other felids, paints a different picture, one in which CDV strains from a variety of geographic lineages and with a variety of amino acid residues in the hemagglutinin gene binding site can infect cats and cause disease. Although CDV has been known as a multihost disease since its discovery in domestic dogs in 1905, perhaps it is time to reconsider whether these noncanid species are not just incidental or "spillover" hosts but, rather, a normal part of the complex ecology of this infectious disease. PMID- 24045643 TI - A highly conducting organic metal derived from an organic-transistor material: benzothienobenzothiophene. AB - BTBT ([1]benzothieno[3,2-b][1]benzothiophene) is an organic semiconductor that realizes high mobility in organic transistors. Here we report that the charge transfer (CT) salt, (BTBT)2PF6, shows a high room-temperature conductivity of 1500 S cm(-1). This compound exhibits a resistivity jump around 150 K, but when it is covered with Apiezon N grease the resistivity jump is suppressed, and the metallic conductivity is maintained down to 60 K. Owing to the very high conductivity, the ESR signal shows a significantly asymmetric Dysonian lineshape (A/B ? 3) even at room temperature. Since most organic conductors are based on strong electron donors, it is remarkable that such a weak electron donor as BTBT realizes a stable and highly conducting organic metal. PMID- 24045644 TI - [Rare, but important: Endocrine diseases that every internist needs to know]. PMID- 24045645 TI - [Prevention of recurrent thromboembolisms: WARFASA (aspirin for the prevention of recurrent venous thromboembolism - the Warfarin and Aspirin Study)]. PMID- 24045646 TI - Multi-protein delivery by nanodiamonds promotes bone formation. AB - Bone morphogenetic proteins (BMPs) are well-studied regulators of cartilage and bone development that have been Food and Drug Administration (FDA)-approved for the promotion of bone formation in certain procedures. BMPs are seeing more use in oral and maxillofacial surgeries because of recent FDA approval of InFUSE((r)) for sinus augmentation and localized alveolar ridge augmentation. However, the utility of BMPs in medical and dental applications is limited by the delivery method. Currently, BMPs are delivered to the surgical site by the implantation of bulky collagen sponges. Here we evaluate the potential of detonation nanodiamonds (NDs) as a delivery vehicle for BMP-2 and basic fibroblast growth factor (bFGF). Nanodiamonds are biocompatible, 4- to 5-nm carbon nanoparticles that have previously been used to deliver a wide variety of molecules, including proteins and peptides. We find that both BMP-2 and bFGF are readily loaded onto NDs by physisorption, forming a stable colloidal solution, and are triggered to release in slightly acidic conditions. Simultaneous delivery of BMP-2 and bFGF by ND induces differentiation and proliferation in osteoblast progenitor cells. Overall, we find that NDs provide an effective injectable alternative for the delivery of BMP-2 and bFGF to promote bone formation. PMID- 24045650 TI - Potassium-paraaminobenzoic acid (Potaba(r))-associated DRESS syndrome. PMID- 24045651 TI - Microcystin-LR removal from aqueous solutions using a magnetically separable N doped TiO2 nanocomposite under visible light irradiation. AB - The performance of magnetically separable N-doped TiO2 was found to be significantly improved when compared with non-magnetic N-doped TiO2 for the removal of cyanotoxin microcystin-LR from aqueous medium. The observed enhanced photocatalytic activity may be related to the presence of ferrite nanoparticles in the composition of the magnetically separable composite N-doped TiO2. PMID- 24045647 TI - The exopolysaccharide matrix: a virulence determinant of cariogenic biofilm. AB - Many infectious diseases in humans are caused or exacerbated by biofilms. Dental caries is a prime example of a biofilm-dependent disease, resulting from interactions of microorganisms, host factors, and diet (sugars), which modulate the dynamic formation of biofilms on tooth surfaces. All biofilms have a microbial-derived extracellular matrix as an essential constituent. The exopolysaccharides formed through interactions between sucrose- (and starch-) and Streptococcus mutans-derived exoenzymes present in the pellicle and on microbial surfaces (including non-mutans) provide binding sites for cariogenic and other organisms. The polymers formed in situ enmesh the microorganisms while forming a matrix facilitating the assembly of three-dimensional (3D) multicellular structures that encompass a series of microenvironments and are firmly attached to teeth. The metabolic activity of microbes embedded in this exopolysaccharide rich and diffusion-limiting matrix leads to acidification of the milieu and, eventually, acid-dissolution of enamel. Here, we discuss recent advances concerning spatio-temporal development of the exopolysaccharide matrix and its essential role in the pathogenesis of dental caries. We focus on how the matrix serves as a 3D scaffold for biofilm assembly while creating spatial heterogeneities and low-pH microenvironments/niches. Further understanding on how the matrix modulates microbial activity and virulence expression could lead to new approaches to control cariogenic biofilms. PMID- 24045652 TI - Identifying symptom co-occurrence in persons with multiple sclerosis. AB - Patients with multiple sclerosis (MS) experience a myriad of symptoms. There is some evidence that symptoms may co-occur, or happen in particular combinations. Yet most existing studies focus on single symptoms and practitioners make a priori care decisions based on individual symptoms alone. We examined symptom co occurrences in patients with relapsing-remitting MS (RRMS), collecting qualitative and quantitative data (mixed methods; N = 140). Content analysis revealed fatigue, heat intolerance, numbness, balance problems, and leg weakness as the most common symptoms. Factor analysis revealed the following factors: urinary, problems with balance, vision, heat, depression, and sleep. These preliminary findings indicate co-occurrence of several disabling symptoms from the overall self-report MS-Related Symptom Scale and 3-month recall. This information will guide health care professionals in developing targeted interventions and improve outcomes. PMID- 24045653 TI - Intimate partner abuse among older women: qualitative systematic review. AB - The purpose of this qualitative systematic review was to more fully understand intimate partner abuse (IPA) among older women and to explicate strategies for enhancing their well-being. The sample (N = 20) was assembled based on an expansive search of the peer-reviewed literature using multiple electronic databases. Qualitative findings were extracted and coded/categorized. Reflective memos were developed, and a cohesive interpretation of the raw data emerged. IPA tends to be a multigenerational problem that older women are reluctant to discuss. With age, IPA assumes different forms, and many older women actively choose to make the best of their situations. Older women cope by trying to make sense of their lives and nurturing themselves in small ways. Occasionally, events occur that enable permanent change. Nurses are encouraged to nonjudgmentally assist older women to enhance their well-being, despite IPA. They are also urged to actively intervene when opportunities for significant change arise. PMID- 24045654 TI - Confocal microscopy to guide erbium:yttrium aluminum garnet laser ablation of basal cell carcinoma: an ex vivo feasibility study. AB - For the removal of superficial and nodular basal cell carcinomas (BCCs), laser ablation provides certain advantages relative to other treatment modalities. However, efficacy and reliability tend to be variable because tissue is vaporized such that none is available for subsequent histopathological examination for residual BCC (and to confirm complete removal of tumor). Intra-operative reflectance confocal microscopy (RCM) may provide a means to detect residual tumor directly on the patient and guide ablation. However, optimization of ablation parameters will be necessary to control collateral thermal damage and preserve sufficient viability in the underlying layer of tissue, so as to subsequently allow labeling of nuclear morphology with a contrast agent and imaging of residual BCC. We report the results of a preliminary study of two key parameters (fluence, number of passes) vis-a-vis the feasibility of labeling and RCM imaging in human skin ex vivo, following ablation with an erbium:yttrium aluminum garnet laser. PMID- 24045655 TI - Properties and applications of chemically functionalized graphene. AB - The vast and yet largely unexplored family of graphene materials has great potential for future electronic devices with novel functionalities. The ability to engineer the electrical and optical properties in graphene by chemically functionalizing it with a molecule or adatom is widening considerably the potential applications targeted by graphene. Indeed, functionalized graphene has been found to be the best known transparent conductor or a wide gap semiconductor. At the same time, understanding the mechanisms driving the functionalization of graphene with hydrogen is proving to be of fundamental interest for energy storage devices. Here we discuss recent advances on the properties and applications of chemically functionalized graphene. PMID- 24045656 TI - Iodine-131 dose-dependent gene expression: alterations in both normal and tumour thyroid tissues of post-Chernobyl thyroid cancers. AB - BACKGROUND: A strong, consistent association between childhood irradiation and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis. METHODS: We evaluated gene expression in 63 paired RNA specimens from frozen normal and tumour thyroid tissues with individual iodine-131 (I-131) doses (0.008-8.6 Gy, no unirradiated controls) received from Chernobyl fallout during childhood (Ukrainian-American cohort). Approximately half of these randomly selected samples (32 tumour/normal tissue RNA specimens) were hybridised on 64 whole-genome microarrays (Agilent, 4 * 44 K). Associations between I-131 dose and gene expression were assessed separately in normal and tumour tissues using Kruskal-Wallis and linear trend tests. Of 155 genes significantly associated with I-131 after Bonferroni correction and with >=2-fold increase per dose category, we selected 95 genes. On the remaining 31 RNA samples these genes were used for validation purposes using qRT-PCR. RESULTS: Expression of eight genes (ABCC3, C1orf9, C6orf62, FGFR1OP2, HEY2, NDOR1, STAT3, and UCP3) in normal tissue and six genes (ANKRD46, CD47, HNRNPH1, NDOR1, SCEL, and SERPINA1) in tumour tissue was significantly associated with I-131. PANTHER/DAVID pathway analyses demonstrated significant over-representation of genes coding for nucleic acid binding in normal and tumour tissues, and for p53, EGF, and FGF signalling pathways in tumour tissue. CONCLUSION: The multistep process of radiation carcinogenesis begins in histologically normal thyroid tissue and may involve dose-dependent gene expression changes. PMID- 24045657 TI - Comment on 'Prevalence of the metabolic syndrome and cardiovascular disease risk in chemotherapy-treated testicular germ cell tumour survivors'. PMID- 24045658 TI - Emergency presentation of cancer and short-term mortality. AB - BACKGROUND: The short-term survival following a cancer diagnosis in England is lower than that in comparable countries, with the difference in excess mortality primarily occurring in the months immediately after diagnosis. We assess the impact of emergency presentation (EP) on the excess mortality in England over the course of the year following diagnosis. METHODS: All colorectal and cervical cancers presenting in England and all breast, lung, and prostate cancers in the East of England in 2006-2008 are included. The variation in the likelihood of EP with age, stage, sex, co-morbidity, and income deprivation is modelled. The excess mortality over 0-1, 1-3, 3-6, and 6-12 months after diagnosis and its dependence on these case-mix factors and presentation route is then examined. RESULTS: More advanced stage and older age are predictive of EP, as to a lesser extent are co-morbidity, higher income deprivation, and female sex. In the first month after diagnosis, we observe case-mix-adjusted excess mortality rate ratios of 7.5 (cervical), 5.9 (colorectal), 11.7 (breast ), 4.0 (lung), and 20.8 (prostate) for EP compared with non-EP. CONCLUSION: Individuals who present as an emergency experience high short-term mortality in all cancer types examined compared with non-EPs. This is partly a case-mix effect but EP remains predictive of short-term mortality even when age, stage, and co-morbidity are accounted for. PMID- 24045659 TI - Lysyl oxidase secreted by tumour endothelial cells promotes angiogenesis and metastasis. AB - BACKGROUND: Molecules that are highly expressed in tumour endothelial cells (TECs) may be candidates for specifically targeting TECs. Using DNA microarray analysis, we found that the lysyl oxidase (LOX) gene was upregulated in TECs compared with its expression in normal endothelial cells (NECs). LOX is an enzyme that enhances invasion and metastasis of tumour cells. However, there are no reports on the function of LOX in isolated TECs. METHODS: TECs and NECs were isolated to investigate LOX function in TECs. LOX inhibition of in vivo tumour growth was also assessed using beta-aminopropionitrile (BAPN). RESULTS: LOX expression was higher in TECs than in NECs. LOX knockdown inhibited cell migration and tube formation by TECs, which was associated with decreased phosphorylation of focal adhesion kinase (Tyr 397). Immunostaining showed high LOX expression in human tumour vessels in vivo. Tumour angiogenesis and micrometastasis were inhibited by BAPN in an in vivo tumour model. CONCLUSION: LOX may be a TEC marker and a possible therapeutic target for novel antiangiogenic therapy. PMID- 24045660 TI - Aerosolised 5-azacytidine suppresses tumour growth and reprogrammes the epigenome in an orthotopic lung cancer model. AB - BACKGROUND: Epigenetic silencing by promoter methylation and chromatin remodelling affects hundreds of genes and is a causal event for lung cancer. Treatment of patients with low doses of the demethylating agent 5-azacytidine in combination with the histone deacetylase inhibitor entinostat has yielded clinical responses. The subcutaneous dosing route for consecutive days and reduced bioavailability of 5-azacytidine because of inactivation by cytidine deaminase may limit the expansion of epigenetic therapy into Phase III trials. To mitigate these barriers, an aerosol of 5-azacytidine was generated and characterised. METHODS: The effect of aerosol vs systemic delivery of 5 azacytidine on tumour burden and molecular response of engrafted lung tumours in the nude rat was compared. RESULTS: Pharmacokinetics revealed major improvement in the half-life of 5-azacytidine in lung tissue with aerosol delivery. Aerosolised 5-azacytidine significantly reduced lung tumour burden and induced global demethylation of the epigenome at one-third of the comparable effective systemic dose. High commonality for demethylation of genes was seen in tumours sampled throughout lung lobes and across treated animals receiving the aerosolised drug. CONCLUSION: Collectively, these findings show that aerosolised 5-azacytidine targets the lung, effectively reprogrammes the epigenome of tumours, and is a promising approach to combine with other drugs for treating lung cancer. PMID- 24045661 TI - Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma. AB - BACKGROUND: We previously reported that expressions of the pro-angiogenic cytokines angiopoietin-2 (Ang-2), follistatin, granulocyte colony-stimulating factor, hepatocyte growth factor, leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor were associated with the response to sorafenib in patients with advanced hepatocellular carcinoma (HCC). The aim of the present study is to examine the same relationship in a larger cohort. METHODS: In the current retrospective cohort study, we measured serum levels of the eight cytokines in 120 consecutive HCC patients who were treated with sorafenib. We evaluated the effects of increased expression of serum cytokines on progression-free survival (PFS) and overall survival (OS). RESULTS: Elevated expression of Ang-2 correlated both with significantly shorter PFS (hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.21-2.81), and OS (HR, 1.95; 95% CI, 1.21-3.17). Patients with more than three cytokines expressed above the median similarly had significantly shorter PFS (HR, 1.98; 95% CI, 1.30-3.06) and OS (HR, 1.94; 95% CI, 1.19-3.22). Differences in OS were evident in cases with the evidence of macroscopic vascular invasion or extrahepatic metastasis. CONCLUSION: High expression of Ang-2 or more than cytokines in serum is associated with poor PFS and OS in HCC patients treated with sorafenib. PMID- 24045662 TI - gamma-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate. AB - BACKGROUND: gamma-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect. METHODS: We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo. RESULTS: Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased. CONCLUSION: Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects. PMID- 24045663 TI - Mean overall survival gain with aflibercept plus FOLFIRI vs placebo plus FOLFIRI in patients with previously treated metastatic colorectal cancer. AB - BACKGROUND: Mean survival in cancer trials can be estimated with statistical techniques to extrapolate study survival curves. This methodology was applied to data from the VELOUR trial, where use of the novel biologic aflibercept (ziv aflibercept in the United States) in combination with fluorouracil+leucovorin+irinotecan (FOLFIRI), had significantly increased median overall survival (OS) by 1.44 months, vs placebo plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) resistant to, or that had progressed following, an oxaliplatin-containing regimen. METHODS: Parametric survival analyses were used to identify distributions with the best fit to the empirical VELOUR data. Mean OS for the two treatment groups (and pre-defined subgroups) was calculated from the fitted curves over a 15-year survival period. RESULTS: Overall, the log-logistic distribution was the best-fitting for both treatment arms and, with it, the estimated difference in mean OS over 15 years between aflibercept+FOLFIRI and placebo+FOLFIRI was 4.7 months. In addition, the survival advantage with aflibercept was at least 3 months for the ITT population, whichever distribution was used to extrapolate survival. CONCLUSION: Extrapolation of survival curves suggests the mean OS difference for aflibercept in the VELOUR trial is at least 3 months in the ITT population and selected subgroups. PMID- 24045664 TI - Reply: 'Comment on Prevalence of the metabolic syndrome and cardiovascular disease risk in chemotherapy-treated testicular germ cell tumour survivors'. PMID- 24045665 TI - The FGFR1 inhibitor PD173074 induces mesenchymal-epithelial transition through the transcription factor AP-1. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) is a crucial process in cancer progression that provides cancer cells with the ability to escape from the primary focus, invade stromal tissues and migrate to distant regions. Cell lines that lack E-cadherin show increased tumorigenesis and metastasis, and the expression levels of E-cadherin and Snail correlate inversely with the prognosis of patients suffering from breast cancer or oral squamous cell carcinoma (OSCC). Moreover, recent studies have shown that most EMT cases are regulated by soluble growth factors or cytokines. Among these factors, fibroblast growth factors (FGFs) execute diverse functions by binding to and activating members of the FGF receptor (FGFR) family, including FGFR1-4. Fibroblast growth factor receptor 1 is an oncoprotein that is involved in tumorigenesis, and PD173074 is known to be a selective inhibitor of FGFR1. However, the roles of FGFR1 and FGFR1 inhibitors have not yet been examined in detail. METHODS: Here, we investigated the expression of FGFR1 in head and neck squamous cell carcinoma (HNSCC) and the role of the FGFR1 inhibitor PD173074 in carcinogenesis and the EMT process. RESULTS: Fibroblast growth factor receptor 1 was highly expressed in 54% of HNSCC cases and was significantly correlated with malignant behaviours. Nuclear FGFR1 expression was also observed and correlated well with histological differentiation, the pattern of invasion and abundant nuclear polymorphism. Fibroblast growth factor receptor 1 was also overexpressed in EMT cell lines compared with non-EMT cell lines. Furthermore, treatment of HOC313 cells with PD173074 suppressed cellular proliferation and invasion and reduced ERK1/2 and p38 activation. These cells also demonstrated morphological changes, transforming from spindle- to cobble stone-like in shape. In addition, the expression levels of certain matrix metalloproteinases (MMPs), whose genes contain activator protein-1 (AP-1) promoter sites, as well as Snail1 and Snail2 were reduced following PD173074 treatment. CONCLUSION: Taken together, these data suggest that PD173074 inhibits the MAPK pathway, which regulates the activity of AP-1 and induces MET. Furthermore, this induction of MET likely suppresses cancer cell growth and invasion. PMID- 24045666 TI - EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer-related morbidity and mortality worldwide. Epidermal growth factor receptor (EGFR)-targeted therapy is an attractive strategy alternative to conventional cancer treatments for HNSCC, but its efficacy remains controversial. T-cell-based immunotherapy has been proposed as a novel therapeutic approach to improve the clinical outcome for HNSCC. In this study, we report human epidermal receptor (HER) family epitopes that induced CD4 T-cell responses to HNSCC. The results provide support for a novel strategy to treat HNSCC by combining EGFR targeted therapy with T-cell-based immunotherapy. METHODS: We evaluated the capacity of predicted CD4 T-cell peptide epitopes from EGFR to induce antitumour immune responses in vitro. In addition, EGFR inhibitors were evaluated for their ability to augment tumour MHC class II expression in HNSCC cell lines and subsequently increase T-cell recognition. RESULTS: Among several predicted peptide epitopes, EGFR875-889 elicited CD4 T-cell responses that were restricted by HLA-DR4, DR15, or DR53 molecules, indicating that the peptide functions as a promiscuous T-cell epitope. The peptide-reactive T cells responded to autologous dendritic cells loaded with EGFR-expressing tumour cell lysates, indicating that these epitopes are naturally processed. In addition, the CD4 T cells were capable of directly recognising and killing HNSCC cells expressing EGFR and the appropriate HLA class II molecule. T cells reactive with the EGFR875-889 epitope could be detected in the blood of HNSCC patients. EGFR875-889-reactive CD4 T cells were also able to recognise several peptide analogues derived from homologous regions of EGFR family members, HER-2, HER-3 and c-MET. Finally, we examined the effects of EGFR tyrosine kinase inhibition or EGFR-blocking antibodies on CD4 T-cell tumour reactivity. Treatment of tumour cells with the EGFR inhibitors enhanced tumour recognition by EGFR875-889-reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells. CONCLUSION: We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR875-889 functions as a promiscuous helper T-cell epitope that can elicit effective antitumour T-cell responses against tumours expressing HER family members and c-MET. These observations should facilitate the translation of T-cell based immunotherapy into the clinic for the treatment of HNSCC and provide a rational basis for EGFR inhibition, immune-targeted combination therapy. PMID- 24045667 TI - PICT1 regulates TP53 via RPL11 and is involved in gastric cancer progression. AB - BACKGROUND: The TP53 pathway is frequently inactivated in human cancers. PICT1 (also known as GLTSCR2) is a novel regulator of the MDM2-TP53 pathway via its interaction with the ribosomal protein RPL11 in the nucleolus. However, the clinical significance of PICT1 in gastric cancer remains unknown. METHODS: To evaluate PICT1 function, we used shRNA to inhibit PICT1 expression in gastric cancer cells that expressed wild-type TP53. PICT1 expression and TP53 mutation status were quantified in 110 cases of primary gastric cancer to explore the impact of PICT1 expression levels on gastric cancer. RESULTS: Deficiency of PICT1 significantly impaired cell proliferation and colony formation via TP53-mediated cell cycle arrest. Following induction of PICT1 deficiency, RPL11 translocated out of the nucleolus. Of the 110 gastric cancer samples tested, 70 (63.6%) and 40 (36.4%) tumours expressed wild-type and mutant TP53, respectively. In gastric cancer patients with wild-type TP53 tumours, patients with relatively low PICT1 expression levels had a better prognosis compared with high expression level patients (P=0.046). CONCLUSION: The findings suggest that PICT1 has a crucial role in gastric cancer progression by regulating the MDM2-TP53 pathway through RPL11. Clinically, PICT1 expression is a novel prognostic parameter in gastric cancer patients with wild-type TP53 tumours. PMID- 24045668 TI - Buccodental side effects of sunitinib in patients with metastatic renal cell carcinoma. AB - BACKGROUND: Sunitinib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma (RCC). Few data evaluated severe buccodental adverse events. The aim of this study was to evaluate sunitinib buccodental toxicity in patients with metastatic RCC and to compare it with that of standard chemotherapy in patients with other solid cancers. METHODS: Patients with RCC treated with sunitinib and patients with other solid tumours treated with chemotherapy were followed for 3 months. Data on dental appliances, oral hygiene/care practices before and during treatment were collected. RESULTS: A total of 116 patients were included (58 RCC treated by sunitinib: group S, and 58 treated by chemotherapy: group C). No differences in dental care habits were noted before treatment. In group S, patients reported significantly more frequent pain (P<0.01), teeth instability (P=0.01), gingival bleeding (P=0.01) and change in teeth colour (P=0.02). In all, 58% of patients in this group had to modify their diet (P<0.01). Frequency of dentist visits for teeth removal was increased (25% vs 8%, P=0.01). CONCLUSION: Sunitinib seems to increase buccodental toxicity as compared with chemotherapy. This finding emphasises the need for optimal dental care and standardised dental follow-up in patients treated with sunitinib. PMID- 24045670 TI - Heavy fermion properties of the Kondo Lattice model. AB - We study the S = 1/2 Kondo lattice model which is widely used to describe heavy fermion behavior. In conventional treatments of the model the Kondo interaction is decoupled in favour of a hybridization of conduction and localized f electrons. However, such an approximation breaks the local gauge symmetry and implicates that the local f-occupation is no longer conserved. To avoid these problems, we use in this work an alternative approach to the model based on the Projective Renormalization Method (PRM). Thereby, within the conduction electron spectral function we identify the lattice Kondo resonance as an almost flat excitation near the Fermi surface which is composed of conduction electron creation operators combined with localized spin fluctuations. This leads to an alternative description of the Kondo resonance without having to resort to an artificial symmetry breaking. PMID- 24045669 TI - Randomised phase II study of S-1/cisplatin plus TSU-68 vs S-1/cisplatin in patients with advanced gastric cancer. AB - BACKGROUND: This study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and the novel oral antiangiogenic agent TSU-68 could contribute to gastric cancer treatment. METHODS: Ninety-three patients with chemotherapy naive unresectable or recurrent advanced gastric cancers were randomised into two groups: TSU-68 plus S-1/CDDP (group A) and S-1/CDDP (group B) groups. Both patient groups received identical S-1 and CDDP dosages. TSU-68 was orally administered for 35 consecutive days. Group B patients received S-1 orally twice daily for three consecutive weeks, followed by intravenous CDDP on day 8. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS periods were 208 and 213 days in groups A and B, respectively (P=0.427). Median survival periods for groups A and B were 497.0 and 463.5 days, respectively (P=0.219). No statistically significant differences were noted for PFS, survival or the adverse event (AE) incidence rate. All AEs were expected according to previous reports for TSU-68, TS-1, and CDDP. CONCLUSION: Combination therapy involving TSU-68, S 1, and CDDP was safe and well tolerated in patients with chemotherapy-naive unresectable or recurrent advanced gastric cancers. However, factors related to therapeutic efficacy should be investigated further. PMID- 24045671 TI - A robust amino-functionalized titanium(iv) based MOF for improved separation of acid gases. AB - A combination of adsorption, microcalorimetry, infra-red spectroscopy and modeling has been implemented to reveal the potential of the H2S resistant amino functionalized Ti MOF MIL-125 porous solid for the concomitant elimination of CO2 and H2S from biogas and natural gas. PMID- 24045672 TI - Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women: findings from the Women's Health Initiative Observational Study. AB - OBJECTIVE: Research comparing hormone therapy (HT) doses, regimens, and routes of delivery in relation to cardiovascular disease (CVD) outcomes has been limited. This study directly compared different estrogen doses, routes of delivery, and HT formulations in postmenopausal women in relation to the risk of coronary heart disease (CHD), stroke, CVD mortality, total CVD, and all-cause mortality. METHODS: The Women's Health Initiative Observational Study is a multicenter prospective cohort study that was conducted at 40 US sites. Analyses included 93,676 postmenopausal women aged 50 to 79 years at study entry who were recruited from September 1994 to December 1998, with annual follow-up through August 14, 2009. RESULTS: The mean follow-up was 10.4 years. In direct comparisons, oral estradiol was associated with lower hazard ratios (HRs) for stroke than oral conjugated equine estrogens (CEE; HR, 0.64; 95% CI, 0.40-1.02), but statistical power was limited. Similarly, transdermal estradiol was associated with a moderate but nonsignificantly lower risk of CHD compared with oral CEE (HR, 0.63; 95% CI, 0.37-1.06). For other outcomes, comparisons revealed no appreciable differences by estrogen doses, formulations, or routes of delivery. Absolute risks of CVD events and all-cause mortality were markedly lower in younger women compared with older women. CONCLUSIONS: In direct comparisons, various HT doses and regimens are associated with similar rates of cardiovascular events and all cause mortality. However, oral estradiol may be associated with a lower risk of stroke, and transdermal estradiol may be associated with a lower risk of CHD, compared with conventional-dose oral CEE. Additional research is needed to confirm these hypotheses. PMID- 24045673 TI - Efficacy of yoga for vasomotor symptoms: a randomized controlled trial. AB - OBJECTIVE: This study aims to determine the efficacy of yoga in alleviating vasomotor symptoms (VMS) frequency and bother. METHODS: This study was a three-by two factorial, randomized controlled trial. Eligible women were randomized to yoga (n = 107), exercise (n = 106), or usual activity (n = 142), and were simultaneously randomized to a double-blind comparison of omega-3 fatty acid (n = 177) or placebo (n = 178) capsules. Yoga intervention consisted of 12 weekly 90 minute yoga classes with daily home practice. Primary outcomes were VMS frequency and bother assessed by daily diaries at baseline, 6 weeks, and 12 weeks. Secondary outcomes included insomnia symptoms (Insomnia Severity Index) at baseline and 12 weeks. RESULTS: Among 249 randomized women, 237 (95%) completed 12-week assessments. The mean baseline VMS frequency was 7.4 per day (95% CI, 6.6 to 8.1) in the yoga group and 8.0 per day (95% CI, 7.3 to 8.7) in the usual activity group. Intent-to-treat analyses included all participants with response data (n = 237). There was no difference between intervention groups in the change in VMS frequency from baseline to 6 and 12 weeks (mean difference [yoga--usual activity] from baseline at 6 wk, -0.3 [95% CI, -1.1 to 0.5]; mean difference [yoga--usual activity] from baseline at 12 wk, -0.3 [95% CI, -1.2 to 0.6]; P = 0.119 across both time points). Results were similar for VMS bother. At week 12, yoga was associated with an improvement in insomnia symptoms (mean difference [yoga - usual activity] in the change in Insomnia Severity Index, 1.3 [95% CI, 2.5 to -0.1]; P = 0.007). CONCLUSIONS: Among healthy women, 12 weeks of yoga class plus home practice, compared with usual activity, do not improve VMS frequency or bother but reduce insomnia symptoms. PMID- 24045675 TI - Polymorphisms within the FANCA gene associate with premature ovarian failure in Korean women. AB - OBJECTIVE: This study investigated whether polymorphisms within the Fanconi anemia complementation group A (FANCA) gene contribute to the increased risk of premature ovarian failure (POF) in Korean women. METHODS: Ninety-eight women with POF and 218 controls participated in this study. Genomic DNA from peripheral blood was isolated, and GoldenGate genotyping assay was used to identify single nucleotide polymorphisms (SNPs) within the FANCA gene. RESULTS: Two significant SNPs (rs1006547 and rs2239359; P < 0.05) were identified by logistic regression analysis, but results were insignificant after Bonferroni correction. Six SNPs formed a linkage disequilibrium block, and three main haplotypes were found. Two of three haplotypes (AAAGAA and GGGAGG) distributed highly in the POF group, whereas the remaining haplotype (GGAAGG) distributed highly in the control group by logistic regression analysis (highest odds ratio, 2.515; 95% CI, 1.515-4.175; P = 0.00036). CONCLUSIONS: Our observations suggest that genetic variations in the FANCA gene may increase the risk for POF in Korean women. PMID- 24045674 TI - Association of GALNT3 gene polymorphisms with bone mineral density in Chinese postmenopausal women: the Peking Vertebral Fracture study. AB - OBJECTIVE: GALNT3 gene encodes the glycosyltransferase polypeptide N acetylgalactosaminyltransferase-3 (ppGalNacT3), which initiates the O glycosylation of fibroblast growth factor 23 (FGF23) that is important in phosphorous regulation. Inactivating mutations of the GALNT3 gene can cause familial tumoral calcinosis. The aim of present study is to investigate the association of GALNT3 polymorphisms with osteoporosis phenotypes in Chinese postmenopausal women. METHODS: A community-based population of 1,353 postmenopausal women was randomly selected in Beijing. Bone mineral densities (BMDs) of the lumbar spine, femoral neck (FN), and total hip (TH) were measured by dual-energy x-ray absorptiometry. Vertebral fracture phenotypes were ascertained by vertebral x-ray reading. Osteoporotic fracture phenotypes were obtained from questionnaires. Single nucleotide polymorphisms of GALNT3 were determined by TaqMan allelic discrimination assay. Differences in BMD, serum phosphorus, or serum calcium across diverse genotypes or haplotypes were analyzed by general linear model analysis of covariance. Linear regression or logistic regression was used for association analyses of different osteoporosis phenotypes, phosphorous, or calcium. Partial correlation was used to investigate the relationship between phosphorus or calcium and BMD. RESULTS: We found that polymorphisms of rs1863196, rs6710518, and rs13429321 were significantly associated with FN BMD (P values of 0.002, 0.003, and 0.002, respectively). Polymorphisms of rs1863196, rs6710518, rs4667492, rs13429321, and rs6721582 were associated with TH BMD (P values of 0.002, 0.004, 0.037, 0.005, and 0.014, respectively). Haplotype-1 additive and dominant models were found to be associated with TH BMD (P values of 0.035 and 0.024, respectively). Haplotype-2 dominant model was found to be associated with FN BMD (P = 0.003) and TH BMD (P = 0.001). CONCLUSIONS: GALNT3 may play a role in genetic susceptibility to osteoporosis among Chinese postmenopausal women. Efforts should be exerted to replicate our findings in other similar and ethnically diverse populations. PMID- 24045676 TI - Genome-wide association studies and epistasis analyses of candidate genes related to age at menarche and age at natural menopause in a Korean population. AB - OBJECTIVE: The aim of this study was to identify polymorphisms and gene-gene interactions that are significantly associated with age at menarche and age at menopause in a Korean population. METHODS: A total of 3,452 and 1,827 women participated in studies of age at menarche and age at natural menopause, respectively. Linear regression analyses adjusted for residence area were used to perform genome-wide association studies (GWAS), candidate gene association studies, and interactions between the candidate genes for age at menarche and age at natural menopause. RESULTS: In GWAS, four single nucleotide polymorphisms (SNPs; rs7528241, rs1324329, rs11597068, and rs6495785) were strongly associated with age at natural menopause (lowest P = 9.66 * 10). However, GWAS of age at menarche did not reveal any strong associations. In candidate gene association studies, SNPs with P < 0.01 were selected to test their synergistic interactions. For age at natural menopause, there was a significant interaction between intronic SNPs on ADAM metallopeptidase with thrombospondin type I motif 9 (ADAMTS9) and SMAD family member 3 (SMAD3) genes (P = 9.52 * 10). For age at menarche, there were three significant interactions between three intronic SNPs on follicle-stimulating hormone receptor (FSHR) gene and one SNP located at the 3' flanking region of insulin-like growth factor 2 receptor (IGF2R) gene (lowest P = 1.95 * 10). CONCLUSIONS: Novel SNPs and synergistic interactions between candidate genes are significantly associated with age at menarche and age at natural menopause in a Korean population. PMID- 24045677 TI - Prevention of falls, prevention of osteoporosis, or both: what is the best strategy for preventing fractures in older women? PMID- 24045678 TI - Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. AB - OBJECTIVE: The efficacy and safety of low-dose paroxetine 7.5 mg for the treatment of menopausal vasomotor symptoms were evaluated in two multicenter, double-blind, placebo-controlled, phase 3 studies of 12 and 24 weeks' duration. METHODS: Postmenopausal women were randomly assigned 1:1 to receive paroxetine 7.5 mg or placebo once daily. The four primary efficacy endpoints included mean changes in the frequency and severity of moderate to severe vasomotor symptoms on weeks 4 and 12; an additional endpoint was persistence of treatment benefit on week 24. RESULTS: Five hundred ninety-one participants were randomly assigned to treatment with paroxetine 7.5 mg, and 593 participants were randomly assigned to treatment with placebo. All primary endpoints were met in the 24-week study; three of four primary endpoints were met in the 12-week study. In both studies, paroxetine 7.5 mg significantly reduced the mean weekly vasomotor symptom frequency compared with placebo on week 4 (P < 0.0001 for both studies) and week 12 (P = 0.0090, 12-wk study; P = 0.0001, 24-wk study). Mean weekly reduction in vasomotor symptom severity was significantly greater for paroxetine 7.5 mg than for placebo on week 4 (P = 0.0048) in the 12-week study and on week 4 (P = 0.0452) and week 12 (P = 0.0114) in the 24-week study. Persistence of treatment benefit was demonstrated in the 24-week study. Most treatment-emergent adverse events were mild or moderate in severity. No clinically significant changes in laboratory values or vital signs were noted, and no short-term discontinuation of symptoms followed treatment cessation. CONCLUSIONS: Paroxetine 7.5 mg is well tolerated, is effective in reducing the frequency and severity of menopausal vasomotor symptoms, and demonstrates persistence of treatment benefit through 24 weeks of treatment. PMID- 24045679 TI - Silibinin inhibits the production of pro-inflammatory cytokines through inhibition of NF-kappaB signaling pathway in HMC-1 human mast cells. AB - BACKGROUND: Silibinin is the major active molecule of silymarin, the mixture of flavonolignans extracted from Cirsium japonicum. It has been used for the treatment of hepatitis and inflammation-related diseases. In the present study, the effects of silibinin on allergic inflammation and its signaling were investigated in the induced human mast cells. METHODS: Cell growth inhibition induced by silibinin was measured by MTS assay. Histamine release was measured by enzyme immunoassay. The tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-8 (IL-8) secreted protein levels and mRNA levels were measured by the ELISA assay and RT-PCR, respectively. The NF-kappaB promoter activity was examined by a luciferase assay. RESULTS: Silibinin suppressed the growth of HMC-1 cells and also reduced the production and mRNA expression of pro inflammatory cytokines such as TNF-alpha, IL-6, and IL-8. Moreover, silibinin inhibited the nuclear translocation of nuclear factor (NF)-kappaB through inhibition of the phosphorylation of IkappaBalpha and suppressed NF-kappaB transcriptional activity in stimulated HMC-1 cells. CONCLUSIONS: Taken together, these results indicate that silibinin inhibits the production of pro-inflammatory cytokines through inhibition of NF-kappaB signaling pathway in HMC-1 human mast cells, suggesting that silibinin could be used for the treatment of mast cell derived allergic inflammatory diseases. PMID- 24045691 TI - Trans-illuminated laser speckle imaging of collateral artery blood flow in ischemic mouse hindlimb. AB - The mouse ischemic hindlimb model is used widely for studying collateral artery growth (i.e., arteriogenesis) in response to increased shear stress. Nonetheless, precise measurements of regional shear stress changes along individual collateral arteries are lacking. Our goal is to develop and verify trans-illumination laser speckle flowmetry (LSF) for this purpose. Studies of defibrinated bovine blood flow through tubes embedded in tissue-mimicking phantoms indicate that trans illumination LSF better maintains sensitivity with an increasing tissue depth when compared to epi-illumination, with an ~50% reduction in the exponential decay of the speckle velocity signal. Applying trans-illuminated LSF to the gracilis muscle collateral artery network in vivo yields both improved sensitivity and reduced noise when compared to epi-illumination. Trans illuminated LSF images reveal regional differences in collateral artery blood velocity after femoral artery ligation and are used to measure an ~2-fold increase in the shear stress at the entrance regions to the muscle. We believe these represent the first direct measurements of regional shear stress changes in individual mouse collateral arteries. The ability to capture deeper vascular signals using a trans-illumination configuration for LSF may expand the current applications for LSF, which could have bearing on determining how shear stress magnitude and direction regulate arteriogenesis. PMID- 24045689 TI - Integrative approaches for finding modular structure in biological networks. AB - A central goal of systems biology is to elucidate the structural and functional architecture of the cell. To this end, large and complex networks of molecular interactions are being rapidly generated for humans and model organisms. A recent focus of bioinformatics research has been to integrate these networks with each other and with diverse molecular profiles to identify sets of molecules and interactions that participate in a common biological function - that is, 'modules'. Here, we classify such integrative approaches into four broad categories, describe their bioinformatic principles and review their applications. PMID- 24045692 TI - Spatiotemporal analysis for indocyanine green-aided imaging of rheumatoid arthritis in hand joints. AB - Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease, with a prevalence of 0.5 to 1% in the general population. Imaging can possibly aid in early diagnosis, crucial to effective personalized therapeutic strategies and treatment follow-up. The intravenous administration of indocyanine green (ICG) has been considered for identifying synovial hyperperfusion as an RA physiological biomarker. However, while the distribution of ICG in the human hand is a time-dependent process, the particular biodistribution dynamic patterns established following intravenous administration have not yet been studied. For this reason, the dynamic relationships of ICG distribution in the human hand in RA patients using a method based on principal component analysis are analyzed. In vivo analyses were corroborated by simulations of clinical scenarios using a finite element method. Observations of spatiotemporal characteristics are contrasted to fluorescence intensity images and magnetic resonance images of the hand joints, employed as the anatomical and diagnostic reference. Processing results for 450 joints from 5 healthy volunteers and 10 patients show that image features obtained from the spatiotemporal analysis offer good congruence with synovitis and reveal better detection performance compared to observations of raw fluorescence intensity images. PMID- 24045690 TI - The interplay between cell signalling and mechanics in developmental processes. AB - Force production and the propagation of stress and strain within embryos and organisms are crucial physical processes that direct morphogenesis. In addition, there is mounting evidence that biomechanical cues created by these processes guide cell behaviours and cell fates. In this Review we discuss key roles for biomechanics during development to directly shape tissues, to provide positional information for cell fate decisions and to enable robust programmes of development. Several recently identified molecular mechanisms suggest how cells and tissues might coordinate their responses to biomechanical cues. Finally, we outline long-term challenges in integrating biomechanics with genetic analysis of developing embryos. PMID- 24045693 TI - Femtosecond laser etching of dental enamel for bracket bonding. AB - The aim is to investigate femtosecond laser ablation as an alternative method for enamel etching used before bonding orthodontic brackets. A focused laser beam is scanned over enamel within the area of bonding in a saw tooth pattern with a varying number of lines. After patterning, ceramic brackets are bonded and bonding quality of the proposed technique is measured by a universal testing machine. The results are compared to the conventional acid etching method. Results show that bonding strength is a function of laser average power and the density of the ablated lines. Intrapulpal temperature changes are also recorded and observed minimal effects are observed. Enamel surface of the samples is investigated microscopically and no signs of damage or cracking are observed. In conclusion, femtosecond laser exposure on enamel surface yields controllable patterns that provide efficient bonding strength with less removal of dental tissue than conventional acid-etching technique. PMID- 24045694 TI - Preventative health advice for families moving to developing countries. PMID- 24045695 TI - Flexible all solid-state supercapacitors based on chemical vapor deposition derived graphene fibers. AB - Flexible all-solid-state supercapacitors based on graphene fibers are demonstrated in this study. Surface-deposited oxide nanoparticles are used as pseudo-capacitor electrodes to achieve high capacitance. This supercapacitor electrode has an areal capacitance of 42 mF cm(-2), which is comparable to the capacitance for fiber-based supercapacitors reported to date. During the bending and cycling of the fiber-based supercapacitor, the stability could be maintained without sacrificing the electrochemical performance, which provides a novel and simple way to develop flexible, lightweight and efficient graphene-based devices. PMID- 24045697 TI - Trends in alcohol consumption in Europe and their impact on major alcohol-related cancers. PMID- 24045696 TI - Proteomic analysis of detergent-resistant membrane microdomains in trophozoite blood stage of the human malaria parasite Plasmodium falciparum. AB - Intracellular pathogens contribute to a significant proportion of infectious diseases worldwide. The successful strategy of evading the immune system by hiding inside host cells is common to all the microorganism classes, which exploit membrane microdomains, enriched in cholesterol and sphingolipids, to invade and colonize the host cell. These assemblies, with distinct biochemical properties, can be isolated by means of flotation in sucrose density gradient centrifugation because they are insoluble in nonionic detergents at low temperature. We analyzed the protein and lipid contents of detergent-resistant membranes from erythrocytes infected by Plasmodium falciparum, the most deadly human malaria parasite. Proteins associated with membrane microdomains of trophic parasite blood stages (trophozoites) include an abundance of chaperones, molecules involved in vesicular trafficking, and enzymes implicated in host hemoglobin degradation. About 60% of the identified proteins contain a predicted localization signal suggesting a role of membrane microdomains in protein sorting/trafficking. To validate our proteomic data, we raised antibodies against six Plasmodium proteins not characterized previously. All the selected candidates were recovered in floating low-density fractions after density gradient centrifugation. The analyzed proteins localized either to internal organelles, such as the mitochondrion and the endoplasmic reticulum, or to exported membrane structures, the parasitophorous vacuole membrane and Maurer's clefts, implicated in targeting parasite proteins to the host erythrocyte cytosol or surface. The relative abundance of cholesterol and phospholipid species varies in gradient fractions containing detergent-resistant membranes, suggesting heterogeneity in the lipid composition of the isolated microdomain population. This study is the first report showing the presence of cholesterol-rich microdomains with distinct properties and subcellular localization in trophic stages of Plasmodium falciparum. PMID- 24045699 TI - Direct synthesis of ethylene glycol from methanol by dielectric barrier discharge. AB - Ethylene glycol (EG) has been obtained with 71.53% selectivity and 15.77% methanol conversion under optimized conditions using a double dielectric barrier discharge (DDBD) reactor. The importance of the discharge intensity and the obvious catalytic effect of the hydrogen co-feed were observed. PMID- 24045698 TI - Nephrons require Rho-kinase for proximal-distal polarity development. AB - Epithelial tubules must have the right length and pattern for proper function. In the nephron, planar cell polarity controls elongation along the proximal-distal axis. As the tubule lengthens, specialized segments (proximal, distal etc.) begin to differentiate along it. Other epithelia need Rho-kinase for planar cell polarity but it is not known whether Rho-kinase is involved in this way in the nephron. We show that Rho-kinase is essential for the morphogenesis of nephrons, specifically for correct cell orientation and volume. We use fluorescent reporter models and progenitor-specific markers to demonstrate that inhibition of Rho kinase prevents proper proximal-distal axis formation, causes segments to develop abnormally, and progenitor-cell segregation to fail. Our data demonstrate the importance of Rho-kinase in normal nephron tubulogenesis and patterning. PMID- 24045700 TI - An extraordinarily stable catalyst: Pt NPs supported on two-dimensional Ti3C2X2 (X = OH, F) nanosheets for oxygen reduction reaction. AB - High dispersion Pt nanoparticles supported on 2D Ti3C2X2 (X = OH, F) nanosheets are presented and electro-chemical measurements confirm that the Pt/Ti3C2X2 catalyst shows enhanced durability and improved ORR activity compared with the commercial Pt/C catalyst. PMID- 24045701 TI - Enhanced by-product desorption via laser assisted electron beam induced deposition of W(CO)6 with improved conductivity and resolution. AB - Nanowires with higher tungsten (W) concentration and enhanced conductivity were grown via the laser assisted electron beam induced deposition (LAEBID) technique using tungsten hexacarbonyl W(CO)6 as the gas precursor. Periodic, pulsed laser irradiation facilitated CO desorption during growth by heating the deposit. Deposit purity improved with laser pulse width up to the threshold for pyrolytic laser chemical vapor deposition (LCVD). Higher resolution was also observed and was attributed to reduced CO incorporation and higher deposit density. The optimal composition and lowest resistivity was achieved by synchronizing the electron beam induced deposition and laser assist such that (1) the electron beam induced deposit is less than a monolayer per cycle and (2) the laser induced heating is just below the LCVD threshold. PMID- 24045703 TI - Importance of spiritual care for cardiac patients admitted to coronary care units in the Gaza Strip: patients' perception. AB - PURPOSE: This study aimed to assess the perception of hospitalized cardiac patients in coronary care units (CCUs) in the Gaza Strip about the importance of assessing and providing spiritual care to them. DESIGN: This was a cross sectional study. METHODS: A valid and reliable instrument previously developed by Musa was used to assess patients' perception about the importance of assessing spiritual needs and providing spiritual care to cardiac patients admitted to CCUs. FINDINGS: Out of 279 cardiac patients, 275 (response rate of 98.6%) agreed to be involved in this study. Results revealed that both assessing spiritual needs (69.69%) and providing spiritual care (76.97%) were very important to cardiac patients with rating spiritual care intervention as more important than spiritual assessment. CONCLUSIONS: Assessing and providing spiritual care is crucial to cardiac patients. Therefore, health policy makers need to pay more attention to this group of vulnerable patients and need to adopt a spiritual care policy into the Palestinian health care system, which might help to decrease their stress, length of hospitalization, and the cost of treatment. PMID- 24045702 TI - Aptamers: multifunctional molecules for biomedical research. AB - Aptamers are single-stranded oligonucleotides that fold into well-defined three dimensional shapes, allowing them to bind their targets with high affinity and specificity. They can be generated through an in vitro process called "Systemic Evolution of Ligands by Exponential Enrichment" and applied for specific detection, inhibition, and characterization of various targets like small organic and inorganic molecules, proteins, and whole cells. Aptamers have also been called chemical antibodies because of their synthetic origin and their similar modes of action to antibodies. They exhibit significant advantages over antibodies in terms of their small size, synthetic accessibility, and ability to be chemically modified and thus endowed with new properties. The first generation of aptamer drug "Macugen" was available for public use within 25 years of the discovery of aptamers. With others in the pipeline for clinical trials, this emerging field of medical biotechnology is raising significant interest. However, aptamers pose different problems for their development than for antibodies that need to be addressed to achieve practical applications. It is likely that current developments in aptamer engineering will be the basis for the evolution of improved future bioanalytical and biomedical applications. The present review discusses the development of aptamers for therapeutics, drug delivery, target validation and imaging, and reviews some of the challenges to fully realizing the promise of aptamers in biomedical applications. PMID- 24045704 TI - Place knowing of persons and populations: restoring the place work of nursing. AB - Place emerges when space acquires definition in social constructions of meaning as landscape-languages, which reflect assumptions about physical and social realities. The place work of nursing, which resonated throughout Nightingale's work and the profession's evolution, focuses on human health and healing in the historical transitions and landscape-languages of populations. However, evidence based practice dominated by empirical knowing inadequately addresses complex health and illness dynamics between place and populations. Translating evidence to the life course experiences of individuals and populations requires place knowing of human situated embodiment within discrete space. An exploration of the concept of place, its application to nursing, and the need for a place paradigm for practice is presented. A sense of salience and situated cognition has been identified as the essential element of the transformation needed in the education of nurses. Place knowing integrates other patterns of knowing (empirical, ethical, aesthetical, personal, unknowing, sociopolitical, and emancipatory) in a situated cognition. Place knowing, like other established patterns of knowing, is a significant epistemological foundation of nursing. Place knowing allows the nuanced intricately complex dynamics of embodied situated human health and illness to be examined, the salience of the particulars to be considered, and the whole of the landscape-languages to emerge. PMID- 24045708 TI - Biomarkers: new biomarker for Sjogren's syndrome--time to treat patients. PMID- 24045709 TI - Gout: multinational gout guidelines: how do we move beyond 'deja vu'? PMID- 24045706 TI - Carbon dioxide-sensing in organisms and its implications for human disease. AB - The capacity of organisms to sense changes in the levels of internal and external gases and to respond accordingly is central to a range of physiologic and pathophysiologic processes. Carbon dioxide, a primary product of oxidative metabolism is one such gas that can be sensed by both prokaryotic and eukaryotic cells and in response to altered levels, elicit the activation of multiple adaptive pathways. The outcomes of activating CO2-sensitive pathways in various species include increased virulence of fungal and bacterial pathogens, prey seeking behavior in insects as well as taste perception, lung function, and the control of immunity in mammals. In this review, we discuss what is known about the mechanisms underpinning CO2 sensing across a range of species and consider the implications of this for physiology, disease progression, and the possibility of developing new therapeutics for inflammatory and infectious disease. PMID- 24045710 TI - Fibromyalgia: fibromyalgia-all in the brain? PMID- 24045705 TI - Defending the genome from the enemy within: mechanisms of retrotransposon suppression in the mouse germline. AB - The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline. PMID- 24045707 TI - Towards a mechanism-based approach to pain management in osteoarthritis. AB - Pain is the defining symptom of osteoarthritis (OA), yet available treatment options, of which NSAIDs are the most common, provide inadequate pain relief and are associated with serious health risks when used long term. Chronic pain pathways are subject to complex levels of control and modulation, both in the periphery and in the central nervous system. Ongoing clinical and basic research is uncovering how these pathways operate in OA. Indeed, clinical investigation into the types of pain associated with progressive OA, the presence of central sensitization, the correlation with structural changes in the joint, and the efficacy of novel analgesics affords new insights into the pathophysiology of OA pain. Moreover, studies in disease-specific animal models enable the unravelling of the cellular and molecular pathways involved. We expect that increased understanding of the mechanisms by which chronic OA-associated pain is generated and maintained will offer opportunities for targeting and improving the safety of analgesia. In addition, using clinical and genetic approaches, it might become possible to identify subsets of patients with pain of different pathophysiology, thus enabling a tailored approach to pain management. PMID- 24045711 TI - Integration-specific In Vitro Evaluation of Lentivirally Transduced Rhesus CD34(+) Cells Correlates With In Vivo Vector Copy Number. AB - Hematopoietic stem cell (HSC) gene therapy using integrating vectors has a potential leukemogenic risk due to insertional mutagenesis. To reduce this risk, a limitation of <=2 average vector copy number (VCN) per cell is generally accepted. We developed an assay for VCN among transduced CD34(+) cells that reliably predicts in vivo VCN in 16 rhesus recipients of CD34(+) cells transduced with a green fluorescent protein (GFP) (or yellow fluorescent protein (YFP)) encoding lentiviral vector. Using GFP (or YFP)-specific probe/primers by real time PCR, VCN among transduced CD34(+) cells had no correlation with VCN among granulocytes or lymphocytes in vivo assayed 6 months post-transplantation. This was a likely result of residual plasmids present in the vector preparation. We then designed self-inactivating long terminal repeat (SIN-LTR)-specific probe/primers, which detect only integrated provirus. Evaluation with SIN-LTR probe/primers resulted in a positive correlation of VCN among transduced CD34(+) cells with granulocytes and lymphocytes in vivo. The transduced CD34(+) cells had higher VCN (25.1 +/- 5.6) as compared with granulocytes (2.8 +/- 1) and lymphocytes (2.4 +/- 0.7). In summary, an integrated provirus-specific real-time PCR system demonstrated nine- to tenfold higher VCN in transduced CD34(+) cells in vitro, as compared with VCN in vivo. Therefore, the restriction of <=2 VCN before infusion might unnecessarily limit gene transfer efficacy.Molecular Therapy-Nucleic Acids (2013) 2, e122; doi:10.1038/mtna.2013.49; published online 17 September 2013. PMID- 24045712 TI - Minimal-length Synthetic shRNAs Formulated with Lipid Nanoparticles are Potent Inhibitors of Hepatitis C Virus IRES-linked Gene Expression in Mice. AB - We previously identified short synthetic shRNAs (sshRNAs) that target a conserved hepatitis C virus (HCV) sequence within the internal ribosome entry site (IRES) of HCV and potently inhibit HCV IRES-linked gene expression. To assess in vivo liver delivery and activity, the HCV-directed sshRNA SG220 was formulated into lipid nanoparticles (LNP) and injected i.v. into mice whose livers supported stable HCV IRES-luciferase expression from a liver-specific promoter. After a single injection, RNase protection assays for the sshRNA and (3)H labeling of a lipid component of the nanoparticles showed efficient liver uptake of both components and long-lasting survival of a significant fraction of the sshRNA in the liver. In vivo imaging showed a dose-dependent inhibition of luciferase expression (>90% 1 day after injection of 2.5 mg/kg sshRNA) with t1/2 for recovery of about 3 weeks. These results demonstrate the ability of moderate levels of i.v.-injected, LNP-formulated sshRNAs to be taken up by liver hepatocytes at a level sufficient to substantially suppress gene expression. Suppression is rapid and durable, suggesting that sshRNAs may have promise as therapeutic agents for liver indications.Molecular Therapy-Nucleic Acids (2013) 2, e123; doi:10.1038/mtna.2013.50; published online 17 September 2013. PMID- 24045713 TI - Trichloromethyl ketones: asymmetric transfer hydrogenation and subsequent Jocic type reactions with amines. AB - Amino-amides are important pharmaceutical building-blocks. The enantioselective reduction of trichloromethyl ketones using ruthenium transfer hydrogenation catalysts is reported. The products react in a range of Jocic-type reactions to give enantiomerically enriched amino-amides. PMID- 24045715 TI - Surfactant-free hydrothermal synthesis of sub-10 nm gamma-Fe2O3-polymer porous composites with high catalytic activity for reduction of nitroarenes. AB - Porous gamma-Fe2O3-polymer composites were synthesized by a novel one-pot surfactant-free hydrothermal approach. The gamma-Fe2O3-polymer composites consisting of 3.5 nm gamma-Fe2O3 nanoparticles and porous polymers exhibited high catalytic activity and recycling performance in the reduction of nitroarenes. PMID- 24045716 TI - Interpregnancy interval and risk of autistic disorder. AB - BACKGROUND: A recent California study reported increased risk of autistic disorder in children conceived within a year after the birth of a sibling. METHODS: We assessed the association between interpregnancy interval and risk of autistic disorder using nationwide registry data on pairs of singleton full siblings born in Norway. We defined interpregnancy interval as the time from birth of the first-born child to conception of the second-born child in a sibship. The outcome of interest was autistic disorder in the second-born child. Analyses were restricted to sibships in which the second-born child was born in 1990-2004. Odds ratios (ORs) were estimated by fitting ordinary logistic models and logistic generalized additive models. RESULTS: The study sample included 223,476 singleton full-sibling pairs. In sibships with interpregnancy intervals <9 months, 0.25% of the second-born children had autistic disorder, compared with 0.13% in the reference category (>= 36 months). For interpregnancy intervals shorter than 9 months, the adjusted OR of autistic disorder in the second-born child was 2.18 (95% confidence interval 1.42-3.26). The risk of autistic disorder in the second-born child was also increased for interpregnancy intervals of 9-11 months in the adjusted analysis (OR = 1.71 [95% CI = 1.07-2.64]). CONCLUSIONS: Consistent with a previous report from California, interpregnancy intervals shorter than 1 year were associated with increased risk of autistic disorder in the second-born child. A possible explanation is depletion of micronutrients in mothers with closely spaced pregnancies. PMID- 24045718 TI - Swimmer illness associated with marine water exposure and water quality indicators: impact of widely used assumptions. AB - BACKGROUND: Studies of health risks associated with recreational water exposure require investigators to make choices about water quality indicator averaging techniques, exposure definitions, follow-up periods, and model specifications; however, investigators seldom describe the impact of these choices on reported results. Our objectives are to report illness risk from swimming at a marine beach affected by nonpoint sources of urban runoff, measure associations between fecal indicator bacteria levels and subsequent illness among swimmers, and investigate the sensitivity of results to a range of exposure and outcome definitions. METHODS: In 2009, we enrolled 5674 people in a prospective cohort at Malibu Beach, a coastal marine beach in California, and measured daily health symptoms 10-19 days later. Concurrent water quality samples were analyzed for indicator bacteria using culture and molecular methods. We compared illness risk between nonswimmers and swimmers, and among swimmers exposed to various levels of fecal indicator bacteria. RESULTS: Diarrhea was more common among swimmers than nonswimmers (adjusted odds ratio = 1.88 [95% confidence interval = 1.09-3.24]) within 3 days of the beach visit. Water quality was generally good (fecal indicator bacteria levels exceeded water quality guidelines for only 7% of study samples). Fecal indicator bacteria levels were not consistently associated with swimmer illness. Sensitivity analyses demonstrated that overall inference was not substantially affected by the choice of exposure and outcome definitions. CONCLUSIONS: This study suggests that the 3 days following a beach visit may be the most relevant period for health outcome measurement in recreational water studies. Under the water quality conditions observed in this study, fecal indicator bacteria levels were not associated with swimmer illness. PMID- 24045717 TI - Susceptibility to mortality in weather extremes: effect modification by personal and small-area characteristics. AB - BACKGROUND: Extremes of temperature have been associated with short-term increases in daily mortality. We identified subpopulations with increased susceptibility to dying during temperature extremes, based on personal demographics, small-area characteristics, and preexisting medical conditions. METHODS: We examined Medicare participants in 135 US cities and identified preexisting conditions based on hospitalization records before their deaths, from 1985 to 2006. Personal characteristics were obtained from the Medicare records, and area characteristics were assigned based on zip code of residence. We conducted a case-only analysis of over 11 million deaths and evaluated modification of the risk of dying associated with extremely hot days and extremely cold days, continuous temperatures, and water vapor pressure. Modifiers included preexisting conditions, personal characteristics, zip code-level population characteristics, and land cover characteristics. For each effect modifier, a city-specific logistic regression model was fitted and then an overall national estimate was calculated using meta-analysis. RESULTS: People with certain preexisting conditions were more susceptible to extreme heat, with an additional 6% (95% confidence interval = 4%-8%) increase in the risk of dying on an extremely hot day in subjects with previous admission for atrial fibrillation, an additional 8% (4%-12%) in subjects with Alzheimer disease, and an additional 6% (3%-9%) in subjects with dementia. Zip code level and personal characteristics were also associated with increased susceptibility to temperature. CONCLUSIONS: We identified several subgroups of the population who are particularly susceptible to temperature extremes, including persons with atrial fibrillation. PMID- 24045722 TI - CAP/EOM-CCSD method for the study of potential curves of resonant states. AB - The equation-of-motion coupled-cluster (EOM-CC) method along with the complex absorbing potential (CAP) is used for the study of resonance in e(-)-N2 and e(-) CO. Resonance position and width are studied as a function of bond length. We report the potential curves (PC) of the resonance states. PMID- 24045720 TI - Immortal time bias in the study of stillbirth risk factors: the example of gestational diabetes. AB - BACKGROUND: Current understanding of the increased risk for stillbirth in gestational diabetes mellitus is often based on large cohort studies in which the risk of stillbirth in women with this disease is compared with the risk in women without. However, such studies could be susceptible to immortal time bias because, although many cohorts begin at 20 weeks' gestation, pregnancies must "survive" until 24-28 weeks in order to be screened and diagnosed with gestational diabetes. METHODS: We describe the theoretical potential for immortal time bias in studies of stillbirth and gestational diabetes and then quantify the magnitude of the bias using 2006 United States vital statistics data. RESULTS: Although gestational diabetes was protective against stillbirth when including all births (relative risk = 0.88 [95% confidence interval = 0.79-0.99]), restricting analyses to births at >28 weeks' gestation reversed the effect and diabetes became associated with an increased risk of stillbirth (1.25 [1.11 1.41]). CONCLUSION: Immortal time before diagnosis of gestational diabetes may bias our understanding of the stillbirth risk associated with this condition. PMID- 24045721 TI - Do interviewer and physician health ratings predict mortality?: a comparison with self-rated health. AB - BACKGROUND: Despite the serious biases that characterize self-rated health, researchers rely heavily on these ratings to predict mortality. Using newly collected survey data, we examine whether simple ratings of participants' health provided by interviewers and physicians can markedly improve mortality prediction. METHODS: We use data from a prospective cohort study based on a nationally representative sample of older adults in Taiwan. We estimate proportional-hazard models of all-cause mortality between the 2006 interview and 30 June 2011 (mean 4.7 years' follow-up). RESULTS: Interviewer ratings were more strongly associated with mortality than physician or self-ratings, even after controlling for a wide range of covariates. Neither respondent nor physician ratings substantially improve mortality prediction in models that include interviewer ratings. The predictive power of interviewer ratings likely arises in part from interviewers' incorporation of information about the respondents' physical and mental health into their assessments. CONCLUSIONS: The findings of this study support the routine inclusion of a simple question at the end of face to-face interviews, comparable to self-rated health, asking interviewers to provide an assessment of respondents' overall health. The costs of such an undertaking are minimal and the potential gains substantial for demographic and health researchers. Future work should explore the strength of the link between interviewer ratings and mortality in other countries and in surveys that collect less detailed information on respondent health, functioning, and well-being. PMID- 24045719 TI - Case fatality risk of influenza A (H1N1pdm09): a systematic review. AB - BACKGROUND: During the 2009 influenza pandemic, uncertainty surrounding the seriousness of human infections with the H1N1pdm09 virus hindered appropriate public health response. One measure of seriousness is the case fatality risk, defined as the probability of mortality among people classified as cases. METHODS: We conducted a systematic review to summarize published estimates of the case fatality risk of the pandemic influenza H1N1pdm09 virus. Only studies that reported population-based estimates were included. RESULTS: We included 77 estimates of the case fatality risk from 50 published studies, about one-third of which were published within the first 9 months of the pandemic. We identified very substantial heterogeneity in published estimates, ranging from less than 1 to more than 10,000 deaths per 100,000 cases or infections. The choice of case definition in the denominator accounted for substantial heterogeneity, with the higher estimates based on laboratory-confirmed cases (point estimates = 0-13,500 per 100,000 cases) compared with symptomatic cases (point estimates = 0-1,200 per 100,000 cases) or infections (point estimates = 1-10 per 100,000 infections). Risk based on symptomatic cases increased substantially with age. CONCLUSIONS: Our review highlights the difficulty in estimating the seriousness of infection with a novel influenza virus using the case fatality risk. In addition, substantial variability in age-specific estimates complicates the interpretation of the overall case fatality risk and comparisons among populations. A consensus is needed on how to define and measure the seriousness of infection before the next pandemic. PMID- 24045725 TI - Landscape with two poplars: Wassily Kandinsky. PMID- 24045726 TI - Efforts stall to curb nursing home antipsychotic use. PMID- 24045727 TI - CDC estimates 300,000 US cases of Lyme disease annually. PMID- 24045728 TI - Early treatment of ischemic stroke with intravenous tPA reduces disability risk. PMID- 24045738 TI - A piece of my mind. Recon man. PMID- 24045739 TI - Managing substance dependence as a chronic disease: is the glass half full or half empty? PMID- 24045740 TI - Chronic care management for dependence on alcohol and other drugs: the AHEAD randomized trial. AB - IMPORTANCE: People with substance dependence have health consequences, high health care utilization, and frequent comorbidity but often receive poor-quality care. Chronic care management (CCM) has been proposed as an approach to improve care and outcomes. OBJECTIVE: To determine whether CCM for alcohol and other drug dependence improves substance use outcomes compared with usual primary care. DESIGN, SETTING, AND PARTICIPANTS: The AHEAD study, a randomized trial conducted among 563 people with alcohol and other drug dependence at a Boston, Massachusetts, hospital-based primary care practice. Participants were recruited from September 2006 to September 2008 from a freestanding residential detoxification unit and referrals from an urban teaching hospital and advertisements; 95% completed 12-month follow-up. INTERVENTIONS: Participants were randomized to receive CCM (n=282) or no CCM (n=281). Chronic care management included longitudinal care coordinated with a primary care clinician; motivational enhancement therapy; relapse prevention counseling; and on-site medical, addiction, and psychiatric treatment, social work assistance, and referrals (including mutual help). The no CCM (control) group received a primary care appointment and a list of treatment resources including a telephone number to arrange counseling. MAIN OUTCOMES AND MEASURES: The primary outcome was self reported abstinence from opioids, stimulants, or heavy drinking. Biomarkers were secondary outcomes. RESULTS: There was no significant difference in abstinence from opioids, stimulants, or heavy drinking between the CCM (44%) and control (42%) groups (adjusted odds ratio, 0.84; 95% CI, 0.65-1.10; P=.21). No significant differences were found for secondary outcomes of addiction severity, health-related quality of life, or drug problems. No subgroup effects were found except among those with alcohol dependence, in whom CCM was associated with fewer alcohol problems (mean score, 10 vs 13; incidence rate ratio, 0.85; 95% CI, 0.72 1.00; P=.048). CONCLUSIONS AND RELEVANCE: Among persons with alcohol and other drug dependence, CCM compared with a primary care appointment but no CCM did not increase self-reported abstinence over 12 months. Whether more intensive or longer-duration CCM is effective requires further investigation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00278447. PMID- 24045741 TI - Mobility limitation in the older patient: a clinical review. AB - IMPORTANCE: Mobility limitations are common in older adults, affecting the physical, psychological, and social aspects of an older adult's life. OBJECTIVE: To identify mobility risk factors, screening tools, medical management, need for physical therapy, and efficacy of exercise interventions for older primary care patients with limited mobility. EVIDENCE ACQUISITION: Search of PubMed and PEDro from January 1985 to March 31, 2013, using the search terms mobility limitation, walking difficulty, and ambulatory difficulty to identify English-language, peer reviewed systematic reviews, meta-analyses, and Cochrane reviews assessing mobility limitation and interventions in community-dwelling older adults. Articles not appearing in the search referenced by reviewed articles were also evaluated. FINDINGS: The most common risk factors for mobility impairment are older age, low physical activity, obesity, strength or balance impairment, and chronic diseases such as diabetes or arthritis. Several tools are available to assess mobility in the ambulatory setting. Referral to physical therapy is appropriate, because physical therapists can assess mobility limitations and devise curative or function-enhancing interventions. Relatively few studies support therapeutic exercise to improve mobility limitation. Strong evidence supports resistance and balance exercises for improving mobility-limiting physical weakness and balance disorders. Assessing a patient's physical environment and the patient's ability to adapt to it using mobility devices is critical. CONCLUSIONS AND RELEVANCE: Identification of older adults at risk for mobility limitation can be accomplished through routine screening in the ambulatory setting. Addressing functional deficits and environmental barriers with exercise and mobility devices can lead to improved function, safety, and quality of life for patients with mobility limitations. PMID- 24045742 TI - Antioxidant supplements to prevent mortality. AB - CLINICAL QUESTION: Are antioxidant supplements associated with higher or lower all-cause mortality? BOTTOM LINE: Antioxidant supplements are not associated with lower all-cause mortality. Beta carotene, vitamin E, and higher doses of vitamin A may be associated with higher all-cause mortality. PMID- 24045743 TI - Trends in adult emergency department visits in California by insurance status, 2005-2010. PMID- 24045744 TI - Early parenteral nutrition in critical illness. PMID- 24045745 TI - Early parenteral nutrition in critical illness. PMID- 24045746 TI - Statin therapy for hyperlipidemia. PMID- 24045747 TI - Early parenteral nutrition in critical illness--reply. PMID- 24045748 TI - Statin therapy for hyperlipidemia. PMID- 24045749 TI - Statin therapy for hyperlipidemia--reply. PMID- 24045752 TI - Environment and the senses. PMID- 24045753 TI - JAMA patient page. Seizures. PMID- 24045755 TI - Stump appendicitis: a relatively under-reported reality. AB - Stump appendicitis (SA) is a rare and under-reported complication of open as well as laparoscopic appendicectomy. Diagnosis of SA is often delayed and requires a high index of suspicion in those presenting with signs and symptoms of appendicitis and a history of appendicectomy.We presented a case of SA in a 20 year-old man with a history of open appendicectomy. He was managed conservatively using intravenous antibiotics. The risk of SA is influenced by surgical technique; however, it is unclear whether the incidence is higher with laparoscopic or open procedures. There is little evidence guiding the management of SA with the majority of reported cases treated operatively. This diagnosis should be suspected on the basis of history and examination and CT scanning is a useful tool in most adult cases aiding diagnosis. Management may be guided by the progression of the patient's symptoms either towards operative intervention or a conservative approach. PMID- 24045756 TI - Prenatal diagnosis of i(18q) and dup(18q) cases by quantitative fluorescent PCR. AB - Particular sonographic fetal malformations are common in chromosome 18 aberrations, requiring invasive prenatal tests to confirm the diagnosis. Karyotyping is the gold standard assay in these cases, although it is a high complexity, expensive and approximately 2 weeks turnaround time test. On the contrary, quantitative fluorescent PCR is considered an accurate, simple, low cost and rapid assay, particularly useful for the diagnosis of aneuploidies of chromosomes 13, 18 and 21 and for the detection of maternal cell contamination of the sample. Clinical presentation of two cases of rare chromosome 18 defects, diagnosed using both techniques. One case was an isochromosome and the other was a partial duplication. Quantitative fluorescent PCR was an invaluable tool for the cytogenetics laboratory. PMID- 24045757 TI - Laparoscopic resection of a large hepatic cyst compressing the inferior vena cava. PMID- 24045758 TI - Acute urinary retention in an adolescent girl and important learning points. AB - We presented a case of a 13-year-old girl who attended the emergency department with acute urinary retention and 1400 mL residual urine after catheterisation. She had no significant medical history, neurological examination was normal and she had not reached menarche. She was found to have a haematocolpos on ultrasound scan which was compressing the urinary bladder. Examination under anaesthesia confirmed an imperforate hymen and therefore an incision was performed and the haematocolpos drained. She managed to pass urine normally the day following her procedure. In this article, we emphasise on the differential diagnosis in this case and the learning points derived from it. PMID- 24045759 TI - Desmoplastic ameloblastoma of mandible. AB - Desmoplastic ameloblastoma is one of the six histopathological subtypes of ameloblastoma. The age and gender groups affected by desmoplastic are similar to those affected by the conventional ameloblastoma. It usually presents as a painless enlargement of the jaw. Owing to its deceptive radiological appearance as a mixed radiopaque-radiolucent lesion, it is often mistaken as a fibro-osseous lesion. Histologically, desmoplastic ameloblastoma has a densely collagenised and hypocellular stroma, where the epithelium tends to proliferate in the form of cords and nests instead of cellular islands. Most desmoplastic ameloblastomas display occasional classic islands of follicular ameloblastoma among the predominant strands and cords. Studies have shown that desmoplastic ameloblastoma shows a tendency to recur. We present a rare case of a tumour occurring in the anterior mandibular region in a 60-year-old man over a period of 11/2 months. PMID- 24045760 TI - Dystypia in acute stroke not attributable to aphasia or neglect. AB - A 68-year-old right-handed man had a sudden onset of impaired typing ability due to an ischaemic stroke that recovered over 2 months. The typing impairment was grossly out of proportion to his transient handwriting disturbance. Diffusion MRI showed a recent acute left temporoparietal infarct. There was no evidence of aphasia, alexia, agraphia, visuospatial inattention, sensory loss, neglect or poor coordination that could account for his isolated typing impairment. This example of a stroke that disproportionately affected typing more than handwriting abilities has practical implications for what deficits to look for in patients with stroke when assessing their fitness for work and rehabilitation requirements. PMID- 24045761 TI - A 52-year-old-male patient with metastatic non-small-cell lung cancer and recurrent venous thromboembolism in unusual sites despite anticoagulation. AB - The link between cancer and venous thromboembolism is well known, with an annual incidence rate of venous thromboembolism between 0.5% and 20% depending on the primary site and background risk factors. Current guidelines suggest treatment with low-molecular-weight heparin over oral vitamin K antagonists. However, data regarding the management of recurrent venous thromboembolism when the patient is under treatment with anticoagulants are sparse. In this article we present a patient with multiple thromboembolic events in unusual sites despite anticoagulant treatment and we discuss the management options. PMID- 24045762 TI - Endoscopic adhesiolysis for extensive tibialis posterior tendon and Achilles tendon adhesions following compound tendon rupture. AB - Tendon adhesion is one of the most common causes of disability following tendon surgery. A case of extensive peritendinous adhesions of the Achilles tendon and tibialis posterior tendon after compound rupture of the tendons was reported. This was managed by endoscopic adhesiolysis of both tendons. The endoscopic approach allows early postoperative mobilisation which can relieve the tendon adhesion. PMID- 24045763 TI - A patient with Loeys-Dietz syndrome treated with chemoradiotherapy for an oropharyngeal carcinoma. AB - We present the first published case of a patient with Loeys-Dietz syndrome (LDS) who was treated with radical chemoradiotherapy for an oropharyngeal carcinoma. In view of this newly recognised connective tissue disease, the uncertainty of severe toxicity from chemoradiotherapy to treat a potentially curative cancer posed a management challenge. The patient was treated with chemoradiotherapy and remains well with no evidence of recurrence at 3 years. Furthermore, we have observed minimal late effects secondary to chemoradiotherapy at 3 years following the completion of treatment suggesting that the underlying pathogenesis of LDS may provide an interesting human model to further elucidate the complex interactions of transforming growth factor beta1 (TGF-beta1) and tissue fibrosis secondary to chemoradiotherapy. A review of LDS as well as the association of TGF beta1 expression and tissue fibrosis is presented. PMID- 24045764 TI - Ring-shaped thrombus in left atrial appendage: a contraindication for valvotomy. PMID- 24045765 TI - Torpor in the Patagonian opossum (Lestodelphys halli): implications for the evolution of daily torpor and hibernation. AB - Hibernation and daily torpor are two distinct forms of torpor, and although they are related, it is not known how and in which sequence they evolved. As the pattern of torpor expressed by the oldest marsupial order the opossums (Didelphimorphia) may provide insights into the evolution of torpor, we aimed to provide the first quantitative data on the thermal biology and torpor expression of the rare Patagonian opossum (Lestodelphys halli). It is the opossum with the southernmost distribution, has a propensity of autumnal fattening, and therefore, is likely to hibernate. We captured two male Lestodelphys, which while in captivity displayed strong daily fluctuations of body temperatures (Tb) measured with implanted miniature data loggers even when they remained normothermic. In autumn and early winter, torpor was expressed occasionally when food was available, but cold exposure and food withdrawal increased torpor use. The mean Tb throughout the study was 32.2 +/- 1.4 degrees C, the minimum Tb measured in torpid Lestodelphys was 7.7 degrees C, average torpor bout duration was 10.3 h, and the maximum torpor bout duration was 42.5 h. Thus, the pattern of torpor expressed by Lestodelphys was intermediate between that of daily heterotherms and hibernators suggesting that it may represent an ancestral opportunistic torpor pattern from which the derived patterns of daily torpor and seasonal hibernation diverged. PMID- 24045766 TI - Femtosecond laser irradiation of metallic surfaces: effects of laser parameters on superhydrophobicity. AB - This work studies in detail the effect of femtosecond laser irradiation process parameters (fluence and scanning speed) on the hydrophobicity of the resulting micro/nano-patterned morphologies on stainless steel. Depending on the laser parameters, four distinctly different nano-patterns were produced, namely nano rippled, parabolic-pillared, elongated sinusoidal-pillared and triple roughness nano-structures. All of the produced structures were classified according to a newly defined parameter, the laser intensity factor (LIF); by increasing the LIF, the ablation rate and periodicity of the asperities increase. In order to decrease the surface energy, all of the surfaces were coated with a fluoroalkylsilane agent. Analysis of the wettability revealed enhanced superhydrophobicity for most of these structures, particularly those possessing the triple roughness pattern that also exhibited low contact angle hysteresis. The high permanent superhydrophobicity of this pattern is due to the special micro/nano-structure of the surface that facilitates the Cassie-Baxter state. PMID- 24045767 TI - MnO nanoparticle@mesoporous carbon composites grown on conducting substrates featuring high-performance lithium-ion battery, supercapacitor and sensor. AB - We demonstrate a facile, two-step coating/calcination approach to grow a uniform MnO nanoparticle@mesoporous carbon (MnO@C) composite on conducting substrates, by direct coating of the Mn-oleate precursor solution without any conducting/binding reagents, and subsequent thermal calcination. The monodispersed, sub-10 nm MnO nanoparticles offer high theoretical energy storage capacities and catalytic properties, and the mesoporous carbon coating allows for enhanced electrolyte transport and charge transfer towards/from MnO surface. In addition, the direct growth and attachment of the MnO@C nanocomposite in the supporting conductive substrates provide much reduced contact resistances and efficient charge transfer. These excellent features allow the use of MnO@C nanocomposites as lithium-ion battery and supercapacitor electrodes for energy storage, with high reversible capacity at large current densities, as well as excellent cycling and mechanical stabilities. Moreover, this MnO@C nanocomposite has also demonstrated a high sensitivity for H2O2 detection, and also exhibited attractive potential for the tumor cell analysis. PMID- 24045768 TI - Anxiety is associated with a reduction in both mortality and major adverse cardiovascular events five years after coronary stenting. AB - OBJECTIVE: Previous studies in post-myocardial infarction patients with heart failure have documented that high anxiety levels are associated with increased mortality. In this prospective study, we determined the impact of anxiety on long term event risk in stable coronary heart disease (CHD) patients treated with percutaneous coronary interventions (PCIs). METHODS: A total of 470 patients referred for PCI completed the Hospital Anxiety and Depression Scale (HADS) before undergoing stent implantation. Over a five-year follow-up period, data on survival, occurrence of major adverse cardiovascular events (MACEs) and repeat revascularization were obtained from n = 462 participants (98.3%). RESULTS: All cause mortality rates differed significantly across the four quartiles of the HADS anxiety subscale, the lowest number of deaths (1.9%) being seen in patients with the highest HADS-A quartile (scores >= 10) as compared to those in the three lower quartiles (11.8%, odds ratio = 0.14, 95%-confidence interval (95% CI): 0.03 0.60, p = 0.002). Cox regression models adjusted for a variety of potential somatic and procedural confounders confirmed the results from the univariate analyses (hazard ratio (HR) = 0.21, 95% CI: 0.05-0.91, p = 0.037). There were also fewer MACEs in anxious patients as compared to non-anxious subjects (HR = 0.34, 95% CI: 0.14-0.80, p = 0.014). In contrast, anxious patients had a higher rate of repeat revascularization (26.4% versus 16.6%, p = 0.033). CONCLUSIONS: In CHD patients undergoing elective PCI, higher anxiety levels are positively associated with survival and reduce the risk for MACE during the first five years after index PCI. The beneficial effects of anxiety on cardiovascular mortality and morbidity suggest that a differentiated approach to diagnosing and treating anxiety in CHD patients is warranted. PMID- 24045769 TI - Dynamic changes in left ventricular mass and in fat-free mass in top-level athletes during the competitive season. AB - BACKGROUND: Previous cross-sectional studies have demonstrated that fat-free mass (FFM) is an important determinant of left ventricular mass (LVM) in athletes. However, cross-sectional investigations have not the ability to detect the dynamic adaptation occurring with training. We hypothesized that LVM adapts concurrently with the increase of FFM induced by exercise conditioning. We sought to study the relationship between the variations of LVM and of FFM occurring in top-level soccer players during the season. METHODS: Twenty-three male top-level athletes were recruited. LVM was assessed by echocardiography and FFM by dual energy X-ray absorptiometry. Serial measurements were performed pre-season, after 1 month, at mid- and end-season, and after 2 months of detraining. RESULTS: LVM significantly increased at mid-season versus pre-season values, reaching the highest value at the end of the season (p < 0.05). While body weight did not vary during the study period, FFM significantly increased (p < 0.05 for mid-/end season vs. pre-season data). After the detraining, no significant differences were observed between pre-season and detraining echocardiographic data. The only independent predictors of LVM were left ventricular stroke volume and FFM (R = 0.36, p = 0.005; R = 0.35, p = 0.005, respectively). When DeltaLVM index was set as dependent variable, the only independent predictor was DeltaFFM (R = 0.87, p = 0.002). CONCLUSIONS: Changes in LVM occur in close association with changes in FFM, suggesting that the left ventricle adapts concurrently with the increase of the metabolically active tissue induced by training, i.e. the FFM. Therefore, the dynamic changes in FFM and LVM may reflect a physiological adaptation induced by intensive training. PMID- 24045771 TI - Language matters. PMID- 24045770 TI - Position statement on ethics, equipoise and research on charged particle radiation therapy. AB - The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research. PMID- 24045772 TI - Bridging the gap between transcriptome and proteome measurements identifies post translationally regulated genes. AB - MOTIVATION: Despite much dynamical cellular behaviour being achieved by accurate regulation of protein concentrations, messenger RNA abundances, measured by microarray technology, and more recently by deep sequencing techniques, are widely used as proxies for protein measurements. Although for some species and under some conditions, there is good correlation between transcriptome and proteome level measurements, such correlation is by no means universal due to post-transcriptional and post-translational regulation, both of which are highly prevalent in cells. Here, we seek to develop a data-driven machine learning approach to bridging the gap between these two levels of high-throughput omic measurements on Saccharomyces cerevisiae and deploy the model in a novel way to uncover mRNA-protein pairs that are candidates for post-translational regulation. RESULTS: The application of feature selection by sparsity inducing regression (l1 norm regularization) leads to a stable set of features: i.e. mRNA, ribosomal occupancy, ribosome density, tRNA adaptation index and codon bias while achieving a feature reduction from 37 to 5. A linear predictor used with these features is capable of predicting protein concentrations fairly accurately (R2 = 0.86). Proteins whose concentration cannot be predicted accurately, taken as outliers with respect to the predictor, are shown to have annotation evidence of post translational modification, significantly more than random subsets of similar size P < 0.02. In a data mining sense, this work also shows a wider point that outliers with respect to a learning method can carry meaningful information about a problem domain. PMID- 24045773 TI - Integrated profiling of three dimensional cell culture models and 3D microscopy. AB - MOTIVATION: Our goal is to develop a screening platform for quantitative profiling of colony organizations in 3D cell culture models. The 3D cell culture models, which are also imaged in 3D, are functional assays that mimic the in vivo characteristics of the tissue architecture more faithfully than the 2D cultures. However, they also introduce significant computational challenges, with the main barriers being the effects of growth conditions, fixations and inherent complexities in segmentation that need to be resolved in the 3D volume. RESULTS: A segmentation strategy has been developed to delineate each nucleus in a colony that overcomes (i) the effects of growth conditions, (ii) variations in chromatin distribution and (iii) ambiguities formed by perceptual boundaries from adjacent nuclei. The strategy uses a cascade of geometric filters that are insensitive to spatial non-uniformity and partitions a clump of nuclei based on the grouping of points of maximum curvature at the interface of two neighboring nuclei. These points of maximum curvature are clustered together based on their coplanarity and proximity to define dissecting planes that separate the touching nuclei. The proposed curvature-based partitioning method is validated with both synthetic and real data, and is shown to have a superior performance against previous techniques. Validation and sensitivity analysis are coupled with the experimental design that includes a non-transformed cell line and three tumorigenic cell lines, which covers a wide range of phenotypic diversity in breast cancer. Colony profiling, derived from nuclear segmentation, reveals distinct indices for the morphogenesis of each cell line. PMID- 24045774 TI - RNA-Pareto: interactive analysis of Pareto-optimal RNA sequence-structure alignments. AB - Incorporating secondary structure information into the alignment process improves the quality of RNA sequence alignments. Instead of using fixed weighting parameters, sequence and structure components can be treated as different objectives and optimized simultaneously. The result is not a single, but a Pareto set of equally optimal solutions, which all represent different possible weighting parameters. We now provide the interactive graphical software tool RNA Pareto, which allows a direct inspection of all feasible results to the pairwise RNA sequence-structure alignment problem and greatly facilitates the exploration of the optimal solution set. PMID- 24045775 TI - Pattern search in BioPAX models. AB - MOTIVATION: BioPAX is a standard language for representing complex cellular processes, including metabolic networks, signal transduction and gene regulation. Owing to the inherent complexity of a BioPAX model, searching for a specific type of subnetwork can be non-trivial and difficult. RESULTS: We developed an open source and extensible framework for defining and searching graph patterns in BioPAX models. We demonstrate its use with a sample pattern that captures directed signaling relations between proteins. We provide search results for the pattern obtained from the Pathway Commons database and compare these results with the current data in signaling databases SPIKE and SignaLink. Results show that a pattern search in public pathway data can identify a substantial amount of signaling relations that do not exist in signaling databases. AVAILABILITY: BioPAX-pattern software was developed in Java. Source code and documentation is freely available at http://code.google.com/p/biopax-pattern under Lesser GNU Public License. PMID- 24045776 TI - Use of autocorrelation scanning in DNA copy number analysis. AB - MOTIVATION: Data quality is a critical issue in the analyses of DNA copy number alterations obtained from microarrays. It is commonly assumed that copy number alteration data can be modeled as piecewise constant and the measurement errors of different probes are independent. However, these assumptions do not always hold in practice. In some published datasets, we find that measurement errors are highly correlated between probes that interrogate nearby genomic loci, and the piecewise-constant model does not fit the data well. The correlated errors cause problems in downstream analysis, leading to a large number of DNA segments falsely identified as having copy number gains and losses. METHOD: We developed a simple tool, called autocorrelation scanning profile, to assess the dependence of measurement error between neighboring probes. RESULTS: Autocorrelation scanning profile can be used to check data quality and refine the analysis of DNA copy number data, which we demonstrate in some typical datasets. CONTACT: lzhangli@mdanderson.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24045777 TI - A novel treatment regimen for Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is the most common, X-linked genetic, skeletal muscle disease, with various regimens of treatment. The objective of this study was to determine the safety and efficacy of a novel treatment regimen for this disease. Thirty boys with DMD were administered prednisone according to the following regimen: in the first year, 1.5 mg/kg/day for the first 3 months, 1.0 mg/kg/day for the next 3 months, 0.75 mg/kg/day for the next 3 months, and 0.5 mg/kg/day for the last 3 months. In the second year, prednisone was administered 0.5 mg/kg on the alternate day for 12 months. The muscle strength (Medical Research Council sum score and Gower's sign), serum enzymes (creatine kinase, creatine kinase isoenzyme-2, and lactate dehydrogenase), pulmonary function (forced vital capacity, maximum voluntary ventilation), body weight, height, and BMI were determined before treatment and 3, 6, 9, 12, and 24 months after treatment. The results showed that the patients' mean Medical Research Council sum score increased from 46.1 at the baseline to 53.6 at 12 months and was maintained at 24 months. Gower's sign disappeared in 22 (73.3%) patients at 12 months and 21 (70.0%) at 24 months. The serum levels of creatine kinase, creatine kinase isoenzyme-2, and lactate dehydrogenase decreased and pulmonary function improved after 24 months of treatment. Significantly increased weight gain, osteoporosis, and cushingoid features were not observed. Our results suggested that this novel prednisone regimen for DMD has similar efficacy and safety as other regimens. PMID- 24045778 TI - Expression of presynaptic markers in a neurodevelopmental animal model with relevance to schizophrenia. AB - Administration of N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) to rat pups at postnatal day (PND) 7, 9, and 11 [neonatal PCP (neoPCP) model] induces cognitive deficits similar to those observed in schizophrenia. Expression of presynaptic SNARE protein, synaptosomal-associated protein of 25 kDa (Snap25), has been shown to be downregulated in postmortem brains from patients with schizophrenia. The present study was designed to investigate the long-term effects of neoPCP administration on expression of presynaptic markers altered in schizophrenia. Using radioactive in-situ hybridization, the expression of Snap25 was measured in the prefrontal cortex and the hippocampal formation (CA1, CA3, CA4, and dentate gyrus) at PND 29 and 80 in neoPCP and control rats. As a secondary presynaptic marker, the expressional level of synaptophysin was also measured in the same areas. Stereological estimation of the number of neurons and volume was used to exclude potential bias in cell numbers. A significant reduction in the expression of Snap25 in the hippocampal CA4 region was observed in adult neoPCP rats (PND 80, P<0.01), but not in preadolescent rats (PND 29), indicating a late developmental manifestation of a presynaptic pathology. The number of neurons and volume of the CA4 region showed no change in PCP rats compared with the controls. Furthermore, expression of another presynaptic marker, synaptophysin, remained unaffected by the PCP treatment. These findings indicate that perinatal PCP injections induce a delayed presynaptic impact on the vesicle fusion machinery in a brain region important for cognitive processes. PMID- 24045780 TI - Intrauterine instillation of diluted seminal plasma at oocyte pick-up does not increase the IVF pregnancy rate: a double-blind, placebo controlled, randomized study. AB - STUDY QUESTION: Does intrauterine application of diluted seminal plasma (SP) at the time of ovum pick-up improve the pregnancy rate by >=14% in IVF treatment? SUMMARY ANSWER: Intrauterine instillation of diluted SP at the time of ovum pick up is unlikely to increase the pregnancy rate by >=14% in IVF. WHAT IS KNOWN ALREADY: SP modulates endometrial function, and sexual intercourse around the time of embryo transfer has been suggested to increase the likelihood of pregnancy. A previous randomized double-blind pilot study demonstrated a strong trend towards increased pregnancy rates following the intracervical application of undiluted SP. As this study was not conclusive and as the finding could have been confounded by sexual intercourse, the intrauterine application of diluted SP was investigated in the present trial. STUDY DESIGN, SIZE, DURATION: A single centre, prospective, double-blind, placebo-controlled, randomized, superiority trial on women undergoing IVF was conducted from April 2007 until February 2012 at the University Department of Gynaecological Endocrinology and Reproductive Medicine, Heidelberg, Germany. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was powered to detect an 14% increase in the clinical pregnancy rate and two sequential tests were planned using the Pocock spending function. At the first interim analysis, 279 women had been randomly assigned to intrauterine diluted SP (20% SP in saline from the patients' partner) (n = 138) or placebo (n = 141) at the time of ovum pick-up. MAIN RESULTS AND THE ROLE OF CHANCE: The clinical pregnancy rate per randomized patient was 37/138 (26.8%) in the SP group and 41/141 (29.1%) in the placebo group (difference: -2.3%, 95% confidence interval of the difference: -12.7 to +8.2%; P = 0.69). The live birth rate per randomized patient was 28/138 (20.3%) in the SP group and 33/141 (23.4%) in the placebo group (difference: -3.1%, 95% confidence interval of the difference: 12.7 to +6.6%; P = 0.56). It was decided to terminate the trial due to futility at the first interim analysis, at a conditional power of 62%. LIMITATIONS, REASONS FOR CAUTION: The confidence interval of the difference remains wide, thus clinically relevant differences cannot reliably be excluded based on this single study. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study cast doubt on the validity of the concept that SP increases endometrial receptivity and thus implantation in humans. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the department's own research facilities. TRIAL REGISTRATION NUMBER: DRKS00004615. PMID- 24045779 TI - Vascular endothelial growth factor and angiopoietin production by primate follicles during culture is a function of growth rate, gonadotrophin exposure and oxygen milieu. AB - STUDY QUESTION: What is the time course of production of vascular endothelial growth factor-A (VEGF-A), angiopoietin (ANGPT)-1 and ANGPT-2 by primate follicles during encapsulated three-dimensional culture, and what conditions affect their production? SUMMARY ANSWER: Primate follicles produce VEGF-A and ANGPT-2 in vitro, particularly after developing to the antral stage, with VEGF production influenced by FSH concentration and O(2) tension. WHAT IS KNOWN ALREADY: Folliculogenesis, i.e. the development of primordial follicles into mature, antral follicles, requires the creation of a vascular network in the follicle wall via a process called angiogenesis. Angiogenic factors including VEGFs and ANGPTs have documented roles in angiogenesis. However, direct studies on the production and regulation of angiogenic factors by individual, growing follicles are limited. STUDY DESIGN, SIZE, DURATION: Ovaries (n = 9 pairs) were obtained from rhesus macaques during the early follicular phase of the menstrual cycle (cycle days 1-4). Secondary (125-225 um) follicles were isolated mechanically, encapsulated into alginate (0.25% w/v) and cultured for 40 days. MATERIALS, SETTING, METHODS: Individual follicles were cultured in a 5 or 20% O(2) environment in alpha minimum essential medium supplemented with recombinant human (h) FSH. Half of the follicles had recombinant hLH added to the media from Days 30 to 40. Follicle diameters were measured weekly. Follicles were categorized at Week 5 as no-grow (NG; <250 MUm in diameter), slow-grow (SG; 251-499 MUm) and fast-grow (FG; >500 MUm). VEGF-A, ANGPT-1 and -2 concentrations in media were measured by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: VEGF concentrations were low throughout the culture for NG follicles. SG and FG follicles had detectable VEGF concentrations at Week 2, which continued to rise throughout culture. VEGF concentrations were distinct (P < 0.05) among all three follicle categories during Weeks 4 and 5. VEGF concentrations were higher (P < 0.05) in SG follicles in the presence of high/mid-dose FSH at 5% O(2). In contrast, there were no dose dependent differences in VEGF production for FG follicles based on FSH concentrations or O(2) tension. At Week 5, follicles that produced metaphase II oocytes, following exposure to an ovulatory hCG dose, secreted higher concentrations of VEGF than those containing germinal vesicle-intact oocytes. Media concentrations of ANGPT-1 were low throughout culture for all three follicle categories. ANGPT-2 concentrations were low throughout culture for NG follicles. In contrast, ANGPT-2 concentrations of SG and FG follicles continued to rise from Weeks 1 to 4. During Weeks 2-4, ANGPT-2 concentrations in FG follicles were significantly higher than those of SG and NG follicles (P < 0.05). LIMITATION, REASONS FOR CAUTION: This study reports VEGF-A, ANGPT-1 and -2 production by in vitro-developed individual primate (macaque) follicles, that is limited to the interval from the secondary to small antral stage. After VEGF and ANGPT-1 assays, the limited remaining samples did not allow assessment of the independent effects of gonadotrophin and O(2) on the ANGPT-2 production by cultured follicles. Findings await translation to human follicles. WIDER IMPLICATION OF THE FINDINGS: The above findings provide novel information on the process of primate follicle maturation. We hypothesize that a symbiotic relationship between elevated concentrations of ANGPT-2 and VEGF allows FG antral follicles to excel in follicle maturation, e.g. by promoting its vascularization. Elevated ANGPT-2 may also offer possible insight into future oocyte quality as early as Week 2, compared with Week 4 for VEGF and follicle size. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the following grants: NIH U54 RR024347/HD058294/PL1-EB008542 (Oncofertility Consortium), NIH U54-HD018185 (SCCPIR), NIH ORWH/NICHD 2K12HD043488 (BIRCWH), NIH FIC TW/HD-00668, ONPRC 8P51OD011092. There are no conflicts of interest to declare. PMID- 24045781 TI - Sleep efficiency in patients with polycystic ovarian syndrome. PMID- 24045782 TI - Reply: sleep efficiency in patients with polycystic ovarian syndrome. PMID- 24045783 TI - Physician recommendation for invasive prenatal testing: the case of the 'precious baby'. AB - STUDY QUESTION: Do clinicians manage pregnancies conceived by assisted reproductive technologies (ART) differently from spontaneous pregnancies? SUMMARY ANSWER: Clinicians' decisions about prenatal testing during pregnancy depend, at least partially, on the method of conception. WHAT IS KNOWN ALREADY: Research thus far has shown that patients' decisions regarding prenatal screening are different in ART pregnancies compared with spontaneous ones, such that ART pregnancies may be considered more valuable or 'precious' than pregnancies conceived without treatment. STUDY DESIGN, SIZE AND DURATION: In this cross sectional study, preformed during the year 2011, 163 obstetricians and gynecologists in Israel completed an anonymous online questionnaire. PARTICIPANTS, SETTING, METHODS: Clinicians were randomly assigned to read one of two versions of a vignette describing the case of a pregnant woman. The two versions differed only with regard to the method of conception (ART; n = 78 versus spontaneous; n = 85). Clinicians were asked to provide their recommendations regarding amniocentesis. MAIN RESULTS AND THE ROLE OF CHANCE: The response rate among all clinicians invited to complete the questionnaire was 16.7%. Of the 85 clinicians presented with the spontaneous pregnancy scenario, 37 (43.5%) recommended amniocentesis. In contrast, of the 78 clinicians presented with the ART pregnancy scenario, only 15 (19.2%) recommended the test. Clinicians were 3.2 (95% confidence interval [CI]: 1.6-6.6) times more likely to recommend amniocentesis for a spontaneous pregnancy than for an ART pregnancy. LIMITATIONS AND REASONS FOR CAUTION: The study is limited by a low response rate, the relatively small sample and the hypothetical nature of the decision, as clinician recommendations may have differed in an actual clinical setting. WIDER IMPLICATIONS OF THE FINDINGS: Our findings show that fertility history and use of ART may affect clinicians' recommendations regarding amniocentesis following receipt of screening test results. This raises the question of how subjective factors influence clinicians' decisions regarding other aspects of pregnancy management. STUDY FUNDING AND COMPETING INTEREST: There was no funding source to this study. The authors declare no conflicts of interest. PMID- 24045784 TI - How much energy is locked in the USA? Alternative metrics for characterising the magnitude of overweight and obesity derived from BRFSS 2010 data. AB - OBJECTIVES: Four metrics to characterise population overweight are described. METHODS: Behavioural Risk Factors Surveillance System data were used to estimate the weight the US population needed to lose to achieve a BMI < 25. The metrics for population level overweight were total weight, total volume, total energy, and energy value. RESULTS: About 144 million people in the US need to lose 2.4 million metric tonnes. The volume of fat is 2.6 billion litres-1,038 Olympic size swimming pools. The energy in the fat would power 90,000 households for a year and is worth around 162 million dollars. CONCLUSIONS: Four confronting ways of talking about a national overweight and obesity are described. The value of the metrics remains to be tested. PMID- 24045786 TI - Spatiotemporal catalytic dynamics within single nanocatalysts revealed by single molecule microscopy. AB - This review discusses the latest advances in using single-molecule microscopy of fluorogenic reactions to examine and understand the spatiotemporal catalytic behaviors of single metal nanoparticles of various shapes including pseudospheres, nanorods, and nanoplates. Real-time single-turnover kinetics reveal size-, catalysis-, and metal-dependent temporal activity fluctuations of single pseudospherical nanoparticles (<20 nm in diameter). These temporal catalytic dynamics can be related to nanoparticles' dynamic surface restructuring whose timescales and energetics can be quantified. Single-molecule super resolution catalysis imaging further enables the direct quantification of catalytic activities at different surface sites (i.e., ends vs. sides, or corner, edge vs. facet regions) on single pseudo 1-D and 2-D nanocrystals, and uncovers linear and radial activity gradients within the same surface facets. These spatial activity patterns within single nanocrystals can be attributed to the inhomogeneous distributions of low-coordination surface sites, including corner, edge, and defect sites, among which the distribution of defect sites is correlated with the nanocrystals' morphology and growth mechanisms. A brief discussion is given on the extension of the single-molecule imaging approach to catalysis that does not involve fluorescent molecules. PMID- 24045787 TI - Heterometallic clusters with a new {Re3Mo3S8} core: direct synthesis, properties and DFT calculations. AB - We report the direct facile high-temperature synthesis and investigation of heterometallic rhenium-molybdenum cluster K6[Re3Mo3S8(CN)4(CN)2/2] (1) with a new {Re3Mo3S8} core. Dissolution of polymeric compound 1 resulted in subsequent oxidation and formation of stable 23e paramagnetic anionic cluster complex [Re3Mo3S8(CN)6](6-). PMID- 24045785 TI - Anesthesia-induced hypothermia mediates decreased ARC gene and protein expression through ERK/MAPK inactivation. AB - Several anesthetics have been reported to suppress the transcription of a number of genes, including Arc, also known as Arg3.1, an immediate early gene that plays a significant role in memory consolidation. The purpose of this study was to explore the mechanism of anesthesia-mediated depression in Arc gene and protein expression. Here, we demonstrate that isoflurane or propofol anesthesia decreases hippocampal Arc protein expression in rats and mice. Surprisingly, this change was secondary to anesthesia-induced hypothermia. Furthermore, we confirm in vivo and in vitro that hypothermia per se is directly responsible for decreased Arc protein levels. This effect was the result of the decline of Arc mRNA basal levels following inhibition of ERK/MAPK by hypothermia. Overall, our results suggest that anesthesia-induced hypothermia leads to ERK inhibition, which in turns decreases Arc levels. These data give new mechanistic insights on the regulation of immediate early genes by anesthesia and hypothermia. PMID- 24045788 TI - Immunization with cross-conserved H1N1 influenza CD4+ T-cell epitopes lowers viral burden in HLA DR3 transgenic mice. AB - The emergence of the pandemic H1N1 strain of influenza in 2009 was associated with a unique w-shaped age-related susceptibility curve, with higher incidence of morbidity and mortality among young persons and lower incidence among older persons, also observed during the 1918 influenza pandemic. Pre-existing H1N1 antibodies were not cross-reactive with the prior seasonal vaccine, forcing influenza experts to scramble to develop a new vaccine specific for the pandemic virus. We hypothesized that response to T-cell epitopes that are cross-conserved between pandemic H1N1 and the 2008 seasonal influenza vaccine strains might have contributed to partial protection from clinical illness among older adults, despite the lack of cross-reactive humoral immunity. Using immunoinformatics tools, we previously identified hemagglutinin and neuraminidase epitopes that were highly conserved between seasonal and pandemic H1N1. Here, we validated predicted CD4(+) T-cell epitopes for their ability to bind HLA and to stimulate interferon-gamma production in peripheral blood mononuclear cells from a cohort of donors presenting with influenza-like illness during the 2009 pandemic and a separate cohort immunized with trivalent influenza vaccine in 2011. A limited epitope heterologous DNA-prime/peptide-boost vaccine composed of these sequences stimulated immune responses and lowered lung viral loads in HLA DR3 transgenic mice challenged with pandemic 2009 H1N1 influenza. Cross-priming with conserved influenza T-cell epitopes such as these may be critically important to T cell mediated protection against pandemic H1N1 in the absence of cross-protective antibodies. PMID- 24045789 TI - Effect of a carbohydrate-containing late-evening snack on energy metabolism and fasting substrate utilization in adults with acute-on-chronic liver failure due to Hepatitis B. AB - BACKGROUND/OBJECTIVES: This study investigates the effects of a carbohydrate (CHO; lotus-root starch) predominant, late-evening snack (LES), containing 200 kcal (50 g CHO) on fasting resting energy expenditure (REE) and nutrient oxidation in hospitalized adults with acute-on-chronic liver failure (ACLF). SUBJECTS/METHODS: Adults with ACLF were randomized to receive daily LES (treatment; n=35) or standard care (n=35; non-supplemented control) for 14 days. REE and respiratory quotient (RQ) were measured by indirect calorimetry, nutrient oxidation (CHO, protein and fat), intake and biochemical parameters were measured in both groups at baseline and after 14 days using validated techniques. Disease severity was measured using the model for end-stage liver disease (MELD). RESULTS: No significant differences in macronutrient intake, anthropometric, demographic characteristics or MELD scores were observed between groups at baseline (P>0.05). Fasting RQ was significantly higher in the LES supplemented verses the control group after 2 weeks (P=0.02). CHO oxidation was significantly higher (P=0.001) and fat oxidation (P=0.02) was lower in the LES-supplemented group when compared with controls after 2 weeks. Fasting RQ and REE in the LES supplemented group increased significantly (0.83 verses 0.88; P=0.007/1301+/-409 vs 1687+/-718 kcal/day; P=0.02) in patients with MELD scores ?30 when compared with patients with MELD scores >30 (0.82 verses 0.84; P=0.27/ 1361+/-405 vs 1437+/-429 kcal/day; P=0.67) after supplementation. CONCLUSIONS: A carbohydrate predominant LES is associated with increases in fasting carbohydrate oxidation, REE and reductions in fat oxidation in adults with ACLF. Therapeutic strategies utilizing LES may promote improved nutritional status in adults with ACLF. PMID- 24045790 TI - Increased sedentary behaviour is associated with unhealthy dietary patterns in European adolescents participating in the HELENA study. AB - BACKGROUND/OBJECTIVES: To assess dietary patterns (DPs) in European adolescents and to examine their relationship with several indicators of sedentary behaviour. SUBJECTS/METHODS: A multinational cross-sectional study was carried out in 2202 adolescents (45.4% boys) aged 12.5-17.5 years. A self-reported questionnaire with information on sedentary behaviours, separately for weekdays and weekend days, and two non-consecutive 24 h-recalls were used. Principal component analysis was used to obtain DPs, and linear regression examined the association between DPs scores and sedentary behaviour. RESULTS: Four DPs for boys ('plant based', 'snacking', 'breakfast' and 'health conscious') and five DPs for girls ('confectionary and snacking', 'plant based', 'breakfast', 'animal protein' and 'health conscious') were obtained. Boys who spent >4 h/day watching television (TV) had lower adherence to the 'plant based', 'breakfast' and 'health conscious' DPs, and higher adherence to the 'snacking' DP. Higher computer use and internet use for recreational reason were associated with higher adherence to the 'snacking' DP. In girls, TV viewing and using internet for recreational reasons for >4 h/day was associated with higher adherence to the 'confectionary and snacking' and lower adherence with 'health conscious' DP. Also, studying between 2 and 4 h during weekend days was associated with lower adherence to the 'snacking' and with higher adherence to the 'plant based' and 'breakfast' DPs. CONCLUSION: Adolescents' DPs are related with the time spent in several sedentary behaviours. Such findings may help to generate interventions focusing on decreasing unhealthy dietary habits and specific sedentary behaviours. PMID- 24045791 TI - Measuring diet cost at the individual level: a comparison of three methods. AB - BACKGROUND/OBJECTIVES: Household-level food spending data are not suitable for population-based studies of the economics of nutrition. This study compared three methods of deriving diet cost at the individual level. SUBJECTS/METHODS: Adult men and women (n=164) completed 4-day diet diaries and a food frequency questionnaire (FFQ). Food expenditures over 4 weeks and supermarket prices for 384 foods were obtained. Diet costs (US$/day) were estimated using: (1) diet diaries and expenditures; (2) diet diaries and supermarket prices; and (3) FFQs and supermarket prices. Agreement between the three methods was assessed on the basis of Pearson correlations and limits of agreement. Income-related differences in diet costs were estimated using general linear models. RESULTS: Diet diaries yielded mean (s.d.) diet costs of $10.04 (4.27) based on Method 1 and $8.28 (2.32) based on Method 2. FFQs yielded mean diet costs of $7.66 (2.72) based on Method 3. Correlations between energy intakes and costs were highest for Method 3 (r(2)=0.66), lower for Method 2 (r(2)=0.24) and lowest for Method 1 (r(2)=0.06). Cost estimates were significantly associated with household incomes. CONCLUSION: The weak association between food expenditures and food intake using Method 1 makes it least suitable for diet and health research. However, merging supermarket food prices with standard dietary assessment tools can provide estimates of individual diet cost that are more closely associated with food consumed. The derivation of individual diet cost can provide insights into some of the economic determinants of food choice, diet quality and health. PMID- 24045792 TI - Proportions and concentrations of serum n-3 fatty acids can be increased by dietary counseling during pregnancy. AB - BACKGROUND/OBJECTIVES: The mother is an important mediator to the infant of polyunsaturated fatty acids (PUFA), the essential constituents of membranes particularly in the brain and retina. We here aimed in a prospective study initiated in early pregnancy to establish whether serum fatty acid (FA) compositions and concentrations in the mother can be modified by dietary means emphasizing counseling on a recommended diet. SUBJECTS/METHODS: Ninety women in the first trimester of pregnancy were randomized into intervention (n=45) or control (n=45) groups. The intervention comprised individual dietary counseling advocating choice of foods that will increase the intake of unsaturated and reduce that of saturated FA. To support this, appropriate products, including spreads, were provided for consumption at home. Dietary intakes were measured from food records and serum phospholipids, cholesteryl esters and triacylglycerols FA were analyzed by gas chromatography. RESULTS: Dietary counseling resulted in lower intake of saturated and higher intake of unsaturated FA compared with the controls. These changes were reflected in higher proportions of serum phospholipid PUFA (mean difference between groups 0.61% (95% confidence interval, CI 0.05-1.17), P=0.03), docosahexaenoic acid (0.5% (0.15-0.85), P=0.01), sum of n-3 FA (0.61% (0.07-1.15), P=0.03) and lower ratio of n-6/n-3 FA (-0.42% (-0.81-0.03), P=0.03) in the intervention group at the third trimester of pregnancy but not at 1 month postpartum. Similar changes were seen in the FA of cholesteryl esters and triacylglycerols. CONCLUSION: Maternal serum n-3 FA status during pregnancy can be improved by dietary means emphasizing the importance of dietary advice. PMID- 24045793 TI - Effects of various food ingredients on gall bladder emptying. AB - BACKGROUND/OBJECTIVES: The emptying of the gall bladder in response to feeding is pivotal for the digestion of fat, but the role of various food ingredients in contracting the gall bladder postprandially is not well understood. We hypothesized that different food ingredients, when consumed, will have a different effect on stimulating gall bladder emptying. To investigate this we designed two randomized, investigator-blind, cross-over studies in healthy subjects using magnetic resonance imaging (MRI) to measure gall bladder volumes serially and non-invasively. SUBJECTS/METHODS: Study 1: exploratory study evaluating the effects of 10 different food ingredients on gall bladder emptying in eight healthy subjects. The choice of ingredients varied from common items like coffee, tea and milk to actives like curcumin and potato protease inhibitor. Study 2: mechanistic study investigating the cholecystokinin (CCK) dose response to the best performer ingredient from Study 1 in 21 healthy subjects four ways. RESULTS: The largest gall bladder volume change in Study 1 was observed with fat, which therefore became the dose-response ingredient in Study 2, where the maximum % gall bladder volume change correlated well with CCK. CONCLUSIONS: These serial test-retest studies showed that the fasted gall bladder volume varied remarkably between individuals and that individual day-to-day variability had wide coefficients of variation. Improved knowledge of how to stimulate bile release using food ingredients will be useful to improve in vitro-in vivo correlation of bioavailability testing of hydrophobic drugs. It could improve performance of cholesterol-lowering plant stanol and sterol products and possibly aid understanding of some cholesterol gallstone disease. PMID- 24045794 TI - Association of dietary patterns with insulin resistance and clinically silent carotid atherosclerosis in apparently healthy people. AB - BACKGROUND/OBJECTIVES: Dietary habits are important determinants of individual cardiovascular and metabolic risk. This study investigated the association between dietary patterns and asymptomatic carotid atherosclerosis, defined as the presence of plaques and/or increased intima-media thickness, and metabolic biomarkers of insulin resistance, including the homeostasis model assessment of insulin resistance (HOMA-IR) and the trygliceride/high-density lipoprotein (HDL) cholesterol (Tg/HDL) ratio in a cohort of adults without known diabetes or atherosclerotic cardiovascular disease. SUBJECTS/METHODS: Nine hundred and twenty nine randomly selected participants were cross-sectionally investigated. Each participant answered a food frequency questionnaire, and underwent high resolution ultrasonographic evaluation of both carotid arteries. Laboratory blood measurements were obtained in a subsample of 507 participants. RESULTS: A dietary pattern that could be defined as unhealthy (high consumption of soft drinks, fried foods, seed oils, cured meats, butter, red meat and sweets) was identified in 21% of the cohort, whereas 34% of the cohort exhibited a dietary pattern that resembled the Mediterranean diet (high intakes of fruit, milk and cheese, olive oil, vegetables, pasta and bread). Intermediate habits characterized the remaining 45%. After adjusting for age, body mass index (BMI), waist circumference, glycated hemoglobin (HbA1c) and hypertension on treatment, the Mediterranean dietary pattern was associated with significantly lower HOMA-IR (beta-coefficient=-0.51; P=0.003). After adjusting for gender, BMI and HbA1c, the unhealthy dietary pattern was associated with a significantly higher Tg/HDL cholesterol ratio (beta-coefficient=0.43; P=0.006). No significant association was found between dietary patterns and carotid atherosclerosis. CONCLUSIONS: This study suggests that, independent of measures of adiposity, a Mediterranean dietary pattern is associated with lower insulin resistance. PMID- 24045795 TI - Parental concerns about complementary feeding: differences according to interviews with mothers with children of 7 and 13 months of age. AB - BACKGROUND/OBJECTIVES: To investigate and analyze differences in parental concerns during earlier and later phases of complementary feeding. SUBJECT/METHODS: Eight focus group interviews were conducted with 45 mothers of children aged 7 or 13 months. Deductive and inductive coding procedures were applied in the analysis. RESULTS: There were marked differences in mothers' health concerns in early and in later phases of complementary feeding. In the early phase, feeding a child healthy food was an unquestioned and self-evident practice. The child's food was a specific category, separated from the rest of the family's food, and the mother's focus was on the immediate well-being and safety of the child. In the later phase, health concerns shifted towards a longer term perspective, and the aim of integrating the child into the family's social world became as important as concerns about well-being and safety. Contested and partly contradictory practices resulted, including conscious acceptance of some intake of sugar and unhealthy fats. Perceived relevance of nutritional guidelines on complementary feeding was high in the early phase but declined later. CONCLUSION: Mothers' concerns and practices in the feeding of a young child vary considerably across the early and later phases of complementary feeding. This should be explored further and taken into consideration in the targeting and timing of dietary guideline communications. PMID- 24045796 TI - A secreted Plasmodium falciparum kinase reveals a signature motif for classification of tyrosine kinase-like kinases. AB - Thorough bioinformatic and phylogenetic analyses of Plasmodium falciparum tyrosine kinase-like kinase (TKL) sequences revealed a clear evolutionary relationship of PF3D7_1121300 (thereafter called PfTKL2) to the IL-1 receptor associated kinase (IRAK)/receptor-like kinase (RLK)/Pelle protein family. We identified a novel conserved motif that is unique to this family, as well as an insertion whose length allows distribution of its members into two distinct subfamilies, in a way that matches exactly the dichotomy between 'Tube/Tube-like kinases' (TTLKs) and 'Pelle-like kinases' (PLKs) distinguished previously on the basis of features in accessory domains. The PfTKL2 protein is expressed ubiquitously in asexual blood stages and in gametocytes, and the recombinant enzyme displays kinase activity in vitro. The protein is exported to the host erythrocyte; furthermore, in accordance with data from a previous study of the extracellular proteome of Plasmodium-infected erythrocytes, we show that PfTKL2 is secreted into the culture medium. Considering the functions of other members of the RLK/Pelle family in immunity, and its secretion to the extracellular medium, we speculate that PfTKL2 functions may include an immunomodulatory role promoting parasite survival in the human host. PMID- 24045797 TI - Finding yourself. PMID- 24045798 TI - Upgrading protein synthesis for synthetic biology. PMID- 24045807 TI - Structural biology: Torqueing about pores. AB - Cryo-EM, crystallography, biochemical experiments and computational approaches have been used to study different intermediate states of the Aeromonas hydrophila toxin aerolysin en route to pore formation. These results reveal that an unexpected and marked rotation of the core aerolysin machinery is required to unleash the membrane-spanning regions. PMID- 24045808 TI - Enhanced photovoltaic performance of a quantum dot-sensitized solar cell using a Nb-doped TiO2 electrode. AB - In this work Nb-doped anatase TiO2 nanocrystals are used as the photoanode of quantum-dot-sensitized solar cells. A solar cell with CdS/CdSe quantum dots co sensitized 2.5 mol% Nb-doped anatase TiO2 nanocrystals can achieve a photovoltaic conversion efficiency of 3.3%, which is almost twice as high as the 1.7% obtained by a cell based on undoped TiO2 nanocrystals. The incident photon-to-current conversion efficiency can reach as high as 91%, which is a record for all quantum dot-sensitized solar cells. Detailed analysis shows that such an enhancement is due to improved lifetime and diffusion length of electrons in the solar cell. PMID- 24045809 TI - Patient-education tips for new nurses. PMID- 24045811 TI - I want to be one of them. PMID- 24045815 TI - Sepsis: recognizing the next event. PMID- 24045817 TI - Patient education series. Mononucleosis. PMID- 24045819 TI - Behind the facade. PMID- 24045820 TI - Help your patients access government health information. PMID- 24045822 TI - Caring for patients undergoing bariatric surgery. PMID- 24045823 TI - Human trafficking: crime in our own backyard. PMID- 24045824 TI - Addressing pharmacology challenges in older adults. PMID- 24045825 TI - Does the BCG vaccine protect against TB? PMID- 24045826 TI - A closer look at pyelonephritis. PMID- 24045827 TI - Making an ethical plan for treating patients in pain. PMID- 24045830 TI - Pitch sensation involves stochastic resonance. AB - Pitch is a complex hearing phenomenon that results from elicited and self generated cochlear vibrations. Read-off vibrational information is relayed higher up the auditory pathway, where it is then condensed into pitch sensation. How this can adequately be described in terms of physics has largely remained an open question. We have developed a peripheral hearing system (in hardware and software) that reproduces with great accuracy all salient pitch features known from biophysical and psychoacoustic experiments. At the level of the auditory nerve, the system exploits stochastic resonance to achieve this performance, which may explain the large amount of noise observed in the working auditory nerve. PMID- 24045831 TI - Contact lens in vitro wettability by interferometry measures of drying dynamics. AB - PURPOSE: To develop with a thin film interferometer new parameters to describe the drying properties of contact lenses; these are: time to first break-up (onset latency), duration of lens surface drying (drying duration), maximum speed of increase in the drying area (maximum speed), and the time to reach maximum drying speed (peak latency). These new parameters were compared with the contact angle (CA) measurement of contact lenses by the captive bubble (CB) technique. METHODS: A thin film interferometer was connected to a digital camera, which captured images of the pre-lens liquid film of seven soft contact lenses in vitro: 1-Day Acuvue Moist, ACUVUE Oasys (Johnson & Johnson Vision Care); SofLens 38, PureVision (Bausch & Lomb); AirOptix Night & Day, AirOptix Aqua (CIBA Vision, Corp); and Proclear (Cooper Vision). The images were obtained from the lens surface when it was wet until it became dry (7 images per second) to generate video clips. A program was created in MATLAB to analyze the results. The CAs of the lens surfaces were measured by the CB technique with an OCA-20 contact angle analyzer (Data Physics Instruments). RESULTS: There were no significant relationships found between the CA and the new drying parameters (P > 0.05). Analysis of the results using analysis of variance and post hoc tests showed that the surface drying dynamics measures effectively differentiated between more of the soft lenses than the CA. CONCLUSIONS: A new technique is described for assessing the drying characteristics of contact lenses by observations of the pattern, size, and speed of pre-lens liquid film break-up observed by a thin film interferometry. The interferometry method allowed evaluation and differentiation between lens materials. This new technique has the major advantage that it can be applied to evaluate contact lens wettability in vivo and in vitro. PMID- 24045832 TI - Exophiala jeanselmei keratitis: case report and review of literature. AB - PURPOSE: To describe a patient with Exophiala jeanselmei keratitis and to review the prior cases reported in the literature. METHODS: We report one patient with keratitis after remote injury and chronic steroid use and review the six prior reported cases. RESULTS: Culture plates from corneal scraping revealed growth of the dematiaceous fungi, E. jeanselmei, a rare causative organism of ocular infection. The patient underwent therapy with topical and intracameral antifungals and subsequently required a corneal transplant. Biopsy of the donor graft confirmed the diagnosis of E. jeanselmei. This is the first reported case to use intracameral antifungal agents and the first biopsy proven case. Half of reported cases experienced associated trauma, and severity was generally related to delay in diagnosis. CONCLUSIONS: Trauma and chronic topical steroid use contributed to the development of severe keratitis in this patient. Patients on chronic steroids should be monitored closely. Topical, subconjunctival, and intracameral antifungals have all been effective in treating this pathogen. If diagnosed and treated early, E. jeanselmei keratitis can have a good visual outcome. PMID- 24045833 TI - New-generation hybrid contact lens for the management of extreme irregularity in a thin cornea after unsuccessful excimer laser refractive surgery. AB - PURPOSE: To report a very successful outcome obtained with the fitting of a new generation hybrid contact lens of reverse geometry in a thin cornea with extreme irregularity due to the presence of a central island after unsuccessful myopic excimer laser refractive surgery. METHODS: A 32-year-old man attended to our clinic complaining of very poor vision in his right eye after bilateral laser in situ keratomileusis (treatment or surgery) for myopia correction and some additional retreatments afterward. After a comprehensive ocular evaluation, contact lens fitting with a reverse geometry hybrid contact lens (SynergEyes PS, SynergEyes, Carlsbad, CA) was proposed as a solution for this case. Visual, refractive, and ocular aberrometric outcomes with the contact lens were evaluated. RESULTS: Distance visual acuity improved from a prefitting uncorrected value of 20/200 to a postfitting corrected value of 20/16. Prefitting manifest refraction was +6.00 sphere and -3.00 cylinder at 70 degrees , with a corrected distance visual acuity of 20/40. Higher order root mean square for a 5-mm pupil changed from a prefitting value of 1.45 to 0.34 um with the contact lens. The contact lens wearing was reported as comfortable, and the patient was very satisfied with this solution. CONCLUSIONS: The SynergEyes PS contact lens seems to be an excellent option for the visual rehabilitation of corneas with extreme irregularity after myopic excimer laser surgery, minimizing the level of higher order aberrations and providing an excellent visual outcome. PMID- 24045834 TI - Paracoccus yeei keratitis in a contact lens wearer. AB - OBJECTIVES: Paracoccus yeei is an environmental bacterium suspected to be responsible for ocular infections. In this study, culture-based and polymerase chain reaction (PCR) sequencing-based investigations of a corneal scraping specimen confirmed P. yeei keratitis in one contact lens wearer. METHODS: A 34 year-old male patient, who was a contact lens wearer, presented with a unilateral corneal ulcer. A corneal scraping was performed to conduct a microbiological investigation. Disease progress was favorable after a 5-week topical treatment, which combined rifampicin, ciprofloxacine, tobramycine, and dexamethasone. The final visual acuity of the right eye was 5/10 with correction, limited by a central corneal scar. RESULTS: Culturing the corneal scraping specimen yielded P. yeei, which was also directly detected by PCR sequencing the bacterial 16S rDNA in the presence of negative controls. The P. yeei isolate was susceptible to ticarcillin, with a minimal inhibitory concentration (MIC) of <4 mg/L of ceftazidime (MIC of 0.5 mg/L), imipenem (MIC < 0.5 mg/L), gentamycin (MIC of 0.5 mg/L), tobramycin (MIC < 0.06 mg/L), rifampicin (MIC < 0.125 mg/L), ciprofloxacin (MIC < 0.5 mg/L), and colimycin (MIC < 2 mg/L). The isolate was resistant to fosfomycine with a MIC 32 > mg/L. CONCLUSIONS: P. yeei is a new cause of keratitis that must be diagnosed by a laboratory analysis of corneal scrapings due to the potentially poor outcome of infection. PMID- 24045835 TI - [Defect coverage of progressive aseptic necrosis]. PMID- 24045837 TI - Metal-organic frameworks for upgrading biogas via CO2 adsorption to biogas green energy. AB - In the midst of the global climate change phenomenon, mainly caused by fossil fuel burning to provide energy for our daily life and discharge of CO2 into the atmosphere, biogas is one of the important renewable energy sources that can be upgraded and applied as a fuel source for energy in daily life. The advantages of the production of hybrid materials, metal-organic framework (MOF) adsorbents, expected for the biogas upgrading, rely on the bulk separation of CO2 under near ambient conditions. This review highlights the challenges for MOF adsorbents, which have the greatest upgrading abilities for biogas via selective passage of methane. The key factors improving the ideal MOF materials for these high CO2 capture and selectivity uses for biogas upgrading to produce bio-methane and reduce fossil-fuel CO2 emission will be discussed. PMID- 24045836 TI - Oligopeptides stimulate glucagon-like peptide-1 secretion in mice through proton coupled uptake and the calcium-sensing receptor. AB - AIMS/HYPOTHESIS: Ingested protein is a well-recognised stimulus for glucagon-like peptide-1 (GLP-1) release from intestinal L cells. This study aimed to characterise the molecular mechanisms employed by L cells to detect oligopeptides. METHODS: GLP-1 secretion from murine primary colonic cultures and Ca(2+) dynamics in L cells were monitored in response to peptones and dipeptides. L cells were identified and purified based on their cell-specific expression of the fluorescent protein Venus, using GLU-Venus transgenic mice. Pharmacological tools and knockout mice were used to characterise candidate sensory pathways identified by expression analysis. RESULTS: GLP-1 secretion was triggered by peptones and di-/tripeptides, including the non-metabolisable glycine-sarcosine (Gly-Sar). Two sensory mechanisms involving peptide transporter-1 (PEPT1) and the calcium-sensing receptor (CaSR) were distinguishable. Responses to Gly-Sar (10 mmol/l) were abolished in the absence of extracellular Ca(2+) or by the L-type calcium-channel blocker nifedipine (10 MUmol/l) and were PEPT1-dependent, as demonstrated by their sensitivity to pH and 4-aminomethylbenzoic acid and the finding of impaired responses in tissue from Pept1 (also known as Slc15a1) knockout mice. Peptone (5 mg/ml)-stimulated Ca(2+) responses were insensitive to nifedipine but were blocked by antagonists of CaSR. Peptone-stimulated GLP-1 secretion was not impaired in mice lacking the putative peptide-responsive receptor lysophosphatidic acid receptor 5 (LPAR5; also known as GPR92/93). CONCLUSIONS/INTERPRETATION: Oligopeptides stimulate GLP-1 secretion through PEPT1 dependent electrogenic uptake and activation of CaSR. Both pathways are highly expressed in native L cells, and likely contribute to the ability of ingested protein to elevate plasma GLP-1 levels. Targeting nutrient-sensing pathways in L cells could be used to mobilise endogenous GLP-1 stores in humans, and could mimic some of the metabolic benefits of bariatric surgery. PMID- 24045838 TI - Identification of MHC class I sequences in four species of Macaca of China. AB - Tibetan macaques (Macaca thibetana), stump-tailed macaques (M. arctoides), Assamese macaques (M. assamensis), and northern pig-tailed macaques (M. leonina) are four major species of Macaca in China. In order to effectively use these species in biomedical research, thorough investigations of their MHC immunogenetics are required. In this study, we identified MHC class I sequences using cDNA cloning and sequencing on a cohort of six M. thibetana, three M. arctoides, three M. assamensis, and three M. leonina derived from Sichuan and Yunnan provinces of China. Eighty new alleles were identified, including 26 MHC-A alleles, 46 MHC-B alleles, and 8 MHC-I alleles. Among them, Math-A1*126:01, Math B*190:01, Math-B*191:01, Math-B*192:01, Maar-A1*127:01, Maar-A1*129:01, and Maas A1*128:01 represent lineages that had not been reported earlier in Macaca. Phylogenetic analyses show that no obvious separation of lineages among these species of Macaca. This study provides important information about the MHC immunogenetics for the four major species of Chinese macaques and adds value to these species as model organisms in biomedical research. PMID- 24045839 TI - Expansion of a 12-kb VNTR containing the REXO1L1 gene cluster underlies the microscopically visible euchromatic variant of 8q21.2. AB - Copy number variants visible with the light microscope have been described as euchromatic variants (EVs) and EVs with extra G-light material at 8q21.2 have been reported only once before. We report four further patients with EVs of 8q21.2 ascertained for clinical (3) or reproductive reasons (1). Enhanced signal strength from two overlapping bacterial artificial chromosomes (BACs) and microarray analysis mapped the EV to a 284-kb interval in the reference genome. This interval consists of a sequence gap flanked by segmental duplications that contain the 12-kb components of one of the largest Variable Number Tandem Repeat arrays in the human genome. Using digital NanoString technology with a custom probe for the RNA exonuclease 1 homologue (S. cerevisiae)-like 1 (REXO1L1) gene within each 12-kb repeat, significantly enhanced diploid copy numbers of 270 and 265 were found in an EV family and a median diploid copy number of 166 copies in 216 controls. These 8q21.2 EVs are not thought to have clinical consequences as the phenotypes of the probands were inconsistent, those referred for reproductive reasons were otherwise phenotypically normal and the REXO1L1 gene has no known disease association. This EV was found in 4/3078 (1 in 770) consecutive referrals for chromosome analysis and needs to be distinguished from pathogenic imbalances of medial 8q. The REXO1L1 gene product is a marker of hepatitis C virus (HCV) infection and a possible association between REXO1L1 copy number and susceptibility to HCV infection, progression or response to treatment has not yet been excluded. PMID- 24045840 TI - Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction. AB - The ABCB4 gene encodes for MDR3, a protein that translocates phosphatidylcholine from the inner to the outer leaflet of the hepatocanalicular membrane; its deficiency favors the formation of 'toxic bile'. Several forms of hepatobiliary diseases have been associated with ABCB4 mutations, but the detrimental effects of most mutations on the encoded protein needs to be clarified. Among subjects with cholangiopathies who were screened for mutations in ABCB4 by direct sequencing, we identified the new mutation p.(L481R) in three brothers. According to our model of tertiary structure, this mutation affects the Q-loop, whereas the p.(Y403H) mutation, that we already described in two other families, involves the A-loop. This study was aimed at analyzing the functional relevance of these two ABCB4 mutations: MDR3 expression and lipid content in the culture supernatant were evaluated in cell lines stably transfected with the ABCB4 wild-type clone and corresponding mutants. No differences of expression were observed between wild-type and mutant gene products. Instead, both mutations caused a reduction of phosphatidylcholine secretion compared with the wild-type transfected cell lines. On the contrary, cholesterol (Chol) release, after 1 and 3 mM sodium taurocholate stimulation, was higher in the mutant-transfected cell lines than that in the wild-type and was particularly enhanced in cells transfected with the p.Y403H construct.In summary, our data show that both mutations do not seem to affect protein expression, but are able to reduce the efflux of phosphatidylcholine associated with increase of Chol, thereby promoting the formation of toxic bile. PMID- 24045841 TI - A novel intermediate mucolipidosis II/IIIalphabeta caused by GNPTAB mutation in the cytosolic N-terminal domain. AB - Mucolipidosis (ML) II and ML IIIalpha/beta are allelic autosomal recessive metabolic disorders due to mutations in GNPTAB. The gene encodes the enzyme UDP GlcNAc-1-phosphotransferase (GNPT), which is critical to proper trafficking of lysosomal acid hydrolases. The ML phenotypic spectrum is dichotomous. Criteria set for defining ML II and ML IIIalpha/beta are inclusive for all but the few patients with phenotypes that span the archetypes. Clinical and biochemical findings of the 'intermediate' ML in eight patients with the c.10A>C missense mutation in GNPTAB are presented to define this intermediate ML and provide a broader insight into ML pathogenesis. Extensive clinical information, including radiographic examinations at various ages, was obtained from a detailed study of all patients. GNPTAB was sequenced in probands and parents. GNPT activity was measured and cathepsin D sorting assays were performed in fibroblasts. Intermediate ML patients who share the c.10A>C/p.K4Q mutation in GNPTAB demonstrate a distinct, consistent phenotype similar to ML II in physical and radiographic features and to ML IIIalpha/beta in psychomotor development and life expectancy. GNPT activity is reduced to 7-12% but the majority of newly synthesized cathepsin D remains intracellular. The GNPTAB c.10A>C/p.K4Q missense allele results in an intermediate ML II/III with distinct clinical and biochemical characteristics. This delineation strengthens the utility of the discontinuous genotype-phenotype correlation in ML II and ML IIIalpha/beta and prompts additional studies on the tissue-specific pathogenesis in GNPT-deficient ML. PMID- 24045842 TI - Isolated foveal hypoplasia with secondary nystagmus and low vision is associated with a homozygous SLC38A8 mutation. AB - Foveal hypoplasia, always accompanied by nystagmus, is found as part of the clinical spectrum of various eye disorders such as aniridia, albinism and achromatopsia. However, the molecular basis of isolated autosomal recessive foveal hypoplasia is yet unknown. Individuals of apparently unrelated non consanguineous Israeli families of Jewish Indian (Mumbai) ancestry presented with isolated foveal hypoplasia associated with congenital nystagmus and reduced visual acuity. Genome-wide homozygosity mapping followed by fine mapping defined a 830 Kb disease-associated locus (LOD score 3.5). Whole-exome sequencing identified a single missense mutation in the homozygosity region: c.95T>G, p.(Ile32Ser), in a conserved amino acid within the first predicted transmembrane domain of SLC38A8. The mutation fully segregated with the disease-associated phenotype, demonstrating an ~10% carrier rate in Mumbai Jews. SLC38A8 encodes a putative sodium-dependent amino-acid/proton antiporter, which we showed to be expressed solely in the eye. Thus, a homozygous SLC38A8 mutation likely underlies isolated foveal hypoplasia. PMID- 24045843 TI - Molecular prioritization strategies to identify functional genetic variants in the cardiovascular disease-associated expression QTL Vanin-1. AB - There is now good evidence that non-coding sequence variants are involved in the heritability of many common complex traits. The current 'gold standard' approach for assessing functionality is the in vitro reporter gene assay to assess allelic differences in transcriptional activity, usually followed by electrophoretic mobility shift assays to assess allelic differences in transcription factor binding. Although widely used, these assays have inherent limitations, including the lack of endogenous chromatin context. Here we present a more contemporary approach to assessing functionality of non-coding sequence variation within the Vanin-1 (VNN1) promoter. By combining 'gold standard' assays with in vivo assessments of chromatin accessibility, we greatly increase our confidence in the statistically assigned functional relevance. The standard assays revealed the 137 single nucleotide variant to be functional but the -587 variant to have no functional relevance. However, our in vivo tests show an allelic difference in chromatin accessibility surrounding the -587 variant supporting strong functional potential at both sites. Our approach advances the identification of functional variants by providing strong in vivo biological evidence for function. PMID- 24045844 TI - Clinical utility gene card for: cystinosis. PMID- 24045847 TI - Light-controllable reflection wavelength of blue phase liquid crystals doped with azobenzene-dimers. AB - A new series of azobenzene-dimers were synthesized and doped into the blue phase liquid crystals to broaden the temperature range of BPs. It is found that not only can the reflection wavelength of BPI be reversibly controlled but BPI can also be transformed into the cholesteric phase owing to isomerization of azobenzene induced by light. PMID- 24045846 TI - All carbon-based photodetectors: an eminent integration of graphite quantum dots and two dimensional graphene. AB - Photodetectors with ultrahigh sensitivity based on the composite made with all carbon-based materials consisting of graphite quantum dots (QDs), and two dimensional graphene crystal have been demonstrated. Under light illumination, remarkably, a photocurrent responsivity up to 4 * 10(7) AW(-1) can be obtained. The underlying mechanism is attributed to the spatial separation of photogenerated electrons and holes due to the charge transfer caused by the appropriate band alignment across the interface between graphite QDs and graphene. Besides, the large absorptivity of graphite QDs and the excellent conductivity of the graphene sheet also play significant roles. Our result therefore demonstrates an outstanding illustration for the integration of the distinct properties of nanostructured carbon materials with different dimensionalities to achieve highly efficient devices. Together with the associated mechanism, it paves a valuable step for the further development of all carbon-based, cheap, and non-toxic optoelectronics devices with excellent performance. PMID- 24045848 TI - Controlled step-wise isomerization of the Keggin-type Al(13) and determination of the gamma-Al(13) structure. AB - Partial hydrolysis of AlCl3 with Ca(OH)2 and the amino acid glycine enables the selective transformation of the Al13 Keggin structures, outlining the epsilon -> delta -> gamma isomerization process. Through this, a new gamma-Al13 Keggin structure was able to be isolated and characterized through (27)Al NMR and single crystal XRD. PMID- 24045845 TI - Autosomal recessive mutations in nuclear transport factor KPNA7 are associated with infantile spasms and cerebellar malformation. AB - Nuclear import receptors of the KPNA family recognize the nuclear localization signal in proteins and together with importin-beta mediate translocation into the nucleus. Accordingly, KPNA family members have a highly conserved architecture with domains that contact the nuclear localization signal and bind to importin beta. Here, we describe autosomal recessive mutations in KPNA7 found by whole exome sequencing in a sibling pair with severe developmental disability, infantile spasms, subsequent intractable epilepsy consistent with Lennox-Gastaut syndrome, partial agenesis of the corpus callosum, and cerebellar vermis hypoplasia. The mutations mapped to exon 7 in KPNA7 result in two amino-acid substitutions, Pro339Ala and Glu344Gln. On the basis of the crystal structure of the paralog KPNA2 bound to a bipartite nuclear localization signal from the retinoblastoma protein, the amino-acid substitutions in the affected subjects were predicted to occur within the seventh armadillo repeat that forms one of the two nuclear localization signal-binding sites in KPNA family members. Glu344 is conserved in all seven KPNA proteins, and we found that the Glu354Gln mutation in KPNA2 is sufficient to reduce binding to the retinoblastoma nuclear localization signal to approximately one-half that of wild-type protein. Our data show that compound heterozygous mutations in KPNA7 are associated with a human neurodevelopmental disease, and provide the first example of a human disease associated with mutation of a nuclear transport receptor. PMID- 24045849 TI - Sensory information and associative cues used in food detection by wild vervet monkeys. AB - Understanding animals' spatial perception is a critical step toward discerning their cognitive processes. The spatial sense is multimodal and based on both the external world and mental representations of that world. Navigation in each species depends upon its evolutionary history, physiology, and ecological niche. We carried out foraging experiments on wild vervet monkeys (Chlorocebus pygerythrus) at Lake Nabugabo, Uganda, to determine the types of cues used to detect food and whether associative cues could be used to find hidden food. Our first and second set of experiments differentiated between vervets' use of global spatial cues (including the arrangement of feeding platforms within the surrounding vegetation) and/or local layout cues (the position of platforms relative to one another), relative to the use of goal-object cues on each platform. Our third experiment provided an associative cue to the presence of food with global spatial, local layout, and goal-object cues disguised. Vervets located food above chance levels when goal-object cues and associative cues were present, and visual signals were the predominant goal-object cues that they attended to. With similar sample sizes and methods as previous studies on New World monkeys, vervets were not able to locate food using only global spatial cues and local layout cues, unlike all five species of platyrrhines thus far tested. Relative to these platyrrhines, the spatial location of food may need to stay the same for a longer time period before vervets encode this information, and goal-object cues may be more salient for them in small-scale space. PMID- 24045850 TI - Validation of a novel cognitive bias task based on difference in quantity of reinforcement for assessing environmental enrichment. AB - Cognitive bias tasks purport to assess affective states via responses to ambiguous stimuli. We hypothesized that a novel cognitive bias task based on positive reinforcement using quantity differences would detect changes in affect in captive grizzly bears (Ursus arctos horribilis). We trained bears (n = 8) to respond differently (nose or paw touch) to two stimuli (light or dark gray cue cards), with responses counterbalanced across bears. The two cues signaled a small or large food reward, respectively. Responses to ambiguous probe stimuli (i.e., shades of gray) intermediate to the trained stimuli were classified as either 'optimistic,' appropriate for the larger reward, or 'pessimistic,' appropriate for the smaller reward. In Experiment 1, we explored the contrast in reward size necessary to detect a change in response across probe stimuli (large reward, 3 or 6 apple slices: small reward, 1 slice). We observed a change in response across probe stimuli, with no difference in response between reward value groups, indicating that a contrast of 3:1 apple slices was sufficient to affect responses. In Experiment 2, we investigated cognitive bias after 2.1 h of exposure to enrichment items varying in attractiveness. Results were unaffected by enrichment type or time spent interacting with enrichments, indicating that the task failed to demonstrate criterion validity for comparing mood following exposure to different enrichment items. However, greater time spent pacing prior to testing was associated with 'optimistic' judgments. The data provide some support for use of cognitive bias tasks based on quantity differences in animal welfare assessments involving captive wildlife. PMID- 24045851 TI - Effects of barium concentration on oropharyngeal swallow timing measures. AB - Videofluoroscopy is commonly used for evaluating oropharyngeal swallowing but requires radiopaque contrast (typically barium). Prior studies suggest that some aspects of swallowing, including timing measures of oral and pharyngeal bolus transit, vary depending on barium concentration. The aim of our study was to identify timing differences in healthy swallowing between "thin" (40 % w/v concentration) and "ultrathin" (22 % w/v concentration) barium solutions. Twenty healthy adults (Ten women; mean age = 31 years) each performed a series of three noncued 5-ml swallows each of ultrathin and thin liquid barium solutions in videofluoroscopy. Timing measures were compared between barium concentrations using a mixed-model ANOVA. The measures of interest were stage transition duration, pharyngeal transit time, and duration of upper esophageal sphincter opening. Significant differences were observed in the timing measures of swallowing with respect to barium concentration. In all cases, longer durations were seen with the higher barium concentration. Barium concentration influences timing parameters in healthy swallowing, even between ultrathin and thin concentrations. Clinicians need to understand and control for the impact of different barium stimuli on swallowing physiology. PMID- 24045852 TI - Reliability of measurements of tongue and hand strength and endurance using the Iowa Oral Performance Instrument with healthy adults. AB - The purpose of this study was to investigate the reliability of tongue and handgrip strength and endurance measurements in healthy adults using the Iowa Oral Performance Instrument. Fifty-one healthy participants (21 males, 30 females; age range = 19-57 years) were tested on four occasions 1 week apart to determine test-retest reliability. The primary outcome measures were isometric tongue and handgrip strength (best of three trials) and sustained isometric endurance. Small increases (changes in group mean) in both anterior (1.7 %) and posterior (2.5 %) tongue strength and handgrip strength (5 %) between weeks 1 and 2 were observed with no change in subsequent weeks, suggesting that there is only a small learning effect for these measurements. The within-subject variation (mean-typical error expressed as a coefficient of variation [CV]) indicated higher than desirable initial variation for anterior (CV 10.8 %) and posterior (CV 11.8 %) tongue strength and handgrip strength (CV 15.2 %) but this was reduced in weeks 2-4. Intraclass correlation coefficients (ICC) indicated acceptable and improved reliability for both anterior (ICC 0.77-0.90) and posterior (ICC 0.79-0.86) tongue strength and handgrip strength (ICC 0.69-0.91) after week 1. Additional exploratory analyses were conducted with a subset of data to determine whether two values within 5 kPa (tongue) or 15 kPa (handgrip) provide superior strength reliability. Neither tongue nor hand endurance measurements were sufficiently reliable. These findings suggest that tongue and handgrip strength values demonstrate acceptable reliability, especially if familiarization is provided. Further investigation is needed to reduce sources of variability in tongue endurance measurements. PMID- 24045853 TI - The Ehrenfest force topology: a physically intuitive approach for analyzing chemical interactions. AB - Modified ANO-RCC basis sets are used to determine twelve molecular graphs of the Ehrenfest force for H2, CH4, CH2O, CH3NO, C2H2, C2H4, C3H3NO, N4H4, H2O, (H2O)2, (H2O)4 and (H2O)6. The molecular graphs include all types of topological critical points and a mix of bonding types is chosen to include sigma-, pi- and hydrogen bonding. We then compare a wide range of point properties: charge density, trace of the Hessian, eigenvalues, ellipticity, stiffness, total local energy and the eigenvectors are calculated at the bond critical points (BCPs) and compared for the Ehrenfest, QTAIM and stress tensor schemes. QTAIM is found to be the only partitioning scheme that can differentiate between shared- and closed-shell chemical bond types. Only the results from the Ehrenfest force partitioning, however, are demonstrated to be physically intuitive. This is demonstrated for the water molecule, the water-dimer and the water clusters (H2O)4 and (H2O)6. In particular, both the stiffness and the trace of the Hessians of the appropriate quantities of the sigma-bond BCPs for the water clusters are found to depend on the quantum topology dimension of the molecular graph. The behavior of all the stress tensor point properties is found to be erratic. This is explained by the ambiguity in the theoretical definition of the stress tensor. As a complementary approach the Ehrenfest force provides a new indicator of the mixed chemical character of the hydrogen-bond BCP, which arises from the collinear donor sigma bond donating a degree of covalent character to the hydrogen-bond. This indicator takes the form of the relative orientation of the shallowest direction of the Ehrenfest potential of the hydrogen-bond BCPs and the corresponding direction for the collinear sigma-bond BCP. PMID- 24045854 TI - Minimally invasive Achilles tendon repair: a modification of the Achillon technique. AB - BACKGROUND: The purpose of the study was to present the results of a new minimally invasive operative method for Achilles tendon (AT) ruptures that could reduce nerve injuries and add no extra cost. METHODS: Thirteen patients with acute AT ruptures who were treated with minimally invasive surgery and followed for a minimum of 12 months were included. At the latest follow-up, American Orthopaedic Foot & Ankle Society (AOFAS) score, calf diameters, ability to walk on tiptoe, and ultrasound examination were evaluated. The average age was 42.8 years (range, 31-62 years). Average follow up was 24.5 months (range, 12-34 months). RESULTS: AOFAS score was 92.5 (range, 85-100). Average calf diameters on the operated and nonoperated extremities were 38.9 cm (range, 36-44 cm) and 38.9 cm (range, 36-41 cm), respectively. On ultrasound examination, the site of the rupture was found to be 46.2 mm proximal from the calcaneal insertion, and the operated side was found to be significantly thicker than the nonoperated side (P = .008). There was 1 deep vein thrombosis, which recovered without sequelae. There were no wound problems, reruptures, or nerve injuries. CONCLUSIONS: This new minimally invasive operative method was successful, showing good functional results and low complication rates. In our experience, the use of 3 continuous polyester sutures was less irritable with 3 knots. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 24045856 TI - Effect of the Danish return-to-work program on long-term sickness absence: results from a randomized controlled trial in three municipalities. AB - OBJECTIVES: The aim of this study was to evaluate the effect of the Danish return to-work (RTW) program on long-term sickness absence in a randomized controlled trial in three municipalities. METHODS: The intervention group comprised 1948 participants while the control group comprised 1157 participant receiving ordinary sickness benefit management (OSM). Study participants were working-age adults receiving long-term (>=8 weeks or more) benefits, included regardless of reason for sickness absence or employment status. Each beneficiary was followed up for a maximum period of 52 weeks. Cox proportional hazards model was used to estimate hazard ratios (HR) for return to work (RTW) with 95% confidence intervals (95% CI). RESULTS: The intervention effect differed significantly between the municipalities (P=0.00005). In one municipality (M2) the intervention resulted in a statistically significant increased rate of recovery from long-term sickness absence (HR 1.51, 95% CI 1.31-1.74). In the other two municipalities, the intervention did not show a statistically significant effect (HR M11.12, 95% CI 0.97-1.29, and HR M30.80, 95% CI 0.63-1.03, respectively). Adjustment for a series of possible confounders only marginally altered the estimated HR. CONCLUSION: The effect of the intervention differed substantially between the three municipalities, indicating that that contextual factors are of major importance for success or failure of this complex intervention. PMID- 24045855 TI - The impact of protein supplementation on cognitive performance in frail elderly. AB - PURPOSE: Maintenance of cognitive abilities is important for elderly to stay independent. With the aging of the population, the call for modifiable factors is emerging. Dietary protein might improve cognitive performance; however, this has hardly been studied. Therefore, we studied the impact of 24-week dietary protein supplementation on cognitive performance in pre-frail and frail elderly people. METHODS: Pre-frail and frail elderly subjects, according to the Fried criteria, randomly received a protein drink containing 15 g protein or a placebo drink twice a day. Cognitive performance was measured at baseline and after 24 weeks by means of a sensitive neuropsychological test battery. In addition, reaction time was assessed after both 12 and 24 weeks of intervention. Domain scores were calculated for the domains episodic memory, attention and working memory, information processing speed, and executive functioning. Analyses of covariance were used to determine differences between groups. Linear mixed models were used to determine differences in reaction time over time and per treatment. RESULTS: In total, 65 subjects (79 +/- 8 years) with a median Mini-Mental State Examination score of 28 (interquartile range 26-30) were included. Reaction time improved more in the protein group (68 ms) than in the placebo group (18 ms, P = 0.03). Dietary protein had no significant effect on any of the cognitive domain scores. CONCLUSIONS: Protein supplementation might improve reaction time performance in pre-frail and frail elderly, but did not improve other cognitive functions. PMID- 24045857 TI - Utilisation of an outpatient sedation unit in paediatric ophthalmology: safety and effectiveness of chloral hydrate in 1509 sedation episodes. AB - OBJECTIVE: To report the largest study on the safety and effectiveness of sedation in paediatric ophthalmology in a nurse-led outpatient sedation unit. DESIGN: Retrospective cohort study reviewing all children who underwent sedation from January 2006 to December 2010. Patients were sedated with 80 mg/kg of chloral hydrate (CH) given orally with top up dose given at half dose as required. All demographic data, sedation and procedure duration, sedation success and adverse events were recorded. Univariate and multiple regression analyses were performed to assess factors associated with success and complications. RESULTS: Data was collected for 1509 sedation episodes. More boys were sedated compared with girls (56.3% vs 43.7% p=0.0003) with an average age of 23.86 months and weight of 11.76 kg. A higher proportion of patients had an American Society of Anaesthesiologists status of II than I (58.5%:41.5%, p=0.0001). Successful sedation was obtained in 96.69% of children with 4.77% requiring a top up dose to achieve this. The average sedation duration was 53.4 min (SD=21.5) with an average of 1.7 procedures performed; the most common being a detailed examination (93.5%) and electroretinogram (45.1%). Adverse events included paradoxical reaction (1.33%), oxygen desaturation (0.99%) and vomiting (0.53%). There were no serious complications or hospital admission. Multiple logistic regression analysis found weight greater than 15 kg and needing a top up dose to be significant risk factors for Failure (OR=2.49 and 8.69, respectively) and Adverse events (OR=2.1 and 3.97, respectively). Sex and American Society of Anesthesiologists Physical Status score did not significantly affect outcomes. CONCLUSIONS: CH sedation allows detailed examination and investigations in the majority of children with few side effects. Patients over 15 kg and need for a top up dose are risk factors for failure and adverse events. This is the largest study in the current literature looking at the use of CH sedation in ophthalmology and confirms its safety and effectiveness. PMID- 24045859 TI - Diffuse scattering from hemispherical nanoparticles at the air-silicon interface. AB - There has been much recent interest in the application of plasmonics to improve the efficiency of silicon solar cells. In this paper we use finite difference time domain calculations to investigate the placement of hemispherical gold nanoparticles on the rear surface of a silicon solar cell. The results indicate that nanoparticles protruding into the silicon, rather than into air, have a larger scattering efficiency and diffuse scattering into the semiconductor. This finding could lead to improved light trapping within a thin silicon solar cell device. PMID- 24045860 TI - Water-soluble diiron hexacarbonyl complex as a CO-RM: controllable CO-releasing, releasing mechanism and biocompatibility. AB - A water soluble diiron hexacarbonyl complex, [Fe2{MU-SCH2CH(OH)CH2(OH)}2(CO)6] (1), was synthesised by reacting thioglycol with Fe3(CO)12 in THF. This diiron complex was employed as carbon monoxide releasing molecule (CO-RM). The CO releasing was initiated via substitution of the bound CO by cysteamine (CysA, a clinic medicine). Further decomposition of the substituted products led to at least partially the formation of monoiron(II) dicarbonyl species via oxidative process while releasing more CO under inert atmosphere. Three intermediates generated in the CO-releasing process were spectroscopically identified. The kinetics of the decomposition of complex 1 was first-order process for both the complex and CysA, respectively. Under open atmosphere, the CO-releasing mechanism altered due to the involvement of oxygen in the decomposition of complex 1. The system showed minimal cytotoxicity in two selected arbitrarily cell lines, QSG 7701 and HepG2, with IC50 at the scale of 100 MUmol L(-1). PMID- 24045858 TI - The tiger genome and comparative analysis with lion and snow leopard genomes. AB - Tigers and their close relatives (Panthera) are some of the world's most endangered species. Here we report the de novo assembly of an Amur tiger whole genome sequence as well as the genomic sequences of a white Bengal tiger, African lion, white African lion and snow leopard. Through comparative genetic analyses of these genomes, we find genetic signatures that may reflect molecular adaptations consistent with the big cats' hypercarnivorous diet and muscle strength. We report a snow leopard-specific genetic determinant in EGLN1 (Met39>Lys39), which is likely to be associated with adaptation to high altitude. We also detect a TYR260G>A mutation likely responsible for the white lion coat colour. Tiger and cat genomes show similar repeat composition and an appreciably conserved synteny. Genomic data from the five big cats provide an invaluable resource for resolving easily identifiable phenotypes evident in very close, but distinct, species. PMID- 24045861 TI - Concentration, sources and human exposure of polybrominated diphenyl ethers in indoor dust in Heilongjiang Province, China. AB - Fourteen indoor dust samples were collected in 2010 winter from four cities in Heilongjiang Province, China. Fourteen polybrominated diphenyl ethers (PBDEs) were identified and quantified. Concentration of the total 14 PBDEs ranged from 240 to 9,270 ng/g, with the median of 2,520 ng/g. BDE209 was the dominant congener with concentrations ranged from 234 to 9,190 ng/g, accounting for 97.2 % of the total concentration. Positive correlations (r > 0.8, p < 0.005) were found between the group of BDE17, 28, 66, 47 and the group of BDE85, 99, 100, between BDE153 and BDE154, between BDE209 and BDE183, indicating the similar sources and/or pathways in indoor environment. Principal component analysis showed that the major sources of PBDEs were commercial Penta-BDEs and Deca-BDEs. Human exposure analysis showed that children of 1-5 years old had the highest exposure to PBDEs. PMID- 24045862 TI - Postimplantation host tissue response and biodegradation of biologic versus polymer meshes implanted in an intraperitoneal position. AB - BACKGROUND: This study compared the in vitro and in vivo behaviors at the peritoneal interface of a new polymer material (Bio-A) and of two biologic non cross-linked materials (Tutomesh [Tuto] and Strattice [St]), all biodegradable. METHODS: Omentum mesothelial cells from rabbits were seeded onto the three prosthetic materials tested. At 1, 4, 8, 16, and 24 h after implantation, mesothelial cover was performed using a scanning electron microscope (SEM). In the in vivo study, 3 * 3 cm mesh fragments were placed on the parietal peritoneum of the same rabbits and fixed at the four corners with individual stitches. The implants were randomized such that six fragments of each material were implanted in nine animals (2 per animal). Adhesion formation was quantified by sequential laparoscopy and image analysis 3, 7, and 14 days after implantation. The animals were killed at 90 days, and the meshes were subjected to microscopy and immunohistochemistry. RESULTS: The in vitro mesothelial cover was significantly greater for St than for Bio-A at each time point. The percentage of cover for St was also higher than for Tuto 16 and 24 h after seeding and higher for Tuto than for Bio-A at all time points. Compared with the biologic meshes, significantly higher adhesion percentages were recorded for Bio-A. At 90 days after implantation, differences in absorption measured as percentage of reduction in mesh thickness were detected among all the meshes. The least absorbed was St. The neoperitoneum thickness was significantly greater for the biologic meshes than for the polymer mesh, although this variable also differed significantly between St and Tuto. Macrophage counts were higher for Bio-A than for the biologic meshes. CONCLUSIONS: Greater mesothelial cover was observed in vitro for St. In vivo, adhesion formation and the macrophage response induced by Bio-A were greater than those elicited by the biologic materials. Bio-A and Tuto showed substantial biodegradation compared with St. PMID- 24045863 TI - Antioxidant status of serum, muscle, intestine and hepatopancreas for fish fed graded levels of biotin. AB - Lipid peroxidation, protein oxidation and antioxidant activities of muscle, intestine, hepatopancreas and serum in juvenile Jian carp (Cyprinus carpio var. Jian) were investigated after feeding graded levels of biotin (0.010, 0.028, 0.054, 0.151, 0.330, 1.540 and 2.680 mg kg(-1) diet) for 63 days. Both malondialdehyde and protein carbonyl content in all studied tissues and serum were the lowest in fish fed diets containing 0.151-0.330 mg biotin kg(-1) diet and then increased in fish fed the diet with 2.680 mg biotin kg(-1) diet (P < 0.05). Similarly, glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase activities in serum significantly decreased with biotin levels up to 0.151 mg kg(-1) diet (P < 0.05). Conversely, capacities of anti-hydroxyl radical (AHR) and anti-superoxide anion (ASA) in the detected tissues and serum significantly improved with biotin levels up to 0.054-1.540 mg kg(-1) diet and then decreased in 2.680 mg biotin kg(-1) diet group for muscle and intestinal AHR as well as hepatopancreas ASA (P < 0.05). Activities of superoxide dismutase in all studied tissues and serum significantly elevated with biotin levels up to 0.330 mg kg(-1) diet and then decreased when fish fed the diet with 2.680 mg biotin kg(-1) diet, except intestine (P < 0.05). Meanwhile, activities of catalase, glutathione peroxidase, glutathione-S-transferase and glutathione reductase and total thiol content in all studied tissues and serum showed the upward trend with biotin supplementations (P < 0.05). These results indicated that biotin improved antioxidant status and depressed lipid peroxidation and protein oxidation in all studied tissues and serum. PMID- 24045864 TI - The effect of allostatic load on hypothalamic-pituitary-interrenal (HPI) axis before and after secondary vaccination in Atlantic salmon postsmolts (Salmo salar L.). AB - The experiment consisted of three experimental groups: (1) "vaccine and stress", (2) "stress and vaccine" and (3) control. All groups have previously been vaccinated 6 months prior to the start of the experiment. At the start of the experiment, the "vaccine and stress" group was vaccinated with Pentium Forte Plus for the second time (25.02.2008) and then given a daily stressor (confinement stressor 267 kg m-3 in 15 min) for a period of 4 weeks. The "stress and vaccine" group was given a similar daily stressor for 4 weeks and then vaccinated for the second time. The control group was neither stressed nor vaccinated a second time. The results indicates that fish in the "stress and vaccine" group may have entered an allostatic overload type 2 due to oversensitivity to ACTH, a reduced efficient negative feedback system with elevated baseline levels of plasma cortisol and reduced immune response with pronounced effects on the well-being of the animal. The "vaccine and stress" group may likewise have entered an allostatic overload type 1 response, with oversensitivity to ACTH and transient reduced efficient negative feedback system. This study shows that if plasma cortisol becomes elevated prior to vaccination, it could perhaps instigate an allostatic overload type 2 with dire consequences on animal welfare. To reduce the risk of compromising the animal welfare during commercial vaccination of salmon, one propose to grade the fish minimum a week prior to vaccination or grade simultaneously with vaccination. This could reduce the overall allostatic load during handling and vaccination and secure a healthy fish with intact immune response and improved animal welfare. PMID- 24045865 TI - Aerobic exercise but not resistance exercise reduces intrahepatic lipid content and visceral fat and improves insulin sensitivity in obese adolescent girls: a randomized controlled trial. AB - It is unclear whether regular exercise alone (no caloric restriction) is a useful strategy to reduce adiposity and obesity-related metabolic risk factors in obese girls. We examined the effects of aerobic (AE) vs. resistance exercise (RE) alone on visceral adipose tissue (VAT), intrahepatic lipid, and insulin sensitivity in obese girls. Forty-four obese adolescent girls (BMI >=95th percentile, 12-18 yr) with abdominal obesity (waist circumference 106.5 +/- 11.1 cm) were randomized to 3 mo of 180 min/wk AE (n = 16) or RE (n = 16) or a nonexercising control group (n = 12). Total fat and VAT were assessed by MRI and intrahepatic lipid by proton magnetic resonance spectroscopy. Intermuscular AT (IMAT) was measured by CT. Insulin sensitivity was evaluated by a 3-h hyperinsulinemic (80 mU.m(2).min(-1)) euglycemic clamp. Compared with controls (0.13 +/- 1.10 kg), body weight did not change (P > 0.1) in the AE (-1.31 +/- 1.43 kg) and RE (-0.31 +/- 1.38 kg) groups. Despite the absence of weight loss, total body fat (%) and IMAT decreased (P < 0.05) in both exercise groups compared with control. Compared with control, significant (P < 0.05) reductions in VAT (Delta-15.68 +/- 7.64 cm(2)) and intrahepatic lipid (Delta-1.70 +/- 0.74%) and improvement in insulin sensitivity (Delta0.92 +/- 0.27 mg.kg(-1).min(-1) per MUU/ml) were observed in the AE group but not the RE group. Improvements in insulin sensitivity in the AE group were associated with the reductions in total AT mass (r = -0.65, P = 0.02). In obese adolescent girls, AE but not RE is effective in reducing liver fat and visceral adiposity and improving insulin sensitivity independent of weight loss or calorie restriction. PMID- 24045866 TI - The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis. AB - Plasma levels of uric acid, the final product of purine degradation in humans, are elevated in metabolic syndrome and are strongly associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD). Hepatic and blood levels of purine metabolites (inosine, hypoxanthine, and xanthine) are also altered in pathophysiological states. We optimized a rat hepatocyte model to test the hypothesis that the production of uric acid by hepatocytes is a potential marker of compromised homeostasis of hepatocellular inorganic phosphate (Pi) and/or ATP. The basal rate of uric acid production from endogenous substrates in rat hepatocytes was comparable to that in human liver and was <10% of the maximum rate with saturating concentrations of purine substrates. It was marginally (~20%) decreased by insulin and increased by glucagon but was stimulated more than twofold by substrates (fructose and glycerol) that lower both cell ATP and Pi, and by inhibitors of mitochondrial respiration (complexes I, III, and V) that lower ATP but raise cell Pi. Clearance of inosine and its degradation to uric acid were also inhibited by cell Pi depletion. Analysis of gene expression in NAFLD biopsies showed an association between mRNA expression of GCKR, the glucokinase regulatory protein that is functionally linked to uric acid production, and mRNA expression of the phosphate transporters encoded by SLC17A1/3. Uric acid production by hepatocytes is a very sensitive index of ATP depletion irrespective of whether cell Pi is lowered or raised. This suggests that raised plasma uric acid may be a marker of compromised hepatic ATP homeostasis. PMID- 24045867 TI - Pancreatic beta-cell function increases in a linear dose-response manner following exercise training in adults with prediabetes. AB - Although some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic beta-cell function is unknown. Thirty-five older obese adults with prediabetes underwent a progressive 12-wk supervised exercise intervention (5 days/wk for 60 min at ~85% HRmax). Insulin and C-peptide responses to an OGTT were used to define the first- and second-phase disposition index (DI; beta-cell function = glucose-stimulated insulin secretion * clamp-derived insulin sensitivity). Maximum oxygen consumption (Vo2max) and body composition (dual energy X-ray absorptiometry and computed tomography) were also measured before and after the intervention. Exercise dose was computed using Vo2/heart-rate derived linear regression equations. Subjects expended 474.5 +/- 8.8 kcal/session (2,372.5 +/- 44.1 kcal/wk) during the intervention and lost ~8% body weight. Exercise increased first- and second-phase DI (P < 0.05), and these changes in DI were linearly related to exercise dose (DIfirst phase: r = 0.54, P < 0.001; DIsecond phase: r = 0.56, P = 0.0005). Enhanced DI was also associated with increased Vo2max (DIfirst phase: r = 0.36, P = 0.04; DIsecond phase: r = 0.41, P < 0.02) but not lower body fat (DIfirst phase: r = -0.21, P = 0.25; DIsecond phase: r = -0.30, P = 0.10) after training. Low baseline DI predicted an increase in DI after the intervention (DIfirst phase: r = -0.37; DIsecond phase: r = 0.41, each P < 0.04). Thus, exercise training plus weight loss increased pancreatic beta-cell function in a linear dose-response manner in adults with prediabetes. Our data suggest that higher exercise doses (i.e., >2,000 kcal/wk) are necessary to enhance beta-cell function in adults with poor insulin secretion capacity. PMID- 24045868 TI - Preferential impact of pregnancy-associated plasma protein-A deficiency on visceral fat in mice on high-fat diet. AB - Accumulation of visceral fat, more so than subcutaneous fat, is strongly associated with severe metabolic complications. However, the factors regulating depot-specific adipogenesis are poorly understood. In this study, we show differential expression of pregnancy-associated plasma protein-A (PAPP-A), a secreted regulator of local insulin-like growth factor (IGF) action, in adipose tissue of mice. PAPP-A mRNA expression was fivefold higher in visceral (mesenteric) fat compared with subcutaneous (inguinal, subscapular), perirenal, and brown fat of mice. To investigate the possible role of depot-specific PAPP-A expression in fat accumulation, wild-type (WT) and PAPP-A knockout (KO) mice were fed a high-fat diet (HFD) for up to 20 wk. Adipocyte size increased in subcutaneous and perirenal depots similarly in WT and PAPP-A KO mice. However, fat cell size and in vivo lipid uptake were significantly reduced in mesenteric fat of PAPP-A KO compared with WT mice. After 20 wk on HFD, phosphorylation of AKT, a downstream signaling intermediate of IGF-I and insulin receptor activation, was significantly decreased by 50% in mesenteric compared with subcutaneous fat in WT mice, but was significantly increased threefold in mesenteric compared with subcutaneous fat in PAPP-A KO mice. This appeared to be because of enhanced insulin-stimulated signaling in mesenteric fat of PAPP-A KO mice. These data establish fat depot-specific expression of PAPP-A and indicate preferential impact of PAPP-A deficiency on visceral fat in the mouse that is associated with enhanced insulin receptor signaling. Thus, PAPP-A may be a potential target for treatment and/or prevention strategies for visceral obesity and related morbidities. PMID- 24045869 TI - Nutritional manipulations in the perinatal period program adipose tissue in offspring. AB - Epidemiological studies demonstrated initially that maternal undernutrition results in low birth weight with increased risk for long-lasting energy balance disorders. Maternal obesity and diabetes associated with high birth weight, excessive nutrition in neonates, and rapid catchup growth also increase the risk of adult-onset obesity. As stated by the Developmental Origin of Health and Disease concept, nutrient supply perturbations in the fetus or neonate result in long-term programming of individual body weight set point. Adipose tissue is a key fuel storage unit involved mainly in the maintenance of energy homeostasis. Studies in numerous animal models have demonstrated that the adipose tissue is the focus of developmental programming events in a sex- and depot-specific manner. In rodents, adipose tissue development is particularly active during the perinatal period, especially during the last week of gestation and during early postnatal life. In contrast to rodents, this process essentially takes place before birth in bigger mammals. Despite these different developmental time windows, altricial and precocial species share several mechanisms of adipose tissue programming. Offspring from malnourished dams present adipose tissue with a series of alterations: impaired glucose uptake, insulin and leptin resistance, low-grade inflammation, modified sympathetic activity with reduced noradrenergic innervations, and thermogenesis. These modifications reprogram adipose tissue metabolism by changing fat distribution and composition and by enhancing adipogenesis, predisposing the offspring to fat accumulation. Subtle adipose tissue circadian rhythm changes are also observed. Inappropriate hormone levels, modified tissue sensitivity (especially glucocorticoid system), and epigenetic mechanisms are key factors for adipose tissue programming during the perinatal period. PMID- 24045870 TI - The dual face of parathyroid hormone and prostaglandins in the osteoimmune system. AB - The microenvironment of bone marrow, an extraordinarily heterogeneous and dynamic system, is populated by bone and immune cells, and its functional dimension has been at the forefront of recent studies in the field of osteoimmunology. The interaction of both marrow niches supports self-renewal, differentiation, and homing of the hematopoietic stem cells and provides the essential regulatory molecules for osteoblast and osteoclast homeostasis. Impaired signaling within the niches results in a pathological tableau and enhances disease, including osteoporosis and arthritis, or the rejection of hematopoietic stem cell transplants. Discovering the anabolic players that control these mechanisms has become warranted. In this review, we focus on parathyroid hormone (PTH) and prostaglandins (PGs), potent molecular mediators, both of which carry out a multitude of functions, particularly in bone lining cells and T cells. These two regulators proved to be promising therapeutic agents when strictly clinical protocols on dose treatments were applied. PMID- 24045871 TI - Human blood contains both the uncleaved precursor of anti-Mullerian hormone and a complex of the NH2- and COOH-terminal peptides. AB - Anti-Mullerian hormone (AMH) in blood is a marker of ovarian status in women and the presence of cryptic testes in babies. Despite this, the molecular form of AMH in blood has not been verified. AMH is synthesized as an inert proprotein precursor (proAMH), which can be cleaved to yield NH2-terminal (AMHN) and COOH terminal (AMHC) fragments, that can complex noncovalently (AMHN,C). Developing males have 10-fold more AMH than young adults. We report here that human blood is a mixture of inactive proAMH and receptor-binding AMHN,C. The AMH in the blood of boys, men, and premenopausal women was immunoprecipitated using antibodies to the NH2- and COOH-terminal peptides. The precipitated proteins were then analyzed by Western blots, using recombinant proteins as markers. The glycosylation status of AMH was verified using deglycosylating enzymes. The NH2-terminal antibody precipitated a major protein that migrated alongside rhproAMH and was detected by anti-AMHN and anti-AMHC. This antibody also precipitated significant levels of AMHN and AMHC from all participants. Antibodies specific to AMHC precipitated rhAMHC but did not precipitate AMHC from human blood. Hence, all the AMHC in human blood appears to be bound to AMHN. Both AMHN and proAMH were glycosylated, independent of age and sex. In conclusion, boys and young adults have the same form of AMH, with a significant proportion being the inactive precursor. This raises the possibility that the endocrine functions of AMH are partly controlled by its cleavage in the target organ. The presence of proAMH in blood may confound the use of AMH for diagnosis. PMID- 24045872 TI - Rasmussen encephalitis: an unusual cause for intractable seizures in elderly. PMID- 24045873 TI - Good agreements make good friends. AB - When starting a new collaborative endeavor, it pays to establish upfront how strongly your partner commits to the common goal and what compensation can be expected in case the collaboration is violated. Diverse examples in biological and social contexts have demonstrated the pervasiveness of making prior agreements on posterior compensations, suggesting that this behavior could have been shaped by natural selection. Here, we analyze the evolutionary relevance of such a commitment strategy and relate it to the costly punishment strategy, where no prior agreements are made. We show that when the cost of arranging a commitment deal lies within certain limits, substantial levels of cooperation can be achieved. Moreover, these levels are higher than that achieved by simple costly punishment, especially when one insists on sharing the arrangement cost. Not only do we show that good agreements make good friends, agreements based on shared costs result in even better outcomes. PMID- 24045874 TI - Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats. AB - We sought to determine the hepatic fibrosis-reversal effects upon simultaneous administration of lithospermate B (LAB), an anti-oxidant, and nivocasan, a caspase inhibitor, to rats compared with each compound alone. Liver fibrosis was induced in Sprague-Dawley rats by thioacetamide (TAA). Rats were treated with TAA and then given LAB and (or) nivocasan. Fibrotic areas were evaluated quantitatively by computerized morphometry. Apoptosis was assessed using a TUNEL assay, and immunohistochemical staining for malondialdehyde (MDA) and 4-hydroxy-2 nonenal (4HNE) was performed to assess oxidative stress levels. Real-time quantitative PCR was used to quantify expression of fibrosis-related genes. The degree of hepatic fibrosis was significantly reduced in rats treated with LAB and nivocasan compared to either treatment alone (P < 0.001). Treatment with each compound significantly decreased expression of fibrosis-related genes, such as type I collagen alpha1 (col1alpha1), alpha-SMA and TGF-beta1 (P < 0.05). Co treatment with LAB and nivocasan further reduced col1alpha1 expression compared to treatment with either compound. A TUNEL assay revealed that hepatocyte apoptosis was significantly decreased in the group treated with nivocasan compared to other groups (P < 0.01). Immunohistochemistry showed a decrease in MDA and 4HNE, reflecting amelioration of oxidative stress, when LAB or LAB+nivocasan was administered compared to nivocasan alone (P < 0.01). Nivocasan was found to inhibit caspase-1, -3, -7, -9 and gliotoxin-induced death of rat derived hepatic stellate cells was inhibited by nivocasan administration without overexpression of alpha-SMA. CONCLUSIONS: Co-incidental administration of LAB and nivocasan suppressed oxidative stress and apoptosis, resulting in enhanced reversal of hepatic fibrosis in rat. PMID- 24045875 TI - 2-(Pyridinium-1-yl)-1,1-bis(triflyl)ethanides: structural behaviour and availability as bis(triflyl)ethylating reagents. AB - Stable and easy-to-handle zwitterions containing carbanion and pyridinium moieties were synthesized, and their structural studies by both X-ray crystallography and theoretical methods revealed the stereoelectronic effect in the zwitterionic 'C(-)-C-N(+)' system. PMID- 24045876 TI - Simultaneous purifying selection on the ancestral MC1R allele and positive selection on the melanoma-risk allele V60L in south Europeans. AB - In humans, the geographical apportionment of the coding diversity of the pigmentary locus melanocortin-1 receptor (MC1R) is, unusually, higher in Eurasians than in Africans. This atypical observation has been interpreted as the result of purifying selection due to functional constraint on MC1R in high UV-B radiation environments. By analyzing 3,142 human MC1R alleles from different regions of Spain in the context of additional haplotypic information from the 1000 Genomes (1000G) Project data, we show that purifying selection is also strong in southern Europe, but not so in northern Europe. Furthermore, we show that purifying and positive selection act simultaneously on MC1R. Thus, at least in Spain, regions at opposite ends of the incident UV-B radiation distribution show significantly different frequencies for the melanoma-risk allele V60L (a mutation also associated to red hair and fair skin and even blonde hair), with higher frequency of V60L at those regions of lower incident UV-B radiation. Besides, using the 1000G south European data, we show that the V60L haplogroup is also characterized by an extended haplotype homozygosity (EHH) pattern indicative of positive selection. We, thus, provide evidence for an adaptive value of human skin depigmentation in Europe and illustrate how an adaptive process can simultaneously help to maintain a disease-risk allele. In addition, our data support the hypothesis proposed by Jablonski and Chaplin (Human skin pigmentation as an adaptation to UVB radiation. Proc Natl Acad Sci U S A. 2010;107:8962-8968), which posits that habitation of middle latitudes involved the evolution of partially depigmented phenotypes that are still capable of suitable tanning. PMID- 24045877 TI - Time-dependent expression of SNAT2 mRNA in the contused skeletal muscle of rats: a possible marker for wound age estimation. AB - To estimate the age of skeletal muscle contusion, the expression of SNAT2 mRNA in contused skeletal muscle of rats was detected by real-time polymerase chain reaction (PCR). In total, 78 Sprague-Dawley male rats were divided into control and contusion groups. At 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 h (n = 6) after contusion, the rats were sacrificed with a lethal dose of pentobarbital. Another 24 rats received contusion injuries at 6, 12, 18, and 24 h (n = 6) after death. Total RNA was isolated from muscle specimens using the TRIzol reagent and reverse-transcribed into first-strand cDNA. Sequence-specific primers and TaqMan fluorogenic probes for SNAT2 mRNA and RPL13 mRNA were designed using the AlleleID 6 software, and the expression levels of SNAT2 mRNA were determined by real-time PCR. At 4, 16, 20, and 24 h after contusion, expression levels of SNAT2 mRNA normalized to RPL13 mRNA increased by 2.07 (P < 0.05), 2.53 (P < 0.05), 2.68 (P < 0.05), and 2.06 fold (P < 0.05) respectively, versus that in the control group. However, there was no significant change in the expression level of SNAT2 mRNA from 24 to 48 h (P > 0.05) after contusion, when normalized to RPL13 mRNA. There was no change in the expression level of SNAT2 mRNA between the normal skeletal muscle from the left limb of the same injured rat and the control. Also, no degradation of SNAT2 mRNA was detected in the postmortem samples (P > 0.05). This result suggests that the determination of SNAT2 mRNA levels by real-time PCR may be useful for estimating wound age. PMID- 24045878 TI - Treatment of rabbit intervertebral disc degeneration with co-transfection by adeno-associated virus-mediated SOX9 and osteogenic protein-1 double genes in vivo. AB - Degeneration of the lumbar intervertebral disc is a common cause of low back pain and leg pain that affects the physical and mental health of the patient and increases the social burden. This study was performed to observe the biological effects of adeno-associated virus (AAV)-mediated osteogenic protein-1 (OP1) and SOX9 double gene co-transfection in rabbit intervertebral disc degeneration in vivo. The animals were randomly grouped into models of disc degeneration. After injecting 20 ul of double-gene mixed solution, OP1, SOX9, enhanced green fluorescent protein (EGFP) and PBS buffer into the disc of each group, X-ray analysis, magnetic resonance imaging (MRI), reverse transcription PCR (RT-PCR) and western blotting were performed on the 3rd, 6th and 9th week of surgery. On the 3rd, 6th and 9th week of the transfection, X-ray and MRI showed that the intervertebral height and T2-weighted signal intensity were restored significantly in groups A, B and C, whereas significant differences in intervertebral space and T2-weighted signal intensity were observed between group A and groups B and C (P<0.05). RT-PCR and western blotting showed that the expression of type II collagen and proteoglycan mRNA was upregulated in groups A, B and C. The expression in group A was significantly higher than that in the other groups (P<0.05). Recombinant AAV-mediated SOX9 and OP1 double-gene transfection significantly ameliorated the height of the degenerative intervertebral disc and significantly promoted the high expression of degenerative disc proteoglycan and type II collagen. It can therefore be concluded that dual-gene therapy has a synergistic effect. PMID- 24045879 TI - The protective role of optimism and self-esteem on depressive symptom pathways among Canadian Aboriginal youth. AB - Aboriginal youth are at disproportionate risk for depression and substance use problems. Increasingly, developmental theories have shifted from focusing on vulnerabilities to protective factors for adolescent depression. In particular, theories emphasizing protective factors are relevant when understanding the mental health of Aboriginal youth. However, it is unclear which factors protect against depressive symptomatology among Aboriginal adolescents to promote optimal development. Using multilevel growth curve modeling, the present study had three main objectives. First, we aimed to model the developmental trajectory of depressive symptoms using a sample of off-reserve Aboriginal youth from a national Canadian dataset (ages 12-23). Second, we sought to examine the relationship between alcohol use behaviors, self-esteem, optimism, and the trajectories of depressive symptoms. Lastly, we investigated whether self-esteem and optimism mediated the relationship between alcohol use and depressive symptoms. Gender differences were also examined within each of the study objectives. A sample of off-reserve Aboriginal youth (N = 283; 48.3% male) was selected from cycles 4-7 of the National Longitudinal Survey of Children and Youth. Heavy drinking was a risk factor for depressive symptoms, while self esteem and optimism were key protective factors for depressive symptoms among early adolescent Aboriginal youth. Further, the developmental trajectory of depressive symptoms among Canadian Aboriginal youth differed for boys and girls once accounting for risk and protective factors. Thus, it is valuable to integrate the protective role of self-esteem and optimism into developmental theories of depression and mental health intervention programs for early adolescent Aboriginal youth. PMID- 24045881 TI - Sodium oxybate in maintaining alcohol abstinence in alcoholic patients according to Lesch typologies: a pilot study. AB - Sodium oxybate (SO) is a gamma-amino-butyric acid (GABA)-ergic drug currently used for the treatment of alcohol dependence (AD) in some European countries. The aim of this study was to describe the effect of SO administration in alcoholics classified according to Lesch alcoholism typology (LAT). Forty-eight patients were enrolled and classified into four groups according to LAT. All patients were treated with oral SO (50 mg/kg of body weight t.i.d.) for 12 weeks. All patients significantly reduced their alcohol intake (p<0.001). Alcohol abstinence during the 12 weeks of treatment did not differ between the four groups at the end of treatment. Craving for SO did not significantly differ amongst groups; cases of SO abuse were very limited and were observed in almost 10% of patients. In conclusion, our study showed an overall efficacy of SO in the treatment of AD irrespective of LAT categories. However, our results confirm that alcoholics with psychiatric co-morbidity, particularly with a borderline personality disorder of Axis II, are at a greater risk of developing craving for and abuse of the drug: until craving for alcohol and craving for SO are characterized in depth, SO should be used with caution in these patients. PMID- 24045882 TI - Prevention and reversal of ketamine-induced schizophrenia related behavior by minocycline in mice: Possible involvement of antioxidant and nitrergic pathways. AB - It has been hypothesized that oxidative imbalance and alterations in nitrergic signaling play a role in the neurobiology of schizophrenia. Preliminary evidence suggests that adjunctive minocycline treatment is efficacious for cognitive and negative symptoms of schizophrenia. This study investigated the effects of minocycline in the prevention and reversal of ketamine-induced schizophrenia-like behaviors in mice. In the reversal protocol, animals received ketamine (20 mg/kg per day intraperitoneally or saline for 14 days, and minocycline (25 or 50 mg/kg daily), risperidone or vehicle treatment from days 8 to 14. In the prevention protocol, mice were pretreated with minocycline, risperidone or vehicle prior to ketamine. Behaviors related to positive (locomotor activity and prepulse inhibition of startle), negative (social interaction) and cognitive (Y maze) symptoms of schizophrenia were also assessed. Glutathione (GSH), thiobarbituric acid-reactive substances (TBARS) and nitrite levels were measured in the prefrontal cortex, hippocampus and striatum. Minocycline and risperidone prevented and reversed ketamine-induced alterations in behavioral paradigms, oxidative markers (i.e. ketamine-induced decrease and increase in GSH levels and TBARS content, respectively) as well as nitrite levels in the striatum. These data provide a rationale for evaluating minocycline as a novel psychotropic agent and suggest that its mechanism of action includes antioxidant and nitrergic systems. PMID- 24045883 TI - Effect of modafinil on cognitive functions in alcohol dependent patients: a randomized, placebo-controlled trial. AB - Cognitive deficits are highly prevalent in alcohol-dependent (AD) patients and may have a detrimental impact on treatment response and treatment outcome. Enhancing cognitive functions may improve treatment success. Modafinil is a promising compound in this respect. Therefore, a randomized double-blind placebo controlled trial was conducted with modafinil (300 mg/d) or placebo in 83 AD patients for 10 weeks. Various cognitive functions (digit span task, Tower of London task, Stroop task) were measured at baseline, during and after treatment. Compared to placebo, modafinil improved verbal short-term memory (number of forward digit spans) (p=0.030), but modafinil exerted a negative effect on the working memory score of the digit span task (p=0.003). However, subgroup analyses revealed that modafinil did improve both working memory and verbal short-term memory in AD patients with a poor working memory ability at baseline (25% worst performers), whereas no significant treatment effect of modafinil was found on these two dependent variables in patients with good working memory skills at baseline (25% best performers). No effect of modafinil was found on measures of planning (Tower of London task) and selective attention (Stroop task). Further research is needed to better understand the relationship between cognitive remediation and treatment outcome in order to design targeted treatments. PMID- 24045884 TI - Synthesis of 6-deoxymollugins and their inhibitory activities on tyrosinase. AB - A series of 6-deoxymollugins were prepared five steps from benzaldehyde and its derivatives via phenylboronic acid-catalyzed chromenylation as a key step. Their inhibitory activities against tyrosinase from mushroom were evaluated to show that the parent, methyl 2,2-dimethyl-2H-benzo[h]chromene-5-carboxylate (9a) showed best and promising inhibitory activity at IC50 = 18.3 MUM. PMID- 24045880 TI - Repeated aripiprazole treatment causes dopamine D2 receptor up-regulation and dopamine supersensitivity in young rats. AB - Aripiprazole is a second-generation antipsychotic that is increasingly being prescribed to children and adolescents. Despite this trend, little preclinical research has been done on the neural and behavioral actions of aripiprazole during early development. In the present study, young male and female Sprague Dawley rats were pretreated with vehicle, haloperidol (1 mg/kg), or aripiprazole (10 mg/kg) once daily on postnatal days (PD) 10-20. After 1, 4, or 8 days (i.e. on PD 21, PD 24, or PD 28), amphetamine-induced locomotor activity and stereotypy, as well as dorsal striatal D2 receptor levels, were measured in separate groups of rats. Pretreating young rats with aripiprazole or haloperidol increased D2 binding sites in the dorsal striatum. Consistent with these results, dopamine supersensitivity was apparent when aripiprazole- and haloperidol pretreated rats were given a test day injection of amphetamine (2 or 4 mg/kg). Increased D2 receptor levels and altered behavioral responding persisted for at least 8 days after conclusion of the pretreatment regimen. Contrary to what has been reported in adults, repeated aripiprazole treatment caused D2 receptor up regulation and persistent alterations of amphetamine-induced behavior in young rats. These findings are consistent with human clinical studies showing that children and adolescents are more prone than adults to aripiprazole-induced side effects, including extrapyramidal symptoms. PMID- 24045885 TI - Nutritional quality changes throughout shelf-life of fresh-cut kailan-hybrid and 'Parthenon' broccoli as affected by temperature and atmosphere composition. AB - The nutritional quality changes of the fresh-cut kailan-hybrid broccoli were compared with those of the 'Parthenon' cv. throughout 15 days at 2 C, 5 C and 8 C under air and modified atmosphere packaging. Florets showed higher dietary fiber content than stems. The total protein content of kailan-hybrid florets was 2.2 fold higher than that of 'Parthenon' cv. and higher amounts of S, Ca, Mg, Fe, Sr, Mn, Zn and Cu were found. However, 'Parthenon' florets registered higher initial total phenolics content than the kailan-hybrid edible part, followed by an increase throughout shelf-life favored at 5 C and 8 C under modified atmosphere packaging (5-7 kPa O2 + 14-15 kPa CO2). Modified atmosphere packaging stored samples at 8 C showed higher individual phenolics content than modified atmosphere packaging stored samples at 2 C. The initial total antioxidant capacity of the kailan-hybrid edible part was higher than that of 'Parthenon' cv. florets. In conclusion, the kailan-hybrid florets generally showed healthier properties on the analyzed bioactive compounds, except total phenolic content, compared to the conventional 'Parthenon' cv. PMID- 24045887 TI - Implementation of a combo videolaryngoscope for intubation in critically ill patients: a before-after comparative study. AB - PURPOSE: Airway management in intensive care unit (ICU) patients is challenging. The main objective of this study was to compare the incidence of difficult laryngoscopy and/or difficult intubation between a combo videolaryngoscope and the standard Macintosh laryngoscope in critically ill patients. METHODS: In the context of the implementation of a quality-improvement process for airway management, we performed a prospective interventional monocenter before-after study which evaluated a new combo videolaryngoscope. The primary outcome was the incidence of difficult laryngoscopy (defined by Cormack grade 3-4) and/or difficult intubation (more than two attempts). The secondary outcomes were the severe life-threatening complications related to intubation in ICU and the rate of difficult intubation in cases of predicted difficult intubation evaluated by a specific score (MACOCHA score >=3). RESULTS: Two hundred and ten non-selected consecutive intubation procedures were included, 140 in the standard laryngoscope group and 70 in the combo videolaryngoscope group. The incidence of difficult laryngoscopy and/or difficult intubation was 16 % in the laryngoscope group vs. 4 % in the combo videolaryngoscope group (p = 0.01). The severe life-threatening complications related to intubation did not differ between groups (16 vs. 14 %, p = 0.79). Among the 32 patients with a MACOCHA score >=3, there were significantly more patients with difficult intubation in the standard laryngoscope group in comparison to the combo videolaryngoscope group [12/23 (57 %) vs. 0/9 (0 %), p < 0.01]. CONCLUSIONS: The systematic use of a combo videolaryngoscope in ICU was associated with a decreased incidence of difficult laryngoscopy and/or difficult intubation. PMID- 24045886 TI - Clinical implications of antibiotic pharmacokinetic principles in the critically ill. AB - Successful antibiotic therapy in the critically ill requires sufficient drug concentrations at the site of infection that kill or suppress bacterial growth. The relationship between antibiotic exposure and achieving the above effects is referred to as pharmacokinetics/pharmacodynamics (PK/PD). The associated indices therefore provide logical targets for optimal antibiotic therapy. While dosing regimens to achieve such targets have largely been established from studies in animals and non-critically ill patients, they are often poorly validated in the ICU. Endothelial dysfunction, capillary leak, altered major organ blood flow, deranged plasma protein concentrations, extremes of body habitus, the application of extracorporeal support modalities, and a higher prevalence of intermediate susceptibility, independently, and in combination, significantly confound successful antibiotic treatment in this setting. As such, the prescription of standard doses are likely to result in sub-therapeutic concentrations, which in turn may promote treatment failure or the selection of resistant pathogens. This review article considers these issues in detail, summarizing the key changes in antibiotic PK/PD in the critically ill, and suggesting alternative dosing strategies that may improve antibiotic therapy in these challenging patients. PMID- 24045888 TI - Temporal and geographic clustering of polyomavirus-associated olfactory tumors in 10 free-ranging raccoons (Procyon lotor). AB - Reports of primary nervous system tumors in wild raccoons are extremely rare. Olfactory tumors were diagnosed postmortem in 9 free-ranging raccoons from 4 contiguous counties in California and 1 raccoon from Oregon within a 26-month period between 2010 and 2012. We describe the geographic and temporal features of these 10 cases, including the laboratory diagnostic investigations and the neuropathologic, immunohistochemical, and ultrastructural characteristics of these tumors in the affected animals. All 9 raccoons from California were found within a localized geographic region of the San Francisco Bay Area (within a 44.13-km radius). The tight temporal and geographic clustering and consistent anatomic location in the olfactory system of tumor types not previously described in raccoons (malignant peripheral nerve sheath tumors and undifferentiated sarcomas) strongly suggest either a common cause or a precipitating factor leading to induction or potentiation of neuro-oncogenesis and so prompted an extensive diagnostic investigation to explore possible oncogenic infectious and/or toxic causes. By a consensus polymerase chain reaction strategy, a novel, recently reported polyomavirus called raccoon polyomavirus was identified in all 10 tumors but not in the normal brain tissue from the affected animals, suggesting that the virus might play a role in neuro-oncogenesis. In addition, expression of the viral protein T antigen was detected in all tumors containing the viral sequences. We discuss the potential role of raccoon polyomavirus as an oncogenic virus. PMID- 24045889 TI - Immune system cells in healthy ferrets: an immunohistochemical study. AB - The ferret has emerged as an excellent animal model to characterize several physiologic and pathologic conditions. The distribution and characterization of different types of immune system cells were studied in healthy ferret tissues. Eight primary antibodies were tested for immunohistochemistry in formalin-fixed tissues: anti-CD3, anti-CD79alpha, anti-CD20, anti-HLA-DR, anti-lysozyme, anti CD163, anti-SWC3, and anti-Mac387. The anti-CD3 antibody labeled T cells mainly in interfollicular and paracortical areas of lymph nodes, cortex and thymic medulla, and periarteriolar lymphoid sheaths in the spleen. The anti-CD79alpha and anti-CD20 antibodies immunolabeled B cells located in lymphoid follicles at lymph nodes, spleen, and Peyer patches. The CD79alpha and CD20 antibodies also labeled cells with nonlymphoid morphology in atypical B-cell locations. The anti HLA-DR antibody labeled macrophages, some populations of B and T lymphocytes, and different populations of dendritic cells in lymph nodes, Peyer patches, spleen, and thymus. The anti-lysozyme antibody immunolabeled macrophages in the liver, lymph nodes, spleen, and thymus. The Mac-387, CD163, and SWC3 antibodies did not show any positive reaction in formalin-fixed or frozen tissues. To elucidate the origin of the uncommon CD79alpha/CD20 positive cells, a double immunohistochemistry was carried out using the anti-HLA-DR + the anti-CD79alpha, the anti-HLA-DR + the anti-CD20, and the anti-lysozyme + the anti-CD79alpha antibodies. Double labeling was mainly observed when the anti-HLA-DR + the anti CD79alpha antibodies were combined. The immunohistologic characterization and distribution of these immune system cells in healthy ferret tissues should be of value in future comparative studies of diseases in ferrets. PMID- 24045891 TI - Proteomics in veterinary medicine: applications and trends in disease pathogenesis and diagnostics. AB - Advancement in electrophoresis and mass spectrometry techniques along with the recent progresses in genomics, culminating in bovine and pig genome sequencing, widened the potential application of proteomics in the field of veterinary medicine. The aim of the present review is to provide an in-depth perspective about the application of proteomics to animal disease pathogenesis, as well as its utilization in veterinary diagnostics. After an overview on the various proteomic techniques that are currently applied to veterinary sciences, the article focuses on proteomic approaches to animal disease pathogenesis. Included as well are recent achievements in immunoproteomics (ie, the identifications through proteomic techniques of antigen involved in immune response) and histoproteomics (ie, the application of proteomics in tissue processed for immunohistochemistry). Finally, the article focuses on clinical proteomics (ie, the application of proteomics to the identification of new biomarkers of animal diseases). PMID- 24045892 TI - The common ancestor process revisited. AB - We consider the Moran model in continuous time with two types, mutation, and selection. We concentrate on the ancestral line and its stationary type distribution. Building on work by Fearnhead (J. Appl. Probab. 39 (2002), 38-54) and Taylor (Electron. J. Probab. 12 (2007), 808-847), we characterise this distribution via the fixation probability of the offspring of all individuals of favourable type (regardless of the offspring's types). We concentrate on a finite population and stay with the resulting discrete setting all the way through. This way, we extend previous results and gain new insight into the underlying particle picture. PMID- 24045893 TI - Complex dynamics in an eco-epidemiological model. AB - The presence of infectious diseases can dramatically change the dynamics of ecological systems. By studying an SI-type disease in the predator population of a Rosenzweig-MacArthur model, we find a wealth of complex dynamics that do not exist in the absence of the disease. Numerical solutions indicate the existence of saddle-node and subcritical Hopf bifurcations, turning points and branching in periodic solutions, and a period-doubling cascade into chaos. This means that there are regions of bistability, in which the disease can have both a stabilising and destabilising effect. We also find tristability, which involves an endemic torus (or limit cycle), an endemic equilibrium and a disease-free limit cycle. The endemic torus seems to disappear via a homoclinic orbit. Notably, some of these dynamics occur when the basic reproduction number is less than one, and endemic situations would not be expected at all. The multistable regimes render the eco-epidemic system very sensitive to perturbations and facilitate a number of regime shifts, some of which we find to be irreversible. PMID- 24045890 TI - MicroRNAs: history, biogenesis, and their evolving role in animal development and disease. AB - The discovery of microRNAs (miRNAs) in 1993 followed by developments and discoveries in small RNA biology have redefined the biological landscape by significantly altering the longstanding dogmas that defined gene regulation. These small RNAs play a significant role in modulation of an array of physiological and pathological processes ranging from embryonic development to neoplastic progression. Unique miRNA signatures of various inherited, metabolic, infectious, and neoplastic diseases have added a new dimension to the studies that look at their pathogenesis and highlight their potential to be reliable biomarkers. Also, altering miRNA functionality and the development of novel in vivo delivery systems to achieve targeted modulation of specific miRNA function are being actively pursued as novel approaches for therapeutic intervention in many diseases. Here we review the current body of knowledge on the role of miRNAs in development and disease and discuss future implications. PMID- 24045895 TI - 7,8-dihydroxyflavone, a small-molecule tropomyosin-related kinase B (TrkB) agonist, attenuates cerebral ischemia and reperfusion injury in rats. AB - 7,8-dihydroxyflavone (7,8-DHF) is a recently identified potent agonist of tropomyosin-related kinase B that can cross the blood-brain barrier after oral or intraperitoneal administration. The aim of the present study was to determine whether 7,8-DHF has neuroprotective effects against cerebral ischemia and reperfusion (I/R) injury and, if so, to investigate the possible underlying mechanisms. Cerebral I/R injury rats were induced by middle cerebral artery occlusion for 90 min followed by reperfusion for 24 h. 7,8-DHF was administered intraperitoneally at a dose of 5 mg/kg immediately after ischemia. Our results showed that 7,8-DHF significantly reduced neurological deficit scores, infarct volumes, and neuronal apoptosis in brains of I/R rats. Meanwhile, 7,8-DHF also increased Bcl-2 expression, decreased expression of cleaved caspase-3, Bax and inducible nitric oxide synthase, and inhibited nuclear factor-kappaB activation in ischemic cortex. Finally, malondialdehyde and nitric oxide contents were reduced, but activities of glutathione, glutathione peroxidase and superoxide dismutase were restored in ischemic cortex treated with 7,8-DHF. Taken together, our findings demonstrated that 7,8-DHF is able to protect against cerebral I/R injury, which may be, at least in part, attributable to its anti-apoptotic, anti oxidative and anti-inflammatory actions. PMID- 24045897 TI - Which type of inflammation can be controlled by Foxp3+ Tregs? PMID- 24045896 TI - Overexpression of integrin-linked kinase (ILK) promotes glioma cell invasion and migration and down-regulates E-cadherin via the NF-kappaB pathway. AB - Integrin-linked kinase (ILK) is a ubiquitously expressed serine/threonine protein kinase that has been implicated in cancer development, progression and metastasis. The aim of the present study was to characterize the role of ILK in glioma cell invasion and migration. We generated a recombinant eukaryotic expression vector containing the human ILK gene and transfected it into human glioma SHG-44 cells. Real-time PCR and western blot analysis were used to identify the stable transformants. The wound healing and Transwell invasion assays showed that ectopic overexpression of ILK in SHG-44 cells significantly promoted their migration and invasion capabilities in culture. This was accompanied by a decrease in expression of E-cadherin and an increase in expression of Snail and Slug. Moreover, the decrease in E-cadherin expression induced by ILK overexpression was greatly restored by the nuclear factor-kappaB (NF-kappaB) inhibitor BAY 11-7028 or small interfering RNA targeting NF-kappaB p65, indicating an involvement of NF-kappaB in ILK-induced down-regulation of E cadherin. In conclusion, our data underscore a novel role for ILK in glioma invasion and metastasis processes, implicating potential for therapeutic interference. PMID- 24045898 TI - Pathogenic T helper 1 cells reach the brain before T helper 17 cells, and T regulatory cells suppress them albeit incompletely. PMID- 24045899 TI - Synergistic mutations in SLC3A1 and SLC7A9 leading to heterogeneous cystinuria phenotypes: pitfalls in the diagnostic workup. AB - BACKGROUND: Cystinuria is an inherited disorder of a renal tubular amino acid transporter and leads to increased cystine excretion with the risk of urinary stone formation. Phenotypical classification is based on urinary amino acid concentration as type I (silent), type non-I (hyper-excretors), mixed or untyped. Genotypic classification is based on mutations in SLC3A1 (type A) or SLC7A9 (type B). CASE-DIAGNOSIS/TREATMENT: We present six family members with a complex phenotypic profile based on mutations in both genes. The index patient presents a known homozygous mutation (p.T189M) in SLC3A1 and a homozygous mutation (c.225C > T) in SLC7A9. Based on a bioinformatics analysis and published findings, we considered p.T189M to be pathogenic and initially classified c.225C > T as a silent variant. However, segregation analysis detected homozygosity for p.T189M also in non-affected individuals, whereas homozygous c.225C > T segregated with the phenotype. RNA studies confirmed c.225C > T to cause aberrant splicing. CONCLUSIONS: Based on our findings, we conclude that c.225C > T in SLC7A9 determines the clinical phenotype in this family, whereas additional SLC3A1 mutations aggravate the phenotype in heterozygotes for c.225C > T in SLC7A9 without resulting in cystinuria in the homozygous state. Our results underline the need for careful biochemical characterization of family members of an index case of cystinuria. Genetic analysis of both cystinuria genes may be necessary due to the synergistic effects of mutations in two genes. PMID- 24045900 TI - Efficient PdNi and PdNi@Pd-catalyzed hydrogen generation via formic acid decomposition at room temperature. AB - Formic acid (FA) holds great potential as a convenient source of hydrogen for sustainable chemical synthesis and renewable energy storage. Herein, the non noble metal nickel (Ni) exhibits superior promoting effect in improving the catalytic activity of Pd toward high activity and selectivity for FA decomposition at room temperature. PMID- 24045901 TI - Isolation of lactic acid bacteria from kuruma shrimp (Marsupenaeus japonicus) intestine and assessment of immunomodulatory role of a selected strain as probiotic. AB - Fifty-one lactic acid bacteria (LAB) strains were isolated and identified based on 16S ribosomal DNA sequence from the intestinal tracts of 142 kuruma shrimps (Marsupenaeus japonicus) collected from Kanmon Strait, Fukuoka and Tachibana Bay, Nagasaki, Japan. Cellular immunomodulatory function of 51 isolated LAB strains was assessed by measuring the level of interferon (IFN)-gamma induction in mouse spleen cell culture. The strain Lactococcus lactis D1813 exhibited the highest amount of IFN-gamma production and also bactericidal activity and was selected for testing its immunomodulatory role as a probiotic in kuruma shrimp. We also assessed the effect of dietary incorporation of this probiotic on resistance to Vibrio penaeicida infection in the kuruma shrimp. Our results demonstrate that probiotic L. lactis D1813-containing diet-fed (105 cfu g-1) shrimps displayed a significant up-regulation of lysozyme gene expressions in the intestine and hepatopancreas. However, insignificantly higher expression of anti lipopolysaccharide factor, super oxide dismutase, prophenoloxidase, and toll-like receptor 1 was recorded in the intestine of shrimps fed the probiotic diet. Moreover, significantly increased (P < 0.01) resistance to the bacterial pathogen in term of better post-infection survival (61.7 %) was observed in the shrimps fed with the probiotic-incorporated diet compared with the control diet-fed group (28.3 %). The present study indicates the immunomodulatory role of the LAB L. lactis D1813 on the kuruma shrimp immune system and supports its potential use as an effective probiotic in shrimp aquaculture. PMID- 24045902 TI - Sexual values as the key to maintaining satisfying sex after prostate cancer treatment: the physical pleasure-relational intimacy model of sexual motivation. AB - Sexual dysfunction is the most significant long lasting effect of prostate cancer (PrCa) treatment. Despite the many medical treatments for erectile dysfunction, many couples report that they are dissatisfied with their sexual relationship and eventually cease sexual relations altogether. We sought to understand what distinguishes successful couples from those who are not successful in adjusting to changes in sexual function subsequent to PrCa treatment. Ten couples who maintained satisfying sexual intimacy after PrCa treatment and seven couples that did not were interviewed conjointly and individually. Interviews were transcribed and analyzed using grounded theory methodology. The theory that resulted suggests that individuals are motivated to engage in sex primarily because of physical pleasure and relational intimacy. The couples who valued sex primarily for relational intimacy were more likely to successfully adjust to changes in sexual function than those who primarily valued sex for physical pleasure. The attributes of acceptance, flexibility, and persistence helped sustain couples through the process of adjustment. Based on these findings, a new theory, the Physical Pleasure-Relational Intimacy Model of Sexual Motivation (PRISM) is presented. The results elucidate the main motives for engaging in sexual activity physical pleasure and/or relational intimacy-as a determining factor in the successful maintenance of satisfying sexual intimacy after PrCa treatment. The PRISM model predicts that couples who place a greater value on sex for relational intimacy will better adjust to the sexual challenges after PrCa treatment than couples who place a lower value on sex for relational intimacy. Implications of the model for counselling are discussed. This model remains to be tested in future research. PMID- 24045903 TI - Biological markers of asexuality: Handedness, birth order, and finger length ratios in self-identified asexual men and women. AB - Human asexuality is defined as a lack of sexual attraction to anyone or anything and it has been suggested that it may be best conceptualized as a sexual orientation. Non-right-handedness, fraternal birth order, and finger length ratio (2D:4D) are early neurodevelopmental markers associated with sexual orientation. We conducted an Internet study investigating the relationship between self identification as asexual, handedness, number of older siblings, and self measured finger-lengths in comparison to individuals of other sexual orientation groups. A total of 325 asexuals (60 men and 265 women; M age, 24.8 years), 690 heterosexuals (190 men and 500 women; M age, 23.5 years), and 268 non heterosexuals (homosexual and bisexual; 64 men and 204 women; M age, 29.0 years) completed online questionnaires. Asexual men and women were 2.4 and 2.5 times, respectively, more likely to be non-right-handed than their heterosexual counterparts and there were significant differences between sexual orientation groups in number of older brothers and older sisters, and this depended on handedness. Asexual and non-heterosexual men were more likely to be later-born than heterosexual men, and asexual women were more likely to be earlier-born than non-heterosexual women. We found no significant differences between sexual orientation groups on measurements of 2D:4D ratio. This is one of the first studies to test and provide preliminary empirical support for an underlying neurodevelopmental basis to account for the lack of sexual attraction characteristic of asexuality. PMID- 24045904 TI - Exploring the effects of sexual desire discrepancy among married couples. AB - Previous studies have found associations between the individual discrepancy of desired sexual frequency and actual sexual frequency and relational outcomes among premarital couples. The present study extended this research by using a sample of 1,054 married couples to explore how actor and partner individual sexual desire discrepancy (SDD) scores were associated with relationship satisfaction, stability, communication, and conflict during marriage. All participants took an online survey which assessed both couple sexual dynamics and relationship outcomes. Findings suggested that higher actor individual SDD was generally associated with negative relational outcomes, including lower reported relationship satisfaction, stability, and more reported couple conflict. These effects were found after controlling for background factors, baseline sexual frequency and desire, and couple desire discrepancies. Some partner effects were also found and were generally in the same direction. Marital length did not moderate the effects found although gender moderated associations between individual SDD and reported couple communication. Negative associations between individual SDD and communication were particularly strong when the husband reported high discrepancies between desired and actual sexual frequency. Results suggested that higher individual sexual desire discrepancies among married individuals may undermine relationship well-being. Applications of these findings to a clinical setting are also discussed. PMID- 24045905 TI - Goal setting, problem solving and feedback improve short-term adherence to physical activity in people with stable heart failure. PMID- 24045906 TI - Thoracic outlet syndromes in sport: a practical review in the face of limited evidence--unusual pain presentation in an athlete. AB - Despite thoracic outlet syndrome (TOS) being first described early in the 19th century, the subsequent literature seems limited, focusing on case reports and investigations providing little assistance in the management of equivocal presentations. Best practice clinical management, with little evidence base, poses great challenges for clinicians in deciding how to manage TOS, when to operate and which procedure should be undertaken. Furthermore, the implications of TOS and its surgical effects are poorly documented, with little evidence in the literature as to the impact of surgical intervention on athletes and their physiology or function. This paper describes a clinical example of TOS highlighting salient issues and examining the evidence to guide clinical management at each stage, in the case of a 26-year-old professional football player who suffered an acute onset of unilateral right shoulder to bicep pain associated with tingling in the hand. Clinicians managing similar cases in the future will have a reference point to assist their diagnosis, management and promote much needed research to further our understanding of this difficult syndrome. PMID- 24045908 TI - Mediastinal hepatocellular carcinoma with unknown primary: an unusual and rare presentation. PMID- 24045907 TI - Predicting changes in hypertension control using electronic health records from a chronic disease management program. AB - OBJECTIVE: Common chronic diseases such as hypertension are costly and difficult to manage. Our ultimate goal is to use data from electronic health records to predict the risk and timing of deterioration in hypertension control. Towards this goal, this work predicts the transition points at which hypertension is brought into, as well as pushed out of, control. METHOD: In a cohort of 1294 patients with hypertension enrolled in a chronic disease management program at the Vanderbilt University Medical Center, patients are modeled as an array of features derived from the clinical domain over time, which are distilled into a core set using an information gain criteria regarding their predictive performance. A model for transition point prediction was then computed using a random forest classifier. RESULTS: The most predictive features for transitions in hypertension control status included hypertension assessment patterns, comorbid diagnoses, procedures and medication history. The final random forest model achieved a c-statistic of 0.836 (95% CI 0.830 to 0.842) and an accuracy of 0.773 (95% CI 0.766 to 0.780). CONCLUSIONS: This study achieved accurate prediction of transition points of hypertension control status, an important first step in the long-term goal of developing personalized hypertension management plans. PMID- 24045909 TI - Biomechanical evaluation of augmented and nonaugmented primary repair of the anterior cruciate ligament: an in vivo animal study. AB - PURPOSE: The purpose of this study was to evaluate in a sheep model the biomechanical performance of augmented and nonaugmented primary repair of the anterior cruciate ligament (ACL) following transection at the femoral end during a 12-month postoperative observation. METHODS: Forty sheep were randomly assigned to nonaugmented or augmented primary ACL repair using a polyethylene terephthalate (PET) band. At two, six, 16, 26 and 52 weeks postoperatively four sheep in each group were sacrificed and biomechanical testing performed. RESULTS: Compared with nonaugmented primary ACL repair, the PET-augmented repair demonstrated superior biomechanical results from 16 weeks postoperatively onwards in terms of anterioposterior (AP) laxity, tensile strength and ligament stiffness. The augmentation device works as a stress shield during the ligament healing process. The nonaugmented ACL repair also resulted in ligament healing, but the biomechanical properties were at a significantly lower level. CONCLUSION: These results support the previously reported histological findings following augmented primary ACL repair. This animal study on the healing capacity of the ACL may provide some important contributions to how primary healing in certain types of ruptures can be achieved. CLINICAL RELEVANCE: I. PMID- 24045910 TI - Fibula head is a useful landmark to predict the location of posterior cruciate ligament footprint prior to total knee arthroplasty. AB - PURPOSE: The hypothesis of our study is that a routine tibial cut during cruciate retaining TKA may result in a partial or a total removal of the PCL footprint. Therefore providing a reliable landmark is essential to estimate the probability of PCL damage with a tibial cut and to enable the surgeon to decide pre operatively whether a cruciate retaining implant design is suitable. METHODS: In a case series of 175 cruciate retaining TKA, the routinely made standing postoperative AP-view radiographs were evaluated to determine the distance between fibula head and tibial cutting plane. In a second case series knee MRI of 223 subjects were consecutively used to measure the vertical distance between tibial attachment of PCL and fibula head. The probability of partial or total PCL damage was calculated for different vertical distances between tibial cut and fibula head. RESULTS: The vertical distance between the tibial cut and the most proximal point of the fibula head averaged 6.1 mm +/-4.8 mm. The mean vertical distance from fibula head to proximal and to distal PCL footprint revealed to be 11.4 mm +/-3.7 mm and 5.4 mm +/-2.9 mm, respectively. The location of the insertion was not significantly different between subgroups such as age (<50 or >50 years), gender and side. Based on our results 11 (7%) knees were considered at high risk of an entire PCL removal after implantation of a cruciate retaining TKA design. CONCLUSIONS: Currently available routine tibial preparation techniques result in partial or total posterior cruciate ligament detachment. Fibula head as a landmark aids to predict the PCL location and to estimate its disruption pre- and postoperatively on AP-view radiographs. PMID- 24045911 TI - The contributions of maternity care to reducing adverse pregnancy outcomes: a cohort study in Dabat district, northwest Ethiopia. AB - This study was designed to evaluate the effect of maternity care by skilled providers on the occurrence of adverse pregnancy outcomes. A community-based cohort study was conducted at Dabat district, northwest Ethiopia, from December 1, 2011 to August 31, 2012. During the study period, 763 pregnant women were registered and followed until 42 days of their postpartum period. Use of skilled maternal care was the exposure variable. Reductions in occurrence of serious complications or death (adverse pregnancy outcomes) were used as outcome indicators. Data was collected at four time points; first contact, during the 9th month of pregnancy, within 1 week after delivery and at 42 days of postpartum. The effects of the exposure variable were evaluated by controlling potential confounders using logistic regression. One hundred and fifty-three (21%) of the women encountered at least one obstetric complication or death during delivery and postpartum period. Hemorrhage and prolonged labor were the major types. Pregnancy outcomes for 41 women (5.6%) were fetal, neonatal, or maternal deaths. Four or more ANC (antenatal care) visits, <4 ANC visits and delivery by skilled attendant showed 25% (OR 0.75; 95% CI 0.25, 2.75), 9% (OR 0.91; 95% CI 0.43, 1.69) and 31% (OR 0.69; 95% CI 0.36, 1.33) reduction in the occurrence of adverse pregnancy outcomes, respectively. Skilled maternal care showed reduction in adverse pregnancy outcomes (complications and deaths). However, the associations were not significant. Improving the quality of maternity care services and ensuring continuum of care in the health care system are imperative for effective maternal health care in the study area. PMID- 24045912 TI - Barriers to adequate prenatal care utilization in American Samoa. AB - The objective of this study is to describe the utilization of prenatal care in American Samoan women and to identify socio-demographic predictors of inadequate prenatal care utilization. Using data from prenatal clinic records, women (n = 692) were categorized according to the adequacy of prenatal care utilization index as having received adequate plus, adequate, intermediate or inadequate prenatal care during their pregnancy. Categorical socio-demographic predictors of the timing of initiation of prenatal care (week of gestation) and the adequacy of received services were identified using one way analysis of variance and independent samples t tests. Between 2001 and 2008 85.4 % of women received inadequate prenatal care. Parity (P = 0.02), maternal unemployment (P = 0.03), and both parents being unemployed (P = 0.03) were negatively associated with the timing of prenatal care initiation. Giving birth in 2007-2008, after a prenatal care incentive scheme had been introduced in the major hospital, was associated with earlier initiation of prenatal care (20.75 vs. 25.12 weeks; P < 0.01) and improved adequacy of received services (95.04 vs. 83.8 %; P = 0.02). The poor prenatal care utilization in American Samoa is a major concern. Improving healthcare accessibility will be key in encouraging women to attend prenatal care. The significant improvements in the adequacy of prenatal care seen in 2007 2008 suggest that the prenatal care incentive program implemented in 2006 may be a very positive step toward addressing issues of prenatal care utilization in this population. PMID- 24045913 TI - Electron paramagnetic resonance study of tumor affected bone marrow. AB - To study the mechanism of interaction of tumor cells with bone marrow cells continuous wave electron paramagnetic resonance (EPR) experiments at 9 GHz including a spin trapping of superoxide were carried out. The common features of the EPR spectra in healthy and tumor affected tissues of donors and rats as well as their difference are presented and discussed. It is proposed that labile iron pool plays a significant role in mechanisms of tumor invasion. We hope that the observed EPR features could be used to study the mechanisms of invasion and progression of tumor in different organs. PMID- 24045915 TI - Knee kinematics is altered post-fatigue while performing a crossover task. AB - PURPOSE: To examine the effect of a sequential fatigue protocol on lower extremity biomechanics during a crossover cutting task in female soccer players. METHODS: Eighteen female collegiate soccer players alternated between a fatigue protocol and two consecutive unanticipated crossover trials until fatigue was reached. Lower extremity biomechanics were evaluated during the crossover using a 3D motion capture system and two force plates. Repeated-measures ANOVAs analysed differences between three sequential stages of fatigue (pre, 50, 100%) for each dependent variable (alpha = 0.05). RESULTS: Knee flexion angles at initial contact (IC) for pre (-32 +/- 9 degrees ) and 50% (-29 +/- 11 degrees ) were significantly higher than at 100% fatigue (-22 +/- 9 degrees ) (p < 0.001 and p = 0.015, respectively). Knee adduction angles at IC for pre (9 +/- 5 degrees ) and 50% (8 +/- 4 degrees ) were significantly higher (p = 0.006 and p = 0.049, respectively) than at 100% fatigue (6 +/- 4 degrees ). CONCLUSIONS: Fatigue altered sagittal and frontal knee kinematics after 50% fatigue whereupon participants had diminished knee control at initial contact. Interventions should attempt to reduce the negative effects of fatigue on lower extremity biomechanics by promoting appropriate frontal plane alignment and increased knee flexion during fatigue status. LEVEL OF EVIDENCE: III. PMID- 24045916 TI - Dynamic KINE-MRI in patellofemoral instability in adolescents. AB - PURPOSE: The impact of kinematic MRI (KINE-MRI) in the patellofemoral instability and anterior knee pain of the adolescents is rarely reported. Our special interest was to evaluate the patellofemoral joint biomechanics with KINE-MRI in adolescents with affected and unaffected knees in a case-control study. METHODS: KINE-MRI was performed in 29 adolescents (affected knee group, n = 29 and unaffected knee group, n = 26) aged 11-16 years with unilateral patellofemoral instability. For the control group, we enrolled ten healthy age- and sex-matched volunteers (healthy knee group, n = 19). The study parameters, bisect offset, lateral patellar displacement, patellar tilt angle, sulcus angle and Insall Salvati ratio at 0, 10, 20 and 30 degrees of flexion-extension, were measured for the affected knee patients (n = 29), unaffected knee patients (n = 26) and the healthy knee subjects (n = 19). RESULTS: The affected knee and the healthy knee subjects had a significant difference in the bisect offset ratio, lateral patellar displacement test and patellar tilt angle test. In these parameters, the difference between the affected knee patients and the healthy knee subjects progressively increased towards the full extension of the knee. In the affected knee and unaffected knee patients, bisect offset ratio at 0 degrees ranged between 0.50 and 1.20 in both groups, whereas the bisect offset ratio in the healthy knee subjects ranged between 0.33 and 0.75 (p < 0.001). At the 0 degrees , the lateral patellar displacement test ranged between 0 and 10 mm in the affected knee patients and between 0 and 35 mm in the unaffected knee patients, whereas the lateral displacement test ranged between 0 and 5 mm in the healthy knee subjects (p = 0.003). Patellar tilt angle test ranged between -30 and 20 degrees in the affected knee patients and between -30 and 24 degrees in the unaffected knee patients, and in the healthy knee subjects, the patellar tilt angle test ranged between 10 and 24 degrees (p < 0.001). CONCLUSIONS: The KINE MRI was able to detect significant differences in patellofemoral joint kinematics between the patients and the healthy subjects. A new finding with clinical relevance in our work is that the unaffected knee is very similar to the dislocated knee in adolescents and this should be taken in account in rehabilitation of patients. LEVEL OF EVIDENCE: II. PMID- 24045917 TI - Beta-tricalcium phosphate shows superior absorption rate and osteoconductivity compared to hydroxyapatite in open-wedge high tibial osteotomy. AB - PURPOSE: The purpose of this study was to clinically and radiologically compare the utility, osteoconductivity, and absorbability of hydroxyapatite (HAp) and beta-tricalcium phosphate (TCP) spacers in medial open-wedge high tibial osteotomy (HTO). METHODS: Thirty-eight patients underwent medial open-wedge HTO with a locking plate. In the first 19 knees, a HAp spacer was implanted in the opening space (HAp group). In the remaining 19 knees, a TCP spacer was implanted in the same manner (TCP group). All patients underwent clinical and radiological examinations before surgery and at 18 months after surgery. RESULTS: Concerning the background factors, there were no statistical differences between the two groups. Post-operatively, the knee score significantly improved in each group. Concerning the post-operative knee alignment and clinical outcome, there was no statistical difference in each parameter between the two groups. Regarding the osteoconductivity, the modified van Hemert's score of the TCP group was significantly higher (p = 0.0009) than that of the HAp group in the most medial osteotomy zone. The absorption rate was significantly greater in the TCP group than in the HAp group (p = 0.00039). CONCLUSIONS: The present study demonstrated that a TCP spacer was significantly superior to a HAp spacer concerning osteoconductivity and absorbability at 18 months after medial open-wedge HTO. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 24045919 TI - The effect of a six-month training program followed by a marathon run on knee joint cartilage volume and thickness in marathon beginners. AB - PURPOSE: The purpose of this study was to investigate the effect of a 6-month period of intensive running followed by the participation at a marathon run on cartilage volume and thickness in knees of marathon beginners. METHODS: Ten asymptomatic marathon beginners underwent a supervised 6-month training program, which was finalized by the participation at a marathon run. Three-dimensional quantitative magnetic resonance imaging was performed before the training program (baseline measurements) and 1 day after the marathon (follow-up measurements). Cartilage volume and thickness of the medial and lateral femur, medial and lateral tibia, and patella were measured using semiautomated cartilage segmentation and three dimensional data postprocessing. RESULTS: Significant differences between baseline and follow-up measurements were observed at the lateral femur, where cartilage volume and thickness decreased by a mean of 3.2 +/ 3.0% (p = 0.012) and 1.7 +/- 1.6% (p = 0.010), respectively. No significant changes in cartilage volume and thickness were observed at the medial and lateral tibia, the medial femur, and the patella. CONCLUSION: Significant cartilage loss was observed at the lateral femur; however, the measured values are comparable to previously reported precision errors for quantitative cartilage measurement and thus most likely not of clinical relevance. High-impact forces during long distance running are well tolerated even in marathon beginners and do not lead to clinical relevant cartilage loss. LEVEL OF EVIDENCE: IV. PMID- 24045918 TI - Treatment of osteochondral defects of the talus in children. AB - PURPOSE: Osteochondral talar defects are infrequent in children, and little is known about the treatment and clinical outcome of these defects. The purpose of this study was to evaluate the clinical and radiographic outcomes of conservative and primary surgically treated osteochondral talar defects in skeletally immature children. METHODS: Thirty-six (97%) of 37 eligible patients with a symptomatic primary osteochondral talar defect were evaluated after a median follow-up of 4 years (range 1-12 years). Clinical assessment included the Berndt and Harty outcome question, Ogilvie-Harris score, Visual Analog Scale pain score (at rest, during walking and during running), the American Orthopaedic Foot and Ankle Society (AOFAS) score, and the SF-36. Weight-bearing radiographs were compared with preoperative radiographs with the use of an ankle osteoarthritis classification system. RESULTS: Ninety-two per cent of the initially conservatively treated children [mean age 13 years (SD 2)] were eventually scheduled to undergo surgery. After fixation of the fragment, seven cases (78%) reported a good Berndt and Harty outcome, and two cases (22%) a fair outcome; the median AOFAS score was 95.0 (range 77-100). After debridement and bone marrow stimulation, 13 cases (62%) reported a good Berndt and Harty outcome, three cases (14%) a fair outcome, and five cases (24%) a poor outcome; the median AOFAS score was 95.0 (range 45-100). No signs of degenerative changes were seen in both groups at follow-up. CONCLUSIONS: Fixation and debridement and bone marrow stimulation of an osteochondral talar defect are both good surgical options after failed conservative treatment. LEVEL OF EVIDENCE: Retrospective case series, Therapeutic, Level IV. PMID- 24045921 TI - Projecting the yearly mortality reductions due to a cancer screening programme. AB - The decision on whether to implement a 20-year screening programme for a cancer requires weighing the harms and costs against the health benefits (such as the number of cancer deaths averted every year). The evidence of the benefits is often based on a single-number summary, such as the mortality reduction over the entire follow-up time in a single trial, or an average of such one-number measures from a meta-analysis of several trials. There are several problems associated with using the traditional one-number summaries from trials to deduce the yearly mortality reductions expected from a sustained screening programme. We here propose using a rate ratio curve, and its complement (a mortality reduction curve), to address the mortality impact (timing, magnitude, and duration) of a screening programme. This curve is easy to interpret, as it shows when mortality reductions begin, how big they are, and how long they last. We illustrate when and how such rate ratio curves from screening trials could be computed, and how they could be used to compare reduction patterns expected with different screening regimens. We encourage trialists to report the necessary data to arrive at such projections. PMID- 24045920 TI - Patient attitudes towards faecal immunochemical testing for haemoglobin as an alternative to colonoscopic surveillance of groups at increased risk of colorectal cancer. AB - OBJECTIVES: To examine attitudes towards an annual faecal immunochemical test for haemoglobin (FIT) versus three-yearly colonoscopic surveillance of individuals at intermediate risk of colorectal cancer (CRC). SETTING: A London hospital. METHODS: Five semi-structured discussion groups were conducted with 28 adults (aged 60-74, 61% female) with different levels of CRC risk and experience of colonoscopy or colonoscopic surveillance. Information was presented sequentially using a step-by-step discussion guide. Results were analyzed using thematic analysis. RESULTS: When evaluating FIT in the context of a surveillance programme, all respondents readily made comparisons with related tests that they had been exposed to previously. Those with no experience of surveillance were enthusiastic about an annual FIT to replace three-yearly colonoscopy, because they felt that the higher testing frequency could improve detection of advanced lesions. Those with experience of colonoscopic surveillance did not perceive FIT to be as accurate as colonoscopy, and therefore either preferred colonoscopy on its own or wanted an annual FIT in addition to three-yearly colonoscopy. CONCLUSIONS: FIT may be well-received as an additional method of surveillance for new patients at intermediate risk of CRC. More research is required to better understand potential barriers associated with FIT surveillance for patients with experience of colonoscopic surveillance. PMID- 24045922 TI - Prediagnostic serum tocopherol levels and the risk of non-hodgkin lymphoma: the multiethnic cohort. AB - BACKGROUND: Compromised immunity and chronic inflammation are thought to contribute to the development of non-Hodgkin lymphoma (NHL). Because tocopherols protect cells through antioxidant mechanisms, they may play a role in NHL etiology. METHODS: This nested case-control study within the Multiethnic Cohort examined the association of prediagnostic serum tocopherols levels measured in 271 NHL cases and 538 matched controls by high-pressure liquid chromatography/photodiode array detection with NHL risk. Conditional logistic regression was used to calculate ORs and 95% confidence intervals (CI). RESULTS: We observed U-shaped associations with NHL for total and alpha-tocopherols [Ptrend < 0.01 for polynomial terms (3 df)]. The ORs (95% CI) for total tocopherols, which consisted primarily of alpha-tocopherol, were 0.41 (0.25 0.68), 0.52 (0.32-0.85), 0.39 (0.23-0.65), and 0.78 (0.47-1.29) for the second to fifth quintiles as compared with the first. The risk estimates were similar for alpha-tocopherol but nonsignificant for beta- and gamma-tocopherol combined and for gamma-tocopherol. Adjustment for serum lipids strengthened the nonlinear associations for total and alpha-tocopherols. Serum total tocopherol levels were higher for vitamin E supplement users at cohort entry than nonusers (21.32 +/- 9.04 vs. 17.72 +/- 7.43 MUg/mL; P < 0.0001), but supplement use was not associated with NHL risk. No heterogeneity in risk estimates was detected by sex, ethnicity, vitamin E supplement use, or NHL subtype. CONCLUSIONS: Circulating tocopherols, at levels likely reflecting adequate dietary intakes, may be protective against NHL, whereas higher intakes from supplementation may not be beneficial. IMPACT: The association between serum tocopherol levels and NHL risk provides possible new insights into the etiology of NHL. PMID- 24045923 TI - Serum biomarkers of immune activation and subsequent risk of non-hodgkin B-cell lymphoma among HIV-infected women. AB - BACKGROUND: There is increasing evidence that chronic immune activation predisposes to non-Hodgkin lymphoma (NHL). Whether this association exists among women representative of the current HIV epidemic in the United States who are at high risk of HIV-associated NHL (AIDS-NHL), remains to be determined. METHODS: We conducted a nested case-control study within the Women's Interagency HIV Study with longitudinally collected risk factor data and sera. Cases were HIV-infected women with stored sera collected at three time-windows 3 to 5 years, 1 to 3 years, and 0 to 1 year before AIDS-NHL diagnosis (n = 22). Three to six HIV infected controls, without AIDS-NHL, were matched to each case on age, race, CD4(+) T-cell count, and study follow-up time (n = 78). ORs and 95% confidence intervals (CI) for the association between one unit increase in log-transformed biomarker levels and AIDS-NHL were computed using random effect multivariate logistic regression models. RESULTS: Elevated levels of sCD27 (OR = 7.21; 95% CI, 2.62-19.88), sCD30 (OR = 2.64; 95% CI, 1.24-5.64), and CXCL13 (OR = 2.56; 95% CI, 1.32-4.96) were associated with subsequent diagnosis of AIDS-NHL overall. Elevated sCD23 was associated with a two to three-fold increased risk of AIDS-NHL in certain subgroups, whereas elevated interleukin 6 was associated with a two fold increased risk in the 0 to 1 year time-window, only. CONCLUSIONS: These findings support the hypothesis that chronic B-cell activation contributes to the development of AIDS-NHL in women. IMPACT: Soluble CD23 (sCD23), sCD27, sCD30, and CXCL13 may serve as biomarkers for AIDS-NHL. PMID- 24045924 TI - Genetic variation in the inflammation and innate immunity pathways and colorectal cancer risk. AB - BACKGROUND: It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways. METHODS: In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for more than 600 tagSNPs and 99 single-nucleotide polymorphisms (SNP) were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls). RESULTS: The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (OR per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the "effective" number of markers in stage II (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency < 0.03) in whites, Japanese Americans, Latinos, and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, body mass index (BMI) levels, regular aspirin use, or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822. CONCLUSIONS: Our results provide new evidence of association between PPARG variants and colorectal cancer risk. IMPACT: Further replication in independent samples is warranted. PMID- 24045925 TI - Helicobacter pylori protein-specific antibodies and risk of colorectal cancer. AB - BACKGROUND: There is biologic plausibility as to why infection with Helicobacter pylori, the leading cause of gastric cancer, may also increase the risk of colorectal cancer, but the epidemiologic findings have been inconsistent. We assessed the association of H. pylori protein-specific infection and colorectal cancer risk in the prospective cohort, the Southern Community Cohort Study. METHODS: Multiplex serology was used to measure antibodies to 15 H. pylori proteins in prediagnostic blood among 188 incident colorectal cancer cases and 370 controls matched by age, race, sex, and blood collection timing. Conditional logistic regression was used to calculate ORs and 95% confidence intervals (CI). RESULTS: Overall H. pylori prevalence was not associated with colorectal cancer risk (OR, 1.03; 95% CI, 0.59-1.77). However, seropositivity to any of five specific H. pylori proteins (VacA, HP231, HP305, NapA, and HcpC) was associated with a significant 60% to 80% increase in odds of risk. These associations became even stronger when limited to colon cancer risk, particularly for the known H. pylori toxin VacA (OR, 2.24; 95% CI, 1.22-4.11), including a significant, positive dose-response association by VacA antibody levels in quartiles (P < 0.05). Associations with VacA seropositivity were especially strong for early onset and late-stage cancers. CONCLUSIONS: The findings raise the hypothesis that individuals with high levels of antibodies to specific H. pylori proteins may be at higher risk of colon cancer. IMPACT: Further investigation of the H. pylori colorectal cancer association is warranted to determine the possibility of protein-specific antibody levels as a risk biomarker. PMID- 24045926 TI - Collaborative cancer epidemiology in the 21st century: the model of cancer consortia. AB - During the last two decades, epidemiology has undergone a rapid evolution toward collaborative research. The proliferation of multi-institutional, interdisciplinary consortia has acquired particular prominence in cancer research. Herein, we describe the characteristics of a network of 49 established cancer epidemiology consortia (CEC) currently supported by the Epidemiology and Genomics Research Program (EGRP) at the National Cancer Institute (NCI). This collection represents the largest disease-based research network for collaborative cancer research established in population sciences. We describe the funding trends, geographic distribution, and areas of research focus. The CEC have been partially supported by 201 grants and yielded 3,876 publications between 1995 and 2011. We describe this output in terms of interdisciplinary collaboration and translational evolution. We discuss challenges and future opportunities in the establishment and conduct of large-scale team science within the framework of CEC, review future prospects for this approach to large-scale, interdisciplinary cancer research, and describe a model for the evolution of an integrated Network of Cancer Consortia optimally suited to address and support 21st-century epidemiology. PMID- 24045927 TI - Impact of cardiovascular comorbidity on ovarian cancer mortality. AB - BACKGROUND: A retrospective cohort study utilizing prospectively collected data was conducted from August 2003 until March 2008 at M.D. Anderson Cancer Center. It is unknown whether cardiovascular comorbidity and chronic stress impact ovarian cancer outcome, which remains poor despite advances in therapy. The purpose of this study was to determine whether cardiovascular disease and markers that may be associated with stress are also associated with survival in patients with ovarian cancer. METHODS: Participants with newly diagnosed epithelial ovarian cancer were followed until time of death or truncation of study period (median follow-up = 4.2 years; n = 271). Tumor characteristics (stage, tumor grade, histology, debulking status), demographic variables, and cardiovascular comorbidity were documented and compared to overall survival. RESULTS: Of the nine cardiovascular events tracked during follow-up, venous thromboembolism [VTE; HR, 3.2; 95% confidence interval (CI), 1.8-5.5] and pulmonary hypertension (HR, 8.5; 95% CI, 3.9-18.7) were associated with shorter survival in multivariate analysis. In addition, high tumor grade, suboptimal cytoreduction, and baseline heart rate (HR, 1.02; 95% CI, 1.01-1.04) were related to decreased survival. CONCLUSION: Careful management of certain cardiovascular comorbidities may extend survival in patients with ovarian cancer. Our findings suggest that increased baseline heart rate and the development of VTE and pulmonary hypertension after cancer diagnosis may be significant predictors of survival in women with ovarian cancer. IMPACT: Our study emphasizes the importance of identifying and optimally treating tachycardia, VTE, and pulmonary hypertension in conjunction with cancer therapy. PMID- 24045929 TI - Iron status and lipopolysaccharide regulate Ndfip1 by activation of nuclear factor-kappa B. AB - Nedd4 family interacting protein 1 (Ndfip1) is an adaptor protein for the Nedd4 family of ubiquitin ligases that target proteins for degradation. Recent studies confirmed the role of Ndfip1 as a regulator of iron metabolism and pointed out that Ndfip1 was involved in iron homeostasis by regulating the degradation of iron importer divalent metal transporter 1 (DMT1). However, little is known about how Ndfip1 is regulated. The aim of this article was to investigate the regulation of Ndfip1 levels and the possible mechanisms. In this study, we investigated the effect of various stimuli, including iron status and lipopolysaccharide (LPS) on Ndfip1 expression in MES23.5 dopaminergic cell lines. Results showed that Ndfip1 expression in these cells was enhanced by ferrous iron overload, but not ferric iron overload, and decreased after iron deprivation by deferoxamine. In addition, LPS could significantly increase the expression of Ndfip1. Furthermore, we demonstrated that the regulation of Ndfip1 expression by these various stimuli was achieving by activation of nuclear factor-kappa B. We speculate that iron status and LPS may contribute to the changes of Ndfip1 expression by activation of nuclear factor-kappa B. PMID- 24045930 TI - Introduction to special issue on cardiac metabolism in hypertrophy and failure. PMID- 24045928 TI - Plasma levels of adiponectin and primary liver cancer risk in middle-aged Japanese adults with hepatitis virus infection: a nested case-control study. AB - BACKGROUND: Excess body weight is an independent risk factor for primary liver cancer, and the role of adiponectin in the pathogenesis of obesity-related malignancies is a focus of research interest. Few prospective studies have examined the association between circulating adiponectin and liver cancer risk, so we investigated this association in a nested case-control study of a population-based prospective cohort in Japan. METHODS: From 18,628 target participants of ages 40 to 69 years who returned the baseline questionnaire and provided blood samples, we selected those with either hepatitis B or C virus infection at baseline (n = 1,544). Among these, 90 were newly diagnosed with primary liver cancer from 1993 through 2006, and matched to 177 controls. The ORs of liver cancer development based on plasma levels of adiponectin were estimated with a conditional logistic regression model. RESULTS: Median values of total and high-molecular-weight (HMW) adiponectin tended to be higher in the patients with liver cancer, and plasma levels of adiponectin were positively associated with liver cancer risk. Body mass index- and diabetes-adjusted ORs for the highest tertile of total and HMW adiponectin levels versus the lowest were 3.30 [95% confidence interval (CI), 1.45-7.53; Ptrend < 0.01] and 3.41 (95% CI, 1.50-7.73; Ptrend < 0.01), respectively. There was no effect modification by body mass index and diabetes. CONCLUSIONS: Higher plasma adiponectin levels were associated with an increased risk of primary liver cancer in middle-aged Japanese adults with hepatitis virus infection. IMPACT: Circulating adiponectin levels may be a risk marker for primary liver cancer. PMID- 24045931 TI - Unfavorable cancers of unknown primaries: presentation and prognostic factors. A population-based 8-year experience. AB - Cancer of unknown primary is a mostly disseminated malignancy where detailed investigations cannot reveal a probable origin. A few subsets may respond to specific therapy, but the large majority of cases have a median survival of 3-4 months in the few population-based reports, which, however, did not use current investigations and therapy. It is not known if survival can be prolonged by chemotherapy or if supportive care is preferable, especially in the most unfavorable cases in whom chemotherapy may impair the quality of life without prolonging it. We therefore studied prognosis of 134 recent population-based consecutive unfavorable patients. Multiple involvements of the liver, nodes, lungs and skeleton, polysymptomatology, and biochemical abnormalities were common. The median survival time was 103 days, and the 1-year survival was 19%. Hypoalbuminemia, weight loss, and anemia in this order were the strongest negative prognostic factors in multivariate analysis, but univariate analysis added involvement of multiple sites or of the liver, high age, male gender, adenocarcinoma histology, and tobacco use as unfavorable factors. About 10% of patients became long-term survivors, sometimes in the presence of one or more of negative prognostic factors but in particular those with limited nodal spread. A previously unreported finding was that nodal involvement of squamous cell carcinoma limited to the iliacoinguinal region could seemingly be cured by surgery +/- radiotherapy. In the absence of efficient treatment and controlled therapeutic trials, supportive care alone seems justified for patients with the worst prognostic factors. PMID- 24045932 TI - Sorghum bmr6 mutant analysis demonstrates that a shared MYB1 transcription factor binding site in the promoter links the expression of genes in related pathways. AB - Sorghum is not only an important cereal crop but also a biofuel crop. The sorghum brown midrib mutant 6 (bmr6) has a reduced lignin content in the cell walls and vascular tissues, which could potentially be advantageous for cellulosic biofuel production. Meanwhile, both dry matter yield and plant height were decreased in the bmr6 mutant. To identify genes affected in the mutant, differential gene expression analysis was performed for bmr6 and the wild type. As a result, a total of 1,052 differentially expressed genes were detected between the two samples, of which 166 genes were downregulated and 886 genes were upregulated. Five hundred seventy-nine of the 1,052 differentially expressed genes could be assigned to 154 documented pathways. These pathways mainly included primary and secondary metabolism. Therefore, mutation of the bmr6 gene, which impaired the biosynthesis of lignin, ultimately affected the expression of these genes associated with the growth and development of sorghum. Except for the bmr6 gene, 11 key enzyme genes of monolignols biosynthesis were upregulated. Promoter analysis identified that these genes have common MYB sites. It revealed that a feedback mechanism existed in the pathway and a MYB1 transcription factor (Sb02g031190) could associate with the upregulation of these genes in sorghum. In this study, we investigated gene expressions at a global level in sorghum bmr6 mutant and provided valuable insights into the mechanisms of lignin biosynthesis. PMID- 24045933 TI - Skin ulcer: a long-term complication after massive liquid silicone oil infiltration. AB - BACKGROUND: Despite scientific literature replete with stories of disastrous results and disfigurement, illicit subcutaneous injections of highly viscous fluids in massive quantities still are performed, often by unqualified persons. The authors present a devastating long-term outcome from a massive volume of silicone oil injected subcutaneously into the buttocks of a 48-year-old transsexual patient and its ulceration treated only through regular medications. METHODS: The therapeutic protocol consisted of wound disinfection with iodopovidone, washing with saline solution, disinfection with sodium hypochlorite 0.05 %, and application of ointment containing Vibrio alginolyticus collagenase and hyaluronan. The follow-up evaluation was at 1 and 2 weeks and then at 1, 2, and 3 months. Weekly photographs were taken, and measurements of the lesion and evolution were estimated every 7 days. RESULTS: After 3 months of regular medications, the authors succeeded in closing the ulcer, avoiding invasive therapeutic options. CONCLUSION: In the presence of the cutaneous ulceration above a massively infiltrated area, if the removal of all the injected oil is surgically definitely impossible, other conservative procedures should be considered. Our experience demonstrated how it is possible to manage a so prickly a case with a noninvasive approach such as periodic medications. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24045934 TI - Use of mycological, nested PCR, and real-time PCR methods on BAL fluids for detection of Aspergillus fumigatus and A. flavus in solid organ transplant recipients. AB - Invasive aspergillosis continues to be a significant cause of morbidity and mortality in solid organ transplant (SOT) recipients. A reliable and early diagnostic method is needed to improve survival. In this study, four methods direct microscopy, culture, nested PCR on internal transcribed spacer region, and TaqMan real-time PCR targeted beta-tubulin gene were examined for the detection of Aspergillus fumigatus and A. flavus in sixty-four bronchoalveolar lavage (BAL) fluids that were obtained from SOT recipients. Direct examination with 20 % KOH (potassium hydroxide) and culture on mycological media were also performed. Of the 64 samples, seven (10.9 %) were positive in direct examination (five with septate hyphae and two with aseptate hyphae), and 15 (23 %) had positive culture including five A. flavus, four A. niger, two Penicillium spp., two Rhizopus spp., one Fusarium spp. and one mixed A. flavus/A. niger. Twenty five (39 %) samples had positive nested PCR with A. flavus and 6 (9.4 %) with A. fumigatus-specific primers. Only eight (12.5 %) had positive real-time PCR for A. flavus and nine (14 %) for A. fumigatus. The incidence of aspergillosis in these patients included proven invasive pulmonary aspergillosis (IPA) in two (3 %), probable IPA in 14 (22 %), possible IPA in 38 (59 %), and not IPA in 10 (16 %). A. flavus was the most common cause of pulmonary aspergillosis (PA) in the study. The results suggest that because nested PCR is too sensitive it may increase the number of false-positive results and is not recommended for BAL samples for diagnosis of PA. Although further studies with significant number of proved positive/negative standard BAL samples are necessary for better evaluation, the novel multiplex real-time PCR developed in the study could be promising as a valid diagnostic method for IPA. PMID- 24045935 TI - Environmental isolates of fungi from aquarium pools housing killer whales (Orcinus orca). AB - Systemic mycoses in killer whales (Orcinus orca) are rare diseases, but have been reported. Two killer whales died by fungal infections at the Port of Nagoya Public Aquarium in Japan. In this study, the fungal flora of the pool environment at the aquarium was characterized. Alternaria spp., Aspergillus spp. (A. fumigatus, A. niger, A. versicolor), Fusarium spp. and Penicillium spp. were isolated from the air and the pool surroundings. The other isolates were identified as fungal species non-pathogenic for mammals. However, the species of fungi isolated from the environmental samples in this study were not the same as those isolated from the cases of disease in killer whales previously reported. PMID- 24045936 TI - Are patients' personal goals achieved after pelvic reconstructive surgery? AB - INTRODUCTION AND HYPOTHESIS: Our goal was to describe patients' personal treatment goals before pelvic floor dysfunction (PFD) surgery and goals achieved and not achieved 12 months after surgery, and to evaluate the association between postoperative symptoms and successful goal achievement. MATERIALS AND METHODS: We performed a secondary analysis using a de-identified database from a randomized trial comparing native tissue vs. graft-augmented rectocele repair. In their own words, women listed their top four treatment goals and 12 months after surgery whether those goals were or were not achieved. We categorized goals into symptom improvement (defecatory, bulge, incontinence, pain/discomfort) and functioning (physical, social, emotional, sexual). Women completed symptom questionnaires pre and postoperatively. Goals were described using simple statistics. The association between defecatory, bulge, and incontinence symptoms and goal achievement was described using the chi-square test. RESULTS: Of 160 participants in the database, 125 (78 %) met inclusion criteria. The most common preoperative goals were improvement in bulge (26.7 %), defecation (23.9 %), urinary incontinence (18.1 %), and pain/discomfort (6.2 %). Functioning goal categories included: sexual (7 %), emotional (7 %), physical (6.2 %), and social function (3.3 %). Postoperatively, goal categories in which improvement was achieved were urinary continence (70.5 %), sexual function (58.8 %), bulge reduction (56.9 %), defecation (51.7 %), physical (33.3 %), emotional (29.4 %), and social functioning (25 %). Of the women reporting postoperative defecatory or incontinence symptoms, half reported successful improvement in both goals. CONCLUSIONS: Women predominantly reported symptom-related goals, and those goals are most frequently achieved postoperatively. Of women who reported defecatory and incontinence symptoms postoperatively, many still reported successful goal achievement in those areas. PMID- 24045937 TI - Potential regulatory interactions of Escherichia coli RraA protein with DEAD-box helicases. AB - Members of the DEAD-box family of RNA helicases contribute to virtually every aspect of RNA metabolism, in organisms from all domains of life. Many of these helicases are constituents of multicomponent assemblies, and their interactions with partner proteins within the complexes underpin their activities and biological function. In Escherichia coli the DEAD-box helicase RhlB is a component of the multienzyme RNA degradosome assembly, and its interaction with the core ribonuclease RNase E boosts the ATP-dependent activity of the helicase. Earlier studies have identified the regulator of ribonuclease activity A (RraA) as a potential interaction partner of both RNase E and RhlB. We present structural and biochemical evidence showing how RraA can bind to, and modulate the activity of RhlB and another E. coli DEAD-box enzyme, SrmB. Crystallographic structures are presented of RraA in complex with a portion of the natively unstructured C-terminal tail of RhlB at 2.8-A resolution, and in complex with the C-terminal RecA-like domain of SrmB at 2.9 A. The models suggest two distinct mechanisms by which RraA might modulate the activity of these and potentially other helicases. PMID- 24045938 TI - Dhrs3 protein attenuates retinoic acid signaling and is required for early embryonic patterning. AB - All-trans-retinoic acid (atRA) is an important morphogen involved in many developmental processes, including neural differentiation, body axis formation, and organogenesis. During early embryonic development, atRA is synthesized from all-trans-retinal (atRAL) in an irreversible reaction mainly catalyzed by retinal dehydrogenase 2 (aldh1a2), whereas atRAL is converted from all-trans-retinol via reversible oxidation by retinol dehydrogenases, members of the short-chain dehydrogenase/reductase family. atRA is degraded by cytochrome P450, family 26 (cyp26). We have previously identified a short-chain dehydrogenase/reductase 3 (dhrs3), which showed differential expression patterns in Xenopus embryos. We show here that the expression of dhrs3 was induced by atRA treatment and overexpression of Xenopus nodal related 1 (xnr1) in animal cap assay. Overexpression of dhrs3 enhanced the phenotype of excessive cyp26a1. In embryos overexpressing aldh1a2 or retinol dehydrogenase 10 (rdh10) in the presence of their respective substrates, Dhrs3 counteracted the action of Aldh1a2 or Rdh10, indicating that retinoic acid signaling is attenuated. Knockdown of Dhrs3 by antisense morpholino oligonucleotides resulted in a phenotype of shortened anteroposterior axis, reduced head structure, and perturbed somitogenesis, which were also found in embryos treated with an excess of atRA. Examination of the expression of brachyury, not, goosecoid, and papc indicated that convergent extension movement was defective in Dhrs3 morphants. Taken together, these studies suggest that dhrs3 participates in atRA metabolism by reducing atRAL levels and is required for proper anteroposterior axis formation, neuroectoderm patterning, and somitogenesis. PMID- 24045939 TI - In vivo substrate diversity and preference of small heat shock protein IbpB as revealed by using a genetically incorporated photo-cross-linker. AB - Small heat shock proteins (sHSPs), as ubiquitous molecular chaperones found in all forms of life, are known to be able to protect cells against stresses and suppress the aggregation of a variety of model substrate proteins under in vitro conditions. Nevertheless, it is poorly understood what natural substrate proteins are protected by sHSPs in living cells. Here, by using a genetically incorporated photo-cross-linker (p-benzoyl-l-phenylalanine), we identified a total of 95 and 54 natural substrate proteins of IbpB (an sHSP from Escherichia coli) in living cells with and without heat shock, respectively. Functional profiling of these proteins (110 in total) suggests that IbpB, although binding to a wide range of cellular proteins, has a remarkable substrate preference for translation-related proteins (e.g. ribosomal proteins and amino-acyl tRNA synthetases) and moderate preference for metabolic enzymes. Furthermore, these two classes of proteins were found to be more prone to aggregation and/or inactivation in cells lacking IbpB under stress conditions (e.g. heat shock). Together, our in vivo data offer novel insights into the chaperone function of IbpB, or sHSPs in general, and suggest that the preferential protection on the protein synthesis machine and metabolic enzymes may dominantly contribute to the well known protective effect of sHSPs on cell survival against stresses. PMID- 24045940 TI - Binding of the sialic acid-binding lectin, Siglec-9, to the membrane mucin, MUC1, induces recruitment of beta-catenin and subsequent cell growth. AB - Because MUC1 carries a variety of sialoglycans that are possibly recognized by the siglec family, we examined MUC1-binding siglecs and found that Siglec-9 prominently bound to MUC1. An immunochemical study showed that Siglec-9-positive immune cells were associated with MUC1-positive cells in human colon, pancreas, and breast tumor tissues. We investigated whether or not this interaction has any functional implications for MUC1-expressing cells. When mouse 3T3 fibroblast cells and a human colon cancer cell line, HCT116, stably transfected with MUC1cDNA were ligated with recombinant soluble Siglec-9, beta-catenin was recruited to the MUC1 C-terminal domain, which was enhanced on stimulation with soluble Siglec-9 in dose- and time-dependent manners. A co-culture model of MUC1 expressing cells and Siglec-9-expressing cells mimicking the interaction between MUC1-expressing malignant cells, and Siglec-9-expressing immune cells in a tumor microenvironment was designed. Brief co-incubation of Siglec-9-expressing HEK293 cells, but not mock HEK293 cells, with MUC1-expressing cells similarly enhanced the recruitment of beta-catenin to the MUC1 C-terminal domain. In addition, treatment of MUC1-expressing cells with neuraminidase almost completely abolished the effect of Siglec-9 on MUC1-mediated signaling. The recruited beta-catenin was thereafter transported to the nucleus, leading to cell growth. These findings suggest that Siglec-9 expressed on immune cells may play a role as a potential counterreceptor for MUC1 and that this signaling may be another MUC1-mediated pathway and function in parallel with a growth factor-dependent pathway. PMID- 24045941 TI - The adaptor molecule signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is essential in mechanisms involving the Fyn tyrosine kinase for induction and progression of collagen-induced arthritis. AB - Signaling lymphocytic activation molecule-associated protein (SAP) is an Src homology 2 domain-only adaptor involved in multiple immune cell functions. It has also been linked to immunodeficiencies and autoimmune diseases, such as systemic lupus erythematosus. Here, we examined the role and mechanism of action of SAP in autoimmunity using a mouse model of autoimmune arthritis, collagen-induced arthritis (CIA). We found that SAP was essential for development of CIA in response to collagen immunization. It was also required for production of collagen-specific antibodies, which play a key role in disease pathogenesis. These effects required SAP expression in T cells, not in B cells. In mice immunized with a high dose of collagen, the activity of SAP was nearly independent of its ability to bind the protein tyrosine kinase Fyn and correlated with the capacity of SAP to promote full differentiation of follicular T helper (TFH) cells. However, with a lower dose of collagen, the role of SAP was more dependent on Fyn binding, suggesting that additional mechanisms other than TFH cell differentiation were involved. Further studies suggested that this might be due to a role of the SAP-Fyn interaction in natural killer T cell development through the ability of SAP-Fyn to promote Vav-1 activation. We also found that removal of SAP expression during progression of CIA attenuated disease severity. However, it had no effect on disease when CIA was clinically established. Together, these results indicate that SAP plays an essential role in CIA because of Fyn-independent and Fyn-dependent effects on TFH cells and, possibly, other T cell types. PMID- 24045942 TI - Role of Janus kinase 3 in mucosal differentiation and predisposition to colitis. AB - Janus kinase 3 (Jak3) is a nonreceptor tyrosine kinase expressed in both hematopoietic and nonhematopoietic cells. Previously, we characterized the functions of Jak3 in cytoskeletal remodeling, epithelial wound healing, and mucosal homeostasis. However, the role of Jak3 in mucosal differentiation and inflammatory bowel disease was not known. In this report, we characterize the role of Jak3 in mucosal differentiation, basal colonic inflammation, and predisposition toward colitis. Using the Jak3 knock-out (KO) mouse model, we show that Jak3 is expressed in colonic mucosa of mice, and the loss of mucosal expression of Jak3 resulted in reduced expression of differentiation markers for the cells of both enterocytic and secretory lineages. Jak3 KO mice showed reduced expression of colonic villin, carbonic anhydrase, secretory mucin muc2, and increased basal colonic inflammation reflected by increased levels of pro inflammatory cytokines IL-6 and IL-17A in colon along with increased colonic myeloperoxidase activity. The inflammations in KO mice were associated with shortening of colon length, reduced cecum length, decreased crypt heights, and increased severity toward dextran sulfate sodium-induced colitis. In differentiated human colonic epithelial cells, Jak3 redistributed to basolateral surfaces and interacted with adherens junction (AJ) protein beta-catenin. Jak3 expression in these cells was essential for AJ localization of beta-catenin and maintenance of epithelial barrier functions. Collectively, these results demonstrate the essential role of Jak3 in the colon where it facilitated mucosal differentiation by promoting the expression of differentiation markers and enhanced colonic barrier functions through AJ localization of beta-catenin. PMID- 24045943 TI - Transmembrane domain II of the human bile acid transporter SLC10A2 coordinates sodium translocation. AB - Human apical sodium-dependent bile acid transporter (hASBT, SLC10A2) is responsible for intestinal reabsorption of bile acids and plays a key role in cholesterol homeostasis. We used a targeted and systematic approach to delineate the role of highly conserved transmembrane helix 2 on the expression and function of hASBT. Cysteine mutation significantly depressed transport activity for >60% of mutants without affecting cell surface localization of the transporter. All mutants were inaccessible toward chemical modification by membrane-impermeant MTSET reagent, strongly suggesting that transmembrane 2 (TM2) plays an indirect role in bile acid substrate translocation. Both bile acid uptake and sodium dependence of TM2 mutants revealed a distinct alpha-helical periodicity. Kinetic studies with conservative and non-conservative mutants of sodium sensitive residues further underscored the importance of Gln(75), Phe(76), Met(79), Gly(83), Leu(86), Phe(90), and Asp(91) in hASBT function. Computational analysis indicated that Asp(91) may coordinate with sodium during the transport cycle. Combined, our data propose that a consortium of sodium-sensitive residues along with previously reported residues (Thr(134), Leu(138), and Thr(149)) from TM3 may form the sodium binding and translocation pathway. Notably, residues Gln(75), Met(79), Thr(82), and Leu(86) from TM2 are highly conserved in TM3 of a putative remote bacterial homologue (ASBTNM), suggesting a universal mechanism for the SLC10A transporter family. PMID- 24045944 TI - Agonist-dependent signaling by group I metabotropic glutamate receptors is regulated by association with lipid domains. AB - Group I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, play critical functions in forms of activity-dependent synaptic plasticity and synapse remodeling in physiological and pathological states. Importantly, in animal models of fragile X syndrome, group I mGluR activity is abnormally enhanced, a dysfunction that may partly underlie cognitive deficits in the condition. Lipid rafts are cholesterol- and sphingolipid-enriched membrane domains that are thought to form transient signaling platforms for ligand-activated receptors. Many G protein-coupled receptors, including group I mGluRs, are present in lipid rafts, but the mechanisms underlying recruitment to these membrane domains remain incompletely understood. Here, we show that mGluR1 recruitment to lipid rafts is enhanced by agonist binding and is supported at least in part by an intact cholesterol recognition/interaction amino acid consensus (CRAC) motif in the receptor. Substitutions of critical residues in the motif reduce mGluR1 association with lipid rafts and agonist-induced, mGluR1-dependent activation of extracellular-signal-activated kinase1/2 MAP kinase (ERK-MAPK). We find that alteration of membrane cholesterol content or perturbation of lipid rafts regulates agonist-dependent activation of ERK-MAPK by group I mGluRs, suggesting a potential function for cholesterol as a positive allosteric modulator of receptor function(s). Together, these findings suggest that drugs that alter membrane cholesterol levels or directed to the receptor-cholesterol interface could be employed to modulate abnormal group I mGluR activity in neuropsychiatric conditions, including fragile X syndrome. PMID- 24045945 TI - Auto-inhibition of Drs2p, a yeast phospholipid flippase, by its carboxyl-terminal tail. AB - Drs2p, a yeast type IV P-type ATPase (P4-ATPase), or flippase, couples ATP hydrolysis to phosphatidylserine translocation and the establishment of membrane asymmetry. A previous study has shown that affinity-purified Drs2p, possessing an N-terminal tandem affinity purification tag (TAPN-Drs2), retains ATPase and translocase activity, but Drs2p purified using a C-terminal tag (Drs2-TAPC) was inactive. In this study, we show that the ATPase activity of N-terminally purified Drs2p associates primarily with a proteolyzed form of Drs2p lacking the C-terminal cytosolic tail. Truncation of most of the Drs2p C-terminal tail sequence activates its ATPase activity by ~4-fold. These observations are consistent with the hypothesis that the C-terminal tail of Drs2p is auto inhibitory to Drs2p activity. Phosphatidylinositol 4-phosphate (PI(4)P) has been shown to positively regulate Drs2p activity in isolated Golgi membranes through interaction with the C-terminal tail. In proteoliposomes reconstituted with purified, N-terminally TAP-tagged Drs2p, both ATPase and flippase activity were significantly higher in the presence of PI(4)P. In contrast, PI(4)P had no significant effect on the activity of a truncated form of Drs2p, which lacked the C-terminal tail. This work provides the first direct evidence, in a purified system, that a phospholipid flippase is subject to auto-inhibition by its C terminal tail, which can be relieved by a phosphoinositide to stimulate flippase activity. PMID- 24045946 TI - Histone deacetylase 3 unconventional splicing mediates endothelial-to-mesenchymal transition through transforming growth factor beta2. AB - Histone deacetylase 3 (HDAC3) plays a critical role in the maintenance of endothelial integrity and other physiological processes. In this study, we demonstrated that HDAC3 undergoes unconventional splicing during stem cell differentiation. Four different splicing variants have been identified, designated as HD3alpha, -beta, -gamma, and -delta, respectively. HD3alpha was confirmed in stem cell differentiation by specific antibody against the sequences from intron 12. Immunofluorescence staining indicated that the HD3alpha isoform co-localized with CD31-positive or alpha-smooth muscle actin-positive cells at different developmental stages of mouse embryos. Overexpression of HD3alpha reprogrammed human aortic endothelial cells into mesenchymal cells featuring an endothelial-to-mesenchymal transition (EndMT) phenotype. HD3alpha directly interacts with HDAC3 and Akt1 and selectively activates transforming growth factor beta2 (TGFbeta2) secretion and cleavage. TGFbeta2 functioned as an autocrine and/or paracrine EndMT factor. The HD3alpha-induced EndMT was both PI3K/Akt- and TGFbeta2-dependent. This study provides the first evidence of the role of HDAC3 splicing in the maintenance of endothelial integrity. PMID- 24045947 TI - Identification of a bifunctional maize C- and O-glucosyltransferase. AB - Flavonoids accumulate in plant vacuoles usually as O-glycosylated derivatives, but several species can also synthesize flavonoid C-glycosides. Recently, we demonstrated that a flavanone 2-hydroxylase (ZmF2H1, CYP93G5) converts flavanones to the corresponding 2-hydroxy derivatives, which are expected to serve as substrates for C-glycosylation. Here, we isolated a cDNA encoding a UDP-dependent glycosyltransferase (UGT708A6), and its activity was characterized by in vitro and in vivo bioconversion assays. In vitro assays using 2-hydroxyflavanones as substrates and in vivo activity assays in yeast co-expressing ZmF2H1 and UGT708A6 show the formation of the flavones C-glycosides. UGT708A6 can also O-glycosylate flavanones in bioconversion assays in Escherichia coli as well as by in vitro assays with the purified recombinant protein. Thus, UGT708A6 is a bifunctional glycosyltransferase that can produce both C- and O-glycosidated flavonoids, a property not previously described for any other glycosyltransferase. PMID- 24045948 TI - Glycoepitopes of staphylococcal wall teichoic acid govern complement-mediated opsonophagocytosis via human serum antibody and mannose-binding lectin. AB - Serum antibodies and mannose-binding lectin (MBL) are important host defense factors for host adaptive and innate immunity, respectively. Antibodies and MBL also initiate the classical and lectin complement pathways, respectively, leading to opsonophagocytosis. We have shown previously that Staphylococcus aureus wall teichoic acid (WTA), a cell wall glycopolymer consisting of ribitol phosphate substituted with alpha- or beta-O-N-acetyl-d-glucosamine (GlcNAc) and d-alanine, is recognized by MBL and serum anti-WTA IgG. However, the exact antigenic determinants to which anti-WTA antibodies or MBL bind have not been determined. To answer this question, several S. aureus mutants, such as alpha-GlcNAc glycosyltransferase-deficient S. aureus DeltatarM, beta-GlcNAc glycosyltransferase-deficient DeltatarS, and DeltatarMS double mutant cells, were prepared from a laboratory and a community-associated methicillin-resistant S. aureus strain. Here, we describe the unexpected finding that beta-GlcNAc WTA deficient DeltatarS mutant cells (which have intact alpha-GlcNAc) escape from anti-WTA antibody-mediated opsonophagocytosis, whereas alpha-GlcNAc WTA-deficient DeltatarM mutant cells (which have intact beta-GlcNAc) are efficiently engulfed by human leukocytes via anti-WTA IgG. Likewise, MBL binding in S. aureus cells was lost in the DeltatarMS double mutant but not in either single mutant. When we determined the serum concentrations of the anti-alpha- or anti-beta-GlcNAc specific WTA IgGs, anti-beta-GlcNAc WTA-IgG was dominant in pooled human IgG fractions and in the intact sera of healthy adults and infants. These data demonstrate the importance of the WTA sugar conformation for human innate and adaptive immunity against S. aureus infection. PMID- 24045949 TI - Pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) gene is suppressed by transglutaminase 2 activation. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) functions as a neuroprotective factor through the PACAP type 1 receptor, PAC1. In a previous work, we demonstrated that nerve growth factor augmented PAC1 gene expression through the activation of Sp1 via the Ras/MAPK pathway. We also observed that PAC1 expression in Neuro2a cells was transiently suppressed during in vitro ischemic conditions, oxygen-glucose deprivation (OGD). Because endoplasmic reticulum (ER) stress is induced by ischemia, we attempted to clarify how ER stress affects the expression of PAC1. Tunicamycin, which induces ER stress, significantly suppressed PAC1 gene expression, and salubrinal, a selective inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase signaling pathway of ER stress, blocked the suppression. In luciferase reporter assay, we found that two Sp1 sites were involved in suppression of PAC1 gene expression due to tunicamycin or OGD. Immunocytochemical staining demonstrated that OGD-induced transglutaminase 2 (TG2) expression was suppressed by salubrinal or cystamine, a TG activity inhibitor. Further, the OGD-induced accumulation of cross-linked Sp1 in nuclei was suppressed by cystamine or salubrinal. Together with cystamine, R283, TG2-specific inhibitor, and siRNA specific for TG2 also ameliorated OGD induced attenuation of PAC1 gene expression. These results suggest that Sp1 cross linking might be crucial in negative regulation of PAC1 gene expression due to TG2 in OGD-induced ER stress. PMID- 24045950 TI - The ferredoxin:NAD+ oxidoreductase (Rnf) from the acetogen Acetobacterium woodii requires Na+ and is reversibly coupled to the membrane potential. AB - The anaerobic acetogenic bacterium Acetobacterium woodii has a novel Na(+) translocating electron transport chain that couples electron transfer from reduced ferredoxin to NAD(+) with the generation of a primary electrochemical Na(+) potential across its cytoplasmic membrane. In previous assays in which Ti(3+) was used to reduce ferredoxin, Na(+) transport was observed, but not a Na(+) dependence of the electron transfer reaction. Here, we describe a new biological reduction system for ferredoxin in which ferredoxin is reduced with CO, catalyzed by the purified acetyl-CoA synthase/CO dehydrogenase from A. woodii. Using CO-reduced ferredoxin, NAD(+) reduction was highly specific and strictly dependent on ferredoxin and occurred at a rate of 50 milliunits/mg of protein. Most important, this assay revealed for the first time a strict Na(+) dependence of this electron transfer reaction. The Km was 0.2 mm. Na(+) could be partly substituted by Li(+). Na(+) dependence was observed at neutral and acidic pH values, indicating the exclusive use of Na(+) as a coupling ion. Electron transport from reduced ferredoxin to NAD(+) was coupled to electrogenic Na(+) transport, indicating the generation of DeltaMUNa(+). Vice versa, endergonic ferredoxin reduction with NADH as reductant was possible, but only in the presence of DeltaMUNa(+), and was accompanied by Na(+) efflux out of the vesicles. This is consistent with the hypothesis that Rnf also catalyzes ferredoxin reduction at the expense of an electrochemical Na(+) gradient. The physiological significance of this finding is discussed. PMID- 24045951 TI - The Rho family member RhoE interacts with Skp2 and is degraded at the proteasome during cell cycle progression. AB - RhoE/Rnd3 is an atypical member of the Rho family of small GTPases. In addition to regulating actin cytoskeleton dynamics, RhoE is involved in the regulation of cell proliferation, survival, and metastasis. We examined RhoE expression levels during cell cycle and investigated mechanisms controlling them. We show that RhoE accumulates during G1, in contact-inhibited cells, and when the Akt pathway is inhibited. Conversely, RhoE levels rapidly decrease at the G1/S transition and remain low for most of the cell cycle. We also show that the half-life of RhoE is shorter than that of other Rho proteins and that its expression levels are regulated by proteasomal degradation. The expression patterns of RhoE overlap with that of the cell cycle inhibitor p27. Consistently with an involvement of RhoE in cell cycle regulation, RhoE and p27 levels decrease after overexpression of the F-box protein Skp2. We have identified a region between amino acids 231 and 240 of RhoE as the Skp2-interacting domain and Lys(235) as the substrate for ubiquitylation. Based on our results, we propose a mechanism according to which proteasomal degradation of RhoE by Skp2 regulates its protein levels to control cellular proliferation. PMID- 24045952 TI - Regulation of the Na+/Ca2+ exchanger by pyridine nucleotide redox potential in ventricular myocytes. AB - The cardiac Na(+)/Ca(2+) exchanger (NCX) is the major Ca(2+) efflux pathway on the sarcolemma, counterbalancing Ca(2+) influx via L-type Ca(2+) current during excitation-contraction coupling. Altered NCX activity modulates the sarcoplastic reticulum Ca(2+) load and can contribute to abnormal Ca(2+) handling and arrhythmias. NADH/NAD(+) is the main redox couple controlling mitochondrial energy production, glycolysis, and other redox reactions. Here, we tested whether cytosolic NADH/NAD(+) redox potential regulates NCX activity in adult cardiomyocytes. NCX current (INCX), measured with whole cell patch clamp, was inhibited in response to cytosolic NADH loaded directly via pipette or increased by extracellular lactate perfusion, whereas an increase of mitochondrial NADH had no effect. Reactive oxygen species (ROS) accumulation was enhanced by increasing cytosolic NADH, and NADH-induced INCX inhibition was abolished by the H2O2 scavenger catalase. NADH-induced ROS accumulation was independent of mitochondrial respiration (rotenone-insensitive) but was inhibited by the flavoenzyme blocker diphenylene iodonium. NADPH oxidase was ruled out as the effector because INCX was insensitive to cytosolic NADPH, and NADH-induced ROS and INCX inhibition were not abrogated by the specific NADPH oxidase inhibitor gp91ds-tat. This study reveals a novel mechanism of NCX regulation by cytosolic NADH/NAD(+) redox potential through a ROS-generating NADH-driven flavoprotein oxidase. The mechanism is likely to play a key role in Ca(2+) homeostasis and the response to alterations in the cytosolic pyridine nucleotide redox state during ischemia-reperfusion or other cardiovascular diseases. PMID- 24045953 TI - Architectural organization of the metabolic regulatory enzyme ghrelin O acyltransferase. AB - Ghrelin O-acyltransferase (GOAT) is a polytopic integral membrane protein required for activation of ghrelin, a secreted metabolism-regulating peptide hormone. Although GOAT is a potential therapeutic target for the treatment of obesity and diabetes and plays a key role in other physiologic processes, little is known about its structure or mechanism. GOAT is a member of the membrane-bound O-acyltransferase (MBOAT) family, a group of polytopic integral membrane proteins involved in lipid-biosynthetic and lipid-signaling reactions from prokaryotes to humans. Here we use phylogeny and a variety of bioinformatic tools to predict the topology of GOAT. Using selective permeabilization indirect immunofluorescence microscopy in combination with glycosylation shift immunoblotting, we demonstrate that GOAT contains 11 transmembrane helices and one reentrant loop. Development of the V5Glyc tag, a novel, small, and sensitive dual topology reporter, facilitated these experiments. The MBOAT family invariant residue His-338 is in the ER lumen, consistent with other family members, but conserved Asn-307 is cytosolic, making it unlikely that both are involved in catalysis. Photocross linking of synthetic ghrelin analogs and inhibitors demonstrates binding to the C terminal region of GOAT, consistent with a role of His-338 in the active site. This knowledge of GOAT architecture is important for a deeper understanding of the mechanism of GOAT and other MBOATs and could ultimately advance the discovery of selective inhibitors for these enzymes. PMID- 24045954 TI - A mutation in the nuclear pore complex gene Tmem48 causes gametogenesis defects in skeletal fusions with sterility (sks) mice. AB - Skeletal fusions with sterility (sks) is an autosomal recessive mutation of mouse that results in male and female sterility because of defects in gametogenesis. The mutants also have skeletal malformations with fused vertebrae and ribs. We examined testicular phenotypes of sks/sks mice to investigate the defects in spermatogenesis. Histological and immunocytochemical analyses and expression analyses of the marker genes demonstrated that spermatogenesis is arrested at mid to late pachytene stage of meiotic prophase with defective synapsis of the homologous chromosomes. Next, we determined the precise chromosomal localization of the sks locus on a 0.3-Mb region of mouse chromosome 4 by linkage analysis. By sequencing the positional candidate genes in this region and whole exome sequencing, we found a GG to TT nucleotide substitution in exon 6 of the Tmem48 gene that encodes a putative transmembrane protein with six transmembrane domains. The nucleotide substitution causes aberrant splicing, which deletes exon 6 of the Tmem48 transcript. Specific expression of TMEM48 was observed in germ cells of males and females. Furthermore, the phenotypes of the sks mutant were completely rescued by the transgenesis of a genomic fragment containing the wild type Tmem48 gene. These findings indicate that the Tmem48 mutation is responsible for the gametogenesis defects and skeletal malformations in the sks mice. The TMEM48 protein is a nuclear membrane protein comprising the nuclear pore complex; its exact function in the nuclear pore complex is still unknown. Our finding suggested that the nuclear pore complex plays an important role in mammalian gametogenesis and skeletal development. PMID- 24045957 TI - The reliability of counting actinic keratosis. AB - Many epidemiological studies and clinical trials have been performed concerning actinic keratoses. The most eligible endpoint in the majority of articles is counting of actinic keratoses before and after treatments, nevertheless some authors support that this is not a reliable form of evaluation. The aim of this study was to evaluate the actinic keratoses counting by various raters and suggest approaches to increase the reliability. Cross-sectional study: forty three patients were evaluated by four raters (inter- and intra-rater assessment) on the face and forearms. The mean actinic keratoses counts on the face and forearms were 7.7 and 9.1. The overall agreement among the raters for the facial and forearm actinic keratoses was 0.74 and 0.77. The intra-rater assessment showed high rates of agreement for the face (ICC=0.93) and forearms (ICC=0.83). Higher agreement occurred when counting up to five lesions. Four raters led to increased measurement variability and loss of reliability. Higher rates of agreement may be achieved with small number of lesions, limitation and/or segmentation of body areas to reduce their number, in AK prevention designs, are strategies that may lead to a greater reliability of these measurements. PMID- 24045955 TI - Epidermal growth factor (EGF)-enhanced vascular cell adhesion molecule-1 (VCAM-1) expression promotes macrophage and glioblastoma cell interaction and tumor cell invasion. AB - Activated EGF receptor (EGFR) signaling plays an instrumental role in glioblastoma (GBM) progression. However, how EGFR activation regulates the tumor microenvironment to promote GBM cell invasion remains to be clarified. Here, we demonstrate that the levels of EGFR activation in tumor cells correlated with the levels of macrophage infiltration in human GBM specimens. This was supported by our observation that EGFR activation enhanced the interaction between macrophages and GBM cells. In addition, EGF treatment induced up-regulation of vascular cell adhesion molecule-1 (VCAM-1) expression in a PKCepsilon- and NF-kappaB-dependent manner. Depletion of VCAM-1 interrupted the binding of macrophages to GBM cells and inhibited EGF-induced and macrophage-promoted GBM cell invasion. These results demonstrate an instrumental role for EGF-induced up-regulation of VCAM-1 expression in EGFR activation-promoted macrophage-tumor cell interaction and tumor cell invasion and indicate that VCAM-1 is a potential molecular target for improving cancer therapy. PMID- 24045958 TI - Aspirin discontinuation syndromes: clinical implications of basic research studies. AB - Abrupt discontinuation of many drugs used in medicine causes withdrawal syndromes, some of which can be fatal. Discontinuation of a number of cardiovascular drugs can increase the risk of cardiovascular events. Whereas aspirin administration is known to decrease the risk of vascular ischemic problems, aspirin withdrawal may temporarily increase the risk of thrombotic events. Indeed, aspirin withdrawal has been associated with an increased risk of thrombosis both in clinical and fundamental research studies. Such complications occur within the first month after interrupting aspirin therapy and their mechanism remains unexplained. We have previously demonstrated that aspirin, when injected as a single high dose (100 mg/kg), induces a prothrombotic state in the rat, similar to that described above, 8 and 10 days after administration. This effect in the rat may be reproduced 1 hour after a single injection of ultra-low dose aspirin. Caution is therefore required regarding the possibility of drug discontinuation effects within the framework of drug safety evaluation. PMID- 24045959 TI - Robustness, canalyzing functions and systems design. AB - We study a notion of knockout robustness of a stochastic map (Markov kernel) that describes a system of several input random variables and one output random variable. Robustness requires that the behaviour of the system does not change if one or several of the input variables are knocked out. Gibbs potentials are used to give a mechanistic description of the behaviour of the system after knockouts. Robustness imposes structural constraints on these potentials. We show that robust systems can be described in terms of suitable interaction families of Gibbs potentials, which allows us to address the problem of systems design. Robustness is also characterized by conditional independence constraints on the joint distribution of input and output. The set of all probability distributions corresponding to robust systems can be decomposed into a finite union of components, and we find parametrizations of the components. PMID- 24045960 TI - All-cause, cardiovascular, and cancer mortality rates in postmenopausal white, black, Hispanic, and Asian women with and without diabetes in the United States: the Women's Health Initiative, 1993-2009. AB - Using data from the Women's Health Initiative (1993-2009; n = 158,833 participants, of whom 84.1% were white, 9.2% were black, 4.1% were Hispanic, and 2.6% were Asian), we compared all-cause, cardiovascular, and cancer mortality rates in white, black, Hispanic, and Asian postmenopausal women with and without diabetes. Cox proportional hazard models were used for the comparison from which hazard ratios and 95% confidence intervals were computed. Within each racial/ethnic subgroup, women with diabetes had an approximately 2-3 times higher risk of all-cause, cardiovascular, and cancer mortality than did those without diabetes. However, the hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups. Population attributable risk percentages (PARPs) take into account both the prevalence of diabetes and hazard ratios. For all-cause mortality, whites had the lowest PARP (11.1, 95% confidence interval (CI): 10.1, 12.1), followed by Asians (12.9, 95% CI: 4.7, 20.9), blacks (19.4, 95% CI: 15.0, 23.7), and Hispanics (23.2, 95% CI: 14.8, 31.2). To our knowledge, the present study is the first to show that hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups when stratified by diabetes status. Because of the "amplifying" effect of diabetes prevalence, efforts to reduce racial/ethnic disparities in the rate of death from diabetes should focus on prevention of diabetes. PMID- 24045961 TI - Effects of OX40-OX40L interaction on the nuclear factor of activated T cells c1 in ApoE-deficient mice. AB - We previously reported the emerging role of OX40-OX40L interaction in inflammation and atherosclerosis. However, the mechanism by which OX40-OX40L interaction contributes to pathogenesis is poorly understood. This study investigated the effects of OX40-OX40L interaction on the nuclear factor of activated T cells c1 (NFATc1) in ApoE(-/-) mice. Atherosclerotic plaque was induced via rapid perivascular carotid collar placement in ApoE(-/-) mice. The expression levels of OX40, OX40L, and NFATc1 in the lymphocytes were measured via real-time polymerase chain reaction and flow cytometry. The presence of NFATc1 in the atherosclerotic plaque was detected via immunohistochemistry, and the level of IL-4 was measured via enzyme-linked immunosorbent assay. The expression level of NFATc1 significantly increased in atherosclerotic lesion and in the leukocytes from the ApoE(-/-) mice. After stimulating OX40-OX40L interaction, the mRNA and protein expression levels of NFATc1 in the lymphocytes significantly increased. Meanwhile, anti-OX40LmAb significantly suppressed the expression of NFATc1 in the leukocytes and substantially elevated the level of IL-4. NFATc1 inhibitor markedly suppressed IL-4 production. This study suggests that OX40-OX40L interaction regulates the expression of NFATc1, which may play a critical role in atherosclerotic plaque formation, and may therefore have implications with pathophysiology of atherosclerosis. PMID- 24045962 TI - Cepharanthine, an alkaloid from Stephania cepharantha Hayata, inhibits the inflammatory response in the RAW264.7 cell and mouse models. AB - The aim of this study was to investigate the protective effects of cepharanthine (CEP) on inflammation in lipopolysaccharide (LPS)-stimulated RAW264.7 cells in vitro and a LPS-induced lung injury model in vivo. RAW264.7 cells were treated with various concentrations of CEP for 1 h followed by incubation with or without 1 MUg/ml LPS for 18 h. TNF-alpha, IL-6, and IL-1beta in the supernatants were measured by ELISA. Nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase pathways were analyzed by Western blot. Mice were randomly divided into control group, LPS group, CEP + LPS group, and dexamethasone + LPS group. A male BALB/c mouse model of acute lung injury was induced by LPS. Bronchoalveolar lavage fluid was collected for inflammatory cell count and cytokine assays. Histopathologic examination was performed on mice that were not subjected to bronchoalveolar lavage fluid collection. CEP dose-dependently inhibited the release of TNF-alpha, IL-6, and IL-1beta in LPS-stimulated RAW264.7 cells. Significantly, CEP dose-dependently suppressed NF-kappaB activation, IkappaBalpha degradation, and phosphorylation of ERK, JNK, and p38 induced by LPS. In vivo, it was also observed that CEP attenuated lung histopathologic changes and down regulated the level of pro-inflammatory cytokines, including TNF-alpha, IL-1beta, and IL-6, in the mouse acute lung injury model. These results suggest that CEP potentially decreases inflammation in vitro and in vivo and might be a therapeutic agent against inflammatory diseases. PMID- 24045963 TI - York Mason procedure to repair iatrogenic rectourinary fistula: our experience. AB - BACKGROUND: Rectourinary fistula (RUF) is an uncommon but devastating condition in men. It usually occurs as a complication of prostatic cancer treatment, whether this is by radiation therapy or surgery. It can also occur in patients with benign pathology of the prostate, inflammatory bowel disease, or Fournier's gangrene, and following pelvic trauma. RUF represents a challenge for the surgeon because spontaneous closure is a rare event. Several techniques have been described for surgical repair of fistula. The goal of the present study was to demonstrate that the York Mason posterior, transrectal correction of an iatrogenic RUF is a reliable approach that offers good postoperative outcomes. METHODS: We retrospectively reviewed the medical records of 39 patients who underwent York Mason repair from 1998 to 2012 at the University of Southern California (USC) and Campus Bio-Medico University of Rome (UCBM). The most frequent common causes of RUF were itemized, and statistical analysis was performed to determine correlations between the fistula's etiology and surgical outcome. Patients were then divided into two different cohorts: those who had undergone only one previous procedure (group 1) and those who had undergone two or more surgeries (group 2). We performed a statistical analysis between the two groups and calculated the percentage of fistula repair by means of the posterior trans-sphincteric approach with the York Mason technique in each groups We evaluated the presence of comorbidities (diabetes and infection) and their influence on the surgical outcome. Finally, we reported patient outcomes during follow-up. RESULTS: In the present series, the RUF was iatrogenic in every case. The onset of the fistula followed prostate cancer treatment, most commonly after laparoscopic procedures. The success rate of fistula repair was found to be independent of the fistula's etiology. Diabetes and infections did not influence the surgical outcome. Overall, more than 50 % of patients treated with the York Mason posterior, transanal, transrectal approach remained free of fistula during follow-up. Almost 90 % of those who were previously operated only once remained free of fistula. CONCLUSIONS: The posterior trans-sphincteric approach of the York Mason technique is effective in treating RUF. PMID- 24045964 TI - Evaluating the morbidity and efficacy of reoperative surgery in the central compartment for persistent/recurrent papillary thyroid carcinoma. AB - BACKGROUND: Although reoperative surgery in the central compartment (RCND) is indicated for bulky or progressive persistent/recurrent papillary thyroid carcinoma (PTC), its associated morbidity and disease outcomes remain unclear. We evaluated RCND outcomes by comparing them with those of patients who underwent primary central neck dissection (CND). METHODS: After matching for age, sex, tumor size, and initial tumor stage, the morbidity and outcomes of 50 consecutive patients who underwent RCND were compared with data from 75 patients who underwent primary therapeutic CND during the same period. Matching was performed blind to the morbidity and disease outcome of each patient. A stimulated thyroglobulin (sTg) <2 ng/ml was considered undetectable. RESULTS: Relative to primary CND, the incidence of extranodal extension (p = 0.010) and size of metastatic lymph nodes (p < 0.001) were significantly greater in the RCND group. Postoperative hypoparathyroidism and vocal cord palsy rates were comparable in the groups. There were two esophageal injuries in the RCND group and none in the primary CND group. The secondary CND group achieved a significantly lower undetectable postablation sTg rate (12.0 vs. 52.0 %, p = 0.001) and worse 10-year disease-free survival (35.6 vs. 91.8 %, p = 0.001) and cancer-specific survival (82.0 vs. 98.5 %, p = 0.001) than the primary CND group. CONCLUSIONS: Although RCND for persistent/recurrent PTC was performed with morbidity comparable to that seen with primary CND, it was associated with some serious complications. Short- and long-term disease control appeared moderate with approximately one-tenth of patients having an undetectable sTg level 6 months after ablation and one-third remaining clinically disease-free after 10 years. PMID- 24045965 TI - Prognostic significance of microRNA-16 expression in human colorectal cancer. AB - BACKGROUND: MicroRNAs (miRNAs), small noncoding RNAs, have been reported to be highly involved in the formation and progression of all types of human cancer including colorectal cancer (CRC). Therefore, miRNAs are also potential prognostic biomarkers in CRC patients. The aim of this study was to detect the expression of miR-16 in human CRC tissues and investigate its clinicopathologic or prognostic significance. METHODS: TaqMan quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay was performed to determine the expression of miR-16 in 143 primary CRC tissues and 18 corresponding normal colonic mucosa from patients who had undergone surgery. The association of miR-16 expression with clinicopathologic features of CRC patients was statistically analyzed. Kaplan-Meier analyses were used to assess patient survival. Univariate and multivariate Cox analyses were performed. RESULTS: The relative level of miR 16 in 18 CRC tissues was significantly lower than that in corresponding normal colonic mucosa (p < 0.001). Statistical analyses revealed that the status of miR 16 expression was closely associated with tumor differentiation, lymph node metastasis, L category, V category, TNM stage, and tumor recurrence of CRC (p = 0.001, 0.003, 0.001, 0.005, 0.003, and 0.017, respectively). Kaplan-Meier analyses indicated that patients with low-miR-16 had lower 5-year overall survival than those with high-miR-16 (31.2 vs. 58.3 %; p = 0.0012). Multivariate Cox regression analyses indicated that the status of miR-16 expression might be an independent prognostic factor for CRC patients (hazard ratio 1.67; 95 % confidence interval 1.22-2.54; p = 0.018). CONCLUSIONS: Down-regulation of miR-16 plays critical roles in CRC progression. Low miR-16 expression is an independent factor predicting a poor prognosis for CRC patients. PMID- 24045966 TI - Attenuation of postmenopausal bone loss in patients with transient hypoparathyroidism after total thyroidectomy. AB - BACKGROUND: Increased bone mineral density (BMD) has been reported in patients with postsurgical permanent hypoparathyroidism. Hypoparathyroidism may attenuate the high-turnover bone loss in postmenopausal women. We reported previously that patients who had transient hypoparathyroidism postoperatively were at subclinical hypoparathyroid (hP) status even 5 years after surgery. We hypothesized that patients with transient hypoparathyroidism (ThP) may have altered BMD. METHODS: A total of 140 women who underwent total thyroidectomy had BMD measurements of the lumbar spine, femoral neck, and radius 3 years after surgery. At surgery, 99 patients were >=50 years and 41 were <50 years. They were divided into three groups according to their postoperative parathyroid function: There were 80 patients in the no hP (NhP) group, 54 in the ThP group, and 6 in the permanent hP (PhP) group. RESULTS: Among the 99 patients aged >=50 years, 36 ThP patients had median Z scores of the BMD in all three areas (lumbar spine, femoral neck, radius) that were significantly higher (by 1.083, 0.533, and 1.047, respectively) than those in the 60 NhP patients aged >=50 years. The BMDs in the three PhP patients >=50 years were higher than those in the NhP and ThP patients, but the difference did not reach significance except for in the femoral neck. Multivariate logistic regression analyses showed that Z scores > 0 were significantly associated only with the presence of ThP postoperatively. In the patients <50 years, the BMD values were not significantly different among the three groups except at the radius in PhP patients, which was significantly lower than those of the other patients. CONCLUSIONS: We found that ThP was associated with increased BMD in postmenopausal women. This may be due to attenuation of the high-turnover bone loss in postmenopausal women. PMID- 24045967 TI - Effect of delayed autologous breast reconstruction on breast cancer recurrence and survival. AB - BACKGROUND: The goal of the present study was to evaluate the impact of delayed autologous breast reconstruction on disease relapse in breast cancer patients treated with mastectomy. MATERIAL AND METHODS: The study was based on 503 consecutive patients younger than 70 years of age who underwent mastectomy between January 2000 and December 2003. Overall, 391 (78 %) received mastectomy alone and 112 (22 %) underwent a delayed breast reconstruction. The median time from mastectomy to delayed breast reconstruction was 34 months. The median duration of follow-up was 102 months. RESULTS: There were no locoregional recurrences (LRR) in patients who underwent delayed reconstruction (0.0 %); 21 LRR developed in patients treated with mastectomy only (5.4 %), P = 0.011. Distant metastases occurred less frequently in the reconstruction group (12.5 %) than in the patients who underwent mastectomy alone (21.5 %); P = 0.0343. The 8 year breast cancer specific survival in the reconstruction group was 98.2 and 85.7 % for the mastectomy only group, P = 0.000. CONCLUSIONS: Delayed autologous breast reconstruction does not appear to adversely influence disease progression when compared to patients treated with mastectomy only. PMID- 24045968 TI - Atypical and malignant meningioma: outcome and prognostic factors in 68 irradiated patients. AB - Meningiomas account for up to 20 % of all primary intracranial neoplasms; although the majority of these have a benign course, as many as 5-10 % can display more aggressive behavior and a higher incidence of disease progression. The benefit of immediate adjuvant radiotherapy is still being debated for atypical and malignant meningiomas. This study aimed to retrospectively assess prognostic factors and outcome in 68 patients with atypical and malignant meningiomas. Sixty-eight meningioma patients were treated with radiotherapy after initial resection or for recurrence, between January 1993 and December 2011. Surgery was macroscopically complete in 80 % of the patients; histology was atypical and malignant in 51 patients and 17 patients, respectively. Mean dose of radiotherapy was 54.6 Gy. Fifty-six percent of all patients received radiotherapy after surgical resection, 26 % at the first relapse, and 18 % at the second relapse. Median follow-up was 6.7 years, (range 1.5-19.9 years). The 5- and 10 year actuarial overall survival (OS) rates were 74.1 and 45.6 %, respectively. At univariate analysis age >60 years, radiotherapy dose >52 Gy showed statistical significance, (p = 0.04 and p = 0.03, respectively). At the multivariate analysis radiotherapy dose >52 Gy maintained the statistical significance, (p = 0.037). OS of patients treated with radiotherapy at diagnosis was longer than the survival of patients treated with salvage radiotherapy; however this difference did not reach statistical significance when tested for the entire series or for the subgroups of grade 2 and grade 3 patients. The 5- and 10-year disease-free survival (DFS) rates were 76.5 and 69.5 %, respectively, and were significantly influenced by size >5 cm (p = 0.04) and grading (p = 0.003) on univariate analysis. At multivariate analysis, size and grading both remained significant prognostic factors, p = 0.044 and p = 0.0006, respectively. Grade <= 2 acute side effects were seen during radiotherapy treatment in 16 % of the patients, with no >= grade 3 acute toxicity, based on the Common Terminology Criteria for Adverse Events. In this mono-institutional retrospective study, age and radiotherapy dose were associated with a longer OS, while preoperative size and grading of the tumor influenced DFS. Although there were some advantages in terms of OS for patients treated with postoperative radiotherapy, the benefit did not reach the significance. Multicenter prospective studies are necessary to clarify the management and the correct timing of radiotherapy in such a rare disease. PMID- 24045969 TI - Cortical hemosiderin is associated with seizures in patients with newly diagnosed malignant brain tumors. AB - Hemorrhage is common in brain tumors. Due to characteristic magnetic field changes induced by hemosiderin it can be detected using susceptibility weighted MRI (SWI). Its relevance to clinical syndromes is unclear. Here we investigated the patterns of intra-tumoral SWI positivity (SWI(pos)) as a surrogate for hemosiderin with regard to the prevalence of epilepsy. We report on 105 patients with newly diagnosed supra-tentorial gliomas and brain metastasis. The following parameters were recorded from pre-operative MRI: (1) SWI(pos) defined as dot-like or fine linear signal changes; (2) allocation of SWI(pos) to tumor compartments (contrast enhancement, central hypointensity, non-enhancing area outside contrast enhancement); (3) allocation of SWI(pos) to include the cortex, or SWI(pos) in subcortical tumor parts only; (4) tumor size on T2 weighted and gadolinium enhanced T1 images. 80 tumors (76 %) showed SWI(pos) (4/14 diffuse astrocytoma WHO II, 5/9 anaplastic astrocytoma WHO III, 41/46 glioblastoma WHO IV, 30/36 metastasis). The presence of SWI(pos) depended on tumor size but not on patient's age, medication with antiplatelet drugs or anticoagulation. Seizures occurred in 60 % of patients. Cortical SWI(pos) significantly correlated with seizures in brain metastasis (p = 0.044), and as a trend in glioblastoma (p = 0.062). Cortical SWI(pos) may confer a risk for seizures in patients with newly diagnosed brain metastasis and glioblastoma. Whether development of cortical SWI(pos) induced by treatment or by the natural course of tumors also leads to the new onset of seizures has to be addressed in longitudinal studies in larger patient cohorts. PMID- 24045970 TI - Results of a questionnaire regarding practice patterns for the diagnosis and treatment of intracranial radiation necrosis after SRS. AB - Although stereotactic radiosurgery (SRS) is an effective treatment option for patients with brain tumors, its increased use has raised concern for increased incidence of radiation necrosis (RN). No established standard or guidelines exists regarding non-invasive techniques to diagnose or treat RN. This study was conducted to assess current patterns of evaluation and treatment of RN among physicians who treat intracranial malignancies. A questionnaire consisting of 20 questions was sent to 3,041 members of the American Society for Radiation Oncology (ASTRO) and the Society for Neurologic Oncology (SNO). Questions addressed demographics, utilization of SRS, perceptions regarding RN diagnosis treatment, approach to steroid-refractory RN, and management of two clinical scenarios using Kwiksurvey(c) software. The survey response rate was 8.74 % (266/3,041). Most respondents practice in an academic and/or university setting (62 %) at a facility that performs SRS (94 %) with a variety of systems. The number of annual cases performed at the participant's institution varied from <50 to >400, with a wide degree of variability. Most respondents practice at an institution that performs 50-100 cases/year (28 %). The most common range of symptomatic RN seen in clinical practice was 1-5 % (61 %). Most respondents reported that asymptomatic RN occurs in 6-10 % (33 %). Favored non-invasive diagnostic mechanisms were clinical evaluation (37 %) and MRI (19 %). In response to a clinical scenario depicting an asymptomatic patient post-SRS for brain metastasis with an enlarging lesion and edema at the treatment site, most respondents felt the image represented RN or a combination of RN and tumor progression. Most (58 %) favored short-term follow-up with repeat MRI. Ninety three percent of the respondents initiated steroids as a first-line approach if patient was to develop symptoms. Steroids were the preferred first therapy in symptomatic patients on initial follow-up (81 %). In steroid-refractory patients, most recommend surgical intervention (63 %). Most physicians who responded to this questionnaire believe that post-SRS RN is uncommon (<=10 % of cases). The approach to establish the diagnosis of RN is variable. Steroids are the most commonly utilized first-line treatment for suspected RN. Considerable variation exists in the management of steroid-refractory RN. Additional studies are required to establish guidelines for evaluation and treatment of RN. PMID- 24045971 TI - Escitalopram block of hERG potassium channels. AB - Escitalopram, a selective serotonin reuptake inhibitor, is the pharmacologically active S-enantiomer of the racemic mixture of RS-citalopram and is widely used in the treatment of depression. The effects of escitalopram and citalopram on the human ether-a-go-go-related gene (hERG) channels expressed in human embryonic kidney cells were investigated using voltage-clamp and Western blot analyses. Both drugs blocked hERG currents in a concentration-dependent manner with an IC50 value of 2.6 MUM for escitalopram and an IC50 value of 3.2 MUM for citalopram. The blocking of hERG by escitalopram was voltage-dependent, with a steep increase across the voltage range of channel activation. However, voltage independence was observed over the full range of activation. The blocking by escitalopram was frequency dependent. A rapid application of escitalopram induced a rapid and reversible blocking of the tail current of hERG. The extent of the blocking by escitalopram during the depolarizing pulse was less than that during the repolarizing pulse, suggesting that escitalopram has a high affinity for the open state of the hERG channel, with a relatively lower affinity for the inactivated state. Both escitalopram and citalopram produced a reduction of hERG channel protein trafficking to the plasma membrane but did not affect the short-term internalization of the hERG channel. These results suggest that escitalopram blocked hERG currents at a supratherapeutic concentration and that it did so by preferentially binding to both the open and the inactivated states of the channels and by inhibiting the trafficking of hERG channel protein to the plasma membrane. PMID- 24045972 TI - Hostile sexist male patients and female doctors: a challenging encounter. AB - BACKGROUND: Patient characteristics and attitudes can affect how patients react to the physician's communication style, and this reaction can then influence consultation outcomes. OBJECTIVE: The goal of the present study was to investigate whether the attitude of a sexist male patient affects how he perceives a female physician's nonverbal communication and whether this then results in expecting less positive consultation outcomes. STUDY DESIGN AND SETTING: Participants were analog patients who viewed four videotaped male and four videotaped female physicians in a consultation with one of their patients. Physician videos were preselected to represent a range of high and low patient centered physician nonverbal behavior. Participants filled in questionnaires to assess how patient-centered they perceived the female and male physicians' nonverbal communication to be, and participants indicated how positive they expected the consultation outcomes to be. Moreover, we assessed the participants' sexist attitudes with a questionnaire measuring hostile and benevolent sexism. PARTICIPANTS: Students (N = 60) from a French-speaking university in Switzerland were recruited on campus. MAIN OUTCOME MEASURE: The main outcome measures were the extent to which analog patients expect the consultation outcomes to be positive (high satisfaction, increased trust in the physician, intention to adhere to treatment recommendations, and perceived physician competence) and the extent to which analog patients perceive physicians as patient-centered (judged from the physicians' nonverbal cues). RESULTS: Male analog patients' hostile sexism was negatively related to perceiving the physicians as patient-centered, and male analog patients' hostile sexism was also negatively related to expected positive consultation outcomes. For male patients viewing female physicians, mediation analysis revealed that perceived physician patient-centeredness mediated the negative relationship between hostile sexism and expected positive consultation outcomes. CONCLUSION: Male hostile sexist patients perceive a female physician's nonverbal communication as less patient-centered and this negatively affects their expectation of positive outcomes from the consultation. PMID- 24045973 TI - miR-106a represses the Rb tumor suppressor p130 to regulate cellular proliferation and differentiation in high-grade serous ovarian carcinoma. AB - The degree of differentiation in human cancers generally reflects the degree of malignancy, with the most undifferentiated cancer being also the highest grade and the most aggressive. High-grade serous ovarian carcinomas (HGSOC) are poorly differentiated and fast-growing malignancies. The molecular mechanisms underlying the poor differentiation of HGSOC has not been completely characterized. Evidence suggests that miRNA, miR are dysregulated in HGSOC. Therefore, we focused on those miRNAs that are relevant to tumor differentiation. Expression profiling of miRNAs in HGSOC, indicated miR-106a and its family members were significantly upregulated. Upregulation of miR-106a was further validated by real-time reverse transcriptase PCR (qRT-PCR) and miRNA in situ hybridization in a large cohort of HGSOC specimens. Overexpression of miR-106a in benign and malignant ovarian cells significantly increased the cellular proliferation rate and expanded the side population fraction. In particular, SKOV3 cells with miR-106a overexpression had significantly higher tumor initial/stem cell population (CD24- and CD133-positive cells) than control SKOV3 cells. Among many miR-106a predicated target genes, p130 (RBL2), an retinoblastoma (Rb) tumor suppressor family member, was not only confirmed as a specific target of miR-106a but also related to tumor growth and differentiation. The importance of mir-106a and RBL2 was further demonstrated in vivo, in which, SKOV3 cells overexpressing miR-106a formed poorly differentiated carcinomas and had reduced RBL2 levels. To our knowledge, this is the first study of miR-106a mediating proliferation and tumor differentiation in HGSOC. IMPLICATIONS: The current study suggests that the RB tumor suppressor pathway is a critical regulator of growth and differentiation in HGSOC. PMID- 24045974 TI - Effects of a westernized diet on the reflexes and physical maturation of male rat offspring during the perinatal period. AB - This study evaluates the effects of a westernized diet during the perinatal period on the maternal performance and growth and development of rat offspring. Female Wistar rats were fed with either a control (C) diet, with casein as the protein source or a westernized (W) diet, during pregnancy and lactation. The pups were divided, eight per group, into the same diet groups as their dams. During lactation, the body weight (day 1, W = 6.85 +/- 0.62 g, C = 5.81 +/- 0.49, p < 0.05; day 21, W = 55.42 +/- 3.78, C = 47.75 +/- 3.45, p < 0.001) and somatic growth (body length day 1, W = 53.24 +/- 2.16, C = 50.641 +/- 1.79, p < 0.05; day 21, W = 124.8, C = 119.903 +/- 3.71, p < 0.001) in the male offspring showed significant differences among the groups. The physical appearance and reflex maturation showed differences between day 1 and day 3. With the westernized diet, during the perinatal period, no alterations in maternal weight gain, gestation or performance were observed; however, changes in the coefficients of feed efficiency and energy during lactation were noted. Besides, blood glucose was found to be elevated at the end of lactation (C = 3.67 +/- 0.35 mmol/l, W = 5.2 0 +/- 0.49 mmol/l). At 21 days, the male pups from the dams on the westernized diet were 15 % heavier, and the maturation of the neural reflexes and physical characteristics were found to occur earlier. Therefore, the consumption of a westernized diet during the perinatal period was independent of maternal energy intake, and influenced the growth and development of offspring. PMID- 24045976 TI - A rare cause of bile duct rupture. PMID- 24045977 TI - An intriguing design concept to enhance the pulsatile fatigue life of self expanding stents. AB - Intravascular stenting has emerged as the primary treatment for vascular diseases and has received great attention from the medical community since its introduction two decades ago. The endovascular self-expanding stent is used to treat peripheral artery diseases; however, once implanted, these stents suffer from various cyclic motions caused by pulsatile blood pressure and daily activities. Due to this challenging environment, fatigue performance has become a critical issue for stent design. In this paper, a simple yet intriguing concept of stent design aimed at enhancing pulsatile fatigue life is investigated. The concept of this design is to shift the highly concentrated stresses/strains away from the crown and re-distribute them along the stress-free bar arm by tapering its strut width. Finite element models were developed to evaluate the mechanical integrity and pulsatile fatigue resistance of the stent to various loading conditions. Results show that the fatigue safety factor jumped to 2.5-3.0 times that of the standard stent with constant strut width. This is astonishing considering that the stent profile and scaffolding were not compromised. The findings of this paper provide an excellent approach to the optimization of future stent design to greatly improve stent fatigue performance. PMID- 24045975 TI - Increased lipid synthesis and decreased beta-oxidation in the liver of SHR/NDmcr cp (cp/cp) rats, an animal model of metabolic syndrome. AB - SHR/NDmcr-cp (cp/cp) rats (SHR/NDcp) are an animal model of metabolic syndrome. A previous study of ours revealed drastic increases in the mass of palmitic (16:0), oleic (18:1n-9), palmitoleic (16:1n-7), cis-vaccenic (18:1n-7) and 5,8,11 eicosatrienoic acids in the liver of SHR/NDcp. However, detailed information on the class of lipid accumulated and the mechanism responsible for the overproduction of the accumulated lipid in the liver was not obtained. This study aimed to characterize the class of lipid accumulated and to explore the mechanism underlying the lipid accumulation in the liver of SHR/NDcp, in comparison with SHR/NDmcr-cp (+/+) (lean hypertensive littermates of SHR/NDcp) and Wistar Kyoto rats. In the liver of SHR/NDcp, de novo synthesis of fatty acids (16:0, 18:1n-9 and 16:1n-7) and triacylglycerol (TAG) synthesis were up-regulated and fatty acid beta-oxidation was down-regulated. These perturbations of lipid metabolism caused fat accumulation in hepatocytes and accumulation of TAG, which were enriched with 16:0, 18:1n-9 and 16:1n-7, in the liver of SHR/NDcp. On the other hand, no changes were found in hepatic contents of diacylglycerol and unesterified fatty acid (FFA); among FFA, there were no differences in the hepatic concentrations of unesterified 16:0 and stearic acid between SHR/NDcp and two other groups of rats. Moreover, little change was brought about in the expression of genes responsive to endoplasmic reticulum stress in the liver of SHR/NDcp. These results may reinforce the pathophysiological role of stearoyl-CoA desaturase 1 and fatty acid elongase 6 in the liver of SHR/NDcp. PMID- 24045978 TI - Supplemental screening ultrasound increases cancer detection yield in BRCA1 and BRCA2 mutation carriers. AB - INTRODUCTION: This study aimed at evaluating the efficacy of ultrasound for the early detection of breast cancers in BRCA1/2 mutation carriers. METHODS: Between 01/1997 and 10/2008 221 BRCA1/2 mutation carriers participated in a breast cancer screening program which included semi-annual ultrasound in combination with annual mammography and magnetic resonance imaging (MRI). Women underwent on average (median) five semi-annual screening rounds with a range of one to 22 appointments, totaling 1,855 rounds of screening. All three imaging modalities were coded according to the American College of Radiology (BI-RADS classification). RESULTS: In total, we detected 27 BRCA-associated breast cancers in 25 patients. The sensitivity was 77% for ultrasound, 27% for mammography, and 100% for MRI. Three tumors were detected directly as a result of only the semi annual ultrasound screen. CONCLUSIONS: Due to the specific tumor morphology and the considerably elevated tumor doubling time, mutation carriers benefit from the addition of semi-annual ultrasound screening as a sensitive and cost-effective method. PMID- 24045979 TI - Sublingual misoprostol versus intravenous oxytocin in prevention of post-partum hemorrhage. AB - BACKGROUND: Post-partum hemorrhage (PPH) is the most common direct cause of maternal mortality and timely intervention can save many lives. OBJECTIVE: To compare the effectiveness of sublingual misoprostol to intravenous oxytocin in preventing post-partum hemorrhage in low risk vaginal birth. METHODS: One hundred patients with no risk factor for PPH were randomly allocated to receive 600 MUg misoprostol administered sublingually or 10 IU of intravenous oxytocin immediately after the delivery of baby. Main outcome measures were post-partum blood loss, drop in hemoglobin in 24 h, duration of third stage of labor, and drug-related adverse effects. RESULTS: Mean age, parity and gestational age were similar in both groups. Mean blood loss was significantly lower in oxytocin group (114.28 +/- 26.75 versus 149.50 +/- 30.78 ml; p = 0.00). Drop in hemoglobin was 0.31 +/- 0.16 versus 0.49 +/- 0.21 g% (p = 0.01) in oxytocin and misoprostol group, respectively. Duration of third stage labor was shorter in oxytocin group (median 5 min, IQR: 4.5-5.5 versus 5.5 min, IQR: 5-6 min, p < 0.01). Although fever and shivering were common adverse effects with misoprostol but were not clinically significant. CONCLUSION: Intravenous oxytocin is more efficacious than sublingual misoprostol in preventing PPH in institutional deliveries. PMID- 24045980 TI - Disc prosthesis replacement and interbody fusion in the treatment of degenerative cervical disc disease: comparative analysis of 176 consecutive cases. AB - PURPOSE: The purpose of this retrospective analysis is to determine whether disc prosthesis replacement can be equivalent or superior compared with the disc interbody fusion. METHODS: Between January, 2005 and June, 2011 we performed microdiscetomy by the anterior approach in 176 patients. We subdivided the total set of patients into two groups. Group A is made up of 84 patients in whom the prosthetic disc was implanted; Group B is made up of 92 patients in whom disc fusion was performed. RESULTS: In both groups, the radicular pain disappeared and the signs of spinal cord compression improved or remained stable. Patients of Group A required significantly fewer days of hospitalization and shorter absence from work, and had significant lower scores in the Neck Disability Index (NDI) at 12 months. CONCLUSIONS: Our experience demonstrates that the use of disc prosthesis is a safe and effective alternative to interbody fusion. PMID- 24045981 TI - Social impairments in chromosome 22q11.2 deletion syndrome (22q11.2DS): autism spectrum disorder or a different endophenotype? AB - High prevalence of autism spectrum disorders (ASD) has been reported in 22q11.2DS, although this has been based solely on parent report measures. This study describes the presence of ASD using a procedure more similar to that used in clinical practice by incorporating history (Social Communication Questionnaire) AND a standardized observation measure (Autism Diagnostic Observation Schedule) and suggests that ASD is not as common as previously reported in 22q11.2DS. Differences in methodology, along with comorbid conditions such as anxiety, likely contribute to false elevations in ASD prevalence and information from multiple sources should be included in the evaluation of ASD. PMID- 24045982 TI - An EXAFS study of the binding of Cd and Pb ions to lipid films. AB - Extended X-ray Absorption Fine Structure (EXAFS) measurements performed on Langmuir-Blodgett (LB) films containing cadmium and lead ions reveal the different coordination structures of the two cations in lipid membranes. We describe the local atomic environment of cadmium and lead in LB films prepared with stearic and 1,2 distearoyl-Lalpha-phosphatidic acids. The measurements have been performed on films of two different thicknesses, one and seven molecular layers, and at two different values of relative humidity. The local atomic environment of Cd ions in stearate films is consistent with unidentate coordination in which a Cd ion binds two stearate molecules, while that of Pb ions is consistent with a bidentate coordination in which a Pb ion binds one stearate molecule. Furthermore, in lead stearate films, there is Pb-Pb coordination as already observed in Langmuir films. In films of Pb-phosphatidic acid, oxygen atoms of the organic phosphate and oxygen atoms of bound water form two distinct shells. PMID- 24045983 TI - Debonding energy of PDMS: A new analysis of a classic adhesion scenario. AB - We investigated the debonding energy between confined layers of a soft elastic solid (PDMS) and a circular steel indenter in a flat punch geometry. PDMS is extensively used in applications, but also a widespread model system for fundamental research. Varying systematically the pulling speed and the viscoelastic properties, notably the modulus, we determined scaling laws for the debonding energy. We showed that the debonding energy is independent of the sample thickness. Applying a new approach and separating the crack initiation and the propagation part of the force curves, we analyzed the thickness dependence more precisely and we demonstrated that the energy to propagate the crack at given average speed does not only depend on the modulus, but also on the sample thickness. PMID- 24045984 TI - Counter-ions at single charged wall: Sum rules. AB - For inhomogeneous classical Coulomb fluids in thermal equilibrium, like the jellium or the two-component Coulomb gas, there exists a variety of exact sum rules which relate the particle one-body and two-body densities. The necessary condition for these sum rules is that the Coulomb fluid possesses good screening properties, i.e. the particle correlation functions or the averaged charge inhomogeneity, say close to a wall, exhibit a short-range (usually exponential) decay. In this work, we study equilibrium statistical mechanics of an electric double layer with counter-ions only, i.e. a globally neutral system of equally charged point-like particles in the vicinity of a plain hard wall carrying a fixed uniform surface charge density of opposite sign. At large distances from the wall, the one-body and two-body counter-ion densities go to zero slowly according to the inverse-power law. In spite of the absence of screening, all known sum rules are shown to hold for two exactly solvable cases of the present system: in the weak-coupling Poisson-Boltzmann limit (in any spatial dimension larger than one) and at a special free-fermion coupling constant in two dimensions. This fact indicates an extended validity of the sum rules and provides a consistency check for reasonable theoretical approaches. PMID- 24045985 TI - Mechanism of the hairpin folding transformation of thymine-cytosine-rich oligonucleotides induced by Hg(II) and Ag(I) ions. AB - The metal-induced folding of thymine-cytosine-rich oligonucleotides into hairpin like structures was characterised by isothermal titration calorimetry, secondary structure analysis, equilibrium titrations, and fluorescence study. We find that designed thymine-cytosine-rich oligonucleotides can specifically bind with Hg(II) or Ag(I) ions to generate metal-mediated base pairs in a hairpin-like structure from a random coil structure. Isothermal titration calorimetry experiments were performed to reveal the detail of the whole binding process. The thermodynamic result exhibits two possible pathways of significant change upon the addition of Hg(II) ions. Furthermore, this transformation can be enhanced by the presence of Ag(I) ions. The fluorescence decreases through fluorescence resonance energy transfer (FRET) between the fluorophore and quencher confirms the process of formation of the hairpin-like structure. The analysis of optical titration data demonstrates that the saturated binding stoichiometries are 12:1 and 4:1 for Hg(II) and Ag(I) ions, respectively. Our result provides a promising strategy for the investigation of the mechanism of structural transformation of oligonucleotides influenced by metal-mediated base pairs, which may eventually lead to progress in constructing a metal-triggered DNA origami system and metal containing DNA nanotechnology. PMID- 24045986 TI - Structural, morphological, and functional correlates of corneal endothelial toxicity following corneal exposure to sulfur mustard vapor. AB - PURPOSE: Sulfur mustard (SM) is a highly reactive vesicant that causes severe ocular injuries. Following exposure to moderate or high doses, a subset of victims develops a chronic injury known as mustard gas keratopathy (MGK) involving a keratitis of unknown etiopathogenesis with secondary keratopathies such as persistent epithelial lesions, corneal neovascularization, and progressive corneal degeneration. This study was designed to determine whether SM exposure evokes acute endothelial toxicity and to determine whether endothelial pathologies were specifically observed in MGK corneas as opposed to healed corneas. METHODS: Corneas of New Zealand white rabbits were exposed to SM vapor, and the corneal endothelium was evaluated at 1 day and 8 weeks using scanning electron microscopy (SEM), transmission electron microscopy (TEM), in vivo confocal microscopy (IVM), and fluorescent microscopy. Barrier function was measured by uptake of a fluorescent dye injected into the anterior chamber. RESULTS: A centripetal endothelial injury at 1 day was observed by SEM, TEM, IVM, and fluorescent microscopy. In vivo confocal microscopy revealed additional cytotoxicity between 1 and 13 days. In contrast to healed corneas, which appeared similar to sham-exposed naive eyes at 8 weeks, MGK corneas exhibited significant evidence of continued pathological changes in the endothelium. CONCLUSIONS: Endothelial toxicity occurs at the right time and with the appropriate pathophysiology to contribute to MGK. Based on these findings, we propose a model that explains the relationships among SM dose, the biphasic progression, and the various clinical trajectories of corneal SM injury and that provides a mechanism for temporal variations in MGK onset. Finally, we discuss the implications for the management of SM casualties. PMID- 24045987 TI - The age-regulating protein klotho is vital to sustain retinal function. AB - PURPOSE: To determine whether the age-regulating protein klotho was expressed in the retina and determine whether the absence of klotho affected retinal function. METHODS: Immunohistochemistry and qPCR of klotho knockout and wild-type mice were used to detect klotho expression in retina. Immunohistochemistry was used to probe for differences in expression of proteins important in synaptic function, retinal structure, and ionic flux. Electroretinography (ERG) was conducted on animals across lifespan to determine whether decreased klotho expression affects retinal function. RESULTS: Klotho mRNA and protein were detected in the wild-type mouse retina, with protein present in all nuclear layers. Over the short lifespan of the knockout mouse (~8 weeks), no overt photoreceptor cell loss was observed, however, function was progressively impaired. At 3 weeks of age neither protein expression levels (synaptophysin and glutamic acid decarboxylase [GAD67]) nor retinal function were distinguishable from wild-type controls. However, by 7 weeks of age expression of synaptophysin, glial fibrillary acidic protein (GFAP), and transient receptor potential cation channel subfamily member 1 (TRPM1) decreased while GAD67, post synaptic density 95 (PSD95), and wheat germ agglutinin staining, representative of glycoprotein sialic acid residues, were increased relative to wild-type mice. Accompanying these changes, profound functional deficits were observed as both ERG a-wave and b-wave amplitudes compared with wild-type controls. CONCLUSIONS: Klotho is expressed in the retina and is important for healthy retinal function. Although the mechanisms for the observed abnormalities are not known, they are consistent with the accelerating aging phenotype seen in other tissues. PMID- 24045988 TI - The dynamic response of intraocular pressure and ocular pulse amplitude to acute hemodynamic changes in normal and glaucomatous eyes. AB - PURPOSE: To evaluate the effects of acute arterial blood pressure (ABP) and venous pressure changes on IOP in rats with experimental glaucoma. METHODS: Unilateral experimental ocular hypertension was established in Sprague-Dawley rats by weekly intracameral injection of microbeads. Ocular pulse amplitude (OPA) and IOP were recorded from the anterior chamber using 1.2-Fr microsensors under urethane anesthesia. The effects on IOP during hemodynamic challenges using phenylephrine (PE) (50 MUg/kg/min intravenous [IV]) and rapid saline loading (20 mL/kg/min IV) were studied. RESULTS: Over an 8-week period, IOP was significantly elevated by 60% in the unilateral ocular hypertensive eyes. Both ABP and IOP were significantly increased by PE infusion. A significantly greater IOP increase was found in the experimental eyes compared with control eyes (1.32 +/- 0.18 mm Hg vs. 0.90 +/- 0.09 mm Hg). Correspondingly, higher OPAs and an amplification of the OPA during arterial hypertension were found in the experimental eyes. A sustained rise in IOP secondary to IV saline loading was observed, with a greater rise observed among experimental eyes (0.74 +/- 0.13 mm Hg vs. 0.37 +/- 0.005 mm Hg). CONCLUSIONS: Sympathetic acceleration of ABP using PE resulted in surges in IOP and OPA. In contrast, increased venous pressure resulted in a more sustained rise in IOP but to a lesser extent. These responses were more pronounced in eyes with experimental glaucoma compared with control eyes, which may reflect the higher starting IOP contributing to a reduced ocular compliance. Our results suggest that eyes with ocular hypertension are more susceptible to IOP variability induced by hemodynamic fluctuations. PMID- 24045989 TI - GABAergic control of arteriolar diameter in the rat retina. AB - PURPOSE: To investigate the role of gamma-aminobutryic acid (GABA) in the regulation of arteriolar diameter in the rat retina. METHODS: The actions of GABA on arteriolar diameter were examined using ex vivo retinal whole-mount preparations and isolated vessel segments. In most experiments, arterioles were partially preconstricted with endothelin (Et)-1. The expression levels of GABAA and GABAB receptors on isolated rat retinal Muller cells were assessed by immunohistochemistry. RESULTS: GABA (0.1-1 mM) evoked vasodilation or vasoconstriction of arterioles in whole-mount preparations. No such effects were observed with isolated vessel segments. In whole mount samples, the GABAA receptor agonist muscimol caused vasomotor responses in only a small proportion of vessels. In contrast, arteriolar responses to the GABAB receptor agonists baclofen and SKF97541 more closely resembled those observed with GABA. No responses were seen with the GABAC receptor agonist 5-methylimidazoleacetic acid. GABA-induced vasodilator responses were, for the most part, repeatable in the presence of the GABAA receptor antagonist bicuculline. These responses, however, were completely blocked in the presence of the GABAB receptor inhibitor 2 hydroxysaclofen. Strong immunolabeling for both GABAA and GABAB receptors was detected in isolated Muller cells. In the absence of Et-1-induced preconstriction, most vessels were unresponsive to bicuculline or 2 hydroxysaclofen. CONCLUSIONS: GABA exerts complex effects on arteriolar diameter in the rat retina. These actions appear largely dependent upon the activation of GABAB receptors in the retinal neuropile, possibly those located on perivascular Muller cells. Despite these findings, endogenous GABA appears to contribute little to the regulation of basal arteriolar diameter in the rat retina. PMID- 24045990 TI - Functional analysis of HSF4 mutations found in patients with autosomal recessive congenital cataracts. AB - PURPOSE: The goal of this study was to functionally evaluate three previously uncharacterized heat shock factor protein 4 (HSF4) mutations (c.595_599delGGGCC, c.1213C>T, c.1327+4A>G) encoding mutant HSF4 proteins (G199EfsX15, R405X, and M419GfsX29) with missing C-terminal ends. These HSF4 mutations were previously identified in families with congenital autosomal recessive cataracts. METHODS: FLAG-tagged recombinant wild type (WT) and mutant HSF4 proteins were analyzed using the protein stability assay, cellular immunofluorescence, Western blotting, electrophoretic mobility shift assay (EMSA), and reporter activation. RESULTS: HSF4 mutant proteins did not differ in the protein turnover rate when compared with WT HSF4. Immunofluorescence revealed that WT and mutant HSF4 proteins were properly trafficked to the nucleus. EMSA analysis revealed that the G199EfsX15 and M419GfsX29 proteins exhibited decreased heat shock element (HSE)-mediated DNA binding, whereas the R405X mutant exhibited increased HSE-mediated DNA binding when compared with WT HSF4. All three HSF4 mutant proteins exhibited abolished HSE-mediated luciferase reporter activation. Detailed evaluation of the C terminal region identified three novel domains: two activation domains and one repression domain. CONCLUSIONS: The three HSF4 autosomal recessive mutations evaluated here result in a loss of HSF4 function due to a loss of regulatory domains present at the C-terminal end. These findings collectively indicate that the transcriptional activation of HSF4 is mediated by interactions between activator and repressor domains within the C-terminal end. PMID- 24045991 TI - Gene expression signatures in tree shrew sclera in response to three myopiagenic conditions. AB - PURPOSE: We compared gene expression signatures in tree shrew sclera produced by three different visual conditions that all produce ocular elongation and myopia: minus-lens wear, form deprivation, and dark treatment. METHODS: Six groups of tree shrews (n = 7 per group) were used. Starting 24 days after normal eye opening (days of visual experience [DVE]), two minus-lens groups wore a monocular -5 diopter (D) lens for 2 days (ML-2) or 4 days (ML-4); two form-deprivation groups wore a monocular translucent diffuser for 2 days (FD-2) or 4 days (FD-4). A dark-treatment (DK) group was placed in continuous darkness for 11 days after experiencing a light/dark environment until 17 DVE. A normal colony-reared group was examined at 28 DVE. Quantitative PCR was used to measure the relative differences in mRNA levels for 55 candidate genes in the sclera that were selected, either because they showed differential expression changes in previous ML studies or because a whole-transcriptome analysis suggested they would change during myopia development. RESULTS: The treated eyes in all groups responded with a significant myopic shift, indicating that the myopia was actively progressing. In the ML-2 group, 27 genes were significantly downregulated in the treated eyes, relative to control eyes. In the treated eyes of the FD-2 group, 16 of the same genes also were significantly downregulated and one was upregulated. The two gene expression patterns were significantly correlated (r(2) = 0.90, P < 0.001). After 4 days of treatment, 31 genes were significantly downregulated in the treated eyes of the ML-4 group and three were upregulated. Twenty-nine of the same genes (26 down- and 3 up-regulated) and six additional genes (all downregulated) were significantly affected in the FD-4 group. The response patterns were highly correlated (r(2) = 0.95, P < 0.001). When the DK group (mean of right and left eyes) was compared to the control eyes of the ML-4 group, the direction and magnitude of the gene expression patterns were similar to those of the ML-4 (r(2) = 0.82, P < 0.001, excluding PENK). Similar patterns also were found when the treated eyes of the ML-4, FD-4, and DK groups were compared to the age-matched normal eyes. CONCLUSIONS: The very similar gene expression signatures produced in the sclera by the three different myopiagenic visual conditions at different time points suggests that there is a "scleral remodeling signature" in this mammal, closely related to primates. The scleral genes examined did not distinguish between the specific visual stimuli that initiate the signaling cascade that results in axial elongation and myopia. PMID- 24045992 TI - Quantitative analysis of retinal layer optical intensities on three-dimensional optical coherence tomography. AB - PURPOSE: To investigate the optical intensities of all retinal layers on three dimensional (3D) spectral-domain optical coherence tomography (SD-OCT) in normal subjects using an automatic measurement. METHODS: Forty normal subjects underwent Topcon 3D OCT-1000 macula-centered scan. The raw data were automatically segmented into 10 layers using the 3D graph search approach. Then the mean and standard deviation of intensities of each layer were calculated. The image quality index was given by the OCT software. Correlation analysis was performed between the optical intensities in each layer and image quality and subject's age. RESULTS: The correlation of optical intensities was strong from ganglion cell layer (GCL) to outer nuclear layer (ONL) with r > 0.934; moderate among retinal nerve fiber layer (RNFL), photoreceptor, retinal pigment epithelium (RPE), and choroid (0.410 < r < 0.800); and low in the vitreous (0.251 < r < 0.541). The optical intensities were also correlated with the image quality, r > 0.869 from GCL to ONL, 0.748 < r < 0.802 for RNFL, photoreceptor layer, RPE, and the choroid, r = 0.528 for the vitreous. The optical intensity in RNFL was negatively correlated with age (r = -0.365). CONCLUSIONS: Automatic assessment of the layers' intensities was achieved. In normal subjects, the retinal layers' optical intensities were affected by image quality. Normalization with optical intensity of ONL, all areas, or image quality index is recommended. The optical intensity of RNFL decreased with age. PMID- 24045993 TI - Reproducibility of SD-OCT-based ganglion cell-layer thickness in glaucoma using two different segmentation algorithms. AB - PURPOSE: To compare the reproducibility of spectral-domain optical coherence tomography (SD-OCT)-based ganglion cell-layer-plus-inner plexiform-layer (GCL+IPL) thickness measurements for glaucoma patients obtained using both a publicly available and a commercially available algorithm. METHODS: Macula SD-OCT volumes (200 * 200 * 1024 voxels, 6 * 6 * 2 mm(3)) were obtained prospectively from both eyes of patients with open-angle glaucoma or with suspected glaucoma on two separate visits within 4 months. The combined GCL+IPL thickness was computed for each SD-OCT volume within an elliptical annulus centered at the fovea, based on two algorithms: (1) a previously published graph-theoretical layer segmentation approach developed at the University of Iowa, and (2) a ganglion cell analysis module of version 6 of Cirrus software. The mean overall thickness of the elliptical annulus was computed as was the thickness within six sectors. For statistical analyses, eyes with an SD-OCT volume with low signal strength (<6), image acquisition errors, or errors in performing the commercial GCL+IPL analysis in at least one of the repeated acquisitions were excluded. RESULTS: Using 104 eyes (from 56 patients) with repeated measurements, we found the intraclass correlation coefficient for the overall elliptical annular GCL+IPL thickness to be 0.98 (95% confidence interval [CI]: 0.97-0.99) with the Iowa algorithm and 0.95 (95% CI: 0.93-0.97) with the Cirrus algorithm; the intervisit SDs were 1.55 MUm (Iowa) and 2.45 MUm (Cirrus); and the coefficients of variation were 2.2% (Iowa) and 3.5% (Cirrus), P < 0.0001. CONCLUSIONS: SD-OCT-based GCL+IPL thickness measurements in patients with early glaucoma are highly reproducible. PMID- 24045994 TI - Effects of semaphorin 3A on retinal pigment epithelial cell activity. AB - PURPOSE: Semaphorin 3A (Sema3A), a chemorepellant guidance protein, has been shown to be crucial for neural and vascular remodeling. This study is designed to examine the effects of Sema3A on RPE cell activity both in vitro and in vivo. METHODS: Retinal pigment epithelial were incubated with Sema3A, or VEGF- and Sema3A-containing medium. Cell proliferation, migration, cell cycle, apoptosis, cocultured human umbilical vein endothelial cells tube formation, VEGF receptor 2 (VEGFR2) and neuropilin 1 (Nrp1) receptor expression, VEGF- and pigment epithelium-derived factor (PEDF) concentration, and c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (p38MAPK) signaling pathway studies were measured. A rabbit proliferative vitreoretinopathy (PVR) model was used for in vivo study. Subconfluent ARPE19 cells were injected intravitreously with or without Sema3A. Data were analyzed with Graphpad Prism 5.0 software. RESULTS: In vitro, Sema3A not only induced RPE cell cycle arrest and inhibited RPE migration under normal culture conditions, but also inhibited exogenous and endogenous VEGF165-induced cell activities. These activities included proliferation, migration, cell cycle arrest, JNK and p38MAPK signaling pathway phosphorylation, and cocultured endothelial cell tube formation. It is shown that both VEGF165 and Sema3A induced the upregulation of VEGFR2 and Nrp1 receptors. Activity inhibition was mediated by impeding VEGF165 utilization and possibly mediated by competitive inhibition of VEGF165 binding to its receptor VEGFR2, but not by the suppression of VEGF165 secretion. In vivo, Sema3A inhibited PVR, which is induced by RPE proliferation. CONCLUSIONS: These results suggested that Sema3A could be a useful therapeutic strategy for preventing RPE malfunction. PMID- 24045996 TI - Phagocytosis of photoreceptor outer segments by transplanted human neural stem cells as a neuroprotective mechanism in retinal degeneration. AB - PURPOSE: Transplantation of human central nervous system stem cells (HuCNS-SC) into the subretinal space of Royal College of Surgeons (RCS) rats preserves photoreceptors and visual function. To explore possible mechanism(s) of action underlying this neuroprotective effect, we performed a detailed morphologic and ultrastructure analysis of HuCNS-SC transplanted retinas. METHODS: The HuCNS-SC were transplanted into the subretinal space of RCS rats. Histologic examination of the transplanted retinas was performed by light and electron microscopy. Areas of the retina adjacent to HuCNS-SC graft (treated regions) were analyzed and compared to control sections obtained from the same retina, but distant from the transplant site (untreated regions). RESULTS: The HuCNS-SC were detected as a layer of STEM 121 immunopositive cells in the subretinal space. In treated regions, preserved photoreceptor nuclei, as well as inner and outer segments were identified readily. In contrast, classic signs of degeneration were observed in the untreated regions. Interestingly, detailed ultrastructure analysis revealed a striking preservation of the photoreceptor-bipolar-horizontal cell synaptic contacts in the outer plexiform layer (OPL) of treated areas, in stark contrast with untreated areas. Finally, the presence of phagosomes and vesicles exhibiting the lamellar structure of outer segments also was detected within the cytosol of HuCNS-SC, indicating that these cells have phagocytic capacity in vivo. CONCLUSIONS: This study reveals the novel finding that preservation of specialized synaptic contacts between photoreceptors and second order neurons, as well as phagocytosis of photoreceptor outer segments, are potential mechanism(s) of HuCNS-SC transplantation, mediating functional rescue in retinal degeneration. PMID- 24045995 TI - IQCB1 and PDE6B mutations cause similar early onset retinal degenerations in two closely related terrier dog breeds. AB - PURPOSE: To identify the causative mutations in two early-onset canine retinal degenerations, crd1 and crd2, segregating in the American Staffordshire terrier and the Pit Bull Terrier breeds, respectively. METHODS: Retinal morphology of crd1- and crd2-affected dogs was evaluated by light microscopy. DNA was extracted from affected and related unaffected controls. Association analysis was undertaken using the Illumina Canine SNP array and PLINK (crd1 study), or the Affymetrix Version 2 Canine array, the "MAGIC" genotype algorithm, and Fisher's Exact test for association (crd2 study). Positional candidate genes were evaluated for each disease. RESULTS: Structural photoreceptor abnormalities were observed in crd1-affected dogs as young as 11-weeks old. Rod and cone inner segment (IS) and outer segments (OS) were abnormal in size, shape, and number. In crd2-affected dogs, rod and cone IS and OS were abnormal as early as 3 weeks of age, progressing with age to severe loss of the OS, and thinning of the outer nuclear layer (ONL) by 12 weeks of age. Genome-wide association study (GWAS) identified association at the telomeric end of CFA3 in crd1-affected dogs and on CFA33 in crd2-affected dogs. Candidate gene evaluation identified a three bases deletion in exon 21 of PDE6B in crd1-affected dogs, and a cytosine insertion in exon 10 of IQCB1 in crd2-affected dogs. CONCLUSIONS: Identification of the mutations responsible for these two early-onset retinal degenerations provides new large animal models for comparative disease studies and evaluation of potential therapeutic approaches for the homologous human diseases. PMID- 24045997 TI - Effects of L'Aquila earthquake on the prescribing pattern of antidepressant and antipsychotic drugs. AB - BACKGROUND: Natural disasters provoke an increase in mental and medical disorders in survivors. Monitoring drug prescription changes after natural disasters can provide an indirect evaluation of trauma impact in the population. Moreover, it could be useful to both identify risk categories that require special assistance and assess possible drug abuse or misuse. OBJECTIVE: To assess the effects of earthquake that occurred on April 6, 2009 on the use of antidepressant and antipsychotic drugs in the province of L'Aquila. SETTING: General population of L'Aquila and Caserta provinces from Southern Italy. METHOD: In a retrospective, drug utilization study we identified all the persons who received at least one dispensing of antidepressant and/or antipsychotic drugs during the period April 1st, 2008-March 31st, 2010. MAIN OUTCOME MEASURE: The monthly prevalence of use of these drugs, 1 year prior and after the date of earthquake in L'Aquila was compared between the two provinces, L'Aquila and Caserta. All the analyses were stratified by age groups, gender and drug classes. RESULTS: We observed an increase in the use of antipsychotic drugs and, to lesser extent, of antidepressant agents (mostly typicals and tryciclics, respectively) in the first 2 months after the earthquake in L'Aquila but not in Caserta. This increase was almost two-fold higher in women older than 75 years. After the first 2 months from the earthquake, the use of antidepressants and antipsychotics was stabilized at the pre-earthquake levels in L'Aquila. CONCLUSION: The earthquake determined a short-term increase in the use of antipsychotics (mostly haloperidol and promazine) and, to lesser extent, of antidepressants (i.e. tryciclics), especially in older women of L'Aquila. PMID- 24045998 TI - Embolization of direct carotid cavernous fistula with Onyx and coils under transarterial balloon protection. AB - PURPOSE: Endovascular management with good preservation of the internal carotid artery (ICA) has become the first-line choice for the treatment of direct carotid cavernous fistulas (CCFs). Multiple treatments have been tried with variable success. This article elucidates the effectiveness and safety of embolization with Onyx and coils under transarterial balloon protection. MATERIALS AND METHODS: We reviewed 18 cases with direct CCFs in our case library. All cases were treated with transarterial or transvenous embolization with Onyx and coils under intra-arterial balloon protection. RESULTS: Immediate angiography after embolization showed total occlusions in 16 patients and small residual fistulas in 2 patients. Good preservation of the ICA was observed in all cases. The average volume of Onyx was 2.6 ml, and the average length of bare coils was 102.0 cm. Hydrogel-coated coils with an average length of 75.2 were used in five cases. Angiographic follow-ups of 16 patients showed no residual or recurrent fistula within 8 months (average 3.4). For the 2 patients with small residual fistulas, both received short-time angiographic follow-up within 3 month after the procedure. All follow-up angiograms showed no residual or recurrent fistula. Clinical follow-up of the other two recent patients showed no relapsing symptoms. There were no procedure-related complications, and no new symptoms occured in any patient. CONCLUSION: The technique of embolization using Onyx and coils under intra-arterial balloon protection is feasible for the treatment of direct CCFs, especially for patients with large fistula ostium and large cavernous sinus. This technique is an effective and safe option with rare complications. PMID- 24045999 TI - Outcome study of real-time MR-guided cervical periradicular injection therapy in an open 1.0 Tesla MRI system. AB - PURPOSE: To evaluate the accuracy, safety, and efficacy of cervical nerve root injection therapy using magnetic resonance guidance in an open 1.0 T MRI system. METHODS: Between September 2009 and April 2012, a total of 21 patients (9 men, 12 women; mean age 47.1 +/- 11.1 years) underwent MR-guided cervical periradicular injection for cervical radicular pain in an open 1.0 T system. An interactive proton density-weighted turbo spin echo (PDw TSE) sequence was used for real-time guidance of the MR-compatible 20-gauge injection needle. Clinical outcome was evaluated on a verbal numeric rating scale (VNRS) before injection therapy (baseline) and at 1 week and 1, 3, and 6 months during follow-up. RESULTS: All procedures were technically successful and there were no major complications. The mean preinterventional VNRS score was 7.42 and exhibited a statistically significant decrease (P < 0.001) at all follow-up time points: 3.86 +/- 1.53 at 1 week, 3.21 +/- 2.19 at 1 month, 2.58 +/- 2.54 at 3 months, and 2.76 +/- 2.63 at 6 months. At 6 months, 14.3 % of the patients reported complete resolution of radicular pain and 38.1 % each had either significant (4-8 VNRS score points) or mild (1-3 VNRS score points) relief of pain; 9.5 % experienced no pain relief. CONCLUSION: Magnetic resonance fluoroscopy-guided periradicular cervical spine injection is an accurate, safe, and efficacious treatment option for patients with cervical radicular pain. The technique may be a promising alternative to fluoroscopy- or CT-guided injections of the cervical spine, especially in young patients and in patients requiring repeat injections. PMID- 24046000 TI - Signaling between tumor cells and the host bone marrow microenvironment. AB - Tumor cells with high skeletal homing affinity express numerous cell surface receptors that bind ligands produced in bone. Upon arrival, these cells survive in the host environment, encompassed in close proximity to bone marrow cells. Interactions between tumor cells and cells of the host microenvironment are essential to not only tumor cell survival but also their activation and proliferation into environment-modifying tumors. Through the production of RANKL, PTHrP, cytokines, and integrins, activated tumor cells stimulate osteoclastogenesis, enhance bone resorption, and subsequently release matrix bound proteins that further promote tumor growth and bone resorption. In addition, alterations in the TGF-beta/BMP and Wnt signaling pathways via tumor cell growth can either stimulate or suppress osteoblastic bone formation and function, leading to sclerotic or lytic bone disease, respectively. Hence, the presence of tumor cells in bone dysregulates bone remodeling, dramatically impairing skeletal integrity. Furthermore, through complex mechanisms, cells of the immune system interact with tumor cells to further impact bone remodeling. Lastly, with alterations in bone cell activity, the environment is permissive to promoting tumor growth further, suggesting an interdependence between tumor cells and bone cells in metastatic bone disease and multiple myeloma. PMID- 24046002 TI - Clinical management of renovascular hypertension: practical recommendations from the Italian Society of Hypertension (SIIA). AB - Renovascular hypertension (RVH) is one of the most frequent forms of secondary hypertension but this diagnosis is often missed because of insufficient care taken in collecting patient's history and clinical signs. Herein we summarize the clinical, instrumental and laboratory clues which should raise the suspicion of RVH. In addition we briefly discuss the available evidence in favour and against the revascularization therapy and, at the light of the uncertain benefit of this procedure, the alternative approach with pharmacological treatment. PMID- 24046001 TI - Plasma florescent oxidation products and breast cancer risk: repeated measures in the Nurses' Health Study. AB - Reactive oxygen species (ROS), normally generated through biologic processes, may damage DNA, lipids, and proteins. ROS are balanced through enzymatic mechanisms and exogenous antioxidants; imbalance results in oxidative stress. Limited data suggest an association between oxidative stress and breast cancer. We evaluated pre-diagnostic plasma fluorescent oxidation products (FlOP), a global biomarker of oxidative stress, and breast cancer risk in a nested case-control study in the Nurses' Health Study. Participants provided two blood samples (1989-1990 and 2000 2002) (N = 18,743). 377 women developed breast cancer between the second collection and June 1, 2006. Cases were matched to 377 controls. Relative fluorescent intensity at three different excitation/emission wavelengths (FlOP_360, FlOP_320, FlOP_400) were quantified in both samples, providing distant (>=10 years before diagnosis) and proximate (<=6 years before diagnosis) measures of oxidative stress. We observed no association between FlOP and breast cancer risk in proximate or distant samples (e.g., proximate extreme quartiles: FlOP_360, RR 0.8, 95 % CI 0.5-1.3, p trend = 0.49; FlOP_320, RR 1.1, 95 % CI 0.7 1.7, p trend = 0.53; FlOP_400, RR 1.3, 95 % CI 0.8-2.0, p trend = 0.80). In general no association was observed when cross-classifying or averaging proximate and distant exposure (e.g., extreme quartile of averages: FlOP_360, OR 0.9, 95 % CI 0.6-1.4, p trend = 0.82; FlOP_400, OR 0.9, 95 % CI 0.6-1.4, p trend = 0.55), with the exception of a significant trend for average FlOP_320 (extreme quartiles, OR 1.6, 95 % CI 1.0-2.4, p trend = 0.02). We did not observe important associations between FlOP and breast cancer risk in this large prospective study, though our data suggest women with consistently high FlOP_320 may be at increased risk. PMID- 24046004 TI - Observations on the effects of Suppressor of Cytokine Signaling 7 (SOCS7) knockdown in breast cancer cells: their in vitro response to Insulin Like Growth Factor I (IGF-I). AB - PURPOSE: Suppressor of cytokine signaling 7 (SOCS7) is a member of the SOCS family and is known to interact with phospholipase Cgamma-1 (PLCgamma-1), one of the insulin-like growth factor-I (IGF-I) receptor downstream molecules. In this study, we sought to observe the effect of knocking down SOCS7 gene on breast cancer cells in vitro growth and migration and to elucidate whether this involves IGF-I-PLCgamma1 route using the PLCgamma-1 blocker U73122. METHODS: Suitable breast cancer cells (MCF7 and MDA-MB-231) were transfected with anti-SOCS7 ribozymal transgene, to create sub-lines with SOCS7 knockdown verified by RT-PCR. The growth and migration of the cells were evaluated in the presence or absence of IGF-I and PLCgamma-1 inhibitor using growth assay, scratch-wound and electrical cell impedance sensing (ECIS) migration assays. RESULTS: IGF-I treatment produced more pronounced influence on MCF7 growth and migration and on MDA-MB-231 migration when SOCS7 gene was knocked down in both lines (p < 0.05). The absence of IGF-I-induced growth response in MDA-MB-231 could be due to the intrinsic characteristics of these cells. PLCgamma-1 pharmacological inhibition during their in vitro migration seemed to only occur when SOCS7 gene was knocked down. CONCLUSIONS: To the best of our knowledge, this is the first report of the SOCS7 regulatory role in IGF-I induced in vitro functions in ER-positive and ER negative breast cancer cells. IGF-I treatment and SOCS7 loss have synergistically resulted in increased growth and migration of MCF7 and in increased migration of MDA-MB-231 cells. The migratory effects could be due to a precise anti-PLCgamma-1 role. PMID- 24046005 TI - [Professional absenteeism in the pediatric service of the general hospital of Loandjili in Pointe-Noire (Congo)]. AB - The supply and the quality of care dispensed in a service depend on the quality of the technical and human tray, but also from effective presence of the staff during the work time. The purpose of this study is to determine the absenteeism level of the paramedical staff in General Pediatric and Neonatology of Loandjili General Hospital (Pointe Noire) and identifying causes. A cross-sectional study has been conducted from January 1(st) to June 30(th) 2011 on 21 nurses in General Pediatric and 20 in Neonatology. The absenteeism level was obtained by the link of the number of missing days out of the number of the work days x 100. The absence was justified when it relieved from a reason informed by the administrative texts of the firm; and authorized when it requested the authorization of the administration of the firm. In total, 370 absences have been unregistered, the average absenteeism level was of 8.4%. The absence was justified in 242 cases (65.4%) and authorized in 178 cases (48.1%) which 84 times in writing and 94 times verbally. When the absence was justified, it was the fact of the disease of a member of the family in 82 cases, of the death or the burial of a member of the family in 81 cases, of the agent disease, 84 cases, or other reasons in the remains of cases. The absence occurred between 7 a.m. and 14 p.m. in 57.3%, 14 p.m. and 7 p.m.in, 25.7% and between 7 p.m. and 7 a.m. in 17.0%. The absenteeism was mainly observed (85.7%) for the nurses of about 30 years old and those (59.5%) whom the seniority in the service was inferior or equal 5 years. The absences justified were more observed (p< 10(-4)) for nurses of about 30 years old and those whom the seniority did not pass 5 years. The absenteeism of nurses constitutes a real social and administrative problem that deserves a particular attention considering its impact on the supply and the quality of cares. PMID- 24046007 TI - Letter by Aries et al regarding article, "Systolic blood pressure after intravenous antihypertensive treatment and clinical outcomes in hyperacute intracerebral hemorrhage: the Stroke Acute Management with Urgent Risk-Factor Assessment and Improvement-Intracerebral Hemorrhage Study". PMID- 24046006 TI - Does socioeconomic status or acculturation modify the association between ethnicity and hypertension treatment before stroke? AB - BACKGROUND AND PURPOSE: Socioeconomic status and acculturation may modify the association between ethnicity and hypertension treatment before stroke. We assessed prestroke treatment of hypertension by ethnicity, education (proxy for socioeconomic status), and English proficiency (EP; proxy for acculturation) in a population-based stroke surveillance project. METHODS: Among 763 patients with first-ever stroke aged >=45 years in the Brain Attack Surveillance in Corpus Christi project from 2000 to 2006, we examined self-reported hypertension treatment at the time of the stroke by ethnicity (Mexican American [MA] versus non-Hispanic white [NHW]) in the overall sample, within education strata (high school), and after dichotomizing MAs by self-reported EP (limited versus proficient). Logistic regression adjusted associations for age, sex, education, diabetes mellitus, coronary artery disease, hypercholesterolemia, and health insurance. RESULTS: NHWs and MAs reported similar hypertension treatment (84% versus 86%; P=0.53). Hypertension treatment was 84% for NHWs and 90% for MAs (P=0.18) in high school stratum (ethnicity-by-education interaction, P=0.09). Hypertension treatment was 83% for NHWs, 87% for MAs with EP (PvsNHWs=0.35), and 90% for MAs with limited EP (PvsNHWs=0.13; ethnicity-by-EP interaction, P=0.22). Hypertension treatment was lower in uninsured patients (adjusted odds ratio, 0.13; 95% confidence interval, 0.03-0.60) or those with no physician visit <=6 months (adjusted odds ratio, 0.09; 95% confidence interval, 0.03-0.24). CONCLUSIONS: We found no evidence that socioeconomic status or acculturation modifies the association between ethnicity and hypertension treatment before stroke. PMID- 24046008 TI - Carotid wars episode VI: Return of the standard. PMID- 24046009 TI - Response to letter regarding article, "Systolic blood pressure after intravenous antihypertensive treatment and clinical outcomes in hyperacute intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment and improvement-intracerebral hemorrhage study". PMID- 24046010 TI - Aggressive medical therapy alone is not adequate in certain patients with severe symptomatic carotid stenosis. PMID- 24046011 TI - Fog on the crystal ball? Missing atrial fibrillation in forecasting the future of stroke. PMID- 24046012 TI - Effector T cells require fatty acid metabolism during murine graft-versus-host disease. AB - Activated T cells require increased energy to proliferate and mediate effector functions, but the metabolic changes that occur in T cells following stimulation in vivo are poorly understood, particularly in the context of inflammation. We have previously shown that T cells activated during graft-versus-host disease (GVHD) primarily rely on oxidative phosphorylation to synthesize adenosine 5' triphosphate. Here, we demonstrate that alloreactive effector T cells (Teff) use fatty acids (FAs) as a fuel source to support their in vivo activation. Alloreactive T cells increased FA transport, elevated levels of FA oxidation enzymes, up-regulated transcriptional coactivators to drive oxidative metabolism, and increased their rates of FA oxidation. Importantly, increases in FA transport and up-regulation of FA oxidation machinery occurred specifically in T cells during GVHD and were not seen in Teff following acute activation. Pharmacological blockade of FA oxidation decreased the survival of alloreactive T cells but did not influence the survival of T cells during normal immune reconstitution. These studies suggest that pathways controlling FA metabolism might serve as therapeutic targets to treat GVHD and other T-cell-mediated immune diseases. PMID- 24046013 TI - High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis. AB - To validate current donor selection strategies based on previous international studies, we retrospectively analyzed 2646 transplantations performed for hematologic malignancies in 28 German transplant centers. Donors and recipients were high resolution typed for HLA-A, -B, -C, -DRB1, and -DQB1. The highest mortality in overall survival analysis was seen for HLA-A, -B, and DRB1 mismatches. HLA-DQB1 mismatched cases showed a trend toward higher mortality, mostly due to HLA-DQB1 antigen disparities. HLA incompatibilities at >1 locus showed additive detrimental effects. HLA mismatching had no significant effect on relapse incidence and primary graft failure. Graft source had no impact on survival end points, neither in univariate nor in multivariate analysis. Higher patient age, advanced disease, transplantations before 2004, patient C2C2 killer cell immunoglobulin-like receptor (KIR)-ligand phenotype, and unavailability of a national donor adversely influenced outcomes in multivariate analysis. Our study confirms the association of HLA-A, -B, -C, and -DRB1 incompatibilities with adverse outcome in hematopoietic stem cell transplantation (HSCT). The relevance of HLA-DQB1 disparities in single mismatched transplantations remains unclear. Similar hazard ratios for allele and antigen mismatches (possibly with an exception for HLA-DQB1) highlight the importance of allele level typing and matching in HSCT. The number of incompatibilities and their type significantly impact survival. PMID- 24046014 TI - Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia. AB - FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcomes. Although initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3 ITD-positive patients, subsequent relapse often occurs upon acquisition of secondary FLT3 kinase domain (KD) mutations, primarily at residues D835 and F691. Using biochemical assays, we determined that crenolanib, a novel TKI, demonstrates type I properties and is active against FLT3 containing ITD and/or D835- or F691-activating mutations. Potent activity was observed in FLT3-ITD positive AML cell lines. Crenolanib delayed the outgrowth of MV4-11 cells in a xenograft mouse model, whereas in combination with the type II TKI sorafenib, a significant decrease in leukemic burden (P < .001) and prolonged survival (P < .01) was observed compared with either type I or II TKI alone. Crenolanib was active against Ba/F3 cells harboring FLT3-ITD and secondary KD mutations and sorafenib-resistant MOLM-13 cells containing FLT3-ITD/D835Y both in vitro and in vivo. In addition, crenolanib inhibited drug-resistant AML primary blasts with FLT3-ITD and D835H/Y mutations. These preclinical data demonstrate that crenolanib is effective against FLT3-ITD containing secondary KD mutations, suggesting that crenolanib may be a useful therapeutic agent for TKI-naive and drug-resistant FLT3-ITD-positive AML. PMID- 24046017 TI - Long-term results of external auditory canal closure and mastoid obliteration in cochlear implantation after radical mastoidectomy: a clinical and radiological study. AB - Cochlear implant candidates with mastoid cavity present a significant challenge to safe cochlear implantation because of possible spread of infection to the inner ear as well as an increased risk of electrode array extrusion. Closure of the external auditory canal is one of the several surgical techniques utilized to block the potential entry routes for infection and to protect the implanted device. The main concern after external auditory canal closure is the risk of developing a cholesteatoma, which can lead to an asymptomatic erosion of the temporal bone and/or cochlear implant failure. In this study we present the results of very long-term (mean 12 years) clinical and radiological follow-up in 12 patients who underwent external auditory canal closure associated with mastoid and Eustachian tube obliteration to facilitate cochlear implantation. To date, with a mean +/- SD follow-up of 12 +/- 4.7 years (range 5-21 years), the only complication experienced was the breakdown of the EAC closure in one patient, successfully treated by performing a rotation skin flap. The results of this study confirmed that external auditory canal closure is a reliable technique in cochlear implantation after radical mastoidectomy provided that a rigorous surgical technique is performed. A right balance between the need to reduce costs and to avoid unnecessary doses of radiation to patients and the task of a radiological surveillance may be represented by performing computed tomography 12 18 months postoperatively and then, only if clinically warranted. PMID- 24046015 TI - FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1beta in macrophages. AB - Hematopoietic stem and progenitor cells with inactivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cytokines. One of these, tumor necrosis factor alpha (TNF-alpha), is also overproduced by FA mononuclear phagocytes in response to certain Toll-like receptor (TLR) agonists, creating an autoinhibitory loop that may contribute to the pathogenesis of progressive bone marrow (BM) failure and selection of TNF-alpha-resistant leukemic stem cell clones. In macrophages, the TNF-alpha overproduction phenotype depends on p38 mitogen-activated protein kinase (MAPK), an enzyme also known to induce expression of other inflammatory cytokines, including interleukin 1beta (IL-1beta). Reasoning that IL-1beta might be involved in a like autoinhibitory loop, we determined that (1) TLR activation of FANCA- and FANCC-deficient macrophages induced overproduction of both TNF-alpha and IL-1beta in a p38 dependent manner; (2) exposure of Fancc-deficient BM progenitors to IL-1beta potently suppressed the expansion of multipotent progenitor cells in vitro; and (3) although TNF-alpha overexpression in FA cells is controlled posttranscriptionally by the p38 substrate MAPKAPK-2, p38-dependent overproduction of IL-1beta is controlled transcriptionally. We suggest that multiple inflammatory cytokines overproduced by FANCA- and FANCC-deficient mononuclear phagocytes may contribute to the progressive BM failure that characterizes FA, and that to achieve suppression of this proinflammatory state, p38 is a more promising molecular therapeutic target than either IL-1beta or TNF alpha alone. PMID- 24046022 TI - On the polyphasic quenching kinetics of chlorophyll a fluorescence in algae after light pulses of variable length. AB - This study reports on kinetics of the fluorescence decay in a suspension of the alga Scenedesmus quadricauda after actinic illumination. These are monitored as the variable fluorescence signal in the dark following light pulses of variable intensity and duration. The decay reflects the restoration of chlorophyll fluorescence quenching of the photosystem II (PSII) antennas and shows a polyphasic pattern which suggests the involvement of different processes. The overall quenching curve after a fluorescence-saturating pulse (SP) of 250-ms duration, commonly used in pulse amplitude modulation applications as the tool for estimating the maximal fluorescence (F m), has been termed P-O, in which P and O have the same meaning as used in the OJIP induction curve in the light. Deconvolution of this signal shows at least three distinguishable exponential phases with reciprocal rate constants of the order of 10, 10(2), and 10(3) ms. The size of the long (>10(3) ms) and moderate (~10(2) ms) lasting components relative to the complete quenching signal after an SP increases with the duration of the actinic pulse concomitantly with an increase in the reciprocal rate constants of the fast (~10 ms) and moderate quenching phases. Fluorescence responses upon single turnover flashes of 30-MUs duration (STFs) given at discrete times during the P-O quenching were used as tools for identifying the quencher involved in the P-O quenching phase preceding the STF excitation. Results are difficult to interpret in terms of a single-hit two-state trapping mechanism with distinguishable quenching properties of open and closed reaction centers only. They give support for an earlier hypothesis on a double-hit three state trapping mechanism in which the so-called semi-closed reaction centers of PSII are considered. In these trapping-competent centers the single reduced acceptor pair [PheQ A](1-), depending on the size of photoelectrochemically induced pH effects on the Q B-binding site, functions as an efficient fluorescence quencher. PMID- 24046023 TI - The impact of semen quality, occupational exposure to environmental factors and lifestyle on recurrent pregnancy loss. AB - PURPOSE: This study aimed to investigate the effect of male semen quality, occupational exposure, and lifestyle on recurrent pregnancy loss (RPL). METHODS: Information on couples' occupational exposure and lifestyle was collected using a detailed questionnaire from 68 RPL couples and 63 randomly selected healthy controls. Semen parameters were estimated by computer-assisted sperm analysis, and sperm nuclear status was detected with aniline blue (AB) staining. RESULTS: Patients in the RPL group had significantly lower viability, normal morphology, and total progressive motility of sperm, and a higher mean percentage of AB staining positive sperm compared with those of controls (P < 0.05). There were no differences in sperm concentration, and motility between the groups (P > 0.05). Significant odds ratio (OR) was found when occupational exposure and unhealthy habits were superimposed (OR: 11.965, P = 0.005). CONCLUSIONS: In addition to standard female factors for evaluating the risk for RPL, the use of male factors should also be taken into consideration. We found that sperm quality, occupational exposure, and lifestyle are factors that affect RPL. Consequently, occupational exposure and lifestyle factors should constitute an important section of questionnaires given to patients, and these factors should be evaluated by a clinician or trained staff. PMID- 24046024 TI - A brief history of the development of the KSOM family of media. PMID- 24046025 TI - A novel clade of unique eukaryotic ribonucleotide reductase R2 subunits is exclusive to apicomplexan parasites. AB - Apicomplexa are protist parasites of tremendous medical and economic importance, causing millions of deaths and billions of dollars in losses each year. Apicomplexan-related diseases may be controlled via inhibition of essential enzymes. Ribonucleotide reductase (RNR) provides the only de novo means of synthesizing deoxyribonucleotides, essential precursors for DNA replication and repair. RNR has long been the target of antibacterial and antiviral therapeutics. However, targeting this ubiquitous protein in eukaryotic pathogens may be problematic unless these proteins differ significantly from that of their respective host. The typical eukaryotic RNR enzymes belong to class Ia, and the holoenzyme consists minimally of two R1 and two R2 subunits (alpha2beta2). We generated a comparative, annotated, structure-based, multiple-sequence alignment of R2 subunits, identified a clade of R2 subunits unique to Apicomplexa, and determined its phylogenetic position. Our analyses revealed that the apicomplexan specific sequences share characteristics with both class I R2 and R2lox proteins. The putative radical-harboring residue, essential for the reduction reaction by class Ia R2-containing holoenzymes, was not conserved within this group. Phylogenetic analyses suggest that class Ia subunits are not monophyletic and consistently placed the apicomplexan-specific clade sister to the remaining class Ia eukaryote R2 subunits. Our research suggests that the novel apicomplexan R2 subunit may be a promising candidate for chemotherapeutic-induced inhibition as it differs greatly from known eukaryotic host RNRs and may be specifically targeted. PMID- 24046026 TI - The effect of iterative reconstruction on quantitative computed tomography assessment of coronary plaque composition. AB - To compare coronary plaque size and composition as well as degree of coronary artery stenosis on coronary Computed Tomography angiography (CCTA) using three levels of iterative reconstruction (IR) with standard filtered back projection (FBP). In 63 consecutive patients with a clinical indication for CCTA 55 coronary plaques were analysed. Raw data were reconstructed using standard FBP and levels 2, 4 and 6 of a commercially available IR algorithm (iDose(4)). CT attenuation and noise were measured in the aorta and two coronary arteries. Both signal-to noise-ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. The amount of lipid, fibrous and calcified plaque components and mean cross-sectional luminal area were analysed using dedicated software. Image noise was reduced by 41.6% (p < 0.0001) and SNR and CNR in the aorta were improved by 73.4% (p < 0.0001) and 72.9% (p < 0.0001) at IR level 6, respectively. IR improved objective image quality measures more in the aorta than in the coronary arteries. Furthermore, IR had no significant effect on measurements of plaque volume and cross-sectional luminal area. The application of IR significantly improves objective image quality, and does not alter quantitative analysis of coronary plaque volume, composition and luminal area. PMID- 24046027 TI - NSAIDs and opioids in management of fragility fractures. AB - Fragility fractures and their care are a major burden on individuals, health systems, and social care systems in industrialized countries. Fragility fracture can lead to long lasting painful and disabling condition. The level of pain is a major determinant for the outcome of any treatment of these fractures regardless of its location. The treatment of pain in patient with fragility fracture is rarely considered a priority in the care pathway. PMID- 24046028 TI - Mechanobiology of bone. AB - Bone is a tissue that dynamically adapts mass and architecture to the mechanical loads that occur in daily life in a world with gravity. Bone architecture and mass are influenced by the applied tension peak, whereas the bone formation rate is modulated by the stimulus frequency. In bone tissue, osteocytes govern the detection of mechanical afferents and their transformation into biochemical messages, therefore these cells can be considered a mechanosensor that directs osteogenesis to where it is most needed to increase bone strength. The stimulation of osteocytes occurs with several modalities: shear stress and stretch, extracellular pressure modifications, strains, variations of electric field in and around osteocytes lacunae. The osteocyte network, under physiological conditions, activates osteoclastogenesis and suppresses osteoblast function enhancing bone resorption and inhibiting bone formation. In the unloaded condition, the functions of the osteocyte network are augmented, whereas exercise could decrease inhibitory effects on bone mass by reducing both osteoclastogenesis and inhibition on osteoblast function. PMID- 24046029 TI - Sarcopenia in women with vertebral fragility fractures. AB - We performed a pilot study with the purpose to evaluate the prevalence of sarcopenia in osteoporotic women with vertebral fractures. Dual-energy X-ray absorptiometry (DXA) was used to measure the whole and regional body composition. Appendicular lean mass (aLM) was calculated as the sum of lean mass in arms and legs. We calculated the skeletal muscle mass index (aLM/h(2)), and we measured bone mineral density and T scores by DXA scan at total-body and at femoral neck. Participants were divided according to the number of vertebral fractures (single or multiple fractures). A total of 67 women were included. Thirty-five women (52.23%) had a vertebral fracture, of them 8 (22.85%) were sarcopenic and 32 women (47.76%) had multiple vertebral fractures, of them 14 (43.75%) were sarcopenic. Our results suggest that sarcopenia is common among osteoporotic women increasing along with the number of vertebral fragility fractures. PMID- 24046030 TI - Osseointegration in the elderly. AB - Osseointegration is a term that refers to the formation of a direct interface between an implant and bone without intervening soft tissue. Cementless femoral fixation in total hip arthroplasty is dependent on mechanical and biological factors that affect implant stability and long-term outcome. Osteoporosis leads to morphological and biological alterations in the proximal femur that adversely affect both mechanical stability of implant and biological response of bone, making it more challenging to achieve a valid osseointegration. PMID- 24046031 TI - Osteosynthesis and hip replacement in proximal femur fractures. AB - Proximal femur fractures are common in elderly osteoporotic patients. The consequences of hip fractures in elderly individuals are significant in terms of years of life lost and reduction of the quality of life. The goal of the treatment is to return the patients to their pre-fracture level of quality of life and avoid complications during the surgery. To achieve this goal, surgery is usually required for the vast majority of hip fracture patients. The proximal femur fractures are classified into medial and lateral fractures; usually the former fractures are treated with hip replacement and the latter are treated with osteosynthesis. The best way to treat this type of injury is mandatory and requires an accurate pre-operative classification of the lesion, considering also the comorbidity associated with the hip fractures. PMID- 24046032 TI - Stress fractures in the elderly: different pathogenetic features compared with young patients. AB - Stress fractures mainly occur in the lower limb as a result of cyclic submaximal stresses. Most commonly affected by this specific type of fractures are young athletes, military or elderly subjects with metabolic bone diseases like osteoporosis. In consideration of the heterogeneity of affected patients is presumable that there are different pathogenic mechanisms. In young person bone tissue, although metabolically intact, is not able to withstand the stresses to which it is chronically subjected, also because of muscle fatigue. This leads to a macrostructural failure and to the development of "fatigue" fractures. Instead, in elderly patients, there are numerous physiological conditions that determine a bone metabolism alteration. This is the main reason for the structural changes in trabecular and cortical bone, which is reflected in reduced biomechanical strength. In addition, muscular situation, such as muscle fiber atrophy, is unable to correctly support bone tissue, leading to the development of insufficiency fractures. PMID- 24046033 TI - Vitamin D: role and opportunity to prescribe. AB - The major role of vitamin D in humans is to increase the absorption of calcium and phosphatase for the mineralization of the skeleton. The synthesis of vitamin D3 in the skin under influence of UV light decreases with aging due to insufficient sunlight exposure, and a decreased functional capacity of the skin. Deficiency in vitamin D causes secondary hyperparathyroidism, high bone turnover, bone loss, mineralization defects, proximal myopathy, falls and hip and other fractures. The goal of therapy of hypovitaminosis D is to restore normal serum and deposits of 25 (OH) D. The daily supplementation of vitamin D indicated is about 800-1,000 IU/day but may increase up to a maximum dose of 2,000 IU/day in conditions of severe vitamin D deficiency with a concomitant reduced or no sun exposure, reduced dietary intake and reduced calcium absorption. PMID- 24046035 TI - Rehabilitative approach in patients with vertebral fragility fracture. AB - Osteoporosis is a skeleton disease characterized by low bone mineral density and deterioration of bone tissue, resulting in an increased risk of fragility fracture. Osteoporotic vertebral fractures are recognized as a significant health problem particularly in older people with an impact on the quality of life, mobility and mortality. A well-timed diagnosis and treatment is necessary in preventing further vertebral fracture and their consequences. Exercise alone or as part of physical therapy management is often recommended as a non pharmacological intervention. The exercise protocols, designed specifically for individuals with vertebral fracture, should include postural correction, trunk and lower extremity muscle strengthening, balance exercises and falls prevention program. The aim of this short communication is to examine the rationale of a rehabilitation protocol after a vertebral fracture. PMID- 24046034 TI - Total hip arthroplasty revision in elderly patients. AB - In the last years, the number of total hip arthroplasty is increased both in young patients and elderly with a poor bone quality due to extension of surgical indications. According to this trend, also revision surgery showed a growth of its number, especially in elderly patients, because of implant loosening, failed osseointegration of prosthetic components, errors in biomechanical restoration and infections. The aim of this study is to analyze life quality improvement through evaluation of articular functionality and postoperative pain, and to examine osseointegration of implant components with periprosthetic bone. During total hip arthroplasty revision, the orthopedic surgeon often has to face complex cases, especially in elderly patients with a preexisting status of poor bone quality and sarcopenia. In these cases, a correct planning and a surgical procedure well-executed are able to ensure a good outcome that led to pain relief and functional recovery. Furthermore anti-osteoporotic therapy surely represents a useful resource both in primary total hip arthroplasty and in revisions, mainly for elderly patients with a poor bone quality. PMID- 24046036 TI - Characteristics and circumstances of falls in hip fractures. AB - Osteoporosis is a chronic disease characterized by a loss of bone mass and deterioration of bone microstructure that lead to a greater risk of fragility fractures. Fall is generally the main cause of fractures. Hip fractures are the most common ones and are usually correlated to a greater morbidity and mortality. The aim of our observational study was to evaluate, among patients with hip fragility fracture, characteristics and circumstances of falls. We conducted a national epidemiological survey, involving 80 physiatrists. They were asked to collect data on patients over 55 years of age who underwent a fragility fracture in the 12 months prior to recruitment. For each patient they had to fill a form including questions on different aspects of patients' medical history: age, gender, reason for the visit, type of fracture, number of falls in the last year and the year before the fall. Among 419 patients who sustained hip fracture, 70 had experienced a fall, while 119 were incurred in more falls in the 12 months before the fracture. In most people of our cohort, hip fracture was caused by a fall that occurred on the side during the morning. PMID- 24046038 TI - Osteoporosis drugs in real-world clinical practice: an analysis of persistence. AB - The aim of our retrospective cohort study is to analyze the persistence rates in relation to antiosteoporotic drugs using administrative databases in the Campania Region. Patients, aged >=40 years, were included if at least one prescription for any antiosteoporotic drugs had been filled in between January 1, 2009 and December 31, 2009. Overall, 37,594 patients were incident users of antiosteoporotic drugs. Among them, 15,978 patients had undergone spot-therapies. A total of 2,618 (14.1%) were classified as switchers. Switching rates were highest for patients taking Alendronate 18.9 or Strontium Ranelate 15.0 and lower for patients taking Ibandronate 12.8 or Risedronate 10.8. In the overall population, 33.5% of subjects were still on therapy after 6 months. At 1 year, persistence rates were: Ibandronate 21.6%, Risedronate 15.8%, Alendronate + Vitamin D 15.7%, Raloxifene 14.3%, Alendronate 12.6% and Strontium Ranelate 5.0%. PMID- 24046039 TI - "Osteoporotic fragility fractures: medical and surgical approaches" II National Congress of the Italian Orthopedic Group for the Study of Severe Osteoporosis (GISOOS). PMID- 24046037 TI - Update on the role of melatonin in the prevention of cancer tumorigenesis and in the management of cancer correlates, such as sleep-wake and mood disturbances: review and remarks. AB - The aim of this article was to perform a systematic review on the role of melatonin in the prevention of cancer tumorigenesis--in vivo and in vitro--as well as in the management of cancer correlates, such as sleep-wake and mood disturbances. The International Agency for Research on Cancer recently classified "shift-work that involves circadian disruption" as "probably carcinogenic to humans" (Group 2A) based on "limited evidence in humans for the carcinogenicity of shift-work that involves night-work", and "sufficient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)". The clinical implications and the potential uses of melatonin in terms of biologic clock influence (e.g. sleep and mood), immune function, cancer initiation and growth, as well as the correlation between melatonin levels and cancer risk, are hereinafter recorded and summarized. Additionally, this paper includes a description of the newly discovered effects that melatonin has on the management of sleep-wake and mood disturbances as well as with regard to cancer patients' life quality. In cancer patients depression and insomnia are frequent and serious comorbid conditions which definitely require a special attention. The data presented in this review encourage the performance of new clinical trials to investigate the possible use of melatonin in cancer patients suffering from sleep wake and mood disturbances, also considering that melatonin registered a low toxicity in cancer patients. PMID- 24046040 TI - The incidence of fragility fractures in Italy. AB - Osteoporosis can significantly impact on the risk of developing a fracture. Thus, fragility fractures represent a challenge for health professionals and decision makers of the twenty-first century. The aim of this work is to review the literature concerning osteoporotic fractures in Italy in terms of incidence, rate of hospitalization, relative risk of a new fragility fracture, and costs for the national health system. It was estimated that the costs of treating proximal femur fragility fractures in 2002 summed up to 1 billion Euros. The number of fragility fractures in Italy was calculated as follows: 91.494 hip fractures, 61.009 clinical vertebral fractures, 57.401 humeral fragility fractures, and 94.045 forearm/wrist fragility fractures. The incidence of fragility fractures in Italy is very high, and osteoporosis is the leading cause of morbidity in the Italian population. PMID- 24046041 TI - The vertebral biomechanic previous and after kyphoplasty. AB - The biomechanical understanding of increasing anterior column load with progressing kyphosis leading to subsequent vertebral compression fracture (VCF) established the basic rationale for kyphoplasty. The lumbar spine can support an effort of 500 kg in the axis of the vertebral body, and a bending moment of 20 Nm in flexion. Consequently, if this effort is forward deviated of only 10 cm, the acceptable effort will be reduced to 20 kg so it is important to restore the vertebral anterior wall after a VCF: the authors describe the biomechanical modifications in the spine after kyphoplasty. PMID- 24046042 TI - Bone mineral density evaluation in osteoporosis: why yes and why not? AB - Osteoporosis is a diffuse skeletal disease in which a decrease in bone strength leads to an increased risk of fractures. A wide variety of types of bone densitometry measurements are available, including quantitative computed tomography measurements of the spine, quantitative ultrasound devices for measurements of the heel and other peripheral sites and dual-energy X-ray absorptiometry (DXA) for measurement of bone mineral density (BMD) at the lumbar spine, proximal femur, forearm and total body scans. Compared with alternative bone densitometry techniques, hip and spine DXA examinations have a number of advantages that include a consensus that BMD results can be interpreted using the World Health Organization T score definition of osteoporosis, a proven ability to predict fracture risk, proven effectiveness at targeting anti-fracture therapies, and the ability to monitor response to treatment. However, in recent years, the authors have raised some important questions about the objective limits of this method that have led to doubts about its effectiveness in terms of clinical outcome. PMID- 24046043 TI - Surgical versus conservative treatment of distal radius fractures in elderly. AB - The distal radius fractures (DRFs) are the second most common fracture in the elderly population. Despite their frequency, the optimal treatment of these fractures remains controversial. Several dogmatic myths on DRFs management may adversely affect their outcome and despite a strong trend versus surgical options, systematic reviews suggest that conservative treatment remains the safest option for DRFs in most cases. PMID- 24046044 TI - Ankle fractures in elderly patients. AB - The incidence of ankle fractures (AFs) in the elderly is rising due to the increase in life expectancy. Rather than directly related to osteoporosis, AFs are a predictor of osteoporotic fractures in other sites. In women AFs are associated with weight and BMI. AFs are difficult to categorize; therapeutic options are non-operative treatment with plaster casts or surgical treatment with Kirschner's wires, plates and screws. The choice of treatment should be based not only on the fracture type but also on the local and general comorbidity of the patient. Considering the new evidence that postmenopausal women with AFs have disrupted microarchitecture and decreased stiffness of the bone compared with women with no fracture history, in our opinion low-trauma AFs should be considered in a similar way to the other classical osteoporotic fractures. PMID- 24046045 TI - Proximal humeral fractures in elderly patients. AB - Proximal humeral fractures are common in the setting of osteoporosis and they represent a problem not only for increased mortality risk factors, but also in terms of costs and management. Their increased incidence has resulted in an evolution of treatment options, but currently there is no scientific evidence that defines the best treatment to choose. The choice of treatment depends on a variety of factors, such as fracture dislocation, fracture classification, bone quality, patient's age, functional requirements and general medical conditions. The debate about the treatment is still open, both for the decision between surgical and conservative treatment, and between different types of surgical techniques; nowadays it remains unclear whether surgery will produce better outcomes in function and quality of life in elderly osteoporotic patients. PMID- 24046046 TI - Current options to surgical treatment in osteoporotic fractures. AB - Treatment of osteoporotic fractures leads to significant challenges for the surgeon, including poor implant fixation related to low bone quality and compromised capacity of fracture healing. This article reviews the osteosynthesis and arthroplasty results in the surgical treatment of proximal femur, proximal humerus and wrist fractures to define the current options to decrease failure in fragility fracture management. PMID- 24046047 TI - A new antiresorptive approach to the treatment of fragility fractures: long-term efficacy and safety of denosumab. AB - An imbalance of the remodeling process for bone resorption leads to a loss of tissue with consequent microarchitectural damage, evident in conditions such as osteoporosis and related fragility fractures. Currently, pharmacological therapies are able to prevent or slow down bone resorption by inhibiting osteoclast activity. An innovative and targeted anti-resorptive approach is represented by the inhibition of RANK ligand (RANK-L), essential for the proliferation and activity of osteoclastic cells. The human monoclonal antibody against RANK-L (denosumab) has been approved for the treatment of osteoporosis. In clinical trials of patients with osteoporosis, inhibition of RANK-L has reduced bone loss and damage to the microarchitecture and was associated with an increase in mass and resistance at different skeletal sites, with most significant effects than those demonstrated by any other antiresorptive drugs. In addition, after 3 years of treatment, it showed a reduction in vertebral and non vertebral fracture risk. Denosumab treatment also has not revealed any alteration in the physiological processes of fracture repair, showing no increase in the onset of complications 3 years after the fracture. The data show that denosumab offers an effective alternative therapeutic approach for the treatment of severe osteoporosis, with positive effects on BMD and reduction of fragility fractures risk. So, promising results in terms of therapeutic efficacy and reliability make desirable the wide clinical use of denosumab for the treatment of osteoporotic fractures in the near future. PMID- 24046048 TI - The clinical significance of wrist fracture in osteoporosis. AB - Wrist fracture is the most common fragility fracture in perimenopausal and young postmenopausal women in USA and Northern Europe. Recent studies based on high resolution imaging have shown microarchitectural deterioration of trabecular bone even in premenopausal women presenting with a wrist fracture. These fractures increase the risk of subsequent fractures, especially in the first 7 years. So, wrist fracture female patients must be appropriately screened and treated for osteoporosis in order to preserve bone quality and prevent future, more severe, fractures. PMID- 24046049 TI - Considerations on evolution and healing of vertebral fractures. AB - Only little is known when talking about the evolution of a vertebral fracture. From the few studies available in the literature, we can deduce that the risk a vertebral compression fracture has to worsen its deformity is consistent. It is important to try to make a prognosis on how the fracture is going to heal based on the type of fracture encountered. A chapter of its own is the occurrence of a vertebral fracture non-union that is difficult to diagnose and treat, but comes along with a poor prognosis. PMID- 24046050 TI - Effects of denosumab on cortical and trabecular microarchitecture: evidences from clinical studies. AB - Excess of bone remodeling is still the major pathogenic factor in involutional osteoporosis. This phenomenon is linked to an imbalance between neoformation (by osteoblasts) and resorption (by osteoclasts). Recently, research in drug development is focused on new and more "physiological" approach to balance bone remodeling. The efficacy of denosumab was proved in the prevention of vertebral and non-vertebral fractures and related to the ability of the drug to penetrate in cortical and trabecular bone. Recently, data from several clinical studies confirm that denosumab improves fracture outcomes, also at skeletal sites rich in cortical bone. PMID- 24046051 TI - Autograft, allograft and bone substitutes in reconstructive orthopedic surgery. AB - Reconstruction of bone defects is a challenge for all orthopedic surgeons worldwide; to overcome this problem there are different options: the use of autografts, allografts and bone substitutes (BSs) to enhance and accelerate bone repair. Autografts have excellent biological properties but are associated with morbidity of the donor site and are restricted in volume. Allografts are available in adequate quantity but concerns still remain about the risk of infections, moreover they do not have osteogenetic properties. Bone substitutes have different indications and are very attractive for orthopedic surgeons. The present paper briefly reviews the advantages and disadvantages of autografts, allografts and BSs for bone reconstruction. PMID- 24046052 TI - Fragility fractures: the clinical pathway. AB - The clinical management of fragility fracture is simple but complex at the same time. Patients are different from one another, and advancing age increases the prevalence of comorbidities and conditions that can impair bone quality and healing, while increasing the risk of falls and fractures. Keeping in mind some principles and key points can help identify patients at risk, thus following an ideal path for the identification, treatment and prevention of fragility fractures. PMID- 24046053 TI - Osteoporosis detection by 3T diffusion tensor imaging and MRI spectroscopy in women older than 60 years. AB - Aim of this study was to evaluate the cancellous bone quality of postmenopausal women (age >60 years) by diffusion tensor imaging (DTI) using mean diffusivity (MD) and fractional anisotropy (FA) in combination with proton magnetic resonance spectroscopy (1H-MRS). 20 postmenopausal women older than 60 years were introduced to dual-energy X-ray absorptiometry (DXA) examination in femoral neck and to an MRI spectroscopy and DTI evaluation at 3T. We observed that fat fraction (FF) can discriminate healthy and osteoporotic patients. Water mean diffusivity (MD) and FA can discriminate the healthy group from osteopenic and osteoporotic group. MD/FF vs FA/FF graph extracted from the femoral neck identifies all healthy individuals, according to DXA results. DTI and spectroscopy protocol performed in the femoral neck could be highly sensitive and specific in identifying healthy subjects. PMID- 24046054 TI - Post-surgical rehabilitative approach to fragility fractures. AB - Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. The most frequent sites of fragility fractures are the hip, the distal radius, the spine, the proximal humerus, and the ankle. In most cases, a surgical approach with subsequent rehabilitative treatment is required. The general aims of rehabilitation are to increase functioning and improve patients' activities, participation level, and quality of life. PMID- 24046055 TI - Microstructural differences between osteoporotic and osteoarthritic femoral cancellous bone: an in vitro magnetic resonance micro-imaging investigation. AB - Recently has been highlighted that topological properties of trabecular microstructure and microarchitectural deterioration of bone tissue are important factors in determining bone strength and its resistance to fracture. Magnetic resonance (MR) techniques allow investigation of both trabecular networks and bone marrow providing precious information on the physiological and functional changes associated with osteoporosis. The aim of the present work was to show the ability of MR micro-imaging investigation to describe cancellous bone status as related to its trabecular bone density and quality. For this purpose we measured in vitro, at high magnetic field (9.4T), the MR parameter [Formula: see text] of cancellous bone samples extracted from femoral head of osteoporotic and osteoarthritic women as classified by dual energy X ray absorptiometry bone mineral density. We assessed T2(APP) associations with T-scores, Harris Hip score and age. Results show that T2(APP) is able to discriminate between osteoarthritic and osteoporotic bone samples. Moreover, the micro-imaging T2(APP) investigation has highlighted a different trabecular bone density in cancellous bone specimens of osteoarthritic patients only, which is higher in subchondral compared to metaphysis section of each sample. PMID- 24046056 TI - Osteoporosis and sarcopenia: the connections. AB - Osteoporosis and sarcopenia are the most frequent musculoskeletal disorders affecting older people. Osteoporosis is a widespread disorder affecting millions of individuals of all ethnic backgrounds worldwide, particularly among older women. It is characterized by reduced bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in the risk of fracture. Sarcopenia is considered to be one of the major factors responsible for functional limitations and motor dependency in elderly persons. In age-related muscle atrophy, a decrease in muscle fiber size and number, and a preferential loss of type II fibers have been reported. A decrease in the circulating levels of specific hormones (e.g., estrogen, testosterone, growth hormone, and insulin like growth factor-1) has been shown to be associated with sarcopenia and this appears to play an important role in its pathogenesis. PMID- 24046057 TI - Factors affecting bone strength other than osteoporosis. AB - Osteoporosis is the most common cause of bone fragility, especially in post menopausal women. Bone strength may be compromised by several other medical conditions and medications, which must be ruled out in the clinical management of patients affected by fragility fractures. Indeed, 20-30% of women and up to 50% of men affected by bone fragility are diagnosed with other conditions affecting bone strength other than osteoporosis. These conditions include disorders of bone homeostasis, impaired bone remodeling, collagen disorders, and medications qualitatively and quantitatively affecting bone strength. Proper diagnosis allows correct treatment to prevent the occurrence of fragility fractures. PMID- 24046058 TI - A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors. AB - PURPOSE: Nimotuzumab is a humanized IgG1 monoclonal antibody to the epidermal growth factor receptor (EGFR) and has demonstrated the absence of severe dermatological toxicity commonly caused by other EGFR-targeting antibodies. We conducted a phase I study to assess toxicities, pharmacokinetics, pharmacodynamics, and predictive biomarkers of nimotuzumab administered in Japanese patients with advanced solid tumors. METHODS: Three dose levels, 100, 200, and 400 mg, of weekly i.v. nimotuzumab were given until disease progression or drug intolerability. Four patients with solid tumors were enrolled in each dose level. The expression and gene copy number of EGFR or its downstream transducers were investigated using skin biopsy samples and tumor specimens. RESULTS: Planned dose escalation was completed without dose-limiting toxicity, and maximum tolerated dose was not reached. No allergic reaction and hypomagnesaemia were observed, and grade 3 or 4 toxicity did not occur. The common toxicity was skin rash (58 %); however, all of them were grade 1 or 2. In skin biopsies, no correlation was shown between doses and the phosphorylation of EGFR or its downstream signal transducers. Of 11 evaluable patients, no objective response was obtained, while 8 patients had stable disease (73 %). Patients with a higher-EGFR gene copy number level measured by FISH showed a longer time to progression. CONCLUSIONS: Nimotuzumab administered weekly was feasible and well tolerated up to 400 mg in Japanese patients. A low dermatological toxicity could be a notable advantage as anti-EGFR mAb, and further evaluation is warranted. PMID- 24046059 TI - Extramedullary plasmacytoma of the trachea. AB - Extramedullary plasmacytomas are plasma cell tumors that occur outside the bone marrow. They constitute around 4 % of all plasma cell neoplasms. The most common site of extramedullary plasmacytoma is the upper aerodigestive tract-nasal cavity, paranasal sinuses and oronasopharynx. We are presenting a case of extramedullary plasmacytoma of the trachea. Trachea is an extremely rare site of plasmacytoma. When extraosseous plasmacytoma occur in uncommon sites, the distinction from B cell lymphomas showing extensive plasmacytic differentiation can be difficult and diagnostically challenging. PMID- 24046060 TI - Microsurgical management of distal anterior cerebral artery aneurysms: from basic to complex, a video review of four cases. AB - BACKGROUND: Distal anterior cerebral artery (DACA) aneurysms represent 2-9 % of intracranial aneurysms. They are often more amenable to surgical rather than endovascular treatment due to the size of parent vessels. METHOD: We illustrate surgical approaches for DACA aneurysms arising from different segments of the anterior cerebral artery. Cases range from simple unruptured aneurysms to complex ruptured aneurysms requiring reconstruction and intracranial bypass. CONCLUSION: The interhemispheric approach typically provides an adequate surgical corridor for surgical clipping of DACA aneurysms. Patient positioning, image guidance, and preoperative angiography help maximize safety and efficacy of surgery. PMID- 24046061 TI - SALT-RESPONSIVE ERF1 is a negative regulator of grain filling and gibberellin mediated seedling establishment in rice. AB - Grain quality is an important agricultural trait that is mainly determined by grain size and composition. Here, we characterize the role of the rice transcription factor (TF) SALT-RESPONSIVE ERF1 (SERF1) during grain development. Through genome-wide expression profiling and chromatin immunoprecipitation, we found that SERF1 directly regulates RICE PROLAMIN-BOX BINDING FACTOR (RPBF), a TF that functions as a positive regulator of grain filling. Loss of SERF1 enhances RPBF expression resulting in larger grains with increased starch content, while SERF1 overexpression represses RPBF resulting in smaller grains. Consistently, during grain filling, starch biosynthesis genes such as GRANULE-BOUND STARCH SYNTHASEI (GBSSI), STARCH SYNTHASEI (SSI), SSIIIa, and ADP-GLUCOSE PYROPHOSPHORYLASE LARGE SUBUNIT2 (AGPL2) are up-regulated in SERF1 knockout grains. Moreover, SERF1 is a direct upstream regulator of GBSSI. In addition, SERF1 negatively regulates germination by controlling RPBF expression, which mediates the gibberellic acid (GA)-induced expression of RICE AMYLASE1A (RAmy1A). Loss of SERF1 results in more rapid seedling establishment, while SERF1 overexpression has the opposite effect. Our study reveals that SERF1 represents a negative regulator of grain filling and seedling establishment by timing the expression of RPBF. PMID- 24046062 TI - Plastid signals and the bundle sheath: mesophyll development in reticulate mutants. AB - The development of a plant leaf is a meticulously orchestrated sequence of events producing a complex organ comprising diverse cell types. The reticulate class of leaf variegation mutants displays contrasting pigmentation between veins and interveinal regions due to specific aberrations in the development of mesophyll cells. Thus, the reticulate mutants offer a potent tool to investigate cell-type specific developmental processes. The discovery that most mutants are affected in plastid-localized, metabolic pathways that are strongly expressed in vasculature associated tissues implicates a crucial role for the bundle sheath and their chloroplasts in proper development of the mesophyll cells. Here, we review the reticulate mutants and their phenotypic characteristics, with a focus on those in Arabidopsis thaliana. Two alternative models have been put forward to explain the relationship between plastid metabolism and mesophyll cell development, which we call here the supply and the signaling hypotheses. We critically assess these proposed models and discuss their implications for leaf development and bundle sheath function in C3 species. The characterization of the reticulate mutants supports the significance of plastid retrograde signaling in cell development and highlights the significance of the bundle sheath in C3 photosynthesis. PMID- 24046063 TI - Characterization of evolutionarily conserved motifs involved in activity and regulation of the ABA-INSENSITIVE (ABI) 4 transcription factor. AB - In recent years, the transcription factor ABI4 has emerged as an important node of integration for external and internal signals such as nutrient status and hormone signaling that modulates critical transitions during the growth and development of plants. For this reason, understanding the mechanism of action and regulation of this protein represents an important step towards the elucidation of crosstalk mechanisms in plants. However, this understanding has been hindered due to the negligible levels of this protein as a result of multiple posttranscriptional regulations. To better understand the function and regulation of the ABI4 protein in this work, we performed a functional analysis of several evolutionarily conserved motifs. Based on these conserved motifs, we identified ortholog genes of ABI4 in different plant species. The functionality of the putative ortholog from Theobroma cacao was demonstrated in transient expression assays and in complementation studies in plants. The function of the highly conserved motifs was analyzed after their deletion or mutagenesis in the Arabidopsis ABI4 sequence using mesophyll protoplasts. This approach permitted us to immunologically detect the ABI4 protein and identify some of the mechanisms involved in its regulation. We identified sequences required for the nuclear localization (AP2-associated motif) as well as those for transcriptional activation function (LRP motif). Moreover, this approach showed that the protein stability of this transcription factor is controlled through protein degradation and subcellular localization and involves the AP2-associated and the PEST motifs. We demonstrated that the degradation of ABI4 protein through the PEST motif is mediated by the 26S proteasome in response to changes in the sugar levels. PMID- 24046064 TI - LRRK2 G2385R variant carriers of female Parkinson's disease are more susceptible to motor fluctuation. AB - The relation between the LRRK2 mutation and its effect on Parkinson's disease (PD) has always caught a lot attention. Recent studies found that the G2385R polymorphism of LRRK2 may increase the risk of PD in Asian populations. Here we tried to clarify the relationship between the LRRK2 G2385R variant and the clinical profiles including motor complication in Chinese PD patients. We identified the LRRK2 variant in the Chinese Han population in northern China and evaluated the relationship between the G2385R variant and clinical profiles through comparison between 36 carriers and 139 non-carriers. We found that G2385R carriers scored significantly higher in motor fluctuation and dyskinesia than non carriers. Logistic regression analysis showed that the G2385R variant was an independent risk factor for motor fluctuation in females (odds ratio = 12.538, 95 % CI 2.216-70.942, P = 0.004), and a Chi-squared test showed that the frequency of dyskinesia tended to be higher in the carrier group compared to the non carrier group (16 vs. 4.4 %, P = 0.050, OR = 4.127, 95 % CI 1.074-15.864). These findings indicate that the variant was closely related to the occurrence of motor complication. Additionally, the G2385R variant was significantly related to the early-onset of PD in female carriers (20.0 vs. 1.5 %, odds ratio = 16.25, 95 % CI 1.557-169.618, P = 0.020). Our study found that the G2385R variant was significantly associated with motor complications and that this variant was an independent risk factor for motor fluctuation in females. These findings provide the necessary preliminary data to better understand the unique profile of PD G2385R variant carriers. PMID- 24046065 TI - Novel CACNA1A mutation(s) associated with slow saccade velocities. AB - Mutations in the voltage-gated Cav2.1 P/Q-type calcium channel (CACNA1A) can cause a wide spectrum of phenotypes, including the episodic ataxia type 2. Beside the growing number of descriptions of novel CACNA1A mutations with episodic ataxia type 2 phenotype; there are only rare reports on interictal oculomotor signs other than nystagmus. We describe a novel CACNA1A mutation and an unclassified CACNA1A in-frame variant in a Swiss family presenting as the episodic ataxia type 2 phenotype associated with reduced saccade velocity. In this case series interictal clinical examination showed only minimal neurological findings as mild limb ataxia and nystagmus, but most interestingly saccade analysis of all three affected individuals demonstrated reduced mean saccade velocity. Genetic testing of CACNA1A revealed a de novo frame-shift mutation (c.2691dupC/p.Thyr898Leufs 170) in the index patient in addition to an unclassified in-frame variant (c.6657_6659dupCCA/p.His2220dup) segregating in all three affected individuals. The de novo frame-shift CACNA1A mutation and the unclassified in-frame CACNA1A variant were associated with the episodic ataxia type 2 phenotype and reduced mean saccade velocity, which suggests involvement of brainstem or neural pathways connecting brainstem and the cerebellum in this disease. PMID- 24046066 TI - Prominent psychiatric symptoms in patients with Parkinson's disease and concomitant argyrophilic grain disease. AB - In Parkinson's disease (PD), cognitive decline and psychiatric symptoms may occur and very often co-exist, eventually leading to PD-dementia. We report three patients with PD who presented striking psychiatric manifestations along with mild cognitive decline not progressing to dementia across the course of disease and in which postmortem neuropathological study revealed, besides alpha-synuclein inmunoreactive Lewy-body pathology, concomitant four-repeat tau positive argyrophilic grain pathology. We consider that argyrophilic grains might have modulated the clinical presentation of PD in these patients, being the main substrate of their prominent psychiatric symptoms in the absence of definite dementia. PMID- 24046068 TI - ATRA-induced cerebral sinus thrombosis. AB - All-trans retinoic acid (ATRA) and Idarubicin are part of the AIDA protocol employed for the treatment of Acute promyelocytic leaukaemia (APML) and has been associated with marked improvement in the prognosis. However, it is known to worsen the haematological picture during the course of induction of therapy. Herein, we present a case of an APML patient who developed a rare documented incidence of cerebral sinus thrombosis, first noticed as an ophthalmology referral. This 22 year old lady, a known APML patient was then started on chemotherapy based on AIDA protocol but 17 days into the initiation of therapy, she began to complain of blurred vision on the right eye. Anterior segments were normal but both fundi showed papilloedema with peripapillary haemorrhages. A contrast MRI that was then ordered showed multiple filling defects in numerous venous sinuses. She was started on anticoagulant treatment and the findings resolved. Though a rare case of its side-effects, ATRA usage in APML has a multitude of presentations since its primary pathology lies in the inherent pro coagulant potential. PMID- 24046067 TI - Emerging paradigms in arterial thrombosis. AB - A traditional perspective of arterial thrombosis begins with vessel wall injury and exposure of subendothelial proteins, including collagen and tissue factor, to circulating cellular and non-cellular components. Adhesion and activation of platelets, mediated by their interaction with von Willebrand protein and collagen, respectively, coupled with tissue factor-mediated activation of coagulation proteins, results in thrombin generation and fibrin formation. While this time-honored paradigm remains firm and soundly based, emerging evidence suggests that arterial thrombosis is much more complex and dynamic than originally believed. Several novel triggers, templates and facilitators, such as cell-free nucleic acids, histones, DNA-histone complexes, polyphosphates, and microvesicles have recently been identified and require inclusion in the expanding universe of thrombosis as a dominant phenotype of human disease. Because these mediators appear to have modest if any effect on physiologic hemostasis, they likely represent acquired and disease or condition-dependent processes that are highly attractive targets for pharmacologic intervention. PMID- 24046071 TI - Retraction: Critical role of notch signaling in osteosarcoma invasion and metastasis. PMID- 24046070 TI - Isocitrate dehydrogenase 1 is a novel plasma biomarker for the diagnosis of non small cell lung cancer. AB - PURPOSE: Effective biomarkers for the diagnosis of non-small cell lung cancer (NSCLC) are needed. We previously showed that isocitrate dehydrogenase 1 (IDH1) is significantly increased in NSCLC tumors. This study aimed to examine the plasma levels of IDH1 in a large patient population to evaluate its effectiveness in NSCLC diagnosis. EXPERIMENTAL DESIGN: The plasma levels of IDH1, CA125, Cyfra21-1, and CEA were assayed by ELISA. Blood samples were obtained from 1,422 participants (943 patients with NSCLC and 479 healthy controls). The samples were randomly divided into a training set and a test set. Receiver operating characteristic and binary logistic regression analyses were applied to evaluate diagnostic efficacy and establish diagnostic mathematical models. RESULTS: Plasma IDH1 levels were significantly higher in patients with NSCLCs than in healthy controls (P < 0.001). The diagnostic use of IDH1 in lung adenocarcinoma [area under curve (AUC): 0.858 and 0.810; sensitivity: 77.1% and 76.2%; specificity: 82.9% and 76.6%; in the training set and test set, respectively] was significantly greater than that of CA125, Cyfra21-1, or CEA (P < 0.001). The model combining IDH1 with CEA, CA125, and Cyfra21-1 was more effective for lung adenocarcinoma diagnosis than IDH1 alone (sensitivity and specificity in the training set: 75.8%, 89.6%; test set: 86.3%, 70.7%). In addition, the plasma levels of IDH1 could contribute to the diagnostic model of lung squamous cell carcinoma. CONCLUSIONS: IDH1 can be used as a plasma biomarker for the diagnosis of NSCLCs, particularly lung adenocarcinoma, with relatively high sensitivity and specificity. PMID- 24046072 TI - Increasing spatial resolution of 3T MRI scanning improves reproducibility of carotid arterial wall dimension measurements. AB - OBJECTIVE: To improve carotid 3T magnetic resonance imaging (MRI) dimension measurements in patients with overt atherosclerotic carotid artery disease. MATERIALS AND METHODS: In 31 patients with advanced atherosclerotic carotid artery disease, two high resolution (0.25 * 0.25 mm(2); HR) and two routinely used low resolution (0.50 * 0.50 mm(2); LR) carotid 3T MRI scans were performed within 1 month. After manual delineation of carotid wall contours in a dedicated image analyses program in eight slices covering the atherosclerotic plaque, image reproducibility, as well as the within-reader and between-reader variability were determined. RESULTS: We found significantly higher intraclass correlation coefficients for total wall volume, mean wall area and mean wall thickness for the HR measurements (all p < 0.05). We found a significant lower signal-to-noise and contrast-to-noise ratio for the HR compared to the LR measurements. The carotid arterial wall dimension measurements of all parameters were significantly lower for the HR compared to the LR measurements. No significant differences were observed between the within-reader and between-reader reproducibility for HR versus LR measurements. CONCLUSION: Increasing the in-plane resolution improves the reproducibility of 3T MRI carotid arterial wall dimension measurements. The use of HR imaging will contribute to a reduced sample size needed in intervention trials using MRI scanning of the carotid artery as surrogate marker for atherosclerosis progression. PMID- 24046073 TI - Bacterial community structure in the rhizosphere of a Cry1Ac Bt-brinjal crop and comparison to its non-transgenic counterpart in the tropical soil. AB - To elucidate whether the transgenic crop alters the rhizospheric bacterial community structure, a 2-year study was performed with Cry1Ac gene-inserted brinjal crop (Bt) and their near isogenic non-transformed trait (non-Bt). The event of Bt crop (VRBT-8) was screened using an insect bioassay and enzyme-linked immunosorbent assay. Soil moisture, NH4 (+)-N, NO3 (-)-N, and PO4 (-)-P level had non-significant variation. Quantitative polymerase chain reaction revealed that abundance of bacterial 16S rRNA gene copies were lower in soils associated with Bt brinjal. Microbial biomass carbon (MBC) showed slight reduction in Bt brinjal soils. Higher MBC values in the non-Bt crop soil may be attributed to increased root activity and availability of readily metabolizable carbon compounds. The restriction fragment length polymorphism of PCR-amplified rRNA gene fragments detected 13 different bacterial groups with the exclusive presence of beta Proteobacteria, Chloroflexus, Planctomycetes, and Fusobacteria in non-Bt, and Cyanobacteria and Bacteroidetes in Bt soils, respectively, reflecting minor changes in the community structure. Despite the detection of Cry1Ac protein in the rhizospheric soil, the overall impact of Cry1Ac expressing Bt brinjal was less compared to that due to seasonal changes. PMID- 24046074 TI - Seasonal dynamics and community structure of bacterioplankton in upper Parana River floodplain. AB - Knowing the bacterial community, as well as understanding how it changes during a hydrological pulse, is very important to understand nutrient cycles in floodplain systems. The bacterial community structure was analyzed in the 12 sites of upper Parana River floodplain, and its changes during a flood pulse were described. In order to understand how high and low water phases change bacterial community by changing abiotical variables, the bacterial community distribution was determined in superficial water of 12 different sampling stations, every 3 months, from December 2010 to September 2011. The bacterial community structure and diversity was analyzed by fluorescent in situ hybridization, considering the main domains Bacteria and Archaea and the subdivisions of the phylum Proteobacteria (Alphaproteobacteria, Betaproteobacteria, and Gammaproteobacteria) and the Cytophaga-Flavobacterium cluster. Smaller densities were observed on ebb and low water periods and the highest density was observed in March 2011. The high water period caused a decrease in diversity because of the lost of equitability. The highest values of Shannon-Wiener index were found on December 2010 and September 2011. The nutrients runoff to the aquatic environments of the floodplain promoted an increase in the total bacterial density during the high water phase as well as changes in bacterial community composition. The bacterial community presented both spatial and temporal differences. Yet, temporal changes in limnological characteristics of the floodplain were the most important predictor of bacterial community and also influenced its diversity. PMID- 24046075 TI - Long-term rice and green manure rotation alters the endophytic bacterial communities of the rice root. AB - This study focuses on the effects of long-term rice rotated with milk vetch being as green manure on the composition of bacteria in rice roots. The endophytic bacterial communities in rice roots of the rice-rice-milk vetch (R-R-MV) and the rice-rice-winter fallow (R-R-WF) crop rotations with a 28-year research history were investigated using combined culture-dependent and culture-independent methods. It was found that the endophytic bacterial population in rice roots with the green manure was significantly higher than that of without it. There were 169 and 77 strains of endophytic bacteria that were isolated from rice roots of the R R-MV and the R-R-WF, respectively. The 16S rRNA gene analysis shows that the 77 R R-WF bacteria belong to 15 species of 14 genera while the other 169 R-R-MV bacteria belong to 21 species of 19 genera, in which Herbaspirillum and Cedecea were two mutually dominant populations and Burkholderia, Pseudomonas, Sphingomonas, and Pantoea accounted for large proportions of the endophytic bacteria in rice roots through R-R-MV rotation. The analysis of 16S rDNA clone libraries showed that the Shannon-Weaver diversity index of endophytic bacteria in R-R-MV approximates that in R-R-WF rotation, whereas the richness indexes of Chao 1 and ACE in R-R-MV rotation system were significantly higher than those in R-R-WF rotation. The diversity of endophytic bacteria was richer in R-R-MV. Both the culture-dependent and the culture-independent method revealed significant effect of long-term different tillage systems on the microbial community. PMID- 24046076 TI - Physiological correspondence dictates cortical long-term potentiation and depression by thalamic induction. AB - The auditory cortex exhibits frequency-specific plasticity over a life cycle. Although thalamocortical long-term potentiation (LTP) and depression (LTD) are components of a widely held model underlying the receptive field (RF) plasticity of cortical neurons, the model lacks direct supporting evidence. We show here that conventional high-frequency tetanic stimulation (TS) of the auditory thalamus induced long-term changes in cortical field excitatory postsynaptic potentials, including both LTP and LTD, in mice. Thalamic TS induced LTP when the stimulated thalamic and recorded cortical neurons were tuned to the same frequency and induced LTD when they were tuned to different frequencies. The thalamocortical LTP was N-methyl-d-aspartate-dependent, but the LTD also involved cortical gamma-amino-butyric acidergic inhibition. Notably, the frequency specificity of cortical LTP/LTD was in accordance with the frequency-specific plasticity of spike-based RFs of cortical neurons. Our results suggest that cortical LTP and LTD induced by thalamic induction can be a consequence of identical stimuli, occur in an input-specific manner, and account for frequency specific remodeling of RFs of auditory cortical neurons. PMID- 24046077 TI - In vitro recordings of human neocortical oscillations. AB - Electrophysiological oscillations are thought to create temporal windows of communication between brain regions. We show here that human cortical slices maintained in vitro can generate oscillations similar to those observed in vivo. We have characterized these oscillations using local field potential and whole cell recordings obtained from neocortical slices acquired during epilepsy surgery. We confirmed that such neocortical slices maintain the necessary cellular and circuitry components, and in particular inhibitory mechanisms, to manifest oscillatory activity when exposed to glutamatergic and cholinergic agonists. The generation of oscillations was dependent on intact synaptic activity and muscarinic receptors. Such oscillations differed in electrographic and pharmacological properties from epileptiform activity. Two types of activity, theta oscillations and high gamma activity, uniquely characterized this model activity not typically observed in animal cortical slices. We observed theta oscillations to be synchronous across cortical laminae suggesting a novel role of theta as a substrate for interlaminar communication. As well, we observed cross frequency coupling (CFC) between theta phase and high gamma amplitude similar to that observed in vivo. The high gamma "bursts" generated by such CFC varied in their frequency content, suggesting that this variability may underlie the broadband nature of high gamma activity. PMID- 24046078 TI - The default mode network in chimpanzees (Pan troglodytes) is similar to that of humans. AB - The human default mode network (DMN), comprising medial prefrontal cortex, precuneus, posterior cingulate cortex, lateral parietal cortex, and medial temporal cortex, is highly metabolically active at rest but deactivates during most focused cognitive tasks. The DMN and social cognitive networks overlap significantly in humans. We previously demonstrated that chimpanzees (Pan troglodytes) show highest resting metabolic brain activity in the cortical midline areas of the human DMN. Human DMN is defined by task-induced deactivations, not absolute resting metabolic levels; ergo, resting activity is insufficient to define a DMN in chimpanzees. Here, we assessed the chimpanzee DMN's deactivations relative to rest during cognitive tasks and the effect of social content on these areas' activity. Chimpanzees performed a match-to-sample task with conspecific behavioral stimuli of varying sociality. Using [(18)F]-FDG PET, brain activity during these tasks was compared with activity during a nonsocial task and at rest. Cortical midline areas in chimpanzees deactivated in these tasks relative to rest, suggesting a chimpanzee DMN anatomically and functionally similar to humans. Furthermore, when chimpanzees make social discriminations, these same areas (particularly precuneus) are highly active relative to nonsocial tasks, suggesting that, as in humans, the chimpanzee DMN may play a role in social cognition. PMID- 24046079 TI - Listener-speaker perceived distance predicts the degree of motor contribution to speech perception. AB - Listening speech sounds activates motor and premotor areas in addition to temporal and parietal brain regions. These activations are somatotopically localized according to the effectors recruited in the production of particular phonemes. Previous work demonstrated that transcranial magnetic stimulation (TMS) of speech motor centers somatotopically altered speech perception, suggesting a role for the motor system. However, these effects seemed to occur only under adverse listening conditions, suggesting that degraded speech may stimulate listeners to adopt unnatural neural strategies relying on motor centers. Here, we investigated whether naturally occurring interspeaker variability, which did not affect task difficulty, made a speech discrimination task sensitive to TMS interference. In this paradigm, TMS over tongue and lips motor representations somatotopically altered the discrimination time of speech. Furthermore, the TMS induced effect correlated with listeners' similarity judgments between listeners' and speakers' speech productions. Thus, the degree of motor recruitment depends on the perceived distance between listener and speaker. This result supports the claim that discriminating others' speech pattern requires the contribution of the listener's own motor repertoire. We conclude that motor recruitment in speech perception can be a natural product of discriminating speech in a normally variable and unpredictable environment, not merely related to task difficulty. PMID- 24046080 TI - Environmental enrichment reveals effects of genotype on hippocampal spine morphologies in the mouse model of Fragile X Syndrome. AB - Fragile X Syndrome (FXS) and the Fmr1 knockout (KO) mouse model of this disorder exhibit abnormal dendritic spines in neocortex, but the degree of spine disturbances in hippocampus is not clear. The present studies tested if the mutation influences dendritic branching and spine measures for CA1 pyramidal cells in Fmr1 KO and wild-type (WT) mice provided standard or enriched environment (EE) housing. Automated measures from 3D reconstructions of green fluorescent protein (GFP)-labeled cells showed that spine head volumes were ~ 40% lower in KOs when compared with WTs in both housing conditions. With standard housing, average spine length was greater in KOs versus WTs but there was no genotype difference in dendritic branching, numbers of spines, or spine length distribution. However, with EE rearing, significant effects of genotype emerged including greater dendritic branching in WTs, greater spine density in KOs, and greater numbers of short thin spines in KOs when compared with WTs. Thus, EE rearing revealed greater effects of the Fmr1 mutation on hippocampal pyramidal cell morphology than was evident with standard housing, suggesting that environmental enrichment allows for fuller appreciation of the impact of the mutation and better representation of abnormalities likely to be present in human FXS. PMID- 24046082 TI - Haptic working memory for grasping: the role of the parietal operculum. AB - We investigated how haptic information on object geometry is encoded in the parietal operculum (OP) and is used for guiding object-directed motor acts in humans. We tested the effects of conditioning single-pulse transcranial magnetic stimulation (spTMS) applied to the left OP on corticospinal excitability assessed by a test spTMS applied to the ipsilateral motor cortex (M1) 5 ms after conditioning spTMS. Participants explored the size of a graspable object visually or haptically and waited for a go-signal to grasp it in the dark. They received TMS during the delay phase. In a separate group of participants performing the same task, conditioning spTMS was applied to the ventral premotor cortex (vPM) 7 ms before test spTMS. Results showed that conditioning TMS over OP modulated M1 output according to the information on object size that had been acquired haptically but not visually. Vice versa, conditioning TMS over vPM modulated M1 output according to information on object size acquired by vision but not haptically. Moreover spTMS over OP produced a significant modulation of the upcoming reaching behavior only when the object had been explored haptically. We show that OP contains a haptic memory of objects' macrogeometry and the appropriate motor plan for grasping them. PMID- 24046081 TI - Developmental expression of N-methyl-D-aspartate (NMDA) receptor subunits in human white and gray matter: potential mechanism of increased vulnerability in the immature brain. AB - The pathophysiology of perinatal brain injury is multifactorial and involves hypoxia-ischemia (HI) and inflammation. N-methyl-d-aspartate receptors (NMDAR) are present on neurons and glia in immature rodents, and NMDAR antagonists are protective in HI models. To enhance clinical translation of rodent data, we examined protein expression of 6 NMDAR subunits in postmortem human brains without injury from 20 postconceptional weeks through adulthood and in cases of periventricular leukomalacia (PVL). We hypothesized that the developing brain is intrinsically vulnerable to excitotoxicity via maturation-specific NMDAR levels and subunit composition. In normal white matter, NR1 and NR2B levels were highest in the preterm period compared with adult. In gray matter, NR2A and NR3A expression were highest near term. NR2A was significantly elevated in PVL white matter, with reduced NR1 and NR3A in gray matter compared with uninjured controls. These data suggest increased NMDAR-mediated vulnerability during early brain development due to an overall upregulation of individual receptors subunits, in particular, the presence of highly calcium permeable NR2B-containing and magnesium-insensitive NR3A NMDARs. These data improve understanding of molecular diversity and heterogeneity of NMDAR subunit expression in human brain development and supports an intrinsic prenatal vulnerability to glutamate mediated injury; validating NMDAR subunit-specific targeted therapies for PVL. PMID- 24046083 TI - Opiates do not violate the viability and proliferative activity of human articular chondrocytes. AB - Articular cartilage injuries present a challenge for the clinician. Autologous chondrocyte implantation embedded in scaffolds are used to treat cartilage defects with favorable outcomes. Autologous serum is often used as a medium for chondrocyte cell culture during the proliferation phase of the process of such products. A previous report showed that opiate analgesics (fentanyl, alfentanil and diamorphine) in the sera have a significant inhibitory effect on chondrocyte proliferation. In order to determine if opiates in serum inhibit chondrocyte proliferation, twenty two patients who underwent knee arthroscopy and were anesthetized with either fentanyl or remifentanil were studied. Blood was drawn before and during opiate administration and up to 2 h after its discontinuation. The sera were used as medium for in vitro proliferation of both cryopreserved and freshly isolated chondrocytes, and the number and viability of cells were measured. There was no difference in the yield or cell viability between the serum samples of patients anesthetized with fentanyl when either fresh or cryopreserved human articular chondrocytes (hACs) were used. Some non-significant reduction in the yield of cells was observed in the serum samples of patients anesthetized with remifentanil when fresh hAC were used. We conclude that Fentanyl in human autologous serum does not inhibit in vitro hAC proliferation. Remifentanil may show minimal inhibitory effect on in vitro fresh hAC proliferation. PMID- 24046084 TI - Direct and interactive influence of explanatory variables on properties of a calcium phosphate cement for vertebral body augmentation. AB - We used the response surface methodology to investigate the direct and interactive effects of three explanatory variables on three properties of a calcium phosphate cement (CPC) for use in vertebroplasty (VP) and balloon kyphoplasty (BKP). The variables were poly(ethylene glycol) content of the cement liquid (PEG), powder-to-liquid ratio (PLR), and the amount of Na2HPO4 added to an aqueous solution of 4 wt/wt% poly(acrylic acid) (as the cement liquid) (SPC). The properties were injectability (I), final setting time (F), and 5-day compressive strength (UCS). We found that (1) there was an interactive effect between the variables on I and F but not on UCS; (2) the maximum I (98%) was obtained with PEG = 20 wt/wt% and PLR = 2 g mL(-1); (3) F = 15 min (the proposed optimum value for a CPC for use in VP and BKP) was obtained with PEG = 4 wt/wt% and PLR = 2.9 g mL(-1); and (4) the maximum UCS (39 MPa) was obtained with SPC = 0 and PLR = 3.5 g mL(-1). PMID- 24046085 TI - Ultrasensitivity in independent multisite systems. AB - Multisite modifications are widely recognized as an essential feature of many switch-like responses in signal transduction. It is usually assumed that the modification of one site directly or indirectly increases the rate of modification of neighboring sites. In this paper we provide a new set of assumptions for a multisite system to become highly ultrasensitive even in the absence of cooperativity or allostery. We assume that the individual sites are modified independently of each other, and that protein activity is an ultrasensitive function of the fraction of modified sites. These assumptions are particularly useful in the context of multisite systems with a large (8+) number of sites. We estimate the apparent Hill coefficient of the dose responses in the sequential and nonsequential cases, highlight their different qualitative properties, and discuss a formula to approximate dose responses in the nonsequential case. As an example we describe a model of bacterial chemotaxis that features robust ultrasensitivity and perfect adaptation over a wide range of ligand concentrations, based on non-allosteric multisite behavior at the level of receptors and flagella. We also include a model of the inactivation of the yeast pheromone protein Ste5 by cell cycle proteins. PMID- 24046086 TI - Molecular differentiation and phylogenetic analysis of the Egyptian foot-and mouth disease virus SAT2. AB - In February 2012, a massive new foot-and-mouth disease (FMD) outbreak struck Egypt. In this work, one-step RT-PCR assays were used for in-house detection and differentiation of foot-and-mouth disease virus (FMDV) in Egypt in this year using pan-serotypic and serotype-targeting sequence primers. FMDV SAT2 was the dominant virus in the examined isolates from the epidemic. The complete VP1 coding regions of two isolates were sequenced. The two isolates had 99.2 % sequence identity to most contemporary Egyptian SAT2 reference viruses, whereas they had 89.7-90.1 % identity to the SAT2/EGY/2/2012 isolate, which was collected from Alexandria, Egypt, and previously sequenced by WRLFMD. Phylogenetic analysis showed that Egypt had one topotype and two lineage of FMDV SAT2 in 2012. The Egyptian and the Palestinian 2012 strains were associated mainly with topotype VII, lineage SAT2/VII/Ghb-12, while the virus isolated from Alexandria Governorate belonged to the SAT2/VII/Alx-12 lineage. Topotype VII also comprised lineages that included strains isolated from Libya in 2012 and 2003. Furthermore, within the same topotype, the Egyptian SAT2/2012 isolates were related to strains from Saudi Arabia, Sudan, Eritrea, Cameroon and Nigeria. Nevertheless, more epidemiological work with neighboring countries is needed to prevent cross-border spread of disease and to reach a precise conclusion about the origin of the 2012 FMDV SAT2 emergency in the Middle East. PMID- 24046087 TI - Topical application of polyethylenimine as a candidate for novel prophylactic therapeutics against genital herpes caused by herpes simplex virus. AB - Herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) cause genital herpes, which can enhance the acquisition of human immunodeficiency virus. The development of anti-HSV agents with novel mechanisms of action is urgently required in the topical therapy of genital herpes. In this study, the in vitro and in vivo anti HSV effects of Epomin SP-012((r)), a highly cationic polyethylenimine, were evaluated. When the in vitro antiviral effects of SP-012 were assessed, this compound showed potent activity against HSV-1 and HSV-2. It inhibited the attachment of HSV-2 to host cells and cell-to-cell spread of infection in a concentration-dependent manner and exerted a virucidal effect. No SP-012 resistant HSV-2 was found when the virus was successively passaged in the presence of SP-012. In a mouse genital herpes model, topically administered SP 012 inhibited the progression of the disease caused by HSV infection. These data illustrate that SP-012 may be a novel class of HSV inhibitor that would be acceptable for long-term topical application. PMID- 24046088 TI - Structural requirements of glycosaminoglycans for their interaction with HIV-1 envelope glycoprotein gp120. AB - Heparan sulfate proteoglycans are known to assist HIV-1 entry into host cells, mediated by the viral envelope glycoprotein gp120. We aimed to determine the general structural features of glycosaminoglycans that enable their binding to gp120, by surface plasmon resonance. Binding was found to be dependent on sequence type, size and sulfation patterns. HIV-1 gp120 prefers heparin and heparan sulfate (with at least 16 monomers in length) over chondroitin and dermatan. Sulfate groups were essential to promote this interaction. These results advance the understanding of the molecular-level requirements for virus attachment and cell entry. PMID- 24046089 TI - Quantitative assessment of the association between TP53 Arg72Pro polymorphism and risk of glioma. AB - Many studies have investigated on the association between TP53 Arg72Pro polymorphism and risk of glioma, but the impact of TP53 Arg72Pro polymorphism on glioma risk is unclear owing to the obvious inconsistence among those studies. To shed light on these inconclusive findings and get a quantitative assessment of the association between the TP53 Arg72Pro polymorphism and risk of glioma, we conducted a meta-analysis of eligible studies. We searched PubMed and Embase databases for studies investigating on the association between the TP53 Arg72Pro polymorphism and risk of glioma. The pooled odds ratios (OR) with their 95% confidence intervals (95% CI) was calculated to assess the association between the TP53 Arg72Pro polymorphism and risk of glioma. A total of 12 studies were finally included into the meta-analysis. Meta-analysis of the 12 studies showed that TP53 Arg72Pro polymorphism was not associated with the risk of glioma (OR(Pro vs. Arg) = 1.07, 95% CI 0.93~1.22; OR(ProPro vs. ArgArg) = 1.02, 95% CI 0.85~1.22; OR(ProPro/ArgPro vs. ArgArg )= 1.06, 95% CI 0.85~1.34; and OR(ProPro vs. ArgArg/ArgPro) = 1.07, 95% CI 0.91~1.27). Subgroup analyses by ethnicity further identified that TP53 Arg72Pro polymorphism was not associated with the risk of glioma in Caucasians. However, there was a mild association between the TP53 Arg72Pro polymorphism and risk of glioma in Asians (OR(ProPro vs. ArgArg/ArgPro) = 1.42, 95% CI 1.00~2.02). Thus, there is limited evidence for the association between the TP53 Arg72Pro polymorphism and risk of glioma, and more studies are needed to provide a more comprehensive assessment of the association in Asians. PMID- 24046090 TI - The association between HIF-1alpha polymorphism and cancer risk: a systematic review and meta-analysis. AB - Epidemiological studies have assessed the association between HIF-1alpha polymorphisms and cancer risk. However, the results remained conflicting rather than conclusive. Therefore, we performed a systematic review to provide a complete picture and conducted a meta-analysis to derive a precise estimation. We searched PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases until July 2013 to identify eligible studies. Data sets (43) from 39 studies with a total of 10,841 cases and 14,682 controls were included. The most commonly investigated polymorphism was C1772T, followed by G1790A, C111A, and rs2057482. Overall, C1772T and G1790A but not rs2057482 were associated with increased risk for cancer. When stratified by cancer type, C1772T was associated with increased risk for cervical cancer (T/T vs. C/T+C/C: OR = 8.80, 95 % CI = 2.30-33.70), prostate cancer (T vs. C: OR = 1.54, 95 % CI = 1.04-2.30), and other cancers (T vs. C: OR = 1.42, 95 % CI = 1.07-1.89), but not oral, breast, colorectal, endometrial, lung, and bladder cancers or renal cell carcinoma. G1790A was associated with marginal but insignificant risk for prostate cancer (A vs. G: OR = 1.46, 95 % CI = 1.00-2.13, P = 0.056) and with increased risk for oral (A vs. G: OR = 9.66, 95 % CI = 1.31-71.15), lung (A vs. G: OR = 2.27, 95 % CI = 1.74-2.96), and other cancers (A vs. G: OR = 2.06, 95 % CI = 1.26-3.37) and renal cell carcinoma (A/A vs. G/A+G/G: OR = 3.05, 95 % CI = 1.36-6.84), but not breast, colorectal, cervical, or bladder cancer. Furthermore, we detected increased cancer risk in haplotypes TA and CA and in those carrying at least one risk allele, and decreased cancer risk in haplotype TG regarding C1772T and G1790A polymorphisms. Further well-designed studies on various cancer types are warranted to verify our findings. PMID- 24046091 TI - Corticotropin-releasing factor reduces tumor volume, halts further growth, and enhances the effect of chemotherapy in 4T1 mammary carcinoma in mice. AB - The present study examines the effect of the endogenous neuroendocrine factor, corticotropin-releasing factor (CRF), alone or in combination with 5-fluorouracil (5-FU), on 4T1 mammary tumor cells in vitro and in vivo. CRF has been detected in breast cancer tissues; however, the biological effects reported in the literature are sparse and variable. We found that exogenously administered CRF significantly reduced tumor growth without influencing angiogenesis or cell death. Furthermore, CRF reduced tumor interstitial fluid pressure (Pif) and potentiated the effect of 5-FU. These results show that CRF has antitumor effect on mammary carcinoma in mice. PMID- 24046093 TI - Differential diagnosis of trampoline fracture from osteomyelitis by bone scan with pinhole collimator. AB - A 2-year-old girl with recent history of trampoline fall presented to the A&E Department for complete functional impairment of the left lower extremity and fever. Blood examination revealed an inflammatory syndrome, while plain radiographs were normal. As magnetic resonance imaging was unavailable, a bone scintigraphy was performed. While standard acquisition found an intense uptake focused on the left proximal tibial metaphysis whose appearance was suggestive of acute hematogenous osteomyelitis, complementary acquisition with the pinhole collimator demonstrated that this abnormal uptake was clearly distinct from the cartilage growth plate. One month follow-up radiographs showed a fracture that confirmed the diagnosis of trampoline fracture. PMID- 24046092 TI - Mendelian forms of structural cardiovascular disease. AB - Clinical and molecular genetics are inextricably linked. In the last two decades genetic studies have revealed the causes of several forms of structural heart disease. Recent work is extending the insights from inherited arrhythmias and cardiomyopathies to other forms of heart disease. In this review we outline the current state of the art for the genetics of adult structural heart disease, in particular the cardiomyopathies, valvular heart disease and aortic disease. The general approaches are described with a focus on clinical relevance, while potential areas for imminent innovation in diagnosis and therapeutics are highlighted. PMID- 24046097 TI - Applying a weed risk assessment approach to GM crops. AB - Current approaches to environmental risk assessment of genetically modified (GM) plants are modelled on chemical risk assessment methods, which have a strong focus on toxicity. There are additional types of harms posed by plants that have been extensively studied by weed scientists and incorporated into weed risk assessment methods. Weed risk assessment uses robust, validated methods that are widely applied to regulatory decision-making about potentially problematic plants. They are designed to encompass a broad variety of plant forms and traits in different environments, and can provide reliable conclusions even with limited data. The knowledge and experience that underpin weed risk assessment can be harnessed for environmental risk assessment of GM plants. A case study illustrates the application of the Australian post-border weed risk assessment approach to a representative GM plant. This approach is a valuable tool to identify potential risks from GM plants. PMID- 24046095 TI - Laparoscopic surgery of liver tumors. AB - INTRODUCTION: Despite initial concerns regarding safety and oncological adequacy, the use of laparoscopic liver resections for benign and malignant diseases has spread worldwide. As in open liver surgery, anatomical orientation and the ability to control intraoperative challenges as bleeding have to be combined with expertise in advanced laparoscopic techniques. METHODS: In this review, we provide an overview regarding the literature on laparoscopic liver resection for benign and malignant liver tumors with the aim to discuss the current standards and define remaining challenges. Although numerous case series and meta-analyses have addressed the evolving field of laparoscopic liver surgery recently, data from randomized controlled trials are still not available. RESULTS AND CONCLUSIONS: Laparoscopic liver resection is feasible and safe in selected patients and experienced hands. Even major liver resections can be performed laparoscopically. The minimal invasive approach offers benefits in perioperative short-term outcome without compromising oncological outcomes compared to open liver resections. Further randomized trials are needed to formally prove these statements and to define the optimal indication and techniques for the individual patient. PMID- 24046098 TI - A case of anastomosis malposition of the Blalock-Taussig shunt diagnosed using perioperative transesophageal echocardiography monitoring. AB - The perioperative transesophageal echocardiography (TEE) is a very useful and minimal invasive monitoring not only for the cardiac anesthesia management, but also for the anesthesia management of the non-cardiac operations of the heart high risk patients. In this case report, we report a case of the urgent Blalock Taussig shunt (BT shunt) operation for a small patient of Fallot's tetralogy with anoxic spell, which showed an atypical change of hemodynamics and SpO2 with the shunt opening. After the BT shunt anastomosis, the diastolic blood pressure decreased with the shunt opening, however, the expected rise of SpO2 was not provided. By the perioperative TEE monitoring with the single plane TEE transducer for neonate; UST-52110S (Hitachi Aloka Medical, Tokyo, Japan) with 4.5 mm in diameter, the cause of this atypical change of hemodynamics and SpO2 was diagnosed to be an accidental anastomosis malposition of the BT shunt to the right pulmonary vein and reported to the operator during the operation, and the operation was performed correctly. PMID- 24046099 TI - GlideScope video laryngoscopy use tracheal intubation in patients with ankylosing spondylitis: a series of four cases and literature review. AB - Airway management in patients with ankylosing spondylitis (AS) is a challenging problem for anesthesiologists. The GlideScope video laryngoscope (GVL) is designed to assist tracheal intubation for patients with a difficult airway. The aim of the study was to report the successful intubation by GVL of four AS patients, and to discuss the use of GVL for tracheal intubation in patients with AS by performing a review of the literature. Four patients with chronic, severe AS were evaluated preoperatively; all had features associated with a difficult direct laryngoscopy. We performed the necessary preparations for difficult airway and intubation. Patients were kept in supine position, with their head and neck supported on pillows. Following sufficient preoxygenation, patients received i.v. remifentanil at 1 MUg kg(-1), propofol at 2 mg kg(-1), and succinylcholine at 1 mg kg(-1). GVL intubation was provided after full muscle relaxation. GVL is reasonable alternative to awake fiberoptic bronchoscopy or any other device, as it appears that less training and skill is involved in the actual intubation process. Adequate laryngeal exposure was obtained in all patients were successfully intubated in the first attempt. As with any challenging airway management, it is essential to have a rescue strategy. We believe that GVL can be a good alternative for oral endotracheal intubation in patients with AS. This series is very small and the reader should be very cautious about drawing broad conclusions regarding the GVL and patients with AS. PMID- 24046100 TI - Survival after resection of colorectal cancer based on anatomical segment of involvement. AB - PURPOSE: To determine survival differences for patients undergoing colonic or rectal resection for cancer on the basis of the specific anatomical location of primary tumor. METHODS: A total of 143,747 patients undergoing segmental colectomy, hemicolectomy, anterior resection, or abdominoperineal resection (APER) for adenocarcinoma from 1995 to 2009 were identified from 13 Surveillance, Epidemiology, and End Results regions. The primary end point was overall survival determined by adjusted hazard ratios (HRs); the secondary end point was lymph node yield. RESULTS: Total lymph node yield significantly decreased from proximal to distal resected segment in stage 0-II cancer, but not in stage III cancer. Lymph node ratio increased from cecum to hepatic flexure and then decreased distally (p < 0.001). Adjusted HRs revealed that survival after right colonic resection for ascending hepatic flexure and transverse colon cancer was not significantly different from cecal cancer. Survival after left colonic resection for descending colon cancer was not different from splenic flexure cancer, but sigmoid colectomy carried improved survival (HR 0.95, p = 0.027). APER carried worse survival compared to anterior resection (HR 1.28, p < 0.001) or right colonic resection for cecal cancer (HR 1.61, p < 0.001). CONCLUSIONS: Survival after resection from colorectal cancer depends on specific anatomical segment and not just the division between colon and rectum, or left and right colon. This may be related to inherent differences in the anatomical characteristics of the particular colorectal segment, with varying lymph node yields contributing to understaging. This supports an individualized approach to colorectal cancer, with particular attention to surgical technique, leading to survival improvement. PMID- 24046101 TI - Long-term survival after adrenalectomy for stage I/II adrenocortical carcinoma (ACC): a retrospective comparative cohort study of laparoscopic versus open approach. AB - BACKGROUND: Laparoscopic adrenalectomy (LA) is the standard treatment for benign adrenal lesions. The laparoscopic approach has also been increasingly accepted for adrenal metastases but remains controversial for adrenocortical carcinoma (ACC). In a retrospective cohort study we compared the outcome of LA versus open adrenalectomy (OA) in the treatment of stage I and II ACC. METHODS: This was a double cohort study comparing the outcome of patients with stage I/II ACC and a tumor size <10 cm submitted to LA or OA at Lille University Hospital referral center from 1985 to 2011. Main outcomes analyzed were: postoperative morbidity, overall survival, and disease-free survival. RESULTS: Among 111 consecutive patients operated on for ACC, 34 met the inclusion criteria. LA and OA were performed in 13 and 21 patients, respectively. Baseline patient characteristics (gender, age, tumor size, hormonal secretion) were similar between groups. There was no difference in postoperative morbidity, but patients in LA group were discharged earlier (p < 0.02). After a similar follow-up (66 +/- 52 for LA and 51 +/- 43 months for OA), Kaplan-Meier estimates of disease-specific survival and disease-free survival were identical in both groups (p = 0.65, p = 0.96, respectively). CONCLUSIONS: LA was associated with a shorter length of stay and did not compromise the long-term oncological outcome of patients operated on for stage I/II ACC <= 10 cm ACC. Our results suggest that LA can be safely proposed to patients with potentially malignant adrenal lesions smaller than 10 cm and without evidence of extra-adrenal extension. PMID- 24046102 TI - Limitations of lymph node ratio, evidence-based benchmarks, and the importance of a thorough lymph node dissection in melanoma. AB - BACKGROUND: Stage III melanoma is currently stratified by number of lymph nodes (LNs) involved. However, given the variability of LN retrieval counts we hypothesize that lymph node ratio (LNR) may also provide prognostic information. METHODS: Retrospective cohort study of 411 patients with stage III melanoma were divided into two groups based on LNR (<0.15, n = 291 and >=0.15, n = 120). RESULTS: In multivariate analysis N stage (N3 vs. N1, hazard ratio [HR] = 2.13, p < 0.001), extranodal extension (HR = 1.92, p = 0.002), macrometastasis (HR = 1.70, p = 0.005), non-SLN involvement (HR = 1.65, p = 0.005), risk of N2 disease exceeding 35 % (HR = 1.51, p = 0.03), and LNR >=0.15 (HR = 1.46, p = 0.03) were associated with overall survival (OS). LNR failed to further stratify stage III melanoma; however, the number of LNs examined was an independent prognostic factor. Patients who had >8 inguinal, >15 axillary, or >20 cervical LNs examined had fewer same nodal basin recurrences (26 [8 %] vs. 20 [20 %], p = 0.0009) and for N1 patients an improved OS (3-year OS 84 % vs. 76 %, 10-year OS 53 % vs. 34 %, p = 0.06) compared with N1 patients who had fewer LNs examined. CONCLUSIONS: LNR is an important prognostic factor in stage III melanoma; however, it was not independent over the current AJCC TNM staging system. Diligence by the surgeon and pathologist to retrieve and examine >8 inguinal, >15 axillary, or >20 cervical LNs is associated with fewer same nodal basin recurrences and improved survival and is critical to reliable prognostication. PMID- 24046103 TI - Predicting dysplasia and invasive carcinoma in intraductal papillary mucinous neoplasms of the pancreas: development of a preoperative nomogram. AB - BACKGROUND: Clinical decision making for patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas is challenging. Even with strict criteria for resection, most resected lesions lack high-grade dysplasia (HGD) or invasive carcinoma. METHODS: We evaluated patients who underwent resection of histologically confirmed IPMN and had preoperative imaging available for review. A hepatobiliary radiologist blinded to histopathologic subtype reviewed preoperative imaging and recorded cyst characteristics. Patients with mixed-type IPMN were grouped with main-duct lesions for this analysis. Based on an ordinal logistic regression model, we devised two independent nomograms to predict the findings of adenoma, high-grade dysplasia (HGD-CIS), and invasive carcinoma, separately in both main and branch-duct IPMN. Bootstrap validation was used to evaluate the performance of these models, and a concordance index was derived from this internal validation. RESULTS: There were 219 patients who met criteria for this study. Branch-duct IPMN (bdIPMN) comprised 56 % of the resected lesions. The proportion of HGD-CIS was 15 % for bdIPMN and 33 % for main-duct lesions (mdIPMN); P = 0.003. Invasive carcinoma was identified in 15 % of bdIPMN and 41 % of main-duct lesions (P < 0.001). On multivariate regression, patient gender, history of prior malignancy, presence of solid component, and weight loss were found to be significantly associated with the ordinal outcome for patients with mdIPMN and built into the nomogram (concordance index 0.74). For patients with bdIPMN weight loss, solid component, and lesion diameter were associated with the outcome; (concordance index 0.74). CONCLUSION: Based on the analysis of patients selected for resection, two nomograms were created that predict a patient's individual likelihood of harboring HGD or invasive malignancy in radiologically diagnosed IPMN. External validation is ongoing. PMID- 24046104 TI - Intraoperative imaging of nipple perfusion patterns and ischemic complications in nipple-sparing mastectomies. AB - BACKGROUND: Nipple-sparing mastectomies (NSM) have gained acceptance in the field of breast oncology. Ischemic complications involving the nipple-areolar complex (NAC) occur in 3-37 % of cases. Skin perfusion can be monitored intraoperatively using indocyanine green (IC-GREENTM, ICG) and a specialized infrared camera computer system (SPY EliteTM). The blood flow pattern to the breast skin and the NAC were evaluated and a classification scheme was developed. METHODS: Preincision baseline and postmastectomy skin perfusion studies were performed intraoperatively using 3 mL of ICG. The pattern of arterial blood inflow was classified according to whether perfusion appeared to originate predominantly from the underlying breast tissue (V1), the surrounding skin (V2), or a combination of V1 and V2 (V3). Ischemia, resection, or delayed complications of NAC were recorded. RESULTS: Thirty-nine breasts were interrogated. Seven (18 %) demonstrated a V1 pattern, 18 (46 %) a V2 pattern, and 14 (36 %) a V3 pattern. Seven (18 %) NACs were removed; six intraoperatively and the seventh in a delayed fashion. Notably, five of the seven resected NACs had a V1 pattern. Overall, 71 % of all V1 cases demonstrated profound ischemic changes by intraoperative clinical judgment and SPY imaging. The rates of resection of the NAC differed significantly between perfusion patterns (Fisher's exact test, p = 0.0003). CONCLUSIONS: Three perfusion patterns for the NAC are defined. The V1 pattern had the highest rate of NAC ischemia in NSM. Imaging NAC and skin perfusion during NSMs is a useful adjunctive tool with potential to direct placement of mastectomy incisions and minimize ischemic complications. PMID- 24046105 TI - Predictors of treatment with mastectomy, use of sentinel lymph node biopsy and upstaging to invasive cancer in patients diagnosed with breast ductal carcinoma in situ (DCIS) on core biopsy. AB - BACKGROUND: There are few established indications for sentinel lymph node biopsy (SLNB) in breast ductal carcinoma in situ (DCIS). This study examines factors contributing to the high rate of SLNB in DCIS in Alberta, Canada. METHODS: Patients who underwent definitive surgery from January 2009 to July 2011 for DCIS diagnosed on preoperative core-needle biopsy were identified using a provincial synoptic operative report database (WebSMR). The relationship between baseline patient and tumor characteristics and treatment with total mastectomy (TM), use of SLNB, and upstaging were examined. RESULTS: There were 394 patients identified in the study cohort. Mean age was 57 years, and average preoperative tumor size was 3 cm. Overall, 148 patients (37.6 %) underwent TM; predictors were preoperative tumor size [odds ratio (OR), 1.92 per 1-cm increase in size; 95 % CI 1.65-2.24] and surgeon. Upstaging to invasive cancer at surgery occurred in 23 %, predicted only by preoperative tumor size (OR 1.14 per 1 cm; 95 % CI 1.03-1.27). SLNB was performed in 306 patients overall (77 %) and 140 of those treated with BCS (61 %). Predictors of SLNB were larger preoperative tumor size (OR 1.55 per 1 cm; 95 % CI 1.18-2.04) and the surgeon. In patients treated with BCS, 3 patients who were upstaged had positive SLNs (>0.2 mm), and no patients with DCIS had a positive SLN. CONCLUSIONS: SLNB use is high in patients undergoing BCS for DCIS. Tumor size and the operating surgeon predicted SLNB use. Despite a 23 % upstaging rate, the rate of clinically significant positive SLNs in patients treated with BCS is low, supporting omission of upfront SLNB. PMID- 24046106 TI - A differential microRNA profile distinguishes cholangiocarcinoma from pancreatic adenocarcinoma. AB - BACKGROUND: Cancers of the bile duct and the pancreas are virtually indistinguishable using conventional histopathological and clinical characteristics. We sought to use microRNA (miR) profiling to differentiate these two cancers. METHODS: RNA was harvested from the tumors of patients undergoing curative resection for cholangiocarcinoma or pancreatic adenocarcinoma and compared with adjacent normal bile duct or pancreas, respectively. There were 31 pairs of cholangiocarcinoma with matched tumor and adjacent bile duct and nine pairs of pancreatic cancer with matched tumor and adjacent uninvolved pancreas that had sufficient quantity of RNA that were included in the final analysis. Differential microRNA expression profiles were determined using the nCounter System from nanoString Technologies (Seattle, WA,USA). RESULTS: A total of 41 differentially expressed miRs were identified in cholangiocarcinoma (25 overexpressed, 16 underexpressed) and 52 differentially expressed miRs were found in pancreatic adenocarcinoma (30 overexpressed, 22 underexpressed) relative to adjacent normal tissue. Of these two profiles, 15 miRs were commonly dysregulated between tumor types. Also, eight miRs were similarly overexpressed or underexpressed in cholangiocarcinoma and pancreatic adenocarcinoma, whereas the other seven miRs had inverse expression levels. CONCLUSIONS: Cholangiocarcinoma has a distinct miR profile from pancreatic adenocarcinoma. Discrimination between these two tumor types may be possible with as few as seven miRs. PMID- 24046108 TI - Overexpression of L1CAM is associated with tumor progression and prognosis via ERK signaling in gastric cancer. AB - BACKGROUND: L1 cell adhesion molecule (L1CAM), which belongs to the immunoglobulin superfamily, has recently been observed in a variety of human malignancies. However, its clinical implication in gastric cancer remains unclear. The aim of this study was to explore the role of L1CAM in gastric cancer and to analyze its correlation with tumor progression and prognosis. METHODS: L1CAM expression was measured in human gastric cancer cell lines and knockdown was conducted using siRNA. Cell proliferation, invasion and migration ability was assessed in vitro. The downstream pathway of L1CAM was explored by western blot analysis. L1CAM expression was measured in 112 pairs of human gastric cancer and adjacent noncancerous tissues using real-time quantitative RT-PCR, and the correlation with clinicopathological features and prognosis was analyzed. RESULTS: L1CAM downregulation by siRNA significantly decreased cell proliferation, migration, and invasion in gastric cancer cell lines. Phosphorylated ERK levels began to decline more rapidly in L1CAM knockdown cells compared with parental cells. L1CAM overexpression was significantly correlated with local tumor cell growth (P = 0.041), distant metastasis (P = 0.047), and tumor stage (P = 0.031). The overall survival in patients with high L1CAM expression was significantly shorter than that of patients with low L1CAM expression (P = 0.02). CONCLUSIONS: L1CAM overexpression may be a critical prognostic factor in patients with gastric cancer, and was strongly associated with tumor proliferation, migration, and invasion through the ERK pathway. L1CAM might be an attractive therapeutic molecular target for the treatment of gastric cancer patients. PMID- 24046107 TI - Extrathoracic location and "borderline" histology are associated with recurrence of solitary fibrous tumors after surgical resection. AB - BACKGROUND: Most solitary fibrous tumors (SFTs) are cured by complete resection, but many recurrent and metastatic SFTs do not respond to treatment and are fatal. Malignant histology, defined by England's pathologic criteria, is strongly associated with recurrence, but some benign SFTs still behave aggressively. Several studies have suggested that extrathoracic SFTs have a worse prognosis. We reviewed thoracic and extrathoracic SFTs from our institution to determine if extrathoracic location is associated with recurrence, independent of malignant histology. METHODS: With IRB approval, we retrieved patient pathology reports from the Johns Hopkins Surgical Pathology database between 1991 and 2011 and included 83 SFT patients in our analysis. Patient history and outcomes were obtained from the medical record and primary care physicians. Predictors of recurrence were analyzed by univariate and multivariate analysis and survival determined by the Kaplan-Meier method. RESULTS: Of the 83 patients, 59 had extrathoracic SFTs in neurologic (n = 24), extremity or head/neck (n = 13), or visceral/intraabdominal (n = 22) sites. A total of 74 SFTs were classified benign and 9 as malignant. Of the 14 recurrences, 13 occurred in extrathoracic SFTs; only 7 were classified as malignant. Multivariate analysis confirmed that malignant histology had the strongest association with recurrence, but extrathoracic location also independently predicted recurrence. A total of 20 benign SFTs possessed 1 or more of England's criteria but to an insufficient degree for malignant classification. These "borderline" SFTs were more likely to recur than benign SFTs without these features. CONCLUSIONS: Extrathoracic and "borderline" SFTs with any of England's criteria have a higher risk of recurrence. PMID- 24046109 TI - Epithelioid sarcoma: need for a multimodal approach to maximize the chances of curative conservative treatment. AB - OBJECTIVE: This study was designed to evaluate the impact of multimodal management on a series of epithelioid sarcoma (ES) patients treated with curative intent. METHODS: Data were collected on 69 consecutive patients treated from 1982 to 2012. Univariate and multivariate analyses were performed for tumor control and overall survival (OS). RESULTS: In total, 54 (78 %) patients had localized ES (M0 group). In the M0 group, 85 % of patients received multimodal management (surgery n = 50, radiotherapy n = 37, chemotherapy n = 30). Among 42 patients with limb ES, 9 (21 %) underwent amputation, and isolated limb perfusion (ILP) was required in 17 (40.5 %) to allow conservative management. Among the 45 patients who underwent conservative surgery, flap reconstructions were required in 13 (28.8 %). The median follow-up was 5.7 years. The 5-year actuarial OS rates were 54, 62, and 24 % in the entire group and the M0 and M1 groups, respectively. In the M0 group, the 5-year actuarial distant control, local control (LC), and locoregional control rates were 67, 75, and 66 %, respectively. Prognostic factors for poor OS in the multivariate analysis were tumors that were deep to the fascia (p = 0.04) and grade 3 (p = 0.005). In the univariate analysis, age <30 years (p = 0.04), the T2 stage (p = 0.04), and mass presentation (p = 0.03) correlated with decreased LC, whereas patients who underwent ILP had a significantly higher LC rate (hazard ratio 3; 95 % confidence interval 0.9-9.4; p = 0.05). CONCLUSIONS: Multimodal management including ILP and flap reconstruction is necessary to achieve optimal conservative LC. High rates of metastasis and lymphatic spread require innovative systemic treatments. PMID- 24046110 TI - Sentinel lymph node biopsy versus axillary lymphadenectomy in patients treated with lumpectomy: an analysis of short-term outcomes. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) has been shown to reduce many of the long-term complications associated with a traditional axillary lymph node dissection (ALND); however, short-term outcomes have yet to be characterized. This study was designed to identify trends and differences in 30-day outcomes of partial mastectomy with concurrent SLNB or complete ALND to more effectively determine which patients may be at risk for perioperative complications. METHODS: A retrospective review of the National Surgical Quality Improvement Program database from 2010 to 2011 was performed to identify all female patients undergoing partial mastectomy with concurrent ALND or SLNB. Logistic regression analysis was used to investigate the relationship between surgical management of the axilla and 30-day complications and readmissions. RESULTS: Of the 6,841 patients identified, 1,877 (27.4 %) received a complete ALND. Overall, the ALND cohort demonstrated significantly more readmissions and reoperations, as well as longer operative times and fewer outpatient procedures. No difference was detected in postoperative complications between the two groups. However, after adjusting for potential confounders, ALND did not predict increased risk of 30 day morbidity or unplanned 30-day readmission compared with SLNB in patients undergoing partial mastectomy. CONCLUSIONS: After adjusting for potential confounders, ALND does not significantly increase the risk of 30-day postoperative overall morbidity or readmission compared with SLNB. Improvement of postoperative outcomes should focus on management of high-risk patients and perioperative complications regardless of surgical management of the axilla. PMID- 24046111 TI - Intraoperative clinical assessment and pressure measurements of sentinel lymph nodes in breast cancer. AB - BACKGROUND: Clinicians have long regarded firm enlarged axillary nodes as suspicious for metastasis, and this has been confirmed to represent increased pressure in sentinel lymph nodes (SLN) in vivo in breast cancer. We hypothesized that measuring intranodal pressure (INP) in the operating room would correlate with metastasis size and be more sensitive than clinical observation. METHODS: Intranodal pressure mmHg was measured in SLNs #1 and #2 (N = 134 and 32) in 122 patients with T1/2 cN0 and 6 controls (T0) (8 bilateral). Clinical "Level of Suspicion" (LOS) was: 0 = benign; 1 = slightly suspicious; 2 = obvious metastasis. Statistical analysis was performed to compare INP, LOS, and SLN metastasis size mm. RESULTS: Sentinel lymph nodes met size correlated with INP (r = 0.65; p < 0.001). INP was 22.0 +/- 1.3 mmHg in 35 SLNs with metastases compared with 9.3 +/- 0.7 mmHg in 132 without (p < 0.001). Six groups created by combining LOS 0, 1, and 2 with INP >17 or <=17 mmHg showed a significant (p < 0.001) correlation with SLN histology; sensitivity and specificity for LOS = 2/INP >17 mmHg = 100 % at predicting metastases; LOS = 0/INP <=17 mmHg most often correct at predicting negative nodes (sensitivity 50 %, specificity 92.9 %, positive predictive value 55 %, negative predictive value 90.7 %). INP was better than LOS at predicting positive nodes in eight patients where INP was >17 mmHg. INP and LOS correlated significantly (p < 0.001). CONCLUSIONS: Clinical suspicion of metastasis correlated well with INP particularly at predicting macrometastases. INP was slightly better at predicting micrometastases. Measurement of INP may be valuable adjunct when performing SLN biopsy when further axillary surgery is contemplated. PMID- 24046112 TI - Neoadjuvant chemotherapy for gastric cancer: what are we trying to accomplish? PMID- 24046113 TI - Intensity of follow-up after breast cancer surgery: low versus high? AB - The incidence of breast cancer has been on the rise in the United States over the past several decades. The advanced longevity of the population during this same time period, specifically of elderly women, translates to increases in the absolute number of women diagnosed with breast cancer yearly. This, in combination with decreasing mortality rates, has now led to an increase in the number of breast cancer survivors who need long-term follow-up. There has been significant debate over what tests should be obtained, how often they should be obtained, how long surveillance should be continued, and by whom this should be performed. We review the published guidelines for surveillance, available data regarding low- versus high-intensity surveillance plans, current practice patterns, and recommendations for future strategies. PMID- 24046114 TI - Impact of margin assessment method on positive margin rate and total volume excised. AB - BACKGROUND: For breast-conserving surgery, the method of margin assessment that most frequently achieves negative margins without increasing the volume of tissue excised is uncertain. We examined our institutional experience with three different margin assessment methods used by six experienced breast surgeons. METHODS: Patients undergoing breast-conserving surgery for invasive carcinoma during July to December of a representative year during which each method was performed (perpendicular, 2003; tangential, 2004; cavity shave, 2011) were included. The effect of margin method on the positive margin rate at first excision and the total volume excised to achieve negative margins were evaluated by multivariable analysis, by surgeon, and by tumor size and presence of extensive intraductal component (EIC). RESULTS: A total of 555 patients were identified, as follows: perpendicular, 140; tangential, 124; and cavity shave, 291. The tangential method had a higher rate of positive margins at first excision than the perpendicular and cavity-shave methods (49, 15, 11 %, respectively; p < 0.0001). Median volumes to achieve negative margins were similar (55 ml perpendicular; 64 ml tangential; 62 ml cavity shave; p = 0.24). Four of six surgeons had the lowest rate of positive margins with the cavity shave method, which was significant when compared to the tangential method (p < 0.0001) but not the perpendicular method (p = 0.37). The volume excised by the three methods varied by surgeon (p < 0.0001). The perpendicular method was optimal for T1 tumors without EIC; the cavity-shave method tended to be superior for T2-T3 tumors and/or EIC. CONCLUSIONS: Although the cavity-shave method may decrease the rates of positive margins, its effect on volume is variable among surgeons and may result in an increase in the total volume excised for some surgeons and for small tumors without EIC. PMID- 24046115 TI - Risk group stratification based on preoperative factors to predict survival after nephroureterectomy in patients with upper urinary tract urothelial carcinoma. AB - BACKGROUND: After radical nephroureterectomy (RNU), substantial numbers of patients with upper urinary tract urothelial carcinoma (UUT-UC) are ineligible for adjuvant chemotherapy owing to diminished renal function. Accurate preoperative prediction of survival is considered important because neoadjuvant chemotherapy may be as effective for high-risk UUT-UC as for muscle-invasive bladder cancer. We performed risk group stratification to predict survival based on specific preoperative factors. METHODS: We enrolled 536 UUT-UC patients treated with RNU in this retrospective cohort study and assessed preoperative clinical and laboratory variables influencing disease-specific survival. RESULTS: The median follow-up was 40.9 months. Using univariate analysis, tumor location; number of tumors; hydronephrosis; clinical T stage; clinical N category; voided urine cytology; neoadjuvant chemotherapy; hemoglobin; white blood cell (WBC) counts; and C-reactive protein had a significant influence on disease-specific survival (P < 0.05). Multivariate analysis revealed that clinical T stage, voided urine cytology, and WBC were independent predictors (P = 0.041, P = 0.020, and P = 0.017, respectively). We divided patients into three risk groups based on the number of the three independent predictors: 0, low risk; 1, intermediate risk; 2 and 3, high risk. Significant differences in disease-specific survival were found among these risk groups (P <= 0.0047). CONCLUSIONS: Our results suggest that risk group stratification based on preoperative clinical T stage, voided urine cytology, and WBC counts may be useful for selection of UUT-UC patients for neoadjuvant chemotherapy. Prospective studies with larger numbers of patients and a longer follow-up period are needed to confirm our results. PMID- 24046116 TI - Androgen receptor-positive triple negative breast cancer: a unique breast cancer subtype. AB - BACKGROUND: The significance of androgen receptor (AR) expression in triple negative breast cancer (TNBC) is unclear, and published studies so far have been inconclusive. METHODS: A tissue microarray was constructed using tissue obtained from 119 patients with primary TNBC and stained for AR expression. Other tissue types obtained included recurrent TNBC, normal breast tissue, adjacent ductal carcinoma-in situ (DCIS), lymph node (LN) and distant metastases. Positive AR expression was defined as >=10% nuclear staining. RESULTS: Epithelial tissue was present and evaluable in 94 TNBC patients with a total of 177 tissue cores. AR expression in TNBC was 22 of 94 (23%). AR expression was higher in normal breast tissue (88%) and adjacent DCIS (73% overall). All LN metastases from AR-positive TNBC patients were also AR positive; in addition, no AR-negative TNBC patient had AR-positive LNs. AR expression was associated with older patient age (63 vs. 57 years, respectively, p = 0.051) and LN metastases (p = 0.033). Locoregional recurrence and overall/disease-specific survival were similar between AR-positive and AR-negative patients, although AR-positive patients had more advanced disease. On multivariate analysis, the presence of LN metastases was associated with poorer recurrence-free survival in AR-positive patients (hazard ratio, 4.34) (p = 0.031). CONCLUSIONS: The AR is expressed in normal breast tissue, and expression decreases with advancement to DCIS and invasive cancer. AR-positive TNBC was more common in older patients and had a higher propensity for LN metastases. AR-positive TNBC may represent a breast cancer subtype with unique features that may be amenable to treatment with alternative targeted therapies. PMID- 24046117 TI - Pseudomyxoma peritonei: inflammatory responses in the peritoneal microenvironment. AB - BACKGROUND: Pseudomyxoma peritonei (PMP), a peritoneal mucinous neoplasm of appendiceal origin, is associated with inflammation and fibrosis, which is central to its biology. The significance of the microenvironment in PMP has not been well characterized. METHODS: Immunoassays were used to measure cytokines and C-reactive protein (CRP). Forty-two cytokines were initially measured in 23 PMP ascites and 10 PMP peritoneal washings. On the basis of these results, matching serum and ascites samples were analyzed for ten relevant cytokines (n = 32) and CRP (n = 28). Immunohistochemistry was performed on formalin-fixed tissue sections. Statistical analysis was by Wilcoxon signed rank test, Mann-Whitney U test, and bivariate analysis. RESULTS: Serum CRP was elevated in PMP and correlated to CRP level in ascites. Interleukin (IL)-6, IL-8 (CXCL8), interferon gamma-induced protein 10 (IP-10), (CXCL10), monocyte chemotactic protein (MCP)-1 (CCL2), and macrophage inflammatory protein (MIP)-1alpha (CCL3) levels were grossly elevated in ascites but did not correlate with serum levels. Cytokines normally associated with infection or tissue injury (e.g., IL-1, IL-2, interferon gamma) were not elevated. Immunohistochemistry localized IL-6 to stroma, IP-10, and MCP-1 to tumor cells and IL-8 to adipose tissue. There were complex interactions among cytokines. IL-6, in particular, had many significant correlations in ascites. Serum IL-8, MIP-1beta, and CRP were higher in PMP compared to controls. CONCLUSIONS: The pattern of cytokines in PMP is distinct from infection- or injury-associated inflammation. The results support peritoneal synthesis for cytokines. CRP, IL-8, and MIP-1beta are potential serum markers for PMP. IL-6 appears to play a central role in PMP biology. This study provides new details about PMP tumor biology and identifies possible therapeutic targets. PMID- 24046119 TI - Accurate staging with internal mammary chain sentinel node biopsy for breast cancer. AB - BACKGROUND: Although internal mammary chain (IMC) metastases are an independent predictor of prognosis, collecting IMC sentinel nodes (SN) remains controversial. We sought to determine predictors for IMC nodal positivity and the role positive IMC-SNs have on changing staging and management. METHODS: We reviewed a prospectively collected database (1997-2012) to identify patients who had IMC drainage detected on lymphoscintigraphy and underwent biopsy. Chi square tests and logistic regression models were used to determine trends and factors associated with IMC node positivity. RESULTS: A total of 122 patients with cTis T2cN0M0 breast cancer underwent IMC-SN biopsy. Mean age of the cohort was 53 years, and mean tumor size was 2.0 cm. Identification of IMC nodes was successful in 100% of the cases. There were no complications. Sentinel nodes mapped to the IMC alone in 14 of 122 (11%) patients. Overall, 26% of patients were node positive, with 12 of 122 (10%) patients having a positive IMC-SN. In patients with a positive axilla, IMC-SN was positive in 33% of patients, whereas in patients with a negative axilla, IMC-SN was positive in 3% of cases (P < 0.001). The number of positive axillary nodes was the only independent predictor of IMC positivity (1-3 positive axillary nodes odds ratio 16.9, 95% CI 3.1-91.1; >=4 positive axillary nodes odds ratio 45.0, 95% CI 4.0-500.7). IMC-SN positivity led to a more advanced nodal category in all patients and more accurate staging in 4 of 12 (33%) patients. CONCLUSIONS: IMC-SN biopsy is predictable and safe. Identification of IMC metastases though IMC-SN biopsy has the potential to alter the stage and adjuvant therapy of breast cancer patients. PMID- 24046118 TI - Low total lymphocyte count is associated with poor survival in patients with resected pancreatic adenocarcinoma receiving a GM-CSF secreting pancreatic tumor vaccine. AB - BACKGROUND: Low total lymphocyte count (TLC) and lymphocyte-to-neutrophil ratio have been found to be poor prognostic indicators in several different tumor types at various stages. Although immune-based therapies are under rapid development, it is not known whether baseline complete blood counts, particularly lymphocytes, are associated with the clinical outcomes of patients receiving immunotherapies. METHODS: We performed a retrospective analysis of complete blood count for 59 patients enrolled onto a phase II trial evaluating the integration of an adjuvant immunotherapy-irradiated granulocyte-macrophage colony-stimulating factor (GM CSF) secreting allogeneic pancreatic tumor vaccine (GVAX)-with standard chemoradiation. RESULTS: After adjusting for nodal status, individuals with a TLC of <1,500 cells/mm(3) (10 patients) had significantly higher risk, both in terms of overall survival (OS) [adjusted hazard ratio 2.63, 95 % confidence interval (CI) 1.22-5.67, p = 0.013] and progression-free survival (adjusted hazard ratio 3.07, 95 % CI 1.03-6.93, p = 0.003), compared to those with a TLC of <= 1,500 cells/mm(3) (49 patients). Adjuvant chemoradiation significantly reduced lymphocyte counts from baseline values. Patients with suppression of their lymphocytes to <500 cells/mm(3) after chemoradiation also had shorter disease free and OS. CONCLUSIONS: Immunosuppressive conditions associated with surgical procedures and chemoradiation may affect the efficacy of immunotherapy. PMID- 24046120 TI - Up-regulation of NEK2 by microRNA-128 methylation is associated with poor prognosis in colorectal cancer. AB - BACKGROUND: NIMA-related kinase 2 (NEK2), an enzyme involved in the development and progression of cancer, is abnormally expressed in a wide variety of human cancers, including colorectal cancer (CRC), and is known to have roles in cell division and mitotic regulation through centrosome splitting. We investigated the clinical significance of NEK2 in CRC. In particular, we examined miR-128 expression, which is thought to target NEK2. METHODS: We measured NEK2 mRNA and miR-128 levels in clinical samples by quantitative reverse transcription real time PCR and analyzed the associations between NEK2 levels, miR-128 levels, clinicopathological factors, and prognoses. Furthermore, we performed in vitro assays using a pre-miR-128 precursor and conducted miR-128 methylation analyses. RESULTS: MiR-128 inhibited NEK2 expression and cancer cell proliferation via cell cycle arrest. Moreover, miR-128 was silenced by DNA methylation. Increased NEK2 expression was associated with serosal invasion, lymphatic invasion, and peritoneal dissemination. Patients with high NEK2 expression also had significantly poorer prognoses. Multivariate analysis indicated that high NEK2 expression was an independent prognostic factor for survival. Patients with high miR-128 expression had significantly lower NEK2 expression and lower recurrence rates than those with low miR-128 expression. CONCLUSIONS: NEK2 may be an independent prognostic factor for CRC and was regulated by miR-128, a microRNA that was subjected to epigenetic regulation. Thus, this miR-128/NEK2 pathway may be a prospective therapeutic target for patients with CRC. PMID- 24046121 TI - Proposed modification of the seventh American Joint Committee on Cancer staging system for esophageal squamous cell carcinoma in Chinese patients. AB - BACKGROUND: More data are essential to test the efficacy of the American Joint Committee on Cancer (AJCC) system for staging esophageal squamous cell carcinoma (ESCC). On the basis of previous studies, we propose a modification to this system to better represent the survival characteristics of ESCC in the Chinese population. METHODS: We used data from two centers to establish the generating (n = 1006) and validation (n = 783) cohorts. All of the patients underwent curative surgical treatment. On the basis of previous studies, we excluded tumor location as a variable in the modified pathological staging system and defined the modified nodal categories as follows: N0, node negative; N1, 1 positive node; N2, 2 to 3 positive nodes; and N3, >3 positive nodes. The pathological T categories, pathological M categories, and cell differentiation in the seventh AJCC staging system for adenocarcinoma were used in the modified pathological staging system for ESCC. RESULTS: The median survival times for ESCC patients with stage 0 and Ia, stage Ib, stage IIa, stage IIb, stage IIIa, stage IIIb, stage IIIc were as follows: not reached, 221.2, 151.8, 88.5, 25.0, 19.0, and 13.0 months, respectively, for the entire cohort of patients (n = 1789). The corresponding 5 year survival rates were 86.7, 76.4, 64.9, 55.3, 29.9, 16.9, and 9.7 %, respectively. The survival rates significantly differed between the modified staging groups (p < 0.01). CONCLUSIONS: This modified staging system better discriminates the survival differences between stages than the seventh edition of the AJCC staging system for ESCC in Chinese patients. PMID- 24046123 TI - Perioperative complications in the cancer patient: a robust prognostic factor. PMID- 24046122 TI - The addition of radiation to chemotherapy does not improve outcome when compared to chemotherapy in the treatment of resected pancreas cancer: the results of a single-institution experience. AB - BACKGROUND: Pancreas cancer is highly lethal even at early stages. Adjuvant therapy with chemotherapy (CT) or chemoradiation (CRT) is standard following surgery to delay recurrence and improve survival. There is no consensus on the added value of radiotherapy (RT). We conducted a retrospective analysis of clinical outcomes in pancreas cancer patients treated with CT or CRT following surgery. METHODS: Patients with resected pancreas adenocarcinoma were identified in our institutional database. Relevant clinicopathologic and demographic data were collected. Patients were grouped according to adjuvant treatment: group A: no treatment; group B: CT; group C: CRT. The primary endpoint of overall survival was compared between groups B vs. C. Univariate and multivariate analyses of potential prognostic factors were conducted including all patients. RESULTS: A total of 146 evaluable patients were included (group A: n = 33; group B: n = 45; group C: n = 68). Demographics and pathologic characteristics were comparable. There was no significant survival benefit for CRT compared with CT (mOS 16.8 months vs. 21.5 months, respectively, p = 0.76). Local recurrence rates were similar in all three groups. Univariate analyses identified absence of lymph node involvement (hazards ratio [HR] 1.43, p = 0.0082) and administration of adjuvant therapy (HR 0.496, p = 0.0008) as significant predictors for improved survival. Multivariate analyses suggested that patients without nodal involvement derived the most benefit from adjuvant treatment. CONCLUSIONS: The addition of RT to CT did not improve survival over CT. Lymph node involvement predicts inferior clinical outcome. PMID- 24046124 TI - Complete cytoreduction and HIPEC improves survival in desmoplastic small round cell tumor. AB - BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare tumor of adolescents and young adults. Less than 100 cases per year are reported in North America. Extensive peritoneal metastases are characteristic of this disease. We performed cytoreductive surgery and hyperthermic peritoneal perfusion with chemotherapy (HIPEC) using cisplatin (CDDP) for DSRCT. METHODS: A retrospective cohort study was performed on 26 pediatric and adult patients who underwent cytoreduction/HIPEC using CDDP for DSRCT at a single cancer center. Neoadjuvant chemotherapy, adjuvant chemotherapy, and postoperative enteral nutrition were given to all patients. Postoperative radiation therapy was given to most patients. Follow-up was from 6 months to 6 years. Outcome variables were evaluated for disease-free and overall survival (OS). RESULTS: Five patients (19 %) were less than 12 years of age at surgery. Patients who had disease outside the abdomen at surgery had a larger risk of recurrence or death than those who did not (p = 0.0158, p = 0.0393 time from surgery to death respectively). Age, liver metastasis, and peritoneal cancer index level did not significantly predict disease-free or OS. Patients who had CR0 or CR1 and HIPEC had significantly longer median survival compared with patients who had HIPEC and CR2 cytoreduction (63.4 vs. 26.7 months). CONCLUSIONS: HIPEC may be an effective therapy for children and young adults with DSRCT. Patients with DSRCT require complete cytoreduction before HIPEC to optimize outcome. Patients with DSRCT and disease outside the abdomen at the time of surgery do not benefit from HIPEC. PMID- 24046125 TI - Prediction for recurrence using F-18 FDG PET/CT in pathologic N0 lung adenocarcinoma after curative surgery. AB - BACKGROUND: The aim of this study was to investigate risk factors for recurrence in patients with lung adenocarcinoma (LAD) who were pathologically N0 (pN0) after curative surgical resection. METHODS: A total of 102 LAD patients (M/F = 55/47, mean age, 62.6 +/- 9.4 years) diagnosed as pN0 after curative surgery were included in this study. Clinical, biochemical, radiologic, and pathologic findings were reviewed and analyzed for recurrence. Metabolic parameters [SUVmax, metabolic tumor volume (MTV), total lesion glycolysis (TLG)] on pretreatment F-18 FDG PET/CT were also obtained and analyzed for recurrence. RESULTS: Of 102 patients, 38 (37.3%) were found to experience recurrence for 33.6 +/- 16.3 months. SUVmax, MTV, and TLG were significantly higher in patients with recurrence. The optimal cutoff values determined using a receiver-operating characteristic curve were 6.90 for SUVmax, 10.78 cm(3) for MTV, and 39.68 for TLG. Univariate analysis showed that tumor size, tumor marker, SUVmax, MTV, and TLG were prognostic factors for recurrence. In multivariate analyses, after adjusting for age, sex, tumor size, pathologic T stage, and tumor marker, high SUVmax, MTV, and TLG showed an association with an increased risk of recurrence. CONCLUSIONS: Metabolic parameters on pretreatment F-18 FDG PET/CT can predict recurrence in pN0 LAD patients who underwent curative surgery. Therefore, patients with high metabolic parameters on PET can be considered as candidates for adjuvant therapy to reduce recurrence and should be monitored carefully for early detection of possible recurrence. PMID- 24046127 TI - Thrombolysis for acute submassive pulmonary embolism: CON viewpoint. PMID- 24046126 TI - Impact of identification of internal mammary sentinel lymph node metastasis in breast cancer patients. AB - BACKGROUND: Accurate assessment of the internal mammary (IM) nodal basin can impact prognosis and treatment in breast cancer. The goal of this study was to identify characteristics associated with positive IM sentinel lymph nodes (SLNs) and the impact on adjuvant treatment. METHODS: Clinically node-negative breast cancer patients who underwent SLN dissection including removal of IM SLNs were identified and medical records were reviewed. Statistical analysis was performed using Fisher's exact test and rank-sum tests with a significance level of 0.05. RESULTS: IM SLNs were removed in 71 patients, 60 (85 %) had negative IM SLNs, whereas 11 (15 %) had positive IM SLNs. Clinicopathologic characteristics were similar between the groups. The majority of patients in both groups had axillary SLNs removed (95 % in the node-negative group vs. 91 % in the node-positive group). Four patients (36 %) with positive IM SLNs had axillary metastasis; thus, IM nodal metastases were the only nodal metastases in 64 % of patients with positive IM SLNs. The identification of IM metastases altered adjuvant therapy in 5 (45 %) patients with positive IM SLNs. CONCLUSIONS: Patients with positive IM SLNs have clinicopathologic features similar to those of patients with negative IM SLNs limiting the ability to predict IM nodal metastasis preoperatively. The identification of IM nodal metastases significantly impacts treatment decisions, especially when IM nodes are the only site of nodal metastasis. Removal of IM SLNs should be considered when lymphoscintigraphy reveals IM drainage. PMID- 24046128 TI - The Hispanic paradox further unraveled? PMID- 24046129 TI - [Coccidioidomycosis with manifestation on the tongue]. AB - Systemic mycoses are rare but important differential diagnoses in patients with imported infections. We report the case of a 51-year-old German traveller who acquired coccidioidomycosis during a holiday in Arizona, USA. The disease became apparent several months later primarily as a swelling of the tongue. Subsequent diagnostic investigations revealed infiltration of both lungs. The causal agent Coccidioides posadasii could be cultivated from transbronchial biopsy samples. PMID- 24046130 TI - [How are vegetarian food and mortality associated?--Finally reliable data: vegetarianism reduces mortality]. PMID- 24046131 TI - [Clinical research to improve health care in cardiology]. PMID- 24046132 TI - [Treatment of ST-segment elevation acute myocardial infarction in hospitals with and without cardiac catheterization laboratory]. AB - BACKGROUND AND OBJECTIVE: The goal of treatment of patients with ST-segment elevation acute myocardial infarction (STEMI) is to restore perfusion as soon as possible, preferably by primary percutaneous coronary intervention (PCI). The aim of this study of the German Myocardial Infarction Registry (DHR) was to document acute care and in-hospital course of STEMI patients in Germany. METHODS: Over three months patients with STEMI were consecutively included and their basic data, treatments and in-hospital complications were centrally recorded using an internet-based standardized questionnaire. RESULTS: Included were 6,330 patients from 243 hospitals, in group 1 (primary admission in 136 hospitals with cath lab) 4,656 patients (74%) and in group 2 (primary admission in 107 hospitals without cath lab) 1,674 (26%). Reperfusion therapy was performed more frequently in patients of group 1 (91.1% PCI, 2.7% fibrinolysis) than in group 2 (80.7% PCI after transfer, 6.4% fibrinolysis). In-hospital mortality was 7.3% in all patients, 7.0% in group 1 and 8.3% in group 2. CONCLUSION: The DHR data show that about three quarters of patients with STEMI are primarily admitted to hospitals with cath labs. Primary PCI is the preferred treatment option both in hospitals with and without cath labs (in the latter after transfer); it is performed in about 85% of STEMI patients. In-hospital mortality is with over 7% higher in real life than in randomized studies. PMID- 24046133 TI - [74-year-old woman with dyspnea on exertion]. PMID- 24046134 TI - [Occlusion of the left main stem after transcatheter aortic valve implantation (TAVI)--a rare complication]. AB - HISTORY: In an 85-year-old woman with severe symptomatic aortic stenosis transcatheter aortic valve implantation (TAVI) was performed via a transfemoral access. A 26 mm Sapien Edwards XTTM prosthesis was implanted. FINDINGS: Shortly after the implantation arterial blood pressure began to drop. Aortic root angiography demonstrated occlusion of the left main stem and the small right coronary artery. TREATMENT: Mechanical resuscitation had to be started, while a 6 French guiding catheter was inserted. A guide wire could be inserted into the left main stem, which resulted in slow antegrade flow (TIMI grade II), with an almost immediate rise in the arterial pressure. Implantation of a bare metal stent into the ostium of the left main stem resulted in a normal flow to the left coronary artery and arterial blood pressure returned to normal. COURSE: Further clinical course was uneventful and the patient could be discharged one week later. Sixteen months after the procedure, she is still well. CONCLUSION: TAVI should be performed by experienced staff with a cardiac surgery unit in stand-by; the compartment should be equipped with all facilities of an interventional catheterization laboratory. PMID- 24046135 TI - [17-year-old student with recurrent seizures]. AB - HISTORY: A 17-year-old female student presented in our emergency room after a seizure with motoric fits and enuresis. It was the second event of this kind within 3 weeks. INVESTIGATIONS: The resting ECG on admission showed sinus bradycardia at 45 bpm and a remarkable repolarisation with notched or bifurcated T waves in several leads. Further clinical investigations were unremarkable. TREATMENT AND COURSE: As an arrhythmogenic syncope (bradycardia or tachycardia related) was presumed, beta-blocker therapy was initiated and an implantable loop recorder (ILR) was inserted. Approximately one year after the index event, the student was brought to the emergency room by ambulance after another seizure. Interrogation of the ILR revealed torsade de pointes tachycardia with spontaneous termination after 1 min and 24 s. A dual-chamber ICD for secondary prophylaxis of sudden cardiac death was therefore implanted and the dose of beta-blocker was increased. Genetic analysis for long-QT-syndrome (LQTS) was negative with regards to the most frequent known gene loci. For 6 months the patient has been free of symptoms. CONCLUSION: Arrhythmogenic syncopes can clinically resemble epileptic seizures ("convulsive syncope"). During basic work-up of syncope, the 12 lead ECG may provide valuable clues indicating an arrhythmogenic cause of syncope, showing excitation as well as repolarisation abnormalities. If an arrhythmogenic cause of syncope is suspected but ECG documentation as a proof of diagnosis is missing, implantation of an ILR can be useful. In LQTS, multiple gene mutations are known but cover only a fraction of clinical LQTS. PMID- 24046136 TI - [Indications for catheter ablation of ventricular tachycardia]. AB - Ventricular tachyarrhythmias (VT) can cause sudden cardiac death. This can be prevented by an implantable cardioverter-defibrillator (ICD) but approximately 25% of patients with an ICD develop electrical storm (>= 3 VTs within 24 hours) during the course of 4-5 years. This is a life-threatening event even in the presence of an ICD, particularly if incessant VT is present, and may significantly deteriorate the patient's psychological state if multiple shocks are discharged. Catheter ablation of VT has developed into a standard procedure in many specialized electrophysiology centers. Patients with hemodynamically stable and unstable VT are amendable to substrate-based ablation strategies. Catheter ablation can be performed as emergency procedure in patients with electrical storm as well as electively in patients with monomorphic VT stored in ICD memory. In patients with ischemic or non-ischemic cardiomyopathy, VT ablation is complementary to ICD implantation and can reduce the number of ventricular arrhythmia episodes and shocks and should be performed early. In patients with electrical storm, catheter ablation can acutely achieve rhythm stabilization and may improve prognosis in the long term. Further indications for catheter ablation exist in patients with idiopathic VT where catheter ablation represents a curative therapy, and in patients with symptomatic or asymptomatic frequent premature ventricular beats which may improve prognosis in patients with heart failure and cardiac resynchronization therapy. PMID- 24046137 TI - [Current status of transcatheter aortic valve implantation (TAVI) for patients with severe symptomatic aortic stenosis]. AB - Percutaneous trans-catheter aortic valve implantation (TAVI) has been established as an alternative to surgical valve replacement in surgical high-risk patients. TAVI is also considered the treatment of choice for symptomatic with severe aortic stenosis who are judged to be in-operable. In current practice in Germany more than one third of all aortic valve replacement interventions are performed as a TAVI procedure. It is of crucial importance that proper selection of patients as well as the treatment modality is performed by a so called "heart team", consisting of at least a cardiologist and a cardiac surgeon. PMID- 24046138 TI - [Treatment of cardiogenic shock: what is proven?]. AB - This review will address the pathophysiology, incidence, current outcome and treatment options of patients with cardiogenic shock complicating acute myocardial infarction. The major focus will be on the current evidence based on randomized clinical trials and the current guideline recommendations for the treatment of cardiogenic shock. PMID- 24046139 TI - [Triple therapy for patients with stent and atrial fibrillation? Yes!]. PMID- 24046140 TI - [Triple therapy for patients with stent and atrial fibrillation? No!]. PMID- 24046141 TI - [ESC Guidelines on Pacemaker Therapy 2013: what is new and relevant for daily practice?]. AB - The European Society of Cardiology (ESC) and the European Heart Rhythm Association (EHRA) published new guidelines for pacemaker and cardiac resynchronisation therapy in June 2013. The most important recommendations for daily clinical practice of pacemaker therapy firstly refer to the diagnosis of bradycardia and bradycardia-symptom-correlation. Bradycardia is classified into persistent and intermittent, the latter with and without documentation of spontaneous bradycardia. Evidence for pacemaker therapy depends on the quality of bradycardia-symptom-correlation. The indication for pacing in sick-sinus-syndrome and AV block is significantly simplified and the use of implantable loop recording in syncope of unknown origin encouraged. If loop recorders document long asymptomatic pauses, the authors felt that an indication for pacing exists if pauses exceed 6 sec. Other newly defined pacing indications are syncope in bundle branch block and very long PR (> 300 ms), particularly in older patients and those with structural heart disease. New insights and recommendations are further provided for complications of pacemaker therapy, right ventricular pacing sites, perioperative anticoagulation, pacing and magnetic resonance imaging and remote monitoring. In conclusion, the new ESC guidelines elegantly summarize results of new trials and studies in bradycardia and pacemaker therapy and provide valuable recommendations for daily practice. PMID- 24046142 TI - [New data evaluating interventional closure of a patent foramen ovale after cryptogenic embolism]. PMID- 24046143 TI - miR-125b inhibits Connexin43 and promotes glioma growth. AB - MicroRNA is strongly associated with tumor growth and development. This study examined the potential roles of miR-125b in glioma growth. We found that miR-125b promotes glioma cell line growth and clone formation, and protects the glioma cells from apoptosis in vitro. The miR-125b-transfected glioma cells also demonstrated increased growth after in vivo transplantation. We further identified that miR-125b inhibits Connexin43 expression, and the overexpression of Connexin43 antagonizes the effects of miR-125b in cell growth and anti apoptosis. We conclude that miR-125b regulates glioma growth partly through Connexin43 protein. PMID- 24046144 TI - Nitrogen, phosphorus, carbon, and suspended solids loads from forest clear cutting and site preparation: long-term paired catchment studies from eastern Finland. AB - The long-term impacts of current forest management methods on surface water quality in Fennoscandia are largely unexplored. We studied the long-term effects of clear-cutting and site preparation on runoff and the export of total nitrogen (total N), total organic nitrogen (TON), ammonium (NH(4)-N), nitrate (NO(3)-N), total phosphorus (total P), phosphate (PO(4)-P), total organic carbon, and suspended solids (SS) in three paired-catchments in Eastern Finland. Clear cutting and soil preparation were carried out on 34 % (C34), 11 % (C11), and 8 % (C8) of the area of the treated catchments and wide buffer zones were left along the streams. Clear-cutting and soil preparation increased annual runoff and total N, TON, NO(3)-N, PO(4)-P, and SS loads, except for SS, only in C34. Runoff increased by 16 % and the annual exports of total N, TON, NO(3)-N, and PO(4)-P by 18, 12, 270, and 12 %, respectively, during the 14-year period after clear cutting. SS export increased by 291 % in C34, 134 % in C11, and 16 % in C8 during the 14, 6, and 11-year periods after clear-cutting. In the C11 catchment, NO(3)-N export decreased by 12 %. The results indicate that while current forest management practices can increase the export of N, P and SS from boreal catchments for many years (>10 years), the increases are only significant when the area of clear cutting exceeds 30 % of catchment area. PMID- 24046145 TI - Interleukin-15 and its receptor (IL-15Ralpha) serve as new therapeutic implications for Behcet's disease. PMID- 24046147 TI - Synthesis and Spectroscopic Studies of N,N'-dialkyl Derivatives of Antisymmetrical 2H,5H-Dihydropyrrolo[3,4-c]pyrrole-1,4-diones. AB - 2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione derivatives (DPP) are chemically stable, fluorescent molecules, known as High Performance Pigments. Preparation of the soluble derivatives of DPPs provides great advantage in designing the optic sensor for new and existing applications and overcoming aggregation problems in solid matrices. For this purpose, the synthesis of antisymmetric DPPs and the formation of new organic dyes through N,N'-dialkylation and their spectroscopic studies have been carried out both in solutions and in solid phase. PMID- 24046146 TI - Technology to optimize pediatric diabetes management and outcomes. AB - Technology for diabetes management is rapidly developing and changing. With each new development, there are numerous factors to consider, including medical benefits, impact on quality of life, ease of use, and barriers to use. It is also important to consider the interaction between developmental stage and technology. This review considers a number of newer diabetes-related technologies and explores issues related to their use in the pediatric diabetes population (including young adults), with a focus on psychosocial factors. Areas include trend technology in blood glucose monitoring, continuous glucose monitoring, sensor-augmented insulin pumps and low glucose suspend functions, internet applications including videoconferencing, mobile applications (apps), text messaging, and online gaming. PMID- 24046148 TI - Fluorescence Modulation and Photochromism in Azobismaleimide Derivatives. AB - A fluorophore-photochrome system incorporating an aryleneimine type fluorophore and an azobismaleimide photochrome was developed and the photochemical properties of this system were investigated. The photoisomerization of trans-azoaromatic chromophore leads to the increase of the fluorescence intensity of fluorophore. The cis azobismaleimide isomers revert photochemically to the trans form and the emission intensity decreases. The fluorescence intensity of the imine fluorophore can be modulated under irradiation with UV and visible (436 nm) light due to reversible trans-cis-trans photoisomerization of azobismaleimide partner. The photoisomerization kinetics was obeyed a first-order relationship with a rate constant of 1.95 * 10(-2) s(-1) for azobismaleimide/imine fluorophore system and for polyazothioetherimide/imine derivative the kinetics was described by a biexponential equation. PMID- 24046149 TI - Longitudinal relationships between depression and functioning in people with type 2 diabetes. AB - BACKGROUND: The reciprocal relationship between depression and functioning in people with chronic conditions is poorly understood. PURPOSE: The aim of the present study was to analyze the dynamic relationship between depression and functioning in a community sample of people with diabetes. METHODS: Participants with diabetes were assessed at baseline and three yearly follow-up assessments (n = 1,403). Depression was assessed using the Patient Health Questionnaire. Global functioning was assessed using the World Health Organization Disability Assessment Schedule II. RESULTS: Path analysis suggested a reciprocal relationship between depression and functioning. Baseline depression was associated with functioning at 3 years follow-up through depression and functioning at 1 and 2 years follow-up assessments. CONCLUSIONS: Depression and functioning might interact with each other in a dynamic way: depression at one assessment point might predict poor functioning at the next assessment point, which in turn might predict depression at the next assessment point. This should be taken into account in both treatment and research programs. PMID- 24046150 TI - How do prompts for attempts to quit smoking relate to method of quitting and quit success? AB - BACKGROUND: Understanding how prompts for quit attempts relate to quitting methods and success may improve smoking cessation interventions. PURPOSE: This study aims to establish whether prompts for quitting are associated with quitting method and success. METHODS: Using a cross-sectional design, 6,126 past-year smokers who had tried to quit in the last 12 months, were asked to identify prompts contributing to their most recent attempt. RESULTS: Attempts prompted by health professional advice were significantly more likely to involve use of treatments and gradual rather than abrupt cessation (odds ratios (ORs; 95 % confidence interval (CIs)) = 3.64 (3.14-4.22), 0.68 (0.59-0.78); respectively) but were not more likely to succeed. Attempts prompted by concern about current or future health, or cost, were more likely to succeed (OR (95 % CIs) = 1.79 (1.38-2.32), 1.25 (1.01-1.54), and 1.41 (1.13-1.76)). CONCLUSIONS: Quit attempts prompted by health professional advice appear to be more likely to involve gradual reduction and use of treatments. Those prompted by health concerns and cost appear more likely to succeed. PMID- 24046151 TI - Kinematic and kinetic interactions during normal and ACL-deficient gait: a longitudinal in vivo study. AB - The interactions between different tissues within the knee joint and between different kinematic DOF and joint flexion during normal gait were investigated. These interactions change following ACL transection, in both short (4 weeks) and long (20 weeks) term. Ten skeletally mature sheep were used in control (N = 5) and experimental (N = 5) groups. The 6-DOF stifle joint motion was first measured during normal gait. The control group were then euthanized and mounted on a unique robotic testing platform for kinetic measurements. The experimental group underwent ACL transection surgery, and kinematics measurements were repeated 4 and 20 weeks post-operatively. The experimental group were then euthanized and underwent kinetic assessment using the robotic system. Results indicated significant couplings between joint flexion vs. abduction and internal tibial rotation, as well as medial, anterior, and superior tibial translations during both normal and ACL-deficient gait. Distinct kinetic interactions were also observed between different tissues within the knee joint. Direct relationships were found between ACL vs. LM/MM, and PCL vs. MCL loads during normal gait; inverse relationships were detected between ACL vs. PCL and PCL vs. LM/MM loads. These kinetic interaction patterns were considerably altered by ACL injury. Significant inter-subject variability in joint kinematics and tissue loading patterns during gait was also observed. This study provides further understanding of the in vivo function of different tissues within the knee joint and their couplings with joint kinematics during normal gait and over time following ACL transection. PMID- 24046152 TI - Prolonged leptin treatment increases transient outward K+ current via upregulation of Kv4.2 and Kv4.3 channel subunits in adult rat ventricular myocytes. AB - Circulating leptin levels are elevated in obesity and hyperleptinaemia has been postulated to be an independent risk factor for the development of cardiovascular diseases. Although many studies have been published on the mechanisms involved in the effects of leptin on cardiac function and pathological remodeling, scarce information is currently available analyzing the influence of prolonged leptin treatment on ionic cardiac channels remodeling in adult ventricular myocytes. Enzymatically isolated adult rat ventricular myocytes were treated with leptin or vehicle for 48h. Real-Time RT-PCR were used to analyze mRNA expression of Kir2.1, Cav1.2, Cav 3.1, Kv4.2 and Kv4.3 alpha-subunits and KChIP2 auxiliary subunit. The fast transient outward potassium channels (Itof) alpha-subunits Kv4.2, Kv4.3 and KChIP2 were analyzed by Western-blot. The fast transient outward potassium current and the action potentials were recorded in isolated myocytes by the whole cell patch-clamp technique. Leptin treatment induced an up-regulation of Kv4.2, Kv4.3 and KChIP2 subunits mRNA expression. However, transcriptional levels of Kir2.1, Cav1.2, or Cav3.1 alpha-subunit channels were unmodified by leptin. Protein expression levels of Kv4.2, Kv4.3 and KChIP2 subunits were also increased by leptin. The electrophysiological study showed that leptin increases the fast transient outward potassium current amplitudes and densities shortening action potential duration. In addition, leptin activated Akt signaling in cardiomyocytes and this mechanism was involved in the effect of leptin on Itof channels. In conclusion, leptin increases both the expression and function of Itof channels in adult ventricular myocytes and this mechanism involves Akt signaling. Altogether these data suggest that leptin could exert beneficial or detrimental effects depending on the initial ventricular myocyte repolarizing reserve. PMID- 24046153 TI - The role of ENaC in vascular endothelium. AB - Once upon a time, the expression of the epithelial sodium channel (ENaC) was mainly assigned to the kidneys, colon and sweat glands where it was considered to be the main determinant of sodium homeostasis. Recent, though indirect, evidence for the possible existence of ENaC in a non-epithelial tissue was derived from the observation that the vascular endothelium is a target for aldosterone. Inhibitory actions of the intracellular aldosterone receptors by spironolactone and, more directly, by ENaC blockers such as amiloride supported this view. Shortly after, direct data on the expression of ENaC in vascular endothelium could be demonstrated. There, endothelial ENaC (EnNaC) could be defined as a major regulator of cellular mechanics which is a critical parameter in differentiating between vascular function and dysfunction. Foremost, the mechanical stiffness of the endothelial cell cortex, a layer 50-200 nm beneath the plasma membrane, has been shown to play a crucial role as it controls the production of the endothelium-derived vasodilator nitric oxide (NO) which directly affects the tone of the vascular smooth muscle cells. In contrast to soft endothelial cells, stiff endothelial cells release reduced amounts of NO, the hallmark of endothelial dysfunction. Thus, the combination of endothelial stiffness and myogenic tone might increase the peripheral vascular resistance. An elevation of arterial blood pressure is supposed to be the consequence of such functional changes. In this review, EnNaC is discussed as an aldosterone regulated plasma membrane protein of the vascular endothelium that could significantly contribute to maintaining of an appropriate arterial blood pressure but, if overexpressed, could participate in the pathogenesis of arterial hypertension. PMID- 24046154 TI - Risk factors associated with inadequate veins for placement of arteriovenous fistulas for hemodialysis. AB - An arteriovenous fistula (AVF) between the radial artery and cephalic vein at the wrist is the preferred type of hemodialysis vascular access. However, in the practice of access placement, we are aware that some patients fail to form the standard forearm radial-cephalic AVF, owing to naturally small veins or acquired abnormal lesions of the veins. To identify the risk factors for failure to form the standard AVF, we examined 305 consecutive patients who underwent first-time access surgery at our hospital from January 2006 to December 2010. We compared the patients' characteristics between those having normal vessels and successfully forming the standard AVF, and those having apparently abnormal vessels and thus forming alternative types of access instead. Histories of major and minor surgery were specifically evaluated, assuming that surgical procedures in the past could potentially damage the superficial veins. We created 207 standard and 98 alternative accesses during the period and found that significantly more patients with alternative accesses (31 %) had undergone major surgery of a variety of specialties, in comparison with those with the standard AVF (15.0 %). Multivariate logistic analysis revealed that a history of major surgery (OR = 2.39, 95 %CI 1.29-4.47, p = 0.006) and female gender (OR = 1.87, 95 %CI 1.10-3.20, p = 0.02) were independent risk factors associated with failure to construct the standard AVF. Our results indicate that previous surgery can damage the superficial veins and cause venous abnormality, which makes construction of the standard AVF difficult. We propose that care should be taken to preserve the superficial veins when patients for whom dialysis therapy is a future possibility undergo surgical procedures, especially invasive ones. PMID- 24046156 TI - Homeopaths Without Borders practice exploitation not humanitarianism. PMID- 24046155 TI - Impact of 2008 global economic crisis on suicide: time trend study in 54 countries. AB - OBJECTIVE: To investigate the impact of the 2008 global economic crisis on international trends in suicide and to identify sex/age groups and countries most affected. DESIGN: Time trend analysis comparing the actual number of suicides in 2009 with the number that would be expected based on trends before the crisis (2000-07). SETTING: Suicide data from 54 countries; for 53 data were available in the World Health Organization mortality database and for one (the United States) data came the CDC online database. POPULATION: People aged 15 or above. MAIN OUTCOME MEASURES: Suicide rate and number of excess suicides in 2009. RESULTS: There were an estimated 4884 (95% confidence interval 3907 to 5860) excess suicides in 2009 compared with the number expected based on previous trends (2000 07). The increases in suicide mainly occurred in men in the 27 European and 18 American countries; the suicide rates were 4.2% (3.4% to 5.1%) and 6.4% (5.4% to 7.5%) higher, respectively, in 2009 than expected if earlier trends had continued. For women, there was no change in European countries and the increase in the Americas was smaller than in men (2.3%). Rises in European men were highest in those aged 15-24 (11.7%), while in American countries men aged 45-64 showed the largest increase (5.2%). Rises in national suicide rates in men seemed to be associated with the magnitude of increases in unemployment, particularly in countries with low levels of unemployment before the crisis (Spearman's rs=0.48). CONCLUSIONS: After the 2008 economic crisis, rates of suicide increased in the European and American countries studied, particularly in men and in countries with higher levels of job loss. PMID- 24046157 TI - Economic recession and suicide. PMID- 24046158 TI - [Development and implementation of a state-wide "train the trainer" model of the school-based prevention programme "Join the Healthy Boat - Primary School"]. AB - STUDY AIM: This paper shows how a state-wide health-promotion intervention at primary schools can be implemented by considering the example of the programme "Join the Healthy Boat - Primary School". Additionally, it is illustrated how quality control throughout the whole process can be incorporated. METHODS: To operate long-term and target-group orientated in the whole state of Baden Wurttemberg, the school-based prevention programme "Join the Healthy Boat" uses a "train the trainer" model. The trainers are teachers who were instructed by the project team. In the school year 2009/10, these trainers offered quadrinominal training courses for further teachers. Every urban and rural district is covered by 1 trainer. The trainers evaluated the 6 preparatory training courses they had been given using questionnaires. The following 4 training courses the trainers offered to the teachers were reviewed by the trainers as well as the teachers using questionnaires, too. Additionally, at the end of the school year 2009/10, the teachers completed a questionnaire about their satisfaction regarding the programme itself and the work with the trainer. RESULTS: During the school year 2009/10, 453 teachers were trained by 32 trainers. According to indications on the questionnaires about the preparatory training courses, all trainers felt themselves "very well" or "well" prepared for their task. The teachers evaluated the expertise of the respective trainer, the quality of the training courses and the satisfaction with the programme itself throughout highly. CONCLUSION: Based on the excellent results of the process evaluation and the programme's wide coverage, an adoption of a "train the trainer" model seems worthwhile for other school-based prevention programmes, as well. PMID- 24046160 TI - [The new STIKO-SOP: ethical considerations]. PMID- 24046159 TI - [Patient satisfaction in oncological aftercare--differential results of gender aspects in doctor-patient dyads]. AB - OBJECTIVE: The aim of this study was to explore the role of gender of the physician and gender of the patient in explaining differences in patient satisfaction. MATERIAL AND METHODS: Overall, 1,130 patients were assigned to one of 4 possible physician-patient sex dyads and were interviewed with a questionnaire about their patient satisfaction. RESULTS: Female patients in a dyad with a female physician were most satisfied with the overall judgment of practice visit and the inclusion of life situation in comparison to all other dyads. Male patients in a dyad with a male physician were least satisfied. CONCLUSION: In the future, the specific role of patient-physician dyads has to be considered more in the assessment of subdimensions of patient satisfaction. PMID- 24046161 TI - HPLC analysis of carotenoids from tomatoes using cross-linked C18 column and MS detection. AB - This study was conducted to analyze carotenoids from tomatoes by high-performance liquid chromatography using reversed-phase C18 silica having cross-linked end capping with diode array and mass spectrometric detection. An efficient gradient elution system was developed to achieve good and reliable separation of both major and minor carotenoids as well as their isomers. Resolution of lycopene, beta-carotene and their isomers was 0.91-3.97 and 1.02-2.86 with cross-linked and conventional C18 column, respectively. The % recovery for zeaxanthin, lycopene and beta-carotene was found to be in the range of 89-97%. Limits of detection and quantification of 19.44 and 64.79 ng/mL for zeaxanthin, 15.6 and 52.4 ng/mL for lycopene and 8.28 and 27.61 ng/mL for beta-carotene were determined. More carotenoid compounds could be separated and detected with the new method as compared with conventional C18 column. Hyphenation of HPLC with photodiode array and mass spectrometry detectors assisted in detection of tetra-dehydrocarotenoid and fatty acid diesters of xanthophylls in tomato products. Content of all-trans lycopene, beta-carotene and total carotenoid in different industrial tomatoes tested was found to range between 41.87 and 84.65, 0.89 and 1.50 and 53.22 and 112.60 ug/g fresh weight, respectively. PMID- 24046162 TI - Microextraction by packed sorbent-high-pressure liquid chromatographic-ultra violet analysis of endocrine disruptor pesticides in various matrices. AB - Microextraction by a packed sorbent (MEPS) is the miniaturized version of solid phase extraction whereby sample volumes as small as 10 MUL can be used. A syringe (100-250 MUL) is used in MEPS technique, which generally contains 4 mg of solid packing material inserted as a plug. The sample preparation occurs on the surface of this bed which can be modified to provide varied sampling conditions. In the present work, MEPS has been employed as a sample preparation technique for the analysis of endocrine disruptor (ED) and suspected ED pesticides in biological and environmental samples. The pesticides aldicarb, dimethoate, propazine and terbutryn have been successfully separated by high performance liquid chromatography-ultra violet (HPLC-UV) system with acetonitrile/water as the mobile phase in the ratio 60/40. Several factors affecting the performance of MEPS technique such as the number of extraction cycles, type of washing and elution solvent were optimized. This method has been applied to the analysis of these pesticides in urine, soil and tap water samples with good recoveries in the range of 81.4-97.8%. The detection limit ranged between 0.05 and 0.6 ng mL for the analyzed pesticides. PMID- 24046163 TI - Combination trans arterial chemoembolization (TACE) plus sorafenib for the management of unresectable hepatocellular carcinoma: a systematic review of the literature. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the most common liver neoplasm and the fifth most common cancer worldwide. Intermediate stage HCC [traditionally defined as Barcelona Clinic Liver Cancer (BCLC) B disease and traditionally treated with trans arterial chemoembolization (TACE)] and advanced stage HCC (traditionally defined as BCLC C disease and traditionally treated with sorafenib) are two distinct disease entities with rapidly evolving multimodality treatment approaches. In this systematic review we explore the evidence surrounding the value of using a TACE/sorafenib combination in these two subsets of HCC. METHODS: PubMed, Medline, the Cochrane Library, EMBASE and Google Scholar were searched using the terms "HCC" OR "Hepatoma" or "Liver cancer" AND "TACE" OR "Chemoembolization" AND "Sorafenib" and specifying only English literature. Outcomes of interest included time to progression and overall survival (TTP and OS), tumor response, and toxicities. RESULTS: A total of 17 potentially relevant trials were identified, of which six studies were excluded. Hence, 11 trials involving 1,000 patients were included, encompassing two phase 1 studies, one phase 3 study, two retrospective analyses and six phase 2 studies. Median TTP was reported in five out of 11 studies and it ranged from 6.3 to 9.0 months. Median OS was reported in five out of 11 studies and it was similarly variable as PFS, ranging from 12 to 29 months. The DCR (disease control rate) was reported in eight out of 11 studies, ranging from 32 to 95%. Frequently reported grade 3/4 toxicities were increased aspartate transaminase/alanine transaminase, fatigue, hypertension, hand-foot skin reaction and diarrhea. CONCLUSIONS: The sorafenib/TACE combination shows promise as an effective and tolerable treatment strategy for intermediate stage/advanced HCC. The reported efficacy of a sorafenib/TACE combination appears to compare favorably with sorafenib or TACE monotherapies, the most commonly implemented strategies for unresectable HCC. Further clinical studies are warranted to accurately determine which patients are expected to benefit most from such combination strategies. PMID- 24046164 TI - Can the effective potential of a linear quadrupole be extended to values of the Mathieu parameter q up to 0.90? AB - The motion of ions in a linear quadrupole is usually described by solutions to the Mathieu equation. A simplifying approximation to this theory that is widely used for low values of the Mathieu parameters a and q describes ion motion in an effective potential. In this work, we have calculated the effective potential for any q from displacements of calculated ion trajectories caused by a dipole DC electric field. It is assumed that the dipole DC electric field at the center of the displaced trajectory is countered by an "effective" electric field. For all q values, the effective electric field is found to increase linearly with the distance from the center of the quadrupole. The trapping forces probed in this way increase continuously with q up to the first stability region boundary at q=0.908. The well depth (D) at any q can be described by D = q[V(rf)/c], where c=3.955+/-0.005, very similar to the standard effective potential model with c=4.000. PMID- 24046165 TI - [Pharmacology in vitreoretinal surgery]. PMID- 24046166 TI - [Pharmacological vitreolysis]. AB - Posterior vitreous detachment (PVD) is a physiological ageing process. In many cases PVD is incomplete and pathological adhesions of vitreous collagen may be associated with tractional forces in the periphery where they can cause retinal breaks and lead to detachment of the neurosensory retina. In the macular area such tractional forces at the vitreoretinal interface can contribute to the formation of specific entities such as vitreomacular traction syndrome and macular holes which are associated with an impairment of visual acuity and disturbing metamorphopsia. Currently, pars plana vitrectomy with induction of PVD, peeling of epiretinal membranes and the ILM represents an effective and safe treatment option for these conditions. Pharmacological vitreolysis is a new and alternative, non-surgical approach to release tractional forces at the vitreoretinal interface by injecting an enzyme with proteolytic activity against fibronectin and laminin into the vitreous cavity. Certain forms of vitreomacular traction and smaller macular holes can be successfully treated in this way without surgical manipulation of the retinal surface. The role of the concept of pharmacological vitreolysis as a treatment option even for exudative macular diseases or as an adjunct to assist vitreoretinal surgical procedures is currently under investigation. PMID- 24046167 TI - [VEGF inhibitors in vitreoretinal interventions]. AB - Vascular endothelial growth factor (VEGF) inhibitors are being used for an increasing number of indications. Beyond the classical use in exudative macular degeneration and macular edema, they are being used, for example off-label as additive treatment together with panretinal laser photocoagulation or in preparation for vitrectomy for ischemic retinopathy. In preparation for vitreoretinal surgery VEGF inhibitors are usually given prior to surgery. When given as an adjunct to laser treatment, VEGF inhibitors can be given either consecutively or parallel to laser photocoagulation. In most cases, however, anti VEGF treatment does not render laser coagulation dispensable. The greatest danger with anti-VEGF treatment in the context of ischemic retinopathies lies in the fact that proliferative membranes are misjudged or overlooked. In these cases, anti-VEGF treatment can induce contraction of these membranes with induction of consecutive tractional retinal detachment. This review summarizes the current knowledge on VEGF inhibition as an adjunct to vitreoretinal surgery and also points out the gaps in the current knowledge and the need for further research. PMID- 24046168 TI - [Neuroprotective approaches]. AB - After introduction of vitreoretinal surgery more than 40 years ago, further development of the procedure involved a continuous reduction of potential toxic effects by irrigating solutions, endoillumination or mechanical manipulation. Recently, additional efforts were made to prevent neurodegeneration via pharmacological intervention. Taurine as additive for irrigating solutions can be considered as an example for neuroprotectants in vitreoretinal surgery. Approval of neuroprotective agents demands an increased effort for preclinical and clinical evaluation. To date, only few neuroprotective substances are used in clinical routine in the context of vitreoretinal surgery, however, experimental data suggest a high potential of various neuroprotective agents. The following article gives an overview of current neuroprotective approaches feasible for vitreoretinal surgery and a critical analysis of their clinical relevance. PMID- 24046169 TI - [Pharmacological approach to treatment of proliferative vitreoretinopathy]. AB - Proliferative vitreoretinopathy (PVR) is the major cause of persistent loss of vision after retinal detachment surgery and is characterized by the formation of scar-like fibrocellular membranes on the neuroretina giving rise to tractional retinal (re-)detachment. Epithelial-mesenchymal transition, adhesion, migration and proliferation of retinal pigment epithelial (RPE) cells disseminated from the normal site at Bruch's membrane in concert with an activation of glial cells, hyalocytes and immune cells are key cellular events in the onset of the disease. The interplay between the cellular events and various growth factors, cytokines and matrix proteins thereby drives the undesirable formation of PVR membranes. Blocking these pathological events would greatly enhance the overall prognosis of surgical treatment. Clinical trials assessing the efficacy of antiproliferative and anti-inflammatory substances have yielded mixed results. Thus no safe or sufficiently effective pharmacological agent has so far been established in the clinical routine. Recent advances in the fundamental understanding of the pathogenesis of PVR aided in the identification of several new therapeutic targets to block the cellular events intrinsic to the disease. This article gives an overview of the results for adjunct therapies already tested in clinical studies and highlights experimental concepts for novel treatment strategies. PMID- 24046170 TI - [Tear in retinal pigment epithelium under anti-VEGF therapy for exudative age related macular degeneration : function recovery under intensive therapy]. AB - This article reports the case of a 72-year-old woman with pigment epithelial detachment with occult choroidal neovascularization (CNV) in exudative age related macular degeneration (AMD) which developed under anti-vascular endothelial growth factor (VEGF) therapy of a tear in the retinal pigment epithelium (RPE). In the area of free RPE autofluorescence was completely absent and the microperimetry in this area showed an absolute scotoma. The visual acuity was 0.1. After continuation of anti-VEGF therapy because of persistent subretinal and intraretinal fluid over 3 years an increased autofluorescence was observed and the microperimetry showed an increase in central retinal sensitivity. The central visual acuity improved to 0.5 and in this area a whitish subretinal tissue formed morphologically. In the spectral domain optical coherence tomography (SD-OCT) image this structure was hyperreflective which might suggest a certain regeneration process of the RPE under anti-VEGF-therapy. PMID- 24046171 TI - [Therapy refractory stromal Herpes keratitis under aciclovir]. AB - We report the case of a patient with suspected ulcerating necrotizing herpetic stromal keratitis who showed no improvement despite intensive (amongst others antiherpetic) topical and systemic therapy. The ulcer healed following amniotic membrane transplantation and penetrating excimer laser keratoplasty was performed to improve visual acuity. The excision showed deep stromal proof of herpes simplex virus (HSV) type 1 antigens. PMID- 24046172 TI - [Recurrent unilateral pupillary distortion]. PMID- 24046173 TI - [Peripheral ulcerative keratitis in a 24-year-old patient]. AB - A 24-year-old female patient was admitted to hospital with a deep stromal corneal defect on the right eye and a melting marginal keratitis on the left eye with a differential diagnosis of Mooren's ulcer. Despite intensive topical and systemic therapy, the ulcer perforated 3 days later and perforating keratoplasty a chaud was performed. The histological examination of the cornea showed a mainly intact corneal structure with a sharp demarcation line between the melting process close to the limbus and the unaffected tissue. The limbal area was interspersed with inflammatory cells. During the subsequent clinical course, despite intensive immunosuppressive therapy with Cellcept, systemic and local cyclosporin and methotrexate the left eye perforated and was subsequently treated by perforating keratoplasty. Under immunosuppression with methotrexate and local steroids no recurrence or progression has occurred so far. PMID- 24046174 TI - [Chronic dacryocystitis in a pediatric patient: transcanalicular endoscopic assisted removal of iatrogenic foreign body from the lacrimal sac]. AB - Congenital dacryostenoses are frequent problems in pediatric ophthalmology. For surgical intervention various transcanalicular techniques by lining the tear ducts with silicone tubes are available. A 5-year-old child was presented with severe chronic dacryocystitis of both eyes after several interventions for lacrimal duct surgery with silicone intubation had been carried out. Using endoscopy the fragments of intrasaccal silicone tubes could be localized and the foreign bodies could be removed by endoscopic transcanicular surgery. The complete removal of silicone tubes is obligatory otherwise severe complications can occur. PMID- 24046175 TI - Outcomes of peritoneal dialysis catheter reinsertion: does the cause of initial removal matter? AB - PURPOSE: In this study, we aimed to compare patient and technique survival between the patients, in whom peritoneal dialysis (PD) catheter was removed due to severe peritonitis and then it was reinserted, and those, in whom PD catheter was removed due to non-peritonitis causes and then it was reinserted. METHOD: Sixty-two patients, in whom PD catheter was reinserted surgically, were retrospectively analyzed in this cohort study. Group 1 consisted of 27 patients in whom PD catheter was removed due to severe peritonitis, whereas Group 2 consisted of 35 patients in whom PD catheter was removed due to non-peritonitis causes. RESULTS: There was no significant difference between Group 1 and Group 2 in terms of the estimation of overall patient survival [43 months (95 % CI 43.6 83.7) versus 80 months (95 % CI 52.8-107.3, p 0.362]. Similarly, there was no significant difference between Group 1 and Group 2 in terms of the estimation of overall technique survival [82 months (95 % CI 0-166.0) versus 31 months (95 % CI 9.7-52.3), p 0.346]. CONCLUSION: Our results suggest that there was no significant effect of causes of PD catheter removal (peritonitis vs. non peritonitis) on the outcomes of PD treatment. PMID- 24046176 TI - Vascular access for hemodialysis: postoperative evaluation and function monitoring. AB - Vascular access (VA) survival is a crucial issue associated with morbidity and mortality of patients undergoing maintenance hemodialysis. The development of stenosis is the major factor that leads to VA failure. Strategies for early detection of lesions within a VA system before serious complications arise are therefore crucial. The implementation of a VA surveillance program could lead to timely detection of VA dysfunction and referral for correction, reduction in central venous catheter use and decrease in hospitalization and VA-related cost. Suggested methods for arteriovenous fistulae and grafts surveillance include blood flow measurement, static pressure evaluation and duplex ultrasonography. Physical examination is an accepted method in contrast to nonstandardized dynamic pressure measurement for grafts. Access recirculation (not urea based) and dynamic pressure measurements are accepted methods for fistulae. Decreasing URR or Kt/V (otherwise unexplained) and increased (negative) arterial pressure in the dialysis machine are methods of limited sensitivity and specificity for both fistulae and grafts. Measurement of access blood flow has been proposed as the gold standard for the screening of all types of VA. Access flow can be measured by various techniques which are direct or indirect. Several studies about VA surveillance programs have demonstrated conflicting results. Larger, randomized controlled trials need to be carried out in order to clarify whether surveillance programs are necessary and which is the best surveillance strategy for each type of VA. PMID- 24046177 TI - Sexual dysfunction is more than twice as frequent in Danish female predialysis patients compared to age- and gender-matched healthy controls. AB - PURPOSE: This study aimed to compare sexual dysfunction in Danish female predialysis patients with chronic kidney disease (CKD) stage 4-5 with age-matched healthy women in Denmark. METHODS: Twenty-seven adult female predialysis patients (CKD stage 4-5 ~ creatinine clearance <= 30 ml/min) without diagnosed depression and 54 randomly assigned healthy female controls completed the questionnaires Female Sexual Function Index, Female Sexual Distress Scale, and the Major Depression Inventory. RESULTS: Predialysis patients reported lower Female Sexual Function Index scores compared to the controls (14.2 +/- 2.1 vs. 20.1 +/- 1.7, respectively, p = 0.048), more frequent sexual distress (44 vs. 22 %, respectively, p = 0.044), and more frequent sexual dysfunction (41 vs. 17 %, respectively, p = 0.041). There was no difference between the patients' and the controls' depression scores (12.2 +/- 2.2 vs. 8.6 +/- 1.1, respectively, p = 0.180). CONCLUSION: Sexual dysfunction was found to be more than two times as frequent in Danish female predialysis patients with CKD stage 4-5 compared to age and gender-matched healthy controls, and this result emphasizes the need for attention towards sexual function in the treatment for CKD. PMID- 24046179 TI - Erdheim-Chester disease and Schnitzler syndrome: so near, and yet so far. PMID- 24046178 TI - TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells. AB - Acute myelogenous leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), which represent the ultimate therapeutic target for AML. Recent studies have identified several AML LSC-specific surface antigens as candidate targets of therapeutic molecules. T cell immunoglobulin mucin-3 (TIM-3) is expressed on LSCs in most types of AML, with the exception of acute promyelocytic leukemia, but not on normal hematopoietic stem cells (HSCs). In xenograft models reconstituted with human AML LSCs or HSCs, an anti-human TIM-3 mouse IgG2a antibody with cytotoxic activities eradicates AML LSCs in vivo, but does not affect normal human hematopoiesis. Thus, TIM-3 is a promising therapeutic target for the eradication of AML LSCs. PMID- 24046180 TI - Myeloid/NK cell acute leukemia with unique blast morphology: de novo or secondary leukemia? PMID- 24046181 TI - Genetic screening services provided in Turkey. AB - In Turkey, the rate of consanguineous marriage is quite high (22-24 %) and as a result, the incidence of autosomal recessive diseases and congenital anomalies is also very high and gives rise to a serious public health problem. In the last three decades, great effort has been made to avoid increases in the prevalence of these hereditary diseases. For this purpose, population-based premarital, prenatal, neonatal and adult genetic screening programs are performed in various centers such as Community Health Centers, Early Diagnosis of Cancer and Education Centers (KETEM), Prenatal and Neonatal Departments of Universities and State Hospitals and Thalessemia Screening Centers. Such centers are staffed by health professionals including physicians, family physicians, nurses, midwives, biologists and medical geneticists. Genetic counseling is also provided to patients attending these centers after screening tests are performed. Since there are no specialized training programs for genetic counselors, genetic counseling is generally provided by doctors or medical geneticists. The aim of this paper is to give an overview of the genetic screening services provided in Turkey, the prevalence of genetic diseases and the design of intensive educational programs for health professionals. PMID- 24046182 TI - Coagulopathy associated with traumatic brain injury. AB - Coagulopathy is often observed after traumatic brain injury (TBI), but the pathogenic mechanisms of this phenomenon remain elusive. Brain injury is the leading cause of trauma deaths, and the development of coagulopathy after TBI is associated with increased morbidity and mortality in these patients. The coagulopathy after TBI comprises a hypocoagulable and a hypercoagulable state with hemorrhagic and thrombotic phenotypes that are both associated with worse outcome. Some theories of its pathogenesis include massive release of tissue factor, altered protein C homeostasis, microparticle upregulation, and platelet hyperactivity. This article aims to examine the coagulopathy associated with blunt head injury, to review its effect on progression of hemorrhagic injury, and to discuss the possible relevant pathophysiological mechanisms. PMID- 24046184 TI - Defining engagement in adolescent substance abuse treatment. AB - Youth engagement in substance use treatment is an important construct for research and practice, but it has been thinly and inconsistently defined in the literature. Most research has measured engagement by initiation, attendance, and retention in treatment. Because youth generally enter substance use treatment as a result of compliance with external requirements, defining engagement in this way might be insufficient. This qualitative participatory research study describes five focus groups with 31 adults working with youth in substance use treatment. Focus groups were designed and conducted by youth researchers in collaboration with university-based partners. We categorized participants' descriptions of engagement into five domains, identified as "CARES": Conduct, Attitudes, Relationships, Empowerment, and Social Context. These domains represent a comprehensive and ecologically-based definition of engagement that situates engagement in the context and trajectory of youth development, has clear implications for assertive clinical practice, and provides a foundation for developing an operationalized measure. PMID- 24046183 TI - The evolving role of diffusion magnetic resonance imaging in movement disorders. AB - Significant advances have allowed diffusion magnetic resonance imaging (MRI) to evolve into a powerful tool in the field of movement disorders that can be used to study disease states and connectivity between brain regions. Diffusion MRI is a promising potential biomarker for Parkinson's disease and other forms of parkinsonism, and may allow the distinction of different forms of parkinsonism. Techniques such as tractography have contributed to our current thinking regarding the pathophysiology of dystonia and possible mechanisms of penetrance. Diffusion MRI measures could potentially assist in monitoring disease progression in Huntington's disease, and in uncovering the nature of the processes and structures involved the development of essential tremor. The ability to represent structural connectivity in vivo also makes diffusion MRI an ideal adjunctive tool for the surgical treatment of movement disorders. We review recent studies using diffusion MRI in movement disorders research and present the current state of the science as well as future directions. PMID- 24046186 TI - 4-methoxychalcone enhances cisplatin-induced oxidative stress and cytotoxicity by inhibiting the Nrf2/ARE-mediated defense mechanism in A549 lung cancer cells. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator for the protection of cells against oxidative and xenobiotic stresses. Recent studies have demonstrated that high constitutive expression of Nrf2 is observed in many types of cancer cells showing resistance to anti-cancer drugs, suggesting that the suppression of overexpressed Nrf2 could be an attractive therapeutic strategy to overcome cancer drug resistance. In the present study, we aimed to find small molecule compounds that enhance the sensitivity of tumor cells to cisplatin induced cytotoxicity by suppressing Nrf2-mediated defense mechanism. A549 lung cancer cells were shown to be more resistant to the anti cancer drug cisplatin than HEK293 cells, with higher Nrf2 signaling activity; constitutively high amounts of Nrf2-downstream target proteins were observed in A549 cells. Among the three chalcone derivatives 4-methoxy-chalcone (4-MC), hesperidin methylchalcone, and neohesperidin dihydrochalcone, 4-MC was found to suppress transcriptional activity of Nrf2 in A549 cells but to activate it in HEK293 cells. 4-MC was also shown to down-regulate expression of Nrf2 and the downstream phase II detoxifying enzyme NQO1 in A549 cells. The PI3K/Akt pathway was found to be involved in the 4-MC-induced inhibition of Nrf2/ARE activity in A549 cells. This inhibition of Nrf2 signaling results in the accelerated generation of reactive oxygen species and exacerbation of cytotoxicity in cisplatin-treated A549 cells. Taken together, these results suggest that the small molecule compound 4-MC could be used to enhance the sensitivity of tumor cells to the therapeutic effect of cisplatin through the regulation of Nrf2/ARE signaling. PMID- 24046188 TI - [Diagnosis of and therapy for choroidal melanoma]. AB - BACKGROUND: Prognosis evaluation of patients with choroidal and ciliary melanoma has experienced recent progress through tumour sampling and cytogenetic analysis of metastatic risk. By allocating tumor extension, height and linear basal diameter to defined TNM stages, an estimation of prognosis can also be made without invasive tissue sampling. METHODS: Therapeutic strategies of organ preserving irradiation using different sources have clearly come to the forefront. RESULTS: Due to microscopic haematogenous spreading of tumour cells prior to treatment, the metastatic risk following radiation of any form is not influenced in comparison to primary enucleation. CONCLUSION: However, metastatic disease still remains a fatal condition which currently may only be influenced by early detection and treatment of uveal melanomas. PMID- 24046187 TI - S-adenosyl methionine prevents endothelial dysfunction by inducing heme oxygenase 1 in vascular endothelial cells. AB - S-adenosyl methionine (SAM) is a key intermediate in the metabolism of sulfur amino acids and is a major methyl donor in the cell. Although the low plasma level of SAM has been associated with atherosclerosis, the effect of SAM administration on atherosclerosis is not known. Endothelial dysfunction is an early prerequisite for atherosclerosis. This study was undertaken to investigate the possible preventive effect of SAM on endothelial dysfunction and the molecular mechanism of its action. SAM treatment prevented endothelial dysfunction in high fat diet (HFD)-fed rats. In cultured human aortic endothelial cells, linoleic acid (LA) increased and SAM decreased cell apoptosis and endoplasmic reticulum stress. Both LA and SAM increased heme oxygenase-1 (HO-1) expression in an NF-E2-related factor 2-dependent manner. However, knockdown of HO-1 reversed only the SAM-induced preventive effect of cell apoptosis. The LA induced HO-1 expression was dependent on PPARalpha, whereas SAM induced HO-1 in a PPAR-independent manner. These data demonstrate that SAM treatment prevents endothelial dysfunction in HFDfed animals by inducing HO-1 in vascular endothelial cells. In cultured endothelial cells, SAM-induced HO-1 was responsible for the observed prevention of cell apoptosis. We propose that SAM treatment may represent a new therapeutic strategy for atherosclerosis. PMID- 24046189 TI - Nutrition support is a relatively new field. PMID- 24046190 TI - Integrating patient-centered care and clinical ethics into nutrition practice. AB - The purpose of this article is to present the application of patient-centered care and clinical ethics into nutrition practice, illustrate the process in a case study, and promote change in the current healthcare clinical ethics model. Nutrition support clinicians have an opportunity to add another dimension to their practice with the incorporation of patient-centered care and clinical ethics. This represents a culture change for healthcare professionals, including nutrition support clinicians, patients and their family. All of these individuals are stakeholders in the process and have the ability to modify the current healthcare system to improve communication and facilitate a change by humanizing nutrition support practice. Nutrition support is a medical, life-sustaining treatment, and the use of this therapy requires knowledge by the nutrition support clinician of patient-centered care concepts, preventive clinical ethics, religion/spirituality and cultural diversity, palliative care team role, and advance care planning. Integrating these into the practice of nutrition support is an innovative approach and results in new knowledge that requires a change in the culture of care and engagement and empowerment of the patient and their family in the process. This is more than a healthcare issue; it involves a social/family conversation movement that will be enhanced by the nutrition support clinician's participation. PMID- 24046191 TI - Evidence for the involvement of epigenetics in the progression of renal fibrogenesis. AB - Epigenetics are omnipresent in eukaryotic cells and influence cell differentiation and maintenance of cell metabolism in health and disease. Here, we discuss how the 'second genetic code' impacts the fate of the injured kidney. We provide a glimpse of how recent insights into epigenetic mechanisms of chronic kidney disease might lead to novel diagnostic and therapeutic tools. PMID- 24046192 TI - Molecular genetics of familial hematuric diseases. AB - The familial hematuric diseases are a genetically heterogeneous group of monogenic conditions, caused by mutations in one of several genes. The major genes involved are the following: (i) the collagen IV genes COL4A3/A4/A5 that are expressed in the glomerular basement membranes (GBM) and are responsible for the most frequent forms of microscopic hematuria, namely Alport syndrome (X-linked or autosomal recessive) and thin basement membrane nephropathy (TBMN). (ii) The FN1 gene, expressed in the glomerulus and responsible for a rare form of glomerulopathy with fibronectin deposits (GFND). (iii) CFHR5 gene, a recently recognized regulator of the complement alternative pathway and mutated in a recently revisited form of inherited C3 glomerulonephritis (C3GN), characterized by isolated C3 deposits in the absence of immune complexes. A hallmark feature of all conditions is the age-dependent penetrance and a broad phenotypic heterogeneity in the sense that subsets of patients progress to added proteinuria or proteinuria and chronic renal failure that may or may not lead to end-stage kidney disease (ESKD) anywhere between the second and seventh decade of life. In addition to other excellent laboratory tools that assist the clinician in reaching the correct diagnosis, the molecular analysis emerges as the gold standard in establishing the diagnosis in many cases of doubt due to equivocal findings that complicate the differential diagnosis. Recent work led to the description of candidate genetic modifiers which confer a variable risk for progressing to chronic renal failure when co-inherited on the background of a primary glomerulopathy. Finally, more families are still waiting to be studied and more genes to be mapped and cloned that are responsible for other forms of heritable hematuric diseases. The study of such genes and their protein products will likely shed more light on the structure and function of the glomerular filtration barrier and other important glomerular components. PMID- 24046193 TI - A new equation to estimate the glomerular filtration rate in children, adolescents and young adults. AB - BACKGROUND: A new estimated glomerular filtration rate (eGFR) equation, designed for isotope dilution mass spectrometry-standardized serum creatinine (Scr), is presented for use in children, adolescent boys and girls and young adults. METHODS: The new equation, eGFR = 107.3/(Scr/Q), is based on the concept of normalized Scr: Q is the normalization value and is considered as the Scr concentration for the average healthy child, adolescent or young adult of a specific height (L) and is modeled as a height-dependent polynomial of the fourth degree. RESULTS: The well-known Schwartz equation [eGFR = kL/Scr, k = 0.413 (Schwartz) or k = 0.373 (Schwartz-Lyon)] for children between 1 and 14 years can be seen as a special case of the new equation for which the Q-polynomial is simplified to a linear equation: Q = 0.0035 * L (cm). The new eGFR equation has been validated in a data set of n = 750 children, adolescents and young adults aged 10-25, against the true GFR (inulin method), and outperforms the selected (but most used) creatinine-based eGFR equations for children, mainly in the healthy GFR region. CONCLUSIONS: The new Q(height)-eGFR equation serves as an excellent screening tool for kidney disease in 1-25-year-old children, adolescents and young adults. PMID- 24046194 TI - Definition, identification and treatment of resistant hypertension in chronic kidney disease patients. AB - Resistant hypertension, the inability to achieve goal blood pressure despite the use of three or more appropriately dosed antihypertensive drugs (including a diuretic), remains a common clinical problem, especially in patients with chronic kidney disease (CKD). While the exact prevalence and prognosis of resistant hypertension in CKD patients remain unknown, resistant hypertension likely contributes significantly to increased cardiovascular risk and progression of kidney disease in this population. We review the identification and evaluation of patients with resistant hypertension, including the importance of 24-h ambulatory blood pressure monitoring in the identification of 'white-coat', 'masked' and 'non-dipper' hypertension, the latter of which has particular clinical and therapeutic importance in patients with resistant hypertension and CKD. We then discuss treatment strategies for resistant hypertension that target the pathophysiologic mechanisms underlying resistance to treatment, including persistent volume excess, incomplete renin-angiotensin-aldosterone system blockade and inadequate nocturnal blood pressure control. Finally, we propose a treatment algorithm for evaluation and treatment of resistant hypertension in patients with CKD. PMID- 24046195 TI - Hepcidin--a well-known iron biomarker with prognostic implications in chronic kidney disease. PMID- 24046196 TI - Informative cues can slow search: the cost of matching a specific template. AB - During visual search, observers hold in mind a search template, which they match against the stimulus. To characterize the content of this template, we trained observers to discriminate a set of artificial objects at an individual level and at a category level. The observers then searched for the objects on backgrounds that camouflaged the features that defined either the object's identity or the object's category. Each search stimulus was preceded by the target's individual name, its category name, or an uninformative cue. The observers' task was to locate the target, which was always present and always the only figure in the stimulus. The results showed that name cues slowed search when the features associated with the name were camouflaged. Apparently, the observers required a match between their mental representation of the target and the stimulus, even though this was unnecessary for the task. Moreover, this match involved all distinctive features of the target, not just the features necessary for a definitive identification. We conclude that visual search for a specific target involves a verification process that is performed automatically on all of the target's distinctive features. PMID- 24046198 TI - Latin American course in pediatric neurosurgery: 10 years of history. PMID- 24046197 TI - Cattle egrets as a biosentinels of persistent organic pollutants exposure. AB - We investigated selected chlorinated pollutants (beta-HCH, gamma-HCH, DDDs, DDEs, o,p'-DDT, p,p'-DDT, heptachlor, aldrin, dieldrin, and endrin) in the Lahore and the Sialkot districts of Pakistan, using eggs of cattle egret (Bubulcus ibis) collected during May and June 2007. The pollutant with highest level and frequency was SigmaDDT, followed by beta-HCH, gamma-HCH, heptachlor, aldrin, dieldrin, and endrin in descending order. The concentration(s) were significantly higher in Sialkot heronry for all the pollutants (except p,p'-DDT) than in Lahore. The values for DDTs, beta-HCH, gamma-HCH, and heptachlor were significantly higher (p < 0.05) in the egg(s) than in sediment(s) and in the chicks' diet, due to biomagnification. Among DDTs analogues, p,p'-DDD was the major contaminant with >60 % of total DDT burden, reflecting the widespread aged as well as recent use of DDT as well as anaerobic degradation (DDD/DDE > 1 in many cases) in the nearby paddy soils. In few samples, p,p'-DDT/(DDD + DDE) > 0.5 suggested the recent emission patterns from surrounding contaminated areas of demolished DDT units and obsolete pesticide stores. The higher levels of HCHs (i.e., beta-HCH) in the samples collected from Sialkot indicate exposure from long-term agricultural use. Overall, concentrations of all studied POPs were less than the threshold levels known to affect reproduction. Nevertheless, total DDTs and/or HCHs burdens in some eggs contained concentrations of greater than what would educe adverse effects on birds. This is among few studies on OCPs exposure to avian species, which provide the evidence of Pakistan's contribution toward the Global POPs emission. PMID- 24046199 TI - Genomics of cervical cancer and the role of human papillomavirus pathobiology. PMID- 24046200 TI - Cannabinoids in exhaled breath following controlled administration of smoked cannabis. AB - BACKGROUND: Delta(9)-Tetrahydrocannabinol (THC), 11-nor-9-carboxy-THC (THCCOOH), and cannabinol (CBN) were measured in breath following controlled cannabis smoking to characterize the time course and windows of detection of breath cannabinoids. METHODS: Exhaled breath was collected from chronic (>=4 times per week) and occasional (10 % of the total) were identified as C19:0 omega8c cyclo (24.6 %), C16:0 (24.3 %) and C18:1 omega7c (13.1 %). The DNA G+C content was determined to be 71.5 mol%. The major polar lipids were identified as phosphatidylglycerol, phosphatidylethanolamine, one unknown phospholipid and one unknown aminolipid. The major ubiquinone was determined to be Q-10. A phylogenetic tree based on 16S rRNA gene sequences showed that strain 04SU4-P(T) forms an evolutionary lineage within the genus Dongia and its nearest neighbour is Dongia mobilis LM22(T) (98.0 % sequence similarity). Genomic DNA-DNA hybridization of stain 04SU4-P(T) with D. mobilis LM22(T) showed relatedness of only 34.2 %. The phenotypic characteristics indicate the strain 04SU4-P(T) can be distinguished from the sole member of the genus Dongia. On the basis of the data presented in this study, strain 04SU4-P(T) represents a novel species, for which the name Dongia rigui is proposed. The type strain is 04SU4-P(T) (KCTC 23341(T) = JCM 17521(T)). PMID- 24046207 TI - Altuibacter lentus gen. nov., sp. nov., a novel member of family Flavobacteriaceae isolated from deep seawater of the South China Sea. AB - A novel chemoheterotrophic, aerobic, Gram-negative, rod-shaped, yellow-pigmented, bacterial strain JLT2010(T) was isolated from deep seawater of the South China Sea. Phylogenetic analysis based on the 16S rRNA gene sequences revealed that strain JLT2010(T) belongs to the family Flavobacteriaceae and is most closely related to Ulvibacter antarcticus IMCC3101(T) with 95.7 % similarity. Some phenotypic characteristics such as the absence of flexirubin-type pigments, growth at 37 degrees C, hydrolysis of casein differentiated strain JLT2010(T) from the genus Ulvibacter as well as other genera in the family Flavobacteriaceae. The DNA G+C content of the strain JLT2010(T) was found to be 35.7 mol% and the major respiratory quinone was found to be MK-6. On the basis of phenotypic and phylogenetic features, JLT2010(T) is classified as a novel genus and species within the family Flavobacteriaceae, for which the name Altuibacter lentus gen. nov., sp. nov. is proposed. The type strain is JLT2010(T) (=JCM 18884(T) = CGMCC 1.12167(T)). PMID- 24046209 TI - The tobacco endgame in Hong Kong: public support for a total ban on tobacco sales. AB - BACKGROUND: Tobacco endgame policies are increasingly advocated to end tobacco use. This study investigated public support for a total ban on tobacco sales, use and possession in Hong Kong. METHODS: A telephone survey was conducted among 1537 randomly selected residents in 2012 to assess their support for a total ban on tobacco sales, usage and possession. Information on sociodemographic characteristics, smoking, and second hand smoke exposure were collected. Logistic regression was used to investigate factors associated with support for a total ban. RESULTS: Most of the never smokers (75.3%), ex-smokers (63.9%), and nearly half of current smokers (48.9%) backed some form of a total ban on tobacco. A total ban on tobacco sales was the most popular option among the three groups, with over half (64.8%) of all respondents supporting a ban within 10 years. Current smoking and higher educational attainment were associated with less support for a total ban on tobacco sales. Among current smokers, having quit intentions and attempts to quit were associated with support for a total ban. CONCLUSIONS: A total ban on tobacco sales was supported by most respondents. Ex smokers and current smokers also voiced substantial support, although less than never smokers. A total ban on tobacco sales before 2022 should be the goal as it is supported by most of the respondents. Interim tobacco control measures, such as tax increases, expansion of smoking cessation services and plain packaging should be implemented to help current smokers quit and reduce smoking initiation before implementation of the ban. PMID- 24046210 TI - Youth exposure to in-vehicle second-hand smoke and their smoking behaviours: trends and associations in repeated national surveys (2006-2012). AB - OBJECTIVE: To extend the limited international evidence on youth in-vehicle second-hand smoke (SHS) exposure by examining trends in New Zealand, a country with a national smoke-free goal and indoors smoke-free environment legislation. METHODS: We tracked exposure rates and explored the associations between in vehicle SHS exposure and smoking behaviours. In-home exposure was also examined for comparative purposes. Data were collected in annual surveys of over 25 000 year 10 school students (14-15-year olds) for a 7-year period (2006-2012). Questions covered smoking behaviour, exposure to smoking and demographics. RESULTS: Youth SHS exposure rates in-vehicle and in-home trended down slightly over time (p<0.0001 for both) with 23% exposed in-vehicle in the previous week in 2012. However, marked inequalities in exposure between ethnic groups, and by school-based socioeconomic position, persisted. The strongest association with SHS exposure was parental smoking (eg, for both parents versus neither smoking in 2012: in-vehicle SHS exposure adjusted OR: 7.4; 95% CI: 6.5 to 8.4). After adjusting for seven other factors associated with initiation, logistic regression analyses revealed statistically significant associations of in-vehicle SHS exposure with susceptibility to initiation and smoking. CONCLUSIONS: The slow decline in SHS exposure in vehicles and the lack of progress in reducing relative inequalities is problematic. To accelerate progress, the New Zealand Government could follow the example of other jurisdictions and prohibit smoking in cars carrying children. Other major policy interventions, beside enhanced smoke-free environments, will also likely be required if New Zealand is to achieve its 2025 smoke-free nation goal. PMID- 24046208 TI - Inflammatory stress and sarcomagenesis: a vicious interplay. AB - Chronic inflammation represents one of the hallmarks of cancer, but its role in sarcomagenesis has long been overlooked. Sarcomas are a rare and heterogeneous group of tumors of mesenchymal origin accounting for less than 1 % of cancers in adults but 21 % of cancers in the pediatric population. Sarcomas are associated with bad prognosis, and their management requires a multidisciplinary team approach. Several lines of evidence indicate that inflammation has been implicated in sarcomagenesis leading to the activation of the key transcription factors HIF-1, NF- kappaB, and STAT-3 involved in a complex inflammatory network. In the past years, an increasing number of new targets have been identified in the treatment of sarcomas leading to the development of new drugs that aim to interrupt the vicious connection between inflammation and sarcomagenesis. This article makes a brief overview of preclinical and clinical evidence of the molecular pathways involved in the inflammatory stress response in sarcomagenesis and the most targeted therapies. PMID- 24046211 TI - Impact of tobacco control interventions on socioeconomic inequalities in smoking: review of the evidence. AB - OBJECTIVE: We updated and expanded a previous systematic literature review examining the impact of tobacco control interventions on socioeconomic inequalities in smoking. METHODS: We searched the academic literature for reviews and primary research articles published between January 2006 and November 2010 that examined the socioeconomic impact of six tobacco control interventions in adults: that is, price increases, smoke-free policies, advertising bans, mass media campaigns, warning labels, smoking cessation support and community-based programmes combining several interventions. We included English-language articles from countries at an advanced stage of the tobacco epidemic that examined the differential impact of tobacco control interventions by socioeconomic status or the effectiveness of interventions among disadvantaged socioeconomic groups. All articles were appraised by two authors and details recorded using a standardised approach. Data from 77 primary studies and seven reviews were synthesised via narrative review. RESULTS: We found strong evidence that increases in tobacco price have a pro-equity effect on socioeconomic disparities in smoking. Evidence on the equity impact of other interventions is inconclusive, with the exception of non-targeted smoking cessation programmes which have a negative equity impact due to higher quit rates among more advantaged smokers. CONCLUSIONS: Increased tobacco price via tax is the intervention with the greatest potential to reduce socioeconomic inequalities in smoking. Other measures studied appear unlikely to reduce inequalities in smoking without specific efforts to reach disadvantaged smokers. There is a need for more research evaluating the equity impact of tobacco control measures, and development of more effective approaches for reducing tobacco use in disadvantaged groups and communities. PMID- 24046212 TI - Pro-smoking apps: where, how and who are most at risk. AB - BACKGROUND: Pro-smoking applications (app) provide information about brands of tobacco products, where to buy them, and encourage their use. It is unclear in which countries these apps are being downloaded, or whether app stores play a role in promoting or regulating these apps, particularly those that appear to target children. METHOD: The lifetime popularity of 107 pro-smoking apps was investigated, using a third-party app metrics service that aggregates data from app stores about app download popularity by country. Apps were deemed popular if at any time in their lifespan they achieved a top 25 ranking overall across all apps, or a top 25 ranking in any particular category of apps, such as 'educational games'. RESULTS: Fifty-eight pro-smoking apps reached 'popularity' status in Apple and Android stores in one or more of 49 countries, particularly Italy, Egypt, Germany, Belgium and the USA. The daily downloads in each country ranged from approximately 2000 to 80 000. The Apple store featured five of the pro-smoking apps in various categories, and two apps were featured by the Android market. Two pro-smoking apps in the Apple store were extremely popular in the 'Educational Games' and 'Kids' Games' categories. CONCLUSIONS: Pro-smoking apps were popular in many countries. Most apps were assigned to entertainment and games categories, with some apps specifically targeting children through placement in categories directed at children. App stores that feature pro-smoking apps may be in violation of tobacco control laws. PMID- 24046213 TI - Using a new, low-cost air quality sensor to quantify second-hand smoke (SHS) levels in homes. AB - OBJECTIVE: To determine if a low-cost particle counter, the Dylos DC 1700, can be used in homes to quantify second-hand smoke (SHS) concentrations. METHODS: Participants were recruited from a hospital-based study of attitudes on smoking. Two photometric devices (Dylos DC1700 and Sidepak AM510 Personal Aerosol Monitor) capable of measuring and logging concentrations of particulate matter were placed in smoking and non-smoking homes for approximately 24h. Acquired data were randomly allocated to one of two groups: one was used to generate a calibration equation using regression techniques; the second was used for validation of the generated model. The mean difference and limits of agreement between the two instruments were calculated using the validation dataset. Summary air-quality results were also compared across the entire dataset. RESULTS: Over 500 001 minute concentration measurements were collected from 34 homes. 25 301 randomly selected paired-measurements were used to generate a calibration equation (R(2) 0.86) converting the particle number concentration from the Dylos to a mass concentration of PM2.5 as measured by the Sidepak. The mean difference (limits of agreement) between the remaining 25 102 paired measurements was -0.09 (-49.7 to 49.5) with 3.2% of values outside the limits of agreement. Differences in the air quality information generated by the two instruments were generally small and unlikely to impact on user interpretation. CONCLUSIONS: The Dylos appears to be a valid instrument for measuring PM2.5 in household settings. The Dylos may be useful in air quality-based interventions designed to change smokers' behaviours with the possibility of encouraging cessation and/or smoke-free homes. PMID- 24046214 TI - Weight change and health related quality of life: population-based longitudinal study of the effects of health related quality of life on the success of weight management. AB - Our aim was to investigate how health related quality of life (HRQoL) influence on the success of weight management and how to utilize this information. Population-based longitudinal study. A community sample of apparently healthy middle-aged individuals living in Western Finland were invited to clinical survey in order to assess total cardiovascular risk among people who had at least one cardiovascular risk factor but no previous diagnoses of any long-lasting disease. A total of 2,752 individuals, aged 45-70 years, enrolled. The individuals completed HRQoL questionnaire before laboratory tests were completed and overweight people were instructed to lose weight at least 5 %. A physician examined 1950 high risk people during the years 2005-2007. Three years later a trained nurse invited them for a control examination, 1,287 high risk subjects participated, 1,049 had completely filled the questionnaires and 906 of them were overweight or obese at baseline. We assessed the success in weight management in this group of participants. The subjects (53 % women with mean age of 59 +/- 7 years) had mean body mass index of 39.6 +/- 4.6 kg/m2. During the 3 years follow up period 18 % of them had lost weight >=5, 70 % had stabilized their weight and 12 % had gained weight >=5 %. Subjects who had gained weight had worse results in every item of HRQoL both mental and physical at baseline. The results of the HRQoL questionnaire suggested that obesity and deteriorating quality of life interrelate. PMID- 24046215 TI - Social determinants of childhood asthma symptoms: an ecological study in urban Latin America. AB - Asthma is an important public health problem in urban Latin America. This study aimed to analyze the role of socioeconomic and environmental factors as potential determinants of asthma symptoms prevalence in children from Latin American (LA) urban centers. We selected 31 LA urban centers with complete data, and an ecological analysis was performed. According to our theoretical framework, the explanatory variables were classified in three levels: distal, intermediate, and proximate. The association between variables in the three levels and prevalence of asthma symptoms was examined by bivariate and multivariate linear regression analysis weighed by sample size. In a second stage, we fitted several linear regression models introducing sequentially the variables according to the predefined hierarchy. In the final hierarchical model Gini Index, crowding, sanitation, variation in infant mortality rates and homicide rates, explained great part of the variance in asthma prevalence between centers (R(2) = 75.0 %). We found a strong association between socioeconomic and environmental variables and prevalence of asthma symptoms in LA urban children, and according to our hierarchical framework and the results found we suggest that social inequalities (measured by the Gini Index) is a central determinant to explain high prevalence of asthma in LA. PMID- 24046216 TI - Antioxidant lignans from the roots of Vladimiria muliensis. AB - Three new lignans (1, 2, and 8) and ten known ones (3-7, 9-13) were isolated from the roots of Vladimiria muliensis. Their structures and configurations were elucidated by means of spectroscopic techniques (IR, MS, NMR, and CD) and chemical methods. The isolated compounds were evaluated for their antioxidant and antibacterial activities. The antioxidant activity was the greatest for lignans 7 and 10 with IC50 values of 11.2 and 7.3 uM against DPPH radical, and of 1.6 and 1.7 uM against ABTS+ radical, respectively. Moreover, 7 also displayed broad spectrum antibacterial activity with MIC values around 7.25 ug/mL. PMID- 24046217 TI - Triterpene glycosides from the leaves of Pittosporum angustifolium. AB - Phytochemical investigation of the leaves of Pittosporum angustifolium resulted in the isolation and structural elucidation of nine new triterpene saponins, named pittangretosides A-I (1-9), together with a known compound (10). Mainly by NMR and HRESIMS experiments, eight compounds were identified as A1-barrigenol glycosides (1-7, 10), whereas two compounds exhibited an unusual 17,22-seco backbone of oleanolic acid (8, 9). All compounds were evaluated for their in vitro cytotoxicities against human urinary bladder carcinoma cells (5637). Only compounds with an angeloyl-residue at C-22 of the aglycone (1-4 and 10) showed antiproliferative effects with IC50 values of 4.1, 5.2, 2.1, 17.9, and 2.4 uM, respectively. PMID- 24046218 TI - Death causes and pathogens analysis of systemic lupus erythematosus during the past 26 years. AB - Different causes of mortality have been described over different decades followed by description of pathogens identified from infective episodes that led to death. A retrospective review was performed in 3,831 hospitalized systemic lupus erythematosus (SLE) patients in Peking Union Medical College Hospital from January 1986 to April 2012. The primary causes of death were identified, and the constituent ratio of specific death causes during different periods was compared. Among 3,831 hospitalized SLE patients, 268 patients died, accounting for 7.0 %. No significant difference of death rate was found between men and women, P = 0.404. The three most frequent death causes according to decade were as follows: for 1986-1995, renal involvement, lupus encephalopathy, and infections; for 1996 2005, infections, lupus encephalopathy, and renal involvement; and for 2006-2012, infections, lupus encephalopathy, and pulmonary hypertension. Certain types of deaths, primarily related to lupus activity, have decreased over time, whereas infections, often attributed to the use of corticosteroid and immunosuppressant medications, have increased gradually and changed to the most frequent death causes of SLE. Early mortality (<3 years) occurred more commonly in lupus encephalopathy, while late death (>3 years) happened more frequently in renal involvement, pulmonary artery hypertension, cardiovascular events, and cancer. In SLE death cases mainly dying from infection, mixed infections were more frequent than single pathogen infection (60.5 vs. 39.5 %), including common bacteria, fungal infection, and cytomegalovirus. Aspergillus fumigatus and Pneumocystis carinii were the two most commonly infected pathogens, and Cytomegalovirus was a frequent pathogen of mixed infection. Aggressive therapy has effectively reduced the mortality related to disease activity but also was associated with life threatening infections. Mixed and fungal infection should be considered when SLE patients have severe infection. PMID- 24046219 TI - Nasopharyngeal carriage of Streptococcus pneumoniae in healthy Turkish children after the addition of PCV7 to the national vaccine schedule. AB - The aim of this study was to determine serotype distribution and investigate antimicrobial resistance patterns of Streptococcus pneumoniae in healthy Turkish children in the era of community-wide pneumococcal conjugate vaccine (PCV7). The study was conducted on 1,101 healthy children less than 18 years of age. Specimens were collected with nasopharyngeal swabs between April 2011 and June 2011. Penicillin and ceftriaxone susceptibilities were determined by E-test according to the 2008 Clinical Laboratory Standards Institute, and serotypes of the isolates were determined by Quellung reaction. The nasopharyngeal pneumococcal carriage rate was 21.9 % (241/1,101). Using the meningitis criteria of minimum inhibitory concentration values, 73 % of the isolates were resistant to penicillin and 47.7 % of them were resistant to ceftriaxone. Half of all pneumococcal isolates were serotyped as 19F (15.2 %), 6A (15.2 %), 23F (10.3 %), and 6B (9.3 %) and surprisingly, no serotype 19A was isolated. Serotype coverage rates of PCV7 and non-PCV7 were 46.2 and 53.8 %, respectively. The most common penicillin- and ceftriaxone-resistant serotypes were 6A, 6B, 14, 19F, and 23F. Penicillin- and ceftriaxone-resistant isolates were more prevalent in serotypes covered by PCV7 than the non-PCV7 serotypes. CONCLUSION: After the community-wide PCV7 vaccination, more non-PCV7 serotypes were isolated from the carriers compared to the time before PCV7 was used especially the serotype 6A, and the antimicrobial resistance of pneumococci was significantly increased. PMID- 24046220 TI - Moving life science ethics debates beyond national borders: some empirical observations. AB - The life sciences are increasingly being called on to produce "socially robust" knowledge that honors the social contract between science and society. This has resulted in the emergence of a number of "broad social issues" that reflect the ethical tensions in these social contracts. These issues are framed in a variety of ways around the world, evidenced by differences in regulations addressing them. It is important to question whether these variations are simply regulatory variations or in fact reflect a contextual approach to ethics that brings into question the existence of a system of "global scientific ethics". Nonetheless, within ethics education for scientists these broad social issues are often presented using this scheme of global ethics due to legacies of science ethics pedagogy. This paper suggests this may present barriers to fostering international discourse between communities of scientists, and may cause difficulties in harmonizing (and transporting) national regulations for the governance of these issues. Reinterpreting these variations according to how the content of ethical principles is attributed by communities is proposed as crucial for developing a robust international discourse. To illustrate this, the paper offers some empirical fieldwork data that considers how the concept of dual-use (as a broad social issue) was discussed within African and UK laboratories. Demonstrating that African scientists reshaped the concept of dual-use according to their own research environmental pressures and ascribed alternative content to the principles that underpin it, suggests that the limitations of a "global scientific ethics" system for these issues cannot be ignored. PMID- 24046221 TI - Plagiarism, beyond CrossCheck, figure and conceptual theft. PMID- 24046222 TI - Suffering related to dignity among patients at a psychiatric hospital. AB - This article discusses dignity from a Q-methodological study among patients at a psychiatric hospital. The aim of this study is to gain a deeper understanding of the subjective experiences of patients in a psychiatric hospital with respect to dignity. A Q-sample of 51 statements was developed. A total of 15 participants ranked these statements from those they most agreed with to those they most disagreed with. Post-interviews were also conducted. Principal Component Factor Analysis and varimax rotation followed by hand rotation produced the clearest results. Four different viewpoints emerged: being met as equal human being, experience of dignity despite suffering, suffering due to inferior feelings and suffering and fighting for one's own dignity. There seem to be variations in those with dignity-promoting experiences in Viewpoint 1 and to some extent in Viewpoint 2, to those with dignity-inhibiting experiences in Viewpoints 3 and 4. PMID- 24046223 TI - Meta-analysis of diagnostic performance studies. PMID- 24046224 TI - Why air quality in the Alps remains a matter of concern. The impact of organic pollutants in the alpine area. AB - In the middle of Europe, the Alps form a geographical and meteorological trap for atmospheric pollutants including volatile and semi-volatile organic compounds emitted in the surrounding lowlands. This is due to their barrier effects, high precipitation rates, and low ambient temperatures. Also the pollutants emitted in the cities inside the Alps spread in the region depending on orographic and meteorological conditions. Although a number of studies on the distribution and effect of pollutants in the Alps has been published, comprehensive information on potential hazards, and ways to improve this sensible environment are lacking. This opinion paper is the result of a discussion during the Winterseminar of the AlpsBioCluster project in Munich. It summarizes the current literature and presents some case studies on local pollution sources in the Alps, and the possibility of using biomonitoring techniques to assess critical pollution loads and distributions. PMID- 24046225 TI - Utilization of water chestnut for reclamation of water environment and control of cyanobacterial blooms. AB - Overgrowth of water chestnut (Trapa spp.) is a regional problem throughout Asia and North America because of waterway blockage and water fouling upon decomposition. In the present study, we investigated the potential of water chestnut to control cyanobacterial blooms, via a high content of phenolic compounds. In addition, we assessed the impact of biomass harvesting and crude extract application on nutrient balance. We showed that the floating parts of water chestnut contained high concentrations of total phenolics (89.2 mg g(-1) dry weight) and exhibited strong antioxidant activity (1.31 mmol g(-1) dry weight). Methanol-extracted phenolics inhibited growth of Microcystis aeruginosa; the half maximal effective concentration (EC50) of the extracted phenolics was 5.8 mg L(-1), which was obtained from only 103 mg L(-1) of dry biomass (the floating and submerged parts). However, the crude extracts also added important quantities of nitrogen, phosphorus, and potassium (1.49, 1.05, and 16.3 mg g(-1), respectively; extracted dry biomass weight basis); therefore, in practice, nutrient removal before and/or after the extraction is essential. On the other hand, biomass harvesting enables recovery of nitrogen, phosphorus, and potassium from the water environment (23.1, 2.9, and 18.7 mg g(-1), respectively; dry biomass weight basis). Our findings indicate that water chestnut contains high concentrations of phenolics and exhibits strong antioxidant activity. Utilization of these resources, including nutrients, will contribute to reclamation of the water environment, and also to disposal of wet biomass. PMID- 24046226 TI - In vitro exposure of Ostrya carpinifolia and Carpinus betulus pollen to atmospheric levels of CO, O3 and SO 2. AB - Ostrya spp. and Carpinus spp. pollen was in vitro exposed to three atmospheric pollutants: CO, O3 and SO2. Two levels of each pollutant were used, and the first level corresponds to a concentration about the atmospheric hour-limit value acceptable for human health protection in Europe and the second level to about the triple of the first level. Experiments were done under artificial solar light with temperature and relative humidity controlled. The viability of the exposed pollen samples showed a significant decrease. Also, the germination percentage showed a significant decrease in both exposed pollens, and the effect was most pronounced for SO2, followed by O3 and CO. A general decreasing trend in the total soluble protein content of the exposed pollen samples when compared with the control was observed, but it was only statistically significant for the Ostrya spp pollen. The results showed marked effects were observed on the Ostrya spp. and Carpinus spp. pollen when exposed to air pollutant levels that can be considered safe for human health protection. PMID- 24046227 TI - Tracking the spectroscopic and chromatographic changes of algal derived organic matter in a microbial fuel cell. AB - Changes in the characteristics of algae-derived organic matter (AOM) were examined upon the operation of a microbial fuel cell (MFC) using multiple analytical methods. Temporal variations in the UV absorption and fluorescence excitation-emission matrix of the AOM revealed that less condensed humic-like components and large-sized protein-like fluorescent compounds were preferentially decomposed over the period of electricity generation. They also showed that low UV-absorbing extracellular organic matters (EOM) were produced at the end of the operation. SEC chromatograms demonstrated that smaller-sized UV-absorbing components were initially decomposed, followed by the net production of EOM with an intermediate molecular weight. Fourier transform infrared (FT-IR) spectra showed that proteins and polysaccharides were the two most dominant structures of the AOM in the MFC. Two-dimensional correlation spectroscopy combined with FT-IR provided additional valuable information on the sequential changes of the AOM, which occurred in the order of proteins -> acidic functional groups -> polysaccharides -> amino acids/proteins. PMID- 24046228 TI - Metal uptake capacity of modified Saccharomyces pastorianus biomass from different types of solution. AB - In this paper, we investigate the effect of different biomass pretreatments on metal ion uptake by various biosorbents. Heat-treated as well as caustic-treated and ground biomass of Saccharomyces pastorianus was used to remove copper, lead and cadmium from various solutions. Untreated yeast was used as the control sample. The effect of yeast modification on sorption capacity depended on the different types of heavy metal ions and whether they were in single- or multi component solutions. The highest uptake of copper and lead from a single-metal solution was obtained from heat-treated cells. Ground biomass was the most efficient at cadmium removal. However, the sorption capacity of the modified biomass did not improve when metal ions were removed from multi-component solutions. Indeed, the results in this paper show that optimizing metal removal from single-cation solutions can lead to decreased sorption capacity in multi component solutions. Therefore, while adjusting the procedure of biomass modification, not only the nature of the metal ion being sorbed but also the chemical composition of the metal ion solution should be taken into account. PMID- 24046229 TI - Assessment of indoor air concentrations of VOCs and their associated health risks in the library of Jawaharlal Nehru University, New Delhi. AB - The present work investigated the levels of total volatile organic compounds (TVOC) and benzene, toluene, ethylbenzene, m/p-xylene, and o-xylene (BTEX) in different microenvironments in the library of Jawaharlal Nehru University in summer and winter during 2011-2012. Carcinogenic and non-carcinogenic health risks due to organic compounds were also evaluated using US Environmental Protection Agency (USEPA) conventional approaches. Real-time monitoring was done for TVOC using a data-logging photo-ionization detector. For BTEX measurements, the National Institute for Occupational Safety and Health (NIOSH) standard method which consists of active sampling of air through activated charcoal, followed by analysis with gas chromatography, was performed. Simultaneously, outdoor measurements for TVOC and BTEX were carried out. Indoor concentrations of TVOC and BTEX (except benzene) were higher as compared to the outdoor for both seasons. Toluene and m/p-xylene were the most abundant organic contaminant observed in this study. Indoor to outdoor (I/O) ratios of BTEX compounds were generally greater than unity and ranged from 0.2 to 8.7 and 0.2 to 4.3 in winter and summer, respectively. Statistical analysis and I/O ratios showed that the dominant pollution sources mainly came from indoors. The observed mean concentrations of TVOC lie within the second group of the Molhave criteria of indoor air quality, indicating a multifactorial exposure range. The estimated lifetime cancer risk (LCR) due to benzene in this study exceeded the value of 1 * 10(-6) recommended by USEPA, and the hazard quotient (HQ) of non-cancer risk came under an acceptable range. PMID- 24046230 TI - Isolation and characterization of novel phorate-degrading bacterial species from agricultural soil. AB - Based upon 16S rDNA sequence homology, 15 phorate-degrading bacteria isolated from sugarcane field soils by selective enrichment were identified to be different species of Bacillus, Pseudomonas, Brevibacterium, and Staphylococcus. Relative phorate degradation in a mineral salt medium containing phorate (50 MUg ml(-1)) as sole carbon source established that all the bacterial species could actively degrade more than 97 % phorate during 21 days. Three of these species viz. Bacillus aerophilus strain IMBL 4.1, Brevibacterium frigoritolerans strain IMBL 2.1, and Pseudomonas fulva strain IMBL 5.1 were found to be most active phorate metabolizers, degrading more than 96 % phorate during 2 days and 100 % phorate during 13 days. Qualitative analysis of phorate residues by gas liquid chromatography revealed complete metabolization of phorate without detectable accumulation of any known phorate metabolites. Phorate degradation by these bacterial species did not follow the first-order kinetics except the P. fulva strain IMBL 5.1 with half-life period (t1/2) ranging between 0.40 and 5.47 days. PMID- 24046231 TI - [New aspects on the pathogenesis of psoriatic arthritis]. AB - Psoriasis and psoriatic arthritis (PsA) are immune-mediated inflammatory diseases with a high burden of disability and increased mortality. The pathogenesis of the disease comprises a dysregulated interaction between stromal and immune cells and a dysfunctional cytokine network supporting chronic inflammation of the skin, entheses and joints. In addition to recent advances in the understanding of TNF blockade, more targets have been discovered delivering insights into the pathogenesis of PsA. This article gives a translational approach by utilizing current clinical development programs providing an insight into the IL-12/IL-23 and the IL-17 axes and also focuses on tissue damage and new small molecules. PMID- 24046232 TI - [Screening and early diagnosis of psoriasis arthritis]. AB - Psoriasis arthritis (PsA) encompasses many diverse clinical symptoms. Epidemiological data about the prevalence in general, predisposed age groups, prevalence of joint, spine, enthesis, and extra-articular manifestations are very heterogeneous. Even for the PsA specialist the clinical picture is not always easy to differentiate from other overlapping or clinically similar disease entities. This paper tries to give some guidance on how to screen for and how to detect PsA early in the population of psoriasis patients on the basis of the Mainz PsA screening and early diagnosis algorithm. PMID- 24046233 TI - Production of monoclonal antibody against ORF72 of koi herpesvirus isolated in Taiwan. AB - A monoclonal antibody (MAb) was generated against the capsid protein (ORF 72) of koi herpesvirus (KHV) isolated from diseased koi Cyprinus carpio in Taiwan. The clone of MAb-B2 was obtained by immunizing mice with whole virus particles and further identified using indirect enzyme-linked immunosorbent assay and Western blot assay. In addition, it detected KHV in KHV-infected cells but not in those of mock-infected cells as demonstrated by indirect immunofluorescence assay. The neutralization test showed that MAb-B2 neutralized KHV. Furthermore, we uncovered that MAb-B2 recognizes the ORF72 of KHV as revealed by liquid chromatography tandem mass spectrometry and Western blot assays. Additionally, MAb-B2 has been used as a diagnostic tool for detection of KHV in clinical samples by immunohistochemistry. Collectively, our results indicated that MAb-B2 could be used in the development of a diagnostic kit for diagnosis of KHV infections and ORF72 protein of KHV might be a candidate for future vaccine development. PMID- 24046234 TI - CORR Insights (r): Is TKA using patient-specific instruments comparable to conventional TKA? A randomized controlled study of one system. PMID- 24046235 TI - Quality and cost improvement of healthcare via complementary measurement and diagnosis of patient general health outcome using electronic health record data: research rationale and design. AB - In this evolving 'third era of health', one of the US Health Care Reform Act's goals is to effectively facilitate the primary care physician's ability to better diagnose and manage the health outcome of the outpatient. That goal must include research on the complementary quantitative-qualitative assessment and rating of the patient's health status. This paper proposes an overview of the rationale and design of a research program for a balanced measurement and diagnostic clinical decision support system (CDSS) of the changing general health status of the patient -including disease- using electronic health record (EHR) data. The rationale, objectives, health metric-diagnostic tools architecture, simulation optimization, and clinical trials are outlined. Resources, time frames, costs, feasibility, healthcare benefits and data-integration of the project are delineated. The basis and components of the research program to achieve an automated-CDSS to complement physician's clinical judgment, calculating a mathematical 'health equation' from each patient's EHR database, assisting physician-patient collaboration to diagnose, and improve general health outcomes is described. Use of multiple dimensional index, ways of classification, and causal factors' assessments, to arrive at the EHR-based CDSS algorithm-software providing a general health level and state rating of the patient are proposed. Its application could provide a compass for the general practitioner's best choice and use of the myriad of healthcare educational and technological options available with lower costs for everyday clinical practice and research. It could advance the approaches and focus of the 'eras of diseases', to the promising 'era of health', in an integrated, general approach to 'health.' PMID- 24046236 TI - Organizational implementation of evidence-based substance abuse treatment in racial and ethnic minority communities. AB - We evaluated organizational factors associated with the implementation of contingency management treatment (CMT) and medication-assisted treatment (MAT) in substance abuse treatment (SAT) programs serving racial and ethnic minority communities. Analysis of cross-sectional data collected in 2010-2011 from a random sample of 148 publicly funded SAT programs showed that accepting private insurance was positively associated with CMT and MAT implementation, whereas larger programs were associated with greater implementation of MAT. Supervisorial openness to and expectations about implementing evidence-based practices (EBPs) and attributes for change were strongly associated with CMT, whereas the interactions between openness to EBPs and programs that accept private insurance and that are governed by parent organizations were positively associated with MAT. These external expectations and managerial attitudes supported the implementation of psychosocial and pharmacotherapy treatments in SAT. Implications for improving standards of care in minority communities are discussed. PMID- 24046238 TI - Oasis land-use change and its effects on the eco-environment in Yanqi Basin, Xinjiang, China. AB - Satellite data and the published coefficients about the world's and China's ecosystem were used to analyze the effects of land-use changes on the ecosystem service in the Yanqi Basin. Both economic developments and arid, fragile ecosystems have strongly affected the land use. A sensitivity analysis determined the effect of manipulating the coefficients on the estimated values. Results indicated that (1) the total value of ecosystem services in the Yanqi Basin were 9,374.66, 10,450.52, 9,964.20, and 9,8707.77 million Yuan in 1990, 2000, 2005, and 2011, respectively. The net increase in ecosystem service values were about 496.11 million Yuan within 1990-2011; (2) The aggregated ecosystem service values of water body, wetlands, grasslands, and croplands were about 99.25 % of the total value; (3) Waste treatment and soil formation were the top two ecological functions with high service values and contributing about 61.70 % of the total service values; and (4) Ecosystem service values estimated in this study were inelastic with respect to the value coefficients; therefore, the estimation was robust in spite of uncertainties on the value coefficients. A reasonable land-use plan should be based on rigorous environmental impact analyses for maintaining stability and sustainable development of the Yanqi Basin. PMID- 24046239 TI - Bioaccumulation and toxicity of arsenic in cyanobacteria cultures separated from a eutrophic reservoir. AB - The bioaccumulation and toxicity of arsenate (arsenic (As)(V)) was studied using three cultures of cyanobacterial species-Oscillatoria tenuisa, Anabaena affinis, and Microcystis aeruginosa-that were isolated from a eutrophic reservoir. The As(V) uptake depended on the cyanobacterial species, the growth phase of the cyanobacteria, the duration of exposure, and the initial concentration of As(V). The specific growth rates of the three cultures immediately following the logarithmic phase were 0.033-0.041 L/day when the initial concentration of As(V) was 50 mg/L. These rates were 2.3-3.6 times less than those in the original culture medium without As(V). The rate of intake of As(V) in the logarithmic phase cultures greatly exceeded that in the stationary cultures. The accumulation of As(V) by the three cultures increased rapidly within 1 week from the initial value of 3.23 * 10(-2)-5.40 * 10(-2) to 5.06 * 10(-1)-6.73 * 10(-1) ng/cell in the logarithmic phase. The effective concentrations (EC50) of As(V) for inhibiting the growth of the three cyanobacterial species growth of at 72 h followed the order Oscillatoria tenuisa (3.8 mg/L) > A. affinis (2.6 mg/L) > M. aeruginosa (1.2 mg/L). The cyanobacterial species that was most sensitive to As(V) was M. aeruginosa. Preliminary results from SEM-map studies suggest most of the As(V) in Microcystis aeruginosa accumulated in the cytoplasm (intercellular), while in O. tenuisa and A. affinis, a large proportion of As(V) bound to the cell wall (extracellular). These differences were understood with reference to the variation among the metabolic properties and morphological characteristics of the cyanobacterial species. PMID- 24046237 TI - Molecular targets and mechanisms of cancer prevention and treatment by withaferin a, a naturally occurring steroidal lactone. AB - The plants used in Ayurvedic medicine, which has been practiced in India for thousands of years for the treatment of a variety of disorders, are rich in chemicals potentially useful for prevention and treatment of cancer. Withania somnifera (commonly known as Ashwagandha in Ayurvedic medicine) is one such medicinal plant whose anticancer value was realized over four decades ago after isolation of a crystalline steroidal compound (withaferin A) from the leaves of this shrub. The root and leaf extracts of W. somnifera are shown to confer protection against chemically-induced cancers in experimental rodents, and retard tumor xenograft growth in athymic mice. Anticancer effect of W. somnifera is generally attributable to steroidal lactones collectively referred to as withanolides. Withaferin A (WA) appears most active against cancer among structurally divergent withanolides isolated from the root or leaf of W. somnifera. Cancer-protective role for WA has now been established using chemically-induced and oncogene-driven rodent cancer models. This review summarizes the key in vivo preclinical studies demonstrating anticancer effects of WA. Molecular targets and mechanisms likely contributing to the anticancer effects of WA are also discussed. Finally, challenges in clinical development of WA for the prevention and treatment of cancer are highlighted. PMID- 24046240 TI - Influence of land use and climate on the load of suspended solids in catchments of Andean rivers. AB - Understanding the interaction between anthropogenic land use and the rainfall pattern can be crucial to predict changes in total suspended solids (TSS) in streams and rivers. We assessed the effects of land use and annual rainfall on the TSS load of 19 southern Chilean catchments. The results indicated that the concentration of TSS increased in catchments with a rainy regime and greater annual precipitation. TSS load also increased as the surface of open areas increased at the catchment scale and decreased with increasing cover of glaciers and perennial snow. However, we did not find support for models with interaction terms between climate and land use. Results suggest that a regional decrease in annual rainfall accompanied by an increase in the altitude of the zero isotherms, as predicted by climate models, should have multiple effects on TSS. In particular, increased TSS load can be expected from a contraction of glaciers and perennial snow areas as well as the intensification of new crops and urban expansion. PMID- 24046241 TI - Evaluation of wireless sensor networks (WSNs) for remote wetland monitoring: design and initial results. AB - Here, we describe and evaluate two low-power wireless sensor networks (WSNs) designed to remotely monitor wetland hydrochemical dynamics over time scales ranging from minutes to decades. Each WSN (one student-built and one commercial) has multiple nodes to monitor water level, precipitation, evapotranspiration, temperature, and major solutes at user-defined time intervals. Both WSNs can be configured to report data in near real time via the internet. Based on deployments in two isolated wetlands, we report highly resolved water budgets, transient reversals of flow path, rates of transpiration from peatlands and the dynamics of chromophoric-dissolved organic matter and bulk ionic solutes (specific conductivity)-all on daily or subdaily time scales. Initial results indicate that direct precipitation and evapotranspiration dominate the hydrologic budget of both study wetlands, despite their relatively flat geomorphology and proximity to elevated uplands. Rates of transpiration from peatland sites were typically greater than evaporation from open waters but were more challenging to integrate spatially. Due to the high specific yield of peat, the hydrologic gradient between peatland and open water varied with precipitation events and intervening periods of dry out. The resultant flow path reversals implied that the flux of solutes across the riparian boundary varied over daily time scales. We conclude that WSNs can be deployed in remote wetland-dominated ecosystems at relatively low cost to assess the hydrochemical impacts of weather, climate, and other perturbations. PMID- 24046243 TI - [No new psychotropic drugs in the pipeline: psychiatry in crisis?]. PMID- 24046242 TI - Spatial and temporal patterns of dissolved nitrogen and phosphorus in surface waters of a multi-land use basin. AB - Research on relationships between dissolved nutrients and land-use at the watershed scale is a high priority for protecting surface water quality. We measured dissolved nitrogen (DN) and ortho-phosphorus (P) along 130 km of the Calapooia River (Oregon, USA) and 44 of its sub-basins for 3 years to test for associations with land-use. Nutrient concentrations were analyzed for spatial and seasonal patterns and for relationships with land-use and stream discharge. Ortho P and DN were higher in lower-elevation sub-basins dominated by poorly drained soils and agricultural production compared with higher-elevation sub-basins dominated by well-drained soils and forests. Eight lower basins had at least one sample period with nitrate-N > 10 mg L(-1). The Calapooia River had lower concentrations of dissolved nutrients compared with lower sub-basins, often by an order of magnitude. Dissolved organic N represented a greater proportion of DN in the upper forested sub-basins. Seasonal nutrient concentrations had strong positive correlations to the percent of a sub-basin that was managed for agriculture in all seasons (p values <= 0.019) except summer. Results suggest that agricultural lands are contributing to stream nutrient concentrations. However, poorly drained soils in agricultural areas may also contribute to the strong relationships that we found between dissolved nutrients and agriculture. PMID- 24046244 TI - [Forcing patients with bipolar disorder to make a financial contribution to secondary psychiatric care may make them forsake care completely]. AB - BACKGROUND: In 2012 patients were required to make a personal financial contribution for secondary mental health care over and above their standard insurance fee. According to current guidelines, the majority of patients with bipolar disorder must be treated as outpatients at psychiatric clinics. It was to be expected that some patients would decide to discontinue their outpatient treatment on account of the newly imposed personal financial contribution. AIM: To obtain insight into the size and characteristics of the group of patients with bipolar disorder who were thinking about giving up treatment or had already decided to give it up because of the imposition of the personal financial contribution; also to find out which factors influenced patients' decisions and to discover how patients perceived the role of the GP as the provider of subsequent psychiatric care. METHOD: We conducted an exploratory study by sending a survey to all outpatients receiving treatment at three clinics specialising in the treatment of bipolar disorder. RESULTS: 640 patients responded to the survey (55% response); 15% of these patients were thinking about giving up treatment or had already decided to stop their treatment. They were influenced primarily by financial considerations. Two-thirds of the respondents did not consider that the GP was as a suitable alternative to outpatient care at a clinic. Even patients with moderate to serious symptoms were considering leaving secondary care. CONCLUSION: The obligatory financial contribution for secondary mental health care could have considerable consequences for a small number of patients with severe mood disorder who are currently treated as outpatients in secondary facilities. The increase in the compulsory & squo;own risk' insurance fee as from 2013 could have similar consequences. PMID- 24046245 TI - [Patients with brain injury in a psychiatric setting; assessment of health care needs and received care]. AB - BACKGROUND: In some Dutch mental health care organisations specific neuropsychiatric departments have been developed for patients with brain injury. AIM: To identify the characteristics of patients with brain injury who form a specific population in mental health care and to determine whether such patients require either specialised care or a special type of care. METHOD: A cross sectional analysis of typical brain injury inpatients was performed. We noted the age and gender of these patients and recorded any previous periods of inpatient care. We listed patients' impairments, the diagnoses they had been given and the treatment they had received. This inventory formed the basis of our conclusions. RESULTS: The typical clinical patient with brain injury in this setting was a male of 51 years or older, most probably affected by a stroke or traumatic brain injury, admitted for a period of 6 months, many years after the incident. He was mostly referred from home or hospital by a physician and was expected to return home again. A combination of cognitive and psychiatric impairments was often found. Physically the patient had no or only mild disabilities, but societal participation was low and many cognitive-affective disorders were seen. Treatment was relatively infrequent and mostly directed at daily activities. The most frequent diagnosis was & lquo;cognitive deficits not otherwise specified'. Irritability, agitation, apathy and depression were frequent symptoms. CONCLUSION: This inventory suggests that brain injury patients in a mental health care setting need special care which is not available in other health care settings. PMID- 24046246 TI - [Adolescent binge drinking: neurocognitive consequences and gender differences]. AB - BACKGROUND: Binge drinking by adolescents and young adults is on the increase and is having serious medical and social consequences. Over the last ten years more and more research has been done into the neurocognitive effects of binge drinking and into the possibility that these effects are gender-specific. However, so far, findings have been inconsistent. AIM: To collect evidence for the negative impact of binge drinking on the neurocognitive functioning of adolescents and young adults and to find out whether binge drinking has a more serious effect on neurocognition in females than in males. METHOD: We searched the literature using PubMed and Web of Science. RESULTS: Nineteen studies satisfied our selection criteria. Eleven studies examined the binge/gender interaction. CONCLUSION: There is considerable evidence that binge drinking does have a negative effect on neurocognition in adolescents and young adults, particularly with regard to executive functioning and memory. Females seem to be more susceptible than males to deficits in spatial working memory and impulse control. PMID- 24046247 TI - [Early alcohol initiation and increased alcohol consumption during adult life: the importance of alcohol campaigns targeting the youth]. PMID- 24046248 TI - [Tricyclic antidepressant plasma levels in depression: a practical guide]. AB - BACKGROUND: Plasma levels can be used to monitor the clinical efficacy of tricyclic antidepressants (TCAs). In practice, the interpretation of plasma levels can be problematical, for several reasons: varying time-intervals between ingestion and blood sampling, the number of times per day a particular antidepressant is administered, the presence of active metabolites and the use of slow-release substances. AIM: To present realistic recommendations regarding the interpretation of plasma levels of TCA in clinical practice. METHOD: We studied the relevant literature. CONCLUSION: On the basis of the literature we make the following recommendations: PMID- 24046249 TI - [Dutch guideline on Schizophrenia 2012: basic care within the areas of psychosocial interventions and nursing care]. AB - BACKGROUND: An updated version of the Dutch multidisciplinary guideline on schizophrenia was published in 2012. AIM: We aim to provide an overview of the psychosocial interventions and nursing care which, according to the guideline, should be included in basic care programmes for patients with schizophrenia. We consider which interventions are effective and which are optional. In addition, we argue for continuous updating of the guideline so that it reflects current developments. METHOD: We conducted a systematic review on the basis of specific predefined search terms. We included articles published up to February 2010. We used the method for evidence-based guideline development in order to formulate treatment recommendations. CONCLUSION: Cognitive behavioural therapy and family interventions are scientifically proven interventions that should be included in the care programmes. Although there is no clear evidence that psycho-education is effective, it is nevertheless recommended. Optional interventions are peer support groups and, in the case of negative symptoms, psychomotor therapy. Although scientific evidence concerning nursing care is limited, we do make some recommendations. We are strongly in favour of a living guideline & rsquo; that is constantly developed and updated. PMID- 24046250 TI - [ADHD and addiction; application of the Belgian guideline with particular reference to comorbid affective disorders]. AB - Two patients with a multi-substance use disorder and an apparent comorbid ADHD disorder were given psychiatric treatment for both illnesses. Each patient had a comorbid affective disorder. In both cases the approach was based on the Belgian guideline Good clinical practice in the recognition and treatment of young adults with addiction problems& squo. We use the case-reports to demonstrate the usefulness and relevance of the guideline in an outpatient setting compared to an inpatient setting and look particularly at the implications of other kinds of comorbidity encompassed by the guideline. PMID- 24046251 TI - Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of patients with relapsed or refractory multiple myeloma and light chain-induced renal failure. AB - INTRODUCTION: Serious renal failure represents a severe complication of multiple myeloma (MM), with an estimated 25-50 % of patients being affected. Both bortezomib and bendamustine have been identified as quickly acting, effective and well-tolerated drugs and might therefore constitute an adequate combination regimen for patients presenting with light chain-induced renal failure. METHODS: Between March 2005 and March 2013, 36 patients with relapsed/refractory MM and light chain-induced renal failure (creatinine clearance <60 ml/min) were treated with bendamustine 60 mg/m(2) on days 1 and 2, bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 and prednisone 100 mg on days 1, 2, 4, 8 and 11 (BPV). Patients were divided according to severity of renal impairment into group A (n = 20) with moderate or severe renal dysfunction (eGFR 15-59 ml/min) and group B (n = 16) with renal failure/dialysis (eGFR <15 ml/min). RESULTS: Twenty-four patients (67 %) responded with three CR, three nCR, six VGPR and 12 PR. Six patients had minor response, two stable and four progressive disease. With a median follow-up period of 22 months, median progression-free survival (PFS) and overall survival (OS) for patients of group A were 10 and 25 months, respectively. This outcome was significantly better compared to patients of group B with a median PFS and OS of 3 and 7 months, respectively. Eleven patients showed a CRrenal, five a PRrenal and 15 a MRrenal. These results indicate that this BPV combination is feasible, effective and well tolerated in patients with relapsed/refractory MM and light chain-induced renal failure. PMID- 24046252 TI - Prospective memory: effects of divided attention on spontaneous retrieval. AB - We examined the effects of divided attention on the spontaneous retrieval of a prospective memory intention. Participants performed an ongoing lexical decision task with an embedded prospective memory demand, and also performed a divided attention task during some segments of lexical decision trials. In all experiments, monitoring was highly discouraged, and we observed no evidence that participants engaged monitoring processes. In Experiment 1, performing a moderately demanding divided-attention task (a digit detection task) did not affect prospective memory performance. In Experiment 2, performing a more challenging divided-attention task (random number generation) impaired prospective memory. Experiment 3 showed that this impairment was eliminated when the prospective memory cue was perceptually salient. Taken together, the results indicate that spontaneous retrieval is not automatic and that challenging divided attention tasks interfere with spontaneous retrieval and not with the execution of a retrieved intention. PMID- 24046253 TI - Illness narrative, depression, and sainthood: an analysis of the writings of Mother Teresa. AB - In 2007, the letters of The Blessed Mother Teresa to her confessors were published for the public in a book entitled Come Be My Light. What surprised many readers was that Mother Teresa felt very distant from God and described feeling great "darkness" for many years. This paper draws parallels between the writings of Mother Teresa and those of writers' illness narratives describing the psychiatric condition of Depression. The author provides this textual analysis to explore Mother Teresa's experience within a psychiatric paradigm (Major Depressive Disorder), in comparison with and contrast to the spiritual paradigm of a "Dark Night of the Soul." PMID- 24046254 TI - Genome mining for new alpha-amylase and glucoamylase encoding sequences and high level expression of a glucoamylase from Talaromyces stipitatus for potential raw starch hydrolysis. AB - Mining fungal genomes for glucoamylase and alpha-amylase encoding sequences led to the selection of 23 candidates, two of which (designated TSgam-2 and NFamy-2) were advanced to testing for cooked or raw starch hydrolysis. TSgam-2 is a 66-kDa glucoamylase recombinantly produced in Pichia pastoris and originally derived for Talaromyces stipitatus. When harvested in a 20-L bioreactor at high cell density (OD600 > 200), the secreted TSgam-2 enzyme activity from P. pastoris strain GS115 reached 800 U/mL. In a 6-L working volume of a 10-L fermentation, the TSgam-2 protein yield was estimated to be ~8 g with a specific activity of 360 U/mg. In contrast, the highest activity of NFamy-2, a 70-kDa alpha-amylase originally derived from Neosartorya fischeri, and expressed in P. pastoris KM71 only reached 8 U/mL. Both proteins were purified and characterized in terms of pH and temperature optima, kinetic parameters, and thermostability. TSgam-2 was more thermostable than NFamy-2 with a respective half-life (t1/2) of >300 min at 55 degrees C and >200 min at 40 degrees C. The kinetic parameters for raw starch adsorption of TSgam-2 and NFamy-2 were also determined. A combination of NFamy-2 and TSgam-2 hydrolyzed cooked potato and triticale starch into glucose with yields, 71-87 %, that are competitive with commercially available alpha-amylases. In the hydrolysis of raw starch, the best hydrolysis condition was seen with a sequential addition of 40 U of a thermostable Bacillus globigii amylase (BgAmy)/g starch at 80 degrees C for 16 h, and 40 U TSgam-2/g starch at 45 degrees C for 24 h. The glucose released was 8.7 g/10 g of triticale starch and 7.9 g/10 g of potato starch, representing 95 and 86 % of starch degradation rate, respectively. PMID- 24046255 TI - The challenging measurement of protein in complex biomass-derived samples. AB - Measurement of the protein content in samples from production of lignocellulosic bioethanol is an important tool when studying the adsorption of cellulases. Several methods have been used for this, and after reviewing the literature, we concluded that one of the most promising assays for simple and fast protein measurement on this type of samples was the ninhydrin assay. This method has also been used widely for this purpose, but with two different methods for protein hydrolysis prior to the assay-alkaline or acidic hydrolysis. In samples containing glucose or ethanol, there was significant interference from these compounds when using acid hydrolysis, which was not the case when using the alkaline hydrolysis. We evaluated the interference from glucose, cellulose, xylose, xylan, lignin and ethanol on protein determination of BSA, Accellerase((r)) 1500 and Cellic((r)) CTec2. The experiments demonstrated that the presence of cellulose, lignin and glucose (above 50 g/kg) could significantly affect the results of the assay. Comparison of analyses performed with the ninhydrin assay and with a CN analyser revealed that there was good agreement between these two analytical methods, but care has to be taken when applying the ninhydrin assay. If used correctly, the ninhydrin assay can be used as a fast method to evaluate the adsorption of cellulases to lignin. PMID- 24046256 TI - Biodesulfurization of model compounds and de-asphalted bunker oil by mixed culture. AB - In this study, complicated model sulfur compounds in bunker oil and de-asphalted bunker oil were biodesulfurized in a batch process by microbial consortium enriched from oil sludge. Dibenzothiophene (DBT) and benzo[b]naphtho[1,2 d]thiophene (BNT1) were selected as model sulfur compounds. The results show that the mixed culture was able to grow by utilizing DBT and BNT1 as the sole sulfur source, while the cell density was higher using DBT than BNT1 as the sulfur source. GC-MS analysis of their desulfurized metabolites indicates that both DBT and BNT1 could be desulfurized through the sulfur-specific degradation pathway with the selective cleavage of carbon-sulfur bonds. When DBT and BNT1 coexisted, the biodesulfurization efficiency of BNT1 decreased significantly as the DBT concentrations increased (>0.1 mmol/L). BNT1 desulfurization efficiency also decreased along with the increase of 2-hydroxybiphenyl as the end product of DBT desulfurization. For real bunker oil, only 2.8 % of sulfur was removed without de asphalting after 7 days of biotreatment. After de-asphalting, the biodesulfurization efficiency was significantly improved (26.2-36.5 %), which is mainly attributed to fully mixing of the oil and water due to the decreased viscosity of bunker oil. PMID- 24046257 TI - Probing the binding of Syzygium-derived alpha-glucosidase inhibitors with N- and C-terminal human maltase glucoamylase by docking and molecular dynamics simulation. AB - Human maltase glucoamylase (MGAM) is a potent molecular target for controlling post prandial glucose surplus in type 2 diabetes. Binding of small molecules from Syzygium sp. with alpha-glucosidase inhibitory potential in MGAM has been investigated in silico. Our results suggest that myricetin was the most potent inhibitor with high binding affinity for both N- and C-terminals of MGAM. Molecular dynamics revealed that myricetin interacts in its stretched conformation through water-mediated interactions with C-terminal of MGAM and by normal hydrogen bonding with the N-terminal. W1369 of the extended 21 amino acid residue helical loop of C-terminal plays a major role in myricetin binding. Owing to its additional sugar sites, overall binding of small molecules favours C terminal MGAM. PMID- 24046258 TI - The effects of Mg supplementation in diets with different calcium levels on the bone status and bone metabolism in growing female rats. AB - Previous studies have revealed that magnesium (Mg) plays a significant role in bone health; however, few studies have investigated the effects of Mg supplementation in diets with different calcium (Ca) levels on the bone status and bone metabolism in a growing stage. In this present study, we tested the effects of Mg supplementation on bone status in growing female rats, relative to Ca intake levels. A total of 40 Sprague-Dawley female rats aged 6 weeks were divided into the following four groups and fed for 12 weeks as indicated: (1) LCaAMg: low Ca (Ca, 0.1 % of total diet) and adequate Mg (Mg, 0.05 % of total diet), (2) LCaHMg: low Ca and high Mg ( Mg, 0.1 % of total diet), (3) ACaAMg: adequate Ca (Ca, 0.5 % of total diet) and adequate Mg, and (4) ACaHMg: adequate Ca and high Mg. Our results showed that Mg supplementation with the adequate Ca diet significantly increased the bone mineral contents, bone size (bone area and bone thickness), and bone mineral density of femur or tibia by improving bone metabolism without changing Ca absorption. Mg supplementation significantly increased the serum osteocalcin in the adequate-Ca-diet group (p < 0.05), while the Mg supplementation significantly decreased the serum level of C-telopeptide cross-links of type I collagen in the adequate-Ca-diet group (p < 0.001). This study suggests that Mg supplementation with adequate Ca intake in the growing stage may increase the bone mineral density and bone size by improving bone metabolism. PMID- 24046259 TI - Time trends in glioblastoma multiforme survival: the role of temozolomide. AB - BACKGROUND: In 2005, maximum safe surgical resection, followed by radiotherapy with concomitant temozolomide (TMZ), followed by adjuvant TMZ became the standard of care for glioblastoma (GBM). Furthermore, a modest, but meaningful, population based survival improvement for GBM patients occurred in the US between 1999 (when TMZ was first introduced) and 2008. We hypothesized that TMZ usage explained this GBM survival improvement. METHODS: We used national Veterans Health Administration (VHA) databases to construct a cohort of GBM patients, with detailed treatment information, diagnosed 1997-2008 (n = 1645). We compared survival across 3 periods of diagnosis (1997-2000, 2001-2004, and 2005-2008) using Kaplan-Meier curves. We used proportional hazards models to calculate period hazard rate ratios (HRs) and 95% confidence intervals (CIs), adjusted for demographic, clinical, and treatment covariates. RESULTS: Survival increased over calendar time (stratified log-rank P < .0001). After adjusting for age and Charlson comorbidity score, for cases diagnosed in 2005-2008 versus 1997-2000, the HR was 0.72 (95% CI, 0.64-0.82; p-trend < .0001). Sequentially adding non-TMZ treatment variables (ie, surgery, radiotherapy, non-TMZ chemotherapy) to the model did not change this result. However, adding TMZ to the model containing age, Charlson comorbidity score, and all non-TMZ treatments eliminated the period effect entirely (HR = 1.01; 95% CI, 0.86-1.19; p-trend = 0.84). CONCLUSIONS: The observed survival improvement among GBM patients diagnosed in the VHA system between 1997 and 2008 was completely explained by TMZ. Similar studies in other populations are warranted to test the generalizability of our finding to other patient cohorts and health care settings. PMID- 24046260 TI - Serum-free culture success of glial tumors is related to specific molecular profiles and expression of extracellular matrix-associated gene modules. AB - BACKGROUND: Recent molecular characterization studies have identified clinically relevant molecular subtypes to coexist within the same histological entities of glioma. Comparative studies between serum-supplemented and serum-free (SF) culture conditions have demonstrated that SF conditions select for glioma stem like cells, which superiorly conserve genomic alterations. However, neither the representation of molecular subtypes within SF culture assays nor the molecular distinctions between successful and nonsuccessful attempts have been elucidated. METHODS: A cohort of 261 glioma samples from varying histological grades was documented for SF culture success and clinical outcome. Gene expression and single nucleotide polymorphism arrays were interrogated on a panel of tumors for comparative analysis of SF+ (successful cultures) and SF- (unsuccessful cultures). RESULTS: SF culture outcome was correlated with tumor grade, while no relation was found between SF+ and patient overall survival. Copy number-based hierarchical clustering revealed an absolute separation between SF+ and SF- parental tumors. All SF+ cultures are derived from tumors that are isocitrate dehydrogenase 1 (IDH1) wild type, chromosome 7 amplified, and chromosome 10q deleted. SF- cultures derived from IDH1 mutant tumors demonstrated a fade-out of mutated cells during the first passages. SF+ tumors were enriched for The Cancer Genome Atlas Classical subtype and intrinsic glioma subtype-18. Comparative gene ontology analysis between SF+ and SF- tumors demonstrated enrichment for modules associated with extracellular matrix composition, Hox-gene signaling, and inflammation. CONCLUSION: SF cultures are derived from a subset of parental tumors with a shared molecular background including enrichment for extracellular matrix-associated gene modules. These results provide leads to develop enhanced culture protocols for glioma samples not propagatable under current SF conditions. PMID- 24046261 TI - Stereotactic iodine-125 brachytherapy for the treatment of WHO grades II and III gliomas located in the central sulcus region. AB - BACKGROUND: Resection of gliomas located in eloquent brain areas remains a neurosurgical challenge. The reported incidence of transient or permanent neurological deficits after microsurgery in eloquent brain ranges 20%-100%, or 0% 47% among contemporary neurosurgical series. The aim of this study was to assess the feasibility of stereotactic brachytherapy (SBT) as a local treatment alternative to microsurgical resection for patients with gliomas in highly eloquent areas, located in the central sulcus region (CSR). METHOD: Between 1997 and 2010, 60 patients with World Health Organization (WHO) grades II and III gliomas located in the CSR were treated with SBT (iodine-125 seeds; cumulative therapeutic dose, 50-65 Gy). Following SBT, WHO grade III glioma patients additionally received percutaneous radiotherapy (median boost dose, 25.2 Gy). We evaluated procedure-related complications, clinical outcome, and progression-free survival. RESULTS: Procedure-related mortality was zero. Within 30 days of SBT, 3 patients (5%) had transient neurological deficits, and 8 patients (13%) had temporarily increased seizure activity. One patient (1.6%) deteriorated permanently. Space-occupying cysts (6 patients) and radiation necrosis (1 patient) developed after a median of 38 months and required surgical intervention. Seizure activity, rated 12 months following SBT, decreased in 82% of patients (Engel classes I-III). Median progression-free survivals were 62.2 +/ 19.7 months (grade II gliomas) and 26.1 +/- 17.9 months (grade III gliomas). CONCLUSIONS: Compared with microsurgical resection, SBT harbors a low risk of procedural complications, is minimally invasive, and seems to be an effective local treatment option for patients with inoperable, eloquent WHO grade II and III gliomas in the CSR. However, the value of SBT for treating gliomas still needs to be determined in prospective, randomized studies. PMID- 24046262 TI - In vitro and in vivo screening of anthelmintic activity of ginger and curcumin on Ascaridia galli. AB - Intestinal helmintic infection, continue to be a cause of major concern in several parts of the world, particularly in the developing nations. The use of plant extracts to control poultry helminths is increasing in different rearing systems. The anthelmintic activity of ginger and curcumin was studied on the nematode Ascaridia galli. In vitro and in vivo studies were allocated. Live parasites for in vitro studies were collected from the intestine of naturally infected chickens. Some living worms were incubated at 37 degrees C in media containing ginger at three concentration levels (25, 50, and 100 mg/ml), and others were incubated in media containing curcumin at the same concentration levels. Another living worm group was incubated in media containing albendazole at a dose of 7.5 mg/ml. The extracts' efficacy was exhibited in a concentration time-dependent manner mainly at 100 mg/ml and after 48 h. The in vivo study takes place on experimentally infected chickens. Group of infected chickens was treated with ginger extract at dose of 100 mg, another group was treated with curcumin extract at dose of 100 mg, and a third group was treated with albendazole at dose of 7.5 mg. In vivo study of ginger and curcumin recorded lower mortality rates than the in vitro study. It is concluded that ginger and curcumin extracts have potential anthelmintic properties against A. galli. Ginger in all concentrations used exhibited a higher death rate observed than curcumin. Their wormicidal effect is concentration-time dependent. PMID- 24046263 TI - Waterborne parasites and physico-chemical assessment of selected lakes in Malaysia. AB - The objective of this study was to assess the physico-chemical parameters and waterborne parasites in selected recreational lakes from Malaysia. Samples were collected from seven stations of Recreational Lake A (RL-A) and six stations of Recreational Lake B (RL-B). The samples were processed to detect the presence of Giardia spp. and Cryptosporidium spp. using immunomagnetic separation kit, helminth eggs or ova by bright field microscopy and Acanthamoeba spp. by cultivation in non-nutrient agar. Chemical parameters such as ammonia, chlorine, fluoride, nitrate and nitrite and physical parameters such as dissolved oxygen, electrical conductivity, pH, salinity, temperature and total dissolved solid were also measured. Both lakes were freshwater with salinity ranging from 0.05 to 0.09 ppt. Most stations of these lakes were contaminated with Cryptosporidium spp., Giardia spp., Ascaris spp. and hookworm. Schistosoma spp. was found in RL-B only, while Acanthamoeba spp. was found in all stations. Of all sampling sites, station 5 of RL-B is the most contaminated. Linear regression and correlation analysis revealed that Giardia spp. and Schistosoma spp. showed a significant negative correlation with turbidity (p < 0.01). Based on the preliminary data obtained, it is clearly shown that there is a necessity to implement the detection of waterborne parasites and physico-chemical analysis in Malaysia. Future work on heavy metals (chromium, copper, mercury and zinc) is recommended to enhance the overall water quality monitoring and to take appropriate safety measures to ensure maintenance of good water standards. PMID- 24046264 TI - Cross-linguistic similarity norms for Japanese-English translation equivalents. AB - Formal and semantic overlap across languages plays an important role in bilingual language processing systems. In the present study, Japanese (first language; L1) English (second language; L2) bilinguals rated 193 Japanese-English word pairs, including cognates and noncognates, in terms of phonological and semantic similarity. We show that the degree of cross-linguistic overlap varies, such that words can be more or less "cognate," in terms of their phonological and semantic overlap. Bilinguals also translated these words in both directions (L1-L2 and L2 L1), providing a measure of translation equivalency. Notably, we reveal for the first time that Japanese-English cognates are "special," in the sense that they are usually translated using one English term (e.g., ??? /kooru/ is always translated as "call"), but the English word is translated into a greater variety of Japanese words. This difference in translation equivalency likely extends to other non-etymologically related, different-script languages in which cognates are all loanwords (e.g., Korean-English). Norming data were also collected for L1 age of acquisition, L1 concreteness, and L2 familiarity, because such information had been unavailable for the item set. Additional information on L1/L2 word frequency, L1/L2 number of senses, and L1/L2 word length and number of syllables is also provided. Finally, correlations and characteristics of the cognate and noncognate items are detailed, so as to provide a complete overview of the lexical and semantic characteristics of the stimuli. This creates a comprehensive bilingual data set for these different-script languages and should be of use in bilingual word recognition and spoken language research. PMID- 24046265 TI - Therapeutic concentrations of mitoxantrone elicit energetic imbalance in H9c2 cells as an earlier event. AB - Mitoxantrone (MTX) is a chemotherapeutic agent that emerged as an alternative to anthracycline therapy. However, MTX also causes late cardiotoxicity, being oxidative stress and mitochondrial-impaired function proposed as possible mechanisms. This work aimed to investigate the relevance of these mechanisms to the MTX toxicity in H9c2 cells, using therapeutic concentrations. The observed cytotoxicity of MTX was time and concentration dependent in both lactate dehydrogenase leakage assay and MTT reduction assay. Two therapeutic concentrations (100 nM and 1 MUM) and three time points were selected (24, 48, and 96 h) for further studies. Both MTX concentrations caused a significant increase in caspase-3 activity, which was not prevented by inhibiting MTX CYP450 metabolism. Significant decreases were observed in the total and reduced glutathione levels only in MTX 100 nM at 96 h; however, neither alterations in oxidized glutathione nor increases in the malondialdehyde levels were observed at any time or concentrations tested. On the other hand, changes in the intracellular ATP levels, mitochondrial membrane potential, and intracellular calcium levels were observed in both concentrations and all time tested. Noteworthy, decreased levels of ATP-synthase expression and activity and increases in the reactive species generation were observed at 96 h in both working concentrations. However, the radical scavenger N-acetylcysteine or the mitochondrial function enhancer L-carnitine did not prevent MTX cytotoxicity. Thus, this work evidenced the early MTX-induced energetic crisis as a possible key factor in the cell injury. PMID- 24046266 TI - Unbanked direct blood transfusions should be legal, say Indian surgeons. PMID- 24046267 TI - GP contracts should be simplified to allow more "professional discretion," says England's health secretary. PMID- 24046268 TI - Doctors condemn Hunt's plan to link emergency department funding to staff flu vaccination rates. PMID- 24046269 TI - MPs condemn UK clinical trials system for its "invisible" results. PMID- 24046270 TI - UK government is to reconsider claims of children who developed narcolepsy after vaccination. PMID- 24046271 TI - Lilly challenges Canada's decision to strike down patents for not meeting "inventive promise". PMID- 24046272 TI - IgA nephropathy factors that predict and accelerate progression to end-stage renal disease. AB - IgA nephropathy (IgAN) or Berger's disease is a slowly progressing disease that leads to end-stage renal disease in 50 % of the patients within 25 years of the disease. However, several factors are associated with the accelerated progression of this disease causing early development of end-stage disease. Persistent proteinuria or hematuria, poorly controlled hypertension, elevated serum creatinine and prevalent glomerulosclerosis are some of the risk factors that expedite the deteriorative effects of IgAN. Thus, the progression of the disease can be delayed if the associated risk factors are handled and addressed in the nick of time. PMID- 24046273 TI - The usefulness of a yearly head and neck surgery trip to rural Kenya. AB - OBJECTIVE: Surgical specialty trips to third world countries have been praised and criticized. Our objective was to learn the usefulness of a yearly head and neck surgery trip through initial analysis of 2 years of patient data. METHODS: We reviewed data from a prospectively maintained repository of surgical patients treated during head and neck surgical trips to Malindi, Kenya, in 2010 and 2011. Basic demographics, distance traveled for care, access to physicians, preoperative diagnosis, surgical procedure(s), and pathology were recorded when available. RESULTS: In 2 years, 226 surgeries were performed. Patient age ranged between 3 months and 85 years, and gender was evenly split. Half of patients came from outside the town of Malindi, and a third traveled over 100 kilometers for care. The majority reported access to a local physician, yet very few patients were offered prior surgical treatment. The most common operations performed were adenotonsillectomy and hemithyroidectomy. A wide variety of cases were performed, including parotidectomies, maxillectomies, mandibulectomies, cleft lip and palate repair, and free flap reconstructions. Local and national visiting otolaryngologist-head and neck surgeons participated or observed throughout our visits with teaching emphasis based on their skills and specific learning goals. CONCLUSIONS: Annual surgical specialty trips to rural, resource-limited regions are useful and worthwhile and offer procedures not otherwise available. On such trips, it is important to collect patient, surgical, and pathology data to help visiting surgeons determine the best procedures to teach local physicians and provide needed resources. PMID- 24046274 TI - Electrophysiologic monitoring characteristics of the recurrent laryngeal nerve preoperatively paralyzed or invaded with malignancy. AB - OBJECTIVE: To elucidate electrophysiologic responses of the recurrent laryngeal nerves that were preoperatively paralyzed or invaded by malignancy and to use this information as an added functional parameter for intraoperative management of recurrent laryngeal nerves with malignant invasion. STUDY DESIGN: Case series with chart review. SETTINGS: Academic, tertiary care center. SUBJECTS AND METHODS: All consecutive neck surgeries with nerve monitoring performed by senior author (GWR) between December 1995 and January 2007 were reviewed after obtaining Institutional Review Board approval from Massachusetts Eye and Ear Infirmary Human Subjects Committee and the Partners Human Research Committee. Electrophysiologic parameters in all cases with preoperative vocal cord paralysis/paresis, and the recurrent laryngeal nerve invasion by cancer, were studied. RESULTS: Of the 1138 surgeries performed, 25 patients (2.1%) had preoperative vocal cord dysfunction. In patients with preoperative vocal cord dysfunction, recognizable recurrent laryngeal nerve electrophysiologic activity was preserved in over 50% of cases. Malignant invasion of the recurrent laryngeal nerve was found in 22 patients (1.9%). Neural invasion of the recurrent laryngeal nerve was associated with preoperative vocal cord paralysis in only 50% of these patients. In nerves invaded by malignancy, 60% maintained recognizable electrophysiologic activity, which was more commonly present and robust when vocal cord function was preserved. CONCLUSION: Knowledge of electrophysiologic intraoperative neural monitoring provides additional functional information and, along with preoperative vocal cord function information, aids in constructing decision algorithms regarding intraoperative management of the recurrent laryngeal nerve, in prognosticating postoperative outcomes, and in patient counseling regarding postoperative expectations. PMID- 24046275 TI - CT measured normative cartilage growth in children requiring costochondral grafting. AB - OBJECTIVE: Careful operative timing is required for children undergoing microtia repair using autologous costochondral grafting. This operation is performed as early as age 6 in efforts to treat children before school matriculation while allowing for sufficient rib growth. There remains a paucity of data regarding cartilaginous growth of the ribs and synchondrosis routinely harvested during microtia repair. This study employs CT imaging to generate normative costochondral growth characteristics in children. STUDY DESIGN: A population based study was performed. SETTING: Tertiary care children's hospital. SUBJECTS AND METHODS: Chest CTs were reviewed in 360 children ages 3 to 20 years. Measurements included: length of ribs 6, 7, and 8 and the height and width of the synchondrosis between ribs 6 and 7. Growth charts are presented for gender and laterality. RESULTS: At age 6: ribs 6, 7, and 8 measure 5.96 +/- 0.69, 7.79 +/- 0.84, and 6.33 +/- 1.01 cm, respectively. In adulthood the mean length of ribs 6, 7, and 8 are 8.29 +/- 1.00, 11.10 +/- 1.19, and 8.95 +/- 1.99 cm, respectively. The vertical height of the synchondrosis at years 6 and 20 are 2.42 +/- 0.39 and 3.59 +/- 0.53 cm, respectively. Ribs 6, 7, and 8 as well as the synchondrosis grow in a nearly linear fashion. CONCLUSIONS: Cartilaginous growth of ribs 6 to 8 during early childhood is nearly linear. Synchondrosis height approaches adult auricle width at 8 years. Rib size is consistently larger in males and on the left side. These data are useful for the pediatric otolaryngologist and facial plastics and reconstructive surgeon performing microtia surgery. PMID- 24046276 TI - Dosimetric anchoring of in vivo and in vitro studies for perfluorooctanoate and perfluorooctanesulfonate. AB - In order to compare between in vivo toxicity studies, dosimetry is needed to translate study-specific dose regimens into dose metrics such as tissue concentration. These tissue concentrations may then be compared with in vitro bioactivity assays to perhaps identify mechanisms relevant to the lowest observed effect level (LOEL) dose group and the onset of the observed in vivo toxicity. Here, we examine the perfluorinated compounds (PFCs) perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS). We analyzed 9 in vivo toxicity studies for PFOA and 13 in vivo toxicity studies for PFOS. Both PFCs caused multiple effects in various test species, strains, and genders. We used a Bayesian pharmacokinetic (PK) modeling framework to incorporate data from 6 PFOA PK studies and 2 PFOS PK studies (conducted in 3 species) to predict dose metrics for the in vivo LOELs and no observed effect levels (NOELs). We estimated PK parameters for 11 combinations of chemical, species, strain, and gender. Despite divergent study designs and species-specific PK, for a given effect, we found that the predicted dose metrics corresponding to the LOELs (and NOELs where available) occur at similar concentrations. In vitro assay results for PFOA and PFOS from EPA's ToxCast project were then examined. We found that most in vitro bioactivity occurs at concentrations lower than the predicted concentrations for the in vivo LOELs and higher than the predicted concentrations for the in vivo NOELs (where available), for a variety of nonimmunological effects. These results indicate that given sufficient PK data, the in vivo LOELs dose regimens, but not necessarily the effects, could have been predicted from in vitro studies for these 2 PFCs. PMID- 24046277 TI - A genomics-based analysis of relative potencies of dioxin-like compounds in primary rat hepatocytes. AB - Toxic equivalency factors (TEFs) for dioxin-like compounds are largely based on relative potency (REP) values derived from biochemical endpoints such as enzyme activity. As of yet, REPs based on gene expression changes have not been accounted for in the TEF values. In this study, primary rat hepatocytes were treated for 24h with 11 concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), or 2,3,7,8-tetrachlorodibenzofuran (TCDF) ranging from 0.00001 to 100 nM. Differential changes in gene expression were analyzed using analysis of variance to assess the relative contributions of concentration, congener, and the interaction between concentration and congener for each gene. A total of 3283 genes showed significant changes with concentration (false discovery rate < .05 and fold-change +/- 1.5 in at least 1 concentration for 1 congener). Among these genes, 399 were significant for both concentration and congener effects indicating parallel concentration-response curves with significant differences in potency. Only 8 genes showed a significant concentration and congener interaction term indicating a minority of genes show nonparallel dose-response curves among the 3 congeners. Benchmark dose (BMD) modeling was used to derive BMD values for induced individual genes and signaling pathways. The REP values for 4-PeCDF and TCDF were generally 3- to 5-fold lower than the World Health Organization (WHO) TEF values on both a gene and pathway basis. These findings suggest that the WHO TEF values may possibly overpredict the potency of these polychlorinated dibenzofuran congeners and demonstrate the importance of identifying functional pathways relevant to the toxicological modes of action for establishing pertinent REPs. PMID- 24046278 TI - The atopic dermatitis-like symptoms induced by MC903 were alleviated in JNK1 knockout mice. AB - Atopic dermatitis (AD) is a common allergic disease, imposing large social and economic burdens worldwide. Atopic dermatitis is characterized by eczematous skin lesions and immunoglobulin E (IgE) hypersecretion. We investigated the role of JNK1 on the development of AD in mice. The vitamin D3 analogue MC903, a psoriasis therapeutic drug, was used to induce AD-like symptoms in wild-type (WT) and JNK1 /- mice. The symptoms of AD were less severe in JNK1-/- mice compared with WT mice. JNK1-/- mice showed less ear thickening and infiltration of eosinophils and mast cells in AD-like lesions than did WT mice when treated with MC903. MC903 treated JNK1-/- mice also showed significantly lower level of serum IgE, which was elevated in MC903-treated WT mice. Splenocytes isolated from MC903-treated WT and JNK1-/- mice were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. Splenocytes from JNK1-/- mice produced lower levels of T-helper (Th2) cytokines (interleukin-4 and -13) and transcription factor GATA-binding protein 3, and produced increased levels of the Th1 cytokines interferon-gamma and transcription factor T-box expressed in T cells. Our results indicate that JNK1 plays an important role in the pathogenesis of AD and may be a useful target for therapies to ameliorate AD. PMID- 24046279 TI - Quantity of glucose transporter and appetite-associated factor mRNA in various tissues after insulin injection in chickens selected for low or high body weight. AB - Chickens from lines selected for low (LWS) or high (HWS) body weight differ by 10 fold in body weight at 56 days old with differences in food intake, glucose regulation, and body composition. To evaluate if there are differences in appetite-regulatory factor and glucose transporter (GLUT) mRNA that are accentuated by hypoglycemia, blood glucose was measured, and hypothalamus, liver, pectoralis major, and abdominal fat collected at 90 days of age from female HWS and LWS chickens, and reciprocal crosses, HL and LH, at 60 min after intraperitoneal injection of insulin. Neuropeptide Y (NPY) and receptor (NPYR) subtypes 1 and 5 mRNA were greater in LWS compared with HWS hypothalamus (P < 0.05), but greater in HWS than LWS in fat (P < 0.05). Expression of NPYR2 was greater in LWS than HWS in pectoralis major (P < 0.05). There was greater expression in HWS than LWS for GLUT1 in hypothalamus and liver (P < 0.05), GLUT2 in fat and liver (P < 0.05), and GLUT9 in liver (P < 0.05). Insulin was associated with reduced blood glucose in all populations (P < 0.05) and reduced mRNA of insulin receptor (IR) and GLUT 2 and 3 in liver (P < 0.05). There was heterosis for mRNA, most notably NPYR1 (-78%) and NPYR5 (-81%) in fat and GLUT2 ( 70%) in liver. Results suggest that NPY and GLUTs are associated with differences in energy homeostasis in LWS and HWS. Reduced GLUT and IR mRNA after insulin injection suggest a compensatory mechanism to prevent further hypoglycemia. PMID- 24046281 TI - Feeding soy protein isolate and treatment with estradiol have different effects on mammary gland morphology and gene expression in weanling male and female rats. AB - Isoflavones are phytochemical components of soy diets that bind weakly to estrogen receptors (ERs). To study potential estrogen-like actions of soy in the mammary gland during early development, we fed weanling male and female Sprague Dawley rats a semipurified diet with casein as the sole protein source from postnatal day 21 to 33, the same diet substituting soy protein isolate (SPI) for casein, or the casein diet supplemented with estradiol (E2) at 10 MUg/kg/day. In contrast to E2, the SPI diet induced no significant change in mammary morphology. In males, there were 34 genes for which expression was changed >=2-fold in the SPI group vs. 509 changed significantly by E2, and 8 vs. 174 genes in females. Nearly half of SPI-responsive genes in males were also E2 responsive, including adipogenic genes. Serum insulin was found to be decreased by the SPI diet in males. SPI and E2 both downregulated the expression of ERalpha (Esr1) in males and females, and ERbeta (Esr2) only in males. Chromatin immunoprecipitation revealed an increased binding of ERalpha to the promoter of the progesterone receptor (Pgr) and Esr1 in both SPI- and E2-treated males compared with the casein group but differential recruitment of ERbeta. ER promoter binding did not correlate with differences in Pgr mRNA expression. This suggests that SPI fails to recruit appropriate co-activators at E2-inducible genes. Our results indicate that SPI behaves like a selective estrogen receptor modulator rather than a weak estrogen in the developing mammary gland. PMID- 24046282 TI - Analyses of synovial tissues from arthritic and protected congenic rat strains reveal a new core set of genes associated with disease severity. AB - Little is known about the genes regulating disease severity and joint damage in rheumatoid arthritis (RA). In the present study we analyzed the gene expression characteristics of synovial tissues from four different strains congenic for non MHC loci that develop mild and nonerosive arthritis compared with severe and erosive DA rats. DA.F344(Cia3d), DA.F344(Cia5a), DA.ACI(Cia10), and DA.ACI(Cia25) rats developed mild arthritis compared with DA. We found 685 genes with significantly different expression between congenics and DA, independent of the specific congenic interval, suggesting that these genes represent a new nongenetic core group of mediators of arthritis severity. This core group includes genes not previously implicated or with unclear role in arthritis severity, such as Tnn, Clec4m, and Spond1 among others, increased in DA. The core genes also included Scd1, Selenbp1, and Slc7a10, increased in congenics. Genes implicated in nuclear receptor activity, xenobiotic and lipid metabolism were also increased in the congenics, correlating with protection. Several disease mediators were among the core genes reduced in congenics, including IL-6, IL-17, and Ccl2. Analyses of upstream regulators (genes, pathways, or chemicals) suggested reduced activation of Stat3 and TLR-related genes and chemicals in congenics. Additionally, cigarette smoking was among the upstream regulators activated in DA, while p53 was an upstream regulator activated in congenics. We observed congenic-specific differential expression and detection in each individual strain. In conclusion, this new nongenetically regulated core genes of disease severity or protection in arthritis should provide new insight into critical pathways and potential new environmental risk factor for arthritis. PMID- 24046280 TI - RNA viruses and microRNAs: challenging discoveries for the 21st century. AB - RNA viruses represent the predominant cause of many clinically relevant viral diseases in humans. Among several evolutionary advantages acquired by RNA viruses, the ability to usurp host cellular machinery and evade antiviral immune responses is imperative. During the past decade, RNA interference mechanisms, especially microRNA (miRNA)-mediated regulation of cellular protein expression, have revolutionized our understanding of host-viral interactions. Although it is well established that several DNA viruses express miRNAs that play crucial roles in their pathogenesis, expression of miRNAs by RNA viruses remains controversial. However, modulation of the miRNA machinery by RNA viruses may confer multiple benefits for enhanced viral replication and survival in host cells. In this review, we discuss the current literature on RNA viruses that may encode miRNAs and the varied advantages of engineering RNA viruses to express miRNAs as potential vectors for gene therapy. In addition, we review how different families of RNA viruses can alter miRNA machinery for productive replication, evasion of antiviral immune responses, and prolonged survival. We underscore the need to further explore the complex interactions of RNA viruses with host miRNAs to augment our understanding of host-virus interplay. PMID- 24046283 TI - miR in melanoma development: miRNAs and acquired hallmarks of cancer in melanoma. AB - Melanoma is a very aggressive skin cancer with increasing incidence worldwide. MicroRNAs are small, noncoding RNAs that regulate gene expression of targeted gene(s). The hallmark of cancer model outlined by Hanahan and Weinberg offers a meaningful framework to consider the roles of microRNAs in melanoma development and progression. In this systematic review of the literature, we associate what is known about deregulation of microRNAs and their targeted genes in melanoma development with the hallmarks and characteristics of cancer. The diagnostic and therapeutic potential of microRNAs for future melanoma management will also be discussed. PMID- 24046285 TI - Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison. AB - OBJECTIVE: To evaluate whether smoking status is associated with the efficacy of antiplatelet treatment in the prevention of cardiovascular events. DESIGN: Systematic review, meta-analysis, and indirect comparisons. DATA SOURCES: Medline (1966 to present) and Embase (1974 to present), with supplementary searches in databases of abstracts from major cardiology conferences, the Cumulative Index to Nursing and Allied Health (CINAHL) and the CAB Abstracts databases, and Google Scholar. STUDY SELECTION: Randomized trials of clopidogrel, prasugrel, or ticagrelor that examined clinical outcomes among subgroups of smokers and nonsmokers. DATA EXTRACTION: Two authors independently extracted all data, including information on the patient populations included in the trials, treatment types and doses, definitions of clinical outcomes and duration of follow-up, definitions of smoking subgroups and number of patients in each group, and effect estimates and 95% confidence intervals for each smoking status subgroup. RESULTS: Of nine eligible randomized trials, one investigated clopidogrel compared with aspirin, four investigated clopidogrel plus aspirin compared with aspirin alone, and one investigated double dose compared with standard dose clopidogrel; these trials include 74,489 patients, of whom 21,717 (29%) were smokers. Among smokers, patients randomized to clopidogrel experienced a 25% reduction in the primary composite clinical outcome of cardiovascular death, myocardial infarction, and stroke compared with patients in the control groups (relative risk 0.75, 95% confidence interval 0.67 to 0.83). In nonsmokers, however, clopidogrel produced just an 8% reduction in the composite outcome (0.92, 0.87 to 0.98). Two studies investigated prasugrel plus aspirin compared with clopidogrel plus aspirin, and one study investigated ticagrelor plus aspirin compared with clopidogrel plus aspirin. In smokers, the relative risk was 0.71 (0.61 to 0.82) for prasugrel compared with clopidogrel and 0.83 (0.68 to 1.00) for ticagrelor compared with clopidogrel. Corresponding relative risks were 0.92 (0.83 to 1.01) and 0.89 (0.79 to 1.00) among nonsmokers. CONCLUSIONS: In randomized clinical trials of antiplatelet drugs, the reported clinical benefit of clopidogrel in reducing cardiovascular death, myocardial infarction, and stroke was seen primarily in smokers, with little benefit in nonsmokers. PMID- 24046284 TI - Pregnancy-associated genes contribute to antiluteolytic mechanisms in ovine corpus luteum. AB - The hypothesis that ovine luteal gene expression differs due to pregnancy status and day of estrous cycle was tested. RNA was isolated from corpora lutea (CL) on days 12 and 14 of the estrous cycle (NP) or pregnancy (P) and analyzed with the Affymetrix bovine microarray. RNA also was isolated from luteal cells on day 10 of estrous cycle that were cultured for 24 h with luteolytic hormones (OXT and PGF) and secretory products of the conceptus (IFNT and PGE2). Differential gene expression (>1.5-fold, P < 0.05) was confirmed using semiquantitative real-time PCR. Serum progesterone concentrations decreased from day 12 to day 15 in NP ewes (P < 0.05) reflecting luteolysis and remained >1.7 ng/ml in P ewes reflecting rescue of the CL. Early luteolysis (days 12-14) was associated with differential expression of 683 genes in the CL, including upregulation of SERPINE1 and THBS1. Pregnancy on day 12 (55 genes) and 14 (734 genes) also was associated with differential expression of genes in the CL, many of which were ISGs (i.e., ISG15, MX1) that were induced when culturing luteal cells with IFNT, but not PGE2. Finally, many genes, such as PTX3, IL6, VEGF, and LHR, were stabilized during pregnancy and downregulated during the estrous cycle and in response to culture of luteal cells with luteolytic hormones. In conclusion, pregnancy circumvents luteolytic pathways and activates or stabilizes genes associated with interferon, chemokine, cell adhesion, cytoskeletal, and angiogenic pathways in the CL. PMID- 24046287 TI - Commentary: How the BMJ selects guideline summaries for publication. PMID- 24046286 TI - Ensuring the integrity of clinical practice guidelines: a tool for protecting patients. PMID- 24046288 TI - NHS competition rules are "not fit for purpose," think tank chief says. PMID- 24046289 TI - CDC calls for urgent action to combat rise of drug resistant pathogens. PMID- 24046290 TI - Review rates of pathology findings for head and neck cancer vary hugely between hospitals, report finds. PMID- 24046291 TI - Charity calls for routine BRCA testing of ovarian cancer patients. PMID- 24046292 TI - Incidence of postoperative death and acute kidney injury associated with i.v. 6% hydroxyethyl starch use: systematic review and meta-analysis. AB - BACKGROUND: Trials suggest that the use of i.v. hydroxyethyl starch (HES) solutions is associ-ated with increased risk of death and acute kidney injury (AKI) in critically ill patients. It is uncertain whether similar adverse effects occur in surgical patients. METHODS: Systematic review and meta-analysis of trials in which patients were randomly allocated to 6% HES solutions or alternative i.v. fluids in patients undergoing surgery. Ovid Medline, Embase, Cinhal, and Cochrane Database of Systematic Reviews were searched for trials comparing 6% HES with clinically relevant non-starch comparator. The primary end point was hospital mortality. Secondary endpoints were requirement for renal replacement therapy (RRT) and author-defined AKI. Pre-defined subgroups were cardiac and non-cardiac surgery. RESULTS: Four hundred and fifty-six papers were identified; of which 19 met the inclusion criteria. In total, 1567 patients were included in the analysis. Dichotomous outcomes were expressed as a difference of proportions [risk difference (RD)]. There was no difference in hospital mortality [RD 0.00, 95% confidence interval (CI) -0.02, 0.02], requirement for RRT (RD 0.01, 95% CI -0.04, 0.02), or AKI (RD 0.02, 95% CI -0.02 to 0.06) between compared arms overall or in predefined subgroups. CONCLUSIONS: We did not identify any differences in the incidence of death or AKI in surgical patients receiving 6% HES. Included studies were small with low event rates and low risk of heterogeneity. Narrow CIs suggest that these findings are valid. Given the absence of demonstrable benefit, we are unable to recommend the use of 6% HES solution in surgical patients. PMID- 24046293 TI - Early diastolic dysfunction is associated with intensive care unit mortality in cancer patients presenting with septic shock. AB - BACKGROUND: Cancer patients present a high risk of sepsis and are exposed to cardiotoxic drugs during chemotherapy. Myocardial dysfunction is common during septic shock and can be evaluated at bedside using echocardiography. The aim of this study was to identify early cardiac dysfunctions associated with intensive care unit (ICU) mortality in cancer patients presenting with septic shock. METHODS: Seventy-two cancer patients admitted to the ICU underwent echocardiography within 48 h of developing septic shock. History of malignancies, anticancer treatments, and clinical characteristics were prospectively collected. RESULTS: ICU mortality was 48%. Diastolic dysfunction (e' <=8 cm s(-1)) was an independent echocardiographic parameter associated with ICU mortality {odds ratio (OR) 7.7 [95% confidence interval (CI), 2.58-23.38]; P<0.001}. Overall, three factors were independently associated with ICU mortality: sepsis-related organ failure assessment score at admission [OR 1.35 ( 95% CI, 1.05-1.74); P=0.017], occurrence of diastolic dysfunction [OR 16.6 (95% CI, 3.28-84.6); P=0.001], and need for conventional mechanical ventilation [OR 16.6 (95% CI, 3.6-77.15); P<0.001]. Diastolic dysfunction was not associated with exposure to cardiotoxic drugs. CONCLUSIONS: Early diastolic dysfunction is a strong and independent predictor of mortality in cancer patients presenting with septic shock. It is not associated with exposure to cardiotoxic drugs. Further studies incorporating monitoring of diastolic function and therapeutic interventions improving cardiac relaxation need to be evaluated in cancer patients presenting with septic shock. PMID- 24046294 TI - Bispecific antibody to ErbB2 overcomes trastuzumab resistance through comprehensive blockade of ErbB2 heterodimerization. AB - The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2 specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TPL, retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TPL showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TPL potently abrogated ErbB2 signaling in trastuzumab-resistant breast cancer cell lines. In addition, we showed that TPL was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both in vitro and in vivo. Importantly, TPL treatment eradicated established trastuzumab resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TPL to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic. PMID- 24046295 TI - Screening with serum galactomannan might be associated with better outcome than symptom-triggered galactomannan testing in allogeneic HSCT recipients with invasive aspergillosis. PMID- 24046296 TI - A multistep voriconazole-related phototoxic pathway may lead to skin carcinoma: results from a French nationwide study. AB - BACKGROUND: Voriconazole long-term therapy is suspected to induce cutaneous squamous cell carcinoma (SCC), as suggested by 18 case reports worldwide and 3 retrospective studies. METHODS: To better characterize the natural history of these potentially voriconazole-associated tumors, a nationwide call for notification of skin cancers and other skin lesions observed between 2002 and 2012 in patients treated by voriconazole was launched in France. A multidisciplinary committee evaluated voriconazole involvement in each case. RESULTS: Nineteen SCCs were reported. The committee determined the likelihood of voriconazole involvement to be high in 15 cases, intermediate in 2, and low in 2. In the 17 patients with high/intermediate likelihood of voriconazole involvement, the mean time between voriconazole initiation and SCC diagnosis was 39 +/- 18 months (range, 28-84 months), and was shorter in transplant recipients (35 vs 45 months, P < .05). Cumulative mean duration of voriconazole therapy at SCC diagnosis was 35 months (range, 7-63 months). A multistep process was noted in 14 of 17 patients: acute phototoxicity during the first year of voriconazole therapy (mean time, 6 months [range, 0-18 months]), actinic keratosis (AK) of the same sun-exposed skin area in the second/third year (mean, 30 months [range, 11-57 months]), followed by SCC during the third year or later. Five cases of AK without SCC and 37 cases of other skin lesions were also reported. CONCLUSIONS: Our results suggest that long-term voriconazole prescription may be associated with a multistep phototoxic process involving acute skin lesions followed by AK then by SCC. Discontinuation of voriconazole should be strongly considered in patients experiencing chronic phototoxicity. PMID- 24046297 TI - Reply to Mikulska et al. PMID- 24046298 TI - Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia. AB - BACKGROUND: Higher daptomycin doses are advocated for select methicillin resistant Staphylococcus aureus (MRSA)-related infections, but the probabilities of target attainment (PTA) and toxicity of these doses have not been characterized in critically ill patients. METHODS: We evaluated the plasma pharmacokinetics (PK) and clinical outcomes of a cohort of critically ill patients treated with daptomycin 6-8 mg/kg/day for primarily Staphylococcus species-related infections. Daptomycin concentrations were measured intensively over the initial 96-hour dosing period. Data were modeled by population PK analyses, and Monte Carlo simulation was used to estimate the probabilities of effect and toxicity with standard and alternate dosing regimens. RESULTS: Fifty patients with a mean (SD) age of 69.7 (12.2) years, weight 74.5 (20.3) kg, and creatinine clearance 56.8 (38.2) mL/minute were enrolled with measurements of 12 (2.2) daptomycin samples per patient. Significantly lower daptomycin exposures were observed despite comparable doses in a subset of patients (n = 13) with augmented clearance (CL). No covariates of CL were identified, but this subset was significantly more likely to be in severe sepsis or septic shock, have higher Sequential Organ Failure Assessment scores, and MRSA bacteremia. In-hospital mortality was significantly higher (30.7% vs 10.8%) in patients with augmented daptomycin CL. Use of an empiric fixed dose of 750 mg of daptomycin is predicted to achieve a comparable PTA with a lower probability of toxicity as compared to the use of 10 mg/kg in critically ill patients. CONCLUSIONS: A reappraisal of current daptomycin dosing recommendations is needed to improve the PTA and reduce toxicity among critically ill patients. PMID- 24046299 TI - Impact of hepatitis B-active combination antiretroviral therapy on hepatitis B susceptibility in newly diagnosed HIV patients. PMID- 24046300 TI - Editorial commentary: community-associated Clostridium difficile infection in children. PMID- 24046301 TI - Effect of influenza vaccination of healthcare personnel on morbidity and mortality among patients: systematic review and grading of evidence. AB - BACKGROUND: Influenza vaccination of healthcare personnel (HCP) is recommended in >40 countries. However, there is controversy surrounding the evidence that HCP vaccination reduces morbidity and mortality among patients. Key factors for developing evidence-based recommendations include quality of evidence, balance of benefits and harms, and values and preferences. METHODS: We conducted a systematic review of randomized trials, cohort studies, and case-control studies published through June 2012 to evaluate the effect of HCP influenza vaccination on mortality, hospitalization, and influenza cases in patients of healthcare facilities. We pooled trial results using meta-analysis and assessed evidence quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We identified 4 cluster randomized trials and 4 observational studies conducted in long-term care or hospital settings. Pooled risk ratios across trials for all-cause mortality and influenza-like illness were 0.71 (95% confidence interval [CI], .59-.85) and 0.58 (95% CI, .46 .73), respectively; pooled estimates for all-cause hospitalization and laboratory confirmed influenza were not statistically significant. The cohort and case control studies indicated significant protective associations for influenza-like illness and laboratory-confirmed influenza. No studies reported harms to patients. Using GRADE, the quality of the evidence for the effect of HCP vaccination on mortality and influenza cases in patients was moderate and low, respectively. The evidence quality for the effect of HCP vaccination on patient hospitalization was low. The overall evidence quality was moderate. CONCLUSIONS: The quality of evidence is higher for mortality than for other outcomes. HCP influenza vaccination can enhance patient safety. PMID- 24046303 TI - Distinguishing community-associated from hospital-associated Clostridium difficile infections in children: implications for public health surveillance. AB - BACKGROUND: Children are increasingly recognized as being at risk for C. difficile infection (CDI), even without prior exposure to antibiotics or the healthcare environment. We aimed to distinguish risk factors, clinical course, and outcomes between healthcare facility-associated (HA) and community-associated (CA) CDI. METHODS: This was a retrospective, observational cohort study conducted at the Johns Hopkins Children's Center, Baltimore, Maryland. All inpatients, aged >=1 year, hospitalized from July 2003 to July 2012 and diagnosed with CDI based on clinical characteristics and confirmatory laboratory testing were included. The main outcome was CDI, categorized as HA-CDI, CA-CDI, and "indeterminate" (classified as disease onset in the community, 4-12 weeks from hospital discharge). RESULTS: Two hundred two pediatric inpatients were diagnosed with CDI, of whom 38 had CA-CDI, 144 had HA-CDI, and 20 had indeterminate CDI. Children with indeterminate CDI had baseline characteristics similar to those identified for HA-CDI. Children hospitalized with CA-CDI were less likely to have comorbidities (odds ratio [OR], 0.14; 95% confidence interval [CI], .03-.65; P = .013), to have been exposed to antibiotics (OR, 0.17; 95% CI, .07-.44; P < .001), or prior surgeries (OR, 0.03; 95% CI, .00-.24; P = .001), compared to children with HA-CDI. Compared with HA-CDI, children with CA-CDI had a trend toward more episodes of septic shock (P = .07), toxic megacolon (P = .04), and recurrences (P = .04). CONCLUSIONS: In a hospitalized cohort, CA-CDI is more often seen in previously healthy children without antibiotic exposure or comorbid conditions and has more frequent complications and recurrences compared to HA-CDI. For surveillance purposes, "indeterminate" CDI should be allocated to HA-CDI rather than CA-CDI. PMID- 24046302 TI - Racial differences in response to antiretroviral therapy for HIV infection: an AIDS clinical trials group (ACTG) study analysis. AB - BACKGROUND: In the United States, black individuals infected with human immunodeficiency virus (HIV) have higher rates of virologic failure on antiretroviral therapy (ART) and of death compared to white individuals. The cause for these disparities is uncertain. We sought to examine differences in virologic outcomes among antiretroviral-naive clinical trial participants starting randomized ART and to investigate factors to explain the differences. METHODS: Individual-level data from participants initiating ART in 5 AIDS Clinical Trials Group studies were analyzed. Included studies were those conducted during 1998-2006 with a primary outcome of virologic failure. The primary outcome measure was time to virologic failure, regardless of ART changes. RESULTS: A total of 2495 individuals (1151 black; 1344 white) were included with a median follow-up of 129 weeks. Compared to whites, blacks had an increased hazard of virologic failure (hazard ratio [HR]; 1.7; 95% confidence interval [CI], 1.4-1.9; P < .001), with no evidence of heterogeneity across regimens (P = .97); the association remained after adjustment for measured confounders (HR, 1.4; 95% CI, 1.2-1.6; P < .001). Increased hazard of virologic failure was associated with younger age, higher pretreatment HIV type 1 RNA level, lower pretreatment CD4 cell count, hepatitis C antibody, less education, and recent nonadherence to treatment. Sensitivity analyses with different endpoint definitions demonstrated similar results. CONCLUSIONS: In this analysis, blacks had a 40% higher virologic failure risk than whites that was not explained by measured confounders. The observation was consistent over a range of regimens, suggesting that the difference may be driven by social factors; however, biological factors cannot be ruled out. Further research should identify the sources of racial disparities and develop strategies to reduce them. PMID- 24046304 TI - Histoplasmosis after solid organ transplant. AB - BACKGROUND: To improve our understanding of risk factors, management, diagnosis, and outcomes associated with histoplasmosis after solid organ transplant (SOT), we report a large series of histoplasmosis occurring after SOT. METHODS: All cases of histoplasmosis in SOT recipients diagnosed between 1 January 2003 and 31 December 2010 at 24 institutions were identified. Demographic, clinical, and laboratory data were collected. RESULTS: One hundred fifty-two cases were identified: kidney (51%), liver (16%), kidney/pancreas (14%), heart (9%), lung (5%), pancreas (2%), and other (2%). The median time from transplant to diagnosis was 27 months, but 34% were diagnosed in the first year after transplant. Twenty eight percent of patients had severe disease (requiring intensive care unit admission); 81% had disseminated disease. Urine Histoplasma antigen detection was the most sensitive diagnostic method, positive in 132 of 142 patients (93%). An amphotericin formulation was administered initially to 73% of patients for a median duration of 2 weeks; step-down therapy with an azole was continued for a median duration of 12 months. Ten percent of patients died due to histoplasmosis with 72% of deaths occurring in the first month after diagnosis; older age and severe disease were risk factors for death from histoplasmosis. Relapse occurred in 6% of patients. CONCLUSIONS: Although late cases occur, the first year after SOT is the period of highest risk for histoplasmosis. In patients who survive the first month after diagnosis, treatment with an amphotericin formulation followed by an azole for 12 months is usually successful, with only rare relapse. PMID- 24046306 TI - Spread of hepatitis C virus infection in men who have sex with men. PMID- 24046305 TI - The effectiveness of conjugate Haemophilus influenzae type B vaccine in The Gambia 14 years after introduction. AB - BACKGROUND: The Gambia was the first country in Africa to introduce conjugate Haemophilus influenzae type b (Hib) vaccine, which, as in other developing countries but unlike industrialized countries, is delivered as a 3-dose primary series with no booster. This study assessed its effectiveness 14 years after introduction. METHODS: Using methods standardized during >20 years in the study site, clinical and microbiological surveillance for invasive Hib disease (primarily meningitis) in the Western Region of The Gambia from 2007 to 2010 was complemented with studies of Hib carriage in children aged 1 to <2 years, Hib antibody levels in children aged <5 years, and Hib vaccine coverage and timing in children aged 1 to <2 years. RESULTS: The incidence of Hib meningitis remained low (averaging 1.3 per 100 000 children aged <5 years annually), as did the Hib oropharyngeal carriage rate (0.9%). Hib antibody levels were protective in >99% of those surveyed, albeit with lower titers in older children; and coverage of conjugate Hib vaccination was high (91% having 3 doses at 1-2 years of age) using a schedule that was delivered at median ages of 2.6 months, 4.3 months, and 6 months for the first, second, and third doses, respectively. CONCLUSIONS: Conjugate Hib vaccine was delivered on time in a 3-dose primary series without booster to a high proportion of eligible children and this was associated with effective disease control up to 14 years after introduction. It is important that surveillance continues in this first African country to introduce the vaccine to determine if effective control persists or if a booster dose becomes necessary as has been the case in industrialized countries. PMID- 24046307 TI - Community-acquired bacterial bloodstream infections in HIV-infected patients: a systematic review. AB - Information on community-acquired bacterial bloodstream infections (BSIs) in individuals infected with human immunodeficiency virus (HIV) is limited. We conducted a systematic literature review. The case fraction of community-acquired bacterial BSIs in hospitalized patients is 20% and 30% in adults and children, respectively, compared to 9% in HIV-negative adults and children. Worldwide, the main pathogens of community-acquired BSI are nontyphoid salmonellae (NTS), Streptococcus pneumoniae, Escherichia coli, and Staphylococcus aureus, but regional differences are apparent, especially for S. pneumoniae. Compared to HIV negative populations, HIV patients are particularly at risk to develop NTS bacteremia. Bacteremia incidence is related to immunosuppression, and antiretroviral therapy reduces the incidence of BSI in HIV patients (rate ratios, 0.63-0.02). Mortality rates varied between 7% and 46%. These results suggest that bacterial BSI is more likely to be found in HIV-positive than in HIV-negative patients upon hospitalization, and that causative pathogens vary by region. PMID- 24046308 TI - Reply to Bradshaw and Danta. PMID- 24046309 TI - A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza a and B infections. AB - BACKGROUND: It is unclear if higher-dose oseltamivir provides benefit beyond the standard dose in influenza patients who require hospitalization. METHODS: A prospective intervention study was performed in 2 acute care general hospitals in Hong Kong over 4 seasonal peaks (2010-2012). Adults (>=18 years) with laboratory confirmed influenza (85 A/H3N2, 34 A/H1N1pdm09, 36 B) infections who presented within 96 hours were recruited. Study regimen of either 150 mg or 75 mg oseltamivir twice daily for 5 days was allocated by site, which was switched after 2 seasons. Subjects with preexisting renal impairment (creatinine clearance, 40-60 mL/minute) received 75 mg oseltamivir twice daily. Viral clearance by day 5 and clinical responses were compared between groups. Plasma steady-state trough oseltamivir carboxylate (OC) concentration was measured by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Altogether, 41 and 114 patients received 150 mg and 75 mg twice-daily oseltamivir, respectively; their enrollment characteristics (mean age, 61 +/- 18 vs 66 +/- 16 years) and illness severity were comparable. Trough OC levels were higher in the 150-mg group (501.0 +/- 237.0 vs 342.6 +/- 192.7 ng/mL). There were no significant differences in day 5 viral RNA (44.7% vs 40.2%) or culture negativity (100.0% vs 98.1%), RNA decline rate, and durations of fever, oxygen supplementation, and hospitalization. Results were similar when analyzed by study arm (all cases and among those without renal impairment). Subanalysis of influenza B patients showed faster RNA decline rate (analysis of variance, F = 4.14; P = .05) and clearance (day 5, 80.0% vs 57.1%) with higher-dose treatment. No oseltamivir resistance was found. Treatments were generally well tolerated. CONCLUSIONS: We found no additional benefit of higher-dose oseltamivir treatment in adults hospitalized with influenza A, but an improved virologic response in influenza B. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT01052961. PMID- 24046310 TI - Safety of tenofovir during pregnancy for the mother and fetus: a systematic review. AB - Tenofovir disoproxil fumarate (TDF) safety during pregnancy has important public health implications. This review summarizes TDF safety during pregnancy, focusing on pregnancy outcomes, congenital anomaly risk, and other potential toxicities on neonates. Although information is limited, TDF appears to be safe during pregnancy. In 6 studies of human immunodeficiency virus type 1 (and/or hepatitis B virus)-infected women receiving TDF during pregnancy, adverse events were mild to moderate; none were considered to be TDF-related. Five studies that followed in utero TDF-exposed infants showed no increased risk of growth or bone abnormalities. One study showed slightly lower infant height at age 1 year, but the significance is unclear. The Antiretroviral Pregnancy Registry database, with 1800 pregnancies exposed to TDF in the first trimester, does not indicate increased congenital anomaly risk with TDF exposure. More evidence collected prospectively, ideally with bone density measurements and randomized trial design, will be optimal to determine the effects of antenatal TDF exposure on children's health. PMID- 24046312 TI - Influenza vaccination of healthcare workers: making the grade for action. PMID- 24046311 TI - Clinical characteristics of Dengue shock syndrome in Vietnamese children: a 10 year prospective study in a single hospital. AB - BACKGROUND: Dengue shock syndrome (DSS) is a severe manifestation of dengue virus infection that particularly affects children and young adults. Despite its increasing global importance, there are no prospective studies describing the clinical characteristics, management, or outcomes of DSS. METHODS: We describe the findings at onset of shock and the clinical evolution until discharge or death, from a comprehensive prospective dataset of 1719 Vietnamese children with laboratory-confirmed DSS managed on a single intensive care unit between 1999 and 2009. RESULTS: The median age of patients was 10 years. Most cases had secondary immune responses, with only 6 clear primary infections, and all 4 dengue virus serotypes were represented during the 10-year study. Shock occurred commonly between days 4 and 6 of illness. Clinical signs and symptoms were generally consistent with empirical descriptions of DSS, although at presentation 153 (9%) were still febrile and almost one-third had no bleeding. Overall, 31 (2%) patients developed severe bleeding, primarily from the gastrointestinal tract, 26 of whom required blood transfusion. Only 8 patients died, although 123 of 1719 (7%) patients had unrecordable blood pressure at presentation and 417 of the remaining 1596 (26%) were hypotensive for age. The majority recovered well with standard crystalloid resuscitation or following a single colloid infusion. All cases were classified as severe dengue, while only 70% eventually fulfilled all 4 criteria for the 1997 World Health Organization classification of dengue hemorrhagic fever. CONCLUSIONS: With prompt intervention and assiduous clinical care by experienced staff, the outcome of this potentially fatal condition can be excellent. PMID- 24046313 TI - Impact of postpartum influenza vaccination of mothers and household contacts in preventing febrile episodes, influenza-like illness, healthcare seeking, and administration of antibiotics in young infants during the 2012-2013 influenza season. AB - BACKGROUND: Influenza is associated with an increased risk for serious illness, hospitalization, and mortality in infants aged <6 months. However, influenza vaccines are not licensed for administration in this age group. The study evaluated the effectiveness of postpartum influenza vaccination of mothers and household members in infants. METHODS: The influenza vaccine was offered to mothers and household members of neonates born or hospitalized in 3 hospitals prior to the 2012-2013 season. Mothers were contacted every 2 weeks during the influenza season, and data regarding the onset of fever and/or respiratory symptoms in infants, healthcare seeking, hospitalization, and administration of antibiotics were collected. RESULTS: The study group consisted of 553 mothers who delivered 573 neonates. The influenza vaccine was administered to 841 of 1844 (45.6%) household contacts. Vaccination coverage rates ranged between 41.9% for neonates siblings and 49% for mothers. Five hundred thirty infants were analyzed for vaccine effectiveness. For outcomes in the infant, postpartum maternal vaccination had 37.7% effectiveness against acute respiratory illness (ARI), 50.3% against a febrile episode, 53.5% against influenza-like illness (ILI), 41.8% against related healthcare seeking, and 45.4% against administration of antibiotics. Multiple logistic regression analyses showed that maternal influenza vaccination was significantly associated with a decreased probability for febrile episodes, ARIs, and/or ILIs in infants, related healthcare seeking, and/or administration of antibiotics during the influenza season. Vaccination of other household contacts had no impact. CONCLUSIONS: Maternal postpartum vaccination against influenza was associated with a significant reduction of influenza related morbidity, healthcare seeking, and antibiotic prescription in infants during the influenza season. PMID- 24046314 TI - Developing insights into cardiac regeneration. AB - Owing to its intrinsic beauty and biomedical importance, the heart has been the focus of intensive research. The recent EMBO/EMBL-sponsored symposium 'Cardiac Biology: From Development to Regeneration' gathered cardiovascular scientists from across the globe to discuss the latest advances in our understanding of the development and growth of the heart, and application of these advances to improving the limited innate regenerative capacity of the mammalian heart. Here, we summarize some of the exciting results and themes that emerged from the meeting. PMID- 24046316 TI - The regulation of Hox gene expression during animal development. AB - Hox genes encode a family of transcriptional regulators that elicit distinct developmental programmes along the head-to-tail axis of animals. The specific regional functions of individual Hox genes largely reflect their restricted expression patterns, the disruption of which can lead to developmental defects and disease. Here, we examine the spectrum of molecular mechanisms controlling Hox gene expression in model vertebrates and invertebrates and find that a diverse range of mechanisms, including nuclear dynamics, RNA processing, microRNA and translational regulation, all concur to control Hox gene outputs. We propose that this complex multi-tiered regulation might contribute to the robustness of Hox expression during development. PMID- 24046317 TI - Hemogenic endothelium specification and hematopoietic stem cell maintenance employ distinct Scl isoforms. AB - Recent studies have shown that nascent hematopoietic stem cells (HSCs) derive directly from the ventral aortic endothelium (VAE) via endothelial to hematopoietic transition (EHT). However, whether EHT initiates from a random or predetermined subpopulation of VAE, as well as the molecular mechanism underlying this process, remain unclear. We previously reported that different zebrafish stem cell leukemia (scl) isoforms are differentially required for HSC formation in the ventral wall of the dorsal aorta. However, the exact stage at which these isoforms impact HSC development was not defined. Here, using in vivo time-lapse imaging of scl isoform-specific reporter transgenic zebrafish lines, we show that prior to EHT scl-beta is selectively expressed in hemogenic endothelial cells, a unique subset of VAE cells possessing hemogenic potential, whereas scl-alpha is expressed later in nascent HSCs as they egress from VAE cells. In accordance with their expression, loss-of-function studies coupled with in vivo imaging analysis reveal that scl-beta acts earlier to specify hemogenic endothelium, which is later transformed by runx1 into HSCs. Our results also reveal a previously unexpected role of scl-alpha in maintaining newly born HSCs in the aorta-gonads mesonephros. Thus, our data suggest that a defined hemogenic endothelial population preset by scl-beta supports the deterministic emergence of HSCs, and unravel the cellular mechanisms by which scl isoforms regulate HSC development. PMID- 24046315 TI - The developmental origins of adipose tissue. AB - Adipose tissue is formed at stereotypic times and locations in a diverse array of organisms. Once formed, the tissue is dynamic, responding to homeostatic and external cues and capable of a 15-fold expansion. The formation and maintenance of adipose tissue is essential to many biological processes and when perturbed leads to significant diseases. Despite this basic and clinical significance, understanding of the developmental biology of adipose tissue has languished. In this Review, we highlight recent efforts to unveil adipose developmental cues, adipose stem cell biology and the regulators of adipose tissue homeostasis and dynamism. PMID- 24046319 TI - Filopodia are dispensable for endothelial tip cell guidance. AB - Actin filaments are instrumental in driving processes such as migration, cytokinesis and endocytosis and provide cells with mechanical support. During angiogenesis, actin-rich filopodia protrusions have been proposed to drive endothelial tip cell functions by translating guidance cues into directional migration and mediating new contacts during anastomosis. To investigate the structural organisation, dynamics and functional importance of F-actin in endothelial cells (ECs) during angiogenesis in vivo, we generated a transgenic zebrafish line expressing Lifeact-EGFP in ECs. Live imaging identifies dynamic and transient F-actin-based structures, such as filopodia, contractile ring and cell cortex, and more persistent F-actin-based structures, such as cell junctions. For functional analysis, we used low concentrations of Latrunculin B that preferentially inhibited F-actin polymerisation in filopodia. In the absence of filopodia, ECs continued to migrate, albeit at reduced velocity. Detailed morphological analysis reveals that ECs generate lamellipodia that are sufficient to drive EC migration when filopodia formation is inhibited. Vessel guidance continues unperturbed during intersegmental vessel development in the absence of filopodia. Additionally, hypersprouting induced by loss of Dll4 and attraction of aberrant vessels towards ectopic sources of Vegfa165 can occur in the absence of endothelial filopodia protrusion. These results reveal that the induction of tip cells and the integration of endothelial guidance cues do not require filopodia. Anastomosis, however, shows regional variations in filopodia requirement, suggesting that ECs might rely on different protrusive structures depending on the nature of the environment or of angiogenic cues. PMID- 24046318 TI - Daam1a mediates asymmetric habenular morphogenesis by regulating dendritic and axonal outgrowth. AB - Although progress has been made in resolving the genetic pathways that specify neuronal asymmetries in the brain, little is known about genes that mediate the development of structural asymmetries between neurons on left and right. In this study, we identify daam1a as an asymmetric component of the signalling pathways leading to asymmetric morphogenesis of the habenulae in zebrafish. Daam1a is a member of the Formin family of actin-binding proteins and the extent of Daam1a expression in habenular neuron dendrites mirrors the asymmetric growth of habenular neuropil between left and right. Local loss and gain of Daam1a function affects neither cell number nor subtype organisation but leads to a decrease or increase of neuropil, respectively. Daam1a therefore plays a key role in the asymmetric growth of habenular neuropil downstream of the pathways that specify asymmetric cellular domains in the habenulae. In addition, Daam1a mediates the development of habenular efferent connectivity as local loss and gain of Daam1a function impairs or enhances, respectively, the growth of habenular neuron terminals in the interpeduncular nucleus. Abrogation of Daam1a disrupts the growth of both dendritic and axonal processes and results in disorganised filamentous actin and alpha-tubulin. Our results indicate that Daam1a plays a key role in asymmetric habenular morphogenesis mediating the growth of dendritic and axonal processes in dorsal habenular neurons. PMID- 24046320 TI - A global pattern of mechanical stress polarizes cell divisions and cell shape in the growing Drosophila wing disc. AB - Organismal development is under genetic control. Ultimately, mechanical forces shape embryos. If we want to understand the precise regulation of size and shape in animals, we must dissect how forces are distributed in developing tissues, and how they drive cell behavior to shape organs. This has not been addressed fully in the context of growing tissues. As cells grow and divide, they exert a pressure on their neighbors. How these local stresses add up or dissipate as the tissue grows is an unanswered question. We address this issue in the growing wing imaginal disc of Drosophila larvae, the precursor of the adult wing. We used a quantitative approach to analyze the strains and stresses of cells of the wing pouch, and found a global pattern of stress whereby cells in the periphery of the tissue are mechanically stretched and cells in the center are compressed. This pattern has important consequences on cell shape in the wing pouch: cells respond to it by polarizing their acto-myosin cortex, and aligning their divisions with the main axis of cell stretch, thereby polarizing tissue growth. Ectopic perturbations of tissue growth by the Hippo signaling pathway reorganize this pattern in a non-autonomous manner, suggesting a synergy between tissue mechanics and growth control during wing disc morphogenesis. PMID- 24046322 TI - The mechanical anisotropy in a tissue promotes ordering in hexagonal cell packing. AB - Many epithelial tissues pack cells into a honeycomb pattern to support their structural and functional integrity. Developmental changes in cell packing geometry have been shown to be regulated by both mechanical and biochemical interactions between cells; however, it is largely unknown how molecular and cellular dynamics and tissue mechanics are orchestrated to realize the correct and robust development of hexagonal cell packing. Here, by combining mechanical and genetic perturbations along with live imaging and Bayesian force inference, we investigate how mechanical forces regulate cellular dynamics to attain a hexagonal cell configuration in the Drosophila pupal wing. We show that tissue stress is oriented towards the proximal-distal axis by extrinsic forces acting on the wing. Cells respond to tissue stretching and orient cell contact surfaces with the stretching direction of the tissue, thereby stabilizing the balance between the intrinsic cell junction tension and the extrinsic force at the cell population level. Consequently, under topological constraints of the two dimensional epithelial sheet, mismatches in the orientation of hexagonal arrays are suppressed, allowing more rapid relaxation to the hexagonal cell pattern. Thus, our results identify the mechanism through which the mechanical anisotropy in a tissue promotes ordering in cell packing geometry. PMID- 24046321 TI - The parallel growth of motoneuron axons with the dorsal aorta depends on Vegfc/Vegfr3 signaling in zebrafish. AB - Blood vessels and neurons grow often side by side. However, the molecular and cellular mechanisms underlying their parallel development remain unclear. Here, we report that a subpopulation of secondary motoneurons extends axons ventrally outside of the neural tubes and rostrocaudally as a fascicle beneath the dorsal aorta (DA) in zebrafish. We tried to clarify the mechanism by which these motoneuron axons grow beneath the DA and found that Vegfc in the DA and Vegfr3 in the motoneurons were essential for the axon growth. Forced expression of either Vegfc in arteries or Vegfr3 in motoneurons resulted in enhanced axon growth of motoneurons over the DA. Both vegfr3 morphants and vegfc morphants lost the alignment of motoneuron axons with DA. In addition, forced expression of two mutant forms of Vegfr3 in motoneurons, potentially trapping endogenous Vegfc, resulted in failure of growth of motoneuron axons beneath the DA. Finally, a vegfr3 mutant fish lacked the motoneuron axons beneath the DA. Collectively, Vegfc from the preformed DA guides the axon growth of secondary motoneurons. PMID- 24046323 TI - Sdc2 and Tbx16 regulate Fgf2-dependent epithelial cell morphogenesis in the ciliated organ of asymmetry. AB - Heparan sulfate proteoglycans (HSPGs) control many cellular processes and have been implicated in the regulation of left-right (LR) development by as yet unknown mechanisms. Using lineage-targeted knockdowns, we found that the transmembrane HSPG Syndecan 2 (Sdc2) regulates LR patterning through cell autonomous functions in the zebrafish ciliated organ of asymmetry, Kupffer's vesicle (KV), including regulation of cell proliferation and adhesion, cilia length and asymmetric fluid flow. Exploring downstream pathways, we found that the cell signaling ligand Fgf2 is exclusively expressed in KV cell lineages, and is dependent on Sdc2 and the transcription factor Tbx16. Strikingly, Fgf2 controls KV morphogenesis but not KV cilia length, and KV morphogenesis in sdc2 morphants can be rescued by expression of fgf2 mRNA. Through an Fgf2-independent pathway, Sdc2 and Tbx16 also control KV ciliogenesis. Our results uncover a novel Sdc2-Tbx16-Fgf2 pathway that regulates epithelial cell morphogenesis. PMID- 24046324 TI - Genome-wide shRNA screening to identify factors mediating Gata6 repression in mouse embryonic stem cells. AB - The use of whole-genome pooled shRNA libraries in loss-of-function screening in tissue culture models provides an effective means to identify novel factors acting in pathways of interest. Embryonic stem cells (ESCs) offer a unique opportunity to study processes involved in stem cell pluripotency and differentiation. Here, we report a genome-wide shRNA screen in ESCs to identify novel components involved in repression of the Gata6 locus, using a cell viability-based screen, which offers the benefits of stable shRNA integration and a robust and simple protocol for hit identification. Candidate factors identified were enriched for transcription factors and included known Polycomb proteins and other chromatin-modifying factors. We identified the protein Bcor, which is known to associate in complexes with the Polycomb protein Ring1B, and verified its importance in Gata6 repression in ESCs. Potential further applications of such a screening strategy could allow the identification of factors important for regulation of gene expression and pluripotency. PMID- 24046327 TI - Ionic mechanisms underlying the effects of vasoactive intestinal polypeptide on canine atrial myocardium. AB - BACKGROUND: Vasoactive intestinal polypeptide (VIP) is released from intracardiac neurons during vagal stimulation, ischemia, and heart failure, which are associated with increased vulnerability to atrial fibrillation. VIP shortens atrial effective refractory periods in dogs. Endogenous VIP contributes to vagally mediated acceleration of atrial electric remodeling. VIP is also shown to prolong the duration of acetylcholine-induced atrial fibrillation. However, the ionic mechanisms underlying VIP effects are largely unknown. METHODS AND RESULTS: The effects of VIP on transmembrane ion channels were studied in canine atrial cardiomyocytes using patch-clamp techniques. VIP increased delayed rectifier K+ current and L-type calcium current but decreased the transient outward K+ current and sodium current. Optical mapping technique was used to assess effects of VIP on action potential durations (APDs) in isolated canine left atria. VIP shortened APD and slowed conduction velocity in a dose-dependent manner. Furthermore, VIP increased spatial heterogeneity of APD and conduction velocity, as assessed by the SDs of APD and conduction velocity, and atrial fibrillation inducibility. CONCLUSIONS: Through its diverse effects on ion channels, VIP shortens APD with increased APD spatial heterogeneity and decreases intra-atrial conduction velocity, which may play an important role in the pathogenesis of atrial arrhythmias in scenarios where VIP release is increased. PMID- 24046328 TI - A variant in LDLR is associated with abdominal aortic aneurysm. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance. METHODS AND RESULTS: A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter>=30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1*10(-4) were carried through to in silico replication in 1292 AAA cases and 30,503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome wide significance (odds ratio, 0.76; 95% confidence interval, 0.70-0.83; P=2.08*10(-10)). CONCLUSIONS: LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA. PMID- 24046329 TI - Pygopus maintains heart function in aging Drosophila independently of canonical Wnt signaling. AB - BACKGROUND: Heart function declines with age, but the genetic factors underlying such deterioration are largely unknown. Wnt signaling is known to play a role in heart development, but it has not been shown to be important in adult heart function. We have investigated the nuclear adapter protein encoded by pygopus (pygo), which mediates canonical Wnt signaling, for roles in aging-related cardiac dysfunction. METHODS AND RESULTS: Using the Drosophila heart model, we show that cardiac-specific pygo knockdown in adult flies causes a significant (4- to 5-fold) increase in cardiac arrhythmias (P<0.001) that worsened with age and caused a significant decrease in contractility (-54%; P<0.001) with systolic dysfunction. Immunohistochemistry revealed structural abnormalities that worsened with age, and both functional and morphological alterations were ameliorated by pygo overexpression. Unexpectedly, knockdown of 2 other Wnt signaling components, beta-cat/armadillo or TCF/pangolin, had relatively milder effects on cardiac function. Double-heterozygous combinations of mutants for pygo and canonical Wnt signaling components had no additional effect on heart function over pygo heterozygotes alone. However, double knockdown of pygo and Ca2+/calmodulin dependent protein kinase II caused additional arrhythmia compared with pygo knockdown alone, suggesting that some of the effects of pygo are mediated by Ca2+ signaling. In the isoproterenol-induced hypertrophic mouse model, we show that Pygo1 protein levels are increased. CONCLUSIONS: Our data indicate that Pygo plays a critical role in adult heart function that is Wnt signaling independent and is likely conserved in mammals. PMID- 24046330 TI - Characterization of inhibition kinetics of (S)-warfarin hydroxylation by noscapine: implications in warfarin therapy. AB - Noscapine is an antitussive and potential anticancer drug. Clinically significant interactions between warfarin and noscapine have been previously reported. In this study, to provide a basis for warfarin dosage adjustment, the inhibition kinetics of noscapine against warfarin metabolism was characterized. Our enzyme kinetics data obtained from human liver microsomes and recombinant CYP2C9 proteins indicate that noscapine is a competitive inhibitor of the (S)-warfarin 7 hydroxylation reaction by CYP2C9. Interestingly, noscapine also inhibited (S) warfarin metabolism in a NADPH- and time-dependent manner, and removal of unbound noscapine and its metabolites by ultrafiltration did not reverse inhibition of (S)-warfarin metabolism by noscapine, suggesting mechanism-based inhibition of CYP2C9 by noscapine. Spectral scanning of the reaction between CYP2C9 and noscapine revealed the formation of an absorption spectrum at 458 nm, indicating the formation of a metabolite-intermediate complex. Surprisingly, noscapine is a 2- to 3-fold more efficient inactivator of CYP2C9.2 and CYP2C9.3 variants than it is of the wild type, by unknown mechanisms. Based on the inhibitory kinetic data, (S)-warfarin exposure is predicted to increase up to 7-fold (depending on CYP2C9 genotypes) upon noscapine coadministration, mainly due to mechanism-based inactivation of CYP2C9 by noscapine. Together, these results indicate that mechanism-based inhibition of CYP2C9 by noscapine may dramatically alter pharmacokinetics of warfarin and provide a basis for warfarin dosage adjustment when noscapine is coadministered. PMID- 24046331 TI - Targeted precise quantification of 12 human recombinant uridine-diphosphate glucuronosyl transferase 1A and 2B isoforms using nano-ultra-high-performance liquid chromatography/tandem mass spectrometry with selected reaction monitoring. AB - Quantification methods employing stable isotope-labeled peptide standards and liquid chromatography-tandem mass spectrometry are increasingly being used to measure enzyme amounts in biologic samples. Isoform concentrations, combined with catalytic information, can be used in absorption, distribution, metabolism, and excretion studies to improve accuracy of in vitro/in vivo predictions. We quantified isoforms of uridine-diphosphate glucuronosyltransferase (UGT) 1A and 2B in 12 commercially available recombinant UGTs (recUGTs) (n = 49 samples) using nano-ultra-high-performance liquid chromatography-tandem mass spectrometry with selected reaction monitoring). Samples were trypsin-digested and analyzed using our previously published method. Two MRMs were collected per peptide and averaged. Where available, at least two peptides were measured per UGT isoform. The assay could detect UGTs in all recombinant preparations: recUGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17, with limit of detection below 1.0 pmol/mg protein for all isoforms. The assay had excellent linearity in the range observed (2-15.5 pmol/mg, after dilution). Examples of concentrations determined were 1465, 537, 538, 944, 865, 698, 604, 791, 382, 1149, 307, and 740 pmol/mg protein for the respective isoforms. There was a 6.9-fold difference between the maximum and minimum recUGT concentrations. The range of concentrations determined indicates that catalytic rates per mg total protein in vitro will not accurately reflect isoform inherent specific activity for a particular drug candidate. This is the first report of a targeted precise quantification of commercially available recUGTs. The assay has potential for use in comparing UGT amounts with catalytic activity determined using probe substrates, thus allowing representation of catalysis as per pmol of UGT isoform. PMID- 24046332 TI - Characterization of transplacental transfer of paroxetine in perfused human placenta: development of a pharmacokinetic model to evaluate tapered dosing. AB - The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma. PMID- 24046333 TI - Metabolism and excretion of 6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl) 9H-purin-2-ylamine, an HSP90 inhibitor, in rats and dogs and assessment of its metabolic profile in plasma of humans. AB - 6-Chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine (BIIB021), a synthetic HSP90 inhibitor, exhibited promising antitumor activity in preclinical models and was in development for the treatment of breast cancer. The metabolism and excretion of BIIB021 was investigated in rats and dogs after oral administration of [(14)C]BIIB021. The administered radioactive dose was quantitatively recovered in both species, and feces/bile was the major route of excretion. Metabolic profiling revealed that BIIB021 is extensively metabolized primarily via hydroxylation of the methyl group (M7), O-demethylation (M2), and to a lesser extent by glutathione conjugation (M8 and M9). M7 was further metabolized to form the carboxylic acid (M3) and glucuronide conjugate (M4). Human plasma obtained from the phase I study in cancer patients were also analyzed to assess the metabolism of BIIB021 in humans and to ensure that selected animal species were exposed to all human major metabolites. Results suggested that BIIB021 is metabolized via hydroxylation followed by carboxylation and glucuronidation in humans consistent with rat and dog; however, an additional dominant circulating metabolite, hydroxylation at the purine ring (M10), was identified in humans. Preliminary in vitro studies using liver cytosolic fractions indicated that M10 formation is primarily catalyzed by aldehyde oxidase (AO). AO catalytic activity for M10 formation was the highest in the monkey, followed by mouse, human, and rat. The apparent K(m) and V(max) values of M10 formation were 174 +/- 8 uM and 14.0 +/- 0.3 pmol*min(-1)*mg protein(-1) in human and 132 +/- 9 uM and 131 +/- 4 pmol*min(-1)*mg protein(-1) in monkey, respectively. PMID- 24046334 TI - Monogamy with a purpose. PMID- 24046336 TI - How far we have come & the places we will go! PMID- 24046337 TI - History of dental hygiene research. AB - Dental hygiene is defined as the science and practice of the recognition, treatment and prevention of oral diseases. The history of dental hygiene research is considered in the context of the development of the discipline and an emerging infrastructure. Research-related events supporting the growth and maturation of the profession are considered from the early years to the most recent. The benefits of preventive oral health services provided by dental hygienists have been supported by research, and the practice of dental hygiene has expanded as a result of research findings since its inception 100 years ago. Dental hygienists' engagement in research, however, did not begin until the 1960s as research associates or administrators, primarily with dental researchers as primary investigators. The Journal of Dental Hygiene (JDH) has provided information for dental hygiene practice since 1927, and has been the primary venue for dissemination of dental hygiene research since 1945. Graduate education in dental hygiene at the master's degree level and the work of early dental hygiene researchers led to the first conference on dental hygiene research in 1982. Over 30 years later, dental hygiene has established a meta-paradigm and defined conceptual models, built an initial infrastructure to support research endeavors and contributed much to the development of dental hygiene as a unique discipline. A doctoral degree in the discipline, continued theory-based research, initiatives to foster collaborations between dental hygiene and other researchers and enhanced capabilities to attract funding to support large scale studies are goals that must be attained through the efforts of future researchers to address the needs for additional development in the discipline of dental hygiene. Dental hygiene research supports the growing discipline and its value to society. PMID- 24046338 TI - Developing a scholarly identity and building a community of scholars. AB - Progress in the dental hygiene discipline is predicated on the development of a community of scholars who explore questions related to the art and science of dental hygiene and clients in need of oral health care. Graduate dental hygiene education is challenged to develop programs that stimulate and nurture dental hygiene scholars as well as scientists. The need for the development of doctoral dental hygiene education is discussed. PMID- 24046339 TI - Advancing the profession through doctoral education. AB - Doctoral education in dental hygiene is necessary to create a cadre of dental hygiene researchers and scholars, and to develop educators who will expand the body of knowledge for the profession. Dental hygienists with advanced degrees will require skill sets that parallel those of other professionals if they are to function productively as credible, equal members of interprofessional teams. Doctorally-prepared dental hygienists will be working as leaders, administrators and researchers, and will be influential in creating models that increase access to care, developing collaborative health care teams and improving health outcomes. The doctorate of philosophy is the terminal graduate degree for any discipline, and is the pinnacle for the profession. This paper explores the development of doctoral degrees for dental hygiene, and encourages educators to develop models for graduate programs based upon considerations presented here. PMID- 24046340 TI - Keeping current: a commitment to patient care excellence through evidence based practice. AB - The desire to improve the oral health of clients begins with the hygienist's commitment to keeping current with useful scientific knowledge. The challenge is mastering the skills to discriminate between the many claims and what actually has been shown to be effective. One approach is through evidence-based decision making (EBDM), which helps practitioners find relevant clinical evidence when it is needed for treatment decisions and for answering client questions. The purpose of this article is to discuss EBDM and its use in practice, potential challenges, future developments and resources that will assist in keeping current. PMID- 24046341 TI - Interprofessional collaboration: if not now, when? AB - Interprofessional collaboration (IPC) is a driving force behind state-of-the art health care delivery. Health care experts, governmental bodies, health professions organizations and academicians support the need for collaborative models. Dental hygienists possess unique qualities that can enhance a collaborative team. As preventive therapists, health educators and holistic providers, they are positioned to contribute richly and meaningfully to team models. Health care reform, overwhelming oral health needs and growing associations between oral and systemic wellness add to the dental hygienist's relevance in collaborative arrangements. Dental hygiene clinical and educational models that speak to collaboration are operational in many U.S. states and the future bodes well for their continued growth. PMID- 24046342 TI - The intersection of education and technology at the century mark. AB - Since the inception of dental hygiene in 1913, we have witnessed the tremendous evolution of the profession. Within the past couple two decades a significant game changer has been technology. The ability to expand access to education through technology has resulted in an increasing number of dental hygienists seeking advanced degrees and gaining new skills and certifications. The evidence shows that dental hygienists are using their advanced education to address lack of access to oral health care services. The profession should remain focused on advocating for the increased education of the dental hygienist, by finding solutions to barriers that presently prevent the realization of this ultimate advancement. PMID- 24046343 TI - Public policy and legislation for oral health: a convergence of opportunities. AB - The first surgeon general's report regarding oral health, Oral Health in America, called for a national effort to improve oral health among Americans and raised awareness of the importance of oral health; however, many Americans continue to experience poor oral health and are unable to access oral health care. Renewed national interest in oral health and access to oral health care through recent public policy documents and legislation presents a convergence of opportunities for the dental hygiene profession to continue to serve as a strong voice for the prevention of oral disease and the promotion of oral health for all segments of the population. PMID- 24046344 TI - ADHA's refereed publications in the 1980s. PMID- 24046345 TI - Journal of Dental Hygiene, 1991 to 1997. PMID- 24046346 TI - Dental hygiene's unique treasure. PMID- 24046347 TI - Can dental hygiene become a developing profession? 1979. PMID- 24046348 TI - The origin and history of the dental hygienists. 1926. PMID- 24046349 TI - The Forsyth experiment in training of advanced skills hygienists. 1974. PMID- 24046350 TI - Evaluating the impact of air pollution on the incidence of out-of-hospital cardiac arrest in the Perth Metropolitan Region: 2000-2010. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) remains a major public health issue. Several studies have found that an increased level of ambient particulate matter (PM) smaller than 2.5 microns (PM2.5) is associated with an increased risk of OHCA. We investigated the relationship between air pollution levels and the incidence of OHCA in Perth, Western Australia. METHODS: We linked St John Ambulance OHCA data of presumed cardiac aetiology with Perth air pollution data from seven monitors which recorded hourly levels of PM smaller than 2.5 and 10 microns (PM2.5/PM10), carbon monoxide (CO), sulfur dioxide (SO2), nitrogen dioxide (NO2) and ozone (O3). We used a case-crossover design to estimate the strength of association between ambient air pollution levels and risk of OHCA. RESULTS: Between 2000 and 2010, there were 8551 OHCAs that met the inclusion criteria. Of these, 5624 (65.8%) occurred in men. An IQR increase in the 24 and 48 h averages of PM2.5 was associated with 10.6% (OR 1.106, 95% CI 1.038 to 1.180) and 13.6% (OR 1.136, 95% CI 1.051 to 1.228) increases, respectively, in the risk of OHCA. CO showed a consistent association with increased risk of an OHCA. An IQR increase in the 4 h average concentration of CO was associated with a 2.2% (OR 1.022, 95% CI 1.002 to 1.042) increase in risk of an OHCA. When we restricted our analysis of CO to arrests occurring between 6:00 and 10:00, we found a 4.4% (95% CI 1.1% to 7.8%) increase in risk of an OHCA. CONCLUSIONS: Elevated ambient PM2.5 and CO are associated with an increased risk of OHCA. PMID- 24046351 TI - Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice. AB - Fras1-related extracellular matrix protein 1 (FREM1) is required for epidermal adhesion during embryogenesis, and mice lacking the gene develop fetal skin blisters and a range of other developmental defects. Mutations in members of the FRAS/FREM gene family cause diseases of the Fraser syndrome spectrum. Embryonic epidermal blistering is also observed in mice lacking PdgfC and its receptor, PDGFRalpha. In this article, we show that FREM1 binds to PDGFC and that this interaction regulates signalling downstream of PDGFRalpha. Fibroblasts from Frem1 mutant mice respond to PDGFC stimulation, but with a shorter duration and amplitude than do wild-type cells. Significantly, PDGFC-stimulated expression of the metalloproteinase inhibitor Timp1 is reduced in cells with Frem1 mutations, leading to reduced basement membrane collagen I deposition. These results show that the physical interaction of FREM1 with PDGFC can regulate remodelling of the extracellular matrix downstream of PDGFRalpha. We propose that loss of FREM1 function promotes epidermal blistering in Fraser syndrome as a consequence of reduced PDGFC activity, in addition to its stabilising role in the basement membrane. PMID- 24046352 TI - A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. AB - The gut barrier, composed of a single layer of intestinal epithelial cells (IECs) held together by tight junctions, prevents the entrance of harmful microorganisms, antigens and toxins from the gut lumen into the blood. Small intestinal homeostasis is normally maintained by the rate of shedding of senescent enterocytes from the villus tip exactly matching the rate of generation of new cells in the crypt. However, in various localized and systemic inflammatory conditions, intestinal homeostasis can be disturbed as a result of increased IEC shedding. Such pathological IEC shedding can cause transient gaps to develop in the epithelial barrier and result in increased intestinal permeability. Although pathological IEC shedding has been implicated in the pathogenesis of conditions such as inflammatory bowel disease, our understanding of the underlying mechanisms remains limited. We have therefore developed a murine model to study this phenomenon, because IEC shedding in this species is morphologically analogous to humans. IEC shedding was induced by systemic lipopolysaccharide (LPS) administration in wild-type C57BL/6 mice, and in mice deficient in TNF-receptor 1 (Tnfr1(-/-)), Tnfr2 (Tnfr2(-/-)), nuclear factor kappa B1 (Nfkappab1(-/-)) or NfKb2 (NfKb2(-/-)). Apoptosis and cell shedding was quantified using immunohistochemistry for active caspase-3, and gut-to circulation permeability was assessed by measuring plasma fluorescence following fluorescein-isothiocyanate-dextran gavage. LPS, at doses >=0.125 mg/kg body weight, induced rapid villus IEC apoptosis, with peak cell shedding occurring at 1.5 hours after treatment. This coincided with significant villus shortening, fluid exudation into the gut lumen and diarrhea. A significant increase in gut-to circulation permeability was observed at 5 hours. TNFR1 was essential for LPS induced IEC apoptosis and shedding, and the fate of the IECs was also dependent on NFkappaB, with signaling via NFkappaB1 favoring cell survival and via NFkappaB2 favoring apoptosis. This model will enable investigation of the importance and regulation of pathological IEC apoptosis and cell shedding in various diseases. PMID- 24046353 TI - The pathophysiology of traumatic brain injury at a glance. AB - Traumatic brain injury (TBI) is defined as an impact, penetration or rapid movement of the brain within the skull that results in altered mental state. TBI occurs more than any other disease, including breast cancer, AIDS, Parkinson's disease and multiple sclerosis, and affects all age groups and both genders. In the US and Europe, the magnitude of this epidemic has drawn national attention owing to the publicity received by injured athletes and military personnel. This increased public awareness has uncovered a number of unanswered questions concerning TBI, and we are increasingly aware of the lack of treatment options for a crisis that affects millions. Although each case of TBI is unique and affected individuals display different degrees of injury, different regional patterns of injury and different recovery profiles, this review and accompanying poster aim to illustrate some of the common underlying neurochemical and metabolic responses to TBI. Recognition of these recurrent features could allow elucidation of potential therapeutic targets for early intervention. PMID- 24046355 TI - Experimental crescentic glomerulonephritis: a new bicongenic rat model. AB - Crescentic glomerulonephritis (CRGN) is a major cause of human kidney failure, but the underlying mechanisms are not fully understood. Wistar Kyoto (WKY) rats are uniquely susceptible to CRGN following injection of nephrotoxic serum, whereas Lewis (LEW) rats are resistant. Our previous genetic studies of nephrotoxic nephritis (NTN), a form of CRGN induced by nephrotoxic serum, identified Fcgr3 and Jund as WKY genes underlying the two strongest quantitative trait loci for NTN phenotypes: Crgn1 and Crgn2, respectively. We also showed that introgression of WKY Crgn1 or Crgn2 individually into a LEW background did not lead to the formation of glomerular crescents. We have now generated a bicongenic strain, LEW.WCrgn1,2, in which WKY Crgn1 and Crgn2 are both introgressed into the LEW genetic background. These rats show development of NTN phenotypes, including glomerular crescents. Furthermore, we characterised macrophage function and glomerular cytokine profiles in this new strain. Additionally, we show that LEW.WCrgn1,2 rats are resistant to the development of glomerular crescents that is usually induced following immunisation with recombinant rat alpha3(IV)NC1, the specific Goodpasture autoantigen located in the glomerular basement membrane against which the immune response is directed in experimental autoimmune glomerulonephritis. Our results show that the new bicongenic strain responds differently to two distinct experimental triggers of CRGN. This is the first time that CRGN has been induced on a normally resistant rat genetic background and identifies the LEW.WCrgn1,2 strain as a new, potentially valuable model of macrophage-dependent glomerulonephritis. PMID- 24046354 TI - Towards clinical management of traumatic brain injury: a review of models and mechanisms from a biomechanical perspective. AB - Traumatic brain injury (TBI) is a major worldwide healthcare problem. Despite promising outcomes from many preclinical studies, the failure of several clinical studies to identify effective therapeutic and pharmacological approaches for TBI suggests that methods to improve the translational potential of preclinical studies are highly desirable. Rodent models of TBI are increasingly in demand for preclinical research, particularly for closed head injury (CHI), which mimics the most common type of TBI observed clinically. Although seemingly simple to establish, CHI models are particularly prone to experimental variability. Promisingly, bioengineering-oriented research has advanced our understanding of the nature of the mechanical forces and resulting head and brain motion during TBI. However, many neuroscience-oriented laboratories lack guidance with respect to fundamental biomechanical principles of TBI. Here, we review key historical and current literature that is relevant to the investigation of TBI from clinical, physiological and biomechanical perspectives, and comment on how the current challenges associated with rodent TBI models, particularly those involving CHI, could be improved. PMID- 24046356 TI - A strategy for the generation, characterization and distribution of animal models by The Michael J. Fox Foundation for Parkinson's Research. AB - Progress in Parkinson's disease (PD) research and therapeutic development is hindered by many challenges, including a need for robust preclinical animal models. Limited availability of these tools is due to technical hurdles, patent issues, licensing restrictions and the high costs associated with generating and distributing these animal models. Furthermore, the lack of standardization of phenotypic characterization and use of varying methodologies has made it difficult to compare outcome measures across laboratories. In response, The Michael J. Fox Foundation for Parkinson's Research (MJFF) is directly sponsoring the generation, characterization and distribution of preclinical rodent models, enabling increased access to these crucial tools in order to accelerate PD research. To date, MJFF has initiated and funded the generation of 30 different models, which include transgenic or knockout models of PD-relevant genes such as Park1 (also known as Park4 and SNCA), Park8 (LRRK2), Park7 (DJ-1), Park6 (PINK1), Park2 (Parkin), VPS35, EiF4G1 and GBA. The phenotypic characterization of these animals is performed in a uniform and streamlined manner at independent contract research organizations. Finally, MJFF created a central repository at The Jackson Laboratory (JAX) that houses both non-MJFF and MJFF-generated preclinical animal models. Funding from MJFF, which subsidizes the costs involved in transfer, rederivation and colony expansion, has directly resulted in over 2500 rodents being distributed to the PD community for research use. PMID- 24046357 TI - A novel transgenic mouse model of growth plate dysplasia reveals that decreased chondrocyte proliferation due to chronic ER stress is a key factor in reduced bone growth. AB - Disease mechanisms leading to different forms of chondrodysplasia include extracellular matrix (ECM) alterations and intracellular stress resulting in abnormal changes to chondrocyte proliferation and survival. Delineating the relative contribution of these two disease mechanisms is a major challenge in understanding disease pathophysiology in genetic skeletal diseases and a prerequisite for developing effective therapies. To determine the influence of intracellular stress and changes in chondrocyte phenotype to the development of chondrodysplasia, we targeted the expression of the G2320R mutant form of thyroglobulin to the endoplasmic reticulum (ER) of resting and proliferating chondrocytes. Previous studies on this mutant protein have shown that it induces intracellular aggregates and causes cell stress and death in the thyroid gland. The expression and retention of this exogenous mutant protein in resting and proliferating chondrocytes resulted in a chronic cell stress response, growth plate dysplasia and reduced bone growth, without inducing any alterations to the architecture and organization of the cartilage ECM. More significantly, the decreased bone growth seemed to be the direct result of reduced chondrocyte proliferation in the proliferative zone of growth plates in transgenic mice, without transcriptional activation of a classical unfolded protein response (UPR) or apoptosis. Overall, these data show that mutant protein retention in the ER of resting and proliferative zone chondrocytes is sufficient to cause disrupted bone growth. The specific disease pathways triggered by mutant protein retention do not necessarily involve a prototypic UPR, but all pathways impact upon chondrocyte proliferation in the cartilage growth plate. PMID- 24046358 TI - Fragile X mental retardation protein regulates trans-synaptic signaling in Drosophila. AB - Fragile X syndrome (FXS), the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (FMR1) gene product (FMRP), an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1) null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs): GPI-anchored glypican Dally-like protein (Dlp) and transmembrane Syndecan (Sdc). Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways that drive synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg) ligand abundance and downstream Frizzled-2 (Fz2) receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly belly (Jeb), and downstream ERK phosphorylation (dpERK) are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass bottom boat (Gbb) and downstream signaling via phosphorylation of the transcription factor MAD (pMAD) seem not to be affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both (1) Wg and Jeb trans-synaptic signaling, and (2) synaptic architecture and transmission strength back to wild type levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS disease state. PMID- 24046359 TI - An insert-based enzymatic cell culture system to rapidly and reversibly induce hypoxia: investigations of hypoxia-induced cell damage, protein expression and phosphorylation in neuronal IMR-32 cells. AB - Ischemia-reperfusion injury and tissue hypoxia are of high clinical relevance because they are associated with various pathophysiological conditions such as myocardial infarction and stroke. Nevertheless, the underlying mechanisms causing cell damage are still not fully understood, which is at least partially due to the lack of cell culture systems for the induction of rapid and transient hypoxic conditions. The aim of the study was to establish a model that is suitable for the investigation of cellular and molecular effects associated with transient and long-term hypoxia and to gain insights into hypoxia-mediated mechanisms employing a neuronal culture system. A semipermeable membrane insert system in combination with the hypoxia-inducing enzymes glucose oxidase and catalase was employed to rapidly and reversibly generate hypoxic conditions in the culture medium. Hydrogen peroxide assays, glucose measurements and western blotting were performed to validate the system and to evaluate the effects of the generated hypoxia on neuronal IMR-32 cells. Using the insert-based two-enzyme model, hypoxic conditions were rapidly induced in the culture medium. Glucose concentrations gradually decreased, whereas levels of hydrogen peroxide were not altered. Moreover, a rapid and reversible (on-off) generation of hypoxia could be performed by the addition and subsequent removal of the enzyme-containing inserts. Employing neuronal IMR-32 cells, we showed that 3 hours of hypoxia led to morphological signs of cellular damage and significantly increased levels of lactate dehydrogenase (a biochemical marker of cell damage). Hypoxic conditions also increased the amounts of cellular procaspase-3 and catalase as well as phosphorylation of the pro-survival kinase Akt, but not Erk1/2 or STAT5. In summary, we present a novel framework for investigating hypoxia-mediated mechanisms at the cellular level. We claim that the model, the first of its kind, enables researchers to rapidly and reversibly induce hypoxic conditions in vitro without unwanted interference of the hypoxia-inducing agent on the cultured cells. The system could help to further unravel hypoxia-associated mechanisms that are clinically relevant in various tissues and organs. PMID- 24046360 TI - A mouse model for inducible overexpression of Prdm14 results in rapid-onset and highly penetrant T-cell acute lymphoblastic leukemia (T-ALL). AB - PRDM14 functions in embryonic stem cell (ESC) maintenance to promote the expression of pluripotency-associated genes while suppressing differentiation genes. Expression of PRDM14 is tightly regulated and typically limited to ESCs and primordial germ cells; however, aberrant expression is associated with tumor initiation in a wide variety of human cancers, including breast cancer and leukemia. Here, we describe the generation of a Cre-recombinase-inducible mouse model for the spatial and temporal control of Prdm14 misexpression [ROSA26 floxed stop Prdm14 (R26PR)]. When R26PR is mated to either of two Cre lines, Mx1-cre or MMTV-cre, mice develop early-onset T-cell acute lymphoblastic leukemia (T-ALL) with median overall survival of 41 and 64 days for R26PR;Mx1-cre and R26PR;MMTV cre, respectively. T-ALL is characterized by the accumulation of immature single positive CD8 cells and their widespread infiltration. Leukemia is preceded by a dramatic expansion of cells resembling hematopoietic stem cells and lymphoid committed progenitors prior to disease onset, accompanied by a blockage in B-cell differentiation at the early pro-B stage. Rapid-onset PRDM14-induced T-ALL requires factors that are present in stem and progenitor cells: R26PR;dLck-cre animals, which express Prdm14 starting at the double-positive stage of thymocyte development, do not develop disease. PRDM14-induced leukemic cells contain high levels of activated NOTCH1 and downstream NOTCH1 targets, including MYC and HES1, and are sensitive to pharmacological inhibition of NOTCH1 with the gamma secretase inhibitor DAPT. Greater than 50% of human T-ALLs harbor activating mutations in NOTCH1; thus, our model carries clinically relevant molecular aberrations. The penetrance, short latency and involvement of the NOTCH1 pathway will make this hematopoietic R26PR mouse model ideal for future studies on disease initiation, relapse and novel therapeutic drug combinations. Furthermore, breeding R26PR to additional Cre lines will allow for the continued development of novel cancer models. PMID- 24046361 TI - Sestrin-2, a repressor of PDGFRbeta signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD is caused by chronic exposure to cigarette smoke and/or other environmental pollutants that are believed to induce reactive oxygen species (ROS) that gradually disrupt signalling pathways responsible for maintaining lung integrity. Here we identify the antioxidant protein sestrin-2 (SESN2) as a repressor of PDGFRbeta signalling, and PDGFRbeta signalling as an upstream regulator of alveolar maintenance programmes. In mice, the mutational inactivation of Sesn2 prevents the development of cigarette-smoke-induced pulmonary emphysema by upregulating PDGFRbeta expression via a selective accumulation of intracellular superoxide anions (O2(-)). We also show that SESN2 is overexpressed and PDGFRbeta downregulated in the emphysematous lungs of individuals with COPD and to a lesser extent in human lungs of habitual smokers without COPD, implicating a negative SESN2-PDGFRbeta interrelationship in the pathogenesis of COPD. Taken together, our results imply that SESN2 could serve as both a biomarker and as a drug target in the clinical management of COPD. PMID- 24046362 TI - Establishment of a novel extracorporeal bowel model to study luminal approaches to treat inflammatory bowel disease. AB - We have established an extracorporeal bowel model system for the analysis of early events in inflammatory bowel disease (IBD) and therapeutic applications. This model consists of an intestinal segment that is cannulated and perfused in situ, allowing the investigation of cellular responses of apical mucosa cells on luminal applied substances. Short-term treatment with iodoacetamide mimicked experimental intestinal inflammation in IBD, as indicated by histological alterations such as hemorrhage, hyperemia and loss of regular crypt architecture, as well as enhanced expression of cytokines (e.g. IL-6, IL-10 and MCP-1) compared with control segments perfused with media. Perfusion of therapeutic agents (e.g. dexamethasone or Mutaflor) in the small intestine segment significantly reduced the features of early inflammation that are induced by iodoacetamide. Moreover, similar data were obtained for Resormin((r)), a montmorillonite-illite mixed layer mineral (smectite), indicating that smectites might be a newly identified therapeutic option for IBD. In summary, this model could provide novel insights into epithelial injury as well as genesis of IBD and, therefore, be useful in testing the therapeutic potential of compounds for IBD therapy. PMID- 24046363 TI - Cosmic impact or natural fires at the Allerod-Younger Dryas boundary: a matter of dating and calibration. PMID- 24046364 TI - Public goods dilemma in asexual ant societies. AB - Cooperation in biological, social, and economic groups is underpinned by public goods that are generated by group members at some personal cost. Theory predicts that public goods will be exploited by cheaters who benefit from the goods by not paying for them, thereby leading to the collapse of cooperation. This situation, described as the "public goods dilemma" in game theory, makes the ubiquity of cooperation a major evolutionary puzzle. Despite this generalization, the demonstration of genetic background and fitness effects of the public goods dilemma has been limited to interactions between viruses and between cells, and thus its relevance at higher levels of organismal complexity is still largely unexplored. Here we provide experimental evidence for the public goods dilemma in a social insect, the ant Pristomyrmex punctatus. In this species, all workers are involved in both asexual reproduction and cooperative tasks. Genetic cheaters infiltrate field colonies, reproducing more than the workers but shunning cooperative tasks. In laboratory experiments, cheaters outcompeted coexisting workers in both survival and reproduction, although a group composed only of cheaters failed to produce offspring. The operations of the public goods dilemma in P. punctatus showed a remarkable convergence with those in microbial societies, not only in fitness consequences but also in behavioral mechanisms. Our study reinforces the evolutionary impact of cheaters on diverse cooperative systems in the laboratory and in the field. PMID- 24046365 TI - TRA-1 ChIP-seq reveals regulators of sexual differentiation and multilevel feedback in nematode sex determination. AB - How sexual regulators translate global sexual fate into appropriate local sexual differentiation events is perhaps the least understood aspect of sexual development. Here we have used ChIP followed by deep sequencing (ChIP-seq) to identify direct targets of the nematode global sexual regulator Transformer 1 (TRA-1), a transcription factor acting at the interface between organism-wide and cell-specific sexual regulation to control all sex-specific somatic differentiation events. We identified 184 TRA-1-binding sites in Caenorhabditis elegans, many with temporal- and/or tissue-specific TRA-1 association. We also identified 78 TRA-1-binding sites in the related nematode Caenorhabditis briggsae, 19 of which are conserved between the two species. Some DNA segments containing TRA-1-binding sites drive male-specific expression patterns, and RNAi depletion of some genes adjacent to TRA-1-binding sites results in defects in male sexual development. TRA-1 binds to sites adjacent to a number of heterochronic regulatory genes, some of which drive male-specific expression, suggesting that TRA-1 imposes sex specificity on developmental timing. We also found evidence for TRA-1 feedback regulation of the global sex-determination pathway: TRA-1 binds its own locus and those of multiple upstream masculinizing genes, and most of these associations are conserved in C. briggsae. Thus, TRA-1 coordinates sexual development by reinforcing the sex-determination decision and directing downstream sexual differentiation events. PMID- 24046366 TI - Clusters of cerebellar Purkinje cells control their afferent climbing fiber discharge. AB - Climbing fibers, the projections from the inferior olive to the cerebellar cortex, carry sensorimotor error and clock signals that trigger motor learning by controlling cerebellar Purkinje cell synaptic plasticity and discharge. Purkinje cells target the deep cerebellar nuclei, which are the output of the cerebellum and include an inhibitory GABAergic projection to the inferior olive. This pathway identifies a potential closed loop in the olivo-cortico-nuclear network. Therefore, sets of Purkinje cells may phasically control their own climbing fiber afferents. Here, using in vitro and in vivo recordings, we describe a genetically modified mouse model that allows the specific optogenetic control of Purkinje cell discharge. Tetrode recordings in the cerebellar nuclei demonstrate that focal stimulations of Purkinje cells strongly inhibit spatially restricted sets of cerebellar nuclear neurons. Strikingly, such stimulations trigger delayed climbing-fiber input signals in the stimulated Purkinje cells. Therefore, our results demonstrate that Purkinje cells phasically control the discharge of their own olivary afferents and thus might participate in the regulation of cerebellar motor learning. PMID- 24046367 TI - Bacterial cytological profiling rapidly identifies the cellular pathways targeted by antibacterial molecules. AB - Identifying the mechanism of action for antibacterial compounds is essential for understanding how bacteria interact with one another and with other cell types and for antibiotic discovery efforts, but determining a compound's mechanism of action remains a serious challenge that limits both basic research and antibacterial discovery programs. Here, we show that bacterial cytological profiling (BCP) is a rapid and powerful approach for identifying the cellular pathway affected by antibacterial molecules. BCP can distinguish between inhibitors that affect different cellular pathways as well as different targets within the same pathway. We use BCP to demonstrate that spirohexenolide A, a spirotetronate that is active against methicillin-resistant Staphylococcus aureus, rapidly collapses the proton motive force. BCP offers a simple, one-step assay that can be broadly applied, solving the longstanding problem of how to rapidly determine the cellular target of thousands of compounds. PMID- 24046368 TI - Ionizing irradiation-induced radical stress stalls live meiotic chromosome movements by altering the actin cytoskeleton. AB - Meiosis generates haploid cells or spores for sexual reproduction. As a prelude to haploidization, homologous chromosomes pair and recombine to undergo segregation during the first meiotic division. During the entire meiotic prophase of the yeast Saccharomyces cerevisiae, chromosomes perform rapid movements that are suspected to contribute to the regulation of recombination. Here, we investigated the impact of ionizing radiation (IR) on movements of GFP-tagged bivalents in live pachytene cells. We find that exposure of sporulating cultures with >40 Gy (4-krad) X-rays stalls pachytene chromosome movements. This identifies a previously undescribed acute radiation response in yeast meiosis, which contrasts with its reported radioresistance of up to 1,000 Gy in survival assays. A modified 3'-end labeling assay disclosed IR-induced dsDNA breaks (DSBs) in pachytene cells at a linear dose relationship of one IR-induced DSB per cell per 5 Gy. Dihydroethidium staining revealed formation of reactive oxygen species (ROS) in irradiated cells. Immobility of fuzzy-appearing irradiated bivalents was rescued by addition of radical scavengers. Hydrogen peroxide-induced ROS did reduce bivalent mobility similar to 40 Gy X IR, while they failed to induce DSBs. IR- and H2O2-induced ROS were found to decompose actin cables that are driving meiotic chromosome mobility, an effect that could be rescued by antioxidant treatment. Hence, it appears that the meiotic actin cytoskeleton is a radical sensitive system that inhibits bivalent movements in response to IR- and oxidant induced ROS. This may be important to prevent motility-driven unfavorable chromosome interactions when meiotic recombination has to proceed in genotoxic environments. PMID- 24046369 TI - Entropic factors provide unusual reactivity and selectivity in epoxide-opening reactions promoted by water. AB - Despite the myriad of selective enzymatic reactions that occur in water, chemists have rarely capitalized on the unique properties of this medium to govern selectivity in reactions. Here we report detailed mechanistic investigations of a water-promoted reaction that displays high selectivity for what is generally a disfavored product. A combination of structural and kinetic data indicates not only that synergy between substrate and water suppresses undesired pathways but also that water promotes the desired pathway by stabilizing charge in the transition state, facilitating proton transfer, doubly activating the substrate for reaction, and perhaps most remarkably, reorganizing the substrate into a reactive conformation that leads to the observed product. This approach serves as an outline for a general strategy of exploiting solvent-solute interactions to achieve unusual reactivity in chemical reactions. These findings may also have implications in the biosynthesis of the ladder polyether natural products, such as the brevetoxins and ciguatoxins. PMID- 24046370 TI - Inappropriate heat dissipation ignites brown fat thermogenesis in mice with a mutant thyroid hormone receptor alpha1. AB - Thyroid hormone is a major regulator of thermogenesis, acting both in peripheral organs and on central autonomic pathways. Mice heterozygous for a point mutation in thyroid hormone receptor alpha1 display increased thermogenesis as a consequence of high sympathetic brown fat stimulation. Surprisingly, despite the hypermetabolism, their body temperature is not elevated. Here we show, using isolated tail arteries, that defective thyroid hormone receptor alpha1 signaling impairs acetylcholine-mediated vascular relaxation as well as phenylephrine induced vasoconstriction. Using infrared thermography on conscious animals, we demonstrate that these defects severely interfere with appropriate peripheral heat conservation and dissipation, which in turn leads to compensatory alterations in brown fat activity. Consequently, when the vasoconstrictive defect in mice heterozygous for a point mutation in thyroid hormone receptor alpha1 was reversed with the selective alpha1-adrenergic agonist midodrine, the inappropriate heat loss over their tail surface was reduced, normalizing brown fat activity and energy expenditure. Our analyses demonstrate that thyroid hormone plays a key role in vascular heat conservation and dissipation processes, adding a unique aspect to its well-documented functions in thermoregulation. The data thus facilitate understanding of temperature hypersensitivity in patients with thyroid disorders. Moreover, the previously unrecognized connection between cardiovascular regulation and metabolic activity revealed in this study challenges the interpretation of several experimental paradigms and questions some of the currently derived hypotheses on the role of thyroid hormone in thermogenesis. PMID- 24046371 TI - Tumor suppressor p16INK4A is necessary for survival of cervical carcinoma cell lines. AB - The tumor suppressor p16(INK4A) inhibits formation of enzymatically active complexes of cyclin-dependent kinases 4 and 6 (CDK4/6) with D-type cyclins. Oncogenic stress induces p16(INK4A) expression, which in turn triggers cellular senescence through activation of the retinoblastoma tumor suppressor. Subversion of oncogene-induced senescence is a key step during cancer development, and many tumors have lost p16(INK4A) activity by mutation or epigenetic silencing. Human papillomavirus (HPV)-associated tumors express high levels of p16(INK4A) in response to E7 oncoprotein expression. Induction of p16(INK4A) expression is not a consequence of retinoblastoma tumor suppressor inactivation but is triggered by a cellular senescence response and is mediated by epigenetic derepression through the H3K27-specific demethylase (KDM)6B. HPV E7 expression causes an acute dependence on KDM6B expression for cell survival. The p16(INK4A) tumor suppressor is a critical KDM6B downstream transcriptional target and its expression is critical for cell survival. This oncogenic p16(INK4A) activity depends on inhibition of CDK4/CDK6, suggesting that in cervical cancer cells where retinoblastoma tumor suppressor is inactivated, CDK4/CDK6 activity needs to be inhibited in order for cells to survive. Finally, we note that HPV E7 expression creates a unique cellular vulnerability to small-molecule KDM6A/B inhibitors. PMID- 24046372 TI - Cell motility and drug gradients in the emergence of resistance to chemotherapy. AB - The emergence of resistance to chemotherapy by cancer cells, when combined with metastasis, is the primary driver of mortality in cancer and has proven to be refractory to many efforts. Theory and computer modeling suggest that the rate of emergence of resistance is driven by the strong selective pressure of mutagenic chemotherapy and enhanced by the motility of mutant cells in a chemotherapy gradient to areas of higher drug concentration and lower population competition. To test these models, we constructed a synthetic microecology which superposed a mutagenic doxorubicin gradient across a population of motile, metastatic breast cancer cells (MDA-MB-231). We observed the emergence of MDA-MB-231 cancer cells capable of proliferation at 200 nM doxorubicin in this complex microecology. Individual cell tracking showed both movement of the MDA-MB-231 cancer cells toward higher drug concentrations and proliferation of the cells at the highest doxorubicin concentrations within 72 h, showing the importance of both motility and drug gradients in the emergence of resistance. PMID- 24046373 TI - Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival. AB - Most current cancer therapies focus on killing malignant cells, but these cells are often genetically unstable and can become resistant to chemotherapy. Tumor associated macrophages (TAMs) facilitate disease progression by promoting angiogenesis and tumor cell growth, as well as by suppressing the adaptive immune response. TAMs are therefore potential targets for adjuvant anticancer therapies. However, resident macrophages are critical to host defense, and preferential ablation of TAMs remains challenging. Macrophage activation is broadly categorized as classically activated, or M1, and alternatively activated, or M2, and TAMs in the tumor microenvironment have been shown to adopt the anti inflammatory, M2-like phenotype. To date, there are no methods for specific molecular targeting of TAMs. In this work, we report the discovery of a unique peptide sequence, M2pep, identified using a subtractive phage biopanning strategy against whole cells. The peptide preferentially binds to murine M2 cells, including TAMs, with low affinity for other leukocytes. Confocal imaging demonstrates the accumulation of M2pep in TAMs in vivo after tail vein injection. Finally, tail vein injection of an M2pep fusion peptide with a proapoptotic peptide delays mortality and selectively reduces the M2-like TAM population. This work therefore describes a molecularly targeted construct for murine TAMs and provides proof of concept of this approach as an anticancer treatment. In addition, M2pep is a useful tool for murine M2 macrophage identification and for modulating M2 macrophages in other murine models of disease involving M2 cells. PMID- 24046374 TI - Neurons generated by direct conversion of fibroblasts reproduce synaptic phenotype caused by autism-associated neuroligin-3 mutation. AB - Recent studies suggest that induced neuronal (iN) cells that are directly transdifferentiated from nonneuronal cells provide a powerful opportunity to examine neuropsychiatric diseases. However, the validity of using this approach to examine disease-specific changes has not been demonstrated. Here, we analyze the phenotypes of iN cells that were derived from murine embryonic fibroblasts cultured from littermate wild-type and mutant mice carrying the autism-associated R704C substitution in neuroligin-3. We show that neuroligin-3 R704C-mutant iN cells exhibit a large and selective decrease in AMPA-type glutamate receptor mediated synaptic transmission without changes in NMDA-type glutamate receptor- or in GABAA receptor-mediated synaptic transmission. Thus, the synaptic phenotype observed in R704C-mutant iN cells replicates the previously observed phenotype of R704C-mutant neurons. Our data show that the effect of the R704C mutation is applicable even to neurons transdifferentiated from fibroblasts and constitute a proof-of-concept demonstration that iN cells can be used for cellular disease modeling. PMID- 24046375 TI - Using machine learning to identify disease-relevant regulatory RNAs. PMID- 24046376 TI - Right ventricular strain in pulmonary hypertension: flavor du jour or enduring prognostic index? PMID- 24046377 TI - Value and challenges of measuring left ventricular mass in clinical research: implications for the practitioner. PMID- 24046378 TI - Fatty heart and subclinical left ventricular dysfunction: rediscovery of a pathological metabolic process: with a twist. PMID- 24046379 TI - Coronary anatomy to predict physiology: fundamental limits. PMID- 24046380 TI - Cardiac magnetic resonance assessment of myocarditis. PMID- 24046381 TI - Stress echocardiography in regurgitant valve disease. PMID- 24046382 TI - Limitations of Doppler echocardiography in the evaluation of serial stenoses. PMID- 24046383 TI - Letter by Yalcin et al regarding article, "Left ventricular wall thickness and the presence of asymmetric hypertrophy in healthy young army recruits: data from the LARGE Heart Study". PMID- 24046384 TI - Response to Letter about article, "Left ventricular wall thickness and the presence of asymmetric hypertrophy in healthy young army recruits: data from the LARGE heart study". PMID- 24046385 TI - A gutsy approach to stem cells and signalling: an interview with Hans Clevers. PMID- 24046389 TI - Inflammatory breast cancer: yet another risk of the obesity epidemic? PMID- 24046387 TI - The emerging use of zebrafish to model metabolic disease. AB - The zebrafish research community is celebrating! The zebrafish genome has recently been sequenced, the Zebrafish Mutation Project (launched by the Wellcome Trust Sanger Institute) has published the results of its first large-scale ethylnitrosourea (ENU) mutagenesis screen, and a host of new techniques, such as the genome editing technologies TALEN and CRISPR-Cas, are enabling specific mutations to be created in model organisms and investigated in vivo. The zebrafish truly seems to be coming of age. These powerful resources invoke the question of whether zebrafish can be increasingly used to model human disease, particularly common, chronic diseases of metabolism such as obesity and type 2 diabetes. In recent years, there has been considerable success, mainly from genomic approaches, in identifying genetic variants that are associated with these conditions in humans; however, mechanistic insights into the role of implicated disease loci are lacking. In this Review, we highlight some of the advantages and disadvantages of zebrafish to address the organism's utility as a model system for human metabolic diseases. PMID- 24046386 TI - Modeling human endothelial cell transformation in vascular neoplasias. AB - Endothelial cell (EC)-derived neoplasias range from benign hemangioma to aggressive metastatic angiosarcoma, which responds poorly to current treatments and has a very high mortality rate. The development of treatments that are more effective for these disorders will be expedited by insight into the processes that promote abnormal proliferation and malignant transformation of human ECs. The study of primary endothelial malignancy has been limited by the rarity of the disease; however, there is potential for carefully characterized EC lines and animal models to play a central role in the discovery, development and testing of molecular targeted therapies for vascular neoplasias. This review describes molecular alterations that have been identified in EC-derived neoplasias, as well as the processes that underpin the immortalization and tumorigenic conversion of ECs. Human EC lines, established through the introduction of defined genetic elements or by culture of primary tumor tissue, are catalogued and discussed in relation to their relevance as models of vascular neoplasia. PMID- 24046391 TI - Review: lithium reduces the risk of suicide compared with placebo in people with depression and bipolar disorder. PMID- 24046392 TI - Neurological picture: Clinicoradiological correlation of singultus centre. PMID- 24046390 TI - Risk factors for inflammatory breast cancer and other invasive breast cancers. AB - BACKGROUND: We investigated risk factors for inflammatory breast cancer (IBC), a rare, aggressive, and poorly understood breast cancer that is characterized by diffuse breast skin erythema and edema. METHODS: We included 617 IBC case subjects in a nested case-control study from the Breast Cancer Surveillance Consortium database (1994-2009). We also included 1151 noninflammatory, locally advanced, invasive breast cancers with chest wall/breast skin involvement (LABC), 7600 noninflammatory invasive case subjects without chest wall/breast skin involvement (BC), and 93 654 control subjects matched to case subjects on age and year at diagnosis and mammography registry. We present estimates of rate ratios (RRs) and 95% confidence intervals (CI) from conditional logistic regression analyses for each case group vs control subjects based on multiply imputed datasets. RESULTS: First-degree family history of breast cancer and high mammographic breast density increased risk of IBC, LABC, and BC. High body mass index (BMI) increased IBC risk irrespective of menopausal status and estrogen receptor (ER) expression; rate ratios for BMI 30 and greater vs BMI less than 25 were 3.90 (95% CI = 1.50 to 10.14) in premenopausal women and 3.70 (95% CI = 1.98 to 6.94) in peri/postmenopausal women not currently using hormones. BMI 30 and greater slightly increased risk of ER-positive BC (RR = 1.40; 95% CI = 1.11 to 1.76). Statistically significant reductions in risk of ER-negative IBC with older age at first birth and of ER-positive IBC with higher education were not seen for LABC and BC of the same ER status. CONCLUSIONS: Different associations with BMI, age at first birth, and education between IBC and/or LABC and BC suggest a distinct etiology for IBC. PMID- 24046393 TI - Oral laquinimod for multiple sclerosis: beyond the anti-inflammatory effect. PMID- 24046394 TI - Overcoming artefact: anticipation in 284 Portuguese kindreds with familial amyloid polyneuropathy (FAP) ATTRV30M. AB - BACKGROUND: Early-onset (<=40 years) and later-onset (>=50 years) cases of familial amyloid polyneuropathy (FAP) ATTRV30M are not different entities, often coexisting in the same family, and showing anticipation (earlier age-at-onset (AO) in younger generations, usually associated with more severe phenotype). Historically, anticipation has been ascribed to ascertainment biases. Our aim was to study anticipation in a very large number of FAP kindreds, removing possible biases, and gain further insight into parent-of-origin effects. METHODS: We analysed 926 parent-offspring pairs (from the Unidade Clinica de Paramiloidose roster, collected in 70 years), both clinically observed and had well-established AO, correcting for intrafamilial correlations. RESULTS: Women had a significantly higher AO, either for daughters (mean: 33.70, SD: 6.84) vs sons (29.43, 6.08); or mothers (39.57, 11.75) vs. fathers (35.62, 11.62). Also, 291 pairs showed marked anticipation (>=10 years); the transmitting parent was the mother in 203 pairs. Mother-son pairs showed larger anticipation (10.43, 9.34), while father-daughter pairs showed only a residual anticipation (1.23, 9.77). Gender of offspring and parents was highly significant (with no interaction). To remove possible biases, we repeated analyses: (1) excluding the proband; (2) removing pairs with simultaneous onset; and (3) excluding offspring born after 1960. Anticipation was found in all subsamples, with the same trend for a parent-of-origin effect. Noteworthy, parents with AO <=40 years never had offspring with AO >=50. CONCLUSIONS: These findings confirm anticipation as a true biological phenomenon, also in FAP ATTRV30M. Acknowledgment of anticipation may have important clinical implications in genetic counselling of offspring and in follow-up of mutation carriers. PMID- 24046395 TI - NICE guideline: feverish illness in children--assessment and initial management in children younger than 5 years. PMID- 24046396 TI - Epigenetics--a novel concept with exciting prospects for paediatric research. PMID- 24046397 TI - Fifteen-minute consultation: The infant with frequent infections. AB - Children with frequent or recurrent infections commonly present to medical practitioners in both primary and secondary care. Here we provide a structured approach to the consultation of the infant under 2 years of age with frequent infections. The key is a focused history and examination to elicit red flags to an underlying diagnosis, while at the same time seeking benign explanations for the frequency of infections, which account for the majority of children, thereby avoiding unnecessary investigations. PMID- 24046398 TI - Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at Get With The Guidelines Stroke hospitals. AB - BACKGROUND: Substantial efforts over the past decade have increased rates of intravenous tissue plasminogen activator (tPA) use in the United States. We sought to determine changes in patient characteristics and rates of tPA use over time among hospitalized acute ischemic stroke (AIS) patients. METHODS AND RESULTS: We analyzed all AIS patients (n=1 093 895) and those arriving <= 2 hours and treated with tPA <= 3 hours after onset (n=50 798) from 2003 to 2011 in the American Heart Association's Get with the Guideline-Stroke (GWTG-Stroke). Categorical data were analyzed by Pearson chi(2) and continuous data by Wilcoxon test. Intravenous tPA use <= 3 hours after onset increased from 4.0% to 7.0% in all AIS admissions and 42.6% to 77.0% in AIS patients arriving <= 2 hours and fully eligible for tPA (P<0.001). In univariate analysis, tPA use increased over time, especially in those aged >85 years, nonwhite, and with milder strokes (National Institutes of Health Stroke Scale 0-4). Door-to-image time (median 24 versus 20 minutes) and door-to-tPA time (median 81 versus 72 minutes) also improved, with ~65% of tPA-treated patients getting brain imaging <= 25 minutes after arrival. Multivariable analysis showed that with each additional calendar year, the odds that an eligible patient would receive tPA increased by 1.37-fold, adjusting for other covariates. CONCLUSIONS: The frequency of IV tPA use among all AIS patients, regardless of contraindications, nearly doubled from 2003 to 2011. Treatment with tPA has expanded to include more patients with mild deficits, nonwhite race/ethnicity, and oldest old age. PMID- 24046399 TI - Designation as "unfit for open repair" is associated with poor outcomes after endovascular aortic aneurysm repair. AB - BACKGROUND: Endovascular aortic aneurysm repair (EVAR) is often offered to patients with abdominal aortic aneurysms (AAAs) considered preoperatively to be unfit for open AAA repair (oAAA). This study describes the short- and long-term outcomes of patients undergoing EVAR with AAAs <6.5 cm who are considered unfit for oAAA. METHODS AND RESULTS: We analyzed elective EVARs for AAAs <6.5 cm diameter in the Vascular Study Group of New England (2003-2011). Patients were designated as fit or unfit for oAAA by the treating surgeon. End points included in-hospital major adverse events and long-term mortality. We identified patient characteristics associated with being unfit for open repair and predictors of survival using multivariable analyses. Of 1653 EVARs, 309 (18.7%) patients were deemed unfit for oAAA. These patients were more likely to have advanced age, cardiac disease, chronic obstructive pulmonary disease, and larger aneurysms at the time of repair (54 versus 56 mm, P=0.001). Patients unfit for oAAA had higher rates of cardiac (7.8% versus 3.1%, P<0.01) and pulmonary (3.6 versus 1.6, P<0.01) complications and worse survival rates at 5 years (61% versus 80%; log rank P<0.01) compared with those deemed fit for oAAA. Finally, patients designated as unfit for oAAA had worse survival, even adjusting for patient characteristics and aneurysm size (hazard ratio, 1.6; 95% confidence interval, 1.2-2.2; P<0.01). CONCLUSIONS: In patients with AAAs <6.5 cm, designation by the operating surgeon as unfit for oAAA provides insight into both short- and long term efficacy of EVAR. Patients unable to tolerate oAAA may not benefit from EVAR unless their risk of AAA rupture is very high. PMID- 24046400 TI - Effects of the commercial in ovo injection of 25-hydroxycholecalciferol on the hatchability and hatching chick quality of broilers. AB - The effects of the in ovo injection of commercial diluent containing various levels of 25-hydroxycholecalciferol [25(OH)D3] on hatchability and hatching chick quality variables in Ross * Ross 708 broilers were examined in 2 trials. All treatment groups, each containing 21 and 40 eggs in trials 1 and 2, respectively, were randomly represented on each of 10 replicate tray levels of a single-stage incubator. On 18 d of incubation (doi), eggs were subjected to 1 of 6 treatments using a commercial multi-egg injector. Treatments included noninjected and diluent-injected controls, along with those that received diluent containing 0.15, 0.30, 0.60, or 1.20 ug of 25(OH)D3 in trial 1 and 0.20, 0.60, 1.80, or 5.4 ug of 25(OH)D3 in trial 2. Hatchability of injected eggs (HI) was recorded on 20.5, 21.0, and 21.5 doi, and embryonic mortalities through 21.5 doi were determined. On 21.0 doi in each trial, the BW, body length, and weights and moisture concentrations of the livers and yolk sacs of male and female chicks in each replicate group were determined. In a preliminary trial, the in ovo injection of 0.60 ug of 25(OH)D3 on 18 doi significantly elevated its serum level concentrations in embryos on 19.25 doi. In both trials, the HI of noninjected controls through 21.0 doi was higher than that of diluent-injected controls. In trial 1, the HI of eggs on 21.0 doi after being injected with 0.30, 0.60, or 1.20 ug of 25(OH)D3 was higher compared with that of diluent-injected controls, and in trial 2, the HI of eggs on 21.0 and 21.5 doi after being injected with 0.60 ug of 25(OH)D3 was higher compared with that of diluent-injected controls. In conclusion, the in ovo injection of 0.60 ug of 25(OH)D3 may be used to alleviate depressions in HI in Ross * Ross 708 broiler hatching eggs that can occur in response to the in ovo injection of commercial diluent. PMID- 24046401 TI - Application of slightly acidic electrolyzed water for inactivating microbes in a layer breeding house. AB - Lots of microorganisms exist in layer houses can cause bird diseases and worker health concerns. Spraying chemical disinfectants is an effective way to decontaminate pathogenic microorganisms in the air and on surfaces in poultry houses. Slightly acidic electrolyzed water (SAEW, pH 5.0-6.5) is an ideal, environmentally friendly broad-spectrum disinfectant to prevent and control bacterial or viral infection in layer farms. The purpose of this work was to investigate the cleaning effectiveness of SAEW for inactivating the microbes in layer houses. The effect of SAEW was evaluated by solid materials and surface disinfection in a hen house. Results indicate that SAEW with an available chlorine concentration of 250 mg/L, pH value of 6.19, and oxygen reduction potential of 974 mV inactivated 100% of bacteria and fungi in solid materials (dusts, feces, feather, and feed), which is more efficient than common chemical disinfectant such as benzalkonium chloride solution (1:1,000 vol/vol) and povidone-iodine solution (1:1,000 vol/vol). Also, it significantly reduced the microbes on the equipment or facility surfaces (P < 0.05), including floor, wall, feed trough, and water pipe surfaces. Moreover, SAEW effectively decreased the survival rates of Salmonella and Escherichia coli by 21 and 16 percentage points. In addition, spraying the target with tap water before disinfection plays an important role in spray disinfection. PMID- 24046402 TI - Social interaction of juvenile Japanese quail classified by their permanence in proximity to a high or low density of conspecifics. AB - One challenge faced by ethologists in poultry welfare is helping birds to form functionally successful groups over time through the expression of appropriate behaviors. Searching for phenotypic variability, we developed in Japanese quail a density-related permanence (DRP) test that enables us to classify young birds (while in groups) according to their individual permanence in boxes containing a high or low density of confined conspecifics (HD or LD, respectively). This study addressed the question of whether contrasting DRP quail behavior may reflect underlying differences in social responses. Birds were classified at 11 d of age in an apparatus consisting of 2 boxes interconnected by a central region delimited by sliding doors. Each box contained at its distal end either 12 or 3 conspecifics confined behind a glass (high or low density, respectively). The doors were closed 9 times every 1 h, and positioning of 36 experimental birds was registered. If birds were found in the box containing high density, low density, or in the central region, they received a 1, -1, or a 0 score, respectively. Birds with final summed scores of >=3 or <=-3 were categorized as HD or LD, respectively. Same category groups (HD or LD) were evaluated in their home box (undisturbed) and in a resident/intruder test when 38 d old. A higher proportion of LD than HD groups (5/6 vs. 1/6, respectively) showed at least one aggressive pecking event during a 1-h trial. The LD groups also showed a higher number of aggressive pecking events than HP groups. When an unfamiliar intruder (either HD or LD) was incorporated during 5 min in the HD or LD box, LD resident quail showed shorter latencies and a higher number of aggressive pecking events toward the intruder bird than their HD counterparts. The early individual permanence in the DRP test could be considered a consequence of a different adaptability strategy for group living. This novel test could be relevant for selection programs aiming to obtain birds better suited for rearing in high-density conditions. PMID- 24046403 TI - Epidemiology of influences on the performance in broiler flocks--a field study in Germany. AB - To establish which factors influence performance and bird welfare during a fattening period and to identify those factors to be investigated during routine monitoring of farms by veterinary authorities, a questionnaire-based field study was conducted in districts of Lower Saxony, Germany, with the highest density of broiler chickens. Mortality and BW of farms with different stocking densities (<=33, 33.1-39, and >39 kg/m(2)) were investigated. Analyses of 79 farms with 176 stables and 634 fattening periods revealed that flock mortality and BW appeared to be greatly influenced by weather conditions and litter material. In general, it is an advantage to grow broilers under warm weather conditions. However, the longer the fattening period lasts the more important it becomes that the outside weather conditions are not too warm. Therefore, weather conditions should be considered when determining the length of the fattening period, especially before the background of the growing demands of broilers regarding ventilation, absorption of feces by the litter material, and so on. Apart from the length of the fattening period, the weather conditions determine the choice of the litter material, as well. Under cold-humid weather conditions, it is better to use litter material other than wood shavings. In particular in older buildings it is not possible to provide the required conditions, which results in a lower weight gain the longer the fattening period lasts. The study identified differences in the final BW of flocks, which indicate different (farm) management policies. Regardless of the underlying policy, the performance of a fattening period can be improved by optimizing the farm management according to the prevalent conditions. Future routine monitoring, which should be cost effective regarding personnel and finance, should be generally risk based and consider weather conditions, litter material, the age of the building, and the length of the fattening period. PMID- 24046404 TI - Welfare assessment in broiler farms: transect walks versus individual scoring. AB - Current scientific approaches to welfare assessment in broilers are based on individual sampling that can be time consuming under field conditions. On the other hand, farmers conduct routine checks based on walks through the house to screen birds' health condition. We adapted the walks through following line transect methodology used in wildlife studies to explore their feasibility as a welfare assessment tool. The aim of this study was to compare broiler welfare assessed by individual sampling and transect walks. We evaluated 6 identically managed flocks. For individual sampling, we collected measures on 150 birds, including weight, breast dirtiness, hock and footpad dermatitis, lameness, and immobility. Transect observations were conducted by slowly walking on randomized paths within each house recording: immobility, lameness, back dirtiness, sickness, agony, and dead. Transect walks allowed detection of small variations (P < 0.003) in the prevalence of most welfare indicators considered with consistency in interobserver reliability (P >= 0.05). In addition, assessments across transects were highly consistent (P >= 0.05). Individual sampling was also sensitive to differences across houses (P < 0.01) with the exception of immobility (P = 0.783). No differences were found across sampling locations (P >= 0.05). However, both methods differed greatly in the frequency of the incidence of the parameters considered. For example, immobility varied from 0.2 +/- 0.02% for transect walks to 4 +/- 2.3% for individual sampling, whereas lameness varied between 0.8 +/- 0.07% and 24.2 +/- 4.7% for transect and samplings, respectively. It is possible that the transect approach may have overlooked walking deficiencies because a large number of birds were scored, although if this was the case, the consistency obtained in the scoring across observers and transects would be surprising. Differences may also be related to possibly biased individual sampling procedures, where less mobile and passive individuals may be more likely to be caught. Furthermore the procedure may cause fatigue and fear reactions reducing mobility. Current study provides new insights into constraints and advantages of broiler on-farm assessment methods, which should be considered for designing on-farm welfare assessment protocols. PMID- 24046405 TI - Dissection of Koch's residual feed intake: implications for selection. AB - For 50 yr, residual feed intake (RFI) has remained a black box even though many researchers have touted it as a more biological estimate of efficiency of feed utilization than feed conversion ratio (FCR). We successfully dissected the efficiency of feed utilization by decomposing the components of RFI and ascertained the contributions of its components. Currently, a fixed effect model is used to predict RFI, which we term RFIF. We used a random effect model to predict RFIR, which allowed a separate estimation of RFI for maintenance (RFIM) and for growth (RFIG) and also ascertained their respective efficiencies. Judged by residual variance, R(2) and deviance information criterion, the random effect model was superior to the traditional fixed effect model used to generate RFIF. Under the traditional method, the h(2) of RFIF was 0.13 but h(2) of RFIR was 0.35. The heritability of RFIM and RFIG were moderate (~0.50), but the genetic correlation between them was highly negative (-0.95), suggesting that these 2 efficiencies contribute in an opposing way toward RFI. As a result, there should be caution in ascribing a biological basis to RFI. Under the current methodology, a biological basis can be ascribed to RFIM and RFIG. Selecting on RFIM will lead to smaller but efficient birds. The genetic gains in feed efficiency will be achieved by reductions in feed required for maintenance. The RFIG is not an efficiency parameter and should not be used as a sole criterion for selection. The ability of the current method to estimate efficiency values for metabolic BW and BW gain provides geneticists with additional parameters to use to discriminate between animals with similar RFIR. It also provides the flexibility to impose weights on RFIM and RFIG to meet a desired objective. PMID- 24046406 TI - Estimation of the genetic parameters of semen quality in Beijing-You chickens. AB - By estimating the genetic parameters of various semen quality traits in Beijing You chickens, this study aims to elucidate the inheritance patterns of these traits and the correlations between them to facilitate setting up appropriate breeding strategies for enhanced semen quality. Semen samples were collected from 518 Beijing-You roosters at 43 wk of age from 3 selection lines related to meat flavor traits. Seven semen quality traits, consisting of semen volume, pH, and color, and sperm viability, motility, percent deformity, and concentration, were determined. Sizeable variations (18-24% CV) were observed for all traits, except for semen pH. The effects of semen collection time and origin of the chickens (line) were analyzed to optimize the proper models for estimating genetic parameters for each trait. The multiple-trait derivative-free restricted maximum likelihood method was used for estimating variance components. The results revealed that sperm viability, motility, and percent deformity exhibited high heritabilities (h(2) = 0.52, 0.85, and 0.60, respectively). Semen volume, semen color, and sperm concentration had moderate heritabilities (h(2) = 0.28, 0.19, and 0.12, respectively). Semen pH showed low heritability (h(2) = 0.03). Genetic and phenotypic correlations between sperm motility and viability were positive and high (rA = 0.88 and rP = 0.59). In addition, these 2 traits were genetically negatively correlated with percent deformity. This implied the possibility of reducing sperm deformity, which is difficult to measure, by indirect selection. It is concluded from this study that semen quality can be improved by selection. The traits with high variations and heritabilities such as semen volume are promising traits for selection to improve semen quality and likely reproductive performance of native chicken breeds. PMID- 24046407 TI - Cryoconservation of avian gonads in Canada. AB - Avian genetic resources have declined dramatically over the past half century as the cost of maintaining populations has exceeded the perceived benefit of keeping them. Despite the early importance of poultry in the development of cryopreservation techniques, very little avian germplasm has been conserved. Cryopreservation and recovery of avian gonads preserve the W chromosome and overcome problems of freezing and recovering semen or conserving and manipulating embryonic cells, and the use of vitrification procedures for preserving gonads minimizes cellular damage. On the basis of research demonstrating the biological possibility of cryopreserving and transplanting avian gonads, 5,125 testicles and 2,667 ovaries from 10 populations of Japanese quail, 9 populations of chickens, and 1 population of Chilean tinamou were cryopreserved and sent to the Canadian Animal Genetic Resources program for long-term storage. These gonads represent 20 of the 33 distinct avian populations currently maintained at Canadian public institutions of agricultural research. PMID- 24046408 TI - Identification and expression profiling analysis of goose melanoma differentiation associated gene 5 (MDA5) gene. AB - Melanoma differentiation associated gene 5 (MDA5) is an important cytoplasmic receptor that recognizes long molecules of viral double-stranded RNA and single stranded RNA with 5' triphosphate and mediates type I interferon secretion. In this study, the full-length MDA5 gene in the goose was identified and characterized. The cDNA of goose MDA5 was 3,306 bp in length with an open reading frame of 3,018 bp, which encoded a polypeptide of 1,005 amino acids. The deduced amino acid sequence contained 6 main structure domains including 2 caspase activation and recruitment domains, one DExD/H-box helicase domain, one type III restriction enzyme domain, one helicase conserved C-terminal domain, and one RIG I C-terminal domain. Quantitative real-time PCR analysis indicated that goose MDA5 mRNA was constitutively expressed in all sampled tissues. It was highly expressed in the jejunum, trachea, ileum, colon, and kidney, and lowly expressed in the muscular stomach, glandular stomach, and muscle. A significant increase in the transcription of MDA5 was detected in the brain, spleen, and lungs of geese after infection with H5N1 highly pathogenic avian influenza virus compared with uninfected tissues. These findings indicated that goose MDA5 was an important receptor, involved in the antiviral innate immune defense to H5N1 highly pathogenic avian influenza virus in geese. PMID- 24046409 TI - Immune effects of dietary anethole on Eimeria acervulina infection. AB - The effects of anethole on in vitro and in vivo parameters of chicken immunity during experimental avian coccidiosis were evaluated. Anethole reduced the viability of invasive Eimeria acervulina sporozoites after 2 or 4 h of treatment in vitro by 45 and 42%, respectively, and stimulated 6.0-fold greater chicken spleen cell proliferation compared with controls. Broiler chickens continuously fed from hatch with an anethole-supplemented diet and orally challenged with live E. acervulina oocysts showed enhanced BW gain, decreased fecal oocyst excretion, and greater E. acervulina profilin antibody responses compared with infected chickens given an unsupplemented standard diet. The levels of transcripts encoding the immune mediators IL6, IL8, IL10, and tumor necrosis factor ligand superfamily member 15 (TNFSF15) in intestinal lymphocytes were increased in E. acervulina-infected chickens fed the anethole-containing diet compared with untreated controls. Global gene expression analysis by microarray hybridization identified 1,810 transcripts (677 upregulated, 1,133 downregulated) whose levels were significantly altered in intestinal lymphocytes of anethole-fed birds compared with unsupplemented controls. From this transcriptome, 576 corresponding genes were identified. The most significant biological function associated with these genes was "Inflammatory Response" in the "Disease and Disorders" category. This new information documents the immunologic and genomic changes that occur in chickens following anethole dietary supplementation that may be relevant to host protective immune response to avian coccidiosis. PMID- 24046411 TI - Effect of 3',5'-cyclic diguanylic acid in a broiler Clostridium perfringens infection model. AB - In an effort to explore strategies to control Clostridium perfringens, we investigated the synergistic effect of a ubiquitous bacterial second messenger 3',5'-cyclic diguanylic acid (c-di-GMP) with penicillin G in a broiler challenge model. All chicks were inoculated in the crop by gavage on d 14, 15, and 16 with a mixture of 4 C. perfringens strains. Birds were treated with saline (control group) or 20 nmol of c-di-GMP by gavage or intramuscularly (IM) on d 24, all in conjunction with penicillin G in water for 5 d. Weekly samplings of ceca and ileum were performed on d 21 to 35 for C. perfringens and Lactobacillus enumeration. On d 35 of age, the IM treatment significantly (P < 0.05) reduced C. perfringens in the ceca, suggesting possible synergistic activity between penicillin G and c-di-GMP against C. perfringens in broiler ceca. Moreover, analysis of ceca DNA for the presence of a series of C. perfringens virulence genes showed a prevalence of 30% for the Clostridium perfringens alpha-toxin gene (cpa) from d 21 to 35 in the IM-treated group, whereas the occurrence of the cpa gene increased from 10 to 60% in the other 2 groups (control and gavage) from d 21 to 35. Detection of beta-lactamase genes (blaCMY-2, blaSHV, and blaTEM) indicative of gram-negative bacteria in the same samples from d 21 to 35 did not show significant treatment effects. Amplified fragment-length polymorphism showed a predominant 92% similarity between the ceca of 21-d-old control birds and the 35-d-old IM-treated c-di-GMP group. This suggests that c-di-GMP IM treatment might be effective at restoring the normal microflora of the host on d 35 after being challenged by C. perfringens. Our results suggest that c-di-GMP can reduce the colonization of C. perfringens in the gut without increasing the selection pressure for some beta-lactamase genes or altering the commensal bacterial population. PMID- 24046410 TI - Dietary Curcuma longa enhances resistance against Eimeria maxima and Eimeria tenella infections in chickens. AB - The effects of dietary supplementation with an organic extract of Curcuma longa on systemic and local immune responses to experimental Eimeria maxima and Eimeria tenella infections were evaluated in commercial broiler chickens. Dietary supplementation with C. longa enhanced coccidiosis resistance as demonstrated by increased BW gains, reduced fecal oocyst shedding, and decreased gut lesions compared with infected birds fed a nonsupplemented control diet. The chickens fed C. longa-supplemented diet showed enhanced systemic humoral immunity, as assessed by greater levels of serum antibodies to an Eimeria microneme protein, MIC2, and enhanced cellular immunity, as measured by concanavalin A-induced spleen cell proliferation, compared with controls. At the intestinal level, genome-wide gene expression profiling by microarray hybridization identified 601 differentially expressed transcripts (287 upregulated, 314 downregulated) in gut lymphocytes of C. longa-fed chickens compared with nonsupplemented controls. Based on the known functions of the corresponding mammalian genes, the C. longa-induced intestinal transcriptome was mostly associated with genes mediating anti-inflammatory effects. Taken together, these results suggest that dietary C. longa could be used to attenuate Eimeria-induced, inflammation-mediated gut damage in commercial poultry production. PMID- 24046412 TI - Comparison of 3 kinds of Toll-like receptor ligands for inactivated avian H5N1 influenza virus intranasal immunization in chicken. AB - To evaluate the effects of co-administration of inactivated avian influenza H5N1 virus (IAIV) and different Toll-like receptor (TLR) ligands in chickens, 10-d-old chickens were immunized intranasally with IAIV and TLR ligand [Bacillus subtilis spores, polyinosinic-polycytidylic acid, and CpG oligodeoxynucleotides (CpG-ODN), respectively]. The results showed that both anti-avian influenza virus (AIV) specific secretory IgA level in respiratory tract and anti-AIV specific IgG level in serum significantly increased, as well as the expressions of IL-12, interferon gamma, IL-6, and TLR in the nasal cavity and trachea after intranasal immunization with IAIV and TLR ligand. Among the used TLR ligands, B. subtilis spores as the adjuvant for nasal IAIV had the strongest effect on the expression of IL-6 and IL-12 (P < 0.01), whereas the CpG-ODN could present an advantageous effect on the induction of anti-AIV specific IgG and neutralization antibodies (P < 0.01). The chickens that were previously co-administrated with IAIV and B. subtilis spores could survive at an improved rate upon challenge by live AIV H5N1 virus. Our study suggested that B. subtilis spores, polyinosinic-polycytidylic acid, or CpG-ODN all could effectively enhance the local and systemic immune responses to IAIV in chickens. Considering of the effects and cost of these TLR ligands, we prospected that B. subtilis spores might serve as a more affordable and efficacious mucosal adjuvant for nasal IAIV in chickens. PMID- 24046413 TI - Characterization and antimicrobial resistance analysis of avian pathogenic Escherichia coli isolated from Italian turkey flocks. AB - This study investigated the occurrence of avian pathogenic Escherichia coli (APEC) in a finishing turkey commercial farm, carrying out longitudinal surveys involving 3 consecutive flocks. The diversity and the distribution of the E. coli strains detected during colisepticemia outbreaks were examined. The strains were isolated, serogrouped, assessed for the presence of virulence-associated genes, typed by random amplification of polymorphic DNA (RAPD), and antimicrobial resistance analysis was then carried out. Escherichia coli O78 and O2 were predominantly found. Moreover, based on the somatic antigens used in the study, strains were recovered that were nontypeable. On one occasion, an E. coli O111 strain was found in turkeys. The E. coli isolates differed in terms of antibiotic resistance and RAPD profile. All strains possessed the virulence genes that enabled them to be considered APEC. Strains not only differed between flocks, but also within the same flock. These findings point out the importance of addressing colibacillosis therapy on the basis of a sensitivity test. PMID- 24046414 TI - Atherosclerosis-susceptible and atherosclerosis-resistant pigeon aortic cells express different genes in vivo. AB - Spontaneous atherosclerosis in the White Carneau (WC-As) pigeon is inherited as a single gene disorder, and its progression closely mirrors the human disease. Representational difference analysis and microarray were used to identify genes that were differentially expressed between the susceptible WC-As and resistant Show Racer (SR-Ar) aortic tissue. The RNA extracted from 1-d-old squab aortas was used to make cDNA for each experiment. Fifty-six unique genes were found using representational difference analysis, with 25 exclusively expressed in the WC-As, 15 exclusive to the SR-Ar, and 16 nonexclusive genes having copy number variation between breeds. Caveolin and beta-actin were expressed in the WC-As, whereas the proteasome maturation protein and the transcription complex CCR4-NOT were exclusive to the SR-Ar. Microarray analysis revealed 48 genes with differential expression. Vascular endothelial growth factor and p53 binding protein were among the 17 genes upregulated in the WC-As. Thirty-one genes were upregulated in the SR-Ar including the transforming growth factor-beta signaling factor SMAD2 and heat shock protein 90. Genes representing several biochemical pathways were distinctly different between breeds. The most striking divergences were in cytoskeletal remodeling, proteasome activity, cellular respiration, and immune response. Actin cytoskeletal remodeling appears to be one of the first differences between susceptible and resistant breeds, lending support to the smooth muscle cell phenotypic reversion hypothesis of human atherogenesis. PMID- 24046415 TI - Phylogenetic analysis and genetic characterization of chicken anemia virus isolates from Cambodia. AB - Three chicken anemia viruses (CAV) were detected by PCR during screening of field samples from village chickens collected in Cambodia in 2011/2012. Nearly full length VP1 viral structural protein genes (nt 1-1,293) from the 3 CAV were sequenced and characterized. Phylogenetic analysis revealed that all 3 of the Cambodian CAV were clustered with CAV strains belonging to genotype II and were most closely related to CAV strains from Guangdong province, China. On the amino acid level, major substitutions were observed at 12 residues in the VP1 protein (positions 22, 75, 97, 125, 139, 144, 254, 287, 290, 370, 376, and 413) when compared with published reference CAV strains. In motifs associated with virulence, all Cambodian CAV had virulence-associated motifs composed of 75I, 89T, 125I, 139Q, 141Q, 144Q, and 394Q, which are commonly found in highly virulent genotype II viruses and some genotype III viruses. This is the first report of CAV isolated from village chickens in Southeast Asia as well as Cambodia. PMID- 24046416 TI - Effects of balanced dietary protein levels on egg production and egg quality parameters of individual commercial layers. AB - The effects of a series of balanced dietary protein levels on egg production and egg quality parameters of laying hens from 18 through 74 wk of age were investigated. One hundred forty-four pullets (Bovans) were randomly assigned to individual cages with separate feeders including 3 different protein level series of isocaloric diets. Diets were separated into 4 phases of 18-22, 23-32, 33-44, and 45-74 wk of age. The high protein (H) series contained 21.62, 19.05, 16.32, and 16.05% CP, respectively. Medium protein (M) and low protein (L) series were 2 and 4% lower in balanced dietary protein. The results clearly demonstrated that the balanced dietary protein level was a limiting factor for BW, ADFI, egg weight, hen day egg production (HDEP), and feed per kilogram of eggs. Feeding with the L series resulted in lower ADFI and HDEP (90.33% peak production) and more feed per kilogram of eggs compared with the H or M series (HDEP; 93.23 and 95.68% peak production, monthly basis). Egg weight responded in a linear manner to balanced dietary protein level (58.78, 55.94, and 52.73 g for H, M, and L, respectively). Feed intake of all hens, but especially those in the L series, increased considerably after wk 54 when the temperature of the house decreased due to winter conditions. Thus, hens fed the L series seemed particularly dependent on house temperature to maintain BW, ADFI, and HDEP. For egg quality parameters, percent yolk, Haugh units, and egg specific gravity were similar regardless of diets. Haugh units were found to be greatly affected by the variation of housing temperature (P = 0.025). Maximum performance cannot always be expected to lead to maximum profits. Contrary to the idea of a daily amino acid requirement for maximum performance, these results may be used to determine profit-maximizing levels of balanced dietary protein based on the cost of protein and returns from different possible protein levels that may be fed. PMID- 24046417 TI - Conjugated linoleic acids alter body composition differently according to physiological age in Moulard ducks. AB - Conjugated linoleic acids (CLA) have been shown to have remarkable yet inconsistent metabolic effects in mice, rats, hamsters, chickens, cattle, and humans. In particular, effects on lipogenesis vary with tissue, physiological state, and species. In this study we tested the hypothesis that CLA would differentially affect ducks of the same genetic background but of differing age. Growing (7 wk) and maintenance (11 wk) Moulard ducks were grouped by age and fed a standard diet supplemented with 5% soybean oil (control) or 5% CLA isomer mixture. Birds were slaughtered after 3 or 6 wk for assessment of body composition including adipose, liver, viscera, and empty carcass weight. Serum nonesterified fatty acid (NEFA) and glucose concentrations were evaluated, and gene targets were cloned from the duck to use in quantifying mRNA abundance for genes involved in lipogenesis (fatty acid synthase, FAS; acetyl-CoA carboxylase, ACC) and lipid oxidation (carnitine palmitoyl transferase-1, CPT-1) in liver tissue from maintenance birds. After 3 wk, the growing CLA group exhibited a 24% decrease in dissectible adipose tissue (P < 0.05), whereas maintenance birds showed no significant diet effect. After 6 wk, the growing CLA group exhibited a 20% increase in liver mass compared with the control (P < 0.05), but no diet effect on adipose tissue. Maintenance birds receiving dietary CLA had a 42% decrease in adipose tissue mass after 6 wk; increased serum NEFA, ACC, and CPT-1 mRNA after 3 and 6 wk (P < 0.05); and increased FAS mRNA after 3 wk of treatment (P < 0.05). These data indicate that CLA have potent effects on lipid metabolism in ducks, but these effects differ depending on physiological age. PMID- 24046418 TI - Effect of dietary lysine on hepatic lysine catabolism in broilers. AB - Lysine is frequently a first- or second-limiting amino acid in poultry diets. Improving the efficiency of lysine use for protein synthesis would effectively lower the lysine requirement and decrease feed costs. Understanding how lysine is degraded and how the degradation is regulated would identify potential molecular targets for interventions to decrease lysine degradation. To better understand lysine degradation in poultry, 3 experiments were conducted. In experiment 1, one day-old chicks were fed 1.07, 1.25, 1.73, or 3.28% dietary lysine for 2 wk. In experiments 2 and 3, fourteen-day-old chicks were fed 1.07 or 1.25% dietary lysine for 2 wk. Measures of liver lysine catabolism including lysine alpha ketoglutarate reductase (LKR) and lysine oxidation (LOX) were assessed. The alpha aminoadipate delta-semialdehyde synthase (AASS) is a bifunctional enzyme composed of both LKR and saccharopine dehydrogenase activities, and the relative abundance of this protein and mRNA were likewise assessed. Moreover, potential alternative pathways of lysine catabolism that depend on l-amino acid oxidase (AAOX) and on lysyl oxidase (LYLOX) were considered. In experiment 1, chicks fed lysine deficient diets had decreased (P < 0.05) LKR activities compared with chicks fed at or above the requirement. However, the lowered LKR activities were not associated with a decreased (P > 0.05) LOX as measured in vitro. In experiments 2 and 3, chicks 28 d of age did not decrease LKR activity (P > 0.05) in response to a lysine-deficient diet. No changes in AASS protein abundance or mRNA were detected. Likewise, no differences in the mRNA abundances of AAOX or LYLOX were detected. The activity of AAOX did increase (P < 0.05) in birds fed a lysine adequate diets compared with those fed a lysine-deficient diet. Based on kinetic parameters and assumed concentrations, AAOX could account for about 20% of liver lysine oxidation in avians. PMID- 24046419 TI - Ileal microbiota composition of broilers fed various commercial diet compositions. AB - Microbiota plays a role in the release and absorption of nutrients from feed components, thereby affecting digesta composition and moisture content of the excreta. The objective of the current study was to determine the effects of 5 different diets varying in ingredients (medium-chain fatty acids, nonstarch polysaccharides, and starch) on the microbiota composition of ileal digesta of broiler chickens and excreta DM content. Each treatment was repeated 6 times in cages each containing 18 Ross 308 broilers, with growth performance measured from 0 to 34 d of age and excreta DM and ileal microbiota composition analyzed at 34 d of age. Microbiota composition was evaluated using a novel ribosomal RNA microarray technology containing 370 different probes covering various genera, groups of microbial species, and individual species of the chicken gut microbiota, of which 321 had a signal above the background threshold. Replacing part of the animal fat and soybean oil in the wheat-based diet with medium-chain fatty acids (MCFA; 0.3% C10 and 2.7% C12) improved feed efficiency compared with the other dietary treatments. This coincided with a suppression of gram-positive bacteria belonging to the phylum of the Firmicutes, including Lactobacillus species, and species belonging to the family of the Enterococcaceae and Micrococcaceae, whereas the gram-negative bacteria belonging to the family of the Enterobacteriaceae were promoted. None of the other diets used in the present study notably changed the ileal digesta bacteria composition. Excreta DM content was not affected by dietary treatment. The variation between individual birds per dietary treatment was more pronounced than variation caused by feed composition, with the exception of the digesta microbiota of the birds fed the MCFA diet. It is concluded that a diet with MCFA significantly changes the ileal microbiota composition, whereas the effect of the other diets on the composition of the microbiota and excreta DM content is small in broiler chickens. PMID- 24046420 TI - Supplemental glycine and threonine effects on performance, intestinal mucosa development, and nutrient utilization of growing broiler chickens. AB - A study was conducted to evaluate Gly requirements in low-CP diets with different levels of digestible (dig) Thr, and their effects on performance, intestinal mucosal development, and nutrient utilization of broiler chickens from 21 to 35 d age. A total of 240 twenty-one-day-old Cobb-Vantress male broiler chickens were distributed in a completely randomized 4 * 2 factorial arrangement for a total of 8 treatments with 5 replicates of 6 birds each. The treatments consisted of 4 levels of Gly+Ser (1.47, 1.57, 1.67, or 1.77%) and 2 levels of dig Thr (0.70 or 0.77%, corresponding to 100 or 110% of Thr requirements, respectively). Common diets were fed to broilers until 20 d of age. At d 35, an interaction (P <= 0.01) was observed between the Gly+Ser and dig Thr levels for G:F. Glycine supplementation resulted in a linear increase (P < 0.05) in BW gain, G:F, intestinal mucin secretion, apparent digestibility of fat, and AME values of the experimental diets. Threonine levels greater than the levels required (0.77%) improved (P < 0.05) G:F and increased (P < 0.05) intestinal mucin secretion. However, intestinal morphometry and the number of goblet cells in the duodenum, jejunum, and ileum were not affected by the treatments. The dietary Gly+Ser level necessary to optimize G:F in low-CP diets containing 0.77% Thr for broiler chickens during growth was estimated to be 1.54%; however, this requirement may be greater than 1.77% in diets with 0.70% Thr. Supplemental Gly may be essential to support maximum performance for broiler chickens from 21 to 35 d of age when they are fed diets based exclusively on vegetable ingredients and with low protein levels. Glycine can directly or indirectly influence the proper function of the intestinal mucosa and improve dietary energy utilization. PMID- 24046421 TI - Live production and carcass characteristics of broilers fed a blend of poultry fat and corn oil derived from distillers dried grains with solubles. AB - Corn distillers dried grains with solubles (DDGS) are now being further processed to remove corn oil, which may be used as a dietary energy source for poultry. The objectives of this study were to compare the effects of a poultry fat (PF) and a new DDGS-derived corn oil blend (CO) on live performance and carcass characteristics of 49-d-old broilers. Four corn-soybean meal based diets were formulated with differing blends of PF and CO. All diets contained the same percentage of total fat, but differed in the fat source. One diet had the sole source of fat as PF (100:0% PF:CO) and was then replaced with 25% CO, 75% CO, and a 100% replacement of CO. Each of the diets was fed in a 3-phase feeding program to 6 replicate pens. At day of hatch, Ross * Ross 708 broilers were randomly allocated to 24 pens composed of 42 birds of equal sex. On d 49, 10 birds from each pen were processed, and carcass, abdominal fat pad, and breast muscle components were determined. There were no significant differences in live performance for the starter phase (0-18 d). For the grower phase (19-35 d), birds fed 75:25% PF:CO significantly (P <= 0.05) increased BW, BW gain, and decreased feed conversion compared with the control (100:0% PF:CO). Birds fed 0:100% PF:CO also observed similar improvements in BW, BW gain, and feed conversion during the grower phase. There were no significant differences for the finisher phase (36-48 d). On d 49, live weights for birds fed the 0:100% PF:CO diets were significantly lower compared with other treatments. A trend for lower carcass and breast weights and increased abdominal fat was also observed for birds fed the 0:100% PF:CO. The addition of CO led to significant improvements in pellet durability for grower and finisher pellets. The results of this study indicate that DDGS derived CO can be used to partially replace PF in broiler diets without any detrimental effects. PMID- 24046422 TI - Breed-dependent transcriptional regulation of phosphoenolpyruvate carboxylase, cytosolic form, expression in the liver of broiler chickens. AB - Hepatic gluconeogenesis is the main source of glucose during chicken embryonic development, and it plays a major role in glucose homeostasis for developing embryos. Phosphoenolpyruvate carboxylase (PEPCK) catalyzes the rate-limiting step of gluconeogenesis, yet how hepatic PEPCK expression is differentially regulated between chicken breeds remains elusive. In this study, fertile eggs from a slow growing Chinese Yellow Feathered Chicken and a fast-growing White Recessive Rock Chicken were incubated under the same standard conditions, and serum and liver samples were collected on embryonic d 18 (18E). The fast-growing breed had a significantly higher fetal weight (P < 0.01) and serum glucose concentration (P < 0.05) compared with the slow-growing breed. The fast-growing breed also had significantly higher hepatic mRNA expression levels of the cystolic form of PEPCK (PEPCK-c; P < 0.05) and significantly higher hepatic mRNA and protein expression levels of cAMP response element binding protein 1 (CREB-1; P < 0.05). Moreover, the binding of phosphorylated CREB-1 to the PEPCK-c promoter tended to be higher in the fast-growing breed (P = 0.08). Breed-specific epigenetic modifications of the PEPCK-c promoter were also observed; the fast-growing breed demonstrated lower CpG methylation (P < 0.05) and histone H3 (P < 0.05) levels but more histone H3 acetylation (H3ac) and histone H3 lysine 27 trimethylation (H3K27me3; P < 0.05) compared with the slow-growing breed. Our results suggest that hepatic PEPCK-c expression is transcriptionally regulated in a breed-specific manner and that fast- and slow-growing broiler chicken fetuses exhibit different epigenetic modifications on their PEPCK-c promoter regions. PMID- 24046423 TI - Cerulenin upregulates heat shock protein-70 gene expression in chicken muscle. AB - Lines of evidence suggested that systems involved in the regulation of the stress responses and energy homeostasis are highly integrated. Because cerulenin, the natural antibiotic product of the fungus Cephalosporium ceruleans and a broad spectrum fatty acid synthesis (FAS) inhibitor, has been shown to affect food intake and energy balance, and because the biomarker of stress Hsp-70 gene was found to interact directly with fatty acids, we hypothesized that cerulenin may regulate Hsp-70 gene expression. Therefore, the present study was undertaken to examine this issue. Cerulenin administration significantly (P < 0.05) decreased food intake and induced Hsp-70 mRNA levels in muscle, but not in liver or hypothalamus of 2-wk-old broiler chickens. These changes were accompanied by an unpregulation of muscle uncoupling protein and carnitine palmitoyltransferase 1 mRNA levels. This result indicated that the regulation of Hsp-70 gene expression in normal chickens, as estimated by oxidative stress indices [TBA reacting substances, ferric reducing/antioxidant power, and ceruloplasmin oxidase activity] levels, is tissue-specific. In attempt to discriminate between the effect of cerulenin and cerulenin-reduced food intake on Hsp-70 gene expression, we also evaluated the effect of food deprivation on the same cellular responses. Food deprivation for 16 h did not affect Hsp-70 gene expression in all tissues examined, indicating that the effect of cerulenin is independent of the inhibition of food intake. To ascertain whether the effect of cerulenin is direct or indirect, we carried out in vitro studies. Cerulenin treatment did not affect Hsp-70 gene expression in Leghorn male hepatoma and quail myoblast cell lines, suggesting that the observed effect in vivo may be mediated through the central nervous system. PMID- 24046424 TI - Developmental specificity in skeletal muscle of late-term avian embryos and its potential manipulation. AB - Unlike the mammalian fetus, development of the avian embryo is independent of the maternal uterus and is potentially vulnerable to physiological and environmental stresses close to hatch. In contrast to the fetus of late gestation in mammals, skeletal muscle in avian embryos during final incubation shows differential developmental characteristics: 1) muscle mobilization (also called atrophy) is selectively enhanced in the type II fibers (pectoral muscle) but not in the type I fibers (biceps femoris and semimembranosus muscle), involving activation of ubiquitin-mediated protein degradation and suppression of S6K1-mediated protein translation; 2) the proliferative activity of satellite cells is decreased in the atrophied muscle of late-term embryos but enhanced at the day of hatch, probably preparing for the postnatal growth. The mobilization of muscle may represent an adaptive response of avian embryos to external (environmental) or internal (physiological) changes, considering there are developmental transitions both in hormones and requirements for glycolytic substrates from middle-term to late-term incubation. Although the exact mechanism triggering muscle fiber atrophy is still unknown, nutritional and endocrine changes may be of importance. The atrophied muscle fiber recovers as soon as feed and water are available to the hatchling. In ovo feeding of late-term embryos has been applied to improve the nutritional status and therein enhances muscle development. Similarly, in ovo exposure to higher temperature or green light during the critical period of muscle development are also demonstrated to be potential strategies to promote pre- and posthatch muscle growth. PMID- 24046425 TI - Changes in expression levels of neurotensin precursor and receptor mRNA in chicken intestinal tissues and liver during late embryonic and early posthatching development. AB - Neurotensin is a tridecapeptide that has multiple functions as a neurotransmitter and as a circulating hormone. Neurotensin and its related peptide, LANT6, have been isolated in the chicken, but the mRNA encoding these peptides has not been identified. In this study, we first cloned the cDNA for the chicken neurotensin precursor mRNA from the duodenum and characterized its primary structure and then investigated tissue expression patterns of neurotensin precursor and receptor mRNA. The cDNA encoded a protein of 495 amino acids that contains the sequences of chicken neurotensin and LANT6 in the C-terminal region. Real-time PCR analysis showed that the neurotensin precursor mRNA is preferentially expressed in intestinal tissues, such as the duodenum, jejunum, ileum, and colon/rectum, with temporal increases during the hatching period. The expression levels of neurotensin receptor 1 mRNA were relatively higher during the late embryonic period compared with the posthatching period in the duodenum and jejunum, whereas the expression levels were higher in the colon/rectum during the posthatching period. In the liver, the expression levels of neurotensin receptor 1 were markedly increased during the early posthatching period. These results suggest that chicken neurotensin is involved in the regulation of gastrointestinal and hepatic functions, especially during the hatching period. PMID- 24046426 TI - A model for cryobanking female germplasm in Japanese quail (Coturnix japonica). AB - Cryopreservation and transplantation of ovarian tissue can be used for cryobanking female germplasm of avian species. Here we report a model of cryobanking ovarian tissue of Japanese quail. Ovaries of 1-wk-old quail chicks from the recessive white-breasted (WB) line were cryopreserved using a vitrification method. The cryopreserved tissue was warmed and transplanted orthotopically into ovariectomized, 1-wk-old female quail chicks from the homozygous wild-type QO line. At sexual maturation, recipients were mated with WB males and the plumage coloration was used as a marker to determine the origin of their ovaries. Seven of the 15 recipients laid eggs and produced donor-derived offspring, and 5 produced 100% donor-derived offspring. No difference was seen in egg production between recipients and untreated birds. The high efficiency of the vitrification and transplantation procedures in preserving and recovering quail ovarian tissue shows that this model can be used for maintaining commercial and experimental quail strains and may benefit other poultry species and endangered avian species. PMID- 24046427 TI - Comparison of carcass yields and meat quality between Baicheng-You chickens and Arbor Acres broilers. AB - This study examined carcass yields and meat quality traits between Baicheng-You (BCY) chickens and Arbor Acres (AA) broilers. Thirty birds for each strain were selected and slaughtered at market ages of 49 d for AA broilers and 120 d for BCY. The results showed that BCY chickens had lower dressing (2.99%), semi evisceration (5.10%), breast muscle (5.80%), and abdominal fat (1.55%) than those for AA broilers (P < 0.05). However, the leg muscle (%) of BCY chickens was greater (3.14%) than that of AA broilers (P < 0.05). The meat pH45min and pH24h value variations of these 2 breeds were within the normal range (5.53-6.70). The meat color density (optical density, OD) of thigh muscle was darker than breast muscles in both strains (P < 0.05). The cooking loss (%) of breast and thigh muscles of BCY chickens (18.81 and 20.20%, respectively) was also significantly lower (P < 0.05) than that of same muscles of AA broilers (26.41 and 27.33%, respectively). The shear force of breast meat in both breeds was lower (P < 0.05) than that of their thigh meat. The moisture of breast muscle of BCY chickens (72.93%) was lower (P < 0.05) than breast muscles of AA broilers (74.43%). The CP content of breast muscles was greater (P < 0.05) than its thigh muscles of same strain, but it had no significant (P > 0.05) difference of CP content in the same muscles of the 2 strains. The intramuscular fat (IMF) content was greater (P < 0.05) in thigh muscles of BCY chickens (6.80%) than those of AA broilers (4.28%), and inosine-5'-monophosphate (IMP) content was greater (P < 0.05) in breast and thigh muscles of BCY chickens (IMP: 3.79 and 1.47 mg/g) than same muscles in AA broilers (1.42 and 0.47 mg/g). In this study, muscle from 120-d-old BCY chickens was judged to have better quality traits with regard to cooking loss, drip loss, contents of IMF, and IMP compared with meat from 42-d-old AA broilers. At the same time, greater carcass yields, greater thigh pH24, and lower IMF content were observed in AA broilers compared with the BCY chickens. PMID- 24046428 TI - The location of protoporphyrin in the eggshell of brown-shelled eggs. AB - Protoporphyrin has been identified as the main eggshell pigment in brown-shelled eggs. However, there has been some uncertainty concerning the distribution of the pigment within the shell (and cuticle) in brown-shelled eggs. Most previous studies have suggested that the bulk of the shell pigment is deposited in the cuticle of the shell. The present study measured the levels of protoporphyrin in intact eggshells and in shells from which the cuticle had been removed, using eggs from flocks at 3 different ages. This enabled the calculation of the relative amount of protoporphyrin in the calcareous eggshell and the cuticle layer of the eggshell. The majority of the protoporphyrin pigment was located in the calcareous part of the eggshell (80-87%) with a minority contained within the cuticle (13-20%). These findings suggest that studies focused on maintenance of shell color in brown-shelled eggs need to consider the stage of egg formation at which the reduction in pigment deposition is occurring. PMID- 24046429 TI - Prevalence, characterization, and antimicrobial susceptibility of Salmonella Gallinarum isolated from eggs produced in conventional or organic farms in South Korea. AB - To determine the prevalence of Salmonella serotype Enteritidis in eggs in South Korea, we conducted a microbiological survey of commercially available eggs produced in conventional or organic farms during the period from 2010 to 2012. The contents of 7,000 raw shell eggs (6,000 of conventional and 1,000 of organic origin) were examined to evaluate the extent and type of Salmonella Enteritidis contamination. A total of 26 salmonellae (7.4% of all pooled samples) were isolated from 350 homogenized pools, each containing the contents from 20 eggs. An unexpected and particularly surprising finding was that all the Salmonella isolates were serotyped as Salmonella Gallinarum. Salmonella Gallinarum was more common in eggs from organic farms: 10 of 50 egg pools (20.0%) from organic and 16 of 300 egg pools (5.3%) from conventional farms tested positive for Salmonella Gallinarum. However, organic and conventional isolates showed similar antimicrobial susceptibilities. All the isolates and a vaccine strain, SG 9R, which has been widely used in South Korea, were further characterized using the automated repetitive sequence-based PCR (rep-PCR) system, DiversiLab, to ascertain the molecular subtypes and to identify differences from the vaccine strain. The rep-PCR identified 2 distinct clusters among the 26 Salmonella Gallinarum isolates with a greater than 96% similarity index. These were clearly differentiated from the vaccine strain, SG 9R, with which there was a less than 86% similarity index. We found there was low genetic heterogeneity among isolates within each cluster and were able to distinguish wild type strains from the live vaccine strain (SG 9R) using the DiversiLab system. PMID- 24046430 TI - The effects of a short-term molt method using cassava meal, broken rice, or corn on ovarian regression, bone integrity, and postmolt egg production and quality in older (95 week) laying hens. AB - This study was conducted to determine the ability of different molt diets to induce molt in 95-wk-old hens. The hens were randomly assigned to 4 treatments of 60 birds each: 1) molted by full feeding with broken rice (BROK), 2) corn (CRN), 3) cassava (CASS), or 4) nonmolted control (CONT) for 14 d. At 15 d, all hens were fed a layer diet (17% CP), and production performance was measured for 20 wk. Feed intake was depressed (P < 0.05) in the CASS treatment compared with BROK and CRN treatments during the 14 d. The most significant BW loss occurred in the CASS treatment (21.9%), whereas BROK and CRN treatments were 7.6 and 9.3%, respectively. The CASS treatment resulted in total cessation of egg production within 7 d, whereas those of BROK and CRN treatments decreased to 3.7 and 8.7%, respectively. Ovary weights, oviduct weights, and oviduct lengths of the CASS treatment were not significantly different from those of BROK and CRN treatments (P > 0.05). The weight of spleen and thymus glands, blood heterophil:lymphocyte ratios, bone parameters, and mortality during the 14-d treatment were not affected by treatments. No significant differences were found among treatments for postmolt cumulative egg production, egg weight, feed intake, and mortality. Significant (P < 0.05) improvements in albumen quality were observed in the CASS treatment, although shell thickness of this treatment was reduced (P < 0.05) compared with the CONT treatment in wk 2 after the 14-d treatment. With respect to shell ultrastructural traits, the palisade layer of CASS eggs was shorter (P < 0.05) than that of CONT eggs determined in wk 2 after the 14-d treatment. In addition, evidence of abnormal mammillae was detected in an egg produced by the CASS hens. This research indicates that cassava diets can induce molt in hens. Nonetheless, the technique needs to be adjusted to improve postmolt egg production and shell quality. PMID- 24046431 TI - Moving from political declaration to action on reducing the global burden of cardiovascular diseases: a statement from the Global Cardiovascular Disease Taskforce. PMID- 24046432 TI - Persisting gender differences and attenuating age differences in cardiovascular drug use for prevention and treatment of coronary heart disease, 1998-2010. AB - BACKGROUND: Evidence on recent time trends in age-gender differences in cardiovascular drug use is scarce. We studied time trends in age-gender-specific cardiovascular drug use for primary prevention, secondary prevention, and in hospital treatment of coronary heart disease. METHODS AND RESULTS: The PHARMO database was used for record linkage of drug dispensing, hospitalization, and population data to identify drug use between 1998 and 2010 in 1 203 290 persons >=25 years eligible for primary prevention, 84 621 persons hospitalized for an acute coronary syndrome (ACS), and 15 651 persons eligible for secondary prevention. The use of cardiovascular drugs increased over time in all three settings. In primary prevention, the proportion of women that used lipid-lowering drugs was lower than men between 2003 and 2010 (5.7 vs. 7.3% in 2010). The higher proportion of women that used blood pressure-lowering drugs for primary prevention, compared with men, attenuated over time (15.1 vs. 13.8% in 2010). During hospital admission for an ACS, the proportion of women that used cardiovascular drugs was lower than men. In secondary prevention (36 months after hospital discharge), drug use was lowest in young women. The proportion receiving lipid-lowering drugs declined after the age of 75 in all three settings. This age difference attenuated over time. CONCLUSION: Age differences in drug use tended to attenuate over time, whereas gender differences persisted. Areas potentially for improvement are in the hospital treatment of ACS in young women, in secondary prevention among young women and the elderly, and in the continuity of drug use in secondary prevention. PMID- 24046433 TI - Learning from regional heterogeneity in outcomes of patients with acute myocardial infarction. PMID- 24046435 TI - Clinical significance of electrocardiographic right ventricular hypertrophy in athletes: comparison with arrhythmogenic right ventricular cardiomyopathy and pulmonary hypertension. AB - AIMS: Pre-participation cardiovascular screening of young athletes may prevent sports-related sudden cardiac deaths. Recognition of physiological electrocardiography (ECG) changes in healthy athletes has improved the specificity of screening while maintaining sensitivity for disease. The study objective was to determine the clinical significance of electrocardiographic right ventricular hypertrophy (RVH) in athletes. METHODS AND RESULTS: Between 2010 and 2012, 868 subjects aged 14-35 years (68.8% male) were assessed using ECG and echocardiography (athletes; n = 627, sedentary controls; n = 241). Results were compared against patients with established right ventricular (RV) pathology (arrhythmogenic right ventricular cardiomyopathy, n = 68; pulmonary hypertension, n = 30). Sokolow-Lyon RVH (R[V1]+S[V5orV6] > 1.05 mV) was more prevalent in athletes than controls (11.8 vs. 6.2%, P = 0.017), although RV wall thickness (RVWT) was similar (4.0 +/- 1.0 vs. 3.9 +/- 0.9 mm, P = 0.18). Athletes exhibiting electrocardiographic RVH were predominantly male (95.9%), and demonstrated similar RV dimensions and function to athletes with normal electrocardiograms (RVWT; 4.0 +/- 1.1 vs. 4.0 +/- 0.9 mm, P = 0.95, RV basal dimension; 42.7 +/- 5.2 vs. 42.1 +/- 5.9 mm, P = 0.43, RV fractional area change; 40.6 +/- 7.6 vs. 42.2 +/- 8.1%, P = 0.14). Sensitivity and specificity of Sokolow Lyon RVH for echocardiographic RVH (>5 mm) were 14.3 and 88.2%, respectively. Further evaluation including cardiac magnetic resonance imaging did not diagnose right ventricular pathology in any athlete. None of the cardiomyopathic or pulmonary hypertensive patients exhibited voltage RVH without additional ECG abnormalities. CONCLUSION: Electrocardiographic voltage criteria for RVH are frequently fulfilled in healthy athletes without underlying RV pathology, and should not prompt further evaluation if observed in isolation. Recognition of this phenomenon should reduce the burden of investigations after pre participation ECG screening without compromising sensitivity for disease. PMID- 24046434 TI - A signature of circulating microRNAs differentiates takotsubo cardiomyopathy from acute myocardial infarction. AB - AIMS: Takotsubo cardiomyopathy (TTC) remains a potentially life-threatening disease, which is clinically indistinguishable from acute myocardial infarction (MI). Today, no established biomarkers are available for the early diagnosis of TTC and differentiation from MI. MicroRNAs (miRNAs/miRs) emerge as promising sensitive and specific biomarkers for cardiovascular disease. Thus, we sought to identify circulating miRNAs suitable for diagnosis of acute TTC and for distinguishing TTC from acute MI. METHODS AND RESULTS: After miRNA profiling, eight miRNAs were selected for verification by real-time quantitative reverse transcription polymerase chain reaction in patients with TTC (n = 36), ST-segment elevation acute myocardial infarction (STEMI, n = 27), and healthy controls (n = 28). We quantitatively confirmed up-regulation of miR-16 and miR-26a in patients with TTC compared with healthy subjects (both, P < 0.001), and up-regulation of miR-16, miR-26a, and let-7f compared with STEMI patients (P < 0.0001, P < 0.05, and P < 0.05, respectively). Consistent with previous publications, cardiac specific miR-1 and miR-133a were up-regulated in STEMI patients compared with healthy controls (both, P < 0.0001). Moreover, miR-133a was substantially increased in patients with STEMI compared with TTC (P < 0.05). A unique signature comprising miR-1, miR-16, miR-26a, and miR-133a differentiated TTC from healthy subjects [area under the curve (AUC) 0.835, 95% CI 0.733-0.937, P < 0.0001] and from STEMI patients (AUC 0.881, 95% CI 0.793-0.968, P < 0.0001). This signature yielded a sensitivity of 74.19% and a specificity of 78.57% for TTC vs. healthy subjects, and a sensitivity of 96.77% and a specificity of 70.37% for TTC vs. STEMI patients. Additionally, we noticed a decrease of the endothelin-1 (ET-1) regulating miRNA-125a-5p in parallel with a robust increase of ET-1 plasma levels in TTC compared with healthy subjects (P < 0.05). CONCLUSION: The present study for the first time describes a signature of four circulating miRNAs as a robust biomarker to distinguish TTC from STEMI patients. The significant up-regulation of these stress- and depression-related miRNAs suggests a close connection of TTC with neuropsychiatric disorders. Moreover, decreased levels of miRNA125a-5p as well as increased plasma levels of its target ET-1 are in line with the microvascular spasm hypothesis of the TTC pathomechanism. PMID- 24046436 TI - Mechanical dyssynchrony in CRT: still searching for the Holy Grail. PMID- 24046437 TI - Spontaneous limb movements and posturing secondary to acute basilar artery occlusion: a potentially devastating seizure mimic. AB - Basilar artery occlusion is a devastating but treatable form of ischaemic stroke with high morbidity and mortality rates. The diagnosis is often challenging due to considerable heterogeneity of clinical signs and symptoms. We report a case of an acute basilar artery occlusion presenting with decreased level of consciousness associated with rhythmic tonic movements of the four extremities, mimicking seizure activity. The patient was treated with intravenous thrombolysis and subsequently gained good recovery. Awareness of this entity is required to recognise this potentially treatable, but otherwise devastating seizure mimic. PMID- 24046438 TI - Addressing polyspecificity of antibodies selected from an in vitro yeast presentation system: a FACS-based, high-throughput selection and analytical tool. AB - Low expression, poor solubility, and polyspecificity are significant obstacles that have impeded the development of antibodies discovered from in vitro display libraries. Current biophysical characterization tools that identify these 'developability' problems are typically only applied after the discovery process, and thus limited to perhaps a few hundred candidates. We report a flow cytometric assay using a polyspecificity reagent (PSR) that allows for the identification and counter selection of polyspecific antibodies both during and after the selection process. The reported assay correlates well with cross-interaction chromatography, a surrogate for antibody solubility, as well as a baculovirus particle enzyme-linked immunosorbent assay, a surrogate for in vivo clearance. However, unlike these assays, PSR labeling is compatible both with screening of individual antibodies as well as selections of large antibody libraries. To this end, we demonstrate the ability to counter-select against polyspecificity while enriching for antigen affinity from a diverse antibody library, which enables simultaneous evolution of both antigen binding and superior non-target-related properties during the discovery process. PMID- 24046439 TI - Construction of proteins with molecular recognition capabilities using alpha3beta3 de novo protein scaffolds. AB - The molecular recognition ability of proteins is essential in biological systems, and therefore a considerable amount of effort has been devoted to constructing desired target-binding proteins using a variety of naturally occurring proteins as scaffolds. However, since generating a binding site in a native protein can often affect its structural properties, highly stable de novo protein scaffolds may be more amenable than the native proteins. We previously reported the generation of de novo proteins comprising three alpha-helices and three beta strands (alpha3beta3) from a genetic library coding simplified amino acid sets. Two alpha3beta3 de novo proteins, vTAJ13 and vTAJ36, fold into a native-like stable and molten globule-like structures, respectively, even though the proteins have similar amino acid compositions. Here, we attempted to create binding sites for the vTAJ13 and vTAJ36 proteins to prove the utility of de novo designed artificial proteins as a molecular recognition tool. Randomization of six amino acids at two linker sites of vTAJ13 and vTAJ36 followed by biopanning generated binding proteins that recognize the target molecules, fluorescein and green fluorescent protein, with affinities of 10(-7)-10(-8) M. Of note, the selected proteins from the vTAJ13-based library tended to recognize the target molecules with high specificity, probably due to the native-like stable structure of vTAJ13. Our studies provide an example of the potential of de novo protein scaffolds, which are composed of a simplified amino acid set, to recognize a variety of target compounds. PMID- 24046440 TI - Antimicrobial stewardship programmes: the need for wider engagement. PMID- 24046441 TI - Physician self-referral: frequency of negative findings at MR imaging of the knee as a marker of appropriate utilization. AB - PURPOSE: To determine whether ownership of magnetic resonance (MR) imaging equipment by ordering physicians affects the likelihood of positive findings at MR imaging of the knee and to evaluate rates of knee abnormalities seen at MR imaging as a metric for comparison of utilization. MATERIALS AND METHODS: The institutional review board approved this retrospective HIPAA-compliant study and waived the need for informed consent. A retrospective review was performed of consecutive diagnostic MR images of the knee interpreted by one radiology practice between January and April 2009 for patients who had been referred by two separate physician groups serving the same geographic community: one with financial interest (FI) in the MR imaging equipment used and one with no FI (NFI) in the MR imaging equipment used. The percentage of examinations with negative results was tabulated for both groups, and the relative frequency of each abnormality subtype was calculated among the studies with positive findings in each group. To examine frequency differences among groups, chi(2) tests were used, and to examine mean differences among groups, t tests were used. RESULTS: Of 700 examinations, 205 had negative results (117 of 350 in the FI group and 88 of 350 in the NFI group, P = .016). Among the examinations with positive results, the mean total number of positive abnormality subtypes per image did not significantly differ between groups: 1.52 for the FI group and 1.53 for the NFI group (P = .96). CONCLUSION: MR images of the knee among patients referred by the FI group were significantly more likely to be negative than those among patients referred by the NFI group. Frequency of abnormality subtype and distribution among examinations with positive results suggests a highly similar distribution and severity of abnormalities between the two patient groups. PMID- 24046442 TI - Activity-dependent secretion of progranulin from synapses. AB - The secreted growth factor progranulin (PGRN) has been shown to be important for regulating neuronal survival and outgrowth, as well as synapse formation and function. Mutations in the PGRN gene that result in PGRN haploinsufficiency have been identified as a major cause of frontotemporal dementia (FTD). Here we demonstrate that PGRN is colocalized with dense-core vesicle markers and is co transported with brain-derived neurotrophic factor (BDNF) within axons and dendrites of cultured hippocampal neurons in both anterograde and retrograde directions. We also show that PGRN is secreted in an activity-dependent manner from synaptic and extrasynaptic sites, and that the temporal profiles of secretion are distinct in axons and dendrites. Neuronal activity is also shown to increase the recruitment of PGRN to synapses and to enhance the density of PGRN clusters along axons. Finally, treatment of neurons with recombinant PGRN is shown to increase synapse density, while decreasing the size of the presynaptic compartment and specifically the number of synaptic vesicles per synapse. Together, this indicates that activity-dependent secretion of PGRN can regulate synapse number and structure. PMID- 24046443 TI - M-cadherin-mediated intercellular interactions activate satellite cell division. AB - Adult muscle stem cells and their committed myogenic precursors, commonly referred to as the satellite cell population, are involved in both muscle growth after birth and regeneration after damage. It has been previously proposed that, under these circumstances, satellite cells first become activated, divide and differentiate, and only later fuse to the existing myofiber through M-cadherin mediated intercellular interactions. Our data show that satellite cells fuse with the myofiber concomitantly to cell division, and only when the nuclei of the daughter cells are inside the myofiber, do they complete the process of differentiation. Here we demonstrate that M-cadherin plays an important role in cell-to-cell recognition and fusion, and is crucial for cell division activation. Treatment of satellite cells with M-cadherin in vitro stimulates cell division, whereas addition of anti-M-cadherin antibodies reduces the cell division rate. Our results suggest an alternative model for the contribution of satellite cells to muscle development, which might be useful in understanding muscle regeneration, as well as muscle-related dystrophies. PMID- 24046444 TI - The Mos-MAPK pathway regulates Diaphanous-related formin activity to drive cleavage furrow closure during polar body extrusion in starfish oocytes. AB - Maintenance of spindle attachment to the cortex and formation of the cleavage furrow around the protruded spindle are essential for polar body extrusion (PBE) during meiotic maturation of oocytes. Although spindle movement to the cortex has been well-studied, how the spindle is maintained at the cortex during PBE is unknown. Here, we show that activation of Diaphanous-related formin mediated by mitogen-activated protein kinase (MAPK) is required for tight spindle attachment to the cortex and cleavage furrow closure during PBE in starfish (Asterina pectinifera) oocytes. A. pectinifera Diaphanous-related formin (ApDia) had a distinct localization in immature oocytes and was localized to the cleavage furrow during PBE. Inhibition of the Mos-MAPK pathway or the actin nucleating activity of formin homology 2 domain prevented cleavage furrow closure and resulted in PBE failure. In MEK/MAPK-inhibited oocytes, activation of ApDia by relief of its intramolecular inhibition restored PBE. In summary, this study elucidates a link between the Mos-MAPK pathway and Diaphanous-related formins, that is responsible for maintaining tight spindle attachment to the cortex and cleavage furrow closure during PBE. PMID- 24046445 TI - A new kind of membrane-tethered eukaryotic transcription factor that shares an auto-proteolytic processing mechanism with bacteriophage tail-spike proteins. AB - MrfA, a transcription factor that regulates Dictyostelium prestalk cell differentiation, is an orthologue of the metazoan myelin gene regulatory factor (MRF) proteins. We show that the MRFs contain a predicted transmembrane domain, suggesting that they are synthesised as membrane-tethered proteins that are then proteolytically released. We confirm this for MrfA but report a radically different mode of processing from that of paradigmatic tethered transcriptional regulators, which are cleaved within the transmembrane domain by a dedicated protease. Instead, an auto-proteolytic cleavage mechanism, previously only described for the intramolecular chaperone domains of bacteriophage tail-spike proteins, processes MrfA and, by implication, the metazoan MRF proteins. We also present evidence that the auto-proteolysis of MrfA occurs rapidly and constitutively in the ER and that its specific role in prestalk cell differentiation is conferred by the regulated nuclear translocation of the liberated fragment. PMID- 24046446 TI - Hepatic biliary epithelial cells acquire epithelial integrity but lose plasticity to differentiate into hepatocytes in vitro during development. AB - In developing organs, epithelial tissue structures are mostly developed by the perinatal period. However, it is unknown whether epithelial cells are already functionally mature and whether they are fixed in their lineage. Here we show that epithelial cells alter their plasticity during postnatal development by examining the differentiation potential of epithelial cell adhesion molecule (EpCAM)(+) cholangiocytes (biliary epithelial cells) isolated from neonatal and adult mouse livers. We found that neonatal cholangiocytes isolated from 1-week old liver converted into functional hepatocytes in the presence of oncostatin M and Matrigel(r). In contrast, neither morphological changes nor expression of hepatocyte markers were induced in adult cholangiocytes. The transcription factors hepatocyte nuclear factor 4alpha and CCAAT/enhancer binding protein alpha (C/EBPalpha), which are necessary for hepatocytic differentiation, were induced in neonatal cholangiocytes but not in adult cells, whereas grainyhead-like 2 (Grhl2) and hairy-enhance of slit 1 (Hes1), which are implicated in cholangiocyte differentiation, were continuously expressed in adult cells. Overexpression of C/EBPalpha and Grhl2 promoted and inhibited hepatocytic differentiation, respectively. Furthermore, adult cholangiocytes formed a monolayer with higher barrier function than neonatal ones did, suggesting that cholangiocytes are still in the process of epithelial maturation even after forming tubular structures during the neonatal period. Taken together, these results suggest that cholangiocytes lose plasticity to convert into hepatocytes during epithelial maturation. They lose competency to upregulate hepatocytic transcription factors and downregulate cholagiocytic ones under conditions inducing hepatocytic differentiation. Our results suggest that a molecular machinery augmenting epithelial integrity limits lineage plasticity of epithelial cells. PMID- 24046447 TI - eNOS-derived nitric oxide regulates endothelial barrier function through VE cadherin and Rho GTPases. AB - Transient disruption of endothelial adherens junctions and cytoskeletal remodeling are responsible for increases in vascular permeability induced by inflammatory stimuli and vascular endothelial growth factor (VEGF). Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is crucial for VEGF-induced changes in permeability in vivo; however, the molecular mechanism by which endogenous NO modulates endothelial permeability is not clear. Here, we show that the lack of eNOS reduces VEGF-induced permeability, an effect mediated by enhanced activation of the Rac GTPase and stabilization of cortical actin. The loss of NO increased the recruitment of the Rac guanine-nucleotide-exchange factor (GEF) TIAM1 to adherens junctions and VE-cadherin (also known as cadherin 5), and reduced Rho activation and stress fiber formation. In addition, NO deficiency reduced VEGF-induced VE-cadherin phosphorylation and impaired the localization, but not the activation, of c-Src to cell junctions. The physiological role of eNOS activation is clear given that VEGF-, histamine- and inflammation-induced vascular permeability is reduced in mice bearing a non phosphorylatable knock-in mutation of the key eNOS phosphorylation site S1176. Thus, NO is crucial for Rho GTPase-dependent regulation of cytoskeletal architecture leading to reversible changes in vascular permeability. PMID- 24046448 TI - A role for the Golgi matrix protein giantin in ciliogenesis through control of the localization of dynein-2. AB - The correct formation of primary cilia is central to the development and function of nearly all cells and tissues. Cilia grow from the mother centriole by extension of a microtubule core, the axoneme, which is then surrounded with a specialized ciliary membrane that is continuous with the plasma membrane. Intraflagellar transport moves particles along the length of the axoneme to direct assembly of the cilium and is also required for proper cilia function. The microtubule motor, cytoplasmic dynein-2 mediates retrograde transport along the axoneme from the tip to the base; dynein-2 is also required for some aspects of cilia formation. In most cells, the Golgi lies adjacent to the centrioles and key components of the cilia machinery localize to this organelle. Golgi-localized proteins have also been implicated in ciliogenesis and in intraflagellar transport. Here, we show that the transmembrane Golgi matrix protein giantin (GOLGB1) is required for ciliogenesis. We show that giantin is not required for the Rab11-Rabin8-Rab8 pathway that has been implicated in the early stages of ciliary membrane formation. Instead we find that suppression of giantin results in mis-localization of WDR34, the intermediate chain of dynein-2. Highly effective depletion of giantin or WDR34 leads to an inability of cells to form primary cilia. Partial depletion of giantin or of WDR34 leads to an increase in cilia length consistent with the concept that giantin acts through dynein-2. Our data implicate giantin in ciliogenesis through control of dynein-2 localization. PMID- 24046449 TI - Dynamin triple knockout cells reveal off target effects of commonly used dynamin inhibitors. AB - Dynamin, which is encoded by three genes in mammals, is a GTPase implicated in endocytic membrane fission. Dynamin 1 and 3 are predominantly expressed in brain, whereas dynamin 2 is ubiquitously expressed. With the goal of assessing the impact of the lack of dynamin on cell physiology, we previously generated and characterized dynamin 1 and 2 double knockout (DKO) fibroblasts. These DKO cells were unexpectedly viable in spite of a severe impairment of clathrin-mediated endocytosis. As low-level expression of the dynamin 3 gene in these cells could not be excluded, we have now engineered dynamin 1, 2 and 3 triple KO (TKO) fibroblasts. These cells did not reveal any additional defects beyond what was previously observed in DKO fibroblasts. Surprisingly, although fluid-phase endocytosis and peripheral membrane ruffling were not impaired by the lack of all three dynamins, two structurally similar, widely used dynamin inhibitors, dynasore and Dyngo-4a, robustly inhibited these two processes both in wild-type and TKO cells. Dynamin TKO cells will be useful tools for the further exploration of dynamin-dependent processes and the development of more specific dynamin inhibitors. PMID- 24046450 TI - The nebulin SH3 domain is dispensable for normal skeletal muscle structure but is required for effective active load bearing in mouse. AB - Nemaline myopathy (NM) is a congenital myopathy with an estimated incidence of 150,000 live births. It is caused by mutations in thin filament components, including nebulin, which accounts for about 50% of the cases. The identification of NM cases with nonsense mutations resulting in loss of the extreme C-terminal SH3 domain of nebulin suggests an important role of the nebulin SH3 domain, which is further supported by the recent demonstration of its role in IGF-1-induced sarcomeric actin filament formation through targeting of N-WASP to the Z-line. To provide further insights into the functional significance of the nebulin SH3 domain in the Z-disk and to understand the mechanisms by which truncations of nebulin lead to NM, we took two approaches: (1) an affinity-based proteomic screening to identify novel interaction partners of the nebulin SH3 domain; and (2) generation and characterization of a novel knockin mouse model with a premature stop codon in the nebulin gene, eliminating its C-terminal SH3 domain (NebDeltaSH3 mouse). Surprisingly, detailed analyses of NebDeltaSH3 mice revealed no structural or histological skeletal muscle abnormalities and no changes in gene expression or localization of interaction partners of the nebulin SH3 domain, including myopalladin, palladin, zyxin and N-WASP. Also, no significant effect on peak isometric stress production, passive tensile stress or Young's modulus was found. However, NebDeltaSH3 muscle displayed a slightly altered force frequency relationship and was significantly more susceptible to eccentric contraction-induced injury, suggesting that the nebulin SH3 domain protects against eccentric contraction-induced injury and possibly plays a role in fine tuning the excitation-contraction coupling mechanism. PMID- 24046452 TI - Activation of the SUMO modification system is required for the accumulation of RAD51 at sites of DNA damage. AB - Genetic information encoded in chromosomal DNA is challenged by intrinsic and exogenous sources of DNA damage. DNA double-strand breaks (DSBs) are extremely dangerous DNA lesions. RAD51 plays a central role in homologous DSB repair, by facilitating the recombination of damaged DNA with intact DNA in eukaryotes. RAD51 accumulates at sites containing DNA damage to form nuclear foci. However, the mechanism of RAD51 accumulation at sites of DNA damage is still unclear. Post translational modifications of proteins, such as phosphorylation, acetylation and ubiquitylation play a role in the regulation of protein localization and dynamics. Recently, the covalent binding of small ubiquitin-like modifier (SUMO) proteins to target proteins, termed SUMOylation, at sites containing DNA damage has been shown to play a role in the regulation of the DNA-damage response. Here, we show that the SUMOylation E2 ligase UBC9, and E3 ligases PIAS1 and PIAS4, are required for RAD51 accretion at sites containing DNA damage in human cells. Moreover, we identified a SUMO-interacting motif (SIM) in RAD51, which is necessary for accumulation of RAD51 at sites of DNA damage. These findings suggest that the SUMO-SIM system plays an important role in DNA repair, through the regulation of RAD51 dynamics. PMID- 24046451 TI - Drosophila importin-7 functions upstream of the Elmo signaling module to mediate the formation and stability of muscle attachments. AB - Establishment and maintenance of stable muscle attachments is essential for coordinated body movement. Studies in Drosophila have pioneered a molecular understanding of the morphological events in the conserved process of muscle attachment formation, including myofiber migration, muscle-tendon signaling, and stable junctional adhesion between muscle cells and their corresponding target insertion sites. In both Drosophila and vertebrate models, integrin complexes play a key role in the biogenesis and stability of muscle attachments through the interactions of integrins with extracellular matrix (ECM) ligands. We show that Drosophila importin-7 (Dim7) is an upstream regulator of the conserved Elmo-Mbc >Rac signaling pathway in the formation of embryonic muscle attachment sites (MASs). Dim7 is encoded by the moleskin (msk) locus and was identified as an Elmo interacting protein. Both Dim7 and Elmo localize to the ends of myofibers coincident with the timing of muscle-tendon attachment in late myogenesis. Phenotypic analysis of elmo mutants reveal muscle attachment defects similar to those previously described for integrin mutants. Furthermore, Elmo and Dim7 interact both biochemically and genetically in the developing musculature. The muscle detachment phenotype resulting from mutations in the msk locus can be rescued by components in the Elmo signaling pathway, including the Elmo-Mbc complex, an activated Elmo variant, or a constitutively active form of Rac. In larval muscles, the localization of Dim7 and activated Elmo to the sites of muscle attachment is attenuated upon RNAi knockdown of integrin heterodimer complex components. Our results show that integrins function as upstream signals to mediate Dim7-Elmo enrichment to the MASs. PMID- 24046453 TI - Sox4-mediated caldesmon expression facilitates differentiation of skeletal myoblasts. AB - Caldesmon (CaD), which was originally identified as an actin-regulatory protein, is involved in the regulation of diverse actin-related signaling processes, including cell migration and proliferation, in various cells. The cellular function of CaD has been studied primarily in the smooth muscle system; nothing is known about its function in skeletal muscle differentiation. In this study, we found that the expression of CaD gradually increased as differentiation of C2C12 myoblasts progressed. Silencing of CaD inhibited cell spreading and migration, resulting in a decrease in myoblast differentiation. Promoter analysis of the caldesmon gene (Cald1) and gel mobility shift assays identified Sox4 as a major trans-acting factor for the regulation of Cald1 expression during myoblast differentiation. Silencing of Sox4 decreased not only CaD protein synthesis but also myoblast fusion in C2C12 cells and myofibril formation in mouse embryonic muscle. Overexpression of CaD in Sox4-silenced C2C12 cells rescued the differentiation process. These results clearly demonstrate that CaD, regulated by Sox4 transcriptional activity, contributes to skeletal muscle differentiation. PMID- 24046454 TI - Osteoblast-specific expression of Fra-2/AP-1 controls adiponectin and osteocalcin expression and affects metabolism. AB - Recent studies have established that the skeleton functions as an endocrine organ affecting metabolism through the osteoblast-derived hormone osteocalcin (Ocn). However, it is not fully understood how many transcription factors expressed in osteoblasts regulate the endocrine function. Here, we show that mice with osteoblast-specific deletion of Fra-2 (Fosl2) have low bone mass but increased body weight. In contrast, transgenic expression of Fra-2 in osteoblasts leads to increased bone mass and decreased body weight accompanied by reduced serum glucose and insulin levels, improved glucose tolerance and insulin sensitivity. In addition, mice lacking Fra-2 have reduced levels of circulating Ocn, but high adiponectin (Adipoq), whereas Fra-2 transgenic mice exhibit high Ocn and low Adipoq levels. Moreover, we found that Adipoq was expressed in osteoblasts and that this expression was transcriptionally repressed by Fra-2. These results demonstrate that Fra-2 expression in osteoblasts represents a novel paradigm for a transcription factor controlling the endocrine function of the skeleton. PMID- 24046456 TI - Flotillin microdomains stabilize cadherins at cell-cell junctions. AB - Cadherins are essential in many fundamental processes and assemble at regions of cell-cell contact in large macromolecular complexes named adherens junctions. We have identified flotillin 1 and 2 as new partners of the cadherin complexes. We show that flotillins are localised at cell-cell junctions (CCJs) in a cadherin dependent manner. Flotillins and cadherins are constitutively associated at the plasma membrane and their colocalisation at CCJ increases with CCJ maturation. Using three-dimensional structured illumination super-resolution microscopy, we found that cadherin and flotillin complexes are associated with F-actin bundles at CCJs. The knockdown of flotillins dramatically affected N- and E-cadherin recruitment at CCJs in mesenchymal and epithelial cell types and perturbed CCJ integrity and functionality. Moreover, we determined that flotillins are required for cadherin association with GM1-containing plasma membrane microdomains. This allows p120 catenin binding to the cadherin complex and its stabilization at CCJs. Altogether, these data demonstrate that flotillin microdomains are required for cadherin stabilization at CCJs and for the formation of functional CCJs. PMID- 24046455 TI - A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation. AB - The angiotensin type 1 receptor (AT1R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, however, the molecular mechanisms involved have not yet been resolved. To address this, we performed a functional siRNA screen of the human kinome in human mammary epithelial cells that demonstrate a robust AT1R-EGFR transactivation. We identified a suite of genes encoding proteins that both positively and negatively regulate AT1R-EGFR transactivation. Many candidates are components of EGFR signalling networks, whereas others, including TRIO, BMX and CHKA, have not been previously linked to EGFR transactivation. Individual knockdown of TRIO, BMX or CHKA attenuated tyrosine phosphorylation of the EGFR by angiotensin II stimulation, but this did not occur following direct stimulation of the EGFR with EGF, indicating that these proteins function between the activated AT1R and the EGFR. Further investigation of TRIO and CHKA revealed that their activity is likely to be required for AT1R-EGFR transactivation. CHKA also mediated EGFR transactivation in response to another G protein-coupled receptor (GPCR) ligand, thrombin, indicating a pervasive role for CHKA in GPCR-EGFR crosstalk. Our study reveals the power of unbiased, functional genomic screens to identify new signalling mediators important for tissue remodelling in cardiovascular disease and cancer. PMID- 24046458 TI - Ventilatory response to carbon dioxide output in subjects with congestive heart failure and in patients with COPD with comparable exercise capacity. AB - BACKGROUND: Patients with congestive heart failure or COPD may share an increased response in minute ventilation (VE) to carbon dioxide output (VCO2 ) during exercise. The goal of this study was to ascertain whether the VE/VCO2 slope and VE/VCO2 intercept can discriminate between subjects with congestive heart failure and those with COPD at equal peak oxygen uptake (VO2 ). METHODS: We studied 46 subjects with congestive heart failure (mean age 61 +/- 9 y) and 46 subjects with COPD (mean age 64 +/- 8 y) who performed a cardiopulmonary exercise test. RESULTS: The VE/VCO2 slope was significantly higher in subjects with congestive heart failure compared with those with COPD (39.5 +/- 9.5 vs 31.8 +/- 7.4, P < .01) at peak VO2 < 16 mL/kg/min, but not >= 16 mL/kg/min (28.3 +/- 5.3 vs 28.9 +/ 6.6). The VE/VCO2 intercept was significantly higher in both subgroups of subjects with COPD compared with the corresponding values in the subjects with congestive heart failure (3.60 +/- 1.7 vs -0.16 +/- 1.7 L/min, P < .01; 3.63 +/- 2.7 vs 0.87 +/- 1.5 L/min, P < .01). According to receiver operating characteristic curve analysis, when all subjects with peak VO2 < 16 mL/kg/min were considered, subjects with COPD had a higher likelihood to have the VE/VCO2 intercept > 2.14 L/min (0.92 sensitivity, 0.96 specificity). Regardless of peak VO2 , the end-tidal pressure of CO2 (PETCO2 ) at peak exercise was not different in subjects with congestive heart failure (P = .42) and was significantly higher in subjects with COPD (P < .01) compared with the corresponding unloaded PETCO2 . CONCLUSIONS: The ventilatory response to VCO2 during exercise was significantly different between subjects with congestive heart failure and those with COPD in terms of the VE/VCO2 slope with moderate-to-severe reduction in exercise capacity and in terms of the VE/VCO2 intercept regardless of exercise capacity. PMID- 24046459 TI - Laboratory evaluation of four different devices for secretion mobilization: Acapella choice, green and blue versus water bottle. AB - BACKGROUND: Secretion removal is a key issue in patients with respiratory diseases, and is known to be most effective at vibration frequencies of ~ 13 Hz and with the greatest amplitudes possible. The Acapella devices and the water bottle are used for secretion removal in daily clinical practice but without detailed knowledge on optimal settings. The aim of this study was to evaluate the 3 different Acapella devices and the water bottle at various settings and flows to determine the optimal devices and settings for effective secretion removal. METHODS: Three different Acapella devices were tested at flows of 6, 12, 20, 30, 40, and 50 L/min, and at all 5 settings. The water bottle was filled with 5, 10, or 15 cm of water, and tested at flows of 3, 6, 10, 12, and 20 L/min. For all devices and combinations of settings, we measured the frequency and amplitude of the vibrations, as well as the required pressure to generate vibrations. RESULTS: Setting 4 was the best for all 3 Acapella devices, and the filling height of the water bottle should be 5 cm. At these settings, all devices elicited vibration frequencies between 12 and 15 Hz, which is theoretically optimal for secretion mobilization. The resistance pressures of the devices to elicit these vibrations were between 5 and 11 cm H2O. However, the Acapella devices elicit higher vibration amplitudes (5-8 cm H2O) than the water bottle (1.8 cm H2O) CONCLUSIONS:: Setting 4 was optimal for all 3 Acapella devices. The Acapella devices may be more efficient for secretion mobilization than the water bottle, because they elicit greater amplitude of vibrations. PMID- 24046460 TI - Computerized adventitious respiratory sounds as outcome measures for respiratory therapy: a systematic review. AB - INTRODUCTION: There is a need to develop simple, noninvasive, and sensitive outcome measures for respiratory therapy. Adventitious respiratory sounds (ie, crackles and wheezes) can be objectively characterized with computerized respiratory sound analysis (CORSA) and have been shown to contribute for diagnosis purposes; however, their potential for use as outcome measures is unknown. Thus, this systematic review synthesizes the evidence on the use of computerized adventitious respiratory sounds as outcome measures. METHODS: The Web of Knowledge, MEDLINE, EMBASE, and SCOPUS databases were searched. Reviewers independently selected studies according to the eligibility criteria. Effect sizes and 95% CIs were computed. RESULTS: Twelve studies with different designs (observational, n = 3; quasi-experimental n = 7; and randomized controlled trial, n = 2) were included. Eight studies were conducted with adults, and 4 studies with children. Most studies explored only one type of adventitious respiratory sound. For wheezes, the occupation rate seemed to be the most promising parameter to be used as an outcome measure, with high/medium effect sizes (0.62-1.82). For crackles, the largest deflection width showed high effect sizes (1.31 and 1.04); however, this was explored in only one study. Crackle number and 2-cycle duration presented conflicting information, with high/poor effect sizes depending on the study. CONCLUSIONS: Specific variables of each adventitious respiratory sound detected and characterized by CORSA showed high effect sizes and, thus, the potential to be used as outcome measures. Further research with robust study designs and larger samples (both of children and adult populations), and following CORSA guidelines is needed to build evidence-based knowledge on this topic. PMID- 24046461 TI - Reproducibility of cadence-free 6-minute step test in subjects with COPD. AB - BACKGROUND: Six-minute step test (6MST) has been used to assess functional capacity in chronic conditions; however, its reproducibility in the COPD population has not been evaluated. Our study objective was to evaluate 6MST reproducibility. METHODS: The test was performed in a single 20-cm height step, and subjects were instructed to step up and down (cadence-free) for 6 min. Subjects underwent three tests. The first and second were controlled by the same assessor with a 30-min interval. The third test was controlled by a different assessor one week later. For intra-rater comparison, the first and second performances of the test were used, and for inter-assessor comparison, the better performance of the first two tests was compared with the third test. RESULTS: Excellent intra-rater and inter-rater relative reproducibility was observed (intraclass correlation coefficient > 0.8), and there was no statistical difference (repeated measures of analysis of variance) among the performances of the three tests. Intra-rater error values were acceptable (mean error of 5.7 steps and limits of agreement between -7 and 18 steps). Inter-rater error values were not acceptable (mean error of 4.4 steps and limits of agreement between -20 and 29 steps. CONCLUSIONS: 6MST proved to be reproducible in the COPD population when performed by the same assessor. PMID- 24046462 TI - High-flow nasal cannula versus conventional oxygen therapy after endotracheal extubation: a randomized crossover physiologic study. AB - OBJECTIVE: Compare the short-term benefit of high-flow nasal cannula (HFNC) with non-rebreathing mask in terms of change in dyspnea, physiologic variables, and patient comfort in subjects after endotracheal extubation. METHODS: A randomized crossover study was conducted in a 10-bed respiratory care unit in a university hospital. Seventeen mechanically ventilated subjects were randomized after extubation to either Protocol A (applied HFNC for 30 min, followed by non rebreathing mask for another 30 min) or Protocol B (applied non-rebreathing mask for 30 min, followed by HFNC for another 30 min). The level of dyspnea, breathing frequency, heart rate, blood pressure, oxygen saturation, and patient comfort were recorded. The results were expressed as mean +/- SD, frequency, or percentage. Categorical variables were compared by chi-square test or Fisher exact test, and continuous variables were compared by dependent or paired t test. Statistical significance was defined as P < .05. RESULTS: Seventeen subjects were divided into 2 groups: 9 subjects in Protocol A and 8 subjects in Protocol B. The baseline characteristics and physiologic parameters before extubation were not significantly different in each protocol. At the end of study, HFNC indicated less dyspnea (P = .04) and lower breathing frequency (P = .009) and heart rate (P = .006) compared with non-rebreathing mask. Most of the subjects (88.2%) preferred HFNC to non-rebreathing mask. CONCLUSIONS: HFNC can improve dyspnea and physiologic parameters, including breathing frequency and heart rate, in extubated subjects compared with conventional oxygen therapy. This device may have a potential role for use after endotracheal extubation. PMID- 24046463 TI - Prevalence of supranormal pulmonary function test values between a military and nonmilitary cohort. AB - BACKGROUND: The study objective was to determine differences in the proportion of supranormal pulmonary function tests (PFTs) between active duty (AD) military personnel and a similar non-active duty (non-AD) population. Given the emphasis on cardiovascular fitness in the military, it has been hypothesized that regular exercise in this cohort leads to an increased proportion of supranormal PFTs. We hypothesized that a comparison of PFTs would identify no differences in the ratio of supranormal to normal PFTs between the AD and non-AD populations. METHODS: A retrospective chart review was conducted of all PFT studies at the Brooke Army Medical Center from 2006 to 2011. Studies were included with either an FVC or FEV1 > 110% of predicted, with both values > 100% of predicted. A comparative analysis was performed for patients between 18 and 50 years of age based on AD status. Further analysis was performed on all ages to determine the distribution of supranormal findings in the entire study population. RESULTS: A total of 16,600 interpreted PFTs were queried. Of those, 4,303 (31.6%) were AD patients, and 9,306 (68.4%) were non-AD patients. From all of the PFTs reviewed, a total of 912 (6.7%) were identified as supranormal. When further analyzed, 381 (9.4%) of AD patients 18-50 years old were supranormal, 175 (12.4%) of non-AD patients 18 50 years old were supranormal, and 356 (4.7%) of non-AD patients older than 50 years were supranormal. CONCLUSIONS: This study revealed no significant difference in the proportion of supranormal-to-normal PFTs in an AD versus non-AD duty population of the same age range. Based on these findings, no assumption should be made that supranormal PFTs are more common in military personnel. Interpretation of normal PFTs in AD personnel undergoing evaluation should not differ from that in any typical patient. PMID- 24046464 TI - Corticosteroid therapy for severe community-acquired pneumonia: a meta-analysis. AB - BACKGROUND: The debate about the efficacy of corticosteroids in the treatment of severe community-acquired pneumonia (CAP) is still a longstanding dilemma. We performed a meta-analysis including 4 randomized controlled trials (RCTs) to evaluate the effect of corticosteroids on the treatment of severe CAP in adults. METHODS: We performed a systematic review of published and unpublished clinical trials. Databases, including PubMed, Embase, CINAHL, and Cochrane (from their establishment to July 2013), were searched for relevant articles. Only RCTs of corticosteroids as adjunctive therapy in adult patients with severe CAP were selected. RESULTS: Four trials enrolling 264 patients with severe CAP were included. Use of corticosteroids significantly reduced hospital mortality compared with conventional therapy and placebo (Peto odds ratio = 0.39, 95% CI 0.17-0.90). The quality of the evidence underlying the pooled estimate of effect on hospital mortality was low, downgraded for inconsistency and imprecision. CONCLUSIONS: On the basis of the current limited evidence, we suggest that, although corticosteroid therapy may reduce mortality and improve the prognosis of adult patients with severe CAP, the results should be interpreted with caution due to the instability of pooled estimates. Reliable treatment recommendations will be raised only when large sufficiently powered multi-center RCTs are conducted. PMID- 24046465 TI - Management of the first confirmed case of avian influenza A H7N9. AB - In March 2013, the first patient infected with the avian influenza A H7N9 virus was identified in China. The infection progressed rapidly, and the patient died of ARDS. During hospitalization, the patient was suspected of having an infectious respiratory disease, and contingency plans for public health emergencies were promptly started. When the viral infection was identified, strict procedures for disinfection and protection were carried out. None of the health care workers involved in the management of the patient were infected. PMID- 24046466 TI - Lung volume changes during cleaning of closed endotracheal suction catheters: a randomized crossover study using electrical impedance tomography. AB - BACKGROUND: Airway suctioning in mechanically ventilated patients is required to maintain airway patency. Closed suction catheters (CSCs) minimize lung volume loss during suctioning but require cleaning post-suction. Despite their widespread use, there is no published evidence examining lung volumes during CSC cleaning. The study objectives were to quantify lung volume changes during CSC cleaning and to determine whether these changes were preventable using a CSC with a valve in situ between the airway and catheter cleaning chamber. METHODS: This prospective randomized crossover study was conducted in a metropolitan tertiary ICU. Ten patients mechanically ventilated via volume-controlled synchronized intermittent mandatory ventilation (SIMV-VC) and requiring manual hyperinflation (MHI) were included in this study. CSC cleaning was performed using 2 different brands of CSC (one with a valve [Ballard Trach Care 72, Kimberly-Clark, Roswell, Georgia] and one without [Portex Steri-Cath DL, Smiths Medical, Dublin, Ohio]). The maneuvers were performed during both SIMV-VC and MHI. Lung volume change was measured via impedance change using electrical impedance tomography. A mixed model was used to compare the estimated means. RESULTS: During cleaning of the valveless CSC, significant decreases in lung impedance occurred during MHI (-2563 impedance units, 95% CI 2213-2913, P < .001), and significant increases in lung impedance occurred during SIMV (762 impedance units, 95% CI 452-1072, P < .001). In contrast, cleaning of the CSC with a valve in situ resulted in non-significant lung volume changes and maintenance of normal ventilation during MHI and SIMV-VC, respectively (188 impedance units, 95% CI -136 to 511, P = .22; and 22 impedance units, 95% CI -342 to 299, P = .89). CONCLUSIONS: When there is no valve between the airway and suction catheter, cleaning of the CSC results in significant derangements in lung volume. Therefore, the presence of such a valve should be considered essential in preserving lung volumes and uninterrupted ventilation in mechanically ventilated patients. PMID- 24046467 TI - Protective effect of an ERAP1 haplotype in ankylosing spondylitis: investigating non-MHC genes in HLA-B27-positive individuals. AB - OBJECTIVE: The association of non-MHC genes with AS has been recently suggested. We aimed to investigate the association of the ERAP1, IL23R and TNFSF15 regions and the susceptibility to and protection from AS in HLA-B27-positive individuals. METHODS: A total of 200 unrelated AS patients and 559 healthy unrelated subjects, all HLA-B27 positive, were tested. Twenty single nucleotide polymorphisms (SNPs) were investigated in and near IL23R (nine SNPs), in ERAP1 (five SNPs) and in TNFSF15 (six SNPs). RESULTS: ERAP1 rs30187 [odds ratio (OR) = 1.5, P = 4.7 * 10( 3)] had the strongest association with AS susceptibility. A protective effect was found in three of the ERAP1 SNPs: rs17482078 (OR = 0.7, P = 2.8 * 10(-2)), rs10050860 (OR = 0.7, P = 2.3 * 10(-2)), rs2287987 (OR = 0.6, P = 1.3 * 10(-2)). The ERAP1 haplotype rs17482078/rs10050860/rs30187/rs2287987-CCTT showed an association with AS susceptibility (P = 6.8 * 10(-3)) and a protective effect was identified in rs17482078/rs10050860/rs30187/rs2287987-TTCC (P = 3.1 * 10(-2)). Significant association with AS susceptibility was found in one IL23R marker (rs1004819, P = 4.3 * 10(-2), OR = 1.3). No associations were observed in the TNFSF15 region. CONCLUSION: The identification of a new protection haplotype in ERAP1 and the lack of association of the TNFSF15 region can provide new insights into the understanding of the mechanisms underlying the susceptibility to and protection from AS. PMID- 24046468 TI - Patient self-assessment and physician's assessment of rheumatoid arthritis activity: which is more realistic in remission status? A comparison with ultrasonography. AB - OBJECTIVE: The objective of this study was to compare disease activity assessed by the patient, the physician and musculoskeletal US in patients with RA in clinical remission. METHODS: We evaluated 69 patients with RA in clinical remission according to their attending rheumatologist. Tenderness and swelling in 28 joints were blindly assessed by patients and physicians. The presence of B mode and Doppler synovitis was blindly investigated in the above joints. The DAS28 and Simplified Disease Activity Index (SDAI) were calculated. RESULTS: The percentage of patients in remission according to the self-derived DAS28 (26.1%) was significantly less than that according to the physician-derived DAS28 (52.2%) (P < 0.0005). There was no significant difference in the percentage of patients in remission according to the self-derived SDAI (14.5%) and the physician-derived SDAI (11.6%) (P = 0.172). We found moderate agreement between the patient-derived and physician-derived DAS28 and SDAI [intraclass correlation coefficient (ICC) = 0.620 and ICC = 0.678, respectively]. Agreement between patient and physician was better for the tender joint count (TJC; ICC = 0.509) than for the swollen joint count (SJC; ICC = 0.279). The mean (S.D.) count for B-mode synovitis [4.09 (3.25)] was significantly greater than the SJC assessed by both the patient and physician [2 (3.71) and 1.42 (2.03), respectively] (P < 0.0005 and P = 0.033, respectively). We found moderate agreement between the physician-assessed SJC and the joint count for Doppler synovitis (ICC = 0.528). CONCLUSION: Patient-assessed and physician-assessed overall RA activity showed acceptable agreement. Patient self-assessment overestimated disease activity determined by the DAS28. At the patient level, physician-assessed joint swelling showed an acceptable concordance with Doppler US synovitis. PMID- 24046469 TI - Gout as a risk factor for myocardial infarction and stroke in England: evidence from record linkage studies. AB - OBJECTIVE: Some studies suggest that gout is a risk factor for cardiovascular disease. There is more evidence about the association between gout and acute myocardial infarction (MI) than about gout and stroke, and only limited information about risks by age group and sex. We aimed to study MI and stroke following gout, including types of stroke, by age group and comparing men and women. METHODS: We analysed an all-England national linked dataset of hospital admissions and death records from 1999 to 2011, and a similar dataset in the Oxford Record Linkage Study spanning 1963-98. The occurrence of MI and stroke was estimated in cohorts of patients admitted to hospital with gout, compared with MI and stroke in control cohorts, and the comparisons were expressed as rate ratios (RRs). RESULTS: The risk of MI and stroke was elevated, and similar, in both datasets. In the all-England dataset, which included 202 033 hospital patients with gout, the RR for MI following gout was 1.82 (95% CI 1.78, 1.85), for all stroke 1.71 (1.68, 1.75), ischaemic stroke 1.68 (1.64, 1.73), haemorrhagic stroke 1.69 (1.61, 1.77) and stroke of unspecified type 2.00 (1.95, 2.06). Associations were stronger in younger than older age groups, and in the younger were stronger in women than men. CONCLUSION: Gout was associated with increased risk of stroke as well as MI. These findings should be considered by clinicians and may have implications for preventive management of circulatory disease risks in people with gout. PMID- 24046470 TI - Comparison of clinical burden between patients with erosive hand osteoarthritis and inflammatory arthritis in symptomatic community-dwelling adults: the Keele clinical assessment studies. AB - OBJECTIVE: To investigate in the general population the clinical impact of erosive OA in interphalangeal joints (IPJs) compared with symptomatic radiographic hand OA and inflammatory arthritis. METHODS: Standardized assessments with hand radiographs were performed in participants of two population-based cohorts in North Staffordshire with hand symptoms lasting >=1 day in the past month. Erosive OA was defined as the presence of an eroded or remodelled phase in >=1 IPJ using the Verbruggen-Veys method. Radiographic hand OA was defined as the presence of >=1 IPJ/first carpometacarpal joint with a Kellgren-Lawrence score of >=2. Diagnoses of inflammatory arthritis were based on medical records. Hand pain and disability were assessed with the Australian/Canadian Hand Osteoarthritis Index (AUSCAN). Linear regression analyses were used to compare clinical determinants between groups and calculate mean differences with 95% CIs, adjusted for age and sex. RESULTS: Of 1076 participants with hand symptoms [60% women, mean age 64.8 years (s.d. 8.3 years)]; 80 persons (7.4%) had erosive OA. The population prevalence of erosive OA in >=1 IPJ was 2.4% (95% CI 1.8, 3.0). Persons with erosive OA reported more pain and disability than persons with symptomatic radiographic hand OA [adjusted mean difference 1.3 (95% CI 0.3, 2.3) and 2.3 (95% CI 0.4, 4.2), respectively]. Individuals with inflammatory arthritis (n = 44) reported more pain and disability than those with erosive OA [adjusted mean difference 1.7 (95% CI 0.05, 3.4) and 6.3 (95% CI 2.8, 9.9), respectively]. CONCLUSION: While erosive OA has a greater impact than symptomatic radiographic hand OA in the general population, it is not as severe in terms of hand pain and disability as inflammatory RA. PMID- 24046471 TI - Comparison between colour duplex sonography findings and different histological patterns of temporal artery. AB - OBJECTIVE: To assess the findings of temporal artery colour duplex sonography (CDS) in GCA characterized by a histological pattern of periadventitial small vessel vasculitis (SVV) and/or vasa vasorum vasculitis (VVV) and compare it with those observed in classic GCA with transmural vasculitis. METHODS: We studied 30 patients with SVV and/or VVV, 63 patients with classic GCA and 67 biopsy-negative patients identified over a 9-year period. CDS of the temporal arteries was performed in all patients by one ultrasonographer. Temporal artery biopsy was used as the reference standard. Sensitivities, specificities and likelihood ratios (LRs) were calculated. RESULTS: The frequency of the halo sign on CDS was significantly lower in the patients with SVV and/or VVV compared with those with classic GCA (20% vs 82.5%, P = 0.0001). The halo sign had a sensitivity of only 20% (95% CI 8.4, 39.1%) and a specificity of 80.6% (95% CI 68.7, 88.9%) for the diagnosis of SVV and/or VVV. The negative LR was 0.992 (CI 0.824, 1.195), and the positive LR was 1.030 (CI 0.433, 2.451). The halo sign for the diagnosis of biopsy-proven classic GCA had a higher sensitivity of 82.5% (CI 70.5, 90.5%), the same specificity of 80.6% (CI 68.7, 88.9%) and a higher positive LR (4.253; CI 2.577, 7.021). CONCLUSION: The halo sign is infrequently found in GCA characterized by a histological pattern of SVV and/or VVV. This limits the sensitivity of CDS in correctly identifying patients with GCA. PMID- 24046472 TI - Laser Doppler imaging for assessment of microcirculation in juvenile systemic sclerosis. AB - OBJECTIVES: The objectives of this study were to evaluate the dynamic behaviour of digital skin microvascular blood flow before and after cold stimulation using laser Doppler imaging (LDI) in children and adolescents with RP secondary to juvenile systemic sclerosis (JSS), primary RP (PRP) and healthy controls and to compare functional abnormalities measured by LDI with structural microvascular abnormalities evaluated by nailfold capillaroscopy (NFC). METHODS: Five JSS patients, five children and adolescents with PRP and five healthy controls matched for gender and age were included. All subjects had NFC performed. Finger blood flow (FBF) was measured using the LDI system (Moor Instruments) at baseline and after cold stimulus (CS). RESULTS: There were a decreased number of capillaries, a greater number of enlarged capillaries and a higher deletion score in JSS patients compared with controls and patients with PRP. The mean baseline FBF was significantly lower in JSS patients compared with controls. There was no difference between the mean baseline FBF in JSS patients compared with patients with PRP. There was a significant decrease in FBF 1 min after CS in all groups followed by blood flow recovery at 20 min after CS in comparison with basal FBF values in controls, but not in JSS and PRP patients. CONCLUSION: In JSS patients, LDI showed a lower FBF before and after CS compared with healthy controls and may be an objective and sensitive method for the measurement of digital skin blood flow in RP children. PMID- 24046473 TI - Predictive models in heart failure: who cares? PMID- 24046474 TI - Measuring nonpulsatile blood pressure: say goodbye to the Doppler? PMID- 24046477 TI - Cellular reprogramming: a new avenue to cardiac regeneration? PMID- 24046478 TI - Pericardial constriction attributable to graft-versus-host disease: importance of early immunosuppression. PMID- 24046479 TI - Peripartum cardiomyopathy associated with left ventricular noncompaction phenotype and reversible rigid body rotation. PMID- 24046475 TI - Targeting the kidney in acute heart failure: can old drugs provide new benefit? Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE AHF) trial. PMID- 24046476 TI - Timing and duration of interventions in clinical trials for patients with hospitalized heart failure. PMID- 24046481 TI - Specific features of telomerase RNA from Hansenula polymorpha. AB - Telomerase, a ribonucleoprotein, is responsible for the maintenance of eukaryotic genome integrity by replicating the ends of chromosomes. The core enzyme comprises the conserved protein TERT and an RNA subunit (TER) that, in contrast, displays large variations in size and structure. Here, we report the identification of the telomerase RNA from thermotolerant yeast Hansenula polymorpha (HpTER) and describe its structural features. We show further that the H. polymorpha telomerase reverse transcribes the template beyond the predicted boundary and adds a nontelomeric dT in vitro. Sequencing of the chromosomal ends revealed that this nucleotide is specifically present as a terminal nucleotide at the 3' end of telomeres. Mutational analysis of HpTER confirmed that the incorporation of dT functions to limit telomere length in this species. PMID- 24046483 TI - Correlation of embryonic skeletal muscle myotube physical characteristics with contractile force generation on an atomic force microscope-based bio microelectromechanical systems device. AB - Rigorous analysis of muscle function in in vitro systems is needed for both acute and chronic biomedical applications. Forces generated by skeletal myotubes on bio microelectromechanical cantilevers were calculated using a modified version of Stoney's thin-film equation and finite element analysis (FEA), then analyzed for regression to physical parameters. The Stoney's equation results closely matched the more intensive FEA and the force correlated to cross-sectional area (CSA). Normalizing force to measured CSA significantly improved the statistical sensitivity and now allows for close comparison of in vitro data to in vivo measurements for applications in exercise physiology, robotics, and modeling neuromuscular diseases. PMID- 24046484 TI - Erratum: "Kinase detection with gallium nitride based high electron mobility transistors" [Appl. Phys. Lett. 103, 013701 (2013)]. AB - [This corrects the article on p. 013701 in vol. 103.]. PMID- 24046482 TI - Group II intron-ribosome association protects intron RNA from degradation. AB - The influence of the cellular environment on the structures and properties of catalytic RNAs is not well understood, despite great interest in ribozyme function. Here we report on ribosome association of group II introns, which are ribozymes that are important because of their putative ancestry to spliceosomal introns and retrotransposons, their retromobility via an RNA intermediate, and their application as gene delivery agents. We show that group II intron RNA, in complex with the intron-encoded protein from the native Lactoccocus lactis host, associates strongly with ribosomes in vivo. Ribosomes have little effect on intron ribozyme activities; rather, the association with host ribosomes protects the intron RNA against degradation by RNase E, an enzyme previously shown to be a silencer of retromobility in Escherichia coli. The ribosome interacts strongly with the intron, exerting protective effects in vivo and in vitro, as demonstrated by genetic and biochemical experiments. These results are consistent with the ribosome influencing the integrity of catalytic RNAs in bacteria in the face of degradative nucleases that regulate intron mobility. PMID- 24046485 TI - High-resolution X-ray diffraction and imaging. AB - This issue of Journal of Applied Crystallography includes some highlights of the 11th Biennial Conference on High-Resolution X-ray Diffraction and Imaging (XTOP), held in St Petersburg in 2012. PMID- 24046486 TI - Three-dimensional rocking curve imaging to measure the effective distortion in the neighbourhood of a defect within a crystal: an ice example. AB - Rocking curve imaging (RCI) is a quantitative version of monochromatic beam diffraction topography that involves using a two-dimensional detector, each pixel of which records its own 'local' rocking curve. From these local rocking curves one can reconstruct maps of particularly relevant quantities (e.g. integrated intensity, angular position of the centre of gravity, FWHM). Up to now RCI images have been exploited in the reflection case, giving a quantitative picture of the features present in a several-micrometre-thick subsurface layer. Recently, a three-dimensional Bragg diffraction imaging technique, which combines RCI with 'pinhole' and 'section' diffraction topography in the transmission case, was implemented. It allows three-dimensional images of defects to be obtained and measurement of three-dimensional distortions within a 50 * 50 * 50 um elementary volume inside the crystal with angular misorientations down to 10-5-10-6 rad. In the present paper, this three-dimensional-RCI (3D-RCI) technique is used to study one of the grains of a three-grained ice polycrystal. The inception of the deformation process is followed by reconstructing virtual slices in the crystal bulk. 3D-RCI capabilities allow the effective distortion in the bulk of the crystal to be investigated, and the predictions of diffraction theories to be checked, well beyond what has been possible up to now. PMID- 24046487 TI - Crack propagation and fracture in silicon wafers under thermal stress. AB - The behaviour of microcracks in silicon during thermal annealing has been studied using in situ X-ray diffraction imaging. Initial cracks are produced with an indenter at the edge of a conventional Si wafer, which was heated under temperature gradients to produce thermal stress. At temperatures where Si is still in the brittle regime, the strain may accumulate if a microcrack is pinned. If a critical value is exceeded either a new or a longer crack will be formed, which results with high probability in wafer breakage. The strain reduces most efficiently by forming (hhl) or (hkl) crack planes of high energy instead of the expected low-energy cleavage planes like {111}. Dangerous cracks, which become active during heat treatment and may shatter the whole wafer, can be identified from diffraction images simply by measuring the geometrical dimensions of the strain-related contrast around the crack tip. Once the plastic regime at higher temperature is reached, strain is reduced by generating dislocation loops and slip bands and no wafer breakage occurs. There is only a small temperature window within which crack propagation is possible during rapid annealing. PMID- 24046488 TI - Dose optimization approach to fast X-ray microtomography of the lung alveoli. AB - A basic prerequisite for in vivo X-ray imaging of the lung is the exact determination of radiation dose. Achieving resolutions of the order of micrometres may become particularly challenging owing to increased dose, which in the worst case can be lethal for the imaged animal model. A framework for linking image quality to radiation dose in order to optimize experimental parameters with respect to dose reduction is presented. The approach may find application for current and future in vivo studies to facilitate proper experiment planning and radiation risk assessment on the one hand and exploit imaging capabilities on the other. PMID- 24046489 TI - Three-wave X-ray diffraction in distorted epitaxial structures. AB - Three-wave diffraction has been measured for a set of GaN, AlN, AlGaN and ZnO epitaxial layers grown on c-sapphire. A Renninger scan for the primary forbidden 0001 reflection was used. For each of the three-wave combinations, theta-scan curves were measured. The intensity and angular width of both phi- and theta-scan three-wave peaks were analyzed. The experimental data were used to determine properties of the multiple diffraction pattern in highly distorted layers. It is shown that the FWHM of theta scans is highly sensitive to the structural perfection and strongly depends on the type of three-wave combination. The narrowest peaks are observed for multiple combinations with the largest l index of the secondary hkl reflection. An influence of the type of the dislocation structure on the theta-scan broadening was revealed. These experimental facts are interpreted by considering the scanning geometry in the reciprocal space and taking into account the disc-shaped reciprocal-lattice points. The total integrated intensities of all the three-wave combinations were determined and their ratios were found to be in only a qualitative agreement with the theory. For AlGaN layers, the presence of the nonzero 0001 reflection was revealed, in contrast to AlN and GaN films. PMID- 24046490 TI - X-ray characterization of Ge dots epitaxially grown on nanostructured Si islands on silicon-on-insulator substrates. AB - On the way to integrate lattice mismatched semiconductors on Si(001), the Ge/Si heterosystem was used as a case study for the concept of compliant substrate effects that offer the vision to be able to integrate defect-free alternative semiconductor structures on Si. Ge nanoclusters were selectively grown by chemical vapour deposition on Si nano-islands on silicon-on-insulator (SOI) substrates. The strain states of Ge clusters and Si islands were measured by grazing-incidence diffraction using a laboratory-based X-ray diffraction technique. A tensile strain of up to 0.5% was detected in the Si islands after direct Ge deposition. Using a thin (~10 nm) SiGe buffer layer between Si and Ge the tensile strain increases to 1.8%. Transmission electron microscopy studies confirm the absence of a regular grid of misfit dislocations in such structures. This clear experimental evidence for the compliance of Si nano-islands on SOI substrates opens a new integration concept that is not only limited to Ge but also extendable to semiconductors like III-V and II-VI materials. PMID- 24046491 TI - A look inside epitaxial cobalt-on-fluorite nanoparticles with three-dimensional reciprocal space mapping using GIXD, RHEED and GISAXS. AB - In this work epitaxial growth of cobalt on CaF2(111), (110) and (001) surfaces has been extensively studied. It has been shown by atomic force microscopy that at selected growth conditions stand-alone faceted Co nanoparticles are formed on a fluorite surface. Grazing-incidence X-ray diffraction (GIXD) and reflection high-energy electron diffraction (RHEED) studies have revealed that the particles crystallize in the face-centered cubic lattice structure otherwise non-achievable in bulk cobalt under normal conditions. The particles were found to inherit lattice orientation from the underlying CaF2 layer. Three-dimensional reciprocal space mapping carried out using X-ray and electron diffraction has revealed that there exist long bright <111> streaks passing through the cobalt Bragg reflections. These streaks are attributed to stacking faults formed in the crystal lattice of larger islands upon coalescence of independently nucleated smaller islands. Distinguished from the stacking fault streaks, crystal truncation rods perpendicular to the {111} and {001} particle facets have been observed. Finally, grazing-incidence small-angle X-ray scattering (GISAXS) has been applied to decouple the shape-related scattering from that induced by the crystal lattice defects. Particle faceting has been verified by modeling the GISAXS patterns. The work demonstrates the importance of three-dimensional reciprocal space mapping in the study of epitaxial nanoparticles. PMID- 24046492 TI - Defect structure transformation after thermal annealing in a surface layer of Zn implanted Si(001) substrates. AB - A combination of high-resolution X-ray diffractometry, Rutherford back scattering spectroscopy and secondary-ion mass spectrometry (SIMS) methods were used to characterize structural transformations of the damaged layer in Si(001) substrates heavily doped by Zn ions after a multistage thermal treatment. The shape of the SIMS profiles for Zn atoms correlates with the crystal structure of the damaged layer and depends on the presence of the following factors influencing the mobility of Zn atoms: (i) an amorphous/crystalline (a/c) interface, (ii) end-of-range defects, which are located slightly deeper than the a/c interface; (iii) a surface area enriched by Si vacancies; and (iv) the chemical interaction of Zn with Si atoms, which leads to the formation of Zn containing phases in the surface layer. PMID- 24046493 TI - Grazing-incidence X-ray diffraction of single GaAs nanowires at locations defined by focused ion beams. AB - Grazing-incidence X-ray diffraction measurements on single GaAs nanowires (NWs) grown on a (111)-oriented GaAs substrate by molecular beam epitaxy are reported. The positions of the NWs are intentionally determined by a direct implantation of Au with focused ion beams. This controlled arrangement in combination with a nanofocused X-ray beam allows the in-plane lattice parameter of single NWs to be probed, which is not possible for randomly grown NWs. Reciprocal space maps were collected at different heights along the NW to investigate the crystal structure. Simultaneously, substrate areas with different distances from the Au-implantation spots below the NWs were probed. Around the NWs, the data revealed a 0.4% decrease in the lattice spacing in the substrate compared with the expected unstrained value. This suggests the presence of a compressed region due to Au implantation. PMID- 24046494 TI - Alloy formation during molecular beam epitaxy growth of Si-doped InAs nanowires on GaAs[111]B. AB - Vertically aligned InAs nanowires (NWs) doped with Si were grown self-assisted by molecular beam epitaxy on GaAs[111]B substrates covered with a thin SiO x layer. Using out-of-plane X-ray diffraction, the influence of Si supply on the growth process and nanostructure formation was studied. It was found that the number of parasitic crystallites grown between the NWs increases with increasing Si flux. In addition, the formation of a Ga0.2In0.8As alloy was observed if the growth was performed on samples covered by a defective oxide layer. This alloy formation is observed within the crystallites and not within the nanowires. The Ga concentration is determined from the lattice mismatch of the crystallites relative to the InAs nanowires. No alloy formation is found for samples with faultless oxide layers. PMID- 24046495 TI - Characterization of SiGe thin films using a laboratory X-ray instrument. AB - The technique of reciprocal space mapping using X-rays is a recognized tool for the nondestructive characterization of epitaxial films. X-ray scattering from epitaxial Si0.4Ge0.6 films on Si(100) substrates using a laboratory X-ray source was investigated. It is shown that a laboratory source with a rotating anode makes it possible to investigate the material parameters of the super-thin 2-6 nm layers. For another set of partially relaxed layers, 50-200 nm thick, it is shown that from a high-resolution reciprocal space map, conditioned from diffuse scattering on dislocations, it is possible to determine quantitatively from the shape of a diffraction peak (possessing no thickness fringes) additional parameters such as misfit dislocation density and layer thickness as well as concentration and relaxation. PMID- 24046496 TI - In situ X-ray crystallographic study of the structural evolution of colloidal crystals upon heating. AB - The structural evolution of colloidal crystals made of polystyrene hard spheres has been studied in situ upon incremental heating of a crystal in a temperature range below and above the glass transition temperature of polystyrene. Thin films of colloidal crystals having different particle sizes were studied in transmission geometry using a high-resolution small-angle X-ray scattering setup at the P10 Coherence Beamline of the PETRA III synchrotron facility. The transformation of colloidal crystals to a melted state has been observed in a narrow temperature interval of less than 10 K. PMID- 24046497 TI - Enhancement of field-effect mobility due to structural ordering in poly(3 hexylthiophene) films by the dip-coating technique. AB - Organic field-effect transistors (OFETs) were fabricated by depositing a regioregular poly(3-hexylthiophene) (P3HT) active layer using a dip-coating method. The field-effect mobility in OFETs depends on chain orientation and crystallinity and is related to direction and withdrawal speed with respect to the source/drain orientation. In this paper, how to control the structural and transport properties of P3HT films by coating parallel and perpendicular to the dipping direction is demonstrated. X-ray diffraction curves taken in the perpendicular direction exhibit a higher degree of crystalline ordering and edge on conformation compared with those in the parallel direction; this finding correlates with the directional anisotropy of the OFET mobility. Both structural anisotropy and transport properties are enhanced upon thermal treatment. PMID- 24046498 TI - Modified statistical dynamical diffraction theory: analysis of model SiGe heterostructures. AB - A modified version of the statistical dynamical diffraction theory (mSDDT) permits full-pattern fitting of high-resolution X-ray diffraction scans from thin film systems across the entire range from fully dynamic to fully kinematic scattering. The mSDDT analysis has been applied to a set of model SiGe/Si thin film samples in order to define the capabilities of this approach. For defect free materials that diffract at the dynamic limit, mSDDT analyses return structural information that is consistent with commercial dynamical diffraction simulation software. As defect levels increase and the diffraction characteristics shift towards the kinematic limit, the mSDDT provides new insights into the structural characteristics of these materials. PMID- 24046499 TI - Covariant description of X-ray diffraction from anisotropically relaxed epitaxial structures. AB - A general theoretical approach to the description of epitaxial layers with essentially different cell parameters and in-plane relaxation anisotropy has been developed. A covariant description of relaxation in such structures has been introduced. An iteration method for evaluation of these parameters on the basis of the diffraction data set has been worked out together with error analysis and reliability checking. The validity of the presented theoretical approaches has been proved with a-ZnO on r-sapphire samples grown in the temperature range from 573 K up to 1073 K. A covariant description of relaxation anisotropy for these samples has been estimated with data measured for different directions of the diffraction plane relative to the sample surface. PMID- 24046500 TI - Nonlinear continuum growth model of multiscale reliefs as applied to rigorous analysis of multilayer short-wave scattering intensity. I. Gratings. AB - It is shown that taking into proper account certain terms in the nonlinear continuum equation of thin-film growth makes it applicable to the simulation of the surface of multilayer gratings with large boundary profile heights and/or gradient jumps. The proposed model describes smoothing and displacement of Mo/Si and Al/Zr boundaries of gratings grown on Si substrates with a blazed groove profile by magnetron sputtering and ion-beam deposition. Computer simulation of the growth of multilayer Mo/Si and Al/Zr gratings has been conducted. Absolute diffraction efficiencies of Mo/Si and Al/Zr gratings in the extreme UV range have been found within the framework of boundary integral equations applied to the calculated boundary profiles. It has been demonstrated that the integrated approach to the calculation of boundary profiles and of the intensity of short wave scattering by multilayer gratings developed here opens up a way to perform studies comparable in accuracy to measurements with synchrotron radiation, at least for known materials and growth techniques. PMID- 24046501 TI - Processing of projections containing phase contrast in laboratory micro computerized tomography imaging. AB - Free-space-propagation-based imaging belongs to several techniques for achieving phase contrast in the hard X-ray range. The basic precondition is to use an X-ray beam with a high degree of coherence. Although the best sources of coherent X rays are synchrotrons, spatially coherent X-rays emitted from a sufficiently small spot of laboratory microfocus or sub-microfocus sources allow the transfer of some of the modern imaging techniques from synchrotrons to laboratories. Spatially coherent X-rays traverse a sample leading to a phase shift. Beam deflection induced by the local change of refractive index may be expressed as a dark-bright contrast on the edges of the object in an X-ray projection. This phenomenon of edge enhancement leads to an increase in spatial resolution of X ray projections but may also lead to unpleasant artefacts in computerized tomography unless phase and absorption contributions are separated. The possibilities of processing X-ray images of lightweight objects containing phase contrast using phase-retrieval methods in laboratory conditions are tested and the results obtained are presented. For this purpose, simulated and recorded X ray projections taken from a laboratory imaging system with a microfocus X-ray source and a high-resolution CCD camera were processed and a qualitative comparison of results was made. PMID- 24046502 TI - High-quality quartz single crystals for high-energy-resolution inelastic X-ray scattering analyzers. AB - Spherical analyzers are well known instruments for inelastic X-ray scattering (IXS) experiments. High-resolution IXS experiments almost always use Si single crystals as monochromators and spherical analyzers. At higher energies (>20 keV) Si shows a high energy resolution (<10 meV), at an exact symmetric back diffraction condition, since the energy resolution is given by the real part of the susceptibility or polarizability. However, at low energies (<10 keV), high energy resolution is difficult to achieve with Si. alpha-SiO2 (quartz) can be an option, since it offers high energy resolution at low energies. In this work, the characterization of high-quality alpha-SiO2 is presented. Such characterization is made by high-resolution rocking curve, topography and lattice parameter mapping in different samples from a single block. X-ray optics with alpha-SiO2 for IXS at lower energies (from 2.5 to 12.6 keV) with medium to high energy resolution (from 90 to 11 meV) are proposed and theoretically exploited. PMID- 24046503 TI - Potential use of V-channel Ge(220) monochromators in X-ray metrology and imaging. AB - While channel-cut crystals, in which the diffracting surfaces in an asymmetric cut are kept parallel, can provide beam collimation and spectral beam shaping, they can in addition provide beam compression or expansion if the cut is V shaped. The compression/expansion ratio depends in this case on the total asymmetry factor. If the Ge(220) diffraction planes and a total asymmetry factor in excess of 10 are used, the rocking curves of two diffractors will have a sufficient overlap only if the second diffractor is tuned slightly with respect to the first one. This study compares and analyses several ways of overcoming this mismatch, which is due to refraction, when the Cu Kalpha1 beam is compressed 21-fold in a V21 monochromator. A more than sixfold intensity increase was obtained if the matching was improved either by a compositional variation or by a thermal deformation. This provided an intensity gain compared with the use of a simple slit in a symmetrical channel-cut monochromator. The first attempt to overcome the mismatch by introducing different types of X-ray prisms for the required beam deflection is described as well. The performance of the V-shaped monochromators is demonstrated in two applications. A narrow collimated monochromatic beam obtained in the beam compressing mode was used for high resolution grazing-incidence small-angle X-ray scattering measurements of a silicon sample with corrupted surface. In addition, a two-dimensional Bragg magnifier, based on two crossed V15 channel monochromators in beam expansion mode and tuned by means of unequal asymmetries, was successfully applied to high resolution imaging of test structures in combination with a Medipix detector. PMID- 24046504 TI - A novel small-angle neutron scattering detector geometry. AB - A novel 2pi detector geometry for small-angle neutron scattering (SANS) applications is presented and its theoretical performance evaluated. Such a novel geometry is ideally suited for a SANS instrument at the European Spallation Source (ESS). Motivated by the low availability and high price of 3He, the new concept utilizes gaseous detectors with 10B as the neutron converter. The shape of the detector is inspired by an optimization process based on the properties of the conversion material. Advantages over the detector geometry traditionally used on SANS instruments are discussed. The angular and time resolutions of the proposed detector concept are shown to satisfy the requirements of the particular SANS instrument. PMID- 24046505 TI - A prototype direct-detection CCD for protein crystallography. AB - The fabrication and testing of a prototype deep-depletion direct-conversion X-ray CCD detector are described. The device is fabricated on 600 um-thick high resistivity silicon, with 24 * 24 um pixels in a 4k * 4k pixel format. Calibration measurements and the results of initial protein crystallography experiments at the Cornell High Energy Synchrotron Source (CHESS) F1 beamline are described, as well as suggested improvements for future versions of the detector. PMID- 24046506 TI - Composition-dependent structure of polycrystalline magnetron-sputtered V-Al-C-N hard coatings studied by XRD, XPS, XANES and EXAFS. AB - V-Al-C-N hard coatings with high carbon content were deposited by reactive radio frequency magnetron sputtering using an experimental combinatorial approach, deposition from a segmented sputter target. The composition-dependent coexisting phases within the coating were analysed using the complementary methods of X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), X-ray absorption near edge spectroscopy (XANES) and extended X-ray absorption fine-structure spectroscopy (EXAFS). For the analysis of the X-ray absorption near-edge spectra, a new approach for evaluation of the pre-edge peak was developed, taking into account the self-absorption effects in thin films. Within the studied composition range, a mixed face-centred cubic (V,Al)(C,N) phase coexisting with a C-C containing phase was observed. No indication of hexagonal (V,Al)(N,C) was found. The example of V-Al-C-N demonstrates how important a combination of complementary methods is for the detection of coexisting phases in complex multi-element coatings. PMID- 24046507 TI - Validation of three-dimensional diffraction contrast tomography reconstructions by means of electron backscatter diffraction characterization. AB - Microstructure reconstructions resulting from diffraction contrast tomography data of polycrystalline bulk strontium titanate were reinvestigated by means of electron backscatter diffraction (EBSD) characterization. Corresponding two dimensional grain maps from the two characterization methods were aligned and compared, focusing on the spatial resolution at the internal interfaces. The compared grain boundary networks show a remarkably good agreement both morphologically and in crystallographic orientation. Deviations are critically assessed and discussed in the context of diffraction data reconstruction and EBSD data collection techniques. PMID- 24046508 TI - xrayutilities: a versatile tool for reciprocal space conversion of scattering data recorded with linear and area detectors. AB - General algorithms to convert scattering data of linear and area detectors recorded in various scattering geometries to reciprocal space coordinates are presented. These algorithms work for any goniometer configuration including popular four-circle, six-circle and kappa goniometers. The use of commonly employed approximations is avoided and therefore the algorithms work also for large detectors at small sample-detector distances. A recipe for determining the necessary detector parameters including mostly ignored misalignments is given. The algorithms are implemented in a freely available open-source package. PMID- 24046509 TI - A non-discrete method for computation of residence time in fluid mechanics simulations. AB - Cardiovascular simulations provide a promising means to predict risk of thrombosis in grafts, devices, and surgical anatomies in adult and pediatric patients. Although the pathways for platelet activation and clot formation are not yet fully understood, recent findings suggest that thrombosis risk is increased in regions of flow recirculation and high residence time (RT). Current approaches for calculating RT are typically based on releasing a finite number of Lagrangian particles into the flow field and calculating RT by tracking their positions. However, special care must be taken to achieve temporal and spatial convergence, often requiring repeated simulations. In this work, we introduce a non-discrete method in which RT is calculated in an Eulerian framework using the advection-diffusion equation. We first present the formulation for calculating residence time in a given region of interest using two alternate definitions. The physical significance and sensitivity of the two measures of RT are discussed and their mathematical relation is established. An extension to a point-wise value is also presented. The methods presented here are then applied in a 2D cavity and two representative clinical scenarios, involving shunt placement for single ventricle heart defects and Kawasaki disease. In the second case study, we explored the relationship between RT and wall shear stress, a parameter of particular importance in cardiovascular disease. PMID- 24046511 TI - RP-LC and TLC Densitometric Determination of Paracetamol and Pamabrom in Presence of Hazardous Impurity of Paracetamol and Application to Pharmaceuticals. AB - Two simple, accurate and reproducible methods were developed and validated for the simultaneous determination of paracetamol (PARA) and pamabrom (PAMB) in pure form and in tablets. The first method was based on reserved-phase high performance liquid chromatography, on a Thermo Hypersil ODS column using methanol:0.01 M sodium hexane sulfonate:formic acid (67.5:212.5:1 v/v/v) as the mobile phase. The flow rate was 2 mL/min and the column temperature was adjusted to 35 degrees C. Quantification was achieved with UV detection at 277 nm over concentration range of 100-600 and 4-24 MUg/mL, with mean percentage recoveries were found to be 99.90 +/- 0.586 and 99.26 +/- 0.901 for PARA and PAMB, respectively. The second method was based on thin-layer chromatography separation of PARA and PAMB followed by densitometric measurement of the spots at 254 nm and 277 nm for PARA and PAMB respectively. Separation was carried out on aluminum sheet of silica gel 60F254 using dichloromethane:methanol:glacial acetic acid (7.5:1:0.5 v/v/v) as the mobile phase over concentration range of 1-10 and 0.32 3.20 MUg per spot, with mean percentage recovery of 100.52 +/- 1.332 and 99.71 +/ 1.478 for PARA and PAMB, respectively. The methods retained their accuracy in presence of up to 50% of P-aminophenol and could be successfully applied in tablets. PMID- 24046510 TI - Perspectives on the value of biomarkers in acute cardiac care and implications for strategic management. AB - Biomarkers in acute cardiac care are gaining increasing interest given their clinical benefits. This study is a review of the major conditions in acute cardiac care, with a focus on biomarkers for diagnostic and prognostic assessment. Through a PubMed search, 110 relevant articles were selected. The most commonly used cardiac biomarkers (cardiac troponin, natriuretic peptides, and C-reactive protein) are presented first, followed by a description of variable acute cardiac conditions with their relevant biomarkers. In addition to the conventional use of natriuretic peptides, cardiac troponin, and C-reactive protein, other biomarkers are outlined in variable critical conditions that may be related to acute cardiac illness. These include ST2 and chromogranin A in acute dyspnea and acute heart failure, matrix metalloproteinase in acute chest pain, heart-type fatty acid binding protein in acute coronary syndrome, CD40 ligand and interleukin-6 in acute myocardial infarction, blood ammonia and lactate in cardiac arrest, as well as tumor necrosis factor-alpha in atrial fibrillation. Endothelial dysfunction, oxidative stress and inflammation are involved in the physiopathology of most cardiac diseases, whether acute or chronic. In summary, natriuretic peptides, cardiac troponin, C-reactive protein are currently the most relevant biomarkers in acute cardiac care. Point-of-care testing and multi-markers use are essential for prompt diagnostic approach and tailored strategic management. PMID- 24046512 TI - Regenerative injection therapy with whole bone marrow aspirate for degenerative joint disease: a case series. AB - Regenerative therapeutic strategies for joint diseases usually employ either enriched concentrates of bone marrow-derived stem cells, chondrogenic preparations such as platelet-rich plasma, or irritant solutions such as hyperosmotic dextrose. In this case series, we describe our experience with a simple, cost-effective regenerative treatment using direct injection of unfractionated whole bone marrow (WBM) into osteoarthritic joints in combination with hyperosmotic dextrose. Seven patients with hip, knee or ankle osteoarthritis (OA) received two to seven treatments over a period of two to twelve months. Patient-reported assessments were collected in interviews and by questionnaire. All patients reported improvements with respect to pain, as well as gains in functionality and quality of life. Three patients, including two whose progress under other therapy had plateaued or reversed, achieved complete or near-complete symptomatic relief, and two additional patients achieved resumption of vigorous exercise. These preliminary findings suggest that OA treatment with WBM injection merits further investigation. PMID- 24046513 TI - Cardiac Electrophysiology in Lebanon-Part II. AB - Systematic national effort to improve cardiac electrophysiology practice in Lebanon is lacking, and the quality improvement program mainly relates to individual efforts along with regulations, which are set as a "Road Map" by the Lebanese Arrhythmia Working Group. Lebanon currently has five electrophysiology laboratories. The "Road Map" mainly consists of creating a registry and a National Card for Electronic Device Holder, centralization of complex electrophysiology procedures in institutions where electrophysiologists are available, setting regulations to conform to international guidelines, and creating a National Arrhythmia Website and E-Journal. Most importantly, we emphasize that the practice of device checking must be performed by physicians with expertise and not by industry technicians. PMID- 24046514 TI - Brachial-ankle pulse wave velocity predicts decline in renal function and cardiovascular events in early stages of chronic kidney disease. AB - OBJECTIVE: In this study, we investigated the predictive capacity of the brachial ankle aortic pulse wave velocity (baPWV), a marker of arterial stiffness, for the decline in renal function and for cardiovascular events in the early stages of chronic kidney disease (CKD). METHOD: Two hundred forty-one patients who underwent a comprehensive check-up were included and were divided into two groups according to their estimated glomerular filtration rates (eGFR): patients with CKD categories G2, G3a and G3b (30 <= eGFR < 90 ml/min/1.73m(2), eGFR < 90 group; n=117) and those with eGFR >= 90 ml/min/1.73 m(2) (eGFR >= 90 group; n=124). The change in renal function, the eGFR change, was determined by the slope of eGFR against time. We analysed whether baPWV was associated with eGFR change or predicted cardiovascular events. RESULTS: baPWV was independently associated with eGFR change in a multivariate analysis of the total patients (beta=-0.011, p=0.011) and remained significantly associated with eGFR change in a subgroup analysis of the eGFR < 90 group (beta=-0.015, p=0.035). baPWV was independently associated with cardiovascular events (odds ratio=1.002, p=0.048) in the eGFR < 90 group, but not in the eGFR >= 90 group. The receiver operative characteristic curve analysis showed that 1,568 cm/sec was the cut-off value of baPWV for predicting CV events in the eGFR < 90 group (area under curve=0.691, p=0.03) CONCLUSIONS: In patients with early stages of CKD, baPWV was independently associated with the decline in renal function and short-term cardiovascular events. PMID- 24046515 TI - Association of increased arterial stiffness and p wave dispersion with left ventricular diastolic dysfunction. AB - BACKGROUND: The association between increased arterial stiffness and left ventricular diastolic dysfunction (LVDD) may be influenced by left ventricular performance. P wave dispersion is not only a significant determinant of left ventricular performance, but is also correlated with LVDD. This study is designed to compare left ventricular diastolic function among patients divided by brachial ankle pulse wave velocity (baPWV) and corrected P wave dispersion (PWDC) and assess whether the combination of baPWV and PWDC can predict LVDD more accurately. METHODS: This cross-sectional study enrolled 270 patients and classified them into four groups according to the median values of baPWV and PWDC. LVDD was defined as impaired relaxation and pseudonormal/restrictive mitral inflow patterns. RESULTS: The ratio of transmitral E wave velocity to early diastolic mitral annulus velocity (E/Ea) was higher in group with higher baPWV and PWDC than in the other groups (all p <0.001). The prevalence of LVDD was higher in group with higher baPWV and PWDC than in the two groups with lower baPWV (p <= 0.001). The baPWV and PWDC were correlated with E/Ea and LVDD in multivariate analysis (p <= 0.030). The addition of baPWV and PWDC to a clinical mode could significantly improve the R square in prediction of E/Ea and C statistic and integrated discrimination index in prediction of LVDD (p <= 0.010). CONCLUSIONS: This study showed increased baPWV and PWDC were correlated with high E/Ea and LVDD. The addition of baPWV and PWDC to a clinical model improved the prediction of high E/Ea and LVDD. Screening patients by means of baPWV and PWDC might help identify the high risk group of elevated left ventricular filling pressure and LVDD. PMID- 24046516 TI - Respiratory magnetogram detected with a MEMS device. AB - Magnetic fields generated by the brain or the heart are very useful in clinical diagnostics. Therefore, magnetic signals produced by other organs are also of considerable interest. Here we show first evidence that thoracic muscles can produce a strong magnetic flux density during respiratory activity, that we name respiratory magnetogram. We used a small magnetometer based on microelectromechanical systems (MEMS), which was positioned inside the open thoracic cage of anaesthetized and ventilated rats. With this new MEMS sensor of about 20 nT resolution, we recorded a strong and rhythmic respiratory magnetogram of about 600 nT. PMID- 24046517 TI - A canine model of femoral head osteonecrosis induced by an ethanol injection navigated by a novel template. AB - There is no consensus on how to establish models of osteonecrosis of the femoral head (ONFH) in large mammals. The aim of this study was to investigate the effectiveness of a novel canine model of ONFH, induced by a navigated injection of absolute ethanol. Using three-dimensional reconstruction and rapid prototyping manufacturing techniques, a new template was designed and processed to navigate the ethanol injection. The femoral heads of 18 adult dogs were injected with ethanol. Macroscopic, X-ray and histological examinations were performed at 3, 6, and 9 weeks after the operation. Further, computed tomography (CT), magnetic resonance imaging (MRI), and radionuclide scans were performed 6 weeks postoperatively. Three weeks after the operation, the femoral heads showed evidence of osteonecrosis including increasing numbers of empty lacunae, decreased hematopoietic cells, and destroyed adipose tissue in the medullary cavity, which increased in severity at the subsequent follow-up evaluations at 6 and 9 weeks. Fractured trabeculae and fibrous tissue were noted 9 weeks postoperatively. Image analysis also revealed evidence of osteonecrosis, such as several osteopenic areas with sclerotic rims on the X-ray, several areas of low bone mineral density with sclerosis on the CT scan, increased uptake of the nuclide species in MRI, and an inhomogeneous long T2 signal on the radioisotopic images. Ethanol injection navigated by our novel template was successful in establishing a canine model of ONFH. This model can be used to test new treatment modalities for human ONFH. PMID- 24046518 TI - Evaluating epidemiological evidence: a simple test. AB - Epidemiological studies that investigate the relationships between health behaviors and diseases may be affected by both known and unknown confounding factors. Alcohol use is one of these behaviors that have been intensively investigated in epidemiological studies. This manuscript introduced a simple test that can identify confounded epidemiological studies. This approach is sensitive to both known and unknown confounders. It provides a new perspective to develop measures for evidence selection in the future. PMID- 24046519 TI - Totally laparoscopic distal gastrectomy with D2 lymphadenectomy and Billroth II gastrojejunostomy for gastric cancer: short- and medium-term results of 139 consecutive cases from a single institution. AB - OBJECTIVE: The goal of this study was to investigate the feasibility, safety, and associated 3-year survival outcomes of the totally laparoscopic distal gastrectomy (TLDG) for the treatment of gastric cancer. METHODS: Herein, we analyzed the clinical data from 139 consecutive patients with gastric cancer who received TLDG at our institution from March of 2007 to March of 2013. RESULTS: TLDG was successfully carried out in 139 patients; no cases were converted to open surgery. The mean operation time was 228.6 +/- 51.0 minutes, mean blood loss was 131.2 +/- 85.2 mL, and mean number of dissected lymph nodes was 31.1 +/- 9.0. The average time to flatus, time to fluid diet, and length of hospital stay were 3.6 +/- 1.1 days, 4.8 +/- 1.6 days, and 9.8 +/- 4.0 days, respectively. The postoperative morbidity was 10.1%. A total of 135 patients were followed for a subsequent 1-73 months (median, 24.0 months). The 3-year disease-free survival (DFS) and overall survival (OS) rates were 82.3% and 82.9%, respectively. When divided by stage, the 3-year DFS for stage I, II, and III were 100%, 86.2%, and 48.8%, respectively; and the 3-year OS for stage I, II, and III were 98.0%, 92.3%, and 51.6%, respectively. CONCLUSIONS: In this preliminary report, TLDG was found to be a safe, feasible, and efficacious procedure for the treatment of gastric cancer with encouraging 3-year overall and stage-by-stage survival rates. PMID- 24046520 TI - Burnout, job satisfaction, and medical malpractice among physicians. AB - OBJECTIVES: Our objective was to estimate the incidence of recent burnout in a large sample of Taiwanese physicians and analyze associations with job related satisfaction and medical malpractice experience. METHODS: We performed a cross sectional survey. Physicians were asked to fill out a questionnaire that included demographic information, practice characteristics, burnout, medical malpractice experience, job satisfaction, and medical error experience. There are about 2% of total physicians. Physicians who were members of the Taiwan Society of Emergency Medicine, Taiwan Surgical Association, Taiwan Association of Obstetrics and Gynecology, The Taiwan Pediatric Association, and Taiwan Stroke Association, and physicians of two medical centers, three metropolitan hospitals, and two local community hospitals were recruited. RESULTS: There is high incidence of burnout among Taiwan physicians. In our research, Visiting staff (VS) and residents were more likely to have higher level of burnout of the emotional exhaustion (EE) and depersonalization (DP), and personal accomplishment (PA). There was no difference in burnout types in gender. Married had higher-level burnout in EE. Physicians who were 20~30 years old had higher burnout levels in EE, those 31~40 years old had higher burnout levels in DP, and PA. Physicians who worked in medical centers had a higher rate in EE, DP, and who worked in metropolitan had higher burnout in PA. With specialty-in-training, physicians had higher-level burnout in EE and DP, but lower burnout in PA. Physicians who worked 13-17hr continuously had higher level burnout in EE. Those with >=41 times/week of being on call had higher-level burnout in EE and DP. Physicians who had medical malpractice experience had higher-level burnout in EE, DP, and PA. Physicians who were not satisfied with physician-patient relationships had higher-level burnout than those who were satisfied. CONCLUSION: Physicians in Taiwan face both burnout and a high risk in medical malpractice. There is high incidence of burnout among Taiwan physicians. This can cause shortages in medical care human resources and affect patient safety. We believe that high burnout in physicians was due to long working hours and several other factors, like mental depression, the evaluation assessment system, hospital culture, patient-physician relationships, and the environment. This is a very important issue on public health that Taiwanese authorities need to deal with. PMID- 24046521 TI - Association between Helicobacter Pylori infection and ulcerative colitis--a case control study from China. AB - AIMS: To investigate the association between H. pylori infection and UC prevalence in China. MATERIALS AND METHODS: Subjects were selected from patients admitted in Department of Gastroenterology for abdominal pain, hematochezia, diarrhea and other GI symptoms during 2009-2012. UC diagnosis was based on both colonoscopy and biopsy. H. pylori detection was based on (14)C urea breath test (UBT) and biopsy sample culture. Patients' demographic, anthropometric and serologic data were selected. H. pylori infection rate was compared between UC and control groups, followed by a subgroup analysis on the association between H. pylori infection and extent and severity degree of UC. RESULTS: Totally, 153 and 121 patients were selected and divided into UC and control groups. There were no significant differences in age, gender, BMI, hypertension and diabetes. However, smoking history was significantly lower while WBC and CRP levels were significantly higher in UC group. The H. pylori infection rate in UC group was 30.5%, significantly lower than that of 57.0% in control group. The H. pylori infection rate in UC of left colon and whole colon were 33,9% and 24.2% (p<0.05 between them), both significantly lower than that in control group. In addition, the H. pylori infection rates in mild, moderate and severe UC subgroups were 37.8%, 32.3% and 22.2% (p>0.05 among them), all of which were significantly lower than that in control group. CONCLUSION: We reported a significantly lower H. pylori infection rate in UC patients with different extent and severity degree, which provides evidence for bacteria involvement in UC pathogenesis and reminder clinicians to keep cautious in considering H. pylori eradication in UC patients. PMID- 24046522 TI - Cadmium induced cell apoptosis, DNA damage, decreased DNA repair capacity, and genomic instability during malignant transformation of human bronchial epithelial cells. AB - Cadmium and its compounds are well-known human carcinogens, but the mechanisms underlying the carcinogenesis are not entirely understood. Our study was designed to elucidate the mechanisms of DNA damage in cadmium-induced malignant transformation of human bronchial epithelial cells. We analyzed cell cycle, apoptosis, DNA damage, gene expression, genomic instability, and the sequence of exons in DNA repair genes in several kinds of cells. These cells consisted of untreated control cells, cells in the fifth, 15th, and 35th passage of cadmium treated cells, and tumorigenic cells from nude mice using flow cytometry, Hoechst 33258 staining, comet assay, quantitative real-time polymerase chain reaction (PCR), Western blot analysis, random amplified polymorphic DNA (RAPD)-PCR, and sequence analysis. We observed a progressive increase in cell population of the G0/G1 phase of the cell cycle and the rate of apoptosis, DNA damage, and cadmium induced apoptotic morphological changes in cerebral cortical neurons during malignant transformation. Gene expression analysis revealed increased expression of cell proliferation (PCNA), cell cycle (CyclinD1), pro-apoptotic activity (Bax), and DNA damage of the checkpoint genes ATM, ATR, Chk1, Chk2, Cdc25A. Decreased expression of the anti-apoptotic gene Bcl-2 and the DNA repair genes hMSH2, hMLH1, ERCC1, ERCC2, and hOGG1 was observed. RAPD-PCR revealed genomic instability in cadmium-exposed cells, and sequence analysis showed mutation of exons in hMSH2, ERCC1, XRCC1, and hOGG1 in tumorigenic cells. This study suggests that Cadmium can increase cell apoptosis and DNA damage, decrease DNA repair capacity, and cause mutations, and genomic instability leading to malignant transformation. This process could be a viable mechanism for cadmium-induced cancers. PMID- 24046523 TI - Genotype-phenotype analysis of CYP2C19 in healthy saudi individuals and its potential clinical implication in drug therapy. AB - CYP2C19 is a cytochrome P450 enzyme, which is involved in the metabolism of some clinically important medications and is encoded by a highly polymorphic gene. There is no available data on the distribution of the CYP2C19 *4 and *17 mutant alleles in the Saudi Arabian population. The aim of the study was to determine different CYP2C19 mutant allele (*2, *4 and *17) frequencies in healthy Saudi subjects and to determine genotype frequencies for these mutations. The CYP2C19 genotypes were then classified into phenotypes. RESULT: In 201 adults of Saudi ethnicity, the allele frequencies were CYP2C19*1 (62.9%), *17 (25.7%), *2 (11.2%) and *4 (0.2%). The most prevalent genotype combinations were CYP2C19 *1/*1 (40.3%) and *1/*17 (30.4%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM) 77.6%, intermediate metabolizers (IM) 14.9%, ultra-rapid metabolizers (UM) 7% and poor metabolizers (PM) 0.4%. This finding has important clinical implications for the use of CYP2C19 metabolized medications in the Saudi population and further studies are needed. PMID- 24046524 TI - Discoloration of provisional restorations after oral rinses. AB - PURPOSE: Oral rinses are widely used to promote periodontal health with provisional restorations during the interim period. The aim of this study was to compare the discoloration of provisional restoration materials with different oral rinses. MATERIAL AND METHODS: A total of 140 disc-shaped specimens (shade A2) (10 mm x 2 mm) were prepared from one PMMA-based (TemDent Classic((r))) and three different bis-acrylic-based (Protemp II((r)), Luxatemp((r)) and Fill In((r))) provisional restoration materials (n=7). The color values (L*, a*, and b*) of each specimen were measured before and after exposure with a colorimeter, and the color changes (?E) were calculated according to the CIE L*a*b* system. The specimens were immersed in each of the 4 oral rinses (alcohol-containing mouthwash, chlorhexidine, benzydamine HCl, benzydamine HCl and chlorhexidine) twice a day for 2 minutes. After 2 minutes of immersion in the oral rinses, the specimens were immersed in artificial saliva. The specimens were exposed to the oral rinses and the artificial saliva for 3 weeks. Two-way ANOVA, the Bonferroni test and the paired sample t-test were used for statistical analyses (p<0.05). RESULTS: Comparison of the discoloration from the oral rinses after immersion for three weeks revealed no significant differences (p>0.05). The lowest color change was observed in PMMA-based Temdent in all oral rinses (p<0.05). There were no significant differences between the bis-acryl composites after immersion in saliva or the mixture of benzydamine HCl and chlorhexidine and the alcohol containing mouthwash for 3 weeks (p>0.05). After immersion in chlorhexidine, the color change values of Protemp II and Fill-in showed significant differences (p=0.018). Protemp II also showed less discoloration than the other bis-acryl composites, and this color change was statistically significant (p <0.05). For all oral rinses, the L* value decreased while b* values increased, and this color change was found to be statistically significant (p <0.05). A* values were found to be significantly higher with oral rinses (p<0.05), except Protemp II immersed in benzydamine HCl or alcohol-containing mouthwash. CONCLUSIONS: The type of the oral rinse did not affect the discoloration process. For long-term esthetic results, choosing MMA-based materials for provisional restorations appears to be more effective. PMID- 24046525 TI - Analysis of immunoglobulin and T cell receptor gene rearrangement in the bone marrow of lymphoid neoplasia using BIOMED-2 multiplex polymerase chain reaction. AB - The evaluation of bone marrow (BM) involvement is important for diagnosis and staging in patients with lymphoid neoplasia. We evaluated of immunoglobulin (Ig) and/or T-cell receptor (TCR) gene rearrangements in the BM using the standardized BIOMED-2 multiplex PCR clonality assays and compared the results with microscopic findings such as histology and CD10, CD20, CD79a, CD3 and CD5 immunohistochemistry. A total of 151 samples were enrolled; 119 B cell neoplasia, 29 T cell neoplasia, and 3 Hodgkin's lymphoma. The molecular clonality assay and microscopic diagnosis were concordant in 66.9% (n=101) and discordant in 33.1 % (n=50). Ig/TCR gene clonality assay detected 43 cases of BM involvement which was not presented in the morphology. Two cases among them turned into microscopic BM involvement during a close follow up. Clonal TCR gene rearrangements were detected in 12.6% of B cell neoplasia and Ig gene rearrangement were found in 3.4% of T cell neoplasia. This molecular clonality assay is valuable particularly in diagnosing BM involvement of lymphoid neoplasia if it is morphologically uncertain. But it should be carefully interpreted because molecular clonality may be present in the reactive lymphoproliferation. Therefore, comprehensive analysis with morphologic analysis should be important to reach a final diagnosis. PMID- 24046526 TI - Prone versus modified supine position in percutaneous nephrolithotomy: a prospective randomized study. AB - OBJECTIVE: To perform a prospective randomized trial comparing the efficacy and safety of percutaneous nephrolithotomy (PCNL) in the prone and modified supine positions. METHODS: Between August 2010 and August 2011, 102 patients with renal calculi and 20 patients with ureteral calculi were randomized to undergo fluoroscopy and ultrasound-guided PCNL procedures in the prone or modified supine position. Baseline characteristics, puncture position, numbers of punctures, operation time, stone free rate, loss of blood, hospital stay and second phase PCNL were compared in the two groups. RESULTS: There were no significant differences in gender, age, body mass index, stone location, stone size and the presence of hydronephrosis between the two groups. The rate of second PCNL was significantly higher and the stone clearance rate was significantly lower in the modified supine than in the prone position group. Mean operation time was significantly lower in the prone than in the modified supine position group (78 min vs 88 min, P<0.05). There were no significant differences in rates of rib and calyx puncture, numbers of punctures, mean blood loss, and mean hospital stay between the two groups. CONCLUSIONS: Both the prone and modified supine positions are effective and safe for PCNL. Operation time was longer in the modified supine group, and patients undergoing PCNL in the modified supine position more frequently required a second operation due to a lower stone clearance rate. PMID- 24046527 TI - The -159C/T polymorphism in the CD14 gene and tuberculosis risk: a meta-analysis. AB - BACKGROUND: The -159C/T polymorphism in the CD14 gene has been implicated in susceptibility to tuberculosis, but the results were inconclusive. The present meta-analysis aimed to perform a comprehensive assessment of the literature on the possible association between the -159C/T polymorphism and tuberculosis risk. METHODS: We searched in Pubmed and Embase for studies evaluating the association between the -159C/T gene polymorphism and tuberculosis risk. Data were extracted and statistical analysis was performed using Revman 5.1 and STATA 12.0 software. RESULTS: A total of seven case-control studies involving 3253 subjects (1,574 tuberculosis cases and 1,679 controls) were included. Combined analysis revealed an obvious association between this polymorphism and tuberculosis risk (odds ratio=1.66 and 95% confidence interval: 1.23-2.25, P<0.05 for TT vs. TC+ CC). Sub group analysis by ethnicity suggested that the risk of tuberculosis associated with the -159C/T polymorphism was significantly elevated among Asians (odds ratio=1.87 and 95% confidence interval: 1.58-2.21, P<0.05 for TT vs. TC+ CC). CONCLUSION: This meta-analysis suggests that the -159C/T polymorphism in the CD14 gene contributes to tuberculosis susceptibility. To further investigate gene-gene and gene-environment interactions between this polymorphism and tuberculosis risk, more studies are needed. PMID- 24046528 TI - Relationship between plasma fibrinogen levels and pulmonary function in the japanese population: the Takahata study. AB - BACKGROUND: Plasma fibrinogen is considered a biomarker of respiratory disease, owing to the relationship between plasma fibrinogen and pulmonary function established in Western populations. However, such a relationship has not yet been confirmed in an Asian population. We assessed this relationship in the general Japanese population. METHODS: Totally, 3,257 men and women aged >=40 years who participated in a community-based annual health checkup in Takahata, Japan, from 2004 to 2006, underwent spirometry, and their plasma fibrinogen levels were determined. RESULTS: We found an inverse relationship between spirometric measures (percent predicted forced vital capacity [%FVC] and forced expiratory volume in 1s [%FEV1], and FEV1/FVC) and plasma fibrinogen levels in men, but not in women. The plasma fibrinogen levels were significantly higher in subjects with restrictive, obstructive, and mixed ventilatory disorders than in those with normal spirometry results. Multiple linear regression analysis revealed that in men, plasma fibrinogen levels were predictive for %FVC and %FEV1 (independent of age, body mass index, and cigarette smoking) but not for FEV1/FVC. CONCLUSIONS: Plasma fibrinogen was significantly associated with pulmonary function in Japanese men, and as such, plasma fibrinogen might be a potent biomarker for pulmonary dysfunction in men. PMID- 24046530 TI - Shifting towards an opt-out system in Greece: a general practice based pilot study. AB - New legislation in Greece towards presumed consent for organ donation, effective as of June 2013, has come at a critical moment. This pilot study aims to explore awareness, specific concerns and intentions about the new organ donation framework among patients attending Greek general practices in a rural and urban setting. Only 2.6% of respondents had a donor card, a mere 9.6% was aware of new legislation, whereas only 3.8% considered that the public had been adequately informed. Higher income respondents were more likely to be aware that they would be considered organ donors upon death, unless declared differently. Urban practice respondents were less likely to have previously discussed with a significant other their intentions in regards to presumed consent. One quarter of all respondents (22.4%) intended to carry out their right to prohibit organ removal upon death. Survey results reveal that organ donation reform has yet to be disseminated by the Greek society, underscoring the urgency for targeted information campaigns. PMID- 24046529 TI - Association of the rs7395662 SNP in the MADD-FOLH1 and several environmental factors with serum lipid levels in the Mulao and Han populations. AB - BACKGROUND: The rs7395662 single nucleotide polymorphism (SNP) in the MADD-FOLH1 has been associated with serum lipid traits, but the results are inconsistent in different populations. The present study was undertaken to investigate the association of rs7395662 SNP and several environmental factors with serum lipid levels in the Guangxi Mulao and Han populations. METHOD: A total of 721 subjects of Mulao and 727 subjects of Han Chinese were randomly selected from our previous stratified randomized samples. Genotyping of the SNP was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and confirmed by direct sequencing. RESULTS: Serum apolipoprotein (Apo) B levels were higher in Mulao than in Han (P < 0.01). The allelic and genotypic frequencies in Han were different between males and females (P < 0.05 for each), but there was no difference between Mulao and Han or between Mulao males and females. The levels of low-density lipoprotein cholesterol (LDL C) and ApoB in Mulao females were different among the genotypes (P < 0.05), the G allele carriers had higher LDL-C and ApoB levels than the G allele non-carriers. The levels of total cholesterol (TC), triglyceride (TG), LDL-C and ApoB in Han males and TC, TG and high-density lipoprotein cholesterol (HDL-C) in Han females were different among the genotypes (P < 0.05-0.01), the subjects with GG genotype in Han males had higher TC, TG, and ApoB and lower LDL-C levels than the subjects with AA or AG genotype, and the G allele carriers in Han females had lower TC and HDL-C levels than the G allele non-carriers. The levels of LDL-C and ApoB in Mulao females were correlated with the genotypes (P < 0.05 for each). The levels of HDL-C and ApoAI in Han males and HDL-C in Han females were correlated with genotypes (P < 0.05-0.001). Serum lipid parameters were also correlated with several environmental factors in both ethnic groups (P < 0.05-0.01). CONCLUSION: The association of rs7395662 SNP and serum lipid levels is different between the Mulao and Han populations, and between males and females in both ethnic groups. PMID- 24046531 TI - S100A11 is a migration-related protein in laryngeal squamous cell carcinoma. AB - OBJECTIVE: As a member of the S100 proteins family, the involvement of S100A11 has been suggested in a wide range of biological processes such as cell growth and motility, cell-cycle progression, transcription, differentiation and smooth muscle cell migration. However, the expression of S100A11 and its exact function in laryngeal squamous cell carcinoma (LSCC) have not been elucidated. METHODS: The protein and mRNA expression levels of S100A11 were analyzed in primary tumors and matched tumor-adjacent tissues of LSCC by western blotting and semi quantitative reverse transcription polymerase chain reaction (RT-PCR) or quantitative real time PCR (Q-RT-PCR), respectively. Cell proliferation, colony formation, migration and wound-healing assays were performed to assess whether the knockdown of S100A11 by small interfering RNA (siRNA) could influence the biological behavior of human laryngeal carcinoma Hep-2 cells in vitro. RESULTS: We found that both protein and mRNA levels of S100A11 were overexpressed in laryngeal tumor tissues when compared to the corresponding noncancerous tissues. Further, it was demonstrated that the expression of S100A11 could induce migration but not proliferation of Hep-2 cells. Additionally, S100A11 altered a series of intracellular events, including the down-regulation of epidermal growth factor receptor (EGFR), CD44 and MMP2. CONCLUSIONS: These results highlight the significance of S100A11 in LSCC progression and suggest that the dysregulation of S100A11 might contribute to the metastatic progression of LSCC. PMID- 24046532 TI - Relationship between microstructure, material distribution, and mechanical properties of sheep tibia during fracture healing process. AB - The aim of this study was to investigate the relationship between microstructural parameters, material distribution, and mechanical properties of sheep tibia at the apparent and tissue levels during the fracture healing process. Eighteen sheep underwent tibial osteotomy and were sacrificed at 4, 8, and 12 weeks. Radiographs and micro-computed tomography (micro-CT) scanning were taken for microstructural assessment, material distribution evaluation, and micro-finite element analysis. A displacement of 5% compressive strain on the longitudinal direction was applied to the micro-finite element model, and apparent and tissue level mechanical properties were calculated. Principle component analysis and linear regression were used to establish the relationship between principle components (PCs) and mechanical parameters. Visible bony callus formation was observed throughout the healing process from radiographic assessment. Apparent mechanical property increased at 8 weeks, but tissue-level mechanical property did not increase significantly until 12 weeks. Three PCs were extracted from microstructural parameters and material distribution, which accounted for 87.592% of the total variation. The regression results showed a significant relationship between PCs and mechanical parameters (R>0.8, P<0.05). Results of this study show that microstructure and material distribution based on micro-CT imaging could efficiently predict bone strength and reflect the bone remodeling process during fracture healing, which provides a basis for exploring the fracture healing mechanism and may be used as an approach for fractured bone strength assessment. PMID- 24046533 TI - Direct portal vein thrombosis visualization with t2*--weighted magnetic resonance imaging. AB - BACKGROUND AND PURPOSE: To investigate the feasibility of direct magnetic resonance portal vein thrombosis (PVT) visualization with T2*-weighted imaging (T2*WI) without contrast agent. METHODS: Thirty patients with PVT were included in this study. All of them were imaged with contrast-enhanced CT (CE-CT) as well as non-contrast MRI T1, T2 and T2*WI. Imaging data was independently analyzed by two experienced radiologists. T2*WI of all PVT was compared slice-by-slice with each of the comparison sequences (T1WI, T2WI and CE-CT) on the following categories: the location, size, boundary, and conspicuity of thrombus and portal veins. RESULTS: The average score of PVT visualization in T2*WI was higher than T1WI and T2WI in location, size, boundary and conspicuity (t = 7.54 - 84.16, P<0.05), and higher than CE-CT in boundary and conspicuity (t = 3.03- 6.98, P<0.05). For portal vein visualization, there was no significant score difference in left, middle and right portal veins between CE-CT and T2*WI (t = -1.76- 1.35, P>0.05). CONCLUSIONS: Our results suggest T2*WI can characterize PVT accurately with high quality without the use of intravenous contrast agents. PMID- 24046534 TI - Metabolome analysis of erythrocytes from patients with chronic hepatitis C reveals the etiology of ribavirin-induced hemolysis. AB - Ribavirin is one of the major agents used in combination therapy with interferon for chronic hepatitis C, but is often associated with hemolytic anemia as a serious adverse event. Employing metabolome analysis, we demonstrated that the concentrations of intermediate metabolites produced by glycolysis and the pentose phosphate cycle in patients' erythrocytes were significantly decreased after administration of ribavirin. Our findings suggest that hemolysis associated with ribavirin is triggered by an energy crisis and consequent oxidative stress, thus having implications for the prevention of such hemolysis. PMID- 24046535 TI - Risk factors for pulmonary complications following cardiac surgery with cardiopulmonary bypass. AB - BACKGROUND: Pulmonary complications following cardiac surgery with cardiopulmonary bypass (CPB) are often associated with significant morbidity and mortality. However, few reports have focused on evaluating intra- and post operative independent risk factors for pulmonary complications following cardiac surgery with CPB. This study aimed to evaluate peri-operative independent risk factors for postoperative pulmonary complications through investigating and analyzing 2056 adult patients undergoing cardiac surgery with CPB. METHODS: From January 2005 to December 2012, the relevant pre-, intra-, and post-operative data of adult patients undergoing cardiac surgery with CPB in the department of cardiovascular surgery of Tongji Hospital of Tongji University in Shanghai were investigated and retrospectively analyzed. The independent risk factors for pulmonary complications following cardiac surgery with CPB were obtained through descriptive analysis and then logistic regression analysis. RESULTS: One hundred and forty-three adult patients suffered from pulmonary complications following cardiac surgery with CPB, with an incidence of 6.96%. Through descriptive analysis and then logistic regression, independent risk factors for postoperative pulmonary complications were as follows: older age (>65 years) (OR=3.31, 95%CI 1.71-7.13), preoperative congestive heart failure (OR=2.95, 95%CI 1.41-5.84), preoperative arterial oxygenation (PaO2) (OR=0.67, 95%CI 0.33-0.85), duration of CPB (OR=3.15, 95%CI 1.55-6.21), intra-operative phrenic nerve injury (OR=4.59, 95%CI 2.52-9.24), and postoperative acute kidney injury (OR=3.21, 95%CI 1.91 6.67). Postoperative pulmonary complication was not a risk factor for hospital death (OR=2.10, 95%CI 0.89-4.33). CONCLUSIONS: A variety of peri-operative factors increased the incidence of pulmonary complications following cardiac surgery with cardiopulmonary bypass. PMID- 24046536 TI - The ratio of second to fourth digit length (2D:4D) and coronary artery disease in a Han Chinese population. AB - BACKGROUND: The association between index finger to ring finger length ratio (2D:4D) and cardiac disorders has been reported, however it has not been discussed in terms of coronary artery disease (CAD). We investigated whether 2D:4D could be used as a marker for predisposition to CAD as assessed by coronary angiography in Chinese men and women. METHODS: This study included 1764 persons divided into 4 groups, 441 cases with CAD and 441 persons without CAD as control in each sex of the same age. Finger lengths were measured twice for both hands using electronic calipers. Student t test was used to detect the difference of 2D:4D among groups. The receiver operator characteristic curves (ROCs) were used to detect the diagnostic effect of 2D:4D for CAD. RESULTS: There were no significant differences in age among the four groups. A significant difference of 2D:4D ratios between right and left hand were observed only in men in both control and CAD groups. On the right hand in the control group and on both hands in the CAD group, the 2D:4D ratios were higher in women than in men (all, P < 0.001). In men with CAD, mean 2D:4D was higher than mean 2D:4D in control men (right hand 0.962+/-0.042:0.927+/-0.038; left hand 0.950+/-0.044:0.934+/-0.048; both hands, P < 0.001), but this was not observed in women. No relationship was found between 2D:4D and age (all, P >0.05). The area under the curve of right hand 2D:4D in male was 0.72 (95% CI 0.683-0.753, p<0.001), while it was 0.602 (95% CI 0.565-0.639, p<0.001) in left hand. CONCLUSIONS: The present study showed an association between high 2D:4D ratio and CAD in both hands in men. There were no significant differences in mean 2D:4D between women with CAD and controls. PMID- 24046537 TI - Magnitude of gene mutations conferring drug resistance in mycobacterium tuberculosis isolates from lymph node aspirates in ethiopia. AB - OBJECTIVE: Resistance to drugs is due to particular genomic mutations in the specific genes of Mycobacterium tuberculosis. Timely genetic characterization will allow identification of resistance mutations that will optimize an effective antibiotic treatment regimen. We determine the magnitude of gene mutations conferring resistance to isoniazid (INH), rifampicin (RMP) and ethambutol (EMB) among tuberculosis (TB) lymphadenitis patients. METHODS: A cross sectional prospective study was conducted among 226 M.tuberculosis isolates from culture positive lymph node aspirates collected from TB lymphadenitis patients between April 2012 and May 2012. Detection of mutations conferring resistance to drugs was carried out using GenoType((r)) MTBDRplus and GenoType(r) MTBDRsl assay. RESULTS: Out of the 226 strains, mutations conferring resistance to INH, RMP, multidrug resistance tuberculosis (MDR-TB) and EMB were 8, 3, 2 and 2 isolates, respectively. There was no isolated strain that showed mutation in the inhA promoter region gene. All INH resistant strains had mutations in the katG gene at codon 315 with amino acid change of S315T1. Among rifampicin resistant strains, two isolates displayed mutations at codon 531 in the rpoB gene with amino acid change of S531L and one isolate was by omission of wild type probes at Q513L. According to mutations associated with ethambutol resistance, all of the isolates had mutations in the embB gene with aminoacid change of M306I. All isolates resistant to INH, RMP and MDR using BacT/AlerT 3D system were correctly identified by GenoType(r) MTBDRplus assay. CONCLUSION: We observed mutations conferring resistance to INH at S315T1 of the katG gene, RMP at S531L and Q513L in the rpoB genes and EMB at M306I of the embB gene. In the absence of conventional drug susceptibility testing, the effort to develop easy, rapid and cost effective molecular assays for drug resistance TB monitoring is definitely desirable and the GenoType(r) MTBDRplus assay was found to be a useful method for diagnosis of resistance to INH, RMP and MDR from lymph node aspirates. Further molecular cluster analysis to determine transmission dynamics of mutated strain is required. PMID- 24046538 TI - Eight-year seroprevalence of HBV, HCV and HIV in Diyarbakir training and research hospital. AB - Distribution of HBV, HCV and HIV results of the inpatients or outpatients, who had been treated for various diagnoses in Diyarbakir Training and Research Hospital between 2005 and 2012, among years was investigated. Files of the patients, who had been treated as inpatient or outpatient 992. to any diagnosis between 01/01/2005 and 31/12/2012 in the clinics or policlinics of Diyarbakir 581 due Training and Research Hospital, were retrospectively reviewed using patient file database. Serum samples (235.534 for HBsAg, 196.727 for Anti-HBs antibody, 98.497 for HBeAg, 97.417 for Anti-HBe antibody, 225.483 for HCV and 138.923 for HIV) of these patients, which had been processed in microbiology laboratory, were studied by chemiluminescence technique using Roche E-170 (Modular Analytics System) device. Prevalence rates between 2005 and 2012 were as follows: 15.9%-9% for HBsAg, 32.9%-52.3% for Anti-HBs, 2.5%-1.8% for HBeAg, 30.4%-25.2% for Anti HBe, 1%-0.7% for Anti-HCV, and 0.1%-1% for Anti-HIV. Increase in Anti-HBs prevalence is the successful outcome of routine immunization in population. This suggests that, governmental policies focused on this subject have resulted in successful outcomes and that people also take care about this. A prevalence rate decreasing to 9% from 15.9% for HBsAg and prevalence rate increasing to 52.3% from 32.9% for Anti-HBs antibody positivity in 8-year period in our region is quite meaningful. Such favorable developments in our region are of great valuable in terms of indicating to what extent could struggle against HBV is controlled by education and awareness. PMID- 24046539 TI - Directional data analysis under the general projected normal distribution. AB - The projected normal distribution is an under-utilized model for explaining directional data. In particular, the general version provides flexibility, e.g., asymmetry and possible bimodality along with convenient regression specification. Here, we clarify the properties of this general class. We also develop fully Bayesian hierarchical models for analyzing circular data using this class. We show how they can be fit using MCMC methods with suitable latent variables. We show how posterior inference for distributional features such as the angular mean direction and concentration can be implemented as well as how prediction within the regression setting can be handled. With regard to model comparison, we argue for an out-of-sample approach using both a predictive likelihood scoring loss criterion and a cumulative rank probability score criterion. PMID- 24046540 TI - Erratum: 1-[4-(Di-methyl-amino)-benzyl-idene]-4-o-tolyl-thio-semicarbazide. Corrigendum. AB - The correspondence address in the paper by Huang et al. [Acta Cryst. (2013), E69, o906-o907] is corrected.[This corrects the article DOI: 10.1107/S1600536813012890.]. PMID- 24046541 TI - A new mixed-valence lead(II) mangan-ese(II/III) phosphate(V): PbMn(II) 2Mn(III)(PO4)3. AB - The title compound, lead trimanganese tris(orthophosphate), has been synthesized by hydro-thermal methods. In this structure, only two O atoms are in general positions and all others atoms are in the special positions of the Imma space group. Indeed, the atoms in the Wyckoff positions are namely: Pb1 and P1 on 4e (mm2); Mn1 on 4b (2/m); Mn2 and P2 on 8g (2); O1 on 8h (m); O2 on 8i (m). The crystal structure can be viewed as a three-dimensional network of corner- and edge-sharing PO4 tetra-hedra and MnO6 octa-hedra, building two types of chains running along the b axis. The first is an infinite linear chain, formed by alternating Mn(III)O6 octa-hedra and PO4 tetra-hedra which share one vertex. The second chain is built up from two adjacent edge-sharing octa-hedra (Mn(II) 2O10 dimers) whose ends are linked to two PO4 tetra-hedra by a common edge. These chains are linked together by common vertices of polyhedra in such a way as to form porous layers parallel to (001). These sheets are bonded by the first linear chains, leading to the appearance of two types of tunnels, one propagating along the a axis and the other along b. The Pb(II) ions are located within the inter sections of the tunnels with eight neighbouring O atoms in form of a trigonal prism that is capped by two O atoms on one side. The three-dimensional framework of this structure is compared with similar phosphates such as Ag2Co3(HPO4)(PO4)2 and Ag2Ni3(HPO4)(PO4)2. PMID- 24046543 TI - Tetra-ammine-(carbonato-kappa(2) O,O')cobalt(III) nitrate: a powder X-ray diffraction study. AB - Practical chemistry courses at universities very frequently propose the synthesis and characterization of [Co(CO3)(NH3)4]NO3, but this goal is never achieved since students only obtain the hemihydrated form. The anhydrous form can be prepared, however, and its structure is presented here. Similar to the hemihydrate form, the anhydrous phase contains the Co(III) ion in an octahedral O2N4 coordination by a chelating carbonate group and four ammine ligands. The structure reveals an intricate array of N-H?O hydrogen bonds involving both the chelating and the non chelating O atoms of the carbonate ligand as hydrogen-bond acceptors of the amine H atoms, which are also involved in hydrogen-bonding inter-actions with the nitrate O atoms. The structure of the anhydrous form is close to that of the hemihydrate phase, suggesting a probable topotactic reaction with relatively small rotations and translations of the [Co(CO3)(NH3)4](+) and NO3 (-) groups during the dehydration process, which produces an unusual volume increase of 4.3%. PMID- 24046542 TI - Redetermination of katayamalite, KLi3Ca7Ti2(SiO3)12(OH)2. AB - The crystal structure of katayamalite, ideally KLi3Ca7Ti2(SiO3)12(OH)2 (potassium trilithium hepta-calcium dititanium dodeca-silicate di-hydroxide), was previously reported in triclinic symmetry (C-1), with isotropic displacement parameters for all atoms and without the H-atom position [Kato & Murakami (1985 ?). Mineral. J. 12, 206-217]. The present study redetermines the katayamalite structure with monoclinic symmetry (space group C2/c) based on single-crystal X-ray diffraction data from a sample from the type locality, Iwagi Island, Ehime Prefecture, Japan, with anisotropic displacement parameters for all non-H atoms, and with the H atoms located by difference Fourier analysis. The structure of katayamalite contains a set of six-membered silicate rings inter-connected by sheets of Ca atoms on one side and by an ordered mixture of Li, Ti and K atoms on the other side, forming layers which are stacked normal to (001). From the eight different metal sites, three are located on special positions, viz. one K and one Li atom on twofold rotation axes and one Ca atom on an inversion center. The Raman spectrum of kataymalite shows a band at 3678 cm(-1), similar to that observed for hydroxyl-amphiboles, indicating no or very weak hydrogen bonding. PMID- 24046544 TI - Tris(N,N-di-methyl-anilinium) tri-MU-bromido-bis[tribromido-anti-monate(III)]. AB - In the title compound, (C8H12N)3[Sb2Br9], two of the three unique N,N dimethyanilinium cations exhibit flip-flop disorder with an occupancy ratio of 0.58 (1):0.42 (1). N-H?Br hydrogen bonds link the organic cations and bioctahedral face-sharing anions into a three-dimensional network. PMID- 24046545 TI - Aqua-(5,10,15,20-tetra-phenyl-porphyrin-ato-kappa(4) N)cadmium(II)-18-crown-6 (1/1). AB - The title compound, [Cd(C44H28N4)(H2O)].(C12H24O6), was made by the reaction of the [Cd(TPP)] with an excess of 18-crown-6 in chloro-benzene (where TPP is tetra phenyl-porphyrinate). The Cd(II) cation is chelated by a TPP anion and coordinated by a water mol-ecule in a distorted N4O square-pyramidal geometry, the Cd(II) cation being displaced by 0.7533 (9) A from the mean plane of four N atoms of TPP anion. The porphyrin core presents a significant distortion, the maximum atomic deviation from the 24-atom mean plane is 0.1517 (2) A. The 18 crown-6 mol-ecule is linked with the Cd(II) complex via classical O-H?O hydrogen bonds. In the crystal, weak C-H?pi inter-actions link the complex and 18-crown-6 mol-ecules into a three-dimensional supra-molecular architecture. PMID- 24046546 TI - Bis(3-chloro-benzoato-kappa(2) O,O')bis-(nicotinamide-kappaN)copper(II). AB - The mol-ecule of the title Cu(II) complex, [Cu(C7H4ClO2)2(C6H6N2O)2], contains two 3-chloro-benzoate (CB) and two nicotinamide (NA) ligands; the CB act as bidentate ligands, while the NA are monodentate ligands. The resulting CuN2O4 coordination polyhedron is a considerably distorted octahedron. The dihedral angles between the carboxyl-ate groups and the adjacent benzene rings are 17.92 (12) and 24.69 (16) degrees , while the two benzene rings and the two pyridine rings are oriented at dihedral angles of 52.20 (8) and 1.56 (6) degrees . In the crystal, N-H?N and C-H?O hydrogen bonds link the mol-ecules into a three dimensional network. The pi-pi contact between the benzene rings [centroid centroid distance = 3.982 (2) A] may further stabilize the crystal structure. PMID- 24046547 TI - Poly[[tetra-aqua-tetra-kis-[MU3-5-(pyridine-4-carboxamido) isophthalato]nickel(II)diterbium(III)] tetra-hydrate]. AB - In the title compound, {[NiTb2(C14H8N2O5)4(H2O)4].4H2O} n , the Tb(III) ion is coordinated by one water mol-ecule and seven O atoms from four 5-(pyridine-4 carboxamido)-isophthalate (L) ligands in a distorted square-anti-prismatic arrangement, while the Ni(II) ion, lying on an inversion center, is six coordinated in an octa-hedral geometry by two pyridine N atoms, two carboxyl-ate O atoms and two water mol-ecules. One L ligand bridges two Tb(III) ions and one Ni(II) ion through two carboxyl-ate groups and one pyridine N atom. The other L ligand bridges two Tb(III) ions and one Ni(II) ion through two carboxyl-ate groups, while the uncoordinating pyridine N atom is hydrogen bonded to an adjacent coordinating water mol-ecule. Extensive O-H?O, N-H?O and O-H?N hydrogen bonds play an important role in stabilizing the crystal structure. PMID- 24046548 TI - Bis{[2,2'-(5,8,11-tri-thia-2,14-di-aza-penta-deca-1,14-diene-1,15-di yl)diphenolato]palladium(II)} aceto-nitrile monosolvate. AB - The asymmetric unit of the title compound, [Pd(C22H26N2O2S3)]2.CH3CN, contains two complex mol-ecules and a single uncoordinated lattice aceto-nitrile solvent mol-ecule. The Pd(II) cations have a trans-N2O2 square-planar geometry and the superposition of the two crystallographically independent Pd(II) complexes yields an overall r.m.s. deviation of 0.292 A. The Pd?Pd separation in the asymmetric unit is 3.3776 (3) A, while the PdN2O2 plane-plane fold angle is 1.62 (7) degrees . A short inter-molecular S?S contact between the central S atom of one complex and its inversion-related symmetry equivalent of 3.663 (2) A is observed. Part of the ligand chain (S-C-C-S) in each complex mol-ecule is disordered over two orientations and refined occupancies that converged to 0.450 (10) and 0.550 (10) for the one complex mol-ecule, and 0.789 (9) and 0.211 (9) for the other. PMID- 24046549 TI - {4-Bromo-2-[(2-{(ethyl-sulfan-yl)[(2-oxido-benzyl-idene-kappaO)amino kappaN]methyl-idene}hydrazinyl-idene-kappaN (1))meth-yl]phenolato-kappaO}(ethanol kappaO)dioxido-uranium(VI). AB - In the title complex, [U(C17H14BrN3O2S)O2(C2H5OH)], the U(VI) cation has a distorted penta-gonal-bipyramidal environment with the penta-gonal plane defined by two N and two O atoms of the tetra-dentate Schiff base ligand and the O atom of the ethanol mol-ecule. Two oxide O atoms occupy the axial positions. The azomethine C=N group and the Br atom are disordered over two positions in a 0.8356 (18):0.1644 (18) ratio. The ethyl-thiolyl group is disordered over three conformations in a 0.8356 (18):0.085 (6):0.079 (6) ratio, and the ethanol ligand is also disordered over three orientations in a 0.470 (16):0.277 (19):0.253 (18) ratio. In the crystal, mol-ecules form centrosymmetric dimers through hydrogen bonding between ethanol O-H donors and phenolate O-atom acceptors. Weak C-H?O inter-actions consolidate the crystal packing. PMID- 24046550 TI - Dichloridobis(pyridine-2-seleno-lato-kappa(2) N,Se)tin(IV). AB - The title compound, [SnCl2(C5H4NSe)2], is the product of a reaction of 2,2' dipyridyl diselenide with tin tetra-chloride. The mol-ecule is located about a twofold rotation axis. The coordination environment of the Sn(IV) atom is a distorted octa-hedron, with two bidentate 2-pyridine-seleno-late ligands inclined to each other at an angle of 83.96 (7) degrees . The two Sn-Cl and two Sn-N bonds are in cis configurations, while the two Sn-Se bonds of 2.5917 (3) A are in a trans configuration, with an Se-Sn-Se angle of 157.988 (15) degrees . In the crystal, pi-pi inter-actions between the pyridine rings [centroid-to-centroid distance of 3.758 (3) A] and weak inter-molecular C-H?Cl hydrogen bonds link the mol-ecules into chains along the c axis. PMID- 24046551 TI - Poly[[penta-aqua-bis-(MU3-hydrogen squarato)barium] monohydrate]. AB - The crystal structure of the title compound, {[Ba(C4HO4)2(H2O)5].H2O} n , consists of discrete double chains propagating along [010]. The chains are formed by Ba(II) ions linked by bridging hydrogen squarate ligands in a trans-bis monodentate mode. In addition, the bridging hydrogen squarate ligands connect the chains into a ladder structure via a third coordinating O atom. The remaining coordination sites are occupied by five aqua ligands and a second mondendate hydrogen squarate ligand, forming a slightly distorted tricapped trigonal prismatic geometry. O-H?O hydrogen bonds link the chains and solvent water mol ecules into a three-dimensional network. PMID- 24046552 TI - N,N,N,N',N',N'-Hexa-kis-(2-hy-droxy-ethyl)butane-1,4-diaminium bis-(2-sul-fan ylidene-1,3-di-thiole-4,5-dithiolato-kappa(2) S (4),S (5))zincate. AB - In the asymmetric unit of the title compound, (C16H38N2O6)[Zn(C3S5)2], two independent cations lie across inversion centers. In one of the cations, the three symmetry-unique O-H groups are disordered over two sets of sites with refined occupancy ratios of 0.701 (9):0.299 (9), 0.671 (8):0.329 (8) and 0.566 (7):0.434 (7). In the anion, the Zn(II) ion is coordinated in a distorted tetra hedral environment by four S atoms of two chelating 1,3-di-thiole-2-thione-4,5 dithiolato ligands. The dihedral angle between the mean planes [maximun deviations = 0.022 (3) and 0.0656 (6) A] of the two ligands is 87.76 (3) degrees . An intamolecular O-H?O hydrogen bond occurs in the disordered cation. In the crystal, O-H?O and O-H?S hydrogen bonds link the components into a two dimensional network parallel to (0-11). PMID- 24046553 TI - Potassium N-bromo-4-chloro-2-methyl-benzene-sulfonamidate monohydrate. AB - In the title compound, K(+).C7H6BrClNO2S(-).H2O, the K(+) cation is hepta coordinated by two water O atoms, four sulfonyl O atoms of four different N-bromo 4-chloro-2-methyl-benzene-sulfonamidate anions, and one Br atom of one of the anions. The S-N distance of 1.584 (3) A is consistent with an S=N double bond. In the crystal, the anions are linked into layers by O-H?Br and O-H?N hydrogen bonds. PMID- 24046554 TI - Poly[[diaqua-tris(MU2-4,4'-bi-pyridine)-bis[MU2-2-(carb-oxylato-methyl-sulfan yl)nicotinato]dicobalt(II)] 1.3-hydrate]. AB - The title complex, [Co2(C8H5NO4S)2(C10H8N2)3(H2O)2].1.3H2O, was synthesized under hydro-thermal conditions. The Co(II) ion is six-coordinated in a slightly distorted octa-hedral environment resulting from two carboxyl-ate O atoms of two 2-carb-oxy-methyl-sulfanyl nicotinate (2-CMSN(2-)) anions, one water mol-ecule and three N atoms of three 4,4'-bi-pyridine ligands, with one 4,4'-bi-pyridine ligand situated on a centre of inversion. Two neighboring Co(II) ions are linked by two anions, giving a dinuclear [Co2(2-CMSN)2] subunit with a Co?Co separation of 6.8600 (3) A. The dinuclear subunits are joined by bridging 4,4'-bi-pyridine linkers, generating a three-dimensional network structure. Disordered water mol ecules are situated in the free space of this network. O-H?O hydrogen bonding within and between the subunits enhances the stability of the structure. PMID- 24046555 TI - Chlorido{1-[(dimethylamino)methyl]ferrocenyl-kappa(2) C (2),N}(tri-phenyl-stibine kappaSb)palladium(II). AB - In the title compound, [FePdCl(C5H5)(C8H11N)(C18H15Sb)], obtained by reaction of diphen-yl(N,N-di-methyl-amino-methyl-ferrocen-yl)stibine with sodium tetra chlorido-palladate(II) in acetone, the Pd(II) atom is coordinated in a slightly distorted square-planar geometry by a C atom of the ferrocenyl ring, and by N, Cl and Sb atoms. The Sb and N atoms are trans to each other. PMID- 24046556 TI - Penta-aqua-(di-methyl-formamide)-cobalt(II) sulfate di-methyl-formamide monosolvate. AB - The title compound, [Co(C3H7NO)(H2O)5]SO4.C3H7NO, contains five aqua ligands, a Co(II) atom, a sulfate ion and both a coordinating and a non-coordinating di methyl-formamide (DMF) mol-ecule. The DMF solvent mol-ecule lies between the complex units, which are located along the b axis. The sulfate ion is for charge balance. The Co(II) atom has distorted octa-hedral coordination geometry, being ligated by five aqua ligands and the O atom of the DMF ligand. O-H?O hydrogen bonds between the aqua ligands and the sulfate anion and non-coordinating DMF molecule lead to the formation of a three-dimensional network. Since all constituents lie on a mirror plane, the H atoms of all methyl groups and of one of the aqua ligands are equally disordered over two positions. PMID- 24046557 TI - cis-Bromido(methyl-amine)-bis-(propane-1,3-di-amine)-cobalt(III) dibromide. AB - In the title compound, [CoBr(CH5N)(C3H10N2)2]Br2, the cobalt(III) ion has a distorted octa-hedral coordination environment and is surrounded by four N atoms in the equatorial plane, with an additional N atom and the Br atom occupying the axial positions. In the crystal, the complex cation and the two counter anions are linked via N-H?Br and C-H?Br hydrogen bonds, forming a three-dimensional network. PMID- 24046558 TI - cis-(1,4,8,11-Tetra-aza-cyclo-tetra-decane-kappaN (4))bis(-thio-cyanato kappaN)chromium(III) thio-cyanate. AB - The crystal structure of [Cr(NCS)2(cyclam)]NCS (cyclam = 1,4,8,11-tetra-aza-cyclo tetra-deca-ne, C10H24N4) has been determined by using synchrotron radiation at 98 K. The Cr(III) atom is in a slightly distorted octa-hedral environment with four N atoms of the macrocyclic ligand and two N-coordinated NCS(-) anions in cis positions. The average Cr-N(cyclam) and Cr-NCS bond lengths are 2.085 (5) and 1.996 (15) A, respectively. In the crystal, the uncoordinating SCN(-) anion is hydrogen bonded through N-H?S and N-H?N inter-actions to neighbouring complex cations. PMID- 24046559 TI - 2-Ferrocenyl-3-nitro-2H-chromene. AB - In the title compound, [Fe(C5H5)(C14H10NO3)], the cyclo-penta-dienyl rings are in an eclipsed conformation and the pyran ring adopts a half-chair conformation. The mean plane of the pyran ring makes dihedral angles of 79.33 (1) and 80.73 (1) degrees , respectively, with the substituted and unsubstituted cyclo-penta-dienyl rings. In the crystal, pairs of C-H?O hydrogen bonds link the mol-ecules into inversion dimers with R 2 (2)(16) motifs. PMID- 24046560 TI - 4-(Di-methyl-amino)-pyridinium trichlorido[4-(di-methyl-amino)-pyridine kappaN]cobaltate(II). AB - In the anion of the title compound, (C7H11N2)[CoCl3(C7H10N2)], the Co(II) ion is coordinated by one N atom from a 4-(di-methyl-amino)-pyridine (DMAP) ligand and three Cl atoms, forming a CoNCl3 polyhedron with a distorted tetra-hedral geometry. In the crystal, cations and anions are linked via weak N-H?Cl and C H?Cl hydrogen bonds. Double layers of complex anions stack along the b- axis direction, which alternate with double layers of 4-(di-methyl-amino)-pyridinium cations. PMID- 24046561 TI - catena-Poly[aqua-bis-(MU-3-chloro-benzo-ato-kappa(2) O:O')zinc]. AB - In the polymeric title compound, [Zn(C7H4ClO2)2(H2O)] n , the Zn(II) cation is located on a twofold rotation axis and is coordinated by carboxylate O atoms of four monodentate chloro-benzoate anions and by one water mol-ecule, located on a twofold rotation axis, in a distorted square-pyramidal geometry. In the anion, the carboxyl-ate group is twisted away from the attached benzene ring by 44.16 (11) degrees . The chloro-benzoate anion bridges Zn(II) cations, forming polymeric chains running along the c-axis direction. O-H?O hydrogen bonds between coordinating water mol-ecules and carboxyl-ate groups link adjacent chains into layers parallel to the bc plane. PMID- 24046562 TI - Poly[bis-{MU-N'-[(pyridin-4-yl)methyl-idene]benzohydrazidato}copper(II)]. AB - In the title complex, [Cu(C13H10N3O)2] n , the copper(II) cation is located on a crystallographic inversion centre and adopts an elongated octa-hedral coordination geometry with the equatorial plane provided by trans-arranged bis N,O-chelating acyl-hydrazine groups from two ligands and the apices by the N atoms of two pyridine rings belonging to symmetry-related ligands. The ligand adopts a Z conformation about the C=N double bond. The dihedral angle between the pyridine and phenyl rings is 2.99 (13) degrees . An intra-ligand C-H?N hydrogen bond is observed. In the crystal, each ligand bridges two adjacent metal ions, forming a (4,4) grid layered structure. pi-pi stacking inter-actions [centroid centroid distances in the range 3.569 (4)-3.584 (9) A] involving rings of adjacent layers result in the formation of a three-dimensional supra-molecular network. PMID- 24046563 TI - Poly[hexa-aqua-(MU9-cyclo-hexane-1,2,3,4,5,6-hexa-carboxyl-ato)trimanganese(II)]. AB - The asymmetric unit of the title compound, [Mn3(C12H6O12)(H2O)6] n , comprises one Mn(II) ion, one third of a cyclo-hexane-1,2,3,4,5,6-hexa-carboxyl-ate anion and two aqua ligands. The anion is completed by application of a -3 axis. The Mn(II) ion is six-coordinated by six O atoms from two aqua ligands and three different cyclo-hexa-carboxyl-ate anions in an octa-hedral geometry. The six carboxyl-ate groups adopt a bridging bidentate mode to ligate the Mn(II) ions. Thus, each cyclo-hexane-1,2,3,4,5,6-hexa-carboxyl-ate anion adopts a MU9 connected mode, ligating nine different Mn(II) ions and forming a three dimensional framework. In the framework, there are strong O-H?O hydrogen-bonding inter-actions, which further stabilize the crystal structure. PMID- 24046564 TI - Bis(dicyanamido-kappaN)[tris-(3-amino-propyl)amine-kappa(4) N]nickel(II). AB - In the title complex, [Ni(C2N3)2(C9H24N4)], the Ni(II) atom is coordinated in a distorted octa-hedral geometry by one tris-(3-amino-prop-yl)amine (tris-apa) ligand and two dicyanamide (dca) ligands [one of them disordered in a 0.681 (19):0319 (19) ratio]. Inter-molecular N-H?N hydrogen bonds involving the N atoms of the dca anions and the tris-apa amine H atoms result in the formation of a three-dimensional network. PMID- 24046565 TI - (4,7,13,16,21,24-Hexaoxa-1,10-di-aza-bicyclo-[8.8.8]hexa-cosa-ne)sodium iodide 1,1,2,2,tetra-fluoro-1,2-diiodo-ethane (2/3). AB - The title complex (CX1), [Na(C18H36N2O6)]I.1.5C2F4I2, is a three-component adduct containing a [2.2.2]-cryptand, sodium iodide and 1,1,2,2-tetra-fluoro-1,2-di-iodo ethane. The di-iodo-ethane works as a bidentate halogen-bonding (XB) donor, the [2.2.2]-cryptand chelates the sodium cation, and the iodide counter-ion acts as a tridentate XB acceptor. A (6,3) network is formed in which iodide anions are the nodes and halocarbons the sides. The network symmetry is C 3i and the I?I(-) XB distance is 3.4492 (5) A. This network is strongly deformed and wrinkled. It forms a layer 9.6686 (18) A high and the inter-layer distance is 4.4889 (10) A. The cations, inter-acting with each other via weak O?H hydrogen bonds, are confined between two anionic layers and also form a (6,3) net. The structure of CX1 is closely related to that of the KI homologue (CX2). The 1,1,2,2, tetrafluoro-1,2-diiodoethane molecule is rotationally disordered around the I?I axis, resulting in an 1:1 disorder of the C2F4 moiety. PMID- 24046566 TI - Di-MU-nicotinamide-kappa(2) N (1):O;kappa(2) O:N (1)-bis-[aqua-bis-(3-chloro benzoato-kappa(2) O,O')cadmium]. AB - In the centrosymmetric dinuclear title compound, [Cd2(C7H4ClO2)4(C6H6N2O)2(H2O)2], the Cd(II) atom is coord-inated by one N atom from one bridging nicotinamide ligand and one O atom from another symmetry related bridging nicotinamide ligand, four O atoms from two 3-chloro-benzoate ligands and one water mol-ecule in an irregular geometry. The dihedral angles between the carboxyl-ate groups and the adjacent benzene rings are 6.98 (12) and 2.42 (13) degrees , while the benzene rings are oriented at a dihedral angle of 4.33 (6) degrees . Inter-molecular O-H?O, N-H?O and weak C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. pi-pi inter-actions, indicated by short centroid-centroid distances [3.892 (1) A between the pyridine rings and 3.683 (1) A between the benzene rings] further stabilize the structure. PMID- 24046567 TI - Bis[chloridobis(1,10-phenanthroline)copper(II)] penta-cyanido-nitro-soferrate(II) di-methyl-formamide monosolvate. AB - The title complex [CuCl(C12H8N2)2]2[Fe(CN)5(NO)].C3H7NO, consists of discrete [Cu(phen)2Cl](+) cations (phen is 1,10-phenanthroline), [Fe(CN)5NO](2-) anions and one di-methyl-formamide (DMF) solvent mol-ecule of crystallization per asymmetric unit. The Cu(II) atom is coordinated by two phenanthroline ligands and one chloride ion in a distorted trigonal-bipyramidal geometry. The dihedral angle between the phen ligands is 77.92 (7) degrees . The cation charge is balanced by a disordered nitro-prusside counter-anion with the Fe(II) atom located on an inversion center with a slightly distorted octa-hedral coordination geometry. In the crystal, weak C-H?N and C-H?Cl hydrogen bonds connect anions and cations into a two-dimensional network parallel to (100). In addition, pi-pi stacking inter actions are observed with centroid-centroid distances in the range 3.565 (2) 3.760 (3)A. The di-methyl-formamide solvent mol-ecule was refined as disordered about an inversion center. PMID- 24046568 TI - MU3-Acetato-MU2-acetato-(di-methyl-form-amide)-penta-kis-(MU-N,2-dioxido-benzene 1-carboximidato)penta-kis-(1-methyl-1H-imidazole)-penta manganese(III)manganese(II)-diethyl ether-di-methyl-formamide-methanol-water (1/1/1/1/0.49). AB - The title compound, [Mn6(C7H4NO3)5(CH3CO2)2(C4H6N2)4.62(C3H7NO)1.38].(C2H5)2O.C3H7NO.CH3OH.0.49H2O or Mn(II)(OAc)2[15-MCMn(III)N(shi)-5](Me-Im)4.62(DMF)1.38.diethyl ether.DMF.MeOH.0.49H2O (where MC is metallacrown, (-)OAc is acetate, shi(3-) is salicyl-hydroximate, Me-Im is 1-methyl-imidazole, DMF is N,N-di-methyl-formamide, and MeOH is methanol), is comprised of five Mn(III) ions in the metallacrown ring and an Mn(II) ion which is encapsulated in the central cavity. Four of the ring Mn(III) ions are six-coordinate with distorted octa-hedral geometries. Two of these Mn(III) ions have a planar configuration, while the other two Mn(III) have Lambda absolute stereoconfiguration. The fifth Mn(III) is five-coordinated with distorted square-pyramidal geometry. Four of the ring Mn(III) ions each bind one 1-methyl-imidazole, while the final ring Mn(III) ion binds a DMF solvent mol ecule in an axial position and located in a trans position is either a Me-Im or a DMF mol-ecule. The occupancy ratio of Me-Im to DMF is 0.62 (2) to 0.38 (2). The central Mn(II) is seven-coordinate with a geometry best described as distorted face-capped trigonal-prismatic. DMF, diethyl ether, MeOH, and water mol-ecules are located in the inter-stitial voids between the metallacrown mol-ecules. The methanol mol-ecule is positionally disordered [0.51 (1):0.49 (1)] and associated with a partially occupied water mol-ecule [0.49 (1)]. This disorder is also associated with the positional disorder of the diethyl ether mol-ecule [0.51 (1):0.49 (1)]. PMID- 24046569 TI - cis-Dichlorido-tetra-kis-(dimethyl sulfoxide-kappaO)chromium(III) chloride dimethyl sulfoxide monosolvate. AB - The structure of the title compound, [CrCl2(C2H6OS)4]Cl.C2H6OS, consists of a Cr(III) ion coordinated by four O atoms of dimethyl sulfoxide (DMSO) ligands and two chloride ions in cis positions, forming a distorted CrCl2O4 octa-hedron. An isolated Cl(-) counter-anion and a positionally disordered DMSO mol-ecule [occupancy ratio 0.654 (4):0.346 (4)] are also present. In the structure, the complex cations inter-act with the Cl(-) counter-anions and the DMSO solvent mol ecules via weak C-H?Cl and C-H?O inter-actions, forming a three-dimensional network. PMID- 24046570 TI - catena-Poly[bis-(MU3-2-phenyl-acetato-kappa(3) O,O':O)bis-(MU2-2-phenyl-acetato kappa(2) O:O')dicopper(II)(Cu-Cu)]. AB - The title polymeric compound, [Cu2(C8H7O2)4] n , was synthesized by the reaction of copper acetate with aqueous phenyl-acetic acid. The unique Cu(II) atom is coordinated by five O atoms from the carboxyl-ate groups of phenyl-acetate ligands, and the strongly distorted octa-hedral coordination environment is completed by a Cu-Cu bond of 2.581 (2) A, at whose mid-point is located an inversion centre. The crystal structure consists of infinite polymeric linear chains of Cu(2+) ions, running along [100], linked by bridging phenyl-acetate groups. PMID- 24046571 TI - Poly[(aceto-nitrile-kappaN)-MU3-thio-cyanato-kappa(3) N:S:S-MU2-thio-cyanato kappa(2) N:S-cadmium]. AB - The asymmetric unit of the title compound, [Cd(NCS)2(CH3CN)] n , consists of one Cd(II) cation, two thio-cyanate anions and one aceto-nitrile ligand, all in general positions. The Cd(II) cation is coordinated by three N atoms of two thio cyanate anions and one aceto-nitrile ligand, as well as three S atoms of symmetry related thio-cyanate anions within a slightly distorted octa-hedral coordination environment. The Cd(II) cations are linked by MU-1,3(N,S) and MU-1,1,3(S,S,N) thio-cyanate anions into layers that are located in the ab plane. PMID- 24046572 TI - Di-aqua-{2,2'-dimeth-oxy-6,6'-[(1E,1'E)-propane-1,3-diylbis(aza-nylyl-idene)bis (methanylyl-idene)]diphenolato}nickel(II). AB - In the mol-ecule of the title compound, [Ni(C19H20N2O4)(H2O)2], the central Ni(II) ion lies on a mirror plane and is surrounded by an N2O4 coordination set in the form of a distorted octa-hedron defined by the O atoms of two water mol ecules and by two phenolic O and two imine N atoms of the tetra-dentate Schiff base ligand. In the crystal, O-H?O hydrogen bonds between the water mol-ecules and the phenolic and meth-oxy O atoms of neighbouring mol-ecules lead to the formation of rods propagating parallel to [100]. PMID- 24046573 TI - Poly[di-methyl-ammonium [(MU2-benzene-1,2-di-carboxyl-ato-kappa(2) O (1):O (3))[MU2-3-(pyri-din-4-yl)-1H-pyrazol-1-ido-kappa(2) N (1):N (3)]cuprate(II)]]. AB - In the title complex, {(C2H8N)[Cu(C8H4O4)(C8H6N3)]} n , there are two Cu(II) cations (each located on a centre of inversion), one benzene-1,2-di-carboxyl-ate dianion, one 3-(pyridin-4-yl)-1H-pyrazol-1-ide anion and one di-methyl-ammonium cation in the asymmetric unit. The di-methyl-ammonium cation was highly disordered and was treated with the SQUEEZE routine in PLATON [Spek (2009 ?). Acta Cryst. D65, 148-155]; the crystallographic data takes into account the presence of the cation. Each Cu(II) cation exhibits a square-planar coordination geometry. A benzene-1,2-di-carboxyl-ate dianion bridges two Cu(II) cations, building a linear chain along [001]. The chains are connected by 3-(pyridin-4-yl) 1H-pyrazol-1-ide anions, constructing a layer parallel to (101). The layers are assembled into a three-dimensional supra-molecular network through C-H?pi inter actions. PMID- 24046574 TI - Bis{3-amino-1-carbamo-thioyl-5-[(2-{[(5-methyl-1H-imidazol-3-ium-4-yl)meth yl]sulfan-yl}eth-yl)amino]-1H-1,2,4-triazol-4-ium} hexa-chloridobismuthate(III) nitrate dihydrate. AB - The asymmetric unit of the title hydrated salt, (C10H18N8S2)2[BiCl6]NO3.2H2O, contains two independent 3-amino-1-carbamo-thioyl-5-[(2-{[(5-methyl-1H-imidazol-3 ium-4-yl)meth-yl]sulfan-yl}eth-yl)amino]-1H-1,2,4-triazol-4-ium cations, one hexa chloridobismuthate anion, one nitrate anion and two solvent water mol-ecules. The dihedral angles between the imidazole and triazole rings in the cations are 44.7 (3) and 89.4 (3) degrees . The Bi(III) ion is coordinated by six chloride ligands in a slightly distorted octa-hedral geometry. In each cation, an intra-molecular N-H?S hydrogen bond is observed. In the crystal, N-H?Cl, N-H?S, N-H?O, O-H?Cl, O H?S and O-H?O hydrogen bonds connect the components into a three-dimensional network. In addtion, pi-pi stacking inter-actions between inversion-related triazole rings are observed, with a centroid-centroid distance of 3.322 (3) A PMID- 24046575 TI - Chlorido[2,2'-[1,2-phenyl-enebis(nitrilo-methanylyl-idyne)]diphenolato-kappa(4) O,N,N',O']manganese(III) methanol monosolvate. AB - In the title complex, [Mn(C20H14N2O2)Cl].CH3OH, the central Mn(III) atom displays a distorted square-pyramidal coordination by two N and two O atoms from the tetradentate 2,2'-[1,2-phenyl-enebis(nitrilo-methanylyl-idyne)]diphenolate ligand and one chloride ligand. The Mn(III) atom is 0.525 (4) A out of the square basal N2O2 least-squares plane. The complex mol-ecule is hydrogen bonded to the methanol solvent mol-ecule. PMID- 24046576 TI - Bis{1-[(E)-(2-chloro-phen-yl)diazen-yl]naphthalen-2-olato}copper(II). AB - The Cu(II) atom in the title compound, [Cu(C16H10ClN2O)2], is located on an inversion center and is tetra-coordinated by two N and two O atoms from two bidentate 1-[(E)-(2-chloro-phen-yl)diazen-yl]naphthalen-2-olate ligands, forming a square-planar complex. In the crystal, mol-ecules are linked via weak C-H?O and C-H?Cl hydrogen bonds, forming chains propagating along [010]. There are also pi pi inter-actions present involving adjacent naphthalene rings [centroid-centroid distance = 3.661 (13) A]. PMID- 24046577 TI - Poly[tetra-butyl-ammonium [chlorido-hexa-methyl-MU3-sulfato-distannate(IV)]]. AB - In the structure of the title coordination polymer, {(C16H36N)[Sn2(CH3)6Cl(SO4)]} n , the two independent Sn(IV) atoms are coordinated in a trigonal-bipyramidal manner by three methyl groups in the equatorial plane and in the axial positions by either two O atoms of bridging SO4 (2-) anions or by a Cl atom and one O atom of a bridging SO4 (2-) anion, respectively. The [Sn2(CH3)6Cl(SO4)](-) anion forms an infinite zigzag chain parallel to the c axis. The cations are situated between these chains. Two of the four butyl groups of the cation are partially disordered over two sets of sites with site occupancies of 0.79 (2):0.21 (2) and 0.75 (2):0.25 (2), respectively. Weak C-H?O hydrogen-bonding inter-actions help to consolidate the crystal packing. PMID- 24046578 TI - cis-Bis(O-methyl-dithio-carbonato-kappa(2) S,S')bis-(tri-phenyl-phosphane kappaP)ruthenium(II). AB - In the title compound, [Ru(CH3OCS2)2(C18H15P)2], the Ru(II) atom is in a distorted octa-hedral coordination by two xanthate anions (CH3OCS2) and two tri phenyl-phosphane (PPh3) ligands. Both bidentate xanthate ligands coordinate the Ru(II) atom with two slightly different Ru-S bond lengths but with virtually equal bite angles [71.57 (4) and 71.58 (3) degrees ]. The packing of the complexes is assured by C-H?O and C-H?pi inter-actions. PMID- 24046579 TI - trans-Diamminedichloridobis(1H-imidazole-kappaN (3))nickel(II). AB - The whole mol-ecule of the title compound, [NiCl2(C3H4N2)2(NH3)2], is generated by inversion symmetry. The Ni(II) ion, which is located on an inversion center, has a distorted octa-hedral coordination environment and is surrounded by two ammine N atoms and two Cl atoms in the equatorial plane, with two N atoms of two imidazole groups occupying the axial positions. The imidazole ring makes a dihedral angle of 81.78 (18) degrees with the Ni/N/Cl equatorial plane. In the crystal, mol-ecules are linked via N-H?Cl hydrogen bonds and C-H?pi inter actions, forming a three-dimensional network. PMID- 24046580 TI - catena-Poly[di-MU3-bromido-bis-[(1-ethyl-1H-imidazole-kappaN (3))disilver(I)]]. AB - The asymmetric unit of the title coordination complex, [Ag2Br2(C5H8N2)2] n , comprises a monodentate 1-ethyl-imida-zole ligand, an Ag(+) cation and a MU3 bridging Br(-) anion, giving a distorted tetra-hedral AgNBr3 stereochemistry about the Ag(+) cation [Ag-N = 2.247 (2) A and Ag-Br = 2.7372 (4)-2.7523 (4) A]. Two bridging bromide anions generate the dimeric [Ag2Br2(C5H8N)2] repeat unit [Ag?Ag = 3.0028 (5) A], while a third Br(-) anion links the units through corner sharing in an inversion-related Ag2Br2 association [Ag?Ag = 3.0407 (4) A], generating a one-dimensional ribbon step-polymer structure, extending along the c axis. PMID- 24046581 TI - Bis{2-[(5-hy-droxy-pent-yl)imino-meth-yl]phenolato-kappa(2) N,O (1)}copper(II). AB - In the title compound, [Cu(C12H16NO2)2], the Cu(II) ion, located on a center of inversion, is coordinated by two singly deprotonated Schiff base ligands derived from condensation of salicyldehyde and 1-amino-pentan-5-ol. The imino N and phenol O atoms from both ligands offer a square-planar arrangement around the metal ion. The Cu-N and Cu-O bond lengths are 2.0146 (15) and 1.8870 (12) A, respectively. Since the Cu-O and Cu-N bond lengths are different, it can be concluded that the resulting geometry of the complex is distorted. The aliphatic OH group of the ligand is not coordinated and points away from the metal coordination zone and actively participates in hydrogen bonding connecting two other units and thus stabilizing the crystal lattice. This results in a two dimensional extended array parallel to (201). PMID- 24046582 TI - catena-Poly[[silver(I)-MU-N-(pyridin-3-ylmeth-yl)pyridine-2-amine-kappa(2) N:N'] tri-fluoro-methane-sulfonate]. AB - In the asymmetric unit of the title polymeric complex, {[Ag(C11H11N3)](CF3SO3)} n , there are two Ag(I) atoms, two N-(pyridin-3-ylmeth-yl)pyridine-2-amine ligands (A and B) and two CF3SO3 (-) anions. One Ag(I) atom is coordinated by two pyridine N atoms from two symmetry-related A ligands in a geometry slightly distorted from linear [N-Ag-N = 173.2 (3) degrees ], forming a left-handed helical chain, while the other Ag(I) atom is coordinated by two pyridine N atoms from two symmetry-related B ligands in a bent arrangement [N-Ag-N = 157.1 (3) degrees ], forming a right-handed helical chain. Both helical chains have the same pitch length [10.4007 (7) A], propagate along the b-axis direction and are alternately arranged via Ag?Ag [3.0897 (12) A] and pi-pi stacking inter-actions [centroid-centroid distances = 3.564 (7) and 3.518 (6) A], resulting in the formation of a two-dimensional supra-molecular network extending parallel to the ab plane. Inter-molecular N-H?O, C-H?O and C-H?F hydrogen-bonding inter-actions occur between the helical chains and the anions. PMID- 24046583 TI - catena-Poly[(di-aqua-cadmium)-MU-iminodi-acetato-kappa(4) O,N,O':O'']. AB - In the title compound, [Cd(C4H5NO4)(H2O)2] n , the Cd(II) atom exhibits a distorted octa-hedral coordination geometry, defined by one N atom and three O atoms from two iminodi-acetate (IDA) ligands and two water molecules. The tridentate IDA ligand additionally bridges via one of its carboxylate O atoms to another Cd(II) atom, thus forming a zigzag chain along [001]. A three-dimensional network is completed by inter-molecular O-H?O and N-H?O hydrogen bonds. PMID- 24046584 TI - (3-Acetyl-4-methyl-1H-pyrazol-1-ide-5-carboxyl-ato)bis-(1,10 phenanthroline)nickel(II) 3.5-hydrate. AB - The title compound, [Ni(C7H6N2O3)(C12H8N2)2].3.5H2O, crystallizes as a neutral mononuclear complex with 3.5 solvent water mol-ecules. One of the water mol ecules lies on an inversion centre, so that its H atoms are disordered over two sites. The coordination environment of Ni(II) has a slightly distorted octa hedral geometry, which is formed by one O and five N atoms belonging to the N,O chelating pyrazol-1-ide-5-carboxyl-ate and two N,N'-chelating phenanthroline mol ecules. In the crystal, O-H?O, N-H?O and O-H?N hydrogen bonds involving the solvent water mol-ecules and pyrazole-5-carboxyl-ate ligands form layers parallel to the ab plane. These layers are linked further via weak pi-pi inter-actions between two adjacent phenanthroline mol-ecules, with centroid-to-centroid distances in the range 3.886 (2)-4.018 (1) A, together with C-H?pi contacts, forming a three-dimensional network. PMID- 24046585 TI - {2,2'-[(1,2-Di-cyano-ethene-1,2-di-yl)bis-(nitrilo-methanylyl-idyne)]diphenolato kappa(4) O,N,N',O'}(methanol-kappaO)zinc. AB - In the title complex, [Zn(C18H10N4O2)(CH4O)], the Zn(2+) cation is located on a mirror plane and is coordinated by a tetradentate Schiff base ligand anion (L (2 )) and a methanol mol-ecule. The Zn(2+) cation is surrounded by two N atoms and two O atoms from L (2-), in a nearly planar configuration, and one methanol O atom, forming a slightly distorted square-pyramidal geometry. The methanol molecule is disordered over two sets of sites in a 0.5:0.5 ratio. In the crystal, O-H?O hydrogen bonds link the mol-ecules into chains parallel to [001]. PMID- 24046586 TI - trans-Di-aqua-bis-(pyridazine-3-carboxyl-ato-kappa(2) N (2),O)cobalt(II) dihydrate. AB - The title compound, [Co(C5H3N2O2)2(H2O)2].2H2O, contains a Co(II) ion on an inversion center, exhibiting an octa-hedral coordination geometry. The equatorial plane is formed by two trans-related N,O-bidentate pyridazine-3-carboxyl-ate ligands and the axial positions are occupied by two water mol-ecules. The Co(II) complex mol-ecules are stacked in a column along the a-axis direction by an O-H?N hydrogen bond between the non-coordinating pyridazine N atom and the coordinating water mol-ecule. These columns are further connected into a layer parallel to the ac plane by additional hydrogen bonds involving the coordinating and non coordinating water mol-ecules, and the non-coordinating carboxyl-ate O atom. The crystal packing is completed by inter-layer weak C-H?O inter-actions. PMID- 24046587 TI - Poly[MU2-aqua-MU4-[1-(4-chloro-phen-yl)-4,4,4-tri-fluoro-butane-1,3-dionato] potassium]. AB - In the title compound, [K(C10H5ClO2F3)(H2O)] n , the two independent K(+) ions are located on a twofold rotation axis. For each of the cations, the distorted cubic coordination environment is defined by two F and four O atoms of symmetry related 1,4-chloro-phenyl-4,4,4-tri-fluoro-butane-1,3-dionate anions and by two O atoms of water mol-ecules. The MU4-bridging character of the anion and the MU2 bridging of the water mol-ecule lead to the formation of layers parallel to (100). The coordinating water mol-ecules are also involved in O-H?O hydrogen bonds that reinforce the mol-ecular cohesion within the layers, which are stacked along [100]. The beta-diketonate anion is not planar, with an angle of 31.78 (10) degrees between the mean planes of the diketonate group and the chloro-phenyl ring. PMID- 24046588 TI - Di-MU-bromido-bis-[(diethyl ether-kappaO)(2,4,6-tri-methyl-phen-yl)magnesium]: the mesityl Grignard reagent. AB - The crystal structure of the title compound, [Mg2Br2(C9H11)2(C4H10O)2], features a centrosymmetric two-centre magnesium complex with half a mol-ecule in the asymmetric unit. The Mg atom is in a considerably distorted Br2CO coordination. Bond lengths and angles are comparable with already published values. The crystal packing is stabilized by C-H?pi inter-actions linking the complexes into sheets parallel to (0-11). PMID- 24046589 TI - Bis(MU-6-meth-oxy-2-{[(3-oxidoprop-yl)imino]-meth-yl}phenolato)nickel(II) methanol monosolvate. AB - The mol-ecular structure of the title complex, [Ni2(C11H13NO3)2].CH3OH, contains two Ni(II) atoms and two doubly deprotonated 6-meth-oxy-2-{[(3-oxidoprop yl)imino]-meth-yl}phenolate ligands. The Ni(II) atoms are each four-coordinated in a distorted square-planar geometry by three O atoms and one N atom derived from the phenolate ligands. The solvent mol-ecule is linked to the complex mol ecule by two O-H?O hydrogen bonds. PMID- 24046590 TI - Calixarene-based mol-ecular capsule from olefin metathesis. AB - The reaction of tetra-kis-(all-yloxy)calix[4]arene with the first-generation Grubbs catalyst, followed by catalytic hydrogenation, gave the novel bis calixarene 15,20,46,51,64,69,74,79-octa oxatridecacyclo[32.28.8.8(3,28).1(13,53).1(22,44).0(9,14).0(21,26).0(38,70).0(40, 5).0(52,57).0(59,63).0(7,80).0(32,73)]octa-conta 1(63),3,5,7(80),9(14),10,12,21,23,25,28(73),29,31,34,36,38(70),40,42,44,52,54,56, 9,61-tetra-cosa-ene benzene monosolvate, C72H72O8.C6H6. The structure consists of two calix[4]arene units connected by four-carbon chains at each of the four O atoms on their narrow rims, to form a cage. Each of the calix[4]arene units has a flattened cone conformation in which two of the opposite aryl groups are closer together and nearly parallel [dihedral angle between planes = 7.35 (16) degrees ], and the other two aryl groups are splayed outward [dihedral angle between planes = 72.20 (8) degrees ]. While the cavity contains no solvent or other guest mol-ecule, there is benzene solvent mol-ecule in the lattice. Two of the alkyl linking arms were disordered over two conformations with occupancies of 0.582 (3)/0.418 (3) and 0.33 (4)/0.467 (4). They were constrained to have similar metrical and thermal parameters. PMID- 24046591 TI - 2-[(5-Methyl-thio-phen-2-yl)methyl-idene]malono-nitrile. AB - There are two independent molecules in the asymmetric unit of the title compound, C9H6N2S, which is an inter-mediate compound of a cardiovascular drug. The two molecules are nearly planar, displaying dihedral angles of 3.5 (2) and 5.7 (2) degrees between the thiophene ring and the malononitrile moiety. In the crystal, C-H?N inter-actions lead to the formation of a sheet structure that packs in a parallel fashion. PMID- 24046592 TI - (E)-1-(2-Amino-phen-yl)-3-(thio-phen-2-yl)prop-2-en-1-one. AB - The mol-ecule of the title heteroaryl chalcone derivative, C13H11NOS, exists in a trans-configuaration and is almost planar with a dihedral angle of 3.73 (8) degrees between the phenyl and thio-phene rings. An intra-molecular N-H?O hydrogen bond generates an S(6) ring motif. In the crystal, two adjacent mol ecules are linked into a dimer in an anti-parallel face-to-face manner by a pair of C-H?O inter-actions. Neighboring dimers are further linked into chains along the c-axis direction by N-H?N hydrogen bonds. PMID- 24046593 TI - 4-(4,5-Diphenyl-1H-imidazol-2-yl)-N,N-di-methyl-aniline. AB - The asymmetric unit of the title compound, C23H21N3, consists of two symmetry independent and conformationally different mol-ecules [the comparable dihedral angles between the imidazole ring and the three benzene rings being 38.5 (2)/61.5 (3)/3.37 (17) and 45.8 (2)/36.01 (19)/46.94 (17) degrees ]. In the crystal, inter molecular imidazole N-H?N hydrogen-bonding inter-actions give a one-dimensional chain extending along [101]. PMID- 24046594 TI - {2-[(1,3-Benzo-thia-zol-2-yl)meth-oxy]-5-fluoro-phen-yl}(4-chloro-phen yl)methanone. AB - The asymmetric unit of the title compound, C21H13ClFNO2S, contains two independent mol-ecules with similar conformations. In the mol-ecules, the thia zole ring is essentially planar [maximum atomic deviations = 0.014 (4) and 0.023 (5) A] and is oriented with respect to the fluoro-phenyl ring and chloro-phenyl rings at 9.96 (18) and 70.39 (18) degrees in one mol-ecule and at 7.50 (18) and 68.43 (18) degrees in the other; the dihedral angles between the fluoro-phenyl and chloro-phenyl rings are 64.9 (2) and 64.6 (2) degrees , respectively. Inter molecular C-H?O and C-H?F hydrogen bonds stabilize the three-dimensional supra molecular architecture. Weak C-H?pi and pi-pi inter-actions [centroid-centroid distance = 3.877 (3) A] lead to a criss-cross mol-ecular packing along the c axis. PMID- 24046595 TI - 1,3-Alternate conformer 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetra-kis-(4 methyl-sulfanylbenz-yloxy)-2,8,14,20-tetra-thia-calix[4]arene. AB - The title thia-calix[4]arene derivative, C72H80O4S8, adopts a 1,3-alternate conformation, where the four 4-methyl-sul-fan-yl-benzyl groups are located alternately at the two sides of a virtual plane defined by the four bridging S atoms. In the crystal, there are no significant inter-molecular inter-actions present. Some of the peripheral tert-butyl and methyl-sulfanyl groups are disordered over two positions. A region of disordered electron density, occupying voids of ca 700 A(3) for an electron count of 124, was treated using the SQUEEZE routine in PLATON [Spek (2009 ?). Acta Cryst. D65, 148-155]. PMID- 24046596 TI - rac-3-(4-Hy-droxy-benz-yl)chroman-4-one. AB - In the racemic title compound, C16H14O3, the ring of the 4-hy-droxy-benzyl substituent group forms a dihedral angle of 80.12 (12) degrees with the benzene ring of the chromanone system. Two C atoms of the pyran-one ring and the H atoms on the benzyl alpha-C atom are disordered over two sites, with site-occupation factors of 0.818 (8) and 0.182 (8). The crystal structure is stabilized by O-H?O hydrogen bonds, which form parallel one-dimensional zigzag chains down the c axis and are inter-connected by both methine C-H?O hydrogen bonds and weak aromatic C H?pi inter-actions, giving a sheet structure lying parallel to [011]. PMID- 24046597 TI - Ethyl 2-[5-(4-fluoro-phen-yl)pyridin-3-yl]-1-[3-(2-oxopyrrolidin-1-yl)prop-yl]-1H benzimidazole-5-carboxyl-ate. AB - In the title compound, C28H27FN4O3.H2O, the benzimidazole ring system is essentially planar with a maximum deviation of 0.028 (1) A. It makes dihedral angles of 47.59 (5) and 60.31 (5) degrees , respectively, with the pyridine and benzene rings, which make a dihedral angle of 22.58 (6) degrees with each other. The pyrrolidine ring shows an envelope conformation with one of the methyl-ene C atoms as the flap. In the crystal, the components are connected into a tape along the b-axis direction through O-H?O and O-H?N hydrogen bonds and a pi-pi inter action between the pyridine and benzene rings [centroid-centroid distance of 3.685 (8) A]. The tapes are further linked into layers parallel to the ab plane by C-H?O and C-H?F inter-actions. PMID- 24046598 TI - 1-[(6-Chloro-pyridin-3-yl)meth-yl]-10-nitro-1,2,3,5,6,7,8,9-octa-hydro-5,9 methano-imidazo[1,2-a]azocin-5-ol. AB - In the title compound, C16H19ClN4O3, the cyclo-hexane ring displays a chair formation and the tetra-hydro-pyridine ring displays an envelope conformation with the methyl-ene C atom as the flap; the imidazolidine ring also displays an envelope conformation with a methyl-ene C atom as the flap. In the crystal, O-H?N hydrogen bonds between hy-droxy groups and pyridine rings link inversion-related mol-ecules into dimers. Weak C-H?O hydrogen bonds further link the dimers into supra-molecular chains running along the c axis. PMID- 24046599 TI - N-[(3-Ethyl-phen-yl)carbamo-thio-yl]-2,2-di-phenyl-acetamide. AB - In the title mol-ecule, C23H22N2OS, the di-phenyl-acetyl and ethyl-benzene groups adopt a trans-cis conformation, respectively, with respect to the S atom across the (S=)C-N bonds. This conformation is stabilized by an intra-molecular N-H?O hydrogen bond and a weak C-H?S hydrogen bond. The ethyl-substituted benzene ring forms dihedral angles of 87.53 (15) and 73.94 (15) degrees with the phenyl rings. In the crystal, N-H?O hydrogen bonds link mol-ecules into chains along [100]. A weak C-H?pi inter-action is also observed. PMID- 24046600 TI - 4,7-Diphenyl-1,10-phenanthroline methanol hemisolvate. AB - The asymmetric unit of the title compound, C24H16N2.0.5CH3OH, is comprised of two independent bathophenanthroline mol-ecules (systematic name: 4,7-diphenyl-1,10 phenanthroline) and one methanol mol-ecule. The bathophenanthroline mol-ecules are not planar as there is a considerable rotation of all terminal phenyl rings with respect to the central phenanthroline units [dihedral angles in the range 52.21 (12)-62.14 (10) degrees ]. In addition, a non-negligible torsion is apparent in one of the phenanthroline units: the angle between the mean planes of the two pyridine rings is 14.84 (13) degrees . The methanol solvent mol-ecule is linked to both N atoms of a bathophenanthroline mol-ecule through a bifurcated O H?(N,N) hydrogen bond. PMID- 24046601 TI - N,N,N-Trimethyl-N-(methyl 5-de-oxy-2,3-O-iso-propyl-idene-beta-d-ribo-furan-osid 5-yl)ammonium 4-methyl-benzene-sulfonate sesquihydrate. AB - The structure of the title compound, [C12H24NO4][C7H7O3S].1.5H2O, contains alternating layers parallel to (001) of hydro-phobic and polar character, stabilized by C-H?O hydrogen bonding. The furan ring adopts an envelope conformation with the C(OMe) atom as the flap, and the dioxolane ring is twisted about one of the O-C(methine) bonds. A comparison to related compounds is presented. The tosyl-ate-O atoms were disordered over two positions with the major component having a site occupancy factor = 0.566 (12). The structure was refined as a rotary twin with regard to rotation about the c axis with the contribution of the second component being 0.0048 (6). Solvate water mol-ecules are highly disordered and were removed using the SQUEEZE procedure; the unit cell characteristics take into account the presence of the disordered solvent. High resolution (1)H and (13)C NMR spectroscopic data are also presented. PMID- 24046602 TI - (E)-1-(3-Chloro-phen-yl)-2-(2-oxidonaphthalen-1-yl)diazen-1-ium. AB - The title zwitterion,, C16H11ClN2O, is approximately planar, the dihedral angle between the benzene ring and naphthalene ring system is 1.55 (13) degrees ; an intra-molecular N-H?O hydrogen bond stabilizes the planar conformation. In the crystal, pi-pi stacking between the benzene ring and the naphthalene ring system of adjacent mol-ecules links the mol-ecules into supra-molecular chains running along the b axis, the centroid-centroid distance being 3.765 (2) A. PMID- 24046603 TI - 2-Methyl-1,1-diphenyl-2-[(4S)-4-phenyl-4,5-di-hydro-1,3-oxazol-2-yl]propan-1-ol. AB - In the title compound, C25H25NO2, the phenyl ring on the 1,3-oxazole ring is disordered over two positions with occupancies of 0.600 (4) and 0.400 (4). The inter-planar angle between these two disordered rings is 77.8 (2) degrees . There is an intra-molecular O-H?N hydrogen bond of moderate strength. In the crystal, C H?pi inter-actions interconnect neighbouring molecules. The absolute structure has been derived from the known absolute structure of the reagents. PMID- 24046604 TI - (1R*,21S*,22R*,24S*)-Methyl ethyl 2-[23-hy-droxy-22,24-diphenyl-8,11,14-trioxa-25 aza-tetra-cyclo-[19.3.1.0(2,7).0(15,20)]penta-cosa-2,4,6,15(20),16,18-hexaen-25 yl]but-2-enedioate. AB - The title compound, C40H41NO8, is a product of the reduction of the cyclic carbonyl group of the gamma-piperidone subunit of the aza-14-crown-4 ether with subsequent re-esterification of its dimethyl butenoate substituent into a monoethyl monomethyl group. The aza-crown macrocycle exhibits a bowl conformation with a dihedral angle of 70.82 (5) degrees between the benzene rings fused to it. The piperidine ring adopts a chair conformation and the methyl ethyl ethyl enedi-carboxyl-ate fragment has a cis conformation, with a dihedral angle of 66.51 (7) degrees between the two carboxyl-ate groups. The ethyl group is disordered over two sites with occupancies of 0.70 (1):0.30 (1). In the crystal, mol-ecules form inversion dimers, via pairs of O-H?O hydrogen bonds, that stack along the a axis. PMID- 24046605 TI - (E)-N-(3,3-Di-phenyl-allyl-idene)naph-thal-en-1-amine. AB - The title compound, C25H19N, adopts an E conformation about the C=N bond. The naphthalene ring system and the phenyl rings form dihedral angles 38.1 (1), 46.9 (8) and 48.5 (1) degrees , respectively, with the mean plane of the central enimino fragment. The crystal packing exhibits no directional close contacts. PMID- 24046606 TI - 5-Cyclo-hexyl-3-(3-fluoro-phenyl-sulfin-yl)-2-methyl-1-benzo-furan. AB - In the title compound, C21H21FO2S, the cyclo-hexyl ring adopts a chair conformation. The 3-fluoro-phenyl ring makes a dihedral angle of 83.16 (4) degrees with the mean plane [r.m.s. deviation = 0.005 (1) A] of the benzo-furan ring system. In the crystal, mol-ecules are linked by pairs of C-H?pi inter actions into inversion dimers, which are further packed into stacks along the a axis direction by C-H?pi inter-actions. PMID- 24046607 TI - Theobrominium perchlorate dibenzo-18-crown-6 3.25-hydrate. AB - The co-crystal, C7H9N4O2 (+).ClO4 (-).C20H24O6.3.25H2O, consists of theobrominium (3,7-di-methyl-2,6-dioxo-1H-purin-9-ium) cations, perchlorate anions and dibenzo 18-crown-6 and water mol-ecules. The crown ether is in a bent conformation, in which the planes of the aromatic rings subtend an angle of 63.7 (1) degrees . Inter-molecular O-H?O hydrogen bonding between the water mol-ecules and the O atoms of the cyclic ether delimit an empty space reminiscent of a hollow cage. The water mol-ecules are additionally linked to the cations by N-H?O hydrogen bonding. One of the positions of the water molecules is occupied only fractionally (25%) and is located outside this framework. PMID- 24046608 TI - 5-[(1R,2R,4R)-2-Meth-oxy-1,7,7-tri-methylbi-cyclo-[2.2.1]hept-2-yl]-1H-tetra zole. AB - The title compound, C12H20N4O, undergoes a phase transition on cooling. The room temperature structure is tetra-gonal (P43212, Z' = 1), with the meth-oxy-bornyl group being extremely disordered. Below 213 K the structure is ortho-rhom-bic (P212121, Z' = 2), with ordered mol-ecules. The two independent mol-ecules (A and B) have very similar conformations; significant differences only occur for the torsion angles about the Cborn-yl-Ctetra-zole bonds. The independent mol-ecules are approximately related by the pseudo-symmetry relation: xB = -1/4 + yA , yB = 3/4 - xA and zB = 1/4 + zA . In the crystal, mol-ecules are connected by N-H?N hydrogen bonds between the tetra-zole groups, forming a pseudo-43 helix parallel to the c-axis direction. The crystal studied was a merohedral twin with a refined twin fraction value of 0.231 (2). PMID- 24046609 TI - 6-Bromo-1,3-bis-[(1,3-dioxolan-2-yl)meth-yl]-1H-imidazo[4,5-b]pyridin-2(3H)-one. AB - In the title compound, C14H16BrN3O5, the N atoms adjacent to the carbonyl group in the five-membered ring are substituted by (1,3-dioxolan-2-yl)methyl groups. The fused ring system is essentially planar, with the largest deviation from the mean plane being 0.014 (2) A for the C atom bearing the Br atom. The first oxolane ring, attached on the side of the N atom belonging to the pyridine ring, has an envelope conformation with one of the O atoms as the flap, whereas the second oxolane ring displays a twisted boat conformation. The two oxolane rings display envelope and twisted boat conformations. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, building chains parallel to the a-axis direction. PMID- 24046610 TI - 8-Chloro-methyl-5-(2,5-dioxooxolan-3-yl)-3,3a,4,5-tetra-hydro-1H-naphtho-[1,2 c]furan-1,3-dione. AB - The title compound, C17H13ClO6, is an asymmetric alicyclic dianhydride containing a chloro-methyl-substituted tetra-hydro-naphthalene moiety. The cyclo-hexene ring in the tetra-hydro-naphthalene moiety exhibits an envelope conformation with the tertiary C atom as the flap The dihedral angle between the two anhydride rings is 79.96 (6) degrees , while those between the benzene ring and the non-fused and fused anhydride rings are 71.03 (5) and 42.57 (7) degrees , respectively. In the crystal, mol-ecules are connected by weak C-H?O inter-actions, forming a three dimensional supramolecular structure. PMID- 24046611 TI - 8-[(3-Phenyl-1,2,4-oxa-diazol-5-yl)meth-oxy]quinoline monohydrate. AB - In the title compound, C18H13N3O2.H2O, the oxa-diazole ring forms dihedral angles 7.21 (10) and 21.25 (11) degrees with the quinoline and benzene rings, respectively. The crystal structure features O-H?N hydrogen bonds and is further consolidated by C-H?O hydrogen-bonding inter-actions involving the water molecule of hydration. PMID- 24046612 TI - Methyl 11,14,16-triphenyl-8,12-dioxa-14,15-di-aza-tetra-cyclo [8.7.0.0(2,7).0(13,17)]hepta-deca-2(7),3,5,13(17),15-penta-ene-10-carboxyl-ate. AB - In the title compound, C33H26N2O4, the pyrazole ring makes dihedral angles of 15.13 (7) and 60.80 (7) degrees with the adjacent phenyl rings. Both di-hydro pyran rings exhibit half-chair conformations. A weak intra-molecular C-H?O inter action occurs. In the crystal, mol-ecules are linked into inversion dimers through pairs of C-H?N inter-actions. Weak C-H?pi inter-actions are also observed. PMID- 24046613 TI - 3,3-Bis(methyl-sulfan-yl)-1-(4-nitro-phen-yl)prop-2-en-1-one. AB - In the title compound, C11H11NO3S2, the S-Csp (2) bonds are shorter [1.746 (3) and 1.750 (2) A] than the S-CH3 bonds [1.794 (3) and 1.806 (3) A], which we attribute to d-pi inter-actions between the S atoms and the C=C bond. The 1,1-bis (methyl-sulfan-yl)-3-oxo-propyl-ene fragment and the 4-nitro-phenyl group are both almost planar, with the largest deviations from their mean planes being 0.053 (1) and 0.017 (2) A, respectively. The dihedral angle between the two planes is 35.07 (7) degrees . Mol-ecules in the crystal are linked into a three dimensional network by C-H?S and C-H?O hydrogen bonds. PMID- 24046614 TI - (1S,2R,7R,8S,10R)-9,9-Di-bromo-2,6,6,10-tetra-methyl-1alpha,2alpha-ep-oxy-tri cyclo-[5.5.0.0(8,10)]dodeca-ne. AB - The title compound, C16H24Br2O, was synthesized from the reaction of beta himachalene (3,5,5,9-tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzo-cyclo heptene), which was isolated from Atlas cedar (Cedrus atlantica) essential oil, after reaction with di-bromo-carbene. The asymmetric unit contains two independent mol-ecules with similar conformations. Each mol-ecule is built up from fused six-and seven-membered rings and two three-membered rings. In both mol ecules, the six-membered ring has an envelope conformation with the flap provided by the C atom of the ep-oxy ring, whereas the seven-membered ring displays a chair conformation. The crystal packing is governed only by van der Waals inter actions. The absolute configuration was established from anomalous dispersion effects. PMID- 24046615 TI - (E)-1-(2,4-Di-nitro-benzyl-idene)-2,2-di-phenyl-hydrazine. AB - In the crystal of the title compound, C19H14N4O4, the asymmetric unit consists of two discrete mol-ecules. The C=N bonds in both mol-ecules show an E conformation. The dihedral angles between the C atoms of the 2,4-dinitrobenzene rings and the C=N-N planes are 13.52 (9) and 13.82 (9) degrees for the two mol-ecules. In the crystal, C-H?O hydrogen bonds, mainly between the phenyl ring and the nitro group along the b axis. PMID- 24046616 TI - N-[3-(Di-methyl-amino)-prop-yl]-N,N',N',N'',N''-penta-methyl-guanidinium tetra phenyl-borate. AB - In the title salt, C11H27N4 (+).C24H20B(-), the C-N bond lengths in the central CN3 unit of the guanidinium ion are 1.333 (4), 1.334 (4) and 1.351 (4) A, indicating partial double-bond character. The C atom of this unit is bonded to the three N atoms in a nearly ideal trigonal-planar geometry [N-C-N angles = 118.8 (3), 120.0 (3) and 121.2 (3) degrees ] and the positive charge is delocalized in the CN3 plane. The bonds between the N atoms and the terminal C methyl groups of the guanidinium moiety have values in the range 1.459 (4)-1.478 (4) A, close to a typical single bond. In the crystal, there are C-H?pi inter actions between the guanidinium H atoms and the phenyl rings of the tetra-phenyl borate ion. These inter-actions combine to form a ladder of linked chains of ions which runs parallel to the c axis. PMID- 24046617 TI - 4-(5-{2-[5-(4-Cyano-phen-yl)-3-methyl-thio-phen-2-yl]-3,3,4,4,5,5-hexa-fluoro cyclo-pent-1-en-1-yl}-4-methyl-thio-phen-2-yl)benzo-nitrile chloro-form hemisolvate. AB - The crystal structure of the title compound, C29H16F6N2S2.0.5CHCl3, consists of mol-ecules with disordered perfluoro-cyclo-pentene rings [occupancy ratio 0.685 (3):0.315 (3)] and close F?F contacts (in the range 2.45-2.73 A) between mol ecules. The short contacts are associated with the disorder. The dihedral angle between thiophene rings is 57.44 (8) degrees . The 5-(4-cyano-phen-yl)-3-methyl-2 thienyl groups of adjacent mol-ecules are parallel, leading to zigzag chains of mol-ecules along [101]. The dihedral angles between each thiophene ring and its adjacent cyanobenzene ring are 8.9 (2) and 7.15 (10) degrees . PMID- 24046618 TI - O,O-Dimethyl O-(4-sulfamoylphen-yl) phospho-rothio-ate (cythio-ate). AB - The title mol-ecule, C8H12NO5PS2, exhibits a crystallographic mirror plane that is perpendicular to the ring and bis-ects the sulfamoyl and thio-phosphate ester groups. In the crystal, mol-ecules are linked by N-H?O hydrogen-bonding inter actions reminiscent of carb-oxy-lic acid hydrogen bonding pairs, forming chains parallel to the b-axis direction. PMID- 24046619 TI - Bruceolline D: 3,3-dimethyl-1H,4H-cyclo-penta-[b]indol-2(3H)-one. AB - The title compound, C13H13NO, crystallizes with four independent mol-ecules in the asymmetric unit. The 12-membered penta-[b]indole rings are essentially planar, with maximum deviations ranging from 0.034 (4) to 0.036 (4) A in the four unique mol-ecules. In the crystal, weak C-H?O inter-actions are observed, which link the mol-ecules into chains along [010]. PMID- 24046620 TI - 4-Nitro-phenol-piperazine (2/1). AB - In the title adduct, C6H5NO3.0.5C4H10N2, the piperazine ring possesses inversion symmetry and has a chair conformation. Its mean plane makes a dihedral angle of 65.45 (7) degrees with the 4-nitro-phenol ring. In the crystal, the piperazine ring is linked to two 4-nitro-phenol mol-ecules via O-H?N hydrogen bonds. The mol ecules are also linked via bifurcated N-H?(O,O) hydrogen bonds involving the NO2 O atoms, forming a two-dimensional network lying parallel to (102). The networks are linked via C-H?O hydrogen bonds, forming a three-dimensional structure. PMID- 24046621 TI - 2-Methyl-4-(naphthalen-2-yl)-3a-nitro-3,3a,4,9b-tetra-hydro-2H-spiro [chromeno[3,4-c]pyrrole-1,3'-indolin]-2'-one. AB - In the title compound, C29H23N3O4, the 2-methylpyrrolidine ring adopts a twist conformation on the N-C bond involving the spiro C atom, while the hydropyran ring adopts an envelope conformation with the methine C atom bonded to the O atom as the flap. The mean plane of the indoline-2-one ring system is almost perpendicular to the mean plane of the pyrrolidine ring, making a dihedral angle of 89.73 (8) degrees . The latter ring makes dihedral angles of 47.80 (8) with the naphthalene ring system and 32.38 (8) degrees with the hydropyran ring mean plane. There is an intra-molecular C-H?O hydrogen bond involving the indoline-2 one O atom. In the crystal, adjacent mol-ecules are linked via N-H?O hydrogen bonds, forming chains propagating along [100]. The chains are linked via weak C H?O hydrogen bonds, forming two-dimensional networks, lying parallel to (101), and consolidated by C-H?pi inter-actions. PMID- 24046622 TI - 6-(4-Meth-oxy-phen-yl)-6a-nitro-6,6a,6b,7,8,9,10,12a-octa-hydro-spiro [chromeno[3,4-a]indolizine-12,3'-indolin]-2'-one. AB - In the title compound, C29H27N3O5, the hydropyran ring adopts an envelope conformation with the methine C atom bearing the para-meth-oxy-benzene ring as the flap. The central pyrrolidine ring has a twist conformation on the N-C bond involving the spiro C atom. The piperidine ring adopts a chair conformation. An intra-molecular C-H?O contact closes an S(7) ring. In the crystal, inversion dimers linked by C-H?O inter-actions generate R 2 (2)(18) loops and N-H?O hydrogen bonds connect the dimers into [100] chains. PMID- 24046623 TI - 5,15-Bis(4-pentyl-oxyphen-yl)porphyrin. AB - In the title compound, C42H42N4O2, the complete molecule is generated by a crystallographic inversion centre. The porphyrin system exhibits a near planar macrocycle conformation with an average deviation from the least-squares plane of the 24 macrocycle atoms of 0.037 (5) A. The phenyl ipso C atoms are positioned above and below the porphyrin plane by 0.35 (1) A and the macrocycle shows evidence of in-plane rectangular elongation with N?N separations of 3.032 (5) and 2.803 (5) A. Two intramolecular N-H?N hydrogen bonds occur. PMID- 24046624 TI - Ethyl 4-acetyl-5-anilino-3-methyl-thio-phene-2-carboxyl-ate. AB - In the title compound, C16H17NO3S, a thio-phene derivative with amino phenyl, acetyl, methyl and ethyl carboxyl susbtituents attached to a central thio-phene ring, the phenyl and thio-phene rings form a dihedral angle of 36.92 (9) A. The mol-ecular conformation is stabilized by an intra-molecular N-H?O hydrogen bond, which forms an S(6) ring motif. PMID- 24046625 TI - 5-Chloro-2-methyl-3-(4-methyl-phenyl-sulfon-yl)-1-benzo-furan. AB - The title compound, C16H13ClO3S, crystallized with two independent mol-ecules in the asymmetric unit. The 4-methyl-phenyl rings make dihedral angles of 75.15 (4) degrees and 72.18 (4) degrees with the planes of the benzo-furan ring systems in the two mol-ecules. In the crystal, mol-ecules are linked by weak C-H?O and C H?pi inter-actions, forming a three-dimensional network. PMID- 24046626 TI - 2-Methyl-1,2,4-triazolo[4,3-a]pyridin-2-ium tetra-fluoroborate. AB - In the title salt, C7H8N3 (+).BF4 (-), the 1,2,4-triazolo[4,3-a]pyridinium cation is planar [maximum deviation of 0.016 (2) A for all non-H atoms]. The cation and anion constitute a tight ionic pair with an F?N [2.911 (4) A] inter-molecular attractive inter-action. The ionic pairs form dimers via stacking inter-actions between inversion-related cations, the normal distance between the cation planes being 3.376 (5) A. The dimers are packed in stacks along the a axis and linked via C-H?F hydrogen bond, forming a three-dimensional network. PMID- 24046627 TI - 1-(3-Acetyl-phen-yl)-2-(2-oxidonaph-thalen-1-yl)diazen-1-ium. AB - The title compound, C18H14N2O2, crystallized with two independent zwitterion mol ecules (A and B) in the asymmetric unit. They are both close to planar, the dihedral angle between the benzene ring and naphthalene ring system being 4.30 (9) degrees in A and 4.69 (9) degrees in B. Each mol-ecule has an E conformation with respect to the azo double bond. In each of the independent mol ecules, an intra-molecular N-H?O hydrogen bond forms an S(6) ring motif. In the crystal, mol-ecules are linked via C-H?O hydrogen bonds, forming -A-A-A- and -B-B B- chains parallel to one another and propagating along the a-axis direction. There are also pi-pi inter-actions between adjacent mol-ecules involving benzene and naphthalene rings [centroid-centroid distance of 3.626 (3) A for adjacent A mol-ecules and 3.652 (3) A for adjacent B mol-ecules]. PMID- 24046628 TI - rac-4-(4-Chloro-phen-yl)-2-methyl-amino-3-nitro-5,6,7,8-tetra-hydro-4H-chromen-5 one. AB - The title compound, C16H15ClN2O4, contains a chiral centre and crystallizes as a racemate. The methyl-ene group beta-positioned to the carbonyl group is partially (21%) disordered. It flips to the opposite sides of the corresponding six membered carbocycle by -0.304 (3) and 0.197 (11) A, producing alternative envelope conformations. The planes of the pyran and chloro-phenyl rings form a dihedral angle of 86.25 (9) degrees . The mol-ecular structure is characterized by an intra-molecular N-H?O inter-action, which generates an S(6) ring motif. The corresponding amino N atom deviates from the plane of the pyran ring by 0.1634 (19) A. In the crystal, mol-ecules are linked via C-H?O hydrogen bonds, forming C(8) chains running parallel to the b-axis direction. The crystal structure also features C-H?pi inter-actions. PMID- 24046629 TI - Methyl 4-anilino-2',5-dioxo-1',2'-di-hydro-5H-spiro-[furan-2,3'-indole]-3 carboxyl-ate. AB - In the title compound, C19H14N2O5, the spiro junction links an oxindole moeity and a furan ring, which subtend a dihedral angle of 83.49 (6) degrees . The mol ecular structure features an N-H?O hydrogen bond, which generates an S(6) ring motif. The crystal packing is governed by two N-H?O inter-actions, one of which generates a centrosymmetric R 2 (2)(14) dimer. The other N-H?O inter-action along with a C-H?O hydrogen bond contributes to the formation of a C 2 (2)[R 2 (2)(9)] dimeric chain running along the b-axis direction. PMID- 24046630 TI - 4-Bromo-methyl-6-tert-butyl-2H-chromen-2-one. AB - In the crystal structure of the title compound, C14H15BrO2, weak C-H?O inter actions link the mol-ecules into zigzag chains extending along the c-axis direction. These chains are further assembled into (100) layers via pi-pi stacking inter-actions between inversion-related chromenone fragments [inter planar distance = 3.376 (2) A]. PMID- 24046631 TI - meso-4,4'-Dimeth-oxy-2,2'-{[(3aR,7aS)-2,3,3a,4,5,6,7,7a-octa-hydro-1H-benz imidazole-1,3-di-yl]bis-(methyl-ene)}diphenol. AB - The title compound, C23H30N2O4, a di-Mannich base derived from 4-meth-oxy-phenol and cis-1,2-di-amine-cyclo-hexane, has a perhydro-benzimidazolidine nucleus, in which the cyclo-hexane ring adopts a chair conformation and the heterocyclic ring has a half-chair conformation with a C-N-C-C torsion angles of -48.14 (15) and 14.57 (16) degrees . The mean plane of the heterocycle makes dihedral angles of 86.29 (6) and 78.92 (6) degrees with the pendant benzene rings. The mol-ecular structure of the title compound shows the presence of two inter-actions between the N atoms of the imidazolidine ring and the hydroxyl groups through intra molecular O-H?N hydrogen bonds with graph-set motif S(6). The unobserved lone pairs of the N atoms are presumed to be disposed in a syn conformation, being only the second example of an exception to the typical 'rabbit-ears' effect in 1,2-di-amines. PMID- 24046632 TI - 4,4'-Dimethyl-2,2'-{[2,3,3a,4,5,6,7,7a-octa-hydro-1H-benzimidazole-1,3-di-yl]bis (methyl-ene)}diphenol. AB - The asymmetric unit of the title compound, C23H30N2O2, contains one half-mol ecule, with a twofold axis splitting the mol-ecule in two identical halves. The structure of the racemic mixture has been reported previously [Rivera et al. (2009 ?) J. Chem. Crystallogr. 39, 827-830] but the enanti-omer reported here crystallized in the ortho-rhom-bic space group P21212 (Z = 2), whereas the racemate occurs in the triclinic space group P-1 (Z = 2). The observed mol-ecular conformation is stabilized by two intra-molecular O-H?N hydrogen bonds, which generate rings with graph-set motif S(6). In the crystal, mol-ecules are linked via non-classical C-H?O inter-actions, which stack the mol-ecules along the b axis. PMID- 24046633 TI - 2-Amino-pyridin-1-ium triiodide. AB - The asymmetric unit of the title compound, C5H7N2 (+.)I3 (-), consists of one 2 amino-pyridin-1-ium cation (apyH(+)) and one triiodide anion, both located in general postions. The apyH(+) cation is planar within the experimental uncertainties. The short N-C distance [1.328 (5) A] of the exocyclic NH2 group is typical for the imino-form of protonated 2-amino-pyridines. Consequently, the bond lengths within the six-membered ring vary significantly. The geometric parameters of the triiodide anion are in the typical range, with bond lengths of 2.8966 (3) and 2.9389 (3) A and a bond angle of 176.02 (1) degrees . In the crystal, N-H ? I hydrogen bonds connect adjacent ions into screwed chains along the b-axis direction. These chains are twisted pairwise into rectangular rods. The pyridinium moieties of neighbouring rods are arranged parallel to each other with a plane-to-plane distance of 3.423 (5) A. PMID- 24046634 TI - Ethyl 8''-chloro-1'-methyl-2,12''-dioxo-12''H-di-spiro-[indoline-3,2'-pyrrolidine 3',6''-indolo[2,1-b]quinazoline]-4'-carboxyl-ate. AB - In the title compound, C29H23ClN4O4, the quinazoline-indole system and the indolin-2-one system are each essentially planar, with maximum deviations from their mean planes of 0.150 (2) and 0.072 (2) A, respectively. The central pyrrolidine ring adopts a twisted conformation on the C-C bond involving the spiro C atoms. Its mean plane forms dihedral angles of 83.37 (9) and 86.56 (8) degrees , respectively, with the indole rings of the indolin-2-one and quinazoline-indole systems. In the crystal, mol-ecules are linked via pairs of N H?O hydrogen bonds, forming inversion dimers. The dimers are linked via C-H?O hydrogen bonds, forming chains propagating along [001]. PMID- 24046635 TI - 3-(2,5-Di-methyl-phen-yl)-8-meth-oxy-2-oxo-1-aza-spiro-[4.5]dec-3-en-4-yl 3-(2 bromo-4-fluoro-phen-yl)acrylate. AB - In the title compound, C27H27BrFNO4, which is an inhibitor of acetyl-CoA carboxyl ase, the cyclo-hexane ring displays a chair comformation with the spiro-C and meth-oxy-bearing C atoms deviating by 0.681 (7) and -0.655 (1) A, resppectively, from the mean plane formed by the other four C atoms of the spiro-C6 ring. The mean planes of the cyclo-hexane and 2-bromo-4-fluoro-phenyl rings are nearly perpendicular to that of the pyrrolidine ring, making dihedral angles 89.75 (6) and 87.60 (9) degrees , respectively. In the crystal, mol-ecules are linked via pairs of N-H?O hydrogen bonds, forming inversion dimers. PMID- 24046636 TI - 2-[4-(Carbazol-9-yl)phen-yl]-1,3-diethyl-1,3-di-phenyl-guanidine. AB - In the title compound, C35H32N4, the C-N bond lengths in the guanidine part are 1.286 (3), 1.387 (2) and 1.414 (2) A, indicating double- and single-bond character. The N-C-N angles are 114.48 (17), 118.78 (17) and 126.72 (17) degrees , showing a deviation of the CN3 plane from an ideal trigonal-planar geometry. The carbazole ring system is almost planar (r.m.s. deviation = 0.002 A). In the crystal, mol-ecules are connected by weak C-H?N hydrogen bonds, generating a zigzag chain along the ac plane. Weak pi-pi inter-actions [centroid-centroid distance = 3.785 (1) A] between two phenyl rings of the guanidine moiety are also present. PMID- 24046637 TI - 1-O-Benzyl-2,3-O-iso-propyl-idene-6-O-tosyl-alpha-l-sorbo-furan-ose. AB - IN THE TITLE COMPOUND (SYSTEMATIC NAME: {(3aS,5S,6R,6aS)-3a-[(benz-yloxy)meth-yl] 6-hy-droxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl}methyl 4-methyl benzene-sulfonate), C23H28O8S, the absolute structure and relative stereochemistry of the four chiral centres have been established by X-ray crystallography, with the absolute configuration inferred from the use of l sorbose as the starting material. The central furan-ose ring adopts a slightly twisted envelope conformation (with the C atom bearing the methyl-benzene sulfonate substituent as the flap) from which three substituents depart pseudo axially (-CH2-O-benzyl, -OH and one acetonide O atom) and two substituents pseudo equatorially (-CH2-O-tosyl and second acetonide O atom). The dioxalane ring is in a flattened envelope conformation with the fused CH C atom as the flap. In the crystal, mol-ecules pack in columns along [010] linked by O-H?O hydrogen bonds involving the furan-ose hy-droxy group and furan-ose ether O atom. PMID- 24046638 TI - (3E,5E)-1-Allyl-3,5-bis(4-meth-oxy-benzyl-idene)-piperidin-4-one. AB - The piperidine ring in the title compound, C24H25NO3, adopts an envelope conformation with the N atom being the flap atom, and each C=C double bond exhibits an E conformation. In the crystal, C-H?O hydrogen bonds link the mol ecules, forming supramolecular layers that stack along the a axis. PMID- 24046639 TI - 10-{4-[(2-Hy-droxy-benzyl-idene)amino]-phen-yl}-5,5-di-fluoro-1,3,7,9-tetra methyl-5H-di-pyrrolo-[1,2-c:2',1'-f][1,3,2]di-aza-borinin-4-ium-5-uide. AB - The title compound, C26H24BF2N3O, comprises a boron-dipyrromethene (BODIPY) framework and a phenolic Schiff base substituent group. The BODIPY unit is close to planar [maximum deviation from the least-squares plane = 0.040 (3) A], and forms a dihedral angle of 80.38 (13) degrees with the meso-substituent phenyl ring and an angle of 56.57 (13) degrees with the phenolic ring in the extended substituent chain. An intra-molecular O-H?N hydrogen bond is formed between the phenolic hydroxyl group and the Schiff base N-atom. The crystal studied was a non merohedral twin with a BASF factor of 0.447 (3) for the two components. PMID- 24046640 TI - 4-Nitro-N^2^-(pyridin-4-ylmethylidene)benzene-1,2-diamine. AB - In the title compound, C12H10N4O2, the dihedral angle between the aromatic rings is 43.18 (16) degrees . The nitro group is rotated from its attached ring by 7.8 (2) degrees and a short intra-molecular N-H?N contact occurs. In the crystal, the mol-ecules are linked by N-H?N and C-H?O hydrogen bonds, generating a three dimensional network. PMID- 24046641 TI - 3-(Prop-2-yn-1-yl-oxy)phthalo-nitrile. AB - In the title compound, C11H6N2O {systematic name: 3-(prop-2-yn-1-yl-oxy)benzene 1,2-dicarbo-nitrile}, the 14 non-H atoms are approximately coplanar (r.m.s. deviation = 0.051 A) with the terminal ethyne group being syn with the adjacent cyano residue. In the crystal, centrosymmetric dimers are connected by pairs of C H?N inter-actions and these are linked into a supra-molecular tape parallel to (1 30) via C-H?N inter-actions involving the same N atom as acceptor. PMID- 24046642 TI - rac-(E,E)-N,N'-Bis(2-chloro-benzyl-idene)cyclo-hexane-1,2-di-amine. AB - In the title racemic Schiff base ligand, C20H20Cl2N2, which was prepared by the condensation of 2-chloro-benzaldehyde and cyclo-hexane-1,2-di-amine, the cyclo hexane ring adopts a chair conformation and the dihedral angle between the aromatic rings of the 2-chloro-phenyl substituent groups is 62.52 (8) degrees . In the structure, there are two short intra-molecular methine C-H?Cl inter actions [C?Cl = 3.066 (2) and 3.076 (3) A], and in the crystal there are also weak inter-molecular aromatic C-H?Cl [3.464 (3), 3.553 (3) and 3.600 (3) A] and Cl?Cl [3.557 (3) and 3.891 (3) A] contacts. PMID- 24046643 TI - (2E)-1-(Pyridin-2-yl)-3-(2,4,5-tri-meth-oxy-phen-yl)prop-2-en-1-one. AB - The title heteroaryl chalcone derivative, C17H17NO4, is close to planar: the dihedral angle between the pyridine and benzene rings is 3.71 (11) degrees and the meth-oxy C atoms deviate from their attached ring by 0.046 (3), -0.044 (2) and 0.127 (3) A. The disposition of the pyridine N atom and the carbonyl group is anti [N-C-C-O = -177.7 (2) degrees ]. In the crystal, mol-ecules are linked by weak C-H?N and C-H?O inter-actions into (100) sheets and an aromatic pi-pi stacking inter-action between the pyridine and benzene ring, with a centroid centroid separation of 3.7036 (14) A also occurs. PMID- 24046644 TI - 2,2'-(Disulfanedi-yl)dianilinium dichloride dihydrate. AB - In the title hydrated mol-ecular salt, C12H14N2S2 (2+).2Cl(-).2H2O, the dihedral angle between the benzene rings in the dication is 9.03 (17) degrees and the C-S S-C torsion angle is 96.8 (2) degrees . The crystal packing can be described as alternating organic and anionic water layers lying parallel to (100), which are linked by N-H?Cl and N-H?O hydrogen bonds. O-H?Cl hydrogen bonds and aromatic pi pi stacking inter-actions [centroid-centroid separation = 3.730 (3) A] are also observed. PMID- 24046645 TI - Bis(ethyl-eneglycolato-kappa(2) O,O')tellurium(IV). AB - The title compound, C4H8O4Te, crystallized from a solution of Te(4+) in ethyl-ene glycol. The Te(IV) atom is in a distorted seesaw coordination defined by four O atoms from two different ethyl-eneglycate ligands. The C atoms of the ethyl eneglycate ligands are disorderd over two positions, with population parameters of 50.3 (6) and 49.7 (6)% indicating a statistical distribution. Due to the possibility to transform the primitive monoclinic unit cell into a metrically ortho-rhom-bic C unit cell, the data are twinned and were refined with the twin law -100/0-10/101 with the relative scale factor refining to 1.82 (4)% for the minor component. PMID- 24046646 TI - 2-Oxo-2H-chromen-4-yl 4-methyl-benzoate. AB - The asymmetric unit of the title compound, C17H12O4, consists of two independent mol-ecules. The chromen-2-one ring and the 4-methyl-benzoate side chain are inclined to one another at a dihedral angle of 64.79 (10) degrees in one mol ecule and 88.3 (1) degrees in the other. In the crystal, mol-ecules form R 2 (2)(8) centrosymmetric dimers via C-H?O hydrogen bonds. These dimers are stacked by C-H?O hydrogen bonds, resulting in R 2 (2)(18) and R 3 (2)(16) ring motifs. pi pi stacking inter-actions between two parallel chromen-2-one rings, with centroid centroid distances of 3.743 (1) and 3.771 (1) A, are also present. PMID- 24046647 TI - 4-{5-[(2-Bromo-benz-yl)sulfan-yl]-1H-tetra-zol-1-yl}benzoic acid. AB - In the title compound, C15H11BrN4O2S, the tetra-zole ring makes dihedral angles of 45.97 (10) and 75.41 (1) degrees , respectively, with the benzoyl and bromo benzene rings while the dihedral angle between the benzene rings is 73.77 (1) degrees . In the crystal, mol-ecules are linked through O-H? N and C-H? O hydrogen bonds, giving infinite chains in both the [110] and [1-10] directions. These chains are further connected by C-Br?pi and C-O?pi inter-actions and also by pi-pi stacking between tetra-zole rings [centroid-centroid distance = 3.312 (1) A], generating a three-dimensional network. PMID- 24046648 TI - 2-{(E)-[(2-Methyl-3-nitro-phen-yl)imino]-meth-yl}-4-nitro-phenol. AB - The title compound, C14H11N3O5, is a Schiff base that adopts the enol-imine tautomeric form in the solid state. The dihedral angle between the aromatic rings is 37.4 (3) degrees and the dihedral angles between the nitro groups and their attached rings are 4.0 (6) and 46.2 (8) degrees . The mol-ecular structure is stabilized by an intra-molecular O-H?N hydrogen bond, which generates an S(6) ring motif. In the crystal, molecules are linked by C-H?O interactions, forming a two-dimensional network parallel to the bc plane. PMID- 24046649 TI - Carbamo-yl(di-amino-methyl-idene)aza-nium 3-nitro-5-oxo-4,5-di-hydro-1H-1,2,4 triazol-4-ide. AB - In the anion of the title salt, C2H7N4O(+).C2HN4O3 (-), the negative charge resides formally on the N(3) atom of the triazole ring. In the crystal, the N(3) and exocyclic O atoms are hydrogen-bond acceptors with respect to the formally double-bond iminium and amido N atoms of the cation. The cation and anion are almost planar (r.m.s. deviations = 0.012 and 0.051 A, respectively), but they are slightly bent with respect to each other [dihedral angle = 12.6 (1) degrees ]. In the crystal, adjacent anions and cations are linked by extensive N-H?N and N-H?O hydrogen bonds, generating a ribbon running along the b-axis direction. PMID- 24046650 TI - 8beta-Eth-oxy-eremophil-3,7(11)-diene-8alpha,12;6alpha,15-diolide. AB - The title compound, C17H20O5, an eremophilane sesquiternoid, was isolated from the roots of Ligularia lapathifolia. The mol-ecule contains four fused rings of which the six-membered ring A adopts a half-chair conformation, the six-membered ring B adopts a chair conformation, the five-membered ring C is almost planar (r.m.s. deviation = 0.015 A) and the five-membered ring D adopts an envelope conformation with the quaternary C atom as the flap. The methyl and the eth-oxy groups adopt a syn conformation and the A/B ring junction is cis-fused. No directional inter-molecular inter-actions could be identified in the crystal. PMID- 24046651 TI - 2-Meth-oxy-4-(prop-2-en-1-yl)phenyl benzoate. AB - In the title compound, C17H16O3, the benzene rings are twisted by 63.54 (5) degrees . The twist is similar to that found in the unsubstituted compound, phenyl benzoate. The crystal packing features C-H?O hydrogen bonds. PMID- 24046652 TI - 2-Meth-oxy-4-(prop-2-en-1-yl)phenyl 2,4-di-chloro-benzoate. AB - In the title compound, C17H14Cl2O3, the two benzene rings are twisted by 73.6 (2) degrees . The twist is similar to that found in the unsubstituted compound, viz. phenyl benzoate. In the crystal, inversion dimers are linked by pairs of C-H?O inter-actions. PMID- 24046653 TI - N-[(2-Chloro-phen-yl)sulfon-yl]-3-nitro-benzamide. AB - In the title compound, C13H9ClN2O5S, the dihedral angle between the benzene rings is 74.86 (11) degrees . The mol-ecule is twisted at the S atom, with a dihedral angle of 82.53 (13) degrees between the sulfonyl benzene ring and the S-N-C=O segment. In the crystal, mol-ecules are linked into inversion dimers through pairs of N-H?O hydrogen bonds, thereby forming R 2 (2)(8) loops. Mol-ecules are linked into C(7) [010] chains by weak C-H?O hydrogen bonds, and C-H?pi inter actions are also observed. PMID- 24046654 TI - 2-[1-(4-Bromo-phen-yl)-3-hy-droxy-3-(4-meth-oxy-phen-yl)prop-yl]cyclo-hexa-nol. AB - In the title compound, C22H27BrO3, the cyclo-hexane ring adopts a chair conformation. The dihedral angle between the benzene rings is 41.9 (4) degrees . In the crystal, mol-ecules are linked by O-H?O and C-H?O hydrogen bonds, forming a three-dimensional network. In addition, pi-pi stacking inter-actions [centroid centroid distance = 3.953 (6) A] between the benzene rings of the meth-oxy benzene groups occur. PMID- 24046655 TI - 3-Ethyl-sulfinyl-2-(3-fluoro-phen-yl)-5-phenyl-1-benzo-furan. AB - In the title compound, C22H17FO2S, the dihedral angles between the mean plane [r.m.s. deviation = 0.005 (1) A] of the benzo-furan ring system and the pendant 3 fluoro-phenyl and phenyl rings are 23.92 (5) and 32.44 (5) degrees , respectively. In the crystal, mol-ecules are linked by two weak C-H?O(sulfin-yl) hydrogen bonds and a C-H?pi inter-action, forming a sheet, which lies in the ab plane. A pi-pi inter-action between the benzene and furan rings of neighbouring mol-ecules [centroid-centroid distance = 3.976 (2) A] links the mol-ecules into inversion dimers and connects adjacent sheets, resulting in a three-dimensional network. PMID- 24046656 TI - 3-Methyl-2-(3,3,3-tri-chloro-2-hy-droxy-prop-yl)quinazolin-4(3H)-one. AB - The title mol-ecule, C12H11Cl3N2O2, contains planar quinazolin-4(3H)-one (r.m.s. deviation = 0.0257 A) and propyl fragments, forming a dihedral angle of 10.4 (2) degrees . An intra-molecular O-H?N hydorgen bond occurs. In the crystal, O-H?O hydrogen bonds link the mol-ecules into an infinite chain running parallel to the b axis. PMID- 24046657 TI - 2-(1-Methyl-2-oxoindolin-3-yl-idene)malono-nitrile. AB - The title mol-ecule, C12H7N3O, is almost planar, with an r.m.s. deviation of 0.026 A. No directional interactions could be detected in the crystal. PMID- 24046658 TI - 5,6-Dihy-droxy-7,8-di-meth-oxy-flavone. AB - THE TITLE COMPOUND (SYSTEMATIC NAME: 5,6-dihy-droxy-7,8-dimeth-oxy-2-phenyl chromen-4-one), C17H14O6, is a flavone that was isolated from the petroleum ether soluble fraction of the rare traditional Chinese medicinal herb Saussurea involucrata. The flavone mol-ecule is almost planar, with a dihedral angle between the planes of the benzo-pyran-4-one group and the attached phenyl group of 1.89 (6) degrees . The 5-hy-droxy group forms a strong intra-molecular hydrogen bond with the carbonyl group, resulting in a six-membered hydrogen bonded ring. The 6-hy-droxy group also forms an intra-molecular O-H?O contact. In the crystal, the molecules are linked by O-H?O and C-H?O hydrogen bonds and pi-pi inter-actions [3.37 (2)-3.39 (2) A], which build up a three-dimensional network. PMID- 24046659 TI - 5-Bromo-4-(3,5-di-bromo-2-hy-droxy-phen-yl)-2-(piperidin-1-yl)-1,3-di-thiol-2 ylium bromide. AB - In the title salt, C14H13Br3NOS2 (+).Br(-), synthesized by bromination of mesoionic 2-[2-(piperidin-1-yl)-1,3-di-thiol-2-ylium-4-yl]phenolate in glacial acetic acid, the dihedral angle between the 1,3-di-thiol-ium ring and the phenolic substituent ring is 45.9 (3) degrees due to the steric influence of the ortho-Br group on the 1,3-di-thiol-ium ring. The piperidine ring adopts a chair conformation. In the crystal, the cation and anion are linked by an O-H?Br hydrogen bond. PMID- 24046660 TI - 2-(2,5-Di-meth-oxy-phen-yl)-4,5-diphenyl-1-(prop-2-en-1-yl)-1H-imidazole. AB - In the title compound, C26H24N2O2, the two phenyl and the 2,5-di-meth-oxy-phen-yl rings are inclined to the imidazole ring at dihedral angles of 30.38 (8), 56.59 (9) and 73.11 (9) degrees , respectively. In the crystal, mol-ecules are linked by pairs of C-H?O inter-actions into centrosymmetric dimers with graph-set notation R 2 (2)(8). C-H?pi inter-actions are also observed. PMID- 24046661 TI - (-)-Norfluoro-curarine ethanol monosolvate. AB - The title compound, C19H20N2O.C2H5OH, is an ethanol solvate of an indol alkaloid which was extracted from the plant Vinca erecta. The fused piperidine ring adopts an approximate boat conformation and the pyrrolidine ring an envelope conformation with one of the methyl-ene C atoms at the flap. An intra-molecular N H?O hydrogen bond forms an S6 ring motif. In the crystal, norfulorocurarine and ethanol mol-ecules are linked into a chain along the c-axis direction through N H?O and O-H?N hydrogen bonds. PMID- 24046662 TI - (2S*,5R*)-2,5-Dimethyl-1,4-bis-(pyridin-2-ylmeth-yl)piperazine. AB - The title compound, C18H24N4, resides on a crystallographic inversion centre, so that the asymmetric unit comprises one half-mol-ecule. The piperazine ring adopts a chair conformation, with the mean planes of the two equatorial pyridine rings parallel to each other and separated by 2.54 (3) A. No classical hydrogen bonds are observed. PMID- 24046663 TI - 3-(4-Bromo-phen-yl)-1-butyl-5-[1-(2-chloro-6-methyl-phen-yl)-1H-tetra-zol-5 yl]imidazolidine-2,4-dione. AB - In the title mol-ecule, C21H20BrClN6O2, the chloro-substituted benzene ring forms a dihedral angle of 77.84 (7) degrees with the tetra-zole ring and the bromo substituted ring forms a dihedral angle of 43.95 (6) degrees with the imidazole ring. The dihedral angle between the tetra-zole and imidazole rings is 67.42 (8) degrees . The terminal methyl group of the butyl substituent is disordered over two sets of sites, with refined occupancies 0.67 (3) and 0.33 (3). In the crystal, there is a short Br?N contact of 3.183 (2) A. PMID- 24046664 TI - (4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-dicarbo-nitrile. AB - The title compound, C7H8N2O2, formed by dehydration of the corresponding dicarboxamide, crystallizes as rectangular prisms. The mol-ecules have a C 2 axis of symmetry through the C atom bearing the methyl groups and the mid-point of the ring C-C bond, and the 1,3-dioxolane ring adopts the extreme twist conformation of the two possible with this symmetry. This brings the two nitrile groups nearest to a linear arrangement when the mol-ecule is viewed along the ring C-C bond. The correct absolute configuration of the mol-ecule was defined by that of the original starting material, (2R,3R)-tartaric acid. The packing is largely controlled by a number of C-H?N interactions. PMID- 24046665 TI - Prop-2-en-1-yl 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoate. AB - The title compound, C25H20N2O2, crystallized with two mol-ecules in the asymmetric unit, in one of which the atoms of the terminal propenyl group are disordered over two sets of sites, with a refined occupancy ratio of 0.870 (4):0.130 (4). The central imidazole ring makes dihedral angles of 25.51 (11), 40.73 (11) and 27.36 (11) degrees with the three pendant rings in one molecule and 22.56 (10), 60.72 (10) and 5.85 (10) degrees in the other. In the crystal, mol-ecules are linked by N-H?N and C-H?O hydrogen bonds, forming a three dimensional network. The crystal structure also features C-H?pi inter-actions and pi-pi stacking [centroid-centroid distances = 3.8834 (18) and 3.9621 (17) A] inter-actions. PMID- 24046666 TI - O-Benzoyl-naltrexone. AB - In the title compound, C27H27NO5 (systematic name: 17-cyclopropylmethyl-14 hydroxy-6-oxo-4,5-epoxymorphin-an-6-yl benzoate), which is the benzoate ester of the opioid receptor antagonist naltrexone, the dihedral angle between the two phenyl rings is 77.1 (1) degrees . In the crystal, a weak aromatic C-H?Ocarbox-yl hydrogen bond involving the benzoate groups of adjacent mol-ecules gives rise to a chain extending along the a-axis direction. The known absolute configuration for the mol-ecule was inferred from a previous naltrexone structure. PMID- 24046667 TI - 1,4,10,13-Tetra-oxa-7,16-diazo-nia-cyclo-octa-decane bis-(1H-pyrrole-2-carboxyl ate). AB - In the title salt, C12H28N2O4 (2+).2C5H4NO2 (-), the 1,4,10,13-tetra-oxa-7,16-di aza-cyclo-octa-decane dication possesses inversion symmetry. In the crystal, the pyrrole-carboxyl-ate anions are linked via pairs of N-H?O hydrogen bonds, forming inversion dimers. These dimers are linked by the dications, via N-H?O hydrogen bonds, forming chains propagating along [110]. PMID- 24046668 TI - 3beta,6alpha-Diacet-oxy-5,9alpha-dihy-droxy-5alpha-cholest-7-en-11-one. AB - The title compound, C31H48O7, a polyoxygenated steroid, was obtained by chemical oxidation of 7-de-hydro-cholesteryl acetate. The mol-ecular geometry features trans A/B and C/D junctions at the steroid core with the acetyl groups in the equatorial position and a fully extended conformation for the alkyl side chain. A chair conformation is observed for rings A and C while ring B adopts a half-chair conformation. The five-membered ring D has an envelope conformation, with the C atom bearing the methyl group at the flap. The terminal isopropyl group and one acetyl group are disordered over two sets of sites with 0.774 (8):0.226 (8) and 0.843 (7):0.157 (7) ratios, respectively. An intra-molecular S(6) O-H?O hydrogen bonding motif involving a hy-droxy donor and acceptor is observed. In the crystal, chains of mol-ecules running along the b axis are formed via O-H?O hydrogen bonds between hy-droxy donors and carbonyl acceptors of the ordered acetyl group, giving rise to a C(14) motif. The chains are wrapped around the 21 screw axes. PMID- 24046669 TI - Methyl 3-[(6-nitro-4-oxo-3-phenyl-3,4-di-hydro-quinazolin-2-yl)sulfan-yl]propano ate. AB - In the title compound, C18H15N3O5S, the approximately planar quinazoline ring system [maximum deviation = 0.097 (3) A] forms a dihedral angle of 76.53 (19) degrees with the phenyl ring. The terminal -C(=O)-O-C group is disordered over two sets of sites with a site-occupancy ratio of 0.811 (17):0.189 (17). In the crystal, mol-ecules are linked via weak C-H?O hydrogen bonds into sheets parallel to the ac plane. PMID- 24046670 TI - 4-(4-Methyl-phenyl-sulfon-yl)piperazin-1-ium tri-fluoro-acetate. AB - In the title salt, C11H17N2O2S(+).CF3COO(-), the cation is protonated at the secondary piperazine N atom. The dihedral angle between the benzene ring and the piperazine mean plane is 85.54 (10) degrees . In the crystal, cations and anions are connected by two types of strong N-H?O hydrogen bonds into chains extending along [101]. The chains are further assembled into (10-1) layers via stacking inter-actions between benzene rings of the cations [centroid-centroid distance = 3.7319 (13) A] and a C-H?O inter-action involving a piperazine C-H group and a sulfonyl O atom. Another C-H?O inter-action between the piperazine ring and the sulfonyl group connects the ions into a three-dimensional network. PMID- 24046671 TI - 2-(1,3-Benzodioxol-5-yl)-3-phenyl-quinazolin-4(3H)-one. AB - In the mol-ecule of the title compound, C21H14N2O3, the quinazoline ring system [maximum deviation = 0.076 (1) A] makes dihedral angles of 40.57 (9) and 42.31 (11) degrees , respectively, with the phenyl and 1,3-benzodioxole rings. The dihedral angle between the phenyl ring and the 1,3-benzodioxole ring is 4.34 (10) degrees . In the crystal, C-H?O hydrogen bonds link the mol-ecules into infinite zigzag chains extending along [100]. PMID- 24046672 TI - Benzamidinium 2-meth-oxy-benzoate. AB - The title mol-ecular salt, C7H9N2 (+.)C8H7O3 (-), was synthesized by reaction between benzamidine (benzene-carboximidamide) and 2-meth-oxy-benzoic acid. In the cation, the amidinium group has two similar C-N bonds [1.3070 (17) and 1.3145 (16) A] and is almost coplanar with the benzene ring, making a dihedral angle of 5.34 (12) degrees . In the anion, the meth-oxy substituent forces the carboxyl ate group to be twisted by 69.45 (6) degrees with respect to the plane of the aromatic fragment. In the crystal, the components are connected by two N(+)-H?O( ) (+/-)CAHB (charge-assisted hydrogen bonds), forming centrosymmetric ionic dimers with graph-set motif R 2 (2)(8). These ionic dimers are then joined in ribbons running along the b-axis direction by another R 4 (2)(8) motif involving the remaining N(+)-H?O(-) hydrogen bonds. Remarkably, at variance with the well known carb-oxy-lic dimer R 2 (2)(8) motif, the carboxyl-ate-amidinium pair is not planar, the dihedral angle between the planes defined by the CN2 (+) and CO2 (-) atoms being 18.57 (12) degrees . PMID- 24046673 TI - Ethyl 2-[(2-hy-droxy-benzyl-idene)amino]-6-methyl-4,5,6,7-tetra-hydro-thieno[2,3 c]pyridine-3-carboxyl-ate. AB - The title compound, C18H20N2O3S, exists as the phenol-imine form in the crystal and there are bifurcated intra-molecular O-H?(N/O) hydrogen bonds present. The conformation about the C=N bond is anti (1E); the C=N imine bond length is 1.287 (4) A and the C=N-C angle is 122.5 (3) degrees . In the tetrahydrothienopyridine moiety, the six-membered ring has a flattened-boat conformation. In the crystal, mol-ecules are stacked nearly parallel to (110) and a weak C-H?pi inter-action is observed. The carbonyl O atom is disordered over two positions and was refined with a fixed occupancy ratio of 0.7:0.3. PMID- 24046674 TI - 2-Amino-5-methyl-pyridinium 3-hy-droxy-pyridine-2-carboxyl-ate. AB - In the 3-hy-droxy-picolinate anion of the title salt, C6H9N2 (+).C6H4NO3 (-), an intra-molecular O-H?O hydrogen bond with an S(6) graph-set motif is formed, so that the anion is essentially planar, with a dihedral angle of 9.55 (9) degrees between the pyridine ring and the carboxyl-ate group. In the crystal, the cations and anions are linked via N-H?O hydrogen bonds, forming a centrosymmetric 2 + 2 aggregate with R 2 (2)(8) and R 4 (2)(8) ring motifs. The crystal structure also features N-H?N and weak C-H?pi inter-actions. PMID- 24046675 TI - 2-Amino-4-methyl-pyridinium 3-hy-droxy-benzoate. AB - In the title salt, C6H9N2 (+).C7H5O3 (-), the anion is essentially planar, with a dihedral angle of 2.72 (17) degrees between the benzene ring and the carboxyl ate group. In the crystal, the anions are connected by O-H?O hydrogen bonds, forming a 41 helical chain along the c axis. The protonated N atom and the 2 amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H?O hydrogen bonds with an R 2 (2)(8) ring motif. The ion pairs are further connected via another N-H?O hydrogen bond, resulting in a three dimensional network. PMID- 24046676 TI - 3-[(E)-2-(4-Chloro-phen-yl)ethen-yl]-5,5-di-methyl-cyclo-hex-2-en-1-one. AB - In the title compound, C16H17ClO, the cyclo-hexene ring adopts a half-chair conformation and the best plane through the six ring atoms makes a dihedral angle of 6.69 (7) degrees with the chlorophenyl ring. In the crystal, pairs of C-H?O hydrogen bonds link the mol-ecules into centrosymmetric R 2 (2)(20) dimers. The dimers are linked into an infinite chains along the b-axis direction by further C H?O hydrogen bonds. PMID- 24046677 TI - 4-Carb-oxy-pyridin-1-ium 2,4,5-tri-carb-oxy-benzoate monohydrate. AB - The title hydrated salt, C6H6NO2 (+).C10H5O8 (-).H2O, was isolated from the 1:1 cocrystallization of benzene-1,2,4,5-tetra-carb-oxy-lic acid and isonicotinic acid in ethanol solution. In the crystal, the cation is close to planar [r.m.s. deviation = 0.085 A for the nine fitted atoms; the C-C-C-O(carbon-yl) torsion angle = -8.7 (4) degrees ], but twists are evident in the anion, with all but the carb-oxy-lic acid group diagonally opposite the carboxyl-ate group being significantly twisted out of the plane of the benzene ring [C-C-C-O(carbon-yl) torsion angles = -118.1 (2), -157.6 (2), 4.3 (3) and 77.3 (3) degrees ]. In the crystal, the ions and water mol-ecules are consolidated into a three-dimensional architecture by O-H?O and N-H?O hydrogen bonding along with C-H?O inter-actions. PMID- 24046678 TI - {2-[(1,3-Benzo-thia-zol-2-yl)meth-oxy]-5-chloro-phen-yl}(4-chloro-phen-yl)methan one. AB - In the title compound, C21H13Cl2NO2S, the benzo-thia-zole ring makes dihedral angles of 0.94 (1) and 70.65 (5) degrees with the 4-chloro-phenyl-methanone unit and the 5-chloro-phenyl ring, respectively. The dihedral angle between the 4 chloro-phenyl-methanone unit and the 5-chloro-phenyl ring is 66.20 (5) degrees . The crystal structure consists of dimeric units generated by C-H?N hydrogen bonds, further linked by C-H?O and C-H?pi inter-actions, leading to a three dimensional network. PMID- 24046679 TI - 2-Oxo-2H-chromen-4-yl propionate. AB - In the title compound, C12H10O4, the atoms of the 2-oxo-2H-chromene ring system and the non-H atoms of the 4-substituent all lie on a crystallographic mirror plane. The mol-ecular structure exhibits an intra-molecular C-H?O hydrogen bond, which generates an S(6) ring. In the crystal, mol-ecules form R 3 (2)(12) trimeric units via C-H?O inter-actions which propagate into layers parallel to the ac plane. These layers are linked by weak C-H?O inter-actions along the [010] direction, generating a three-dimensional network. PMID- 24046680 TI - Ethyl 4-(4-chloro-phen-yl)-2-methyl-5-oxo-5,6,7,8-tetra-hydro-quinoline-3 carboxyl-ate. AB - In the title compound, C19H18ClNO3, the non-aromatic part of the fused ring system adopts an envelope conformation with the central methyl-ene C atom as the flap. The dihedral angle between the pyridine and benzene rings is 56.98 (3) degrees . In the crystal, mol-ecules are linked into double layers parallel to (100) by a network of weak C-H?O inter-actions. PMID- 24046681 TI - 3-[(5-Chloro-2-hy-droxy-benzyl-idene)amino]-2-sulfanyl-idene-1,3-thia-zolidin-4 one. AB - In the title compound, C10H7ClN2O2S2, the mean plane of the thioxo-thia-zolidine ring [maximum deviation = 0.032 (2) A] is inclined to the benzene ring by 12.25 (4) degrees . There is a strong intra-molecular O-H?N hydrogen bond present. In the crystal, mol-ecules are linked via pairs of C-H?Cl hydrogen bonds, forming inversion dimers. PMID- 24046682 TI - 7-Bromo-3,3-dibutyl-8-meth-oxy-2,3-di-hydro-1,5-benzothia-zepin-4(5H)-one. AB - In the title compound C18H26BrNO2S, the thia-zepine ring adopts a boat conformation. The dihedral angle between the mean planes through the benzene ring and the four C atoms making up the basal plane of the boat is 35.8 (2) degrees . In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R 2 (2)(8) loops. PMID- 24046683 TI - Ethyl 4-(2-eth-oxy-2-oxoeth-yl)-3-oxo-4,13-di-aza-penta-cyclo [11.8.0.0(2,11).0(5,10).0(14,19)]henicosa-1,5(10),6,8,11,14(19),15,17,20-nona-ene 12-carboxyl-ate. AB - In the title compound, C26H22N2O5, the system consisting of five fused rings, being essentially planar with an r.m.s. deviation from the least-squares plane of 0.049 (3) A, makes a dihedral angle of 58.72 (12) degrees with the plane of the ethyl carboxyl-ate group immediately attached to it, and a dihedral angle of 89.48 (14) degrees with the plane of the ethyl carboxyl-ate group attached via the -CH2- bridge. Bond lengths indicate pi-delocalization over the whole penta cyclic system. The mol-ecular conformation is stabilized by a weak intra molecular C-H?O hydrogen bond. In the crystal, mol-ecules form stacks along the b axis direction, neighboring mol-ecules within each stack being related by inversion and the shortest distance between the centroids of the pyridine rings within the stack being 3.667 (2) A. PMID- 24046684 TI - 4,5-Di-amino-3-[(E,E)-4-(4,5-di-amino-4H-1,2,4-triazol-3-yl)buta-1,3-dien-yl]-4H 1,2,4-triazol-1-ium chloride. AB - The title compound, C8H13N10 (+).Cl(-), is the monochlorhydrate salt of an aromatic bis-(di-amino-triazole). The cation is centrosymmetric, lying about an inversion centre (Ci symmetry) because the acidic H atom is disordered over two centrosymmetrically related ring N atoms, with equal multiplicity. It is noteworthy that protonation occurs at an N atom of the ring, instead of at the C NH2 or N-NH2 amino groups. The chloride anions are also in special positions, as they lie on binary axes, and so the crystallographically independent unit contains half of a formula unit. The N atom of the C-NH2 group is sp (2) hybridized and the amino group is coplanar with the triazole ring [dihedral angle = 5 (3) degrees ], while the N atom of the N-NH2 amino group is pyramidal. The C=C bonds are in E conformations and the cation is flat because the conformation of the carbon chain is fully extended. The chloride anions are hexa-coordinated, in a distorted trigonal-prismatic geometry, and they are involved, as acceptors, in six hydrogen bonds. Chains of hydrogen-bonded cations, running along c and a + c, are generated by c-glide and C 2 rotation, respectively. This combination of N H?Cl and N-H?N hydrogen bonds leads to the formation of a three-dimensional network. PMID- 24046685 TI - Naphthalene-1,8-di-amine-2-(pyrimidin-2-yl)-1H-perimidine (2/1). AB - In the title adduct, C15H10N4.2C10H10N2, the pyrimidine ring is nearly co-planar with the heteroatomic perimidine ring, as indicated dihedral angle between their mean planes of 3.21 (11) degrees . The di-aminona-phthalene mol-ecules are slightly twisted [dihedral angles = 4.2 (2) and 3.0 (2) degrees ] because of the steric encumbrance of NH2 groups. The perimidine and di-aminona-phthalene mol ecules are linked by N-H?N hydrogen bonds, forming an R (4) 4(12) graph-set motif across an inversion center. In the crystal, alternating layers of the perimidine and di-aminona-phthalene mol-ecules are formed along [100]. In the perimidine layer, mol-ecules are pi-pi stacked along the c-axis direction with an inter plane separation of approximately 3.4 A. PMID- 24046686 TI - 5-Bromo-2-(4-fluoro-phen-yl)-7-methyl-3-phenyl-sulfinyl-1-benzo-furan. AB - In the title compound, C21H14BrFO2S, the dihedral angles between the mean plane [r.m.s. deviation = 0.005 (1) A] of the benzo-furan ring system and the pendant 4 fluoro-phenyl and phenyl rings are 1.50 (8) and 81.47 (6) degrees , respectively. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds into supra molecular chains running along the a-axis direction. A short S?O contact [2.9623 (13) A] involving the sulfinyl groups is observed between inversion-related chains. PMID- 24046687 TI - 1-Benzyl-5-ethyl-5-hy-droxy-1H-pyrrol-2(5H)-one. AB - The title compound, C13H15NO2, was obtained as a by-product in the Grignard reaction of malimide. The dihedral angle between the five-memebred ring (r.m.s. deviation = 0.005 A) and the benzene ring is 67.20 (14) degrees . The benzene ring and the ethyl chain lie to the same side of the five-membered ring. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds, generating C(6) chains propagating in [010]. PMID- 24046688 TI - 5-Chloro-N'-cyclo-hexyl-idene-3-methyl-1H-indole-2-carbohydrazide. AB - In the title compound, C16H18ClN3O, the cyclo-hexane ring adopts a distorted chair conformation. In the crystal, pairs of mol-ecules are linked by N-H?O hydrogen bonds into inversion dimers, forming R 2 (2)(10) ring motifs. These dimers are connected through C-H?N hydrogen bonds into chains along the a axis, forming layers parallel to (101). PMID- 24046689 TI - (E)-Methyl 3-(10-bromo-anthracen-9-yl)acrylate. AB - In the title mol-ecule, C18H13BrO2, the anthracene unit forms an angle of 46.91 (2) degrees with the mean plane of the methyl acrylate moiety. In the crystal, the mol-ecules arrange themselves into strands parallel to [010] and, due to the crystal symmetry, there are eight strands crossing the unit cell. In each strand, mol-ecules form short C-H?O and C-H?pi contacts and have their anthracene groups parallel to each other. Neighboring strands, related by a c-glide operation, are connected via C-H?O inter-actions and form a layer parallel to (100). The arrangement of the acrylate and anthracene groups in the crystal do not allow for [2 + 2] or [4 + 4] cyclo-addition. PMID- 24046690 TI - 2-{4-[(1,3-Benzodioxol-5-yl)meth-yl]piperazin-1-yl}pyrimidine. AB - In the title compound, C16H18N4O2, known also as peribedil, the dihedral angle between the mean planes of the pyrimidine and benzene rings is 56.5 (8) degrees . The 1,3-dioxole fragment adopts an envelope conformation with the methyl-ene C atom forming the flap; this atom deviates by 0.232 (3) A from the plane defined by the remaining atoms of the 1,3-benzodioxole unit. In the crystal, C-H?pi inter actions between c-glide-related mol-ecules arrange them into columns extending along the c-axis direction. The columns related by a unit translation along the b axis are packed into (100) layers via another C-H?pi inter-action involving the pyrimidine ring as an acceptor. PMID- 24046691 TI - N'-[(E)-4-Bromo-benzyl-idene]pyrazine-2-carbohydrazide. AB - In the title compound, C12H9BrN4O, the N'-methyl-idene-pyrazine-2-carbohydrazide and 4-bromobenzene groups are oriented at a dihedral angle of 10.57 (7) degrees . The hydrazide N-H group is involved in intra-molecular N-H?N inter-action, which generates an S(5) motif. A short C-H?O inter-action is formed between the methyl idene H atom and the carbonyl O atom. It connects mol-ecules into chains extending along [100]. In addition, mol-ecules are arranged into stacks extending along [010] via pi-pi inter-actions between pyrazine and benzene rings, with centroid-centroid distances of 3.837 (2) and 3.860 (2) A. PMID- 24046692 TI - 3-Acetyl-2,4-di-methyl-quinolin-1-ium chloride. AB - In the title salt, C13H14NO(+).Cl(-), the dihedral angle between the fused ring system (r.m.s. deviation = 0.039 A) and the attached aldehyde group is 75.27 (16) degrees . In the crystal, the cation and anion are linked by an N-H?Cl hydrogen bond and the resulting pairs are connected into four-ion aggregates by pi-pi inter-actions between the C6 and pyridinium rings [3.6450 (9) A] of inversion related quinolinium residues. PMID- 24046693 TI - (2E)-1-(4-Bromo-phen-yl)-3-[3-(4-meth-oxy-phen-yl)-1-phenyl-1H-pyrazol-4-yl]prop 2-en-1-one. AB - The pyrazole ring in the title compound, C25H19BrN2O2, is almost planar (r.m.s. deviation = 0.003 A) and forms dihedral angles of 7.56 (13) and 56.48 (13) degrees with the N- and C-bound benzene rings, respectively. The prop-2-en-1-one residue has an E conformation about the C=C double bond [1.328 (4) A] and is almost coplanar with the pyrazole ring [C-C-C-C torsion angle = -174.4 (3) degrees ]. A twist between the prop-2-en-1-one unit and the terminal benzene ring is evident [C-C-C-C torsion angle = -15.4 (4) degrees ]. In the crystal, mol ecules are consolidated into a three-dimensional architecture by C-H?O, C-H?pi and pi-pi [centroid-centroid separation = 3.7597 (16) A] inter-actions. PMID- 24046694 TI - Bis[1-(2,3-di-methyl-phen-yl)piperazine-1,4-diium] bis-(oxonium) cyclo-hexa phosphate dihydrate. AB - In the title compound, 2C12H20N2 (2+).2H3O(+).P6O18 (6-).2H2O, a protonated water mol-ecule bridges the centrosymmetrical anionic P6O18 ring via O-H?O hydrogen bonds. The centrosymmetric hydrogen-bonded rings formed by four oxonium cations and four phosphate anions can be described by an R 4 (8)(36) graph-set motif. The ring motifs are connected by hydrogen bonds into inorganic layers perpendicular to [100]. The 1-(2,3-di-methyl-phen-yl)piperazine-1,4-diium cations are located between the layers, compensating their negative charge and establishing N-H?O hydrogen bonds with the O atoms of the anionic framework. PMID- 24046695 TI - 1,5-Bis(2-meth-oxy-benzyl-idene)thio-carbonohydrazide methanol monosolvate. AB - The title compound, C17H18N4O2S.CH3OH, was synthesized by the condensation reaction of o-meth-oxy-benzaldehyde with thio-carbohydrazide in methanol. The two benzene rings are inclined each to other at 31.7 (1) degrees . Inter-molecular N H?O and bifurcated O-H?N(S) hydrogen bonds link two thio-carbonohydrazide and two solvent mol-ecules into a centrosymmetric unit. These units, related by translation along the b axis, are further aggregated into columns through N-H?S hydrogen bonds. PMID- 24046696 TI - 7-Bromo-2-(4-methyl-phen-yl)-1-(methyl-sulfin-yl)naphtho-[2,1-b]furan. AB - In the title compound, C20H15BrO2S, the dihedral angle between the mean plane [r.m.s. deviation = 0.030 (2) A] of the naphtho-furan ring system and the 4 methyl-phenyl ring is 38.49 (9) degrees . In the crystal, mol-ecules are linked by C-H?pi and C-Br?pi [3.871 (2) A] inter-actions into stacks along the b-axis direction. These stacks are further linked by weak C-H?O hydrogen bonds, forming a three-dimensional network. PMID- 24046697 TI - 1,6-Di-bromo-naphthalen-2-ol methanol monosolvate. AB - The naphthol-containing mol-ecule of the title compound, C10H6Br2O.CH3OH, crystallized as a methanol monosolvate and is planar to within 0.069 (1) A for all non-H atoms. In the crystal, mol-ecules are linked by two pairs of O-H?O hydrogen bonds, involving the methanol mol-ecule, forming dimer-like arrangements. The crystal structure is further stabilized by pi-pi stacking [centroid-centroid distance = 3.676 (2) A] and Br?Br inter-actions [3.480 (4) and 3.786 (1) A], forming a three-dimensional structure. PMID- 24046698 TI - 1,3-Bis(chloro-meth-yl)benzene. AB - The title compound, C8H8Cl2, used in the synthesis of many pharmaceutical inter mediates, forms a three-dimensional network through chlorine-chlorine inter actions in the solid-state that measure 3.513 (1) and 3.768 (3) A. PMID- 24046699 TI - (1H-Imidazol-4-yl)methanol. AB - The title compound, C4H6N2O, displays two predominant hydrogen-bonding inter actions in the crystal structure. The first is between the unprotonated imidazole N atom of one mol-ecule and the hy-droxy H atom of an adjacent mol-ecule. The second is between the hy-droxy O atom of one mol-ecule and the imidazole N-H group of a corresponding mol-ecule. These inter-actions lead to the formation of a two-dimnensional network parallel to (10-1). C-H?O inter-actions also occur. PMID- 24046700 TI - N,N'-Di-hydroxy-benzene-1,2:4,5-tetra-carboximide dihydrate. AB - In the title compound, C10H4N2O6.2H2O, the organic mol-ecule has crystallographically imposed inversion symmetry. The atoms of the three fused rings of the mol-ecule are coplanar within 0.0246 (8) A, while the two hy-droxy O atoms are displaced from the mean plane of the mol-ecule by 0.127 (1) A. In the crystal, infinite near-planar layers of close-packed mol-ecules are formed by hydrogen bonding between water O-H donor groups and carbonyl O-atom acceptors, and by weak inter-actions between C-H donor groups and water O-atom acceptors. The layers are parallel to the {102} family of planes. The stacked planes are held together by hydrogen bonding between N-OH donor groups and water O-atom acceptors. PMID- 24046701 TI - 1-(3-Meth-oxy-phen-yl)-4,5-dimethyl-2-phenyl-1H-imidazole. AB - In the title compound, C18H18N2O, the imidazole ring makes dihedral angles of 68.26 (7) and 22.45 (9) degrees with the meth-oxy-phenyl and phenyl rings, respectively. The dihedral angle between the meth-oxy-phenyl and phenyl ring is 71.86 (7) degrees . In the crystal, weak inter-molecular C-H?O and C-H?N hydrogen bonds link the mol-ecules into columns propagated in [101]. PMID- 24046702 TI - Pallidol hexa-acetate ethyl acetate monosolvate. AB - The entire mol-ecule of pallidol hexa-acetate {systematic name: (+/-) (4bR,5R,9bR,10R)-5,10-bis-[4-(acet-yloxy)phen-yl]-4b,5,9b,10-tetra-hydro-indeno [2,1-a]indene-1,3,6,8-tetrayl tetra-acetate} is completed by the application of twofold rotational symmetry in the title ethyl acetate solvate, C40H34O12.C4H8O2. The ethyl acetate mol-ecule was highly disordered and was treated with the SQUEEZE routine [Spek (2009 ?). Acta Cryst. D65, 148-155]; the crystallographic data take into account the presence of the solvent. In pallidol hexa-acetate, the dihedral angle between the fused five-membered rings (r.m.s. deviation = 0.100 A) is 54.73 (6) degrees , indicating a significant fold in the mol-ecule. Significant twists between residues are also evident as seen in the dihedral angle of 80.70 (5) degrees between the five-membered ring and the pendent benzene ring to which it is attached. Similarly, the acetate residues are twisted with respect to the benzene ring to which they are attached [C-O(carb-oxy)-C-C torsion angles = -70.24 (14), -114.43 (10) and -72.54 (13) degrees ]. In the crystal, a three-dimensional architecture is sustained by C-H?O inter-actions which encompass channels in which the disordered ethyl acetate mol-ecules reside. PMID- 24046703 TI - 2-(1,3-Di-thiol-2-yl-idene)-1,3-di-thiole-4-carbaldehyde. AB - The structure of the title compound, C7H4OS4, at 100 K has ortho-rhom-bic symmetry. In the crystal, tetra-thia-fulvalene mol-ecules form pi-stacks along the a axis, with a stacking distance of 3.4736 (6) A. Along the b axis, parallel stacks are inter-connected with each other through a network of weak C-H?O hydrogen bonds and short S?S contacts [3.4813 (7) A]. Additional short S?S contacts [3.4980 (9) A] join parallel stacks along the c axis. PMID- 24046704 TI - 4-Methyl-5-(4-nitro-benzyl-idene)-2-oxo-2,5-di-hydro-1H-pyrrole-3-carbo-nitrile. AB - Mol-ecules of the potential non-linear optical title compound, C13H9N3O3, form dimeric stacks of mol-ecules along the a axis cross-linked around inversion centers by N-H?O hydrogen bonds and weak (phen-yl)C-H?O inter-molecular inter actions, forming a 'collaboration' of R 2 (2)(8) and R 2 (2)(16) ring motifs. The mol-ecules are then further linked by weak C-H?O and C-H?N inter-actions into sheets parallel to (121). PMID- 24046705 TI - 5-Nitro-1,3-bis-(prop-2-yn-yl)-1H-1,3-benzimidazol-2(3H)-one. AB - The title compound, C13H9N3O3, crystallizes with two identical but differently oriented mol-ecules in the asymmetric unit, the dihedral angle between the fused ring systems of the two molecules being 64.39 (7) degrees . The two prop-2-ynyl chains are located on opposite sides of the mol-ecule and are nearly perpendicular to the fused ring plane, as indicated by the C-N-C-C torsion angles in the range 106.0 (3)-113.4 (3) degrees . In the crystal, the two mol-ecules are linked through C-H?O hydrogen bonds into dimers, which are subsequently linked by further C-H?O inter-actions, building a three-dimensional network. PMID- 24046706 TI - N'-[(E)-4-Benz-yloxy-2-hy-droxy-benzyl-idene]-4-nitro-benzohydrazide di-methyl formamide monosolvate. AB - The title compound, C21H17N3O5.C3H7NO, exists in an E conformation with respect to the azomethine double bond of the hydrazide mol-ecule. This mol-ecule contains an intra-molecular O-H?N hydrogen bond, while an inter-molecular N-H?O hydrogen bond links the hydrazide to the formamide mol-ecule of solvation. Nonclassical C H?O inter-molecular hydrogen bonds build up a supra-molecular architecture, together with two C-H?pi inter-actions and a weak pi-pi inter-action, with a centroid-centroid distance of 3.650 (13) A. PMID- 24046707 TI - (3R*,6R*,4'S*,8'R*,3''R*,6''R*)-3,3''-Diisopropyl-6,6''-dimethyl-2',6'-di-phenyl dispiro-[cyclo-hexane-1,4'-(3,7-dioxa-2,6-di-aza-bicyclo-[3.3.0]octa-ne)-8',1'' cyclo-hexa-ne]-2,2''-dione. AB - The two oxazolidine rings (A and B) of the title compound, C34H44N2O4, display roughly half-chair conformations, which could be described as twisted on the C-O bond. Together, the fused oxazolidine rings have a butterfly shape, with the H atoms attached to the ring junction C atoms in a cis orientation. The cyclo hexane rings of both p-menthone fragments display chair conformations. The absolute configuration could not be determined from the X-ray diffraction data, but the relative configuration of the stereocentres could be deduced. PMID- 24046708 TI - 4-(4-Nitro-benz-yl)pyridine. AB - The title compound, C12H10N2O2, has a twisted conformation, with a dihedral angle between the planes of the pyridine and benzene rings of 78.4 (2) degrees . The nitro group is coplanar with the attached benzene ring within experimental error. The mol-ecules form centrosymmetric dimers via Car-H?O inter-actions (H?O = 2.49 A) and the dimers are pi-stacked along the b axis [the separation between ring centroids is 3.788 (2) A]. PMID- 24046709 TI - 8-Phenyl-16-thia-penta-cyclo-[6.6.5.0(1,18).0(2,7).0(9,14)]nona-deca 2,4,6,9,11,13,18-hepta-ene. AB - In the title compound, C24H18S, the dihedral angles between the phenyl ring and the two benzene rings of the anthracene moiety are 51.92 (9) and 68.24 (9) degrees , whereas the dihedral angle between the two anthracene benzene rings is 120.13 (9) degrees . The three non-aromatic six-membered rings are in boat conformations, while the five-membered ring has an envelope conformation on the S atom. In the crystal, there are three C-H?pi inter-actions, which facilitate the packing of the mol-ecules. PMID- 24046710 TI - 4,4'-Di-tert-butyl-2,2'-[imidazolidine-1,3-diylbis(methyl-ene)]diphenol. AB - In the title compound, C25H36N2O2, the two tert-butyl-substituted benzene rings are inclined at an angle of 53.5 (3) degrees to one another. The imidazolidine ring has an envelope conformation with with one of the C atoms of the ethylene fragment as the flap. The structure displays two intra-molecular O-H?N hydrogen bonds that generate S(6) ring motifs. The crystal studied was a non-merohedral twin with a fractional contribution of 0.281(6) for the minor domain. PMID- 24046711 TI - (E)-2-Meth-oxy-9-(2-meth-oxy-9H-xanthen-9-yl-idene)-9H-xanthene. AB - The title compound, C28H20O4, was synthesized by a bimolecular Zn-HCl reduction in glacial acetic acid using the meth-oxy-substituted xanthone as a starting material. The crystal structure shows that the 2,2'-meth-oxy-bixanthenyl-idene unit is an E-type conformation anti-folded conformer. The mol-ecule lies on an inversion center. The meth-oxy group is almost coplanar with the attached benzene ring, with a C-O-C-C torsion angle of 179.38 (14) degrees . PMID- 24046712 TI - 2,6-Dimethyl-4-oxo-3-oxatri-cyclo-[5.2.1.0(2,6)]decane-1-carboxamide. AB - In the title compound, C12H17NO3, which was synthesized by Wagner-Meerwein rearrangement of the N-nitro-imine, the ring-junction C-C bond length is comparatively long [1.573 (2) A] due to a steric repulsion between the methyl groups at these atoms, which also leads to an increase in the C-C-C angles along this C4 chain [118.10 (13) and 115.04 (15) degrees , respectively]. In the crystal, N-H?O-C and N-H?O=C hydrogen bonds are formed between the amide group and the two O-atom acceptors of the lactone group, forming a chain along [001]. PMID- 24046713 TI - rac-1-(5-Bromo-2-hy-droxy-phen-yl)-1-oxopropan-2-yl morpholine-4-carbo-dithio ate. AB - In the racemic title compound, C14H16BrNO3S2, synthesized from the corresponding omega-bromo-propio-phenone, the dihedral angle between the plane of the phenol group and that of the planar section [maximum deviation = 0.040 (2) A] of the morpholine-4-carbodi-thiol-ate moiety is 76.36 (10) degrees . A strong intra molecular phenol O-H?O hydrogen bond if present in the mol-ecule. In the crystal, only weak C-H?S and C-H?O inter-actions are found. PMID- 24046714 TI - 4-Bromo-2-[5-methyl-2-(morpholin-4-yl)-1,3-thia-zol-4-yl]phenol. AB - In the title compound, C14H15BrN2O2S, synthesized by the reaction of the corresponding phenacyl thio-cyanate with morpholine, the dihedral angle between the 1,3-thia-zole ring and the phenolic substituent ring is 23.46 (10) degrees as a result of the steric influence of the ortho-methyl group on the thia-zole ring. A strong intra-molecular phenolic O-H?N hydrogen bond is present in the mol ecule. In the crystal, a weak C-H?Ophenol hydrogen bond gives rise to chains lying parallel to [20-1]. A short inter-molecular Br?Omorpholine inter-action is also present [3.1338 (19) A]. PMID- 24046715 TI - MU-(Acetic acid)-di-MU-chlorido-bis[tri-phenyl-tellurium(IV)] monohydrate. AB - The asymmetric unit of the title compound, C38H34Cl2O2Te2.H2O, contains two independent Te(IV) cations, each coordinated by three phenyl ligands, two Cl(-) anions and one acetic acid mol-ecule in a distorted octa-hedral C3Cl2O geometry; the longer Te?Cl distances ranging from 3.2007 (11) to 3.4407 (11) A and the longer Te?O distances of 3.067 (3) and 3.113 (3) A indicate the weak bridge coordination. The Cl(-) anion and acetic acid mol-ecule bridge the two independent Te(IV) cations, forming the dimeric complex mol-ecule, in which the Te?Te separation is 3.7314 (4) A. In the crystal, the water molecules of crystallization link the Te(IV) complex mol-ecules into chains running along the b-axis direction via O-H?O and O-H?Cl hydrogen bonds. PMID- 24046716 TI - N,N'-Diphenyl-9,10-dioxo-9,10-di-hydro-anthracene-2,7-disulfonamide. AB - The title mol-ecule, C26H18N2O6S2, has an overall Z-shaped conformation, in which the benzene rings are inclined to the anthra-quinone mean plane by 60.60 (9) and 50.66 (13) degrees . In the crystal, N-H?O and C-H?O hydrogen bonds link the mol ecules into layers parallel to the bc plane. PMID- 24046717 TI - (2Z)-3-(2,4-Di-chloro-phen-yl)-3-hy-droxy-N-phenyl-prop-2-ene-thio-amide. AB - In the title mol-ecule, C15H11Cl2NOS, the dihedral angle between the phenyl and benzene rings is 72.24 (1) degrees . In the crystal, pairs of N-H?S hydrogen bonds form dimers with twofold rotational symmetry. The dimers are connected by weak C-H?O hydrogen bonds, forming a two-dimensional network parallel to (001). An intra-molecular O-H?S hydrogen bond is also observed. PMID- 24046718 TI - (E)-1-[2-(2-Cyano-phen-yl)diazen-2-ium-1-yl]naphthalen-2-olate. AB - There are two independent zwitterion mol-ecules (A and B) in the asymmetric unit of the title compound, C17H11N3O, which belongs to the family of azo dyes. The dihedral angle between the benzene ring and the naphthalene ring system is 6.99 (6) degrees in mol-ecule A and 4.38 (6) degrees in mol-ecule B. The azo group adopts an E conformation with respect to the -N=N- bond and each of the independent mol-ecules has an intra-molecular N-H?O hydrogen bond. In the crystal, mol-ecules are linked by C-H?O and C-H?N hydrogen bonds, forming ribbons propagating along [-110]. The ribbons are linked via pi-pi inter-actions involving the benzene and naphthalene rings of inversion-related A and inversion related B mol-ecules, forming a three-dimensional structure. The most significant centroid-centroid distances vary from 3.6599 (6) to 3.7538 (9) A. PMID- 24046719 TI - (E)-N'-(4-Meth-oxy-benzyl-idene)pyridine-3-carbohydrazide dihydrate. AB - In the title compound, C14H13N3O2.2H2O, the hydrazone mol-ecule adopts an E conformation with respect to the C=N bond. The dihedral angle between the benzene and pyridine rings is 8.55 (10) degrees . The methyl-idene-hydrazide [-C(=O)-N N=C-] fragment is essentially planar, with a maximum deviation of 0.0375 (13) A. The mean planes of the benzene and pyridine rings make dihedral angles of 2.71 (14) and 11.25 (13) degrees , respectively, with mean plane of the methyl-idene hydrazide fragment. In the crystal, the benzohydrazide and water mol-ecules are linked by N-H?O, O-H?O and O-H?N hydrogen bonds into a three-dimensional network. PMID- 24046720 TI - 1-(3,4-Di-fluoro-benz-yl)-4-(4-methyl-phenyl-sulfon-yl)piperazine. AB - In the title compound, C18H20F2N2O2S, the central piperazine ring adopts a chair conformation. The dihedral angle between the two benzene rings is 40.20 degrees , whereas those between the piperazine ring (considering the best fit plane through all the non-H atoms) and the sulfonyl-bound benzene and di-fluoro-benzene rings are 74.96 and 86.16 degrees , respectively. In the crystal, mol-ecules are stacked along the a axis through weak C-H?O and C-H?F inter-actions. PMID- 24046721 TI - N'-Hy-droxy-pyridine-2-carboximidamide. AB - The title mol-ecule, C6H7N3O, is almost planar (r.m.s. deviation = 0.0068 A) and adopts an E conformation about the C=N double bond. In the crystal, mol-ecules are linked by pairs of strong N-H?N hydrogen bonds, forming inversion dimers with R 2 (2)(10) motifs. The dimers are further linked into C(3) chains through O-H?N hydrogen bonds. PMID- 24046722 TI - (+/-)-3-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-benzo-furan-1(3H)-one. AB - In the title compound, C18H15N3O2, the benzo-furan ring system is essentially planar, the rings making a dihedral angle of 0.57 (9) degrees . The phenyl, furan and benzene rings subtend dihedral angles of 47.07 (10), 85.76 (7) and 86.04 (7) degrees , respectively, with the pyrazole ring. In the crystal, mol-ecules are linked by weak N-H?N, N-H?O and C-H?O inter-actions, generating edge-fused R 4 (4)(20), and R 1 (2)(7) rings linked into sheets which are parallel to (010). PMID- 24046723 TI - 3-({[Bis(2-methyl-prop-yl)carbamo-thio-yl]amino}-carbon-yl)benzamide. AB - In the title compound, C17H25N3O2S, the terminal and central amide groups are, respectively, twisted and coplanar with the attached benzene ring [O-C-C-C torsion angles = 22.7 (3) and 5.4 (3) degrees ]. In the central part of the mol ecule, the amide and thio-amide residues are approximately perpendicular [C-N-C-S torsion angle = -104.98 (18) degrees ]. Supra-molecular layers with a zigzag topology are formed in the crystal packing by N-H?O, N-H?S and C-H?O inter actions; these stack along c, being separated by hydro-phobic inter-actions. PMID- 24046724 TI - 3-{[(Di-benzyl-carbamo-thio-yl)amino]-carbon-yl}benzamide. AB - Two independent mol-ecules with quite similar conformations, A and B, comprise the asymmetric unit of the title compound, C23H21N3O2S. The terminal amide substituent is coplanar with the attached benzene ring [the O-C-C-C torsion angles are 174.0 (2) (A) and 6.3 (3) degrees (B)]. In the same way, the central amide group [C-C-C-O = 7.8 (3) (A) and 11.5 (3) degrees (B)] is approximately coplanar with the ring to which it is attached. A major twist is noted between the amide and adjacent thio-amide residues [C-N-C-S = -109.29 (19) (A) and 112.29 (19) degrees (B)]. In the crystal, supra-molecular chains along [100] are formed by N-H?O and N-H?S hydrogen bonding. These are connected into a three dimensional architecture by C-H?pi and pi-pi inter-actions [inter-centroid distance = 3.9157 (12) A]. PMID- 24046725 TI - Methyl 3-[(chloro-meth-oxy)carbon-yloxy]-7-hy-droxy-cholan-24-oate. AB - The title compound, C27H43ClO6, is a derivative of urso-deoxy-cholic acid, in which the OH group at the 3-position is substituted by a chloro-meth-oxy-carbon yloxy substituent and the carb-oxy-lic acid group at the 24-position is methyl ated. The A and B rings are cis-fused, while all other rings are trans-fused. In the crystal, two adjacent mol-ecules located along the b-axis direction are inter locked head-to-tail due to weak C-H?O hydrogen bonds. Therefore each mol-ecule is linked to four neighbouring mol-ecules by four C-H?O hydrogen bonds, with the OH group at the 7-position and the carbonyl O atom of the ester group acting as the acceptor sites. PMID- 24046726 TI - 5-Fluoro-2-(4-fluoro-phen-yl)-7-methyl-3-phenyl-sulfinyl-1-benzo-furan. AB - In the title compound, C21H14F2O2S, the dihedral angles between the mean plane [r.m.s. deviation = 0.007 (2) A] of the benzo-furan ring system and the pendant 4 fluoro-phenyl and phenyl rings are 5.93 (9) and 80.23 (5) degrees , respectively. In the crystal, mol-ecules are linked by weak C-H?O and C-H?pi inter-actions, forming a three-dimensional network. PMID- 24046727 TI - Methyl N-(di-meth-oxy-phosphor-yl)carbamate. AB - In the title compound, CH3OC(O)NHP(O)(OCH3)2, the P atom has a slightly distorted tetra-hedral configuration. The mixed imide moiety can be described as cisoid transoid in which the two opposing dipoles (P=O and C=O) are oriented with a O=C?P=O torsion angle of 150.88(18) degrees . In the crystal, molecules are linked by pairs of N-H?O hydrogen bonds, forming inversion dimers. PMID- 24046728 TI - 2,4-Di-bromo-6-{[(5-chloro-2-methyl-phen-yl)imino]-meth-yl}phenol. AB - In the mol-ecular structure of the title Schiff base, C14H10Br2ClNO, the chloro phenyl ring and di-bromo-phenol ring are almost coplanar; the dihedral angle between the planes of the two rings is 10.50 (18) degrees . There is an intra molecular O-H?N hydrogen bond, with an O?N distance of 2.576 (4)A. The crystal structure is stabilized by pi-pi stacking of neighbouring aromatic rings along the b-axis direction [centroid-centroid distance = 3.6896 (5) A]. PMID- 24046729 TI - RNA pathogenesis via Toll-like receptor-activated inflammation in expanded repeat neurodegenerative diseases. AB - Previously, we hypothesized that an RNA-based pathogenic pathway has a causal role in the dominantly inherited unstable expanded repeat neurodegenerative diseases. In support of this hypothesis we, and others, have characterized rCAG.rCUG 100 repeat double-strand RNA (dsRNA) as a previously unidentified agent capable of causing pathogenesis in a Drosophila model of neurodegenerative disease. Dicer, Toll, and autophagy pathways have distinct roles in this Drosophila dsRNA pathology. Dicer dependence is accompanied by cleavage of rCAG.rCUG 100 repeat dsRNA down to r(CAG) 7 21-mers. Among the "molecular hallmarks" of this pathway that have been identified in Drosophila, some [i.e., r(CAG) 7 and elevated tumor necrosis factor] correlate with observations in affected people (e.g., Huntington's disease and amyotrophic lateral sclerosis) or in related animal models (i.e., autophagy). The Toll pathway is activated in the presence of repeat-containing dsRNA and toxicity is also dependent on this pathway. How might the endogenously expressed dsRNA mediate Toll-dependent toxicity in neuronal cells? Endogenous RNAs are normally shielded from Toll pathway activation as part of the mechanism to distinguish "self" from "non-self" RNAs. This typically involves post-transcriptional modification of the RNA. Therefore, it is likely that rCAG.rCUG 100 repeat dsRNA has a characteristic property that interferes with or evades this normal mechanism of shielding. We predict that repeat expansion leads to an alteration in RNA structure and/or form that perturbs RNA modification, causing the unshielded repeat RNA (in the form of its Dicer-cleaved products) to be recognized by Toll-like receptors (TLRs), with consequent activation of the Toll pathway leading to loss of cell function and then ultimately cell death. We hypothesize that the proximal cause of expanded repeat neurodegenerative diseases is the TLR recognition (and resultant innate inflammatory response) of repeat RNA as "non-self" due to their paucity of "self" modification. PMID- 24046730 TI - Modulation of adult-born neurons in the inflamed hippocampus. AB - Throughout life new neurons are continuously added to the hippocampal circuitry involved with spatial learning and memory. These new cells originate from neural precursors in the subgranular zone of the dentate gyrus, migrate into the granule cell layer, and integrate into neural networks encoding spatial and contextual information. This process can be influenced by several environmental and endogenous factors and is modified in different animal models of neurological disorders. Neuroinflammation, as defined by the presence of activated microglia, is a common key factor to the progression of neurological disorders. Analysis of the literature shows that microglial activation impacts not only the production, but also the migration and the recruitment of new neurons. The impact of microglia on adult-born neurons appears much more multifaceted than ever envisioned before, combining both supportive and detrimental effects that are dependent upon the activation phenotype and the factors being released. The development of strategies aimed to change microglia toward states that promote functional neurogenesis could therefore offer novel therapeutic opportunities against neurological disorders associated with cognitive deficits and neuroinflammation. The present review summarizes the current knowledge on how production, distribution, and recruitment of new neurons into behaviorally relevant neural networks are modified in the inflamed hippocampus. PMID- 24046732 TI - Rhythm sensitivity in macaque monkeys. AB - This study provides evidence that monkeys are rhythm sensitive. We composed isochronous tone sequences consisting of repeating triplets of two short tones and one long tone which humans perceive as repeating triplets of two weak and one strong beat. This regular sequence was compared to an irregular sequence with the same number of randomly arranged short and long tones with no such beat structure. To search for indication of rhythm sensitivity we employed an oddball paradigm in which occasional duration deviants were introduced in the sequences. In a pilot study on humans we showed that subjects more easily detected these deviants when they occurred in a regular sequence. In the monkeys we searched for spontaneous behaviors the animals executed concomitant with the deviants. We found that monkeys more frequently exhibited changes of gaze and facial expressions to the deviants when they occurred in the regular sequence compared to the irregular sequence. In addition we recorded neuronal firing and local field potentials from 175 sites of the primary auditory cortex during sequence presentation. We found that both types of neuronal signals differentiated regular from irregular sequences. Both signals were stronger in regular sequences and occurred after the onset of the long tones, i.e., at the position of the strong beat. Local field potential responses were also significantly larger for the durational deviants in regular sequences, yet in a later time window. We speculate that these temporal pattern-selective mechanisms with a focus on strong beats and their deviants underlie the perception of rhythm in the chosen sequences. PMID- 24046731 TI - Transient dynamics and rhythm coordination of inferior olive spatio-temporal patterns. AB - The inferior olive (IO) is a neural network belonging to the olivo-cerebellar system whose neurons are coupled with electrical synapses and display subthreshold oscillations and spiking activity. The IO is frequently proposed as the generator of timing signals to the cerebellum. Electrophysiological and imaging recordings show that the IO network generates complex spatio-temporal patterns. The generation and modulation of coherent spiking activity in the IO is one key issue in cerebellar research. In this work, we build a large scale IO network model of electrically coupled conductance-based neurons to study the emerging spatio-temporal patterns of its transient neuronal activity. Our modeling reproduces and helps to understand important phenomena observed in IO in vitro and in vivo experiments, and draws new predictions regarding the computational properties of this network and the associated cerebellar circuits. The main factors studied governing the collective dynamics of the IO network were: the degree of electrical coupling, the extent of the electrotonic connections, the presence of stimuli or regions with different excitability levels and the modulatory effect of an inhibitory loop (IL). The spatio-temporal patterns were analyzed using a discrete wavelet transform to provide a quantitative characterization. Our results show that the electrotonic coupling produces quasi-synchronized subthreshold oscillations over a wide dynamical range. The synchronized oscillatory activity plays the role of a timer for a coordinated representation of spiking rhythms with different frequencies. The encoding and coexistence of several coordinated rhythms is related to the different clusterization and coherence of transient spatio-temporal patterns in the network, where the spiking activity is commensurate with the quasi synchronized subthreshold oscillations. In the presence of stimuli, different rhythms are encoded in the spiking activity of the IO neurons that nevertheless remains constrained to a commensurate value of the subthreshold frequency. The stimuli induced spatio-temporal patterns can reverberate for long periods, which contributes to the computational properties of the IO. We also show that the presence of regions with different excitability levels creates sinks and sources of coordinated activity which shape the propagation of spike wave fronts. These results can be generalized beyond IO studies, as the control of wave pattern propagation is a highly relevant problem in the context of normal and pathological states in neural systems (e.g., related to tremor, migraine, epilepsy) where the study of the modulation of activity sinks and sources can have a potential large impact. PMID- 24046733 TI - Graph theory reveals dysconnected hubs in 22q11DS and altered nodal efficiency in patients with hallucinations. AB - Schizophrenia is postulated to be the prototypical dysconnection disorder, in which hallucinations are the core symptom. Due to high heterogeneity in methodology across studies and the clinical phenotype, it remains unclear whether the structural brain dysconnection is global or focal and if clinical symptoms result from this dysconnection. In the present work, we attempt to clarify this issue by studying a population considered as a homogeneous genetic sub-type of schizophrenia, namely the 22q11.2 deletion syndrome (22q11.2DS). Cerebral MRIs were acquired for 46 patients and 48 age and gender matched controls (aged 6-26, respectively mean age = 15.20 +/- 4.53 and 15.28 +/- 4.35 years old). Using the Connectome mapper pipeline (connectomics.org) that combines structural and diffusion MRI, we created a whole brain network for each individual. Graph theory was used to quantify the global and local properties of the brain network organization for each participant. A global degree loss of 6% was found in patients' networks along with an increased Characteristic Path Length. After identifying and comparing hubs, a significant loss of degree in patients' hubs was found in 58% of the hubs. Based on Allen's brain network model for hallucinations, we explored the association between local efficiency and symptom severity. Negative correlations were found in the Broca's area (p < 0.004), the Wernicke area (p < 0.023) and a positive correlation was found in the dorsolateral prefrontal cortex (DLPFC) (p < 0.014). In line with the dysconnection findings in schizophrenia, our results provide preliminary evidence for a targeted alteration in the brain network hubs' organization in individuals with a genetic risk for schizophrenia. The study of specific disorganization in language, speech and thought regulation networks sharing similar network properties may help to understand their role in the hallucination mechanism. PMID- 24046734 TI - Cyborg psychiatry to ensure agency and autonomy in mental disorders. A proposal for neuromodulation therapeutics. AB - Neuromodulation therapeutics-as repeated Transcranial Magnetic Stimulation (rTMS) and neurofeedback-are valuable tools for psychiatry. Nevertheless, they currently face some limitations: rTMS has confounding effects on neural activation patterns, and neurofeedback fails to change neural dynamics in some cases. Here we propose how coupling rTMS and neurofeedback can tackle both issues by adapting neural activations during rTMS and actively guiding individuals during neurofeedback. An algorithmic challenge then consists in designing the proper recording, processing, feedback, and control of unwanted effects. But this new neuromodulation technique also poses an ethical challenge: ensuring treatment occurs within a biopsychosocial model of medicine, while considering both the interaction between the patients and the psychiatrist, and the maintenance of individuals' autonomy. Our solution is the concept of Cyborg psychiatry, which embodies the technique and includes a self-engaged interaction between patients and the neuromodulation device. PMID- 24046735 TI - The role of potential agents in making spatial perspective taking social. AB - A striking relationship between visual spatial perspective taking (VSPT) and social skills has been demonstrated for perspective-taking tasks in which the target of the imagined or inferred perspective is a potential agent, suggesting that the presence of a potential agent may create a social context for the seemingly spatial task of imagining a novel visual perspective. In a series of studies, we set out to investigate how and when a target might be viewed as sufficiently agent-like to incur a social influence on VSPT performance. By varying the perceptual and conceptual features that defined the targets as potential agents, we find that even something as simple as suggesting animacy for a simple wooden block may be sufficient. More critically, we found that experience with one potential agent influenced the performance with subsequent targets, either by inducing or eliminating the influence of social skills on VSPT performance. These carryover effects suggest that the relationship between social skills and VSPT performance is mediated by a complex relationship that includes the task, the target, and the context in which that target is perceived. These findings highlight potential problems that arise when identifying a task as belonging exclusively to a single cognitive domain and stress instead the highly interactive nature of cognitive domains and their susceptibility to cross-domain individual differences. PMID- 24046736 TI - Watch me if you can: imagery ability moderates observational learning effectiveness. AB - Recent research has revealed similarities in brain activity during observational learning and motor execution. However, whilst action develops visual, motor and afferent representations during acquisition, action-observation has been proposed to only develop visual-spatial learning via visual representation. In addition, it has been suggested that the vividness of visual representations are determined by imagery ability. Thus, the purpose of the current investigation was to explore the possible moderating role of imagery ability in the effectiveness of observational learning. Participants (n = 40) were assessed on their imagery ability via the Vividness of Movement Imagery Questionnaire-2 (VMIQ-2) and then assigned to one of four groups; high imagery ability and observational learning (HIA-OL), low imagery ability and observational learning (LIA-OL), high imagery ability control (HIA-C) and low imagery ability control (LIA-C). Following group allocation all participants performed a pre-test consisting of five actual practice trials of a novel gymnastics routine. The HIA-OL and LIA-OL groups then participated in a 14 day observational learning intervention whilst the HIA-C and LIA-C groups acted as controls. Following this, participants performed a post test, which was identical in nature to the pre-test, before finally completing the VMIQ-2 again. Performance on both the pre-test and post test was evaluated by two qualified gymnastics judges. Results revealed that gymnastics performance increased from pre-test to post test for both the HIA-OL and LIA-OL groups. However, this effect was greater in the HIA-OL group suggesting that the relationship between observational learning and successful imitation performance is moderated by imagery ability. PMID- 24046737 TI - An examination of auditory processing and affective prosody in relatives of patients with auditory hallucinations. AB - Research on auditory verbal hallucinations (AVHs) indicates that AVH schizophrenia patients show greater abnormalities on tasks requiring recognition of affective prosody (AP) than non-AVH patients. Detecting AP requires accurate perception of manipulations in pitch, amplitude and duration. Schizophrenia patients with AVHs also experience difficulty detecting these acoustic manipulations; with a number of theorists speculating that difficulties in pitch, amplitude and duration discrimination underlie AP abnormalities. This study examined whether both AP and these aspects of auditory processing are also impaired in first degree relatives of persons with AVHs. It also examined whether pitch, amplitude and duration discrimination were related to AP, and to hallucination proneness. Unaffected relatives of AVH schizophrenia patients (N = 19) and matched healthy controls (N = 33) were compared using tone discrimination tasks, an AP task, and clinical measures. Relatives were slower at identifying emotions on the AP task (p = 0.002), with secondary analysis showing this was especially so for happy (p = 0.014) and neutral (p = 0.001) sentences. There was a significant interaction effect for pitch between tone deviation level and group (p = 0.019), and relatives performed worse than controls on amplitude discrimination and duration discrimination. AP performance for happy and neutral sentences was significantly correlated with amplitude perception. Lastly, AVH proneness in the entire sample was significantly correlated with pitch discrimination (r = 0.44) and pitch perception was shown to predict AVH proneness in the sample (p = 0.005). These results suggest basic impairments in auditory processing are present in relatives of AVH patients; they potentially underlie processing speed in AP tasks, and predict AVH proneness. This indicates auditory processing deficits may be a core feature of AVHs in schizophrenia, and are worthy of further study as a potential endophenotype for AVHs. PMID- 24046738 TI - Familiarity mediates the relationship between emotional arousal and pleasure during music listening. AB - Emotional arousal appears to be a major contributing factor to the pleasure that listeners experience in response to music. Accordingly, a strong positive correlation between self-reported pleasure and electrodermal activity (EDA), an objective indicator of emotional arousal, has been demonstrated when individuals listen to familiar music. However, it is not yet known to what extent familiarity contributes to this relationship. In particular, as listening to familiar music involves expectations and predictions over time based on veridical knowledge of the piece, it could be that such memory factors plays a major role. Here, we tested such a contribution by using musical stimuli entirely unfamiliar to listeners. In a second experiment we repeated the novel music to experimentally establish a sense of familiarity. We aimed to determine whether (1) pleasure and emotional arousal would continue to correlate when listeners have no explicit knowledge of how the tones will unfold, and (2) whether this could be enhanced by experimentally-induced familiarity. In the first experiment, we presented 33 listeners with 70 unfamiliar musical excerpts in two sessions. There was no relationship between the degree of experienced pleasure and emotional arousal as measured by EDA. In the second experiment, 7 participants listened to 35 unfamiliar excerpts over two sessions separated by 30 min. Repeated exposure significantly increased EDA, even though individuals did not explicitly recall having heard all the pieces before. Furthermore, increases in self-reported familiarity significantly enhanced experienced pleasure and there was a general, though not significant, increase in EDA. These results suggest that some level of expectation and predictability mediated by prior exposure to a given piece of music play an important role in the experience of emotional arousal in response to music. PMID- 24046739 TI - Age differences in neural response to stereotype threat and resiliency for self referenced information. AB - To investigate the contribution of cortical midline regions to stereotype threat and resiliency, we compared age groups in an event-related functional MRI study. During scanning, 17 younger and 16 older adults judged whether words stereotypical of aging and control words described them. Judging stereotype words versus control words revealed higher activations in posterior midline regions associated with self-referencing, including the precuneus, for older adults compared to younger adults. While heightening salience of stereotypes can evoke a threat response, detrimentally affecting performance, invoking stereotypes can also lead to a phenomenon called resilience, where older adults use those stereotypes to create downward social-comparisons to "other" older adults and elevate their own self-perception. In an exploration of brain regions underlying stereotype threat responses as well as resilience responses, we found significant activation in older adults for threat over resilient responses in posterior midline regions including the precuneus, associated with self-reflective thought, and parahippocampal gyrus, implicated in autobiographical memory. These findings have implications for understanding how aging stereotypes may affect the engagement of regions associated with contextual and social processing of self relevant information, indicating ways in which stereotype threat can affect the engagement of neural resources with age. PMID- 24046740 TI - tDCS over the left inferior frontal cortex improves speech production in aphasia. AB - In this study, we investigated the combined effect of transcranial direct current stimulation (tDCS) and an intensive Conversational therapy treatment on discourse skills in 12 persons with chronic aphasia. Six short video clips depicting everyday life contexts were prepared. Three videoclips were used to elicit spontaneous conversation during treatment. The remaining three were presented only before and after the therapy. Participants were prompted to talk about the contents of each videoclip while stimulated with tDCS (20 min 1 mA) over the left hemisphere in three conditions: anodic tDCS over the Broca's area, anodic tDCS over the Wernicke's area, and a sham condition. Each experimental condition was performed for 10 consecutive daily sessions with 14 days of intersession interval. After stimulation over Broca's area, the participants produced more Content Units, verbs and sentences than in the remaining two conditions. Importantly, this improvement was still detectable 1 month after the end of treatment and its effects were generalized also to the three videoclips that had been administered at the beginning and at the end of the therapy sessions. In conclusion, anodic tDCS applied over the left Broca's area together with an intensive "Conversational Therapy" treatment improves informative speech in persons with chronic aphasia. We believe that positive tDCS effects may be further extended to other language domains, such as the recovery of speech production. PMID- 24046741 TI - Articulation-based sound perception in verbal repetition: a functional NIRS study. AB - Verbal repetition is a fundamental language capacity where listening and speaking are inextricably coupled with each other. We have recently reported that the left inferior frontal gyrus (IFG) harbors articulation-based codes, as evidenced by activation during repetition of meaningless speech sounds, i.e., pseudowords. In this study, we aimed at confirming this finding and further investigating the possibility that sound perception as well as articulation is subserved by neural circuits in this region. Using functional near-infrared spectroscopy (fNIRS), we monitored changes of hemoglobin (Hb) concentration at IFG bilaterally, while subjects verbally repeated pseudowords and words. The results revealed that the proportion of oxygenated hemoglobin (O2Hb) over total Hb was significantly higher at the left IFG during repetition of pseudowords than that of words, replicating the observation by functional MRI and indicating that the region processes articulatory codes for verbal repetition. More importantly for this study, hemodynamic modulations were observed at both IFG during passive listening without repetition to various sounds, including natural environmental sounds, animal vocalizations, and human non-speech sounds. Furthermore, the O2Hb concentration increased at the left IFG but decreased at the right IFG for both speech and non-speech sounds. These findings suggest that both speech and non speech sounds may be processed and maintained by a neural mechanism for sensorimotor integration using articulatory codes at the left IFG. PMID- 24046742 TI - Type of gesture, valence, and gaze modulate the influence of gestures on observer's behaviors. AB - The present kinematic study aimed at determining whether the observation of arm/hand gestures performed by conspecifics affected an action apparently unrelated to the gesture (i.e., reaching-grasping). In 3 experiments we examined the influence of different gestures on action kinematics. We also analyzed the effects of words corresponding in meaning to the gestures, on the same action. In Experiment 1, the type of gesture, valence and actor's gaze were the investigated variables Participants executed the action of reaching-grasping after discriminating whether the gestures produced by a conspecific were meaningful or not. The meaningful gestures were request or symbolic and their valence was positive or negative. They were presented by the conspecific either blindfolded or not. In control Experiment 2 we searched for effects of the sole gaze, and, in Experiment 3, the effects of the same characteristics of words corresponding in meaning to the gestures and visually presented by the conspecific. Type of gesture, valence, and gaze influenced the actual action kinematics; these effects were similar, but not the same as those induced by words. We proposed that the signal activated a response which made the actual action faster for negative valence of gesture, whereas for request signals and available gaze, the response interfered with the actual action more than symbolic signals and not available gaze. Finally, we proposed the existence of a common circuit involved in the comprehension of gestures and words and in the activation of consequent responses to them. PMID- 24046743 TI - Subliminal unconscious conflict alpha power inhibits supraliminal conscious symptom experience. AB - Our approach is based on a tri-partite method of integrating psychodynamic hypotheses, cognitive subliminal processes, and psychophysiological alpha power measures. We present ten social phobic subjects with three individually selected groups of words representing unconscious conflict, conscious symptom experience, and Osgood Semantic negative valence words used as a control word group. The unconscious conflict and conscious symptom words, presented subliminally and supraliminally, act as primes preceding the conscious symptom and control words presented as supraliminal targets. With alpha power as a marker of inhibitory brain activity, we show that unconscious conflict primes, only when presented subliminally, have a unique inhibitory effect on conscious symptom targets. This effect is absent when the unconscious conflict primes are presented supraliminally, or when the target is the control words. Unconscious conflict prime effects were found to correlate with a measure of repressiveness in a similar previous study (Shevrin et al., 1992, 1996). Conscious symptom primes have no inhibitory effect when presented subliminally. Inhibitory effects with conscious symptom primes are present, but only when the primes are supraliminal, and they did not correlate with repressiveness in a previous study (Shevrin et al., 1992, 1996). We conclude that while the inhibition following supraliminal conscious symptom primes is due to conscious threat bias, the inhibition following subliminal unconscious conflict primes provides a neurological blueprint for dynamic repression: it is only activated subliminally by an individual's unconscious conflict and has an inhibitory effect specific only to the conscious symptom. These novel findings constitute neuroscientific evidence for the psychoanalytic concepts of unconscious conflict and repression, while extending neuroscience theory and methods into the realm of personal, psychological meaning. PMID- 24046744 TI - Visual perspective taking and laterality decisions: Problems and possible solutions. AB - Perspective taking plays an important role in different areas of psychological and neuroscientific research. Visual perspective taking is an especially prominent approach generally using one of two experimental tasks: in the own-body transformation task observers are asked to judge the laterality of a salient feature of a human figure (e.g., is the glove on the left or right hand?) from the figure's perspective. In the avatar-in-scene task they decide about the laterality of objects in a scene (e.g., is the flower on the left or right?) from the avatar's point of view. Increases in latencies and/or errors are interpreted as originating from additional cognitive processes predominately described as observer-based perspective transformations. A closer look reveals that such an account is disputable on grounds related to the use of laterality judgments. Other transformation accounts, i.e., object or array transformations, as well as non-transformational accounts, i.e., extra processing due to spatial conflicts, have not been adequately considered, tested, or ruled out by existing research. Our review examines visual perspective tasks in detail, identifies problems and makes recommendations for future research. PMID- 24046745 TI - Basal ganglia modulation of thalamocortical relay in Parkinson's disease and dystonia. AB - Basal ganglia dysfunction has being implied in both Parkinson's disease and dystonia. While these disorders probably involve different cellular and circuit pathologies within and beyond basal ganglia, there may be some shared neurophysiological pathways. For example, pallidotomy and pallidal Deep Brain Stimulation (DBS) are used in symptomatic treatment of both disorders. Both conditions are marked by alterations of rhythmicity of neural activity throughout basal ganglia-thalamocortical circuits. Increased synchronized oscillatory activity in beta band is characteristic of Parkinson's disease, while different frequency bands, theta and alpha, are involved in dystonia. We compare the effect of the activity of GPi, the output nuclei of the basal ganglia, on information processing in the downstream neural circuits of thalamus in Parkinson's disease and dystonia. We use a data-driven computational approach, a computational model of the thalamocortical (TC) cell modulated by experimentally recorded data, to study the differences and similarities of thalamic dynamics in dystonia and Parkinson's disease. Our analysis shows no substantial differences in TC relay between the two conditions. Our results suggest that, similar to Parkinson's disease, a disruption of thalamic processing could also be involved in dystonia. Moreover, the degree to which TC relay fidelity is impaired is approximately the same in both conditions. While Parkinson's disease and dystonia may have different pathologies and differ in the oscillatory content of neural discharge, our results suggest that the effect of patterning of pallidal discharge is similar in both conditions. Furthermore, these results suggest that the mechanisms of GPi DBS in dystonia may involve improvement of TC relay fidelity. PMID- 24046746 TI - Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. AB - Caloric restriction (CR), fasting, and exercise have long been recognized for their neuroprotective and lifespan-extending properties; however, the underlying mechanisms of these phenomena remain elusive. Such extraordinary benefits might be linked to the activation of sirtuins. In mammals, the sirtuin family has seven members (SIRT1-7), which diverge in tissue distribution, subcellular localization, enzymatic activity, and targets. SIRT1, SIRT2, and SIRT3 have deacetylase activity. Their dependence on NAD(+) directly links their activity to the metabolic status of the cell. High NAD(+) levels convey neuroprotective effects, possibly via activation of sirtuin family members. Mitochondrial sirtuin 3 (SIRT3) has received much attention for its role in metabolism and aging. Specific small nucleotide polymorphisms in Sirt3 are linked to increased human lifespan. SIRT3 mediates the adaptation of increased energy demand during CR, fasting, and exercise to increased production of energy equivalents. SIRT3 deacetylates and activates mitochondrial enzymes involved in fatty acid beta oxidation, amino acid metabolism, the electron transport chain, and antioxidant defenses. As a result, the mitochondrial energy metabolism increases. In addition, SIRT3 prevents apoptosis by lowering reactive oxygen species and inhibiting components of the mitochondrial permeability transition pore. Mitochondrial deficits associated with aging and neurodegeneration might therefore be slowed or even prevented by SIRT3 activation. In addition, upregulating SIRT3 activity by dietary supplementation of sirtuin activating compounds might promote the beneficial effects of this enzyme. The goal of this review is to summarize emerging data supporting a neuroprotective action of SIRT3 against Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. PMID- 24046748 TI - Pathophysiological roles of FGF signaling in the heart. AB - Cardiac remodeling progresses to heart failure, which represents a major cause of morbidity and mortality. Cardiomyokines, cardiac secreted proteins, may play roles in cardiac remodeling. Fibroblast growth factors (FGFs) are secreted proteins with diverse functions, mainly in development and metabolism. However, some FGFs play pathophysiological roles in cardiac remodeling as cardiomyokines. FGF2 promotes cardiac hypertrophy and fibrosis by activating MAPK signaling through the activation of FGF receptor (FGFR) 1c. In contrast, FGF16 may prevent these by competing with FGF2 for the binding site of FGFR1c. FGF21 prevents cardiac hypertrophy by activating MAPK signaling through the activation of FGFR1c with beta-Klotho as a co-receptor. In contrast, FGF23 induces cardiac hypertrophy by activating calcineurin/NFAT signaling without alphaKlotho. These FGFs play crucial roles in cardiac remodeling via distinct action mechanisms. These findings provide new insights into the pathophysiological roles of FGFs in the heart and may provide potential therapeutic strategies for heart failure. PMID- 24046747 TI - Peroxisomes and sexual development in fungi. AB - Peroxisomes are versatile and dynamic organelles that are essential for the development of most eukaryotic organisms. In fungi, many developmental processes, such as sexual development, require the activity of peroxisomes. Sexual reproduction in fungi involves the formation of meiotic-derived sexual spores, often takes place inside multicellular fruiting bodies and requires precise coordination between the differentiation of multiple cell types and the progression of karyogamy and meiosis. Different peroxisomal functions contribute to the orchestration of this complex developmental process. Peroxisomes are required to sustain the formation of fruiting bodies and the maturation and germination of sexual spores. They facilitate the mobilization of reserve compounds via fatty acid beta-oxidation and the glyoxylate cycle, allowing the generation of energy and biosynthetic precursors. Additionally, peroxisomes are implicated in the progression of meiotic development. During meiotic development in Podospora anserina, there is a precise modulation of peroxisome assembly and dynamics. This modulation includes changes in peroxisome size, number and localization, and involves a differential activity of the protein-machinery that drives the import of proteins into peroxisomes. Furthermore, karyogamy, entry into meiosis and sorting of meiotic-derived nuclei into sexual spores all require the activity of peroxisomes. These processes rely on different peroxisomal functions and likely depend on different pathways for peroxisome assembly. Indeed, emerging studies support the existence of distinct import channels for peroxisomal proteins that contribute to different developmental stages. PMID- 24046749 TI - The association of fetal and early childhood growth with adult mental distress: evidence from the johns hopkins collaborative perinatal study birth cohort. AB - OBJECTIVES: Early childhood physical growth may have an impact on the development of adult mental distress. The primary objectives were to (1) assess the association of early growth in weight (adjusted for height) with adult mental distress, and (2) determine if specific sub-types, or patterns, of early physical growth are associated with adult mental distress. METHODS: Subjects were all Johns Hopkins Collaborative Perinatal Study cohort subjects with complete birth size information that successfully completed the Pathways to Adulthood follow-up in early adulthood. Variability in the timing of growth in weight adjusted for height from birth to age 7.5 years was taken into account using a non hierarchical linear model. Two critical periods of growth were considered as tertiles of change in weight adjusted for height from birth to age 7 and birth to age 1 year. Mental distress in adulthood (ages 29-32) was measured using the General Health Questionnaire (GHQ-28). RESULTS: Small for gestational age subjects were at increased risk of later mental distress, but not uniformly so. Those born with low weight and length for gestational age were a distinct subgroup of those born small for gestational age, and had unique patterns of risk for adult mental distress when early growth was considered. CONCLUSION: Acceleration and deceleration in weight for height change is associated with mental distress over multiple periods of early life and acts differentially between those periods. Furthermore, the association of early childhood growth with the likelihood of adult mental distress is dependent on prenatal growth. PMID- 24046750 TI - Cocaine users manifest impaired prosodic and cross-modal emotion processing. AB - BACKGROUND: A small number of previous studies have provided evidence that cocaine users (CU) exhibit impairments in complex social cognition tasks, while the more basic facial emotion recognition is widely unaffected. However, prosody and cross-modal emotion processing has not been systematically investigated in CU so far. Therefore, the aim of the present study was to assess complex multisensory emotion processing in CU in comparison to controls and to examine a potential association with drug use patterns. METHOD: The abbreviated version of the comprehensive affect testing system (CATS-A) was used to measure emotion perception across the three channels of facial affect, prosody, and semantic content in 58 CU and 48 healthy control (HC) subjects who were matched for age, sex, verbal intelligence, and years of education. RESULTS: CU had significantly lower scores than controls in the quotient scales of "emotion recognition" and "prosody recognition" and the subtests "conflicting prosody/meaning - attend to prosody" and "match emotional prosody to emotional face" either requiring to attend to prosody or to integrate cross-modal information. In contrast, no group difference emerged for the "affect recognition quotient." Cumulative cocaine doses and duration of cocaine use correlated negatively with emotion processing. CONCLUSION: CU show impaired cross-modal integration of different emotion processing channels particularly with regard to prosody, whereas more basic aspects of emotion processing such as facial affect perception are comparable to the performance of HC. PMID- 24046751 TI - N-Acetyl-Aspartate Level is Decreased in the Prefrontal Cortex in Subjects At Risk for Schizophrenia. AB - Reduced N-acetyl-aspartate (NAA) levels have been reported in the prefrontal cortex (PFC) in patients with schizophrenia using proton magnetic resonance spectroscopy. However, it is unclear whether this NAA reduction predates the illness onset and is reported in subjects at-risk for developing schizophrenia (HRS). The aim of this study was to assess NAA levels in the PFC in HRS. We hypothesized that HRS display lower NAA levels than healthy controls in the PFC. Studies assessing levels of NAA/Creatine (NAA/Cr) in the PFC in HRS were extracted from literature. Meta-analysis tools were used to compute effect sizes of nine selected studies meeting our inclusion criteria (clinical and/or genetic HRS, groups of HRS, and healthy controls matched for age and gender, spectral acquisition in the PFC). We reported that HRS exhibited a significant lower NAA/Cr level (2.15 +/- 0.29; n = 208) than healthy controls (2.21 +/- 0.32; n = 234) in the PFC with a medium pooled effect size [Hedges's g = -0.42; 95% confidence interval: (-0.61; -0.23); p < 0.0001] corresponding to an average 5.7% of NAA/Cr decrease. Secondary analysis revealed that this reduction was observed in young HRS (<40 years old) who have not reached the peak age of risk for schizophrenia (-11%, g = -0.82, p < 0.00001) but not in old HRS (>40 years old) who have already passed the peak age (g = 0.11, p = 0.56), when they are compared with their matched healthy controls. Our findings suggest that the NAA/Cr reduction in the PFC reported in patients with schizophrenia is observable only in HRS who have not passed the peak age of risk for schizophrenia. NAA/Cr level in the PFC could therefore be considered as a biological vulnerability marker of schizophrenia. PMID- 24046752 TI - Psychotherapy and brain plasticity. AB - In this paper, I will review why psychotherapy is relevant to the question of how consciousness relates to brain plasticity. A great deal of the research and theorizing on consciousness and the brain, including my own on hallucinations for example (Collerton and Perry, 2011) has focused upon specific changes in conscious content which can be related to temporal changes in restricted brain systems. I will argue that psychotherapy, in contrast, allows only a focus on holistic aspects of consciousness; an emphasis which may usefully complement what can be learnt from more specific methodologies. PMID- 24046753 TI - Mind wandering at the fingertips: automatic parsing of subjective states based on response time variability. AB - RESEARCH FROM THE LAST DECADE HAS SUCCESSFULLY USED TWO KINDS OF THOUGHT REPORTS IN ORDER TO ASSESS WHETHER THE MIND IS WANDERING: random thought-probes and spontaneous reports. However, none of these two methods allows any assessment of the subjective state of the participant between two reports. In this paper, we present a step by step elaboration and testing of a continuous index, based on response time variability within Sustained Attention to Response Tasks (N = 106, for a total of 10 conditions). We first show that increased response time variability predicts mind wandering. We then compute a continuous index of response time variability throughout full experiments and show that the temporal position of a probe relative to the nearest local peak of the continuous index is predictive of mind wandering. This suggests that our index carries information about the subjective state of the subject even when he or she is not probed, and opens the way for on-line tracking of mind wandering. Finally we proceed a step further and infer the internal attentional states on the basis of the variability of response times. To this end we use the Hidden Markov Model framework, which allows us to estimate the durations of on-task and off-task episodes. PMID- 24046754 TI - The third wave of biological psychiatry. AB - In this article I will argue that we are witnessing at this moment the third wave of biological psychiatry. This framework conceptualizes mental disorders as brain disorders of a special kind that requires a multilevel approach ranging from genes to psychosocial mechanisms. In contrast to earlier biological psychiatry approaches, the mental plays a more prominent role in the third wave. This will become apparent by discussing the recent controversy evolving around the recently published DSM-5 and the competing transdiagnostic Research Domain Criteria approach of the National Institute of Mental Health that is build on concepts of cognitive neuroscience. A look at current conceptualizations in biological psychiatry as well as at some discussions in current philosophy of mind on situated cognition, reveals that the thesis, that mental brain disorders are brain disorders has to be qualified with respect to how mental states are constituted and with respect to multilevel explanations of which factors contribute to stable patterns of psychopathological signs and symptoms. PMID- 24046755 TI - Reverse correlating trustworthy faces in young and older adults. AB - Little is known about how older persons determine if someone deserves their trust or not based on their facial appearance, a process referred to as "facial trustworthiness."In the past few years, Todorov and colleagues have argued that, in young adults, trustworthiness judgments are an extension of emotional judgments, and therefore, that trust judgments are made based on a continuum between anger and happiness (Todorov, 2008; Engell et al., 2010). Evidence from the literature on emotion processing suggest that older adults tend to be less efficient than younger adults in the recognition of negative facial expressions (Calder et al., 2003; Firestone et al., 2007; Ruffman et al., 2008; Chaby and Narme, 2009). Based on Todorov';s theory and the fact that older adults seem to be less efficient than younger adults in identifying emotional expressions, one could expect that older individuals would have different representations of trustworthy faces and that they would use different cues than younger adults in order to make such judgments. We verified this hypothesis using a variation of Mangini and Biederman's (2004) reverse correlation method in order to test and compare classification images resulting from trustworthiness (in the context of money investment), from happiness, and from anger judgments in two groups of participants: young adults and older healthy adults. Our results show that for elderly participants, both happy and angry representations are correlated with trustworthiness judgments. However, in young adults, trustworthiness judgments are mainly correlated with happiness representations. These results suggest that young and older adults differ in their way of judging trustworthiness. PMID- 24046756 TI - Can singular examples change implicit attitudes in the real-world? AB - Implicit attitudes about social groups persist independently of explicit beliefs and can influence not only social behavior, but also medical and legal practices. Although examples presented in the laboratory can alter such implicit attitudes, it is unclear whether the same influence is exerted by real-world exemplars. Following the 2008 US election, Plant et al. reported that the Implicit Association Test or "IAT" revealed a decrease in negative implicit attitudes toward African-Americans. However, a large-scale study also employing the IAT found little evidence for a change in implicit attitudes pre- and post-election. Here we present evidence that the 2008 US election may have facilitated at least a temporary change in implicit racial attitudes in the US. Our results rely on the Affective Lexical Priming Score or "ALPS" and pre- and post-election measurements for both US and non-US participants. US students who, pre-election, exhibited negative associations with black faces, post-election showed positive associations with black faces. Canadian students pre- and post-election did not show a similar shift. To account for these findings, we posit that the socio cognitive processes underlying ALPS are different from those underlying the IAT. Acknowledging that we cannot form a causal link between an intervening real-world event and laboratory-measured implicit attitudes, we speculate that our findings may be driven by the fact that the 2008 election campaign included extremely positive media coverage of President Obama and prominently featured his face in association with positive words-similar to the structure of ALPS. Even so, our real-world finding adds to the literature demonstrating the malleability of implicit attitudes and has implications for how we understand the socio-cognitive mechanisms underlying stereotypes. PMID- 24046758 TI - What does music express? Basic emotions and beyond. AB - Numerous studies have investigated whether music can reliably convey emotions to listeners, and-if so-what musical parameters might carry this information. Far less attention has been devoted to the actual contents of the communicative process. The goal of this article is thus to consider what types of emotional content are possible to convey in music. I will argue that the content is mainly constrained by the type of coding involved, and that distinct types of content are related to different types of coding. Based on these premises, I suggest a conceptualization in terms of "multiple layers" of musical expression of emotions. The "core" layer is constituted by iconically-coded basic emotions. I attempt to clarify the meaning of this concept, dispel the myths that surround it, and provide examples of how it can be heuristic in explaining findings in this domain. However, I also propose that this "core" layer may be extended, qualified, and even modified by additional layers of expression that involve intrinsic and associative coding. These layers enable listeners to perceive more complex emotions-though the expressions are less cross-culturally invariant and more dependent on the social context and/or the individual listener. This multiple-layer conceptualization of expression in music can help to explain both similarities and differences between vocal and musical expression of emotions. PMID- 24046759 TI - Maternal status regulates cortical responses to the body odor of newborns. AB - Studies in non-human mammals have identified olfactory signals as prime mediators of mother-infant bonding and they have been linked with maternal attitudes and behavior in our own species as well. However, although the neuronal network processing infant cues has been studied for visual and auditory signals; to date, no such information exists for chemosensory signals. We contrasted the cerebral activity underlying the processing of infant odor properties in 15 women newly given birth for the first time and 15 women not given birth while smelling the body odor of unfamiliar 2 day-old newborn infants. Maternal status-dependent activity was demonstrated in the thalamus when exposed to the body odor of a newly born infant. Subsequent regions of interest analyses indicated that dopaminergic neostriatal areas are active in maternal-dependent responses. Taken together, these data suggests that body odors from 2 day-old newborns elicit activation in reward-related cerebral areas in women, regardless of their maternal status. These tentative data suggests that certain body odors might act as a catalyst for bonding mechanisms and highlights the need for future research on odor-dependent mother-infant bonding using parametric designs controlling for biological saliency and general odor perception effects. PMID- 24046757 TI - Separating acoustic deviance from novelty during the first year of life: a review of event-related potential evidence. AB - Orienting to salient events in the environment is a first step in the development of attention in young infants. Electrophysiological studies have indicated that in newborns and young infants, sounds with widely distributed spectral energy, such as noise and various environmental sounds, as well as sounds widely deviating from their context elicit an event-related potential (ERP) similar to the adult P3a response. We discuss how the maturation of event-related potentials parallels the process of the development of passive auditory attention during the first year of life. Behavioral studies have indicated that the neonatal orientation to high-energy stimuli gradually changes to attending to genuine novelty and other significant events by approximately 9 months of age. In accordance with these changes, in newborns, the ERP response to large acoustic deviance is dramatically larger than that to small and moderate deviations. This ERP difference, however, rapidly decreases within first months of life and the differentiation of the ERP response to genuine novelty from that to spectrally rich but repeatedly presented sounds commences during the same period. The relative decrease of the response amplitudes elicited by high-energy stimuli may reflect development of an inhibitory brain network suppressing the processing of uninformative stimuli. Based on data obtained from healthy full-term and pre-term infants as well as from infants at risk for various developmental problems, we suggest that the electrophysiological indices of the processing of acoustic and contextual deviance may be indicative of the functioning of auditory attention, a crucial prerequisite of learning and language development. PMID- 24046760 TI - Unexpected benefits of deciding by mind wandering. AB - The mind wanders, even when people are attempting to make complex decisions. We suggest that mind wandering-allowing one's thoughts to wander until the "correct" choice comes to mind-can positively impact people's feelings about their decisions. We compare post-choice satisfaction from choices made by mind wandering to reason-based choices and randomly assigned outcomes. Participants chose a poster by mind wandering or deliberating, or were randomly assigned a poster. Whereas forecasters predicted that participants who chose by mind wandering would evaluate their outcome as inferior to participants who deliberated (Experiment 1), participants who used mind wandering as a decision strategy evaluated their choice just as positively as did participants who used deliberation (Experiment 2). In some cases, it appears that people can spare themselves the effort of deliberation and instead "decide by wind wandering," yet experience no decrease in satisfaction. PMID- 24046761 TI - Erratum: Music structure determines heart rate variability of singers. AB - [This corrects the article on p. 334 in vol. 4, PMID: 23847555.]. PMID- 24046762 TI - The virtual-hand illusion: effects of impact and threat on perceived ownership and affective resonance. AB - The rubber hand illusion refers to the observation that participants perceive "body ownership" for a rubber hand if it moves, or is stroked in synchrony with the participant's real (covered) hand. Research indicates that events targeting artificial body parts can trigger affective responses (affective resonance) only with perceived body ownership, while neuroscientific findings suggest affective resonance irrespective of ownership (e.g., when observing other individuals under threat). We hypothesized that this may depend on the severity of the event. We first replicated previous findings that the rubber hand illusion can be extended to virtual hands-the virtual-hand illusion. We then tested whether hand ownership and affective resonance (assessed by galvanic skin conductance) are modulated by the experience of an event that either "impacted" (a ball hitting the hand) or "threatened" (a knife cutting the hand) the virtual hand. Ownership was stronger if the virtual hand moved synchronously with the participant's own hand, but this effect was independent from whether the hand was impacted or threatened. Affective resonance was mediated by ownership however: In the face of mere impact, participants showed more resonance in the synchronous condition (i.e., with perceived ownership) than in the asynchronous condition. In the face of threat, in turn, affective resonance was independent of synchronicity participants were emotionally involved even if a threat was targeting a hand that they did not perceive as their own. Our findings suggest that perceived body ownership and affective responses to body-related impact or threat can be dissociated and are thus unlikely to represent the same underlying process. We argue that affective reactions to impact are produced in a top-down fashion if the impacted effector is assumed to be part of one's own body, whereas threatening events trigger affective responses more directly in a bottom-up fashion-irrespective of body ownership. PMID- 24046763 TI - Optogenetics as a neuromodulation tool in cognitive neuroscience. PMID- 24046764 TI - Mild strain cross protection of tristeza: a review of research to protect against decline on sour orange in Florida. AB - Tristeza, caused by Citrus tristeza virus (CTV), has long been present in Florida but outbreaks of decline on sour orange rootstock were occasional events until the late 1970s. Sour orange rootstock was valued for the high quality of fruit produced and was widely used because of its tolerance of citrus blight, a disease of unknown etiology. Research was directed towards the selection and screening of mild strains of CTV which could protect against sour orange decline strains. Following the introduction of Toxoptera citricida (also known as the brown citrus aphid) in 1995 there was a greater concern for maintaining production of existing blocks of citrus on sour orange rootstock. Availability of the CTV genome sequence around the same time as well as molecular characterization of in planta CTV populations led to the selection of mild CTV isolates which when inoculated into existing field trees, extended the productive life of the groves and enabled a more graduate replanting of trees on CTV-tolerant rootstocks. The history of CTV in Florida and the methods developed to select mild isolates for use for mild strain cross protection will be reviewed. PMID- 24046765 TI - Animal models for Ebola and Marburg virus infections. AB - Ebola and Marburg hemorrhagic fevers (EHF and MHF) are caused by the Filoviridae family, Ebolavirus and Marburgvirus (ebolavirus and marburgvirus), respectively. These severe diseases have high mortality rates in humans. Although EHF and MHF are endemic to sub-Saharan Africa. A novel filovirus, Lloviu virus, which is genetically distinct from ebolavirus and marburgvirus, was recently discovered in Spain where filoviral hemorrhagic fever had never been reported. The virulence of this virus has not been determined. Ebolavirus and marburgvirus are classified as biosafety level-4 (BSL-4) pathogens and Category A agents, for which the US government requires preparedness in case of bioterrorism. Therefore, preventive measures against these viral hemorrhagic fevers should be prepared, not only in disease-endemic regions, but also in disease-free countries. Diagnostics, vaccines, and therapeutics need to be developed, and therefore the establishment of animal models for EHF and MHF is invaluable. Several animal models have been developed for EHF and MHF using non-human primates (NHPs) and rodents, which are crucial to understand pathophysiology and to develop diagnostics, vaccines, and therapeutics. Rhesus and cynomolgus macaques are representative models of filovirus infection as they exhibit remarkably similar symptoms to those observed in humans. However, the NHP models have practical and ethical problems that limit their experimental use. Furthermore, there are no inbred and genetically manipulated strains of NHP. Rodent models such as mouse, guinea pig, and hamster, have also been developed. However, these rodent models require adaptation of the virus to produce lethal disease and do not mirror all symptoms of human filovirus infection. This review article provides an outline of the clinical features of EHF and MHF in animals, including humans, and discusses how the animal models have been developed to study pathophysiology, vaccines, and therapeutics. PMID- 24046767 TI - Conservation vs. variation of dinucleotide frequencies across bacterial and archaeal genomes: evolutionary implications. AB - During the long history of biological evolution, genome structures have undergone enormous changes. Nevertheless, some traits or vestiges of the primordial genome (defined as the most primitive nucleic acid genome for life on earth in this paper) may remain in modern genetic systems. It is of great importance to find these traits or vestiges for the study of the origin and evolution of genomes. As the shorter is a sequence, the less probable it would be modified during genome evolution. And if mutated, it would be easier to reappear at the same site or another site. Consequently, the genomic frequencies of very short nucleotide sequences, such as dinucleotides, would have considerable chances to be conserved during billions of years of evolution. Prokaryotic genomes are very diverse and with a wide range of GC content. Therefore, in order to find traits or vestiges of the primordial genome remained in modern genetic systems, we have studied the characteristics of dinucleotide frequencies across bacterial and archaeal genomes. We analyzed the dinucleotide frequency patterns of the whole-genome sequences from more than 1300 prokaryotic species (bacterial and archaeal genomes available as of December 2012). The results show that the frequencies of the dinucleotides AC, AG, CA, CT, GA, GT, TC, and TG are well-conserved across various genomes, while the frequencies of other dinucleotides vary considerably among species. The dinucleotide frequency conservation/variation pattern seems to correlate with the distributions of dinucleotides throughout a genome and across genomes. Further analysis indicates that the phenomenon would be determined by strand symmetry of genomic sequences (the second parity rule) and GC content variations among genomes. We discussed some possible origins of strand symmetry. And we propose that the phenomenon of frequency conservation of some dinucleotides may provide insights into the genomic composition of the primordial genetic system. PMID- 24046766 TI - Prerequisites for amplicon pyrosequencing of microbial methanol utilizers in the environment. AB - The commercial availability of next generation sequencing (NGS) technologies facilitated the assessment of functional groups of microorganisms in the environment with high coverage, resolution, and reproducibility. Soil methylotrophs were among the first microorganisms in the environment that were assessed with molecular tools, and nowadays, as well with NGS technologies. Studies in the past years re-attracted notice to the pivotal role of methylotrophs in global conversions of methanol, which mainly originates from plants, and is involved in oxidative reactions and ozone formation in the atmosphere. Aerobic methanol utilizers belong to Bacteria, yeasts, Ascomycota, and molds. Numerous bacterial methylotrophs are facultatively aerobic, and also contribute to anaerobic methanol oxidation in the environment, whereas strict anaerobic methanol utilizers belong to methanogens and acetogens. The diversity of enzymes catalyzing the initial oxidation of methanol is considerable, and comprises at least five different enzyme types in aerobes, and one in strict anaerobes. Only the gene of the large subunit of pyrroloquinoline quinone (PQQ) dependent methanol dehydrogenase (MDH; mxaF) has been analyzed by environmental pyrosequencing. To enable a comprehensive assessment of methanol utilizers in the environment, new primers targeting genes of the PQQ MDH in Methylibium (mdh2), of the nicotinamide adenine dinucleotide-dependent MDH (mdh), of the methanol oxidoreductase of Actinobacteria (mdo), of the fungal flavin adenine nucleotide dependent alcohol oxidase (mod1, mod2, and homologs), and of the gene of the large subunit of the methanol:corrinoid methyltransferases (mtaC) in methanogens and acetogens need to be developed. Combined stable isotope probing of nucleic acids or proteins with amplicon-based NGS are straightforward approaches to reveal insights into functions of certain methylotrophic taxa in the global methanol cycle. PMID- 24046768 TI - Cellular-level versus receptor-level response threshold hierarchies in T-cell activation. AB - Peptide-MHC (pMHC) ligand engagement by T-cell receptors (TCRs) elicits a variety of cellular responses, some of which require substantially more TCR-mediated stimulation than others. This threshold hierarchy could reside at the receptor level, where different response pathways branch off at different stages of the TCR/CD3 triggering cascade, or at the cellular level, where the cumulative TCR signal registered by the T-cell is compared to different threshold values. Alternatively, dual-level thresholds could exist. In this study, we show that the cellular hypothesis provides the most parsimonious explanation consistent with data obtained from an in-depth analysis of distinct functional responses elicited in a clonal T-cell system by a spectrum of biophysically defined altered peptide ligands across a range of concentrations. Further, we derive a mathematical model that describes how ligand density, affinity, and off-rate all affect signaling in distinct ways. However, under the kinetic regime prevailing in the experiments reported here, the TCR/pMHC class I (pMHCI) dissociation rate was found to be the main governing factor. The CD8 coreceptor modulated the TCR/pMHCI interaction and altered peptide ligand potency. Collectively, these findings elucidate the relationship between TCR/pMHCI kinetics and cellular function, thereby providing an integrated mechanistic understanding of T-cell response profiles. PMID- 24046769 TI - The role of type 1 interferon in systemic sclerosis. AB - Systemic Sclerosis (Scleroderma, SSc) is an autoimmune disease characterized by vasculopathy, inflammation, and fibrosis that can lead to loss of organ function. Type I interferons (IFNs) are family of cytokines that mitigate the deleterious effects of viral and bacterial infections in the innate immunity system. Past several years, research efforts have been focused on the role of type I IFN and IFN-inducible genes in the pathogenesis of SSc. Polymorphisms in the Interferon regulatory factor (IRF)-5, IRF7, and IRF8 are associated with SSc, Similarly, polymorphism of Signal Transducer and Activator of Transcription (STAT)-4, has been established as a genetic risk factor of SSc. IRFs and STAT4 proteins are key activators of type I IFN signaling pathways. An IFN signature (increased expression and activation of IFN-regulated genes) has been observed in the peripheral blood and skin biopsy samples of patients with SSc. Furthermore, a plasma IFN-inducible chemokine score correlated with markers of disease severity and autoantibody subtypes in SSc. In this review, we summarize our current knowledge of the role of type I IFNs and IFN-inducible genes in the pathogenesis of SSc and their potential role as biomarkers and therapeutic targets. PMID- 24046770 TI - In silico comparison of genomic regions containing genes coding for enzymes and transcription factors for the phenylpropanoid pathway in Phaseolus vulgaris L. and Glycine max L. Merr. AB - Legumes contain a variety of phytochemicals derived from the phenylpropanoid pathway that have important effects on human health as well as seed coat color, plant disease resistance and nodulation. However, the information about the genes involved in this important pathway is fragmentary in common bean (Phaseolus vulgaris L.). The objectives of this research were to isolate genes that function in and control the phenylpropanoid pathway in common bean, determine their genomic locations in silico in common bean and soybean, and analyze sequences of the 4CL gene family in two common bean genotypes. Sequences of phenylpropanoid pathway genes available for common bean or other plant species were aligned, and the conserved regions were used to design sequence-specific primers. The PCR products were cloned and sequenced and the gene sequences along with common bean gene-based (g) markers were BLASTed against the Glycine max v.1.0 genome and the P. vulgaris v.1.0 (Andean) early release genome. In addition, gene sequences were BLASTed against the OAC Rex (Mesoamerican) genome sequence assembly. In total, fragments of 46 structural and regulatory phenylpropanoid pathway genes were characterized in this way and placed in silico on common bean and soybean sequence maps. The maps contain over 250 common bean g and SSR (simple sequence repeat) markers and identify the positions of more than 60 additional phenylpropanoid pathway gene sequences, plus the putative locations of seed coat color genes. The majority of cloned phenylpropanoid pathway gene sequences were mapped to one location in the common bean genome but had two positions in soybean. The comparison of the genomic maps confirmed previous studies, which show that common bean and soybean share genomic regions, including those containing phenylpropanoid pathway gene sequences, with conserved synteny. Indels identified in the comparison of Andean and Mesoamerican common bean 4CL gene sequences might be used to develop inter-pool phenylpropanoid pathway gene-based markers. We anticipate that the information obtained by this study will simplify and accelerate selections of common bean with specific phenylpropanoid pathway alleles to increase the contents of beneficial phenylpropanoids in common bean and other legumes. PMID- 24046771 TI - Context-dependency of arbuscular mycorrhizal fungi on plant-insect interactions in an agroecosystem. AB - Plants interact with a variety of other community members that have the potential to indirectly influence each other through a shared host plant. Arbuscular mycorrhizal fungi (AMF) are generally considered plant mutualists because of their generally positive effects on plant nutrient status and growth. AMF may also have important indirect effects on plants by altering interactions with other community members. By influencing plant traits, AMF can modify aboveground interactions with both mutualists, such as pollinators, and antagonists, such as herbivores. Because herbivory and pollination can dramatically influence plant fitness, comprehensive assessment of plant-AMF interactions should include these indirect effects. To determine how AMF affect plant-insect interactions, we grew Cucumis sativus (Cucurbitaceae) under five AMF inoculum treatments and control. We measured plant growth, floral production, flower size, and foliar nutrient content of half the plants, and transferred the other half to a field setting to measure pollinator and herbivore preference of wild insects. Mycorrhizal treatment had no effect on plant biomass or floral traits but significantly affected leaf nutrients, pollinator behavior, and herbivore attack. Although total pollinator visitation did not vary with AMF treatment, pollinators exhibited taxon-specific responses, with honey bees, bumble bees, and Lepidoptera all responding differently to AMF treatments. Flower number and size were unaffected by treatments, suggesting that differences in pollinator preference were driven by other floral traits. Mycorrhizae influenced leaf K and Na, but these differences in leaf nutrients did not correspond to variation in herbivore attack. Overall, we found that AMF indirectly influence both antagonistic and mutualistic insects, but impacts depend on the identity of both the fungal partner and the interacting insect, underscoring the context-dependency of plant AMF interactions. PMID- 24046773 TI - Mitochondrial iron transport and homeostasis in plants. AB - Iron (Fe) is an essential nutrient for plants and although the mechanisms controlling iron uptake from the soil are relatively well understood, comparatively little is known about subcellular trafficking of iron in plant cells. Mitochondria represent a significant iron sink within cells, as iron is required for the proper functioning of respiratory chain protein complexes. Mitochondria are a site of Fe-S cluster synthesis, and possibly heme synthesis as well. Here we review recent insights into the molecular mechanisms controlling mitochondrial iron transport and homeostasis. We focus on the recent identification of a mitochondrial iron uptake transporter in rice and a possible role for metalloreductases in iron uptake by mitochondria. In addition, we highlight recent advances in mitochondrial iron homeostasis with an emphasis on the roles of frataxin and ferritin in iron trafficking and storage within mitochondria. PMID- 24046772 TI - Small RNAs in plant defense responses during viral and bacterial interactions: similarities and differences. AB - Small non-coding RNAs constitute an important class of gene expression regulators that control different biological processes in most eukaryotes. In plants, several small RNA (sRNA) silencing pathways have evolved to produce a wide range of small RNAs with specialized functions. Evidence for the diverse mode of action of the small RNA pathways has been highlighted during plant-microbe interactions. Host sRNAs and small RNA silencing pathways have been recognized as essential components of plant immunity. One way plants respond and defend against pathogen infections is through the small RNA silencing immune system. To deal with plant defense responses, pathogens have evolved sophisticated mechanisms to avoid and counterattack this defense strategy. The relevance of the small RNA-mediated plant defense responses during viral infections has been well-established. Recent evidence points out its importance also during plant-bacteria interactions. Herein, this review discusses recent findings, similarities and differences about the small RNA-mediated arms race between plants and these two groups of microbes, including the small RNA silencing pathway components that contribute to plant immune responses, the pathogen-responsive endogenous sRNAs and the pathogen delivered effector proteins. PMID- 24046774 TI - New insights into Fe localization in plant tissues. AB - Deciphering cellular iron (Fe) homeostasis requires having access to both quantitative and qualitative information on the subcellular pools of Fe in tissues and their dynamics within the cells. We have taken advantage of the Perls/DAB Fe staining procedure to perform a systematic analysis of Fe distribution in roots, leaves and reproductive organs of the model plant Arabidopsis thaliana, using wild-type and mutant genotypes affected in iron transport and storage. Roots of soil-grown plants accumulate iron in the apoplast of the central cylinder, a pattern that is strongly intensified when the citrate effluxer FRD3 is not functional, thus stressing the importance of citrate in the apoplastic movement of Fe. In leaves, Fe level is low and only detected in and around vascular tissues. In contrast, Fe staining in leaves of iron-treated plants extends in the surrounding mesophyll cells where Fe deposits, likely corresponding to Fe-ferritin complexes, accumulate in the chloroplasts. The loss of ferritins in the fer1,3,4 triple mutant provoked a massive accumulation of Fe in the apoplastic space, suggesting that in the absence of iron buffering in the chloroplast, cells activate iron efflux and/or repress iron influx to limit the amount of iron in the cell. In flowers, Perls/DAB staining has revealed a major sink for Fe in the anthers. In particular, developing pollen grains accumulate detectable amounts of Fe in small-size intracellular bodies that aggregate around the vegetative nucleus at the binuclear stage and that were identified as amyloplasts. In conclusion, using the Perls/DAB procedure combined to selected mutant genotypes, this study has established a reliable atlas of Fe distribution in the main Arabidopsis organs, proving and refining long-assumed intracellular locations and uncovering new ones. This "iron map" of Arabidopsis will serve as a basis for future studies of possible actors of iron movement in plant tissues and cell compartments. PMID- 24046775 TI - Regulation of Arabidopsis root development by small signaling peptides. AB - Plant root systems arise de novo from a single embryonic root. Complex and highly coordinated developmental networks are required to ensure the formation of lateral organs maximizes plant fitness. The Arabidopsis root is well-suited to dissection of regulatory and developmental networks due to its highly ordered, predictable structure. A myriad of regulatory signaling networks control the development of plant roots, from the classical hormones such as auxin and cytokinin to short-range positional signaling molecules that relay information between neighboring cells. Small signaling peptides are a growing class of regulatory molecules involved in many aspects of root development including meristem maintenance, the gravitropic response, lateral root development, and vascular formation. Here, recent findings on the roles of regulatory peptides in these aspects of root development are discussed. PMID- 24046776 TI - Meta4: a web application for sharing and annotating metagenomic gene predictions using web services. AB - Whole-genome shotgun metagenomics experiments produce DNA sequence data from entire ecosystems, and provide a huge amount of novel information. Gene discovery projects require up-to-date information about sequence homology and domain structure for millions of predicted proteins to be presented in a simple, easy-to use system. There is a lack of simple, open, flexible tools that allow the rapid sharing of metagenomics datasets with collaborators in a format they can easily interrogate. We present Meta4, a flexible and extensible web application that can be used to share and annotate metagenomic gene predictions. Proteins and predicted domains are stored in a simple relational database, with a dynamic front-end which displays the results in an internet browser. Web services are used to provide up-to-date information about the proteins from homology searches against public databases. Information about Meta4 can be found on the project website, code is available on Github, a cloud image is available, and an example implementation can be seen at. PMID- 24046778 TI - Performance of double reading mammography in an Iranian population and its effect on patient outcome. AB - BACKGROUND: Considering the importance and responsibility of reporting mammography and the necessity to notice details with a high degree of precision, double reading mammography has been introduced and recommended. OBJECTIVES: This study aimed to assess the performance of double reading of mammograms and its effect on patient outcomes. PATIENTS AND METHODS: Throughout this cross sectional study, 1284 digitized mammographic views of 642 breasts which belonged to 339 women (of which 303 were bilateral and 36 were unilateral mammographies) were enrolled. Two independent radiologists interpreted these mammograms and BI-RADS categories of both reports were compared. Discordant results were determined and assumed significant if they were in the positive (BI-RADS 0, 4, 5) versus negative (BI-RADS 1, 2, 3) groups and then significant discordant cases were followed up to determine benign versus malignant final diagnosis. The recall rate was calculated for each reader. Inter-observer agreement in breast density was determined by Kappa test. RESULTS: Readers had consensus on BI-RADS categories in 459 breasts (71%), but diverse categories were used for 183 breasts (29%), including 132 significant and 51 non-significant discrepancies. According to weighted Kappa test, agreement between two readers in positive or negative reports was 0.78 (95% CI=0.73-0.83) and in parenchymal density, it was 0.73 (95% CI=0.7-0.77). Most of the discrepancies were between category zero versus categories 1 and 2 (63.4%). The recall rate was 36% for the first and 44% for the second reader. Among 132 significant discordant results, one case had the final diagnosis of malignancy and the others had benign or negative diagnosis. There was 0.2% increase in cancer detection rate by double reading. CONCLUSION: This study shows no significant improvement in the cancer detection rate by double reading; however, a lower recall rate could be a more helpful consequence. PMID- 24046777 TI - Trash or Treasure: extracellular microRNAs and cell-to-cell communication. AB - Circulating RNAs in human body fluids are promising candidates for diagnostic purposes. However, the biological significance of circulating RNAs remains elusive. Recently, small non-coding RNAs, microRNAs (miRNAs), were isolated from multiple human body fluids, and these "circulating miRNAs" have been implicated as novel disease biomarkers. Concurrently, miRNAs were also identified in the extracellular space associated with extracellular vesicles (EVs), which are small membrane vesicles secreted from various types of cells. The function of these secreted miRNAs has been revealed in several papers. Circulating miRNAs have been experimentally found to be associated with EVs; however, other types of extracellular miRNAs were also described. This review discusses studies related to extracellular miRNAs, including circulating miRNAs and secreted miRNAs, to highlight the importance of studying not only secreted miRNAs, but also circulating miRNAs to determine the contribution of extracellular miRNAs especially in cancer development. PMID- 24046779 TI - Does Repeating CT-Guided Transthoracic Fine Needle Aspiration Increase Diagnostic Yield and Complication Rate? A Single Institution Experience. AB - BACKGROUND: Transthoracic fine needle aspiration biopsy is a well-established and safe technique for obtaining pulmonary tissue. However, there is very little data about repeating procedure. OBJECTIVES: We aimed to investigate whether repeating CT-guided transthoracic fine needle aspiration (TFNA) increases diagnostic yield and complication rate. PATIENTS AND METHODS: Patients underwent TFNA and the final diagnoses achieved were included in the study. Consequently, 316 TFNA procedures performed in 240 patients were investigated retrospectively. A diagnosis was not reached in the first TFNA in 64 patients, then they underwent repeated TFNA. The factors that affected the diagnostic yield and complication rate were recorded. RESULTS: The final diagnoses of 199 (82.9%) patients were malignant and 41 patients were benign. One hundred seventy six patients underwent the TFNA procedure only once. Sixty-four patients underwent a second procedure, while 12 underwent a third one. The diagnosis rate in the first procedures (diagnosis obtained in 142 out of 240 patients) was 59%. With the repeated procedures, 30 other patients were diagnosed. The diagnosis rate increased to 72% (172 out of 240 patients) (P<0.001). Twenty-nine (9.2%) pneumothoraces in 26 patients were detected in 316 TFNA procedures. In the repeated TFNA group (64 patients) there were seven pneumothoraces (11%) in the first TFNA procedure and six pneumothoraces (9%) in the repeated TFNA procedures (P=0.41). In three patients, pneumothorax was detected in the first and repeated procedures. Pneumothorax was significantly associated with the maximum diameter of the lesion (P=0.003), distance to pleura (P=0.001), contact to the pleura (P=0.0001) and smoking history (pack/year) (P=0.04). CONCLUSION: This study demonstrated that repeating the TFNA procedure in pulmonary lesions improves the diagnostic yield without an increase in the rate of pneumothorax. PMID- 24046780 TI - The Cost-Utility Analysis of PET-Scan in Diagnosis and Treatment of Non-Small Cell Lung Carcinoma in Iran. AB - BACKGROUND: PET scan is a non-invasive, complex and expensive medical imaging technology that is normally used for the diagnosis and treatment of various diseases including lung cancer. OBJECTIVES: The purpose of this study is to assess the cost effectiveness of this technology in the diagnosis and treatment of non- small cell lung carcinoma (NSCLC) in Iran. MATERIALS AND METHODS: The main electronic databases including The Cochrane Library and Medline were searched to identify available evidence about the performance and effectiveness of technology. A standard decision tree model with seven strategies was used to perform the economic evaluation. Retrieved studies and expert opinion were used to estimate the cost of each treatment strategy in Iran. The costs were divided into three categories including capital costs (depreciation costs of buildings and equipment), staff costs and other expenses (including cost of consumables, running and maintenance costs). The costs were estimated in both IR-Rials and US Dollars with an exchange rate of 10.000 IR Rials per one US Dollar according to the exchange rate in 2008. RESULTS: The total annual running cost of a PET scan was about 8850 to 13000 million Rials, (0.9 to 1.3 million US$). The average cost of performing a PET scan varied between 3 and 4.5 million Rials (300 to 450US$). The strategies 3 (mediastinoscopy alone) and 7 (mediastinoscopy after PET scan) were more cost-effective than other strategies, especially when the result of the CT-scan performed before PET scan was negative. CONCLUSION: The technical performance of PET scan is significantly higher than similar technologies for staging and treatment of NSCLC. In addition, it might slightly improve the treatment process and lead to a small level of increase in the quality adjusted life year (QALY) gained by these patients making it cost-effective for the treatment of NSCLC. PMID- 24046781 TI - Effectiveness of puncture-aspiration-injection-reaspiration in the treatment of hepatic hydatid cysts. AB - BACKGROUND: Hydatid disease of the liver is endemic in cattle rearing areas of the world. A variety of treatment options are available in its management. The common treatment options are medical therapy, surgery and puncture-aspiration injection-reaspiration (PAIR) therapy. OBJECTIVES: This study was performed to evaluate the effectiveness of PAIR therapy in the treatment of hepatic hydatid disease. PATIENTS AND METHODS: This cross sectional study was carried out on 15 consecutive patients (Male: 2, Female: 13; Age group: 11-80 years) with hepatic hydatid disease and were treated by PAIR therapy and followed up for a period of 1 year. The cysts were punctured under local anesthesia with an 18G needle using sonographic guidance. Betadine (10% povidone iodine + 1% free iodine) was used as scolicidal agent and allowed to act for 30 min. Cysts larger than 5 cm (n = 5) were drained using an 8F pig tail catheter. The therapeutic response was studied by assessing the reduction in the cyst size, progressive solidification of the cyst, calcification of the wall and increase in the echogenicity of the cyst with pseudomass appearance on serial ultrasound examinations performed on the next day, after 1 month, at 3 months, 6 months and 1 year after the procedure. RESULTS: Ten patients (66.7%) had Gharbi type I cysts, two (13.3%) had type II and three (20%) had type III cysts. All the patients (100%) showed reduction in cyst size over a 3-6 month period. Pseudomass appearance with solidification was seen in 73% of the patients and calcification was seen in 46.6%. None of the patients developed anaphylaxis, recurrence or peritoneal seedlings. Pain at the injection site was the most common complication observed. CONCLUSION: PAIR therapy is an effective minimally invasive treatment for Gharbi type I-III hepatic hydatid cysts. It is a cost effective and safe procedure with significant reduction in the duration of hospital stay. PMID- 24046782 TI - Peripheral osteoma of the mandibular notch: report of a case. AB - Osteoma is a benign, slow-growing osteogenic tumor that sometimes arises from the craniomaxillofacial region, such as the sinus, temporal or jaw bones. Osteoma consists of compact or cancellous bone that may be peripheral, central or extraskeletal type. Peripheral osteoma arises from the periosteum and is commonly a unilateral, pedunculated mushroom-like mass. Peripheral osteoma of the mandible is relatively uncommon, and peripheral osteoma of the mandibular notch is extremely rare, although many cases arise from the mandibular body, angle, condyle, or coronoid process. We report here an unusual peripheral osteoma of the mandibular notch in a 78-year-old nonsyndromic female. PMID- 24046783 TI - Solitary osteochondroma of the thoracic spine with compressive myelopathy; a rare presentation. AB - A 19-year-old man presented with a 5-year history of back pain radiating to the lower extremities and paresthesis of the toes during the last year. Plain X-ray revealed a large cauliflower shaped exophytic mass at the level of T8, T9 and T10 vertebrae. Computed tomography (CT) and magnetic resonance imaging (MRI) showed an abnormal bony mass arising from the posterior arch of T9 with protrusion to the spinal canal and marked cord compression. The cortex and medulla of the lesion had continuity with those of the T9 vertebra. Surgical en bloc resection was performed and the patient's symptoms resolved. The histopathologic diagnosis was osteochondroma. In patients with symptoms of myelopathy, in addition to more common etiologies, one should also be aware of rare entities such as osteochondroma. PMID- 24046784 TI - Successful catheter-directed venous thrombolysis in an ankylosing spondylitis patient with phlegmasia cerulea dolens. AB - Ankylosing spondylitis (AS) is an inflammatory rheumatic disease. Phlegmasia cerulea dolens is a severe form of deep vein thrombosis characterized by swelling, pain, and bluish discoloration. Treatment delay may cause venous gangrene, tissue ischemia, limb loss or death. Here, we present an AS case who presented with phlegmasia cerulea dolens and treated by catheter-directed thrombolysis. PMID- 24046785 TI - Benign mediastinal teratoma with intrapulmonary and bronchial rupture presenting with recurrent hemoptysis. AB - Mediastinal teratomas are usually asymptomatic tumors, located most commonly in the anterior mediastinum. Very rarely, such tumors may rupture into the tracheobronchial tree, lung, pleura or pericardium. Computed Tomography (CT) is helpful in the diagnosis and differentiation of ruptured and unruptured tumors. We report a case of ruptured anterior mediastinal teratoma in a 20-year-old female presenting with recurrent hemoptysis and cough; thus, mimicking a lung malignancy or tuberculosis. CT demonstrated a heterogeneous fat containing lesion in the anterior mediastinum with extension into the lingular lobe. Subsequent fine needle aspiration cytology (FNAC) yielded plenty of anucleate squames and debris, and a clear cut diagnosis could not be made. Total excision of the tumor was performed and histopathology of the surgically excised mass confirmed the CT diagnosis. PMID- 24046786 TI - Colloid carcinoma of the extrahepatic biliary tract with metastatic lymphadenopathy mimicking cystic neoplasm: a case report. AB - The patient is a previously healthy 52-year-old woman who presented with dyspepsia for two months. Multiple imaging modalities including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) showed diffuse bile duct dilatation with an obstructive lesion of the distal extrahepatic biliary duct (EHD) as well as two masses in the peripancreatic area. The peripancreatic masses appeared cystic with posterior acoustic enhancement on ultrasound, low density on CT imaging, and high signal intensity on T2-weighted MRI. The lesion in the distal EHD exhibited similar characteristics on CT and MRI. A Whipple procedure was performed and histological specimens showed malignant cells with large mucin pools that was consistent with a diagnosis of colloid carcinoma of the EHD with metastatic lymphadenopathies. Colloid carcinoma, also called mucinous carcinoma, is classified as a histologic variant of adenocarcinoma. Because the colloid carcinoma of the biliary tree is exceedingly rare, the imaging characteristics and the clinical features of colloid carcinoma remain relatively unknown. We report a case of colloid carcinoma of the common bile duct and its accompanied metastatic lymphadenopathies with characteristic imaging findings reflecting abundant intratumoral mucin pools. PMID- 24046787 TI - Radiologic findings in cutis laxa syndrome and unusual association with hypertrophic pyloric stenosis. AB - Cutis laxa (CL) is a rare congenital and acquired disorder characterized by loose and redundant skin with reduced elasticity. Three types of congenital cutis laxa have been recognized. Other findings are pulmonary emphysema, bronchiectasia, hernia and diverticulosis. We describe a female neonate involved by cutis laxa syndrome and a positive family history. We focus on the radiologic findings of this case such as multiple bladder diverticulosis, GI diverticulosis and very rare accompanying hypertrophic pyloric stenosis (HPS). PMID- 24046788 TI - Breast ductal carcinoma in situ: morphologic and kinetic MRI findings. AB - BACKGROUND: Adequate diagnosis of ductal carcinoma in situ (DCIS) could lead to efficacious treatment. Due to the fact that DCIS lesions can progress to invasive carcinomas and that the sensitivity of the standard examination - mammography - is between 70 and 80%, use of a more sensitive diagnostic tool was needed. In detection of DCIS, contrast-enhanced magnetic resonance imaging (CE-MRI) has the sensitivity up to 96%. OBJECTIVES: Morphological features and kinetic parameters were evaluated to define the most regular morphological, kinetic and morpho kinetic patterns on MRI assessment of breast ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: We retrospectively assessed eighteen patients with 23 histologically confirmed lesions (mean age, 52.4 +/- 10.5 years). All patients were clinically and mammographically examined prior to MRI examination. RESULTS: DCIS appeared most frequently as non-mass-like lesions (12 lesions, 52.17%). The differences in the frequency of lesion types were statistically significant (P<0.05). The following morphological patterns were detected: A: no specific morphologic features, B: linear/branching enhancement, C: focal mass-like enhancement, D: segmental enhancement, E: segmental enhancement in triangular shape, F: diffuse enhancement, G: regional heterogeneous enhancement in one quadrant not conforming to duct distribution and H: dotted or granular type of enhancement with patchy distribution. The difference in the frequency of the proposed patterns was statistically significant (P<0.05). There were eight lesions with mass enhancement, and six with segmental lesions: regional and triangular. There was no statistically significant difference in the frequency of enhancement curve types (P>0.05). There was no significant difference in the frequency of morpho-kinetic patterns. CONCLUSION: Non-mass-like lesions, lesions with focal or segmental distribution, with a "plateau" enhancement curve type were the most frequent findings of DCIS lesions on MRI. PMID- 24046789 TI - Appearance of uterine scar due to previous cesarean section on hysterosalpingography: various shapes, locations and sizes. AB - Hysterosalpingography (HSG) is the radiographic evaluation of the uterus and fallopian tubes that is used predominantly in the assessment of infertility and evaluation of abnormalities of the uterus and fallopian tubes. Some of the abnormalities that can be detected by HSG include congenital anomalies, polyps, leiomyomas, synechiae and adenomyosis. HSG is also used to evaluate any scarring on the uterus and fallopian tubes. Cesarean section is the most commonly performed surgical procedure involving the uterus in fertile women. Cesarean section involves an incision made in the lower uterine segment or isthmus. Various changes in the site of the cesarean incision may be seen due to wall weakness and fibrosis. The scar may have various shapes; unilateral or bilateral, single or multiple, wedge-shaped or linear. Awareness of the appearance and locations of uterine defects due to previous cesarean section is necessary in order to differentiate them from normal variations and other pathologies mimicking it. In this study, we demonstrate the appearance of anatomic defects of the uterine cavity on HSG after cesarian section. We define different shapes such as thin linear defect, focal saccular outpouching, unilateral or bilateral diverticula (dog-ear like) and fistula and different locations such as the uterine body, lower uterine segment, uterine isthmus and the upper endocervical canal. PMID- 24046791 TI - The 24 hour urine creatinine clearance for prediction of glomerular filtration rate in liver cirrhosis patients: have we considered all elements? PMID- 24046790 TI - Egy-score predicts severe hepatic fibrosis and cirrhosis in Egyptians with chronic liver diseases: a pilot study. AB - BACKGROUND: Non-invasive methods for assessment of hepatic fibrosis are increasingly needed. Recent studies showed that combined elevation of tumor markers CA 19-9 and CA 125 is predictive of severe hepatic fibrosis or cirrhosis with high specificity. OBJECTIVES: We aimed at developing a new panel of surrogate biomarkers for prediction of the stage of hepatic fibrosis by combining tumor markers with other known biomarkers of hepatic fibrosis. PATIENTS AND METHODS: A total of 92 patients with different types of chronic liver diseases (chronic hepatitis B, chronic hepatitis C and autoimmune hepatitis), were prospectively enrolled in our cohort. They were subjected to: ALT, AST, GGT, ALP, total bilirubin, INR, total cholesterol, albumin, platelet count, cancer antigen 19-9 (CA 19-9), cancer antigen 125 (CA 125), cancer antigen 15-3 (CA 15-3), haptoglobin, alpha-2-macroglobulin, apolipoprotein A1, abdominal ultrasound, liver biopsy and histological staging of hepatic fibrosis using the METAVIR system. RESULTS: Combined elevation of CA 19-9 and CA 125 with a summated value > 37 U/mL is predictive of severe hepatic fibrosis or cirrhosis (stage F3-F4 METAVIR) with a probability of 77.6%. Multivariate analysis showed that the most relevant collection of biomarkers for prediction of stage of hepatic fibrosis is: CA 19-9, age, alpha-2- macroglobulin, total bilirubin, platelet count & albumin. We developed a new score, named the "Egy-Score", using a regression equation composed of this panel of biomarkers. Egy-Score could differentiate no or early fibrosis (stage F0-F2 METAVIR) from severe fibrosis or cirrhosis (stage F3-F4 METAVIR) with 83.7% accuracy. CONCLUSIONS: Non-invasive assessment of hepatic fibrosis could be done using the Egy-Score. Egy-Score could differentiate no or early fibrosis (stage F0-F2 METAVIR) from severe fibrosis or cirrhosis (stage F3 F4 METAVIR) with 83.7% accuracy. PMID- 24046792 TI - Same journal, new publisher. PMID- 24046794 TI - Parotid abscess: mini-pictorial essay. AB - Bacterial and viral infection of the intraparotideal and periparotideal lymph nodes, or of the glandular parenchyma, can lead to inflammatory and subsequently suppurative changes, which can result in abscess formation. Sonography allows a detailed morphological evaluation of the gland and has an important value, complementary to clinical examination, in the study of parotid inflammatory diseases. Specifically, sonography defines lesion's characteristics and, in a large number of cases, also its nature and, among the various imaging techniques, it is considered first-line imaging for the evaluation of parotid abscesses, which are characterized by hypo-anechoic lesions, with irregular margins. Color Doppler signals are peripheral to the abscess. If combined with color Doppler, sonography is important not only in diagnosis, but also in the evaluation of therapeutic efficacy and as a guide to the aspiration and drainage of abscesses. The rarity of some of these lesions led us to publish this mini-pictorial essay. PMID- 24046793 TI - Ultrasound in sialadenitis. AB - The salivary glands are located superficially and are therefore easily accessible to ultrasound (US) examination, particularly if a high-frequency probe designed for small parts is used. Hence, US examination of these organs is widely applied particularly in non-neoplastic pathologies. In this way, it is possible to obtain adequate images without the use of ionizing radiation or complex instrumentation such as magnetic resonance imaging. However, US examination requires an expert clinical knowledge and familiarity with the normal and pathological US anatomy of the area. Limitations and pitfalls linked to US examination of this area should also be kept in mind. PMID- 24046795 TI - Branchial cleft cyst. AB - Branchial cleft cysts are benign lesions caused by anomalous development of the brachial cleft. This report describes a 20-year-old girl with swelling on the right lateral aspect of the neck, which expanded slowly but progressively. The clinical suspicion was that of a branchial cleft cyst. Sonography revealed a homogeneously hypo- to anechoic mass with well-defined margins and no intralesional septa. Color Doppler reviewed no internal vascularization. The ultrasound examination confirmed the clinical diagnosis of a second branchial cleft cyst, demonstrating the cystic nature of the mass and excluding the presence of complications. For superficial lesions like these, ultrasound is the first-level imaging study of choice because it is non-invasive, rapid, low-cost, and does not involve exposure to ionizing radiation. PMID- 24046796 TI - Contrast-enhanced ultrasound findings in soft-tissue lesions: preliminary results. AB - OBJECTIVES: There is currently no widely available, minimally invasive first level examination that allows physicians to identify soft-tissue lesions that are likely to be malignant. The aim of this pilot study was to explore the potential suitability of dynamic contrast-enhanced ultrasound (DCE-US) for this purpose. MATERIALS AND METHODS: 23 patients were referred to the Veneto Oncological Institute for work-up of superficial soft-tissue lesions. Fourteen lesions were examined with CEUS and enhancement kinetics was analyzed. Subsequently, all lesions were surgically removed and subjected to histological analysis. RESULTS: The 14 lesions included in the study were histologically classified as malignant (n = 7) or benign (n = 7, including 3 schwannomas). A statistically significant difference between benign and malignant lesions was found in terms of mean times to peak enhancement intensity (p = 0.03) but not mean filling times (FT). When schwannomas were analyzed as a separate group, their mean FT was found to be significantly different from that of the other benign lesions (p = 0.001) and from that of the group comprising other benign lesions as well as malignant lesions (p < 0.005). CONCLUSIONS: CEUS with analysis of contrast-enhancement kinetics is a relatively low-cost, minimally invasive imaging technique, which appears to be a potentially effective first-level method for identifying suspicious soft-tissue masses. PMID- 24046797 TI - An antecubital fossa "cyst" caused by postoperative kinking of the brachial artery. AB - A 77-year-old woman was referred to our staff for evaluation of a "cystic" mass in the antecubital fossa. The recent medical history included surgical excision of a median-nerve schwannoma. The postoperative course had been uneventful. The sonographic examination revealed kinking of the brachial artery; color Doppler imaging showed aliasing at the level of the kink. The case illustrates the value of ultrasound in the diagnosis of fluid-filled lesions of the elbow, including those that are rare and unexpected. PMID- 24046798 TI - Palpable inguinal mass in a girl after omphalocele repair: US findings. AB - Hydrocele of the canal of Nuck is a rare cause of inguinal swelling in females. We present the case of a 9-year-old girl, who underwent omphalocele repair shortly after birth. She presented with a painless swelling in the right inguinal region; it was of a hard elastic consistency and ultrasound image showed an oval lesion containing fluid, located in the subcutaneous soft tissue. Removal of the lesion and histological examination of the surgical specimen confirmed cyst of the canal of Nuck. PMID- 24046799 TI - Imperforate hymen causing congenital hydrometrocolpos. AB - A 3-day-old girl in good health was referred to our department for the evaluation of an abdominal mass detected at birth. Prenatal ultrasound (US) examinations had shown no anomaly. US examination revealed the presence of a hypoechoic and corpusculated cystic formation of about 8 * 5 * 4 cm located in the mid region of the abdomen. The uterus was not visible and the kidneys were normal with no sign of hydronephrosis. The ovaries were normal. Physical examination confirmed US findings revealing the presence of a curved membrane which covered the vaginal opening. Based on these findings, the patient was diagnosed to have hydrometrocolpos. Hymenectomy was performed and about 100 ml of milky fluid was subsequently removed by aspiration. The patient presented no other congenital anomalies and US follow-up showed a normal structure of the uterus. PMID- 24046800 TI - Uterine arteriovenous malformation. AB - Uterine arteriovenous vascular malformations (UAVM) are uncommon vascular diseases, occurring during reproductive age. Patients affected by UAMVs usually present with recurrent pregnancy loss or menorrhagia. Initial evaluation of UAVMs is made with ultrasonography (US) and US-Doppler. Magnetic resonance is used when a UAMV is suspected at US. Treatment can be surgical (hysterectomy or surgical removal of AVM), or with selective uterine arterial embolization. We report a case of UAMV, from its clinical signs to diagnostic confirmation and subsequent treatment. PMID- 24046801 TI - Erratum: Publisher's Note: "Label-free electronic probing of nucleic acids and proteins at the nanoscale using the nanoneedle biosensor" [Biomicrofluidics 7, 044114 (2013)]. AB - [This corrects the article on p. 044114 in vol. 7.]. PMID- 24046802 TI - Venous outflow obstruction and portopulmonary hypertension after orthotopic liver transplantation. AB - PATIENT: Female, 54 FINAL DIAGNOSIS: Suprahepatic inferior vena cava anastomosis stricture Symptoms: Ascites * fatigue * lower limb edema * hepatomegaly MEDICATION: - Clinical Procedure: - Specialty: Transplantology * Critical Care Medicine. OBJECTIVE: Unusual clinical course. BACKGROUND: Suprahepatic inferior vena cava anastomosis stricture is an unusual vascular complication after orthotopic liver transplantation with the "piggyback" technique. Clinical manifestations are dependent upon the severity of the stenosis. Portopulmonary hypertension after orthotopic liver transplantation is a complication that carries high mortality due to cardiopulmonary dysfunction. The pathogenesis of pulmonary vascular disorders after orthotopic liver transplantation remains uncertain. CASE REPORT: We report a case of acute right heart pressure overload after surgical correction of the suprahepatic inferior vena cava anastomotic stricture in a 54-year-old woman who had preexisting pulmonary arterial hypertension associated with portal hypertension after orthotopic liver transplantation. Twenty months posttransplantation, she developed fatigue and progressive ascites. On admission, the patient had hepatomegaly, ascites, and lower limb edema. Symptoms in the patient developed gradually over time. CONCLUSIONS: Recurrent portal hypertension by vascular complications is a cause of pulmonary arterial hypertension after orthotopic liver transplantation. Clinical manifestations of suprahepatic inferior vena cava anastomotic stenosis are dependent upon their severity. Sildenafil is an effective drug for treatment of pulmonary arterial hyper-tension after portal hypertension by vascular complications. PMID- 24046803 TI - Pyridostigmine-induced high grade SA-block in a patient with myasthenia gravis. AB - PATIENT: Female, 70 FINAL DIAGNOSIS: SA block induced by pyridostigmine Symptoms: Asymptomatic Medication: Pyridostigmine Clinical Procedure: Pacemaker insertion Specialty: Electrophysiology. OBJECTIVE: Unusual clinical course. BACKGROUND: Myasthenia gravis requires a long-term treatment with a parasympathomimetic agent, which may result in bradycardia and asystole. Pharmacologic treatment with a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) and Methylprednisolone is seen to improve the muscular symptoms but may reinforce potential bradyarrhythmias. This potential side effect can be treated with the levo isomer of atropine, Hyoscyamine, or Glycopyrollate in an intact conduction system. CASE REPORT: A 70-year old Caucasian female patient with a family history of myasthenia gravis presented with mild weakness of the bilateral facial muscles, moderate dysarthria, dysphagia, diplopia predominantly on the right side and difficulty tracking ocular movements bilaterally. The treatment with pharmacological agents was initiated. Subsequently she developed asymptomatic bradycardia and SA-block. An improvement on Hyoscyamine failed to appear. A dual chamber pacemaker was placed. CONCLUSIONS: In symptomatic or asymptomatic bradycardia with significant high grade SA-block in patients with myasthenia gravis the insertion of a permanent pacemaker can be the definitive solution. PMID- 24046804 TI - A case of Hashimoto's encephalopathy misdiagnosed as viral encephalitis. AB - PATIENT: Male, 61 FINAL DIAGNOSIS: Hashimoto's encephalopathy Symptoms: Neuropsychiatric or neurological manifestations Medication: Steroids and immunoglobulins Clinical Procedure: Immunoglobulin combined with corticosteroid therapy Specialty: Neurology. OBJECTIVE: Mistake in diagnosis. BACKGROUND: Hashimoto's encephalopathy is a rare autoimmune syndrome characterized by various neuropsychiatric or neurological manifestations and associated with Hashimoto's thyroiditis, responsive to steroids. Until now, misdiagnosis and delay of treatment of Hashimoto's encephalopathy are very common because of the diversity of the symptoms. CASE REPORT: This recent case of a 61-year-old man presented with unconsciousness, spasms and a previous misdiagnosis as viral encephalitis. Response to anti-viral and steroid therapy was unsatisfactory, but treatment with immunoglobulin combined with corticosteroid therapy achieved rapid and complete recovery. CONCLUSIONS: Any patient presenting with acute or subacute unexplained encephalopathy should be considered Hashimoto's encephalopathy, even if the thyroid function is normal. Thyroid antibody testing should be performed because this may be the most important clue to diagnosis. As soon as the diagnosis is made, steroid therapy is the first choice. If the steroid therapy does not lead to immediate improvement, IVIG is an effective alternative treatment. PMID- 24046805 TI - Genome-wide and candidate gene association studies of placental abruption. AB - Placental abruption (PA), a pregnancy-related vascular disorder, is a leading cause of maternal and perinatal morbidity and mortality. The success of identifying genetic susceptibility loci for PA, a multi-factorial heritable disorder, has been limited. We conducted a genome-wide association study (GWAS) and candidate gene association study using 470 PA cases and 473 controls from Lima, Peru. Genotyping for common genetic variations (single nucleotide polymorphisms, SNPs) was conducted using the Illumina Cardio-Metabo Chip platform. Common variations in 35 genes that participate in mitochondrial biogenesis (MB) and oxidative phosphorylation (OS) were selected for the candidate gene study. Regression models were fit to examine associations of each SNP with risk of PA. In pathway analyses, we examined functions and functional relationships of genes represented by the top GWAS hits. Genetic risk scores (GRS), based on top hits of the GWAS and candidate gene analyses, respectively, were computed using the risk allele counting method. The top hit in the GWAS analyses was rs1238566 (empirical P-value=1.04e-4 and FDR-adjusted P-value=5.65E 04) in FLI-1 gene, a megakaryocyte-specific transcription factor. Networks of genes involved in lipid metabolism and cell signaling were significantly enriched by the 51 genes whose SNPs were among the top 200 GWAS hits (P-value <2.1e-3). SNPs known to regulate MB (e.g. CAMK2B, NR1H3, PPARG, PRKCA, and THRB) and OP (e.g., COX5A, and NDUF family of genes) were associated with PA risk (P-value <0.05). GRS was significantly associated with PA risk (trend P-value <0.001 and 0.01 for GWAS and candidate gene based GRS, respectively). Our study suggests that integrating multiple analytical strategies in genetic association studies can provide opportunities for identifying genetic risk factors and novel molecular mechanisms that underlie PA. PMID- 24046806 TI - Phospholipase A2G1B polymorphisms and risk of colorectal neoplasia. AB - Pancreatic phospholipase A2, product of PLA2G1B, catalyzes the release of fatty acids from dietary phospholipids.Diet is the ultimate source of arachidonic acid in cellular phospholipids, precursor of eicosanoid signaling molecules, linked to inflammation, cell proliferation and colorectal carcinogenesis. We evaluated the association of PLA2G1B tagging single-nucleotide polymorphisms with colorectal neoplasia risk. A linkage-disequilibrium-based tagSNP algorithm (r(2)=0.90, MAF>=4%) identified three tagSNPs. The SNPs were genotyped on the Illumina platform in three population-based, case-control studies: colon cancer (1424 cases/1780 controls); rectal cancer (583/775); colorectal adenomas (485/578). Evaluating gene-wide associations, principal-component and haplotype analysis were conducted, individual SNPs were evaluated by logistic regression. Two PLA2G1B variants were statistically significantly associated with reduced risk of rectal cancer (rs5637, 3702 G>A Ser98Ser, p-trend=0.03; rs9657930, 1593 C>T, p trend=0.01); principal component analysis showed that genetic variation in the gene overall was statistically significantly associated with rectal cancer (p=0.02). NSAID users with the rs2070873 variant had a reduced rectal cancer risk (P-inter=0.02). Specific associations were observed with tumor subtypes (TP53/KRAS). The results suggest that genetic polymorphisms in PLA2G1B affect susceptibility to rectal cancer. PMID- 24046807 TI - Implication of androgen receptor in urinary bladder cancer: a critical mini review. AB - Cancer is probably the most dreaded disease of mankind and the bladder cancer is the fifth most common type of cancer worldwide. It is a major cause of cancer morbidity and mortality. From amongst the bladder cancer, the Transitional Cell Carcinoma (TCC) is the most prevalent cancer of the bladder and accounts for 90% of all bladder cancer cases. Despite such a high prevalence, the molecular mechanism involved in the induction of bladder carcinoma and its progression are poorly understood. Tumorigenesis and tumor progression of bladder carcinomas are thought to result from the accumulation of multiple genetic alterations. The Androgen Receptor (AR) gene is located on the q arm of X chromosome (q11-12) and considered as a ligand-inducible transcription factor that regulates target gene expression. The Androgen plays a vital role in the development and maintenance of the normal urinary bladder. The AR is also involved in the development and progression of urinary bladder carcinoma, which is the most common type of carcinoma. Mutation in AR alters the ligand binding ability that may cause the progression and development of bladder cancer. Tumorigenesis and tumor progression are thought to result from changes in the function of hormonal receptor gene. The accumulation of the changes in AR expressions, determines the tumor's phenotype and ultimately the patient's clinical outcome. The early detection of which may help in management and prediction, how will it behave and respond to the therapeutic regimen. The present review aimed to study the mechanism and alteration of AR gene that play a vital role in the tumorIgenesis of bladder carcinoma. PMID- 24046808 TI - Obesity-related markers and breast cancer in CPS-II Nutrition Cohort. AB - Low circulating levels of adiponectin and high levels of insulin-like growth factor-1 (IGF-1), C-reactive protein (CRP), and C-peptide have been shown to be related to postmenopausal breast cancer risk, and to partially mediate the obesity-postmenopausal breast cancer association; however, data from prospective studies, especially those limited to non-users of postmenopausal hormones, are sparse. To further evaluate these associations, we measured these markers in a case-control study nested in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort. Plasma samples from 302 postmenopausal breast cancer cases and matched controls were analyzed. None of the women were taking postmenopausal hormones at blood draw. Multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. Low levels of total adiponectin and high levels of total IGF-1 and CRP were associated with increased breast cancer risk, but associations were not statistically significant. The association with C-peptide was statistically significant (T3 vs. T1: OR=1.63, 95% CI 1.08-2.45; p-value for linear trend=0.001), but was slightly attenuated after further adjustment for BMI (T3 vs. T1: OR=1.51, 95% CI 0.99 2.31; p-value for linear trend=0.004). The association between BMI and breast cancer risk was attenuated toward the null after controlling for C-peptide (from OR=1.43 to OR=1.25 for BMI >=30 kg/m(2) compared to <25 kg/m>(2)). The elevated risk of postmenopausal breast cancer associated with higher circulating levels of C-peptide is consistent with a role of hyperinsulinemia in breast carcinogenesis, and might account for some of the higher risk associated with obesity. PMID- 24046809 TI - Molecular epidemiology of selected sexually transmitted infections. AB - Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG) are established pathogens for human genital tract. However, the role of Ureaplasma urealyticum (UU) and Ureaplasma parvum (UP) in genital pathology is poorly unerstood. A prospective study to investigate the prevalence of above infections was performed on a cohort of 1,718 consecutive patients attending a Genitourinary Medicine (GUM) clinic. A previously published in-house real-time PCR assay, for the detection of CT DNA in genital swabs, was modified for this study. Two amplification reactions detected the DNAs of TV, NG, MG, CT, UU and UP in genital swabs from 4 (0.2%), 11 (0.6%), 17 (1%), 129 (8%), 282 (16%) and 636 (37%) patients, respectively. 594 (70%) of 848 women and 333 (38%) of 870 men were infected with at least one type of microorganism. Among 594 infected females, 485 (82%) had a single infection, 97 (16%) had a double infection, and 12 (2%) had a triple infection. Of the 333 infected men, 304 (91%) had a single infection, 27 (8%) had a double infection, and 2 (1%) had a triple infection. The prevalence of infection in both genders decreased with increasing age. The prevalence proportion of UP was significantly higher in women (54%) compared with men (18%). The high prevalence of UU and UP suggests that these bacteria are commensals of genital tract. PMID- 24046810 TI - The epidemiology of gastroesophageal reflux disease: a survey on the prevalence and the associated factors in a random sample of the general population in the Northern part of Iran. AB - Many people with gastro-esophageal reflux symptoms do not consult a physician; therefore studies on gastro-esophageal reflux in general practice or in hospitals may not accurately describe the burden of gastro-esophageal reflux symptoms in the general population. The aim of this study was to assess the prevalence of gastro-esophageal reflux disease and its association with some life-style parameters in Rasht-Iran. A telephone survey was performed. Phone numbers was randomly collected from the telecommunication service center of Rasht. 1473 people (Mean age: 38.31 +/- 13.09) were included in the study. People who didn't answer the phone after three times or didn't have consent to enter the study were excluded. Data were collected by an examiner using a GerdQ questionnaire. The validity and reliability of the questionnaire was tested by translation and retranslation and a pilot study was performed to assess its appropriateness. The prevalence of gastro-esophageal reflux was achieved 2.4% daily, 9.1% weekly and 11.3% monthly. Among the patients with gastro-esophageal reflux, 69.5% were female. There was a significant positive association between gastro-esophageal reflux prevalence and body mass index, smoking habits, eating salted or smoked foods, lying down immediately after the meal, taking certain drugs as non steroidal anti-inflammatory drugs/Amino salicylic acid and the age group of 30-45 year old. Overall, the prevalence of the weekly gastro-esophageal reflux in the present survey was 9.1% which was less than other similar studies in Iran and some other countries. PMID- 24046811 TI - Concentration dependent Electrospray Ionisation Mass Spectrometry and Tandem Mass Spectrometry (MS/MS ) studies on (E,E)-1-[5-(1,3-benzodioxol-5yl)-1-oxo-2,4 pentadienyl]- piperidine (Piperine) and its analogues. AB - Studies on piperine ((M 1 )) and its synthetic analogues (M 2-18 ) by positive electrospray ionisation mass spectrometry were carried out in the flow injection mode of analysis in methanol. The MS experiments on these compounds at concentration 5 ng/MUL or above yielded dimeric ionic species [2 M + Na](+) which revealed that piperine and its analogues exhibit clustering of ions when the solutions of these compounds at concentrations 5 ng/MUL or above were allowed to move through the electrospray interface of the mass spectrometer. The same clustering of the ions was not observed when the solutions of the same compounds at concentrations below 5 ng/MUL were used for similar studies. The formation of the clusters was further confirmed by tandem mass spectrometry (MS/MS) studies wherein the fragmentation of dimeric ionic species [2 M + Na](+) led to the formation of sodium adducted monomeric ionic species [M + Na](+). The MS measurements of these compounds by Atmospheric Pressure Chemical Ionisation (APCI) were on expected lines as there was no clustering of the ions in case of APCI-MS measurements. PMID- 24046812 TI - Analysis on genetic diversification and heterosis in autotetraploid rice. AB - Polyploidization has played an important role in plant evolution and is a pathway for plants to increase genetic diversification and to get higher heterosis comparing with that of diploid does. This study was undertaken to assess the genetic variation and relationships among 40 autotetraploid rice genotypes and their counterpart diploid cultivars with 99 SSR markers screened from published rice genome. The 99 SSR markers detected polymorphism among autotetraploid genotypes and revealed a total of 291 alleles with an average of 2.949 alleles per locus. Autotetraploid lines showed higher genetic diversity and significant variation in agronomic traits than diploid cultivars. Phylogenetic analysis revealed that most of autotetraploid lines were genetically different from their diploid parents, and inter-subspecific hybrids were prepared on the basis of genetic distance between parents. Inter-subspecific autotetraploid hybrids showed a higher and positive heterobeltiosis and competitive heterosis than diploid hybrids, especially for grain yield. Genetic distance appeared not to predict heterosis in diploid rice for all traits; however, it showed a significant correlation with grain yield, grain length and grain length to width ratio in autotetraploid rice. This extensive research on autotetraploid heterosis and genetic diversity will be useful for the development of autotetraploid rice hybrids. PMID- 24046813 TI - Butorphanol-midazolam combination therapy for the treatment of intracranial hypertension in a patient with tuberculous meningitis: a case study. AB - INTRODUCTION: Intracranial hypertension, which often occurs in patients with tuberculous meningitis, is associated with high morbidity and mortality. We describe a patient with tuberculous meningitis who had intracranial hypertension induced fulminant headache that responded to intravenous butorphanol-midazolam combination therapy. CASE PRESENTATION: A 50-year-old woman with a fever and headache for 24 days was given a diagnosis of tuberculous meningitis on the basis of the results of polymerase chain reaction amplification and Ziehl-Neelsen staining. Headache with vomiting developed despite administration of steroids, osmotic, and antituberculosis treatments. The patient was admitted in a confusional state. The initial pressure (420 mmHg) in cerebrospinal fluid was increased. She was given intravenous mannitol, dexamethasone, pentazocine and diazepam, or she was sedated with propofol, with no response. Next, a combination of butorphanol and midazolam was infused intravenously and finally resolved the confusional state. The initial pressure decreased, and she no longer complained of headache requiring medication. DISCUSSION AND EVALUATION: The butorphanol midazolam combination therapy may have reduced intracranial pressure, leading to down-regulation of headache. Sedation induced by such combination of drugs was not accompanied by amnesia or impaired psychomotor function. CONCLUSIONS: The butorphanol-midazolam combination therapy might be an option for the management of intracranial hypertension in central nervous system infections. PMID- 24046814 TI - Accessory renal arteries in a Caribbean population: a computed tomography based study. AB - INTRODUCTION: The commonest variation to the classic anatomic description of renal arterial supply is the presence of accessory renal arteries. The incidence varies widely according to ethnicity. There is no data on the prevalence of these anomalies in persons of Caribbean ethnicity. METHODS: All CT scans done over two years from July 1, 2010 to June 30, 2012 were retrospectively evaluated. The anatomy of the renal arterial supply was reported from these studies and the anatomy of accessory renal arteries was documented. RESULTS: There were 302 CT scans evaluated and accessory renal arteries were present in 109/302 (36.1%) CT scans, 95% confidence interval 30.6%, 41.4%. There were 71/309 (23.5%) patients with accessory arteries on the left and 54/309 (17.9%) had them on the right (p 0.087). Of these, 16 (14.7%) patients had bilateral accessory renal arteries present. The most common origin for the accessory arteries was the abdominal aorta in 108 (99.1%) cases and in 1 case the accessory artery arose from the coeliac trunk. There were 80 left sided accessory renal arteries: 17 (21.3%) upper polar and 27 (33.8%) lower polar arteries. Of 62 right sided accessory arteries, 14 (22.6%) were upper polar and 26 (42%) were lower polar arteries. CONCLUSION: This is the first population-based report of anatomic anomalies in renal arterial supply in a Caribbean population. These are important findings that may affect vascular and urologic procedures on persons of Caribbean ethnicity. PMID- 24046815 TI - The potential impact of adding genetic markers to clinical parameters in managing high-risk prostate cancer patients. AB - PURPOSE: High-risk prostate cancer is a potentially lethal disease that is increasing in the diagnosis of prostate cancer patients. Compared to other prostate cancer patients (medium or low risk), management, diagnosis and treatment are not as successful among high-risk patients. Because the genetic characterization of prostate cancer patients is increasing, we aimed to determine whether genetic information in one of the primary associated genes, such as RNASEL (2', 5'-oligoadenylate-dependent RNase L), could be used as a biomarker to improve the quality of life and treatment among high-risk patients. The main objective is to identify genetic variants of RNASEL that could be associated with high-risk prostate cancer to improve the clinical managing of these patients. METHODS: A total of 231 prostate cancer patients were genotyped for 7 variants of RNASEL gene. Clinical information was obtained from medical examinations and genetic analysis (amplification and sequencing 7 variants of RNASEL gene) were performed by the researchers. Data were processed by statistical analysis (Chi square and logistic regression) using SPSS v.15.0. RESULTS: Comparisons between genotypes and clinical characteristics of patients revealed that individuals with GG in D541E, AA in R462Q and AG in I97L in RNASEL gene were high-risk patients according to the European Urology Guidelines. CONCLUSIONS: Genotyping the RNASEL gene with routine diagnostic techniques could confer a more precise diagnosis of high-risk prostate cancer patients and increase the diagnostic accuracy above the current rate of 70% due to the relation between the genetic variants of RNASEL gene and the risk of this cancer. PMID- 24046816 TI - The case for clinical pathways in radiation oncology. PMID- 24046817 TI - Relationship between the induction of inflammatory processes and infectious diseases in patients with ischemic stroke. AB - Pro-inflammatory cytokines participate in the induction of ischemic stroke. So far, their participation in the cerebral ischemia was proven for the tumor necrosis factor TNF-alpha, interleukin-1 (IL-1), and interleukin-6 (IL-6). The release of the pro-inflammatory cytokines into the extracellular space causes the enlargement of the brain damage region, and consequently increases the neurological deficit and negatively affects the survival rate prognoses. That is confirmed by the increased concentration of pro-inflammatory cytokines in blood and the cerebrospinal fluid of patients with brain stroke, as well as by the research on the induced/experimental cerebral ischemia in animals. The pro inflammatory cytokines participate in the migration of the reactive T lymphocytes to the regions of brain ischemia where they enhance the nerve tissue damage by down-regulation of microcirculation, induce the pro-thrombotic processes and release other neurotoxic cytokines. Also, in the early stage of cerebral ischemia, cytokines activate the axis hypothalamus-pituitary gland-adrenal cortex and increase the cortisol concentration in blood, what results in the decreased resistance to infectious diseases. Administration of the inhibitor of the interleukin-1 receptor (IL-1Ra) inhibits the inflammatory processes in the region of brain ischemia, and subsequently improves the prognosis for the size of the neurological deficit and the survival rate, as well as resistance to infectious diseases. PMID- 24046818 TI - Pre-analytical-related variability influencing serum peptide profiles demonstrated in a mass spectrometry-based search for colorectal and prostate cancer biomarkers. AB - Although the degradome, which comprises proteolytic fragments of blood proteins, presents a potential source of diagnostic biomarkers, studies on cancer peptide biomarkers have provided inconsistent conclusions. In the present study, we reevaluated the usefulness of serum degradome analyses for searching peptide cancer biomarker candidates. Particular attention was paid to pre-analytical factors influencing the variability of determined peptide levels, including clotting time and control group selection. Studies were conducted on 44 and 86 serum samples collected from cancer patients and healthy individuals, respectively, using liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS)-based analyses. We identified 1373 unique peptides, nearly 40% of which originated from five blood proteins: fibrinogen alpha chain, apolipoprotein A-IV (APOA4), complement C3, apolipoprotein A-I, and alpha-1 antitrypsin. A set of 118 and 88 peptides exhibited highly significant differences (adjusted p-value <= 0.01 and fold change >= 2) in pair-wise comparisons of control vs. prostate cancer and control vs. colorectal cancer, respectively, with 37 peptides displaying a consistent direction of change for these pair-wise comparisons. The levels of 67 peptides differed significantly in serum samples collected from healthy individuals immediately prior to colonoscopy and those who underwent colonoscopic examination at least four weeks earlier. Of them, 49 peptides originated from APOA4. Whereas earlier studies, including ours, have utilized fragments of fibrinopeptide A (FPA) to distinguish cancer from healthy cases, here we show that their absolute abundance is a sensitive indicator of clotting time. These observations may have implications for future serum peptidome studies since these issues have not previously been recognized. PMID- 24046819 TI - Development and pretesting of an electronic learning module to train health care professionals on the use of the Pediatric Respiratory Assessment Measure to assess acute asthma severity. AB - BACKGROUND: Severity-specific guidelines based on the Pediatric Respiratory Assessment Measure (PRAM), a validated clinical score, reduce pediatric asthma hospitalization rates. OBJECTIVE: To develop, pretest the educational value of and revise an electronic learning module to train health care professionals on the use of the PRAM. METHODS: The respiratory efforts of 32 children with acute asthma were videotaped and pulmonary auscultation was recorded. A pilot module, composed of a tutorial and 18 clinical cases, was developed in French and English. Health care professionals completed the module and provided feedback. The performance of participants, case quality and difficulty, and learning curve were assessed using the Rasch test; quantitative and qualitative feedback served to revise the module. RESULTS: Seventy-two participants (19 physicians, 22 nurses, four respiratory therapists and 27 health care trainees) with a balanced distribution across self-declared expertise (26% beginner, 35% competent and 39% expert) were included. The accuracy of experts was superior to beginners (OR 1.79, 1.15 and 2.79, respectively). Overall performance significantly improved between the first and latter half of cases (P<0.001). Participants assessed the module to be clear (96%), relevant (98%), realistic (94%) and useful (99%) to learn the PRAM. The qualitative/quantitative analysis led to the deletion of three cases, modification of remaining cases to further enhance quality and reordering within three levels of difficulty. DISCUSSION: Using rigorous educational methods, an electronic module was developed to teach health care professionals on use of the PRAM score. Using the back-translation technique, both French and English versions were developed and validated simultaneously. The pilot module comprised a tutorial and three case-scenario sections, and was tested on a target audience of physicians, nurses, respiratory therapists and medical trainees. CONCLUSION: The final electronic learning module met the clarity and quality requirements of a good teaching tool, with a demonstrated learning effect and high appreciation by health care professionals. Available in French and English, it is offered to facilitate implementation of PRAM-based acute pediatric asthma guidelines. PMID- 24046820 TI - Diffuse pulmonary ossification as a rare cause of interstitial lung disease. AB - Diffuse pulmonary ossification (DPO) is a rare form of interstitial lung disease. The present article describes a case of DPO in an elderly man who presented with progressive dyspnea on exertion and an isolated reduction in diffusing capacity for carbon monoxide. DPO may occur as sequelae of mitral stenosis, left heart failure, idiopathic pulmonary fibrosis, recurrent aspiration pneumonia, solid organ transplant, adult respiratory distress syndrome or may arise idiopathically. In the absence of other findings of interstitial lung disease, a lung biopsy is unlikely to be helpful in the management of these patients. PMID- 24046821 TI - Effect of toothbrushing discontinuation on morning volatile sulfur compounds in periodontally healthy subjects. AB - PURPOSE: To follow up the variations of early morning concentrations of oral volatile sulfur compounds (VSCs) in periodontally healthy subjects who refrained from toothbrushing during a period of 5 days while continuing with other hygiene procedures. MATERIALS AND METHODS: Thirteen subjects volunteered for this study. At baseline, all subjects stopped brushing their teeth for 5 days, but continued using dental floss and a tongue scraper twice daily. Organoleptic measurements, VSC quantification and plaque index were recorded in all subjects at baseline and on days 3 and 5 of the study period. RESULTS: At baseline, the visible plaque index was significantly lower than that observed on days 3 and 5 (P = 0.0001). However, no significant differences in the amount of plaque were observed between days 3 and 5 (P > 0.05). The results of the organoleptic measurements and VSC quantifications did not show any statistically significant differences between baseline and day 3, or between days 3 and 5 (P > 0.05). However, a significant increase was observed in both VSCs (P = 0.008) and organoleptic scores (P = 0.032) when baseline values were compared to day 5. A positive correlation between VSCs and organoleptic scores was observed in all measurements (r = 0.67, P < 0.0001). CONCLUSION: The results of this study suggest that the lack of toothbrushing may affect VSC levels and the organoleptic perception of oral malodour due to the development of biofilm on buccal and lingual surfaces of teeth in healthy subjects. PMID- 24046823 TI - Toothbrushing methods to use in children: a systematic review. AB - PURPOSE: To identify the most effective methods of toothbrushing in children, assessed according to their ability to remove dental plaque. MATERIALS AND METHODS: After electronic research, randomised clinical studies in children which compared different toothbrushing techniques or different frequencies with the same technique were included. The evaluation criterion was plaque index. RESULTS: Six of 534 identified articles were included. Because the protocols differed, regrouping of data was not possible. The level of evidence was moderate due to imprecise methods. The horizontal technique was found to be the most effective up to 6 to 7 years of age. For older children, there was no statistical difference between the techniques. No randomised clinical trial assessed different frequencies of toothbrushing. CONCLUSION: Based on current knowledge, it would appear prudent to propose that, at the stage of the late mixed dentition, the technique adopted by the child be modified to improve brushing quality without favouring a particular technique. In younger children, the horizontal technique should be advised. The recommendations published via the Internet by national and international associations should be reconsidered. PMID- 24046822 TI - Antimicrobial Effect of Jasminum grandiflorum L. and Hibiscus rosa-sinensis L. Extracts Against Pathogenic Oral Microorganisms--An In Vitro Comparative Study. AB - PURPOSE: To assess and compare the antimicrobial potential and determine the minimum inhibitory concentration (MIC) of Jasminum grandiflorum and Hibiscus rosa sinensis extracts as potential anti-pathogenic agents in dental caries. MATERIALS AND METHODS: Aqueous and ethanol (cold and hot) extracts prepared from leaves of Jasminum grandiflorum and Hibiscus rosa-sinensis were screened for in vitro antimicrobial activity against Streptococcus mutans and Lactobacillus acidophilus using the agar well diffusion method. The lowest concentration of every extract considered as the minimum inhibitory concentration (MIC) was determined for both test organisms. Statistical analysis was performed with one-way analysis of variance (ANOVA). RESULTS: At lower concentrations, hot ethanol Jasminum grandiflorum (10 MUg/ml) and Hibiscus rosa-sinensis (25 MUg/ml) extracts were found to have statistically significant (P<=0.05) antimicrobial activity against S. mutans and L. acidophilus with MIC values of 6.25 MUg/ml and 25 MUg/ml, respectively. A proportional increase in their antimicrobial activity (zone of inhibition) was observed. CONCLUSION: Both extracts were found to be antimicrobially active and contain compounds with therapeutic potential. Nevertheless, clinical trials on the effect of these plants are essential before advocating large-scale therapy. PMID- 24046824 TI - Association between sickle cell anaemia and periodontal diseases among 12- to 16 year-old Sudanese children. AB - PURPOSE: The principal objective was to investigate the association between periodontal diseases and sickle cell anaemia (SCA). MATERIALS AND METHODS: A group of 59 children with SCA (ages 12 to 16 years) were examined and compared to 54 healthy controls, matched by age and gender. Oral clinical examination included: plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment loss (CAL), presence of calculus and tooth mobility. Clinical severity of SCA and oral hygiene habits were also assessed. RESULTS: There was no statistically significant difference between cases and controls in terms of PI, PD, CAL and tooth mobility at the 5% significance level. However, there was a statistically significant association between GI and SCA (P = 0.002). The mean gingival index of SCA patients was 1.35 +/- 0.19 compared to 1.18 +/- 0.16 for the controls (P = 0.00001). There was a probability of 76.1% that the GI of SCA patients was greater than the GI of controls. The percentage of teeth with PD = 4 mm was greater in SCA patients compared to controls (2.5% vs 0.6%). Moreover, SCA patients had a higher percentage of teeth with CAL= 3 mm (0.7% vs 0.3%). There was a statistically significant association between having mild, moderate or severe gingival inflammation and the severity of sickle cell anemia (P = 0.028). CONCLUSIONS: The results showed a statistically significantly higher prevalence of inflammed periodontium in children with SCA compared to a similar healthy population. PMID- 24046825 TI - Inhibitory effect of yogurt extract on dental enamel demineralisation - an in vitro study. AB - PURPOSE: To test the effectiveness of yogurt extract as an agent to protect tooth enamel from demineralisation in vitro. MATERIALS AND METHODS: The crowns of 80 intact caries-free human premolars were selected, and standardised 5 x 3 mm2 enamel windows were isolated on the buccal and lingual surface of each tooth. The baseline weight of each specimen was recorded. Four demineralising solutions were prepared: S1: lactic acid (LA) at pH 4.8; S2: LA at pH 3.97; S3: LA + yogurt supernatant (YS) at pH 4.8; S4: LA + YS at pH 3.97. The calcium content of each solution was determined using compleximetric titration with Eriochrome black-T. The 80 teeth were randomly divided into 4 groups. Each group was incubated in its corresponding solution at 37 degrees C for 96 h. The specimens were weighed again and the calcium content of the four solutions determined. Five samples from each group were randomly chosen, sectioned through the treatment windows, stained with rhodamine-B and viewed under a confocal laser scanning microscope (CLSM). Lesion area (LeA) and average fluorescence (AF) were calculated using Image J software. Total fluorescence (TF) values were obtained by LeA x AF. RESULTS: There was a statistically significant difference between groups in terms of LeA and TF. No statistically significant difference was found between groups in terms of difference in weight. CONCLUSION: Probiotic yogurt extract is effective in reducing demineralisation of enamel under experimental conditions. PMID- 24046826 TI - Haemodynamic response and psychometric test measuring dental anxiety in a spanish population in galicia. AB - PURPOSE: To evaluate haemodynamic changes during dental checkups and preventive treatments and establish the relationship between haemodynamic parameters and psychometric tests. MATERIALS AND METHODS: Seventy-one paediatric patients (39 boys and 32 girls ages 6 to 14 years, mean age 8.04) scheduled to receive dental procedures fulfilled the inclusion criteria for this prospective study. Anxiety was measured at three time points by using the following haemodynamic parameters: heart rate (HR), systolic and diastolic blood pressure (SBP and DBP) and oxygen saturation (SaO2). The Children's Fear Survey Schedule Dental Subscale (CFSS-DS) and the Facial Image Scale (FIS) were used as psychometric tests before and after child attendance, respectively. RESULTS: Variations in HR and BP during dental procedures were statistically significant while SaO2 values were not. The highest mean HR, SBP and DBP values were obtained during dental procedures, while the lowest SBP and DBP were recorded at baseline. HR and BP changes (r = 0.32, P < 0.01) were statistically correlated. The most anxious children based on both CFSS DS and FIS scales also had the highest mean HR. Changes in BP and oxygen saturation parameters were found to have no relationship with anxiety groups in either scale. CONCLUSIONS: Dental checkups and preventive treatments cause significant changes in HR and BP. However, the CFSS-DS questionnaire does not adequately predict these changes. PMID- 24046827 TI - Increased expression of CIP2A in cholangiocarcinoma and correlation with poor prognosis. AB - BACKGROUND/AIMS: To explore the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A) in human cholangiocarcinoma tissues and adjacent non cancerous normal bile duct tissues, and to investigate the clinicopathological signinficance of the CIP2A protein in cholangiocarcinoma patients. METHODOLOGY: Immunohistochemical staining was used to detect the expression of CIP2A protein in 57 cases (35 men and 22 women) of cholangiocarcinoma samples and 23 cases of para-cancerous normal bile duct samples. The results were analyzed with clinicopathological patameters and overall median survival time. RESULTS: The positive rate of CIP2A protein expression in cholangiocarcinoma tissues was significantly higher than para-cancerous normal bile duct tissues. The expression of CIP2A was found to be not correlated with age, gender, smoking, grading, staging, lymph node metastasis, tumor site and hepatitis B virus (HBV) (p>0.05). Kaplan-Meier survival analysis showed that the overall survival time in patients with positive expression of CIP2A protein were shorter than in patients with negative expression of CIP2A (long rank=5.180, p=0.023). COX regression analysis implied that expression of CIP2A protein was an independent prognostic factor for cholangiocarcinoma patients (p<0.05). CONCLUSIONS: CIP2A is overexpressed in human cholangiocarcinoma tissues, and overexpression of CIP2A correlates with poor prognosis. CIP2A expression may be a potential marker for biological malignancy. PMID- 24046828 TI - Clinicopathological features of early distal cholangiocarcinoma. AB - BACKGROUND/AIM: The purpose of this study was to evaluate the clinicopathological features of early distal cholangiocarcinoma compared with advanced tumors. METHODOLOGY: This was a retrospective study of 45 patients who underwent resection for distal cholangiocarcinoma. There were 17 cases of early and 28 cases of advanced tumors. Data on demographic and clinical features, surgical procedures, and pathological diagnoses were collected retrospectively. RESULTS: Preoperative mean serum levels of bilirubin, alkaline phosphatase, and gamma glutamyltransferase were statistically different between the early and advanced groups. There were no significant differences in the diameter of the common hepatic duct between groups, and there were significant differences in all tests but intraductal ultrasonography (IDUS) in tumor detection, meaning that IDUS is a very useful modality for detecting early and advanced cancer although early cancer is difficult to detect using other modalities. CONCLUSIONS: We believe that early cancer detection will generally lead to better prognosis. Further studies are needed, and efforts should continue to identify patients with suspicious findings. PMID- 24046829 TI - The use of radial endosonography findings in the prediction of cholangiocarcinoma in cases with distal bile duct obstructions. AB - BACKGROUND/AIMS: We retrospectively collected the data of radial endosonographic (EUS) imaging findings of the patients with the distal bile duct obstructions due to different benign and malignant conditions. We aimed to assess and analyze the EUS findings in the distal bile duct obstruction which can predict or detect the existence of cholangiocarcinoma originating from the distal bile duct wall. METHODOLOGY: We gathered the data of 192 cases with distal biliary stricture due to various causes which all were diagnosed. RESULTS: With EUS, The sensitivity and specificity for diagnosis of cholangiocarcinoma in lesions were respectively as following: Firstly, small hypoechoic mass which interrupts to see lumen and choledoch wall with total occlusion at distal choledoch: 75.8%, 88.1%. Secondly, hypoechoic and irregular thickening than surrounding regions at distal choledoch wall: 68.1%, 87.3%. Thirdly, appearance of lumen prompt termination at distal choledoch: 57.1%, 87.6%. Lastly, appearance where lumen narrows short segment: 13.6 %, 59.3 %. CONCLUSIONS: EUS findings including hypoechoic mass appearance completely occluding the lumen or heterogeneously increased irregular wall thickness in the distal bile duct were found to be highly predictive and sensitive for detecting malignancy originating from the distal bile duct. PMID- 24046830 TI - Diffusion-weighted MRI for differential diagnosis in gallbladder lesions with special reference to ADC cut-off values. AB - BACKGROUND/AIMS: We retrospectively evaluated the usefulness of the apparent diffusion coefficient (ADC) measured from high-b value diffusion-weighted imaging (DWI) of magnetic resonance imaging for the differential diagnosis of gallbladder lesions among patients with cancer, adenoma and inflammatory disease. METHODOLOGY: Forty patients with gallbladder lesions (22 patients with cancer, 7 patients with adenoma, and 11 patients with inflammatory disease) were enrolled in this study. All patients underwent high-b value DWI, and the ADC value was measured. The cut-off values were determined by receiver operating characteristic analysis. RESULTS: The ADC values of gallbladder cancers (1.31+/-0.57x10-3 mm2/s) were smallest and those of adenomas (2.66+/-0.43x10-3 mm2/s) were largest among the diseases. Inflammatory diseases took a middle position (1.97+/-0.54x10-3 mm2/s) between them. There were significant differences among the 3 groups of diseases (p<0.05). The cut-off value within ADC values to discriminate cancer from the other diseases was 1.64x10-3 mm2/s (accuracy 87.5%), and that to discriminate adenoma was 2.25x10-3 mm2/s (accuracy 90.0%). CONCLUSIONS: The ADC values measured from high-b value DWI would be useful for the differential diagnosis of gallbladder lesions. PMID- 24046831 TI - Sphincter-preserving surgery for rectal cancer: a population-based study in Taiwan. AB - BACKGROUND/AIMS: Sphincter-preserving surgery (SPS) has been considered a surrogate for surgical quality for rectal cancer. This study aims to assess its rate for rectal cancer between centers and over time in Taiwan. METHODOLOGY: Data from 1997 to 2006 on patients undergoing sphincter-preserving surgery (anterior resection or AR) and proctectomy with colostomy (abdominoperineal resection or APR) were extracted from a national health insurance database. Hierarchical logistic regression was used to identify independent factors associated with SPS. RESULTS: Data on 19,919 patients were analyzed. Among them, 12,164 (61%) received AR and 7,755 (39%) underwent APR at total of 115 centers. Multifactorial analysis revealed higher SPS rates with female gender (p<0.001) and patients paying higher insurance premiums (p=0.005). Higher APR rates were seen in those receiving surgery at metropolitan hospitals (p=0.001) and hospitals outside higher volume regions (Taipei City and North, p?0.005). For hospitals with initial low surgical volumes, significant improvement of SPS rate was found (p<0.001) with increasing volume over the study period. CONCLUSIONS: The disparity due to sphincter loss in rectal cancer between hospitals of various regions and levels narrowed in Taiwan. Characteristics of hospital (level, region, volume) and patient (gender, premium level) influenced SPS rate. PMID- 24046832 TI - Perianal adenocarcinoma associated with anal fistula: a report of 11 cases in a single institution focusing on treatment and literature review. AB - BACKGROUND/AIMS: Perianal adenocarcinoma associated with anal fistula is a rare disease with a poor prognosis. The relatively small number of patients with this disease has led to a lack of any consensus regarding diagnosis and appropriate treatment. The purpose of this study was to present our experience of 11 cases of this disease, and to highlight its clinical features, treatments and outcomes. METHODOLOGY: The patients were divided into three groups according to the modality of treatment. Four patients received surgical resection without preoperative therapy (operation group), 3 patients were treated with radiotherapy prior to surgery (RT group), and 4 were treated with combined chemoradiation therapy prior to surgery (CRT group). RESULTS: The resection stump was pathologically negative for cancer in 6 (85.7%) patients in RT or CRT group, and 3 of 6 are alive with no evidence of disease recurrence. However, the resection stump was negative in only 1 (25%) patient in the operation group. Moreover, among the patients who underwent neoadjuvant RT/CRT and abdominoperineal resection with a cancer-free resection stump, 2 patients with postoperative adjuvant therapy had no recurrence of disease. CONCLUSIONS: Multimodality therapy including neoadjuvant RT or CRT and adjuvant chemotherapy is considered to be effective for treatment of this disease. PMID- 24046833 TI - Long term observation of 367 cases of radical excision with anus preservation by casing anastomosis in low-rectal cancers. AB - BACKGROUND/AIMS: To evaluate the clinical curative effect, feasibility and safety of a newly designed anus-preserving operation in low rectal cancer; a retrospective analysis was carried out in 367 cases of low rectal cancer that underwent anus-preserving operation with casing anastomosis. METHODOLOGY: Postoperative histopathology and Dukes stage were analyzed; 293 (293/367, 79.8%) cases were followed-up, the median time of the follow-up was 5.9 years. RESULTS: Postoperative complications were observed in 20 patients, 13 (4.4%) cases of stoma leak, and 7 (2.4%) cases of stoma stenosis. Normal gastrointestinal function (defecation) occurred in all patients 12-24 weeks of post operation, 1-3 times per day. Local recurrence was 6.1% (18/293). Hepatic and lung metastasis was 14.7% (43/293) and 2.4% (7/293), respectively. The five year survival rate was 68.6%. CONCLUSIONS: The casing anastomosis procedure designed in this study was safety and efficacy for low rectal cancer. With the procedure, anal function could be preserved well, stoma leak was decreased, and the 5-year survival rate was the same as Miles operation. PMID- 24046834 TI - Feasibility of microvascular head and neck reconstruction in the setting of calcified arteriosclerosis of the vascular pedicle. AB - OBJECTIVE To report outcomes in free flap reconstructive surgery in the setting of calcified arteriosclerosis affecting the flap pedicle. DESIGN Retrospective review, including a detailed analysis of medical records, histopathologic findings, and a comprehensive review of the literature. METHODS A total of 1329 consecutive microvascular free tissue transfers were performed by 2 reconstructive surgeons at a university-affiliated tertiary care medical center from January 1, 1996, through December 31, 2011. Clinical notes, operative notes, and pathology reports were systematically reviewed to identify 44 patients (3%) with calcified arteriosclerosis involving the flap vascular pedicle. A comprehensive medical record review was performed for the included patients, detailing patient-related characteristics, flap survival, and incidence of perioperative complications. RESULTS A history of arteriosclerosis was identified preoperatively in 18 patients (41%). Eight patients (18%) were specifically recognized clinically and histologically to have a variant of arteriosclerosis known as Monckeberg medial calcific sclerosis. In total, fibula osteocutaneous free flap was performed in 30 patients, radial forearm in 8 patients, rectus abdominus in 3 patients, latissimus dorsi in 2 patients, and parascapular in 1 patient. Perioperative complications occurred in 17 patients (39%), with the most common being pulmonary (14%) and cardiac (9%). Patient follow-up ranged from 3 to 137 months, with a mean postoperative follow-up of 21 months. The mean length of hospital stay was 12 days. There was a 0% incidence of total flap failure and a 7% incidence of partial flap necrosis. CONCLUSION Although technically challenging, successful microvascular free flap reconstruction can be achieved despite the presence of vascular calcifications affecting the flap vascular pedicle. PMID- 24046835 TI - An interview with Jose Rino Neto. Interview by Adilson Ramos, Gilberto Vilanova Queiroz, Joao Batista de Paiva, Jose Valladares Neto, and Roberto Macoto. PMID- 24046836 TI - Abstracts of the Society for Social Medicine 57th Annual Scientific Meeting. September 11-13, 2013. Brighton, United Kingdom. PMID- 24046837 TI - From the archives. A contribution to the study of apraxia with a review of the literature. PMID- 24046838 TI - CENCALC: a computational tool for conformational entropy calculations from molecular simulations. AB - We present the CENCALC software that has been designed to estimate the conformational entropy of single molecules from extended Molecular Dynamics (MD) simulations in the gas-phase or in solution. CENCALC uses both trajectory coordinates and topology information in order to characterize the conformational states of the molecule of interest by discretizing the time evolution of internal rotations. The implemented entropy methods are based on the mutual information expansion, which is built upon the converged probability density functions of the individual torsion angles, pairs of torsions, triads, and so on. Particularly, the correlation-corrected multibody local approximation selects an optimum cutoff in order to retrieve the maximum amount of genuine correlation from a given MD trajectory. We illustrate these capabilities by carrying out conformational entropy calculations for a decapeptide molecule either in its unbound form or in complex with a metalloprotease enzyme. CENCALC is distributed under the GNU public license at http://sourceforge.net/projects/cencalc/. PMID- 24046839 TI - Building on the BRAIN initiative. PMID- 24046840 TI - Regulatory T cells: distilling regulatory T cell inducers. PMID- 24046841 TI - Abstracts of the EuroSpine Annual Meeting 2013. October 2-4, 2013. Liverpool, United Kingdom. PMID- 24046842 TI - [Abstracts of the 28th Congress of Physical Medicine and Rehabilitation. October 17-19, 2013. Reims, France]. PMID- 24046843 TI - The circle of life. PMID- 24046844 TI - Rape in South Africa - call to action. PMID- 24046845 TI - Carcinoma of the cervix - the hopeless disease. PMID- 24046847 TI - Will the Department of Health and the Minister make the same mistake twice? PMID- 24046846 TI - Child sexual abuse exacerbated by inadequate services. PMID- 24046848 TI - Ebola outbreak in Uganda: what we can and can not see from query trends. PMID- 24046849 TI - Epitomising hope: from poverty to world-class healer. PMID- 24046850 TI - Neglected high-risk groups a top priority in AIDS prevention/treatment. PMID- 24046851 TI - RWOPS abuse 'eroding ethical standards of juniors'. PMID- 24046852 TI - RWOPS abuse could cost, or even ruin, offenders. PMID- 24046853 TI - Social disparity potentially revealed in parental perceptions of HPV vaccine. PMID- 24046854 TI - Conserved polymer holds potential for broad-spectrum vaccine. PMID- 24046855 TI - Drugs prohibition is criminals' gain, neuroscience's loss. PMID- 24046856 TI - Catherine Tallon-Baudry. PMID- 24046857 TI - Stand-alones suffering. Small hospitals finding fewer options. PMID- 24046858 TI - The rural route. Hospitals in underserved areas taking different roads to recruit, retain physicians. PMID- 24046859 TI - Low-density lipoprotein receptors in liver: old acquaintances and a newcomer. AB - The lipoprotein receptors low-density lipoprotein receptor (LDLR), the low density lipoprotein receptor-related protein 1 (LRP1) and megalin/LRP2 share characteristic structural elements. In addition to their well-known roles in endocytosis of lipoproteins and systemic lipid homeostasis, it has been established that LRP1 mediates the endocytotic clearance of a multitude of extracellular ligands and regulates diverse signaling processes such as growth factor signaling, inflammatory signaling pathways, apoptosis, and phagocytosis in liver. Here, possible functions of LRP1 expression in hepatocytes and non parenchymal cells in healthy and injured liver are discussed. Recent studies indicate the expression of megalin (LRP2) by hepatic stellate cells, myofibroblasts and Kupffer cells and hypothesize that LRP2 might represent another potential regulator of hepatic inflammatory processes. These observations provide the experimental framework for the systematic and dynamic analysis of the LDLR family during chronic liver injury and fibrogenesis. PMID- 24046860 TI - Fatty acids induce leukotriene C4 synthesis in macrophages in a fatty acid binding protein-dependent manner. AB - Obesity results in increased macrophage recruitment to adipose tissue that promotes a chronic low-grade inflammatory state linked to increased fatty acid efflux from adipocytes. Activated macrophages produce a variety of pro inflammatory lipids such as leukotriene C4 (LTC4) and 5-, 12-, and 15 hydroxyeicosatetraenoic acid (HETE) suggesting the hypothesis that fatty acids may stimulate eicosanoid synthesis. To assess if eicosanoid production increases with obesity, adipose tissue of leptin deficient ob/ob mice was analyzed. In ob/ob mice, LTC4 and 12-HETE levels increased in the visceral (but not subcutaneous) adipose depot while the 5-HETE levels decreased and 15-HETE abundance was unchanged. Since macrophages produce the majority of inflammatory molecules in adipose tissue, treatment of RAW264.7 or primary peritoneal macrophages with free fatty acids led to increased secretion of LTC4 and 5-HETE, but not 12- or 15-HETE. Fatty acid binding proteins (FABPs) facilitate the intracellular trafficking of fatty acids and other hydrophobic ligands and in vitro stabilize the LTC4 precursor leukotriene A4 (LTA4) from non-enzymatic hydrolysis. Consistent with a role for FABPs in LTC4 synthesis, treatment of macrophages with HTS01037, a specific FABP inhibitor, resulted in a marked decrease in both basal and fatty acid-stimulated LTC4 secretion but no change in 5-HETE production or 5-lipoxygenase expression. These results indicate that the products of adipocyte lipolysis may stimulate the 5-lipoxygenase pathway leading to FABP-dependent production of LTC4 and contribute to the insulin resistant state. PMID- 24046861 TI - Malfunctioning of adipocytes in obesity is linked to quantitative surfaceome changes. AB - Increased triglyceride accumulation in adipocytes caused by a misbalance between energy intake and energy consumption, results in increased adipocyte size, excess adipose tissue, increased body weight and ultimately, obesity. It is well established that enlarged adipocytes exhibit malfunctions that contribute to whole body insulin resistance, a key factor for the development of type 2 diabetes. However, the underlying molecular cause for dysfunctional adipocyte behavior and signaling is poorly understood. Since the adipocyte cell surface proteome, or surfaceome, represents the cellular signaling gateway to the microenvironment, we studied the contribution of this subproteome to adipocyte malfunctions in obesity. By using the chemoproteomic Cell Surface Capture (CSC) technology, we established surfaceome maps of primary adipocytes derived from different mouse models for metabolic disorders. Relative quantitative comparison between these surfaceome maps revealed a set of cell surface glycoproteins with modulated location-specific abundance levels. RNAi mediated targeting of a subset of the detected obesity modulated cell surface glycoproteins in an in vitro model system provided functional evidence for their role in adiponectin secretion and the lipolytic activity of adipocytes. Thus, we conclude that the identified cell surface glycoproteins which exhibit obesity induced abundance changes and impact adipocyte function at the same time contribute to adipocyte malfunction in obesity. The regulation of their concerted activities could improve adipocyte function in obesity. PMID- 24046863 TI - Cholesterol-mediated membrane surface area dynamics in neuroendocrine cells. AB - How cholesterol, a key membrane constituent, affects membrane surface area dynamics in secretory cells is unclear. Using methyl-beta-cyclodextrin (MbetaCD) to deplete cholesterol, we imaged melanotrophs from male Wistar rats in real-time and monitored membrane capacitance (C(m)), fluctuations of which reflect exocytosis and endocytosis. Treatment with MbetaCD reduced cellular cholesterol and caused a dose-dependent attenuation of the Ca(2+)-evoked increase in C(m) (IC50 = 5.3 mM) vs. untreated cells. Cytosol dialysis of MbetaCD enhanced the attenuation of C(m) increase (IC50 = 3.3 mM), suggesting cholesterol depletion at intracellular membrane sites was involved in attenuating exocytosis. Acute extracellular application of MbetaCD resulted in an immediate C(m) decline, which correlated well with the cellular surface area decrease, indicating the involvement of cholesterol in the regulation of membrane surface area dynamics. This decline in C(m) was three-fold slower than MbetaCD-mediated fluorescent cholesterol decay, implying that exocytosis is the likely physiological means for plasma membrane cholesterol replenishment. MbetaCD had no effect on the specific C(m) and the blockade of endocytosis by Dyngo 4a, confirmed by inhibition of dextran uptake, also had no effect on the time-course of MbetaCD-induced C(m) decline. Thus acute exposure to MbetaCD evokes a C(m) decline linked to the removal of membrane cholesterol, which cannot be compensated for by exocytosis. We propose that the primary contribution of cholesterol to surface area dynamics is via its role in regulated exocytosis. PMID- 24046862 TI - Cellular senescence involves an intracrine prostaglandin E2 pathway in human fibroblasts. AB - Cyclooxygenase 2 and release of prostaglandin E2 are involved in many responses including inflammation and are upregulated during cellular senescence. However, little is known about the role of lipid inflammatory mediators in senescence. Here, we investigated the mechanism by which the COX-2/PGE2 axis induces senescence. Using the NS398 specific inhibitor of COX-2, we provide evidence that reactive oxygen species by-produced by the COX-2 enzymatic activity are negligible in front of the total senescence-associated oxidative stress. We therefore investigated the role of PGE2 by invalidating the PGE2 synthases downstream of COX-2, or the specific PGE2 receptors, or by applying PGE2 or specific agonists or antagonists. We evaluated the effect on senescence by evaluating the senescence-associated proliferation arrest, the percentage of senescence-associated beta-galactosidase-positive cells, and the expression of senescent molecular markers such as IL-6 and MCP1. We show that PGE2 acting on its EP specific receptors is able to induce both the onset of senescence and the maintenance of the phenotype. It did so only when the PGE2/lactate transporter activity was enhanced, indicating that PGE2 acts on senescence more via the pool of intracellular EP receptors than via those localized at the cell surface. Treatment with agonists, antagonists and silencing of the EP receptors by siRNA revealed that EP3 was the most involved in transducing the intracrine effects of PGE2. Immunofluorescence experiments confirmed that EP3 was more localized in the cytoplasm than at the cell surface. Taken together, these results suggest that COX-2 contributes to the establishment and maintenance of senescence of normal human fibroblasts via an independent-ROS and a dependent-PGE2/EPs intracrine pathway. PMID- 24046864 TI - Structural identities of four glycosylated lipids in the oral bacterium Streptococcus mutans UA159. AB - The cariogenic bacterium Streptococcus mutans is an important dental pathogen that forms biofilms on tooth surfaces, which provide a protective niche for the bacterium where it secretes organic acids leading to the demineralization of tooth enamel. Lipids, especially glycolipids are likely to be key components of these biofilm matrices. The UA159 strain of S. mutans was among the earliest microorganisms to have its genome sequenced. While the lipids of other S. mutans strains have been identified and characterized, lipid analyses of UA159 have been limited to a few studies on its fatty acids. Here we report the structures of the four major glycolipids from stationary-phase S. mutans UA159 cells grown in standing cultures. These were shown to be monoglucosyldiacylglycerol (MGDAG), diglucosyldiacylglycerol (DGDAG), diglucosylmonoacylglycerol (DGMAG) and, glycerophosphoryldiglucosyldiacylglycerol (GPDGDAG). The structures were determined by high performance thin-layer chromatography, mass spectrometry and nuclear magnetic resonance spectroscopy. The glycolipids were identified by accurate, high resolution, and tandem mass spectrometry. The identities of the sugar units in the glycolipids were determined by a novel and highly efficient NMR method. All sugars were shown to have alpha-glycosidic linkages and DGMAG was shown to be acylated in the sn-1 position by NMR. This is the first observation of unsubstituted DGMAG in any organism and the first mass spectrometry data for GPDGDAG. PMID- 24046865 TI - The calcium-stimulated lipid A 3-O deacylase from Rhizobium etli is not essential for plant nodulation. AB - The lipid A component of lipopolysaccharide from the nitrogen-fixing plant endosymbiont, Rhizobium etli, is structurally very different from that found in most enteric bacteria. The lipid A from free-living R. etli is structurally heterogeneous and exists as a mixture of species which are either pentaacylated or tetraacylated. In contrast, the lipid A from R. etli bacteroids is reported to consist exclusively of tetraacylated lipid A species. The tetraacylated lipid A species in both cases lack a beta-hydroxymyristoyl chain at the 3-position of lipid A. Here, we show that the lipid A modification enzyme responsible for 3-O deacylation in R. etli is a homolog of the PagL protein originally described in Salmonella enterica sv. typhimurium. In contrast to the PagL proteins described from other species, R. etli PagL displays a calcium dependency. To determine the importance of the lipid A modification catalyzed by PagL, we isolated and characterized a R. etli mutant deficient in the pagL gene. Mass spectrometric analysis confirmed that the mutant strain was exclusively tetraacylated and radiochemical analysis revealed that 3-O deacylase activity was absent in membranes prepared from the mutant. The R. etli mutant was not impaired in its ability to form nitrogen-fixing nodules on Phaseolus vulgaris but it displayed slower nodulation kinetics relative to the wild-type strain. The lipid A modification catalyzed by R. etli PagL, therefore, is not required for nodulation but may play other roles such as protecting bacterial endosymbionts from plant immune responses during infection. PMID- 24046866 TI - Inhibitory effects of tannic acid on fatty acid synthase and 3T3-L1 preadipocyte. AB - Tannic acid is a hydrolyzable tannin that exists in many widespread edible plants with a variety of biological activities. In this study, we found that tannic acid potently inhibited the activity of fatty acid synthase (FAS) in a concentration dependent manner with a half-inhibitory concentration value (IC50) of 0.14 microM. The inhibition kinetic results showed that the inhibition of FAS by tannic acid was mixed competitive and noncompetitive manner with respect to acetyl-CoA and malonyl-CoA, but uncompetitive to NADPH. Tannic acid prevented the differentiation of 3T3-L1 pre-adipocytes, and thus repressed intracellular lipid accumulation. In the meantime, tannic acid decreased the expression of FAS and down-regulated the mRNA level of FAS and PPARgamma during adipocyte differentiation. Further studies showed that the inhibitory effect of tannic acid did not relate to FAS non-specific sedimentation. Since FAS was believed to be a therapeutic target of obesity, these findings suggested that tannic acid was considered having potential in the prevention of obesity. PMID- 24046867 TI - Alpha-MSH signalling via melanocortin 5 receptor promotes lipolysis and impairs re-esterification in adipocytes. AB - The melanocortin system has a clear effect on the mobilisation of stored lipids in adipocytes. The aim of the current study was to investigate the role of melanocortin 5 receptor (MC5R) on alpha-melanocyte-stimulating hormone (alpha MSH)-induced lipolysis in 3T3-L1 adipocytes. To this end, MC5R expression was decreased by small interfering RNA (siRNA), which significantly impaired the alpha-MSH stimulation of lipolysis, as determined by glycerol and nonesterified fatty-acid (NEFA) quantification. The functional role of alpha-MSH/MC5R on triglyceride (TG) hydrolysis was mediated by hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), perilipin 1 (PLIN1) and acetyl-CoA carboxylase (ACC). Immunofluorescence microscopy revealed that phosphorylated HSL clearly surrounded lipid droplets in alpha-MSH-stimulated adipocytes, whereas PLIN1 left the immediate periphery of lipids. These observations were lost when the expression of MC5R was suppressed. In 3T3-L1 adipocytes, alpha-MSH-activated MC5R signals through the cAMP/PKA and MAPK/ERK1/2 pathways. PKA was fundamental for HSL and PLIN1 activation and lipolysis regulation. ERK1/2 inhibition strongly interfered with the release of NEFAs but not glycerol. In addition, the intracellular TG levels, which were decreased after MC5R activation, were restored after ERK1/2 inhibition, indicating that these kinases are involved in NEFA re-esterification rather than lipolysis regulation. This notion is also supported by the observation that the alpha-MSH-mediated activation of phosphoenolpyruvate carboxykinase (PEPCK) was abolished in the presence of ERK1/2 inhibitors. Altogether, these results indicate that alpha-MSH-activated MC5R regulates two tightly coupled pathways in adipocytes: lipolysis and re esterification. The global effect is a decrease in adipocyte fat mass, which is important for strategies to ameliorate obesity. PMID- 24046868 TI - Altered hepatic retinyl ester concentration and acyl composition in response to alcohol consumption. AB - Retinoids (vitamin A and its metabolites) are essential micronutrients that regulate many cellular processes. Greater than 70% of the body's retinoid reserves are stored in the liver as retinyl ester (RE). Chronic alcohol consumption induces depletion of hepatic retinoid stores, and the extent of this has been correlated with advancing stages of alcoholic liver disease. The goal of this study was to analyze the mechanisms responsible for depletion of hepatic RE stores by alcohol consumption A change in the fatty-acyl composition of RE in alcohol-fed mice was observed within two weeks after the start of alcohol consumption. Specifically, alcohol-feeding was associated with a significant decline in hepatic retinyl palmitate levels; however, total RE levels were maintained by a compensatory increase in levels of usually minor RE species, particularly retinyl oleate. Our data suggests that alcohol feeding initially stimulates a futile cycle of RE hydrolysis and synthesis, and that the change in RE acyl composition is associated with a change in the acyl composition of hepatic phosphatidylcholine. The alcohol-induced change in RE acyl composition was specific to the liver, and was not seen in lung or white adipose tissue. This shift in hepatic RE fatty acyl composition is a sensitive indicator of alcohol consumption and may be an early biomarker for events associated with the development of alcoholic liver disease. PMID- 24046869 TI - Apolipoprotein M promotes mobilization of cellular cholesterol in vivo. AB - OBJECTIVE: The HDL associated apolipoprotein M (apoM) protects against experimental atherosclerosis but the mechanism is unknown. ApoM increases prebeta HDL formation. We explored whether plasma apoM affects mobilization of cholesterol from peripheral cells in mice. METHODS AND RESULTS: ApoM-enriched HDL from apoM-transgenic mice increased the in vitro efflux of 3H-cholesterol from macrophages by 24 +/- 3% (p < 0.05) as compared with HDL from wild type (WT) mice, thus confirming previous findings. However, apoM-free HDL was not poorer than that of WT HDL to mobilize 3H-cholesterol. 3H-cholesterol-labeled foam cells were implanted in the peritoneal cavity of apoM-/-, WT and apoM-transgenic mice to assess the mobilization of cholesterol from foam cells in vivo and subsequent excretion into feces. The results showed a statistically non-significant trend towards increased mobilization of cellular cholesterol to plasma with increasing plasma apoM. However, the apoM-genotype did not affect the excretion of 3H cholesterol in feces. Nevertheless, when apoM-/-, apoM-transgenic and WT mice received a constant intravenous infusion of 13C2-cholesterol/intralipid for 5 h, the rate of enrichment of blood free cholesterol with free 13C2-cholesterol was significantly lower (consistent with an increase in flux of unlabeled free cholesterol into the plasma) in the apoM-transgenic (3.0 +/- 0.9 per thousand/h) as compared to WT (5.7 +/- 0.9 per thousand/h, p < 0.05) and apoM-/- (6.5 +/- 0.6 per thousand/h, p < 0.01) mice. CONCLUSION: The present data indicate that the plasma apoM levels modulate the ability of plasma to mobilize cellular cholesterol, whereas apoM has no major effect on the excretion of cholesterol into feces. PMID- 24046870 TI - Partial deletion of beta9 loop in pancreatic lipase-related protein 2 reduces enzyme activity with a larger effect on long acyl chain substrates. AB - Structural studies on pancreatic lipase have revealed a complex architecture of surface loops surrounding the enzyme active site and potentially involved in interactions with lipids. Two of them, the lid and beta loop, expose a large hydrophobic surface and are considered as acyl chain binding sites based on their interaction with an alkyl phosphonate inhibitor. While the role of the lid in substrate recognition and selectivity has been extensively studied, the implication of beta9 loop in acyl chain stabilization remained hypothetical. The characterization of an enzyme with a natural deletion of the lid, guinea pig pancreatic lipase-related protein 2 (GPLRP2), suggests however an essential contribution of the beta9 loop in the stabilization of the acyl enzyme intermediate formed during the lipolysis reaction. A GPLRP2 mutant with a seven residue deletion of beta9 loop (GPLRP2-deltabeta9) was produced and its enzyme activity was measured using various substrates (triglycerides, monoglycerides, galactolipids, phospholipids, vinyl esters) with short, medium and long acyl chains. Whatever the substrate tested, GPLRP2-deltabeta9 activity is drastically reduced compared to that of wild-type GPLRP2 and this effect is more pronounced as the length of substrate acyl chain increases. Changes in relative substrate selectivity and stereoselectivity remained however weak. The deletion within beta9 loop has also a negative effect on the rate of enzyme inhibition by alkyl phosphonates. All these findings indicate that the reduced enzyme turnover observed with GPLRP2-deltabeta9 results from a weaker stabilization of the acyl enzyme intermediate due to a loss of hydrophobic interactions. PMID- 24046871 TI - Molecular lipidomics of exosomes released by PC-3 prostate cancer cells. AB - The molecular lipid composition of exosomes is largely unknown. In this study, sophisticated shotgun and targeted molecular lipidomic assays were performed for in-depth analysis of the lipidomes of the metastatic prostate cancer cell line, PC-3, and their released exosomes. This study, based in the quantification of approximately 280 molecular lipid species, provides the most extensive lipid analysis of cells and exosomes to date. Interestingly, major differences were found in the lipid composition of exosomes compared to parent cells. Exosomes show a remarkable enrichment of distinct lipids, demonstrating an extraordinary discrimination of lipids sorted into these microvesicles. In particular, exosomes are highly enriched in glycosphingolipids, sphingomyelin, cholesterol, and phosphatidylserine (mol% of total lipids). Furthermore, lipid species, even of classes not enriched in exosomes, were selectively included in exosomes. Finally, it was found that there is an 8.4-fold enrichment of lipids per mg of protein in exosomes. The detailed lipid composition provided in this study may be useful to understand the mechanism of exosome formation, release and function. Several of the lipids enriched in exosomes could potentially be used as cancer biomarkers. PMID- 24046872 TI - Rumble over jailhouse healthcare. As states broaden outsourcing to private vendors, critics question quality of care and cost savings. AB - The trend for states to outsource prison healthcare has met opposition from inmate advocates and legal aid groups. They fear quality of care will suffer, while others debate whether outsourcing care saves any money. Corizon, the largest U.S. private prison healthcare provider, says it definitely delivers savings. "We are the model because we've been doing capitated rates since we've been in business. Our cost per individual is significantly less than in the 'free world,' "says Corizon CEO Rich Hallworth. PMID- 24046873 TI - [Current status and future of tomosynthesis: possibilities in orthopedics]. PMID- 24046874 TI - [Basis and image characteristics of tomosynthesis]. PMID- 24046875 TI - Camouflaged or tanned: plasticity in freshwater snail pigmentation. AB - By having phenotypically plastic traits, many organisms optimize their fitness in response to fluctuating threats. Freshwater snails with translucent shells, e.g. snails from the Radix genus, differ considerably in their mantle pigmentation patterns, with snails from the same water body ranging from being completely dark pigmented to having only a few dark patterns. These pigmentation differences have previously been suggested to be genetically fixed, but we propose that this polymorphism is owing to phenotypic plasticity in response to a fluctuating environment. Hence, we here aimed to assess whether common stressors, including ultraviolet radiation (UVR) and predation, induce a plastic response in mantle pigmentation patterns of Radix balthica. We show, in contrast to previous studies, that snails are plastic in their expression of mantle pigmentation in response to changes in UVR and predator threats, i.e. differences among populations are not genetically fixed. When exposed to cues from visually hunting fish, R. balthica increased the proportion of their dark pigmentation, suggesting a crypsis strategy. Snails increased their pigmentation even further in response to UVR, but this also led to a reduction in pattern complexity. Furthermore, when exposed to UVR and fish simultaneously, snails responded in the same way as in the UVR treatment, suggesting a trade-off between photoprotection and crypsis. PMID- 24046876 TI - The molecular signal for the adaptation to cold temperature during early life on Earth. AB - Several lines of evidence such as the basal location of thermophilic lineages in large-scale phylogenetic trees and the ancestral sequence reconstruction of single enzymes or large protein concatenations support the conclusion that the ancestors of the bacterial and archaeal domains were thermophilic organisms which were adapted to hot environments during the early stages of the Earth. A parsimonious reasoning would therefore suggest that the last universal common ancestor (LUCA) was also thermophilic. Various authors have used branch-wise non homogeneous evolutionary models that better capture the variation of molecular compositions among lineages to accurately reconstruct the ancestral G + C contents of ribosomal RNAs and the ancestral amino acid composition of highly conserved proteins. They confirmed the thermophilic nature of the ancestors of Bacteria and Archaea but concluded that LUCA, their last common ancestor, was a mesophilic organism having a moderate optimal growth temperature. In this letter, we investigate the unknown nature of the phylogenetic signal that informs ancestral sequence reconstruction to support this non-parsimonious scenario. We find that rate variation across sites of molecular sequences provides information at different time scales by recording the oldest adaptation to temperature in slow-evolving regions and subsequent adaptations in fast-evolving ones. PMID- 24046877 TI - Prenatal exposure to testosterone impairs oxidative damage repair efficiency in the domestic chicken (Gallus gallus). AB - Elevated levels of maternal androgens in avian eggs affect numerous traits, including oxidative stress. However, current studies disagree as to whether prenatal androgen exposure enhances or ameliorates oxidative stress. Here, we tested how prenatal testosterone exposure affects oxidative stress in female domestic chickens (Gallus gallus) during the known oxidative challenge of an acute stressor. Prior to incubation, eggs were either injected with an oil vehicle or 5 ng testosterone. At either 17 or 18 days post-hatch, several oxidative stress markers were assessed from blood taken before and after a 20 min acute stressor, as well as following a 25 min recovery from the stressor. We found that, regardless of yolk treatment, during both stress and recovery all individuals were in a state of oxidative stress, with elevated levels of oxidative damage markers accompanied by a reduced total antioxidant capacity. In addition, testosterone-exposed individuals exhibited poorer DNA damage repair efficiencies in comparison with control individuals. Our work suggests that while yolk androgens do not alter oxidative stress directly, they may impair mechanisms of oxidative damage repair. PMID- 24046878 TI - Warmer ambient temperatures depress liver function in a mammalian herbivore. AB - Diet selection in mammalian herbivores is thought to be mainly influenced by intrinsic factors such as nutrients and plant secondary compounds, yet extrinsic factors like ambient temperature may also play a role. In particular, warmer ambient temperatures could enhance the toxicity of plant defence compounds through decreased liver metabolism of herbivores. Temperature-dependent toxicity has been documented in pharmacology and agriculture science but not in wild mammalian herbivores. Here, we investigated how ambient temperature affects liver metabolism in the desert woodrat, Neotoma lepida. Woodrats (n = 21) were acclimated for 30 days to two ambient temperatures (cool = 21 degrees C, warm = 29 degrees C). In a second experiment, the temperature exposure was reduced to 3.5 h. After temperature treatments, animals were given a hypnotic agent and clearance time of the agent was estimated from the duration of the hypnotic state. The average clearance time of the agent in the long acclimation experiment was 45% longer for animals acclimated to 29 degrees C compared with 21 degrees C. Similarly, after the short exposure experiment, woodrats at 29 degrees C had clearance times 26% longer compared with 21 degrees C. Our results are consistent with the hypothesis that liver function is reduced at warmer environmental temperatures and may provide a physiological mechanism through which climate change affects herbivorous mammals. PMID- 24046879 TI - Special issue in honor of John W. Griffin. PMID- 24046881 TI - Medicaid program; state disproportionate share hospital allotment reductions. Final rule. AB - The statute, as amended by the Affordable Care Act, requires aggregate reductions to state Medicaid Disproportionate Share Hospital (DSH) allotments annually from fiscal year (FY) 2014 through FY 2020. This final rule delineates a methodology to implement the annual reductions for FY 2014 and FY 2015. The rule also includes additional DSH reporting requirements for use in implementing the DSH health reform methodology. PMID- 24046882 TI - Medicare determinations and income-related monthly adjustment amounts to Medicare Part B premiums; conforming changes to regulations. Interim final rule with request for comments. AB - We are modifying our regulations regarding Medicare Part B income-related monthly adjustment amounts (IRMAA) in order to conform to changes made to the Social Security Act (Act) by the Affordable Care Act. This rule freezes the modified adjusted gross income threshold and ranges from 2011 through 2019 and removes the requirement that beneficiaries consent to our release of Internal Revenue Service (IRS) information to the U.S. Department of Health and Human Services (HHS) for the purpose of adjudicating any appeal of an IRMAA to the Part B premium subsidy. We are also removing provisions that phased in IRMAA between 2007 and 2009 and updating a citation to reflect the transfer of authority for hearing appeals under Title XVIII of the Act from the Social Security Administration to HHS. PMID- 24046883 TI - RP summary: recommended practices for a safe environment of care. PMID- 24046884 TI - Evidence for practice. Evidence appraisal of Chen CF, Han CL, Kan CP, Chen SG, Hung PW. Effect of surgical site infections with waterless and traditional hand scrubbing protocols on bacterial growth. Am J Infect Control. 2012;40(4):e15-e17. PMID- 24046885 TI - [Application of translational research to drug discovery and development]. PMID- 24046886 TI - [Reductions of artifacts by metals in tomosynthesis and its clinical application]. PMID- 24046887 TI - [Dawn of cutting-edge therapy for patients with hearing disorder]. PMID- 24046888 TI - [Linda Morneault: pioneer in neonatology and neonatal nursing]. PMID- 24046889 TI - [Pap test]. PMID- 24046890 TI - [Bachelor nursing education: formidable economic leverage]. PMID- 24046892 TI - [Improving hand hygiene]. PMID- 24046891 TI - [Immigrant care]. PMID- 24046893 TI - [Breast feeding in the era of tablets]. PMID- 24046894 TI - [Professional development groups]. PMID- 24046895 TI - [Behavioral and psychological symptoms on dementia. What do we know?]. PMID- 24046896 TI - [Venous leg ulcers. Recognizing atherosclerosis]. PMID- 24046897 TI - [The link between obesity and ADHD]. PMID- 24046898 TI - [Propofol infusion syndrome. Diagnosis and clinical surveillance]. PMID- 24046899 TI - [Zoonoses in Quebec]. PMID- 24046900 TI - [Motorcycle accident injuries. Because there is more than just the head....]. PMID- 24046901 TI - [Rotigotine. One patch, two targets!]. PMID- 24046902 TI - [Chronicles of a nurse in Ethiopia]. PMID- 24046903 TI - In vitro degradation of poly (D, L-lactide-co-glycolide) nanoparticles loaded with linamarin. AB - Linamarin-loaded poly (lactide-co-glycolide) (PLGA) nanoparticles (NPs) were prepared by the double emulsion solvent evaporation technique. The formulated PLGA (50:50) and PLGA (85:15) NPs were spherically shaped, having an average particle size < 190 nm, drug entrapment efficiency (50-52%) and zeta potentials ranging from -25 to -30 mV. Interestingly, all formulated PLGA NPs exhibited a controlled biphasic release profile. Polymer degradation was investigated in the current research to determine the major degradation products and then the polymer biocompatibility as well as safety. The PLGA NPs degradation behaviour was investigated by measuring water uptake, mass loss, change of pH of the degradation medium, morphological changes, and lactic and glycolic acid concentrations. Gravimetrical methods, pH meter, scanning electron microscope and high-performance liquid chromatography were employed, respectively. PLGA (50:50) NPs were found to degrade faster than PLGA (85:15) NPs. With regard to water uptake, mass loss and pH change, the degradation behaviour of PLGA (50:50) NPs was significantly (rho < 0.05) different from that of PLGA (85:15) NPs. A complete degradation of PLGA (50:50) NPs was achieved after 102 days, whereas, only about 60% of PLGA (85:15) NPs were degraded within the same period. Complete degradation and release of the degradation products naturally by the body ensures safety of the delivery carrier. PMID- 24046904 TI - Spectroscopic and microscopic analyses of rod-shaped gold nanoparticles interacting with single-stranded DNA oligonucleotides. AB - The application of rod-shaped gold nanoparticles as probes and carriers in biological systems have recently attracted great interest. UV-vis spectroscopy, circular dichroism, Fourier transform infrared spectroscopy, scanning electron microscopy and atomic force microscopy were used to study optical and structural properties of rod-shaped gold nanoparticles when interacting with DNA oligomers in phosphate sodium salt buffer. The morphological transformation process of rod shaped gold nanoparticles resulting from the interaction with single-stranded DNA (ssDNA) showed the role of hexadecyltrimethylammonium bromide (CTAB) in nanostructures as the main interacting agent. The obtained results confirmed that the CTAB coat of rod-shaped gold nanoparticles have powerful positive charges for conjugations with surface negative charges of phosphate groups on ssDNA oligomers. The CTAB also inhibit the formation of covalent sulphide bonds between the gold core of rod-shaped nanoparticles and alkanethiol oligonucleotides. The authors found that when the nanorods were exposed to ssDNA oligonucleotides, the gold nanorods changed their shapes and sizes, and exposed some microscopic malformations which could be used in the development of colorimetric assays of nucleic acids. PMID- 24046905 TI - Predicting the fluorescent enhancement rate by gold and silver nanospheres using finite-difference time-domain analysis. AB - Metal-induced fluorescence enhancement (MIFE) is a promising strategy for increasing the sensitivity of fluorophores used in biological sensors. This study uses the finite-difference time-domain technique to predict the fluorescent enhancement rate of a fluorophore molecule in close proximity to a gold or silver spherical nanoparticle. By considering commercially available fluorescent dyes the computed results are compared with the published experimental data. The results show that MIFE is a complex coupling process between the fluorophore molecule and the metal nanoparticle. Nevertheless using computational electromagnetic techniques to perform calculations it is possible to calculate, with reasonable accuracy, the fluorescent enhancement. Using this methodology it will be possible to consider different shaped metal nanoparticles and any supporting substrate material in the future, an important step in building reliable biosensors capable of detecting low levels of proteins tagged with fluorescence molecules. PMID- 24046906 TI - Advanced deep reactive-ion etching technology for hollow microneedles for transdermal blood sampling and drug delivery. AB - Using an SPTS Technologies Ltd. Pegasus deep reactive-ion etching (DRIE) system, an advanced two-step etching process has been developed for hollow microneedles in applications of transdermal blood sampling and drug delivery. Because of the different etching requirements of both narrow deep hollow and large open cavity, hollow etch and cavity etch steps have been achieved separately. This novel two step etching process is assisted with a bi-layer etching mask. Results show that the etch rate of silicon during this hollow etch step was about 7.5 microm/min and the etch rate of silicon during this cavity etch step was about 8-10 microm/min, using the coil plasma etching power between 2.0 and 2.8 kW. Especially for the microneedle bores etch, the deeper it etched, the slower the etch rate was. The microneedle bores have successfully been obtained 75-150 microm in inner diametre and 700-1000 microm long with high aspect ratio DRIE, meanwhile, the vertical sidewall structures have been achieved with the high etch load exposed area over 70% for the cavity etch step. PMID- 24046907 TI - Polymeric nanocapsules with controllable crosslinking degree via combination of surface-initiated atom transfer radical polymerisation and photocrosslinking techniques. AB - The crosslinked polystyrene nanocapsules with controllable crosslinking degree have been prepared by the ultraviolet (UV)-induced photocrosslinking of the polystyrene grafted silica nanoparticles (SN-PS), which was obtained by the surface-initiated atom transfer radical polymerisation of styrene from the modified silica nanoparticle templates, after the silica templates were etched with hydrofluoric acid. The effect of the UV-irradiating time on the inner diameter of the nanocapsules, and the degree of crosslinking and the thickness of the shells was investigated. The dynamic light scattering results showed that the degree of crosslinking of the obtained nanocapsules increased with the prolongation of the UV-irradiation time, therefore the inner diameter of the nanocapsules increased. However, the percentage of grafting of the crosslinked polymer shells decreased with increasing the UV-irradiation time because of the photodecomposition of the polystyrene grafted during the UV-irradiated crosslinking process, according to the thermogravimetric analysis. PMID- 24046908 TI - Type I reaction in leprosy--a histopathological analysis. AB - Even though type 1 lepra reaction (TIR) is a commonly encountered clinical problem, its histology has not yet been clearly delineated. This study attempts to enumerate the most sensitive parameters for the histological diagnosis of TIR. Case records between March 2007 and September 2007 of patients with TIR were reviewed and the biopsies were evaluated by a pathologist blinded to the previous diagnoses. Twenty three patients were included in the study. The most sensitive parameters in our study were dermal edema, intra-granuloma edema and giant cell size. Though clinical findings should remain the mainstay of diagnosis of TIR, the above mentioned parameters should be evaluated in biopsies of leprosy to look for signs of reaction which might otherwise be missed. PMID- 24046910 TI - Differential trend of leprosy in rural and urban area of western Maharashtra. AB - Leprosy, major public health problem in Satara District with prevalence rate of 61/10000 population in 1990. With a view to eliminate Leprosy, Government of India launched National Leprosy Eradication Programme (NLEP) in Satara district during July 1990 to overcome the burden of Leprosy with Multi-Drug Treatment and subsequently Modified Leprosy Elimination Campaign and Block Leprosy Awareness Campaign. The objective of the study is to assess the differential trend of Leprosy in rural and urban area of Satara district. Record based retrospective time series study was conducted in Urban Leprosy Control Units and Primary Health Centers of Satara district on NLEP evaluation indicators; prevalence rate, new case detection rate, percentage of cases released from treatment, proportion of female cases among new cases, proportion of multi bacillary cases among new cases, proportion of grade-II disability among new cases and proportion of child cases among new cases. Leprosy elimination was achieved in rural area i.e. prevalence rate < 1/10000 population but disease was still endemic in urban area of Satara district i.e. prevalence rate of leprosy was 1.3/10000 population in March 2007-08. Not a single case of grade-II disability was reported in both urban and rural area since March 2006-07 onward. New case detection rate was decreased to 0.7/10000 population in rural area but upward trend was recorded in urban area from 0.1/10000 population to 1.1/10000 population since March 2006-07 and trend was statistically significant (chi2 trend = 37.26, p < 0.001*). Proportion of female cases among new cases decreased from 63% to 46.7% in rural area but reverse trend was observed in urban area from 39.6% to 52.8% with significant difference (chi2 trend = 5.42, p = 0.01*). Proportion of multi bacillary cases among new cases showed little fluctuation in rural area from 57% to 55.2% but proportion was decreased in urban area from 59.1% to 44.4% and trend was statistically significant (chi2 trend = 29.82, p < 0.001*). Proportion of child cases among new cases decreased from 23.7% to 10.4% in rural but reverse trend was observed in urban area from 7% to 22.2% since March 2005-06 and proportion was significant (chi2 trend = 15.90, p = 0.0001*). More than 90% cases were released from treatment in rural area but proportion was low in urban area and trend was statistically significant (chi2 trend = 19.38, p < 0.001*). The National Leprosy Eradication Programme showed favorable impact in rural area as compared to urban area in Satara District of Maharashtra. PMID- 24046909 TI - Status of free radicals and antioxidants in leprosy patients. AB - Oxidative stress is a condition associated with an increased rate of cellular damage induced by the oxygen derived oxidants commonly known as reactive oxygen species (ROS). ROS are capable of damaging cellular constituents generated in excess during the chronic, inflammatory, neurodegenerative disease process of leprosy. Severe oxidative stress has been reported in leprosy patients because of malnutrition and poor immunity. The decreased levels of SOD, glutathione and total antioxidant status in leprosy patients may indicate a degradation of these antioxidant enzymes by free radicals during detoxification processes. The subjects for this study comprises of Normal human volunteers (NHV, n = 20) and treated MB patients (MB, n = 20). The levels of lipid peroxidation products are increased in MB Patients (*P < 0.001). SOD (**P < 0.0001) and glutathione levels (***P < 0.0001) decreased in MB Patients in comparision with normal human volunteers. The present study of estimation of antioxidants conclude that the free radical activity was increased and the total antioxidant status was decreased in all MB patients, indicating that there was an oxidative stress even after the treatment with MDT. The decreased levels of SOD, glutathione indicate a link between oxidative stress and leprosy. Since the MB patients are unable to produce sufficient amount of antioxidant to cope up with the increased oxidative stress in them. Providing nutritional supplementation may present a novel approach for fast recovery. Administration of exogenous antioxidants like vitamin C, tocopherols would prevent tissue damage and make the patient therapeutically benefited. PMID- 24046911 TI - Nursing interventions to manage anxiety levels of female inpatients admitted first time in a leprosy hospital. AB - Leprosy causes not just physical disabilities but mental and psycho social problems which are further more enhanced in women due to their submissive and secondary role in an Indian culture. This is reflected in their reluctance and delay in seeking hospitalization and generates great anxiety while admitted as inpatients. Appropriate nursing care can relieve much anxiety and help in faster healing. This paper presents the findings from such research carried out at a leprosy referral hospitalin north India. Adult female leprosy patients newly admitted for the first time in a leprosy referral hospital were interviewed in depth using Hamilton Anxiety Rating Scale and observed before and after implementing a customized nursing care plan. On admission, out of 40 women admitted more than 80% showed moderate or severe anxiety. After well planned nursing interventions only 2 continued to have severe anxiety, and a majority in all age groups showed significant reductions in anxiety levels, and responded well to leprosy care at the hospital. Well planned nursing care reduces or minimizes anxiety levels of female leprosy patients admitted first time in the hospital, and should become a standard practice in all hospital admissions. PMID- 24046912 TI - Lepromatous leprosy with an uncommon presentation: a case report. AB - 28 yr old male presented with asymptomatic nodules and few well to ill defined papules on ears, asymmetrical nerve enlargement and evanescent tender nodules on the extremities without any infiltration of the skin and madarosis. Slit skin smear done from normal skin was BI 6+. Skin biopsy showed features of lepromatous leprosy. PMID- 24046913 TI - Silicone implants for muscular wasting of first web and the hypothenar muscles. AB - Medial nerve and Ulnar nerve palsy are still very common in spite of MDT. While most surgeons are concerned with the function of the hand, few have paid attention to the aesthetics of it. However 'white-collar' patients are concerned about the appearance of their hands -besides the function, therefore they would like us to do something for the muscular wasting which is so common. We propose here a new technique, used for the last 10 years, and demonstrate its results. PMID- 24046914 TI - Oral health status in leprosy. PMID- 24046915 TI - An AQP1 allele associated with co(a-b-) phenotype. AB - The Colton (CO) blood group system consists of four antigens, Co(a), Co(b), Co3, and Co4, located on aquaporin-1 (AQP1), with Co(a) highly prevalent in all populations (99.8%). The Colton null phenotype, Co(a-b-), is very rare, and individuals with this phenotype lack the high-prevalence antigen Co3. To date, only six Co(a-b-) probands have been reported and four silencing alleles characterized. We identified an AQP1-null allele in a white woman with anti-Co3 caused by deletion of a G at nucleotide 601 (nt601delG) that results in a frameshift and premature termination (Val201Stop). Available family members were tested for the allele. Although anti-Co3 has been associated with mild to severe hemolytic disease of the fetus and newborn, the antibody was not clinically significant as evidenced by a low titer and delivery of asymptomatic newborns with moderate to weakly positive direct antiglobulin tests for all four pregnancies. PMID- 24046916 TI - Warm autoantibodies: time for a change. AB - Routine adsorption procedures to remove autoantibodies from patients' serum often require many hours to perform. This time-consuming process can create significant delays that affect patient care. This study modified the current adsorption method to reduce total adsorption time to 1 hour. A ratio of one part serum to three parts red blood cells (RBCs; 1:3 method) was maintained for all samples. The one part serum was split into three tubes. Each of these three aliquots of serum was mixed with one full part RBCs, creating three adsorbing tubes. All tubes were incubated for 1 hour with periodic mixing. Adsorbed serum from the three tubes was harvested, combined, and tested for reactivity. Fifty-eight samples were evaluated using both the current method and the 1:3 method. Forty eight (83%) samples successfully adsorbed using both methods. Twenty (34.5%) samples contained underlying alloantibodies. The 1:3 method demonstrated the same antibody specificities and strengths in all 20 samples. Eight samples failed to adsorb by either method. The 1:3 method found previously undetected alloantibodies in three samples. Two samples successfully autoadsorbed but failed to alloadsorb by either method. The 1:3 method proved to be efficient and effective for quick removal of autoantibodies while allowing for the detection of underlying alloantibodies. PMID- 24046917 TI - Major non-ABO incompatibility caused by anti-Jk(a) in a patient before allogeneic hematopoietic stem cell transplantation. AB - A 49-year-old white man with blood group AB, D+ was found to have alloanti-Jk(a) and -K when he developed a delayed hemolytic transfusion reaction before allogeneic hematopoietic stem cell transplant (HSCT). Given that his stem cell donor was blood group O, D+, Jk(a+), K-, rituximab was added to his conditioning regimen of fludarabine and melphalan to prevent hemolysis of engrafting Jk(a+) donor red blood cells. The patient proceeded to receive a peripheral blood stem cell transplant from a matched unrelated donor with no adverse events. To our knowledge, this is the first case of successful management of major non-ABO incompatibility caused by anti-Jk(a) in a patient receiving an allogeneic HSCT reported in the literature. PMID- 24046918 TI - A case of autoimmune hemolytic anemia with anti-D specificity in a 1-year-old child. AB - Although antibodies to antigens in the Rh blood group system are common causes of warm autoimmune hemolytic anemia, specificity for only the D antigen is rare in autoimmune hemolysis in pediatric patients. This case reports an anti-D associated with severe hemolytic anemia (Hb = 2.1 g/dL) in a previously healthy 14-month-old child who presented with a 3-day history of low-grade fevers and vomiting. Because of his severe anemia, on admission to the hospital he was found to have altered mental status, metabolic acidosis, abnormal liver function tests, and a severe coagulopathy. He was successfully resuscitated with uncrossmatched units of group O, D- blood, and after corticosteroid therapy he had complete resolution of his anti-D-mediated hemolysis. PMID- 24046919 TI - An update on the GLOB blood group system and collection. AB - The P blood group antigen of the GLOB system is a glycolipid structure, also known as globoside, on the red blood cells (RBCs) of almost all individuals worldwide. The P antigen is intimately related to the Pk and NOR antigens discussed in the review about the P1PK blood group system. Naturally occurring anti-P is present in the serum of individuals with the rare globoside-deficient phenotypes p, P1k, and P2k and has been implicated in hemolytic transfusion reactions as well as unfavorable outcomes of pregnancy. The molecular genetic basis of globoside deficiency is absence of functional P synthase as a result of mutations at the B3GALNT1 locus. Other related glycolipid structures, the LKE and PX2 antigens, remain in the GLOB blood group collection pending further evidence about the genes and gene products responsible for their synthesis. PMID- 24046920 TI - P1PK: the blood group system that changed its name and expanded. AB - The antigens in the P1PK blood group system are carried on glycosphingolipids. The system currently includes three different antigens, P1, Pk, and NOR. The P1 antigen was disovered in 1927 by Landsteiner and Levine, and Pk and NOR were described in 1951 and 1982, respectively. As in the ABO system, naturally occurring antibodies of the immunoglobulin (Ig) M or IgG class, against the missing carbohydrate structures, can be present in the sera of people lacking the corresponding antigen. Anti-P1 is generally a weak and cold-reactive antibody not implicated in hemolytic transfusion reaction (HTR) or hemolytic disease of the fetus and newborn while Pk antibodies can cause HTR, and anti-NOR is regarded as a polyagglutinin. A higher frequency of miscarriage is seen in women with the rare phenotypes p, P1k, and P2k. Furthermore, the Pk and P1 antigens have wide tissue distributions and can act as host receptors for various pathogens and toxins. Why p individuals lack not only Pk and P expression but also P1 has been a longstanding enigma. Recently, it was shown that the same A4GALT-encoded galactosyltransferase synthesizes both the P1 and Pk antigens and that a polymorphism in a new exon in this gene predicts the P1 and P2 phenotypes. PMID- 24046921 TI - New blood group allele report. PMID- 24046922 TI - Right nurse, right skills? PMID- 24046923 TI - Interventions to promote treatment adherence in type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is associated with increasing levels of morbidity and mortality. Full adherence to treatment recommendations such as pharmacological agents, dietary changes, physical activity and regular self monitoring of blood glucose is essential to achieve good metabolic control. Cost effective interventions such as individualised self-management education, cue dose training and use of adherence aids have a positive impact on adherence to treatment recommendations, resulting in better glycaemic control. The application of these interventions could improve clinical outcomes within the NHS. PMID- 24046924 TI - COPD in primary care settings in Ireland: stories from usual care. AB - The aim of the PRINCE study was to determine the effectiveness of a structured education pulmonary rehabilitation programme for those living with COPD in primary care in Ireland. This qualitative element of the larger PRINCE trial aims to describe the constituents of 'usual care' for patients allocated to the control arm of the study. A descriptive qualitative study was used to explore the constituents of usual care. A convenience sample of participants (n=20) allocated to the usual care group were interviewed. Three main themes arose from the study: experiences of having and managing COPD, lifestyle advice, and factors that helped or hindered self-management. Usual care left many people grappling in the dark trying to manage their COPD. It was found that usual care was not at its optimum for people with COPD in the control arm of the PRINCE study. PMID- 24046925 TI - When I'm dead and gone: organ donation and the community nurse. PMID- 24046926 TI - Dementia care and offender populations. PMID- 24046927 TI - Differences between heart failure clinics and primary health care. AB - There is a paucity of knowledge concerning how people with heart failure experience differences between specialised heart failure clinics and primary healthcare in Sweden. This study aimed to describe differences regarding information and follow-up in heart failure clinics and primary healthcare. The study was conducted in Sweden in 2011. Four people (three men, one woman; aged 60 to 84) with heart failure (NYHA II) were interviewed. The interviews were analysed with qualitative content analysis. The findings revealed after referral from the heart failure clinic to primary healthcare, follow-ups were omitted. Still, the patients needed care, support and information. The findings are illuminated in four themes. The patients' varying and individual needs can be difficult to recognise and manage unless they are followed-up from either HFC or PHC on a regular basis. PMID- 24046928 TI - Developing cultural competence in palliative care. PMID- 24046929 TI - Bringing compassion back into caring: an equation of reciprocation. PMID- 24046930 TI - Shared decision-making: nurses must respect autonomy over paternalism. AB - Shared decision-making lies at the heart of the Government's reforms of the NHS in England. The slogan, 'No decision about me without me', underpins shared decision-making that sees patients as active participants in their treatment decisions. In this article, Richard Griffith and Cassam Tengnah argue that for 'no decision about me, without me' to be a reality, district nurses must guard against paternalistic decision-making that excludes the views and wishes of their patients. PMID- 24046931 TI - Keeping fit into old age. PMID- 24046932 TI - Drug shortages. PMID- 24046933 TI - Complying with Occupational Safety and Health Administration regulations: a guide for compounding pharmacists. AB - In the compounding pharmacy, compliance with Occupational Safety and Health Administration regulations is essential to protect employees and customers from exposure to hazardous substances and a dangerous environment, to avert heavy fines and penalties levied for noncompliance, and to fulfill the moral obligation of pharmacists to do no harm. Without adequate vigilance, compounders are vulnerable to lapses in adherence to Occupational Safety and Health Administration requirements, the results of which can be dire in a climate of increased scrutiny about the safety and integrity of pharmaceutical compounding. Proactively addressing necessary compliance with essential safety regulations can only benefit compounders and their staff and clients, and guidance from an expert in Occupational Safety and Health Administration requirements can be a key factor in accomplishing that goal. PMID- 24046934 TI - Decontamination technology: the missing element. AB - Understanding decontamination technology as it applies to compounding sterile preparations and its role in achieving an acceptable level of sterility assurance in compounded preparations is essential. Delivering safe preparations to patients requires the key elements that make up an acceptable sterility-assurance level. Those key elements are decontamination of the preparation components and the environment in which they are compounded, aseptic technique, and proper air quality of the compounding environment. This article explores the concept of sterility assurance as it applies to sterile preparations. PMID- 24046935 TI - Optimizing third-party reimbursement for compounded medications. AB - Recently, third-party payers have been closely scrutinizing compounded medications that are dispensed in hospital-based outpatient pharmacies. Insurance claims are being rejected for reasons that defy logic. Working with third-party payers and receiving reimbursement for compounded medications can be frustrating and complicated; however, simple measures can be taken to optimize reimbursement for the medications. This article discusses some of these simple measures. PMID- 24046936 TI - International Academy of Compounding Pharmacists' legislative/regulatory update. PMID- 24046938 TI - Basics of compounding: potency and stability testing. AB - Potency (strength) tests are designed to determine how much of an active drug is in a sample. Stability tests are used to determine an expiration date of a product or a beyond-use date of a preparation. Being able to employ the proper method to determine potency or stability is the key to understanding the difference between potency testing versus stability testing. In order to determine potency, a method may or may not be stability indicating. When determining stability, the method must be stability indicating. When using a stability-indicating method, both potency and stability can be determined. Quality-assurance programs are essential to establishing standards for compounded preparations. It is important that compounding pharmacists understand the differences between potency and stability tests and that these tests are made an integral part of the quality-assurance program. PMID- 24046937 TI - A summarized discussion of current good manufacturing practice regulations. AB - In light of recent events and discussions of compounding pharmacy, it is important to discuss and understand the purpose of good manufacturing practices. This article provides a summary of the current Good Manufacturing Practice Regulations which were established by the U.S. Food and Drug Administration. PMID- 24046939 TI - Assessing the stability of common radiopharmaceuticals compounded and utilized outside package insert guidelines. AB - The objective of this study was to evaluate the stability of radiopharmaceuticals compounded using activities and expiration times in excess of manufacturers' recommendations. Proof of the compounded sterile preparation quality when compounding outside of manufacturers' recommendations has become a key component of maintaining compliance with the guidelines set forth in United States Pharmacopeia General Chapter <797> Pharmaceutical Compounding-Sterile Preparations, originally released in 2008. Seven commercial nuclear pharmacies compounded various radiopharmaceuticals for patient use as part of daily pharmacy protocol. Samples of radiopharmaceuticals were tested using instant thin- layer chromatography testing to determine the radiochemical purity of the final compounded sterile preparation at t = 0, t = 6, t = 12, and t = 24 hours post compounding. Data submitted was summarized and divided into activity ranges allowing for calculation of average radiochemical purity for various activity levels at each of the four time points. Data was presented in graph form showing the average radiochemical purity values versus time with inclusion of error bars to indicate standard deviation data. The stability of each kit at different activity levels and at different time points post compounding showed that many of the radiopharmaceutical kits prepared today may have an unacceptable decrease in radiochemical purity at higher activity levels and at extended times post compounding. The data submitted provides a general guideline for the stability of radiopharmaceuticals compounded outside of manufacturer guidelines and can be used as a tool to support the practices that are being carried out at individual institutions. However, this data should be used in conjunction with in-house data review to assure that the preparations being compounded and dispensed are of the highest quality for administration to the patient. PMID- 24046940 TI - Effect of formulation pH on transdermal penetration of antiemetics formulated in poloxamer lecithin organogel. AB - The purpose of this study was to assess the impact of altering formulation pH on the transdermal penetration of several commonly used antiemetic, weakly basic drugs incorporated into poloxamer lecithin organogel vehicle. Poloxamer lecithin organogel formulations containing promethazine hydrochloride (25 mg/mL), metoclopramide hydrochloride (10 mg/mL), and ondansetron hydrochloride (8 mg/mL) were examined for both drug release and transdermal penetration across porcine skin in modified Franz diffusion cells for a period of 24 hours. For the transdermal studies, each antiemetic drug was formulated at a pH above and below their acid dissociation constant (pKa) in an attempt to assure that the drug would be primarily in their respective ionized or non-ionized states. In addition, drug content in skin was assessed at the end of the 24-hour experiment. Drug content analysis was determined via high-performance liquid chromatography. As a percent of total drug release from the poloxamer lecithin organogel vehicle, promethazine hydrochloride demonstrated the most transdermal drug penetration after 24 hours (30.2% +/- 20.2%), followed by ondansetron hydrochloride (2.7% +/- 1.1%) and metoclopramide hydrochloride (1.8% +/- 1.6%). Subsequently, the pH of the Pluronic F-127 gel was adjusted in order to ensure that each antiemetic drug would be primarily in its unionized state. The transdermal permeation of each antiemetic drug primarily in its unionized state increased over that observed with the drug primarily in its ionized state after 24 hours (promethazine: 1.6 fold increase; metoclopramide: 1.3-fold increase; ondansetron: 1.8-fold increase). A similar trend was noted in the amount of each drug found in the skin after 24 hours (promethazine: 1.2-fold increase; metoclopramide: 2.4-fold increase; ondansetron: 3.0-fold increase). These results suggest that proper optimization of drug ionization state may be a useful strategy for compounding pharmacists to increase the efficacy of drugs intended for inclusion in transdermal formulations. PMID- 24046942 TI - The pharmacist's role in the treatment of cancer: a personal plea and testimonial. PMID- 24046941 TI - Physicochemical compatibility of nebulizable drug admixtures containing budesonide and colistimethate or hypertonic saline. AB - Knowledge of the physicochemical compatibility of admixtures of nebulizable drugs is an important issue. In this article, the results of our recent study dealing with the compatibility of drug admixtures containing budesonide and colistin methanesulfonate (brand name Colistin CF) or budesonide and 5.85% sodium chloride solution are presented, as well as the up-to-date version of our compatibility table. Admixtures were prepared by mixing 2.0 mL Pulmicort either with 3.0 mL Colistin CF or 4.0 mL 5.85% sodium chloride solution. Test solutions were stored for 24 hours at room temperature under ambient light conditions. Physical compatibility was determined by measuring pH and osmolality. Concentrations of budesonide were measured by a high-performance liquid chromatography assay. The antibiotic activity of colistin methanesulfonate was determined in comparison to standard solutions using a microbiological assay. No loss in drug concentration of budesonide and no change in antibiotic activity of colistin methanesulfonate were detected over a test period of 24 hours. Osmolality remained unchanged in both types of admixtures. In admixtures of budesonide with colistin methanesulfonate, pH increased during the first 4 hours of storage, while in admixtures of budesonide and hypertonic saline pH remained unchanged. No visible changes could be detected. Due to these results admixtures of budesonide and colistin methanesulfonate or 5.85% sodium chloride solution are designated to be compatible, but it is recommended that mixing should take place immediately before administration. Further investigations are needed to determine whether or not drug delivery is affected by mixing the drugs and to ensure simultaneous nebulization is recommendable. PMID- 24046943 TI - Bone marrow, adipose tissue derives from the mesenchyme. PMID- 24046944 TI - Analysis of the karyotype of expanded human adipose-derived stem cells for bone reconstruction of the maxillo-facial region. AB - Mesenchymal stem cells (MSC) and adipose-derived stem cells (ASC) were recently proposed for bone maxillofacial reconstruction in association with biomaterials. For this application MSC must be ex-vivo expanded in order to obtain, for a given volume of implanted biomaterial, a relevant number of bone forming cells. Previously conducted pre-clinical studies suggested that a concentration of 6 x 10(8) ASC associated with 900 mg of anorganic bovine bone (ABB) could be effective for human maxillary sinus floor elevation. A keystone issue to guarantee the quality and safety of Advanced Therapy Medicinal Products containing expanded MSC and ASC is their chromosome stability in culture: this topic has been widely investigated and conflicting results have been published. Abnormal karyotype of human ex-vivo expanded MSC and ASC was found by some authors, while, at the same time, several other studies showed the MSC and ASC karyotype to be normal. It is therefore important that all the results obtained on MSC and ASC karyotype analysis be published. Given this context, the aim of this manuscript, aim of this manuscript is to verify the karyotype stability of ASC in view of their applications in clinical trials. ASC obtained from the adipose tissue of 4 donors were expanded over extended culture time. Based on previous ASC expansions we hypothesized to be able to obtain 6 x 10(8) cells by passage 7. Karyotype analysis of 30 metaphases was planned to be investigated at passage 2, 7, and 15 in all the cultures. No abnormalities were found in the karyotype of two donors at all the passages tested, while a translocation was found in 2 metaphases of a donor at passage 7, but not at passage 15, and in the fourth donor in 5 metaphases a trisomy was found at passage 15. Chromosomal abnormalities were detected only after extended ASC expansion. Whether these anomalies can be related to risk for the patient's safety will have to be demonstrated by in-vivo studies. PMID- 24046945 TI - Stemness and osteogenic and adipogenic potential are differently impaired in subcutaneous and visceral adipose derived stem cells (ASCs) isolated from obese donors. AB - Today adipose tissue is not just considered as the primary energy storage organ, but it is also recognized as an important endocrine tissue and an abundant source of mesenchymal stem cells (adipose-derived stem cells, ASCs). During the last decade, several studies have provided preclinical data on the safety and efficacy of ASCs, supporting their use in cell-based therapy for regenerative medicine purposes. Little is known about the effect of obesity on ASCs properties. Since ASCs differentiation and proliferation are determined by their niche, the differences in body fat distribution and the obesity-related co-morbidities may have several consequences. In this study we compared ASCs of subcutaneous adipose tissue from obese (obS-ASCs) and non-obese (nS-ASCs) donors in order to compare their immunophenotype and osteogenic and adipogenic potential. Moreover, in order to evaluate the possible difference between subcutaneous and visceral fat, obS ASCs were also compared to ASCs derived from visceral adipose tissue of the same obese donors (obV-ASCs). Our results show that subcutaneous and visceral ASCs derived from obese donors have an impaired cell proliferation, clonogenic ability and immunophenotype. Nevertheless, obS-ASCs are able to differentiate toward osteogenic and adipogenic lineages, although to a small extent with respect to non-obese donors, whereas obV-ASCs lose most of their stem cell characteristics, including multi-differentiation potential. Taken together our findings confirm that not all ASCs present the same behavior, most likely due to their biological microenvironment in vivo. The specific stimuli which can play a key role in ASCs impairment, including the effects of the obesity-related inflammation, should be further investigated to have a complete picture of the phenomenon. PMID- 24046946 TI - Influence on chondrogenesis of human osteoarthritic chondrocytes in co-culture with donor-matched mesenchymal stem cells from infrapatellar fat pad and subcutaneous adipose tissue. AB - Co-culture of mesenchymal stem cells (MSCs) and articular chondrocytes (ACs) has been proposed for autologous cartilage cell-based therapies, to overcome the issues associated to limited availability of articular chondrocytes (ACs). To evaluate the potentiality of a co-culture approach in aged osteoarthritic patients, MSCs from infrapatellar fat pad (IFP-MSCs) and knee subcutaneous adipose tissue (ASCs) were co-cultured with donor-matched osteoarthritic, expanded and cryopreserved, ACs in a 75%/25% ratio. Co-cultures were prepared also from nasal chondrocytes (NCs) to evaluate their possible use as an alternative to ACs. Pellets were differentiated for 14 days, using mono-cultures of each cell type as reference. Chondrogenic genes SOX9, COL2A1, ACAN were less expressed in co-cultures compared to ACs and NCs. Total GAGs content in co cultures did not differ significantly from values predicted as the sum of each cell type contribution corrected for the co-culture ratio, as confirmed by histology. No significant differences were observed for GAGs/DNA in mono cultures, demonstrating a reduced chondrogenic potential of ACs and NCs. In conclusion, a small percentage of expanded and cryopreserved ACs and NCs did not lead to IFP-MSCs and ASCs chondro-induction. Our results suggest that chondrogenic potential and origin of chondrocytes may play a relevant role in the outcome of co-cultures, indicating a need for further investigations to demonstrate their clinical relevance in the treatment of aged osteoarthritic patients. PMID- 24046947 TI - Adipose tissue-derived stromal cells primed in vitro with paclitaxel acquire anti tumor activity. AB - Many strategies, including those based on genetically modified Mesenchymal Stromal Cells (MSCs), have been developed in recent years in order to obtain high concentrations of anticancer drugs effective on tumor mass. In previous studies, we showed that human and murine bone marrow-derived MSCs (BM-MSCs) and human skin derived stromal fibroblasts (hSDFs) acquired strong anti-tumor capacity, both in vitro and in vivo, once primed with Paclitaxel (PTX). In this report we investigate whether adipose tissue-derived MSCs (AT-MSCs) behave similarly to BM MSCs in their uptake and release of PTX in sufficient amounts to inhibit tumor proliferation in vitro. According to a standardized procedure, PTX primed AT-MSCs (AT-MSCsPTX) were washed and then subcultured to harvest their conditioned medium, which was then tested to evaluate its in vitro anti-tumor potential. We observed that AT-MSCsPTX were able to uptake PTX and release it in a time dependent manner and that the released drug was active in vitro against proliferation of leukemia, anaplastic osteosarcoma, prostatic carcinoma and neuroblastoma cell lines. These data confirm that AT-MSCs, as well as BM-MSCs, can be loaded in vitro with anti-cancer drugs. While the harvesting of BM-MSCs requires invasive procedures, AT-MSCs can be prepared from fat samples taken with little patient discomfort. For this reason, this source of stromal cells represents an important alternative to BM-MSCs in developing new tools for carrying and delivering anti-cancer drugs into tumor microenvironments. PMID- 24046948 TI - Formulation and characterization of silk fibroin films as a scaffold for adipose derived stem cells in skin tissue engineering. AB - Skin substitutes are epidermal, dermal or complete bilayered constructs, composed by natural or synthetic scaffolds and by adherent cells such as fibroblasts, keratinocytes or mesenchymal stem cells. Silk fibroin is a promising polymer to realize scaffolds, since it is biocompatible, biodegradable, and exhibits excellent mechanical properties in terms of tensile strength. Moreover, fibroin can be added of others components in order to modify the biomaterial properties for the purpose. The aim of this work is to prepare silk fibroin films for adipose-derived stem cell (ADSCs) culture as a novel feeder layer for skin tissue engineering. Pectin has been added to promote the protein conformational transition and construct strength, while glycerol as plasticizer, providing biomaterial flexibility. Eighteen formulations were prepared by casting method using fibroin, pectin (range 1-10% w/w), and glycerol (range 0-20% w/w); films were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry assay, to select the optimal composition. A stable fibroin conformation was obtained using 6% w/w pectin, and the best mechanical properties were obtained using 12% w/w glycerol. Films were sterilized, and human ADSCs were seeded and cultured for 15 days. Cells adhere to the support assuming a fibroblastic-like shape and reaching confluence. The ultrastructural analysis evidences typical active-cell features and adhesion structures that promote cell anchorage to the film, thus developing a multilayered cell structure. This construct could be advantageously employed in cutaneous wound healing or where the use of ADSCs scaffold is indicated either in human or veterinary field. PMID- 24046949 TI - Two bone substitutes analyzed in vitro by porcine and human adipose-derived stromal cells. AB - Nowadays, the repair of large bone defects is an important goal in orthopaedic and dental fields. Tissue engineering, applied to increase the bone regeneration process, combines suitable scaffolds with either terminally differentiated cells or Mesenchymal Stromal Cells. In vitro studies with Adipose-derived Stromal Cells (ASCs) may identify new bioactive supports, to be tested in preclinical model. In this study, we evaluated the biocompatibility and the osteoinductive properties of two bone substitutes, RegenOSS (RO-1) and a new generation scaffold (RO-2), on both porcine and human ASCs. Porcine ASCs need a prolonged initial phase to adapt to both substitutes; indeed, their growth was initially reduced respect to cells cultured in their absence. In contrast, human ASCs were not negatively affected. However, no toxicity of RO-1 and -2 was observed on both ASC populations which are able to stick to both biomaterials. RO-1 and -2 supported osteogenic differentiation of porcine and human ASCs in a different manner: the presence of RO-1 up-regulated both alkaline phosphatase (ALP) activity and collagen production of human ASCs, whereas in porcine ASCs, RO-2 seemed to up-regulate ALP activity, while the production of collagen is mainly stimulated by the presence of RO-1. We suggest to use not just human ASCs, but also animal ones to select suitable scaffolds to generate bio-constructs in vitro, which then need to be tested in animal model before reaching the market. PMID- 24046950 TI - Allogeneic adipose tissue-derived mesenchymal stem cells in combination with platelet rich plasma are safe and effective in the therapy of superficial digital flexor tendonitis in the horse. AB - Overstrain tendonitis are common pathologies in the sport horses. Therapeutic approaches to tendon healing do not always result in a satisfactory anatomical and functional repair, and healed tendon is often characterized by functional impairment and high risk of reinjury. Recently, mesenchymal stem cells (MSCs) and platelet rich plasma (PRP) have been proposed as novel therapeutic treatments to improve the tendon repair process. MSCs are multipotent, easy to culture and being originated from adult donors do not pose ethical issues. To date, autologous MSCs have been investigated mainly in the treatment of large bone defects, cardiovascular diseases, osteogenesis imperfecta and orthopaedic injuries both in human and veterinary medicine. The clinical applications in which autologous MSCs can be used are limited because patient-specific tissue collection and cell expansion require time. For clinical applications in which MSCs should be used right away, it would be more practical to use cells collected from a donor, expanded in vitro and banked to be readily available when needed. However, there are concerns over the safety and the efficacy of allogeneic MSCs. The safety and efficacy of a therapy based on the use of allogeneic adipose tissue-derived mesenchymal stem cells (ASCs) associated to platelet rich plasma (PRP) were evaluated in 19 horses affected by acute or subacute overstrain superficial digital flexor tendonitis (SDFT). The application of allogeneic ASCs neither raised clinical sign of acute or chronic adverse tissue reactions, nor the formation of abnormal tissue in the long-term. After a follow-up of 24 months, 89.5% horses returned to their previous level of competition, while the reinjury rate was 10.5%, comparable to those recently reported for SDFT treated with autologous bone marrow derived MSCs. This study suggests that the association between allogeneic ASCs and PRP can be considered a safe and effective strategy for the treatment of SDF tendonitis in the horse. PMID- 24046951 TI - [Forgettable - unforgettable]. PMID- 24046952 TI - [Insidiously into the crisis]. PMID- 24046953 TI - [Family centered nursing anamnesis as the key]. PMID- 24046954 TI - [Step by step to a better well-being]. PMID- 24046955 TI - [Incontinence is a challenge]. PMID- 24046956 TI - [Building trust, providing security, reducing anxiety]. PMID- 24046957 TI - [Learning research competence for general practice]. PMID- 24046958 TI - [How free is freedom of expression?]. PMID- 24046959 TI - [Engaged campaign against indifference]. PMID- 24046960 TI - [Major challenges]. PMID- 24046962 TI - [An invitation for ethics reflection]. PMID- 24046961 TI - ["A little more love than usual"]. PMID- 24046963 TI - [Bathing the elderly person]. PMID- 24046964 TI - [A French language school of reflexology]. PMID- 24046965 TI - [Antibiotic resistance, intensive livestock breeding and nursing care]. PMID- 24046966 TI - [The candy mom]. PMID- 24046967 TI - [The story is important]. PMID- 24046968 TI - What you need to know to become a MEG technologist. AB - Magnetoencephalography (MEG) is a way to noninvasively localize sources of electrical activity within the human brain, by measuring the very weak magnetic fields just outside of the head. This paper is an introduction to MEG for technologists who are interested in performing MEG studies. We have organized the paper into a brief overview of what MEG measures and how it does it, as well as a short history of the MEG manufacturers. There is a discussion of the differences in coils/sensors used to detect the magnetic fields, followed by a detailed description of what an average MEG technologist does to perform a MEG study. Some MEG centers may require more duties from the MEG technologist than are listed here and others may require fewer duties. We finish the paper with the contraindications for a MEG study, a job description for the MEG technologist, and a MEG procedure checklist to help keep the tasks organized. PMID- 24046969 TI - Diagnostic yield of electroencephalography in a general inpatient population. AB - OBJECTIVE: To determine the frequency and clinical predictors of seizures and markers of epileptiform activity in a noncritically ill general inpatient population. PATIENTS AND METHODS: We performed a retrospective cohort study of patients 18 years and older who underwent inpatient electroencephalography (EEG) between January 1, 2005, and December 31, 2010, for an indication of spells or altered mental status. The EEGs and reports were reviewed for ictal activity, interictal epileptiform abnormalities, and nonepileptiform abnormalities. Demographic and clinical data were gathered from the electronic medical record to determine seizure predictors. RESULTS: Of 2235 patients screened, 1048 met the inclusion criteria, of which 825 (78.7%) had an abnormal EEG finding. Seizures occurred in 78 of 1048 patients (7.4%), and interictal epileptiform discharges were noted in 194 of 1048 patients (18.5%). An intracranial mass and spells as the indication for the EEG were independently associated with the group of patients experiencing seizures in a multivariate logistic regression model (adjusted for age, sex, EEG indication, intracranial mass, stroke, and history of epilepsy). Ninety-seven percent of patients (69 of 71) experienced their first seizure within 24 hours of monitoring, and the presence of seizures was associated with a lower likelihood of being discharged (odds ratio, 0.45; 95% CI, 0.27-0.76). CONCLUSION: Seizures occurred at a high frequency in hospitalized patients with spells and altered mental status. The EEG may be an underused investigative tool in the hospital with the potential to identify treatable causes of these common disorders. PMID- 24046970 TI - Epileptiform transients of the occipital lobe in pediatrics. AB - Differentiating between benign occipital transients and epileptic discharges from the occipital lobes is imperative. Focal occipital spikes and sharp waves are not always associated with benign disorders. The occurrence of occipital spikes and spike and wave complexes depends on the child's age, the maturation of the occipital cortex, and the cortex's connection with other structures (Beaumanoir et al. 1993). Clinical manifestations also evolve as the patient ages. Seizure semiology is due to the maturation of the visual system and its connections. An infant from birth to twelve months of age could experience autonomic symptoms such as pallor and vomiting with possible minor motor movements. Visual symptoms and/or headaches are usually not noticed until between five and seven years of age. These visual phenomena can continue into adulthood. PMID- 24046971 TI - Technical tips: MEG and EEG with sedation. AB - Magnetoencephalography (MEG) measures the field generated by the brain's electrical currents noninvasively. MEG is currently used for localization of epileptiform activity sources and for presurgical functional brain mapping. Such mapping with MEG requires the patients to be cooperative and lie still on their back for as long as ten minutes at a time. Hence, acquiring successful MEG in very young children, developmentally delayed individuals, and patients with skeletal abnormalities proves to be a challenge. Over the past several years, our group has undertaken research aimed at the effective use of sedation during MEG to identify epileptogenic areas and perform functional brain mapping in very young or developmentally delayed individuals. We summarize our experience of MEG data acquisition with sedation and demonstrate that epileptogenic areas can be identified and functional brain mapping can be successfully performed under sedation with propofol. PMID- 24046972 TI - Technical tips: methods of warming and maintaining limb temperature during nerve conduction studies. AB - Many physiologic and nonphysiologic factors contribute to performing correct or incorrect nerve conduction studies. Nonphysiologic factors such as filter settings, averaging techniques, stimulus artifact, and supramaximal stimulation are just a few of the ones encountered during the nerve conduction study examination. Physiologic factors such as muscle atrophy, tremors and spasticity, edema, and profuse sweating are physical conditions that may pose technical problems during the study. Other general physiologic conditions such as height, aging and nerve maturation, variation between various nerve segments, and temperature may also contribute to the obtaining an accurate and correct nerve conduction study, as well as the electromyogram (EMG) itself. Obtaining and keeping the patient's surface temperature between 31 to 34 or 33 to 34 degrees Celsius, depending on which literature you read, is essential to obtaining and presenting correct nerve conduction studies. Cold limb temperature results in discrepancies in basic nerve conduction values such as amplitude, distal latency, conduction velocity, and duration in both motor and sensory studies. Cold to cool temperature also adversely affects the EMG. Repetitive stimulation studies for neuromuscular junction disease are greatly affected by decreasing the limb temperature. How to warm these patients and maintain a desirable temperature throughout the examination is vitally important. Methods of warming patients may vary from inexpensive to expensive in cost and simple to complex in nature. PMID- 24046973 TI - Unusual causes for asymmetry on EEG. PMID- 24046974 TI - Letter to the Editor. PMID- 24046975 TI - Colorectal cancer through simulation and experiment. AB - Colorectal cancer (CRC) has formed a canonical example of tumourigenesis ever since its use in Fearon and Vogelstein's linear model of genetic mutation, and continues to generate a huge amount of research interest. Over time, the field has witnessed a transition from solely experimental work to the inclusion of mathematical and computational modelling. The fusion of these disciplines has the potential to provide valuable insights into oncologic processes, but also presents the challenge of uniting many diverse perspectives. Furthermore, the cancer cell phenotype defined by the 'Hallmarks of Cancer' has been extended in recent times and provides an excellent basis for future research. The authors present a timely summary of the literature relating to CRC, addressing the traditional experimental findings, summarising the key mathematical and computational approaches, and emphasising the role of the Hallmarks in current and future developments. The authors conclude with a discussion of interdisciplinary work, outlining areas of experimental interest which would benefit from the insight that theoretical modelling can provide. PMID- 24046976 TI - Theoretical analysis on the relationship between left ventricular energetic efficiency and acute infarct size. AB - Energetic efficiency is an important indicator of cardiac function in acute myocardial infarction. However, the relationship between cardiac energetic efficiency and infarct size is not perfectly elucidated. In this study, the relationship is analysed by means of simulation using a theoretical model of the guinea pig left ventricle. In simulation with varied ratios of infarct area, pressure-volume area (PVA), which is an index of total mechanical energy by ventricular contraction, and myocardial oxygen consumption (MVO2) are calculated for each infarct ratio. Then, change of PVA when MVO2 alters (PVA/MVO2) as a well known index of energy conversion efficiency is evaluated. In addition, PVA/VO2, which represents a ratio of PVA change to alteration of mean oxygen consumption of myocytes except for infarct myocytes, is introduced as an index for real energetic efficiency. In simulation results, PVA/MVO2 increases but PVA/VO2 decreases as infarct area expands, because with expansion of infarct area PVA decreases but VO2 remains almost unchanged because of larger shortening of myocytes. This implies that the enlargement of shortening of noninfarcted myocyte to compensate for depression of cardiac output is a potential cause of myocardial remodelling. PMID- 24046977 TI - Constant drug dose in human immuno-deficiency virus-infected patients to induce long-term non-progressor status: bifurcation and controllability approach. AB - The authors propose a therapy consisting of a constant dosage of reverse transcription inhibitor and protease inhibitor to achieve long-term non progressor (LTNP) status in human immuno-deficiency virus (HIV) patients. Based on the authors analyses of cytotoxic T lymphocyte precursor (CTLp) concentration at several equilibrium points and the bifurcation of these equilibrium points, they find that administration of drugs with an efficacy lower than a certain level induces a higher CTLp concentration. As a result, drug doses of moderate efficacy result in more patients with LTNP status than doses with high efficacy. In analyses of controllability, they show that a treatment of moderate efficacy is more efficient than one of very high efficacy in terms of controlling the immune system. Using simulations, they demonstrate that their proposed method results in LTNP status in HIV patients. PMID- 24046978 TI - Oral hygiene habits, dental home, and toothbrushing among immigrant and native low socioeconomic class populations. AB - About 45,000 people immigrated to Israel from Ethiopia over the last 30 years. The purpose of this study was to compare oral hygiene habits in preschool children from low socioeconomic neighborhoods offspring of immigrants from Ethiopia to offspring of native Israelis. METHOD: Parents of children attending 21 nursery schools were asked to respond anonymously to 7 questions about their children's visits to a dentist and toothbrushing habits. RESULTS: Parents of 719 children (382 Ethiopian and 337 native Israeli) responded. Of children aged 49-82 months, 15% offspring of Ethiopian and 25% of native Israelis were reported to have visited a dentist; and 45% and 65%, respectively, to brush their teeth at least once daily. More than 90% of children of both populations were reported to have toothbrushes. Of children aged 18-48 months, 28% of Ethiopian and 65% of native Israelis were reported to brush their teeth at least once daily. CONCLUSION: After more than 20 years residence in a new country, the dental home of an immigrant population was significantly different from that of the native population, of the same low socioeconomic neighborhoods. Discrepancies in parental responses highlight the importance of addressing information bias. PMID- 24046979 TI - Determining treatibility of primary teeth with pulpal exposure. AB - OBJECTIVES: To determine rates of pulpal exposure during caries removal with an excavator or a bur, to assess success rates of vital pulp therapies in both cases, to analyze pulpal bleeding as an indicator of primary teeth treatability. STUDY DESIGN: Of the 352 primary mandibular molars with deep carious lesions, 141 with pulp exposed during the removal of caries were grouped according to type of instrument causing pulpal exposure and existence of bleeding at the exposure site. Teeth suitable for direct pulp capping or formocresol pulpotomy were treated and followed up for two years. RESULTS: The difference between the rates of pulpal exposure with an excavator (52.5%) or a bur (47.5%) was insignificant. The treatment success rate of teeth with pulp exposed by an excavator (15.8%) was significantly lower than teeth with pulp exposed by a bur (48.8%), regardless of whether bleeding existed at the exposure site or not; however when bleeding existed, this difference was insignificant (15.8% and 40.6%, respectively). CONCLUSIONS: Pulpal exposure possibility during caries removal caused by an excavator and a bur was similar the treatment success rate was lower when the exposure was caused by an excavator the existence of pulpal bleeding resulted in mistakes in diagnoses. PMID- 24046980 TI - Pediatric dental practice and changing population demographics: a commentary. AB - US. Census Bureau reports for the 2010 census detail the slowing overall growth of the number of children with specific emphasis on the increasing proportion of Hispanic children in the population. A review of these data is considered in terms of the potential impact on pediatric dental practices. PMID- 24046981 TI - Impact of socio-cultural practice of infant/young child gum lancing during teething. AB - BACKGROUND: Fever and diarrhea are among the common morbidities that do occur during infancy and are sometimes wrongly associated with teething by the community. Some societies practice gum lancing, ordinarily referred to as gum cutting, as a remedy for the "teething diarrhoea". These myths have a potential of giving false security with the belief that these symptoms are part of the teething process, and so medical attention may not be sought when necessary. There are few studies focusing on the outcome of such practices despite their known potential dangers. OBJECTIVE: To describe various methods of gum lancing and clinical presentation, management and outcome of gum lancing among the Akamba people as seen in Kangundo District Hospital. METHOD: One hundred and fifteen infants/children who were brought to the hospital with a positive history of gum lancing. RESULTS: The common presenting complaints were persistent diarrhoea (74.0%), fever (44.3%), difficulty in breathing (27.8%) and refusal to feed (20.9%). 58.3% cases warranted admission and these included severe dehydration and shock (47.8%), severe and very severe pneumonia (40.3%), meningitis (26.9%) and generalized sepsis (17.9%). There were a total of 7 mortalities (6.1%), 3 on arrival and 4 within the pediatric ward. Invasive gum lancing procedures and delayed seeking of medical attention were associated with severe disease and poorer outcomes. CONCLUSION: The impact of gum lancing is of both a public health and economic significance. It is associated with unfavorable outcome if prompt measures are not put in place. There is need to conduct community sensitization and educate caregivers on the truths of teething and dangers of gum lancing as well as seeking health services for fever and diarrhoea. Use of broad-spectrum antibiotics and adequate rehydration are necessary in management of the victims. PMID- 24046982 TI - Molecular detection of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis in subgingival plaque of healthy young children. AB - OBJECTIVE: The aim of the present study was to evaluate the presence of Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) and Porphyromonas gingivalis (P. gingivalis) in subgingival plaque of healthy young children aged between 3 and 15 years using Polymerase Chain Reaction (PCR) and to compare their presence in children in their primary, mixed and permanent dentitions. METHOD: Subgingival plaque samples were collected from 120 healthy children and were grouped as Group I-Deciduous dentition, Group II- Mixed dentition and Group III- Permanent dentition, and were subjected to PCR assay. RESULTS: Binomial test and Proportions test were used for statistical analysis. A. actinomycetemcomitans and P. gingivalis were detected in 5% and 35%, 12.5% and 20%, and 0% and 27.5% samples in group I, II and III respectively. CONCLUSION: Both the microorganisms were present in group I and II. In group III only P. gingivalis was present. The results from this study do not necessarily pertain to differences in dentition but possibly to inter-individual differences. PMID- 24046983 TI - Evaluation of microbial profile in dental unit waterlines and assessment of antimicrobial efficacy of two treating agents. AB - OBJECTIVE: The quality of water in a dental unit used for cooling and flushing the high and low speed handpiece, air/water syringes and the scalers is of considerable importance. The present study was carried out to enumerate and identify the microorganisms present in water samples collected from dental unit waterlines of different dental specialty clinics and to find out the efficacy of two treating agents in disinfecting dental unit waterlines. STUDY DESIGN: Sample included 70 dental unit waterlines from different speciality dental clinics which were checked for microbial contamination. From these dental units 40 units were randomly selected and divided into two groups of 20 each. Group A, treatment was done in 20 dental units with 0.2% Chlorhexidine gluconate solution and Group B, treatment was done in 20 dental units with 10% Povidone iodine solution and the reduction in the microbial levels were assessed. Five dental units were randomly selected and checked the microbial contamination using mineral water sterile distilled water fresh tap water as a water source in the dental unit reservoir bottles. Also from the test group, five from each group were checked for the duration of efficacy of treating agent for one week by analyzing the water samples collected on 3,5 and 7 day intervals. RESULTS: Most of the identified microorganisms are Gram negative and pseudomonas predominating up to 98.59% of the total isolates. Usage of disinfectants 0.2% Chlorhexidine and 10% Povidone Iodine were found to be very effective in reducing the microbial contamination and 10% Povidone iodine was found to be more efficient (97.13%) and active for a period of 3 days and gradually loosing its efficacy by 7th day. No significant difference were found in microbial contamination of water samples collected from different water outlets such as handpiece outlets, air water syringe outlets, scaler lines. CONCLUSION: To continue maintaining the sterility of the Dental unit waterlines and to complete the infection control measures adopted in the dental clinics, suitable disinfectants like 0.2% Chlorhexidine on daily basis or 10% Povidone iodine on every 3rd day basis intermittently maintain the sterility of dental unit waterlines it is essential to have a good water source and an effective disinfectant. PMID- 24046984 TI - Propolis and commonly used intracanal irrigants. Comparative evaluation of inflammatory potential. AB - AIM: The present study evaluated the inflammatory/irritant potential of propolis in comparison with commonly used intracanal irrigants such as chlorhexidine and calcium hydroxide, with normal saline solution as control using an animal (Wistar rats) model. METHOD: 2% Evans blue was intravenously injected into the lateral caudal vein. 0.1 ml each of the test solutions was intradermally injected into the experimental sites designed on their shaved backs. The animals were then sacrificed after 1 1/2 and 3 hours respectively. Each piece of skin containing the injected solution was excised, immersed in 4 ml formamide and incubated at 45 degrees C for 72 hours. After filtration with glass wool, optical density(OD) was measured using a spectro-photometer and analyzed statistically. RESULTS: At 620 nm irrespective of time, the mean optical density with Calcium Hydroxide was found to be maximum (0.197 +/- 0.095) while that with DMSO Propolis was found to be minimum (0.070 +/- 0.016). Both at 90 min and 180 min, the mean optical density with Calcium Hydroxide was found to be maximum. CONCLUSIONS: On short term evaluation, maximum inflammation was seen with calcium hydroxide followed by chlorhexidine and DMSO extract of propolis. Minimum inflammation was seen with sterile physiologic saline. With progress of time, maximum inflammation was seen with calcium hydroxide followed by chlorhexidine and DMSO extract of propolis which was non-significant. PMID- 24046985 TI - Salivary interleukin-8 levels in children suffering from type 1 diabetes mellitus. AB - OBJECTIVE: The aim of this study was to investigate the differences between the salivary levels of IL-8 in patients with Type 1 diabetes mellitus (DM) with (DM+P) or without (DM-P) concomitant periodontitis and healthy subjects. The correlations between the levels of these cytokines and clinical periodontal parameters were also established. METHODS: Twenty children and adolescents with Type 1 DM (10 diagnosed with periodontitis, 10 presenting no signs of periodontitis) and a control group consisting of 20 healthy children and adolescents aged 7-18 years were recruited for this study. RESULTS: The Salivary IL-8 level was statistically significantly (p < 0.005) elevated in subjects with Type 1 DM (474.47 +/- 716.76) compared to non-diabetic control group (101.99 +/- 68.32). There was no difference (p > 0.05) in the salivary IL-8 level when subjects with Type 1 DM with concomitant periodontitis were compared to diabetics without periodontitis. When the salivary IL-8 level in subjects with Type 1 DM was correlated with the clinical parameters, no statistical significance was found. CONCLUSION: An elevated salivary IL-8 level in subjects with Type 1 DM without concomitant periodontitis plays a major role in the development of diabetic micro and macroangiopathy and pathogenesis of atherosclerosis. Consequently, this may offer a basis for the assessment of risk, prophylaxis and treatment of diabetic complications. PMID- 24046986 TI - Measuring the impact of quality of life of children treated for orofacial clefts: a case-control study. AB - OBJECTIVE: The aim of this study was to assess the quality of life (QoL) of children previously treated for cleft lip and/or palate (CL/P) and compare with non-cleft children. METHOD: A case-control study with 70 children between 5 and 12 years old was carried out. The case group consisted of 35 individuals previously treated for non-syndromic CL/P and presently receiving assessment at a rehabilitation hospital in Brazil. The children had received primary surgical treatment for CL/P reconstruction during early childhood. The control group consisted of 35 healthy children selected to ensure close similarity to the cleft group in age, gender and socioeconomic status. QoL was measured using the AUQEI questionnaire. RESULTS: Cleft lip and palate had no significant influence on the QoL in children (p = 0.44). A higher percentage of the cleft lip and palate group of children reported a lower QoL than the cleft lip or cleft palate groups. Gender had no significant difference on the quality of life in CL/P children (p = 0.2) and in control group (p = 1.0). CONCLUSION: The QoL in children with CL/P was found to be similar to the non-cleft group. Our results confirm that clefts repaired during earlier childhood associated with a health care program, including psychological support, is beneficial for CL/P children. PMID- 24046987 TI - Knowledge of care providers regarding the oral health care of visually impaired children. AB - OBJECTIVE: To assess the awareness of care providers of visually impaired children regarding their oral hygiene. METHOD: A simple pre-structured questionnaire was given to the care providers and the awareness regarding their oral health was assessed. RESULTS: There was a general lack of awareness among the care providers of these children regarding dental diseases and its prevention. Furthermore, the importance of oral hygiene was found to be very low. CONCLUSION: The results obtained showed that most of the caretakers were unaware of the difficulties faced by these children in the maintenance of their oral health. PMID- 24046988 TI - Enamel defects in the primary dentition of preterm and full-term children. AB - AIM: This study compared enamel defects in children born prematurely and at term. METHOD: 96 children born at term (G1), and with 96 children born prematurely (G2) were studied. RESULTS: A higher prevalence of enamel defects was found in the premature group, with a predominance of hypoplasia. In G1, 64 teeth displayed enamel defects (51 opacities and 13 hypoplasias). In G2, 110 defective teeth were found, (29 opacities and 81 hypoplasias). A significant correlation was found between very low birth weight (VLBW) and the presence of these defects (p < or = 0.001). The teeth most affected were the incisors, canines and molars. CONCLUSION: Prematurity, in conjunction with other factors, can predispose children to enamel defects. PMID- 24046989 TI - Bond strength to unground enamel and sealing ability in pits and fissures of a new self-adhering flowable resin composite. AB - OBJECTIVE: To evaluate the applicability as a sealant of a new self-adhering flowable resin composite (Vertise Flow, Kerr, VF) by assessing shear bond strength (SBS) to unground enamel and microleakage (microLKG) in sealed pits and fissures. STUDY DESIGN: Marketed sealants to be used in combination with phosphoric acid (Guardian Seal, Kerr, GS) or with a self-etch adhesive (Adper Prompt-L-Pop/Clinpro Sealant, 3M ESPE, CS) were compared to VF. For SBS testing on unground enamel 10 molars per group were used. For microLKG assessment, pits and fissures sealing was performed in 12 molars per group. The sealed teeth were immersed in a 50% weight silver nitrate solution for 24 hours and the extent of interfacial leakage was measured. Between-group differences in SBS were assessed using One-Way Analysis of Variance (ANOVA), followed by Tukey test (p < 0.05). microLKG data were analyzed with Kruskall-Wallis ANOVA (p > 0.05). RESULTS: SBS of VF was statistically similar to that measured by CS and higher than that of GS. Interfacial leakage was similar in the three groups. CONCLUSIONS: The finding of satisfactory bond strength and sealing ability of VF when compared to the marketed sealants encourages the use of VF in pit and fissure sealing. PMID- 24046990 TI - Biocompatibility of a conventional glass ionomer, ceramic reinforced glass ionomer, giomer and resin composite to fibroblasts: in vitro study. AB - OBJECTIVE: This aim of this study was at compare the fibroblast cytotoxicicty of four restorative materials--a conventional glass ionomer cement (GC Fuji Type II GIC), a ceramic reinforced glass ionomer cement (Amalgomer), a giomer (Beautifl II) and a resin composite (Filtek Z350) at three different time periods (24, 48 and 72 hours). METHOD: The succinyl dehydrogenase (MTT) assay was employed Cylindrical specimens of each material (n = 15) were prepared and stored in Dulbecco's modified Eagle medium, following which L929 fibroblasts were cultured in 96 well plates. After 24 hours of incubation, the MTT assay was performed to detect the cell viability. The method was repeated after 48 and 72 hours. The impact of materials and exposure times on cytotoxicity of fibroblasts was statistically analyzed using two way ANOVA (P = 0.05). RESULTS: Both time and material had an impact on cell viability, with giomer demonstrating the maximum cell viability at all time periods. The cell viability in the giomer group was significantly different from all other materials at 24 and 72 hours (P < 0.05), while at 48 hours giomer was significantly different only with resin composite (P < 0.05). CONCLUSIONS: Giomers showed better biocompatibility than conventional and ceramic reinforced glass ionomer cements and, resin composite. Ceramic reinforced glass ionomer demonstrated superior biocompatibility compared to conventional glass ionomer. PMID- 24046991 TI - Long-term maxillofacial effects of radiotherapy in young nasopharyngeal carcinoma patients: report of 3 cases. AB - Nasopharyngeal carcinoma (NPC) is a rare and distinct malignancy that arises from the epithelium of the nasopharynx. It accounts almost 1% of all pediatric malignancies. Oral complications of radiotherapy in the head and neck region are the result of the deleterious effects of radiation on salivary glands, oral mucosa, bone, dentition, masticatory musculature, and temporomandibular joints. Here we present 3 male NPC patients 13, 14 and 15 years old. One of them had stage III and the others stage IV diseases. Administered dose of radiation was 66 Gy for case I, 70 Gy for case II and 68 Gy for case III. The follow-up period was more than 12 months except for case III and all of them were disease free in their last visit. All attended dental clinics for dental and TMJ problems. Dentitions were severely affected, trismus and severe xerostomia. Long-term effects of radiotherapy which has a great impact on patients' quality of life and the role of supportive care and minimizing the late effects of ionizing radiation are discussed. PMID- 24046993 TI - A double blind randomized trial of ketofol versus propofol for endodontic treatment of anxious pediatric patients. AB - OBJECTIVE: To find out the safe and efficient sedative agent for primary molar pulpectomy in uncooperative pediatric patients. STUDY DESIGN: This double blind randomized trial enrolled 40 anxious and healthy 2-6 year olds. All subjects received IV propofol (1-1.5 mg/kg) or ketofol (1-1.5 mg/kg propofol with 0.25 mg/kg ketamine) as per group assignment after oral midazolam premedication (0.5 mg/kg). Sedation maintenance was done with propofol infusion at 25-75 microg/kg/min titrated to a predefined Worse level as per Houpt's sedation rating scale. Additional bolus/es was/were administered in the dosage similar to induction dose in case of inadequate sedation. Primary outcomes were intraoperative and postoperative adverse events. Secondary outcomes were vital signs, success of procedure, operator satisfaction, sedation quality, treatment time, recovery time and total propofol dose. RESULTS: Significantly greater incidence of respiratory depression was reported for ketofol group (11/20; 55%) when compared to propofol group (3/20; 15%) (p = 0.008). Desaturation was the most common adverse respiratory event with significantly greater incidence in ketofol group (9/20; 45%) when compared to propofol only group (3/20; 15%) (p = 0.033). No significant differences regarding secondary outcomes were reported in two groups. CONCLUSION: Both the regimen exhibited similar sedation profile while propofol alone emerged as a safer option. PMID- 24046992 TI - Dental findings in a child with osteopathia striata with cranial sclerosis (OS CS): a case report. AB - The dental management of an 8-year-old girl with osteopathia striata with cranial sclerosis (OS-CS) is described. The girl presented with various oral abnormalities. The aim of this case report was to describe in detail the dental findings in a patient with OC-CS and the precautions to be taken when planning treatment. In the present case, many dental anomalies, such as delayed eruption of the permanent teeth, obliteration of the dental pulp, short roots, fused roots and taurodontism, were detected. In patients with OS-CS, routine dental care from an early stage is recommended to manage this anomaly properly. PMID- 24046995 TI - Challenges of training in pulmonary medicine in India. PMID- 24046994 TI - Orthodontic treatment of hypodontia and delayed development of a maxillary second premolar. AB - It can be difficult to formulate a definitive diagnosis and treatment plan for patients with hypodontia while dental development is still in progress. Proper radiographs should be used periodically to check for the possibility of delayed tooth development to reduce the potential of misdiagnosis and improper treatment. This article presents a case with orthodontic treatment of hypodontia and delayed development of a maxillary second premolar. PMID- 24046996 TI - Profile of lung cancer in predominantly Bidi smoking rural population of northern Himachal Pradesh. AB - BACKGROUND: Lung cancer is a leading cause of morbidity and mortality among both genders. The histopathological patterns of lung cancer in different parts of India appear to be variable. OBJECTIVE: To study the profile of lung cancer in northern Himachal Pradesh. METHODS: Patients of all age groups and either gender with history and complaints suggestive of lung cancer were subjected to further investigations to study the histopathological types of lung cancer over a period of 14 months. RESULTS: Out of 105 histopathologically confirmed patients with lung cancer (mean age 62.7 +/- 11.6 years; 96 males), 89.5% were "ever smokers" and 82.9% were "current smokers"; 92% of current smokers were bidi smokers. Most common presenting complaints were chest pain (46.7%) and cough (35.2%). Mean duration of longest presenting complaint was 64 days. The histopathological types included squamous cell carcinoma (37.1%), adenocarcinoma (36.2%), small cell carcinoma (8.6%), un-classifiable (16.2%), and other types (1.9%). CONCLUSIONS: Majority of the lung cancer patients in northern Himachal Pradesh were bidi smoking males from rural areas and the incidence of adenocarcinoma and squamous cell carcinoma is almost equal. PMID- 24046997 TI - Correlation of atopy and FeNO in allergic rhinitis: an Indian study. AB - BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a non-invasive marker of airway inflammation. Limited published data are available on the effect of atopy on FeNO in allergic rhinitis. OBJECTIVES: To investigate the relationship between atopy and FeNO in patients with allergic rhinitis. METHODS: Patients with allergic rhinitis were assessed for atopy and exhaled breath analysis of nitric oxide. Atopy was assessed by skin prick testing (SPT) against 58 common aero allergens; a wheal size of 3mm or more as compared to buffer saline was considered positive. Patients were labelled to be atopic if they had at least one positive SPT result. The measurement of FeNO level was done by using NIOX chemiluminescence analyser. RESULTS: Forty-nine participants (26 males) aged between 8-50 years were studied and 31 of them were found to be atopic. The average value of FeNO in the subjects studied (n = 49) was 26.0 +/- 22.7 parts per billion (ppb) with significantly higher values being observed in atopic group as compared to non-atopic group (34.2 +/- 24.3 versus 11.9 +/- 9.0 ppb; p < 0.05). CONCLUSION: As FeNO is a marker of lower airway inflammation, significantly higher FeNO levels in atopic allergic rhinitis patients suggest that it may be a predictor for onset of asthma in these patients. PMID- 24046998 TI - Manifestations of pulmonary disease in adults with congenital heart disease. AB - Children with congenital heart disease (CHD) are more frequently living into adulthood as their survival has improved due to availability of better medical and surgical management in recent times. Management of adults with CHD is emerging as new challenge in the field of medical science. Adults surviving with CHD for longer duration have been observed to develop more complications as compared to children. It is important to recognise and treat these complications early to reduce the morbidity. Pulmonary diseases are the most common systemic complications associated with adults having CHD. These individuals are presenting to clinics or emergency for pulmonary complaints, hence, pulmonologist must be aware about the pulmonary manifestations of CHD and their management. PMID- 24046999 TI - Pulmonary fibrosis and emphysema. PMID- 24047000 TI - Single lung transplantation in India: an initial experience. AB - The science of lung transplantation has evolved from an experimental procedure, to be accepted as a legitimate mainstream therapy for patients with end-stage pulmonary disease. Now lung transplantation offers patients with end-stage lung disease acceptable quality of life and matches a 5-year survival rate of other solid organ transplants. In the present report, we present our initial experience in performing two single lung transplantations done in our centre. PMID- 24047001 TI - Angiotensin-converting enzyme inhibitors in the treatment of sarcoidosis and association with ACE gene polymorphism: case series. AB - Angiotensin-converting enzyme (ACE) is used as a marker for sarcoid disease activity. We present an observational study of four African-American patients all of whom demonstrated improvement in their sarcoidosis after treatment with ACE inhibitors for hypertension. PMID- 24047002 TI - Agenesis of the hemidiaphragm: a rare presentation in an adult. AB - Unilateral diaphragmatic agenesis is a rare finding in adult patients. We report a case of unilateral agenesis of diaphragm in a 22-year-old male patient to highlight the fact that a rare entity of agenesis of diaphragm can have a misleading presentation in adulthood due to both pulmonary and abdominal symptoms. PMID- 24047003 TI - Silent rupture of aortic aneurysm mimicking lung malignancy. AB - Extra-pulmonary diseases may mimic pulmonary lesions on chest radiography. We report a case of a silent rupture of an atherosclerotic thoracic aortic aneurysm with peripheral thrombus formation, that closely mimicked a complicated lung malignancy. PMID- 24047004 TI - Stepping down in asthma. AB - Beta-2-agonists continue to find a dominant role in all the current guidelines on the management of chronic persistent bronchial asthma. However, the safety of the drugs remains doubtful. Thus, there is a case for review of the "Step up-Step down" approach in the management of chronic persistent bronchial asthma. Based on the currently available experimental and clinical data on bronchial asthma, the authors are of the opinion that chronic persistent bronchial asthma is best managed by a modified "Step I-Step II" approach. PMID- 24047005 TI - Association of levels of N-terminal-pro-BNP-type natriuretic peptide with localisation of thrombus in acute pulmonary embolism. PMID- 24047006 TI - Author's reply: To PMID 24047005. PMID- 24047007 TI - Trans-septal suturing following septoplasty: an alternative for nasal packing. AB - Septoplasty is one of the most common otorhinolaryngologic surgical procedure. It is customary to place a pack in the nose as a part of nasal surgery to stop bleeding, enhance apposition of mucosal flaps, and stabilize the operated septal cartilage and bones. But nasal packing is not an innocuous procedure. The most common problem encountered by the patients after septoplasty with nasal pack is the pain and discomfort in post operative period. The study has been performed to compare the complications and outcome of septoplasty with or without nasal packing. Forty four patients were randomly allocated into two groups, Group A (n = 21) and Group B (n = 23). In Group A trans-septal suture and in Group B intranasal pack was used following septoplasty. Both groups were compared for postoperative pain, postoperative complications and surgical outcome. Among 44 patients 31 patients were male and 13 patients were female. Most of the patients ie 79.5% were operated for nasal obstruction. Only one patient had postoperative nasal bleeding requiring nasal pack in Group A. Higher Postoperative pain score, longer hospital stay and more complications were observed in Group B patients. No difference was found in patients' satisfaction after the operation. Septoplasty can be safely performed without postoperative nasal packing and is preferred to avoid postoperative pain, discomfort and other complications. PMID- 24047008 TI - Study on carrier rate of Streptococcus pyogenes among the school children and antimicrobial susceptibility pattern of isolates. AB - This study was done to investigate the rate of Streptococcus pyogenes or Group A streptococcus (GAS) and antimicrobial susceptibility pattern of isolates in asymptomatic school children in Kathmandu and Sindhuli districts. Pharyngeal swabs were collected and subjected to crystal violet blood agar (CVBA). A total of 468 asymptomatic school aged children were included and 51 (10.8%) were found to be GAS carrier. Among the isolates 23 (12.0%) were from boys where 28 (10.1%) were from girls. The GAS colonization rate was statistically insignificant (P > 0.05) with sex and age sub-group, although the rate was slightly higher among the boys and age sub group 10-12 years. GAS was significantly higher in large family size (p < 0.05). Out of 51 isolates, 100.0% isolates were sensitive to antibiotic penicillin where as 7.8% and 5.8% isolates were resistant to antibiotic ampicillin and erythromycin respectively. PMID- 24047009 TI - Patients' satisfaction with eye care services at Nepal Medical College. AB - Patient satisfaction surveys are conducted to evaluate and improve the quality of health care services. A patient satisfaction survey was conducted in the Department of Ophthalmology, Nepal Medical College Teaching Hospital. The objective of the study was to assess patients' satisfaction with respect to services received from the hospital: ease with which patients accessed care, perception of waiting time, patient- service provider relationship, payment and hospital facilities/environment. Slightly more than three quarters of the participants expressed overall satisfaction. Satisfaction with access to health facility was75.5%, patient doctor relationship was 87.9%, affordability was 76.8% and waiting time was 62.0% respectively. Patient satisfaction surveys should be carried out periodically not only to determine the level of patient satisfaction about the various services of the hospital but also to get the patients' feedback which could be incorporated into the hospital service improvement plans. PMID- 24047010 TI - Understanding clinical features of adenomyosis: a case control study. AB - Adenomyosis is largely under diagnosed before hysterectomy and commonly co-exists with uterine fibroid. Thus this study aimed to elicit the clinical profile of adenomyosis by comparison with uterine fibroid. This is a hospital based prospective case-control study carried out from 1st April 2010 to 31st May 2011 which comprise of women undergoing hysterectomy with a histological diagnosis of sole adenomyosis without fibroid, women with both adenomyosis and fibroid and women with fibroid but no adenomyosis. Ambulatory records were performed. The study comprised 150 women, 78 (52%) women with adenomyosis without fibroid, 27 (18%) women with both adenomyosis and fibroid, 45 (30%) women with fibroid but no adenomyosis. Among women with adenomyosis alone, 78.2% had menorrhagia, 73.1% had dysmenorrhoea, 76.9% had chronic pelvic pain and women with adenomyosis and fibroid had menorrhagia in 85.2%, dysmenorrhoea in 51.9%, chronic pelvic pain in 48.1% compared with women of fibroid alone had menorrhagia in 75.6%, dysmenorrhoea in 66.77%, chronic pelvic pain in 51.1%. Women with adenomyosis group had significantly more of chronic pelvic pain (p-value: 0.003) and had significantly greater parity (p-value: 0.002). Size of uterus was significantly smaller in adenomyosis group (p-value: 0.018) as well as significantly more tender uterus was found in adenomyosis group (p-value: 0.000). Adenomyosis is more frequent among women reporting dysmenorrhoea, menometrorrhagia, chronic pelvic pain and along with bulky uterus. Women with fibroid alone has more of menorrhagia than pain and is associated with enlarge uterus. If women have small fibroid uterus but have more symptoms--think about co-existence of "ADENOMYOSIS". PMID- 24047011 TI - Nepal's noble echocardiography-database with video clips and color still images: a single individual's 6 years' experience at the Echocardiography Lab of Nepal Medical College, Teaching Hospital. AB - Echocardiographic reporting system is very poor in Nepal. No long-term feasibility and efficacy data about the echocardiography database with video clips has been studied. Snazzi Movie Studio S4 was used to convert analog video signals into MPEG2 and color photographs were converted into JPEG format for storage and use for the database. All together 2272 patients' echocardiography were performed by one individual prospectively at the Nepal Medical College Teaching Hospital from 10th January 2007 to 9th January 2012. Echocardiographic findings of these patients were evaluated. Mean age +/- SD were 44.4 +/- 28.7 years. Male female ratio was 0.8:1. Brahman/Chhetri were the usual ethnic group to undergo echocardiography (943, 41.5%), followed byjanajati (631, 27.8%) and newar (496, 21.8%). Age group of 60-69 years was the most common echo users (519, 22.8%). Total time for echocardiography/report writing with database compared to non database was 13.9 +/- 2.4 minutes vs. 12.3 +/- 0.8 minutes, p = 0.51. Out of all lesions, valvular lesions were the most common lesions detected (4885, 215%). Mild tricuspid regurgitation (1213, 53.4%) was the most common valvular lesion followed by mild mitral regurgitation (742, 32.7%). Patent foramen ovale was the most common congenital heart disease (32, 45.7%) followed by atrial septal defect (12, 17.1%). About one seventh of the total patients (318, 13.9%) had systolic dysfunction. Out of total chronic cor pulmonale (383, 16.9%), severe Pulmonary arterial dysfulction (PAH) was noted in more than one third of the patients (169, 44.1%). PMID- 24047012 TI - Patterns of hematological and non-hematological malignancies in bone marrow in a tertiary care hospital in Nepal--11 years study. AB - Developing countries bear more than half of the global cancer burden and the leukemia comprises of 3% of all malignancies with an incidence of 300,500 per year. The patterns of subtypes of leukemias vary in different populations and geographic areas. Here, we analyze both the hematological and non-hematological malignancies in the Western region of Nepal. This is a retrospective study done from Janauary 2000 to June 2011. All cases of bone marrow malignancies including leukemias, multiple myeloma and infiltration/metastasis to bone marrow were included in the study. Morphological subtypes {FAB (French, American and British) classification}, gender, age at diagnosis and peripheral blood counts of all the cases were analyzed. A total of 155 cases of hematological and non-hematological malignancies were reported during this period. Age ranged from 1 year to 82 years. Among 123 leukemia cases, acute myeloid leukemia (AML) was the commonest (80 cases) followed by chronic myeloid leukemia (CML) (20 cases), acute lymphoid leukemia (ALL) (16 cases) and chronic lymphoid leukemia (CLL) (7 cases). The commonest childhood leukemia below 15 years was AML followed by ALL. The commonest subtypes of AML and ALL were M2 and L2 respectively. CML cases in our study were less common and females were more affected than other parts of the country. There were 23 cases of multiple myeloma and 9 cases of infiltration/metastasis to marrow. Males were more affected by multiple myeloma in our study. Our data reflects bone marrow malignancies in the Western region of Nepal which is more comparable to the Central than Eastern region of Nepal. PMID- 24047013 TI - Dermatological problems in geriatric patients: a hospital based study. AB - Geriatric health care has become a major issue worldwide. There are no data regarding geriatric dermatologic diseases are available from Nepal. Patients of 60 years and above were enrolled in the Nepali fiscal year 2067(April 2010-April 2011). The data included age, sex, place, and diagnosis. The aim of the study is to determine the characteristic pattern and frequency of dermatoses in dermatologic patients aged 60 years and above. There were total of 6442 patients who visited out patients department. Out of which frequency of geriatric patients were 330, which constitute about 5.1%. The male to female ratio was 50% each. The most common cutaneous dermatoses was eczema 35.8%, fungal infection 13.6%, viral infection 7%, followed by pruritus 7.3%, scabies and photodermatitis 4.5% each, Inflammatory papulosquamous disorder 3.3%, Bacterial infection and Icthyosis 2.1% each, vesiculobullous 1.8%, tumors and pigmentary disorder 0.6% and Miscellaneous group (keratoderma, callus, urticaria, diabetic ulcer, burgers disease, burning feet syndrome, Rosacea, Drug rash-amoxicillin, senile acne, prurigo nodularis, hansens disease, pellagra, Actinic cheilitis) 15.8%. Few patients had more than one dermatoses which constitute < 1% .Photodermatitis was found to be statistically significant. The most common dermatoses were Eczema in females followed by Photodermatitis and comparatively in males viral and fungal infections were common. This study depicts various characteristic patterns of dermatoses seen in elderly. Eczema and infections was found to be most common diseases seen in elderly. Further epidemiologic studies including treatment, follow-up of elderly patients has to be carried out to know the burden of the disease and decrease morbidity and psychological concern associated with diseases. PMID- 24047014 TI - Economic impact of pulmonary tuberculosis on patients and their families of Dharan municipality, Nepal. AB - Tuberculosis (TB) affects mostly economically active population in underdeveloped and developing countries, therefore TB can have far reaching economic and social consequences among infected people and their household members. The objectives of this study were to estimate the household expenditure before and during the course of disease, to explore the direct and indirect cost burden of tuberculosis in terms of annual family income and to compare the total cost burden in a family of case treated with directly observed treatment shortcourse (DOTS) and without DOTS. A total of 160 treatment completed, pulmonary tuberculosis (PTB) cases fulfilling the inclusion criteria were interviewed. The median patients income before and during illness was US$1.95 and US$0.9 respectively. Similarly, household expenditure before illness was US$3.24 and during illness was US$4.28. Direct cost burden in terms of annual family income was higher (15.2%) than indirect cost burden (8.2%). But, free distribution of anti tuberculosis therapy (ATT) through DOTS reduced the total cost burden of patient by more than 8%. In conclusion, overall cost burden of pulmonary tuberculosis is high even though the treatment is free of cost. PMID- 24047015 TI - A randomized study comparing intravaginal prostaglandin (PGE2) with oxytocin for induction of labour in premature rupture of membrane at term. AB - This is a prospective randomized study conducted in Tribhuvan University Teaching Hospital from February 2008 to January 2009. Total 72 women with Premature rupture of membranes (PROM) were included. Thirty-six women received PGE2 vaginal gel and thirty-six received iv oxytocin. Induction was successful in majority of cases in both the groups; 88.8% in PGE2 and 83.3% in oxytocin group (p value = 0.063). Time duration from induction to active stage was comparable (p value = 0.273). Induction to delivery interval was significantly low in oxytocin group (p value = 0.002) but leaking to delivery interval was similar in both the groups (p value = 0.083). PGE2 had slightly higher side effect than oxytocin. PGE2 and oxytocin were both effective and safe for induction of labour in women with PROM at term. There was no significant difference in maternal and fetal outcome, hospital stay, leaking to delivery interval, maternal and neonatal side effects, though induction to delivery interval was significantly less with oxytocin. PMID- 24047016 TI - Studies on extended spectrum beta lactamase (ESBL) producing salmonella isolates from clinical samples of Nepal. AB - Present study was carried out among the patients of age 2-60 years from November 2009 to November 2011 to assess the production of Extended Spectrum Beta Lactamase (ESBL) by salmonella enterica serotype (Typhi and paratyphi A) at Kanti Children's Hospital (KCH), Nepal Medical College (NMC), Kathmandu Medical College (KMC), National Public Health Laboratory (NPHL) and Sankata Laboratory (SKL) of Nepal. Blood cultures were obtained from 4,820 patients with febrile illnesses. 400 strains of salmonella enterica were isolated. Antibiotic susceptibility testing was carried out using disk diffusion method by Kirby-Bauer technique and ESBL screening were done by Double Disk Synergy Test (DDST), following the Clinical and Laboratory Standard Institute (CLSI) recommendations for Escherichia coli. Male had higher infection (56%) than female (44%). Highest number of culture positive cases were (37%) in 10-19 years of age groups. Highest episodes of enteric fever cases occurred during April - June (45%) followed by July September (35%). Among the total isolates 286 (72%) were Multidrug resistance (MDR). All the Multidrugs resistance salmonella, resistant to third generation Cephlospornis were ESBL producers. PMID- 24047017 TI - How to decannulate tracheostomised severe head trauma patients: a comparison of gradual vs abrupt technique. AB - Tracheostomy is a common surgical procedure performed in patients with severe head injury to facilitate prolonged airway and ventilatory support. Decannulation is the procedure of removing the tracheostomy tube either gradually by downsizing the tube or abruptly in a single sitting. This prospective study was done to evaluate gradual vs abrupt techniques for successful decannulation in tracheostomised severe head trauma patients in Post Graduate Institute of Medical Education and Research (PGIMER), a central government tertiary centre in Chandigarh, India. A total of 118 patients, recruited over one and half years duration were arbitrarily divided into 2 groups: Gradual and Abrupt. Particulars were taken. Time since tracheostomy, timing of decannulation, Glasgow Coma Scale, amount of secretions, breath holding time, CXR and STN radiographs and cough reflex were all assessed. Follow up was done at one month to classify those who were re-tracheostomised or re-intubated as decannulation failures. Sixty-eight patients were decannulated gradually and 50 abruptly. Of the various factors assessed, only cough reflex, number of suctioning required per day, X-ray STN and use of antibiotics for more than 7 days were found to be statistically significant. One hundred and fourteen patients, 67 out of 68 in the GD group and 47 out of 50 in the AD group, had successful outcome. The study showed that success or failure of decannulation is independent of mode of decannulation. PMID- 24047018 TI - Study of medically important Vibrios in the sewage of Katmandu Valley, Nepal. AB - A total of 42 samples were collected from the different sites of sewer system of Kathmandu Valley during rainy summer season (June to September 2008) using Moore's technique. Samples (on Moore's swabs) were submersed in alkaline peptone water (pH 8.6) and transported to Research Laboratory of National Institute of Tropical Medicine and Public Health Research, Kathmandu in cold condition (ice chest) followed by incubation at 37 degrees C for 8 hours. After incubation, culture was done on thiosulfate-citrate-bile salt-sucrose (TCBS) agar and incubated at 37 degrees C for overnight (15 hrs). Both yellow and green colonies measuring from 2 to 9 mm in diameter on TCBS agar were subjected for gram staining, biochemical testing as well as sero-typing using antisera (poly O1, Ogawa and Inaba) (Denka Seiken Co. Ltd, Japan). Altogether 46 medically important Vibrios were isolated from 42 samples studied. The isolates were identified as V. cholerae (n = 20; 43.5%), V. vulnificus (n = 11; 23.9%), V. parahaemolyticus (n = 5; 10.9%), V. furnissi (n = 5; 10.9%), V. fluvialis (n = 3; 6.5%) and V. alginolyticus (n = 2; 4.3%). Of the 20 V. cholerae isolates, 13 (65.0%) and 7 (35.0%) isolates were V. cholerae O1 and non-O1, respectively. Among the V. cholerae O1 (n = 13), classical Hikojima strain was most frequently isolated (n = 10) followed by V. cholerae O1 Ogawa (El Tor = 2 and classical = 1). High frequency of V. cholerae isolation from sewer system of Kathmandu Valley is an indication of possible outbreak of cholera anytime in future and, therefore, demands improvement in sanitary condition, supply/consumption of safe drinking water and personal hygiene. PMID- 24047019 TI - Assessment of characteristics of patient with delirium tremens. AB - Delirium tremens is the severe form of alcohol withdrawal. It carries a certain degree of mortality and there has been and advancement in the understanding of pathophysiology and risk factors for the development of the condition. This prospective study is carried out to study the characteristic of the patient of delirium tremens in our setting using ICD-10 diagnostic criteria. Thirty seven cases of delirium tremens with majority of males and of all hill origin people were identified. Patients with delirium tremens has been using alcohol for average of 24.8 years with an average intake of around 2.2 litres per day. Most of the patient has seizure and similar episodes in past and using alcohol from morning time. PMID- 24047020 TI - Etiological agents of corneal ulcer: five years prospective study in eastern Nepal. AB - To identify the most common isolates from the corneal ulcers with antimicrobial pattern of bacterial isolates. All patients with suspected corneal ulceration presenting to BP Koirala Institute of Health Sciences from Jan 2004 - Dec 2008 were evaluated. Corneal scraping was performed and processed for direct microscopy, bacteriological and fungal culture. Bacterial isolates were subjected to antimicrobial susceptibility testing. Of 351 specimens examined, growth of etiological agents were obtained in 278 (79.20%). Of these, 113 (40.65%) had pure fungal growth, 108 (38.85%) had pure bacterial growth and 57 (20.50%) had mixed fungal and bacterial infection. The commonest fungal pathogen was Aspergillus spp 50 (33.33%) followed by Fusarium spp 19 (12.66%). Staphylococcal aureus 57 (44.53%) was isolated as commonest bacterial agent. Coagulase Negative Staphylococci 20 (15.6%) was second in the list. Pseudomonas spp 12 (9.40%) was the most common gram negative bacilli isolated. Most of the bacterial isolates were sensitive to commonly used antibiotics. Corneal Ulcer is a common problem in eastern Nepal. Knowledge of both fungal and bacterial agents associated with this condition is of value for the prevention and management of corneal ulcers and their complications. PMID- 24047021 TI - Rise in liver enzymes after laproscopic cholecystectomy: a transient phenomenon. AB - The purpose of this study was to investigate the effect of laparoscopic surgery on liver function in humans and the possible mechanisms behind such effect. Blood samples from 30 patients who underwent laparoscopic cholecystectomy (LC) and 20 patients who underwent open cholecystectomy (OC) were tested for liver function by measuring the level of serum alanine aminotrasferase (ALT) and aspartate aminotrasferase (AST) before and after surgery. The level of serum ALT and AST increased significantly during the first 24 hours after surgery in laparoscopic cholecystectomy. However, no significant change of the serum liver enzymes was detected in open cholecystectomy patients. As a result, there was statistically significant difference in change of both ALT and AST levels between LC and OC patients. The effect was transient and reverted back to normal by the 7th day post operation. Transient elevation of hepatic transaminases occurred after laparoscopic surgery. The major causative factor seemed to be the CO2 pneumoperitoneum. In most of the laparoscopic surgery patients, the transient elevation of serum liver enzymes showed no apparent clinical implications. PMID- 24047022 TI - Virtual panendoscopy--a new tool to help evaluating oral cancer. AB - Virtual panendoscopy (VP) is a new, non-invasive diagnostic technique available to assess luminal structures. It involves the use of the data obtained from scanning of patients using multidetector CT scanners. The data is manipulated using a software programme to generate 3D models with fly through capability to examine various anatomical tubes. Its use has been studied in colonoscopy and bronchoscopy. However its use in head and neck cancer assessment has not been extensively studied. Therefore this diagnostic tool was used to stage 10 consecutive head and neck cancer patients. The ability of this tool in staging and identification of synchronous primary was assessed. The findings from the VP were also compared with the findings of nasendoscopy. In our pilot study, the virtual panendoscopy has been a useful tool in the assessment of the upper aero digestive tract. Although it has not picked up synchronous primaries, good quality assessment of lumen and the mucosal wall was done in areas not accessed by nasendoscope. It is most useful in areas not accessed by nasendoscope i.e. trachea, bronchus etc. The outcome, its usefulness and shortcomings are discussed. PMID- 24047023 TI - Prevalence study of H. pylori infection in dyspeptic patients coming to Nepal Medical College Teaching Hospital, Jorpati, Kathmandu. AB - Helicobacter pylori (H. pylori) is one of the most common human infections worldwide particularly in the developing countries. It has been established as etiology of chronic gastritis and peptic ulcer disease, gastric adenocarcinoma and mucosal associated lymphoid tissue lymphoma (MALT). During this decade, there have been some reports showing a decline in global prevalence of H. pylori infection and peptic diseases including many Asian countries. Hence to determine prevalence of Helicobacter pylori infection in dyspeptic patients, this descriptive, non-interventional study was carried out at the Endoscopy sub-unit of the Surgery Department from April 2011 to February 2012. Three hundred nineteen dyspeptic patients (Male 161 and female 152) with a mean age of 20.12 years were examined for the presence of H. pylori infection by histology staining. The prevalence of H. pylori infection was 50.47%. The most common endoscopic findings was gastritis (47.6%) followed by normal findings 57 (17.87%). A total of 8.47% of gastric Ulcer, oesophagitis 5.64% and gastric cancer 0.94% were detected. All three cases of gastric cancer were positive for H. pylori infection. Among gastritis, H. pylori was observed in 67 (44%) cases and 18 out of 57 (5.6%) of normal gastric mucosa showed H. pylori. The endoscopic findings such as gastritis, gastric ulcer, duodenal ulcer and gastro duodenal reflux are significantly associated with H. pyloric infection. The prevalence of H. pylori infection is still high in peptic diseases. H. pylori infection is significantly correlated with peptic ulcer diseases than with non-ulcer dyspepsia. Further studies are required to establish the H. pylori positive cases with that of other tests such as serological detection of anti H. pylori antibody by ELISA/ICT and culture to establish a diagnosis quickly without any invasive method and institute proper management thus reducing morbidity. PMID- 24047024 TI - A large-scale study of bacterial contamination of drinking water and its public health impact in Nepal. AB - Bacterial contamination of drinking water is a major public health in Nepal. A large scale study on contamination of drinking water was done covering all three ecological belts (mountain, hill and Terai) in all five (eastern, central, western, mid-western and far-western) development regions of Nepal during 2009 2011. Of the total 506 water samples studied, one-forth (25.1%; 127/506) were visually turbid. Bacteriologically, 88.5% (448/506) samples were positive for total coliform (TC) whereas 56.5% (286/506) were positive for fecal coliform (FC) (Esch. coli). The TC positive rate ranged from 53.8% in Damak (Jhapa) to 100.0% in different districts. The FC positive rate varied more widely ranging from 10.0% in Bharatpur City (Chitawan) to 100.0% in Baglung Township (Baglung) with over 50.0% in most of the districts (over 75.0% in eight districts). Both TC and FC positive rate were highest in Far-western Development Region (DR). High TC positive rate (96.7%) in Far-western DR was followed by Western DR (93.9%), Eastern DR (89.2%), Central DR (87.0%) and Mid-western DR (74.6%). Highest FC positive rate (65.5%) in Far-western DR was followed by Med-western DR (63.5%), Western DR (55.9%), Central DR (53.2%) and Eastern DR (52.0%). TC positive was highest (90.7%) in hills followed by mountain (89.7%) and Terai (plain) (84.1%) belt. In contrast, FC positive rate was highest (66.2%) in mountain, followed by hills (58.0%) and Terai (49.7%). Of the total 506, 335 were piped tap water, 129 were boring water, 16 natural tap (spout), 16 were well (sallow/deep well) and 10 were mineral/uroguard treated water. TC positive rate was very high (81.2% to 100.0%) in different type water samples (piped tap: 90.1%; boring water: 85.2%; natural spout/tap: 81.2%; well water 100.0% and mineral water/uroguard treated water: 80.0%). FC positive rate ranged from 0.0% in mineral water/uroguard treated water to 93.7% in well water samples. These findings are of serious public health concern with regard to both endemicity and outbreak of waterborne diseases in the country. PMID- 24047025 TI - The etiology of fever in patients presented at KIST Medical College, Teaching Hospital, Lalitpur, Nepal. AB - In Nepal, febrile illness is one of the most common reasons for seeking medical attention, but there is limited information on the frequency of specific etiology of fever. This is a retrospective study. Patients presented with fever admitted in medicine ward and Intensive care unit of KIST Medical College, Imadol, Lalitpur from January 2010 to January 2012 are included in the study. Of the 898 patients enrolled, 23.5% had infective exacerbation of COPD. Enteric fever, urinary tract infection, acute gastroenteritis, tuberculosis and community acquired pneumonia were the cause of fever in 20%, 13%, 10%, 7.3% and 6% cases of respectively. Findings confirm the heavy burden of infection was a cause of fever requiring hospitalization. This highlights the importance of simple diagnostic tests and cost effective treatment required to manage these patients. PMID- 24047026 TI - Tuberculosis in patients undergoing maintenance hemodialysis: one year follow up study from Nepal. AB - In Nepal where tuberculosis is endemic and data regarding the prevalence of tuberculosis in patients undergoing maintenance haemodialysis is not known we tried to see the cumulative incidence of tuberculosis in these higher risk groups' patients. Forty patients were followed up for one year after initial screening for tuberculosis. Among forty patients 34 (85%) were male and 6 (15%) were female. During initial screening four patients had sputum positive tuberculosis and three more patients had sputum positive tuberculosis during follow up. Among nine patients with pleural effusion two patients had pulmonary tuberculosis. One patient had tubercular cervical lymphadenitis. Two patients died during follow up and the rest improved with anti tubercular treatment. So in the part of the world where tuberculosis is endemic patients undergoing maintenance haemodialysis should be screened for tuberculosis regularly. PMID- 24047027 TI - Screening for osteopenia and osteoporosis in an urban community in India. AB - Osteoporosis is a disease characterized by reduction in the bone mass and disruption of bone architecture leading to impaired skeletal strength and an increased susceptibility of fractures. It is a major public health problem associated with substantial morbidity and socio-economic burden worldwide. The present study was planned to screen bone status of adults over 20 years (when peak bone mass is formed) utilizing calcaneal quantitative ultrasound (QUS) (Hologic Sahara 0058 USG) as a diagnostic tool. A screening camp was conducted in the 1st week of February 2008 at the Terna Hospital and Research Centre along with the Orthopedic Department. A questionnaire was administered to all the screened individuals which included socio-demographic data, assessment of susceptibility to osteoporosis and dietary habits. The bone mineral density (BMD) was measured at the calcaneus by QUS and T-scores were calculated based on WHO criteria. The study yielded a prevalence of 41.4% among women and 33.33% among men for Osteopenia and 12.85% among women 3.7% among men for Osteoporosis respectively. The mean age of the screened sample was 44.25 years. The mean weight, height and body mass index was 56.95 kg, 157.47 cms and 23.047 respectively. The mean bone density was -0.749. A total of 97 individuals screened; of which 70 (72.1%) were females and 27 (27.9%) were males. There was a significant trend of decreasing bone density with an increase in age. Age had an influence on the outcome of osteopenic and osteoporosis score in present study. The subjects with low bone mineral density (BMD) were advised to undergo a Dual energy X-ray absorptiometry (DEXA) scan in order to confirm the diagnosis. The US Preventive Services Task Force recommends routine screening for Osteoporosis in women over 65 years. In India we need to carry out further studies on whether we need to consider screening at an earlier age and also to study osteoporosis in males. PMID- 24047028 TI - Study of menopausal symptoms among peri and postmenopausal women attending NMCTH. AB - This is a prospective study conducted in the department of OBGYN, Nepal medical college teaching hospital (NMCTH), Kathmandu Nepal. The main objective of this study being to find out the major health problem in mid-life of female, to see the age of menopause and to see prevalence of menopausal symptoms and common menopausal symptom among Nepalese women. Total 500 women were included in the study with effect from 1st of January 1012 till 500 respondents were interviewed, it took almost 10 months and ended on November 1012 for the study. Age wise all women from 45 years to 60 years are included, surgical menopause, diagnosed Hypertensive, diabetes and thyroid disorder were excluded from the study. Informed consent was taken and standard questionnaire were administered to women after history and clinical examination. Data were collected and analysed. The mean age of menopause found to be 49.9% with urinary tract infection being the major clinical diagnosis and physical menopausal symptoms being the commonest. About 20% of respondent had MRS (menopausal rating scale) score more than 16. PMID- 24047029 TI - PG medical training and accreditation: responsibility of the government for the adequate health service delivery. AB - On one hand there is obvious inadequate health coverage to the rural population and on the other hand the densely populated urban area is facing the triple burden of increasing non-communicable and communicable health problems and the rising health cost. The postgraduate medical training is closely interrelated with the adequate health service delivery and health economics. In relation to the prevailing situation, the modern medical education trend indicates the five vital issues. These are i). Opportunity needs to be given to all MBBS graduates for General Specialist and Sub-Specialist Training inside the country to complete their medical education, ii). Urgent need for review of PG residential training criteria including appropriate bed and teacher criteria as well as entry criteria and eligibility criteria, iii). Involvement of all available units of hospitals fulfilling the requirements of the residential PG training criteria, iv). PG residential trainings involve doing the required work in the hospitals entitling them full pay and continuation of the service without any training fee or tuition fee, and v). Planning of the proportions of General Specialty and Sub-Specialty Training fields, particularly General Practice (GP) including its career and female participation. With increased number of medical graduates, now it seems possible to plan for optimal health coverage to the populations with appropriate postgraduate medical training. The medical professionals and public health workers must make the Government aware of the vital responsibility and the holistic approach required. PMID- 24047030 TI - Lateral sinus thrombosis and haemorrhagic ischemic stroke with protein S deficiency in a young. AB - Stroke or cerebro-vascular disease is one of the most important causes of high morbidity and mortality throughout the world. Stroke in young individuals poses a major problem as these individuals are the earning members of the family. Ischemic strokes are increasingly being attributed to causes other than athero thrombotic disease. Protein S deficiency is a disorder with increased risk of venous thrombosis. Our patient, 19 years old lady presented with haemorrhagic venous infarction in right temporo-occipito-parietal region with right sided lateral sinus thrombosis. PMID- 24047031 TI - Ovarian cyst mimicking ascites on abdominal ultrasonography in a prepubertal female. AB - Ultrasonography has been commonly used in the diagnosis of intraabdominal cysts like ovarian cysts. Massive ovarian cysts can mimic ascites clinically (a condition termed pseudoascites) and ultrasonographically and can cause delay in the diagnosis and management. Clinicians should therefore consider other differential diagnoses in cases of large intraabdominal fluid collection. We report such a case in a prepubertal female which was diagnosed as ascites by ultrasonography initially but later turned out to be an ovarian cyst. PMID- 24047032 TI - Giant benign solitary fibrous tumour of the pleura (> 15 cm): role of radiological pathological correlations in management. Report of 3 cases and review of the literature. AB - OBJECTIVES: Solitary fibrous tumour pleura (SFTP) is a localized tumour arising from the submesothelial areolar mesenchyme. In the present study, we defined "giant" lesions with diameter greater than 15 cm. We have studied the role of radiological-histological correlations of three cases in the management of the disease with review of the literature. METHODS: We conducted a retrospective review of the clinical records of three patients who had undergone surgical resection for giant benignant SFTP between 2007 and 2011. RESULTS: Three symptomatic patients (all woman, mean age 80 years) with a giant benign SFTP (mean diameter 19.3 cm and mean weight 1290 gm) underwent surgery with full excision of the tumour. All tumours showed histological features of benignancy and intense immunopositivity for CD34. CONCLUSIONS: The integration of CT and pathological findings is essential in the optimal management of giant benign SFTP. Chest radiograph and CT cannot differentiate between benign and malignant giant SFTP. Surgical resection is necessary to determine the nature of tumour. The immunohistochemical staining pattern assists in differentiating SFTPs from other spindle cell neoplasms of the pleura including diffuse malignant mesothelioma. The choice of surgical approach is determined by the location of the tumour and by spatial relations in the imaging study rather than by the radiologist's impressions. Recurrence after complete resection is possible in giant benign SFTP, as a consequence of incomplete excision. Long-term follow-up is highly recommended because of the possibility of late recurrence. Due to rarity of these tumours, further studies and multicentre trials are needed to confirm these preliminary findings. PMID- 24047033 TI - The cancer screening monitoring system: indicators for organised programmes and possible extension to spontaneous screening. AB - European Commission recommends the implementation of organized screening programs for cervical cancer based on active invitation of the target population and with a systematic monitoring system and quality assurance. Nevertheless, in many Member States opportunistic screening is still the only or the main way to access Pap test. In Italy, Pap test coverage in women aged 25-64 is close to 80%, about half of them are screened in organized programs and half by opportunistic screening. Organized programs are diffused in the vast majority of the country (78% in 2009) even if in some cases they are not able to actively invite all the target population every three years (actual extension 67%); furthermore, participation rate after invitation is quite low (39%). Organized screening programs showed performance indicators in line with most of the international standards: low referral rates (2.4%), low inadequate cytological results (4.7%), and high positive predictive value for high grade cervical intraepithelial neoplasia (16.2%). Opportunistic screening has no systematic monitoring system. The coexistence of the two screening models, organized programs and opportunistic, can be a source of inappropriate use of secondary prevention duplicating the tests and favoring deviations from recommended protocols. The Italian Ministry of Health recommends re-organizing cervical cancer prevention favoring organized programs or integrating spontaneous Pap testing in an organized system. To implement such integration it is necessary to have monitoring system and quality assurance for all providers and to integrate archives in order to avoid over-testing and deviation from protocols. PMID- 24047034 TI - A complex association between derivatives from the neural crest. A case report. AB - We report the case of a very complex proliferation arose in the context of the soft tissues of the axilla, composed of elements derived from the neural crest: several of hamartomatous significance: ("cafe au lait spots without neurofibroma, groups of nevoids cells), others clearly neoplastic with the characters of the melanoma and the MPNST. The melanoma cells express, furthermore, neuroendocrine markers. Differential diagnostic characters are discussed and emphasizes the importance of this kaleidoscopic, transient, structure in determining the phylogeny and ontogeny of living beings. PMID- 24047035 TI - Gangliocytic paraganglioma of duodenum metastatic to lymph nodes and liver and extending into the retropancreatic space. AB - Gangliocytic paraganglioma (GP) is a rare benign neuroendocrine tumour found most often in the duodenum. To our knowledge, only a dozen cases of possibly malignant duodenal GP with local lymph node metastasis and only one case with liver metastasis have previously been published. Herein, we report an unusual case of GP of the duodenum spreading to the retropancreatic space and metastatic to the liver and lymph nodes. Additionally, the present tumour secreted pancreatic polypeptide (PP) which was detected in the serum during the follow-up period. We suggest that serum PP could be a valuable marker in the diagnosis and follow-up of patients with GP. PMID- 24047036 TI - A case of sclerosing angiomatoid nodular transformation of the spleen. AB - Sclerosing angiomatoid nodular transformation of the spleen is a rare benign vascular lesion with extensive sclerosis and unknown aetiology. Although its pathogenesis is not clear, it has been postulated that it may represent a peculiar hamartomatous transformation of red pulp in response to an exaggerated non-neoplastic stromal proliferation. However, it is unclear whether SANT is the end stage of a variety of benign splenic conditions including inflammatory pseudotumour, hamartoma or hematoma. Considering that the lesion is benign, splenectomy is curative. We report a new case of SANT, discussing differential diagnosis, immunohistochemical profile and pathogenesis. PMID- 24047037 TI - Epithelioid fibrous histiocytoma EMA positivity: a case report. AB - A case of epithelioid fibrous histiocytoma diagnosed in a 5-year-old female with a skin lesion: morphological description and immunohistochemical investigations performed. PMID- 24047038 TI - About a challenging tumour, elastofibroma dorsi: an eight-case study. AB - Elastofibroma dorsi is an uncommon benign soft tissue pseudotumour usually located at the lower pole of the scapula, deep to the serratus anterior and often attached to the periosteum of the ribs. This lesion is usually seen in patients over the age of 50 years and is commonly misdiagnosed as a malignant tumour because of its size and deep location. We describe 8 cases of elastofibroma dorsi diagnosed over a 10-year-period. Our study contained 5 females and 3 males with a mean age at diagnosis of 62.5 years (range 47-75 years). We aim to highlight the clinical and radiologic presentation of elastofibroma dorsi in order to increase awareness of its existence and management. PMID- 24047039 TI - Leiomyomatosis peritonealis disseminata: pregnancy, contraception and myomectomy of its pathogenesis. AB - Leiomyomatosis peritonealis disseminata (LPD) is a rare smooth muscle tumour characterized by multiple small nodules on the omentum and peritoneal surface, composed of benign smooth muscle cells with minimal mitotic activity, frequently admixed with decidual cells. The possible pathogenetic mechanisms include hormonal dysfunction, differentiation of subperitoneal mesenchymal stem cells, myofibroblastic metaplasia and genetic and iatrogenic causes (resection of myomas during laparoscopic surgery). Diagnosis is easily made on biopsy specimens. Reduction of oestrogen exposure, surgical castration or gonadotrophin releasing hormone agonists are generally sufficient to cause regression of LPD. We report a case of an asymptomatic 36-year-old pregnant woman with long-term use of oral contraceptives, and previous myomectomy, who had a mass of uncertain origin which was, histopathologically, diagnosed as leiomyomatosis peritonealis diffusa with foci of ectopic decidua. Ectopic decidua was also present in a pelvic lymph node. To the best of our knowledge, this is the first case of LPD containing foci of ectopic decidua in a pregnant woman with a past history of myomectomy and use of oral contraception for three years; ectopic decidua was also detected in a pelvic lymph node. PMID- 24047040 TI - Mothers and infants exposed to intimate partner violence compensate. AB - Reasons for the developmental variability in children exposed to intimate partner violence (IPV) are unclear and under studied. This article presents exploratory findings on (a) the potential impact of IPV on mother-child relationships and child development and (b) the association between these maternal-child relationship impacts and child development. The fit of findings with compensatory, spillover, and compartmentalization hypotheses was explored. Participants were 49 mothers and 51 children younger than 3 years of age affected by IPV. Data were collected on maternal-child interactions, child development, social support, difficult life circumstances, family functioning, child temperament, and parental depression. The findings suggested developmental impacts on children in the sample, along with children's high sensitivity and responsiveness to their caregivers. Although some spillover effects were observed, the predominant observation was of mothers and infants compensating for exposure to IPV in their interactions. PMID- 24047041 TI - Assessing the heterogeneity of aggressive behavior traits: exploratory and confirmatory analyses of the reactive and instrumental aggression Personality Assessment Inventory (PAI) scales. AB - The heterogeneity of violent behavior is often overlooked in risk assessment despite its importance in the management and treatment of psychiatric and forensic patients. In this study, items from the Personality Assessment Inventory (PAI) were first evaluated and rated by experts in terms of how well they assessed personality features associated with reactive and instrumental aggression. Exploratory principal component analyses (PCA) were then conducted on select items using a sample of psychiatric and forensic inpatients (n = 479) to examine the latent structure and construct validity of these reactive and instrumental aggression factors. Finally, a confirmatory factor analysis (CFA) was conducted on a separate sample of psychiatric inpatients (n = 503) to evaluate whether these factors yielded acceptable model fit. Overall, the exploratory and confirmatory analyses supported the existence of two latent PAI factor structures, which delineate personality traits related to reactive and instrumental aggression. PMID- 24047042 TI - Driving frequency and Its impact on road rage offending and victimization: a view from opportunity theory. AB - Road rage has been described as a key criminal justice and public health concern. Although research attention to this issue has expanded dramatically, most of this work has focused on the identification of predisposing individual factors. It is equally important to begin to assess those factors that may modify the likelihood of road rage including the broader structural opportunities that are connected with the propensity to be involved in a road rage incident. Drawing on opportunity theory, this article examines whether there is a relationship between increased opportunities to be involved in road rage and an increased likelihood of being a road rage victim or offender. The analysis is further extended to specifically test whether this relationship is linear, thereby examining the applicability of the opportunity saturation hypothesis. Using data from the Centre for Addiction and Mental Health (CAMH) Monitor, our findings support both the application of opportunity theory to understanding road rage and the presence of opportunity saturation. Although a clear relationship exists between kilometers driven and experiences of road rage, evidence emerged suggesting there may be a threshold whereby increased opportunities for road rage do not lead to road rage behavior. PMID- 24047043 TI - Northern European adolescent attitudes toward dating violence. AB - A focus group methodology was used to examine attitudes toward dating violence among 86 adolescents (aged 12-17) from four northern European countries (England, Sweden, Germany, and Belgium). Four superordinate themes were identified from thematic analyses: gender identities, television as the educator, perceived acceptability of dating violence, and the decision to seek help/tell someone. Although violence in relationships was generally not condoned, when violence was used by females, was unintended (despite its consequences), or was in retaliation for infidelity, violence was perceived as acceptable. Adolescents indicated that their views were stereotypical and based solely on stereotypical television portrayals of violence in relationships. Stereotypical beliefs and portrayals generate barriers for victimized males to seek help because of fear of embarrassment. PMID- 24047044 TI - Children exposed to intimate partner violence and the reported effects of psychosocial interventions. AB - Using a repeated measures design posttraumatic stress (PTS), psychological and behavioral problems significantly decreased following intervention in children exposed to intimate partner violence (IPV), with use of traditional group analyses. Analyses using the reliable change index (RCI), however, revealed that few children were improved or recovered, implying that interventions in common use should be evaluated for their significant impact on the individual level in addition to group level statistics. Positive changes in children's behavioral problems were related to the mother's improvement of their own mental health. Direct victimization by the perpetrator was not associated with treatment changes but with higher symptom levels at study entry. Amount of contact with the perpetrator was neither related to symptom load nor to changes following treatment. PMID- 24047045 TI - Emotionally abusive behavior in young couples: exploring a role for implicit aggression. AB - Emotionally abusive behaviors reported across a 6-month period in intimate relationships were examined. There were 269 participants aged 18-25 years who took part (98 men, 171 women). All completed the Multidimensional Measure of Emotional Abuse (MMEA) and a measure of implicit aggression, the Puzzle Test. Implicit processing refers to subtle cognitive processing that occurs outside of conscious awareness. This study focused on aggressive implicit processing. Overall emotional victimization by a partner was associated with increased implicit aggressive levels, particularly for women. Those classified as perpetrators/victims (mutual aggressors and victims) were also predicted by increased implicit aggression. Women reported higher levels of implicit aggression than men. Results are discussed regarding future research and the value of theory in understanding the association between emotional abuse and implicit aggression. PMID- 24047046 TI - Exploring the impact of dysfunctional posttraumatic survival responses on crime revictimization. AB - This study investigated the association between posttraumatic stress disorder (PTSD) symptoms and repeat victimization across crime types in survivors of traumatic interpersonal violence. An evolutionary psychological perspective was adopted to propose that symptoms of hyperarousal (particularly hypervigilance, exaggerated startle response, and irritability or outbursts of anger) and numbing predict revictimization. These symptoms may act as manifestations of dysfunctional survival responses. Survival responses are adaptive in life threatening situations but may work counter-productive in the absence of immediate threat. Participants were recruited through the Dutch Victim Compensation Fund (DVCF; N = 233). PTSD symptomatology was assessed between October and December 2007. Revictimization was measured 6 months later. Results were partly in line with expectations. Exaggerated startle response and symptoms of irritability or outbursts of anger but not hypervigilance and numbing were related to revictimization. PMID- 24047047 TI - Police officers' collaboration with rape victim advocates: barriers and facilitators. AB - Secondary victimization may occur when rape victims make police reports. This can compromise the quality of official statements and jeopardize criminal cases. Rape reporters receive better treatment by police officers when advocates are involved and best practice police work includes such collaboration. Studies of advocates have described tension, role confusion, and poor communication with police officers. Many variables, including rape myth acceptance (RMA) and training on sexual assault dynamics, may affect officers' collaboration with advocates. There were 429 police officers who responded to a survey measuring their victim interviewing skill, formal training about rape, years on the job, number of victims known personally, number of recent rape cases, RMA, and collaboration with advocates. Results suggest that officers' interviewing skill, years on the job, and specific training are related to collaboration with victim advocates on rape cases. Professional, rather than personal, variables were most predictive of collaboration. Implications for officer selection and training are explored. PMID- 24047048 TI - The relationship between protective factors and outcomes for children exposed to violence. AB - To develop prevention and intervention programs for children exposed to violence, it is necessary to understand what factors might help alleviate the negative effects of violence exposure. In this study, we sought to test whether relationships exist between certain protective factors and subsequent adjustment and to examine whether violence re-exposure contributed to changes in outcomes over time. The analyses revealed that caregiver reports of both child self control and the quality of the parent-child relationship were related to changes in child posttraumatic stress disorder (PTSD) symptoms and behavior problems. Furthermore, children experiencing more categories of violence re-exposure had increased behavior problems at follow-up compared to those without re-exposure. These findings advance our understanding of the relationship between these protective factors and outcomes for children exposed to violence and suggest that intervening to bolster these protective factors could improve outcomes. PMID- 24047049 TI - The assessment of cyberstalking: an expanded examination including social networking, attachment, jealousy, and anger in relation to violence and abuse. AB - Because the first antistalking statute was enacted in California in 1990, stalking research has been expanded immensely, yet been largely confined to exploring traditional pursuit tactics. This study instead examined the prevalence and correlates of cyberstalking behaviors while examining the phenomenon in a more inclusive manner than previous studies focusing on cyberstalking by including social networking avenues. In addition to a measure assessing cyberstalking-related behaviors, questionnaires assessing pathological aspects of personality, including attachment style, interpersonal jealousy, interpersonal violence, and anger were also provided to participants. Results indicate that, given preliminary evidence, cyberstalking-related behaviors are related to past measures of traditional stalking and cyberstalking, although prior attachment, jealousy, and violence issues within relationships are significant predictors of cyberstalking-related behaviors. In addition, unexpected gender differences emerged. For example, women admitted greater frequencies of cyberstalking perpetration than males, signaling that further research on frequency and motivation for cyberstalking among the sexes is necessary. PMID- 24047050 TI - Examining the offender-victim overlap among police officers: the role of social learning and job-related stress. AB - This study uses data from the Police Stress and Domestic Violence in Police Families in Baltimore, Maryland 1997-1999 to examine the offender-victim overlap among police officers in the context of intimate partner violence (IPV). Specifically, the study examines the role of parental violence, child maltreatment, and job-related stress on perpetrating violence and victimization. Results from two logistic regression models indicate that one element of job related stress (negative emotions) was positive and significant in predicting IPV perpetration, whereas parental violence, child maltreatment, and negative emotions were found to be positive and significant in predicting victimization. The study's limitations and future research are discussed. PMID- 24047051 TI - Reply to comment on Increased evaporation kinetics of sessile droplets by using nanoparticles. PMID- 24047052 TI - Deciphering bacterial universal language by detecting the quorum sensing signal, autoinducer-2, with a whole-cell sensing system. AB - Bacteria communicate with neighboring bacteria of the same species or of other species by means of chemical signaling molecules. The concentration of such signaling molecules is proportional to the bacterial population size; upon reaching a threshold concentration, corresponding to a threshold cell density, certain specialized genes are expressed. This system of communication among bacteria is known as quorum sensing (QS). QS regulates diverse behaviors, such as formation of biofilms and production of pathogenic factors. Autoinducer-2 (AI-2) is a QS signaling molecule that is used for interspecies communication by both Gram-positive and Gram-negative bacteria. Bacteria are known to play an important role in many diseases, from infections to chronic inflammation. Therefore, QS is involved in a variety of disorders of bacterial origin or where bacteria play a crucial pathogenic role. One such condition is inflammatory bowel disease (IBD), a chronic inflammation of the gastrointestinal (GI) tract that includes debilitating diseases, such as ulcerative colitis (UC) and Crohn's disease (CD). To date, noninvasive methods are unavailable for the diagnosis and monitoring of IBD. We hypothesized that detection of QS molecules in physiological samples, specifically saliva and stool specimens, would provide with a method for the noninvasive, early diagnosis and monitoring of IBD conditions. To that end, we developed and optimized a whole-cell sensing system for AI-2, which is based on Vibrio harveyi strain BB170. Furthermore, we standardized and applied the biosensing system for the quantitative detection of AI-2 in saliva, stool, and intestinal samples from IBD patients. PMID- 24047053 TI - Generating tunable white light by resonance energy transfer in transparent dye conjugated metal oxide nanocrystals. AB - We report the design and properties of hybrid white-light-emitting nanophosphors obtained by electronic coupling of defect states in colloidal Ga2O3 nanocrystals emitting in blue-green with selected organic molecules emitting in orange-red. Coupling between the two components is enabled by the nanocrystal's size dependent resonance energy transfer, allowing the photoluminescence chromaticity to be precisely tuned by changing the nanocrystal size and selecting the complementary organic dye molecule. Using this approach, we demonstrate the generation of pure white light with quantum yield of ~30%, color rendering index up to 95, and color temperature of 5500 K. These results provide a guideline for the design of a new class of hybrid white-light-emitting nanophosphors and other multifunctional nanostructures based on transparent metal oxides. PMID- 24047054 TI - Controlled growth of high-quality monolayer WS2 layers on sapphire and imaging its grain boundary. AB - Atomically thin tungsten disulfide (WS2), a structural analogue to MoS2, has attracted great interest due to its indirect-to-direct band-gap tunability, giant spin splitting, and valley-related physics. However, the batch production of layered WS2 is underdeveloped (as compared with that of MoS2) for exploring these fundamental issues and developing its applications. Here, using a low-pressure chemical vapor deposition method, we demonstrate that high-crystalline mono- and few-layer WS2 flakes and even complete layers can be synthesized on sapphire with the domain size exceeding 50 * 50 MUm(2). Intriguingly, we show that, with adding minor H2 carrier gas, the shape of monolayer WS2 flakes can be tailored from jagged to straight edge triangles and still single crystalline. Meanwhile, some intersecting triangle shape flakes are concomitantly evolved from more than one nucleus to show a polycrystalline nature. It is interesting to see that, only through a mild sample oxidation process, the grain boundaries are easily recognizable by scanning electron microscopy due to its altered contrasts. Hereby, controlling the initial nucleation state is crucial for synthesizing large-scale single-crystalline flakes. We believe that this work would benefit the controlled growth of high-quality transition metal dichalcogenide, as well as in their future applications in nanoelectronics, optoelectronics, and solar energy conversions. PMID- 24047055 TI - A 3-year M.D.--accelerating careers, diminishing debt. PMID- 24047056 TI - The 3-year medical school--change or shortchange? PMID- 24047057 TI - Autism at 70--redrawing the boundaries. PMID- 24047058 TI - Lessons in pain relief--a personal postgraduate experience. PMID- 24047059 TI - Long-term colorectal-cancer incidence and mortality after lower endoscopy. AB - BACKGROUND: Colonoscopy and sigmoidoscopy provide protection against colorectal cancer, but the magnitude and duration of protection, particularly against cancer of the proximal colon, remain uncertain. METHODS: We examined the association of the use of lower endoscopy (updated biennially from 1988 through 2008) with colorectal-cancer incidence (through June 2010) and colorectal-cancer mortality (through June 2012) among participants in the Nurses' Health Study and the Health Professionals Follow-up Study. RESULTS: Among 88,902 participants followed over a period of 22 years, we documented 1815 incident colorectal cancers and 474 deaths from colorectal cancer. With endoscopy as compared with no endoscopy, multivariate hazard ratios for colorectal cancer were 0.57 (95% confidence interval [CI], 0.45 to 0.72) after polypectomy, 0.60 (95% CI, 0.53 to 0.68) after negative sigmoidoscopy, and 0.44 (95% CI, 0.38 to 0.52) after negative colonoscopy. Negative colonoscopy was associated with a reduced incidence of proximal colon cancer (multivariate hazard ratio, 0.73; 95% CI, 0.57 to 0.92). Multivariate hazard ratios for death from colorectal cancer were 0.59 (95% CI, 0.45 to 0.76) after screening sigmoidoscopy and 0.32 (95% CI, 0.24 to 0.45) after screening colonoscopy. Reduced mortality from proximal colon cancer was observed after screening colonoscopy (multivariate hazard ratio, 0.47; 95% CI, 0.29 to 0.76) but not after sigmoidoscopy. As compared with colorectal cancers diagnosed in patients more than 5 years after colonoscopy or without any prior endoscopy, those diagnosed in patients within 5 years after colonoscopy were more likely to be characterized by the CpG island methylator phenotype (CIMP) (multivariate odds ratio, 2.19; 95% CI, 1.14 to 4.21) and microsatellite instability (multivariate odds ratio, 2.10; 95% CI, 1.10 to 4.02). CONCLUSIONS: Colonoscopy and sigmoidoscopy were associated with a reduced incidence of cancer of the distal colorectum; colonoscopy was also associated with a modest reduction in the incidence of proximal colon cancer. Screening colonoscopy and sigmoidoscopy were associated with reduced colorectal-cancer mortality; only colonoscopy was associated with reduced mortality from proximal colon cancer. Colorectal cancer diagnosed within 5 years after colonoscopy was more likely than cancer diagnosed after that period or without prior endoscopy to have CIMP and microsatellite instability. (Funded by the National Institutes of Health and others.). PMID- 24047060 TI - Long-term mortality after screening for colorectal cancer. AB - BACKGROUND: In randomized trials, fecal occult-blood testing reduces mortality from colorectal cancer. However, the duration of the benefit is unknown, as are the effects specific to age and sex. METHODS: In the Minnesota Colon Cancer Control Study, 46,551 participants, 50 to 80 years of age, were randomly assigned to usual care (control) or to annual or biennial screening with fecal occult blood testing. Screening was performed from 1976 through 1982 and from 1986 through 1992. We used the National Death Index to obtain updated information on the vital status of participants and to determine causes of death through 2008. RESULTS: Through 30 years of follow-up, 33,020 participants (70.9%) died. A total of 732 deaths were attributed to colorectal cancer: 200 of the 11,072 deaths (1.8%) in the annual-screening group, 237 of the 11,004 deaths (2.2%) in the biennial-screening group, and 295 of the 10,944 deaths (2.7%) in the control group. Screening reduced colorectal-cancer mortality (relative risk with annual screening, 0.68; 95% confidence interval [CI], 0.56 to 0.82; relative risk with biennial screening, 0.78; 95% CI, 0.65 to 0.93) through 30 years of follow-up. No reduction was observed in all-cause mortality (relative risk with annual screening, 1.00; 95% CI, 0.99 to 1.01; relative risk with biennial screening, 0.99; 95% CI, 0.98 to 1.01). The reduction in colorectal-cancer mortality was larger for men than for women in the biennial-screening group (P=0.04 for interaction). CONCLUSIONS: The effect of screening with fecal occult-blood testing on colorectal-cancer mortality persists after 30 years but does not influence all-cause mortality. The sustained reduction in colorectal-cancer mortality supports the effect of polypectomy. (Funded by the Veterans Affairs Merit Review Award Program and others.). PMID- 24047061 TI - Surgery versus physiotherapy for stress urinary incontinence. AB - BACKGROUND: Physiotherapy involving pelvic-floor muscle training is advocated as first-line treatment for stress urinary incontinence; midurethral-sling surgery is generally recommended when physiotherapy is unsuccessful. Data are lacking from randomized trials comparing these two options as initial therapy. METHODS: We performed a multicenter, randomized trial to compare physiotherapy and midurethral-sling surgery in women with stress urinary incontinence. Crossover between groups was allowed. The primary outcome was subjective improvement, measured by means of the Patient Global Impression of Improvement at 12 months. RESULTS: We randomly assigned 230 women to the surgery group and 230 women to the physiotherapy group. A total of 49.0% of women in the physiotherapy group and 11.2% of women in the surgery group crossed over to the alternative treatment. In an intention-to-treat analysis, subjective improvement was reported by 90.8% of women in the surgery group and 64.4% of women in the physiotherapy group (absolute difference, 26.4 percentage points; 95% confidence interval [CI], 18.1 to 34.5). The rates of subjective cure were 85.2% in the surgery group and 53.4% in the physiotherapy group (absolute difference, 31.8 percentage points; 95% CI, 22.6 to 40.3); rates of objective cure were 76.5% and 58.8%, respectively (absolute difference, 17.8 percentage points; 95% CI, 7.9 to 27.3). A post hoc per-protocol analysis showed that women who crossed over to the surgery group had outcomes similar to those of women initially assigned to surgery and that both these groups had outcomes superior to those of women who did not cross over to surgery. CONCLUSIONS: For women with stress urinary incontinence, initial midurethral-sling surgery, as compared with initial physiotherapy, results in higher rates of subjective improvement and subjective and objective cure at 1 year. (Funded by ZonMw, the Netherlands Organization for Health Research and Development; Dutch Trial Register number, NTR1248.). PMID- 24047063 TI - Clinical practice. Carotid stenosis. PMID- 24047062 TI - Variation in surgical-readmission rates and quality of hospital care. AB - BACKGROUND: Reducing hospital-readmission rates is a clinical and policy priority, but little is known about variation in rates of readmission after major surgery and whether these rates at a given hospital are related to other markers of the quality of surgical care. METHODS: Using national Medicare data, we calculated 30-day readmission rates after hospitalization for coronary-artery bypass grafting, pulmonary lobectomy, endovascular repair of abdominal aortic aneurysm, open repair of abdominal aortic aneurysm, colectomy, and hip replacement. We used bivariate and multivariate techniques to assess the relationships between readmission rates and other measures of surgical quality, including adherence to surgical process measures, procedure volume, and mortality. RESULTS: For the six index procedures, there were 479,471 discharges from 3004 hospitals. The median risk-adjusted composite readmission rate at 30 days was 13.1% (interquartile range, 9.9 to 17.1). In a multivariate model adjusting for hospital characteristics, we found that hospitals in the highest quartile for surgical volume had a significantly lower composite readmission rate than hospitals in the lowest quartile (12.7% vs. 16.8%, P<0.001), and hospitals with the lowest surgical mortality rates had a significantly lower readmission rate than hospitals with the highest mortality rates (13.3% vs. 14.2%, P<0.001). High adherence to reported surgical process measures was only marginally associated with reduced readmission rates (highest quartile vs. lowest quartile, 13.1% vs. 13.6%; P=0.02). Patterns were similar when each of the six major surgical procedures was examined individually. CONCLUSIONS: Nearly one in seven patients hospitalized for a major surgical procedure is readmitted to the hospital within 30 days after discharge. Hospitals with high surgical volume and low surgical mortality have lower rates of surgical readmission than other hospitals. PMID- 24047064 TI - Images in clinical medicine. Prelaminated free flap for auricular reconstruction. PMID- 24047065 TI - Case records of the Massachusetts General Hospital. Case 29-2013. A 32-year-old HIV-positive African man with dyspnea and skin lesions. PMID- 24047066 TI - Colorectal-cancer screening--coming of age. PMID- 24047067 TI - Tracking drugs. PMID- 24047068 TI - Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. PMID- 24047069 TI - Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. PMID- 24047070 TI - Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. PMID- 24047071 TI - Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. PMID- 24047072 TI - Acquired resistance to crizotinib from a mutation in CD74-ROS1. PMID- 24047073 TI - Acquired resistance to crizotinib from a mutation in CD74-ROS1. PMID- 24047074 TI - Case 16-2013: A girl with irritability, hypersomnia, and somatic symptoms. PMID- 24047075 TI - Case 16-2013: A girl with irritability, hypersomnia, and somatic symptoms. PMID- 24047076 TI - Case 16-2013: A girl with irritability, hypersomnia, and somatic symptoms. PMID- 24047077 TI - More on U.S. outpatient antibiotic prescribing, 2010. PMID- 24047078 TI - More on U.S. outpatient antibiotic prescribing, 2010. PMID- 24047079 TI - Rickettsia sibirica subspecies sibirica BJ-90 as a cause of human disease. PMID- 24047080 TI - Human infection with Candidatus Rickettsia tarasevichiae. PMID- 24047081 TI - Images in clinical medicine. Pulsatile chest swelling. PMID- 24047083 TI - The usefulness of the universal culture-based screening and the efficacy of intrapartum prophylaxis of group B Streptococcus infection. AB - OBJECTIVE: To evaluate the usefulness of universal culture-based GBS screening at 35-37 weeks of gestation, assess the efficacy of intrapartum antibiotic administration (IAP) and investigate factors influencing the infection rate in neonates. METHODS: Out of 1653 pregnant women 304 (18.4%) further analyzed were GBS positive directly before the delivery, among them 69 were false GBS negative on antenatal screening. Various variables regarding parturients' and newborns' characteristics were taken into account in order to achieve the objective of the study. RESULTS: Out of 304 GBS-positive patients directly before the delivery, culture-based screening was positive in 72.4%, while 22.7% presented with GBS negative screening and received no IAP. No single culture-confirmed early-onset GBS disease was observed. CONCLUSIONS: IAP is an effective way of early-onset GBS disease prevention, however prenatal screening would be most efficient if performed intrapartal. PMID- 24047082 TI - Over-expression of the special AT rich sequence binding protein 1 (SATB1) promotes the progression of nasopharyngeal carcinoma: association with EBV LMP-1 expression. AB - BACKGROUND: Special AT rich sequence binding protein 1 (SATB1) plays a crucial role in the biology of various types of human cancer. However, the role of SATB1 in human nasopharyngeal carcinoma (NPC) remains unknown. In the present study, we sought to investigate the contribution of aberrant SATB1 expression in the progression of NPC and its association with the Epstein Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1). METHODS: Immunohistochemical analysis was performed to detect SATB1 and LMP-1 protein in clinical samples, and the association of SATB1 protein expression with patient clinicopathological characteristics and LMP-1 expression were analyzed. SATB1 expression profiles were evaluated in well-differentiated NPC cell line CNE1, poorly-differentiated CNE2Z, undifferentiated C666-1 and immortalized nasopharyngeal epithelia NP-69 cells using quantitative RT-PCR, western blotting and fluorescent staining. After inhibition the SATB1 expression by using SATB1 specific small interfering RNA in these cell lines, the change of cell proliferation was investigated by western blotting analysis of PCNA (proliferating cell nuclear antigen) expression and CCK 8 assay, and the cell migration was assessed by Transwell migration assay. Finally, the expressions of SATB1 and PCNA were examined in CNE1 cells that forced LMP-1 expression by fluorescent staining and RT-PCR. RESULTS: Immunohistochemical analysis revealed that SATB1 protein expression was elevated in NPC tissues compared to benign nasopharyngeal tissues (P = 0.005). Moreover, high levels of SATB1 protein expression were positively correlated with clinical stage (P = 0.025), the status of lymph node metastasis (N classification) (P = 0.018), distant metastasis (M classification) (P = 0.041) and LMP-1 expression status (r = 2.35, P < 0.01) in NPC patients. In vitro experiments demonstrated that an inverse relationship between SATB1 expression and NPC differentiation status, with SATB1 weakly expressed in NP-69 cells and CNE1 cells, and significant increasingly expressed in CNE-2Z and C666-1 cells. Targeted knockdown of SATB1 expression obviously attenuated the proliferation and migration of highly SATB1-expressing CNE2Z and C666-1 cells, but not NP-69 and CNE1 cells. Interestingly, forced LMP-1 expression in CNE1 cells led to a surprisingly increasing SATB1 expression and nuclear location, companying with an up-regulated PCNA expression. CONCLUSIONS: Our results reveal that EBV LMP-1-mediated over expression of SATB1 is associated with NPC progression, suggesting SATB1 may represent a promising biomarker and therapeutic target for NPC. PMID- 24047084 TI - Progress in the pathogenesis of pterygium. AB - Pterygium is a type of benign uncontrolled growth of the conjunctive tissue that lays over the sclera. It can significantly alter visual function in advanced cases and become inflamed, leading to redness and irritation in the area. Although the exact etiology of pterygium remains uncertain, recent advances have provided important insight into the pathogenesis of pterygium. These studies indicate that tumor suppressor gene p53 and other genes associated with DNA repair, cell proliferation, migration and angiogenesis are critical for the development of pterygium. In addition, Human papillomavirus infection has been shown to be a risk factor in some populations. In this article, the current understanding of the pathogenesis of pterygium is reviewed. PMID- 24047085 TI - Homoisoflavones as the antioxidants responsible from bulbs of Scilla scilloides. AB - Scilla scilloides Druce has been used as a folk medicine to treat dermal inflammation; however, the medicinal property of this plant remains to be entirely clarified. The ethyl acetate extract prepared from bulbs of S. scilloides exhibited antioxidative activities on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, hydrogen peroxide (H2O2) and nitric oxide (NO) scavenging assays. Nine homoisoflavones (1-9) yielded from this extract were further examined for their antioxidative activities. Among these chemicals tested, five homoisoflavones (1-3, 5 and 7), six homoisoflavones (1-3 and 5-7) and two homoisoflavones (4 and 5) resulted in showing higher activities than the others in DPPH radical, H2O2 and NO scavenging assays, respectively. Calculated EC50 values indicate 3 as the strongest in the DPPH radical scavenging analysis. These results may indicate a potential role of S. scilloides for its medicinal use and homoisoflavones as the antioxidants responsible. PMID- 24047086 TI - Cardiac toxicity of some echinocandin antifungals. AB - BACKGROUND: Unexplained cardiovascular decompensation has been observed during central venous administration of some echinocandins. OBJECTIVE: The purpose of this study was to assess cardiac toxicity associated with the echinocandins. METHODS: Isolated rat hearts (Langendorff model) were perfused with anidulafungin (ANID), caspofungin (CASP), or micafungin (MICA) at exposures of 1, 4, and 10 times therapeutic concentrations. Changes in left ventricular contractility with experimental exposure were compared to control, and histologic and transmission electron microscopy (TEM) examinations of tissue were performed. RESULTS: Mean concentrations of ANID (10 - 80 ug/ml) and CASP (6 - 48 ug/ml) were associated with significant decreases in contractility (-77.1 +/- 9.4% and -40.6 +/- 15.6%, respectively; p < 0.05). MICA was associated with an increase in contractility (13.6 +/- 2.8%, p = NS). On TEM, samples exposed to ANID and CASP had enlarged mitochondria and disintegrating myofibrils. Samples exposed to MICA showed some enlarged mitochondria. CONCLUSION: Mean concentrations of ANID and CASP were associated with statistically significant decreases in left ventricular contractility at concentrations that may be achievable in humans after peripheral administration, while MICA caused no change. TEM studies suggest this may be a result of mitochondrial damage. Caution may be warranted with central administration of these agents to patients with preexisting cardiac dysfunction. PMID- 24047087 TI - Biology, precaution, and consumption. PMID- 24047088 TI - Precautionary discourse. Thinking through the distinction between the precautionary principle and the precautionary approach in theory and practice. AB - This paper addresses the distinction, arising from the different ways the European Union and United States have come to adopt precaution regarding various environmental and health-related risks, between the precautionary principle and the precautionary approach in both theory and practice. First, this paper addresses how the precautionary principle has been variously defined, along with an exploration of some of the concepts with which it has been associated. Next, it addresses how the distinction between the precautionary principle and precautionary approach manifested itself within the political realm. Last, it considers the theoretical foundation of the precautionary principle in the philosophy of Hans Jonas, considering whether the principled-pragmatic distinction regarding precaution does or doesn't hold up in Jonas' thought. PMID- 24047089 TI - Rethinking stereotype reliance. Understanding the connection between female candidates and gender stereotypes. AB - Increasing numbers of female candidates are running for Congress in American national elections. Despite the rise in female candidates running for office, women are not significantly increasing their presence in the House and Senate. A much hypothesized influence over the electoral fates of female candidates is the role of gender stereotypes. However, political science scholars have struggled to pinpoint the effect of stereotypes on vote choice, if there is any effect. This essay compares the way social psychology and political science scholars theoretically, conceptually and empirically test for gender stereotype influence over evaluations of female candidates and politicians. Differences emerge in the theoretical assumptions made in the two disciplines, the types of measures used in research, and the empirical tests conducted to demonstrate the presence or absence of stereotypes in evaluations of women. The discussion explores how scholars studying female candidates and politicians can integrate insights from social psychology to clarify the role of stereotypes in candidate evaluation and choice. PMID- 24047090 TI - Cattle scourge no more. The eradication of rinderpest and its lessons for global health campaigns. AB - In 2011, the Food and Agriculture Organization of the United Nations (FAO) officially declared rinderpest eradicated. This cattle virus, which has historically had significant political, economic, and social consequences, is only the second infectious disease to disappear from the face of the planet due to concerted human actions. This paper explores the effects that rinderpest has had historically, chronicles the actions of the Global Rinderpest Eradication Campaign (GREP), and discusses the lessons that GREP can offer for combating other infectious diseases. I argue that rinderpest's unique viral characteristics made eradication particularly feasible, but that GREP's activities offer important lessons for fostering international cooperation on controlling infectious disease outbreaks. PMID- 24047091 TI - The consuming instinct. What Darwinian consumption reveals about human nature. AB - Editor's note: In this engaging talk given last February on a particularly cold and blustery day at Texas Tech University, Professor Gad Saad of Concordia University discusses his work in the area of evolutionary consumption. In making the case for understanding consumerism from a Darwinian perspective, Saad addresses several key tenets from his books The Consuming Instinct (1) and The Evolutionary Bases of Consumption. (2) In particular, Saad argues that: (1) many consumption acts can be mapped onto four key Darwinian modules (survival, mating, kin selection, and reciprocal altruism); and, (2) cultural products such as song lyrics and movie plotlines are fossils of the human mind that highlight a shared, biologically based human nature. In this wide-ranging inquiry, Saad summarizes several of his other empirical works, including the effects of conspicuous consumption on men's testosterone levels (3) and how the ovulatory cycle in the human female influences consumption. (4) Overall, Professor Saad contends that an infusion of evolutionary and biologically based perspectives into the discipline of consumer behavior and related government regulatory policies yields myriad benefits, notably greater consilience, more effective practices, an ethos of interdisciplinarity, and methodological pluralism. PMID- 24047092 TI - Labeling of genetically modified food: closer to reality in the United States? AB - Within the broader context of several related biotech developments, including the proliferation of GM food in American grocery stories, the recent decision by Whole Foods Market, Inc. to require the labeling of all genetically modified (GM) organism products sold in its stores by 2018, and the development of GM animals for consumption, this essay asks whether the United States is inching towards a policy of mandatory GM food labeling. The analysis highlights aspects of the biotechnology policy debate in the United States and European Union, and traces public opinion as well as grassroots and legislative efforts aimed at GM food labeling. Findings show that activities at the federal level do not suggest any major regulatory changes regarding labeling in the near future; however, a growing number of individual states are considering GM food labeling legislation and political momentum in favor of labeling has picked up in recent years. Voluntary labeling by food companies may also become increasingly common. PMID- 24047093 TI - In praise of a modest postmodernism comment in response to Liesen and Walsh. PMID- 24047094 TI - Biopolitics via political psychology. Comment in response to Liesen and Walsh. PMID- 24047095 TI - The two cultures of 'biopolitics'. Comment in response to Liesen and Walsh. PMID- 24047096 TI - Embracing intellectual humility. A response to the biopolitics forum. PMID- 24047101 TI - Advances in lipid-based platforms for RNAi therapeutics. AB - Sequence-specific gene silencing, known as RNA interference (RNAi), is a natural process that can be exploited for knocking-down specific genes involved in the insurgence/development of pathological processes. In 2001 the discovery that small interfering RNA (siRNA) can induce gene silencing without immunoresponse turned RNAi into a promising technique for the control of post-transcriptional gene expression. Nowadays, the major challenge remains infusion in vivo. Therefore, vehicles providing protection and selective transport are to be developed for efficient systemic delivery. The most used vectors are lipid-based, offering a wide range of biocompatible formulations. Here their application in molecular medicine is discussed, especially with regard to recent clinical trials where conventional therapies have failed. The role played by extended physicochemical characterization for the success of RNAi therapeutics is also evidenced. PMID- 24047102 TI - The A(1166)C polymorphism of the AT1R gene is associated with an early onset of hypertension and high waist circumference in Jordanian males attending the Jordan University Hospital. AB - There is no agreement on the involvement of angiotensin II type 1 receptor (AT1R) gene A(1166)C variant and essential hypertension. The purpose of this study was to investigate the association between angiotensin II type 1 receptor (AT1R) gene A(1166)C variants with essential hypertension and some related parameters in a sample of Jordanian hypertensive patients. DNA samples from 108 hypertensive individuals and 102 age- and gender-matched non-hypertensive controls of the Jordanian population were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism assay (PCR-RFLP) methods to determine the frequency of A(1166)C variants alleles. No statistically significant differences were found in the distribution of alleles and genotypes between hypertensive and non-hypertensive individuals, not even after gender segregation. The frequency of the variant allele (C(1166)) was significantly higher in the early-onset compared to the late-onset group of hypertensive males, in subjects with positive family history of hypertension, and in subjects with high waist circumference. In conclusion, the A(1166)C polymorphism is not associated with essential hypertension in Jordanian hypertensive individuals. However, it was associated with an early onset of hypertension in males, with positive family history of hypertension, and with high waist circumference irrespective of blood pressure status. PMID- 24047103 TI - Polysaccharides from Cordyceps sinensis mycelium ameliorate exhaustive swimming exercise-induced oxidative stress. AB - CONTEXT: Cordyceps sinensis (Berk.) Sacc. (Clavicipitaceae) is a famous medicinal fungus (mushroom) in Chinese herbal medicine. Polysaccharides from Cordyceps sinensis (CSP) have been identified as active ingredients responsible for its biological activities. Although many pharmacological actions of CSP have received a great deal of attention, research in this area continues. OBJECTIVE: The current study was designed to investigate the effects of CSP on exhaustive exercise-induced oxidative stress. MATERIALS AND METHODS: The mice were divided into four groups: control (C), low-dose CSP treated (LC), intermediate-dose CSP treated (IC) and high-dose CSP treated (HC). The treated groups received CSP (100, 200 and 400 mg/kg, ig), while the control group received drinking water for 28 days, followed by being forced to undergo exhaustive swimming exercise, and some biochemical parameters including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), malondialdehyde (MDA) and 8-hydroxy-2' deoxyguanosine (8-OHdG) were measured using detection kits according to the manufacturers' instructions. RESULTS: Compared with the C group, exhaustive swimming time was significantly prolonged in the LC, IC and HC groups (p < 0.05); SOD activities in serum, liver and muscle were significantly higher in the IC and HC groups (p < 0.05); GPx activities in serum, liver and muscle were significantly higher in the LC, IC and HC groups (p < 0.05); CAT activities in serum, liver and muscle were significantly higher in the HC groups (p < 0.05); MDA and 8-OHdG levels in serum, liver and muscle were significantly lower in the LC, IC and HC groups (p < 0.05). DISCUSSION AND CONCLUSION: The results obtained herein indicate that CSP could ameliorate exhaustive exercise-induced oxidative stress. PMID- 24047104 TI - A three-dimensional culture method to expand limbal stem/progenitor cells. AB - The current standard method to culture human limbal stem/progenitor cells (LSCs) in vitro is to culture limbal epithelial cells directly on a layer of murine 3T3 feeder cells (standard method). The direct contact between human cells and murine feeder cells poses the potential risk of incomplete removal of feeder cells after culture and cross-contamination in clinical applications. We present here a novel three-dimensional (3D) sandwich method in which LSCs and feeder cells were separately cultured on opposite sides of a porous membrane. Limbal epithelial cells in the form of single-cell suspensions, cell clusters, and tissue explants were subjected to standard culture or to a 3D sandwich culture method. The 3D sandwich method consistently yielded LSCs derived from cell clusters and tissue explants. The expanded LSCs exhibited a small, compact, cuboidal stem-cell morphology and stem cell phenotypes comparable to those of LSCs derived from the standard culture method. Limbal epithelial cell clusters cultured with the sandwich method had a significantly higher proliferation rate than did those cultured with the standard method. The 3D sandwich method did not favor the propagation of single LSCs. In summary, the 3D sandwich method permits complete separation between cultured cells and feeder cells, while providing an even and maximal proximity between them. This alternative method permits culturing of LSCs without the risk of feeder cell contamination. PMID- 24047106 TI - The impact of neurochemical mediators on antidepressant effectiveness. AB - Despite marked differences in the psychobiological profiles of depressed patients, clinical research has not supported selection of antidepressant (AD) medications based on neurochemistry. Prescribers have been advised to start all patients on the same class of ADs and then switch or combine them until benefit is achieved. New research may transform this practice. By matching clinical moderators to neurochemical mediators, health professionals may finally be able to overcome the disappointing remission rates associated with initial AD treatments and avoid the progressively worsening results associated with current trial and error approaches. PMID- 24047107 TI - Autoimmune cytopenias in chronic lymphocytic leukemia at disease presentation in the modern treatment era: is stage C always stage C? AB - Abstract Anemia and thrombocytopenia at chronic lymphocytic leukemia (CLL) presentation have long been considered to be predictive of a poor prognosis, irrespective of the cause of cytopenia, yielding an advanced stage of the disease. We identified 86 patients with CLL who were diagnosed after year 2000 with Binet C disease at first presentation. Cytopenia was considered related to autoimmune conditions in 27 (31.3%; stage C "immune") or secondary to bone marrow failure in 59 (68.6%; stage C "infiltrative"). No difference in clinical characteristics, mutational status, cytogenetics, TP53 and NOTCH1 mutations was observed between stage C "immune" and "infiltrative." Patients with stage C "immune" had a trend toward a better overall survival than patients with stage C "infiltrative" (median 74 vs. 63 months), but the difference was not statistically significant (p = 0.30). This difference was not modified by adjustment for CLL tumor burden at presentation, and survival of stage C "immune" patients was significantly inferior compared to an unselected cohort of patients with stage A, but similar to stage B. Our findings suggest that autoimmune cytopenias at CLL diagnosis have a negative impact on patient outcome. PMID- 24047108 TI - Efficient utilization of aerobic metabolism helps Tibetan locusts conquer hypoxia. AB - BACKGROUND: Responses to hypoxia have been investigated in many species; however, comparative studies between conspecific geographical populations at different altitudes are rare, especially for invertebrates. The migratory locust, Locusta migratoria, is widely distributed around the world, including on the high altitude Tibetan Plateau (TP) and the low-altitude North China Plain (NP). TP locusts have inhabited Tibetan Plateau for over 34,000 years and thus probably have evolved superior capacity to cope with hypoxia. RESULTS: Here we compared the hypoxic responses of TP and NP locusts from morphological, behavioral, and physiological perspectives. We found that TP locusts were more tolerant of extreme hypoxia than NP locusts. To evaluate why TP locusts respond to extreme hypoxia differently from NP locusts, we subjected them to extreme hypoxia and compared their transcriptional responses. We found that the aerobic metabolism was less affected in TP locusts than in NP locusts. RNAi disruption of PDHE1beta, an entry gene from glycolysis to TCA cycle, increased the ratio of stupor in TP locusts and decreased the ATP content of TP locusts in hypoxia, confirming that aerobic metabolism is critical for TP locusts to maintain activity in hypoxia. CONCLUSIONS: Our results indicate that TP and NP locusts have undergone divergence in hypoxia tolerance. These findings also indicate that insects can adapt to hypoxic pressure by modulating basic metabolic processes. PMID- 24047109 TI - A new lumbar posterior fixation system, the memory metal spinal system: an in vitro mechanical evaluation. AB - BACKGROUND: Spinal systems that are currently available for correction of spinal deformities or degeneration such as lumbar spondylolisthesis or degenerative disc disease use components manufactured from stainless steel or titanium and typically comprise two spinal rods with associated connection devices (for example: DePuy Spines Titanium Moss Miami Spinal System). The Memory Metal Spinal System of this study consists of a single square spinal rod made of a nickel titanium alloy (Nitinol) used in conjunction with connecting transverse bridges and pedicle screws made of Ti-alloy. Nitinol is best known for its shape memory effect, but is also characterized by its higher flexibility when compared to either stainless steel or titanium. A higher fusion rate with less degeneration of adjacent segments may result because of the elastic properties of the memory metal. In addition, the use of a single, unilateral rod may be of great value for a TLIF procedure. Our objective is to evaluate the mechanical properties of the new Memory Metal Spinal System compared to the Titanium Moss Miami Spinal System. METHODS: An in-vitro mechanical evaluation of the lumbar Memory Metal Spinal System was conducted. The test protocol followed ASTM Standard F1717-96, "Standard Test Methods for Static and Fatigue for Spinal Implant Constructs in a Corpectomy Model." 1. Static axial testing in a load to failure mode in compression bending, 2. Static testing in a load to failure mode in torsion, 3. Cyclical testing to estimate the maximum run out load value at 5.0 x 10^6 cycles. RESULTS: In the biomechanical testing for static axial compression bending there was no statistical difference between the 2% yield strength and the stiffness of the two types of spinal constructs. In axial compression bending fatigue testing, the Memory Metal Spinal System construct showed a 50% increase in fatigue life compared to the Titanium Moss Miami Spinal System. In static torsional testing the Memory Metal Spinal System constructs showed an average 220% increase in torsional yield strength, and an average 30% increase in torsional stiffness. CONCLUSIONS: The in-vitro mechanical evaluation of the lumbar Memory Metal Spinal System showed good results when compared to a currently available spinal implant system. Throughout testing, the Memory Metal Spinal System showed no failures in static and dynamic fatigue. PMID- 24047110 TI - Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study. AB - The Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial randomized patients receiving a living or standard criteria deceased donor kidney transplant to a more (MI) or less intensive (LI) regimen of belatacept or cyclosporine A (CsA). The 5-year results of the long term extension (LTE) cohort are reported. A total of 456 (68.5% of intent-to treat) patients entered the LTE at 36 months; 406 patients (89%) completed 60 months. Between Months 36 and 60, death occurred in 2%, 1% and 5% of belatacept MI, belatacept LI and CsA patients, respectively; graft loss occurred in 0% belatacept and 2% of CsA patients. Acute rejection between Months 36 and 60 was rare: zero belatacept MI, one belatacept LI and one CsA. Rates for infections and malignancies for Months 36-60 were generally similar across belatacept groups and CsA, respectively: fungal infections (14%, 15%, 12%), viral infections (21%, 18%, 16%) and malignancies (6%, 6%, 9%). No new posttransplant lymphoproliferative disorder cases occurred after 36 months. Mean calculated GFR (MDRD, mL/min/1.73 m(2) ) at Month 60 was 74 for belatacept MI, 76 for belatacept LI and 53 for CsA. These results show that the renal function benefit and safety profile observed in belatacept-treated patients in the early posttransplant period was sustained through 5 years. PMID- 24047111 TI - Habitable zone lifetimes of exoplanets around main sequence stars. AB - The potential habitability of newly discovered exoplanets is initially assessed by determining whether their orbits fall within the circumstellar habitable zone of their star. However, the habitable zone (HZ) is not static in time or space, and its boundaries migrate outward at a rate proportional to the increase in luminosity of a star undergoing stellar evolution, possibly including or excluding planets over the course of the star's main sequence lifetime. We describe the time that a planet spends within the HZ as its "habitable zone lifetime." The HZ lifetime of a planet has strong astrobiological implications and is especially important when considering the evolution of complex life, which is likely to require a longer residence time within the HZ. Here, we present results from a simple model built to investigate the evolution of the "classic" HZ over time, while also providing estimates for the evolution of stellar luminosity over time in order to develop a "hybrid" HZ model. These models return estimates for the HZ lifetimes of Earth and 7 confirmed HZ exoplanets and 27 unconfirmed Kepler candidates. The HZ lifetime for Earth ranges between 6.29 and 7.79*109 years (Gyr). The 7 exoplanets fall in a range between ~1 and 54.72 Gyr, while the 27 Kepler candidate planets' HZ lifetimes range between 0.43 and 18.8 Gyr. Our results show that exoplanet HD 85512b is no longer within the HZ, assuming it has an Earth analog atmosphere. The HZ lifetime should be considered in future models of planetary habitability as setting an upper limit on the lifetime of any potential exoplanetary biosphere, and also for identifying planets of high astrobiological potential for continued observational or modeling campaigns. PMID- 24047112 TI - Morphological biosignatures in gypsum: diverse formation processes of Messinian (~6.0 Ma) gypsum stromatolites. AB - The ~5.3-6.0 million-year-old evaporitic gypsum deposits of Cyprus and Crete contain a variety of stromatolites that formed during the Messinian salinity crisis. We recognize four stromatolite morphotypes, including domical, conical, columnar, and flat-laminated structures. Observations of morphological and textural variations among the different morphotypes reveal significant diversity and complexity in the nature of interactions between microorganisms, gypsum deposition, and gypsum crystal growth. Nonbiological processes (detrital gypsum deposition, in situ crust precipitation, syntaxial crystal growth, subsurface crystal growth, and recrystallization) interacted with inferred microbial processes (including localized growth of biofilms, trapping and binding of grains in mats, nucleation of gypsum on cells) to produce distinct morphological textural assemblages. Evidence for biological origins is clear in some stromatolite morphotypes and can come from the presence of microfossils, the spatial distribution of organic matter, and stromatolite morphology. In one stromatolite morphotype, the presence of the stromatolite, or the biota associated with it, may have determined the morphology of gypsum crystals. In some stromatolite morphotypes, definitive evidence of a microbial influence is not as clear. There are broad similarities between the Messinian gypsum stromatolites and carbonate stromatolites elsewhere in the geologic record, such as the formation of precipitated and granular layers; the development of domed, columnar, and conical morphotypes; the potential for microbes to influence mineral precipitation; and the recrystallization of deposits during burial. However, in detail the array of microbial-sedimentary-diagenetic process interactions is quite distinct in gypsiferous systems due to differences in the way gypsum typically forms and evolves in the paleoenvironment compared to carbonate. Unique aspects of the taphonomy of gypsum compared to carbonate chemical sediments, generally speaking, include the following: the potential for growth of individual crystals to determine the shape of a stromatolite (and possibly vice versa), a more diverse set of outcomes relating to preservation versus destruction of textures through crystal growth and recrystallization, and a greater likelihood of preserving microfossils through encapsulation in large crystals. These insights gained from the study of terrestrial gypsum sedimentary rocks provide valuable guidance for the search for clues to past life in sulfate chemical sediments on Mars. PMID- 24047113 TI - Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): formulation design and optimization studies. AB - The penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was incorporated into a solid dispersion for oral administration by the solvent evaporation method using blends of polyvinylpyrrolidone (PVP), Eudragit(r) RL PO and alpha-tocopherol. D-optimal mixture design was used to optimize the formulation. Formulations that had a high concentration of both Eudragit(r) RL PO and alpha-tocopherol exhibited low water absorption and enhanced stability of the DTPA prodrug. Physicochemical properties of the optimal formulation were evaluated using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). In vitro release of the prodrug was evaluated using the USP Type II apparatus dissolution method. DSC studies indicated that the matrix had an amorphous structure, while FTIR spectrometry showed that DTPA penta-ethyl ester and excipients did not react with each other during formation of the solid dispersion. Dissolution testing showed that the optimized solid dispersion exhibited a prolonged release profile, which could potentially result in a sustained delivery of DTPA penta-ethyl to enhance bioavailability. In conclusion, DTPA penta-ethyl ester was successfully incorporated into a solid matrix with high drug loading and improved stability compared to prodrug alone. PMID- 24047114 TI - DigitalVHI--a freeware open-source software application to capture the Voice Handicap Index and other questionnaire data in various languages. AB - In this short report we introduce DigitalVHI, a free open-source software application for obtaining Voice Handicap Index (VHI) and other questionnaire data, which can be put on a computer in clinics and used in clinical practice. The software can simplify performing clinical studies since it makes the VHI scores directly available for analysis in a digital form. It can be downloaded from http://www.christian-herbst.org/DigitalVHI/. PMID- 24047115 TI - Adiponectin offers protection against L166P mutant DJ-1-induced neuronal cytotoxicity mediated by APPL1-dependent AMPK activation. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. L166P mutant DJ-1 has been linked with a genetic form of the disease. Preventing neurotoxicity of DJ-1 familial mutations has become a new therapeutic target for PD. Adiponectin, the most abundantly secreted adipokine, has displayed its protective roles in pathologies of various types of diseases. In this study, we investigate whether adiponectin is protective against neurotoxicity induced by familial L166P mutant DJ-1 in PD. Our results demonstrate that adiponectin treatment could attenuate increased levels of reactive oxygen species and nitric oxide induced by the DJ-1L166P mutation. In addition, adiponectin could rescue impaired mitochondrial membrane potential induced by DJ-1L166P. Importantly, we verified that both adiponectin receptors, type 1 (AdipoR1) and type 2 (AdipoR2), are expressed in human neuroblastoma M17 cells. Our results also demonstrate that the protective effects of adiponectin against DJ-1L166P-induced neuronal cytotoxicity under 1-methyl-4-phenylpyridinium ion (MPP+) treatment require binding of adiponectin to its cell surface receptors. Finally, we found that the protective effects of adiponectin against DJ-1L166P depend on AMP-activated protein kinase (AMPK) activation mediated by the endosomal adaptor protein, APPL1 (adaptor protein with phosphotyrosine binding, pleckstrin homology domains and leucine zipper motif). These data suggest that adiponectin may have potential for implementation in novel therapies against PD. PMID- 24047116 TI - MicroRNAs induced in melanoma treated with combination targeted therapy of Temsirolimus and Bevacizumab. AB - BACKGROUND: Targeted therapies directed at commonly overexpressed pathways in melanoma have clinical activity in numerous trials. Little is known about how these therapies influence microRNA (miRNA) expression, particularly with combination regimens. Knowledge of miRNAs altered with treatment may contribute to understanding mechanisms of therapeutic effects, as well as mechanisms of tumor escape from therapy. We analyzed miRNA expression in metastatic melanoma tissue samples treated with a novel combination regimen of Temsirolimus and Bevacizumab. Given the preliminary clinical activity observed with this combination regimen, we hypothesized that we would see significant changes in miRNA expression with combination treatment. METHODS: Using microarray analysis we analyzed miRNA expression levels in melanoma samples from a Cancer Therapy Evaluation Program-sponsored phase II trial of combination Temsirolimus and Bevacizumab in advanced melanoma, which elicited clinical benefit in a subset of patients. Pre-treatment and post-treatment miRNA levels were compared using paired t-tests between sample groups (patients), using a p-value < 0.01 for significance. RESULTS: microRNA expression remained unchanged with Temsirolimus alone; however, expression of 15 microRNAs was significantly upregulated (1.4 to 2.5-fold) with combination treatment, compared to pre-treatment levels. Interestingly, twelve of these fifteen miRNAs possess tumor suppressor capabilities. We identified 15 putative oncogenes as potential targets of the 12 tumor suppressor miRNAs, based on published experimental evidence. For 15 of 25 miRNA-target mRNA pairings, changes in gene expression from pre-treatment to post combination treatment samples were inversely correlated with changes in miRNA expression, supporting a functional effect of those miRNA changes. Clustering analyses based on selected miRNAs suggest preliminary signatures characteristic of clinical response to combination treatment and of tumor BRAF mutational status. CONCLUSIONS: To our knowledge, this is the first study analyzing miRNA expression in pre-treatment and post-treatment human metastatic melanoma tissue samples. This preliminary investigation suggests miRNAs that may be involved in the mechanism of action of combination Temsirolimus and Bevacizumab in metastatic melanoma, possibly through inhibition of oncogenic pathways, and provides the preliminary basis for further functional studies of these miRNAs. PMID- 24047117 TI - Detecting alpha spindle events in EEG time series using adaptive autoregressive models. AB - BACKGROUND: Rhythmic oscillatory activity is widely observed during a variety of subject behaviors and is believed to play a central role in information processing and control. A classic example of rhythmic activity is alpha spindles, which consist of short (0.5-2 s) bursts of high frequency alpha activity. Recent research has shown that alpha spindles in the parietal/occipital area are statistically related to fatigue and drowsiness. These spindles constitute sharp changes in the underlying statistical properties of the signal. Our hypothesis is that change point detection models can be used to identify the onset and duration of spindles in EEG. In this work we develop an algorithm that accurately identifies sudden bursts of narrowband oscillatory activity in EEG using techniques derived from change point analysis. Our motivating example is detection of alpha spindles in the parietal/occipital areas of the brain. Our goal is to develop an algorithm that can be applied to any type of rhythmic oscillatory activity of interest for accurate online detection. METHODS: In this work we propose modeling the alpha band EEG time series using discounted autoregressive (DAR) modeling. The DAR model uses a discounting rate to weigh points measured further in the past less heavily than points more recently observed. This model is used together with predictive loss scoring to identify periods of EEG data that are statistically significant. RESULTS: Our algorithm accurately captures changes in the statistical properties of the alpha frequency band. These statistical changes are highly correlated with alpha spindle occurrences and form a reliable measure for detecting alpha spindles in EEG. We achieve approximately 95% accuracy in detecting alpha spindles, with timing precision to within approximately 150 ms, for two datasets from an experiment of prolonged simulated driving, as well as in simulated EEG. Sensitivity and specificity values are above 0.9, and in many cases are above 0.95, for our analysis. CONCLUSION: Modeling the alpha band EEG using discounted AR models provides an efficient method for detecting oscillatory alpha activity in EEG. The method is based on statistical principles and can generally be applied to detect rhythmic activity in any frequency band or brain region. PMID- 24047118 TI - Adaptation of impression cytology to enable conjunctival surface cell transcriptome analysis. AB - PURPOSE: This study investigates the extent of the human transcriptome that can be quantified from conjunctival impression cytology extracts. The aim is to determine if sufficient RNA can be isolated from a patient's conjunctival surface to identify differences in gene expression between dry eye and normal patients of (a) an array of 96 inflammatory biomarkers and associated receptors, and (b) if this comparison can be expanded to the entire transcriptome. MATERIALS AND METHODS: CIC was used to collect conjunctival surface cells from 53 qualifying normal and dry eye patients. Based on prior optimization of all assay steps, RNA was isolated from the samples using a Qiagen RNeasy Plus Mini Kit and qRT-PCR was used to determine gene expression of 96 genes using TaqMan Low Density Array cards. Samples from six normal and six dry eye patients were then assayed on an Illumina Human HT-12 BeadChip. RESULTS: Optimization steps yielded an RNA processing procedure that improved yield from an initial 12 genes through 96, then to the entire human transcriptome. For the HT-12 BeadChip, more than 30 genes differed by a factor of >1.5 between the dry eye and normal groups and seven genes were down-regulated by a factor of >2.0 in the dry eye group: HLA DRB5, PSCA, FOS, lysozyme, TSC22D1, CAPN13 and CXCL6. CONCLUSIONS: Conjunctival impression cytology can be used to collect sufficient RNA from conjunctival surface cells that, when processed optimally, allows successful transcriptome wide expression analysis. While the current transcriptome analysis used a limited patient group, larger studies of patients with various types and severities of dry eye should reveal significant gene expression trends that can then be targeted to improve dry eye treatment options. PMID- 24047119 TI - Previous forensic mental examination is a useful marker indicating effective violence relapse prevention among psychotic patients. AB - BACKGROUND: Patients with schizophrenia have an increased risk of violent behavior. AIMS: The aim of this study was to find predictive indicators of high risk of violent behavior among outpatients with psychosis. METHODS: A total of 206 individuals were involuntarily ordered to hospital treatment as forensic patients after a forensic mental examination in Finland from 1995-1999. The information was collected from the registers of the National Authority for Medicolegal Affairs, and was obtained from 194 persons of which 184 had been accused of a violent crime. RESULTS: Twenty percent (22/110) of those forensic patients, who had received a psychosis diagnosis before the index crime, had previously undergone a forensic examination. This subgroup was 12% of the total study population (22/184), which is about 300 times higher than expected (i.e. if no risk increase assumed). Ten of the 22 persons in this subgroup had been committed in forensic psychiatric inpatient care and later discharged. The same number of persons had been sentenced to prison and subsequently released after the previous forensic mental examination. CONCLUSIONS: While primary prevention of crime for the larger population of all patients with psychosis is not feasible, secondary prevention (prevention of reoffending) might be possible by focusing on the small subgroup, which had undergone a previous forensic mental examination. Obligatory follow-up and treatment in outpatient care would probably decrease recidivistic offending among discharged forensic psychiatric patients and among those offenders found not guilty by reason of insanity but not considered to fulfill criteria for involuntary hospital treatment. PMID- 24047120 TI - Relationships of personality dimensions with impulsivity in alcohol-dependent inpatient men. AB - BACKGROUND: Impulsivity is closely related to substance use and abuse, both as a contributor to use and as a consequence of use. Particular dimensions of temperament and character were reported to be associated with trait impulsivity in different populations. AIM: The aim of the present study was to evaluate the relationship of personality dimensions with impulsivity among men with alcohol dependence. Also we wanted to control the effect of depression and anxiety symptoms on this relationship. METHODS: Participants were consecutively admitted male alcohol-dependent inpatients (n = 94) and healthy controls (n = 63). Patients were investigated with the Barratt Impulsiveness Scale, version 11 (BIS 11), the Temperament and Character Inventory (TCI) and the Symptom Checklist Revised (SCL-90-R). RESULTS: Severity of impulsivity and dimensions of impulsivity were higher in alcohol-dependent inpatients than in healthy controls. Impulsivity was negatively correlated with reward dependence, persistence, self directedness and cooperativeness, but positively correlated with novelty seeking, harm avoidance, depression and anxiety. Although high depression and temperament dimensions (high novelty seeking, harm avoidance and low reward dependence) predicted impulsivity, combinations of personality dimensions that predict dimensions of impulsivity differed. CONCLUSIONS: RESULTS may suggest that together with depression when impulsivity is the problem, both dimensions of impulsivity and personality must be evaluated and the treatment should be shaped accordingly for alcohol-dependent inpatients. PMID- 24047121 TI - Unsynchronized nasal intermittent positive pressure versus nasal continuous positive airway pressure in preterm infants after extubation. AB - OBJECTIVE: To determine the effect of unsynchronized nasal intermittent positive pressure ventilation compared to continuous positive airway pressure in preterm infants after extubation. METHODS: A total of 67 premature infants who were <35 weeks gestation and/or <2000 g birth weight and received mechanical ventilation because of respiratory distress syndrome (RDS) were studied. Infants were randomized to receive either unsynchronized nasal intermittent positive pressure ventilation (NIPPV) with shortened endotracheal tube (Group 1) or nasal continuous positive airway pressure (NCPAP) with binasal prongs (Group 2) after extubation. Extubation failure and neonatal outcomes were recorded in each group. RESULTS: There were no significant differences in clinical characteristics between the two groups. The prevalence of re-intubation and post-extubation atelectasis were higher in CPAP group (p = 0.03 and p = 0.01). No differences were observed in the prevalence of IVH, ROP, PDA, NEC, sepsis, pneumothorax, BPD and BPD/death between the groups while the mortality was higher in NCPAP group (p < 0.01). Neither procedure had any serious side effects such as intestinal perforation. CONCLUSION: NIPPV (although non-synchronized and delivered by single nasal prong) had a better effect than NCPAP after extubation of preterm infants on mechanical ventilation in respect to reducing the prevalence of post extubation atelectasis, re-intubation and also death. PMID- 24047122 TI - A new triterpenoid saponin from the root of Croton lachnocarpus Benth. AB - A new triterpenoid saponin, 3-O-beta-D-xylopyranosyl spathodic acid (1), was isolated from the EtOH extract of the root of Croton lachnocarpus Benth., together with four known compounds. These compounds were characterised on the basis of their spectral data and compatible with values in the literature. Compound 1 was the first triterpenoid glucoside isolated from the genus Croton. The known compound myriaboric acid (2) showed cytotoxic activity against human hepatocellular carcinoma SMMC-7721 cell line with an IC50 value of 42.2 MUM. PMID- 24047123 TI - Lack of association between postactivation potentiation and subsequent jump performance. AB - Postactivation potentiation (PAP) is a strategy that has been used to acutely enhance the performance of explosive activities. Although, isometric maximal voluntary contractions (MVCs) have previously been shown to enhance subsequent explosive performance, no information currently exists regarding (1) the optimal variables (intensity/volume) of a MVC that best elicits a PAP response, and (2) the utilisation of evoked isometric twitch contractions in combination with performance measures to directly ascertain the presence of PAP following a MVC, and its relationship to performance. Thus, the purpose of this study was to (1) investigate the influence of isometric contraction duration on the PAP response, and (2) to determine the relationship between PAP, indicated as potentiation of muscle twitch force and subsequent jump performance following different-duration MVCs. Eight males (age: 21 +/- 0.99) were assessed using performance measures [countermovement jumps] and evoked twitch contractions, before and 4 minutes after three different conditioning contractions (CCs), (1) a 3-second MVC (MVC3), (2) a 5-second MVC (MVC5) and (3) a 7-second MVC (MVC7). Following all CCs, peak twitch torque of the knee extensor muscles was found to increase (MVC3, + 3.9%; MVC5, + 9.6%; MVC7, + 5.2%), although not significantly (P > 0.05). No significant increases in jump height, jump power, rate of force development or takeoff velocity were observed following any of the CCs (P > 0.05). There was also a lack of association between the changes in PAP (twitch torque) and jump height following all CCs (MVC3, r = 0.25; MVC5, r = 0.28; MVC7, r = -0.47). These data indicate that PAP as assessed via twitch contractions is not associated with performance measures subsequent to single-set isometric CCs of varying durations. PMID- 24047124 TI - Size-dependent correlations between strain and phonon frequency in individual ZnO nanowires. AB - The effect of uniaxial tensile strain on individual ZnO nanowires with diameters ranging from 500 nm to 2.7 MUm and the effect of pure bending strain on ZnO microwires are systematically investigated by Raman spectroscopy. It is found for the first time that the tensile and compressive strains result in a linear downshift and upshift of the phonon frequencies of the E2L, E2H, E1TO, and second order modes compared with the strain-free state, respectively, while the A1TO mode is not influenced by the strain. Furthermore, the strain modulation on phonons depends strongly on the nanowire diameter. The E2H phonon deformation potential is ~3 cm(-1)/% for the 500 nm nanowire, while 1% tensile strain results only in ~1 cm(-1) downward frequency shift for the 2.7 MUm ZnO wire. The results provide a versatile "local-self-calibration" and nondestructive method to measure and monitor the local strains in ZnO micro/nanostructures. PMID- 24047125 TI - Type 2 diabetes-induced cardiovascular complications: comparative evaluation of spironolactone, atenolol, metoprolol, ramipril and perindopril. AB - The present study was carried out to study the effect of spironolactone, atenolol, metoprolol, ramipril and perindopril on cardiovascular complications in neonatal model of diabetes in rats, induced by administering 90 mg/kg streptozotocin (STZ), i.p. in 2-day-old rats. Our data suggest that spironolactone, metoprolol and perindopril prevent not only the STZ-induced metabolic abnormalities but also cardiovascular complications as evident from the reduction in cholesterol, triglyceride and decrease in cardiac hypertrophy which are the initial symptoms of congestive heart failure. Metoprolol and perindopril appears to be beneficial agents as compared to atenolol and ramipril. PMID- 24047127 TI - Surfactant-free synthesis of biodegradable, biocompatible, and stimuli-responsive cationic nanogel particles. AB - Nanogels have attracted much attention lately because of their many potential applications, including as nanocarriers for drug and gene delivery. Most nanogels reported previously, however, are not biodegradable, and their synthesis often requires the use of surfactants. Herein we report a surfactant-free method for the preparation of biodegradable, biocompatible, and stimuli-responsive cationic nanogels. The nanogels were synthesized by simply coaservating linear polymer precursors in mixed solvents followed by in situ cross-linking with homobifunctional cross-linkers. The versatility of this approach has been demonstrated by employing two different polymers and various cross-linkers to prepare nanogel particles with diameters ranging from 170 to 220 nm. Specifically, disulfide-containing tetralysine (TetK)- and oligoethylenimine (OEI)-based prepolymers were prepared and the subsequent nanogels were formed by covalently cross-linking the polymer coacervate phase. Nanogel particles are responsive to pH changes, increasing in size and zeta-potential with concomitant lowering of solution pH. Furthermore, as revealed by AFM imaging, nanogel particles were degradable in the presence of glutathione at concentrations similar to those in intracellular environment (10 mM). Both the nanogel and the polymer precursors were determined to exhibit minimal cytotoxicity against fibroblast 3T3 cells by flow cytometric analyses and fluorescent imaging. This study demonstrates a new surfactant-free method for preparing biodegradable, biocompatible, and stimuli-responsive nanogels as potential nanocarriers for the delivery of drugs and genes. PMID- 24047126 TI - Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder: a post hoc analysis of a randomized European-Australian Phase 3 trial. AB - BACKGROUND: Antimuscarinic agents are currently the predominant treatment option for the clinical management of the symptoms of overactive bladder (OAB). However, low rates of persistence with these agents highlight the need for novel, effective and better-tolerated oral pharmacological agents. Mirabegron is a beta3 adrenoceptor agonist developed for the treatment of OAB, with a mechanism of action distinct from that of antimuscarinics. In a randomized, double-blind, placebo- and active-controlled Phase 3 trial conducted in Europe and Australia (NCT00689104), mirabegron 50 mg and 100 mg resulted in statistically significant reductions from baseline to final visit, compared with placebo, in the co-primary end points - mean number of incontinence episodes/24 h and mean number of micturitions/24 h. We conducted a post hoc, subgroup analysis of this study in order to evaluate the efficacy of mirabegron in treatment-naive patients and patients who had discontinued prior antimuscarinic therapy because of insufficient efficacy or poor tolerability. METHODS: Patients were randomized to placebo, mirabegron 50 or 100 mg, or tolterodine extended release (ER) 4 mg orally, once-daily, for 12 weeks. For the post hoc analysis, the primary patient population was divided into the following subgroups: (1) patients who had not received any prior antimuscarinic OAB medication (treatment-naive) and (2) patients who had received prior antimuscarinic OAB medication. The latter subgroup was further subdivided into patients who discontinued due to: (3) insufficient efficacy or (4) poor tolerability. Analysis of the co-primary efficacy endpoints by subgroup was performed using analysis of covariance with treatment group, subgroup, sex, geographical region, and subgroup-by-treatment interaction as fixed factors; and baseline value as a covariate. RESULTS: Mirabegron, 50 mg and 100 mg once-daily, demonstrated similar improvements in the frequency of incontinence episodes and micturitions in OAB patients who were antimuscarinic-naive and who had discontinued prior antimuscarinic therapy. While mirabegron demonstrated improvements in incontinence and micturition frequency in patients who had discontinued prior antimuscarinic therapy due to insufficient efficacy, the response to tolterodine was similar to that of placebo. CONCLUSION: In this post hoc subgroup analysis, mirabegron provided treatment benefits in OAB patients who were antimuscarinic treatment-naive and in patients who had received prior antimuscarinic treatment. PMID- 24047128 TI - o-Phenylene octamers as surface modifiers for homeotropic columnar ordering of discotic liquid crystals. AB - Large-area homeotropic columnar ordering of pi-conjugated discotic liquid crystals (LCs) is crucial for certain device applications but generally hard to achieve. Here we report polymeric o-phenylene octamer poly-1 and its monomer 1 as the first surface modifiers for homeotropic columnar order of a variety of discotic LCs up to a macroscopic length scale. Their octameric o-phenylene parts are known to fold helically into a cylinder that is reminiscent of a pi-stacked column of discotic LCs. Through-view X-ray diffraction patterns of 1 suggested that this molecule adheres to the glass substrate and directs its cylindrical axis perpendicular to the glass surface. This "face-on" orientation likely nucleates the homeotropic columnar order of discotic LC materials. PMID- 24047129 TI - Electrogenerated chemiluminescence of iridium-containing ROMP block copolymer and self-assembled micelles. AB - The electrochemical properties and electrogenerated chemiluminescence (ECL) of an Ir(ppy)2(bpy)(+)-containing ROMP monomer, block copolymer (containing Ir(ppy)2(bpy)(+) complexes, PEG chains, and butyl moieties), and self-assembled micelles were investigated. Following polymerization of the iridium complex, we observed multiple oxidation peaks for the block copolymer in cyclic voltammograms (CV) and differential pulse voltammograms (DPV), suggesting the presence of multiple environments for the iridium complexes along the polymer backbone. The ECL signals from monomer 1 and polymer 2 were reproducible over continuous CV cycles and stable over prolonged potential biases, demonstrating their robustness toward ECL-based detection. Comparison of the ECL signal of the block copolymer, containing multiple iridium complexes attached to the backbone, and the monomeric complex showed enhanced signals for the polymer. In fact, formation and reopening of the self-assembled micelles allowed recovery of the polymer and near complete retention of its original ECL intensity. PMID- 24047130 TI - Exploring the energy disposal immediately after bond-breaking in solution: the wavelength-dependent excited state dissociation pathways of para methylthiophenol. AB - A wavelength-resolved (lambdapump = 295, 285, 270, and 267 nm) photodissociation study of para-methylthiophenol (p-MePhSH) in ethanol solution has been performed using femtosecond transient absorption (TA) spectroscopy, and the results compared with those from studies of the corresponding photodissociation in cyclohexane solution at 270 nm. Anisotropy spectra are used to identify the electronic character of the initially populated excited state(s). S-H bond fission is found to occur via the dissociative S2(1(1)pisigma*) state, which can be populated directly, or by ultrafast nonradiative transitions from the S3(2(1)pipi*) state, or by very efficient tunneling from the S1(1(1)pipi*) state, depending on the excitation wavelength, in line with conclusions from previous gas-phase studies of this same molecular photodissociation (Oliver, T. A. A.; King, G. A.; Tew, D. P.; Dixon R. N.; Ashfold, M. N. R. J. Phys. Chem. A 2012, 116, 12444). p-MePhS radicals are observed on a time scale faster than the instrument response at all wavelengths, but the available time resolution affords a rare opportunity to explore the branching between different electronic states of a product (the A and X states of the p-MePhS radical in this case). The present study provides estimates of this branching in the products formed immediately after the first pass through the conical intersection (CI) between the S2 and S0 states. At 270 nm, for example, we identify a marked population inversion in the radical products, in contrast to the reported gas phase behavior. The finding that the contrast in branching ratio is largest between cyclohexane solution and the gas phase, with ethanol being intermediate, can be rationalized by recognizing the differing distributions of the S-H torsion angle (relative to the ring plane) in a room temperature solution compared with those in a jet-cooled molecular beam. The available time resolution also allows exploration of the electronic quenching of nascent A state radicals as solvent motion encourages recrossing of the S2/S0 CI. The average separation distance, , between the H + p-MePhS products arising in successful dissociation events is seen to increase with decreasing photolysis wavelength. This finding accords with the previous gas phase results, which determined that most of the excess energy following population of the dissociative S2 state (directly, or by ultrafast coupling from the S3 state) is released as product translation, and the expectation that should scale with the total kinetic energy release. The present work also confirms that geminate recombination of the H + p-MePhS products leads not just to reformation of parent p-MePhSH molecules but also to alternative adducts wherein the H atom bonds to the benzene ring. Analysis of the present data and results of high level ab initio calculations together with recent UV-IR pump-probe measurements (Murdock, D.; Harris, S. J.; Karsili, T. N. V.; Greetham, G. M.; Clark, I. P.; Towrie, M.; Orr-Ewing, A. J.; Ashfold, M. N. R. J. Phys. Chem. Lett. 2012, 3, 3715) allows identification of the likely adduct structures. PMID- 24047131 TI - Four-way junction formation promoting ultrasensitive electrochemical detection of microRNA. AB - MicroRNAs (miRNAs) represent a class of biomarkers that are frequently deregulated in cancer cells and have shown a great promise for cancer classification and prognosis. Here, we endeavored to develop a DNA four-way junction based electrochemical sensor (4J-SENS) for ultrasensitive miRNA analysis. The developed sensor can be operated within the dynamic range from 10 aM to 1 fM and detect as low as 2 aM of miR-122 (~36 molecules per sample), without PCR amplification. Furthermore, the 4J-SENS was employed to profile endogenouse hsa-miR-122 in healthy human and chronic lymphocyitc leukemia (CLL) patient serum, and the results were validated by qPCR analysis. PMID- 24047132 TI - Regional water implications of reducing oil imports with liquid transportation fuel alternatives in the United States. AB - The Renewable Fuel Standard (RFS) is among the cornerstone policies created to increase U.S. energy independence by using biofuels. Although greenhouse gas emissions have played a role in shaping the RFS, water implications are less understood. We demonstrate a spatial, life cycle approach to estimate water consumption of transportation fuel scenarios, including a comparison to current water withdrawals and drought incidence by state. The water consumption and land footprint of six scenarios are compared to the RFS, including shale oil, coal-to liquids, shale gas-to-liquids, corn ethanol, and cellulosic ethanol from switchgrass. The corn scenario is the most water and land intense option and is weighted toward drought-prone states. Fossil options and cellulosic ethanol require significantly less water and are weighted toward less drought-prone states. Coal-to-liquids is an exception, where water consumption is partially weighted toward drought-prone states. Results suggest that there may be considerable water and land impacts associated with meeting energy security goals through using only biofuels. Ultimately, water and land requirements may constrain energy security goals without careful planning, indicating that there is a need to better balance trade-offs. Our approach provides policymakers with a method to integrate federal policies with regional planning over various temporal and spatial scales. PMID- 24047133 TI - Simultaneous etching and doping of TiO2 nanowire arrays for enhanced photoelectrochemical performance. AB - We developed a postgrowth doping method of TiO2 nanowire arrays by a simultaneous hydrothermal etching and doping in a weakly alkaline condition. The obtained tungsten-doped TiO2 core-shell nanowires have an amorphous shell with a rough surface, in which W species are incorporated into the amorphous TiO2 shell during this simultaneous etching/regrowth step for the optimization of photoelectrochemical performance. Photoanodes made of these W-doped TiO2 core shell nanowires show a much enhanced photocurrent density of ~1.53 mA/cm(2) at 0.23 V vs Ag/AgCl (1.23 V vs reversible hydrogen electrode), almost 225% of that of the pristine TiO2 nanowire photoanodes. The electrochemical impedance spectroscopy measurement and the density functional theory calculation demonstrate that the substantially improved performance of the dual W-doped and etched TiO2 nanowires is attributed to the enhancement of charge transfer and the increase of charge carrier density, resulting from the combination effect of etching and W-doping. This unconventional, simultaneous etching and doping of pregrown nanowires is facile and takes place under moderate conditions, and it may be extended for other dopants and host materials with increased photoelectrochemical performances. PMID- 24047134 TI - Extraction of DNA from orange juice, and detection of bacterium Candidatus Liberibacter asiaticus by real-time PCR. AB - Orange juice processed from Huanglongbing (HLB) affected fruit is often associated with bitter taste and/or off-flavor. HLB disease in Florida is associated with Candidatus Liberibacter asiaticus (CLas), a phloem-limited bacterium. The current standard to confirm CLas for citrus trees is to take samples from midribs of leaves, which are rich in phloem tissues, and use a quantitative real-time polymerase chain reaction (qPCR) test to detect the 16S rDNA gene of CLas. It is extremely difficult to detect CLas in orange juice because of the low CLas population, high sugar and pectin concentration, low pH, and possible existence of an inhibitor to DNA amplification. The objective of this research was to improve extraction of DNA from orange juice and detection of CLas by qPCR. Homogenization using a sonicator increased DNA yield by 86% in comparison to mortar and pestle extraction. It is difficult to separate DNA from pectin; however, DNA was successfully extracted by treating the juice with pectinase. Application of an elution column successfully removed the unidentified inhibitor to DNA amplification. This work provided a protocol to extract DNA from whole orange juice and detect CLas in HLB-affected fruit. PMID- 24047135 TI - The evolution of cytochrome P450 enzymes as biocatalysts in drug discovery and development. AB - Engineered biocatalysts offer the opportunity to introduce modifications into complex lead molecules and drug candidates in a chemo-, regio- and stereoselective manner that is difficult to accomplish using traditional synthetic organic chemistry. As candidate biocatalysts, the cytochrome P450 enzymes that metabolize drugs and other xenobiotics are amongst the most versatile agents known. Not only can they mediate an exceptional range of biotransformation reactions, but they act on an unparalleled diversity of substrates. However, this versatility comes at the cost of relatively poor catalytic efficiency and low rates of coupling of cofactor consumption to product formation. Directed evolution is being used to redefine the substrate specificity of P450 enzymes while at the same time improving their efficiency, thermostability and other properties. This review will outline the key successes with bacterial P450s used as biocatalysts, examine the studies done to date with mammalian forms, and assess the prospects for exploiting xenobiotic-metabolizing P450s for applications in medicinal chemistry. PMID- 24047136 TI - Cytochrome P450 2C8 and drug metabolism. AB - CYP 2C8, which carries out the oxidative metabolism of at least 5% of clinical drugs, has attracted increasing attention in recent years. New drugs (substances), inducers and inhibitors of CYP 2C8 have been developed and the drug metabolism has been investigated to understand the clinical role of CYP2C8. The cases of CYP2C8 genetic polymorphisms linked to diseases have increased and have been investigated. Herein, important progress in these areas has been reviewed with an emphasis on drug metabolism. Polymorphisms, diseases related to CYP2C8, some important drugs (substances) and inhibitors are reviewed and discussed. PMID- 24047137 TI - Generation, validation, and application of a P450 homology model. AB - In vitro validation of a protein homology model is critical for determining the predictivity of a computationally generated structure. Here we discuss the generation, validation, and application of a homology model for CYP1A1. Validation of the CYP1A1 homology model, generated using the highly homologous crystal template of human CYP1A2 (pdb 2HI4), was achieved using the prototypic substrate 7-ethoxyresorufin (Eres). The model was subsequently applied to generate CYP1A1 mutants with increased catalytic efficiency (Vmax/Km) towards the anticancer prodrug dacarbazine (DTIC). Thirty-three directed CYP1A1 mutants were generated and expressed in E. coli; six of these were generated to rationalise docking data obtained from in silico experiments using Eres. DTIC N-demethylation by the CYP1A1 E161K, E256K, and I458V mutants exhibited Michaelis-Menten kinetics, with decreases in Km that doubled the catalytic efficiency relative to wild-type (P < 0.05). As a chemotherapeutic agent, DTIC has relatively poor clinical activity in human malignancies and exhibits numerous adverse effects, which presumably arise from bioactivation in the liver and other tissues resulting in systemic exposure to the cytotoxic metabolite. The successful generation of CYP1A1 enzymes with catalytically enhanced DTIC activation highlights their potential use as a strategy for P450-based gene directed enzyme prodrug therapy (GDEPT) in the treatment of metastatic malignant melanoma. Moreover, the combination of in vitro kinetic analyses with in silico docking data from a validated homology model has allowed interpretation of the structure activity relationships of this enzyme-substrate pair. PMID- 24047138 TI - Overview on theoretical studies discriminating the two-oxidant versus two-state reactivity models for substrate monoxygenation by cytochrome P450 enzymes. AB - There is a major controversy in cytochrome P450 chemistry regarding the nature of the active oxidant responsible for substrate monoxygenation. Part of this controversy originates from the fact that the later stages in the catalytic cycle of P450 enzymes proceed so fast that little experimental evidence is available. Early studies suggested an iron(IV)- oxo heme cation radical ([heme((+*)) Fe(IV)=O] or Compound I) as the active species able to abstract a hydrogen atom from a substrate and rebind the hydroxyl group to form an alcohol product. Such simplistic early models involving a single active species have subsequently been invalidated by several experimental studies which clearly indicates that there must be at least two active species of some description. Based on these and other data, a two-oxidant hypothesis was put forward where Compound I and its precursor in the catalytic cycle ([heme-Fe(III)-OOH]- or Compound 0) are competitive oxidants. Density functional theory studies, however, suggest an alternative hypothesis involving a two-state-reactivity scenario where Compound I has two close-lying spin states that react differently with substrates and masquerade as two distinct oxidants. These theoretical studies show that the two spin states of Compound I react with substrates via aliphatic and aromatic C-H hydroxylation, C=C epoxidation and sulfoxidation reactions, and explain experimentally observed product distributions and kinetic isotope effects. This review will give an overview of recent studies on the two-oxidant versus two-state-reactivity hypotheses and how theory contributes to the understanding of enzymatic reaction processes. PMID- 24047139 TI - The medicinal chemistry of the cytochrome P450s. PMID- 24047140 TI - Copper-catalyzed one-pot trifluoromethylation/aryl migration/desulfonylation and C(sp2)-N bond formation of conjugated tosyl amides. AB - A novel copper-catalyzed one-pot trifluoromethylation/aryl migration/desulfonylation and C(sp(2))-N bond formation with conjugated tosyl amides as starting materials is presented here. The reaction affords alpha-aryl beta-trifluoromethyl amides bearing a quaternary stereocenter or trifluoromethylated oxindoles in a regioselective manner. PMID- 24047141 TI - Design, synthesis, and biological evaluation of novel investigational nonapeptide KISS1R agonists with testosterone-suppressive activity. AB - Metastin/kisspeptin is a 54 amino acid peptide ligand of the KISS1R receptor and is a critical regulator of GnRH secretion. The N-terminally truncated peptide, metastin(45-54), possesses a 10-fold higher receptor-binding affinity than full length metastin and agonistic KISS1R activity but is rapidly inactivated in rodent plasma. We have developed a decapeptide analog [D-Tyr(45),D Trp(47),azaGly(51),Arg(Me)(53)]metastin(45-54) with improved serum stability compared with metastin(45-54) but with decreased KISS1R agonistic activity. Amino acid replacements at positions 45-47 led to an enhancement of KISS1R agonistic activity and metabolic stability. N-terminal truncation resulted in a stable nonapeptide, [D-Tyr(46),D-Pya(4)(47),azaGly(51),Arg(Me)(53)]metastin(46-54), compound 26, which displayed KISS1R binding affinities comparable to metastin(45 54) and had improved serum stability. Compound 26 reduced plasma testosterone in male rats and is the first short-length metastin analog to possess testosterone suppressive activities. Compound 26 has led to the elucidation of investigational analogs TAK-683 and TAK-448, both of which have undergone clinical evaluation for hormone-dependent diseases such as prostate cancer. PMID- 24047142 TI - Preparation and in vitro characterization of glibenclamide-loaded alginate hexyl amide beads: a novel drug delivery system to improve the dissolution rate. AB - OBJECTIVE: This investigation aimed to synthesize amphiphilic hexyl amidic derivative of alginate to be used in the preparation of glibenclamide-loaded release system of improved dissolution rate. MATERIALS AND METHODS: Hexyl amine was associated to the activated carboxylic acid moieties of alginate to synthesize alginate hexyl amide polymer (AHAP). This polymer in comparison to alginate was used in different concentrations for preparing beads containing glibenclamide by an ionic gelation using Ca(++) as gelling ion. The prepared beads were characterized by DSC, FTIR and scanning electron microscope. The swelling behavior, drug loading capacity and release behavior were studied. RESULTS AND DISCUSSION: The results showed that the prepared AHAP beads were smaller in size and more spherical. The surface was highly corrugated with much and wider pore size. The beads showed a high drug loading capacity and efficacy that was affected by the polymer concentration. The drug release rate from AHAP beads reached 100% after 4, 8 and 12 hours in comparison to 75.3%, 73.2% and 69.2% from alginate beads at 3%, 2% and 1% polymer concentrations, respectively. CONCLUSION: It can thus be concluded that the amphiphilic AHAP-based bead is a simple and efficient delivery system of promising industrial significance for the improvement of the dissolution rate. PMID- 24047143 TI - Rare diseases in Italy: analysis of the costs and pharmacotherapy. AB - Purpose of this research was to analyse the rare diseases drug supply paths in the Italian region of Campania (Health District 47 of the Local Medical Company Naples 1), with a particular focus on current regulations in this field, and quantify the economic incidence of such pathologies in each quarter of 2007 and 2008. Rare, or orphan, diseases are especially serious and onerous from every point of view. Patients meet significant difficulties in obtaining information and in identifying the most appropriate treatment path within the health care system. Pharmaceutical prescriptions were analysed in order to identify the number of patients for each pathology in each quarter of the years 2007 and 2008, the drugs used, the quantity of each drug, and the costs for treatments. Data show a significant increase of costs during each quarter of the year 2008, as well as from 2007 to 2008. In the absence of specific guidelines for the Campania Region, the Local Medical Company of Naples 1 has established a procedure for patients affected by rare diseases that enables them to receive at no cost products that otherwise would not be distributed for free by the health care system. PMID- 24047144 TI - [Development of financial participation of patients in the costs of pharmacotherapy in the years 2008-2012]. AB - This paper deals with the financial participation of patients in the costs of pharmacotherapy in dependence on legislative regulations (in the period of 2008 2012). It describes the individual stages of selection of regulatory fees in pharmacies in connection with the appropriate legal regulations. The practical part lists the monthly values of the extent of financial participation of all patients who frequented a particular pharmacy in the period under study (1 April 2009 - 31 March 2010 and 1 January 2012 - 30 June 2012), the values of mutually corresponding months in both periods being compared. The development of the extent of financial participation in pharmacotherapy was monitored in ten individual patients in the period from 1 January 2008 to 30 June 2012; the course of the financial participation of two patients is analyzed in greater detail including the factors which influenced it. PMID- 24047145 TI - [Effect of abiotic elicitation on the sanguinarine production and polyphenol oxidase activity in the suspension culture of Eschscholtzia californica CHAM]. AB - Elicitation of plant in vitro cultures represents a biotechnological tool to improve the production of secondary metabolites. In this study, the effect of AgNO3 and CdCl2 on the sanguinarine production by the suspension culture of Eschscholtzia californica CHAM. was investigated. Elicitors were added to the cultures at the 14th day of subcultivation and their effect on the sanguinarine production was evaluated after a 48 h exposure. AgNO3 at the concentration of 0.075 mmol.l-1 and CdCl2 at the concentration of 4 mmol.l-1 induced a ca. 5.2- and 5.6-multiple increase in sanguinarine synthesis, respectively. This amount represents probably the maximal production, because a further increase in the elicitors concentrations did not increase sanguinarine production. Both abiotic elicitors induced a polyphenol oxidase specific activity increase. Polyphenol oxidase is probably involved in the biosynthesis of sanguinarine at the level of dopamine formation. Dopamine is a precursor of (S)-norcoclaurine, the first intermediate with the benzylisoquinoline structure. PMID- 24047146 TI - [Antioxidant activity of extracts and HPLC analysis of flavonoids from Capsella bursa-pastoris (L.) Medik]. AB - The flavonoid profile of Capsella bursa-pastoris (L.) Medik. (Brassicaceae) and the antioxidant activity of its methanolic and aqueous extracts were studied. Glycosides of quercetin, chrysoeriol, kaempferol, and isorhamnetin were identified. Chrysoeriol O-glucoside and isorhamnetin O-rutinoside were detected in this species for the first time. The extracts presented an antioxidant activity against DPPH radicals, peroxyl radicals, hydroxyl radicals, and hydrogen peroxide. PMID- 24047147 TI - [Content uniformity of warfarin-containing mixtures and tablets]. AB - This experimental study describes the method of direct compression of powder mixtures composed of warfarinum sodium salt. Warfarinum is a drug with a narrow therapeutics index. The aim of this study is to find a suitable composition and a process of preparing tablets with the best uniformity. The content uniformity is very important for the safety of the therapy. This study links up with the already published article including the results of content uniformity of mixtures and tablets prepared by direct compression. These mixtures contain fillers with different density and distribution size of the particles (excipients with digger particles were used in this experiment). The study is focused on the influence of magnesium stearate, which was added at the beginning of the homogenization or after the mixing of the other components. In addition to content uniformity and physical characteristics of the tablets, the study also evaluated the uniformity and physical characteristics of the mixtures. In this experimental study it has been found out that content uniformity is influenced by the total time of homogenization and the addition of magnesium stearate and much less by the distribution size of the particles of excipients in the mixtures. The appropriate selection of process parameters is important for obtaining tablets respecting the strict criterion of Bergum distribution. This distribution is a part of the GMP by the evaluation of the content uniformity in the U.S. PMID- 24047148 TI - PLS and shape-based similarity analysis of maleimides--GSK-3 inhibitors. AB - CONTEXT: Glycogen synthase kinase-3 (GSK-3) overactivity was correlated with several pathologies including type 2 diabetes mellitus, Alzheimer's disease, cancer, inflammation, obesity, etc. OBJECTIVE: The aim of the current investigation was to model the inhibitory activity of maleimide derivatives- inhibitors of GSK-3, to evaluate the impact of alignment on statistical performances of the Quantitative Structure-Activity Relationship (QSAR) and the effect of the template on shape-similarity--binding affinity relationship. MATERIALS AND METHODS: Dragon descriptors were used to generate Projection to Latent Structures (PLS) models in order to identify the structural prerequisites of maleimides to inhibit GSK-3. Additionally, shape/volume structural analysis of binding site interactions was evaluated. RESULTS: Reliable statistics R(2)(Y(CUM)) = 0.938/0.920, Q((2)(Y)(CUM)) = 0.866/0.838 for aligned and alignment free QSAR models and significant (Pearson, Kendall and Spearman) correlations between shape/volume similarity and affinities were obtained. DISCUSSION AND CONCLUSIONS: The crucial structural features modulating the activity of maleimides include topology, charge, geometry, 2D autocorrelations, 3D-MoRSE as well as shape/volume and molecular flexibility. PMID- 24047150 TI - Research potential of multi-lineage chicken amniotic mesenchymal stem cells. AB - Amniotic mesenchymal stem cells (AMSCs) express octamer binding transcription factor 4 (Oct-4), which is necessary for maintaining the undifferentiated state of pluripotent stem cells. AMSCs also express CD29, CD44 and vimentin, which are specific markers of mesenchymal cells. We studied the biological characteristics and potential for cell therapy of AMSCs derived from 8-day-old chicken embryos. We induced the AMSCs to differentiate into adipocytes, osteoblasts and myocardial cells and used immunofluorescence, reverse transcription-polymerase chain reaction (RT-PCR) assays to detect the expressions of specific markers of AMSCs and differentiated cells. To assess the differentiation capacity of AMSCs, passage four cells were induced to differentiate into adipocytes, osteoblasts and myocardial cells. These results suggested that AMSCs isolated from chicken embryos exhibited the characteristics of multipotent stem cells. AMSCs, therefore, may be potential candidates for cellular transplantation therapy and tissue engineering. PMID- 24047151 TI - Finding the best antibody dilution by repeated immunostaining of the same tissue section. AB - One can find the optimal antibody dilution for immunostaining by repeated staining on the same tissue section by using a less dilute antibody for each attempt. Using secondary antibody and horseradish peroxidase conjugated to a dextran polymer, a section stained repeatedly with several dilutions of antibody appears as good as a section stained with only the last dilution. PMID- 24047149 TI - Identical effects of VEGF and serum-deprivation on phenotype and function of adipose-derived stromal cells from healthy donors and patients with ischemic heart disease. AB - BACKGROUND: Adipose-derived stromal cells (ASCs) stimulated with vascular endothelial growth factor (VEGF) and serum-deprived, are applied in the first in man double-blind placebo-controlled MyStromalCell Trial, as a novel therapeutic option for treatment of ischemic heart disease (IHD). This in vitro study explored the effect of VEGF and serum deprivation on endothelial differentiation capacity of ASCs from healthy donors and IHD patients. METHODS: ASCs stimulated with rhVEGF(A165) in serum-deprived medium for one to three weeks were compared with ASCs in serum-deprived (2% fetal bovine serum) or complete medium (10% fetal bovine serum). Expression of VEGF receptors, endothelial and stem cell markers was measured using qPCR, flow cytometry and immunocytochemistry. In vitro tube formation and proliferation was also measured. RESULTS: ASCs from VEGF-stimulated and serum-deprived medium significantly increased transcription of transcription factor FOXF1, endothelial marker vWF and receptor VEGFR1 compared with ASCs from complete medium. ASCs maintained stem cell characteristics in all conditions. Tube formation of ASCs occurred in VEGF-stimulated and serum-deprived medium. The only difference between healthy and patient ASCs was a variation in proliferation rate. CONCLUSIONS: ASCs from IHD patients and healthy donors proved equally inclined to differentiate in endothelial direction by serum-deprivation, however with no visible additive effect of VEGF stimulation. The treatment did not result in complete endothelial differentiation, but priming towards endothelial lineage. PMID- 24047154 TI - Low serum vit. B12 level does not mean vit. B12 deficiency - problems related to the diagnosis of vitamin B12 deficiency. PMID- 24047152 TI - Rapid targeted gene disruption in Bacillus anthracis. AB - BACKGROUND: Anthrax is a zoonotic disease recognized to affect herbivores since Biblical times and has the widest range of susceptible host species of any known pathogen. The ease with which the bacterium can be weaponized and its recent deliberate use as an agent of terror, have highlighted the importance of gaining a deeper understanding and effective countermeasures for this important pathogen. High quality sequence data has opened the possibility of systematic dissection of how genes distributed on both the bacterial chromosome and associated plasmids have made it such a successful pathogen. However, low transformation efficiency and relatively few genetic tools for chromosomal manipulation have hampered full interrogation of its genome. RESULTS: Group II introns have been developed into an efficient tool for site-specific gene inactivation in several organisms. We have adapted group II intron targeting technology for application in Bacillus anthracis and generated vectors that permit gene inactivation through group II intron insertion. The vectors developed permit screening for the desired insertion through PCR or direct selection of intron insertions using a selection scheme that activates a kanamycin resistance marker upon successful intron insertion. CONCLUSIONS: The design and vector construction described here provides a useful tool for high throughput experimental interrogation of the Bacillus anthracis genome and will benefit efforts to develop improved vaccines and therapeutics. PMID- 24047155 TI - Spectroscopic study of N2(b1Piu, nu = 8) by atmospheric-pressure resonant enhanced multiphoton ionization and fluorescence detection. AB - A spectroscopic analysis of the strongly perturbed N2(b(1)Piu, nu = 8) state has been conducted, accounting for b(1)Piu(nu = 8) <- X (1)Sigmag(+)(nu = 0) transitions, for the first time, up to J' = 20. A novel laser spectroscopy technique, using a combination of resonant-enhanced multiphoton ionization and fluorescence detection at atmospheric pressure, avoids the severe effects of perturbation reported in past extreme vacuum ultraviolet absorption experiments that produced weak and unusable spectra for the nu = 8 level. The R, Q, and P branches of the three-photon absorption transition b(1)Piu(nu = 8) <- X(1)Sigmag(+)(nu = 0) were fit, allowing rotational term energy assignment up to J' = 20 and molecular constants to be determined. Evidence of the previously suspected perturbation in b(1)Piu(nu = 8) is clear in this data, with significant Lambda-type doubling at higher J' along with an anomalous negative value determined for the centrifugal distortion coefficient. PMID- 24047156 TI - Left atrial appendage function in prediction of paroxysmal atrial fibrilation in patients with untreated hypertension. AB - Abstract The onset of AF results in a significant increase in mortality rates and morbidity in hypertensive patients and this rhythm disorder exposes patients to a significantly increased risk of cerebral or peripheral embolisms. Tissue Doppler imaging was found to be useful in early detection of myocardial dysfunction in several diseases. It was shown that tissue Doppler analysis of the walls of the left atrial appendage (LAA) can give accurate information about the function of the LAA in hypertensive patients. In this study, we aimed to investigate and identify the specific predictive parameters for the onset of AF in patients with hypertension with tissue Doppler imaging of LAA. We studied age and sex matched 57 untreated hypertensive patients with paroxysmal atrial fibrillation (PAF) and 27 untreated hypertensive subjects without PAF. With transthoracic echocardiography, diastolic mitral A-velocity and LA maximal volume index which reflects reservoir function of left atrium was measured, with transesophageal echocardiography, LAA emptying velocity (LAA-PW D2) and tissue Doppler contracting velocity of LAA (LAA-TDI-D2) were measured. LA maximal volume index of the groups (22.28 +/- 3.59 mL/m(2) in Group 1 versus 20.37 +/- 3.97 mL/m(2) in Group 2, p = 0.07) and diastolic mitral A-velocity [0.93 (0.59-1.84) m/s in patients with PAF versus 0.90 (0.62-1.76) m/s in patients without PAF, p = 0.26] was not significantly different between study groups, during TEE, LAA-PW D2 (0.31 +/- 0.04 m/s in Group 1 versus 0.33 +/- 0.03 m/s in Group 2, p = 0.034) and LAA TDI-D2 (0.18 +/- 0.04 m/s in Group 1 versus 0.21 +/- 0.05 m/s in Group 2, p = 0.014) were significantly decreased in Group 1. In this study, we found that in hypertensive PAF patients despite normal global LA functions, LAA contracting function was deteriorated. Tissue Doppler analysis of LAA is clinically usefull approach to detect the risk of developing PAF in hypertensives. PMID- 24047158 TI - Mitochondrial DNA mutations may not be frequent in patients with oral cancer. PMID- 24047157 TI - Long-term results of treatment with bosentan in adult Eisenmenger's syndrome patients with Down's syndrome related to congenital heart disease. AB - BACKGROUND: Patients with Down's syndrome and shunt lesions are at high risk of developing pulmonary arterial hypertension (PAH) earlier than patients without Down's syndrome. However, data on the efficacy of PAH-specific therapy in patients with Down's syndrome are limited. The aim of this retrospective analysis was to determine the long-term efficacy of the dual endothelin receptor antagonist, bosentan, in Eisenmenger's syndrome (ES) patients with Down's syndrome. METHODS: In this observational study adults with Down's syndrome with a confirmed diagnosis of ES (World Health Organization functional class III) and receiving bosentan therapy and were followed up long term. Clinical evaluation at baseline and follow-up visits included resting transcutaneous arterial oxygen saturation and laboratory assessments. Exercise capacity was evaluated using a 6 minute walk test where transcutaneous arterial oxygen saturation at peak exercise (SpO2), 6-minute walk distance (6MWD) and Borg dyspnoea index were assessed. A full echocardiographic assessment was conducted at baseline and follow-up visits. RESULTS: Overall, seven adults (mean age 29.6 +/- 11.2 years; 57% male) received bosentan at a starting dose of 62.5 mg twice daily. This was increased to the target dose of 125 mg twice daily 4 weeks later. All patients remained on bosentan until the end of the study. After a mean (+/- standard deviation) duration of 52.2 +/- 3.9 months (range: 46.0-55.5 months), 6MWD had increased from 199.6 +/- 69.1 metres to 303.7 +/- 99.9 metres (P < 0.05) and SpO2 at the end of the 6-minute walk test had increased from 61.6 +/- 7.6% to 74.7 +/- 6.2% (P < 0.05). Echocardiography demonstrated a significant change in acceleration time from 62.9 +/- 11.6 m/s to 83.0 +/- 9.6 m/s (P = 0.0156), and acceleration time/ejection time ratio from the pulmonary flow from 0.24 +/- 0.04 at baseline to 0.30 +/- 0.02 (P = 0.0156) at final follow-up. CONCLUSIONS: Long-term treatment with bosentan significantly improved exercise capacity and oxygen saturation following exercise in adult ES patients with Down's syndrome. These data confirm that the presence of Down's syndrome does not affect the response to oral bosentan therapy. PMID- 24047159 TI - Complete mitochondrial genome of the Olympia oyster Ostrea lurida (Bivalvia, Ostreidae). AB - The complete mitochondrial (mt) genome of the Olympia oyster Ostrea lurida (16,344 bp), an economically important bivalve, was newly sequenced and annotated. Ostrea lurida is the largest reported Ostrea oyster mt genomes to date and has a comparatively highest overall A + T content (65%) among the available genomes of marine oysters. High levels of variability of nad2 and nad6 genes and that of major non-coding region (MNR) indicate their potential value as useful molecular markers for population and conservation genetic studies in the future. Phylogenetic analyses based on concatenated nucleotide sequences from all 13 PCGs and 2 rRNA genes show that the European flat oyster Ostrea edulis is sister to the Asian slipper oyster Ostrea denselamellosa, while O. lurida is put at the most basal position of the clade, and indicate that Ostrea are closer to Saccostrea than Crassostrea, although gene arrangement shows a closer relationship between Ostrea and Crassostrea. The observations of the evolutionary pattern of start codon usage among the three congeneric oysters indicate that variation in start codon usage is species-correlated rather than gene-correlated, and to some extent, bears useful phylogenetic information. PMID- 24047160 TI - A comparative study of COI and 16 S rRNA genes for DNA barcoding of cultivable carps in India. AB - The 5' region of the mitochondrial DNA gene cytochrome c oxidase subunit I (COI) is the standard marker for DNA barcoding. However, 16 S rRNA has also been advocated for DNA barcoding in many animal species. Herein, we directly compare the usefulness of COI and 16 S rRNA in discriminating six cultivable carp species: Labeo rohita, Catla catla, Cirrhinus mrigala, Labeo fimbriatus, Labeo bata and Cirrhinus reba from India. Analysis of partial sequences of these two gene fragments from 171 individuals indicated close genetic relationship between Catla catla and Labeo rohita. The results of the present study indicated COI to be more useful than 16 S rRNA for DNA barcoding of Indian carps. PMID- 24047161 TI - The complete mitochondrial genome of a flea, Jellisonia amadoi (Siphonaptera: Ceratophyllidae). AB - The complete mitogenome sequence of the flea, Jellisonia amadoi (Siphonaptera: Ceratophyllidae), was sequenced. The 17,031 bp long genome has the standard metazoan complement of 37 genes, in the insect ancestral genome arrangement. The very large (2338 bp) A + T rich region is marked by two macro-repeats and multiple microsatellite and homopolymer regions. The protein-coding, rRNA and tRNA genes are all highly similar to homologues in related insect orders - similar length, few indels and high proportion of invariant sites. Sequencing of a flea mitogenome provides data for one of the last three insect orders from which data were lacking and provides further proof that parasitic life histories alone do not cause aberrant mitogenomes. PMID- 24047162 TI - Complete sequence and characterization of mitochondrial genome in great snakehead, Channa marulius (Hamilton, 1822). AB - The complete nucleotide sequence of mitogenome of the great snakehead, Channa marulius (Channidae), was determined and found to be 16,569 base pairs in length. The content and arrangement of different genes on the mitogenome was found similar to other typical teleosts. The overall base composition of the L-strand was found to be T (19.1%), C (31.5%), A (34.8%) and G (14.6%). The control region was 915 nt long and without any repetitive region. The mitogenome sequence data would be useful for studying phylogenetic relationship of C. marulius with other perciform species. PMID- 24047163 TI - Complete mitochondrial genome of the pelagic thresher Alopias pelagicus (Lamniformes: Alopiidae). AB - The complete mitochondrial genome of the pelagic thresher Alopias pelagicus is first presented in this study. It is 16,692 bp in length and contains the 37 genes and 1 control region with the typical gene order and transcriptional direction in the vertebrates. The overall base composition is 32.1% A, 29.3% T, 25.3% C and 13.3% G. Totally, 27 bp overlaps and 25 bp short intergenic spaces are dispersal in the mitogenome. The tRNA-Ser2 (GCU) cannot be folded into the typical cloverleaf structure because of lacking the dihydrouridine arm. Two start codons (ATG and GTG) and three stop codons (AGG, TAG and TAA/T) were used in the 13 protein-coding genes. PMID- 24047164 TI - Complete mitochondrial DNA genome of Microphysogobio brevirostris (Cypriniformes: Cyprinidae). AB - In this study, we sequenced the complete mitochondrial genome of Microphysogobio brevirostris (Cypriniformes, Cyprinidae), an endemic primary freshwater fish in Taiwan. This mitochondrial genome, consisting of 16,608 base pairs (bp), encoded 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs, and a non-coding control region as those found in other vertebrates, with the gene synteny identical to that of typical vertebrates. Control region (D-Loop), of 929 bp lengths long, is located between tRNA(Pro) and tRNA(Phe). The overall base composition of the heavy strand shows T 26.28%, C 26.62%, A 30.26%, and G 16.85%, with a slight AT bias of 56.53%. PMID- 24047165 TI - Complete mitochondrial genome of Trimeresurus albolabris (Squamata: Viperidae: Crotalinae). AB - Trimeresurus albolabris is the most widely distributed species in the genus Trimeresurus and mainly in East and South-East Asia. In this study, we first sequenced and characterized the whole mitochondrial genome of T. albolabris. The total length of the complete mitochondrial genome was 17,220 bp with 13 protein coding genes, 22 tRNAs, 2 rRNAs and 2 control regions. The overall base composition of T. albolabris was 33.40% A, 27.04% T, 27.28% C, and 12.28% G. Except for ND6 subunit gene and eight tRNA genes which were encoded on the L stand, all the genes in T. albolabris were distributed on the H-strand. PMID- 24047166 TI - Complete mitochondrial genome of Rhinogobius giurinus (Perciformes: Gobiidae: Gobionellinae). AB - In this study, we present the complete mitochondrial gene for the freshwater goby Rhinogobius giurinus. The genome is a circular molecule of 16,520 bp in length and consists of 13 protein-coding genes, 22 tRNA genes, 2 ribosomal RNA genes and 2 main non-coding regions (the control region and the origin of the light strand replication). The overall base composition of R. giurinus is 26.08% for T, 29.56% for C, 27.73% for A and 16.63% for G, with a slight A + T bias of 53.81%. It has the typical vertebrate mitochondrial gene arrangement. PMID- 24047167 TI - Mitochondrial genome of the Anas acuta (Anatidae: Anas). AB - The Northern Pintail (Anas acuta) is a common large duck with widely geographic distribution. In this study, the complete mitochondrial genome of A. acuta (16,599 bp in length) was been analyzed for building the database. Similar to the typical mtDNA of vertebrates, it contained 37 genes (13 protein-coding genes, 2 rRNA genes and 22 tRNA genes) and a non-coding region (D-loop). All the genes in A. acuta were distributed on the H-strand, except for the ND6 subunit gene and 10 tRNA genes which were encoded on the L-strand. PMID- 24047168 TI - Mitochondrial genome of the Emberiza cioides (Emberizidae: Emberiza). AB - Emberiza cioides is a passerine bird of eastern Asia which belongs to the genus Emberiza in the bunting family Emberizidae. The complete mitochondrial genome of E. cioides was obtained for the first time. The circular genome (16,765 bp in length) consists of 37 typical animal mitochondrial genes (13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes) and 1 control region. Except for 8 tRNA genes and ND6 gene, all the genes were distributed in plus strand which were identical to those of most vertebrates. PMID- 24047169 TI - Complete mitochondrial DNA genome of Zacco platypus (Cypriniformes: Cyprinidae). AB - The complete mitochondrial genome of Zacco platypus (Cypriniformes, Cyprinidae), which has broader distribution range and diverse genetic structure than other species under the genus Zacco, was first determined in this study. The mitochondrial genome is 16,612 base pairs (bp) in length, encoding 13 protein coding genes, 2 ribosomal RNAs, 22 transfer RNAs and 1 non-coding control region. Its gene arrangement and translation direction were identical to those of other typical vertebrate. Control region (D-Loop), of 929 bp lengths long, is located between tRNA(Pro) and tRNA(Phe). The overall base composition of the heavy strand shows T 27.02%, C 26.23%, A 28.94% and G 17.82%, with a slight AT bias of 55.95%. PMID- 24047170 TI - The complete mitochondrial genome of the Rhodeus shitaiensis (Teleostei, Cypriniformes, Acheilognathidae). AB - The complete mitochondrial genome of the Rhodeus shitaiensis was determined by using a PCR-based method. The total length of mitochondrial DNA of this bitterling is 16,774 bp and includes 13 protein-coding genes, 2 ribosomal RNA, 22 transfer RNA genes, 1 replication origin region and 1 control region. The mitochondrial gene arrangement of the R. shitaiensis is also matching the one observed in the most vertebrate creatures. Base composition of the genome is A (28.7%), T (26.5%), C (27.4%) and G (17.4%) with an A + T rich hallmark as that of other vertebrate mitochondrial genomes. PMID- 24047171 TI - Complete mitochondrial genome of the freshwater goby Odontobutis potamophila (Perciformes: Odontobutidae). AB - In this study, we cloned and sequenced the complete mitochondrial genome of Odontobutis potamophila. The genome was found to be 16,932 bp in size with a mostly conserved structural organization when compared with that of other teleost fish. It contained 37 genes (13 protein-coding genes, 22 transfer RNA genes, and 2 ribosomal RNA genes) and 2 main non-coding regions (the control region and the origin of the light strand replication). Rearrangements of tRNAs (tRNA-Ser, tRNA Leu, tRNA-His) and three additional longer non-coding regions (43 bp, 336 bp and 76 bp, respectively) were present between the ND4 and ND5 genes. Within the control region, typical conserved domains, such as the termination-associated sequence, central and conserved sequence blocks domains were identified. This mitogenome sequence data would contribute to better understanding population genetics and phylogenetic analysis of the Odontobutidae. PMID- 24047172 TI - The complete mitochondrial genome of the Shaziling pig. AB - In this study, the complete mitochondrial genome sequence of the Shaziling pig was reported in Human Province, which was determined through PCR-based method. The total length of the mitogenome is 16,690 bp. It contains the typical structure, including 2 ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes and 1 non-coding control region (D-loop region) as that of most other vertebrates. The overall composition of the mitogenome was estimated to be 34.67% for A, 25.84% for T, 26.17% for C and 13.32% for G, with an A + T (60.51%)-rich feature in the Shaziling pig. All the protein initiation codons are ATG, except for ND2, ND3 and ND5 are ATA, ND4L is GTG, ND6 is TTA. The complete mitochondrial genome sequence of the Shaziling pig in Human Province provides an important data set for the study in genetic mechanism. PMID- 24047173 TI - The complete mitochondrial genome of the shortfin mako, Isurus oxyrinchus (Chondrichthyes, Lamnidae). AB - The complete mitochondrial genome of the shortfin mako (Isurus oxyrinchus) was determined by using a PCR-based method. The total length of mitochondrial DNA is 16,701 bp and includes 13 protein-coding genes, 2 ribosomal RNA, 22 transfer RNA genes, 1 replication origin region, and 1 control region. The mitochondrial gene arrangement of the tiger tail seahorse is also matching the one observed in the most vertebrate creatures. Base composition of the genome is A (28.8%), T (28.0%), C (28.0%), and G (15.2%) with an A + T rich hallmark as that of other vertebrate mitochondrial genomes. PMID- 24047174 TI - Whole mitogenome of the Endangered dwarf sawfish Pristis clavata (Rajiformes: Pristidae). AB - In this study, we describe the first complete mitochondrial sequence for the Endangered dwarf sawfish Pristis clavata. The base composition of the 16,804 bp long mitogenome is 31.9% A, 26.5% C, 13.3% G and 28.3% T and the gene arrangement and transcriptional direction are the same as those found in most vertebrates. All protein-coding genes start with ATG except the COI gene, which starts with GTG. Stop codons include incomplete T, AGG and TAA; however, TAG is not found in the mitogenome of this euryhaline elasmobranch species. PMID- 24047175 TI - Organization of the mitochondrial genome of Odontobutis sinensis (Perciformes: Odontobutidae): rearrangement of tRNAs and additional non-coding regions. AB - In this study, we cloned and sequenced the complete mitochondrial genome of Odontobutis sinensis. The genome was found to be 17,441 bp in size with a mostly conserved structural organization when compared with that of other teleost fish. It contained 37 genes (13 protein-coding genes, 22 transfer RNA genes and two ribosomal RNA genes) and two main non-coding regions (the control region and the origin of the light strand replication). Rearrangements of tRNAs (tRNA-Ser, tRNA Leu, tRNA-His) and three additional longer non-coding regions (51 bp, 622 bp and 66 bp, respectively) were present between the ND4 and ND5 genes. Within the control region, one 322 bp long tandem repeat area (7*46 bp) and some typical conserved domains were identified. The molecular data here we presented could play a useful role to study the evolutionary relationships and population genetics of the Odontobutidae. PMID- 24047176 TI - The complete mitochondrial genome of the Ningxiang pig. AB - In this work, we reported the complete mitochondrial genome sequence of the Ningxiang pig (Human Province), which was determined through PCR-based method. The total length of the mitogenome is 16,690 bp. The overall composition of the mitogenome was estimated to be 34.70% for A, 25.81% for T, 26.18% for C, 13.30% for G, respectively, indicating that an A + T(60.52%)-rich feature occurs in the Ningxiang pig. It contains the typical structure, including 2 ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes and 1 non-coding control region (D-loop region). The arrangement of these genes was the same as that found in the Landrace pig. All the protein initiation codons are ATG, except for ND2. ND3 and ND5 are ATA, ND4L is GTG. The complete mitochondrial genome sequence of the Ningxiang pig in Human Province provides an important data for further study about genetic mechanism. PMID- 24047177 TI - Complete mitochondrial genome of the Burmese giant earthworm, Tonoscolex birmanicus (Clitellata: Megascolecidae). AB - Until now the complete mitochondrial genome (mitogenome) sequences of only three species of clitellate have been available. We have determined the complete mitogenome sequences of the elusive Burmese giant earthworm Tonoscolex birmanicus (Clitellata: Megascolecidae), which is endemic to Myanmar. The 15,170-bp long genome contains the 37 genes typical of metazoan mitogenomes [13 protein-coding genes (PCG), 2 rRNA genes and 22 tRNA genes] and 1 major non-coding region. All of the 37 genes are transcribed from the same DNA strand. The arrangement of the T. birmanicus mitogenome is identical to that of two within-ordinal species Lumbricus terrestris and Perionyx excavates. All 13 PCGs start with the ATG. For the stop codon, only six PCGs end with the TAA, whereas the remaining ones ends with the incomplete stop codon, T. Genes overlap in a total of 14 bp in five locations, and harbor a total of 16 bp of intergenic spacer sequences in nine locations. PMID- 24047178 TI - Complete mitochondrial genome of Takydromus sexlineatus (Squamata, Lacertidae). AB - The complete sequence mitochondrial genome of Takydromus sexlineatus was determined using long PCR and conserved primers walking approaches. The genome was 18,943 bp in length and contained 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and 1 control region (CR). The gene composition and order of T. sexlineatus were similar to most other squamate reptiles. All protein-coding genes begin with ATG as initiation codon except COI using GTG. Seven genes (ATP8. ND4L. ND5. Cytb. ND1. COI and ND6) ended with TAA, TAG, AGGA and AGA stop codon, the remaining 6 genes had incomplete stop codons T/TA. The overall base composition of the genome in descending order was 31.48% A, 24.67% C, 30.79% T and 13.05% G, with a slight A + T bias of 62.27%. CR is located between the tRNA Pro and tRNA-Phe genes and is 3562 bp in length, some tandem repeat sequences, conserved elements (CSB1-3) and termination associated sequences (TAS1-3) were found in the control region. PMID- 24047179 TI - Complete mitochondrial genome of the scalloped hammerhead Sphyrna lewini (Carcharhiniformes: Sphyrnidae). AB - The complete mitochondrial genome of the endangered scalloped hammerhead Sphyrna lewini was firstly determined in this study. It is 16,726 bp in length with the typical gene composition and orders in vertebrates. The overall base composition is 31.4% A, 26.3% C, 13.2% G and 29.1% T. Two start codon (ATG and GTG) and three stop codon (TAG, AGA and TAA/TA/T) patterns were found in protein-coding genes. Except for the tRNA-Ser2, the remaining 21 tRNAs can be folded into the typical cloverleaf structure. The control region possess the highest A + T content (66.1%) and lowest G content (12.6%) among all mitochondrial partitions. PMID- 24047180 TI - The complete mitochondrial genome of the stonefly Dinocras cephalotes (Plecoptera, Perlidae). AB - The complete mitochondrial genome of the perlid stonefly Dinocras cephalotes (Curtis, 1827) was sequenced using a combined 454 and Sanger sequencing approach using the known sequence of Pteronarcys princeps Banks, 1907 (Pteronarcyidae), to identify homologous 454 reads. The genome is 15,666 bp in length and includes 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and a control region. Gene order resembles that of basal arthropods. The base composition of the genome is A (33.5%), T (29.0%), C (24.4%) and G (13.1%). This is the second published mitogenome for the order Plecoptera and will be useful in future phylogenetic analysis. PMID- 24047181 TI - Complete mitochondrial genome of the two-spotted stag beetle, Metopodontus blanchardi (Coleoptera: Lucanidae). AB - We have completely sequenced the mitochondrial genome (mitogeome) of the two spotted stag beetle, Metopodontus blanchardi, which is listed as a first-degree endangered species in Korea. The complete mitogenome of M. blanchardi was determined to be 21,628 bp, indicating at least 5 kb larger in size than typical animal mitogenomes. Such a long M. blanchardi genome stems from a 3100-bp long A + T-rich region and a 4051-bp long, large non-coding sequence located between tRNA(Ile) and tRNA(Gln). The A + T-rich region is composed of duplicated repeat sequences (each 965 bp and 969 bp), and three non-repeat sequences encompassing the repeat sequences. The 4051-bp long non-coding sequence is composed of ~ 17 tandem repeat sequences, each of which is composed of two subunits (113-bp and 104-bp long subunits) and this is encompassed by non-repeat sequences. The start codon for COI gene of M. blanchardi was designated as unconventional AAG (Lysine) by following a previous study. PMID- 24047182 TI - Complete mitochondrial genome of the Amur weatherfish, Misgurnus mohoity (Teleostei: Cypriniformes: Cobitididae). AB - The complete mitochondrial genome of the Amur weatherfish, Misgurnus mohoity is a circular molecule of 16,566 bp in size, containing 13 protein-coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes, and 2 main non-coding regions (the control region and the origin of the light strand replication). Most of the genes are encoded on the heavy strand, except for ND6 and eight tRNAs. The control region is 915 bp in length and located between the tRNA(Pro) and tRNA(Phe) genes, some typical conserved elements (TAS, CSB1-3 and CSB D-F) were found in this region. All these features reflect a typical vertebrate mitochondrial gene arrangement of the M. mohoity. PMID- 24047183 TI - DNA barcoding of gobiid fishes (Perciformes, Gobioidei). AB - Gobiids constitute a major proportion of fish population in both tropical and temperate freshwater as well as marine ecosystem. Due to their small size, cryptic ecology and ambiguous morphological characters, gobiids diversity was not documented completely. In this study, DNA barcodes were generated for 11 species of gobiids, collected from the Ashtamudi Lake, India. The mitochondrial COI gene was amplified using universal primers and the resulted 650 bp amplicon was sequenced. The COI barcodes clearly distinguished all the species with high inter specific genetic distance values than intra-specific values based on K2P (Kimura 2 Parameter) model. The average genetic distance (K2P model) within species, genus and family was 1.2%, 22.2% and 25.3%, respectively. In addition to barcode based species identification system, Nucleotide Diagnostic (ND) characters specific for species were identified. The Neighbor-Joining tree revealed distinct clusters shared by the species of same genera. PMID- 24047184 TI - The mitochondrial genome of Diadromus collaris (Hymenoptera: Ichneumonidae). AB - We sequenced the nearly complete mitochondrial genome of the parasitic wasps Diadromus collaris, the fourth sequenced mitogenome in the family Ichneumonidae (Insecta: Hymenoptera). The sequenced segment is 14,621 bp, including 13 protein coding genes, 19 transfer RNA genes and 2 ribosomal RNA genes. Four tRNAs are rearranged comparing to the ancestral insect mitochondrial gene arrangements, which coincides with the fact that the most rearranged genes are tRNA genes in the Ichneumonidae, and trnI-trnQ-trnM is a hot-spot of gene rearrangement. The lrRNA secondary structure was predicted, containing six domains (I-VI) and 49 helics. PMID- 24047185 TI - The complete mitochondrial genome of Neopanorpa pulchra (Mecoptera: Panorpidae). AB - We describe the complete mitochondrial genome sequence of Neopanorpa pulchra (Mecoptera: Panorpidae). The sequence has a length of 16,314 bp (GenBank accession number JX569848) and the A + T content is as high as 77.46%. The genome contains 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and an A + T-rich region. The gene arrangement is conserved. All protein-coding genes start with ATN start codon. Seven protein-coding genes use TAA as stop codon while others use incomplete stop codons "T" or "TA". The A + T-region is located between rrnS and trnI with a length of 1531 bp. PMID- 24047186 TI - Mitochondrial evolution across lineages of the vampire barnacle Notochthamalus scabrosus. AB - Eight whole mitochondrial genomes from the barnacle Notochthamalus scabrosus, with one from the northern lineage and seven from the divergent southern lineage, are presented. The annotated and aligned data were analyzed for signals of non neutral evolution. Overall, these data are consistent with purifying selection operating on the protein-coding regions of the mitochondrion. However, a notable region of nonsynonymous substitution at the 3' end of the ND2 gene region, along with unusual site frequency spectra in two other gene regions, was identified. PMID- 24047187 TI - Complete mitochondrial genome of the blue shark Prionace glauca (Elasmobranchii: Carcharhiniformes). AB - In this study, we first presented the complete mitochondrial genome of the blue shark Prionace Glauca, a pelagic and oceanic species. It is 16,705 bp in length and contains 2 rRNA genes, 22 tRNA genes, 13 protein-coding genes and 1 putative control region. The overall base composition is 31.6% A, 24.4% C, 13.1% G and 30.9% T. Overlaps and short inter-genic spaces are located in the genome. The tRNA-Ser2 loses the dihydrouridine arm and cannot be folded into the typical clover-leaf secondary structure. Two start codons (GTG and ATG) with two stop codons (TAG and TAA) or with one incomplete stop codon (T) are found in the 13 protein-coding genes. The control region contains high A + T (69.9%) and low G (12.0%). PMID- 24047188 TI - Root exudate enhanced contaminant desorption: an abiotic contribution to the rhizosphere effect. AB - Despite reports in the literature of superior contaminant degradation in the root zone of plants, this phenomenon, known as the rhizosphere effect, is poorly understood. We investigated whether root exudates could enhance desorption of residual pollutants, thus improving bioavailability and subsequent biodegradation potential. Root exudates were harvested from three species of hydroponically grown plants, and artificial root exudates (AREs) were created using a literature recipe. Aliquots of the exudates were metabolized by soil bacteria to investigate whether biotransformed exudates exhibited different chemical characteristics or had different effects on contaminant bioavailability than 'raw exudates.' Slurries of naphthalene-aged soil containing raw exudates had a significantly lower soil-water distribution coefficient (Kd) than slurries with metabolized exudates or no-exudate controls, exhibiting median reductions of 50% and 55%, respectively. Raw exudates had a significantly lower surface tension while not increasing overall solubility, indicating the presence of surface-active compounds below the critical micelle concentration; this is a newly observed mechanism of the rhizosphere effect. Exudate samples were characterized by specific UV absorbance, spectral slope, fluorescence index, and excitation emission matrices. Substantial changes in organic carbon character pre- and postmetabolism, and between harvested exudates and AREs, suggest that AREs are not chemically representative of plant root exudates. Overall, we present evidence that enhanced contaminant desorption in the presence of exudates provides an abiotic contribution to the rhizosphere effect. PMID- 24047189 TI - Randomised controlled clinical trial of standard versus echocardiographically guided ibuprofen treatment for patent ductus arteriosus in preterm infants: a pilot study. AB - OBJECTIVE: The aim of this study was to explore the efficacy of echocardiographically guided (EchoG) pharmacological closure of the ductus arteriosus in reducing the number of required ibuprofen doses without increasing the reopening rate. METHODS: We performed a randomised controlled trial that included 49 infants with a duct >=1.5 mm who were randomised to either EchoG or standard ibuprofen treatment. Echocardiography was serially performed on days 1, 2, 3, 4, 7, 10 and 17 after inclusion. The primary outcome was the ductus reopening rate, and an intention-to-treat analysis was performed. RESULTS: Twenty eight (EchoG treatment) and 21(standard treatment) infants were enrolled (27.2 versus 27.3 weeks, p = 0.3). The patients received 2 (1-5.7) and 3 (3-4) doses of ibuprofen in the EchoG and standard treatment groups, respectively (p = 0.04) and experienced a similar ductus reopening rate (11% versus 5%, p = 0.6). CONCLUSION: Echocardiographically guided ibuprofen treatment of patent ductus arteriosus is feasible and reduces unnecessary doses of medication. PMID- 24047190 TI - Near superhydrophobic fibrous scaffold for endothelialization: fabrication, characterization and cellular activities. AB - In this work, we have applied an electrospinning method to control wettability and further hydrophobic modification of a hydrophobic polymer mat of poly(vinylidene fluoride-co-hexafluoropropylene). A correlation between the processing parameters, rheological properties of polymer solutions, and electrospinning ability was made using the polymer's critical entanglement concentration, the boundary between the semidilute unentangled regime and the semidilute entangled regime. The wetting behavior, structural and thermal characteristics of electrospun (ES) mats were evaluated and compared with solvent cast sample using advancing and receding contact angle analyses, differential scanning calorimetry, and small-angle X-ray scattering. To demonstrate the feasibility, the best optimized ES samples were examined for their potential and ability to support bone marrow derived endothelial cell seeding efficiency, adhesion and proliferation. Our studies show that, while different processing techniques can effectively modulate physical and morphological changes such as porosity and hydrophobicity, the cellular adhesion and proliferation are highly time-dependent and controlled by chemical factors. As such, these results suggest that it is the interplay of both physical and chemical factors that determine the endothelialization of porous near superhydrophobic scaffolds. The developed electrospun samples demonstrate their feasibility for endothelialization. PMID- 24047191 TI - Survey of brain temperature management in patients with traumatic brain injury in the Japan neurotrauma data bank. AB - The goal of this study was to evaluate the clinical characteristics and effects of brain temperature management in patients with severe traumatic brain injury (TBI). A total of 1091 patients were registered from the Japan Neurotrauma Data Bank Project 2009. Those with a Glasgow Coma Scale (GCS) score of 9 or more, a GCS score of 3, bilateral dilated pupils, or cardiopulmonary arrest on arrival were excluded. This left a total of 401 patients. Patients were classified into three groups: no temperature management, with no intervention for brain temperature (225 patients, 56.1%), intensive normothermia (129 patients, 32.2%), and hypothermia (47 patients, 11.7%). Patient age, GCS score, pupillary abnormality, Injury Severity Score (ISS), intracranial pressure (ICP) monitoring, and outcome according to CT classification (Traumatic Coma Data Bank classification) on admission were examined. Patients were significantly older in the no temperature management group (average age 61.5 years) compared with normothermia (53.6 years) and hypothermia (46.9 years). ICP monitoring was significantly decreased in 85.1% of patients with hypothermia, 42.6% with normothermia, and 14.7% in no temperature management group. Favorable outcome rate was significantly higher with hypothermia (52.4%) compared with normothermia (26.9%) and no temperature management (20.7%) with evacuated mass lesions in contrast to diffuse injury. Multivariate analysis in patients with evacuated mass lesions showed that GCS (>=6 pts), and hypothermia were independent factors related to a favorable outcome. Appropriate thermoregulation of the brain for individual patients with various types of TBI are important. PMID- 24047192 TI - The relative age effect in the German Football TID Programme: biases in motor performance diagnostics and effects on single motor abilities and skills in groups of selected players. AB - This study examined the disturbing effects of relative age on the talent identification process in the talent development programme of the German Football Association. The bias in the selection rate was examined via the extent of relative age effects. The bias in motor performance diagnostics was analysed by comparing the motor performance of selected players with normal motor development. The mechanisms underlying the relative age biases in motor performance were examined by modelling the direct and indirect effects of relative age on single motor performance tests for sprint, running agility, dribbling and ball passing and control. Data from 10,130 selected football players from the U12 to U15 age groups were collected in autumn 2010. The birth distribution differed significantly from the reference population with approximately 61% of the players born in the first half of the year. The selection probability was approximately two times higher for players born in the first quarter of the year than for players born in the last quarter. Revised motor performance diagnostics showed better results on average for relatively younger players. Path analysis revealed significant direct and indirect relative age effects for physiologically demanding tests and almost no effects for technically demanding tests. Large sample sizes allowed high resolution in relative age with additional informational content and multivariate modelling of the complex relationships among relative age, physical development and motor performance. The results are discussed on how relative age affects the effectiveness and fairness of talent identification and development processes. PMID- 24047193 TI - Mediastinal kaposiform hemangioendothelioma and Kasabach-Merritt phenomenon in a patient with no skin changes and a normal chest CT. AB - A 16-month-old previously healthy boy was admitted to the hospital with respiratory distress and thrombocytopenia. Initial workup demonstrated large pleural and pericardial effusions. The patient had no cutaneous abnormality on physical examination, and his initial chest CT (computed tomography) was nondiagnostic. He required multiple platelet transfusions, chest tube placement, and pericardiocentesis. Sixteen days after admission, a chest MRI (magnetic resonance imaging) revealed a large infiltrative mass of the superior mediastinum, consistent with kaposiform hemangioendothelioma (KHE). The patient's thrombocytopenia was due to associated Kasabach-Merritt phenomenon (KMP). The patient now has complete resolution of KMP after medical treatment with prednisolone, aminocaproic acid, vincristine, and aspirin. PMID- 24047194 TI - Order-disorder transition of dipolar rotor in a crystalline molecular gyrotop and its optical change. AB - Successful control of the orientation of the pi-electron systems in media has been achieved in certain liquid crystals, making them applicable to devices for optical systems because of the variation in the optical properties with the orientation of the pi-electron system. However, because of close packing, changing the orientation of molecules in the crystalline state is usually difficult. A macrocage molecule with a bridged thiophene rotor was synthesized as a molecular gyrotop having a dipolar rotor, given that the dipole derived from the thiophene can rotate even in the crystal. The thermally induced change in the orientation of the dipolar rotors (thiophene ring) inside the crystal, i.e., order-disorder transition, and the variation in the optical properties in the crystalline state were observed. PMID- 24047195 TI - The role of osmoregulation in the pathophysiology and management of severe ovarian hyperstimulation syndrome. AB - Severe ovarian hyperstimulation syndrome (OHSS), with an incidence of 1-2% of superovulation cycles, remains one of the most important complications of gonadotrophin use in assisted reproductive technologies because of its associated morbidity and rarely, mortality. Despite the wealth of scientific and clinical interest that this iatrogenic complication has generated, its pathophysiology is still not adequately elucidated and its management has thus remained empirical. Disorders of salt and water balance are two very important features that have been reported during severe OHSS. Some of the clinical and biochemical changes resulting from this disorder of salt and water balance are similar to those previously reported in pregnancy and liver cirrhosis. The pathophysiology of these clinical changes has been explained in part in pregnancy and liver cirrhosis by changes in osmoregulation function. It is this similarity in the clinical and biochemical changes in OHSS, pregnancy and liver cirrhosis that has prompted the investigation of the role of osmoregulation function in the pathophysiology of OHSS. The current article has been written to provide further details in support of recent excellent articles and guidelines, highlighting the physiological basis and rationale governing some aspects of, and the role of osmoregulation in the management of the OHSS syndrome. PMID- 24047196 TI - Do dopamine agonists prevent or reduce the severity of ovarian hyperstimulation syndrome in women undergoing assisted reproduction? A systematic review and meta analysis. AB - Controlled ovarian stimulation is an integral part of assisted reproduction treatment. This can result in ovarian hyperstimulation syndrome (OHSS), which is associated with significant morbidity and potentially mortality. Recent approaches to ovarian stimulation have led to a reduction in the prevalence of OHSS but it still occurs. Dopamine agonists (DAs) have been used with some success during the ovarian stimulation phase when there are early signs of OHSS but there is no consensus on when to start and stop treatment or on the dose and specific agonist to use. EMBRASE, MEDLINE and Cochrane were searched using the following terms: ovarian hyperstimulation syndrome, controlled ovarian hyperstimulation, DAs, cabergoline, quinagolide, bromocriptide, pergolide, talipexole, ropinirole and pranipexole. The search yielded 20 publications. In total 1646 woman were included and 914 received a DA. In the treated group 86 (9.41%) developed OHSS, compared with 157 (21.45%) in the non-treated group. Nine studies were suitable for meta-analysis. This showed a benefit to the use of DAs (RR 0.51 [0.33, 0.78], Chi2 = 16.07). The use of DAs appears to be effective for the prevention of OHSS. DAs are useful but less effective for the treatment of OHSS. No conclusions can be made regarding the most effective drug, the optimal dose or the most appropriate drug regimen. PMID- 24047197 TI - Endothelial nitric oxide synthase gene variants and haplotypes associated with an increased risk of idiopathic recurrent miscarriage. AB - We investigated the association of endothelial nitric oxide synthase (NOS3) polymorphisms rs2070744 (-786T> C), 27-bp repeat 4b/4a, rs1799983 (Glu298Asp), rs3918188 (-734C> A), and rs743507 (113G> A) with idiopathic recurrent miscarriage (IRM). This was a case-control study involving women with confirmed IRM (n = 296), and 305 age- and ethnically matched control women. NOS3 rs2070744, rs1799983, rs3918188, and rs743507 genotyping was done by TaqMan assays; NOS3 4b/4a genotyping was done by PCR-ASA. A higher frequency of -786C and 298Asp alleles was seen in IRM cases, which remained associated independently with IRM on multivariate analysis. Allele and genotype distribution of 4b/4a, rs3918188 ( 734C> A) and rs743507 (113A> G) were comparable between IRM cases and control women. Taking homozygous wild-type genotype as a reference, regression analysis confirmed the association of Glu298Asp and -786T/C, and rs743507 homozygous carriers with IRM risk. Marked linkage disequilibrium was seen between tested NOS3 variants, thus allowing the construction of 5-locus [-786T> C/4b4a/Glu298Asp/-734C> A/113G> A] haplotypes. Taking the common T4bGCA haplotype as a reference, multivariate analysis confirmed the positive association of C4bTCG haplotype with IRM, after controlling for traditional covariates. Genetic variation at the NOS3 locus represents a genetic risk factor for increased susceptibility to IRM. PMID- 24047198 TI - Selective and sensitive detection of intracellular O2(*-) using Au NPs/cytochrome c as SERS nanosensors. AB - A novel surface-enhanced Raman scattering (SERS) nanosensor was developed by modifying oxidized cytochrome c (Cyt c) on gold nanoparticles (Au NPs) for the sensitive and selective determination of intracellular superoxide anion radical (O2(*-)). On the basis of the differences in the SERS spectra between the oxidized and reduced form of Cyt c, this nanosensor could be employed to investigate O2(*-) concentration by measuring the SERS spectra of the reduced Cyt c. Using this SERS nanosensor, a detection limit of 1.0 * 10(-8) M for O2(*-) could be attained. Additionally, the selectivity of the SERS nanosensor for O2(* ) was examined, showing that other reactive oxygen species (ROS) and biologically relevant species did not influence the detection of O2(*-). More importantly, the nanosensor could be delivered to the living HeLa and normal human liver cells and permitted the concentration of O2(*-) to be monitored in real time and in a noninvasive manner, which indicates that this nanosensor will be suitable for the qualitative and quantitative analysis of O2(*-) in biosystems, thus leading to a greater understanding of oxidative-stress-related diseases at a cellular level. PMID- 24047199 TI - Carbon K-edge X-ray absorption spectroscopy and time-dependent density functional theory examination of metal-carbon bonding in metallocene dichlorides. AB - Metal-carbon covalence in (C5H5)2MCl2 (M = Ti, Zr, Hf) has been evaluated using carbon K-edge X-ray absorption spectroscopy (XAS) as well as ground-state and time-dependent hybrid density functional theory (DFT and TDDFT). Differences in orbital mixing were determined experimentally using transmission XAS of thin crystalline material with a scanning transmission X-ray microscope (STXM). Moving down the periodic table (Ti to Hf) has a marked effect on the experimental transition intensities associated with the low-lying antibonding 1a1* and 1b2* orbitals. The peak intensities, which are directly related to the M-(C5H5) orbital mixing coefficients, increase from 0.08(1) and 0.26(3) for (C5H5)2TiCl2 to 0.31(3) and 0.75(8) for (C5H5)2ZrCl2, and finally to 0.54(5) and 0.83(8) for (C5H5)2HfCl2. The experimental trend toward increased peak intensity for transitions associated with 1a1* and 1b2* orbitals agrees with the calculated TDDFT oscillator strengths [0.10 and 0.21, (C5H5)2TiCl2; 0.21 and 0.73, (C5H5)2ZrCl2; 0.35 and 0.69, (C5H5)2HfCl2] and with the amount of C 2p character obtained from the Mulliken populations for the antibonding 1a1* and 1b2* orbitals [8.2 and 23.4%, (C5H5)2TiCl2; 15.3 and 39.7%, (C5H5)2ZrCl2; 20.1 and 50.9%, (C5H5)2HfCl2]. The excellent agreement between experiment, theory, and recent Cl K-edge XAS and DFT measurements shows that C 2p orbital mixing is enhanced for the diffuse Hf (5d) and Zr (4d) atomic orbitals in relation to the more localized Ti (3d) orbitals. These results provide insight into how changes in M-Cl orbital mixing within the metallocene wedge are correlated with periodic trends in covalent bonding between the metal and the cyclopentadienide ancillary ligands. PMID- 24047200 TI - Realizing high-efficiency omnidirectional n-type Si solar cells via the hierarchical architecture concept with radial junctions. AB - Hierarchical structures combining micropyramids and nanowires with appropriate control of surface carrier recombination represent a class of architectures for radial p-n junction solar cells that synergizes the advantageous features including excellent broad-band, omnidirectional light-harvesting and efficient separation/collection of photoexcited carriers. The heterojunction solar cells fabricated with hierarchical structures exhibit the efficiency of 15.14% using cost-effective as-cut Czochralski n-type Si substrates, which is the highest reported efficiency among all n-type Si nanostructured solar cells. We also demonstrate the omnidirectional solar cell that exhibits the daily generated power enhancement of 44.2% by using hierarchical structures, as compared to conventional micropyramid control cells. The concurrent improvement in optical and electrical properties for realizing high-efficiency omnidirectional solar cells using as-cut Czochralski n-type Si substrates demonstrated here makes a hierarchical architecture concept promising for large-area and cost-effective mass production. PMID- 24047201 TI - Synthesis and biological evaluation of 8-aminomethyltetracycline derivatives as novel antibacterial agents. AB - The C-8 position of the tetracyclines has been largely underexplored because of limitations in traditional semisynthetic techniques. Employing a total synthetic approach allowed for modifications at the C-7 and C-8 positions, enabling the generation of structure-activity relationships for overcoming the two most common tetracycline bacterial-resistance mechanisms: ribosomal protection (tet(M)) and efflux (tet(A)). Ultimately, several compounds were identified with balanced activity against both Gram-positive and Gram-negative bacteria, including pathogens bearing both types of tetracycline-resistance mechanisms. Compounds were screened in a murine systemic infection model to rapidly identify compounds with oral bioavailability, leading to the discovery of several compounds that exhibited efficacy when administered orally in murine pyelonephritis and pneumonia models. PMID- 24047202 TI - Birthing in the Barkly: births to Barkly women in 2010. AB - INTRODUCTION: A 2007 review of maternity services in Australia's Northern Territory (NT) noted the dissatisfaction of women in the Barkly region where the birthing service closed in 2006. The review recommended improved integration of maternity services, a consumer focus, and a pilot study of birthing in Tennant Creek Hospital (TCH) in the Barkly region. Barkly region is sparsely populated, with 5700 people in 320,000 km2. The town of Tennant Creek with 3100 population is the only centre of more than 1000 people. In the Barkly region, 64% of the population and 74% of birthing women are Aboriginal. Current NT Department of Health (NT DoH) policy requires all women to give birth in a town with facilities for operative delivery. For most Barkly women this means travelling 500 km to Alice Springs with limited support for travel and accommodation. Emergency air evacuation is arranged for all women who enter labour or give birth while in the Barkly region, whether at TCH or elsewhere. This project was a collaboration between Anyinginyi Health Aboriginal Corporation and NT DoH to examine clinical data to inform a discussion of re-introducing birthing to TCH. METHODS: Women who were resident in the Barkly region and gave birth in NT in 2010 were identified from the NT Midwives Data Collection. Women who gave birth in Central Australia were managed at Alice Springs Hospital (ASH), either for the birth or afterwards. Antenatal, birthing, postnatal and neonatal data were extracted from ASH records. RESULTS: In total 99 women were identified as residents in the Barkly region from all those who gave birth in 2010. Of these, 83 gave birth in Central Australia, and their records were reviewed for this study, showing that 69 (83%) were Aboriginal; 42 were resident in Tennant Creek; and 29% were aged under 20 years with one under 16 years. Regarding delivery, 53 (64%) women had an unassisted vaginal birth; of 18 women who had had a previous caesarean section, 5 (28%) had a vaginal birth; of the 25 women who had had a normal vaginal birth previously and had no indications for obstetric consultation at the time of labour, three underwent emergency caesarean section. There were 86 infants, all liveborn; 16% were preterm; 21% were of low birth weight; and 6% weighed more than 4.5 kg. Six women gave birth in the Barkly region, two at TCH and four in health centres in remote townships. These mothers and babies were evacuated immediately following birth to ASH, irrespective of indications for referral. Eleven women were evacuated to ASH in labour and six of these were preterm. CONCLUSION: Opportunities exist to improve maternity care through improved collaboration, even when women cannot give birth in or near their home community due to the absence of birthing services. The remote location of the Barkly region presents challenges to providing maternity care that addresses medical, cultural, psychological and social needs of the childbearing population. Because of this, every opportunity should be taken to optimise maternity care by improvements in continuity of care and carer, improved communication between service providers, and the use of evidence-based guidelines. PMID- 24047203 TI - Low temperature rate coefficients for the reaction CN + HC3N. AB - The reaction of CN radicals with HC3N is of interest for interstellar and circumstellar chemistry as well as for the chemistry of Titan's atmosphere, as part of a general scheme for cyanopolyyne synthesis within these low temperature environments. Here, we present the first experimental measurements of its rate coefficient below room temperature down to 22 K, employing the CRESU (Cinetique de Reaction en Ecoulement Supersonique Uniforme or Reaction Kinetics in Uniform Supersonic Flow) technique coupled with pulsed laser photolysis-laser-induced fluorescence. A novel pulsed version of the CRESU technique employing a new spinning disk valve was used for some of the kinetics measurements. The measurements were in excellent agreement with the only previous determination at room temperature and show a marked increase in the rate coefficient as the temperature is lowered, with the results being well represented by the equation k(T) = 1.79 * 10(-11)(T/300 K)(-0.67) cm(3) molecule(-1) s(-1), with a root-mean square (statistical) error of 0.61 * 10(-11) cm(3) molecule(-1) s(-1), to which should be added 10% estimated likely systematic error. High accuracy ab initio quantum chemical calculations coupled with variational two-transition state theory calculations were also performed and demonstrate excellent agreement within the combined experimental and predicted theoretical uncertainties. The theoretical rate coefficients, adjusted within expected uncertainties, can be accurately reproduced over the 5 to 400 K temperature range by the expression [(1.97 * 10(-8)) T (-1.51) exp(-3.24/T) + (4.85 * 10(-13)) T (0.563) exp (17.6/T)] cm(3) molecule(-1) s(-1), where T is in K. The new measurements are likely to be of interest to astrochemical and planetary atmospheric modelers. PMID- 24047204 TI - Using the framework method for the analysis of qualitative data in multi disciplinary health research. AB - BACKGROUND: The Framework Method is becoming an increasingly popular approach to the management and analysis of qualitative data in health research. However, there is confusion about its potential application and limitations. DISCUSSION: The article discusses when it is appropriate to adopt the Framework Method and explains the procedure for using it in multi-disciplinary health research teams, or those that involve clinicians, patients and lay people. The stages of the method are illustrated using examples from a published study. SUMMARY: Used effectively, with the leadership of an experienced qualitative researcher, the Framework Method is a systematic and flexible approach to analysing qualitative data and is appropriate for use in research teams even where not all members have previous experience of conducting qualitative research. PMID- 24047205 TI - Electrochemically hydrogenated TiO2 nanotubes with improved photoelectrochemical water splitting performance. AB - One-dimensional anodic titanium oxide (ATO) nanotube arrays hold great potential as photoanode for photoelectrochemical (PEC) water splitting. In this work, we report a facile and eco-friendly electrochemical hydrogenation method to modify the electronic and PEC properties of ATO nanotube films. The hydrogenated ATO (ATO-H) electrodes present a significantly improved photocurrent of 0.65 mA/cm2 in comparison with that of pristine ATO nanotubes (0.29 mA/cm2) recorded under air mass 1.5 global illumination. The incident photon-to-current efficiency measurement suggests that the enhanced photocurrent of ATO-H nanotubes is mainly ascribed to the improved photoactivity in the UV region. We propose that the electrochemical hydrogenation induced surface oxygen vacancies contribute to the substantially enhanced electrical conductivity and photoactivity. PMID- 24047206 TI - A potential use for injectable oxygen microparticles in anaphylaxis. PMID- 24047208 TI - Abstracts of the 21st World Congress for Sexual Health. Porto Alegre, Brazil. September 21-24, 2013. PMID- 24047207 TI - Organization of Plasmodium falciparum spliceosomal core complex and role of arginine methylation in its assembly. AB - BACKGROUND: Splicing and alternate splicing are the two key biological processes that result in the generation of diverse transcript and protein isoforms in Plasmodium falciparum as well as in other eukaryotic organisms. Not much is known about the organization of splicing machinery and mechanisms in human malaria parasite. Present study reports the organization and assembly of Plasmodium spliceosome Sm core complex. METHODS: Presence of all the seven Plasmodium Sm like proteins in the intra-erythrocytic stages was assessed based on the protein(s) expression analysis using immuno-localization and western blotting. Localization/co-localization studies were performed by immunofluorescence analysis on thin parasite smear using laser scanning confocal microscope. Interaction studies were carried out using yeast two-hybrid analysis and validated by in vitro pull-down assays. PfPRMT5 (arginine methyl transferase) and PfSmD1 interaction analysis was performed by pull-down assays and the interacting proteins were identified by MALDI-TOF spectrometry. RESULTS: PfSm proteins are expressed at asexual blood stages of the parasite and show nucleo-cytoplasmic localization. Protein-protein interaction studies showed that PfSm proteins form a heptameric complex, typical of spliceosome core complex as shown in humans. Interaction of PfSMN (survival of motor neuron, tudor domain containing protein) or PfTu-TSN (Tudor domain of Tudor Staphylococcal nuclease) with PfSmD1 proteins was found to be methylation dependent. Co-localization by immunofluorescence and co-immunoprecipitation studies suggested an association between PfPRMT5 and PfSmD1, indicating the role of arginine methylation in assembly of Plasmodium spliceosome complex. CONCLUSIONS: Plasmodium Sm-like proteins form a heptameric ring-like structure, although the arrangement of PfSm proteins slightly differs from human splicing machinery. The data shows the interaction of PfSMN with PfSmD1 and this interaction is found to be methylation dependent. PfPRMT5 probably exists as a part of methylosome complex that may function in the cytoplasmic assembly of Sm proteins at asexual blood stages of P. falciparum. PMID- 24047211 TI - Blood pressure changes across gestation in patients with twin pregnancies. AB - OBJECTIVE: To report blood pressure (BP) across gestation in patients with twin pregnancy. METHODS: Historical cohort of all twin pregnancies managed by one maternal-fetal medicine practice from 2005 to 2012. Patients with chronic hypertension were excluded. We reviewed all outpatient BP measurements taken during pregnancy and compared systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) for every 2-week interval starting at 6 weeks. All BP measurements were taken manually in the seated upright position. RESULTS: There were 520 patients with twin pregnancies managed over the study period, 19 (3.7%) were excluded for chronic hypertension, leaving 501 patients for analysis. There were a total of 4985 BP measurements (9.95 per patient) during pregnancy. Starting at 6 weeks' gestation, the SBP, DBP and MAP remained stable until 30 weeks' gestation, when all three began to rise significantly until 38 weeks (p < 0.001). There was no drop in BP in the second trimester. The 95th percentile for systolic BP did not exceed 121 mmHg until 30 weeks and the 95th percentile for diastolic BP did not exceed 80 mmHg until 34 weeks. The 4 - to 10-week postpartum DBP and MAP were significantly higher than the initial DBP and MAP <10 weeks. CONCLUSIONS: In patients with twin pregnancies, the BP remains stable from 6 weeks until 30 weeks, at which time it begins to rise steadily. The 95th percentile for SBP and DBP prior to 30 weeks are ~120 and 80 mmHg, respectively. PMID- 24047213 TI - Design and evaluation of mucoadhesive beads of glipizide as a controlled release drug delivery system. AB - The present work aims at the development of a low-cost controlled release system of glipizide beads embedded in pectin to overcome the problem of frequent dosing of drug. The method of preparation has been optimised by experimental design to achieve satisfactory responses with respect to controlling variables. The controlling variables are X1, drug-polymer ratio; X2, surfactant concentration and X3, isooctane-acetone ratio. The most effective combination is X1(1:6), X2(1%), X3(50:50). Various parameters such as mucoadhesivity and swellability of beads, characterisation, dissolution, stability, ex vivo absorption and in vivo (Oral glucose tolerance test in rat) studies were performed with the optimised product. The optimised product was found quiet satisfactory that showed yield of 86.78%, drug entrapment efficiency (DEE) of 87.38% and drug release was extended up to 18 h. The present formulation of glipizide is a promising multiparticulate system of glipizide with significant hypoglycemic effect, and moreover it was prepared rapidly with ease. PMID- 24047212 TI - Obstructive sleep apnea in patients with central serous chorioretinopathy. AB - PURPOSE: In this study, we aimed to evaluate the relation between obstructive sleep apnea (OSA) and central serous retinopathy (CSR). METHODS: Twenty-three consecutive subjects aged >18 years with the diagnosis of CSR were included in this prospective study. Overnight polysomnography was performed to all subjects. Desaturation index and apnea-hypopnea index (AHI) were recorded. Obstructive sleep apnea was classified according to AHI as mild, moderate, or severe. Statistical analysis was performed using chi-square test, Fisher's exact test, and Mann-Whitney U test. RESULTS: Fourteen of 23 CSR patients (60.9%) had OSA. Prevalence of OSA was significantly higher in male subjects with CSR compared to female subjects with CSR (p = 0.018). One (16.7%) female subject with CSR had OSA whereas thirteen (76.5%) male subjects were found to have OSA. Desaturation index was found to be 5.1 +/- 4.2 in females and 12.9 +/- 11.1 in males (p = 0.036). CONCLUSION: Obstructive sleep apnea is seen nearly in 2/3 of patients with the diagnosis of CSR. There are possible common pathophysiological mechanisms like oxidative stress, vasoconstriction, or blood coagulation abnormalities. Screening for OSA should be considered in subjects with the diagnosis of CSR. PMID- 24047214 TI - Discovery of novel lead in the group of N-substituted piperazine ether derivatives with potential histamine H3 receptor activity. AB - The search for novel lead from the group of various substituted N-piperazine ether derivatives was performed. Acyl- and pyridylpiperazine ethyl/propyl ethers were obtained via three different synthetic pathways. Affinity to histamine H3 receptor was established, as well as, for selected compounds, selectivity towards histamine H4R. Docking studies to the histamine H3R homology model strengthened the position of (4-(3-(4-(3-chlorobenzoyl)piperazin-1- yl)propoxy)phenyl)(cyclopropyl)methanone (compound 26) as a novel lead for further studies on histamine H3 receptor antagonist/inverse agonist. PMID- 24047215 TI - Design, synthesis and cytotoxic activity evaluation of new aminosubstituted benzofurans. AB - A number of new aminosubstituted benzofuran analogues have been prepared and their cytotoxic/cytostatic activity was investigated against five human tumor cell lines (MCF-7, SKBR3, SKOV3, HCT-116 and HeLa). Certain compounds showed noticeable tumor cell growth inhibition, indicative of possible structure activity relationships. PMID- 24047216 TI - Synthesis of aryl-substituted naphthalenoids as potent topoisomerase inhibitors. AB - Twelve new aryl-substituted naphthalenoids (1-7, 9, 10, and 13-16) together with four known ones (8, and 11- 13) have been designed and synthesized. Their antitumor activities were evaluated by sulforhodamine B assay on human breast cancer MDA-MB-231, human lung cancer A549 and human cervical cancer HeLa cell lines. Four compounds (2, 4, 10 and 12) showed potent inhibitory activities against the growth of the three cell lines with IC50 between 0.34-3.49 uM, and were more potent than the reference etoposide (IC50 3.67-13.78 uM). DNA relaxation assay revealed that compound 2 showed potent inhibitory activity against Topo IIalpha in vitro. The structure-activity relationships of these compounds were discussed, suggesting that further structural optimizations of aryl-substituted naphthalenoids could lead to the discovery of potent antitumor agents targeting topoisomerases. PMID- 24047217 TI - Ru(0) and Ru(II) nitrosyl pincer complexes: structure, reactivity, and catalytic activity. AB - Despite considerable interest in ruthenium carbonyl pincer complexes and their substantial catalytic activity, there has been relatively little study of the isoelectronic ruthenium nitrosyl complexes. Here we describe the synthesis and reactivity of several complexes of this type as well as the catalytic activity of complex 6. Reaction of the PNP ligand (PNP = 2,6-bis((t)Bu2PCH2)pyridine) with RuCl3(NO)(PPh3)2 yielded the Ru(II) complex 3. Chloride displacement by BAr(F-) (BAr(F-) = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate) gave the crystallographicaly characterized, linear NO Ru(II) complex 4, which upon treatment with NaBEt3H yielded the Ru(0) complexes 5. The crystallographically characterized Ru(0) square planar complex 5.BF4 bears a linear NO ligand located trans to the pyridilic nitrogen. Further treatment of 5.BF4 with excess LiOH gave the crystallographicaly characterized Ru(0) square planar, linear NO complex 6. Complex 6 catalyzes the dehydrogenative coupling of alcohols to esters, reaching full conversion under air or under argon. Reaction of the PNN ligand (PNN = 2 ((t)Bu2PCH2)-6-(Et2NCH2)pyridine) with RuCl3(NO)(H2O)2 in ethanol gave an equilibrium mixture of isomers 7a and 7b. Further treatment of 7a + 7b with 2 equivalent of sodium isopropoxide gave the crystallographicaly characterized, bent-nitrosyl, square pyramidal Ru(II) complex 8. Complex 8 was also synthesized by reaction of PNN with RuCl3(NO)(H2O)2 and Et3N in ethanol. Reaction of the "long arm" PN(2)N ligand (PN(2)N = 2-((t)Bu2PCH2-)-6-(Et2NCH2CH2)pyridine) with RuCl3(NO)(H2O)2 in ethanol gave complex 9, which upon treatment with 2 equiv of sodium isopropoxide gave complex 10. Complex 10 was also synthesized directly by reaction of PN(2)N with RuCl3(NO)(H2O)2 and a base in ethanol. A noteworthy aspect of these nitrosyl complexes is their preference for the Ru(0) oxidization state over Ru(II). This preference is observed with both aromatized and dearomatized pincer ligands, in contrast to the Ru(II) oxidation state which is preferred by the analogous carbonyl complexes. PMID- 24047218 TI - Depression and anxiety are associated with abnormal nocturnal blood pressure fall in hypertensive patients. AB - BACKGROUND: Previous studies have shown that depression and anxiety were independent risk factors for hypertension. Non-dipper hypertension is associated with higher cardiovascular mortality. The aim of this study was to evaluate the anxiety and depression scores in patients with dipper and non-dipper hypertension. METHODS: The study sample consisted of 153 hypertensive patients. All patients underwent 24-h blood pressure monitoring. Patients were classified into two groups according to their dipper or non-dipper hypertension status. We evaluated results of the Hospital Anxiety and Depression Scale between groups. RESULTS: Seventy-eight patients (38 male, mean age: 51.6 +/- 12.5 years) had dipper hypertension while 75 patients (27 male, mean age: 55.4 +/- 14.1 years) had non-dipper hypertension (p = 0.141, 0.072, respectively). Clinical characteristics were similar for both groups. Patients with non-dipper hypertension had significantly higher depression and anxiety scores compared to patients with dipper hypertension. Dipper and non-dipper status significantly correlated with anxiety (p: 0.025, r: 0.181) and depression score (p: 0.001, r: 0.255). In univariate analysis, smoking, alcohol usage, presence of diabetes, hyperlipidemia, anxiety score >8 and depression score >7 were predictors of dipper versus non-dipper status. In multivariate logistic regression analyses only depression score >7 was independent predictor of dipper versus non-dipper status (odds ratio: 2.74, confidence intervals: 1.41-5.37). A depression score of 7 or higher predicted non-dipper status with a sensitivity of 62.7% and specificity of 62.8%. CONCLUSION: Non-dipper patients have significantly higher anxiety and depression scores compared to dipper patients. Evaluation of anxiety and depression in patients with hypertension might help to detect non-dipper group and hence guide for better management. PMID- 24047220 TI - UVA-1 laser in the treatment of palmoplantar pustular psoriasis. AB - OBJECTIVE: The purpose of this study was to assess the efficacy of monochromatic UVA laser in the treatment of palmoplantar pustular psoriasis (PPP). BACKGROUND DATA: UVA-1 laser (355 nm) has been reported to be safe and effective in the treatment of psoriasis, but the range of potential applications has not been fully explored. METHODS: Thirty-three patients were enrolled in an open prospective study. Patients were treated from two to four times weekly at a fixed dose of 80-140 J/cm(2). Follow-up was 3 months. Clinical remission was observed in all patients who completed the study, with limited side effects (mild post treatment erythema). CONCLUSIONS: We report for the first time that UVA-1 laser produces a therapeutic response in PPP. PMID- 24047221 TI - Dental enamel irradiated with a low-intensity infrared laser and photoabsorbing cream: a study of microhardness, surface, and pulp temperature. AB - OBJECTIVE: The aim of this study was to assess the effect of low-intensity infrared laser light (lambda=810 nm, 100 mW/cm(2), 90 sec, 4.47 J/cm(2), 9 J) with or without indocyanine green cream fluorinated or not fluorinated, using Knoop surface microhardness analysis. BACKGROUND DATA: Lasers can be used as tools for the prevention of tooth enamel demineralization. METHODS: The surface and pulp temperatures of the human deciduous tooth enamel were measured. For the analysis of surface hardness, a total of 48 specimens were prepared and randomly assigned into six groups (n=8/group): C (+), which received laser light; C(-), which received no treatment; cream (IV); cream and fluoride (IVF); cream and light (IVL); and cream and fluoride and light (IVFL). The specimens were subjected to treatment before demineralizing challenge by pH cycling. To analyze the surface and pulp temperatures, the samples were divided into the following groups (n=10): C(+), IVL, and IVFL. RESULTS: The hardness analysis indicated that the groups that received irradiation had less hardness reduction following the demineralizing challenge (p<0.001), with IVFL and IVL presenting the lowest percentages of surface microhardness loss at 3.98% and 9.3%, respectively. Surface temperature analysis indicated a maximum increase of 74 degrees C and a mean of 45.25 degrees C and 45.95 degrees C for the IVL and IVFL groups, respectively. Pulp temperature analysis indicated a higher mean increase of 2.40 degrees C+/-0.65 in the IVL group. CONCLUSIONS: These results suggest that the combination of cream and laser light possibly promoted protein denaturation of the tooth enamel organic matrix, which possibly decreased the loss of hardness without causing pulp damage. PMID- 24047222 TI - Effect of low-level laser irradiation on oxygen free radicals and ventricular remodeling in the infarcted rat heart. AB - OBJECTIVE: The purpose of this study was to assess the effects of low-level laser irradiation (LLLI) on the expression of oxygen free radicals (OFR) and ventricular remodeling (VR) in the model of rat myocardial infarction (RMMI). BACKGROUND DATA: LLLI reduces the infarct size and formation of scar tissue in the rat heart after myocardial infarction (MI). However, the exact mechanism has not been demonstrated so far. METHODS: RMMI was induced by ligating the left anterior descending coronary artery (LAD). After 3 weeks, LLLI (635 nm, 6 mW laser, 7.64 mW/cm(2), 125 sec, 0.96 J/cm(2)) was applied to the surface of heart directly. Four to six rats were euthanized at 1 h, 24 h, 48 h, 72 h, and 1 week after LLLI, and the infarcted myocardia were excised for the measurement of the activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA). At the end of 4 weeks after MI, the hearts were harvested for histological analysis. RESULTS: Myocardial SOD activity with LLLI was lower compared with control (p<0.05), and myocardial MDA content with LLLI was higher compared with control (p<0.05), at all the time points. In all rats, the activity of SOD was down to the minimum and the content of MDA was up to the peak at 48 h after laser irradiation. The infarct size was reduced (35+/-10% vs. 18+/-9%, p<0.05), the left ventricular wall thickness was increased (0.31+/-0.03 vs. 0.84+/-0.02 mm, p<0.05) and the percentage of collagen fibers in the infarcted area was attenuated (64.34+/-2.20% vs. 30.97+/-2.60%) by LLLI. CONCLUSIONS: LLLI could cause OFR accumulation, reduce infarct size, increase ventricular wall thickness, and attenuate the formation of collagen fibers, suggesting the beneficial effects of LLLI on improvement of VR after MI. PMID- 24047223 TI - Er,Cr:YSGG laser dentine conditioning improves adhesion of a glass ionomer cement. AB - OBJECTIVE: The purpose of this study was to evaluate the bond strength (BS) of different surface treatments, including laser irradiation, between conventional glass ionomer cement (GIC) and dentine. METHODS: Eighty-five human third molars were divided into five groups with one of the following treatments: G1- control group, had no treatment; G2, G3, and G4 were treated with Er,Cr:YSGG laser irradiation at 0.5 W, 20 Hz, 25 mJ, 9 J/cm(2) (G2); 1.0 W, 20 Hz, 50 mJ, 18 J/cm(2)(G3); and 1.5 W, 20 Hz, 75 mJ, 27 J/cm(2) (G4); and G5 was treated with GIC liquid, which contains polyacrylic acid. Scanning electron microscopy (SEM) evaluation (n=2) and micro-shear bond strength test (n=15) using the GIC bonded to dentine were performed after 24 h of water immersion. The data were analyzed by one way analysis of variance (ANOVA), according to irradiation protocol (p<0.001). RESULTS: G2 specimens presented the highest BS results (in MPa) (10.50+/-0.84), followed by G1 (4.77+/-0.59) and G5 (4.26+/-1.02), which were statistically similar. G3 (3.32+/-0.39) and G4 (2.94+/-0.50) demonstrated the lowest BS values, and the difference between these groups was not statistically significant (p>0.001). SEM analysis of G1 revealed that the smear layer covered the entire dentine surface, whereas in G2, G3, and G4, irregular dentine was detected with open dentinal tubules and protruded peritubular dentine. Laser pulses could easily be distinguished in G2 but not in G3 and G4. G5 revealed a thin smear layer with dentinal tubule apertures clearly detectable. CONCLUSIONS: Dentine treatment with an Er,Cr:YSGG laser irradiation at a power of 0.5 W increased the BS of conventional GIC. PMID- 24047224 TI - Photobiomodulation of aqueous interfaces: finding evidence to support the exclusion zone in experimental and clinical studies. AB - OBJECTIVE: To present clinical and experimental evidence of the role of exclusion zone (EZ) water in photobiomodulation. BACKGROUND: Water at the interface of most hydrophilic surfaces forms a solute-free area, or EZ, that can project for hundreds of microns. To date, EZ phenomena had been documented in nafion, resins, and biologic membranes. METHODS: Retrospective analysis of published experimental and clinical data using an infrared pulsed laser device (IPLD). RESULTS: Photo induced effects on the water dynamics of burned rat tissue monitored by 1H-NMR transverse relaxation times (1/T2) indicate significantly greater structuring of water. A microdensitometry study of T2 weighted tumor heterogeneities from a phase I clinical trial in patients with advanced neoplasias and an algorithm for tumor characterization also shows significantly increased structuring of water associated with biopolymers and macromolecules. CONCLUSIONS: To the best of our knowledge, this is the first known demonstration of the EZ in medicine. Data support the premise that photobiomodulation can increase potential energy in the EZ, which then acts as an energy repository that can selectively supplement cell energy demands. It further suggests EZ structuring may be used as a predicator of anticancer response before measurable tumor volume reduction. PMID- 24047225 TI - A systematic review of proton magnetic resonance spectroscopy findings in sport related concussion. AB - Traditional structural neuroimaging techniques are normal in athletes who sustain sport-related concussions and are only considered to be clinically helpful in ruling out a more serious brain injury. There is a clinical need for more sophisticated, non-invasive imaging techniques capable of detecting changes in neurophysiology after injury. Concussion is associated with neurometabolic changes including neuronal depolarization, release of excitatory neurotransmitters, ionic shifts, changes in glucose metabolism, altered cerebral blood flow, and impaired axonal function. Proton magnetic resonance spectroscopy ((1)H-MRS, or simply MRS) is capable of measuring brain biochemistry and has the potential to identify and quantify physiologic changes after concussion. The focus of the current review is to provide an overview of research findings using MRS in sport-related concussion. A systematic review of articles published in the English language, up to February 2013, was conducted. Articles were retrieved via the databases: PsychINFO, Medline, Embase, SportDiscus, Scopus, Web of Science, and Informit using key terms: magnetic resonance spectroscopy, nuclear magnetic resonance spectroscopy, neurospectroscopy, spectroscopy, two-dimensional nuclear magnetic resonance spectroscopy, correlation spectroscopy, J-spectroscopy, exchange spectroscopy, nuclear overhauser effect spectroscopy, NMR, MRS, COSY, EXSY, NOESY, 2D NMR, craniocerebral trauma, mild traumatic brain injury, mTBI, traumatic brain injury, brain concussion, concussion, brain damage, sport, athletic, and athlete. Observational, cohort, correlational, cross-sectional, and longitudinal studies were all included in the current review. The review identified 11 publications that met criteria for inclusion, comprised of data on 200 athletes and 116 controls. Nine of 11 studies reported a MRS abnormality consistent with an alteration in neurochemistry. The results support the use of MRS as a research tool for identifying altered neurophysiology and monitoring recovery in adult athletes, even beyond the resolution of post-concussive symptoms and other investigation techniques returning to normative levels. Larger cross-sectional, prospective, and longitudinal studies are needed to understand the sensitivity and prognostic value of MRS within the field of sport-related concussion. PMID- 24047226 TI - Clinical significance of multidrug-resistant Acinetobacter baumannii isolated from central venous catheter tip cultures in patients without concomitant bacteremia. AB - BACKGROUND: The purpose of this study was to examine the clinical implications of a positive central venous catheter (CVC) tip culture with multidrug-resistant Acinetobacter baumannii (MRAB) in patients without concurrent bacteremia. METHODS: This retrospective, multicenter study was conducted in 9 teaching hospitals in the Republic of Korea from May 2008 to April 2012. Study subjects included adult patients (aged >= 18 y) who yielded an MRAB-positive CVC tip culture without concurrent MRAB bacteremia. All patients were observed for the development of subsequent MRAB bacteremia for 6 months after CVC removal. Multivariable Firth logistic regression analysis was performed to determine predictors independently associated with subsequent MRAB bacteremia. RESULTS: During the study period, subsequent MRAB bacteremia was observed in 18.8% of patients (21/112). Of the 112 patients, 23 (20.5%) did not show systemic inflammatory response syndrome (SIRS). None of the 23 patients without SIRS presented with subsequent MRAB bacteremia. Multivariable logistic regression analysis showed that prior administration of carbapenems (odds ratio (OR) 7.04, 95% confidence interval (CI) 1.43-34.77) or corticosteroids (OR 6.67, 95% CI 1.19 37.44), and C-reactive protein >= 40 mg/l (OR 18.11, 95% CI 2.22-148.07) were positive predictive factors. Prior acquisition of MRAB at a site other than the catheter (OR 0.10, 95% CI 0.03-0.39) was a negative predictive factor for developing MRAB bacteremia. CONCLUSIONS: Our results suggest that patients with a CVC tip colonized with MRAB should be closely monitored for signs and symptoms of subsequent MRAB bacteremia. PMID- 24047227 TI - Late onset Mycobacterium tuberculosis infection after total knee arthroplasty: a systematic review and pooled analysis. AB - BACKGROUND: Mycobacterium tuberculosis (TB) is a rare cause of prosthetic joint infection. The purpose of this study was to provide an evidence-based summarization of the outcomes of TB infection after total knee arthroplasty (TKA) with a pooled analysis of the reported cases. METHODS: We conducted a systematic review of published studies that have evaluated the outcomes of prosthetic knee joint infections due to TB. A structured literature review of multiple databases referenced articles from January 1950 to July 2012. RESULTS: A total of 15 patients were identified from 13 published studies. Tuberculosis was confirmed in all cases by histological examination and positive culture or histochemical stain/polymerase chain reaction (PCR). Treatment consisted of anti-tuberculosis medication therapy (AMT) only in 2 patients, AMT plus debridement and retention of the arthroplasty in 5 patients, and AMT plus removal/exchange of the arthroplasty in 8 patients. The average follow-up after TB infection was 29 months (range 1-96 months) and there were 3 deaths, giving a crude death rate of 0.7 per 100 person-months. At the final follow-up, the outcomes of TB infection after TKA were good except in the 3 patients who died. CONCLUSIONS: TB infection after TKA is a rare disease, however good clinical outcomes can be achieved with proper management including AMT and surgical intervention. PMID- 24047228 TI - Is creatinine clearance enough to predict sufficient kidneys for telaprevir? PMID- 24047229 TI - Detecting substrates bound to the secondary multidrug efflux pump EmrE by DNP enhanced solid-state NMR. AB - Escherichia coli EmrE, a homodimeric multidrug antiporter, has been suggested to offer a convenient paradigm for secondary transporters due to its small size. It contains four transmembrane helices and forms a functional dimer. We have probed the specific binding of substrates TPP(+) and MTP(+) to EmrE reconstituted into 1,2-dimyristoyl-sn-glycero-3-phosphocholine liposomes by (31)P MAS NMR. Our NMR data show that both substrates occupy the same binding pocket but also indicate some degree of heterogeneity of the bound ligand population, reflecting the promiscuous nature of ligand binding by multidrug efflux pumps. Direct interaction between (13)C-labeled TPP(+) and key residues within the EmrE dimer has been probed by through-space (13)C-(13)C correlation spectroscopy. This was made possible by the use of solid-state NMR enhanced by dynamic nuclear polarization (DNP) through which a 19-fold signal enhancement was achieved. Our data provide clear evidence for the long assumed direct interaction between substrates such as TPP(+) and the essential residue E14 in transmembrane helix 1. Our work also demonstrates the power of DNP-enhanced solid-state NMR at low temperatures for the study for secondary transporters, which are highly challenging for conventional NMR detection. PMID- 24047230 TI - Polymersome shape transformation at the nanoscale. AB - Polymer vesicles, also named polymersomes, are valuable candidates for drug delivery and micro- or nanoreactor applications. As far as drug delivery is concerned, the shape of the carrier is believed to have a strong influence on the biodistribution and cell internalization. Polymersomes can be submitted to an osmotic imbalance when injected in physiological media leading to morphological changes. To understand these osmotic stress-induced variations in membrane properties and shapes, several nanovesicles made of the graft polymer poly(dimethylsiloxane)-g-poly(ethylene oxide) (PDMS-g-PEO) or the triblock copolymer PEO-b-PDMS-b-PEO were osmotically stressed and observed by light scattering, neutron scattering (SANS), and cryo-transmission electron microscopy (cryo-TEM). Hypotonic shock leads to a swelling of the vesicles, comparable to optically observable giant polymersomes, and hypertonic shock leads to collapsed structures such as stomatocytes and original nested vesicles, the latter being only observed for bilayers classically formed by amphiphilic copolymers. Complementary SANS and cryo-TEM experiments are shown to be in quantitative agreement and highlight the importance of the membrane structure on the behavior of these nanopolymersomes under hypertonic conditions as the final morphology reached depends whether or not the copolymers assemble into a bilayer. The vesicle radius and membrane curvature are also shown to be critical parameters for such transformations: the shape evolution trajectory agrees with theoretical models only for large enough vesicle radii above a threshold value around 4 times the membrane thickness. PMID- 24047231 TI - Design, synthesis and discovery of picomolar selective alpha4beta2 nicotinic acetylcholine receptor ligands. AB - Developing novel and selective compounds that desensitize alpha4beta2 nicotinic acetylcholine receptors (nAChRs) could provide new effective treatments for nicotine addiction, as well as other disorders. Here we report a new class of nAChR ligands that display high selectivity and picomolar binding affinity for alpha4beta2 nicotinic receptors. The novel compounds have Ki values in the range of 0.031-0.26 nM and properties that should make them good candidates as drugs acting in the CNS. The selected lead compound 1 (VMY-2-95) binds with high affinity and potently desensitizes alpha4beta2 nAChRs. At a dose of 3 mg/kg, compound 1 significantly reduced rat nicotine self-administration. The overall results support further characterizations of compound 1 and its analogues in preclinical models of nicotine addiction and perhaps other disorders involving nAChRs. PMID- 24047232 TI - Fearful, surprised, happy, and angry facial expressions modulate gaze-oriented attention: behavioral and ERP evidence. AB - The impact of emotions on gaze-oriented attention was investigated in non-anxious participants. A neutral face cue with straight gaze was presented, which then averted its gaze to the side while remaining neutral or expressing an emotion (fear/surprise in Exp.1 and anger/happiness in Exp.2). Localization of a subsequent target was faster at the gazed-at location (congruent condition) than at the non-gazed-at location (incongruent condition). This Gaze-Orienting Effect (GOE) was enhanced for fear, surprise, and anger, compared to neutral expressions which did not differ from happy expressions. In addition, Event Related Potentials (ERPs) to the target showed a congruency effect on P1 for fear and surprise and a left lateralized congruency effect on P1 for happy faces, suggesting that target visual processing was also influenced by attention to gaze and emotions. Finally, at cue presentation, early postero-lateral (Early Directing Attention Negativity (EDAN)) and later antero-lateral (Anterior Directing Attention Negativity (ADAN)) attention-related ERP components were observed, reflecting, respectively, the shift of attention and its holding at gazed-at locations. These two components were not modulated by emotions. Together, these findings show that the processing of social signals such as gaze and facial expression interact rather late and in a complex manner to modulate spatial attention. PMID- 24047233 TI - Proteome analysis of cold response in spring and winter wheat (Triticum aestivum) crowns reveals similarities in stress adaptation and differences in regulatory processes between the growth habits. AB - A proteomic response to cold treatment (4 degrees C) has been studied in crowns of a frost-tolerant winter wheat cultivar Samanta and a frost-sensitive spring wheat cultivar Sandra after short-term (3 days) and long-term (21 days) cold treatments. Densitometric analysis of 2-D differential in gel electrophoresis (2D DIGE) gels has resulted in the detection of 386 differentially abundant protein spots, which reveal at least a two-fold change between experimental variants. Of these, 58 representative protein spots have been selected for MALDI-TOF/TOF identification, and 36 proteins have been identified. The identified proteins with an increased relative abundance upon cold in both growth habits include proteins involved in carbohydrate catabolism (glycolysis enzymes), redox metabolism (thioredoxin-dependent peroxidase), chaperones, as well as defense related proteins (protein revealing similarity to thaumatin). Proteins exhibiting a cold-induced increase in the winter cultivar include proteins involved in regulation of stress response and development (germin E, lectin VER2), while proteins showing a cold-induced increase in the spring cultivar include proteins involved in restoration of cell division and plant growth (eIF5A2, glycine-rich RNA-binding protein, adenine phosphoribosyltransferase). These results provide new insights into cold acclimation in spring and winter wheat at the proteome level and enrich our previous work aimed at phytohormone dynamics in the same plant material. PMID- 24047234 TI - Solid contact ion-selective electrodes with a well-controlled Co(II)/Co(III) redox buffer layer. AB - Solid contact ion-selective electrodes (ISEs) typically have an intermediate layer between the ion-selective membrane and the underlying solid electron conductor that is designed to reduce the irreproducibility and instability of the measured electromotive force (emf). Nevertheless, the electrode-to-electrode reproducibility of the emf of current solid contact ISEs is widely considered to be unsatisfactory. To address this problem, we report here a new method of constructing this intermediate layer based on the lipophilic redox buffer consisting of the Co(III) and Co(II) complexes of 1,10-phenanthroline ([Co(phen)3](3+/2+)) paired with tetrakis(pentafluorophenyl)borate as counterion. The resulting electrodes exhibit emf values with an electrode-to-electrode standard deviation as low as 1.7 mV after conditioning of freshly prepared electrodes for 1 h. While many prior examples of solid contact ISEs also used intermediate layers that contained redox active species, the selection of a balanced ratio of the reduced and oxidized species has typically been difficult and was often ignored, contributing to the emf irreproducibility. The ease of the control of the [Co(phen)3](3+)/[Co(phen)3](2+) ratio explains the high emf reproducibility, as confirmed by the emf decrease of 58 mV per 10-fold increase in the ratio of the reduced and oxidized redox buffer species. Use of a gold electrode modified with a self-assembled 1-hexanethiol monolayer as underlying electron conductor suppresses the formation of a water layer and results in an electrode-to-electrode standard deviation of E degrees of 1.0 mV after 2 weeks of exposure to KCl solution. PMID- 24047235 TI - Ground and excited state surfaces for the photochemical bond cleavage in phenylmethylphenylphosphonium ions. AB - Photolytic bond cleavage is a well-established method to generate carbocations for organic synthesis. Changes in the leaving group have a large influence on the chemical yield. The underlying potential energy surfaces governing the initial process are mostly unknown. We provide potential energy surfaces of ground and excited states on the CASSCF/CASPT2 level of theory for the charged precursor phenylmethylphenylphosphonium ion. We present the electronic and structural changes accompanying the excitation process and the subsequent bond cleavage. Inter-ring charge-transfer processes play a crucial role in the Franck-Condon region. Beyond the Franck-Condon region, competing reaction pathways emerge connected through conical intersections. The phenylmethylphenylphosphonium ion is used as a model system for the commonly used diphenylmethyltriphenylphosphonium ion. The appropriateness of the model is tested by CC2 calculations of the excitation spectrum. PMID- 24047236 TI - A study protocol to investigate the management of depression and challenging behaviors associated with dementia in aged care settings. AB - BACKGROUND: The high occurrence and under-treatment of clinical depression and behavioral and psychological symptoms of dementia (BPSD) within aged care settings is concerning, yet training programs aimed at improving the detection and management of these problems have generally been ineffective. This article presents a study protocol to evaluate a training intervention for facility managers/registered nurses working in aged care facilities that focuses on organisational processes and culture as well as knowledge, skills and self efficacy. METHODS: A Randomised Control Trial (RCT) will be implemented across 18 aged care facilities (divided into three conditions). Participants will be senior registered nurses and personal care attendants employed in the aged care facility. The first condition will receive the training program (Staff as Change Agents - Enhancing and Sustaining Mental Health in Aged Care), the second condition will receive the training program and clinical support, and the third condition will receive no intervention. RESULTS: Pre-, post-, 6-month and 12 month follow-up measures of staff and residents will be used to demonstrate how upskilling clinical leaders using our transformational training approach, as well as the use of a structured screening, referral and monitoring protocol, can address the mental health needs of older people in residential care. CONCLUSIONS: The expected outcome of this study is the validation of an evidence-based training program to improve the management of depression and BPSD among older people in residential care settings by establishing routine practices related to mental health. This relatively brief but highly focussed training package will be readily rolled out to a larger number of residential care facilities at a relatively low cost. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): The Universal Trial Number (UTN) is U1111-1141-0109. PMID- 24047237 TI - Extracellular matrix protein fibronectin induces matrix metalloproteinases in human prostate adenocarcinoma cells PC-3. AB - Studies on interaction of tumor cells with ECM components showed increased extracellular protease activity mediated by the family of matrix metalloproteinases (MMPs). Here we studied the effect of human prostate adenocarcinoma PC-3 cells-fibronectin (FN) interaction on MMPs and the underlying signaling pathways. Culturing of PC-3 cells on FN-coated surface upregulated MMP 9 and MMP-1. This response is abrogated by the blockade of alpha5 integrin. siRNA and inhibitor studies indicate possible involvement of phosphatidyl-inositol-3 kinase (PI-3K), focal adhesion kinase (FAK) and nuclear factor-kappaB (NF-kappaB) in FN-induced upregulation of MMPs. FN treatment also enhanced phosphorylation of FAK, PI3K, protein kinase B (PKB or Akt), nuclear translocation of NF-kappaB, surface expression of CD-44, and cell migration. Our findings indicate that, binding of PC-3 cells to FN, possibly via alpha5beta1 integrin, induces signaling involving FAK, PI-3K, Akt, NF-kappaB followed by upregulation of MMP-9 and MMP-1. CD-44 may have role in modulating MMP-9 activity. PMID- 24047239 TI - Validity of self-reported lunch recalls in Swedish school children aged 6-8 years. AB - BACKGROUND: Previous studies have suggested that young children are inaccurate reporters of dietary intake. The purpose of this study was to validate a single recall of the previous day's school lunch reported by 6-8 year old Swedish children and to assess teacher-recorded intake of the same meal in a standardized food journal. An additional research question was whether parents could report their child's intake of the previous day's lunch. Subjects constituted a convenience sample from the large, multi-country study Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS (IDEFICS). Validations of both children's recalls and teachers' records were made by comparing results with the duplicate plate reference method. FINDINGS: Twenty-five children (12 boys/13 girls) aged 6-8 years participated in the validation study at one school in western Sweden. Children were accurate self reporters of their dietary intake at lunch, with no significant difference between reported and weighed intake (Mean difference (SD): 7(50) kcals, p=0.49). Teachers significantly over-reported intake (Mean difference (SD): 65(79) kcals, p=0.01). For both methods, child-reported and teacher-recorded, correlations with weighed intake were strong (Pearson's correlations r=0.92, p<0.001 and r=0.83, p<0.001 respectively). Bland-Altman plots showed strong agreement between child reported and weighed intakes but confirmed systematic differences between teacher records and weighed intakes. Foods were recalled by children with a food-match rate of 90%. In all cases parents themselves were unable to report on quantities consumed and only four of 25 children had parents with knowledge regarding food items consumed. CONCLUSIONS: Children 6-8 years of age accurately recalled their school lunch intake for one occasion while teachers recorded with less accuracy. Our findings suggest that children as young as six years of age may be better able to report on their dietary intake than previously suggested, at least for one main meal at school. Teacher-recorded intake provides a satisfactory estimate but with greater systematic deviation from the weighed intake. Parents were not able to report on their children's school lunches consumed on the previous day. PMID- 24047240 TI - The tomato kinome and the tomato kinase library ORFeome: novel resources for the study of kinases and signal transduction in tomato and solanaceae species. AB - Protein kinase-driven phosphorylation constitutes the core of cellular signaling. Kinase components of signal transduction pathways are often targeted for inactivation by pathogens. The study of kinases and immune signal transduction in the model crop tomato (Solanum lycopersicum) would benefit from the availability of community-wide resources for large scale and systems-level experimentation. Here, we defined the tomato kinome and performed a comprehensive comparative analysis of the tomato kinome and 15 other plant species. We constructed a tomato kinase library (TOKN 1.0) of over 300 full-length open reading frames (ORF) cloned into a recombination-based vector. We developed a high-throughput pipeline to isolate and transform tomato protoplasts. A subset of the TOKN 1.0 library kinases were expressed in planta, were purified, and were used to generate a functional tomato protein microarray. All resources created were utilized to test known and novel associations between tomato kinases and Pseudomonas syringae DC3000 effectors in a large-scale format. Bsk7 was identified as a component of the plant immune response and a candidate effector target. These resources will enable comprehensive investigations of signaling pathways and host-pathogen interactions in tomato and other Solanaceae spp. PMID- 24047238 TI - Antagonist molecules in the treatment of angina. AB - INTRODUCTION: Management of chronic angina has evolved dramatically in the last few decades with several options for pharmacotherapy outlined in various evidence based guidelines. AREAS COVERED: There is a growing list of drugs that are currently being investigated for treatment of chronic angina. These also include several herbal medications, which are now being scientifically evaluated as potential alternative or even adjunctive therapy for angina. Gene- and cell-based therapies have opened yet another avenue for management of chronic refractory angina in 'no-option' patients who are not candidates for either percutaneous or surgical revascularization and are on optimal medical therapy. An extensive review of literature using PUBMED, Cochrane database, clinical trial databases of the USA and European Union was done and summarized in this review. This review will attempt to discuss the traditional as well as novel therapeutic agents for angina. EXPERT OPINION: Several pharmacological and non-pharmacological therapeutic options are now available for treatment and management of chronic refractory angina. Renewed interest in traditional therapies and cell- and gene based modalities with targeted drug delivery systems will open the doors for personalized therapy for patients with chronic refractory angina. PMID- 24047241 TI - Comparing sociocultural features of cholera in three endemic African settings. AB - BACKGROUND: Cholera mainly affects developing countries where safe water supply and sanitation infrastructure are often rudimentary. Sub-Saharan Africa is a cholera hotspot. Effective cholera control requires not only a professional assessment, but also consideration of community-based priorities. The present work compares local sociocultural features of endemic cholera in urban and rural sites from three field studies in southeastern Democratic Republic of Congo (SE DRC), western Kenya and Zanzibar. METHODS: A vignette-based semistructured interview was used in 2008 in Zanzibar to study sociocultural features of cholera related illness among 356 men and women from urban and rural communities. Similar cross-sectional surveys were performed in western Kenya (n = 379) and in SE-DRC (n = 360) in 2010. Systematic comparison across all settings considered the following domains: illness identification; perceived seriousness, potential fatality and past household episodes; illness-related experience; meaning; knowledge of prevention; help-seeking behavior; and perceived vulnerability. RESULTS: Cholera is well known in all three settings and is understood to have a significant impact on people's lives. Its social impact was mainly characterized by financial concerns. Problems with unsafe water, sanitation and dirty environments were the most common perceived causes across settings; nonetheless, non-biomedical explanations were widespread in rural areas of SE-DRC and Zanzibar. Safe food and water and vaccines were prioritized for prevention in SE DRC. Safe water was prioritized in western Kenya along with sanitation and health education. The latter two were also prioritized in Zanzibar. Use of oral rehydration solutions and rehydration was a top priority everywhere; healthcare facilities were universally reported as a primary source of help. Respondents in SE-DRC and Zanzibar reported cholera as affecting almost everybody without differentiating much for gender, age and class. In contrast, in western Kenya, gender differentiation was pronounced, and children and the poor were regarded as most vulnerable to cholera. CONCLUSIONS: This comprehensive review identified common and distinctive features of local understandings of cholera. Classical treatment (that is, rehydration) was highlighted as a priority for control in the three African study settings and is likely to be identified in the region beyond. Findings indicate the value of insight from community studies to guide local program planning for cholera control and elimination. PMID- 24047242 TI - Real-time observation of interlayer vibrations in bilayer and few-layer graphene. AB - We report real-time observation of the interlayer shearing mode, corresponding to the lateral oscillation of graphene planes, for bi- and few-layer graphene. Using a femtosecond pump-probe technique, we have followed coherent oscillations of this vibrational mode directly in the time domain. The shearing-mode frequency, as expected for an interlayer mode, exhibits a strong and systematic dependence on the number of layers, varying from 1.32 THz for the bulk limit to 0.85 THz for bilayer graphene. We explored the role of interactions with the external environment on this vibrational mode by comparing the response observed for graphene layers supported by different substrates and suspended in free space. No significant frequency shifts were observed. PMID- 24047243 TI - Interception of benzo[a]pyrene-7,8-dione by UDP glucuronosyltransferases (UGTs) in human lung cells. AB - Polycyclic aromatic hydrocarbons (PAHs) are environmental and tobacco carcinogens. Proximate carcinogenic PAH trans-dihydrodiols are activated by human aldo-keto reductases (AKRs) to yield electrophilic and redox-active o-quinones. Interconversion among benzo[a]pyrene (B[a]P)-7,8-dione, a representative PAH o quinone, and its corresponding catechol generates a futile redox-cycle with the concomitant production of reactive oxygen species (ROS). We investigated whether glucuronidation of B[a]P-7,8-catechol by human UDP glucuronosyltransferases (UGTs) could intercept the catechol in three different human lung cells. RT-PCR showed that UGT1A1, 1A3, and 2B7 were only expressed in human lung adenocarcinoma A549 cells. The corresponding recombinant UGTs were examined for their kinetic constants and product profile using B[a]P-7,8-catechol as a substrate. B[a]P-7,8 dione was reduced to B[a]P-7,8-catechol by dithiothreitol under anaerobic conditions and then further glucuronidated by the UGTs in the presence of uridine 5'-diphosphoglucuronic acid as a glucuronic acid group donor. UGT1A1 catalyzed the glucuronidation of B[a]P-7,8-catechol and generated two isomeric O monoglucuronsyl-B[a]P-7,8-catechol products that were identified by RP-HPLC and by LC-MS/MS. By contrast, UGT1A3 and 2B7 catalyzed the formation of only one monoglucuronide, which was identical to that formed in A549 cells. The kinetic profiles of three UGTs followed Michaelis-Menten kinetics. On the basis of the expression levels of UGT1A3 and UGT2B7 and the observation that a single monoglucuronide was produced in A549 cells, we suggest that the major UGT isoforms in A549 cells that can intercept B[a]P-7,8-catechol are UGT1A3 and 2B7. PMID- 24047245 TI - Complexation behavior of Eu(III) and Am(III) with CMPO and Ph2CMPO ligands: insights from density functional theory. AB - A series of extraction complexes of Eu(III) and Am(III) with CMPO (n octyl(phenyl)-N,N-diisobutyl-methylcarbamoyl phosphine oxide) and its derivative Ph2CMPO (diphenyl-N,N-diisobutyl carbamoyl phosphine oxide) have been studied using density functional theory (DFT). It has been found that for the neutral complexes of 2:1 and 3:1 (ligand/metal) stoichiometry, CMPO and Ph2CMPO predominantly coordinate with metal cations through the phosphoric oxygen atoms. Eu(III) and Am(III) prefer to form the neutral 2:1 and 3:1 type complexes in nitrate-rich acid solutions, and in the extraction process the reactions of [M(NO3)(H2O)7](2+) + 2NO3(-) + nL -> ML(n)(NO3)3 + 7H2O (M = Eu, Am; n = 2, 3) are the dominant complexation reactions. In addition, CMPO and Ph2CMPO show similar extractability properties. Taking into account the solvation effects, the metal-ligand binding energies are obviously decreased, i.e., the presence of solvent may have an significant effect on the extraction behavior of Eu(III) and Am(III) with CMPOs. Moreover, these CMPOs reagents have comparable extractability for Eu(III) and Am(III), confirming that these extractants have little lanthanide/actinide selectivity in acidic media. PMID- 24047244 TI - Foot massage and physiological stress in people with dementia: a randomized controlled trial. AB - BACKGROUND: The anxiety associated with unfamiliar surroundings, the disorientation and mental confusion, and the social isolation that accompanies dementia can often create increased stress for people living in long-term care settings. Such a response is thought to affect the autonomic nervous system and result in emotional and physical symptoms of distress that may be manifested as agitation. There is the potential for such distress to influence the physiological response and in particular Blood Pressure and Heart Rate. A relaxation intervention such as massage may influence the physiological stress response. METHODS: This randomized controlled trial aimed to compare the effect of foot massage (FM) versus a control activity (quiet presence, QP) on physiological stress response (i.e., blood pressure [BP] and heart rate [HR]) in people living with moderate-to-severe dementia in long-term-care settings. RESULTS: Fifty-three residents were randomized to intervention (10-minute FM) or control group (QP). While the FM group experienced a greater reduction in HR than the control group, these reductions were not significantly different between groups (p=0.83; see Table 1 ), or across time (p=0.46). Both groups experienced a reduction in systolic BP and diastolic BP, while the mean reduction in systolic BP was greater for those in the FM group. CONCLUSIONS: While the findings do not provide strong support for FM, the finding that both conditions allowed the person with dementia to rest in the presence of another human being is of importance in the care of people with dementia. The close presence of another person may in fact promote relaxation and therefore improve BP and HR measures. PMID- 24047246 TI - Blood pressure reduction by Japanese traditional Miso is associated with increased diuresis and natriuresis through dopamine system in Dahl salt-sensitive rats. AB - OBJECTIVES: We investigated the antihypertensive mechanism of long-term Miso soup consumption in Dahl salt-sensitive (Dahl S) rats with salt-induced hypertension. MATERIAL AND METHODS: Female Dahl S rats fed a low-salt (0.3% NaCl) diet were divided into three groups: (1) six rats given water, (2) six rats given 0.65% (w/v) saline solution or (3) eight rats given 5% (w/v) Miso soup containing 0.65% (w/v) saline solution. They were followed for 12 weeks. Variables in the plasma or 24-h urine were determined. Systolic blood pressure (SBP) was measured by the tail-cuff method. RESULTS: The SBP increased in an age-dependent manner in Dahl S rats drinking saline solutions. The elevation of SBP was significantly attenuated in Dahl S rats given Miso soup although the ultimate cumulative salt loading was much greater in the Miso group than those given the saline solutions. This SBP reduction in the Miso group was associated with an increase in fractional excretion of Na (FENa) and free water clearance in the kidney. Urinary dopamine excretions were increased in the Miso group compared with that in the saline group. The increase in urinary dopamine excretions was associated with a decrease in brain oxidative stress. Urinary dopamine excretions were an independent predictor of SBP in the Miso group. CONCLUSIONS: Long-term consumption of Miso soup attenuated blood pressure elevation in Dahl salt-sensitive rats with salt induced hypertension. The blood pressure reduction was due to, at least in part, constituent(s) of the Miso that increase natriuresis and diuresis and enhance dopaminergic nervous activity in the kidney. PMID- 24047248 TI - Occupational stress and employee turnover. AB - Questionnaire data captured in January-March 2007 were examined in relation to turnover in males and females during the next five years. In general, most of the workplace stressors (such as role conflict or peer support) were not antecedents of turnover in any group. Junior personnel with psychological strain in 2007 had an increased risk of turnover in the next five years. Low commitment to the service in 2007 increased the odds of turnover in male and female juniors and in female officers. Female juniors with less effective skills for coping with stress and who exercised less frequently on a weekly basis were more likely to leave. An incidental finding was that the odds of turnover were three times greater in female officers with children than in female officers with no children. Stress management interventions focusing on effective coping and sports and exercise participation which are targeted appropriately may improve retention. PMID- 24047249 TI - How can Saudi Arabia use the Decade of Action for Road Safety to catalyse road traffic injury prevention policy and interventions? AB - Motor vehicle accidents are the leading cause of death in adolescents and young adults worldwide. Nearly three-quarters of road deaths occur in developing countries and men comprise a mean 80% of casualties. The rate of road traffic accidents caused by four-wheeled vehicles is the highest globally reported road traffic accidents statistic. In Saudi Arabia, the motor vehicle is the main means of transportation with one person killed and four injured every hour. Over 65% of accidents occur because of vehicles travelling at excess speed and/or drivers disobeying traffic signals. Road traffic injuries cause considerable economic losses to victims, their families, and to nations as a whole. Strategic prevention plans should be implemented soon by various sectors (health, police, transport, and education) to decrease the mortality and morbidity among adolescent and young age group. Strong and effective coordination between ministry of health and other ministries together with World Health Organization and other related organisations will be an important step towards implementing the international Decade of Action for Road Safety (2011-2020). The aim of this review article is to highlight some aspects of the health impacts of road traffic accidents. PMID- 24047250 TI - Leaf gas exchange and chlorophyll a fluorescence in wheat plants supplied with silicon and infected with Pyricularia oryzae. AB - This study investigated the effect of silicon (Si) on the photosynthetic gas exchange parameters (net CO2 assimilation rate [A], stomatal conductance to water vapor [gs], internal CO2 concentration [Ci], and transpiration rate [E]) and chlorophyll fluorescence a parameters (maximum quantum quenching [Fv/Fm and Fv'/Fm'], photochemical [qP] and nonphotochemical [NPQ] quenching coefficients, and electron transport rate [ETR]) in wheat plants grown in a nutrient solution containing 0 mM (-Si) or 2 mM (+Si) Si and noninoculated or inoculated with Pyricularia oryzae. Blast severity decreased due to higher foliar Si concentration. For the inoculated +Si plants, A, gs, and E were significantly higher in contrast to the inoculated -Si plants. For the inoculated +Si plants, significant differences of Fv/Fm between the -Si and +Si plants occurred at 48, 96, and 120 h after inoculation (hai) and at 72, 96, and 120 hai for Fv'/Fm'. The Fv/Fm and Fv'/Fm', in addition to total chlorophyll concentration (a + b) and the chlorophyll a/b ratio, significantly decreased in the -Si plants compared with the +Si plants. Significant differences between the -Si and +Si inoculated plants occurred for qP, NPQ, and ETR. The supply of Si contributed to decrease blast severity in addition to improving gas exchange performance and causing less dysfunction at the photochemical level. PMID- 24047251 TI - Characterization of resistance to Pratylenchus thornei (Nematoda) in wheat (Triticum aestivum): attraction, penetration, motility, and reproduction. AB - Lines from a cross between two wheat (Triticum aestivum) cultivars with contrasting resistance phenotypes to Pratylenchus thornei (Nematoda) were investigated to determine the stage at which resistance occurs. Host resistance was examined at nematode attraction to and penetration of roots and nematode motility, maturation, and reproduction within roots. There was no significant difference in the rate at which P. thornei was attracted toward or penetrated resistant or susceptible roots. However, suppression of migration, juvenile maturation, and reproduction in and near resistant roots was evident, suggesting that resistance acts post penetration. No preferential root penetration zone was observed in contrast to other studies. The inhibitory compounds from resistant wheat plants appeared to be constitutively expressed and water soluble because nematode migration was suppressed in roots and root exudates of unchallenged seedlings. The effects of these compounds were reversible and affected P. thornei but not P. neglectus. Apart from migration, nematode multiplication was greatly inhibited by resistance because only a few juveniles (10%) developed past stage three in roots of resistant compared with susceptible plants. Earlier in the life cycle, egg deposition and hatch of P. thornei were also significantly reduced in resistant roots and root exudates, suggesting the presence of hatching inhibitors. PMID- 24047252 TI - Systemic resistance to gray mold induced in tomato by benzothiadiazole and Trichoderma harzianum T39. AB - Gray mold (Botrytis cinerea) is an important disease of tomato (Solanum lycopersicum). This study examined defense-related gene expression involved in the resistance to B. cinerea that is induced in tomato plants by benzothiadiazole and Trichoderma harzianum T39 soil drench. In whole plants, transcriptional changes related to salicylic acid and ethylene were induced by the application of a 0.01% benzothiadiazole solution, whereas changes related to jasmonic acid were induced by the application of a 0.4% T39 suspension. On detached leaves, soil treatment by T39 led to enhanced resistance to B. cinerea infection that was proportional to the concentration of the T39 suspension. By 5 days after pathogen inoculation, the plants that had received the 0.04% T39 drench exhibited 62% less severe disease than the untreated plants. The 0.4% T39 drench led to an 84% reduction in disease severity. Observations of B. cinerea infection in leaves harvested from plants grown in the treated soils revealed that drenching with a T39 suspension induces systemic resistance against B. cinerea and primes salicylic acid- and ethylene-related gene expression in a manner proportional to the concentration of the biocontrol agent. Benzothiadiazole treatment induced resistance to gray mold independently of salicylic acid and led to strong priming of two genes known to be involved in defense against B. cinerea, Pti5 and PI2. PMID- 24047253 TI - Southern rice black-streaked dwarf virus alters insect vectors' host orientation preferences to enhance spread and increase rice ragged stunt virus co-infection. AB - In recent years, Southern rice black-streaked dwarf virus (SRBSDV), a tentative species in the genus Fijivirus (family Reoviridae), has spread rapidly and caused serious rice losses in eastern and southeastern Asia. With this virus spread, Rice ragged stunt virus (RRSV, genus Oryzavirus, family Reoviridae) became more common in southern China, usually in co-infection with the former. SRBSDV and RRSV are transmitted by two different species of planthoppers, white-backed planthopper (WBPH, Sogatella furcifera) and brown planthopper (BPH, Nilaparvata lugens), respectively, in a persistent, circulative, propagative manner. In this study, using a Y-shape olfactometer-based device, we tested the host preference of three types of macropterous WBPH adults for healthy or SRBSDV-infected rice plants. The results showed that virus-free WBPHs significantly preferred infected rice plants to healthy plants, whereas both the viruliferous and nonviruliferous WBPHs preferred healthy plants to infected plants. In additional tests, we found that the BPHs significantly preferred healthy plants when they were virus free, whereas RRSV-carrying BPHs preferred SRBSDV-infected rice plants. From these findings, we propose that plant viruses may alter host selection preference of vectors to enhance their spread and that of insects vectoring another virus to result in co-infection with more than one virus. PMID- 24047254 TI - Total solids content and degree of hydrolysis influence proteolytic inactivation kinetics following whey protein hydrolysate manufacture. AB - The kinetics and thermodynamics of the thermal inactivation of Corolase PP in two different whey protein concentrate (WPC) hydrolysates with degree of hydrolysis (DH) values of ~10 and 21%, and at different total solids (TS) levels (from 5 to 30% w/v), were studied. Inactivation studies were performed in the temperature range from 60 to 75 degrees C, and residual enzyme activity was quantified using the azocasein assay. The inactivation kinetics followed a first-order model. Analysis of the activation energy, thermodynamic parameters, and D and z values, demonstrated that the inactivation of Corolase PP was dependent on solution TS. The intestinal enzyme preparation was more heat sensitive at low TS. Moreover, it was also found that the enzyme was more heat sensitive in solutions at higher DH. PMID- 24047256 TI - Electrically driven biofouling release of a poly(tetrafluoroethylene) membrane modified with an electrically induced reversibly cross-linked polymer. AB - Electrically induced reversible reactions between ferrocene (Fc) and beta cyclodextrin (beta-CD) groups have been utilized for preparation of poly(tetrafluoroethylene) (PTFE) membranes exhibiting electrically driven biofouling release properties. PTFE membrane is surface-modified with polymer chains possessing Fc pendant groups. The surface layer is then cross-linked with a difunctional beta-CD compound by means of the Fc/beta-CD complexation reaction. The electrically induced reversibly cross-linking and de-cross-linking behaviors of the surface layer of the modified PTFE membrane have been characterized with Fourier transform Infrared, X-ray photoelectron spectroscopy, and scanning electron microscopy. The surface-modified PTFE membrane has been fouled with protein absorption. Electrical treatment of the fouled membrane results in a protein detachment from the membrane surface driven by the surface structure change accompanied with the electrically induced de-cross-linking reaction of the Fc/beta-CD linkages. A smart membrane exhibiting a novel cleaning technology for membrane fouling has been developed. PMID- 24047255 TI - Crystal structures of the LsrR proteins complexed with phospho-AI-2 and two signal-interrupting analogues reveal distinct mechanisms for ligand recognition. AB - Quorum sensing (QS) is a cell-to-cell communication system responsible for a variety of bacterial phenotypes including virulence and biofilm formation. QS is mediated by small molecules, autoinducers (AIs), including AI-2 that is secreted by both Gram-positive and -negative microbes. LsrR is a key transcriptional regulator that governs the varied downstream processes by perceiving AI-2 signal, but its activation via autoinducer-binding remains poorly understood. Here, we provide detailed regulatory mechanism of LsrR from the crystal structures in complexes with the native signal (phospho-AI-2, D5P) and two quorum quenching antagonists (ribose-5-phosphate, R5P; phospho-isobutyl-AI-2, D8P). Interestingly, the bound D5P and D8P molecules are not the diketone forms but rather hydrated, and the hydrated moiety forms important H-bonds with the carboxylate of D243. The D5P-binding flipped out F124 of the binding pocket, and resulted in the disruption of the dimeric interface-1 by unfolding the alpha7 segment. However, the same movement of F124 by the D8P'-binding did not cause the unfolding of the alpha7 segment. Although the LsrR-binding affinity of R5P (Kd, ~1 mM) is much lower than that of D5P and D8P (~2.0 and ~0.5 MUM), the alpha-anomeric R5P molecule fits into the binding pocket without any structural perturbation, and thus stabilizes the LsrR tetramer. The binding of D5P, not D8P and R5P, disrupted the tetrameric structure and thus is able to activate LsrR. The detailed structural and mechanistic insights from this study could be useful for facilitating design of new antivirulence and antibiofilm agents based on LsrR. PMID- 24047257 TI - Pharmacophore-based discovery of new human dihydroorotate dehydrogenase inhibitor. AB - Pharmacophore models of human dihydroorotate dehydrogenase (HsDHODH) have been developed using Discovery Studio V2.1 with a training set of 27 HsDHODH inhibitors. With one hydrogen bond receptor, two hydrophobic, one ring aromatic and one neg ionizable features, Hypo 1 has a correlation coefficient of 0.948, cost difference of 78.894, and RMSD 0.926. This model was validated by test set and Fischer randomization test. Hypo 1 was employed as a 3D query to identify potent molecules from our lab chemical database. Compound 38-C11 had Hypo 1 estimated IC50 of 489 nM. Then 38-C11 was synthesized and evaluated in HsDHODH inhibition assay. The IC50 of 38-C11 was 136.9 nM suggesting that 38-C11 could be proceeded for further evaluation in future study. PMID- 24047258 TI - Impact of gray matter reductions on theory of mind abilities in patients with schizophrenia. AB - To identify the brain regions involved in the interpretation of intentional movement by patients with schizophrenia, we investigated the association between cerebral gray matter (GM) volumes and performance on a theory of mind (ToM) task using voxel-based morphometry. Eighteen patients with schizophrenia and thirty healthy controls participated in the study. Participants were given a moving shapes task that employs the interpretation of intentional movement. Verbal descriptions were rated according to intentionality. ToM performance deficits in patients were found to be positively correlated with GM volume reductions in the superior temporal sulcus and medial prefrontal cortex. Our findings confirm that divergent brain regions contribute to mentalizing abilities and that GM volume reductions impact behavioral deficits in patients with schizophrenia. PMID- 24047259 TI - Anti-inflammatory asterosaponins from the starfish Astropecten monacanthus. AB - Four new asterosaponins, astrosteriosides A-D (1-3 and 5), and two known compounds, psilasteroside (4) and marthasteroside B (6), were isolated from the MeOH extract of the edible Vietnamese starfish Astropecten monacanthus. Their structures were elucidated by chemical and spectroscopic methods including FTICRMS and 1D and 2D NMR experiments. The effects of the extracts and isolated compounds on pro-inflammatory cytokines were evaluated by measuring the production of IL-12 p40, IL-6, and TNF-alpha in LPS-stimulated bone marrow derived dendritic cells. Compounds 1, 5, and 6 exhibited potent anti-inflammatory activity comparable to that of the positive control. Further studies are required to confirm efficacy in vivo and the mechanism of effects. Such potent anti inflammatory activities render compounds 1, 5, and 6 important materials for further applications including complementary inflammation remedies and/or functional foods and nutraceuticals. PMID- 24047260 TI - BMI of the firstborn offspring at age 12 reflects maternal LDL and HDL cholesterol levels at term pregnancy and postpartum. AB - OBJECTIVE: The aim of this study was to assess the relationship between the body mass index (BMI) of the firstborn offspring at age 12 and maternal lipid levels at term and at 6 months postpartum. DESIGN AND METHODS: The study included children born in the 2nd Department of Obstetrics and Gynecology of the Medical University of Warsaw between 1 November 1991 and 31 May 1993. The end point was BMI in the upper quartile - considered high BMI of the firstborn offspring at age 12. RESULTS: The risk of high BMI in the offspring at age 12 significantly increased with an increase in the LDL-C level at term (OR = 2.41 per SD increase, 95% CI: 1.01-5.80; p < 0.049), a decrease in the HDL-C% at term (OR = 0.35 per SD increase, 95% CI: 0.14-0.84; p < 0.019) and a decrease in the HDL-C level at 6 months postpartum (OR = 0.25 per SD increase, 95% CI: 0.08-0.82; p < 0.022), regardless of maternal weight status before pregnancy and at 6 months postpartum, gestational weight gain, the offspring's gender and birth weight. CONCLUSION: LDL and HDL cholesterol levels at term are markers of maternal adaptation to a first pregnancy and predict the future growth of firstborn offspring. PMID- 24047261 TI - Modelling the impact of chlamydia screening on the transmission of HIV among men who have sex with men. AB - BACKGROUND: Recent studies have found high prevalences of asymptomatic rectal chlamydia among HIV-infected men who have sex with men (MSM). Chlamydia could increase the infectivity of HIV and the susceptibility to HIV infection. We investigate the role of chlamydia in the spread of HIV among MSM and the possible impact of routine chlamydia screening among HIV-infected MSM at HIV treatment centres on the incidence of chlamydia and HIV in the overall MSM population. METHODS: A mathematical model was developed to describe the transmission of HIV and chlamydia among MSM. Parameters relating to sexual behaviour were estimated from data from the Amsterdam Cohort Study among MSM. Uncertainty analysis was carried out for model parameters without confident estimates. The effects of different screening strategies for chlamydia were investigated. RESULTS: Among all new HIV infections in MSM, 15% can be attributed to chlamydia infection. Introduction of routine chlamydia screening every six months among HIV-infected MSM during regular HIV consultations can reduce the incidence of both infections among MSM: after 10 years, the relative percentage reduction in chlamydia incidence would be 15% and in HIV incidence 4%, compared to the current situation. Chlamydia screening is more effective in reducing HIV incidence with more frequent screening and with higher participation of the most risky MSM in the screening program. CONCLUSIONS: Chlamydia infection could contribute to the transmission of HIV among MSM. Preventive measures reducing chlamydia prevalence, such as routine chlamydia screening of HIV-infected MSM, can result in a decline in the incidence of chlamydia and HIV. PMID- 24047262 TI - Relationship status and depressive symptoms among older co-resident caregivers. AB - OBJECTIVES: Informal caregiving has been found to be burdensome and is associated with depression among older caregivers. These outcomes are often accentuated when caregivers and care recipients co-reside. The current study aims to examine whether the status of the relationship between caregiver and care recipient lessens the negative outcomes commonly associated with informal caregiving. METHODS: The study focused on the subsample of co-resident caregivers (N = 3280) in the fourth wave of the Survey of Health Ageing and Retirement in Europe, of persons aged 50 or above, collected in 2011. A logged count of depressive symptoms, measured on the EURO-D scale, was hierarchically regressed on relationship status, measured as relationship type and closeness (confidant) controlling for sociodemographic background, health and country. RESULTS: Co resident caregivers of spouse and children experienced more depressive symptoms than other relationship co-resident caregiving dyads. However, those who cared for a confidant experienced fewer depressive symptoms, independent of the relationship type. CONCLUSIONS: The provision of informal care is stressful and results in a heightened experience of depressive symptoms. Nonetheless, the type and closeness of the relationship between the caregiver and the care recipient can lessen caregiver depression. When informal caregivers care for a confidant, the emotional bond may reduce the depressive symptoms. PMID- 24047263 TI - Transport rectification in nanopores with outer membranes modified with surface charges and polyelectrolytes. AB - This work reports a comprehensive theoretical study of the transport rectification properties of cylindrical nanopores with neutral inner walls and chemically modified outer membrane. The chemical species on the two outer sides of the membrane have charges of opposite sign and can be either surface-confined species (i.e., surface charges) or polyelectrolyte brushes. The advantage of this design over other types of rectifying nanopores is that it requires controlling the composition of the outer walls of the pore (which are easy to access) rather than the inner walls, thus simplifying the fabrication process. Ion-current rectification in nanopores with charged outer walls is ascribed to applied potential-induced changes in the ionic concentration within the pore. The rectification efficiency is studied as a function of pore length, radius, surface charge and bulk electrolyte concentration. An analytical model is derived for the case of surface-confined charges that predicts the current-potential curves in very good agreement with the numerical calculations. Neutral nanopores with polyelectrolyte-modified outer walls have two distinct advantages compared to surface-charged systems: (i) they exhibit higher rectification factors due to the large charge density immobilized by the polyelectrolyte brushes, and (ii) the applied potential deforms the polyelectrolyte chains toward the oppositely charged electrode. This deformation brings the polyelectrolyte brushes into the pore in the low conductivity state and expels them from the pore in the high conductivity regime. Calculations of the potentials of mean-force suggest that the applied-field-induced conformational changes can be used to control the translocation of cargoes larger than ions, such as proteins and nanoparticles. PMID- 24047264 TI - Innovation in restorative dental materials: another new age or the end of the line? PMID- 24047265 TI - FT-Raman spectroscopy: a useful tool in measuring resin composite degradation? PMID- 24047268 TI - Design of brain imaging agents for positron emission tomography: do large bioconjugates provide an opportunity for in vivo brain imaging? AB - The development of brain imaging agents for positron emission tomography and other in vivo imaging modalities mostly relies on small compounds of low MW as a result of the restricted transport of larger molecules, such as peptides and proteins, across the blood-brain barrier. Besides passive transport, only a few active carrier mechanisms, such as glucose transporters and amino acid transporters, have so far been exploited to mediate the accumulation of imaging probes in the brain. An important question for the future is whether some of the abundant active carrier systems located at the blood-brain barrier can be used to shuttle potential, but non-crossing, imaging agents into the brain. What are the biological and chemical constrictions toward such bioconjugates and is it worthwhile to persue such a delivery strategy? PMID- 24047269 TI - Denture polymers with antimicrobial properties: a review of the development and current status of anionic poly(methyl methacrylate) polymers. AB - The denture base polymer poly(methyl methacrylate) (PMMA) is highly susceptible for microbial colonization resulting in denture-associated infections. Over the years research has focused on ways to modify the PMMA properties via surface and chemical modification. These studies led to the development of new denture polymers that include anionic PMMA polymers. The new anionic polymers presented the possibility of compromising the physical and mechanical properties required for denture fabrication. These obstacles were overcome by generating anionic PMMA polymers with physical and mechanical properties suitable for denture fabrication. A large body of literature is available on the anionic PMMA polymers, their antimicrobial properties and their potential for the commercial and clinical application as dental biomaterials. This article describes a review and evaluation of the anionic PMMA polymers for their suitability to serve as denture base polymers, their antimicrobial properties, their efficacy to prevent denture-induced infection and their safety in the oral environment. PMID- 24047267 TI - Therapeutic potential of PDE modulation in treating heart disease. AB - Altered cyclic nucleotide-mediated signaling plays a critical role in the development of cardiovascular pathology. By degrading cAMP/cGMP, the action of cyclic nucleotide PDEs is essential for controlling cyclic nucleotide-mediated signaling intensity, duration, and specificity. Altered expression, localization and action of PDEs have all been implicated in causing changes in cyclic nucleotide signaling in cardiovascular disease. Accordingly, pharmacological inhibition of PDEs has gained interest as a treatment strategy and as an area of drug development. While targeting of certain PDEs has the potential to ameliorate cardiovascular disease, inhibition of others might actually worsen it. This review will highlight recent research on the physiopathological role of cyclic nucleotide signaling, especially with regard to PDEs. While the physiological roles and biochemical properties of cardiovascular PDEs will be summarized, the primary emphasis will be pathological. Research into the potential benefits and hazards of PDE inhibition will also be discussed. PMID- 24047270 TI - Chromenes: potential new chemotherapeutic agents for cancer. AB - Cancer is a major devastating disease, and is a leading cause of death worldwide. Despite the progress in cancer treatment, cancer mortality rate remains high. Therefore, the discovery and development of improved anticancer drugs to treat cancer are needed. 4H-chromenes have strong cytotoxicity against a panel of human cancer cell lines involving pathways that include microtubule depolarization and tumor vasculature disruption. A chromene analog, CrolibulinTM (EPC2407) is currently in Phase I/II clinical trials for the treatment of advanced solid tumors. This article reviews the general synthesis, biological activities and structure-activity relatinships of different classes of chromenes. PMID- 24047271 TI - Recent progress in the discovery of small-molecule inhibitors of the HMT EZH2 for the treatment of cancer. AB - The histone lysine methyltransferase EZH2 is the catalytic component of the multi protein PRC2 complex and methylates lysine 27 on histone H3. EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumor types. Inhibition of aberrant EZH2 activity might attenuate tumorigenesis resulting from misregulated gene transcription derived from aberrant EZH2 activity. In the last year, the first reports of small molecules demonstrating potent and selective inhibition of EZH2 have been published by multiple groups. Herein, we review recent progress reported in the discovery of small molecule inhibitors of EZH2. PMID- 24047272 TI - The role of small molecules in bone regeneration. AB - Although several methods have been used in bone regeneration medicine, current methods still have many limitations. The tissue used for autogenous bone graft is limited and allograft has weak osteoinductive activity. Tissue engineering provides a good choice for bone regeneration. However, the growth factors needed have a high price and short half-life. Recently, a number of small molecules have been confirmed to have osteoinductive activity and some have been clinically used. Natural small molecules including decalpenic acid, flavonoids, quinones can be extracted from plants and others can be synthesized according to the structure designed or mimicking the structure of natural small molecules. Small molecules can act as co-activator of BMP2 pathway or activate Wnt pathway; others can be the inhibitors of NF-kappaB signaling pathway. This review gives an overview on the small molecules with osteoinductive activity and discusses the mechanism of the small molecules. PMID- 24047273 TI - Therapeutic strategies impacting cancer cell glutamine metabolism. AB - The metabolic adaptations that support oncogenic growth can also render cancer cells dependent on certain nutrients. Along with the Warburg effect, increased utilization of glutamine is one of the metabolic hallmarks of the transformed state. Glutamine catabolism is positively regulated by multiple oncogenic signals, including those transmitted by the Rho family of GTPases and by c-Myc. The recent identification of mechanistically distinct inhibitors of glutaminase, which can selectively block cellular transformation, has revived interest in the possibility of targeting glutamine metabolism in cancer therapy. Here, we outline the regulation and roles of glutamine metabolism within cancer cells and discuss possible strategies for, and the consequences of, impacting these processes therapeutically. PMID- 24047275 TI - Leukocyte infiltration in experimental stroke. AB - Stroke is one of the leading causes of death worldwide. At present, the only available treatment is thrombolysis, which should be initiated no later than 4.5 hours after onset of symptoms. Several studies have shown that an attenuation of the inflammatory response in relation to stroke could widen the therapeutic window. However, the immune system has important functions following infarction, such as removal of dead cells and the subsequent astrocytosis as well as prevention of post-ischemic infection. Hence, detailed knowledge concerning the temporal profile of leukocyte infiltration is necessary in order to develop new and effective treatments.The purpose of this review is to determine the temporal profile of leukocyte (neutrophil granulocytes, macrophages and T-cells) infiltration following experimental stroke. We found that the number of neutrophil granulocytes peaks between day 1 and 3 after experimental stroke, with short occlusion times (30 and 60 minutes of middle cerebral artery occlusion (MCAO)) leading to a later peak in response (P <0.001). Macrophages/microglia were found to peak later than day 3 and stay in the infarcted area for longer time periods, whereas duration of occlusion had no influence on the temporal infiltration (P = 0.475). Studies on T-cell infiltration are few; however, a tendency towards infiltration peak at later time points (from day 4 onwards) was seen.This review provides a framework for the instigation of post-stroke anti inflammatory treatment, which could prove beneficial and widen the therapeutic window compared to current treatment options. PMID- 24047277 TI - Re: perceived tutor benefits of teaching near peers: insights from two near peer teaching programmes in South East Scotland. PMID- 24047276 TI - Sarcoidosis lymphoma syndrome - the value of PET-CT in the diagnosis. AB - We report a 52-year-old patient who developed B-cell non-Hodgkin's lymphoma subsequent to sarcoidosis. Sarcoidosis was diagnosed 16 years ago and remained asymptomatic for 14 years after steroid treatment. She presented with new symptoms of arthralgia, photosensitivity, butterfly erythema, autoimmune antibodies (ANA, chromatin positivity) associated with progression of the known left upper lobe lesion on the chest X-ray suggesting primary autoimmune disease (systemic lupus erythematosus). As steroid treatment was not effective, we started bolus cyclophosphamide therapy after which progression was seen on the chest X-ray. Computed tomography (CT)-guided needle biopsy confirmed malignancy of indefinable origin. Despite of the well-known fluorodeoxyglucose (FDG) avidity in active sarcoidosis, a FDG-positron emission tomography (PET) scan was performed to stage the primary tumour. Intensive FDG uptake was detected in the affected lung segment, with moderate uptake in mediastinal lymph nodes. The patient underwent left upper lobectomy. The histology showed pulmonary mucosa associated lymphoma (bronchus-associated lymphoid tissue (BALT) lymphoma) in the lung tissue, while only sarcoidosis was present in the mediastinal lymph nodes. Bone marrow biopsy was negative.The association between sarcoidosis and lymphoma is known as sarcoidosis lymphoma syndrome, which is a rare disease. PET-CT was helpful in the differentiation of sarcoidosis and malignancy in this patient. It is important to be aware of the risk of lymphoma in sarcoidosis and FDG-PET, used for adequate purpose, can help the diagnosis. PMID- 24047278 TI - Methodological basics and evolution of the Belgian health interview survey 1997 2008. AB - BACKGROUND: The Belgian Health Interview Survey (BHIS) is organised every 4 to 5 years and collects health information from around 10,000 individuals in a face-to face setting. This manuscript describes the methodological choices made in the sampling design, the outcomes of the previous surveys in terms of participation rates and achieved targets and the factors to be accounted for in data-analysis. METHODS: The BHIS targets all persons residing in Belgium with no restrictions on age or nationality. Trimestral copies of the National Population Registry are used as the sampling frame. To select the respondents, a multistage sampling design is applied involving a geographical stratification, a selection of clusters, a selection of households within each cluster and a selection of respondents within each household. Using matched substitution of non participating households assures the realisation of the predefined net-sample. RESULTS: For each BHIS the required number of participants is achieved, including the years when an oversampling of provinces and of the elderly occurred. The sampling design guarantees that the survey is implemented in large cities as well as in small municipalities. A growing problem is related to the sampling frame: it is increasingly subject of deterioration, especially in the Brussels-Capital Region. CONCLUSIONS: The methodological approach developed for the first BHIS proves to be accurate and was kept nearly unchanged throughout the following surveys. Fieldwork substitution contributes to a considerable extent to the success of the fieldwork but yields in higher percentages of non-participation. The sampling design requires special attention when analysing the data: the unequal selection probability, e.g. due to the non-proportional stratification at the regional level, necessitates the use of weights. The BHIS is progressively embedded in the European Health Survey, a process that doesn't jeopardise the comparability of the Belgian results throughout time. PMID- 24047279 TI - Base-catalyzed diastereoselective [3 + 3] annulation of 3-isothiocyanatooxindoles and azomethine imines. AB - An unprecedented diastereoselective [3 + 3] annulation of 3 isothiocyanatooxindoles and azomethine imines was catalyzed by Et3N, affording 3,3'-triazinyl spirooxindoles in excellent yields and diastereoselectivities under mild conditions. PMID- 24047280 TI - The association between serum ferritin level, microalbuminuria and non-alcoholic fatty liver disease in non-diabetic, non-hypertensive men. AB - BACKGROUND: Iron-mediated cell injury may cause glomerular endothelial dysfunction, which precedes microalbumuria. However, there have been no reports on the relationship between serum ferritin level and microalbuminuria. The aim of this study is to assess the relationship between serum ferritin level and microalbuminuria in apparently healthy men and to evaluate how non-alcoholic fatty liver disease (NAFLD) affects this association. METHODS: Microalbuminuria and serum ferritin level were measured, and hepatic ultrasound was performed in a sample of 2489 non-diabetic, non-hypertensive men. The patients were classified into two groups according to urinary albumin-creatinine ratio (UACR) in morning urine specimens: normoalbuminuria (<30 ug/mg) and microalbuminuria (30-300 ug/mg). RESULTS: The overall prevalence of microalbuminuria and NAFLD based on ultrasound findings were 4.5% (113 subjects) and 41.9% (1042 subjects), respectively. The microalbuminuric group had significantly higher levels of serum ferritin than the normoalbuminuric group (255.4 pmol/L versus 207.5 pmol/L, p<0.001). In the multivariate regression analysis, serum ferritin level was independently associated with microalbuminuria irrespective of multiple covariates (OR [95% CI] 1.746 [1.221-2.497]). Subgroup analyses according to NAFLD revealed that the NAFLD group had higher serum ferritin level and a higher prevalence of microalbuminuria compared with the non-NAFLD group (233.8 pmol/L versus 194.3 pmol/L, p<0.001) (6.3% versus 3.2%, p<0.001). However, in the multivariate regression analysis, there was a significant association between serum ferritin level and microalbuminuria in both the non-NAFLD and the NAFLD group. CONCLUSIONS: Our results indicate that serum ferritin level is associated with microalbuminuria in non-hypertensive, non-diabetic men, irrespective of NAFLD. PMID- 24047281 TI - Evaluation of the agreement between modeled and monitored ambient hazardous air pollutants in California. AB - Elevated breast cancer incidence rates in urban areas have led to speculation regarding the potential role of air pollution. In order to inform the exposure assessment for a subsequent breast cancer study, we evaluated agreement between modeled and monitored hazardous air pollutants (HAPs). Modeled annual ambient concentrations of HAPs in California came from the US Environmental Protection Agency's National Air Toxics Assessment database for 1996, 1999, 2002, and 2005 and corresponding monitored data from the California Air Resources Board's air quality monitoring program. We selected 12 compounds of interest for our study and focused on evaluating agreement between modeled and monitored data, and of temporal trends. Modeled data generally underestimated the monitored data, especially in 1996. For most compounds agreement between modeled and monitored concentrations improved over time. We concluded that 2002 and 2005 modeled data agree best with monitored data and are the most appropriate years for direct use in our subsequent epidemiologic analysis. PMID- 24047282 TI - Synthesis of zwitterionic triphosphenium transition metal complexes: a boron atom makes the difference. AB - A collection of zwitterionic phosphanide metal carbonyl coordination complexes has been synthesized and fully characterized, representing the first isolated series of metal complexes for the triphosphenium family of compounds. The dicoordinate phosphorus atom of the zwitterion is formally in the +1 oxidation state and can coordinate to one metal, 2M (M = Cr, Mo, W) and 2Fe, or two metals, a Co2(CO)6 fragment 4, depending on the starting reagents. All complexes have been isolated in greater than 80% yield, and structures were confirmed crystallographically. Metrical parameters are consistent with 1 being a weak donor and results in long metal-phosphorus bonds being observed in all cases. Unique bimetallic structures, 3M (M = Cr, Mo, W), consisting of a M(CO)5 fragment on phosphorus and a piano-stool M(CO)3 fragment on a boron phenyl group have been identified in the (31)P{(1)H} NMR spectra and confirmed using X-ray diffraction studies. Use of the borate backbone in 1, which renders the molecule zwitterionic, proves to be a determining factor in whether these metal complexes will form; the halide salt of a cationic triphosphenium ion, 6[Br], shows no evidence for formation of the analogous metal complexes by (31)P{(1)H} NMR spectroscopy, and tetraphenylborate salts, 6[BPh4] and 7[BPh4], produce complexes that are unstable. PMID- 24047284 TI - CdSe-CdS nanoheteroplatelets with efficient photoexcitation of central CdSe region through epitaxially grown CdS wings. AB - We synthesized a new type of optically active semiconductor nanoheterostructure based on CdSe nanoplatelets with epitaxially grown CdS flat branches or wings. CdS branches work as efficient photonic antenna in the blue spectral region, enhancing the excitation of CdSe band edge emission. The formation of CdSe-CdS nanoheteroplatelets instead of CdSe/CdS core-shell nanoplatelets was achieved using short-chain Cd ethylhexanoate and sulfur in octadecene as precursors for CdS overgrowth in the presence of acetate salt. PMID- 24047286 TI - A control problem for a cross-diffusion system in a nonhomogeneous medium. AB - We study a model, motivated by a bioremediation process, describing a cross diffusion movement of a bacteria population b attracted by a chemoattractant signal c, in a nonhomogeneous stratified medium with n layers. We assume that this reaction-diffusion process is characterized by a low rate of degradation and a low diffusion coefficient of the chemoattractant, expressed in the model by a small parameter epsilon. The model consists of n systems of nonlinear parabolic equations with transmission conditions between layers. We prove a global-in-time solution for the asymptotic model setup with respect to the small parameter of the problem, for arbitrarily large initial data. Next, we deal with the control problem focusing mainly on the reduction of the chemoattractant concentration, by acting upon the initial distribution of the bacteria population b0. To this end, we prove the existence of a solution to the control problem and determine the optimality conditions. PMID- 24047285 TI - Discovery and characterization of a new cell-penetrating protein. AB - We describe a new cell-penetrating protein, B1, capable of delivering conjugated proteins and nucleic acids into mammalian cells. B1 is a 244-amino-acid product of a single-base frameshift in the gene encoding enhanced green fluorescent protein (eGFP). The molecule has a net positive charge of 43 and a very high charge-to-mass ratio of 1.5. eGFP-fused B1 potently penetrates both adherent and suspension cells with >80% of cells taking up the protein when exposed to concentrations as low as 1 MUM. The protein was found to cluster in the paranuclear region of TZM-bl cells. Most importantly, we show that B1 not only facilitates cellular uptake but allows biomolecular cargo to reach sites of biological relevance. For example, baby hamster kidney cells underwent DNA recombination when exposed to B1-tagged Cre recombinase at protein concentrations as low as 2.5 MUM, indicating potent nuclear delivery of functional protein cargos. Additionally, B1 delivers noncovalently conjugated RNA and DNA across the cell membrane to cytosolic and nuclear sites accessible to the cellular translation and transcription machinery, as gauged by detection of encoded reporter functions, with efficiency comparable to commercially available cationic lipid reagents. B1 appears to utilize cell-surface glycans and multiple competing endocytic pathways to enter and traffic through cells. These studies provide both a new tool for intracellular delivery of biomolecules and insights that could aid in the design of more effective cell penetrating proteins. PMID- 24047287 TI - Hen egg white lysozyme permeabilizes Escherichia coli outer and inner membranes. AB - Natural preservatives answer the consumer demand for long shelf life foods, synthetic molecules being perceived as a health risk. Lysozyme is already used because of its muramidase activity against Gram-positive bacteria. It is also described as active against some Gram-negative bacteria; membrane disruption would be involved, but the mechanism remains unknown. In this study, a spectrophotometric method using the mutant Escherichia coli ML-35p has been adapted to investigate membrane disruption by lysozyme for long durations. Lysozyme rapidly increases the permeability of the outer membrane of E. coli due to large size pore formation. A direct delayed activity of lysozyme against the inner membrane is also demonstrated, but without evidence of perforations. PMID- 24047288 TI - Isolated forearm - or isolated brain? Interpreting responses during anaesthesia - or 'dysanaesthesia'. PMID- 24047289 TI - The ability of bispectral index to detect intra-operative wakefulness during isoflurane/air anaesthesia, compared with the isolated forearm technique. AB - Clinical signs are unreliable for guiding anaesthetic administration and it is suggested that using the bispectral index can improve anaesthetic delivery. In the current study, isoflurane administration was guided to a bispectral index range of 55-60. Intra-operative responsiveness, as assessed by the isolated forearm technique, was compared with whether the bispectral index predicted/identified a patient's appropriate hand movements in response to commands. Thirty-four women underwent major gynaecological surgery with isoflurane/air and atracurium. Eleven women responded on 32 occasions with appropriate hand movements to commands given during surgery, of which the bispectral index detected 17 (sensitivity 53%). The bispectral index suggested consciousness 660 times in the absence of any movement responses (specificity 69%). The positive predictive value of the bispectral index was 3%. The median (IQR [range]) bispectral index value associated with an intra-operative response was significantly lower than that associated with eye opening after surgery: 60 (50-68 [36-83]) vs 77 (75-84 [59-90]), respectively (p = 2.25 * 10(-8)). Conversely, end-tidal isoflurane concentration was significantly higher at intra operative response than at eye opening: 0.3 (0.3-0.4 [0.2-0.9]) vs 0.2 (0.1-0.2 [0.1-0.3]), respectively (p = 7.36 * 10(-8)). For patients who responded more than once during surgery, the bispectral index value associated with a response was not constant. No patient had recall for surgery or the taped commands, and only one could remember dreaming (a good dream). Titrating isoflurane to target a bispectral index range of 55-60 may result in an unacceptable number of patients who are conscious during surgery (albeit without recall). PMID- 24047290 TI - Dental injury after conventional direct laryngoscopy: a prospective observational study. AB - This observational study assessed the frequency and risk factors of dental damage after classic direct laryngoscopy for tracheal intubation in 536 adult patients. The patients' sex, age, height, weight, dental condition, dental mobility, Mallampati class, interincisor gap, thyromental distance, neck circumference, and head and neck extension were recorded. From anaesthesia records, the difficulty of intubation, the number of attempts, type of neuromuscular blocking agent used and duration of anaesthesia were recorded. After anaesthesia, examination revealed that 134 patients (25.0%) had dental damage affecting 162 teeth (147 maxillary; 15 mandibular). Enamel fracture was the commonest injury. In tooth number 21, the interincisor gap (OR 2.5 (95% CI 1.0-5.9)) and in tooth number 22, the number of intubation attempts (OR 5.3 (95% CI 1.3-22.0)) were considered a risk factor for dental injury. Conventional direct laryngoscopy is associated with a strikingly high incidence of dental damage, although specific risk factors remain unclear. PMID- 24047291 TI - Cogito, ergo thumb. PMID- 24047292 TI - Oesophageal Doppler monitoring - the emperor's new clothes? PMID- 24047293 TI - Yes, what about prions? PMID- 24047294 TI - Oesophageal Doppler monitoring: maintaining equipoise. PMID- 24047295 TI - What about prions? PMID- 24047296 TI - Ultrasound-guided out-of-plane obturator nerve block. PMID- 24047297 TI - Ultrasound-guided retrograde intubation. PMID- 24047298 TI - Ultrasound-guided digital sympathectomy using botulinum toxin. PMID- 24047299 TI - Falsely low arterial blood pressure due to transducer slippage. PMID- 24047300 TI - Reverse labelling of a nasogastric tube. PMID- 24047301 TI - Checking the secondary oxygen supply. PMID- 24047302 TI - Cardiopulmonary resuscitation in the pregnant patient. PMID- 24047303 TI - Military experience of human factors in airway complications. PMID- 24047304 TI - Vapour pressure and boiling. PMID- 24047305 TI - Opioids and glottis closure. PMID- 24047306 TI - Bispectral index changes during generalised tonic-clonic seizures. PMID- 24047307 TI - Transient paralysis after cyclizine administration. PMID- 24047308 TI - Patient information sheet for plasma cholinesterase deficiency. PMID- 24047312 TI - Association of chronic kidney disease (CKD) and failure to monitor renal function with adverse outcomes in people with diabetes: a primary care cohort study. AB - BACKGROUND: Chronic kidney disease (CKD) is a known risk factor for cardiovascular events and all-cause mortality. We investigate the relationship between CKD stage, proteinuria, hypertension and these adverse outcomes in the people with diabetes. We also study the outcomes of people who did not have monitoring of renal function. METHODS: A cohort of people with type 1 and 2 diabetes (N = 35,502) from the Quality Improvement in Chronic Kidney Disease (QICKD) cluster randomised trial was followed up over 2.5 years. A composite of all-cause mortality, cardiovascular events, and end stage renal failure comprised the outcome measure. A multilevel logistic regression model was used to determine correlates with this outcome. Known cardiovascular and renal risk factors were adjusted for. RESULTS: Proteinuria and reduced estimated glomerular filtration rate (eGFR) were independently associated with adverse outcomes in people with diabetes. People with an eGFR < 60 ml/min, proteinuria, and hypertension have the greatest odds ratio (OR) of adverse outcome; 1.58 (95% CI 1.36-1.83). Renal function was not monitored in 4460 (12.6%) people. Unmonitored renal function was associated with adverse events; OR 1.35 (95% CI 1.13-1.63) in people with hypertension and OR 1.32 (95% CI 1.07-1.64) in those without. CONCLUSIONS: Proteinuria, eGFR < 60 ml/min, and failure to monitor renal function are associated with cardiovascular and renal events and mortality in people with diabetes. PMID- 24047313 TI - Histologic chorioamnionitis: different histologic features at different gestational ages. AB - OBJECTIVE: The aim of this study was to investigate the rate of the different histological chorioamnionitis (HCA) grade in relation to the gestational age in term and preterm delivery. METHODS: Three hundred and ninety-two women with singleton pregnancy with spontaneous onset of labor either prematurely or at term, with histologic diagnosis of HCA, were enrolled. Placentas were classified as: deciduitis and/or histologic chorioamnionitis within the membranes (HCA1); amnionitis or inflammation of the chorionic plate without funisitis (HCA2); and histologic chorioamnionitis with funisitis (HCA3). Microbiological culture was performed on both placental and fetal membrane samples. RESULTS: HCA1 was more frequent in women delivering at term than in preterm (p < 0.001). HCA2 was more represented in women delivering between 32 and 36 weeks (p < 0.001) and HCA3 occurred more frequently in those delivering within 32 weeks (p < 0.001). The positive bacterial culture was higher (p = 0.008) in presence of HCA3 in comparison with HCA1 and HCA2. CONCLUSIONS: This study showed a significantly different distribution of HCA grades in relation to gestational age at delivery. HCA may represent the expression of different subtending etiologies and may also reflect specific immune competence of gestational tissues at different gestational ages, strengthening as pregnancy advances. PMID- 24047314 TI - Pet ownership may attenuate loneliness among older adult primary care patients who live alone. AB - OBJECTIVES: Older adults who report feelings of loneliness are at increased risk for a range of negative physical and mental health outcomes, including early mortality. Identifying potential sources of social connectedness, such as pet ownership, could add to the understanding of how to promote health and well-being in older adults. The aim of this study is to describe the association of pet ownership and loneliness. METHOD: The current study utilizes cross-sectional survey data from a sample (N = 830) of older adult primary care patients (age >= 60 years). RESULTS: Pet owners were 36% less likely than non-pet owners to report loneliness, in a model controlling for age, living status (i.e., alone vs. not alone), happy mood, and seasonal residency (adjOR = 0.64, 95% CI = 0.41-0.98, p < 0.05). An interaction was found between pet ownership and living status (b = 1.60, p < 0.001) in which living alone and not owning a pet was associated with the greatest odds of reporting feelings of loneliness. CONCLUSION: The findings suggest that pet ownership may confer benefits for well-being, including attenuating feelings of loneliness and its related sequelae, among older adults who live alone. PMID- 24047315 TI - TV programs that denounce unfair advantage impact women's sensitivity to defection in the public goods game. AB - We explore the neural underpinnings of gender differences in cooperation and their modulation by intensive media watching. We compared cooperative decisions and electroencephalograph data between genders from who participated in repeated rounds of the public goods game (PGG) and investigated within groups changes that occurred after watching a TV program known as "investigative reporting" that denounces unfair advantages taken by free-riders against the public. Women tended to be more cooperative than men during early rounds of PGG, mostly because they react differently to the defection of others; women also had greater beta and gamma band activity in regions estimated to be associated with social cognition. These gender differences disappeared after participants watched the TV programs: women were more likely to choose free-riding in response to the defection of others that elicits significant increases in gamma band activities that were estimated to be right insula. Greater activity in social cognition leads women to make decisions considering the motives of others, while men tend to make a decision by complying with the social norm. Watching the investigative TV reports produced a greater negative emotion to the defection and led women, in a similar manner as men, to opt for a "tit-for-tat" strategy. PMID- 24047316 TI - Stress, appraisal and work routine in wartime: do men and women differ? AB - Past research has devoted little attention to the role of work routine (i.e., adherence to a consistent pattern of attending work in a regular, predictable manner) in civilians' lives during wartime. The current study offers competing theoretical arguments on how work routine and gender combine to moderate the association between primary appraisal and war-related stress among civilians during the second Lebanon war (July-August 2006). Data were collected using telephone interviews (based on a structured questionnaire) with 2072 civilians. The sample was obtained using a within-strata random-sampling method. Our results suggest that negative affect (a symptom of stress) is associated with more negative primary appraisal of the war situation (i.e., higher threat appraisal). The association between negative affect and appraisal was attenuated among individuals engaging in regular work routine and among men. Moreover, the positive relationship between work routine and appraisal was stronger among women than among men. This study provides insight into the role of the workplace in the lives of civilians exposed to continuing in unsafe situations. In light of the past research suggesting that women are more vulnerable to war-related stress than men, this study proposes that regular work routine may be particularly beneficial for women. PMID- 24047318 TI - Complete classification of the macroscopic behavior of a heterogeneous network of theta neurons. AB - We design and analyze the dynamics of a large network of theta neurons, which are idealized type I neurons. The network is heterogeneous in that it includes both inherently spiking and excitable neurons. The coupling is global, via pulselike synapses of adjustable sharpness. Using recently developed analytical methods, we identify all possible asymptotic states that can be exhibited by a mean field variable that captures the network's macroscopic state. These consist of two equilibrium states that reflect partial synchronization in the network and a limit cycle state in which the degree of network synchronization oscillates in time. Our approach also permits a complete bifurcation analysis, which we carry out with respect to parameters that capture the degree of excitability of the neurons, the heterogeneity in the population, and the coupling strength (which can be excitatory or inhibitory). We find that the network typically tends toward the two macroscopic equilibrium states when the neuron's intrinsic dynamics and the network interactions reinforce one another. In contrast, the limit cycle state, bifurcations, and multistability tend to occur when there is competition among these network features. Finally, we show that our results are exhibited by finite network realizations of reasonable size. PMID- 24047319 TI - Bayesian sparse partial least squares. AB - Partial least squares (PLS) is a class of methods that makes use of a set of latent or unobserved variables to model the relation between (typically) two sets of input and output variables, respectively. Several flavors, depending on how the latent variables or components are computed, have been developed over the last years. In this letter, we propose a Bayesian formulation of PLS along with some extensions. In a nutshell, we provide sparsity at the input space level and an automatic estimation of the optimal number of latent components. We follow the variational approach to infer the parameter distributions. We have successfully tested the proposed methods on a synthetic data benchmark and on electrocorticogram data associated with several motor outputs in monkeys. PMID- 24047317 TI - Immune adaptor ADAP in T cells regulates HIV-1 transcription and cell-cell viral spread via different co-receptors. AB - BACKGROUND: Immune cell adaptor protein ADAP (adhesion and degranulation promoting adaptor protein) mediates aspects of T-cell adhesion and proliferation. Despite this, a connection between ADAP and infection by the HIV-1 (human immunodeficiency virus-1) has not been explored. RESULTS: In this paper, we show for the first time that ADAP and its binding to SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) regulate HIV-1 infection via two distinct mechanisms and co-receptors. siRNA down-regulation of ADAP, or expression of a mutant that is defective in associating to its binding partner SLP-76 (termed M12), inhibited the propagation of HIV-1 in T-cell lines and primary human T-cells. In one step, ADAP and its binding to SLP-76 were needed for the activation of NF-kappaB and its transcription of the HIV-1 long terminal repeat (LTR) in cooperation with ligation of co-receptor CD28, but not LFA-1. In a second step, the ADAP-SLP-76 module cooperated with LFA-1 to regulate conjugate formation between T-cells and dendritic cells or other T-cells as well as the development of the virological synapse (VS) and viral spread between immune cells. CONCLUSIONS: These findings indicate that ADAP regulates two steps of HIV-1 infection cooperatively with two distinct receptors, and as such, serves as a new potential target in the blockade of HIV-1 infection. PMID- 24047320 TI - Deficient GABAergic gliotransmission may cause broader sensory tuning in schizophrenia. AB - We examined how the depression of intracortical inhibition due to a reduction in ambient GABA concentration impairs perceptual information processing in schizophrenia. A neural network model with a gliotransmission-mediated ambient GABA regulatory mechanism was simulated. In the network, interneuron-to-glial cell and principal-cell-to-glial-cell synaptic contacts were made. The former hyperpolarized glial cells and let their transporters import (remove) GABA from the extracellular space, thereby lowering ambient GABA concentration, reducing extrasynaptic GABAa receptor-mediated tonic inhibitory current, and thus exciting principal cells. In contrast, the latter depolarized the glial cells and let the transporters export GABA into the extracellular space, thereby elevating the ambient GABA concentration and thus inhibiting the principal cells. A reduction in ambient GABA concentration was assumed for a schizophrenia network. Multiple dynamic cell assemblies were organized as sensory feature columns. Each cell assembly responded to one specific feature stimulus. The tuning performance of the network to an applied feature stimulus was evaluated in relation to the level of ambient GABA. Transporter-deficient glial cells caused a deficit in GABAergic gliotransmission and reduced ambient GABA concentration, which markedly deteriorated the tuning performance of the network, broadening the sensory tuning. Interestingly, the GABAergic gliotransmission mechanism could regulate local ambient GABA levels: it augmented ambient GABA around stimulus-irrelevant principal cells, while reducing ambient GABA around stimulus-relevant principal cells, thereby ensuring their selective responsiveness to the applied stimulus. We suggest that a deficit in GABAergic gliotransmission may cause a reduction in ambient GABA concentration, leading to a broadening of sensory tuning in schizophrenia. The GABAergic gliotransmission mechanism proposed here may have an important role in the regulation of local ambient GABA levels, thereby improving the sensory tuning performance of the cortex. PMID- 24047321 TI - Speech emotional features extraction based on electroglottograph. AB - This study proposes two classes of speech emotional features extracted from electroglottography (EGG) and speech signal. The power-law distribution coefficients (PLDC) of voiced segments duration, pitch rise duration, and pitch down duration are obtained to reflect the information of vocal folds excitation. The real discrete cosine transform coefficients of the normalized spectrum of EGG and speech signal are calculated to reflect the information of vocal tract modulation. Two experiments are carried out. One is of proposed features and traditional features based on sequential forward floating search and sequential backward floating search. The other is the comparative emotion recognition based on support vector machine. The results show that proposed features are better than those commonly used in the case of speaker-independent and content independent speech emotion recognition. PMID- 24047322 TI - Supervised spike-timing-dependent plasticity: a spatiotemporal neuronal learning rule for function approximation and decisions. AB - How can an animal learn from experience? How can it train sensors, such as the auditory or tactile system, based on other sensory input such as the visual system? Supervised spike-timing-dependent plasticity (supervised STDP) is a possible answer. Supervised STDP trains one modality using input from another one as "supervisor." Quite complex time-dependent relationships between the senses can be learned. Here we prove that under very general conditions, supervised STDP converges to a stable configuration of synaptic weights leading to a reconstruction of primary sensory input. PMID- 24047323 TI - Reinforcement learning of two-joint virtual arm reaching in a computer model of sensorimotor cortex. AB - Neocortical mechanisms of learning sensorimotor control involve a complex series of interactions at multiple levels, from synaptic mechanisms to cellular dynamics to network connectomics. We developed a model of sensory and motor neocortex consisting of 704 spiking model neurons. Sensory and motor populations included excitatory cells and two types of interneurons. Neurons were interconnected with AMPA/NMDA and GABAA synapses. We trained our model using spike-timing-dependent reinforcement learning to control a two-joint virtual arm to reach to a fixed target. For each of 125 trained networks, we used 200 training sessions, each involving 15 s reaches to the target from 16 starting positions. Learning altered network dynamics, with enhancements to neuronal synchrony and behaviorally relevant information flow between neurons. After learning, networks demonstrated retention of behaviorally relevant memories by using proprioceptive information to perform reach-to-target from multiple starting positions. Networks dynamically controlled which joint rotations to use to reach a target, depending on current arm position. Learning-dependent network reorganization was evident in both sensory and motor populations: learned synaptic weights showed target-specific patterning optimized for particular reach movements. Our model embodies an integrative hypothesis of sensorimotor cortical learning that could be used to interpret future electrophysiological data recorded in vivo from sensorimotor learning experiments. We used our model to make the following predictions: learning enhances synchrony in neuronal populations and behaviorally relevant information flow across neuronal populations, enhanced sensory processing aids task-relevant motor performance and the relative ease of a particular movement in vivo depends on the amount of sensory information required to complete the movement. PMID- 24047324 TI - Dynamical regimes in neural network models of matching behavior. AB - The matching law constitutes a quantitative description of choice behavior that is often observed in foraging tasks. According to the matching law, organisms distribute their behavior across available response alternatives in the same proportion that reinforcers are distributed across those alternatives. Recently a few biophysically plausible neural network models have been proposed to explain the matching behavior observed in the experiments. Here we study systematically the learning dynamics of these networks while performing a matching task on the concurrent variable interval (VI) schedule. We found that the model neural network can operate in one of three qualitatively different regimes depending on the parameters that characterize the synaptic dynamics and the reward schedule: (1) a matching behavior regime, in which the probability of choosing an option is roughly proportional to the baiting fractional probability of that option; (2) a perseverative regime, in which the network tends to make always the same decision; and (3) a tristable regime, in which the network can either perseverate or choose the two targets randomly approximately with the same probability. Different parameters of the synaptic dynamics lead to different types of deviations from the matching law, some of which have been observed experimentally. We show that the performance of the network depends on the number of stable states of each synapse and that bistable synapses perform close to optimal when the proper learning rate is chosen. Because our model provides a link between synaptic dynamics and qualitatively different behaviors, this work provides us with insight into the effects of neuromodulators on adaptive behaviors and psychiatric disorders. PMID- 24047325 TI - Some remarks on "almost periodic dynamics of a class of delayed neural networks with discontinuous activations". PMID- 24047326 TI - Fulminant hepatic failure necessitating transplantation following the initiation of infliximab therapy: a cautionary tale times two. PMID- 24047327 TI - Solution-based stoichiometric control over charge transport in nanocrystalline CdSe devices. AB - Using colloidal CdSe nanowire (NW) field-effect transistors (FETs), we demonstrated the dependence of carrier transport on surface stoichiometry by chemically manipulating the atomic composition of the NW surface. A mild, room temperature, wet-chemical process was devised to introduce cadmium, selenium, or sulfur adatoms at the surface of the NWs in completed devices. Changes in surface composition were tested for by energy dispersive spectroscopy and inductively coupled plasma-atomic emission spectroscopy and through the use of the vibrational reporter thiocyanate. We found that treatment with cadmium acetate enhances electron currents, while treatment with sodium selenide or sodium sulfide suppressed them. The efficacy of doping CdSe NWs through subsequent thermal diffusion of indium was highly dependent on the surface composition. While selenium-enriched CdSe NW FETs were characterized by little to no electron currents, when combined with indium, they yielded semimetallic devices. Sulfur enriched, indium-doped devices also displayed dramatically enhanced electron currents, but to a lesser extent than selenium and formed FETs with desirable ION/IOFF >10(6). The atomic specificity of the electronic behavior with different surface chalcogens suggested indium was bound to chalcogens at the NW surface, indicating commonalities with and implications for indium-containing CdSe nanocrystal films. Low temperature measurements of indium-doped CdSe NW FETs showed no evidence of impurity scattering, further supporting the existence of an indium-chalcogen interaction at the surface rather than in the core of the NW. PMID- 24047328 TI - Public health reasoning: much more than deduction. AB - The deductive paradigm has produced notable successes in epidemiology and public health. But while deductive logic has made a substantial contribution to the public health field, it must be recognized that there are also limits to that contribution. This report examines one such limit: the need for non-deductive models in public health reasoning. The findings of a study of public health reasoning in 879 members of the public are reported. Four non-deductive strategies were chosen for their capacity to bridge gaps in one's knowledge. It emerged that subjects were adept at using these strategies in the absence of knowledge to arrive at judgements about public health problems. The implications of this finding for public health communication are discussed. PMID- 24047329 TI - Modeling the impact of prevention policies on future diabetes prevalence in the United States: 2010-2030. AB - BACKGROUND: Although diabetes is one of the most costly and rapidly increasing serious chronic diseases worldwide, the optimal mix of strategies to reduce diabetes prevalence has not been determined. METHODS: Using a dynamic model that incorporates national data on diabetes prevalence and incidence, migration, mortality rates, and intervention effectiveness, we project the effect of five hypothetical prevention policies on future US diabetes rates through 2030: 1) no diabetes prevention strategy; 2) a "high-risk" strategy, wherein adults with both impaired fasting glucose (IFG) (fasting plasma glucose of 100-124 mg/dl) and impaired glucose tolerance (IGT) (2-hour post-load glucose of 141-199 mg/dl) receive structured lifestyle intervention; 3) a "moderate-risk" strategy, wherein only adults with IFG are offered structured lifestyle intervention; 4) a "population-wide" strategy, in which the entire population is exposed to broad risk reduction policies; and 5) a "combined" strategy, involving both the moderate-risk and population-wide strategies. We assumed that the moderate- and high-risk strategies reduce the annual diabetes incidence rate in the targeted subpopulations by 12.5% through 2030 and that the population-wide approach would reduce the projected annual diabetes incidence rate by 2% in the entire US population. RESULTS: We project that by the year 2030, the combined strategy would prevent 4.6 million incident cases and 3.6 million prevalent cases, attenuating the increase in diabetes prevalence by 14%. The moderate-risk approach is projected to prevent 4.0 million incident cases, 3.1 million prevalent cases, attenuating the increase in prevalence by 12%. The high-risk and population approaches attenuate the projected prevalence increases by 5% and 3%, respectively. Even if the most effective strategy is implemented (the combined strategy), our projections indicate that the diabetes prevalence rate would increase by about 65% over the 23 years (i.e., from 12.9% in 2010 to 21.3% in 2030). CONCLUSIONS: While implementation of appropriate diabetes prevention strategies may slow the rate of increase of the prevalence of diabetes among US adults through 2030, the US diabetes prevalence rate is likely to increase dramatically over the next 20 years. Demand for health care services for people with diabetes complications and diabetes-related disability will continue to grow, and these services will need to be strengthened along with primary diabetes prevention efforts. PMID- 24047330 TI - Higher extracellular fluid volume in women is concealed by scaling to body surface area. AB - OBJECTIVE: The objective was to assess body surface area (BSA) for scaling extracellular fluid volume (ECV) in comparison with estimated lean body mass (LBM) and total body water (TBW) across a range of body mass indices (BMI). METHODS: This was a multi-centre study from 15 centres that submitted raw data from routine measurement of GFR in potential kidney transplant donors. There were 819 men and 1059 women in total. ECV was calculated from slope-intercept and slope-only measurements of GFR. ECV was scaled using two methods: Firstly, division of ECV by the scaling variable (ratio method), and secondly the regression method of Turner and Reilly. Subjects were placed into five BMI groups: < 20, 20-24.9, 25-29.9, 30-34.9, and 35 + kg/m(2). LBM and TBW were estimated from previously published, gender-specific prediction equations. RESULTS: Ratio and regression scaling gave almost identical results. ECV scaled to BSA by either method was higher in men in all BMI groups but ECV scaled to LBM and TBW was higher in women. There was, however, little difference between men and women in respect to ECV per unit weight in any BMI group, even though women have 10% more adipose tissue. The relations between TBW and BSA and between LBM and BSA, but not between LBM and TBW, were different between men and women. CONCLUSION: Lean tissue in women contains more extracellular water than in men, a difference that is obscured by scaling to BSA. The likely problem with BSA is its insensitivity to body composition. PMID- 24047331 TI - Lower hemoglobin with lower ferritin: It is not just a question of anemia. AB - AIM: To study the association between blood hemoglobin concentration (b hemoglobin) and serum ferritin concentration (s-ferritin) in an ambulant patient population without inflammation and with normal kidney function. METHODS: In ambulant, adult patients with normal values of s-CRP and s-creatinine, median b hemoglobin and the fraction with anemia was compared in groups with lower s ferritin from a level of 100 MUg/L. The 10, 50 and 90 percentiles of b-hemoglobin were modelled as functions of s-ferritin using quantile regression. RESULTS: Among 3206 women the entire b-hemoglobin distribution was shifted downwards in patients with s-ferritin less than 20 MUg/L. Accordingly, the median b-hemoglobin was statistically significantly lower and the fraction with anemia was higher. In 1246 men the findings were similar, except that the turning point toward lower b hemoglobin was at a s-ferritin level of 30 MUg/L. CONCLUSIONS: Low s-ferritin is associated with decreased b-hemoglobin in many more subjects than those labelled anemic. PMID- 24047332 TI - New monoclinic phase at the composition Cu2SnSe3 and its thermoelectric properties. AB - A new monoclinic phase (m2) of ternary diamond-like compound Cu2SnSe3 was synthesized by reaction of the elements at 850 K. The crystal structure of m2 Cu2SnSe3 was determined through electron diffraction tomography and refined by full-profile techniques using synchrotron X-ray powder diffraction data (space group Cc, a = 6.9714(2) A, b = 12.0787(5) A, c = 13.3935(5) A, beta = 99.865(5) degrees , Z = 8). Thermal analysis and annealing experiments suggest that m2 Cu2SnSe3 is a low-temperature phase, while the high-temperature phase has a cubic crystal structure. According to quantum chemical calculations, m2-Cu2SnSe3 is a narrow-gap semiconductor. A study of the chemical bonding, applying the electron localizability approach, reveals covalent polar Cu-Se and Sn-Se interactions in the crystal structure. Thermoelectric properties were measured on a specimen consolidated using spark plasma sintering (SPS), confirming the semiconducting character. The thermoelectric figure of merit ZT reaches a maximum value of 0.33 at 650 K. PMID- 24047333 TI - Palladium-catalyzed beta-arylation of silyl ketene acetals and application to the synthesis of benzo-fused delta-lactones. AB - Silyl ketene acetals are shown to be competent nucleophiles in Pd-catalyzed migrative C(sp(3))-H arylations. Compared to the parent ester lithium enolates, they possess decreased reactivity but enhanced chemoselectivity. This behavior was exploited through the synthesis of valuable benzo-fused delta-lactones such as 1-isochromanones and dihydrocoumarins. PMID- 24047335 TI - Blood pressure measurements, blood pressure variability and endothelial function in renal transplant recipients. AB - BACKGROUND/AIMS: Hypertension is an important cardiovascular risk factor in renal transplant recipients. Elevated blood pressure variability (BPV) during 24-h ambulatory blood pressure monitoring (ABPM) is associated with increased risk of target organ damage and cardiovascular events, independent of mean blood pressure levels. We aimed to evaluate the relationship between endothelial function, blood pressure levels obtained by various measurement methods, and BPV in renal transplant recipients. METHODS: In total, 73 hypertensive renal transplant recipients were included in the study. Office blood pressure measurements, central blood pressure measurements, home blood pressure measurements and 24-h ABPM were obtained from the subjects. BPV was calculated using the average real variability index. All patients underwent brachial flow-mediated vasodilatation tests. Predictive values of blood pressures obtained by different measurement techniques and BPV on endothelial functions were investigated. RESULTS: Endothelial dysfunction was present in 68.5% of the patients. No difference was found between the group with and without endothelial dysfunction with regard to office systolic or diastolic blood pressure, central blood pressure or home systolic blood pressure. In the group with endothelial dysfunction, 24-h ambulatory systolic blood pressure and night-time ambulatory systolic blood pressure were higher. In patients with endothelial dysfunction, the 24-h systolic, diastolic and mean BPV were all higher. There was also a negative correlation between the percentage of flow-mediated vasodilatation with 24-h mean and systolic BPV. CONCLUSION: Patients with endothelial dysfunction had significantly higher ambulatory blood pressure values and higher BPV. There was a significant negative correlation between endothelial function and BPV. PMID- 24047336 TI - Diagnosis and subtyping of de novo and relapsed mediastinal lymphomas by endobronchial ultrasound needle aspiration. AB - RATIONALE: The current management of lymphoma requires accurate diagnosis and subtyping of de novo lymphoma and of relapsed or refractory lymphoma in known cases. The role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the clinical management of lymphomas is unclear. OBJECTIVES: To investigate the use of EBUS-TBNA in the diagnosis of de novo and relapsed mediastinal lymphomas. METHODS: A total of 2,256 consecutive patients who underwent EBUS-TBNA in a tertiary center between February 2008 and April 2013 were prospectively evaluated. The diagnostic accuracy and clinical use of EBUS TBNA in 100 cases of de novo or suspected relapsed mediastinal lymphoma was investigated by comparing EBUS-TBNA diagnosis with the final diagnosis. MEASUREMENTS AND MAIN RESULTS: De novo mediastinal lymphoma was correctly diagnosed by EBUS-TBNA in 45 (88%) of 51 and relapsed lymphoma in 15 (100%) of 15 lymphoma cases. EBUS-TBNA accurately established a diagnosis other than lymphoma in 32 (97%) of 33 patients with suspected lymphoma relapse. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBUS-TBNA in the diagnosis of mediastinal lymphoma were 89%, 97%, 98%, 83%, and 91%, respectively. Sensitivity of EBUS-TBNA in subtyping lymphomas into high grade non-Hodgkin lymphoma, low-grade non-Hodgkin lymphoma, and Hodgkin lymphoma was 90%, 100%, and 79%, respectively. EBUS-TBNA diagnosis was adequate for clinical management in 84 (84%) of 100 cases. CONCLUSIONS: Multimodality evaluation of EBUS-TBNA can be successful in the diagnosis of de novo mediastinal lymphomas and is ideally suited in distinguishing lymphoma relapse from alternative pathologies; it is least sensitive in subtyping Hodgkin lymphoma. PMID- 24047337 TI - Stability of FDG-PET Radiomics features: an integrated analysis of test-retest and inter-observer variability. AB - PURPOSE: Besides basic measurements as maximum standardized uptake value (SUV)max or SUVmean derived from 18F-FDG positron emission tomography (PET) scans, more advanced quantitative imaging features (i.e. "Radiomics" features) are increasingly investigated for treatment monitoring, outcome prediction, or as potential biomarkers. With these prospected applications of Radiomics features, it is a requisite that they provide robust and reliable measurements. The aim of our study was therefore to perform an integrated stability analysis of a large number of PET-derived features in non-small cell lung carcinoma (NSCLC), based on both a test-retest and an inter-observer setup. METHODS: Eleven NSCLC patients were included in the test-retest cohort. Patients underwent repeated PET imaging within a one day interval, before any treatment was delivered. Lesions were delineated by applying a threshold of 50% of the maximum uptake value within the tumor. Twenty-three NSCLC patients were included in the inter-observer cohort. Patients underwent a diagnostic whole body PET-computed tomography (CT). Lesions were manually delineated based on fused PET-CT, using a standardized clinical delineation protocol. Delineation was performed independently by five observers, blinded to each other. Fifteen first order statistics, 39 descriptors of intensity volume histograms, eight geometric features and 44 textural features were extracted. For every feature, test-retest and inter-observer stability was assessed with the intra-class correlation coefficient (ICC) and the coefficient of variability, normalized to mean and range. Similarity between test-retest and inter-observer stability rankings of features was assessed with Spearman's rank correlation coefficient. RESULTS: Results showed that the majority of assessed features had both a high test-retest (71%) and inter-observer (91%) stability in terms of their ICC. Overall, features more stable in repeated PET imaging were also found to be more robust against inter-observer variability. CONCLUSION: Results suggest that further research of quantitative imaging features is warranted with respect to more advanced applications of PET imaging as being used for treatment monitoring, outcome prediction or imaging biomarkers. PMID- 24047338 TI - Prognostic value of metabolic metrics extracted from baseline positron emission tomography images in non-small cell lung cancer. AB - BACKGROUND: Maximum, mean and peak SUV of primary tumor at baseline FDG-PET scans, have often been found predictive for overall survival in non-small cell lung cancer (NSCLC) patients. In this study we further investigated the prognostic power of advanced metabolic metrics derived from intensity volume histograms (IVH) extracted from PET imaging. METHODS: A cohort of 220 NSCLC patients (mean age, 66.6 years; 149 men, 71 women), stages I-IIIB, treated with radiotherapy with curative intent were included (NCT00522639). Each patient underwent standardized pre-treatment CT-PET imaging. Primary GTV was delineated by an experienced radiation oncologist on CT-PET images. Common PET descriptors such as maximum, mean and peak SUV, and metabolic tumor volume (MTV) were quantified. Advanced descriptors of metabolic activity were quantified by IVH. These comprised five groups of features: absolute and relative volume above relative intensity threshold (AVRI and RVRI), absolute and relative volume above absolute intensity threshold (AVAI and RVAI), and absolute intensity above relative volume threshold (AIRV). MTV was derived from the IVH curves for volumes with SUV above 2.5, 3 and 4, and of 40% and 50% maximum SUV. Univariable analysis using Cox Proportional Hazard Regression was performed for overall survival assessment. RESULTS: Relative volume above higher SUV (80%) was an independent predictor of OS (p = 0.05). None of the possible surrogates for MTV based on volumes above SUV of 3, 40% and 50% of maximum SUV showed significant associations with OS [p (AVAI3) = 0.10, p (AVAI4) = 0.22, p (AVRI40%) = 0.15, p (AVRI50%) = 0.17]. Maximum and peak SUV (r = 0.99) revealed no prognostic value for OS [p (maximum SUV) = 0.20, p (peak SUV) = 0.22]. CONCLUSIONS: New methods using more advanced imaging features extracted from PET were analyzed. Best prognostic value for OS of NSCLC patients was found for relative portions of the tumor above higher uptakes (80% SUV). PMID- 24047339 TI - Factors associated with acute and late dysphagia in the DAHANCA 6 & 7 randomized trial with accelerated radiotherapy for head and neck cancer. AB - BACKGROUND: Dysphagia is a common and debilitating side effect in head and neck radiotherapy (RT). Prognostic factors are numerous and their interrelationship not well understood. The aim of this study was to establish a multivariate prognostic model for acute and late dysphagia after RT, based on information from a prospective trial. MATERIAL AND METHODS: The DAHANCA 6&7 randomized study included 1476 patients with head and neck cancer eligible for primary RT alone. Patients were randomized between 5 and 6 weekly fractions of conventional RT, and received 62-70 Gy in 31-35 fractions. Patients were scored for dysphagia weekly during treatment and at regular intervals until five years after treatment. Dysphagia scores were available from 1461 patients. RESULTS: Acute dysphagia according to DAHANCA grades 1, 2, 3 and 4 occurred in 83%, 71%, 43% and 23%, respectively. Severe dysphagia occurred in 47% and 38% of patients receiving accelerated or conventional radiotherapy, respectively (p = 0.001). At one, two, three, four and five years the prevalence of chronic dysphagia above grade 0, was 46%, 32%, 29%, 24%, 23%, respectively with no difference between 5 and 6 fractions. In multivariate analysis, the following parameters were independent factors for severe acute dysphagia: T3-T4 tumors, N-positive disease, non-glottic cancer, age> median, baseline dysphagia > 1 and accelerated radiotherapy. The following factors were prognostic factors for late dysphagia: non-glottic cancer, T3-T4, N-positive disease and baseline dysphagia > 1. The data confirmed previously published predictive models, as it was possible to separate patients in groups with low, medium and high risk of dysphagia, respectively, based on pre treatment risk scores. CONCLUSION: Prognostic models were established to characterize patients at risk of developing acute or late dysphagia in the DAHANCA 6&7 trial. The results may be useful to identify patients at risk of dysphagia and thus candidates for prophylactic measures against swallowing dysfunction. PMID- 24047340 TI - The effect on esophagus after different radiotherapy techniques for early stage Hodgkin's lymphoma. AB - INTRODUCTION: The cure rate of early stage Hodgkin's lymphoma (HL) is excellent; investigating the late effects of treatment is thus important. Esophageal toxicity is a known side effect in patients receiving radiotherapy (RT) to the mediastinum, although little is known of this in HL survivors. This study investigates the dose to the esophagus in the treatment of early stage HL using different RT techniques. Estimated risks of early esophagitis, esophageal stricture and cancer are compared between treatments. MATERIAL AND METHODS: We included 46 patients >= 15 years with supradiaphragmatic, clinical stage I-II HL, who received chemotherapy followed by involved node RT (INRT) to 30.6 Gy at our institution. INRT was planned with three-dimensional conformal RT (3DCRT). For each patient a volumetric modulated arc therapy (VMAT), proton therapy (PT) and mantle field (MF) treatment plan was simulated. Mean, maximum and minimum dose to the esophagus were extracted from the treatment plans. Risk estimates were based on dose-response models from clinical series with long-term follow-up. Statistical analyses were performed with repeated measures ANOVA using Bonferroni corrections. RESULTS: Mean dose to the esophagus was 16.4, 16.4, 14.7 and 34.2 Gy (p < 0.001) with 3DCRT, VMAT, PT and MF treatment, respectively. No differences were seen in the estimated risk of developing esophagitis, stricture or cancer with 3DCRT compared to VMAT (p = 1.000, p = 1.000, p = 0.356). PT performed significantly better with the lowest risk estimates on all parameters compared to the photon treatments, except compared to 3DCRT for stricture (p = 0.066). On all parameters the modern techniques were superior to MF treatment (p < 0.001). CONCLUSIONS: The estimated dose to the esophagus and the corresponding estimated risks of esophageal complications are decreased significantly with highly conformal RT compared to MF treatment. The number of patients presenting with late esophageal side effects will, thus, likely be minimal in the future. PMID- 24047341 TI - Deep inspiration breath hold radiotherapy for locally advanced lung cancer: comparison of different treatment techniques on target coverage, lung dose and treatment delivery time. PMID- 24047342 TI - Aromatizing olefin metathesis by ligand isolation inside a metal-organic framework. AB - The aromatizing ring-closing metathesis has been shown to take place inside an extended porous framework. Employing a combination of solvent-assisted linker exchange and postsynthesis modification using olefin metathesis, the noninterpenetrated SALEM-14 was formed and converted catalytically into PAH-MOF-1 with polycyclic aromatic hydrocarbon (PAH) pillars. The metal-organic framework in SALEM-14 prevents "intermolecular" olefin metathesis from occurring between the pillars in the presence of the first generation Hoveyda-Grubbs catalyst, while favoring the production of a PAH, which can be released from the framework under acidic conditions in dimethylsulfoxide. PMID- 24047343 TI - Proteomics approaches advance our understanding of plant self-incompatibility response. AB - Self-incompatibility (SI) in plants is a genetic mechanism that prevents self fertilization and promotes out-crossing needed to maintain genetic diversity. SI has been classified into two broad categories: the gametophytic self incompatibility (GSI) and the sporophytic self-incompatibility (SSI) based on the genetic mechanisms involved in 'self' pollen rejection. Recent proteomic approaches to identify potential candidates involved in SI have shed light onto a number of previously unidentified mechanisms required for SI response. SI proteome research has progressed from the use of isoelectric focusing in early days to the latest third-generation technique of comparative isobaric tag for relative and absolute quantitation (iTRAQ) used in recent times. We will focus on the proteome-based approaches used to study self-incompatibility (GSI and SSI), recent developments in the field of incompatibility research with emphasis on SSI and future prospects of using proteomic approaches to study self-incompatibility. PMID- 24047345 TI - Editorial for the Ultrapath XVI dedicated Ultrastructural Pathology issue. PMID- 24047344 TI - Antibacterial activity of and resistance to small molecule inhibitors of the ClpP peptidase. AB - There is rapidly mounting evidence that intracellular proteases in bacteria are compelling targets for antibacterial drugs. Multiple reports suggest that the human pathogen Mycobacterium tuberculosis and other actinobacteria may be particularly sensitive to small molecules that perturb the activities of self compartmentalized peptidases, which catalyze intracellular protein turnover as components of ATP-dependent proteolytic machines. Here, we report chemical syntheses and evaluations of structurally diverse beta-lactones, which have a privileged structure for selective, suicide inhibition of the self compartmentalized ClpP peptidase. beta-Lactones with certain substituents on the alpha- and beta-carbons were found to be toxic to M. tuberculosis. Using an affinity-labeled analogue of a bioactive beta-lactone in a series of chemical proteomic experiments, we selectively captured the ClpP1P2 peptidase from live cultures of two different actinobacteria that are related to M. tuberculosis. Importantly, we found that the growth inhibitory beta-lactones also inactivate the M. tuberculosis ClpP1P2 peptidase in vitro via formation of a covalent adduct at the ClpP2 catalytic serine. Given the potent antibacterial activity of these compounds and their medicinal potential, we sought to identify innate mechanisms of resistance. Using a genome mining strategy, we identified a genetic determinant of beta-lactone resistance in Streptomyces coelicolor, a non pathogenic relative of M. tuberculosis. Collectively, these findings validate the potential of ClpP inhibition as a strategy in antibacterial drug development and define a mechanism by which bacteria could resist the toxic effects of ClpP inhibitors. PMID- 24047346 TI - What's in a name?-"Lipolysosome": ultrastructural features of a lipid-containing organelle. AB - The prevalence of fatty liver is rising not only in adults but also in children and adolescents. The authors describe the ultrastructure of 12 biopsies from 10 males and 2 females aged 7-18 years. All subjects had fatty liver by ultrasonography and were overweight or obese according to BMI classification. They all had elevated aminotransferases and/or lipid/cholesterol levels, ultimately confirmed by biopsy. Steatosis was mild in 2, moderate in 3, and severe in 7 cases. Nonalcoholic steatohepatitis was diagnosed in 7 and nonalcoholic fatty liver disease in 5 patients. Lipolysosomes, identified in all 12 biopsies, were defined as fat droplets surrounded by a trilaminar membrane and lipofuscin-like deposits within or adjacent to the enveloping membrane. The lysosome marker CD68 revealed lysosomal activity in all lipolysosomes identified by electron microscopy. The ultrastructural features, here illustrated in diverse human biopsies, enabled lipolysosome classification in 3 types: monolocular (type I), multilocular (type II), and giant multilocular (type III). Type II, previously described in some conditions with abnormal lipid metabolism, was found in all biopsies, though with variable frequency. Type III was observed only in severe steatosis and associated with prominent connective tissue and conspicuous lipofuscin deposits. These new findings demonstrate the presence of lipolysosomes in a variety of fatty livers, in conditions hitherto unknown, in relation to the severity of steatosis, fibrogenic process, autophagy, lipolysis, and lipofuscin formation. PMID- 24047348 TI - Experimental respiratory syncytial virus infection of human peribronchial gland cells in vitro. AB - Respiratory syncytial virus (RSV) is a relevant agent of respiratory tract infections, especially in exacerbations of chronic lung diseases. Peribronchial submucosal glands are the main source of tracheobronchial mucus and therefore of major interest. The authors isolated and cultured human peribronchial gland cells and infected them with RSV. The course of infection was monitored by transmission electron, immuno-, and lectin fluorescence microscopy. Morphology shows virus factories with budding particles within cytoplasmatic vacuoles and virus release after 44 h of infection. Experimental infection of human peribronchial gland cells in primary culture appears to be a suitable model in pulmonary research. PMID- 24047347 TI - Formation of gelsolin amyloid fibrils in the rough endoplasmic reticulum of skeletal muscle in the gelsolin mouse model of inclusion body myositis: comparative analysis to human sporadic inclusion body myositis. AB - Sporadic inclusion body myositis has a significant impact on the life of the elderly. Despite some similarities to other myopathies with established genetic defects, little is known about mechanisms of its development and no effective treatment is available. Therefore, there is a need for animal models that can faithfully reconstitute important aspects of this human disease. The authors recently expressed a mutant form of human gelsolin in mice under the control of a muscle-specific promoter. This induced myopathic changes reminiscent of human inclusion body myositis. In this study, immunogold labeling is used to further characterize this model. The study demonstrates a presence of gelsolin amyloid deposits within the rough endoplasmic reticulum. It further compares this mouse model to human sporadic inclusion body myositis. PMID- 24047349 TI - Ultrastructural assessment of the differentiation potential of human multipotent mesenchymal stromal cells. AB - Mesenchymal stromal (stem) cells (MSCs) are defined by plastic adherent growth, multiple phenotype expressions, and tripotential mesodermal capability. The authors report examples where electron microscopy (EM) plays a role in stem cell research. MSCs isolated from human arteries are ultrastructurally heterogeneous and become more homogenous after plastic adhesion. EM shows a moderate complement of organelles, mainly mitochondria, rough endoplasmic reticulum, and glycogen aggregates. Clear vacuoles and vesicles are prominent when cells are recovered from plates using an enzymatic method. Since the mesengenic plasticity is the single most important criterion to define a cell as mesenchymal stromal, the authors induced experimentally adipogenic, leiomyogenic, cardiomyogenic, osteo chondrogenic differentiations. In no case did EM reveal the achievement of complete differentiation. The authors obtained multivacuolated pre-adipocytes and never univacuolated adipocytes typical of mature white fat; myofibroblast and rhabdomyoblast morphotypes, where contractile filaments were not organized to form functional complexes, i.e., dense bodies and sarcomeres. Chondrogenesis and osteogenesis assays resulted in extracellular matrix changes. Collagen and proteoglycan filament/particle deposition was seen when chondrogenesis was promoted. Hydroxyapatite crystals, psammoma bodies, and plaque-like calcified matrix deposits were found in the osteogenic matrix. EM provides detailed structural information on the degree of differentiation induced in stem cells and demonstrates that the methods so far developed are not able to promote complete cell differentiation. These observations contribute to explain why clinical applications with hMSCs have produced results far lower than initial expectations. PMID- 24047350 TI - Ultrastructural myopathology in the molecular era. AB - Electron microscopy is an essential component of myopathology, both in diagnostics and research of neuromuscular diseases. Although recently reduced in the diagnostic armamentarium, it has greatly been expanded to mouse models in research. Mostly it is descriptive, but a few additional techniques in combination with transmission electron microscopy have been employed. Foremost among them is immunoelectron microscopy, which assists in guiding molecular analysis in hereditary conditions, but may be vital in diagnostics of certain acquired entities, e.g., undulating tubules in dermatomyositis and in those congenital myopathies where genes and mutations remain to be identified, as in cylindrical spirals myopathy and hexagonal crystalloid-body myopathy. PMID- 24047351 TI - Ultrastructural characterization of genetic diffuse lung diseases in infants and children: a cohort study and review. AB - Pediatric diffuse lung diseases are rare disorders with an onset in the neonatal period or in infancy, characterized by chronic respiratory symptoms and diffuse interstitial changes on imaging studies. Genetic disorders of surfactant homeostasis represent the main etiology. Surfactant protein B and ABCA3 deficiencies typically cause neonatal respiratory failure, which is often lethal within a few weeks or months. Although heterozygous ABCA3 mutation carriers are mostly asymptomatic, there is growing evidence that monoallelic mutations may affect surfactant homeostasis. Surfactant protein C mutations are dominant or sporadic disorders leading to a broad spectrum of manifestations from neonatal respiratory distress syndrome to adult pulmonary fibrosis. The authors performed pathology and ultrastructural studies in 12 infants who underwent clinical lung biopsy. One carried a heterozygous SP-B mutation, 3 carried SP-C mutations, and 7 carried ABCA3 mutations (5 biallelic and 2 monoallelic). Optical microscopy made it possible to distinguish between surfactant-related disorders and other forms. One of the ABCA3 monoallelic carriers had morphological features of alveolar capillary dysplasia, a genetic disorder of lung alveolar, and vascular development. One patient showed no surfactant-related anomalies but had pulmonary interstitial glycogenosis, a developmental disorder of unknown origin. Electron microscopy revealed specific lamellar bodies anomalies in all SP-B, SP-C, and ABCA3 deficiency cases. In addition, the authors showed that heterozygous ABCA3 mutation carriers have an intermediate ultrastructural phenotype between homozygous carriers and normal subjects. Lung biopsy is an essential diagnostic procedure in unexplained diffuse lung disorders, and electron microscopy should be performed systematically, since it may reveal specific alterations in genetic disorders of surfactant homeostasis. PMID- 24047352 TI - Ultrastructural analysis of neuronal and non-neuronal lysosomal storage in mucolipidosis type II knock-in mice. AB - The GlcNAc-1-phosphotransferase catalyzes the first step in the formation of mannose 6-phosphate (M6P) residues on lysosomal acid hydrolases that is essential for the efficient transport of newly synthesized lysosomal enzymes to lysosomes and the maintenance of lysosomal functions. Mutations in the GlcNAc-1 phosphotransferase cause the lysosomal storage disease mucolipidosis type II (MLII), resulting in mistargeting and hypersecretion of multiple lysosomal hydrolases and subsequent lysosomal accumulation of nondegraded material in several tissues. To describe cell-type specificity, compositional differences, and subcellular distribution of the stored material we performed an in-depth ultrastructural analysis of lysosomal storage in brain and retina of MLII knock in mice using electron microscopy. Massive vacuoles filled with heterogeneous storage material have been found in the soma, swollen axons, and dendrites of Purkinje, and granular cells in 9-month-old MLII mice. In addition, non-neuronal cells, such as microglial, astroglial, and endothelial cells, exhibit storage material. Fucose-specific lectin histochemistry demonstrated the accumulation of fucose-containing oligosaccharides, indicating that targeting of the lysosomal alpha-fucosidase is strongly impaired in all cerebellar cell types. The data suggest that the accumulation of storage material might affect neuronal function and survival in a direct cell-autonomous manner, as well as indirectly by disturbed metabolic homeostasis between glial and neuronal cells or by cerebrovascular complications. PMID- 24047353 TI - Male infertility: assessment of juvenile testicular dysfunction and risk for malignancy in cryptorchid boys based on resin section evaluation. AB - Infertility is sometimes more a man's problem than a woman's, failure of one or both of the testes to descend (cryptorchidism) being the most frequent genital malformation in boys. Untreated, the undescended testis impairs germ cell development and significantly reduces adult fertility. A-dark spermatogonia are the stem cells for all future spermatozoa, and their depletion can be reliably estimated in resin semithin sections. Additionally, there is an increased risk of testicular preneoplasia in the form of carcinoma in situ (CIS) cells. The authors report how the pathologic biopsy examination of juvenile cryptorchid testes can assess infertility and malignancy risk. PMID- 24047354 TI - Effect of ripening, heat processing, and fat type on the micellarization of pigments from jalapeno peppers. AB - Raw and heat-processed (boiled and grilled) jalapeno peppers at three intermediate ripening stages (brown, 50% red, and 75% red) were digested in vitro without fat and in the presence of soybean oil (SO) or beef tallow (BT), and the micellarization of their lipid soluble pigments (LSP) was measured. The micelles from digestions with brown, 50% red, and 75% red peppers contained up to 27, 35, and 29 different LSP, respectively. Boiling and grilling decreased the micellarization of LSP from brown peppers, whereas the opposite was observed with 75% red peppers. Heat processing did not clearly affect the micellarization of LSP from 50% red fruits. The impact of fat on LSP micellarization was ripening dependent, but the micellarization of the less polar carotenoids was always increased by SO or BT. This positive effect of fat was higher with SO than with BT. PMID- 24047355 TI - Measurement of heat and moisture exchanger efficiency. AB - Deciding between a passive heat and moisture exchanger or active humidification depends upon the level of humidification that either will deliver. Published international standards dictate that active humidifiers should deliver a minimum humidity of 33 mg.l(-1); however, no such requirement exists, for heat and moisture exchangers. Anaesthetists instead have to rely on information provided by manufacturers, which may not allow comparison of different devices and their clinical effectiveness. I suggest that measurement of humidification efficiency, being the percentage moisture returned and determined by measuring the temperature of the respired gases, should be mandated, and report a modification of the standard method that will allow this to be easily measured. In this study, different types of heat and moisture exchangers for adults, children and patients with a tracheostomy were tested. Adult and paediatric models lost between 6.5 mg.l(-1) and 8.5 mg.l(-1) moisture (corresponding to an efficiency of around 80%); however, the models designed for patients with a tracheostomy lost between 16 mg.l(-1) and 18 mg.l(-1) (60% efficiency). I propose that all heat and moisture exchangers should be tested in this manner and percentage efficiency reported to allow an informed choice between different types and models. PMID- 24047356 TI - NAP5 and depth of anaesthesia monitoring. PMID- 24047357 TI - Extubation over a bougie in difficult airways: are we missing a trick? PMID- 24047358 TI - Epidural anaesthesia and analgesia for liver resection. PMID- 24047359 TI - Speed of spinal vs general anaesthesia. PMID- 24047360 TI - Accidental underdosing of intrathecal diamorphine. PMID- 24047361 TI - Laryngoscope forces in humans and manikins. PMID- 24047362 TI - Laryngeal reflex responses in anaesthetised children: breach of international research governance. PMID- 24047363 TI - Electrocardiographic changes associated with intra-operative pneumothorax in children. PMID- 24047364 TI - Editor-in-Chief's reply. PMID- 24047365 TI - Residual anaesthesia drugs - silent threat, visible solutions. PMID- 24047366 TI - Unalarmed interruption of continuous drug infusion by Perfusor Space GC syringe pumps. PMID- 24047367 TI - Duration of lidocaine gel for squint surgery. PMID- 24047368 TI - Manufacturer's reply. PMID- 24047369 TI - A reply. PMID- 24047370 TI - Editor-in-Chief's reply. PMID- 24047371 TI - Local anaesthetic nomenclature. PMID- 24047376 TI - Predictive value of non-invasive hemodynamic measurement by means of impedance cardiography in hypertensive subjects older than 50 years of age. AB - The prognostic value of impedance cardiography (ICG; cardiac index [CI] and systemic vascular resistance index [SVRI] were measured) was assessed in this retrospective cohort study. A total of 1151 hypertensive outpatients >50 years with a baseline ICG were included. After median follow-up of 3.9 years, for the composite endpoint of cardiovascular events and stroke, adjusted HR for each 500 ml/min/m(2) CI increase was 0.85 (CI95% 0.73-0.9, p = 0.039), and for each 500 dynes s cm(-5) SVRI increase was 1.11 (CI95% 1.01-1.23, p = 0.046), whereas adjusted HR for all-cause mortality was not significant. ICG adds prognostic value to conventional risk factors in hypertensive patients. PMID- 24047375 TI - Partial loss of Smad signaling during in vitro progression of HPV16-immortalized human keratinocytes. AB - BACKGROUND: Disruption of the transforming growth factor-beta (TGF-beta) signaling pathway is observed in many cancers, including cervical cancer, resulting in TGF-beta resistance. While normal human keratinocytes (HKc) and human papillomavirus type 16-immortalized HKc (HKc/HPV16) are sensitive to the growth inhibitory effects of TGF-beta, HKc/HPV16 develop resistance to TGF-beta1 as they progress in vitro to a differentiation resistant phenotype (HKc/DR). The loss of sensitivity to the antiproliferative effects of TGF-beta1 in HKc/DR is due, at least partially, to decreased expression of the TGF-beta receptor type I. In the present study, we explored in detail whether alterations in Smad protein levels, Smad phosphorylation, or nuclear localization of Smads in response to TGF beta could contribute to the development of TGF-beta resistance during in vitro progression of HKc/HPV16, and whether TGF-beta induction of a Smad-responsive reporter gene was altered in HKc/DR. METHODS: Western blot analysis was used to assess Smad protein levels. In order to study Smad nuclear localization we performed indirect immunofluorescence. In addition, we determined Smad-mediated TGF-beta signaling using a luciferase reporter construct. RESULTS: We did not find a decrease in protein levels of Smad2, Smad3 or Smad4, or an increase in the inhibitory Smad7 that paralleled the loss of sensitivity to the growth inhibitory effects of TGF-beta1 observed in HKc/DR. However, we found diminished Smad2 phosphorylation, and delayed nuclear Smad3 localization in response to TGF-beta1 in HKc/DR, compared to normal HKc and TGF-beta sensitive HKc/HPV16. In addition, we determined that TGF-beta1 induction of a Smad responsive promoter is reduced by about 50% in HKc/DR, compared to HKc/HPV16. CONCLUSIONS: These results demonstrate that alterations in Smad protein levels are not associated with the loss of response to the antiproliferative effects of TGF-beta in HKc/DR, but that diminished and delayed Smad phosphorylation and nuclear localization, and decreased Smad signaling occur in response to TGF-beta in HKc/DR. PMID- 24047377 TI - A dorsal visual route necessary for global form perception: evidence from neuropsychological fMRI. AB - Hierarchical models of visual processing assume that global pattern recognition is contingent on the progressive integration of local elements across larger spatial regions, operating from early through intermediate to higher-level cortical regions. Here, we present results from neuropsychological fMRI that refute such models. We report two patients, one with lesions to intermediate ventral regions and the other with damage around the intraparietal sulcus (IPS). The patient with ventral damage showed normal behavioral and BOLD responses to global Glass patterns. The patient with IPS damage was impaired in discriminating global patterns and showed a lack of significant responses to these patterns in intermediate visual regions spared by the lesion. However, this patient did show BOLD activity to translational patterns, where local element relations are important. These results suggest that activation of intermediate ventral regions is not necessary to code global patterns; instead global patterns are coded in a heterarchical fashion. High-level regions of dorsal cortex are necessary to generate global pattern coding in intermediate ventral regions; in contrast, local integration processes are not sufficient. PMID- 24047378 TI - Recurrent processing enhances visual awareness but is not necessary for fast categorization of natural scenes. AB - Humans are rapid in categorizing natural scenes. Electrophysiological recordings reveal that scenes containing animals can be categorized within 150 msec, which has been interpreted to indicate that feedforward flow of information from V1 to higher visual areas is sufficient for visual categorization. However, recent studies suggest that recurrent interactions between higher and lower levels in the visual hierarchy may also be involved in categorization. To clarify the role of recurrent processing in scene categorization, we recorded EEG and manipulated recurrent processing with object substitution masking while the participants performed a go/no-go animal/nonanimal categorization task. The quality of visual awareness was measured with a perceptual awareness scale after each trial. Masking reduced the clarity of perceptual awareness, slowed down categorization speed for scenes that were not clearly perceived, and reduced the electrophysiological difference elicited by animal and nonanimal scenes after 150 msec. The results imply that recurrent processes enhance the resolution of conscious representations and thus support categorization of stimuli that are difficult to categorize on the basis of the coarse feedforward representations alone. PMID- 24047379 TI - Not lost in translation: generalization of the primary systems hypothesis to Japanese-specific language processes. AB - The emergentist-connectionist approach assumes that language processing reflects interaction between primary neural systems (Primary Systems Hypothesis). This idea offers an overarching framework that generalizes to various kinds of (English) language and nonverbal cognitive activities. The current study advances this approach with respect to language in two new and important ways. The first is the provision of a neuroanatomically constrained implementation of the theory. The second is a test of its ability to generalize to a language other than English (in this case Japanese) and, in particular, to a feature of that language (pitch accent) for which there is no English equivalent. A corpus analysis revealed the presence and distribution of typical and atypical accent forms in Japanese vocabulary, forming a quasiregular domain. Consequently, according to the Primary Systems Hypothesis, there should be a greater semantic impact on the processing of words with an atypical pitch accent. In turn, when word meaning is intrinsically less rich (e.g., abstract words), speakers should be prone to regularization errors of pitch accent. We explored these semantic-phonological interactions, first, in a neuroanatomically constrained, parallel-distributed processing model of spoken language processing. This model captured the accent typicality effect observed in nonword repetition in Japanese adults and children and exhibited the predicted semantic impact on repetition of words with atypical accent patterns. Second, also as predicted, in word repetition and immediate serial recall of spoken words, human participants exhibited reduced pitch-accent accuracy and/or slower RT for low imageability words with atypical accent patterns, and they generated accent errors reflecting the more typical accent patterns found in Japanese. PMID- 24047380 TI - Trade-off between capacity and precision in visuospatial working memory. AB - Limitations in the performance of working memory (WM) tasks have been characterized in terms of the number of items retained (capacity) and in terms of the precision with which the information is retained. The neural mechanisms behind these limitations are still unclear. Here we used a biological constrained computational model to study the capacity and precision of visuospatial WM. The model consists of two connected networks of spiking neurons. One network is responsible for storage of information. The other provides a nonselective excitatory input to the storage network. Simulations showed that this excitation boost could temporarily increase storage capacity but also predicted that this would be associated with a decrease in precision of the memory. This prediction was subsequently tested in a behavioral (38 participants) and fMRI (22 participants) experiment. The behavioral results confirmed the trade-off effect, and the fMRI results suggest that a frontal region might be engaged in the trial by-trial control of WM performance. The average effects were small, but individuals differed in the amount of trade-off, and these differences correlated with the frontal activation. These results support a two-module model of WM where performance is determined both by storage capacity and by top-down influence, which can vary on a trial-by-trial basis, affecting both the capacity and precision of WM. PMID- 24047381 TI - Extensive left temporal pole damage does not impact on theory of mind abilities. AB - The temporal poles (TPs) are among the brain regions that are often considered as the brain network sustaining our ability to understand other people's mental states or "Theory of Mind" (ToM). However, so far the functional role of the left and right TPs in ToM is still debated, and it is even not clear yet whether these regions are necessary for ToM. In this study, we tested whether the left TP is necessary for ToM by assessing the mentalizing abilities of a patient (C.M.) diagnosed with semantic dementia. Converging evidence from detailed MRI and (18)F fluoro-2-deoxy-d-glucose PET examinations showed a massive atrophy of the left TP with the right TP being relatively unaffected. Furthermore, C.M.'s atrophy encompassed most regions of the left TP usually activated in neuroimaging studies investigating ToM. Given C.M.'s language impairments, we used a battery of entirely nonverbal ToM tasks. Across five tasks encompassing 100 trials, which probed the patient's ability to attribute various mental states (intentions, knowledge, and beliefs), C.M. showed a totally spared performance. This finding suggests that, despite its consistently observed activation in neuroimaging studies involving ToM tasks, the left TP is not necessary for ToM reasoning, at least in nonverbal conditions and as long as its right counterpart is preserved. Implications for understanding the social abilities of patients with semantic dementia are discussed. PMID- 24047382 TI - Veto and vacillation: a neural precursor of the decision to withhold action. AB - The capacity to inhibit a planned action gives human behavior its characteristic flexibility. How this mechanism operates and what factors influence a decision to act or not act remain relatively unexplored. We used EEG readiness potentials (RPs) to examine preparatory activity before each action of an ongoing sequence, in which one action was occasionally omitted. We compared RPs between sequences in which omissions were instructed by a rule (e.g., "omit every fourth action") and sequences in which the participant themselves freely decided which action to omit. RP amplitude was reduced for actions that immediately preceded a voluntary omission but not a rule-based omission. We also used the regular temporal pattern of the action sequences to explore brain processes linked to omitting an action by time-locking EEG averages to the inferred time when an action would have occurred had it not been omitted. When omissions were instructed by a rule, there was a negative-going trend in the EEG, recalling the rising ramp of an RP. No such component was found for voluntary omissions. The results are consistent with a model in which spontaneously fluctuating activity in motor areas of the brain could bias "free" decisions to act or not. PMID- 24047383 TI - Embodied comprehension of stories: interactions between language regions and modality-specific neural systems. AB - The embodied view of language processing proposes that comprehension involves multimodal simulations, a process that retrieves a comprehender's perceptual, motor, and affective knowledge through reactivation of the neural systems responsible for perception, action, and emotion. Although evidence in support of this idea is growing, the contemporary neuroanatomical model of language suggests that comprehension largely emerges as a result of interactions between frontotemporal language areas in the left hemisphere. If modality-specific neural systems are involved in comprehension, they are not likely to operate in isolation but should interact with the brain regions critical to language processing. However, little is known about the ways in which language and modality-specific neural systems interact. To investigate this issue, we conducted a functional MRI study in which participants listened to stories that contained visually vivid, action-based, and emotionally charged content. Activity of neural systems associated with visual-spatial, motor, and affective processing were selectively modulated by the relevant story content. Importantly, when functional connectivity patterns associated with the left inferior frontal gyrus (LIFG), the left posterior middle temporal gyrus (pMTG), and the bilateral anterior temporal lobes (aTL) were compared, both LIFG and pMTG, but not the aTL, showed enhanced connectivity with the three modality-specific systems relevant to the story content. Taken together, our results suggest that language regions are engaged in perceptual, motor, and affective simulations of the described situation, which manifest through their interactions with modality-specific systems. On the basis of our results and past research, we propose that the LIFG and pMTG play unique roles in multimodal simulations during story comprehension. PMID- 24047384 TI - TMS over M1 reveals expression and selective suppression of conflicting action impulses. AB - Goal-directed action control comes into play when selecting between competing action alternatives. Response capture reflects the susceptibility of the motor system to incitement by task-irrelevant action impulses; the subsequent selective suppression of incorrect action impulses aims to counteract response capture and facilitate the desired response. The goal of this experiment was to clarify physiological mechanisms of response capture and suppression of action impulses during conflict at the level of the motor system. We administered single-pulse TMS at various intervals preceding speeded choice responses. The correct response side was designated by stimulus color, whereas stimulus location (which could match or conflict with response side) was to be ignored. TMS pulses triggered motor evoked potential and silent period, providing sensitive indices of cortico spinal excitation and inhibition. Motor evoked potential data showed the typical progressive increase in cortico-spinal motor excitability leading up to the imminent (correct) response, which started earlier on nonconflict than on conflict trials. On conflict trials, the irrelevant stimulus location captured the incorrect response, as expressed by an early and transient rise in excitability. Silent period data showed that, already early during the response process, inhibition of the incorrect response was stronger for conflict than for nonconflict trials. Furthermore, inhibition decreased over time for nonconflict trials facilitating the imminent correct response while maintaining higher levels of inhibition on conflict trials. In conclusion, dynamic patterns of cortico spinal excitability provide unique physiological evidence for the expression and selective suppression of action impulses captured by competing action alternatives. PMID- 24047385 TI - "Change deafness" arising from inter-feature masking within a single auditory object. AB - Our ability to detect prominent changes in complex acoustic scenes depends not only on the ear's sensitivity but also on the capacity of the brain to process competing incoming information. Here, employing a combination of psychophysics and magnetoencephalography (MEG), we investigate listeners' sensitivity in situations when two features belonging to the same auditory object change in close succession. The auditory object under investigation is a sequence of tone pips characterized by a regularly repeating frequency pattern. Signals consisted of an initial, regularly alternating sequence of three short (60 msec) pure tone pips (in the form ABCABC...) followed by a long pure tone with a frequency that is either expected based on the on-going regular pattern ("LONG expected"-i.e., "LONG-expected") or constitutes a pattern violation ("LONG-unexpected"). The change in LONG-expected is manifest as a change in duration (when the long pure tone exceeds the established duration of a tone pip), whereas the change in LONG unexpected is manifest as a change in both the frequency pattern and a change in the duration. Our results reveal a form of "change deafness," in that although changes in both the frequency pattern and the expected duration appear to be processed effectively by the auditory system-cortical signatures of both changes are evident in the MEG data-listeners often fail to detect changes in the frequency pattern when that change is closely followed by a change in duration. By systematically manipulating the properties of the changing features and measuring behavioral and MEG responses, we demonstrate that feature changes within the same auditory object, which occur close together in time, appear to compete for perceptual resources. PMID- 24047386 TI - Task- and experience-dependent cortical selectivity to features informative for categorization. AB - In this study, we bridge the gap between monkey electrophysiological recordings that showed selective responses to informative features and human fMRI data that demonstrated increased and selective responses to trained objects. Human participants trained with computer-generated fish stimuli. For each participant, two features of the fish were informative for category membership and two features were uninformative. After training, participants showed higher perceptual sensitivity to the informative dimensions. An fMRI adaptation paradigm revealed that during categorization the right inferior frontal gyrus and occipitotemporal cortex were selectively responsive to the informative features. These selective cortical responses were experience dependent; they were not present for the entire trained object, but specific for those features that were informative for categorization. Responses in the inferior frontal gyrus showed category selectivity. Moreover, selectivity to the informative features correlated with performance on the categorization task during scanning. This all suggests that the frontal cortex is involved in actively categorizing objects and that it uses informative features to do so while ignoring those features that do not contribute category information. Occipitotemporal cortex also showed selectivity to the informative features during the categorization task. Interestingly, this area showed a positive correlation of performance during training and selectivity to the informative features and a negative correlation with selectivity to the uninformative features. This indicates that training enhanced sensitivity to trained items and decreased sensitivity to uninformative features. The absence of sensitivity for informative features during a color change detection task indicates that there is a strong component of task-related processing of these features. PMID- 24047387 TI - The impact of early amygdala damage on juvenile rhesus macaque social behavior. AB - The present experiments continue a longitudinal study of rhesus macaque social behavior following bilateral neonatal ibotenic acid lesions of the amygdala or hippocampus, or sham operations. Juvenile animals (approximately 1.5-2.5 years) were tested in four different social contexts--alone, while interacting with one familiar peer, while interacting with one unfamiliar peer, and in their permanent social groups. During infancy, the amygdala-lesioned animals displayed more interest in conspecifics (indexed by increased affiliative signaling) and paradoxically demonstrated more submission or fear (Bauman, Lavenex, Mason, Capitanio, & Amaral, 2004a, this journal). When these animals were assessed as juveniles, differences were less striking. Amygdala-lesioned animals generated fewer aggressive and affiliative signals (e.g., vocalizations, facial displays) and spent less time in social interactions with familiar peers. When animals were observed alone or with an unfamiliar peer, amygdala-lesioned animals, compared with other subjects, spent more time being inactive and physically explored the environment less. Despite the subtle, lesion-based differences in the frequency and duration of specific social behaviors, there were lesion-based differences in the organization of behavior such that lesion groups could be identified based on the patterning of social behaviors in a discriminant function analysis. The findings indicate that, although overall frequencies of many of the observed behaviors do not differ between groups, the general patterning of social behavior may distinguish the amygdala-lesioned animals. PMID- 24047388 TI - Generic inhibition of the selected movement and constrained inhibition of nonselected movements during response preparation. AB - Previous studies have identified two inhibitory mechanisms that operate during action selection and preparation. One mechanism, competition resolution, is manifest in the inhibition of the nonselected response and attributed to competition between candidate actions. The second mechanism, impulse control, is manifest in the inhibition of the selected response and is presumably invoked to prevent premature response. To identify constraints on the operation of these two inhibitory mechanisms, we manipulated the effectors used for the response alternatives, measuring changes in corticospinal excitability with motor-evoked potentials to TMS. Inhibition of the selected response (impulse control) was independent of the task context, consistent with a model in which this form of inhibition is automatically triggered as part of response preparation. In contrast, inhibition of the nonselected response (competition resolution) was context-dependent. Inhibition of the nonselected response was observed when the response alternatives involved movements of the upper limbs but was absent when one response alternative involved an upper limb and the other involved a lower limb. Interestingly, competition resolution for pairs of upper limbs did not require homologous effectors, observed when a left index finger response was pitted with either a nonhomologous right index finger movement or a right arm movement. These results argue against models in which competition resolution is viewed as a generic or fully flexible process, as well as models based on strong anatomical constraints. Rather, they are consistent with models in which inhibition for action selection is constrained by the similarity between the potential responses, perhaps reflecting an experience-dependent mechanism sensitive to the past history of competitive interactions. PMID- 24047389 TI - Neural network configuration and efficiency underlies individual differences in spatial orientation ability. AB - Spatial orientation is a complex cognitive process requiring the integration of information processed in a distributed system of brain regions. Current models on the neural basis of spatial orientation are based primarily on the functional role of single brain regions, with limited understanding of how interaction among these brain regions relates to behavior. In this study, we investigated two sources of variability in the neural networks that support spatial orientation- network configuration and efficiency--and assessed whether variability in these topological properties relates to individual differences in orientation accuracy. Participants with higher accuracy were shown to express greater activity in the right supramarginal gyrus, the right precentral cortex, and the left hippocampus, over and above a core network engaged by the whole group. Additionally, high performing individuals had increased levels of global efficiency within a resting state network composed of brain regions engaged during orientation and increased levels of node centrality in the right supramarginal gyrus, the right primary motor cortex, and the left hippocampus. These results indicate that individual differences in the configuration of task-related networks and their efficiency measured at rest relate to the ability to spatially orient. Our findings advance systems neuroscience models of orientation and navigation by providing insight into the role of functional integration in shaping orientation behavior. PMID- 24047390 TI - Attention to detail: why considering task demands is essential for single-trial analysis of BOLD correlates of the visual P1 and N1. AB - Single-trial fluctuations in the EEG signal have been shown to temporally correlate with the fMRI BOLD response and are valuable for modeling trial-to trial fluctuations in responses. The P1 and N1 components of the visual ERP are sensitive to different attentional modulations, suggesting that different aspects of stimulus processing can be modeled with these ERP parameters. As such, different patterns of BOLD covariation for P1 and N1 informed regressors would be expected; however, current findings are equivocal. We investigate the effects of variations in attention on P1 and N1 informed BOLD activation in a visual oddball task. Simultaneous EEG-fMRI data were recorded from 13 healthy participants during three conditions of a visual oddball task: Passive, Count, and Respond. We show that the P1 and N1 components of the visual ERP can be used in the integration-by-prediction method of EEG-fMRI data integration to highlight brain regions related to target detection and response production. Our data suggest that the P1 component of the ERP reflects changes in sensory encoding of stimulus features and is more informative for the Passive and Count conditions. The N1, on the other hand, was more informative for the Respond condition, suggesting that it can be used to model the processing of stimulus, meaning specifically discriminating one type of stimulus from another, and processes involved in integrating sensory information with response selection. Our results show that an understanding of the underlying electrophysiology is necessary for a thorough interpretation of EEG-informed fMRI analysis. PMID- 24047391 TI - Isolating the neural mechanisms of interference during continuous multisensory dual-task performance. AB - The need to engage in multiple tasks simultaneously is often encountered in everyday experience, but coordinating between two or more tasks can lead to impaired performance. Typical investigations of multitasking impairments have focused on the performance of two tasks presented in close temporal proximity on discrete trials; however, such paradigms do not match well with the continuous performance situations more typically encountered outside the laboratory. As a result, the stages of information processing that are affected during multisensory continuous dual tasks and how these changes in processing relate to behavior remain unclear. To address these issues, participants were presented simultaneous rapid visual and auditory stimulus sequences under three conditions: attend visual only, attend auditory only, and dual attention (attend both visual and auditory). Performance, measured in terms of response time and perceptual sensitivity (d'), revealed dual-task impairments only in the auditory task. Neural activity, measured by the ERP technique, revealed that both early stage sensory processing and later cognitive processing of the auditory task were affected by dual-task performance, but similar stages of processing of the visual task were not. Critically, individual differences in neural activity at both early and late stages of information processing accurately rank-ordered individuals based on the observed difference in behavioral performance between the single and dual attention conditions. These results reveal relationships between behavioral performance and the neural correlates of both early and late stage information processing that provide key insights into the complex interplay between the brain and behavior when multiple tasks are performed continuously. PMID- 24047392 TI - Systematic review of the diagnosis of gastric premalignant conditions and neoplasia with high-resolution endoscopic technologies. AB - AIM. The aim of the article is to systematically review the current evidence on the diagnostic use of narrow band imaging (NBI), flexible spectral imaging color enhancement (FICE) and endoscopic image enhancement technology i-scan endoscopies for gastric precancerous and cancerous lesions. MATERIALS AND METHODS. Original manuscripts were searched in PubMed until October 2012. Pertinent data were collected and pooled diagnostic accuracy measures were estimated when possible. RESULTs. In total, 38 studies were evaluated. Thirty-one studies were included for NBI and 7 studies for FICE assessment in this systematic review. No article was found meeting inclusion criteria for i-scan endoscopy. The most defined and evaluated outcomes were cancer-related (n = 26). Quality Assessment of Diagnostic Accuracy Studies score varied from 9 to 12 (out of 14). Only few studies assessed the interobserver reliability. On a patient level analysis, NBI's pooled sensitivity, specificity and diagnostic odds ratio were 0.67 (95% CI: 0.61-0.73), 0.81 (95% CI: 0.76-0.85) and 22.71 (95% CI: 12.53-41.1), respectively for diagnosing normal mucosa; 0.86 (95% CI: 0.82-0.90), 0.77 (95% CI: 0.73-0.80) and 17.01 (95% CI: 1.4-207.2) for intestinal metaplasia and 0.90 (95% CI: 0.84-0.94), 0.83 (95% CI: 0.80-0.86) and 47.61 (95% CI: 4.61-491.34) for dysplasia. Owing to the insufficient data and different definitions, we could not aggregate the results for FICE. CONCLUSION. Gastric pattern descriptions have been proposed for NBI and FICE studies by gathering all descriptions in one single description. The classification systems varied between studies, a single description of gastric mucosal features with HR--scopes or at least per technology--will have to be agreed on. PMID- 24047393 TI - Esophageal barrier function and tight junction expression in healthy subjects and patients with gastroesophageal reflux disease: functionality of esophageal mucosa exposed to bile salt and trypsin in vitro. AB - BACKGROUND AND AIMS. Gastroesophageal reflux disease (GERD) is associated with impaired epithelial barrier function. However, the influence of acid and/or bile acids on human esophageal epithelial barrier function and the tight junction (TJ) proteins has not been fully elucidated. The aim of the study is to investigate the esophageal barrier function and TJ expression in healthy subjects and patients with GERD. The functionality of esophageal mucosa exposed to bile salt deoxycholic acid (DCA) and trypsin has been studied in vitro. MATERIAL AND METHODS. Endoscopic biopsies from healthy controls and patients with GERD-related symptom with endoscopic erosive signs, as well as esophageal mucosa taken from patients undergoing esophagectomy were evaluated in Ussing chambers and by western blot and immunohistochemistry. RESULTS. The esophageal epithelium from GERD patients had lower electrical resistance and higher epithelial currents than controls. Claudin-1 and -4 were significantly decreased in GERD patients. The bile salt DCA in the low concentration of 1.5 mM and trypsin increased the resistance and claudin-1 expression, while the higher concentration of 2.5 mM DCA and trypsin decreased the resistance and the claudin-3, -4 and E-cadherin expressions. CONCLUSION. In addition to acidic reflux, duodenal reflux components, such as bile salts and trypsin, have the potential to disrupt the esophageal barrier function, partly by modulating the TJ proteins. However, the expression of TJ is dependent on both the refluxed material as well as the concentration of the bile salt. PMID- 24047394 TI - Dipeptidyl peptidase-4 inhibitor anagliptin facilitates restoration of dextran sulfate sodium-induced colitis. AB - OBJECTIVE. Inflammatory bowel disease (IBD) is a chronic debilitating disease associated with severe damage to the intestinal mucosa. Glucagon-like peptide-2 (GLP-2) is a potent and specific gastrointestinal growth factor. GLP-2 released from enteroendocrine cells is inactivated by dipeptidyl peptidase-4 (DPP-4). The aim of this study was to examine whether the DPP-4 inhibitor anagliptin improves experimental murine colitis. MATERIAL AND METHODS. Male C57BL/6 mice aged 8 weeks were exposed to 1.5% dextran sulfate sodium (DSS) in drinking water for 7 days to induce experimental colitis. Anagliptin (0.1% in diet) was administrated from 2 days before the beginning of DSS to 7 days after the end of DSS. Changes in body weight and disease activity index were evaluated daily. Histological colitis severity, cellular proliferation and gene expression were determined in colonic tissues. RESULTS. Treatment with anagliptin clearly improved body weight loss and disease activity index in the recovery phase. Histological score in the DSS + anagliptin group at day 14 was significantly lower than that in the DSS alone group. Treatment with anagliptin increased the Ki67-positive rate at days 10 and 14, and tended to increase insulin-like growth factor-1 mRNA expression in the DSS + anagliptin group. CONCLUSION. In this model of experimental colitis, the DPP-4 inhibitor anagliptin facilitated the restoration of mucosal damage, thereby resulting in the acceleration of healing. These findings suggest a new and novel therapeutic approach for the treatment of IBD. PMID- 24047395 TI - Phenotypic characterization and familial risk in hyperplastic polyposis syndrome. AB - BACKGROUND. Hyperplastic polyposis syndrome (HPS) is a rare condition characterized by numerous hyperplastic polyps (HP) with a pancolonic distribution. Genetic and environmental factors, including smoking, may be responsible for phenotypic differences. OBJECTIVE. To characterize HPS patients' phenotype and to determine HPS risk and colorectal cancer (CRC) risk in the first degree relatives (FDRs). PATIENTS AND METHODS. Eight HPS patients were followed at our Gastroenterology Department (2008-2012). The data included (1) macroscopic and histological analysis of polyps, (2) demographic information about patients and their families and (3) colonoscopy results of FDR that accepted a screening exam. RESULTS. Six of the eight index cases (ICs) had family history of CRC. Of the 24 FDRs screened, 5 were diagnosed with HPS. In our study, HPS and CRC prevalence in FDR was 625 and 9 times higher than the risk of the general population. Polyps over 10 mm were preferentially located in proximal colon (p < 0.001). Advanced polyps were larger (p < 0.001) than HP and more frequent in older patients (p = 0.0054). Nonsmokers had smaller polyps (p = 0.037) preferentially in the proximal colon (p = 0.04) and a lower age at HPS diagnosis. Patients with CRC family history manifest HPS at an earlier age and patients whose relatives had CRC before 50 years had larger polyps (p = 0.0475). Smokers with CRC family history had larger polyps than nonsmokers (p = 0.048). CONCLUSION. Despite the small sample, the results reflect the phenotypic heterogeneity of HPS as well as the increased family risk of HPS and CRC. This study points out that CRC family history and smoking influence HPS expression. PMID- 24047396 TI - Comparison of MUC4 expression in primary pancreatic cancer and paired lymph node metastases. AB - OBJECTIVE. Mucin 4 (MUC4) is a transmembrane glycoprotein that is expressed in pancreatic ductal adenocarcinoma (PDAC), but not in normal pancreatic tissue. MUC4 has a proposed role in pancreatic tumor progression and metastasis. The purpose of this pilot study was to investigate MUC4 expression during PDAC metastasis by comparing the expression in the primary tumor and paired lymph node metastases from the same patient. MATERIAL AND METHODS. Surgical specimens from 17 cases of primary PDAC and paired lymph node metastases were immunohistochemically analyzed for MUC4 expression. The modified histochemical score (H-score) was used for staining assessment. RESULTS. Positive staining for MUC4 was detected in most primary and metastatic PDAC tumors (15/17 vs. 14/17). The concordance for MUC4 expression in primary tumors and corresponding lymph node metastases was 82%. In two cases, the primary tumor was MUC4-positive and the lymph node metastases were negative, while in one patient with a MUC4 negative primary tumor, the lymph node metastasis was positive. The distribution of H-score for expression of MUC4 significantly correlated (r = 0.615; p = 0.009) between primary tumors and paired metastatic lesions. CONCLUSIONS: MUC4 was observed in both primary and matched metastatic tumors with a high level of concordance, suggesting that MUC4 expression is retained following PDAC metastasis. PMID- 24047397 TI - Card15 mutations and gastric cancer in a Portuguese population. AB - BACKGROUND. CARD15 is involved in the innate immune response and mutations of this gene have been linked with increased risk of Crohn's disease and colorectal cancer. The relation between CARD15 mutations and gastric cancer (GC) remains controversial. AIMS. To assess whether CARD15 mutations are risk factors for GC in Portugal and whether there are genotype-phenotype correlations in these patients. METHODS. The 3 main CARD15 mutations (3020insC, R702W and G908R) were searched in 150 patients with GC and in 202 healthy controls. RESULTS. Overall, CARD15 mutations were found in 28 patients (18.7%) and in 27 controls (13.4%) (p = 0.176). Individually, the incidence of 3020insC was significantly higher in patients than in controls (6.0% vs. 1.0%, p = 0.021). This polymorphism was linked with an increased risk for the intestinal-type of GC (p = 0.002), while no association was found with the diffuse and/or mixed types. Genotype frequencies for R702W (10.0% vs. 7.9%) and G908R (4.0% vs. 4.0%) were not statistically different between the two groups. Similarly, no significant associations were detected between these two polymorphisms and the different histological GC types. No correlations were observed between CARD15 mutations and family history, mean age at diagnosis or GC stage. CONCLUSIONS. The CARD15 3020insC variant is a risk factor for intestinal GC in Portugal. CARD15 variants are not correlated with age of diagnosis or family aggregation of the disease neither with the GC stage. PMID- 24047398 TI - A retrospective comparative study of histoacryl injection and banding ligation in the treatment of acute type 1 gastric variceal hemorrhage. AB - BACKGROUND. Esophageal varices extending along lesser curvature side of stomach is classified as GOV1. The optimal therapy for GOV1 bleeding is still undetermined. METHODS. One hundred and sixty-two patients diagnosed as acute hemorrhage from GOV1 were enrolled. At endoscopists' discretion, 118 patients received glue injection (Glue group) and 44 patients received ligation to arrest bleeding [endoscopic variceal ligation (EVL) group]. This study aimed to compare hemostasis, rebleeding, complications and mortality within 42 days. RESULTS. Both groups were comparable in baseline data. In 109 patients (92%) in the Glue group and 36 patients (82%) in the EVL group (p = 0.07) 48-h hemostasis was achieved . Hemostasis of active bleeding was achieved in 49 of 55 patients (89%) in the Glue group and 24 of 28 patients (85%) in the EVL group (p = 0.70). Treatment failure was noted in 14% of the Glue group and 23% in the EVL group (p = 0.22). Eight patients in the Glue group and four patients in the EVL group rebled between 5 and 42 days (p = 0.73). A total of 48 and 19 adverse events occurred in the Glue and EVL groups, respectively (p = 0.85). Six patients in the Glue group and seven patients in the EVL group encountered posttreatment gastric ulcer bleeding (p = 0.04). Seventeen patients (14%) in the Glue group and 10 (23%) patients in the EVL group died within 42 days (p < 0.001). CONCLUSIONS. Banding ligation was similar to glue injection in achieving successful hemostasis of acute bleeding from GOV1. However, a higher incidence of posttreatment ulcer bleeding and mortality may be associated with banding ligation. PMID- 24047400 TI - Synthesis of dabsyl-appended cyclophanes and their heterodimer formation with pyrene-appended cyclophanes. AB - As a quencher-type host, dabsyl-appended cyclophanes bearing positively and negatively charged side chains (1a and 1b, respectively) were synthesized. Formation of cyclophane heterodimers of 1a with anionic fluorescent cyclophane bearing a pyrene moiety 2b was confirmed by fluorescence titration experiments. The 1:1 binding constant (K) of 1a toward 2b was calculated to be 1.6 * 10(5) M( 1). On the other hand, almost no complexation affinity of 1a toward cationic analogue of fluorescent cyclophane 2a was confirmed by the identical methods, indicating that electrostatic interactions became effective in the formation of cyclophane heterodimers. In addition, van't Hoff analysis applied to the temperature-dependent K values for the heterodimer formation gave negative enthalpy (DeltaH) and entropy changes (DeltaS). The large and negative DeltaH values as well as small and also negative DeltaS values showed that the complexation is an exothermic and enthalpy-controlled but not entropy-driven process. A similar trend of molecular recognition was also confirmed for formation of cyclophane heterodimers of 1b with 2a by the identical methods. PMID- 24047399 TI - Genetic and biological characterisation of an avian-like H1N2 swine influenza virus generated by reassortment of circulating avian-like H1N1 and H3N2 subtypes in Denmark. AB - BACKGROUND: The influenza A virus subtypes H1N1, H1N2 and H3N2 are the most prevalent subtypes in swine. In 2003, a reassorted H1N2 swine influenza virus (SIV) subtype appeared and became prevalent in Denmark. In the present study, the reassortant H1N2 subtype was characterised genetically and the infection dynamics compared to an "avian-like" H1N1 virus by an experimental infection study. METHODS: Sequence analyses were performed of the H1N2 virus. Two groups of pigs were inoculated with the reassortant H1N2 virus and an "avian-like" H1N1 virus, respectively, followed by inoculation with the opposite subtype four weeks later. Measurements of HI antibodies and acute phase proteins were performed. Nasal virus excretion and virus load in lungs were determined by real-time RT-PCR. RESULTS: The phylogenetic analysis revealed that the reassorted H1N2 virus contained a European "avian-like" H1-gene and a European "swine-like" N2-gene, thus being genetically distinct from most H1N2 viruses circulating in Europe, but similar to viruses reported in 2009/2010 in Sweden and Italy. Sequence analyses of the internal genes revealed that the reassortment probably arose between circulating Danish "avian-like" H1N1 and H3N2 SIVs. Infected pigs developed cross reactive antibodies, and increased levels of acute phase proteins after inoculations. Pigs inoculated with H1N2 exhibited nasal virus excretion for seven days, peaking day 1 after inoculation two days earlier than H1N1 infected pigs and at a six times higher level. The difference, however, was not statistically significant. Pigs euthanized on day 4 after inoculation, had a high virus load in all lung lobes. After the second inoculation, the nasal virus excretion was minimal. There were no clinical sign except elevated body temperature under the experimental conditions. CONCLUSIONS: The "avian-like" H1N2 subtype, which has been established in the Danish pig population at least since 2003, is a reassortant between circulating swine "avian-like" H1N1 and H3N2. The Danish H1N2 has an "avian-like" H1 and differs from most other reported H1N2 viruses in Europe and North America/Asia, which have H1-genes of human or "classical-swine" origin, respectively. The variant seems, however, also to be circulating in countries like Sweden and Italy. The infection dynamics of the reassorted "avian like" H1N2 is similar to the older "avian-like" H1N1 subtype. PMID- 24047401 TI - AMP-activated protein kinase as a promoting factor, but complement and thrombin as limiting factors for acquisition of cytoprotection: implications for induction of accommodation. AB - Accommodation has been termed as a condition without graft rejection even in the presence of antidonor antibody. We previously reported an in vitro accommodation model, which demonstrated that preincubation of A/B antigen-expressing endothelial cells with anti-A/B antibody resulted in ERK inactivation followed by resistance to complement-mediated cytotoxicity through the induction of complement regulatory genes. However, under the in vivo condition, the effects of complement and coagulation system cannot be ignored. The purpose of this study is to find effective ways to navigate accommodation by exploring the relevant signal transduction. Preincubation with a low level of complement or thrombin failed to induce resistance to complement-mediated cytotoxicity. AMP-activated protein kinase (AMPK) activators such as resveratrol, AICAR and metformin protected endothelial cells against complement-mediated cytotoxicity through the increase in CD55, CD59, haem oxygenase-1 (HO-1) and ferritin heavy chain (ferritin H) genes, all of which were attenuated by AMPKalpha knock-down. Resveratrol counteracted the inhibitory effect of pretreated complement and thrombin on acquisition of resistance to complement-mediated cytotoxicity through AMPKalpha. AMPK regulation in endothelial cells could become the potential strategy to induce accommodation in clinical pro-inflammation and pro-coagulation. PMID- 24047402 TI - State politics and the fate of the safety net. PMID- 24047404 TI - Binding of the N-terminal domain of the lactococcal bacteriophage TP901-1 CI repressor to its target DNA: a crystallography, small angle scattering, and nuclear magnetic resonance study. AB - In most temperate bacteriophages, regulation of the choice of lysogenic or lytic life cycle is controlled by a CI repressor protein. Inhibition of transcription is dependent on a helix-turn-helix motif, often located in the N-terminal domain (NTD), which binds to specific DNA sequences (operator sites). Here the crystal structure of the NTD of the CI repressor from phage TP901-1 has been determined at 1.6 A resolution, and at 2.6 A resolution in complex with a 9 bp double stranded DNA fragment that constitutes a half-site of the OL operator. This N terminal construct, comprising residues 2-74 of the CI repressor, is monomeric in solution as shown by nuclear magnetic resonance (NMR), small angle X-ray scattering, and gel filtration and is monomeric in the crystal structures. The binding interface between the NTD and the half-site in the crystal is very similar to the interface that can be mapped by NMR in solution with a full palindromic site. The interactions seen in the complexes (in the crystal and in solution) explain the observed affinity for the OR site that is lower than that for the OL site and the specificity for the recognized DNA sequence in comparison to that for other repressors. Compared with many well-studied phage repressor systems, the NTD from TP901-1 CI has a longer extended scaffolding helix that, interestingly, is strongly conserved in putative repressors of Gram-positive pathogens. On the basis of sequence comparisons, we suggest that these bacteria also possess repressor/antirepressor systems similar to that found in phage TP901 1. PMID- 24047403 TI - Redox signaling in pathophysiology of hypertension. AB - Reactive oxygen species (ROS) are products of normal cellular metabolism and derive from various sources in different cellular compartments. Oxidative stress resultant from imbalance between ROS generation and antioxidant defense mechanisms is important in pathogenesis of cardiovascular diseases, such as hypertension, heart failure, atherosclerosis, diabetes, and cardiac hypertrophy. In this review we focus on hypertension and address sources of cellular ROS generation, mechanisms involved in regulation of radical homeostasis, superoxide dismutase isoforms in pathophysiology of hypertension; as well as radical intracellular signaling and phosphorylation processes in proteins of the affected cardiovascular tissues. Finally, we discuss the transcriptional factors involved in redox-sensitive gene transcription and antioxidant response, as well as their roles in hypertension. PMID- 24047405 TI - Magnetic nanobeads as potential contrast agents for magnetic resonance imaging. AB - Metal-oxo clusters have been used as building blocks to form hybrid nanomaterials and evaluated as potential MRI contrast agents. We have synthesized a biocompatible copolymer based on a water stable, nontoxic, mixed-metal-oxo cluster, Mn8Fe4O12(L)16(H2O)4, where L is acetate or vinyl benzoic acid, and styrene. The cluster alone was screened by NMR for relaxivity and was found to be a promising T2 contrast agent, with r1 = 2.3 mM(-1) s(-1) and r2 = 29.5 mM(-1) s( 1). Initial cell studies on two human prostate cancer cell lines, DU-145 and LNCap, reveal that the cluster has low cytotoxicity and may be potentially used in vivo. The metal-oxo cluster Mn8Fe4(VBA)16 (VBA = vinyl benzoic acid) can be copolymerized with styrene under miniemulsion conditions. Miniemulsion allows for the formation of nanometer-sized paramagnetic beads (~80 nm diameter), which were also evaluated as a contrast agent for MRI. These highly monodispersed, hybrid nanoparticles have enhanced properties, with the option for surface functionalization, making them a promising tool for biomedicine. Interestingly, both relaxivity measurements and MRI studies show that embedding the Mn8Fe4 core within a polymer matrix decreases r2 effects with little effect on r1, resulting in a positive T1 contrast enhancement. PMID- 24047407 TI - Opening interrupter technique in pre-school children with chronic respiratory diseases: a perspective case-control study in the diagnosis of airway hyperesponsiveness. AB - BACKGROUND: Optimal treatment for pediatric respiratory diseases is strictly related to follow-up evaluations of lung function. The aim of our study was to show the efficacy of the Opening Interrupter Technique in diagnosing the presence of airway obstruction in pre-school children. MATERIALS AND METHODS: Our study was a prospective case-control study, evaluating 82 patients affected by asthma and/or cystic fibrosis (CF) and 50 healthy pre-school children, as control group. All patients were 3- to 5-years old and they were followed by our Pediatric Department, University of Catania, Italy, from February 2011 to June 2012. Measurements of respiratory resistance (o-Rint) by the opening interrupter technique were made with the MasterScreen PFT device, Jaeger GmbH, Wurzburg, Germany, during quiet breathing. The presence of airway obstruction was detected as a value of o-Rint higher than two standard deviations (SD) compared with the theoretical data. RESULTS: We found higher values of o-Rint in asthmatic patients than in the control group, with a high statistical difference (p < 0.0001). The same results were found when we compared patients with CF and the control group (p < 0.0001). Nevertheless, we did not find any significant statistical difference between respiratory resistances measured in asthmatic and patients with CF (p > 0.05). There was a significant inverse correlation between o-Rint and height only in asthmatic and patients with CF, but not in healthy controls (p < 0.05). CONCLUSIONS: In our study, the opening interrupter technique was efficient in detecting the presence of obstruction in chronic patients affected by asthma and CF. PMID- 24047406 TI - Direct transdifferentiation of spermatogonial stem cells to morphological, phenotypic and functional hepatocyte-like cells via the ERK1/2 and Smad2/3 signaling pathways and the inactivation of cyclin A, cyclin B and cyclin E. AB - BACKGROUND: Severe shortage of liver donors and hepatocytes highlights urgent requirement of extra-liver and stem cell source of hepatocytes for treating liver related diseases. Here we hypothesized that spermatogonial stem cells (SSCs) can directly transdifferentiate to hepatic stem-like cells capable of differentiating into mature hepatocyte-like cells in vitro without an intervening pluripotent state. RESULTS: SSCs first changed into hepatic stem-like cells since they resembled hepatic oval cells in morphology and expressed Ck8, Ck18, Ck7, Ck19, OV6, and albumin. Importantly, they co-expressed CK8 and CK19 but not ES cell markers. Hepatic stem-like cells derived from SSCs could differentiate into small hepatocytes based upon their morphological features and expression of numerous hepatic cell markers but lacking of bile epithelial cell hallmarks. Small hepatocytes were further coaxed to differentiate into mature hepatocyte-like cells, as identified by their morphological traits and strong expression of Ck8, Ck18, Cyp7a1, Hnf3b, Alb, Tat, Ttr, albumin, and CYP1A2 but not Ck7 or CK19. Notably, these differentiated cells acquired functional attributes of hepatocyte like cells because they secreted albumin, synthesized urea, and uptake and released indocyanine green. Moreover, phosphorylation of ERK1/2 and Smad2/3 rather than Akt was activated in hepatic stem cells and mature hepatocytes. Additionally, cyclin A, cyclin B and cyclin E transcripts and proteins but not cyclin D1 or CDK1 and CDK2 transcripts or proteins were reduced in mature hepatocyte-like cells or hepatic stem-like cells derived from SSCs compared to SSCs. CONCLUSIONS: SSCs can transdifferentiate to hepatic stem-like cells capable of differentiating into cells with morphological, phenotypic and functional characteristics of mature hepatocytes via the activation of ERK1/2 and Smad2/3 signaling pathways and the inactivation of cyclin A, cyclin B and cyclin E. This study thus provides an invaluable source of mature hepatocytes for treating liver related diseases and drug toxicity screening and offers novel insights into mechanisms of liver development and cell reprogramming. PMID- 24047408 TI - Thrombocytopenia in patients with hepatitis B virus-related chronic hepatitis: evaluation of the immature platelet fraction. AB - The immature platelet fraction (IPF) measures the number of reticulated platelets in peripheral blood, and can be used to help determine if thrombocytopenia is secondary to low-platelet production or increased platelet turnover. The aim of this study was to determine whether abnormalities in the IPF were associated with thrombocytopenia in patients with hepatitis B virus-related chronic hepatitis (CHB). One hundred fifty-six patients with chronic hepatitis B, including 80 thrombocytopenia, 76 without thrombocytopenia, and 48 healthy controls were enrolled in the study. The IPF percentages (IPF%) were measured using a XE-2100 multiparameter automatic hematology analyzer. We demonstrated that in the thrombocytopenic group, the IPF% was significantly increased compared with that in healthy controls and the non-thrombocytopenic group (both p < 0.001). Multivariate analysis demonstrated that IPF%, splenomegaly, and the model for end stage liver disease score were independent predictors for thrombocytopenia (both p < 0.001). High IPF% during the course of thrombocytopenia suggests that platelet destruction/sequestration due to hypersplenism is a major factor contributing to thrombocytopenia in patients with CHB. PMID- 24047409 TI - Arylation of lithium sulfinates with diaryliodonium salts: a direct and versatile access to arylsulfones. AB - An efficient, transition-metal-free arylation of lithium sulfinates, which are readily accessible from reactions of organolithium reagents with sulfur dioxide, is described. Based on this method, a practical protocol for the direct transformation of (hetero)arenes and (hetero)aromatic halides into diarylsulfones was developed. PMID- 24047410 TI - Investigating the alpha-effect in gas-phase S(N)2 reactions of microsolvated anions. AB - The alpha-effect-enhanced reactivity of nucleophiles with a lone-pair adjacent to the attacking center-was recently demonstrated for gas-phase S(N)2 reactions of HOO(-), supporting an intrinsic component of the alpha-effect. In the present work we explore the gas-phase reactivity of microsolvated nucleophiles in order to investigate in detail how the alpha-effect is influenced by solvent. We compare the gas-phase reactivity of the microsolvated alpha-nucleophile HOO( )(H2O) to that of microsolvated normal alkoxy nucleophiles, RO(-)(H2O), in reaction with CH3Cl using a flowing afterglow-selected ion flow tube instrument. The results reveal enhanced reactivity of HOO(-)(H2O) and clearly demonstrate the presence of an alpha-effect for the microsolvated alpha-nucleophile. The association of the nucleophile with a single water molecule results in a larger Bronsted betanuc value than is the case for the unsolvated nucleophiles. Accordingly, the reactions of the microsolvated nucleophiles proceed through later transition states in which bond formation has progressed further. Calculations show a significant difference in solvent interaction for HOO(-) relative to the normal nucleophiles at the transition states, indicating that differential solvation may well contribute to the alpha-effect. The reactions of the microsolvated anions with CH3Cl can lead to formation of either the bare Cl( ) anion or the Cl(-)(H2O) cluster. The product distributions show preferential formation of the Cl(-) anion even though the formation of Cl(-)(H2O) would be favored thermodynamically. Although the structure of the HOO(-)(H2O) cluster resembles HO(-)(HOOH), we demonstrate that HOO(-) is the active nucleophile when the cluster reacts. PMID- 24047411 TI - Thorium and uranium carbide cluster cations in the gas phase: similarities and differences between thorium and uranium. AB - Laser ionization of AnC4 alloys (An = Th, U) yielded gas-phase molecular thorium and uranium carbide cluster cations of composition An(m)C(n)(+), with m = 1, n = 2-14, and m = 2, n = 3-18, as detected by Fourier transform ion-cyclotron resonance mass spectrometry. In the case of thorium, Th(m)C(n)(+) cluster ions with m = 3-13 and n = 5-30 were also produced, with an intriguing high intensity of Th13C(n)(+) cations. The AnC13(+) ions also exhibited an unexpectedly high abundance, in contrast to the gradual decrease in the intensity of other AnC(n)(+) ions with increasing values of n. High abundances of AnC2(+) and AnC4(+) ions are consistent with enhanced stability due to strong metal-C2 bonds. Among the most abundant bimetallic ions was Th2C3(+) for thorium; in contrast, U2C4(+) was the most intense bimetallic for uranium, with essentially no U2C3(+) appearing. Density functional theory computations were performed to illuminate this distinction between thorium and uranium. The computational results revealed structural and energetic disparities for the An2C3(+) and An2C4(+) cluster ions, which elucidate the observed differing abundances of the bimetallic carbide ions. Particularly noteworthy is that the Th atoms are essentially equivalent in Th2C3(+), whereas there is a large asymmetry between the U atoms in U2C3(+). PMID- 24047413 TI - Featural processing in recognition of emotional facial expressions. AB - The present study aimed to clarify the role played by the eye/brow and mouth areas in the recognition of the six basic emotions. In Experiment 1, accuracy was examined while participants viewed partial and full facial expressions; in Experiment 2, participants viewed full facial expressions while their eye movements were recorded. Recognition rates were consistent with previous research: happiness was highest and fear was lowest. The mouth and eye/brow areas were not equally important for the recognition of all emotions. More precisely, while the mouth was revealed to be important in the recognition of happiness and the eye/brow area of sadness, results are not as consistent for the other emotions. In Experiment 2, consistent with previous studies, the eyes/brows were fixated for longer periods than the mouth for all emotions. Again, variations occurred as a function of the emotions, the mouth having an important role in happiness and the eyes/brows in sadness. The general pattern of results for the other four emotions was inconsistent between the experiments as well as across different measures. The complexity of the results suggests that the recognition process of emotional facial expressions cannot be reduced to a simple feature processing or holistic processing for all emotions. PMID- 24047412 TI - S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. AB - RATIONALE: A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined. OBJECTIVES: The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB. METHODS: The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques. MEASUREMENTS AND MAIN RESULTS: We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB. CONCLUSIONS: Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB. PMID- 24047415 TI - Assessment of global proteome dynamics in carp: a model for investigating environmental stress. AB - Fish have to respond to a range of natural and man-made environmental stressors, which can lead to molecular changes within their tissues. Many studies focused on environmental stress in fish have examined the change in protein abundance or mRNA level. However, it is well-known that there is a disconnect between mRNA and protein expression. In order to bridge this gap, protein turnover must also be considered. We have developed an experimental strategy to determine the synthesis rates of individual proteins in the tissues of fish on a proteome-wide scale. This approach has been applied to the common carp ( Cyprinus carpio ), a key model species for investigating environmentally induced physiological plasticity. We have calculated the rates of protein synthesis for over a thousand individual proteins from the skeletal muscle and liver of carp. The median synthesis rate of proteins from liver was higher than that of skeletal muscle. The analysis further revealed that the same protein can have a different rate of synthesis depending on the tissue type. Our strategy permits a full investigation of proteome dynamics in fish and will have relevance to the fields of integrative biology and ecotoxicology. PMID- 24047414 TI - Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions. AB - Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by the increasing prevalence of target-mediated drug resistance. Greater than 90% of mutations that confer quinolone resistance act by disrupting enzyme-drug interactions coordinated by a critical water-metal ion bridge. Quinazolinediones are quinolone-like drugs but lack the skeletal features necessary to support the bridge interaction. These compounds are of clinical interest, however, because they retain activity against the most common quinolone resistance mutations. We utilized a chemical biology approach to determine how quinazolinediones overcome quinolone resistance in Bacillus anthracis topoisomerase IV. Quinazolinediones that retain activity against quinolone-resistant topoisomerase IV do so primarily by establishing novel interactions through the C7 substituent, rather than the drug skeleton. Because some quinolones are highly active against human topoisomerase IIalpha, we also determined how clinically relevant quinolones discriminate between the bacterial and human enzymes. Clinically relevant quinolones display poor activity against topoisomerase IIalpha because the human enzyme cannot support drug interactions mediated by the water-metal ion bridge. However, the inclusion of substituents that allow quinazolinediones to overcome topoisomerase IV-mediated quinolone resistance can cause cross-reactivity against topoisomerase IIalpha. Therefore, a major challenge in designing drugs that overcome quinolone resistance lies in the ability to identify substituents that mediate strong interactions with the bacterial, but not the human, enzymes. On the basis of our understanding of quinolone-enzyme interactions, we have identified three compounds that display high activity against quinolone-resistant B. anthracis topoisomerase IV but low activity against human topoisomerase IIalpha. PMID- 24047419 TI - PyDPI: freely available python package for chemoinformatics, bioinformatics, and chemogenomics studies. AB - The rapidly increasing amount of publicly available data in biology and chemistry enables researchers to revisit interaction problems by systematic integration and analysis of heterogeneous data. Herein, we developed a comprehensive python package to emphasize the integration of chemoinformatics and bioinformatics into a molecular informatics platform for drug discovery. PyDPI (drug-protein interaction with Python) is a powerful python toolkit for computing commonly used structural and physicochemical features of proteins and peptides from amino acid sequences, molecular descriptors of drug molecules from their topology, and protein-protein interaction and protein-ligand interaction descriptors. It computes 6 protein feature groups composed of 14 features that include 52 descriptor types and 9890 descriptors, 9 drug feature groups composed of 13 descriptor types that include 615 descriptors. In addition, it provides seven types of molecular fingerprint systems for drug molecules, including topological fingerprints, electro-topological state (E-state) fingerprints, MACCS keys, FP4 keys, atom pair fingerprints, topological torsion fingerprints, and Morgan/circular fingerprints. By combining different types of descriptors from drugs and proteins in different ways, interaction descriptors representing protein-protein or drug-protein interactions could be conveniently generated. These computed descriptors can be widely used in various fields relevant to chemoinformatics, bioinformatics, and chemogenomics. PyDPI is freely available via https://sourceforge.net/projects/pydpicao/. PMID- 24047420 TI - Molecular basis of binding and stability of curcumin in diamide-linked gamma cyclodextrin dimers. AB - Curcumin is a naturally occurring molecule with medicinal properties that is unstable in water, whose efficacy as a drug can potentially be enhanced by encapsulation inside a host molecule. In this work, the thermodynamics and mechanism of binding of curcumin to succinamide- and urea-linked gamma cyclodextrin (gamma-CD) dimers in water are investigated by molecular dynamics simulations. The simulated binding constants of curcumin to succinamide- and urea linked gamma-CD dimers at 310 K are 11.3 * 10(6) M(-1) and 1.6 * 10(6) M(-1), respectively, matching well with previous experimental results of 8.7 * 10(6) M( 1) and 2.0 * 10(6) M(-1). The simulations reveal structural information about the encapsulation of curcumin inside the diamide-linked gamma-CD dimers, with distinct qualitative differences observed for the two dimers. In particular, (1) the predominant orientation of curcumin inside the urea-linked gamma-CD dimer is perpendicular to that in the succinamide-linked gamma-CD dimer; (2) the magnitude of the angle between the planes of the cyclodextrins is larger for the succinamide-linked gamma-CD dimer; and (3) curcumin exhibits greater configurational freedom inside the urea-linked gamma-CD dimer. A consequence of some of these structural differences is that the dimer interior is more accessible to water in the succinamide-linked gamma-CD dimer. These observations explain the higher stability and lower binding constant observed experimentally for curcumin in the urea-linked cyclodextrin gamma-CD dimer compared with the succinamide-linked gamma-CD dimer. More generally, the results demonstrate how stability and binding strength can be decoupled and thus separately optimized in host-guest systems used for drug delivery. PMID- 24047422 TI - Gender difference in association of NEDD4L gene variants among southern Han Chinese with essential hypertension - a population-based case-control study. AB - Genetic variation of NEDD4L has been associated with hypertension and related phenotypes with conflicting results, probably attributable to gender-, age- and ethnicity-related variations in its phenotypic expression. We evaluated the association of three representative polymorphisms in NEDD4L (rs2288774, rs3865418 and rs4149601) with essential hypertension (EH) in a community-based sample of men (n = 1029) and women (n = 869) belonging to Han Chinese, Southern China, to probe whether gender interacts with NEDD4L in contributing to the risk of EH. In this population sample, rs4149601 was excluded from further analysis due to deviation from Hardy-Weinberg equilibrium. For two other variants tested, the allele frequencies and genotype distributions did not differ between cases and controls (p > 0.05) when both genders were combined. However, sex-stratified analysis revealed that the distribution of the dominant model of rs2288774 (TC + CC versus TT) and the additive and dominant (CT + TT versus CC) models of rs3865418 differed significantly between cases and controls in men (p = 0.044, 0.041 and 0.016, respectively) but not in women. After adjusting for confounding factors, logistic regression analysis showed that rs2288774 and rs3865418 (in the dominant model) were still significantly associated with EH (rs2288774: OR = 0.73, 95% CI = 0.57-0.95, p = 0.017 and rs3865418: OR = 0.71, 95% CI = 0.55-0.92, p = 0.009) in men. There was a significant interaction between the NEDD4L genotype and gender (p for interaction: 0.046 for rs2288774 and 0.033 for rs3865418). Genetic variation in NEDD4L may have sex-dependent effects in the development of EH in Han Chinese. Previous studies that ignore gender-specific effects in their design and interpretation could have failed to identify a uniform conclusion. PMID- 24047423 TI - New hope from an old drug: fighting Alzheimer's disease with the cancer drug bexarotene (targretin)? AB - Despite decades of research, there is no cure for Alzheimer disease (AD), and current pharmacological treatments only partially mask the symptoms while the disease progresses within the brain. AD is associated with impaired clearance of beta-amyloid (Abeta) from the brain, a process facilitated by apolipoprotein E (ApoE), whose expression is transcriptionally regulated by the ligand-activated nuclear receptors peroxisome proliferator-activated receptor-gamma (PPARgamma) and liver X receptor (LXR), in conjunction with retinoid X receptor (RXR). A very interesting study performed by G.E. Landreth's group in three murine models of AD has shown that the RXR agonist bexarotene (Targretin), Food and Drug Administration (FDA) approved and used since 1999 for the treatment of cutaneous T cell lymphoma, promotes a fast ApoE-dependent clearance of soluble Abeta peptides from the brain, reduces Abeta plaques, and stimulates the reversal of cognitive, social, and olfactory deficits. Four independent studies tried to replicate these observations; the clearance of soluble Abeta peptides and the reversal of cognitive deficits were replicated in two studies, but all of the studies failed to replicate the reduction of Abeta plaques. In a second report, G.E. Landreth's group formulates some hypotheses to explain these discrepancies. Although observations in mouse models of AD might not necessarily extrapolate to humans, bexarotene is a very interesting potential drug against AD; phase I and II clinical trials are under way. PMID- 24047421 TI - Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness-a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer. AB - BACKGROUND: The role of estrogen receptor beta (ER-beta) in breast cancer (BC) remains unclear. Some studies have suggested that ER-beta may oppose the actions of estrogen receptor alpha (ER-alpha), and clinical evidence has indicated that the loss of ER-beta expression is associated with a poor prognosis and resistance to endocrine therapy. The objective of the present study was to determine the role of ER-beta and the ER-alpha/ER-beta ratio in predicting the response to endocrine therapy and whether different regimens have any effect on ER-beta expression levels. METHODS: Ninety postmenopausal patients with primary BC were recruited for a short-term double-blinded randomized prospective controlled study. To determine tumor cell proliferation, we measured the expression of Ki67 in tumor biopsy samples taken before and after 26 days of treatment with anastrozole 1 mg/day (N = 25), tamoxifen 20 mg/day (N = 24) or placebo (N = 29) of 78 participants. The pre- and post-samples were placed in tissue microarray blocks and submitted for immunohistochemical assay. Biomarker statuses (ER-beta, ER-alpha and Ki67) were obtained by comparing each immunohistochemical evaluation of the pre- and post-surgery samples using the semi-quantitative Allred's method. Statistical analyses were performed using an ANOVA and Spearman's correlation coefficient tests, with significance at p <= 0.05. RESULTS: The frequency of ER beta expression did not change after treatment (p = 0.33). There were no significant changes in Ki67 levels in ER-beta-negative cases (p = 0.45), but in the ER-beta-positive cases, the anastrozole (p = 0.01) and tamoxifen groups (p = 0.04) presented a significant reduction in post-treatment Ki67 scores. There was a weak but positive correlation between the ER-alpha and ER-beta expression levels. Only patients with an ER-alpha/ER-beta expression ratio between 1 and 1.5 demonstrated significant differences in Ki67 levels after treatment with anastrozole (p = 0.005) and tamoxifen (p = 0.026). CONCLUSIONS: Our results provide additional data that indicate that the measurement of ER-beta in BC patients may help predict tamoxifen and anastrozole responsiveness in the neoadjuvant setting. These effects of hormonal treatment appear to be dependent on the ratio of ER-alpha/ER-beta expression. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89801719. PMID- 24047424 TI - The relationship of cognitive impairment with neurological and psychiatric variables in multiple sclerosis patients. AB - OBJECTIVE: Cognitive impairment (CI) in multiple sclerosis (MS) can develop any time. CI is associated with the degree of neuronal loss, but disease duration, fatigue, comorbid affective disorder, and drug dose may also affect cognition. Our aim was to assess which cognitive domain was disturbed primarily in mild MS patients and to see whether CI was related with clinical and psychiatric features. METHOD: Neurological and psychiatric evaluation of 31 MS patients and 31 age, sex, and education-matched healthy controls were made with Structured Clinical Interview for Axis I Disorders (SCID-I). Depression, anxiety, functionality, fatigue, and disability scoring were determined with Hamilton Depression-Anxiety scales, Global Assessment of Functionality, Fatigue Severity and Expanded Disability Status Scales. Cognitive functions were assessed using Mini Mental, Serial Digit Learning, Verbal and Nonverbal Cancellation, Stroop and Rey Auditory Verbal Learning tests. RESULTS: Retrieval from long-term memory and psychomotor speed were significantly worse in MS group. CI was correlated with disease duration, number of attacks, and physical disability but not with depression and anxiety severity. Disease duration predicted disturbances in recall and psychomotor speed, whereas fatigue and disability predicted depression. CONCLUSION: Psychomotor speed and memory were primarily impaired in MS patients, and CI was closely associated with clinical aspects of MS rather than with depression and anxiety. PMID- 24047425 TI - Neurocognitive functioning in patients with first-episode schizophrenia 1 year from onset in comparison with patients 5 years from onset. AB - OBJECTIVE: The course of neurocognitive deficits in schizophrenia has not yet been established. Therefore, we followed patients with first-episode schizophrenia to verify the course of these deficits. METHODS: In Study 1, tests of neurocognitive functioning were administered to patients with first-episode schizophrenia (FE group) every 6 months. Of the 26 patients who completed the baseline assessment, 19 completed a 6-month follow-up, and 13 completed a 1-year follow-up. In Study 2, 19 patients in FE group at 6-months when the neuropsychological measures was less influenced by psychotic symptoms and other patients who experienced schizophrenia 5-years earlier (5-year group) were compared. RESULTS: In Study 1, verbal memory, motor speed, and executive functions significantly improved at the 1-year follow-up. In Study 2, patients in 5-year group performed worse in verbal memory and executive functions than patients in FE at 6-month group, but marginally but significantly better in verbal fluency. CONCLUSIONS: Verbal memory, executive functions, and verbal fluency were significantly different between 5-year group and FE at 6-month group, and may indicate progression of schizophrenia. Executive functions may reflect the state of psychosis. Working memory and processing speed which did not change significantly from onset are needed to verify the course in further research. PMID- 24047426 TI - Treatment adherence and quality of sleep in schizophrenia outpatients. AB - OBJECTIVE: Patients with schizophrenia (SZ) often present sleep complaints, and patients with sleep disturbances are at a greater risk for symptom worsening after antipsychotic discontinuation. Long-term adherence to antipsychotic treatment remains a challenge for clinicians, and the relationship between quality of sleep and treatment adherence in SZ outpatients has been poorly studied. METHODS: In this cross-sectional, non-interventional study, 811 adult outpatients with a diagnosis of SZ were divided into two groups according to the presence (or absence) of sleep disturbances, and assessed using measures of symptom severity, quality and patterns of sleep, adherence/compliance to treatment, and family support degree. RESULTS: Patients with sleep disturbances were significantly more symptomatic (p < 0.0001), and scored significantly higher on the Pittsburgh Sleep Quality Index (PSQI) as compared with patients without sleep disturbances (p < 0.0001). More compliant patients showed less sleep disturbances (p < 0.0001); moreover, patients with worse compliance to pharmacological treatment showed significantly higher scores on the PSQI (p < 0.0001). Regarding family support degree, patients with sleep disorders presented a lower family support (p = 0.0236), and patients with worse treatment adherence had worse family support (p < 0.0001). CONCLUSIONS: Our findings show that SZ outpatients reporting sleep disturbances show greater symptom severity, and worse adherence/compliance to treatment, as well as a lower family support. PMID- 24047427 TI - The influence of switching from risperidone to paliperidone on the extrapyramidal symptoms and cognitive function in elderly patients with schizophrenia: a preliminary open-label trial. AB - OBJECTIVE: This study was to evaluate the effects on clinical symptoms and cognitive function of switching the treatment of elderly patients with schizophrenia from risperidone to paliperidone (PAL). METHODS: This study was a 12-weeks, preliminary open-label trial. The subjects were 17 inpatients. Their extrapyramidal symptoms (EPS) were assessed using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Scale (BAS), and their cognitive function was assessed using the Brief Assessment Cognition in Schizophrenia: Japanese language version (BACS-J), and their clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity of illness scale (CGI-S) at the 0 and 12 weeks. RESULTS: The DIEPSS and BAS significantly improved after switching from risperidone to PAL. Furthermore, improvement was found on AIMS. The mean change from baseline in z-score of the digit sequencing task was significantly increased. All items on the PANSS and CGI-S were not significant; however, changes in some cognitive function were correlated with changes in EPS. CONCLUSIONS: The results of this study suggest the possibility that switching elderly patients from risperidone to PAL may have improved pre-existing EPS, and may also have helped improve working memory. PMID- 24047428 TI - Testosterone and dehydroepiandrosterone sulfate in female anxious and non-anxious major depression. AB - OBJECTIVES: Major Depression with severe anxiety has been proposed as a distinct clinical variant of Major Depressive Disorder (MDD). This proposal invites the investigation of the differential biological correlates of the anxious versus non anxious MDD. One such research area might be their possible differential associations with androgens. METHODS: Plasma total testosterone and dehydroepiandrosterone were assessed in adequately matched female inpatients with anxious MDD, non-anxious MDD and normal controls. RESULTS: Androgen levels were significantly lower in both patient groups compared to those of controls. Moreover, they were significantly lower in anxious MDD patients compared to those of their non-anxious MDD counterparts. The limitations of this study were cross sectional design of the study, the small sample size of the study sample and the outpatient status of the control group. In addition, free testosterone levels were not measured. CONCLUSIONS: Our findings indicate that female major depression is associated with lower androgen levels, a deficiency aggravated by the severity of their concomitant anxiety. PMID- 24047429 TI - Alternative synthesis of the Colorado potato beetle pheromone. AB - A concise preparation of the pheromone secreted by the male Colorado potato beetle [viz. (3S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one] was accomplished in four steps starting from 2-fluoronerol or 2-fluorogeraniol. The key step in the synthesis involves a 6-endo epoxide ring-opening with ester participation that simultaneously inverts the 3R-configuration of the (3R)-2,3-epoxy-2-fluoroprenyl acetate intermediate and installs the ketone functionality of the semiochemical. Extensive NMR studies validate the proposed 6-endo mechanism of the featured rearrangement, which under anhydrous conditions resulted in the formation of two bicyclic 1,3-dioxan-5-ones via an unprecedented intramolecular Prins cyclization. PMID- 24047430 TI - Interactions between microbial biofilms and marine fouling algae: a mini review. AB - Natural and artificial substrata immersed in the marine environment are typically colonized by microorganisms, which may moderate the settlement/recruitment of algal spores and invertebrate larvae of macrofouling organisms. This mini-review summarizes the major interactions occurring between microbial biofilms and marine fouling algae, including their effects on the settlement, growth and morphology of the adult plants. The roles of chemical compounds that are produced by both bacteria and algae and which drive the interactions are reviewed. The possibility of using such bioactive compounds to control macrofouling will be discussed. PMID- 24047431 TI - Acquisition of an instrumental activity of daily living in patients with Korsakoff's syndrome: a comparison of trial and error and errorless learning. AB - Patients with Korsakoff's syndrome show devastating amnesia and executive deficits. Consequently, the ability to perform instrumental activities such as making coffee is frequently diminished. It is currently unknown whether patients with Korsakoff's syndrome are able to (re)learn instrumental activities. A good candidate for an effective teaching technique in Korsakoff's syndrome is errorless learning as it is based on intact implicit memory functioning. Therefore, the aim of the current study was two-fold: to investigate whether patients with Korsakoff's syndrome are able to (re)learn instrumental activities, and to compare the effectiveness of errorless learning with trial and error learning in the acquisition and maintenance of an instrumental activity, namely using a washing machine to do the laundry. Whereas initial learning performance in the errorless learning condition was superior, both intervention techniques resulted in similar improvement over eight learning sessions. Moreover, performance in a different spatial layout showed a comparable improvement. Notably, in follow-up sessions starting after four weeks without practice, performance was still elevated in the errorless learning condition, but not in the trial and error condition. The current study demonstrates that (re)learning and maintenance of an instrumental activity is possible in patients with Korsakoff's syndrome. PMID- 24047432 TI - Iron oxide nanoparticles suppress the production of IL-1beta via the secretory lysosomal pathway in murine microglial cells. AB - BACKGROUND: Superparamagnetic iron oxide nanoparticles (IONPs) have been used as magnetic resonance imaging contrast agents for various research and diagnostic purposes, such as the detection of neuroinflammation and blood-brain-barrier integrity. As the central resident macrophage-like cells, microglia are responsible for managing foreign agents invading the CNS. The present study investigated the direct effect of IONPs on the production of pro-inflammatory cytokines by murine microglia stimulated with lipopolysaccharide (LPS). METHODS: Primary murine microglial cells were pretreated with IONPs (1-50 MUg Fe/mL) for 30 min and then stimulated with LPS (100 ng/mL) for 24 h. Confocal microscopy is used to visualize the intracellular IONP distribution and secretory lysosomes after staining with LysoTracker and Rab27a, respectively. The production of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha was quantified by ELISA. The activity of IL-1beta converting enzyme (ICE) and TNF-alpha converting enzyme (TACE) was measured by fluorescent microplate assay using specific substrates. The lysosomal number, alkalinity, permeability and cathepsin B activity were determined by flow cytometry with ectodermal dysplasia-1, lysosensor and acridine orange staining, and using cathepsin B specific substrate, respectively. RESULTS: Confocal imaging revealed that IONPs were markedly engulfed by microglia. Exposure to IONPs attenuated the production of IL 1beta, but not TNF-alpha. Concordantly, the activity of ICE, but not the TACE, was suppressed in IONP-treated cells. Mechanistic studies showed that IONPs accumulated in lysosomes and the number of lysosomes was increased in IONP treated cells. In addition, exposure to IONPs increased lysosomal permeability and alkalinity, but decreased the activity of cathepsin B, a secretory lysosomal enzyme involved in the activation of ICE. CONCLUSIONS: Our results demonstrated a contrasting effect of IONPs on the production of IL-1beta and TNF-alpha by LPS stimulated microglia, in which the attenuation of IL-1beta by IONPs was mediated by inhibiting the secretory lysosomal pathway of cytokine processing. PMID- 24047434 TI - Conductive gold nanoparticle mirrors at liquid/liquid interfaces. AB - Gold nanoparticle (Au NP) mirrors, which exhibit both high reflectance and electrical conductance, were self-assembled at a [heptane + 1,2 dichloroethane]/water liquid/liquid interface. The highest reflectance, as observed experimentally and confirmed by finite difference time domain calculations, occurred for Au NP films consisting of 60 nm diameter NPs and approximate monolayer surface coverage. Scanning electrochemical microscopy approach curves over the interfacial metallic NP films revealed a transition from an insulating to a conducting electrical material on reaching a surface coverage at least equivalent to the formation of a single monolayer. Reflectance and conductance transitions were interpreted as critical junctures corresponding to a surface coverage that exceeded the percolation threshold of the Au NP films at the [heptane + 1,2-dichloroethane]/water interface. PMID- 24047433 TI - Aggravation of myocardial dysfunction by injurious mechanical ventilation in LPS induced pneumonia in rats. AB - BACKGROUND: Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI) and may thereby contribute to fatal multiple organ failure. We tested the hypothesis that injurious MV of lipopolysaccharide (LPS) pre-injured lungs induces myocardial inflammation and further dysfunction ex vivo, through calcium (Ca2+)-dependent mechanism. MATERIALS AND METHODS: N = 35 male anesthetized and paralyzed male Wistar rats were randomized to intratracheal instillation of 2 mg/kg LPS or nothing and subsequent MV with lung-protective settings (low tidal volume (Vt) of 6 mL/kg and 5 cmH2O positive end-expiratory pressure (PEEP)) or injurious ventilation (high Vt of 19 mL/kg and 1 cmH2O PEEP) for 4 hours. Myocardial function ex vivo was evaluated in a Langendorff setup and Ca2+ exposure. Key mediators were determined in lung and heart at the mRNA level. RESULTS: Instillation of LPS and high Vt MV impaired gas exchange and, particularly when combined, increased pulmonary wet/dry ratio; heat shock protein (HSP)70 mRNA expression also increased by the interaction between LPS and high Vt MV. For the heart, C-X-C motif ligand (CXCL)1 and Toll-like receptor (TLR)2 mRNA expression increased, and ventricular (LV) systolic pressure, LV developed pressure, LV +dP/dtmax and contractile responses to increasing Ca2+ exposure ex vivo decreased by LPS. High Vt ventilation aggravated the effects of LPS on myocardial inflammation and dysfunction but not on Ca2+ responses. CONCLUSIONS: Injurious MV by high Vt aggravates the effects of intratracheal instillation of LPS on myocardial dysfunction, possibly through enhancing myocardial inflammation via pulmonary release of HSP70 stimulating cardiac TLR2, not involving Ca2+ handling and sensitivity. PMID- 24047435 TI - Examination of mental health status and aggravation level among mothers of children with isolated oral clefts. AB - OBJECTIVE: To examine self-reported mental health status and aggravation level in mothers of children with isolated oral clefts. METHODS: Population-based sample of children (aged 4 to 9 years) with isolated oral clefts was enumerated from births from 1998 through 2003 in Arkansas, Iowa, and New York State. Mothers of 294 children completed the Mental Health Inventory 5-item questionnaire and Aggravation in Parenting Scale. The Mental Health Inventory and Aggravation in Parenting Scale scores, stratified by poor (Mental Health Inventory <= 67) and better (Mental Health Inventory > 67) mental health status or high (Aggravation in Parenting Scale <= 11), moderate (Aggravation in Parenting Scale = 12 to 15) and low (Aggravation in Parenting Scale = 16) aggravation, were compared by selected maternal and child characteristics. Mean scores for each instrument and proportion of mothers with poor mental health or high aggravation were compared with those reported in the National Survey of American Families. RESULTS: Mean scores for each instrument and proportion of mothers with poor mental health or high aggravation differed little from published data. Mothers with poor mental health tended to be less educated, to have lower household incomes, and to rate their health and their child's health lower than those in better mental health. Mothers with high aggravation tended to have lower household incomes, to have more children, and to rate their health and their child's health lower than those with moderate or low aggravation. CONCLUSIONS: Mothers of affected children were not more likely to experience poor mental health or high aggravation compared with published data; however, sociodemographic characteristics were associated with maternal psychosocial adaptation. Brief screeners for mental health and parenting administered during routine appointments may facilitate identifying at risk caregivers. PMID- 24047436 TI - Changes in grafted autogenous bone during edgewise treatment in patients with unilateral cleft lip/palate or alveolus. AB - Objective : To examine the changes in autogenous bone from 6 to 12 months after alveolar bone grafting (ABG) (T1) through completion of edgewise treatment (T2). Design : Retrospective longitudinal study. Setting : Multidisciplinary long-term follow-up at Kagoshima University Hospital. Patients : Forty-three patients with unilateral cleft lip and palate or alveolus. Main Outcome Measures : At T1 and T2, the bone bridge and quantity of grafted bone were evaluated using the Chelsea scale and the ABG scale. The cleft-adjacent tooth angles before ABG and at T2, as well as the number of orthodontic space closures, were examined. Patients were classified as having either adequate (type A or C; adequate group) or poor bone bridges (type B, D, E, or F; poor group) by the assessment at T1. Results : At T1, the ABG scores for the cleft-adjacent central incisor side of patients in the adequate group were higher than those of patients in the poor group (P < .001). At T2, the adequate group had higher ABG scores for the cleft-adjacent central incisor side (P = .022) and the canine sides (P = .034). No significant differences in tooth angles or the number of orthodontic space closures were noted between the groups. Conclusions : These results suggest that the quantity of grafted bone in the cleft-adjacent central incisor at 6 to 12 months post-ABG may be an indicator of the quantity of grafted bone that will be present after edgewise treatment. PMID- 24047437 TI - AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression in human chondrosarcoma. AB - Chemokine (C-C motif) ligand 3 (CCL3), also known as macrophage inflammatory protein-1alpha, is a cytokine involved in inflammation and activation of polymorphonuclear leukocytes. CCL3 has been detected in infiltrating cells and tumor cells. Chondrosarcoma is a highly malignant tumor that causes distant metastasis. However, the effect of CCL3 on human chondrosarcoma metastasis is still unknown. Here, we found that CCL3 increased cellular migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells. Pre treatment of cells with the MMP-2 inhibitor or transfection with MMP-2 specific siRNA abolished CCL3-induced cell migration. CCL3 has been reported to exert its effects through activation of its specific receptor, CC chemokine receptor 5 (CCR5). The CCR5 and AMP-activated protein kinase (AMPK) inhibitor or siRNA also attenuated CCL3-upregulated cell motility and MMP-2 expression. CCL3-induced expression of MMP-2 and migration were also inhibited by specific inhibitors, and inactive mutants of AMPK, p38 mitogen activated protein kinase (p38 or p38-MAPK), and nuclear factor kappaB (NF-kappaB) cascades. On the other hand, CCL3 treatment demonstrably activated AMPK, p38, and NF-kappaB signaling pathways. Furthermore, the expression levels of CCL3, CCR5, and MMP-2 were correlated in human chondrosarcoma specimens. Taken together, our results indicate that CCL3 enhances the migratory ability of human chondrosarcoma cells by increasing MMP-2 expression via the CCR5, AMPK, p38, and NF-kappaB pathways. PMID- 24047439 TI - Highly efficient generation of hydrogen from the hydrolysis of silanes catalyzed by [RhCl(CO)2]2. AB - Catalytic hydrolysis of silanes mediated by chlorodicarbonylrhodium(I) dimer [RhCl(CO)2]2 to produce silanols and dihydrogen efficiently under mild conditions is reported. Second-order kinetics and activation parameters are determined by monitoring the rate of dihydrogen evolution. The mixing of [RhCl(CO)2]2 and HSiCl3 results in rapid formation of a rhodium silane sigma complex. PMID- 24047438 TI - Evaluation of single-dose azithromycin versus standard azithromycin/doxycycline treatment and clinical assessment of regression course in patients with adult inclusion conjunctivitis. AB - BACKGROUND: Single-dose azithromycin (AZT) has been proved efficient in treating various human Chlamydia infections. However, it has not been thoroughly tested in patients with adult inclusion conjunctivitis (AIC). It is the aim of this study to perform a comparative evaluation of efficacy and safety of one-day AZT with long-term AZT and doxycycline (DOX) regimens in AIC and to present a clinical profile of regression course of the disease. MATERIALS: Eighty-three consecutive adults, with symptoms and signs of chronic conjunctivitis and positive Polymerase Chain Reaction (PCR) for chlamydia, were randomly assigned in four treatment groups; AZT 1-day 1000 mg orally, AZT 500 mg daily 9 and 14 days and DOX 200 mg 21 days orally. Follow-up visits were scheduled 1 and 2 weeks, 1, 3 and 6 months after treatment completion. PCR was repeated at the 2nd post-treatment week to confirm elimination of infectious agent. Detailed record of subjective symptoms and objective signs was performed at all visits. Retreatment rate among groups was evaluated as primary outcome. Regression rate of symptoms/signs among groups was recorded as secondary outcomes. RESULTS: All treatment groups provided statistically equivalent results of retreatment rate. Statistically significant regression of symptoms/signs was documented, initially from the 1st post treatment week in general, but 1 month was required for complete patients' relief. Follicles were the most common clinical sign with the earliest regression after successful treatment. CONCLUSION: Single-dose azithromycin should be considered as equally reliable treatment option, comparing to long-term alternative regimens for AIC. Patients should wait for one week, until first signs of significant regression become obvious and should consider approximately one month to total relief. Follicles could be reasonably used as a key sign for clinical assessment of treatment success. PMID- 24047440 TI - Synthesis of 3H-pyrazolo[3,4-c]isoquinolines and thieno[3,2-c]isoquinolines via cascade imination/intramolecular decarboxylative coupling. AB - A general approach for the synthesis of 3H-pyrazolo[3,4-c]isoquinolines and thieno[3,2-c]isoquinolines is described involving the implementation of a cascade imination/intramolecular decarboxylative coupling between potassium 2 amino(hetero)benzoates and 2-haloarylaldehydes. The reactions of pyrazole-based substrates require a Pd-Cu bimetallic system for superior yields whereas the thienyl-based substrates afford the products in excellent yields with a Pd catalyst only. PMID- 24047442 TI - Distinctive activation and functionalization of hydrocarbon C-H bonds initiated by Cp*W(NO)(eta(3)-allyl)(CH2CMe3) complexes. AB - Converting hydrocarbon feedstocks into value-added chemicals continues to offer challenges to contemporary preparative chemists. A particularly important remaining challenge is the selective activation and functionalization of the C(sp(3))-H linkages of alkanes, which are relatively abundant but chemically inert. This Account outlines the discovery and development of C-H bond functionalization mediated by a family of tungsten organometallic nitrosyl complexes. Specifically, it describes how gentle thermolyses of any of four 18 electron Cp*W(NO)(eta(3)-allyl)(CH2CMe3) complexes (Cp* = eta(5)-C5Me5; eta(3) allyl = eta(3)-H2CCHCHMe, eta(3)-H2CCHCHSiMe3, eta(3)-H2CCHCHPh, or eta(3) H2CCHCMe2) results in the loss of neopentane and the transient formation of a 16 electron intermediate species, Cp*W(NO)(eta(2)-allene) and/or Cp*W(NO)(eta(2) diene). We have never detected any of these species spectroscopically, but we infer their existence based on trapping experiments with trimethylphosphine (PMe3) and labeling experiments using deuterated hydrocarbon substrates. This Account first summarizes the syntheses and properties of the four chiral Cp*W(NO)(eta(3)-allyl)(CH2CMe3) complexes. It then outlines the various types of C-H activations we have effected with each of the 16-electron (eta(2)-allene) or (eta(2)-diene) intermediate nitrosyl complexes, and presents the results of mechanistic investigations of some of these processes. It next describes the characteristic chemical properties of the Cp*W(NO)(eta(3)-allyl)(eta(1) hydrocarbyl) compounds formed by the single activations of C(sp(3))-H bonds, with particular emphasis on those reactions that result in the selective functionalization of the original hydrocarbon substrate. We are continuing development of methods to release the acyl ligands from the metal centers while keeping the Cp*W(NO)(eta(3)-allyl) fragments intact, with the ultimate aim of achieving these distinctive conversions of alkanes into functionalized organics in a catalytic manner. PMID- 24047441 TI - Nur77 suppresses pulmonary artery smooth muscle cell proliferation through inhibition of the STAT3/Pim-1/NFAT pathway. AB - The orphan nuclear receptor 4A (NR4A) family plays critical roles in the regulation of cell proliferation, differentiation, and survival in the cardiovascular system. However, the molecular mechanisms underlying the regulation of NR4A receptor expression and its role in pulmonary artery smooth muscle cell (PASMC) function remain unclear. Here, we investigated whether the NR4A family regulates PASMC proliferation, and if so, which mechanisms are involved. By using quantitative real-time RT-PCR, we showed that the orphan nuclear receptor Nur77 was the most abundant member of NR4A family expressed in rat PASMCs, as compared with the two other members, NOR-1 and Nurr1. In rat PASMCs, expression of Nur77 was robustly induced in response to several pathologic stimuli of pulmonary arterial hypertension (PAH), such as hypoxia, 5 hydroxytryptamine (5-HT), platelet-derived growth factor, and endothelin-1. Importantly, Nur77 was also significantly increased in lungs of rats with monocrotaline-induced PAH. Furthermore, we demonstrated that 5-HT markedly up regulated Nur77 expression through the mitogen-activated protein kinases/extracellular signal-regulated kinase 1/2 pathway. Overexpression of Nur77 inhibited 5-HT-induced PASMC proliferation, as well as the expression of cyclin D1 and proliferating cell nuclear antigen. Mechanistically, we demonstrated that Nur77 specifically interacts with signal transducer and activator of transcription 3, thus inhibiting its phosphorylation and expression of its target genes, such as Pim-1, nuclear factor of activated T cells c2, and survivin in PASMCs. These results indicate that Nur77 is a novel negative feedback regulator of PASMC proliferation through inhibition of the signal transducer and activator of transcription 3/Pim-1/nuclear factor of activated T cells axis. Modulation of Nur77 activity may potentially represent a novel therapeutic strategy for the treatment of PAH. PMID- 24047443 TI - Antimycobacterial activity of cyclic dipeptides isolated from Bacillus sp. N strain associated with entomopathogenic nematode. AB - CONTEXT: Tuberculosis (TB) is one of the leading causes of morbidity and mortality with a global mortality rate of two million deaths per year; one-third of the world's population is infected with Mycobacterium tuberculosis. OBJECTIVE: The aim of this study was to determine the antimycobacterial activity of six diketopiperazines (DKPs) purified from a Bacillus sp. N strain associated with entomopathogenic nematode Rhabditis (Oscheius) sp. MATERIALS AND METHODS: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration of DKPs were determined using the broth dilution method on Middlebrook 7H11 against M. tuberculosis H37Rv. Time-kill assay was used to determine the rate of killing of M. tuberculosis H37Rv by DKPs. The cytotoxicity of the DKPs was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay against the VERO cell line. RESULTS: Out of six DKP-tested cyclo-(D-Pro-L-Leu), cyclo-(L-Pro L-Met) and cyclo-(D-Pro-L-Phe) recorded antimycobacterial activity, the cyclo-(L Pro-L-Met) showed the highest activity and MIC values of 4 MUg/ml for M. tuberculosis H37Rv. The MIC value for rifampicin was 0.06 MUg/ml. Growth curve study by the MIC concentration of cyclic dipeptides recorded significant inhibition when compared with control. Time-kill curve showed maximum reduction of colony count was between 3 and 5 weeks. The DKPs are nontoxic to the VERO cell line up to 200 ug/ml. The antimycobacterial activity of cyclo-(D-Pro-L-Leu), cyclo-(L-Pro-L-Met) and cyclo-(D-Pro-L-Phe) is reported in this study for the first time. DISCUSSION AND CONCLUSION: In conclusion, the potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for treatment against TB. PMID- 24047444 TI - Total synthesis of maoecrystal V: early-stage C-H functionalization and lactone assembly by radical cyclization. AB - A total synthesis of the unusual ent-kaurane maoecrystal V is described. The synthesis strategy features a counterintuitive early disconnection of the lactone subunit to a polycyclic enol ether intermediate in order to preserve the central tetrahydrofuran ring until the beginning stages of the synthesis. This strategy enables an application of C-H functionalization at the early phase of the synthesis during the construction of a dihydrobenzofuran intermediate. PMID- 24047445 TI - Searching for likeness in a database of macromolecular complexes. AB - A software tool and workflow based on distance geometry is presented that can be used to search for local similarity in substructures in a comprehensive database of experimentally derived macromolecular structure. The method does not rely on fold annotation, specific secondary structure assignments, or sequence homology and may be used to locate compound substructures of multiple segments spanning different macromolecules that share a queried backbone geometry. This generalized substructure searching capability is intended to allow users to play an active part in exploring the role specific substructures play in larger protein domains, quaternary assemblies of proteins, and macromolecular complexes of proteins and polynucleotides. The user may select any portion or portions of an existing structure or complex to serve as a template for searching, and other structures that share the same structural features are identified, retrieved and overlaid to emphasize substructural likeness. Matching structures may be compared using a variety of integrated tools including molecular graphics for structure visualization and matching substructure sequence logos. A number of examples are provided that illustrate how generalized substructure searching may be used to understand both the similarity, and individuality of specific macromolecular structures. Web-based access to our substructure searching services is freely available at https://drugsite.msi.umn.edu. PMID- 24047446 TI - Genome-wide association study of co-occurring anxiety in major depression. AB - OBJECTIVES: Co-morbidity between depression and anxiety disorders is common. In this study we define a quantitative measure of anxiety by summating four anxiety items from the SCAN interview in a large collection of major depression (MDD) cases to identify genes contributing to this complex phenotype. METHODS: A total of 1522 MDD cases dichotomised according to those with at least one anxiety item scored (n = 1080) and those without anxiety (n = 442) were analysed, and also compared to 1588 healthy controls at a genome-wide level, to identify genes that may contribute to anxiety in MDD. RESULTS: For the quantitative trait, suggestive evidence of association was detected for two SNPs, and for the dichotomous anxiety present/absent ratings for three SNPs at genome-wide level. In the genome wide analysis of MDD cases with co-morbid anxiety and healthy controls, two SNPs attained P values of < 5 * 10-6. Analysing candidate genes, P values <= 0.0005 were found with three SNPs for the quantitative trait and three SNPs for the dichotomous trait. CONCLUSIONS: This study provides an initial genome-wide assessment of possible genetic contribution to anxiety in MDD. Although suggestive evidence of association was found for several SNPs, our findings suggest that there are no common variants strongly associated with anxious depression. PMID- 24047447 TI - Entangled photon-pair two-dimensional fluorescence spectroscopy (EPP-2DFS). AB - We introduce a new method, called entangled photon-pair two-dimensional fluorescence spectroscopy (EPP-2DFS), to sensitively probe the nonlinear electronic response of molecular systems. The method incorporates a separated two photon ('Franson') interferometer, which generates time-frequency-entangled photon pairs, into the framework of a fluorescence-detected 2D optical spectroscopic experiment. The entangled photons are temporally shaped and phase modulated in the interferometer, and are used to excite a two-photon-absorbing (TPA) sample, whose excited-state population is selectively detected by simultaneously monitoring the sample fluorescence and the exciting fields. In comparison to 'classical' 2DFS techniques, major advantages of this scheme are the suppression of uncorrelated background signals, the enhancement of simultaneous time-and-frequency resolution, the suppression of diagonal 2D spectral features, and the enhancement and narrowing of off-diagonal spectral cross-peaks that contain information about electronic couplings. These effects are a consequence of the pure-state field properties unique to a parametric down conversion light source, which must be included in the quantum mechanical description of the composite field-molecule system. We numerically simulate the EPP-2DFS observable for the case of an electronically coupled molecular dimer. The EPP-2DFS spectrum is greatly simplified in comparison to its classical 2D counterpart. Our results indicate that EPP-2DFS can provide previously unattainable resolution to extract model Hamiltonian parameters from electronically coupled molecular dimers. PMID- 24047448 TI - Highly specific and reversible fluoride sensor based on an organic semiconductor. AB - A novel sulfonamide-conjugated benzo-[2,1-b:3,4-b']bithiophene semiconductor has been designed and synthetized in order to develop a probe for specific detection of anions both in the homogeneous (solution) and heterogeneous phase. Its photophysical and electrochemical data were reported in this study. On the basis of the optical and NMR titrations analysis, the chelator was found to be highly selective for fluoride compared to others anions (Ka = 1.6 * 10(4) M(-1) in dimethyl sulfoxide (DMSO)). In addition, from an intricate sample, the novel chelator shows exceptional specificity toward fluoride and reveals a complete reversibility after addition of trifluoroacetic acid (TFA). Sensing films were obtained by electrochemical polymerization of the probe on an electrode surface, which clearly show effective detection of fluoride. PMID- 24047449 TI - Characteristics of white coat hypertension in Chinese Han patients with type 2 diabetes mellitus. AB - OBJECTIVES: This study documented the prevalence and clinical features of white coat hypertension (WCH) among Chinese Han patients with type 2 diabetes mellitus (T2DM). METHODS: Clinic and ambulatory blood pressure (BP) measurements were compared in 856 patients with T2DM to determine the frequency of WCH (WCH was defined as clinical blood pressure >=140/90 mmHg and daytime blood pressure <135/85 mmHg and/or 24-h ambulatory BP (ABP) mean value of <130/80 mmHg on ambulatory BP monitoring (ABPM). Weight, waist circumference (WC), body mass index (BMI), waist to height ratio (WHtR), fasting blood glucose, glycosylated hemoglobin level and circadian BP patterns were also measured to find clinical features predictive of WCH in T2DM. RESULTS: The prevalence of WCH was 7.36% (63/856) in the overall population, 6.13% (29/473) in male and 8.88% (34/383) in female (p < 0.05). WCH accounted for 14.03% (63/449) of diagnosed hypertension. Age, course of T2DM, male WC were independent protective factors, whereas female sex, smoking and alcohol consumption were independent risk factors for WCH in T2DM. Non-dippers and reverse dippers made up larger proportion of the WCH group (p < 0.01). CONCLUSION: WCH is relatively common among T2DM patients, it is a unique condition distinct from essential hypertension (EH), and WCH patients also exhibit significant differences in clinical parameters. PMID- 24047450 TI - Optimizing expectations to prevent side effects and enhance quality of life in breast cancer patients undergoing endocrine therapy: study protocol of a randomized controlled trial. AB - BACKGROUND: Adjuvant endocrine therapy can improve disease-free survival and time before recurrence in breast cancer patients. However, it is associated with considerable side effects that negatively affect patients' quality of life and cause non-adherence. The recently demonstrated effect of individual expectations on side-effect development (nocebo effect) suggests that psychological factors play a role in the prevention of side effects. The aim of this study is to evaluate cognitive-behavioral side-effect prevention training (SEPT) for breast cancer patients. This article describes the study protocol and applied research methods. METHODS/DESIGN: In a randomized controlled trial, 184 female breast cancer patients are assigned to receive either SEPT, standard medical care or a manualized supportive therapy at the start of adjuvant endocrine treatment. SEPT consists of three sessions of cognitive-behavioral training including psychoeducation to provide a realistic view of endocrine therapy, imagination training to integrate positive aspects of medication into daily life, and side effect management to enhance expectations about coping ability. Side effects three months after the start of endocrine therapy serve as primary outcomes. Secondary outcomes include quality of life, coping ability and patients' medication adherence. Patients' expectations (i.e., expectations about side effects, coping ability, treatment and illness) are analyzed as mediators. DISCUSSION: The optimization of expectations might be a potential pathway in health care to improve patients' quality of life during long-term medication intake. The results will provide implications for a possible integration of evidence-based prevention training into clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT01741883). PMID- 24047451 TI - Death rattle is not associated with patient respiratory distress: is pharmacologic treatment indicated? AB - BACKGROUND: Studies examining the effectiveness of treatment in reducing the noises of death rattle have been conducted; however, the physical impact of death rattle on the patient experiencing the phenomenon has not been investigated. Treatments may be undertaken to appease family and staff but these treatments may be more burdensome than beneficial to the patient. Further, nonbeneficial treatments increase the cost of care. OBJECTIVE: To determine if patients with naturally occurring death rattle experience respiratory distress. DESIGN: A prospective, two-group observation study was conducted. Patients who were near death were stratified into those with and without death rattle. SETTING/SUBJECTS: Seventy-one dying patients were recruited from three palliative care and hospice settings. Patients were excluded if they had an artificial airway or if their clinical condition caused a secondary source of death rattle, identified as pseudo-death rattle. MEASUREMENTS: Daily observations were made for death rattle intensity and respiratory distress along with use of antisecretory medications. RESULTS: About half of the sample had no death rattle (55%).There were no differences in respiratory distress when patients with and without death rattle were compared (t=1.48, p=0.143). Death rattle intensity and respiratory distress were not correlated (r=-0.13, p=0.477). Few patients (17%) were medicated with antisecretory agents. Many (58%) patients receiving an antisecretory agent did not experience a reduction in death rattle. CONCLUSIONS: Respiratory distress was not associated with death rattle among patients who were near death. In many cases, antisecretory agents did not produce quiet breathing. PMID- 24047452 TI - Depressive symptoms among cancer patients in a Philippine tertiary hospital: prevalence, factors, and influence on health-related quality of life. AB - BACKGROUND: The World Health Organization recognizes depression as one of the most burdensome diseases in the world. Among cancer patients, depression is significantly associated with shorter survival, independent of the influence of biomedical prognostic factors. Although cancer is the third leading cause of morbidity and mortality among Filipinos, little is known about depressive symptoms and their influence on health-related quality of life in this population. We assessed the prevalence of, and factors associated with, depressive symptoms and their influence on health-related quality of life in Filipino patients with cancer. METHODS: The Patient Health Questionnaire (PHQ)-8 and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 were administered to all inpatients and outpatients, age >=18 years presenting for cancer treatment. RESULTS: Twenty-two percent (n=53/247) were categorized as depressed, using a PHQ-8 cutoff of >=10. Depressed patients scored lower on cognitive, emotional, role, physical, and social functioning than those who scored PHQ<10 (all P<0.001). Depression varied by disease status, performance status and marital status (all P<0.001). However, only performance status (OR [odds ratio]=2.20; 95% CI=1.60, 3.00) and disease status (OR=2.4; 95% CI=1.13, 5.22) were significantly associated with depression in the multivariable model. CONCLUSIONS: Depression is prevalent in Filipino cancer patients. The findings provide empirical support for the development of mental health services in this understudied population. This study, the first to assess the prevalence of and factors associated with depression in Filipino cancer patients, needs further validation. PMID- 24047453 TI - The Parkinson's disease-associated H50Q mutation accelerates alpha-Synuclein aggregation in vitro. AB - alpha-Synuclein (alpha-Syn) aggregation is directly linked with Parkinson's disease (PD) pathogenesis. Here, we analyzed the aggregation of newly discovered alpha-Syn missense mutant H50Q in vitro and found that this mutation significantly accelerates the aggregation and amyloid formation of alpha-Syn. This mutation, however, did not alter the overall secondary structure as suggested by two-dimensional nuclear magnetic resonance and circular dichroism spectroscopy. The initial oligomerization study by cross-linking and chromatographic techniques suggested that this mutant oligomerizes to an extent similar to that of the wild-type alpha-Syn protein. Understanding the aggregation mechanism of this H50Q mutant may help to establish the aggregation and phenotypic relationship of this novel mutant in PD. PMID- 24047454 TI - The use of multilevel analysis for integrating single-case experimental design results within a study and across studies. AB - The use of multilevel models as a method for synthesising single-case experimental design results is receiving increased consideration. In this article we discuss the potential advantages and limitations of the multilevel modelling approach. We present a basic two-level model where observations are nested within cases, and then discuss extensions of the basic model to accommodate trends, moderators of the intervention effect, non-continuous outcomes, heterogeneity, autocorrelation, the nesting of cases within studies, and more complex single case design types. We then consider methods for standardising the effect estimates and alternative approaches to estimating the models. These modelling and analysis options are followed by an illustrative example. PMID- 24047455 TI - Effects of bracing in adolescents with idiopathic scoliosis. AB - BACKGROUND: The role of bracing in patients with adolescent idiopathic scoliosis who are at risk for curve progression and eventual surgery is controversial. METHODS: We conducted a multicenter study that included patients with typical indications for bracing due to their age, skeletal immaturity, and degree of scoliosis. Both a randomized cohort and a preference cohort were enrolled. Of 242 patients included in the analysis, 116 were randomly assigned to bracing or observation, and 126 chose between bracing and observation. Patients in the bracing group were instructed to wear the brace at least 18 hours per day. The primary outcomes were curve progression to 50 degrees or more (treatment failure) and skeletal maturity without this degree of curve progression (treatment success). RESULTS: The trial was stopped early owing to the efficacy of bracing. In an analysis that included both the randomized and preference cohorts, the rate of treatment success was 72% after bracing, as compared with 48% after observation (propensity-score-adjusted odds ratio for treatment success, 1.93; 95% confidence interval [CI], 1.08 to 3.46). In the intention-to-treat analysis, the rate of treatment success was 75% among patients randomly assigned to bracing, as compared with 42% among those randomly assigned to observation (odds ratio, 4.11; 95% CI, 1.85 to 9.16). There was a significant positive association between hours of brace wear and rate of treatment success (P<0.001). CONCLUSIONS: Bracing significantly decreased the progression of high-risk curves to the threshold for surgery in patients with adolescent idiopathic scoliosis. The benefit increased with longer hours of brace wear. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and others; BRAIST ClinicalTrials.gov number, NCT00448448.). PMID- 24047456 TI - Spinal bracing in adolescent idiopathic scoliosis. PMID- 24047457 TI - Stereodivergent resolution of oxabicyclic ketones: preparation of key intermediates for platensimycin and other natural products. AB - An improved methodology for the preparation of enantiopure oxabicyclo[3.2.1]octadienes via a stereodivergent resolution is reported. High catalyst control proximal to the oxabridged stereocenter produces readily separable diastereomers in high yield (>92%) and with excellent optical purity (>95% ee). This resolution strategy is amenable to large-scale preparations, and the utility of the resolution was further demonstrated in the asymmetric preparation of a key intermediate used in the synthesis of the antibiotic (-) platensimycin. PMID- 24047458 TI - Understanding urinary conditioning film components on ureteral stents: profiling protein components and evaluating their role in bacterial colonization. AB - Ureteral stents are fraught with problems. A conditioning film attaches to the stent surface within hours of implantation; however, differences between stent types and their role in promoting encrustation and bacterial adhesion and colonization remain to be elucidated. The present work shows that the most common components do not differ between stent types or patients with the same indwelling stent, and contain components that may drive stent encrustation. Furthermore, unlike what was previously thought, the presence of a conditioning film does not increase bacterial adhesion and colonization of stents by uropathogens. Genitourinary cytokeratins are implicated in playing a significant role in conditioning film formation. Overall, stent biomaterial design to date has been unsuccessful in discovering an ideal coating to prevent encrustation and bacterial adhesion. This current study elucidates a more global understanding of urinary conditioning film components. It also supports specific focus on the importance of physical characteristics of the stent and how they can prevent encrustation and bacterial adhesion. PMID- 24047459 TI - On-surface azide-alkyne cycloaddition on Au(111). AB - We present [3 + 2] cycloaddition reactions between azides and alkynes on a Au(111) surface at room temperature and under ultrahigh vacuum conditions. High resolution scanning tunneling microscopy images reveal that these on-surface cycloadditions occur highly regioselectively to form the corresponding 1,4 triazoles. Density functional theory simulations confirm that the reactions can occur at room temperature, where the Au(111) surface does not participate as a catalytic agent in alkyne C-H activation but acts solely as a two-dimensional constraint for the positioning of the two reaction partners. The on-surface azide alkyne cycloaddition offers great potential toward the development and fabrication of functional organic nanomaterials on surfaces. PMID- 24047460 TI - Membrane protein orientation and refinement using a knowledge-based statistical potential. AB - BACKGROUND: Recent increases in the number of deposited membrane protein crystal structures necessitate the use of automated computational tools to position them within the lipid bilayer. Identifying the correct orientation allows us to study the complex relationship between sequence, structure and the lipid environment, which is otherwise challenging to investigate using experimental techniques due to the difficulty in crystallising membrane proteins embedded within intact membranes. RESULTS: We have developed a knowledge-based membrane potential, calculated by the statistical analysis of transmembrane protein structures, coupled with a combination of genetic and direct search algorithms, and demonstrate its use in positioning proteins in membranes, refinement of membrane protein models and in decoy discrimination. CONCLUSIONS: Our method is able to quickly and accurately orientate both alpha-helical and beta-barrel membrane proteins within the lipid bilayer, showing closer agreement with experimentally determined values than existing approaches. We also demonstrate both consistent and significant refinement of membrane protein models and the effective discrimination between native and decoy structures. Source code is available under an open source license from http://bioinf.cs.ucl.ac.uk/downloads/memembed/. PMID- 24047461 TI - Incidence, predictors, and outcome of intermediate syndrome in cholinergic insecticide poisoning: a prospective observational cohort study. AB - CONTEXT: Clinical manifestations and outcome of cholinergic insecticide poisoning is well studied. There are limited data on neuroparalytic features, predictors, and impact on mortality of intermediate syndrome. METHODS: Patients admitted with history of insecticide exposure and cholinergic signs in a tertiary care center between April 2011 and March 2012 were followed up till recovery or death. While on standard care, development of intermediate syndrome was noted by neck and proximal muscle weakness, and/or signs of respiratory failure in the absence of cholinergic signs. RESULTS: In 176 patients studied, incidence of intermediate syndrome was 17.6% (n = 31) with mean time of appearance of 44.5 +/- 22.1 h after exposure (range 26 h- 5 days). Intermediate syndrome occurred in organophosphorus and carbamate poisoning (38.7% and 41.9%) and lasted for 1-7 days. All patients with intermediate syndrome developed weakness of neck and proximal muscles during the course; neck muscle weakness was the initial feature in majority of patients with respiratory failure (20/26). Age >= 45 (RR 2.23, 95% CI 1.14-4.38, p = 0.02), and dimethyl organophosphorus compounds (RR 4.87, 95% CI 1.82-13.04, p = 0.01) were found to be associated with development of intermediate syndrome while multiple gastric lavage was protective (RR 0.44, 95% CI 0.22-0.87, p = 0.001). Receiver operating characteristic curves were plotted for International Program on Chemical Safety Poison Severity Score (IPCS PSS) and Glasgow coma scale (GCS) on admission (AUC/sensitivity/specificity 0.77/0.94/0.6 for IPCS PSS > 2 and 0.64/0.71/0.65 for GCS <= 10). Overall mortality was 28.4% (n = 50); 40% (n = 20/50) occurred among intermediate syndrome patients with respiratory failure. CONCLUSION: As with exposure to organophosphorus, carbamate also result in intermediate syndrome; risk may be high with age >= 45, admission score of PSS > 2, and GCS <= 10. It can be detected early by identifying neck muscle weakness which aids in anticipating respiratory failure. Multiple gastric lavages may be protective; needs larger studies for clarification. PMID- 24047464 TI - Quantitation of in vitro alpha-1 adrenergic receptor antagonist binding capacity to biologic melanin using tandem mass spectrometry. AB - PURPOSE: The purpose of this study was to develop methods to allow evaluation of the binding characteristics for a series of alpha-1 antagonists to biologically derived melanin. METHODS: Fresh bovine globes were used to obtain iridal and choroid/retinal pigment epithelial (CRPE) derived melanin. Binding characteristics of chloroquine, tamsulosin and doxazosin were then evaluated in vitro using tandem mass spectroscopy. RESULTS: Tandem mass spectrometry-based assays were developed for three alpha-1 antagonists that provided linear assay ranges which spanned (minimally) 0.01-10 ug/mL, while exhibiting excellent inter assay precision and accuracy. When applied to the evaluation of binding characteristics for iridal melanin, mean chloroquine and tamsulosin fractions were found to be 41.9 +/- 14.2 pmoles mg(-1) and 25.34 +/- 6.186 pmoles mg(-1), respectively. Mean iridal doxazosin binding was found to be 6.36 +/- 2.19 pmoles mg(-1). Interestingly, mean levels of tamsulosin, but not doxazosin found bound to choroid/CRPE derived melanin approached that of chloroquine (27.91 ug/mL, 25.68 ug/mL and 5.94 ug/mL for chloroquine, tamsulosin and doxazosin, respectively). One way ANOVA for binding affinity for chloroquine, tamsulosin and doxazosin was statistically significant for both iridal and CRPE-derived melanin (p = 0.0012 and 0.0023), respectively. A Bonferroni post-hoc analysis demonstrated a statistically significant difference in the amount of binding between tamsulosin, doxazosin and chloroquine to iridal but not CRPE derived melanin (p < 0.05). CONCLUSIONS: Tamsulosin appears to demonstrate melanin binding affinity which approaches chloroquine and exceeds doxazosin for both iridal and CRPE-derived bovine melanin. PMID- 24047462 TI - B-cell translocation gene 2 mediates crosstalk between PI3K/Akt1 and NFkappaB pathways which enhances transcription of MnSOD by accelerating IkappaBalpha degradation in normal and cancer cells. AB - BACKGROUND: B-cell translocation gene 2 (BTG2) belongs to antiproliferative (ARPO) gene family and the expression of BTG2, human ortholog of rat PC3 and mouse TIS21 gene, has been shown to render cancer cells more sensitive to doxorubicin treatment by upregulating MnSOD expression without regulating any other reactive oxygen species (ROS) scavenging enzymes. RESULTS: In the present study, by employing exogenous and endogenous BTG2/TIS21/Pc3 expression by transfection and transduction analyses, and by knockdown of gene expression using RNA interference or using gene knockout cells, we observed that BTG2 increased the binding of activated NF-kappaB (p65/RelA) to the enhancer element of MnSOD gene in the 2nd intron, which was regulated by p-Akt1, and the induction of MnSOD by BTG2 was accompanied with subsequent downregulation of ROS level and cyclin B1 biosynthesis along with the increase of p21WAF1, resulting in the G2/M arrest independent of p53. CONCLUSIONS: These results show for the first time that BTG2 mediates crosstalk between PI3K-Akt1 and NF-kappaB pathways, which regulates p53 independent induction of G2/M phase arrest both in normal and cancer cells. PMID- 24047463 TI - Structural characteristics of hospitals and nurse-reported care quality, work environment, burnout and leaving intentions. AB - AIM: To investigate whether hospital characteristics not readily susceptible to change (i.e. hospital size, university status, and geographic location) are associated with specific self-reported nurse outcomes. BACKGROUND: Research often focuses on factors within hospitals (e.g. work environment), which are susceptible to change, rather than on structural factors in their own right. However, numerous assumptions exist about the role of structural factors that may lead to a sense of pessimism and undermine efforts at constructive change. METHOD: Data was derived from survey questions on assessments of work environment and satisfaction, intention to leave, quality of care and burnout (measured by the Maslach Burnout Inventory), from a population-based sample of 11 000 registered nurses in Sweden. Mixed model regressions were used for analysis. RESULT: Registered nurses in small hospitals were slightly more likely to rank their working environment and quality of nursing care better than others. For example 23% of staff in small hospitals were very satisfied with the work environment compared with 20% in medium-sized hospitals and 21% in large hospitals. Registered nurses in urban areas, who intended to leave their job, were more likely to seek work in another hospital (38% vs. 32%). CONCLUSION: While some structural factors were related to nurse-reported outcomes in this large sample, the associations were small or of questionable importance. IMPLICATIONS FOR NURSING MANAGEMENT: The influence of structural factors such as hospital size on nurse-reported outcomes is small and unlikely to negate efforts to improve work environment. PMID- 24047465 TI - pi-Electron conjugation in two dimensions. AB - Organic oligomers and polymers with extended pi-conjugation are the fundamental building blocks of organic electronic devices. Novel routes are being explored to create tailor-made organic materials, and recent progress in organic chemistry and surface chemistry has led to the synthesis of planar 2D polymers. Here we show how extending pi-conjugation in the second dimension leads to novel materials with HOMO-LUMO gaps smaller than in 1D polymers built from the same parent molecular repeat unit. Density functional theory calculations on experimentally realized 2D polymers grant insight into HOMO-LUMO gap contraction with increasing oligomer size and show fundamental differences between 1D and 2D "band gap engineering". We discuss how the effects of cross-conjugation and dihedral twists affect the electronic gaps. PMID- 24047467 TI - Reactivity of nitrido complexes of ruthenium(VI), osmium(VI), and manganese(V) bearing Schiff base and simple anionic ligands. AB - Nitrido complexes (M=N) may be key intermediates in chemical and biological nitrogen fixation and serve as useful reagents for nitrogenation of organic compounds. Osmium(VI) nitrido complexes bearing 2,2':6',2"-terpyridine (terpy), 2,2'-bipyridine (bpy), or hydrotris(1-pyrazolyl)borate anion (Tp) ligands are highly electrophilic: they can react with a variety of nucleophiles to generate novel osmium(IV)/(V) complexes. This Account describes our recent results studying the reactivity of nitridocomplexes of ruthenium(VI), osmium(VI), and manganese(V) that bear Schiff bases and other simple anionic ligands. We demonstrate that these nitrido complexes exhibit rich chemical reactivity. They react with various nucleophiles, activate C-H bonds, undergo N...N coupling, catalyze the oxidation of organic compounds, and show anticancer activities. Ruthenium(VI) nitrido complexes bearing Schiff base ligands, such as [Ru(VI)(N)(salchda)(CH3OH)](+) (salchda = N,N'-bis(salicylidene)o cyclohexyldiamine dianion), are highly electrophilic. This complex reacts readily at ambient conditions with a variety of nucleophiles at rates that are much faster than similar reactions using Os(VI)=N. This complex also carries out unique reactions, including the direct aziridination of alkenes, C-H bond activation of alkanes and C-N bond cleavage of anilines. The addition of ligands such as pyridine can enhance the reactivity of [Ru(VI)(N)(salchda)(CH3OH)](+). Therefore researchers can tune the reactivity of Ru=N by adding a ligand L trans to nitride: L-Ru=N. Moreover, the addition of various nucleophiles (Nu) to Ru(VI)=N initially generate the ruthenium(IV) imido species Ru(IV)-N(Nu), a new class of hydrogen-atom transfer (HAT) reagents. Nucleophiles also readily add to coordinated Schiff base ligands in Os(VI)=N and Ru(VI)=N complexes. These additions are often stereospecific, suggesting that the nitrido ligand has a directing effect on the incoming nucleophile. M=N is also a potential platform for the design of new oxidation catalysts. For example, [Os(VI)(N)Cl4](-) catalyzes the oxidation of alkanes by a variety of oxidants, and the addition of Lewis acids greatly accelerates these reactions. [Mn(V)(N)(CN)4]2(-) is another highly efficient oxidation catalyst, which facilitates the epoxidation of alkenes and the oxidation of alcohols to carbonyl compounds using H2O2. Finally, M=N can potentially bind to and exert various effects on biomolecules. For example, a number of Os(VI)=N complexes exhibit novel anticancer properties, which may be related to their ability to bind to DNA or other biomolecules. PMID- 24047466 TI - Sirtuin 3 deficiency does not augment hypoxia-induced pulmonary hypertension. AB - Alveolar hypoxia elicits increases in mitochondrial reactive oxygen species (ROS) signaling in pulmonary arterial (PA) smooth muscle cells (PASMCs), triggering hypoxic pulmonary vasoconstriction. Mice deficient in sirtuin (Sirt) 3, a nicotinamide adenine dinucleotide-dependent mitochondrial deacetylase, demonstrate enhanced left ventricular hypertrophy after aortic banding, whereas cells from these mice reportedly exhibit augmented hypoxia-induced ROS signaling and hypoxia-inducible factor (HIF)-1 activation. We therefore tested whether deletion of Sirt3 would augment hypoxia-induced ROS signaling in PASMCs, thereby exacerbating the development of pulmonary hypertension (PH) and right ventricular hypertrophy. In PASMCs from Sirt3 knockout (Sirt3(-/-)) mice in the C57BL/6 background, we observed that acute hypoxia (1.5% O2; 30 min)-induced changes in ROS signaling, detected using targeted redox-sensitive, ratiometric fluorescent protein sensors (roGFP) in the mitochondrial matrix, intermembrane space, and the cytosol, were indistinguishable from Sirt3(+/+) cells. Acute hypoxia-induced cytosolic calcium signaling in Sirt3(-/-) PASMCs was also indistinguishable from Sirt3(+/+) cells. During sustained hypoxia (1.5% O2; 16 h), Sirt3 deletion augmented mitochondrial matrix oxidant stress, but this did not correspond to an augmentation of intermembrane space or cytosolic oxidant signaling. Sirt3 deletion did not affect HIF-1alpha stabilization under normoxia, nor did it augment HIF-1alpha stabilization during sustained hypoxia (1.5% O2; 4 h). Sirt3( /-) mice housed in chronic hypoxia (10% O2; 30 d) developed PH, PA wall remodeling, and right ventricular hypertrophy that was indistinguishable from Sirt3(+/+) littermates. Thus, Sirt3 deletion does not augment hypoxia-induced ROS signaling or its consequences in the cytosol of PASMCs, or the development of PH. These findings suggest that Sirt3 responses may be cell type specific, or restricted to certain genetic backgrounds. PMID- 24047468 TI - Pd(0)-catalyzed 1,1-diarylation of ethylene and allylic carbonates. AB - An efficient protocol for the one-step synthesis of biologically relevant 1,1 diarylalkanes has been described. This reaction introduces two different aryl groups across the terminal end of simple feedstock alkenes such as ethylene and allylic carbonates. The propensity to generate pi-benzylpalladium intermediates dictates the exclusive 1,1-regioselectivity observed in the product. PMID- 24047469 TI - Immunophenotypic features and t(14;18) (q32;q21) translocation of Chinese follicular lymphomas helps to distinguish subgroups. AB - BACKGROUND: The revised 2008 World Health Organization classification maintains a histological grading system (grades 1-3) for follicular lymphoma (FL). The value of grading FL has been debated. This study will yield deeper insights into the morphologic, immunophenotypic characterization and t(14;18) translocation in FL and explore their significance of diagnosis of Chinese FL subgroups. METHODS: We retrospectively reviewed the FL diagnoses according to the 2008 WHO classification in all diagnostic specimens from a multicentric cohort of 122 Chinese patients. Upon review, 115 cases proved to be truly FL. CD10, BCL6, MUM1, BCL2 and t(14;18) (q32;q21) translocation were detected by Envision immunostaining technique and fluorescence in situ hybridization. RESULTS: FL1 has larger proportion of follicular pattern (93.0%) than that of FL2 (73.7%, P = 0.036), FL3B (63.6%, P = 0.003) and FL3A (77.4%, P = 0.053), although the last P value was more than 0.05 (Pearson's chi-squared test). Areas of DLBCL were present in 25.8% (8/31) of FL3A and more frequent in FL3B (59.1%, 13/22; P = 0.015). The positivity of CD10 and BCL2 in FL1-2 were significantly higher than those in FL3 (P < 0.001, P = 0.043, respectively). The positivity of MUM1 in FL1 2 was significantly lower than that in FL3 (10.2% vs. 51.0%; P < 0.001). Furthermore the positivity of MUM1 in FL3A was significantly lower than that in FL3B (37.9% vs. 68.2%; P = 0.032). The positivity of t(14;18) was higher in FL1-2 than in FL3 (73.5% vs. 35.6%, P < 0.001), and was higher in FL3A than in FL3B (51.9% vs. 11.1%, P = 0.005). t(14;18) was significantly correlated with CD10+ (R = 0.453, P < 0.001) and MUM1+ (R = -0.482, P < 0.001). CONCLUSIONS: FL1 and FL2 were immunophenotypically and genomically similar, while FL3A and FL3B were partly immunophenotypically similar but morphologically, genomically distinct. FL3A was genomically closer to FL1-2, whereas FL3A was genomically closer DLBCL. Thus we hypothesize that FL may in fact be a heterogeneous indolent lymphoma encompassing entities with distinct molecular pathogenesis and genetic characteristics. Immunohistochemical and genetic characterization helps to distinguish subgroups of FLs. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1334018129864616. PMID- 24047470 TI - Potential effect of the medicinal plants Calotropis procera, Ficus elastica and Zingiber officinale against Schistosoma mansoni in mice. AB - CONTEXT: Calotropis procera (Ait.) R. Br. (Asclepiadaceae), Ficus elastica Roxb. (Moraceae) and Zingiber officinale Roscoe (Zingiberaceae) have been traditionally used to treat many diseases. OBJECTIVE: The antischistosomal activity of these plant extracts was evaluated against Schistosoma mansoni. MATERIALS AND METHODS: Male mice exposed to 80 +/- 10 cercariae per mouse were divided into two batches. The first was divided into five groups: (I) infected untreated, while groups from (II-V) were treated orally (500 mg/kg for three consecutive days) by aqueous stem latex and flowers of C. procera, latex of F. elastica and ether extract of Z. officinale, respectively. The second batch was divided into four comparable groups (except Z. officinale-treated group) similarly treated as the first batch in addition to the antacid ranitidine (30 mg/kg) 1 h before extract administration. Safety, worm recovery, tissues egg load and oogram pattern were assessed. RESULTS: Calotropis procera latex and flower extracts are toxic (50-70% mortality) even in a small dose (250 mg/kg) before washing off their toxic rubber. Zingiber officinale extract insignificantly decrease (7.26%) S. mansoni worms. When toxic rubber was washed off and ranitidine was used, C. procera (stem latex and flowers) and F. elastica extracts revealed significant S. mansoni worm reductions by 45.31, 53.7 and 16.71%, respectively. Moreover, C. procera extracts produced significant reductions in tissue egg load (~34-38.5%) and positively affected oogram pattern. CONCLUSION: The present study may be useful to supplement information with regard to C. procera and F. elastica antischistosomal activity and provide a basis for further experimental trials. PMID- 24047471 TI - Cationic fluorescent polymeric thermometers with the ability to enter yeast and mammalian cells for practical intracellular temperature measurements. AB - An accurate method for measuring intracellular temperature is potentially valuable because the temperature inside a cell can correlate with diverse biological reactions and functions. In a previous study, we reported the use of a fluorescent polymeric thermometer to reveal intracellular temperature distributions, but this polymer required microinjection for intracellular use, such that it was not user-friendly; furthermore, it could not be used in small cells or cells with a cell wall, such as yeast. In the present study, we developed several novel cationic fluorescent copolymers, including NN-AP2.5 and NN/NI-AP2.5, which exhibited spontaneous and rapid entry (<=20 min) into yeast cells and subsequent stable retention in the cytoplasm. The fluorescence lifetime of NN-AP2.5 in yeast cells was temperature-dependent (6.2 ns at 15 degrees C and 8.6 ns at 35 degrees C), and the evaluated temperature resolution was 0.09-0.78 degrees C within this temperature range. In addition, NN-AP2.5 and NN/NI-AP2.5 readily entered and functioned within mammalian cells. Taken together, these data show that our novel cationic fluorescent polymeric thermometers enable accurate and practical intracellular thermometry in a wide range of cells without the need for a microinjection procedure. PMID- 24047472 TI - Chemerin is associated with inflammatory markers and metabolic syndrome phenotypes in hypertension patients. AB - BACKGROUND: Chemerin is a new adipokine elevated in states of obesity and metabolic syndrome. In order to identify the role of chemerin in hypertension, we conducted a case--control study to evaluate the role of chemerin in hypertension. METHODS: Two hundred and thirty-seven new-diagnosed essential hypertensive (EH) patients and one hundred and ten normotensive healthy subjects (NT) were enrolled. After an overnight fasting, participants underwent an oral glucose tolerance test (OGTT). Anthropometric measurements and serum analyses were checked, including body mass index (BMI), waist circumference, insulin, triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol, glucose, chemerin, hs-CRP, TNF-alpha and IL-6. RESULTS: Compared with healthy controls, subjects with hypertension had significantly higher chemerin serum levels (p < 0.001). In hypertensive patients, chemerin level was significantly associated with metabolic characteristics including BMI, systolic blood pressure, fasting glucose and insulin, OGTT 2-hour glucose, plasma triglycerides, plasma total cholesterol, HOMA-IR and markers of inflammation including hs-CRP, TNF-alpha and IL-6, independent of age and gender. Only gender, HOMA-IR, TNF-alpha and TG were independently related factors to plasma chemerin level after multiple regression analysis. In logistic regression analysis, high chemerin level was an independent predictor of the presence of hypertension (OR: 1.045, p < 0.001) when metabolic variables were adjusted for. However, the association was lost when further adjustment for inflammatory markers including hs-CRP, TNF-alpha and IL-6 (OR: 1.022, p = 0.289). CONCLUSIONS: Chemerin is strongly associated with markers of inflammation and components of the metabolic syndrome in hypertensive subjects and was independently associated with hypertension after adjustment for age, gender and metabolic risk factors. PMID- 24047473 TI - Exploring the possible role of Glu286 in CcO by electrostatic energy computations combined with molecular dynamics. AB - Cytochrome c oxidase (CcO) is a central enzyme in aerobic life catalyzing the conversion of molecular oxygen to water and utilizing the chemical energy to pump protons and establish an electrochemical gradient. Despite intense research, it is not understood how CcO achieves unidirectional proton transport and avoids short circuiting the proton pump. Within this work, we analyzed the potential role of Glu286 as a proton valve. We performed unconstrained MD simulations of CcO with an explicit membrane for up to 80 ns. Those MD simulations revealed that deprotonated Glu286 (Glu286-) is repelled by the negatively charged propionic acid PRD of heme a3. Thus, it destabilizes a potential linear chain of waters in the hydrophobic cavity connecting Glu286 with PRD and the binuclear center (BNC). Conversely, protonated Glu286 (Glu286H) may remain in an upward position (oriented toward PRD) and can stabilize the connecting linear water chain in the hydrophobic cavity. We calculated the pKa of Glu286 under physiological conditions to be above 12, but this value decreases to about 9 under increased water accessibility of Glu286. The latter value is in accordance with experimental measurements. In the time course of MD simulation, we also observed conformations where Glu286 bridges between water molecules located on both sides (the D channel being connected to the N side and the hydrophobic cavity), which might lead to proton backflow. PMID- 24047474 TI - Seasonal variation in the prevalence of acute undernutrition among children under five years of age in east rural Ethiopia: a longitudinal study. AB - BACKGROUND: Malnutrition is a deficiency state of both macro and micronutrients (under--nutrition) and their over consumption (over- nutrition) causing measurable adverse effects on human body structure and function, resulting in specific physical and clinical outcomes. Little has been known about the seasonal variation in the magnitude of acute child under-nutrition and its determinants in low and middle-income countries making difficult the choice of a better nutrition intervention. The objective of this study was to determine the prevalence of acute under-nutrition and its associated factors on children aged 6 to 36 months in east rural Ethiopia in wet and dry seasons. METHODS: A longitudinal study was conducted on children aged 6 to 36 months and their mothers (mother-child pairs) from July/August 2010/2011 to January/ February 2011/2012 in east rural Ethiopia. Data were collected from 2,132 mother-child pairs using a pretested structured questionnaire and the UNICEF recommended anthropometric measuring instruments after standardization. The Odds Ratio with 95% confidence interval was estimated to identify the predictors of acute child under nutrition (wasting) using a conditional fixed- effects logistic regression. RESULTS: The prevalence of acute child under-nutrition was 7.4%; 95% CI: (6.3%, 8.5%) in wet and 11. 2%; 95% CI: (9.8%, 12.5%) in dry seasons. Child wasting was more common among children of poor households who had no cooperative bank saving accounts [AOR (95% CI) = 8.2. (1.8, 37.6)], and access to health facilities [AOR (95% CI) = 2.2 (1.4, 3.6)]. CONCLUSION: Acute child under-nutrition was relatively higher in the dry season. Although season was not significantly associated with child under--nutrition, poverty and poor access to health services were important predictors of wasting in the study setting. Thus, effective community-based nutrition interventions that require a multi--disciplinary approach should be scaled up to curb childhood under-nutrition. PMID- 24047475 TI - The impact of change in pregnancy body mass index on cesarean delivery. AB - OBJECTIVE: To examine the impact of pregnancy changes in body mass index (BMI) on the incidence of cesarean delivery. METHODS: This is a retrospective cohort study using linked birth certificate and discharge diagnosis data from the year 2007. Adjusted odds ratios (aOR) were calculated for the outcome of cesarean delivery, as a function of a categorical change in pregnancy BMI (kg/m(2)): BMI loss (BMI change<-0.5), no change (-0.5 to 0.5), minimal (0.6 to 5), moderate (5.1 to 10) and excessive (>10). The impact of pregnancy change in BMI was determined for the entire cohort and then stratified by prepregnancy BMI category. RESULTS: The study population consisted of 436 414 women with singleton gestations. When compared to women with no net change in BMI, women with excessive BMI changes collectively had a 80% increased incidence of cesarean delivery (aOR = 1.78). By prepregnancy obesity class, the aOR for cesarean delivery in women with excessive BMI change were: normal weight (aOR = 2.25), overweight (aOR = 2.39), obese class I (aOR = 2.23), obese class II (aOR = 2.56) and obese class III (aOR = 2.08). CONCLUSIONS: The odds of cesarean delivery were uniformly increased in all prepregnancy BMI categories as net BMI change increased. These data illustrate that all women, not just the overweight and obese, are at significantly increased risk of cesarean delivery with excessive BMI change during pregnancy. PMID- 24047476 TI - The BCL2L10 Leu21Arg variant and risk of therapy-related myeloid neoplasms and de novo myelodysplastic syndromes. AB - Therapy-related myeloid neoplasms (t-MNs) are an increasingly recognized complication in patients previously treated with radiotherapy and/or chemotherapy for cancer or autoimmune disease. Single nucleotide variants (SNVs) in genes involved in the cellular pathways of detoxification, DNA repair and apoptosis may modify the individual risk of developing a t-MN. We studied the frequency of the SNVs of six genes involved in xenobiotic detoxification (CYP3A4, NQO1, GSTA1, GSTM1, GSTP1 and GSTT1), two DNA repair genes (RAD51 and XRCC3) and one key regulator of apoptosis (BCL2L10) in a case-control study including 111 cases of t MN and 259 controls. This is the first report on the prevalence of BCL2L10 Leu21Arg polymorphism in myeloid malignancies. In this line, we also tested 146 cases of de novo myelodysplastic syndrome (MDS) and 109 cases of de novo acute myeloid leukemia (AML). Our results showed a significantly lower frequency of the BCL2L10-21Arg allele in patients with t-MN and de novo MDS compared to controls (Leu/Arg + Arg/Arg: 50.6% vs. 65.9%, p = 0.017 and 45.8% vs. 65.9%, p = 0.0003, respectively). Carriers of the BCL2L10-21Arg variant have a reduced risk of developing t-MN and de novo MDS. PMID- 24047477 TI - New opportunities for anti-CD20 monoclonal antibody to give a direct punch to the tumor. PMID- 24047478 TI - De novo B-cell prolymphocytic leukemia with central nervous system involvement. PMID- 24047479 TI - Genomic imbalance defines three prognostic groups for risk stratification of patients with chronic lymphocytic leukemia. AB - Array comparative genomic hybridization (aCGH) has yet to be fully leveraged in a prognostic setting in chronic lymphocytic leukemia (CLL). Genomic imbalance was assessed in 288 CLL specimens using a targeted array. Based on 20 aberrations in a hierarchical manner, all 228 treatment-naive specimens were classified into a group with poor outcome (20.6%) exhibiting at least one aberration that was univariately associated with adverse outcome (gain: 2p, 3q, 8q, 17q, loss: 7q, 8p, 11q, 17p, 18p), good outcome (32.5%) showing 13q14 loss without any of the other 10 aberrations (gain: 1p, 7p, 12, 18p, 18q, 19, loss: 4p, 5p, 6q, 7p) or intermediate outcome (remainder). The three groups were significantly separated with respect to time to first treatment and overall survival (p < 0.001), and validation of the stratification scheme was performed in two independent datasets. Gain of 3q and 8q, and 17p loss were determined to be independent unfavorable prognostic biomarkers. TP53, NOTCH1 and SF3B1 mutations correlated with the presence of one poor outcome aCGH marker, at a considerably higher frequency than when only considering poor risk aberrations routinely detected by fluorescence in situ hybridization (FISH). These data support genomic imbalance evaluation in CLL by aCGH to assist in risk stratification. PMID- 24047480 TI - The ABC of chronic lymphocytic leukemia: etiology of cytopenias is important in staging and management. PMID- 24047481 TI - Vancomycin-resistant enterococci in patients with hematological malignancy: curbing an endemic pathogen. PMID- 24047482 TI - Dosimetric impact of reduced nozzle-to-isocenter distance in intensity-modulated proton therapy of intracranial tumors in combined proton-carbon fixed-nozzle treatment facilities. AB - BACKGROUND: In combined proton-carbon fixed-nozzle treatment facilities with raster scanning delivery, the scattering of proton pencil beams caused by nozzle elements and the relatively large nozzle-to-isocenter distance cause a beam broadening. This may pose limitations to the achievable dose conformity. One way to counteract this effect is by delivering the treatment in a position closer to the nozzle than the room isocenter. Purpose of this study was to assess the potential dosimetric benefit of such solution, in terms of dose conformity and normal tissue sparing, in intensity-modulated proton therapy (IMPT) of intracranial tumors. MATERIAL AND METHODS: For 12 patients with intracranial lesions, IMPT-plans were created at two treatment positions: nozzle-to-treatment isocenter distance: 100 cm (room isocenter) and nozzle-to-treatment-isocenter distance: 60 cm. The resulting plans were compared in terms of dose distributions, dose-volume histograms and selected dosimetric indexes. RESULTS: With comparable target coverage, statistically significant normal tissue sparing was achieved through the reduction of the distance between nozzle and treatment isocenter. The decrease in mean dose (Dmean) was 12.5% to the whole brain, 16.2% to the brainstem, 9.7% and 15.4% to the temporal lobes, 10.0% and 12.9% to the hippocampi, 11.8% and 12.5% to the optic nerves and 0.2% to the chiasm. The volume receiving at least 10% of the prescribed dose (V10%) was reduced by more than 10% for most organs at risk (OARs). The maximum dose (Dnear-max) values to most OARs remained without significant difference. CONCLUSION: A reduced distance between nozzle and treatment isocenter leads to steeper lateral dose gradients and significantly reduces the volume of OARs adjacent to the target, which receives low to intermediate doses. Technical solutions shifting the treatment isocenter closer to the nozzle should be considered in clinical situations, where critical OARs are adjacent to the beam channel and where the integral dose should be minimized. PMID- 24047483 TI - Protection-group-free semisyntheses of parthenolide and its cyclopropyl analogue. AB - Parthenolide showed extensive bioactivities including selective eradication of AML stem cells. Herein we report protection-free semisyntheses of parthenolide and its cyclopropyl analogue (compound 10) from the abundant natural product costunolide with an overall yield of 55 and 60%, respectively. Compound 10 was more stable than parthenolide, and it maintained comparable activities against AML cell lines and AML stem cells. Therefore, compound 10 might be a superior small molecule than parthenolide as a tool for investigation of cancer stem cell biology. PMID- 24047484 TI - Brugada phenocopy in a patient with pectus excavatum: systematic review of the ECG manifestations associated with pectus excavatum. AB - Brugada phenocopies (BrP) have emerged as new clinical entities that are etiologically distinct from true Brugada syndrome (BrS). BrP are characterized by an ECG pattern that is phenotypically identical to true BrS (type 1 or type 2); however, BrP are caused by various other factors such as mechanical mediastinal compression, myocardial ischemia, pericarditis, myocarditis, pulmonary embolism, and metabolic disturbances. We report a case of an electrocardiographic BrP in a patient with pectus excavatum deformity in the absence of true BrS using currently defined BrP diagnostic criteria. A systematic review of ECG manifestations associated with pectus excavatum is also discussed. PMID- 24047485 TI - Positive Brugada challenge test in V1 R-V3 R as a predictor of malignant prognosis in Brugada patients. AB - BACKGROUND: The Brugada syndrome is a heterogeneous genetic disease that predisposes to life-threatening ventricular tachyarrhythmias and sudden cardiac death (SCD). The only proven way to prolong the survival of patients with Brugada syndrome is to implant an implantable cardioverter-defibrillator (ICD). This should be implanted for high-risk patients only. METHOD: The patients with type 2 or 3 Brugada ECG pattern were selected for the study. We evaluated 126 patients with Brugada type ECG patterns. Nineteen patients had positive response. Those who had positive result in right side located leads had poorer prognosis. CONCLUSION: Positive flecainide challenge test in right side located pericordial leads can be used as a predictor of poor prognosis in Brugada patients. This can be evaluated in another research for its role in the implantation of ICD. Also, the oral flecainide is not sensitive enough to rule out the presence of Brugada syndrome and it should not be trusted as a screening test for suspected cases. PMID- 24047486 TI - ECG quantification of myocardial scar and risk stratification in MADIT-II. AB - BACKGROUND: Low left ventricular ejection fraction (LVEF) increases risk for both sudden cardiac death (SCD) and for heart failure (HF) death; however, implantable cardioverter-defibrillators (ICDs) reduce the incidence of SCD, not HF death. Distinguishing individuals at risk for HF death (non-SCD) versus SCD could improve ICD patient selection. OBJECTIVE: This study evaluated whether electrocardiogram (ECG) quantification of myocardial infarction (MI) could discriminate risk for SCD versus non-SCD. METHODS: Selvester QRS scoring was performed on 995 MADIT-II trial subjects' ECGs to quantify MI size. MIs were categorized as small (0-3 QRS points), medium (4-7) or large (>= 8). Mortality, SCD and non-SCD rates in the conventional medical therapy (CMT) arm and mortality and ventricular tachycardia/fibrillation (VT/VF) rates in the ICD arm were analyzed by QRS score group. Both arms were analyzed to determine ICD efficacy by QRS score group. RESULTS: In the CMT arm, mortality, SCD and non-SCD rates were similar across QRS score groups (P = 0.73, P = 0.92, and P = 0.77). The ICD arm showed similar rates of mortality (P = 0.17) and VT/VF (P = 0.24) across QRS score groups. ICD arm mortality was lower than CMT arm mortality across QRS score groups with greatest benefit in the large scar group. CONCLUSION: Recently, QRS score was shown to be predictive of VT/VF in the SCD-HeFT population consisting of both ischemic and nonischemic HF and having a maximum LVEF of 35% versus 30% for MADIT-II. Our study found that QRS score did not add prognostic value in the MADIT-II population exhibiting relatively more severe cardiac dysfunction. PMID- 24047487 TI - Prevalence of early repolarization patterns in a French military population at low cardiovascular risk: implications for preventive medicine. AB - BACKGROUND: Early repolarization pattern (ERP) associated with a risk of sudden death has recently been described. Very few studies have examined the prevalence of this pattern in a military population characterized by a predominance of young, active male subjects. Therefore, the main objective of this study was to evaluate the prevalence of ERP in a healthy military population free of heart disease but subjected to extreme and potentially arrhythmogenic physical activity. METHODS: This prospective, multicenter study was carried out from November 2010 to November 2011 and included 746 individuals undergoing ECG screening; 466 were men (62.4%) and 280 were women (37.5%). Each ECG was interpreted twice by trained cardiologists. RESULTS: The total prevalence of ERP was 13.8% (103/746); 16% (46/280) in women and 12% (57/466) in men (P > 0.05). It declined with age and the pattern of slurring in inferior location was the most common. Heart rate was significantly lower in military officers with ERP. CONCLUSIONS: ERP was commonly found in this healthy military population. Preventing the risk of sudden death in this population requires systematic ECG screening, medical history analysis and clinical examination to identify symptomatic patients. PMID- 24047488 TI - Electrocardiographic abnormalities and elevated cTNT at admission for intracerebral hemorrhage: predictors for survival? AB - BACKGROUND: Cerebrovascular lesions are often associated with electrocardiographic (ECG) abnormalities. The main purpose of this work was to investigate the prognostic value of ECG abnormalities and/or elevated cardiac troponin (cTNT) on admission in patients with nontraumatic intracerebral hemorrhage (ICH). METHODS: Ninety-seven consecutive patients with ICH were included. The predictive value of ECG abnormalities and increased TNT on survival were evaluated using Cox proportional hazard model. RESULTS: The most frequently observed ECG abnormalities were the presence of a Q wave (39.6%), followed by prolonged QTc (>0.44 s; 35.4%), which was an independent predictor for long-term mortality (P = 0.019). No difference in QTc was observed between patients with right versus left ICH. Increased cTNT levels at admission had no prognostic value. CONCLUSION: Various ECG changes were common in patients presenting with an ICH, but only prolonged QTc was found to be an independent predictor of poor survival during follow-up after ICH. PMID- 24047489 TI - Heart rate variability and heart rate turbulence in HIV-infected patients receiving combination antiretroviral therapy. AB - BACKGROUND: Previous studies have demonstrated the presence of autonomic dysfunction in human immunodeficiency virus (HIV)-infected patients. However, the data in those receiving combination antiretroviral therapy (cART) are conflicting. The aim of this study was to assess the autonomic function using heart rate variability (HRV) and heart rate turbulence (HRT) analysis in HIV infected patients receiving cART. METHODS: Eighty-one HIV-infected patients receiving cART and 42 control subjects were enrolled in the study. The HRV and HRT parameters were assessed on 24-hour digital Holter electrocardiogram recordings. RESULTS: Baseline characteristics were comparable between HIV infected and control subjects, except the higher fasting glucose and triglyceride and lower high-density lipoprotein cholesterol observed in HIV-infected patients. All components of HRV were significantly reduced in HIV-infected patients. After adjustment with biochemical parameters, most of the HRV parameters were still significantly reduced in HIV-infected patients. However, HRV parameters reflecting vagal activity were no longer different between 2 groups. In addition, HRT parameters did not differ between HIV-infected and control subjects. The standard deviation of normal-to-normal intervals significantly correlated with CD4 lymphocyte counts in HIV-infected patients but did not with protease inhibitors therapy. CONCLUSIONS: We demonstrated the overall decrease in HRV in HIV-infected patients receiving cART. The metabolic disturbance observed in HIV infected patients possibly accounted for decreased vagal activity. PMID- 24047490 TI - Reduction of the inappropriate ICD therapies by implementing a new fuzzy logic based diagnostic algorithm. AB - AIMS: The aim of the study was to analyze the value of a completely new fuzzy logic-based detection algorithm (FA) in comparison with arrhythmia classification algorithms used in existing ICDs in order to demonstrate whether the rate of inappropriate therapies can be reduced. METHODS: On the basis of the RR intervals database containing arrhythmia events and controls recordings from the ICD memory a diagnostic algorithm was developed and tested by a computer program. This algorithm uses the same input signals as existing ICDs: RR interval as the primary input variable and two variables derived from it, onset and stability. However, it uses 15 fuzzy rules instead of fixed thresholds used in existing devices. The algorithm considers 6 diagnostic categories: (1) VF (ventricular fibrillation), (2) VT (ventricular tachycardia), (3) ST (sinus tachycardia), (4) DAI (artifacts and heart rhythm irregularities including extrasystoles and T-wave oversensing-TWOS), (5) ATF (atrial and supraventricular tachycardia or fibrillation), and 96) NT (sinus rhythm). This algorithm was tested on 172 RR recordings from different ICDs in the follow-up of 135 patients. RESULTS: All diagnostic categories of the algorithm were present in the analyzed recordings: VF (n = 35), VT (n = 48), ST (n = 14), DAI (n = 32), ATF (n = 18), NT (n = 25). Thirty-eight patients (31.4%) in the studied group received inappropriate ICD therapies. In all these cases the final diagnosis of the algorithm was correct (19 cases of artifacts, 11 of atrial fibrillation and 8 of ST) and fuzzy rules algorithm implementation would have withheld unnecessary therapies. Incidence of inappropriate therapies: 3 vs. 38 (the proposed algorithm vs. ICD diagnosis, respectively) differed significantly (p < 0.05). VT/VF were detected correctly in both groups. Sensitivity and specificity were calculated: 100%, 97.8%, and 100%, 72.9% respectively for FA and tested ICDs recordings (p < 0.05). CONCLUSIONS: Diagnostic performance of the proposed fuzzy logic based algorithm seems to be promising and its implementation could diminish ICDs inappropriate therapies. We found FA usefulness in correct diagnosis of sinus tachycardia, atrial fibrillation and artifacts in comparison with tested ICDs. PMID- 24047491 TI - Role of bisoprolol in patients with long QT syndrome. AB - BACKGROUND: Long QT syndrome (LQTS) is a disorder of ventricular repolarization usually treated with beta-blockers, mostly with propanolol and nadolol. The aim of our study was to evaluate the role of bisoprolol in LQTS patients. METHODS: A total of 34 patients were evaluated in an average follow-up time of 93 months: 31 months without treatment, 31 months in treatment with nadolol or propanolol and 31 months in treatment with bisoprolol. The average age of patients at diagnosis was 17.3 years. The enrolled patients were followed through a semiannual electrocardiogram and an annual 24-hour Holter monitoring. All patients underwent genotyping, routine hematologic tests, and an echocardiogram. RESULTS: In 93 months there were 2 major and 12 minor cardiovascular events. Both the major events occurred in absence of beta-blocking therapy. Of the 12 minor cardiovascular events 3 occurred in absence of treatment, 7 during treatment with nadolol or propranolol, and 2 during treatment with bisoprolol. The mean heart rate at 24 h Holter was 87 bpm without treatment, 71 bpm in patients treated with propanolol and nadolol, and 70 bpm in patients treated with bisoprolol. There were not statistically significant differences between the three groups in the mean QTc. CONCLUSIONS: Beta-blocking therapy is the cornerstone of LQTS therapy but actually there is no clear indication about which beta-blocker should be used. In our experience bisoprolol proved to be less harmful and easier to manage than propranolol and nadolol in patients with LQTS, with the same effectiveness in preventing major cardiovascular events. PMID- 24047492 TI - Novel mutation in the KCNJ2 gene is associated with a malignant arrhythmic phenotype of Andersen-Tawil syndrome. AB - BACKGROUND: Andersen-Tawil syndrome (ATS) is a rare inherited multisystem disorder associated with mutations in KCNJ2 and low prevalence of life threatening ventricular arrhythmias. Our aim was to describe the clinical course of ATS in a family, in which the proband survived aborted cardiac arrest (ACA) and genetic screening revealed a previously unknown mutation (c.271_282del12[p.Ala91_Leu94del]) in the KCNJ2 gene. METHODS: A cascade family screening was performed in a 5-generation family after identification of the KCNJ2 mutation in the proband. Subsequently, 10 of 21 screened individuals appeared to be mutation carriers (median age 38 [range 10-75] years, 3 female). Mutation carriers underwent clinical examination including biochemistry panel, cardiac ultrasound, Holter ECG, and exercise stress test. RESULTS: (1) At baseline, 2 patients had survived ACA, 3 had syncope or presyncopal attacks, and 2 reported palpitations. Exercise-induced nonsustained bidirectional ventricular tachycardia was documented in 4 patients, 2 received implantable cardioverter defibrillators (ICD) for primary prevention and 2 for secondary prevention. (2) During follow-up, 1 primary prevention and 1 secondary prevention patient received in total 4 adequate ICD shocks. Life-threatening ventricular arrhythmias were documented during childhood in 5 of 10 mutation carriers. (3) All mutation carriers presented with characteristic mild dysmorphic features. Only 1 patient suffered from periodic paralysis. All had normal serum potassium level at repeated assessments and none had any other extracardiac disease manifestation. CONCLUSION: Our findings suggest that the novel KCNJ2 mutation is associated with a predominantly cardiac phenotype of Andersen-Tawil syndrome with high propensity to life-threatening ventricular arrhythmias presenting from childhood and young adulthood. PMID- 24047493 TI - A rare cause of pacemaker failure: interatrial block. AB - Pacemaker and implantable cardioverter defibrillators (ICD) systems are useful in detection and differentiation of many symptomatic and asymptomatic arrhythmias. In this report, we described a rare condition that caused by failure in detection of a clinical tachyarrhythmia by a dual chamber pacemaker that implanted because of intermittent atrioventricular (AV) block and sinus node disease in a 46-year old patient. In our case, bidirectional interatrial block was demonstrated; and the symptoms associated with high ventricular rate caused by left atrial tachyarrhythmias relieved after AV node ablation. PMID- 24047494 TI - The presence of epsilon waves in all precordial leads (V1 -V6 ) in a 13-year-old boy with arrhythmogenic right ventricular dysplasia (ARVD). AB - Electrocardiographic feature is included in the diagnostic criteria for arrhythmogenic right ventricular dysplasia (ARVD) based on the Revised Task Force criteria 2010. The epsilon wave, which reflects delayed conduction of the right ventricle, is considered to be one of the major diagnostic criteria. We reported a 13-year-old Thai boy with ARVD who presented with ventricular tachycardia. The presence of epsilon wave in all precordial leads (V1 -V6 ) was observed in standard 12-lead EKG. Extensive scarring of the right and left ventricle was seen on cardiac MRI. The extensive Epsilon wave found in this patient may reflect the extensive ventricular wall involvement. PMID- 24047495 TI - Successful use of wearable cardioverter defibrillator in a patient with dextrocardia and persistent left superior vena cava. AB - Congenital disorders, such as dextrocardia and persistent left superior vena cava, are rare. However, their presence is often associated with other cardiac anomalies, and may lead to lethal ventricular tachyarrhythmias, which result in sudden cardiac death. Treating patients with these disorders can present a challenge to clinicians, as it may cause technical difficulties during interventional procedures, and more often, altered defibrillation techniques in a setting of prehospital sudden cardiac arrest. This report describes the first case of successful defibrillation therapy delivered by the wearable cardioverter defibrillator to a patient with dextrocardia and persistent left superior vena cava during a ventricular tachycardia arrest. PMID- 24047496 TI - Third-degree atrioventricular block following commotio cordis. PMID- 24047497 TI - Efficacy as an intrinsic property of the M(2) muscarinic receptor in its tetrameric state. AB - Muscarinic and other G protein-coupled receptors exhibit an agonist-specific heterogeneity that tracks efficacy and commonly is attributed to an effect of the G protein on an otherwise homogeneous population of sites. To examine this notion, M2 muscarinic receptors were purified from Sf9 cells as monomers devoid of G protein and reconstituted as tetramers in phospholipid vesicles. In assays with N-[(3)H]methylscopolamine, seven agonists revealed a dispersion of affinities indicative of two or more classes of sites. Unlabeled N methylscopolamine and the antagonist quinuclidinylbenzilate recognized one class of sites; atropine recognized two classes with a preference that was the opposite of that of agonists, as indicated by the effects of N-ethylmaleimide. The data were inconsistent with an explicit model of constitutive asymmetry within a tetramer, and the fit improved markedly upon the introduction of cooperative interactions (P < 0.00001). Purified monomers appeared to be homogeneous or nearly so to all ligands except the partial agonists pilocarpine and McN-A-343, where heterogeneity emerged from intramolecular cooperativity between the orthosteric site and an allosteric site. The breadth of each dispersion was quantified empirically as the area between the fitted curve for two classes of sites and the theoretical curve for a single class of lower affinity, which approximates the expected effect of GTP if a G protein were present. The areas measured for 10 ligands at reconstituted tetramers correlated with similar measures of heterogeneity and with intrinsic activities reported previously for binding and response in natural membranes (P <= 0.00002). The data suggest that the GTP-sensitive heterogeneity typically revealed by agonists at M2 receptors is intrinsic to the receptor in its tetrameric state. It exists independently of the G protein, and it appears to arise at least in part from cooperativity between linked orthosteric sites. PMID- 24047498 TI - Chemical constituents and biological activities from roots of Enkleia siamensis. AB - Chemical investigation from roots of Enkleia siamensis (Kurz) Nervling resulted in the isolation of 10 compounds. Their structures were established on the basis of 1D and 2D NMR spectroscopic data as linobiflavonoid (1), chamaejasmin (2), 7-O beta-D-glucopyranosylchamaejasmin (3), ormocarpin (4), (-)-wikstromol (5), matairesinol (6), (+)-lariciresinol (7), umbelliferone (8), daphnoretin (9) and carthamidin (10). Compounds 2 and 8 showed cytotoxicity against KB, MCF-7 and NCI H187 cancer cell lines. Compounds 1, 2 and 5 showed weak minimum inhibitory requirements to acetylcholinesterase with values ranging from 50 to 1000 ng. In addition, compound 2 exhibited antimalarial activity against Plasmodium falciparum with an IC50 value of 2.32 MUg/mL. PMID- 24047500 TI - Genomic selection in sugar beet breeding populations. AB - BACKGROUND: Genomic selection exploits dense genome-wide marker data to predict breeding values. In this study we used a large sugar beet population of 924 lines representing different germplasm types present in breeding populations: unselected segregating families and diverse lines from more advanced stages of selection. All lines have been intensively phenotyped in multi-location field trials for six agronomically important traits and genotyped with 677 SNP markers. RESULTS: We used ridge regression best linear unbiased prediction in combination with fivefold cross-validation and obtained high prediction accuracies for all except one trait. In addition, we investigated whether a calibration developed based on a training population composed of diverse lines is suited to predict the phenotypic performance within families. Our results show that the prediction accuracy is lower than that obtained within the diverse set of lines, but comparable to that obtained by cross-validation within the respective families. CONCLUSIONS: The results presented in this study suggest that a training population derived from intensively phenotyped and genotyped diverse lines from a breeding program does hold potential to build up robust calibration models for genomic selection. Taken together, our results indicate that genomic selection is a valuable tool and can thus complement the genomics toolbox in sugar beet breeding. PMID- 24047499 TI - Bradykinin-induced Ca2+ signaling in human subcutaneous fibroblasts involves ATP release via hemichannels leading to P2Y12 receptors activation. AB - BACKGROUND: Chronic musculoskeletal pain involves connective tissue remodeling triggered by inflammatory mediators, such as bradykinin. Fibroblast cells signaling involve changes in intracellular Ca2+ ([Ca2+]i). ATP has been related to connective tissue mechanotransduction, remodeling and chronic inflammatory pain, via P2 purinoceptors activation. Here, we investigated the involvement of ATP in bradykinin-induced Ca2+ signals in human subcutaneous fibroblasts. RESULTS: Bradykinin, via B2 receptors, caused an abrupt rise in [Ca2+]i to a peak that declined to a plateau, which concentration remained constant until washout. The plateau phase was absent in Ca2+-free medium; [Ca2+]i signal was substantially reduced after depleting intracellular Ca2+ stores with thapsigargin. Extracellular ATP inactivation with apyrase decreased the [Ca2+]i plateau. Human subcutaneous fibroblasts respond to bradykinin by releasing ATP via connexin and pannexin hemichannels, since blockade of connexins, with 2 octanol or carbenoxolone, and pannexin-1, with 10Panx, attenuated bradykinin induced [Ca2+]i plateau, whereas inhibitors of vesicular exocytosis, such as brefeldin A and bafilomycin A1, were inactive. The kinetics of extracellular ATP catabolism favors ADP accumulation in human fibroblast cultures. Inhibition of ectonucleotidase activity and, thus, ADP formation from released ATP with POM-1 or by Mg2+ removal from media reduced bradykinin-induced [Ca2+]i plateau. Selective blockade of the ADP-sensitive P2Y12 receptor with AR-C66096 attenuated bradykinin [Ca2+]i plateau, whereas the P2Y1 and P2Y13 receptor antagonists, respectively MRS 2179 and MRS 2211, were inactive. Human fibroblasts exhibited immunoreactivity against connexin-43, pannexin-1 and P2Y12 receptor. CONCLUSIONS: Bradykinin induces ATP release from human subcutaneous fibroblasts via connexin and pannexin-1-containing hemichannels leading to [Ca2+]i mobilization through the cooperation of B2 and P2Y12 receptors. PMID- 24047501 TI - The effects of mild ocular surface stimulation and concentration on spontaneous blink parameters. AB - PURPOSE: This exploratory, pilot study compared the effects of concentrating on a visual task and a very mild ocular surface air stimulus on multiple blink parameters. METHODS: Ten subjects participated in this study. There were two visits, one with an ocular surface air stimulus (AS) and one without (NS). The AS was set at a level barely perceptible by subjects (approximately 0.6 m/s at the eye). At each visit, subjects performed a high-concentration (HC) and low concentration (LC) task. Blinking was tracked and tear-film breakup (TBU) was monitored simultaneously to measure blink parameters, including the interblink interval (IBI), blink amplitude, duration, maximum velocity and TBU before and after each blink. RESULTS: During the HC tasks, IBI was significantly higher and blink duration was lower (repeated measures ANOVA, p < 0.05) than the LC tasks. The IBI in the AS-LC condition was significantly lower and less variable than in the NS-HC condition, whereas blink duration showed the opposite effect (Hotelling T2 test, p < 0.005). There was high individual variation in correlations between blink amplitude and maximum velocity. The area of TBU was not significantly correlated with any blink parameter. CONCLUSIONS: The lack of correlation between TBU and blinking suggests that many blinks are stimulated by internal controls, rather than direct stimulation of the ocular surface by TBU. This pilot study suggests that even very mild ocular surface stimulation produces opposite effects on the timing and duration of the blink, when compared to concentrating on a visual task. The HC task tends to decrease blink frequency and duration, presumably to minimize interruption by the eyelids, whereas mild ocular surface AS increased blink frequency and duration, most likely to increase protection of the ocular surface. PMID- 24047503 TI - Doxycycline in ATTRY69H (p.ATTRY89H) amyloidosis with predominant leptomeningeal manifestation. PMID- 24047502 TI - Pattern of brain injury in the acute setting of human septic shock. AB - BACKGROUND: Sepsis-associated brain dysfunction has been linked to white matter lesions (leukoencephalopathy) and ischemic stroke. Our objective was to assess the prevalence of brain lesions in septic shock patients requiring magnetic resonance imaging (MRI) for an acute neurologic change. METHOD: Seventy-one septic shock patients were included in a prospective observational study. Patients underwent daily neurological examination. Brain MRI was obtained in patients who developed focal neurological deficit, seizure, coma, or delirium. Electroencephalogy was performed in case of coma, delirium, or seizure. Leukoencephalopathy was graded and considered present when white matter lesions were either confluent or diffuse. Patient outcome was evaluated at 6 months with the Glasgow Outcome Scale (GOS). RESULTS: We included 71 patients with median age of 65 years (56 to 76) and SAPS II at admission of 49 (38 to 60). MRI was indicated on focal neurological sign in 13 (18%), seizure in 7 (10%), coma in 33 (46%), and delirium in 35 (49%). MRI was normal in 37 patients (52%) and showed cerebral infarcts in 21 (29%), leukoencephalopathy in 15 (21%), and mixed lesions in 6 (8%). EEG malignant pattern was more frequent in patients with ischemic stroke or leukoencephalopathy. Ischemic stroke was independently associated with disseminated intravascular coagulation (DIC), focal neurologic signs, increased mortality, and worse GOS at 6 months. CONCLUSIONS: Brain MRI in septic shock patients who developed acute brain dysfunction can reveal leukoencephalopathy and ischemic stroke, which is associated with DIC and increased mortality. PMID- 24047505 TI - Biological activity of HPLC-characterized ethanol extract from the aerial parts of Haplophyllum tuberculatum. AB - CONTEXT: The search for new sources of natural antioxidants from plant material may have beneficial therapeutic potential for those diseases associated with oxidative stress. The medicinal plant Haplophyllum tuberculatum (Forsskal) A. Juss. (Rutaceae) contains phenolic compounds as main phytochemicals; however, there are no reports on its antioxidant properties. OBJECTIVE: To evaluate antioxidant and cytoprotective potential of ethanol extract of Haplophyllum tuberculatum aerial parts. MATERIALS AND METHODS: Total phenol content was determined using Folin-Ciocalteu reagent; antiradical activity was measured using ORAC assay and the analysis of the major polyphenols was carried out using a HPLC MS method. The antioxidant and cytoprotective effect were also investigated by the MTT assay and DCFH-DA method. The human astrocytoma U373-MG cell line was pretreated with ethanol extract (from 0.025 to 250 ug/mL) for 24 h, prior to 1 mM H2O2 exposure (30 min). RESULTS AND CONCLUSION: Total phenol content was 46.2 mg gallic acid/g sample and ORAC value was 1.283 umol TE/mg sample. Chemical constituents were methoxyflavones, flavonols (mainly quercetin derivatives), cinnamic acids and benzoic acids. In cell system model of oxidative stress, pretreatments with ethanol extract at the concentrations of 2.5, 0.25 and 0.025 ug/mL significantly attenuated H2O2-induced loss in viability by 13.5, 17 and 20.5%, respectively. Furthermore, these ethanol extract concentrations markedly inhibited intracellular ROS production with IC50 0.026 ug/mL. These findings demonstrate the beneficial properties of ethanol extract of Haplophyllum tuberculatum aerial parts, rich in phenolic compounds, as antioxidant and radical scavenger ameliorating ROS-related processes and diseases such as several neurodegenerative disorders. PMID- 24047506 TI - gamma-Carbonyl quinones: radical strategy for the synthesis of evelynin and its analogues by C-H activation of quinones using cyclopropanols. AB - Cyclopropanols, on oxidative ring opening with AgNO3-K2S2O8 in DCM-H2O at room temperature and under open flask conditions, produced beta-keto radicals which were successfully added to quinones to furnish gamma-carbonyl quinones. This mild method has been applied to the synthesis of cytotoxic natural products, 4,6 dimethoxy-2,5-quinodihydrochalcone and evelynin. PMID- 24047507 TI - Imaging of plasmonic heating in a living organism. AB - Controlling and monitoring temperature at the single cell level has become pivotal in biology and medicine. Indeed, temperature influences many intracellular processes and is also involved as an activator in novel therapies. Aiming to assist such developments, several approaches have recently been proposed to probe cell temperature in vitro. None of them have so far been extended to a living organism. Here we present the first in vivo intracellular temperature imaging. Our technique relies on measuring the fluorescence polarization anisotropy of green fluorescent protein (GFP) on a set of GFP expressing neurons in Caenorhabditis elegans (C. elegans). We demonstrate fast and noninvasive monitoring of subdegree temperature changes on a single neuron induced by local photoheating of gold nanoparticles. This simple and biocompatible technique is envisioned to benefit several fields including hyperthermia treatment, selective drug delivery, thermal regulation of gene expression and neuron laser ablation. PMID- 24047509 TI - Classics in chemical neuroscience: clozapine. AB - Clozapine was the first true breakthrough in schizophrenia treatment since the discovery of chlorpromazine in 1950, effectively treating positive, negative, and some cognitive symptoms, as well as possessing unprecedented efficacy in treatment-resistant patients. Despite over 30 years of intense study, the precise molecular underpinnings that account for clozapine's unique efficacy remain elusive. In this Viewpoint, we will showcase the history and importance of clozapine to neuroscience in general, as well as for the treatment of schizophrenia, and review the synthesis, pharmacology, drug metabolism, and adverse events of clozapine. PMID- 24047511 TI - Comment on "Increased evaporation kinetics of sessile droplets by using nanoparticles". PMID- 24047510 TI - Subclinical avian influenza A(H5N1) virus infection in human, Vietnam. AB - Laboratory-confirmed cases of subclinical infection with avian influenza A(H5N1) virus in humans are rare, and the true number of these cases is unknown. We describe the identification of a laboratory-confirmed subclinical case in a woman during an influenza A(H5N1) contact investigation in northern Vietnam. PMID- 24047512 TI - Male disadvantage for neonatal complications of term infants, especially in small for-gestational age neonates. AB - OBJECTIVE: Sex differences in long and short-term outcomes for infants are observed. This has also been shown for several neonatal complications in preterm neonates. We aimed to evaluate whether sex impacts neonatal outcome among term neonates. Furthermore, we were interested in whether small-for-gestational age male and female neonates at term presented with different patterns of neonatal complications. METHODS: Data on all term singleton deliveries and respective neonatal outcomes between 2004 and 2008 at a single tertiary medical center were utilized for this retrospective cohort study. Immediate neurological complications were defined as one or more of the following: intraventricular hemorrhage, convulsions, asphyxia and acidosis. Neonatal complications were compared between male and female term infants, as well as male and female term small-for-gestational age (SGA) neonates. RESULTS: 37,342 singleton neonates were born >=37 weeks' gestation. 19,112 neonates were males. Birth weight, cesarean sections and operative deliveries were significantly higher for males. Neonatal hypoglycemia and immediate neurological complications were significantly more frequent in males. For term SGA's, low 5-min apgar scores (<7) at 39-40 weeks were 2.65 times higher for males compared with females, as was hypoglycemia. CONCLUSIONS: Male infants at term, especially male SGA infants, are more likely to encounter complications during labor and require special neonatal care due to metabolic and/or neurological complications. PMID- 24047513 TI - Reassortant avian influenza A(H5N1) viruses with H9N2-PB1 gene in poultry, Bangladesh. AB - Bangladesh has reported a high number of outbreaks of highly pathogenic avian influenza (HPAI) (H5N1) in poultry. We identified a natural reassortant HPAI (H5N1) virus containing a H9N2-PB1 gene in poultry in Bangladesh. Our findings highlight the risks for prolonged co-circulation of avian influenza viruses and the need to monitor their evolution. PMID- 24047514 TI - Metabolic profiling directly from the Petri dish using nanospray desorption electrospray ionization imaging mass spectrometry. AB - Understanding molecular interaction pathways in complex biological systems constitutes a treasure trove of knowledge that might facilitate the specific, chemical manipulation of the countless microbiological systems that occur throughout our world. However, there is a lack of methodologies that allow the direct investigation of chemical gradients and interactions in living biological systems, in real time. Here, we report the use of nanospray desorption electrospray ionization (nanoDESI) imaging mass spectrometry for in vivo metabolic profiling of living bacterial colonies directly from the Petri dish with absolutely no sample preparation needed. Using this technique, we investigated single colonies of Shewanella oneidensis MR-1, Bacillus subtilis 3610, and Streptomyces coelicolor A3(2) as well as a mixed biofilm of S. oneidensis MR-1 and B. subtilis 3610. Data from B. subtilis 3610 and S. coelicolor A3(2) provided a means of validation for the method while data from S. oneidensis MR-1 and the mixed biofilm showed a wide range of compounds that this bacterium uses for the dissimilatory reduction of extracellular metal oxides, including riboflavin, iron-bound heme and heme biosynthetic intermediates, and the siderophore putrebactin. PMID- 24047515 TI - Substrate-mediated proton relay mechanism for the religation reaction in topoisomerase II. AB - The DNA religation reaction of yeast type II topoisomerase (topo II) was investigated to elucidate its metal-dependent general acid/base catalysis. Quantum mechanical/molecular mechanical calculations were performed for the topo II religation reaction, and the proton transfer pathway was examined. We found a substrate-mediated proton transfer of the topo II religation reaction, which involves the 3' OH nucleophile, the reactive phosphate, water, Arg781, and Tyr782. Metal A stabilizes the transition states, which is consistent with a two metal mechanism in topo II. This pathway may be required for the cleavage/religation reaction of topo IA and II and will provide a general explanation for the catalytic mechanism in the topo IA and II. PMID- 24047516 TI - Monitoring of seasonality of norovirus and other enteric viruses in Cameroon by real-time PCR: an exploratory study. AB - We studied the seasonal fluctuation of norovirus and other enteric viruses in Cameroon. Two hundred participants aged between 1 and 69 years were prospectively followed up. Each participant provided monthly faecal samples over a 12-month period. A total of 2484 samples were tested using multiplex real-time PCR assay for the detection of norovirus, rotavirus and enterovirus. The effect of weather variables and risk factors were analysed by Pearson correlation and bivariate analysis. Overall, enterovirus was the most commonly detected virus (21.6% of specimens), followed by norovirus (3.9%) and rotavirus (0.4%). Norovirus and enterovirus were detected throughout the year with a peak of norovirus detection at the beginning of the rainy season and a significant alternation of circulation of norovirus genogroups from one month to the next. Age <5 years and consumption of tap water were risk factors for norovirus infection. Better understanding of factors influencing transmission and seasonality may provide insights into the relationship between physical environment and risk of infection for these viruses. PMID- 24047517 TI - "MiRNAcles" in brain. PMID- 24047518 TI - Microglia--a therapeutic target in neurological diseases and disorders. PMID- 24047519 TI - Role of microglia in the pathogenesis of sepsis-associated encephalopathy. AB - Sepsis-associated encephalopathy (SAE) is a neurological dysfunction induced by sepsis, which is associated with high morbidity and mortality. However, at present, the cellular and molecular mechanisms of SAE have remained elusive. The pathogenesis of SAE is complex and multifactorial, in which activated inflammation is recognized as a major factor. Pathological characteristics of SAE include blood- brain barrier (BBB) disruption, reduction of cerebral blood fluid (CBF) and glucose uptake, inflammatory response and activation of microglia and astrocytes. The BBB disruption induces the leakage of immune cells and inflammatory mediators, which trigger an inflammatory response in the brain. Inflammatory mediators released by activated microglia and astrocytes cause neuronal loss and brain function defect. In the review we describe the most recent findings in the pathogenesis of SAE and focus on summarizing the major mechanisms related to SAE pathogenesis. PMID- 24047520 TI - Screening for inhibitors of microglia to reduce neuroinflammation. AB - BACKGROUND: Despite the significant role microglia play in the pathology of multiple sclerosis (MS), medications that act within the central nervous system (CNS) to inhibit microglia have not yet been identified as treatment options. OBJECTIVE: We screened 1040 compounds with the aim of identifying inhibitors of microglia to reduce neuroinflammation. METHODS: The NINDs collection of 1040 compounds, where most are therapeutic medications, was tested at 10 uM final concentration on lipopolysaccharide (LPS)-activated human microglia. An ELISA was run on the media to measure the level of TNF-alpha as an indicator of microglia activity. For compounds that reduce LPS-activated TNF-alpha levels by over 50%, considered as a potential inhibitor of interest, toxicity tests were conducted to exclude non-specific cytotoxicity. Promising compounds were subjected to further analyses, including toxicity to other CNS cell types, and multiplex assays. RESULTS: Of 1040 compounds tested, 123 reduced TNF-alpha levels of LPS-activated microglia by over 50%. However, most of these were cytotoxic to microglia at the concentration tested while 54 were assessed to be non-toxic. Of the latter, spironolactone was selected for further analyses. Spironolactone reduced TNF alpha levels of activated microglia by 50-60% at 10 uM, and this concentration did not kill microglia, neurons or astrocytes. In multiplex assays, spironolactone reduced several molecules in activated microglia. Finally, during the screening, we identified 9 compounds that elevated further the TNF-alpha levels in LPS-activated microglia. CONCLUSION: Many of the non-toxic compounds identified in this screen as inhibitors of microglia, including spironolactone, may be explored as viable therapeutic options in MS. PMID- 24047521 TI - Microglial senescence. AB - In order to understand microglial senescence it is important to also understand neuroinflammation because the distinction between senescent and activated microglia is a fine one to make and not always made easily. Indeed, it is not easy to reliably identify activated microglia which is why we spend some effort here discussing intricacies associated with both acute and chronic neuroinflammation before addressing the subject of microglial senescence. The idea of microglial senescence in the context of aging-related neurodegenerative disease (NDD) pathogenesis represents a relatively recent idea that emerged largely because of the many caveats and inconsistencies found to be associated with the belief that neuroinflammation is a critical event in NDD pathogenesis. In this paper, we discuss most of these discrepancies and explain why microglial senescence can provide a better conceptual framework for understanding NDD mechanisms and for devising radically different pharmacological approaches to treatment. PMID- 24047522 TI - Potential drugs targeting microglia: current knowledge and future prospects. AB - Inflammation in the central nervous system (CNS) may occur as a result of trauma, infection or neurodegenerative stimuli and is characterized by activation of microglia, the resident immune cells of the CNS. Activated microglia proliferate rapidly, migrate to the site of injury or infection and elicit immune response by phagocytosis of cell debris, production of cytokines, chemokines and reactive oxygen species, and presentation of antigens to other immune cells. In addition, microglia participate in tissue repair by producing neurotrophic factors. However, when microglia are chronically activated, they become neurotoxic to the surrounding CNS parenchyma. Chronic activation of microglia has been shown to augment neurodegeneration in Parkinson's disease (PD), Alzheimer's disease (AD), brain injury and number of other CNS pathologies. Identification of factors that control microglial activation, therefore, has become the major focus of recent research. A number of herbal and chemical compounds have been shown to attenuate microglial activation. However, these compounds exhibit non-specificity and produce unpleasant side-effects. Here, we provide a comprehensive review on some of the currently available drugs known to reduce microglial activation, their molecular targets and the subcellular signaling networks on which they act. We also review some of the newly emerging therapeutic avenues such as 'epidrugs' and finally emphasize on the importance of targeted drug delivery systems for alleviating microglia-mediated neurotoxicity. PMID- 24047523 TI - Glutamate receptors in microglia. AB - Expression of functional glutamate receptors (GluR) on glial cells in the developing and mature brain has been recently established. Over the last decade there has been physiological, molecular and biochemical evidence suggesting the presence of GluR on microglia. However, the significance of GluR activation in microglia remains largely unknown. In this review, we discuss the expression of GluR on microglia and the effect of GluR activation on microglial function. Microglia are the resident immune cells of the central nervous system, and activation of GluR in them has been shown to regulate their immunological response which may be either neuroprotective or neurotoxic. Microglial activation is known to initiate a myriad of molecular events such as nitric oxide production, free radicals generation, disruption of calcium regulation and release of proinflammatory cytokines, proteases, neurotransmitters, and excitatory amino acids, primarily glutamate. Since microglial activation has been implicated in several neuropathologies, an understanding of the pathway coupled to the various microglial GluR will help to develop therapeutic interventions for ameliorating microglia-mediated damage. PMID- 24047524 TI - Relationship between the chemokine receptor CCR5 and microglia in neurological disorders: consequences of targeting CCR5 on neuroinflammation, neuronal death and regeneration in a model of epilepsy. AB - Chemokines may play a role in leukocyte migration across the blood-brain barrier (BBB) during neuroinflammation and other neuropathological processes, such as epilepsy. The CC chemokine receptor 5 (CCR5) is a member of CC-chemokine receptor family that binds several chemokines, including CCL3 (macrophage inflammatory protein-1alpha, MIP-1alpha), CCL4 (macrophage inflammatory protein-1beta, MIP 1beta) and CCL5 (RANTES). The current review examines the relationship between CCR5 and the microglia in different neurological disorders and models of CNS injury. CCR5 expression is upregulated in different neurological diseases, where it is often immunolocalized in microglial cells. A multistep cascade couples CCR5 activation by chemokines to Ca(2+) increases in human microglia. Because changes in [Ca(2+)] (i) affect chemotaxis, secretion, and gene expression, pharmacologic modulation of this pathway may alter inflammatory and degenerative processes in the CNS. Consequently, targeting CCR5 by using CCR5 antagonists may attenuate critical aspects of neuroinflammation in different models of neurological disorders. To illustrate the interaction between CCR5 and microglia in the CNS, we used a model of excitotoxicity, and demonstrate the intimate involvement of CCR5 in neuron injury and inflammation attendant to kainic acid (KA)-induced neurotoxicity. CCR5 participates in neuronal injury caused by the excitotoxin, KA, brings inflammatory cells to the sites of KA-induced CNS injury, defines the extent of tissue loss after KA exposure and limits reparative responses. We used a SV40-derived vector carrying an interfering RNA (RNAi) that targets CCR5. Delivered directly to the bone marrow, this vector decreased CCR5 expression in circulating cells. Animals so treated showed greatly reduced expression of CCR5 and its ligands (MIP-1alpha and RANTES) in the CNS, including in the brain vasculature, decreased BBB leakage, demonstrated greater KA-stimulated neurogenesis and increased migration of bone marrow-derived cells to the brain to become neurons. Thus, therapeutic targeting of CCR5 may allow control of potentially injurious neuroinflammatory responses, including decrease in microglial cells activation and proliferation, and facilitate neurogenic repair in seizure-induced and, potentially, other forms of CNS injury. PMID- 24047525 TI - Notch signaling in the central nervous system with special reference to its expression in microglia. AB - Notch signaling pathway is a major player in normal development in neurons, oligodendrocytes and astrocytes as well as neurological disorders of the central nervous system (CNS). Microglia, one of the major types of glial cells in the CNS, partakes in diverse roles within the CNS mainly related to normal brain development and inflammatory diseases, yet the involvement of Notch signaling pathway in microglia has remained elusive and has only recently been recognized suggesting its putative role in microglial maturation and activation. Notch ligands and receptors are constitutively expressed by microglia in developing brain. Notch signaling pathway is important for the maintenance of microglial population during early development as in other glial cells in normal development. Remarkably, Notch signaling pathway is also involved in microglial activation and inflammation process in neuroinflammatory diseases in both postnatal and adult rats. Targeting Notch signaling is therefore a promising strategy for prevention of neurodevelopmental diseases and development of future therapies for the treatment of neuroinflammatory disorders. This review highlights some recent findings of Notch signaling in microglia, both in normal development and pathological conditions. PMID- 24047528 TI - Consequences of iron accumulation in microglia and its implications in neuropathological conditions. AB - Iron is a vital element required by almost all cells for their normal functioning. The well-established role of iron in oxidative metabolism, myelination and synthesis of neurotransmitter makes it an indispensable nutrient required by the brain. Both iron deficiency and excess have been associated with numerous patho-physiologies of the brain, suggesting a need for iron homeostasis. Various studies have reported that the immune effector cells of the brain, the microglial cells, are involved in iron homeostasis in the brain. Microglial cells, which accumulate iron during the developmental period, have a role in myelination process. Along with the increased iron accumulation documented in neurodegenerative diseases, the striking finding is the presence of iron positive microglial cells at the foci of lesion. Though excess iron within activated microglia is demonstrated to enhance the release of pro-inflammatory cytokines and free radicals, a complete understanding of the role of iron in microglia is lacking. The present knowledge on iron mediated changes, in the functions of microglia is summarized in this review. PMID- 24047529 TI - Microglia and neuropathic pain. AB - Neuropathic pain is a serious consequence of injury or disease in the nervous system itself. Current treatment options for this condition are often unsatisfactory. From being originally viewed as a diseased caused by neuronal dysfunction, a growing body of evidence implicate activated microglia as a key player in the development of this pain condition. In this review, some of the evidence for this proposal is briefly discussed and placed in a translational context, pointing out the difficulties in translating commonly used animal models of neuropathic pain to the clinical condition, as well as emphasizing the broader role of activated microglia in the injured or diseased nervous system. PMID- 24047530 TI - Individual personalities predict social behaviour in wild networks of great tits (Parus major). AB - Social environments have an important effect on a range of ecological processes, and form a crucial component of selection. However, little is known of the link between personality, social behaviour and population structure. We combine a well understood personality trait with large-scale social networks in wild songbirds, and show that personality underpins multiple aspects of social organisation. First, we demonstrate a relationship between network centrality and personality with 'proactive' (fast-exploring) individuals associating weakly with greater numbers of conspecifics and moving between flocks. Second, temporal stability of associations relates to personality: 'reactive' (slow-exploring) birds form synergistically stable relationships. Finally, we show that personality influences social structure, with males non-randomly distributed across groups. These results provide strong evidence that songbirds follow alternative social strategies related to personality. This has implications not only for the causes of social network structure but also for the strength and direction of selection on personality in natural populations. PMID- 24047526 TI - The potential for genetically altered microglia to influence glioma treatment. AB - Diffuse and unstoppable infiltration of brain and spinal cord tissue by neoplastic glial cells is the single most important therapeutic problem posed by the common glioma group of tumors: astrocytoma, oligoastrocytoma, oligodendroglioma, their malignant variants and glioblastoma. These neoplasms account for more than two thirds of all malignant central nervous system tumors. However, most glioma research focuses on an examination of the tumor cells rather than on host-specific, tumor micro-environmental cells and factors. This can explain why existing diffuse glioma therapies fail and why these tumors have remained incurable. Thus, there is a great need for innovation. We describe a novel strategy for the development of a more effective treatment of diffuse glioma. Our approach centers on gaining control over the behavior of the microglia, the defense cells of the CNS, which are manipulated by malignant glioma and support its growth. Armoring microglia against the influences from glioma is one of our research goals. We further discuss how microglia precursors may be genetically enhanced to track down infiltrating glioma cells. PMID- 24047531 TI - Appendiceal stump closure by metal endoclip in the management of complicated acute appendicitis. AB - BACKGROUND: Closure of appendicular stump has been performed in different ways; however, the use of the metal endoclip in complicated grades of acute appendicitis, has not been evaluated yet in a prospective way. OBJECTIVE: To establish the effectiveness of appendiceal stump closure by metal endoclip for complicated appendicitis. METHOD: From January 2009 to January 2011 were evaluated 131 consecutive patients who underwent a laparoscopic appendectomy for complicated acute appendicitis. From those, 118 underwent appendiceal stump closure by metal endoclip. The patient's age ranged from 12 to 75 years old (31.7 +/- 13.3) and 52.7% were male. Complicated appendicitis refers to gangrenous and/or perforated appendix, which may lead to abscess formation and degrees of peritonitis. The outcomes viability, operative time, infection complication, operative complications, and conversion rate were chosen to evaluate the procedure. RESULTS: The appendiceal stump closure by metal endoclip was used in 90% of cases. The presence of appendix base necrosis was the most important factor involved in failure of the procedure. Laparoscopic knot (1.5%), laparoscopic endo-suture (3.8%) and video assisted laparotomy (4.7%) were the alternatives used in difficult cases. The mean operative time was (67.54 +/- 28.13 minutes). The wound and intra-abdominal infection rates were 2.54% and 5.08%, respectively. There were no operative complications and the conversion rate was 0.85%. CONCLUSION: The appendiceal stump closure by metal endoclip, in complicated grades of acute appendicitis, is a safe and effective procedure. In patients with appendix base necrosis it should be avoided in favor of other alternatives. PMID- 24047532 TI - FishMicrosat: a microsatellite database of commercially important fishes and shellfishes of the Indian subcontinent. AB - BACKGROUND: Microsatellite DNA is one of many powerful genetic markers used for the construction of genetic linkage maps and the study of population genetics. The biological databases in public domain hold vast numbers of microsatellite sequences for many organisms including fishes. The microsatellite data available in these data sources were extracted and managed into a database that facilitates sequences analysis and browsing relevant information. The system also helps to design primer sequences for flanking regions of repeat loci for PCR identification of polymorphism within populations. DESCRIPTION: FishMicrosat is a database of microsatellite sequences of fishes and shellfishes that includes important aquaculture species such as Lates calcarifer, Ctenopharyngodon idella, Hypophthalmichthys molitrix, Penaeus monodon, Labeo rohita, Oreochromis niloticus, Fenneropenaeus indicus and Macrobrachium rosenbergii. The database contains 4398 microsatellite sequences of 41 species belonging to 15 families from the Indian subcontinent. GenBank of NCBI was used as a prime data source for developing the database. The database presents information about simple and compound microsatellites, their clusters and locus orientation within sequences. The database has been integrated with different tools in a web interface such as primer designing, locus finding, mapping repeats, detecting similarities among sequences across species, and searching using motifs and keywords. In addition, the database has the ability to browse information on the top 10 families and the top 10 species, through record overview. CONCLUSIONS: FishMicrosat database is a useful resource for fish and shellfish microsatellite analyses and locus identification across species, which has important applications in population genetics, evolutionary studies and genetic relatedness among species. The database can be expanded further to include the microsatellite data of fishes and shellfishes from other regions and available information on genome sequencing project of species of aquaculture importance. PMID- 24047533 TI - Scoring accuracy of automated sleep staging from a bipolar electroocular recording compared to manual scoring by multiple raters. AB - OBJECTIVES: Electroencephalography (EEG) assessment in research and clinical studies is limited by the patient burden of multiple electrodes and the time needed to manually score records. The objective of our study was to investigate the accuracy of an automated sleep-staging algorithm which is based on a single bipolar EEG signal. METHODS: Three raters each manually scored the polysomnographic (PSG) records from 44 patients referred for sleep evaluation. Twenty-one PSG records were scored by Rechtschaffen and Kales (R&K) criteria (group 1) and 23 PSGs were scored by American Academy of Sleep Medicine (AASM) 2007 criteria (group 2). Majority agreement was present in 98.4% of epochs and was used for comparison to automated scoring from a single EEG lead derived from the left and right electrooculogram. RESULTS: The kappa coefficients for interrater manual scoring ranged from 0.46 to 0.89. The kappa coefficient for the auto algorithm vs manual scoring by rater ranged from 0.42 to 0.63 and was 0.61 (group 1, kappa=0.61 and group 2, kappa=0.62) for majority agreement for all studies. The mean positive percent agreement across subjects and stages was 72.6%, approximately 80% for stages wake (78.3%), stage 2 sleep (N2) (80.9%), and stage 3 sleep (N3) (78.1%); the percentage slightly decreased to 73.2% for rapid eye movement (REM) sleep and dropped to 31.9% for stage 1 sleep (N1). Differences in agreement were observed based on raters, obstructive sleep apnea (OSA) severity, medications, and signal quality. CONCLUSIONS: Our study demonstrated that automated scoring of sleep obtained from a single-channel of forehead EEG results in agreement to majority manual scoring are similar to results obtained from studies of manual interrater agreement. The benefit in assessing auto staging accuracy with consensus agreement across multiple raters is most apparent in patients with OSA; additionally, assessing auto-staging accuracy limited disagreements in patients on medications and in those with compromised signal quality. PMID- 24047534 TI - Characterization of the acute pulse transit time response to obstructive apneas and hypopneas in preschool children with sleep-disordered breathing. AB - BACKGROUND: Surges in heart rate (HR) and blood pressure (BP) at apnea termination contribute to the hypertension seen in obstructive sleep apnea (OSA). Because childhood OSA prevalence peaks in the preschool years, we aimed to characterize the cardiovascular response to obstructive events in preschool-aged children. METHODS: Clinically referred children aged 3-5 years were grouped by obstructive apnea-hypopnea index (OAHI) into the following: primary snoring (PS) (OAHI<=1 event/h [n=21]), mild OSA (OAHI>1-<=5 [n=32]), and moderate to severe (MS) OSA (OAHI>5 [n=28]). Beat-to-beat pulse transit time (PTT), an inverse continuous indicator of BP changes, and HR were averaged during the two halves (early and late) and during the peak after (post) each obstructive event and were expressed as percentage change from late- to post-event. RESULTS: We analyzed 422 events consisting of 55 apneas and 367 hypopneas. A significant post-event increase in HR and fall in PTT occurred in all severity groups (P<.05 for all). A greater response was associated with OSA, nonrapid eye movement sleep (NREM), cortical arousal, hypopneas, and oxygen desaturation (P<.05 for all). CONCLUSIONS: Obstructive events elicit acute cardiovascular changes in preschool children. Such circulatory perturbations have been implicated in the development of hypertension, and our findings complement previous studies to suggest a cumulative impact of snoring on the cardiovascular system from childhood into adulthood. PMID- 24047535 TI - Waking under pressure. PMID- 24047536 TI - Electrical stimulation of the rostral ventrolateral medulla promotes wakefulness in rats. AB - OBJECTIVES: Previous studies suggest that central sympathetic activity might carry information on wakefulness, so we tested the hypothesis that direct activation of the rostral ventrolateral medulla (RVLM), a well-studied sympathetic vasomotor center, promotes wakefulness. METHODS: A bipolar stimulating electrode was implanted in the right RVLM of Wistar-Kyoto rats or in a brainstem control site. Bioelectrical signals were recorded using a telemetry system. The experiment comprised a baseline session and a 6-h electrical stimulation session (50 MUA, 50 Hz for 3 min every 20 min). Sleep-wake stages were defined by the electroencephalogram (EEG) and electromyogram (EMG) as active waking (AW), nonrapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Autonomic function was assessed using cardiovascular variability analysis. RESULTS: During the RVLM stimulation session, AW time increased from 38.48+/-5.82 to 99.91+/-8.23 min compared with baseline (P<.001), while REM sleep was decreased from 110.10+/-4.91 to 50.74+/-13.01 min (P=.004). Analysis of the RVLM stimulation bouts delivered during NREM sleep showed a significantly higher probability of awakening; it also showed that the latency to arousal was significantly shorter than the latency for 10% blood pressure (BP) increase (1.50+/-0.30 vs 7.42+/-1.83 s; P=.009). CONCLUSIONS: Our findings show that direct stimulation of the RVLM promotes wakefulness, suggesting that sleep disturbance may result from central sympathetic activation. PMID- 24047537 TI - Correlations between night eating, sleep quality, and excessive daytime sleepiness in a severely obese UK population. AB - OBJECTIVE: The relationships between night eating, poor sleep quality, and obesity-related comorbidity in a severely obese UK clinic population is unknown. We used validated tools to identify prevalence and to explore this relationship. METHODS: Consecutive consenting clinic attendees completed the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Score (ESS), and Night Eating Questionnaire (NEQ) to identify sleep quality, excessive daytime sleepiness (EDS) (a surrogate marker for suspected obstructive sleep apnea [OSA]), and night eating, respectively. Proportions of individuals above and below tool cutoff points were compared. Pearson product moment correlation coefficients examined relationships between total scores. RESULTS: Reported prevalence from 144 participants (mean body mass index [BMI] 46.9 [9.5] kg/m(2); age 44.6 [12.1]years; 68% women) had poor sleep quality (73.0%), suspected OSA (30.8%), and night-eating behavior (2.8%). The strongest correlation between PSQI and NEQ scores (r=0.54; P<.001) was undiminished after controlling for EDS. Although significantly correlated, PSQI and ESS scores (r=0.31; P<.001) reduced after controlling for night eating (r=0.21; P=.02). Correlation between NEQ and ESS scores (r=0.26; P=.002) was smaller and nonsignificant after controlling for sleep quality (r=0.12; P=.18). CONCLUSIONS: Poor sleep quality is common in severe obesity, though night eating is rare. The association between poor sleep quality and night eating is not influenced by the presence of EDS. PMID- 24047538 TI - Spontaneous ventilation-high PEEP upon severe ARDS: an erratum to further the analysis. PMID- 24047539 TI - [Aflibercept (Zaltrap((r))) approved in metastatic colorectal cancer]. AB - Aflibercept (Zaltrap((r)) : aflibercept is a recombinant fusion protein, anti angiogenic, which blocks activation of VEGF and PIGF receptor), obtained its European approval February 2(nd), 2013 in combination with Folinic Acid, 5FU and irinotecan (FOLFIRI) in adults with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin containing regimen. This decision was based on the efficacy and safety results of the VELOUR Phase III trial. This study showed an improved overall survival, with the combination of aflibercept and FOLFIRI versus FOLFIRI + placebo (13.5 months vs 12.06 months ; HR = 0,817, IC a 95 %, 0,714 a 0,935 ; p = 0,003 2). Adverse effects reported with aflibercept combined with FOLFIRI included the specific anti-vascular endothelial growth factor effects and also reflected an increased incidence of some chemotherapy-related toxicities. Aflibercept is the second anti-angiogenic agent after bevacizumab with a FDA and a EMEA approval for patients with metastatic colorectal cancer. PMID- 24047540 TI - A novel estrogen-regulated avian apolipoprotein. AB - In search for yet uncharacterized proteins involved in lipid metabolism of the chicken, we have isolated a hitherto unknown protein from the serum lipoprotein fraction with a buoyant density of <=1.063 g/ml. Data obtained by protein microsequencing and molecular cloning of cDNA defined a 537 bp cDNA encoding a precursor molecule of 178 residues. As determined by SDS-PAGE, the major circulating form of the protein, which we designate apolipoprotein-VLDL-IV (Apo IV), has an apparent Mr of approximately 17 kDa. Northern Blot analysis of different tissues of laying hens revealed Apo-IV expression mainly in the liver and small intestine, compatible with an involvement of the protein in lipoprotein metabolism. To further investigate the biology of Apo-IV, we raised an antibody against a GST-Apo-IV fusion protein, which allowed the detection of the 17-kDa protein in rooster plasma, whereas in laying hens it was detectable only in the isolated <=1.063 g/ml density lipoprotein fraction. Interestingly, estrogen treatment of roosters caused a reduction of Apo-IV in the liver and in the circulation to levels similar to those in mature hens. Furthermore, the antibody crossreacted with a 17-kDa protein in quail plasma, indicating conservation of Apo-IV in avian species. In search for mammalian counterparts of Apo-IV, alignment of the sequence of the novel chicken protein with those of different mammalian apolipoproteins revealed stretches with limited similarity to regions of ApoC-IV and possibly with ApoE from various mammalian species. These data suggest that Apo-IV is a newly identified avian apolipoprotein. PMID- 24047541 TI - Thermoresponsive biodegradable HEMA-lactate-Dextran-co-NIPA cryogels for controlled release of simvastatin. AB - Abstract NIPA and HEMA-lactate-Dextran-based biodegradable and thermoresponsive cryogels were synthesized at different compositions by cryogelation. Chemical and morphological properties of the HEMA-lactate-Dextran-co-NIPA cryogel matrices were demonstrated by FTIR, SEM, and ESEM. Thermoresponsivity of the prepared cryogels was investigated by DSC, imaging NMR, and swelling studies. For possible use of the cryogels in potential bone tissue engineering applications, either hydrophobic simvastatin was embedded, or hydrophilic simvastatin was incorporated in the cryogels. Release profiles of simvastatin delivering cryogel scaffolds depending on their composition, hydrophobicity or hydrophilicity of loaded simvastatin and the medium temperature were demonstrated. PMID- 24047542 TI - Rational design of a biomimetic cell penetrating peptide library. AB - Cell penetrating peptides have demonstrated potential to facilitate the cellular delivery of therapeutic molecules. Here we develop a set of 50 cell penetrating peptide based formulations with potential to deliver small interfering RNAs intercellularly. The transfection efficacy of siRNA containing lipid-like nanoparticles decorated with different peptides was evaluated both in vitro and in vivo and correlated with the peptide physical and chemical properties. In vitro, these particles were internalized primarily through macropinocytosis. When the peptides were presented to bone marrow-derived dendritic cells, they induce low immunoactivation relative to control cell penetrating peptides including the antennapedia homeodomain and TAT, as quantified by the expression of activation specific surface proteins like CD80, CD86, and major histocompatibility complex class II. In vivo, peptide decorated nanoparticles primarily accumulated in the lungs and the liver. Three human peptides derived from surfactant protein B (a lung surfactant protein), orexin (a neuropeptide hormone, and lactoferricin (a globular glycoprotein) that exist in many physiological fluids facilitated the in vivo delivery of siRNA and induce significant knock down (90%) of a hepatocyte expressed protein, coagulation Factor VII. PMID- 24047543 TI - Chikungunya fever outbreak, Bhutan, 2012. AB - In 2012, chikungunya virus (CHIKV) was reported for the first time in Bhutan. IgM ELISA results were positive for 36/210 patient samples; PCR was positive for 32/81. Phylogenetic analyses confirmed that Bhutan CHIKV belongs to the East/Central/South African genotype. Appropriate responses to future outbreaks require a system of surveillance and improved laboratory capacity. PMID- 24047544 TI - Variant human T-cell lymphotropic virus type 1c and adult T-cell leukemia, Australia. AB - Human T-cell lymphotropic virus type 1 is endemic to central Australia among Indigenous Australians. However, virologic and clinical aspects of infection remain poorly understood. No attempt has been made to control transmission to indigenous children. We report 3 fatal cases of adult T-cell leukemia/lymphoma caused by human T-cell lymphotropic virus type 1 Australo-Melanesian subtype c. PMID- 24047545 TI - Symptom validity and neuropsychological assessment: a survey of practices and beliefs of neuropsychologists in six European countries. AB - During the last decades, symptom validity has become an important topic in the neuropsychological and psychiatric literature with respect to how it relates to malingering, factitious disorder, and somatoform complaints. We conducted a survey among neuropsychologists (N = 515) from six European countries (Germany, Italy, Denmark, Finland, Norway, and the Netherlands). We queried the respondents about the tools they used to evaluate symptom credibility in clinical and forensic assessments and other issues related to symptom validity testing (SVT). Although the majority of the respondents demonstrated technical knowledge about symptom validity, a sizeable minority of the respondents relied on outdated notions (e.g., the idea that clinicians can determine symptom credibility based on intuitive judgment). There is little consensus among neuropsychologists on how to instruct patients when they are administered SVTs and how to handle test failure. Our findings indicate that the issues regarding how to administer and communicate the SVT results to patients warrant systematic research. PMID- 24047546 TI - Passive sampling: an effective method for monitoring seasonal and spatial variability of dissolved hydrophobic organic contaminants and metals in the Danube river. AB - Application of passive samplers is demonstrated for assessment of temporal and spatial trends of dissolved polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and priority metals in the middle stretch of the Danube river. Free dissolved concentrations of PAHs, measured using SPMD samplers, ranged from 5 to 72 ng L(-1). Dissolved PCBs in water were very low and they ranged from 5 to 16 pg L(-1). Concentration of mercury, cadmium, lead and nickel, measured using DGT samplers, were relatively constant along the monitored Danube stretch and in the range <0.1, <1-20, 18-74, and 173-544 ng L(-1), respectively. Concentrations of PAHs decreased with increasing temperature, which reflects the seasonality in emissions to water. This has an implication for the design of future monitoring programs aimed at assessment of long term trends. For such analysis time series should be constructed of data from samples collected always in the same season of the year. PMID- 24047547 TI - Spatial distribution of PAH concentrations and stable isotope signatures (delta13C, delta15N) in mosses from three European areas--characterization by multivariate analysis. AB - Polycyclic aromatic hydrocarbon (PAH) concentrations and N, C stable isotope signatures were determined in mosses Hypnum cupressiforme Hedw. from 61 sites of 3 European regions: Ile-de-France (France); Navarra (Spain); the Swiss Plateau and Basel area (Switzerland). Total PAH concentrations of 100-700 ng g(-1), as well as delta(13)C values of -32 to -290/00 and delta(15)N values of -11 to 30/00 were measured. Pearson correlation tests revealed opposite trends between high molecular weight PAH (4-6 aromatic rings) content and delta(13)C values. Partial Least Square regressions explained the very significant correlations (r > 0.91, p < 0.001) between high molecular weight PAH concentrations by local urban land use (<10 km) and environmental factors such as elevation and pluviometry. Finally, specific correlations between heavy metal and PAH concentrations were attributed to industrial emissions in Switzerland and road traffic emissions in Spain. PMID- 24047548 TI - Synergistic role of different soil components in slow sorption kinetics of polar organic contaminants. AB - We observed that the sorption kinetics of nitrobenzene and 2,4-dinitrotoluene (two model polar compounds) was significantly slower than that of 1,4 dichlorobenzene and phenanthrene (two model apolar compounds). The difference was attributable to the strong non-hydrophobic interactions between the polar molecules and soil. Interestingly, sorption kinetics of the polar sorbates to the soil organic matter-free soil, humic/fulvic acid-free soil, and extracted humic acids was very fast, indicating that different soil components played a synergetic role in the observed slow kinetics. We propose that slow sorption kinetics of highly polar sorbates stems mainly from the strong specific interactions (H-bonding, electron donor-acceptor interactions, etc.) with humic/fulvic acids; such specific interactions occur when sorbate molecules diffuse through humic/fulvic acids coiled, in relatively compressed confirmations, within the complex, tortuous, and porous soil matrices formed by mineral grains/particles and soil organic matter. PMID- 24047549 TI - Comparing black carbon types in sequestering polybrominated diphenyl ethers (PBDEs) in sediments. AB - Polybrominated diphenyl ethers (PBDEs) are widely found in sediments, especially congeners from the penta-BDE formula. Due to their strong affinity for black carbon (BC), bioavailability of PBDEs may be decreased in BC-amended sediments. In this study, we used a matrix-SPME method to measure the freely dissolved concentration (Cfree) of PBDEs as a parameter of their potential bioavailability and evaluated the differences among biochar, charcoal, and activated carbon. Activated carbon displayed a substantially greater sequestration capacity than biochar or charcoal. At 1% amendment rate in sediment with low organic carbon (OC) content (0.12%), Cfree of six PBDEs was reduced by 47.5-78.0%, 47.3-77.5%, and 94.1-98.3% with biochar, charcoal, and activated carbon, respectively, while the sequestration was more limited in sediment with high OC content (0.87%). Therefore, it is important to consider the type and properties of the BC and the sediment in BC-based remediation or mitigation. PMID- 24047550 TI - Polycyclic aromatic hydrocarbons in surface soil across the Tibetan Plateau: spatial distribution, source and air-soil exchange. AB - There are limited data on polycyclic aromatic hydrocarbons (PAHs) in both the atmosphere and soil of the Tibetan Plateau (TP). Concentrations of PAHs were therefore measured in 13 XAD resin-based passive air samplers and 41 surface (0-5 cm) soil samples across the TP. The average concentration of atmospheric PAHs was 5.55 ng/m(3), which was lower than that reported for other background areas, but higher than the Arctic. Concentrations in the soils fell in a wide range from 5.54 to 389 ng/g, with an average of 59.9 ng/g. Elevation was found to play an important role in determining the spatial distribution of soil PAHs. The air-soil exchange state showed that the soils of the TP will likely remain as a sink for high molecular weight PAHs, but may become a potential "secondary source" for low molecular weight PAHs. PMID- 24047551 TI - Phenanthrene binding by humic acid-protein complexes as studied by passive dosing technique. AB - This work investigated the binding behavior of phenanthrene by humic acids (HA-2 and HA-5), proteins (bovine serum albumin (BSA)), lysozyme and pepsin), and their complexes using a passive dosing technique. All sorption isotherms were fitted well with Freundlich model and the binding capability followed an order of HA-5 > HA-2 > BSA > pepsin > lysozyme. In NaCl solution, phenanthrene binding to HA-BSA complexes was much higher than the sum of binding to individual HA and BSA, while there was no enhancement for HA-pepsin. Positively charged lysozyme slightly lowered phenanthrene binding on both HAs due to strong aggregation of HA-lysozyme complexes, leading to reduction in the number of binding sites. The binding enhancement by HA-BSA was observed under all tested ion species and ionic strengths. This enhancement can be explained by unfolding of protein, reduction of aggregate size and formation of HA-BSA complexes with favorable conformations for binding phenanthrene. PMID- 24047552 TI - Integrative demographic modeling reveals population level impacts of PCB toxicity to juvenile snapping turtles. AB - A significant challenge in ecotoxicology and risk assessment lies in placing observed contaminant effects in a meaningful ecological context. Polychlorinated biphenyls (PCBs) have been shown to affect juvenile snapping turtle survival and growth but the ecological significance of these effects is difficult to discern without a formal, population-level assessment. We used a demographic matrix model to explore the potential population-level effects of PCBs on turtles. Our model showed that effects of PCBs on juvenile survival, growth and size at hatching could translate to negative effects at the population level despite the fact that these life cycle components do not typically contribute strongly to population level processes. This research points to the utility of using integrative demographic modeling approaches to better understand contaminant effects in wildlife. The results indicate that population-level effects are only evident after several years, suggesting that for long-lived species, detecting adverse contaminant effects could prove challenging. PMID- 24047553 TI - Effect of platelet-rich plasma and porcine dermal collagen graft augmentation for rotator cuff healing in a rabbit model. AB - BACKGROUND: The rate of healing failure after surgical repair of chronic rotator cuff tears is considerably high. PURPOSE: To verify the effect of platelet-rich plasma (PRP) with and without porcine dermal collagen graft augmentation on tendon-to-bone healing, using the rabbit supraspinatus tendon. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 80 rabbits were randomly allocated into 4 groups (20 rabbits per group: 12 for histological and 8 for mechanical testing): repair (R), repair + patch augmentation (RPa), repair + PRP (RPr), and repair + patch + PRP (RPaPr). The right shoulder was used for experimental interventions, and the left served as a control. Six weeks after the detachment of the supraspinatus, the torn tendon was repaired in a transosseous manner, simulating double-row repair in all groups. Platelet-rich plasma was prepared and applied onto the repair site in the RPr and RPaPr groups, and the patch was used to augment the repair in the RPa and RPaPr groups. The mechanical tensile strength test was performed at 8 weeks after repair and the histological evaluation at 4 and 8 weeks. RESULTS: At 4 weeks, the collagen fibers were poorly organized, and fiber continuity was not established in all groups. However, vascularity and cellularity were higher with granulation tissue formation in the PRP-treated groups (RPr and RPaPr) than the nontreated groups (R and RPa). At 8 weeks, tendon-to-bone integration was much improved with more collagen fibers, and longitudinally oriented collagen fibers were visible in all groups. The PRP treated groups showed better collagen fiber continuity and orientation than the nontreated groups; however, no distinctive difference was found between the patch augmented groups (RPa and RPaPr) and nonaugmented groups (R and RPr). The mean load-to-failure results were 61.57 +/- 29.99 N, 76.84 +/- 16.08 N, 105.35 +/- 33.82 N, and 117.93 +/- 12.60 N for the R, RPa, RPr, and RPaPr groups, respectively, and they were significantly different between the R and RPr (P = .018), R and RPaPr (P = .002), and RPa and RPaPr (P = .029) groups. CONCLUSION: This animal study showed the enhancement of tendon-to-bone healing after local administration of autologous PRP assessed by histological and biomechanical testing in a rabbit model of chronic rotator cuff tears. However, there was little additive effect of the patch graft. CLINICAL RELEVANCE: The use of PRP might be a biological supplement to increase the rotator cuff healing rate, which still remains low even after successful cuff repair, but this result should be interpreted with caution regarding clinical applications. PMID- 24047554 TI - In vivo evolution of antimicrobial resistance in a series of Staphylococcus aureus patient isolates: the entire picture or a cautionary tale? AB - OBJECTIVES: To obtain an expanded understanding of antibiotic resistance evolution in vivo, particularly in the context of vancomycin exposure. METHODS: The whole genomes of six consecutive methicillin-resistant Staphylococcus aureus blood culture isolates (ST239-MRSA-III) from a single patient exposed to various antimicrobials (over a 77 day period) were sequenced and analysed. RESULTS: Variant analysis revealed the existence of non-susceptible sub-populations derived from a common susceptible ancestor, with the predominant circulating clone(s) selected for by type and duration of antimicrobial exposure. CONCLUSIONS: This study highlights the dynamic nature of bacterial evolution and that non-susceptible sub-populations can emerge from clouds of variation upon antimicrobial exposure. Diagnostically, this has direct implications for sample selection when using whole-genome sequencing as a tool to guide clinical therapy. In the context of bacteraemia, deep sequencing of bacterial DNA directly from patient blood samples would avoid culture 'bias' and identify mutations associated with circulating non-susceptible sub-populations, some of which may confer cross-resistance to alternate therapies. PMID- 24047555 TI - National health expenditure projections, 2012-22: slow growth until coverage expands and economy improves. AB - Health spending growth through 2013 is expected to remain slow because of the sluggish economic recovery, continued increases in cost-sharing requirements for the privately insured, and slow growth for public programs. These factors lead to projected growth rates of near 4 percent through 2013. However, improving economic conditions, combined with the coverage expansions in the Affordable Care Act and the aging of the population, drive faster projected growth in health spending in 2014 and beyond. Expected growth for 2014 is 6.1 percent, with an average projected growth of 6.2 percent per year thereafter. Over the 2012-22 period, national health spending is projected to grow at an average annual rate of 5.8 percent. By 2022 health spending financed by federal, state, and local governments is projected to account for 49 percent of national health spending and to reach a total of $2.4 trillion. PMID- 24047556 TI - Effect of water content on strontium retardation factor and distribution coefficient in Chinese loess. AB - Geological burial and landfill are often employed for disposal of nuclear wastes. Typically, radionuclides from nuclear facilities transport through the unsaturated zone before reaching the groundwater aquifer. However, transport studies are often conducted under saturated and steady-state flow conditions. This research aimed to examine the effects of unsaturated flow conditions and soil water content (theta) on Sr sorption and retardation in Chinese loess through 1D column transport experiments. Reagent SrCl2 was used as a surrogate for the radioactive isotope ((90)Sr) in the experiment because of their analogous adsorption and transportation characteristics. The spatial distribution of Sr along the column length was determined by segmenting the soil bed and analysing the Sr content in each soil segment following each column breakthrough test. The single-region (SR) and two-region (TR) models were employed to interpret the transport data of Sr as well as a tracer (Br(-)), which resulted in the dispersion coefficient (D) and retardation factor (Rd) under a given set of unsaturated flow conditions. For the tracer, the SR and TR models offered nearly the same goodness of fitting to the breakthrough curves (R(2) ~ 0.97 for both models). For the highly sorptive Sr, however, the TR model provided better fitting (R(2), 0.80-0.96) to the Sr retention profiles than the SR model (R(2), 0.20-0.89). The Sr retention curves exhibited physical non-equilibrium characteristics, particularly at lower water content of the soil. For the unsaturated soil, D and the pore water velocity (v) displayed a weak linear correlation, which is attributed to the altering dispersivity as the water content varies. A much improved linear correlation was observed between D and v/theta. The retardation factor of Sr increased from 69.1 to 174.2 as theta decreased from 0.46 to 0.26 (cm(3) cm(-3)), while the distribution coefficient (Kd) based on Rd remained nearly unchanged at various theta levels. These results illustrated that water content must be taken into account in determining radionuclide Rd values in Chinese loess, while Kd values can be derived from the unsaturated column experiments and can be considered constant at various levels of theta. PMID- 24047557 TI - [Regorafenib approved in Metastatic Colorectal cancer]. AB - Regorafenib, oral multi-kinase inhibitor that targets oncogenesis, tumor angiogenesis and maintenance of the tumor microenvironment, obtained its European approval, August 26, 2013 after favorable review of the European Medecines Agency in the following indication: treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy or are not considered candidates for available therapies and, if KRAS wild type, an anti-EGFR therapy. This decision was based on the efficacy and safety results of an international phase III trial. This study showed an improved overall survival, with regorafenib versus placebo (6.4 months vs 4 months; HR = 0.774, IC a 95%, 0.64 a 0.94; p = 0,005 2). Reported grade 3-4 adverse events with regorafenib were hand-foot syndrome (17%), asthenia (10%), diarrhea (7%), hypertension (7%), rash and desquamation (6%). PMID- 24047559 TI - Identification and characterization of regulatory elements in the promoter of ACVR1, the gene mutated in Fibrodysplasia Ossificans Progressiva. AB - BACKGROUND: The ACVR1 gene encodes a type I receptor for bone morphogenetic proteins (BMPs). Mutations in the ACVR1 gene are associated with Fibrodysplasia Ossificans Progressiva (FOP), a rare and extremely disabling disorder characterized by congenital malformation of the great toes and progressive heterotopic endochondral ossification in muscles and other non-skeletal tissues. Several aspects of FOP pathophysiology are still poorly understood, including mechanisms regulating ACVR1 expression. This work aimed to identify regulatory elements that control ACVR1 gene transcription. METHODS AND RESULTS: We first characterized the structure and composition of human ACVR1 gene transcripts by identifying the transcription start site, and then characterized a 2.9 kb upstream region. This region showed strong activating activity when tested by reporter gene assays in transfected cells. We identified specific elements within the 2.9 kb region that are important for transcription factor binding using deletion constructs, co-transfection experiments with plasmids expressing selected transcription factors, site-directed mutagenesis of consensus binding site sequences, and by protein/DNA binding assays. We also characterized a GC rich minimal promoter region containing binding sites for the Sp1 transcription factor. CONCLUSIONS: Our results showed that several transcription factors such as Egr-1, Egr-2, ZBTB7A/LRF, and Hey1, regulate the ACVR1 promoter by binding to the -762/-308 region, which is essential to confer maximal transcriptional activity. The Sp1 transcription factor acts at the most proximal promoter segment upstream of the transcription start site. We observed significant differences in different cell types suggesting tissue specificity of transcriptional regulation. These findings provide novel insights into the molecular mechanisms that regulate expression of the ACVR1 gene and that could be targets of new strategies for future therapeutic treatments. PMID- 24047558 TI - Antigenic variation in African trypanosomes: the importance of chromosomal and nuclear context in VSG expression control. AB - African trypanosomes are lethal human and animal parasites that use antigenic variation for evasion of host adaptive immunity. To facilitate antigenic variation, trypanosomes dedicate approximately one third of their nuclear genome, including many minichromosomes, and possibly all sub-telomeres, to variant surface glycoprotein (VSG) genes and associated sequences. Antigenic variation requires transcription of a single VSG by RNA polymerase I (Pol-I), with silencing of other VSGs, and periodic switching of the expressed gene, typically via DNA recombination with duplicative translocation of a new VSG to the active site. Thus, telomeric location, epigenetic controls and monoallelic transcription by Pol-I at an extranucleolar site are prominent features of VSGs and their expression, with telomeres, chromatin structure and nuclear organization all making vitally important contributions to monoallelic VSG expression control and switching. We discuss VSG transcription, recombination and replication control within this chromosomal and sub-nuclear context. PMID- 24047561 TI - Leptotrichia trevisanii sepsis after bone marrow transplantation. PMID- 24047560 TI - c-Jun N-terminal kinase regulates mGluR-dependent expression of post-synaptic FMRP target proteins. AB - Fragile X syndrome (FXS) is caused by the loss of functional fragile X mental retardation protein (FMRP). Loss of FMRP results in an elevated basal protein expression profile of FMRP targeted mRNAs, a loss of local metabotropic glutamate receptor (mGluR)-regulated protein synthesis, exaggerated long-term depression and corresponding learning and behavioral deficits. Evidence shows that blocking mGluR signaling in FXS models ameliorates these deficits. Therefore, understanding the signaling mechanisms downstream of mGluR stimulation may provide additional therapeutic targets for FXS. Kinase cascades are an integral mechanism regulating mGluR-dependent protein translation. The c-Jun N-terminal kinase (JNK) pathway has been shown to regulate mGluR-dependent nuclear transcription; however, the involvement of JNK in local, synaptic signaling has not been explored. Here, we show that JNK is both necessary and sufficient for mGluR-dependent expression of a subset of FMRP target proteins. In addition, JNK activity is basally elevated in fmr1 knockout mouse synapses, and blocking JNK activity reduces the over-expression of post-synaptic proteins in these mice. Together, these data suggest that JNK may be an important signaling mechanism downstream of mGluR stimulation, regulating FMRP-dependent protein synthesis. Furthermore, local, post-synaptic dysregulation of JNK activity may provide a viable target to ameliorate the deficits involved in FXS. Expression of many FMRP target proteins is enhanced in FXS. Here, we evaluated the role of JNKs in FXS. We found that JNK signaling is activated upon mGluR stimulation in wild-type neurons. Conversely, JNK activity is basally elevated in fmr1 knockout. Inhibiting JNK reduced the expression of FMRP target proteins and driving JNK activity increased the expression of these proteins. PMID- 24047562 TI - Obstructive sleep apnea syndrome causes a pseudo-Cushing's state in Japanese obese patients with type 2 diabetes mellitus. AB - Activation of the hypothalamic-pituitary-adrenal axis has been reported in some patients with the obstructive sleep apnea syndrome (OSAS). In current study, we investigated whether OSAS affect the screening test for subclinical Cushing's disease using 0.5 mg overnight dexamethasone suppression test (DST) in Japanese obese diabetic patients with OSAS. Among Japanese obese patients with type 2 diabetes mellitus who had been hospitalized in our department, we selected 20 patients with moderate to severe untreated OSAS (apnea-hypoxia index, AHI, of >=15 events/hour). All patients underwent 0.5 mg DST. The same test was repeated in patients with positive response of it within a few days after continuous positive airway pressure (CPAP) therapy. We found that five patients showed positive response of DST (25%). Three of these patients continued to use CPAP, and they showed normal response of DST after CPAP therapy. Serum cortisol after 0.5 mg DST measured before CPAP therapy correlated significantly with fasting serum cortisol level (r=0.764, p<0.0001), but not with various clinical parameters, including AHI (p=0.784), body mass index (p=0.984), waist circumference (p=0.957), HbA1c (p=0.261), fasting plasma glucose (p=0.420) and HOMA-IR (p=0.500). Our study show that OSAS causes a pseudo-Cushing's syndrome in obese patients with type 2 diabetes mellitus, which phenomena can be reversed by CPAP therapy. PMID- 24047563 TI - The association between non-alcoholic fatty liver disease and carotid atherosclerosis in subjects with within-reference range alanine aminotransferase levels. AB - Our aim was to investigate whether the evaluation of non-alcoholic fatty liver disease (NAFLD) by ultrasound provides additional benefit in assessing carotid atherosclerotic burden in subjects with alanine aminotransferase (ALT) concentrations within the reference range. This was a cross-sectional analysis of 769 healthy individuals (326 men and 443 women) with an ALT concentration <= 40 IU/L and alcohol consumption < 140 g/week. Mean carotid artery intima-media thickness (C-IMT) was measured using ultrasound. NAFLD was defined as a mild or greater degree of hepatic steatosis on ultrasound. Although all subjects had an ALT concentration within the reference range, the prevalence of NAFLD increased with increasing quartiles of ALT concentration (27.1%, 40.0%, 54.7%, 75.3% in men, P for trend < 0.001; 22.0%, 34.4%, 35.7%, 55.0% in women, P for trend < 0.001). In the 3rd and 4th quartiles of ALT concentration, women with NAFLD had a significantly higher C-IMT than those without NAFLD (0.671+/-0.019 mm vs. 0.742+/ 0.025 mm, P=0.023 in Q3; 0.651+/-0.023 mm vs. 0.737+/-0.021 mm, P=0.005 in Q4). These differences remained significant even after adjusting for a broad spectrum of potential confounders. In contrast, although men with NAFLD tended to have a higher C-IMT than those without NAFLD in each quartile, these differences were not statistically significant. Women with an upper normal range ALT concentration showed increased C-IMT only when they had NAFLD. Therefore, in women with an elevated ALT level within the reference range, further evaluation for NAFLD, such as liver ultrasound, could potentially identify those patients at high risk for cardiovascular disease. PMID- 24047564 TI - Testosterone replacement elevates the serum uric acid levels in patients with female to male gender identity disorder. AB - Gender identity disorder (GID) results from a disagreement between a person's biological sex and the gender to which he or she identifies. With respect to the treatment of female to male GID, testosterone replacement therapy (TRT) is available. The uric acid (UA) level can be influenced by testosterone; however, the early effects and dose-dependency of TRT on the serum UA concentration have not been evaluated in this population. We herein conducted a dose-response analysis of TRT in 160 patients with female to male GID. The TRT consisted of three treatment groups who received intramuscular injections of testosterone enanthate: 125 mg every two weeks, 250 mg every three weeks and 250 mg every two weeks. Consequently, serum UA elevation was observed after three months of TRT and there was a tendency toward testosterone dose-dependency. The onset of hyperuricemia was more prevalent in the group who received the higher dose. We also demonstrated a positive correlation between increased levels of serum UA and serum creatinine. Since the level of serum creatinine represents an individual's muscle volume and the muscle is a major source of purine, which induces UA upregulation, the serum UA elevation observed during TRT is at least partially attributed to an increase in muscle mass. This is the first study showing an association between serum UA elevation and a TRT-induced increase in muscle mass. The current study provides important information regarding TRT for the follow-up and management of the serum UA levels in GID patients. PMID- 24047565 TI - Source identification through social networks in an epidemiological investigation of a hepatitis A outbreak at an elementary school in Anhui province, China. AB - In May 2011, the Center for Disease Control and Prevention of a Chinese county found a rapid increase in the number of hepatitis A case notification; these were traced to an outbreak in an elementary school. Twenty-eight cases aged between 7 and 13 years with onset between 7 May and 8 June were serologically confirmed. Network method was conducted to reconstruct an outbreak network and to quantify the relative importance of those involved in the outbreak. A case-control study was used to study the association between the outbreak and putative risk factors. The network analysis suggested this was a disseminated outbreak originating from a 4-year-old boy with propagated spread. Evidence from the case-control study supported consumption of well water as a potential risk factor; however, this was unable to be established through field investigation. Outbreak networks can be used to identify the possible source of infectious disease outbreak, especially when the environmental investigation information is negative or not available. PMID- 24047566 TI - Transition in the cause of fever from malaria to dengue, Northwestern Ecuador, 1990-2011. AB - In tropical areas, the predominant cause of fever has historically been malaria. However by 2011, among febrile patients in northwestern Ecuador, dengue was identified in 42% and malaria in none. This finding suggests a transition in the cause of fever from malaria to other illnesses, such as dengue. PMID- 24047567 TI - Sources of bias in clinical ethics case deliberation. AB - A central task for clinical ethics consultants and committees (CEC) is providing analysis of, and advice on, prospective or retrospective clinical cases. However, several kinds of biases may threaten the integrity, relevance or quality of the CEC's deliberation. Bias should be identified and, if possible, reduced or counteracted. This paper provides a systematic classification of kinds of bias that may be present in a CEC's case deliberation. Six kinds of bias are discussed, with examples, as to their significance and risk factors. Possible remedies are suggested. The potential for bias is greater when the case deliberation is performed by an individual ethics consultant than when an entire clinical ethics committee is involved. PMID- 24047568 TI - Ultra-structural analysis of the brain in a Drosophila model of Alzheimer's disease using FIB/SEM microscopy. AB - Alzheimer's disease (AD), one of the most prevalent neurodegenerative brain diseases, has been extensively researched for years. However, its synaptic structure, which is a basis for understanding neurodegenerative disorders, has not yet been understood clearly. Defining the structures of neurons and their synaptic connections is the significant goal of brain research. To study synaptic connectivity, three-dimensional (3D) reconstructions of the nervous system are very helpful. In this study, the 3D structure of brain synapses in the Drosophila melanogaster Swedish amyloid precursor protein (APP) mutant, which is characterized by early onset AD, was analyzed using focused ion beam/scanning electron microscopy (FIB/SEM). This technique is one of the most useful for 3D reconstruction, as the process of obtaining serial images is fully automated and thus avoids the problems inherent in hand-operated ultrathin serial sectioning. The 3D images of normal and AD brains reported in this study reveal characteristic features of AD such as appearance of autophagy, abnormal axon formation and increased mitochondrial size. This 3D analysis reveals structural change as a basis for understanding neurodegenerative disorder. PMID- 24047569 TI - Traffic-related air pollution and noise and children's blood pressure: results from the PIAMA birth cohort study. AB - AIMS: Elevation of a child's blood pressure may cause possible health risks in later life. There is evidence for adverse effects of exposure to air pollution and noise on blood pressure in adults. Little is known about these associations in children. We investigated the associations of air pollution and noise exposure with blood pressure in 12-year-olds. METHODS: Blood pressure was measured at age 12 years in 1432 participants of the PIAMA birth cohort study. Annual average exposure to traffic-related air pollution [NO2, mass concentrations of particulate matter with diameters of less than 2.5 um (PM2.5) and less than 10 um (PM10), and PM2.5 absorbance] at the participants' home and school addresses at the time of blood pressure measurements was estimated by land-use regression models. Air pollution exposure on the days preceding blood pressure measurements was estimated from routine air monitoring data. Long-term noise exposure was assessed by linking addresses to modelled equivalent road traffic noise levels. Associations of exposures with blood pressure were analysed by linear regression. Effects are presented for an interquartile range increase in exposure. RESULTS: Long-term exposure to NO2 and PM2.5 absorbance were associated with increased diastolic blood pressure, in children who lived at the same address since birth [adjusted mean difference (95% confidence interval) [mmHg] 0.83 (0.06 to 1.61) and 0.75 (-0.08 to 1.58), respectively], but not with systolic blood pressure. We found no association of blood pressure with short-term air pollution or noise exposure. CONCLUSIONS: Long-term exposure to traffic-related air pollution may increase diastolic blood pressure in children. PMID- 24047570 TI - Effect of rapid weight loss on performance in combat sport male athletes: does adaptation to chronic weight cycling play a role? AB - BACKGROUND: Studies failing to show a negative effect of rapid weight loss (RWL) on performance have been conducted in athletes who have been cycling weight for years. It has been suggested that chronic weight cycling could lead combat athletes to become resistant to the stresses associated with weight loss. To investigate the effects of RWL up to 5% of body mass on high-intensity intermittent performance in weight cyclers (WC) and non-weight cyclers (non-WC). METHODS: Eighteen male combat athletes (WC: n=10; non-WC: n=8) reduced up to 5% of their body mass in 5 days. Body composition, high-intensity performance and plasma lactate were assessed preweight loss and postweight loss. Athletes had 4 h to re-feed and rehydrate following the weigh-in. Food intake was recorded during the weight loss and the recovery periods. RESULTS: Athletes significantly decreased body mass, lean body mass (most likely due to fluid loss) and fat mass following weight loss. No significant changes in performance were found from preweight loss to postweight loss in both groups. Plasma lactate was significantly elevated after exercise in both groups, but no differences were found between groups and in response to RWL. For all these variables no differences were observed between groups. Athletes from both groups ingested high amounts of energy and carbohydrates during the recovery period after the weigh in. CONCLUSIONS: Chronic weight cycling does not protect athletes from the negative impact of RWL on performance. The time to recover after weigh-in and the patterns of food and fluid ingestion during this period is likely to play the major role in restoring performance to baseline levels. PMID- 24047571 TI - What do community football players think about different exercise-training programmes? Implications for the delivery of lower limb injury prevention programmes. AB - BACKGROUND: Players are the targeted end-users and beneficiaries of exercise training programmes implemented during coach-led training sessions, and the success of programmes depends upon their active participation. Two variants of an exercise-training programme were incorporated into the regular training schedules of 40 community Australian Football teams, over two seasons. One variant replicated common training practices, while the second was an evidence-based programme to alter biomechanical and neuromuscular factors related to risk of knee injuries. This paper describes the structure of the implemented programmes and compares players' end-of-season views about the programme variants. METHODS: This study was nested within a larger group-clustered randomised controlled trial of the effectiveness of two exercise-training programmes (control and neuromuscular control (NMC)) for preventing knee injuries. A post-season self report survey, derived from Health Belief Model constructs, included questions to obtain players' views about the benefits and physical challenges of the programme in which they participated. RESULTS: Compared with control players, those who participated in the NMC programme found it to be less physically challenging but more enjoyable and potentially of more benefit. Suggestions from players about potential improvements to the training programme and its future implementation included reducing duration, increasing range of drills/exercises and promoting its injury prevention and other benefits to players. CONCLUSIONS: Players provide valuable feedback about the content and focus of implemented exercise-training programmes, that will directly inform the delivery of similar, or more successful, programmes in the future. PMID- 24047572 TI - The usefulness of subtraction ictal SPECT and ictal near-infrared spectroscopic topography in patients with West syndrome. AB - The recent findings on subtraction ictal SPECT and ictal near-infrared spectroscopic topography in patients with West syndrome were summarized and its availability for presurgical evaluation was discussed. The subtraction ictal SPECT study in patients with West syndrome demonstrated the cortical epileptic region and subcortical involvement, which may consist of epilepsy networks related to the spasms. Moreover, subtraction ictal SPECT may have predictive power for short-term seizure outcome. Patients with a symmetric hyperperfusion pattern are predicted to have a better seizure outcome, whereas patients with asymmetric hyperperfusion pattern may develop poor seizure control. Importantly, asymmetric MRI findings had no predictive power for seizure outcome. Multichannel near-infrared spectroscopic topography applied to the patients with West syndrome detected an increase in regional cerebral blood volume in multiple areas which were activated either simultaneously or sequentially during spasms. Topographic changes in cerebral blood volume were closely correlated with spasm phenotype, suggesting that the cortex is involved in the generation of spasms. In conclusion, subtraction ictal SPECT may be considered as a useful tool for presurgical evaluation of patients with West syndrome and investigation of the pathophysiology of spasms. The ictal near-infrared spectroscopic topography should be more investigated to see if this is useful tool for presurgical evaluation. PMID- 24047573 TI - Website design: technical, social and medical issues for self-reporting by elderly patients. AB - There is growing interest in the use of the Internet for interacting with patients, both in terms of healthcare information provision and information gathering. In this article, we examine the issues in designing healthcare websites for elderly users. In particular, this article uses a year-long case study of the development of a web-based system for self-reporting of symptoms and quality of life with a view to examine the issues relating to website design for elderly users. The issues identified included the technical, social and medical aspects of website design for elderly users. The web-based system developed was based on the European Quality of Life 5-Dimensions health-status questionnaire, a commonly used tool for patient self-reporting of quality of life, and the more specific coronary revascularisation outcome questionnaire. Currently, self reporting is generally administered in the form of paper-based questionnaires to be completed in the outpatient clinic or at home. There are a variety of issues relating to elderly users, which imply that websites for elderly patients may involve different design considerations to other types of websites. PMID- 24047574 TI - Reply: To PMID 23763783. PMID- 24047575 TI - Dutch teachers and parents about overweight prevention in pre-vocational schools. AB - Healthier lifestyles may contribute to prevent overweight in adolescents. Although school-based interventions show promising results, adoption and implementation by secondary schools and involvement of parents is difficult. Our study aims to gain a better understanding of the problem awareness and beliefs of school staff and parents regarding adolescents' overweight and energy balance related behaviour, their motivation for health-promoting activities and suggested actions in the school environment. Focus group interviews were conducted with three groups of parents and three groups of school staff at three pre-vocational schools in the Netherlands. Comments concerning awareness, motivation to intervene and possible actions were analysed with the Atlas.ti program. Results showed that school staff and parents were aware of overweight as a health problem, but underestimated the prevalence and impact of overweight and unhealthy behaviour in their school. Health-related behaviour of adolescents was considered primarily the responsibility of parents, but the school staff also had a pedagogical responsibility. Parents and school staff agreed that health promotion efforts would have more impact on adolescents' behaviour, when school-based activities were supported by parents and parental efforts were supported by school health promotion. Therefore, parental efforts and school-based activities should be aligned by developing and expressing shared norms about healthy behaviour and parents should be taught how to discuss healthy dietary and physical activity behaviour with their children. To tackle peer group culture and the obese environment, parents' and school staff's efforts should be part of an integrated community approach. PMID- 24047576 TI - The 100-year old collection of wax moulages at the Department of Dermatology of the University of Bonn. AB - The tradition of wax models in Dermatology, also named moulages, is about 200 years old. Dermatology departments all over the world created wax moulages collections to teach students and doctors as well as to document research. In 1910 Erich Hoffmann, who discovered Spirochaeta pallida together with Fritz Schaudinn, became head of the department of dermatology in Bonn. He founded one of the largest moulage collections in Germany. This almost unknown collection consists of more than 1,000 delicate and well conserved wax models. Two excellent wax moulage makers, Auguste Kaltschmidt and Hermann Hessling, produced most of these masterpieces between 1913 and 1937. Until recently, A. Kaltschmidt has only been known to have worked as moulage maker in Rostock, while the biographic details of both her and H. Hessling remained obscure. This paper aims (i) to outline Erich Hoffmann's role for and his contribution to the moulage collection and (ii) to give the first biographic details about the two outstanding dermatologic moulage makers of the collection of Bonn. PMID- 24047577 TI - Comparative histology and immunohistochemistry of porcine versus human skin. AB - BACKGROUND: Porcine skin is increasingly being employed as a model of human skin in various research fields, including pharmacology, toxicology and immunology, with particular interest in percutaneous permeation and organ transplantation. Porcine skin shows several anatomical and physiological similarities, but also some differences, with human skin, but few in depth comparative studies are so far available. OBJECTIVES: To study the immunohistochemical properties of normal porcine skin in comparison with human skin. MATERIALS AND METHODS: We performed a histological and immunohistochemical study on frozen and formalin-fixed, paraffin embedded skin biopsies from domestic swine and normal human skin, using a panel of 93 monoclonal or polyclonal antibodies recognizing various human and porcine skin cell types or structures. RESULTS: We found that several antibodies used to detect normal human skin cells showed equivalent immunoreactivity on normal porcine skin. However, some antibodies commonly used to detect human skin antigens remained unreactive on porcine skin. CONCLUSIONS: Our findings highlight the main immunohistochemical properties of porcine skin in comparison with those of human skin and provide a morphological and immunohistochemical basis useful to researchers using porcine skin. PMID- 24047578 TI - Severe xanthomatosis with prominent tuberous xanthomas on the cheeks and the nasal dorsum in a patient with type IIa hyperlipoproteinemia. PMID- 24047579 TI - Soluble Fas serum levels are not associated with FAS-1377 G>A genotypes in vitiligo patients. PMID- 24047580 TI - Hair regrowth following TNF-alpha blockade in coexisting psoriasis vulgaris and alopecia areata. PMID- 24047581 TI - Generalized orf superinfection in a child with atopic dermatitis. PMID- 24047582 TI - Chronic perianal ulceration as the initial symptom of Langerhans cell histiocytosis in adults. PMID- 24047583 TI - Mask-induced pressure ulcer of the nasal bridge. PMID- 24047585 TI - Residents'corner July 2013. sQUIZ your knowledge! A dome-shaped pigmented papule appeared in a congenital lesion. PMID- 24047586 TI - Residents' corner July 2013. DeRmpath & Clinic: Differential diagnosis in subepidermal bullous diseases. PMID- 24047587 TI - Residents' corner July 2013. Clues in DeRmosCopy: Entodermoscopy. PMID- 24047589 TI - Inactivation of Myosin binding protein C homolog in zebrafish as a model for human cardiac hypertrophy and diastolic dysfunction. AB - BACKGROUND: Sudden cardiac death due to malignant ventricular arrhythmia is a devastating manifestation of cardiac hypertrophy. Sarcomere protein myosin binding protein C is functionally related to cardiac diastolic function and hypertrophy. Zebrafish is a better model to study human electrophysiology and arrhythmia than rodents because of the electrophysiological characteristics similar to those of humans. METHODS AND RESULTS: We established a zebrafish model of cardiac hypertrophy and diastolic dysfunction by genetic knockdown of myosin binding protein C gene (mybpc3) and investigated the electrophysiological phenotypes in this model. We found expression of zebrafish mybpc3 restrictively in the heart and slow muscle, and mybpc3 gene was evolutionally conservative with sequence homology between zebrafish and human mybpc3 genes. Zebrafish with genetic knockdown of mybpc3 by morpholino showed ventricular hypertrophy with increased myocardial wall thickness and diastolic heart failure, manifesting as decreased ventricular diastolic relaxation velocity, pericardial effusion, and dilatation of the atrium. In terms of electrophysiological phenotypes, mybpc3 knockdown fish had a longer ventricular action potential duration and slower ventricular diastolic calcium reuptake, both of which are typical electrophysiological features in human cardiac hypertrophy and heart failure. Impaired calcium reuptake resulted in increased susceptibility to calcium transient alternans and action potential duration alternans, which have been proved to be central to the genesis of malignant ventricular fibrillation and a sensitive marker of sudden cardiac death. CONCLUSIONS: mybpc3 knockdown in zebrafish recapitulated the morphological, mechanical, and electrophysiological phenotypes of human cardiac hypertrophy and diastolic heart failure. Our study also first demonstrated arrhythmogenic cardiac alternans in cardiac hypertrophy. PMID- 24047590 TI - Estonian waterworks treatment plants: clearance of residues, discharge of effluents and efficiency of removal of radium from drinking water. AB - Considerable levels of radium were detected in a certain fraction of the Estonian drinking water supply network. Some of these waterworks have treatment systems for the removal of (mainly) iron and manganese from drinking water. Three of these waterworks and another one equipped with a radium removal pilot plant were examined, and a specific study was conducted in order to assess the environmental compatibility of effluents and residues produced in the plants. (226)Ra and (228)Ra activity concentrations were analysed in both liquid (backwash water) and solid (sand filter and sediment) materials to evaluate their compliance, from the radiological point of view, with current Estonian legislation and international technical documents that propose reference levels for radium in effluents and residues. Also with regard to water treatment by-products, a preliminary analysis was done of possible consequences of the transposition of the European Basic Safety Standards Draft into Estonian law. Radium removal efficiency was also tested in the same plants. Iron and manganese treatment plants turned out to be scarcely effective, whilst the radium mitigation pilot plant showed a promising performance. PMID- 24047591 TI - A comparison of Quincke and Whitacre needles with respect to risk of intravascular uptake in S1 transforaminal epidural steroid injections: a randomized trial of 1376 cases. AB - BACKGROUND: Transforaminal epidural steroid injection (TFESI) is a useful treatment modality for pain management. Most complications of TFESI are minor and transient. However, there is a risk of serious complications such as nerve injury, spinal cord infarct, or paraplegia. Some of the risks are related to direct injury to the vessel or intravascular injection of the particulate steroid. We prospectively tested the hypothesis that the intravascular injection rate of the Whitacre needle is lower than that of the Quincke needle during TFESI. METHODS: This study was a randomized trial of 1376 TFESIs at the S1 level. We collected data of age, gender, height, weight, laterality (right/left), history of lumbosacral spine operation, history of appropriate interval discontinuation of anticoagulation medicines, and underlying disease. During the S1 TFESI, intrasacral bone contact, a blood aspiration test, and real-time fluoroscopy of the intravascular injection using contrast media were investigated. RESULTS: There were no significant differences in the intravascular injection rate with respect to age, gender, height, weight, hypertension, diabetes mellitus, laterality, history of lumbosacral spine operation, or history of appropriate interval discontinuation of anticoagulation medicines. Intravascular injection was significantly associated with a blood aspiration test (P < 0.001), needle tip type (P = 0.002), intrasacral bone contact (P < 0.001), and physicians (some P < 0.05). The use of Quincke needles and intrasacral bone contact increased the rate of intravascular injection. CONCLUSIONS: To reduce the risk of intravascular injection, the use of Whitacre needles without intrasacral bone contact may be a safer and more effective approach. PMID- 24047592 TI - Reputation rankings for pediatric urology moderately reflect academic productivity. PMID- 24047593 TI - Objective measures of binaural masking level differences and comodulation masking release based on late auditory evoked potentials. AB - The audibility of important sounds is often hampered due to the presence of other masking sounds. The present study investigates if a correlate of the audibility of a tone masked by noise is found in late auditory evoked potentials measured from human listeners. The audibility of the target sound at a fixed physical intensity is varied by introducing auditory cues of (i) interaural target signal phase disparity and (ii) coherent masker level fluctuations in different frequency regions. In agreement with previous studies, psychoacoustical experiments showed that both stimulus manipulations result in a masking release (i: binaural masking level difference; ii: comodulation masking release) compared to a condition where those cues are not present. Late auditory evoked potentials (N1, P2) were recorded for the stimuli at a constant masker level, but different signal levels within the same set of listeners who participated in the psychoacoustical experiment. The data indicate differences in N1 and P2 between stimuli with and without interaural phase disparities. However, differences for stimuli with and without coherent masker modulation were only found for P2, i.e., only P2 is sensitive to the increase in audibility, irrespective of the cue that caused the masking release. The amplitude of P2 is consistent with the psychoacoustical finding of an addition of the masking releases when both cues are present. Even though it cannot be concluded where along the auditory pathway the audibility is represented, the P2 component of auditory evoked potentials is a candidate for an objective measure of audibility in the human auditory system. PMID- 24047594 TI - Transmission of bone conducted sound - correlation between hearing perception and cochlear vibration. AB - The vibration velocity of the lateral semicircular canal and the cochlear promontory was measured on 16 subjects with a unilateral middle ear common cavity, using a laser Doppler vibrometer, when the stimulation was by bone conduction (BC). Four stimulation positions were used: three ipsilateral positions and one contralateral position. Masked BC pure tone thresholds were measured with the stimulation at the same four positions. Valid vibration data were obtained at frequencies between 0.3 and 5.0 kHz. Large intersubject variation of the results was found with both methods. The difference in cochlear velocity with BC stimulation at the four positions varied as a function of frequency while the tone thresholds showed a tendency of lower thresholds with stimulation at positions close to the cochlea. The correlation between the vibration velocities of the two measuring sites of the otic capsule was high. Also, relative median data showed similar trends for both vibration and threshold measurements. However, due to the high variability for both vibration and perceptual data, low correlation between the two methods was found at the individual level. The results from this study indicated that human hearing perception from BC sound can be estimated from the measure of cochlear vibrations of the otic capsule. It also showed that vibration measurements of the cochlea in cadaver heads are similar to that measured in live humans. PMID- 24047595 TI - Septins in the glial cells of the nervous system. AB - The capacity of cytoskeletal septins to mediate diverse cellular processes is related to their ability to assemble as distinct heterooligomers and higher order structures. However, in many cell types the functional relevance of septins is not well understood. This minireview provides a brief overview of our current knowledge about septins in the non-neuronal cells of the vertebrate nervous system, collectively termed 'glial cells', i.e., astrocytes, microglia, oligodendrocytes, and Schwann cells. The dysregulation of septins observed in various models of myelin pathology is discussed with respect to implications for hereditary neuralgic amyotrophy (HNA) caused by mutations of the human SEPT9 gene. PMID- 24047596 TI - Highlight: NRW Research School BioStruct--biological structures in molecular medicine and biotechnology. PMID- 24047598 TI - Knowledge and perceptions of HIV/AIDS among Cameroonian nursing students. AB - The HIV/AIDS pandemic impacts people throughout the world and is complicated by fear, prejudice, and stigma. Nurses play a major role in the health care delivery systems, yet in many parts of the world with high HIV sero-prevalence rates, nurses lack sufficient training and education to provide care to patients with HIV/AIDS. In an effort to build capacity and improve knowledge, attitudes and beliefs regarding care of patients with HIV/AIDS, a 4-day workshop was provided by American nursing students for Cameroonian nursing students. The training program included HIV epidemiology, disease management, and natural course of the disease, testing, legal and ethical issues, and infection control practices. Pre- and post-test scores were calculated using a series of surveys that measured HIV related knowledge, attitudes, and beliefs. Results indicated that these measures of HIV-related perceptions improved due to the train-the-trainer workshop. PMID- 24047599 TI - Power considerations for trials of two experimental arms versus a standard active control or placebo. AB - The power of the two-experimental arm trial depends on three choices: (1) when one arm is dropped (if at all); (2) the final testing procedure, assuming no dropping; and (3) the sampling ratio for the three arms. Multiple-arm designs require critical values which were calculated using Mathematica. Power calculations were exact based on probabilities from binomial distributions. The "drop the loser" strategy is optimal for the primary endpoint. The equal sized two treated arm trial gives reasonable power for the primary as well as good power to select the best treated arm. The best power was provided by the 3:3:4 sampling, but it was only marginally better. PMID- 24047600 TI - A comparison of machine learning methods for classification using simulation with multiple real data examples from mental health studies. AB - BACKGROUND: Recent literature on the comparison of machine learning methods has raised questions about the neutrality, unbiasedness and utility of many comparative studies. Reporting of results on favourable datasets and sampling error in the estimated performance measures based on single samples are thought to be the major sources of bias in such comparisons. Better performance in one or a few instances does not necessarily imply so on an average or on a population level and simulation studies may be a better alternative for objectively comparing the performances of machine learning algorithms. METHODS: We compare the classification performance of a number of important and widely used machine learning algorithms, namely the Random Forests (RF), Support Vector Machines (SVM), Linear Discriminant Analysis (LDA) and k-Nearest Neighbour (kNN). Using massively parallel processing on high-performance supercomputers, we compare the generalisation errors at various combinations of levels of several factors: number of features, training sample size, biological variation, experimental variation, effect size, replication and correlation between features. RESULTS: For smaller number of correlated features, number of features not exceeding approximately half the sample size, LDA was found to be the method of choice in terms of average generalisation errors as well as stability (precision) of error estimates. SVM (with RBF kernel) outperforms LDA as well as RF and kNN by a clear margin as the feature set gets larger provided the sample size is not too small (at least 20). The performance of kNN also improves as the number of features grows and outplays that of LDA and RF unless the data variability is too high and/or effect sizes are too small. RF was found to outperform only kNN in some instances where the data are more variable and have smaller effect sizes, in which cases it also provide more stable error estimates than kNN and LDA. Applications to a number of real datasets supported the findings from the simulation study. PMID- 24047601 TI - Extracellular signal-regulated kinase (ERK) activity during sleep consolidates cortical plasticity in vivo. AB - Ocular dominance plasticity (ODP) in the cat primary visual cortex (V1) is induced during waking by monocular deprivation (MD) and consolidated during subsequent sleep. The mechanisms underlying this process are incompletely understood. Extracellular signal-regulated kinase (ERK) is activated in V1 during sleep after MD, but it is unknown whether ERK activation during sleep is necessary for ODP consolidation. We investigated the role of ERK in sleep dependent ODP consolidation by inhibiting the ERK-activating enzyme MEK in V1 (via U0126) during post-MD sleep. ODP consolidation was then measured with extracellular microelectrode recordings. Western blot analysis was used to confirm the efficacy of U0126 and to examine proteins downstream of ERK. U0126 abolished ODP consolidation and reduced both phosphorylation of eukaryotic initiation factor 4E (eIF4E) and levels of the synaptic marker PSD-95. Furthermore, interfering with ERK-mediated translation by inhibiting MAP kinase interacting kinase 1 (Mnk1) with CGP57380 mimicked the effects of U0126. These results demonstrate that ODP consolidation requires sleep-dependent activation of the ERK-Mnk1 pathway. PMID- 24047603 TI - Preclinical and translational research to discover potentially effective antifibrotic therapies in systemic sclerosis. AB - PURPOSE OF REVIEW: To discuss the strategies for preclinical and early clinical characterization of targeted antifibrotic therapies in order to optimize the probability of positive results in later stage clinical trials. RECENT FINDINGS: There is a high unmet clinical need for effective antifibrotic therapies in systemic sclerosis (SSc), and in parallel a rapid development in the identification of potential molecular targets in preclinical research. Herein, we discuss the strategies for the improvement of preclinical and early clinical trials. These strategies include identification and characterization of molecular targets for therapy in vitro, selection of relevant parameters in translational animal models, confirmation of target activation in human SSc, analysis of successful target coverage after drug exposure in human SSc, and conduct of biomarker-driven proof-of-concept studies as a bridge between animal studies and Phase IIB/III studies with clinical endpoints. SUMMARY: These strategies could increase the possibility to develop successful drugs against the fibrotic manifestations of SSc. PMID- 24047602 TI - The early fetal development of human neocortical GABAergic interneurons. AB - GABAergic interneurons are crucial to controlling the excitability and responsiveness of cortical circuitry. Their developmental origin may differ between rodents and human. We have demonstrated the expression of 12 GABAergic interneuron-associated genes in samples from human neocortex by quantitative rtPCR from 8 to 12 postconceptional weeks (PCW) and shown a significant anterior to posterior expression gradient, confirmed by in situ hybridization or immunohistochemistry for GAD1 and 2, DLX1, 2, and 5, ASCL1, OLIG2, and CALB2. Following cortical plate (CP) formation from 8 to 9 PCW, a proportion of cells were strongly stained for all these markers in the CP and presubplate. ASCL1 and DLX2 maintained high expression in the proliferative zones and showed extensive immunofluorescent double-labeling with the cell division marker Ki-67. CALB2 positive cells increased steadily in the SVZ/VZ from 10 PCW but were not double labeled with Ki-67. Expression of GABAergic genes was generally higher in the dorsal pallium than in the ganglionic eminences, with lower expression in the intervening ventral pallium. It is widely accepted that the cortical proliferative zones may generate CALB2-positive interneurons from mid-gestation; we now show that the anterior neocortical proliferative layers especially may be a rich source of interneurons in the early neocortex. PMID- 24047604 TI - Measuring response in the gastrointestinal tract in systemic sclerosis. AB - PURPOSE OF REVIEW: Gastrointestinal tract (GIT) involvement in systemic sclerosis (scleroderma, SSc) is the most common internal complication. This review discusses the outcome measures to capture GIT involvement in clinical care and trials. RECENT FINDINGS: Patient-reported outcome measures have been validated (UCLA Scleroderma Clinical Trial Consortium GIT 2.0 and NIH PROMIS scales) in SSc GIT. Multiple objective measures are available to assess mucosal involvement and motility in GIT. However, these need to be validated in SSc for trials. SUMMARY: GIT is a common cause of morbidity and has negative impact on quality of life in SSc. Recommendations are given for trial design and evaluation of GIT involvement in SSc. PMID- 24047605 TI - The diagnostic utility of autoantibodies in adult and juvenile myositis. AB - PURPOSE OF REVIEW: The purpose of this study is to review recent advances in the diagnostic utility of autoantibodies in dermatomyositis. RECENT FINDINGS: Alternative nonspecialist testing methods have been developed for anti transcription intermediary factor 1 gamma, anti-MDA5 and anti-nuclear matrix protein 2, which are potentially exploitable by any hospital laboratory. Although these have yet to be validated for diagnostic use, it is likely that testing for myositis-specific antibodies will soon become readily available. SUMMARY: The identification of myositis-specific autoantibodies provides both diagnostic and prognostic information and offers a unique opportunity to adopt a stratified approach to treatment. Their identification, in many cases, should prevent the need for invasive diagnostic tests such as muscle biopsy. PMID- 24047606 TI - Registries in idiopathic inflammatory myopathies. AB - PURPOSE OF REVIEW: The idiopathic inflammatory myopathies myositis are rare diseases with limited information on risk factors for disease and prognosis. The aim of this review is to give an overview of how registries can be used in myositis research. RECENT FINDINGS: Population-based registries have been used in a number of incidence and prevalence studies in the review period and have shown myositis to be more common than previously reported. Disease-specific registries have been used for detailed studies on subphenotypes and longitudinal studies to identify prognostic markers and treatment outcomes. SUMMARY: Registries, both national healthcare and health insurance registries, as well as disease-specific clinical registries, are useful sources to investigate a rare disease like myositis. To achieve increased understanding of whether different subphenotypes differ in treatment outcome and prognosis, a large number of patients need to be followed longitudinally in a systematic way. A novel international, multidisciplinary registry, EUROMYOSITIS, has been developed. This is an open source registry with to date 20 centers and more than 2500 patients with myositis, many of whom are followed longitudinally. This registry has clear potentials for clinical and epidemiological research, as well as for clinical trial in myositis, and welcomes investigators from all over the world. PMID- 24047607 TI - Stem cell transplantation in systemic sclerosis. AB - PURPOSE OF REVIEW: The purpose of this review is to discuss recent published clinical and mechanistic studies on stem cell transplantation for systemic sclerosis and their implications for clinical practice. RECENT FINDINGS: Retrospective analyses of independent cohorts of systemic sclerosis patients treated with autologous stem cell transplantation showed significant improvement of skin thickening, lung function and quality of life, but at the expense of 6 17% treatment-related mortality. Right heart catheterization was employed in one study to identify and exclude patients at risk of serious cardiopulmonary toxicity. The superior efficacy of stem cell transplantation versus intravenous pulses cyclophosphamide was demonstrated in a small randomized, controlled phase 2 trial in 19 systemic sclerosis patients and a large randomized phase 3 trial in 156 patients with severe diffuse cutaneous systemic sclerosis. The latter also showed a survival benefit of transplanted patients despite a 10% transplant related mortality. Mechanistic studies in transplanted patients have shown major shifts in circulating natural killer cells, T and B lymphocytes immediately after stem cell transplantation, similar to those observed in other autoimmune conditions. Stem cell transplantation of systemic sclerosis patients with lung involvement resulted in demonstrable attenuation of thoracic high-resolution CT (HRCT) abnormalities and serum markers of lung fibrosis. SUMMARY: Stem cell transplantation is an effective treatment option for patients with severe systemic sclerosis, but is associated with toxicity and treatment-related mortality. The available data suggest that patient selection and comprehensive cardiopulmonary screening are critical factors in determining outcome. VIDEO ABSTRACT AVAILABLE: See the Supplementary Digital content 1 (http://links.lww.com/COR/A7). PMID- 24047608 TI - Validation of the Caregiver Guilt Questionnaire (CGQ) in a sample of British dementia caregivers. AB - BACKGROUND: Depression is well documented as a key outcome variable for dementia caregivers; however, guilt has been under-researched, which may be in part due to the lack of an appropriate measure. The Caregiver Guilt Questionnaire (CGQ) was originally developed and piloted with a Spanish population but has not yet been tested in an English-speaking population. METHODS: A cross-sectional postal survey was undertaken with a sample of 221 dementia caregivers in the UK, as part of a larger study of dementia caregiver outcome measures. RESULTS: The five factor structure identified for the CGQ in the Spanish sample was replicated in this study. The five factors, "guilt about doing wrong by the care recipient," "guilt about failing to meet the challenges of caregiving," 'guilt over experience of negative emotions in relation to caregiving," "guilt about self care," and "guilt about neglecting other relatives" accounted for 60% of the variance. Internal consistencies for the whole scale and factors were acceptable, and convergent validity was established with the Zarit Burden Interview guilt factor. A higher score on the CGQ was associated with a higher score on the Center for Epidemiological Studies Depression scale (CES-D) and a new cut-off score of 22 was established, which predicted a clinical score on the CES-D with 80.0% sensitivity and 61.5% specificity. CONCLUSIONS: The replication of the five factor structure suggests that these are relevant themes within the feelings of guilt to both Hispanic and British dementia caregivers. The CGQ has been demonstrated to be a valid measure for use with British dementia caregivers and is likely to be of use in clinical and research settings. PMID- 24047609 TI - Migraine Mistakes: Error Awareness. AB - Error awareness or detection is the conscious and subconscious processing to evaluate physiological signals that are different from a baseline or homeostatic level. Migraine is a unique neurological disorder in which there are repeated attacks interspersed by attack-free periods. These attacks are dynamic and multidimensional in the sense that sensory, affective, autonomic, and cognitive functions are altered and these changes evolve differently before (pre-ictal), during (ictal), and immediately after (post-ictal) an attack. Thus migraine serves as a model disease to understand how the brain monitors and react to the presence of errors. PMID- 24047610 TI - The ontogeny of the human connectome: development and dynamic changes of brain connectivity across the life span. AB - The human brain comprises distributed cortical regions that are structurally and functionally connected into a network that is known as the human connectome. Elaborate developmental processes starting in utero herald connectome genesis, with dynamic changes in its architecture continuing throughout life. Connectome changes during development, maturation, and aging may be governed by a set of biological rules or algorithms, forming and shaping the macroscopic architecture of the brain's wiring network. To explore the presence of developmental patterns indicative of such rules, this review considers insights from studies on the cellular and the systems level into macroscopic connectome genesis and dynamics across the life span. We observe that in parallel with synaptogenesis, macroscopic connectome formation and transformation is characterized by an initial overgrowth and subsequent elimination of cortico-cortical axonal projections. Furthermore, dynamic changes in connectome organization throughout the life span are suggested to follow an inverted U-shaped pattern, with an increasingly integrated topology during development, a plateau lasting for the majority of adulthood and an increasingly localized topology in late life. Elucidating developmental patterns in brain connectivity is crucial for our understanding of the human connectome and how it may give rise to brain function, including the occurrence of brain network disorders across the life span. PMID- 24047611 TI - Dietary composition and its associations with insulin sensitivity and insulin secretion in youth. AB - The objectives of the present study were to examine the associations between macronutrient intake and insulin sensitivity (IS) and insulin secretion (ISct), taking into consideration moderate-to-vigorous physical activity (MVPA), fitness and sedentary behaviour. Caucasian youth (n 630) aged 8-10 years at recruitment, with at least one obese biological parent, were studied (QUebec Adipose and Lifestyle InvesTigation in Youth cohort). IS was measured using the homeostasis model assessment (HOMA) of insulin resistance and Matsuda IS index. ISct was measured using HOMA2%-beta, the ratio of the AUC of insulin:glucose over the first 30 min (AUC I/G(t= 30 min)) of the oral glucose tolerance test and AUC I/G(t= 120 min) over 2 h. Fitness was measured using VO2(peak), percentage of fat mass by dual-energy X-ray absorptiometry, and 7 d MVPA using accelerometry; screen time (ST) by average daily hours of self-reported television, video game or computer use. Dietary composition was measured using three non-consecutive dietary recalls. Non-parametric smoothing splines were used to model non-linear associations; all models were adjusted for age, sex, season, pubertal stage, MVPA, fitness, ST and adiposity. The percentage of total daily energy from dietary protein, fat, saturated fat and carbohydrate and the consumption of dietary vitamin D, sugar-sweetened beverages, fibre and portions of fruits and vegetables were taken into consideration. No dietary component was associated with any measure of IS after adjusting for MVPA, fitness, ST and adiposity. For every 1% increase in daily protein intake (%), AUC I/G(t= 30 min) decreased by 1.1% (P= 0.033). Otherwise, dietary composition was not associated with ISct. While long-term excess of energy intake has been shown to lead to overweight and obesity, dietary macronutrient composition is not independently correlated with IS or ISct in youth. PMID- 24047612 TI - The first detection of influenza in the Finnish pig population: a retrospective study. AB - BACKGROUND: Swine influenza is an infectious acute respiratory disease of pigs caused by influenza A virus. We investigated the time of entry of swine influenza into the Finnish pig population. We also describe the molecular detection of two types of influenza A (H1N1) viruses in porcine samples submitted in 2009 and 2010.This retrospective study was based on three categories of samples: blood samples collected for disease monitoring from pigs at major slaughterhouses from 2007 to 2009; blood samples from pigs in farms with a special health status taken in 2008 and 2009; and diagnostic blood samples from pigs in farms with clinical signs of respiratory disease in 2008 and 2009. The blood samples were tested for influenza A antibodies with an antibody ELISA. Positive samples were further analyzed for H1N1, H3N2, and H1N2 antibodies with a hemagglutination inhibition test. Diagnostic samples for virus detection were subjected to influenza A M-gene specific real-time RT-PCR and to pandemic influenza A H1N1-specific real-time RT PCR. Positive samples were further analyzed with RT-PCRs designed for this purpose, and the PCR products were sequenced and sequences analyzed phylogenetically. RESULTS: In the blood samples from pigs in special health class farms producing replacement animals and in diagnostic blood samples, the first serologically positive samples originated from the period July-August 2008. In samples collected for disease monitoring, < 0.1%, 0% and 16% were positive for antibodies against influenza A H1N1 in the HI test in 2007, 2008, and 2009, respectively. Swine influenza A virus of avian-like H1N1 was first detected in diagnostic samples in February 2009. In 2009 and 2010, the avian-like H1N1 virus was detected on 12 and two farms, respectively. The pandemic H1N1 virus (A(H1N1)pdm09) was detected on one pig farm in 2009 and on two farms in 2010. CONCLUSIONS: Based on our study, swine influenza of avian-like H1N1 virus was introduced into the Finnish pig population in 2008 and A(H1N1)pdm09 virus in 2009. The source of avian-like H1N1 infection could not be determined. Cases of pandemic H1N1 in pigs coincided with the period when the A(H1N1)pdm09 virus was spread in humans in Finland. PMID- 24047613 TI - Decreasing the cardiovascular disease burden in Maori children: the interface of pathophysiology and cultural awareness. PMID- 24047614 TI - Eicosapentaenoic acid (EPA) reduces cardiovascular events: relationship with the EPA/arachidonic acid ratio. AB - The clinical efficacy of fish oil and high-purity eicosapentaenoic acid ethyl ester (hp-EPA-E) for treating cardiovascular disease (CVD) has been reported. Fish oil contains saturated and monounsaturated fatty acids that have pharmacological effects opposite to those of omega3 fatty acids (omega3). Moreover, omega3, such as EPA and docosahexaenoic acid (DHA), do not necessarily have the same metabolic and biological actions. This has obscured the clinical efficacy of omega3. Recently, the Japan EPA Lipid Intervention Study (JELIS) of hp-EPA-E established the clinical efficacy of EPA for CVD, and higher levels of blood EPA, not DHA, were found to be associated with a lower incidence of major coronary events. A significant reduction in the risk of coronary events was observed when the ratio of EPA to arachidonic acid (AA) (EPA/AA) was > 0.75. Furthermore, the ratio of prostaglandin (PG) I3 and PGI2 to thromboxane A2 (TXA2) ([PGI2 + PGI3]/TXA2) was determined to have a linear relationship with the EPA/AA ratio as follows: (PGI2 + PGI3)/TXA2 =lambda + pi* (EPA/AA). Like PGI2, PGI3 not only inhibits platelet aggregation and vasoconstriction, but also is assumed to reduce cardiac ischemic injury and arteriosclerosis and promote angiogenesis. Thus, the effects of EPA in reducing the risk of CVD could be mediated by biological action of PGI3 in addition to hypotriglyceridemic action of EPA. Compared with DHA, EPA administration increases the EPA/AA ratio and the (PGI2 + PGI3)/TXA2 balance to a state that inhibits the onset and/or progression of CVD. PMID- 24047615 TI - Use of primary care data for detecting impetigo trends, United kingdom, 1995 2010. AB - Using a primary care database, we identified a major increase in impetigo in the United Kingdom during 1995-2010. Despite a doubled rate of primary care consultations, this increase was not identified by routine surveillance. Primary care databases are a valuable and underused source of surveillance data on infectious diseases. PMID- 24047616 TI - Alzheimer's disease-like pathology in senescence-accelerated OXYS rats can be partially retarded with mitochondria-targeted antioxidant SkQ1. AB - We previously showed that mitochondria-targeted antioxidant SkQ1 (plastoquinonyl decyltriphenylphosphonium) at nanomolar concentrations is capable of preventing and slowing down some cerebral dysfunctions in accelerated-senescence OXYS rats. Here we demonstrate that OXYS rats develop behavior, learning, and memory deficits against a background of neurodegeneration signs detected by magnetic resonance tomography and amyloid-beta (Abeta) pathology similar to those seen in Alzheimer's disease (AD). Long-term treatment with SkQ1 (250 nmol/kg body weight daily from the age of 1.5 to 23 months) reduced the age-related alterations in behavior and spatial memory deficit in Morris water maze in OXYS and Wistar rats. Furthermore, this is the first report that SkQ1 treatment slows down pathological accumulation of AbetaPP, Abeta, and hyperphosphorylation of tau-protein in OXYS rats, as well as age-dependent changes in healthy Wistar rats. Our results support the possibility of using the OXYS strain as a rat model of AD-like pathology. It seems probable that the mitochondria-targeted antioxidant SkQ1 can be a good prophylactic strategy to maintain brain health and to treat AD. PMID- 24047617 TI - IL12/23 p40 inhibition ameliorates Alzheimer's disease-associated neuropathology and spatial memory in SAMP8 mice. AB - Progressively increased proinflammatory status is a major characteristic of the aging process and associated with age-related diseases such as Alzheimer's diseases (AD). However, the regulation and role of common proinflammatory cytokines, including interleukin-12 (IL-12) and IL-23, in the aged brain are still unclear. Using the senescence-accelerated mouse prone-8 (SAMP8) model, we screened the cerebral expression of IL-12/23 in 3-, 7-, and 11-month-old mice and observed that their levels in the brain were upregulated during aging. To further examine whether the heightened activation of inflammatory cytokines may contribute to age-related brain dysfunction, we employed direct in vivo infusion of nonviral small interfering RNA (siRNA) to knock down the common IL-12/23 signaling subunit p40 in the brain. We found that these p40-deficient mice had significantly decreased cerebral amyloid-beta levels, reduced synaptic and neuronal loss, and reversed cognitive impairments. Furthermore, in vivo delivery of a neutralizing p40-specific antibody likewise ameliorated AD-associated pathology and cognitive deficits in SAMP8 mice. Thus, our data indicate that the upregulated cerebral IL-12/23 during aging is involved in age-associated brain dysfunction and point to the modulation of IL-12/23 signaling molecule p40 as a promising strategy for the development of an AD therapy. PMID- 24047618 TI - Clinical profile of children with norovirus disease in rotavirus vaccine era. PMID- 24047619 TI - [Hipogonadism and testosterone deficit syndrome (TDS)]. PMID- 24047620 TI - [Hipogonadism. Global epidemiology and transversal relationships]. AB - The progressive aging of the population and the wish to keep a good quality of life in advanced ages makes testosterone deficit syndrome associated with aging a health issue of increasing relevance. It is a proved fact there is a decrease of androgen levels associated with aging. Nevertheless, there are some difficulties to establish what is the actual prevalence, since there are some ambiguities about which clinical and biochemical parameters allow us to state a correct clinical diagnosis. The figures on prevalence are variable, specially taking into consideration the different age ranges found in the studies, but we could say there would be a global prevalence of around 6% to 12% of symptomatic hypogonadism in the age range between 30/40 and 70 years, with a progressive increase with age There is a series of factors that may favor androgen deficit increasing the prevalence in different population groups. The main factors are those entities related with metabolic syndrome (obesity, hyperglycemia (insulin resistance,high blood pressure and dyslipemia) in addition to chronic diseases such us AIDS, cancer, and certain pharmacological treatments. PMID- 24047621 TI - [Clinical and biochemical diagnosis of androgenic deficit in adult men]. AB - The diagnosis of testosterone deficit (TD) in adult men is made upon the finding of consistent symptoms or signs associated with confirmed low Testosterone levels. TD can be caused by primary testicular failure, decreased LH secretion (secondary)or a combination of both (mixed type). The clinical features of TD depend on the age of onset. Before completion of pubertal development it results in eunuchoid traits that can be easily detected. The clinical expression of adult onset TD is protean, with varied symptoms and signs often overlapping with those of aging and several chronic conditions. Sexual problems as low desire and difficult erections are frequently reported by TD patients. Several symptom questionnaires have been proposed for detecting TD. However, poor specificity and weak correlation with serum testosterone make them unsuitable as diagnostic tools, although their scores can help for monitoring future treatments. Physical examination usually yields few significant data but it can help for detecting unidentified cases of early onset TD. Measuring serum total testosterone (TT)levels is mandatory. It is available in most laboratories although commonly used methods are not fully satisfactory. In adult men the lower limit for the normal reference range is around 10 nmol/ L, but this figure can vary among laboratories. "Grey zone" values falling within a +/-20% interval around this limit need further clarification. To this aim most hospital laboratories can calculate the free (FT)or bioavailable fractions (BioT) of TT, SHBG, and albumin levels. When TD diagnosis is confirmed, a number of additional tests, such as measuring gonadotropins and prolactin, should be used to find out its etiology. They are summarized here in a diagnostic algorithm. There is a need for laboratory tests giving a reliable estimate of the androgen sensitivity of each subject. PMID- 24047622 TI - [Patient with TDS and increased PSA (implications in prostate biopsy)]. AB - Since 70 years ago testosterone is considered a risk factor for prostate cancer and its supplementation in men with testosterone deficit syndrome is considered a risk for the development of a prostatic neoplasia. We discuss the case of a man with hypogonadism and increased PSA, the indications for biopsy and risks involved in testosterone supplementation, as well as recommended follow up. Over this practical base, we expose the current evidence on prostatic safety in men with testosterone supplementation. PMID- 24047623 TI - [Patient with TDS and lower urinary tract symptoms (LUTS)]. AB - OBJECTIVE: [corrected] New investigations focus on the relationship between benign prostatic hyperplasia, lower urinary tract symptoms, erectile dysfunction and testosterone deficit; giving to this last one a common role in all of them. In this paper, we present a typical patient who complains of symptoms related to BPH, to treat him in terms of micturition quality, sexual function and hypogonadism . METHODS/RESULTS: 61 year-old male, with obesity, hypertension and hypercholesterolemia, who complains of long term mixed urinary symptoms, with an IPSS of 12 and IIEF-5 of 22. DRE: II/IVprostate, adenomatous. Blood parameters: PSA 1.9 ng/dl, total testosterone 238 ng/dl, triglycerides 213 mg/dl, glucose 89 mg/dl. Uroflowmetry :total volume 256 ml, maximum flow 12 ml/s, average 5.7 ml/s and post-void volume of 15 ml. Urinary ultra- sound: 5 mm detrusor and prostate volume of 39 cm3. Nowadays, LUTS are considered multietiologic, including testosterone as one of the causes. According to the classic criteria, this patient fits for treatment with combination therapy, as well as for daily PDE5i, recently approved for LUTS therapy. Administration of testosterone to treat LUTS is still controversial. It could restore the patient's levels of testosterone, improving the metabolic syndrome and creating an optimal environment for the 5PDEi. Nevertheless, according to some current scientific evidences, it could help improving LUTS. CONCLUSIONS: Given the necessity of larger studies, testosterone supplementation therapy seems to not worsen the evolution of BHP. It could even improve them if the testosterone deficit is documented. PMID- 24047624 TI - [Patient with testosterone deficit syndrome after radical prostatectomy]. AB - Testosterone Deficiency Syndrome is associated with age. Recent studies advocate for the safety of hormonal treatment with testosterone in patients with history of Prostate Cancer (PC) ,once disease-free survival is confirmed. A total of five publications describe 110 patients treated with testosterone replacement therapy, having a history of PC, who had undergone radical prostatectomy (RP). Only one patient had biochemical recurrence during replacement therapy. Testosterone replacement therapy must be indicated in selected patients with history of low risk localized prostate cancer treated satisfactorily who are symptomatic and have good oncological control. The testosterone levels to achieve should be the minimum effective to obtain a symptomatic response. Adequate information on the benefits and potential risks must be understood and accepted by the patient. PMID- 24047625 TI - [Patient with testosterone deficit syndrome after external beam radiotherapy]. AB - Testosterone deficit syndrome is a clinical and biochemical syndrome associated with advanced age and characterized by some symptomsassociated with serum testosterone levels deficiency, which may result in a decrease of quality of life and negatively affect the function of multiple organs or systems. Clinical guidelines recommend testosterone replacement therapy (TRT) in patients with testosterone decrease that associate muscle mass and strength loss, lumbar spinal column bone density decrease, or libido and erection decrease. Contraindications for treatment would include active prostate cancer or without treatment, PSA >4 ng/ml waiting for diagnostic workup, breast cancer, severe sleep apnea, infertility, hematocrit over 50% or severe lower urinary tract symptoms secondary to benign prostatic hypertrophy. In certain situations there is still great controversy, without enough evidence to establish an action. References in case of patientstreated with brachytherapy or radiotherapy are unspecific: they only recommend caution in the treatment with TRT in these patients and strict monitoring of the possible recurrence. In our opinion, low-intermediate risk prostate cancer patients treated with radiotherapy only, without evidence of residual or recurrent disease, are candidates for TRT if symptoms justify it, leaving a free period of never less than one year after nadir (or 24 months after the end of therapy) which guarantees, on the possible means, the absence of biochemical or clinical recurrence,with strict follow up of clinical and biochemical usual parameters (hematocrit, hemoglobin, DRE, PSA). PMID- 24047626 TI - [Testosterone deficit syndrome in fertile or subfertile men]. AB - Spermatogenesis is a well defined, complex,long and very orderlyprocess of cellular division and differentiation that is under regulation by endocrine signals (GnRH, LH, Inhibin and FSH ): paracrine signals, derived from the interrelation of the various types of cells in the tubules and interstitium (even in a juxtacrine way), and autocrine signals of self communication of the cell with itself. Testosterone plays an essential role in this process. In the testicular tubules, testosterone reaches concentrations 100 times higher than circulating testosterone in the blood stream. From a reproduction point of view, we can find two completely different scenarios in relation to testosterone deficit syndrome with a similar final clinical result: The difficulties of the male to have children. On one side the presence of hypogonadism, which requires a different management depending of the clinical priority and wishes of parenthood of the patient an his partner. On the other side, the opposite situation, the patient who requires or is already under testosterone therapy. In patients with hypogonadotropic hypogonadism, when patient's clinical priority is fertility, the treatment to restore normal spermatogenesis requires external administration of gonadotropins. Treatment must be prolonged, at least 12-18 months. 95% of the cases will have a favorable response, meaning the finding of spermatozoids in ejaculation sperm as a consequence of spermatogenesis restoration. PMID- 24047627 TI - [Testosterone deficit syndrome in the old male]. AB - Epidemiological studies have demonstrated that prevalence of hypogonadism in old males increases with every additional decade of life. These males present various symptoms including decrease of sexual function, decrease of cognitive function, altered lipid profile, increased visceral adiposity, changes in bone density and muscular strength secondary to atrophy. Currently, testosterone injections and gel preparations are the most used. Testosterone replacement therapy provides significant symptomatic improvements for men with late start hypogonadism. Long term benefits and risks of testosterone replacement therapy will be more evident when testosterone effects are studied on all health related parameters over a prolonged period of time. There is a large ongoing multicentric randomized clinical trial sponsored by NIH for testosterone control in old men with low testosterone levels. Its results may give answers to the possible benefits and risks of testosterone replacement in aging males. If an aging male is diagnosed as late-start hypogonadism, the urologist should discuss with the patient potential benefits and risks of testosterone therapy. Aging males with significant erythrocytosis, untreated sleep apnea, prostate cancer and high risk of cardiovascular events must be excluded from testosterone replacement therapy. Currently, there are not enough evidences to clearly state that the benefits of testosterone replacement therapy in aging males are better than the risks of this treatment. A general recommendation cannot be given that testosterone replacement therapy may be applied to all aging males with low testosterone levels independently of significant signs or symptoms. PMID- 24047628 TI - [Testosterone and coronary artery disease]. AB - Elderly patients present testosterone deficit syndrome (TDS) in a prevalent manner. TDS is defined as a clinical and biochemical syndrome with total fasting testosterone below normal levels in two consecutive measurements. A significant relationship with comorbidities such as diabetes mellitus, obesity or metabolic syndrome has been observed in these patients. These latter are recognized risk factors of coronary artery disease (CAD) and arteriosclerosis. It seems logical to think that CAD is more frequent in patients with TDS, and it is supported on multiple works demonstrating the correlation of theses two pathologies. We intend to illustrate the management of patients with TDS and CAD presenting a clinical case and the recommended diagnostic and therapeutic approach. A Sixty-four year old male with hypertension, non-insulin dependent diabetes mellitus and obesity consulted for erectile dysfunction and diminished sexual desire. Fasting total testosterone and glycosylate hemoglobin were determined. IIEF-5 was 12, Erection hardness Score was 2 and IIEF item 12 1 point over 5. His total testosterone was 150 ng/dl, which was confirmed in a second test; HDL cholesterol level was 30 mg/dl. Interrogated again, the patient referred oppressive chest pain appearing after running 50 meters for the last three months that never happened in rest or with minor efforts. APPROACH: It is a patient with high cardiovascular risk and atypical chest pain so recommendation was given to consult a cardiologist. Stress test was performed. It was a submaximal, evaluable test (reached 80% of his maximum theoretical heart rate) stopped due to angina. Clinically and electrically it was positive at medium charge. Coronary angiogram was indicated showing a severe (85%percnt;%) lesion at the medial third of anterior descendant artery. Balloon angioplasty was performed and a 3.0 x 24 mm drug-coated stent was placed. Cardiologic treatment was prescribed as well as combination therapy for his erectile dysfunction and diminished libido with testosterone and a PDE 5 inhibitor. PMID- 24047629 TI - [Patient with testosterone deficit syndrome and HIV infection]. AB - Testosterone deficit sindrome (TDS) is more frequent in males with HIV infection than in general population, being in fact the most frequent endocrine disorder in these patients. There are multiple physiopathological mechanisms favoring this testosterone deficit but they are only partially known. Identification of these patients and their adequate treatment will have important consequences not only in their sexual health but also in their general health. PMID- 24047630 TI - [Testosterone deficit syndrome in the chronic renal failure patient]. AB - Hypogonadism may affect as much as 70% of the patients with chronic renal failure (CRF) in comparison with general population. Physiopathologically, it is a hypergonadotropic hypogonadism, with alterations in the pulsatile production of GnRH, FSH, LH and testicular testosterone, that is a general disorder of the hypothalamic-hypophysis-testicular axis. This disorder may determine important consequences in this population of patients, with varied sexual dysfunction, trophic and functional muscular and fatty tissue disorders, bone demineralization, anemia and increase of cardiovascular disease associated mortality.Treatment in these patients must be focused from a general point of view, increasing their clinical condition, the systemic complications associated with CRF, complementing in this way with exogenous testosterone replacement therapy. If possible, it seems that the most efficacious therapy will be renal transplantation. PMID- 24047631 TI - Patients with testosterone deficiency syndrome and type 2 diabetes. AB - The prevalence of diabetes mellitus (DM) is increasing worldwide for all ages due to population growth, aging, and increased prevalence of obesity and physical inactivity. Sexual dysfunction and in particular erectile dysfunction (ED) are frequent complications of DM. In patients with DM, ED can be considered as a useful sign of silent myocardial ischemia. A large body of evidence also supports a strong association between DM, cardiovascular risk (CV) and testosterone deficiency syndrome. Despite this evidence, the screening of ED and hypogonadism in the diabetic population remains poorly implemented. In addition, data regarding the role of testosterone replacement therapy (TRT) for glycometabolic control and CV risk remains contradictory. In the present paper we have reviewed the available evidence and based our discussion on data derived from a specific clinical case. Hypogonadism is frequently observed in subjects with type 2 DM (T2DM) and especially those complaining of ED. Obesity and insulin-resistance are probably the most important pathogenetic factors involved, and, according to the current guidelines, subjects with T2DM should be screened for hypogonadism. TRT is the first line option in hypogonadal subjects with ED, however, the possible role of TRT in improving glycometabolic control and CV outcomes needs to be confirmed through longer and larger studies. PMID- 24047632 TI - [Patient with testosterone deficit syndrome and erectile dysfunction non responder to PDE-5 inhibitors]. AB - Androgens play an essential role in the corporo-venous occlusive mechanism that provokes erection. Accordingly to various studies based on animal models,testosterone deficit syndrome causes an endothelial disorder in the corpora cavernosa with diminished secretion of NO, alteration of penile smooth muscle and tunica albuginea structure, and increase of the number of adipocytes within the erectile tissue, which favors fibrosis and impairs erection. All these alterations are reversible with the exogenous administration of androgens. There are not enough studies to get definitive conclusions about androgen supply improving erectile dysfunction in patients with hypogonadism. Studies have been published in which seems that exogenous testosterone could be useful in the treatment of this type of patients. Nevertheless,in most published randomized double blind studies comparing with placebo, testosterone supply does not provide greater benefit on erectile dysfunction than PDE-5 Inhibitors exclusively. All studies coincide in the need to optimize the treatment with PDE-5 Inhibitors since they do have proven to be effective for the treatment of erectile dysfunction in patients with testosterone deficit syndrome. PMID- 24047633 TI - Patients with testosterone deficit syndrome and depression. AB - Prevalence of depression in men increases with age, so does the prevalence of hypogonadism. Depression and anxiety are the most common psychopathological symptoms associated with male hypogonadism.The question is whether the age related gradual decline in testosterone levels contributes to the rising rate of depression in older men. Many studies have demonstrated the improvement in depressive symptoms in hypogonadal men with testosterone supplementation. However, a subpopulation of hypogonadal men appear to be better responders to TRT when treated for depression. Testosterone deficiency is associated with numerous non-specific symptoms including decline in libido, erectile dysfunction, increased fat deposition, decreased muscle mass, decreased energy and depression. The relationship between increased depressive symptoms and declining testosterone levels is complex because many conditions are independently associated with depression and testosterone deficiency. These conditions include medical illnesses, such as HIV/AIDS, and obesity, stress, smoking, and alcohol abuse. While the literature does not support a consistent relationship between testosterone levels and depressive symptoms most studies do suggest that lower testosterone levels are associated with depressive symptoms. Furthermore, TRT has been shown to improve depressive symptoms in most men. This could be due to the fact that testosterone is a modulator of GABAA receptors and inhibits 5-HT3 receptors centrally. However there appears to be a subpopulation of depressed male patients that tend to respond best to TRT. These patients include men who have HIV/AIDS, mild depression, more severe testosterone deficiency, use transdermal testosterone as opposed to IM testosterone, and those not responding to SSRIs. However, patients taking SSRIs also experience a significant improvement in depressive symptoms once treated with TRT. Men with depressive symptoms and testosterone deficiency syndrome should be given a trial of testosterone replacement therapy for at least 3 months as TRT alone may improve clinical symptoms of depression. Furthermore, men already on SSRIs may also experience further improvement in depressive symptoms after initiating TRT. PMID- 24047634 TI - [Current recommendations about the diagnosis and treatment of testosterone deficit syndrome: Clinical guidelines]. AB - Testosterone deficit syndrome (TDS) is a clinical and biochemical syndrome associated with advanced age and characterized by some typical symptoms and decrease in serum testosterone levels, which can affect multiple organs and systems, deteriorating the quality of life of the males who suffer it. Due to the low specificity of the clinical picture, as well as that of the commonly used questionnaires, when there is a diagnostic suspicion, serum testosterone determination is necessary, without a current universally accepted determination method. The increased survival of males in the western world and their demand of a better quality of life,including the preservation of sexual activity, up to increasingly more advanced ages: together with the appearance of new ways of testosterone delivery, make this entity, clinical-biochemical, acquirean increasingly greater importance. From a therapeutic point of view, testosterone replacement therapy has precise indications, with individualized evaluation in each patient on the basis of risk/benefit, and with an adequate, well defined follow up, that will allow the control of possible adverse events. TRT is recommended in patients with diminished testosterone associated with muscle mass and strength loss, decrease of bone density of the lumbar spine or diminished libido and quality of erection. Contraindications for therapy would include active or non treated prostate cancer, PSA >4 ng/ml before evaluation, breast cancer, severe sleep apnea, infertility, hematocrit over 50% or severe LUTS due to BPH. PMID- 24047635 TI - [Patient with late-start hypogonadism and sexual dysfunction]. AB - OBJECTIVES: Testosterone deficit syndrome (TDS)is a clinical and biochemical entity characterized by low testosterone levels and androgenic deprivation clinic, which can cause a decrease in the quality of life. However, today there are doubts about its diagnosis and therapeutic management. METHODS: Bibliographic review using the MedLine database and detailed presentation of one clinical case. RESULTS: Testosterone deficit syndrome is associated with metabolic syndrome (visceral obesity, arterial hypertension, diabetes mellitus and dyslipemia). Currently, the performance of TDS screening in all males over the age of 45 years is under discussion. We propose a diagnostic-therapeutic algorithm for the management of TDS and erectile dysfunction. CONCLUSIONS: The treatment of erectile dysfunction associated with late start hypogonadism follows the same steps tha other generic cases of erectile dysfunction. PMID- 24047636 TI - [Patient with testosterone deficit syndrome and dyslipemia]. AB - We define dyslipemia as the abnormally elevated presence of lipids in the blood. The main ones are hypercholesterolemia (cholesterol over 240 mg/dl), hypertrigliceridemia (triglicerides level over 200 mg/dl) and hipo alphalipoproteinemia (High density lipoproteins,also called HDL Cholesterol, below 40 mg/dl). The presence of excessive lipids contributes to arteriosclerosis and they are an independent cardiovascular risk factor. It may be primary, if they have genetic origin and they are not associated with other diseases, but in most cases they are secondary to other pathological entities such as diabetes, hypothyroidism, obesity and metabolic syndrome (MS). In our current society, sedentary lifestyle and unadequatelly hypercaloric diets are making obesity and MS prevalences grow, and their relation to dyslipemias has become tighter. Obesity is related with all the criteria for MS. But obesity is not at all synonymous of MS. On the one hand neither fat distribution is the same in all individualas nor confers the same risk. Accordingly, we know that abdominal localization of fat is related to higher intensity of insulin resistance (IR) and MS. On the other hand, it seems that certain components of MS are determined by genetic factors, since there are morbid obese persons that are metabolically healthy and other patients develop insulin resistance without obesity. So that, it seems that the excess in visceral adiposity in the presence of certain genetic factors would be the most related cause of the appearance of peripheral insulin resistance and diabetes mellitus, hyperlipidemia (increase of very low density pipoproteins (VLDL), decrease of highdensity lipoproteins (HDL) arterial hypertension, and hypogonadotropic hypogonadism, composing what we call metabolic syndrome. In this scenario, we urologists are being first-hand witnesses.On the one hand, and in relation with cardiovascular risk factors, we know that all of them, and independently,not only can produce erectile dysfunction due to endothelial dysfunction, but also it generally appears years before the cardiovascular event. On the other hand, and in relation to the hypogonadotropic hypogonadism of patients with MS, we urologists may contributein greatly to the detection of patients with MS whose only symptom is erectile dysfunction or diminished libido, but specially we may play a key role in the improvement of these patients, since it is known that testosterone replacement therapy has a major potential to diminish or stop the progression of MS or its cardiovascular effects. Testosterone treatment not only improves the lipid profile, hypertension, insulin resistance, or reduces the abdominal circumference, but also it may help to get a better adherence to diet and exercise, so contributing to change unhealthy lifestyle habits whch are the origin of the problem. PMID- 24047637 TI - Monitoring toxicity of polycyclic aromatic hydrocarbons in intertidal sediments for five years after the Hebei Spirit oil spill in Taean, Republic of Korea. AB - Ecotoxicological monitoring of intertidal sediments was performed for 5 years after the Hebei Spirit oil spill in Taean, Korea. Sediment toxicity was observed on most of the beaches 4 months after the spill and later decreased rapidly to nontoxic levels 8 months after the spill. The concentrations of total polycyclic aromatic hydrocarbons (TPAHs) in the sediments ranged from 2 to 530,000 ng/g during the monitoring. More than half of the samples exhibited significant toxicity 5 years after the Hebei Spirit oil spill. Using a logistic regression model, the median lethal concentration of TPAHs to amphipod Monocorophium uenoi was estimated to be 36,000 ng/g. From the 63 chemistry and toxicity data, the effect range-low, effect range median, threshold effect level, and probable effect level were derived to be 3190, 54,100, 2480, and 29,000 ng/g, respectively. The relative compositions of the PAH groups indicated that the weathering process is still ongoing. PMID- 24047638 TI - Research on the nitrogen cycle in rhizosphere of Kandelia obovata under ammonium and nitrate addition. AB - The present study investigated nitrogen process in rhizosphere of Kandelia obovata under nitrogen input. Results showed that nitrogen additions significantly increased 4 kinds of enzyme activities (Urease, Nitrate reductase, Nitrite reductase and hydroxylamine reductase). The pH value increased to 7.1 under ammonium addition, but decreased to 6.9 under nitrate addition. Potential Nitrification Intensity (PNI) increased 200-1500% compared with control under ammonium addition, and Potential Denitrification Intensity (PDI) increased more than 200% under nitrate addition. Ten types of organic acids were detected from root exudates, which mainly included oxalic acid, tartaric acid, formic acid, acetic acid, and citric acid. The abundance of 5 kinds of microbial functional groups (nifH, AOA, AOB, nirS, nirK) responded differently. Total nitrogen in organs of K. obovata increased more than 200%. This indicated that nitrogen additions accelerated the transformation of nitrogen directly and stimulated the exudation of root exudates and 5 kinds of genes indirectly. PMID- 24047639 TI - Sources, trends and ecotoxicological risks of PAH pollution in surface sediments from the northern Adriatic Sea (Croatia). AB - In this study, the levels, sources and historical trends (2007-2012) of PAH pollution in surface sediments in the northern Adriatic Sea (Croatia) have been assessed. In addition, ecotoxicological risks have been estimated by evaluating the PAH dataset against Sediment Quality Guidelines (SQGs). The results indicate that PAH in surface sediments are of pyrolitic origin with no clear positive or negative trend in PAH concentration over the investigated period. Evaluations against SQG and mSQGq indicate that surface sediments at all sampling sites have a low to medium ecotoxicological risk. In order to improve trend analysis and characterization of PAH pollution in surface sediments in this region an increase in spatial resolution of sampling points is recommended. PMID- 24047642 TI - Pregnancy loss. AB - Women who lose desired pregnancies by miscarriage, stillbirth, or genetic termination are at risk of suffering from grief, anxiety, guilt and self-blame that may even present in subsequent pregnancies. It is important to find effective means of helping women deal with these losses. The approach to stillbirth has shifted from immediately removing the child from the mother to encouraging the parents to view and hold the baby. This approach has been questioned as possibly causing persistent anxiety and post-traumatic stress disorder. Women who miscarry are currently encouraged to find ways to memorialise the lost fetus. Couples who decide to terminate a pregnancy after discovering a defect may deal not only with sadness but also guilt. Immediate crisis intervention and follow-up care should be available, recognising that individual women may experience different reactions and their specific post-loss needs must be assessed. PMID- 24047641 TI - The impact of prenatal employment on breastfeeding intentions and breastfeeding status at 1 week postpartum. AB - BACKGROUND: Postpartum employment is associated with non-initiation and early cessation of breastfeeding, but less is known about the relationship between prenatal employment and breastfeeding intentions and behaviors. OBJECTIVE: This study aimed to estimate the relationship between prenatal employment status, a strong predictor of postpartum return to work, and breastfeeding intentions and behaviors. METHODS: Using data from the Listening to Mothers II national survey (N = 1573), we used propensity score matching methods to account for non-random selection into employment patterns and to measure the impact of prenatal employment status on breastfeeding intentions and behaviors. We also examined whether hospital practices consistent with the Baby-Friendly Hospital Initiative (BFHI), assessed based on maternal perception, were differentially associated with breastfeeding by employment status. RESULTS: Women who were employed (vs unemployed) during pregnancy were older, were more educated, were less likely to have had a previous cesarean delivery, and had fewer children. After matching, these differences were eliminated. Although breastfeeding intention did not differ by employment, full-time employment (vs no employment) during pregnancy was associated with decreased odds of exclusive breastfeeding 1 week postpartum (adjusted odds ratio = 0.48; 95% confidence interval, 0.25-0.92; P = .028). Higher BFHI scores were associated with higher odds of breastfeeding at 1 week but did not differentially impact women by employment status. CONCLUSION: Women employed full-time during pregnancy were less likely to fulfill their intention to exclusively breastfeed, compared to women who were not employed during pregnancy. Clinicians should be aware that employment circumstances may impact women's breastfeeding decisions; this may help guide discussions during clinical encounters. PMID- 24047640 TI - Improvement in coronary haemodynamics after percutaneous coronary intervention: assessment using instantaneous wave-free ratio. AB - OBJECTIVE: To determine whether the instantaneous wave-free ratio (iFR) can detect improvement in stenosis significance after percutaneous coronary intervention (PCI) and compare this with fractional flow reserve (FFR) and whole cycle Pd/Pa. DESIGN: A prospective observational study was undertaken in elective patients scheduled for PCI with FFR <= 0.80. Intracoronary pressures were measured at rest and during adenosine-mediated vasodilatation, before and after PCI. iFR, Pd/Pa and FFR values were calculated using the validated fully automated algorithms. SETTING: Coronary catheter laboratories in two UK centres and one in the USA. PATIENTS: 120 coronary stenoses in 112 patients were assessed. The mean age was 63 +/- 10 years, while 84% were male; 39% smokers; 33% with diabetes. Mean diameter stenosis was 68 +/- 16% by quantitative coronary angiography. RESULTS: Pre-PCI, mean FFR was 0.66 +/- 0.14, mean iFR was 0.75 +/- 0.21 and mean Pd/Pa 0.83 +/- 0.16. PCI increased all indices significantly (FFR 0.89 +/- 0.07, p<0.001; iFR 0.94 +/- 0.05, p<0.001; Pd/Pa 0.96 +/- 0.04, p<0.001). The change in iFR after intervention (0.20 +/- 0.21) was similar to DeltaFFR 0.22 +/- 0.15 (p=0.25). DeltaFFR and DeltaiFR were significantly larger than resting DeltaPd/Pa (0.13 +/- 0.16, both p<0.001). Similar incremental changes occurred in patients with a higher prevalence of risk factors for microcirculatory disease such as diabetes and hypertension. CONCLUSIONS: iFR and FFR detect the changes in coronary haemodynamics elicited by PCI. FFR and iFR have a significantly larger dynamic range than resting Pd/Pa. iFR might be used to objectively document improvement in coronary haemodynamics following PCI in a similar manner to FFR. PMID- 24047643 TI - Psychosocial correlates of nutritional status of family caregivers of persons with dementia. AB - BACKGROUND: This exploratory study investigated the associations of individual characteristics of both persons with dementia and family caregivers with the nutritional status of caregivers. METHODS: This cross-sectional study was conducted at home by psychogerontologist within the frame of a community gerontological center in rural areas of south west France. The study participants comprised 56 community-dwelling persons with dementia (mean 80.7 years, SD 6.5) and 56 family caregivers (mean 70.9 years, SD 11.0). Persons with dementia were assessed with Mini-Mental State Examination (MMSE), Basic Activities Of Daily Living (ADL), Instrumental ADL (IADL), and NeuroPsychiatric Inventory (NPI), and family caregivers with the Burden Interview (Zarit scale), the State-Trait Anxiety Inventory (STAI Y-B), the Center for Epidemiologic Studies Depression Scale (CES-D), the emotional impact measure of NPI and the Autonomy, Gerontology and Group Resources scale (AGGIR scale). For both, nutritional status was evaluated using the Mini Nutritional Assessment (MNA(r)). RESULTS: Among family caregivers, 32.1% were at risk of malnutrition and 5.4% were malnourished, and among people with dementia, 58.9% and 23.2%, respectively. NPI severity score of apathy of persons with dementia (Beta = -0.342, p = 0.001), dependency on AGGIR scale (Beta = -0.336, p = 0.002), and CES-D score of caregivers (Beta = -0.365, p = 0.001) were associated with caregivers' MNA score (Adjusted R 2 = 0.480, p < 0.001). CONCLUSION: These preliminary findings emphasize the need for routine assessment of depressive symptoms, functional and nutritional status in dementia family caregivers, and confirm the value of investigating caregivers' nutritional risk through an integrative view including psychosocial approach. PMID- 24047644 TI - The effectiveness of a physical activity stimulation programme for children with cerebral palsy on social participation, self-perception and quality of life: a randomized controlled trial. AB - OBJECTIVE: To determine the effects of a six-month physical activity stimulation programme on social participation, self-perception and quality of life in children with cerebral palsy. DESIGN: Multicentre randomized controlled trial with concealed allocation, blinded assessments and intention-to-treat analysis. SETTING: Paediatric physiotherapy practices, special schools for children with a disability, and the child's own home. SUBJECTS: Forty-nine children with spastic cerebral palsy (28 male), aged 7-13 years, able to walk with and without walking aids. INTERVENTIONS: The intervention group followed a six-month physical activity stimulation programme involving counselling through motivational interviewing, home-based physiotherapy and four months of fitness training. The control group continued regular paediatric physiotherapy. MAIN MEASURES: Outcomes included social participation in domestic life, social participation in recreation and leisure (Life-Habits for Children questionnaire and Children's Assessment of Participation and Enjoyment questionnaire), self-perception (Harter's Self-Perception Profile for Children) and parent-reported quality of life (Cerebral Palsy Quality of Life Questionnaire). Assessments were performed at baseline, at six months (except quality of life) and at twelve months. RESULTS: Intervention resulted in a positive effect on social participation in domestic life at twelve months (mean between-group difference = 0.9, 95% confidence interval (CI) = 0.1 to 1.7 [1-10 scale], P = 0.03), but not at six months. No significant effects were found for social participation in recreation and leisure, self-perception at six months and twelve months or for quality of life at twelve months. CONCLUSIONS: The combination of counselling, home-based physiotherapy and fitness training was not effective in improving social participation in recreation and leisure, self-perception or quality of life, but did show a potential for improving social participation in domestic life over the longer term. PMID- 24047646 TI - Pom1 and cell size homeostasis in fission yeast. AB - Cells sense their size and use this information to coordinate cell division with cell growth to maintain a constant cell size within a given population. A model has been proposed for cell size control in the rod-shaped cells of the fission yeast, Schizosaccharomyces pombe. This involves a protein localized to the cell ends, which inhibits mitotic activators in the middle of the cell in a cell size dependent manner. This protein, Pom1, along with another tip-localized protein, Nif1, have been implicated as direct sensors of cell size controlling the onset of mitosis. Here we have investigated cell size variability and size homeostasis at the G 2/M transition, focusing on the role of pom1 and nif1. Cells deleted for either of these 2 genes show wild-type size homeostasis both in size variability analyses and size homeostasis experiments. This indicates that these genes do not have a critical role as direct cell size sensors in the control mechanism. Cell size homeostasis also seems to be independent of Cdc2-Tyr15 phosphorylation, suggesting that the size sensing mechanism in fission yeast may act through an unidentified pathway regulating CDK activity by an unknown mechanism. PMID- 24047645 TI - Growth of Arabidopsis seedlings on high fungal doses of Piriformospora indica has little effect on plant performance, stress, and defense gene expression in spite of elevated jasmonic acid and jasmonic acid-isoleucine levels in the roots. AB - The endophytic fungus Piriformospora indica colonizes the roots of many plant species including Arabidopsis and promotes their performance, biomass, and seed production as well as resistance against biotic and abiotic stress. Imbalances in the symbiotic interaction such as uncontrolled fungal growth result in the loss of benefits for the plants and activation of defense responses against the microbe. We exposed Arabidopsis seedlings to a dense hyphal lawn of P. indica. The seedlings continue to grow, accumulate normal amounts of chlorophyll, and the photosynthetic parameters demonstrate that they perform well. In spite of high fungal doses around the roots, the fungal material inside the roots was not significantly higher when compared with roots that live in a beneficial symbiosis with P. indica. Fifteen defense- and stress-related genes including PR2, PR3, PAL2, and ERF1 are only moderately upregulated in the roots on the fungal lawn, and the seedlings did not accumulate H2O2/radical oxygen species. However, accumulation of anthocyanin in P. indica-exposed seedlings indicates stress symptoms. Furthermore, the jasmonic acid (JA) and jasmonic acid-isoleucine (JA Ile) levels were increased in the roots, and consequently PDF1.2 and a newly characterized gene for a 2-oxoglurate and Fe2+ -dependent oxygenase were upregulated more than 7-fold on the dense fungal lawn, in a JAR1- and EIN3 dependent manner. We conclude that growth of A. thaliana seedlings on high fungal doses of P. indica has little effect on the overall performance of the plants although elevated JA and JA-Ile levels in the roots induce a mild stress or defense response. PMID- 24047647 TI - Dissemination of antibiotic resistant Enterococcus spp. and Escherichia coli from wild birds of Azores Archipelago. AB - Antibiotic-resistant is profoundly important to human and animal health, but the environmental reservoirs of resistance determinants are poorly understood, in particular in wild environments in remote Archipelagos. Moreover, the prevalence of antibiotic-resistant bacteria in wild bird populations is rather unknown. In the present study, we used the Azores Islands as a model study for antimicrobial resistance in a remote Archipelago, and examined the antibiotic resistance profile in enterococci and Escherichia coli recovered from faecal samples of wild birds collected in this Archipelago. A total of 138 enterococci and 115 E. coli isolates were analyzed for resistance to antimicrobial agents. Of the enterococcal isolates, Enterococcus faecalis was the most prevalent detected species (59 isolates), followed by Enterococcus faecium (40 isolates), Enterococcus durans (27 isolates) and Enterococcus hirae (12 isolates). The enterococci strains showed high percentages of resistance to tetracycline (32.6%), to ciprofloxacin (19.6%) and to erythromycin (11.6%). Lower level of resistance (<10%) was detected for ampicillin, chloramphenicol and teicoplanin. One vancomycin-resistant E. faecalis isolate was detected and harbored the vanA resistant gene. Resistance genes detected included tet(M) and/or tet(L), ermB in all tetracycline and erythromycin-resistant isolates. Resistance in E. coli isolates was detected for ampicillin, tetracycline, sulfamethoxazole/trimethoprim, streptomycin, and tobramycin. The blaTEM, aadA, aadA5, strA, strB, tet(A) and/or tet(B), and the intI genes were found in all ampicillin, streptomycin, tetracycline, and sulfamethoxazole/trimethoprim resistant isolates respectively. The data shown in this study are essential to improve knowledge about the dissemination of resistant strains through wild birds from remote archipelagos such as the Azores Archipelago and the possible implications involved in transferring these resistances either to other animals or to humans. PMID- 24047648 TI - The use of botulinum toxin for the treatment of urologic pain. AB - PURPOSE OF REVIEW: Botulinum toxin injections into the bladder have become established in the management of refractory detrusor overactivity and overactive bladder. Mechanism of action of the toxin appears to involve both efferent and afferent nerve pathways, as well as having an antinociceptive effect. Over the years, several reports of its use in refractory bladder pain syndrome and interstitial cystitis have emerged. We review the literature with a view to assessing efficacy and adverse events in this setting. RECENT FINDINGS: Small open-labelled studies have suggested botulinum neurotoxin serotype A (BoNT-A) to be an effective treatment for the majority of patients with refractory bladder pain syndrome/interstitial cystitis. A single set of injections result in demonstrable improvements in symptom scores and bladder pain, although some studies suggest repeated injections may be better. BoNT-A is more effective in nonulcer-type patients. In chronic pelvic pain syndrome, a recent placebo controlled trial showed only a modest benefit for BoNT-A over placebo with a response rate of 30%. SUMMARY: Although botulinum neurotoxin for refractory bladder pain syndrome/interstitial cystitis appears promising, larger-scale studies with adequate follow-up and in particular randomized placebo-controlled studies are required to confirm these findings. PMID- 24047649 TI - The protective effect of clay minerals against damage to adsorbed DNA induced by cadmium and mercury. AB - The adsorption of Salmon Sperm DNA on three kinds of raw clay (rectorite, montmorillonite and sericite) was investigated as a function of pH, ionic strength and the concentrations of DNA and phosphate ions in solution. The DNA adsorption was reduced in the following order: rectorite>montmorillonite>sericite. Based on these findings, there is a strong evidence that the mechanisms for DNA adsorption on clay involve electrostatic forces, cation bridging and ligand exchange. Cyclic voltammetry (CV) and UV-vis absorption and fluorescence spectroscopy were used to compare the properties of unbound DNA and the absorbed DNA on rectorite, both in the absence and presence of Cd(2+) and Hg(2+) inaqueous solutions. The interaction of heavy metals with the unbound DNA was evidenced by the disappearance of reduction peaks in CV, a small bathochromic shift in UV-vis spectroscopy and an incomplete quenching in the emission spectra. Such changes were not observed in the DNA-rectorite hybrids, which is evidence that adsorption on the clay can reduce the extent of the DNA damage caused by heavy metals. Therefore, in these experience the rectorite played an important role in protecting DNA against Cd(2+) and Hg(2+) induced damage. PMID- 24047650 TI - Prostaglandin E2 enhances long-term repopulation but does not permanently alter inherent stem cell competitiveness. AB - Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for malignant and nonmalignant hematologic diseases and metabolic disorders. Although successful, hematopoietic transplantation can be hindered by inadequate stem cell number or poor engrafting efficiency. To overcome these deficits, we and others have previously reported the HSC-enhancing ability of a short-term exposure of prostaglandin E2 (PGE2); this strategy has now progressed to phase 1 clinical trials in double cord blood transplantation. To further analyze the short- and long-term effects of HSC exposure to PGE2, we followed the repopulation kinetics of PGE2-treated hematopoietic grafts through 5 serial transplantations and compared inherent long-term competitiveness in a HSC head-to-head secondary transplantation model. Treatment with PGE2 did not result in a long-term increase in HSC competitiveness, lineage bias, or enhanced proliferative potential, demonstrating that pulse exposure to PGE2 results in transient increases in HSC homing and engraftment potential. PMID- 24047652 TI - [Current status of aspiration pneumonia in highly-aged society]. PMID- 24047651 TI - BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders. AB - Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to acute myeloid leukemia (AML) remain a challenge in disease management. Using whole-exome sequencing of an MDS patient, we identified a somatic mutation in the BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified 4.2% and 0.8% of mutations respectively. BCOR mutations were associated with RUNX1 (P = .002) and DNMT3A mutations (P = .015). BCOR is also mutated in chronic myelomonocytic leukemia patients (7.4%) and BCORL1 in AML patients with myelodysplasia-related changes (9.1%). Using deep sequencing, we show that BCOR mutations arise after mutations affecting genes involved in splicing machinery or epigenetic regulation. In univariate analysis, BCOR mutations were associated with poor prognosis in MDS (overall survival [OS]: P = .013; cumulative incidence of AML transformation: P = .005). Multivariate analysis including age, International Prognostic Scoring System, transfusion dependency, and mutational status confirmed a significant inferior OS to patients with a BCOR mutation (hazard ratio, 3.3; 95% confidence interval, 1.4-8.1; P = .008). These data suggest that BCOR mutations define the clinical course rather than disease initiation. Despite infrequent mutations, BCOR analyses should be considered in risk stratification. PMID- 24047653 TI - [Evaluation of dysphagia and prevention of aspiration pneumonia]. PMID- 24047654 TI - [The significance of oral care in dysphagia patients]. AB - As society ages the number of dysphagia patients and elderly people who cannot independently manage oral care will also increase. Maintaining or improving proper swallowing and oral functions is an important issue from the perspective of retaining quality of life (QOL) and motivation in living. Dysphagia patients are susceptible to aspiration pneumonia, and are also more likely to be malnourished. Oral care for dysphagia patients does not involve simply cleaning the oral cavity, but also preventing aspiration pneumonia, which can be fatal. At the same time, it is related to improving eating and swallowing function and preventing dehydration and malnutrition. It is therefore very important from the perspective of improving QOL. Mechanical stimulation in oral care also plays a role as indirect training in eating and swallowing rehabilitation. The significance of oral care therefore lies in three points: (1) preventing aspiration pneumonia, (2) preventing malnutrition, and (3) indirect training in eating and swallowing rehabilitation. An oral care system of standardized oral care that can be completed in 5 minutes is promising as an effective means of oral rehabilitation. PMID- 24047655 TI - [A family doctor's activities in the home medical care]. PMID- 24047656 TI - [Japan Association of Medical and Care Facilities proposal for medical challenges of elderly home care, including emergency]. PMID- 24047657 TI - [About a too little or superfluous medical care? From the position of a nursing home and group home medical examination]. PMID- 24047659 TI - [What is a futile or fruitful medical treatment and care?]. PMID- 24047658 TI - [Overmedication in bedridden patients]. PMID- 24047660 TI - [How to provide medical and nursing care that respects the wishes of older patients with diminished competence]. PMID- 24047661 TI - [Palliative care in patients without cancer: Impact of the end-of-life care team]. AB - Palliative care improves the quality of life of patients and their families facing problems associated with life-threatening illnesses by promoting the prevention and relief of suffering. Palliative care in Japan has been developed mainly for cancer patients. At the National Center for Geriatrics and Gerontology, an end-of-life care team (EOLCT) has been developed to promote palliative care for patients without cancer. In the first 6 months of its operation, 109 requests were received by the team, 40% of which were for patients without cancer or related disease, including dementia, frailty due to advanced age, chronic respiratory failure, chronic heart failure, and intractable neurologic diseases. The main purpose of the EOLCT is to alleviate suffering. The relevant activities of the team include the use of opioids, providing family care, and giving support in decision-making (advance care planning) regarding withholding; enforcement; and withdrawal of mechanical ventilators, gastric feeding tubes, and artificial alimentation. The EOLCT is also involved in ongoing discussions of ethical problems. The team is actively engaged in the activities of the Japanese Geriatric Society and contributes to the development of decision making guidelines for end-of-life by the Ministry of Health, Labour and Welfare. The EOLCT can be helpful in promoting palliative care for patients with diseases other than cancer. The team offers support during times of difficulty and decision-making. PMID- 24047662 TI - [Prescribing for older people--Concerns about underuse of drug and inadequate medication assistance]. PMID- 24047663 TI - [Problem of tube feeding for Japanese older adults; Questionnaire survey to geriatricians and registered nurse]. PMID- 24047664 TI - [Education in the medical school]. PMID- 24047665 TI - [Emergency medicine for the elderly]. PMID- 24047666 TI - [Actions of the Japan Geriatric Society on the 2011 Great East Japan Earthquake: Emerging issues of a "super-aging" society]. PMID- 24047667 TI - [Evaluation of the association between cognitive impairment and the vitamin D levels among community-dwelling Japanese pre-frail elderly individuals]. AB - AIM: Cognitive impairment is the second leading cause of long-term care, and the number of cognitively impaired elderly individuals is increasing. Cognitive impairment has been reported to be associated with a low vitamin D level. However, many elderly individuals are deficient in vitamin D due to undernutrition and a house-bound status. It is unknown whether cognitive impairment is independently associated with the vitamin D level. The aim of this study was to examine the association between cognitive impairment and the levels of vitamin D among community-dwelling Japanese pre-frail elderly individuals. METHODS: A cross-sectional survey was conducted in two towns (latitude: 36 degrees north) from June 2006 to January 2011. The subjects included 316 community-dwelling pre-frail elderly individuals 65 years of age or older (mean+/ SD: 77.0+/-5.7 yr) who attended a program for nursing care prevention. A questionnaire-based interview was conducted regarding activities of daily living. The serum levels of intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured. Age and gender were recorded, as well as the presence of cognitive impairment determined according to the Mini Mental State Examination (MMSE). The factors associated with an MMSE score of <=23 were examined using a multiple logistic regression analysis. RESULTS: Of the subjects, 21.2% were men and 30.6% had an MMSE score of <=23. The mean MMSE score was 25.3+/-3.7. The prevalence of severe deficiency of 25(OH)D was 1.7%, and only 14.0% of the participants had a sufficient vitamin D level. The multiple logistic regression analysis suggested that an MMSE score of less than 23 was significantly associated with the levels of iPTH and 25(OH)D among the pre-frail men, but not the women. CONCLUSIONS: Our data suggest that the vitamin D level is significantly associated with cognitive impairment in pre frail elderly men. PMID- 24047668 TI - [Influence of comprehensive intervention composed of nutrition and exercise on the development of exercise habits and self-perceived health among community dwelling elderly individuals]. AB - AIM: The purpose of this study was to investigate the effects of comprehensive intervention on the development of exercise habits and self-perceived health among community-dwelling elderly individuals. METHODS: A total of 44 elderly individuals (mean age: 71.1+/-5.0SD) who had provided consent to participate in the study were randomly allocated to either an intervention (n=23) or control group (n=21). The intervention group participated in a comprehensive intervention program (including nutrition classes, group exercise and enjoying meals with other community members). The following factors were measured: age, the frequency of going out, a history of falls, the frequency of exercise, the duration of exercise, self-efficacy for exercise, the stage model of change, self-perceived health before, immediately after and one month after the intervention. RESULTS: The attendance rate in the intervention group was over 90%. The intervention group exhibited significant improvements in the frequency of exercise (p=0.001), duration of exercise (p=0.02) and self-efficacy for exercise (p=0.012) compared with the control group following the intervention program. On follow-up, the intervention group demonstrated significant improvements in the frequency of exercise (p=0.027) and self-efficacy for exercise (p=0.043) compared with the control group. CONCLUSIONS: These findings suggested that a comprehensive intervention program composed of nutrition and exercise can improve the developing exercise habits and self-perceived health. Self-perceived health was improved by several factors, which appeears to have contributed to the results. These factors include sharing and exchanging ideas and having the opportunity to enjoy meals with other community members. Further activities promoting such interactions and exercise habits are therefore necessary. PMID- 24047669 TI - [Are gait parameters related to knee pain, urinary incontinence and a history of falls in community-dwelling elderly women?]. AB - AIM: To examine the association between gait parameters and knee pain, urinary incontinence, and a history of falls. METHODS: Comprehensive health examinations were conducted in 2009 among 971 elderly women over 70 years of age, in which the questionnaire and gait parameter results of 870 participants were analyzed. Knee pain, urinary incontinence and a history of falls were assessed through face-to face interview surveys. Gait parameters were measured using a walk-way to assess walking speed, cadence, stride, stride length, step width, walking angle, toe angle and the differences in each parameter between the right and left foot. Multiple logistic regression analyses were performed to examine the associations between the gait parameters and knee pain, urinary incontinence and a history of falls. RESULTS: The elderly women with knee pain, urinary incontinence and a history of falls had slower walking speeds, smaller strides and strides length, and wider step width and walking angles. The multiple logistic regression analysis showed the walking speed to be significantly associated with mild knee pain and urinary incontinence and single a history of fall; moderate/severe knee pain was significantly associated with step width (OR=0.58, 95%CI=0.40-0.84) and walking angle (OR=1.62, 95%CI=1.30-2.01); moderate/severe urinary incontinence was significantly associated with walking speed (OR=0.97, 95%CI=0.96-0.99), walking angle (OR=1.14, 95%CI=1.02-1.26), and difference in walking angle between the right and left foot (OR=1.43, 95%CI=1.09-1.86); multiple a history of falls was significantly associated with stride length (OR=0.85, 95%CI=0.79-0.93) and the difference in walking angle between the right and left foot (OR=1.36, 95%CI=1.01-1.85). CONCLUSIONS: The data suggest that combining assessments of walking speed and other gait parameters may be an effective screening method for the early detection of geriatric syndromes. PMID- 24047670 TI - [Age at the time of gastrostomy placement as a prognostic factor in long-term hospitalized patients]. AB - OBJECTIVE: To evaluate the influence of age at the time of gastrostomy placement as a prognostic factor and examine the survival rate in long-term hospitalized patients with gastrostomy. METHODS: The subjects were 408 inpatients with gastrostomy admitted to our hospital between December 2005 and March 2012. All inpatients, including the present subjects, received oral care in the form of attendant care by nurses or caregivers. First, the subjects were divided into two groups according to sex. Second, the subjects were divided into four groups according to the age at the time of gastrostomy placement: the sixties group (60 69 years), seventies group (70-79 years), eighties group (80-89 years), and nineties group (90-99 years). Each survival curve was drawn using the Kaplan Meier method, and the log-rank tests were used for statistical analysis. The Cox proportional hazard models were used to calculate hazard ratios. RESULTS: The overall survival rates at one year and five years after gastrostomy placement were 75.4% and 23.2%, respectively. The median survival period was 32.2 months. A significantly better prognosis was observed in women than in men; the age adjusted hazard ratio was 1.748 (95% CI, 1.364-2.242) for men. The eighties and nineties groups exhibited significantly poorer prognoses than that of the sixties group (p<0.008); the sex-adjusted hazard ratios were 2.173 (95% CI, 1.341-3.521) and 3.071 (95% CI, 1.627-5.797), respectively. CONCLUSIONS: These results suggest that oral care, even after gastrostomy placement, can improve the prognosis in patients with gastrostomy. Physicians should therefore be cautious when recommending gastrostomy placement for patients aged>80 years. PMID- 24047671 TI - [Mecobalamin improved pernicious anemia in an elderly individual with Hashimoto's disease and diabetes mellitus]. AB - A 73-year-old Japanese man with Hashimoto's disease and diabetes mellitus received regular medical checkups for type 2 diabetes care. Blood tests indicated macrocytic anemia (red blood cell count, 279*104 /MUL; hemoglobin, 12.2 g/dL; hematocrit, 34.0%; mean corpuscular volume, 121.9 fL). The laboratory data demonstrated a normal folic acid level with a low vitamin B12 level. An endoscopic examination indicated no signs of gastric or intestinal bleeding. Positive results for anti-intrinsic factor antibodies were strongly suggestive of pernicious anemia. The patient refused cobalamin injections to treat the anemia. However, the oral administration of mecobalamin for the treatment of diabetic neuropathy was simultaneously initiated. Subsequently, the anemia gradually improved. Oral mecobalamin was presumably effective for pernicious anemia management. Anemia is frequently observed in elderly patients, and the incidence of pernicious anemia increases with age. Anemia is conventionally treated with cobalamin injections. Currently, the oral administration of mecobalamin is not the typical treatment for anemia. However, as in our case, a few reports have documented positive results following oral mecobalamin treatment. Moreover, oral mecobalamin is a fairly recent, novel, noninvasive mode of treatment, making it ideal for elderly patients, who are generally frail. This case suggests the efficacy of mecobalamin for the treatment of pernicious anemia. PMID- 24047672 TI - [A combination of ramelteon and Yi-gan san successfully improved post-surgical delirium in a patient with subarachnoid hemorrhage]. AB - A 68-year-old woman presented with a sudden severe headache, vomiting, and disturbed consciousness. She was admitted to the emergency room. Computed tomography (CT) revealed a hemorrhage in the right temporal lobe. Angiography demonstrated a ruptured aneurysm in the right middle cerebral artery (MCA) and an unruptured aneurysm in the left MCA. The subarachnoid hemorrhage was grade 3 (Hunt and Kosnik classification). Emergency craniotomy, clipping of the ruptured aneurysm and removal of the hematoma were performed. The left hemiparesis improved, and the patient was able to walk. We prescribed triazolam (0.25 mg/day) to treat the patient's insomnia. The unruptured aneurysm was additionally clipped on the 15th hospital day. After the second operation, the patient complained of delirium with restlessness, excitement, disorganized behavior, and sleep disturbance. Treatment with thiapride (150 mg/day) did not improve the delirium. We additionally administered Yi-gan san (7.5 g/day) and switched the triazolam to ramelteon (8 mg/day). The Memorial Delirium Assessment Scale score improved dramatically (from 16 at onset to 5 on day 7 and 1 at two months). Yi-gan san is reported to be effective for the treatment of behavioral and psychological symptoms of dementia. Ramelteon, a melatonin receptor agonist, is implicated in the regulation of the sleep-wake cycle. Ramelteon, unlike other hypnotic drugs, does not cause oversedation, rebound insomnia, withdrawal symptoms or dependence. In addition, we have noted no adverse effects, including oversedation or clinically significant changes in laboratory data, during combination therapy. A combination of ramelteon and Yi-gan san may therefore be beneficial in elderly patients with delirium, especially when there is a risk of oversedation. PMID- 24047673 TI - [A case of hypoglycemia caused by the accidental ingestion of glimepiride in an elderly dementia patient diagnosed based on the serum glimepiride concentration]. AB - A 77-year-old man being treated for Alzheimer-type dementia and an old cerebral infarction was admitted to our hospital due to disturbance of consciousness. The patient's Mini-mental State Examination and Hasegawa Dementia Scale scores were 23 and 17 points, respectively. His blood glucose level was low (18 mg/dl), with a relatively high insulin level (15.2 MUU/ml). Computed tomography and an 18-hour fasting test showed no signs of insulinoma. Since his wife had been taking medications for dementia and diabetes, including Glimepiride, we considered the possibility that he may have taken glimepiride by mistake. Five months later, he was admitted again due to severe hypoglycemia with a relatively high insulin level (23.4 MUU/ml). More than 660 g of glucose and 100 mg of hydrocortisone were administered, and the hypoglycemia resolved approximately 24 hours after admission. Again, there were no signs of insulinoma. We asked Sanofi-Aventis to measure the level of glimepiride in a blood sample obtained six hours after admission. Glimepiride was detected at a concentration of 24.48 ng/ml, which roughly corresponded to the accidental ingestion of 6 mg of the drug. We were later informed by the patient's home doctor that he had visited the emergency department of another prefecture hospital with the same symptoms. Thereafter, the couple received counseling by their home doctor, and the hypoglycemia has not recurred since. Given the increase in the number of elderly households, an increase in the number of episodes of accidental ingestion of medicine is expected. Clinicians should be aware of the potential for accidental exposure to drugs prescribed to other family members especially, in elderly patients. PMID- 24047674 TI - [The appearance of antibiotic-resistant bacteria on admission to long term care beds]. PMID- 24047675 TI - [Starting a medical consultation room through inter-professional collaboration]. PMID- 24047676 TI - The composition, heating value and renewable share of the energy content of mixed municipal solid waste in Finland. AB - For the estimation of greenhouse gas emissions from waste incineration it is essential to know the share of the renewable energy content of the combusted waste. The composition and heating value information is generally available, but the renewable energy share or heating values of different fractions of waste have rarely been determined. In this study, data from Finnish studies concerning the composition and energy content of mixed MSW were collected, new experimental data on the compositions, heating values and renewable share of energy were presented and the results were compared to the estimations concluded from earlier international studies. In the town of Lappeenranta in south-eastern Finland, the share of renewable energy ranged between 25% and 34% in the energy content tests implemented for two sample trucks. The heating values of the waste and fractions of plastic waste were high in the samples compared to the earlier studies in Finland. These high values were caused by good source separation and led to a low share of renewable energy content in the waste. The results showed that in mixed municipal solid waste the renewable share of the energy content can be significantly lower than the general assumptions (50-60%) when the source separation of organic waste, paper and cardboard is carried out successfully. The number of samples was however small for making extensive conclusions on the results concerning the heating values and renewable share of energy and additional research is needed for this purpose. PMID- 24047677 TI - Atrioventricular valve regurgitation at diagnosis in single-ventricle patients: does it affect longitudinal outcomes? AB - INTRODUCTION: Significant atrioventricular valve regurgitation at diagnosis in single-ventricle patients has been associated with mortality and morbidity. However, longitudinal data on the effect of valve regurgitation at diagnosis on outcomes in the era of surgical valve interventions are scarce. MATERIALS AND METHODS: This is a retrospective review of single-ventricle patients admitted to a regional centre from 2005 to 2008. Data were reviewed from birth to 18 months, and association of atrioventricular valve regurgitation at diagnosis with mortality and morbidity was evaluated. RESULTS: A total of 118 patients were studied, 73% with a single right ventricle. At diagnosis, 37 patients (31%) had mild, 5 (4%) had mild to moderate, and 4 (3%) had >= moderate atrioventricular valve regurgitation. Moderate or greater valve regurgitation was associated with mortality (HR 5.51, 95% CI 1.24-24.61, p = 0.025), and all four patients with >= moderate valve regurgitation died. However, valve regurgitation was not associated with mortality for left ventricle patients. In all, 12 patients (10%) had surgical atrioventricular valve interventions. There were no independent predictors of valve intervention, and no patient having an intervention had > mild valve regurgitation at diagnosis. There was no association between valve regurgitation and days of hospitalisation or chest tube drainage. CONCLUSION: Significant atrioventricular valve regurgitation at diagnosis remains a risk factor for mortality in single-ventricle patients, although it may be less important for single left ventricle patients. However, it is not associated with increased morbidity or surgical atrioventricular valve intervention in survivors. Reliably predicting surgical atrioventricular valve intervention remains a challenge in single-ventricle patients. PMID- 24047679 TI - Phonon-drag magnetothermopower in Rashba spin-split two-dimensional electron systems. AB - We study the phonon-drag contribution to the thermoelectric power in a quasi-two dimensional electron system confined in GaAs/AlGaAs heterostructure in the presence of both Rashba spin-orbit interaction and perpendicular magnetic field at very low temperature. It is observed that the peaks in the phonon-drag thermopower split into two when the Rashba spin-orbit coupling constant is strong. This splitting is a direct consequence of the Rashba spin-orbit interaction. We show the dependence of phonon-drag thermopower on both magnetic field and temperature numerically. A power-law dependence of phonon-drag magnetothermopower on the temperature in the Bloch-Gruneisen regime is found. We also extract the exponent of the temperature dependence of phonon-drag thermopower for different parameters like electron density, magnetic field, and the spin-orbit coupling constant. PMID- 24047678 TI - Primary multidrug-resistant Mycobacterium tuberculosis in 2 regions, Eastern Siberia, Russian Federation. AB - Of 235 Mycobacterium tuberculosis isolates from patients who had not received tuberculosis treatment in the Irkutsk oblast and the Sakha Republic (Yakutia), eastern Siberia, 61 (26%) were multidrug resistant. A novel strain, S 256, clustered among these isolates and carried eis-related kanamycin resistance, indicating a need for locally informed diagnosis and treatment strategies. PMID- 24047680 TI - Effects of carbon-nitrogen ratio on nitrogen removal in a sequencing batch reactor enhanced with low-intensity ultrasound. AB - A sequencing batch reactor (SBR) enhanced with low-intensity ultrasound was designed to study the removal of nitrogen under different carbon-nitrogen (C/N) ratios. The results showed that the removal efficiencies of CODCr and nitrogen were inversely proportional to C/N ratios. The CODCr of the effluent in the control reactor (CR) and the low-intensity ultrasound-enhanced reactor (UER) were lower than 40 mg L(-1). With a decrease in C/N ratio, the NH4(+)-N removal load of the CR showed little change, while the NH4(+)-N removal load of UER increased from 21.2 to 56.1mg NH4(+)-N/g mixed liquid suspended solids per day. To further understand effects of low-intensity ultrasound, the denaturing gel gradient electrophoresis (DGGE) analysis showed that the similar coefficients of the community structures in the UER and CR were 86%, 52% and 29% when the C/N ratios were 15:1, 10:1, 5:1, respectively. PMID- 24047681 TI - Comparison of biochar properties from biomass residues produced by slow pyrolysis at 500 degrees C. AB - Application of biochar from biomass pyrolysis to soil is gaining greater interest; this can ameliorate the soil quality, reduce fertilizer consumption, and sequestrate carbon. This study compares the characteristics of biochar produced by slow pyrolysis at 500 degrees C for agricultural residues: sugarcane bagasse, cocopeat, paddy straw, palm kernel shell (PKS) and umbrella tree. In the biochar yield, the influence of the inert and lignin contents was significant. The wood stem, bagasse and paddy straw had biochar yields of 24-28 wt.% from the organic fraction while cocopeat had 46 wt.%. The carbon content of biochar ranged from 84 wt.% to 89 wt.%, which corresponded to 43-63% of carbon in the biomass. The biochar from wood stem and bagasse had well-developed pores of various sizes with large surface areas. Although the surface area was significant, PKS biochar had dense matrix with few large pores. The elemental composition and pH of biochars were also compared. PMID- 24047682 TI - Separation of competitive microorganisms using anaerobic membrane bioreactors as pretreatment to microbial electrochemical cells. AB - Anaerobic membrane bioreactors (AnMBRs) as pretreatment to microbial electrochemical cells (MECs) were first assessed for improving energy recovery. A dual-chamber MEC was operated at hydraulic retention time (HRT) ranging from 1 to 8d, while operating conditions for an AnMBR were fixed. Current density was increased from 7.5 +/- 0 to 14 +/- 1A/m(2) membrane with increasing HRT. MEC tests with AnMBR permeate (mainly propionate and acetate) and propionate medium confirmed that propionate was fermented to acetate and hydrogen gas, and anode respiring bacteria (ARB) utilized these fermentation products as substrate. Membrane separation in the AnMBR excluded fermenters and methanogens from the MEC, and thus no methane production was found in the MEC. The lack of fermenters, however, slowed down propionate fermentation rate, which limited current density in the MEC. To symphonize fermenters, H2-consumers, and ARB in biofilm anode is essential for improving current density, and COD removal. PMID- 24047683 TI - Model based optimization of high cell density cultivation of nitrogen-fixing cyanobacteria. AB - In the present study, fed-batch cultivation of Cyanothece sp. ATCC 51142, a known hydrogen producer, was optimized for maximizing biomass production. Decline in growth of this organism in dense cultures was attributed to increased substrate consumption for maintenance and respiration, and photolimitation due to self shading. A model incorporating these aspects was developed, and by using control vector parameterization (CVP), substrate feeding recipe was optimized to achieve 12-fold higher biomass concentration. The optimization results were verified experimentally on shake flask and bioreactor. The latter resulted in greater exponential growth rate possibly by overcoming photolimitation by simulating flashing light effect. Such a strategy can be readily applied for mixotrophic cultivation of cyanobacterial cultures in the first stage followed by photoautotrophic growth at the production stage. PMID- 24047684 TI - Safe pseudovirus-based assay for neutralization antibodies against influenza A(H7N9) virus. AB - Serologic studies are urgently needed to assist in understanding an outbreak of influenza A(H7N9) virus. However, a biosafety level 3 laboratory is required for conventional serologic assays with live lethal virus. We describe a safe pseudovirus-based neutralization assay with preliminary assessment using subtype H7N9-infected samples and controls. PMID- 24047685 TI - Effect of infection control strategy on knowledge, attitude and practice towards hepatitis B transmission and prevention in vulnerable populations. AB - BACKGROUND: Health care workers (HCWs) and hematological patients needing blood/ blood product transfusion are particularly vulnerable to blood born infections (BBI) including viral hepatitis. OBJECTIVE: To evaluate knowledge, attitude and practice (KAP) of these target groups regarding viral hepatitis B (HBV) transmission and its change with implementing infection control policy and procedures. METHODS: An anonymous questionnaire with closed questions was used to evaluate KAP including vaccination status in 2 target groups, in Children Hospital, Ain Shams University, Cairo, Egypt: 184 nurses and 210 children and adolescents with blood diseases. One year after instituting infection control as a part of hospital procedures, the same questionnaire was reused to evaluate KAP towards HBV. RESULTS: Baseline knowledge regarding HBV transmission, sequelae and preventive measures, was poor in both groups. Among nurses, only 62% wore gloves on withdrawing or giving blood to patients, 43.5% routinely washed hands between patients and 37.5% reported exposure after sharp injury. Only 38% of patients and 40% of nurses received HBV vaccination. Targeted infection control policy and procedures significantly improved KAP regarding HBV in both groups. Vaccination coverage significantly increased and reached 88.7% for nurses and 72% for patients. CONCLUSIONS: Hospital based infection control units with established policy and procedures against BBI significantly improved KAP towards HBV including a significant increase in vaccination intake. PMID- 24047686 TI - All I have is a void: women's perceptions of the benefits and side effects of ECT. AB - BACKGROUND: Recent reviews of the benefits and risks associated with electroconvulsive therapy (ECT) have often reported mixed and conflicting results. Although there are very few qualitative studies on ECT, qualitative research offers the advantage of in-depth explorations into how people perceive and experience ECT. OBJECTIVE: The objective of this qualitative study was to explore women's experiences and perceptions of the benefits and side effects associated with having ECT. METHODS: The authors used narrative inquiry and in depth interviews to obtain nine women's accounts and stories of ECT, focusing particularly on their accounts of perceived benefits and side effects associated with ECT. RESULTS: Qualitative thematic analysis of the interviews with nine women resulted in four main themes emerging from the interviews: "it's sort of like housecleaning," "I don't remember the wedding," made me stupider," and "putting them in a cage with a bear." CONCLUSIONS: Three of the women were able to articulate some perceived benefit arising from ECT, although these women also acknowledged the benefits did not last more than two weeks. The majority of women complained of significant and persistent autobiographical memory loss, cognitive deficits, and fear of the procedure. PMID- 24047687 TI - Dependence and withdrawal reactions to benzodiazepines and selective serotonin reuptake inhibitors. How did the health authorities react? AB - AIM: Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time. METHODS: Documentary study. We searched the web sites of the European Medicines Agency and the drug agencies in USA, UK, and Denmark for documents mentioning benzodiazepines or SSRIs. We supplemented with other relevant literature that could contribute to our study. The searches were performed in 2009 in PubMed, Google, BMJ and JAMA. RESULTS: It took many years before the drug regulators acknowledged benzodiazepine dependence and SSRI withdrawal reactions and before the prescribers and the public were informed. Drug regulators relied mainly on the definitions of dependence and withdrawal reactions from the diagnostic psychiatric manuals, which contributed to the idea that SSRIs do not cause dependence, although it is difficult for many patients to stop treatment. In the perspective of a precautionary principle, drug agencies have failed to acknowledge that SSRIs can cause dependence and have minimised the problem with regard to its frequency and severity. In the perspective of a risk management principle, the drug agencies have reacted in concordance with the slowly growing knowledge of adverse drug reactions and have sharpened the information to the prescribers and the public over time. However, solely relying on spontaneous reporting of adverse effects leads to underestimation and delayed information about the problems. CONCLUSION: Given the experience with the benzodiazepines, we believe the regulatory bodies should have required studies from the manufacturers that could have elucidated the dependence potential of the SSRIs before marketing authorization was granted. PMID- 24047688 TI - The validity of the Nordic patient safety culture questionnaire (TUKU). AB - BACKGROUND: Patient safety culture (PSC) has been postulated to have a significant influence on the quality of health care. OBJECTIVE: This study aims to evaluate the psychometric properties of the TUKU PSC questionnaire. METHODS: The questionnaire development was based on the view that patient safety constitutes not only the absence of adverse events, but also the presence of certain organizational attributes that enable safety. The TUKU questionnaire has two parts: a measure of psychological dimensions, and a measure of employees' perceptions of organizational functions. The TUKU questionnaire was validated using a sample of 1162 health care professionals from seven Finnish health care organizations. Two studies were carried out, one focusing on construct validity and the other on criterion validity. RESULTS: Regarding construct validity, the empirical model matched the theory quite well. The results of Study 2 concerning criterion validity were more ambiguous. Four of the organizational dimensions and two of the psychological dimensions were related to patient safety incidents occurring 16 months after administering the questionnaire. CONCLUSIONS: The study provided evidence on the key organizational dimensions that comprise patient safety culture and affect patient safety. The study further contributed towards validation of an instrument for measuring these dimensions. PMID- 24047689 TI - Adverse drug reactions as a reason for admission to an internal medicine ward in Argentina. AB - BACKGROUND: Adverse Drug Reactions (ADR) are a major cause of morbidity and mortality worldwide. In spite of this, ADR are largely underreported and unrecognized. PURPOSE: Identify and characterize ADR related admissions to our internal medicine ward using a proactive multidisciplinary pharmacovigilance approach. METHODS: Within 24 hrs of admission 1045 patients admitted to the Internal Medicine Ward between August 2010 and February 2012 were screened for possible or probable ADR related admissions. RESULTS: Probable ADR accounted for 112 of 1045 admissions (10.7%, 95% Confidence Interval [CI]: 8.8-12.6%), of which only 16 (14.3%) were classified as unavoidable. NSAIDs were the drug group more commonly implicated in probable ADR-related admissions (17.0%), followed by antiplatelets (16.1%). In-hospital mortality of patients admitted due to probable ADR was 8.0% (95% CI: 2.9-13.1%). During this study period, 6% of internal medicine ward and 4% of critical care unit beds were occupied by patients with probable ADR. The estimated cost of care of these patients was 641,000 US dollars (USD). CONCLUSION: ADR are a frequent reason for admission to an Internal Medicine Ward in Argentina. The culprit drugs and interactions are similar to those reported in the literature. The cost is substantial and most of the ADR are potentially avoidable. PMID- 24047690 TI - UMC's ground-breaking web tool brings patient safety into focus. PMID- 24047691 TI - Impact of geographical region on urinary metabolomic and plasma fatty acid profiles in subjects with the metabolic syndrome across Europe: the LIPGENE study. AB - The application of metabolomics in multi-centre studies is increasing. The aim of the present study was to assess the effects of geographical location on the metabolic profiles of individuals with the metabolic syndrome. Blood and urine samples were collected from 219 adults from seven European centres participating in the LIPGENE project (Diet, genomics and the metabolic syndrome: an integrated nutrition, agro-food, social and economic analysis). Nutrient intakes, BMI, waist:hip ratio, blood pressure, and plasma glucose, insulin and blood lipid levels were assessed. Plasma fatty acid levels and urine were assessed using a metabolomic technique. The separation of three European geographical groups (NW, northwest; NE, northeast; SW, southwest) was identified using partial least squares discriminant analysis models for urine (R2 X: 0.33, Q2: 0.39) and plasma fatty acid (R2 X: 0.32, Q2: 0.60) data. The NW group was characterised by higher levels of urinary hippurate and N-methylnicotinate. The NE group was characterised by higher levels of urinary creatine and citrate and plasma EPA (20 : 5 n-3). The SW group was characterised by higher levels of urinary trimethylamine oxide and lower levels of plasma EPA. The indicators of metabolic health appeared to be consistent across the groups. The SW group had higher intakes of total fat and MUFA compared with both the NW and NE groups (P<= 0.001). The NE group had higher intakes of fibre and n-3 and n-6 fatty acids compared with both the NW and SW groups (all P< 0.001). It is likely that differences in dietary intakes contributed to the separation of the three groups. Evaluation of geographical factors including diet should be considered in the interpretation of metabolomic data from multi-centre studies. PMID- 24047692 TI - Acute coronary syndrome. AB - Acute coronary syndrome (ACS) is a major health care and economic burden in the United States and accounts for more than 1 million hospitalizations annually. The morbidity and mortality due to ACS are substantial-nearly half of all deaths due to coronary heart disease occur following an ACS. This review provides an up-to date summary of the pathophysiology, diagnosis, and treatment of ACS. We also provide an overview of the management of common hemodynamic disturbances and myocardial infarction complications that physicians often encounter in an intensive care setting. PMID- 24047693 TI - SAD-A and AMPK kinases: the "yin and yang" regulators of mTORC1 signaling in pancreatic beta cells. PMID- 24047694 TI - Chromatin PTEN is involved in DNA damage response partly through regulating Rad52 sumoylation. AB - A pool of PTEN localizes to the nucleus. However, the exact mechanism of action of nuclear PTEN remains poorly understood. We have investigated PTEN's role during DNA damage response. Here we report that PTEN undergoes chromatin translocation after DNA damage, and that its translocation is closely associated with its phosphorylation on S366/T370 but not on S380. Deletional analysis reveals that the C2 domain of PTEN is responsible for its nuclear translocation after exposure to genotoxin. Both casein kinase 2 and GSK3beta are involved in the phosphorylation of the S366/T370 epitope, as well as PTEN's association with chromatin after DNA damage. Significantly, PTEN specifically interacts with Rad52 and colocalizes with Rad52, as well as gammaH2AX, after genotoxic stress. Moreover, PTEN is involved in regulating Rad52 sumoylation. Combined, our studies strongly suggest that nuclear/chromatin PTEN mediates DNA damage repair through interacting with and modulating the activity of Rad52. PMID- 24047695 TI - Proliferative status regulates HDAC11 mRNA abundance in nontransformed fibroblasts. AB - Histone deacetylases (HDACs) are important determinants of gene transcription and other biological processes. HDAC11 is one of the least characterized HDACs and is the only member of the class IV HDAC family. Our studies examined the events that control the expression of the HDAC11 transcript. We show that platelet-derived growth factor (PDGF) rapidly reduces the abundance of HDAC11 mRNA when added to density-arrested Balb/c-3T3 cells, which are nontransformed fibroblasts. Reduction required mRNA and protein synthesis, but not AKT or ERK activity, and resulted from accelerated turnover of the HDAC11 transcript. Reduction was transient in cells receiving PDGF alone but sustained in cells receiving both PDGF and platelet-poor plasma, which together promote G0/G1 traverse and S phase entry. Plasma alone did not appreciably reduce HDAC11 mRNA abundance, nor did epidermal growth factor, insulin-like growth factor, or insulin. HDAC11 mRNA accumulated in Balb/c-3T3 cells exiting the cell cycle due to density-dependent growth inhibition or serum deprivation. Of note, HDAC11 mRNA did not accumulate in a spontaneously transformed Balb/c-3T3 clonal variant (clone 2) that does not density arrest. The HDAC11 promoter was active in Balb/c-3T3 but not clone 2 cells; inactivity in clone 2 cells did not result from methylation of CpG islands. Overexpression of HDAC11 inhibited the cell cycle progression of both transformed and nontransformed fibroblasts. Our studies identify the HDAC11 transcript as a PDGF target and show that HDAC11 mRNA abundance correlates inversely with proliferative status. PMID- 24047696 TI - Cellular senescence or EGFR signaling induces Interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR). AB - Interleukin 6 (IL-6) signaling plays a role in inflammation, cancer, and senescence. Here, we identified soluble IL-6 receptor (sIL-6R) as a member of the senescence-associated secretory phenotype (SASP). Senescence-associated sIL-6R upregulation was mediated by mammalian target of rapamycin (mTOR). sIL-6R was mainly generated by a disintegrin and metalloprotease 10 (ADAM10)-dependent ectodomain shedding to enable IL-6 trans-signaling. In vivo, heterozygous PTEN knockout mice exhibited higher mTOR activity and increased sIL-6R levels. Moreover, aberrant EGF receptor (EGFR) activation triggered IL-6 synthesis. In analogy to senescence, EGFR-induced activation of mTOR also induced IL-6R expression and sIL-6R generation. Hence, mTOR activation reprograms IL-6 non responder cells into IL-6 responder cells. Our data suggest that mTOR serves as a central molecular switch to facilitate cellular IL-6 classic and trans-signaling via IL-6R upregulation with direct implications for cellular senescence and tumor development. PMID- 24047697 TI - The estrogen receptor alpha is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness. AB - The role of the Forkhead box class O (FoxO)3a transcription factor in breast cancer migration and invasion is controversial. Here we show that FoxO3a overexpression decreases motility, invasiveness, and anchorage-independent growth in estrogen receptor alpha-positive (ERalpha+) cancer cells while eliciting opposite effects in ERalpha-silenced cells and in ERalpha-negative (ERalpha-) cell lines, demonstrating that the nuclear receptor represents a crucial switch in FoxO3a control of breast cancer cell aggressiveness. In ERalpha+ cells, FoxO3a mediated events were paralleled by a significant induction of Caveolin-1 (Cav1), an essential constituent of caveolae negatively associated to tumor invasion and metastasis. Cav1 induction occurs at the transcriptional level through FoxO3a binding to a Forkhead responsive core sequence located at position -305/-299 of the Cav1 promoter. 17beta-estradiol (E2) strongly emphasized FoxO3a effects on cell migration and invasion, while ERalpha and Cav1 silencing were able to reverse them, demonstrating that both proteins are pivotal mediators of these FoxO3a controlled processes. In vivo, an immunohistochemical analysis on tissue sections from patients with ERalpha+ or ERalpha- invasive breast cancers or in situ ductal carcinoma showed that nuclear FoxO3a inversely (ERalpha+) or directly (ERalpha-) correlated with the invasive phenotype of breast tumors. In conclusion, FoxO3a role in breast cancer motility and invasion depends on ERalpha status, disclosing a novel aspect of the well-established FoxO3a/ERalpha interplay. Therefore FoxO3a might become a pursuable target to be suitably exploited in combination therapies either in ERalpha+ or ERalpha- breast tumors. PMID- 24047699 TI - Administration of budesonide in children with graft-versus-host disease. PMID- 24047698 TI - Stem cell-like ALDH(bright) cellular states in EGFR-mutant non-small cell lung cancer: a novel mechanism of acquired resistance to erlotinib targetable with the natural polyphenol silibinin. AB - The enrichment of cancer stem cell (CSC)-like cellular states has not previously been considered to be a causative mechanism in the generalized progression of EGFR-mutant non-small cell lung carcinomas (NSCLC) after an initial response to the EGFR tyrosine kinase inhibitor erlotinib. To explore this possibility, we utilized a pre-clinical model of acquired erlotinib resistance established by growing NSCLC cells containing a TKI-sensitizing EGFR exon 19 deletion (DeltaE746 A750) in the continuous presence of high doses of erlotinib. Genome-wide analyses using Agilent 44K Whole Human Genome Arrays were evaluated via bioinformatics analyses through GSEA-based screening of the KEGG pathway database to identify the molecular circuitries that were over-represented in the transcriptomic signatures of erlotinib-refractory cells. The genomic spaces related to erlotinib resistance included a preponderance of cell cycle genes (E2F1, - 2, CDC2, -6) and DNA replication-related genes (MCM4, - 5, - 6, - 7), most of which are associated with early lung development and poor prognosis. In addition, metabolic genes such as ALDH1A3 (a candidate marker for lung cancer cells with CSC-like properties) were identified. Thus, we measured the proportion of erlotinib-resistant cells expressing very high levels of aldehyde dehydrogenase (ALDH) activity attributed to ALDH1/3 isoforms. Using flow cytometry and the ALDEFLUOR(r) reagent, we confirmed that erlotinib-refractory cell populations contained drastically higher percentages (> 4500%) of ALDH(bright) cells than the parental erlotinib responsive cells. Notably, strong decreases in the percentages of ALDH(bright) cells were observed following incubation with silibinin, a bioactive flavonolignan that can circumvent erlotinib resistance in vivo. The number of lung cancer spheres was drastically suppressed by silibinin in a dose-dependent manner, thus confirming the ability of this agent to inhibit the self-renewal of erlotinib-refractory CSC-like cells. This report is the first to show that: (1) loss of responsiveness to erlotinib in EGFR-mutant NSCLC can be explained in terms of erlotinib-refractory ALDH(bright) cells, which have been shown to exhibit stem cell-like properties; and (2) erlotinib-refractory ALDH(bright) cells are sensitive to the natural agent silibinin. Our findings highlight the benefit of administration of silibinin in combination with EGFR TKIs to target CSCs and minimize the ability of tumor cells to escape cell death in EGFR-mutant NSCLC patients. PMID- 24047700 TI - Human milk secretory immunoglobulin a and lactoferrin N-glycans are altered in women with gestational diabetes mellitus. AB - Very little is known about the effects of gestational diabetes mellitus (GDM) on lactation and milk components. Recent reports suggested that hyperglycemia during pregnancy was associated with altered breast milk immune factors. Human milk oligosaccharides (HMOs) and N-glycans of milk immune-modulatory proteins are implicated in modulation of infant immunity. The objective of the current study was to evaluate the effect of GDM on HMO and protein-conjugated glycan profiles in breast milk. Milk was collected at 2 wk postpartum from women diagnosed with (n = 8) or without (n = 16) GDM at week 24-28 in pregnancy. Milk was analyzed for HMO abundances, protein concentrations, and N-glycan abundances of lactoferrin and secretory immunoglobulin A (sIgA). HMOs and N-glycans were analyzed by mass spectrometry and milk lactoferrin and sIgA concentrations were analyzed by the Bradford assay. The data were analyzed using multivariate modeling confirmed with univariate statistics to determine differences between milk of women with compared with women without GDM. There were no differences in HMOs between milk from women with vs. without GDM. Milk from women with GDM compared with those without GDM was 63.6% lower in sIgA protein (P < 0.05), 45% higher in lactoferrin total N-glycans (P < 0.0001), 36-72% higher in lactoferrin fucose and sialic acid N-glycans (P < 0.01), and 32-43% lower in sIgA total, mannose, fucose, and sialic acid N-glycans (P < 0.05). GDM did not alter breast milk free oligosaccharide abundances but decreased total protein and glycosylation of sIgA and increased glycosylation of lactoferrin in transitional milk. The results suggest that maternal glucose dysregulation during pregnancy has lasting consequences that may influence the innate immune protective functions of breast milk. PMID- 24047701 TI - Expression of the placental transcriptome in maternal nutrient reduction in baboons is dependent on fetal sex. AB - Maternal undernutrition increases the risk of perinatal complications and predisposes offspring to obesity, diabetes, and cardiovascular disease later in life. Emerging evidence suggests that changes in placental function play a role in linking altered maternal nutrition in pregnancy to the subsequent development of adult disease. The susceptibility for disease in response to an adverse intrauterine environment differs distinctly between boys and girls, with girls typically having better outcomes. Here, we tested the hypothesis that regulation of the placental transcriptome by maternal nutrient reduction (NR) is dependent on fetal sex. We used a nonhuman primate model of NR in which maternal global food intake was reduced by 30% in baboons starting at gestational day (GD) 30. At GD 165 (term = GD 183), placental genome expression profiling of 6 control (n = 3 females, 3 males) and 6 nutrient restricted (n = 3 females, 3 males) fetuses was carried out followed by bioinformatic analysis. Surprisingly, there was no coordinated placental molecular response to decreased nutrient availability when analyzing the data without accounting for fetal sex. In contrast, female placentas exhibited a highly coordinated response that included upregulation of genes in networks, pathways, and functional groups related to programmed cell death and downregulation of genes in networks, pathways, and functional groups associated with cell proliferation. These changes were not apparent in the male placentas. Our data support the concept that female placentas initiate complex adaptive responses to an adverse intrauterine environment, which may contribute to increased survival and better pregnancy outcomes in girls. PMID- 24047702 TI - Whey protein processing influences formula-induced gut maturation in preterm pigs. AB - Immaturity of the gut predisposes preterm infants to nutritional challenges potentially leading to clinical complications such as necrotizing enterocolitis. Feeding milk formulas is associated with greater risk than fresh colostrum or milk, probably due to loss of bioactive proteins (e.g., immunoglobulins, lactoferrin, insulin-like growth factor, transforming growth factor-beta) during industrial processing (e.g., pasteurization, filtration, spray-drying). We hypothesized that the processing method for whey protein concentrate (WPC) would affect gut maturation in formula-fed preterm pigs used as a model for preterm infants. Fifty-five caesarean-delivered preterm pigs were distributed into 4 groups given 1 of 4 isoenergetic diets: formula containing conventional WPC (filtration, multi-pasteurization, standard spray-drying) (CF); formula containing gently treated WPC (reduced filtration and pasteurization, gentle spray-drying) (GF); formula containing minimally treated WPC (rennet precipitation, reduced filtration, heat treatment <40 degrees C, freeze-drying) (MF); and bovine colostrum (used as a positive reference group) (BC). Relative to CF, GF, and MF pigs, BC pigs had greater villus heights, lactose digestion, and absorption and lower gut permeability (P < 0.05). MF and BC pigs had greater plasma citrulline concentrations than CF and GF pigs and intestinal interleukin-8 was lower in BC pigs than in the other groups (P < 0.05). MF pigs had lower concentrations of intestinal claudin-4, cleaved caspase-3, and phosphorylated c Jun than CF pigs (P < 0.05). The conventional and gently treated WPCs had similar efficacy in stimulating proliferation of porcine intestinal epithelial cells. We conclude that processing of WPC affects intestinal structure, function, and integrity when included in formulas for preterm pigs. Optimization of WPC processing technology may be important to preserve the bioactivity and nutritional value of formulas for sensitive newborns. PMID- 24047703 TI - Higher fecal bile acid hydrophobicity is associated with exacerbation of dextran sodium sulfate colitis in mice. AB - Increased luminal bile acid hydrophobicity is associated with cytotoxicity and has been suggested to contribute to gut barrier dysfunction. The aim of this study was to compare 2 high-fat diets and a low-fat diet as to whether they modify fecal bile acid profile and hydrophobicity and/or susceptibility to dextran sodium sulfate (DSS) colitis in C57Bl/6J mice. Control and DSS-Control groups received a low-fat control diet [5.5% of total energy (E%) soy oil, 4.5 E% lard], and the DSS-Lard (5.5 E% soy oil, 54.5 E% lard) and DSS-Fish oil (5.5 E% soy oil, 27.2 E% lard and 27.2% menhaden oil) groups received high-fat diets. Feces for bile acid analysis were collected after 3-wk feeding, followed by induction of dextran DSS colitis (2 d 5% DSS in drinking water + 2 d tap water). Fecal bile acid hydrophobicity was elevated 76% in the lard group (P = 0.051) and 122% in the fish oil group (P = 0.001) compared with control, indicating potentially increased cytotoxicity. DSS caused severe colitis symptoms, evaluated as rectal bleeding, whereas all the controls were symptom free. The median symptom scores were: DSS-Control, 2.3 (IQR = 0.6, 3.0); DSS-Lard, 0.3 (IQR = 0, 2.3); and DSS-Fish oil, 2.4 (IQR = 1.9, 2.8). The only differences were DSS Control vs. control (P < 0.001) and DSS-Fish oil vs. control (P < 0.001). Severity of symptoms in all colitic mice was positively correlated with fecal bile acid hydrophobicity (Spearman's rho = 0.43; P = 0.028) and fecal deoxycholic acid concentration (Spearman's rho = 0.39; P = 0.048). These results suggest that luminal bile acid modification, induced by altered dietary fat composition, may alter susceptibility to DSS colitis. PMID- 24047704 TI - Bile acids induce glucagon-like peptide 2 secretion with limited effects on intestinal adaptation in early weaned pigs. AB - Early weaning is a stressful event characterized by a transient period of intestinal atrophy that may be mediated by reduced secretion of glucagon-like peptide (GLP) 2. We tested whether enterally fed bile acids or plant sterols could increase nutrient-dependent GLP-2 secretion and improve intestinal adaptation in weanling pigs. During the first 6 d after weaning, piglets were intragastrically infused once daily with either deionized water (control), chenodeoxycholic acid (CDC; 60 mg/kg body weight), or beta-sitoesterol (BSE; 100 mg/kg body weight). Infusing CDC increased plasma GLP-2 (P < 0.05) but did not affect plasma GLP-1 and feed intake. The intestinal expression of glucagon-like peptide 2 receptor, sodium-dependent bile acid transporter, farnesoid X receptor, and guanosine protein-coupled bile acid receptor genes were not affected by CDC treatment. The intragastric administration of CDC did not alter the weight and length of the intestine, yet increased the activation of caspase-3 in ileal villi (P < 0.02) and the expression of interleukin 6 (P < 0.002) in the jejunum. In contrast, infusing BSE did not affect any of the variables that were measured. Our results show that the enteral administration of the bile acid CDC potentiates the nutrient-induced secretion of endogenous GLP-2 in early-weaned pigs. Bile acid-enhanced release of GLP-2, however, did not result in improved intestinal growth, morphology, or inflammation during the postweaning degenerative phase. PMID- 24047705 TI - Interplay of electrical wavefronts as determinant of the response to cardiac resynchronization therapy in dyssynchronous canine hearts. AB - BACKGROUND: The relative contribution of electromechanical synchronization and ventricular filling to the optimal hemodynamic effect in cardiac resynchronization therapy (CRT) during adjustment of stimulation-timings is incompletely understood. We investigated whether optimal hemodynamic effect in CRT requires collision of pacing-induced and intrinsic activation waves and optimal filling of the left ventricle (LV). METHODS AND RESULTS: CRT was performed in dogs with chronic left bundle-branch block (n=8) or atrioventricular (AV) block (n=6) through atrial (A), right ventricular (RV) apex, and LV basolateral pacing. A 100 randomized combinations of A-LV/A-RV intervals were tested. Total activation time (TAT) was calculated from >100 contact mapping electrodes. Mechanical interventricular dyssynchrony was determined as the time delay between upslopes of LV and RV pressure curves. Settings providing an increase in LVdP/dtmax (maximal rate of rise of left ventricular pressure) of >=90% of the maximum LVdP/dtmax value were defined as optimal (CRTopt). Filling was assessed by changes in LV end-diastolic volume (EDV; conductance catheter technique). In all hearts, CRTopt was observed during multiple settings, providing an average LVdP/dtmax increase of ~15%. In AV-block hearts, CRTopt exclusively depended on interventricular-interval and not on AV-interval. In left bundle-branch block hearts, CRTopt occurred at A-LV intervals that allowed fusion of LV-pacing-derived activation with right bundle-derived activation. In all animals, CRTopt occurred at settings resulting in the largest decrease in TAT and mechanical interventricular dyssynchrony, whereas LV EDV hardly changed. CONCLUSIONS: In left bundle-branch block and AV-block hearts, optimal hemodynamic effect of CRT depends on optimal interplay between pacing-induced and intrinsic activation waves and the corresponding mechanical resynchronization rather than filling. PMID- 24047706 TI - Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2), and the risk of thromboembolic events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. AB - BACKGROUND: There are limited data on the predictive value of stroke risk scores for thromboembolic events (TEs) after catheter ablation of atrial fibrillation (AF). Our objectives were to report the incidence of TEs after AF ablation in a large contemporary AF ablation cohort and to investigate the impact of renal dysfunction and the value of stroke risk stratification scores (CHADS2, CHA2DS2 VASc, and R2CHADS2) for predicting TE after AF ablation. METHODS AND RESULTS: Using the Leipzig Heart Center AF Ablation Registry, we documented TEs in patients undergoing radiofrequency AF catheter ablation. TE was defined as stroke, transient ischemic attack, or systemic embolism. Study population (N=2069; 66% men; 60+/-10 years; 62% paroxysmal AF; mean CHADS2, 1.2+/-0.9; CHA2DS2-VASc, 2.1+/-1.4; and R2CHADS2, 1.3+/-1.1) were followed up for a median 18 (Q1-Q3, 12-29) months (ie, 3078 patient-years). Overall, 31 TEs occurred, with 16 events within 30 days of ablation and 15 TEs (0.72%) during the follow-up period. On multivariate analysis, CHADS2 (P<0.001), R2CHADS2 (P<0.001), and CHA2DS2-VASc (P=0.003) scores were independent predictors of TEs during follow up, and AF recurrence conferred a nonsignificant trend for increased TE risk (P=0.071-0.094). The CHA2DS2-VASc score further differentiated TE risk in patients with CHADS2 and R2CHADS2 0 to 1 (0.13% if CHA2DS2-VASc was 0-1 and 0.71% if CHA2DS2-VASc was >2) and had the best predictive value in patients with AF recurrences (c-index 0.894, P=0.022 versus CHADS2, P=0.031 versus R2CHADS2). CONCLUSIONS: CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were associated with TE risk. The CHA2DS2-VASc score differentiated TE risk in the low-risk strata based on CHADS2 and R2CHADS2 scores and may be superior in the subgroup with AF recurrences. PMID- 24047707 TI - Neonatal right ventricle to pulmonary connection as a palliative procedure for pulmonary atresia with ventricular septal defect or severe tetralogy of Fallot. AB - OBJECTIVES: Right ventricle to pulmonary artery connection (RVPA connection) without prosthetic material has been our ideal strategy to palliate pulmonary atresia with ventricular septal defect (VSD) or severe tetralogy of Fallot for the last decade. We speculate that RVPA connection ensures adequate postoperative haemodynamics for symptomatic neonates and promotes pulmonary artery rehabilitation. The present study was undertaken to assess the outcome of this strategy. METHODS: Between 2000 and 2010, among 107 patients who benefited from an RVPA connection, 57 were neonates. Forty-eight of these underwent autologous tissue reconstruction, 5 using left atrial appendage. Median weight was 2.9 kg (range 1.8-4.4). Median Nakata index was 100 mm2/m2 (range 17-185 mm2/m2); 12% had major aortopulmonary collaterals. All patients were reviewed retrospectively. End-points were death or complete repair; reintervention for restrictive pulmonary blood flow was considered as failure. At follow-up, we evaluated reintervention after complete repair, and quality of life. RESULTS: There were 2 early deaths (RV hypoplasia and RV failure) and 3 late sudden deaths (range 3-6 months). Pulmonary blood flow required to be increased in 8 patients: 4 underwent shunt after a median delay of 1 month; RVPA connection enlargement was needed in 3; 1 patient had percutaneous angioplasty. Finally, 47 patients (81%) had a complete repair, of which 70% were performed without prosthetic material at a median age of 7 months (range 2-53), with a median Nakata index of 221 mm2/m2 (range 102-891). One patient died early and 1 was a failure with opening of the VSD after intracardiac repair. At last follow-up, 4 patients were still awaiting repair, with 1 late death and 5 who had required reintervention after intracardiac repair; there were 3 conduit replacements and 2 balloon dilatation patch enlargements. CONCLUSIONS: The neonatal RVPA connection approach (i) provides an acceptable survival rate with a satisfactory haemodynamic adaptation, (ii) facilitates rehabilitation of PAs and (iii) avoids the use of prosthetic graft at correction. PMID- 24047708 TI - A piece of cake. PMID- 24047709 TI - Reply to Garcia franco et al. PMID- 24047710 TI - Bronchogenic carcinoid tumours that are 18F-fluorodeoxyglucose avid on positron emission tomography. AB - OBJECTIVES: Bronchogenic carcinoid tumours are widely cited as non fluorodeoxyglucose (FDG) avid. However, three case reports of FDG-avid bronchogenic carcinoid tumours have been published, leading to speculation as to which clinicopathological factors may be associated with increased activity on FDG-positron emission tomography. We reviewed a series of cases from our institution and compared them with the available reports in the literature, to attempt to identify the factors associated with FDG avidity in bronchogenic carcinoids. METHODS: We performed a single-institution retrospective review. RESULTS: One patient was identified at our institution who had a typical carcinoid tumour with a standardized uptake value (SUV) of 26, oncocytic features on histology and positive staining for glucose transporter 1 (GLUT1). Three additional patients were identified in the literature with typical bronchogenic carcinoids with SUVs of 39, 38 and 33. Two of these tumours stained positive for GLUT1, and the remaining patient was not tested. Two of these patients had oncocytic features on histology, and results on the remaining patient are not reported. Additionally, 4 patients at our institution were identified with bronchogenic carcinoids with average SUV of 2.6. All were GLUT1 negative, and none had oncocytic features. In the reported literature, excluding the four most FDG-avid tumours described above, atypical carcinoids had a higher mean SUV than typical carcinoids (5.7 vs 3.4, P = 0.02), but size was not correlated with SUV (r = 0.7, P = 0.3). CONCLUSIONS: FDG uptake is commonly associated with worse prognosis in malignancy; however, bronchogenic carcinoids, particularly oncocytic typical carcinoids, are a possible source of extremely high SUVs on FDG-PET. PMID- 24047711 TI - Reduced amount of gaseous microemboli in the arterial line of minimized extracorporeal circulation systems compared with conventional extracorporeal circulation. PMID- 24047712 TI - The FREEDOM trial: a definitive answer to coronary artery bypass grafting or stents in patients with diabetes and multivessel coronary artery disease. PMID- 24047713 TI - This is My Story: participatory performance for HIV and AIDS education at the University of Malawi. AB - University students represent a subset of young men and women at risk for HIV in high prevalence settings. Innovative programs are needed to raise awareness on the unique issues around HIV and AIDS in the university campus, while training student leaders for peer-based education. The Process and Collaboration for Empowerment and Discussion (PACED) method engages artists and people living with HIV and AIDS (PLWHA) to create a performance that encourages community dialog about HIV and AIDS and empowers PLWHA. 'This is My Story' was a program at the University of Malawi, Chancellor College, which adapted the PACED approach for university students. A qualitative evaluation conducted 1 year later among students and PLWHA participants and audience members demonstrated retention of the following themes: (i) trust in a relationship and how it affects women,(ii) equality for PLWHA and (iii) life after HIV and AIDS. All of the PLWHA and 90.9% of student participants reported a greater sense of empowerment. Of the audience members, 82.1% discussed the performance with friends and family. We thus present the PACED approach as a valuable tool in HIV and AIDS education and prevention among university students in Malawi. PMID- 24047714 TI - Do specialized flowers promote reproductive isolation? Realized pollination accuracy of three sympatric Pedicularis species. AB - BACKGROUND AND AIMS: Interest in pollinator-mediated evolutionary divergence of flower phenotype and speciation in plants has been at the core of plant evolutionary studies since Darwin. Specialized pollination is predicted to lead to reproductive isolation and promote speciation among sympatric species by promoting partitioning of (1) the species of pollinators used, (2) when pollinators are used, or (3) the sites of pollen placement. Here this last mechanism is investigated by observing the pollination accuracy of sympatric Pedicularis species (Orobanchacae). METHODS: Pollinator behaviour was observed on three species of Pedicularis (P. densispica, P. tricolor and P. dichotoma) in the Hengduan Mountains, south-west China. Using fluorescent powder and dyed pollen, the accuracy was assessed of stigma contact with, and pollen deposition on, pollinating bumble-bees, respectively. KEY RESULTS: All three species of Pedicularis were pollinated by bumble-bees. It was found that the adaptive accuracy of female function was much higher than that of male function in all three flower species. Although peak pollen deposition corresponded to the optimal location on the pollinator (i.e. the site of stigma contact) for each species, substantial amounts of pollen were scattered over much of the bees' bodies. CONCLUSIONS: The Pedicularis species studied in the eastern Himalayan region did not conform with Grant's 'Pedicularis Model' of mechanical reproductive isolation. The specialized flowers of this diverse group of plants seem unlikely to have increased the potential for reproductive isolation or influenced rates of speciation. It is suggested instead that the extreme species richness of the Pedicularis clade was generated in other ways and that specialized flowers and substantial pollination accuracy evolved as a response to selection generated by the diversity of co-occurring congeners. PMID- 24047715 TI - Stabilization of yield in plant genotype mixtures through compensation rather than complementation. AB - BACKGROUND AND AIMS: Plant genotypic mixtures have the potential to increase yield stability in variable, often unpredictable environments, yet knowledge of the specific mechanisms underlying enhanced yield stability remains limited. Field studies are constrained by environmental conditions which cannot be fully controlled and thus reproduced. A suitable model system would allow reproducible experiments on processes operating within crop genetic mixtures. METHODS: Phenotypically dissimilar genotypes of Arabidopsis thaliana were grown in monocultures and mixtures under high levels of competition for abiotic resources. Seed production, flowering time and rosette size were recorded. KEY RESULTS: Mixtures achieved high yield stability across environments through compensatory interactions. Compensation was greatest when plants were under high levels of heat and nutrient stress. Competitive ability and mixture performance were predictable from above-ground phenotypic traits even though below-ground competition appeared to be more intense. CONCLUSIONS: This study indicates that the mixing ability of plant genotypes can be predicted from their phenotypes expressed in a range of relevant environments, and implies that a phenotypic screen of genotypes could improve the selection of suitable components of genotypic mixtures in agriculture intended to be resilient to environmental stress. PMID- 24047717 TI - Evaluation of the placenta with relative apparent diffusion coefficient and T2 signal intensity analysis. AB - PURPOSE: We aimed to test the null hypothesis that relative apparent diffusion coefficient (rADC) and relative signal intensity values (rSI(HASTE)) do not change in the evaluation of placental maturation with advancing gestational age. MATERIALS AND METHODS: Fifty-six fetuses with diffusion-weighted magnetic resonance imaging (DW-MRI) data were enrolled in this retrospective study. Fetuses were analyzed in three different gestational age groups: group 1, 18-23 weeks; group 2, 24-28 weeks; and group 3, 29-38 weeks. The rADC (mean ADC/ADC(globe)) and rSI(HASTE) values (mean SI(HASTE)/SI(globe)) were obtained. Two radiologists experienced in fetal MRI who were blinded to the patient information reviewed MRI images independently. Kruskal-Wallis Test was used to compare the rADC and rSI(HASTE) with gestational age groups. The agreement between the two blinded readers was tested using Krippendorff's alpha ratio. RESULTS: Both placental rADC values and placental rSI(HASTE) values were not significantly different between the gestational age groups (P = 0.688 and P = 0.280, respectively). rADC and rSI(HASTE) measurements were reproducible with a good agreement between the two readers (Krippendorff's alpha ratio was 0.613 and 0.778, respectively). CONCLUSION: The rADC and rSI(HASTE) values do not change with advancing gestational age. PMID- 24047716 TI - NnSR1, a class III non-S-RNase constitutively expressed in styles, is induced in roots and stems under phosphate deficiency in Nicotiana alata. AB - BACKGROUND AND AIMS: Non-S-ribonucleases (non-S-RNases) are class III T2 RNases constitutively expressed in styles of species with S-RNase-based self incompatibility. So far, no function has been attributed to these RNases. The aim of this work is to examine if NnSR1, a non-S-RNase from Nicotiana alata, is induced under conditions of phosphate (Pi) deprivation. The hypothesis is that under Pi-limited conditions, non-S-RNase functions may resemble the role of S like RNases. To date, the only RNases reported to be induced by Pi deficiency are class I and class II S-like RNases, which are phylogenetically different from the class III clade of RNases. METHODS: Gene and protein expression of NnSR1 were assayed in plants grown hydroponically with and without Pi, by combining RT-PCR, immunoblot and enzymatic activity approaches. KEY RESULTS: NnSR1 transcripts were detected in roots 7 d after Pi deprivation and remained stable for several days. Transcript expression was correlated based on Pi availability in the culture medium. Antiserum against a peptide based on a hypervariable domain of NnSR1 recognized NnSR1 in roots and stems but not leaves exposed to Pi shortage. NnSR1 was not detected in culture medium and was pelleted with the microsomal fraction, suggesting that it was membrane-associated or included in large compartments. The anti-NnSR1 inhibited selectively the enzymatic activity of a 31-kDa RNase indicating that NnSR1 was induced in an enzymatically active form. CONCLUSIONS: The induction of NnSR1 indicates that there is a general recruitment of all classes of T2 RNases in response to Pi shortage. NnSR1 appears to have regained ancestral functions of class III RNases related to strategies to cope with Pi limitation and also possibly with other environmental challenges. This constitutes the first report for a specific function of class III RNases other than S-RNases. PMID- 24047719 TI - Applications of the Amplatzer Vascular Plug to various vascular lesions. AB - The Amplatzer(r) Vascular Plug (AVP) can be used to embolize medium-to-large high flow vessels in various locations. Between 2009 and 2012, 41 AVPs (device size, 6 22 mm in diameter) were used to achieve occlusion in 31 patients (24 males, seven females) aged 9-92 years (mean age, 54.5 years). The locations and indications for embolotherapy were as follows: internal iliac artery embolization before stent-graft repair for aorto-iliac (n=6) and common iliac artery (n=3) aneurysms, subclavian artery embolization before stent-graft repair for thoracic aorta (n=3) and arcus aorta (n=1) aneurysms, brachiocephalic trunk embolization before stent graft repair for a thoracic aorta aneurysm (n=1), embolization of aneurysms and pseudoaneurysms (n=5), embolization for carotid blow-out syndrome (n=3), closure of arteriovenous fistula (n=8), and closure of a portosystemic fistula (n=1). Of the 41 AVPs, 30 were AVP 2 and 11 were AVP 4. The mean follow-up duration was 4.7 months (range, 1-24 months). During follow-up, there was one migration, one insufficient embolization, and one recanalization. The remaining vascular lesions were successfully excluded from the circulation. The AVP, which can be used in a wide spectrum of pathologies, is easy to use and causes few complications. This essay presents our experience with the AVP. PMID- 24047718 TI - Measurement of liver fat fraction and iron with MRI and MR spectroscopy techniques. AB - Diffuse liver disease is a widespread global healthcare burden, and the abnormal accumulation of lipid and/or iron is common to important disease processes. Developing the improved methods for detecting and quantifying liver lipid and iron is an important clinical need. The inherent risk, invasiveness, and sampling error of liver biopsy have prompted the development of noninvasive imaging methods for lipid and iron assessment. Ultrasonography and computed tomography have the ability to detect diffuse liver disease, but with limited accuracy. The purpose of this review is to describe the current state-of-the-art methods for quantifying liver lipid and iron using magnetic resonance imaging and spectroscopy, including their implementation, benefits, and potential pitfalls. Imaging- and spectroscopy-based methods are naturally suited for lipid and iron quantification. Lipid can be detected and decomposed from the inherent chemical shift between lipid and water signals, whereas iron imparts significant paramagnetic susceptibility to tissue, which accelerates proton relaxation. However, measurements of these biomarkers are confounded by technical and biological effects. Current methods must address these factors to allow a precise correlation between the lipid fraction and iron concentration. Although this correlation becomes increasingly challenging in the presence of combined lipid and iron accumulation, advanced techniques show promise for delineating these quantities through multi-lipid peak analysis, T2 water mapping, and fast single voxel water-lipid spectroscopy. PMID- 24047720 TI - Adrenal venous sampling for stratifying patients for surgery of adrenal nodules detected using dynamic contrast enhanced CT. AB - PURPOSE: We aimed to assess the value of adrenal venous sampling (AVS) for diagnosing primary aldosteronism (PA) subtypes in patients with a unilateral nodule detected on adrenal computed tomography (CT) and scheduled for adrenalectomy. MATERIALS AND METHODS: This retrospective study included 80 consecutive patients with PA undergoing CT and AVS. Different lateralization indices were assessed, and a cutoff established using receiver operating characteristic curve analysis. The value of CT alone versus CT with AVS for differentiating PA subtypes was compared. The adrenalectomy outcome was assessed, and predictors of cure were determined using univariate analysis. RESULTS: AVS was successful in 68 patients. A cortisol-corrected aldosterone affected-to unaffected ratio cutoff of 2.0 and affected-to-inferior vena cava ratio cutoff of 1.4 were the best lateralization indices, with accuracies of 82.5% and 80.4%, respectively. CT and AVS diagnosed 38 patients with aldosterone-producing adenomas, five patients with unilateral adrenal hyperplasia, and 25 patients with bilateral adrenal hyperplasia. Of the 52 patients with a nodule detected on CT, subsequent AVS diagnosed bilateral adrenal hyperplasia in 14 patients (27%). Compared to the results of combining CT with AVS, the accuracy of CT alone for diagnosing aldosterone-producing adenomas was 71.1% (P < 0.001). The cure rate for hypertension after adrenalectomy was 39.2%, with improvement in 53.5% of patients. On univariate analysis, predictors of persistent hypertension were male gender and preoperative systolic blood pressure. CONCLUSION: To avoid inappropriate surgery, AVS is necessary for diagnosing unilateral nodules with aldosterone hypersecretion detected by CT. PMID- 24047721 TI - Sequential morphological changes in follow-up CT of pulmonary mucormycosis. AB - PURPOSE: We aimed to describe the computed tomography (CT) features of pulmonary mucormycosis including sequential changes between follow-ups. MATERIALS AND METHODS: Between June 2001 and May 2011, five patients (three males and two females; median age, 43 years; age range, 13-73 years) who had been pathologically diagnosed with pulmonary mucormycosis constituted our study population. Their clinical and CT features including sequential changes over follow-ups were evaluated retrospectively. RESULTS: All patients were immunocompromised due to either hematologic diseases (n=3), diabetes mellitus (n=1), or steroid administration for autoimmune hepatitis (n=1). All patients had symptoms such as fever (n=5), tachycardia (n=1), or pleuritic chest pain (n=1) on admission. Regarding the clinical outcome after treatment, one patient died, and the remaining four recovered from the disease. In terms of initial CT features, the morphologies of pulmonary mucormycosis included a single mass (n=3), consolidation (n=1), or multiple masses (n=1). There were seven pulmonary lesions in total, 3-7 cm in size, which showed a CT halo sign (n=3), reversed-halo sign (n=2), or air-fluid levels (n=2). On follow-up CTs, the lesions of all patients contained necrosis. All three patients with a mass or masses with a CT halo sign on initial CT had a decreased surrounding halo followed by central necrosis, and the lesions gradually decreased in size on recovery. CONCLUSION: Pulmonary mucormycosis usually manifests as a mass or masses with a halo or reversed-halo sign on the initial CT scan followed by a decreased extent of surrounding ground glass opacities with the development of internal necrosis during follow-up. PMID- 24047722 TI - MRI in the evaluation of breast cancer patient response to neoadjuvant chemotherapy: predictive factors for breast conservative surgery. AB - PURPOSE: We aimed to prospectively assess the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the evaluation of predictive factors for breast conservative surgery during neoadjuvant chemotherapy. MATERIALS AND METHODS: Sixty-six patients were evaluated before the first treatment cycle, after the second cycle, and upon the completion of neoadjuvant chemotherapy according to largest tumor diameter, tumor volume, postcontrast enhancement, and tumor regression pattern. The patients were divided into responders (pathologic complete and near complete response) and nonresponders. Each subgroup was re evaluated according to morphokinetic criteria for identification of candidates for breast conservative surgery. RESULTS: In responders (n=27), the lesion size upon the completion of neoadjuvant chemotherapy was significantly smaller compared to nonresponders (1.5 +/- 0.6 vs. 3.2 +/- 0.9 cm; P < 0.001), as was the volume (1.2 vs. 11.0 cm(3); P < 0.001). The measured lesion size did not differ from the histologic size (1.5 +/- 0.6 vs. 1.2 +/- 0.6 cm; P = 0.09) and had a high correlation (r=0.93). In responders, the following parameters were significantly different before and after neoadjuvant chemotherapy: size (3.6 +/- 1.4 to 1.5 +/- 0.6 cm; P < 0.001), volume (17.6 to 1.2 cm(3); P < 0.001), predominant concentric regression, plateau and continuous time-intensity curves (P < 0.001). DCE-MRI has the sensitivity of 87% and the accuracy of 77% to identify candidates for breast conservative surgery. CONCLUSION: Selected morphokinetic DCE-MRI parameters may contribute to the multidisciplinary decision when considering the selection of candidates for breast conservative surgery. PMID- 24047723 TI - Why should we report posterior fossa emissary veins? AB - Posterior fossa emissary veins are valveless veins that pass through cranial apertures. They participate in extracranial venous drainage of the posterior fossa dural sinuses. The mastoid emissary vein, condylar veins, occipital emissary vein, and petrosquamosal sinus are the major posterior fossa emissary veins. We believe that posterior fossa emissary veins can be detected by radiologists before surgery with a thorough understanding of their anatomy. Describing them using temporal bone computed tomography (CT), CT angiography, and cerebral magnetic resonance (MR) venography examinations results in more detailed and accurate preoperative radiological interpretation and has clinical importance. This pictorial essay reviews the anatomy of the major and clinically relevant posterior fossa emissary veins using high-resolution CT, CT angiography, and MR venography images and discusses the clinical importance of reporting these vascular variants. PMID- 24047724 TI - Systemic karyomegaly with primary pulmonary presentation. AB - Systemic karyomegaly is a distinct disorder characterized by progressive renal failure and enlarged, bizarre renal tubular epithelial cells. We report the first case of systemic karyomegaly with primary pulmonary presentation and present the first detailed characterization of the karyomegalic cells in lung tissue. A 33 year-old woman was evaluated for chronic and progressive restrictive lung disease, ultimately necessitating single-lung transplantation. Her post transplant course was marked by graft dysfunction, respiratory decline and renal failure culminating in her death 97 days post-transplant. At autopsy, karyomegalic cells were identified in her kidneys, prompting a careful examination of her native lung and other tissue. Karyomegalic cells were identified in the alveolar epithelium and airway walls. Viral studies were negative. DNA ploidy studies revealed an abnormal ploidy status of the karyomegalic cells. The identification and characterization of systemic karyomegaly with symptomatic lung involvement expands the differential diagnosis for relatively young patients presenting with interstitial lung disease. PMID- 24047725 TI - Universal scheme to generate metal-insulator transition in disordered systems. AB - We propose a scheme to generate metal-insulator transition in the random binary layer (RBL) model, which is constructed by randomly assigning two types of layers along the longitudinal direction. Based on a tight-binding Hamiltonian, the localization length is calculated for a variety of RBLs with different cross section geometries by using the transfer-matrix method. Both analytical and numerical results show that a band of extended states could appear in the quasi one-dimensional RBLs and the systems behave as metals by properly tuning the model parameters, due to the existence of a completely ordered subband, leading to a metal-insulator transition in parameter space. Furthermore, the extended states are irrespective of the diagonal and off-diagonal disorder strengths. Our results can be generalized to two- and three-dimensional disordered systems with arbitrary layer structures, and may be realized in Bose-Einstein condensates. PMID- 24047726 TI - Pretreatment of spent mushroom substrate for enhancing the conversion of fermentable sugar. AB - To develop a cost-effective biopesticide, spent mushroom substrate (SMS) extract was studied as a potential carbon source for cultivating Bacillus thuringiensis (Bt). Several pretreatments were compared to determine the optimal method for degrading cellulose to produce reducing sugars, including dilute sulfuric acid (0.5-2.0% v/v, 50-121 degrees C, 1h), sodium hydroxide (0.5-2% w/v, 50-121 degrees C, 1h), calcium hydroxide (0.2-4% w/v, 50-121 degrees C, 1h), and hot water (50-121 degrees C, 1h). Pretreatment was followed by standard enzymatic hydrolysis and fermentation. Results showed that the highest cellulose degradation was obtained using 2% dilute sulfuric acid pretreatment at 121 degrees C for 1h, resulting in a high yield of reducing sugar (284.24 g/kg SMS). Sporulation was also highest using the same pretreatment. Use of SMS is not only an alternative way to commercialize Bt-based biopesticide, but also a potential solution for the environmental pollution associated with accumulation of the spent substrate of the mushroom industry. PMID- 24047727 TI - Long-term absolute and relative survival after aortic valve replacement: a prospective cohort study. AB - BACKGROUND: Aortic valve replacement is one of the most common cardiac surgical procedures, especially in elderly patients. Whether or not there is a net life gain over a long period of time is a matter for debate. OBJECTIVE: To compare survival of patients with that of the age, sex, and follow-up year-matched normal population (relative survival). DESIGN: Single-centre, prospectively collected data. SETTING: Tertiary care centre, Vienna, Austria. PATIENTS: We enrolled 1848 patients undergoing elective aortic valve replacement between 1997 and the end of 2008. INTERVENTIONS: None. MAIN OUTCOME MEASUREMENT: Relative survival at the end of 2011 as determined by relative Cox regression analysis. RESULTS: Sixty-nine patients (3.7%) died within the first 30 days. Another 70 patients (3.8%) died within the first year and 429 (23.2%) died during the remaining follow-up period. The longest follow-up period was 14 years (median, 5.8; interquartile range, 3.2 to 8.9). Medical risk indicators for relative survival were diabetes mellitus [hazard ratio 1.69, 95% confidence interval, CI 1.37 to 2.07, P<0.001], pulmonary disease (hazard ratio 1.45, 95% CI 1.16 to 1.81, P=0.001), history of atrial fibrillation (hazard ratio 1.35, 95% CI 1.10 to 1.66, P=.005) and angiotensin converting enzyme inhibitor medication (hazard ratio 1.21, 95% CI 1.02 to 1.44, P=0.031). Perioperative risk indicators were urgent surgery (hazard ratio 1.40, 95% CI 1.00 to 1.94, P=0.047), resternotomy at 48 h or less (hazard ratio 1.87, 95% CI 1.29 to 2.70, P=0.001), resternotomy at more than 48 h (hazard ratio 1.80, 95% CI 1.32 to 2.45, P<0.001), blood transfusion (hazard ratio 1.06, 95% CI 1.01 to 1.12, P=0.018) and renal replacement therapy (hazard ratio 2.02, 95% CI 1.41 to 2.90, P<0.001). Relative survival was highest in the oldest age quartile (76 to 94 years) and lowest in the youngest (19 to 58 years) (hazard ratio 0.27, 95% CI 0.21 to 0.36; P<0.001). CONCLUSION: Patients who survived the first year after aortic valve replacement had a similar chance of survival as the matched normal population. Relative survival benefit was higher in the oldest age quartile. PMID- 24047728 TI - Doppler sonography as a potential screening tool for preanaesthetic evaluation. PMID- 24047729 TI - Clonal distribution and virulence of Campylobacter jejuni isolates in blood. AB - Campylobacter jejuni bacteria are highly diverse enteropathogens. Seventy-three C. jejuni isolates from blood collected in Finland were analyzed by multilocus sequence typing and serum resistance. Approximately half of the isolates belonged to the otherwise uncommon sequence type 677 clonal complex. Isolates of this clonal complex were more resistant than other isolates to human serum. PMID- 24047730 TI - Physico chemical properties of L-asparagine L-tartaric acid single crystals: a new nonlinear optical material. AB - L-asparagine L-tartaric acid single crystals of size 14 mm*12 mm*5 mm were grown. The morphology was recorded during its live growth process using inverted microscope. Structural confirmation of grown crystals was done by powder X-ray diffraction. The grown crystals are optically transparent. The Highest occupied molecular orbital and lowest unoccupied molecular orbital energy gap was obtained using the RHF/6-31G(d,p) and B3LYP/6-31G(d,p) level of theoretical calculations. The dipole moment calculated by RHF is 5.1716 D and by B3LYP is 2.8302 D. The calculated gas phase polarizability is 16.63791A(3). PMID- 24047731 TI - Outbreak of febrile respiratory illness caused by adenovirus at a South Korean military training facility: clinical and radiological characteristics of adenovirus pneumonia. AB - Adenovirus often causes respiratory disease outbreaks in military training soldiers. Compared with adenovirus pneumonia in young military adults, symptoms arising from febrile respiratory illness (FRI) caused by adenovirus have not been previously evaluated in Korean soldiers. We conducted an event-based outbreak investigation involving 712 male soldiers aged 19 to 21 years from March 14 to 30, 2012 to evaluate the epidemiological and clinical characteristics of patients with pneumonia and FRI caused by adenovirus. We described the laboratory and radiological characteristics of patients with adenovirus pneumonia. Among these, 407 cases of FRI and 15 cases of pneumonia were identified through active surveillance (attack rate of FRI, 57.16%; attack rate of pneumonia, 2.11%). Fire training and march training may present environmental risk factors for adenovirus associated outbreaks. Most symptoms were mild. The most frequent symptom in patients with pneumonia and FRI was cough. Patients with pneumonia were associated with an increased incidence of dizziness (crude odds ratio [cOR], 9.65; 95% confidence interval [CI], 2.38-37.15) and a decreased incidence of rhinorrhea (cOR, 0.15; 95% CI, 0.04-0.53) during adenovirus-associated outbreaks. Differential leukocyte count revealed high monocytes, low lymphocytes, and low eosinophils, and chest computed tomography revealed a consolidation pattern and right lobar pneumonia. These findings warrant a high level of suspicion for adenovirus pneumonia. PMID- 24047732 TI - Correlation between complement component levels and disease severity in dengue patients in Indonesia. AB - Dengue hemorrhagic fever (DHF) is a severe form of dengue fever (DF). Recent in vitro studies indicate that complement reduces the infection-enhancing activity of dengue antibodies, suggesting its in vivo role in controlling viremia levels and disease severity. In this study, the complement hemolytic activity (CH50) and levels of complement components and related factors in dengue patients in Indonesia were assessed. Based on the number of days since fever onset, DF patients were compared with patients at the DHF pre-critical phase who showed deterioration within 2 days. The mean CH50 values and levels of C2, C4, and factors B and H in the DHF pre-critical phase group were significantly lower than those in the DF group. The mean CH50 values were significantly correlated with C4, factor B, or factor H levels, indicating their responsibility for reduced CH50 values. Furthermore, a significantly higher proportion of the DHF pre critical phase group (78%) than the DF group (33%) was positive for the nonstructural protein 1 (NS1) antigen. These results suggested that antibody dependent enhancement of infection occurs during a period of low complement activity, which is associated with NS1 levels during the acute phase in some patients, thereby leading to increased viremia levels and greater disease severity. PMID- 24047733 TI - Changing burden of HIV/AIDS to clinical settings in Northern Thailand over 15 years. AB - We conducted a hospital-based descriptive study to describe the changing pattern of patient numbers, characteristics, and mortality rates among human immunodeficiency virus (HIV)-infected patients in northern Thailand over 15 years. The survival status on October 31, 2010 of all HIV-infected adults who attended an HIV center in a government hospital between 1995 and 2010 was ascertained. In total, 3,706 patients were registered, 2,118 (57.2%) of which were male. The survival status of 3,439 patients (92.9%) was available. In addition, 1,543 deaths were identified out of 12,858 person-year-observations (PYO) resulting in a mortality rate of 12.4 deaths/100 PYO (95% confidence interval [CI], 11.3-13.0). An initial decline in mortality rates was observed prior to 1999, probably because of an increase in the proportion of less symptomatic patients. After the introduction of the national highly active antiretroviral therapy (HAART) program, a profound decline in mortality rates was observed, reaching 2.0 deaths/100 PYO (95% CI, 1.4-2.9) in 2010. Simultaneously, the number of patients on follow-up increased by nearly fourfold. Although HAART has drastically improved the survival of HIV-infected patients, the number of patients receiving therapy at this HIV clinic has substantially increased. While referral of HIV patients to general physicians' care should be urged, we cannot overemphasize the importance of preventing new HIV infections. PMID- 24047734 TI - Clostridium difficile Infection in lung cancer patients. AB - Clostridium difficile infection (CDI) is a common nosocomial infection. Lung cancer patients have a high risk of developing CDI because of continuous antibiotic treatment or chemotherapy, prolonged hospitalization, and general weakness. This study aimed to analyze predisposing or associated risk factors for CDI in lung cancer patients receiving chemotherapy. This study was a retrospective review of 188 lung cancer patients who were admitted to the Wonkwang University Hospital between 2008 and 2009. Of the 188 patients, 44 were diagnosed with CDI. The albumin levels were significantly lower and the performance status (PS) score was significantly higher in lung cancer patients with CDI than in those without CDI (P < 0.05). In conclusion, clinicians should consider the possibility of CDI occurrence in lung cancer patients receiving chemotherapy, particularly in those with low albumin levels and high PS scores, because most lung cancer patients have a high risk of developing CDI. PMID- 24047735 TI - Detection and identification of genotypes of Prototheca zopfii in clinical samples by quantitative PCR analysis. AB - In this study, a specific quantitative PCR system for the detection and identification of Prototheca zopfii genotypes was developed using a TaqMan((r)) MGB probe and ResoLight dye. The P. zopfii-specific primers 18PZF1 and 18PZR1 were generated on the basis of the alignment of the small subunit ribosomal DNA domain base sequences of the genera Chlorella and Prototheca obtained from DDBJ/EMBL/GenBank, and the TaqMan((r)) MGB probe PZP1 was designed corresponding to this amplification region. Analysis of the melting curves of the amplicons using ResoLight dye was able to differentiate between P. zopfii genotypes 1 and 2. The specificity of this detection system was examined using strains from a culture collection (28 strains) and clinical isolates (140 strains). The TaqMan((r)) MGB probe amplicon was detected only in reference strains of P. zopfii (n = 12) and clinical isolates (n = 135). Ninety-two clinical specimens from cows with mastitis (36 samples) and healthy controls (56 samples) were also tested. All isolates from milk samples (n = 92) and clinical isolates (n = 135) were identified as P. zopfii genotype 2. PMID- 24047736 TI - Potential role of mannose-binding lectin in intrauterine transmission of hepatitis B virus. AB - Intrauterine transmission of hepatitis B virus (HBV) is the main cause of the high prevalence of HBV in endemic areas; however, the mechanisms underlying intrauterine transmission of HBV remain unknown. To explore the role of mannose binding lectin (MBL), a pattern recognition molecule of the innate immune system, in intrauterine transmission of HBV, we determined MBL levels using an enzyme linked immunosorbent assay (ELISA) in cord serum of 7 intrauterine-infected neonates and 30 non-infected neonates born to HBV-positive mothers, and 30 control neonates born to HBV-negative mothers. We observed significant differences in cord serum MBL levels among the three groups (P < 0.001). Non infected neonates had significantly higher MBL levels than controls (P < 0.001), and intrauterine-infected neonates had significantly lower serum MBL levels than non-infected neonates (P < 0.001). However, serum MBL levels were not significantly different between intrauterine-infected neonates and controls (P = 0.800). Our results indicate that maternal HBV infection induces an increase in fetal MBL levels and the absence of this increase is possibly associated with intrauterine transmission of HBV, suggesting that MBL plays a role in intrauterine transmission of HBV. PMID- 24047737 TI - Determination of enterohemorrhagic Escherichia coli serotype O165:HNM infection in a hemolytic uremic syndrome patient with adenovirus seroype 41. AB - A 4-year-old girl who was positive for adenovirus according to a rapid immunochromatographic test conducted at a hospital, progressed to hemorrhagic diarrhea and hemolytic uremic syndrome (HUS). The presence of adenovirus serotype 41 (AdV-41) was confirmed by TaqMan real-time PCR and sequence analysis. However, most enteric viral infections cause mild to moderate diarrhea. In the present case, enterohemorrhagic Escherichia coli (EHEC) O165:HNM was isolated concomitantly with AdV-41. In addition, O165 antibody was specifically detected in patient sera. The EHEC isolate was positive for the virulence genes stx1, stx2a, eae type epsilon, ehxA, and norV. Therefore, we concluded that EHEC O165:HNM was the precise pathogen leading to HUS in this patient. PMID- 24047738 TI - Detection and characterization of enteric viruses in flood water from the 2011 thai flood. AB - Severe flooding, which is associated with numerous outbreaks of a wide range of infectious diseases, particularly those caused by enteric viruses, occurred in all areas of Thailand in 2011. To determine the prevalence of five human enteric viruses, namely enterovirus, rotavirus (RV), norovirus (NV), hepatitis A virus (HAV), and hepatitis E virus, in the flood water, 100 water samples were collected from flood-damaged areas in central Thailand. Viral RNA was extracted from concentrated samples and analyzed by RT-PCR and sequencing. NV was the most commonly detected pathogen in the tested samples (14%). RV and HAV were detected in 9% and 7% of samples, respectively. This study is the first to detect enteric viral genes in flood water in Thailand. Furthermore, it is the first to detect an NV gene in any type of environmental water in Thailand. These results provide useful information for estimating the risk of flood waterborne viral infection. PMID- 24047739 TI - Characterization of DNA polymerase-associated acyclovir-resistant herpes simplex virus type 1: mutations, sensitivity to antiviral compounds, neurovirulence, and in-vivo sensitivity to treatment. AB - Acyclovir (ACV)-resistant (ACV(r)) mutants were generated from plaque-purified ACV-sensitive herpes simplex virus type 1 (HSV-1) by culturing the virus in Vero cells in the presence of 2-amino-7-(1,3-dihydroxy-2-propoxymethyl) purine (S2242). Three DNA polymerase (DNApol)-associated ACV(r) HSV-1 generated under ACV selection in a previous study (Suzutani, T., Ishioka, K., De Clercq, E., et al., Antimicrob. Agents Chemother., 47, 1707-1713, 2003) were also included. The sensitivity of the mutants to other antivirals and their neurovirulence were determined. The treatment efficacy of ACV and ganciclovir (GCV) against ACV(r) HSV-1 infections was evaluated in mice. Amino acid substitutions were demonstrated in conserved regions II and III in DNApol in 5 of the 6 mutants, while the other substitution was located in non-conserved regions. DNApol associated ACV(r) clones showed cross-resistance to foscarnet, penciclovir, and vidarabine but were sensitive or hypersensitive to GCV, brivudin, sorivudine, and spongothymidine. The ACV(r) clone with an N815S mutation in DNApol showed similar neurovirulence to that of the parent virus; however, those with other mutations showed attenuation. GCV was effective in the treatment of the ACV(r) clone with similar virulence to that of parent HSV-1, while ACV was less effective in mice. These results indicate the importance of the characterization of HSV-1 isolates for the proper treatment of HSV-1 infections exhibiting ACV-resistance. PMID- 24047740 TI - Seroprevalence of measles- and mumps-specific immunoglobulin G among Japanese healthcare students increased during 2007-2012. AB - We evaluated the seroprevalence of vaccine-preventable infectious diseases among Japanese healthcare students to create immunization guidelines. Between 2007 and 2012, a total of 1746 Japanese medical, nursing, and paramedical students were serologically screened for measles, mumps, rubella, varicella, and hepatitis B virus (HBV) antibodies at the time of admission. In 2007, the seroprevalence of measles and mumps was 52.7% and 65.6%, respectively. The seroprevalence of measles dramatically increased to 96.6% in 2009 and was then sustained at >90%. The seroprevalence of mumps gradually increased to >80.0% between 2010 and 2012. The seroprevalence of rubella remained at >90% except in 2008 (85.6%), and the seroprevalence of varicella was sustained at >92% throughout 2007-2012. The seroprevalence of HBV antibody remained at <7% during 2007-2012. Although the seroprevalence of vaccine-preventable infectious diseases among Japanese healthcare students increased during the 2007-2012 study period, a substantial number of students were susceptible to vaccine-preventable infectious diseases. Therefore, we propose targeted immunization of Japanese healthcare students using serological screening prior to clinical training. PMID- 24047741 TI - Clinical aspects of infection with methicillin-resistant Staphylococcus aureus USA300 strain, generally regarded as community-acquired, in Japan. AB - The characteristics of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection in Japan have not yet been completely established compared with those in Europe and the United States. CA-MRSA infections with the USA300 clone are very rare in Japan. In this study, we describe 4 cases of CA MRSA infections, particularly the USA300 clone. Case 1 involved a 21-year-old man without any remarkable medical history or risk factors of CA-MRSA who suffered from a rapidly progressive infection in his left arm. Case 2 involved a 34-year old man and Case 3 a 22-year-old man who presented with recurrent and refractory furuncles. Both men were members of a combat sports gym where other members also had skin infections. Case 4 involved a 60-year-old man with lumbar canal stenosis who suffered from surgical site infection 7 days after lumbar laminectomy and posterolateral fusion. Only 5 cases of USA300 infections were reported in Japan from 2007 to 2009, and 4 cases were detected at Tokyo Medical University Hospital from 2010 to 2011. The diversity of the routes of infection in these cases may indicate the possible spread of the USA300 clone in Japan. PMID- 24047742 TI - Projection of human immunodeficiency virus among high-risk groups in Malaysia. AB - Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) presents a serious healthcare threat to young individuals in Malaysia and worldwide. This study aimed to identify trends in HIV-related risk behaviors among recognized high-risk groups and to estimate HIV transmission up to the year 2015. Data and necessary information were obtained from the Ministry of Health Malaysia, published reports from the World Health Organization and United Nations Program on HIV/AIDS, and other articles. The Estimation and Projection Package was used to estimate HIV transmission. The results of the present study revealed that within the high-risk groups, intravenous drug users (IDUs) had the highest prevalence rate of HIV transmission, followed by patients with sexually transmitted infections (STIs), female sex workers (SWs), and men who have sex with men (MSM). Within these at-risk populations, patients with STIs have the highest prevalence of HIV, followed by IDUs, MSM, and SWs. If the transmission rate continues to increase, the situation will worsen; therefore, there is an urgent need for a comprehensive prevention program to control HIV transmission in Malaysia. PMID- 24047743 TI - Virological clearance rate of high-dose oseltamivir or triple-combination antiviral therapy in complicated 2009 pandemic influenza A (H1N1) infection. AB - The 2009 pandemic influenza A (H1N1) was a considerable public health concern worldwide. Significant morbidity and mortality were observed in complicated cases, despite the early administration of neuramidase inhibitors. The limitations of neuramidase inhibitor monotherapy have renewed interest in combination antiviral therapy or higher-dose oseltamivir therapy. Herein, we report our clinical experience and virological outcomes with high-dose oseltamivir or combination antiviral therapy in seriously complicated 2009 pandemic influenza A (H1N1) infection. Eight patients were treated with high-dose oseltamivir (150 mg twice a day), and 6 patients were treated with triple combination antiviral drugs (150 mg oseltamivir twice a day, 100 mg amantadine twice a day, and 300 mg ribavirin three times a day). Nine of 14 patients (64%) developed acute respiratory distress syndrome and 6 (43%) required mechanical ventilation. Viral clearance was obtained in 9 of 12 patients (75%) after 5 days of antiviral therapy. Two patients died within 5 days of antiviral therapy. The overall mortality rate was 29% (4/14). PMID- 24047744 TI - Plasmid-mediated quinolone resistance genes, aac(6')-Ib-cr, qnrS, qnrB, and qnrA, in urinary isolates of Escherichia coli and Klebsiella pneumoniae at a teaching hospital, Thailand. AB - A total of 121 Escherichia coli (47 extended-spectrum beta-lactamase [ESBL] and 74 non-ESBL producers) and 75 Klebsiella pneumoniae isolates (49 ESBL and 26 non ESBL producers) were collected from urine samples between October 2010 and April 2011 at a university hospital and assessed for the presence of plasmid-mediated quinolone resistance (PMQR) genes. Twenty-seven E. coli (22.3%) and 49 K. pneumoniae (65.3%) isolates harbored PMQR genes, which mostly consisted of aac(6')-Ib-cr and qnrS, followed by qnrB and qnrA. Among the 76 PMQR-positive isolates, 15 (19.7%) and 2 (2.6%) carried 2 and 3 different PMQR genes, respectively. However, qnrC, qnrD, and qepA were not found in any isolate. The PMQR genes were more prevalent in ESBL producers than in non-ESBL producers (42.6% versus 9.5% in E. coli and 81.6% versus 34.6% in K. pneumoniae). Approximately 35%-60% of the PMQR-positive isolates were susceptible or intermediately susceptible to fluoroquinolones. The enterobacterial repetitive intergenic consensus-PCR method revealed that most PMQR-positive isolates belonged to different strains, indicating the spread of these resistance determinants. PMQR gene transfer by conjugation was successful in 10%-25% of the test donors. This study showed a high prevalence of PMQR genes among both organisms. Clinical use of fluoroquinolones for the treatment of infections caused by fluoroquinolone-susceptible strains harboring PMQR genes may lead to decreased therapeutic efficacy. PMID- 24047745 TI - Helicobacter pylori infection among children with Phenylketonuria. AB - This study aimed to determine the frequency of Helicobacter pylori infections in children with phenylketonuria (PKU). Sixty-six children with PKU (35 boys, 31 girls; mean age, 8.2 +/- 6.7 years) and 32 outpatient controls (15 boys, 17 girls; mean age, 9.6 +/- 4.7 years) were studied. Socioeconomic factors did not differ between the two groups. The frequency of H. pylori infections was higher in patients with PKU (28.1%) than in healthy controls (9.4%). In particular, a higher frequency of infection was detected in patients with PKU with poor metabolic control (51.8%). The frequency of H. pylori infection in patients with PKU with good metabolic control was only 10.2%. There was no difference in the mean total WISC-R score between the poor and good metabolic control groups. A high frequency of H. pylori infection in children with PKU with poor metabolic control could be related to many factors. Advanced and standardized clinical studies on H. pylori infections in children with PKU are required. PMID- 24047746 TI - Molecular epidemiology of human adenoviruses d associated with epidemic keratoconjunctivitis in Osaka, Japan, 2001-2010. AB - Isolation of novel types of human adenovirus D (HAdV-53, -54, and -56) from keratoconjunctivitis patients has been reported since 2008. We examined the molecular epidemiology of HAdV-D strains using 39 field isolates collected from epidemic keratoconjunctivitis (EKC) patients from 2001 to 2010 in the province of Osaka, Japan. The molecular types were analyzed by sequencing partial penton base gene, loop 1 in the hexon, and complete fiber genes. Of the 39 isolates, the majority were HAdV-19 (14/39, 35.9%) and -37 (13/39, 33.3%), followed by -53 (4/39, 10.3%) and -54 (8/39, 20.5%). Analysis of annual distribution showed that HAdV-19 and -37 were detected before 2004, whereas HAdV-53 and -54 were first identified in 2001 and 2003, respectively, and persistently detected during the study period. It is noted that both HAdV-53 and -54 isolates were misclassified by the serological method. Altogether, the molecular analysis elucidated the epidemiology of HAdV-D and presence of novel types from the early 2000s in Osaka. Further genetic analysis of serologically classified HAdV-D isolates may provide insights into the epidemiology of EKC. PMID- 24047747 TI - The first report on the outbreak of OXA-24/40-like carbapenemase-producing Acinetobacter baumannii in Turkey. AB - Carbapenem resistance due to OXA-type carbapenemases seriously limits therapeutic options in nosocomial infections caused by Acinetobacter baumannii. Previous studies have shown the presence of OXA-51, OXA-58, and OXA-23 carbapenemases but not OXA-24/40 in A. baumannii in Turkey. In this study, we investigated carbapenem-hydrolyzing class D beta-lactamases (CHDLs) in A. baumannii and the molecular epidemiology of CHDL producers at the Dokuz Eylul Hospital, Izmir Turkey, and detected blaOXA-24/40 in a clinical isolate from a patient in the medical intensive care unit (ICU). The specific enzyme type was OXA-72. Additional studies revealed 22 more isolates from 20 patients and that the OXA-72 producing strain caused an outbreak in the medical ICU from September 2012 to March 2013, which still continues. To our knowledge, this is the first report of OXA-24/40 carbapenemases in A. baumannii in Turkey. Emergency infection control should be implemented following the arrival of a new OXA at a hospital where A. baumannii is highly endemic. PMID- 24047748 TI - Meningococcemia due to the 2000 Hajj-associated outbreak strain (Serogroup W-135 ST-11) with immunoreactive complications. AB - We present the first reported case of systemic infection with Neisseria meningitidis serogroup W-135 sequence type (ST)-11 in Japan. A 44-year-old woman presented with high fever, sore throat, and fatigue and was diagnosed with N. meningitidis bacteremia. The causative strain was identified as serogroup W-135 ST-11 by polymerase chain reaction and multilocus sequence typing. Approximately 1 month after treatment, she developed high fever, dyspnea, chest pain, and shoulder pain due to pericarditis, polyarthritis, and tenosynovitis, which are all relatively common immunoreactive complications of W-135 ST-11 meningococcal infections. This causative strain was the same as that responsible for an outbreak of meningitis among Hajj pilgrims in 2000. The strain is now found worldwide because it can attain a high carriage rate and has a long duration of carriage. We suspect that our patient's infection was acquired from an imported chronic carrier. PMID- 24047749 TI - Frequency of diarrheagenic Escherichia coli among children in Surabaya, Indonesia. AB - Diarrheagenic Escherichia coli (DEC) is a major etiologic agent of childhood diarrhea in developing countries. We investigated the frequency of DEC in stool samples from 125 diarrheal children (age, 1-10 years) and 92 non-diarrheal children in Surabaya, Indonesia. The non-diarrheal children served as healthy controls. DEC was detected in 23 of 125 (18.4%) and 47 of 92 (51.1%) samples in the diarrheal and non-diarrheal children, respectively. Enteropathogenic E. coli was the most prevalent in the non-diarrheal children (25.0%), and its prevalence was significantly higher than that in the diarrheal children (0.8%) (P < 0.0001). Interestingly, Shiga toxin-producing E. coli (4.3%) was detected only in the non diarrheal children (P = 0.031). This is the first study comparing between diarrheal children with non-diarrheal or healthy children to investigate the role of DEC in pediatric diarrheal diseases in Indonesia. PMID- 24047750 TI - Measles epidemiology and survey of measles immunity level among healthy population in Baoji City, Shaanxi Province, China. AB - In this study, we analyzed the epidemiology of measles cases from January 2004 to December 2011 and measles immunity levels among a healthy population from January to June 2012, in Baoji, Shaanxi Province. This study aimed to identify susceptible populations to measles and to establish methods of measles prevention and control. Measles incidence was at the lowest level in 2011 (0.32 per 100,000 populations). Among these patients, the proportion of those younger than 8 months and those older than 27 years of age was relatively high. The overall antibody positive rate was 78.90%, and the average antibody geometric mean concentration was 562.15 mIU/ml. Measles immunity level was high among children aged 8 months to 6 years and low among infants aged 1-7 months. To reduce the incidence of measles among infants younger than 8 months, implementation of measles vaccine (MV) for women of childbearing age is recommended. Measles immunity level was low among some individuals vaccinated with aqueous MV and lyophilized MV. Supplementary immunization will be recommended for freshmen in universities and colleges, where many students are recruited from various parts of China. PMID- 24047752 TI - beta-Glucuronidase-negative enterohemorrhagic Escherichia coli O26 infections associated with a calf. PMID- 24047751 TI - Phylogenetic analysis of the nonstructural and structural protein encoding region sequences, indicating successive appearance of genomically diverse sapovirus strains from gastroenteritis patients. PMID- 24047753 TI - Which age group is spreading measles in Japan? PMID- 24047754 TI - In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial. AB - We performed a first-in-disease trial of in vivo CD28:CD80/86 costimulation blockade with abatacept for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT). All patients received cyclosporine/methotrexate plus 4 doses of abatacept (10 mg/kg/dose) on days -1, +5, +14, +28 post-HCT. The feasibility of adding abatacept, its pharmacokinetics, pharmacodynamics, and its impact on aGVHD, infection, relapse, and transplantation-related mortality (TRM) were assessed. All patients received the planned abatacept doses, and no infusion reactions were noted. Compared with a cohort of patients not receiving abatacept (the StdRx cohort), patients enrolled in the study (the ABA cohort) demonstrated significant inhibition of early CD4(+) T cell proliferation and activation, affecting predominantly the effector memory (Tem) subpopulation, with 7- and 10-fold fewer proliferating and activated CD4(+) Tem cells, respectively, at day+28 in the ABA cohort compared with the StdRx cohort (P < .01). The ABA patients demonstrated a low rate of aGVHD, despite robust immune reconstitution, with 2 of 10 patients diagnosed with grade II-IV aGVHD before day +100, no deaths from infection, no day +100 TRM, and with 7 of 10 evaluable patients surviving (median follow-up, 16 months). These results suggest that costimulation blockade with abatacept can significantly affect CD4(+) T cell proliferation and activation post-transplantation, and may be an important adjunct to standard immunoprophylaxis for aGVHD in patients undergoing unrelated-donor HCT. PMID- 24047755 TI - Prevalence of congenital heart disease among Palestinian children born in the Gaza Strip. AB - OBJECTIVE: This study was designed to estimate the birth prevalence of children with congenital heart disease born in the Gaza Strip during 2010 and to compare these with estimates from elsewhere. METHODS: We reviewed the medical records of all children born in 2010 who were diagnosed, treated, and/or followed up in the four paediatric cardiology clinics in the Gaza Strip. Data were also obtained from El Makassed Hospital in East Jerusalem and from the Schneider Hospital, Wolfson Medical Center, and Tel HaShomer Hospital in Israel, where we had referred some of our patients for percutaneous or surgical treatment. RESULTS: A total of 598 children with congenital heart disease were detected among the 59,757 children born alive in the Gaza Strip during 2010, yielding a birth incidence of 10 per 1000 live births. The most frequently occurring conditions were ventricular septal defects (28%), ostium secundum atrial septal defects (17%), patent ductus arteriosus (8.5%), and pulmonary valve abnormalities (8%). In this study, 7% of the children died. The actuarial survival at 6 months and 1 year of age was 94% and 93%, respectively, and remained stable over 18 months of follow-up. CONCLUSION: The birth incidence of congenital heart disease in the Gaza Strip in 2010 (10 per 1000) is higher than most estimates in Western Europe (8.2 per 1000 live births) and North America (6.9 per 1000 live births) but is similar to estimates from other parts of Asia (9.3 per 1000 live births). PMID- 24047756 TI - Anodal transcranial direct current stimulation in early rehabilitation of patients with post-stroke non-fluent aphasia: a randomized, double-blind, sham controlled pilot study. AB - PURPOSE: Recent research in patients with chronic aphasia shows an association between excitatory anodal transcranial direct current stimulation (A-tDCS) of the stroke-affected left hemisphere coupled with speech and language therapy (SLT) and better language performance. The present study aimed to investigate this association during the early post-stroke rehabilitation period, when adaptive changes are most possible on neurophysiological and behavioral levels. METHODS: We randomized 24 patients with non-fluent aphasia to receive 15 consecutive sessions (5 days/week for 3 weeks) of A-tDCS (1 mA, 10 min; n = 14) or sham tDCS (S-tDCS: 1 mA, 25 sec; n = 10) over Broca's area followed by 45-min SLT. Naming ability was assessed before the rehabilitation, after its completion, and three months later. RESULTS: Both groups significantly improved after the therapy. There were no statistically significant between-group differences in the short term or long-term tDCS effects on naming accuracy and naming time. The A-tDCS group obtained higher effect sizes in naming time, both post-treatment and at the 3-month follow-up, suggesting potential benefits of the stimulation. CONCLUSIONS: The findings provide only weak evidence for A-tDCS-related language gains during early neurorehabilitation of post-stroke aphasia. Further research is needed to explore the effectiveness of this kind of neuromodulation. PMID- 24047758 TI - Psychotic Disorder in Neurodegeneration with Brain Iron Accumulation. PMID- 24047757 TI - Effects of lutein and lycopene on carotid intima-media thickness in Chinese subjects with subclinical atherosclerosis: a randomised, double-blind, placebo controlled trial. AB - The aim of the present study was to evaluate the effects of lutein and lycopene supplementation on carotid artery intima-media thickness (CAIMT) in subjects with subclinical atherosclerosis. A total of 144 subjects aged 45-68 years were recruited from local communities. All the subjects were randomly assigned to receive 20 mg lutein/d (n 48), 20 mg lutein/d+20 mg lycopene/d (n 48) or placebo (n 48) for 12 months. CAIMT was measured using Doppler ultrasonography at baseline and after 12 months, and serum lutein and lycopene concentrations were determined using HPLC. Serum lutein concentrations increased significantly from 0.34 to 1.96 MUmol/l in the lutein group (P< 0.001) and from 0.35 to 1.66 MUmol/l in the combination group (P< 0.001). Similarly, serum lycopene concentrations increased significantly from 0.18 to 0.71 MUmol/l in the combination group at month 12 (P< 0.001), whereas no significant change was observed in the placebo group. The mean values of CAIMT decreased significantly by 0.035 mm (P= 0.042) and 0.073 mm (P< 0.001) in the lutein and combination groups at month 12, respectively. The change in CAIMT was inversely associated with the increase in serum lutein concentrations (P< 0.05) in both the active treatment groups and with that in serum lycopene concentrations (beta = - 0.342, P= 0.031) in the combination group. Lutein and lycopene supplementation significantly increased the serum concentrations of lutein and lycopene with a decrease in CAIMT being associated with both concentrations. In addition, the combination of lutein and lycopene supplementation was more effective than lutein alone for protection against the development of CAIMT in Chinese subjects with subclinical atherosclerosis, and further studies are needed to confirm whether synergistic effects of lutein and lycopene exist. PMID- 24047759 TI - Rapid Re-challenge with Clozapine Following Pronounced Myocarditis in a Treatment Resistance Schizophrenia Patient. AB - Clozapine is an atypical antipsychotic which is often effective in patients who fail to respond to other antipsychotics, but its use carries substantial risk. Myocarditis is one of the life-threatening adverse effects which occurs in about 1% of exposed patients. Re-challenge with clozapine is controversial, particularly shortly after the occurrence of the myocarditis and when there is clear and convincing evidence of cardiac damage. Aggressive use of clozapine, however, may be critical for the recovery of patients early in the course of their illness. Here we report a successful case of clozapine rechallenge following an initial aggressive dosage titration in an inpatient setting. PMID- 24047760 TI - Anxiety symptoms in psychotic disorders. AB - BackgroundThe prevalence of anxiety symptoms among Australians with psychotic disorders was examined as part of the Survey of High Impact Psychosis (SHIP).MethodsA two-phase design was used. Of 7,955 people who were screen positive for psychosis and eligible, 1825 participants (18-34 years and 35-64 years) were interviewed. Data were collected on symptomatology, substance use, cognitive ability, functioning, disability, physical health, mental health service utilisation, medication use, education, employment and housing. Anxiety symptomatology was divided into generalized anxiety, panic, phobic, social anxiety and obsessive-compulsive symptoms.ResultsThe most common ICD-10 diagnoses were schizophrenia or schizoaffective disorder (63.0%) and bipolar (mania) disorder (17.5%). Overall, 59.8% (n = 1092) of participants reported experiencing anxiety symptoms in the previous 12 months. Female gender was highly associated with all domains of anxiety. Smoking was significantly associated with all domains of anxiety, except generalized anxiety. The presence of any depressive symptoms in the previous 12 months was significantly associated with all anxiety symptoms. Medication side-effects were associated with phobic and obsessive compulsive symptoms. Social dysfunction was associated with social anxiety, and less so for obsessive-compulsive symptoms.ConclusionsAnxiety symptoms are common in people with psychotic disorders. Appropriate screening and treatment should be a clinical priority. PMID- 24047761 TI - Treatment of Paroxysmal Perceptual Alteration in Catatonic Schizophrenia by Switching to Aripiprazole from Risperidone: A Case Report. AB - Paroxysmal perceptual alteration (PPA) is the occurrence of brief and recurrent episodes of perceptual changes. It is mainly caused by the treatment of schizophrenia patients with antipsychotics. However, diagnosis of PPA is not very prevalent among psychiatrists, partly due to underrecognition or misunderstanding that it is a worsening of psychiatric symptoms. If psychiatrists do not understand PPA, they cannot treat it appropriately, and the patient's quality of life is impaired. We present a case of PPA in catatonic schizophrenia that was successfully treated by switching to aripiprazole from risperidone. We suggest that the disappearance of PPA in our case was due to both discontinuing risperidone, which completely blocks D2 receptors, and replacing it with aripiprazole, which is characterized as a partial agonist of D2 receptors. Treatment of PPA will improve medication adherence and quality of life. It is important to recognize PPA as a possible side effect of treatment with antipsychotics. PMID- 24047763 TI - Effect of in-utero HIV exposure and antiretroviral treatment strategies on measles susceptibility and immunogenicity of measles vaccine. AB - INTRODUCTION: The high burden of maternal HIV-infection in sub-Saharan Africa may affect measles control. We evaluated the effect of in-utero HIV-exposure and antiretroviral treatment (ART) strategies on measles antibody kinetics prior and following measles vaccination. METHODS: Infants aged 6-12 weeks were enrolled. This included HIV-uninfected infants born to HIV-uninfected (HUU) and HIV infected mothers (HEU). Additionally, we enrolled perinatal HIV-infected infants with CD4% equal or greater than 25% randomized to deferred-ART until clinically or immunologically indicated (Group-3) or immediate-ART initiation (Group-4). Group-4 was further randomized to interrupt ART at 1 year (Group-4a) or 2 years of age (Group-4b). Additionally, a convenience sample of HIV-infected infants with CD4+ less than 25% initiated on immediate-ART was enrolled (Group-5). Measles immunoglobulin-G antibodies were quantified by an indirect enzyme immunoassay with titers 330 mIU/ml or more considered 'sero-protective'. The referent group was HUU-children. RESULTS: The proportion with sero-protective titers at 7.3 weeks of age was higher in HUU (65.2%) compared with any HIV infected group (range: 16.7-41.8%), but dropped to less than 17% in all groups at age 19.6 weeks. Twenty-eight weeks following the first measles vaccine, Group-4a was less likely to have sero-protective titers (79.3%) as compared to HUU (91.1%; P<0.0001), Group-3 (95.7%; P=0.003) or Group-4b (92.1%; P=0.018). Although the proportion with sero-protective levels were similar between groups immediately postbooster dose, this was lower in HEU (79.6%; P=0.002) and Group-4a (80.3%; P=0.010) compared with HUU (94.3%) 41-weeks later. CONCLUSION: Greater waning of immunity among HIV-infected children in whom ART was interrupted and in HEU following a booster-dose, indicate the possible need for further measles-booster doses after 2 years of age in these children. PMID- 24047762 TI - Older HIV-infected patients on antiretroviral therapy have B-cell expansion and attenuated CD4 cell increases with immune activation reduction. AB - BACKGROUND: The contribution of immune activation to accelerated HIV-disease progression in older individuals has not been delineated. METHODS: Prospective multicenter cohort of older (>=45 years) and younger (18-30 years) HIV-infected adults initiating 192 weeks of antiretroviral therapy (ART). Longitudinal models of CD4 cell restoration examined associations with age-group, thymic volume, immune activation, and viral load. RESULTS: Forty-five older and 45 younger adults (median age 50 and 26 years, respectively) were studied. Older patients had fewer naive CD4 cells (P<0.001) and higher HLA-DR/CD38 expression on CD4 (P=0.05) and CD8 cells (P=0.07) than younger patients at any time on ART. The rate of naive and total CD4 cell increase was similar between age groups, but older patients had a faster mean rate of B-cell increase (by +0.7 cells/week; P=0.01), to higher counts than healthy controls after 192 weeks (P=0.003). Naive CD4 increases from baseline were associated with immune activation reductions (as declines from baseline of %CD8 cells expressing HLA-DR/CD38; P<0.0001), but these increases were attenuated in older patients, or in those with small thymuses. A 15% reduction in activation was associated with naive gains of 29.9 and 6.2 cells/MUl in younger, versus older patients, or with gains of 25.7, 23.4, and 2.1 cells/MUl in patients with the largest, intermediate, and smallest thymuses, respectively (P<0.01 for interactions between activation reduction and age-group or thymic volume). CONCLUSION: Older patients had significant B-cell expansion, higher levels of immune activation markers, and significantly attenuated naive CD4 cell gains associated with activation reduction. PMID- 24047765 TI - Towards a better understanding of Kaposi sarcoma-associated immune reconstitution inflammatory syndrome. PMID- 24047764 TI - Grassroots community organizations' contribution to the scale-up of HIV testing and counselling services in Zimbabwe. AB - OBJECTIVE: To investigate whether community engagement (participation in grassroots organizations) contributed to increases in HIV testing in Zimbabwe. METHODS: Prospective data on membership of local community organizations (e.g. women's groups and burial societies) and uptake of HIV testing and counselling (HTC) and prevention-of-mother-to-child transmission (PMTCT) services were collected from 5260 adults interviewed in two consecutive rounds of a general population cohort survey in eastern Zimbabwe between 2003 and 2008. The effects of community engagement on uptake of services during the follow-up period were measured using logistic regression to adjust for observed confounding factors. RESULTS: Sixteen percent of men and 47% of women were consistent members of community organizations; 58 and 35% of these people discussed HIV in their meetings and were members of externally sponsored organizations, respectively. Fewer men (10.1%) than women (32.4%) took up HTC during follow-up [adjusted odds ratio (aOR)=4.08, 95% confidence interval (CI) 3.43-4.86, P<0.001]. HTC uptake was higher for members of community organizations than for nonmembers: men, 15.0 versus 9.2% (1.67, 1.15-2.43, P=0.007); women, 35.6 versus 29.6% (1.26, 1.06 1.49, P=0.008). Membership of community organizations showed a nonsignificant association with PMTCT uptake amongst recently pregnant women (42.3 versus 34.2%; 1.30, 0.94-1.78, P=0.1). The most consistent positive associations between community participation and HTC and PMTCT uptake were found in organizations that discussed HIV and when external sponsorship was absent. CONCLUSION: Grassroots organizations contributed to increased uptake of HTC services in eastern Zimbabwe in the mid-2000s. Partnerships with these organizations could harness community support for the further increases in HIV testing needed in sub-Saharan Africa. PMID- 24047766 TI - Test performance of beta-glucan for Pneumocystis jirovecii pneumonia put in a clinical context. PMID- 24047767 TI - Anomalous surface segregation behaviour of some 3d elements in ferromagnetic iron. AB - The segregation of Cr in Fe is known to be anomalous since the barrier for surface segregation of Cr is not determined by the topmost surface layer, as one would expect, but rather by the subsurface layer where the energy of segregation is much larger and endothermic. This has been attributed to a complex interaction involving the antiferromagnetism of Cr and the ferromagnetism of Fe. We report in this paper the results of our ab initio electronic structure calculations on the segregation behaviour of all the 3d elements on the (1 0 0) surface of ferromagnetic iron in the hope of better understanding this phenomenon. We find a similar behaviour for the segregation of the next antiferromagnetic 3d element Mn in Fe, where the subsurface layer is also found to block the segregation of Mn to the surface. On the other hand, ferromagnetic Co exhibits a normal segregation behaviour. The elements Sc, Cu and Ni do not form solid solutions with ferromagnetic iron. The early elements Ti and V are non-magnetic in their metallic states, but are strongly polarized by Fe, and develop magnetic moments which are aligned antiferromagnetically to those of Fe atoms. While the subsurface layer blocks the segregation of Ti to the surface, no blocking behaviour is found for the segregation of V. The segregation behaviour of all these elements is strongly correlated with the displacement of the solute atoms on the surface of Fe. The elements showing anomalous segregation behaviour are all displaced upwards on the surface, while those showing normal segregation are pulled inwards. These results indicate that the antiferromagnetism of the segregating element plays the key role in the anomalous segregation behaviour in Fe. PMID- 24047768 TI - Positioning of double-lumen tubes based on the minimum peak inspiratory pressure difference between the right and left lungs in short patients: a prospective observational study. AB - BACKGROUND: Peak inspiratory pressures (PIPs) during one-lung ventilation (OLV) have served as a clinical marker that could indirectly verify the proper positioning of double-lumen tubes (DLTs). Patients of short stature are highly susceptible to initial DLT malpositioning. OBJECTIVES: We investigated the usefulness of positioning left-sided DLTs using minimum PIP differences between the right and left lungs by comparing with the previously used method of auscultation without fibreoptic bronchoscopy (FOB). We also evaluated the difference in PIPs between the two lungs during OLV after the DLT was ideally positioned with FOB examination. DESIGN: Prospective, observational study. SETTING: A university hospital. PATIENTS: One hundred and two female patients of short stature (<=160 cm). INTERVENTIONS: Verification of DLT position was conducted by three sequential steps: auscultation; minimising the difference in PIP during each OLV; and verifying the resulting position by FOB. MAIN OUTCOME MEASUREMENTS: Fibreoptic bronchoscopic view results of DLT position followed by the position adjustment using the minimum PIP difference method. RESULTS: Repositioning the DLT using the minimum PIP difference led to clinically successful positioning of the DLT in 88% of patients and a more ideal placement of the tube than auscultation alone (69.6 vs. 11.8%, P <0.001). Additionally, the ideal position of DLTs verified by FOB showed that PIP differences were zero or +/-1 mmHg in 93% of patients. CONCLUSION: Positioning the DLT based on the minimum PIP difference between the right and left lungs as a supplementation to routine auscultation serves as an easy and reliable method for DLT positioning and may improve the accuracy of DLT positioning as an adjuvant to FOB in short patients. TRIAL REGISTRATION: Clinicaltrial.gov identifier: NCT01533012. PMID- 24047769 TI - [Rehabilitation for cancer patients]. AB - In Japan, the number of patients with cancer is increasing drastically with the increase in number of elderly people. Therefore, recently, the necessity of rehabilitation for cancer patients has been realized. Cancer rehabilitation can be classified as preventive, restorative, supportive, or palliative and is administered according to the degree of cancer progression. Rehabilitation is of great significance even for patients with progressive cancer as it helps maintain their quality of life. Various forms of impairment, disability, and handicap are associated with cancer rehabilitation. Examples of impairments that cancer patients experience are hemiplegia and higher brain dysfunction in brain tumor cases, paraplegia and quadriplegia in spinal or spinal cord tumor cases, neuropathy and radiculopathy in cases of tumor invasion, complications after surgery, peripheral neuropathy after chemotherapy, and dysphagia after radiotherapy. It is important to evaluate these impairments and the risks associated with rehabilitation. PMID- 24047770 TI - [History of and novel developments in cancer immunotherapy - introduction to the special issue]. AB - Over the last 50 years, development in the field of cancer immunotherapy has been fluctuating, ranging from exciting expectations to disappointing clinical outcomes. Now, the time has come again, for cancer immunotherapy. Since 2010, new immunotherapeutics have been approved one after another in the United States of America and other countries. Thus, immunotherapy has definitely been recognized as the fourth therapy for cancer after surgery, radiotherapy, and chemotherapy. Under this establishment, there has been progress not only in the fundamental understanding of the immune system but also in the design of scientific clinical trials, in which delayed-type tumor responses and survival benefits with less tumor shrinkage are used as indicators. The next 3 papers provide exciting insights on novel cancer immunotherapy as an innovative treatment modality for cancer. PMID- 24047771 TI - [Ipilimumab]. AB - Ipilimumab(MDX-010, BMS-734016)is a fully human monoclonal immunoglobulin(IgG1k)specific for human cytotoxic T lymphocyte antigen 4(CTLA-4, CD152), which is expressed on a subset of activated T-cells as a negative regulator of T-cell activation. Blockade of CTLA-4 can potentiate a robust antitumor immune response and lead to long-term tumor regression. Moreover, 2 global phase 3 clinical studies(MDX010-20 and CA184-024)on ipilimumab have demonstrated an improved survival in patients with both untreated and treated advanced melanoma. Ipilimumab(Yervoy TM)has been approved for clinical use for the treatment of advanced melanoma in over 40 countries, including the United States(March 2011)and the European Union(July 2011), as the first agent to show overall survival benefit in patients with advanced melanoma. In Japan, several clinical trials for ipilimumab are ongoing in patients with conditions such as melanoma, non-small cell lung cancer, small-cell lung cancer, and gastric cancer. On the basis of experiences in both clinical development and clinical use of ipilimumab in more than 13,000 patients, several unique features of immunotherapy have been identified. In this article, clinical data on ipilimumab along with its unique effects and safety profile will be introduced, and some possible options for the further development of ipilimumab will be briefly discussed. PMID- 24047772 TI - [Anti-PD-1 antibody: basics and clinical application]. AB - Although the treatment of cancer with monoclonal antibodies has long been pursued, T cell-directed immunotherapy has met with limited success. Recently, much attention has been devoted to the blockade of PD-1 signaling to activate an immune response to cancer. PD-1, a protein expressed on T cells, is a member of the CD28 superfamily, and it transmits coinhibitory signals upon engagement with its ligands PD-L1 and PD-L2. Accumulating evidence suggests that the PD-1 system plays pivotal roles in the regulation of autoimmunity, transplantation immunity, infectious immunity, and tumor immunity. Because the interaction of PD-1 with its ligands occurs in the effector phase of killer T cell responses in peripheral blood, anti-PD-1 and anti-PD-L1 monoclonal antibodies are ideal as specific agents to augment T cell responses to tumors with fewer adverse events than with the inhibition of CTLA-4, because the interaction of CTLA-4 with its ligands occurs in the priming phase of T cell responses within lymph nodes. In recent phase I clinical trials, objective responses were observed in patients with melanoma, renal cell carcinoma, and non-small cell lung cancer who underwent immunotherapy with an anti-PD-1 monoclonal antibody. In addition, the antitumor activity of an anti-PD-L1 monoclonal antibody was observed in patients with melanoma, renal cell carcinoma, non-small cell lung cancer, and ovarian cancer. The next frontier of immunotherapy targeting the PD-1 axis is to define patient selection criteria and explore combination therapy with other therapeutic manipulations such as adoptive immunotherapies. PMID- 24047773 TI - [Anti-CCR4 mAb and regulatory T cells]. AB - Despite receiving multidisciplinary therapy, patients with advanced or recurrent cancer experience poor survival. Therefore, novel and effective therapies should be developed. In various malignancies, tumor cells can evade the host immune defenses, in which CD4+CD25+ regulatory Tcells (Treg) play an important role. Tregs maintain self-tolerance and homeostasis in the immune system, thereby suppressing the antitumor immune responses in cancer patients. Thus, Tregs are crucial in controlling antitumor immune responses. Several clinical studies have shown that the presence of Tregs at the tumor site was correlated with poor prognosis, and Tregs reportedly suppress the antigen-specific T-cell induction in immunotherapy. Therefore, controlling Treg function may be a promising immunotherapy. Based on the findings of adult T-cell leukemia-lymphoma research, Tregs have been shown to display high cell-surface expression of the CC chemokine receptor, CCR4. The anti-CCR4 monoclonal antibody recognizes the CCR4 molecule and induces robust ADCC activity against CCR4-positive cells such as Tregs. Thus, Treg depletion using humanized anti-CCR4 monoclonal antibodies may enhance the host immune response against tumors. The current ongoing clinical trial investigates the use of humanized anti-human-CCR4 monoclonal antibody, mogamulizumab, in the treatment of advanced solid tumors. PMID- 24047774 TI - [Phase I study of sequential S-1 and cyclophosphamide therapy in patients with metastatic breast cancer]. AB - S-1 is a novel oral anticancer agent consisting of tegafur, a prodrug of 5 fluorouracil, and 2 modulators. A phase I study of sequential S-1 and cyclophosphamide(CPA)therapy was conducted to determine the dose-limiting toxicities(DLTs)and recommended doses(RDs)in patients with metastatic or recurrent breast cancer(MBC). Patients with MBC received sequential S-1 and CPA. Chemotherapy consisted of administration of S-1 twice daily on days 1-14 at escalating doses of 40, 50, 65, and 80mg/m2/day and CPA at 100 mg/body/day on days 15-28. The schedule was repeated twice at a 4-week interval. The purposes of this study were to determine the RDs, safety, and efficacy of the regimen. A total of 12 patients were registered. No patients experienced DLTs, and the RDs of S-1 and CPA were 80mg/m2/day and 100 mg/body/day, respectively. The response rate was 50. 0%. In conclusion, sequential therapy with S-1 and CPA could be safely and effectively used for the treatment of MBC, and the RDs for this regimen were determined to be 80mg/m2/day for S-1 and 100 mg/m2/day for CPA. PMID- 24047775 TI - [Promising effects of pregabalin in the treatment of oxaliplatin-induced sensory neuropathy in patients with colorectal carcinoma]. AB - Thirteen patients with metastatic colorectal cancer who suffered from oxaliplatin induced sensory neuropathy were evaluated to determine the neuropathy Grade before and after the administration of pregabalin. All patients received oxaliplatin as adjuvant or first-line chemotherapy. The mFOLFOX6 and CapeOX groups included 3 and 10 cases, respectively, and the average treatment regimens were 8 and 5 doses, respectively. Before receiving pregabalin, sensory neuropathy was classified as Grade 3 in 2 patients, as Grade 2 in 8 patients, and as Grade 1 in 3 patient. The average amount of pregabalin administered to patients was 237 (range: 150-450) mg. After administering pregabalin, we observed improvements in 8 neuropathy cases (61. 5%)within approximately 2 weeks. All side effects were mild. In this study, pregabalin was shown to positively impact sensory neuropathy resulting from oxaliplatin treatment and to enable the long-term use of oxaliplatin-based chemotherapy. PMID- 24047776 TI - [Nutritional assessment employing the malnutrition universal screening tool for patients with colorectal cancer undergoing outpatient chemotherapy]. AB - OBJECTIVE: We surveyed the nutritional status of patients with colorectal cancer undergoing outpatient chemotherapy using the malnutrition universal screening tool(MUST)to examine its usefulness and association with adverse events. METHODS: We examined the use of the MUST and the incidences of adverse events in 34 patients with advanced or recurrent colorectal cancer who had undergone outpatient chemotherapy between April and December 2010. RESULTS: The high-risk patients requiring nutritional care intervention comprised 47. 1%(16 patients)of the study population, and these patients exhibited significant decreases in body weight and body mass index. The incidences of appetite loss and fatigue were significantly higher in the high-risk group than in the low-risk group. DISCUSSION: Precautions against adverse events may prevent a worsening of the nutritional status of patients with colorectal cancer. Thus, nutritional assessment is necessary in patients undergoing outpatient chemotherapy. Furthermore, the MUST appears to represent a very useful simplified nutritional screening method for the nutritional management for these patients. PMID- 24047777 TI - [Efficacy and safety of pregabalin for oxaliplatin- and paclitaxel-induced peripheral neuropathy]. AB - This study included patients who were prescribed pregabalin, vitamin B12, amitriptyline, clonazepam, or carbamazepine to improve oxaliplatin(L-OHP)- or paclitaxel(PTX)-induced peripheral neuropathy at Iwate Medical University Hospital between April 2011 and July 2012. The efficacy and safety of pregabalin was evaluated by comparing 27 patients with L-OHP-induced peripheral neuropathy and 28 with PTX-induced peripheral neuropathy prescribed pregabalin(pregabalin group) with 20 patients with L-OHP-induced peripheral neuropathy and 25 with PTX induced peripheral neuropathy prescribed other drugs(non-pregabalin group). Response was defined as a decrease in neuropathy of at least 1 grade from baseline. The response rates were 40.7% and 10.0% for L-OHP-induced peripheral neuropathy patients and 28.6% and 12.0% for PTX-induced peripheral neuropathy patients in the pregabalin and non-pregabalin groups, respectively. The severity of peripheral neuropathy before and after the administration of pregabalin differed significantly[L-OHP, 1.33+/-0.48(mean+/-SD) vs. 1.00+/-0.78 and PTX, 1.46+/-0.69 vs. 1.21+/-0.88]. In 28-37% of patients, pregabalin was associated with adverse events, with drowsiness and dizziness being frequently observed. In conclusion, pregabalin was efficacious in reducing the severity of L-OHP- and PTX induced peripheral neuropathy. PMID- 24047778 TI - [An evaluation of the current status and the reported problems of the cancer support group "Hidamari" in our hospital-results of a questionnaire survey completed by group participants]. AB - PURPOSE: Peer support is a very important support intervention for cancer patients and their families. Our hospital has offered cancer support in the form of a support group "Hidamari" to cancer patients and their families since February 2012. This study analyzed and examined the current group status and the results of a questionnaire survey completed by group participants in order, to evaluate the functioning of the group and identify problems. METHODS: The current group status was determined as per the records of practice. A questionnaire survey that consisted of both multiple choice and open-ended questions was administered to the participants after the sessions. ETHICAL CONSIDERATIONS: The subjects were informed about the study purpose and confidentiality provisions in both oral and written forms, and return of the anonymous survey was considered to be consent. RESULTS: A group session was performed every 2 months(to date, a total of 4 sessions), and a total of 48 patients(68%)and 23 family members(32%)participated in the sessions. Each session included 9-25 subjects(mean: 17. 7 subjects/session). The response rate of the survey was 95. 8%. Responses to the question, "Are you satisfied with the sessions ?" were very satisfied, satisfied, dissatisfied, or very dissatisfied in 63%, 37%, 0%, and 0% of the participants, respectively. Responses to the question, "Do you wish to participate in further sessions ?" were yes, no, undecided, or gave no response in 94%, 0%, 2%, and 4% of the subjects, respectively. Reasons for satisfaction with the sessions were "It gives me courage and strength," "Useful information can be obtained," and "Good advice from nurses." DISCUSSION: All participants were satisfied with the sessions and most of the participants wished to participate in future sessions, indicating that the sessions had some positive effects. In future, we must consider initiatives covering the whole region, such as the implementation of a workshop that meets the needs of the participants and increases the number of participants with wider variety of cancer. PMID- 24047779 TI - [A case of recurrent non-small cell lung cancer successfully treated with multiple modality therapies including S-1 monotherapy as fifth-line chemotherapy hospital)]. AB - An 80-year-old man with no complaint was referred to our department because of high serum CEA level. He was diagnosed as non-small cell lung cancer(adenocarcinoma)of the left lower lobe(c-T2aN0M0, stage I B), and therefore the left lower lobectomy with lymph node dissection was performed. Pathological staging was p-T2aN1(#10)M0, stage II A, and EGFR mutation was negative. Adjuvant chemotherapy with UFT was started, but multiple hilar and mediastinal lymph nodes metastases soon appeared. Carboplatin(CBDCA)+paclitaxel(PTX), erlotinib, and docetaxel(DOC)were attempted after that, but the lymph nodes increased in size and the CEA level was up to 159.8 ng/mL. At about the same time, brain and pulmonary metastases were recognized. After radiation for the chest lymph nodes and stereotactic radiosurgery(SRS)for the brain metastasis, oral S-1 monotherapy was introduced. Soon after, the lymph nodes shrinked and the CEA level decreased. Also, the pulmonary metastasis disappeared. Although a right supraclavicular lymph node metastasis was resected during the clinical course, the S-1 monotherapy has been continued with no serious adverse event. He is well(PS 0)without recurrent lesion, and his serum CEA level is within the normal limit. PMID- 24047780 TI - [An elderly patient with large cell neuroendocrine carcinoma(LCNEC)for whom chemotherapy with irinotecan and split-dose cisplatin(CDDP)proved very effective]. AB - Large cell neuroendocrine carcinoma(LCNEC)is a rare malignant disease with a poor and the clinical outcome. Although no standard chemotherapy regimen has been developed, LCNEC should be treated in a manner similar to that used for small cell lung cancer because of their similar chemosensitivity and aggressive characteristics, even though LCNEC is classified as non-small cell lung cancer. A 78-year-old man was admitted with the complaint of convulsions on the left side of his body. A chest computed tomographic(CT)scan on admission demonstrated a 4 cm mass in a left lung S9. Brain magnetic resonance imaging(MRI)revealed enhanced tumors in the left occipital lobe. The brain tumor was surgically resected and histological findings were diagnosed as LCNEC. After induction of 4 courses with irinotecan and split-dose cisplatin chemotherapy, a partial response was obtained. After 4 courses, the tumor size was increased, and the chemotherapy was changed to amrubicin. The patient is alive and with no relapse. PMID- 24047781 TI - [A case of advanced esophageal cancer revealed a pathological complete response and survived more than 8 years, treated by radiation therapy combined with nedaplatin and 5-FU chemotherapy]. AB - We report here the long-term survival case of advanced esophageal cancer treated with definitive chemoradiotherapy (CRT). A 61-year-old woman visited our hospital because of a disturbance in her swallowing in September, 2003. She was diagnosed with a middle esophageal type 3 tumor, which was 9 cm in length by endoscopy. Squamous cell carcinoma was diagnosed by pre-operative endoscopic biopsy. CT revealed the tumor with direct invasion to the aorta, and multiple metastases of the lymph nodes(T4, N1, M0: Stage IVa). CRT(combination of 5-FU and nedaplatin with 40 Gy of radiation)was administered. After the completion of CRT, the tumor size was remarkably reduced, but stenosis of the lumen of the esophagus remained partially. Therefore, we performed sub-total esophagectomy in February, 2004. A pathological complete response was diagnosed with no carcinoma cells evident in the resected specimen. Pathological therapeutic evaluation of the esophageal cancer was grade 3. The patient had received no adjuvant chemotherapy, but she is alive and healthy now with no relapse of carcinoma for more than 8 years after operation. PMID- 24047782 TI - [A case of esophageal cancer with septic disseminated intravascular coagulation treated with recombinant human soluble thrombomodulin during chemoradiation therapy]. AB - A 70-year-old woman was diagnosed with synchronous advanced esophageal cancer and early renal cancer. During chemoradiation therapy for the esophageal cancer, she suffered from septic shock due to pneumonia. She got worse despite the administration of antibiotics and gglobulin. On the following day, she was diagnosed with septic disseminated intravascular coagulation(DIC)on the basis of the diagnostic criterion for acute DIC. Recombinant human soluble thrombomodulin(rTM) was administered to treat the DIC. The patient responded promptly to rTM treatment and recovered from the DIC in just 1 day. rTM is thought to be an effective drug for sepsis-induced DIC during chemoradiation therapy. PMID- 24047783 TI - [A case of gastric cancer with virchow and para-aortic node metastasis treated successfully by neo-adjuvant chemotherapy with S-1/CDDP]. AB - A 61-year-old female visited our hospital with the complaint of a left cervical hard tumor. Systemic examination revealed advanced gastric carcinoma with nodal involvement of para -aortic and Virchow's lymph nodes. Neoadjuvant chemotherapy with S-1/cisplatin(CDDP)combination therapy was scheduled. Three courses of chemotherapy resulted in marked tumor regression and a reduction of lymph nodes. Total gastrectomy and D2+para-aortic node dissection were performed. The histological examination revealed complete disappearance of cancer cells in the gastric and nodal specimens, confirming a pathological complete response. The patient underwent postoperative adjuvant chemotherapy, and has been alive 5 years postoperatively without recurrence. PMID- 24047784 TI - [Curative resection of a case of advanced gastric cancer with peritoneal dissemination responding well to combination chemotherapy of docetaxel,cisplatin and S-1]. AB - We report a curative resection of a case with advanced gastric cancer responding remarkably well to combination chemotherapy of docetaxel, cisplatin and S-1. The patient was a 71-year-old man with gastric cancer of Borrmann type 3 accompanied with N3. Staging laparoscopy revealed peritoneal dissemination. He was administered docetaxel intravenously at 40mg/ m2 on day 1, cisplatin intravenously at 60 mg/m2 on day 1, and S-1 orally at 80 mg/m2 on days 1 to 14. This treatment was repeated every 28 days as one course. According to gastroscope and CT findings, a significant tumor reduction was obtained after 4 courses. After 6 courses, a CT scan revealed partial response of the lymph node metastasis, and the serum CEA value was normalized. Curative total gastrectomy was performed. The histological effect of the primary lesion was judged to be grade 2. Combination chemotherapy of S-1, cisplatin and docetaxel can be effective and feasible for advanced gastric cancer. PMID- 24047785 TI - [A case of advanced gastric cancer with tumor embolus in portal vein successfully treated by neoadjuvant chemotherapy, operation and chemoradiotherapy]. AB - A 66-year-old man was admitted to our hospital with a diagnosis of advanced gastric cancer, with a tumor embolus in the portal vein and lymph node metastases. Since curative surgery was deemed impossible, we started neoadjuvant chemotherapy using S-1 plus CDDP. After 1 course of chemotherapy, the embolus in the portal vein disappeared. After additional chemotherapy, the primary tumor and lymph nodes were reduced in size, and a total gastrectomy with splenectomy and lymph node dissection was performed. Although he received S-1 medication as adjuvant chemotherapy, a tumor embolus in the portal vein appeared 8 months after the operation. Chemoradiotherapy(S-1+total of 50.4 Gy)was performed and the tumor embolus disappeared. PMID- 24047786 TI - [Primary small intestinal Burkitt lymphoma treated with rituximab-combined CODOX M/IVAC therapy without surgical resection]. AB - A 38-year-old man complaining of abdominal pain was admitted to our hospital and diagnosed with small bowel obstruction. Whole body computed tomography(CT)scan showed moderate right pleural effusion with pleural and anterior chest wall thickening, with a mass approximately 100 mm in diameter at the terminal ileum. Histopathological and immunohistorical analysis of the endoscopic biopsy from the terminal ileum mass revealed diffuse infiltration of medium-sized, monotonous, atypical B lymphocytes with scanty basophilic cytoplasms carrying the so-called "starry sky" appearance, and primary small intestinal Burkitt lymphoma(BL)was diagnosed. Because of his advanced clinical stage(stage IV with Ann Arbor staging system)and the need for immediate treatment, he was promptly treated with cyclophosphamide and doxorubicin without surgical resection. Fortunately this initial therapy was received without the occurrence of bowel perforation. After initiating additional rituximab combined high-dose chemotherapy consisting of alternating courses of rituximab, cyclophosphamide, vincristine, doxorubicin, and methotrexate(R-CODOX-M)and rituximab, ifosfamide, etoposide, and cytarabine(R IVAC), he achieved complete remission and remains without signs of disease now more than seven years after his last treatment. While further investigation will of course be needed, if possible, immediate chemotherapy without surgical resection is a treatment worth considering for improving the prognosis of those with small intestinal BL. PMID- 24047787 TI - [A case of rectal cancer which showed complete response to chemotherapy for para aortic lymph node metastases remaining after surgery, for which resection of Virchow's lymph node recurrence led to long-term survival]. AB - A 55-year-old man with a positive fecal occult blood test visited our department, and after a thorough medical evaluation, was diagnosed with Stage IV Rs rectal cancer with marked para-aortic lymph node metastasis. In December 2007, the patient underwent low anterior rectal resection with D3 lymph node dissection, but the para-aortic lymph nodes were left. The metastatic lymph nodes showed a complete response(CR)to post-operative chemotherapy with FOLFOX, FOLFIRI, IRIS, and irinotecan+cetuximab, and the complete response was sustained for 18 months after surgery. Later, he developed Virchow's lymph node metastasis, which was also resected. At present, 5 years after the first surgery, the patient, whose chemotherapy has been discontinued, is alive without recurrence. It appears that using key drugs, such as 5-fluorouracil, leukovorin, oxaliplatin, irinotecan, and cetuximab, and performing aggressive salvage surgery for Virchow's lymph node recurrence, led to long-term recurrence-free survival. PMID- 24047788 TI - [A case report of a well-differentiated neuroendocrine tumor in which sunitinib treatment resulted in stable disease]. AB - A 52-year-old woman had a primary neuroendocrine tumor, Grade 2(NET G2)with multiple liver metastases and a mesenteric tumor. Since no drugs were approved for NET at that time in Japan, we treated her with sunitinib after approval by the Ethics Committee of Mie University Hospital and obtaining informed consent. Sunitinib was administered at a daily dose of 37.5mg/day, but the dose was reduced to 12.5mg/day because of thrombocytopenia(G3)and neutropenia(G3). CT revealed stable disease after 3 months of treatment, but disease progression was observed after 11 months. The non-hematological toxicity was hypertension(G3), which was controlled with antihypertensive agents. Although there are no previous reports of the treatment of well-differentiated NET with sunitinib in Japan, sunitinib may be effective against this disease. PMID- 24047789 TI - [A long-term control of gastrointestinal stromal tumor with sunitinib]. AB - The patient was a 70-year-old woman with gastrointestinal stromal tumor(GIST)of the small intestine, accompanied by liver metastasis. Multiple liver metastases were pointed out 3 months after R0 surgery(jejunectomy and hepatectomy). Although she was given radiofrequency ablation(RFA)therapy and imatinib, metastatic tumors progressed. In a further examination at our institution 21 months after R0 surgery, multiple liver, bone, and lung metastases were indicated, and she was given sunitinib once daily at a 50mg in 6-week courses, with 4 weeks on and 2 weeks off treatment. Although sunitinib dosage was decreased to 25mg/day because of adverse events, 21 courses of this treatment were administered, and it took 137 weeks to progress her disease with this sunitinib treatment. At our institution, seven cases of GIST were treated with sunitinib, and the median time to progression was 30-weeks. That was almost the same result as for Japan and international clinical trials. Sunitinb treatment may be one of the most important therapeutic options for unresectable imatinib-resistant GIST. PMID- 24047790 TI - [A case on hemodialysis with castration-resistant prostate cancer which responded to combination chemotherapy with docetaxel and prednisolone]. AB - A 71-year-old man on hemodialysis was admitted for castration-resistant prostate cancer. He received chemotherapy with docetaxel(60mg/m2 every 3 weeks)and prednisolone(10mg/day). As severe adverse reactions due to chemotherapy were not encountered, he could receive chemotherapy in our outpatient clinic. A total of four courses of chemotherapy resulted in a 56% reduction in PSA, which was judged as PR. Chemotherapy with docetaxel and prednisolone can be safely carried out for a patient with castration-resistant prostate cancer, even while on hemodialysis with the usual dose of docetaxel. PMID- 24047791 TI - [Carcinosarcoma of the ovary treated with paclitaxel and carboplatin chemotherapy - a report of 4 cases]. AB - Ovarian carcinosarcoma is a rare gynecologic malignancy that tends to develop in elderly women. This tumor consists of both carcinomatous and sarcomatous components and is associated with a poor prognosis. Because of its rarity, the optimal chemotherapeutic regimen to treat this tumor is yet to be determined. We report 4 cases of ovarian carcinosarcoma treated with paclitaxel/carboplatin(PC)therapy. The median age was 67 years(range, 64-72 years). Two patients with stage II c disease underwent a primary debulking surgery; one had microscopic residual and the other had<1 cm residual disease, and both patients received adjuvant PC therapy. In 2 other patients, a stage III patient and a stage IV patient, a partial response was achieved with neoadjuvant chemotherapy. They underwent an interval debulking surgery(residual disease<1 cm in both patients)followed by additional PC therapy. Recurrence developed in 3 patients except for 1 stage II c patient with microscopic residual disease. These 3 recurrences developed in the pelvis. Progression-free survival ranged 3-15 months; in the stage II c patient, disease progressed during adjuvant PC therapy. Overall survival of the 3 patients with recurrence ranged 6- 41 months. In conclusion, paclitaxel and carboplatin chemotherapy is an effective regimen for ovarian carcinosarcoma, although the duration of response is relatively short. PMID- 24047792 TI - [A case of blastic plasmacytoid dendritic cell neoplasm involving the skin]. AB - A 81 year-old male patient visited our hospital on February, 2011 because he found the subcutaneous tumor on his back. The dermatologist performed skin biopsy and found that large atypical cells diffusely proliferated in the sub-epidermal and subcutaneous tissue. Two month later, we diagnosed him as blastic plasmacytoid dendritic cell tumor, as the blastic cells in the lymph node were CD4+, CD56+, CD3-, CD5-, CD20-, CD138-, MPO-, granzyme B-, TCL1+. None of the gene rearrangements of T-cell receptor and immunoglobulin was negative in the lymph node. The tumor was relapsed after 3 courses of COP therapy and the patient failed to respond to the salvage therapies such as CEPP and FMD therapy. As this tumor is rare and there are no standard regimens, we reviewed the past case series and discussed about the pathogenesis, clinical course and treatment options of this tumor in this article. PMID- 24047793 TI - [Effect of transarterial chemoembolization for recurrent desmoid tumor - a case report]. AB - Desmoid fibromatosis is classified as a benign soft tissue tumor regardless of its local invasive behavior and its, local recurrence rate is 57-85% after local resection. A 19 y/o male patient with post-operative recurrence of a desmoid tumor in the shoulder was initially treated by arterial embolization; however, no improvement of symptoms was obtained. As second-line treatment, 20 mg of epirubicin, 50 mg of cisplatin and 250 mg of 5-FU were infused to tumor-related arteries and embolization was performed with a super absorbent polymer microsphere. After a single session of treatment, reduction of tumor size and improvement of symptoms were achieved. The same treatment was repeated three times without major complications. Considerable reduction of tumor was obtained after treatment. Chemo-embolization should be considered for the postoperative recurrence of desmoid fibromatosis, in order to prevent loss of function and maintain a high QOL for the patient. PMID- 24047794 TI - Plasma gelsolin levels are decreased and correlate with fibrosis in IgA nephropathy. AB - IgA nephropathy (IgAN) is an immune complex glomerulonephritis that is characterized by recurrent hematuria as the main clinical manifestation. In this study, we used the IgAN mouse model which was previously established to investigate the possible mechanism by which IgAN fibrosis correlates with decreased plasma gelsolin (pGSN) levels. We investigated the levels of pGSN, transforming growth factor beta1 (TGFbeta1), and oxidative stress markers including superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and malondialdehyde (MDA) in the serum and renal tissues of different groups. The between-group differences and correlations in the results for the IgAN group were analyzed with statistical methods. The pathological and urinalysis results obtained from the IgAN mouse model showed that this model conforms to the basic lesion characteristics observed in human IgAN. The serum pGSN levels and SOD, CAT, GSH levels in renal tissues were decreased in the IgAN group (P < 0.01), and pGSN, TGFbeta1, MDA levels in renal tissues of the IgAN group were increased which compared with those in the other groups (P < 0.01). The correlation analysis for serum pGSN levels in the IgAN group showed a significant correlation with different test results (P < 0.01). The possible mechanism by which IgAN fibrosis correlates with decreased pGSN levels involves the regulation of TGFbeta1 and oxidative stress. PMID- 24047795 TI - Mutant PAX6 downregulates prohormone convertase 2 expression in mouse islets. AB - Transcriptional factor paired box 6 (PAX6) is very important for the development of the eyes, central nervous system, and pancreas. PAX6 mutations are associated with a diabetic phenotype and abnormal glucose metabolism. Our previous study showed that PAX6 directly bound to and activated the prohormone convertase 1/3 (Pc1/3) gene promoter and subsequently regulated proinsulin processing. Prohormone convertase 2 (PC2) is the essential enzyme for pancreatic proinsulin processing. To study the regulation of PAX6 in Pc2 expression, we did research on the pancreas of Pax6 R266Stop mutant mice, where truncated mutations happened in the C-terminal of the PAX6 protein. Our studies showed that the mutant PAX6 protein was stable and regulated the activity of Pc2 promoter as shown by luciferase activity assays. We found that the wild-type PAX6 protein imparts a transcriptional effect, and the mutant PAX6 can also regulate the downstream molecules. The results provide new insights into the mechanism of truncated PAX6 in regulating the functions of the pancreas and endocrine system. PMID- 24047796 TI - Hydrodynamic cavitation kills prostate cells and ablates benign prostatic hyperplasia tissue. AB - Hydrodynamic cavitation is a physical phenomenon characterized by vaporization and bubble formation in liquids under low local pressures, and their implosion following their release to a higher pressure environment. Collapse of the bubbles releases high energy and may cause damage to exposed surfaces. We recently designed a set-up to exploit the destructive nature of hydrodynamic cavitation for biomedical purposes. We have previously shown that hydrodynamic cavitation could kill leukemia cells and erode kidney stones. In this study, we analyzed the effects of cavitation on prostate cells and benign prostatic hyperplasia (BPH) tissue. We showed that hydrodynamic cavitation could kill prostate cells in a pressure- and time-dependent manner. Cavitation did not lead to programmed cell death, i.e. classical apoptosis or autophagy activation. Following the application of cavitation, we observed no prominent DNA damage and cells did not arrest in the cell cycle. Hence, we concluded that cavitation forces directly damaged the cells, leading to their pulverization. Upon application to BPH tissues from patients, cavitation could lead to a significant level of tissue destruction. Therefore similar to ultrasonic cavitation, we propose that hydrodynamic cavitation has the potential to be exploited and developed as an approach for the ablation of aberrant pathological tissues, including BPH. PMID- 24047797 TI - Emu oil expedites small intestinal repair following 5-fluorouracil-induced mucositis in rats. AB - Mucositis resulting from cancer chemotherapy is characterized by intestinal inflammation and ulceration. Previously, emu oil (EO) improved intestinal architecture (Br J Nutr, 2010) in a rat model of chemotherapy-induced mucositis. We investigated EO for its further potential to promote intestinal repair in this mucositis model. Female Dark Agouti rats (n = 8/group) were gavaged with water, olive oil (OO) or EO once daily (1 mL), injected with 5-fluorouracil (5-FU) or saline on day 5 and euthanized on day 8, 9, 10 or 11. Intestinal villus height (VH) and crypt depth (CD), neutral mucin-secreting goblet cell (GC) count, myeloperoxidase (MPO) activity and selected cytokines were quantified; P < 0.05 was considered significant. In 5-FU-injected rats, only EO administration significantly increased VH in the ileum (day 8), jejunum and jejunum-ileum junction (days 8 and 9) compared to 5-FU controls (P < 0.05). GC count was significantly reduced by 5-FU (jejunum: days 8 and 9; ileum: day 8; P < 0.05) and EO increased ileal GC on days 10 and 11 compared to 5-FU controls. MPO activity was significantly increased in jejunum (days 8 and 9) and ileum (day 8) following 5-FU injection, compared to normal controls (P < 0.05). Both EO and OO significantly reduced jejunal MPO on days 8 and 9; however, only EO decreased ileal MPO on day 8. Cytokine levels were not significantly affected by either oil or 5-FU administration at the day 8 time point. Promotion of repair from injury could represent a new mechanism of action for EO, suggesting potential as an adjunct to conventional treatment approaches for cancer management. PMID- 24047798 TI - Melioidosis in traveler from Africa to Spain. AB - The worldwide epidemiology of melioidosis is changing. We describe a case of acute melioidosis in Spain in a patient who had traveled to Africa. A novel sequence type of Burkholderia pseudomallei was identified in this patient. Clinicians should be aware of the possibility of melioidosis in travelers returning from melioidosis-nonendemic regions. PMID- 24047799 TI - The human rotavirus vaccine RotarixTM in infants: an integrated analysis of safety and reactogenicity. AB - An integrated analysis of safety and reactogenicity data was undertaken for 28 randomized, placebo-controlled, double-blind Phase II and III trials (DBRCTs) of the oral live-attenuated human rotavirus vaccine, RotarixTM (GlaxoSmithKline Vaccines). Healthy infants aged 6-20 wk received 2 or 3 doses of vaccine (n=56562) or placebo (n=45512) at 4- to 8-wk intervals. Solicited adverse events (AEs) were recorded for 8 d after each dose of vaccine or placebo. Unsolicited AEs, serious AEs (SAEs), and deaths were evaluated over 31-d post-vaccination follow-up periods. 95% confidence intervals (CIs) for the relative risk (RR) across studies excluding "1.0" signified potential imbalances between the 2 groups. The incidence of each solicited AE of any or Grade 3 severity was similar between groups. The incidence of all unsolicited AEs of any (RR=0.99 [95% CI: 0.94-1.04]; P=0.72) or Grade 3 severity (RR=0.91 [95% CI: 0.77-1.08]; P=0.31) was similar between groups. A significantly higher proportion of SAEs were reported in the placebo group compared with the vaccine group (RR=0.9 [95% CI: 0.82-0.98]; P=0.01). The incidence of death was low and similar between the 2 groups (0.13% in the vaccine group and 0.11% in the placebo group; RR=1.14 [95% CI: 0.78-1.68]; P=0.54). Very few cases of intussusception were reported (11 and 7 in the vaccine and placebo groups, respectively; RR=1.39 [95% CI: 0.49-4.27]; P=0.66). In conclusion, results of this analysis of DBRCTs show that the human rotavirus vaccine RotarixTM has a reactogenicity and safety profile similar to placebo. PMID- 24047800 TI - Evaluation of licorice flavonoids as protein tyrosine phosphatase 1B inhibitors. AB - Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator in insulin- and leptin-signaling cascades as well as a positive regulator in tumorigenesis, and much attention has been paid to PTP1B inhibitors as potential therapies for diabetes, obesity, and cancer. In the present study, the screening of a compound library of licorice flavonoids allowed for the discovery of several compounds, including licoagrone (3), licoagrodin (4), licoagroaurone (5), and isobavachalcone (6), as new PTP1B inhibitors. It was revealed that these compounds inhibit the activity of PTP1B in different modes and with different selectivities and that they exhibit different cellular activity in the insulin signaling pathway. Glycybenzofuran (1), a competitive PTP1B inhibitor, showed both excellent inhibitory selectivity against PTP1B and cellular activity on the insulin-stimulated Akt phosphorylation level. The similarity of its action profiling in the insulin-signaling pathway suggested its potential as a new anti insulin-resistant drug candidate. PMID- 24047801 TI - Quality of life of patients with atrial septal defect following percutaneous closure. AB - INTRODUCTION: Quality of life has become an important outcome measure in addition to mortality and morbidity in patients with congenital heart disease. Atrial septal defect is a common congenital heart disease, and transcatheter atrial septal defect closure has become an accepted treatment modality. The aim of this study is to assess the quality of life of patients with atrial septal defect who underwent percutaneous closure. MATERIALS AND METHODS: We examined the quality of life of 69 patients with atrial septal defect and 69 healthy controls matched according to age, sex, educational level, and economic, marital, and employment status. Quality of life was investigated using the Turkish version of Short Form 36. RESULTS: The mean age of the patients was 39.7 +/- 14.2 and 26% were male. The quality of life assessment was performed at a mean follow-up time of 18.0 +/- 13.8 months after the intervention. The mean scores of the domains of the Short Form-36, namely, physical functioning, role functioning, social functioning, mental health, vitality, pain, and general health, were similar in patients with atrial septal defect who underwent percutaneous closure and the control group. CONCLUSION: Adult patients who underwent percutaneous atrial septal defect closure perceive their quality of life to be as good as their healthy counterparts. PMID- 24047802 TI - [Pay more attention to basic and clinical study for pleural effusions]. PMID- 24047803 TI - [Is pleurodesis superior to indwelling pleural catheter in the management of malignant pleural effusion]. PMID- 24047804 TI - [Evaluation of febrinolytic therapy for treatment of pleural infection]. PMID- 24047805 TI - [Idiopathic pleuroparenchymal fibroelastosis: a new subtype of idiopathic interstitial pneumonia]. PMID- 24047806 TI - [The diagnostic value of medical thoracoscopy for unexplained pleural effusion]. AB - OBJECTIVE: To explore the endoscopic features of patients with unexplained pleural effusion, and to evaluate the diagnostic value of medical thoracoscopy. METHODS: A retrospective analysis of 2380 patients with unexplained pleural effusion (1320 males and 1060 females; age 15-94 years) in Shandong Provincial Hospital from 1992 to 2011 were performed .The diagnosis was confirmed by medical thoracoscopy. RESULTS: The endoscopic findings of malignant pleural effusion mostly showed nodules of varying sizes. The nodules could be grape-like, cauliflower-like, fused into masses, or diffused small nodules . The appearance of cancerous nodules was more diversified compared to tuberculous nodules. Tuberculous pleurisy was manifested as diffuse pleural congestion and miliary changes, multiple small gray-white nodules, fibrin deposition and adhesion in the pleural cavity, pleural thickening and loculation . The pathological diagnosis was as follows: pleural metastases in 899 (37.8%), primary pleural mesothelioma in 439 (18.4%), tuberculous pleurisy in 514 (21.6%), non-specific inflammation in 226 (9.5%), empyema in 190 (8.0%), hepatic pleural effusion in 36 (1.5%) and pleural effusion of unknown causes in 76 (3.2%) cases. The diagnostic positive rate of medical thoracoscopy was 96.8%. No serious complications were observed. CONCLUSION: Medical thoracoscopy is a relatively safe procedure and has an important application value in the diagnosis of unexplained pleural effusion. PMID- 24047807 TI - [Effects of different cytokines on proliferation and apoptosis of pleural mesothelial cells in human Mycobacterium tuberculosis infection]. AB - OBJECTIVE: To investigate the effects of different cytokines (IL-22, IL-17, IFN gamma) on proliferation and apoptosis of human pleural mesothelial cells (PMC) during Mycobacterium tuberculosis infection. METHODS: The expressions of IL-22R, IL-17R and IFN-gammaR1 on PMC purified from tuberculous pleural effusion (TPE) were determined by flow cytometry. The effects of one or more of IL-22, IL-17, and IFN-gamma on Ki-67 expression and apoptosis of PMC were explored. Ki-67 expression of PMC under the conditions of the absence or presence of exogenous TPE and with a combination of control IgG, or anti-IL-22, -IL-17 or -IFN-gamma mAbs were determined. RESULTS: (1) During Mycobacterium tuberculosis infection, IL-22R, IL-17R and IFN-gammaR1 were highly expressed on the surface of PMC [(86.2 +/- 2.9)%, (41.5 +/- 4.4)% and (64.9 +/- 5.8)% respectively]. (2) In group IL-22 + IL-17, the percentage of Ki-67(+)PMC was (31.5 +/- 2.0) % and (26.1 +/- 2.4) % respectively, which were both higher than that in the medium group [ (14.6 +/- 0.7)%] (q = 6.8 and 4.9, respectively, both P < 0.05). In group IFN-gamma, the percentage of Ki-67(+)PMC was (5.2 +/- 1.2) %, which was lower than that in the medium group (q = 5.0, P < 0.05). In group IFN-gamma+IL-22 and IFN-gamma+IL-17, the percentages of Ki-67(+)PMC were (23.4 +/- 1.7)% and (21.8 +/- 3.8)% respectively, which were both higher than that in group IFN-gamma (q = 7.3 and 6.7, respectively, both P < 0.05). In group TPE and TPE+IgG, the percentages of Ki-67(+)PMC were (63 +/- 9) % and (63 +/- 11) % respectively, which were both higher than that in the medium group (q = 19.6 and 19.7, respectively, both P < 0.05). In group TPE+ anti-IFN-gamma mAb, the percentage of Ki-67(+)PMC was (82 +/ 4) %, which was even higher than that in group TPE+IgG (q = 7.5,P < 0.05) . In group TPE + anti-IL-22 mAb, the percentage of Ki-67(+)PMC was (34 +/- 3) %, which was lower than that in group TPE+IgG (q = 11.8, P < 0.05). In group TPE + anti-IL 17 mAb, the percentage of Ki-67(+)PMC was (58 +/- 5) %, which showed no significant difference compared to that in group TPE+IgG (q = 2.1, P > 0.05). (3) The percentage of apoptotic PMC in group IFN-gamma was (19.3 +/- 1.1)%, which was higher than that in the medium group[ (4.3 +/- 0.6)%] (q = 33.4,P < 0.05) . The percentage of apoptotic PMC in group IL-22 + IL-17 was (3.8 +/- 0.6)% and (5.7 +/ 0.8)% respectively, which had no significant difference compared to that in the medium group (q = 1.3 and 3.0, respectively, both P > 0.05). The percentage of apoptotic PMC in group IFN-gamma + IL-22 and IFN-gamma+ IL-17 were (6.5 +/- 0.7) % and (8.7 +/- 1.7)% respectively, which were both lower than that in group IFN gamma (q = 28.5 and 23.6, respectively, both P < 0.05). CONCLUSION: During Mycobacterium tuberculosis infection, IFN-gamma inhibited PMC proliferation and contributed to apoptosis, while IL-22 and IL-17 promoted PMC proliferation without influencing PMC apoptosis and succeeded in reversing the effect induced by IFN-gamma. PMID- 24047808 TI - [Antimicrobial susceptibility of community-acquired respiratory tract pathogens isolated from patients in primary hospitals in Shanghai from 2007 to 2010]. AB - OBJECTIVE: To investigate the etiology of community-acquired respiratory tract infections (CARTI) and the antimicrobial resistance of the major pathogens in primary hospitals in Shanghai. METHODS: Patients with CARTI were prospectively recruited from 30 primary hospitals from December 2007 to July 2010. Those who had used antimicrobials within previous 2 weeks were excluded from the study. The clinical information such as temperature, white blood cell (WBC) count and percentage of neutrophils was recorded, and throat swab or deep cough sputum was collected to isolate pathogens. The specimens were collected and couriered to the Zhongshan Hospital microbiology laboratory within 2 h for bacterial culture. The minimal inhibition concentrations (MIC) of penicillin G, amoxicillin, cephradine, cephalexin, cefadroxil, sulfamethoxazole/trimethoprim and azithromycin were determined using the agar dilution test. RESULTS: Totally 806 qualified cases were enrolled in this study. Fever (T >= 38 degrees C) was present in 51.7% (n = 417) , and increased WBC count (>10*10(9)/L) was noted in 68.5% (n = 552 cases) of the patients. For bacterial culture, 184 strains were isolated from throat swabs of 688 patients with upper respiratory infection; the most frequently isolated bacteria were Haemophilus influenzae (44, 23.9%), Staphylococcus aureus (44, 23.9%) and Group G streptococcus (43, 23.0%). Thirty-three strains were isolated from 118 patients with lower respiratory infections, with Haemophilus influenza (21, 63.6%), Group G streptococcus (6,18.2%) and Streptococcus pneumoniae (3,9.1%) as the leading pathogens. All strains of Haemophilus influenzae were susceptible to azithromycin. The susceptibility rate of Streptococcus pneumoniae to penicillin was as high as 94.7%, while that to azithromycin was significantly decreased (21.1%). The MIC90 values of cephalexin, cefadroxil and ceftazidime for beta-hemolytic streptococcus spp were <= 2 mg/L. CONCLUSIONS: Upper respiratory infections were responsible for most cases of CARTI. The commonly used antimicrobials in primary hospitals kept a high susceptibility to the frequent pathogens for CARTI. However, Streptococcus pneumoniae showed a decreased susceptibility to macrolides, which should be used carefully as a single agent when treating CARTI. PMID- 24047809 TI - [Diagnostic investigation of the detection of granulocyte-macrophage colony stimulating factor antibody in serum for pulmonary alveolar proteinosis]. AB - OBJECTIVE: To evaluate the diagnostic value of granulocyte-macrophage colony stimulating factor (GM-CSF) antibody in serum for pulmonary alveolar proteinosis (PAP). METHODS: Twelve PAP patients visiting Peking University People's Hospital or Fujian Provincial Hospital from January 1, 2002 to December 31, 2012, 25 patients with other pulmonary diseases (disease control), and 25 healthy volunteers (healthy control) were recruited in the study. The titer level of GM CSF antibody in serum was determined with enzyme-linked immunosorbent assay (ELISA), and the clinical characteristics were collected in the PAP patients. RESULTS: The geometric mean titers of GM-CSF antibody in the PAP patients, the disease controls and the healthy controls were 1: 25 349, 1: 311 and 1: 256, respectively. The differences between the disease controls and the healthy controls were of no statistic significance (t = -1.14, P = 0.261) . With 3 times standard error (3s) above the mean value as the higher limit of X value(X = lgT, T standing for the reciprocal of the titer), the upper limit for T was 1698. With the T value >= 1698 as the diagnostic threshold for PAP, both the sensitivity and the specificity were 100%. The diagnostic value of GM-CSF antibody was similar to that of surgical lung biopsy and higher than that of transbronchial lung biopsy. CONCLUSION: The detection of serum GM-CSF is non-invasive, convenient and efficient for the diagnosis of PAP with high sensitivity and specificity. PMID- 24047810 TI - [Clinical analysis of 15 cases of saddle pulmonary embolism]. AB - OBJECTIVE: To improve recognition of saddle pulmonary embolism (SPE). METHODS: A retrospectively review was performed for patients diagnosed with SPE determined by CTPA from Jan 2004 to Jan 2012. RESULTS: Fifteen SPE patients(4.44%) were found in 338 documented PE patients confirmed by CTPA. There were 7 males and 8 females, with an average age of (57 +/- 13) years. The bifurcation of the main pulmonary artery was completely blocked in one case, while partial obstruction was found in the others. Hemodynamic stability was observed in 11 cases, shock in 1 case, and hypotension in 3 cases. Thromboembolectomy was performed in 1 case accompanied by patent foramen ovale straddling thrombus, and thrombolytic therapy was administered in 5 cases while anticoagulant therapy alone in 9 cases. All the cases survived. Minor bleeding was observed in 2 patients and no major bleeding occurred. CONCLUSION: The prevalence of SPE in this series was similar to that reported in the literature. But the incidence might be underestimated. Mortality rate was low. No more aggressive therapeutic interventions (thrombolytics or catheter thrombectomy) were needed in those patients with hemodynamic stability and without patent foramen ovale straddling thrombus. PMID- 24047811 TI - [Evaluation of the reliability of thiophen-2-carboxylic acid hydrazine result for the identification of Mycobacterium bovis]. AB - OBJECTIVE: To evaluate the reliability of thiophen-2-carboxylic acid hydrazine (TCH) test for identification of Mycobacterium bovis (M. bovis). METHODS: A total of 4069 clinically isolated strains were identified by P-Nitrobenzoic acid medium (500 mg/L) and TCH medium (5 mg/L). Mycobacterium tuberculosis (M. tuberculosis) complex strains susceptible to 5 mg/L TCH were further tested for susceptibility to 2 mg/L TCH. Spacer oligonucleotide typing (spoligotyping) and multi-loci PCR were also performed to identify TCH susceptible strains. RESULTS: Among the 4069 isolated strains there were 3929 strains belonging to M. tuberculosis complex (MTBC) of which 245 were susceptible to 5 mg/L TCH. Of these 245 strains, 20 were also susceptible to 2 mg/L TCH, while only 1 strain was identified to be M. bovis by both spoligotyping and multi-loci PCR. CONCLUSION: TCH susceptibility test (either 5 mg/L or 2 mg/L) is not a reliable method for identification of M. bovis. PMID- 24047812 TI - [Establishment of a Mycobacterium tuberculosis proteasome inhibitor model in vitro]. AB - OBJECTIVE: To establish a model for screening Mycobacterium tuberculosis (M. tuberculosis) proteasome inhibitors in vitro. METHODS: The proteasome inhibitor in vitro screening model was established according to the principle that the fluorescent substrate Suc-Leu-Leu-Val-AMC (S-LLVY-AMC) was hydrolyzed by the proteasome and released AMC (7-amino-4-methylcoumarin) which was fluorescent, and the fluorescence value was proportional to the proteasome activity. Conditions which could affect proteasome activity including the time of the reaction, concentration of proteasome, or SDS, were evaluated. The model was validated by using the known proteasome inhibitor MG132 and 8 natural products. Linear correlation and regression analysis were performed by the factors affecting fluorescence values. RESULTS: In the model for screening M. tuberculosis proteasome inhibitors in vitro, the reaction system consisted of 0.34 mg/L SDS, 25 mg/L protein and 64 umol/L S-LLVT-AMC, and the reaction time was 30 min. By using MG132 and natural compounds A-H to validate the MTB proteasome screening model, the calculated IC50 of MG132 was 49 umol/L. In a final concentration of 200 umol/L, the inhibition rates of 8 drugs on MTB proteasome were 0.0%, 3.1%, 7.8%, 45.2%, 52.4%, 69.5%, 69.6%, 88.7% respectively, confirming that the model was repeatable and reliable. CONCLUSIONS: In this study, we established a model for screening M. tuberculosis proteasome inhibitors in vitro, which could provide a technical platform for fast and large scale screening of mycobacterial proteasome inhibitors. PMID- 24047813 TI - [New insight into the airway remodeling of asthma:IgE]. PMID- 24047814 TI - [Advances in pathophysiology hypoxia inducible factor-1 in obstructive sleep apnea syndrome]. PMID- 24047815 TI - [Advances in venous thromboembolism]. PMID- 24047816 TI - [Recent progress in the genotyping studies of Mycobacterium tuberculosis]. PMID- 24047817 TI - A phase II study of an investigational tetravalent influenza vaccine formulation combining MF59(r): adjuvanted, pre-pandemic, A/H5N1 vaccine and trivalent seasonal influenza vaccine in healthy adults. AB - An investigational tetravalent vaccine combining pre-pandemic, MF59(r)-adjuvanted A/H5N1 vaccine with non-adjuvanted, trivalent, seasonal influenza vaccine has been developed, which has the potential to be used for pre-pandemic priming and to improve levels of compliance and coverage. It is important to determine whether the safety and immunogenicity of the combination vaccine is equivalent to that of the two separate vaccines when administered concomitantly. Healthy adults (n=601) were randomly assigned to three vaccination groups to receive either: (1) tetravalent vaccine and placebo concomitantly (in separate arms) on Day 1, followed by A/H5N1 vaccine on Day 22; (2) A/H5N1 vaccine and placebo concomitantly on Day 1, followed by tetravalent vaccine on Day 22; or (3) A/H5N1 and seasonal vaccines concomitantly on Day 1, followed by A/H5N1 vaccine on Day 22. Antibody responses were measured using single radial hemolysis (SRH), haemagglutination inhibition (HI), and microneutralization (MN) assays on Days 1, 22, and 43. Solicited adverse reactions were recorded for seven days after vaccination. Spontaneous adverse events were recorded throughout the study. The tetravalent vaccine elicited antibody titers equivalent to those for separate A/H5N1 and seasonal vaccines, and sufficient to meet the European licensure criteria against A/H5N1 and all three seasonal strains. Local and systemic reactions were mainly mild to moderate. No vaccine-related serious adverse events occurred. These findings demonstrate that MF59-adjuvanted A/H5N1 and seasonal influenza vaccines had an acceptable safety profile and could be effectively administered as a tetravalent formulation, supporting the possibility of integrating pre-pandemic priming into seasonal influenza vaccination programs. PMID- 24047818 TI - Postdischarge complications predict reoperation and mortality after otolaryngologic surgery. AB - OBJECTIVES: (1) Determine procedure-specific rates of postdischarge complications (PDCs) and their risk factors in the first 30 days following inpatient otolaryngologic surgery. (2) Evaluate association between PDCs and risk of reoperation and mortality. STUDY DESIGN: Retrospective cohort study. SETTING: American College of Surgeons National Surgical Quality Improvement Program (2005 2011). SUBJECTS AND METHODS: We identified 48,028 adult patients who underwent inpatient otolaryngologic surgery. Outcomes of interest included complications, reoperation, and mortality in the first 30 days following surgery. Statistical analysis included chi-square, t tests, and multivariate regression. RESULTS: Laryngectomy, lip, and tongue/floor of mouth surgery had the highest PDC rates (8.0%, 7.4%, and 4.1%, respectively). Within the first 48 hours, week, and 2 weeks post discharge, 10%, 44%, and 73% of PDCs occurred, respectively. Common PDCs included surgical site infections (53.6%), other infections (37.4%), and venous thromboembolic events (7.4%). Multivariate analysis demonstrated that increasing age (odds ratio [OR] = 1.01; 95% confidence interval [CI], 1.01-1.02), prolonged operative time (OR = 1.68; 95% CI, 1.39-2.03), hospital stay >1 day (OR = 1.49; 95% CI, 1.18-1.86), and American Society of Anesthesiologists (ASA) class >= 3 (OR = 1.45; 95% CI, 1.18-1.78) were independently associated with PDCs. Patients with PDCs were more likely to die (0.9% vs 0.1%, P < .001) or have a reoperation (10.4% vs 1.2%, P < .001). CONCLUSION: This is the first study of overall postdischarge events after otolaryngologic surgery. PDC rates in otolaryngology occur soon after discharge, are procedure specific, and are associated with reoperation and mortality. Targeted procedure-specific triage and follow-up plans for high-risk patients may improve outcomes. PMID- 24047819 TI - PrP mRNA and protein expression in brain and PrP(c) in CSF in Creutzfeldt-Jakob disease MM1 and VV2. AB - Creutzfeldt-Jakob disease (CJD) is a heterogenic neurodegenerative disorder associated with abnormal post-translational processing of cellular prion protein (PrP(c)). CJD displays distinctive clinical and pathological features which correlate with the genotype at the codon 129 (methionine or valine: M or V respectively) in the prion protein gene and with size of the protease-resistant core of the abnormal prion protein PrP(sc) (type 1: 20/21 kDa and type 2: 19 kDa). MM1 and VV2 are the most common sporadic CJD (sCJD) subtypes. PrP mRNA expression levels in the frontal cortex and cerebellum are reduced in sCJD in a form subtype-dependent. Total PrP protein levels and PrP(sc) levels in the frontal cortex and cerebellum accumulate differentially in sCJD MM1 and sCJD VV2 with no relation between PrP(sc) deposition and spongiform degeneration and neuron loss, but with microgliosis, and IL6 and TNF-alpha response. In the CSF, reduced PrP(c), the only form present in this compartment, occurs in sCJD MM1 and VV2. PrP mRNA expression is also reduced in the frontal cortex in advanced stages of Alzheimer disease, Lewy body disease, progressive supranuclear palsy, and frontotemporal lobe degeneration, but PrP(c) levels in brain varies from one disease to another. Reduced PrP(c) levels in CSF correlate with PrP mRNA expression in brain, which in turn reflects severity of degeneration in sCJD. PMID- 24047820 TI - Common variation contributes to the genetic architecture of social communication traits. AB - BACKGROUND: Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype. METHODS: We performed a genome-wide association study on parent-reported social communication problems using items of the children's communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364). RESULTS: Two of our seven independent top signals (P-discovery <1.0E-05) were replicated (0.009 = 0.40). The 96 patients for whom follow-up was obtained included 53 in the operative and 43 in the nonoperative groups. At baseline, there were no significant differences between these groups based on age, pain score, body mass index, smoking, or gender (P >= 0.25). Mean follow-up was 63 months for operative and 58 months for nonoperative patients (P = 0.20). The mean pain score at last follow-up improved significantly for operative and nonoperative patients (P < 0.001). At follow-up, operative and nonoperative groups did not differ significantly with regard to pain scores, Oswestry disability index, short form-12, or satisfaction scale. CONCLUSIONS: Comparison of long-term outcomes for patients with back pain and concordant discography did not demonstrate a significant difference in outcome measures of pain, health status, satisfaction, or disability based on whether the patient elected for fusion or nonoperative treatment. PMID- 24047822 TI - Reliability of laser speckle flow imaging for intraoperative monitoring of cerebral blood flow during cerebrovascular surgery: comparison with cerebral blood flow measurement by single photon emission computed tomography. AB - OBJECTIVE: To determine the clinical utility of laser speckle flow imaging (LSFI) and its comparability to (123)I-iodoamphetamine single photon emission computed tomography (IMP-SPECT), we used LSFI to monitor cerebral blood flow (CBF) during extracranial-intracranial (EC-IC) bypass surgery. METHODS: Intraoperative intensity of CBF (iCBF) by LSFI and preoperative and postoperative CBF by IMP SPECT were measured in 3 patients with internal carotid artery (ICA) aneurysms who were undergoing ICA trapping surgery and in 16 patients with major cerebral artery occlusion who were undergoing EC-IC bypass surgery. RESULTS: The decrease in iCBF (16.9% +/- 2.3%) with ICA interruption was equivalent to the decrease in CBF during the preoperative balloon test occlusion, as measured by IMP-SPECT (12.2% +/- 4.4%). Whether preserved iCBF in LSFI promised postoperative intact CBF was not determined, as no patient showed ischemic tolerance by ICA occlusion. The increase in iCBF resulting from EC-IC bypass correlated moderately with the increase in postoperative CBF as measured by IMP-SPECT. However, the increase in iCBF was too small to be recognized intraoperatively by visual inspection. CONCLUSIONS: Although LSFI clearly demonstrated a decrease in CBF, the information is taken only from the surface of the brain. Combined use of LFSI with an electrophysiologic examination is required for intraoperative diagnosis of ischemia. LSFI was not sensitive enough to detect increased CBF by superficial temporal artery-to-middle cerebral artery anastomosis, because CBF changes are minimized during anesthesia, probably owing to low metabolic activity. PMID- 24047823 TI - Ce electronic states in Nd(0.45-x)Ce(x)Sr0.55MnO3 probed by x-ray absorption spectroscopy and photoemission. AB - We have investigated the Ce 4f electronic states in the Ce-doped manganites Nd(0.45-x)Ce(x)Sr0.55MnO3 (NCSMO) by means of x-ray absorption spectroscopy (XAS) and hard x-ray photoelectron spectroscopy (HAXPES). The Ce 3d XAS shows that the Ce ions exist in the form of the Ce(3+) and Ce(4+) mixed-valent states, and we have found that the XAS spectral features change with temperature. The Ce 3d XAS and HAXPES spectra for NCSMO agree reasonably well with calculated results based on the single-impurity Anderson model, which takes into account the atomic multiplets and two valence bands. The estimated Ce bulk valence of Nd0.15Ce0.3Sr0.55MnO3 decreases from 3.44 to 3.30 with cooling. PMID- 24047825 TI - Open letter: let us treat patients in Syria. PMID- 24047826 TI - Genome-wide association study identifies 3 genomic loci significantly associated with serum levels of homoarginine: the AtheroRemo Consortium. AB - BACKGROUND: Low serum levels of the amino acid derivative, homoarginine, have been associated with increased risk of total and cardiovascular mortality. Homoarginine deficiency may be related to renal and heart diseases, but the pathophysiologic role of homoarginine and the genetic regulation of its serum levels are largely unknown. METHODS AND RESULTS: In 3041 patients of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study referred for coronary angiography and 2102 participants of the Young Finns Study (YFS), we performed a genome-wide association study to identify genomic loci associated with homoarginine serum levels and tested for associations of identified single nucleotide polymorphisms with mortality in LURIC. We found genome-wide significant associations with homoarginine serum levels on chromosome 2 at the carbamoyl phosphate synthetase I locus, on chromosome 5 at the alanine-glyoxylate aminotransferase 2 locus, and on chromosome 15 at the glycine amidinotransferase locus, as well as a suggestive association on chromosome 6 at the Homo sapiens mediator complex subunit 23 gene/arginase I locus. All loci harbor enzymes located in the mitochondrium are involved in arginine metabolism. The strongest association was observed for rs1153858 at the glycine amidinotransferase locus with a P value of 1.25E-45 in the combined analysis and has been replicated in both the Die Deutsche Diabetes Dialyse Studie (4D study) and the Graz Endocrine Causes of Hypertension (GECOH) study. CONCLUSIONS: In our genome-wide association study, we identified 3 chromosomal regions significantly associated with serum homoarginine and another region with suggestive association, providing novel insights into the genetic regulation of homoarginine. PMID- 24047827 TI - Trends in dietary fat and high-fat food intakes from 1991 to 2008 in the Framingham Heart Study participants. AB - Few longitudinal studies carried out in US adults have evaluated long-term dietary fat intakes and compared them with the national recommendations during the two-decade period when the prevalence of obesity and insulin resistance increased substantively. In the present study, we examined trends in the intakes of dietary fats and rich dietary sources of fats in the Framingham Heart Study Offspring Cohort over a 17-year period. The cohort was established in 1971-75 with follow-up examinations being conducted approximately every 4 years. Dietary data were collected using a semi-quantitative FFQ beginning in 1991 (exam 5). We included 2732 adults aged >= 25 years with complete dietary data in at least three examinations from 1991 to 2008. Descriptive statistics were generated using SAS version 9.3, and a repeated-measures model was used to examine trends in macronutrient and food intakes using R. Over the 17 years of follow-up, the percentage of energy derived from total fat and protein increased (27.3-29.8% of energy and 16.8-18.0% of energy, respectively) and that derived from carbohydrate decreased (51.0-46.8% of energy; P-trend < 0.001). Increases in the percentage of energy derived from all fat subtypes were observed, except for that derived from trans-fats, which decreased over time (P-trend < 0.001). Trends were similar between the sexes, although women exhibited a greater increase in the percentage of energy derived from saturated fat and less reduction in the percentage of energy derived from trans-fats (P interaction < 0.05). Trends in fat intake were similar across the BMI categories. The number of weekly servings of cheese, eggs, ice cream desserts, nuts, butter and sausages/processed meats increased, whereas the intake of milk, margarine, poultry, confectioneries, chips and breads decreased (P-trend < 0.001). In this cohort of predominantly Caucasian older adults, the percentage of energy derived from dietary fats increased over time, but it remained within the national recommendations of less than 35 % of total energy, on average. PMID- 24047828 TI - Assessment of antimicrobial potential of 10% ginger extract against Streptococcus mutans, Candida albicans, and Enterococcus faecalis: an in vitro study. AB - BACKGROUND: Streptococcus mutans, Candida albicans, and Enterococcus faecalis are the three oral microorganisms most commonly implicated in the causation of oral infections. All these oral microorganisms have shown resistant to routinely used antimicrobials. There is a need for an antimicrobial agent which is effective, safe, and economical. Zingiber officinale, commonly known as ginger is one such plant product which has been used from ancient time. It has been shown to possess promising inhibitory effect on many of the oral microorganisms. On review of dental literature, there was scarcity of studies which had tried to assess antimicrobial potential of ginger extract against S. mutans, E. faecalis, and C. albicans; hence, the present study was designed. AIM: To evaluate the in vitro antimicrobial potential of 10% ginger extract against S. mutans, E. faecalis, and C. albicans. SETTINGS AND DESIGN: Laboratory setting and experimental design. MATERIALS AND METHODS: In the first part of the study, 10% ethanolic ginger extract was prepared in the laboratory of Pharmacy College. It was then subjected to microbiological assay to determine its zone of inhibition using Agar disk diffusion test and minimum inhibitory concentration (MIC) using serial broth dilution method against S. mutans, C. albicans, and E. faecalis. RESULTS: 10% ethanolic ginger extract showed: (a) Maximum zone of inhibition of 8 mm, 14 mm, and 11 mm against S. mutans, C. albicans, and E. faecalis respectively. (b) MIC of 1.25%, 2.5%, and 2.5% against S. mutans, C. albicans, and E. faecalis respectively. CONCLUSION: 10% ethanolic ginger extract was found to possess antimicrobial potential against all the three pathogens used in the study. PMID- 24047829 TI - Antimicrobial activity of plant extracts on Candida albicans: an in vitro study. AB - BACKGROUND AND OBJECTIVES: Plants as sources of medicinal compounds have continued to play a predominant role in the maintenance of human health since ancient times. Even though several effective antifungal agents are available for oral candida infections, the failure is not uncommon because isolates of Candida albicans may exhibits resistance to the drug during therapy. The present study was conducted to evaluate the antimicrobial effects of few plant extracts on Candida albicans. An additional objective was to identify an alternative, inexpensive, simple, and effective method of preventing and controlling Candida albicans. MATERIALS AND METHODS: Fine texture powder or paste form of leaves was soaked in sterile distilled water and 100% ethyl alcohol, which were kept in refrigerator at 4 degrees C for 24 h. Then filtrates were prepared and kept in a hot air oven to get a black shining crystal powder/paste form. Stock solutions of plant extracts were inoculated on petri plates containing species of Candida albicans and incubated at 25 +/- 2 degrees C for 72 h. RESULTS: Alcoholic curry leaves showed the maximum zone of inhibition on Candida albicans followed by aqueous tea leaves. The other plant extracts like alcoholic onion leaves, alcoholic tea leaves, alcoholic onion bulb, alcoholic aloe vera, and alcoholic mint leaves also inhibited the growth of Candida albicans but lesser extent. CONCLUSION: The present study renders few medicinal plants as an alternative medicines to the field of dentistry which can be used adjunct to conventional therapy of oral candidasis. PMID- 24047830 TI - Prevalence of dentofacial abnormalities in children and adolescents with beta thalassaemia major. AB - BACKGROUND: beta-thalassaemia major is a hereditary hemolytic anemia and the patients often experience growth retardation, protrusive maxilla, and depressed nasal bride leading to various degrees of malocclusion. AIM: The purpose of this investigation is to find the prevalence of dentofacial abnormalities in beta thalassaemia major patients. SUBJECTS AND METHODS: Seventy-two patients between 6 and 18 years of age diagnosed with beta-thalassaemia major were examined for extraoral abnormalities, malocclusion, oral hygiene, and dental caries. Data obtained were tabulated and statistically analyzed using Chi-square and paired t test. RESULTS: Thirty-nine (54.2%) were males and 33 (45.8%) were females. Prominent extraoral abnormalities were found in 41 (56.9%) of the individuals. Study population predominantly had class I occlusion (59.7%) followed by class II occlusion (23.6%) and no class III occlusion. Mean oral hygiene index-simplified score was 2.43 +/- 1.24, mean decayed missing filled teeth (DMFT) score was 7.10 +/- 3.92, and deft was 5.68 +/- 3.12. CONCLUSION: Despite starting regular blood transfusion at an early age, beta-thalassaemia major patients showed marked facial abnormalities. When compared with individuals with no systemic disease, oral hygiene status was similar, but the caries experience was higher in beta thalassaemia major patients. Therefore, emphasis to educate these patients in the prevention and control of dental caries and maintenance of good oral hygiene should be considered. PMID- 24047831 TI - Effect of ion-implantation on surface characteristics of nickel titanium and titanium molybdenum alloy arch wires. AB - AIM: To evaluate the changes in surface roughness and frictional features of 'ion implanted nickel titanium (NiTi) and titanium molybdenum alloy (TMA) arch wires' from its conventional types in an in-vitro laboratory set up. MATERIALS AND METHODS: 'Ion-implanted NiTi and low friction TMA arch wires' were assessed for surface roughness with scanning electron microscopy (SEM) and 3 dimensional (3D) optical profilometry. Frictional forces were studied in a universal testing machine. Surface roughness of arch wires were determined as Root Mean Square (RMS) values in nanometers and Frictional Forces (FF) in grams. STATISTICAL ANALYSIS USED: Mean values of RMS and FF were compared by Student's 't' test and one way analysis of variance (ANOVA). RESULTS: SEM images showed a smooth topography for ion-implanted versions. 3D optical profilometry demonstrated reduction of RMS values by 58.43% for ion-implanted NiTi (795.95 to 330.87 nm) and 48.90% for TMA groups (463.28 to 236.35 nm) from controls. Nonetheless, the corresponding decrease in FF was only 29.18% for NiTi and 22.04% for TMA, suggesting partial correction of surface roughness and disproportionate reduction in frictional forces with ion-implantation. Though the reductions were highly significant at P < 0.001, relations between surface roughness and frictional forces remained non conclusive even after ion-implantation. CONCLUSION: The study proved that ion-implantation can significantly reduce the surface roughness of NiTi and TMA wires but could not make a similar reduction in frictional forces. This can be attributed to the inherent differences in stiffness and surface reactivity of NiTi and TMA wires when used in combination with stainless steel brackets, which needs further investigations. PMID- 24047832 TI - Evaluation of biological, physical and chemical properties of mineral trioxide aggregate mixed with 4-META/MMA-TBB. AB - AIM: To evaluate the change in physical, chemical and biological properties when mineral trioxide aggregate (MTA) is mixed with a resin 4-methacryloxyethyl trimellitate anhydride (4-META)/methyl methacrylate-tri-n-butyl-borane (MMA)-TBB. MATERIALS AND METHODS: For biological evaluation MTA was inoculated in Wistar rat's subcutaneous tissue and peripheral tissue response was checked after 72 h, 7 days, 15 days and 30 days. Setting time was evaluated using Gillmore needle. The Ca++ release at the end of 24 h was checked using ethylenediaminetetraacetic acid titration method. For all the trials MTA mixed with water was kept as a control and the ratio of MTA with resin was 1:1 by weight. RESULTS: The biological reaction was verified by two observers and their readings were matched using kappa test and there was an excellent relevance. There was no significant difference in the tissue reaction at the end of 30 days where both the groups seemed to show healing. Setting time of MTA with 4-META/MMA-TBB was coming to a mean of 26 min (approx.), which is almost 6 times lesser than that of MTA with water. After applying t test, the difference in Ca++ release was found significant (P = 0.00), with mean of 0.044 and 0.031 mol/L of MTA with water and MTA with 4-META/MMA-TBB respectively. CONCLUSION: Under the parameters of this study, this new experimental cement has better handling, physical and chemical properties. Even its subcutaneous tissue reaction is comparable to MTA mixed with water. PMID- 24047833 TI - Finite element stress analysis on the influence of cuspal angle and superstructure materials in an implant-supported prosthesis. AB - PURPOSE: To investigate the effect of superstructure materials and cuspal angle in an implant-supported fixed partial denture. MATERIALS AND METHODS: This finite element analysis study was carried out with varying cuspal angulations of 0 degrees , 20 degrees and 33 degrees and superstructure materials. The simulated models were loaded with 300N forces under different axial and non-axial angulations. The graphical and numerical stresses were investigated. RESULTS: The results demonstrated that the maximum stress occurred in the metal framework in all the materials except acrylic, for which it occurred in the coronal part of the implant. In the acrylic, the maximum stress recorded was 78 MPa with the 20 degrees angulation. Ni Cr recorded a maximum stress of 111 MPa with the 33 degrees angulation. CONCLUSION: The cuspal morphology and type of superstructure material plays a pivotal role in controlling the stress transferred to the implant and the supporting bone. PMID- 24047834 TI - Prevalence of work-related musculoskeletal complaints among dentists in India: a national cross-sectional survey. AB - CONTEXT: Work-related musculoskeletal disorders (WRMSD) had been previously reported to have a high prevalence among dentists in different parts of the world. AIMS: The study aimed to assess the prevalence of self-reported WRMSD among dental professionals in India. MATERIAL AND METHODS: A cross-sectional survey of 646 dentists (response rate of 82.97%) was done using self-administered questionnaire which consisted of 27 items based on Nordic questionnaire for screening WRMSDs. Additional items of the questionnaire were added after preliminary content validation from six experienced dentists. Participant socio demographic characteristics, work-related physical load characteristics, musculoskeletal symptom characteristics were evaluated. STATISTICAL ANALYSIS USED: All data were analyzed descriptively using percentiles and association between work-related physical load and WRMSD prevalence was done using Chi-square test. RESULTS: All 536 dentists had at least one work-related musculoskeletal symptom in the previous year with an overall period prevalence rate of 100%. The type of symptoms present were pain (99.06%), stiffness (3.35%), fatigue (8.39%), discomfort (12.87%), clicks/sounds (4.1%), and other neurogenic (20.14%). The regions of symptoms were neck (75.74%), wrist/hand (73.13%), lower back (72.01%), shoulder (69.4%), hip (29.85%), upper back (18.65%), ankle (12.31%), and elbow (7.46%). Number of regions affected were two (82.83%), three (51.86%), four, or more (15.11%). Recurrent symptoms were present in 76.11%. Strong association was noted between sustained work postures and symptom regions for pain in WRMSD. CONCLUSION: The study found an overall one-year period prevalence rate of 100% for WRMSDs among Indian dentists. Measures for improving education and ergonomic evaluations are indicated on a large scale to prevent decline in work performance and incidence of WRMSDs among Indian dentists. PMID- 24047835 TI - Comparative evaluation of stresses in tooth implant connected fixed partial denture by varying the implant design and position: a 3D finite element study. AB - AIM: This study aims at evaluating stresses generated in a fixed tooth to implant connected fixed partial denture (FPD) by finite element method by varying implant design and position, in unilateral distal extension cases, i.e. for replacing mandibular 1 st and 2 nd molars. MATERIALS AND METHODS: Four models were created, Model 1-A finite element model (FEA) model of a crestal implant-tooth connected metal ceramic FPD with pontic in 36 region. The 35 region simulated the second premolar. Model 2-A FEA model of a basal implant-tooth connected metal ceramic FPD. Model 3-A FEA model of a crestal implant in 36 region connected to tooth 35 and cantilevered posteriorly with pontic in 37 region, made of metal ceramic. Model 4-A FEA model of a basal implant in 36 region connected to tooth 35 and cantilevered posteriorly with pontic in 37 region, made of metal ceramic. A vertical force of 100N directed evenly on the nodes on the occlusal surface of each of the three crowns. The models displayed stress both numerically and by color coding. RESULTS: On comparing models 1 and 2, the model 1 showed comparatively more stresses in crestal bone area of the implant. On comparing models 3 and 4, model 3 showed lesser von misses stress values. CONCLUSION: In case of tooth implant connected FPDs without any cantilevers, basal implants show better stress distribution when compared to crestal implants. In case of cantilever designs, crestal implant design showed lower stress values, but the difference in stresses were less. PMID- 24047836 TI - Comparison of marginal accuracy of castings fabricated by conventional casting technique and accelerated casting technique: an in vitro study. AB - BACKGROUND: Conventional casting technique is time consuming when compared to accelerated casting technique. In this study, marginal accuracy of castings fabricated using accelerated and conventional casting technique was compared. MATERIALS AND METHODS: 20 wax patterns were fabricated and the marginal discrepancy between the die and patterns were measured using Optical stereomicroscope. Ten wax patterns were used for Conventional casting and the rest for Accelerated casting. A Nickel-Chromium alloy was used for the casting. The castings were measured for marginal discrepancies and compared. RESULTS: Castings fabricated using Conventional casting technique showed less vertical marginal discrepancy than the castings fabricated by Accelerated casting technique. The values were statistically highly significant. CONCLUSION: Conventional casting technique produced better marginal accuracy when compared to Accelerated casting. The vertical marginal discrepancy produced by the Accelerated casting technique was well within the maximum clinical tolerance limits. CLINICAL IMPLICATION: Accelerated casting technique can be used to save lab time to fabricate clinical crowns with acceptable vertical marginal discrepancy. PMID- 24047837 TI - Assessment of precipitate formation on interaction of irrigants used in different combinations: an in vitro study. AB - INTRODUCTION: Irrigants play an essential role in the successful debridement and disinfection of pulp space. Various combination of irrigants used during root canal treatment enhance their efficacy, but some form precipitates which affects the diffusion of intracanal medicaments and the seal of the obturated root canal. AIM: To evaluate the combination of various irrigants whether it forms the precipitate and also to quantify the amount of precipitate formed. MATERIALS AND METHODS: Five different irrigants were taken in ten test tubes each having the combination of two irrigants and observed for 2 min for precipitate formation. RESULTS: One-way-ANOVA test revealed more amounts of precipitate with 2% Chlorhexidine (CHX) 5% Tulsi followed by 2% CHX, 5% Neem and 3% Sodium hypochlorite 2% CHX. CONCLUSION: Precipitate formation is seen more with the 2% CHX-5% Neem followed by 2% CHX-5% Tulsi when compared with the control group. When these combinations of irrigants were used, intermediate flushes of saline or distilled water reduced the amount of precipitate. PMID- 24047838 TI - Determination of craniofacial relation among the subethnic Indian population: a modified approach (vertical evaluation). AB - AIM: To measure the vertical linear cephalometric dimensions of the anterior and posterior segments of the craniofacial complex and establish ratios between vertical linear dimensions in subjects with normal occlusion, pleasing profile, and facial harmony. SETTING AND SAMPLE POPULATION: Department of Orthodontics, Saveetha University. Lateral cephalograms of 120 subjects of both sexes in the age group of 17-28 years with normal occlusion belonging to Chennai, India. MATERIALS AND METHODS: The vertical segments measured are anterior maxilla, posterior maxilla, and ramus-cranial floor vertical. The facial heights were measured in the anterior and posterior region of the craniofacial complex. Establish ratios and proportions between the vertical segments and different facial heights. RESULTS: In both the sexes, the ratio between anterior maxilla, posterior maxilla, and ramus-cranial floor vertical is 1:1:1, PTFH:ATFH is 1:1, AUFH:ATFH is 2:5, ALFH:ATFH is 3:5, PUFH:PTFH is 1:2, PLFH:PTFH is 1:2, AUDH:ALDH is 2:3, and facial depth is 2:1. PUDH:PLDH is 7:9 in females and 3:4 in males. There was a statistically significant difference in posterior total facial height:anterior total facial height ratio between the two sexes with a "P" value of 95%. CONCLUSION: Thus, the anterior maxilla, posterior maxilla, and cranial floor-ramus vertical composite are in dimensional balance in subjects with normal occlusion and facial harmony. This analysis helps to identify skeletal deviations in size and position in the vertical dimension and allows the clinician to outline an appropriate treatment. PMID- 24047839 TI - Efficacy of crystallization test for screening of oral squamous cell carcinoma with clinico-pathological correlation. AB - AIM: To determine the efficacy of crystallization test for screening oral squamous cell carcinoma (OSCC) with clinico-pathologic correlation. MATERIALS AND METHODS: Fifty patients of OSCC and 30 healthy individuals were selected. One drop of blood was collected into 1 cc of doubled distilled water at room temperature to give a final dilution of 6% hemolyzed blood. 0.1 to 0.2 cc of blood sample was then subjected to crystallization test using 10% cupric chloride solution. RESULTS: In healthy control group, the typical pattern was an eccentrically placed center of gravity with needles arranged in radiating fashion, while in OSCC group, there was 'transverse form' (TF) formation. The sensitivity and specificity of this test was found to be 96% and 96.66%, respectively. The positive and negative predictive values were found to be 97.96% and 98.55%, respectively. The mean TF frequency was found to be increasing from grade I (3.20 +/- 1.5%) to grade II (653 +/- 2.23%) and difference was statistically significant (P = 0.0001). However, there was no correlation between mean TF frequency and TNM stages of OSCC. CONCLUSION: Crystallization test is a simple, reliable, economical, less time-consuming, and less invasive screening procedure, which can be used for early detection of OSCC. PMID- 24047840 TI - Evaluation of micronutrient (zinc, copper and iron) levels in periodontitis patients with and without diabetes mellitus type 2: a biochemical study. AB - CONTEXT: Periodontal tissue destruction is caused by an inappropriate host response to microorganisms. Diabetes is a metabolic disease and most of its complications are due to hyperglycemia. Periodontitis is considered as its sixth complication. Micronutrients such as zinc, copper and iron are essential for human health. There is accumulating evidence that the metabolism of several trace elements is altered in diabetes mellitus and that these nutrients might have specific roles in the pathogenesis and progress of this disease and its complication. An association between micronutrients and periodontitis has also been suggested by preliminary studies. However, till date there is a lack of relevant clinical data. AIM: This study was designed to estimate and compare the serum levels of zinc, copper and iron in diabetes mellitus type 2 patients and healthy individuals with and without periodontitis. SETTING AND DESIGN: Single centre case-control study. SUBJECTS AND MATERIALS: This study included 150 subjects, 50 in each group. Group 1 comprised of 50 subject with diabetes mellitus type 2 and periodontitis. Group 2 comprised of 50 subjects with chronic periodontitis and Group 3 comprised of 50 control subjects. Atomic absorption spectrophotometry method was used to measure clinical level of zinc and copper in serum. Estimation of serum iron levels was done by bathophenanthroline method. STATISTICAL ANALYSIS: The results obtained were tabulated and subjected to statistical analysis by analysis of variance and Tukey multiple comparison tests using statistical software SPSS version 17. RESULTS: The results showed that the serum levels of zinc decreased and serum levels of iron and copper increased in diabetes patients with periodontitis compared to healthy individuals with and without periodontitis. CONCLUSION: Imbalance of Zinc, copper and iron levels in the serum can predispose an individual to the risk of developing periodontitis. PMID- 24047841 TI - Comparing the sealing properties of mineral trioxide aggregate and an experimental ceramic based root end filling material in different environments. AB - BACKGROUND: An apical seal is an important factor in achieving success in surgical endodontics. AIM: The purpose of this study was to compare the sealing properties of mineral trioxide aggregate (MTA) with a new ceramic based root end filling material (Cold Ceramic) in different environments. MATERIALS AND METHODS: One hundred teeth were selected. The root canals were instrumented and obturated. Except for the apical 2 mm, the root surfaces were sealed. After root resection, 3 mm depth root-end cavities were prepared. For each material, roots were divided into 3 equal subgroups and the root-end filling was done in different environments (dry, saliva contaminated, blood contaminated). Five roots served as positive and 5 roots as negative controls. Samples were immersed in 2% methylene blue dye. Roots were sectioned longitudinally and examined under stereomicroscope to record the extension of dye penetration. RESULTS: All experimental groups demonstrated dye penetration. The lowest linear leakage was seen in Cold Ceramic blood contaminated group while the highest leakage was observed in MTA blood contaminated group. The linear dye penetration of both MTA and Cold Ceramic (CC) groups did not show any significant differences among different environments. Also, the difference between MTA and CC was not significant in dry and saliva contaminated subgroups. Only the difference between dye penetration of MTA and CC in blood contaminated subgroups showed significant difference ( P = 0.008). CONCLUSION: The sealing property of this ceramic based root end filling material (Cold Ceramic) is better than MTA in blood contaminated condition and at least similar to MTA in other conditions. PMID- 24047842 TI - Effect of fluoride-free and fluoridated carbamide peroxide gels on the hardness and surface roughness of aesthetic restorative materials. AB - BACKGROUND: Bleaching products may show some side effects on soft and hard tissues and restorative materials in the oral cavity. This study evaluated the effect of carbamide peroxide gel with and without fluoride ions on the microhardness and surface roughness of tooth-colored restorative materials. MATERIALS AND METHODS: In this in-vitro study, 76 cubic specimens (4 mm3 * 4 mm3 * 3 mm3) were fabricated from 4 aesthetic A3-shade restorative materials. These materials consisted of two composite resins and two glass ionomers. The specimens made from each material were treated with the following surface treatments: 1. CONTROL GROUP: The specimens were not bleached and were stored in normal saline. Group 2. Fluoridated 20% carbamide peroxide gel, treated 3 h a day for 4 weeks. Group 3. Treated 1 h a day with fluoride-less 22% carbamide peroxide for two weeks. From each group, three other specimens were selected to be evaluated in terms of changes in surface roughness, under scanning electron microscopy (SEM). RESULTS: In this study, fluoridated 20% carbamide peroxide gel increased the microhardness of the four aesthetic restorative materials. The fluoride-free carbamide peroxide 22% reduced the microhardness of the four used materials, which this change was significant for Vitremer and Amelogen. SEM analyses showed changes in surface roughness of glass ionomer specimens. CONCLUSION: The effect of bleaching on the microhardness of restorative materials is material dependent. Before the application of bleaching systems on the glass ionomer materials, the application of a protective barrier should be considered. PMID- 24047843 TI - Maxillary repositioning according to Frankfort horizontal plane during orthognathic surgery. AB - CONTEXT: There are a lot of disagreements among surgeons over controlling the maxillary position during orthognathic surgery. AIM: To investigate maxillary repositioning according to Frankfort horizontal plane in orthognathic surgery. MATERIALS AND METHODS: Fourteen patients were selected who were submitted to maxillary or bimaxillary surgery. Maxillary model surgery was performed based on the treatment planning and an intermediate splint was made. The surgical technique in this study was based on maxillary osteotomy according to the findings of the model surgery, in a manner that the osteotomy line was parallel to the Frankfort horizontal plane. Intermediate splint was used for repositioning of the maxilla in the new position and the vertical position of that was determined according to external reference point and fixed on this position. The upper central incisor designed from prediction tracing and post-operative cephalometry on the first tracing. The new position of maxilla was evaluated horizontally and vertically. STATISTICAL ANALYSIS USED: A paired t-test was used to compare the predicted maxillary position and the actual position. Association between these two groups of variables was evaluated with Pearson correlation. RESULTS: The mean difference between the maxillary planned position and post operative cephalometric radiography varied between 0.3 mm and 0.9 mm vertically (P value = 0.315) and 0.0 mm and 0.9 mm horizontally (P value = 0.034). The averages of horizontally and vertically observed changes were 0.3 mm and 0.17 mm respectively (P < 0.001). CONCLUSION: Good surgical accuracy in repositioning of the maxilla can be achieved according to Frankfort horizontal plane during the surgery. By eliminating the ramping effect the accuracy of surgery increases. PMID- 24047844 TI - Assessment of chemomechanical removal of carious lesions using Papacarie DuoTM: randomized longitudinal clinical trial. AB - BACKGROUND: Chemomechanical removal of carious lesions consists of the dissolution of carious tissue by the application of a natural or synthetic agent, followed by atraumatic mechanical removal. AIM: The aim of the present study was to assess the effectiveness of Papacarie Duo (r) gel in the chemomechanical removal of carious lesions in primary teeth in comparison to the traditional method (low-speed bur). SETTINGS AND DESIGN: A randomized clinical trial was conducted with 20 children between 5 and 8 years of age. MATERIALS AND METHODS: Two teeth were treated in each child (split-mouth design), with the randomization of two methods: Group 1 - chemomechanical caries removal with Papacarie DuoTM; and Group 2 - removal of carious dentin tissue using a low-speed bur. Both methods involved restoration with glass ionomer cement and follow up. The following aspects were evaluated: time required for the procedure; pain (face evaluation scale); retention of the restorative material in the cavity; and the presence of secondary caries after 30 days. STATISTICAL ANALYSIS USED: Chi squared test, Student's t-test, and Wilcoxon test. RESULTS: No statistically significant differences between methods were found regarding time required for the procedure (P = 0.13), the occurrence of pain (P = 0.585), or restoration status at the 30-day clinical evaluation (P = 0.713). CONCLUSION: The findings of the present study demonstrate that the two methods achieve similar results. The advantages of minimally invasive treatment, such as chemomechanical caries removal with Papacarie DuoTM, are its ease of use, patient comfort, and the fact that it causes less damage to dental tissue. PMID- 24047845 TI - Prediction of the size of unerupted canines and premolars in an Iranian population. AB - BACKGROUND AND AIM: One of the important aspects of diagnosis and treatment planning in the mixed dentition is estimation of the size of unerupted permanent canines and premolars. One of the most commonly used the prediction methods are Tanaka and Johnston, which are based on data from a sample of Northern European descent children. The accuracy of this method when applied to a different ethnic population is questionable. The aim of this study was to determine the modified equations from Tanaka and Johnston for Iranian population. MATERIALS AND METHODS: This study was an analytic and cross-sectional investigation with the randomized cluster sampling in Ahwaz. Fifty four students of 14-18 years age (32 girls, 22 boys) were selected between 320 students and plaster models of their maxillary and mandibular arches were prepared. Subjects had fully erupted teeth, class I canine and molar relationship and presented no proximal caries or fillings, morphological anomalies, missing teeth or occlusal abrasion, and bruxism. The mesiodistal crown diameters of the permanent teeth were measured with using the sharpened boley gauge (accuracy 0.01 mm). The data were analyzed by using the regression correlation analyses and t-test. RESULTS: The size of permanent canines and premolars were larger in maxilla than mandible and males than females. These values in Iran were different from other countries. CONCLUSION: In this study to predict the space (in mm) required for alignment of unerupted canine and premolars in Iranian children, halve the sum of mesiodistal dimension of the four mandibular incisors and add the respective constants 10.5 for upper jaw and 10 for lower jaw. PMID- 24047846 TI - Evaluation of total soluble solids content (TSSC) and endogenous pH in antimicrobials of pediatric use. AB - BACKGROUND: The use of liquid pharmaceutical preparations is a daily occurrence for some children. Evidences show a significant relation between the intake of oral sucrose based medicines and an increase incidence in dental caries. AIM: This in vitro experimental study evaluated the Total Soluble Solids Content (TSSC) by means of Brix scale refractometry and the endogenous pH of antimicrobials of pediatric use presented as oral suspensions. MATERIALS AND METHODS: Nine medications (6 chemotherapics and 3 antibiotics) were evaluated by random experiment with 3 repetitions for each sample. The analysis of TSSC readings were performed by Brix refractometry using the Abbe refractometer, and the pH values were determined by potentiometry. RESULTS: The mean TSS contents ranged from 11.73 (Keflaxina) to 63.83 (Azitromed). The minimum and maximum mean pH values were 4.12 (Keflaxina) and 10.97 (Zitroneo), respectively. CONCLUSIONS: The chemotherapic antimicrobials evaluated in this study presented the highest TSSC means, while the antibiotics showed pHs below the values considered as critical, which may contribute to the development of caries lesions in case of inadequate administration of these medications to children. PMID- 24047847 TI - Hereditary ectodermal dysplasia: report of 11 patients from a family. AB - Hereditary Ectodermal Dysplasia is an inherited disorder commonly involving skin, teeth, hair, and nails. We have observed ectodermal dysplasia (EDs) in 11 individuals over two generations in one family. Smooth, dry, thin skin was seen in most affected individuals. All had fine, slow-growing scalp hair and body hair and some had sparse eyebrows and short eyelashes. Nearly all showed decrease in sweating. Severe teeth abnormalities were seen in all patients and fingernail abnormalities were not so severe but toenail abnormalities were seen in all patients. No other abnormalities were seen in affected individuals in this family. It is very rare to find such a large family having ectodermal dysplasia. PMID- 24047848 TI - Modified snap-on attachment with 'O-ring' for two piece hollow bulb obturator. AB - Restoration of near normal functions in patients who have been treated with hemimaxillectomy is generally difficult, in view of the restriction in mouth opening following healing of large surgical wound. Further, the extent and nature of the surgical defect differ from patient to patient. Thus, design of an obturator needs to be patient oriented. In this report, we describe a novel snap on attachment with O-ring in a conventional two piece hollow bulb obturator for a 70-year-old male treated for carcinoma of the left maxilla and sinus. PMID- 24047849 TI - McGibbon Syndrome: a report of three siblings. AB - Amelogenesis Imperfecta (AI) is a collective term for a number of developmental conditions characterized by abnormal enamel formation. Only a few cases of AI have been reported to occur in association with syndromes and metabolic conditions. McGibbon Syndrome or AI and Nephrocalcinosis Syndrome are such disorders with defective enamel and renal calcifications. Early diagnosis of this condition is essential to prevent renal failure and death of the patient. PMID- 24047850 TI - A new and simple infant assessment table. AB - Oral examination of an infant forms an important first step toward a lifetime of excellent oral health. Examining an infant during the first visit and the subsequent preventive examination visits may be challenging to dentists and pediatric dentists. There are few concerns regarding the effective oral examination using the traditional "knee-to-knee" position. This paper presents a new, simple infant examination table (INFANTT) to facilitate this examination. This table has many advantages, which includes its stability and simplicity. It is non-threatening and resembles common household furniture. Various modifications of the basic design are also possible to suit the individual dentist's preferences and dental office needs. Additionally, it is possible to use this INFANTT for performing fluoride varnish applications, taking radiographs of the anterior teeth and extraction of natal, neonatal teeth and traumatized teeth. PMID- 24047851 TI - Restoration of an endodontically treated premolar with limited interocclusal clearance. AB - Endodontically treated teeth with the loss of coronal tooth structure when left untreated for a long period may cause supraeruption, drifting, tipping, and rotation of adjacent and opposing teeth. This may be challenging to the clinician, when fabricating a crown because of inadequate interocclusal space. This case report describes a simple technique to restore an endodontically treated maxillary first premolar with the loss of coronal tooth structure and lack of interocclusal space. The maxillary first premolar had a single root canal and was endodontically treated. The lower premolar had supraerupted reducing the interocclusal space. A minimally invasive and esthetic technique was used to restore the tooth with limited interocclusal clearance. The tooth was restored with a Richmond crown, which had the morphology of a canine instead of a premolar. Thus, the tooth was salvaged by changing the morphology of the crown and the desired functional and esthetic results were obtained. PMID- 24047852 TI - Facial nerve injury following surgery for temporomandibular joint ankylosis: a prospective clinical study. AB - OBJECTIVE: The purpose of this prospective study was to evaluate the incidence and degree of facial nerve damage and time taken for its recovery following surgery for temporomandibular joint (TMJ) ankylosis. MATERIALS AND METHODS: A total of 30 subjects with the TMJ ankylosis with or without history of previous surgery were included in this prospective study. House-Brackmann grading system was used to assess the function of the facial nerve post-operatively. RESULTS: Most of the subjects were in the age range of 13-15 years. Eight subjects had bilateral ankylosis and remaining 22 had unilateral ankylosis. Out of 32 joints in which gap arthroplasty was performed, 4 had Grade 1 injury, 14 had Grade 2 injury, 12 had Grade 3, and 2 with the Grade 4 injury 24 h post-operatively. Whereas, out of 6 cases of interpositional arthroplasty 4 had Grade 1 injury and 2 had Grade 4 injury. According to House-Brackmann grading system, at 24 h, 78.9% patients had different grades of facial nerve injury, which gradually improved and came to normal limits within 1-3 months post-operatively. Comparison of change in the Grade of injury at 3 months follow-up as compared to baseline (24 h) showed full recovery in all the cases (100%) showing a statistically significant difference from baseline (P < 0.001). CONCLUSION: When proper care is taken during surgery for TMJ ankylosis, permanent facial nerve injury is rare. However, the incidence and degree of temporary nerve injury could be either due to the heavy retraction causing compression and or stretching of nerve fiber resulting in neuropraxia. PMID- 24047853 TI - Comparative evaluation of antibacterial property and substantivity of chlorhexidine containing dentifrices with sodium lauryl sulfate and Tween as surfactants: an in vivo study. AB - AIM: The aim of the study was to determine the antibacterial property and substantivity of chlorhexidine containing dentifrices with sodium lauryl sulfate (SLS) and Tween as surfactants. MATERIALS AND METHODS: It is a double-blind cross over the study, a total of 20 children within their mixed dentition period (7-13 year) having Streptococci mutans count more than 10(6) were selected for the main study. Three types of chlorhexidine containing dentifrices were used with a washout period of 1 week. Out of the three toothpastes, one was without surfactant and other two toothpastes contained SLS and Tween as surfactants respectively. 20 volunteers brushed for 1 min during the study day with their assigned toothpaste. Saliva samples were collected before brushing, immediately after brushing and 1, 3, 5, and 7 hand sent for microbial analysis. The culture carried out by inoculating saliva sample onto Mitis salivarius agar for selective isolation of S. mutans followed by counting of colony forming unit. RESULTS: Group I and III (Chlorhexidine and CHX + Tween) had shown statistically significant reduction in bacterial count until 7 h when compared to their baseline values ( P < 0.001). Group II toothpaste (CHX + SLS) had shown significant reduction in bacterial count until 3 h only. On inter group comparison, Group III had shown good amount of percentage reduction in bacterial count when compared to other groups. CONCLUSION: CHX + Tween toothpaste had shown statistically significant reduction in antibacterial activity and substantivity than other groups. These findings show chlorhexidine containing toothpaste with non-ionic surfactant will be able to maintain the antibacterial property and substantivity of chlorhexidine. PMID- 24047854 TI - Calcium phosphate cement as an alternative for formocresol in primary teeth pulpotomies. AB - BACKGROUND: Formocresol remains to be the preferred medicament in pulpotomy, despite the concerns regarding tissue devitalization and systemic toxicity. Several materials were used as alternatives, but none proved significantly advantageous. Of recent, calcium phosphate cement (CPC) has been projected as an ideal pulpotomy material considering its tissue compatibility and dentinogenic properties. This study explores the suitability of a CPC formulation for pulpotomy, in comparison with formocresol. MATERIALS AND METHODS: This comparative case study included 10 children (8-12 age group) having a pair of non carious primary canines (both maxillary and mandibular) posted for extraction. Pulpotomy was performed with CPC in the right canines and formocresol in the left and sealed with IRM (r) (Dentsply). The teeth were extracted at 70 +/- 5 days and sectioned and stained for the histopathological evaluation. Parameters such as pulpal inflammation, tissue reaction to material, dentine bridge formation, location of dentine bridge, quality of dentine formation in bridge, and connective tissue in bridge etc. were evaluated. RESULTS: The histological assessment after 70 days showed no statistically significant difference between the two groups in any of the parameters. However, CPC gave more favorable results in pulpal inflammation, with a lower score of 1.6 against 2.6 for formocresol. CPC samples showed better formation of dentine bridge in quantity and quality. The mean scores for CPC for the extent of dentine bridge formation, quality of dentine bridge and connective tissue in the bridge, were 2.0, 1.4, and 1.2 respectively, whereas the corresponding values for formocresol were 0.8, 0.2, and 1.0. CONCLUSION: CPC is more compatible to pulp tissues than formocresol and it shows good healing potential. CPC is capable of inducing dentine formation without an area of necrosis. PMID- 24047855 TI - Oral health status of children with acute lymphoblastic leukemia undergoing chemotherapy. AB - OBJECTIVE: The aim of this study was to evaluate the oral health status of children with acute lymphoblastic leukemia (ALL) undergoing chemotherapy. STUDY DESIGN: A total of 94 patients of both sexes in the age group of 2-14 years who were diagnosed with acute lymphoblastic leukemia were selected for the study. The oral cavity was examined for dental caries using def-t and DMF-T indices, gingival status was evaluated by using the modified gingival index, and the WHO oral toxicity scale was used to record oral mucositis. RESULTS: Statistical analysis was done by using Kruskal-Wallis and Mann-Whitney tests. Both DMF-T and def-t were highest in children during the maintenance phase of the chemotherapy followed by the induction therapy with radiotherapy (I 2 ) and induction therapy (I 1 ) phases. The prevalence of gingival inflammation was highest in the maintenance phase of the chemotherapy followed by the induction therapy with radiotherapy (I 2 ) and Induction therapy (I 1 ) phases. Signs and severity of oral mucositis were highest in children undergoing induction therapy with radiotherapy (I 2 ). CONCLUSION: Good oral care is essential to maintain healthy oral cavity in children with acute lymphoblastic leukemia, as improvement in oral conditions may diminish their sufferings and prevent the spread of serious infections from oral cavity. PMID- 24047856 TI - Reliability of the frontal sinus index as a maturity indicator. AB - AIM: The aim of this study was to compare the reliability of frontal sinus as a skeletal maturity indicator in males and females. SETTING AND SAMPLE POPULATION: Lateral cephalograms of 75 males and 75 females, both in pre- and post-pubertal stages of development as determined by Middle phalanx of the third finger (MP3) radiographs. MATERIALS AND METHODS: Lateral cephalograms were analyzed for frontal sinus maturity. Maximum height, maximum width and height to width ratio of the sinus were calculated. The mean height to width ratio of the sinus at respective MP3 stages were tabulated and subjected to statistical analysis to determine the correlation. Correlation at different MP3 stages between males and females was also determined. RESULTS: Statistically significant differences were observed between the mean values of F and FG along with F and I stage in males, significant difference between the values of FG stage among males and females were also observed. CONCLUSION: Based on statistical and direct comparison of raw data, study concludes that frontal sinus is not reliable as a sole criterion for prediction of skeletal maturity. PMID- 24047857 TI - Postpneumonectomy syndrome: a case of shifting priorities. PMID- 24047858 TI - Sleep, respiration, and pain: a potential nexus for chronic pain risk? PMID- 24047859 TI - The clinical significance of antimicrobial serologic responses within an Irish Crohn's disease population. AB - INTRODUCTION: A hyper-responsive adaptive immunologic response to a variety of microbial antigens has been described in Crohn's disease (CD) patients and elevated levels of a number of antibodies have been identified in the sera of CD patients. To date, the serological profiles of an Irish CD population have not been characterized. OBJECTIVES: The aim of this study is to determine the serological profile of Irish patients with CD. Second, we aim to assess the correlation, if any, between serological profile and disease phenotype within this cohort. METHODS: A total of 179 consecutive adults with CD attending a specialist inflammatory bowel disease clinic at a university hospital were recruited. Blood samples were taken and sera were analysed for the expression of pANCA and Crohn's related antibodies. RESULTS: pANCA was present in 47/179 (26.3%), anti-OmpC antibodies were present in 49/179 (27.4%), anti-Saccharomyces cervisiae (ASCA) in 64/179 (35.75%), ASCA IgA in 56/179 (31.28%) and ASCA IgG in 37/179 (20.67%), and anti-CBir antibodies in 97/179 (54.18%). The presence of ASCA IgA (P=0.031), ASCA IgG (P=0.007) and anti-CBir antibodies (P=0.003) were all significantly associated with small bowel involvement. Anti-OmpC, ASCA IgA and anti-CBir antibodies' positivity were all associated with complicated disease behaviour, whereas ANCA positivity was associated with inflammatory disease. CONCLUSION: Our study supports previous findings of an association between serological profiles and disease behaviour and a corresponding association with increased need for surgery. In this genetically homogenous Irish CD study group, the levels of specific antibody responses to commensal gut flora are lower than reported previously in other European and American populations. PMID- 24047860 TI - How patients with long-term experience of living with irritable bowel syndrome manage illness in daily life: a qualitative study. AB - OBJECTIVES: Irritable bowel syndrome (IBS) is a chronic, disabling and functional gastrointestinal disorder. Effective treatments are lacking. Self-care and coping with symptoms are considered important but little is known about what patients with IBS actually do to manage their illness. The aim of this study was to explore how patients with long-term experience of living with IBS perceive their situation and manage illness in daily life. PATIENTS AND METHODS: The study adopted a qualitative approach - an interpretative phenomenological analysis. Twenty patients with IBS (16 women) with a mean age of 46 (27-74) years were interviewed. The mean IBS duration was 24 (7-65) years. RESULTS: Two themes emerged from the analysis: Healed but not cured and Take control of daily life. Healed but not cured is about mastering IBS. Even though the patients feel there has been an improvement, their abdomen is constantly present. The patients live with intermittent interaction between well-being and illness and construct explanations for the cause of the IBS symptoms. Taking control of daily life is about the activities the patients perform to master IBS symptoms: self centredness, disciplined self-care, control over daily routines and finding social support. CONCLUSION: These results suggest that the negative impact of IBS on daily life can be reduced. Over time, the patients had found effective strategies for symptom improvement, although this is a long-term learning process. The healthcare system could be more effective in supporting patients to find solutions to problems caused by IBS that are consistent with person-centred care and could be adopted as part of different supportive/educational interventions. PMID- 24047861 TI - Refractory GERD: increased body mass index is associated with persisting acid exposure but not hypersensitive esophagus or functional heartburn. AB - OBJECTIVE: To compare the incidence of persistent abnormal acid exposure, hypersensitive esophagus (HE), and functional heartburn (FH) in obese/overweight and normal-weight patients referred for impedance-pH monitoring, because of persisting gastroesophageal reflux disease (GERD) symptoms despite therapy with proton pump inhibitors (PPIs). MUETHODS: Patients with normal endoscopy and typical GERD symptoms, despite PPI therapy twice daily, underwent 24-h impedance pH monitoring while on therapy. Distal esophageal acid exposure (% time pH<4) was measured and reflux episodes were classified into acid or nonacid. A positive symptom index was defined when at least 50% of symptom events were preceded by reflux episodes. Patients were categorized as those with persistent abnormal acid exposure, those with HE, and those with FH. The incidence of persistent abnormal acid exposure, HE, and FH between overweight/obese patients (BMI>=25 kg/m) and normal-weight patients (BMI<25 kg/m) was subsequently evaluated. RESULTS: A total of 246 patients (women: 158, men: 88, increased BMI: 151, normal BMI: 95, mean age 55, range 18-75 years) were included. Persistent abnormal acid exposure was found in 39 patients (increased BMI: 31, normal BMI: 8), HE in 77 patients (increased BMI: 43, normal BMI: 34), and FH in 118 patients (increased BMI: 69, normal BMI: 49). When comparing BMI among all three groups, patients with increased BMI were more likely to have acid reflux than HE or FH (P=0.03). CONCLUSION: In patients with GERD symptoms refractory to double-dose PPI therapy, those with increased BMI are more likely to have persistent abnormal acid exposure than HE or FH. PMID- 24047862 TI - Influence of housing and season on pubertal development, boar taint compounds and skin lesions of male pigs. AB - Rearing entire pigs may lead to meat quality and welfare problems in relation to pubertal development. A better knowledge of the sources of variation of pubertal development, behaviour and boar taint is needed before generalizing entire male pigs. From 84 days of age, entire male pigs were reared in groups of 10 either in a conventional (C, 1 m2/animal, slatted floor) or an enriched (E, 2.5 m2/animal, straw bedding, outdoor run) housing during spring or autumn and fed ad libitum (n=10/housing/season). Mounting behaviour was observed for 3 h during the third (M3), fourth (M4) and fifth (M5) months of age. The total number of skin lesions was counted on both sides of the pigs 1 day before the behavioural recordings. The time spent in the outdoor run was also recorded during 3 days per month. The animals were slaughtered at 161+/-1 days of age (122+/-9 kg live weight). Blood samples were collected at 89 (M3), 119 (M4) and 152 (M5) days of age and at slaughter for the testosterone and oestradiol measurements. The testes were collected at slaughter, freed from the surrounding tissues and weighed. The fat samples were collected for the androstenone and skatole concentration measurement. Plasma testosterone and oestradiol-17beta (oestradiol), fat androstenone and skatole and weight of the testes did not differ between the housing systems. Plasma testosterone (8.3 v. 3.9 nmol/l, P<0.05) and oestradiol (12.0 v. 9.2 pmol/l, P<0.1) at M3, fat skatole (0.124 v. 0.043, P<0.03) and weight of the testes (587 v. 512 g, P<0.05) were higher in the autumn than in the spring trial, suggesting that the pubertal development was accelerated. The number of received mounting behaviours was slightly higher in the autumn (P=0.08) trial and was markedly higher in the E than in the C environment (P<0.003). Skin lesions were more numerous in the C than in the E housing at M4 and M5 and in the spring than in the autumn trial at M3 and M4 (P<0.05). Fat androstenone and the number of performed mounting behaviours were significantly correlated between each other and with numerous indicators of the pubertal development (P<0.05). The number of skin lesions was correlated with plasma testosterone and live weight (P<0.05). Overall, this study suggests the effect of season on sexual development, the effect of the housing system on behaviour, and demonstrates the links between sexual hormones, behaviour and boar taint. PMID- 24047863 TI - Water uptake along the length of grapevine fine roots: developmental anatomy, tissue-specific aquaporin expression, and pathways of water transport. AB - To better understand water uptake patterns in root systems of woody perennial crops, we detailed the developmental anatomy and hydraulic physiology along the length of grapevine (Vitis berlandieri * Vitis rupestris) fine roots from the tip to secondary growth zones. Our characterization included the localization of suberized structures and aquaporin gene expression and the determination of hydraulic conductivity (Lpr) and aquaporin protein activity (via chemical inhibition) in different root zones under both osmotic and hydrostatic pressure gradients. Tissue-specific messenger RNA levels of the plasma membrane aquaporin isogenes (VvPIPs) were quantified using laser-capture microdissection and quantitative polymerase chain reaction. Our results highlight dramatic changes in structure and function along the length of grapevine fine roots. Although the root tip lacked suberization altogether, a suberized exodermis and endodermis developed in the maturation zone, which gave way to the secondary growth zone containing a multilayer suberized periderm. Longitudinally, VvPIP isogenes exhibited strong peaks of expression in the root tip that decreased precipitously along the root length in a pattern similar to Arabidopsis (Arabidopsis thaliana) roots. In the radial orientation, expression was always greatest in interior tissues (i.e. stele, endodermis, and/or vascular tissues) for all root zones. High Lpr and aquaporin protein activity were associated with peak VvPIP expression levels in the root tip. This suggests that aquaporins play a limited role in controlling water uptake in secondary growth zones, which contradicts existing theoretical predictions. Despite having significantly lower Lpr, woody roots can constitute the vast majority of the root system surface area in mature vines and thus provide for significant water uptake potential. PMID- 24047865 TI - Eosinophilic myocarditis with left ventricular apical aneurysm. PMID- 24047864 TI - The importance of size and disorder in the cryoprotective effects of dehydrins. AB - Dehydrins protect plant proteins and membranes from damage during drought and cold. Vitis riparia K2 is a 48-residue protein that can protect lactate dehydrogenase from freeze-thaw damage by preventing the aggregation and denaturation of the enzyme. To further elucidate its mechanism, we used a series of V. riparia K2 concatemers (K4, K6, K8, and K10) and natural dehydrins (V. riparia YSK2, 60 kilodalton peach dehydrin [PCA60], barley dehydrin5 [Dhn5], Thellungiella salsuginea dehydrin2 [TsDHN-2], and Opuntia streptacantha dehydrin1 [OpsDHN-1]) to test the effect of the number of K-segments and dehydrin size on their ability to protect lactate dehydrogenase from freeze-thaw damage. The results show that the larger the hydrodynamic radius of the dehydrin, the more effective the cryoprotection. A similar trend is observed with polyethylene glycol, which would suggest that the protection is simply a nonspecific volume exclusion effect that can be manifested by any protein. However, structured proteins of a similar range of sizes did not show the same pattern and level of cryoprotection. Our results suggest that with respect to enzyme protection, dehydrins function primarily as molecular shields and that their intrinsic disorder is required for them to be an effective cryoprotectant. Lastly, we show that the cryoprotection by a dehydrin is not due to any antifreeze protein-like activity, as has been reported previously. PMID- 24047866 TI - Assessment of left ventricular systolic function by deformation imaging derived from speckle tracking: a comparison between 2D and 3D echo modalities. AB - AIMS: Deformation imaging is undergoing continuous development with the emergence of new technologies allowing the evaluation of the different components of strain simultaneously in three dimensions. Assessment of all global strain parameters in 2D and 3D modes and comparison with LVEF have been the focus of our study. METHODS AND RESULTS: Out of 166 patients, 147 were evaluated with the use of both 2D and 3D speckle-tracking echocardiography (STE). Global strain parameters including longitudinal (GLS), circumferential (GCS), radial (GRS) and area strain (AS), as well as left ventricular volumes and ejection fraction were examined. Analysis of strain with 3D STE was faster than with 2D STE (7 +/- 2 vs. 24 +/- 4 min, P < 0.05). GLS values were similar between 2D and 3D modes (-14 +/- 4 vs. 13 +/- 3, NS), while slight differences were observed for GCS (-24 +/- 7 vs. -27 +/- 7, P < 0.05) and GRS (27 +/- 9 vs. 24 +/- 9, P < 0.05). All 2D and 3D strain parameters showed good accuracy in the identification of 2D-LVEF <55% with AS demonstrating superiority over GCS and GRS but not GLS. CONCLUSION: Three dimensional STE allows accurate and faster analysis of deformation when compared with 2D STE and might represent a viable alternative in the evaluation of global LV function. PMID- 24047867 TI - Effects of enteral nutrition on the barrier function of the intestinal mucosa and dopamine receptor expression in rats with traumatic brain injury. AB - BACKGROUND: Impaired intestinal mucosal barrier (IMB) function is common in traumatic brain injury (TBI), but dopamine receptors (DRs) change in intestinal mucosa after TBI, and effects of enteral nutrition (EN) and supplements on IMB function remain unclear. Our purpose was to study the effects of EN and supplements on intestinal mucosal permeability (IMPB) and the expression of DRs DRD1 and DRD2 in the intestinal mucosa of rats with TBI. METHODS: Forty-eight rats were divided into 8 groups; control, animals with TBI, dopamine group, animals with TBI treated with dopamine antagonist, EN alone, or EN combined with glutamine, probiotics, or a combination of probiotics and glutamine daily after TBI. RESULTS: The IMPB was improved in the glutamine, probiotics, and combination groups. Including probiotics improved IMPB more than adding glutamine, and bacterial translocation in the intestines after TBI was reduced in the probiotics and combination groups (all Ps < .01). TBI led to elevated DRD1 and DRD2 mRNA and protein levels, which were reduced in the DA antagonist, glutamine, probiotics, and combination groups. DRD2 mRNA and protein levels in the probiotics and combination groups were decreased more than in the DA antagonist group (all Ps < .01). The increased IMPB after TBI correlated with increased DRD1 and DRD2 levels in the rat intestinal mucosa. CONCLUSION: EN supplemented with probiotics or combining glutamine and probiotics lowers the increased IMPB, bacterial translocation, and DRD1 and DRD2 mRNA and protein expression in rat intestinal mucosa caused by TBI. PMID- 24047868 TI - Declining influenza vaccination coverage among nurses, Hong Kong, 2006-2012. AB - Seasonal influenza vaccination of nurses in Hong Kong fell from 57% in 2005 to 24% in 2012, paralleling concern for adverse reactions associated with vaccination. Decreased acceptance of vaccination was most prominent among nurses who had less work experience and more frequent contact with patients. PMID- 24047869 TI - Racial disparities in knee and hip total joint arthroplasty: an 18-year analysis of national Medicare data. AB - OBJECTIVE: To examine whether racial disparities in usage and outcomes of total knee and total hip arthroplasty (TKA and THA) have declined over time. METHODS: We used data from the US Medicare Program (MedPAR data) for years 1991-2008 to identify four separate cohorts of patients (primary TKA, revision TKA, primary THA, revision THA). For each cohort, we calculated standardised arthroplasty usage rates for Caucasian and African-American Medicare beneficiaries for each calendar year, and examined changes in disparities over time. We examined unadjusted and adjusted outcomes (30-day readmission rate, discharge disposition etc.) for Caucasians and African-Americans, and whether disparities decreased over time. RESULTS: In 1991, the use of primary TKA was 36% lower for African Americans compared with Caucasians (20.6 per 10,000 for African-Americans; 32.1 per 10,000 for Caucasians; p<0.0001); in 2008, usage of primary TKA was 40% lower for African-Americans (41.5 per 10,000 for African-Americans; 68.8 per 10,000 for Caucasians; p<0.0001) with similar findings for the other cohorts. Black-White disparities in 30-day hospital readmission increased significantly from 1991-2008 among three patient cohorts. For example in 1991 30-day readmission rates for African-Americans receiving primary TKA were 6% higher than for Caucasians; by 2008 readmission rates for African-Americans were 24% higher (p<0.05 for change in disparity). Similarly, black-white disparities in the proportion of patients discharged to home after surgery increased across the study period for all cohorts (p<0.05). CONCLUSIONS: In an 18-year analysis of US Medicare data, we found little evidence of declines in racial disparities for joint arthroplasty usage or outcomes. PMID- 24047870 TI - Hand osteoarthritis in relation to mortality and incidence of cardiovascular disease: data from the Framingham heart study. AB - OBJECTIVES: To study whether hand osteoarthritis (OA) is associated with increased mortality and cardiovascular events in a large community based cohort (Framingham Heart Study) in which OA, mortality and cardiovascular events have been carefully assessed. METHODS: We examined whether symptomatic (>=1 joint(s) with radiographic OA and pain in the same joint) and radiographic hand OA (>=1 joint(s) with radiographic OA without pain) were associated with mortality and incident cardiovascular events (coronary heart disease, congestive heart failure and/or atherothrombotic brain infarction) using Cox proportional hazards models. In the adjusted models, we included possible confounding factors from baseline (eg, metabolic factors, medication use, smoking/alcohol). We also adjusted for the number of painful joints in the lower limb and physical inactivity. RESULTS: We evaluated 1348 participants (53.8% women) with mean (SD) age of 62.2 (8.2) years, of whom 540 (40.1%) and 186 (13.8%) had radiographic and symptomatic hand OA, respectively. There was no association between hand OA and mortality. Although there was no significant relation to incident cardiovascular events overall or a relation of radiographic hand OA with events, we found a significant association between symptomatic hand OA and incident coronary heart disease (myocardial infarction/coronary insufficiency syndrome) (HR 2.26, 95% CI 1.22 to 4.18). The association remained after additional adjustment for pain in the lower limb or physical inactivity. CONCLUSIONS: Symptomatic hand OA, but not radiographic hand OA, was associated with an increased risk of coronary heart disease events. The results suggest an effect of pain, which may be a possible marker of inflammation. PMID- 24047871 TI - Why is combinatorial communication rare in the natural world, and why is language an exception to this trend? AB - In a combinatorial communication system, some signals consist of the combinations of other signals. Such systems are more efficient than equivalent, non combinatorial systems, yet despite this they are rare in nature. Why? Previous explanations have focused on the adaptive limits of combinatorial communication, or on its purported cognitive difficulties, but neither of these explains the full distribution of combinatorial communication in the natural world. Here, we present a nonlinear dynamical model of the emergence of combinatorial communication that, unlike previous models, considers how initially non communicative behaviour evolves to take on a communicative function. We derive three basic principles about the emergence of combinatorial communication. We hence show that the interdependence of signals and responses places significant constraints on the historical pathways by which combinatorial signals might emerge, to the extent that anything other than the most simple form of combinatorial communication is extremely unlikely. We also argue that these constraints can be bypassed if individuals have the socio-cognitive capacity to engage in ostensive communication. Humans, but probably no other species, have this ability. This may explain why language, which is massively combinatorial, is such an extreme exception to nature's general trend for non-combinatorial communication. PMID- 24047872 TI - The role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach. AB - The calcitonin gene-related peptide (CGRP) receptor is a complex of a calcitonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271-294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2 modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely structures for receptor activation are discussed. PMID- 24047873 TI - Modelling and inference reveal nonlinear length-dependent suppression of somatic instability for small disease associated alleles in myotonic dystrophy type 1 and Huntington disease. AB - More than 20 human genetic diseases are associated with inheriting an unstable expanded DNA simple sequence tandem repeat, for example, CTG (cytosine-thymine guanine) repeats in myotonic dystrophy type 1 (DM1) and CAG (cytosine-adenine guanine) repeats in Huntington disease (HD). These sequences mutate by changing the number of repeats not just between generations, but also during the lifetime of affected individuals. Levels of somatic instability contribute to disease onset and progression but as changes are tissue-specific, age- and repeat length dependent, interpretation of the level of somatic instability in an individual is confounded by these considerations. Mathematical models, fitted to CTG repeat length distributions derived from blood DNA, from a large cohort of DM1-affected or at risk individuals, have recently been used to quantify inherited repeat lengths and mutation rates. Taking into account age, the estimated mutation rates are lower than predicted among individuals with small alleles (inherited repeat lengths less than 100 CTGs), suggesting that these rates may be suppressed at the lower end of the disease-causing range. In this study, we propose that a length specific effect operates within this range and tested this hypothesis using a model comparison approach. To calibrate the extended model, we used data derived from blood DNA from DM1 individuals and, for the first time, buccal DNA from HD individuals. In a novel application of this extended model, we identified individuals whose effective repeat length, with regards to somatic instability, is less than their actual repeat length. A plausible explanation for this distinction is that the expanded repeat tract is compromised by interruptions or other unusual features. We quantified effective length for a large cohort of DM1 individuals and showed that effective length better predicts age of onset than inherited repeat length, thus improving the genotype-phenotype correlation. Under the extended model, we removed some of the bias in mutation rates making them less length-dependent. Consequently, rates adjusted in this way will be better suited as quantitative traits to investigate cis- or trans-acting modifiers of somatic mosaicism, disease onset and progression. PMID- 24047874 TI - An energetic model for macromolecules unfolding in stretching experiments. AB - We propose a simple approach, based on the minimization of the total (entropic plus unfolding) energy of a two-state system, to describe the unfolding of multi domain macromolecules (proteins, silks, polysaccharides, nanopolymers). The model is fully analytical and enlightens the role of the different energetic components regulating the unfolding evolution. As an explicit example, we compare the analytical results with a titin atomic force microscopy stretch-induced unfolding experiment showing the ability of the model to quantitatively reproduce the experimental behaviour. In the thermodynamic limit, the sawtooth force-elongation unfolding curve degenerates to a constant force unfolding plateau. PMID- 24047875 TI - Use of kernel-based Bayesian models to predict late osteolysis after hip replacement. AB - We studied the relationship between osteolysis and polyethylene wear, age at surgery, body mass index and height in 463 subjects (180 osteolysis and 283 controls) after cemented Charnley total hip arthroplasty (THA), in order to develop a kernel-based Bayesian model to quantitate risk of osteolysis. Such tools may be integrated into decision-making algorithms to help personalize clinical decision-making. A predictive model was constructed, and the estimated posterior probability of the implant failure calculated. Annual wear provided the greatest discriminatory information. Age at surgery provided additional predictive information and was added to the model. Body mass index and height did not contain valuable discriminatory information over the range in which observations were densely sampled. The robustness and misclassification rate of the predictive model was evaluated by a five-times cross-validation method. This yielded a 70% correct predictive classification of subjects into osteolysis versus non-osteolysis groups at a mean of 11 years after THA. Finally, the data were divided into male and female subsets to further explore the relationship between wear rate, age at surgery and incidence of osteolysis. The correct classification rate using age and wear rate in the model was approximately 66% for males and 74% for females. PMID- 24047877 TI - The relationship between modularity and robustness in signalling networks. AB - Many biological networks tend to have a high modularity structural property and the dynamic characteristic of high robustness against perturbations. However, the relationship between modularity and robustness is not well understood. To investigate this relationship, we examined real signalling networks and conducted simulations using a random Boolean network model. As a result, we first observed that the network robustness is negatively correlated with the network modularity. In particular, this negative correlation becomes more apparent as the network density becomes sparser. Even more interesting is that, the negative relationship between the network robustness and the network modularity occurs mainly because nodes in the same module with the perturbed node tend to be more sensitive to the perturbation than those in other modules. This result implies that dynamically similar nodes tend to be located in the same module of a network. To support this, we show that a pair of genes associated with the same disease or a pair of functionally similar genes is likely to belong to the same module in a human signalling network. PMID- 24047876 TI - Contact inhibition of locomotion probabilities drive solitary versus collective cell migration. AB - Contact inhibition of locomotion (CIL) is the process whereby cells collide, cease migrating in the direction of the collision, and repolarize their migration machinery away from the collision. Quantitative analysis of CIL has remained elusive because cell-to-cell collisions are infrequent in traditional cell culture. Moreover, whereas CIL predicts mutual cell repulsion and 'scattering' of cells, the same cells in vivo are observed to undergo CIL at some developmental times and collective cell migration at others. It remains unclear whether CIL is simply absent during collective cell migration, or if the two processes coexist and are perhaps even related. Here, we used micropatterned stripes of extracellular matrix to restrict cell migration to linear paths such that cells polarized in one of two directions and collisions between cells occurred frequently and consistently, permitting quantitative and unbiased analysis of CIL. Observing repolarization events in different contexts, including head-to head collision, head-to-tail collision, collision with an inert barrier, or no collision, and describing polarization as a two-state transition indicated that CIL occurs probabilistically, and most strongly upon head-to-head collisions. In addition to strong CIL, we also observed 'trains' of cells moving collectively with high persistence that appeared to emerge from single cells. To reconcile these seemingly conflicting observations of CIL and collective cell migration, we constructed an agent-based model to simulate our experiments. Our model quantitatively predicted the emergence of collective migration, and demonstrated the sensitivity of such emergence to the probability of CIL. Thus CIL and collective migration can coexist, and in fact a shift in CIL probabilities may underlie transitions between solitary cell migration and collective cell migration. Taken together, our data demonstrate the emergence of persistently polarized, collective cell movement arising from CIL between colliding cells. PMID- 24047878 TI - Magnetic order in the Hubbard model in three dimensions and the crossover to two dimensions. AB - Systems of fermions described by the three-dimensional (3D) repulsive Hubbard model on a cubic lattice have recently attracted considerable attention due to their possible experimental realization via cold atoms in an optical lattice. Analytical and numerical results are limited away from half-filling. We study the ground state of the doped system from weak to intermediate interaction strengths within the generalized Hartree-Fock approximation. The exact solution to the self consistent-field equations in the thermodynamic limit is obtained and the ground state is shown to exhibit antiferromagnetic order and incommensurate spin-density waves (SDW). At low interaction strengths, the SDW has unidirectional character with a leading wavevector along the [100]-direction, and the system is metallic. As the interaction increases, the system undergoes a simultaneous structural and metal-to-insulator transition to a unidirectional SDW state along the [111] direction, with a different wavelength. We systematically determine the real and momentum space properties of these states. The crossover from 3D to two dimensions (2D) is then studied by varying the inter-plane hopping amplitude, which can be experimentally realized by tuning the distance between a stack of square-lattice layers. Detailed comparisons are made between the exact numerical results and predictions from the pairing model, a variational ansatz based on the pairing of spins in the vicinity of the Fermi surface. Most of the numerical results can be understood quantitatively from the ansatz, which provides a simple picture for the nature of the SDW states. PMID- 24047879 TI - Dosed myofascial release in three-dimensional bioengineered tendons: effects on human fibroblast hyperplasia, hypertrophy, and cytokine secretion. AB - OBJECTIVE: The purpose of this study was to investigate potential differences of magnitudes and durations associated with dosed myofascial release (MFR) on human fibroblast proliferation, hypertrophy, and cytokine secretions. METHODS: Bioengineered tendons (BETs) attached to nylon mesh anchors were strained uniaxially using a vacuum pressure designed to model MFR varying in magnitudes (0%, 3%, 6%, 9%, and 12% elongation) and durations (0.5 and 1-5 minutes). Conditioned media were analyzed for cytokine secretion via protein microarray (n = 2). Bioengineered tendons were weighted and fibroblasts extracted from the BET were assessed for total cell protein and proliferation via double-stranded DNA quantification (n = 5). All data were compared by a 1-way analysis of variance with post hoc Dunnett test and Student t test. RESULTS: Changing MFR magnitude and duration did not have an effect on total fibroblast cellular protein or DNA accumulation. However, we observed a stepwise increase in BET weight with higher magnitude MFR treatments. Longer durations of MFR resulted in progressive increase in the secretions of angiogenin, interleukin (IL)-3, IL-8, growth colony stimulating factor, and thymus activation-regulated chemokine. Alternatively, increasing strain magnitude induced secretions of IL-1beta, monocyte chemoattractant cytokine, and regulated and normal T cell expressed and secreted chemotactic cytokine. CONCLUSION: Cellular proliferation and hypertrophy were not significantly changed by any treatment. However, the change in total BET dry weight suggests that production of extracellular matrix protein may be up regulated. Different MFR parameters induce secretions of a unique subset of cytokines and growth factors that can be further enhanced by increasing the magnitude and duration of treatment. If clinically translatable, these results suggest that variations to manual therapy biomechanical parameters may differentially affect physiological responses in vivo. PMID- 24047880 TI - HIV transmission, the Law and the work of the clinical team, January 2013. PMID- 24047881 TI - Improved sexual history taking in the 2012 BASHH asymptomatic screening re-audit. AB - Effective asymptomatic screening for sexually transmitted infections is an important public health service because a significant proportion of sexually transmitted infections do not present with symptoms. In 2009, the National Audit Group of the British Association of Sexual Health and HIV (BASHH) audited the management of asymptomatic patients and recommended increased documentation about oral and anal sex, regional strategies for nucleic acid amplification test (NAAT) use for gonorrhoea, improved screening for hepatitis B in men who have sex with men and an increase in screening for HIV. The 2012 audit used web-based forms to collect submissions from 180 consultant-led centres (65% response rate) that included episodes of care from 6669 asymptomatic patients. An improvement was demonstrated for all the areas measured during the 2009 audit. A doubling of gonorrhoea testing using NAATs was seen and yet 10% of asymptomatic patients continued to have microscopy despite these tests not being recommended by BASHH guidelines. This audit recommends universal adoption of gonorrhoea NAATs across the United Kingdom. PMID- 24047882 TI - Acute kidney injury as a presentation of primary renal diffuse large B-cell lymphoma in HIV. AB - We report a case of acute kidney injury due to primary renal diffuse large B-cell lymphoma, which developed after initiation of tenofovir-containing antiretroviral therapy in a 28-year-old HIV-positive man. PMID- 24047883 TI - Coagulase-negative staphylococci in an HIV-infected child causing pancytopaenia. AB - Although coagulase-negative staphylococci (CONS) constitute normal flora of the human body, some species can produce human infections, particularly when the host defense is breached. There is little evidence of the pathogenicity of CONS in HIV infected individuals. We present the case of a 14-year-old HIV-infected boy who presented with a right lower zone pneumonia and a cutaneous abscess, following which he developed pancytopaenia due to underlying CONS infection that responded to antibiotic treatment. PMID- 24047884 TI - Bacterial loads of Ureaplasma urealyticum contribute to development of urethritis in men. AB - Ureaplasma urealyticum could be a pathogen of non-gonococcal urethritis (NGU) in men. However, ureaplasma is often detected in men without NGU, and the proportion of cases possibly attributable to this pathogen is still undefined. We attempted to determine the bacterial loads of U. urealyticum significantly associated with NGU. The 16S rRNA genes of U. urealyticum were quantified by a real-time polymerase chain reaction-based assay in first-void urine (FVU) from 26 asymptomatic and 25 symptomatic men positive for U. urealyticum. The leucocyte counts in first-void urine (FVU) were determined as an objective measure of inflammatory response to ureaplasma in the hosts by automated quantitative urine particle analysis. Positive correlations were observed between copies of the 16S rRNA genes of U. urealyticum per ml and the leucocyte counts per ul in FVU (r = 0.49, p = 0.0003). Loads of >=10(4) copies of the 16S rRNA gene of U. urealyticum/ml, corresponding to >=5 * 10(3) cells of U. urealyticum/ml in FVU, were significantly associated with the presence of urethritis symptoms (p < 0.0001) and with higher leukocyte counts in FVU (p < 0.0001). The bacterial load of U. urealyticum, possibly of >=5 * 10(3) cells of U. urealyticum/ml in FVU, could be significantly associated with the development of symptomatic NGU. PMID- 24047886 TI - Care of HIV-positive women aged 50 and over - can we do better? AB - A sample of 123 HIV-positive women aged 50 years and over showed high rates of late diagnosis with CD4 count <350 (71%), significant co-morbidities (90%), high rates of premature menopause (6.8%) and early menopause (6.8%) and cervical cytological abnormalities (47%). Specific interventions to improve care in this group should include yearly cervical cytology, early counselling with regard to reproductive options, menopause management and screening for sexually transmitted infections (STIs). PMID- 24047885 TI - Individual and partner risk factors associated with abnormal cervical cytology among women in HIV-discordant relationships. AB - Individual and sexual partner characteristics may increase the risk of abnormal cervical cytology among women in human immunodeficiency virus (HIV)-discordant relationships. Papanicolaou smears were obtained in a prospective cohort of Kenyan HIV-discordant couples. Of 441 women, 283 (64%) were HIV-infected and 158 (36%) were HIV-uninfected with HIV-infected partners. Overall, 79 (18%) had low grade and 25 (6%) high-grade cervical abnormalities. Male herpes simplex virus type 2 (HSV-2) seropositivity and lower couple socioeconomic status were associated with cervical abnormalities (p < 0.05). HIV-uninfected women with HIV infected male sex partners (CD4 > 350 cells/uL) had the lowest prevalence of high grade cervical lesions. HIV-infected women (CD4 > 350 cells/uL) and HIV uninfected women with HIV-infected partners (CD4 <= 350 cells/uL) were at similar intermediate risk (p > 0.05), and HIV-infected women (CD4 <= 350 cells/uL) had significantly higher risk of high-grade cervical abnormalities (p = 0.05). Women in HIV-discordant relationships have high rates of cervical lesions and this may be influenced by couple-level factors, including HIV status and CD4 count of the infected partner. PMID- 24047887 TI - Comparison between human and porcine thromboelastograph parameters in response to ex-vivo changes to platelets, plasma, and red blood cells. AB - In the acute care setting, both the tracings and numeric outputs (R time, angle, and MA) of thrombelastography (TEG) may be used to inform treatment decisions. The objective was to determine the sensitivity of TEG to isolated changes in platelet count, hematocrit and fibrinogen concentration in human blood. As pigs have a similar coagulation system, we also compared the responses of the pig blood. Eight volunteers (>18 years of age, no anticoagulation or nonsteroidal anti-inflammatory therapy, not pregnant) were enrolled into this study. Four female anesthetized donor pigs were instrumented percutaneously with a catheter for blood collection. All blood was collected into sodium citrate. The concentration of each component (platelets, fibrinogen, and red blood cells) was changed while keeping the other components constant by use of centrifugation or preparation of each individual's plasma into platelet poor plasma, platelet rich plasma, cryoprecipitate, purified washed platelets, and packed red blood cells as appropriate. TEG (Haemoscope) analysis was performed and compared with the patients' whole blood diluted with lactated Ringer's solution. We demonstrated that the major factor affecting the MA and angle was the platelet count. In fact, reducing platelets alone resulted in TEG profiles and parameters that were similar to lactated Ringer's dilution profiles. Swine blood responses were parallel to that of human blood, although there were offsets especially of TEG-R and angle that confirmed that the swine are hypercoagulable compared with humans. Superficially similar TEG tracing patterns can be produced by divergent mechanisms associated with altered concentrations of blood components. PMID- 24047888 TI - The nature of lipopolysaccharide-stimulated monocyte tissue factor activity. AB - There are several contradictory hypotheses that attempt to explain changes in cell tissue factor (TF) activity upon treatment with various agents ('encryption decryption'). We evaluated the influence of lipopolysaccharide stimulation on expression of TF antigen and activity on/in THP-1 human leukemia monocytic cells. Prior to stimulation, there were 240 +/- 60 TF molecules/cell on the cell surface and 510 +/- 180 molecules/cell in lysates (n = 8). Upon stimulation, TF antigen increased 10-fold on the cell surface and 16.5-fold in lysates. Coincidently, the intact cell factor (F)Xa generation by TF/FVIIa increased 11-fold. Correspondingly, TF-induced clotting activity increased 35.7 +/- 4.9-fold. The KM of the TF/FVIIa complex formed on the THP-1 surface and cell lysates for FX was 0.73 +/- 0.07 and 0.41 +/- 0.02 MUmol/l and the kcat 59.4 +/- 1.8 and 44.6 +/- 0.1 s, respectively. For isolated and relipidated THP-1 cell TF, the efficiency of FXase was lower (KM = 1.54 MUmol/l and kcat = 12.0 s). A similar comparison of isolated/relipidated vs. cell-surface TF in the synthetic coagulation proteome and corn trypsin inhibitor blood showed that the cell-surface TF-induced thrombin generation is more than 100-fold more efficient than that induced by purified/relipidated TF. These data indicate that the increase in monocytic cell TF activity upon stimulation is primarily related to an increased expression of TF protein, and that significantly higher specific activity of TF presented on cells than that of purified and relipidated protein suggests the presence of the cell membrane components which substantially enhance TF function. PMID- 24047889 TI - Assessment of characteristics associated with pharmacologic thromboprophylaxis use in hospitalized patients: a cohort study of 10,016 patients. AB - The aim of the study was to evaluate patient characteristics associated with pharmacologic thromboprophylaxis (PTP) use/nonuse in a general tertiary hospital cohort. Eligible patients were classified according to venous thromboembolism (VTE) risk category by trained nurses. Either standard or low-molecular weight heparin was recommended to intermediate or high-risk VTE patients. Adopting the recommended PTP was at the physician's discretion. At discharge, PTP use was recorded. PTP was recommended to 10,016 patients, of whom 2165 (21.6%) received the recommended thromboprophylaxis. In the multivariate logistic regression, PTP use/nonuse remained independently associated with female sex [odds ratio (OR) 0.75; 95% confidence interval (CI) 0.68-0.84], age (OR 1.04; 95% CI 1.03-1.04), being admitted to the Gynecology-Obstetrics (OR 0.31; 95% CI 0.25-0.39) or surgery (OR 1.26; 95% CI 1.12-1.42), thrombophilia (OR 5.15; 95% CI 2.04-12.98), previous VTE event (OR 2.98; 95% CI 1.78-4.98), diabetes (OR 1.84; 95% CI 1.61 2.10), acute myocardial infarction (OR 5.87; 95% CI 4.81-7.17), and admission to a major orthopedic surgery (OR 3.03; 95% CI 1.98-4.64). PTP in this hospital population was grossly underused. Eight independent variables predicted use/nonuse of PTP. Targeting variables related to the use and nonuse of PTP is important to direct the application of thromboprophylaxis. PMID- 24047890 TI - Screening the ability of natural feed ingredients to interfere with the adherence of enterotoxigenic Escherichia coli (ETEC) K88 to the porcine intestinal mucus. AB - The inhibition of the attachment of bacteria to the intestine by receptor analogues could be a novel approach to prevent enterotoxigenic Escherichia coli (ETEC) K88-induced diarrhoea in piglets. The objective of the present study was to screen the ability of different feed ingredients (FI) to bind to ETEC K88 (adhesion test, AT) and to block its attachment to the porcine intestinal mucus (blocking test, BT) using in vitro microtitration-based models. In the AT, wheat bran (WB), casein glycomacropeptide (CGMP) and exopolysaccharides exhibited the highest adhesion to ETEC K88 (P< 0.001). In the BT, WB, CGMP and locust bean (LB) reduced the number of ETEC K88 attached to the intestinal mucus (P< 0.001). For WB and LB, fractionation based on their carbohydrate components was subsequently carried out, and each fraction was evaluated individually. None of the WB fractions reduced the adhesion of ETEC K88 to the mucus as did the original extract, suggesting that a protein or glycoprotein could be involved in the recognition process. With regard to the LB fractions, the water-extractable material reduced the adhesion of ETEC K88 (P< 0.001) to the mucus similar to the original extract (P< 0.001), indicating, in this case, that galactomannans or phenolic compounds could be responsible for the recognition process. In conclusion, among the FI screened, the soluble extracts obtained from WB, LB and CGMP exhibited the highest anti-adhesive properties against ETEC K88 in the BT. These results suggest that they may be good candidates to be included in diets of weaned piglets for the prevention of ETEC K88-induced diarrhoea. PMID- 24047891 TI - The trypsin inhibitor panulirin regulates the prophenoloxidase-activating system in the spiny lobster Panulirus argus. AB - The melanization reaction promoted by the prophenoloxidase-activating system is an essential defense response in invertebrates subjected to regulatory mechanisms that are still not fully understood. We report here the finding and characterization of a novel trypsin inhibitor, named panulirin, isolated from the hemocytes of the spiny lobster Panulirus argus with regulatory functions on the melanization cascade. Panulirin is a cationic peptide (pI 9.5) composed of 48 amino acid residues (5.3 kDa), with six cysteine residues forming disulfide bridges. Its primary sequence was determined by combining Edman degradation/N terminal sequencing and electrospray ionization-MS/MS spectrometry. The low amino acid sequence similarity with known proteins indicates that it represents a new family of peptidase inhibitors. Panulirin is a competitive and reversible tight binding inhibitor of trypsin (Ki = 8.6 nm) with a notable specificity because it does not inhibit serine peptidases such as subtilisin, elastase, chymotrypsin, thrombin, and plasmin. The removal of panulirin from the lobster hemocyte lysate leads to an increase in phenoloxidase response to LPS. Likewise, the addition of increasing concentrations of panulirin to a lobster hemocyte lysate, previously depleted of trypsin-inhibitory activity, decreased the phenoloxidase response to LPS in a concentration-dependent fashion. These results indicate that panulirin is implicated in the regulation of the melanization cascade in P. argus by inhibiting peptidase(s) in the pathway toward the activation of the prophenoloxidase enzyme. PMID- 24047892 TI - Epidermal growth factor receptor (EGFR) signaling regulates epiphyseal cartilage development through beta-catenin-dependent and -independent pathways. AB - The epidermal growth factor receptor (EGFR) is an essential player in the development of multiple organs during embryonic and postnatal stages. To understand its role in epiphyseal cartilage development, we generated transgenic mice with conditionally inactivated EGFR in chondrocytes. Postnatally, these mice exhibited a normal initiation of cartilage canals at the perichondrium, but the excavation of these canals into the cartilage was strongly suppressed, resulting in a delay in the formation of the secondary ossification center (SOC). This delay was accompanied by normal chondrocyte hypertrophy but decreased mineralization and apoptosis of hypertrophic chondrocytes and reduced osteoclast number at the border of marrow space. Immunohistochemical analyses demonstrated that inactivation of chondrocyte-specific EGFR signaling reduced the amounts of matrix metalloproteinases (MMP9, -13, and -14) and RANKL (receptor activator of NF-kappaB ligand) in the hypertrophic chondrocytes close to the marrow space and decreased the cartilage matrix degradation in the SOC. Analyses of EGFR downstream signaling pathways in primary epiphyseal chondrocytes revealed that up regulation of MMP9 and RANKL by EGFR signaling was partially mediated by the canonical Wnt/beta-catenin pathway, whereas EGFR-enhanced MMP13 expression was not. Further biochemical studies suggested that EGFR signaling stimulates the phosphorylation of LRP6, increases active beta-catenin level, and induces its nuclear translocation. In line with these in vitro studies, deficiency in chondrocyte-specific EGFR activity reduced beta-catenin amount in hypertrophic chondrocytes in vivo. In conclusion, our work demonstrates that chondrocyte specific EGFR signaling is an important regulator of cartilage matrix degradation during SOC formation and epiphyseal cartilage development and that its actions are partially mediated by activating the beta-catenin pathway. PMID- 24047893 TI - Insights into the mechanism of initial transcription in Escherichia coli RNA polymerase. AB - It has long been known that during initial transcription of the first 8-10 bases of RNA, complexes are relatively unstable, leading to the release of short abortive RNA transcripts. An early "stressed intermediate" model led to a more specific mechanistic model proposing "scrunching" stress as the basis for the instability. Recent studies in the single subunit T7 RNA polymerase have argued against scrunching as the energetic driving force and instead argue for a model in which pushing of the RNA-DNA hybrid against a protein element associated with promoter binding, while likely driving promoter release, reciprocally leads to instability of the hybrid. In this study, we test these models in the structurally unrelated multisubunit bacterial RNA polymerase. Via the targeted introduction of mismatches and nicks in the DNA, we demonstrate that neither downstream bubble collapse nor compaction/scrunching of either the single stranded template or nontemplate strands is a major force driving abortive instability (although collapse from the downstream end of the bubble does contribute significantly to the instability of artificially halted complexes). In contrast, pushing of the hybrid against a mobile protein element (sigma3.2 in the bacterial enzyme) results in substantially increased abortive instability and is likely the primary energetic contributor to abortive cycling. The results suggest that abortive instability is a by-product of the mechanistic need to couple the energy of nucleotide addition (RNA chain growth) to driving the timed release of promoter contacts during initial transcription. PMID- 24047894 TI - How natalizumab binds and antagonizes alpha4 integrins. AB - Natalizumab antibody to alpha4-integrins is used in therapy of multiple sclerosis and Crohn's disease. A crystal structure of the Fab bound to an alpha4 integrin beta-propeller and thigh domain fragment shows that natalizumab recognizes human mouse differences on the circumference of the beta-propeller domain. The epitope is adjacent to but outside of a ligand-binding groove formed at the interface with the beta-subunit betaI domain and shows no difference in structure when bound to Fab. Competition between Fab and the ligand vascular cell adhesion molecule (VCAM) for binding to cell surface alpha4beta1 shows noncompetitive antagonism. In agreement, VCAM docking models suggest that binding of domain 1 of VCAM to alpha4-integrins is unimpeded by the Fab, and that bound Fab requires a change in orientation between domains 1 and 2 of VCAM for binding to alpha4beta1. Mapping of species-specific differences onto alpha4beta1 and alpha4beta7 shows that their ligand-binding sites are highly conserved. Skewing away from these conserved regions of the epitopes recognized by current therapeutic function blocking antibodies has resulted in previously unanticipated mechanisms of action. PMID- 24047895 TI - Novel insights into eukaryotic gamma-glutamyltranspeptidase 1 from the crystal structure of the glutamate-bound human enzyme. AB - The enzyme gamma-glutamyltranspeptidase 1 (GGT1) is a conserved member of the N terminal nucleophile hydrolase family that cleaves the gamma-glutamyl bond of glutathione and other gamma-glutamyl compounds. In animals, GGT1 is expressed on the surface of the cell and has critical roles in maintaining cysteine levels in the body and regulating intracellular redox status. Expression of GGT1 has been implicated as a potentiator of asthma, cardiovascular disease, and cancer. The rational design of effective inhibitors of human GGT1 (hGGT1) has been delayed by the lack of a reliable structural model. The available crystal structures of several bacterial GGTs have been of limited use due to differences in the catalytic behavior of bacterial and mammalian GGTs. We report the high resolution (1.67 A) crystal structure of glutamate-bound hGGT1, the first of any eukaryotic GGT. Comparisons of the active site architecture of hGGT1 with those of its bacterial orthologs highlight key differences in the residues responsible for substrate binding, including a bimodal switch in the orientation of the catalytic nucleophile (Thr-381) that is unique to the human enzyme. Compared with several bacterial counterparts, the lid loop in the crystal structure of hGGT1 adopts an open conformation that allows greater access to the active site. The hGGT1 structure also revealed tightly bound chlorides near the catalytic residue that may contribute to catalytic activity. These are absent in the bacterial GGTs. These differences between bacterial and mammalian GGTs and the new structural data will accelerate the development of new therapies for GGT1-dependent diseases. PMID- 24047896 TI - Cotranscriptional recruitment of RNA exosome cofactors Rrp47p and Mpp6p and two distinct Trf-Air-Mtr4 polyadenylation (TRAMP) complexes assists the exonuclease Rrp6p in the targeting and degradation of an aberrant messenger ribonucleoprotein particle (mRNP) in yeast. AB - The cotranscriptional mRNA processing and packaging reactions that lead to the formation of export-competent messenger ribonucleoprotein particles (mRNPs) are under the surveillance of quality control steps. Aberrant mRNPs resulting from faulty events are retained in the nucleus with ensuing elimination of their mRNA component. The molecular mechanisms by which the surveillance system recognizes defective mRNPs and stimulates their destruction by the RNA degradation machinery are still not completely elucidated. Using an experimental approach in which mRNP formation in yeast is disturbed by the action of the bacterial Rho helicase, we have shown previously that the targeting of Rho-induced aberrant mRNPs is mediated by Rrp6p, which is recruited cotranscriptionally in association with Nrd1p following Rho action. Here we investigated the specific involvement in this quality control process of different cofactors associated with the nuclear RNA degradation machinery. We show that, in addition to the main hydrolytic action of the exonuclease Rrp6p, the cofactors Rrp47p, Mpp6p as well as the Trf-Air-Mtr4 polyadenylation (TRAMP) components Trf4p, Trf5p, and Air2p contribute significantly by stimulating the degradation process upon their cotranscriptional recruitment. Trf4p and Trf5p are apparently recruited in two distinct TRAMP complexes that both contain Air2p as component. Surprisingly, Rrp47p appears to play an important role in mutual protein stabilization with Rrp6p, which highlights a close association between the two partners. Together, our results provide an integrated view of how different cofactors of the RNA degradation machinery cooperate to target and eliminate aberrant mRNPs. PMID- 24047897 TI - Identification of proteins at active, stalled, and collapsed replication forks using isolation of proteins on nascent DNA (iPOND) coupled with mass spectrometry. AB - Both DNA and chromatin need to be duplicated during each cell division cycle. Replication happens in the context of defects in the DNA template and other forms of replication stress that present challenges to both genetic and epigenetic inheritance. The replication machinery is highly regulated by replication stress responses to accomplish this goal. To identify important replication and stress response proteins, we combined isolation of proteins on nascent DNA (iPOND) with quantitative mass spectrometry. We identified 290 proteins enriched on newly replicated DNA at active, stalled, and collapsed replication forks. Approximately 16% of these proteins are known replication or DNA damage response proteins. Genetic analysis indicates that several of the newly identified proteins are needed to facilitate DNA replication, especially under stressed conditions. Our data provide a useful resource for investigators studying DNA replication and the replication stress response and validate the use of iPOND combined with mass spectrometry as a discovery tool. PMID- 24047898 TI - Immunogenicity of membrane-bound HIV-1 gp41 membrane-proximal external region (MPER) segments is dominated by residue accessibility and modulated by stereochemistry. AB - Structural characterization of epitope-paratope pairs has contributed to the understanding of antigenicity. By contrast, few structural studies relate to immunogenicity, the process of antigen-induced immune responses in vivo. Using a lipid-arrayed membrane-proximal external region (MPER) of HIV-1 glycoprotein 41 as a model antigen, we investigated the influence of physicochemical properties on immunogenicity in relation to structural modifications of MPER/liposome vaccines. Anchoring the MPER to the membrane via an alkyl tail or transmembrane domain retained the MPER on liposomes in vivo, while preserving MPER secondary structure. However, structural modifications that affected MPER membrane orientation and antigenic residue accessibility strongly impacted induced antibody responses. The solvent-exposed MPER tryptophan residue (Trp-680) was immunodominant, focusing immune responses, despite sequence variability elsewhere. Nonetheless, immunogenicity could be readily manipulated using site directed mutagenesis or structural constraints to modulate amino acid surface display. These studies provide fundamental insights for immunogen design aimed at targeting B cell antibody responses. PMID- 24047899 TI - Structure of a PLS-class pentatricopeptide repeat protein provides insights into mechanism of RNA recognition. AB - Pentatricopeptide repeat (PPR) proteins are sequence-specific RNA-binding proteins that form a pervasive family of proteins conserved in yeast, plants, and humans. The plant PPR proteins are grouped mainly into the P and PLS classes. Here, we report the crystal structure of a PLS-class PPR protein from Arabidopsis thaliana called THA8L (THA8-like) at 2.0 A. THA8L resembles THA8 (thylakoid assembly 8), a protein that is required for the splicing of specific group II introns of genes involved in biogenesis of chloroplast thylakoid membranes. The THA8L structure contains three P-type PPR motifs flanked by one L-type motif and one S-type motif. We identified several putative THA8L-binding sites, enriched with purine sequences, in the group II introns. Importantly, THA8L has strong binding preference for single-stranded RNA over single-stranded DNA or double stranded RNA. Structural analysis revealed that THA8L contains two extensive patches of positively charged residues next to the residues that are proposed to comprise the RNA-binding codes. Mutations in these two positively charged patches greatly reduced THA8L RNA-binding activity. On the basis of these data, we constructed a model of THA8L-RNA binding that is dependent on two forces: one is the interaction between nucleotide bases and specific amino acids in the PPR motifs (codes), and the other is the interaction between the negatively charged RNA backbone and positively charged residues of PPR motifs. Together, these results further our understanding of the mechanism of PPR protein-RNA interactions. PMID- 24047900 TI - Complexes of Trypanosoma cruzi sterol 14alpha-demethylase (CYP51) with two pyridine-based drug candidates for Chagas disease: structural basis for pathogen selectivity. AB - Chagas disease, caused by the eukaryotic (protozoan) parasite Trypanosoma cruzi, is an alarming emerging global health problem with no clinical drugs available to treat the chronic stage. Azole inhibitors of sterol 14alpha-demethylase (CYP51) were proven effective against Chagas, and antifungal drugs posaconazole and ravuconazole have entered clinical trials in Spain, Bolivia, and Argentina. Here we present the x-ray structures of T. cruzi CYP51 in complexes with two alternative drug candidates, pyridine derivatives (S)-(4-chlorophenyl)-1-(4-(4 (trifluoromethyl)phenyl)-piperazin-1-yl)-2-(pyridin-3-yl)ethanone (UDO; Protein Data Bank code 3ZG2) and N-[4-(trifluoromethyl)phenyl]-N-[1-[5-(trifluoromethyl) 2-pyridyl]-4-piperi-dyl]pyridin-3-amine (UDD; Protein Data Bank code 3ZG3). These compounds have been developed by the Drugs for Neglected Diseases initiative (DNDi) and are highly promising antichagasic agents in both cellular and in vivo experiments. The binding parameters and inhibitory effects on sterol 14alpha demethylase activity in reconstituted enzyme reactions confirmed UDO and UDD as potent and selective T. cruzi CYP51 inhibitors. Comparative analysis of the pyridine- and azole-bound CYP51 structures uncovered the features that make UDO and UDD T. cruzi CYP51-specific. The structures suggest that although a precise fit between the shape of the inhibitor molecules and T. cruzi CYP51 active site topology underlies their high inhibitory potency, a longer coordination bond between the catalytic heme iron and the pyridine nitrogen implies a weaker influence of pyridines on the iron reduction potential, which may be the basis for the observed selectivity of these compounds toward the target enzyme versus other cytochrome P450s, including human drug-metabolizing P450s. These findings may pave the way for the development of novel CYP51-targeted drugs with optimized metabolic properties that are very much needed for the treatment of human infections caused by eukaryotic microbial pathogens. PMID- 24047901 TI - Kinetic intermediates en route to the final serpin-protease complex: studies of complexes of alpha1-protease inhibitor with trypsin. AB - Serpin protein protease inhibitors inactivate their target proteases through a unique mechanism in which a major serpin conformational change, resulting in a 70 A translocation of the protease from its initial reactive center loop docking site to the opposite pole of the serpin, kinetically traps the acyl-intermediate complex. Although the initial Michaelis and final trapped acyl-intermediate complexes have been well characterized structurally, the intermediate stages involved in this remarkable transformation are not well understood. To better characterize such intermediate steps, we undertook rapid kinetic studies of the FRET and fluorescence perturbation changes of site-specific fluorophore-labeled derivatives of the serpin, alpha1-protease inhibitor (alpha1PI), which report the serpin and protease conformational changes involved in transforming the Michaelis complex to the trapped acyl-intermediate complex in reactions with trypsin. Two kinetically resolvable conformational changes were observed in the reactions, ascribable to (i) serpin reactive center loop insertion into sheet A with full protease translocation but incomplete protease distortion followed by, (ii) full conformational distortion and movement of the protease and coupled serpin conformational changes involving the F helix-sheet A interface. Kinetic studies of calcium effects on the labeled alpha1PI-trypsin reactions demonstrated both inactive and low activity states of the distorted protease in the final complex that were distinct from the intermediate distorted state. These studies provide new insights into the nature of the serpin and protease conformational changes involved in trapping the acyl-intermediate complex in serpin-protease reactions and support a previously proposed role for helix F in the trapping mechanism. PMID- 24047902 TI - cAMP-responsive element modulator alpha (CREMalpha) trans-represses the transmembrane glycoprotein CD8 and contributes to the generation of CD3+CD4-CD8- T cells in health and disease. AB - T cell receptor-alphabeta(+) CD3(+)CD4(-)CD8(-) "double-negative" T cells are expanded in the peripheral blood of patients with systemic lupus erythematosus and autoimmune lymphoproliferative syndrome. In both disorders, double-negative T cells infiltrate tissues, induce immunoglobulin production, and secrete proinflammatory cytokines. Double-negative T cells derive from CD8(+) T cells through down-regulation of CD8 surface co-receptors. However, the molecular mechanisms orchestrating this process remain unclear. Here, we demonstrate that the transcription factor cAMP-responsive element modulator alpha (CREMalpha), which is expressed at increased levels in T cells from systemic lupus erythematosus patients, contributes to transcriptional silencing of CD8A and CD8B. We provide the first evidence that CREMalpha trans-represses a regulatory element 5' of the CD8B gene. Therefore, CREMalpha represents a promising candidate in the search for biomarkers and treatment options in diseases in which double-negative T cells contribute to the pathogenesis. PMID- 24047903 TI - A novel analysis of excitatory currents during an action potential from suprachiasmatic nucleus neurons. AB - A new application of the action potential (AP) voltage-clamp technique is described based on computational analysis. An experimentally recorded AP is digitized. The resulting Vi vs. ti data set is applied to mathematical models of the ionic conductances underlying excitability for the cell from which the AP was recorded to test model validity. The method is illustrated for APs from suprachiasmatic nucleus (SCN) neurons and the underlying tetrodotoxin-sensitive Na(+) current, INa, and the Ca(2+) current, ICa. Voltage-step recordings have been made for both components from SCN neurons (Jackson et al. 2004). The combination of voltage-step and AP clamp results provides richer constraints for mathematical models of voltage-gated ionic conductances than either set of results alone, in particular the voltage-step results. For SCN neurons the long term goal of this work is a realistic mathematical model of the SCN AP in which the equations for I(Na) and I(Ca) obtained from this analysis will be a part. Moreover, the method described in this report is general. It can be applied to any excitable cell. PMID- 24047904 TI - Working memory performance and neural activity in prefrontal cortex of peripubertal monkeys. AB - The dorsolateral prefrontal cortex matures late into adolescence or early adulthood. This pattern of maturation mirrors working memory abilities, which continue to improve into adulthood. However, the nature of the changes that prefrontal neuronal activity undergoes during this process is poorly understood. We investigated behavioral performance and neural activity in working memory tasks around the time of puberty, a developmental event associated with the release of sex hormones and significant neurological change. The developmental stages of male rhesus monkeys were evaluated with a series of morphometric, hormonal, and radiographic measures. Peripubertal monkeys were trained to perform an oculomotor delayed response task and a variation of this task involving a distractor stimulus. We found that the peripubertal monkeys tended to abort a relatively large fraction of trials, and these were associated with low levels of task-related neuronal activity. However, for completed trials, accuracy in the delayed saccade task was high and the appearance of a distractor stimulus did not impact performance significantly. In correct trials delay period activity was robust and was not eliminated by the presentation of a distracting stimulus, whereas in trials that resulted in errors the sustained cue-related activity was significantly weaker. Our results show that in peripubertal monkeys the prefrontal cortex is capable of generating robust persistent activity in the delay periods of working memory tasks, although in general it may be more prone to stochastic failure than in adults. PMID- 24047905 TI - Body posture modulates imagined arm movements and responds to them. AB - Imagined movements are thought to simulate physical ones, with similar behavioral constraints and neurophysiological activation patterns and with an inhibition mechanism that suppresses movement execution. When upper body movements such as reaching with the arm are made from an upright stance, lower body and trunk muscles are also activated to maintain body posture. It is not clear to what extent parameters of imagined manual movements are sensitive to the postural adjustments their execution would necessitate, nor whether such postural responses are as effectively inhibited as the imagined movements themselves. We asked healthy young participants to imagine reaching movements of the arm while in upright stance, and we measured their self-reported movement times and postural sway during imagined movements. We manipulated mediolateral stance stability and the direction of arm movement (mediolateral or anteroposterior). Imagined arm movements were reportedly slower when subjects were standing in a mediolaterally less stable stance, and the body swayed more when arm movements were imagined in the direction of postural vulnerability. The results suggest that the postural state of the whole body, not just the involved limbs, informs trajectory planning during motor imagery and that measurable adjustments to body posture accompany imagined manual actions. It has been suggested that movement is suppressed during motor imagery by a premotor inhibitory mechanism operating at brain stem or spinal level. Any such inhibition must be incomplete because, for example, it does not eliminate autonomic arousal. Our results suggest that it also does not effectively suppress postural adjustments planned in support of imagined movements. PMID- 24047906 TI - Medullary serotonin neurons are CO2 sensitive in situ. AB - Brainstem central chemoreceptors are critical to the hypercapnic ventilatory response, but their location and identity are poorly understood. When studied in vitro, serotonin-synthesizing (5-HT) neurons within the rat medullary raphe are intrinsically stimulated by CO2/acidosis. The contributions of these neurons to central chemosensitivity in vivo, however, are controversial. Lacking is documentation of CO2-sensitive 5-HT neurons in intact experimental preparations and understanding of their spatial and proportional distribution. Here we test the hypothesis that 5-HT neurons in the rat medullary raphe are sensitive to arterial hypercapnia. We use extracellular recording and hypercapnic challenge of spontaneously active medullary raphe neurons in the unanesthetized in situ perfused decerebrate brainstem preparation to assess chemosensitivity of individual cells. Juxtacellular labeling of a subset of recorded neurons and subsequent immunohistochemistry for the 5-HT-synthesizing enzyme tryptophan hydroxylase (TPH) identify or exclude this neurotransmitter phenotype in electrophysiologically characterized chemosensitive and insensitive cells. We show that the medullary raphe houses a heterogeneous population, including chemosensitive and insensitive 5-HT neurons. Of 124 recorded cells, 16 cells were juxtacellularly filled, visualized, and immunohistochemically identified as 5-HT synthesizing, based on TPH-immunoreactivity. Forty-four percent of 5-HT cells were CO2 stimulated (increased firing rate with hypercapnia), while 56% were unstimulated. Our results demonstrate that medullary raphe neurons are heterogeneous and clearly include a subset of 5-HT neurons that are excited by arterial hypercapnia. Together with data identifying intrinsically CO2-sensitive 5-HT neurons in vitro, these results support a role for such cells as central chemoreceptors in the intact system. PMID- 24047908 TI - Age-related neuromuscular function and dynamic balance control during slow and fast balance perturbations. AB - This study investigated age-related differences in dynamic balance control and its connection to reflexes and explosive isometric plantar flexor torque in 19 males (9 Young aged 20-33 yr, 10 Elderly aged 61-72 yr). Dynamic balance was measured during Slow (15 cm/s) and Fast (25 cm/s) anterior and posterior perturbations. H/M-ratio was measured at 20% of maximal M-wave (H/M20%) 10, 30, and 90 ms after perturbations. Stretch reflexes were measured from tibialis anterior and soleus during anterior and posterior perturbations, respectively. In Slow, Elderly exhibited larger peak center-of-pressure (COP) displacement (15%; P < 0.05) during anterior perturbations. In Fast, Young showed a trend for faster recovery (37%; P = 0.086) after anterior perturbations. M-wave latency was similar between groups (6.2 +/- 0.7 vs. 6.9 +/- 1.2 ms), whereas Elderly showed a longer H-reflex latency (33.7 +/- 2.3 vs. 36.4 +/- 1.7 ms; P < 0.01). H/M20% was higher in Young 30 ms after Fast anterior (50%; P < 0.05) and posterior (51%; P < 0.05) perturbations. Plantar flexor rapid torque was also higher in Young (26%; P < 0.05). After combining both groups' data, H/M20% correlated negatively with Slow peak COP displacement (r = -0.510, P < 0.05) and positively with Fast recovery time (r = 0.580, P < 0.05) for anterior perturbations. Age-related differences in balance control seem to be more evident in anterior than posterior perturbations, and rapid sensory feedback is generally important for balance perturbation recovery. PMID- 24047907 TI - Functional significance of cortical NMDA receptors in somatosensory information processing. AB - N-methyl-d-aspartate receptor (NMDAR)-mediated activity is required for whisker related neural patterning in the rodent brain. Deletion of the essential NMDAR subunit NR1 gene in excitatory cortical neurons prevents whisker-specific barrel formation and impairs thalamocortical afferent patterning. We used electrophysiological and voltage-sensitive dye imaging methods to assess synaptic and sensory evoked cortical activity and immunohistochemistry to examine immediate early gene expression following whisker stimulation in cortex-specific NR1 knockout (CxNR1KO) mice. In mutant mice, layer IV neurons lacked NMDAR mediated excitatory postsynaptic currents, and temporal summation of excitatory postsynaptic potentials (EPSPs) was impaired. Barrel neurons showed both phasic and tonic responses to whisker deflection. The averaged tonic response in CxNR1KO mice was significantly less than that in control mice due to impaired EPSP temporal summation. Electrophysiological estimation of the number of thalamic neurons innervating single barrel neurons indicated a significant increase in CxNR1KO mice. Similarly, voltage-sensitive dye optical signals in response to whisker stimulation were widespread. Immediate early gene expression following whisker stimulation also showed a diffuse expression pattern in the CxNR1KO cortex compared with whisker-specific expression patterns in controls. Thus, when NMDAR function is impaired, spatial discrimination of whisker inputs is severely compromised, and sensory stimulation evokes diffuse, topographically misaligned activity in the barrel cortex. PMID- 24047909 TI - The specificity of stimulus-specific adaptation in human auditory cortex increases with repeated exposure to the adapting stimulus. AB - The neural response to a sensory stimulus tends to be more strongly reduced when the stimulus is preceded by the same, rather than a different, stimulus. This stimulus-specific adaptation (SSA) is ubiquitous across the senses. In hearing, SSA has been suggested to play a role in change detection as indexed by the mismatch negativity. This study sought to test whether SSA, measured in human auditory cortex, is caused by neural fatigue (reduction in neural responsiveness) or by sharpening of neural tuning to the adapting stimulus. For that, we measured event-related cortical potentials to pairs of pure tones with varying frequency separation and stimulus onset asynchrony (SOA). This enabled us to examine the relationship between the degree of specificity of adaptation as a function of frequency separation and the rate of decay of adaptation with increasing SOA. Using simulations of tonotopic neuron populations, we demonstrate that the fatigue model predicts independence of adaptation specificity and decay rate, whereas the sharpening model predicts interdependence. The data showed independence and thus supported the fatigue model. In a second experiment, we measured adaptation specificity after multiple presentations of the adapting stimulus. The multiple adapters produced more adaptation overall, but the effect was more specific to the adapting frequency. Within the context of the fatigue model, the observed increase in adaptation specificity could be explained by assuming a 2.5-fold increase in neural frequency selectivity. We discuss possible bottom-up and top-down mechanisms of this effect. PMID- 24047910 TI - Dendritic SK channels convert NMDA-R-dependent LTD to burst timing-dependent plasticity. AB - Feedback and descending projections from higher to lower brain centers play a prominent role in all vertebrate sensory systems. Feedback might be optimized for the specific sensory processing tasks in their target brain centers, but it has been difficult to connect the properties of feedback synapses to sensory tasks. Here, we use the electrosensory system of a gymnotiform fish (Apteronotus leptorhynchus) to address this problem. Cerebellar feedback to pyramidal cells in the first central electrosensory processing region, the electrosensory lateral line lobe (ELL), is critical for canceling spatially and temporally redundant electrosensory input. The ELL contains four electrosensory maps, and we have previously analyzed the synaptic and network bases of the redundancy reduction mechanism in a map (centrolateral segment; CLS) believed to guide electrolocation behavior. In the CLS, only long-term depression was induced by pairing feedback presynaptic and pyramidal cell postsynaptic bursts. In this paper, we turn to an ELL map (lateral segment; LS) known to encode electrocommunication signals. We find remarkable differences in synaptic plasticity of the morphologically identical cerebellar feedback input to the LS. In the LS, pyramidal cell SK channels permit long-term potentiation (LTP) of feedback synapses when pre- and postsynaptic bursts occur at the same time. We hypothesize that LTP in this map is required for enhancing the encoding of weak electrocommunication signals. We conclude that feedback inputs that appear morphologically identical in sensory maps dedicated to different tasks, nevertheless display different synaptic plasticity rules contributing to differential sensory processing in these maps. PMID- 24047911 TI - Anesthesia differentially modulates spontaneous network dynamics by cortical area and layer. AB - Anesthesia is widely used in medicine and research to achieve altered states of consciousness and cognition. Whereas changes to macroscopic cortical activity patterns by anesthesia measured at the spatial resolution of electroencephalography have been widely studied, modulation of mesoscopic and microscopic network dynamics by anesthesia remain poorly understood. To address this gap in knowledge, we recorded spontaneous mesoscopic (local field potential) and microscopic (multiunit activity) network dynamics in primary visual cortex (V1) and prefrontal cortex (PFC) of awake and isoflurane anesthetized ferrets (Mustela putoris furo). This approach allowed for examination of activity as a function of cortical area, cortical layer, and anesthetic depth with much higher spatial and temporal resolution than in previous studies. We hypothesized that a primary sensory area and an association cortical area would exhibit different patterns of network modulation by anesthesia due to their different functional roles. Indeed, we found effects specific to cortical area and cortical layer. V1 exhibited minimal changes in rhythmic structure with anesthesia but differential modulation of input layer IV. In contrast, anesthesia profoundly altered spectral power in PFC, with more uniform modulation across cortical layers. Our results demonstrate that anesthesia modulates spontaneous cortical activity in an area- and layer-specific manner. These finding provide the basis for 1) refining anesthesia monitoring algorithms, 2) reevaluating the large number of systems neuroscience studies performed in anesthetized animals, and 3) increasing our understanding of differential dynamics across cortical layers and areas. PMID- 24047912 TI - Frontoparietal regions may become hypoactive after intermittent theta burst stimulation over the contralateral homologous cortex in humans. AB - Brain injury to the dorsal frontoparietal networks, including the posterior parietal cortex (PPC) and dorsolateral prefrontal cortex (DLPFC), commonly cause spatial neglect. However, the interaction of these different regions in spatial attention is unclear. The aim of the present study was to investigate whether hyperexcitable neural networks can cause an abnormal interhemispheric inhibition. The Attention Network Test was used to test subjects following intermittent theta burst stimulation (iTBS) to the left or right frontoparietal networks. During the Attention Network Test task, all subjects tolerated each conditioning iTBS without any obvious iTBS-related side effects. Subjects receiving real-right-PPC iTBS showed significant enhancement in both alerting and orienting efficiency compared with those receiving either sham-right-PPC iTBS or real-left-PPC iTBS. Moreover, subjects exposed to the real-right-DLPFC iTBS exhibited significant improvement in both alerting and executive control efficiency, compared with those exposed to either the sham-right-DLPFC or real-left-DLPFC conditioning. Interestingly, compared with subjects exposed to the sham-left-PPC stimuli, subjects exposed to the real-left-PPC iTBS had a significant deficit in the orienting index. The present study indicates that iTBS over the contralateral homologous cortex may induce the hypoactivity of the right PPC through interhemispheric competition in spatial orienting attention. PMID- 24047913 TI - Thrombosis versus thermal coagulum formation as a result of endovenous laser treatment: biochemistry versus photophysics. PMID- 24047915 TI - Vitamin A isotope dilution predicts liver stores in line with long-term vitamin A intake above the current Recommended Dietary Allowance for young adult women. AB - BACKGROUND: The Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for vitamin A are 1.7 and 2.4 MUmol/d (500 and 700 MUg retinol activity equivalents/d), respectively, for nonpregnant, nonlactating women aged >19 y. This intake is presumed to maintain a minimally acceptable liver concentration of 0.07 MUmol (20 MUg) retinol/g; however, liver reserves have not been evaluated with respect to vitamin A intake in women of any age group defined in the Dietary Reference Intakes. OBJECTIVE: This cross-sectional study examined vitamin A intake and liver reserves estimated by stable-isotope dilution testing. DESIGN: Forty nonpregnant, nonlactating women (mean +/- SD age: 22.4 +/- 2.3 y) completed a Harvard food-frequency questionnaire (FFQ) and 3-d diet record (3DDR) before undergoing vitamin A status assessment by using a [(13)C2]retinol stable isotope dilution test. RESULTS: Vitamin A intake was 70% higher than the RDA by both dietary-assessment methods (P < 0.001). The mean (+/-SD) liver concentration of vitamin A was 0.45 +/- 0.31 MUmol/g (129 +/- 89 MUg/g) and ranged from 0.09 (26 MUg/g) to 1.79 MUmol/g (513 MUg/g). Liver and total-body vitamin A were highly correlated with intake measured by FFQ (P <= 0.009), but 3DDR was not (P >= 0.22). Prediction equations were developed for 3- and 7-d data. CONCLUSIONS: In this well-nourished population, vitamin A consumption was considerably higher than recommended, and liver reserves were consistent with intake. Because of their sensitivity, stable-isotope techniques can help to describe the vitamin A status and better characterize the intake needs of all groups defined in the Dietary Reference Intakes. Registration was not required for this trial. PMID- 24047914 TI - Heritability of objectively assessed daily physical activity and sedentary behavior. AB - BACKGROUND: Twin and family studies that estimated the heritability of daily physical activity have been limited by poor measurement quality and a small sample size. OBJECTIVE: We examined the heritability of daily physical activity and sedentary behavior assessed objectively by using combined heart rate and movement sensing in a large twin study. DESIGN: Physical activity traits were assessed in daily life for a mean (+/- SD) 6.7 +/- 1.1 d in 1654 twins from 420 monozygotic and 352 dizygotic same-sex twin pairs aged 56.3 +/- 10.4 y with body mass index (in kg/m(2)) of 26.1 +/- 4.8. We estimated the average daily movement, physical activity energy expenditure, and time spent in moderate-to-vigorous intensity physical activity and sedentary behavior from heart rate and acceleration data. We used structural equation modeling to examine the contribution of additive genetic, shared environmental, and unique environmental factors to between-individual variation in traits. RESULTS: Additive genetic factors (ie, heritability) explained 47% of the variance in physical activity energy expenditure (95% CI: 23%, 53%) and time spent in moderate-to-vigorous intensity physical activity (95% CI: 29%, 54%), 35% of the variance in acceleration of the trunk (95% CI: 0%, 44%), and 31% of the variance in the time spent in sedentary behavior (95% CI: 9%, 51%). The remaining variance was predominantly explained by unique environmental factors and random error, whereas shared environmental factors played only a marginal role for all traits with a range of 0-15%. CONCLUSIONS: The between-individual variation in daily physical activity and sedentary behavior is mainly a result of environmental influences. Nevertheless, genetic factors explain up to one-half of the variance, suggesting that innate biological processes may be driving some of our daily physical activity. PMID- 24047916 TI - Comparison of 2 weight-loss diets of different protein content on bone health: a randomized trial. AB - BACKGROUND: It has been hypothesized that hip-fracture rates are higher in developed than in developing countries because high-protein (HP) Western diets induce metabolic acidosis and hypercalciuria. Confounders include interactions between dietary protein and calcium, sodium, and potassium. OBJECTIVE: We determined whether an HP or a high-normal-protein (HNP) weight-loss diet caused greater loss in bone mineral density (BMD) over 24 mo. DESIGN: The Weight Loss, Protein and Bone Density Study was conducted from 2008 to 2011 in 323 overweight [body mass index (BMI; in kg/m(2)) >27] postmenopausal women, with a total hip BMD t score less than -2.0. Subjects were randomly assigned to receive an isocaloric calcium-replete HP (>=90 g protein/d) or HNP (<80 g protein/d) weight loss diet, with the aim of a difference of 20 g protein/d. A total of 186 subjects (90 subjects in the HP group, 96 subjects in the HNP group) completed 12 mo, and 137 subjects (69 subjects in the HP group, 68 subjects in the HNP group) completed 24 mo. RESULTS: Biomarkers confirmed a difference in protein intake of 16 and 13.1 g at 12 and 24 mo, respectively. Mean (+/-SE) weight loss was equal; HP subjects lost 7.9 +/- 0.9 kg and HNP subjects lost 8.9 +/- 0.9 kg at 24 mo. Subjects lost 1-2% BMD annually at lumbar spine vertebrae 2-4, the forearm, the femoral neck, and hip. ANCOVA showed no effect of the HP or HNP diet (P > 0.05 for diet and diet-time interactions). A diet-by-time analysis showed that the HNP diet increased C-terminal telopeptide and osteocalcin (P <= 0.001 for each) despite hypercalciuria (P = 0.029). CONCLUSION: High dietary protein intake during weight loss has no clinically significant effect on bone density but slows bone turnover. This trial was registered at the Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au) as ACTRN12608000229370. PMID- 24047917 TI - Dietary intake of young twins: nature or nurture? AB - BACKGROUND: The early years in life are increasingly recognized as a critical period for the development of diet-related behavioral traits. However, discussions continue on the relative role of genes and the environment in determining dietary intake, particularly in young children for whom detailed dietary information is limited. OBJECTIVES: This study tested the hypothesis that diet in early childhood is primarily determined by the environment rather than by genes. A secondary aim was to characterize the early childhood diet. DESIGN: A classic twin design used 3-d dietary data collected at age 21 mo from the Gemini cohort. From the full sample of 2402 families with twins, dietary diaries were available for 1216 twin pairs (384 monozygotic and 832 dizygotic pairs) after exclusions. Intakes of macronutrients, food, and beverages were estimated. Twin analyses quantified the contributions of genetic and environmental factors to population variation in intake. RESULTS: At age 21 mo, children consumed small portions of a wide range of family foods. The shared environment was the predominant determinant, contributing between 66% (95% CI: 52%, 77%; milk-based desserts) and 97% (95% CI: 95%, 98%; juice) of the variation in intake. Genetic factors were estimated to account for between 4% (95% CI: 0%, 10%; savory snacks) and 18% (95% CI: 14%, 23%; bread) of dietary intake variation. CONCLUSION: Shared environmental influences are the predominant drivers of dietary intake in very young children, indicating the importance of factors such as the home food environment and parental behaviors. PMID- 24047918 TI - Adherence to the 2006 American Heart Association Diet and Lifestyle Recommendations for cardiovascular disease risk reduction is associated with bone health in older Puerto Ricans. AB - BACKGROUND: Cardiovascular disease (CVD) and osteoporosis are 2 major public health problems that share common pathophysiological mechanisms. It is possible that strategies to reduce CVD risk may also benefit bone health. OBJECTIVE: We tested the hypothesis that adherence to the 2006 American Heart Association Diet and Lifestyle Recommendations (AHA-DLR) is associated with bone health. DESIGN: We previously developed a unique diet and lifestyle score (American Heart Association Diet and Lifestyle Score; AHA-DLS) to assess adherence to the AHA DLR. In a cross-sectional study of 933 Puerto Ricans aged 47-79 y, we modified the AHA-DLS to test associations with bone health. Bone mineral density (BMD) at the femoral neck, trochanter, total hip, and lumbar spine (L2-L4) was measured by using dual-energy X-ray absorptiometry. RESULTS: For every 5-unit increase in the modified AHA-DLS, BMD at the femoral neck, trochanter, total hip, and lumbar spine (L2-L4) was associated with a 0.005-0.008-g/cm(2) (P < 0.05) higher value. No component of the AHA-DLR alone was responsible for the observed positive associations. For every 5-unit increase in the modified AHA-DLS, the odds for osteoporosis or osteopenia at the trochanter, total hip, and lumbar spine (L2-L4) were lower by 14% (OR: 0.86; 95% CI: 0.79, 0.92), 17% (OR: 0.83; 95% CI: 0.76, 0.92), and 9% (OR: 0.91; 95% CI: 0.84, 0.99), respectively. CONCLUSIONS: Dietary guidelines for CVD risk reduction may also benefit bone health in this Hispanic cohort. Synchronizing dietary guidelines for these 2 common diseases may provide a simplified public health message. This trial was registered at clinicaltrials.gov as NCT01231958. PMID- 24047919 TI - Long-term calcium supplementation may have adverse effects on serum cholesterol and carotid intima-media thickness in postmenopausal women: a double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Several studies have focused on the effects of calcium intake on serum lipid concentrations in postmenopausal women. However, many premenopausal women are taking calcium supplements in China. To our knowledge, no studies have assessed whether the effects of calcium supplementation on blood lipids are similar between premenopausal and postmenopausal women. OBJECTIVE: We assessed the effects of calcium supplementation on blood lipid concentrations in premenopausal and postmenopausal women with dyslipidemia. DESIGN: A total of 190 premenopausal women (30-40 y old) and 182 postmenopausal women (50-60 y old) with dyslipidemia were given 800 mg Ca/d or a placebo for 2 y in a double-blind, randomized, placebo-controlled trial. Blood pressure, fasting glucose and serum lipid concentrations, carotid intima-media thickness (CIMT), dietary nutrient intakes, and physical activity levels were determined at baseline and after 2 y. RESULTS: There was a significant interaction between calcium supplementation and menopausal status on serum cholesterol concentrations (P < 0.001) and CIMT (P = 0.017). Serum cholesterol concentrations and CIMT were significantly increased in postmenopausal women (P < 0.01) after 2 y. Serum triglyceride, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol concentrations were not affected after 2 y. CONCLUSIONS: Calcium supplementation in postmenopausal women with dyslipidemia increases serum total cholesterol concentrations and CIMT. In postmenopausal women with dyslipidemia, calcium supplements should be prescribed with caution. This trial was registered at http://www.chictr.org/cn/ as ChiCTR-TRC-12002806. PMID- 24047920 TI - Associations between gestational weight gain and BMI, abdominal adiposity, and traditional measures of cardiometabolic risk in mothers 8 y postpartum. AB - BACKGROUND: Researchers have proposed biologically plausible mechanisms linking excessive gestational weight gain (GWG) to maternal metabolic and cardiovascular diseases later in life. OBJECTIVE: The objective was to determine the extent to which GWG was associated with abdominal adiposity and other cardiometabolic risk factors in a sample of women 4-12 y after delivery. DESIGN: We used data from The Women's and Infants' Study of Healthy Hearts, a cohort of women who gave birth between 1997 and 2002 at Magee-Womens Hospital in Pittsburgh, PA. By design, women with small-for-gestational-age and preterm births were oversampled. Women with preeclampsia, prepregnancy hypertension, or diabetes were excluded. GWG was ascertained from prenatal records, and GWG adequacy was assessed according to 2009 Institute of Medicine/National Research Council guidelines. Abdominal obesity was defined as waist circumference (WC) >88 cm and weight change as current weight - prepregnancy weight. RESULTS: The prevalence of inadequate, adequate, and excessive GWG was 22% (107/478), 30% (145/478), and 47% (226/478), respectively. The analyses were adjusted for age at outcome assessment, prepregnancy BMI, marital status and insurance at delivery, race, smoking during target pregnancy, and current education, parity, and smoking. Associations between excessive GWG and blood pressure, lipids, glucose, insulin, and metabolic syndrome were null. However, women with excessive GWG had a 3.6-kg (1.5, 5.6) greater weight change, a 3.2-cm (1.2, 5.2) greater WC, and 3-fold greater odds of abdominal obesity (2.9; 1.6, 5.1) compared with women who gained weight as recommended. CONCLUSION: Excessive GWG is associated with long-term maternal abdominal adiposity, which may increase a woman's risk of cardiovascular and metabolic disease. PMID- 24047921 TI - Validity of predictive equations for 24-h urinary sodium excretion in adults aged 18-39 y. AB - BACKGROUND: Collecting a 24-h urine sample is recommended for monitoring the mean population sodium intake, but implementation can be difficult. OBJECTIVE: The objective was to assess the validity of published equations by using spot urinary sodium concentrations to predict 24-h sodium excretion. DESIGN: This was a cross sectional study, conducted from June to August 2011 in metropolitan Washington, DC, of 407 adults aged 18-39 y, 48% black, who collected each urine void in a separate container for 24 h. Four timed voids (morning, afternoon, evening, and overnight) were selected from each 24-h collection. Published equations were used to predict 24-h sodium excretion with spot urine by specimen timing and race-sex subgroups. We examined mean differences with measured 24-h sodium excretion (bias) and individual differences with the use of Bland-Altman plots. RESULTS: Across equations and specimens, mean bias in predicting 24-h sodium excretion for all participants ranged from -267 to 1300 mg (Kawasaki equation). Bias was least with International Cooperative Study on Salt, Other Factors, and Blood Pressure (INTERSALT) equations with morning (-165 mg; 95% CI: -295, 36 mg), afternoon (-90 mg; -208, 28 mg), and evening (-120 mg; -230, -11 mg) specimens. With overnight specimens, mean bias was least when the Tanaka (-23 mg; 95% CI: -141, 95 mg) or Mage (-145 mg; -314, 25 mg) equations were used but was statistically significant when using the Tanaka equations among females (216 to 243 mg) and the Mage equations among races other than black (-554 to -372 mg). Significant over- and underprediction occurred across individual sodium excretion concentrations. CONCLUSIONS: Using a single spot urine, INTERSALT equations may provide the least biased information about population mean sodium intakes among young US adults. None of the equations evaluated provided unbiased estimates of individual 24-h sodium excretion. PMID- 24047923 TI - Hepatitis E virus among persons who inject drugs, San Diego, California, USA, 2009-2010. AB - Data about prevalence of hepatitis E virus infection in persons who inject drugs are limited. Among 18-40-year-old persons who inject drugs in California, USA, prevalence of antibodies against hepatitis E virus was 2.7%. This prevalence was associated with age but not with homelessness, incarceration, or high-risk sexual behavior. PMID- 24047922 TI - Prospective study of Dietary Approaches to Stop Hypertension- and Mediterranean style dietary patterns and age-related cognitive change: the Cache County Study on Memory, Health and Aging. AB - BACKGROUND: Healthy dietary patterns may protect against age-related cognitive decline, but results of studies have been inconsistent. OBJECTIVE: We examined associations between Dietary Approaches to Stop Hypertension (DASH)- and Mediterranean-style dietary patterns and age-related cognitive change in a prospective, population-based study. DESIGN: Participants included 3831 men and women >=65 y of age who were residents of Cache County, UT, in 1995. Cognitive function was assessed by using the Modified Mini-Mental State Examination (3MS) <=4 times over 11 y. Diet-adherence scores were computed by summing across the energy-adjusted rank-order of individual food and nutrient components and categorizing participants into quintiles of the distribution of the diet accordance score. Mixed-effects repeated-measures models were used to examine 3MS scores over time across increasing quintiles of dietary accordance scores and individual food components that comprised each score. RESULTS: The range of rank order DASH and Mediterranean diet scores was 1661-25,596 and 2407-26,947, respectively. Higher DASH and Mediterranean diet scores were associated with higher average 3MS scores. People in quintile 5 of DASH averaged 0.97 points higher than those in quintile 1 (P = 0.001). The corresponding difference for Mediterranean quintiles was 0.94 (P = 0.001). These differences were consistent over 11 y. Higher intakes of whole grains and nuts and legumes were also associated with higher average 3MS scores [mean quintile 5 compared with 1 differences: 1.19 (P < 0.001), 1.22 (P < 0.001), respectively]. CONCLUSIONS: Higher levels of accordance with both the DASH and Mediterranean dietary patterns were associated with consistently higher levels of cognitive function in elderly men and women over an 11-y period. Whole grains and nuts and legumes were positively associated with higher cognitive functions and may be core neuroprotective foods common to various healthy plant-centered diets around the globe. PMID- 24047924 TI - Subdural effusions and lack of early pontocerebellar hypoplasia in siblings with RARS2 mutations. AB - Mutations in the recently described RARS2 gene encoding for mitochondrial arginyl transfer RNA synthetase give rise to a disorder characterised by early onset seizures, progressive microcephaly and developmental delay. The disorder was named pontocerebellar hypoplasia type 6 (PCH6) based on the corresponding radiological findings observed in the original cases. We report two siblings with the RARS2 mutation who displayed typical clinical features of PCH6, but who had distinct neuroimaging features. Early scans showed marked supratentorial, rather than infratentorial, atrophy, and the pons remained preserved throughout. One sibling also had bilateral subdural effusions at presentation. The deceleration in head growth pointed to an evolving genetic/metabolic process giving rise to cerebral atrophy and secondary subdural effusions. RARS2 mutations should be considered in infants presenting with seizures, subdural effusions, decelerating head growth and evidence of cerebral atrophy even in the absence of pontocerebellar hypoplasia on imaging. PMID- 24047926 TI - Diabetes self-management and leptin in Mexican Americans with type 2 diabetes: the Starr County border health initiative. AB - PURPOSE: The purpose of the study was to (1) characterize leptin in Mexican Americans with poorly controlled type 2 diabetes, (2) examine relationships among leptin and indicators of diabetes status (body mass index and A1C), and (3) explore the effects of a culturally tailored diabetes self-management education intervention on leptin. METHODS: In Starr County, an impoverished Texas-Mexico border community, 252 Mexican Americans with type 2 diabetes were recruited to test a diabetes self-management education intervention culturally tailored in terms of language, dietary recommendations, social emphasis, family participation, and incorporation of cultural health beliefs. Groups of 8 participants were randomized to experimental or wait-listed control conditions. Outcomes were measured at 3, 6, and 12 months; by 12 months, 109 had complete leptin data. RESULTS: Most participants were women and, on average, 55 years of age, diagnosed with diabetes for 8 years, obese, and in poor glycemic control. Three variables-body mass index, sex, A1C-explained 36% of the variance in baseline leptin; there were no intervention effects on leptin. Sex, time, and gender * time interaction effects on leptin were statistically significant; greater increases in leptin over time occurred in women compared to men. In women, fasting blood glucose changes from baseline to 12 months significantly predicted leptin changes from baseline to 12 months; in men, body mass index changes predicted leptin change. CONCLUSIONS: With increasing obesity rates, further research is warranted to determine if leptin is a useful intervention target in type 2 diabetes. PMID- 24047929 TI - Motion artefact in multidetector CT in a child with severe chest injury resembling serious pathology. PMID- 24047927 TI - MicroRNA-26a regulates pathological and physiological angiogenesis by targeting BMP/SMAD1 signaling. AB - RATIONALE: The rapid induction and orchestration of new blood vessels are critical for tissue repair in response to injury, such as myocardial infarction, and for physiological angiogenic responses, such as embryonic development and exercise. OBJECTIVE: We aimed to identify and characterize microRNAs (miR) that regulate pathological and physiological angiogenesis. METHODS AND RESULTS: We show that miR-26a regulates pathological and physiological angiogenesis by targeting endothelial cell (EC) bone morphogenic protein/SMAD1 signaling in vitro and in vivo. MiR-26a expression is increased in a model of acute myocardial infarction in mice and in human subjects with acute coronary syndromes. Ectopic expression of miR-26a markedly induced EC cycle arrest and inhibited EC migration, sprouting angiogenesis, and network tube formation in matrigel, whereas blockade of miR-26a had the opposite effects. Mechanistic studies demonstrate that miR-26a inhibits the bone morphogenic protein/SMAD1 signaling pathway in ECs by binding to the SMAD1 3'-untranslated region, an effect that decreased expression of Id1 and increased p21(WAF/CIP) and p27. In zebrafish, miR 26a overexpression inhibited formation of the caudal vein plexus, a bone morphogenic protein-responsive process, an effect rescued by ectopic SMAD1 expression. In mice, miR-26a overexpression inhibited EC SMAD1 expression and exercise-induced angiogenesis. Furthermore, systemic intravenous administration of an miR-26a inhibitor, locked nucleic acid-anti-miR-26a, increased SMAD1 expression and rapidly induced robust angiogenesis within 2 days, an effect associated with reduced myocardial infarct size and improved heart function. CONCLUSIONS: These findings establish miR-26a as a regulator of bone morphogenic protein/SMAD1-mediated EC angiogenic responses, and that manipulating miR-26a expression could provide a new target for rapid angiogenic therapy in ischemic disease states. PMID- 24047930 TI - Delayed bilateral massive stroke following a road traffic accident. PMID- 24047931 TI - Tailoring of defect levels by deformations: Te-antisite in CdTe. AB - The properties of the Te-antisite defect in the neutral state in CdTe were examined using ab initio calculations. The influence of three types of deformations (1D, 2D and 3D) on the defect energy levels and formation energies was investigated. It was found that the 2D deformation is the most effective for pushing the defect levels towards the band edges and opening up the bandgap of the semiconductor, and hence may improve the performance of CdTe as a detector material. We studied the defect levels and their occupancies including Jahn Teller distortions. The Jahn-Teller distorted configuration places the 2A1(a) defect level closer to the valence band and this defect level position coincides with the 'unknown deep donor' measured in some experiments. Partial densities of states and band structures have been analysed to understand the arrangement of the defect bonds. PMID- 24047928 TI - Anaemia and zidovudine-containing antiretroviral therapy in paediatric antiretroviral programmes in the IeDEA Paediatric West African Database to evaluate AIDS. AB - INTRODUCTION: There is a risk of anaemia among HIV-infected children on antiretroviral therapy (ART) containing zidovudine (ZDV) recommended in first line regimens in the WHO guidelines. We estimated the risk of severe anaemia after initiation of a ZDV-containing regimen in HIV-infected children included in the IeDEA West African database. METHODS: Standardized collection of data from HIV-infected children (positive PCR<18 months or positive serology >= 18 months) followed up in HIV programmes was included in the regional IeDEA West Africa collaboration. Ten clinical centres from seven countries contributed (Benin, Burkina Faso, Cote d'Ivoire, Gambia, Ghana, Mali and Senegal) to this collection. Inclusion criteria were age <16 years and starting ART. We explored the data quality of haemoglobin documentation over time and the incidence and predictors of severe anaemia (Hb<7 g/dL) per 100 child-years of follow-up over the duration of first-line antiretroviral therapy. RESULTS: As of December 2009, among the 2933 children included in the collaboration, 45% were girls, median age was five years; median CD4 cell percentage was 13%; median weight-for-age z-score was-2.7; and 1772 (60.4%) had a first-line ZDV-containing regimen. At baseline, 70% of the children with a first-line ZDV-containing regimen had a haemoglobin measure available versus 76% in those not on ZDV (p <= 0.01): the prevalence of severe anaemia was 3.0% (n=38) in the ZDV group versus 10.2% (n=89) in those without (p<0. 01). Over the first-line follow-up, 58.9% of the children had >= 1 measure of haemoglobin available in those exposed to ZDV versus 60.4% of those not (p=0.45). Severe anaemia occurred in 92 children with an incidence of 2.47 per 100 child-years of follow-up in those on a ZDV-containing regimen versus 4.25 in those not (p <= 0.01). Adjusted for age at ART initiation and first-line regimen, a weight-for-age z-score <=-3 was a strong predictor associated with a 5.59 times risk of severe anaemia (p<0.01). CONCLUSIONS: Severe anaemia is frequent at baseline and guides the first-line ART prescription, but its incidence seems rare among children on ART. Severe malnutrition at baseline is a strong predictor for development of severe anaemia, and interventions to address this should form an integral component of clinical care. PMID- 24047933 TI - Emergence of vaccine-derived polioviruses, Democratic Republic of Congo, 2004 2011. AB - Polioviruses isolated from 70 acute flaccid paralysis patients from the Democratic Republic of Congo (DRC) during 2004-2011 were characterized and found to be vaccine-derived type 2 polioviruses (VDPV2s). Partial genomic sequencing of the isolates revealed nucleotide sequence divergence of up to 3.5% in the viral protein 1 capsid region of the viral genome relative to the Sabin vaccine strain. Genetic analysis identified at least 7 circulating lineages localized to specific geographic regions. Multiple independent events of VDPV2 emergence occurred throughout DRC during this 7-year period. During 2010-2011, VDPV2 circulation in eastern DRC occurred in an area distinct from that of wild poliovirus circulation, whereas VDPV2 circulation in the southwestern part of DRC (in Kasai Occidental) occurred within the larger region of wild poliovirus circulation. PMID- 24047934 TI - Strategies in the nutritional management of gestational diabetes. AB - Elucidating the optimal macronutrient composition for dietary management of gestational diabetes mellitus has enormous potential to improve perinatal outcomes. Diet therapy may result in significant cost savings if effective in deterring the need for expensive medical management within this growing population. In only 6 randomized controlled trials in 250 women, data suggest that a diet higher in complex carbohydrate and fiber, low in simple sugar, and lower in saturated fat may be effective in blunting postprandial hyperglycemia, preventing worsened insulin resistance and excess fetal growth. The use of diet in gestational diabetes mellitus remains an area in grave need for high-quality randomized controlled trials. PMID- 24047935 TI - Vitamin D and calcium: what do we need to know? AB - This chapter provides a summary of the literature including results from large trials, meta-analyses, and recent major recommendations. Two well-accepted and recent recommendations include those from the Agency for Health Research and Quality on calcium and vitamin D supplementation and from the Institute of Medicine's dietary reference intakes for calcium and vitamin D. This review suggests that there is strong evidence for synergistic roles of calcium and vitamin D in maintaining bone health in postmenopausal women, but the correlation between vitamin D alone and bone health is overall inconclusive. PMID- 24047936 TI - Osteoporosis prevention and management: nonpharmacologic and lifestyle options. AB - The purpose of this review is to evaluate current evidence regarding the use of dietary and exercise interventions to prevent fractures in postmenopausal women with osteoporosis. The key lifestyle modifications that can decrease risk of fracture in postmenopausal women include regular weight-bearing exercise and a balanced diet with adequate calcium and vitamin D intake. Other modifiable lifestyle factors critical to bone health and to decrease fracture risk include the avoidance of smoking, an excessively low body weight, excessive alcohol intake, and fall risks at home. Emerging modifiable factors may include B vitamin, omega-3 fatty acid, soy isoflavone, and dehydroepiandrosterone supplementation. PMID- 24047937 TI - Parents seeking health-related information on the Internet: cross-sectional study. AB - BACKGROUND: The Internet represents an increasingly common source of health related information, and it has facilitated a wide range of interactions between people and the health care delivery system. OBJECTIVE: To establish the extent of Internet access and use to gather information about health topics and the potential implications to health care among the adult population in Calabria region, Italy. METHODS: This cross-sectional study was conducted from April to June 2012. The sample consisted of 1544 adults aged >=18 years selected among parents of public school students in the geographic area of Catanzaro in southern Italy. A 2-stage sample design was planned. A letter summarizing the purpose of the study, an informed consent form, and a questionnaire were given to selected student to deliver to their parents. The final survey was formulated in 5 sections: (1) sociodemographic characteristics, (2) information about chronic diseases and main sources of health care information, (3) information about Internet use, (4) data about the effects of using the Internet to search for health information, and (5) knowledge and use of social networks. RESULTS: A total of 1039 parents completed the questionnaire, with a response rate equivalent to 67.29%. Regarding health-related information types, 84.7% of respondents used the Internet to search for their own medical conditions or those of family members or relatives, 40.7% of parents reported looking for diet, body weight, or physical activity information, 29.6% searched for vaccines, 28.5% for screening programs, and 16.5% for smoking cessation tools and products. The results of the multiple logistic regression analysis showed that parents who looked for health-related information on the Internet were more likely to be female (OR 1.53, 95% CI 1.05-2.25), with a high school diploma (OR 1.69, 95% CI 1.02-2.81) or college degree (OR 2.14, 95% CI 1.21-3.78), younger aged (OR 0.96, 95% CI 0.94-0.99), with chronic conditions (OR 1.94, 95% CI 1.17-3.19), not satisfied with their general practitioner's health-related information (OR 0.6, 95% CI 0.38-0.97), but satisfied with information from scientific journals (OR 1.99, 95% CI 1.33-2.98). CONCLUSIONS: Our analyses provide important insights into Internet use and health information-seeking behaviors of the Italian population and contribute to the evidence base for health communication planning. Health and public health professionals should educate the public about acquiring health information online and how to critically appraise it, and provide tools to navigate to the highest-quality information. The challenge to public health practice is to facilitate the health-promoting use of the Web among consumers in conjunction with their health care providers. PMID- 24047940 TI - Subjective BPPV: to reposition, or not to reposition, that is the question. PMID- 24047941 TI - Auditory processing following consecutive right temporal lobe resections: a prospective case study. AB - BACKGROUND: The role of the right temporal lobe in processing speech is not well understood. Although the left temporal lobe has long been recognized as critical for speech perception, there is growing evidence for right hemisphere involvement. To investigate whether the right temporal lobe is critical for auditory speech processing, we studied prospectively a normal-hearing patient who underwent consecutive right temporal lobe resections for treatment of medically intractable seizures. PURPOSE: To test the hypothesis that the right temporal lobe is critical for auditory speech processing. RESEARCH DESIGN: We used a prospective, repeated-measure, single-case design. Auditory processing was evaluated using behavioral tests of speech recognition (words, sentences) under multiple listening conditions (e.g., quiet, background noise, etc.). Auditory processing of nonspeech sounds was measured by pitch pattern sequencing and environmental sound recognition tasks. DATA COLLECTION: Repeat behavioral testing was performed at four time points over a 2 yr period: before and after consecutive right temporal lobe resection surgeries. RESULTS: Before surgery, the patient demonstrated normal speech recognition in quiet and under real-world listening conditions (background noise, filtered speech). After the initial right anterior temporal resection, speech recognition scores declined under adverse listening conditions, especially for the left ear, but remained largely within normal limits. Following resection of the right superior temporal gyrus 1 yr later, speech recognition in quiet and nonspeech sound processing (pitch patterns, environmental sounds) remained intact. However, speech recognition under adverse listening conditions was severely impaired. CONCLUSIONS: The right superior temporal gyrus appears to be critical for auditory processing of speech under real-world listening conditions. PMID- 24047942 TI - Improving tinnitus with mechanical treatment of the cervical spine and jaw. AB - BACKGROUND: Tinnitus affects approximately 30-50 million Americans. In approximately 0.5-1.0% of the population, tinnitus has a moderate to severe impact on their quality of life. Musculature and joint pathologies of the head and neck are frequently associated with tinnitus and have been hypothesized to play a contributing role in its etiology. However, specific physical therapy interventions to assist in improving tinnitus have not yet been reported. PURPOSE: To describe the examination and treatment intervention of a patient with subjective tinnitus. PATIENT DESCRIPTION: The patient was a 42-yr-old male experiencing intermittent bilateral tinnitus, headaches, blurred vision, and neck tightness. His occupation required long-term positioning into neck protraction. Examination found limitations in cervical extension, bilateral rotation, and side bending. Asymmetry was also noted with temporomandibular joint (TMJ) movements. Upon initial evaluation the patient demonstrated functional, physical, and emotional deficits per neck, headache, and dizziness self-report scales and a score on the Tinnitus Handicap Inventory (THI) of 62. Resisted muscle contractions of the cervical spine in flexion, extension, and rotation increased his tinnitus. INTERVENTION: Treatment focused on normalizing cervical spine mobility through repetitive movements, joint mobilization, and soft tissue massage. RESULTS: At 2.5 mo, the patient demonstrated a complete reversal of his tinnitus after 10 physical therapy sessions as noted by his score of 0 on the THI upon discharge. He also demonstrated objective improvements in his cervical motion. This case reflected treatment targeted at cervical and TMJ impairments and notable improvements to tinnitus. Future studies should further explore the direct and indirect treatment of tinnitus by physical therapists through clinical trials. PMID- 24047943 TI - Lateralized auditory symptoms in central neuroaudiology disorder. AB - Many individuals with central auditory nervous system (CANS) pathology/disorder report a variety of auditory symptoms with difficulty hearing in noise being one of the most common complaints (Chermak and Musiek, 1992) Interestingly, there seems to be a paucity of information in the literature on lateralized hearing loss symptoms in patients with central auditory disorders. Reported here is a case where the patient reported auditory symptoms, specifically hearing loss that was lateralized distinctly to the right ear. This ear was contralateral to a stroke that involved the left hemisphere with neural compromise limited primarily to the left Heschl's gyrus. Although the patient reported other hearing difficulties, the lateralized symptom of right-sided hearing loss seemed to be the most noticed. While the pure-tone audiogram was totally disassociated from the right ear auditory symptoms, central auditory tests revealed a marked and consistent right ear deficit, which was consistent with the site of lesion. It is rare that a relatively small lesion in Heschl's gyrus results in the perception of hearing loss so specifically localized to the right ear. It is also of interest that a patient with definite complaints of hearing loss would yield a normal, highly symmetrical pure-tone audiogram. The triad of patient symptoms, anatomy of the lesion, and central auditory test findings in this case are discussed, and theories as to possible underlying mechanisms for the patient's auditory deficits are provided. PMID- 24047944 TI - Serial auditory-evoked potentials in the diagnosis and monitoring of a child with Landau-Kleffner syndrome. AB - BACKGROUND: A boy, aged 2 1/2 yr, experienced sudden deterioration of speech and language abilities. He saw multiple medical professionals across 2 yr. By almost 5 yr, his vocabulary diminished from 50 words to 4, and he was referred to our speech and hearing center. PURPOSE: The purpose of this study was to heighten awareness of Landau-Kleffner syndrome (LKS) and emphasize the importance of an objective test battery that includes serial auditory-evoked potentials (AEPs) to audiologists who often are on the front lines of diagnosis and treatment delivery when faced with a child experiencing unexplained loss of the use of speech and language. RESEARCH DESIGN: Clinical report. RESULTS: Interview revealed a family history of seizure disorder. Normal social behaviors were observed. Acoustic reflexes and otoacoustic emissions were consistent with normal peripheral auditory function. The child could not complete behavioral audiometric testing or auditory processing tests, so serial AEPs were used to examine central nervous system function. Normal auditory brainstem responses, a replicable Na and absent Pa of the middle latency responses, and abnormal slow cortical potentials suggested dysfunction of auditory processing at the cortical level. The child was referred to a neurologist, who confirmed LKS. At age 7 1/2 yr, after 2 1/2 yr of antiepileptic medications, electroencephalographic (EEG) and audiometric measures normalized. Presently, the child communicates manually with limited use of oral information. CONCLUSIONS: Audiologists often are one of the first professionals to assess children with loss of speech and language of unknown origin. Objective, noninvasive, serial AEPs are a simple and valuable addition to the central audiometric test battery when evaluating a child with speech and language regression. The inclusion of these tests will markedly increase the chance for early and accurate referral, diagnosis, and monitoring of a child with LKS which is imperative for a positive prognosis. PMID- 24047945 TI - Factors influencing tests of auditory processing: a perspective on current issues and relevant concerns. AB - BACKGROUND: Tests of auditory perception, such as those used in the assessment of central auditory processing disorders ([C]APDs), represent a domain in audiological assessment where measurement of this theoretical construct is often confounded by nonauditory abilities due to methodological shortcomings. These confounds include the effects of cognitive variables such as memory and attention and suboptimal testing paradigms, including the use of verbal reproduction as a form of response selection. We argue that these factors need to be controlled more carefully and/or modified so that their impact on tests of auditory and visual perception is only minimal. PURPOSE: To advocate for a stronger theoretical framework than currently exists and to suggest better methodological strategies to improve assessment of auditory processing disorders (APDs). Emphasis is placed on adaptive forced-choice psychophysical methods and the use of matched tasks in multiple sensory modalities to achieve these goals. Together, this approach has potential to improve the construct validity of the diagnosis, enhance and develop theory, and evolve into a preferred method of testing. RESEARCH DESIGN: Examination of methods commonly used in studies of APDs. Where possible, currently used methodology is compared to contemporary psychophysical methods that emphasize computer-controlled forced-choice paradigms. RESULTS: In many cases, the procedures used in studies of APD introduce confounding factors that could be minimized if computer-controlled forced-choice psychophysical methods were utilized. CONCLUSIONS: Ambiguities of interpretation, indeterminate diagnoses, and unwanted confounds can be avoided by minimizing memory and attentional demands on the input end and precluding the use of response-selection strategies that use complex motor processes on the output end. Advocated are the use of computer-controlled forced-choice psychophysical paradigms in combination with matched tasks in multiple sensory modalities to enhance the prospect of obtaining a valid diagnosis. PMID- 24047946 TI - Aging degrades the neural encoding of simple and complex sounds in the human brainstem. AB - BACKGROUND: Older adults, with or without normal peripheral hearing sensitivity, have difficulty understanding speech. This impaired speech perception may, in part, be due to desynchronization affecting the neural representation of acoustic features. Here we determine if phase-locked neural activity generating the brainstem frequency-following response (FFR) exhibits age-related desynchronization and how this degradation affects the neural representation of simple and complex sounds. PURPOSE: The objectives of this study were to (1) characterize the effects of age on the neural representation of simple tones and complex consonant-vowel stimuli, (2) determine if sustained and transient components of the FFR are differentially affected by age, and (3) determine if the inability to encode a simple signal predicts degradation in representation for complex speech signals. RESEARCH DESIGN: Correlational. STUDY SAMPLE: Thirty four adults (aged 22-77 yr) with hearing thresholds falling within normal limits. DATA COLLECTION AND ANALYSIS: Stimuli used to evoke FFRs were 1000 Hz tone bursts as well as a consonant-vowel /da/ sound. RESULTS: The neural representation of simple (tone) and complex (/da/) stimuli declines with advancing age. Tone-FFR phase coherence decreased as chronological age increased. For the consonant-vowel FFRs, transient onset and offset response amplitudes were smaller, and offset responses were delayed with age. Sustained responses at the onset of vowel periodicity were prolonged in latency and smaller in amplitude as age increased. FFT amplitude of the consonant-vowel FFR fundamental frequency did not significantly decline with increasing age. The ability to encode a simple signal was related to degradation in the neural representation of a complex, speechlike sound. Tone-FFR phase coherence was significantly related to the later vowel response components but not the earlier vowel components. CONCLUSIONS: FFR components representing the tone and consonant-vowel /da/ stimulus were negatively affected by age, showing age-related reductions in response synchrony and amplitude, as well as prolonged latencies. These aging effects were evident in middle age, even in the absence of significant hearing loss. PMID- 24047947 TI - Treatment of objective and subjective benign paroxysmal positional vertigo. AB - BACKGROUND: Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo in adults and is a result of otolithic particles or debris that become free floating within a semicircular canal or adhere to the cupula. Characteristics of BPPV include brief episodes of latent onset vertigo that occur with changes in head position, transient rotary nystagmus beating toward the dependent ear, and reversed nystagmus upon sitting up. Both the vertigo and nystagmus fatigue quickly while maintaining the same head position. The BPPV may be classified as objective or subjective. Objective BPPV presents all the aforementioned symptoms whereas subjective BPPV presents all the symptoms without nystagmus. The accepted method of treatment for objective BPPV is canalith repositioning maneuvers (CRM); however, CRM are not traditionally used as the method of treatment for cases of subjective BPPV. PURPOSE: The purpose of the study was to determine if the subjective report of dizziness using the Dizziness Handicap Inventory (DHI) was different in patients with objective and subjective BPPV and to determine if the two groups showed similar improvements in perceived dizziness handicap following CRM treatment. RESEARCH DESIGN: The present study utilized a retrospective, repeated measures design. STUDY SAMPLE: Sixty-three adults with BPPV that were given the DHI both before and after CRM treatment. DATA COLLECTION AND ANALYSIS: Pre and post DHI results were analyzed for participants with objective versus subjective BPPV. A five-question DHI subscale was also analyzed between the groups. RESULTS: A significant difference was noted between initial and posttreatment DHI scores for patients in both the subjective and objective groups when using the full-scale and subscale DHI. No significant difference was noted between groups for their initial or posttreatment DHI scores. The two groups also did not differ significantly in their initial or posttreatment DHI subscale scores. CONCLUSIONS: The results of the study indicated that individuals with both objective and subjective BPPV demonstrated significant improvement in DHI scores following CRM treatment. Additionally, there was no difference in DHI improvement for the subjective versus objective group suggesting CRM are effective for both subjective BPPV and objective BPPV. This improvement in DHI scores was also noted in the five-question DHI subscale with no significant difference noted between groups. These findings combined with previous studies suggest the presence or absence of nystagmus during Dix-Hallpike maneuvers is not related to the effectiveness of treatment using CRM. PMID- 24047948 TI - Assessment of the efficacy of a hearing screening program for college students. AB - BACKGROUND: The Towson University (TU) Speech-Language-Hearing Center (SLHC) conducts annual hearing screenings for college students entering education or health-care professions. Hearing is screened in therapy rooms, and students who fail the screening are rescreened in a sound-treated booth. Students who fail the rescreening are referred for a comprehensive audiological assessment, which is offered at no cost to students at the SLHC. PURPOSE: The purpose of this study was to examine the efficacy of the hearing screening program, to report trends in hearing screening statistics for the college student population, and to make recommendations regarding ways universities can optimize hearing screening programs. RESEARCH DESIGN: The study included retrospective and prospective portions. Hearing screening records were reviewed from 1999 to 2011. The prospective study involved recruiting students to participate in diagnostic testing following the hearing screening and measuring background noise levels in the therapy rooms. STUDY SAMPLE: Hearing screening records from 1999 to 2011 were reviewed. In addition, during the three-day fall 2011 hearing screenings, 80 students were selected to participate in diagnostic testing. DATA COLLECTION AND ANALYSIS: Data from the retrospective review were used to determine positive predictive value (PPV) between screening and rescreening. Return rates were also examined. For the prospective study, pure tone threshold results were compared to screening results to determine sensitivity, specificity, and PPV. RESULTS: The retrospective file review indicated that the hearing screening in the therapy room had poor PPV compared with the rescreening in the sound booth. Specifically, if a student failed the screening, they had only a 49% chance of failing the rescreening. This may have been due to background noise, as the prospective study found noise levels were higher than allowed by American National Standards Institute (ANSI) standard. Only a third of students referred for diagnostic testing from 1999 to 2010 returned for recommended diagnostic testing. For the prospective study, specificity and sensitivity were good when considering hearing loss present at the same frequencies as those screened (1000, 2000, 4000 Hz) but poor in comparison to hearing loss overall. The screening missed many students with a high frequency notch, which was most prevalent at 6000 Hz. The prevalence of a high frequency notch was 21 and 51%, using two different criteria for establishing the presence of a notch. CONCLUSIONS: If college hearing screenings are conducted in rooms that are not sound treated, poor PPV should be expected; thus, an immediate second stage rescreening for failures should be conducted in a sound booth. Hearing screenings limited to 1000, 2000, and 4000 Hz will miss many cases of hearing loss in the college-age population. College hearing screening program directors should carefully consider the purpose of the screening and adjust screening protocol, such as adding 6000 Hz and a question about noise exposure, in order to identify early signs of noise-induced hearing loss in college students. Programs should focus on ways to promote high return for follow up rates. Estimates of prevalence of a high-frequency audiometric notch are highly dependent on the criteria used to define a notch. PMID- 24047950 TI - Test-retest reliability of probe-microphone verification in children fitted with open and closed hearing aid tips. AB - PURPOSE: To investigate the test-retest reliability of real-ear aided response (REAR) measures in open and closed hearing aid fittings in children using appropriate probe-microphone calibration techniques (stored equalization for open fittings and concurrent equalization for closed fittings). RESEARCH DESIGN: Probe microphone measurements were completed for two mini-behind-the-ear (BTE) hearing aids which were coupled to the ear using open and closed eartips via thin (0.9 mm) tubing. Before probe-microphone testing, the gain of each of the test hearing aids was programmed using an artificial ear simulator (IEC 711) and a Knowles Electronic Manikin for Acoustic Research to match the National Acoustic Laboratories-Non-Linear, version 1 targets for one of two separate hearing loss configurations using an Audioscan Verifit. No further adjustments were made, and the same amplifier gain was used within each hearing aid across both eartip configurations and all participants. Probe-microphone testing included real-ear occluded response (REOR) and REAR measures using the Verifit's standard speech signal (the carrot passage) presented at 65 dB sound pressure level (SPL). Two repeated probe-microphone measures were made for each participant with the probe tube and hearing aid removed and repositioned between each trial in order to assess intrasubject measurement variability. These procedures were repeated using both open and closed domes. STUDY SAMPLE: Thirty-two children, ages ranging from 4 to 14 yr. RESULTS: The test-retest standard deviations for open and closed measures did not exceed 4 dB at any frequency. There was also no significant difference between the open (stored equalization) and closed (concurrent equalization) methods. Reliability was particularly similar in the high frequencies and was also quite similar to that reported in previous research. There was no correlation between reliability and age, suggesting high reliability across all ages evaluated. CONCLUSIONS: The findings from this study suggest that reliable probe-microphone measurements are obtainable on children 4 yr and older for both traditional unvented and open-canal hearing aid fittings. These data suggest that clinicians should not avoid fitting open technology to children as young as 4 y because of concerns regarding the reliability of verification techniques. PMID- 24047949 TI - Some factors underlying individual differences in speech recognition on PRESTO: a first report. AB - BACKGROUND: Previous studies investigating speech recognition in adverse listening conditions have found extensive variability among individual listeners. However, little is currently known about the core underlying factors that influence speech recognition abilities. PURPOSE: To investigate sensory, perceptual, and neurocognitive differences between good and poor listeners on the Perceptually Robust English Sentence Test Open-set (PRESTO), a new high variability sentence recognition test under adverse listening conditions. RESEARCH DESIGN: Participants who fell in the upper quartile (HiPRESTO listeners) or lower quartile (LoPRESTO listeners) on key word recognition on sentences from PRESTO in multitalker babble completed a battery of behavioral tasks and self report questionnaires designed to investigate real-world hearing difficulties, indexical processing skills, and neurocognitive abilities. STUDY SAMPLE: Young, normal-hearing adults (N = 40) from the Indiana University community participated in the current study. DATA COLLECTION AND ANALYSIS: Participants' assessment of their own real-world hearing difficulties was measured with a self-report questionnaire on situational hearing and hearing health history. Indexical processing skills were assessed using a talker discrimination task, a gender discrimination task, and a forced-choice regional dialect categorization task. Neurocognitive abilities were measured with the Auditory Digit Span Forward (verbal short-term memory) and Digit Span Backward (verbal working memory) tests, the Stroop Color and Word Test (attention/inhibition), the WordFam word familiarity test (vocabulary size), the Behavioral Rating Inventory of Executive Function-Adult Version (BRIEF-A) self-report questionnaire on executive function, and two performance subtests of the Wechsler Abbreviated Scale of Intelligence (WASI) Performance Intelligence Quotient (IQ; nonverbal intelligence). Scores on self-report questionnaires and behavioral tasks were tallied and analyzed by listener group (HiPRESTO and LoPRESTO). RESULTS: The extreme groups did not differ overall on self-reported hearing difficulties in real-world listening environments. However, an item-by-item analysis of questions revealed that LoPRESTO listeners reported significantly greater difficulty understanding speakers in a public place. HiPRESTO listeners were significantly more accurate than LoPRESTO listeners at gender discrimination and regional dialect categorization, but they did not differ on talker discrimination accuracy or response time, or gender discrimination response time. HiPRESTO listeners also had longer forward and backward digit spans, higher word familiarity ratings on the WordFam test, and lower (better) scores for three individual items on the BRIEF-A questionnaire related to cognitive load. The two groups did not differ on the Stroop Color and Word Test or either of the WASI performance IQ subtests. CONCLUSIONS: HiPRESTO listeners and LoPRESTO listeners differed in indexical processing abilities, short-term and working memory capacity, vocabulary size, and some domains of executive functioning. These findings suggest that individual differences in the ability to encode and maintain highly detailed episodic information in speech may underlie the variability observed in speech recognition performance in adverse listening conditions using high-variability PRESTO sentences in multitalker babble. PMID- 24047952 TI - Brain inflammation induces post-synaptic changes during early synapse formation in adult-born hippocampal neurons. AB - An inflammatory reaction in the brain is primarily characterized by activation of parenchymal microglial cells. Microglia regulate several aspects of adult neurogenesis, i.e. the continuous production of new neurons in the adult brain. Hippocampal neurogenesis is thought to be important for memory formation, but its role in brain diseases is not clear. We have previously shown that brain inflammation modulates the functional integration of newly formed hippocampal neurons. Here, we explored whether there is a defined time period during synaptic development when new neurons are susceptible to brain inflammation. Newly formed hippocampal neurons, born in an intact environment in the adult mouse brain, were exposed to lipopolysaccharide (LPS)-induced inflammation during either early or late phases of excitatory and inhibitory synaptogenesis. We used intra hippocampal injections of GFP-retroviral vector (RV-GFP) to label the new neurons and ipsilateral LPS injection at either 1 or 4weeks post-RV-GFP injection. A single intra-hippocampal LPS injection induced an inflammatory response for at least 3weeks, including an acute transient pro-inflammatory cytokine release as well as a sub-acute and sustained change in microglial morphology. The general cytoarchitecture of the hippocampal dentate gyrus, including granule cell layer (GCL) volume, and astrocytic glial fibrillary acidic protein expression was not different compared to vehicle controls, and no Fluoro-Jade-positive cell death was observed. New neurons encountering this inflammatory environment exhibited no changes in their gross morphology. However, when inflammation occurred during early stages of synapse formation, we found a region-specific increase in the number of thin dendritic spines and post-synaptic density-95 (PSD-95) cluster formation on spines, suggesting an enhanced excitatory synaptic connectivity in the newborn neurons. No changes were observed in the expression of N-cadherin, an adhesion molecule primarily associated with excitatory synapses. At the inhibitory synapses, alterations due to inflammation were also evident during early but not later stages of synaptic development. Gephyrin, an inhibitory scaffolding protein, was down-regulated in the somatic region, while the adhesion molecules neuroligin-2 (NL-2) and neurofascin were increased in the somatic region and/or on the dendrites. The GABAA receptor-alpha2 subunit (GABAAR-alpha2) was increased, while pre/peri-synaptic GABA clustering remained unaltered. The disproportional changes in post-synaptic adhesion molecules and GABAA receptor compared to scaffolding protein expression at the inhibitory synapses during brain inflammation are likely to cause an imbalance in GABAergic transmission. These changes were specific for the newborn neurons and were not observed when estimating the overall expression of gephyrin, NL-2, and GABAAR-alpha2 in the hippocampal GCL. The expression of interleukin-1-type 1 receptor (IL-1R1) on preferentially the somatic region of new neurons, often in close apposition to NL 2 clusters, may indicate a direct interaction between brain inflammation and synaptic proteins on newborn neurons. In summary, this study provides evidence that adult-born hippocampal neurons alter their inhibitory and excitatory synaptic integration when encountering an LPS-induced brain inflammation during the initial stages of synapse formation. Changes at this critical developmental period are likely to interfere with the physiological functions of new neurons within the hippocampus. PMID- 24047953 TI - SPECT-CT in total hip arthroplasty. AB - Single photon emission computed tomography combined with computed tomography (SPECT-CT), which combines functional and anatomical imaging, provides superior spatial localization to plain radiography and is more tolerant to metallic artefacts than conventional imaging such as magnetic resonance imaging (MRI). It is increasingly used in musculoskeletal imaging to enable accurate anatomical localization of increased tracer uptake, and is particularly useful in assessing metal prosthesis and the surrounding bone following total hip arthroplasty (THA). In addition to detecting complications of THA, SPECT-CT enables multiplanar reconstruction and manipulation of imaging data, which may aid surgical planning. SPECT-CT is an important adjunct to conventional imaging in the management of post-THA complications. It is vital that radiologists are able to identify the specific features of different complications and use this novel imaging technique to guide management. In this article, the use of SPECT-CT to follow post-THA complications, including aseptic loosening, periprosthetic infection, histiocytic reactions, periprosthetic fractures, polyethylene wear, and pseudotumour formation, will be reviewed. PMID- 24047954 TI - Persistent human cosavirus infection in lung transplant recipient, Italy. AB - Human cosavirus is a novel picornavirus recently identified in feces from children in southern Asia. We report infection with human cosavirus in a patient in the Mediterranean area. The patient was an adult double lung transplant recipient who had chronic diarrhea associated with persistent infection with human cosavirus. PMID- 24047955 TI - Cardiomyopathy mutations in the tail of beta-cardiac myosin modify the coiled coil structure and affect integration into thick filaments in muscle sarcomeres in adult cardiomyocytes. AB - It is unclear why mutations in the filament-forming tail of myosin heavy chain (MHC) cause hypertrophic or dilated cardiomyopathy as these mutations should not directly affect contraction. To investigate this, we first investigated the impact of five hypertrophic cardiomyopathy-causing (N1327K, E1356K, R1382W, E1555K, and R1768K) and one dilated cardiomyopathy-causing (R1500W) tail mutations on their ability to incorporate into muscle sarcomeres in vivo. We used adenoviral delivery to express full-length wild type or mutant enhanced GFP-MHC in isolated adult cardiomyocytes. Three mutations (N1327K, E1356K, and E1555K) reduced enhanced GFP-MHC incorporation into muscle sarcomeres, whereas the remainder had no effect. No mutations significantly affected contraction. Fluorescence recovery after photobleaching showed that fluorescence recovery for the mutation that incorporated least well (N1327K) was significantly faster than that of WT with half-times of 25.1 +/- 1.8 and 32.2 +/- 2.5 min (mean +/- S.E.), respectively. Next, we determined the effects of each mutation on the helical properties of wild type and seven mutant peptides (7, 11, or 15 heptads long) from the myosin tail by circular dichroism. R1382W and E1768K slightly increased the alpha-helical nature of peptides. The remaining mutations reduced alpha helical content, with N1327K showing the greatest reduction. Only peptides containing residues 1301-1329 were highly alpha-helical suggesting that this region helps in initiation of coiled coil. These results suggest that small effects of mutations on helicity translate into a reduced ability to incorporate into sarcomeres, which may elicit compensatory hypertrophy. PMID- 24047957 TI - The expression of depression among Javanese patients with major depressive disorder: a concept mapping study. AB - In this study, we explored the presentation of clinical depression in Java, Indonesia. Interviews were conducted with 20 Javanese patients (male and female) with major depressive disorder from both lower and higher socioeconomic levels. The recruited participants came from provincial and private mental health hospitals in the cities of Solo, Yogykarta (Jogja), Jakarta, and Malang on the island of Java, Indonesia. Concept mapping methodology using multidimensional scaling and hierarchical cluster analysis was used to identify underlying themes in the expression of depressive phenomena in this Indonesian population. The results identified themes that grouped into six clusters: interpersonal relationships, hopelessness, physical/somatic, poverty of thought, discourage, and defeat. Findings give support to the view that culture influences the expression of Indonesian depressive phenomenology, which nevertheless has some common roots with Western clinical pictures of the disorder. Cultural influences may mask symptoms of the disorder to clinicians. Diagnostic and assessment tools must be carefully selected to ensure they address culturally specific expressions of depression. PMID- 24047956 TI - Differential effects of continuous exposure to the investigational metastin/kisspeptin analog TAK-683 on pulsatile and surge mode secretion of luteinizing hormone in ovariectomized goats. AB - The aim of the present study was to determine if the estradiol-induced luteinizing hormone (LH) surge is influenced by the constant exposure to TAK-683, an investigational metastin/kisspeptin analog, that had been established to depress the pulsatile gonadotropin-releasing hormone (GnRH) and LH secretion in goats. Ovariectomized goats subcutaneously received TAK-683 (TAK-683 group, n=6) or vehicle (control group, n=6) constantly via subcutaneous implantation of an osmotic pump. Five days after the start of the treatment, estradiol was infused intravenously in both groups to evaluate the effects on the LH surge. Blood samples were collected at 6-min intervals for 4 h prior to the initiation of either the TAK-683 treatment or the estradiol infusion, to determine the profiles of pulsatile LH secretion. They were also collected at 2-h intervals from -4 h to 32 h after the start of estradiol infusion for analysis of LH surges. The frequency and mean concentrations of LH pulses in the TAK-683 group were remarkably suppressed 5 days after the start of TAK-683 treatment compared with those of the control group (P<0.05). On the other hand, a clear LH surge was observed in all animals of both groups. There were no significant differences in the LH concentrations for surge peak and the peak time of the LH surge between the TAK-683 and control groups. These findings suggest that the effects of continuous exposure to kisspeptin or its analog on the mechanism(s) that regulates the pulsatile and surge mode secretion of GnRH/LH are different in goats. PMID- 24047958 TI - Micronutrients in brain function, and traumatic brain injury. PMID- 24047959 TI - Localized serine protease activity and the establishment of Drosophila embryonic dorsoventral polarity. AB - Drosophila embryo dorsoventral polarity is established by a maternally encoded signal transduction pathway in which three sequentially acting serine proteases, Gastrulation Defective, Snake and Easter, generate the ligand that activates the Toll receptor on the ventral side of the embryo. The spatial regulation of this pathway depends upon ventrally restricted expression of the Pipe sulfotransferase in the ovarian follicle during egg formation. Several recent observations have advanced our understanding of the mechanism regulating the spatially restricted activation of Toll. First, several protein components of the vitelline membrane layer of the eggshell have been determined to be targets of Pipe-mediated sulfation. Second, the processing of Easter by Snake has been identified as the first Pipe-dependent, ventrally-restricted processing event in the pathway. Finally, Gastrulation Defective has been shown to undergo Pipe-dependent, ventral localization within the perivitelline space and to facilitate Snake-mediated processing of Easter. Together, these observations suggest that Gastrulation Defective, localized on the interior ventral surface of the eggshell in association with Pipe-sulfated eggshell proteins, recruits and mediates an interaction between Snake and Easter. This event leads to ventrally-restricted processing and activation of Easter and consequently, localized formation of the Toll ligand, and Toll activation. PMID- 24047961 TI - Tailoring magnetism at the nanometer scale in SmCo5 amorphous films. AB - The thickness dependence of magnetic properties has been studied in SmCo5 amorphous films with imprinted in-plane anisotropy for thicknesses ranging down to the nanometer scale (2.5-100 nm). The field induced in-plane magnetic anisotropy decreases considerably when the film thickness is below 20 nm. Analysis of the magnetic anisotropy energy shows that the decrease of the induced in-plane anisotropy is accompanied by the development of an out-of-plane interface anisotropy. Two different regimes for the coercivity (Hc) change are found: below 3.75 nm, the Hc decreases continuously with decrease of the film thickness, whereas at above 3.75 nm, the Hc decreases with increase of the film thickness. This change in Hc can be understood by considering the decrease of the short range chemical order for the thinnest films (<3.75 nm) and the relative decrease of the interface contribution with increasing film thickness. The changes in anisotropy have a profound influence on the domain structure, in which the angle of the zigzag domain boundaries decreases with the inverse thickness of the layers. PMID- 24047962 TI - Production of anti-horse antibodies induced by IgG, F(ab')2 and Fab applied repeatedly to rabbits. Effect on antivenom pharmacokinetics. AB - We separated whole IgG, Fab and F(ab')2 fragments from horse plasma. We previously studied the pharmacokinetics of these immunoglobulins and fragments in rabbits and shown that Fab and F(ab')2 pharmacokinetics were well described by a three-exponential kinetics, while IgG and IgG(T) pharmacokinetics, however, deviated from the three-exponential kinetics 120 h after injecting a bolus of the immunotherapeutics; this departure was shown to be due to a surge of anti-horse antibodies occurring after 120 h, peaking at ~260 h and decaying slowly afterward (Vazquez et al., 2010). We now describe antivenom pharmacokinetics and anti-horse IgG production in rabbits receiving three boluses (300 MUg/kg, I.V.) of Fab, F(ab')2 or IgG separated by 21 days. PMID- 24047960 TI - Recommendations for high-priority research on cancer-related fatigue in children and adults. AB - Over the past decades, some scientific progress has been made in understanding and treating cancer-related fatigue (CRF). However, three major problems have limited further progress: lack of agreement about measurement, inadequate understanding of the underlying biology, and problems in the conduct of clinical trials for CRF. This commentary reports the recommendations of a National Cancer Institute Clinical Trials Planning Meeting and an ongoing National Cancer Institute working group to address these problems so that high-priority research and clinical trials can be conducted to advance the science of CRF and its treatment. Recommendations to address measurement issues included revising the current case definition to reflect more rigorous criteria, adopting the Patient Reported Outcomes Measurement Information System fatigue scales as standard measures of CRF, and linking legacy measures to the scales. With regard to the biology of CRF, the group identified the need for longitudinal research to examine biobehavioral mechanisms underlying CRF and testing mechanistic hypotheses within the context of intervention research. To address clinical trial issues, recommendations included using only placebo-controlled trial designs. setting eligibility to minimize sample heterogeneity or enable subgroup analysis, establishing a CRF severity threshold for participation in clinical trials, conducting dissemination trials of efficacious interventions (such as exercise), and combining nonpharmacologic and pharmacologic interventions to exploit the potential synergy between these approaches. Accomplishing these goals has the potential to advance the science of CRF and improve the clinical management of this troubling symptom. PMID- 24047963 TI - Mastoparan-7 rescues botulinum toxin-A poisoned neurons in a mouse spinal cord cell culture model. AB - Botulinum neurotoxin serotype A (BoNT/A) is the most potent poison of biological origin known to mankind. The toxicity of BoNT/A is due to the inhibition of neurotransmission at cholinergic synapses; this is responsible for the symptom of flaccid paralysis at peripheral neuromuscular junctions. At a molecular level, the BoNT/A effect is due to its inhibition of stimulated acetylcholine (ACh) release from presynaptic nerve terminals. Currently, there is no antidote available to rescue BoNT/A-poisoned synapses. Here, we report an example of rescuing botulinum-poisoned cultured mouse spinal cord neurons by treatment with Mastoparan-7 (Mas-7), which is known to be a phospholipase A2 activator compound. Mas-7, a naturally occurring bee venom peptide, was delivered to botulinum poisoned neurons via a drug delivery vehicle (DDV) construct prepared using the recombinant non-toxic heavy chain (HC) fragment of BoNT/A itself. In this method, the BoNT/A HC component in the DDV served as a neuron specific drug targeting molecule. We found that Mas-7 delivered into BoNT/A intoxicated spinal cord cells restored over 40% their property of stimulated neurotransmitter release. Rescue from cell poisoning did not occur from inhibition of the endopeptidase activity of BoNT/A light chain (LC) against its well-known substrate, SNAP-25 that is mechanistically involved in the cholinergic neuroexocytosis process. Rather, Mas 7 induced a physiological host response apparently unrelated to SNAP-25, but linked to the phospholipase-mediated signal transduction pathway. PMID- 24047964 TI - Microcystin-LR induces autophagy and apoptosis in rat Sertoli cells in vitro. AB - Although microcystin-LR (MC-LR) produced by cyanobacteria has been demonstrated with strong reproductive toxicity, the mechanisms remain unclear. This study aimed to probe the effects of MC-LR on induction of autophagy in Sertoli cells, as well as the relationship between autophagy and apoptosis. After exposure to various concentrations of MC-LR for 24 or 48 h, cell viability and membrane integrity were significantly decreased under high MC-LR conditions (50-500 nM). The autophagosome marker protein LC3 was increased at mild MC-LR concentrations (0.5-5 nM). However, autophagosomes accumulated to their peak level under high MC LR conditions in parallel with significantly up-regulated apoptosis. Treatment with an autophagy inhibitor (3-MA) abrogated autophagosome accumulation and apoptosis. This study demonstrated that MC-LR had toxic effects on Sertoli cells by inducing autophagy and apoptosis. The autophagosome accumulation may be involved in the apoptosis induced by MC-LR. PMID- 24047965 TI - Relationship between clinical features and therapeutic approach for benign paroxysmal positional vertigo outcomes. AB - OBJECTIVE: To examine the clinical features, age and gender distribution of patients, treatment methods, and outcomes of benign paroxysmal positional vertigo. METHODS: This paper reports a review of 357 patients treated for this condition at a single institution over a duration of 5 years. Patients with posterior canal benign paroxysmal positional vertigo were divided into two groups: one group underwent the Epley manoeuvre and the other received medication. The lateral canal canalolithiasis patients were also divided into two groups: one underwent the Lempert manoeuvre and the other received medication. Lastly, the lateral canal cupulolithiasis patients were treated with medication and non-specific physical techniques. RESULTS AND CONCLUSION: For patients with posterior canal benign paroxysmal positional vertigo, resolution time was significantly shorter in the Epley manoeuvre group than in the medication group. For the lateral canal canalolithiasis patients, resolution time was significantly shorter in the Lempert manoeuvre group than in the medication group. Resolution time was significantly longer in the lateral canal cupulolithiasis patients than in the other patients. The average age of patients increased with the number of recurrences, as did predominance in females. Average age and rate of sensorineural hearing loss were significantly higher in patients with intractable benign paroxysmal positional vertigo compared with those in the curable benign paroxysmal positional vertigo group. PMID- 24047967 TI - Correlation between different methods to measure microbial translocation and its association with immune activation in long-term suppressed HIV-1-infected individuals. AB - INTRODUCTION: Microbial translocation (MT) has been proposed as one of the triggering mechanisms of persistent immune activation associated to HIV-1 infection. Our objectives were to determine the correlation between different measurements of MT in suppressed HIV-1-infected individuals and to evaluate its correlation with immune activation. METHODS: Eighteen suppressed HIV-1-infected patients with CD4+ T-cell count above 350 cells per cubic millimeter and undetectable plasma viral load, included in antiretroviral treatment intensification clinical trials, were evaluated. Samples obtained at baseline and at established time points during the trials were analyzed. Lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14), and bacterial 16S ribosomal DNA (16S rDNA), and markers of immune activation were determined. RESULTS: We analyzed 126 plasma samples from the 18 patients. LPS significantly correlated with sCD14 (P < 0.001, r = 0.407) and LBP (P = 0.042, r = 0.260). Also, a significant correlation was found between sCD14 and LBP (P = 0.009, r = 0.325) but not between bacterial 16S rDNA and LPS, sCD14, or LBP (P = 0.346, P = 0.405, and P = 0.644). On the other hand, no significant correlation was found between LPS, sCD14, or LBP and CD4 (P = 0.418, P = 0.619, and P = 0.728) or CD8 T-cell activation (P = 0.352, P = 0.275, and P = 0.124). Bacterial 16S rDNA correlated with activated CD4 T cells (P = 0.005, r = 0.104) but not with activated CD8 T cells (P = 0.171). CONCLUSIONS: There is a good correlation in the quantification of LPS, sCD14, and LBP levels, but not with bacterial 16S rDNA, as measurements of MT. We are unable to ensure that MT directly triggers T cell immune activation at least among these patients with relatively good immune recovery and under treatment intensification. PMID- 24047968 TI - Novel role of HSP40/DNAJ in the regulation of HIV-1 replication. AB - OBJECTIVES: DNAJ/HSP40 is an evolutionarily conserved family of proteins bearing various functions. Historically, it has been emphasized that HSP40/DNAJ family proteins play a positive role in infection of various viruses. We identified DNAJ/HSP40B6 as a potential negative regulator of HIV-1 replication in our genetic screens. In this study, we investigated the functional interactions between HIV-1 and HSP40 family members. DESIGN: We took genetic and comparative virology approaches to expand the primary observation. METHODS: Multiple HSP40/DNAJ proteins were tested for their ability to inhibit replication of adenovirus, herpes simplex virus type 1, HIV-1, and vaccinia virus. The mechanism of inhibition was investigated by using HSP40/DNAJ mutants and measuring the efficiencies of each viral replication steps. RESULTS: HSP40A1, B1, B6, and C5, but not C3, were found to be able to limit HIV-1 production. This effect was specific to HIV-1 for such effects were not detected in adenovirus, herpes simplex virus type 1, and vaccinia virus. Genetic analyses suggested that the conserved DNAJ domain was responsible for the inhibition of HIV-1 production through which HSP40 regulates HSP70 ATPase activity. Interestingly, HSP40s lowered the levels of steady-state viral messenger RNA. This was not attributed to the inhibition of Tat/long terminal repeat-driven transcription but the downregulation of Rev expression. CONCLUSIONS: This is the first report providing evidence that HSP70-HSP40 complex confers an innate resistance specific to HIV-1. For their interferon-inducible nature, HSP40 family members should account for the anti-HIV-1 function of interferon. PMID- 24047969 TI - The effect of churn on "community viral load" in a well-defined regional population. AB - BACKGROUND: The concept of community viral load (CVL) was introduced to quantify the pool of transmissible HIV within a community and to monitor the potential impact of highly active antiretroviral therapy (HAART) on reducing new infections. The implications of churn (patient movement in/out of care in a community) on CVL have not been studied. METHODS: The annual CVL was determined in the entire geographic HIV population receiving care in southern Alberta from 2001 to 2010; the CVL for specific subpopulations was analyzed for 2009. CVL was determined for patients under continuous care, newly diagnosed, new to the region, moved away, returned, and lost to follow-up (LTFU). Viral loads (VLs) <50 or <200 copies per milliliter were deemed undetectable and suppressed, respectively. The mean VL per patient and total VL were used to determine CVL. RESULTS: From 2001 to 2010, the HAART uptake for all patients increased from 62% to 81%, undetectability from 32% to 66%, and suppression from 49% to 72%. The annual total CVL however did not vary significantly after 2003. Incidence rates for new locally diagnosed infections increased from 4.4 to 5.8/100,000 per year. In 2009, newly diagnosed HIV patients (6.6%) contributed 37.5% to the CVL, whereas patients transferring in/out of the region or lost to follow-up contributed 33% to the CVL. Patients in continuous care (79% of all patients) contributed 29.5% to the total CVL. CONCLUSIONS: Increasing HAART coverage did not reduce the CVL or reduce new HIV diagnoses in our population. The effect of churn significantly limited CVL use as a measure for evaluating the impact of HAART in reducing HIV transmissions in our population. PMID- 24047966 TI - Single-nucleotide polymorphisms in TrkB and risk for depression: findings from the women's interagency HIV study. AB - Individuals infected with HIV type 1 are more likely than noninfected individuals to develop depression. HIV lowers brain-derived neurotrophic factor (BDNF), a neurotrophic factor whose receptors play a crucial role in the pathophysiology of depression. Therefore, we examined whether a single-nucleotide polymorphism in the BDNF gene (rs56164415) and related receptors TrkB (rs1212171) and p75 (rs2072446) were associated with depression in HIV-infected individuals. A total of 1365 HIV-positive and 371 HIV-negative female subjects were included. The distribution of alleles was analyzed independently in African Americans (non Hispanic) and Caucasians (non-Hispanic). We have found that the absence of depressive symptoms in HIV-positive subjects is associated with a genetic variation of the TrkB but not with BDNF or p75 genes. This mutation explains 0.8% and 4.4% of the variability for the absence of depression in African Americans and Caucasians, respectively. PMID- 24047970 TI - Impact of late presentation on the risk of death among HIV-infected people in France (2003-2009). AB - OBJECTIVE: A recent consensus defines "late presentation" (LP) during the course of HIV infection as presentation with AIDS whatever the CD4 cell count or with CD4 <350 cells per cubic millimeter. Here, using this new definition, we examined the frequency and predictors of LP and its impact on mortality. METHODS: In antiretroviral-naive patients enrolled in the French Hospital Database on HIV between 2003 and 2009, we studied risk factors for LP by multivariable logistic regression. The impact of LP on mortality was analyzed according to the level of immunodeficiency by using Cox multivariable models adjusted for potential confounders, with follow-up categorized into 0-6, 6-12, and 12-48 months. RESULTS: There were 11,038 (53.9%) late presenters among the 20,496 patients included in the study. Compared with patients presenting for care with CD4 >=350 cells per cubic millimeter, patients presenting with AIDS had a very high risk of death with crude hazard ratio ranging from 48.3 during the first 6 months of follow-up to 4.8 during months 12-48; the corresponding values among AIDS-free patients with CD4 <=200 cells per cubic millimeter were 8.1 and 2.3. Importantly, patients presenting with CD4 between 200 and 350 cells per cubic millimeter also had a significantly increased risk of death beyond 6 months of follow-up (hazard ratio: 3.0 and 1.8 for months 6-12 and 12-48, respectively). Results were similar after adjustment. CONCLUSIONS: LP with HIV infection is still very frequent in France and is associated with higher mortality, even among patients with only moderate immunodeficiency. Encouraging early testing and access to care is still urgently needed. PMID- 24047971 TI - Antiretroviral treatment interruptions induced by the Kenyan postelection crisis are associated with virological failure. AB - BACKGROUND: Antiretroviral treatment interruptions (TIs) cause suboptimal clinical outcomes. Data on TIs during social disruption are limited. METHODS: We determined effects of unplanned TIs after the 2007-2008 Kenyan postelection violence on virological failure, comparing viral load (VL) outcomes in HIV infected adults with and without conflict-induced TI. RESULTS: Two hundred and one patients were enrolled, median 2.2 years after conflict and 4.3 years on treatment. Eighty-eight patients experienced conflict-related TIs and 113 received continuous treatment. After adjusting for preconflict CD4, patients with TIs were more likely to have detectable VL, VL >5,000 and VL >10,000. CONCLUSIONS: Unplanned conflict-related TIs are associated with increased likelihood of virological failure. PMID- 24047972 TI - Proper surgical training and grading of complications for Shang Ring circumcision are necessary. PMID- 24047973 TI - A randomized trial of Mogen clamp versus Plastibell for neonatal male circumcision in Botswana. PMID- 24047974 TI - Response to Calcagno comment on "Higher CNS penetration-effectiveness of long term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid". PMID- 24047975 TI - Lifetime costs and quality-adjusted life years saved from HIV prevention in the test and treat era. PMID- 24047976 TI - Antitumor effect of the antimicrobial peptide GLI13-8 derived from domain of the avian beta-defensin-4. AB - We previously reported that GLI13-8, one of cationic antimicrobial peptides from linear avian beta-defensin-4 (RL38) analogs, exhibited high antimicrobial activities against both Gram-negative and Gram-positive bacteria. In the present study, we reported the in vitro cytotoxicity of GLI13-8 using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results showed that the cytotoxicity of GLI13-8 in three human carcinoma cells (HepG2, SGC7901, and A375) was in a dose-dependent manner. When the concentration of GLI13-8 is <128 MUM, it had no toxicity towards the normal human fibroblasts (MRC-5). The Annexin V-FITC/PI staining assay, the Hoechst 33258/PI staining assay, the permeability of fluorescein macromolecules and scanning electron microscope assays, mitochondrial membrane potential assay, caspases-3 and poly ADP-ribose polymerase (PARP) assays have been carried out. Results indicated that apoptosis was induced by GLI13-8 in HepG2 cells, and demonstrated that GLI13-8 induced loss of mitochondrial membrane potential, disruption of HepG2 cell membranes, and activation of caspase-3 and PARP. These findings suggested that GLI13-8 may be an effective agent for HepG2 cells. PMID- 24047977 TI - Modeling mitochondrial ROS: a great balancing act. PMID- 24047978 TI - Catch me because you can: a mathematical model for mechanosensing. PMID- 24047979 TI - High-speed atomic force microscopy tracks toxin action. PMID- 24047980 TI - Interrogating biology with force: single molecule high-resolution measurements with optical tweezers. AB - Single molecule force spectroscopy methods, such as optical and magnetic tweezers and atomic force microscopy, have opened up the possibility to study biological processes regulated by force, dynamics of structural conformations of proteins and nucleic acids, and load-dependent kinetics of molecular interactions. Among the various tools available today, optical tweezers have recently seen great progress in terms of spatial resolution, which now allows the measurement of atomic-scale conformational changes, and temporal resolution, which has reached the limit of the microsecond-scale relaxation times of biological molecules bound to a force probe. Here, we review different strategies and experimental configurations recently developed to apply and measure force using optical tweezers. We present the latest progress that has pushed optical tweezers' spatial and temporal resolution down to today's values, discussing the experimental variables and constraints that are influencing measurement resolution and how these can be optimized depending on the biological molecule under study. PMID- 24047981 TI - On the activation of integrin alphaIIbbeta3: outside-in and inside-out pathways. AB - Integrin alphaIIbbeta3 is a member of the integrin family of transmembrane proteins present on the plasma membrane of platelets. Integrin alphaIIbbeta3 is widely known to regulate the process of thrombosis via activation at its cytoplasmic side by talin and interaction with the soluble fibrinogen. It is also reported that three groups of interactions restrain integrin family members in the inactive state, including a set of salt bridges on the cytoplasmic side of the transmembrane domain of the integrin alpha- and beta-subunits known as the inner membrane clasp, hydrophobic packing of a few transmembrane residues on the extracellular side between the alpha- and beta-subunits that is known as the outer membrane clasp, and the key interaction group of the betaA domain (located on the beta-subunit head domain) with the betaTD (proximal to the plasma membrane on the beta-subunit). However, molecular details of this key interaction group as well as events that lead to detachment of the betaTD and betaA domains have remained ambiguous. In this study, we use molecular dynamics models to take a comprehensive outside-in and inside-out approach at exploring how integrin alphaIIbbeta3 is activated. First, we show that talin's interaction with the membrane-proximal and membrane-distal regions of integrin cytoplasmic transmembrane domains significantly loosens the inner membrane clasp. Talin also interacts with an additional salt bridge (R734-E1006), which facilitates integrin activation through the separation of the integrin's alpha- and beta-subunits. The second part of our study classifies three types of interactions between RGD peptides and the extracellular domains of integrin alphaIIbbeta3. Finally, we show that the interaction of the Arg of the RGD sequence may activate integrin via disrupting the key interaction group between K350 on the betaA domain and S673/S674 on the betaTD. PMID- 24047982 TI - Model of T-cell nuclear deformation by the cortical actin layer. AB - Deformations of cell nuclei accompany a number of essential intracellular processes. Although evidence is being accumulated on the primary role actin structures play in controlling the shape of the nucleus, the mechanisms behind this phenomenon remain unknown. Here, we consider theoretically a specific paradigm of nuclear deformation, and a related actin rearrangement, in T cells stimulated by contact with a bead covered by surrogate antigens. We suggest that the nucleus is deformed by the elastic forces developed within a cylindrical layer of polymerized actin, which is generated as a result of the receptor mediated T-cell activation. We substantiate this proposal with a theoretical analysis of mutual deformations in the actin layer and the nucleus, which recovers the experimentally observed nuclear shapes. Furthermore, we evaluate the forces developed by the actin polymerization that drives the nuclear deformation. The model predicts the mode of actin polymerization generated by the surrogate antigens covering a bead and the values of the elastic moduli of the nuclear shell. We provide a qualitative experimental support for the model assumptions by visualizing the stages of nuclear shape change and the corresponding evolution of the cortical actin. PMID- 24047983 TI - Measuring affinities of fission yeast spindle pole body proteins in live cells across the cell cycle. AB - Characterizing protein-protein interactions is essential for understanding molecular mechanisms, although reproducing cellular conditions in vitro is challenging and some proteins are difficult to purify. We developed a method to measure binding to cellular structures using fission yeast cells as reaction vessels. We varied the concentrations of Sid2p and Mob1p (proteins of the septation initiation network) and measured their binding to spindle pole bodies (SPBs), the centrosome equivalent of yeast. From our measurements we infer that Sid2p and Mob1p both exist as monomeric, heterodimeric, and homodimeric species throughout the cell cycle. During interphase these species have widely different affinities for their common receptor Cdc11p on the SPB. The data support a model with a subset of Cdc11p binding the heterodimeric species with a Kd < 0.1 MUM when Sid2p binds Mob1p-Cdc11p and Kd in the micromolar range when Mob1p binds Sid2p-Cdc11p. During mitosis an additional species presumed to be the phosphorylated Sid2p-Mob1p heterodimer binds SPBs with a lower affinity. Homodimers of Sid2p or Mob1p bind to the rest of Cdc11p at SPBs with lower affinity: Kds > 10 MUM during interphase and somewhat stronger during mitosis. These measurements allowed us to account for the fluctuations in Sid2p binding to SPBs throughout the cell cycle. PMID- 24047984 TI - Contractile fibers and catch-bond clusters: a biological force sensor? AB - Catch bonds are cellular receptor-ligand pairs whose lifetime, counterintuitively, increases with increasing load. Although their existence was initially pure theoretical speculation, recent years have seen several experimental demonstrations of catch-bond behavior in biologically relevant and functional protein-protein bonds. Particularly notable among these established catch-bond formers is the integrin alpha5beta1, the primary receptor for fibronectin and, as such, a crucial determinant for the characteristics of the mechanical coupling between cell and matrix. In this work, we explore the implications of single catch-bond characteristics for the behavior of a load sharing cluster of such bonds: These clusters are shown to possess a regime of strengthening with increasing applied force, similar to the manner in which focal adhesions become selectively reinforced. Our results may shed new light on the fundamental processes that allow cells to sense and respond to the mechanical properties of their environment and in particular show how single focal adhesions may act, autonomously, as local rigidity sensors. PMID- 24047985 TI - Temperature and carbon assimilation regulate the chlorosome biogenesis in green sulfur bacteria. AB - Green photosynthetic bacteria adjust the structure and functionality of the chlorosome-the light-absorbing antenna complex-in response to environmental stress factors. The chlorosome is a natural self-assembled aggregate of bacteriochlorophyll (BChl) molecules. In this study, we report the regulation of the biogenesis of the Chlorobaculum tepidum chlorosome by carbon assimilation in conjunction with temperature changes. Our studies indicate that the carbon source and thermal stress culture of C. tepidum grows slower and incorporates fewer BChl c in the chlorosome. Compared with the chlorosome from other cultural conditions we investigated, the chlorosome from the carbon source and thermal stress culture displays (a) smaller cross-sectional radius and overall size, (b) simplified BChl c homologs with smaller side chains, (c) blue-shifted Qy absorption maxima, and (d) a sigmoid-shaped circular dichroism spectra. Using a theoretical model, we analyze how the observed spectral modifications can be associated with structural changes of BChl aggregates inside the chlorosome. Our report suggests a mechanism of metabolic regulation for chlorosome biogenesis. PMID- 24047986 TI - Spatial configuration and composition of charge modulates transport into a mucin hydrogel barrier. AB - The mucus barrier is selectively permeable to a wide variety of molecules, proteins, and cells, and establishes gradients of these particulates to influence the uptake of nutrients, the defense against pathogens, and the delivery of drugs. Despite its importance for health and disease, the criteria that govern transport through the mucus barrier are largely unknown. Studies with uniformly functionalized nanoparticles have provided critical information about the relevance of particle size and net charge for mucus transport. However, these particles lack the detailed spatial arrangements of charge found in natural mucus interacting substrates, such as certain viruses, which may have important consequences for transport through the mucus barrier. Using a novel, to our knowledge, microfluidic design that enables us to measure real-time transport gradients inside a hydrogel of mucins, the gel-forming glycoprotein component of mucus, we show that two peptides with the same net charge, but different charge arrangements, exhibit fundamentally different transport behaviors. Specifically, we show that certain configurations of positive and negative charges result in enhanced uptake into a mucin barrier, a remarkable effect that is not observed with either charge alone. Moreover, we show that the ionic strength within the mucin barrier strongly influences transport specificity, and that this effect depends on the detailed spatial arrangement of charge. These findings suggest that spatial charge distribution is a critical parameter to modulate transport through mucin-based barriers, and have concrete implications for the prediction of mucosal passage, and the design of drug delivery vehicles with tunable transport properties. PMID- 24047987 TI - Electrophysiological characterization of the mechanosensitive channel MscCG in Corynebacterium glutamicum. AB - Corynebacterium glutamicum MscCG, also referred to as NCgl1221, exports glutamate when biotin is limited in the culture medium. MscCG is a homolog of Escherichia coli MscS, which serves as an osmotic safety valve in E. coli cells. Patch-clamp experiments using heterogeneously expressed MscCG have shown that MscCG is a mechanosensitive channel gated by membrane stretch. Although the association of glutamate secretion with the mechanosensitive gating has been suggested, the electrophysiological characteristics of MscCG have not been well established. In this study, we analyzed the mechanosensitive gating properties of MscCG by expressing it in E. coli spheroplasts. MscCG is permeable to glutamate, but is also permeable to chloride and potassium. The tension at the midpoint of activation is 6.68 +/- 0.63 mN/m, which is close to that of MscS. The opening rates at saturating tensions and closing rates at zero tension were at least one order of magnitude slower than those observed for MscS. This slow kinetics produced strong opening-closing hysteresis in response to triangular pressure ramps. Whereas MscS is inactivated under sustained stimulus, MscCG does not undergo inactivation. These results suggest that the mechanosensitive gating properties of MscCG are not suitable for the response to abrupt and harmful changes, such as osmotic downshock, but are tuned to execute slower processes, such as glutamate export. PMID- 24047988 TI - The carboxyl terminal residues 220-283 are not required for voltage gating of a chimeric connexin32 hemichannel. AB - Connexin hemichannels display two distinct forms of voltage-dependent gating, corresponding to the operation of Vj- or fast gates and loop- or slow gates. The carboxyl terminus (CT) of connexin 32 has been reported to be required for the operation of the Vj (fast) gates, but this conclusion was inferred from the loss of a fast kinetic component in macroscopic currents of CT-truncated intercellular channels elicited by transjunctional voltage. Such inferences are complicated by presence of both fast and slow gates in each hemichannel and the serial head-to head arrangement of these gates in the intercellular channel. Examination of voltage gating in undocked hemichannels and Vj gate polarity reversal by a negative charge substitution (N2E) in the amino terminal domain allow unequivocal separation of the two gating processes in a Cx32 chimera (Cx32(*)43E1). This chimera expresses currents as an undocked hemichannel in Xenopus oocytes and provides a model system to study the molecular determinants and mechanisms of Cx32 voltage gating. Here, we demonstrate that both Vj- and loop gates are operational in a truncation mutation that removes all but the first four CT residues (ACAR(219)) of the Cx32(*)43E1 hemichannel. We conclude that an operational Cx32 Vj (fast) gate does not require CT residues 220-283, as reported previously by others. PMID- 24047989 TI - Multiphasic effects of cholesterol on influenza fusion kinetics reflect multiple mechanistic roles. AB - The envelope lipid composition of influenza virus differs from that of the cellular plasma membrane from which it buds. Viruses also appear to fuse preferentially to specific membrane compartments, suggesting that the lipid environment may influence permissiveness for fusion. Here, we investigated the influence of the membrane environment on fusion, focusing on cholesterol composition. Strikingly, manipulating cholesterol levels in the viral membrane had different effects on fusion kinetics compared with analogous changes to the target membrane. Increasing cholesterol content in target vesicles increased lipid- and contents-mixing rates. Moderate cholesterol depletion from the viral membrane sped fusion rates, whereas severe depletion slowed the process. The pleiotropic effects of cholesterol include alterations in both membrane-bending moduli and lateral organization. Because influenza virions have demonstrated cholesterol-dependent lateral organization, to separate these effects, we deliberately selected a target vesicle composition that does not support lateral heterogeneity. We therefore postulate that the monotonic response of fusion kinetics to target membrane cholesterol reflects bending and curvature effects, whereas the multiphasic response to viral cholesterol levels reflects the combined effects of lateral organization and material properties. PMID- 24047990 TI - Lipid bilayer composition can influence the orientation of proteorhodopsin in artificial membranes. AB - Artificial membrane systems allow researchers to study the structure and function of membrane proteins in a matrix that approximates their natural environment and to integrate these proteins in ex vivo devices such as electronic biosensors, thin-film protein arrays, or biofuel cells. Given that most membrane proteins have vectorial functions, both functional studies and applications require effective control over protein orientation within a lipid bilayer. In this work, we explored the role of the bilayer surface charge in determining transmembrane protein orientation and functionality during formation of proteoliposomes. We reconstituted a model vectorial ion pump, proteorhodopsin, in liposomes of opposite charges and varying charge densities and determined the resultant protein orientation. Antibody-binding assay and proteolysis of proteoliposomes showed physical evidence of preferential orientation, and functional assays verified the vectorial nature of ion transport in this system. Our results indicate that the manipulation of lipid composition can indeed control orientation of an asymmetrically charged membrane protein, proteorhodopsin, in liposomes. PMID- 24047991 TI - Real-time visualization of assembling of a sphingomyelin-specific toxin on planar lipid membranes. AB - Pore-forming toxins (PFTs) are soluble proteins that can oligomerize on the cell membrane and induce cell death by membrane insertion. PFT oligomers sometimes form hexagonal close-packed (hcp) structures on the membrane. Here, we show the assembling of the sphingomyelin (SM)-binding PFT, lysenin, into an hcp structure after oligomerization on SM/cholesterol membrane. This process was monitored by high-speed atomic force microscopy. Hcp assembly was driven by reorganization of lysenin oligomers such as association/dissociation and rapid diffusion along the membrane. Besides rapid association/dissociation of oligomers, the height change for some oligomers, possibly resulting from conformational changes in lysenin, could also be visualized. After the entire membrane surface was covered with a well-ordered oligomer lattice, the lysenin molecules were firmly bound on the membrane and the oligomers neither dissociated nor diffused. Our results reveal the dynamic nature of the oligomers of a lipid-binding toxin during the formation of an hcp structure. Visualization of this dynamic process is essential for the elucidation of the assembling mechanism of some PFTs that can form ordered structures on the membrane. PMID- 24047992 TI - Model of a raft in both leaves of an asymmetric lipid bilayer. AB - We present a theory of inhomogeneities in the plasma membrane, or rafts, that can exist in both leaves of the plasma membrane. We note that although neither of the major phospholipid components of the outer leaf, sphingomyelin (SM) nor phosphatidylcholine (PC), evinces a tendency to form phases characterized by nonzero curvature, one of the major components of the inner leaf, phosphatidylethanolamine (PE), displays a strong tendency to do so whereas the other, phosphatidylserine (PS), does not. Therefore, we posit that the concentration difference of PS and PE couples to height fluctuations of the plasma membrane bilayer. This brings about a microemulsion in the inner leaf. Coupling of the concentration difference between PS and PE in the inner leaf and SM and PC in the outer leaf propagates the microemulsion to that leaf as well. The characteristic size of the inhomogeneities is equal to the square-root of the ratio of the bending modulus of the bilayer to its surface tension, a size which is ~100 nm for the plasma membrane. If the coupling between leaves were to be provided by the interchange of cholesterol, then our model raft would consist of SM and cholesterol in the outer leaf and PS and cholesterol in the inner leaf floating in a sea of PC and PE in both leaves. PMID- 24047993 TI - Measuring the lamellarity of giant lipid vesicles with differential interference contrast microscopy. AB - Giant unilamellar vesicles are a widely utilized model membrane system, providing free-standing bilayers unaffected by support-induced artifacts. To measure the lamellarity of such vesicles, fluorescence microscopy is one commonly utilized technique, but it has the inherent disadvantages of requiring lipid staining, thereby affecting the intrinsic physical and chemical properties of the vesicles, and it requires a calibration by statistical analysis of a vesicle ensemble. Herein we present what we believe to be a novel label-free optical method to determine the lamellarity of giant vesicles based on quantitative differential interference contrast (qDIC) microscopy. The method is validated by comparison with fluorescence microscopy on a statistically significant number of vesicles, showing correlated quantization of the lamellarity. Importantly, qDIC requires neither sample-dependent calibration nor sample staining, and thus can measure the lamellarity of any giant vesicle without additional preparation or interference with subsequent investigations. Furthermore, qDIC requires only a microscope equipped with differential interference contrast and a digital camera. PMID- 24047994 TI - Number of sialic acid residues in ganglioside headgroup affects interactions with neighboring lipids. AB - Monolayers of binary mixtures of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and asialo-(GA1), disialo-(GD1b) and trisialo-(GT1b) gangliosides were used to determine the effect of ganglioside headgroup charge and geometry on its interactions with the neighboring zwitterionic lipid. Surface pressure versus molecular area isotherm measurements along with concurrent fluorescence microscopy of the monolayers at the air-water interface were complemented with atomic force microscopy imaging of monolayers deposited on solid substrates. Results were used to further develop a proposed geometric packing model that the complementary geometry of DPPC and monosialoganglioside GM1 headgroups affects their close molecular packing, inducing condensation of the layer at small mol % of ganglioside. For GA1, GD1b, and GT1b, a similar condensing effect, followed by a fluidizing effect is seen that varies with glycosphingolipid concentration, but results do not directly follow from geometric arguments because less DPPC is needed to condense ganglioside molecules with larger cross-sectional areas. The variations in critical packing mole ratios can be explained by global effects of headgroup charge and resultant dipole moments within the monolayer. Atomic force microscopy micrographs further support the model of ganglioside-induced DPPC condensation with condensed domains composed of a striped phase of condensed DPPC and DPPC/ganglioside geometrically packed complexes at low concentrations. PMID- 24047995 TI - Membrane partitioning of the pore-forming domain of colicin A. Role of the hydrophobic helical hairpin. AB - The colicins are bacteriocins that target Escherichia coli and kill bacterial cells through different mechanisms. Colicin A forms ion channels in the inner membranes of nonimmune bacteria. This activity resides exclusively in its C terminal fragment (residues 387-592). The soluble free form of this domain is a 10 alpha-helix bundle. The hydrophobic helical hairpin, H8-H9, is buried inside the structure and shielded by eight amphipathic surface helices. The interaction of the C-terminal colicin A domain and several chimeric variants with lipidic vesicles was examined here by isothermal titration calorimetry. In the mutant constructions, natural sequences of the hydrophobic helices H8 and H9 were either removed or substituted by polyalanine or polyleucine. All the constructions fully associated with DOPG liposomes including the mutant that lacked helices H8 and H9, indicating that amphipathic rather than hydrophobic helices were the major determinants of the exothermic binding reactions. Alanine is not specially favored in the lipid-bound form; the chimeric construct with polyalanine produced lower enthalpy gain. On the other hand, the large negative heat capacities associated with partitioning, a characteristic feature of the hydrophobic effect, were found to be dependent on the sequence hydrophobicity of helices H8 and H9. PMID- 24047996 TI - Molecular dynamics and NMR spectroscopy studies of E. coli lipopolysaccharide structure and dynamics. AB - Lipopolysaccharide (LPS), a component of Gram-negative bacterial outer membranes, comprises three regions: lipid A, core oligosaccharide, and O-antigen polysaccharide. Using the CHARMM36 lipid and carbohydrate force fields, we have constructed a model of an Escherichia coli R1 (core) O6 (antigen) LPS molecule. Several all-atom bilayers are built and simulated with lipid A only (LIPA) and varying lengths of 0 (LPS0), 5 (LPS5), and 10 (LPS10) O6 antigen repeating units; a single unit of O6 antigen contains five sugar residues. From (1)H,(1)H-NOESY experiments, cross-relaxation rates are obtained from an O-antigen polysaccharide sample. Although some experimental deviations are due to spin-diffusion, the remaining effective proton-proton distances show generally very good agreement between NMR experiments and molecular dynamics simulations. The simulation results show that increasing the LPS molecular length has an impact on LPS structure and dynamics and also on LPS bilayer properties. Terminal residues in a LPS bilayer are more flexible and extended along the membrane normal. As the core and O-antigen are added, per-lipid area increases and lipid bilayer order decreases. In addition, results from mixed LPS0/5 and LPS0/10 bilayer simulations show that the LPS O-antigen conformations at a higher concentration of LPS5 and LPS10 are more orthogonal to the membrane and less flexible. The O-antigen concentration of mixed LPS bilayers does not have a significant effect on per lipid area and hydrophobic thickness. Analysis of ion and water penetration shows that water molecules can penetrate inside the inner core region, and hydration is critical to maintain the integrity of the bilayer structure. PMID- 24047997 TI - Spatiotemporal dynamics of actomyosin networks. AB - Rhodamine-phalloidin-labeled actin filaments were visualized gliding over a skeletal heavy meromyosin (HMM)-coated surface. Experiments at low filament densities showed that when two filaments collided, their paths were affected in a manner that depended on collision angle. Some collisions resulted in complete alignment of the filament paths; in others, the filaments crossed over one another. Filament crossover or alignment was equally probable at ~40 degrees contact angle. Filaments often underwent significant bending during collision and analysis of filament shape indicated an energy requirement of ~13 kBT. Experiments were performed over a wide range of HMM surface density and actin filament bulk concentration. Actin filament gliding speed and path persistence plateaued above a critical HMM surface density, and at high (micromolar) actin filament concentrations, filament motion became dramatically aligned in a common direction. Spatiotemporal features of alignment behavior were determined by correlation analysis, supported by simulations. The thermal drift of individual filament tracks was suppressed as the population became more oriented. Spatial correlation analysis revealed that long-range alignment was due to incremental recruitment rather than fusion of locally ordered seed domains. The global alignment of filament movement, described by an "order parameter," peaked at optimal actin concentrations and myosin surface densities, in contrast to previous predictions of a critical phase transition. Either hydrodynamic coupling or exchange of filaments between the surface bound and adjacent bulk phase layers might degrade order at high actin filament concentration, and high HMM surface densities might decrease alignment probability during collisions. Our results are compatible with generation of long-range order from mechanical interaction between individual actin filaments. Furthermore, we show that randomly oriented myosin motors align relatively short, submicrometer actin filaments into motile surface domains that extend over many tens of micrometers and these patterns persist for several minutes. PMID- 24047998 TI - The kinetics of mechanically coupled myosins exhibit group size-dependent regimes. AB - Naturally occurring groups of muscle myosin behave differently from individual myosins or small groups commonly assayed in vitro. Here, we investigate the emergence of myosin group behavior with increasing myosin group size. Assuming the number of myosin binding sites (N) is proportional to actin length (L) (N = L/35.5 nm), we resolve in vitro motility of actin propelled by skeletal muscle myosin for L = 0.2-3 MUm. Three distinct regimes were found: L < 0.3 MUm, sliding arrest; 0.3 MUm <= L <= 1 MUm, alternation between arrest and continuous sliding; L > 1 MUm, continuous sliding. We theoretically investigated the myosin group kinetics with mechanical coupling via actin. We find rapid actin sliding steps driven by power-stroke cascades supported by postpower-stroke myosins, and phases without actin sliding caused by prepower-stroke myosin buildup. The three regimes are explained: N = 8, rare cascades; N = 15, cascade bursts; N = 35, continuous cascading. Two saddle-node bifurcations occur for increasing N (mono -> bi -> mono-stability), with steady states corresponding to arrest and continuous cascading. The experimentally measured dependence of actin sliding statistics on L and myosin concentration is correctly predicted. PMID- 24047999 TI - Von Willlebrand adhesion to surfaces at high shear rates is controlled by long lived bonds. AB - Von Willebrand factor (vWF) adsorbs and immobilizes platelets at sites of injury under high-shear-rate conditions. It has been recently demonstrated that single vWF molecules only adsorb significantly to collagen above a threshold shear, and here we explain such counterintuitive behavior using a coarse-grained simulation and a phenomenological theory. We find that shear-induced adsorption only occurs if the vWF-surface bonds are slip-resistant such that force-induced unbinding is suppressed, which occurs in many biological bonds (i.e., catch bonds). Our results quantitatively match experimental observations and may be important to understand the activation and mechanical regulation of vWF activity during blood clotting. PMID- 24048000 TI - Solvation free energy of the peptide group: its model dependence and implications for the additive-transfer free-energy model of protein stability. AB - The group-additive decomposition of the unfolding free energy of a protein in an osmolyte solution relative to that in water poses a fundamental paradox: whereas the decomposition describes the experimental results rather well, theory suggests that a group-additive decomposition of free energies is, in general, not valid. In a step toward resolving this paradox, here we study the peptide-group transfer free energy. We calculate the vacuum-to-solvent (solvation) free energies of (Gly)n and cyclic diglycine (cGG) and analyze the data according to experimental protocol. The solvation free energies of (Gly)n are linear in n, suggesting group additivity. However, the slope interpreted as the free energy of a peptide unit differs from that for cGG scaled by a factor of half, emphasizing the context dependence of solvation. However, the water-to-osmolyte transfer free energies of the peptide unit are relatively independent of the peptide model, as observed experimentally. To understand these observations, a way to assess the contribution to the solvation free energy of solvent-mediated correlation between distinct groups is developed. We show that linearity of solvation free energy with n is a consequence of uniformity of the correlation contributions, with apparent group-additive behavior in the water-to-osmolyte transfer arising due to their cancellation. Implications for inferring molecular mechanisms of solvent effects on protein stability on the basis of the group-additive transfer model are suggested. PMID- 24048001 TI - Proline substitution of dimer interface beta-strand residues as a strategy for the design of functional monomeric proteins. AB - Proteins that exist in monomer-dimer equilibrium can be found in all organisms ranging from bacteria to humans; this facilitates fine-tuning of activities from signaling to catalysis. However, studying the structural basis of monomer function that naturally exists in monomer-dimer equilibrium is challenging, and most studies to date on designing monomers have focused on disrupting packing or electrostatic interactions that stabilize the dimer interface. In this study, we show that disrupting backbone H-bonding interactions by substituting dimer interface beta-strand residues with proline (Pro) results in fully folded and functional monomers, by exploiting proline's unique feature, the lack of a backbone amide proton. In interleukin-8, we substituted Pro for each of the three residues that form H-bonds across the dimer interface beta-strands. We characterized the structures, dynamics, stability, dimerization state, and activity using NMR, molecular dynamics simulations, fluorescence, and functional assays. Our studies show that a single Pro substitution at the middle of the dimer interface beta-strand is sufficient to generate a fully functional monomer. Interestingly, double Pro substitutions, compared to single Pro substitution, resulted in higher stability without compromising native monomer fold or function. We propose that Pro substitution of interface beta-strand residues is a viable strategy for generating functional monomers of dimeric, and potentially tetrameric and higher-order oligomeric proteins. PMID- 24048002 TI - Molecular recognition of CXCR4 by a dual tropic HIV-1 gp120 V3 loop. AB - HIV-1 cell entry is initiated by the interaction of the viral envelope glycoprotein gp120 with CD4, and chemokine coreceptors CXCR4 and CCR5. The molecular recognition of CXCR4 or CCR5 by the HIV-1 gp120 is mediated through the V3 loop, a fragment of gp120. The binding of the V3 loop to CXCR4 or CCR5 determines the cell tropism of HIV-1 and constitutes a key step before HIV-1 cell entry. Thus, elucidating the molecular recognition of CXCR4 by the V3 loop is important for understanding HIV-1 viral infectivity and tropism, and for the design of HIV-1 inhibitors. We employed a comprehensive set of computational tools, predominantly based on free energy calculations and molecular-dynamics simulations, to investigate the molecular recognition of CXCR4 by a dual tropic V3 loop. We report what is, to our knowledge, the first HIV-1 gp120 V3 loop:CXCR4 complex structure. The computationally derived structure reveals an abundance of polar and nonpolar intermolecular interactions contributing to the HIV-1 gp120:CXCR4 binding. Our results are in remarkable agreement with previous experimental findings. Therefore, this work sheds light on the functional role of HIV-1 gp120 V3 loop and CXCR4 residues associated with HIV-1 coreceptor activity. PMID- 24048003 TI - Short-term desensitization of muscarinic K+ current in the heart. AB - Acetylcholine (ACh) rapidly increases cardiac K(+) currents (IKACh) by activating muscarinic K(+) (KACh) channels followed by a gradual amplitude decrease within seconds. This phenomenon is called short-term desensitization and its precise mechanism and physiological role are still unclear. We constructed a mathematical model for IKACh to examine the conditions required to reconstitute short-term desensitization. Two conditions were crucial: two distinct muscarinic receptors (m2Rs) with different affinities for ACh, which conferred an IKACh response over a wide range of ACh concentrations, and two distinct KACh channels with different affinities for the G-protein betagamma subunits, which contributed to reconstitution of the temporal behavior of IKACh. Under these conditions, the model quantitatively reproduced several unique properties of short-term desensitization observed in myocytes: 1), the peak and quasi-steady states with 0.01-100 MUM [ACh]; 2), effects of ACh preperfusion; and 3), recovery from short term desensitization. In the presence of 10 MUM ACh, the IKACh model conferred recurring spontaneous firing after asystole of 8.9 s and 10.7 s for the Demir and Kurata sinoatrial node models, respectively. Therefore, two different populations of KACh channels and m2Rs may participate in short-term desensitization of IKACh in native myocytes, and may be responsible for vagal escape at nodal cells. PMID- 24048004 TI - Epigenetic memory emerging from integrated transcription bursts. AB - Some autonomous bacteria coordinate their actions using quorum-sensing (QS) signals to affect gene expression. However, noise in the gene environment can compromise the cellular response. By exercising precise control over a cell's genes and its microenvironment, we have studied the key positive autoregulation element by which the lux QS system integrates noisy signals into an epigenetic memory. We observed transcriptional bursting of the lux receptor in cells stimulated by near-threshold levels of QS ligand. The bursts are integrated over time into an epigenetic memory that confers enhanced sensitivity to the ligand. An emergent property of the system is manifested in pattern formation among phenotypes within a chemical gradient. PMID- 24048005 TI - Dynamic transition states of ErbB1 phosphorylation predicted by spatial stochastic modeling. AB - ErbB1 overexpression is strongly linked to carcinogenesis, motivating better understanding of erbB1 dimerization and activation. Recent single-particle tracking data have provided improved measures of dimer lifetimes and strong evidence that transient receptor coconfinement promotes repeated interactions between erbB1 monomers. Here, spatial stochastic simulations explore the potential impact of these parameters on erbB1 phosphorylation kinetics. This rule based mathematical model incorporates structural evidence for conformational flux of the erbB1 extracellular domains, as well as asymmetrical orientation of erbB1 cytoplasmic kinase domains during dimerization. The asymmetric dimer model considers the theoretical consequences of restricted transactivation of erbB1 receptors within a dimer, where the N-lobe of one monomer docks with the C-lobe of the second monomer and triggers its catalytic activity. The dynamic nature of the erbB1 phosphorylation state is shown by monitoring activation states of individual monomers as they diffuse, bind, and rebind after ligand addition. The model reveals the complex interplay between interacting liganded and nonliganded species and the influence of their distribution and abundance within features of the membrane landscape. PMID- 24048006 TI - New clonal strain of Candida auris, Delhi, India. AB - A new clonal strain of Candida auris is an emerging etiologic agent of fungemia in Delhi, India. In 12 patients in 2 hospitals, it was resistant to fluconazole and genotypically distinct from isolates from South Korea and Japan, as revealed by M13 and amplified fragment length polymorphism typing. PMID- 24048009 TI - Incident hypertension and its predictors: the Isfahan Cohort Study. AB - OBJECTIVES: The present study aimed to investigate the incidence and predictors of hypertension in an Iranian adult population. METHODS: Isfahan Cohort Study was a longitudinal population-based study that was conducted on adults aged 35 years or older, living in urban and rural areas of three districts in central Iran. After 7 years of follow-up, 3283 participants were re-evaluated using a standard protocol similar to the baseline. At both measurements, participants underwent medical interview, physical examination, and fasting blood measurements. Participants (n = 833) with prevalent hypertension were excluded from the analysis, resulting in a sample size of 2450. RESULTS: The participants' age was 47.3 +/- 9.4 years (mean +/- SD) and 50.7% were men. During the follow-up period, 542 (22.1%) individuals developed hypertension, 49.6% of whom were aware of their disease, 42.4% were treated, but only 24.9% were controlled. Incidence rates have shown no sex-specific difference across age and blood pressure (BP) categories. Multivariate-adjusted model controlled for all study covariates showed that age, male sex, general and central obesity, hypertriglyceridemia, impaired fasting glucose, diabetes mellitus, baseline BP at least 120/80 mmHg (nonoptimal BP), and parental history of hypertension independently contributed to the development of hypertension. Higher education level and more than 10% decrease in waist circumference over 7-year follow-up represented protective effects. In men, weight loss decreased and weight gain increased the risk of developing hypertension. Nonoptimal BP along with central obesity and hypertriglyceridemia together were responsible for 71% of the burden of hypertension. CONCLUSION: Our findings imply that there are other factors in addition to nonoptimal BP that deserve integrating into the risk assessment criteria for developing hypertension. PMID- 24048008 TI - Mitochondrial targeted peptides attenuate residual myocardial damage after reversal of experimental renovascular hypertension. AB - BACKGROUND: Renovascular hypertension (RVHT) increases cardiovascular morbidity and mortality. Renal revascularization with percutaneous transluminal renal angioplasty and stenting (PTRS) may reverse RVHT but may not fully regress cardiac remodeling and damage, possibly due to persistent myocardial insults. Bendavia is a mitochondrial targeted peptide that reduces ischemic cardiomyopathy by improving mitochondrial function. However, its potential for attenuating residual myocardial damage after reversal of RVHT has not been explored. We hypothesized that treatment with Bendavia as an adjunct to PTRS would improve cardiac function and oxygenation, and decrease myocardial injury in swine RVHT. METHODS AND RESULTS: After 6 weeks of RVHT (unilateral renal artery stenosis) or control, pigs underwent PTRS (or sham), with adjunct continuous infusion of Bendavia (0.05 mg/kg intravenously, 30 min before to 3.5 h after PTRS) or vehicle (n = 7 each). Four weeks later, systolic and diastolic function were assessed by multidetector computed tomography, myocardial oxygenation by blood oxygen level-dependent MRI, and myocardial morphology, apoptosis, mitochondrial biogenesis, and fibrosis evaluated ex vivo. PTRS restored blood pressure in both groups, yet E/A ratio remained decreased. Myocardial oxygenation and mitochondrial biogenesis improved, and myocardial inflammation, oxidative stress, and fibrosis normalized in association with improvement in diastolic function in RVHT + PTRS + Bendavia animals. CONCLUSION: Adjunct Bendavia during PTRS in swine RVHT improved diastolic function and oxygenation and reversed myocardial tissue damage. This approach may allow a novel strategy for preservation of cardiac function and structure in RVHT. PMID- 24048010 TI - Can Coronene and/or Benzo(a)pyrene/Coronene ratio act as unique markers for vehicle emission? AB - Coronene is a high molecular weight polycyclic aromatic hydrocarbon with seven aromatic rings. It, more specifically a lower ratio of Benzo[a]pyrene to Coronone (BaP/COR), is suggested as a marker for vehicle emission. In the present study, emissions of Coronene were measured from residential combustions of wood, crop straw, and pellets. The detection of COR in non-vehicle emission sources, and comparable BaP/COR ratios between the solid fuel combustion and vehicle emissions indicated that the generality of COR or the BaP/COR ratio as markers for the vehicle emission would be questionable, especially for the area where solid fuel combustion dominated the PAHs emission. PMID- 24048011 TI - Neonatal uterine bleeding as antecedent of pelvic endometriosis. AB - We elaborate on a new theory to explain pelvic endometriosis, including endometriosis in premenarcheal girls, based on the finding that the neonatal endometrium can display secretory activity immediately after birth and, in some cases, changes analogous to those seen at menstruation in adults. The neonatal uterus is therefore capable of shedding its endometrium. Indeed, occult vaginal bleeding occurs in a majority of neonates, although overt bleeding is estimated to occur in only 5% of neonates. This may be due to functional plugging of the endocervical canal in the neonate, which in turn would promote retrograde flux of endometrial cells contained in menstrual debris. Ectopic endometrial implantation in a newborn with hydrometrocolpos has been documented. These data, coupled with the observation of a significantly increased risk of endometriosis in adolescents with cervical outflow obstruction and patent Fallopian tubes, indicate that endometriosis, especially in children and young adolescents, may originate from retrograde uterine bleeding soon after birth. PMID- 24048012 TI - Preimplantation genetic diagnosis for X;autosome translocations: lessons from a case of misdiagnosis. AB - Preimplantation genetic diagnosis (PGD) is offered to couples carrying a reciprocal translocation in an attempt to increase their chance of phenotypically normal offspring. For the selection of embryos that are balanced for the translocation chromosomes, it is critical to use a combination of DNA probes that can take account of all the segregation patterns of the particular translocation. The frequency of the different segregation types differs depending on the chromosomes involved, the location of the breakpoints and the number of chiasmata and the sex of the carrier. We report on a case of misdiagnosis after PGD fluorescence in situ hybridization in a female translocation 46,X,t(X;5)(q13;p14) carrier. Transfer of two embryos diagnosed as balanced for the translocation chromosomes resulted in a singleton pregnancy that miscarried at 8 weeks' gestational age. The unbalanced karyotype of the fetus was consistent with 3:1 segregation resulting in tertiary trisomy for the derivative chromosome 5: 47,XX,+der(5)t(X;5)(q13;p14)mat. Based on additional molecular cytogenetic studies of fetal tissue and the initially investigated blastomeres, we concluded that the misdiagnosis was most probably due to a technical error, i.e. a partial hybridization failure or co-localization of the Xq/Yq subtelomere probe signals. No evidence for a normal cell line (mosaicism) was found in the fetus, which could have explained the discrepancy. This case demonstrates the importance of using two diagnostic probes or testing 2 cells to detect translocation products with potentially viable imbalance. X;autosome translocations are a special case due to the added complication of X chromosome inactivation and particular caution is advised when designing a PGD strategy. TRIAL REGISTRATION NUMBER: not applicable. PMID- 24048013 TI - The sexual attraction toward disabilities: a preliminary internet-based study. AB - Devotism, defined as sexual attraction toward disabilities, has not undergone extensive study. To verify whether devotees have characteristics suggestive of a paraphilic behavior, an ad hoc internet questionnaire was developed to study a population of 209 subjects enrolled from online devotee communities. With respect to the sexual preference, we observe a first population comprising subjects sexually attracted by disability per se and considers it as an erotic object. In the absence of disability, this group is also unable to become sexually aroused and experiences discomfort due to their condition. The second subpopulation comprises subjects attracted by specific characteristics of people with disabilities such as adaptability, fortitude, courage and ability to overcome obstacles. This group experiences low levels of discomfort for their sexual preference. Further studies will be necessary to confirm these data. PMID- 24048014 TI - Augmented active surface model for the recovery of small structures in CT. AB - This paper devises an augmented active surface model for the recovery of small structures in a low resolution and high noise setting, where the role of regularization is especially important. The emphasis here is on evaluating performance using real clinical computed tomography (CT) data with comparisons made to an objective ground truth acquired using micro-CT. In this paper, we show that the application of conventional active contour methods to small objects leads to non-optimal results because of the inherent properties of the energy terms and their interactions with one another. We show that the blind use of a gradient magnitude based energy performs poorly at these object scales and that the point spread function (PSF) is a critical factor that needs to be accounted for. We propose a new model that augments the external energy with prior knowledge by incorporating the PSF and the assumption of reasonably constant underlying CT numbers. PMID- 24048015 TI - Efficient reconstruction of all-in-focus images through shifted pinholes from multi-focus images for dense light field synthesis and rendering. AB - Scene refocusing beyond extended depth of field for users to observe objects effectively is aimed by researchers in computational photography, microscopic imaging, and so on. Ordinary all-in-focus image reconstruction from a sequence of multi-focus images achieves extended depth of field, where reconstructed images would be captured through a pinhole in the center on the lens. In this paper, we propose a novel method for reconstructing all-in-focus images through shifted pinholes on the lens based on 3D frequency analysis of multi-focus images. Such shifted pinhole images are obtained by a linear combination of multi-focus images with scene-independent 2D filters in the frequency domain. The proposed method enables us to efficiently synthesize dense 4D light field on the lens plane for image-based rendering, especially, robust scene refocusing with arbitrary bokeh. Our novel method using simple linear filters achieves not only reconstruction of all-in-focus images even for shifted pinholes more robustly than the conventional methods depending on scene/focus estimation, but also scene refocusing without suffering from limitation of resolution in comparison with recent approaches using special devices such as lens arrays in computational photography. PMID- 24048016 TI - Antibody responses against Pneumocystis jirovecii in health care workers over time. AB - In a previous cross-sectional study, we showed that clinical staff working in a hospital had significantly higher antibody levels than nonclinical staff to Pneumocystis jirovecii. We conducted a longitudinal study, described here, to determine whether occupation and self-reported exposure to a patient with P. jirovecii pneumonia were associated with antibody levels to P. jirovecii over time. Baseline and quarterly serum specimens were collected and analyzed by using an ELISA that targeted different variants of the Pneumocystis major surface glycoprotein (MsgA, MsgB, MsgC1, MsgC3, MsgC8, and MsgC9). Clinical staff had significantly higher estimated geometric mean antibody levels against MsgC1 and MsgC8 than did nonclinical staff over time. Significant differences were observed when we compared the change in antibody levels to the different MsgC variants for staff who were and were not exposed to P. jirovecii pneumonia-infected patients. MsgC variants may serve as indicators of exposure to P. jirovecii in immunocompetent persons. PMID- 24048017 TI - Oxygenation and ventilation characteristics in obese sedated dogs before and after weight loss: a clinical trial. AB - This prospective clinical study examined the effect of obesity and subsequent weight loss on oxygenation and ventilation during deep sedation in pet dogs. Data from nine dogs completing a formalised weight loss programme were evaluated. Dual energy X-ray absorptiometry (DEXA) was used to quantify body fat mass prior to and after weight loss. Dogs were deeply sedated and positioned in dorsal recumbency. Sedation was scored using a semi-objective scheme. As part of the monitoring of sedation, arterial oxygen partial pressure (PaO2) and arterial carbon dioxide partial pressure (PaCO2) were measured after 10 min in dorsal recumbency. Oxygen saturation of haemoglobin (SpO2) was monitored continuously using pulse oximetry, starting oxygen supplementation where indicated (SpO2<90%) via a face mask. Morphometric measurements were taken from DEXA images and compared before and after weight loss. Several oxygen indices were calculated and correlated with body fat variables evaluated by DEXA. All body fat variables improved significantly after weight loss. PaO2 increased from 27.9+/-19.2 kPa to 34.8+/-24.4 kPa, while FiO2 decreased from 0.74+/-0.31 to 0.66+/-0.35. Morphometric measurements improved significantly after weight loss. PaO2/FiO2 (inspired oxygen fraction) and Pa/AO2 (ratio of PaO2 to alveolar PO2) also improved significantly, but there was no change in f-shunt and PaCO2 after weight loss. On multiple linear regression analysis, all oxygen indices were negatively associated with thoracic fat percentage. In conclusion, obesity decreases oxygenation in dogs during deep sedation. Oxygenation status improves with successful weight loss, but ventilation is not influenced by obesity. PMID- 24048018 TI - Montelukast is as effective as penicillin in treatment of acute otitis media: an experimental rat study. AB - BACKGROUND: Leukotrienes are the major factors in the formation of edema and mucus, as well as development of tuba Eustachii dysfunction in acute otitis media. We developed an experimental acute suppurative otitis media model and compared the responses of rats to penicillin and combinations of leukotriene antagonist with respect to histopathological observations conducted in early and late phases. MATERIAL AND METHODS: A total of 83 ears from 56 Wistar rats were used in this study. Pneumococcus suspension was injected trans-tympanically into all rats. Subjects were classified into 4 different groups with 14 rats in each. In Group A, intramuscular penicillin G was injected for a period of 5 days. In Group B, intraperitoneal montelukast was injected for 21 days in addition to penicillin. In Group C, intraperitoneal montelukast isotonic NaCl in Group D was injected into rats for 21 days. RESULTS: No significant difference was found between the groups, except for mucosal vascularization with respect to mucosal and TM parameters in early phases. Furthermore, considerable deviations were observed for the recuperation of TM and mucosal inflammation for groups in which subjects were injected with montelukast as compared to other groups of the study in the late phases. CONCLUSIONS: When the parameters of inflammation in the rat middle ear were compared with each other, most of these parameters did not show any statistically significant beneficial effects in montelukast and penicillin groups. PMID- 24048019 TI - Targeting transcription factors: promising new strategies for cancer therapy. AB - PURPOSE OF REVIEW: A lack of effective treatments for advanced cancer remains a major challenge in oncology. Because cancer is a disease associated with aberrant gene expression patterns, transcription factors, which serve as the convergence points of oncogenic signaling and are functionally altered in many cancers, hold great therapeutic promise. RECENT FINDINGS: Many human cancers are dependent on the inappropriate activity of oncogenic transcription factors. By contrast, normal cells can often tolerate disruption of these proteins with little toxicity. Direct inhibition of transcription factor expression (e.g., with RNA interference or microRNAs) and DNA binding (e.g., with oligodeoxynucleotide decoys or pyrrole-imidazole polyamides) has demonstrated antitumor responses with minimal side-effects. New strategies of targeting transcription factors include disrupting critical protein-protein interactions, and restricting binding at the epigenetic level by modulating chromatin accessibility. Moreover, targeting transcription factors in tumor-associated immune cells has the potential to overcome tumor immunoresistance. SUMMARY: Transcription factors are an important target for cancer therapy, both through direct anticancer effects and immunomodulatory actions. Newly developed delivery systems that specifically target tumor cells also create opportunities for successes in targeting transcription in cancer. PMID- 24048021 TI - Comparative sensitivity to the fungicide tebuconazole of biofilm and plankton microbial communities in freshwater ecosystems. AB - Stream and lake ecosystems in agricultural watersheds are exposed to fungicide inputs that can threaten the structure and functioning of aquatic microbial communities. This research analyzes the impact of the triazole fungicide tebuconazole (TBZ) on natural biofilm and plankton microbial communities from sites presenting different degrees of agricultural contamination. Biofilm and plankton communities from less-polluted (LP) and polluted (P) sites were exposed to nominal concentrations of 0 (control), 2 and 20 MUg TBZ L(-1) in 3-week microcosm experiments. Descriptors of microbial community structure (bacterial density and chlorophyll-a concentration) and function (bacterial respiration and production and photosynthesis) were analyzed to chart the effects of TBZ and the kinetics of TBZ attenuation in water during the experiments. The results showed TBZ-induced effects on biofilm function (inhibition of substrate-induced respiration and photosynthetic activity), especially in LP-site communities, whereas plankton communities experienced a transitory stimulation of bacterial densities in communities from both LP and P sites. TBZ attenuation was stronger in biofilm (60-75%) than plankton (15-18%) experiments, probably due to greater adsorption on biofilms. The differences between biofilm and plankton responses to TBZ were likely explained by differences in community structure (presence of extracellular polymeric substances (EPS) matrix) and microbial composition. Biofilm communities also exhibited different sensitivity levels according to their in-field pre-exposure to fungicide, with P-site communities demonstrating adaptation capacities to TBZ. This study indicates that TBZ toxicity to non targeted aquatic microbial communities essentially composed by microalgae and bacteria was moderate, and that its effects varied between stream and lake microbial communities. PMID- 24048022 TI - Risk perception, trust, and factors related to a planned new nuclear power plant in Taiwan after the 2011 Fukushima disaster. AB - After the Fukushima nuclear disaster in March 2011, an international review of nuclear safety indicated that two of the three nuclear power plants (NPPs) operating in Taiwan were listed as the most dangerous in the world. To understand the perception of NPP risks by the public in Taiwan and their attitudes regarding a planned fourth NPP after the Fukushima nuclear incident in 2011, a study was conducted in August 2011. A sample of 2819 individuals responded to the survey, with 66% perceiving that Taiwan's safety management of NPPs was inferior to Japan's, while 40% perceived a higher possibility of nuclear accidents like that in Japan. On average, a 'safe' distance of 94 km from an NPP was expected. 56% opposed the planned fourth NPP, with females (adjusted odd ratios (aOR) 2.03; 95% confidence interval (CI) 1.71-2.41), residence near the planned fourth NPP (aOR/CI 13.90/7.79-24.80), distrust of safety management (aOR/CI 1.98/1.45-2.69) and emergency planning (aOR/CI 1.89/1.49-2.40) as the main determinants. Others included those who expected larger safe distances from an NPP (trend test, p < 0.001), perceived excess cancer risks of living within 30 km of an NPP (aOR/CI 2.74/2.02-3.71), and projection of no electric shortage without NPPs (aOR/CI 1.93/1.50-2.49). Given that Taiwan's large population lives close to the existing NPPs and long-term concerns about the safety of these nuclear plants, the Fukushima incident in Japan likely augmented public risk perceptions on nuclear power in general and on the planned fourth NPP. PMID- 24048020 TI - Metabolic regulation of Sirtuins upon fasting and the implication for cancer. AB - PURPOSE OF REVIEW: The purpose of this review is to highlight recent studies on mammalian sirtuins that coordinately regulate cellular metabolic homeostasis upon fasting and to summarize the beneficial effects of fasting on carcinogenesis and cancer therapy. RECENT FINDINGS: Recent studies have demonstrated that fasting may protect normal cells and mice from the metabolic conditions that are harmful as well as decrease the incidence of carcinogenesis. Fasting could also slow the tumor growth and augment the efficacy of certain systemic agents/chemotherapy drugs in various cancers. The mechanism behind this proposed idea may be due to, at least in some part, the metabolic regulation by Sirtuin family proteins whose functions are involved in specific aspects of longevity, stress response and metabolism. Sirtuins, particularly SIRT1 and SIRT3, can be activated by fasting and further exhibit their effects in insulin response, antioxidant defense, and glycolysis. Therefore, sirtuins may have anticancer effects by shifting metabolism to a less proliferative cell phenotype as well as less prone to oxidative stress attack. SUMMARY: The in-depth understanding of the essential role of sirtuins in fasting process may have significant implications in developing a new metabolic diagram of cancer prevention or treatment. PMID- 24048023 TI - Transapical closure of paraprosthetic mitral leak in a patient with inferior vena cava interruption and azygos continuation. AB - Para-valvular leaks represent a relevant post-operative complication of cardiac valve replacement, often causing heart failure or severe hemolysis. We report a case of a 72 year-old woman with aortic and mitral mechanical prostheses who developed hemolytic anemia because of a para-prosthetic mitral leak. Chest tomography in such patient unexpectedly documented inferior vena cava interruption with azygos continuation into superior vena cava. Given the high surgical risk, the venous anomaly and the presence of the aortic valve prosthesis, transcatheter leak closure via antero-lateral mini-thoracotomy and transapical approach was performed. PMID- 24048024 TI - 'Leptorapide' - a one-step assay for rapid diagnosis of human leptospirosis. AB - SUMMARY: Leptospirosis is a globally important zoonotic infection caused by spirochaetes of the genus Leptospira. It is transmitted to humans by direct contact with infected animals or indirectly via contaminated water. It is mainly a problem of the resource-poor developing countries of the tropical and sub tropical regions of the world but outbreaks due to an increase in travel and recreational activities have been reported in developed and more industrialized areas of the world. Current methods of diagnosis are costly, time-consuming and require the use of specialized laboratory equipment and personnel. The purpose of this paper is to report the validation of the 'Leptorapide(r)' test (Linnodee Ltd, Northern Ireland) for the diagnosis of human leptospirosis. It is a simple one-step latex agglutination assay performed using equal volumes of serum sample and antigen-bound latex beads. Evidence of leptospiral antibodies is determined within minutes. Agglutination is scored on a scale of 1-5 and the results interpreted using a score card provided with the kit. Validation has been performed with a large sample size obtained from individuals originating from various parts of the world including Brazil and India. The test has shown sensitivity and specificity values of 97.1% and 94.0%, respectively, relative to the microscopic agglutination test. The results demonstrate that Leptorapide offers a cost-effective and accurate alternative to the more historical methods of antibody detection. PMID- 24048025 TI - Structure of a helicase-helicase loader complex reveals insights into the mechanism of bacterial primosome assembly. AB - During the assembly of the bacterial loader-dependent primosome, helicase loader proteins bind to the hexameric helicase ring, deliver it onto the oriC DNA and then dissociate from the complex. Here, to provide a better understanding of this key process, we report the crystal structure of the ~570-kDa prepriming complex between the Bacillus subtilis loader protein and the Bacillus stearothermophilus helicase, as well as the helicase-binding domain of primase with a molar ratio of 6:6:3 at 7.5 A resolution. The overall architecture of the complex exhibits a three-layered ring conformation. Moreover, the structure combined with the proposed model suggests that the shift from the 'open-ring' to the 'open-spiral' and then the 'closed-spiral' state of the helicase ring due to the binding of single-stranded DNA may be the cause of the loader release. PMID- 24048026 TI - Predicting the likelihood of additional lymph node metastasis in sentinel lymph node positive breast cancer: validation of the Memorial Sloan-Kettering Cancer Centre (MSKCC) nomogram. AB - AIM: To identify important clinicopathological parameters that are most helpful in predicting additional non-sentinel lymph node (SLN) metastasis among patients with a positive SLN biopsy in the Singapore breast cancer population. METHODS: A total of 1409 patients who underwent SLN biopsy were reviewed over a 5 year period from July 2004 to October 2009. A Singapore General Hospital (SGH) nomogram was developed from predictors in the Memorial Sloan-Kettering Cancer Centre (MSKCC) nomogram using 266 patients with primary invasive breast cancer and a positive SLN biopsy who subsequently had an axillary lymph node dissection. The SGH nomogram was calibrated using bootstrapped data, while the MSKCC nomogram was calibrated using SGH data. The performance of these two nomograms was compared with the calculation of the area under the receiver-operator characteristics curve and adequacy indices. RESULTS: The MSKCC nomogram achieved an area under the curve (AUC) of 0.716 (range 0.653-0.779) in our study population, while the SGH nomogram, which used only three pathological parameters, lymphovascular invasion, number of positive and negative SLN biopsies, achieved an AUC of 0.750 (range 0.691-0.808). The SGH nomogram with a higher adequacy index (0.969) provided better estimates compared with the MSKCC nomogram (0.689). CONCLUSIONS: The use of the MSKCC nomogram was validated in our local patient population. The SGH nomogram showed promise to be equally, if not, more predictive as a model in our own population, while using only three pathological parameters. PMID- 24048027 TI - Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6. AB - Glucagon-like peptide 1 (GLP-1), produced in the intestine and the brain, can stimulate insulin secretion from the pancreas and alleviate type 2 diabetes. The cytokine interleukin-6 (IL-6) may enhance insulin secretion from beta-cells by stimulating peripheral GLP-1 production. GLP-1 and its analogs also reduce food intake and body weight, clinically beneficial actions that are likely exerted at the level of the CNS, but otherwise are poorly understood. The cytokines IL-6 and interleukin 1beta (IL-1beta) may exert an anti-obesity effect in the CNS during health. Here we found that central injection of a clinically used GLP-1 receptor agonist, exendin-4, potently increased the expression of IL-6 in the hypothalamus (11-fold) and the hindbrain (4-fold) and of IL-1beta in the hypothalamus, without changing the expression of other inflammation-associated genes. Furthermore, hypothalamic and hindbrain interleukin-associated intracellular signals [phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and suppressor of cytokine signaling-1 (SOCS1)] were also elevated by exendin-4. Pharmacologic disruption of CNS IL-1 receptor or IL-6 biological activity attenuated anorexia and body weight loss induced by central exendin-4 administration in a rat. Simultaneous blockade of IL-1 and IL-6 activity led to a more potent attenuation of exendin-4 effects on food intake. Mice with global IL 1 receptor gene knockout or central IL-6 receptor knockdown showed attenuated decrease in food intake and body weight in response to peripheral exendin-4 treatment. GLP-1 receptor activation in the mouse neuronal Neuro2A cell line also resulted in increased IL-6 expression. These data outline a previously unidentified role of the central IL-1 and IL-6 in mediating the anorexic and body weight loss effects of GLP-1 receptor activation. PMID- 24048028 TI - Unique role for translation initiation factor 3 in the light color regulation of photosynthetic gene expression. AB - Light-harvesting antennae are critical for collecting energy from sunlight and providing it to photosynthetic reaction centers. Their abundance and composition are tightly regulated to maintain efficient photosynthesis in changing light conditions. Many cyanobacteria alter their light-harvesting antennae in response to changes in ambient light-color conditions through the process of chromatic acclimation. The control of green light induction (Cgi) pathway is a light-color sensing system that controls the expression of photosynthetic genes during chromatic acclimation, and while some evidence suggests that it operates via transcription attenuation, the components of this pathway have not been identified. We provide evidence that translation initiation factor 3 (IF3), an essential component of the prokaryotic translation initiation machinery that binds the 30S subunit and blocks premature association with the 50S subunit, is part of the control of green light induction pathway. Light regulation of gene expression has not been previously described for any translation initiation factor. Surprisingly, deletion of the IF3-encoding gene infCa was not lethal in the filamentous cyanobacterium Fremyella diplosiphon, and its genome was found to contain a second, redundant, highly divergent infC gene which, when deleted, had no effect on photosynthetic gene expression. Either gene could complement an Escherichia coli infC mutant and thus both encode bona fide IF3s. Analysis of prokaryotic and eukaryotic genome databases established that multiple infC genes are present in the genomes of diverse groups of bacteria and land plants, most of which do not undergo chromatic acclimation. This suggests that IF3 may have repeatedly evolved important roles in the regulation of gene expression in both prokaryotes and eukaryotes. PMID- 24048029 TI - X-ray analysis of butirosin biosynthetic enzyme BtrN redefines structural motifs for AdoMet radical chemistry. AB - The 2-deoxy-scyllo-inosamine (DOIA) dehydrogenases are key enzymes in the biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics. In contrast to most DOIA dehydrogenases, which are NAD-dependent, the DOIA dehydrogenase from Bacillus circulans (BtrN) is an S-adenosyl-l-methionine (AdoMet) radical enzyme. To examine how BtrN employs AdoMet radical chemistry, we have determined its structure with AdoMet and substrate to 1.56 A resolution. We find a previously undescribed modification to the core AdoMet radical fold: instead of the canonical (beta/alpha)6 architecture, BtrN displays a (beta5/alpha4) motif. We further find that an auxiliary [4Fe-4S] cluster in BtrN, thought to bind substrate, is instead implicated in substrate-radical oxidation. High structural homology in the auxiliary cluster binding region between BtrN, fellow AdoMet radical dehydrogenase anSME, and molybdenum cofactor biosynthetic enzyme MoaA provides support for the establishment of an AdoMet radical structural motif that is likely common to ~6,400 uncharacterized AdoMet radical enzymes. PMID- 24048030 TI - Perceptuo-motor, cognitive, and description-based decision-making seem equally good. AB - Classical studies suggest that high-level cognitive decisions (e.g., choosing between financial options) are suboptimal. In contrast, low-level decisions (e.g., choosing where to put your feet on a rocky ridge) appear near-optimal: the perception-cognition gap. Moreover, in classical tasks, people appear to put too much weight on unlikely events. In contrast, when people can learn through experience, they appear to put too little weight on unlikely events: the description-experience gap. We eliminated confounding factors and, contrary to what is commonly believed, found results suggesting that (i) the perception cognition gap is illusory and due to differences in the way performance is assessed; (ii) the description-experience gap arises from the assumption that objective probabilities match subjective ones; (iii) people's ability to make decisions is better than the classical literature suggests; and (iv) differences between decision-makers are more important for predicting peoples' choices than differences between choice tasks. PMID- 24048031 TI - Usefulness of the SYNTAX and clinical SYNTAX scores in predicting clinical outcome after unrestricted use of sirolimus- and everolimus-eluting Stents. AB - BACKGROUND: The SYNTAX score (SS) and clinical SS (cSS) can assess coronary lesion complexity and are useful indices in predicting outcomes after percutaneous coronary intervention. However, their validity has not been fully investigated in daily practice where "limus"-eluting stents are used. METHODS AND RESULTS: The SS and cSS were independently assessed from the Efficacy of Xience/Promus vs. Cypher in rEducing Late Loss after stENTing (EXCELLENT) registry, together with the 1-year patient-oriented composite endpoint (POCE; all cause death, any myocardial infarction (MI), and any revascularization) and target-lesion failure (TLF; cardiac death, target-vessel MI, and target-lesion revascularization). Among 5,102 patients, tertiles for SS were defined as low-SS <8, 8<=mid-SS<=16, high-SS >16. Both POCE (4.2% vs. 7.7% vs. 12.2%, P<0.001) and TLF (1.6% vs. 2.4% vs. 4.5%, P<0.001) increased significantly with increasing SS tertile, and SS was an independent predictor of POCE (P<0.001 for trend) and TLF (P=0.023 for trend) in multivariate analysis. The predictability of SS and cSS was similar for POCE (area under the curve (AUC): 0.635 vs. 0.629, P=0.599), whereas SS was superior in predicting restenosis-related outcomes such as revascularization (AUC: 0.624 vs. 0.577, P<0.001) and cSS was superior in other components such as death (AUC: 0.654 vs. 0.795, P<0.001). CONCLUSIONS: Both SS and cSS were applicable to unrestricted use of "limus"-eluting stents in predicting the risk of 1-year clinical outcomes. PMID- 24048032 TI - Algorithm for the prophylaxis of septic complications in orthopedics and traumatology of locomotor system at the Department of Orthopedics at the Postgraduate Medical Education Center in Otwock. AB - Current state of knowledge in a matter of septic complications after procedures with orthopaedic device implantation with particular consideration of THA and TKA is presented in the paper. Implant biocompatibility phenomenon as well as systemic reaction to its presence is also discussed. Algorithm for prophylactics of septic complications followed in Orthopaedic Department of PMEC in Otwock is introduced. Article is based on clinical observations of Orthopaedic Department's PMEC team. PMID- 24048033 TI - The Himalayas must be protected. PMID- 24048044 TI - Germany hits science high. PMID- 24048047 TI - Israel in deadlock on Horizon 2020. PMID- 24048046 TI - ALMA strike stirs up Chilean labour unions. PMID- 24048045 TI - Grass gets greener. PMID- 24048049 TI - Global warming: Outlook for Earth. PMID- 24048048 TI - Progress stalled on coronavirus. PMID- 24048050 TI - Climate assessments: 25 years of the IPCC. PMID- 24048051 TI - Climate science: Rising tide. PMID- 24048056 TI - Online education: E-learning booster in developing world. PMID- 24048052 TI - IPCC: The climate chairman. PMID- 24048057 TI - Ecuador: Yasuni oil plans call for vigilance. PMID- 24048058 TI - Enterobacteria: Ban resistant strains from food chain. PMID- 24048059 TI - Research: Boycott challenges research tactics. PMID- 24048060 TI - Climate science: The cause of the pause. PMID- 24048061 TI - Oceanography: Mountain waves in the deep ocean. PMID- 24048062 TI - Parasitology: Molecular one-upmanship. PMID- 24048064 TI - Tumour heterogeneity. PMID- 24048065 TI - Tumour heterogeneity and cancer cell plasticity. AB - Phenotypic and functional heterogeneity arise among cancer cells within the same tumour as a consequence of genetic change, environmental differences and reversible changes in cell properties. Some cancers also contain a hierarchy in which tumorigenic cancer stem cells differentiate into non-tumorigenic progeny. However, it remains unclear what fraction of cancers follow the stem-cell model and what clinical behaviours the model explains. Studies using lineage tracing and deep sequencing could have implications for the cancer stem-cell model and may help to determine the extent to which it accounts for therapy resistance and disease progression. PMID- 24048066 TI - The causes and consequences of genetic heterogeneity in cancer evolution. AB - Recent studies have revealed extensive genetic diversity both between and within tumours. This heterogeneity affects key cancer pathways, driving phenotypic variation, and poses a significant challenge to personalized cancer medicine. A major cause of genetic heterogeneity in cancer is genomic instability. This instability leads to an increased mutation rate and can shape the evolution of the cancer genome through a plethora of mechanisms. By understanding these mechanisms we can gain insight into the common pathways of tumour evolution that could support the development of future therapeutic strategies. PMID- 24048067 TI - Influence of tumour micro-environment heterogeneity on therapeutic response. AB - Tumour formation involves the co-evolution of neoplastic cells together with extracellular matrix, tumour vasculature and immune cells. Successful outgrowth of tumours and eventual metastasis is not determined solely by genetic alterations in tumour cells, but also by the fitness advantage such mutations confer in a given environment. As fitness is context dependent, evaluating tumours as complete organs, and not simply as masses of transformed epithelial cells, becomes paramount. The dynamic tumour topography varies drastically even throughout the same lesion. Heterologous cell types within tumours can actively influence therapeutic response and shape resistance. PMID- 24048068 TI - Tumour heterogeneity in the clinic. AB - Recent therapeutic advances in oncology have been driven by the identification of tumour genotype variations between patients, called interpatient heterogeneity, that predict the response of patients to targeted treatments. Subpopulations of cancer cells with unique genomes in the same patient may exist across different geographical regions of a tumour or evolve over time, called intratumour heterogeneity. Sequencing technologies can be used to characterize intratumour heterogeneity at diagnosis, monitor clonal dynamics during treatment and identify the emergence of clinical resistance during disease progression. Genetic interpatient and intratumour heterogeneity can pose challenges for the design of clinical trials that use these data. PMID- 24048070 TI - Rapid cross-density ocean mixing at mid-depths in the Drake Passage measured by tracer release. AB - Diapycnal mixing (across density surfaces) is an important process in the global ocean overturning circulation. Mixing in the interior of most of the ocean, however, is thought to have a magnitude just one-tenth of that required to close the global circulation by the downward mixing of less dense waters. Some of this deficit is made up by intense near-bottom mixing occurring in restricted 'hot spots' associated with rough ocean-floor topography, but it is not clear whether the waters at mid-depth, 1,000 to 3,000 metres, are returned to the surface by cross-density mixing or by along-density flows. Here we show that diapycnal mixing of mid-depth (~1,500 metres) waters undergoes a sustained 20-fold increase as the Antarctic Circumpolar Current flows through the Drake Passage, between the southern tip of South America and Antarctica. Our results are based on an open ocean tracer release of trifluoromethyl sulphur pentafluoride. We ascribe the increased mixing to turbulence generated by the deep-reaching Antarctic Circumpolar Current as it flows over rough bottom topography in the Drake Passage. Scaled to the entire circumpolar current, the mixing we observe is compatible with there being a southern component to the global overturning in which about 20 sverdrups (1 Sv = 10(6) m(3) s(-1)) upwell in the Southern Ocean, with cross-density mixing contributing a significant fraction (20 to 30 per cent) of this total, and the remainder upwelling along constant-density surfaces. The great majority of the diapycnal flux is the result of interaction with restricted regions of rough ocean-floor topography. PMID- 24048069 TI - Selection and adaptation during metastatic cancer progression. AB - Cancer is often regarded as a process of asexual evolution driven by genomic and genetic instability. Mutation, selection and adaptation are by convention thought to occur primarily within, and to a lesser degree outside, the primary tumour. However, disseminated cancer cells that remain after 'curative' surgery exhibit extreme genomic heterogeneity before the manifestation of metastasis. This heterogeneity is later reduced by selected clonal expansion, suggesting that the disseminated cells had yet to acquire key traits of fully malignant cells. Abrogation of the cells' progression outside the primary tumour implies new challenges and opportunities for diagnosis and adjuvant therapies. PMID- 24048073 TI - Developing an early sepsis alert program. AB - Severe sepsis and septic shock are major health care problems affecting millions of people around the world each year. To aid in early identification and treatment of patients with sepsis, one Midwestern health care system has developed and implemented a computer-assisted sepsis alert system. Despite some limitations, the program has been moderately successful in identifying patients whose condition is declining, and it is having an overall positive effect on patient care. Program modifications continue with experience. PMID- 24048072 TI - Early-light embryonic stimulation suggests a second route, via gene activation, to cerebral lateralization in vertebrates. AB - Genetic factors determine the asymmetrical position of vertebrate embryos allowing asymmetric environmental stimulation to shape cerebral lateralization. In birds, late-light stimulation, just before hatching, on the right optic nerve triggers anatomical and functional cerebral asymmetries. However, some brain asymmetries develop in absence of embryonic light stimulation. Furthermore, early light action affects lateralization in the transparent zebrafish embryos before their visual system is functional. Here we investigated whether another pathway intervenes in establishing brain specialization. We exposed chicks' embryos to light before their visual system was formed. We observed that such early stimulation modulates cerebral lateralization in a comparable vein of late-light stimulation on active retinal cells. Our results show that, in a higher vertebrate brain, a second route, likely affecting the genetic expression of photosensitive regions, acts before the development of a functional visual system. More than one sensitive period seems thus available to light stimulation to trigger brain lateralization. PMID- 24048074 TI - Hybrid reactor based on combined cavitation and ozonation: from concept to practical reality. AB - The present work gives an in depth discussion related to the development of a hybrid advanced oxidation reactor, which can be effectively used for the treatment of various types of water. The reactor is based on the principle of intensifying degradation/disinfection using a combination of hydrodynamic cavitation, acoustic cavitation, ozone injection and electrochemical oxidation/precipitation. Theoretical studies have been presented to highlight the uniform distribution of the cavitational activity and enhanced generation of hydroxyl radicals in the cavitation zone, as well as higher turbulence in the main reactor zone. The combination of these different oxidation technologies have been shown to result in enhanced water treatment ability, which can be attributed to the enhanced generation of hydroxyl radicals, enhanced contact of ozone and contaminants, and the elimination of mass transfer resistances during electrochemical oxidation/precipitation. Compared to the use of individual approaches, the hybrid reactor is expected to intensify the treatment process by 5-20 times, depending on the application in question, which can be confirmed based on the literature illustrations. Also, the use of Ozonix(r) has been successfully proven while processing recycled fluids at commercial sites on over 750 oil and natural gas wells during hydraulic operations around the United States. The superiority of the hybrid process over conventional chemical treatments in terms of bacteria and scale reduction as well as increased water flowability and better chemical compatibility, which is a key requirement for oil and gas applications, has been established. PMID- 24048075 TI - Design of a fluidic circuit-based microcytometer for circulating tumor cell detection and enumeration. AB - Portable devices have been introduced to provide companion diagnostics in many applications such as personalized healthcare monitoring since several decades ago. Recently the polydimethylsiloxane (PDMS)-based microfluidic chip enables a cost effective platform for point of care diagnostics. In this paper, we present a systematic theoretical and experimental study of a novel fluidic circuit-based microcytometer. The working principle of this device is based on the characterization of the bandwidth and amplitude of the bias-voltage pulses induced by the microparticle's physical blockage of the sensing aperture. In the simulation, the amplitude and bandwidth of the bias voltage change is simply related to the microparticle translocation time and resistance change in the sensing aperture. In the modeling part, we simulate the two parameters (peak and translocation time) by considering 7 MUm and 16 MUm, which is used to approximately characterize the Red Blood Cells (RBCs) and Circulating Tumor Cells (CTCs). In the experimental setup, microparticles of different sizes are used to demonstrate the chip performance. Furthermore, RBCs and CTCs are detected and enumerated by the proposed chip. The microcytometry chip is presented and is expected toward the point of care clinical diagnostics. PMID- 24048076 TI - Effectivity of fluoride treatment on hydrogen and corrosion product generation in temporal implants for different magnesium alloys. AB - The increasing interest on magnesium alloys relies on their biocompatibility, bioabsorbility and especially on their mechanical properties. Due to these characteristics, magnesium alloys are becoming a promising solution to be used, as temporary implants. However, magnesium alloys must overcome their poor corrosion resistance. This article analyses the corrosion behaviour in phosphate buffered saline solution of three commercial magnesium alloys (AZ31B, WE43 and ZM21) as well as the influence of fluoride treatment on their corrosion behaviour. It is shown that the corrosion rate of all the alloys is decreased by fluoride treatment. However, fluoride treatment affects each alloy differently. PMID- 24048077 TI - A review of force and resonance sensors used in the clinical study of tissue properties. AB - Tactile sensing is commonly carried out by humans using their fingers or hands to estimate the physical properties of an object. A large body of literature covers a range of applications of these methods in clinical situations. The objective of this work is to show the breadth of application areas explored and the achievements that have been made in the measurement of physical variables of interest to physicians using tactile force and resonance sensors. Although a broad spectrum of applications has been considered, of particular interest is the application of these methods to determine tissue properties in vivo. Progress in this direction has been made by various groups particularly with respect to piezoelectric and capacitance sensors. Also described are the findings of a preliminary study of a tactile system designed to examine the abdomen of the clinically super-obese patient. PMID- 24048078 TI - Spin polarization in electrodeposited thin films of the molecule-based magnetic semiconductor Cr(5.5)(CN)(12).11.5H(2)O. AB - The magnetoresistance (MR) effect of thin films of the Prussian Blue Analogue (PBA) Cr5.5(CN)12.11.5H2O, prepared by electrochemical deposition, has been measured using the standard two-point probe method. This molecule-based ferrimagnetic material, with a Tc = 240 K, exhibits MR up to 2% at 6 T and 200 K. PMID- 24048079 TI - Obstructive sleep apnoea and diabetes: an update. AB - PURPOSE OF REVIEW: The relationship between obstructive sleep apnoea (OSA) and dysglycaemia is well established. However, uncertainty remains as to the extent that obesity mediates this relationship. The impact of OSA treatment on glucose metabolism and the consequences of having OSA in patients with diabetes is unclear. This review aims to summarize the latest evidence regarding the links between OSA and dysglycaemia. RECENT FINDINGS: OSA is associated with insulin resistance in lean individuals and predicts insulin resistance worsening longitudinally. Continuous positive airway pressure (CPAP) lowers insulin resistance in CPAP-compliant patients. OSA is associated with impaired beta-cell function. In patients with type 2 diabetes (T2D), the association between OSA and glycosylated haemoglobin (HbA1c) is related to nocturnal hypoxaemia. Apnoea hypopnoea index (AHI) during rapid eye movement (REM) (not non-REM) sleep is associated with HbA1c. In-laboratory, supervised CPAP improves glycaemia. OSA is associated with and predicts the progression of some diabetic vascular complications. Intensive lifestyle intervention in patients with T2D improves OSA independent of weight loss. SUMMARY: OSA is associated with insulin resistance and beta-cell dysfunction independent of obesity. OSA is associated with HbA1c and vascular complications in patients with T2D. CPAP might improve insulin resistance and glycaemic measures. Lifestyle intervention has a significant impact on AHI in patients with T2D. PMID- 24048080 TI - Gender and survival in cystic fibrosis. AB - PURPOSE OF REVIEW: Survival for patients with cystic fibrosis (CF) continues to improve. The proportion of CF patients over the age of 18 years is nearly 50%, and care providers will need to better understand this patient population. Despite these improvements, young females continue to have a worse prognosis and lower median survival compared with their male counterparts. Contributing factors to the difference in survival remain uncertain. RECENT FINDINGS: The 'gender gap' remains an area of controversy. Recent data suggest that it still exists, though exact reasons remain unclear. For those patients diagnosed in adulthood, outcomes are also improving. Some evidence suggests persistence of the gender gap. Other data suggest a reversal of this effect. Additional work and study are needed. SUMMARY: This review finds supporting evidence for persistence of the gender gap and outlines the effect of age and sex on survival in CF. The majority of patients with CF will now be adults; thus, care providers must be aware of the impact this will have on ongoing patient management. PMID- 24048081 TI - Narcolepsy and H1N1 vaccination: a link? AB - PURPOSE OF REVIEW: A number of European countries have reported a dramatic increase in the rates of childhood narcolepsy with cataplexy in children immunized with a split-virion adjuvanted swine flu vaccine. Here, we review the strengths and weaknesses of these epidemiological studies and possible neuroimmunological mechanisms. RECENT FINDINGS: Initial concerns of a 13-fold increased relative risk of narcolepsy were raised by the Scandinavian health protection agencies in 2010. Subsequent retrospective studies support these findings in Canada, France, Ireland, England and Denmark. The cases are predominantly young children who present with severe and rapid onset of cataplexy as well as narcolepsy often within a few weeks of vaccination. The proposed mechanism for postvaccination narcolepsy is one in which an environmental trigger causes or enhances an antibody-mediated autoimmune response in patients with a preexisting genetic susceptibility. However, there have not yet been any reports of specific autoimmunity, either antibody or T-cell-mediated. SUMMARY: There is a strong association between narcolepsy and H1N1 vaccination. However, whether this reflects a true increase in affected individuals or a hastening of disease onset in individuals who would otherwise have developed narcolepsy later will become clear in the coming years. The pathological explanation of this association and narcolepsy is likely to be autoimmune, although supportive evidence is lacking.Video abstract available: See the Video Supplementary Digital Content 1 (http://links.lww.com/COPM/A9). PMID- 24048082 TI - The nonrapid eye movement parasomnias: recent advances and forensic aspects. AB - PURPOSE OF REVIEW: The aim is to update the readership on recent advances in the diagnosis and classification of nonrapid eye movement (NREM) sleep parasomnias with an emphasis on recent research findings and related forensic consequences of the parasomnias. RECENT FINDINGS: The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) has further refined the classification and diagnostic criteria for the parasomnias, dividing them into non-REM and REM sleep disorders. It has removed confusional arousal disorder and updated the diagnostic criteria in keeping with the evidence-base available at the time of its final drafting. New research subsequent to the final drafting of the DSM-5 has clarified certain aspects including those related to the risk factors ('triggers') for sleepwalking and the impact of sleepwalking on daytime functioning, social and occupational functioning. These new research data should be considered in the development of the next International Classification of Sleep Disorders. The new diagnostic system and research data provide further clarity for the forensic sleep medicine practitioner. SUMMARY: The DSM-5 diagnostic criteria combined with the latest research will inform both clinical and forensic sleep medicine practice and provide further impetus for evidence based practice. PMID- 24048084 TI - Restless legs syndrome: update on pathogenesis. AB - PURPOSE OF REVIEW: Much recent progress has been made in understanding restless legs syndrome (RLS), focusing mainly on genetic predisposition and dysregulation of iron metabolism and the dopaminergic system. We provide in this review an update of the most recent scientific advances on the pathophysiology of primary RLS. RECENT FINDINGS: Genome-wide association studies identified six genetic variants including MEIS1 and BTBD9 with potential relationships with iron. Brain iron level is low in RLS and neuropathological studies have shown significant decreases in dopamine D2 receptors in the putamen that correlated with RLS severity, and increased tyrosine hydroxylase in the substantia nigra. An overly activated dopaminergic system was reported in both animal and cell models of iron insufficiency thus suggesting that in at least a subgroup of RLS patients altered iron metabolism plays a role in the disorder. Also, dysregulation of iron uptake and storage within brain microvessels was recently reported and might play a role in a subgroup of RLS patients. SUMMARY: RLS is a genetically heterogeneous complex trait with high prevalence but large phenotype variability. Current theories of RLS pathophysiology emphasize brain iron deficiency with abnormal dopaminergic consequences, together with a strong underlying genetic background. PMID- 24048085 TI - Nontuberculous mycobacteria: the changing epidemiology and treatment challenges in cystic fibrosis. AB - PURPOSE OF REVIEW: Although patients with cystic fibrosis (CF) face numerous infectious pathogens over the course of their lifespan, increasing attention has recently been paid to nontuberculous mycobacteria (NTM). As reported prevalence rates rise across many countries such as the United States, the ability to recognize disease caused by NTM and subsequently treat such disease has become increasingly important. This review summarizes new observations on the epidemiology of NTM in CF as well as key elements to consider during the treatment phase. RECENT FINDINGS: Although overall rates of NTM isolation appear to be increasing, particular concern has focused on the emerging predominance of Mycobacterium abscessus. New data suggest that chronic macrolide therapy now part of routine CF care has contributed to this rise; however, these have yet to be confirmed prospectively. Transmission of M. abscessus between CF patients has also now been described through the use of genome sequencing. Although the greater virulence of M. abscessus makes it a challenging species to treat, identification of the subspecies type can now determine the presence of inducible macrolide resistance, thereby helping to guide treatment. SUMMARY: Given increasing prevalence rates, clinicians should maintain a high level of suspicion for NTM as disease-causing organisms in CF, particularly for M. abscessus. New knowledge regarding this species, however, can help to tailor appropriate therapy. PMID- 24048083 TI - Pulmonary hypertension survival effects and treatment options in cystic fibrosis. AB - PURPOSE OF REVIEW: This review discusses the current impact of pulmonary hypertension on the outcome and treatment of cystic fibrosis (CF). RECENT FINDINGS: Pulmonary hypertension is commonly encountered in advanced lung diseases such as CF. The prevalence of pulmonary hypertension in CF patients varies based on disease severity and methodology used for diagnosis. Chronic alveolar hypoxia is the most likely cause. The majority of recent studies have shown worse survival in CF patients who develop pulmonary hypertension. The impact of pulmonary hypertension-specific therapies on symptomatology and outcomes in CF patients has not been well studied. SUMMARY: Pulmonary hypertension is common in patients with CF and it occurs largely because of hypoxemia. The presence of pulmonary hypertension in patients with CF is likely associated with worse outcome; however, it remains unknown whether treatment with pulmonary hypertension-specific therapies would be beneficial. PMID- 24048086 TI - Modifying disease in cystic fibrosis: current and future therapies on the horizon. AB - PURPOSE OF REVIEW: Recent therapies directed at proximal targets within cystic fibrosis (CF) pathophysiology hold potential to modulate disease. This review highlights recent clinical trials and future therapies focused on these early steps of disease. RECENT FINDINGS: Recent approval of a CF transmembrane conductance regulator (CFTR) protein modulator, ivacaftor (Kalydeco), has ignited a wave of investigations for other modulators directed at CFTR mutation classes. Gene replacement therapy continues to be pursued at a slower pace in early phase clinical trials. Airway surface liquid strategies such as dry-powder mannitol and alternate ion channel regulation are discussed as genotype-independent methods of early modulation. SUMMARY: The breadth of therapies for early targets of CF holds considerable hope to modify the natural history of this disease. Ongoing focus to develop novel markers of early disease state is paramount. The progress of drug development requires concurrent attention on a spectrum of targets to achieve maximal impact. PMID- 24048087 TI - Complications in pediatric spine surgery using the vertical expandable prosthetic titanium rib: the French experience. AB - STUDY DESIGN: Multicenter retrospective study of 54 children. OBJECTIVE: To describe the complication rate of the French vertical expandable prosthetic titanium rib (VEPTR) series involving patients treated between August 2005 and January 2012. SUMMARY OF BACKGROUND DATA: Congenital chest wall and spine deformities in children are complex entities. Most of the affected patients have severe scoliosis often associated with a thoracic deformity. Orthopedic treatment is generally ineffective, and surgical treatment is very challenging. These patients are good candidates for VEPTR expansion thoracoplasty. The aim of this study was to evaluate the potential complications of VEPTR surgery. METHODS: Of the 58 case files, 54 were available for analysis. The series involved 33 girls and 21 boys with a mean age of 7 years (range, 20 mo-14 yr and 2 mo) at primary VEPTR surgery. During the follow-up period, several complications occurred. RESULTS: Mean follow-up was 22.5 months (range, 6-64 mo). In total, 184 procedures were performed, including 56 VEPTR implantations, 98 expansions, and 30 nonscheduled procedures for different types of complications: mechanical complications (i.e., fracture, device migration), device-related and infectious complications, neurological disorders, spine statics disturbances. Altogether, there were 74 complications in 54 patients: a complication rate of 137% per patient and 40% per surgery. Comparison of the complications in this series with those reported in the literature led the authors to suggest solutions that should help decrease their incidence. CONCLUSION: The complication rate is consistent with that reported in the literature. Correct determination of the levels to be instrumented, preoperative improvement of nutritional status, and better evaluation of the preoperative and postoperative respiratory function are important factors in minimizing the potential complications of a technique that is used in weak patients with complex deformities. PMID- 24048088 TI - A new pre-employment functional capacity evaluation predicts longer-term risk of musculoskeletal injury in healthy workers: a prospective cohort study. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To determine if a job-specific pre-employment functional assessment (PEFA) predicts musculoskeletal injury risk in healthy mineworkers. SUMMARY OF BACKGROUND DATA: Traditional methods of pre employment screening, including radiography and medical screenings, are not valid predictors of occupational musculoskeletal injury risk. Short-form job-specific functional capacity evaluations are increasing in popularity, despite limited evidence of their ability to predict injury risk in healthy workers. METHODS: Participants were recruited from an Australian coal mine between 2002 and 2009 as part of the hiring process. At baseline, participants were screened with the JobFit System PEFA, and classified as PEFA 1 if they met job demands and PEFA>1, if not. Males who completed the PEFA and were employed were included. Injury data from company records were coded for body part, mechanism, and severity. The relationship between PEFA classification and time to first injury was analyzed using Cox proportional hazards regression with adjustments for department and post hoc stratification for time (0-1.3 yr, 1.3-6 yr). RESULTS: Of the 600 participants (median age, 37 yr, range, 17.0-62.6 yr), 427 scored PEFA 1. One hundred ninety-six sprain/strain injuries were reported by 121 workers, including 35 back injuries from manual handling. Significant differences between PEFA groups were found in time to first injury for all injury types during the long term (any injury: adjusted hazard ratio [HR] = 2.3, 95% confidence interval [CI] = 1.4-3.9; manual handling injury: HR = 3.3, CI = 1.6-7.2; any back injury: HR = 3.3, CI = 1.6-6.6; back injuries from manual handling HR = 5.8, CI = 2.0-16.7), but not during the short term. An area under the receiver operator curve value of 0.73 (CI = 0.61-0.86) demonstrated acceptable predictive ability for back injuries from manual handling during the long term. CONCLUSION: JobFit System PEFAs predict musculoskeletal injury risk in healthy mineworkers after 1.3 years of employment. Future research should assess whether use of these assessments as part of a holistic risk management program can decrease workplace musculoskeletal injuries. PMID- 24048089 TI - Do routine radiographs within the first two years following pediatric posterior spinal fusion prompt revision surgery? AB - STUDY DESIGN: This is a retrospective review of 265 consecutive patients with scoliosis treated by posterior spinal fusion (PSF) and 2990 postoperative radiographs at a single institution. OBJECTIVE: To document implant-related complications on postoperative radiographs within the first 2 years after PSF and determine if these led to additional surgical procedures. SUMMARY OF BACKGROUND DATA: To date, there is an absence of studies investing the utility of radiographs after pediatric PSF surgery. METHODS: The patient's average age was 14.9 years (8.2-21.8 yr). Positive radiographical findings included implant loosening, fracture, migration, or loss of fixation. We also noted which patients' required additional surgery for a radiographical finding and/or clinical finding (neurological deficit, intractable back pain, fever, and elevated erythrocyte sedimentation rate, c-reactive protein, or while blood cell count). RESULTS: At an average follow-up of 16.3 months (12-24), only 18 (0.60%) radiographs demonstrated a positive finding. Of these, only 5 (0.17%) radiographs (along with clinical presentation) prompted revision. No patient returned to the operating room purely from a radiographical finding. The remaining 13 (0.37%) abnormal plain images were not associated with a clinical abnormality and were managed nonoperatively. The timing of the second operation was in the range from 1 day to 23 months (average, 11 mo). Postoperative plain radiographs had a sensitivity of 26.5%, a specificity of 99.5%, and a positive predictive value of 25%. CONCLUSION: Only 0.60% of postoperative images (18/2990) demonstrated an implant-related complication, and in the absence of clinical indications, none of these patients required surgical intervention. Isolated postoperative radiographs did not lead to any change in management, and consideration should be given to reviewing current protocols for plain radiographs as a monitoring tool after PSF. PMID- 24048090 TI - Anterior cervical fusion assessment using reconstructed computed tomographic scans: surgical confirmation of 254 segments. AB - STUDY DESIGN: Retrospective study developing diagnostic criteria. OBJECTIVE: To validate 2 computed tomography-based findings, extragraft bone bridging (ExGBB) and intragraft bone bridging (InGBB), as diagnostic criteria for anterior cervical fusion using subsequent surgical confirmation and to demonstrate the different diagnostic accuracy on the basis of the graft material used. SUMMARY OF BACKGROUND DATA: The accuracy and the methodology for evaluating bone bridging on computed tomographic scans to determine anterior cervical fusion status have not been validated or standardized. METHODS: One hundred ten patients with 254 surgically explored segments along with reconstructed computed tomographic scans were included. Bone bridging at each cervical level was assessed for ExGBB and InGBB. ExGBB was defined as complete cortical bridging at any peripheral margins (anterior, posterior, left, or right) of the operated disc space, outside of the graft. InGBB was defined as cortical or trabecular bridging within the confines of the graft only. ExGBB and InGBB were serially evaluated on reformatted coronal and sagittal views by 3 independent raters. The reliabilities and validities correlated with surgical exploration were evaluated. RESULTS: Surgical exploration revealed 123 fused and 131 pseudarthrosis segments. The reliability of 3 raters showed near perfect agreement for ExGBB and substantial agreement for InGBB. ExGBB also had higher validity for all raters than did InGBB. The autocortical graft group had the highest accuracy for both InGBB and ExGBB, with both values being nearly identical. The allograft group had the next highest validity values. For the cage group, InGBB had the lowest specificity (53.2%) and positive predictive value (35.5%), whereas ExGBB had 100% sensitivity and negative predictive value. CONCLUSION: ExGBB seems to be a far more reliable and accurate to determine anterior cervical fusion. The diagnostic criteria using bone bridging should be different based on the intradiscal materials. With cages in particular, InGBB seems unreliable and ExGBB is necessary to determine anterior cervical fusion. PMID- 24048091 TI - Effects of using intravenous antibiotic only versus local intrawound vancomycin antibiotic powder application in addition to intravenous antibiotics on postoperative infection in spine surgery in 907 patients. AB - STUDY DESIGN: A prospective randomized controlled trial. OBJECTIVE: To assess the ability of local vancomycin powder in controlling postoperative infection in spine surgery. SUMMARY OF BACKGROUND DATA: Despite improvements through the use of prophylactic systemic antibiotics, surgical site infections remain a significant problem in spine surgical procedures. Various retrospective and prospective studies have reported the efficacy of local application of vancomycin powder in reducing the infection in animal and human studies. However, there were no randomized control trials that reported on its efficacy. METHODS: Prospective randomized controls of 907 patients with various spinal pathologies were treated surgically during a period of 18 months. The control group received standard systemic prophylaxis only, whereas the treatment group received vancomycin powder in the surgical wound in addition to systemic prophylaxis. Patient demographics, comorbidities, level of spinal pathology, estimated blood loss, nutritional status, and hemoglobin were recorded. Incidence of infection was the primary outcome evaluated. RESULTS: There were 8 infections (1.68%) in the control group (6 instrumented and 2 noninstrumented, 6 deep and 2 superficial) with bacteria cultured in 3 (1 Escherichia coli and 2 Staphylococcus aureus). In the treatment group, 7 infections (1.61%) were observed (6 instrumented and 1 noninstrumented surgical procedures, 6 deep and 1 superficial) with bacteria cultured in 3 (1 Staphylococcus aureus and 2 Klebsiella). No adverse effects were observed from the use of vancomycin powder. Statistically no significant difference was seen in infection rate between the treatment group and control group. CONCLUSION: The local application of vancomycin powder in surgical wounds did not significantly reduce the incidence of infection in patients with surgically treated spinal pathologies. The use of vancomycin powder may not be effective when incidence of infection is low. PMID- 24048092 TI - Recurrence of work-related low back pain and disability: association between self report and workers' compensation data. AB - STUDY DESIGN: Retrospective cohort. OBJECTIVE: To explore the ability to capture low back pain (LBP) recurrence using wage-replacement (WR) data. SUMMARY OF BACKGROUND DATA: LBP can be a recurrent, fluctuating, and disabling condition. Because of its largely nonspecific and subjective nature, the condition poses challenges for research and clinical management, as speaking directly with the affected individuals is not always practical. Little information is available on how indicators of LBP recurrence that can be extracted from administrative databases relate to patients' self-report. METHODS: Participants with a compensated claim for work-related LBP (N = 90) were interviewed regarding their LBP-related experiences after their initial return to work. Interview data were compared with WR data, which was provided by the participants' workers' compensation provider. RESULTS: Concordance was observed between WR-based indicators and self-reports of additional time off due to LBP. The best performing WR-based indicator reflected a payment history that began with more than 7 consecutive days of initial WR payments, followed by a gap in WR payments of more than 7 consecutive days, followed by another WR payment period of more than 7 consecutive days (sensitivity = 55%, specificity = 73%, overall accuracy = 69%). Although concordance was observed between the 2 measures of additional time off, the best performing WR indicator was not related to participants' other self reports of post-return-to-work LBP recurrence which included LBP being significantly worse usual; LBP experiences; seeking health care for LBP; and the experience of difficulties related to the back condition. CONCLUSION: Results indicate that compensation data can be used to capture what a claimant would self report as additional time off after their initial return to work due to their LBP condition. However, the use of self-report recurrence indicators is recommended if there is a desire to capture a fuller extent of workers' ongoing pain and/or disability experiences. LEVEL OF EVIDENCE: N/A. PMID- 24048093 TI - Ultrahigh humidity sensitivity of graphene oxide. AB - Humidity sensors have been extensively used in various fields, and numerous problems are encountered when using humidity sensors, including low sensitivity, long response and recovery times, and narrow humidity detection ranges. Using graphene oxide (G-O) films as humidity sensing materials, we fabricate here a microscale capacitive humidity sensor. Compared with conventional capacitive humidity sensors, the G-O based humidity sensor has a sensitivity of up to 37800% which is more than 10 times higher than that of the best one among conventional sensors at 15%-95% relative humidity. Moreover, our humidity sensor shows a fast response time (less than 1/4 of that of the conventional one) and recovery time (less than 1/2 of that of the conventional one). Therefore, G-O appears to be an ideal material for constructing humidity sensors with ultrahigh sensitivity for widespread applications. PMID- 24048094 TI - Curcumin induces autophagy via activating the AMPK signaling pathway in lung adenocarcinoma cells. AB - Curcumin is a major yellow pigment and active component of turmeric widely used as dietary spice and herbal medicine. This compound has been reported to be a promising antitumor agent, although the underlying molecular mechanisms are not fully understood yet. In this study, we reported that curcumin inhibited growth of lung adenocarcinoma cells, but had no cytotoxic activity to IMR-90 normal lung fibroblast cells. Curcumin induced autophagy in the A549 human lung adenocarcinoma cell line, evidenced by LC3 immunofluorescence analysis and immunoblotting assays on LC3 and SQSTM1. Moreover, the autophagy inhibitor 3-MA partly blocked the inhibitory effect of curcumin on the growth of A549 cells. Curcumin markedly increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetylCoA carboxylase in A549 cells. At last, pharmacological blockade of the AMPK signaling pathway by compound C and genetic disruption of the AMPK signaling pathway with siRNA-mediated AMPKalpha1 knockdown impaired the autophagy inducing effect of curcumin. Collectively, our data suggests that curcumin induces autophagy via activating the AMPK signaling pathway and the autophagy is important for the inhibiting effect of curcumin in lung adenocarcinoma cells. PMID- 24048096 TI - Editorial: an international Riposte to Naysayers of endocrine-disrupting chemicals. PMID- 24048095 TI - Policy decisions on endocrine disruptors should be based on science across disciplines: a response to Dietrich et al. PMID- 24048097 TI - The role of the opioid system in alcohol dependence. AB - The role of the brain opioid system in alcohol dependence has been the subject of much research for over 25 years. This review explores the evidence: firstly describing the opioid receptors in terms of their individual subtypes, neuroanatomy, neurophysiology and ligands; secondly, summarising emerging data from specific neurochemical, behavioural and neuroimaging studies, explaining the characteristics of addiction with a focus on alcohol dependence and connecting the opioid system with alcohol dependence; and finally reviewing the known literature regarding opioid antagonists in clinical use for alcohol dependence. Further interrogation of how modulation of the opioid system, via use of MOP (mu), DOP (delta) and KOP (kappa) agents, restores the balance of a dysregulated system in alcohol dependence should increase our insight into this disease process and therefore guide better methods for understanding and treating alcohol dependence in the future. PMID- 24048099 TI - Peripheral vascular disease in systemic lupus patients. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is an independent risk factor for cardiovascular disease (CVD). Ankle-brachial index (ABI) is a measure of peripheral vascular disease (PVD), low values of which are associated with CVD. OBJECTIVES: Objectives were to identify the prevalence of PVD in SLE, to identify risk factors associated with PVD in SLE, and to determine whether SLE is an independent risk factor for PVD as assessed by ABI. METHODS: In a cross-sectional analysis of SLE subjects and control subjects, free of known CVD, SLE-related variables and cardiovascular risk factors were measured. Peripheral vascular disease was assessed using ABI. The prevalence of PVD (ABI <= 1.0) and comparisons of mean ABI, between SLE and control subjects, were examined. Systemic lupus erythematosus was examined as an independent risk for PVD in the cohort using propensity score matching. Logistic regression was performed to identify independent risk factors for PVD in SLE. RESULTS: Ankle-brachial index was lower in the 134 SLE subjects compared with 77 control subjects: 1.05 versus 1.09 (P = 0.003), and the prevalence of PVD was higher in SLE than in control subjects (33% vs 20%; P = 0.037). Systemic lupus erythematosus was not an independent risk for PVD. In the SLE subjects, the only significant risk factor for PVD was smoking. CONCLUSIONS: Ankle-brachial index, a marker of subclinical CVD, is an inexpensive and easy method in which to assess PVD. There was a 33% prevalence of PVD in SLE, which was independently associated with smoking. As PVD is a coronary artery disease risk equivalent, screening and diagnosis may change lipid management in preventive cardiovascular risk assessment in patients with SLE. The combination of SLE and a smoking history may identify individuals for whom checking an ABI makes particular sense. PMID- 24048098 TI - Female adolescent exposure to cannabinoids causes transgenerational effects on morphine sensitization in female offspring in the absence of in utero exposure. AB - Female adolescent marijuana use is increasing, yet the effect on future offspring is unknown. Here, adolescent female Sprague Dawley rats (postnatal-day 30; PN30) were given subcutaneous (s.c.) injections with the cannabinoid agonist WIN-55,212 (WIN) or its vehicle (VEH) for three consecutive days using a twice-daily, increasing dosage regimen (1 mg/kg day 1; 2 mg/kg day 2; 4 mg/kg day 3). As adults (PN60), females were mated with drug-naive males. Their adult female offspring (VEH-F1 or WIN-F1) were tested for behavioral sensitization by administering morphine (0 or 7.5 mg/kg s.c.) every other day for a total of five administrations. Following five days of abstinence, all animals received a morphine challenge (7.5 mg/kg s.c.) and locomotor activity was monitored. At completion of behavioral testing, mu opioid receptor (OPRM1), FosB, cFos, and dopamine receptor mRNA expression was measured in the nucleus accumbens as well as OPRM1 and corticotropin-releasing hormone mRNA in the paraventricular nucleus. In addition, plasma corticosterone levels were examined. On the day of challenge, morphine-pretreated WIN-F1 animals demonstrated a significantly enhanced response to morphine compared to morphine-pretreated VEH-F1 animals. Also following the morphine challenge, significantly higher levels of OPRM1 in the nucleus accumbens were observed in WIN-F1 animals. Together, these findings demonstrate transgenerational effects of adolescent exposure to cannabinoids in the absence of any in utero exposure. PMID- 24048101 TI - Deformation of female foot binding in China. PMID- 24048102 TI - An emerging role for clarithromycin in adult-onset still disease? PMID- 24048103 TI - Successful etanercept desensitization in a patient with severe injection site reactions. PMID- 24048104 TI - Scleroderma renal crisis in an elderly patient with overlap syndrome. PMID- 24048105 TI - Fatal refractory thrombotic thrombocytopenic purpura complicating systemic lupus erythematosus. PMID- 24048106 TI - Psoriasiform reactions to anti-tumor necrosis factor alpha therapy. AB - OBJECTIVE: Given increasing concern about the adverse effects of anti-tumor necrosis factor alpha (anti-TNF-alpha) medications, we sought to characterize psoriasiform eruptions in patients on these medications. METHODS: In a retrospective review of patients at the Brigham and Women's Hospital combined dermatology-rheumatology clinic, we identified 13 patients (1 male and 12 female patients) who developed psoriasiform eruptions while on anti-TNF-alpha medications. RESULTS: Inciting medications were adalimumab, etanercept, and infliximab. Patients were on their inciting medication for a median time of 24 months and a mean time of 31.3 months before developing eruptions. Five of 7 patients experienced complete resolution of lesions with topical corticosteroids and discontinuation of anti-TNF-alpha medications with the remaining 2 patients having partial improvement. One of the other 6 patients experienced complete resolution with topical corticosteroid treatment only, with the remaining 5 patients experiencing partial improvement. After changing anti-TNF-alpha agents, 1 patient had partial improvement of psoriasiform lesions, and 7 patients had no improvement. CONCLUSIONS: All of the main anti-TNF-alpha medications currently used are capable of causing psoriasiform eruptions. Poor responders to topical agents, such as corticosteroids, may benefit from supplemental therapy aimed at the psoriasiform eruption or changing to a different class of immunomodulatory agents. Switching anti-TNF-alpha medications had a low likelihood of improving psoriasiform skin reactions, further suggesting that these eruptions are a drug class effect. PMID- 24048107 TI - Giant cell arteritis presenting as depressed mood and headache in an elderly patient. AB - Giant cell arteritis (GCA) is an autoimmune disorder characterized by the inflammation of medium to large vessels. Although classic descriptions have centered on features such as vision loss, headaches, fevers, and jaw claudication, there is increasing recognition of more atypical manifestations. We report a case of GCA in a 77-year-old male patient initially presenting with depressed mood and headache. His psychiatric symptoms promptly responded to treatment with corticosteroids without the use of antidepressants. This case adds to the literature that GCA may initially present with affective or psychotic symptoms and highlights the need for clinicians to consider GCA in the differential diagnosis for new-onset psychiatric disorders in the elderly. PMID- 24048108 TI - Fatal acute necrotizing eosinophilic myocarditis temporally related to use of adalimumab in a patient with relapsing polychondritis. AB - Tumor necrosis factor alpha (TNF-alpha) antagonists are being increasingly used as maintenance therapies for rheumatic diseases, and therefore knowledge of their adverse effects is important. We report a case of fatal acute necrotizing eosinophilic myocarditis temporally related to use of a second course of the TNF alpha antagonist, adalimumab. A 51-year-old woman with relapsing polychondritis took adalimumab 2 weeks before presenting with acute myocarditis. Within hours of presentation to the emergency department, she had cardiac arrest due to fulminant heart failure. Autopsy demonstrated necrotizing eosinophilic myocarditis. This is a rare cause of fulminant heart failure. This is the first report of a TNF-alpha antagonist potentially associated with acute necrotizing eosinophilic myocarditis. PMID- 24048109 TI - Manifestations and treatment of the hand in adult congenital erythropoietic porphyria. AB - Congenital erythropoietic porphyria (CEP) is a rare enzymatic disorder of heme metabolism, leading to the accumulation of porphyrins in the skin and subdermal structures. We present the case of a 34-year-old, right-hand-dominant, male patient with CEP. The patient had developed a chronic open subluxation of the left index finger proximal interphalangeal joint due to skin necrosis. We successfully treated the patient with proximal interphalangeal arthrodesis. This case demonstrates that childhood-onset CEP can also manifest in the adult hand. Considering the patient's age, the destructive nature of the disease, and the poor quality of function in older patients with childhood CEP, surgical intervention was necessary to avoid further digital length loss. Although the treatment described in this case report is not uncommon, we found it essential to present this case because the clinical presentation of CEP is rare. PMID- 24048110 TI - Giant cell arteritis causing symmetric bilateral posterior circulation infarcts. AB - An 82-year-old woman presented with bilateral, symmetric posterior circulation infarctions secondary to giant cell arteritis (GCA). Her atypical clinical presentation included a lack of headache and fever, but she exhibited signs of systemic illness including generalized weakness, cachexia, apathy, and anemia. Laboratory testing revealed a markedly elevated erythrocyte sedimentation rate, but only a borderline elevated C-reactive protein. Head and neck vascular imaging demonstrated a pattern of vertebral arterial narrowing consistent with GCA-a diagnosis confirmed by temporal artery biopsy. Her unusual symptomatic, laboratory, and imaging presentation highlights the importance of considering GCA in the differential diagnosis of unusual bilateral stroke syndromes, where early treatment decreases morbid outcomes. PMID- 24048111 TI - Relapsing polychondritis: response to tocilizumab and association with colitis. PMID- 24048112 TI - Churg-Strauss syndrome and persistent heart failure: active disease or damage? AB - Churg-Strauss syndrome (CSS) is a rare small-vessel vasculitis typically associated with adult-onset asthma, peripheral and tissue hypereosinophilia, migratory pulmonary infiltrates, upper respiratory tract symptoms, and clinical evidence of systemic vasculitis. Cardiac involvement is a well-recognized complication with an estimated prevalence of 60%. Heart disease is associated with poor prognosis, accounting for almost 50% mortality in CSS. We present a case of a 48-year-old woman with CSS complicated by congestive heart failure with left ventricular ejection fraction of 25%, who was initially treated with long course of high-dose steroids without any clinical or echocardiographic improvement. She was referred to our hospital 1 year later and was initiated with cyclophosphamide 2 mg/kg per day and prednisone 60 mg/d followed by slow taper. Subsequently, the patient had remarkable improvement. Patient was then transitioned to azathioprine for 1.5 years with sustained disease remission. It may be difficult to determine myocardial disease activity status versus tissue damage in CSS with prolonged duration of heart failure symptoms. This is the first case report demonstrating that CSS cardiac disease may remain active despite 1 year of corticosteroid therapy, and significant improvement or remission can still be achieved by administering more aggressive cytotoxic immunosuppressive therapy. PMID- 24048113 TI - Effective control of polymyalgia rheumatica with tocilizumab. AB - Despite their disadvantages, glucocorticoids (GCs) remain a mainstay of therapy for polymyalgia rheumatica (PMR). Second-line antirheumatic and immune-modulatory drugs are not infrequently required because of disease relapses during GC tapering and GC adverse effects. Therapy with methotrexate or with an anti-tumor necrosis factor drug showed modest efficacy in this situation. Tocilizumab (TCZ) is an anti-interleukin 6 receptor antibody that is being recently studied in the treatment of PMR patients who are intolerant or refractory to GCs, especially after failure of a second-line agent. We report a case of PMR in which GCs were stopped because of adverse effects despite good response. The condition responded to neither methotrexate nor etanercept. Treatment with TCZ has led to significant improvement of the patient's clinical and biochemical PMR activity parameters, and she was kept in a solid remission for 1 year without any TCZ-related adverse effects. Tocilizumab is a promising drug in the management of PMR. Further studies are required to clearly define the indications and duration of TCZ therapy in the management of PMR. PMID- 24048114 TI - Diffuse lymphadenopathy as the presenting manifestation of systemic lupus erythematosus. AB - We report the case of a 27-year-old African American man who presented with 6 months of generalized lymphadenopathy and nothing in his history or examination to suggest systemic lupus erythematosus (SLE). He was thought to have lymphoma, syphilis, or tuberculosis, and an extensive workup was done. Laboratory investigation finally revealed leukopenia (4.0), proteinuria (1.87 g), antinuclear antibodies (640 speckled), anti-double-stranded DNA (640), anticardiolipin immunoglobulins G and M, anti-Smith, Coombs, anti-Ro, anti-La, CK (531 U/L), aldolase (8.5 U/L), high erythrocyte sedimentation rate (130 mm/h), and low complement (C3 15 mg/dL and C4 3 mg/dL). A kidney biopsy showed diffuse proliferative glomerulonephritis, International Society of Nephrology class IV. Generalized lymphadenopathy as the first and only manifestation for 6 months made the diagnosis of SLE challenging. Generalized diffuse lymphadenopathy has been associated with SLE but is much less frequent now than in the past. The differential diagnosis of lymphadenopathy relevant to rheumatologists includes Kikuchi histiocytic necrotizing lymphadenitis, Castleman disease, syphilis, tuberculosis, sarcoidosis, and lymphoma. PMID- 24048115 TI - Assessing the need for improved access to rheumatology care: a survey of Massachusetts community health center medical directors. AB - OBJECTIVE: Access to rheumatology care can expedite diagnosis and treatment of rheumatic diseases and reduce disparities. We surveyed community health center (CHC) medical directors to evaluate rheumatology care in underserved areas and potential strategies for improvement. METHODS: We identified 77 Massachusetts CHCs that provide adult medical services and sent a 40-item survey to their physician medical directors. Survey questions assessed the centers' prevalence of rheumatic diseases, prescribing practices of immunosuppressive medications, and possible interventions to improve care. We compared CHC characteristics and rheumatology-specific items and then stratified our data by the response to whether improved access to rheumatology care was needed. Qualitative data were analyzed thematically. RESULTS: Thirty-six CHC physician medical directors returned surveys (47% response rate). Fifty-five percent indicated a need for better access to rheumatology care. Eighty-six percent of CHC physicians would not start a patient with rheumatoid arthritis on a disease-modifying antirheumatic drug; 94% would not start a patient with systemic lupus erythematosus on an immunosuppressant. When we compared CHCs that reported needing better access to rheumatology care to those that did not, the former described a significantly greater percentage of patients with private insurance or Medicaid who required outside rheumatology referrals (P < 0.05). Language differences and insurance status were highlighted as barriers to obtaining rheumatology care. Sixteen directors (57%) ranked the patient navigator-a layperson to assist with care coordination-as their first-choice intervention. CONCLUSIONS: Community health center medical directors expressed a need for better access to rheumatology services. A patient navigator for rheumatic diseases was proposed to help improve care and reduce health disparities. PMID- 24048116 TI - Educational quality of YouTube videos on knee arthrocentesis. AB - BACKGROUND: Knee arthrocentesis is a commonly performed diagnostic and therapeutic procedure in rheumatology and orthopedic surgery. Classic teaching of arthrocentesis skills relies on hands-on practice under supervision. Video-based online teaching is an increasingly utilized educational tool in higher and clinical education. YouTube is a popular video-sharing Web site that can be accessed as a teaching source. OBJECTIVE: The objective of this study was to assess the educational value of YouTube videos on knee arthrocentesis posted by health professionals and institutions during the period from 2008 to 2012. METHODS: The YouTube video database was systematically searched using 5 search terms related to knee arthrocentesis. Two independent clinical reviewers assessed videos for procedural technique and educational value using a 5-point global score, ranging from 1 = poor quality to 5 = excellent educational quality. As validated international guidelines are lacking, we used the guidelines of the Swiss Society of Rheumatology as criterion standard for the procedure. RESULTS: Of more than thousand findings, 13 videos met the inclusion criteria. Of those, 2 contained additional animated video material: one was purely animated, and one was a check list. The average length was 3.31 +/- 2.28 minutes. The most popular video had 1388 hits per month. Our mean global score for educational value was 3.1 +/- 1.0. Eight videos (62 %) were considered useful for teaching purposes. Use of a "no-touch" procedure, meaning that once disinfected the skin remains untouched before needle penetration, was present in all videos. Six videos (46%) demonstrated full sterile conditions. There was no clear preference of a medial (n = 8) versus lateral (n = 5) approach. CONCLUSIONS: A discreet number of YouTube videos on knee arthrocentesis appeared to be suitable for application in a Web-based format for medical students, fellows, and residents. The low-average mean global score for overall educational value suggests an improvement of future video-based instructional materials on YouTube would be necessary before regular use for teaching could be recommended. PMID- 24048117 TI - Ultrasound assessment of subcutaneous compressibility: a potential adjunctive diagnostic tool in eosinophilic fasciitis. AB - BACKGROUND: Eosinophilic fasciitis (EF) is an autoimmune, fibrotic disorder described initially with scleroderma-like skin changes where deep soft tissue sampling that includes fascia is frequently felt to be necessary to confirm the diagnosis. OBJECTIVE: The objective of this study was to distinguish forearm involvement by EF from other fibrosing diseases and from control subjects with normal skin and fascia using B-mode ultrasound. METHODS: A cross-sectional study over a 4-year period in which clinically involved forearm skin of consecutive patients with EF (n = 12), diabetic cheiroarthropathy (n = 8), diffuse systemic sclerosis (n = 23), and control subjects (n = 8) was evaluated by 12-MHz, B-mode ultrasound for degree of subcutaneous tissue compressibility, and this finding was compared with the criterion standard of clinical diagnostic criteria for each disease process. RESULTS: Subcutaneous compressibility in EF was significantly reduced when compared with diffuse systemic sclerosis and with control subjects. Subcutaneous thinning was observed in some patients with EF (4/12), diabetic cheiroarthropathy (4/8), and diffuse systemic sclerosis (6/23), but not in control subjects. Diabetic cheiroarthropathy and diffuse systemic sclerosis patients with subcutaneous thinning had less than 20% subcutaneous compressibility, whereas only 1 of 12 EF patients had compressibility of more than 20% regardless of subcutaneous thinning. CONCLUSIONS: A 12-MHz, B-mode ultrasound may be used to measure subcutaneous compressibility, thereby serving as an adjunct tool in distinguishing EF from diffuse systemic sclerosis, especially when tissue sampling is less feasible or when the result of tissue sampling is equivocal. PMID- 24048118 TI - Immunity in the tissues. PMID- 24048119 TI - The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells. AB - The skin is a highly complex organ interspersed with a variety of smaller organ like structures and a plethora of cell types that together perform essential functions such as physical sensing, temperature control, barrier maintenance and immunity. In this Review, we outline many of the innate and adaptive immune cell types associated with the skin, focusing on the steady state in mice and men, and include a broad update of dendritic cell function and T cell surveillance. PMID- 24048120 TI - Tissue-resident macrophages. AB - Tissue-resident macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche-specific functions. These range from dedicated homeostatic functions, such as clearance of cellular debris and iron processing, to central roles in tissue immune surveillance, response to infection and the resolution of inflammation. Recent studies highlight marked heterogeneity in the origins of tissue macrophages that arise from hematopoietic versus self-renewing embryo-derived populations. We discuss the tissue niche-specific factors that dictate cell phenotype, the definition of which will allow new strategies to promote the restoration of tissue homeostasis. Understanding the mechanisms that dictate tissue macrophage heterogeneity should explain why simplified models of macrophage activation do not explain the extent of heterogeneity seen in vivo. PMID- 24048121 TI - Immune surveillance by the liver. AB - Receiving both portal vein blood and arterial blood, the liver is an important and critical component in the defense against blood-borne infection. To accomplish this role, the liver contains numerous innate and adaptive immune cells that specialize in detection and capture of pathogens from the blood. Further, these immune cells participate in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes within the vasculature. Finally, this role in host defense must be tightly regulated to ensure that inappropriate immune responses are not raised against nonpathogenic exogenous blood-borne molecules, such as those derived from food. It is this balance between activation and tolerance that characterizes the liver as a frontline immunological organ. PMID- 24048122 TI - Regulatory T cells in nonlymphoid tissues. AB - Both Foxp3(+)CD4(+) regulatory T cells (Treg cells) and local immune responses in nonlymphoid tissues have long been recognized as important elements of a well orchestrated immune system, but only recently have these two fields of study begun to intersect. There is growing evidence that Treg cells are present in various nonlymphoid tissues in health and disease, that they have a unique phenotype and that their functions go beyond the classical modulation of immune responses. Thus, tissue Treg cells might add yet another level to classification of the Treg cell compartment into functional and/or phenotypic subtypes. In this Review, we summarize recent findings in this new field, discussing knowns and unknowns about the origin, phenotype, function and memory of nonlymphoid tissue resident Treg cells. PMID- 24048131 TI - Aegean reflections on innate immunity. AB - Leading scientists from around the globe gathered on the Greek island of Kos in June 2013 to discuss the latest developments in the field of innate immunity and to explore new ideas and research collaborations. PMID- 24048132 TI - IL-1 signaling in atherosclerosis: sibling rivalry. PMID- 24048123 TI - Innate and adaptive immune cells in the tumor microenvironment. AB - Most tumor cells express antigens that can mediate recognition by host CD8(+) T cells. Cancers that are detected clinically must have evaded antitumor immune responses to grow progressively. Recent work has suggested two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment. One major subset shows a T cell-inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These tumors appear to resist immune attack through the dominant inhibitory effects of immune system suppressive pathways. The other major phenotype lacks this T cell-inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect. PMID- 24048133 TI - GATA-3 controls self-renewal in stressed HSCs. PMID- 24048134 TI - Fingerprinting ikaros. PMID- 24048141 TI - Visceral adiposity index, hypertriglyceridemic waist and risk of diabetes: the China Health and Nutrition Survey 2009. AB - BACKGROUND: The visceral adiposity index (VAI) and hypertriglyceridemic waist phenotype (the simultaneous presence of waist circumference (WC)>=90/80 cm for men/women and plasma triglyceride (TG) concentration >=1.7 mmol l(-1) for both genders) have been identified as good indicators of visceral adiposity, which is an independent risk factor for diabetes. The Chinese population is characterized by a predominance of visceral fat accumulation despite having comparatively low weight. These two surrogate markers of visceral adiposity might effectively identify Chinese adults who are at risk of getting diabetes. We aimed to examine the association between VAI and risk of diabetes or between the hypertriglyceridemic waist phenotype and diabetes risk. METHODS: We conducted a cross-sectional analysis of 7639 Chinese men and women aged >=18 years using data from the China Health and Nutrition Survey 2009. Logistic regression was used to evaluate the associations. RESULTS: For men, compared with participants in the lowest quartile of VAI scores, the multivariable-adjusted odds ratios (ORs) (with 95% confidence intervals) for diagnosed diabetes were 1.1 (0.7-1.7), 1.9 (1.3 2.8) and 3.6 (2.5-5.3) for those in the second, third, and top quartile of VAI scores, respectively. For women, the corresponding figures were 0.9 (0.5-1.4), 1.7 (1.1-2.6) and 2.8 (1.9-4.2), respectively. The multivariate-adjusted ORs (with 95% confidence intervals) for diabetes in men with the hypertriglyceridemic waist phenotype compared with men with both WC and TG measurements below the defined cut points were 3.7 (2.6-5.4). For women, the corresponding figure was 3.7 (2.4-5.5). For both men and women, the associations between the 4th quartile of VAI scores and risk of diabetes or between the hypertriglyceridemic waist phenotype and risk of diabetes were consistently seen in various subgroups. CONCLUSION: Among Chinese adults, high VAI scores and the hypertriglyceridemic waist phenotype are strongly associated with diabetes risk. PMID- 24048142 TI - The effect of physical exercise strategies on weight loss in postpartum women: a systematic review and meta-analysis. AB - For women of reproductive age, excessive gestational weight gain and/or postpartum weight retention can increase the risk of obesity. This systematic review evaluates the effectiveness of lifestyle modification control trials that utilize exercise interventions, with or without dietary intervention, on weight loss among postpartum women. A search of randomized clinical trials (RCT) was performed using the follow databases and the bibliography of candidate studies: MEDLINE, Web of Science, EMBASE, CENTRAL/Cochrane and Physiotherapy Evidence Database. English language RCT papers published up to 31 October 2012, which present changes on maternal body weight from baseline to the end of exercise intervention were included. The primary meta-analysis examined the effects of exercise interventions, with or without complementary dietary intervention, on weight loss during the postpartum period compared with usual standard of care. Five subgroup analyses were performed to examine differences in study interventions and exercise modalities: duration of intervention, quality of study methodology, supervision of exercise intervention, exercise intervention goals used and the type of dietary intervention. In total 11 studies met eligibility criteria with 769 participants, 409 under intervention and 360 in the control group. The primary meta-analysis included all 11 studies and found a mean difference (MD) on weight loss of -2.57 kg (95% CI -3.66 to -1.47). The subgroup analysis demonstrated that the most effective interventions in reducing weight in postpartum women were exercise programs with objectively defined goals, such as the use of heart rate monitors or pedometer (MD of -4.09 kg-95% CI -4.94 to 3.25, I(2)=0%) and exercise combined with intensive dietary intervention (MD of 4.34 kg-95% CI -5.15 to -3.52, I(2)=0%). Thus, there is benefit from overall lifestyle interventions on weight loss in postpartum women and exercise plus intensive diet and objective targets are the most effective intervention strategies. PMID- 24048143 TI - Central sleep apnea in obese children with sleep-disordered breathing. AB - OBJECTIVES: In contrast to obstructive sleep apnea (OSA), central sleep apnea (CSA) in obese children has received lesser attention. As pediatric CSA is more prevalent than expected and adversely impacts health, this study aims to elucidate the major factors associated with central apnea index (CAI) and compare CSA between obese and non-obese children. METHODS: Retrospective analysis was performed in a tertiary referral medical center. Children with sleep-disordered breathing (SDB) ranging from 2-18 years old were enrolled. All participants completed history taking, otolaryngological examination and overnight polysomnography. CSA was defined as having CAI exceeding 1 h(-1). CAI and the prevalence of CSA were analyzed in children of different age groups, weight statuses and adenotonsillar sizes. RESULTS: A total of 487 cases were included. The prevalence of CSA was 13.3% (65/487). CAI was negatively correlated with age (r=-0.32, P<0.001). Obese children had a significantly lower CAI than that of non obese ones (0.20 +/- 0.36 vs 0.48 +/- 0.82 h(-1), P<0.001). Multiple linear regression analysis demonstrated a relationship between CAI, age and obesity as 'CAI=0.883-0.055 * Age -0.22 * (Obesity)'. CONCLUSIONS: In children with SDB, younger ones have a significantly higher CAI than older ones. Additionally, obese children had a lower CAI than non-obese ones. PMID- 24048145 TI - Hypertension treatment at the crossroads: a role for economics? PMID- 24048144 TI - Bariatric surgery in adolescents and young adults--safety and effectiveness in a cohort of 345 patients. AB - OBJECTIVE: To examine the safety and effectiveness of adolescent bariatric surgery and to improve treatment recommendations for this age group. DESIGN: Prospective longitudinal registry. Since January 2005, patients undergoing bariatric surgery in Germany are enlisted in an online registry called 'study for quality assurance in obesity surgeries'. SUBJECTS: Adolescents and young adults up to the age of 21 years, operated from January 2005 to December 2010. MEASUREMENTS: Weight, BMI, comorbidities, complication rates. RESULTS: N=345 primary procedures were recorded by 58 hospitals. N=51 patients were under the age of 18 years. Follow-up information was available for 48% (n=167) of patients, with an average observation period of 544+/-412 days (median: 388 days). The most common surgical techniques were gastric banding (n=118, 34.2%), gastric bypass (n=116, 33.6%) and sleeve gastrectomy (n=78, 22.6%). Short-term complications (intra-operative; general postoperative; specific postoperative) were slightly lower for gastric banding (0.8%; 2.5%; 0.8%) than for gastric bypass (2.6%; 5.2%; 1.7%) or sleeve gastrectomy (0%; 9.0%; 7.7%). In accordance with published findings, weight and BMI reduction were lower for gastric banding (-28 kg; -9.5 kg m(-2)) compared to gastric bypass (-50 kg; -16.4 kg m(-2)) P< 0.001 or sleeve gastrectomy (-46 kg; -15.4 kg m(-2)) P< 0.001. Outcomes did not differ between the <18 and >=18-year-old patients. CONCLUSION: Like in adults, bariatric surgery has low short-term complication rates and results in sustained weight loss in adolescents. However, the missing long-term observations prohibit a final conclusion about lasting effectiveness and safety. Clinical trials with structured follow-up programs and mechanisms to ascertain patient adherences are needed. PMID- 24048146 TI - Morning blood pressure surge, dipping, and risk of ischemic stroke in elderly patients treated for hypertension. AB - BACKGROUND: The independent prognostic significance of morning surge (MS) in blood pressure (BP) is not yet clear. We investigated the association between MS in systolic BP (SBP) and risk of ischemic stroke in elderly patients treated for hypertension. METHODS: Occurrence of ischemic stroke was evaluated in 1,191 elderly patients treated for hypertension (aged 60-90 years). Patients were divided according to tertiles of MS in SBP in the population as a whole, dipping status, and group-specific tertiles of MS in SBP in dippers and nondippers. RESULTS: During follow-up (9.1+/-4.9 years, range 0.4-20 years), 139 ischemic strokes occurred. The event rate per 100 patient-years was 1.28. After adjustment for various covariates, Cox regression analysis showed that stroke risk was not significantly associated with tertiles of MS in SBP in the population as a whole. When nondippers and dippers were analyzed separately by group-specific tertiles of MS in SBP, stroke risk was not associated with MS in nondippers. Conversely, in dippers, stroke risk was significantly higher in the third tertile (>23mm Hg) of MS in SBP (hazard ratio, 2.08; 95% confidence interval, 1.03-4.23; P = 0.04). Additional analysis showed that stroke risk was significantly and similarly higher in dippers with MS >23mm Hg and in nondippers than in dippers with MS <23mm Hg. CONCLUSIONS: In elderly patients treated for hypertension, high MS in SBP predicts stroke in dippers but not in nondippers. Nondippers are at high stroke risk with or without MS >23mm Hg. PMID- 24048147 TI - Cost-effectiveness of renin-guided treatment of hypertension. AB - BACKGROUND: A plasma renin activity (PRA)-guided strategy is more effective than standard care in treating hypertension (HTN). However, its clinical implementation has been slow, presumably due in part to economic concerns. We estimated the cost effectiveness of a PRA-guided treatment strategy compared with standard care in a treated but uncontrolled HTN population. METHODS: We estimated costs, quality-adjusted life years (QALYs), and the incremental cost effectiveness ratio (ICER) of PRA-guided therapy compared to standard care using a state-transition simulation model with alternate patient characteristic scenarios and sensitivity analyses. Patient-specific inputs for the base case scenario, males average age 63 years, reflected best available data from a recent clinical trial of PRA-guided therapy. Transition probabilities were estimated using Framingham risk equations or derived from the literature; costs and utilities were derived from the literature. RESULTS: In the base case scenario for males, the lifetime discounted costs and QALYs were $23,648 and 12.727 for PRA-guided therapy and $22,077 and 12.618 for standard care, respectively. The base case ICER was $14,497/QALY gained. In alternative scenario analyses varying patient input parameters, the results were sensitive to age, gender, baseline systolic blood pressure, and the addition of cardiovascular risk factors. Univariate sensitivity analyses demonstrated that results were most sensitive to varying the treatment effect of PRA-guided therapy and the cost of the PRA test. CONCLUSIONS: Our results suggest that PRA-guided therapy compared with standard care increases QALYs and medical costs in most scenarios. PRA-guided therapy appears to be most cost effective in younger persons and those with more cardiovascular risk factors. PMID- 24048149 TI - Acute febrile neutrophilic dermatosis (Sweet's syndrome) in a patient with biliary sepsis. PMID- 24048148 TI - Obesity and overweight associated with increased carotid diameter and decreased arterial function in young otherwise healthy men. AB - BACKGROUND: Obesity is linked to cardiovascular disease, stroke, increased mortality and vascular remodeling. Although increased arterial diameter is associated with multiple cardiovascular risk factors and obesity, it is unknown whether lumen enlargement is accompanied by unfavorable vascular changes in young and otherwise healthy obese individuals. The purpose of this study was to compare carotid and brachial artery diameter, blood pressure, arterial stiffness, and endothelial function in young, apparently healthy, normal-weight, overweight, and obese male subjects. METHODS: One hundred sixty-five male subjects (27.39+/-0.59 years) were divided into 3 groups (normal weight, overweight, and obese) according to body mass index. Subjects underwent cardiovascular measurements to determine arterial diameter, function, and stiffness. RESULTS: After adjusting for age, the obese group had significantly greater brachial, carotid, and aortic pressures, brachial pulse wave velocity, carotid intima media thickness, and carotid arterial diameter compared with both the overweight and normal-weight groups. CONCLUSIONS: Obesity is associated with a much worse arterial profile, as an increased carotid lumen size was accompanied by higher blood pressure, greater arterial stiffness, and greater carotid intima media thickness in obese compared with overweight or normal-weight individuals. These data suggest that although obesity may be a factor in arterial remodeling, such remodeling is also accompanied by other hemodynamic and arterial changes consistent with reduced arterial function and increased cardiovascular risk. PMID- 24048150 TI - On the signal depletion induced by stretching excitation of methane in the reaction with the F atom. AB - Exciting a stretching mode of a chemical bond should help its breaking during a chemical reaction, according to conventional wisdom. In several recent studies of the reactions of stretch-excited methane (and isotopologues) with the F atom, counterintuitively, we found that the induced reactant vibrations instead inhibit the bond rupture and slow down the overall reaction rate. This intriguing observation has been qualitatively ascribed to the vibrationally induced steric effects of the reaction in previous reports. However, quantitative determination of the reactivity suppression in terms of reaction cross sections remains lacking. In this report, we scrutinize the physical meaning of this (product) signal depletion phenomenon and fill the gap. Through a systematic investigation we further elucidate the additional reaction dynamics information that can be retrieved from the depletion measurements. The resultant rotationally state selected reaction cross sections for both the vibrational ground and excited states are presented, and the stereodynamical implications are delineated. PMID- 24048151 TI - Estimated percentages and characteristics of men who have sex with men and use injection drugs--United States, 1999-2011. AB - Male-to-male sex and illicit injection drug use are important transmission routes for human immunodeficiency virus (HIV) infection. Of all new HIV infections in 2010, 80% were among men, of which 78% were among men who have sex with men (MSM), 6% among male injection drug users (IDU), and 4% among men who have sex with men and inject drugs (MSM/IDU). MSM/IDU might have different prevention needs from men who are either MSM or IDU, but not both. A combination of effective, scalable, and evidence-based approaches that address male-to-male sex and injection drug use behaviors might reduce HIV infections among MSM/IDU. To refine calculations of disease rates attributed to MSM and IDU by accounting for MSM/IDU, CDC used data from 1999-2008 National Health and Nutrition Examination Survey (NHANES) to estimate the percentage and number of MSM/IDU in the general population. To further describe demographic similarities and differences of MSM/IDU identified by different surveillance systems, CDC also compared data from four HIV surveillance systems: the 2008 and 2009 National HIV Behavioral Surveillance System (NHBS), the 2011 National HIV Surveillance System (NHSS), and the 2007-2009 Medical Monitoring Project (MMP). Of males aged >= 18 years, MSM/IDU comprised an estimated 0.35% in NHANES, 7%-20% in NHBS, an estimated 4% 8% in NHSS, and 9% in MMP. Across surveillance systems, MSM/IDU accounted for 4% 12% of MSM and 11%-39% of male IDU. Risk reduction programs and interventions targeted toward male IDU populations might be more effective if they also incorporate messages about male-to-male sex. PMID- 24048152 TI - Impact of a national tobacco education campaign on weekly numbers of quitline calls and website visitors--United States, March 4-June 23, 2013. AB - During March 4-June 23, 2013, CDC conducted its second annual national paid-media tobacco education campaign encouraging adult smokers to quit. These campaigns, called Tips from Former Smokers (Tips), feature true stories of former smokers living with serious smoking-related diseases. To assess the immediate impact of the 2013 Tips campaign, CDC analyzed the weekly numbers of calls to the national telephone quitline portal (1-800-QUIT-NOW) and the weekly numbers of unique visitors to the Tips website (http://www.cdc.gov/tips)* during the 16-week campaign and during the 4 weeks before and after the campaign. During the campaign, the average weekly numbers of calls and website visitors increased by 75% and almost 38-fold, respectively, compared with the 4 weeks before the campaign, and quickly decreased almost to pre-campaign levels once the campaign ended. This suggests that the campaign led to 151,536 additional quitline calls and nearly 2.8 million additional unique Tips website visitors above pre-campaign levels. During the first 12 weeks of the campaign,? when the national television ads were on and off air on alternate weeks, average weekly call volume fell by 38% during the 6 weeks when the national television ads were off air compared with the 6 weeks when these ads were running. These results suggest that emotionally evocative tobacco education media campaigns featuring graphic images of the health effects of smoking can increase quitline calls and website visits and that these campaigns' effects decrease rapidly once they are discontinued. PMID- 24048153 TI - Assessing the risks for poliovirus outbreaks in polio-free countries--Africa, 2012-2013. AB - In 2012, the World Health Assembly of the World Health Organization (WHO) declared the completion of polio eradication a programmatic emergency. Indigenous wild poliovirus (WPV) transmission remains uninterrupted in Nigeria (in the WHO African Region [AFR]) and in Afghanistan and Pakistan (in the WHO Eastern Mediterranean Region [EMR]). In the WHO AFR, multiple WPV outbreaks have occurred since 2003 after importation of indigenous West African WPV into 21 previously polio-free countries in a "WPV importation belt"* that extends across the continent. The Global Polio Eradication Initiative (GPEI) and WHO regional offices have used indicators of population immunity, surveillance quality, and other factors (e.g., high-risk subpopulations and proximity to WPV-affected countries) to assess the risk for outbreaks in polio-free countries and guide the implementation of risk mitigation measures to limit poliovirus transmission after WPV importation and prevent the emergence of circulating vaccine-derived poliovirus (cVDPV). Despite risk mitigation efforts, a polio outbreak, first confirmed in May 2013, is ongoing; as of September 10, a total of 178 WPV type 1 (WPV1) cases have been reported in Somalia? (163 cases), Kenya (14 cases) and Ethiopia (1 case), after importation of WPV1 of West African origin. This report summarizes steps taken by the GPEI to assess and mitigate the risks for outbreaks after WPV importation or the emergence of cVDPV in polio-free countries within the WHO AFR's "WPV importation belt." All countries will continue to have some level of risk for WPV outbreaks as long as endemic circulation continues in Afghanistan, Nigeria, and Pakistan. PMID- 24048154 TI - Adaptive radiation of chemosymbiotic deep-sea mussels. AB - Adaptive radiations present fascinating opportunities for studying the evolutionary process. Most cases come from isolated lakes or islands, where unoccupied ecological space is filled through novel adaptations. Here, we describe an unusual example of an adaptive radiation: symbiotic mussels that colonized island-like chemosynthetic environments such as hydrothermal vents, cold seeps and sunken organic substrates on the vast deep-sea floor. Our time calibrated molecular phylogeny suggests that the group originated and acquired sulfur-oxidizing symbionts in the Late Cretaceous, possibly while inhabiting organic substrates and long before its major radiation in the Middle Eocene to Early Oligocene. The first appearance of intracellular and methanotrophic symbionts was detected only after this major radiation. Thus, contrary to expectations, the major radiation may have not been triggered by the evolution of novel types of symbioses. We hypothesize that environmental factors, such as increased habitat availability and/or increased dispersal capabilities, sparked the radiation. Intracellular and methanotrophic symbionts were acquired in several independent lineages and marked the onset of a second wave of diversification at vents and seeps. Changes in habitat type resulted in adaptive trends in shell lengths (related to the availability of space and energy, and physiological trade-offs) and in the successive colonization of greater water depths. PMID- 24048156 TI - A parasitic selfish gene that affects host promiscuity. AB - Selfish genes demonstrate transmission bias and invade sexual populations despite conferring no benefit to their hosts. While the molecular genetics and evolutionary dynamics of selfish genes are reasonably well characterized, their effects on hosts are not. Homing endonuclease genes (HEGs) are one well-studied family of selfish genes that are assumed to be benign. However, we show that carrying HEGs is costly for Saccharomyces cerevisiae, demonstrating that these genetic elements are not necessarily benign but maybe parasitic. We estimate a selective load of approximately 1-2% in 'natural' niches. The second aspect we examine is the ability of HEGs to affect hosts' sexual behaviour. As all selfish genes critically rely on sex for spread, then any selfish gene correlated with increased host sexuality will enjoy a transmission advantage. While classic parasites are known to manipulate host behaviour, we are not aware of any evidence showing a selfish gene is capable of affecting host promiscuity. The data presented here show a selfish element may increase the propensity of its eukaryote host to undergo sex and along with increased rates of non-Mendelian inheritance, this may counterbalance mitotic selective load and promote spread. Demonstration that selfish genes are correlated with increased promiscuity in eukaryotes connects with ideas suggesting that selfish genes promoted the evolution of sex initially. PMID- 24048157 TI - Extended disease resistance emerging from the faecal nest of a subterranean termite. AB - Social insects nesting in soil environments are in constant contact with entomopathogens but have evolved a range of defence mechanisms, resulting in both individual and social immunity that reduce the chance for epizootics in the colony, as in the case of subterranean termites. Coptotermes formosanus uses its faeces as building material for its nest structure that result into a 'carton material', and here, we report that the faecal nest supports the growth of Actinobacteria which provide another level of protection to the social group against entomopathogens. A Streptomyces species with in vivo antimicrobial activity against fungal entomopathogens was isolated from the nest material of multiple termite colonies. Termite groups were exposed to Metarhizium anisopliae, a fungal entomopathogen, during their foraging activity and the presence of Streptomyces within the nest structure provided a significant survival benefit to the termites. Therefore, this report describes a non-nutritional exosymbiosis in a termite, in the form of a defensive mutualism which has emerged from the use of faecal material in the nesting structure of Coptotermes. The association with an Actinobacteria community in the termite faecal material provides an extended disease resistance to the termite group as another level of defence, in addition to their individual and social immunity. PMID- 24048158 TI - Classification of grass pollen through the quantitative analysis of surface ornamentation and texture. AB - Taxonomic identification of pollen and spores uses inherently qualitative descriptions of morphology. Consequently, identifications are restricted to categories that can be reliably classified by multiple analysts, resulting in the coarse taxonomic resolution of the pollen and spore record. Grass pollen represents an archetypal example; it is not routinely identified below family level. To address this issue, we developed quantitative morphometric methods to characterize surface ornamentation and classify grass pollen grains. This produces a means of quantifying morphological features that are traditionally described qualitatively. We used scanning electron microscopy to image 240 specimens of pollen from 12 species within the grass family (Poaceae). We classified these species by developing algorithmic features that quantify the size and density of sculptural elements on the pollen surface, and measure the complexity of the ornamentation they form. These features yielded a classification accuracy of 77.5%. In comparison, a texture descriptor based on modelling the statistical distribution of brightness values in image patches yielded a classification accuracy of 85.8%, and seven human subjects achieved accuracies between 68.33 and 81.67%. The algorithmic features we developed directly relate to biologically meaningful features of grass pollen morphology, and could facilitate direct interpretation of unsupervised classification results from fossil material. PMID- 24048155 TI - Molecular and fossil evidence place the origin of cichlid fishes long after Gondwanan rifting. AB - Cichlid fishes are a key model system in the study of adaptive radiation, speciation and evolutionary developmental biology. More than 1600 cichlid species inhabit freshwater and marginal marine environments across several southern landmasses. This distributional pattern, combined with parallels between cichlid phylogeny and sequences of Mesozoic continental rifting, has led to the widely accepted hypothesis that cichlids are an ancient group whose major biogeographic patterns arose from Gondwanan vicariance. Although the Early Cretaceous (ca 135 Ma) divergence of living cichlids demanded by the vicariance model now represents a key calibration for teleost molecular clocks, this putative split pre-dates the oldest cichlid fossils by nearly 90 Myr. Here, we provide independent palaeontological and relaxed-molecular-clock estimates for the time of cichlid origin that collectively reject the antiquity of the group required by the Gondwanan vicariance scenario. The distribution of cichlid fossil horizons, the age of stratigraphically consistent outgroup lineages to cichlids and relaxed clock analysis of a DNA sequence dataset consisting of 10 nuclear genes all deliver overlapping estimates for crown cichlid origin centred on the Palaeocene (ca 65-57 Ma), substantially post-dating the tectonic fragmentation of Gondwana. Our results provide a revised macroevolutionary time scale for cichlids, imply a role for dispersal in generating the observed geographical distribution of this important model clade and add to a growing debate that questions the dominance of the vicariance paradigm of historical biogeography. PMID- 24048160 TI - Nerve ultrasound in CIDP: poly-parameters for polyneuropathies. PMID- 24048159 TI - Complex environmental drivers of immunity and resistance in malaria mosquitoes. AB - Considerable research effort has been directed at understanding the genetic and molecular basis of mosquito innate immune mechanisms. Whether environmental factors interact with these mechanisms to shape overall resistance remains largely unexplored. Here, we examine how changes in mean ambient temperature, diurnal temperature fluctuation and time of day of infection affected the immunity and resistance of Anopheles stephensi to infection with Escherichia coli. We used quantitative PCR to estimate the gene expression of three immune genes in response to challenge with heat-killed E. coli. We also infected mosquitoes with live E. coli and ran bacterial growth assays to quantify host resistance. Both mosquito immune parameters and resistance were directly affected by mean temperature, diurnal temperature fluctuation and time of day of infection. Furthermore, there was a suite of complex two- and three-way interactions yielding idiosyncratic phenotypic variation under different environmental conditions. The results demonstrate mosquito immunity and resistance to be strongly influenced by a complex interplay of environmental variables, challenging the interpretation of the very many mosquito immune studies conducted under standard laboratory conditions. PMID- 24048161 TI - Fish Oil (SMOFlipid) and olive oil lipid (Clinoleic) in very preterm neonates. AB - OBJECTIVES: Fat emulsions used in Australia for parenteral nutrition in preterm neonates have been based on either soybean oil or olive oil (OO). OO lipid Clinoleic has a high ratio of n-6 to n-3 fatty acids (9:1); this may not be ideal for long-chain polyunsaturated fatty acids supply. Newly available SMOFlipid has an appropriate ratio of n-6 to n-3 fatty acids (2.5:1). SMOFlipid also contains OO (25%), coconut oil (30%), and soybean oil (30%). The aims of the study were to evaluate the safety of the SMOFlipid and to test the hypothesis that SMOFlipid would lead to increased omega-3 long-chain polyunsaturated fatty acid levels and reduced oxidative stress as compared with Clinoleic in preterm neonates (<30 weeks). METHODS: Preterm neonates (23-30 weeks) were randomised to receive Clinoleic or SMOFlipid emulsion for 7 days. Investigators and outcome assessors were masked to allocation. Plasma F2-isoprostanes (lipid peroxidation marker), red blood cell fatty acids, and vitamin E were measured before and after the study. Blood culture positive sepsis and growth were monitored for safety. RESULTS: Thirty of 34 participants completed the study. Both emulsions were well tolerated without any adverse events. F2-isoprostane levels were reduced in the SMOFlipid group as compared with baseline. Eicosapentanoic acid and vitamin E levels were significantly increased in the SMOFlipid group. Oleic acid and linoleic acid levels were increased in both groups. No significant differences were noted in poststudy docosahexaenoic acid levels in both groups despite higher levels of docosahexaenoic acid in SMOFlipid. CONCLUSIONS: SMOFlipid was safe, well tolerated, and showed beneficial effect in terms of reduction of oxidative stress by reducing lipid peroxidation levels in high-risk preterm neonates. PMID- 24048162 TI - Lubiprostone for the treatment of functional constipation in children. AB - OBJECTIVES: Pediatric functional constipation is common; effective, easily administered treatment options are limited. Lubiprostone is an oral chloride channel protein-2 activator that stimulates gastrointestinal fluid secretion, softens stools, and facilitates bowel movements (BMs). We evaluated the safety and effectiveness of lubiprostone in children and adolescents with functional constipation. METHODS: Patients >=12 kg, 17 years or younger, and with <3 spontaneous BMs (SBMs; ie, BMs that did not occur within 24 hours of rescue medication use) per week were enrolled at 22 US general pediatric and pediatric gastroenterology centers (January 2007-October 2008). Patients received 4 weeks of open-label lubiprostone at doses of 12 MUg once daily (QD), 12 MUg twice daily (BID), or 24 MUg BID based on age and weight. The primary endpoint was SBM frequency during week 1 versus baseline. RESULTS: Of 127 enrolled patients, 124 were treated and analyzed (12 MUg QD, n = 27; 12 MUg BID, n = 65; 24 MUg BID, n = 32), and 109 completed the study. The mean age of treated patients was 10.2 years (range 3-17 years); 65 were boys. Mean SBM frequency significantly increased compared with baseline at week 1 (3.1 vs. 1.5 SBMs/week, P < 0.0001). SBM frequency was improved significantly from baseline overall (P < 0.0001) and for individual dose groups (P <= 0.0062) during weeks 2, 3, and 4. Common (>=5%) adverse events included nausea (18.5%), vomiting (12.1%), diarrhea (8.1%), abdominal pain (7.3%), and headache (5.6%). Two patients experienced serious adverse events (unrelated abdominal pain; unrelated sickle cell crisis). CONCLUSIONS: Lubiprostone was efficacious and well tolerated in children and adolescents with functional constipation. PMID- 24048163 TI - ERCP can be safely and effectively performed by a pediatric gastroenterologist for choledocholithiasis in a pediatric facility. AB - OBJECTIVE: The aim of this study was to demonstrate that an appropriately trained pediatric gastroenterologist can perform endoscopic retrograde cholangiopancreatography (ERCP) for suspected choledocholithiasis both safely and effectively. METHODS: Retrospective analysis of ERCP experience from November 2006 to May 2012. Only ERCPs performed by a pediatric gastroenterologist on pediatric patients for the indication of suspected choledocholithiasis were included for formal chart review. Patient characteristics, procedural success, and adverse events were recorded, and subsequently compared with quality standards as defined by the American Society for Gastrointestinal Endoscopy Quality Task Force. RESULTS: A total of 154 ERCPs were performed, of which 65 (42%) were performed on unique patients for the indication of suspected choledocholithiasis. The median age was 15.2 years (range 1 month-18.4 years). The median weight was 65 kg (range 4-127 kg). Biliary cannulation was achieved in 65 (100%). All 65 patients underwent sphincterotomy. Ductal clearance was achieved in 64 (98%) patients during the initial ERCP session. Adverse events included 3 (5%) episodes of mild pancreatitis, 1 episode of moderate bleeding, and 1 episode of sphincterotomy clot causing obstruction and need for repeat ERCP within 1 week. Overall, 5 (8%) unique patients experienced a complication. CONCLUSIONS: Therapeutic ERCP for the indication of choledocholithiasis can be performed by an appropriately trained pediatric gastroenterologist at a pediatric facility with acceptable cannulation rates, stone extraction rates, and adverse event rates as defined by the American Society for Gastrointestinal Endoscopy Quality Task Force. PMID- 24048164 TI - New diagnostic method for lysosomal acid lipase deficiency and the need to recognize its manifestation in infants (Wolman disease). PMID- 24048165 TI - Fecal calprotectin and pediatric juvenile polyps. PMID- 24048166 TI - Bitterness of glucose/galactose: novel mutations in the SLC5A1 gene. AB - Glucose galactose malabsorption (GGM) is a rare autosomal recessive disorder characterized by life-threatening osmotic diarrhea at infancy. When the intake of the offending sugars (namely, glucose, galactose and lactose) is ceased, the diarrhea promptly stops. Mutations in the SLC5A1 gene, encoding the sodium glucose co-transporter located in the brush border of enterocytes, have been shown to cause the disease. More than 300 subjects of diverse origin have been reported worldwide, most of whom are a result of a consanguineous union. We examined 6 patients from 4 families presenting with complaints consistent with GGM and responsive to the appropriate fructose-based diet. Genomic DNA of the patients was polymerase chain reaction amplified for each of the 15 exons of the SLC5A1 gene and analyzed by nucleotide sequencing. The analysis lead to the identification of 2 novel mutations: a 1915 del C mutation, a frameshift mutation leading to a premature stop at codon 645; and a substitution missense mutation of T to C on nucleotide 947 (exon 9) causing a L316P substitution. In addition, G426R and C255W mutations previously described were identified; in both cases, the patients were shown to be homozygous and their parents heterozygous for the mutation. Of note, additional patients who underwent a similar evaluation at our center for suspected GGM did not show mutations in the SLC5A1 gene. Because the latter did not previously undergo a diagnostic algorithm in full, for instance, one that may consist of a glucose breath hydrogen test and an empiric attempt of a dietary switch to galactomin, we suggest that molecular genotyping of such patients should only follow such appropriate clinical evaluation. PMID- 24048167 TI - A novel nonsense mutation in the EpCAM gene in a patient with congenital tufting enteropathy. AB - OBJECTIVES: Tufting enteropathy (TE) is a classical congenital disorder of the intestinal mucosa causing protracted diarrhea in infancy as a result of a dysfunctional epithelial cell barrier, which is mainly caused by mutations in the EpCAM gene and expression of a nonfunctional epithelial cell adhesion molecule in the intestine. We report here a novel nonsense mutation in a patient suspected of having TE, resulting in a complete absence of EpCAM in duodenal enterocytes. METHODS: A patient presenting with congenital diarrhea and suspected of having TE was screened for EpCAM mutations, and duodenal biopsies were stained for EpCAM using immunohistochemistry analysis. RESULTS: We identified a novel homozygous nonsense mutation in the EpCAM gene in a patient suspected of having TE, causing a complete loss of EpCAM expression in duodenal enterocytes. CONCLUSIONS: With screening analysis for EpCAM mutations and immunohistochemistry for EpCAM expression in duodenal enterocytes, we found a novel homozygous mutation in a patient with classical protracted diarrhea in infancy finally diagnosed as TE, which results in a complete absence of EpCAM and in dysfunctional barrier formation in duodenal enterocytes. PMID- 24048168 TI - Nutritional therapy in pediatric Crohn disease: the specific carbohydrate diet. AB - OBJECTIVES: Crohn disease is characterized by chronic intestinal inflammation in the absence of a recognized etiology. Nutritional therapy in the form of exclusive enteral nutrition (EEN) has an established role within pediatric Crohn disease. Following exclusive enteral nutrition's success, many dietary therapies focusing on the elimination of specific complex carbohydrates have been anecdotally reported to be successful. METHODS: Many of these therapies have not been evaluated scientifically; therefore, we reviewed the medical records of our patients with Crohn disease on the specific carbohydrate diet (SCD). RESULTS: Seven children with Crohn disease receiving the SCD and no immunosuppressive medications were retrospectively evaluated. Duration of the dietary therapy ranged from 5 to 30 months, with an average of 14.6+/-10.8 months. Although the exact time of symptom resolution could not be determined through chart review, all symptoms were notably resolved at a routine clinic visit 3 months after initiating the diet. Each patient's laboratory indices, including serum albumin, C-reactive protein, hematocrit, and stool calprotectin, either normalized or significantly, improved during follow-up clinic visits. CONCLUSIONS: This chart review suggests that the SCD and other low complex carbohydrate diets may be possible therapeutic options for pediatric Crohn disease. Further prospective studies are required to fully assess the safety and efficacy of the SCD, or any other low complex SCDs in pediatric patients with Crohn disease. PMID- 24048169 TI - Human milk oligosaccharides protect against enteropathogenic Escherichia coli attachment in vitro and EPEC colonization in suckling mice. AB - Breast-feeding reduces the risk of enteric bacterial infections in newborns in part because of human milk oligosaccharides (HMOs), complex glycans that are present in human milk, but not in infant formula. Enteropathogenic Escherichia coli (EPEC) are attaching/effacing pathogens that cause serious diarrheal illness with potentially high mortality in infants. We isolated HMOs from pooled human milk and found that they significantly reduce EPEC attachment to cultured epithelial cells. In suckling mice, administration of HMOs significantly reduced colonization with EPEC compared with untreated controls. These data suggest an essential role for HMOs in the prevention of EPEC infections in human infants. PMID- 24048170 TI - Outcomes following infliximab therapy for pediatric patients hospitalized with refractory colitis-predominant IBD. AB - OBJECTIVES: Although randomized trials demonstrated the efficacy of infliximab for both pediatric Crohn disease and ulcerative colitis (UC), few patients in these studies exhibited colitis requiring hospitalization. The aims of this study were to determine the rate of subsequent infliximab failure and dose escalation in pediatric patients who started taking infliximab during hospitalization for colitis-predominant IBD, and to identify potential predictors of these endpoints. METHODS: This is a single-center retrospective cohort study of patients admitted from 2005 to 2010 with Crohn colitis, UC, or IBD-unspecified (IBD-U) and initiated on infliximab. RESULTS: We identified 29 patients (12 Crohn colitis, 15 UC, and 2 IBD-U; median age 14 years) with a median follow-up of 923 days. Eighteen patients (62%) required infliximab dose escalation (increased dose or decreased infusion interval). Infliximab failure occurred in 18 patients (62%) because of ineffectiveness in 12 (67%) and adverse reactions in 6 (33%). Twelve patients (41%) underwent colectomy. Subsequent need for infliximab dose escalation was associated with lower body mass index z score (P = 0.01), lower serum albumin (P = 0.03), and higher erythrocyte sedimentation rate (ESR) (P = 0.002) at baseline. ESR predicted subsequent infliximab dose escalation with an area under the curve of 0.89 (95% confidence interval [CI] 0.72-1.00) and a sensitivity and specificity at a cutoff of 38 mm/hour of 0.79 (95% CI 0.49-0.95) and 0.88 (95% CI 0.47-0.99), respectively. CONCLUSIONS: Most hospitalized pediatric patients with colitis treated with infliximab require early-dose escalation and fail the drug long term. Low body mass index and albumin and high ESR, may identify patients who would benefit from a higher infliximab starting dose. PMID- 24048172 TI - A node-based switch for preferential distribution of manganese in rice. AB - Mineral nutrients, such as manganese, are required for the development of plants and their reproductive organs, but these can be toxic if accumulated at high concentrations. Therefore, plants must have a system for preferentially delivering an adequate amount of minerals to these organs for active growth and development, while preventing mineral overaccumulation in the face of changing environments. Here we show that a member of the Nramp transporter family, OsNramp3, functions as a switch in response to environmental Mn changes. OsNramp3 is constitutively expressed in the node, a junction of vasculatures connecting leaves, stems and panicles. At low Mn concentration, OsNramp3 preferentially transports Mn to young leaves and panicles. However, at high Mn concentration, the OsNramp3 protein is rapidly degraded within a few hours, resulting in the distribution of Mn to old tissues. Our results reveal the OsNramp3-mediated strategy of rice for adapting to a wide change of Mn in the environment. PMID- 24048173 TI - Intracoronary electrocardiogram ST-segment elevation in patients with non-ST segment elevation myocardial infarction and its association with culprit lesion location and myocardial injury. AB - AIMS: An intracoronary electrocardiogram (IC-ECG) is a sensitive method to detect local myocardial ischaemia. We investigated the prevalence of IC-ECG ST-segment elevation (STE) with respect to culprit lesion location in patients with non-ST segment elevation myocardial infarction (NSTEMI) and its relationship with elevated levels of cardiac biomarkers. METHODS AND RESULTS: We examined 87 NSTEMI patients who underwent IC-ECG recording by locating the insulated polymer-coated guidewire distal to the culprit lesion before percutaneous coronary intervention (PCI). Cardiac biomarkers were serially examined. IC-ECG STE was observed in 24 patients (27.6%) before PCI, and was significantly more frequent in patients with LCx culprit lesions (LAD vs. LCx vs. RCA, 12.1% vs. 53.3% vs. 16.7%; p<0.001). Peak cardiac troponin I (cTnI) values were associated with IC-ECG STE, ejection fraction (EF), cTnI values on admission, and type B2/C lesions. In multivariate analysis, IC-ECG STE (odds ratio [OR], 5.04; 95% confidence intervals [CI]: 1.51 16.85; p=0.009), and EF (OR, 0.95; 95% CI: 0.90-1.00; p=0.043) were predictors of greater peak cTnI values. CONCLUSIONS: IC-ECG STE was not uncommon in NSTEMI patients, particularly those with LCx culprit lesions. IC-ECG monitoring before PCI may help identify NSTEMI patients with high risk of greater myocardial injury. PMID- 24048171 TI - Anti-LRP/LR specific antibody IgG1-iS18 and knock-down of LRP/LR by shRNAs rescue cells from Abeta42 induced cytotoxicity. AB - Alzheimer's disease (AD) is characterized by neurofibrillary tangles, senile plaques and neuronal loss. Amyloid beta (Abeta) is proposed to elicit neuronal loss through cell surface receptors. As Abeta shares common binding partners with the 37 kDa/67 kDa laminin receptor (LRP/LR), we investigated whether these proteins interact and the pathological significance of this association. An LRP/LR-Alphabeta42 interaction was assessed by immunofluorescence microscopy and pull down assays. The cell biological effects were investigated by 3-(4,5 Dimethylthaizol-2-yl)-2,5-diphenyltetrazolium bromide and Bromodeoxyuridine assays. LRP/LR and Alphabeta42 co-localised on the cell surface and formed immobilized complexes suggesting an interaction. Antibody blockade by IgG1-iS18 and shRNA mediated down regulation of LRP/LR significantly enhanced cell viability and proliferation in cells co-treated with Alphabeta42 when compared to cells incubated with Alphabeta42 only. Results suggest that LRP/LR is implicated in Alphabeta42 mediated cytotoxicity and that anti-LRP/LR specific antibodies and shRNAs may serve as potential therapeutic tools for AD. PMID- 24048174 TI - Explanation of the site-specific spin crossover in Fe(mtz)6(BF4)2. AB - The spin crossover behavior of the two [Fe(mtz)6](2+) complexes occupying different lattice sites in Fe(mtz)6(BF4)2 is addressed by combining quantum chemical calculations with a careful analysis of the crystal structure. It is first established from the calculations that the energy difference between high spin and low spin states depends on the orientation of the tetrazole ligands; small rotation angles favor the low spin state, while for angles larger than ~20 degrees the high spin state is more stable. The crystal structure shows that the two complexes have different average rotation angles of the ligands. It is larger for the site that remains HS down to low temperatures and smaller for the site that shows spin crossover to LS. The origin of the different rotation angles is found to be determined by a subtle interplay amongst steric repulsion between the ligands, HF interactions between the complex and the counterions, and intersite interactions involving NH contacts and pi-pi interactions between the N[double bond, length as m-dash]N double bonds of the tetrazole rings. PMID- 24048175 TI - Music-listening habits with MP3 player in a group of adolescents: a descriptive survey. AB - BACKGROUND: Listening to music through portable MP3 players has become a very popular mode among young people and adolescents. The aim of this study is to investigate the behaviors of adolescents engaged in listening to music with MP3 player and the attendance at clubs (pubs, discotheques) where music is played at high volume. METHODS: Among the 1470 students attending a secondary school in Scandicci (FI) during the school year 2009/2010, 1278 (86.9%) were at school the day of the examination and 1276 completely filled in the questionnaire. Descriptive analysis and univariate and multivariate logistic regression were performed to calculate the degree of association (OR) among the sociodemographic characteristics, listening habits and some factors identified as risky or protective as regards the possibility of developing health disorders. RESULTS: MP3 player users are 88.2% of the sample. Among these, a high proportion engaged behaviours that increase the risk of presenting disorders, including the exposure to high-volume (27.4%). Furthermore, 44.6% use the MP3 while driving. From the regression analysis it emerges that MP3 users showed a sort of addiction: by increasing the time and the occasions of exposure to music, they increased the volume, used maximum or medium-high volume, did not take breaks and did not decrease the volume. CONCLUSIONS: The study points out the spread of risky behavior in music listening, so it is necessary to better inform especially the youngsters and achieve specific preventive interventions. PMID- 24048176 TI - Study for the quality assessment of abstracts presented to Italian public health national conferences: a six years survey. AB - BACKGROUND: Oral and poster presentations at congresses are essential to spread scientific knowledge among the medical community. Many scientific societies have analyzed the quality of papers presented at their meetings but no information on abstracts' evaluation has been presented in Public Health field. DESIGN AND METHODS: This study aims to examine the quality of abstracts presented at annual meetings of Italian Public Health Society (SItI) in the period 2005-2010 through a validated checklist grid, evaluating eight dimensions: Inherency, Structure, Originality, Objectives, Study design, Sources, Results, Conclusions. Each item was scored from 0 to 3 points (max score: 24) and we used the average score in our study (15) as threshold of good quality. A multivariate analysis was performed in order to investigate predictors of score of abstracts presented. RESULTS: A total of 4,399 abstracts (1,172 oral communications, 3,227 posters) was examined. Around 60% were submitted by Universities and around 40% were from Central Italy. The highest quality was found in the fields of Vaccines (average score 18.9), Infectious Diseases (18) and in abstracts submitted by Universities (16.4). Predictors of lower quality identified were geographical area and affiliation (p= 0.002). Abstracts containing well-written Results, Conclusions and Objectives (3 points) were more likely to be of high quality(OR=55.6, OR=41.9, and OR=157.4; p>0.001) CONCLUSIONS: This is the first European study evaluating the quality of abstracts in the public health field. A reliable evaluation tool is fundamental to offer a transparent methodology of assessment and to improve the quality of research. PMID- 24048177 TI - [Hospital care for acute stroke at the Palestrina hospital: comparison of cost and quality of care with an "hospital at home" care model]. AB - INTRODUCTION: In the Lazio Region (Central Italy) the Emergency Care network has been recently re-arranged in order to improve the effectiveness of care. The aim of this paper is to assess the impact of stroke patient care on both cost and organization of the hospital of Palestrina (Lazio Region). METHODOLOGY: An analysis of cost and path of care of all stroke patients (239) with stroke attending the hospital in 2010 has been carried out. RESULTS: The care was more expensive than the one offered to the stroke patients attending the "Hospital at Home" service managed by the San Giovanni Battista Hospital in Turin; moreover the care was incomplete because of the lack of rehabilitation services in the hospital catchment area. CONCLUSION: The care model offered to stroke patient hit by stroke in Palestrina needs to be deeply revised. PMID- 24048178 TI - Perception of smoke-free policies among workers in an Italian Local Health Agency: survey of opinions, knowledge and behaviours. AB - AIM: This study evaluated the opinions and knowledge of the Health-Care-Workers and other employees about smoking in the workplace and investigated their perceptions about the implementation and strengthening of smoke-free policies and their views of proposed smoking cessation course. METHODS: This cross-sectional study analyzed data resulting from a questionnaire administered in the Local Health Agency of Rieti (Italy). Comparisons have been made according to smoking status of participants: Ever Smokers (ES) or Never Smokers (NS). RESULTS: The study was conducted on a sample of 300 workers, the majority of whom think that the smoking ban is not observed in the workplace due to lack of respect for colleagues (59.2% of NS vs 40% of ES, p=0.022). Exposure to Secondhand smoke (SHS) is reported by 15.2% of ES and 30.3% of NS (p=0.006). About 50% of the participants think that the smoking ban has led to an improvement in the quality of interpersonal relationships. Strengthening the smoking ban through frequent inspections would be very effective according to 78% of ES and 88% of NS (p=0.043); having smoking cessation courses within the agency would be considered useful by 56% of ES and 68% of NS (p= 0.064). Relatively few respondents knew of the association between smoking and bladder cancer (35.2% of ES and 47.2% of NS, p=0.061), and asthma exacerbation (66% of ES and 77% of NS, p=0.040). Logistic regression models adjusted for age, gender, work categories and smoking status show that ES report that they are less likely to be exposed to SHS (OR= 0.42, 95% CI 0.22-0.78, p=0.006) and to think that people smoke because of lack of respect (OR= 0.46, 95% CI 0.24-0.87, p=0.018). More frequent inspections (OR= 0.50, 95% CI 0.26-0.95, p=0.037) and smoking cessation courses (OR= 0.61, 95% CI 0.37-1.00, p=0.053) are considered less effective by ES. ES are less likely to know that smoking is a cause of bladder cancer (OR= 0.54, 95% CI 0.32-0.90, p=0.019) and asthma exacerbation (OR= 0.53, 95% CI 0.31-0.92, p=0.023). Fifty-seven percent of current smokers would like to quit, but only 41% would join a cessation course in the agency. CONCLUSION: The results obtained may be used to analyze the effectiveness of tobacco control policy and programs aimed at freeing companies from smoke. Policy makers should provide the best possible protection for workers against exposure to SHS, in particular with enforcement of the smoking ban and smoking cessation courses tailored to maximize potential benefits for both workers and employers. PMID- 24048179 TI - Sustainable healthcare: how to assess and improve healthcare structures' sustainability. AB - BACKGROUND: Sustainability is a broad and debated subject, often difficult to be defined and applied into real projects, especially when dealing with a complex scenario as the one of healthcare. Many research studies and evaluation systems have handled this topic from different perspectives, but many limits and criticalities still have to be overcome to properly cope with actual needs. METHODS: The Sustainable Healthcare project has been developed through three main phases: a deep study of the state of the art, unraveling pros and cons of available sustainability scoring systems; an accurate analysis of the stakeholders network and their needs; the realization of an objective evaluation framework, through scientific methods, as the ANP. RESULTS: The newly developed evaluation system takes into consideration all the three pillars of sustainability, analyzing social, environmental and economic sustainability through a set of criteria, specified by measurable indicators. So the system identifies both global sustainability and specific critical areas, pointing out possible strategic solutions to improve sustainability. The evaluation is achieved through technical analyses and qualitative surveys, which eventually allow to quantitatively assess sustainability, through a sound scoring method. CONCLUSIONS: This study proposes an innovative evaluation method to determine the sustainability of a hospital, already existing or in the design phase, within the European context. The Sustainable Healthcare system overcomes some of the current evaluation systems' limits by establishing a multidisciplinary approach and being an easy-to-use tool. This protocol is intended to be of support in the identification of the main hospital's weaknesses and in setting priorities for implementation of the solutions. PMID- 24048180 TI - Practical method of control of TBC in a population of students belonging to the Sapienza University of Rome, Italy. AB - AIM: To describe the surveillance and control protocol for tuberculosis in healthcare students in use at the CMO of University "Sapienza" and founded on a dedicated database. METHODS: Analysis of health certificates through a dedicated data storage software based on Microsoft Access 2007. RESULTS: Students resulting positive to Mantoux test who did not undergo second-level examination (chest X ray, TB Gold, prophylaxis) are invited to refer themselves within ten days to the infectious disease specialist. CONCLUSION: the methodological analysis, refined over the years by the CMO staff of the Sapienza University of Rome, allowed to match clinical certification data, to rapidly focus upon TBC spread control among healthcare settings, to register new students time zero before their admission to courses and potential professional exposure, to perform epidemiological studies aimed to increase TBC control through healthcare system released clinical certification confirmation. PMID- 24048181 TI - Immunity status against poliomyelitis in childbearing women in a province of northern Italy. A cross-sectional analysis. AB - This cross-sectional seroprevalence study was carried out in 2007 to estimate the immunological status associated with poliomyelitis among fertile women , according to demographic changes. We consecutively enrolled 493 healthy mothers at the time of delivery in order to assess immunity against poliomyelitis by a neutralisation inhibition test. Despite the lack of seronegative subjects, our investigation showed low GMTs, which confirmed a reduction in the "booster effect". The GMTs against poliovirus 1, poliovirus 2 and poliovirus 3 were 25.20, 14.79 and 8.80, respectively. The data that emerged from our survey showed that GMTs have decreased significantly since 1983 and reached low-to-medium values over the past 25 years. The serum prevalence studies, together with the vaccination coverage estimates, are useful and are strongly recommended in order to highlight and identify the possible scenarios in which susceptible subject groups may be present simultaneously as well the possibility of the reintroduction of wild virus in an area that was previously free of polio. PMID- 24048182 TI - Environmental surveillance and molecular investigation of Legionella spp. in Apulia, in the years 2008-2011. AB - Legionella spp. is considered an emerging microorganism involved in aquatic environments contamination and cause of Legionnaires' disease. The aims of the study are to evaluate the level of contamination of Legionella spp. in the water system of the largest Hospital of Apulia region during a 4-year surveillance and to establish, by molecular method, the presence of a predominant genotype of L. pn. sg 1. The results showed that Legionella spp. was present in 36% of water samples with Legionella pneumophila serogroup 1 (L. pn. sg 1) the most prevalent species and serogroup and the wards most contaminated are the high risk units. In addition, despite four main clones of L. pn. sg 1 were identified, a predominant genotype existed. In conclusion the study demonstrates the necessity for periodic evaluation on hospitals water system to assess the potential contamination of Legionella spp., performing decontamination in the presence of bacterial contamination, even low, in particular in high risk wards. Moreover, the switching of the disinfection methods may be suggested in order to prevent resistance phenomenon by some L. pn. sg 1 clones. PMID- 24048183 TI - Vaginal microbiota and viral sexually transmitted diseases. AB - Healthy vaginal microbiota is an important biological barrier to pathogenic microorganisms. When this predominantly Lactobacillus community is disrupted, decreased in abundance and replaced by different anaerobes, bacterial vaginosis (BV) may occur. BV is associated with prevalence and incidence of several sexually transmitted infections. This review provides background on BV, discusses the epidemiologic data to support a role of altered vaginal microbiota for acquisition of sexually transmitted diseases and analyzes mechanisms by which lactobacilli could counteract sexually transmitted viral infections. PMID- 24048184 TI - Peripapillary retinal nerve fiber layer and optic nerve head characteristics in eyes with situs inversus of the optic disc. AB - PURPOSE: This study was performed to investigate the peripapillary retinal nerve fiber layer (RNFL) and optic nerve head (ONH) characteristics, as determined using a spectral-domain optical coherence tomography (OCT), in eyes with situs inversus of the optic disc. METHODS: The peripapillary RNFL and the ONH were assessed in 12 eyes belonging to 6 subjects with situs inversus of the optic disc (situs inversus group) and 24 eyes in 12 age-matched, sex-matched, and refractive error-matched healthy subjects (control group) by using OCT. The average, quadrant, and clock-hour RNFL thicknesses (clock-hour 9 on the scan represented the temporal side of the optic disc in both eyes), the superior/inferior RNFL peak locations, and ONH characteristics such as disc area, rim area, cup-to-disc ratio, vertical cup-to-disc ratio, and cup volume were obtained. The differences in RNFL and ONH characteristics between the 2 groups were analyzed. RESULTS: The situs inversus group had a thicker RNFL in the clock-hour sectors 3 and 4, a thinner RNFL in the clock-hour sectors 7, 8, and 11, and more nasally located superior and inferior RNFL peak locations than the control group (P<=0.001). The situs inversus group had a smaller cup-to-disc area ratio, smaller vertical cup to-disc ratio, and a lesser cup volume than the control group (P<0.01). CONCLUSIONS: Eyes with situs inversus of the optic disc showed different peripapillary RNFL and ONH characteristics from those without this abnormality. These findings should be considered when assessing eyes with situs inversus of the optic disc. PMID- 24048185 TI - Predicting date rape perceptions: the effects of gender, gender role attitudes, and victim resistance. AB - The effects of participant gender and victim resistance on date rape perceptions have been inconsistent. Participant gender role attitudes may contribute to these inconsistencies. We found women with traditional gender role attitudes were least likely to agree that the perpetrator was guilty of rape. Participants were less convinced of the perpetrator's guilt when the victim resisted verbally than when she resisted verbally and physically, and participants with traditional gender role attitudes were less convinced of the negative impact on the victim when she resisted verbally than when she resisted verbally and physically. Perhaps previous inconsistencies resulted from varying proportions of men and women with traditional versus liberal gender role attitudes in the samples. PMID- 24048186 TI - Reading Playboy for the articles: the graying of rape myths in black and white text, 1953 to 2003. AB - This longitudinal investigation analyzes the manner in which rape myths are conveyed through textual material published in Playboy. Results indicate that Playboy (a) portrays rape as a gender-neutral issue, ignoring patriarchal roots of sexual violence against women, and (b) promulgates ambiguous discourse, which is equally likely to endorse and refute rape myths. Interestingly, readers' contributions are most often the source of refutations of rape myths. Overall, findings suggest that little progress has been made over time in deconstructing rape myths promulgated to men, as this particular men's publication has consistently painted a gray picture in which refutations have remained unsuccessful in disempowering rape myths. PMID- 24048187 TI - Client beliefs about a multicouple group service for intimate partner violence: a narrative analysis. AB - Despite the ongoing debate about intervention best practices for intimate partner violence (IPV), few researchers have elicited the perspectives of clients themselves about what interventions most effectively decrease violence and increase safety. Using qualitative narrative analysis methodology, the researchers conducted 48 client participant interviews and 5 staff interviews to better understand couples' perspectives of a multicouple conjoint treatment program for IPV. Several recurring themes included (a) group purpose and general service characteristics, (b) motivation for participation, (c) comparison with other services, (d) benefits of, (e) disadvantages of, and (f) suggestions for Couples Achieving Relationship Enrichment. Important research implications for community intervention are discussed. PMID- 24048188 TI - Intimate partner violence victimization among undergraduate women at Historically Black Colleges and Universities (HBCUs). AB - Despite the evidence that young and minority women may be particularly vulnerable to intimate partner violence (IPV), there is little research on the IPV experiences of minority undergraduate women. This study addresses this gap by estimating the prevalence of IPV and examining factors associated with experiencing IPV among undergraduate women attending Historically Black Colleges or Universities (HBCUs). Findings suggest alarmingly high victimization rates; however, factors associated with IPV among HBCU women are similar to those found in prior research with women in the general population. The results also suggest that some risk factors are differentially associated with experiencing specific types of IPV. PMID- 24048189 TI - Explaining aboriginal/non-aboriginal inequalities in postseparation violence against Canadian women: application of a structural violence approach. AB - Adopting a structural violence approach, we analyzed 2004 Canadian General Social Survey data to examine Aboriginal/non-Aboriginal inequalities in postseparation intimate partner violence (IPV) against women. Aboriginal women had 4.12 times higher odds of postseparation IPV than non-Aboriginal women (p < .001). Coercive control and age explained most of this inequality. The final model included Aboriginal status, age, a seven-item coercive control index, and stalking, which reduced the odds ratio for Aboriginal status to 1.92 (p = .085) and explained 70.5% of the Aboriginal/non-Aboriginal inequality in postseparation IPV. Research and action are needed that challenge structural violence, especially colonialism and its negative consequences. PMID- 24048190 TI - Ambient arylmagnesiation of alkynes catalysed by ligandless nickel(ii). AB - A simple and efficient catalytic arylmagnesiation of diarylacetylenes and aryl(alkyl)acetylenes is accomplished by NiCl2.6H2O at r.t. in the absence of stabilising ligands. The corresponding tetra-substituted alkenes can be obtained in good yields by subsequent treatment with different electrophiles. PMID- 24048191 TI - Synthesis of new styrylarenes via Suzuki-Miyaura coupling catalysed by highly active, well-defined palladium catalysts. AB - An efficient synthetic route for well-defined palladium(0) complexes [Pd(eta(2) dba)(PPh3)2] (2), [Pd(eta(2)-dba)(PCy3)2] (3) and their crystallographic structures is reported. This is the first crystallographic characterization of palladium complexes coordinated with one dibenzylideneacetone and two phosphines. A highly effective, fully controlled method for selective synthesis of mono- (5 9) and distyrylarenes (10-15) via Suzuki-Miyaura coupling is described. PMID- 24048192 TI - Capsazepine concentration dependently inhibits currents in HEK 293 cells mediated by human hyperpolarization-activated cyclic nucleotide-gated 2 and 4 channels. AB - Recent studies indicate that blockade of currents (Ih) mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (particularly HCN1) may partly account for the antinociceptive effects of capsazepine (CPZ). Unfortunately, determining whether capsazepine is a selective HCN channel blocker and determining its adverse effects when it is used for the treatment of neuropathic pain, have been thus far understudied. In this study, we aimed to elucidate the effects of capsazepine on human HCN2 (hHCN2) and HCN4 (hHCN4) channels in HEK293 cells. The vectors that expressed hHCN2 and hHCN4 cDNA were constructed and transfected into HEK293 cells. Enhanced green fluorescent protein (EGFP) fluorescence and the reverse transcription polymerase chain reaction (RT PCR) were used to confirm the successful transfection of the vectors. After G418 (neomycin) screening, cell lines that expressed hHCN2 and hHCN4 were obtained. The whole-cell voltage-clamp technique was used to determine the currents from hHCN2 and hHCN4 channels, which were perfused with five concentrations (0.1 uM, 1 uM, 5 uM, 10 uM and 50 uM) of capsazepine. The results showed that capsazepine at the range from 0.1 to 50 uM markedly inhibited hHCN2 and hHCN4 currents in a concentration-dependent manner, with most inhibition achieved at a concentration of 10 uM of capsazepine. When compared with the control group, a V0.5 for the hHCN2 and hHCN4 channel showed that 10 uM capsazepine significantly shifted the membrane potential towards hyperpolarization. The present results indicate that capsazepine is not a selective HCN1 channel blocker and that it may have adverse effects when used to treat neuropathic pain. PMID- 24048193 TI - Expression and significance of HIF-1alpha in pulmonary fibrosis induced by paraquat. AB - It is commonly accepted that epithelial-mesenchymal transition contributes to fibrotic remodeling, but the molecular pathways involved in paraquat (PQ)-induced epithelial-mesenchymal transition remain uncharacterized. The objective of this study was to evaluate the potential involvement of HIF-1alpha in TGF-beta1/beta Catenin and Snail pathway after PQ poisoning. In our study, 86 Spragne-Dawley rats were randomly divided into control group and PQ group, which received intragastric infusion of 20% PQ solution 50 mg/kg. Rats in the PQ group were subsequently divided into eight subgroups (10 for each subgroup) and samples were collected at different predetermined time points (2, 6, 12, 24, 48, 72, 96 h and 7 d). Fibrosis markers, including beta-catenin, snail and alpha-SMA, were measured by western blot. The activity of HIF-1alpha was determined by western blot and immunofluorescence. We found that in PQ-induced pulmonary fibrosis, the level of PaO2 was significantly reduced in the 6-h subgroup, when compared to the control group (P < 0.01). Interestingly, between 6 and 72 h, there was no significant difference in PaO2. On the other hand, the level of PaCO2 started to increase from 72-h subgroup (P < 0.01). Fibrosis markers including beta-catenin, snail and alpha-SMA, measured by western blot, were significantly increased at 2 h, while the level of p-GSK-3beta was increased at 6 h. And the level of GSK 3beta showed significant reduction beginning at 24 h. The activity of HIF-1alpha measured by western blot assays was significantly increased starting from 2 h with sustained expression. The result of Pearson coefficient analysis showed that HIF-1alpha was positively correlated with Snail (r = 0.935, P < 0.01) and beta catenin (r = 0.761, P < 0.05). Meanwhile, immunofluorescent analysis of HIF 1alpha revealed partial staining appearing from 2 h. Our data illustrated a positive correlation between Snail, beta-catenin signaling and HIF-1alpha, suggesting a potential synergistic role of HIF-1alpha in PQ-induced pulmonary fibrosis, which may be independent of GSK-3beta. It might also represent a potential therapeutic window for treatment of paraquat poisoning. PMID- 24048195 TI - Effect of structural fluctuations on charge carrier mobility in thiophene, thiazole and thiazolothiazole based oligomers. AB - Charge transport properties of thiophene, thiazole and thiazolothiazole based oligomers have been studied using electronic structure calculations. The charge transport parameters such as charge transfer integral and site energy are calculated through matrix elements of Kohn-Sham Hamiltonian. The reorganization energy for the presence of excess positive and negative charges and rate of charge transfer calculated from Marcus theory are used to find the mobility of charge carriers. The effect of structural fluctuations on charge transport was studied through the polaron hopping model. Theoretical results show that for the studied oligomers, the charge transfer kinetics follows the static non-Condon effect and the charge transfer decay at particular site is exponential, non dispersive and the rate coefficient is time independent. It has been observed that the thiazole derivatives have good hole and electron mobility. PMID- 24048194 TI - Functional compensation of glutathione S-transferase M1 (GSTM1) null by another GST superfamily member, GSTM2. AB - The gene for glutathione-S-transferase (GST) M1 (GSTM1), a member of the GST superfamily, is widely studied in cancer risk with regard to the homozygous deletion of the gene (GSTM1 null), leading to a lack of corresponding enzymatic activity. Many of these studies have reported inconsistent findings regarding its association with cancer risk. Therefore, we employed in silico, in vitro, and in vivo approaches to investigate whether the absence of a functional GSTM1 enzyme in a null variant can be compensated for by other family members. Through the in silico approach, we identified maximum structural homology between GSTM1 and GSTM2. Total plasma GST enzymatic activity was similar in recruited individuals, irrespective of their GSTM1 genotype (positive/null). Furthermore, expression profiling using real-time PCR, western blotting, and GSTM2 overexpression following transient knockdown of GSTM1 in HeLa cells confirmed that the absence of GSTM1 activity can be compensated for by the overexpression of GSTM2. PMID- 24048196 TI - Evaluation of online health information on clubfoot using the DISCERN tool. AB - The Internet has become a major source of health information on various aspects of clubfoot diagnosis and management. The World Wide Web becomes the first knowledge portal for a large number of anxious parents seeking information on clubfoot. Thus, a good quality webpage should provide necessary and comprehensive information on clubfoot so as to establish clarity in treatment options, compliance and bracing protocols. In contrast, modest quality information can induce bias and poor follow-up. We objectively evaluated online health information on clubfoot using the DISCERN tool. Using the universal search engine, Google, we conducted a Boolean search for the term 'clubfoot'. Only the first 50 sites providing health information on clubfoot were included in the study. We examined 334 links to include 50 of them. During analysis three websites were excluded because of duplication of content leaving 47 websites that were examined using the DISCERN tool. As per this tool, a score of less than 40% was graded as 'poor', 40-79% as 'fair' and at least 80% as 'good', whereas the overall quality was graded as 'low', 'moderate' and 'high' on similar standards. The overall quality of the publication was 'low' in 40% (19) websites, 'moderate' in 28% (13) and 'high' in 32% (15) of the websites we evaluated. Six (13%) of the publications showed good reliability; 25 (54%) showed fair reliability and 16 (33%) were unreliable. With regard to the quality of information on treatment choices, 44.7% (21) were 'good', 46.8% (22) were 'fair' and 8.5% (four) were 'poor'. We conclude that the quality of websites providing online health information on clubfoot needs significant improvement with emphasis on a universally acceptable template for disease information. PMID- 24048197 TI - Ordered macroporous platinum electrode and enhanced mass transfer in fuel cells using inverse opal structure. AB - Three-dimensional, ordered macroporous materials such as inverse opal structures are attractive materials for various applications in electrochemical devices because of the benefits derived from their periodic structures: relatively large surface areas, large voidage, low tortuosity and interconnected macropores. However, a direct application of an inverse opal structure in membrane electrode assemblies has been considered impractical because of the limitations in fabrication routes including an unsuitable substrate. Here we report the demonstration of a single cell that maintains an inverse opal structure entirely within a membrane electrode assembly. Compared with the conventional catalyst slurry, an ink-based assembly, this modified assembly has a robust and integrated configuration of catalyst layers; therefore, the loss of catalyst particles can be minimized. Furthermore, the inverse-opal-structure electrode maintains an effective porosity, an enhanced performance, as well as an improved mass transfer and more effective water management, owing to its morphological advantages. PMID- 24048198 TI - Loss of collectrin, an angiotensin-converting enzyme 2 homolog, uncouples endothelial nitric oxide synthase and causes hypertension and vascular dysfunction. AB - BACKGROUND: Collectrin is an orphan member of the renin-angiotensin system and is a homolog of angiotensin-converting enzyme 2, sharing ~50% sequence identity. Unlike angiotensin-converting enzyme 2, collectrin lacks any catalytic domain. Collectrin has been shown to function as a chaperone of amino acid transporters. In rodents, the renal expression of collectrin is increased after subtotal nephrectomy and during high-salt feeding, raising the question of whether collectrin has any direct role in blood pressure regulation. METHODS AND RESULTS: Using a susceptible genetic background, we demonstrate that deletion of collectrin results in hypertension, exaggerated salt sensitivity, and impaired pressure natriuresis. Collectrin knockout mice display impaired endothelium dependent vasorelaxation that is associated with vascular remodeling, endothelial nitric oxide synthase uncoupling, decreased nitric oxide production, and increased superoxide generation. Treatment with Tempol, a superoxide scavenger, attenuates the augmented sodium sensitivity in collectrin knockout mice. We report for the first time that collectrin is expressed in endothelial cells. Furthermore, collectrin directly regulates l-arginine uptake and plasma membrane levels of CAT1 and y(+)LAT1 amino acid transporters in endothelial cells. Treatment with l-arginine modestly lowers blood pressure of collectrin knockout mice. CONCLUSIONS: Collectrin is a consequential link between the transport of l arginine and endothelial nitric oxide synthase uncoupling in hypertension. PMID- 24048199 TI - Collectrin, an X-linked, angiotensin converting enzyme 2 homolog, causes hypertension in a rat strain through gene-gene and gene-environment interactions: relevance to human hypertension. PMID- 24048200 TI - Implantable cardioverter-defibrillators for primary prevention of sudden cardiac death: too little and too late? PMID- 24048201 TI - Frequency and determinants of implantable cardioverter defibrillator deployment among primary prevention candidates with subsequent sudden cardiac arrest in the community. AB - BACKGROUND: The prevalence rates and influencing factors for deployment of primary prevention implantable cardioverter defibrillators (ICDs) among subjects who eventually experience sudden cardiac arrest in the general population have not been evaluated. METHODS AND RESULTS: Cases of adult sudden cardiac arrest with echocardiographic evaluation before the event were identified from the ongoing Oregon Sudden Unexpected Death Study (population approximately 1 million). Eligibility for primary ICD implantation was determined from medical records based on established guidelines. The frequency of prior primary ICD implantation in eligible subjects was evaluated, and ICD nonrecipients were characterized. Of 2093 cases (2003-2012), 448 had appropriate pre- sudden cardiac arrest left ventricular ejection fraction information available. Of these, 92 (20.5%) were eligible for primary ICD implantation, 304 (67.9%) were ineligible because of left ventricular ejection fraction >35%, and the remainder (52, 11.6%) had left ventricular ejection fraction <=35% but were ineligible on the basis of clinical guideline criteria. Among eligible subjects, only 12 (13.0%; 95% confidence interval, 6.1%-19.9%) received a primary ICD. Compared with recipients, primary ICD nonrecipients were older (age at ejection fraction assessment, 67.1+/-13.6 versus 58.5+/-14.8 years, P=0.05), with 20% aged >=80 years (versus 0% among recipients, P=0.11). Additionally, a subgroup (26%) had either a clinical history of dementia or were undergoing chronic dialysis. CONCLUSIONS: Only one fifth of the sudden cardiac arrest cases in the community were eligible for a primary prevention ICD before the event, but among these, a small proportion (13%) were actually implanted. Although older age and comorbidity may explain nondeployment in a subgroup of these cases, other determinants such as socioeconomic factors, health insurance, patient preference, and clinical practice patterns warrant further detailed investigation. PMID- 24048202 TI - Paradoxical low-flow, low-gradient aortic stenosis: new evidence, more questions. PMID- 24048203 TI - Flow-gradient patterns in severe aortic stenosis with preserved ejection fraction: clinical characteristics and predictors of survival. AB - BACKGROUND: Among patients with severe aortic stenosis (AS) and preserved ejection fraction, those with low gradient (LG) and reduced stroke volume may have an adverse prognosis. We investigated the prognostic impact of stroke volume using the recently proposed flow-gradient classification. METHODS AND RESULTS: We examined 1704 consecutive patients with severe AS (aortic valve area <1.0 cm(2)) and preserved ejection fraction (>=50%) using 2-dimensional and Doppler echocardiography. Patients were stratified by stroke volume index (<35 mL/m(2) [low flow, LF] versus >=35 mL/m(2) [normal flow, NF]) and aortic gradient (<40 mm Hg [LG] versus >=40 mm Hg [high gradient, HG]) into 4 groups: NF/HG, NF/LG, LF/HG, and LF/LG. NF/LG (n=352, 21%), was associated with favorable survival with medical management (2-year estimate, 82% versus 67% in NF/HG; P<0.0001). LF/LG severe AS (n=53, 3%) was characterized by lower ejection fraction, more prevalent atrial fibrillation and heart failure, reduced arterial compliance, and reduced survival (2-year estimate, 60% versus 82% in NF/HG; P<0.001). In multivariable analysis, the LF/LG pattern was the strongest predictor of mortality (hazard ratio, 3.26; 95% confidence interval, 1.71-6.22; P<0.001 versus NF/LG). Aortic valve replacement was associated with a 69% mortality reduction (hazard ratio, 0.31; 95% confidence interval, 0.25-0.39; P<0.0001) in LF/LG and NF/HG, with no survival benefit associated with aortic valve replacement in NF/LG and LF/HG. CONCLUSIONS: NF/LG severe AS with preserved ejection fraction exhibits favorable survival with medical management, and the impact of aortic valve replacement on survival was neutral. LF/LG severe AS is characterized by a high prevalence of atrial fibrillation, heart failure, and reduced survival, and aortic valve replacement was associated with improved survival. These findings have implications for the evaluation and subsequent management of AS severity. PMID- 24048204 TI - Impact of antithrombotic treatment on short-term outcomes after percutaneous coronary intervention for left main disease: a pooled analysis from REPLACE-2, ACUITY, and HORIZONS-AMI trials. AB - AIMS: Percutaneous coronary intervention (PCI)-related risks are increased among patients with left main disease (LMD). The aim was to evaluate the impact of antithrombotic therapy on outcomes after LMD PCI in a predominantly ACS population. METHODS AND RESULTS: One hundred and seventy-seven patients undergoing LMD PCI were identified in a pooled dataset of 14,326 patients from three large randomised trials comparing treatment with heparin plus glycoprotein IIb/IIIa inhibitors (GPI) or bivalirudin alone, including the REPLACE-2, ACUITY and HORIZONS-AMI trials. Overall, net adverse clinical events (NACE) and non-CABG major bleedings at 30 days occurred more frequently in patients undergoing LMD PCI compared to the overall non-LMD PCI population (NACE: 19.8% vs. 10.6%, p<=0.001, major bleeding: 9.6% vs. 4.6%, p<=0.001). In the LMD group, bivalirudin was associated with significantly less non-CABG related major bleeding compared to heparin+GPI (4.5% versus 14.6%, relative risk [RR] 0.27, 95% CI: 0.09-0.83; p=0.013), while the composite ischaemic endpoint (death/MI/TVR) at 30 days was similar in the two groups (11.4% vs. 12.4%, p=0.513) resulting in a benefit on NACE for bivalirudin over heparin+GPI (14.8% vs. 24.7%; RR 0.53; p=0.039). CONCLUSIONS: Among patients undergoing LMD PCI, the use of bivalirudin instead of heparin+GPI resulted in significantly less major bleeding and improved short-term net clinical outcome. Bivalirudin may be the preferred anticoagulation strategy in LMD PCI patients. PMID- 24048205 TI - Regaining health and wellbeing after traumatic spinal cord injury. AB - OBJECTIVE: Traumatic spinal cord injury is typically a devastating event, leading to permanent physical disability. Despite the severity of the condition, many persons with traumatic spinal cord injury manage to lead both active and independent lives. The aim of this study was to investigate the experience of health and wellbeing of persons living with a traumatic spinal cord injury for at least 20 years. DESIGN AND METHODS: A qualitative design was used. Data was analysed using a phenomenological-hermeneutical method. Rich narratives were obtained from 14 persons with paraplegia due to traumatic spinal cord injury sustained at least 20 years ago. RESULTS: The key finding was that health and wellbeing were attained when persons were able to perceive themselves as being "normal" in everyday relationships and circumstances. The normalization process involved learning to negotiate and/or prevent potentially embarrassing situations by acting in a "parallel world", covertly "behind the scenes". CONCLUSION: The subjective experience of wellbeing and health after traumatic spinal cord injury depends upon the ability to prevent or resolve potentially embarrassing situations without this being noticed by others. Performing this work "behind the scenes", enables persons with traumatic spinal cord injury to interact smoothly with others and thereby be perceived as normal, despite substantial disability. PMID- 24048207 TI - Microbial anaerobic digestion (bio-digesters) as an approach to the decontamination of animal wastes in pollution control and the generation of renewable energy. AB - With an ever increasing population rate; a vast array of biomass wastes rich in organic and inorganic nutrients as well as pathogenic microorganisms will result from the diversified human, industrial and agricultural activities. Anaerobic digestion is applauded as one of the best ways to properly handle and manage these wastes. Animal wastes have been recognized as suitable substrates for anaerobic digestion process, a natural biological process in which complex organic materials are broken down into simpler molecules in the absence of oxygen by the concerted activities of four sets of metabolically linked microorganisms. This process occurs in an airtight chamber (biodigester) via four stages represented by hydrolytic, acidogenic, acetogenic and methanogenic microorganisms. The microbial population and structure can be identified by the combined use of culture-based, microscopic and molecular techniques. Overall, the process is affected by bio-digester design, operational factors and manure characteristics. The purpose of anaerobic digestion is the production of a renewable energy source (biogas) and an odor free nutrient-rich fertilizer. Conversely, if animal wastes are accidentally found in the environment, it can cause a drastic chain of environmental and public health complications. PMID- 24048208 TI - Patterns of smoking prevalence among the elderly in Europe. AB - Scant information is available on determinants of smoking prevalence in the vulnerable population of the elderly, particularly in Europe. Therefore, we analyzed smoking patterns among older adults (>=65 years old), using data from a representative survey based on 3,071 elderly, conducted in 17 European countries in 2010, within the Pricing Policies And Control of Tobacco in Europe (PPACTE) project. Overall smoking prevalence in 17 European countries was 11.5% (15.3% in men and 8.6% in women). An inverse relation with level of education was observed among men, while no specific pattern was evident among women. Smoking prevalence was highest in eastern/central Europe for men (20.3%) and northern Europe for women (13.1%). In both sexes combined, smokers were more frequent in countries with low implementation of tobacco control activities (14.9%). Anti-tobacco campaigns and smoking cessation interventions specifically targeted to the elderly are urgently needed in Europe. PMID- 24048209 TI - Natural exposure of horses to mosquito-borne flaviviruses in south-east Queensland, Australia. AB - In 2011 an unprecedented epidemic of equine encephalitis occurred in south eastern (SE) Australia following heavy rainfall and severe flooding in the preceding 2-4 months. Less than 6% of the documented cases occurred in Queensland, prompting the question of pre-existing immunity in Queensland horses. A small-scale serological survey was conducted on horses residing in one of the severely flood-affected areas of SE-Queensland. Using a flavivirus-specific blocking-ELISA we found that 63% (39/62) of horses older than 3 years were positive for flavivirus antibodies, and of these 18% (7/38) had neutralizing antibodies to Murray Valley encephalitis virus (MVEV), Kunjin virus (WNV(KUN)) and/or Alfuy virus (ALFV). The remainder had serum-neutralizing antibodies to viruses in the Kokobera virus (KOKV) complex or antibodies to unknown/untested flaviviruses. Amongst eight yearlings one presented with clinical MVEV encephalomyelitis, while another, clinically normal, had MVEV-neutralizing antibodies. The remaining six yearlings were flavivirus antibody negative. Of 19 foals born between August and November 2011 all were flavivirus antibody negative in January 2012. This suggests that horses in the area acquire over time active immunity to a range of flaviviruses. Nevertheless, the relatively infrequent seropositivity to MVEV, WNV(KUN) and ALFV (15%) suggests that factors other than pre-existing immunity may have contributed to the low incidence of arboviral disease in SE-Queensland horses during the 2011 epidemic. PMID- 24048211 TI - Structural motif-dependent magnetic diversity observed in three-dimensional tetrazolyl-based MMOFs: synthesis, structures and magnetism. AB - Three extended three-dimensional (3D) magnetic metal-organic frameworks (MMOFs), {[Mn3(H2O)2(atz)4Cl2].2CH3OH}n (1), {[Mn2(H2O)(atz)2(ip)].C2H5OH}n (2) and {[Mn2(H2O)2(atz)(btc)].3H2O.0.7CH3OH}n (3) (atz(-) = 5-aminotetrazolate, ip(2-) = isophthalate and btc(3-) = 1,3,5-benzenetricarboxylate), were respectively obtained by varying the coligands with different numbers of functionalities and molecular topology, and structurally and magnetically characterized. Complex 1 exhibits an eight-connected 3(6).4(18).5(3).6 topological network with linear Mn(II)3 subunits periodically linked by ditopic atz(-) connectors. Complex 2 possesses a pillared-layer framework constructed from undulated {Mn2(atz)2} layers and bidirectional ip(2-) spacers. By contrast, 3 consists of bent one dimensional (1D) {Mn(atz)} ribbons, which are crosslinked through the carboxylate groups of tripodal btc(3-) connectors to generate a 3D architecture. Structural analysis reveals that the interesting motifs of 1-3 and their diverse linkages are significantly dominated by the cooperate coordination of the mixed ligands to the octahedral Mn(II) ion. Magnetically, 1 displays ferrimagnetic behavior resulting from the periodic arrangement of the net moment in the Mn(II)3 subunit, which is scarcely observed in the homometallic azolate systems. Complex 2 features unusual coexistence of spin-canted antiferromagnetic behavior and field induced spin-flop transition due to the asymmetric magnetic superexchange within the two-dimensional (2D) {Mn2(atz)2} sublayer. By contrast, only antiferromagnetic ordering is observed in the 1D {Mn(atz)} ribbon of 3. These interesting results suggest that the diverse structural motifs by the cooperate coordination of octahedral Mn(II) ion with the N-rich tetrazolyl group can more significantly direct the magnetic behaviors and could be hopefully utilized upon the construction of novel MMOFs. PMID- 24048206 TI - Neural tube defects, folic acid and methylation. AB - Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects. PMID- 24048210 TI - Association of posttraumatic stress disorder with reduced in vivo norepinephrine transporter availability in the locus coeruleus. AB - IMPORTANCE: Animal data suggest that chronic stress is associated with a reduction in norepinephrine transporter (NET) availability in the locus coeruleus. However, it is unclear whether such models are relevant to posttraumatic stress disorder (PTSD), which has been linked to noradrenergic dysfunction in humans. OBJECTIVES: To use positron emission tomography and the radioligand [11C]methylreboxetine to examine in vivo NET availability in the locus coeruleus in the following 3 groups of individuals: healthy adults (HC group), adults exposed to trauma who did not develop PTSD (TC group), and adults exposed to trauma who developed PTSD (PTSD group) and to evaluate the relationship between NET availability in the locus coeruleus and a contemporary phenotypic model of PTSD symptoms. DESIGN, SETTING, AND PARTICIPANTS: Cross sectional positron emission tomography study under resting conditions at academic and Veterans Affairs medical centers among 56 individuals in the following 3 study groups: HC (n = 18), TC (n = 16), and PTSD (n = 22). MAIN OUTCOMES AND MEASURES: The [11C]methylreboxetine-binding potential of NET availability in the locus coeruleus and the severity of PTSD symptoms assessed using the Clinician Administered PTSD Scale. RESULTS: The PTSD group had significantly lower NET availability than the HC group (41% lower, Cohen d = 1.07). NET availability did not differ significantly between the TC and HC groups (31% difference, Cohen d = 0.79) or between the TC and PTSD groups (15% difference, Cohen d = 0.28). In the PTSD group, NET availability in the locus coeruleus was independently positively associated with the severity of anxious arousal (ie, hypervigilance) symptoms (r = 0.52) but not with any of the other PTSD symptom clusters. CONCLUSIONS AND RELEVANCE: These results suggest that PTSD is associated with significantly reduced NET availability in the locus coeruleus and that greater NET availability in this brain region is associated with increased severity of anxious arousal symptoms in individuals with PTSD. PMID- 24048212 TI - Bilateral neck of femur fractures secondary to seizure. PMID- 24048213 TI - A neurological letter from UK general practice. PMID- 24048214 TI - Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices--United States, 2013-2014. AB - This report updates the 2012 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccines for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2012;61:613-8). Routine annual influenza vaccination is recommended for all persons aged >= 6 months. For the 2013-14 influenza season, it is expected that trivalent live attenuated influenza vaccine (LAIV3) will be replaced by a quadrivalent LAIV formulation (LAIV4). Inactivated influenza vaccines (IIVs) will be available in both trivalent (IIV3) and quadrivalent (IIV4) formulations. Vaccine virus strains included in the 2013-14 U.S. trivalent influenza vaccines will be an A/California/7/2009 (H1N1)-like virus, an H3N2 virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011, and a B/Massachusetts/2/2012-like virus. Quadrivalent vaccines will include an additional influenza B virus strain, a B/Brisbane/60/2008-like virus, intended to ensure that both influenza B virus antigenic lineages (Victoria and Yamagata) are included in the vaccine. This report describes recently approved vaccines, including LAIV4, IIV4, trivalent cell culture-based inactivated influenza vaccine (ccIIV3), and trivalent recombinant influenza vaccine (RIV3). No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one product is otherwise appropriate. This information is intended for vaccination providers, immunization program personnel, and public health personnel. These recommendations and other information are available at CDC's influenza website (http://www.cdc.gov/flu); any updates also will be found at this website. Vaccination and health-care providers should check the CDC influenza website periodically for additional information. PMID- 24048215 TI - The frequency of and associations with hospitalization secondary to lupus flares from the 1000 Faces of Lupus Canadian cohort. AB - OBJECTIVES: Hospitalization is a major factor in health care costs and a surrogate for worse outcomes in chronic disease. The aim of this study was to determine the frequency of hospitalization secondary to lupus flare, the causes of hospitalization, and to determine risk factors for hospitalization in patients with systemic lupus erythematosus (SLE). METHODS: Data were collected as part of the 1000 Canadian Faces of Lupus, a prospective cohort study, where annual major lupus flares including hospitalizations were recorded over a 3-year period. RESULTS: Of 665 patients with available hospitalization histories, 68 reported hospitalization related to a SLE flare over 3 years of follow-up. The average annual hospitalization rate was 7.6% (range 6.6-8.9%). The most common reasons for hospitalization were: hematologic (22.1%), serositis (20.6%), musculoskeletal (MSK) (16.2%), and renal (14.7%). Univariate risk factors for lupus hospitalization included (OR [95% CI]; p < 0.05): juvenile-onset lupus (2.2 [1.1 4.7]), number of ACR SLE criteria (1.4 [1.1-1.7], baseline body mass index (BMI) (1.1 [1.0-1.1]), psychosis (3.4 [1.2-9.9]), aboriginal race (3.2 [1.5-6.7]), anti Smith (2.6 [1.2-5.4]), erythrocyte sedimentation rate >25 mm/hr (1.9 [1.1-3.4]), proteinuria >0.5 g/d (4.2 [1.9-9.3], and SLAM-2 score (1.1 [1.0-1.2]). After multivariate regression only BMI, number of ACR criteria, and psychosis were associated with hospitalization for lupus flare. CONCLUSIONS: The mean annual rate of hospitalization attributed to lupus was lower than expected. Hematologic, serositis, MSK and renal were the most common reasons. In a regression model elevated BMI, more ACR criteria and psychosis were associated with hospitalization. PMID- 24048216 TI - Hydrostatic pressure activates ATP-sensitive K+ channels in lung epithelium by ATP release through pannexin and connexin hemichannels. AB - Lungs of air-breathing vertebrates are constantly exposed to mechanical forces and therefore are suitable for investigation of mechanotransduction processes in nonexcitable cells and tissues. Freshly dissected Xenopus laevis lungs were used for transepithelial short-circuit current (ISC) recordings and were exposed to increased hydrostatic pressure (HP; 5 cm fluid column, modified Ussing chamber). I(SC) values obtained under HP (I(5cm)) were normalized to values before HP (I(0cm)) application (I(5cm)/I(0cm)). Under control conditions, HP decreased I(SC) (I(5cm)/I(0cm)=0.84; n=68; P<0.0001). This effect was reversible and repeatable >=30 times. Preincubation with ATP-sensitive K(+) channel (K(ATP)) inhibitors (HMR1098 and glibenclamide) prevented the decrease in I(SC) (I(5cm)/I(0cm): HMR1098=1.19, P<0.0001; glibenclamide=1.11, P<0.0001). Similar effects were observed with hemichannel inhibitors (I(5cm)/I(0cm): meclofenamic acid=1.09, P<0.0001; probenecid=1.0, P<0.0001). The HP effect was accompanied by release of ATP (P<0.05), determined by luciferin-luciferase luminescence in perfusion solution from the luminal side of an Ussing chamber. ATP release was abrogated by both meclofenamic acid and probenecid. RT-PCR experiments revealed the expression of pannexin and connexin hemichannels and KATP subunit transcripts in X. laevis lung. These data show an activation of KATP in pulmonary epithelial cells in response to HP that is induced by ATP release through mechanosensitive pannexin and connexin hemichannels. These findings represent a novel mechanism of mechanotransduction in nonexcitable cells. PMID- 24048217 TI - Expansion of screening mammography in the Veterans Health Administration: implications for breast cancer treatment. AB - IMPORTANCE: Women represent the fastest-growing demographic in the Veterans Health Administration. In 2008, we implemented programmatic changes to expand screening mammography, develop on-site breast care resources, and better coordinate care with non-Veterans Affairs (VA) facilities. OBJECTIVE: To determine whether the programmatic changes would increase patient volumes, decrease time to definitive treatment, and increase the rate of breast conservation therapy (BCT). DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study of all breast cancer cases treated from January 1, 2000, to May 31, 2012, at the Baltimore VA Medical Center. MAIN OUTCOMES AND MEASURES: We compared process-of-care metrics before and after 2008, when programmatic changes were implemented. Metrics evaluated included the number of mammograms performed annually, sex shift, the interval from clinical suspicion to tissue diagnosis and definitive treatment, and the rate of BCT. RESULTS: From 2000 to 2012, a total of 7355 mammograms were performed and 76 patients with breast cancer received treatment. Most mammograms (n = 6720) were performed after 2008. A median of 1453 (interquartile range [IQR], 592-1458) mammograms were performed and 6.33 patients received cancer treatment annually after 2008, representing 1200% and 49% increases, respectively, compared with the 2000 to 2007 interval. Most patients (86.7%) received screening and diagnostic imaging, biopsy, and surgery between multiple institutions. The interval between screening mammography and tissue diagnosis was 34 days (IQR, 20-52), with no significant difference between study intervals (P = .18). Time from tissue diagnosis to initiation of definitive treatment increased from 33 days (IQR, 26-51) to 51 days (IQR, 36-75) (P = .03) between 2008 and 2012. Thirty-three patients eligible for BCT (67.3%) received it, while 16 patients (32.7%) underwent mastectomy. CONCLUSIONS AND RELEVANCE: Our institution has rapidly and successfully expanded screening mammography. Higher mammography volumes have been associated with increased use of non-VA breast care services and increased time to definitive treatment. Appropriate counseling regarding BCT was consistently documented, and mastectomy in BCT-eligible patients was largely the result of patient preference or clinical/social factors. Our data suggest that as patient volumes increase with intensified screening, VA hospitals may benefit from acquiring a full complement of on-site breast care services rather than improving flow between VA hospitals and non-VA breast care centers having specialized resources. PMID- 24048218 TI - Effect of cadmium on biomass, pigmentation, malondialdehyde, and proline of Scenedesmus quadricauda var. longispina. AB - Effects of cadmium (Cd(2+)) on biomass, pigmentation (chlorophyll a, b, and total carotene), malondialdehyde (MDA), and proline productions by Scenedesmus quadricauda var. longispina were investigated. Cadmium had inhibitory effect on the productions of biomass and pigmentation. Significant differences were found in pigment content among groups. On the other hand, Cd(2+) had a simulative effect on the production of MDA and proline by the alga. FTIR-ATR spectroscopy was used to examine active groups of algal biomass before and after Cd(2+) exposure. Results confirmed that amino, amide, and anionic groups had significant role on the biosorption of Cd(2+) by the alga. Increased accumulation of MDA and proline seemed to be an important strategy for alleviating metal-induced oxidative stress in S. quadricauda var. longispina. PMID- 24048219 TI - Seasonal variation of black carbon in fine particulate matter (PM2.5) at the tropical coastal city of Mumbai, India. AB - Black Carbon (BC) is a pollutant species primarily emitted from the combustion of fossil fuels. BC levels, associated with fine particulate matter (PM2.5), were monitored from January 2009 to December 2010 at an urban industrial area in Mumbai to study the seasonal and temporal variations and its contribution to fine particulate matter. Air particulate samples were collected in two size fractions, fine particulate matter (PM2.5) and coarse particulate matter (PM2.5-10), using a Gent air sampler. During the study period, arithmetic means of PM2.5 and PM2.5-10 were found to be 30.4 and 68.2 MUg/m(3), respectively. The average value of BC in fine particulate matter was 4.0 MUg/m(3), with a range of 1.0-9.4 MUg/m(3). Studies carried out using Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) model indicated the contribution of BC from the northern and central part of India during days of high BC levels. PMID- 24048220 TI - Dynamically correlated mutations drive human Influenza A evolution. AB - Human Influenza A virus undergoes recurrent changes in the hemagglutinin (HA) surface protein, primarily involved in the human antibody recognition. Relevant antigenic changes, enabling the virus to evade host immune response, have been recognized to occur in parallel to multiple mutations at antigenic sites in HA. Yet, the role of correlated mutations (epistasis) in driving the molecular evolution of the virus still represents a challenging puzzle. Further, though circulation at a global geographic level is key for the survival of Influenza A, its role in shaping the viral phylodynamics remains largely unexplored. Here we show, through a sequence based epidemiological model, that epistatic effects between amino acids substitutions, coupled with a reservoir that mimics worldwide circulating viruses, are key determinants that drive human Influenza A evolution. Our approach explains all the up-to-date observations characterizing the evolution of H3N2 subtype, including phylogenetic properties, nucleotide fixation patterns, and composition of antigenic clusters. PMID- 24048221 TI - How genomics is changing our view of cancer. PMID- 24048222 TI - Association between in-vitro fertilization, birth and melanoma. AB - A link between reproductive hormones and melanoma has long been suspected, and has been examined for numerous hormonal exposures, but the association between in vitro fertilization (IVF) and melanoma has not been studied in depth. We used whole-population linked hospital and registry data to carry out a cohort study of women aged 20-44 years seeking hospital investigation and treatment for infertility in Western Australia from 1982 to 2002 with follow-up to 2010. The cohort comprised a total of 21 604 women followed for an average of 17.2 years. Of these, 7524 had IVF treatment, 14 870 gave birth and 149 women were diagnosed with an incident invasive melanoma. Using Cox regression analysis, we estimated hazard ratios (HRs) for melanoma associated with IVF and parity. Women who had IVF and gave birth had an increased rate of invasive melanoma compared with women who had IVF and remained nulliparous (HR 3.61; 95% confidence interval 1.79 7.26). There was little or no increase in the rate of invasive melanoma associated with giving birth in women who had non-IVF infertility treatment (HR 1.39; 95% confidence interval 0.88-2.20). These results suggest an association between reproductive factors and melanoma in the subgroup of women undergoing IVF treatment. PMID- 24048223 TI - Quality of life in the follow-up of uveal melanoma patients after CyberKnife treatment. AB - To assess quality of life in uveal melanoma patients within the first and second year after CyberKnife radiosurgery. Overall, 91 uveal melanoma patients were evaluated for quality of life through the Short-form (SF-12) Health Survey at baseline and at every follow-up visit over 2 years after CyberKnife radiosurgery. Statistical analysis was carried out using SF Health Outcomes Scoring Software and included subgroup analysis of patients developing secondary glaucoma and of patients maintaining a best corrected visual acuity (BCVA) of the treated eye of 0.5 log(MAR) or better. Analysis of variance, Greenhouse-Geisser correction, Student's t-test, and Fisher's exact test were used to determine statistical significance. Physical Functioning (PF) and Role Physical (RP) showed a significant decrease after CyberKnife radiosurgery, whereas Mental Health (MH) improved (P=0.007, P<0.0001 and P=0.023). MH and Social Functioning (SF) increased significantly (P=0.0003 and 0.026) in the no glaucoma group, MH being higher compared with glaucoma patients (P=0.02). PF and RP were significantly higher in patients with higher BCVA at the second follow-up (P=0.02). RP decreased in patients with BCVA<0.5 log(MAR) (P=0.013). Vitality (VT) increased significantly in patients whose BCVA could be preserved (P=0.031). Neither tumor localization nor size influenced the development of secondary glaucoma or change in BCVA. Although PF and RP decreased over time, MH improved continuously. Prevention of secondary glaucoma has a significant influence on both SF and MH, whereas preservation of BCVA affects VT. Emotional stability throughout follow-up contributes positively toward overall quality of life. CyberKnife radiosurgery may contribute to attenuation of emotional distress in uveal melanoma patients. PMID- 24048224 TI - Study of aqueous phase aggregation of FTY720 (fingolimod hydrochloride) and its effect on DMPC liposomes using fluorescent molecular probes. AB - This work focuses on the study of aqueous phase aggregation of the recently FDA approved oral drug molecule FTY720 (fingolimod hydrochloride) and its effect on dimyristoylphosphatidylcholine (DMPC) liposomes using different fluorescent molecular probes and fluorescence parameters. The variation of the steady state fluorescence intensity of 8-anilino-1-naphthalene sulfonic acid (ANS) with FTY720 in water shows an efficient micellar aggregation with the critical micellar concentration (CMC) at ~75 MUM. The aggregation number calculation from steady state fluorescence quenching of pyrene shows the formation of small micellar aggregates in aqueous solution having an aggregation number of 42 +/- 3 with the free energy of micellization ~-23 kJ mol(-1). Fluorescence intensity and lifetime decay analysis of the molecular probe 1-naphthol indicate that the interaction of FTY720 with the DMPC lipid bilayer membrane prevents partitioning of small molecules such as 1-naphthol to the membrane in both solid gel (SG) and liquid crystalline (LC) phases. Temperature dependent fluorescence intensity studies of 1-naphthol and fluorescence anisotropy measurements of 1,6-diphenyl-1,3,5 hexatriene (DPH) have shown that above the CMC of FTY720, the SG to LC main phase transition temperature (T(M)) of the lipid bilayer membrane decreases from 23 degrees C to 21 degrees C in the aqueous medium. PMID- 24048225 TI - Bacterial diversity associated with the tunic of the model chordate Ciona intestinalis. AB - The sea squirt Ciona intestinalis is a well-studied model organism in developmental biology, yet little is known about its associated bacterial community. In this study, a combination of 454 pyrosequencing of 16S ribosomal RNA genes, catalyzed reporter deposition-fluorescence in situ hybridization and bacterial culture were used to characterize the bacteria living inside and on the exterior coating, or tunic, of C. intestinalis adults. The 454 sequencing data set demonstrated that the tunic bacterial community structure is different from that of the surrounding seawater. The observed tunic bacterial consortium contained a shared community of <10 abundant bacterial phylotypes across three individuals. Culture experiments yielded four bacterial strains that were also dominant groups in the 454 sequencing data set, including novel representatives of the classes Alphaproteobacteria and Flavobacteria. The relatively simple bacterial community and availability of dominant community members in culture make C. intestinalis a promising system in which to investigate functional interactions between host-associated microbiota and the development of host innate immunity. PMID- 24048227 TI - From symmetric to asymmetric design of bio-inspired smart single nanochannels. AB - Biological nanochannels, such as ion channels and ion pumps, existing in cell membranes and intelligently controlling ions through the cell membrane serve as a big source of bio-inspiration for the scientists to build artificial functional nanochannels. In this Feature Article, a general strategy for the design and synthesis of bio-inspired smart single nanochannels is presented, and put into context with recent progress in constructing symmetric and asymmetric smart single polymer nanochannels with single/double artificial gates which can respond to single/multiple external stimuli, e.g., pH, ions, temperature, light, and molecules. This article is intended to utilize specific stimulus-dependent ionic transport properties inside the single nanochannel as an example to demonstrate the feasibility of the design strategy, and provide an overview of this fascinating research field. PMID- 24048226 TI - Trehalose/2-sulfotrehalose biosynthesis and glycine-betaine uptake are widely spread mechanisms for osmoadaptation in the Halobacteriales. AB - We investigated the mechanisms of osmoadaptation in the order Halobacteriales, with special emphasis on Haladaptatus paucihalophilus, known for its ability to survive in low salinities. H. paucihalophilus genome contained genes for trehalose synthesis (trehalose-6-phosphate synthase/trehalose-6-phosphatase (OtsAB pathway) and trehalose glycosyl-transferring synthase pathway), as well as for glycine betaine uptake (BCCT family of secondary transporters and QAT family of ABC transporters). H. paucihalophilus cells synthesized and accumulated ~1.97 3.72 MUmol per mg protein of trehalose in a defined medium, with its levels decreasing with increasing salinities. When exogenously supplied, glycine betaine accumulated intracellularly with its levels increasing at higher salinities. RT PCR analysis strongly suggested that H. paucihalophilus utilizes the OtsAB pathway for trehalose synthesis. Out of 83 Halobacteriales genomes publicly available, genes encoding the OtsAB pathway and glycine betaine BCCT family transporters were identified in 38 and 60 genomes, respectively. Trehalose (or its sulfonated derivative) production and glycine betaine uptake, or lack thereof, were experimentally verified in 17 different Halobacteriales species. Phylogenetic analysis suggested that trehalose synthesis is an ancestral trait within the Halobacteriales, with its absence in specific lineages reflecting the occurrence of gene loss events during Halobacteriales evolution. Analysis of multiple culture-independent survey data sets demonstrated the preference of trehalose-producing genera to saline and low salinity habitats, and the dominance of genera lacking trehalose production capabilities in permanently hypersaline habitats. This study demonstrates that, contrary to current assumptions, compatible solutes production and uptake represent a common mechanism of osmoadaptation within the Halobacteriales. PMID- 24048228 TI - Two-colour pump-probe experiments with a twin-pulse-seed extreme ultraviolet free electron laser. AB - Exploring the dynamics of matter driven to extreme non-equilibrium states by an intense ultrashort X-ray pulse is becoming reality, thanks to the advent of free electron laser technology that allows development of different schemes for probing the response at variable time delay with a second pulse. Here we report the generation of two-colour extreme ultraviolet pulses of controlled wavelengths, intensity and timing by seeding of high-gain harmonic generation free-electron laser with multiple independent laser pulses. The potential of this new scheme is demonstrated by the time evolution of a titanium-grating diffraction pattern, tuning the two coherent pulses to the titanium M-resonance and varying their intensities. This reveals that an intense pulse induces abrupt pattern changes on a time scale shorter than hydrodynamic expansion and ablation. This result exemplifies the essential capabilities of the jitter-free multiple colour free-electron laser pulse sequences to study evolving states of matter with element sensitivity. PMID- 24048229 TI - Fatal case of toxic epidermal necrolysis caused by cefozopran and associated with psoriasis. PMID- 24048230 TI - Surgical management of effusive constrictive pericarditis. AB - OBJECTIVE: The surgical approach for effusive constrictive pericarditis (ECP) has not been extensively studied. We present our institution's early and long-term results of pericardiectomy in our cohort of patients with ECP. METHODS: Diagnosis was made primarily by echocardiography. Right heart catheterisation was performed in eight patients. Pre-operatively, 10 patients had undergone at least one previous attempt at therapeutic pericardiocentesis. Pericardiectomy was performed where appropriate (thickened or inflamed). RESULTS: Of our 12 patients (50% male, median age 48 years, range 17-72 years), the underlying aetiology included idiopathic in five (41.6%), tuberculosis in four (33%), and malignancy in three patients (25%). Elective surgery was performed in nine patients. Median values of both central venous pressure and pulmonary capillary wedge pressure decreased markedly postoperatively (from 16.5 to 11.0 mmHg, p = 0.02; 20.0-15.0 mmHg, p = 0.01, respectively). There was no in-hospital mortality. Follow up ranged from three months to nine years (median three years). Five (41.6%) patients died during the follow-up period, and cumulative two-year survival was 55.6 +/- 1.5%. CONCLUSIONS: Pericardiectomy for ECP was effective, in terms of our early results, in patients unresponsive to medical therapy. Long-term survival depends on the underlying disease. PMID- 24048232 TI - Heart failure: a disease complex with challenging therapeutics. AB - Heart failure (HF) is the most common cause of cardiovascular hospitalization, especially among the elderly. It has a higher mortality and morbidity than several cancers and consumes a significant portion of the health-care budget. HF with preserved ejection fraction (HFpEF) is commoner among women who may have underlying hypertension. Significant progress has been achieved in the development of lifesaving drugs for HF with reduced ejection fraction (HFrEF). However, treatment of HFpEF still poses significant challenges. PMID- 24048236 TI - Heart failure: an update. PMID- 24048237 TI - Contemporary use of devices in heart failure. AB - Devices have become a cornerstone of heart failure (HF) therapy. Implantable cardioverter-defibrillators (ICDs) decrease mortality, and cardiac resynchronization therapy (CRT) improves symptoms and mortality. Most data have been collected in patients with systolic dysfunction. Data in patients with preserved systolic function are scarce, but interesting therapeutic concepts are evolving. Besides therapeutic functions, devices can have add-on diagnostic features such as early detection of fluid overload. In addition, stand-alone diagnostic devices are now also being developed for HF. PMID- 24048238 TI - Do anticoagulants or antiplatelet drugs have a role in treating heart failure in the absence of atrial fibrillation? AB - Patients with atrial fibrillation (AF) and heart failure (HF) are at risk for stroke, and progress in anticoagulation has led to new options for these patients. Patients in sinus rhythm may benefit from antiplatelet agents or anticoagulants, but much work remains to establish efficacy and safety. Additional progress is needed, including better tools for risk stratification and clarity regarding the need for antiplatelet agents in combination with anticoagulants for those with other vascular diseases. PMID- 24048239 TI - Confidence in generic drug substitution. AB - Patients should have confidence that the generic drugs they are prescribed in the United States can be effectively substituted for the brand product or another generic product. Through new bioequivalence study designs for narrow therapeutic index (NTI) drugs and postapproval studies of generic substitution, the US Food and Drug Administration's (FDA's) ongoing generic drug regulatory science activities are designed to ensure successful generic substitution for all drug products. PMID- 24048240 TI - Oral anticancer drugs: back to square one. AB - Szmulewitz and Ratain expressed concerns in their article "Playing Russian Roulette With Tyrosine Kinase Inhibitors," published in the March 2013 issue. This Commentary is intended to add emphasis to the concerns they raised as well as to draw the attention of the clinical pharmacology community to additional critical issues related to oral administration of modern anticancer medication. PMID- 24048241 TI - Reproducibility of EEG-fMRI results in a patient with fixation-off sensitivity. AB - Blood oxygenation level-dependent (BOLD) activation associated with interictal epileptiform discharges in a patient with fixation-off sensitivity (FOS) was studied using a combined electroencephalography-functional magnetic resonance imaging (EEG-fMRI) technique. An automatic approach for combined EEG-fMRI analysis and a subject-specific hemodynamic response function was used to improve general linear model analysis of the fMRI data. The EEG showed the typical features of FOS, with continuous epileptiform discharges during elimination of central vision by eye opening and closing and fixation; modification of this pattern was clearly visible and recognizable. During all 3 recording sessions EEG fMRI activations indicated a BOLD signal decrease related to epileptiform activity in the parietal areas. This study can further our understanding of this EEG phenomenon and can provide some insight into the reliability of the EEG-fMRI technique in localizing the irritative zone. PMID- 24048242 TI - Improving classification accuracy of motor imagery EEG using genetic feature selection. AB - In this study, an electroencephalogram (EEG) analysis system combined with feature selection, is proposed to enhance the classification of motor imagery (MI) data. It principally comprises feature extraction, feature selection, and classification. First, several features, including adaptive autoregressive (AAR) parameters, spectral power, asymmetry ratio, coherence and phase-locking value are extracted for subsequent classification. A genetic algorithm is then used to select features from the combination of the aforementioned features. Finally, the selected features are classified by support vector machine (SVM). Compared with "without feature selection" and back-propagation neural network (BPNN) on MI data from 2 data sets, the proposed system achieves better classification accuracy and is suitable for the applications of brain-computer interface (BCI). PMID- 24048243 TI - Structure of genetic and environmental risk factors for symptoms of DSM-IV borderline personality disorder. AB - IMPORTANCE: Previous studies have indicated that the psychopathological dimensions of borderline personality disorder (BPD) are influenced by a unitary liability factor. However, to our knowledge, the underlying etiological nature of the individual criteria for BPD as defined by the DSM-IV has not been explored. OBJECTIVE: To determine the structure of genetic and environmental risk factors for the symptoms of BPD. DESIGN, SETTING, AND PARTICIPANTS: Multivariate twin study with BPD criteria assessed by personal interview within a general community setting. Participants included 2794 young adults from the Norwegian Institute of Public Health Twin Panel. MAIN OUTCOMES AND MEASURES: The 9 criteria for BPD assessed by the Structured Interview for DSM-IV Personality. RESULTS: A common pathway model dominated by 1 highly heritable (55%) general BPD factor that strongly influenced all 9 BPD criteria (standardized path coefficients, 0.53 0.79) fit the data best. The model also included 2 additional common liability factors, mainly influencing criteria reflecting the affective and interpersonal dimensions. Both of these were mostly influenced by environmental liability factors (heritability, 29.3% and 2.2%). With 1 exception (criterion 2, unstable and intense relationships), the specific criteria were strongly influenced by environmental factors. Five of the 9 criterion-specific genetic effects were either 0 or negligible. CONCLUSIONS AND RELEVANCE: These results indicate that most of the genetic effects on the individual BPD criteria derive from 1 highly heritable general BPD factor, whereas the environmental influences were mostly criterion specific. PMID- 24048244 TI - Estimation of radioactivity level and associated radiological hazards of limestone and gypsum used as raw building materials in Rawalpindi/Islamabad region of Pakistan. AB - This study was undertaken to asses the radioactivity level of limestone and gypsum and its associated radiological hazard due to the presence of naturally occurring radioactive materials. Representative samples of limestone and gypsum were collected from cement factories located in the Rawalpindi/Islamabad region of Pakistan and were analysed by using an N-type high-purity germanium detector of 80 % relative efficiency. The average activity concentration of (40)K, (226)Ra and (232)Th were 60.22+/-3.47, 29.25+/-5.23 and 4.07+/-3.31 Bq kg(-1), respectively, in limestone and 70.86+/-4.1, 5.01+/-2.10 and 4.49+/-3.1 Bq kg(-1), respectively, in gypsum. The radiological hazard parameters radium equivalent activities, absorbed dose rate in air, external hazard index, internal hazard index, annual effective dose equivalent, gamma index and alpha index were computed. The results of the average activity concentrations of (40)K, (226)Ra and (232)Th and radiological hazard parameters were within the range of the reported average worldwide/United Nations Scientific Committee on the Effect of Atomic Radiation values. It is concluded that limestone and gypsum used in the Rawalpindi/Islamabad region does not pose any excessive radiological health hazard as a building raw materials and in industrial uses. PMID- 24048245 TI - Distribution of uranium concentration in groundwater samples from the Peddagattu/Nambapur and Seripally regions using laser fluorimetry. AB - Uranium is a naturally occurring element, which is widespread in nature. It is found in low levels within all rocks, soils and water. Peddagattu and Seripally areas of Nalgonda district, Andhra Pradesh, India were known as a rich uranium mineralised zone. Atomic mineral division and Baba Atomic Research Center proposed a uranium mine in this area. This study was carried out to know the distribution of uranium concentration in the groundwater samples by using laser fluorimetry. The observation reveals that the uranium concentration in the groundwater of this region ranges from 0.6 to 521.15 ppb. About 43 % of the groundwater samples had the uranium concentration above the standards set by United States Environmental Protection Agency (30 ppb). PMID- 24048246 TI - Early experience of a transcatheter aortic valve program at a Veterans Affairs facility. AB - IMPORTANCE: The US Food and Drug Administration recently approved the use of a transcatheter aortic valve in patients for whom traditional valve replacement surgery poses a high or prohibitive risk. Our hospital was one of the first Veterans Affairs facilities to launch a transcatheter aortic valve replacement (TAVR) program. OBJECTIVE: To evaluate our early experience with transfemoral TAVR. DESIGN AND SETTING: We retrospectively reviewed the records of all patients who underwent TAVR during the first year of our program at the Department of Cardiothoracic Surgery, Michael E. DeBakey Veterans Affairs Medical Center. PARTICIPANTS: The mean (SD) age of the patients was 77 (9) years, and their mean (SD) Society of Thoracic Surgeons predicted risk of mortality score was 8.8 (10.7). INTERVENTIONS: All patients underwent TAVR with the SAPIEN transcutaneous valve. MAIN OUTCOME MEASURES: We evaluated operative mortality and major operative morbidity (stroke, myocardial infarction, renal failure necessitating dialysis, and requirement for mechanical circulatory support, as well as vascular complications and requirement for permanent pacemaker), in addition to length of hospital stay and discharge status. RESULTS: Between December 21, 2011, and December 13, 2012, a total of 19 transfemoral TAVR procedures were performed at our center. Implantation was successful in all cases. There were no reports of operative (30-day) mortality, prosthetic valve endocarditis, renal failure necessitating dialysis, perioperative myocardial infarction or stroke, or conversion to surgical aortic valve replacement. Seven patients (37%) had mild paravalvular leak, 3 patients (16%) had moderate paravalvular leak, 2 patients (11%) had groin wound complications, 2 patients (11%) required a permanent pacemaker, 1 patient (5%) had a vascular access complication requiring endovascular repair, and 1 patient (5%) required temporary circulatory support (with extracorporeal membrane oxygenation). The mean (SD) length of hospital stay after TAVR was 8.0 (5.9) days. All patients were discharged home. CONCLUSIONS AND RELEVANCE: Transcatheter aortic valve replacement can be performed safely and with good outcomes at a Veterans Affairs facility with a committed multidisciplinary team and substantial experience in heart valve and endovascular therapies. PMID- 24048247 TI - Adverse impact of diet-induced hypercholesterolemia on cardiovascular tissue homeostasis in a rabbit model: time-dependent changes in cardiac parameters. AB - The present study evaluates a hypothesis that diet-related hypercholesterolemia increases oxidative stress-related burden to cardiovascular tissue, resulting in progressively increased mortality, along with deterioration of electrophysiological and enzymatic function in rabbit myocardium. New Zealand white rabbits were divided into four groups, defined as follows: GROUP I, cholesterol-free rabbit chow for 12 weeks; GROUP II, cholesterol-free chow, 40 weeks; GROUP III, chow supplemented with 2% cholesterol, 12 weeks; GROUP IV, chow supplemented with 2% cholesterol, 40 weeks. At the 12 and 40 weeks time points, animals in each of the aforementioned cohorts were subjected to echocardiographic measurements, followed by sacrifice. Significant deterioration in major outcome variables measured in the present study were observed only in animals maintained for 40 weeks on 2% cholesterol-supplemented chow, with much lesser adverse effects noted in animals fed high cholesterol diets for only 12 weeks. It was observed that rabbits receiving high cholesterol diets for 40 weeks exhibited significantly increased mortality, worsened ejection fraction and general deterioration of cardiac functions, along with increased atherosclerotic plaque formation and infarct size. Additionally, myocardium of GROUP IV animals was observed to contain lower levels of heme oxygenase-1 (HO-1) and cytochrome c oxidase III (COX III) protein relative to the controls. PMID- 24048248 TI - Single-chain fragment variable passive immunotherapies for neurodegenerative diseases. AB - Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). In the past decade, single-chain fragment variable (scFv) -based immunotherapies have been developed to target abnormal proteins or various forms of protein aggregates including Abeta, SNCA, Htt, and PrP proteins. The scFvs are produced by fusing the variable regions of the antibody heavy and light chains, creating a much smaller protein with unaltered specificity. Because of its small size and relative ease of production, scFvs are promising diagnostic and therapeutic reagents for protein misfolded diseases. Studies have demonstrated the efficacy and safety of scFvs in preventing amyloid protein aggregation in preclinical models. Herein, we discuss recent developments of these immunotherapeutics. We review efforts of our group and others using scFv in neurodegenerative disease models. We illustrate the advantages of scFvs, including engineering to enhance misfolded conformer specificity and subcellular targeting to optimize therapeutic action. PMID- 24048249 TI - Small molecules present in the cerebrospinal fluid metabolome influence superoxide dismutase 1 aggregation. AB - Superoxide dismutase 1 (SOD1) aggregation is one of the pathological markers of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. The underlying molecular grounds of SOD1 pathologic aggregation remains obscure as mutations alone are not exclusively the cause for the formation of protein inclusions. Thus, other components in the cell environment likely play a key role in triggering SOD1 toxic aggregation in ALS. Recently, it was found that ALS patients present a specific altered metabolomic profile in the cerebrospinal fluid (CSF) where SOD1 is also present and potentially interacts with metabolites. Here we have investigated how some of these small molecules affect apoSOD1 structure and aggregation propensity. Our results show that as co solvents, the tested small molecules do not affect apoSOD1 thermal stability but do influence its tertiary interactions and dynamics, as evidenced by combined biophysical analysis and proteolytic susceptibility. Moreover, these compounds influence apoSOD1 aggregation, decreasing nucleation time and promoting the formation of larger and less soluble aggregates, and in some cases polymeric assemblies apparently composed by spherical species resembling the soluble native protein. We conclude that some components of the ALS metabolome that shape the chemical environment in the CSF may influence apoSOD1 conformers and aggregation. PMID- 24048250 TI - Probing antigen-antibody interaction using fluorescence coupled capillary electrophoresis. AB - In this report, the use of fluorescence detection coupled capillary electrophoresis (CE-FL) allowed us to fully characterize the antigen-antibody interaction. CE-FL allowed separation of unbound quantum dots (QDs) and ligand bound QDs and also revealed an ordered assembly of biomolecules on QDs. Further, we observed FRET from QDs donor to DyLight acceptor, which were covalently conjugated with human IgG and goat anti-human IgG, respectively. The immunocomplex was formed and the mutual affinity of the antigen and antibody brought QDs and DyLight close enough to allow FRET to occur. This novel CE-based technique can be easily extended to other FRET systems based on QDs and may have potential application in the detection of antibodies. PMID- 24048251 TI - Formation of apatite coatings on an artificial ligament using a plasma- and precursor-assisted biomimetic process. AB - A plasma- and precursor-assisted biomimetic process utilizing plasma and alternate dipping treatments was applied to a Leed-Keio artificial ligament to produce a thin coating of apatite in a supersaturated calcium phosphate solution. Following plasma surface modification, the specimen was alternately dipped in calcium and phosphate ion solutions three times (alternate dipping treatment) to create a precoating containing amorphous calcium phosphate (ACP) which is an apatite precursor. To grow an apatite layer on the ACP precoating, the ACP precoated specimen was immersed for 24 h in a simulated body fluid with ion concentrations approximately equal to those in human blood plasma. The plasma surface modification was necessary to create an adequate apatite coating and to improve the coating adhesion depending on the plasma power density. The apatite coating prepared using the optimized conditions formed a thin-film that covered the entire surface of the artificial ligament. The resulting apatite-coated artificial ligament should exhibit improved osseointegration within the bone tunnel and possesses great potential for use in ligament reconstructions. PMID- 24048252 TI - An experimental proposal for revealing contextuality in almost all qutrit states. AB - Contextuality is a foundational phenomenon underlying key differences between quantum theory and classical realistic descriptions of the world. Here we propose an experimental test which is capable of revealing contextuality in all qutrit systems, except the completely mixed state, provided we choose the measurement basis appropriately. The 3-level system is furnished by the polarization and spatial degrees of freedom of a single photon, which encompass three orthogonal modes. Projective measurements along rays in the 3-dimensional Hilbert space are made by linear optical elements and detectors which are sensitive to single mode. We also discuss the impact of detector inefficiency and losses and review the theoretical foundations of this test. PMID- 24048253 TI - MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation. AB - Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) has provided huge insight into the pathways, mechanisms and transcription factors that control differentiation. Here we use high-throughput RT-PCR technology to take a snapshot of splicing changes in the full spectrum of high- and low expressed genes during induction of fibroblasts, from several donors, into iPSCs and their subsequent redifferentiation. We uncover a programme of concerted alternative splicing changes involved in late mesoderm differentiation and controlled by key splicing regulators MBNL1 and RBFOX2. These critical splicing adjustments arise early in vertebrate evolution and remain fixed in at least 10 genes (including PLOD2, CLSTN1, ATP2A1, PALM, ITGA6, KIF13A, FMNL3, PPIP5K1, MARK2 and FNIP1), implying that vertebrates require alternative splicing to fully implement the instructions of transcriptional control networks. PMID- 24048254 TI - Tissue Doppler imaging in very preterm infants during the first 24 h of life: an observational study. AB - BACKGROUND: Very preterm newborn infants often need cardiovascular support. More knowledge about myocardial function and factors that influence the immature myocardium may be helpful for optimising cardiovascular support in these infants. OBJECTIVE: Serial assessment of global myocardial function by means of colour tissue Doppler imaging (cTDI) in very and extremely preterm infants during the first 24 h of life. STUDY DESIGN: One-centre, prospective, observational longitudinal cohort study in a third level Neonatal Intensive Care Unit. Sixty five infants with median (range) gestational age (GA) 27 (24-31) weeks and birth weight (BW) 1049 (484-1620) g underwent echocardiographic examinations including cTDI at 5, 12 and 24 h after birth. MAIN OUTCOME MEASURES: Peak systolic and peak diastolic annular velocity and peak annular displacement of the left and right ventricle. RESULTS: There was a significant reduction in systolic and diastolic velocities and displacement of both ventricles from 5 to 12 h age. From 12 to 24 h, there was a non-significant increase in myocardial velocities and displacement. At 5 h, babies with haemodynamically significant patent ductus arteriosus (PDA) had significantly higher systolic and diastolic velocities in both ventricles than those with non-significant PDA. CONCLUSIONS: Myocardial tissue velocities decrease significantly from 5 to 12 h after birth in very preterm infants. Further studies are needed to confirm these results and to determine their clinical implications. PMID- 24048255 TI - Surface tuning for oxide-based nanomaterials as efficient photocatalysts. AB - Due to the increasingly polluted environment and the gradual depletion of fossil fuel reserves, the development of renewable technologies for environmental remediation and energy production is highly desirable. Over the past decades, oxide-based semiconductor photocatalysis has attracted much attention. On various frontiers for efficient photocatalysis, surface-tuning strategies for synthesis and modification of oxides on the nanometer scale have progressed at a fast pace. Hence, it is of significance to review recent advances in the development of surface tuning for oxide-based nanomaterials as activity-enhanced photocatalysts. In this review, special emphases, especially for recent advances in our group, are given to surface tuning of novel nanocrystallites for high thermal stability, hierarchical structure assembly, heterojunctional nanocomposites and high-energy facet exposure, along with effective testing tools for photogenerated charge properties at the surfaces and/or interfaces. This is of great significance for fields related to energy and environment from scientific and engineering viewpoints. PMID- 24048256 TI - Cardiac risk assessment, morbidity prediction, and outcome in the vascular intensive care unit. AB - OBJECTIVES: The aim of this study is to examine the predictive value of the Lee revised cardiac risk index (RCRI) for a standard vascular intensive care unit (ICU) population as well as assessing the utility of transthoracic echocardiography and the impact of prior coronary artery disease (CAD) and coronary revascularization on patient outcome. DESIGN: This is a retrospective review of prospectively maintained Vascubase and prospectively collected ICU data. MATERIALS AND METHODS: Data from 363 consecutive vascular ICU admissions were collected. Findings were used to calculate the RCRI, which was then correlated with patient outcomes. All patients were on optimal medical therapy (OMT) in the form of cardioselective beta-blocker, aspirin, statin, and folic acid. RESULTS: There was no relationship found between a reduced ejection fraction and patient outcome. Mortality was significantly increased for patients with left ventricular hypertrophy (LVH) as identified on echo (14.9% vs 6.5%, P = .028). The overall complication rates were significantly elevated for patients with valvular dysfunction. Discrimination for the RCRI on receiver-operating characteristic analysis was poor, with an area under the receiver-operating characteristic curve of .621. Model calibration was reasonable with an Hosmer Lemeshow C statistic of 2.726 (P = .256). Of those with known CAD, 41.22% of the patients receiving best medical treatment developed acute myocardial infarction (AMI) compared to 35.3% of those who previously underwent percutaneous cardiac intervention and 23.5% of those who had undergone coronary artery bypass grafting. There was 3-fold increase in major adverse clinical events in patients with troponin rise and LVH. CONCLUSIONS: The RCRI's discriminatory capacity is low, and this raises difficulties in assessing cardiac risk in patients undergoing vascular intervention. The AMI is highest in the OMT group without prior cardiac intervention, which mandates protocols to identify patients requiring cardiac intervention prior to vascular procedures. PMID- 24048257 TI - Computational fluid dynamics investigation of chronic aortic dissection hemodynamics versus normal aorta. AB - OBJECTIVES: To evaluate hemodynamic changes during aneurysmal dilatation in chronic type B aortic dissections compared to hemodynamic parameters in the healthy aorta with the use of computational fluid dynamics (CFD). METHODS: True lumen (TL)/false lumen (FL) dimensional changes, changes in total pressure (TP), and wall shear stress (WSS) were evaluated at follow-up (FU) compared to initial examination (IE) with transient CFD simulation with geometries derived from clinical image data and inflow boundary conditions from magnetic resonance images. The TL/FL pressure gradient between ascending and descending aorta (DAo) and maximum WSS at the site of largest dilatation was compared to values for the healthy aorta. RESULTS: Hemodynamic changes at site of largest FL dilatation included 77% WSS reduction and 69% TP reduction. Compared to the healthy aorta, pressure gradient between ascending and DAo was a factor of 1.4 higher in the TL and a factor of 1.5 in the FL and increased at FU (1.6 and 1.7, respectively). Maximum WSS at the site of largest dilatation was a factor of 3 lower than that for the healthy aorta at IE and decreased by more than a factor of 2 at FU. CONCLUSIONS: The FL dilatation at FU favorably reduced TP. In contrast, unfavorable increase in pressure gradient between ascending and DAo was observed with higher values than in the healthy aorta. Maximum WSS was reduced at the site of largest dilation compared to healthy aorta. PMID- 24048258 TI - A novel approach for developing and interpreting treatment moderator profiles in randomized clinical trials. AB - IMPORTANCE: Identifying treatment moderators may help mental health practitioners arrive at more precise treatment selection for individual patients and can focus clinical research on subpopulations that differ in treatment response. OBJECTIVE: To demonstrate a novel exploratory approach to moderation analysis in randomized clinical trials. DESIGN, SETTING, AND PARTICIPANTS: A total of 291 adults from a randomized clinical trial that compared an empirically supported psychotherapy with selective serotonin reuptake inhibitor (SSRI) pharmacotherapy as treatments for depression. MAIN OUTCOMES AND MEASURES: We selected 8 relatively independent individual moderators out of 32 possible variables. A combined moderator, M*, was developed as a weighted combination of the 8 selected individual moderators. M* was then used to identify individuals for whom psychotherapy may be preferred to SSRI pharmacotherapy or vice versa. RESULTS: Among individual moderators, psychomotor activation had the largest moderator effect size (0.12; 95% CI, <.01 to 0.24). The combined moderator, M*, had a larger moderator effect size than any individual moderator (0.31; 95% CI, 0.15 to 0.46). Although the original analyses demonstrated no overall difference in treatment response, M* divided the study population into 2 subpopulations, with each showing a clinically significant difference in response to psychotherapy vs SSRI pharmacotherapy. CONCLUSIONS AND RELEVANCE: Our results suggest that the strongest determinations for personalized treatment selection will likely require simultaneous consideration of multiple moderators, emphasizing the value of the methods presented here. After validation in a randomized clinical trial, a mental health practitioner could input a patient's relevant baseline values into a handheld computer programmed with the weights needed to calculate M*. The device could then output the patient's M* value and suggested treatment, thereby allowing the mental health practitioner to select the treatment that would offer the greatest likelihood of success for each patient. PMID- 24048259 TI - Solution-processed nanoparticle super-float-gated organic field-effect transistor as un-cooled ultraviolet and infrared photon counter. AB - High sensitivity photodetectors in ultraviolet (UV) and infrared (IR) range have broad civilian and military applications. Here we report on an un-cooled solution processed UV-IR photon counter based on modified organic field-effect transistors. This type of UV detectors have light absorbing zinc oxide nanoparticles (NPs) sandwiched between two gate dielectric layers as a floating gate. The photon-generated charges on the floating gate cause high resistance regions in the transistor channel and tune the source-drain output current. This "super-float-gating" mechanism enables very high sensitivity photodetectors with a minimum detectable ultraviolet light intensity of 2.6 photons/MUm(2)s at room temperature as well as photon counting capability. Based on same mechansim, infrared photodetectors with lead sulfide NPs as light absorbing materials have also been demonstrated. PMID- 24048260 TI - Group performance is maximized by hierarchical competence distribution. AB - Groups of people or even robots often face problems they need to solve together. Examples include collectively searching for resources, choosing when and where to invest time and effort, and many more. Although a hierarchical ordering of the relevance of the group members' inputs during collective decision making is abundant, a quantitative demonstration of its origin and advantages using a generic approach has not been described yet. Here we introduce a family of models based on the most general features of group decision making, and show that the optimal distribution of competences is a highly skewed function with a structured fat tail. Our results are obtained by optimizing the groups' compositions through identifying the best-performing distributions for both the competences and for the members' flexibilities/pliancies. Potential applications include choosing the best composition for a group intended to solve a given task. PMID- 24048261 TI - Menopause practitioner perspective on the American Society of Bone and Mineral Research Task Force report on atypical femoral fracture. AB - CLINICAL SCENARIO: One of your patients, a 59-year-old postmenopausal Asian woman (menopause, age 52), took hormone therapy for about one year for her menopause symptoms. When she was 54, her mother (age 80) suffered a hip fracture, and she requested a bone density test at her next gynecology visit. The t-score results were spine, -1.1; total hip, -1.8; and femoral neck, -2.1, all in the osteopenic range. After some discussion, she was started on alendronate 70 mg once a week, together with calcium and vitamin D. Follow-up dual-energy x-ray absorptiometry testing after 2 and 5 years of therapy showed increases in bone mineral density, resulting in t-score improvements of about 0.3 to 0.5 units (spine was now normal; femoral neck was -1.8). The Fracture Risk Assessment Tool estimated her 10-year risk of hip fracture to be 0.4% and her 10-year risk of any of 4 major osteoporotic fractures to be 7.5%. During her most recent gynecology visit, she expressed concern about unusual femoral fractures being linked to long-term use of alendronate. She asks if there is reason for her to stop using this drug. PMID- 24048262 TI - What you should know about continuing bisphosphonate osteoporosis medications. PMID- 24048263 TI - Polymorphisms in alcohol-metabolizing enzymes and esophageal carcinoma susceptibility: a Dutch Caucasian case-control study. AB - Esophageal cancer (EC), mainly consisting of squamous cell carcinoma (ESCC) in the Eastern world and adenocarcinoma (EAC) in the Western world, is strongly associated with dietary factors such as alcohol use. We aimed to clarify the modifying role in EC etiology in Caucasians of functional genotypes in alcohol metabolizing enzymes. In all, 351 Caucasian patients with EC and 430 matched controls were included and polymorphisms in CYP2E1, ADH and near ALDH2 genes were determined. In contrast to the results on ESCC in mainly Asian studies, we found that functional genotypes of alcohol-metabolizing enzymes were not significantly associated with EAC or ESCC in an European population. PMID- 24048264 TI - [Manual medicine and orthopedics]. AB - Manual medicine (MM) is a manual medical technique to identify and treat reversible dysfunction especially of the musculoskeletal system. The origins of MM were derived from empirical observations but MM is nowadays based on anatomy, biomechanics and neurophysiology. Besides special training in palpation according to precise topographic anatomic knowledge, the diagnostics of segmental or articular dysfunction are also based on knowledge about afferent convergence of multiceptive neurons located in proprioceptive and nociceptive layers of the brain stem and spinal cord. This leads to activation of motor and sympathetic reactions with the consequence of segmental or regional dysfunction. Manual therapy aims to eliminate noci-afferents as well as to activate inhibitory receptive fields. This can be achieved either by a single high velocity manipulative impulse or by slow-soft rhythmic repetitive mobilization. The special medical education and training in MM is outlined in relation to the Bologna postgraduate concept. As MM is basically used in relation to the musculoskeletal system it should definitely be incorporated into the specialization for orthopedics and traumatology and become part of the examination. In outpatient medicine an orthopedic and trauma surgeon without MM expertise will be inferior to a general practitioner with this expertise. PMID- 24048265 TI - [Rehabilitation in orthopedics and trauma surgery. State of the art]. AB - Diseases and injuries of the musculoskeletal system are the most common reasons for rehabilitation in Germany. The statutory health insurance, pension funds and the German social accident insurance are service providers for rehabilitation. Rehabilitation is based on the international classification of functioning, disability and health (ICF). The extensive possibilities for medical rehabilitation are increasingly being supplemented by options for combined medical and occupational rehabilitation. The demographic changes in Germany are also a challenge for rehabilitation. In a situation of predicted labor deficit, even now it becomes essential to keep employees longer in their jobs. The increasing number of elderly persons causes an increase in frequent age-dependent diseases, such as osteoporosis and osteoarthritis in combination with age dependent injuries. This will be a burden for the health system in acute care medicine and rehabilitation. Improving activities and participation following diseases and injuries of the musculoskeletal system will end in an increase in utilization of rehabilitation. This needs to be considered and reflected in an adjusted higher budget for costs in rehabilitation. PMID- 24048266 TI - Using ensemble SVM to identify human GPCRs N-linked glycosylation sites based on the general form of Chou's PseAAC. AB - As the most frequent drug target, G-protein coupled receptors (GPCRs) are a large family of seven transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways. Glycosylation is one of the most complex post-translational modifications (PTMs) of proteins in eukaryotic cells. It plays important roles in a variety of cellular functions, including protein folding, protein trafficking and localization, cell-cell interactions and epitope recognition. Therefore, investigating the exact position of glycosylation site in GPCR sequence can provide useful clues for drug design and other biotechnology applications. Experimental identification of glycosylation sites is expensive and laborious. Hence, there is a significant interest in the development of computational methods for reliable prediction of glycosylation sites from amino acid sequences. In this article, we presented an effective method to recognize the sites of human GPCRs by combining amino acid hydrophobicity with ensemble support vector machine. The prediction accuracy, sensitivity, specificity, Matthews correlation coefficient and area under the curve values were 94.4, 89.7, 98.9%, 0.895 and 0.989, respectively. The establishment of such a fast and accurate prediction method will speed up the pace of identifying proper GPCRs functional sites to facilitate drug discovery. PMID- 24048267 TI - Protein degradation systems in platelets. AB - Protein synthesis and degradation are essential processes that allow cells to survive and adapt to their surrounding milieu. In nucleated cells, the degradation and/or cleavage of proteins is required to eliminate aberrant proteins. Cells also degrade proteins as a mechanism for cell signalling and complex cellular functions. Although the last decade has convincingly shown that platelets synthesise proteins, the roles of protein degradation in these anucleate cytoplasts are less clear. Here we review what is known about protein degradation in platelets placing particular emphasis on the proteasome and the cysteine protease calpain. PMID- 24048268 TI - Endobronchial ultrasonography-guided transbronchial needle aspiration biopsy for preoperative nodal staging of lung cancer in a veteran population. AB - IMPORTANCE: Recently, preoperative lung cancer staging has evolved to include endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA) biopsies of the hilar and mediastinal lymph nodes, but the feasibility and usefulness of the procedure have not been well studied in the veteran population. OBJECTIVE: To determine the safety and effectiveness of EBUS-TBNA as a key component of a preoperative staging algorithm for lung cancer in veterans. DESIGN, SETTING, AND PARTICIPANTS: Review of a prospectively maintained thoracic surgery database that includes patients who underwent lung resection for lung cancer between January 1, 2009, and December 31, 2012, at a single Veterans Affairs medical center among a consecutive cohort of 166 patients with clinically early-stage (I or II) lung cancer who underwent lobectomy with nodal dissection. INTERVENTIONS: Endobronchial ultrasonography-guided transbronchial needle aspiration mediastinal staging (EBUS group) in 62 patients (37.3%) was compared with noninvasive nodal staging plus integrated positron emission tomography computed tomography only (PET/CT-only group) in 104 patients (62.7%). The accuracy of nodal staging was assessed by comparison with the final pathological staging after complete nodal dissection (the gold standard). MAIN OUTCOMES AND MEASURES: Primary outcomes were feasibility, safety, accuracy, and negative predictive value of EBUS-TBNA for preoperative nodal staging. A secondary outcome was the rate of nontherapeutic lung resection for occult N2 disease, with comparison between the EBUS group and the PET/CT-only group. RESULTS: No significant complications were attributable to the EBUS-TBNA procedure. In the EBUS group, 258 lymph node stations were sampled. N1 hilar metastases were diagnosed in 8 patients (12.9%) before surgery, and the remainder were staged N0. Accuracy and negative predictive value of EBUS-TBNA were 93.5% (58 of 62) and 92.6% (50 of 54), respectively. The overall rate of nontherapeutic lung resection performed in patients with occult N2 disease was 10.8% (18 of 166) (8.1% in the EBUS group and 12.5% in the PET/CT-only group) (P = .37). CONCLUSION AND RELEVANCE: A preoperative lung cancer staging strategy that includes EBUS-TBNA seems to be safe and effective in a veteran population, resulting in a low rate of nontherapeutic operations because of occult N2 nodal disease. PMID- 24048269 TI - The marine natural product manzamine A targets vacuolar ATPases and inhibits autophagy in pancreatic cancer cells. AB - Manzamine A, a member of the manzamine alkaloids, was originally isolated from marine sponges of the genus Haliclona. It was recently shown to have activity against pancreatic cancer cells, but the precise mechanism of action remained unclear. To further our understanding of the mechanism of action of manzamine A, chemogenomic profiling in the yeast S. cerevisiae was performed, suggesting that manzamine A is an uncoupler of vacuolar ATPases. Fluorescence microscopy confirmed this effect on yeast vacuoles, where manzamine A produced a phenotype very similar to that of the established v-ATPase inhibitor bafilomycin A1. In pancreatic cancer cells, 10 uM manzamine A affected vacuolar ATPase activity and significantly increased the level of autophagosome marker LC3-II and p62/SQSTM1 as observed by western blot analysis. Treatment with manzamine A in combination with bafilomycin A1 (inhibitor of autophagosome-lysosome fusion) did not change the levels of LC3-II when compared to cells treated with bafilomycin A1 alone, suggesting that manzamine A is a potential inhibitor of autophagy by preventing autophagosome turnover. As autophagy is essential for pancreatic tumor growth, blocking this pathway with manzamine A suggests a promising strategy for the treatment of pancreatic cancer. PMID- 24048270 TI - Synthesis of glycyrrhetinic acid-modified chitosan 5-fluorouracil nanoparticles and its inhibition of liver cancer characteristics in vitro and in vivo. AB - Nanoparticle drug delivery (NDDS) is a novel system in which the drugs are delivered to the site of action by small particles in the nanometer range. Natural or synthetic polymers are used as vectors in NDDS, as they provide targeted, sustained release and biodegradability. Here, we used the chitosan and hepatoma cell-specific binding molecule, glycyrrhetinic acid (GA), to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by Fourier transformed infrared spectroscopy (FT-IR) and 1H-nuclear magnetic resonance (1H-NMR). By combining GA-CTS and 5-FU (5-fluorouracil), we obtained a GA-CTS/5-FU nanoparticle, with a particle size of 217.2 nm, a drug loading of 1.56% and a polydispersity index of 0.003. The GA-CTS/5-FU nanoparticle provided a sustained release system comprising three distinct phases of quick, steady and slow release. We demonstrated that the nanoparticle accumulated in the liver. In vitro data indicated that it had a dose- and time dependent anti-cancer effect. The effective drug exposure time against hepatic cancer cells was increased in comparison with that observed with 5-FU. Additionally, GA-CTS/5-FU significantly inhibited the growth of drug-resistant hepatoma, which may compensate for the drug-resistance of 5-FU. In vivo studies on an orthotropic liver cancer mouse model demonstrated that GA-CTS/5-FU significantly inhibited tumor growth, resulting in increased survival time. PMID- 24048271 TI - Optimal cleavage and oxidative folding of alpha-conotoxin TxIB as a therapeutic candidate peptide. AB - Alpha6beta2 nicotinic acetylcholine receptors (nAChRs) are potential therapeutic targets for the treatment of several neuropsychiatric diseases, including addiction and Parkinson's disease. Alpha-conotoxin (alpha-CTx) TxIB is a uniquely selective ligand, which blocks alpha6/alpha3beta2beta3 nAChRs only, but does not block the other subtypes. Therefore, alpha-CTx TxIB is a valuable therapeutic candidate peptide. Synthesizing enough alpha-CTx TxIB with high yield production is required for conducting wide-range testing of its potential medicinal applications. The current study optimized the cleavage of synthesized alpha-CTx TxIB resin-bounded peptide and folding of the cleaved linear peptide. Key parameters influencing cleavage and oxidative folding of alpha-CTx TxIB were examined, such as buffer, redox agents, pH, salt, co-solvent and temperature. Twelve conditions were used for cleavage optimization. Fifty-four kinds of one step oxidative solution were used to assess their effects on each alpha-CTx TxIB isomers' yield. The result indicated that co-solvent choices were particularly important. Completely oxidative folding of globular isomer was achieved when the NH4HCO3 or Tris-HCl folding buffer at 4 degrees C contained 40% of co-solvent DMSO, and GSH:GSSG (2:1) or GSH only with pH 8~8.7. PMID- 24048272 TI - Saponin B, a novel cytostatic compound purified from Anemone taipaiensis, induces apoptosis in a human glioblastoma cell line. AB - Glioblastoma multiforme (GBM) is one of the most common malignant brain tumors. Saponin B, a novel compound isolated from the medicinal plant, Anemone taipaiensis, has been found to have a strong time- and dose-dependent cytostatic effect on human glioma cells and to suppress the growth of U87MG GBM cells. In this study, we investigated whether saponin B induces the apoptosis of glioblastoma cells and examined the underlying mechanism(s) of action of saponin B. Saponin B significantly suppressed U87MG cell proliferation. Flow cytometric analysis of DNA in the U87MG cells confirmed that saponin B blocked the cell cycle at the S phase. Furthermore, treatment of the U87MG cells with saponin B induced chromatin condensation and led to the formation of apoptotic bodies, as observed under a fluorescence microscope, and Annexin V/PI assay further suggested that phosphatidylserine (PS) externalization was apparent at higher drug concentrations. Treatment with saponin B activated the receptor-mediated pathway of apoptosis, as western blot analysis revealed the activation of Fas-l. Saponin B increased the Bax and caspase-3 ratio and decreased the protein expression of Bcl-2. The results from the present study demonstrate that the novel compound, saponin B, effectively induces the apoptosis of GBM cells and inhibits glioma cell growth and survival. Therefore, saponin B may be a potential candidate for the development of novel cancer therapeutics with antitumor activity against gliomas. PMID- 24048273 TI - DNA analysis based on toehold-mediated strand displacement on graphene oxide. AB - Fluorescent dye-labeled probe DNA was immobilized on fluorescence-quenching graphene oxide (GO) through a capture DNA. When targets were added, the probes were released from the GO through toehold-mediated strand exchange. Higher emission recovery and more signal contrast were achieved relative to conventional methods that are based on direct adsorption of probes. PMID- 24048274 TI - Malaria rapid diagnostic tests: challenges and prospects. AB - In the last decade, there has been an upsurge of interest in developing malaria rapid diagnostic test (RDT) kits for the detection of Plasmodium species. Three antigens - Plasmodium falciparum histidine-rich protein 2 (PfHRP2), plasmodial aldolase and plasmodial lactate dehydrogenase (pLDH) - are currently used for RDTs. Tests targeting HRP2 contribute to more than 90% of the malaria RDTs in current use. However, the specificities, sensitivities, numbers of false positives, numbers of false negatives and temperature tolerances of these tests vary considerably, illustrating the difficulties and challenges facing current RDTs. This paper describes recent developments in malaria RDTs, reviewing RDTs detecting PfHRP2, pLDH and plasmodial aldolase. The difficulties associated with RDTs, such as genetic variability in the Pfhrp2 gene and the persistence of antigens in the bloodstream following the elimination of parasites, are discussed. The prospect of overcoming the problems associated with current RDTs with a new generation of alternative malaria antigen targets is also described. PMID- 24048275 TI - Development of a novel adenosine-eluting guidewire (Adenowire) for coronary vasodilation during percutaneous coronary intervention. AB - AIMS: Microvascular obstruction (MVO) and "no-reflow phenomenon" (NRP) remain barriers to optimal tissue perfusion after percutaneous coronary intervention (PCI). The purpose of this study was to develop, characterise, and test an adenosine-eluting guidewire (Adenowire) for coronary vasodilation. METHODS AND RESULTS: Utilising polyurethane chemistry, we developed a non-toxic pentameric form of adenosine (PA) that can be coated onto guidewires (Adenowire) and that allows continuous elution of adenosine into the distal vascular bed during PCI. We characterised PA with Fourier transform infrared spectroscopy, NMR and MALDI time-of-flight mass spectrometry, established its stability by calorimetry, and confirmed its safety by extensive toxicological testing. Adenowires reliably released adenosine in vitro over 60 minutes. In pigs, insertion of an Adenowire into the left circumflex or left anterior descending coronary artery resulted in immediate and sustained (40 minutes) vasodilation. Electron microscopy demonstrated smooth thin coating of the terminal portion of guidewires and showed lack of fibrin or platelet adhesion to the Adenowire after in vivo use. CONCLUSIONS: Since guidewires are the first devices to cross a culprit lesion, Adenowires would prophylactically medicate vascular beds with adenosine at the target site without the need for additional manipulations by the interventionalist. PMID- 24048276 TI - CYP2C9 polymorphism is not a major determinant of bosentan exposure in healthy volunteers. PMID- 24048277 TI - Evaluation of various static in vitro-in vivo extrapolation models for risk assessment of the CYP3A inhibition potential of an investigational drug. AB - Nine static models (seven basic and two mechanistic) and their respective cutoff values used for predicting cytochrome P450 3A (CYP3A) inhibition, as recommended by the US Food and Drug Administration and the European Medicines Agency, were evaluated using data from 119 clinical studies with orally administered midazolam as a substrate. Positive predictive error (PPE) and negative predictive error (NPE) rates were used to assess model performance, based on a cutoff of 1.25-fold change in midazolam area under the curve (AUC) by inhibitor. For reversible inhibition, basic models using total or unbound systemic inhibitor concentration [I] had high NPE rates (46-47%), whereas those using intestinal luminal ([I]gut) values had no NPE but a higher PPE. All basic models for time-dependent inhibition had no NPE and reasonable PPE rates (15-18%). Mechanistic static models that incorporate all interaction mechanisms and organ specific [I] values (enterocyte and hepatic inlet) provided a higher predictive precision, a slightly increased NPE, and a reasonable PPE. Various cutoffs for predicting the likelihood of CYP3A inhibition were evaluated for mechanistic models, and a cutoff of 1.25-fold change in midazolam AUC appears appropriate. PMID- 24048278 TI - Intraoperative positioning of the hindfoot with the hindfoot alignment guide: a pilot study. AB - BACKGROUND: In a previous study, intraoperative positioning of the hindfoot by visual means resulted in the wrong varus/valgus position by 8 degrees and a relatively large standard deviation of 8 degrees. Thus, new intraoperative means are needed to improve the precision of hindfoot surgery. We therefore sought a hindfoot alignment guide that would be as simple as the alignment guides used in total knee arthroplasty. METHODS: A novel hindfoot alignment guide (HA guide) has been developed that projects the mechanical axis from the tibia down to the heel. The HA guide enables the positioning of the hindfoot in the desired varus/valgus position and in plantigrade position in the lateral plane. The HA guide was used intraoperatively from May through November 2011 in 11 complex patients with simultaneous correction of the supramalleolar, tibiotalar, and inframalleolar alignment. Pre- and postoperative Saltzman views were taken and the position was measured. RESULTS: The HA guide significantly improved the intraoperative positioning compared with visual means: The accuracy with the HA guide was 4.5 +/ 5.1 degrees (mean +/- standard deviation) and without the HA guide 9.4 +/- 5.5 degrees (P < .05). In 7 of 11 patients, the preoperative plan was changed because of the HA guide (2 avoided osteotomies, 5 additional osteotomies). CONCLUSIONS: The HA guide helped to position the hindfoot intraoperatively with greater precision than visual means. The HA guide was especially useful for multilevel corrections in which the need for and the amount of a simultaneous osteotomy had to be evaluated intraoperatively. LEVEL OF EVIDENCE: Level IV, case series. PMID- 24048279 TI - Supramolecular chemistry and chemical warfare agents: from fundamentals of recognition to catalysis and sensing. AB - Supramolecular chemistry presents many possible avenues for the mitigation of the effects of chemical warfare agents (CWAs), including sensing, catalysis and sequestration. To-date, efforts in this field both to study fundamental interactions between CWAs and to design and exploit host systems remain sporadic. In this tutorial review the non-covalent recognition of CWAs is considered from first principles, including taking inspiration from enzymatic systems, and gaps in fundamental knowledge are indicated. Examples of synthetic systems developed for the recognition of CWAs are discussed with a focus on the supramolecular complexation behaviour and non-covalent approaches rather than on the proposed applications. PMID- 24048280 TI - Adalimumab for the treatment of refractory acne conglobata. PMID- 24048281 TI - In silico ionomics segregates parasitic from free-living eukaryotes. AB - Ion transporters are fundamental to life. Due to their ancient origin and conservation in sequence, ion transporters are also particularly well suited for comparative genomics of distantly related species. Here, we perform genome-wide ion transporter profiling as a basis for comparative genomics of eukaryotes. From a given predicted proteome, we identify all bona fide ion channels, ion porters, and ion pumps. Concentrating on unicellular eukaryotes (n = 37), we demonstrate that clustering of species according to their repertoire of ion transporters segregates obligate endoparasites (n = 23) on the one hand, from free-living species and facultative parasites (n = 14) on the other hand. This surprising finding indicates strong convergent evolution of the parasites regarding the acquisition and homeostasis of inorganic ions. Random forest classification identifies transporters of ammonia, plus transporters of iron and other transition metals, as the most informative for distinguishing the obligate parasites. Thus, in silico ionomics further underscores the importance of iron in infection biology and suggests access to host sources of nitrogen and transition metals to be selective forces in the evolution of parasitism. This finding is in agreement with the phenomenon of iron withholding as a primordial antimicrobial strategy of infected mammals. PMID- 24048282 TI - Quantum conductance in silicon oxide resistive memory devices. AB - Resistive switching offers a promising route to universal electronic memory, potentially replacing current technologies that are approaching their fundamental limits. In many cases switching originates from the reversible formation and dissolution of nanometre-scale conductive filaments, which constrain the motion of electrons, leading to the quantisation of device conductance into multiples of the fundamental unit of conductance, G0. Such quantum effects appear when the constriction diameter approaches the Fermi wavelength of the electron in the medium - typically several nanometres. Here we find that the conductance of silicon-rich silica (SiOx) resistive switches is quantised in half-integer multiples of G0. In contrast to other resistive switching systems this quantisation is intrinsic to SiOx, and is not due to drift of metallic ions. Half integer quantisation is explained in terms of the filament structure and formation mechanism, which allows us to distinguish between systems that exhibit integer and half-integer quantisation. PMID- 24048283 TI - Synthesis and biological evaluation of apigenin derivatives as antibacterial and antiproliferative agents. AB - Two series of apigenin [5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one] derivatives, 3a-3j and 4a-4j, were synthesized. The apigenin and alkyl amines moieties of these compounds were separated by C2 or C3 spacers, respectively. The chemical structures of the apigenin derivatives were confirmed using 1H-NMR, 13C NMR, and electrospray ionization mass spectroscopy. The in vitro antibacterial and antiproliferative activities of all synthesized compounds were determined. Among the tested compounds, 4a-4j displayed significant antibacterial activity against the tested strains (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa). Additionally, 4i showed the best inhibitory activity with minimum inhibitory concentrations of 1.95, 3.91, 3.91, and 3.91 MUg/mL against S. aureus, B. subtilis, E. coli, and P. aeruginosa, respectively. The antiproliferative activity of the apigenin derivatives was evaluated by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. We determined that 4a-4j displayed better growth inhibition activity against four human cancer cell lines, namely, human lung (A549), human cervical (HeLa), human hepatocellular liver (HepG2), and human breast (MCF-7) cancer cells, than the parent apigenin. Compound 4j was found to be the most active antiproliferative compound against the selected cancer cells. Structure-activity relationships were also discussed based on the obtained experimental data. PMID- 24048284 TI - Click reactions as a key step for an efficient and selective synthesis of D xylose-based ILs. AB - D-Xylose-based ionic liquids have been prepared from D-xylose following a five steps reaction sequence, the key step being a click cycloaddition. These ionic liquids (ILs) have been characterized through classical analytical methods (IR, NMR, mass spectroscopy, elemental analysis) and their stability constants, Tg and Tdec, were also determined. Considering their properties and their hydrophilicity, these compounds could be alternative solvents for chemical applications under mild conditions. PMID- 24048285 TI - Effect of tomato industrial processing on phenolic profile and antiplatelet activity. AB - BACKGROUND: Regular consumption of fruits and vegetables (e.g., tomatoes) has been shown to be beneficial in terms of reducing the incidence of cardiovascular diseases. The industrial processing of tomatoes into tomato-based products includes several thermal treatments. Very little is known on the effect of tomato industrial processing on antiaggregatory activity and phenolic profile. METHODS: It was assessed the effect of tomato and by-products extracts on platelet aggregation induced by ADP, collagen, TRAP-6 and arachidonic acid. These in vitro antithrombotic properties were further supported in an in vivo model of thrombosis. A set of antiplatelet compounds has been selected for HPLC analysis in the different extracts. RESULTS: Some natural compounds such as chlorogenic, caffeic, ferulic and p-coumaric acids were identified by HPLC in tomatoes and its products may inhibit platelet activation. Red tomatoes, tomato products (sauce, ketchup and juice) and by-products extracts inhibited platelet aggregation induced adenosine 5'-diphosphate, collagen, thrombin receptor activator peptide-6 and arachidonic acid, but to a different extent. Also, pomace extract presents antithrombotic activity. CONCLUSIONS: Processed tomatoes may have a higher content of health-benefiting compounds than fresh ones. Pomace even presents the best antiplatelet activity. Finally, tomato products may be used as a functional ingredient adding antiplatelet activities to processed foods. PMID- 24048286 TI - Analysis of biotinylated generation 4 poly(amidoamine) (PAMAM) dendrimer distribution in the rat brain and toxicity in a cellular model of the blood-brain barrier. AB - Dendrimers are highly customizable nanopolymers with qualities that make them ideal for drug delivery. The high binding affinity of biotin/avidin provides a useful approach to fluorescently label synthesized dendrimer-conjugates in cells and tissues. In addition, biotin may facilitate delivery of dendrimers through the blood-brain barrier (BBB) via carrier-mediated endocytosis. The purpose of this research was to: (1) measure toxicity using lactate dehydrogenase (LDH) assays of generation (G)4 biotinylated and non-biotinylated poly(amidoamine) (PAMAM) dendrimers in a co-culture model of the BBB, (2) determine distribution of dendrimers in the rat brain, kidney, and liver following systemic administration of dendrimers, and (3) conduct atomic force microscopy (AFM) on rat brain sections following systemic administration of dendrimers. LDH measurements showed that biotinylated dendrimers were toxic to cell co-culture after 48 h of treatment. Distribution studies showed evidence of biotinylated and non-biotinylated PAMAM dendrimers in brain. AFM studies showed evidence of dendrimers only in brain tissue of treated rats. These results indicate that biotinylation does not decrease toxicity associated with PAMAM dendrimers and that biotinylated PAMAM dendrimers distribute in the brain. Furthermore, this article provides evidence of nanoparticles in brain tissue following systemic administration of nanoparticles supported by both fluorescence microscopy and AFM. PMID- 24048287 TI - A pH-sensitive peptide-containing lasso molecular switch. AB - The synthesis of a peptide-containing lasso molecular switch by a self entanglement strategy is described. The interlocked rotaxane molecular machine consists of a benzometaphenylene[25]crown-8 (BMP25C8) macrocycle surrounding a molecular axle. This molecular axle contains a tripeptidic sequence and two molecular stations: a N-benzyltriazolium and a pH-sensitive anilinium station. The tripeptide is located between the macrocycle and the triazolium station, so that its conformation can be tailored depending on the shuttling of the macrocycle from one station to the other. At acidic pH, the macrocycle resides around the anilinium moiety, whereas it shuttles around the triazolium station after deprotonation. This molecular machinery thus forces the lasso to adopt a tightened or a loosened conformation. PMID- 24048288 TI - Synthesis of a novel carbocyclic analog of bredinin. AB - The natural nucleoside antibiotic, bredinin, exhibits antiviral and other biological activities. While various nucleosides related to bredinin have been synthesized, its carbocyclic analog has remained unknown. Synthesis of this heretofore unknown analog of bredinin is described. The key precursor, (3aS,4R,6R,6aR)-6-((methoxy-methoxy)methyl)-2,2-dimethyltetrahydro-3aH cyclopenta[d][1,3]dioxol-4-amine (5), was prepared from the commercially available compound, (1R,4S)-2-azabicyclo[2.2.1] hept-5-en-3-one (4). Our initial approach used intermediate 6, derived in three transformations from 5, for the key photolytic step to produce the desired ring-opened precursor to the target compound. This photochemical transformation was unsuccessful. However, an appropriately protected and related precursor was synthesized from 5 through the following side-chain functional group transformations: elaboration of the amino group through malonyl ester formation, oximation at the central carbon, conversion of ester to amide and catalytic reduction of the oxime group. This precursor, on treatment with triethylorthoformate and catalytic acetic acid in ethanol, underwent cyclization to produce the desired 4-carbamoyl-imidazolium-5 olate ring. Deprotection of the latter product proceeded smoothly to give the carbocyclic analog of bredinin. This target molecule exhibits antiviral activity, albeit low, against a number of RNA viruses. Further biological evaluations are in progress. PMID- 24048289 TI - Plasticity of the human olfactory system: the olfactory bulb. AB - In the last years, an increasing interest has been paid to the olfactory system, particularly to its abilities of plasticity and its potential continuous neurogenesis throughout adult life. Although mechanisms underlying adult neurogenesis have been largely investigated in animals, to some degree they remain unclear in humans. Based on human research findings, the present review will focus on the olfactory bulb as an evidence of the astonishing plasticity of the human olfactory system. PMID- 24048290 TI - Relationship between electrocardiographic left ventricular hypertrophy criteria and vascular structure and function parameters in hypertensive patients. AB - The objective of this study was to determine the electrocardiographic left ventricular hypertrophy (LVH) criterion that best correlated with vascular structure and function parameters in hypertensive patients. A cross-sectional study involving 347 hypertensive patients was performed. The mean age of the subjects was 54.9+/-11.8 years, and 61% were male. Electrocardiography was used to detect LVH based on the evaluation of 10 criteria, and we defined the voltage duration product (VDP) complex criterion. The vascular structure was evaluated according to carotid intima-media thickness (C-IMT), and vascular function was evaluated according to pulse wave velocity (PWV), the ambulatory arterial stiffness index (AASI), the home arterial stiffness index, and the peripheral (PAIx) and central (CAIx) augmentation indices. LVH according to at least some electrocardiographic criteria was recorded in 29.10% of the patients (34.10% of females; 25.90% of males). The vascular structure and function parameters showed higher values in the hypertensive patients with LVH. The criterion most closely correlated with C-IMT was Lewis-VDP (r=0.257); with PWV and AASI, the criterion was the Framingham-adjusted Cornell voltage (r=0.228 and r=0.195, respectively); and with CAIx and PAIx, the criterion was Novacode (r=0.226 and r=0.277, respectively). In the multivariate analysis, the association of the vascular structure and function parameters, the VDP complex (multiple linear regression) and the presence of LVH (logistic regression) disappeared after adjusting for age, sex and antihypertensive drugs. The relationship between the electrocardiographic criteria used to detect LVH in hypertensive patients and the vascular structure and function parameters were fundamentally conditioned by age and antihypertensive drug treatment. PMID- 24048291 TI - A randomised controlled trial evaluating the effect of potassium supplementation on vascular function and the renin-angiotensin-aldosterone system. AB - There is limited evidence on the effect of potassium supplementation on the vasculature in patients at increased cardiovascular risk. Potassium increases aldosterone and there is a strong association of hyperaldosteronism with poor cardiac outcomes. We aimed to determine whether potassium supplementation has a significant medium-term effect on aldosterone levels and, if so, what the overall effect of this is on vascular function in patients at moderate cardiovascular disease risk. Forty patients at moderate cardiovascular disease risk were included in a randomised placebo-controlled crossover study. Patients were assigned to 64 mmol potassium chloride or placebo for 6 weeks. Vascular function was assessed using pulse-wave analysis including the detection of a change in augmentation index to salbutamol and nitroglycerine-induced vasodilation. There was no change in augmentation index with potassium vs placebo (25.2+/-1.4 vs. 26.0+/-1.3%, respectively). Potassium improved brachial systolic blood pressure (131.8+/-2.2 vs. 137.1+/-2.4 mm Hg; P=0.013), central systolic blood pressure (123.2+/-2.3 vs. 128.4+/-2.3 mm Hg; P=0.011) and central diastolic blood pressure (80.3+/-1.3 vs. 83.7+/-1.4 mm Hg; P=0.019). Plasma renin activity and serum aldosterone both increased with potassium (P=0.001 and P=0.048 respectively). We found that potassium supplementation had no effect on endothelial function or pulse-wave analysis. It lowered brachial systolic and central blood pressure. It was associated with increased plasma renin activity and serum aldosterone. PMID- 24048292 TI - Alcohol and psychotropic drugs: risk factors for orthostatic hypotension in elderly fallers. AB - We assess orthostatic hypotension (OH) prevalence in elderly fallers and determine OH-associated risk factors in this patient population. A monocentric prospective study at Lille University Hospital Falls Clinic included 833 consecutive patients who had fallen or were at high risk of falls and who were assessed for the presence of OH. Among 833 patients aged 80.4+/-7.4 years, OH was found in 199 subjects (23.9% of cases). Multivariate analysis showed that selective serotonin reuptake inhibitors (odds ratio (OR) 2.42, 95% confidence interval (CI): 1.56-3.75), serotonin-norepinephrine reuptake inhibitors (OR 5.37, 95% CI: 1.93-14.97), Parkinsonian syndrome (OR 2.54, 95% CI: 1.54-4.19), excessive alcohol consumption (OR 2.17, 95% CI: 1.32-3.56), meprobamate (OR 2.65, 95% CI: 1.12-6.25) and calcium channel blockers (OR 1.79, 95% CI: 1.16-2.76) were all risk factors for OH. In contrast, angiotensin receptor blockers (OR 0.52, 95% CI: 0.30-0.91) appeared to be protective factors against OH. This study demonstrates that a systematic investigation should be made in all elderly fallers and those at high risk of falls to detect the presence of OH. In OH patients, in addition to the usual predisposing factors, excessive alcohol consumption and psychotropic drug intake-in particular, the intake of serotonergic antidepressants-should be taken into account as potential risk factors. PMID- 24048293 TI - Increased plasma norepinephrine levels in previously pre-eclamptic women. AB - A history of pre-eclampsia increases the risk of cardiovascular morbidity by mechanisms yet unknown. The aim of the present study was to assess whether plasma norepinephrine (NE) levels are increased 5-6 years after pre-eclamptic pregnancy and to investigate associations with pathophysiological mechanisms of cardiovascular disease: insulin sensitivity, vascular function and arterial pressure. A total of 28 women with previous pre-eclampsia and 20 controls were examined. Blood pressure (BP) and plasma levels of NE and endothelin-1 (ET-1) were measured at rest and after standing for 5 min. Insulin sensitivity was assessed with minimal model analysis and vascular function was assessed using venous occlusion plethysmography and pulse wave analysis. Twenty-four-hour BP measurements were carried out. Women with previous pre-eclampsia had higher levels of NE at rest (P=0.02), which did not associate significantly with insulin sensitivity or overall vasodilatory capacity. The 24-h mean of systolic and diastolic blood pressures (BPs) and heart rate did not differ between the groups (P=0.30, P=0.10 and P=0.46, respectively), and there was no significant association with NE levels. ET-1 levels were similar between the groups, but a positive correlation with systolic (P=0.04) and diastolic (P=0.03) BPs in the upright position was shown in the patient group. Increased levels of plasma NE are sustained in women with previous pre-eclampsia and may contribute to the increased risk for cardiovascular disease in these women. PMID- 24048294 TI - Early contribution of arterial wave reflection to left ventricular relaxation abnormalities in a community-dwelling population of normotensive and untreated hypertensive men and women. AB - We examined the contribution of arterial wave reflection to early abnormalities in left ventricular relaxation, whether this association was modified by gender or hypertension and the role of reflected wave timing and amplitude. We studied a cohort of normotensive and untreated essential hypertensive Taiwanese participants (675 men, 601 women, mean age 52 years). Doppler flow and applanation tonometry were performed to assess carotid-femoral pulse wave velocity (PWV) and augmentation index (AI). Diastolic parameters including the ratio between the peak velocity of early and late diastolic mitral inflow (E/A), E-deceleration time and left atrial (LA) diameter were measured by echocardiography. In multivariate models predicting E/A, women were more likely to have lower E/A than men (beta=-0.08, P<0.001). AI was significantly associated with lower E/A in both men (beta=-0.09, P=0.005) and women (beta=-0.12, P<0.001) independent of PWV. Inclusion of AI in the overall model reduced the gender difference in E/A by 61% and rendered it nonsignificant. There was a significant interaction between AI and hypertension (P=0.02). The inverse association between AI and E/A was significant only in normotensive men and women, and only for the amplitude but not timing of the reflected wave. In conclusion, the contribution of wave reflection to left ventricular diastolic dysfunction was independent of arterial stiffness, more pronounced in normotensive individuals and explained a significant portion of the gender difference in diastolic function. PMID- 24048295 TI - Adolescents and young adults who are not in employment, education, or training. PMID- 24048297 TI - Possible benefits of being diagnosed as having reduced renal function. PMID- 24048296 TI - Effectiveness of general practice based, practice nurse led telephone coaching on glycaemic control of type 2 diabetes: the Patient Engagement and Coaching for Health (PEACH) pragmatic cluster randomised controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of goal focused telephone coaching by practice nurses in improving glycaemic control in patients with type 2 diabetes in Australia. DESIGN: Prospective, cluster randomised controlled trial, with general practices as the unit of randomisation. SETTING: General practices in Victoria, Australia. PARTICIPANTS: 59 of 69 general practices that agreed to participate recruited sufficient patients and were randomised. Of 829 patients with type 2 diabetes (glycated haemoglobin (HbA1c) >7.5% in the past 12 months) who were assessed for eligibility, 473 (236 from 30 intervention practices and 237 from 29 control practices) agreed to participate. INTERVENTION: Practice nurses from intervention practices received two days of training in a telephone coaching programme, which aimed to deliver eight telephone and one face to face coaching episodes per patient. MAIN OUTCOME MEASURES: The primary end point was mean absolute change in HbA1c between baseline and 18 months in the intervention group compared with the control group. RESULTS: The intervention and control patients were similar at baseline. None of the practices dropped out over the study period; however, patient attrition rates were 5% in each group (11/236 and 11/237 in the intervention and control group, respectively). The median number of coaching sessions received by the 236 intervention patients was 3 (interquartile range 1-5), of which 25% (58/236) did not receive any coaching sessions. At 18 months' follow-up the effect on glycaemic control did not differ significantly (mean difference 0.02, 95% confidence interval -0.20 to 0.24, P=0.84) between the intervention and control groups, adjusted for HbA1c measured at baseline and the clustering. Other biochemical and clinical outcomes were similar in both groups. CONCLUSIONS: A practice nurse led telephone coaching intervention implemented in the real world primary care setting produced comparable outcomes to usual primary care in Australia. The addition of a goal focused coaching role onto the ongoing generalist role of a practice nurse without prescribing rights was found to be ineffective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN50662837. PMID- 24048298 TI - Fraudulent data: an apology and the fate of angiotensin receptor blockers. PMID- 24048299 TI - A stable definition of chronic kidney disease improves knowledge and patient care. PMID- 24048300 TI - Testing times for HIV. PMID- 24048301 TI - "We know where to probe," says Mike Richards, the new chief inspector of hospitals. Interview by Nigel Hawkes. PMID- 24048302 TI - An alternative classification system for chronic kidney disease. PMID- 24048303 TI - Atos Healthcare replies to Greg Wood. PMID- 24048304 TI - Wanted: national regulatory monitoring system for long term opioid prescription. PMID- 24048305 TI - Regulation is needed to support the development of health IT. PMID- 24048306 TI - Deprivation of Liberty Safeguards protect care homes, not patients. PMID- 24048307 TI - Friends, doctors, and tramadol: we might have a problem. PMID- 24048308 TI - Medical manslaughter. PMID- 24048309 TI - Will India deliver on universal health coverage? PMID- 24048310 TI - MPs question government's plan for a paperless NHS by 2018. PMID- 24048311 TI - Ten providers bid to run L800m contract for Cambridgeshire older people's services. PMID- 24048312 TI - CCGs have duty to demand providers be open about mistakes, say MPs. PMID- 24048313 TI - Doctors must ask patients about tobacco use, conference hears. PMID- 24048314 TI - Canadian doctor travelling to Gaza is detained in Egyptian prison. PMID- 24048315 TI - Confidence of NHS finance directors to meet targets has plummeted. PMID- 24048316 TI - Single-male paternity in coelacanths. AB - Latimeria chalumnae, a 'living fossil,' is of great scientific interest, as it is closely related to the aquatic ancestors of land-living tetrapods. Latimeria show internal fertilization and bear live young, but their reproductive behaviour is poorly known. Here we present for the first time a paternity analysis of the only available material from gravid females and their offspring. We genotype two L. chalumnae females and their unborn brood for 14 microsatellite loci. We find that the embryos are closely related to each other and never show more than three different alleles per locus, providing evidence for a single father siring all of the offspring. We reconstruct the father's genotype but cannot identify it in the population. These data suggest that coelacanths have a monogamous mating system and that individual relatedness is not important for mate choice. PMID- 24048317 TI - A polymeric-semiconductor-metal-complex hybrid photocatalyst for visible-light CO(2) reduction. AB - A polymeric carbon nitride semiconductor is demonstrated to photocatalyse CO2 reduction to formic acid under visible light (lambda > 400 nm) with a high turnover number (>200 for 20 hours) and selectivity (>80%), when coupled with a molecular ruthenium complex as a catalyst. PMID- 24048318 TI - Modification of insulin sensitivity and glycemic control by activity and exercise. AB - Type 2 diabetes has progressed into a major contributor to preventable death, and developing optimal therapeutic strategies to prevent future type 2 diabetes and its primary clinical manifestation of cardiovascular disease is a major public health challenge. This article will provide a brief overview of the role of activity and exercise in modulating insulin sensitivity and will outline the effect of physical activity, high-intensity interval training, and resistance training on insulin sensitivity and glycemic control. PMID- 24048319 TI - Thirteen-year trends in child and adolescent fundamental movement skills: 1997 2010. AB - PURPOSE: The objective of this study is to describe 13-yr trends in children's fundamental movement skill (FMS) competency. METHODS: Secondary analysis of representative, cross-sectional, Australian school-based surveys was conducted in 1997, 2004, and 2010 (n = 13,752 children age 9-15 yr). Five FMS (sprint run, vertical jump, catch, kick, and overarm throw) were assessed using process oriented criteria at each survey and children's skills classified as competent or not competent. Covariates included sex, age, cardiorespiratory endurance (20-m shuttle run test), body mass index (kg.m), and socioeconomic status (residential postcode). RESULTS: At each survey, the children's FMS competency was low, with prevalence rarely above 50%. Between 1997 and 2004, there were significant increases in all students' competency in the sprint run, vertical jump, and catch. For boys, competency increased in the kick (primary) and the overarm throw (high school), but among high school girls, overarm throw competency decreased. Between 2004 and 2010, competency increased in the catch (all students), and in all girls, competency increased in the kick, whereas competency in the vertical jump decreased. CONCLUSIONS: Overall, students' FMS competency was low especially in the kick and overarm throw in girls. The observed increase in FMS competency in 2004 was attributed to changes in practice and policy to support the teaching of FMS in schools. In 2010, competency remained low, with improvements in only the catch (all) and kick (girls) and declines in vertical jump. Potentially, the current delivery of FMS programs requires stronger positioning within the school curriculum. Strategies to improve children's physical activity should consider ensuring children are taught FMS to competency level, to enjoy being physically active. PMID- 24048320 TI - Screen time viewing behaviors and isometric trunk muscle strength in youth. AB - PURPOSE: The objective of this study was to examine the association of screen time viewing behavior with isometric trunk muscle strength in youth. METHODS: A cross-sectional study was carried out including 606 adolescents (14-16 yr old) participating in the Danish European Youth Heart Study, a population-based study with assessments conducted in either 1997/1998 or 2003/2004. Maximal voluntary contractions during isometric back extension and abdominal flexion were determined using a strain gauge dynamometer, and cardiorespiratory fitness (CRF) was obtained using a maximal cycle ergometer test. TV viewing time, computer use, and other lifestyle behaviors were obtained by self-report. Analyses of association of screen use behaviors with isometric trunk muscle strength were carried out using multivariable adjusted linear regression. RESULTS: The mean (SD) isometric strength was 0.87 (0.16) N.kg-1. TV viewing, computer use, and total screen time use were inversely associated with isometric trunk muscle strength in analyses adjusted for lifestyle and sociodemographic factors. After further adjustment for CRF and waist circumference, associations remained significant for computer use and total screen time, but TV viewing was only marginally associated with muscle strength after these additional adjustments ( 0.05 SD (95% confidence interval, -0.11 to 0.005) difference in strength per 1 h.d-1 difference in TV viewing time, P = 0.08). Each 1 h.d-1 difference in total screen time use was associated with -0.09 SD (95% confidence interval, -0.14 to 0.04) lower isometric trunk muscle strength in the fully adjusted model (P = 0.001). There were no indications that the association of screen time use with isometric trunk muscle strength was attenuated among highly fit individuals (P = 0.91 for CRF by screen time interaction). CONCLUSIONS: Screen time use was inversely associated with isometric trunk muscle strength independent of CRF and other confounding factors. PMID- 24048321 TI - Two cases of thrombotic stenosis in SAPIEN XT valves after transapical implantation. PMID- 24048323 TI - Immunohistochemical vascular factor expression in canine inflammatory mammary carcinoma. AB - Human inflammatory breast carcinoma (IBC) and canine inflammatory mammary carcinoma (IMC) are considered the most malignant types of breast cancer. IMC has similar characteristics to IBC; hence, IMC has been suggested as a model to study the human disease. To compare the angiogenic and angioinvasive features of IMC with non-IMC, 3 canine mammary tumor xenograft models in female SCID mice were developed: IMC, comedocarcinoma, and osteosarcoma. Histopathological and immunohistochemical characterization of both primary canine tumors and xenografts using cellular markers pancytokeratin, cytokeratin 14, vimentin, and alpha-smooth muscle actin and vascular factors (VEGF-A, VEGF-D, VEGFR-3, and COX-2) was performed. Tumor cell proliferation index was measured by the Ki-67 marker. The xenograft models reproduced histological features found in the primary canine tumor and preserved the original immunophenotype. IMC xenografts showed a high invasive character with tumor emboli in the dermis, edema, and occasional observations of ulceration. In addition, compared with osteosarcoma and comedocarcinoma, the IMC model showed the highest vascular factor expression associated with a high proliferation index. Likewise, IMC xenografts showed higher COX-2 expression associated with VEGF-D and VEGFR-3, as well as a higher presence of dermal lymphatic tumor emboli, suggesting COX-2 participation in IMC lymphangiogenesis. These results provide additional evidence to consider vascular factors, their receptors, and COX-2 as therapeutic targets for IBC. PMID- 24048324 TI - Canine perivascular wall tumors: high prognostic impact of site, depth, and completeness of margins. AB - Canine perivascular wall tumors (cPWTs) arise from vascular mural cells and are included among soft tissue sarcomas (STSs). Most prognostic studies are performed on canine STSs as a general group and regardless of their specific histotype. The aim of this study was to identify pathological parameters and profiles with prognostic impact for cutaneous/subcutaneous cPWTs. Anatomical location, type of growth, surgical margins, and size and depth of the tumor were collected in 56 cPWTs. The association between each pair of variables was evaluated by chi(2) test. Multiple correspondence analysis (MCA) was performed to describe the multivariate association of variables and was followed by cluster analysis to identify specific pathological profiles. The prognostic impact of variables and profiles was assessed by Cox regression model. Size and depth were significantly associated with increased relapse probability. Cases with complete surgical margins did not recur. Other single variables were not significantly associated with relapse. Cluster analysis on MCA considering site, depth, margins, and type of growth identified 3 pathological profiles associated with PWT relapse and having a high prognostic impact. Major prognostic factors for cPWTs were tumor size, depth of growth, and pathological profiles. PMID- 24048325 TI - A nodule in the groin. Primary cutaneous adenoid cystic carcinoma (pcACC). PMID- 24048326 TI - Crosstalk between TLR5 and Notch1 signaling in epithelial cells during intestinal inflammation. AB - During intestinal inflammation, a variety of signaling events are activated to perform several cell functions. Although the distinct roles of these pathways have been elucidated, the effects of their crosstalk activities remain to be clarified. We evaluated the crosstalk between two evolutionary conserved cell signaling systems, toll-like-receptor (TLR) 5 and Notch1, in intestinal epithelial cells during inflammation. Significant induction of the expression of Notch1 and Jagged1 was observed in the distal part of the colon, together with abundant localization of Notch1 intracellular domain (N1ICD) in the surface epithelium of inflamed colonic mucosa. By targeting intestinal epithelial cells, it was shown that recombination-signal-binding-protein-Jkappa (RBP-Jkappa) mediated Notch functions are dependent on a flagellin-TLR5-mediated pathway. Conversely, using a gamma-secretase inhibitor, we demonstrated that Notch synergistically increases TLR5-mediated NF-kappaB activation. In addition, the effects of Notch on the NF-kappaB target gene interleukin-6 (IL-6) expression were revealed by evaluating the RBP-Jkappa responsive element in the IL-6 promoter in vitro. Modulation of TLR5 and Notch crosstalk by transient blocking of Notch during the acute phase of colitis was beneficial for ameliorating colonic inflammation as well as disease status. In conclusion, the results suggest the effectiveness of Notch-targeted drug strategy for the treatment of intestinal inflammation. PMID- 24048327 TI - Interactions of heparin and a covalently-linked antithrombin-heparin complex with components of the fibrinolytic system. AB - Unfractionated heparin (UFH) is used as an adjunct during thrombolytic therapy. However, its use is associated with limitations, such as the inability to inhibit surface bound coagulation factors. We have developed a covalent conjugate of antithrombin (AT) and heparin (ATH) with superior anticoagulant properties compared with UFH. Advantages of ATH include enhanced inhibition of surface-bound coagulation enzymes and the ability to reduce the overall size and mass of clots in vivo. The interactions of UFH or ATH with the components of the fibrinolytic pathway are not well understood. Our study utilised discontinuous second order rate constant (k2) assays to compare the rates of inhibition of free and fibrin associated plasmin by AT+UFH vs ATH. Additionally, we evaluated the effects of AT+UFH and ATH on plasmin generation in the presence of fibrin. The k2 values for inhibition of plasmin were 5.74 +/- 0.28 x 106 M-1 min-1 and 6.39 +/- 0.59 x 106 M-1 min-1 for AT+UFH and ATH, respectively. In the presence of fibrin, the k2 values decreased to 1.45 +/- 0.10 x 106 M-1 min-1 and 3.07 +/- 0.19 x 106 M-1 min 1 for AT+UFH and ATH, respectively. Therefore, protection of plasmin by fibrin was observed for both inhibitors; however, ATH demonstrated superior inhibition of fibrin-associated plasmin. Rates of plasmin generation were also decreased by both inhibitors, with ATH causing the greatest reduction (approx. 38-fold). Nonetheless, rates of plasmin inhibition were 2-3 orders of magnitude lower than for thrombin, and in a plasma-based clot lysis assay ATH significantly inhibited clot formation but had little impact on clot lysis. Cumulatively, these data may indicate that, relative to coagulant enzymes, the fibrinolytic system is spared from inhibition by both AT+UFH and ATH, limiting reduction in fibrinolytic potential during anticoagulant therapy. PMID- 24048328 TI - Cucurbit[n]uril-based coordination chemistry: from simple coordination complexes to novel poly-dimensional coordination polymers. AB - Cucurbit[n]urils are a family of molecular container hosts bearing a rigid hydrophobic cavity and two identical carbonyl fringed portals. They have attracted much attention in supramolecular chemistry because of their superior molecular recognition properties in aqueous media. This review highlights the recent advances and challenges in the field of cucurbit[n]uril-based coordination chemistry. It not only presents progress in the knowledge of such macrocyclic compounds, which range from simple to complicated architectures, but also presents new routes of synthesis and their advantages in hybrid porous solids. The concept of structure "inducer" for their structural design to achieve predictable structures and controlled pores is described. The large pore sizes and hydrophobic cavities of these compounds that lead to unprecedented properties and potential applications are also discussed. PMID- 24048329 TI - Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer--response. PMID- 24048330 TI - Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer--letter. PMID- 24048331 TI - Monoclonal antibody against cell surface GRP78 as a novel agent in suppressing PI3K/AKT signaling, tumor growth, and metastasis. AB - PURPOSE: The ER chaperone GRP78 translocates to the surface of tumor cells and promotes survival, metastasis, and resistance to therapy. An oncogenic function of cell surface GRP78 has been attributed to the activation of the phosphoinositide 3-kinase (PI3K) pathway. We intend to use a novel anti-GRP78 monoclonal antibody (MAb159) to attenuate PI3K signaling and inhibit tumor growth and metastasis. EXPERIMENTAL DESIGN: MAb159 was characterized biochemically. Antitumor activity was tested in cancer cell culture, tumor xenograft models, tumor metastasis models, and spontaneous tumor models. Cancer cells and tumor tissues were analyzed for PI3K activity. MAb159 was humanized and validated for diagnostic and therapeutic application. RESULTS: MAb159 specifically recognized surface GRP78, triggered GRP78 endocytosis, and localized to tumors but not to normal organs in vivo. MAb159 inhibited tumor cell proliferation and enhanced tumor cell death both in vitro and in vivo. In MAb159-treated tumors, PI3K signaling was inhibited without compensatory MAPK pathway activation. Furthermore, MAb159 halted or reversed tumor progression in the spontaneous PTEN loss-driven prostate and leukemia tumor models, and inhibited tumor growth and metastasis in xenograft models. Humanized MAb159, which retains high affinity, tumor specific localization, and the antitumor activity, was nontoxic in mice, and had desirable pharmacokinetics. CONCLUSIONS: GRP78-specific antibody MAb159 modulates the PI3K pathway and inhibits tumor growth and metastasis. Humanized MAb159 will enter human trials shortly. PMID- 24048332 TI - Combination therapy with a second-generation androgen receptor antagonist and a metastasis vaccine improves survival in a spontaneous prostate cancer model. AB - PURPOSE: Enzalutamide, a second-generation androgen antagonist, was approved by the U.S. Food and Drug Administration (FDA) for castration-resistant prostate cancer (CRPC) treatment. Immunotherapy has been shown to be a promising strategy for prostate cancer. This study was performed to provide data to support the combination of enzalutamide and immunotherapy for CRPC treatment. EXPERIMENTAL DESIGN: Male C57BL/6 or TRAMP (transgenic adenocarcinoma of the mouse prostate) prostate cancer model mice were exposed to enzalutamide and/or a therapeutic vaccine targeting Twist, an antigen involved in epithelial-to-mesenchymal transition and metastasis. The physiologic and immunologic effects of enzalutamide were characterized. The generation of Twist-specific immunity by Twist-vaccine was assessed. Finally, the combination of enzalutamide and Twist vaccine to improve TRAMP mice overall survival was evaluated. RESULTS: Enzalutamide mediated immunogenic modulation in TRAMP-C2 cells. In vivo, enzalutamide mediated reduced genitourinary tissue weight, enlargement of the thymus, and increased levels of T-cell excision circles. Because no changes were seen in T-cell function, as determined by CD4(+) T-cell proliferation and regulatory T cell (Treg) functional assays, enzalutamide was determined to be immune inert. Enzalutamide did not diminish the ability of Twist-vaccine to generate Twist-specific immunity. Twist was confirmed as a valid tumor antigen in TRAMP mice by immunohistochemistry. The combination of enzalutamide and Twist vaccine resulted in significantly increased overall survival of TRAMP mice compared with other treatment groups (27.5 vs. 10.3 weeks). Notably, the effectiveness of the combination therapy increased with disease stage, i.e., the greatest survival benefit was seen in mice with advanced-stage prostate tumors. CONCLUSIONS: These data support the combination of enzalutamide and immunotherapy as a promising treatment strategy for CRPC. Clin Cancer Res; 19(22); 6205-18. (c)2013 AACR. PMID- 24048333 TI - Validation of a proliferation-based expression signature as prognostic marker in early stage lung adenocarcinoma. AB - PURPOSE: New prognostic markers to guide treatment decisions in early stage non small cell lung cancer are necessary to improve patient outcomes. In this report, we assess the utility of a predefined mRNA expression signature of cell-cycle progression genes (CCP score) to define 5-year risk of lung cancer-related death in patients with early stage lung adenocarcinoma. EXPERIMENTAL DESIGN: A CCP score was calculated from the mRNA expression levels of 31 proliferation genes in stage I and stage II tumor samples from two public microarray datasets [Director's Consortium (DC) and GSE31210]. The same gene set was tested by quantitative PCR in 381 formalin-fixed paraffin-embedded (FFPE) primary tumors. Association of the CCP score with outcome was assessed by Cox proportional hazards analysis. RESULTS: In univariate analysis, the CCP score was a strong predictor of cancer-specific survival in both the Director's Consortium cohort (P = 0.00014; HR = 2.08; 95% CI, 1.43-3.02) and GSE31210 (P = 0.0010; HR = 2.25; 95% CI, 1.42-3.56). In multivariate analysis, the CCP score remained the dominant prognostic marker in the presence of clinical variables (P = 0.0022; HR = 2.02; 95% CI, 1.29-3.17 in Director's Consortium, P = 0.0026; HR = 2.16; 95% CI, 1.32 3.53 in GSE31210). On a quantitative PCR platform, the CCP score maintained highly significant prognostic value in FFPE-derived mRNA from clinical samples in both univariate (P = 0.00033; HR = 2.10; 95% CI, 1.39-3.17) and multivariate analyses (P = 0.0071; HR = 1.92; 95% CI, 1.18-3.10). CONCLUSIONS: The CCP score is a significant predictor of lung cancer death in early stage lung adenocarcinoma treated with surgery and may be a valuable tool in selecting patients for adjuvant treatment. PMID- 24048335 TI - Impact of weightlessness on cardiac shape and left ventricular stress/strain distributions. AB - In this paper, a finite element model of the heart is developed to investigate the impact of different gravitational loadings of Earth, Mars, Moon, and microgravity on the cardiac shape and strain/stress distributions in the left ventricle. The finite element model is based on realistic 3D heart geometry, detailed fiber/sheet micro-architecture, and a validated orthotropic cardiac tissue model and constitutive relationship that capture the passive behavior of the heart at end-diastole. The model predicts the trend and magnitude of cardiac shape change at different gravitational levels with great fidelity in comparison to recent cardiac sphericity measurements performed during simulated reduced gravity parabolic flight experiments. Moreover, the numerical predictions indicate that although the left ventricular strain distributions remain relatively unaltered across the gravitational fields and the strain extrema values occur at the same relative locations, their values change noticeably with decreasing gravity. As for the stress, however, both the magnitude and location of the extrema change with a decrease in the gravitational field. Consequently, tension regions of the heart on Earth can change into compression regions in space. PMID- 24048334 TI - Labhardt's colpoperineocleisis: subjective results of an alternative treatment for genital prolapse in patients who are not sexually active--2-year follow-up. AB - INTRODUCTION AND HYPOTHESIS: Genital prolapse affects up to 50 % of multiparous women and has an impact on quality of life (QoL) for many. Vaginal obliterative techniques are relevant in older patients who are not sexually active. We performed Labhardt's colpoperineocleisis in such patients. The objective was the evaluation of subjective outcomes of this technique using PGI-I. METHODS: Retrospective cohort analysis of patients. We performed a bivariate, multivariate analysis, and survival curves for subjective improvement. RESULTS: Seventy-four cases were analyzed. Average age of the patients was 72 years, median parity 4, 95.9 % POP-Q stage III or IV, anterior leading edge defect in 61.1 %. Operating time: 54 min, estimated blood loss 70 ml, no intraoperative complications, 12 patients had protocol deviations with changes in the recommended type of suture. Median hospital stay was 2 days and average follow-up 24.9 months. There was 13.5 % anatomical recurrence, 3 of which (30 %) were in patients with protocol deviations. 1.9 % developed clinically significant de novo stress urinary incontinence (SUI). PGI-I: 64 (86 %) reported subjective improvement and 10 did not. In the subjective improvement group, 98.4 % reported being very much or much better. In the non-subjective improvement group 80 % reported that they were the same as before surgery and 20 % were worse. In bivariate analysis anatomical recurrence showed significance and persisted after multivariate analysis with an OR of 8322 for subjective failure. CONCLUSION: Labhardt's colpoperineocleisis is a safe technique with good subjective results. It has few complications, an acceptable recurrence rate, and a low rate of de novo SUI. It may be important to use the #0 or #1 polydioxanone sutures, as these are associated with better outcomes in this series. Comparative studies with other obliterative techniques are needed. PMID- 24048336 TI - Teaching human poses interactively to a social robot. AB - The main activity of social robots is to interact with people. In order to do that, the robot must be able to understand what the user is saying or doing. Typically, this capability consists of pre-programmed behaviors or is acquired through controlled learning processes, which are executed before the social interaction begins. This paper presents a software architecture that enables a robot to learn poses in a similar way as people do. That is, hearing its teacher's explanations and acquiring new knowledge in real time. The architecture leans on two main components: an RGB-D (Red-, Green-, Blue- Depth) -based visual system, which gathers the user examples, and an Automatic Speech Recognition (ASR) system, which processes the speech describing those examples. The robot is able to naturally learn the poses the teacher is showing to it by maintaining a natural interaction with the teacher. We evaluate our system with 24 users who teach the robot a predetermined set of poses. The experimental results show that, with a few training examples, the system reaches high accuracy and robustness. This method shows how to combine data from the visual and auditory systems for the acquisition of new knowledge in a natural manner. Such a natural way of training enables robots to learn from users, even if they are not experts in robotics. PMID- 24048338 TI - NO and NO2 sensing properties of WO3 and Co3O4 based gas sensors. AB - Semiconductor-based gas sensors that use n-type WO3 or p-type Co3O4 powder were fabricated and their gas sensing properties toward NO2 or NO (0.5-5 ppm in air) were investigated at 100 degrees C or 200 degrees C. The resistance of the WO3 based sensor increased on exposure to NO2 and NO. On the other hand, the resistance of the Co3O4-based sensor varied depending on the operating temperature and the gas species. The chemical states of the surface of WO3 or those of the Co3O4 powder on exposure to 1 ppm NO2 and NO were investigated by diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy. No clear differences between the chemical states of the metal oxide surface exposed to NO2 or NO could be detected from the DRIFT spectra. PMID- 24048337 TI - Surface electromyography signal processing and classification techniques. AB - Electromyography (EMG) signals are becoming increasingly important in many applications, including clinical/biomedical, prosthesis or rehabilitation devices, human machine interactions, and more. However, noisy EMG signals are the major hurdles to be overcome in order to achieve improved performance in the above applications. Detection, processing and classification analysis in electromyography (EMG) is very desirable because it allows a more standardized and precise evaluation of the neurophysiological, rehabitational and assistive technological findings. This paper reviews two prominent areas; first: the pre processing method for eliminating possible artifacts via appropriate preparation at the time of recording EMG signals, and second: a brief explanation of the different methods for processing and classifying EMG signals. This study then compares the numerous methods of analyzing EMG signals, in terms of their performance. The crux of this paper is to review the most recent developments and research studies related to the issues mentioned above. PMID- 24048339 TI - A multi-fork z-axis quartz micromachined gyroscope. AB - A novel multi-fork z-axis gyroscope is presented in this paper. Different from traditional quartz gyroscopes, the lateral electrodes of the sense beam can be arranged in simple patterns; as a result, the fabrication is simplified. High sensitivity is achieved by the multi-fork design. The working principles are introduced, while the finite element method (FEM) is used to simulate the modal and sensitivity. A quartz fork is fabricated, and a prototype is assembled. Impedance testing shows that the drive frequency and sense frequency are similar to the simulations, and the quality factor is approximately 10,000 in air. The scale factor is measured to be 18.134 mV/( degrees /s) and the nonlinearity is 0.40% in a full-scale input range of +/-250 degrees /s. PMID- 24048340 TI - Data processing and quality evaluation of a boat-based mobile laser scanning system. AB - Mobile mapping systems (MMSs) are used for mapping topographic and urban features which are difficult and time consuming to measure with other instruments. The benefits of MMSs include efficient data collection and versatile usability. This paper investigates the data processing steps and quality of a boat-based mobile mapping system (BoMMS) data for generating terrain and vegetation points in a river environment. Our aim in data processing was to filter noise points, detect shorelines as well as points below water surface and conduct ground point classification. Previous studies of BoMMS have investigated elevation accuracies and usability in detection of fluvial erosion and deposition areas. The new findings concerning BoMMS data are that the improved data processing approach allows for identification of multipath reflections and shoreline delineation. We demonstrate the possibility to measure bathymetry data in shallow (0-1 m) and clear water. Furthermore, we evaluate for the first time the accuracy of the BoMMS ground points classification compared to manually classified data. We also demonstrate the spatial variations of the ground point density and assess elevation and vertical accuracies of the BoMMS data. PMID- 24048341 TI - Stem cell enrichment with selectin receptors: mimicking the pH environment of trauma. AB - The isolation of hematopoietic stem and progenitor cells (HSPCs) is critical for transplantation therapy and HSPC research, however current isolation techniques can be prohibitively expensive, time-consuming, and produce variable results. Selectin-coated microtubes have shown promise in rapidly isolating HSPCs from human bone marrow, but further purification of HSPCs remains a challenge. Herein, a biomimetic device for HSPC isolation is presented to mimic the acidic vascular microenvironment during trauma, which can enhance the binding frequency between L selectin and its counter-receptor PSGL-1 and HSPCs. Under acidic pH conditions, L selectin coated microtubes enhanced CD34+ HSPC adhesion, as evidenced by decreased cell rolling velocity and increased rolling flux. Dynamic light scattering was utilized as a novel sensor to confirm an L-selectin conformational change under acidic conditions, as previously predicted by molecular dynamics. These results suggest that mimicking the acidic conditions of trauma can induce a conformational extension of L-selectin, which can be utilized for flow-based, clinical isolation of HSPCs. PMID- 24048342 TI - Quantitative assessment of birefringent skin structures in scattered light confocal imaging using radially polarized light. AB - The polarization characteristics of birefringent tissues could be only partially obtained using linearly polarized light in polarization sensitive optical imaging. Here we analyze the change in polarization of backscattered light from birefringent structures versus the orientations of the incident polarizations using linearly, circularly and radially polarized light in a cross-polarized confocal microscope. A spatially variable retardation plate composed of eight sectors of lambda/2 wave plates was used to transform linearly polarized light into a radially polarized light. Based on the experimental data obtained from ex vivo measurements on human scalp hairs and in-vivo measurements on hair and skin, we exemplify that the underestimation of the birefringence content resulting from the orientation related effects associated with the use of linearly polarized light for imaging tissues containing wavy birefringent structures could be minimized by using radially polarized light. PMID- 24048343 TI - Model-based spike detection of epileptic EEG data. AB - Accurate automatic spike detection is highly beneficial to clinical assessment of epileptic electroencephalogram (EEG) data. In this paper, a new two-stage approach is proposed for epileptic spike detection. First, the k-point nonlinear energy operator (k-NEO) is adopted to detect all possible spike candidates, then a newly proposed spike model with slow wave features is applied to these candidates for spike classification. Experimental results show that the proposed system, using the AdaBoost classifier, outperforms the conventional method in both two- and three-class EEG pattern classification problems. The proposed system not only achieves better accuracy for spike detection, but also provides new ability to differentiate between spikes and spikes with slow waves. Though spikes with slow waves occur frequently in epileptic EEGs, they are not used in conventional spike detection. Identifying spikes with slow waves allows the proposed system to have better capability for assisting clinical neurologists in routine EEG examinations and epileptic diagnosis. PMID- 24048344 TI - Transgenerational sex determination: the embryonic environment experienced by a male affects offspring sex ratio. AB - Conditions experienced during embryonic development can have lasting effects, even carrying across generations. Most evidence for transgenerational effects comes from studies of female mammals, with much less known about egg-laying organisms or paternally-mediated effects. Here we show that offspring sex can be affected by the incubation temperature its father experiences years earlier. We incubated eggs of an Australian lizard with temperature-dependent sex determination under three thermal regimes; some eggs were given an aromatase inhibitor to produce sons at temperatures that usually produce only daughters. Offspring were raised to maturity and freely interbred within field enclosures. After incubating eggs of the subsequent generation and assigning parentage, we found that the developmental temperature experienced by a male significantly influences the sex of his future progeny. This transgenerational effect on sex ratio may reflect an epigenetic influence on paternally-inherited DNA. Clearly, sex determination in reptiles is far more complex than is currently envisaged. PMID- 24048345 TI - Delusions, anger, and serious violence: new findings from the MacArthur Violence Risk Assessment Study. AB - INTRODUCTION: Recent research on the association between delusions and violence has suggested complex and differing pathways. Furthermore, it has been emphasized that temporal proximity is fundamental when investigating these relationships. We reanalyzed data from the MacArthur Violence Risk Assessment Study utilizing a different methodological approach to investigate associations between specific delusions and violence. METHODS: Longitudinal study of 1136 male and female civil psychiatric inpatients after discharge. Delusions, affect due to delusions, and violence were measured at baseline and in 5 follow-up assessments. Serious violence was established using the MacArthur Community Violence Interview. Logistic mixed-effect models for repeated measures were performed. RESULTS: A "prospective" model confirmed previous findings that delusions do not predict later violence. However, reanalysis, considering temporal proximity, indicated a relationship between specific delusions and outcome including: being spied upon (adjusted OR [AOR] = 1.62, 95% CI = 1.06-2.47, P = .027), being followed (AOR = 1.90, 95% CI = 1.29-2.80, P = .001), being plotted against (AOR = 1.70, 95% CI = 1.14-2.52, P = .009), being under control of person/force (AOR = 1.92, 95% CI = 1.24-2.97, P = .003), thought insertion (AOR = 1.63, 95% CI = 1.00-2.66, P = .048), and having special gifts/powers (AOR = 1.95, 95% CI = 1.31-2.92, P = .001). All these delusions were associated with angry affect (P < .05). Inclusion of anger in the model significantly attenuated the main effects (except grandiose delusions), indicating an indirect pathway. CONCLUSIONS: Temporal proximity is crucial when investigating relationships between delusions and violence. Anger due to delusions is the key factor in this pathway. Our findings have important implications for identification of psychotic patients at risk for violent behavior and, most importantly, management of their risk. PMID- 24048346 TI - Aerodynamic performance of the feathered dinosaur Microraptor and the evolution of feathered flight. AB - Understanding the aerodynamic performance of feathered, non-avialan dinosaurs is critical to reconstructing the evolution of bird flight. Here we show that the Early Cretaceous five-winged paravian Microraptor is most stable when gliding at high-lift coefficients (low lift/drag ratios). Wind tunnel experiments and flight simulations show that sustaining a high-lift coefficient at the expense of high drag would have been the most efficient strategy for Microraptor when gliding from, and between, low elevations. Analyses also demonstrate that anatomically plausible changes in wing configuration and leg position would have made little difference to aerodynamic performance. Significant to the evolution of flight, we show that Microraptor did not require a sophisticated, 'modern' wing morphology to undertake effective glides. This is congruent with the fossil record and also with the hypothesis that symmetric 'flight' feathers first evolved in dinosaurs for non-aerodynamic functions, later being adapted to form lifting surfaces. PMID- 24048347 TI - Acne vulgaris: A review of causes and treatment options. AB - Acne vulgaris is a disorder of the sebaceous follicle. The cause is multifactorial, and both adolescents and adults can be affected. Acne is associated with a significant financial burden and considerable psychological distress. Treatment options are reviewed, including over-the-counter medications, prescription medications, and in-office procedures. PMID- 24048348 TI - Management of patients with Parkinson disease. AB - Patients with Parkinson disease have prolonged motor and nonmotor symptoms affecting their ability to perform activities of daily living. Providers are tasked not only to provide quality care to afflicted patients but also to offer assistance to their informal caregivers who play a critical supportive role along the illness trajectory. PMID- 24048349 TI - Doping La into the depletion layer of the Cd(0.6)Zn(0.4)S photocatalyst for efficient H(2) evolution. AB - We report a novel strategy for the enhancement of photocatalytic H2 evolution by doping La into the depletion layer of Cd0.6Zn0.4S (CZS: x% La). The apparent quantum yield of the CZS: 2% La photocatalyst at 350 nm is up to 93.3%, which is extremely high for solar water splitting even compared with the noble metal cocatalyst systems. This work may contribute to the design and construction of materials with outstanding capability for charge separation and hence improve the properties of the materials for various applications. PMID- 24048350 TI - The half-cycle correction revisited: redemption of a kludge. AB - Decision-analytic software commonly used to implement discrete Markov models requires transitions to occur between simulated health states either at the beginning or at the end of each cycle. The result is an over- or underestimation, respectively, of quality-adjusted life expectancy and cost, compared with the results that would be obtained if transitions were modeled to occur randomly throughout each cycle. The standard half-cycle correction (HCC) is used to remedy the bias. However, the standard approach to the HCC is problematic: It does not account for discounting or for the shape of intermediate state membership functions. Application of the standard approach to the HCC also has no numerical effect on the resulting incremental cost-effectiveness ratio or change in net health benefit under certain circumstances. Alternatives to the standard HCC, in order of ease of use, include no correction, the life-table approach, the cycle tree method, and a correction based on Simpson's rule. For less complex decision models in which the computational burden is not large, reducing the cycle length to a month or less and using no correction should result in small estimation biases. With more complex models, where cycle lengths larger than 1 month may be necessary to make computation feasible, we recommend the cycle tree approach. The latter is relatively easy to apply and has an intuitive appeal: Hypothetical subjects who transition from one state to another, on average halfway through a cycle, should receive half of the value associated with the state from which they come and half the value of the state to which they are going. PMID- 24048351 TI - Association between copy number variations of HLA-DQA1 and ankylosing spondylitis in the Chinese Han population. AB - Ankylosing spondylitis (AS) is a chronic inflammatory disease with complex genetic traits. Multiple sequence variations have been associated with AS, but explained only a proportion of heritability. The studies herein aimed to explore potential associations between genomic copy number (CN) variation (CNV) and AS in Han Chinese. Five AS patients were examined with the high-density comparative genomic hybridization microarrays in the first screen test for AS-associated CNVs. A total of 533 AS patients and 792 unrelated controls were examined in confirmation studies with the AccuCopy assays. A significant association was observed between the CNV of HLA-DQA1 and that of AS. Compared with controls, AS patients showed an aberrant CN, and a significantly increased number of patients had more than two copies of HLA-DQA1. Therefore, the CNV of HLA-DQA1 may have an important role in susceptibility to AS in the Han Chinese population. PMID- 24048352 TI - Optimizing a global alignment of protein interaction networks. AB - MOTIVATION: The global alignment of protein interaction networks is a widely studied problem. It is an important first step in understanding the relationship between the proteins in different species and identifying functional orthologs. Furthermore, it can provide useful insights into the species' evolution. RESULTS: We propose a novel algorithm, PISwap, for optimizing global pairwise alignments of protein interaction networks, based on a local optimization heuristic that has previously demonstrated its effectiveness for a variety of other intractable problems. PISwap can begin with different types of network alignment approaches and then iteratively adjust the initial alignments by incorporating network topology information, trading it off for sequence information. In practice, our algorithm efficiently refines other well-studied alignment techniques with almost no additional time cost. We also show the robustness of the algorithm to noise in protein interaction data. In addition, the flexible nature of this algorithm makes it suitable for different applications of network alignment. This algorithm can yield interesting insights into the evolutionary dynamics of related species. AVAILABILITY: Our software is freely available for non-commercial purposes from our Web site, http://piswap.csail.mit.edu/. CONTACT: bab@csail.mit.edu or csliao@ie.nthu.edu.tw. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24048353 TI - Assessing the validity and reproducibility of genome-scale predictions. AB - MOTIVATION: Validation and reproducibility of results is a central and pressing issue in genomics. Several recent embarrassing incidents involving the irreproducibility of high-profile studies have illustrated the importance of this issue and the need for rigorous methods for the assessment of reproducibility. RESULTS: Here, we describe an existing statistical model that is very well suited to this problem. We explain its utility for assessing the reproducibility of validation experiments, and apply it to a genome-scale study of adenosine deaminase acting on RNA (ADAR)-mediated RNA editing in Drosophila. We also introduce a statistical method for planning validation experiments that will obtain the tightest reproducibility confidence limits, which, for a fixed total number of experiments, returns the optimal number of replicates for the study. AVAILABILITY: Downloadable software and a web service for both the analysis of data from a reproducibility study and for the optimal design of these studies is provided at http://ccmbweb.ccv.brown.edu/reproducibility.html . PMID- 24048354 TI - Toxygates: interactive toxicity analysis on a hybrid microarray and linked data platform. AB - MOTIVATION: In early stage drug development, it is desirable to assess the toxicity of compounds as quickly as possible. Biomarker genes can help predict whether a candidate drug will adversely affect a given individual, but they are often difficult to discover. In addition, the mechanism of toxicity of many drugs and common compounds is not yet well understood. The Japanese Toxicogenomics Project provides a large database of systematically collected microarray samples from rats (liver, kidney and primary hepatocytes) and human cells (primary hepatocytes) after exposure to 170 different compounds in different dosages and at different time intervals. However, until now, no intuitive user interface has been publically available, making it time consuming and difficult for individual researchers to explore the data. RESULTS: We present Toxygates, a user-friendly integrated analysis platform for this database. Toxygates combines a large microarray dataset with the ability to fetch semantic linked data, such as pathways, compound-protein interactions and orthologs, on demand. It can also perform pattern-based compound ranking with respect to the expression values of a set of relevant candidate genes. By using Toxygates, users can freely interrogate the transcriptome's response to particular compounds and conditions, which enables deep exploration of toxicity mechanisms. PMID- 24048355 TI - Shaping the interaction landscape of bioactive molecules. AB - MOTIVATION: Most bioactive molecules perform their action by interacting with proteins or other macromolecules. However, for a significant fraction of them, the primary target remains unknown. In addition, the majority of bioactive molecules have more than one target, many of which are poorly characterized. Computational predictions of bioactive molecule targets based on similarity with known ligands are powerful to narrow down the number of potential targets and to rationalize side effects of known molecules. RESULTS: Using a reference set of 224 412 molecules active on 1700 human proteins, we show that accurate target prediction can be achieved by combining different measures of chemical similarity based on both chemical structure and molecular shape. Our results indicate that the combined approach is especially efficient when no ligand with the same scaffold or from the same chemical series has yet been discovered. We also observe that different combinations of similarity measures are optimal for different molecular properties, such as the number of heavy atoms. This further highlights the importance of considering different classes of similarity measures between new molecules and known ligands to accurately predict their targets. PMID- 24048356 TI - Assessing gene-level translational control from ribosome profiling. AB - MOTIVATION: The translational landscape of diverse cellular systems remains largely uncharacterized. A detailed understanding of the control of gene expression at the level of messenger RNA translation is vital to elucidating a systems-level view of complex molecular programs in the cell. Establishing the degree to which such post-transcriptional regulation can mediate specific phenotypes is similarly critical to elucidating the molecular pathogenesis of diseases such as cancer. Recently, methods for massively parallel sequencing of ribosome-bound fragments of messenger RNA have begun to uncover genome-wide translational control at codon resolution. Despite its promise for deeply characterizing mammalian proteomes, few analytical methods exist for the comprehensive analysis of this paired RNA and ribosome data. RESULTS: We describe the Babel framework, an analytical methodology for assessing the significance of changes in translational regulation within cells and between conditions. This approach facilitates the analysis of translation genome-wide while allowing statistically principled gene-level inference. Babel is based on an errors-in variables regression model that uses the negative binomial distribution and draws inference using a parametric bootstrap approach. We demonstrate the operating characteristics of Babel on simulated data and use its gene-level inference to extend prior analyses significantly, discovering new translationally regulated modules under mammalian target of rapamycin (mTOR) pathway signaling control. PMID- 24048357 TI - miREval 2.0: a web tool for simple microRNA prediction in genome sequences. AB - RESULT: We have developed miREval 2.0, an online tool that can simultaneously search up to 100 sequences for novel microRNAs (miRNAs) in multiple organisms. miREval 2.0 uses multiple published in silico approaches to detect miRNAs in sequences of interest. This tool can be used to discover miRNAs from DNA sequences or to validate candidates from sequencing data. AVAILABILITY: http://mimirna.centenary.org.au/mireval/. PMID- 24048358 TI - CLIPS-4D: a classifier that distinguishes structurally and functionally important residue-positions based on sequence and 3D data. AB - MOTIVATION: The precise identification of functionally and structurally important residues of a protein is still an open problem, and state-of-the-art classifiers predict only one or at most two different categories. RESULT: We have implemented the classifier CLIPS-4D, which predicts in a mutually exclusively manner a role in catalysis, ligand-binding or protein stability for each residue-position of a protein. Each prediction is assigned a P-value, which enables the statistical assessment and the selection of predictions with similar quality. CLIPS-4D requires as input a multiple sequence alignment and a 3D structure of one protein in PDB format. A comparison with existing methods confirmed state-of-the-art prediction quality, even though CLIPS-4D classifies more specifically than other methods. CLIPS-4D was implemented as a multiclass support vector machine, which exploits seven sequence-based and two structure-based features, each of which was shown to contribute to classification quality. The classification of ligand binding sites profited most from the 3D features, which were the assessment of the solvent accessible surface area and the identification of surface pockets. In contrast, five additionally tested 3D features did not increase the classification performance achieved with evolutionary signals deduced from the multiple sequence alignment. PMID- 24048359 TI - The impact of human-environment interactions on the stability of forest-grassland mosaic ecosystems. AB - Forest-grassland mosaic ecosystems can exhibit alternative stables states, whereby under the same environmental conditions, the ecosystem could equally well reside either in one state or another, depending on the initial conditions. We develop a mathematical model that couples a simplified forest-grassland mosaic model to a dynamic model of opinions about conservation priorities in a population, based on perceptions of ecosystem rarity. Weak human influence increases the region of parameter space where alternative stable states are possible. However, strong human influence precludes bistability, such that forest and grassland either co-exist at a single, stable equilibrium, or their relative abundance oscillates. Moreover, a perturbation can shift the system from a stable state to an oscillatory state. We conclude that human-environment interactions can qualitatively alter the composition of forest-grassland mosaic ecosystems. The human role in such systems should be viewed as dynamic, responsive element rather than as a fixed, unchanging entity. PMID- 24048360 TI - Age-and sex-specific seasonal variation of venous thromboembolism in patients with and without family history: a nationwide family study in Sweden. AB - Seasonal variation in venous thromboembolism (VTE) risk in individuals with familial predisposition to VTE has not been explored. This nationwide study aimed to determine whether there are age- and sex-specific seasonal differences in risk of hospitalisation of VTE among individuals with and without a family history of VTE. The Swedish Multi-Generation Register was linked to Hospital Discharge Register data for the period 1964-2010. Seasonal variation in first VTE events in 1987-2010 for individuals with and without a family history of VTE (siblings or parents) was determined by several independent methods. Stratified analyses were performed according to age, sex, and VTE subtype (pulmonary embolism [PE] or deep venous thrombosis [DVT]). Seasonal variation in VTE incidence, mostly with a peak during the winter, was observed in both sexes in individuals with and without family history with overall peak-to-low ratios (PLRs) of 1.15 and 1.21, respectively. The peak day was December 25 and February 1 for those with and without a family history of VTE, respectively. Seasonal variation was strongest among individuals aged >50 years. Among individuals aged 0-25 years with a family history, the peak for VTE was in July (PLR = 1.20). Significant seasonal variation was observed for PE and DVT with the exception of DVT among those with a family history (PLR = 1.01). In conclusion, our data support the presence of a modest seasonal variation of VTE among individuals with and without a family history of VTE. However, young age and family history may modify and attenuate the effect of season on VTE. PMID- 24048361 TI - Accuracy of self-report in assessing Fitzpatrick skin phototypes I through VI. AB - IMPORTANCE: Determining Fitzpatrick skin phototypes (FST) allows physicians to assess a person's risk of developing sunburn and, by extension, the need for sun protection to prevent the development of skin cancer. Reflectance spectrophotometry objectively measures the melanin index and can assist in determining the accuracy of self-report of FST compared with dermatologist determined FST. OBJECTIVES: To assess whether self-reported or dermatologist determined FST is more accurate in identifying a participant's FST for FST I through VI and to assess the relevance of the burning and tanning measures for a range of skin types among ethnically diverse participants. DESIGN AND SETTING: A convenience sample of participants in an observational study from June 2, 2010, through December 15, 2010, at an ambulatory academic dermatologic practice and employee health center in an urban city. PARTICIPANTS: Participants, staff, and students of Northwestern University, who self-identified as being non-Hispanic white, Hispanic or Latino, Asian or Pacific Islander, or black. MAIN OUTCOMES AND MEASURES: Melanin index as measured with reflectance spectrophotometry compared with dermatologist- and participant-determined FST. RESULTS: Forty-two percent (114 of 270) of the participants' responses to the burning and tanning questions could not be classified using standard FST definitions. The spectrophotometry measurements for dermatologist-determined FST were significantly different for FST III and IV (P < .001) and FST IV and V (P < .001). The spectrophotometry measurements for participant-determined FST were significantly different for FST III and IV (P < .001) but not for FST IV and V (P = .90). Participant responses to burning and the dermatologist-determined FST were significantly correlated (Spearman rho, 0.764; P < .001). Participant responses to tanning and the dermatologist-determined FST were not significantly correlated (Spearman rho, 0.089; P = .15). Spectrophotometry measurements assessing FST were statistically significantly different for FST III through VI (P < .001). CONCLUSIONS AND RELEVANCE: Dermatologist-determined FST is more accurate than self-report for FST III through VI. Rephrasing the questions using specific descriptors that have meaning to people with skin of color, such as skin irritation, tenderness, itching, or skin becoming darker, may allow physicians to more accurately assign a skin phototype and, by inference, assess the risk of these participants developing skin cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01124513. PMID- 24048362 TI - Hydrolysis of mixed Ni(2+)-Fe3+ and Mg(2+)-Fe3+ solutions and mechanism of formation of layered double hydroxides. AB - The hydrolytic behavior of mixed metallic solutions containing Ni(2+)-Fe(3+) and Mg(2+)-Fe(3+) has been studied with respect to the relative proportion of the divalent and trivalent cations in solution as well as the quantity of NaOH added. The combination of X-ray diffraction and vibrational spectroscopy provides a deep insight into both the nature of the phases and the structure of the formed LDH. The relative abundance of each phase is determined by using a mass balance diagram and is in good agreement with the solid characterization. We showed that the slow hydrolysis of mixed metallic solutions involved first the precipitation of Fe(3+) to form an akaganeite phase, and then the formation of a precursor on the iron oxyhydroxide surface, which transforms into LDH by diffusion of Fe(III) species from the akaganeite phase to the precursor. Interestingly, whatever the iron content in solution, the same fraction of Fe(III) is incorporated into the LDH phase which is correlated to the nature of the formed precursor. For Ni(2+) Fe(3+) solution, the precursor is an alpha-Ni hydroxide, which formed a LDH phase with a very low iron content (x(layer) = 0.1), but a high charge density provided by structural hydroxyl default. This result unambiguously demonstrated that the LDH phase is formed from the precursor structure. For Mg(2+)-Fe(3+) solution, the precursor is structurally equivalent to a beta-Mg(OH)2 phase, leading to a LDH with a higher x(layer) value of ~0.2. In both cases, at the end of the titration experiments, a mixture of different phases was systematically observed. Hydrothermal treatment allows the recovery of a pure LDH phase exclusively for the Ni(2+)-Fe(3+) solution. PMID- 24048363 TI - Combined arthroscopic synovectomy and radiosynoviorthesis in the treatment of chronic non-specific synovitis of the knee. AB - INTRODUCTION: Chronic non-specific synovitis has a higher recurrence rate with arthroscopic synovectomy due to the insufficient removal of all pathological tissues. Neither has radiosynoviorthesis been sufficiently effective in treatment in contrast to cases of chronic specific synovitis such as rheumatoid arthritis. This study aimed to investigate the efficiency of combined arthroscopic and radionuclide synovectomy in chronic non-specific synovitis of the knee with the evaluation of clinical and radiological results. MATERIALS AND METHODS: 14 knees of 14 patients (11 female, 3 male) diagnosed as chronic non-specific synovitis were treated with arthroscopic subtotal synovectomy combined with radiosynoviorthesis. The efficiency was evaluated retrospectively by comparing preoperative and postoperative modified cincinnati knee score, Visual Analogue Scale, joint USG and MRI. The mean age was 29.2 +/- 10.3 years and the mean follow-up period was 30.3 +/- 3.7 months. RESULTS: Clinical parameters such as pain, limitation of motion and effusion were regressed. Daily activities at the final follow-up were significantly better than in the preoperative period. The mean modified cincinnati knee score of the patients increased from 25.8 +/- 8.7 preoperatively to 67.8 +/- 13.4 postoperatively (p = 0.002). The mean VAS score was 7.2 +/- 1.1 preoperatively and 1.3 +/- 0.8 postoperatively (p = 0.003). Clinically and radiologically on MRI there was no recurrence. Mean synovial membrane thickness was 4.5 +/- 2.4 mm in the preoperative period. At the final follow-up, noticeable regression of synovial membrane thickness (2.1 +/- 0.5 mm) was recorded in the knee joint USG (p = 0.015). No complications were observed. CONCLUSION: The combination of arthroscopic subtotal synovectomy and radiosynoviorthesis can be an effective treatment modality for chronic non specific synovitis of the knee. PMID- 24048364 TI - Producers and important dietary sources of ochratoxin A and citrinin. AB - Ochratoxin A (OTA) is a very important mycotoxin, and its research is focused right now on the new findings of OTA, like being a complete carcinogen, information about OTA producers and new exposure sources of OTA. Citrinin (CIT) is another important mycotoxin, too, and its research turns towards nephrotoxicity. Both additive and synergistic effects have been described in combination with OTA. OTA is produced in foodstuffs by Aspergillus Section Circumdati (Aspergillus ochraceus, A. westerdijkiae, A. steynii) and Aspergillus Section Nigri (Aspergillus carbonarius, A. foetidus, A. lacticoffeatus, A. niger, A. sclerotioniger, A. tubingensis), mostly in subtropical and tropical areas. OTA is produced in foodstuffs by Penicillium verrucosum and P. nordicum, notably in temperate and colder zones. CIT is produced in foodstuffs by Monascus species (Monascus purpureus, M. ruber) and Penicillium species (Penicillium citrinum, P. expansum, P. radicicola, P. verrucosum). OTA was frequently found in foodstuffs of both plant origin (e.g., cereal products, coffee, vegetable, liquorice, raisins, wine) and animal origin (e.g., pork/poultry). CIT was also found in foodstuffs of vegetable origin (e.g., cereals, pomaceous fruits, black olive, roasted nuts, spices), food supplements based on rice fermented with red microfungi Monascus purpureus and in foodstuffs of animal origin (e.g., cheese). PMID- 24048367 TI - Optical biomarkers for breast cancer derived from dynamic diffuse optical tomography. AB - Diffuse optical tomography (DOT) is a noninvasive, nonionizing imaging modality that uses near-infrared light to visualize optically relevant chromophores. A recently developed dynamic DOT imaging system enables the study of hemodynamic effects in the breast during a breath-hold. Dynamic DOT imaging was performed in a total of 21 subjects (age 54+/-10 years) including 3 healthy subjects and 18 subjects with benign (n=8) and malignant (n=14) masses. Three-dimensional time series images of the percentage change in oxygenated and deoxygenated hemoglobin concentrations ([HbO2] and [Hb]) from baseline are obtained over the course of a breath-hold. At a time point of 15 s following the end of the breath-hold, [Hb] in healthy breasts has returned to near-baseline values (1.6%+/-0.5%), while tumor-bearing breasts have increased levels of [Hb] (6.8%+/-3.6%, p<0.01). Further, healthy subjects have a higher correlation between the breasts over the course of the breath-hold as compared with the subjects with breast cancer (healthy: 0.96+/-0.02; benign: 0.89+/-0.02; malignant: 0.78+/-0.23, p<0.05). Therefore this study shows that dynamic features extracted from DOT measurements can differentiate healthy and diseased breast tissues. These features provide a physiologic method for identifying breast cancer without the need for ionizing radiation. PMID- 24048366 TI - Influence of body mass index on survival in veterans with multiple myeloma. AB - PURPOSE: We investigated the association between body mass index (BMI) at the time of multiple myeloma (MM) diagnosis and overall survival in a cohort of patients within the Veterans Health Administration system. We also evaluated the association between weight loss in the year prior to diagnosis and survival. PATIENTS AND METHODS: Prospective analysis was performed on a retrospectively assembled cohort of 2,968 U.S. veterans diagnosed and treated for MM between September 1, 1999, and September 30, 2009, with follow-up information through October 22, 2011. Cox modeling controlling for patient- and disease-related prognostic variables was used to analyze the data. RESULTS: Underweight patients (BMI <18.5 kg/m2) had increased mortality, whereas patients who were overweight (BMI 25-29.9 kg/m2) and obese (BMI >=30 kg/m2) had lower mortality compared with healthy-weight patients (BMI 18.5-24.9 kg/m2). Weight loss >=10% of baseline in the year before diagnosis was also associated with increased mortality and made the association between increased BMI and survival nonsignificant. CONCLUSION: Disease-related weight loss may be an important and heretofore unknown indicator of poor prognosis in MM. Assessment of weight loss prior to MM diagnosis should become a standard component of the clinical history in patients with newly diagnosed MM. Further research may identify relationships between disease-related weight loss and currently used prognostic factors in MM, further defining the role of this clinical factor in prognostic stratification. PMID- 24048368 TI - When is "too early" too early to start cosmetic procedures? PMID- 24048369 TI - Does combined prednisolone and low molecular weight heparin have a role in unexplained implantation failure? AB - PURPOSE: To study the effect of combined oral prednisolone and LMW heparin in ICSI in women with previously unexplained, failed implantation. METHODS: A prospective quasi-randomized, controlled trial was conducted at a university teaching hospital and a private practice setting. A total of 334 cycles (women with previously unexplained, failed one or two ICSI attempts) were assigned randomly to receive standard treatment or combined prednisolone (20 mg/day), starting on the first day of ovarian stimulation and LMW heparin 1 mg/kg/day starting 1 day after oocyte retrieval in addition to standard treatment. RESULTS: The mean age, number of previously failed IVF attempts, and basal FSH levels were comparable between both groups. The pregnancy and the implantation rates were significantly different between the study and control groups. CONCLUSIONS: A combination of oral prednisolone and low molecular weight heparin may have a significant effect on pregnancy and implantation rates in prior unexplained, failed implantation. PMID- 24048370 TI - 8-Quinolinolate complexes of yttrium and ytterbium: molecular arrangement and fragmentation under laser impact. AB - New 8-quinolinolate (Q) complexes of yttrium (1) and ytterbium (2) were synthesized by the reactions of Cp3Y and Yb[N(SiMe3)2]3 with 3 equiv. of 8 hydroxyquinoline in a DME solution. Single crystal X-ray analysis revealed the trinuclear molecular structure of the compounds Ln3Q9. The LDI-TOFMS investigation displayed that under the laser impact the compounds split off Q(-) anions to give Ln3Q8(+), Ln2Q5(+) and LnQ3(+) moieties. In the negative mode spectra the anions Q(-) and LnQ4(-) were observed. The DFT calculations showed the decreased stability of cationic Ln-quinolinolate as compared with their anionic counterparts. Complex 2 which is used as an emitter in a three-layer OLED displayed a metal-centered emission at 979 nm and an intensity of 50 MUW cm(-2) at 15.5 V. PMID- 24048371 TI - Highly efficient telluride electrocatalysts for use as Pt-free counter electrodes in dye-sensitized solar cells. AB - Two transition metal tellurides, CoTe and NiTe2, were synthesized and for the first time employed as the counter electrodes (CEs) with high catalytic activity for reduction of I3(-) in dye-sensitized solar cells (DSCs). Using CoTe and NiTe2 based CEs, photoelectric conversion efficiencies (PCEs) of 6.92% and 7.21% were achieved for DSCs, respectively, comparable to that of 7.04% achieved when using a Pt-based CE. The results indicated that, serving as a CE in DSCs, telluride could be a cost-effective and efficient alternative to the noble metal Pt. PMID- 24048372 TI - Exome sequencing and in vitro studies identified podocalyxin as a candidate gene for focal and segmental glomerulosclerosis. AB - Our understanding of focal and segmental glomerulosclerosis (FSGS) has advanced significantly from the studies of rare, monogenic forms of the disease. These studies have demonstrated the critical roles of multiple aspects of podocyte function in maintaining glomerular function. A substantial body of research has suggested that the integral membrane protein podocalyxin (PODXL) is required for proper functioning of podocytes, possibly by preserving the patency of the slit diaphragm by negative charge-based repulsion. Exome sequencing of affected cousins from an autosomal dominant pedigree with FSGS identified a cosegregating private variant, PODXL p.L442R, affecting the transmembrane region of the protein. Of the remaining 11 shared gene variants, two segregated with disease, but their gene products were not detected in the glomerulus. In comparison with wild type, this disease-segregating PODXL variant facilitated dimerization. By contrast, this change does not alter protein stability, extracellular domain glycosylation, cell surface expression, global subcellular localization, or interaction with its intracellular binding partner ezrin. Thus, a variant form of PODXL remains the most likely candidate causing FSGS in one family with autosomal dominant inheritance, but its full effect on protein function remains unknown. Our work highlights the challenge faced in the clinical interpretation of whole exome data for small pedigrees with autosomal dominant diseases. PMID- 24048373 TI - Suppressed soluble Fms-like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease. AB - Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PlGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PlGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PlGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted. PMID- 24048374 TI - The clinical and immunological features of patients with combined anti-glomerular basement membrane disease and membranous nephropathy. AB - The association of anti-glomerular basement membrane (GBM) disease, also known as Goodpasture's disease, with membranous nephropathy (MN) has been well documented. However, little is known about the clinical and immunological features of patients with such a combination. This study was designed to investigate the clinical and immunological features of anti-GBM patients with MN and to provide insight into the pathogenesis of this rare entity. Eight patients with combined anti-GBM disease and MN were found to have significantly lower levels of serum creatinine, a significantly lower proportion of oliguria/anuria, and significantly better renal outcomes compared with 30 patients with classical anti GBM disease. Antibody levels against the EB conformational epitope of anti alpha3(IV)NC1 were significantly lower in these patients, as was their levels of anti-alpha3(IV)NC1 immunoglobulin G1 (IgG1) and IgG3. Serum antibodies against the M-type phospholipase A2 receptor were undetectable in anti-GBM patients with MN but presented in 13 of the 20 patients with primary MN. Thus, patients with combined anti-GBM disease and MN have distinct clinical features and a different immunological profile of MN. PMID- 24048375 TI - Nephrotic-range proteinuria is strongly associated with poor blood pressure control in pediatric chronic kidney disease. AB - Despite the importance of blood pressure (BP) control in chronic kidney disease (CKD), few longitudinal studies on its trends exist for pediatric patients with CKD. Here we longitudinally analyzed casual data in 578 children with CKD and annual BP measurements standardized for age, gender, and height. At baseline, 124 children were normotensive, 211 had elevated BP, and 243 had controlled hypertension. Linear mixed-effects models accounting for informative dropout determined factors associated with BP changes over time and relative sub-hazards (RSH) identified factors associated with the achievement of controlled BP in children with baseline elevated BP. Younger age, black children, higher body mass index, and higher proteinuria at baseline were associated with higher standardized BP levels. Overall average BP decreased during follow-up, but nephrotic-range proteinuria and increased proteinuria and body mass index were risk factors for increasing BP over time. Only 46% of hypertensive patients achieved controlled BP during follow-up; least likely were those with nephrotic range proteinuria (RSH 0.19), black children (RSH 0.42), and children with baseline glomerular filtration rate under 40 ml/min per 1.73 m(2) (RSH 0.58). Thus, of many coexisting factors, nephrotic-range proteinuria was most strongly associated with poor BP control and worsening BP over time. Future research should focus on strategies to reduce proteinuria, as this may improve BP control and slow the progression of CKD. PMID- 24048377 TI - Identification of a urine metabolomic signature in patients with advanced-stage chronic kidney disease. AB - The prevalence of chronic kidney disease (CKD) is increasing and frequently progresses to end-stage renal disease. There is an urgent demand to discover novel markers of disease that allow monitoring disease progression and, eventually, response to treatment. To identify such markers, and as a proof of principle, we determined if a metabolite signature corresponding to CKD can be found in urine. In the discovery stage, we analyzed the urine metabolome by NMR of 15 patients with CKD and compared that with the metabolome of 15 healthy individuals and found a classification pattern clearly indicative of CKD. A validation cohort of urine samples from an additional 16 patients with CKD and 15 controls was then analyzed by (Selected Reaction Monitoring) liquid chromatography-triple quadrupole mass spectrometry and indicated that a group of seven urinary metabolites differed between CKD and non-CKD urine samples. This profile consisted of 5-oxoproline, glutamate, guanidoacetate, alpha phenylacetylglutamine, taurine, citrate, and trimethylamine N-oxide. Thus, we identified a panel of urine metabolites differentially present in urine that may help identify and monitor patients with CKD. PMID- 24048376 TI - Mendelian randomization analysis associates increased serum urate, due to genetic variation in uric acid transporters, with improved renal function. AB - Increased serum urate predicts chronic kidney disease independent of other risk factors. The use of xanthine oxidase inhibitors coincides with improved renal function. Whether this is due to reduced serum urate or reduced production of oxidants by xanthine oxidase or another physiological mechanism remains unresolved. Here we applied Mendelian randomization, a statistical genetics approach allowing disentangling of cause and effect in the presence of potential confounding, to determine whether lowering of serum urate by genetic modulation of renal excretion benefits renal function using data from 7979 patients of the Atherosclerosis Risk in Communities and Framingham Heart studies. Mendelian randomization by the two-stage least squares method was done with serum urate as the exposure, a uric acid transporter genetic risk score as instrumental variable, and estimated glomerular filtration rate and serum creatinine as the outcomes. Increased genetic risk score was associated with significantly improved renal function in men but not in women. Analysis of individual genetic variants showed the effect size associated with serum urate did not correlate with that associated with renal function in the Mendelian randomization model. This is consistent with the possibility that the physiological action of these genetic variants in raising serum urate correlates directly with improved renal function. Further studies are required to understand the mechanism of the potential renal function protection mediated by xanthine oxidase inhibitors. PMID- 24048378 TI - Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotype switch in vivo. AB - Alternatively activated macrophages (M2) regulate immune responses and ex vivo polarized splenic M2 are able to ameliorate renal injury including models of renal disease, such as adriamycin nephropathy. Whether M2 derived from other organs have similar protective efficacy is unknown. Here, we report adoptively transferred bone marrow M2 macrophages did not improve renal function or reduce renal injury in adriamycin nephropathy, whereas splenic M2 macrophages were protective. Bone marrow and splenic M2 macrophages showed similar regulatory phenotypes and suppressive functions in vitro. Within the inflamed kidney, suppressive phenotypes in bone marrow but not in splenic M2 macrophages, were dramatically reduced. Loss of the suppressive phenotype in bone marrow M2 was related to strong proliferation of bone marrow M2. Bone marrow M2 proliferation in vivo correlated with M-CSF expression by tubular cells in the inflamed kidney. Inhibition of M-CSF in vitro limited bone marrow M2 proliferation and prevented switch of phenotype. Proliferating cells derived from transfused bone marrow M2 were inflammatory rather than regulatory in their phenotype and function. Thus bone marrow in contrast to splenic M2 macrophages do not protect against renal structural and functional injury in murine adriamycin nephropathy. The failed renoprotection of bone marrow M2 is due to the switch of transfused M2 macrophages from a regulatory to an inflammatory phenotype. PMID- 24048379 TI - Derivation and validation of the renal angina index to improve the prediction of acute kidney injury in critically ill children. AB - Reliable prediction of severe acute kidney injury (AKI) has the potential to optimize treatment. Here we operationalized the empiric concept of renal angina with a renal angina index (RAI) and determined the predictive performance of RAI. This was assessed on admission to the pediatric intensive care unit, for subsequent severe AKI (over 200% rise in serum creatinine) 72 h later (Day-3 AKI). In a multicenter four cohort appraisal (one derivation and three validation), incidence rates for a Day 0 RAI of 8 or more were 15-68% and Day-3 AKI was 13-21%. In all cohorts, Day-3 AKI rates were higher in patients with an RAI of 8 or more with the area under the curve of RAI for predicting Day-3 AKI of 0.74-0.81. An RAI under 8 had high negative predictive values (92-99%) for Day-3 AKI. RAI outperformed traditional markers of pediatric severity of illness (Pediatric Risk of Mortality-II) and AKI risk factors alone for prediction of Day 3 AKI. Additionally, the RAI outperformed all KDIGO stages for prediction of Day 3 AKI. Thus, we operationalized the renal angina concept by deriving and validating the RAI for prediction of subsequent severe AKI. The RAI provides a clinically feasible and applicable methodology to identify critically ill children at risk of severe AKI lasting beyond functional injury. The RAI may potentially reduce capricious AKI biomarker use by identifying patients in whom further testing would be most beneficial. PMID- 24048380 TI - Pharmacokinetics and pharmacodynamics of oral tolvaptan in patients with varying degrees of renal function. AB - The selective vasopressin V2-receptor antagonist tolvaptan is eliminated almost exclusively by non-renal mechanisms. As renal impairment can influence the pharmacokinetics of drugs even when eliminated by non-renal mechanisms, we evaluated the effect of renal insufficiency on the pharmacokinetics/pharmacodynamics of tolvaptan. Thirty-seven patients were grouped by a 24-h creatinine clearance (CrCL) and evaluated for 48 h after a single 60 mg oral dose in the fasting state. Mean tolvaptan exposure was 90% higher in the under 30-ml/min group compared with the over 60-ml/min group with individual values significantly but negatively correlated with increasing baseline CrCL. There was a greater and more rapid increase in urine output and free water clearance in the over 60-ml/min compared with the renal impaired groups, but they returned to baseline more quickly. Serum sodium increased more rapidly in the over 60 as opposed to the under 30-ml/min group, but overall maximum increases were similar across groups. Small decreases in mean CrCL and small increases in mean serum creatinine/potassium were independent of baseline CrCL. The percent fractional free water clearance with respect to CrCL was significantly but negatively correlated with increasing baseline CrCL. No unexpected adverse events were reported. Thus, renal impairment attenuated the increase in 24-h urine volume and free water clearance caused by tolvaptan, consistent with decreased nephron function in renal impairment. The delay in serum sodium increase was consistent with the longer duration needed to excrete sufficient water to cause the increase. PMID- 24048381 TI - Breast arterial calcification in chronic kidney disease: absence of smooth muscle apoptosis and osteogenic transdifferentiation. AB - The pathophysiology of medial arterial calcification in chronic kidney disease (CKD) is unclear but has been ascribed to phenotypic changes in vascular smooth muscle, possibly in conjunction with intimal proliferation and atherosclerosis. As the prevalence of calcification in breast arteries is increased in women with CKD and end-stage renal disease (ESRD), this was examined histologically in mastectomy specimens from 19 women with CKD or ESRD. Arterial calcification was present in 18, was exclusively medial, and occurred in vessels as small as arterioles. Intimal thickening was common but unrelated to calcification. There was no evidence of atherosclerosis. The earliest calcification presented as small punctate lesions scattered throughout the media, often with calcification of the internal elastic lamina. Arterial calcification was present in all samples from an age- and diabetes-matched cohort without CKD but was much milder. While smooth muscle cell density was reduced one-third in arteries from patients with ESRD, the cells appeared normal, expressed SM22alpha, and exhibited no apoptosis. Staining for the bone-specific protein osteocalcin, the osteoblastic transcription factors Runx2 or osterix, or the chondrocytic transcription factor SOX9 was absent in regions of early calcification. Thus, medial calcification in breast arteries of patients with CKD can occur in the absence of smooth muscle cell apoptosis and/or osteogenic transdifferentiation. This suggests that the pathologic mineralization process may differ from one arterial type to the other. PMID- 24048382 TI - Aggressive blood pressure reduction and renin-angiotensin system blockade in chronic kidney disease: time for re-evaluation? AB - Over the past decades, aggressive control of blood pressure (BP) and blockade of the renin-angiotensin-aldosterone system (RAAS) were considered the cornerstones of treatment against progression of chronic kidney disease (CKD), following important background and clinical evidence on the associations of hypertension and RAAS activation with renal injury. To this end, previous recommendations included a BP target of <130/80 mm Hg for all individuals with CKD (and possibly <125/75 mm Hg for those with proteinuria >1 g/day), as well as use of angiotensin converting-enzyme inhibitors and angiotensin receptor blockers as first-line therapy for hypertension in all CKD patients. However, long-term extensions of relevant clinical trials support a low-BP goal only for patients with proteinuria, whereas recent cardiovascular trials questioned the benefits of low systolic BP for diabetic patients, leading to more individualized recommendations. Furthermore, our previous knowledge of the specific renoprotective properties of RAAS blockers in patients with proteinuric CKD is now extended with data on the use of these agents in patients with less advanced nephropathy and/or absence of proteinuria, deriving mostly from subanalyses of cardiovascular trials. This review discusses previous and recent clinical evidence on the issues of BP reduction and RAAS blockade by type and stage of renal damage, aiming to aid clinicians in their treatment decisions for patients with CKD. PMID- 24048384 TI - Broadband energy transfer to sensitizing dyes by mobile quantum dot mediators in solar cells. AB - The efficiency of solar cells depends on absorption intensity of the photon collectors. Herein, mobile quantum dots (QDs) functionalized with thiol ligands in electrolyte are utilized into dye-sensitized solar cells. The QDs serve as mediators to receive and re-transmit energy to sensitized dyes, thus amplifying photon collection of sensitizing dyes in the visible range and enabling up conversion of low-energy photons to higher-energy photons for dye absorption. The cell efficiency is boosted by dispersing QDs in electrolyte, thereby obviating the need for light scattering or plasmonic structures. Furthermore, optical spectroscopy and external quantum efficiency data reveal that resonance energy transfer due to the overlap between QD emission and dye absorption spectra becomes dominant when the QD bandgap is higher than the first excitonic peak of the dye, while co-sensitization resulting in a fast reduction of oxidized dyes is pronounced in the case of lower QD band gaps. PMID- 24048385 TI - Theoretical psychiatry: missing link between academic and clinical psychiatry for further scientific and professional maturation of psychiatry. AB - Psychiatry is in the midst of the paradigm shift. The new field called theoretical psychiatry is fundamental for further scientific and professional maturation of psychiatry at the twenty first century. The cross disciplinary interactions and transdisciplinary systems approach are of great importance in science and the paradigm shift. PMID- 24048383 TI - Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction. AB - A common single-nucleotide polymorphism (SNP) in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This SNP is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism, we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75(NTR) and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand, which modulates neuronal morphology. PMID- 24048386 TI - Clinical potential of cariprazine in the treatment of acute mania. AB - Cariprazine (RGH-188, trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl} N,N-dimethylcarbamoyl-cyclohexyl-amine hydrochloride), is a novel antipsychotic with dopamine D2 and D3 receptors antagonist-partial agonist properties. Cariprazine has also moderate affinity for serotonin 5-hydroxytryptophan (5-HT) 1A receptors, high affinity for 5-HT1B receptors with pure antagonism and low affinity for 5-HT2A receptors. Randomized, double blind, placebo controlled, flexible-dose (3-12 mg/day) studies have demonstrated cariprazine is effective in both schizophrenia and acute manic episodes associated with bipolar disorder. The incidence of serious adverse events in cariprazine arm was no different than in placebo arm in these studies. The most common adverse events were extrapyramidal symptoms, headache, akathisia, constipation, nausea, and dyspepsia which can be explained with cariprazine's partial dopamine agonism. Although cariprazine treatment was associated with a higher incidence of treatment-emergent adverse events, particularly akathisia and tremor, common side effects of marketed second generation antipsychotics such as weight gain, metabolic disturbances, prolactin increase or QTc prolongation were not associated with cariprazine, probably due to its moderate to low binding affinity for histamine H1 and 5-HT2C receptors. Animal studies show that cariprazine may have additional therapeutic benefit on impaired cognitive functioning with D3 receptor activity, however clinical data is still scarce. The aim of this article is to review the potential use of cariprazine for the treatment of acute manic episodes in the light of the preclinical and clinical trials reported to date. PMID- 24048387 TI - Quetiapine as combination treatment with citalopram in unipolar depression with prominent somatic symptoms: a randomised, double-blind, placebo-controlled pilot study. AB - BACKGROUND: Patients with major depressive disorder (MDD) accompanied by physical symptoms may be less responsive to antidepressant treatment. Quetiapine has been evaluated in the treatment of bipolar depression and has been recently approved as an add-on therapy for unipolar depression. Less is known about the efficacy of combination therapies in patients suffering from MDD with somatic symptoms. The aim of the present study was to evaluate the efficacy of quetiapine as adjunctive therapy to the SSRI citalopram in patients with MDD and somatic complaints. SUBJECTS AND METHODS: 41 inpatients with nonpsychotic DSM-IV MDD experiencing significant symptoms of somatic distress as defined by a baseline score on the SCL-90-R somatization subscale greater one standard deviation above adult nonpatient norms were randomly assigned to receive either citalopram 40 mg/day plus placebo (n=20) or citalopram 40 mg/day plus quetiapine, 300 to 600 mg/day (n=21) for 6 weeks. The primary outcome measure was the Hamilton Depression Rating Scale (HDRS) score. RESULTS: Mean changes in HDRS scores from baseline to week 6 using last-observation-carried-forward methods were -12.3+/-6.2 and 10.7+/-5.1 in the citalopram-quetiapine and citalopram-placebo group, respectively. Remission rates were significant higher in the citalopram quetiapine-group (41.1%) than in the citalopram-placebo-group (26.3%), respectively. CONCLUSIONS: Although quetiapine as add-on to citalopram did not separate statistically from placebo on the HDRS score in improving depressive symptoms and somatic symptoms in patients with MDD and prominent somatic complaints, higher remission rates and other second outcome parameters showed advantages for quetiapine. Larger, double-blind, placebo-controlled trials of quetiapine as augmentation therapy in MDD with somatic symptoms are warranted. PMID- 24048388 TI - Dendritic and spinal pathology of the Purkinje cells from the human cerebellar vermis in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease constitutes one of the main causes of dementia. It is clinically characterized by memory impairment, deterioration of intellectual faculties and loss of professional skills. Furthermore changes in equilibrium and limb coordination are clinically demonstrable in persons with Alzheimer's disease. In the present study we tried to figure out possible changes of the Purkinje cells in Alzheimer's disease brains. SUBJECTS AND METHODS: We studied the Purkinje cells from the vermis of the cerebellum in 5 Alzheimer' disease brains Golgi technique. RESULTS: In the Purkinje cells from the inferior surface of the cerebellar hemispheres severe dendritic and spinal pathology consisting of loss of distal dendritic segments and alterations of dendritic spine morphology can be noticed in Alzheimer's disease brains. CONCLUSIONS: The morphological and morphometric estimation of the dendrites and the dendritic spines of the Purkinje cells from the inferior surface of the cerebellar hemispheres in Alzheimer's disease brains revealed substantial alterations of the dendritic arborization and marked loss of the dendritic spines, which may be related to cognitive impairment and motor deficits in Alzheimer's disease. PMID- 24048389 TI - Childhood maltreatment and adult proinflammatory status in patients with major depression. AB - BACKGROUND: An increasing body of research considers the immunological effects of major depression. It remains an open question, whether depression itself acts in an immunomodulatory fashion or whether other factors related to depression result in these immunological effects. Regardless, major depression is often the result of early life stress, the implications of which are not satisfactorily understood. SUBJECTS AND METHODS: Early life stress was retrospectively evaluated in 25 depressed inpatients via the CTQ (Childhood Trauma Questionnaire). Its impact on immunological biomarkers (fibrinogen, SAA, CRP, adiponectin, TNF-alpha, resistin, and sE-selectin) in adulthood was assessed via multiple regression analyses. Parental bonding was assessed via the PBI (Parental bonding questionnaire), severity of depression with the HDRS-17 (Hamilton-Depression Rating Scale). RESULTS: Nearly all patients had experienced a parental style of affectionless control. Physical neglect significantly predicted fibrinogen levels (R(2)=0.42, adjusted R(2)=0.27, beta=0.56, p=0.04). Severity of depression was not associated with immune markers. CONCLUSION: Childhood maltreatment was linked to fibrinogen levels in our sample. Thus, inflammation may be an important mechanism mediating the adverse effects of early life stress on adult health in patients with major depression. PMID- 24048390 TI - Correlation between religious coping and depression in cancer patients. AB - BACKGROUND: Cancer often progresses very rapidly and either leads to various complications or patients eventually die of the disease. One of important consequences of cancer is depression which can increase the morbidity and mortality in non-treated cases. Religious coping is the use of religious beliefs or practices to reduce distress and deal with problems in life. This study aimed to determine the relationship between religious coping and depression in cancer patients. SUBJECTS AND METHODS: A descriptive-correlational study was conducted on 150 consequent cancer patients in three centers: Imam-Reza Hospital in Birjand, Qaem and Omid hospitals in Mashhad. Two questionnaires including Pargament's questionnaire for evaluation of religious coping and the Beck depression inventory were used. Data analysis was performed using multiple regression and correlation. RESULTS: There was no significant difference between men and women in the mean score of avoidant relationship with God and alternate fearfulness and hopefulness (ambivalence coping style). But the mean score of relationship with God in women was higher than men. The rate of depression was higher among patients who had an avoidant strategy. The religious coping method of relationship with God was effective in reducing depression. The rate of depression was lower among patients whose families had a better attitude to religion. CONCLUSIONS: Psychotherapy, individual/familial counseling, and especially increasing of religious beliefs such as praying and trust in God, as well as increasing the knowledge of patient and his/her family cause better acceptance of the disease and better confrontation of psychological problems. PMID- 24048391 TI - The association of poor economic condition and family relations in childhood with late-life depression. AB - BACKGROUND: Late-life depression encompasses both patients with late-life onset of depression (>60 years) and older adults with a prior and current history of depression. The aim of the study was to analyze the impact of the economic condition and family relations in childhood as risk factors for late-life depression. SUBJECTS AND METHODS: This was an analytical cross-sectional study comprising 120 subjects, 60 patients with unipolar depression and 60 subjects without depressive disorders, diagnosed in accordance with the 10-th International Classification of Mental and Behavioural Disorders. All participants in the study were above the age of 60 and there was no significant statistical difference in the sex proportion in both groups (p>0.05). Data for the examination were taken from a self-reported questionnaire designed for our aim. The Geriatric Depression Scale was used to measure depressive symptoms. RESULTS: Our results have shown that severe financial difficulties are important events in childhood and are risk factors for depression in the elderly (Chi square=12.68, df=2, p=0.0018). Our investigation has found the association of family relations with late-life depression. In fact, conflictual relations in the family were more common in the experimental group than in the control group (Chi square=14.32, df=3, p=0.0025). Furthermore, father's addiction to alcohol in childhood was associated with depression in later life (p=0.013). The difference in childhood emotional neglect and unequal treatment between siblings in both groups was insufficient to be confirmed statistically, but the examinees with this trauma had a threefold higher chance of having depression later in life (Odds ratio=3.04, 95% CL0.92 < OR<10.65; Yates chi-square=3.2, df=1, p=0.07). Subjects who have estimated their mother (p=0.019) or father (p=0.046) having negative personal character traits had a significantly greater risk for development of late-life depression. CONCLUSIONS: Negative socio-economic circumstances as well as family conflicts during childhood are associated with late-life depression. Father's addiction to alcohol and parents' negative personal character traits are associated with depression in the elderly. PMID- 24048392 TI - Online media report on a Hungarian double suicide case: comparison of consecutively published articles. AB - BACKGROUND: Certain types of news coverage can increase the likelihood of suicide. This study explores, how media covered a suicide case in a country, where there was no available guideline, though it was among the leading countries in suicide statistics. The specific aim was to compare the first and second waves of reporting on suicide from the same website. METHODS: In 2011, two young women committed double suicide in Budapest, Hungary. We analyzed the first and second waves of the reported articles about this double suicide case, in online daily newspapers, news portals and also the readers' comments. RESULTS: Provocative aspects were present in 38.9-100.0% of the articles, while preventive aspects were found in 0-22.2% of the articles. Readers commented in 49.6% "Other Aspects" (comments about all other aspects not belonging to any other category, i.e. Risk Behavior, Family Relations, Suicide Place and Methods, Prevention, Media Style Reporting) and in 25.4% "Without Content" (comments without a specific content: e.g. chatting), while "Prevention" (comments about possible safety preventive measures) was mentioned only in 1.5% of the comments. In 34.1% the emotional tonality of the comments was "Neutral" (indifferent comments: e.g. chatting). Though articles published for the second time were significantly longer than the firstly published ones, the preventive aspects of reporting were not added to the second articles either, but significantly more provocative aspects were found in them. CONCLUSIONS: The suicide reports, both in the first and second waves of reporting, were not in line with the recommendation of the international guidelines on suicide reporting. It draws the attention of professionals to the importance of developing national guidelines on media suicide coverage. PMID- 24048393 TI - The use of assessment tools in a sample of Croatian professional fire-fighters. AB - BACKGROUND: This article aims at testing of psychometric characteristics of the Beck Depression Inventory (BDI) and the Defense Style Questionnaire - 40 (DSQ-40) in a sample of Croatian professional fire-fighters, so as to justify their use in Occupational Health. A pioneer effort to interrelate mental states and psychological job demands, ranked using the WAI questionnaire, was made as well. SUBJECTS AND METHODS: Upon informed consent, the tools were tested on a sample of 300 members of the operative fire-fighting squad of the City of Zagreb, all men (average age 43; average years of fire-fighting service 18.5). The participation was voluntary and anonymous. RESULTS: The average BDI score was 2.34, revealing a low representation of depression in the target population. The score indicating severe depression was seen in 0.7% of examinees only. Cronbach alpha of 0.92 showed satisfactory inner tool consistency. As for DSQ-40, mature, neurotic and immature defence mechanisms were evaluated. The highest mean score of 75.24 (+/ 26.07) was obtained with immature defence (Cronbach alpha 0.87). Self-assessed current working capacity was revealed to be strongly dependent on total years of service (r=-0.134; p=0.021), while the representation of neurotic defence positively correlated with the respondents' age and total years of service. Immature defence strongly positively correlated with the total years of fire fighting service. CONCLUSIONS: The employed tools were shown to be appropriate for use in Croatian professional fire-fighting population. Nevertheless, the interrelations disclosed by this pioneer research should be investigated further. PMID- 24048394 TI - Preliminary data on validity of the Drug Addiction Treatment Efficacy Questionnaire. AB - BACKGROUND: This study describes the validation process for the Slovenian version of the Drug Addiction Treatment Efficacy Questionnaire (DATEQ). SUBJECTS AND METHODS: DATEQ was constructed from the questionnaires used at the Centre for the Treatment of Drug Addiction, Ljubljana University Psychiatric Hospital, and within the network of Centres for the Prevention and Treatment of Drug Addiction in Slovenia during the past 14 years. The Slovenian version of the DATEQ was translated to English using the 'forward-backward' procedure by its authors and their co-workers. The validation process included 100 male and female patients with established addiction to illicit drugs who had been prescribed opioid substitution therapy. The DATEQ questionnaire was used in the study, together with clinical evaluation to measure psychological state and to evaluate the efficacy of treatment in the last year. To determinate the validity of DATEQ the correlation with the clinical assessments of the outcome was calculated using one way ANOVA. RESULTS: The F value was 44.4, p<0.001 (sum of squares: between groups 210.4, df=2, within groups 229.7, df=97, total 440.1, df=99). At the cut-off 4 the sensitivity is 81% and specificity 83%. CONCLUSION: The validation process for the Slovenian DATEQ version shows metric properties similar to those found in international studies of similar questionnaires, suggesting that it measures the same constructs, in the same way and as similar questionnaires. However, the relatively low sensitivity and specificity suggests caution when using DATEQ as the only measure of outcome. PMID- 24048395 TI - Duloxetine-related galactorrhea and restless legs syndrome: a case report. PMID- 24048396 TI - How to increase treatment effectiveness and efficiency in psychiatry: creative psychopharmacotherapy - part 1: definition, fundamental principles and higher effectiveness polypharmacy. AB - Psychopharmacotherapy is a fascinating field that can be understood in many different ways. It is both a science and an art of communication with a heavily subjective dimension. The advent of a significant number of the effective and well tolerated mental health medicines during and after 1990s decade of the brain has increased our possibilities to treat major mental disorders in more successful ways with much better treatment outcome including full recovery. However, there is a huge gap between our possibilities for achieving high treatment effectiveness and not satisfying results in day-to-day clinical practice. Creative approach to psychopharmacotherapy could advance everyday clinical practice and bridge the gap. Creative psychopharmacotherapy is a concept that incorporates creativity as its fundamental tool. Creativity involves the intention and ability to transcend limiting traditional ideas, rules, patterns and relationships and to create meaningful new ideas, interpretations, contexts and methods in clinical psychopharmacology. PMID- 24048397 TI - How to increase treatment effectiveness and efficiency in psychiatry: creative psychopharmacotherapy - part 2: creating favorable treatment context and fostering patients' creativity. AB - Any medical or psychosocial treatment has two components, one associated with the specific effects of the treatment itself, and the other related to the treatment context, individual perception, imagination, subjective meaning and psychobiological response. Psychopharmacotherapy is a context dependent practice because different contexts affect the meaning of biological variables in different ways. Creation of favorable treatment context as well as creative collaboration with patients and their families may significantly improve treatment outcome. Positive therapeutic context is fundamental for treatment success in psychiatry because it may significantly increase placebo and decrease nocebo responses. Creative approach to psychopharmacotherapy reflects a creative synergism between clinical pharmacology and positive psychology of creativity in the frame of transdisciplinary holistic, integrative and person-centered psychiatry. PMID- 24048398 TI - Algorithms in psychiatry: state of the art. AB - INTRODUCTION: In literature, algorithms (guidelines) are often synonymous with problem-solving procedures. The importance of using algorithms in psychiatry can be seen in many areas. For physicians, algorithms ease clinical decision making, provide an adequate clinical basis for therapy, stimulate research, and stimulate sources of financing. For users of psychiatric services, algorithms tailor treatment to the individual, enhance the standard of care by using efficient therapeutic techniques, improve outcome, cut costs, and provide continuity of care after hospital treatment. AIM: Our goal with this paper is to present the advantages of using algorithms, but also to advise caution in their application. It is important to be aware and critical of limitations present in algorithm use. METHODS: A MEDLINE and KOBSON search was conducted combining the following key words and phrases: "treatment guidelines"; "algorithms"; "psychiatry"; "bipolar"; "depression"; "schizophrenia". RESULTS: We investigated the advantages and disadvantages of algorithms presented in the publications we found in our search. CONCLUSION: We consider algorithms to be a necessary component in the treatment of psychiatric patients, but recommend that one should maintain a critical attitude and remember that guideline proposed therapy should always be tailored to the individual. PMID- 24048399 TI - Bipolar disorder - from endophenotypes to treatment. AB - INTRODUCTION: There are a lot of unresolved issues associated with the classification, diagnosis, clinical management and understanding of the underlying pathogenic mechanisms of bipolar affective disorder. AIM: To search for discrete endophenotypes in BAD. SUBJECTS AND METHODS: We studied various bipolar I and II and recurrent depression patient samples and healthy controls using descriptive data, self and clinician-rated scales for neurological and psychopathological symptoms, neurocognitive instruments, and inventories for temperamental and characterological features. We also looked into the efficacy, tolerability and cost/benefit ratio of sodium valproate in the treatment of acute mania. RESULTS: BAD patients display deficits in the domains of memory, selective attention, working memory and psychomotor speed. Sensory, motor and complex neurological soft signs can be considered part and parcel of the symptomatology of BAD. The evidence linking hyperthymic temperament to the bipolar spectrum is not supported, while cyclothymia seems to be a marker of vulnerability to affective psychopathology. In contrast to others, we found significantly lower self-transcendence in BAD patients compared to controls. Early age of onset, abrupt onset, lability of mood and energy with late-day brightening and activation, discriminate bipolar from unipolar depression. Sodium valproate (especially if started intravenously) is a highly efficacious, cost-effective treatment approach for acute mania. CONCLUSION: The discovery of BAD endophenotypes can enhance early diagnosis, prevent errors in treatment and help elucidate the genetic vulnerability for this grave disease. PMID- 24048400 TI - The role of anti-inflammatory treatment in psychiatric disorders. AB - Anti-inflammatory treatment could be expected to show positive effects in the subgroup of psychiatric patients who show signs of inflammation, i.e. an increase in proinflammatory cytokines and PGE2. Cyclooxygenase-2 (COX-2) not only reduces the levels of proinflammatory cytokines, but also affects glutamatergic neurotransmission and tryptophan/kynurenine metabolism. In the meantime, several studies have been performed with the COX-2 inhibitor celecoxib in schizophrenia; the studies found a therapeutic effect, mainly in the early stages of the disorder. We were able to demonstrate a statistically significant therapeutic effect of celecoxib on depressive symptoms in a study in patients with major depression (MD). Another study in fifty patients with MD also showed a statistically significant better outcome with celecoxib. This paper will discuss immune-based therapeutic approaches in both schizophrenia and depression. PMID- 24048401 TI - Pharmacological modulation of HPA axis in depression - new avenues for potential therapeutic benefits. AB - One of the most consistent biological findings in major depression (MDD) is the altered activity of the hypothalamic-pituitary-adrenal (HPA) axis. It is not surprising that glucocorticoid receptor (GR), the common mechanism for stress related changes in brain function, is a potential target of antidepressant drugs and therapies. All effective antidepressant treatments should trigger and maintain GR-related cellular processes necessary for recovery from MDD. Classic antidepressants act indirectly, by affecting the dynamic interplay between serotonin neurotransmission and HPA. On the other hand, certain compounds acting at supra-hypothalamic, HPA axis, glucocorticoid receptors, and post-receptor levels are being considered as new therapeutic options with the potential to modulate the aforementioned system in affective disorders directly. Different classes of drugs pharmacologically modify the HPA axis. This article summarizes the efficacy of classic antidepressants, as well as drugs classified as "antiglucocorticoids" (GR agonists, GR antagonists, dehydroepiandrosterone- DHEA, steroid synthesis inhibitors drugs, etc) in their capacity to heal glucocorticoid mediated damage in depression. New avenues investigating the potential therapeutic benefits of antiglucocorticoids in affective disorders are at the proof-of-concept stage and future developments in this area deserve the full attention of psychiatrists and neuroscientists, as the current pharmacological treatment of MDD is far from perfect. PMID- 24048402 TI - Antipsychotics: to combine or not to combine? AB - Antipsychotic monotherapy is strongly recommended in the treatment of schizophrenia. However, antipsychotic polypharmacy (APP) is common in clinical practice, and appears to be related to illness severity and duration, treatment refractoriness, hospitalization status, duration of hospitalization, geographic region and age. Given the high number of different antipsychotic combinations reported in the literature and prescribed in clinical practice, there are perhaps more differences than similarities between such combinations. While the majority of combinations increase side-effect burden, limited evidence suggests benefits of certain combinations.Until more data are available, APP should be reserved for difficult-to treat patients, with careful consideration of pharmacodynamics properties and doses of each drug, as well as close monitoring. PMID- 24048403 TI - Creativity, mental disorders and their treatment: recovery-oriented psychopharmacotherapy. AB - This paper discusses interrelations between creativity, mental disorders and their treatment. The psychology of creativity is very important for successful psychopharmacotherapy, but our knowledge about creativity is still insufficient. Even that which is known is not within the armamentarium of most practicing psychiatrists. In the first part of this article creativity and possible associations between creativity, mental health, and well-being are described. The second part deals with the intriguing relationship between creativity and mental disorders. The third part emphasizes the role of creativity in the treatment of mental disorders. This paper ends by underlining the importance of a creativity enhancing oriented, and personal recovery-focused psychopharmacotherapy in helping psychiatric patients achieve fulfilled and purposeful lives. PMID- 24048404 TI - Psychodynamic approach as a creative factor in psychopharmacotherapy. AB - The treatment of psychiatric disorders often consists of a combined approach that integrates both pharmacotherapy and psychotherapy. Unfortunately, psychiatric texts and the educational process in psychiatry training do not adequately address the combined approach. There is a lack of information concerned with the psychological aspect of prescribing medications. This is striking since many patients require both treatments. There is an inevitable psychological aspect of the administration of medication in psychiatry, and the meaning ascribed to the prescription of drugs has an impact on doctor-patient relationship. Understanding the psychodynamic issues is crucial for the success of psychopharmacology. Psychodynamic psychopharmacotherapy represents an integration of biological psychiatry and psychodynamic insights and techniques. This approach recognizes that many of the core discoveries of psychoanalysis are powerful factors in the complex relationship between the patient, the illness, the doctor, and the medications. Scientific pharmacotherapy is, as it should be, based upon patients' responses to treatments of specific target conditions. Enduring personality traits are being increasingly incorporated as targets for pharmacotherapy. However, in the real world of psychiatric practice we see that transference issues and a patient's character or set of personality traits have a greater impact on the selection, dosage, tolerability, and treatment outcome than is generally recognized or admitted. In contemporary psychiatry, a psychodynamic perspective must be preserved. Without it, meaning will be lost, and both diagnostic understanding and informed treatment planning will suffer. PMID- 24048405 TI - Mentalization and psychopharmacotherapy in patients with personality and eating disorders. AB - Contemporary psychiatry pays more and more attention to the patient's capacity regarding acceptance of psychiatric drugs. Understanding the basis of our treatment's effectiveness becomes more challenging. To understand psychiatric treatment psychiatrists must pay full attention to mentalizing and the conditions under which this basic human capacity becomes impaired especially in those suffering from personality and eating disorders. This paper discusses the meaning and clinical applications of the mentalizing related to psychopharmacotherapy for personality and eating disorders patients, including suicidality. PMID- 24048406 TI - Psychobiological model of personality and psychopharmacotherapy outcomes in treatment of depression and schizophrenia. AB - In distinguishing why some patients respond and other do not respond to treatments arraised the clinically very important body of research considering weather patients' personality characteristics might predict outcomes of pharmacotherapeutic treatment. Personality can be a predictor of a psychiatric disorder either owing to their common genetic background or because it enhances exposure of the subject to environmental risk factors. The results of the studies using psychobiological model are reviewed. The studies show that personality temperament dimension Harm Avoidance and character dimension Self-directedness predict outcomes of the pharmacological treatment of depression, but the result for other psychiatric disorders are sparse. The studies are not straightforward in recommendations for treatment choice dependent of personality dimensions. PMID- 24048407 TI - Importance of the newer generations of antipsychotics in reducing schizophrenia hospitalization rates. AB - Throughout history, given the lack of understanding of schizophrenia and lack of effective treatment options, patients were often committed to asylums and later psychiatric institutions, often for prolonged periods of time. First antipsychotic medications helped to bring about changes in approach to these patients and facilitated deinstitutionalization, and discovery of new drugs with differing side-effects profiles introduced new options in treating schizophrenia patients. Data on hospitalization of patients in University Psychiatric Hospital Vrapce from the mid-1990s, as well as data on national level, suggests a trend of drop in hospitalization of schizophrenia patients. At the same time, that period saw significant increase in a number of available newer-generations antipsychotics and the rise in their use compared to first-generation one. Although far from being the only contributing factor, seem to play an important role in continuing the trend of reducing hospitalization rates for schizophrenia patients that started with first antipsychotics. Newer antipsychotics with a more tolerable side-effects profile promote better compliance and further reduce rate of relapse and hospitalizations. No less important is the contribution of newer antipsychotics with new receptor profiles to the personalized psychopharmacotherapy approach that is in tune with emerging conceptualizations of schizophrenia as a complex syndrome with a number of separate symptom domains, whose specific combinations produce specific individual clinical presentation and in turn ask for a specific individual approach to the patient. PMID- 24048408 TI - Obsessive versus delusional jealousy. AB - Although obsessive jealousy is a highly disturbing disorder, frequently it goes unrecognized, as most attention is paid to delusional jealousy, being the more prominent clinical phenomenon. In order to distinguish obsessive from delusional jealousy, the basic clinical characteristics of these two types of jealousy are presented, as well as the mechanism of their respective genesis, and the differences which we must be aware of in order to prevent misdiagnosis and consequent wrong treatment choices. The theoretical considerations are supported by case presentations providing a clear picture of the phenomena discussed. Unlike delusional jealousy, characterized by the presence of strong, false beliefs that the partner is unfaithful, individuals with obsessive jealousy suffer from unpleasant and irrational jealous ruminations that the partner could be unfaithful, accompanied by compulsive checking of partners' behaviour, which is recognised by the patient as ego-dystonic. This jealousy resembles obsessive compulsive phenomenology more closely. Despite the differences, both forms of jealousy result in significant distress for patients and intimate relationships, and carry the risk of abuse, homicide and/or suicide. Delusional jealousy is a psychotic disorder and should be treated mainly with antipsychotics, while obsessive jealousy resembles obsessive-compulsive disorder and should be treated with SSRIs and cognitive-behavioural therapy. Regardless of the presence or absence of insight into the disorder, one of the key factors in the treatment of pathological jealousy is to motivate the sufferers for pharmacological and psychotherapeutic interventions. PMID- 24048409 TI - Computer-aided psychotherapy based on multimodal elicitation, estimation and regulation of emotion. AB - Contemporary psychiatry is looking at affective sciences to understand human behavior, cognition and the mind in health and disease. Since it has been recognized that emotions have a pivotal role for the human mind, an ever increasing number of laboratories and research centers are interested in affective sciences, affective neuroscience, affective psychology and affective psychopathology. Therefore, this paper presents multidisciplinary research results of Laboratory for Interactive Simulation System at Faculty of Electrical Engineering and Computing, University of Zagreb in the stress resilience. Patient's distortion in emotional processing of multimodal input stimuli is predominantly consequence of his/her cognitive deficit which is result of their individual mental health disorders. These emotional distortions in patient's multimodal physiological, facial, acoustic, and linguistic features related to presented stimulation can be used as indicator of patient's mental illness. Real time processing and analysis of patient's multimodal response related to annotated input stimuli is based on appropriate machine learning methods from computer science. Comprehensive longitudinal multimodal analysis of patient's emotion, mood, feelings, attention, motivation, decision-making, and working memory in synchronization with multimodal stimuli provides extremely valuable big database for data mining, machine learning and machine reasoning. Presented multimedia stimuli sequence includes personalized images, movies and sounds, as well as semantically congruent narratives. Simultaneously, with stimuli presentation patient provides subjective emotional ratings of presented stimuli in terms of subjective units of discomfort/distress, discrete emotions, or valence and arousal. These subjective emotional ratings of input stimuli and corresponding physiological, speech, and facial output features provides enough information for evaluation of patient's cognitive appraisal deficit. Aggregated real-time visualization of this information provides valuable assistance in patient mental state diagnostics enabling therapist deeper and broader insights into dynamics and progress of the psychotherapy. PMID- 24048410 TI - A review of PET normalization: striving for count rate uniformity. AB - The advent of PET instrumentation signaled the beginning of a new perspective in nuclear medicine diagnostic imaging. PET systems rely on several corrections that must be applied in order to establish accurate and reliable quantification. The inherent properties of PET detector architecture and the crystals themselves are sources of different types of systematic and random errors with subsequent count rate variability that should be accounted for. Normalization is the correction dealing with these errors. In this work, the reasons resulting in this variability are explored and the different normalization approaches are described. Special focus is paid to component-based normalization, with an attempt to describe the discrete factors and discuss the underlying mechanisms of their contribution to sensitivity variations of the lines of response. PMID- 24048411 TI - Diagnostic value of cone-beam CT in histologically confirmed otosclerosis. AB - This retrospective case review was performed with the aim to asses the value of cone-beam computed tomography (CBCT) in the preoperative diagnosis of otosclerosis. A total of 32 patients with histologically confirmed stapedial otosclerosis, who underwent unilateral stapedectomies were analyzed. Preoperative temporal bone CBCT scans were performed in all cases. CBCT imaging was characterized by a slice thickness of 0.3 mm and multiplanar image reconstruction. Histopathologic examination of the removed stapes footplates was performed in all cases. Findings of CBCT were categorized according to Marshall's grading system (from grade 0 to grade 3). Histopathologic results were correlated to multiplanar reconstructed CBCT scans, respectively. Histologically active foci of otosclerosis (n = 21) were identified by CBCT in all cases with a sensitivity of 100 %. However, CBCT was unable to detect histologically inactive otosclerosis (n = 11, sensitivity = 0 %). According to CBCT scans, no retrofenestral lesions were found and all positive cases were recruited into the grade 1 group indicating solely fenestral lesions at the anterior pole of stapes footplates. In conclusion, CBCT is a reliable imaging method with considerably lower radiation dose than high-resolution CT (HRCT) in the preoperative diagnosis of otosclerosis. These results indicate that CBCT has high sensitivity and specificity in the detection of hypodense lesions due to histologically active otosclerosis. PMID- 24048412 TI - Anti-LRP/LR specific antibodies and shRNAs impede amyloid beta shedding in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most prevalent form of dementia. The amyloid beta (Abeta) peptide is the predominant candidate aetiological agent and is generated through the sequential proteolytic cleavage of the Amyloid Precursor Protein (APP) by beta (beta) and gamma (gamma) secretases. Since the cellular prion protein (PrP(c)) has been shown to regulate Abeta shedding, we investigated whether the cellular receptor for PrP(c), namely the 37 kDa/67 kDa Laminin Receptor (LRP/LR) played a role in Abeta shedding. Here we show that LRP/LR co localises with the AD relevant proteins APP, beta- and gamma-secretase, respectively. Antibody blockage and shRNA knock-down of LRP/LR reduces Abeta shedding, due to impediment of beta-secretase activity, rather than alteration of APP, beta- and gamma-secretase levels. These findings indicate that LRP/LR contributes to Abeta shedding and recommend anti-LRP/LR specific antibodies and shRNAs as novel therapeutic tools for AD treatment. PMID- 24048413 TI - Partial deletion of the alphaC-domain in the Fibrinogen Perth variant is associated with thrombosis, increased clot strength and delayed fibrinolysis. AB - Genetic fibrinogen (FGN) variants that are associated with bleeding or thrombosis may be informative about fibrin polymerisation, structure and fibrinolysis. We report a four generation family with thrombosis and heritable dysfibrinogenaemia segregating with a c.[1541delC];[=] variation in FGA (FGN-Perth). This deletion predicts a truncated FGN alphaC-domain with an unpaired terminal Cys at residue 517 of FGN-Aalpha. In keeping with this, SDS-PAGE of purified FGN-Perth identified a truncated FGN-Aalpha chain with increased co-purification of albumin, consistent with disulphide bonding to the terminal Cys of the variant FGN-Aalpha. Clot visco-elastic strength in whole blood containing FGN-Perth was greater than controls and tPA-mediated fibrinolysis was delayed. In FGN-Perth plasma and in purified FGN-Perth, there was markedly reduced final turbidity after thrombin-mediated clot generation. Consistent with this, FGN-Perth formed tighter, thinner fibrin fibres than controls indicating defective lateral aggregation of protofibrils. Clots generated with thrombin in FGN-Perth plasma were resistant to tPA-mediated fibrinolysis. FGN-Perth clot also displayed impaired tPA-mediated plasmin generation but incorporated alpha2-antiplasmin at a similar rate to control. Impaired fibrinolysis because of defective plasmin generation potentially explains the FGN-Perth clinical phenotype. These findings highlight the importance of the FGN alphaC-domain in the regulation of clot formation and fibrinolysis. PMID- 24048414 TI - Open letter: draft regulation on endocrine-active chemicals. PMID- 24048415 TI - Recurrent JAK1 and JAK3 somatic mutations in T-cell prolymphocytic leukemia. PMID- 24048417 TI - Multidisciplinary management of focal nodular hyperplasia in children: experience with 10 cases. AB - Nonoperative management of focal nodular hyperplasia (FNH) is an accepted paradigm in adults, but current management strategies for children vary substantially between institutions. We reviewed medical records at Johns Hopkins Hospital between January 1, 1998, and December 31, 2008, to investigate the diagnosis, treatment, and outcome of pediatric patients with a pathologic diagnosis of FNH to provide additional data to help formulate management guidelines for this disease. Ten pediatric patients were identified as having a pathologic diagnosis of FNH, either by biopsy sample (n = 5) or hepatic resection (n = 5). The mean age of the patients was 12.1 years, and most were female (n = 7). Mean tumor size was 5.7 cm (range, 0.8-13 cm). Four of 5 patients whose FNH was diagnosed by biopsy alone developed no sequelae, and 1 patient eventually required surgery for mass effect. Patients with either large lesions (>=5 cm) or symptoms were referred for resection. Observational management of small lesions that can be confidently diagnosed as FNH appears to be safe and appropriate. Surgical resection should be reserved for large or symptomatic lesions amenable to resection. PMID- 24048416 TI - Molecular monitoring in NUP214-ABL-positive T-acute lymphoblastic leukemia reveals clonal diversity and helps to guide targeted therapy. PMID- 24048418 TI - A computational approach to chemical etiologies of diabetes. AB - Computational meta-analysis can link environmental chemicals to genes and proteins involved in human diseases, thereby elucidating possible etiologies and pathogeneses of non-communicable diseases. We used an integrated computational systems biology approach to examine possible pathogenetic linkages in type 2 diabetes (T2D) through genome-wide associations, disease similarities, and published empirical evidence. Ten environmental chemicals were found to be potentially linked to T2D, the highest scores were observed for arsenic, 2,3,7,8 tetrachlorodibenzo-p-dioxin, hexachlorobenzene, and perfluorooctanoic acid. For these substances we integrated disease and pathway annotations on top of protein interactions to reveal possible pathogenetic pathways that deserve empirical testing. The approach is general and can address other public health concerns in addition to identifying diabetogenic chemicals, and offers thus promising guidance for future research in regard to the etiology and pathogenesis of complex diseases. PMID- 24048420 TI - [Neuro intensive care]. PMID- 24048419 TI - The MRI contrast agent gadoteridol enhances distribution of rAAV1 in the rat hippocampus. AB - Contrast agents are commonly used in combination with magnetic resonance imaging (MRI) to monitor the distribution of molecules in the brain. Recent experiments conducted in our laboratory have shown that co-infusion of recombinant Adeno associated virus serotype 5 (rAAV5) and the MRI contrast agent gadoteridol (Gd) enhances vector transduction in the rat striatum. The goal of this study was to determine whether gadoteridol may also be used as a tool to enhance transduction efficiency of rAAV1 and rAAV5 within the rat hippocampus. We show that Gd/rAAV1 GFP but not Gd/rAAV5-GFP co-infusion results in significantly higher distribution of the transgene both in the injected hemisphere as well as in the contralateral side and adjacent areas of cortex along the injection track. We also show that Gd/rAAV1-GFP co-infusion has no deleterious effect on hippocampal function as assessed by two tests of spatial memory formation. This work indicates that Gd can be exploited as a method to increase transduction efficiency of AAV1 in the hippocampus for animal studies. PMID- 24048423 TI - Shared neural mechanisms underlying social warmth and physical warmth. AB - Many of people's closest bonds grow out of socially warm exchanges and the warm feelings associated with being socially connected. Indeed, the neurobiological mechanisms underlying thermoregulation may be shared by those that regulate social warmth, the experience of feeling connected to other people. To test this possibility, we placed participants in a functional MRI scanner and asked them to (a) read socially warm and neutral messages from friends and family and (b) hold warm and neutral-temperature objects (a warm pack and a ball, respectively). Findings showed an overlap between physical and social warmth: Participants felt warmer after reading the positive (compared with neutral) messages and more connected after holding the warm pack (compared with the ball). In addition, neural activity during social warmth overlapped with neural activity during physical warmth in the ventral striatum and middle insula, but neural activity did not overlap during another pleasant task (soft touch). Together, these results suggest that a common neural mechanism underlies physical and social warmth. PMID- 24048426 TI - Better living through chemistry. PMID- 24048425 TI - The role of Fcgamma receptor polymorphisms in the response to anti-tumor necrosis factor therapy in psoriasis A pharmacogenetic study. AB - IMPORTANCE: Variability in genes encoding proteins involved in the immunological pathways of biological therapy may account for the differences observed in outcomes of anti-tumor necrosis factor (TNF) treatment of psoriasis. OBJECTIVE: To assess the role of 2 Fcgamma receptor (FcgammaR) polymorphisms in the response to anti-TNF therapy in psoriasis. DESIGN: Retrospective series of patients with psoriasis who received anti-TNF therapy(infliximab, adalimumab, or etanercept) from January 1, 2007, through December 31, 2010. Patients were followed up for 12 weeks. SETTING: Two psoriasis referral centers. PARTICIPANTS: Seventy treatment naive patients with moderate to severe psoriasis who received anti-TNF agents. INTERVENTION: Patients underwent FcgammaRIIA-H131R and FcgammaRIIIA-V158F polymorphism genotyping. MAIN OUTCOMES AND MEASURES: The Psoriasis Area and Severity Index and the body surface area were assessed at baseline and at treatment weeks 6 to 8 and 12. The polymorphism genotypes were correlated with the treatment outcomes. RESULTS: Bivariate analysis showed a nonsignificant association between FcgammaR low-affinity genotypes and greater improvement in the Psoriasis Area and Severity Index and body surface area at the end of treatment. Conversely, patients harboring high-affinity alleles presented a greater reduction in body surface area at the intermediate point, which remained independent in the multivariate analysis. We also detected an additive effect of both polymorphisms in the multivariate analysis. High-affinity alleles may contribute to a quicker response owing to a more efficient removal of relevant cells expressing TNF. CONCLUSIONS AND RELEVANCE: Preliminary results of this pilot study on the pharmacogenetics of FcgammaR and biological therapy in psoriasis suggest a role with clinical implications for FcgammaRIIA-H131R and FcgammaRIIIA-V158F polymorphisms in the outcome of anti-TNF treatment of psoriasis. These results might help dermatologists in guiding therapeutic decisions, especially in very severe cases where a quick response is needed. PMID- 24048427 TI - Presidential practice of dermatology. PMID- 24048428 TI - Hippocrates on ulcers. PMID- 24048429 TI - Abigail Adams, smallpox, and the spirit of 1776. PMID- 24048430 TI - Euphorbia peplus: 18th-century insights on a 21st-century therapy. PMID- 24048431 TI - A variant of AESOP syndrome (adenopathy and extensive skin patch overlying a plasmacytoma). PMID- 24048432 TI - A variant of AESOP syndrome (adenopathy and extensive skin patch overlying a plasmacytoma)--reply. PMID- 24048433 TI - Aetius's reports on genital warts. PMID- 24048434 TI - Morphea (localized scleroderma). PMID- 24048435 TI - Two-step electrodeposition construction of flower-on-sheet hierarchical cobalt hydroxide nano-forest for high-capacitance supercapacitors. AB - A novel flower-on-sheet hierarchical morphology of alpha-Co(OH)2 nanostructures was achieved via an easy two-step synthesis strategy. The method is based on first a galvanostatic electrodeposition (GE) of vertically aligned interconnected Co(OH)2 nanosheets to form a branch layer and second a potentiostatic electrodeposition (PE) of Co(OH)2 microflowers on the obtained branch layer from the secondary growth of their sheet-like precursors. The formation mechanism of this special PE time-dependent nanostructure was proposed and their morphology dependent supercapacitor properties were also investigated. For a given areas mass loading, high specific capacitances of 1822 F g(-1) have been achieved for the electrode obtained after 200 s GE followed by a 300 s PE in a three-electrode configuration, and it maintained 91% of its initial capacity after 1000 constant current charge/discharge cycles. Even when the discharge current density was increased from 1 to 50 mA cm(-2), the capacitance was still as high as 1499 F g( 1), indicating an excellent rate performance of the fabricated electrodes. The high performances of the electrodes are attributed to the special porous structure, 3D hierarchical morphology, vertical aligned orientation, and low contact resistance between active material and charge collector. PMID- 24048437 TI - Age, body mass, usage of exogenous estrogen, and lifestyle factors in relation to circulating sex hormone-binding globulin concentrations in postmenopausal women. AB - BACKGROUND: Circulating concentrations of sex hormone-binding globulin (SHBG) have been associated with cardiovascular diseases, type 2 diabetes, metabolic syndrome, and hormone-dependent cancers; however, correlates of SHBG concentrations are not well understood. METHODS: We comprehensively investigated correlates of SHBG concentrations among 13 547 women who participated in the Women's Health Initiative and who had SHBG measurements. We estimated study- and ethnicity-specific associations of age, reproductive history, usage of exogenous estrogen, body mass index (BMI), and lifestyle factors such as physical activity, smoking, alcohol consumption, coffee intake, and dietary factors with SHBG concentrations. These estimates were pooled using random-effects models. We also examined potential nonlinear associations using spline analyses. RESULTS: There was no significant ethnic difference in the age-adjusted mean concentrations of SHBG. Age, exogenous estrogen use, physical activity, and regular coffee intake were positively associated with SHBG concentrations, whereas BMI was inversely associated with SHBG concentrations after adjustment for potential confounding factors. Similar patterns were observed among both ever users and never users of exogenous estrogen. The spline analysis indicated nonlinear relations of regular intake of coffee, age, and BMI with SHBG concentrations. Two or more cups/day of regular coffee consumption and age of 60 years or older were associated with higher SHBG concentrations; the inverse BMI-SHBG relation was especially strong among women whose BMI was below 30. CONCLUSIONS: In this large sample of postmenopausal women, age, exogenous estrogen use, physical activity, regular coffee intake, and BMI were significant correlates of SHBG concentrations, presenting potential targets for interventions. PMID- 24048438 TI - Cobalt-catalyzed transfer hydrogenation of C=O and C=N bonds. AB - An earth-abundant metal cobalt catalyst has been developed for the transfer hydrogenation of ketones, aldehydes, and imines under mild conditions. Experiments are described which provide insights into the mechanism of the transfer hydrogenation reaction. PMID- 24048436 TI - Draft genome sequence of the mulberry tree Morus notabilis. AB - Human utilization of the mulberry-silkworm interaction started at least 5,000 years ago and greatly influenced world history through the Silk Road. Complementing the silkworm genome sequence, here we describe the genome of a mulberry species Morus notabilis. In the 330-Mb genome assembly, we identify 128 Mb of repetitive sequences and 29,338 genes, 60.8% of which are supported by transcriptome sequencing. Mulberry gene sequences appear to evolve ~3 times faster than other Rosales, perhaps facilitating the species' spread worldwide. The mulberry tree is among a few eudicots but several Rosales that have not preserved genome duplications in more than 100 million years; however, a neopolyploid series found in the mulberry tree and several others suggest that new duplications may confer benefits. Five predicted mulberry miRNAs are found in the haemolymph and silk glands of the silkworm, suggesting interactions at molecular levels in the plant-herbivore relationship. The identification and analyses of mulberry genes involved in diversifying selection, resistance and protease inhibitor expressed in the laticifers will accelerate the improvement of mulberry plants. PMID- 24048439 TI - Terfenadine induces anti-proliferative and apoptotic activities in human hormone refractory prostate cancer through histamine receptor-independent Mcl-1 cleavage and Bak up-regulation. AB - Although the results of several studies have underscored the regulatory effect of H1-histamine receptors in cell proliferation of some cancer cell types, its effect in prostate cancers remains unclear. We have therefore studied the effect of terfenadine (an H1-histamine receptor antagonist) in prostate cancer cell lines. Our data demonstrate that terfenadine was effective against PC-3 and DU 145 cells (two prostate cancer cell lines). In contrast, based on the sulforhodamine B assay, loratadine had less potency while fexofenadine and diphenhydramine had little effect. Terfenadine induced the cleavage of Mcl-1 cleavage into a pro-apoptotic 28-kDa fragment and up-regulation of Bak, resulting in the loss of mitochondrial membrane potential (DeltaPsim) and the release of cytochrome c and apoptosis-inducing factor into the cytosol. The activation of caspase cascades was detected to be linked to terfenadine action. Bak up regulation was also examined at both the transcriptional and translational levels, and Bak activation was validated based on conformational change to expose the N terminus. Terfenadine also induced an indirect-but not direct-DNA damage response through the cleavage and activation of caspase-2, phosphorylation and activation of Chk1 and Chk2 kinases, phosphorylation of RPA32 and acetylation of Histone H3; these processes were highly correlated to severe mitochondrial dysfunction and the activation of caspase cascades. In conclusion, terfenadine induced apoptotic signaling cascades against HRPCs in a sequential manner. The exposure of cells to terfenadine caused the up-regulation and activation of Bak and the cleavage of Mcl-1, leading to the loss of DeltaPsim and activation of caspase cascades which further resulted in DNA damage response and cell apoptosis. PMID- 24048440 TI - Sulforaphane decreases kidney injury after transplantation in rats: role of mitochondrial damage. AB - BACKGROUND: Sulforaphane is a naturally occuring antioxidative and anti inflammatory isothiocyanat. In this study, its impact on experimental kidney transplantation was evaluated. MATERIAL AND METHODS: Male Brown Norway rats (n=112) were used as experimental animals. Donor kidneys were harvested and stored for 12 hours in HTK-solution at 4 degrees C. D,L-Sulforaphane (4.4 mg/kg BW; 0.2ml) or normal saline (0.2 ml) was given i.v. to the recipients 24 and 1 hour before, and 6 hours after transplantation. Recipients were nephrectomized bilaterally and subsequently transplantation was performed. After 6 and 48 hours, biopsies were taken and processed for light and electron microscopy. Graft function was monitored using serum values of creatinine and BUN after 6 and 24 hours. Quantitative real-time PCR was used to detect differences in SOD2-gene expression after 6 hours and apoptotic activity was detected after 6 hours using propidium iodide flow cytometry. RESULTS: Recipient preconditioning improved reperfusion damage index from 12.8+/-1.6 in controls to 8.8+/-1.8 (p<0.001). Serum levels of creatinine and BUN decreased from 4.29+/-0.25 mg/dl and 119+/-23 mg/dl in controls to 3.65+/-0.7 mg/dl and 81+/-19 mg/dl (p<0.05). The number of severely injured tubules decreased (p<0.05). Apoptotic activity was increased in SFN-treated rats. Mitochondrial microstructure was better preserved after SFN, while SOD 2 gene expression increased (p<0.05). CONCLUSIONS: SFN ameliorates ischemia/reperfusion injury after KTx, most likely through anti-oxidative effects. PMID- 24048441 TI - Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy. AB - The tumor microenvironment can promote tumor growth and reduce treatment efficacy. Tumors can occur in many sites in the body, but how surrounding normal tissues at different anatomical sites affect tumor microenvironments and their subsequent response to therapy is not known.We demonstrated that tumors from renal, colon, or prostate cell lines in orthotopic locations responded to immunotherapy consisting of three agonist antibodies, termed Tri-mAb, to a much lesser extent than the same tumor type located subcutaneously. A tissue-specific response to Tri-mAb was confirmed by ex vivo separation of subcutaneous (SC) or orthotopic tumor cells from stromal cells, followed by reinjection of tumor cells into the opposite site. Compared with SC tumors, orthotopic tumors had a microenvironment associated with a type 2 immune response, related to immunosuppression, and an involvement of alternatively activated macrophages in the kidney model. Orthotopic kidney tumors were more highly vascularized than SC tumors. Neutralizing the macrophage- and Th2-associated molecules chemokine (C-C motif) ligand 2 or interleukin-13 led to a significantly improved therapeutic effect. This study highlights the importance of the tissue of implantation in sculpting the tumor microenvironment. These are important fundamental issues in tumor biology and crucial factors to consider in the design of experimental models and treatment strategies. PMID- 24048443 TI - The VA advantage for appropriate TAVR use. PMID- 24048442 TI - Oncolytic virotherapy and immunogenic cancer cell death: sharpening the sword for improved cancer treatment strategies. AB - Oncolytic viruses are novel immunotherapeutics with increasingly promising outcomes in cancer patient clinical trials. Preclinical and clinical studies have uncovered the importance of virus-induced activation of antitumor immune responses for optimal therapeutic efficacy. Recently, several classes of chemotherapeutics have been shown to cause immunogenic cancer cell death characterized by the release of immunomodulatory molecules that activate antigen presenting cells and thus trigger the induction of more potent anticancer adaptive immune responses. In preclinical models, several oncolytic viruses induce immunogenic cell death, which is associated with increased cross-priming of tumor-associated antigens. In this review, we discuss the recent advances in immunogenic cancer cell death as induced by chemotherapeutic treatments, including the roles of relevant danger-associated molecular patterns and signaling pathways, and highlighting the significance of the endoplasmic reticulum (ER) stress response. As virtually all viruses modulate both ER stress and cell death responses, we provide perspectives on future research directions that can be explored to optimize oncolytic viruses, alone or in combination with targeted drug therapies, as potent immunogenic cancer cell death-inducing agents. We propose that such optimized virus-drug synergistic strategies will improve the therapeutic outcomes for many currently intractable cancers. PMID- 24048444 TI - [What must intensive care physicians know about implantable cardioverter defibrillator?]. AB - The first implantable cardioverter defibrillator (ICD) was implanted in the USA in 1980. After the publication of the landmark studies MADIT I and AVID (primary prevention in high risk patients and secondary prevention after sudden cardiac death) implantation rates dramatically increased worldwide. Due to the increasing number of implantations in elderly patients, intensive care units and emergency departments are confronted more often with patients with ICDs. Therefore, intensive care practitioners have to be familiar with these devices. This article summarizes the current literature and focuses on the management of emergencies and malfunction of ICDs. PMID- 24048446 TI - Tuning ligand electronics and peripheral substitution on cobalt salen complexes: structure and polymerisation activity. AB - A series of cobalt salen complexes, where salen represents an N2O2 bis-Schiff base bis-phenolate framework, are prepared, characterised and investigated for reversible-termination organometallic mediated radical polymerisation (RT-OMRP). The salen ligands contain a cyclohexane diimine bridge and systematically altered para-substituted phenoxide moieties as a method to examine the electronic impact of the ligand on complex structure and reactivity. The complexes are characterised by single crystal X-ray diffraction, cyclic voltammetry, X-ray photoelectron spectroscopy, electron paramagnetic resonance spectroscopy and computational methods. Structural studies all support a tailorable metal centre reactivity altered by the electron-donating ability of the salen ligand. RT-OMRP of styrene, methyl methacrylate and vinyl acetate is reported and suggests that cobalt-carbon bond strength varies with the ligand substitution. Competing beta hydrogen abstraction affords long-chain olefin-terminated polymer chains and well controlled vinyl acetate polymerisations, contrasting with the lower temperature associative exchange mechanism of degenerative transfer OMRP. PMID- 24048445 TI - Non-continuous versus continuous wound drainage after total knee arthroplasty: a meta-analysis. AB - PURPOSE: So far, controversy still exists regarding the use of non-continuous or continuous wound drainage after total knee arthroplasty. The aim of this study was to assess the efficacy and safety of these two drainage techniques after total knee arthroplasty. METHODS: We searched the established electronic literature databases of Pubmed, Embase, Cochrane Library, CNKI, VIP and WANFANG. Nine RCTs including a total of 761 patients involving 811 knees were eligible for this meta-analysis. RESULTS: Our results showed that non-continuous drainage was associated with less haemoglobin loss (WMD, -0.43, 95 % CI -0.62 to -0.24; P < 0.00001) and postoperative visible blood loss (WMD, -305.09, 95% CI -408.10 to 202.08; P < 0.00001) compared with continuous drainage. No significant difference was found between the two groups in terms of range of motion (WMD, 0.99, 95% CI 1.01 to 2.98; P = 0.33), incidence of blood transfusion (OR, 0.63, 95% CI 0.38 to 1.06; P = 0.80) or postoperative complications (OR, 1.09, 95% CI 0.35 to 3.40; P = 0.89). CONCLUSION: The existing evidence indicates that non-continuous drainage can achieve less haemoglobin loss (especially the four- to six-hour drain clamping) and postoperative visible blood loss with no increased risk of postoperative complications compared with continuous drainage. PMID- 24048447 TI - Origin of new broad Raman D and G peaks in annealed graphene. AB - Since graphene, a single sheet of graphite, has all of its carbon atoms on the surface, its property is very sensitive to materials contacting the surface. Herein, we report novel Raman peaks observed in annealed graphene and elucidate their chemical origins by Raman spectroscopy and atomic force microscopy (AFM). Graphene annealed in oxygen-free atmosphere revealed very broad additional Raman peaks overlapping the D, G and 2D peaks of graphene itself. Based on the topographic confirmation by AFM, the new Raman peaks were attributed to amorphous carbon formed on the surface of graphene by carbonization of environmental hydrocarbons. While the carbonaceous layers were formed for a wide range of annealing temperature and time, they could be effectively removed by prolonged annealing in vacuum. This study underlines that spectral features of graphene and presumably other 2-dimensional materials are highly vulnerable to interference by foreign materials of molecular thickness. PMID- 24048448 TI - Can Google Trends search queries contribute to risk diversification? AB - Portfolio diversification and active risk management are essential parts of financial analysis which became even more crucial (and questioned) during and after the years of the Global Financial Crisis. We propose a novel approach to portfolio diversification using the information of searched items on Google Trends. The diversification is based on an idea that popularity of a stock measured by search queries is correlated with the stock riskiness. We penalize the popular stocks by assigning them lower portfolio weights and we bring forward the less popular, or peripheral, stocks to decrease the total riskiness of the portfolio. Our results indicate that such strategy dominates both the benchmark index and the uniformly weighted portfolio both in-sample and out-of-sample. PMID- 24048449 TI - Oxysterol-binding protein (OSBP) is required for the perinuclear localization of intra-Golgi v-SNAREs. AB - Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) have been implicated in the distribution of sterols among intracellular organelles. OSBP regulates the Golgi cholesterol level, but how it relates to Golgi function is elusive. Here we report that OSBP is essential for the localization of intra Golgi soluble vesicle N-ethylmaleimide-sensitive fusion attachment protein receptors (v-SNAREs). Depletion of OSBP by small interfering RNA causes mislocalization of intra-Golgi v-SNAREs GS28 and GS15 throughout the cytoplasm without affecting the perinuclear localization of Golgi target-SNARE syntaxin5 and reduces the abundance of a Golgi enzyme, mannosidase II (Man II). GS28 mislocalization and Man II reduction are also induced by cellular cholesterol depletion. Three domains of OSBP-an endoplasmic reticulum-targeting domain, a Golgi-targeting domain, and a sterol-binding domain-are all required for Golgi localization of GS28. Finally, GS28 mislocalization and Man II reduction in OSBP depleted cells are largely restored by depletion of ArfGAP1, a regulator of the budding of coat protein complex (COP)-I vesicles. From these results, we postulate that Golgi cholesterol level, which is controlled by OSBP, is essential for Golgi localization of intra-Golgi v-SNAREs by ensuring proper COP-I vesicle transport. PMID- 24048450 TI - The C-terminal domain of Brd2 is important for chromatin interaction and regulation of transcription and alternative splicing. AB - Brd2 is a member of the bromodomain extra terminal (BET) protein family, which consists of four chromatin-interacting proteins that regulate gene expression. Each BET protein contains two N-terminal bromodomains, which recognize acetylated histones, and the C-terminal protein-protein interaction domain. Using a genome wide screen, we identify 1450 genes whose transcription is regulated by Brd2. In addition, almost 290 genes change their alternative splicing pattern upon Brd2 depletion. Brd2 is specifically localized at promoters of target genes, and our data show that Brd2 interaction with chromatin cannot be explained solely by histone acetylation. Using coimmunoprecipitation and live-cell imaging, we show that the C-terminal part is crucial for Brd2 association with chromatin. Live cell microscopy also allows us to map the average binding time of Brd2 to chromatin and quantify the contributions of individual Brd2 domains to the interaction with chromatin. Finally, we show that bromodomains and the C-terminal domain are equally important for transcription and splicing regulation, which correlates with the role of these domains in Brd2 binding to chromatin. PMID- 24048451 TI - SENP1 and SENP2 affect spatial and temporal control of sumoylation in mitosis. AB - Sumoylation of centromere, kinetochore, and other mitotic chromosome-associated proteins is essential for chromosome segregation. The mechanisms regulating spatial and temporal sumoylation of proteins in mitosis, however, are not well understood. Here we show that the small ubiquitin-related modifier (SUMO) specific isopeptidases SENP1 and SENP2 are targeted to kinetochores in mitosis. SENP2 targeting occurs through a mechanism dependent on the Nup107-160 subcomplex of the nuclear pore complex and is modulated through interactions with karyopherin alpha. Overexpression of SENP2, but not other SUMO-specific isopeptidases, causes a defect in chromosome congression that depends on its precise kinetochore targeting. By altering SENP1 kinetochore associations, however, this effect on chromosome congression could be phenocopied. In contrast, RNA interference-mediated knockdown of SENP1 delays sister chromatid separation at metaphase, whereas SENP2 knockdown produces no detectable phenotypes. Our findings indicate that chromosome segregation depends on precise spatial and temporal control of sumoylation in mitosis and that SENP1 and SENP2 are important mediators of this control. PMID- 24048453 TI - Cell-free plasma microRNA in pancreatic ductal adenocarcinoma and disease controls. AB - OBJECTIVES: There are no tumor-specific biochemical markers for pancreatic ductal adenocarcinoma (PDAC). Tissue-specific gene expression including microRNA (miRNA) profiling, however, identifies specific PDAC signatures. This study evaluates associations between circulating, cell-free plasma-miRNA profiles and PDAC in a disease and disease-control cohort. METHODS: We performed a microarray profiling of 847 different mature miRNAs from plasma in an exploratory cohort of 20 patients with PDAC or other pancreatic diseases, profiling of 45 miRNAs in plasma samples from PDAC (n = 48) and disease controls (n = 47), and evaluation of associations of data with diagnosis, survival, and CA-19-9. RESULTS: We find 7 significantly deregulated miRNAs in PDAC using univariate statistics. At a false discovery rate of 5%, miRNA-375 remained significantly elevated in PDAC. MicroRNA 375 did not improve diagnosis of PDAC in this cohort (70% accuracy) and did not correlate with survival. However, 3 controls (other gastrointestinal cancers) with increased CA-19-9 did not show increased miRNA-375. CONCLUSIONS: In the plasma-miRNA population, we find miRNA-375, which is selectively expressed in the endocrine pancreas under normal conditions, increased in PDAC cases compared with patients with other pancreatic or gastrointestinal diseases. The miRNA-375 does not outperform CA-19-9 diagnostically in the present cohort. However, it shows promising specificity and should be examined in larger prospective studies. PMID- 24048452 TI - Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition. AB - Directional cell movement is universally required for tissue morphogenesis. Although it is known that cell/matrix interactions are essential for directional movement in heart development, the mechanisms governing these interactions require elucidation. Here we demonstrate that a novel protein/protein interaction between blood vessel epicardial substance (Bves) and N-myc downstream regulated gene 4 (NDRG4) is critical for regulation of epicardial cell directional movement, as disruption of this interaction randomizes migratory patterns. Our studies show that Bves/NDRG4 interaction is required for trafficking of internalized fibronectin through the "autocrine extracellular matrix (ECM) deposition" fibronectin recycling pathway. Of importance, we demonstrate that Bves/NDRG4-mediated fibronectin recycling is indeed essential for epicardial cell directional movement, thus linking these two cell processes. Finally, total internal reflectance fluorescence microscopy shows that Bves/NDRG4 interaction is required for fusion of recycling endosomes with the basal cell surface, providing a molecular mechanism of motility substrate delivery that regulates cell directional movement. This is the first evidence of a molecular function for Bves and NDRG4 proteins within broader subcellular trafficking paradigms. These data identify novel regulators of a critical vesicle-docking step required for autocrine ECM deposition and explain how Bves facilitates cell-microenvironment interactions in the regulation of epicardial cell-directed movement. PMID- 24048454 TI - Cisplatin-modified de Gramont in second-line therapy for pancreatic adenocarcinoma. AB - OBJECTIVES: In Belgium, combination chemotherapy of cisplatin and 5-fluorouracil + leucovorin (CFL) according to the modified de Gramont schedule is the treatment of choice in second line for metastatic pancreatic cancer. We retrospectively analyzed survival data in 2 Belgian centers in a nonselected population. METHODS: Between January 2004 and October 2011, 48 patients with histologically proven recurrent or unresectable pancreatic adenocarcinoma who had received CFL as second-line treatment were identified. We retrospectively analyzed the following parameters: progression-free survival (PFS1 and PFS2) for each line (after the start of first and second line), overall survival (OS), and growth modulation index. RESULTS: The median PFS1 was 5.4 months (95% confidence interval [CI], 4.1 6.6). The median PFS2 was 3.6 months (95% CI, 2-5.2). The median OS was 12 months (95% CI, 9.3-14.7). Twenty-three percent of patients had a growth modulation index >1.33. CONCLUSION: We show an OS of 12 months with gemcitabine in first line and CFL in second-line therapy for pancreatic cancer. Sequential therapy with good OS and good quality of life may be preferred to strong upfront therapy in an incurable disease such as pancreatic cancer. PMID- 24048455 TI - Infected pancreatic necrosis increases the severity of experimental necrotizing pancreatitis in mice. AB - OBJECTIVE: Infection of pancreatic necrosis in necrotizing pancreatitis increases the lethality of patients with acute pancreatitis. To examine mechanisms underlying this clinical observation, we developed and tested a model, in which primary infection of necrosis is achieved in taurocholate-induced pancreatitis in mice. METHODS: Sterile necrosis of acute necrotizing pancreatitis was induced by retrograde injection of 4% taurocholate into the common bile duct of Balb/c mice. Primary infection of pancreatic necrosis was induced by coinjecting 10 colony forming units of Escherichia coli. Animals were killed after 6, 12, 24, 48, and 120 hours, and pancreatic damage and pancreatitis-associated systemic inflammatory response were assessed. RESULTS: Mice with pancreatic acinar cell necrosis had an increased bacterial concentration in all tissues and showed sustained bacteremia. Acute pancreatitis was induced only by coinjection of taurocholate and not by bacterial infection alone. Infection of pancreatic necrosis increased pancreatic damage and the pulmonary vascular leak. Serum glucose concentrations serving as a parameter of hepatic function were reduced in mice with infected pancreatic necrosis. CONCLUSIONS: Primary infection of pancreatic necrosis with E. coli increases both pancreatic damage and pulmonary and hepatic complications in acute necrotizing pancreatitis in mice. PMID- 24048456 TI - Aberrant expression miR-196a is associated with abnormal apoptosis, invasion, and proliferation of pancreatic cancer cells. AB - OBJECTIVES: MiR-196a levels inversely correlated with survival in pancreatic adenocarcinoma patients. However, the functional contributions of miR-196a to pancreatic cancer remain unclear. METHODS: Three lentiviral vectors encoding microRNA miR-196a precursor, inhibitor, and scrambled microRNA oligomer were transfected into Panc-1 cells, respectively. Then we explored the regulation of inhibitor of growth 5 (ING5) expression by miR-196a and its impact on apoptosis, invasion, and growth of pancreatic cancer cells. The lentiviral transfected Panc 1 cells were surgically implanted into the pancreas of mice. In vivo tumor growth and ING5 expression were measured. RESULTS: Down-regulation of ING5 expression was detected in cells transfected with miR-196a precursor (P < 0.01), accompanied by less apoptosis, increased invasion, and proliferation compared with control cells (P < 0.05). Cells transfected with miR-196a inhibitor revealed an opposite trend. Smaller detectable tumors were found in only 60% of mice after implantation of Lenti.miR-196a inhibitor-transfected Panc-1 cells compared with controls (360.7 +/- 303.6 mm vs 511.58 +/- 365.9 mm in controls; P < 0.01). CONCLUSION: Our results provide experimental evidence to support aberrant expression of miR-196a is associated with abnormal apoptosis, invasion, and proliferation of pancreatic cancer cells. PMID- 24048457 TI - Fibrosis, atrophy, and ductal pathology in chronic pancreatitis are associated with pancreatic function but independent of symptoms. AB - OBJECTIVES: More knowledge into the pathophysiology underlying pain and other complications in chronic pancreatitis (CP) is needed. The aim was to associate advanced imaging information of the pancreas with etiology and clinical and laboratory parameters of CP. METHODS: Magnetic resonance cholangiopancreatography including diffusion-weighted imaging was obtained in 23 patients with painful CP and 17 controls. Apparent diffusion coefficients, ductal pathology, and pancreas atrophy were assessed. Etiology of CP and clinical and laboratory parameters including pain scores were correlated with the imaging findings. RESULTS: The patients had restricted apparent diffusion coefficients, that is, fibrotic changes, compared with the controls (P = 0.0003). The diffusion coefficients were not associated with atrophy- or ductal-related parameters (all P > 0.7). The fibrotic changes as well as atrophy- and ductal-related parameters were not associated with pain or any other symptom parameters (all P > 0.05). Alcoholic etiology was associated with ductal pathology (both P = 0.02). Furthermore, atrophy- and ductal-related parameters were associated with vitamin D, phosphate, hemoglobin, and glycated hemoglobin levels (all P < 0.03). CONCLUSIONS: Patients with CP have fibrosis, atrophy, and ductal pathology. Although changes in atrophy and ductal-related parameters were, to some degree, associated with exocrine and endocrine insufficiency, pain and other symptoms seem to have a more complex pathogenesis independent of imaging pathology. PMID- 24048458 TI - First fully robotic-assisted total pancreatectomy combined with islet autotransplant for the treatment of chronic pancreatitis: a case report. PMID- 24048459 TI - The vertical length measurement of the normal pancreas in the coronal section using multislice computed tomography. PMID- 24048460 TI - Unsuspected fluorodeoxyglucose positron emission tomography (FDG-PET)-positive pancreatic lesions: prevalence and significance. PMID- 24048461 TI - Comparison of branch duct and main pancreatic duct mural nodules in intraductal papillary mucinous neoplasm. PMID- 24048462 TI - A rare finding of a rare disease: a case report of a giant insulinoma. PMID- 24048463 TI - Erlotinib-induced thrombocytosis in patients with recurrence of pancreatic cancer after distal pancreatectomy. PMID- 24048464 TI - Sarcoidosis in a patient with a circumportal pancreas with a retroportal main pancreatic duct: a case report. PMID- 24048465 TI - Hour-glass magnetic spectrum in a stripeless insulating transition metal oxide. AB - An hour-glass-shaped magnetic excitation spectrum appears to be a universal characteristic of the high-temperature superconducting cuprates. Fluctuating charge stripes or alternative band structure approaches are able to explain the origin of these spectra. Recently, an hour-glass spectrum has been observed in an insulating cobaltate, thus favouring the charge stripe scenario. Here we show that neither charge stripes nor band structure effects are responsible for the hour-glass dispersion in a cobaltate within the checkerboard charge-ordered regime of La(2-x)Sr(x)CoO(4). The search for charge stripe ordering reflections yields no evidence for charge stripes in La(1.6)Sr(0.4)CoO(4), which is supported by our phonon studies. With the observation of an hour-glass-shaped excitation spectrum in this stripeless insulating cobaltate, we provide experimental evidence that the hour-glass spectrum is neither necessarily connected to charge stripes nor to band structure effects, but instead, probably intimately coupled to frustration and arising chiral or non-collinear magnetic correlations. PMID- 24048466 TI - Labelling studies on the biosynthesis of terpenes in Fusarium fujikuroi. AB - Synthetic [2-(13)C]mevalonolactone was fed to the gibberellin producer Fusarium fujikuroi and its incorporation into four known terpenoids was investigated by (13)C NMR analysis of crude culture extracts. The experiments gave detailed insights into the mechanisms of terpene biosynthesis by this fungus. PMID- 24048467 TI - Comparison of the CHADS2, CHA2DS2-VASc and HAS-BLED scores for the prediction of clinically relevant bleeding in anticoagulated patients with atrial fibrillation: the AMADEUS trial. AB - Many of the risk factors for stroke in atrial fibrillation (AF) are also important risk factors for bleeding. Wetested the hypothesis that the CHADS2 and CHA2DS2-VASc scores (used for stroke risk assessment) could be used to predict serious bleeding, and that these scores would compare well against the HAS-BLED score, which is a specific risk score designed for bleeding risk assessment. From the AMADEUS trial, we focused on the trial's primary safety outcome for serious bleeding, which was "any clinically relevant bleeding". The predictive value of HAS-BLED/CHADS2/CHA2DS2-VASc were compared by area under the curve (AUC, a measure of the c-index) and the Net Reclassification Improvement (NRI). Of 2,293 patients on VKA, 251 (11%) experienced at least one episode of "any clinically relevant bleeding" during an average 429 days follow up period. Incidence of "any clinically relevant bleeding" rose with increasing HAS-BLED/CHADS2/CHA2DS2-VASc scores, but was statistically significant only for HAS-BLED (p<0.0001). Only HAS BLED demonstrated significant discriminatory performance for "any clinically relevant bleeding" (AUC 0.60, p<0.0001). There were significant AUC-differences between HAS-BLED (which had the highest AUC) and both CHADS2 (p<0.001) and CHA2DS2VASc (p=0.001). The HAS-BLED score also demonstrated significant NRI for the outcome of "any clinically relevant bleeding" when compared with CHADS2 (p=0.001) and CHA2DS2-VASc (p=0.04). In conclusion, the HAS-BLED score demonstrated significant discriminatory performance for "any clinically relevant bleeding" in anticoagulated patients with AF, whilst the CHADS2 and CHA2DS2-VASc scores did not. Bleeding risk assessment should be made using a specific bleeding risk score such as HAS-BLED, and the stroke risk scores such as CHADS2 or CHA2DS2 VASc scores should not be used. PMID- 24048470 TI - BioC: a minimalist approach to interoperability for biomedical text processing. AB - A vast amount of scientific information is encoded in natural language text, and the quantity of such text has become so great that it is no longer economically feasible to have a human as the first step in the search process. Natural language processing and text mining tools have become essential to facilitate the search for and extraction of information from text. This has led to vigorous research efforts to create useful tools and to create humanly labeled text corpora, which can be used to improve such tools. To encourage combining these efforts into larger, more powerful and more capable systems, a common interchange format to represent, store and exchange the data in a simple manner between different language processing systems and text mining tools is highly desirable. Here we propose a simple extensible mark-up language format to share text documents and annotations. The proposed annotation approach allows a large number of different annotations to be represented including sentences, tokens, parts of speech, named entities such as genes or diseases and relationships between named entities. In addition, we provide simple code to hold this data, read it from and write it back to extensible mark-up language files and perform some sample processing. We also describe completed as well as ongoing work to apply the approach in several directions. Code and data are available at http://bioc.sourceforge.net/. Database URL: http://bioc.sourceforge.net/ PMID- 24048471 TI - Vinylogous chain branching catalysed by a dedicated polyketide synthase module. AB - Bacteria use modular polyketide synthases (PKSs) to assemble complex polyketides, many of which are leads for the development of clinical drugs, in particular anti infectives and anti-tumoral agents. Because these multifarious compounds are notoriously difficult to synthesize, they are usually produced by microbial fermentation. During the past two decades, an impressive body of knowledge on modular PKSs has been gathered that not only provides detailed insight into the biosynthetic pathways but also allows the rational engineering of enzymatic processing lines to yield structural analogues. Notably, a hallmark of all PKS modules studied so far is the head-to-tail fusion of acyl and malonyl building blocks, which leads to linear backbones. Yet, structural diversity is limited by this uniform assembly mode. Here we demonstrate a new type of PKS module from the endofungal bacterium Burkholderia rhizoxinica that catalyses a Michael-type acetyl addition to generate a branch in the carbon chain. In vitro reconstitution of the entire PKS module, X-ray structures of a ketosynthase-branching didomain and mutagenesis experiments revealed a crucial role of the ketosynthase domain in branching the carbon chain. We present a trapped intermediary state in which acyl carrier protein and ketosynthase are covalently linked by the branched polyketide and suggest a new mechanism for chain alkylation, which is functionally distinct from terpenoid-like beta-branching. For the rice seedling blight toxin rhizoxin, one of the strongest known anti-mitotic agents, the non-canonical polyketide modification is indispensable for phytotoxic and anti-tumoral activities. We propose that the formation of related pharmacophoric groups follows the same general scheme and infer a unifying vinylogous branching reaction for PKS modules with a ketosynthase-branching-acyl-carrier-protein architecture. This study unveils the structure and function of a new PKS module that broadens the biosynthetic scope of polyketide biosynthesis and sets the stage for rationally creating structural diversity. PMID- 24048472 TI - Stem cells: Close encounters with full potential. PMID- 24048473 TI - Condensed-matter physics: Rotating molecules as quantum magnets. PMID- 24048469 TI - Assessing behavioural and cognitive domains of autism spectrum disorders in rodents: current status and future perspectives. AB - The establishment of robust and replicable behavioural testing paradigms with translational value for psychiatric diseases is a major step forward in developing and testing etiology-directed treatment for these complex disorders. Based on the existing literature, we have generated an inventory of applied rodent behavioural testing paradigms relevant to autism spectrum disorders (ASD). This inventory focused on previously used paradigms that assess behavioural domains that are affected in ASD, such as social interaction, social communication, repetitive behaviours and behavioural inflexibility, cognition as well as anxiety behaviour. A wide range of behavioural testing paradigms for rodents were identified. However, the level of face and construct validity is highly variable. The predictive validity of these paradigms is unknown, as etiology-directed treatments for ASD are currently not on the market. To optimise these studies, future efforts should address aspects of reproducibility and take into account data about the neurodevelopmental underpinnings and trajectory of ASD. In addition, with the increasing knowledge of processes underlying ASD, such as sensory information processes and synaptic plasticity, phenotyping efforts should include multi-level automated analysis of, for example, representative task-related behavioural and electrophysiological read-outs. PMID- 24048474 TI - Enzymology: Modular biosynthesis branches out. PMID- 24048476 TI - Genomic organization of human transcription initiation complexes. AB - The human genome is pervasively transcribed, yet only a small fraction is coding. Here we address whether this non-coding transcription arises at promoters, and detail the interactions of initiation factors TATA box binding protein (TBP), transcription factor IIB (TFIIB) and RNA polymerase (Pol) II. Using ChIP-exo (chromatin immunoprecipitation with lambda exonuclease digestion followed by high throughput sequencing), we identify approximately 160,000 transcription initiation complexes across the human K562 genome, and more in other cancer genomes. Only about 5% associate with messenger RNA genes. The remainder associates with non-polyadenylated non-coding transcription. Regardless, Pol II moves into a transcriptionally paused state, and TBP and TFIIB remain at the promoter. Remarkably, the vast majority of locations contain the four core promoter elements- upstream TFIIB recognition element (BREu), TATA, downstream TFIIB recognition element (BREd), and initiator element (INR)-in constrained positions. All but the INR also reside at Pol III promoters, where TBP makes similar contacts. This comprehensive and high-resolution genome-wide detection of the initiation machinery produces a consolidated view of transcription initiation events from yeast to humans at Pol II/III TATA-containing/TATA-less coding and non-coding genes. PMID- 24048477 TI - Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. AB - Animal cells harbour multiple innate effector mechanisms that inhibit virus replication. For the pathogenic retrovirus human immunodeficiency virus type 1 (HIV-1), these include widely expressed restriction factors, such as APOBEC3 proteins, TRIM5-alpha, BST2 (refs 4, 5) and SAMHD1 (refs 6, 7), as well as additional factors that are stimulated by type 1 interferon (IFN). Here we use both ectopic expression and gene-silencing experiments to define the human dynamin-like, IFN-induced myxovirus resistance 2 (MX2, also known as MXB) protein as a potent inhibitor of HIV-1 infection and as a key effector of IFN-alpha mediated resistance to HIV-1 infection. MX2 suppresses infection by all HIV-1 strains tested, has equivalent or reduced effects on divergent simian immunodeficiency viruses, and does not inhibit other retroviruses such as murine leukaemia virus. The Capsid region of the viral Gag protein dictates susceptibility to MX2, and the block to infection occurs at a late post-entry step, with both the nuclear accumulation and chromosomal integration of nascent viral complementary DNA suppressed. Finally, human MX1 (also known as MXA), a closely related protein that has long been recognized as a broadly acting inhibitor of RNA and DNA viruses, including the orthomyxovirus influenza A virus, does not affect HIV-1, whereas MX2 is ineffective against influenza virus. MX2 is therefore a cell-autonomous, anti-HIV-1 resistance factor whose purposeful mobilization may represent a new therapeutic approach for the treatment of HIV/AIDS. PMID- 24048478 TI - Observation of dipolar spin-exchange interactions with lattice-confined polar molecules. AB - With the production of polar molecules in the quantum regime, long-range dipolar interactions are expected to facilitate understanding of strongly interacting many-body quantum systems and to realize lattice spin models for exploring quantum magnetism. In ordinary atomic systems, where contact interactions require wavefunction overlap, effective spin interactions on a lattice can be mediated by tunnelling, through a process referred to as superexchange; however, the coupling is relatively weak and is limited to nearest-neighbour interactions. In contrast, dipolar interactions exist even in the absence of tunnelling and extend beyond nearest neighbours. This allows coherent spin dynamics to persist even for gases with relatively high entropy and low lattice filling. Measured effects of dipolar interactions in ultracold molecular gases have been limited to the modification of inelastic collisions and chemical reactions. Here we use dipolar interactions of polar molecules pinned in a three-dimensional optical lattice to realize a lattice spin model. Spin is encoded in rotational states of molecules that are prepared and probed by microwaves. Resonant exchange of rotational angular momentum between two molecules realizes a spin-exchange interaction. The dipolar interactions are apparent in the evolution of the spin coherence, which shows oscillations in addition to an overall decay of the coherence. The frequency of these oscillations, the strong dependence of the spin coherence time on the lattice filling factor and the effect of a multipulse sequence designed to reverse dynamics due to two-body exchange interactions all provide evidence of dipolar interactions. Furthermore, we demonstrate the suppression of loss in weak lattices due to a continuous quantum Zeno mechanism. Measurements of these tunnelling-induced losses allow us to determine the lattice filling factor independently. Our work constitutes an initial exploration of the behaviour of many-body spin models with direct, long-range spin interactions and lays the groundwork for future studies of many-body dynamics in spin lattices. PMID- 24048479 TI - Deterministic direct reprogramming of somatic cells to pluripotency. AB - Somatic cells can be inefficiently and stochastically reprogrammed into induced pluripotent stem (iPS) cells by exogenous expression of Oct4 (also called Pou5f1), Sox2, Klf4 and Myc (hereafter referred to as OSKM). The nature of the predominant rate-limiting barrier(s) preventing the majority of cells to successfully and synchronously reprogram remains to be defined. Here we show that depleting Mbd3, a core member of the Mbd3/NuRD (nucleosome remodelling and deacetylation) repressor complex, together with OSKM transduction and reprogramming in naive pluripotency promoting conditions, result in deterministic and synchronized iPS cell reprogramming (near 100% efficiency within seven days from mouse and human cells). Our findings uncover a dichotomous molecular function for the reprogramming factors, serving to reactivate endogenous pluripotency networks while simultaneously directly recruiting the Mbd3/NuRD repressor complex that potently restrains the reactivation of OSKM downstream target genes. Subsequently, the latter interactions, which are largely depleted during early pre-implantation development in vivo, lead to a stochastic and protracted reprogramming trajectory towards pluripotency in vitro. The deterministic reprogramming approach devised here offers a novel platform for the dissection of molecular dynamics leading to establishing pluripotency at unprecedented flexibility and resolution. PMID- 24048480 TI - Synthesis and biological evaluation of hydroxyl-substituted Schiff-bases containing ferrocenyl moieties. AB - Three new hydroxyl-substituted Schiff-bases containing ferrocenyl moieties were synthesized, and their antioxidant and anticancer activities were evaluated. Among the synthesized hydroxyl-substituted Schiff-bases, compound 1 containing both ferrocenyl and o-dihydroxyl groups exhibits the highest antioxidant and anticancer activities. Flow cytometric analysis showed that compound 1 is capable of disturbing the cancer cell cycle and inducing more cells to be arrested in G2 phase. The excellent biological activities of compound 1 are attributed to the presence of both ferrocenyl and o-dihydroxyl groups. The ferrocenyl moiety has dual functions in compound 1, i.e., increasing the lipophilicity and lowering the redox potentials of o-dihydroxyl groups. In addition, compound 1 could reversibly bind with HSA mainly via a mechanism involving the formation of complexes, in which hydrophobic interaction is the main acting force. Thus, compound 1 containing both ferrocenyl and o-dihydroxyl groups is a potential antioxidant with anticancer activity. PMID- 24048481 TI - [Conservative therapy of acute locked posterior shoulder dislocation: clinical and radiological long-term results]. AB - BACKGROUND: Long-term results of conservative treatment of acute locked posterior shoulder dislocation with a reverse Hill-Sachs defect (Malgaigne lesion) <25% are rare. The aim of the present study was to evaluate the clinical and radiological results of patients after conservative treatment. MATERIAL AND METHODS: In this study 8 patients (8 male, average age 58.4 years) after non-operative treatment consisting of closed reduction and immobilization in 15 degrees of external rotation were retrospectively clinically and radiologically examined (true anteroposterior, axillary and y view) The Constant score (CS), Rowe score (RS), Western Ontario shoulder instability index (WOSI) and the subjective shoulder value (SSV) were evaluated. RESULTS: After a mean follow-up of 5.4 years (range 5 7 years) no patient reported a redislocation or resubluxation or a persistent feeling of instability. None of the patients stated that they had to avoid certain movements or were limited in their everyday life. The clinical tests for posterior instability (jerk test/Kim test) were negative in all patients. The mean CS was 87.4 (range 42-98) points, the RS 96.4 (range 55-100) points, the WOSI 89.1% (range 41-100%) and the SSV 89.1% (range 50-98%). The radiological evaluation of the affected shoulder in true anteroposterior, axillary and y views showed signs of osteoarthritis (grade II according to Samilson and Prieto) in two cases. The humeral head was centered in all eight cases. CONCLUSIONS: Non operative treatment of acute locked posterior shoulder dislocation demonstrated good to excellent clinical and radiological long-term results in this study. It represents the treatment of choice in patients with a reverse Hill-Sachs defect (Malgaigne lesion) < 25% and a duration of dislocation < 3 weeks. PMID- 24048482 TI - Association between blood pressure and target organ damage in patients with chronic kidney disease and hypertension: results of the APrODiTe study. AB - Blood pressure control is the most established practice for preventing the progression of chronic kidney disease. Evidence addressing blood pressure control status or nocturnal blood pressure dipping in Korean hypertensive patients with chronic kidney disease is scarce. We recruited 1317 hypertensive patients (chronic kidney disease stages 2-4, median age 58) from 21 centers in Korea. These patients underwent office and ambulatory blood pressure monitoring. High office and ambulatory blood pressure were defined as >140/90 mm Hg and >135/85 mm Hg (daytime)/ >120/70 mm Hg (nighttime), respectively. The blood pressure control status was as follows: true controlled (19%), white-coat (4.3%), masked (33.9%) and sustained uncontrolled (42.3%) hypertension. The dipping status was as follows: extreme-dipping (14.9%), dipping (33.3%), non-dipping (34.5%) and reverse-dipping (17.3%). Masked and sustained hypertension as well as non dipping/reverse-dipping was more apparent in proportion to renal dysfunction and the extent of proteinuria. Ageing (?58 years), male gender, obesity, diabetic nephropathy and proteinuria (>300 mg g(-1) Cr or dipstick proteinuria?1+) were independently associated with sustained uncontrolled hypertension. Diabetic nephropathy, old age, a history of stable angina/heart failure, advanced renal dysfunction and higher proteinuria levels were also significantly associated with non-dipping and reverse-dipping. Half of Korean chronic kidney disease patients had uncontrolled blood pressure and a non-dipping nocturnal blood pressure pattern. Future studies are warranted to assess the predictive values of ambulatory blood pressure for cardiorenal events in Korean chronic kidney disease patients. PMID- 24048483 TI - Hemodynamic and pathophysiological characteristics of intradialytic blood pressure elevation in patients with end-stage renal disease. AB - An increase in systolic blood pressure (SBP) after hemodialysis (intradialytic HTN) is associated with adverse outcomes in patients on regular hemodialysis. However, the hemodynamic and Doppler echocardiographic characteristics of intradialytic-HTN and its impact on clinical outcomes are unclear. A retrospective analysis of 84 patients (45 men, 70+/-9 years) stratified into three groups on the basis of SBP response from pre- to post-hemodialysis: GHTN (intradialytic-HTN, SBP increase ?10 mm Hg), GDROP<15 mm Hg (SBP drop <15 mm Hg), and GDROP?15 mm Hg (SBP drop ?15 mm Hg). Hemodynamic and echocardiographic assessments were performed pre- and post-hemodialysis, and patients were followed for 41+/-17 months. GHTN had higher blood glucose and lower baseline SBP, serum potassium and total cholesterol. Cardiothoracic ratio was smaller, and peak early diastolic mitral annular velocity (E') was lower in GHTN. During hemodialysis, SBP and diastolic blood pressure increased only in GHTN. After hemodialysis, left ventricular (LV) filling pressure (E/E' ratio) decreased only in GDROP?15 mm Hg, resulting in a higher E/E' ratio in GHTN than GDROP?15 mm Hg. Multivariate logistic regression analysis revealed a positive correlation between blood glucose and intradialytic-HTN, whereas cardiothoracic ratio, pre-hemodialysis SBP and the change in E/E' ratio with hemodialysis were negatively related to intradialytic-HTN. During follow-up, GHTN had more cardiovascular deaths than GDROP?15 mm Hg (P=0.03). Multivariate Cox regression analysis showed that lower serum potassium and previous coronary artery disease, but not intradialytic-HTN, were associated with cardiovascular deaths. A higher LV afterload and elevated filling pressures after hemodialysis, indicative of increased cardiovascular stiffening and impaired diastolic filling, may contribute in part to an increased cardiovascular burden in patients with intradialytic-HTN. PMID- 24048484 TI - Role of gap junctions in the contractile response to agonists in the mesenteric artery of spontaneously hypertensive rats. AB - To investigate the effects of hypertension on the changes in gap junctions between vascular smooth muscle cells (VSMCs) in the mesenteric artery (MA) of spontaneously hypertensive rats (SHRs). Whole-cell patch clamp, pressure myography, real-time quantitative reverse transcription PCR (qRT-PCR), western blot analysis and transmission electron microscopy were used to examine the differences in expression and function of the gap junction between MA VSMCs of SHR and control normotensive Wistar-Kyoto (WKY) rats. (1) Whole-cell patch clamp measurements showed that the membrane capacitance and conductance of in-situ MA VSMCs of SHR were significantly greater than those of WKY rats (P<0.05), suggesting enhanced gap junction coupling between MA VSMCs of SHR. (2) The administration of phenylephrine (PE) and KCl (an endothelium-independent vasoconstrictor) initiated more pronounced vasoconstriction in SHR versus WKY rats (P<0.05). Furthermore, 2-APB (a gap junction inhibitor) attenuated PE- and KCl-induced vasoconstriction, and the inhibitory effects of 2-APB were significantly greater in SHR (P<0.05). (3) The expression of connexin 45 (Cx45) mRNA and protein in the MA was greater in SHR versus WKY rats (P<0.05). The level of phosphorylated Cx43 was significantly higher in SHR versus WKY rats (P<0.05), although the expression of total Cx43 mRNA and protein in the MA was equivalent between SHR and WKY rats. Electron microscopy revealed that the gap junctions were significantly larger in SHR versus WKY rats. Increases in the expression of Cx45 and phosphorylation of Cx43 may contribute to the enhancement of communication across gap junctions between MA VSMCs of SHR, which may increase the contractile response to agonists. PMID- 24048485 TI - Effect of telmisartan vs. ramipril on 'dipping' status and blood pressure variability: pooled analysis of the PRISMA studies. AB - A retrospective pooled analysis of the 'Prospective, Randomized Investigation of the Safety and Efficacy of MICARDIS vs. Ramipril Using ABPM' studies conducted in Europe and South Africa (PRISMA I) and in the United States of America and Canada (PRISMA II) was carried out to investigate the effects of telmisartan and ramipril on dipper status (extreme dippers, dippers, non-dippers, risers/reverse dippers), and blood pressure (BP) variability in 1279 patients (with normal sleeping patterns and valid 24-h ambulatory BP monitoring recordings at baseline and end point). After 14 weeks' treatment, telmisartan had a greater systolic BP (SBP) reduction and higher smoothness index in all four dipper groups compared with ramipril. In addition, the tendency toward dipping was significantly higher in patients treated with) telmisartan than ramipril (P=0.032; odds ratio for telmisartan vs. ramipril: 1.27 (95% confidence interval: 1.102-1.58)). In patients with an early morning SBP surge ?35 mm Hg, telmisartan treatment was associated with significantly greater reductions from baseline in the night-time low mean, early morning mean and early morning SBP surge compared with ramipril (P=0.026, P<0.0001 and P=0.0006, respectively). In this retrospective analysis, telmisartan was shown to normalize the circadian BP pattern to a dipper profile in a larger proportion of patients than ramipril, and reduce early-morning SBP surge in high-risk patients, indicative of a cardioprotective effect. These findings need to be confirmed in long-term prospective trials and observational studies. PMID- 24048486 TI - Positive effects of antihypertensive treatment on aortic stiffness in the general population. AB - Aortic stiffness is strongly related to age and mean arterial pressure (MAP). In the present analysis, we investigated whether antihypertensive treatment modulates the association of the aortic pulse wave velocity (PWV) with age and with MAP in the general population. In the Czech post-MONICA cross-sectional study, we measured the PWV in 735 subjects (mean age 61.2+/-7.8 years, 54.1% women, 44.3% on antihypertensive medication). We used a linear regression model to assess the effect of treatment on the PWV. The independent covariates in our analysis included sex, age, MAP, heart rate, body mass index, plasma glucose, low density lipoprotein cholesterol, smoking and observer. The patients receiving treatment were older (64.1+/-6.7 vs. 58.9+/-7.8 years), had higher systolic blood pressure (135.9+/-16.2 vs. 130.1+/-16.5 mm Hg) and had higher pulse wave velocity (9.1+/-2.2 vs. 8.2+/-2.1 m s(-1); P for all <0.0001) than untreated subjects. After adjustment for MAP, the use of treatment modified the association between age and the PWV (regression equations, treated patients 9.68-0.009 * age vs. untreated subjects 6.98+0.020 * age, difference of regression slopes, F=11.2; P=0.0009). In analyses adjusted for age, treatment was associated with a smaller increase of the PWV with MAP (treated patients 9.63-0.006 * MAP vs. untreated subjects 7.18+0.010 * MAP, F=10.70; P=0.0001). These results were driven primarily by subjects whose blood pressure was below 140/90 mm Hg. In the cross sectional analysis from a random sample of the general population, antihypertensive treatment was associated with a less steep increase in the PWV with age and the mean arterial pressure. Further longitudinal studies are needed to confirm this finding. PMID- 24048487 TI - Japanese Society of Hypertension official comment on valsartan papers. PMID- 24048488 TI - Subservient relationship of the peripheral second systolic pressure peak to the central hemodynamic parameters is preserved, irrespective of atherosclerosis progression in hypercholesterolemic rabbits. AB - We investigated whether the subservient relationship of peripheral to central hemodynamic parameters, such as the augmentation index (AI) and the second systolic (SBP2) and pulse pressures, were preserved with the progression of atherosclerosis in the Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbit, an animal model for hypercholesterolemia and atherosclerosis. Male KHC rabbits, aged 12 and 24 months, were anesthetized with pentobarbital sodium. Two catheter tip transducers were introduced to the central (ascending aorta) and peripheral (distal region of the right brachial artery) arteries through the left common carotid and the right radial arteries, respectively. Pressure waves were simultaneously recorded under regular atrial pacing to investigate changes in response to the intravenous infusion of angiotensin II (Ang II) (30-40 ng kg(-1) min(-1)) and sodium nitroprusside (NTP) (20-30 MUg kg(-1) min(-1)). Central systolic blood pressure (cSBP) and diastolic blood pressure (DBP), peripheral systolic blood pressure (pSBP) and DBP, and peripheral second systolic blood pressure (pSBP2) showed no significant difference between the 12- and 24-month old groups before the administration of vasoactive drugs. There was no significant difference in central AI (cAI) between the two age groups before the drug infusion, even though atherosclerosis progressed with aging. Peripheral AI (pAI) changed in parallel with cAI in response to vasopressor and depressor actions due to the infusion of Ang II and NTP, respectively. We conclude that the subservience of pSBP2 to cSBP and pAI to cAI, in addition to the regression relationship of these parameters between peripheral and central arteries, were well preserved, irrespective of the progression of atherosclerosis. PMID- 24048489 TI - Peripheral administration of nesfatin-1 increases blood pressure in mice. PMID- 24048490 TI - Small proximal aortic diameter is associated with higher central pulse pressure and poor outcome in patients with congestive heart failure. AB - BACKGROUND: A small proximal aortic diameter (AoD) is thought to be associated with a higher characteristic impedance of the proximal aorta. However, there has been no evidence of a relationship between directly evaluated AoD and directly measured central aortic pressure or the outcome of patients with cardiovascular diseases. METHODS AND RESULTS: (a) In 135 patients without heart failure (HF), who underwent coronary catheterization, we retrospectively examined the relationship between the AoD and the central aortic pressure or aortic elastance. The AoD adjusted with covariates was inversely correlated with the central pulse pressure (cPP; coefficient=-0.75; P=0.04; model R(2)=0.575) and the effective arterial elastance index (coefficient=-0.12; P=0.001; model R(2)=0.366). (b) In 197 patients who were hospitalized due to HF, we examined the relationship between the AoD (evaluated using echocardiography) and the outcome using a Cox proportional hazard model. Fifty-three patients died from various causes during the follow-up period (2.2+/-1.1 years). Multivariable analysis revealed that the AoD remained an independent risk factor for all-cause death (hazard ratio for 1 s.d. increase of the AoD: 0.68, 95% confidence interval: 0.50-0.92, P=0.013) and cardiovascular death (hazard ratio for 1 s.d. increase of the AoD: 0.63, 95% confidence interval: 0.43-0.93, P=0.019). CONCLUSIONS: A small AoD was associated with a higher cPP and aortic stiffening in the patients without HF, as well as with a poor outcome for HF patients. Although it is easy to evaluate the AoD, it may offer important information regarding the pulsatile load and may be useful for risk stratification of HF patients. PMID- 24048491 TI - Is validation of non-invasive hemodynamic measurement devices actually required? PMID- 24048492 TI - Effects of salt status and blockade of mineralocorticoid receptors on aldosterone induced cardiac injury. AB - The mineralocorticoid aldosterone regulates sodium and water homeostasis in the human body. The combination of excess aldosterone and salt loading induces hypertension and cardiac damage. However, little is known of the effects of aldosterone on blood pressure and cardiac pathophysiology in the absence of salt loading. We have now investigated the effects of salt status and blockade of mineralocorticoid receptors (MRs) on cardiac pathophysiology in uninephrectomized Sprague-Dawley rats implanted with an osmotic minipump to maintain hyperaldosteronism. The rats were fed a low-salt (0.0466% NaCl in chow) or high salt (0.36% NaCl in chow plus 1% NaCl in drinking water) diet in the absence or presence of treatment with a subdepressor dose of the MR antagonist spironolactone (SPL). Aldosterone excess in the setting of low salt intake induced substantial cardiac remodeling and diastolic dysfunction without increasing blood pressure. These effects were accompanied by increased levels of oxidative stress and inflammation as well as increased expression of genes related to the renin-angiotensin and endothelin systems in the heart. All of these cardiac changes were completely blocked by the administration of SPL. On the other hand, aldosterone excess in the setting of high salt intake induced hypertension and a greater extent of cardiac injury, with the cardiac changes being only partially attenuated by SPL in a manner independent of its antihypertensive effect. The combination of dietary salt restriction and MR antagonism is thus a promising therapeutic option for the management of hypertensive patients with hyperaldosteronism or relative aldosterone excess. PMID- 24048493 TI - Effects of antihypertensive drugs on central blood pressure: new evidence, more challenges. PMID- 24048494 TI - Controlling novel avian influenza A (H7N9) at animal sources. PMID- 24048495 TI - Monitoring excess mortality in Europe. PMID- 24048496 TI - Whatever happened to normal ageing? PMID- 24048497 TI - Infrastructure and IT policies of individual trusts limit health IT. PMID- 24048498 TI - Establishing the context in which doctors write software code. PMID- 24048499 TI - Too many psychiatric beds have been lost. PMID- 24048500 TI - Panel sketches out plan for US neuroscience initiative. PMID- 24048501 TI - Characterisation of novel and rare Y-chromosome short tandem repeat alleles in self-declared South Australian Aboriginal database. AB - Y-chromosome short tandem repeats (Y-STRs) are used in forensic science laboratories all over the world, as their application is wide and often vital in solving casework. Analysis of an in-house database of South Australian self declared Aboriginal males held by Forensic Science South Australia (FSSA) using the Applied Biosystem's AmpFlSTR(r) YfilerTM PCR Amplification Kit revealed 43 variant Y-STR alleles at 6 of the 17 loci. All variant alleles were sequenced to determine the exact repeat structure for each. As a high level of admixture has previously been found within the SA Aboriginal database, samples were haplogrouped using Y-SNPs to determine their likely geographical origin. Although a number of variant alleles were associated with non-Aboriginal Y-haplogroups, a high frequency was observed within the Australian K-M9 lineage. Detailed knowledge of these variant alleles may have further application in the development of new DNA markers for identification purposes, and in population and evolutionary studies of Australian Aborigines. PMID- 24048502 TI - Brain weight in completed suicide and other cases of death-comparison of recent and previous studies. AB - BACKGROUND: The weight of human brains is subject of numerous scientific research studies particularly in anatomy, pathology, and forensic medicine. Just a few investigations deal with a possible correlation between psychiatric disorders, especially suicidality, and brain weight. The results are contradictory. AIMS: This study aims to find out if postmortem brain weight is higher in suicide victims considering the discrepancies of previous studies. METHOD: In a retrospective study, the weight of brains obtained by autopsies performed in the Institute of Legal Medicine in Frankfurt, Germany, was evaluated. Data of 99 suicide cases (64 males, 35 females) were compared with those obtained from similar number cases of sudden death in a matched pair analysis. In each case, body weight, height, and body mass index were also taken into account. RESULTS: No significant differences in brain weight were found in suicide victims compared to those of the control group. CONCLUSIONS: The brain weight depends on various parameters such as gender, age, body height, and weight. The selection criteria for suicide cases as well as for the corresponding control population are essential in evaluating the brain weight in suicide. PMID- 24048503 TI - Influence of an individual's age on the amount and interpretability of DNA left on touched items. AB - In crime scene investigations, DNA left by touch on an object can be found frequently and the significant improvements in short tandem repeat (STR) amplification in recent years built up a high expectation to identify the individual(s) who touched the object by their DNA profile. Nevertheless, the percentage of reliably analysable samples varies considerably between different crime scenes even if the nature of the stains appears to be very similar. Here, it has been proposed that the amount and quality of DNA left at a crime scene may be influenced by external factors (like nature of the surface) and/or individual factors (like skin conditions). In this study, the influence of the age of an individual who left his DNA on an object is investigated. Handprints from 213 individuals (1 to 89 years old) left on a plastic syringe were analysed for DNA amount and STR alleles using Quantifiler(r) and PowerPlex(r) ESX 17. A full profile of the individual could be found in 75 % of all children up to 10 years, 9 % of adolescents (11 to 20 years), 25 % of adults (21 to 60 years) and 8 % of elderly people (older than 60 years). No person older than 80 years displayed a full profile. Drop-in and drop-out artefacts occurred frequently throughout the age groups. A dependency of quantity and quality of the DNA left on a touched object on the age of the individual could be clearly demonstrated at least for children and elderly people. An epithelial abrasion unexpectedly good to interpret may be derived from a child, whereas the suspected skin contact of an elderly person with an object may be impossible to prove. PMID- 24048504 TI - Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non alcoholic steatohepatitis. AB - Non-alcoholic steatohepatitis (NASH) is a primary cause of cirrhosis and hepatocellular carcinoma. Dipeptidyl peptidase (DPP)-4 inhibitors are established therapies for type 2 diabetes and although DPP-4 inhibitors can reduce hepatic steatosis, their impact on local inflammation and fibrosis in NASH remains unknown. Using two different experimental treatment regimens (4- and 2-week treatments) in streptozotocin-treated neonatal mice on a high-fat diet, we show that the DPP-4 inhibitor linagliptin (10 and 30 mg/kg) significantly attenuated the NAS score from 4.9 +/- 0.6 to 3.7 +/- 0.4 and 3.6 +/- 0.3, respectively, in the 4-week study. In the 2-week study, linagliptin 10 mg/kg significantly reduced NAS score from 4.1 +/- 0.4 to 2.4 +/- 0.4. Telmisartan was used as a positive control in both studies and lowered NAS score to 1.9 +/- 0.7 and 1.4 +/- 0.3, respectively. Due to streptozotocin treatment, elevated glucose levels were unchanged by either drug treatment. Further, linagliptin 10 mg/kg significantly reduced mRNA levels of SOCS-3 (from 1.68 +/- 0.2 to 0.83 +/- 0.08), IFN-gamma (from 4.0 +/- 0.5 to 2.3 +/- 0.3), and TNF-alpha (from 5.7 +/- 0.5 to 2.13 +/- 0.3). The latter observation was confirmed by immunohistochemistry of TNF-alpha in liver specimens. In addition, using microautoradiography, we showed that the distribution of radiolabeled linagliptin was heterogeneous with the highest density associated with interlobular bile ducts and portal tracts (acini). In conclusion, these studies confirm that linagliptin has high exposure in hepatic tissue and has both anti-inflammatory and anti-steatotic activity in NASH. PMID- 24048509 TI - Steric hindrance-enforced distortion as a general strategy for the design of fluorescence "turn-on" cyanide probes. AB - For the rational design of fluorescence "turn-on" cyanide probes, a general strategy is developed by introducing a dicyanovinyl group at the sterically demanding position of a large pi framework. PMID- 24048505 TI - Pneumococcal serotypes in adult non-invasive and invasive pneumonia in relation to child contact and child vaccination status. AB - BACKGROUND: On a population level, pneumococcal conjugate vaccination in children has reduced the incidence of vaccine-type disease in all age groups, including older adults. Few individual level studies have been performed describing the pneumococcal serotypes associated with adult community acquired pneumonia (CAP) and quantifying associations with child contact and child vaccination status. METHODS: Pneumococcal serotypes were determined using a validated multiplex immunoassay (Bio-Plex) in a large prospective cohort of adults hospitalised with CAP. Child (<16 years old) contact history and child pneumococcal vaccination status were obtained from patients and public health records, respectively. RESULTS: Of 1130 participants, 329 (29.1%) reported child contact, and pneumococcal infection was identified in 410 (36.3%). Pneumococcal CAP was commoner in adults with child contact (148/329 (45.0%) vs 262/801 (32.7%); adjusted OR 1.63, CI 1.25 to 2.14; p<0.001). A serotype was determined in 263 of 410 (64.1%) adults with pneumococcal CAP; 112 (42.6%) reported child contact, 38 (33.9%) with a vaccinated child. Adults in contact with a vaccinated child were significantly less likely to have vaccine-type CAP compared with adults in contact with an unvaccinated child (6 of 38 (15.8%) vs 25 of 74 (33.8%), respectively; OR 0.37, 95% CI 0.14 to 0.99; p=0.044). CONCLUSIONS: Pneumococcal aetiology in adult CAP is independently associated with child contact and implicated serotypes are influenced by child vaccination status. This is the first study to demonstrate these associations at an individual rather than population level; it affirms that 'herd protection' from childhood vaccination extends beyond adult invasive disease to pneumococcal CAP. PMID- 24048510 TI - Cost-effectiveness of different strategies for stroke prevention in patients with atrial fibrillation in a health resource-limited setting. AB - PURPOSE: To compare the lifetime cost and effectiveness of five alternative chronic atrial fibrillation (AF) management strategies: rivaroxaban, warfarin, aspirin plus clopidogrel, aspirin and no prevention. METHODS: An individual-level state-transition model was developed to track the lifetime disease course associated with AF. The clinical and utility data were derived from published studies. The cost data were estimated based on local charges and current Chinese practices. Sensitivity analyses were used to explore the impact of uncertainty on the results. RESULTS: For base-case patients with a CHADS2 score of 3, the cost per additional quality-adjusted life-years (QALYs) gained for rivaroxaban compared with no prevention, aspirin, aspirin plus clopidogrel and warfarin was $116,884, $153,944, $155,979 and $216,273, respectively. CHADS2 score had a substantial impact on the model outcomes for different prevention strategies. The time distribution of warfarin international normalised ratio (INR), stroke and intracranial haemorrhage (ICH) risks, cost of rivaroxaban and utility of warfarin therapy had substantial impacts on the results. Based on a willingness-to-pay threshold of $16,350/QALY, no prevention strategy was the preferred therapy for a patient with a low risk for stroke and a high risk for ICH; aspirin was preferred for patients with a moderate risk for stroke and ICH; and warfarin was preferred for patients with a high risk for stroke and a low risk of ICH. CONCLUSION: In the context of limited health resources, rivaroxaban is unlikely to be cost effective, although it provided more health benefits comparing with other strategies. Additionally, warfarin with good INR control might be more suitable for AF patients in developing regions. PMID- 24048511 TI - Clinical effectiveness of tolvaptan in patients with acute decompensated heart failure and renal failure: design and rationale of the AQUAMARINE study. AB - PURPOSE: Over half of all admitted acute decompensated heart failure (ADHF) patients have renal failure. Although diuretics represent the mainstay of treatment strategy even in this population, there are unmet needs for safer and more effective treatment. Tolvaptan is a vasopressin-2 receptor antagonist, and we hypothesized that adding tolvaptan to standard diuretic therapy would be more effective in ADHF patients with renal function impairment. METHODS: The Answering question on tolvaptan's efficacy for patients with acute decompensated heart failure and renal failure (AQUAMARINE) is a multicenter, randomized controlled clinical trial, which will enroll 220 patients from 17 hospitals in Japan. ADHF patients whose estimated glomerular filtration rate is above 15 and below 60 mL/min/1.72 m(2) will be randomly assigned within 6 h after admission to usual care with furosemide or tolvaptan add-on therapy. Primary endpoint is achieved urine output within 48 h. Secondary endpoints include dyspnea relief measured by 7-points Likert scale, incidence of worsening renal function, dose of furosemide used within 48 h, and changes of brain natriuretic peptide. CONCLUSION: This study is the first multicenter study in Japan to evaluate clinical effectiveness of tolvaptan add-on therapy in ADHF patients with renal failure. The results of this study address the treatment strategy of this high-risk population (UMIN Clinical Trial Registry Number: UMIN000007109). PMID- 24048512 TI - Factor VII antigen levels are differentially associated to etiological subtypes of ischaemic stroke. PMID- 24048513 TI - A biopsy that sticks with evidence. PMID- 24048515 TI - Patient expectations after breast augmentation: the imperative to audit your sizing system. AB - Patient dissatisfaction with breast size after breast implant surgery can lead to early secondary procedures in a minority of cases. Different systems of sizing a patient preoperatively have been proposed, including detailed measurements and computer-assisted assessment. Whatever system is used, a surgeon needs to obtain feedback to ascertain that the system is effective at producing a satisfactory outcome. In this study, 137 patients who underwent breast augmentation by a single surgeon were prospectively assessed for a 12-week period after surgery to determine their satisfaction with their breast size. Both expectations and desire to change implant size were assessed. Early (week 1) expectations of the patients were a good predictor of their long-term assessment 12 weeks after surgery and their desire to change their implant size. The patients with a greater body mass index (BMI) and larger implant volume were more likely to express a desire for a change in implant size early in the postoperative course. The findings showed that 19.4 % (26/134) of the patients wished to have larger implants by 12 weeks after surgery and that 3.7 % (5/134) felt smaller implants would be preferable. The information produced by this audit is important to the provision of future informed consent for this surgeon. Without similar data from their individual practices, surgeons cannot provide patients with an accurate assessment of their satisfaction after breast augmentation surgery. A similar undertaking is strongly recommended for surgeons performing breast implant surgery. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24048514 TI - QEEG spectral and coherence assessment of autistic children in three different experimental conditions. AB - We studied autistics by quantitative EEG spectral and coherence analysis during three experimental conditions: basal, watching a cartoon with audio (V-A), and with muted audio band (VwA). Significant reductions were found for the absolute power spectral density (PSD) in the central region for delta and theta, and in the posterior region for sigma and beta bands, lateralized to the right hemisphere. When comparing VwA versus the V-A in the midline regions, we found significant decrements of absolute PSD for delta, theta and alpha, and increments for the beta and gamma bands. In autistics, VwA versus V-A tended to show lower coherence values in the right hemisphere. An impairment of visual and auditory sensory integration in autistics might explain our results. PMID- 24048516 TI - In vitro metabolic study of Rhizoma coptidis extract using liver microsomes immobilized on magnetic nanoparticles. AB - Although metabolic study of individual active compounds isolated from herbal plants has been intensive, it cannot truly reflect the fate of herbs because the herbal extracts in use have many constituents. To address this problem, whole extracts of herbs should be investigated. Microsomes have been heavily used in the in vitro metabolic study of drugs, and various materials have been used to immobilize microsomes to develop highly effective and reusable bioreactors in this field. In this work, rat liver microsomes were immobilized on magnetic nanoparticles (LMMNPs) to develop a highly active and recoverable nanoparticle bioreactor. Using this bioreactor, we investigated the in vitro metabolism of Rhizoma coptidis extract. Incubation of berberine, a major active ingredient of R. coptidis, with LMMNPs for 20 min produced two metabolites, i.e., demethyleneberberine and thalifendine, at high levels. From a comparison of the time courses of thalifendine formation obtained by ultraperformance liquid chromatography-mass spectrometry analysis, it was found that LMMNPs had a higher biological activity than free liver microsomes in metabolizing berberine. Further, the activity of LMMNPs remained almost unchanged after six consecutive uses in the incubation tests. Metabolism of R. coptidis extracts by LMMNPs was studied. The same two metabolites of berberine, i.e., demethyleneberberine and thalifendine, were detected. After a thorough study seeking support for this observation, it was found that demethyleneberberine was the common metabolite of five protoberberine-type alkaloids present in R. coptidis extract, including palmatine, jatrorrhizine, columbanine, epiberberine, and berberine. PMID- 24048517 TI - A new methodology involving stable isotope tracer to compare simultaneously short and long-term selenium mobility in soils. AB - A better understanding of Se fate in soils is required for different environmental issues, such as radioactive waste management or soil fertilization procedures. In these contexts, the mobility and speciation of Se have to be studied at both short and long terms after Se inputs. Here, we present a new methodology to monitor simultaneously the reactivity of added (isotopic enriched tracers) and ambient Se at trace level in soils by high-performance liquid chromatography inductively coupled plasma mass spectrometry (ICP-MS) following specific extractions. To do so, the collision/reaction cell of the ICP-MS instrument and the interference corrections were optimized to measure reliably the four major Se isotopes. To exemplify the method capabilities, the behaviors of added (77)Se(IV) and ambient Se were followed up in two soils submitted to an ageing process during 3 months. The solid/liquid distribution of added Se reached a steady state after 1 month while its speciation and distribution among soil solid phases were still changing after 3 months. The results clearly demonstrate that slow processes are involved in Se retention and transformation in soils. The usual short-term experiments (<1 month) performed after Se addition are thus not suitable for long-term risk assessment. Interestingly, the behavior of added Se tended to that of ambient Se, suggesting that ambient Se would be useful to infer the fate of Se input over long time scales. PMID- 24048519 TI - The multiple oral presentations of multiple myeloma. AB - PURPOSE: The purpose of this case series is to show the varied oral presentations of multiple myeloma, illustrating the importance of carefully surveying the oral cavity for suspicious lesions that could be indicative of palpable disease and/or recurrence. The diagnostic criteria and prognostic features for multiple myeloma were also reviewed. CASE SERIES SUMMARY: This report focuses on five patients with myeloma manifestations involving the oral cavity, in which the oral presentation of multiple myeloma was an early indication of disease relapse. Although the clinical presentation may be variable, the majority of patients will develop lytic bone lesions and less commonly, extramedullary involvement during the course of their disease. DISCUSSION: The presentation of myeloma can be varied and the oral presentation, although rare, may be the sole manifestation or part of a group of signs of disease progression. Clinical presentations of patients with myelomatous lesions can mimic common dental pathologies, which then, in turn, can lead to delays in diagnosis and treatment. CONCLUSION: As members of an interdisciplinary oncology team, it is essential to be familiar with oral manifestations of multiple myeloma and proper diagnostic/biopsy techniques in order to avoid misdiagnosis and treatment delays. PMID- 24048521 TI - All signals lost. AB - Inhibitors of bacterial histidine kinases that globally deactivate bacterial signaling may offer a new offensive against antibiotic resistance. PMID- 24048522 TI - Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. AB - Achondroplasia is a rare genetic disease characterized by abnormal bone development, resulting in short stature. It is caused by a single point mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3), which leads to prolonged activation upon ligand binding. To prevent excessive intracellular signaling and rescue the symptoms of achondroplasia, we have developed a recombinant protein therapeutic approach using a soluble form of human FGFR3 (sFGFR3), which acts as a decoy receptor and prevents FGF from binding to mutant FGFR3. sFGFR3 was injected subcutaneously to newborn Fgfr3(ach/+) mice-the mouse model of achondroplasia-twice per week throughout the growth period during 3 weeks. Effective maturation of growth plate chondrocytes was restored in bones of treated mice, with a dose-dependent enhancement of skeletal growth in Fgfr3(ach/+) mice. This resulted in normal stature and a significant decrease in mortality and associated complications, without any evidence of toxicity. These results describe a new approach for restoring bone growth and suggest that sFGFR3 could be a potential therapy for children with achondroplasia and related disorders. PMID- 24048523 TI - MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia. AB - Deregulation of signaling pathways is a hallmark of malignant transformation. Signaling-associated phosphoproteins can be degraded to generate cancer-specific phosphopeptides that are presented by major histocompatibility complex (MHC) class I and II molecules and recognized by T cells; however, the contribution of these phosphoprotein-specific T cells to immune surveillance is unclear. We identified 95 phosphopeptides presented on the surface of primary hematological tumors and normal tissues, including 61 that were tumor-specific. Phosphopeptides were more prevalent on more aggressive and malignant samples. CD8(+) T cell lines specific for these phosphopeptides recognized and killed both leukemia cell lines and human leukocyte antigen-matched primary leukemia cells ex vivo. Notably, healthy individuals showed robust CD8(+) T cell responses against many of these phosphopeptides within the circulating memory compartment. This immunity was significantly reduced or absent in some leukemia patients. This reduction correlated with clinical outcome; however, immunity was restored after allogeneic stem cell transplantation. These results suggest that phosphopeptides may be targets of cancer immune surveillance in humans, and point to their importance for development of vaccine-based and T cell adoptive transfer immunotherapies. PMID- 24048524 TI - A host-based RT-PCR gene expression signature to identify acute respiratory viral infection. AB - Improved ways to diagnose acute respiratory viral infections could decrease inappropriate antibacterial use and serve as a vital triage mechanism in the event of a potential viral pandemic. Measurement of the host response to infection is an alternative to pathogen-based diagnostic testing and may improve diagnostic accuracy. We have developed a host-based assay with a reverse transcription polymerase chain reaction (RT-PCR) TaqMan low-density array (TLDA) platform for classifying respiratory viral infection. We developed the assay using two cohorts experimentally infected with influenza A H3N2/Wisconsin or influenza A H1N1/Brisbane, and validated the assay in a sample of adults presenting to the emergency department with fever (n = 102) and in healthy volunteers (n = 41). Peripheral blood RNA samples were obtained from individuals who underwent experimental viral challenge or who presented to the emergency department and had microbiologically proven viral respiratory infection or systemic bacterial infection. The selected gene set on the RT-PCR TLDA assay classified participants with experimentally induced influenza H3N2 and H1N1 infection with 100 and 87% accuracy, respectively. We validated this host gene expression signature in a cohort of 102 individuals arriving at the emergency department. The sensitivity of the RT-PCR test was 89% [95% confidence interval (CI), 72 to 98%], and the specificity was 94% (95% CI, 86 to 99%). These results show that RT-PCR-based detection of a host gene expression signature can classify individuals with respiratory viral infection and sets the stage for prospective evaluation of this diagnostic approach in a clinical setting. PMID- 24048525 TI - Angiopoietin-1 guides directional angiogenesis through integrin alphavbeta5 signaling for recovery of ischemic retinopathy. AB - Retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR) are ischemic retinal diseases caused by insufficient vascular network formation and vascular regression in addition to aberrant angiogenesis. We examined the role of angiopoietin-1 (Ang1) in retinal vascular network formation during postnatal development using Ang1 gain- and loss-of-function mouse models, and tested the effects of intraocular administration of Ang1 in an oxygen-induced retinopathy (OIR) mouse model that mimics cardinal features of ROP and PDR. We observed that Ang1 plays a substantial role in the formation of the retinal vascular network during postnatal development and that Ang1 supplementation can rescue vascular retinopathies by simultaneously promoting healthy vascular network formation and inhibiting subsequent abnormal angiogenesis, vascular leakage, and neuronal dysfunction in the retinas of the OIR model. We attribute these Ang1-induced effects to a dual signaling pathway-Tie2 signaling in the vascular region and integrin alphavbeta5 signaling in the astrocytes. The activation of integrin alphavbeta5 signaling promoted fibronectin accumulation and radial distribution along the sprouting endothelial cells, which consequently stimulated guided angiogenesis in the retina. These findings shed light on the role of Ang1 in the recovery of ischemic retinopathies such as ROP, PDR, and retinal vascular occlusive disease. PMID- 24048526 TI - Precise dissection of an Escherichia coli O157:H7 outbreak by single nucleotide polymorphism analysis. AB - The current pathogen-typing methods have suboptimal sensitivities and specificities. DNA sequencing offers an opportunity to type pathogens with greater degrees of discrimination using single nucleotide polymorphisms (SNPs) than with pulsed-field gel electrophoresis (PFGE) and other methodologies. In a recent cluster of Escherichia coli O157:H7 infections attributed to salad bar exposures and romaine lettuce, a subset of cases denied exposure to either source, although PFGE and multiple-locus variable-number tandem-repeat analysis (MLVA) suggested that all isolates had the same recent progenitor. Interrogation of a preselected set of 3,442,673 nucleotides in backbone open reading frames (ORFs) identified only 1 or 2 single nucleotide differences in 3 of 12 isolates from the cases who denied exposure. The backbone DNAs of 9 of 9 and 3 of 3 cases who reported or were unsure about exposure, respectively, were isogenic. Backbone ORF SNP set sequencing offers pathogen differentiation capabilities that exceed those of PFGE and MLVA. PMID- 24048527 TI - Rapid subtyping of Yersinia enterocolitica by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for diagnostics and surveillance. AB - In this study, an alternative to the current traditional bioserotyping techniques was developed for subtyping Y. enterocolitica using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The most common pathogenic bioserotypes could easily be distinguished using only a few bioserotype-specific biomarkers. However, biochemical methods should still be used to distinguish biotype 1A from 1B. PMID- 24048528 TI - First case of Streptococcus lutetiensis bacteremia involving a clindamycin resistant isolate carrying the lnuB gene. AB - Here, we describe the first case of a Streptococcus lutetiensis isolate harboring the lnuB gene. PMID- 24048529 TI - Comparison of the Simplexa FluA/B & RSV direct assay and laboratory-developed real-time PCR assays for detection of respiratory virus. AB - The results of the Focus Simplexa FluA/B & RSV Direct assay were compared to those of laboratory-developed reverse transcription PCR tests for 498 nasopharyngeal swabs. Concordance rates were 96.6% (476/493; kappa = 0.91), 97.6% (481/493; kappa = 0.47), and 99.2% (488/492; kappa = 0.94) for influenza A, influenza B, and respiratory syncytial virus, respectively. PMID- 24048530 TI - Comparative evaluation of blood and serum samples in rapid immunochromatographic tests for visceral leishmaniasis. AB - Rapid diagnostic tests (RDTs) based on the detection of specific antibodies in serum are commonly used for the diagnosis of visceral leishmaniasis (VL). Several commercial kits are available, and some of them allow the use of whole-blood samples instead of serum. An RDT is much more user-friendly for blood samples than for serum samples. In this study, we examined the sensitivities and specificities of six different commercially available immunochromatographic tests for their accuracy in detecting Leishmania infection in whole blood and serum of parasitologically confirmed VL cases. This study was performed in areas of India and Nepal where VL is endemic. A total of 177 confirmed VL cases, 208 healthy controls from areas of endemicity (EHCs), 26 malaria patients (MP), and 37 tuberculosis (TB) patients were enrolled. The reproducibilities of the blood and serum results and between-reader and between-laboratory results were tested. In India, the sensitivities of all the RDTs ranged between 94.7 and 100.0%, with no significant differences between whole blood and serum. The specificities ranged between 92.4 and 100.0%, except for the specificity of the Onsite Leishmania Ab RevB kit, which was lower (33.6 to 42.0%). No differences in specificities were observed for blood and serum. In Nepal, the sensitivities of all the test kits, for whole-blood as well as serum samples, ranged between 96.3 and 100.0%, and the specificities ranged between 90.1 and 96.1%, again with the exception of that of the Onsite Leishmania Ab RevB test, which was markedly lower (48.7 to 49.3%). The diagnostic accuracies of all the tests, except for one brand, were excellent for the whole-blood and serum samples. We conclude that whole blood is an adequate alternative for serum in RDTs for VL, with sensitivities and specificities comparable to those obtained in serum samples, provided that the test kit is of overall good quality. PMID- 24048531 TI - Evaluation of the nanosphere verigene gram-positive blood culture assay with the VersaTREK blood culture system and assessment of possible impact on selected patients. AB - The Verigene Gram-positive blood culture (BC-GP) assay (Nanosphere, Northbrook, IL) is a molecular method for the rapid identification of Gram-positive organisms and resistance markers directly from blood culture bottles. A total of 148 VersaTREK REDOX 1 40-ml aerobic bottles demonstrating Gram-positive bacteria were tested. Results were compared with those from conventional biochemical and matrix assisted laser desorption ionization-time of flight (MALDI-TOF) identifications. We obtained isolates of methicillin-resistant Staphylococcus aureus (MRSA) (24), methicillin-susceptible Staphylococcus aureus (MSSA) (14), methicillin-resistant Staphylococcus epidermidis (MRSE) (17), methicillin-susceptible Staphylococcus epidermidis (MSSE) (9), other coagulase-negative staphylococci (19), Streptococcus salivarius (5), Streptococcus parasanguinis (2), Streptococcus sanguinis (1), Streptococcus cristatus (1), the Streptococcus bovis group (5), Streptococcus agalactiae (9), the Streptococcus anginosus group (1), Streptococcus pneumoniae (6), vancomycin-resistant Enterococcus faecium (VRE FCM) (16), vancomycin-susceptible Enterococcus faecalis (3), Aerococcus viridans (2), Bacillus (6), Corynebacterium (8), Lactobacillus (2), Micrococcus (2), Neisseria mucosa (1), Escherichia coli (3), Candida tropicalis (1), Propionibacterium (1), and Rothia (1). Overall agreement with the culture results was 95%. A total of 137 of 138 (99%) monomicrobial cultures were concordant. We tested 9 polymicrobial samples and found 33% agreement. A chart review of 31 patients with MRSA, MSSA, or VRE demonstrated that the Nanosphere BC-GP assay might have led to more appropriate antibiotic selection for these patients an average of 42 h earlier. Additionally, contact isolation could have been initiated an average of 37 h earlier for patients with MRSA or VRE. The BC-GP assay may have a positive impact on patient care, health care costs, and antibiotic stewardship. PMID- 24048532 TI - Sampling and decontamination method for culture of nontuberculous mycobacteria in respiratory samples of cystic fibrosis patients. AB - We confirmed that chlorhexidine decontamination yielded more nontuberculous mycobacteria than did the N-acetyl-l-cysteine-NaOH-oxalic acid procedure from respiratory samples of cystic fibrosis patients on solid cultures. However, this improved recovery is mostly balanced if the latter is combined with liquid culture. Furthermore, none of the 145 cough swabs, used to sample young children, cultured positive, suggesting that swabs are low-quality samples. PMID- 24048533 TI - Simultaneous detection and differentiation of human rhino- and enteroviruses in clinical specimens by real-time PCR with locked nucleic Acid probes. AB - Human rhinoviruses (HRVs) and human enteroviruses (HEVs) are significant respiratory pathogens. While HRV infections are restricted to the respiratory tract, HEV infections may spread to secondary target organs. The method of choice for sensitive specific detection of these viruses is reverse transcription (RT) PCR with primers targeting the conserved 5' noncoding region of the viral RNA. On the other hand, sequence similarities between HRVs and HEVs complicate their differential detection. In this study, we describe the use of locked nucleic acid (LNA) analogues in short double-dye probes which contained only two selectively HRV- or HEV-specific bases. The double-stranded DNA dye BOXTO (4-[6-(benzoxazole 2-yl-(3-methyl-)-2,3-dihydro-(benzo-1,3-thiazole)-2-methylidene)]-1-methyl quinolinium chloride) was used with the LNA probes in a tricolor real-time PCR assay to allow specific detection of HRVs (probes labeled with 6 carboxyfluorescein [FAM] [green]) and HEVs (Cy5 [red]) with additional melting curve analysis (BOXTO [yellow]). The functionality of the probes was validated in PCR and RT-PCR assays using plasmids containing viral cDNA, quantified viral RNA transcripts, cultivated rhino- and enterovirus prototypes, and clinical specimens. Of 100 HRV and 63 HEV prototypes, the probes correctly identified all HEVs except one that produced only a BOXTO signal. Among 118 clinical specimens with sequencing results, concordant results were obtained for 116 specimens. Two specimens were reactive with both probes, but sequencing yielded only a single virus. Real-time PCR with LNA probes allowed sensitive group-specific identification of HRVs and HEVs and would enable relative copy number determination. The assay is suitable for rapid and accurate differential detection of HRVs and HEVs in a diagnostic laboratory setting. PMID- 24048534 TI - BK polyomavirus subtype III in a pediatric renal transplant patient with nephropathy. AB - BK polyomavirus (BKV) is an emerging pathogen in immunocompromised individuals. BKV subtype III is rarely identified and has not previously been associated with disease. Here we provide the whole-genome sequence of a subtype III BKV from a pediatric kidney transplant patient with polyomavirus-associated nephropathy. PMID- 24048535 TI - Quantitative detection of Vibrio cholera toxin by real-time and dynamic cytotoxicity monitoring. AB - We report here the quantitative detection of Vibrio cholerae toxin (CT) in isolates and stool specimens by dynamic monitoring of the full course of CT mediated cytotoxicity in a real-time cell analysis (RTCA) system. Four cell lines, including Y-1 mouse adrenal tumor cells, Chinese hamster ovary (CHO) cells, small intestine epithelial (FHs74Int) cells, and mouse adrenal gland (PC12 Adh) cells, were evaluated for their suitability for CT-induced cytotoxicity testing. Among them, the Y-1 line was demonstrated to be the most sensitive for CT-mediated cytotoxicity, with limits of detection of 7.0 pg/ml for purified CT and 0.11 ng/ml for spiked CT in pooled negative stool specimens. No CT-mediated cytotoxicity was observed for nontoxigenic V. cholerae, non-V. cholerae species, or non-V. cholerae enterotoxins. The CT-RTCA assay was further validated with 100 stool specimens consecutively collected from patients with diarrhea and 200 V. cholerae isolates recovered from patients and the environment, in comparison to a reference using three detection methods. The CT-RTCA assay had sensitivities and specificities of 97.5% and 100.0%, respectively, for V. cholerae isolates and 90.0% and 97.2% for stool specimens. For stool specimens spiked with CT concentrations ranging from 3.5 pg/ml to 1.8 ng/ml, the inoculation-to-detection time was 1.12 +/- 0.38 h, and the values were inversely correlated with CT concentrations (rho = -1; P = 0.01). The results indicate that the CT-RTCA assay with the Y-1 cell line provides a rapid and sensitive tool for the quantitative detection of CT activities in clinical specimens. PMID- 24048536 TI - Factors influencing acquisition of Burkholderia cepacia complex organisms in patients with cystic fibrosis. AB - Burkholderia cepacia complex organisms are important transmissible pathogens found in cystic fibrosis (CF) patients. In recent years, the rates of cross infection of epidemic strains have declined due to effective infection control efforts. However, cases of sporadic B. cepacia complex infection continue to occur in some centers. The acquisition pathways and clinical outcomes of sporadic B. cepacia complex infection are unclear. We sought to determine the patient clinical characteristics, outcomes, incidence, and genotypic relatedness for all cases of B. cepacia complex infection at two CF centers. We also sought to study the external conditions that influence the acquisition of infection. From 2001 to 2011, 67 individual organisms were cultured from the respiratory samples of 64 patients. Sixty-five percent of the patients were adults, in whom chronic infections were more common (68%) (P = 0.006). The incidence of B. cepacia complex infection increased by a mean of 12% (95% confidence interval [CI], 3 to 23%) per year. The rates of transplantation and death were similar in the incident cases who developed chronic infection compared to those in patients with chronic Pseudomonas aeruginosa infection. Multilocus sequence typing revealed 50 individual strains from 65 isolates. Overall, 85% of the patients were infected with unique strains, suggesting sporadic acquisition of infection. The yearly incidence of nonepidemic B. cepacia complex infection was positively correlated with the amount of rainfall in the two sites examined: subtropical Brisbane (r = 0.65, P = 0.031) and tropical Townsville (r = 0.82, P = 0.002). This study demonstrates that despite strict cohort segregation, new cases of unrelated B. cepacia complex infection continue to occur. These data also support an environmental origin of infection and suggest that climate conditions may be associated with the acquisition of B. cepacia complex infections. PMID- 24048537 TI - Advantages of using matrix-assisted laser desorption ionization-time of flight mass spectrometry as a rapid diagnostic tool for identification of yeasts and mycobacteria in the clinical microbiological laboratory. AB - Yeast and mycobacteria can cause infections in immunocompromised patients and normal hosts. The rapid identification of these organisms can significantly improve patient care. There has been an increasing number of studies on using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for rapid yeast and mycobacterial identifications. However, studies on direct comparisons between the Bruker Biotyper and bioMerieux Vitek MS systems for the identification of yeast and mycobacteria have been limited. This study compared the performance of the two systems in their identification of 98 yeast and 102 mycobacteria isolates. Among the 98 yeast isolates, both systems generated species-level identifications in >70% of the specimens, of which Candida albicans was the most commonly cultured species. At a genus-level identification, the Biotyper system identified more isolates than the Vitek MS system for Candida (75/78 [96.2%]versus 68/78 [87.2%], respectively; P = 0.0426) and non-Candida yeasts (18/20 [90.0%]versus 7/20 [35.0%], respectively; P = 0.0008). For mycobacterial identification, the Biotyper system generated reliable identifications for 89 (87.3%) and 64 (62.8%) clinical isolates at the genus and species levels, respectively, from solid culture media, whereas the Vitek MS system did not generate any reliable identification. The MS method differentiated 12/21 clinical species, despite the fact that no differentiation between Mycobacterium abscessus and Mycobacterium chelonae was found by using 16S rRNA gene sequencing. In summary, the MALDI-TOF MS method provides short turnaround times and a standardized working protocol for the identification of yeast and mycobacteria. Our study demonstrates that MALDI-TOF MS is suitable as a first line test for the identification of yeast and mycobacteria in clinical laboratories. PMID- 24048538 TI - Detection of Streptococcus pyogenes by use of Illumigene group A Streptococcus assay. AB - The performance of the Illumigene group A Streptococcus assay was evaluated by comparing it to culture using 437 consecutive throat swabs. The Illumigene assay was also directly compared to PCR with 161 samples. This Illumigene assay is rapid and easy to perform. The assay also has high sensitivity (100%) compared to culture or PCR and high specificity (99.2%) compared to PCR. A total of 8.8% of the isolates were erythromycin resistant, and 6.9% were clindamycin resistant. PMID- 24048539 TI - Clinical evaluation of a real-time PCR assay for identification of Salmonella, Shigella, Campylobacter (Campylobacter jejuni and C. coli), and shiga toxin producing Escherichia coli isolates in stool specimens. AB - Enteric illness affects millions of individuals annually in the United States and results in >50,000 hospitalizations. The rapid and accurate identification of bacterial pathogens associated with gastroenteritis can aid acute patient management decisions, including the use of antibiotic therapy and infection control. This study compared the ProGastro SSCS multiplex real-time PCR assay (Gen-Probe Prodesse, San Diego, CA) to culture for the identification of Campylobacter spp. (Campylobacter jejuni and Campylobacter coli), Salmonella spp., and Shigella spp. and to broth enrichment followed by an FDA-cleared enzyme immunoassay (EIA) for the identification of Shiga toxin-producing Escherichia coli (STEC) isolates in stool specimens. Stool samples submitted in preservatives for routine culture and EIA were prospectively enrolled and tested at four clinical centers. Discrepancies between the ProGastro SSCS assay and culture or EIA were resolved using bidirectional sequencing. The overall prevalence of the pathogens as detected by culture was 5.6% (1.8% Campylobacter, 1.8% Salmonella, 1.3% Shigella, and 0.8% STEC). When results based on the ProGastro SSCS assay and bidirectional sequencing were applied, the overall prevalence increased to 8.3% (2.3% Campylobacter, 2.6% Salmonella, 1.8% Shigella, and 1.6% STEC). Following resolution of the discrepant results, the sensitivity of the ProGastro SSCS assay was 100% for all pathogens, and the specificities ranged from 99.4% to 100%. The sensitivity of culture compared to sequence-confirmed ProGastro SSCS results ranged from 52.9% to 76.9%, with the specificities ranging from 99.9% to 100%. Overall, these results suggest that the ProGastro SSCS assay is highly sensitive and specific in a clinical setting. PMID- 24048540 TI - Two mutations associated with macrolide resistance in Treponema pallidum in Shandong, China. PMID- 24048541 TI - Development and validation of a liquid medium (M7H9C) for routine culture of Mycobacterium avium subsp. paratuberculosis to replace modified Bactec 12B medium. AB - Liquid culture of Mycobacterium avium subsp. paratuberculosis from clinical samples, such as feces, is the most sensitive antemortem test for the diagnosis of Johne's disease in ruminants. In Australia, New Zealand, the United States, and some other countries, the Bactec 460 system with modified Bactec 12B medium (Becton, Dickinson) has been the most commonly used liquid culture system, but it was discontinued in 2012. In this study, a new liquid culture medium, M7H9C, was developed. It consists of a Middlebrook 7H9 medium base with added Casitone, albumin, dextrose, catalase, egg yolk, mycobactin J, and a cocktail of antibiotics. We found that polyoxyethylene stearate (POES) was not essential for the cultivation of M. avium subsp. paratuberculosis in either the Bactec 12B or the M7H9C medium. The limit of detection determined using pure cultures of the C and S strains of M. avium subsp. paratuberculosis was 7 bacilli per 50 MUl inoculum in the two media. The new medium was validated using 784 fecal and tissue samples from sheep and cattle, >25% of which contained viable M. avium subsp. paratuberculosis. Discrepant results for the clinical samples between the two media were mostly associated with samples that contained <10 viable bacilli per gram, but these results were relatively uncommon, and the performances of the two media were not significantly different. M7H9C medium was less than half the cost of the Bactec 12B medium and did not require regular examination during incubation, but a confirmatory IS900 PCR test had to be performed on every culture after the predetermined incubation period. PMID- 24048542 TI - Detection of antibodies against Avian influenza virus subtypes H7 and H9 among veterinarians in Guangdong province, China. PMID- 24048543 TI - Detection of heteroresistant Mycobacterium tuberculosis by pyrosequencing. AB - The ability of pyrosequencing to detect a resistant minority population of a heteroresistant Mycobacterium tuberculosis strain was investigated by performing a titration study. A mutant signal was noted only when the proportion of mutant DNA in the DNA target was 35 to 50%, showing that the sensitivity is significantly lower than that of phenotypic drug susceptibility test methods. PMID- 24048544 TI - Moving towards the pan-European unification of multiple sclerosis nurses: a consensus paper. PMID- 24048545 TI - Risk factors related to cardiovascular diseases and the metabolic syndrome in multiple sclerosis - a systematic review. AB - Despite many epidemiological studies examining comorbidity in people with multiple sclerosis (pMS), there are conflicting opinions on whether pMS are at more or less risk of cardiovascular disease (CVD) and the metabolic syndrome compared with the general population. As pMS can now expect longer survival, this as an important question both at an individual and public health level. This study aimed to systematically review the literature linking MS to CVD risks and to the risk factors constituting the metabolic syndrome. This systematic review is based on a comprehensive literature search of six databases (Swemed+, Pubmed, Embase, Cochrane, PEDro and CINAHL). In total 34 studies were identified. Despite the high number of identified papers, only limited and inconsistent data exist on the risk factors of the metabolic syndrome and MS. Overall, the data suggest an increased CVD risk in pMS. From the existing studies it is not clear whether the increased risk of CVD is related to an increased risk of obesity or changes in body composition, hypertension, dyslipidemia or type II diabetes in pMS, indicating the need for future research in the field, if we are to advise pMS adequately in avoiding preventable comorbidity. PMID- 24048546 TI - Multistationarity in sequential distributed multisite phosphorylation networks. AB - Multisite phosphorylation networks are encountered in many intracellular processes like signal transduction, cell-cycle control, or nuclear signal integration. In this contribution, networks describing the phosphorylation and dephosphorylation of a protein at n sites in a sequential distributive mechanism are considered. Multistationarity (i.e., the existence of at least two positive steady state solutions of the associated polynomial dynamical system) has been analyzed and established in several contributions. It is, for example, known that there exist values for the rate constants where multistationarity occurs. However, nothing else is known about these rate constants. Here, we present a sign condition that is necessary and sufficient for multistationarity in n-site sequential, distributive phosphorylation. We express this sign condition in terms of linear systems, and show that solutions of these systems define rate constants where multistationarity is possible. We then present, for n>=2, a collection of feasible linear systems, and hence give a new and independent proof that multistationarity is possible for n>=2. Moreover, our results allow to explicitly obtain values for the rate constants where multistationarity is possible. Hence, we believe that, for the first time, a systematic exploration of the region in parameter space where multistationarity occurs has become possible. One consequence of our work is that, for any pair of steady states, the ratio of the steady state concentrations of kinase-substrate complexes equals that of phosphatase-substrate complexes. PMID- 24048547 TI - A stronger necessary condition for the multistationarity of chemical reaction networks. AB - Biochemical reaction networks grow bigger and bigger, fed by the high-throughput data provided by biologists and bred in open repositories of models allowing merging and evolution. Nevertheless, since the available data is still very far from permitting the identification of the increasing number of kinetic parameters of such models, the necessity of structural analyses for describing the dynamics of chemical networks appears stronger every day. Using the structural information, notably from the stoichiometric matrix, of a biochemical reaction system, we state a more strict version of the famous Thomas' necessary condition for multistationarity. In particular, the obvious cases where Thomas' condition was trivially satisfied, mutual inhibition due to a multimolecular reaction and mutual activation due to a reversible reaction, can now easily be ruled out. This more strict condition shall not be seen as some version of Thomas' circuit functionality for the continuous case but rather as related and complementary to the whole domain of the structural analysis of (bio)chemical reaction systems, as pioneered by the chemical reaction network theory. PMID- 24048548 TI - Bilateral internuclear ophthalmoplegia associated with pediatric brain tumor progression: a case series and review of the literature. AB - Internuclear ophthalmoplegia (INO) is a rare disorder of conjugate lateral gaze that has been described in a number of neurologic conditions including multiple sclerosis, stroke and less commonly brain tumors. We describe a series of 3 boys (11, 12, 15 years) diagnosed with primary central nervous system tumors (pilomyxoid variant astrocytoma, anaplastic oligoastrocytoma, gliomatosis cerebri) who developed bilateral INO as a manifestation of progressive disease. Time from diagnosis to development of bilateral INO ranged from 13-36 months. All children died of their disease 1-9 months following diagnosis of bilateral INO and had significant dorsal pontine invasion on magnetic resonance imaging at progression. Only one child had brainstem involvement at diagnosis. Our case series highlights this rare ophthalmologic syndrome of bilateral INO in association with tumor progression and provides a literature review of brain tumor associations with INO. PMID- 24048549 TI - [Interdisciplinary neurovascular network: a new structure for treatment of stroke and other cerebrovascular diseases in Germany]. PMID- 24048550 TI - Shared decision making in patients with osteoarthritis of the hip and knee: results of a randomized controlled trial. AB - BACKGROUND: Despite evidence that shared decision-making tools for treatment decisions improve decision quality and patient engagement, they are not commonly employed in orthopaedic practice. The purpose of this study was to evaluate the impact of decision and communication aids on patient knowledge, efficiency of decision making, treatment choice, and patient and surgeon experience in patients with osteoarthritis of the hip or knee. METHODS: One hundred and twenty-three patients who were considered medically appropriate for hip or knee replacement were randomized to either a shared decision-making intervention or usual care. Patients in the intervention group received a digital video disc and booklet describing the natural history and treatment alternatives for hip and knee osteoarthritis and developed a structured list of questions for their surgeon in consultation with a health coach. Patients in the control group received information about the surgeon's practice. Both groups reported their knowledge and stage in decision making and their treatment choice, satisfaction, and communication with their surgeon. Surgeons reported the appropriateness of patient questions and their satisfaction with the visit. The primary outcome measure tracked whether patients reached an informed decision during their first visit. Statistical analyses were performed to evaluate differences between groups. RESULTS: Significantly more patients in the intervention group (58%) reached an informed decision during the first visit compared with the control group (33%) (p = 0.005). The intervention group reported higher confidence in knowing what questions to ask their doctor (p = 0.0034). After the appointment, there was no significant difference between groups in the percentage of patients choosing surgery (p = 0.48). Surgeons rated the number and appropriateness of patient questions higher in the intervention group (p < 0.0001), reported higher satisfaction with the efficiency of the intervention group visits (p < 0.0001), and were more satisfied overall with the intervention group visits (p < 0.0001). CONCLUSIONS: Decision and communication aids used in orthopaedic practice had benefits for both patients and surgeons. These findings could be important in facilitating adoption of shared decision-making tools into routine orthopaedic practice. PMID- 24048551 TI - Novel scaffold-based BST-CarGel treatment results in superior cartilage repair compared with microfracture in a randomized controlled trial. AB - BACKGROUND: Microfracture, the standard of care, is recognized to be an incomplete solution for cartilage damage. BST-CarGel, a chitosan-based medical device, is mixed with autologous whole blood and is applied to a microfractured cartilage lesion in which it physically stabilizes the clot and guides and enhances marrow-derived repair. An international, multicenter, randomized controlled trial was conducted to evaluate BST-CarGel treatment compared with microfracture alone in the repair of cartilage lesions in the knee. METHODS: Eighty patients between the ages of eighteen and fifty-five years with a single, symptomatic focal lesion on the femoral condyles were randomized to BST-CarGel and microfracture treatment (n = 41) or microfracture treatment alone (n = 39). The primary end points of repair tissue quantity and quality at twelve months were assessed by quantitative three-dimensional magnetic resonance imaging measuring the degree of lesion filling and T2 relaxation time with use of standardized one and twelve-month posttreatment scans. The secondary end point at twelve months was clinical benefit determined with the Western Ontario and McMaster Universities Osteoarthritis Index. The tertiary end point was quality of life determined by the Short Form-36. Safety was assessed through the recording of adverse events. RESULTS: Patient baseline characteristics were similar in the two groups, although baseline lesion areas were slightly larger on quantitative magnetic resonance imaging for the BST-CarGel group compared with the microfracture group. Blinded quantitative magnetic resonance imaging analysis demonstrated that, at twelve months, when compared with microfracture treatment alone, BST-CarGel treatment met both primary end points by achieving statistical superiority for greater lesion filling (p = 0.011) and more hyaline cartilage like T2 values (p = 0.033). The lesion filling values were 92.8% +/- 2.0% for the BST-CarGel treatment group and 85.2% +/- 2.1% for the microfracture treatment group, and the mean T2 values were 70.5 +/- 4.5 ms for the BST-CarGel treatment group and 85.0 +/- 4.9 ms for the microfracture treatment group. Western Ontario and McMaster Universities Osteoarthritis Index subscales for pain, stiffness, and function yielded equivalent improvement for both groups at twelve months, which were significant (p < 0.0001) from baseline. Treatment safety profiles were considered comparable. CONCLUSIONS: At twelve months, BST-CarGel treatment resulted in greater lesion filling and superior repair tissue quality compared with microfracture treatment alone. Clinical benefit was equivalent between groups at twelve months, and safety was similar. PMID- 24048552 TI - Efficacy and safety of surgical decompression in patients with cervical spondylotic myelopathy: results of the AOSpine North America prospective multi center study. AB - BACKGROUND: Cervical spondylotic myelopathy is the leading cause of spinal cord dysfunction worldwide. The objective of this study was to evaluate the impact of surgical decompression on functional, quality-of-life, and disability outcomes at one year after surgery in a large cohort of patients with this condition. METHODS: Adult patients with symptomatic cervical spondylotic myelopathy and magnetic resonance imaging evidence of spinal cord compression were enrolled at twelve North American centers from 2005 to 2007. At enrollment, the myelopathy was categorized as mild (modified Japanese Orthopaedic Association [mJOA] score >= 15), moderate (mJOA = 12 to 14), or severe (mJOA < 12). Patients were followed prospectively for one year, at which point the outcomes of interest included the mJOA score, Nurick grade, Neck Disability Index (NDI), and Short Form-36 version 2 (SF-36v2). All outcomes at one year were compared with the preoperative values with use of univariate paired statistics. Outcomes were also compared among the severity classes with use of one-way analysis of variance. Finally, a multivariate analysis that adjusted for baseline differences among the severity groups was performed. Treatment-related complication data were collected and the overall complication rate was calculated. RESULTS: Eighty-five (30.6%) of the 278 enrolled patients had mild cervical spondylotic myelopathy, 110 (39.6%) had moderate disease, and 83 (29.9%) had severe disease preoperatively. One-year follow-up data were available for 222 (85.4%) of 260 patients. There was a significant improvement from baseline to one year postoperatively (p < 0.05) in the mJOA score, Nurick grade, NDI score, and all SF-36v2 health dimensions (including the mental and physical health composite scores) except general health. With the exception of the change in the mJOA, the degree of improvement did not depend on the severity of the preoperative symptoms. These results remained unchanged after adjusting for relevant confounders in the multivariate analysis. Fifty-two patients experienced complications (prevalence, 18.7%), with no significant differences among the severity groups. CONCLUSIONS: Surgical decompression for the treatment of cervical spondylotic myelopathy was associated with improvement in functional, disability-related, and quality-of-life outcomes at one year of follow-up for all disease severity categories. Furthermore, complication rates observed in the study were commensurate with those in previously reported cervical spondylotic myelopathy series. PMID- 24048553 TI - A clinical prediction model to determine outcomes in patients with cervical spondylotic myelopathy undergoing surgical treatment: data from the prospective, multi-center AOSpine North America study. AB - BACKGROUND: Cervical spondylotic myelopathy is a progressive spine disease and the most common cause of spinal cord dysfunction worldwide. The objective of this study was to develop a prediction model, based on data from a prospective multi center study, relating a combination of clinical and imaging variables to surgical outcome in patients with cervical spondylotic myelopathy. METHODS: Two hundred and seventy-eight patients diagnosed with cervical spondylotic myelopathy treated surgically were enrolled at twelve different sites in the multi-center AOSpine North America study. Univariate analyses were performed to evaluate the relationship between outcome, assessed with the modified Japanese Orthopaedic Association (mJOA) score, and various clinical and imaging predictors. A set of important candidate variables for the final model was selected on the basis of author consensus, literature support, and statistical findings. Logistic regression was used to formulate the final model. RESULTS: Univariate analyses demonstrated that the odds of a successful outcome decreased with a longer duration of symptoms (odds ratio [OR] = 0.80, 95% confidence interval [CI] = 0.65 to 0.98, p = 0.030); a lower baseline mJOA score (OR = 0.74, 95% CI = 0.65 to 0.84, p < 0.0001); the presence of psychological comorbidities (OR = 0.51, 95% CI = 0.29 to 0.92, p = 0.024); the presence of broad-based, unstable gait (OR = 2.72, 95% CI = 1.47 to 5.06, p = 0.0018) or other gait impairment (OR = 3.56, 95% CI = 1.75 to 7.22, p = 0.0005); and older age (OR = 0.96, 95% CI = 0.93 to 0.98, p = 0.0004). The dependent variable, the mJOA score at one year, was dichotomized for logistic regression: a "successful" outcome was defined as a final score of >=16 and a "failed" outcome was a score of <16. The final model included age (OR = 0.97, 95% CI = 0.94 to 0.99, p = 0.0017), duration of symptoms (OR = 0.78, 95% CI = 0.61 to 0.997, p = 0.048), smoking status (OR = 0.46, 95% CI = 0.21 to 0.98, p = 0.043), impairment of gait (OR = 2.66, 95% CI = 1.17 to 6.06, p = 0.020), psychological comorbidities (OR = 0.33, 95% CI = 0.15 to 0.69, p = 0.0035), baseline mJOA score (OR = 1.22, 95% CI = 1.05 to 1.41, p = 0.0084), and baseline transverse area of the cord on magnetic resonance imaging (OR = 1.02, 95% CI = 0.99 to 1.05, p = 0.19). The area under the receiver operator characteristic curve was 0.79, indicating good model prediction. CONCLUSIONS: On the basis of the results of the AOSpine North America study, we identified a list of the most important predictors of surgical outcome for cervical spondylotic myelopathy. PMID- 24048554 TI - Iatrogenic nerve injuries during shoulder surgery. AB - INTRODUCTION: The current literature indicates that neurologic injuries during shoulder surgery occur infrequently and result in little if any morbidity. The purpose of this study was to review one institution's experience treating patients with iatrogenic nerve injuries after shoulder surgery. METHODS: A retrospective review of the records of patients evaluated in a brachial plexus specialty clinic from 2000 to 2010 identified twenty-six patients with iatrogenic nerve injury secondary to shoulder surgery. The records were reviewed to determine the operative procedure, time to presentation, findings on physical examination, treatment, and outcome. RESULTS: The average age was forty-three years (range, seventeen to seventy-two years), and the average delay prior to referral was 5.4 months (range, one to fifteen months). Seven nerve injuries resulted from open procedures done to treat instability; nine, from arthroscopic surgery; four, from total shoulder arthroplasty; and six, from a combined open and arthroscopic operation. The injury occurred at the level of the brachial plexus in thirteen patients and at a terminal nerve branch in thirteen. Fifteen patients (58%) did not recover nerve function after observation and required surgical management. A structural nerve injury (laceration or suture entrapment) occurred in nine patients (35%), including eight of the thirteen who presented with a terminal nerve branch injury and one of the thirteen who presented with an injury at the level of the brachial plexus. CONCLUSIONS: Nerve injuries occurring during shoulder surgery can produce severe morbidity and may require surgical management. Injuries at the level of a peripheral nerve are more likely to be surgically treatable than injuries of the brachial plexus. A high index of suspicion and early referral and evaluation should be considered when evaluating patients with iatrogenic neurologic deficits after shoulder surgery. PMID- 24048555 TI - Management of degloving injuries of the foot with a defatted full-thickness skin graft. AB - BACKGROUND: Degloving injuries of the foot with involvement of the heel and sole occur relatively rarely but pose an extreme challenge to the reconstructive surgeon due to the unique anatomy of the foot. Very limited studies are available regarding the outcomes of reattachment of the degloved skin as a full-thickness graft. METHODS: Twenty-one patients, including eight children and thirteen adults, were treated for a degloving injury of the foot with an immediate defatted full-thickness skin graft from September 2002 to January 2010. After reattachment to its original anatomical site, the graft was further secured with multiple sutures and was fenestrated to improve skin graft incorporation. Traditional dressings were applied. At the time of follow-up, the clinical outcome was graded with use of the Maryland Foot Score. RESULTS: Complete incorporation of the graft occurred in ten of the thirteen adults and seven of the eight children (p > 0.05). Follow-up at an average of 32.8 months (range, twenty-four to sixty months) revealed stable wounds in 81% (seventeen) of the twenty-one patients. All stated that they were satisfied with the cosmetic appearance of the affected foot. At the time of the last follow-up, seventeen of the twenty-one patients had a good to excellent score according to the Maryland Foot Score. Sensation restoration in the pediatric group started earlier and progressed faster than that in the adult group, but all patients obtained at least protective sensation eventually and none complained of cold intolerance in the foot. CONCLUSIONS: Degloving injuries can be treated successfully with a defatted full-thickness skin graft followed by conventional dressings in both children and adults. This procedure is relatively simple, without the demands of microsurgical techniques, and can provide good functional and cosmetic results. PMID- 24048556 TI - Impact of hospital volume on postoperative complications and in-hospital mortality after musculoskeletal tumor surgery: analysis of a national administrative database. AB - BACKGROUND: We are aware of only one report describing the relationship between operative volume and outcomes in musculoskeletal tumor surgery, although numerous studies have described such relationships in other surgical procedures. The aim of the present study was to use a nationally representative inpatient database to evaluate the impact of hospital volume on the rates of postoperative complications and in-hospital mortality after musculoskeletal tumor surgery. METHODS: We used the Japanese Diagnostic Procedure Combination administrative database to retrospectively identify 4803 patients who had undergone musculoskeletal tumor surgery during 2007 to 2010. Patients were then divided into tertiles of approximately equal size on the basis of the annual hospital volume (number of patients undergoing musculoskeletal tumor surgery): low, twelve or fewer cases/year; medium, thirteen to thirty-one cases/year; and high, thirty two or more cases/year. Logistic regression analyses were performed to examine the relationships between various factors and the rates of postoperative complications and in-hospital mortality adjusted for all patient demographic characteristics. RESULTS: The overall postoperative complication rate was 7.2% (348 of 4803), and the in-hospital mortality rate was 2.4% (116 of 4803). Postoperative complications included surgical site infections in 132 patients (2.7%), cardiac events in sixty-four (1.3%), respiratory complications in fifty one (1.1%), sepsis in thirty-one (0.6%), pulmonary emboli in sixteen (0.3%), acute renal failure in eleven (0.2%), and cerebrovascular events in seven (0.1%). The postoperative complication rate was related to the duration of anesthesia (odds ratio [OR] for a duration of more than 240 compared with less than 120 minutes, 2.44; 95% confidence interval [CI], 1.68 to 3.53; p < 0.001) and to hospital volume (OR for high compared with low volume, 0.73; 95% CI, 0.55 to 0.96; p = 0.027). The mortality rate was related to the diagnosis (OR for a metastatic compared with a primary bone tumor, 3.67; 95% CI, 1.66 to 8.09; p = 0.001), type of surgery (OR for amputation compared with soft-tissue tumor resection without prosthetic reconstruction, 3.81; 95% CI, 1.42 to 10.20; p = 0.008), and hospital volume (OR for high compared with low volume, 0.26; 95% CI, 0.14 to 0.50; p < 0.001). CONCLUSIONS: We identified an independent effect of hospital volume on outcomes after adjusting for patient demographic characteristics. We recommend regionalization of musculoskeletal tumor surgery to high-volume hospitals in an attempt to improve patient outcomes. PMID- 24048557 TI - Patient-reported outcome after displaced femoral neck fracture: a national survey of 4467 patients. AB - BACKGROUND: Arthroplasty appears to be superior to internal fixation, with regard to complication rates, as a treatment for displaced femoral neck fractures. Less is known about the result as perceived by the patient. The aims of this prospective observational study were (1) to determine whether patient-reported outcomes after a displaced femoral neck fracture can be evaluated on a nationwide basis by means of a mailed survey, and (2) to evaluate differences among treatment methods with respect to patient-reported pain, health-related quality of life, and satisfaction with the surgical result. METHODS: Through collaboration between the Swedish Hip Arthroplasty Register and the Swedish National Hip Fracture Register, 5902 patients (median age, eighty-four years; range, eighteen to 103 years) treated with internal fixation, total hip arthroplasty, or hemiarthroplasty for a displaced femoral neck fracture were identified. A composite questionnaire, including the EQ-5D and visual analog scales for pain and for satisfaction with the surgical result, was mailed to the 4467 patients who remained alive (median follow-up, fourteen months; range, seven to twenty-two months). RESULTS: The total response rate was 79% (n = 3513); 72% to 75% of the patients completed each of the questionnaire sections. Both patients below and patients above seventy years of age treated with total hip arthroplasty reported less pain and were more satisfied compared with those treated with internal fixation or hemiarthroplasty (although the differences between total hip arthroplasty and hemiarthroplasty in patients below seventy years of age did not reach significance). CONCLUSIONS: A mailed patient-reported outcomes questionnaire is a feasible method for national follow-up of hip fractures, with an acceptable response rate. The study also suggests that total hip arthroplasty as a treatment for femoral neck fracture is associated with less pain and greater satisfaction at short-term follow-up compared with internal fixation and hemiarthroplasty, both in patients younger and older than seventy years. PMID- 24048558 TI - Comparison of hemiarthroplasty and reverse arthroplasty for treatment of proximal humeral fractures: a systematic review. AB - BACKGROUND: Complex proximal humeral fractures that are not amenable to surgical fixation represent a difficult treatment problem. The purpose of this systematic review was to critically examine the outcomes of reverse shoulder arthroplasty and hemiarthroplasty (with use of a fracture-specific stem) for the treatment of proximal humeral fractures. METHODS: A systematic review of the literature was performed by means of a search of electronic databases. Two reviewers independently assessed the methodological quality and extracted relevant data from each included study. When outcomes data were similar among studies, the data were pooled by means of frequency-weighted values to generate summary outcomes. RESULTS: Fourteen studies fulfilled all inclusion and exclusion criteria and were included. Patients were followed for a frequency-weighted mean of 43.5 months in the reverse arthroplasty group and 31.1 months in the hemiarthroplasty group (p = 0.228). Subjective outcomes (including the Constant score, Constant pain subscore, and American Shoulder and Elbow Surgeons [ASES] score) and range-of motion parameters (including active forward elevation, abduction, and external rotation) were similar between the two groups. Compared with hemiarthroplasty, reverse arthroplasty was associated with 4.0 times greater odds of a postoperative complication. CONCLUSIONS: The compiled data and frequency-weighted means demonstrated improvement in function, pain, and range of motion after reverse arthroplasty and hemiarthroplasty. Patients and physicians should consider projected functional outcomes, implant costs, and complication rates when selecting an appropriate arthroplasty technique for this indication. PMID- 24048559 TI - Advances in acetabular reconstruction in revision total hip arthroplasty: maximizing function and outcomes after treatment of periacetabular osteolysis around the well-fixed shell. PMID- 24048560 TI - What's new in total hip arthroplasty. PMID- 24048561 TI - Disturbance of rib cage development causes progressive thoracic scoliosis: the creation of a nonsurgical structural scoliosis model in mice. AB - BACKGROUND: The pathomechanism underlying idiopathic scoliosis remains unclear, and, to our knowledge, a consistent and relevant animal model has not been established previously. The goal of this study was to examine whether a disturbance of rib cage development is a causative factor for scoliosis and to establish a nonsurgical mouse model of progressive scoliosis. METHODS: To examine the relationship between rib cage development and the pathogenesis of progressive scoliosis, a plastic restraint limiting anteroposterior rib cage development was placed on the chest of four-week-old mice. All mice were evaluated with whole spine radiographs, and the severity of scoliosis was consecutively measured. The rib cage rotation angle and the anteroposterior chest dimension were measured with use of micro-computed tomography scanning. To examine whether the imbalanced load transmission through the ribs to the vertebral body was involved in our model, we performed a rib-neck osteotomy in a subgroup of the mice. RESULTS: The thoracic restraint did not provoke spinal curvature immediately after it was applied, but nine of ten mice that wore the restraint but did not have rib osteotomy gradually developed progressive scoliosis. Radiographs and computed tomography images showed a right thoracic curvature, vertebral rotation, and narrow chest in the mice that had worn the restraint for eleven weeks but did not have rib osteotomy even after the restraint was removed. The anteroposterior chest dimension was significantly correlated with both the curve magnitude and the rib cage rotation angle. The progression of spinal deformity was observed only during the adolescent growth spurt, and it plateaued thereafter. The left side rib osteotomy led to the development of progressive left-thoracic curvature, whereas the bilateral rib osteotomy did not cause scoliosis, even with restraint wear. CONCLUSIONS: We established a nonsurgical experimental model of progressive scoliosis and also demonstrated that a rib cage deformity with an imbalanced load to the vertebral body resulted in progressive structural scoliosis. PMID- 24048562 TI - Influence of hospital volume on revision rate after total knee arthroplasty with cement. AB - BACKGROUND: The number of total knee replacements has substantially increased worldwide over the past ten years. Several studies have indicated a correlation between high hospital procedure volume and decreased morbidity and mortality following total knee arthroplasty. The purpose of the present study was to evaluate whether there is a correlation between procedure volume and the risk of revision following total knee arthroplasty with use of hospital volume data from the Norwegian Arthroplasty Register. METHODS: Thirty-seven thousand, three hundred and eighty-one total knee arthroplasties that were reported to the Norwegian Arthroplasty Register from 1994 to 2010 were used to examine the annual procedure volume per hospital. Hospital volume was divided into five categories according to the number of procedures performed annually: one to twenty-four (low volume), twenty-five to forty-nine (medium volume), fifty to ninety-nine (medium volume), 100 to 149 (high volume), and >=150 (high volume). Cox regression (adjusted for age, sex, and diagnosis) was used to estimate the proportion of procedures without revision and the risk ratio (RR) of revision. Analyses were also performed for two commonly used prosthesis brands combined. RESULTS: The rate of prosthetic survival at ten years was 92.5% (95% confidence interval, 91.5 to 93.4) for hospitals with an annual volume of one to twenty-four procedures and 95.5% (95% confidence interval, 94.1 to 97.0) for hospitals with an annual volume of >=150 procedures. We found a significantly lower risk of revision for hospitals with an annual volume of 100 to 149 procedures (relative risk = 0.73 [95% confidence interval, 0.56 to 0.96], p = 0.03) and >=150 procedures (relative risk = 0.73 [95% confidence interval, 0.54 to 1.00], p = 0.05) compared with hospitals with an annual volume of one to twenty-four procedures. Similar results were found when we analyzed two commonly used prosthesis brands. CONCLUSIONS: In the present study, there was a significantly higher rate of revision knee arthroplasties at low-volume hospitals as compared with high-volume hospitals. PMID- 24048564 TI - The approach to the evaluation and surgical treatment of mechanical hip pain in the young patient: AAOS exhibit selection. AB - The mechanical causes of hip pain in a young athlete often reflect a complex combination of static and dynamic factors. A comprehensive diagnostic approach is paramount to the development of a rational treatment strategy that will address all underlying pathologic factors. The goals of this paper are to highlight the pertinent biomechanical factors of the hip joint in femoroacetabular impingement and to discuss the clinical history, physical examination, and radiographic findings that are essential to formulating a proper diagnosis and an effective treatment plan. In addition, the current literature and reported outcomes of femoroacetabular impingement surgery in athletic patients are reviewed. PMID- 24048563 TI - The trends in treatment of femoral neck fractures in the Medicare population from 1991 to 2008. AB - BACKGROUND: We examined trends in the treatment of femoral neck fractures over the last two decades. METHODS: We used Medicare Part A administrative data to identify patients hospitalized for closed femoral neck fracture from 1991 to 2008. We used codes from the International Classification of Diseases, Ninth Revision, to categorize treatment as nonoperative, internal fixation, hemiarthroplasty, and total hip arthroplasty. We examined differences in treatment according to hospital hip fracture volume, hospital location (rural or urban), and teaching status. RESULTS: Our sample consisted of 1,119,423 patients with intracapsular hip fractures occurring from 1991 to 2008. We found a generally stable trend over time in the percentage of patients managed with nonoperative treatment, internal fixation, hemiarthroplasty, and total hip arthroplasty. We found little difference in surgical treatment across different groups of hospitals (high volume compared with low volume, urban compared with rural, and teaching compared with nonteaching). The percentage of acute care hospitals treating hip fractures remained fairly constant (74.8% in 1991 to 1993 and 69.0% in 2006 to 2008). The median number of hip fractures treated per hospital did not change (thirty-three in 1991 to 1993 and thirty-three in 2006 to 2008). There was no increase in the percentage of fractures treated in high volume hospitals over time (57.7% in 1991 to 1993 and 57.1% in 2006 to 2008) and little reduction in the percentage of fractures treated in low-volume hospitals (5.8% in 1991 to 1993 and 5.5% in 2006 to 2008). CONCLUSIONS: There has been little change in the trends of operative and nonoperative treatment for proximal femoral fractures over the last two decades, and there was little evidence of regionalization of hip fracture treatment to higher-volume hospitals. PMID- 24048565 TI - The 100 classic papers of pediatric orthopaedic surgery: a bibliometric analysis. AB - BACKGROUND: Pediatric orthopaedic surgery owes its development to many pioneering individuals, and the studies that these individuals have undertaken form the basis for the clinical decisions made on the modern pediatric orthopaedic service. The aim of our study was to use citation analysis to identify the top 100 papers in pediatric orthopaedic surgery. METHODS: Using the Thomson Reuters Web of Knowledge, we searched for citations of all papers relevant to pediatric orthopaedics. The number of citations, authorship, year of publication, journal of publication, and country and institution of origin were recorded for each paper. RESULTS: The most cited paper was found to be the classic paper from 1963 by Salter and Harris that introduced the now-eponymous classification system for physeal injuries in the skeletally immature patient. The second most cited was Salter's paper describing the widely used osteotomy for the treatment of developmental dysplasia of the hip, and the third most cited was Catterall's description of the natural history of Legg-Calve-Perthes disease. Most papers originated in the U.S., and most were published in this journal. A number of authors including Salter, Ponseti, Graf, and Loder had more than one paper in the top-100 list. DISCUSSION: This paper's identification of the classic papers of pediatric orthopaedic surgery gives us a unique insight into the development of pediatric orthopaedic surgery in the twentieth and early twenty-first centuries and identifies those individuals who have contributed the most to the body of knowledge used to guide evidence-based clinical decision-making in pediatric orthopaedics today. PMID- 24048566 TI - Performance of candidates selecting the subspecialty of spine surgery for the Part II American Board of Orthopaedic Surgery oral certification examination. PMID- 24048567 TI - Shared decision making in orthopaedic surgery: more than two to tango?: commentary on an article by Kevin J. Bozic, MD, MBA, et al.: "Shared decision making in patients with osteoarthritis of the hip and knee. Results of a randomized controlled trial". PMID- 24048568 TI - Augmented microfracture: is this the Holy Grail that we have been searching for in the treatment of cartilage injuries?: commentary on an article by William D. Stanish, MD, et al.: "Novel scaffold-based BST-CarGel treatment results in superior cartilage repair compared with microfracture in a randomized controlled trial". PMID- 24048569 TI - Surgery for cervical spondylotic myelopathy: right evidence or evidence right now?: commentary on an article by Michael G. Fehlings, MD, PhD, et al.: "Efficacy and safety of surgical decompression in patients with cervical spondylotic myelopathy. Results of the AOSpine North America prospective multi-center study". PMID- 24048570 TI - Conformational flexibility of the leucine binding protein examined by protein domain coarse-grained molecular dynamics. AB - Periplasmic binding proteins are the initial receptors for the transport of various substrates over the inner membrane of gram-negative bacteria. The binding proteins are composed of two domains, and the substrate is entrapped between these domains. For several of the binding proteins it has been established that a closed-up conformation exists even without substrate present, suggesting a highly flexible apo-structure which would compete with the ligand-bound protein for the transporter interaction. For the leucine binding protein (LBP), structures of both open and closed conformations are known, but no closed-up structure without substrate has been reported. Here we present molecular dynamics simulations exploring the conformational flexibility of LBP. Coarse grained models based on the MARTINI force field are used to access the microsecond timescale. We show that a standard MARTINI model cannot maintain the structural stability of the protein whereas the ELNEDIN extension to MARTINI enables simulations showing a stable protein structure and nanosecond dynamics comparable to atomistic simulations, but does not allow the simulation of conformational flexibility. A modification to the MARTINI-ELNEDIN setup, referred to as domELNEDIN, is therefore presented. The domELNEDIN setup allows the protein domains to move independently and thus allows for the simulation of conformational changes. Microsecond domELNEDIN simulations starting from either the open or the closed conformations consistently show that also for LBP, the apo-structure is flexible and can exist in a closed form. PMID- 24048571 TI - Mechanisms of adverse cardiometabolic consequences of obesity. AB - Obesity is an epidemic that threatens the health of millions of people worldwide and is a major risk factor for cardiovascular diseases, hypertension, diabetes, and dyslipidemia. There are multiple and complex mechanisms to explain how obesity can cause cardiovascular disease. In recent years, studies have shown some limitations in the way we currently define obesity and assess adiposity. This review focuses on the mechanisms involved in the cardiometabolic consequences of obesity and on the relationship between obesity and cardiovascular comorbidities, and provides a brief review of the latest studies focused on normal weight obesity and the obesity paradox. PMID- 24048572 TI - CatSper and the relationship of hyperactivated motility to intracellular calcium and pH kinetics in equine sperm. AB - In vitro fertilization does not occur readily in the horse. This may be related to failure of equine sperm to initiate hyperactivated motility, as treating with procaine to induce hyperactivation increases fertilization rates. In mice, hyperactivated motility requires a sperm-specific pH-gated calcium channel (CatSper); therefore, we investigated this channel in equine sperm. Motility was assessed by computer-assisted sperm motility analysis and changes in intracellular pH and calcium were assessed using fluorescent probes. Increasing intracellular pH induced a rise in intracellular calcium, which was inhibited by the known CatSper blocker mibefradil, supporting the presence of a pH-gated calcium channel, presumably CatSper. Hyperactivation was associated with moderately increased intracellular pH, but appeared inversely related to increases in intracellular calcium. In calcium-deficient medium, high-pH treatment induced motility loss, consistent with influx of sodium through open CatSper channels in the absence of environmental calcium. However, sperm treated with procaine in calcium-deficient medium both maintained motility and underwent hyperactivation, suggesting that procaine did not act via opening of the CatSper channel. CATSPER1 mRNA was identified in equine sperm by PCR, and CATSPER1 protein was localized to the principal piece on immunocytochemistry. Analysis of the predicted equine CATSPER1 protein revealed species-specific differences in structure in the pH-sensor region. We conclude that the CatSper channel is present in equine sperm but that the relationship of hyperactivated motility to calcium influx is weak. Procaine does not appear to act via CatSper in equine sperm, and its initial hyperactivating action is not dependent upon external calcium influx. PMID- 24048573 TI - Stability of DNA methylation patterns in mouse spermatogonia under conditions of MTHFR deficiency and methionine supplementation. AB - Little is known about the conditions contributing to the stability of DNA methylation patterns in male germ cells. Altered folate pathway enzyme activity and methyl donor supply are two clinically significant factors that can affect the methylation of DNA. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme involved in providing methyl groups from dietary folate for DNA methylation. Mice heterozygous for a targeted mutation in the Mthfr gene (Mthfr(+/-)) are a good model for humans homozygous for the MTHFR 677C>T polymorphism, which is found in 10% of the population and is associated with decreased MTHFR activity and infertility. High-dose folic acid is administered as an empirical treatment for male infertility. Here, we examined MTHFR expression in developing male germ cells and evaluated DNA methylation patterns and effects of a range of methionine concentrations in spermatogonia from Mthfr(+/-) as compared to wild-type, Mthfr(+/+) mice. MTHFR was expressed in prospermatogonia and spermatogonia at times of DNA methylation acquisition in the male germline; its expression was also found in early spermatocytes and Sertoli cells. DNA methylation patterns were similar at imprinted genes and intergenic sites across chromosome 9 in neonatal Mthfr(+/+) and Mthfr(+/-) spermatogonia. Using spermatogonia from Mthfr(+/+) and Mthfr(+/-) mice in the spermatogonial stem cell (SSC) culture system, we examined the stability of DNA methylation patterns and determined effects of low or high methionine concentrations. No differences were detected between early and late passages, suggesting that DNA methylation patterns are generally stable in culture. Twenty-fold normal concentrations of methionine resulted in an overall increase in the levels of DNA methylation across chromosome 9, suggesting that DNA methylation can be perturbed in culture. Mthfr(+/-) cells showed a significantly increased variance of DNA methylation at multiple loci across chromosome 9 compared to Mthfr(+/+) cells when cultured with 0.25- to 2-fold normal methionine concentrations. Taken together, our results indicate that DNA methylation patterns in undifferentiated spermatogonia, including SSCs, are relatively stable in culture over time under conditions of altered methionine and MTHFR levels. PMID- 24048574 TI - Decidual angiogenesis and placental orientation are altered in mice heterozygous for a dominant loss-of-function Gja1 (connexin43) mutation. AB - Connexin43 (CX43), encoded by Gja1 in the mouse, is highly expressed in decidual cells and is known to be important for the transformation of stromal cells into the compact decidua and for neoangiogenesis. Here we investigated if the dominant Gja1(Jrt) mutation encoding CX43(G60S) in mice, which results in a phenotype resembling oculodentodigital dysplasia in humans, has an impact on decidualization, angiogenesis, and implantation. We found a reduced mean weight of fetuses at Gestational Day 17.5 in dams carrying this mutation, with the growth deficiency being independent of fetal genotype. Although the mutant implantation sites exhibited a reduction in CX43 protein, with most immunoreactivity being cytoplasmic, the decidua was morphologically intact at Embryonic Days 5.5 to 7.5. However, the mutation resulted in enhanced and irregular angiogenesis and an increased level of expression of the angiogenic factor-encoding genes Vegfa, Flt1, Kdr, and Fgf2 as well as the prolactin-related gene Prl6a. Moreover, immunolocalization of VEGFA, FLT1, and KDR revealed a homogeneous distribution pattern in the mesometrial as well as antimesometrial decidua of the mutants. Most obviously, uterine NK cells are drastically diminished in the mesometrial decidua of the mutant mice. Invasion of ectoplacental cone cells was disoriented, and placentation was established more laterally in the implantation chambers. It was concluded that the CX43(G60S) mutant impairs control of decidual angiogenesis, leading to dysmorphic placentation and fetal growth restriction. This phenomenon could contribute to the reduced fetal weights and viability of pups born of Gja1(Jrt)/+ dams. PMID- 24048575 TI - Expression profiling reveals developmentally regulated lncRNA repertoire in the mouse male germline. AB - In mammals, the transcriptome of large noncoding RNAs (lncRNAs) is believed to be greater than that of messenger RNAs (mRNAs). Some lncRNAs, especially large intergenic noncoding RNAs (lincRNAs), participate in epigenetic regulation by binding chromatin-modifying protein complexes and regulating protein-coding gene expression. Given that epigenetic regulation plays a critical role in male germline development, we embarked on expression profiling of both lncRNAs and mRNAs during male germline reprogramming and postnatal development using microarray analyses. We identified thousands of lncRNAs and hundreds of lincRNAs that are either up- or downregulated at six critical time points during male germ cell development. In addition, highly regulated lncRNAs were correlated with nearby (<30 kb) mRNA gene clusters, which were also significantly up- or downregulated. Large ncRNAs can be localized to both the nucleus and cytoplasm, with nuclear lncRNAs mostly associated with key components of the chromatin remodeling protein complexes. Our data indicate that expression of lncRNAs is dynamically regulated during male germline development and that lncRNAs may function to regulate gene expression at both transcriptional and posttranscriptional levels via genetic and epigenetic mechanisms. PMID- 24048576 TI - Ovarian expression, localization, and function of tissue inhibitor of metalloproteinase 3 (TIMP3) during the periovulatory period of the human menstrual cycle. AB - Ovulation involves reorganization of the extracellular matrix of the follicle. This study examines the expression, localization, and potential function of the tissue inhibitor of metalloproteinase 3 (TIMP3) during ovulation in women. The dominant follicle of the menstrual cycle was collected at specified times throughout the ovulatory process: pre-, early, late, and postovulatory. For quantitative studies, the follicle was bisected; granulosa and theca cells were separated and collected. For immunohistochemistry (IHC), the intact follicle was embedded and TIMP3 was localized. Additionally, granulosa cells were collected from women undergoing in vitro fertilization and treated with increasing concentrations of recombinant TIMP3, and cell viability was assessed. Real-time PCR for TIMP3 mRNA revealed an increase in TIMP3 mRNA expression in granulosa cells from the early to the late ovulatory stage. Thecal TIMP3 mRNA expression was constitutive across the periovulatory period. TIMP3 protein was localized by IHC to the granulosa and theca cell layers in pre-, early, and late ovulatory follicles as well as to the vascular bed. The staining was most intense in the granulosa and theca cells in the late ovulatory group. Treatment of human granulosa-lutein cells with exogenous recombinant TIMP3 for 24 h decreased cell viability by 60%. Using human follicles collected throughout the periovulatory period of the menstrual cycle, we have demonstrated that TIMP3 mRNA expression increases and that TIMP3 protein is in the appropriate cellular layers to regulate proteolytic remodeling as the follicle progresses toward ovulation. In addition, we have shown that elevated levels of TIMP3 lead to decreased cell viability. PMID- 24048577 TI - DNA topoisomerase II is dispensable for oocyte meiotic resumption but is essential for meiotic chromosome condensation and separation in mice. AB - During mitosis, DNA topoisomerase II (TOP2) is required for sister chromatid separation. When TOP2 activity is inhibited, a decatenation checkpoint is activated by entangled chromatin. However, the functions of TOP2 in oocyte meiosis, particularly for homologous chromosome segregation during meiosis I, have not been investigated. In addition, it remains unknown if TOP2 inhibition activates a decatenation checkpoint at the G2/M transition in oocytes. In this study, we used mouse oocytes and specific inhibitors of TOP2 (ICRF-193 and etoposide) to investigate the role of TOP2 in meiosis. Our results indicated that an effective decatenation checkpoint did not exist in fully grown oocytes, as oocytes underwent the G2/M transition and reinitiated meiosis even when TOP2 activity was inhibited. However, oocytes treated with ICRF-193 had severe defects in chromosome condensation and homologous chromosome separation. Furthermore, condensed chromosomes failed to maintain their normal configurations in matured oocytes that were treated with ICRF-193. However, sister chromatid separation and subsequent chromosome decondensation during the exit from meiosis were not blocked by TOP2 inhibitors. These results indicated that TOP2 had a specific, crucial function in meiosis I. Thus, we identified important functions of TOP2 during oocyte maturation and provided novel insights into the decatenation checkpoint during meiosis. PMID- 24048579 TI - Pressure accelerated 1,3-dipolar cycloaddition of azide and alkyne groups in crystals. AB - The cycloaddition of azides and alkynes in the solid state was accelerated by high pressure. In situ Raman scattering and synchrotron X-ray diffraction were employed to study reaction kinetics at different pressures which revealed that the pressure acceleration originates from the elevated substrate energy and decreased activation energy. PMID- 24048578 TI - Inhibitory effects of topical cyclosporine A 0.05% on immune-mediated corneal neovascularization in rabbits. AB - BACKGROUND: We aimed to study the inhibitory effects of topical cyclosporine A (CsA) 0.05% on immune-mediated corneal neovascularization, and to compare its efficacy with those of dexamethasone 0.1% and bevacizumab 0.5%. METHODS: Immune mediated corneal neovascularization was created in 36 right eyes of 36 rabbits. The rabbits were then randomized into four groups. Group I received CsA 0.05%, Group II received dexamethasone 0.1%, Group III received bevacizumab 0.5%, and Group IV received isotonic saline twice a day for 14 days. The corneal surface covered with neovascular vessels was measured on the photographs. The rabbits were then sacrificed and the corneas excised. Paraffin-embedded sections were stained with hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. RESULTS: The means of percent area of corneal neovascularization in Group I, II, III, and IV were 24.4%, 5.9%, 37.1%, and 44.1%, respectively. The inhibitory effect of CsA 0.05% was found to be better than the effect found in the bevacizumab 0.5% and control groups (p = 0.03 and p = 0.02, respectively). CsA 0.05% was found to have significantly lesser inhibitory effects on corneal neovascularization than dexamethasone 0.1% (p < 0.001). Apoptotic cell density was higher in Group III and Group IV than in Group I and Group II. There was no difference between Group I and Group II in terms of apoptotic cell density (p = 0.7). CONCLUSIONS: Topical CsA 0.05% was shown to have an inhibitory effect on immune-mediated corneal neovascularization in rabbits. PMID- 24048580 TI - Chinese smokers' cigarette purchase behaviours, cigarette prices and consumption: findings from the ITC China Survey. AB - BACKGROUND: While cigarette purchasing behaviour has been shown to be linked with certain tobacco use outcomes such as quit intentions and quit attempts, there have been very few studies examining cigarette purchasing behaviours and their impact on cigarette price and consumption in China, the world's largest cigarette consumer. OBJECTIVE: The aim of the present study was to examine the extent and determinants of cost/price-related purchase behaviours, and estimate the impact of these behaviours on cigarette prices paid by Chinese smokers. It also assesses the socioeconomic differences in compensatory purchase behaviours, and examines how they influence the relationship between purchase behaviours, cigarette prices and cigarette consumption. METHODS: Multivariate analyses using the general estimating equations method were conducted using data from the International Tobacco Control China Survey (the ITC China Survey), a longitudinal survey of adult smokers in seven cities in China: Beijing, Changsha, Guangzhou, Kunming, Shanghai, Shenyang and Yinchuan. In each city, about 800 smokers were surveyed in each wave. The first three waves--wave 1 (conducted between March to December 2006), wave 2 (November 2007 to March 2008) and wave 3 (May to October 2009 and February to March 2010)--of the ITC China Survey data were used in this analysis. Various aspects of smokers' self-reported price/cost-related cigarette purchasing behaviours were analysed. RESULTS: Nearly three-quarters (72%) of smokers surveyed indicated that a major reason they chose their most-used cigarette brand was its low cost/price. Almost half (50.6%) of smokers reported buying in cartons in their most recent cigarette purchase. Smokers with lower income and/or low levels of education were more likely to choose a brand because of its low cost/price. However, those with higher income and/or high levels of education were more likely to buy cartons. Gender and age were also related to type of purchase behaviours. Those behaviours led to reductions in purchase prices. The price savings ranged from Y0.54 to Y1.01 per pack of cigarettes, depending on the behaviour examined, representing a price reduction of 8% to 15%. CONCLUSIONS: A significant portion of Chinese urban adult smokers engaged in cost/price-reducing purchase behaviours. Such behaviours reduce cigarette purchase prices and are associated with increased cigarette consumption. Smokers of different socioeconomic status engaged in different purchase behaviours to mitigate the impact of higher cigarette prices. Reducing tobacco use through raising tobacco taxes/prices in China needs to take into account these cost/price-reducing behaviours. PMID- 24048581 TI - Goal-directed fluid therapy in gastrointestinal surgery in older coronary heart disease patients: randomized trial. AB - BACKGROUND: Our aim was to determine whether substitution of goal-directed fluid therapy (GDT) (perioperative fluid administration) for traditional therapy to manage elderly patients with coronary heart disease scheduled for gastrointestinal (GI) surgery was advantageous. We determined if it would reduce cardiac complications and shorten time to recovery and discharge. METHODS: Altogether, 60 of these elderly patients were randomized into GDT (n = 30) and control (n = 30) groups. In the GDT group, fluid management was carried out under guidance of hemodynamic status indicators. Types and quantities of fluids administered, blood loss, intraoperative urine output, time of extubation, intensive care unit (ICU) stay, hospital stay, postoperative adverse cardiac events, and GI complications were recorded. RESULTS: Total fluids infused were 2,910 +/- 645 ml (GDT group) and 3,640 +/- 771 ml (control group) (p < 0.05). Numbers of adverse cardiac events in the two groups were not significantly different (p = 0.121). Return of GI function was significantly faster in the GDT group (p < 0.001). Median ICU stay was 32.5 h in the GDT group and 47.5 h in the control group (p < 0.001). Median hospital stay was 18 days in the GDT group and 22 days in the control group (p < 0.001). CONCLUSIONS: GDT was associated with shorter ICU stay and time to discharge and faster return of GI function compared to traditional fluid therapy. The number of adverse cardiac events was similar in the two groups. PMID- 24048582 TI - Sex differences in interpersonal violence in Malawi: analysis of a hospital-based trauma registry. AB - BACKGROUND: Although interpersonal violence ("assault") exists in every society, the World Health Organization (WHO) estimated that 90 % of the exposure burden occurs in low- and middle-income countries. The objectives of this study were to define the incidence of assault-related injuries among subjects presenting for emergency room care secondary to sustained trauma in Lilongwe, Malawi; to measure the impact of sex on incidence, injury type, and care received; and to measure the effect of both sex and geographic location of the injury on time to presentation for medical care. METHODS: This is a retrospective cohort analysis of data prospectively collected in the Kamuzu Central Hospital Trauma Surveillance Registry from July 2008 to December 2010 (n = 23,625). We used univariate, bivariate, and logistic regression analyses to measure association of sex with variables of interest, and geospatial mapping to evaluate the association of location of assault on time to presentation for care. RESULTS: The mean age of our trauma cohort was 27.7 years. Assaults accounted for 26.8 % of all injuries. Of those assaulted, 21.0 % (1299) were female, who were younger (26.2 vs. 28.1 years, p < 0.001), more likely to arrive to the hospital by minibus (p < 0.001), and less likely to arrive by police (p < 0.001). Altogether 62 % of the females were assaulted in their homes-much more often than their male counterparts (p < 0.001). Females were more likely to sustain contusions (p < 0.001) and males more likely to have lacerations and penetrating stab wounds (p < 0.001) or head injury (p < 0.001). Females had delayed hospital presentation following assault (p = 0.001) and were more likely to be treated as outpatients after adjusting for age, injury type, and injury location (adjusted odds ratio 1.74, 95 % CI 1.3-2.3, p < 0.001). Assaults clustered geographically in the Lilongwe district. Delayed presentation of females occurred irrespective of proximity to the hospital. CONCLUSIONS: This study brings attention to sex differences in assault victims. A prevention strategy focusing on sex roles and domestic abuse of women is paramount. Efforts are needed to stop dischargin female assault victims back into a potentially unsafe, abusive environment. PMID- 24048584 TI - Antithrombotic therapy in atrial fibrillation and stent implantation: treatment or threats by the use of triple or dual antithrombotic therapy. PMID- 24048583 TI - Common genetic variants in selected Ca2+ signaling genes and the risk of appropriate ICD interventions in patients with heart failure. AB - PURPOSE: Defective Ca2+ handling in failing cardiomyocites predisposes patients with heart failure (HF) to ventricular arrhythmia. We investigated whether gene variants of Ca2+ handling proteins are associated with the occurrence of ventricular tachycardia/fibrillation (VT/VF) in HF patients implanted with a primary prevention implantable cardioverter-defibrillator (ICD). METHODS: One hundred thirty-six patients with HF were followed from ICD implantation to the time of first appropriate ICD intervention for VT > 170 bpm. The following polymorphisms were genotyped: ATP2A2 rs1860561 and rs56243033; RYR2 rs4142933; CASQ2 rs4074536; SLC8A1 g.-23449C > A; PLN rs12198461; FKBP1B rs7568163. Hazard ratios (HR) were derived from Cox proportional-hazards regression analysis. RESULTS: After a mean follow-up of 879 days (IQ range, 327 to 1,459), 34 patients (25%) had appropriate ICD intervention. Non-sustained VT (HR, 2.12; 95%CI, 0.87 5.19; p = 0.09) and atrial fibrillation (AF) at ICD implantation (HR, 2.33; 95%CI, 0.89-6.10; p = 0.08) predicted appropriate ICD interventions with borderline statistical significance. Prevalence of ATP2A2 rs1860561 variant was 17% in patients without VT/VF and 4% in those with ventricular arrhythmia (p = 0.009). After adjustment for AF and NSVT, the rs1860561 A mutant allele independently predicted lower incidence of VT/VF (HR, 0.29; 95%CI, 0.09-0.98; p = 0.04). CONCLUSIONS: The observation that ATP2A2 rs1860561 gene variant associated with lower risk of life-threatening arrhythmia in HF patients suggests that selected calcium gene variants may modify the risk of SD even within the complex and polygenic pathological condition of HF. Combining traditional risk factors and genetic profiling could reveal helpful to identify HF patients who will benefit most from ICD implantation. PMID- 24048585 TI - Distribution and evolution of the mobile vma-1b intein. AB - Inteins are self-splicing parasitic genetic elements found in all domains of life. These genetic elements are found in highly conserved positions in conserved proteins. One protein family that has been invaded by inteins is the vacuolar and archaeal catalytic ATPase subunits (vma-1). There are two intein insertion sites in this protein, "a" and "b." The b site was previously thought to be only invaded in archaeal lineages. Here we survey the distribution and evolutionary histories of the b site inteins and show that the intein is present in more lineages than previously annotated, including a bacterial lineage, Mahella australiensis 50-1 BON. We present evidence, through ancestral character state reconstruction and substitution ratios between host genes and inteins, for several transfers of this intein between divergent species, including an interdomain transfer between the archaea and bacteria. Although inteins may persist within a single population or species for long periods of time, transfer of the vma-1b intein between divergent species contributed to the distribution of this intein. PMID- 24048586 TI - Reverse transcription of spliced psbA mRNA in Chlamydomonas spp. and its possible role in evolutionary intron loss. AB - Reverse transcription of mRNA is thought to be an important first step in a model that explains certain evolutionary changes within genes, such as the loss of introns or RNA editing sites. In this model, reverse transcription of mRNA produces cDNA molecules that replace part of the parental gene by homologous recombination. In vivo evidence of reverse transcription of physiologically relevant mRNAs is generally lacking, however, except in genetically engineered cells. Here, we provide in vivo evidence for reverse transcription of the chloroplast psbA mRNA in two naturally occurring species of Chlamydomonas (raudensis and subcaudata) that is based on the presence of spliced cDNAs in both organisms. The psbA cDNAs, which lack the group II intron of the genomic gene, are nearly full length, and the majority of them--though not all--are in the form of RNA-cDNA hybrids. Moreover, the presence in these species of psbA cDNAs is correlated with the loss of an early group I intron from the same psbA gene. The group II intron that interrupts psbA in C. raudensis and C. subcaudata potentially encodes a protein with a reverse transcriptase domain, and the C. raudensis protein was shown to have reverse transcriptase activity in vitro. These results provide strong evidence for reverse transcription of a physiologically important mRNA (psbA) in two species of Chlamydomonas that have also lost an intron from the same gene, possibly through recombination with the cDNA. PMID- 24048587 TI - Adaptive evolution of M3 lysin--a candidate gamete recognition protein in the Mytilus edulis species complex. AB - Marine invertebrate gamete recognition proteins (GRPs) are classic examples of rapid adaptive evolution of reproductive proteins, and hybridizing Mytilus blue mussels allow us to study the evolution of GRPs during speciation following secondary contact. Even with frequent hybridization, positive selection drives divergence of M7 lysin, one of the three Mytilus egg vitelline envelope (VE) lysins. Mytilus trossulus and M. edulis form a broad hybrid zone in the Canadian Maritimes and eastern Maine, isolated by strong (but partial) gamete incompatibility. M7 lysin, however, is an unlikely GRP controlling this gametic incompativility, as earlier studies showed either weak or no positive selection and extensive introgression between the two species. We used reverse transcriptase-polymerase chain reaction and cloned several alleles of M3 lysin, a potent VE lysin encoded by a nonhomologous gene whose evolution has not been studied. McDonald-Kreitman and HKA tests reveal strong positive selection, which PAML branch-site models detect in 19.7% of the codons. Protein structure predictions show that replacements map exclusively to one face of the carbohydrate recognition domain (CRD) of this C-type lectin, with codons under positive selection localizing to CRD regions known to control ligand specificity. Polymorphism/divergence analyses show that selective sweep has purged M. edulis but not M. trossulus of polymorphism, and unique to M3 is an absence of fixed substitutions and broad haplotype sharing between M. edulis and Mediterranean M. galloprovincialis. Taken together, these results suggest that different lysins serve as GRPs in different Mytilus hybrid zones, with M3 likely co-opted to play this role in the western Atlantic. PMID- 24048589 TI - A dominant-negative provides new insights into FAK regulation and function in early embryonic morphogenesis. AB - FAK is a non-receptor tyrosine kinase involved in a wide variety of biological processes and crucial for embryonic development. In this manuscript, we report the generation of a new FAK dominant negative (FF), composed of the C terminus (FRNK) and the FERM domain of the protein. FF, unlike FRNK and FERM, mimics the localization of active FAK in the embryo, demonstrating that both domains are necessary to target FAK to its complexes in vivo. We show that the FERM domain has a role in the recruitment of FAK on focal adhesions and controls the dynamics of the protein on these complexes. Expression of FF blocks focal adhesion turnover and, unlike FRNK, acts as a dominant negative in vivo. FF expression in Xenopus results in an overall phenotype remarkably similar to the FAK knockout in mice, including loss of mesodermal tissues. Expression of FF in the animal cap revealed a previously unidentified role of FAK in early morphogenesis and specifically epiboly. We show that a fibronectin-derived signal transduced by FAK governs polarity and cell intercalation. Finally, failure of epiboly results in severe gastrulation problems that can be rescued by either mechanical or pharmacological relief of tension within the animal cap, demonstrating that epiboly is permissive for gastrulation. Overall, this work introduces a powerful new tool for the study of FAK, uncovers new roles for FAK in morphogenesis and reveals new mechanisms through which the FERM domain regulates the localization and dynamics of FAK. PMID- 24048593 TI - Revised guidelines for occupational HIV exposure include simpler regimens. PMID- 24048590 TI - Myb promotes centriole amplification and later steps of the multiciliogenesis program. AB - The transcriptional control of primary cilium formation and ciliary motility are beginning to be understood, but little is known about the transcriptional programs that control cilium number and other structural and functional specializations. One of the most intriguing ciliary specializations occurs in multiciliated cells (MCCs), which amplify their centrioles to nucleate hundreds of cilia per cell, instead of the usual monocilium. Here we report that the transcription factor MYB, which promotes S phase and drives cycling of a variety of progenitor cells, is expressed in postmitotic epithelial cells of the mouse airways and ependyma destined to become MCCs. MYB is expressed early in multiciliogenesis, as progenitors exit the cell cycle and amplify their centrioles, then switches off as MCCs mature. Conditional inactivation of Myb in the developing airways blocks or delays centriole amplification and expression of FOXJ1, a transcription factor that controls centriole docking and ciliary motility, and airways fail to become fully ciliated. We provide evidence that MYB acts in a conserved pathway downstream of Notch signaling and multicilin, a protein related to the S-phase regulator geminin, and upstream of FOXJ1. MYB can activate endogenous Foxj1 expression and stimulate a cotransfected Foxj1 reporter in heterologous cells, and it can drive the complete multiciliogenesis program in Xenopus embryonic epidermis. We conclude that MYB has an early, crucial and conserved role in multiciliogenesis, and propose that it promotes a novel S-like phase in which centriole amplification occurs uncoupled from DNA synthesis, and then drives later steps of multiciliogenesis through induction of Foxj1. PMID- 24048594 TI - Illegitimate companies threaten patients' receipt of FDA-approved drugs. PMID- 24048591 TI - Efficient site-specific transgenesis and enhancer activity tests in medaka using PhiC31 integrase. AB - Established transgenesis methods for fish model systems allow efficient genomic integration of transgenes. However, thus far a way of controlling copy number and integration sites has not been available, leading to variable transgene expression caused by position effects. The integration of transgenes at predefined genomic positions enables the direct comparison of different transgenes, thereby improving time and cost efficiency. Here, we report an efficient PhiC31-based site-specific transgenesis system for medaka. This system includes features that allow the pre-selection of successfully targeted integrations early on in the injected generation. Pre-selected embryos transmit the correctly integrated transgene through the germline with high efficiency. The landing site design enables a variety of applications, such as reporter and enhancer switch, in addition to the integration of any insert. Importantly, this allows assaying of enhancer activity in a site-specific manner without requiring germline transmission, thus speeding up large-scale analyses of regulatory elements. PMID- 24048595 TI - Pharmacy resident takes care to new height. PMID- 24048598 TI - Fatal bleeding associated with dabigatran. PMID- 24048599 TI - An emergency department pharmacist's experience at the Boston Marathon. PMID- 24048600 TI - Use of an instant messaging application to facilitate pharmacy students' learning during medical rounds. PMID- 24048601 TI - Positive work culture: a catalyst for improving employee commitment. PMID- 24048602 TI - Statins in the treatment of asthma. AB - PURPOSE: Current evidence on statin agents as potential alternatives or adjuncts to corticosteroid therapy for asthma is reviewed. SUMMARY: Research showing antiinflammatory and antioxidant effects of statins in animal models suggested that the cholesterol-lowering drugs might be useful in mitigating the adverse effects of long-term corticosteroid therapy in patients with asthma, but studies in humans have yielded mixed results. Two small placebo-controlled clinical trials indicated that statins were not effective in combating asthmatic inflammatory processes, and trials of statins as adjunctive therapy have indicated minimal steroid-sparing benefits. In two studies involving a total of more than 1000 current and former smokers with asthma, statin use correlated with reduced acute asthma exacerbations and a slower decline of lung function in some patients. A large population-based study (n = 3965) found that statin therapy was associated with a significantly reduced risk of hospitalization for asthma after an average follow-up period of about 4.5 years; a smaller U.S. retrospective cohort study indicated a significantly lower 1-year rate of asthma-related emergency room visits among patients receiving statins relative to those not using statins (9.08% versus 4.18%). Much of the research on statins and asthma has not controlled for confounding influences such as patient comorbidities and concomitant medication use. CONCLUSION: Clinical trials have shown that statin therapy is not superior to and does not enhance the beneficial effects of inhaled corticosteroids for the treatment of asthma. Some evidence suggests that statins may help preserve lung function in cigarette smokers with obstructive pulmonary disease and reduce hospitalizations in asthmatic smokers and nonsmokers. PMID- 24048603 TI - Streamlining the process for initial review of pharmacy residency applications: an analytic approach. AB - PURPOSE: An analytics-driven process for improving the efficiency of initial candidate screening by pharmacy residency programs is described. METHODS: In an initiative to streamline pharmacy resident selection at Johns Hopkins Hospital, retrospective analyses of materials submitted by prospective residents during two application periods (n = 277) were conducted to identify the applicant characteristics most strongly associated with the ultimate extension of an invitation to interview. Multiple two-member teams of pharmacist reviewers independently scored each application on 13 variables, with the resultant item scores tallied to derive rank sum scores. Univariate and multivariate logistic regression analyses were performed to identify the factors most important in distinguishing candidates invited for an interview from those not invited. RESULTS: Univariate analysis indicated that all 13 evaluated applicant characteristics correlated with the likelihood of an interview invitation, but some were relatively less determinative; these factors were excluded from a final multivariate logistic regression model containing only the 7 factors most strongly predictive of an invitation to interview: grade point average, pharmacy work experience, professional association involvement, rotation experiences, presentations, publications, and skills and certifications. The final model was found to be highly explanatory (r(2) = 0.66) of variances in interview-invitation decisions and has been adopted as a guide to future initial screening of candidate applications. CONCLUSION: By analyzing the relative importance of specific residency applicant characteristics and focusing on those deemed most useful in determining which candidates are invited for interviews, a large teaching institution streamlined preliminary application screening while maintaining an equitable candidate selection process. PMID- 24048604 TI - National survey of pharmacy residency on-call programs. AB - PURPOSE: The results of a national survey to evaluate on-call practices and responsibilities of pharmacy residents nationwide, as well as opinions related to duty-hour changes, are reported. METHODS: A 39-question survey was distributed to 1292 residency program directors (RPDs) listed in the American Society of Health System Pharmacists (ASHP) online residency directory, which includes programs in all stages of the accreditation process. The survey opened on November 7, 2011, and closed on November 28, 2011. The survey collected demographic information and answers to questions about the residency's on-call component (if applicable) and barriers to the creation of an on-call component. Respondents were also asked to indicate their support of or opposition to the adoption of the 2011 Accreditation Council for Graduate Medical Education (ACGME) duty-hour rules and identify the areas of greatest concern. RESULTS: Of the 1292 RPDs listed in the ASHP online residency directory to whom the survey was sent, 521 surveys were completed, yielding a response rate of 40%. Of these, 471 identified their residency program as including or excluding an on-call component. Of the 138 programs with on-call services, 102 programs (74%) indicated the inclusion of an overnight experience. Programs that did not utilize an on-call component indicated barriers such as a perceived lack of demand (39%) and duty-hour limitations (21%). Common on-call activities included drug information consults and therapeutic drug monitoring. There was not a clear consensus from RPDs regarding the adoption of the 2011 ACGME duty-hour standards. CONCLUSION: Among usable responses to a survey of pharmacy residency programs, 29% indicated that their program included an on-call component. On-call programs varied greatly in activities, location, hours, and requirements. PMID- 24048605 TI - Cost of venous thromboembolism in hospitalized medically ill patients. AB - PURPOSE: The results of a study to estimate the economic costs of venous thromboembolism (VTE) in hospitalized nonsurgical patients during initial admissions and subsequent to hospital discharge are presented. METHODS: Using a database linking admission records from more than 150 U.S. hospitals to health insurance claims, 49,948 patients 40 years of age or older who were hospitalized at least once during a 6-year period for diagnoses other than VTE or traumatic injury and who met other inclusion criteria were identified. Costs were tallied from the index admission to postdischarge day 180 for patients with and patients without evidence of VTE. Ordinary least-squares regression was used to estimate the independent relationship between VTE and total health care costs, controlling for differences in patient characteristics. RESULTS: Two hundred forty-two patients (0.5%) had VTE during the index admission, 317 (0.6%) had VTE after the index admission discharge; in total, 559 (1.1%) had VTE through postdischarge day 180. Among the 242 patients with VTE during their index admission, the adjusted mean total health care costs over 180 days were $17,848 higher than among those without VTE ($47,416 versus $29,568, p < 0.001); for the 317 patients with postdischarge VTE, the adjusted mean total 180-day costs were $51,863 higher than for those without postdischarge VTE ($74,136 versus $22,273, p < 0.001). CONCLUSION: Among medically ill patients admitted to the hospital, health care costs were significantly higher among those who developed VTE during hospitalization or after discharge compared with those who did not develop VTE. PMID- 24048606 TI - Summary of the executive session on critical threats to the pharmacy supply chain and the effects on patient care. PMID- 24048607 TI - Improvement of medication event interventions through use of an electronic database. AB - PURPOSE: Patient safety enhancements achieved through the use of an electronic Web-based system for responding to adverse drug events (ADEs) are described. SUMMARY: A two-phase initiative was carried out at an academic pediatric hospital to improve processes related to "medication event huddles" (interdisciplinary meetings focused on ADE interventions). Phase 1 of the initiative entailed a review of huddles and interventions over a 16-month baseline period during which multiple databases were used to manage the huddle process and staff interventions were assigned via manually generated e-mail reminders. Phase 1 data collection included ADE details (e.g., medications and staff involved, location and date of event) and the types and frequencies of interventions. Based on the phase 1 analysis, an electronic database was created to eliminate the use of multiple systems for huddle scheduling and documentation and to automatically generate e mail reminders on assigned interventions. In phase 2 of the initiative, the impact of the database during a 5-month period was evaluated; the primary outcome was the percentage of interventions documented as completed after database implementation. During the postimplementation period, 44.7% of assigned interventions were completed, compared with a completion rate of 21% during the preimplementation period, and interventions documented as incomplete decreased from 77% to 43.7% (p < 0.0001). Process changes, education, and medication order improvements were the most frequently documented categories of interventions. CONCLUSION: Implementation of a user-friendly electronic database improved intervention completion and documentation after medication event huddles. PMID- 24048608 TI - Safe and effective use of prostacyclins to treat pulmonary arterial hypertension. PMID- 24048609 TI - Repackaged oral dosage forms: beyond-use dating and product safety concerns. PMID- 24048611 TI - Health education 2.0: the next generation of health education practice. AB - Social, physical, and economic environments are the greatest determinants of our individual and collective health. Inadequate or substandard environments of all types present barriers to health. Addressing these broader determinants will be the quintessential core in the next era of public health practice. The framework for health improvement is shifting to a robust and comprehensive ecological model, wherein the broader constructs of health determinants will be central issues in population health improvement practice requiring expanded partnerships, increased application of scientific evidence, and healthy policy development within and outside of the traditional health sector. Health educators are uniquely positioned to effectively engage essential partners, shape information for policy makers, leverage the evidence base to implement effective interventions and maximize beneficial health outcomes, and add to the evidence base with thorough and systematic evaluation and reporting. PMID- 24048610 TI - Antinociceptive effect of intracerebroventricular administration of D-serine on formalin-induced pain. AB - PURPOSE: In a previous study using the tail-flick test, we found that intracerebroventricular administration of D-serine, an endogenous co-agonist at the glycine sites of N-methyl-D-aspartate (NMDA) receptors, elicited an antinociceptive effect on thermal nociception. The purpose of the present study was to evaluate the effect of intracerebroventricular administration of D-serine on nociception induced by tissue damage or inflammation using the formalin test. METHODS: Infusion of drugs into the third ventricle in rat was performed via indwelling cannulae. Drugs were infused at a volume of 10 MUl over 2 min, and the infusion cannula was left in place for 2 min before removal. The formalin test was performed 10 min after drug administration. RESULTS: Intracerebroventricular administration of D-serine significantly and dose-dependently decreased the number of flinches in both the early and late phases in the formalin test. This antinociceptive effect was antagonized by intracerebroventricular administration of L-701,324, a selective antagonist at the glycine sites of NMDA receptors. CONCLUSION: The present data suggest that activation of NMDA receptors via glycine sites at the supraspinal level induces an antinociceptive effect on both acute and tonic pain. PMID- 24048612 TI - Structural approaches to health promotion: what do we need to know about policy and environmental change? AB - Although the public health literature has increasingly called on practitioners to implement changes to social, environmental, and political structures as a means of improving population health, recent research suggests that articles evaluating organization, community, or policy changes are more limited than those focused on programs with individuals or their social networks. Even when these approaches appear promising, we do not fully understand whether they will benefit all population groups or can be successful in the absence of accompanying individually oriented programs. The role of this broad category of approaches, including both policy and environmental changes, in decreasing health disparities is also unclear, often benefiting some communities more than others. Finally, the political nature of policy and environmental change, including the impact on personal autonomy, raises questions about the appropriate role for public health professionals in advancing specific policies and practices that alter the conditions in which people live. This article addresses these issues and ends with a series of questions about the effectiveness and ethical implementation of what we have termed "structural initiatives." PMID- 24048613 TI - Patterns and prognostic significance of lymph node dissection for surgical treatment of perihilar and intrahepatic cholangiocarcinoma. AB - INTRODUCTION: The prognostic significance of lymph node dissection (LND), the number and status of harvested lymph nodes (LNs), and the lymph node ratio (LNR) are still under debate in intrahepatic (ICC) and perihilar (PCC) cholangiocarcinoma. The aims of this study were to evaluate the prognostic value of the extent of LN dissection, the number of positive LNs, the distribution of positive LNs along different LN stations, and the LNR in a cohort of patients with ICC and PCC who underwent surgical resection and to compare the different prognostic values of lymph node involvement. MATERIAL AND METHODS: A retrospective analysis was done evaluating extent of LND, number, status, and location of harvested LNs in a cohort of 145 patients with cholangiocarcinoma submitted to surgical resection with curative intent from 1990 to 2012. RESULTS: Seventy patients had ICC and 75 had PCC. The median survival times of patients with N0 and N+ tumors were 42 and 19 months in ICC patients (p = 0.05) and 42 and 22 months in PCC patients (p = 0.01). In patients without LN metastases, the median survival times of patients with up to three LNs retrieved and with more than three LNs retrieved were 38 and 69 months in ICC patients (p = 0.05) and 18 and 43 months in PCC patients (p = 0.04), respectively. In N+ patients, the location of positive LNs (hepatoduodenal ligament or other regional stations) did not influence overall survival in ICC or PCC patients (p = 0.6). The median survival times of patients with LNRs of 0 and >0.25 were 43 and 19 months in ICC patients (p = 0.01); the 0-0.25 group did not reach the value. In PCC patients, median survival of 0, 0-0.25, and >0.25 groups of patients were 42, 23, and 11 months (p = 0.01), respectively. CONCLUSIONS: LN metastasis is a major prognostic factor after surgical resection of cholangiocarcinoma. The number of harvested LNs and the LNR showed a high prognostic value in ICC and PCC. PMID- 24048614 TI - Colorectal emergencies: review and controversies in the management of large bowel obstruction. AB - INTRODUCTION: Traditionally, large bowel obstruction (LBO) has been managed as an operative emergency. Its causes and treatments are an important part of general surgical and colon and rectal surgery practices. DISCUSSION: While management has traditionally been emergent laparotomy with resection or removal of underlying pathology, newer methodologies and treatments over the last decade have required treating physicians to consider a number of other options, including nonoperative options such as stenting, when treating these patients. CONCLUSION: Given these changes, treating a patient with LBO requires a thoughtful assessment and comprehensive understanding of underlying pathology, assessment of the patient's comorbidities and up-to-date knowledge of modern options for treatment. PMID- 24048615 TI - Diagnostic errors: moving beyond 'no respect' and getting ready for prime time. PMID- 24048616 TI - The global burden of unsafe medical care: analytic modelling of observational studies. AB - OBJECTIVE: To contextualise the degree of harm that comes from unsafe medical care compared with individual health conditions using the global burden of disease (GBD), a metric to determine how much suffering is caused by individual diseases. DESIGN: Analytic modelling of observational studies investigating unsafe medical care in countries' inpatient care settings, stratified by national income, to identify incidence of seven adverse events for GBD modelling. Observational studies were generated through a comprehensive search of over 16 000 articles written in English after 1976, of which over 4000 were appropriate for full text review. RESULTS: The incidence, clinical outcomes, demographics and costs for each of the seven adverse events were collected from each publication when available. We used disability-adjusted life years (DALYs) lost as a standardised metric to measure morbidity and mortality due to specific adverse events. We estimate that there are 421 million hospitalisations in the world annually, and approximately 42.7 million adverse events. These adverse events result in 23 million DALYs lost per year. Approximately two-thirds of all adverse events, and the DALYs lost from them, occurred in low-income and middle-income countries. CONCLUSIONS: This study provides early evidence that adverse events due to medical care represent a major source of morbidity and mortality globally. Though suffering related to the lack of access to care in many countries remains, these findings suggest the importance of critically evaluating the quality and safety of the care provided once a person accesses health services. While further refinements of the estimates are needed, these data should be a call to global health policymakers to make patient safety an international priority. PMID- 24048617 TI - In response to 'Correspondence: Identification of doctors at risk of recurrent complaints: a national study of healthcare complaints in Australia'. PMID- 24048619 TI - [Urology 2.0 - new social media in urology]. PMID- 24048620 TI - Editorial. PMID- 24048618 TI - Geographic location of antiretroviral clinical trials in HIV infected pediatric patients. AB - BACKGROUND: Some medicines regulatory authorities are encouraging research in pediatrics. However, children are a vulnerable population, and previous studies have suggested that research is increasingly being conducted outside of developed countries. OBJECTIVE: The purpose of this study is to determine the location of trials in the pediatric population with human immunodeficiency virus (HIV). SETTING: Not applicable. METHODS: Clinical trials registered in the largest international clinical trials registry (clinicaltrials.gov) evaluating antiretrovirals in pediatric HIV infected patients were included. Data were collected on the location, funding, study purpose, design, initiation date, age of subjects, and medication classes tested. MAIN OUTCOME MEASURES: We assessed frequencies of characteristics of pediatric HIV trials registered in the clinicaltrials.gov database. RESULTS: Overall, 288 studies were included in the analysis. Most trials were conducted in ages 12-17 years (83 %), followed by studies in those <6 years (25 %) and 6-11 years (21 %). The location of most trials included at least one site in developed countries (83 %). The number of trials completed exclusively in developing countries increased from 1989 to 2011. CONCLUSIONS: The majority of pediatric antiretroviral trials registered in clinicaltrials.gov were conducted in adolescent subjects in developed countries. The number of pediatric HIV studies in developing countries increased while studies conducted in developed countries decreased similar to trends of HIV. PMID- 24048621 TI - Statistics in science and in society: From a state-of-the-art to a new research agenda. AB - Statistics occupies a prominent role in science and citizens' daily life. This article provides a state-of-the-art of the problems associated with statistics in science and in society, structured along the three paradigms defined by Bauer, Allum and Miller (2007). It explores in more detail medicine and public understanding of science on the one hand, and risks and surveys on the other. Statistics has received a good deal of attention; however, very often handled in terms of deficit - either of scientists or of citizens. Many tools have been proposed to improve statistical literacy, the image of and trust in statistics, but with little understanding of their roots, with little coordination among stakeholders and with few assessments of impacts. These deficiencies represent as many new and promising directions in which the PUS research agenda could be expanded. PMID- 24048622 TI - Scientific authority in policy contexts: Public attitudes about environmental scientists, medical researchers, and economists. AB - This paper uses data from the US General Social Survey to examine public support for scientists in policy contexts and its link to scientific disciplines. An analysis of attitudes about the amount of influence that environmental scientists, two kinds of medical researchers, and economists should have over policy decisions reveals that in each discipline the extent to which scientists are thought to serve the nation's best interests is the strongest determinant of attitudes about scientists as policy advisors. Perceptions of scientists' technical knowledge and the level of consensus in the scientific community also have direct, albeit weaker effects on opinions about scientists' appropriate roles in policy settings. Whereas previous research has stressed the importance of local variability in understanding the transfer of scientific authority across institutional boundaries, these results point to considerable homogeneity in the social bases of scientific authority in policy contexts. PMID- 24048624 TI - Correction. PMID- 24048623 TI - Efficacy and feasibility of home-based training for individuals with homonymous visual field defects. AB - BACKGROUND: Homonymous visual field defects (HVFDs) are one of the most common consequences of stroke. Compensatory training encourages affected individuals to develop more efficient eye movements to improve function. However, training is typically supervised, which can be time consuming and costly. OBJECTIVE: To develop and evaluate the efficacy and feasibility of an unsupervised reading and exploration computer training for individuals with HVFDs. METHODS: Seventy individuals with chronic HVFDs were randomly assigned to 1 of 2 groups: intervention or control. The former received 35 hours of reading and exploration training, and the latter received 35 hours of control training. Visual and attentional abilities were assessed before and after training using perimetry, visual search, reading, activities of daily living, the Test of Everyday Attention, and a Sustained Attention to Response task. RESULTS: Eighteen individuals failed to complete the training; analyses were conducted on the remaining 28 intervention and 24 control group participants. Individuals in the intervention group demonstrated significant improvements in the primary outcomes of exploration (12.87%, 95% confidence interval [CI] = 8.44% to 17.30%) and reading (18.45%, 95% CI = 9.93% to 26.97%), which were significantly greater than those observed following the control intervention (exploration = 4.80%, 95% CI = 0.09% to 9.51%; reading = 1.95%, 95% CI = -4.78% to 8.68%). Participants in the intervention group also reported secondary subjective improvements, although these were not matched by objective gains in tasks simulating activities of daily living. CONCLUSIONS: Home-based compensatory training is an inexpensive accessible rehabilitation option for individuals with HVFDs, which can result in objective benefits in searching and reading, as well as improving quality of life. PMID- 24048625 TI - European Public Assessment Report (EPAR) summaries for the public: are they fit for purpose? A user-testing study. AB - OBJECTIVES: Apply 'user testing' methodology to test the readability of a European Public Assessment Report (EPAR) summary-which describes how the decision was made by the European Medicines Agency to approve a medicine. DESIGN: User testing uses mixed methods (questionnaire and semistructured interview), applied iteratively, to assess document performance-can people find and understand key points of information. SETTING AND PARTICIPANTS: Testing was undertaken with 40 members of the public in four consecutive rounds of 10. Inclusion criteria, matched across rounds, included range of ages and educational attainment. TESTED DOCUMENTS: In round 1 we tested 19 key points of information in a printed version of the EPAR summary for Bondronat (a cancer medicine). This was then revised to address the findings, and tested in round 2. In round 3 we tested the summary on screen, and in round 4, tested a revised on-screen version, after addressing findings from both rounds 1 and 3. PRIMARY OUTCOME MEASURE: The target followed European guidance for medicine leaflets: for each point of information 90% of participants should be able to find, and of those, 90% able to show understanding of the point. RESULTS: For the original EPAR summary, 6 of the 19 points of information reached the target (both paper-based and on-screen). After revisions to format and content, using good practice in information writing and design, 14 and 16 points, respectively, met the target. The problems related to both finding (dependent on layout, headings and design) and understanding (words and sentences used, as well as design). We devised a new heading structure, increased use of bullet points, replaced difficult and technical words and divided long sentences. CONCLUSIONS: People had difficulty finding and understanding key messages in the summary, but user testing identified the problems, and application of good practice resulted in a revised format which performed well. PMID- 24048626 TI - Telemonitoring after discharge from hospital with heart failure: cost effectiveness modelling of alternative service designs. AB - OBJECTIVES: To estimate the cost-effectiveness of remote monitoring strategies versus usual care for adults recently discharged after a heart failure (HF) exacerbation. DESIGN: Decision analysis modelling of cost-effectiveness using secondary data sources. SETTING: Acute hospitals in the UK. PATIENTS: Patients recently discharged (within 28 days) after a HF exacerbation. INTERVENTIONS: Structured telephone support (STS) via human to machine (STS HM) interface, (2) STS via human to human (STS HH) contact and (3) home telemonitoring (TM), compared with (4) usual care. MAIN OUTCOME MEASURES: The incremental cost per quality-adjusted life year (QALY) gained by each strategy compared to the next most effective alternative and the probability of each strategy being cost effective at varying willingness to pay per QALY gained. RESULTS: TM was the most cost-effective strategy in the scenario using these base case costs. Compared with usual care, TM had an estimated incremental cost effectiveness ratio (ICER) of L11 873/QALY, whereas STS HH had an ICER of L228 035/QALY against TM. STS HM was dominated by usual care. Threshold analysis suggested that the monthly cost of TM has to be higher than L390 to have an ICER greater than L20 000/QALY against STS HH. Scenario analyses performed using higher costs of usual care, higher costs of STS HH and lower costs of TM do not substantially change the conclusions. CONCLUSIONS: Cost-effectiveness analyses suggest that TM was an optimal strategy in most scenarios, but there is considerable uncertainty in relation to clear descriptions of the interventions and robust estimation of costs. PMID- 24048627 TI - Phase I trial of concurrent sunitinib and radiation therapy as preoperative treatment for soft tissue sarcoma. AB - INTRODUCTION: Although the introduction of multimodal treatment of soft tissue sarcoma improved local tumour control, local failure still occurs in a good number of patients. Therefore, further improvement of current treatment strategies is necessary. The proposed study treatment will combine standard external beam radiation and the orally administered receptor tyrosine kinase inhibitor sunitinib. METHODS AND ANALYSIS: Patients with soft tissue sarcoma will receive sunitinib and irradiation as neoadjuvant treatment. Radiotherapy will be administered as intensity modulated radiation therapy with a total dose of 50.4 Gy in 28 fractions (5 1/2 weeks). Patients will receive sunitinib daily for 2 weeks prior to and then concurrently with irradiation. Sunitinib will be given in two dose levels. The first dose level will be 25 mg sunitinib per os daily. The second dose level will be 37.5 mg. A dose modification schedule according to a 3+3 design will be applied. Restaging and tumour resection will be performed 6 weeks after completion of sunitinib and irradiation. Primary outcome measures will be the dose-limiting toxicity and maximal tolerated dose of sunitinib administered concurrently with irradiation. Toxicity of the study treatment will be documented according to Common Terminology Criteria of Adverse Events (CTCAE) 4.0. Secondary outcome measures will be the response to the study treatment and morbidity of the tumour resection. Imaging response will be determined according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria comparing MRI performed prior to and 6 weeks after completion of study treatment. Pathological response will be determined evaluating the fraction of non-viable tumour in the resection specimen. Resection morbidity will be evaluated according to CTCAE 4.0. ETHICS AND DISSEMINATION: Approval was obtained from the ethics committee II of the University of Heidelberg, Germany (Reference number 2011-064F-MA). Furthermore, the study was approved by the German Federal Institute for Drugs and Medical Devices (Reference number 4037708). TRIAL REGISTRATION EUDRACT: 2007 002864-87 Clinicaltrials.gov: NCT01498835. PMID- 24048630 TI - Antiarrhythmic drugs 2013: state of the art. AB - Antiarrhythmic drugs are widely used, but are of modest efficacy and have important side effects. However, even with the advance of catheter ablation for atrial fibrillation and ventricular tachycardia, antiarrhythmic drugs remain an important tool for treating arrhythmias. Antiarrhythmic drug development has remained slow despite much effort given our limited understanding of what role various ionic currents play in arrhythmogenesis and how they are modified by arrhythmias. This review will focus on promising new antiarrhythmic drugs undergoing clinical investigation or currently approved for clinical use, including amiodarone analogues, agents with novel ionic targets, and new drug combinations. PMID- 24048633 TI - Validation of a new radiographic protocol for Asian elephant feet and description of their radiographic anatomy. AB - Foot problems are extremely common in elephants and radiography is the only imaging method available but the radiographic anatomy has not been described in detail. The aims of this study were to develop a radiographic protocol for elephant feet using digital radiography, and to describe the normal radiographic anatomy of the Asian elephant front and hind foot. A total of fifteen cadaver foot specimens from captive Asian elephants were radiographed using a range of projections and exposures to determine the best radiographic technique. This was subsequently tested in live elephants in a free-contact setting. The normal radiographic anatomy of the Asian elephant front and hind foot was described with the use of three-dimensional models based on CT reconstructions. The projection angles that were found to be most useful were 65-70 degrees for the front limb and 55-60 degrees in the hind limb. The beam was centred 10-15 cm proximal to the cuticle in the front and 10-15 cm dorsal to the plantar edge of the sole in the hind foot depending on the size of the foot. The protocol developed can be used for larger-scale diagnostic investigations of captive elephant foot disorders, while the normal radiographic anatomy described can improve the diagnostic reliability of elephant feet radiography. PMID- 24048632 TI - Altered mitochondrial ATP synthase expression in the rat dorsal root ganglion after sciatic nerve injury and analgesic effects of intrathecal ATP. AB - Mitochondrial ATP synthase has multiple interdependent biological functions in neurons. Among them, ATP generation and regulation are the most important. The present study investigated whether the expression of mitochondrial ATP synthase correlates with symptoms of neuropathic pain in adult rats after axotomy, and whether intrathecal ATP administration is therapeutic in these neuropathic rats. Male Sprague-Dawley rats received left sciatic nerve transection (axotomy) and were randomly designated to a control (sham-operated) group, a neuropathic pain group (axotomy), a neuropathic pain and intrathecal sterile saline group, and a neuropathic pain and intrathecal ATP group. The thermal and mechanical sensitivity tests were performed at 1, 3, 5, and 7 days after axotomy. Left L4-L5 dorsal root ganglions (DRGs) were harvested to assess mitochondrial ATP synthase by immunoblotting and immunohistochemistry. After nerve injury, the expression of mitochondrial ATP synthase was decreased in protein extracts and was found mainly in C-fiber and A-delta fiber neurons of the DRGs. The decreased expression of mitochondrial ATP synthase and its subcellular localization were related to thermal and mechanical hyperalgesia. Administration of intrathecal ATP significantly attenuated thermal and mechanical hypersensitivity throughout the experimental period, which suggests its potential role in the treatment of neuropathic pain. PMID- 24048634 TI - Iron-dependent erythropoiesis in women with excessive menstrual blood losses and women with normal menses. AB - In women of fertile age, iron loss consequent to excessive menstrual discharge is by far the most frequent cause of iron-deficient anemia. However, the relationship between menstrual discharge and iron loss is poorly understood. In this prospective study, total menstrual and iron losses were assayed in a large cohort of non-anemic women and women with excessive menstrual blood losses (menorrhagia) in order to provide data useful for intervention. One hundred and five Caucasian women aged 20-45 years were recruited. Blood cell count and serum ferritin (SF) levels were determined in each case before menses. Menstrual fluid losses (MFL) were determined using a standardized pads' weight method. Hematin concentration was assayed by a variant of the Alkaline Hematin Method from which iron concentration was calculated. Mean SF levels were 36.2 (range 8.6-100) ng/ml in healthy women and 6.4 (range 5-14) ng/ml in patients with menorrhagia. Median values of iron lost/cycle were 0.87 mg in healthy women and 5.2 mg in patients with menorrhagia (ranges 0.102-2.569 and 1.634-8.665 mg, respectively, p < 0.001). In women with menorrhagia, iron lost/cycle strongly correlated (0.789, p < 0.001) with MFL. In conclusion, healthy women with normal menses lose, on average, 1 mg iron/cycle. Average iron losses in patients with menorrhagia are, at least in our cohort, on average, five-to-six times higher than normal. Most women with menorrhagia had totally depleted iron stores. Indirect, quantitative evaluation of iron lost with menses may be useful to assess the risk of developing iron-deficient anemia in individual patients. PMID- 24048635 TI - Sudden blindness due to bilateral central retinal artery occlusion in a patient on eltrombopag. PMID- 24048636 TI - Outcome in porcine acellular dermal matrix reinforcement of infected abdominal wall defects: a prospective study. AB - PURPOSE: Management of infected abdominal wall defects is a subject of debate, and the use of prosthetic mesh repair is not recommended due to the dramatic rate of mesh infection. The aim of this prospective study was to determine the recurrence rate and long-term outcomes of repairing infected abdominal wall defects using the Strattice porcine acellular dermal matrix reinforcement through a single-stage surgical approach. METHODS: From August 2010 to May 2012, consecutive patients treated for infected abdominal wall defects using Strattice, a biologic prosthesis, were enrolled. All data were collected prospectively and all patients were followed for physical examination and CT scan evaluation. The primary outcome measure was the recurrence rate. RESULTS: Eighteen patients were enrolled and 14 were evaluable. Of these, eight patients had mesh infections and six had enterocutaneous fistulas. Median follow-up was 13 months (range, 3-22) and median length of hospitalization was 13 days (range, 4-56). The Strattice was placed in the intraperitoneal underlay position in 12 patients, and in the retro rectus position for two. Post-operative complications included skin dehiscence (n = 3), wound infection (n = 2), skin necrosis (n = 1), and seroma (n = 2). At the end of follow-up, six patients (43 %) experienced abdominal wall defect recurrence. CONCLUSIONS: The utility of biologic prostheses to repair infected abdominal wall defects is controversial; however, currently, they remain the only alternative to a two-staged surgery. Prospective, randomized studies in larger populations of patients are necessary to fully determine the usefulness of biologic prostheses in this setting. PMID- 24048637 TI - Cutaneous adverse events to type I BRAF inhibitors: an analysis of effects associated with each inhibitor and therapeutic time interval to onset. AB - The treatment of malignant melanoma with inhibitors targeting the BRAF V600E mutation has demonstrated dramatic clinical and radiographic response with improved progression-free and overall survival in the majority of patients receiving treatment. However, cutaneous adverse effects-from proliferative processes to more classic drug side effects-are increasingly being reported in patients on BRAF inhibitors. In this comprehensive literature review we provide (1) an all-inclusive list of cutaneous adverse effects associated with selective class I RAF inhibitors, (2) specific adverse effects associated with each inhibitor, and (3) the therapeutic time interval associated with the onset of all reported lesion types. Twenty-two studies reporting cutaneous adverse reactions with selective class I RAF inhibitor therapy were retrieved from PubMed and sourced from relevant articles referenced by other papers. We identified over 45 differently described lesion types, corresponding to close to 2,000 cases. The most commonly reported lesion types in order of decreasing frequency include inflammatory dermatoses, benign lesions, malignant lesions, and hair/nail-related abnormalities. For the most part, the terminologies used in the original studies were retained. Case totals and time-to-lesion onset are presented for every group, and where available, for individual lesion types, by associated BRAF inhibitor. PMID- 24048638 TI - Internal protein dynamics on ps to MUs timescales as studied by multi-frequency (15)N solid-state NMR relaxation. AB - A comprehensive analysis of the dynamics of the SH3 domain of chicken alpha spectrin is presented, based upon (15)N T1 and on- and off-resonance T1rho relaxation times obtained on deuterated samples with a partial back-exchange of labile protons under a variety of the experimental conditions, taking explicitly into account the dipolar order parameters calculated from (15)N-(1)H dipole dipole couplings. It is demonstrated that such a multi-frequency approach enables access to motional correlation times spanning about 6 orders of magnitude. We asses the validity of different motional models based upon orientation autocorrelation functions with a different number of motional components. We find that for many residues a "two components" model is not sufficient for a good description of the data and more complicated fitting models must be considered. We show that slow motions with correlation times on the order of 1-10 MUs can be determined reliably in spite of rather low apparent amplitudes (below 1 %), and demonstrate that the distribution of the protein backbone mobility along the time scale axis is pronouncedly non-uniform and non-monotonic: two domains of fast (tau < 10(-10) s) and intermediate (10(-9) s < tau < 10(-7) s) motions are separated by a gap of one order of magnitude in time with almost no motions. For slower motions (tau > 10(-6) s) we observe a sharp ~1 order of magnitude decrease of the apparent motional amplitudes. Such a distribution obviously reflects different nature of backbone motions on different time scales, where the slow end may be attributed to weakly populated "excited states." Surprisingly, our data reveal no clearly evident correlations between secondary structure of the protein and motional parameters. We also could not notice any unambiguous correlations between motions in different time scales along the protein backbone emphasizing the importance of the inter-residue interactions and the cooperative nature of protein dynamics. PMID- 24048639 TI - Molecular cloning and characterization of two novel fructose-specific transporters from the osmotolerant and fructophilic yeast Candida magnoliae JH110. AB - Sugar transport is very critical in developing an efficient and rapid conversion process of a mixture of sugars by engineered microorganisms. By using expressed sequence tag data generated for the fructophilic yeast Candida magnoliae JH110, we identified two fructose-specific transporters, CmFSY1 and CmFFZ1, which show high homology with known fructose transporters of other yeasts. The CmFSY1 and CmFFZ1 genes harbor no introns and encode proteins of 574 and 582 amino acids, respectively. Heterologous expression of the two fructose-specific transporter genes in a Saccharomyces cerevisiae, which is unable to utilize hexoses, revealed that both transporters are functionally expressed and specifically transport fructose. These results were further corroborated by kinetic analysis of the fructose transport that showed that CmFsy1p is a high-affinity fructose-proton symporter with low capacity (K(M) = 0.13 +/- 0.01 mM, V(max) = 2.1 +/- 0.3 mmol h 1 [gdw]-1) and that CmFfz1p is a low-affinity fructose-specific facilitator with high capacity (K(M) = 105 +/- 12 mM, V max = 8.6 +/- 0.7 mmol h-1 [gdw]-1). These fructose-specific transporters can be used for improving fructose transport in engineered microorganisms for the production of biofuels and chemicals from fructose-containing feedstock. PMID- 24048640 TI - Design of a core-shell type immuno-magnetic separation system and multiplex PCR for rapid detection of pathogens from food samples. AB - We report an immuno-magnetic separation system developed by the immobilization of pathogen-specific antibodies on the core-shell magnetic beads. The magnetic beads were grafted with glycidylmethacrylate (GMA) using surface-initiated atom transfer radical polymerization (SI-ATRP). For immuno-magnetic separation (IMS) of target bacterial cells from others, antibodies for Escherichia coli and Salmonella enterica serovar Typhimurium cells were immobilized on the magnetic beads via glutaraldehyde coupling reaction. Our IMS system successfully separated Salmonella cells when the concentrations of target (i.e., Salmonella) and interfering (i.e., E. coli) cells were at the same level. Polymerase chain reaction (PCR) assays amplifying the rfb/rfbE region of the E. coli genome and a 647-bp fragment of the invA region of Salmonella were performed as the specific selection to accurately confirm the presence of E. coli and Salmonella, respectively. IMS and multiplex PCR methods can be used for specific and quantitative detection of pathogens from food samples. Thus, this study developed a reliable and direct system for rapid detection of Salmonella and E. coli in food samples. In addition, IMS method could be easily adapted to detect other pathogens by selecting the pertinent antibody. PMID- 24048641 TI - Endophytic microorganisms--promising applications in bioremediation of greenhouse gases. AB - Bioremediation is a technique that uses microbial metabolism to remove pollutants. Various techniques and strategies of bioremediation (e.g., phytoremediation enhanced by endophytic microorganisms, rhizoremediation) can mainly be used to remove hazardous waste from the biosphere. During the last decade, this specific technique has emerged as a potential cleanup tool only for metal pollutants. This situation has changed recently as a possibility has appeared for bioremediation of other pollutants, for instance, volatile organic compounds, crude oils, and radionuclides. The mechanisms of bioremediation depend on the mobility, solubility, degradability, and bioavailability of contaminants. Biodegradation of pollutions is associated with microbial growth and metabolism, i.e., factors that have an impact on the process. Moreover, these factors have a great influence on degradation. As a result, recognition of natural microbial processes is indispensable for understanding the mechanisms of effective bioremediation. In this review, we have emphasized the occurrence of endophytic microorganisms and colonization of plants by endophytes. In addition, the role of enhanced bioremediation by endophytic bacteria and especially of phytoremediation is presented. PMID- 24048642 TI - Characterization and prediction of haploinsufficiency using systems-level gene properties in yeast. AB - Variation in gene copy number can significantly affect organism fitness. When one allele is missing in a diploid, the phenotype can be compromised because of haploinsufficiency. In this work, we identified associations between Saccharomyces cerevisiae gene properties and genome-scale haploinsufficiency phenotypes from previous work. We compared the haploinsufficiency profiles against 23 gene properties and found that genes with higher level of connectivity (degree) in a protein-protein interaction network, higher genetic interaction degree, greater gene sequence conservation, and higher protein expression were significantly more likely to be haploinsufficient. Additionally, haploinsufficiency showed negative relationships with cell cycle regulation and promoter sequence conservation. PMID- 24048643 TI - Comparative analyses identify the contributions of exotic donors to disease resistance in a barley experimental population. AB - Introgression of novel genetic variation into breeding populations is frequently required to facilitate response to new abiotic or biotic pressure. This is particularly true for the introduction of host pathogen resistance in plant breeding. However, the number and genomic location of loci contributed by donor parents are often unknown, complicating efforts to recover desired agronomic phenotypes. We examined allele frequency differentiation in an experimental barley breeding population subject to introgression and subsequent selection for Fusarium head blight resistance. Allele frequency differentiation between the experimental population and the base population identified three primary genomic regions putatively subject to selection for resistance. All three genomic regions have been previously identified by quantitative trait locus (QTL) and association mapping. Based on the degree of identity-by-state relative to donor parents, putative donors of resistance alleles were also identified. The successful application of comparative population genetic approaches in this barley breeding experiment suggests that the approach could be applied to other breeding populations that have undergone defined breeding and selection histories, with the potential to provide valuable information for genetic improvement. PMID- 24048644 TI - Evolution after whole-genome duplication: a network perspective. AB - Gene duplication plays an important role in the evolution of genomes and interactomes. Elucidating how evolution after gene duplication interplays at the sequence and network level is of great interest. In this work, we analyze a data set of gene pairs that arose through whole-genome duplication (WGD) in yeast. All these pairs have the same duplication time, making them ideal for evolutionary investigation. We investigated the interplay between evolution after WGD at the sequence and network levels and correlated these two levels of divergence with gene expression and fitness data. We find that molecular interactions involving WGD genes evolve at rates that are three orders of magnitude slower than the rates of evolution of the corresponding sequences. Furthermore, we find that divergence of WGD pairs correlates strongly with gene expression and fitness data. Because of the role of gene duplication in determining redundancy in biological systems and particularly at the network level, we investigated the role of interaction networks in elucidating the evolutionary fate of duplicated genes. We find that gene neighborhoods in interaction networks provide a mechanism for inferring these fates, and we developed an algorithm for achieving this task. Further epistasis analysis of WGD pairs categorized by their inferred evolutionary fates demonstrated the utility of these techniques. Finally, we find that WGD pairs and other pairs of paralogous genes of small-scale duplication origin share similar properties, giving good support for generalizing our results from WGD pairs to evolution after gene duplication in general. PMID- 24048645 TI - Molecular phylogeography of a human autosomal skin color locus under natural selection. AB - Divergent natural selection caused by differences in solar exposure has resulted in distinctive variations in skin color between human populations. The derived light skin color allele of the SLC24A5 gene, A111T, predominates in populations of Western Eurasian ancestry. To gain insight into when and where this mutation arose, we defined common haplotypes in the genomic region around SLC24A5 across diverse human populations and deduced phylogenetic relationships between them. Virtually all chromosomes carrying the A111T allele share a single 78-kb haplotype that we call C11, indicating that all instances of this mutation in human populations share a common origin. The C11 haplotype was most likely created by a crossover between two haplotypes, followed by the A111T mutation. The two parental precursor haplotypes are found from East Asia to the Americas but are nearly absent in Africa. The distributions of C11 and its parental haplotypes make it most likely that these two last steps occurred between the Middle East and the Indian subcontinent, with the A111T mutation occurring after the split between the ancestors of Europeans and East Asians. PMID- 24048646 TI - Dissecting genome-wide association signals for loss-of-function phenotypes in sorghum flavonoid pigmentation traits. AB - Genome-wide association studies are a powerful method to dissect the genetic basis of traits, although in practice the effects of complex genetic architecture and population structure remain poorly understood. To compare mapping strategies we dissected the genetic control of flavonoid pigmentation traits in the cereal grass sorghum by using high-resolution genotyping-by-sequencing single-nucleotide polymorphism markers. Studying the grain tannin trait, we find that general linear models (GLMs) are not able to precisely map tan1-a, a known loss-of function allele of the Tannin1 gene, with either a small panel (n = 142) or large association panel (n = 336), and that indirect associations limit the mapping of the Tannin1 locus to Mb-resolution. A GLM that accounts for population structure (Q) or standard mixed linear model that accounts for kinship (K) can identify tan1-a, whereas a compressed mixed linear model performs worse than the naive GLM. Interestingly, a simple loss-of-function genome scan, for genotype-phenotype covariation only in the putative loss-of-function allele, is able to precisely identify the Tannin1 gene without considering relatedness. We also find that the tan1-a allele can be mapped with gene resolution in a biparental recombinant inbred line family (n = 263) using genotyping-by-sequencing markers but lower precision in the mapping of vegetative pigmentation traits suggest that consistent gene-level resolution will likely require larger families or multiple recombinant inbred lines. These findings highlight that complex association signals can emerge from even the simplest traits given epistasis and structured alleles, but that gene-resolution mapping of these traits is possible with high marker density and appropriate models. PMID- 24048647 TI - A genome-wide association study reveals genes associated with fusarium ear rot resistance in a maize core diversity panel. AB - Fusarium ear rot is a common disease of maize that affects food and feed quality globally. Resistance to the disease is highly quantitative, and maize breeders have difficulty incorporating polygenic resistance alleles from unadapted donor sources into elite breeding populations without having a negative impact on agronomic performance. Identification of specific allele variants contributing to improved resistance may be useful to breeders by allowing selection of resistance alleles in coupling phase linkage with favorable agronomic characteristics. We report the results of a genome-wide association study to detect allele variants associated with increased resistance to Fusarium ear rot in a maize core diversity panel of 267 inbred lines evaluated in two sets of environments. We performed association tests with 47,445 single-nucleotide polymorphisms (SNPs) while controlling for background genomic relationships with a mixed model and identified three marker loci significantly associated with disease resistance in at least one subset of environments. Each associated SNP locus had relatively small additive effects on disease resistance (+/-1.1% on a 0-100% scale), but nevertheless were associated with 3 to 12% of the genotypic variation within or across environment subsets. Two of three identified SNPs colocalized with genes that have been implicated with programmed cell death. An analysis of associated allele frequencies within the major maize subpopulations revealed enrichment for resistance alleles in the tropical/subtropical and popcorn subpopulations compared with other temperate breeding pools. PMID- 24048648 TI - Allelic variation in a cellulose synthase gene (PtoCesA4) associated with growth and wood properties in Populus tomentosa. AB - Lignocellulosic biomass from trees provides a renewable feedstock for biofuels, lumber, pulp, paper, and other uses. Dissecting the mechanism underlying natural variation of the complex traits controlling growth and lignocellulose biosynthesis in trees can enable marker-assisted breeding to improve wood quality and yield. Here, we combined linkage disequilibrium (LD)-based association analysis with traditional linkage analysis to detect the genetic effect of a Populus tomentosa cellulose synthase gene, PtoCesA4. PtoCesA4 is strongly expressed in developing xylem and leaves. Nucleotide diversity and LD in PtoCesA4, sampled from the P. tomentosa natural distribution, revealed that PtoCesA4 harbors high single nucleotide polymorphism (SNP) diversity (piT = 0.0080 and thetaw = 0.0098) and low LD (r(2) >= 0.1, within 1400 bp), demonstrating that the potential of a candidate-gene-based LD approach in understanding the molecular basis underlying quantitative variation in this species. By combining single SNP, multi-SNP, and haplotype-based associations in an association population of 460 individuals with single SNP linkage analysis in a family-based linkage populations (1200 individuals), we identified three strong associations (false discovery rate Q < 0.05) in both populations. These include two nonsynonymous markers (SNP49 associated with alpha-cellulose content and SNP59 associated with fiber width) and a noncoding marker (SNP18 associated with alpha-cellulose content). Variation in RNA transcript abundance among genotypic classes of SNP49 was confirmed in these two populations. Therefore, combining different methods allowed us to examine functional PtoCesA4 allelic variation underlying natural variation in complex quantitative traits related to growth and lignocellulosic biosynthesis. PMID- 24048650 TI - Disappearance of degenerative, non-inflammatory, retro-odontoid pseudotumor following posterior C1-C2 fixation: case series and review of the literature. AB - PURPOSE: Retro-odontoid pseudotumor, not related to inflammatory or traumatic conditions, is an uncommon pathology. Atlanto-axial instability has been advocated to explain the pathophysiology of retro-odontoid pseudotumor's formation and growth. Despite pseudotumor direct removal through transoral or lateral approach represented the main surgical strategy for a long time, in the last decade several authors highlighted the possibility to treat retro-odontoid pseudotumor by occipito-cervical or C1-C2 fixation without removal of the intracanalar tissue. The goal of this study is to analyze the data collected in a series of patients suffering from cervical myelopathy due to non-inflammatory, degenerative retro-odontoid pannus and treated by posterior C1-C2 fixation. The relevant literature is also reviewed. METHODS: Five patients, not suffering from inflammatory diseases, were treated between 2009 and 2012. Abnormalities of cranio-cervical junction and/or lower cervical spondylotic degeneration were observed in all patients. No evidence of atlanto-axial instability was demonstrated. Clinical and radiological evaluation included pre- and post operative Nurick score as well as pre- and post-operative X-rays, CT and MRI. In one case, CT scan highlighted an eggshell calcification of the pannus. All patients underwent either a C1-C2 fixation (C1 lateral mass and C2 isthmus pedicle screws) or occipito-cervical fixation (2 patients) in cases of C0-C1 fusion. RESULTS: Follow-up ranges from 22 to 45 months (mean 32) in four patients. One patient died of surgery-unrelated disease. Nurick score changes suggest a clinical improvement in four cases. Neuro-radiological evaluation shows a progressive but incomplete reduction of thickness of retro-odontoid pseudotumor in one patient, and its disappearance in the other three cases. A second-stage transoral or posterior lateral approach was not required. CONCLUSION: Although the etiopathogenesis of non-inflammatory, i.e., degenerative, retro-odontoid pseudotumor is still controversial, our series (the second largest on degenerative retro-odontoid pannus in the literature) confirms that a posterior approach may be sufficient and transoral surgery is not required. PMID- 24048649 TI - Extension of the Caenorhabditis elegans Pharyngeal M1 neuron axon is regulated by multiple mechanisms. AB - The guidance of axons to their correct targets is a critical step in development. The C. elegans pharynx presents an attractive system to study neuronal pathfinding in the context of a developing organ. The worm pharynx contains relatively few cells and cell types, but each cell has a known lineage and stereotyped developmental patterns. We found that extension of the M1 pharyngeal axon, which spans the entire length of the pharynx, occurs in two distinct phases. The first proximal phase does not require genes that function in axon extension (unc-34, unc-51, unc-115, and unc-119), whereas the second distal phase does use these genes and is guided in part by the adjacent g1P gland cell projection. unc-34, unc-51, and unc-115 had incompletely penetrant defects and appeared to act in conjunction with the g1P cell for distal outgrowth. Only unc 119 showed fully penetrant defects for the distal phase. Mutations affecting classical neuronal guidance cues (Netrin, Semaphorin, Slit/Robo, Ephrin) or adhesion molecules (cadherin, IgCAM) had, at best, weak effects on the M1 axon. None of the mutations we tested affected the proximal phase of M1 elongation. In a forward genetic screen, we isolated nine mutations in five genes, three of which are novel, showing defects in M1, including axon overextension, truncation, or ectopic branching. One of these mutations appeared to affect the generation or differentiation of the M1 neuron. We conclude that M1 axon extension is a robust process that is not completely dependent on any single guidance mechanism. PMID- 24048651 TI - One-stage combined lumbo-sacral fusion, by anterior then posterior approach: clinical and radiological results. AB - INTRODUCTION: We intended to prospectively evaluate the clinical and radiological results of lumbo-sacral fusion achieved by a combined approach, anterior then posterior. MATERIAL AND METHODS: 62 patients were consecutively treated at L5-S1, L4-L5 or L4-S1 for degenerative disc disease or low-grade isthmic spondylolisthesis by combined surgery. RESULTS: Mean operative time and blood loss were 209 min and 308 ml, respectively, including the two approaches. VAS, ODI and Roland-Morris scores significantly improved postoperatively at 1 year (p < 0.005) and fusion was obtained in all cases on the CT scan at 1-year follow-up. Segmental lordosis significantly improved postoperatively (p < 0.05) with a mean gain of 10.2 degrees at L5-S1 and 5.5 degrees at L4-L5. CONCLUSION: The combined procedure meets the requested criteria for a lumbar fusion in terms of clinical results, functional outcomes, fusion rates while restoring segmental lordosis and disc height. It cumulates the advantages of the anterior and posterior approach performed alone, especially for L5-S1. PMID- 24048653 TI - Acromegaly: a Latin American perspective. PMID- 24048652 TI - Toxoplasma gondii, source to sea: higher contribution of domestic felids to terrestrial parasite loading despite lower infection prevalence. AB - Environmental transmission of Toxoplasma gondii, a global zoonotic parasite, adversely impacts human and animal health. Toxoplasma is a significant cause of mortality in threatened Southern sea otters, which serve as sentinels for disease threats to people and animals in coastal environments. As wild and domestic felids are the only recognized hosts capable of shedding Toxoplasma oocysts into the environment, otter infection suggests land-to-sea pathogen transmission. To assess relative contributions to terrestrial parasite loading, we evaluated infection and shedding among managed and unmanaged feral domestic cats, mountain lions, and bobcats in coastal California, USA. Infection prevalence differed among sympatric felids, with a significantly lower prevalence for managed feral cats (17%) than mountain lions, bobcats, or unmanaged feral cats subsisting on wild prey (73-81%). A geographic hotspot of infection in felids was identified near Monterey Bay, bordering a high-risk site for otter infection. Increased odds of oocyst shedding were detected in bobcats and unmanaged feral cats. Due to their large populations, pet and feral domestic cats likely contribute more oocysts to lands bordering the sea otter range than native wild felids. Continued coastal development may influence felid numbers and distribution, increase terrestrial pathogens in freshwater runoff, and alter disease dynamics at the human-animal-environment interface. PMID- 24048654 TI - Cerebrovascular complications and utilization of endovascular techniques following transsphenoidal resection of pituitary adenomas: a study of the Nationwide Inpatient Sample 2001-2010. AB - PURPOSE: Cerebrovascular complications following transsphenoidal resection of pituitary tumors are rare and often evaluated and treated with endovascular techniques. We determined the utilization rate and outcomes of endovascular procedures in transsphenoidal pituitary resection patients using an administrative database. METHODS: Using the Nationwide Inpatient Sample 2001 2010, patients receiving transsphenoidal resection of benign pituitary tumors were identified. The rate of cerebrovascular complications and utilization of endovascular repair procedures and cerebral angiography were compared between high (>= 75 procedures/year) and low volume (<75 procedures/year) centers. Chi squared tests were used to compare categorical variables. RESULTS: 70,878 were patients included in this study. ICH/SAH occurred in 0.9 % of patients (652/70,878) and stroke occurred in 0.5 % of patients (327/70,878). Patients treated at high volume centers had significantly lower rates of stroke (0.5 % vs. 1.0 %, P = 0.04), and ICH/SAH (0.5 vs. 1.0 %, P = 0.05) when compared to patients treated at low-volume centers. Overall, 531 patients (0.7 %) received post operative angiography and 83 patients (0.1 %) received endovascular repair procedures. High volume center patients underwent angiography in 0.4 % of cases compared to 0.9 % for low volume center patients (P = 0.02). There was no significant difference in endovascular repair procedure rates at high and low volume centers (0.1 vs. 0.2 %, P = 0.37). CONCLUSIONS: Cerebrovascular surgical complications requiring cerebral angiography and endovascular repair are rare among transsphenoidal pituitary resection patients. These occur with higher frequency at low volume centers and are associated with high mortality rates. PMID- 24048655 TI - Sex, race, and consideration of bariatric surgery among primary care patients with moderate to severe obesity. AB - BACKGROUND: Bariatric surgery is one of few obesity treatments to produce substantial weight loss but only a small proportion of medically-eligible patients, especially men and racial minorities, undergo bariatric surgery. OBJECTIVE: To describe primary care patients' consideration of bariatric surgery, potential variation by sex and race, and factors that underlie any variation. DESIGN, SETTING, AND PATIENTS: Telephone interview of 337 patients with a body mass index or BMI > 35 kg/m(2) seen at four diverse primary care practices in Greater-Boston. MEASUREMENTS: Patients' consideration of bariatric surgery. RESULTS: Of 325 patients who had heard of bariatric surgery, 34 % had seriously considered surgery. Men were less likely than women and African Americans were less likely than Caucasian patients to have considered surgery after adjustment for sociodemographics and BMI. Comorbid conditions did not explain sex and racial differences but racial differences dissipated after adjustment for quality of life (QOL), which tended to be higher among African American than Caucasian patients. Physician recommendation of bariatric surgery was independently associated with serious consideration for surgery [OR 4.95 (95 % CI 2.81-8.70)], but did not explain variation in consideration of surgery across sex and race. However, if recommended by their doctor, men were as willing and African American and Hispanic patients were more willing to consider bariatric surgery than their respective counterparts after adjustment. Nevertheless, only 20 % of patients reported being recommended bariatric surgery by their doctor and African Americans and men were less likely to receive this recommendation; racial differences in being recommended surgery were also largely explained by differences in QOL. High perceived risk to bariatric surgery was the most commonly cited barrier; financial concerns were uncommonly cited. LIMITATIONS: Single geographic region; examined consideration and not who eventually proceeded with bariatric surgery. CONCLUSION: African Americans and men were less likely to have considered bariatric surgery and were less likely to have been recommended surgery by their doctors. Differences in how obesity affects QOL appear to account for some of these variations. High perceived risk rather than financial barrier was the major deterrent for patients. PMID- 24048657 TI - ["Save A Life - 100 per resuscitation" Greetings from the Federal Minister for Health Daniel Bahr to the campaign]. PMID- 24048656 TI - No detectable association between frequency of marijuana use and health or healthcare utilization among primary care patients who screen positive for drug use. AB - BACKGROUND: Marijuana is the most commonly used illicit drug, yet its impact on health and healthcare utilization has not been studied extensively. METHODS: To assess the cross-sectional association between frequency of marijuana use and healthcare utilization (emergency department and hospitalization) and health (comorbidity, health status), we studied patients in an urban primary care clinic who reported any recent (past 3-month) drug use (marijuana, opioids, cocaine, others) on screening. Frequency of marijuana use in the past 3 months was the main independent variable [daily/ almost daily, less than daily and no use (reference group)]. Outcomes assessed were past 3-month emergency department or hospital utilization, the presence of medical comorbidity (Charlson index >= 1), and health status with the EuroQol. We used separate multivariable regression models adjusting for age, sex, tobacco and other substance use. RESULTS: All 589 participants reported recent drug use: marijuana 84 % (29 % daily, 55 % less than daily), cocaine 25 %, opioid 23 %, other drugs 8 %; 58 % reported exclusive marijuana use. Frequency of marijuana use was not significantly associated with emergency department use {adjusted odds ratio [AOR] 0.67, [95 % confidence interval (CI) 0.36, 1.24] for daily; AOR 0.69 [95 % CI 0.40,1.18] for less than daily versus no use}, hospitalization [AOR 0.79 (95 % CI 0.35, 1.81) for daily; AOR 1.23 (95 % CI 0.63, 2.40) for less than daily versus no use], any comorbidity [AOR 0.62, (95 % CI 0.33, 1.18) for daily; AOR 0.67 (95 % CI 0.38, 1.17) for less than daily versus no use] or health status (adjusted mean EuroQol 69.1, 67.8 and 68.0 for daily, less than daily and none, respectively, global p = 0.78). CONCLUSIONS: Among adults in primary care who screen positive for any recent illicit or non-medical prescription drug use, we were unable to detect an association between frequency of marijuana use and health, emergency department use, or hospital utilization. PMID- 24048659 TI - [Myths and facts in the operating theatre]. AB - Surgical site infections are the most common nosocomial infections. Strategies to prevent these infections are crucial. Evidence based measures like hand hygiene, treatment of nasal carriage of S. aureus, surveillance, prophylactic application of antibiotics or hair removal with electric clippers are listed in national and international guidelines. Beside these measures several myths and traditions like the application of antibiotic prophylaxis for several days or hygienic rituals in a septic operating theatre still exist. These measures are not helpful and should not be used any more. It is helpful to include effective measures in a bundle, the compliance with the bundle should be monitored regularly. Only the consequent implementation of evidence based and effective measures can help to prevent surgical site infections. PMID- 24048660 TI - [Sepsis in emergency medicine--pre-hospital and early in-hospital emergency treatment]. AB - Sepsis is a complex life threatening disease whose outcome decisively depends on a fast diagnosis and treatment. Emergency Medicine is confronted with the task to identify theses septic patients reliably and initiate early goal directed therapy and treatment with antibiotics as soon as possible to avoid a dangerous delay and reduce sepsis-related mortality. This article presents a review focused on the early steps of sepsis therapy in pre-hospital and early in-hospital emergency medicine. PMID- 24048661 TI - [Intensive care quiz--get the diagnosis!]. PMID- 24048662 TI - [Helsinki Declaration on Patient Safety in Anaesthesiology--Part 8: SOP for checking equipment and drugs]. AB - In 2010 the Helsinki Declaration on Patient Safety in Anaesthesiology was launched. In this joined statement under the auspice of the European Society of Anaesthesiology the need for protocols for different aspects of perioperative procedures that could affect patient safety was stated. All participating institutions should have--among others--protocols for checking equipment and drugs required for the delivery of safe anaesthesia. The background for this being the fact that the lack of carefully checking equipment and drugs--or not adhering to existing checklists--is a latent threat to patient safety and thus may increase morbidity and mortality.In this part of a series the authors present protocols existing in their clinic for checking anaesthesia equipment and drugs. PMID- 24048663 TI - [Lay resuscitation--any thing is better than doing nothing]. PMID- 24048664 TI - [Dispatcher assisted resuscitation by laypersons]. AB - ERC Guidelines 2010 highlight the importance of dispatcher assisted cardiopulmonary resuscitation. The concept has been in use in emergency medical services in the USA since the mid-Eighties where it accounted for a considerable rise in bystander resuscitation. Subsequently it was implemented in some major Scandinavian cities. Studies from those countries showed that the rate of survivors in good neurological condition can be raised significantly. Yet, this procedure has not been widely established in Germany so far. In this article the positive effects of the approach are illustrated as well as its limitations some of which can be resolved putting in reasonable effort. The relevance of dispatcher assisted CPR for emergency medical dispatchers as well as the emergency medical crews at the scene is then discussed. PMID- 24048665 TI - [Teaching resuscitation in schools: "The earlier, the better...."]. AB - Sudden cardiac arrest is a major contributor to avoidable deaths in Europe. Immediate start of basic life support (BLS) by laypersons is among the most successful strategies in the treatment of cardiac arrest patients. Despite the fact that more than half of all cardiac arrests in Germany are witnessed by a bystander, only in one fifth of all arrests layperson resuscitation is initiated. One strategy to enhance bystander BLS is to establish cardiac resuscitation tuition in schools. BLS instructions for pupils have been proven to be successfully implemented independent from children's age or physical ability. Although an age-adjusted curriculum seems reasonable even usage of automatic external defibrillators (AED) can be taught effectually. The earlier in the life of a student BLS-instruction begins, the more successful the training is. However a national German curriculum for BLS-training in schools has yet to be established in Germany. PMID- 24048666 TI - [Lay-rescuer cardiopulmonary resuscitation (CPR)--controversies in emergency medicine: lay-rescuer CPR with or without mouth-to-mouth ventilation]. AB - An analysis of literature results reveals differences concerning the need for rescue breathing in lay-rescuer cardiopulmonary-resuscitation (CPR). Observational studies on large registries have shown improved survival rates with standard CPR (chest compressions and rescue breathing) compared to continuous chest compressions (CCC). This applies especially for cardiac arrests of non cardiac origin or prolonged EMS-arrival times. In contrast a public program for lay-rescuers focusing on CCC lead to improved success rates of bystander-CPR, followed by improved survival rates. The 2010 ERC guidelines have resolved this controversy by integrating both aspects. CCC is recommended for everyone. Trained bystanders should use standard-CPR as method of choice. For dispatcher-assisted CPR the results are clear. Giving instructions for mouth-to-mouth ventilation is too complicated and time consuming, thus impairing survival rates. Therefore CCC is recommended for dispatcher-assisted CPR. PMID- 24048667 TI - [Bystander resuscitation: the impact of first aid on survival]. AB - About 75000 people suffer from sudden cardiac arrest in Germany every year. 47% of all out-of-hospital cardiac arrests (OHCA) in Germany are bystander witnessed, but in only 16.1% is bystander-initiated CPR undertaken. In comparison to other countries, Germany is in the last third of bystander-initiated CPR activities. But bystander CPR is one of the most important measures contributing to a good neurological outcome after OHCA. New methods and concepts have to be developed to bring the knowledge of CPR to the general public in Germany and to improve the international standing. PMID- 24048668 TI - [The psychology of children resuscitation]. AB - The management of pre-hospital cardiac arrest in children requires psychosocial as well as medical skills. This paper provides a review of the current literature regarding the psychological aspects of pre-hospital cardiac arrest in children. PMID- 24048671 TI - Do post-translational beta cell protein modifications trigger type 1 diabetes? AB - Type 1 diabetes is considered an autoimmune disease characterised by specific T cell-mediated destruction of the insulin-producing beta cells. Yet, except for insulin, no beta cell-specific antigens have been discovered. This may imply that the autoantigens in type 1 diabetes exist in modified forms capable of specifically triggering beta cell destruction. In other immune-mediated diseases, autoantigens targeted by the immune system have undergone post-translational modification (PTM), thereby creating tissue-specific neo-epitopes. In a similar manner, PTM of beta cell proteins might create beta cell-specific neo-epitopes. We suggest that the current paradigm of type 1 diabetes as a classical autoimmune disease should be reconsidered since the immune response may not be directed against native beta cell proteins. A modified model for the pathogenetic events taking place in islets leading to the T cell attack against beta cells is presented. In this model, PTM plays a prominent role in triggering beta cell destruction. We discuss literature of relevance and perform genetic and human islet gene expression analyses. Both direct and circumstantial support for the involvement of PTM in type 1 diabetes exists in the published literature. Furthermore, we report that cytokines change the expression levels of several genes encoding proteins involved in PTM processes in human islets, and that there are type 1 diabetes-associated polymorphisms in a number of these. In conclusion, data from the literature and presented experimental data support the notion that PTM of beta cell proteins may be involved in triggering beta cell destruction in type 1 diabetes. If the beta cell antigens recognised by the immune system foremost come from modified proteins rather than native ones, the concept of type 1 diabetes as a classical autoimmune disease is open for debate. PMID- 24048672 TI - Proton pump inhibitors and nitric oxide mechanisms in type 2 diabetes. PMID- 24048673 TI - Exaggerated release and preserved insulinotropic action of glucagon-like peptide 1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass. AB - AIMS/HYPOTHESIS: Roux-en-Y gastric bypass (RYGB) improves glycaemic control in part by increasing postprandial insulin secretion through exaggerated glucagon like peptide (GLP)-1 release. However, it is unknown whether islet cell responsiveness to i.v. glucose, non-glucose (arginine) and incretin hormones, including GLP-1, is altered. METHODS: Eleven severely obese glucose-tolerant individuals underwent three hyperglycaemic clamps with arginine bolus and co infusion of either GLP-1, glucose-dependent insulinotropic polypeptide (GIP) or saline before, and at 1 week and 3 months after RYGB. In addition, an OGTT was performed before and 3 months after surgery. RESULTS: After RYGB, insulin sensitivity improved at 1 week and 3 months, while insulin stimulation and glucagon suppression in response to the clamp with saline co-infusion were largely unaltered. The influence of i.v. GLP-1 and GIP on insulin and glucagon secretion was also unchanged postoperatively. In response to the postoperative OGTT at 3 months, insulin and GLP-1, but not GIP, secretion increased. Furthermore, the glucose profile during the OGTT was altered, with a substantial reduction in 2 h plasma glucose and a paradoxical hypersecretion of glucagon. CONCLUSIONS/INTERPRETATION: After RYGB, insulin hypersecretion is linked to the oral, but not the i.v., route of administration and is associated with exaggerated release and preserved insulinotropic action of GLP-1, while both the secretion and action of GIP are unchanged. The results highlight the importance of increased GLP-1 secretion for improving postoperative glucose metabolism. TRIAL REGISTRATION: ClinicalTrials.gov NCT01559779. PMID- 24048674 TI - A phase I and pharmacokinetic study of oxaliplatin and bortezomib: activity, but dose-limiting neurotoxicity. AB - PURPOSE: The potential synergy of modulating platinum-induced DNA damage by combining the proteasome inhibitor bortezomib with oxaliplatin was studied in patients with solid tumors, with special attention to avoidance of cumulative neurotoxicity (NT). PATIENTS AND METHODS: In a 3 + 3 dose escalation design, patients received bortezomib at 1.0-1.5 mg/m2 on days 1 and 4 and oxaliplatin at 60-85 mg/m2 on day 1 of a 14-day cycle. NT assessments were performed at the start of every two cycles. Oxaliplatin pharmacokinetics (PK) were determined pre- and post-bortezomib. RESULTS: Thirty patients were enrolled with 25 (11 men, 14 women) fully evaluable for NT assessments at cycle 2. The median age was 56 years (range 35-74 years); median number of cycles received 2 (range 1-10). At dose levels 2-5 (B 1.3 mg/m2), patients manifested NT grades 3 and 4 at a median 3.4 cycles (range 2-9 cycles): 3 had ataxia (one also with sensory neuropathy or neurogenic hypotension, respectively) and 3 had just sensory neuropathy. A 6th dose-level reducing bortezomib to 1.0 mg/m2 with oxaliplatin 85 mg/m2) was explored and no NT or dose limiting toxicities were noted among 7 evaluable patients (5 receiving two or more cycles). Four patients experienced a partial response--one with platinum-resistant ovarian cancer, another with gastroesophageal cancer, another with ampulla of Vater carcinoma, and a patient with cholangiocarcinoma. PK studies at dose levels 1 and 2 showed greater mean ultrafiltrable platinum when oxaliplatin was dosed after bortezomib. CONCLUSIONS: Bortezomib 1.0 mg/m2 * 2 every 14 days combines safely with oxaliplatin. At higher doses, cumulative NT (i.e., cerebellar signs and sensory neuropathy) occurs at an accelerated pace perhaps from a PK interaction. PMID- 24048675 TI - Predictors of recurrent sickness absence among workers having returned to work after sickness absence due to common mental disorders. AB - OBJECTIVE: The aim of this study was to investigate whether sociodemographic, disease-related, personal, and work-related factors - measured at baseline - are predictors of recurrent sickness absence (SA) at 6 and 12 months follow-up among workers who returned to work after SA due to common mental disorders (CMD). METHODS: Based on a cluster-randomized controlled trial, this prospective study comprised 158 participants, aged 18-63 years, with partial or full return to work (RTW) and an occupational physician-diagnosed CMD. Data on predictors were collected with questionnaires and administrative data. Outcome was the incidence of recurrent SA (ie, decreased work for >=30% of contract hours due to all-cause SA regardless of partial or full RTW) at 6 and 12 months follow-up. Longitudinal logistic regression analysis with backward elimination was used. RESULTS: We found that company size >100 [odds ratio (OR) 2.59, 95% confidence interval (95% CI) 1.40-4.80] and conflicts with the supervisor (OR 2.21, 95% CI 1.21-4.04) were predictive of recurrent SA. Having >=1 chronic diseases decreased the risk of recurrent SA (OR 0.54, 95% CI 0.30-0.96). CONCLUSIONS: Two work- and one disease related factor predicted the incidence of recurrent SA among workers with CMD. Healthcare providers can use these findings to detect and help workers who have returned to work and are at higher risk for recurrent SA. Furthermore, future interventions to prevent recurrent SA could focus on supervisor conflicts. PMID- 24048676 TI - Protein-losing enteropathy--vomiting the diagnosis. PMID- 24048677 TI - Age specific prevalence of hepatitis B and hepatitis C among pregnant women in the northwestern region of Turkey. PMID- 24048678 TI - Liver biopsy for parenchymal liver disease - is routine real time image guidance unnecessary? AB - Liver biopsy even today remains the standard of care for grading and staging chronic hepatitis despite advances in noninvasive markers of liver fibrosis. Literature suggests an expanding role for real-time image guided liver biopsy and declining trend for blind liver biopsies. In our center, where we perform around 400 liver biopsies per year, we performed a prospective clinical audit of our practice of blind outpatient percutaneous liver biopsies. Patients requiring histological grading and staging of chronic hepatitis routinely undergo blind outpatient percutaneous liver biopsies in our endoscopy unit unless there is a definite indication for real-time image guidance. All procedures were assessed for safety, and all specimens were evaluated by a specimen quality grading score for adequacy for grading and staging of chronic hepatitis. Of the 446 patients referred for histological grading and staging of chronic hepatitis C by liver biopsy, only 42 patients (9.5 %) required real-time ultrasound for liver biopsy. The remaining 404 patients underwent blind outpatient percutaneous liver biopsies which were found to be extremely safe with no major complications, yielding adequate liver tissue with high specimen quality score allowing optimal grading and staging of chronic hepatitis. PMID- 24048679 TI - Rectal cancer in young Indians--are these cancers different compared to their older counterparts? AB - BACKGROUND: The incidence of rectal cancer in young Indians is increasing. Recent evidence suggests a probable existence of noncanonical tumorigenesis pathways in early-onset colorectal cancer patients in India. The aim of the study was to evaluate rectal cancer outcomes in patients <=40 years with those >40 years. METHODS: An analysis of a prospective database of surgically treated rectal cancer patients <=40 years (group 1) and those >40 years (group 2) over 2 years was performed. Clinicopathological features, perioperative outcomes, and disease free survival (DFS) were analyzed. RESULTS: Of the 512 patients with colorectal cancer treated surgically, 237 patients (group 1-57 patients; group 2-180 patients) were diagnosed with nonmetastatic rectal adenocarcinoma. Patients in group 1 were more likely to present with locally advanced (stage III) disease (p < 0.005) resulting in a higher proportion of them receiving neoadjuvant chemoradiotherapy (NACT-RT). There was no difference in morbidity and mortality between the two groups. Younger patients had a significantly higher median total and positive lymph node yield (p < 0.003). Patients in group 1 had a significantly lower overall DFS (p < 0.005). Stage-specific DFS also demonstrated a significantly lower trend in stage III patients in group 1. CONCLUSIONS: Young rectal cancer patients in India tended to present more frequently with locally advanced tumors resulting in a higher proportion being treated with NACT-RT. Stapled rectal anastomoses could be performed safely in young patients even after NACT-RT. The significantly poorer DFS in young Indian patients with stage III disease was a novel finding and merits further investigation into tumor biology. PMID- 24048680 TI - Total number of lymph nodes harvested is associated with better survival in stages II and III colorectal cancer. AB - BACKGROUND: Lymph node status is important in staging colorectal cancer (CRC). Presence of metastatic nodes differentiates stage III from stage II. The role of adjuvant therapy is still unclear in stage II CRC. Inadequate node sampling may result in inaccurate staging. METHOD: Records of 131 patients with stages II and III CRC who underwent curative resection, having five or more lymph nodes harvested from the specimen, were prospectively followed up and analyzed. The Kaplan-Meier method was used to analyze survival, based on groups of serially ascending values of lymph nodes harvested. Regression analysis was performed by Cox proportional hazards ratio model with right-censored CRC survival data at a 10 % significance level. The effect of nodal harvest on survival was adjusted for age, sex, preoperative carcinoembryonic antigen (CEA) level, neoadjuvant chemoradiation, pathological tumor stage, histological type, differentiation, margin positivity, angioinvasion, perineural invasion, and lymphovascular infiltration. RESULTS: The total population showed improved survival with 14 or more nodes harvested (p= 0.005). For both rectal (n= 83; p= 0.03) and colon cancers (n= 46; p= 0.08), most significant survival benefits were seen with over 14 nodes harvested, irrespective of the stage. With multiple regression analysis, advanced age (p= 0.003), male sex (p= 0.017), lymphovascular infiltration (p= 0.015), and preoperative CEA levels (p= 0.096) were found to be other significant factors. The lymph node effect remained significant (HR = 0.19, p= 0.004) after adjusting for the above factors. CONCLUSION: A lymph node harvest of 14 or more resulted in better survival outcome from CRC in this population. Staging of the disease could be accurate with increased nodal harvesting. PMID- 24048682 TI - Osteoprotegerin exerts its pro-inflammatory effects through nuclear factor-kappaB activation. AB - BACKGROUND: Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor (TNF) receptor super-family, is a key factor inhibiting the differentiation and activation of osteoclasts. It has recently been implicated as a disease marker for inflammatory bowel disease (IBD) yet its role in the intestinal epithelial inflammatory response remains unknown. AIM: The primary objective of this study was to investigate whether OPG has a role in intestinal inflammation and a potential role in IBD pathogenesis. METHODS: Caco-2 and HT-29 cells were grown in vitro to confluence on culture-permeable supports and then co-cultured with either TNF-alpha or OPG. After exposure to either TNF-alpha or OPG, interleukin (IL)-8 protein and mRNA levels were evaluated. Ussing chamber, western blotting, real-time polymerase chain reaction, and immunofluorescence were used to further investigate the effect of OPG on intestinal barrier integrity and function. RESULTS: Similar to TNF-alpha, treatment of monolayers with OPG caused increased monolayer permeability and diminished tight junction function and integrity, with loss of tight junction proteins from cell membranes. This was accompanied by elevated IL-8 protein and gene levels (P < 0.05). Western blotting also revealed that OPG, similar to TNF-alpha, induced NF-kappaB activation, as shown by inhibition of NF-kappaB kinase subunit-alpha phosphorylation. CONCLUSIONS: These results indicate that OPG has pro-inflammatory properties because it induces gut barrier dysfunction and secretion of other pro-inflammatory cytokines. These results also provide evidence that OPG is likely to exert its pro-inflammatory effects through NF-kappaB activation and may potently contribute to IBD pathogenesis. PMID- 24048683 TI - Characterization of hepatocellular carcinoma related genes and metabolites in human nonalcoholic fatty liver disease. AB - BACKGROUND: The worldwide prevalences of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are estimated to range from 30 to 40 % and 5-17 %, respectively. Hepatocellular carcinoma (HCC) is primarily caused by hepatitis B infection, but retrospective data suggest that 4-29 % of NASH cases will progress to HCC. Currently the connection between NASH and HCC is unclear. AIMS: The purpose of this study was to identify changes in expression of HCC related genes and metabolite profiles in NAFLD progression. METHODS: Transcriptomic and metabolomic datasets from human liver tissue representing NAFLD progression (normal, steatosis, NASH) were utilized and compared to published data for HCC. RESULTS: Genes involved in Wnt signaling were downregulated in NASH but have been reported to be upregulated in HCC. Extracellular matrix/angiogenesis genes were upregulated in NASH, similar to reports in HCC. Iron homeostasis is known to be perturbed in HCC and we observed downregulation of genes in this pathway. In the metabolomics analysis of hepatic NAFLD samples, several changes were opposite to what has been reported in plasma of HCC patients (lysine, phenylalanine, citrulline, creatine, creatinine, glycodeoxycholic acid, inosine, and alpha-ketoglutarate). In contrast, multiple acyl-lyso-phosphatidylcholine metabolites were downregulated in NASH livers, consistent with observations in HCC patient plasma. CONCLUSIONS: These data indicate an overlap in the pathogenesis of NAFLD and HCC where several classes of HCC related genes and metabolites are altered in NAFLD. Importantly, Wnt signaling and several metabolites are different, thus implicating these genes and metabolites as mediators in the transition from NASH to HCC. PMID- 24048684 TI - Clinical significance of microsatellite instability in colorectal cancer. AB - INTRODUCTION: Colorectal cancer is a heterogeneous tumor type with regard to molecular pathogenesis and genetic instability. The majority of colorectal cancers display chromosomal instability and follow the classical adenoma carcinoma sequence of tumor progression. A subset of about 15 % of colorectal cancers, however, displays DNA mismatch repair (MMR) deficiency and the high level microsatellite instability (MSI-H) phenotype. MSI-H colorectal cancers can occur as sporadic tumors or in the context of hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome. CLINICAL RELEVANCE: The MSI-H phenotype is a hallmark of Lynch syndrome-associated cancers, which is of diagnostic relevance for the identification of Lynch syndrome mutation carriers. MSI-H colorectal cancers are characterized by a distinct clinical behavior, which results from their particular molecular pathogenesis and gives microsatellite instability testing its clinical significance. The MSI-H phenotype shows association with proximal tumor localization, a dense local lymphocyte infiltration, and a low frequency of distant organ metastasis. Moreover, MSI-H colorectal cancers have a better prognosis than their microsatellite-stable counterparts. A distinct responsiveness of MSI-H colorectal cancer patients towards chemotherapy has been shown in several studies. CONCLUSIONS: The clinical characteristics of MSI-H cancers are closely linked to their molecular pathogenesis, and research on the molecular alteration characteristic of MSI-H cancers may provide the basis for novel diagnostic or therapeutic approaches. PMID- 24048681 TI - Primary cilia and dendritic spines: different but similar signaling compartments. AB - Primary non-motile cilia and dendritic spines are cellular compartments that are specialized to sense and transduce environmental cues and presynaptic signals, respectively. Despite their unique cellular roles, both compartments exhibit remarkable parallels in the general principles, as well as molecular mechanisms, by which their protein composition, membrane domain architecture, cellular interactions, and structural and functional plasticity are regulated. We compare and contrast the pathways required for the generation and function of cilia and dendritic spines, and suggest that insights from the study of one may inform investigations into the other of these critically important signaling structures. PMID- 24048685 TI - Predictors of malignancy in primary aldosteronism. AB - INTRODUCTION: Primary aldosteronism (PA, also Conn syndrome) is a benign disease in majority of cases. However, malignant transformation has been described. Present study reports on three cases of aldosterone producing adrenocortical carcinoma (APAC) in comparison to patients with benign PA. PATIENTS AND METHODS: Data of patients undergoing adrenalectomy for benign PA were compared to patients with APAC. Retrospective chart analysis was performed. All patients received spironolactone for 6-8 weeks preoperatively. RESULTS: Seventy-four patients underwent adrenalectomy for PA between 1994 and 2011. Three of them revealed an APAC. Patients with APAC presented with a significantly lower serum potassium level (1.7 mmol/l vs. 3.4 mmol/l, p = 0.001) and significant larger tumors (5.2 vs. 1.8 cm, p = 0.002). In addition, aldosterone/renin (A/R) ratio 675 in patients with APAC as compared to 74 in patients with benign PA (p = 0.0001). Sixty-eight of 71 patients with benign PA underwent minimal invasive surgery, whereas all three patients with APAC were operated conventionally. All patients with APAC developed disease recurrence 6-18 months postoperatively. CONCLUSION: Tumor size >4 cm and a very high A/R ratio seems to predictors of malignancy in patients with PA. If these criteria are present, open adrenalectomy should be performed instead of endoscopic procedure. PMID- 24048686 TI - The evolving spectrum of polymyositis and dermatomyositis--moving towards clinicoserological syndromes: a critical review. AB - The idiopathic inflammatory myopathies: polymyositis (PM) and dermatomyositis (DM) have been historically defined by broad clinical and pathological criteria. These conditions affect both adults and children with clinical features including muscle weakness, skin disease and internal organ involvement. Over the last few years, it has become increasingly apparent that using a clinico-serological approach, both DM and PM can be defined into more homogeneous subsets. A large number of antibodies are directed against cytoplasmic or nuclear components involved in key regulatory intra-cellular processes including protein synthesis, translocation and gene transcription within this disease spectrum. In addition, these autoantibodies are found in patients with clinical features other than myositis, in particular 'idiopathic' interstitial pneumonia emphasizing that these patients may in fact be a formes-frustes of autoimmune connective tissue disease. Other important findings are the identification of specific autoantibodies in both cancer-associated dermatomyositis, clinically amyopathic dermatomyositis and juvenile dermatomyositis, which previously were classically described as antibody-negative clinical subsets. Finally, work has highlighted how target autoantigens identified in the myositis-connective tissue disease overlap share common cellular mechanisms, which provides us with further insights into disease pathogenesis. PMID- 24048688 TI - Prediction of hypotension in the beach chair position during shoulder arthroscopy using pre-operative hemodynamic variables. AB - Since hypotension in beach chair position (BCP) can lead to catastrophic neurologic complications, the prediction of hypotension is a matter of concern in the BCP under general anesthesia. We investigated whether pre-induction values of mean arterial pressure (MAP), stroke volume variation (SVV), cardiac index (CI), and stroke volume index (SVI) can predict hypotension in BCP during general anesthesia. Forty healthy adult patients, aged 18-65 years, undergoing elective arthroscopic shoulder surgery, were enrolled. At 5 min after anesthesia induction, patients were placed in the 70 degrees upright position. Receiver operating characteristic (ROC) curves were plotted for preoperative hemodynamic variables, including MAP, SVV, CI and SVI, and their abilities to predict hypotension were investigated. Fifteen patients developed hypotension after being moved from the supine to the BCP. The areas under the ROC curves for pre induction values of MAP, CI, and SVI and post-induction value of SVV before a positional change were 0.556 (95% CI 0.373-0.739; p = 0.557), 0.735 (0.576-0.894; p = 0.014), 0.787 (0.647-0.926; p = 0.003), and 0.691 (0.525-0.857; p = 0.046), respectively. In this study, pre-induction values of CI and SVI and post induction value of SVV before a positional change predicted hypotension in the BCP under general anesthesia. Our findings suggest that not only preload but also preoperative cardiac performances might be the important factors for the development of hypotension after a repositioning supine to the sitting during general anesthesia. PMID- 24048689 TI - WITHDRAWN: Interspace/interdental brushes for oral hygiene in orthodontic patients with fixed appliances. PMID- 24048687 TI - Positive psychological characteristics in diabetes: a review. AB - Positive psychological characteristics, such as optimism, self-efficacy, and resilience, have been increasingly associated with improved outcomes in medically ill individuals. However, there has been minimal systematic review of these characteristics and their associations with outcomes in people with diabetes. We aim to review these associations, their potential mediating mechanisms, and the evidence supporting interventions targeting these qualities. In people with diabetes, positive psychological characteristics are significantly associated with improved glycemic control, fewer complications, and reduced rates of mortality. Potential mechanisms mediating these associations include behavioral factors (e.g., improved treatment adherence), reduced inflammation, and improved neuroendocrine and autonomic functioning. Most psychosocial treatments in this population have focused on improving self-efficacy and resilience; such interventions may improve quality of life, well-being, and diabetes self-care. While untested in diabetes, interventions to boost other positive characteristics have been effective in other medically ill patients and may warrant further study in this cohort. PMID- 24048690 TI - Post-approval safety issues with innovative drugs: a European cohort study. AB - BACKGROUND: At time of approval, knowledge of the full benefit risk of any drug is limited, in particular with regards to safety. Post-approval surveillance of potential drug safety concerns is recognized as an important task of regulatory agencies. For innovative, often first-in-class drugs, safety knowledge at time of approval is often even less extensive and these may require tighter scrutiny post approval. OBJECTIVE: We evaluated whether more post-approval serious safety issues were identified for drugs with a higher level of innovation. METHODS: A cohort study was performed that included all new active substances approved under the European Centralized Procedure and for which serious safety issues were identified post-approval from 1 January 1999 to 1 January 2012. Serious safety issues were defined as issues requiring a Direct Healthcare Professional Communication to alert individual healthcare professionals of a new serious safety issue, or a safety-related drug withdrawal. Data were retrieved from publicly available websites of the Dutch Medicines Evaluation Board and the European Medicines Agency. The level of innovation was scored using a validated algorithm, grading drugs as important (A), moderate (B) or modest (C) innovations or as pharmacological or technological (pharm/tech) innovations. The data were analyzed using appropriate descriptive statistics and Kaplan-Meier analysis, with a Mantel-Cox log-rank test, and Cox-regression models correcting for follow-up duration, to identify a possible trend in serious safety issues with an increasing level of innovation. RESULTS: In Europe, 279 new drugs were approved between 1999 and 2011. Fifty-nine (21 %) were graded as important, 63 (23 %) moderate, or 34 (12 %) modest innovations and 123 (44 %) as non-innovative (pharm/tech), while 15 (25 %), 13 (21 %), 8 (24 %) and 17 (14 %) had post approval safety issues, respectively (p = 0.06, linear-by-linear test). Five drugs were withdrawn from the market. The Kaplan-Meier-derived probability for having a first serious safety issue was statistically significant, log-rank (Mantel-Cox) p = 0.036. In the final adjusted Cox proportional hazard model there was no statistically significant difference in occurrence of a first serious safety issue for important, moderate and modest innovations versus non-innovative drugs; hazard ratios 1.76 (95 % CI 0.82-3.77), 1.61 (95 % CI 0.76-3.41)], and 1.25 (95 % CI 0.51-3.06), respectively. CONCLUSION: A higher level of innovation was not clearly related to an increased risk of serious safety issues identified after approval. PMID- 24048691 TI - Selective induction of P2Y14 receptor by RANKL promotes osteoclast formation. AB - The purinergic receptor P2Y, G protein coupled, 14 (P2Y14) receptor for UDP glucose and other UDP-sugars has been implicated in the regulation of the stem cell compartment as well as neuroimmune function. However, the role of P2Y14 in osteoclast formation is completely unknown. We found that RANKL selectively induced P2Y14 among seven mammalian P2Y receptors when analysed at both the mRNA and protein level, but inhibitors of the mitogenactivated protein (MAP) kinase pathway suppressed induction of P2Y14 proteins. Extracellular addition of UDP sugars such as UDP-glucose, UDP-galactose, UDP-glucuronic acid, and UDP-N-acetyl glucosamine promoted RANKL-induced osteoclastogenesis, while P2Y14 downregulation by RNA interference inhibited osteoclast formation. Taken together, these results suggest that P2Y14 may act as the receptor for UDP-sugars in osteoclast precusors and may regulate RANKL-induced osteoclastogenesis. PMID- 24048692 TI - Cherubism: panoramic and CT features in adults. AB - OBJECTIVES: To describe the panoramic radiographic and CT features of cherubism in an unselected series of 15 adults. METHODS: In this cross-sectional study, 15 individuals aged 29-84 years with familial non-syndromal molecularly confirmed cherubism were examined with panoramic radiography and CT. Bone abnormalities were analysed and described. RESULTS: 11 (73%) of the 15 adults had mandibular abnormalities. These abnormalities ranged from subtly detectable to severe, and were less prevalent and expansive but could be rather similar to the characteristic image features in children. Unilocular radiolucencies were more common than multilocular radiolucencies, and a specific feature of these abnormalities was that they were exclusively found in the anterior mandible. CONCLUSIONS: The radiographic and CT abnormalities of cherubism in adults were frequent and extremely heterogeneous, with some distinct features. PMID- 24048693 TI - Small field of view cone beam CT temporomandibular joint imaging dosimetry. AB - OBJECTIVES: Cone beam CT (CBCT) is generally accepted as the imaging modality of choice for visualisation of the osseous structures of the temporomandibular joint (TMJ). The purpose of this study was to compare the radiation dose of a protocol for CBCT TMJ imaging using a large field of view Hitachi CB MercuRayTM unit (Hitachi Medical Systems, Tokyo, Japan) with an alternative approach that utilizes two CBCT acquisitions of the right and left TMJs using the Kodak 9000((r)) 3D system (Carestream, Rochester, NY). METHODS: 25 optically stimulated luminescence dosemeters were placed in various locations of an anthropomorphic RANDO((r)) Man phantom (Alderson Research Laboratories, Stanford, CT). Dosimetric measurements were performed for each technique, and effective doses were calculated using the 2007 International Commission on Radiological Protection tissue weighting factor recommendations for all protocols. RESULTS: The radiation effective dose for the CB MercuRay technique was 223.6 +/- 1.1 MUSv compared with 9.7 +/- 0.1 MUSv (child), 13.5 +/- 0.9 MUSv (adolescent/small adult) and 20.5 +/- 1.3 MUSv (adult) for the bilateral Kodak acquisitions. CONCLUSIONS: Acquisitions of individual right and left TMJ volumes using the Kodak 9000 3D CBCT imaging system resulted in a more than ten-fold reduction in the effective dose compared with the larger single field acquisition with the Hitachi CB MercuRay. This decrease is made even more significant when lower tube potential and tube current settings are used. PMID- 24048694 TI - Personalization in the health care system: do personal health budgets have an impact on outcomes and cost? AB - OBJECTIVES: In England's National Health Service, personal health budgets are part of a growing trend to give patients more choice and control over how health care services are managed and delivered. The personal health budget programme was launched by the Department of Health in 2009, and a three-year independent evaluation was commissioned with the aim of identifying whether the initiative ensured better health- and care-related outcomes and at what cost when compared to conventional service delivery. METHODS: The evaluation used a pragmatic controlled trial design to compare the outcomes and costs of patients selected to receive a personal health budget with those continuing with conventional support arrangements (control group). Just over 1000 individuals were recruited into the personal health budget group and 1000 into the control group in order to ensure sufficient statistical power, and followed for 12 months. RESULTS: The use of personal health budgets was associated with significant improvement in patients' care-related quality of life and psychological wellbeing at 12 months. Personal health budgets did not appear to have an impact on health status, mortality rates, health-related quality of life or costs over the same period. With net benefits measured in terms of care-related quality of life on the adult social care outcome toolkit measure, personal health budgets were cost-effective: that is, budget holders experienced greater benefits than people receiving conventional services, and the budgets were worth the cost. CONCLUSION: The evaluation provides support for the planned wider roll-out of personal health budgets in the English NHS after 2014 in so far as the localities in the pilot sample are representative of the whole country. PMID- 24048695 TI - The enactment of knowledge translation: a study of the Collaborations for Leadership in Applied Health Research and Care initiative within the English National Health Service. AB - OBJECTIVES: We contribute to existing knowledge translation (KT) literature by developing the notion of 'enactment' and illustrate this through an interpretative, comparative case-study analysis of three Collaborations for Leadership in Applied Health Research and Care (CLAHRC) initiatives. We argue for a focus on the way in which the CLAHRC model has been 'enacted' as central to the different KT challenges and capabilities encountered. METHODS: A comparative, mixed method study created a typology of enactments (Classical, Home-grown and Imported) using qualitative analysis and social network analysis. RESULTS: We identify systematic differences in the enactment of the CLAHRC model. The sources of these different enactments are subsequently related to variation in formative interpretations and leadership styles, the implementation of different governance structures, and the relative epistemic differences between the professional groups involved. CONCLUSIONS: Enactment concerns the creative agency of individuals and groups in constituting a particular context for their work through their local interpretation of a particular KT model. Our theory of enactment goes beyond highlighting variation between CLAHRCs, to explore the mechanisms that influence the way a particular model is interpreted and acted upon. We thus encourage less focus on conceptual models and more on the formative role played by leaders of KT initiatives. PMID- 24048696 TI - Halobellus litoreus sp. nov., a halophilic archaeon isolated from a Chinese marine solar saltern. AB - Halophilic archaeal strain GX31(T) was isolated from a marine solar saltern of China. The cells of the strain were rod-shaped and lysed in distilled water, stain Gram-negative and formed red-pigmented colonies. It was neutrophilic, and required at least 0.9 M NaCl and 0-1.0 M MgCl2 for growth under the optimum growth temperature of 37 degrees C. The major polar lipids of the strain were phosphatidylglycerol (PG), PG phosphate methyl ester, PG sulphate, and two major glycolipids chromatographically identical to sulphated mannosyl glucosyl diether (S-DGD-1) and mannosyl glucosyl diether (DGD-1), respectively. Trace amounts of two unidentified lipids were also detected. On the basis of 16S rRNA gene sequence analysis, strain GX31(T) was closely related to the members of Halobellus of the family Halobacteriaceae with similarities of 94.1-98.7 %. Strain GX31(T) showed 89.8-95.4 % of the rpoB' gene similarity to the members of Halobellus. The DNA G+C content of strain GX31(T) was 66.8 mol%. Strain GX31(T) showed low DNA-DNA relatedness with two most related members of the genus Halobellus. The phenotypic, chemotaxonomic and phylogenetic properties suggest that strain GX31(T) represent a novel species of the genus Halobellus, for which the name Halobellus litoreus sp. nov. is proposed. The type strain is GX31(T) (=CGMCC 1.10387(T) = JCM 17118(T)). PMID- 24048697 TI - Hemolytic factor production by clinical isolates of Candida species. AB - Most cases of fungal bloodstream infections (BIs) are attributed to Candida albicans; however, non-Candida albicans Candida species have recently been identified as common pathogens. Although hemolytic factor is known to be putative virulence factor contributing to pathogenicity in Candida species, its production is poorly evaluated. The present study was undertaken to analyze the production of hemolytic factor by C. albicans (10), C. tropicalis (13), and C. parapsilosis (8) isolates associated with BIs. Data of hemolysis zones on plate assay revealed that the majority of C. albicans isolates produced mild hemolytic activity whereas the majority of C. tropicalis produced strong activity. None of the tested C. parapsilosis isolates exhibited hemolysis on plate assay. We also evaluated the hemolytic activity in the cell-free broth. There were no significant differences (P > 0.05) in the secreted hemolytic activity among intra species isolates. Different levels of secreted hemolytic factor were observed for Candida species, where C. tropicalis exhibited the highest production of hemolytic factor (P < 0.05) followed by C. albicans and C. parapsilosis. Inhibition of hemolysis (up to 89.12 %) from culture supernatant, following incubation with the lectin Concanavalin A (Con A), was observed for all three Candida species. This finding suggests that the secreted hemolytic factor of C. tropicalis and C. parapsilosis may be a mannoprotein, similar to that described for C. albicans. PMID- 24048698 TI - [Moral appeals to donate organs undermine trust]. PMID- 24048699 TI - [Family approach--retrospective analysis of 6,617 donation requests]. AB - BACKGROUND: According to surveys the majority of the German population has a positive attitude towards organ donation. However, declarations of will concerning this matter are often missing in case of death. Thus, in nearly all cases consent must be obtained from the family of the deceased. Compared with refusal rates of other countries the refusal rate in Germany (approximately 40%) is rather high. The modification of the German Transplantation Legislation in November 2012 supports the voluntary documentation of everyone's decision with regard to organ donation. METHODS: Based on 6,617 documented donation requests collected between 2009 and 2011, factors were identified, which--besides personal attitude of morality--could influence the decision about donation. RESULTS: The decedent's will is often unknown (67.4%) and the family's decision is based on the suspected will of the patient. This resulted in 4097 (61.9%) consents and 2520 (38.1%) refusals. 4669 (70.6%) of these donation-requests were carried out by the physician in charge and 1948 (29.4%) with the assistance of a coordinator from the German foundation for organ transplantation (DSO). Predictive (p<0.001) for consent were the presence of a specially trained coordinator and the timing of the request for organ donation. CONCLUSION: There is a big discrepancy between the attitude displayed in surveys and the actual consent rate to organ donation. The major challenge is an improved caregiving for the donor family. Donation requests should be made preferably by trained physicians as well as coordinators. Waiting for the finalized certification of brain death may not be appropriate in all cases. PMID- 24048700 TI - Predicting behavior of solitary fibrous tumor: are we getting closer to more accurate risk assessment? PMID- 24048701 TI - Youth who sexual offended: primary human goods and offense pathways. AB - There has been an increased focus on understanding youth sexual offending in recent years, but there has been limited empirical research on the causes, pathways, and treatment of youth who have sexually offended-especially within a non-Western context. The Good Lives and Self-Regulation Models have often been used to understand and rehabilitate adult sexual offenders, but (unfortunately) there is scant research on youth who sexually offended using these models. The present study aims to describe the different primary goods that are associated with youth sexual offending behaviors in an Asian context. In addition, the study sought to explore whether the age of victim (child vs. nonchild) and nature of sexual offense (penetrative vs. nonpenetrative) influenced the youth's engagement in offense pathways. The results suggest that pleasure, relatedness, and inner peace were the primary human goods that were most sought after by a sample of 168 youth who sexually offended in Singapore. In addition, offender classification (in relation to the age of victim and nature of sexual offense) influenced the pathways to sexual offending. Therefore, these findings have important clinical implications for assessment, management, and intervention planning for youth who sexually offended. PMID- 24048702 TI - Multivariate pattern analysis of DTI reveals differential white matter in individuals with obsessive-compulsive disorder. AB - Diffusion tensor imaging (DTI) studies have revealed group differences in white matter between patients with obsessive-compulsive disorder (OCD) and healthy controls. However, the results of these studies were based on average differences between the two groups, and therefore had limited clinical applicability. The objective of this study was to investigate whether fractional anisotropy (FA) of white matter can be used to discriminate between patients with OCD and healthy controls at the level of the individual. DTI data were acquired from 28 OCD patients and 28 demographically matched healthy controls, scanned using a 3T MRI system. Differences in FA values of white matter between OCD and healthy controls were examined using a multivariate pattern classification technique known as support vector machine (SVM). SVM applied to FA images correctly identified OCD patients with a sensitivity of 86% and a specificity of 82% resulting in a statistically significant accuracy of 84% (P <= 0.001). This discrimination was based on a distributed network including bilateral prefrontal and temporal regions, inferior fronto-occipital fasciculus, superior fronto-parietal fasciculus, splenium of corpus callosum and left middle cingulum bundle. The present study demonstrates subtle and spatially distributed white matter abnormalities in individuals with OCD, and provides preliminary support for the suggestion that that these could be used to aid the identification of individuals with OCD in clinical practice. PMID- 24048703 TI - PHD4 stimulates tumor angiogenesis in osteosarcoma cells via TGF-alpha. AB - Solid tumor growth is intimately associated with angiogenesis, a process that is efficiently triggered by hypoxia. Therefore, oxygen-sensitive signaling pathways are thought to play a critical role in tumor angiogenesis and progression. Here, the function of prolyl hydroxylase-4 (PHD4), a relative of the prolyl hydroxylase domain proteins 1-3 that promote the degradation of hypoxia-inducible factors (HIF), was interrogated. To test the hypothesis that PHD4 might inhibit tumor angiogenesis, it was overexpressed in osteosarcoma cells, and unexpectedly, this manipulation led to increased tumor blood vessel density. However, the newly formed blood vessels were smaller than normal and appeared to be partially nonfunctional, as indicated by poor vessel perfusion. PHD4 overexpression in tumor cells stimulated the expression of TGF-alpha, which was necessary and sufficient to promote angiogenic sprouting of endothelial cells. On the other hand, PHD4 overexpression reduced HIF-2alpha protein levels, which in turn inhibited in vivo tumor growth. Combined, elevated PHD4 levels deregulate angiogenesis via increased TGF-alpha expression in vitro and in vivo. These data support the hypothesis that tumor growth can be uncoupled from vessel density and that the individual PHD family members exert distinct functions in tumors. IMPLICATIONS: PHD4 influences tumor growth and vascularization through discrete mechanisms and molecular pathways that likely have therapeutic potential. PMID- 24048705 TI - Conscious awareness in patients in vegetative states: myth or reality? AB - Do vegetative state (VS) and minimally conscious state (MCS) patients experience emotions and have conscious awareness of themselves and their surroundings? Can neuroimaging clarify these questions? Neuroimaging responses to stimuli are classified into four levels: level 0 indicates no response; level 1 indicates responses limited to the primary sensory cortices; level 2 indicates activation of primary sensory cortices and higher-order associative areas; level 3 indicates activation of cortical regions to either mental imagery tasks or high-level language stimuli requiring distinction of ambiguous from unambiguous words. Level 0 or level 1 was noted in 125 of 193 VS patients (65 %) and 46 of 121 MCS patients (38 %), suggesting no evidence of conscious awareness. Level 2 or level 3 was observed in 68 of 193 VS patients (35 %) and 75 of 121 MCS patients (62 %), indicating some cognitive processing. These data may denote the presence of conscious awareness or may simply identify neuronal processing without phenomenological awareness. The pro and cons of these conflicting interpretations are discussed. PMID- 24048706 TI - Effects of intravenous iloprost therapy in patients with bone marrow oedema of the foot and ankle. AB - OBJECTIVE: Bone marrow oedema (BMO) is a multifactorial condition. The conservative treatment options include immobilisation of the affected region and systemic intravenous iloprost therapy. Whereas many studies confirm the positive effect of iloprost therapy in larger joints, e.g. knee and hip, there have been few studies of BMO in smaller areas such as the ankle joint or midfoot. The purpose of this study is to show that treatment with iloprost leads to positive long-term outcomes for BMO of the foot and ankle. METHODS: Twenty-three patients with BMO of the ankle joint or midfoot, Association Research Circulation Osseous (ARCO) stages 1-2, were included in this study. A questionnaire was used to record the Ankle-hindfoot, Kaikkonen, SF-36 and VAS scores before and after iloprost therapy. In addition, all patients underwent MRI for radiological follow up monitoring 3 months after treatment. RESULTS: A significant improvement in function based on the ankle-hindfoot and Kaikkonen scale was demonstrated after iloprost therapy. In 22 patients, follow-up MRI after 3 months showed complete regression of the oedema. CONCLUSION: Based on the positive results of our study, we recommend treatment with iloprost for BMO of the upper ankle joint and foot at ARCO stages 1-2. PMID- 24048704 TI - EGFR inhibition induces proinflammatory cytokines via NOX4 in HNSCC. AB - Chronic inflammation plays a fundamental role in tumor promotion, migration, and invasion. With the use of microarray profiling, a profound increase was observed for those transcripts involved in proinflammatory signaling in epidermal growth factor receptor (EGFR) inhibitor-treated head and neck squamous cell carcinoma (HNSCC) cells as compared with their respective controls. As such, it was hypothesized that EGFR inhibitor efficacy is offset by the proinflammatory response that these therapeutics conjure in HNSCC. Systematic evaluation of the clinical EGFR inhibitors-erlotinib, cetuximab, lapatinib, and panitumumab revealed increased secretion of proinflammatory cytokines such as interleukins (IL-2, IL-4, IL-6, IL-8), granulocyte-macrophage colony-stimulating factor, TNF alpha, and IFN-gamma. Mechanistic focus on IL-6 revealed that erlotinib induced a time-dependent increase in IL-6 mRNA and protein expression. Importantly, exogenous IL-6 protected HNSCC cells from erlotinib-induced cytotoxicity, whereas tocilizumab, an IL-6 receptor antagonist, sensitized cells to erlotinib in vitro and in vivo. Inhibitors of NF-kappaB, p38, and JNK suppressed erlotinib-induced IL-6 expression, suggesting critical roles for NF-kappaB and MAPK in IL-6 regulation. Furthermore, knockdown of NADPH oxidase 4 (NOX4) suppressed erlotinib induced proinflammatory cytokine expression. Taken together, these results demonstrate that clinical EGFR inhibitors induce the expression of proinflammatory cytokines via NOX4. IMPLICATIONS: The antitumor activity of EGFR inhibitors is reduced by activation of NOX4-mediated proinflammatory pathways in HNSCC. PMID- 24048707 TI - Description and molecular characterization of Plasmodium (Novyella) unalis sp. nov. from the Great Thrush (Turdus fuscater) in highland of Colombia. AB - Plasmodium (Novyella) unalis sp. nov. was found in the Great Thrush, Turdus fuscater (Passeriformes, Turdidae) in Bogota, Colombia, at 2,560 m above sea level where the active transmission occurs. This parasite is described based on the morphology of its blood stages and a fragment of the mitochondrial cytochrome b gene (lineage UN227). Illustrations of blood stages of new species are given, and the phylogenetic analysis identifies closely related species and lineages of avian malaria parasites. The new species is most similar to Plasmodium (Novyella) vaughani (lineage SYAT05), a cosmopolitan avian malaria parasite; these parasites are also closely related genetically, with a genetic difference of 3.2% between them. P. unalis can be readily distinguished from the latter species morphologically, primarily due to the (1) presence of a single large, circular shaped pigment granule in the erythrocytic trophozoites and meronts; (2) presence of prominent vacuoles in trophozoites and growing meronts; and (3) presence of predominantly fan-like shaped erythrocytic meronts. Cytochrome b lineages with high similarity to the new species have been reported in Costa Rica, Brazil, Chile, and USA. It is probable that the new species of malaria parasite is widely distributed in the New World. This parasite has been reported only in the Great Thrush at the study site and might have a narrow range of avian hosts. Records of P. unalis are of particular theoretical interest due to its active transmission at highlands in Andes. Possible influence of urbanization on transmission of this malaria parasite in Bogota is discussed. PMID- 24048708 TI - Genetic counseling/consultation in South-East Asia: a report from the workshop at the 10th Asia pacific conference on human genetics. AB - This paper reports on the workshop 'Genetic Counseling/Consultations in South East Asia' at the 10(th) Asia Pacific Conference on Human Genetics in Kuala Lumpur, Malaysia, in December 2012. The workshop brought together professionals and language/communication scholars from South-East Asia, and the UK. The workshop aimed at addressing culture- and context-specific genetic counseling/consultation practices in South-East Asia. As a way of contextualizing genetic counseling/consultation in South-East Asia, we first offer an overview of communication-oriented research generally, drawing attention to consultation and counseling as part of a communicative continuum with distinctive interactional features. We then provide examples of genetic counseling/consultation research in Hong Kong. As other countries in South-East Asia have not yet embarked on communication-oriented empirical research, we report on the current practices of genetic counseling/consultation in these countries in order to identify similarities and differences as well as key obstacles that could be addressed through future research. Three issues emerged as 'problematic': language, religion and culture. We suggest that communication-oriented research can provide a starting point for evidence-based reflections on how to incorporate a counseling mentality in genetic consultation. To conclude, we discuss the need for creating a platform for targeted training of genetic counselors based on communication-oriented research findings. PMID- 24048710 TI - Telomerase and its extracurricular activities. AB - The classical activity of telomerase is to synthesize telomeric repeats and thus maintain telomere length, which in turn ensures chromosome stability and cellular proliferation. However, there is growing evidence that implicates telomerase in many other functions that are independent of TERC being used as its template. Telomerase has an RNA-dependent RNA polymerase (RdRP) activity in the mitochondria. Other than viral RdRPs, it is the only RNA-dependent RNA polymerase that has been identified in mammals. It also plays a role in the Wnt signaling pathway by acting as a transcriptional modulator. Telomerase acts as a reverse transcriptase independent of its core subunit, TERC. Studies indicate that telomerase is also involved in apoptosis and DNA repair. PMID- 24048712 TI - Impact of fluid-structure interaction on direct tumor-targeting in a representative hepatic artery system. AB - Direct targeting of solid tumors with chemotherapeutic drugs and/or radioactive microspheres can be a treatment option which minimizes side-effects and reduces cost. Briefly, computational analysis generates particle release maps (PRMs) which visually link upstream particle injection regions in the main artery with associated exit branches, some connected to tumors. The overall goal is to compute patient-specific PRMs realistically, accurately, and cost-effectively, which determines the suitable radial placement of a micro-catheter for optimal particle injection. Focusing in this paper on new steps towards realism and accuracy, the impact of fluid-structure interaction on direct drug-targeting is evaluated, using a representative hepatic artery system with liver tumor as a test bed. Specifically, the effect of arterial wall motion was demonstrated by modeling a two-way fluid-structure interaction analysis with Lagrangian particle tracking in the bifurcating arterial system. Clearly, rapid computational evaluation of optimal catheter location for tumor-targeting in a clinical application is very important. Hence, rigid-wall cases were also compared to the flexible scenario to establish whether PRMs generated when based on simplifying assumptions could provide adequate guidance towards ideal catheter placement. It was found that the best rigid (i.e., time-averaged) geometry is the physiological one that occurs during the diastolic targeting interval. PMID- 24048711 TI - Automated classification and identification of slow wave propagation patterns in gastric dysrhythmia. AB - The advent of high-resolution (HR) electrical mapping of slow wave activity has significantly improved the understanding of gastric slow wave activity in normal and dysrhythmic states. One of the current limitations of this technique is it generates a vast amount of data, making manual analysis a tedious task for research and clinical development. In this study we present new automated methods to classify, identify, and locate patterns of interest in gastric slow wave propagation. The classification method uses a similarity metric to classify slow wave propagations, while the identification algorithm uses the divergence and mean curvature of the slow wave propagation to identify and regionalize patterns of interest. The methods were applied to synthetic and experimental datasets and were also compared to manual analysis. The methods classified and identified patterns of slow wave propagation in less than 1 s, compared to manual analysis which took up to 40 min. The automated methods achieved 96% accuracy in classifying AT maps, and 95% accuracy in identifying the propagation pattern with a mean spatial error of 1.5 mm in comparison to manual methods. These new methods will facilitate the efficient translation of gastrointestinal HR mapping techniques to clinical practice. PMID- 24048713 TI - Physical activity is associated with reduced risk of gastric cancer: a systematic review and meta-analysis. AB - Physical activity may be associated with reduced risk of gastric cancer. We performed a systematic review and meta-analysis to evaluate the magnitude of the association and the quality of supporting evidence. After a comprehensive search of bibliographic databases and conference proceedings through February 2013 for observational studies that examined associations between recreational and/or occupational physical activity and gastric cancer risk, we identified 16 studies (seven cohort, nine case control) reporting 11,111 cases of gastric cancer among 1,606,760 patients. Summary adjusted-OR estimates with 95% confidence intervals (CI) were estimated using the random-effects model. Meta-analysis demonstrated that the risk of gastric cancer was 21% lower among the most physically active people as compared with the least physically active people (OR = 0.79; 95% CI, 0.71-0.87) with moderate heterogeneity among studies (I(2) = 55%). This protective effect was seen for gastric cancers in the cardia (four studies; OR = 0.80; 95% CI, 0.63-1.00) and distal stomach (five studies; OR = 0.63; 95% CI, 0.52-0.76). The effect size was significantly smaller in high-quality studies (six studies; OR = 0.86; 95% CI, 0.75-0.99), as compared with low-quality studies (10 studies; OR = 0.74; 95% CI, 0.69-0.81). The results were consistent across sex, study quality, study design, and geographic location. In conclusion, meta analysis of published observational studies indicates that physical activity is associated with reduced risk of gastric cancer. Lifestyle interventions focusing on increasing physical activity may decrease the global burden of gastric cancer, in addition to a myriad of other health benefits. PMID- 24048714 TI - microRNA portraits in human vulvar carcinoma. AB - Unregulated expression of microRNAs is well known and has already been demonstrated in many tumor types. However, in vulvar carcinoma this field has been unknown territory. Our study characterizes microRNA in vulvar tumors through an expression profile of 754 miRNAs, relating this with clinical and anatomopathologic data, and presence of HPV infection. Twenty HPV-negative and 20 HPV-positive samples, genotyped for high-risk HPVs (HPV16, 18, 31, 33) and a pool of seven normal vulvar skin samples were used for the identification of differentially expressed miRNAs by TLDA Quantitative Real Time PCR (qRT-PCR). Twenty-five differentially expressed microRNAs between HPV-positive and HPV negative groups and 79 differentially expressed on the tumor compared with normal samples were obtained. A network between microRNA expression profiles and putative target mRNAs predicted by target prediction algorithms and previously demonstrated as relevant in vulvar carcinomas, such as TP53, RB, PTEN, and EGFR was constructed. Downregulation of both miR-223-5p and miR-19-b1-5p were correlated with the presence of lymph node metastasis; downregulation of miR-100 3p and miR-19-b1-5p were correlated with presence of vascular invasion; overexpression of miR-519b and miR-133a were associated with advanced FIGO staging. In conclusion, our study demonstrates that microRNAs may be clinically important in vulvar carcinomas and our findings may help for further studies on functional implications of miRNA deregulation in this type of cancer. PMID- 24048716 TI - Detection of cytochrome P450 2C19 gene polymorphism from noninvasive samples by cycling probe technology. AB - BACKGROUND: The proportion of poor metabolizers (PMs) of cytochrome P450 (CYP) 2C19 is much higher in the Japanese population than in European populations. Cycling probe technology (CPT) is a simple signal amplification technique for targeting specific DNA sequences. CPT utilizes a chimeric DNA-RNA-DNA probe that is cleaved by the enzyme ribonuclease (RNase H). In this study, using CPT, we aimed to detect the CYP2C19 gene polymorphism from noninvasive samples to determine extensive metabolizers (EMs) and PMs of CYP2C19. METHODS: DNA samples were extracted from hair, buccal mucosa, and blood cells. Primers and cycling probes were designed specifically for region G636A for exon 4 and G681A for exon 5, reported to be gene polymorphisms of CYP2C19. RESULTS: DNA extracted from hair follicle cells and buccal epithelial cells was the same as that collected from invasive blood sampling. The genotype of CYP2C19 was successfully identified as either EM or PM in 71 samples, producing identical results to those for the TaqMan method, except in three samples. CONCLUSIONS: We successfully detected the two gene polymorphisms of CYP2C19 from noninvasive samples using a simple DNA extraction method and CPT. PMID- 24048718 TI - Peri-operative troponin monitoring using a prototype high-sensitivity cardiac troponin I (hs-cTnI) assay: comparisons with hs-cTnT and contemporary cTnI assays. AB - BACKGROUND: Non-cardiac surgery is associated with major vascular complications and higher incidences of elevated plasma troponin (cTn) concentration. Goal directed therapy (GDT) is a stroke volume (SV)-guided approach to intravenous (IV) fluid therapy that improves tissue perfusion, oxygenation and reduces post operative complications. In patients undergoing major gastro-intestinal surgery, we compared high sensitive and contemporary troponin assays and correlated results with patient outcome. METHODS: Patients (n = 135) were randomized to receive IV fluid, guided by either the central venous pressure (CVP group, n = 45) or SV (+/- dopexamine inotrope, n = 45 per group). Serum was obtained pre- and post-operatively (0, 8 and 24 h) for troponin analysis by a prototype hs-cTnI assay (Abbott Laboratories), hs-cTnT (Roche Diagnostics) and contemporary cTnI (Beckman Coulter) assays. RESULTS: All troponin measurements were increased (P <= 0.05) post-operatively but there was no difference (P > 0.05) amongst treatments. Post-operative increases were reported more frequently (P <= 0.05) and earlier with hs-cTnI. Temporal increases (P <= 0.05) were reported in patients with and without complications for hs-cTnI/T assays but only in the complications group for cTnI measurements. Elevations >=99th centile occurred most often (P <= 0.05) for hs-cTnT measurements but with similar frequency for both outcome groups (all assays). Only the hs-cTnI assay showed an increased relative risk of mortality (P <= 0.05) for elevations >=99th centile CONCLUSIONS: Our study may suggest a possible preference for the hs-cTnI assay in the peri-operative setting; however, our findings should be verified for larger cohort studies where emerging reference range data is incorporated for improving risk prediction with hs-cTn assays. PMID- 24048719 TI - Pseudohyperkalaemia is troublesome but 'fictitious normokalaemia' is sinister, insidious and inconspicuous. PMID- 24048715 TI - Adipose tissue inflammation in glucose metabolism. AB - Obesity is now recognised as a low grade, chronic inflammatory disease that is linked to a myriad of disorders including cancer, cardiovascular disease and type 2 diabetes (T2D). With respect to T2D, work in the last decade has revealed that cells of the immune system are recruited to white adipose tissue beds (WAT), where they can secrete cytokines to modulate metabolism within WAT. As many of these cytokines are known to impair insulin action, blocking the recruitment of immune cells has been purported to have therapeutic utility for the treatment of obesity-induced T2D. As inflammation is critical for host defence, and energy consuming in nature, the blockade of inflammatory processes may, however, result in unwanted complications. In this review, we outline the immunological changes that occur within the WAT with respect to systemic glucose homeostasis. In particular, we focus on the role of major immune cell types in regulating nutrient homeostasis and potential initiating stimuli for WAT inflammation. PMID- 24048720 TI - Hyperamylasaemia and dual paraneoplastic syndromes in small cell lung cancer. AB - We hereby describe the rare case of a 59-year-old patient presenting with marked hyperamylasaemia mimicking acute pancreatitis upon admission. Investigation of co existent hypokalemia revealed the presence of ectopic adrenocorticotropic hormone secretion, leading to the final diagnosis of small cell lung cancer, exhibiting dual paraneoplastic syndromes including Cushing Syndrome and hyperamylasaemia. Although, paraneoplastic syndromes occur commonly, paraneoplastic hyperamylasaemia especially in the context of dual paraneoplastic syndromes occurring simultaneously, is extremely rare. Such misleading manifestations require a high index of suspicion on behalf of the physician, so that an underlying malignancy is not missed, and a final diagnosis combining all clinical and laboratory findings is reached. In turn, in rare cases common biochemical markers such as amylase can be used as a useful follow up index driving further management. PMID- 24048721 TI - miR-202 expression concentration and its clinical significance in the serum of multiple myeloma patients. AB - OBJECTIVES: To explore microRNA-202 (miR-202) expression in serum of patients with multiple myeloma (MM), and investigate correlations between serum miR-202 expression and the development and prognosis of MM. DESIGN AND METHODS: RNA was extracted from serum by QIAGEN miRNeasy Mini kit. Reverse transcription was performed with specific stem-loop primers. SYBR Green I QF-PCR was applied to detect the relative expression of miR-202 in 40 MM patients and 30 healthy controls. The linearity, specificity and reproducibility were evaluated. In addition, correlations between the relative expression of serum miR-202 and the concentrations of lactic acid dehydrogenase (LDH), beta2M, lambda light chain and kappa light chain were assessed. RESULTS: The relative expression of miR-202 in MM patients 1.503 (0.161-9.831) was significantly higher than that in healthy controls 1.000 (0.105-3.046) (P < 0.01) and was significantly correlated with serum beta2M and kappa light chain concentrations (r = 0.366, P = 0.0305; r = 0.358, P = 0.0348). CONCLUSIONS: The relative expression of serum miR-202 in MM patients was significantly higher than that in healthy controls, and therefore it may prove to be useful in the auxiliary diagnosis of MM. PMID- 24048722 TI - Atypical femoral fractures: a review of the literature. AB - Bisphosphonates are the most commonly used drugs worldwide for treating osteoporosis. Atypical femoral fractures most commonly are associated with prolonged bisphosphonate use. They also may occur with denosumab use or in patients without a history of using these drugs. In this article, we provide a comprehensive review of the mechanism of action of bisphosphonate and the definition, incidence, epidemiology, pathogenesis, diagnosis, management, and prevention of atypical femoral fractures. PMID- 24048723 TI - Retinal dysfunction and high myopia in association with 48,XXYY syndrome. AB - PURPOSE: 48,XXYY syndrome was first described in 1964 and approximately 100 cases have been reported in the literature. We report a case of 48,XXYY syndrome associated with high myopia and retinal dysfunction. METHODS: Case report. RESULTS: A 28-year-old man was referred with progressive deterioration of visual acuity (VA) bilaterally during the previous 4-5 years. Physical examination revealed tall stature, large feet and irregular teeth. Refraction revealed high myopia with VA 6/60 bilaterally. Fundoscopy revealed a normal vitreous, lightly pigmented retinal pigment epithelium and choroid but no bone spicules or overt signs of retinal degeneration. His visual fields were constricted. Electrodiagnostic testing revealed bilateral generalised retinal dysfunction with severe macular involvement. During follow-up, his ophthalmic examination did not exhibit significant changes while VA was gradually deteriorating. Eight years after presentation, VA was 3/60 bilaterally; electrophysiological testing showed no further change. At that stage, his parents consented for DNA analysis in order to determine the cause of retinal dysfunction. Chromosomal analysis revealed an abnormal male karyotype with two X chromosomes and two Y chromosomes consistent with 48,XXYY syndrome. CONCLUSIONS: The present report is the first to describe retinal dysfunction and high myopia with 48,XXYY syndrome. The severe macular and generalised retinal dysfunction in this case are not those associated with myopia and are in keeping with a primary retinal dysfunction. A coincidental finding cannot be excluded, but ERGs have not previously been reported in 48,XXYY syndrome, and retinal dystrophy may be a previously undiagnosed component of this syndrome. PMID- 24048724 TI - Contrast-enhanced spectral mammography versus MRI: Initial results in the detection of breast cancer and assessment of tumour size. AB - OBJECTIVES: To compare mammography (MG), contrast-enhanced spectral mammography (CESM), and magnetic resonance imaging (MRI) in the detection and size estimation of histologically proven breast cancers using postoperative histology as the gold standard. METHODS: After ethical approval, 80 women with newly diagnosed breast cancer underwent MG, CESM, and MRI examinations. CESM was reviewed by an independent experienced radiologist, and the maximum dimension of suspicious lesions was measured. For MG and MRI, routine clinical reports of breast specialists, with judgment based on the BI-RADS lexicon, were used. Results of each imaging technique were correlated to define the index cancer. Fifty-nine cases could be compared to postoperative histology for size estimation. RESULTS: Breast cancer was visible in 66/80 MG, 80/80 CESM, and 77/79 MRI examinations. Average lesion largest dimension was 27.31 mm (SD 22.18) in MG, 31.62 mm (SD 24.41) in CESM, and 27.72 mm (SD 21.51) in MRI versus 32.51 mm (SD 29.03) in postoperative histology. No significant difference was found between lesion size measurement on MRI and CESM compared with histopathology. CONCLUSION: Our initial results show a better sensitivity of CESM and MRI in breast cancer detection than MG and a good correlation with postoperative histology in size assessment. KEY POINTS: * Contrast-enhanced spectral mammography (CESM) is slowly being introduced into clinical practice. * Access to breast MRI is limited by availability and lack of reimbursement. * Initial results show a better sensitivity of CESM and MRI than conventional mammography. * CESM showed a good correlation with postoperative histology in size assessment. * Contrast-enhanced spectral mammography offers promise, seemingly providing information comparable to MRI. PMID- 24048725 TI - Crystal analyser-based X-ray phase contrast imaging in the dark field: implementation and evaluation using excised tissue specimens. AB - OBJECTIVES: We demonstrate the soft tissue discrimination capability of X-ray dark-field imaging (XDFI) using a variety of human tissue specimens. METHODS: The experimental setup for XDFI comprises an X-ray source, an asymmetrically cut Bragg-type monochromator-collimator (MC), a Laue-case angle analyser (LAA) and a CCD camera. The specimen is placed between the MC and the LAA. For the light source, we used the beamline BL14C on a 2.5-GeV storage ring in the KEK Photon Factory, Tsukuba, Japan. RESULTS: In the eye specimen, phase contrast images from XDFI were able to discriminate soft-tissue structures, such as the iris, separated by aqueous humour on both sides, which have nearly equal absorption. Superiority of XDFI in imaging soft tissue was further demonstrated with a diseased iliac artery containing atherosclerotic plaque and breast samples with benign and malignant tumours. XDFI on breast tumours discriminated between the normal and diseased terminal duct lobular unit and between invasive and in-situ cancer. CONCLUSIONS: X-ray phase, as detected by XDFI, has superior contrast over absorption for soft tissue processes such as atherosclerotic plaque and breast cancer. KEY POINTS: * X-ray dark field imaging (XDFI) can dramatically increase sensitivity of phase detection. * XDFI can provide enhanced soft tissue discrimination. * With XDFI, abnormal anatomy can be visualised with high spatial/contrast resolution. PMID- 24048726 TI - The correlation between Clostridium-difficile infection and human gut concentrations of Bacteroidetes phylum and clostridial species. AB - We aimed to assess differences in bacterial intensities of Bacteroidetes phylum and different clostridial species in the human intestines with respect to C. difficile infection. Patients with a stool assay for C. difficile toxin were identified via the microbiology laboratory in our institute. Bacterial populations were quantified from stool samples of four groups of patients: Group I-patients with C. difficile associated diarrhea (CDAD); Group II-asymptomatic C. difficile carriers; Group III-patients with non-C. difficile diarrhea; Group IV patients with no diarrhea and negative stool samples for the C. difficile toxin (control group). Stool was examined for three genes-C. difficile toxin A gene, 16S rRNA gene from Clostridium thermocellum representing other clostridial species, and 16S rRNA gene from Bacteroides fragilis representing the Bacteroidetes phylum. Fifty-nine patients underwent analysis of the stool (CDAD group 14, carriers group 14, non-C. difficile diarrhea group 16, control group 15). C. difficile concentration was highest in the CDAD group, followed by the carriers group. Higher concentrations of both clostridial species and Bacteriodetes were observed in the control and non-C. difficile diarrhea groups compared to the CDAD and carriers groups. We demonstrated an inverse association between infection with C. difficile and the abundance of Bacteroidetes phylum and other clostridial species in human intestines. Studies with larger samples and broader diagnostic procedures are needed in order to better explore and understand this association. PMID- 24048727 TI - Chromoblastomycosis as an endemic disease in temperate Europe: first confirmed case and review of the literature. AB - This study reports a case of a 56-year-old white male, retired coal-miner, diagnosed with chromoblastomycosis lasting 20 years. The infection site was the burnt skin of the back. For many years the patient had not undertaken any treatment believing that the lesion had been a burn scar. A gradual increase in lesion size prompted the patient to start therapy. The diagnosis was made by histopathological examination and mycological culture. Identification of the causative agent at the species level was achieved by sequence analysis of the internal transcribed spacer (ITS) region and D1/D2 domains of the 26S rDNA. To our knowledge, this is the first documented case of chromoblastomycosis caused by Fonsecaea monophora in temperate Europe, outside the endemic area for the disease. This finding is highly significant for understanding the routes of infection of chromoblastomycosis and radically revises the traditional view of the natural ecology of the etiological agents of the disease. PMID- 24048728 TI - Readmission and death after an acute heart failure event: predictors and outcomes in sub-Saharan Africa: results from the THESUS-HF registry. AB - AIMS: Contrary to elderly patients with ischaemic-related acute heart failure (AHF) typically enrolled in North American and European registries, patients enrolled in the sub-Saharan Africa Survey of Heart Failure (THESUS-HF) were middle-aged with AHF due primarily to non-ischaemic causes. We sought to describe factors prognostic of re-admission and death in this developing population. METHODS AND RESULTS: Prognostic models were developed from data collected on 1006 patients enrolled in THESUS-HF, a prospective registry of AHF patients in 12 hospitals in nine sub-Saharan African countries, mostly in Nigeria, Uganda, and South Africa. The main predictors of 60-day re-admission or death in a model excluding the geographic region were a history of malignancy and severe lung disease, admission systolic blood pressure, heart rate and signs of congestion (rales), kidney function (BUN), and echocardiographic ejection fraction. In a model including region, the Southern region had a higher risk. Age and admission sodium levels were not prognostic. Predictors of 180-day mortality included malignancy, severe lung disease, smoking history, systolic blood pressure, heart rate, and symptoms and signs of congestion (orthopnoea, peripheral oedema and rales) at admission, kidney dysfunction (BUN), anaemia, and HIV positivity. Discrimination was low for all models, similar to models for European and North American patients, suggesting that the main factors contributing to adverse outcomes are still unknown. CONCLUSION: Despite the differences in age and disease characteristics, the main predictors for 6 months mortality and combined 60 days re-admission and death are largely similar in sub-Saharan Africa as in the rest of the world, with some exceptions such as the association of the HIV status with mortality. PMID- 24048729 TI - Low quality of life and depressive symptoms are connected with an unhealthy lifestyle. AB - BACKGROUND: The Lapinlahti 2005 study was carried out to explore cardiovascular disease risk factors, lifestyle and quality of life in Lapinlahti residents in eastern Finland. Our aim was to study the association between lifestyle and health-related quality of life (HRQoL) in the community. SUBJECTS AND METHODS: The present study is based on the baseline data of the followed up (2005-2010) population-based cohort (N = 376, n of males = 184). A trained research nurse measured weight, height, waist circumference and blood pressure. Self-reported HRQoL was measured using a 15D questionnaire. A BDI-21 inventory was used to assess the presence of self-reported depressive symptoms. Lifestyle factors (nutrition, exercise, smoking and alcohol use) were examined with a structured questionnaire. Each lifestyle item was valued as -1, 0 or 1, depending on how well it corresponded to the recommendations. Based on the index the participants were divided into three lifestyle sum tertiles: I = unhealthy, II = neutral and III = healthy. The age- and sex-adjusted linear trend between the tertiles was tested. RESULTS: The 15D score had a positive linear relationship with the lifestyle tertiles (P = .0048 for linearity, age- and sex-adjusted). Respectively, self-reported depressive symptoms were less frequent among subjects with a healthier lifestyle (P = .038). CONCLUSIONS: People who are expected to strive most to change their lifestyle have the lowest quality of life and psychological welfare, which should be taken into account in both clinical work and health promotion. PMID- 24048731 TI - Anaerobic respiration sustains mitochondrial membrane potential in a prolyl hydroxylase pathway-activated cancer cell line in a hypoxic microenvironment. AB - To elucidate how tumor cells produce energy in oxygen-depleted microenvironments, we studied the possibility of mitochondrial electron transport without oxygen. We produced well-controlled oxygen gradients (DeltaO2) in monolayer-cultured cells. We then visualized oxygen levels and mitochondrial membrane potential (DeltaPhim) in individual cells by using the red shift of green fluorescent protein (GFP) fluorescence and a cationic fluorescent dye, respectively. In this two dimensional tissue model, DeltaPhim was abolished in cells >500 MUm from the oxygen source [the anoxic front (AF)], indicating limitations in diffusional oxygen delivery. This result perfectly matched GFP-determined DeltaO2. In cells pretreated with dimethyloxaloylglycine (DMOG), a prolyl hydroxylase domain containing protein (PHD) inhibitor, the AF was expanded to 1,500-2,000 MUm from the source. In these cells, tissue DeltaO2 was substantially decreased, indicating that PHD pathway activation suppressed mitochondrial respiration. The expansion of the AF and the reduction of DeltaO2 were much more prominent in a cancer cell line (Hep3B) than in the equivalent fibroblast-like cell line (COS 7). Hence, the results indicate that PHD pathway-activated cells can sustain DeltaPhim, despite significantly decreased electron flux to complex IV. Complex II inhibition abolished the effect of DMOG in expanding the AF, although tissue DeltaO2 remained shallow. Separate experiments demonstrated that complex II plays a substantial role in sustaining DeltaPhim in DMOG-pretreated Hep3B cells with complex III inhibition. From these results, we conclude that PHD pathway activation can sustain DeltaPhim in an otherwise anoxic microenvironment by decreasing tissue DeltaO2 while activating oxygen-independent electron transport in mitochondria. PMID- 24048730 TI - Pharmacological characterization of the P2 receptors profile in the podocytes of the freshly isolated rat glomeruli. AB - Calcium flux in the podocytes is critical for normal and pathophysiological regulation of these types of cells, and excessive calcium signaling results in podocytes damage and improper glomeruli function. Purinergic activation of P2 receptors is a powerful and rapid signaling process; however, the exact physiological identity of P2 receptors subtypes in podocytes remains essentially unknown. The goal of this study was to determine the P2 receptor profile in podocytes of the intact Sprague-Dawley rat glomeruli using available pharmacological tools. Glomeruli were isolated by differential sieving and loaded with Fluo-4/Fura Red cell permeable calcium indicators, and the purinergic response in the podocytes was analyzed with ratiometric confocal fluorescence measurements. Various P2 receptors activators were tested and compared with the effect of ATP, specifically, UDP, MRS 2365, bzATP, alphabeta-methylene, 2-meSADP, MRS 4062, and MRS 2768, were analyzed. Antagonists (MRS 2500, 5-BDBD, A438079, and NF 449) were tested when 10 MUM ATP was applied as the EC50 for ATP activation of the calcium influx in the podocytes was determined to be 10.7 +/- 1.5 MUM. Several agonists including MRS 2365 and 2-meSADP caused calcium flux. Importantly, only the P2Y1-specific antagonist MRS 2500 (1 nM) precluded the effects of ATP concentrations of the physiological range. Immunohistochemical analysis confirmed that P2Y1 receptors are highly expressed in the podocytes. We conclude that P2Y1 receptor signaling is the predominant P2Y purinergic pathway in the glomeruli podocytes and P2Y1 might be involved in the pathogenesis of glomerular injury and could be a target for treatment of kidney diseases. PMID- 24048732 TI - N-methyl-D-aspartate receptors in human erythroid precursor cells and in circulating red blood cells contribute to the intracellular calcium regulation. AB - The presence of N-methyl-d-aspartate receptor (NMDAR) was previously shown in rat red blood cells (RBCs) and in a UT-7/Epo human myeloid cell line differentiating into erythroid lineage. Here we have characterized the subunit composition of the NMDAR and monitored its function during human erythropoiesis and in circulating RBCs. Expression of the NMDARs subunits was assessed in erythroid progenitors during ex vivo erythropoiesis and in circulating human RBCs using quantitative PCR and flow cytometry. Receptor activity was monitored using a radiolabeled antagonist binding assay, live imaging of Ca(2+) uptake, patch clamp, and monitoring of cell volume changes. The receptor tetramers in erythroid precursor cells are composed of the NR1, NR2A, 2C, 2D, NR3A, and 3B subunits of which the glycine-binding NR3A and 3B and glutamate-binding NR2C and 2D subunits prevailed. Functional receptor is required for survival of erythroid precursors. Circulating RBCs retain a low number of the receptor copies that is higher in young cells compared with mature and senescent RBC populations. In circulating RBCs the receptor activity is controlled by plasma glutamate and glycine. Modulation of the NMDAR activity in RBCs by agonists or antagonists is associated with the alterations in whole cell ion currents. Activation of the receptor results in the transient Ca(2+) accumulation, cell shrinkage, and alteration in the intracellular pH, which is associated with the change in hemoglobin oxygen affinity. Thus functional NMDARs are present in erythroid precursor cells and in circulating RBCs. These receptors contribute to intracellular Ca(2+) homeostasis and modulate oxygen delivery to peripheral tissues. PMID- 24048733 TI - Antidicer RNAse activity of monocyte chemotactic protein-induced protein-1 is critical for inducing angiogenesis. AB - Inflammatory angiogenesis involves the induction of a novel gene ZC3H12A encoding monocyte chemoattractant protein-1 (MCP-1)-induced protein-1 (MCPIP1) that has deubiquitinase and antidicer RNAse activities. If and how these enzymatic activities of MCPIP1 mediate the biological functions of MCPIP1 are unknown. Present studies with human umbilical vein endothelial cells suggest that MCPIP induced angiogenesis is mediated via hypoxia-inducible factor (HIF-1alpha), vascular endothelial growth factor (VEGF), and silent information regulator (SIRT 1) induction that results in the inhibition of angiogenesis inhibitor thrombospondin-1. MCPIP1 expression inhibited the production of the antiangiogenic microRNA (miR)-20b and -34a that repress the translation of HIF 1alpha and SIRT-1, respectively. The RNase-dead MCPIP mutant D141N not only did not induce angiogenesis but also failed to inhibit the production of miR-20b and 34a suggesting that the antidicer RNase activity of MCPIP1 is involved in MCPIP mediated angiogenesis. Mimetics of miR-20b and -34a inhibited MCPIP1-induced angiogenesis confirming that MCPIP1 suppresses the biogenesis of miR-20b and 34a. Furthermore, our results indicate that MCPIP expression induces nuclear translocation of HIF-1alpha. We show that under hypoxia angiogenesis is mediated via induction of MCPIP1 and under normoxia, in vitro, MCPIP deubiquitinates ubiquitinated HIF-1alpha and the stabilized HIF-1alpha enters the nucleus to promote the transcription of its target genes, cyclooxygenase-2 and VEGF, suggesting that the deubiquitinase activity of MCPIP may also promote angiogenesis. The present results show for the first time that the antidicer RNase activity of MCPIP1 is critical in mediating a biological function of MCPIP, namely angiogenesis. PMID- 24048735 TI - Light microscopy is useful to better define NERD and functional heartburn. PMID- 24048734 TI - In oesophageal squamous cells exposed to acidic bile salt medium, omeprazole inhibits IL-8 expression through effects on nuclear factor-kappaB and activator protein-1. AB - OBJECTIVE: Oesophagitis might result from the effects of chemokines produced by oesophageal cells in response to gastro-oesophageal reflux, and not solely from the direct, caustic effects of refluxed gastric juice. Proton pump inhibitors (PPI) can block chemokine production through mechanisms independent of their antisecretory effects. We studied omeprazole effects on chemokine production by oesophageal epithelial cells exposed to acidic bile salts. DESIGN: Human primary and telomerase-immortalised oesophageal squamous cells were exposed to acidic bile salt medium with or without omeprazole pretreatment. Interleukin (IL)-8 expression was determined by RT-PCR and ELISA. IL-8 promoter activity was measured by luciferase reporter assay. Binding of NF-kappaB and AP-1 subunits to the IL-8 promoter was assessed by chromatin immunoprecipitation (ChIP) assay. Immune cell migration induced by conditioned medium was determined by a double chamber migration assay system. RESULTS: Acidic bile salt medium caused oesophageal epithelial cells to express IL-8 mRNA and protein by activating the IL-8 promoter through NF-kappaB and AP-1 binding. Omeprazole inhibited that acidic bile salt-stimulated IL-8 expression by blocking the nuclear translocation of p65 (an NF-kappaB subunit), and by blocking the binding of p65, c-jun and c fos (AP-1 subunits) to the IL-8 promoter. Omeprazole also blocked the ability of conditioned medium from cells exposed to acidic bile salts to induce immune cell migration. CONCLUSIONS: In oesophageal squamous epithelial cells, omeprazole inhibits IL-8 expression through effects on NF-kappaB and AP-1 that are entirely independent of effects on gastric acid secretion. These previously unrecognised PPI effects might contribute to the healing of reflux oesophagitis. PMID- 24048736 TI - A novel urine peptide biomarker-based algorithm for the prognosis of necrotising enterocolitis in human infants. AB - OBJECTIVE: Necrotising enterocolitis (NEC) is a major source of neonatal morbidity and mortality. The management of infants with NEC is currently complicated by our inability to accurately identify those at risk for progression of disease prior to the development of irreversible intestinal necrosis. We hypothesised that integrated analysis of clinical parameters in combination with urine peptide biomarkers would lead to improved prognostic accuracy in the NEC population. DESIGN: Infants under suspicion of having NEC (n=550) were prospectively enrolled from a consortium consisting of eight university-based paediatric teaching hospitals. Twenty-seven clinical parameters were used to construct a multivariate predictor of NEC progression. Liquid chromatography/mass spectrometry was used to profile the urine peptidomes from a subset of this population (n=65) to discover novel biomarkers of NEC progression. An ensemble model for the prediction of disease progression was then created using clinical and biomarker data. RESULTS: The use of clinical parameters alone resulted in a receiver-operator characteristic curve with an area under the curve of 0.817 and left 40.1% of all patients in an 'indeterminate' risk group. Three validated urine peptide biomarkers (fibrinogen peptides: FGA1826, FGA1883 and FGA2659) produced a receiver-operator characteristic area under the curve of 0.856. The integration of clinical parameters with urine biomarkers in an ensemble model resulted in the correct prediction of NEC outcomes in all cases tested. CONCLUSIONS: Ensemble modelling combining clinical parameters with biomarker analysis dramatically improves our ability to identify the population at risk for developing progressive NEC. PMID- 24048737 TI - MTI-101 (cyclized HYD1) binds a CD44 containing complex and induces necrotic cell death in multiple myeloma. AB - Our laboratory recently reported that treatment with the d-amino acid containing peptide HYD1 induces necrotic cell death in multiple myeloma cell lines. Because of the intriguing biological activity and promising in vivo activity of HYD1, we pursued strategies for increasing the therapeutic efficacy of the linear peptide. These efforts led to a cyclized peptidomimetic, MTI-101, with increased in vitro activity and robust in vivo activity as a single agent using two myeloma models that consider the bone marrow microenvironment. MTI-101 treatment similar to HYD1 induced reactive oxygen species, depleted ATP levels, and failed to activate caspase-3. Moreover, MTI-101 is cross-resistant in H929 cells selected for acquired resistance to HYD1. Here, we pursued an unbiased chemical biology approach using biotinylated peptide affinity purification and liquid chromatography/tandem mass spectrometry analysis to identify binding partners of MTI-101. Using this approach, CD44 was identified as a predominant binding partner. Reducing the expression of CD44 was sufficient to induce cell death in multiple myeloma cell lines, indicating that multiple myeloma cells require CD44 expression for survival. Ectopic expression of CD44s correlated with increased binding of the FAM-conjugated peptide. However, ectopic expression of CD44s was not sufficient to increase the sensitivity to MTI-101-induced cell death. Mechanistically, we show that MTI-101-induced cell death occurs via a Rip1-, Rip3 , or Drp1-dependent and -independent pathway. Finally, we show that MTI-101 has robust activity as a single agent in the SCID-Hu bone implant and 5TGM1 in vivo model of multiple myeloma. PMID- 24048738 TI - Isolation of a novel thioflavin S-derived compound that inhibits BAG-1-mediated protein interactions and targets BRAF inhibitor-resistant cell lines. AB - Protein-protein interactions mediated through the C-terminal Bcl-2-associated athanogene (BAG) domain of BAG-1 are critical for cell survival and proliferation. Thioflavin S (NSC71948)-a mixture of compounds resulting from the methylation and sulfonation of primulin base-has been shown to dose-dependently inhibit the interaction between BAG-1 and Hsc70 in vitro. In human breast cancer cell lines, with high BAG-1 expression levels, Thioflavin S reduces the binding of BAG-1 to Hsc70, Hsp70, or CRAF and decreases proliferation and viability. Here, we report the development of a protocol for the purification and isolation of biologically active constituents of Thioflavin S and the characterization of the novel compound Thio-2. Thio-2 blocked the growth of several transformed cell lines, but had much weaker effects on untransformed cells. Thio-2 also inhibited the proliferation of melanoma cell lines that had become resistant to treatment with PLX4032, an inhibitor of mutant BRAF. In transformed cells, Thio-2 interfered with intracellular signaling at the level of RAF, but had no effect on the activation of AKT. Thio-2 decreased binding of BAG-1 to Hsc70 and to a lesser extent BRAF in vitro and in vivo, suggesting a possible mechanism of action. Given that tumors frequently develop resistance to kinase inhibitors during treatment, Thio-2 and related compounds may offer promising alternative strategies to currently available therapies. PMID- 24048739 TI - Immunohistochemical characteristics and distribution of sensory dorsal root Ganglia neurons supplying the urinary bladder in the male pig. AB - The study determined the distribution and immunohistochemical coding of the sensory neurons innervating the male pig urinary bladder. Retrograde tracer Fast Blue was injected bilaterally into the bladder trigone, base or dome. The presence of neuropeptide Y (NPY), somatostatin (SOM), galanin (GAL), vasoactive intestinal polypeptide (VIP), nitric oxide synthase (NOS), calcitonin gene related peptide (CGRP) and substance P (SP) were studied with immunofluorescence. Fast Blue-positive neurons were localized bilaterally in dorsal root ganglia from L1 to L6 and from S3 to S4 with specific differences regarding the injection site. The number of Fast Blue-positive neurons was higher in the right ganglia. Immunohistochemistry revealed that sensory neurons innervating the urinary bladder trigone, base and dome displayed immunoreactivities to CGRP, SP, NOS, GAL and SOM. Differences in the neuropeptide content were observed between the Fast Blue-positive neurons in lumbar and sacral ganglia. Taken together, these data indicate that the lumbar and sacral pathways probably play different roles in sensory transmission from the urinary bladder trigone, base and dome. PMID- 24048740 TI - The clathrin-dependent localization of dopamine transporter to surface membranes is affected by alpha-synuclein. AB - Parkinson's disease (PD) is a progressive age-dependent neurodegenerative disorder, predominantly affecting the dopamine-producing neurons residing at the substantia nigra. Abnormalities in alpha-synuclein (alpha-Syn) and dopamine transporter (DAT) are implicated in the pathogenesis of PD. We tested the hypothesis that alpha-Syn regulates surface DAT localization and DAT activity, in cultured cells co-expressing alpha-Syn and DAT, and in brains of mice modeling PD, transgenic for the mutant A53T alpha-Syn form. The results indicate that alpha-Syn expression affects the partitioning of DAT between the cell surface and intracellular compartments, resulting in lower surface DAT levels. Accordingly, lower uptake of tritiated dopamine was measured in synaptosomes of A53T alpha-Syn transgenic mouse brains. Importantly, we show that the effect of alpha-Syn on surface DAT is mediated by clathrin. Downregulation of clathrin by specific siRNAs directed against its heavy chain abolished the effect of alpha-Syn on phorbol 12-myristate 13-acetate-induced DAT internalization. These results suggest that alpha-Syn plays a role in regulating dopamine homeostasis through its involvement in clathrin-mediated endocytosis. PMID- 24048742 TI - Src contributes to IL6-induced vascular endothelial growth factor-C expression in lymphatic endothelial cells. AB - Formation of lymphatic capillaries by lymphatic endothelial cells (LECs) occurs both in normal tissues as well as in pathological processes including tumor metastasis. Interleukin-6 (IL-6), a potent pro-inflammatory cytokine, has been shown to be highly elevated in various cancers. IL-6 has also been shown to increase tumor lymphangiogenesis through vascular endothelial growth factor-C (VEGF-C) induction in tumor cells. Although lymphangiogenesis is associated with lymph node metastasis and also resistance to conventional therapy in various cancers, the precise mechanisms of lymphangiogenesis in LECs remain unclear. This study aimed to investigate the signaling cascade involved in IL-6-induced VEGF-C expression in murine LECs (SV-LEC). The VEGF-C mRNA and protein levels were increased in SV-LECs exposed to IL-6. IL-6 time-dependently induced Src phosphorylation and downstream phosphorylation of ERK1/2 and p38MAPK. In contrast, PP2, an inhibitor of Src signaling, abrogated IL-6's effects on ERK1/2 and p38MAPK phosphorylation. IL-6 exposure also led to increase in VEGF-C promoter-luciferase activity as well as C/EBPbeta- and kappaB-luciferase activities. VEGF-C promoter-, C/EBPbeta- and kappaB-luciferase activities were all suppressed by Src, ERK1/2 or p38MAPK signaling blockades despite presence of IL-6. Finally, C/EBPbeta and p65 binding to the VEGF-C promoter region were increased after IL-6 exposure in SV-LECs. Taken together, we report a Src mediated ERK1/2 and p38MAPK activation resulting in C/EBPbeta and p65 binding to the promoter region of VEGF-C, leading to VEGF-C expression in IL-6-exposed SV LECs. PMID- 24048741 TI - Update on therapeutic mechanism for bone marrow stromal cells in ischemic stroke. AB - Cerebral ischemia is a major cause of morbidity and mortality in the aged population, as well as a tremendous burden on the healthcare system. Despite timely treatment with thrombolysis and percutaneous intravascular interventions, many patients are often left with irreversible neurological deficits. Bone marrow stromal cells (BMSCs), also referred to as mesenchymal stem cells (MSCs), are a type of nonhematopoietic stem cells which exists in bone marrow mesh, with the potential to self-renew. Unlike cells in the central nervous system, BMSCs differentiate not only into mesodermal cells, but also endodermal and ectodermal cells. Moreover, it has been reported that BMSCs develop into cells with neural and vascular markers and play a role in recovery from ischemic stroke. These findings have fuelled excitement in regenerative medicine for neurological diseases, especially for ischemic stroke. There is now preclinical evidence to suggest that BMSCs grafted into the brain of ischemic models abrogate neurological deficits. Based on the overwhelming evidence from animal studies as well as in clinical trials, BMSC transplantation is considered a promising strategy for treatment of ischemic stroke. The goal of this review is to present an integrated consideration of molecular mechanisms in a chronological fashion and discuss an optimal BMSC delivery route for ischemic stroke. PMID- 24048743 TI - Hepatitis B awareness and knowledge in hepatitis B surface antigen-positive parturient immigrant women from West Africa in the Bronx, New York. AB - An increasing proportion of foreign-born residents in the Bronx, New York are African immigrants from West Africa, a region with a very high hepatitis B surface antigen (HBsAg) prevalence. Charts of 114 HBsAg positive parturients who gave birth between 2004 and 2008 in a community hospital in the Bronx were retrospectively reviewed. Most were of West-African origin (88%). Acute hepatic inflammation was rare (4%). Active viral replication (Hepatitis B e-antigen positivity) was noted in a minority (7%), but in 3/5 (60%) HIV co-infected women. Among the West-African immigrant women who agreed to be interviewed (n = 39), only half (54%) had ever heard of hepatitis B virus (HBV) infection, and their knowledge of HBV was mostly incomplete. This study shows that pregnancy-related health interventions may offer unique opportunities to link such women to specialist care and initiate culturally sensitive HBV-relevant education for the index case and her family. PMID- 24048744 TI - Dramatic phenotypic plasticity within species of Siphomutabilus n. g. (Digenea: Cryptogonimidae) from Indo-Pacific caesionines (Perciformes: Lutjanidae). AB - A survey of Indo-Pacific lutjanids of the subfamily Caesioninae revealed the presence of Siphodera gurukun Machida, 1910 and two new cryptogonimid taxa from off Heron and Lizard Islands on the Great Barrier Reef, Australia, Ningaloo Reef, Western Australia and Rasdhoo Atoll, Maldives. A combined morphological and genetic characterisation of these species shows that they form a clade distinct from the type-species of Siphodera Linton, 1910, S. vinaledwardsii (Linton, 1901), and warrants the proposal of a new genus. Here we propose Siphomutabilus n. g. and transfer Siphodera gurukun Machida, 1986 as the type-species, Siphomutabilus gurukun (Machida, 1986) n. comb. Siphodera aegyptensis Hassanine & Gibson, 2005 is transferred to Siphomutabilus as S. aegyptensis (Hassanine & Gibson, 2005) n. comb. based on morphological and ecological similarities. Siphomutabilus raritas n. sp. is described from Caesio cuning (Bloch) off Lizard Island and S. bitesticulatus n. sp. is described from Pterocaesio marri Schultz off Heron Island. The two new species are unique in that they have two testes, making their morphology broadly consistent with that of Metadena Linton, 1910, yet the molecular analyses conducted here indicates that they are unequivocally united with Siphomutabilus gurukun (which has multiple testes) to the exclusion of Metadena lutiani (Yamaguti, 1942), which was sequenced here. The dramatic phenotypic plasticity observed among such closely related species of Siphomutabilus suggests a secondary modification of what is generally considered a robust generic diagnostic character within this and other digenean families, highlighting the need for a combined morphological and molecular diagnostic approach when characterising these taxa. Siphodera Linton, 1910 is amended to include just two species, the type-species S. vinaledwardsii (Linton, 1901) Linton, 1910 and S. cirrhiti Yamaguti, 1970, which are distinguished by their lack of oral spines and multiple testes that are primarily extracaecal. Siphodera ghanensis Fischthal & Thomas, 1968 is considered a species incertae sedis here based on significant morphological and ecological differences compared with species of Siphodera and Siphomutabilus n. g. PMID- 24048745 TI - Two new gonad-infecting philometrids (Nematoda: Philometridae) from the yellowedge grouper Hyporthodus flavolimbatus (Serranidae) and the great northern tilefish Lopholatilus chamaeleonticeps (Malacanthidae) in the northern Gulf of Mexico. AB - Based on light and scanning electron microscopical studies, two new gonad infecting species of Philometra Costa, 1845 (Nematoda: Philometridae) are described from marine perciform fishes in the northern Gulf of Mexico: P. hyporthodi n. sp. from the ovary of the yellowedge grouper Hyporthodus flavolimbatus (Poey) (Serranidae) and P. lopholatili n. sp. from the ovary of the great northern tilefish Lopholatilus chamaeleonticeps Goode & Bean (Malacanthidae). Philometra hyporthodi is mainly characterised by the body length of both the males (3.62-4.07 mm) and gravid female (105 mm), the length of the spicules (135-138 MUm) and the presence of dorsal transverse lamella-like structures on the distal portion of the gubernaculum. Philometra lopholatili is distinguished by the presence of a distinct dorsal protuberance consisting of two dorsolateral lamellated parts separated from each other by a smooth median field, an uninterrupted mound on the male caudal extremity, the length of the spicules (165-189 MUm) and the body length of the males (2.19-2.34 mm) and gravid female (280 mm). Philometra lopholatili is the first representative of the genus and the second philometrid species reported from fishes of the family Malacanthidae. PMID- 24048746 TI - Five new species of dicyemid mesozoans (Dicyemida: Dicyemidae) from two Australian cuttlefish species, with comments on dicyemid fauna composition. AB - Five new species of dicyemid mesozoans in two genera are described from two Australian cuttlefish species, Sepia apama Gray (giant Australian cuttlefish) and S. novaehollandiae Hoyle (nova cuttlefish): Dicyema coffinense n. sp. from S. apama collected from Coffin Bay, South Australia (SA), Australia; D. koinonum n. sp. from S. apama and S. novaehollandiae collected from Gulf St Vincent (GSV) and Spencer Gulf (SG), SA, Australia; D. multimegalum n. sp. from S. apama collected from Cronulla and North Bondi, New South Wales, Australia; D. vincentense n. sp. from S. novaehollandiae collected from GSV, SA, Australia; and Dicyemennea spencerense n. sp. from S. novaehollandiae and S. apama collected from SG, SA, Australia. Totals of 51 S. apama and 27 S. novaehollandiae individuals were examined, of which all except for four S. apama were infected by at least one dicyemid species. Dicyemid parasites were also observed in host individuals that were held in tanks for 2-3 months prior to examination, including nematogen exclusive infections, leading to questions about persistence of dicyemids after host death and the mechanism responsible for the switch between a nematogen phase and a rhombogen phase. Variations in host size, calotte shape and collection locality are explored as predictors of differences in observed composition of the parasite fauna. In particular, dicyemid parasite fauna varied with host collection locality. As these parasites are highly host-species specific, their use as biological tags to assess cephalopod population structure using a combined morphological and molecular approach is discussed. This study increases the number of dicyemid species described from Australian cephalopods from five to ten, and from 117 to 122 species described worldwide. PMID- 24048747 TI - Microcotyle omanae n. sp. (Monogenea: Microcotylidae), a parasite of Cheimerius nufar (Valenciennes) (Sparidae) from the Arabian Sea. AB - Microcotyle omanae n. sp. (Monogenea: Microcotylidae) is described from the gills of Cheimerius nufar (Valenciennes) (Sparidae) from the Arabian Sea. The new species closely resembles Microcotyle arripis Sandars, 1945, M. helotes Sandars, 1944, M. caudata Goto, 1984 and M. sebastis Goto, 1984, which have also been found in the Indo-Pacific. Microcotyle omanae n. sp. differs from M. arripis, M. helotes and M. caudata by its greater number of testes, from M. arripis, M. helotes by its greater length of the genital atrium, length/width ratio of the genital atrium and length of the eggs, and from M. helotes also in greater width of the clamps, from M. caudata and M. sebastis in its greater number of clamps and additionally from M. sebastis by its smaller genital atrial spines and clamps and by the ratio between length and width of the genital atrium. Moreover, the mature specimens of the new species have greater average body length than all above mentioned species. Correlations between 15 morphometric characters and body length are analysed in the new species, and their significance for species differentiation is discussed. PMID- 24048748 TI - Two new species of Eimeria Schneider, 1875 (Apicomplexa: Eimeriidae) from emerald tree skinks, Lamprolepis smaragdina (Lesson) (Sauria: Scincidae) from Papua New Guinea and the Philippines. AB - Two new species of Eimeria Schneider, 1875, from emerald tree skinks, Lamprolepis smaragdina (Lesson) are described from specimens collected in Papua New Guinea (PNG) and the Philippines. Oocysts of Eimeria nuiailan n. sp. from the only L. smaragdina from PNG are ovoidal, with a smooth, colourless, bi-layered wall, measure 23.7 * 19.1 MUm, and have a length/width (L/W) ratio of 1.3; both micropyle and oocyst residuum are absent, but a fragmented polar granule is present. Sporocysts are ovoidal to ellipsoidal, 11.9 * 7.0 MUm, L/W 1.7, and the wall is composed of two valves joined by a longitudinal suture; neither Stieda nor sub-Stieda bodies are present; a sporocyst residuum is present as a compact mass of granules. Sporozoites are elongate, 14.6 * 2.6 MUm, and contain anterior and posterior refractile bodies with a nucleus between them. Oocysts of Eimeria auffenbergi n. sp. from L. smaragdina collected in the Philippines are ovoidal, with a smooth, colourless, bi-layered wall, measure 19.9 * 15.8 MUm, L/W 1.3; both micropyle and oocyst residuum are absent, but one to four polar granules are present. Sporocysts are ovoidal to ellipsoidal, 10.3 * 5.8 MUm, L/W 1.8, and the wall is composed of two valves joined by a longitudinal suture; neither Stieda nor sub-Stieda bodies are present; a sporocyst residuum is composed of dispersed granules. PMID- 24048749 TI - Parasitic copepods of the common sole, Solea solea (L.), from the Eastern Mediterranean coast of Turkey. AB - There is increasing interest in the common sole, Solea solea (Linnaeus), as an alternative fish species in aquaculture in the Mediterranean region, and parasitic copepods are a potential hazard for farmed finfish. This paper provides taxonomic information on two species of sea lice (family Caligidae) collected from S. solea in eastern Mediterranean waters off the Turkish coast. Caligus brevicaudatus A. Scott, 1901 and Caligus apodus (Brian, 1924) were both found and this is the first report of C. brevicaudatus in Turkish waters. The discovery of C. apodus on S. solea is a new host record. Key diagnostic characters of both species are reported, supported by light and scanning electron microscopy observations. During a 12-month survey a prevalence of 28% was recorded for C. brevicaudatus, whereas for C. apodus peak prevalence was much lower (3%). PMID- 24048750 TI - Demodex microti n. sp. (Acari: Demodecidae) in Microtus arvalis (Pallas) (Rodentia, Cricetidae) with a checklist of the demodecid mites of cricetids. AB - Demodex microti n. sp. (Acari, Demodecidae) is described from the skin of the genital area of the common vole Microtus arvalis (Pallas) in Poland based on the morphology of the adult and immature stages. The new species appears most similar to D. cricetuli Hurley & Desch, 1994 from the gray dwarf hamster, Cricetulus migratorius (Pallas), but differs in the following features: the supracoxal spines are conical and located at the edge of the gnathosoma, the spines of the terminal segment of palp are three, single-tined, the opisthosomal organ is narrow and elongated in males and bubble-shaped in females, the vulva is located below the incision of the fourth pair of epimeral plates, eggs are oval. The differences also relate to body size and proportions, D. microti n. sp. being smaller and slender. The new species occurred in all of the rodents examined. A checklist of demodecid mites in cricetids world-wide is also provided. PMID- 24048751 TI - Hirudinella ventricosa (Pallas, 1774) Baird, 1853 represents a species complex based on ribosomal DNA. AB - Digeneans in the genus Hirudinella de Blainville, 1828 (Hirudinellidae) from three species of pelagic fishes, Acanthocybium solandri (Cuvier), Makaira nigricans Lacepede and Thunnus albacares (Bonnaterre), and one benthic fish, Mulloidichthys martinicus (Cuvier), from the Gulf of Mexico are investigated using comparison of ribosomal DNA. Four species are identified based on molecular differences: Hirudinella ventricosa (Pallas, 1774) Baird, 1853 from A. solandri, Hirudinella ahi Yamaguti, 1970 from T. albacares, and two unidentified but distinct species of Hirudinella, herein referred to as Hirudinella sp. A (from both M. nigricans and M. martinicus) and Hirudinella sp. B from M. nigricans. Additionally, H. ahi, based tentatively on morphological identification, is reported from Thunnus thynnus (Linnaeus). This represents the first record of a hirudinellid from M. martinicus and the first record of H. ahi from T. thynnus. A phylogeny of some Hemiurata Skrjabin & Guschanskaja, 1954 using partial fragments of the 28S rDNA sequences is consistent with earlier phylogenies and the position of the Hirudinellidae Dollfus, 1932 is well-supported as a derived group most closely related to the Syncoeliidae Looss, 1899. PMID- 24048753 TI - A reflection on moral distress in nursing together with a current application of the concept. AB - The concept of moral distress can be extended from clinical settings to larger environmental concerns affecting health care. Moral distress-a common experience in complex societies-arises when individuals have clear moral judgments about societal practices, but have difficulty in finding a venue in which to express concerns. Since health care is large in scale and climate change is proving to be a major environmental problem, scaling down health care is inevitably a necessary element for mitigating climate change. Because it is extremely challenging to discuss these concerns in health care settings, those concerned about climate change and health care experience distress. This article outlines some philosophical concepts and perspectives that may be useful in mitigating this distress. PMID- 24048754 TI - Studies on process optimization methods for rapamycin production using Streptomyces hygroscopicus ATCC 29253. AB - Rapamycin is a high-value product finding immense use as a drug, in organ transplantation, and as a potential immunosuppressant. Optimization of fermentation parameters of rapamycin production by Streptomyces hygroscopicus NRRL 5491 has been carried out. The low titer value of rapamycin in the original producer strain limits its applicability at industrial level. This study aims at improving the production of rapamycin by optimizing the nutrient requirements. Addition of L-lysine increased the production of rapamycin up to a significant level which supports the fact that it acts as precursor for rapamycin production, as found in previous studies. Effect of optimized medium on the Streptomyces growth rate as well as rapamycin production has been studied. The optimization study incorporates one at a time parameter optimization studies followed by tool based hybrid methodology. This methodology includes the Plackett-Burman design (PBD) method, artificial neural networks (ANN), and genetic algorithms (GA). PBD screened mannose, soyabean meal, and L-lysine concentrations as significant factors for rapamycin production. ANN was used to construct rapamycin production model. This strategy has led to a significant increase of rapamycin production up to 320.89 mg/L at GA optimized concentrations of 25.47, 15.39, and 17.48 g/L for mannose, soyabean meal, and L-lysine, respectively. The present study must find its application in scale-up study for industrial level production of rapamycin. PMID- 24048755 TI - Vitamin D receptor gene ApaI polymorphism and breast cancer susceptibility: a meta-analysis. AB - Vitamin D receptor (VDR) principally mediates the anticancer activities of vitamin D. Many studies investigated the association between VDR gene ApaI polymorphism and breast cancer, but the results were inconclusive. We performed this meta-analysis to evaluate the association between VDR gene ApaI polymorphism and breast cancer. Twelve studies with a total of 8,254 subjects were identified from PubMed and Wanfang databases. The pooled odds ratio (OR) and confidence intervals (95% CI) were used to assess the association. The meta-analysis indicated that VDR gene ApaI polymorphism was not associated with risk of breast cancer (a vs. A: OR = 0.97, 95% CI 0.91-1.04, P = 0.378; aa vs. AA: OR = 0.97, 95% CI 0.85-1.10, P = 0.618; aa vs. AA + Aa: OR = 1.00, 95% CI 0.89-1.12, P = 0.972; aa + Aa vs. AA: OR = 0.95, 95% CI 0.82-1.11, P = 0.550). Subgroup analysis by ethnicity further showed that VDR gene ApaI polymorphism was not associated with risk of breast cancer in both Asians and Caucasians. These data from the meta-analysis indicate that VDR gene ApaI polymorphism is not associated with breast cancer susceptibility. PMID- 24048756 TI - Platycodin D, a triterpenoid saponin from Platycodon grandiflorum, induces G2/M arrest and apoptosis in human hepatoma HepG2 cells by modulating the PI3K/Akt pathway. AB - Platycodin D (PD) is one of triterpenoid saponins isolated from the roots of Platycodon grandiflorum. In the present study, we aimed at examining the antitumor activity of PD against human hepatoma HepG2 cancer cells and investigated the underlying molecular mechanisms of PD-induced apoptosis in HepG2 cells. PD significantly inhibited the proliferation of HepG2 cells in a concentration- and time-dependent manner as assessed by MTT assay. Besides, flow cytometry revealed that PD treatment obviously induced G2/M arrest and apoptosis in HepG2 cells. Moreover, Western blot analysis demonstrated that PD induced downregulation of protein expression of PI3K, P-Akt, and Bcl-2, whereas cleaved products of caspase-3 and -9 and PARP were upregulated by PD treatment. Furthermore, the protein level of P-p38, p-38, and Bax in PD-treated HepG2 cells was kept unchanged. In addition, the inhibitors of z-DEVD-fmk (a specific caspase 3 inhibitor) and z-LEHD-fmk (a specific caspase-9 inhibitor), but not z-IETD-fmk (a specific caspase-8 inhibitor), could significantly block PD-triggered apoptosis, whereas LY294002 (Akt inhibitor) could significantly enhance PD induced apoptosis in HepG2 cells. Thus, the increasing ratio of Bax to Bcl-2, activation of caspase-3 and -9 and PARP, and inactivation of the PI3K/Akt signaling pathway significantly enhanced PD-induced apoptosis in HepG2 cells. Our results suggest that PD induced cell cycle G2/M arrest and apoptosis in HepG2 cells by decreasing PI3K/Akt pathway. Therefore, we propose that PD has potential as a liver cancer chemotherapeutic agent. PMID- 24048757 TI - Three polymorphisms of DNA repair gene XRCC1 and the risk of glioma: a case control study in northwest China. AB - Three polymorphisms of X-ray repair cross-complementing groups 1 (XRCC1) Arg194Trp, Arg280His, and Arg399Gln may be associated with the individual susceptibility to glioma. The aim of this study was to investigate any association between three polymorphisms of the XRCC1 gene at codon 194, 280, and 399 and potential glioma risk. We conducted a hospital-based case-control study in northwest China. A total of 1,772 subjects, including 886 glioma patients and 886 healthy controls, were recruited in this study. The peripheral blood samples were extracted. Polymerase chain reaction-restriction fragment length polymorphism method was used to test genotypes. Glioma patients had a significantly higher frequency of XRCC1 194 TT (odds ratio [OR] = 1.76, 95 % confidence interval [CI] = 1.14, 2.72; P = 0.01) and XRCC1 399 AA genotype (OR = 1.62, 95 % CI = 1.09, 2.40; P = 0.02) than controls. When stratified by the grade of glioma, patients with WHO IV glioma had a significantly higher frequency of XRCC1 194 TT (OR = 1.60, 95 % CI = 1.02, 2.51; P = 0.04) and XRCC1 399 AA genotype (OR = 1.59, 95 % CI = 1.04, 2.42; P = 0.03). When stratified by the histology of glioma, there was no significant difference in the distribution of each genotype. This study suggested that XRCC1 Arg194Trp and Arg399Gln polymorphisms were associated with the risk of glioma. PMID- 24048758 TI - Optimal chemotherapy for advanced gastric cancer: is there a global consensus? AB - The optimal medical treatment for advanced gastric cancer is currently the source of debate. Cytotoxic treatment has been shown to prolong survival and provide improved symptom control compared with best supportive care alone, but a global standard has not yet been defined. A literature research was undertaken. Results were evaluated by an international author team. The conclusions of this are presented in this paper. Combination chemotherapy with cisplatin and 5 fluorouracil was the preferred first-line chemotherapy, but oxaliplatin has shown equivalent efficacy to cisplatin. Oral fluoropyrimidines, especially S-1 and capecitabine, can substitute for 5-fluorouracil. Modern doublet regimens are preferred in the majority of patients on the basis of a balanced benefit-to-risk ratio. In selected fit and compliant patients, especially those with a high tumor burden or potential secondary resectability, a third drug may be added because triplet chemotherapy led to higher responses rates and enhanced efficacy. However, docetaxel also adds a significant increase in side effects. Monotherapy and early dose modifications should be considered in elderly and infirm patients. Beyond that, our understanding of gastric cancer tumor biology is increasing. In HER2-positive gastric cancer, the addition of the monoclononal anti-HER2 antibody trastuzumab to cisplatin and fluoropyrimidines has prolonged survival duration. Second-line chemotherapy with single agents has now become a proven treatment option. Alternatively, anti-angiogenic treatment with ramucirumab is on the horizon. In conclusion, combination chemotherapy is regarded as the global standard of care for the first-line treatment of advanced gastric cancer. Molecularly targeted treatments are being explored, preferably in combination with a backbone of chemotherapy doublets. PMID- 24048759 TI - Ultrasonically activated shears versus electrocautery in open gastrectomy for gastric cancer: a randomized controlled trial. AB - BACKGROUND: Use of ultrasonically activated shears (UAS) is gaining popularity in open surgery but without concrete evidence. We conducted a prospectively randomized study to assess the efficacy of ultrasonic dissection in open gastrectomy for gastric cancer. METHODS: Patients with gastric cancer who were to undergo gastrectomy with D2 lymph node dissection were enrolled and assigned to either the conventional surgery group (n = 125) or the UAS group (n = 128). RESULTS: The mean operating time was significantly reduced in the UAS group (89.3 +/- 15.6 min) when compared to the conventional group (97.8 +/- 17.2 min; p < 0.001). However, we did not find any significant difference in operative blood loss, the amount of postoperative abdominal drainage, or the rate of postoperative complications between the groups. A multivariate analysis for operating time revealed that the use of UAS, female gender and BMI less than 25 were significantly associated with reduced operating time. The operating time was significantly longer in the conventional group than in the UAS group (B 7.786; 95 % CI 4.103-11.468; p < 0.001). In the subgroup analysis, the use of UAS significantly reduced the operating time, especially in male patients, regardless of the BMI status. CONCLUSIONS: The use of UAS in gastrectomy for gastric cancer was a safe and efficient method, especially in terms of reducing operating time for male patients. PMID- 24048760 TI - Clinicopathological significance of MMP-7, laminin gamma2 and EGFR expression at the invasive front of gastric carcinoma. AB - BACKGROUND: For several types of cancer, including gastric cancer (GC), tumor cells at the invasive front are considered to have a more aggressive behavior compared with those in the more central region. The aim of the present study was to analyze the expression of MMP-7, laminin gamma2 and EGFR in a large number of GCs and to investigate how these expression patterns correlate with clinicopathologic parameters, infiltrative patterns, histology or mucin phenotype. METHODS: We immunohistochemically examined the expression of MMP-7, laminin gamma2 and EGFR using a tissue microarray analysis of 790 GCs, and evaluated their clinicopathological significance. RESULTS: MMP-7, cytoplasmic laminin gamma2, extracellular laminin gamma2 and EGFR expression were observed in 25, 25, 8 and 21 % of the 790 GC cases, respectively. Expression of MMP-7, cytoplasmic laminin gamma2 and EGFR was associated with advanced T grade, N grade and tumor stage. Extracellular laminin gamma2 expression was not associated with any clinicopathologic parameters, infiltrative patterns, histology or mucin phenotype. Furthermore, we investigated the correlations of MMP-7, laminin gamma2 and EGFR expression. MMP-7 expression was significantly more frequent in positive expression of cytoplasmic laminin gamma2 than negative cases, and EGFR expression was significantly more frequent in positive expression of cytoplasmic laminin gamma2 and MMP-7. CONCLUSIONS: Molecular expression of MMP-7, laminin gamma2 or EGFR, and their combinations, may be associated with GC tumor aggressiveness. Assessment of expression of these molecules at the invasive front of primary tumors is clinically significant in predicting the malignant behavior of GC. PMID- 24048761 TI - The strain pattern, and not Sokolow-Lyon electrocardiographic voltage criteria, is independently associated with anatomic left ventricular hypertrophy. AB - Although obesity and chest-wall thickness influence the Sokolow-Lyon electrocardiographic (ECG) voltage criteria and strain pattern, these factors have not been taken into account in previous studies that evaluate the relationship between the ECG criteria and anatomic left ventricular hypertrophy (LVH). The introduction of multislice computed tomography (MSCT) has enabled assessment of not only coronary artery stenoses but also left ventricular volume and mass, left atrial volume, and chest-wall thickness. We hypothesized that evaluating the relation between the ECG voltage criteria or strain pattern and the aforementioned factors using MSCT would be highly valuable. The study population consisted of 93 patients who required MSCT angiography. The Sokolow Lyon voltage and strain patterns were determined to detect anatomic LVH, which was defined as increased left ventricular mass. The Sokolow-Lyon voltage criteria, as an indicator of anatomic LVH, had a sensitivity of 57 %, specificity of 67 %, positive predictive value of 36 %, and negative predictive value of 82 %. By contrast, the strain pattern had a sensitivity of 65 %, specificity of 87 %, positive predictive value of 63 %, and negative predictive value of 88 %. Multivariate analysis revealed that the strain pattern was associated with the presence of anatomic LVH, whereas the Sokolow-Lyon voltage was not. This MSCT study demonstrated that even after removing the effects of various factors, the strain pattern remained associated with the presence of anatomic LVH, in contrast to the Sokolow-Lyon voltage. PMID- 24048762 TI - Management of pulmonic regurgitation and right ventricular dysfunction in the adult with repaired tetralogy of fallot. AB - OPINION STATEMENT: With surgical repair most children with Tetralogy of Fallot survive into adulthood. The main complications seen after Tetralogy of Fallot repair include arrhythmias, sudden cardiac death, pulmonary regurgitation, and right ventricular dysfunction/heart failure. Pulmonary regurgitation over time may lead to right ventricular dilation and failure. In this article, we will review the literature regarding management of pulmonary regurgitation with specific focus on timing for pulmonary valve replacement and prevention of right ventricular dysfunction. PMID- 24048763 TI - Letter to the editor: Mother's milk: request for essential missing information and a comment on Fujita et al., 2012. PMID- 24048764 TI - A safe combined nephrectomy and right lobectomy using the liver hanging maneuver for huge renal cell carcinoma directly invading the right lobe of the liver: report of a case. AB - We herein discuss a patient who underwent simultaneous combined right nephrectomy and right lobectomy of the liver. A 64-year-old male was diagnosed with a huge right renal cell carcinoma (RCC), 13 cm in diameter, which was invading directly into the right hepatic lobe. This type of RCC has been rarely reported, and an anterior approach using the liver hanging maneuver was extremely useful during hepatic parenchymal dissection. The liver parenchymal dissection was performed prior to mobilization of the liver, because the mobilization of the right lobe of the liver was impossible. During the hepatic parenchymal resection, the liver was suspended with the tape and transected, and thereafter, retroperitoneal dissection, nephrectomy and right lobectomy of the liver were completed. The patient was discharged from the hospital on the 12th postoperative day with an uneventful clinical course. The anterior approach using the liver hanging maneuver during hepatic parenchymal resection can be safe and feasible for huge RCC invading the right hepatic lobe. PMID- 24048765 TI - Volvulus of an ileal pouch-rectal anastomosis after subtotal colectomy for ulcerative colitis: report of a case. AB - Ileal J-pouch rectal anastomosis is a commonly performed procedure for patients who have undergone subtotal colectomy for ulcerative colitis or familial adenomatous polyposis without rectal involvement. We herein report the case of a patient with ileal pouch volvulus that developed 15 years after subtotal colectomy for ulcerative colitis. A 62-year-old female visited our emergency room with complaints of abdominal pain and nausea that had persisted for 12 h. Abdominal radiography and contrast-enhanced computed tomography detected segmental distention of the small intestine around the staples. We diagnosed volvulus of the ileal pouch-rectal anastomosis and performed emergency laparotomy. We released the volvulus and performed pouchpexy. The patient was discharged on postoperative day 10, and recurrence of the volvulus has not been observed for 5 months since the procedure was performed. Our study indicates that an early diagnosis and intervention are needed to avoid serious complications, such as pouch necrosis and perforation, in such cases. PMID- 24048766 TI - Single-port laparoscopic management of adhesive small bowel obstruction. AB - Laparoscopic adhesiolysis has been the focus of much recent attention; however, the role of single-port laparoscopic surgery for adhesive small bowel obstruction remains unclear. We report our experience of performing single-port laparoscopic surgery for adhesive small bowel obstruction through a retrospective review of 15 consecutive patients who underwent single-port laparoscopic surgery for single adhesive small bowel obstruction between 2010 and 2012. We analyzed data on patient demographics, operating time, conversion, and surgical morbidity. Surgery was completed successfully without conversion to laparotomy or the need for additional intraoperative ports in 14 patients, but the remaining patient had peritoneal dissemination from colon cancer. The median operative time was 49 (25 148) min, and the estimated blood loss was 19 (2-182) ml. There were no major postoperative complications. We conclude that single-port laparoscopic surgery is a technically feasible approach for selected patients with adhesive small bowel obstruction when preoperative imaging identifies a single adhesive obstruction. PMID- 24048767 TI - Kinetics of acrylodan-labelled cAMP-dependent protein kinase catalytic subunit denaturation. AB - Fluorescence spectroscopy was used to study denaturation of cAMP-dependent protein kinase catalytic subunit labeled with an acrylodan moiety. The dye was covalently bound to a cystein residue introduced into the enzyme by replacement of arginine in position 326 in the native sequence, located near the enzyme active center. This labeling had no effect on catalytic activity of the enzyme, but provided possibility to monitor changes in protein structure through measuring the fluorescence spectrum of the dye, which is sensitive to changes in its environment. This method was used to monitor denaturation of the protein kinase catalytic subunit and study the kinetics of this process as well as influence of specific ligands on stability of the protein. Stabilization of the enzyme structure was observed in the presence of adenosine triphosphate, peptide substrate RRYSV and inhibitor peptide PKI[5-24]. PMID- 24048768 TI - Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360). AB - A novel cytidine analog fluorocyclopentenylcytosine (RX-3117; TV-1360) was characterized for its cytotoxicity in a 59-cell line panel and further characterized for cytotoxicity, metabolism and mechanism of action in 15 additional cancer cell lines, including gemcitabine-resistant variants. In both panels sensitivity varied 75-fold (IC50: 0.4- > 30 MUM RX-3117). RX-3117 showed a different sensitivity profile compared to cyclopentenyl-cytosine (CPEC) and azacytidine, substrates for uridine-cytidine-kinase (UCK). Dipyridamole, an inhibitor of the equilibrative-nucleoside-transporter protected against RX-3117. Uridine and cytidine protected against RX-3117, but deoxycytidine (substrate for deoxycytidine-kinase [dCK]) not, although it protected against gemcitabine, demonstrating that RX-3117 is a substrate for UCK and not for dCK. UCK activity was abundant in all cell lines, including the gemcitabine-resistant variants. RX 3117 was a very poor substrate for cytidine deaminase (66,000-fold less than gemcitabine). RX-3117 was rapidly metabolised to its nucleotides predominantly the triphosphate, which was highest in the most sensitive cells (U937, A2780) and lowest in the least sensitive (CCRF-CEM). RX-3117 did not significantly affect cytidine and uridine nucleotide pools. Incorporation of RX-3117 into RNA and DNA was higher in sensitive A2780 and low in insensitive SW1573 cells. In sensitive U937 cells 1 MUM RX-3117 resulted in 90% inhibition of RNA synthesis but 100 MUM RX-3117 was required in A2780 and CCRF-CEM cells. RX-3117 at IC50 values did not affect the integrity of RNA. DNA synthesis was completely inhibited in sensitive U937 cells at 1 MUM, but in other cells even higher concentrations only resulted in a partial inhibition. At IC50 values RX-3117 downregulated the expression of DNA methyltransferase. In conclusion, RX-3117 showed a completely different sensitivity profile compared to gemcitabine and CPEC, its uptake is transporter dependent and is activated by UCK. RX-3117 is incorporated into RNA and DNA, did not affect RNA integrity, depleted DNA methyltransferase and inhibited RNA and DNA synthesis. Nucleotide formation is related with sensitivity. PMID- 24048769 TI - The high-level accumulation of n-3 polyunsaturated fatty acids in transgenic pigs harboring the n-3 fatty acid desaturase gene from Caenorhabditis briggsae. AB - Livestock meat is generally low in n-3 polyunsaturated fatty acids (PUFAs), which are beneficial to human health. An alternative approach to increasing the levels of n-3 PUFAs in meat is to generate transgenic livestock animals. In this study, we describe the generation of cloned pigs that express the cbr-fat-1 gene from Caenorhabditis briggsae, encoding an n-3 fatty acid desaturase. Analysis of fatty acids demonstrated that the cbr-fat-1 transgenic pigs produced high levels of n-3 fatty acids from n-6 analogs; consequently, a significantly reduced ratio of n 6/n-3 fatty acids was observed. We demonstrated that the n-3 desaturase gene from C. briggsae was functionally expressed, and had a significant effect on the fatty acid composition of the transgenic pigs, which may allow the production of pork enriched in n-3 PUFAs. PMID- 24048770 TI - Dehydroepiandrosterone and metyrapone partially restore the adaptive humoral and cellular immune response in endotoxin immunosuppressed mice. AB - Prior exposure to endotoxins renders the host temporarily refractory to subsequent endotoxin challenge (endotoxin tolerance). Clinically, this state has also been pointed out as the initial cause of the non-specific humoral and cellular immunosuppression described in these patients. We recently demonstrated the restoration of immune response with mifepristone (RU486), a receptor antagonist of glucocorticoids. Here we report the treatment with other modulators of glucocorticoids, i.e. dehydroepiandrosterone (DHEA), a hormone with anti glucocorticoid properties, or metyrapone (MET) an inhibitor of corticosterone synthesis. These drugs were able to partially, but significantly, restore the humoral immune response in immunosuppressed mice. A significant recovery of proliferative responsiveness was also observed when splenocytes were obtained from DHEA- or MET-treated immunosuppressed mice. In addition, these treatments restored the hypersensitivity response in immunosuppressed mice. Finally, although neither DHEA nor MET improved the reduced CD4 lymphocyte count in spleen from immunosuppressed mice, both treatments promoted spleen architecture reorganization, partially restoring the distinct cellular components and their localization in the spleen. The results from this study indicate that DHEA and MET could play an important role in the restoration of both adaptive humoral and cellular immune response in LPS-immunosuppressed mice, reinforcing the concept of a central involvement of endogenous glucocorticoids on this phenomenon. PMID- 24048772 TI - Protease-activated receptor-2 deficient mice have reduced house dust mite-evoked allergic lung inflammation. AB - Protease-activated receptor-2 (PAR2) is abundantly expressed in the pulmonary compartment. House dust mite (HDM) is a common cause of allergic asthma and contains multiple PAR2 agonistic proteases. The aim of this study was to determine the role of PAR2 in HDM-induced allergic lung inflammation. For this, the extent of allergic lung inflammation was studied in wild type (Wt) and PAR2 knockout (KO) mice after repeated airway exposure to HDM. HDM exposure of Wt mice resulted in a profound influx of eosinophils in bronchoalveolar lavage fluid (BALF) and accumulation of eosinophils in lung tissue, which both were strongly reduced in PAR2 KO mice. PAR2 KO mice demonstrated attenuated lung pathology and protein leak in the bronchoalveolar space, accompanied by lower BALF levels of the anaphylatoxins C3a and C5a. This study reveals, for the first time, an important role for PAR2 in allergic lung inflammation induced by the clinically relevant allergens contained in HDM. PMID- 24048771 TI - MyD88 mediates the decision to die by apoptosis or necroptosis after UV irradiation. AB - UV irradiation-induced cellular damage is classically associated with apoptosis and is known to result in systemic immunosuppression. How the decision to undergo apoptosis is made following UV is not fully understood. We hypothesize that a central mediator of TLR signaling, MyD88, determines cell fate after UV exposure. Survival after UV of immortalized bone marrow-derived macrophages (BMDM) and ex vivo peritoneal macrophages (PM) from MyD88 germline-deficient mice (MyD88(-/-)) was significantly higher than wild type (WT) PM. UV-induced apoptosis (DNA laddering) in PM and epidermis of MyD88(-/-) animals versus WT was decreased. In MyD88(-/-) PM, decreased cleavage of caspase 3, as well as pro-necroptotic protein, RIP1, and a significant increase in transcription and release of pro inflammatory TNF-alpha, suggest that necroptosis, rather than apoptosis, has been initiated. In vivo studies confirm this hypothesis after UV, showing low apoptosis by TUNEL and inflammation in MyD88(-/-) skin sections. Considering that MyD88 participates in many TLR pathways, BMDM from TLR2(-/-), TLR4(-/-) and WT mice were compared for evidence of UV-induced apoptosis. Only TLR4(-/-) BMDM and PM had a similar phenotype to MyD88(-/-), suggesting that the TLR4-MyD88 axis importantly contributes to cell fate decision. Our study describes a new cellular consequence of MyD88 signaling after UV, and may provide rationale for therapies to mitigate UV-induced immunosuppression. PMID- 24048773 TI - N-Acetylcysteine effects on transforming growth factor-beta and tumor necrosis factor-alpha serum levels as pro-fibrotic and inflammatory biomarkers in patients following ST-segment elevation myocardial infarction. AB - BACKGROUND AND AIMS: Ischemia following acute myocardial infarction (AMI) increases the level of pro-fibrotic and inflammatory cytokines, including transforming growth factor (TGF)-beta and tumor necrosis factor (TNF)-alpha. N acetylcysteine (NAC) has therapeutic benefits in the management of patients with AMI. To the best of our knowledge, this is the first study that has evaluated the effect of NAC on TNF-alpha and TGF-beta levels in patients with AMI. METHODS: Following confirmation of AMI, 88 patients were randomly administered NAC 600 mg (Fluimucil((r)), Zambon, Ticino, Switzerland) or placebo orally twice daily for 3 days. For quantification of TGF-beta and TNF-alpha serum levels after 24 and 72 h of NAC or placebo administration, peripheral venous blood (10 mL) samples were collected at these time points. RESULTS: Comparisons between levels of TGF-beta and TNF-alpha after 24 and 72 h within the NAC or placebo groups revealed that there was not any significant difference except for TGF-beta levels in the placebo group, which increased significantly over time (p = 0.042). Significant relationships existed between patients' ejection fraction (p = 0.005) and TGF beta levels. CONCLUSIONS: Receiving NAC could prevent TGF-beta levels from increasing after 72 h as compared with not receiving NAC. As TGF-beta had strong correlations with the ejection fraction, its antagonism seems to be important in the prevention of remodeling. PMID- 24048774 TI - Sorafenib in combination with transarterial chemoembolization and radiofrequency ablation in the treatment for unresectable hepatocellular carcinoma. AB - The purpose of this study is to assess clinical efficacy and safety of sorafenib combined with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) on patients with unresectable hepatocellular carcinoma (HCC). Efficacy and safety profiles of sorafenib in combination with TACE and RFA were evaluated based on retrospective data for thirty patients with unresectable HCC. Patients were treated with TACE initially when admitted to hospital, followed by RFA 3 days after TACE. All TACE and RFA were performed by the same team of doctors. Seven days after the first TACE, patients started taking continuous sorafenib 400 mg bid without breaks until unacceptable toxicities or disease progression. The response to treatment, overall survival (OS), time to progression (TTP), and adverse effects were evaluated. The disease control rate was 33.3% by RECIST criteria. The median TTP was 15.3 months (95% CI 4.8-23.5). The median OS was 28.8 months (95% CI 12.8-39.6). At the time of data record, 13 patients (43.3%) were dead. Median OS in patients with or without portal vein thrombosis was 12.3 months (95% CI 7.6-14.5) and 30.2 months (95% CI 24.2-34.5), respectively, P = 0.018. The most common adverse events related to sorafenib were hand-foot skin reaction (53.3%) and diarrhea (33.3%). The combination of sorafenib, TACE, and RFA proved both safe and effective in the treatment for unresectable hepatocellular carcinoma patients. PMID- 24048775 TI - Physiological Awareness Is Negatively Related to Inhibitory Functioning in Tourette Syndrome. AB - In Tourette syndrome (TS), tics are characteristically preceded by subjective bodily experiences referred to as premonitory sensations. Premonitory sensory phenomena play a key role in behavior therapy for tics, the success of which has also been suggested to be related to inhibitory functioning. We investigated whether TS was associated with altered internal physiological awareness and how this may interact with the neuropsychological characteristics of TS. We compared the awareness of bodily sensations and inhibitory functioning in 18 adult patients with uncomplicated TS and 18 healthy controls. We also explored relationships between these factors, tic severity, and premonitory sensations. Patients with TS exhibited significantly higher scores on the Private Body Consciousness (PBC) scale and inhibitory deficits on traditional and emotional Stroop tests. PBC scores were not correlated with premonitory sensations or tic severity. However, inhibitory functioning was negatively related to PBC scores and premonitory sensations. Relationships between inhibitory performance and tic severity were complex. In conclusion, patients with TS exhibit increased PBC in addition to inhibitory deficits. Aspects of inhibitory functioning are related to PBC, premonitory sensations, and tic severity. Complex interplay between neuropsychological and neurophysiological mechanisms could therefore determine tic severity and the success of behavioral treatments. PMID- 24048777 TI - Chair of NCI scientific counselors board optimistic about research: NCI must continue to combine quality research with budget-cutting measures, he says. PMID- 24048776 TI - [Efficacy and safety of symphytum herb extract cream in the treatment of pressure ulcers]. AB - In an open, prospective use study, 161 patients with 198 decubitus ulcers (pressure ulcers, ITT population) in stages II and III were treated with the topical preparation symphytum herb extract cream. The bandages with the cream were changed every 2-3 days. The primary parameters evaluated were the area of the sore and the depth of the wound (planimetrically in mm). In all, 151 patients with a total of 184 pressure sores (PP population) were included and received treatment over a period of 4 weeks in order to evaluate the treatment results. Complete healing of the pressure sores within 4 weeks was observed in 85.9 % (PP population)/79.8 % (ITT population) of the treated ulcers. Over a treatment duration of 25-30 days, a 89.2 % reduction of the total decubitus area was observed. The same result was found for the depth of the pressure ulcer with a reduction of 88 %. The overall treatment success was from both the perspective of the physician and the patient considered successful in 90.4 % (5-point scale) of cases and 87.9% (100 mm VAS, PP population). Two cases of local irritation were observed after 25/30 days (1.2 % of the patients with exposure), thus showing very good skin compatibility. The efficacy of symphytum herb extract cream is surprisingly good in the treatment of pressure ulcers. PMID- 24048778 TI - Native American ancestry linked to greater risk of disease recurrence in young leukemia patients. PMID- 24048779 TI - Study shows link between dwarfism and cancer/diabetes protection. PMID- 24048780 TI - Gap narrows in African American smoking-related cancers, increases in breast and colorectal cancers. PMID- 24048781 TI - The epidermal growth factor receptor conundrum. PMID- 24048782 TI - Improving our understanding of male urethral cancer: an example of the strengths and limitations of the SEER cancer registry. PMID- 24048783 TI - Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma? AB - BACKGROUND: It is unclear whether delays in commencing adjuvant chemotherapy after surgical resection of colon adenocarcinoma adversely impact survival. METHODS: Patients with stage II-III colon adenocarcinoma who received adjuvant chemotherapy at 2 centers were identified through the institutional tumor registry. Time to adjuvant chemotherapy, overall survival (OS), and relapse-free survival (RFS) were calculated from the day of surgery. Patients were dichotomized into early (time to adjuvant chemotherapy <= 60 days) and late treatment (time to adjuvant chemotherapy >60 days) groups. OS and RFS were compared using log-rank test and multivariate analysis by the Cox proportional hazards model. RESULTS: Of 186 patients included in the study, 49 (26%) had received adjuvant chemotherapy >60 days after surgical resection. Thirty percent of the delays were system related (eg, late referrals, insurance authorizations). Time to adjuvant chemotherapy >60 days was associated with significantly worse OS in both univariate analysis and a Cox proportional hazards model (hazard ratio, 2.17; 95% confidence interval, 1.08-4.36). Although difference in RFS between the 2 groups favored time to adjuvant chemotherapy <60, this did not reach statistical significance. CONCLUSIONS: Adjuvant chemotherapy delay >60 days after surgical resection of colon cancer is associated with worse OS. PMID- 24048784 TI - Validation of the seventh edition of the American Joint Committee on Cancer TNM staging system for gastric cancer. AB - BACKGROUND: The seventh edition of the American Joint Committee on Cancer (AJCC) TNM classification for gastric cancer was published in 2010 and included major revisions. The aim of the current study was to evaluate the validity of the seventh edition TNM classification for gastric cancer based on an Asian population. METHODS: A total of 2916 gastric cancer patients who underwent R0 surgical resection from 1989 through 2008 in a single institute were included, and were analyzed according to the seventh edition of the TNM classification for validation. RESULTS: When adjusted using the seventh edition of the TNM classification, upstaging was observed in 771 patients (26.4%) and downstaging was observed in 178 patients (6.1%) compared with the sixth edition of the TNM classification. The relative risk (RR) of seventh edition pT classification was found to be increased with regular intensity compared with the sixth edition pT classification. The RR of seventh edition pN classification was found to be increased with irregular intensity compared with the sixth edition pN classification. In survival analysis, there were significant differences noted for each stage of disease, but only a marginal difference was demonstrated between stage IA and stage IB (P = .049). In the hybrid TNM classification, which combines the seventh edition pT classification and the sixth edition pN classification, both pT and pN classifications demonstrated a more ideal distribution of the RR, and 5-year survival rates also showed a significant difference for each stage (P <.01). CONCLUSIONS: The seventh edition of the TNM classification was considered valid based on the results of the current study. However, the hybrid TNM classification, comprised of a combination of the seventh edition pT classification and sixth edition pN classification, should be considered for the next edition. PMID- 24048785 TI - John Cunningham virus T-antigen expression in anal carcinoma. AB - BACKGROUND: Anal carcinoma is thought to be driven by human papillomavirus (HPV) infection through interrupting function of cell regulatory proteins such as p53 and pRb. John Cunningham virus (JCV) expresses a T-antigen that causes malignant transformation through development of aneuploidy and interaction with some of the same regulatory proteins as HPV. JCV T-antigen is present in brain, gastric, and colon malignancies, but has not been evaluated in anal cancers. The authors examined a cohort of anal cancers for JCV T-antigen and correlated this with clinicopathologic data. METHODS: Archived anal carcinomas were analyzed for JCV T antigen expression. DNA from tumor and normal tissue was sequenced for JCV with viral copies determined by quantitative polymerase chain reaction and Southern blotting. HPV and microsatellite instability (MSI) status was correlated with JCV T-antigen expression. RESULTS: Of 21 cases of anal cancer (mean age 49 years, 38% female), 12 (57%) were in human immunodeficiency virus (HIV)-positive individuals. All 21 cancers expressed JCV T-antigen, including 9 HPV-negative specimens. More JCV copies were present in cancer versus surrounding normal tissue (mean 32.54 copies/MUg DNA vs 2.98 copies/MUg DNA, P = .0267). There was no correlation between disease stage and viral copies, nor between viral copies and HIV-positive or -negative status (28.7 vs 36.34 copies/MUg DNA, respectively, P = .7804). In subset analysis, no association was found between JCV T-antigen expression and HPV or MSI status. CONCLUSIONS: Anal carcinomas uniformly express JCV T-antigen and contain more viral copies compared with surrounding normal tissue. JCV and its T-antigen oncogenic protein, presumably through interruption of cell regulatory proteins, may play a role in anal cancer pathogenesis. PMID- 24048787 TI - Metabolic factors and the risk of colorectal cancer in 580,000 men and women in the metabolic syndrome and cancer project (Me-Can). AB - BACKGROUND: The metabolic syndrome (MetS) has been related to an increased risk of colorectal cancer, but the modest size of previous studies precluded detailed characterization of the role of individual MetS factors and their interaction on risk. METHODS: In the Metabolic Syndrome and Cancer Project (Me-Can), data on body mass index (BMI), blood pressure, and blood levels of glucose, cholesterol, and triglycerides were available for 578,700 men and women. The mean age of participants at baseline was 44 years, and the mean follow-up was 12 years. Relative risks (RR) of colorectal cancer per 1 standard deviation increment in Z score of factors and for a combined MetS score, were calculated from Cox regression models, including adjustment for potential confounders. RESULTS: During follow-up, 2834 men and 1861 women were diagnosed with colorectal cancer. The RR of colorectal cancer for the MetS score was 1.25 (95% confidence interval [CI], 1.18-1.32) in men, and 1.14 (95% CI, 1.06-1.22) in women. Significant associations also were observed in men for BMI (RR, 1.07; 95% CI, 1.02-1.13), blood pressure (RR, 1.10; 95% CI, 1.02-1.18), and triglycerides (RR, 1.17; 95% CI, 1.06-1.28) and, in women, for BMI (RR, 1.08; 95% CI, 1.01-1.15). There was no significant positive interaction between the metabolic factors on risk. CONCLUSIONS: The combination of metabolic factors and some separate factors was related to an increased risk of colorectal cancer, but there was no interaction between metabolic factors. PMID- 24048786 TI - Induction of MUC5AC mucin by conjugated bile acids in the esophagus involves the phosphatidylinositol 3-kinase/protein kinase C/activator protein-1 pathway. AB - BACKGROUND: Bile reflux contributes to the development of esophageal injury and neoplasia. The mucin 5AC (MUC5AC) is absent in the normal squamous epithelium of the esophagus but is strongly expressed in Barrett esophagus (BE). The objective of this study was to determine whether and how bile acids influence the expression of MUC5AC in the esophagus. METHODS: MUC5AC expression was studied by immunohistochemistry and immunoblotting in human tissues, in tissues from a rat model of BE, and in SKGT-4 cultured esophageal epithelial cells. MUC5AC transcription was studied by real-time polymerase chain reaction and transient transfection assays. RESULTS: MUC5AC was absent from normal squamous epithelium but was present in 100% of Barrett specimens and in 61.5% of human esophageal adenocarcinoma tissues that were examined. MUC5AC protein expression was induced to a greater degree by conjugated bile acids than by unconjugated bile acids, and this occurred at the transcriptional level. In the rat reflux model, MUC5AC mucin was expressed abundantly in tissues of BE stimulated by duodenoesophageal reflux. Conjugated bile acids induced AKT phosphorylation in SKGT-4 cells but had no effect on extracellular signal-regulated protein kinases 1 and 2, c-Jun N terminal kinase, or protein-38 kinase phosphorylation. The phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002 and a dominant-negative protein kinase C (AKT) construct prevented the induction of MUC5AC by conjugated bile acids. Transactivation of AP-1 by conjugated bile acids coincided with MUC5AC induction, and cotransfection with a dominant-negative activator protein-1 (AP-1) vector decreased MUC5AC transcription and its induction. CONCLUSIONS: Conjugated bile acids in the bile refluxate contribute to MUC5AC induction in the esophagus. This occurs at the level of transcription and involves activation of the PI3K/AKT/AP-1 pathway. PMID- 24048788 TI - Epidermal growth factor down-regulates the expression of neutrophil gelatinase associated lipocalin (NGAL) through E-cadherin in pancreatic cancer cells. AB - BACKGROUND: The authors previously reported that neutrophil gelatinase-associated lipocalin (NGAL) overexpression significantly blocked invasion and angiogenesis of pancreatic ductal adenocarcinoma (PDAC). They also demonstrated a loss of NGAL expression in the advanced stages of PDAC. However, little is known regarding the mechanisms of NGAL regulation in PDAC. Because the epidermal growth factor (EGF) EGF receptor (EGFR) axis is up-regulated significantly in PDAC, they examined EGF mediated NGAL regulation in these cells. METHODS: The NGAL-positive cell lines AsPC-1 and BxPC-3 were used as a model system. Quantitative real-time polymerase chain reaction (RT-PCR), Western blot analysis, and immunofluorescence studies were used to investigate EGF-mediated effects on NGAL expression. E-cadherin expression was manipulated using lentiviral overexpression or small hairpin RNA constructs. NGAL promoter activity was assessed by luciferase-reporter assay and electrophoretic mobility shift assay. RESULTS: NGAL expression was positively associated with tumor differentiation and was down-regulated significantly after EGF treatment along with a concomitant reduction of E-cadherin expression in PDAC cells. E-cadherin down-regulation was partly through the EGFR-dependent mitogen activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) (MEK ERK) signaling pathway. In addition, E-cadherin down-regulation reduced NGAL expression in PDAC cells, whereas overexpression of E-cadherin led to increased NGAL expression and partly rescued the inhibition of NGAL expression by EGF. Furthermore, EGF, in part through E-cadherin, reduced NGAL promoter activity by blocking nuclear factor kappaB (NF-kappaB) activation. CONCLUSIONS: The current study demonstrated for the first time that EGF potently blocked NGAL expression in PDAC cells. This effect was mediated in part through activation of the EGFR MEK-ERK signaling pathway, which, in turn, down-regulated E-cadherin with a subsequent reduction in NF-kappaB activation. These findings illustrate a novel mechanism by which EGF regulates NGAL expression in PDAC. PMID- 24048790 TI - Prognostic factors in male urethral cancer. AB - BACKGROUND: Male urethral cancer is a rare neoplasm, with the published literature consisting of small single-institution retrospective series. As such, there is no objective analysis of prognostic factors and treatment outcome. The author sought to use the population-based Surveillance, Epidemiology, and End Results (SEER) database to evaluate prognostic factors in male urethral cancer. METHODS: From 1988 to 2006, 2065 men were identified in the SEER database as having primary urethral cancer. Median follow-up was 2.5 years. Cancer-specific and overall survival was computed using the Kaplan-Meier method, and Cox proportional hazards analysis was used to evaluate patient age at diagnosis, year of diagnosis, race, histologic type, grade, T stage, nodal status, M stage, extent of surgery, and type of radiation as potential significant independent predictors of survival. RESULTS: Overall survival at 5 and 10 years was 46.2% (95% confidence interval [CI], 43.9-48.6%) and 29.3% (95% CI, 26.6-32.0%), respectively, whereas cancer-specific survival at 5 and 10 years was 68.0% (95% CI, 65.5-70.5%) and 60.1% (95% CI, 57.0-63.2%), respectively. Advanced age, higher grade, higher T stage, systemic metastases, other histology versus transitional cell carcinoma (TCC), and no surgery versus radical resection were predictors of death and death from disease, whereas adenocarcinoma was associated with a lower likelihood of death and death from disease as compared with TCC. In addition, nodal metastasis was a predictor of death. Surgery had a better outcome than radiation for stage T2 -T4 nonmetastatic disease. CONCLUSIONS: Age, grade, TNM stage, histology, and extent of surgery were predictive of overall and cancer specific survival. PMID- 24048789 TI - Ixabepilone, mitoxantrone, and prednisone for metastatic castration-resistant prostate cancer after docetaxel-based therapy: a phase 2 study of the Department Of Defense Prostate Cancer Clinical Trials Consortium. AB - BACKGROUND: Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel refractory castration-resistant prostate cancer. Clinical noncross- resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination. METHODS: Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m(2) and mitoxantrone 12 mg/m(2) administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity. RESULTS: Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed >= 50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed >= 30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively. CONCLUSIONS: These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim. PMID- 24048791 TI - The role of technetium-99m methoxyisobutyl isonitrile scintigraphy in predicting the therapeutic effect of chemotherapy against nasopharyngeal carcinoma. AB - BACKGROUND: The authors prospectively evaluated the correlation between technetium-99m methoxyisobutyl isonitrile ((99m) Tc-MIBI) accumulation in tumors and response to induction chemotherapy in patients with nasopharyngeal carcinoma (NPC). METHODS: Eighty-six patients with locally advanced NPC underwent single photon emission computed tomography 15 minutes after an intravenous injection of 740 megabecquerels (20 mCi) (99m) Tc-MIBI before chemotherapy. The tumor uptake ratio (TUR) was calculated. Two weeks after the second cycle of combined chemotherapy with 5-fluorouracil (5-FU) and cisplatin (DDP), the tumor response rate was evaluated. The correlation between (99m) Tc-MIBI accumulation in tumors and response to chemotherapy with 5-FU/DDP was examined. RESULTS: Positive accumulation of (99m) Tc-MIBI in tumors was observed in 76 patients (88.4%). The tumor response was a complete response (CR) in 8 patients, a partial response (PR) in 68 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. The response rate (CR and PR) to 5-FU/DDP chemotherapy in patients who had positive (99m) Tc-MIBI accumulation (tumor uptake ratio [TUR] >1.1) was higher than that in patients who had negative (99m) Tc-MIBI accumulation (TUR <= 1.1; 98.7% vs 10%; P < .001). CONCLUSIONS: Patients with negative (99m) Tc-MIBI accumulation were resistant to 5-FU/DDP chemotherapy. (99m) Tc-MIBI imaging in patients with NPC was capable of predicting tumor response to chemotherapy with 5-FU/DDP and can help in the selection of patients for induction chemotherapy. PMID- 24048793 TI - A comparison of the efficacy and safety of oral and intravenous fludarabine in chronic lymphocytic leukemia in the LRF CLL4 trial. AB - BACKGROUND: An oral formulation of fludarabine was introduced for use in chronic lymphocytic leukemia in 2001 following studies demonstrating the bioequivalence of a 40 mg/m(2) oral dose with a 25 mg/m(2) intravenous dose. We assessed retrospectively the efficacy of these two routes of administration in the LRF CLL4 trial. METHODS: A total of 777 patients were randomized from 1999-2004 to receive fludarabine, alone or with cyclophosphamide, or chlorambucil. In 2001, a protocol amendment allowed the oral formulation. There were 117 assessable patients who received fludarabine intravenously and 252 who received it orally. A total of 387 patients given chlorambucil acted as a control group. RESULTS: Patients given oral fludarabine were less likely to receive the full dose (P = .0004) and experienced more, predominantly gastrointestinal, toxicity. Progression-free survival (PFS) and overall survival were not affected by the route of administration (PFS hazard ratio, 1.10; 95% confidence interval, 0.87 1.40), but the overall rate of response to treatment appeared to be lower with the oral formulation (P = .003). However, patients recruited since 2001 were older (P = .03) and were more likely to have TP53 deletion, and response rates after 2001 were also lower in the chlorambucil group. After excluding patients with TP53 deletion, no significant difference in outcome was attributable to the route of administration. CONCLUSIONS: Although the LRF CLL4 data suggest no important difference in the effectiveness of oral compared with intravenous fludarabine, randomized trials are needed to reliably evaluate this comparison, particularly in combination with rituximab. Meanwhile, it is important to monitor compliance and gastrointestinal side effects with the oral route and to switch to intravenous therapy if a reduced dose is being received. PMID- 24048792 TI - Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. AB - BACKGROUND: In vitro studies in mantle cell lymphoma (MCL) cell lines and patient derived cells have demonstrated synergistic apoptosis with combined rituximab and bortezomib (R-bortezomib) compared with single-agent bortezomib. Therefore, the authors of this report evaluated R-bortezomib in a preclinical model and in a phase 2 clinical trial. METHODS: A Hu-MCL-severe combined immunodeficiency (SCID) model engrafted with the Jeko cell line was treated with R-bortezomib, bortezomib, or rituximab. Twenty-five patients with relapsed follicular lymphoma (n = 11) and MCL (n = 14) received 375 mg/m(2) rituximab on Days 1 and 8 and 1.3 to 1.5 mg/m(2) bortezomib on Days 1, 4, 8, and 11 every 21 days for a median of 3 cycles (range, 1-5 cycles). RESULTS: R-bortezomib resulted in a statistically significant improvement in overall survival in Hu-MCL-SCID mice. In the clinical trial, the overall response rate was 40% in all 25 patients, 55% in patients with follicular lymphoma, and 29% in patients with MCL. The estimated 2-year progression-free survival (PFS) rate was 24% (95% confidence interval [CI], 10% 53%) in all patients and 60% (95% CI, 20%-85%) in responding patients. Thirteen patients (52%) developed grade 3 neurotoxicity, which consisted of constipation/ileus, sensory or motor neuropathy, or orthostatic hypotension. Patients who were heterozygous for the CD32a (Fcgamma receptor IIa) 131 histidine (H) to arginine (R) polymorphism had a significantly decreased PFS (P = .009) after R-bortezomib compared with HH and RR homozygotes. CONCLUSIONS: R-bortezomib had significant activity in patients with relapsed or refractory follicular lymphoma and MCL, although an unexpectedly high incidence of grade 3 neurologic toxicity was a potential limiting factor with this combination. PMID- 24048794 TI - Incidence of gastric involvement in patients with nongastrointestinal extranodal marginal zone lymphoma. AB - BACKGROUND: The current study was conducted to determine the incidence of gastric involvement in patients presenting with extranodal marginal zone lymphoma (MZL) outside the gastrointestinal (GI) tract and to identify clinical or laboratory parameters that predict gastric involvement in such cases. METHODS: The records of 121 consecutive patients who presented with non-GI extranodal MZL and had undergone esophagogastroduodenoscopy (EGD) as part of their initial workup were retrospectively reviewed. The authors assessed the presence of occult gastric MZL in these patients and possible associations with demographic characteristics; anatomic site of initial presentation; Helicobacter pylori (H. pylori) infection; Zubrod score; International Prognostic Index (IPI); B symptoms; and serum lactate dehydrogenase, hemoglobin, albumin, and beta2-microglobulin levels. RESULTS: The median age at diagnosis of non-GI MZL was 59 years. The most common primary tumor sites were the salivary/parotid gland (32 patients), ocular adnexa (26 patients), skin (19 patients), and lung (17 patients). Twenty-two patients (18%) were found to have gastric involvement on EGD. Using logistic regression analysis, factors found to be associated with gastric involvement included: high IPI score (odds ratio [OR], 3.70; P = .03), female sex (OR, 6.50; P = .02), serum beta2 microglobulin level of >= 2.5 mg/L (OR, 3.69; P = .02), and involvement of the aerodigestive mucosal/glandular tissue (OR, 4.50; P = .004). On multivariate logistic analysis, aerodigestive mucosal/glandular sites, H. pylori infection, and an elevated beta2-microglobulin level were found to be associated with gastric involvement. CONCLUSIONS: Routine EGD is recommended for patients with non-GI MZL, particularly those with primary aerodigestive mucosal/glandular tissue involvement or those with a high IPI, female sex, elevated serum beta2 microglobulin level, or H. pylori infection regardless of the primary tumor site. PMID- 24048795 TI - Translocation t(14;18)/IGH-BCL2 in gastrointestinal follicular lymphoma: correlation with clinicopathologic features in 48 patients. AB - BACKGROUND: Chromosomal translocation t(14;18)(q32;q21) involving the immunoglobulin heavy chain gene (IGH) and the BCL2 gene (t[14;18][q32;q21]/IGH BCL2) is present in 60% to 90% of nodal follicular lymphomas. To the authors' knowledge, the prevalence and clinical significance of this translocation have not been examined previously in gastrointestinal follicular lymphomas. METHODS: Clinicopathologic and molecular features were investigated in 48 patients who had gastrointestinal follicular lymphoma. The site of involvement was the duodenum in 54% of patients, the jejunum in 52%, the ileum in 52%, the stomach in 29%, and the colorectum in 15%. The presence of the t(14;18)/IGH-BCL2 translocation was detected by interphase fluorescence in situ hybridization. RESULTS: Treatment modalities included surgical resection (n = 16), rituximab plus chemotherapy (n = 13), rituximab alone (n = 6), antibiotics (n = 5), and watchful waiting (n = 8). Complete remission (CR) of lymphoma was achieved in 31 patients (65%). The overall survival and event-free survival rates after 5 years were 93% and 68%, respectively. The t(14;18)/IGH-BCL2 was detected in 39 patients (81%). The involvement of multiple sites (69% vs 0%), manifestation of the lymphomatous polyposis type (72% vs 22%), and histologic grade 1 or 2 tumors (92% vs 56%) were more frequent in the t(14;18)-positive group than in the negative group. In addition, the CR rate was lower in the t(14;18)-positive group than in the negative group (56% vs 100%; P = .0179), and a trend was observed toward poorer event-free survival in the positive group (P = .089). CONCLUSIONS: The t(14;18)/IGH-BCL2 chromosomal translocation occurred frequently in gastrointestinal follicular lymphomas. The current results indicated that this translocation may be a predictor of an adverse clinical course. PMID- 24048797 TI - Clinical and histologic factors associated with melanoma thickness in New Zealand Europeans, Maori, and Pacific peoples. AB - BACKGROUND: Thickness is the major prognostic indicator for patients with melanoma. In many countries, the incidence of thick melanoma has not decreased. To reduce mortality, knowledge of the characteristics associated with melanoma depth is needed. METHODS: To examine the relation between melanoma thickness and other factors in Europeans, Maori, and Pacific peoples, the authors analyzed the 14,802 melanoma registrations in New Zealand between 1996 and 2006. Notifications of invasive cutaneous melanoma from 1996 to 2006 were extracted from the New Zealand Cancer Registry. Ethnicity was categorized using the Statistics New Zealand prioritization algorithm. The geometric mean tumor thickness was calculated using log-transformed Breslow depth. Multivariate linear regression was used to examine the relation of predictor variables, their interactions, and melanoma thickness. RESULTS: Melanoma thickness increased by 1% per year from 1996 to 2006. Although melanoma is rare in Maori and Pacific peoples, after adjustment, melanoma thickness was significantly greater in those populations compared with Europeans. Among Europeans, melanoma thickness was associated significantly with age at diagnosis, year of registration, sex, histology subtype, and extent of disease at diagnosis. In Maori, thick melanomas were likely to be nodular and to have regional or lymph node spread. The most important determinant of melanoma thickness in Pacific peoples was body site. CONCLUSIONS: Differences in melanoma thickness among ethnic groups were not explained fully by tumor subtype, site, or extent of disease. The current results indicated that the thicker melanomas in darker skinned populations probably can be accounted for in part by more aggressive lesions. Research is needed to identify additional characteristics to explain ethnic variations in melanoma thickness. PMID- 24048796 TI - V-CLIP: Integrating plasma vascular endothelial growth factor into a new scoring system to stratify patients with advanced hepatocellular carcinoma for clinical trials. AB - BACKGROUND: Several staging systems have been proposed for hepatocellular carcinoma (HCC); however, none has incorporated circulating angiogenic biomarkers. The purpose of this study was to determine whether vascular endothelial growth factor (VEGF) could independently predict overall survival in patients with HCC, and whether adding VEGF level into the Cancer of the Liver Italian Program (CLIP) score could improve patient stratification and prediction of overall survival. METHODS: Between 2001 and 2008, baseline plasma VEGF levels were available from 288 patients, and multivariate Cox regression models and median survival (95% confidence intervals) were calculated. Recursive partitioning was used to determine the optimal cutpoint for VEGF, using 10 repeated training/validation samples, each using two-thirds of the data to determine the best cutpoint and the remaining one-third to validate it. Prognostic ability of CLIP and V-CLIP was compared using the concordence index. RESULTS: Plasma VEGF was a significant independent predictor of overall survival, with an optimal VEGF cutpoint of 450 pg/mL. After CLIP validation in our patients, we added VEGF to the CLIP score and found that the new V-CLIP score better separates patients into homogenous prognostic groups (P = .005). CONCLUSIONS: The assessment of baseline plasma VEGF levels increases the precision of the CLIP scoring system for predicting HCC prognosis, which may assist in equally randomizing patients with HCC in clinical trials. Prospective validation of the V-CLIP scoring system is warranted. PMID- 24048798 TI - Additive effect on survival of Raf kinase inhibitor protein and signal transducer and activator of transcription 3 in high-grade glioma. AB - BACKGROUND: Animal studies have shown cooperative contribution of the Ras/Raf/MAPK and PI3K/Akt/mTOR signaling pathways in glioblastoma formation. However, this joint action has not yet been confirmed in human studies. METHODS: The expression of Raf kinase inhibitory protein (RKIP) was examined in 159 patients with high-grade and low-grade gliomas and correlated with previously obtained data on the activation of signal transducer and activator of transcription 3 (STAT3), a downstream effector of the PI3K/Akt/mTOR signaling pathway. RESULTS: RKIP expression was associated with a longer overall survival in high-grade glioma cases without showing a direct or inverse correlation with tyrosine-705 phosphorylation of STAT3 (pSTAT3). Notably, RKIP-positive and pSTAT3 negative cases demarcate a patients group with exceptionally long survival, exceeding the prognostic impact of each single marker. CONCLUSIONS: The results of this study indicated that 1) RKIP expression correlates with tumor grade and is a marker for good prognosis in high-grade gliomas; 2) RKIP expression and lack of pSTAT3 have a cumulative prognostic impact; and 3) RKIP and pSTAT3 are likely to operate independently to influence survival. These findings represented the first human evidence of an additive effect of 2 distinct signaling pathways in high-grade glioma, suggesting that simultaneous inhibition of multiple pathways should be considered as a treatment strategy for these patients. PMID- 24048799 TI - Presentation, patterns of care, and survival in patients with brain metastases: what has changed in the last 20 years? AB - BACKGROUND: It is largely unknown to what extent new oncologic treatment options have improved survival of patients with brain metastasis in recent decades. Therefore, a multi-institutional time-staggered analysis was performed. METHODS: Two cohorts of 103 patients each were analyzed, one treated between 2005 and 2009 and the other between 1983 and 1989, ie, approximately 20 years earlier. Stratified analyses by prognostic groups were also performed (graded prognostic assessment [GPA] and Radiation Therapy Oncology Group recursive partitioning analysis [RTOG-RPA]). RESULTS: Patterns of care have changed significantly. Contemporary patients received focal treatments such as stereotactic radiosurgery and surgical resection far more frequently. Furthermore, systemic treatment was used more often in contemporary patients, both before and after diagnosis of brain metastasis. Improved survival was observed in the contemporary cohort (P = .03). The 1-year survival rate increased from 15% (95% confidence interval [CI], 7%-25%) to 34% (95% CI, 25%-44%). However, this improvement was largely driven by patients with favorable prognostic features. More than 40% of the patients still belong to unfavorable prognostic groups with limited median survival and little improvement. CONCLUSIONS: Contemporary patients were managed on a much more individualized basis, requiring multidisciplinary case discussion and thorough assessment of prognostic features. Progress has been made, but the overall outcome needs to be improved further. Avoiding overtreatment in patients with poor prognosis is as important as aggressive treatment in patients who might survive for several years. PMID- 24048800 TI - Variation in quality of care among older men with localized prostate cancer. AB - BACKGROUND: The objective of this study was to assess the racial and ethnic disparities in outcomes and their association with process-of-care measures for elderly Medicare recipients with localized prostate cancer. METHODS: The Surveillance, Epidemiology, and End Results-Medicare databases for the period from 1995 to 2003 were used to identify African-American men, non-Hispanic white men, and Hispanic men with localized prostate cancer, and data were obtained for the 1-year period before the diagnosis of prostate cancer and up to 8 years postdiagnosis. The short-term outcomes of interest were complications, emergency room visits, readmissions, and mortality; the long-term outcomes of interest were prostate cancer-specific mortality and all-cause mortality; and process-of-care measures of interest were treatment and time to treatment. Cox proportional hazards regression, logistic regression, and Poisson regression were used to study the racial and ethnic disparities in outcomes and their association with process-of-care measures. RESULTS: Compared with non-Hispanic white patients, African-American patients (Hazard ration [HR], 1.43; 95% confidence interval [CE], 1.19-1.86) and Hispanic patients (HR=1.39; 95% CI, 1.03-1.84) had greater hazard of long term prostate specific mortality. African-American patients also had greater odds of emergency room visits (odds ratio, 1.4; 95% CI, 1.2-1.7) and greater all-cause mortality (HR, 1.39; 95% CI, 1.3-1.5) compared with white patients. The time to treatment was longer for African-American patients and was indicative of a greater hazard of all-cause, long-term mortality. Hispanic patients who underwent surgery or received radiation had a greater hazard of long term prostate-specific mortality compared with white patients who received hormone therapy. CONCLUSIONS: Racial and ethnic disparities in outcomes were associated with process-of-care measures (the type and time to treatment). The current results indicated that there is an opportunity to reduce these disparities by addressing these process-of-care measures. PMID- 24048801 TI - Racial differences in the presentation and outcomes of diffuse large B-cell lymphoma in the United States. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is often cured with standard chemoimmunotherapy, but there is great heterogeneity in presentation and outcomes. METHODS: By using Surveillance, Epidemiology, and End Results (SEER) data from 13 registries across the United States, the authors examined differences in incidence and survival for DLBCL by race. International Classification of Diseases for Oncology, third edition histology codes 9678, 9679, 9680, and 9684 were used to identify cases. RESULTS: From 1992 to 2007, 38,522 cases of DLBCL were recorded in SEER. Sixty-five percent of black patients compared with 37% of white patients presented at age <= 60 years, 52% of blacks compared with 44% of whites presented with stage III/IV disease, and 31% of black versus 24% of white patients presented with B symptoms (all P < .001). Although survival improved by era of diagnosis for all races (log rank P < .001), 2-year relative survival rates were better for women than men (61% vs 58%, P < .001) and white than black patients (60% vs 50%, P < .001). Black race, male sex, age at diagnosis >60, advanced stage, and B symptoms at diagnosis were predictors of worse survival (P < .001). CONCLUSIONS: Black patients with DLBCL in the United States present at younger age, more advanced stage, and have inferior survival. Epidemiological studies that examine the biological variants of DLBCL in concert with race are needed to elucidate the etiology of these disparities. PMID- 24048802 TI - Tumor volume and patient weight as predictors of outcome in children with intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group. AB - BACKGROUND: The objectives of this study were to compare tumor volume and patient weight versus traditional factors of tumor size (greatest dimension) and patient age and to determine which parameters best discriminated outcome among pediatric patients with intermediate-risk rhabdomyosarcoma (RMS). METHODS: Complete information was available for 370 patients with nonmetastatic RMS who were enrolled in the Children's Oncology Group (COG) intermediate-risk study D9803 (1999-2005). The Kaplan-Meier method was used to estimate survival distributions. A recursive partitioning model was used to identify prognostic factors that were associated with event-free survival (EFS). Cox proportional hazards regression models were used to estimate the association between patient characteristics and the risk of failure or death. RESULTS: For all patients with intermediate-risk RMS, a recursive partitioning algorithm for EFS suggested that prognostic groups should be defined optimally by tumor volume (with a transition point at 20 cm(3) ), patient weight (with a transition point at 50 kg), and embryonal histology. Tumor volume and patient weight added significant outcome information to the standard prognostic factors, including greatest tumor dimension and patient age (P = .02). The ability to resect the tumor completely was not associated significantly with the size of the patient, and patient weight did not significantly modify the association between tumor volume and EFS after adjustment for standard risk factors (P = .2). CONCLUSIONS: The factors that had the strongest association with EFS were tumor volume, patient weight, and histology. On the basis of regression modeling, tumor volume and patient weight were superior predictors of outcome compared with greatest tumor dimension and patient age in children with intermediate-risk RMS. The current results indicated that the prognostic performance of tumor volume and patient weight should be assessed in an independent prospective study. PMID- 24048803 TI - Novel approach using antimicrobial catheters to improve the management of central line-associated bloodstream infections in cancer patients. AB - BACKGROUND: Central venous catheter (CVC) removal has often been recommended for the treatment of central line-associated bloodstream infections (CLABSIs). However, CVC removal is not always practical in patients with cancer, and changing CVCs with noncoated CVCs over guidewire may result in cross-infection of the new CVC. Therefore, the current matched retrospective cohort study was conducted to evaluate the effectiveness of exchanging infected CVCs for minocycline- and rifampin (MR)-coated CVCs in cancer patients with CLABSIs. METHODS: The authors identified all cancer patients with CLABSIs who had undergone either CVC exchange with MR-coated CVCs or CVC removal at the study institution. All patients were treated with appropriate systemic antibiotics. The exchange group was matched in a 1:2 ratio with the removal group by organism, underlying disease, and neutropenia. The demographics, clinical characteristics, and outcome were compared. Overall response was defined as the resolution of clinical signs and symptoms and eradication of bacteremia within 72 hours after CVC exchange or removal, without disease recurrence or infection-related death. RESULTS: A total of 120 cancer patients were included (40 in the exchange group and 80 in the removal group). Overall response rates were 95% in the exchange group and 76% in the removal group (P = .011). No disease recurrences or infection-related deaths occurred in the exchange group; 8 disease recurrences or deaths (11%) occurred in the removal group (P = .05). Patients in the exchange group also experienced lower rates of mechanical failure (3% vs 15%; P = .049). CONCLUSIONS: Exchanging CVCs for MR-coated CVCs in cancer patients with CLABSIs may improve the overall response rate and decrease the risk of mechanical failure, disease recurrence, and infection-related mortality. PMID- 24048804 TI - How does patient-clinician information engagement influence self-reported cancer related problems?: findings from a longitudinal analysis. AB - BACKGROUND: Past research has linked patient-physician communication with improved emotional, physical, and social health. One component of communication, patient-clinician information engagement (PCIE), predicts improved short-term patient-reported outcomes, such as treatment satisfaction, through perceptions of feeling informed. However, to the authors' knowledge, the relation between PCIE and longer term cancer-related problems has not been examined previously. The authors examined the influence of PCIE on self-reported problems associated with cancer diagnosis and treatment based on a longitudinal survey among a randomly selected sample from the 2005 Pennsylvania Cancer Registry. METHODS: In total, 1293 respondents were surveyed who were diagnosed with colorectal, breast, or prostate cancers during 2006 and 2007. The baseline response rate was 64%, and the retention rate was 65%. The authors predicted an index of cancer-related problems at 1-year follow-up with the baseline cancer-related problem index and PCIE, controlling for demographic and clinical factors using regression analyses. The mean age of participants was 65 years, approximately 50% were women, and 86% were white. RESULTS: Having more cancer-related problems and PCIE at baseline significantly predicted more cancer-related problems at follow-up. In addition, baseline cancer-related problems and PCIE interacted significantly (P = .01): PCIE was associated with more cancer-related problems at follow-up among participants who reported more symptoms rather than fewer symptoms at baseline. CONCLUSIONS: If respondents reported engaging more with their physicians at baseline, then they reported experiencing more cancer-related issues at follow up; this pattern was stronger among those who reported more baseline problems. The current results indicated that increased discussion of cancer information with physicians may maintain the salience of these problems in cancer survivors' minds over time. PMID- 24048805 TI - Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. PMID- 24048807 TI - Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. PMID- 24048809 TI - Provider X-ray exposure in the trauma bay: results of a radiation field analysis. AB - Radiation exposure during trauma care has increased in recent years. Radiation risk to providers during the care of injured patients is not well defined. We aimed to gather environmental exposure data from dosimeters placed at fixed points in the trauma bay to act as surrogates for personnel radiation exposure during trauma team activations. Forty-four (44) radiation dosimeters were placed throughout a single trauma bay in a university level 1 trauma center. We analyzed shallow (SDE) and deep dose equivalents (DDE) over 6 months. We measured distance from the radiation source for each dosimeter. Four controls were included. We recorded patient injury and X-ray data for each patient. During the study period, 417 patients were evaluated in the trauma bay under study. Mean ISS was 14.3 (range 0-75). A total of 2,107 plain X-rays were taken, with a mean of 5.1 X-rays per patient (range 0-32). Extremity films were most often performed, followed by chest and shoulder films. No measurable dose was identified with the dosimeter controls. The majority (27, 68 %) of dosimeters registered the lowest doses (<1 mSv DDE). Five dosimeters revealed doses between 1 and 2 mSv DDE. Four dosimeters registered over 2 mSv DDE, with a mean DDE of 3 mSv. Distances of less than 5 ft from the radiation source had the highest DDE dose. Maximum annual occupational DDE dose is conventionally 50 mSv. None of the dosimeters registered DDE doses over 4.31 mSv during the study period, supporting low radiation risk to providers in the trauma bay. PMID- 24048811 TI - Social cohesion and self-rated health: The moderating effect of neighborhood physical disorder. AB - Using data from the Los Angeles Family and Neighborhood Survey and its companion datasets, we examined how neighborhood disorder, perceived danger and both individually perceived and contextually measured neighborhood social cohesion are associated with self-rated health. Results indicate that neighborhood disorder is negatively associated with health and the relationship is explained by perceived cohesion and danger, which are both also significant predictors of health. Further, individually perceived cohesion emerges as a more important explanation of self-rated health than neighborhood-level social cohesion. Finally, neighborhood disorder and perceived cohesion interact to influence health, such that cohesion is especially beneficial when residents live in neighborhoods characterized by low to moderate disorder; once disorder is at high levels, cohesion no longer offers protection against poor health. We interpret our findings as they relate to prior research on neighborhoods, psychosocial processes, and health, and discuss their implications for intervention efforts that address disorder in urban communities. PMID- 24048810 TI - Solution NMR structure of CD1104B from pathogenic Clostridium difficile reveals a distinct alpha-helical architecture and provides first structural representative of protein domain family PF14203. AB - A high-quality structure of the 68-residue protein CD1104B from Clostridium difficile strain 630 exhibits a distinct all alpha-helical fold. The structure presented here is the first representative of bacterial protein domain family PF14203 (currently 180 members) of unknown function (DUF4319) and reveals that the side-chains of the only two strictly conserved residues (Glu 8 and Lys 48) form a salt bridge. Moreover, these two residues are located in the vicinity of the largest surface cleft which is predicted to contribute to a surface area involved in protein-protein interactions. This, along with its coding in transposon CTn4, suggests that CD1104B (and very likely all members of Pfam 14203) functions by interacting with other proteins required for the transfer of transposons between different bacterial species. PMID- 24048812 TI - The geography of citizen crime reporting. AB - Research has shown variable conceptualizations of neighborhood, often inconsistent with administrative boundaries. The present investigation seeks to quantify the geographic area encompassed by citizens' reporting of crime. Two Chicago violence prevention organizations gathered near real-time citizen reports of crime and other precursors of violence in a south side community. Over the course of 6 months, 48 community residents participated in a weekly telephone survey about incidents occurring in their community, including crime, incivilities, and disorder. For each incident reported in the study community, respondents were asked to specify its location, whether it was witnessed or heard about, and if it occurred within one block of their residence. Incident locations were geocoded and used to compute distance from residence. Incident reporting radii were calculated for all types of incidents. Calculated distances of events reported within a block revealed discrepancies between resident perceptions and geographic apportionments. On average, incident reports spanned just over a half mile geographic radius from respondents' residences. Reporting radii were greater for more violent incidents and shorter for incidents witnessed directly. There was no effect of age, gender, length of residence, or length of participation in the study on reporting radii. Descriptions of reporting radii and implications for crime prevention efforts and research are discussed. PMID- 24048814 TI - Reply to: 10.1007/s00464-013-3134-x: colonic architectural changes after the use of psychotropic drugs: looking at the egg while forgetting the hen? PMID- 24048813 TI - SinoSCORE: a logistically derived additive prediction model for post-coronary artery bypass grafting in-hospital mortality in a Chinese population. AB - This study aims to construct a logistically derived additive score for predicting in-hospital mortality risk in Chinese patients undergoing coronary artery bypass surgery (CABG). Data from 9839 consecutive CABG patients in 43 Chinese centers were collected between 2007 and 2008 from the Chinese Coronary Artery Bypass Grafting Registry. This database was randomly divided into developmental and validation subsets (9:1). The data in the developmental dataset were used to develop the model using logistic regression. Calibration and discrimination characteristics were assessed using the validation dataset. Thresholds were defined for each model to distinguish different risk groups. After excluding 275 patients with incomplete information, the overall mortality rate of the remaining 9564 patients was 2.5%. The SinoSCORE model was constructed based on 11 variables: age, preoperative NYHA stage III or IV, chronic renal failure, extracardiac arteriopathy, chronic obstructive pulmonary disease, preoperative atrial fibrillation or flutter (within 2 weeks), left ventricular ejection fraction, other elective surgery, combined valve procedures, preoperative critical state, and BMI. In the developmental dataset, calibration using a Hosmer Lemeshow (HL) test was at P = 0.44 and discrimination based on the area under the receiver operating characteristic curve (ROC) was 0.80. In the validation dataset, the HL test was at P = 0.34 and the area under the ROC (AUC) was 0.78. A logistically derived additive model for predicting in-hospital mortality among Chinese patients undergoing CABG was developed based on the most up-to-date multi center data from China. PMID- 24048815 TI - Colonic electrical stimulation for the treatment of slow-transit constipation: a preliminary pilot study. AB - BACKGROUND: Electrical stimulation of the gastrointestinal tract is an attractive concept. In this article we report on a procedure for electrical colonic pacing due to intramuscular electrode placement for slow-transit constipation and some preliminary results. METHODS: From January 2011 to December 2012, all consecutive patients affected by constipation and evaluated in our Pelvic Floor Center were prospectively assessed. Patients who underwent colonic electrical stimulation were evaluated for the present study. RESULTS: In the study period, 256 patients were evaluated for constipation; 58% were identified as having obstructed defecation syndrome, 27.3% with irritable bowel syndrome or mixed forms, 4% with pelvic floor dyssynergia, and 10.5% (27 patients) as having slow-transit constipation. After failure of all the maximal conventional therapies, two patients, candidates for colectomy, agreed to undergo colonic electrical stimulation before a resective treatment. Both patients were females, aged 34 and 29 years, and were suffering from severe constipation since childhood. The follow up was 19 and 6 months. The number of bowel movements per week increased from 0.3 to 3.5 in the first patient and from 0.5 to 2.5 in the second patient. Both patients no longer needed laxatives, enemas, or any other treatment. The hospital stay was 4 days, the mean operative time was 120 min, and no complications were reported. CONCLUSIONS: Colonic pacing seems to be feasible and shows positive results. Further studies are required with a larger number of patients and a longer follow-up period to confirm the role of this promising treatment for slow transit constipation. PMID- 24048816 TI - Endostapler or endoloops for securing the appendiceal stump in laparoscopic appendectomy: a retrospective cohort study. AB - BACKGROUND: Laparoscopic appendectomy is the treatment of choice for appendicitis provided sufficient laparoscopic expertise is available. The endostapler possibly provides an easier and safer closure of the appendiceal stump, but at greater expense. This study aimed to compare two strategies for closure of the appendiceal stump in a large retrospective cohort of patients. METHODS: This study reviewed patients who underwent laparoscopic appendectomy for acute appendicitis in three academic hospitals and two regional hospitals in The Netherlands during the period 1 January 2007 to 30 June 2011. The endostapler was routinely used in two hospitals and selectively used in the remaining three hospitals. Both strategies were compared for complications according to the Clavien-Dindo classification. RESULTS: A total of 1,036 patients were analyzed according to the strategy followed. The 571 patients in the first group were routinely treated with the endostapler. For the 465 patients in the second group, the intentional method of stump closure was with endoloops. The endostapler was used when indicated for 69 of these patients. The patient characteristics did not differ between the two groups. The groups also did not differ significantly in number of intra- and postoperative complications. In both groups, 4.3 % of the patients had complications classified as grade 3 or higher. There were no significant differences in the prevalence of intraabdominal abscesses (3.2 % vs. 4.3) or wound infections (0.4 and 1.5 %). In a multivariate analysis, the chosen strategy for stump closure was not a significant predictor for postoperative complications. CONCLUSION: Routine use of the endostapler showed no clinical advantages over the use of endoloops with selective endostapler closure. The latter strategy is preferable because it is more cost effective. PMID- 24048817 TI - A Buddhist perspective on industrial engineering and the design of work. AB - The modern way of life is highly dependent upon the production of goods by industrial organizations that are in turn dependent upon their workers for their ongoing operations. Even though more than a century has passed since the dawn of the industrial revolution, many dangerous aspects of work, both physical and mental, remain in the workplace today. Using Buddhist philosophical principles, this paper suggests that although many sources of the problem reside within the larger society, the industrial engineer is still a key factor in bettering work and providing a workplace suitable for their fellow workers. Drawing on these insights, we present a number of work design guidelines that industrial engineers who abide by Buddhist principles could practice to help overcome some of the many sufferings produced by modern work. PMID- 24048818 TI - Individual and organizational predictors of the ethicality of graduate students' responses to research integrity issues. AB - The development of effective means to enhance research integrity by universities requires baseline measures of individual, programmatic, and institutional factors known to contribute to ethical decision making and behavior. In the present study, master's thesis and Ph.D. students in the fields of biological, health and social sciences at a research extensive university completed a field appropriate measure of research ethical decision making and rated the seriousness of the research issue and importance for implementing the selection response. In addition they were asked to rate their perceptions of the institutional and departmental research climate and to complete a measure of utilitarian and formalistic predisposition. Female students were found to be more ethical in their decision making compared to male students. The research ethical decision measure was found to be related to participants' ethical predisposition and overall perception of organizational and departmental research climate; however, formalism was the only individual predictor to reach statistical significance and none of the individual subscales of the research climate measure were significantly correlated to ethicality. Participants' ratings of the seriousness of the issue were correlated with their ratings of the importance of carrying out their selected response but neither was significantly predictive of the ethicality of their responses. The implications of these findings for the development of more effective training programs and environments for graduate students in research ethics and integrity are discussed. PMID- 24048819 TI - Flow-related noise in patients with ventriculoperitoneal shunt using gravitational adjustable valves. AB - BACKGROUND: Noise disturbance arising from the valve is a rare event of ventriculoperitoneal shunts. We queried and investigated shunt patients for occurrence and evaluated the possible factors related to noise development. METHODS: Fifty ambulatory patients with implanted proGAV valve were investigated consecutively. Patients were asked for any noise arising from the shunt. In all cases, the valve was auscultated in sitting and upright position. The position of the gravitational unit (GU) was determined in respect to the Frankfurt horizontal plane (FHP) and in head reclination. Ten valves were perfused in vitro at different settings. One valve was opened for video documentation, and a frequency analysis of the noise was performed in nine valves. RESULTS: Eight percent (4/50) of the patients reported a noise arising from the valve only in upright position in combination with maximum head reclination, and immediately stopped when performing Vasalva's maneuver. In three out of four of these patients, the noise was also audible for the investigator (FS) with a prepared stethoscope. Patients complaining about a noise had a larger GU deviation from vertical during head reclination (median: -80 vs -43 degrees , p = 0.0007, t-test). A deviations threshold of less than -58.4 degrees excluding audible noise by a negative predictive value of 1 (95 % confidence interval [CI] 0.9 to 1.0). In an experimental setting, the noise came from vibrations of the ball in the cone of the adjustable unit and was restricted to a flow of at least 220 ml/h. The noise frequencies tended to be higher at higher opening pressures. CONCLUSIONS: Valve related noise development may occur in patients with proGAV valves. This event could be prevented during shunt placement by avoiding posterior tilt of the gravitational unit, especially in patients with a good cervical mobility. The noise might indicate transient peak flows and was not associated with clinical or radiological signs of overdrainage. PMID- 24048821 TI - Adjuvants that improve the ratio of antigen-specific effector to regulatory T cells enhance tumor immunity. AB - Antitumor immunity is strongly influenced by the balance of tumor antigen specific effector T cells (Teff) and regulatory T cells (Treg). However, the impact that vaccine adjuvants have in regulating the balance of antigen-specific T-cell populations is not well understood. We found that antigen-specific Tregs were induced following subcutaneous vaccination with either OVA or melanoma derived peptides, with a restricted expansion of Teffs. Addition of the adjuvants CpG-ODN or Poly(I:C) preferentially amplified Teffs over Tregs, dramatically increasing the antigen-specific Teff:Treg ratios and inducing polyfunctional effector cells. In contrast, two other adjuvants, imiquimod and Quil A saponin, favored an expansion of antigen-specific Tregs and failed to increase Teff:Treg ratios. Following therapeutic vaccination of tumor-bearing mice, high ratios of tumor-specific Teffs:Tregs in draining lymph nodes were associated with enhanced CD8(+) T-cell infiltration at the tumor site and a durable rejection of tumors. Vaccine formulations of peptide+CpG-ODN or Poly(I:C) induced selective production of proinflammatory type I cytokines early after vaccination. This environment promoted CD8(+) and CD4(+) Teff expansion over that of antigen-specific Tregs, tipping the Teff to Treg balance to favor effector cells. Our findings advance understanding of the influence of different adjuvants on T-cell populations, facilitating the rational design of more effective cancer vaccines. PMID- 24048820 TI - Taccalonolide binding to tubulin imparts microtubule stability and potent in vivo activity. AB - The taccalonolides are highly acetylated steroids that stabilize cellular microtubules and overcome multiple mechanisms of taxane resistance. Recently, two potent taccalonolides, AF and AJ, were identified that bind to tubulin directly and enhance microtubule polymerization. Extensive studies were conducted to characterize these new taccalonolides. AF and AJ caused aberrant mitotic spindles and bundling of interphase microtubules that differed from the effects of either paclitaxel or laulimalide. AJ also distinctly affected microtubule polymerization in that it enhanced the rate and extent of polymerization in the absence of any noticeable effect on microtubule nucleation. In addition, the resulting microtubules were found to be profoundly cold stable. These data, along with studies showing synergistic antiproliferative effects between AJ and either paclitaxel or laulimalide, suggest a distinct binding site. Direct binding studies demonstrated that AJ could not be displaced from microtubules by paclitaxel, laulimalide, or denaturing conditions, suggesting irreversible binding of AJ to microtubules. Mass spectrometry confirmed a covalent interaction of AJ with a peptide of beta-tubulin containing the cyclostreptin-binding sites. Importantly, AJ imparts strong inter-protofilament stability in a manner different from other microtubule stabilizers that covalently bind to tubulin, consistent with the distinct effects of the taccalonolides as compared with other stabilizers. AF was found to be a potent and effective antitumor agent that caused tumor regression in the MDA-MB-231 breast cancer xenograft model. The antitumor efficacy of some taccalonolides, which stabilize microtubules in a manner different from other microtubule stabilizers, provides the impetus to explore the therapeutic potential of this site. PMID- 24048822 TI - Effects of month of breeding on reproductive efficiency of Holstein cows and heifers inseminated with sex-sorted or conventional semen in a hot environment. AB - The main objective of this study was to assess the effect of month of breeding on reproduction performance of Holstein heifers and cows inseminated with sex-sorted or conventional semen in a hot environment. Pregnancy per artificial insemination (P/AI; 64,666 services over an 8-year period) both in heifers (n = 22,313) and cows (n = 42,353) from a large dairy herd in northern Mexico (26 degrees N) were evaluated with the GENMOD procedure of SAS, with respect to month of AI. Overall, P/AI with sex-sorted semen was greater (P < 0.01) in heifers (41.6 %) than cows (17.3 %). P/AI for cows serviced with conventional semen was 10 % points higher (P < 0.01) in January and December (31 vs. 21 %) than cows serviced with sex sorted semen. While there was no difference in P/AI between the sex-sorted sperm and conventional semen in cows inseminated in July (16 and 18 %, respectively), P/AI plummeted for both groups of cows during the summer and fall (more severe heat stress). P/AI was not different between heifers serviced with sex-sorted or conventional semen during the hottest months of the year (July to October). However, during the coldest month of the year (January and February), P/AI was 10 percentage points greater (P < 0.01) in heifers serviced with conventional than sex-sorted semen. It was concluded that in this hot climate cow and heifer fertility declined in the summer and fall when inseminated with conventional semen. However, the use of sex-sorted semen during summer and fall did not compromise the breeding success in heifers. Thus, this data suggest that sex sorted semen promotes some embryonic thermoprotective mechanism, which leads to a marginal summer and fall fertility depression with this type of semen in this particular hot environment. PMID- 24048823 TI - Adoption of milk cooling technology among smallholder dairy farmers in Kenya. AB - Factors influencing adoption of milk cooling technology were studied with data for 90 smallholder dairy farmers who were randomly selected from seven dairy cooperative societies in Kiambu County, Kenya. Logistic regression identified the age of the household head, daily household milk consumption, freehold land ownership, fodder production area, number of female calves, cooperative membership and cooperative services as significant factors influencing farmers' willingness to invest in milk cooling technology. These findings offer an entry point for increased interventions by policy makers and various dairy sector stakeholders in promoting milk cooling technology with the aim of significantly reducing post-harvest losses and increasing the sector's competitiveness. PMID- 24048824 TI - Performance of tropical dairy cows fed whole crop rice silage with varying levels of concentrate. AB - The objective of this experiment was to evaluate the effect of concentrate/milk yield ratios on feed intake, nutrient digestibility, rumen fermentation efficiency, and milk production in dairy cows fed with a basal diet of whole crop rice silage (WCRS). Sixteen crossbred cows (75 % Holstein-Friesian (HF) and 25 % Thai cows) in mid-lactation were assigned to four dietary treatments in a completely randomized design. Treatments corresponding to four concentrate/milk yield ratios (0, 1:1, 1:2, and 1:3 (kg/kg)) were used. All cows were offered WCRS (with 1.5 % urea and 3 % molasses) ad libitum. Silage and concentrate were fed individually twice a day. Results revealed that dry matter intake (12.8-14.5 kg/day), nutrient digestibility (62.5-68.7 %), and rumen fermentation efficiency were not significantly affected by concentrate supplementation. Milk yield (10.2 11.5 kg/day) and milk composition were similar between cows fed with sole WCRS and those supplemented with concentrate mixture, although milk fat tended to increase in cows fed with sole WCRS. In conclusion, sole WCRS fed to dairy cows without concentrate supplementation resulted in similar feed intake, nutrient digestibility, rumen fermentation, and milk production as compared to those supplemented with concentrate in lactating dairy cows. These results suggest that in tropical areas where rice crop is surplus, WCRS could sustain reasonable levels of milk production among dairy cows with little or no concentrate supplementation provided that urea and molasses are included in the silage. PMID- 24048825 TI - A prominent role for triheteromeric GluN1/GluN2A/GluN2B NMDARs at central synapses. PMID- 24048826 TI - One step closer to a functional vestibular prosthesis. PMID- 24048827 TI - The ability to move to a beat is linked to the consistency of neural responses to sound. AB - The ability to synchronize movement to a steady beat is a fundamental skill underlying musical performance and has been studied for decades as a model of sensorimotor synchronization. Nevertheless, little is known about the neural correlates of individual differences in the ability to synchronize to a beat. In particular, links between auditory-motor synchronization ability and characteristics of the brain's response to sound have not yet been explored. Given direct connections between the inferior colliculus (IC) and subcortical motor structures, we hypothesized that consistency of the neural response to sound within the IC is linked to the ability to tap consistently to a beat. Here, we show that adolescent humans who demonstrate less variability when tapping to a beat have auditory brainstem responses that are less variable as well. One of the sources of this enhanced consistency in subjects who can steadily tap to a beat may be decreased variability in the timing of the response, as these subjects also show greater between-trial phase-locking in the auditory brainstem response. Thus, musical training with a heavy emphasis on synchronization of movement to musical beats may improve auditory neural synchrony, potentially benefiting children with auditory-based language impairments characterized by excessively variable neural responses. PMID- 24048829 TI - Death receptor 6 regulates adult experience-dependent cortical plasticity. AB - Sensory experience alters cortical circuitry by parallel processes of axon outgrowth and pruning, but the mechanisms that control these rearrangements are poorly understood. Using in vivo 2-photon longitudinal imaging, we found a marked reduction in axonal pruning in somatosensory cortex of mice with a knock-out of the DR6 gene, which codes for Death Receptor 6. This effect was seen for both long-range horizontal excitatory connections and for the axons of inhibitory neurons. These results identify a new pathway governing axonal plasticity associated with experience-dependent changes in cortical maps. PMID- 24048828 TI - Circadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells. AB - Spatial variation in light intensity, called spatial contrast, comprises much of the visual information perceived by mammals, and the relative ability to detect contrast is referred to as contrast sensitivity (Purves et al., 2012). Recently, retinal dopamine D4 receptors (D4Rs) have been implicated in modulating contrast sensitivity (Jackson et al., 2012); however, the cellular and molecular mechanisms have not been elucidated. Our study demonstrates a circadian rhythm of contrast sensitivity that peaks during the daytime, and that its regulation involves interactions of D4Rs, the clock gene Npas2, and the clock-controlled gene adenylyl cyclase 1 (Adcy1) in a subset of retinal ganglion cells (RGCs). Targeted disruption of the gene encoding D4Rs reduces the amplitude of the contrast sensitivity rhythm by reducing daytime sensitivity and abolishes the rhythmic expression of Npas2 and Adcy1 mRNA in the ganglion cell layer (GCL) of the retina. Npas2(-/-) and Adcy1(-/-) mice show strikingly similar reductions in the contrast sensitivity rhythm to that in mice lacking D4Rs. Moreover, Adcy1 transcript rhythms were abolished in the GCL of Npas2(-/-) mice. Luciferase reporter assays demonstrated that the Adcy1 promoter is selectively activated by neuronal PAS-domain protein 2 (NPAS2)/BMAL1. Our results indicate that the contrast sensitivity rhythm is modulated by D4Rs via a signaling pathway that involves NPAS2-mediated circadian regulation of Adcy1. Hence, we have identified a circadian clock mechanism in a subset of RGCs that modulates an important aspect of retinal physiology and visual processing. PMID- 24048830 TI - The human cerebral cortex flattens during adolescence. AB - The human cerebral cortex appears to shrink during adolescence. To delineate the dynamic morphological changes involved in this process, 52 healthy male and female adolescents (11-17 years old) were neuroimaged twice using magnetic resonance imaging, approximately 2 years apart. Using a novel morphometric analysis procedure combining the FreeSurfer and BrainVisa image software suites, we quantified global and lobar change in cortical thickness, outer surface area, the gyrification index, the average Euclidean distance between opposing sides of the white matter surface (gyral white matter thickness), the convex ("exposed") part of the outer cortical surface (hull surface area), sulcal length, depth, and width. We found that the cortical surface flattens during adolescence. Flattening was strongest in the frontal and occipital cortices, in which significant sulcal widening and decreased sulcal depth co-occurred. Globally, sulcal widening was associated with cortical thinning and, for the frontal cortex, with loss of surface area. For the other cortical lobes, thinning was related to gyral white matter expansion. The overall flattening of the macrostructural three-dimensional architecture of the human cortex during adolescence thus involves changes in gray matter and effects of the maturation of white matter. PMID- 24048833 TI - Effects of cellular homeostatic intrinsic plasticity on dynamical and computational properties of biological recurrent neural networks. AB - Homeostatic intrinsic plasticity (HIP) is a ubiquitous cellular mechanism regulating neuronal activity, cardinal for the proper functioning of nervous systems. In invertebrates, HIP is critical for orchestrating stereotyped activity patterns. The functional impact of HIP remains more obscure in vertebrate networks, where higher order cognitive processes rely on complex neural dynamics. The hypothesis has emerged that HIP might control the complexity of activity dynamics in recurrent networks, with important computational consequences. However, conflicting results about the causal relationships between cellular HIP, network dynamics, and computational performance have arisen from machine-learning studies. Here, we assess how cellular HIP effects translate into collective dynamics and computational properties in biological recurrent networks. We develop a realistic multiscale model including a generic HIP rule regulating the neuronal threshold with actual molecular signaling pathways kinetics, Dale's principle, sparse connectivity, synaptic balance, and Hebbian synaptic plasticity (SP). Dynamic mean-field analysis and simulations unravel that HIP sets a working point at which inputs are transduced by large derivative ranges of the transfer function. This cellular mechanism ensures increased network dynamics complexity, robust balance with SP at the edge of chaos, and improved input separability. Although critically dependent upon balanced excitatory and inhibitory drives, these effects display striking robustness to changes in network architecture, learning rates, and input features. Thus, the mechanism we unveil might represent a ubiquitous cellular basis for complex dynamics in neural networks. Understanding this robustness is an important challenge to unraveling principles underlying self-organization around criticality in biological recurrent neural networks. PMID- 24048832 TI - Neuregulin-1 impairs the long-term depression of hippocampal inhibitory synapses by facilitating the degradation of endocannabinoid 2-AG. AB - Endocannabinoids play essential roles in synaptic plasticity; thus, their dysfunction often causes impairments in memory or cognition. However, it is not well understood whether deficits in the endocannabinoid system account for the cognitive symptoms of schizophrenia. Here, we show that endocannabinoid-mediated synaptic regulation is impaired by the prolonged elevation of neuregulin-1, the abnormality of which is a hallmark in many patients with schizophrenia. When rat hippocampal slices were chronically treated with neuregulin-1, the degradation of 2-arachidonoylglycerol (2-AG), one of the major endocannabinoids, was enhanced due to the increased expression of its degradative enzyme, monoacylglycerol lipase. As a result, the time course of depolarization-induced 2-AG signaling was shortened, and the magnitude of 2-AG-dependent long-term depression of inhibitory synapses was reduced. Our study reveals that an alteration in the signaling of 2 AG contributes to hippocampal synaptic dysfunction in a hyper-neuregulin-1 condition and thus provides novel insights into potential schizophrenic therapeutics that target the endocannabinoid system. PMID- 24048831 TI - Persistent sodium current drives conditional pacemaking in CA1 pyramidal neurons under muscarinic stimulation. AB - Hippocampal CA1 pyramidal neurons are normally quiescent but can fire spontaneously when stimulated by muscarinic agonists. In brain slice recordings from mouse CA1 pyramidal neurons, we examined the ionic basis of this activity using interleaved current-clamp and voltage-clamp experiments. Both in control and after muscarinic stimulation, the steady-state current-voltage curve was dominated by inward TTX-sensitive persistent sodium current (I(NaP)) that activated near -75 mV and increased steeply with depolarization. In control, total membrane current was net outward (hyperpolarizing) near -70 mV so that cells had a stable resting potential. Muscarinic stimulation activated a small nonselective cation current so that total membrane current near -70 mV shifted to become barely net inward (depolarizing). The small depolarization triggers regenerative activation of I(NaP), which then depolarizes the cell from -70 mV to spike threshold. We quantified the relative contributions of I(NaP), hyperpolarization-activated cation current (I(h)), and calcium current to pacemaking by using the cell's own firing as a voltage command along with specific blockers. TTX-sensitive sodium current was substantial throughout the entire interspike interval, increasing as the membrane potential approached threshold, while both Ih and calcium current were minimal. Thus, spontaneous activity is driven primarily by activation of I(NaP) in a positive feedback loop starting near -70 mV and providing increasing inward current to threshold. These results show that the pacemaking "engine" from I(NaP) is an inherent property of CA1 pyramidal neurons that can be engaged or disengaged by small shifts in net membrane current near -70 mV, as by muscarinic stimulation. PMID- 24048834 TI - Sound localization ability and glycinergic innervation of the superior olivary complex persist after genetic deletion of the medial nucleus of the trapezoid body. AB - The medial nucleus of the trapezoid body (MNTB) in the superior olivary complex (SOC) is an inhibitory hub considered critical for binaural sound localization. We show that genetic ablation of MNTB neurons in mice only subtly affects this ability by prolonging the minimum time required to detect shifts in sound location. Furthermore, glycinergic innervation of the SOC is maintained without an MNTB, consistent with the existence of parallel inhibitory inputs. These findings redefine the role of MNTB in sound localization and suggest that the inhibitory network is more complex than previously thought. PMID- 24048835 TI - Decrease in muscle contraction time complements neural maturation in the development of dynamic manipulation. AB - Developmental improvements in dynamic manipulation abilities are typically attributed to neural maturation, such as myelination of corticospinal pathways, neuronal pruning, and synaptogenesis. However the contributions from changes in the peripheral motor system are less well understood. Here we investigated whether there are developmental changes in muscle activation-contraction dynamics and whether these changes contribute to improvements in dynamic manipulation in humans. We compared pinch strength, dynamic manipulation ability, and contraction time of the first dorsal interosseous muscle in typically developing preadolescent, adolescent, and young adults. Both strength and dynamic manipulation ability increased with age (p < 0.0001 and p < 0.00001, respectively). Surprisingly, adults had a 33% lower muscle contraction time compared with preadolescents (p < 0.01), and contraction time showed a significant (p < 0.005) association with dynamic manipulation abilities. Whereas decreases in muscle contraction time during development have been reported in the animal literature, our finding, to our knowledge, is the first report of this phenomenon in humans and the first finding of its association with manipulation. Consequently, the changes in the muscle contractile properties could be an important complement to neural maturation in the development of dynamic manipulation. These findings have important implications for understanding central and peripheral contributors to deficits in manipulation in atypical development, such as in children with cerebral palsy. PMID- 24048836 TI - Human cortical theta during free exploration encodes space and predicts subsequent memory. AB - Spatial representations and walking speed in rodents are consistently related to the phase, frequency, and/or amplitude of theta rhythms in hippocampal local field potentials. However, neuropsychological studies in humans have emphasized the importance of parietal cortex for spatial navigation, and efforts to identify the electrophysiological signs of spatial navigation in humans have been stymied by the difficulty of recording during free exploration of complex environments. We resolved the recording problem and experimentally probed brain activity of human participants who were fully ambulant. On each of 2 d, electroencephalography was synchronized with head and body movement in 13 subjects freely navigating an extended virtual environment containing numerous unique objects. theta phase and amplitude recorded over parietal cortex were consistent when subjects walked through a particular spatial separation at widely separated times. This spatial displacement theta autocorrelation (STAcc) was quantified and found to be significant from 2 to 8 Hz within the environment. Similar autocorrelation analyses performed on an electrooculographic channel, used to measure eye movements, showed no significant spatial autocorrelations, ruling out eye movements as the source of STAcc. Strikingly, the strength of an individual's STAcc maps from day 1 significantly predicted object location recall success on day 2. theta was also significantly correlated with walking speed; however, this correlation appeared unrelated to STAcc and did not predict memory performance. This is the first demonstration of memory-related, spatial maps in humans generated during active spatial exploration. PMID- 24048837 TI - MEK1/2 inhibition suppresses tamoxifen toxicity on CNS glial progenitor cells. AB - It is increasingly apparent that treatment with a variety of anticancer agents often is associated with adverse neurological consequences. Clinical studies indicate that exposure even to tamoxifen (TMX), a putatively benign antihormonal agent widely used in breast cancer treatment, causes cognitive dysfunction and changes in CNS metabolism, hippocampal volume, and brain structure. We found that TMX is toxic for a variety of CNS cell populations in vitro and also increased cell death in the corpus callosum and reduced cell division in the mouse subventricular zone, the hippocampal dentate gyrus, and the corpus callosum. We further discovered that MEK1/2 inhibition selectively rescued primary glial progenitors from TMX toxicity in vitro while enhancing TMX effects on MCF7 luminal human breast cancer cells. In vivo, MEK1/2 inhibition prevented TMX induced cell death in systemically treated mice. Our results demonstrate unexpected cytotoxicity of this putatively benign antihormonal agent and offer a potential strategy for rescuing CNS cells from adverse effects of TMX. PMID- 24048838 TI - Synaptic input correlations leading to membrane potential decorrelation of spontaneous activity in cortex. AB - Correlations in the spiking activity of neurons have been found in many regions of the cortex under multiple experimental conditions and are postulated to have important consequences for neural population coding. While there is a large body of extracellular data reporting correlations of various strengths, the subthreshold events underlying the origin and magnitude of signal-independent correlations (called noise or spike count correlations) are unknown. Here we investigate, using intracellular recordings, how synaptic input correlations from shared presynaptic neurons translate into membrane potential and spike-output correlations. Using a pharmacologically activated thalamocortical slice preparation, we perform simultaneous recordings from pairs of layer IV neurons in the auditory cortex of mice and measure synaptic potentials/currents, membrane potentials, and spiking outputs. We calculate cross-correlations between excitatory and inhibitory inputs to investigate correlations emerging from the network. We furthermore evaluate membrane potential correlations near resting potential to study how excitation and inhibition combine and affect spike-output correlations. We demonstrate directly that excitation is correlated with inhibition thereby partially canceling each other and resulting in weak membrane potential and spiking correlations between neurons. Our data suggest that cortical networks are set up to partially cancel correlations emerging from the connections between neurons. This active decorrelation is achieved because excitation and inhibition closely track each other. Our results suggest that the numerous shared presynaptic inputs do not automatically lead to increased spiking correlations. PMID- 24048839 TI - Hair cell overexpression of Islet1 reduces age-related and noise-induced hearing loss. AB - Isl1 is a LIM-homeodomain transcription factor that is critical in the development and differentiation of multiple tissues. In the mouse inner ear, Isl1 is expressed in the prosensory region of otocyst, in young hair cells and supporting cells, and is no longer expressed in postnatal auditory hair cells. To evaluate how continuous Isl1 expression in postnatal hair cells affects hair cell development and cochlear function, we created a transgenic mouse model in which the Pou4f3 promoter drives Isl1 overexpression specifically in hair cells. Isl1 overexpressing hair cells develop normally, as seen by morphology and cochlear functions (auditory brainstem response and otoacoustic emissions). As the mice aged to 17 months, wild-type (WT) controls showed the progressive threshold elevation and outer hair cell loss characteristic of the age-related hearing loss (ARHL) in the background strain (C57BL/6J). In contrast, the Isl1 transgenic mice showed significantly less threshold elevation with survival of hair cells. Further, the Isl1 overexpression protected the ear from noise-induced hearing loss (NIHL): both ABR threshold shifts and hair cell death were significantly reduced when compared with WT littermates. Our model suggests a common mechanism underlying ARHL and NIHL, and provides evidence that hair cell-specific Isl1 expression can promote hair cell survival and therefore minimize the hearing impairment that normally occurs with aging and/or acoustic overexposure. PMID- 24048840 TI - Contribution of macrophages to enhanced regenerative capacity of dorsal root ganglia sensory neurons by conditioning injury. AB - Although the central branches of the dorsal root ganglion (DRG) sensory neurons do not spontaneously regenerate, a conditioning peripheral injury can promote their regeneration. A potential role of macrophages in axonal regeneration was proposed, but it has not been critically addressed whether macrophages play an essential role in the conditioning injury model. After sciatic nerve injury (SNI) in rats, the number of macrophages in DRGs gradually increased by day 7. The increase persisted up to 28 d and was accompanied by upregulation of inflammatory mediators, including oncomodulin. A macrophage deactivator, minocycline, reduced the macrophage number and expressions of the inflammatory mediators. Molecular signatures of conditioning effects were abrogated by minocycline, and enhanced regenerative capacity was substantially attenuated both in vitro and in vivo. Delayed minocycline infusion abrogated the SNI-induced long-lasting heightened neurite outgrowth potential, indicating a role for macrophages in the maintenance of regenerative capacity. Intraganglionic cAMP injection also resulted in an increase in macrophages, and minocycline abolished the cAMP effect on neurite outgrowth. However, conditioned media (CM) from macrophages treated with cAMP did not exhibit neurite growth-promoting activity. In contrast, CM from neuron macrophage cocultures treated with cAMP promoted neurite outgrowth greatly, highlighting a requirement for neuron-macrophage interactions for the induction of a proregenerative macrophage phenotype. The growth-promoting activity in the CM was profoundly attenuated by an oncomodulin neutralizing antibody. These results suggest that the neuron-macrophage interactions involved in eliciting a proregenerative phenotype in macrophages may be a novel target to induce long lasting regenerative processes after axonal injuries in the CNS. PMID- 24048841 TI - Enhanced excitability of thalamic sensory neurons and slow-wave EEG pattern after stimuli that induce spinal long-term potentiation. AB - Spinal nociceptive neurons are well known to undergo a process of long-term potentiation (LTP) following conditioning by high-frequency sciatic nerve stimulation (HFS) at intensities recruiting C-fibers. However, little if any information exists as to whether such HFS conditioning that produces spinal LTP affects sensory transmission at supraspinal levels. The present study explored this possibility. Conventional extracellular recording methods were used to examine the consequences of HFS versus sham HFS conditioning on individual wide dynamic range thalamic neurons located in the ventro-postero-lateral (VPL) nucleus in isoflurane-anesthetized rats. Following HFS, the ongoing firing rate and stimulus-evoked (brush, pinch, sciatic nerve) responses were markedly enhanced as were responses to juxtacellular, microiontophoretic applications of glutamate. These HFS-induced enhancements lasted throughout the recording period. Sham stimuli had no effect on VPL neuron excitability. Cortical electroencephalographic (EEG) wave activities were also measured around HFS in conjunction with VPL neuron recordings. The cortical EEG pattern under baseline conditions consisted of recurring short duration bursts of high-amplitude slow waves followed by longer periods of flat EEG. Following HFS, the EEG shifted to a continuous large-amplitude, slow-wave pattern within the 0.5-8.0 Hz bandwidth lasting throughout the recording period. Sham HFS did not alter EEG activity. Sciatic nerve conditioning at A-delta fiber strength, known to reverse spinal LTP, did not alter enhanced neuronal excitability or the EEG slow-wave pattern induced by HFS. These data support the concept that HFS conditioning of the sciatic nerve, which leads to spinal LTP, is associated with distinct, long lasting changes in the excitability of neurons comprising thalamocortical networks. PMID- 24048842 TI - A conserved pattern of differential expansion of cortical areas in simian primates. AB - The layout of areas in the cerebral cortex of different primates is quite similar, despite significant variations in brain size. However, it is clear that larger brains are not simply scaled up versions of smaller brains: some regions of the cortex are disproportionately large in larger species. It is currently debated whether these expanded areas arise through natural selection pressures for increased cognitive capacity or as a result of the application of a common developmental sequence on different scales. Here, we used computational methods to map and quantify the expansion of the cortex in simian primates of different sizes to investigate whether there is any common pattern of cortical expansion. Surface models of the marmoset, capuchin, and macaque monkey cortex were registered using the software package CARET and the spherical landmark vector difference algorithm. The registration was constrained by the location of identified homologous cortical areas. When comparing marmosets with both capuchins and macaques, we found a high degree of expansion in the temporal parietal junction, the ventrolateral prefrontal cortex, and the dorsal anterior cingulate cortex, all of which are high-level association areas typically involved in complex cognitive and behavioral functions. These expanded maps correlated well with previously published macaque to human registrations, suggesting that there is a general pattern of primate cortical scaling. PMID- 24048843 TI - Lateralized odor preference training in rat pups reveals an enhanced network response in anterior piriform cortex to olfactory input that parallels extended memory. AB - The present study examines synaptic plasticity in the anterior piriform cortex (aPC) using ex vivo slices from rat pups given lateralized odor preference training. In the early odor preference learning model, a brief 10 min training session yields 24 h memory, while four daily sessions yield 48 h memory. Odor preference memory can be lateralized through naris occlusion as the anterior commissure is not yet functional. AMPA receptor-mediated postsynaptic responses in the aPC to lateral olfactory tract input, shown to be enhanced at 24 h, are no longer enhanced 48 h after a single training session. Following four spaced lateralized trials, the AMPA receptor-mediated fEPSP is enhanced in the trained aPC at 48 h. Calcium imaging of aPC pyramidal cells within 48 h revealed decreased firing thresholds in the pyramidal cell network. Thus multiday odor preference training induced increased odor input responsiveness in previously weakly activated aPC cells. These results support the hypothesis that increased synaptic strength in olfactory input networks mediates odor preference memory. The increase in aPC network activation parallels behavioral memory. PMID- 24048844 TI - Dendrite complexity of sympathetic neurons is controlled during postnatal development by BMP signaling. AB - Dendrite development is controlled by the interplay of intrinsic and extrinsic signals affecting initiation, growth, and maintenance of complex dendrites. Bone morphogenetic proteins (BMPs) stimulate dendrite growth in cultures of sympathetic, cortical, and hippocampal neurons but it was unclear whether BMPs control dendrite morphology in vivo. Using a conditional knock-out strategy to eliminate Bmpr1a and Smad4 in immature noradrenergic sympathetic neurons we now show that dendrite length, complexity, and neuron cell body size are reduced in adult mice deficient of Bmpr1a. The combined deletion of Bmpr1a and Bmpr1b causes no further decrease in dendritic features. Sympathetic neurons devoid of Bmpr1a/1b display normal Smad1/5/8 phosphorylation, which suggests that Smad independent signaling paths are involved in dendritic growth control downstream of BMPR1A/B. Indeed, in the Smad4 conditional knock-out dendrite and cell body size are not affected and dendrite complexity and number are increased. Together, these results demonstrate an in vivo function for BMPs in the generation of mature sympathetic neuron dendrites. BMPR1 signaling controls dendrite complexity postnatally during the major dendritic growth period of sympathetic neurons. PMID- 24048846 TI - Responses to random dot motion reveal prevalence of pattern-motion selectivity in area MT. AB - How the visual system reconstructs global patterns of motion from components is an important issue in vision. Conventional studies using plaids have shown that approximately one-third of neurons in cortical area MT respond to one-dimensional (1D) components of a moving pattern (component cells), whereas another third responds to the global two-dimensional (2D) motion of a pattern (pattern cells). Conversely, studies using spots of light or random dots that contain multiple orientations have seldom reported directional tuning that is consistent with 1D motion preference. To bridge the gap between these studies, we recorded from isolated neurons in macaque area MT and measured tuning for velocity (direction and speed) using random dot stimuli. We used the "intersection of constraints" principle to classify our population into pattern-direction-selective (PDS) neurons and component-direction-selective (CDS) neurons. We found a larger proportion of PDS cells (68%) and a smaller proportion of CDS cells (8%) compared with prior studies using plaids. We further compared velocity tuning, measured using random dot stimuli, with direction tuning, measured using plaids. Although there was a correlation between the degree of preference for 2D over 1D motion of the two measurements, tuning seemed to prefer 2D motion using random dot stimuli. Modeling analyses suggest that integration across orientations contributes to the 2D motion preference of both dots and plaids, but opponent inhibition mainly contributes to the 2D motion preference of plaids. We conclude that MT neurons become more capable of identifying a particular 2D velocity when stimuli contain multiple orientations. PMID- 24048845 TI - Spatiotemporal properties of optic flow and vestibular tuning in the cerebellar nodulus and uvula. AB - Convergence of visual motion and vestibular information is essential for accurate spatial navigation. Such multisensory integration has been shown in cortex, e.g., the dorsal medial superior temporal (MSTd) and ventral intraparietal (VIP) areas, but not in the parieto-insular vestibular cortex (PIVC). Whether similar convergence occurs subcortically remains unknown. Many Purkinje cells in vermal lobules 10 (nodulus) and 9 (uvula) of the macaque cerebellum are tuned to vestibular translation stimuli, yet little is known about their visual motion responsiveness. Here we show the existence of translational optic flow-tuned Purkinje cells, found exclusively in the anterior part of the nodulus and ventral uvula, near the midline. Vestibular responses of Purkinje cells showed a remarkable similarity to those in MSTd (but not PIVC or VIP) neurons, in terms of both response latency and relative contributions of velocity, acceleration, and position components. In contrast, the spatiotemporal properties of optic flow responses differed from those in MSTd, and matched the vestibular properties of these neurons. Compared with MSTd, optic flow responses of Purkinje cells showed smaller velocity contributions and larger visual motion acceleration responses. The remarkable similarity between the nodulus/uvula and MSTd vestibular translation responsiveness suggests a functional coupling between the two areas for vestibular processing of self-motion information. PMID- 24048847 TI - Broadband cortical desynchronization underlies the human psychedelic state. AB - Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin--prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT2A receptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT2A receptor-mediated excitation of deep pyramidal cells. PMID- 24048848 TI - The memory-enhancing effects of hippocampal estrogen receptor activation involve metabotropic glutamate receptor signaling. AB - Our laboratory has demonstrated that 17beta-estradiol (E2) enhances hippocampal memory consolidation via rapid activation of multiple intracellular signaling cascades, including the ERK/MAPK cascade (Fernandez et al., 2008; Fan et al., 2010). However, the receptor mechanisms responsible for these effects of E2 remain unclear. In vitro, estrogen receptor alpha (ERalpha) signaling through metabotropic glutamate receptor 1a (mGluR1a) leads to ERK-dependent CREB phosphorylation (Boulware et al., 2005), suggesting that interactions between ERs and mGluR1a may be vital to the memory-enhancing effects of E2. As such, the present study tested the roles of classical estrogen receptors (ERalpha and ERbeta) and mGluR1a in mediating the effects of E2 on hippocampal memory consolidation. Dorsal hippocampal (DH) infusion of ERalpha (PPT) or ERbeta (DPN) agonists enhanced novel object recognition and object placement memory in ovariectomized female mice in an ERK-dependent manner, suggesting that these receptors influence memory by rapidly activating hippocampal cell signaling. Next, DH infusion of the mGluR1a antagonist LY367385 blocked the object and spatial memory facilitation induced by E2, PPT, and DPN, demonstrating that ER/mGluR1a signaling is critical for the memory-enhancing effects of E2. Finally, we show that ERalpha, ERbeta, mGluR1, and ERK all reside within specialized membrane microdomains of the DH, and that ERalpha and ERbeta physically interact with mGluR1, providing a means through which ERs may activate mGluRs and downstream signaling. Together, these findings provide the first in vivo evidence demonstrating that ER/mGluR signaling can mediate the beneficial effects of E2 on hippocampal memory consolidation. PMID- 24048849 TI - Transgene expression in target-defined neuron populations mediated by retrograde infection with adeno-associated viral vectors. AB - Tools enabling the manipulation of well defined neuronal subpopulations are critical for probing complex neuronal networks. Cre recombinase (Cre) mouse driver lines in combination with the Cre-dependent expression of proteins using viral vectors--in particular, recombinant adeno-associated viral vectors (rAAVs)- have emerged as a widely used platform for achieving transgene expression in specified neural populations. However, the ability of rAAVs to further specify neuronal subsets on the basis of their anatomical connectivity has been reported as limited or inconsistent. Here, we systematically tested a variety of widely used neurotropic rAAVs for their ability to mediate retrograde gene transduction in the mouse brain. We tested pseudotyped rAAVs of several common serotypes (rAAV 2/1, 2/5, and 2/9) as well as constructs both with and without Cre-dependent expression switches. Many of the rAAVs tested--in particular, though not exclusively, Cre-dependent vectors--showed a robust capacity for retrograde infection and transgene expression. Retrograde expression was successful over distances as large as 6 mm and in multiple neuron types, including olfactory projection neurons, neocortical pyramidal cells projecting to distinct targets, and corticofugal and modulatory projection neurons. Retrograde infection using transgenes such as ChR2 allowed for optical control or optically assisted electrophysiological identification of neurons defined genetically as well as by their projection target. These results establish a widely accessible tool for achieving combinatorial specificity and stable, long-term transgene expression to isolate precisely defined neuron populations in the intact animal. PMID- 24048851 TI - The role of GluA1 in ocular dominance plasticity in the mouse visual cortex. AB - Ocular dominance plasticity is a widely studied model of experience-dependent cortical plasticity. It has been shown that potentiation of open eye responses resulting from monocular deprivation relies on a homeostatic response to loss of input from the closed eye, but the mechanisms by which this occurs are not fully understood. The role of GluA1 in the homeostatic component of ocular dominance (OD) plasticity has not so far been tested. In this study, we tested the idea that the GluA1 subunit of the AMPA receptor is necessary for open eye potentiation. We found that open eye potentiation did not occur in GluA1 knock out (GluA1(-/-)) mice but did occur in wild-type littermates when monocular deprivation was imposed during the critical period. We also found that depression of the closed eye response that normally occurs in the monocular as well as binocular zone is delayed, but only in the monocular zone in GluA1(-/-) mice and only in a background strain we have previously shown lacks synaptic scaling (C57BL/6OlaHsd). In adult mice, we found that OD plasticity and facilitation of OD plasticity by prior monocular experience were both present in GluA1(-/-) mice, suggesting that the GluA1-dependent mechanisms only operate during the critical period. PMID- 24048850 TI - Large-scale, high-resolution neurophysiological maps underlying FMRI of macaque temporal lobe. AB - Maps obtained by functional magnetic resonance imaging (fMRI) are thought to reflect the underlying spatial layout of neural activity. However, previous studies have not been able to directly compare fMRI maps to high-resolution neurophysiological maps, particularly in higher level visual areas. Here, we used a novel stereo microfocal x-ray system to localize thousands of neural recordings across monkey inferior temporal cortex (IT), construct large-scale maps of neuronal object selectivity at subvoxel resolution, and compare those neurophysiology maps with fMRI maps from the same subjects. While neurophysiology maps contained reliable structure at the sub-millimeter scale, fMRI maps of object selectivity contained information at larger scales (>2.5 mm) and were only partly correlated with raw neurophysiology maps collected in the same subjects. However, spatial smoothing of neurophysiology maps more than doubled that correlation, while a variety of alternative transforms led to no significant improvement. Furthermore, raw spiking signals, once spatially smoothed, were as predictive of fMRI maps as local field potential signals. Thus, fMRI of the inferior temporal lobe reflects a spatially low-passed version of neurophysiology signals. These findings strongly validate the widespread use of fMRI for detecting large (>2.5 mm) neuronal domains of object selectivity but show that a complete understanding of even the most pure domains (e.g., faces vs nonface objects) requires investigation at fine scales that can currently only be obtained with invasive neurophysiological methods. PMID- 24048852 TI - Structural covariance of the default network in healthy and pathological aging. AB - Significant progress has been made uncovering functional brain networks, yet little is known about the corresponding structural covariance networks. The default network's functional architecture has been shown to change over the course of healthy and pathological aging. We examined cross-sectional and longitudinal datasets to reveal the structural covariance of the human default network across the adult lifespan and through the progression of Alzheimer's disease (AD). We used a novel approach to identify the structural covariance of the default network and derive individual participant scores that reflect the covariance pattern in each brain image. A seed-based multivariate analysis was conducted on structural images in the cross-sectional OASIS (N = 414) and longitudinal Alzheimer's Disease Neuroimaging Initiative (N = 434) datasets. We reproduced the distributed topology of the default network, based on a posterior cingulate cortex seed, consistent with prior reports of this intrinsic connectivity network. Structural covariance of the default network scores declined in healthy and pathological aging. Decline was greatest in the AD cohort and in those who progressed from mild cognitive impairment to AD. Structural covariance of the default network scores were positively associated with general cognitive status, reduced in APOEepsilon4 carriers versus noncarriers, and associated with CSF biomarkers of AD. These findings identify the structural covariance of the default network and characterize changes to the network's gray matter integrity across the lifespan and through the progression of AD. The findings provide evidence for the large-scale network model of neurodegenerative disease, in which neurodegeneration spreads through intrinsically connected brain networks in a disease specific manner. PMID- 24048853 TI - Role of a ubiquitously expressed receptor in the vertebrate olfactory system. AB - Odorant cues are recognized by receptors expressed on olfactory sensory neurons, the primary sensory neurons of the olfactory epithelium. Odorant receptors typically obey the "one receptor, one neuron" rule, in which the receptive field of the olfactory neuron is determined by the singular odorant receptor that it expresses. Odor-evoked receptor activity across the population of olfactory neurons is then interpreted by the brain to identify the molecular nature of the odorant stimulus. In the present study, we characterized the properties of a C family G-protein-coupled receptor that, unlike most other odorant receptors, is expressed in a large population of microvillous sensory neurons in the zebrafish olfactory epithelium and the mouse vomeronasal organ. We found that this receptor, OlfCc1 in zebrafish and its murine ortholog Vmn2r1, is a calcium dependent, low-sensitivity receptor specific for the hydrophobic amino acids isoleucine, leucine, and valine. Loss-of-function experiments in zebrafish embryos demonstrate that OlfCc1 is required for olfactory responses to a diverse mixture of polar, nonpolar, acidic, and basic amino acids. OlfCc1 was also found to promote localization of other OlfC receptor family members to the plasma membrane in heterologous cells. Together, these results suggest that the broadly expressed OlfCc1 is required for amino acid detection by the olfactory system and suggest that it plays a role in the function and/or intracellular trafficking of other olfactory and vomeronasal receptors with which it is coexpressed. PMID- 24048854 TI - Cyclooxygenase-1-dependent prostaglandins mediate susceptibility to systemic inflammation-induced acute cognitive dysfunction. AB - Systemic inflammatory events often precipitate acute cognitive dysfunction in elderly and demented populations. Delirium is a highly prevalent neuropsychiatric syndrome that is characterized by acute inattention and cognitive dysfunction, for which prior dementia is the major predisposing factor and systemic inflammation is a frequent trigger. Inflammatory mechanisms of delirium remain unclear. We have modeled aspects of delirium during dementia by exploiting progressive neurodegeneration in the ME7 mouse model of prion disease and by superimposing systemic inflammation induced by the bacterial endotoxin lipopolysaccharide (LPS). Here, we have used this model to demonstrate that the progression of underlying disease increases the incidence, severity, and duration of acute cognitive dysfunction. This increasing susceptibility is associated with increased CNS expression of cyclooxygenase (COX)-1 in microglia and perivascular macrophages. The COX-1-specific inhibitor SC-560 provided significant protection against LPS-induced cognitive deficits, and attenuated the disease-induced increase in hippocampal and thalamic prostaglandin E2, while the COX-2-specific inhibitor NS-398 was ineffective. SC-560 treatment did not alter levels of the proinflammatory cytokines interleukin (IL)-1beta, tumor necrosis factor-alpha, IL 6, or C-X-C chemokine ligand 1 in blood or brain, but systemic IL-1RA blocked LPS induced cognitive deficits, and systemic IL-1beta was sufficient to induce similar deficits in the absence of LPS. Furthermore, the well tolerated COX inhibitor ibuprofen was protective against IL-1beta-induced deficits. These data demonstrate that progressive microglial COX-1 expression and prostaglandin synthesis can underpin susceptibility to cognitive deficits, which can be triggered by systemic LPS-induced IL-1beta. These data contribute to our understanding of how systemic inflammation and ongoing neurodegeneration interact to induce cognitive dysfunction and episodes of delirium. PMID- 24048855 TI - Hippocampal hyperexcitability underlies enhanced fear memories in TgNTRK3, a panic disorder mouse model. AB - Panic attacks are a hallmark in panic disorder (PAND). During the panic attack, a strong association with the surrounding context is established suggesting that the hippocampus may be critically involved in the pathophysiology of PAND, given its role in contextual processing. We previously showed that variation in the expression of the neurotrophin tyrosine kinase receptor type 3 (NTRK3) in both PAND patients and a transgenic mouse model (TgNTRK3) may have a role in PAND pathophysiology. Our study examines hippocampal function and activation of the brain fear network in TgNTRK3 mice. TgNTRK3 mice showed increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala-hippocampus-medial prefrontal cortex fear circuit. Moreover, TgNTRK3 mice also showed an unbalanced excitation-to-inhibition ratio in the hippocampal cornu ammonis 3 (CA3)-CA1 subcircuit toward hyperexcitability. The resulting hippocampal hyperexcitability underlies the enhanced fear memories, as supported by the efficacy of tiagabine, a GABA reuptake inhibitor, to rescue fear response. The fearful phenotype appears to be the result of hippocampal hyperexcitability and aberrant fear circuit activation. We conclude that NTRK3 plays a role in PAND by regulating hippocampus-dependent fear memories. PMID- 24048856 TI - Persistent activity in prefrontal cortex during trace eyelid conditioning: dissociating responses that reflect cerebellar output from those that do not. AB - Persistent neural activity, responses that outlast the stimuli that evoke them, plays an important role in neural computations and possibly in processes, such as working memory. Recent studies suggest that trace eyelid conditioning, which involves a temporal gap between the conditioned and unconditioned stimuli (the trace interval), requires persistent neural activity in a region of medial prefrontal cortex (mPFC). This persistent activity, which could be conveyed to cerebellum via a pathway through pons, may engage the cerebellum and allow for the expression of conditioned responses. Given the substantial reciprocity observed among many brain regions, it is essential to demonstrate that persistent responses in mPFC neurons are not simply a reflection of cerebellar feedback to the forebrain, leaving open the possibility that such responses could serve as input to the cerebellum. This concern is highlighted by studies showing that hippocampal learning-related activity is abolished by cerebellar inactivation. We inactivated the cerebellum while recording single-unit activity from the mPFC of rabbits trained with a forebrain-dependent trace eyelid conditioning procedure. We report that, whereas the responses of cells that show an onset of increased spike activity during the trace interval were abolished by cerebellar inactivation, persistent responses that begin during the conditioned stimulus and persisted into the trace interval were unaffected. Therefore, conditioned stimulus-evoked persistent responses remain the strongest candidate input pattern to support the cerebellar expression of learned responses. PMID- 24048857 TI - Individual differences in frontal cortical thickness correlate with the d amphetamine-induced striatal dopamine response in humans. AB - The meso-striatal dopamine system influences responses to rewards and the motivation to seek them out. Marked individual differences in these responses are seen in laboratory animals, related in part to input from the prefrontal cortex. Here we measured the relation between cortical morphology and drug-induced striatal dopamine release in healthy young people. Participants were 24 (17 male, 7 female; age 23.0 +/- 6.2 years) stimulant drug-naive subjects who underwent PET [(11)C]raclopride scans with 0.3 mg/kg d-amphetamine orally and placebo, and an anatomical MRI scan for measuring cortical thickness. As expected, d-amphetamine produced significant reductions in [(11)C]raclopride binding potential in the striatum as a percentage of the value in the placebo condition. There was substantial individual variability in this response, which was correlated with cortical thickness in the frontal lobe as a whole. The association was strongest in the anterior part of the right lateral prefrontal cortex and bilateral supplementary motor area. A thicker cortex was correlated with a smaller dopamine response. Together, this work demonstrates in humans an association between cortical thickness and the striatal dopamine response to drugs of abuse. Although prefrontal regulation of striatal function has been well studied, it was unclear whether the thickness of the prefrontal cortex was an acceptable proxy to the function of that region. These results suggest it is. PMID- 24048858 TI - DDIT4/REDD1/RTP801 is a novel negative regulator of Schwann cell myelination. AB - Signals that promote myelination must be tightly modulated to adjust myelin thickness to the axonal diameter. In the peripheral nervous system, axonal neuregulin 1 type III promotes myelination by activating erbB2/B3 receptors and the PI3K/AKT/mTOR pathway in Schwann cells. Conversely, PTEN (phosphatase and tensin homolog on chromosome 10) dephosphorylates PtdIns(3,4,5)P3 and negatively regulates the AKT pathway and myelination. Recently, the DLG1/SAP97 scaffolding protein was described to interact with PTEN to enhance PIP3 dephosphorylation. Here we now report that nerves from mice with conditional inactivation of Dlg1 in Schwann cells display only a transient increase in myelin thickness during development, suggesting that DLG1 is a transient negative regulator of myelination. Instead, we identified DDIT4/RTP801/REDD1 as a sustained negative modulator of myelination. We show that DDIT4 is expressed in Schwann cells and its maximum expression level precedes the peak of AKT activation and of DLG1 activity in peripheral nerves. Moreover, loss of DDIT4 expression both in vitro and in vivo in Ddit4-null mice provokes sustained hypermyelination and enhanced mTORC1 activation, thus suggesting that this molecule is a novel negative regulator of PNS myelination. PMID- 24048859 TI - Leptin stimulates neuropeptide Y and cocaine amphetamine-regulated transcript coexpressing neuronal activity in the dorsomedial hypothalamus in diet-induced obese mice. AB - Neuropeptide Y (NPY) neurons in both the arcuate nucleus of the hypothalamus (ARH) and the dorsomedial hypothalamus (DMH) have been implicated in food intake and obesity. However, while ARH NPY is highly expressed in the lean animal, DMH NPY mRNA expression is observed only after diet-induced obesity (DIO). Furthermore, while ARH NPY neurons are inhibited by leptin, the effect of this adipokine on DMH NPY neurons is unknown. In this study we show that in contrast to the consistent expression in the ARH, DMH NPY mRNA expression was undetectable until after 10 weeks in mice fed a high-fat diet, and peaked at 20 weeks. Surprisingly, electrophysiological experiments demonstrated that leptin directly depolarized and increased the firing rate of DMH NPY neurons in DIO mice. To further differentiate the regulation of DMH and ARH NPY populations, fasting decreased expression of DMH NPY expression, while it increased ARH NPY expression. However, treatment with a leptin receptor antagonist failed to alter DMH NPY expression, indicating that leptin may not be the critical factor regulating mRNA expression. Importantly, we also demonstrated that DMH NPY neurons coexpress cocaine amphetamine-regulated transcript (CART); however, CART mRNA expression in the DMH peaked earlier in the progression of DIO. This study demonstrates novel and important findings. First, NPY and CART are coexpressed in the same neurons within the DMH, and second, leptin stimulates DMH NPY neurons. These studies suggest that during the progression of DIO, there is an unknown signal that drives the expression of the orexigenic NPY signal within the DMH, and that the chronic hyperleptinemia increases the activity of these NPY/CART neurons. PMID- 24048861 TI - Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for hypoxic preconditioning-mediated delayed cardioprotection. AB - It has been well demonstrated that hypoxic preconditioning (HPC) can attenuate hypoxia/reoxygenation (H/R)-induced oxidant stress and elicit delayed cardioprotection by upregulating the expression of multiple antioxidative enzymes such as heme oxygenase-1 (HO-1), manganese superoxide dismutase (MnSOD) and so on. However, the underlying mechanisms of HPC-induced upregulation of antioxidative enzymes are not fully understood. Nuclear factor erythroid 2 related factor 2 (Nrf2) is an essential transcription factor that regulates expression of several antioxidant genes via binding to the antioxidant response element (ARE) and plays a crucial role in cellular defence against oxidative stress. Here, we wondered whether activation of the Nrf2-ARE pathway is responsible for the induction of antioxidative enzymes by HPC and contributes to the delayed cardioprotection of HPC. Cellular model of HPC from rat heart-derived H9c2 cells was induced 24 h prior to H/R. The results showed that HPC efficiently attenuated H/R-induced viability loss and lactate dehydrogenase leakage. In addition, HPC increased nuclear translocation and ARE binding of Nrf2 during the late phase, upregulated the expression of antioxidative enzymes (HO-1 and MnSOD), inhibited H/R-induced oxidant stress. However, when Nrf2 was specifically knocked down by siRNA, the induction of antioxidative enzymes by HPC was completely abolished and, as a result, the inhibitory effect of HPC on H/R-induced oxidant stress was reversed, and the delayed cardioprotection induced by HPC was also abolished. These results suggest that HPC upregulates antioxidative enzymes through activating the Nrf2-ARE pathway and confers delayed cardioprotection against H/R-induced oxidative stress. PMID- 24048860 TI - Treatment of Niemann--pick type C disease by histone deacetylase inhibitors. AB - Niemann-Pick type C disease (NPC) is a devastating, recessive, inherited disorder that causes accumulation of cholesterol and other lipids in late endosomes and lysosomes. Mutations in 2 genes, NPC1 and NPC2, are responsible for the disease, which affects about 1 in 120,000 live births. About 95% of patients have mutations in NPC1, a large polytopic membrane protein that is normally found in late endosomes. More than 200 missense mutations in NPC1 have been found in NPC patients. The disease is progressive, typically leading to death before the age of 20 years, although some affected individuals live well into adulthood. The disease affects peripheral organs, including the liver, spleen, and lungs, but the most severe symptoms are associated with neurological disease. There are some palliative treatments that slow progression of NPC disease. Recently, it was found that histone deacetylase (HDAC) inhibitors that are effective against HDACs 1, 2, and 3 can reduce the cholesterol accumulation in fibroblasts derived from NPC patients with mutations in NPC1. One example is vorinostat. As vorinostat is a Food and Drug Administration-approved drug for treatment of cutaneous T-cell lymphoma, this opens up the possibility that HDAC inhibitors could be repurposed for treatment of this rare disease. The mechanism of action of the HDAC inhibitors requires further study, but these drugs increase the level of the NPC1 protein. This may be due to post-translational stabilization of the NPC1 protein, allowing it to be transported out of the endoplasmic reticulum. PMID- 24048862 TI - Pyrinomonas methylaliphatogenes gen. nov., sp. nov., a novel group 4 thermophilic member of the phylum Acidobacteria from geothermal soils. AB - An aerobic, thermophilic, moderately acidophilic non-spore-forming bacterium, strain K22(T), was isolated from geothermally heated soil at Mount Ngauruhoe, New Zealand. On the basis of 16S rRNA gene sequence similarity, K22(T) was shown to belong to subdivision 4 of the phylum Acidobacteria and to be most closely related to 'Candidatus Chloracidobacterium thermophilum' (86 %) and Blastocatella fastidiosa (86 %). Cells stained Gram-negative and were catalase and oxidase positive. The major fatty acids detected were iso-C15 : 0, iso-C17 : 0, iso-C19 : 0 and iso-C21 : 0 when standard lipid extraction protocols were employed. Analysis of the total cell lipid acid hydrolysate also detected membrane-spanning and ether lipids, which made up approximately 40 % of the total membrane composition. These lipids included dicarboxylic (iso-diabolic) acid and the glyceryl ether of alkyl analogues of iso-C15 : 0 and iso-diabolic acid. The G+C content of the genomic DNA was 59.6 mol% and the primary respiratory quinone was MK-8. Strain K22(T) grew at 50-69 degrees C with an optimum temperature of 65 degrees C and at pH 4.1-7.8 with an optimum growth pH of 6.5. NaCl tolerance was up to 1 % (w/v). Cells displayed a chemoheterotrophic and obligately aerobic metabolism. Cells grew on nutrient broth, alginate, arabinose, Casamino acids, glucose, lactate, formate, mannose, sodium alginate, peptone, sucrose, tryptone, xanthan, xylan, xylose and yeast extract. Nitrogen sources included nitrate, ammonium, urea, yeast extract and Casamino acids, but not dinitrogen gas. The distinct phylogenetic position and the phenotypic characteristics separate strain K22(T) from all other members of the class Acidobacteria and indicate that it represents a novel species and genus, for which the name Pyrinomonas methylaliphatogenes gen. nov., sp. nov. is proposed. The type strain of the type species is K22(T) ( = DSM 25857(T) = ICMP 18710(T)). PMID- 24048863 TI - Nocardiopsis fildesensis sp. nov., an actinomycete isolated from soil. AB - A filamentous actinomycete strain, designated GW9-2(T), was isolated from a soil sample collected from the Fildes Peninsula, King George Island, West Antarctica. The strain was identified using a polyphasic taxonomic approach. The strain grew slowly on most media tested, producing small amounts of aerial mycelia and no diffusible pigments on most media tested. The strain grew in the presence of 0-12 % (w/v) NaCl (optimum, 2-4 %), at pH 9.0-11.0 (optimum, pH 9.0) and 10-37 degrees C (optimum, 28 degrees C). The isolate contained meso-diaminopimelic acid, no diagnostic sugars and MK-9(H4) as the predominant menaquinone. The major phospholipids were phosphatidylglycerol, phosphatidylcholine and phosphatidylmethylethanolamine. The major fatty acids were iso-C16 : 0, anteiso C17 : 0, C18 : 1omega9c, iso-C15 : 0 and iso-C17 : 0. DNA-DNA relatedness was 37.6 % with Nocardiopsis lucentensis DSM 44048(T), the nearest phylogenetic relative (97.93 % 16S rRNA gene sequence similarity). On the basis of the results of a polyphasic study, a novel species, Nocardiopsis fildesensis sp. nov., is proposed. The type strain is GW9-2(T) ( = CGMCC 4.7023(T) = DSM 45699(T) = NRRL B 24873(T)). PMID- 24048864 TI - Taxonomic study of the genus Tepidiphilus: transfer of Petrobacter succinatimandens to the genus Tepidiphilus as Tepidiphilus succinatimandens comb. nov., emended description of the genus Tepidiphilus and description of Tepidiphilus thermophilus sp. nov., isolated from a terrestrial hot spring. AB - Comparative phenotypic, chemotaxonomic and genetic analysis revealed significant similarities among strains of the genera Tepidiphilus and Petrobacter. Analysis of 16S rRNA gene sequences and DNA-DNA relatedness of the type strains Tepidiphilus margaritifer N2-214(T) and Petrobacter succinatimandens 4BON(T) showed sequence similarity of 98.9 % and less than 40 % relatedness, indicating that these strains represent different species of same genus. Both strains had phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and diphosphatidylglycerol as major polar lipids. Their fatty acid profiles were almost identical, with the predominant fatty acids C16 : 0, C17 : 0 cyclo and C19 : 0 cyclo omega8c. In view of this, we propose to transfer the member of the genus Petrobacter to the genus Tepidiphilus as Tepidiphilus succinatimandens comb. nov. and to emend the description of the genus Tepidiphilus. Further, a novel bacterium, strain JHK30(T), was isolated from a terrestrial hot spring located at Jharkhand, India, and was identified following a polyphasic approach. Cells were non-sporulating, aerobic, Gram-stain-negative rods and motile by a single polar flagellum. Optimum temperature for growth was 50-55 degrees C at pH 6.5-7.0. 16S rRNA gene sequence analysis revealed 99.71 % similarity with P. succinatimandens 4BON(T) ( = DSM 15512(T)) and 98.71 % with T. margaritifer N2 214(T) ( = DSM 15129(T)). However, DNA-DNA relatedness of strain JHK30(T) with these two type strains was well below 70 %. The DNA G+C base composition was 66.1 mol%. Strain JHK30(T) represents a novel species of the genus Tepidiphilus for which the name Tepidiphilus thermophilus sp. nov. is proposed. The type strain is JHK30(T) ( = JCM 19170(T) = LMG 27587(T)= DSM 27220(T)). PMID- 24048865 TI - Halosimplex pelagicum sp. nov. and Halosimplex rubrum sp. nov., isolated from salted brown alga Laminaria, and emended description of the genus Halosimplex. AB - Two halophilic archaeal strains, R2(T) and R27(T), were isolated from the brown alga Laminaria produced at Dalian, Liaoning Province, China. Both had pleomorphic cells that lysed in distilled water, stained Gram-negative and formed red pigmented colonies. They grew optimally at 42 degrees C, pH 7.0 and in the presence of 3.1-3.4 M NaCl and 0.03-0.5 M Mg(2+). The major polar lipids of the two strains were phosphatidylglycerol (PG), phosphatidylglycerol phosphate methyl ester (PGP-Me) and four major glycolipids chromatographically identical to those of Halosimplex carlsbadense JCM 11222(T). 16S rRNA gene analysis revealed that each strain had two dissimilar 16S rRNA genes and both strains were phylogenetically related to Halosimplex carlsbadense JCM 11222(T) (92.7-98.8 % similarities). The rpoB' gene similarities between strains R2(T) and R27(T) and between these strains and Halosimplex carlsbadense JCM 11222(T) were 95.7 %, 96.1 % and 95.8 %, respectively. The DNA G+C contents of strains R2(T) and R27(T) were 62.5 mol% and 64.0 mol%, respectively. The DNA-DNA hybridization values between strains R2(T) and R27(T) and between the two strains and Halosimplex carlsbadense JCM 11222(T) were 43 %, 52 % and 47 %, respectively. It was concluded that strain R2(T) ( = CGMCC 1.10586(T) = JCM 17263(T)) and strain R27(T) ( = CGMCC 1.10591(T) = JCM 17268(T)) represent two novel species of the genus Halosimplex, for which the names Halosimplex pelagicum sp. nov. and Halosimplex rubrum sp. nov. are proposed. An emended description of the genus Halosimplex is also presented. PMID- 24048866 TI - Thermoactinomyces daqus sp. nov., a thermophilic bacterium isolated from high temperature Daqu. AB - Daqu is a fermentation starter used in the production of Chinese liquors. A thermophilic bacterium, designated strain H-18(T), was isolated from a high temperature Daqu sample collected from the manufacturing process of a sesame flavoured liquor in Shandong province, China. It was investigated in a taxonomic study using a polyphasic approach. Strain H-18(T) formed white aerial mycelium and greyish-yellow substrate mycelium, bearing single endospores on aerial and substrate hyphae or on unbranched short sporophores. The cell-wall peptidoglycan contained meso-diaminopimelic acid. The major fatty acids were iso-C15 : 0 and iso-C17 : 0. The predominant menaquinone was MK-7. These chemotaxonomic properties are similar to those of members of the genus Thermoactinomyces. The G+C content of the genomic DNA was 49.1 mol%. 16S rRNA gene sequence comparisons indicated that strain H-18(T) was most closely related to Thermoactinomyces vulgaris KCTC 9076(T) (96.42 % similarity), Thermoactinomyces intermedius KCTC 9646(T) (96.06 %), Laceyella putida KCTC 3666(T) (96.32 %) and Laceyella sacchari KCTC 9790(T) (95.55 %). Strain H-18(T) showed low DNA-DNA relatedness (40.8, 33.4, 20.0 and 14.4 %) with the above strains. Based on morphological and chemotaxonomic characteristics, DNA-DNA hybridization data and physiological properties, strain H-18(T) represents a novel species of the genus Thermoactinomyces, for which the name Thermoactinomyces daqus sp. nov. is proposed. The type strain is H-18(T) ( = DSM 45914(T) = CICC 10681(T)). PMID- 24048867 TI - Methanospirillum stamsii sp. nov., a psychrotolerant, hydrogenotrophic, methanogenic archaeon isolated from an anaerobic expanded granular sludge bed bioreactor operated at low temperature. AB - A psychrotolerant hydrogenotrophic methanogen, strain Pt1, was isolated from a syntrophic propionate-oxidizing methanogenic consortium obtained from granulated biomass of a two-stage low-temperature (3-8 degrees C) anaerobic expanded granular sludge bed (EGSB) bioreactor, fed with a mixture of volatile fatty acids (VFAs) (acetate, propionate and butyrate). The strain was strictly anaerobic, and cells were curved rods, 0.4-0.5*7.5-25 um, that sometimes formed wavy filaments from 25 to several hundred micrometres in length. Cells stained Gram-negative and were non-sporulating. They were gently motile by means of tufted flagella. The strain grew at 5-37 degrees C (optimum at 20-30 degrees C), at pH 6.0-10 (optimum 7.0-7.5) and with 0-0.3 M NaCl (optimum 0 M NaCl). Growth and methane production was found with H2/CO2 and very weak growth with formate. Acetate and yeast extract stimulated growth, but were not essential. The G+C content of the DNA of strain Pt1 was 40 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain Pt1 was a member of the genus Methanospirillum and showed 97.5 % sequence similarity to Methanospirillum hungatei JF1(T) and 94 % sequence similarity to Methanospirillum lacunae Ki8-1(T). DNA-DNA hybridization of strain Pt1 with Methanospirillum hungatei JF1(T) revealed 39 % relatedness. On the basis of its phenotypic characteristics and phylogenetic position, strain Pt1 is a representative of a novel species of the genus Methanospirillum, for which the name Methanospirillum stamsii sp. nov. is proposed. The type strain is Pt1(T) ( = DSM 26304(T) = VKM B-2808(T)). PMID- 24048868 TI - Aquibacter zeaxanthinifaciens gen. nov., sp. nov., a zeaxanthin-producing bacterium of the family Flavobacteriaceae isolated from surface seawater, and emended descriptions of the genera Aestuariibaculum and Gaetbulibacter. AB - A Gram-stain-negative, strictly aerobic, rod-shaped, non-flagellated, non-spore forming and gliding marine bacterium, designated strain CC-AMZ-304(T), was isolated from coastal surface seawater near Taichung harbour, Taiwan. Strain CC AMZ-304(T) predominantly synthesized zeaxanthin and thus formed yellow colonies on marine agar. The novel strain showed an unstable phylogenetic position, although sharing high pairwise 16S rRNA gene sequence similarities of 95.9-94.9, 95.7 and 95.1-93.9 % with Gaetbulibacter species (n = 4), Aestuariibaculum suncheonense SC17(T) and Bizionia species (n = 7), respectively. The polar lipid profile of strain CC-AMZ-304(T) consisted of phosphatidylethanolamine, five unidentified lipids, one unidentified phospholipid, two unidentified aminolipids and one unidentified glycolipid. The major (>5 % of the total) fatty acids were iso-C15 : 0, iso-C15 : 1 G, iso-C17 : 0 3-OH, iso-C15 : 0 3-OH and C15 : 1omega5c. The DNA G+C content was 36.0 mol%. Menaquinone-6 (MK-6) was the sole respiratory quinone and the major polyamine was triamine sym-homospermidine. Phylogenetic distinctiveness, unique polar lipid composition, presence of significant amounts of branched hydroxyl fatty acids (iso-C17 : 0 3-OH and iso C15 : 0 3-OH) and a low amount of anteiso-C15 : 0, and several additional distinguishing biochemical features clearly discriminated strain CC-AMZ-304(T) from the type species of the genera Aestuariibaculum and Gaetbulibacter. Thus, based on data from the present polyphasic study, strain CC-AMZ-304(T) is considered to represent a novel species of a new genus within the family Flavobacteriaceae, for which the name Aquibacter zeaxanthinifaciens gen. nov., sp. nov. is proposed; the type strain of Aquibacter zeaxanthinifaciens is CC-AMZ 304(T) ( = JCM 18557(T) = BCRC 80463(T)). Emended descriptions of the genera Aestuariibaculum and Gaetbulibacter are also proposed. PMID- 24048869 TI - Methyloversatilis thermotolerans sp. nov., a novel thermotolerant facultative methylotroph isolated from a hot spring. AB - A newly isolated facultatively methylotrophic bacterium (strain 3t(T)) was investigated. Cells of the isolate were Gram-stain-negative, asporogenous, non motile rods that multiplied by binary fission. The strain utilized methanol, methylamine and a variety of multicarbon compounds as carbon and energy sources. Growth occurred at pH 6.5-8.5 (optimally at 7.0-7.5) and at 10-45 degrees C (optimally at 30-37 degrees C). The major fatty acids of methanol-grown cells were C16 : 1omega7c and C16 : 0. The predominant phospholipids were phosphatidylethanolamine and phosphatidylglycerol. The major ubiquinone was Q-8. Strain 3t(T) possessed pyrroloquinoline quinone (PQQ)-linked methanol dehydrogenase and assimilated C1 units at the level of formaldehyde and CO2 via the serine cycle. The DNA G+C content of the strain was 63.6 mol% (Tm). On the basis of 16S rRNA gene sequence similarity (98.1 %) and rather low DNA-DNA relatedness (30 %) with the type strain of the type species of the genus Methyloversatilis (Methyloversatilis universalis FAM5(T)), and physiological and biochemical characteristics, the isolate was classified as a representative of a new species of the genus and named Methyloversatilis thermotolerans 3t(T) ( = VKM B-2692(T) = CCUG 61694(T) = DSM 25156(T)). PMID- 24048870 TI - Borrelia kurtenbachii sp. nov., a widely distributed member of the Borrelia burgdorferi sensu lato species complex in North America. AB - Lyme borreliosis group spirochaetes are parasitic bacteria transmitted by vector ticks of the genus Ixodes and distributed mainly between 40 degrees and 60 degrees northern latitudes. Since Borrelia burgdorferi sensu stricto (hereinafter, B. burgdorferi) was described in the north-eastern USA during the early 1980s, an increasing diversity has been noted within the species complex. Here, we describe a novel genomic species, Borrelia kurtenbachii sp. nov. (type strain 25015(T) = ATCC BAA-2495(T) = DSM 26572(T)), that is prevalent in transmission cycles among vector ticks and reservoir hosts in North America. Confirmation of the presence of this species in Europe awaits further investigation. PMID- 24048871 TI - Thermolongibacillus altinsuensis gen. nov., sp. nov. and Thermolongibacillus kozakliensis sp. nov., aerobic, thermophilic, long bacilli isolated from hot springs. AB - Two novel endospore-forming, aerobic bacilli, strains E173a(T) and E265(T), were isolated from soil and sediment samples from Kozakli and Altinsu hot springs, Nevsehir (Turkey). Their young cells in the exponential phase of growth were motile, Gram-stain-positive, straight rods, 0.6-1.1*3.0-8.0 um in size, but they became strikingly long, approximately 0.6-1.2 by 9.0-35.0 um, after the stationary phase of growth. Cells varied in tests for oxidase, and had a weakly positive reaction for catalase. Both strains could grow between 40 and 70 degrees C, with optimal growth at 60 degrees C (E173a(T)) and 55 degrees C (E265(T)). Growth occurred within the range pH 5.0-11.0 with optimal growth at pH 9.0 (E173a(T)) and pH 8.5 (E265(T)). Strain E173a(T) grew within a salinity range from 0 to1.5 % (w/v) NaCl with optimal growth at 0.5 %, while strain E265(T) grew within the range 0-5.0 % (w/v), with an optimum at 3.0 %. The new isolates differed from each other in some phenotypic and chemotaxonomic characters as well as repetitive extragenic palindromic element PCR (rep-PCR) fingerprints. 16S rRNA gene sequence similarities suggested distant relationships with other members of the family Bacillaceae (<95.8 %), although the two strains showed 97.5 % sequence similarity between them, and had 55 % relatedness by DNA-DNA hybridization. The DNA G+C contents were 44.8 (E173a(T)) and 43.5 mol% (E265(T)). Moreover, the chemotaxonomic data of E173a(T) and E265(T) [presence of low amounts of meso diaminopimelic acid, A1gamma to A1gamma' cross-linkage types in peptidoglycan, fatty acids including iso-C15 : 0 (>60 %), iso-C17 : 0 and C16 : 0] supported the consideration of these isolates as members of a novel genus. Based upon phenotypic, phylogenetic and chemotaxonomic characteristics, it is proposed that new isolates represent a novel genus, Thermolongibacillus gen. nov., with two novel species: Thermolongibacillus altinsuensis sp. nov. (type strain E265(T) = DSM 24979(T) = NCIMB 14850(T)) and Thermolongibacillus kozakliensis sp. nov. (type strain E173a(T) = DSM 24978(T) = NCIMB 14849(T)). PMID- 24048872 TI - Undibacterium jejuense sp. nov. and Undibacterium seohonense sp. nov., isolated from soil and freshwater, respectively. AB - Two bacterial strains, designated JS4-4(T) and SHS5-24(T), were isolated from forest soil of Jeju Island and fresh water of Seoho lake in Suwon city, respectively, South Korea. Both strains were Gram-stain-negative, aerobic, motile rods. Strains JS4-4(T) and SHS5-24(T) showed high sequence similarities (97.6 95.8 %) and (96.5-95.6 %), respectively, to the members of the genus Undibacterium. The sequence similarity between strains JS4-4(T) and SHS5-24(T) was 97.0 %. A phylogenetic tree showed that these strains fell within the radius of the genus Undibacterium. The main fatty acids of strains JS4-4(T) and SHS5 24(T) were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) (50.1 and 58.7 %, respectively) and C16 : 0 (28.3 and 24.5 %, respectively). Both strains had ubiquinone 8 as the only respiratory quinone, and phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol as the major polar lipids. Strain JS4-4(T) showed <70 % DNA-DNA hybridization with members of the genus Undibacterium. Thus, based on the evidence of a polyphasic study, it is proposed that strains JS4-4(T) and SHS5-24(T) represent two novel species, for which the names Undibacterium jejuense sp. nov. (type strain JS4-4(T) = KACC 12607(T) = NBRC 108922(T)) and Undibacterium seohonense sp. nov. (type strain SHS5-24(T) = KACC 16656(T) = NBRC 108929(T)) are proposed. PMID- 24048873 TI - Gramella flava sp. nov., a member of the family Flavobacteriaceae isolated from seawater. AB - A novel Gram-negative, yellow-pigmented, aerobic, motile by gliding, rod-shaped marine bacterium (JLT2011(T)) was isolated from surface seawater. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain JLT2011(T) could be assigned to the genus Gramella and was most closely related to Gramella gaetbulicola, with 96.2 % similarity. The genomic DNA G+C content was 42.1 %. The predominant fatty acids were C16 : 0, iso-C15 : 0, C18 : 0 and summed feature 3 (C16 : 1omega6c/C16 : 1omega7c). The major menaquinone was MK-6. The major components of the polar lipid profile were phosphatidylglycerol, diphosphatidylglycerol and sphingoglycolipid. On the basis of phenotypic, genotypic and taxonomic data presented, strain JLT2011(T) is considered to represent a novel species of the genus Gramella, for which the name Gramella flava sp. nov. is proposed; the type strain is JLT2011(T) ( = CGMCC 1.12375(T) = LMG 27360(T)). PMID- 24048874 TI - Youngiibacter fragilis gen. nov., sp. nov., isolated from natural gas production water and reclassification of Acetivibrio multivorans as Youngiibacter multivorans comb. nov. AB - A taxonomic study employing a polyphasic approach was performed on a novel anaerobic bacterium isolated from natural gas production-water. The bacterium stained Gram-negative and consisted of non-motile, non-spore-forming, rod-shaped cells. Products of glucose or starch fermentation were ethanol, CO2, formate, acetate and H2. The predominant fatty acids were C16 : 0 ALDE and summed feature 3 comprising C16 : 1omega7c and/or C16 : 1omega6c. The DNA G+C content was 45.5 mol%. 16S rRNA gene sequence analysis demonstrated that the nearest phylogenetic neighbours of the novel strain were Acetivibrio multivorans DSM 6139(T) (98.5 %) and Proteiniclasticum ruminis JCM 14817(T) (95.4 %). The DNA-DNA hybridization value between the novel organism and Acetivibrio multivorans PeC1 DSM 6139(T) was determined to be only 30.2 %, demonstrating the separateness of the two species. Based on phylogenetic, phenotypic and chemotaxonomic evidence that clearly distinguished strain 232.1(T) from Proteiniclasticum ruminis and other close relatives, it is proposed that the novel isolate be classified as representing a novel species of a new genus within the family Clostridiaceae, Youngiibacter fragilis gen. nov., sp. nov. The type strain of the type species is 232.1(T) ( = ATCC BAA-2257(T) = DSM 24749(T)). In addition, Acetivibrio multivorans is proposed to be reclassified as Youngiibacter multivorans comb. nov. PMID- 24048876 TI - Seizures and epilepsy in children. AB - Seizures and epilepsy in children are common. They are caused by a variety of causes ranging from genetic to neuro -infections. History and actual observation or/video are very important to differentiate true seizure from non-epileptic event. A correct classification of seizure and epilepsy helps to decide need to treat, choice of anti-epileptic drugs (AED) and prognostication. Except for few seizure types, in majority of seizure types regular AED are started after second confirmed seizure. Goal of treatment is seizure control with minimal side effects and ensuring quality of life. With appropriate mono - therapy, about 70 % patients become seizure free and can be easily treated in community. An orderly approach to classify seizure type, holistic management and timely referral of intractable epilepsy will help in improving care of children with epilepsy. PMID- 24048877 TI - Correlation of paraoxonase1 activities with birth weight. AB - OBJECTIVES: To evaluate arylesterase and lactonase activity of paraoxonase (PON)1 in cord blood of neonates in relation to their birth weight. The authors hypothesized that cord blood PON1 arylesterase and lactonase activities will be compromised in neonates having low birth weight. METHODS: Eighty neonates born in authors' hospital, irrespective of mode of delivery were included. Forty children with low birth weight were included in case group and 40 with normal birth weight were included as controls. PON1 arylesterase and lactonase activities were measured. RESULTS: Serum arylesterase activity decreased significantly in low birth weight babies (p < 0.05). Linear regression analysis (R = 0.728) indicated significant correlation between arylesterase and birth weight. Serum lactonase activity was also reduced in low birth weight babies. Its linear regression analysis (R = 0.727) indicated significant correlation between lactonase and birth weight. CONCLUSIONS: PON 1 activity is significantly reduced among low birth weight babies in comparison to normal weight babies. PMID- 24048878 TI - Communication skills in pediatric office practice. PMID- 24048880 TI - Assessment of deterioration in water quality from source to household storage in semi-urban settings of developing countries. AB - This study has investigated the common risks associated with the water quality changes from the source to the consumer households and the associated disease burden in the piped water supplies. Samples from the source to the household storage from Nagpur City were collected and analysed for heavy metals, nutrient and microbial parameters. Sanitary risks were identified at the households during the socio-economic and sanitary survey. The water quality deterioration was the most at household storage around 30.3% indicating that measures need to be taken to safeguard the water quality at the consumer level. Then, 31.2% of the samples collected from public standposts and handpumps were positive for faecal contamination which implies that it is the weaker sections of the society who suffer the consequences of drinking unsafe water the most. On the basis of the laboratory results, risk analysis by surveying the WTPs, point-of-use behaviour at households and sanitary status at different socio-economic strata, the Water Safety Plan for Nagpur City was structured. The aim was to ensure that safe and improved water is reached to the individual household. PMID- 24048879 TI - Role of NUCB2/Nesfatin-1 in the hypothalamic control of energy homeostasis. AB - Hunger and satiety are regulated in a complex fashion by a few food intake stimulatory (orexigenic) and a multitude of inhibitory (anorexigenic) factors produced in the periphery (mainly in the gastrointestinal tract) or directly in the brain. Within the brain, the hypothalamus plays a pivotal role as a production site of food intake regulatory factors. Importantly, this site integrates peripheral and central signaling factors to orchestrate food intake and in the long term body weight. Our knowledge on these regulatory pathways is not static but rather rapidly changing as new factors as well as up- and downstream signaling pathways of already known transmitters are uncovered. Hypothalamic nucleobindin2 (NUCB2), the precursor of nesfatin-1, was first described in 2006 and nesfatin-1 found to be a novel anorexigenic modulator of food intake and body weight. The initial report stimulated several groups to investigate the biological actions of nesfatin-1 and subsequent studies delineated the underlying brain mechanisms involved in its food reducing effect. Of interest was the demonstration that NUCB2 also exerts its anorexigenic action in the paraventricular nucleus of the hypothalamus and is regulated at this site by changes in metabolic status with a diurnal rhythm inversely related to that of feeding in rats. The present review describes the current state-of-knowledge on central nesfatin-1's effects on food intake and body weight and highlights important missing links regarding cellular signaling mechanisms involved in nesfatin-1's action. PMID- 24048881 TI - Personal exposure measurement of students to various microenvironments inside and outside the college campus. AB - This study characterizes the exposure of a typical Indian Institute of Technology Kanpur student to particulate matter and gaseous co-pollutants like carbon monoxide, volatile organic compounds, and nitrogen dioxide in various microenvironments, within and outside the college campus. Chemical analysis of filter, used for the particulate matter measurement, was also carried out to determine the concentration of various elements such as Ca, Cd, Cr, Cu, Fe, Mg, Pb, Zn, and anions like F(-), Cl(-), NO3 (-), and SO4 (2-). Furthermore, time activity diary along with temperature data was maintained for the precise evaluation and analysis of results for various microenvironments. The results showed PM10 and PM2.5 concentrations to be higher at some outdoor microenvironments, particularly near the Ganga riverbank. From the chemical analysis, concentrations of chloride and fluoride were found higher in indoor microenvironments as compared to outdoors. Also, nitrate concentrations were quite higher within the laboratory premises. Concentrations of Ca, Fe, and Mg were significant outdoors, whereas Na, Ca, Fe, and K were prominent indoors. The study highlights the real-time personal exposure of a student cohort to various toxic pollutants typically found within their breathing levels and their potential sources both indoors and outdoors. PMID- 24048882 TI - Exposure pathways of anticoagulant rodenticides to nontarget wildlife. AB - Second-generation anticoagulant rodenticides are widely reported to contaminate and poison nontarget wildlife, primarily predatory birds and mammals. Exposure pathways, however, have not been well defined. Here, we examined potential movement of rodenticides from deployment of bait to exposure of small mammals and other biota. At two adjacent working farms, we placed baits containing either brodifacoum or bromadiolone. We monitored movement of those compounds to the surrounding environment by collecting small mammals, birds, and invertebrates. Similar collections were made at a third agricultural setting without active bait deployment, but located among intensive livestock production and regular rodenticide use by farmers. Livers and whole invertebrate samples were analyzed for rodenticides using a sensitive LC-MSMS method. Norway rats (Rattus norvegicus) from both baited and non-baited farms had residues of brodifacoum or bromadiolone, implicating rats as an important exposure pathway to wildlife. Among 35 analyzed nontarget small mammals, a single vole had high hepatic residues (18.6 MU/g), providing some indication of a small mammal pathway. One song sparrow (Melospiza melodia) sample from a baited farm contained 0.073 MUg/g of brodifacoum in liver, while 0.39 MUg/g of diphacinone was measured in a pool of carrion beetles (Dermestes spp.) from the non-baited farm area, implicating avian and invertebrate components in exposure pathways. Regurgitated pellets of barn owl (Tyto alba) selected randomly from baited farms contained no detectable rodenticide residues, while 90% of owl pellets collected from a variety of farms, and selected for the presence of rat fur, contained detectable anticoagulant residues. We recorded behavior of a captive sample of a representative songbird, the house sparrow (Passer domesticus); they readily entered bait stations and fed on (unloaded) bait. PMID- 24048883 TI - Preoperative prognostic factors for biochemical recurrence after robot-assisted radical prostatectomy in Japan. AB - PURPOSE: We investigated oncological outcomes in Japanese patients who underwent robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: This study included 389 patients who underwent RARP at a single institution with a follow-up period of at least 1 year. Preoperative findings were compared with biochemical recurrence (BCR). Predictors of BCR-free survival (BCRFS) were evaluated by univariate and multivariate Cox proportional hazard model analyses, and a risk stratification model based on the relative risks of BCR was established. RESULTS: Fifty incidences of BCR were noted during a median follow-up period of 28.7 months (range, 12.1-80.0 months). The BCRFS rate for the entire cohort at the median follow-up time was 85.9 %; the 1-, 3-, and 5-year estimates were 91.0, 85.1, and 81.1 %, respectively. From univariate analyses, prostate-specific antigen (PSA), PSA density, biopsy Gleason score, and percent positive core were significantly associated with BCR. Multivariate analysis showed that PSA [hazard ratio (HR), 2.75; p = 0.001], percent positive core (HR, 2.22; p = 0.001), and biopsy Gleason score (HR, 2.61; p = 0.007) were independent predictors of BCR. CONCLUSION: This study at a single Japanese center demonstrates that RARP provides a satisfactory BCRFS rate. This report provides a framework with which to estimate oncological outcomes in patients who underwent RARP for localized prostate cancer. Our results support the increased use of RARP for the treatment of localized prostate cancer in Japan. PMID- 24048884 TI - Physical activity after surgically obtained weight loss: study with a SenseWear armband in subjects undergoing biliopancreatic diversion. AB - BACKGROUND: This study aimed to understand the role of the extra load of body mass in limiting physical activity and in preventing an active lifestyle in severely obese patients. MATERIALS AND METHODS: The study was carried out in a University Hospital setting, and investigates severely obese patients, having undergone biliopancreatic diversion (BPD) for obesity and control subjects with a body weight closely similar to that of the BPD subjects; energy intake was evaluated by alimentary interview and energy expenditure was assessed with the Body Media SenseWear(r) Pro armband (SWA). RESULTS: SWA metabolic efficiency (MET) was negatively associated with body mass index values (rho = -0.464, p < 0.01), and the SWA overall energy expenditure was very similar to the energy alimentary intake in the obese patients and in the control subjects. Among the controls, the MET mean value was higher (p < 0.05) than that observed both in obese and in BPD subjects (1.392 +/- 0.211 vs. 1.149 +/- 0.181 and 1.252 +/- 0.284, respectively); furthermore, in comparison with the obese and the BPD groups, among the control individuals a greater number of active persons (27% vs. 0 and 7%, respectively) and a lower number of sedentary persons (27% vs. 70 and 43%, respectively) was found (p < 0.01). CONCLUSIONS: These preliminary results suggest the reliability of SWA data in assessing energy expenditure and tend to rule out the hypothesis that in severely obese patients the extra load of body mass by itself is a main factor limiting physical activity and leading to a sedentary lifestyle. PMID- 24048885 TI - The endocannabinoid anandamide induces apoptosis of rat decidual cells through a mechanism involving ceramide synthesis and p38 MAPK activation. AB - Anandamide (AEA) belongs to an endogenous family of lipid messengers, called endocannabinoids (ECs), which exert pharmacological effects by binding to selective membrane receptors, the CB1 and CB2 receptors. Increasing evidence suggests that AEA is involved in the regulation of a variety of cell signalling pathways both in experimental models and humans. We have previously demonstrated that ECs machinery operates in decidual cells and found that AEA, the principal EC, induced apoptosis in decidual cells through CB1. Here, we investigated in rat primary decidual cells the signal transduction pathways activated upon AEA binding to CB1. We found that AEA induces a significant increase in the level of intracellular ceramide. These effects were reversed by inhibiting CB1 receptor activation with AM251. The ceramide analogue, C6-ceramide, induced a decrease in decidual cell viability and of p38 MAPK phosphorylation. Additionally, the pharmacologic inhibition of de novo ceramide biosynthesis with L-cycloserine and fumonisin B reduced the AEA-effects on cell viability and p38 MAPK phosphorylation. Furthermore, AEA and C6-ceramide induced a drop in DeltaPsim, an increase in ROS production and caspase-3/-7 activation, effects partially reverted by inhibitors of ceramide synthesis and of p38 MAPK. Taken together, we showed that AEA induces a reduction in decidual cell viability by a mechanism involving CB1 activation, which results in ceramide synthesis de novo and p38 phosphorylation, followed by mitochondrial stress and ROS production, leading to apoptosis. PMID- 24048886 TI - A new ilarvirus isolated from Viola * wittrockiana and its detection in pansy germoplasm by qRT-PCR. AB - An infectious agent was transmitted mechanically from samples of Viola spp. showing white mosaic and leaf deformation to Nicotiana benthamiana. dsRNA extracted from the N. benthamiana plants migrated as four specific bands that were absent in non-inoculated plants. Sequence analysis of cDNA clones generated from the second-smallest dsRNA showed the greatest similarity to the RNA3 of prune dwarf virus (PDV) (genus Ilarvirus, family Bromoviridae). However, because of differences in molecular, biological, and serological properties between this virus isolate and PDV, a new ilarvirus species, named "Viola white distortion associated virus" (VWDaV) is proposed. Specific oligonucleotides and a TaqMan((r)) probe were designed for diagnostic purposes. The possible association between the virus and the original white distortion symptoms is discussed. PMID- 24048887 TI - Sequence analysis of infectious pancreatic necrosis virus isolated from Iranian reared rainbow trout (Oncorhynchus mykiss) in 2012. AB - Infectious pancreatic necrosis virus (IPNV) is the causal agent of a highly contagious disease that affects many species of fish and shellfish. This virus causes economically significant diseases of farmed rainbow trout, Oncorhynchus mykiss (Walbaum), in Iran, which is often associated with the transmission of pathogens from European resources. In this study, moribund rainbow trout fry samples were collected during an outbreak of IPNV in three different fish farms in north and west provinces of Iran in 2012; and we investigated the full genome sequence of Iranian IPNV and compared it with previously identified IPNV sequences. The sequences of different structural and nonstructural-protein genes were compared to those of other aquatic birnaviruses sequenced to date. Our results show that the Iranian isolate falls within genogroup 5, serotype A2 strain SP, having 99% identity with the strain 1146 from Spain. These results suggest that the Iranian isolate may have originated from Europe. PMID- 24048888 TI - Angle stable nails provide improved healing for a complex fracture model in the femur. AB - BACKGROUND: Conventional nails are being used for an expanding range of fractures from simple to more complex. Angle stable designs are a relatively new innovation; however, it is unknown if they will improve healing for complex fractures. QUESTIONS/PURPOSES: When comparing traditional and angle stable nails to treat complex open canine femur fractures, the current study addressed the following questions: do the two constructs differ in (1) radiographic evidence of bone union across the cortices; (2) stability as determined by toggle (torsional motion with little accompanying torque) and angular deformation; (3) biomechanical properties, including stiffness in bending, axial compression, and torsional loading, and construct failure properties in torsion; and (4) degree of bone tissue mineralization? METHODS: Ten hounds with a 1-cm femoral defect and periosteal stripping were treated with a reamed titanium angle stable or nonangle stable nail after the creation of a long soft tissue wound. Before the study, the animals were randomly assigned to receive one of the nails and to be evaluated with biomechanical testing or histology. After euthanasia at 16 weeks, all operative femora were assessed radiographically. Histological or biomechanical evaluation was conducted of the operative bones with nails left in situ compared with the nonoperative contralateral femora. RESULTS: Radiographic and gross inspection demonstrated hypertrophic nonunion in all 10 animals treated with the nonangle stable nail, whereas six of 10 animals treated with the angle stable nail bridged at least one cortex (p = 0.023). The angle stable nail construct demonstrated no toggle in nine of 10 animals, whereas all control femora exhibited toggle. The angle stable nail demonstrated less angular deformation and toggle (p <= 0.005) and increased compressive stiffness (p = 0.001) compared with the conventional nonangle stable nail. Histology demonstrated more nonmineralized tissue in the limbs treated with the conventional nail (p = 0.005). CONCLUSIONS: Angle stable nails that eliminate toggle lead to enhanced yet incomplete fracture healing in a complex canine fracture model. CLINICAL RELEVANCE: Care should be taken in tailoring the nail design features to the characteristics of the fracture and the patient. PMID- 24048889 TI - What is the learning curve for robotic-assisted pedicle screw placement in spine surgery? AB - BACKGROUND: Some early studies with robotic-assisted pedicle screw implantation have suggested these systems increase accuracy of screw placement. However, the relationship between the success rate of screw placement and the learning curve of this new technique has not been evaluated. QUESTIONS/PURPOSES: We determined whether, as a function of surgeon experience, (1) the success rate of robotic assisted pedicle screw placement improved, (2) the frequency of conversion from robotic to manual screw placement decreased, and (3) the frequency of malpositioned screws decreased. METHODS: Between June 2010 and August 2012, the senior surgeon (IHL) performed 174 posterior spinal procedures using pedicle screws, 162 of which were attempted with robotic assistance. The use of the robotic system was aborted in 12 of the 162 procedures due to technical issues (registration failure, software crash, etc). The robotic system was successfully used in the remaining 150 procedures. These were the first procedures performed with the robot by the senior surgeon, and in this study, we divided the early learning curve into five groups: Group 1 (Patients 1-30), Group 2 (Patients 31 60), Group 3 (Patients 61-90), Group 4 (Patients 91-120), and Group 5 (Patients 121-150). One hundred twelve patients (75%) had spinal deformity and 80 patients (53%) had previous spine surgery. The accuracy of screw placement in the groups was assessed based on intraoperative biplanar fluoroscopy and postoperative radiographs. The results from these five groups were compared to determine the effect on the learning curve. The numbers of attempted pedicle screw placements were 359, 312, 349, 359, and 320 in Groups 1 to 5, respectively. RESULTS: The rates of successfully placed screws using robotic guidance were 82%, 93%, 91%, 95%, and 93% in Groups 1 to 5. The rates of screws converted to manual placement were 17%, 7%, 8%, 4%, and 7%. Of the robotically placed screws, the screw malposition rates were 0.8%, 0.3%, 1.4%, 0.8%, and 0%. CONCLUSIONS: The rate of successfully placed pedicle screws improved with increasing experience. The rate of the screws that were converted to manual placement decreased with increasing experience. The frequency of screw malposition was similar over the learning curve at 0% to 1.4%. Future studies will need to determine whether this finding is generalizable to others. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 24048890 TI - Measuring the effect of ion-induced drift-gas polarization on the electrical mobilities of multiply-charged ionic liquid nanodrops in air. AB - The electrical mobilities of multiply-charged nanodrops of the ionic liquid 1 ethyl, 3-methylimidazolium dicyanamide (EMI-N[CN]2) were accurately measured in air at 20 degrees C for mass-selected clusters of composition [EMI-N[CN]2] n [EMI(+)] z , with 2 <= n <= 369 and 1 <= z <= 10. We confirm prior reports that the mobility Z of a globular ion of mass m is given approximately by the modified Stokes-Millikan law for spheres, Z = Z SM,mod (d m + d g , z, m), where d m = (6m/pirho)(1/3) is the nanodrop mass-diameter based on the density rho of the liquid (corrected for the capillary compression and electrostatic deformation of the nanodrop), and d g is an effective air molecule diameter. There is however a measurable (up to 7%) and systematic z-dependent departure of Z from Z SM,mod . As theoretically expected at small epsilon (*) , this effect is accurately described by a simple correction factor of the form Z/Z SM,mod = delta(1 - betaepsilon (*)), where kTepsilon (*) is the potential energy due to the ion induced dipole (polarization) attraction between a perfectly-conducting charged nanodrop and a polarized neutral gas-molecule at a distance (d m + d g )/2 from its center. An excellent fit of this model to hundreds of data points is found for d g ~ 0.26 nm, beta ~ 0.36, and delta ~ 0.954. Accounting for the effect of polarization decreases d g considerably with respect to values inferred from earlier nanodrop measurements that ignored this effect. In addition, and in spite of ambiguities in the mobility calibration scale, the measured constant delta smaller than unity increases Millikan's drag enhancement factor from the accepted value xi m ~ 1.36 to the new value xi ~ xi m /delta ~ 1.42 +/- 0.03. PMID- 24048891 TI - Ambient DESI and LESA-MS analysis of proteins adsorbed to a biomaterial surface using in-situ surface tryptic digestion. AB - The detection and identification of proteins adsorbed onto biomaterial surfaces under ambient conditions has significant experimental advantages but has proven to be difficult to achieve with conventional measuring technologies. In this study, we present an adaptation of desorption electrospray ionization (DESI) and liquid extraction surface analysis (LESA) mass spectrometry (MS) coupled with in situ surface tryptic digestion to identify protein species from a biomaterial surface. Cytochrome c, myoglobin, and BSA in a combination of single and mixture spots were printed in an array format onto Permanox slides, followed by in-situ surface digestion and detection via MS. Automated tandem MS performed on surface peptides was able to identify the proteins via MASCOT. Limits of detection were determined for DESI-MS and a comparison of DESI and LESA-MS peptide spectra characteristics and sensitivity was made. DESI-MS images of the arrays were produced and analyzed with imaging multivariate analysis to automatically separate peptide peaks for each of the proteins within a mixture into distinct components. This is the first time that DESI and LESA-MS have been used for the in-situ detection of surface digested proteins on biomaterial surfaces and presents a promising proof of concept for the use of ambient MS in the rapid and automated analysis of surface proteins. PMID- 24048892 TI - Psychiatric comorbidities in allodynic migraineurs. AB - OBJECTIVES: To evaluate the prevalence and the association of psychological disturbance in migraine patients with allodynia. METHODS: We recruited 434 migraine patients from an outpatient clinic. The participants completed three self-administered questionnaires, including a headache questionnaire, an allodynia symptoms checklist, and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Among the migraineurs, 48.4% participants reported allodynia. The HADS total score (15.5 +/- 7.8 vs. 13.7 +/- 8.5, P = 0.022) and anxiety subscore (9.1 +/- 4.5 vs. 7.6 +/- 4.7, P = 0.001) were higher in migraineurs with allodynia than in those without allodynia. The anxiety subscore in patients with moderate to severe allodynia, mild allodynia, and no allodynia were 10.0 +/- 4.5, 8.4 +/- 4.3, and 7.6 +/- 4.7 ( P < 0.001, by one-way analysis of variance). Among patients with moderate to severe allodynia, there was a trend of higher depression subscore (7.1 +/- 4.0, P = 0.059) than those with no (6.1 +/- 4.4) or mild allodynia (5.8 +/- 4.0). In a regression model, the presence of allodynia is an independent risk factor for clinically significant anxiety. Moderate to severe allodynia is an independent risk factor for clinically significant depression. CONCLUSIONS: In migraineurs, the severity of cutaneous allodynia was associated with their mood status, especially anxiety. PMID- 24048894 TI - Pneumococcal components induce regulatory T cells that attenuate the development of allergic airways disease by deviating and suppressing the immune response to allergen. AB - The induction of regulatory T cells (Tregs) to suppress aberrant inflammation and immunity has potential as a therapeutic strategy for asthma. Recently, we identified key immunoregulatory components of Streptococcus pneumoniae, type 3 polysaccharide and pneumolysoid (T+P), which suppress allergic airways disease (AAD) in mouse models of asthma. To elucidate the mechanisms of suppression, we have now performed a thorough examination of the role of Tregs. BALB/c mice were sensitized to OVA (day 0) i.p. and challenged intranasal (12-15 d later) to induce AAD. T+P was administered intratracheally at the time of sensitization in three doses (0, 12, and 24 h). T+P treatment induced an early (36 h-4 d) expansion of Tregs in the mediastinal lymph nodes, and later (12-16 d) increases in these cells in the lungs, compared with untreated allergic controls. Anti-CD25 treatment showed that Treg-priming events involving CD25, CCR7, IL-2, and TGF beta were required for the suppression of AAD. During AAD, T+P-induced Tregs in the lungs displayed a highly suppressive phenotype and had an increased functional capacity. T+P also blocked the induction of IL-6 to prevent the Th17 response, attenuated the expression of the costimulatory molecule CD86 on myeloid dendritic cells (DCs), and reduced the number of DCs carrying OVA in the lung and mediastinal lymph nodes. Therefore, bacterial components (T+P) drive the differentiation of highly suppressive Tregs, which suppress the Th2 response, prevent the Th17 response and disable the DC response resulting in the effective suppression of AAD. PMID- 24048893 TI - Fatal eosinophilic myocarditis develops in the absence of IFN-gamma and IL-17A. AB - CD4(+) T cells play a central role in inflammatory heart disease, implicating a cytokine product associated with Th cell effector function as a necessary mediator of this pathophysiology. IFN-gamma-deficient mice developed severe experimental autoimmune myocarditis (EAM), in which mice are immunized with cardiac myosin peptide, whereas IL-17A-deficient mice were protected from progression to dilated cardiomyopathy. We generated IFN-gamma(-/-)IL-17A(-/-) mice to assess whether IL-17 signaling was responsible for the severe EAM of IFN gamma(-/-) mice. Surprisingly, IFN-gamma(-/-)IL-17A(-/-) mice developed a rapidly fatal EAM. Eosinophils constituted a third of infiltrating leukocytes, qualifying this disease as eosinophilic myocarditis. We found increased cardiac production of CCL11/eotaxin, as well as Th2 deviation, among heart-infiltrating CD4(+) cells. Ablation of eosinophil development improved survival of IFN-gamma(-/-)IL 17A(-/-) mice, demonstrating the necessity of eosinophils in fatal heart failure. The severe and rapidly fatal autoimmune inflammation that developed in the combined absence of IFN-gamma and IL-17A constitutes a novel model of eosinophilic heart disease in humans. This is also, to our knowledge, the first demonstration that eosinophils have the capacity to act as necessary mediators of morbidity in an autoimmune process. PMID- 24048895 TI - Ablation of peroxiredoxin II attenuates experimental colitis by increasing FoxO1 induced Foxp3+ regulatory T cells. AB - Peroxiredoxin (Prx) II is an intracellular antioxidant molecule that eliminates hydrogen peroxide, employing a high substrate-binding affinity. PrxII deficiency increases the levels of intracellular reactive oxygen species in many types of cells, which may increase reactive oxygen species-mediated inflammation. In this study, we investigated the susceptibility of PrxII knockout (KO) mice to experimentally induced colitis and the effects of PrxII on the immune system. Wild-type mice displayed pronounced weight loss, high mortality, and colon shortening after dextran sulfate sodium administration, whereas colonic inflammation was significantly attenuated in PrxII KO mice. Although macrophages were hyperactivated in PrxII KO mice, the amount of IFN-gamma and IL-17 produced by CD4(+) T cells was substantially reduced. Foxp3(+) regulatory T (Treg) cells were elevated, and Foxp3 protein expression was increased in the absence of PrxII in vitro and in vivo. Restoration of PrxII into KO cells suppressed the increased Foxp3 expression. Interestingly, endogenous PrxII was inactivated through hyperoxidation during Treg cell development. Furthermore, PrxII deficiency stabilized FoxO1 expression by reducing mouse double minute 2 homolog expression and subsequently activated FoxO1-mediated Foxp3 gene transcription. PrxII overexpression, in contrast, reduced FoxO1 and Foxp3 expression. More interestingly, adoptive transfer of naive CD4(+) T cells from PrxII KO mice into immune-deficient mice attenuated T cell-induced colitis, with a reduction in mouse double minute 2 homolog expression and an increase in FoxO1 and Foxp3 expression. These results suggest that inactivation of PrxII is important for the stability of FoxO1 protein, which subsequently mediates Foxp3(+) Treg cell development, thereby attenuating colonic inflammation. PMID- 24048896 TI - Annexin-A1 regulates TLR-mediated IFN-beta production through an interaction with TANK-binding kinase 1. AB - TLRs play a pivotal role in the recognition of bacteria and viruses. Members of the family recognize specific pathogen sequences to trigger both MyD88 and TRIF dependent pathways to stimulate a plethora of cells. Aberrant activation of these pathways is known to play a critical role in the development of autoimmunity and cancer. However, how these pathways are entirely regulated is not fully understood. In these studies, we have identified Annexin-A1 (ANXA1) as a novel regulator of TLR-induced IFN-beta and CXCL10 production. We demonstrate that in the absence of ANXA1, mice produce significantly less IFN-beta and CXCL10, and macrophages and plasmacytoid dendritic cells have a deficiency in activation following polyinosinic:polycytidylic acid administration in vivo. Furthermore, a deficiency in activation is observed in macrophages after LPS and polyinosinic:polycytidylic acid in vitro. In keeping with these findings, overexpression of ANXA1 resulted in enhanced IFN-beta and IFN-stimulated responsive element promoter activity, whereas silencing of ANXA1 impaired TLR3- and TLR4-induced IFN-beta and IFN-stimulated responsive element activation. In addition, we show that the C terminus of ANXA1 directly associates with TANK binding kinase 1 to regulate IFN regulatory factor 3 translocation and phosphorylation. Our findings demonstrate that ANXA1 plays an important role in TLR activation, leading to an augmentation in the type 1 IFN antiviral cytokine response. PMID- 24048897 TI - IL-12-based vaccination therapy reverses liver-induced systemic tolerance in a mouse model of hepatitis B virus carrier. AB - Liver-induced systemic immune tolerance that occurs during chronic hepadnavirus infection is the biggest obstacle for effective viral clearance. Immunotherapeutic reversal of this tolerance is a promising strategy in the clinic but remains to be explored. In this study, using a hepatitis B virus (HBV) carrier mouse model, we report that IL-12-based vaccination therapy can efficiently reverse systemic tolerance toward HBV. HBV-carrier mice lost responsiveness to hepatitis B surface Ag (HBsAg) vaccination, and IL-12 alone could not reverse this liver-induced immune tolerance. However, after IL-12-based vaccination therapy, the majority of treated mice became HBsAg(-) in serum; hepatitis B core Ag was also undetectable in hepatocytes. HBV clearance was dependent on HBsAg vaccine-induced anti-HBV immunity. Further results showed that IL-12-based vaccination therapy strongly enhanced hepatic HBV-specific CD8(+) T cell responses, including proliferation and IFN-gamma secretion. Systemic HBV specific CD4(+) T cell responses were also restored in HBV-carrier mice, leading to the arousal of HBsAg-specific follicular Th-germinal center B cell responses and anti-hepatitis B surface Ag Ab production. Recovery of HBsAg-specific responses also correlated with both reduced CD4(+)Foxp3(+) regulatory T cell frequency and an enhanced capacity of effector T cells to overcome inhibition by regulatory T cells. In conclusion, IL-12-based vaccination therapy may reverse liver-induced immune tolerance toward HBV by restoring systemic HBV-specific CD4(+) T cell responses, eliciting robust hepatic HBV-specific CD8(+) T cell responses, and facilitating the generation of HBsAg-specific humoral immunity; thus, this therapy may become a viable approach to treating patients with chronic hepatitis B. PMID- 24048898 TI - Identification of the cellular sentinels for native immunogenic heat shock proteins in vivo. AB - Select members of the heat shock proteins (HSPs) family, such as gp96, elicit immune responses specific to their chaperoned peptides. Although immunologic effects of HSPs on APCs described to date have largely been demonstrated with cell lines or primary cells in culture, their collective responses in vitro have been consistent with priming immune responses. In this study, we examine the physiologically relevant APCs in mice that are targeted after vaccination with native, murine HSPs, and we characterize those cells. Gp96 accesses the subcapsular region of the draining lymph node, and it is internalized predominantly by CD11b(+) cells in this locale. Cells acquiring gp96 can transfer protective antitumor immunity to naive mice by actively cross-presenting gp96 chaperoned peptides and providing costimulation. Our studies illustrate how HSPs act to alert the immune system of cellular damage and will be of paramount importance in immunotherapy of patients with cancer and infectious disease. PMID- 24048900 TI - Conjugated linoleic acid targets beta2 integrin expression to suppress monocyte adhesion. AB - Chronic recruitment of monocytes and their subsequent migration through the activated endothelium contribute to atherosclerotic plaque development. Integrin mediated leukocyte adhesion is central to this process. Conjugated linoleic acid (CLA) has the unique property of inducing regression of pre-established murine atherosclerosis via modulation of monocyte/macrophage function. Understanding the mechanisms through which CLA mediates its atheroprotective effect may help to identify novel pathways that limit or reverse atherosclerosis. In this study, we identified a novel mechanism through which CLA alters monocyte function. We show that CLA inhibits human peripheral blood monocyte cell adhesion to activated endothelial cells via loss of CD18 expression, the beta2 chain of LFA-1 and Mac-1 integrins. In addition, using a static-adhesion assay, we provide evidence that CLA prevents monocytes from binding to ICAM-1 and subsequently reduces the capacity of these cells to polarize. CXCL12-CXCR4 interactions induce a conformational change in beta2 integrins, facilitating leukocyte adhesion. In this study, we demonstrate that CLA inhibits CXCR4 expression, resulting in a failure of monocytes to directionally migrate toward CXCL12. Finally, using intravital microscopy, we show that, during CLA-induced regression of pre established atherosclerosis in ApoE(-/-) mice, there is reduced leukocyte adhesion and decreased CD18 expression on Gr1(+)/CD115(+) proinflammatory monocytes. In summary, the data presented describe a novel functional role for CLA in the regulation of monocyte adhesion, polarization, and migration. PMID- 24048899 TI - Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-gamma receptor subunit 1 (IFNGR1). AB - Although IFN-gamma is required for resolution of Listeria monocytogenes infection, the identities of the IFN-gamma-responsive cells that initiate the process remain unclear. We addressed this question using novel mice with conditional loss of IFN-gammaR (IFNGR1). Itgax-cre(+)Ifngr1(f/f) mice with selective IFN-gamma unresponsiveness in CD8alpha(+) dendritic cells displayed increased susceptibility to infection. This phenotype was due to the inability of IFN-gamma-unresponsive CD8alpha(+) dendritic cells to produce the initial burst of IL-12 induced by IFN-gamma from TNF-alpha-activated NK/NKT cells. The defect in early IL-12 production resulted in increased IL-4 production that established a myeloid cell environment favoring Listeria growth. Neutralization of IL-4 restored Listeria resistance in Itgax-cre(+)Ifngr1(f/f) mice. We also found that Itgax-cre(+)Ifngr1(f/f) mice survived infection with low-dose Listeria as the result of a second wave of IL-12 produced by Ly6C(hi) monocytes. Thus, an IFN gamma-driven cascade involving CD8alpha(+) dendritic cells and NK/NKT cells induces the rapid production of IL-12 that initiates the anti-Listeria response. PMID- 24048901 TI - Activated platelets enhance IL-10 secretion and reduce TNF-alpha secretion by monocytes. AB - Activated platelets are known to modulate immune responses by secreting or shedding a range of immunomodulatory substances. We examined the influence of activated platelets on cytokine production by normal human mononuclear cells, induced by tetanus toxoid (TT), human thyroglobulin (TG), Escherichia coli LPS, or intact Porphyromonas gingivalis. Addition of platelets activated by thrombin receptor-activating peptide enhanced IL-10 production induced by LPS (p < 0.001), TG (p < 0.05), and P. gingivalis (p < 0.01), and reduced the production of TNF alpha induced by LPS (p < 0.001), TG (p < 0.05), and P. gingivalis (p < 0.001), and of IL-6 in LPS- and P. gingivalis-stimulated cultures (p < 0.001). Similar effects on IL-10 and TNF-alpha production were observed on addition of platelet supernatant to mononuclear cells, whereas addition of recombinant soluble CD40L mimicked the effects on IL-10 production. Moreover, Ab-mediated blockade of CD40L counteracted the effect of platelets and platelet supernatants on TNF-alpha production. Monocytes separated into two populations with respect to IL-10 production induced by TG; the high-secreting fraction increased from 0.8 to 2.1% (p < 0.001) on addition of activated platelets. Adherence of platelets increased TG- and TT-induced IL-10 secretion by monocytes (p < 0.05). In addition, activated platelets inhibited CD4(+) T cell proliferation elicited by TT (p < 0.001) and P. gingivalis (p < 0.001). Our findings suggest that activated platelets have anti-inflammatory properties related to the interaction between CD40L and CD40, and exert a hitherto undescribed immunoregulatory action by enhancing IL-10 production and inhibiting TNF-alpha production by monocytes. PMID- 24048902 TI - The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. AB - NLRP3 assembles an inflammasome complex that activates caspase-1 upon sensing various danger signals derived from pathogenic infection, tissue damage, and environmental toxins. How NLRP3 senses these various stimuli is still poorly understood, but mitochondria and mitochondrial reactive oxygen species have been proposed to play a critical role in NLRP3 activation. In this article, we provide evidence that the mitochondrial antiviral signaling protein MAVS associates with NLRP3 and facilitates its oligomerization leading to caspase-1 activation. In reconstituted 293T cells, full-length MAVS promoted NLRP3-dependent caspase-1 activation, whereas a C-terminal transmembrane domain-truncated mutant of MAVS (MAVS-DeltaTM) did not. MAVS, but not MAVS-DeltaTM, interacted with NLRP3 and triggered the oligomerization of NLRP3, suggesting that mitochondrial localization of MAVS and intact MAVS signaling are essential for activating the NLRP3 inflammasome. Supporting this, activation of MAVS signaling by Sendai virus infection promoted NLRP3-dependent caspase-1 activation, whereas knocking down MAVS expression clearly attenuated the activation of NLRP3 inflammasome by Sendai virus in THP-1 and mouse macrophages. Taken together, our results suggest that MAVS facilitates the recruitment of NLRP3 to the mitochondria and may enhance its oligomerization and activation by bringing it in close proximity to mitochondrial reactive oxygen species. PMID- 24048903 TI - New role of signal peptide peptidase to liberate C-terminal peptides for MHC class I presentation. AB - The signal peptide peptidase (SPP) is an intramembrane cleaving aspartyl protease involved in release of leader peptide remnants from the endoplasmic reticulum membrane, hence its name. We now found a new activity of SPP that mediates liberation of C-terminal peptides. In our search for novel proteolytic enzymes involved in MHC class I (MHC-I) presentation, we found that SPP generates the C terminal peptide-epitope of a ceramide synthase. The display of this immunogenic peptide-MHC-I complex at the cell surface was independent of conventional processing components like proteasome and peptide transporter TAP. Absence of TAP activity even increased the MHC-I presentation of this Ag. Mutagenesis studies revealed the crucial role of the C-terminal location of the epitope and "helix breaking" residues in the transmembrane region just upstream of the peptide, indicating that SPP directly liberated the minimal 9-mer peptide. Moreover, silencing of SPP and its family member SPPL2a led to a general reduction of surface peptide-MHC-I complexes, underlining the involvement of these enzymes in Ag processing and presentation. PMID- 24048905 TI - New therapeutical horizons in the management of postmenopausal osteoporosis. AB - Osteoporosis is a bone metabolic disease characterized by a compromised skeletal fragility, leading to an increased risk of developing spontaneous and traumatic fractures. This disease is the consequence of an imbalance of the physiological process of bone turnover (or coupling), with the lost of the equilibrium between the activity of osteoblasts and osteoclasts. Therapy has been aimed mainly at the correction of the imbalance between bone resorption and bone formation, to protect skeletal integrity and reduce the risk of fractures. Thus, pharmacological treatments have been aimed at modulating the activity of bone cells. PMID- 24048904 TI - Increased susceptibility to pulmonary Pseudomonas infection in Splunc1 knockout mice. AB - The airway epithelium is the first line of host defense against pathogens. The short palate, lung, and nasal epithelium clone (SPLUNC)1 protein is secreted in respiratory tracts and is a member of the bacterial/permeability increasing (BPI) fold-containing protein family, which shares structural similarities with BPI like proteins. On the basis of its homology with BPIs and restricted expression of SPLUNC1 in serous cells of submucosal glands and surface epithelial cells of the upper respiratory tract, SPLUNC1 is thought to possess antimicrobial activity in host defense. SPLUNC1 is also reported to have surfactant properties, which may contribute to anti-biofilm defenses. The objective of this study was to determine the in vivo functions of SPLUNC1 following Pseudomonas aeruginosa infection and to elucidate the underlying mechanism by using a knockout (KO) mouse model with a genetic ablation of Splunc1. Splunc1 KO mice showed accelerated mortality and increased susceptibility to P. aeruginosa infection with significantly decreased survival rates, increased bacterial burdens, exaggerated tissue injuries, and elevated proinflammatory cytokine levels as compared with those of their wild-type littermates. Increased neutrophil infiltration in Splunc1 KO mice was accompanied by elevated chemokine levels, including Cxcl1, Cxcl2, and Ccl20. Furthermore, the expression of several epithelial secretory proteins and antimicrobial molecules was considerably suppressed in the lungs of Splunc1 KO mice. The deficiency of Splunc1 in mouse airway epithelium also results in increased biofilm formation of P. aeruginosa. Taken together, our results support that the ablation of Splunc1 in mouse airways affects the mucociliary clearance, resulting in decreased innate immune response during Pseudomonas-induced respiratory infection. PMID- 24048906 TI - Mutation analysis of PAH gene in patients with PKU in western Iran and its association with polymorphisms: identification of four novel mutations. AB - Phenylketonuria (PKU) is an autosomal recessive disorder characterized by a mutation in the phenylalanine hydroxylase (PAH) gene. Untreated PKU can lead to mental retardation, seizures, and other serious medical problems. This study was designed to investigate the status of molecular defects in the PAH gene and their association with polymorphisms in Kurdish patients with PKU in the Kermanshah province, western Iran. The study was conducted on 27 unrelated patients with PKU over a 2-year period (from 2010 to 2012). All 13 exons plus exon-intron boundaries of the PAH gene were analyzed and we identified 15 different mutations, including two novel mutations, in 51 of the 54 mutant alleles (diagnostic efficiency of 94.4 %). IVS4 + 1G > C (c.441 + 1G > C) and IVS7 - 5 T > C (c.843 - 5 T > C) are novel mutations that have not been reported in the academic literature or the PAH locus database ( http://www.pahdb.mcgill.ca ); therefore, they may be specific to the Kurdish population. IVS2 + 5G > C and IVS9 + 5G > A were the two most prevalent mutations in our sample, with frequencies of 26 % and 17 %, respectively. The second most common mutations were p.R261X, IVS10 - 11G > A, p.K363 > Nfs and IVS7 - 5 T > C, with each showing a relative frequency of 7.4 %. All other detected mutations, including p.F55 > Lfs, p.R176X, p.R243Q, p.V230I, p.R243X, p.R261Q, IVS8 - 7A > G and p.E390G had frequencies of less than 4 %. The present study showed that there is a distinct difference in the characteristics of PAH mutations between the Kermanshah province and other parts of Iran, suggesting that Kermanshah may have a unique population distribution of PAH gene mutations. Iran lies on the route of major ancient movements of the Caucasian people toward the Mediterranean basin, and Kermanshah has previously been called the gateway to Asia. Most of the mutations identified in this study are common in the Mediterranean region. Therefore, our findings are consistent with the historical and geographical links between the Iranian population and the populations of Mediterranean region. PMID- 24048908 TI - Mutation analysis of a large cohort of GNE myopathy reveals a diverse array of GNE mutations affecting sialic acid biosynthesis. PMID- 24048907 TI - Can ECAP measures be used for totally objective programming of cochlear implants? AB - An experiment was conducted with eight cochlear implant subjects to investigate the feasibility of using electrically evoked compound action potential (ECAP) measures other than ECAP thresholds to predict the way that behavioral thresholds change with rate of stimulation, and hence, whether they can be used without combination with behavioral measures to determine program stimulus levels for cochlear implants. Loudness models indicate that two peripheral neural response characteristics contribute to the slope of the threshold versus rate function: the way that neural activity to each stimulus pulse decreases as rate increases and the slope of the neural response versus stimulus current function. ECAP measures related to these two characteristics were measured: the way that ECAP amplitude decreases with stimulus rate and the ECAP amplitude growth function, respectively. A loudness model (incorporating temporal integration and the two neural response characteristics) and regression analyses were used to evaluate whether the ECAP measures could predict the average slope of the behavioral threshold versus current function and whether individual variation in the measures could predict individual variation in the slope of the threshold function. The average change of behavioral threshold with increasing rate was well predicted by the model when using the average ECAP data. However, the individual variations in the slope of the thresholds versus rate functions were not well predicted by individual variations in ECAP data. It was concluded that these ECAP measures are not useful for fully objective programming, possibly because they do not accurately reflect the neural response characteristics assumed by the model, or are measured at current levels much higher than threshold currents. PMID- 24048911 TI - Mechanical effects of defect closure following BPTB graft harvest for ACL reconstruction. AB - Anterior cruciate ligament injury affects roughly 120,000 athletes in the United States every year. One of the most common techniques is the use of a bone patellar tendon-bone graft. Graft harvest creates a sizeable defect in the remaining patellar tendon. Closure of this defect is based on surgeon preference. To date there has been no study on the effects of defect closure on the mechanical properties of remaining donor patellar tendon. The goal of this study was to investigate the effect of closure on both the strength and stiffness of the remaining patellar tendon. 7 pairs of fresh frozen cadaver patellar tendons were matched by tendon dimensions. Bone-patellar tendon-bone grafts were harvested from all of the specimens and then half of the paired tendons underwent defect closure. All of the donor tendons were then tested in a servohydraulic load frame to failure at a constant displacement rate at room temperature. This study found no differences in the load at failure, the engineering failure stress, stiffness or in the engineering modulus between the donor tendons that underwent defect closure versus those that did not. PMID- 24048910 TI - 12 weeks of simulated barefoot running changes foot-strike patterns in female runners. AB - To investigate the effect of a transition program of simulated barefoot running (SBR) on running kinematics and foot-strike patterns, female recreational athletes (n=9, age 29 +/- 3 yrs) without SBR experience gradually increased running distance in Vibram FiveFingers SBR footwear over 12 weeks. Matched controls (n=10, age 30 +/- 4 yrs) continued running in standard footwear. A 3-D motion analysis of treadmill running at 12 km/h(-1) was performed by both groups, barefoot and shod, pre- and post-intervention. Post-intervention data indicated a more-forefoot strike pattern in the SBR group compared to controls; both running barefoot (P>0.05), and shod (P<0.001). When assessed barefoot, there were significant kinematic differences across time in the SBR group for ankle flexion angle at toe-off (P<0.01). When assessed shod, significant kinematic changes occurred across time, for ankle flexion angles at foot-strike (P<0.001) and toe off (P<0.01), and for range of motion (ROM) in the absorptive phase of stance (P<0.01). A knee effect was recorded in the SBR group for flexion ROM in the absorptive phase of stance (P<0.05). No significant changes occurred in controls. Therefore, a 12-week transition program in SBR could assist athletes seeking a more-forefoot strike pattern and "barefoot" kinematics, regardless of preferred footwear. PMID- 24048909 TI - The benefits of a high-intensity aquatic exercise program (HydrOS) for bone metabolism and bone mass of postmenopausal women. AB - This study aimed to evaluate the 24-week effects of a high-intensity aquatic exercise program on bone remodeling markers and bone mass of postmenopausal women. In this randomized, controlled trial we studied 108 women (58.8 +/- 6.4 years), randomized into Aquatic Exercise Group (AEG), n = 64, performing 24 weeks of aquatic exercises, and Control Group (CG), n = 44, sedentary. They had their fasting morning blood sample collected for the measures of intact parathyroid hormone (iPTH), procollagen type 1 amino-terminal propeptide (P1NP) and carboxy terminal cross-linking telopeptide of type I collagen (CTx). Bone mass was measured by dual-energy X-ray absorptiometry before and after the intervention. Participants of both groups received a daily supplementation of 500 mg of elementary calcium and 1,000 IU of vitamin D (cholecalciferol). Results showed an augment in bone formation marker (P1NP) only in the AEG (15.8 %; p = 0.001), and although both groups experienced significant enhancements in bone resorption marker (CTx), this increase was less considerable in the AEG (15 % in the AEG and 29 % in the CG). IPTH was increased by 19 % in the CG (p = 0.003) at the end. The femoral trochanter BMD presented a 1.2 % reduction in the CG (p = 0.009), whereas in the AEG no change was observed (p = 0.069). The proposed aquatic exercise program was efficient in attenuating bone resorption raise and enhancing bone formation, which prevented the participants in the AEG from reducing the femoral trochanter BMD, as happened in the CG. PMID- 24048912 TI - Plasma matrix metalloproteinase-9 response to downhill running in humans. AB - Matrix metalloproteinase-9 is a proteolytic enzyme capable of degrading proteins of the muscle extracellular matrix. Systemic levels of MMP-9 or its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), have the potential to serve as blood markers of exercise-induced muscle damage. The purpose of this study was to determine if an eccentrically-dominated task, downhill running (DHR), produces changes in plasma MMP-9 or TIMP-1 and examine the relationship between MMP-9/TIMP 1 levels and indirect indicators of muscle damage. Subjects were sedentary (SED, n=12) or had a history of concentrically-biased training (CON, n=9). MMP-9 and TIMP-1 were measured before (Pre-Ex), immediately after (Post-Ex), and 1-, 2-, 4 , and 7-days post-DHR (-10 degrees ), and compared to discomfort ratings, creatine kinase activity and strength loss. At 1-day Post-Ex, discomfort increased (5.6 +/- 7.8 to 45.5 +/- 19.9 mm; 0-100 mm scale), strength decreased ( 6.9 +/- 1.6%) and CK increased (162.9 +/- 177.2%). MMP-9 was modestly but significantly increased at Post-Ex in both CONC and SED (32.7 +/- 33.6%) and at 4 days in SED (66.9 +/- 88.1%), Individual responses were variable, however. There were no correlations between MMPs and discomfort ratings, plasma CK or strength. While plasma MMP-9 changes may be detectable in the systemic circulation after DHR, they are small and do not correspond to other markers of damage. PMID- 24048913 TI - Reducing resistance training volume during Ramadan improves muscle strength and power in football players. AB - We aimed to examine the effect of maintaining or reducing resistance training volume during Ramadan-intermittent-fasting (RIF) on short-term maximal performances. 20 footballers (age: 18.4 +/- 0.8 years; body-mass: 72.4 +/- 4.1 kg; height: 183.4 +/- 4.6 cm) were matched and randomly assigned to a normal training-group (G1) or a tapering-group (G2). They were tested for muscular strength (maximal-voluntary-contraction) and power (squat-jump and counter movement-jump) 1 month before RIF (T0), 1 week before RIF (T1), after 2 weeks of fasting (T2) and at the end of RIF (T3). From T1 to T2, subjects performed a whole-body resistance training program (8-repetitions * 4-sets with 4-min recovery in-between). During RIF, G1 maintained the same training program, while G2 performed a period of reduced training volume (3 sets/exercise; - 22%). Muscle strength and power increased significantly from T0 to T1, from T0 to T2 and from T0 to T3 in G1 and G2 and from T1 to T2 and from T1 to T3 only in G2 (p<0.05). Performance was higher in G2 than G1 during T2 (p<0.01). Moreover, the ?-change of performance between T0 and T2 and T3 was significantly higher in G2 than G1 (p<0.05). For young soccer players, a tapering period characterized by a reduced training volume during RIF may lead to significant improvement in muscle strength and power. PMID- 24048914 TI - How much diagnostic safety can we afford, and how should we decide? A health economics perspective. PMID- 24048915 TI - Species- and chamber-specific responses of 12 kDa FK506-binding protein to temperature in fish heart. AB - The sarcoplasmic reticulum (SR) Ca(2+) release channel or ryanodine receptor (RyR) of the vertebrate heart is regulated by the FK506-binding proteins, FKBP12 and FKBP12.6. This study examines whether temperature-related changes in the SR function of fish hearts are associated with changes in FKBP12 expression. For this purpose, a polyclonal antibody against trout FKBP12 was used to compare FKPB12 expression in cold-acclimated (4 degrees C, CA) and warm-acclimated (18 degrees C, WA) rainbow trout (Oncorhynchus mykiss), burbot (Lota lota) and crucian carp (Carassius carassius) hearts. FKBP12 expression was modulated in a species- and tissue-specific manner. Temperature acclimation affected FKBP12 expression only in atrial tissue. Changes in the ventricular FKBP12 expression were not detected in any of the fish species. In the atria of rainbow trout and crucian carp, temperature acclimation produced opposite thermal responses: FKBP12 increased in the trout atrium and decreased in the crucian carp atrium under cold acclimation. In the burbot heart, chronic temperature changes did not affect cardiac FKBP12 levels. Expression of FKBP12 mRNA in rainbow trout and crucian carp hearts suggests that the transcript levels are higher in the ventricle than in the atrium and are elevated by cold acclimation in trout, but not in crucian carp. Since FKBP12 is known to increase the Ca(2+) sensitivity of cardiac RyRs and thereby the opening frequency of the Ca(2+) release channels, temperature related changes in FKBP12 expression may modify the SR function in excitation contraction coupling. The cold-induced increase in FKBP12 in the trout atrium and decrease in the crucian carp atrium are consistent with the previously noted increase and decrease, respectively, of SR Ca(2+) stores in cardiac contraction in these species. PMID- 24048916 TI - An economic evaluation of anonymised information sharing in a partnership between health services, police and local government for preventing violence-related injury. AB - OBJECTIVE: To assess the costs and benefits of a partnership between health services, police and local government shown to reduce violence-related injury. METHODS: Benefit-cost analysis. RESULTS: Anonymised information sharing and use led to a reduction in wounding recorded by the police that reduced the economic and social costs of violence by L6.9 million in 2007 compared with the costs the intervention city, Cardiff UK, would have experienced in the absence of the programme. This includes a gross cost reduction of L1.25 million to the health service and L1.62 million to the criminal justice system in 2007. By contrast, the costs associated with the programme were modest: setup costs of software modifications and prevention strategies were L107 769, while the annual operating costs of the system were estimated as L210 433 (2003 UK pound). The cumulative social benefit-cost ratio of the programme from 2003 to 2007 was L82 in benefits for each pound spent on the programme, including a benefit-cost ratio of 14.80 for the health service and 19.1 for the criminal justice system. Each of these benefit-cost ratios is above 1 across a wide range of sensitivity analyses. CONCLUSIONS: An effective information-sharing partnership between health services, police and local government in Cardiff, UK, led to substantial cost savings for the health service and the criminal justice system compared with 14 other cities in England and Wales designated as similar by the UK government where this intervention was not implemented. PMID- 24048917 TI - Delirium is a predictor of in-hospital mortality in elderly patients with community acquired pneumonia. AB - Community acquired pneumonia (CAP) is a common reason for hospitalization and death in elderly people. Many predictors of in-hospital outcome have been studied in the general population with CAP. However, data are lacking on the prognostic significance of conditions unique to older patients, such as delirium and the coexistence of multiple comorbidities. The aim of this study was to evaluate predictors of in-hospital outcome in elderly patients hospitalized for CAP. In this retrospective study, consecutive patients with CAP aged >=65 years were enrolled between January 2011 and June 2012 in two general wards. Clinical and laboratory characteristics were collected from electronic medical records. The end-point of the study was the occurrence of in-hospital death. 443 patients (mean age 81.8 +/- 7.5, range 65-99 years) were enrolled. More than 3 comorbidities were present in 31 % of patients. Mean confusion, blood urea nitrogen, respiratory rate, blood pressure and age >=65 years (CURB-65) score was 2.5 +/- 0.7 points. Mean length of stay was 7.6 +/- 5.7 days. In-hospital death occurred in 54 patients (12.2 %). At multivariate analysis, independent predictors of in-hospital death were: chronic obstructive pulmonary disease (COPD) (OR 6.21, p = 0.005), occurrence of at least one episode of delirium (OR 5.69, p = 0.017), male sex (OR 5.10, p < 0.0001), and CURB-65 score (OR 3.98, p < 0.0001). Several predictors of in-hospital death (COPD, male gender, CURB-65) in patients with CAP older than 65 years are similar to those of younger patients. In this cohort of elderly patients, the occurrence of delirium was highly prevalent and represented a distinctive predictor of death. PMID- 24048918 TI - Mirror for the other: problem of the self in continental philosophy (from Hegel to Lacan). AB - This essay intends to explore the genesis of one of the key concepts in continental philosophy of personalism-the concept of the 'Other. It attempts to use most influential philosophical and psychological contexts to demonstrate how the Self is linked to the Other logically, notionally and conceptually. The present analysis employs two principal approaches to the problem-philosophical and psychological. From the stand point of the former, the key figure of the hereunder discourse is Hegel and his theory, while the later will be represented predominantly by Lacanian ideas. The present article will also discuss major influences of Hegel's philosophical ideas on the Lacan's theory. PMID- 24048919 TI - Microtransitions and the dynamics of family functioning. AB - This paper presents a qualitative observational study aimed at exploring microtransitions in the relational dynamics of family functioning when the children are adolescents. Three concurrent levels were considered central for family functioning in this period: the acknowledgment of emerging competences, the redefinition of the power structure, and the regulation of interpersonal distances. Twenty-eight non-clinical Italian families with at least one adolescent child were interviewed and video-recorded in their homes. A stance taking process analysis was carried out on the family interactive sequences arising in the course of the interviews. This analysis was based on the stances taken by all family members in relation to their reciprocal evaluations, positions, and alignments, which allowed us to point out the interlocking of competences, power and distances. Out of all the possible theoretical combinations of these three dimensions, we identified four forms of interaction. In two forms, the emerging changes were not incorporated in the families' interactive repertoires by either reconfirming family stability or resisting family changes. In these ways of interacting competences, power, and distances were not reorganized. In the other two forms, instead, family microtransitions were observable in the extent to which family members either explored family changes or legitimated family reorganizations. In these processes, they could redefine and readdress their ways of interacting. PMID- 24048921 TI - Neither property right nor heroic gift, neither sacrifice nor aporia: the benefit of the theoretical lens of sharing in donation ethics. AB - Two ethical frameworks have dominated the discussion of organ donation for long: that of property rights and that of gift-giving. However, recent years have seen a drastic rise in the number of philosophical analyses of the meaning of giving and generosity, which has been mirrored in ethical debates on organ donation and in critical sociological, anthropological and ethnological work on the gift metaphor in this context. In order to capture the flourishing of this field, this article distinguishes between four frameworks for thinking about bodily exchanges in medicine: those of property rights, heroic gift-giving, sacrifice, and gift giving as aporia. These frameworks represent four different ways of making sense of donation of organs as well as tissue, gametes and blood, draw on different conceptions of the relations between the self and the other, and bring out different ethical issues as core ones. The article presents these frameworks, argues that all of them run into difficulties when trying to make sense of reciprocity and relational interdependence in donation, and shows how the three gift-giving frameworks (of heroism, sacrifice and aporia) hang together in a critical discussion about what is at stake in organ donation. It also presents and argues in favour of an alternative intercorporeal framework of giving-through sharing that more thoroughly explicates the gift metaphor in the context of donation, and offers tools for making sense of relational dimensions of live and post mortem donations. PMID- 24048922 TI - Protective effect of curcuminoids on age-related mitochondrial impairment in female Wistar rat brain. AB - The present study demonstrated the neuroprotective effect of curcuminoids, the active polyphenols of Curcuma longa (L.) rhizomes on mitochondrial dysfunctioning in middle aged and aged female Wistar rat brain. Rats were orally treated with curcuminoids (100 mg/kg) for 3 months and their brain was collected for evaluation of mitochondrial enzymes and complexes activity, ultra structural changes in mitochondria, neuronal nitric oxide synthase (nNOS) protein expression, adenosine triphosphate (ATP) and lipofuscin content. Significant alterations were observed in all the tested parameters in highly aged rat brain when compared with young control. Long term curcuminoids administration prevented this age associated loss of mitochondrial enzymes and complexes activity in middle aged rat brain except for malate dehydrogenase, Complex II and IV activity when compared with young control. Among aged rats, curcuminoids treatment specifically elevated isocitrate and NADH dehydrogenase, cytochrome c oxidase, Complex I and total ATP content. A significant down-regulation of nNOS protein expression along with reduced lipofuscin content was also observed in curucminoids treated middle aged and aged rats. Thus, it was suggested that curcuminoids may act as a putative drug candidate for the prevention of deleterious effects of ageing and age associated neurodegenerative disorders through amelioration of aberrant mitochondrial functioning. PMID- 24048923 TI - Immunostaining of the developing embryonic and larval Drosophila brain. AB - Immunostaining is used to visualize the spatiotemporal expression pattern of developmental control genes that regulate the genesis and specification of the embryonic and larval brain of Drosophila. Immunostaining uses specific antibodies to mark expressed proteins and allows their localization to be traced throughout development. This method reveals insights into gene regulation, cell-type specification, neuron and glial differentiation, and posttranslational protein modifications underlying the patterning and specification of the maturing brain. Depending on the targeted protein, it is possible to visualize a multitude of regions of the Drosophila brain, such as small groups of neurons or glia, defined subcomponents of the brain's axon scaffold, or pre- and postsynaptic structures of neurons. Thus, antibody probes that recognize defined tissues, cells, or subcellular structures like axons or synaptic terminals can be used as markers to identify and analyze phenotypes in mutant embryos and larvae. Several antibodies, combined with different labels, can be used concurrently to examine protein co localization. This protocol spans over 3-4 days. PMID- 24048924 TI - Non-fluorescent RNA in situ hybridization combined with antibody staining to visualize multiple gene expression patterns in the embryonic brain of Drosophila. AB - In Drosophila, the brain arises from about 100 neural stem cells (called neuroblasts) per hemisphere which originate from the neuroectoderm. Products of developmental control genes are expressed in spatially restricted domains in the neuroectoderm and provide positional cues that determine the formation and identity of neuroblasts. Here, we present a protocol for non-fluorescent double in situ hybridization combined with antibody staining which allows the simultaneous representation of gene expression patterns in Drosophila embryos in up to three different colors. Such visible multiple stainings are especially useful to analyze the expression and regulatory interactions of developmental control genes during early embryonic brain development. We also provide protocols for whole mount and flat preparations of Drosophila embryos, which allow a more detailed analysis of gene expression patterns in relation to the cellular context of the early brain (and facilitate the identification of individual brain neuroblasts) using conventional light microscopy. PMID- 24048925 TI - Analysis of complete neuroblast cell lineages in the Drosophila embryonic brain via DiI labeling. AB - Proper functioning of the brain relies on an enormous diversity of neural cells generated by neural stem cell-like neuroblasts (NBs). Each of the about 100 NBs in each side of brain generates a nearly invariant and unique cell lineage, consisting of specific neural cell types that develop in defined time periods. In this chapter we describe a method that labels entire NB lineages in the embryonic brain. Clonal DiI labeling allows us to follow the development of a NB lineage starting from the neuroectodermal precursor cell up to the fully developed cell clone in the first larval instar brain. We also show how to ablate individual cells within a NB clone, which reveals information about the temporal succession in which daughter cells are generated. Finally, we describe how to combine clonal DiI labeling with fluorescent antibody staining that permits relating protein expression to individual cells within a labeled NB lineage. These protocols make it feasible to uncover precise lineage relationships between a brain NB and its daughter cells, and to assign gene expression to individual clonal cells. Such lineage-based information is a critical key for understanding the cellular and molecular mechanisms that underlie specification of cell fates in spatial and temporal dimension in the embryonic brain. PMID- 24048926 TI - Flybow to dissect circuit assembly in the Drosophila brain. AB - Visualization of single neurons within their complex environment is a pivotal step towards uncovering the mechanisms that control neural circuit development and function. This chapter provides detailed technical information on how to use Drosophila variants of the mouse Brainbow-2 system, called Flybow, for stochastic labeling of cells with different fluorescent proteins in one sample. We first describe the genetic strategies and the heat shock regime required for induction of recombination events. This is followed by a detailed protocol as to how to prepare samples for imaging. Finally, we provide specifications to facilitate multichannel image acquisition using confocal microscopy. PMID- 24048927 TI - Immunofluorescent labeling of neural stem cells in the Drosophila optic lobe. AB - The Drosophila visual system is an excellent model system to study the switch from proliferating to differentiating neural stem cells. In the developing larval optic lobe, symmetrically dividing neuroepithelial cells transform to asymmetrically dividing neuroblasts in a highly ordered and sequential manner. This chapter presents a protocol to visualize neural stem cell types in the Drosophila optic lobe by fluorescence confocal microscopy. A main focus is given on how to dissect, fix, immunolabel, and mount brains to reveal cellular morphology during early larval brain development. PMID- 24048928 TI - Using MARCM to study Drosophila brain development. AB - Mosaic analysis with a repressible cell marker (MARCM) generates positively labeled, wild-type or mutant mitotic clones by unequally distributing a repressor of a cell lineage marker, originally tubP-driven GAL80 repressing the GAL4/UAS system. Variations of the technique include labeling of both sister clones (twin spot MARCM), the simultaneous use of two different drivers within the same clone (dual MARCM), as well as the use of different repressible transcription systems (Q-MARCM). MARCM can be combined with any UAS-based construct, such as localized GFP fusions to visualize subcellular compartments, genes for rescue and ectopic expression, and modifiers of neural activity. A related technique, the twin spot generator, generates positively labeled clones without the use of a repressor, thus minimizing the lag time between clone induction and appearance of label. The present protocol provides a detailed description of a standard MARCM analysis of brain development that includes generation of MARCM stocks and crosses, induction of clones, brain dissection at various stages of development, immunohistochemistry, and confocal microscopy, and can be modified for similar experiments involving mitotic clones. PMID- 24048929 TI - Dye coupling and immunostaining of astrocyte-like glia following intracellular injection of fluorochromes in brain slices of the grasshopper, Schistocerca gregaria. AB - Injection of fluorochromes such as Alexa Fluor((r)) 568 into single cells in brain slices reveals a network of dye-coupled cells to be associated with the central complex. Subsequent immunolabeling shows these cells to be repo positive/glutamine synthetase positive/horseradish peroxidase negative, thus identifying them as astrocyte-like glia. Dye coupling fails in the presence of n heptanol indicating that dye spreads from cell to cell via gap junctions. A cellular network of dye-coupled, astrocyte-like, glia surrounds and infiltrates developing central complex neuropils. Intracellular dye injection techniques complement current molecular approaches in analyzing the functional properties of such networks. PMID- 24048930 TI - Methods in brain development of molluscs. AB - Representatives of the phylum Mollusca have long been important models in neurobiological research. Recently, the routine application of immunocytochemistry in combination with confocal laser scanning microscopy has allowed fast generation of highly detailed reconstructions of neural structures of even the smallest multicellular animals, including early developmental stages. As a consequence, large-scale comparative analyses of neurogenesis-an important prerequisite for inferences concerning the evolution of animal nervous systems are now possible in a reasonable amount of time. Herein, we describe immunocytochemical staining protocols for both whole-mount preparations of developmental stages-usually 70-300 MUm in size-as well as for vibratome sections of complex brains. Although our procedures have been optimized for marine molluscs, they may easily be adapted for other (marine) organisms by the creative neurobiologist. PMID- 24048931 TI - In situ hybridization and immunostaining of Xenopus brain. AB - The dynamic expression pattern analysis provides the primary information of gene function. Differences of the RNA and/or protein location will provide valuable information for gene expression regulation. Generally, in situ hybridization (ISH) and immunohistochemistry (IHC) are two main techniques to visualize the locations of gene transcripts and protein products in situ, respectively. Here we describe the protocol for the whole brain dissection, the in situ hybridization and immunostaining of the developing Xenopus brain sections. Additionally, we point out the modification of in situ hybridization for microRNA expression detection. PMID- 24048932 TI - Microinjection manipulations in the elucidation of Xenopus brain development. AB - Microinjection has a long and distinguished history in Xenopus and has been used to introduce a surprisingly diverse array of agents into embryos by both intra- and intercellular means. In addition to nuclei, investigators have variously injected peptides, antibodies, biologically active chemicals, lineage markers, mRNA, DNA, morpholinos, and enzymes. While enumerating many of the different microinjection approaches that can be taken, we will focus upon the mechanical operations and options available to introduce mRNA, DNA, and morpholinos intracellularly into early stage embryos for the study of neurogenesis. PMID- 24048933 TI - Morpholino studies in Xenopus brain development. AB - Antisense morpholino oligonucleotides (MOs) have become a valuable method to knock down protein levels, to block mRNA splicing, and to interfere with miRNA function. MOs are widely used to alter gene expression during development of Xenopus and zebra fish, where they are typically injected into the fertilized egg or blastomeres. Here, we present methods to use electroporation to target delivery of MOs to the central nervous system of Xenopus laevis or Xenopus tropicalis tadpoles. Briefly, MO electroporation is accomplished by injecting MO solution into the brain ventricle and driving the MOs into cells in the brain with current passing between two platinum plate electrodes, positioned on either side of the target brain area. The method is straightforward and uses standard equipment found in many neuroscience labs. A major advantage of electroporation is that it allows spatial and temporal control of MO delivery and therefore knockdown. Co-electroporation of MOs with cell-type specific fluorescent protein expression plasmids allows morphological analysis of cellular phenotypes. Furthermore, co-electroporation of MOs with rescuing plasmids allows assessment of specificity of the knockdown and phenotypic outcome. By combining MO-mediated manipulations with sophisticated assays of neuronal function, such as electrophysiological recording, behavioral assays, or in vivo time-lapse imaging of neuronal development, the functions of specific proteins and miRNAs within the developing nervous system can be elucidated. These methods can be adapted to apply antisense morpholinos to study protein and RNA function in a variety of complex tissues. PMID- 24048934 TI - Sensitive whole-mount fluorescent in situ hybridization in zebrafish using enhanced tyramide signal amplification. AB - Whole-mount in situ hybridization is the preferred method for detecting transcript distributions in whole embryos, tissues, and organs. We present here a sensitive fluorescent in situ hybridization method for colocalization analysis of different transcripts in whole embryonic zebrafish brains. The method is based on simultaneous hybridization of differently hapten-labeled RNA probes followed by sequential rounds of horseradish peroxidase (POD)-based transcript detection. Sequential detection involves enhancement of fluorescent signals by tyramide signal amplification (TSA) and effective inactivation of the antibody-POD conjugate prior to the following detection round. We provide a detailed description of embryo preparation, hybridization, antibody detection, POD-TSA reaction, and mounting of embryos for imaging. To achieve high signal intensities, we optimized key steps of the method. This includes improvement of embryo permeability by hydrogen peroxide treatment and efficacy of hybridization and TSA-POD reaction by addition of the viscosity-increasing polymer dextran sulfate. The TSA-POD reaction conditions are further optimized by application of substituted phenol compounds as POD accelerators and use of highly efficient bench-made tyramide substrates. The obtained high signal intensities and cellular resolution of our method allows for co-expression analysis and generation of three-dimensional models. Our protocol is tailored to optimally work in zebrafish embryos, but can surely be modified for application in other species as well. PMID- 24048935 TI - Dynamic neuroanatomy at subcellular resolution in the zebrafish. AB - Genetic means to visualize and manipulate neuronal circuits in the intact animal have revolutionized neurobiology. "Dynamic neuroanatomy" defines a range of approaches aimed at quantifying the architecture or subcellular organization of neurons over time during their development, regeneration, or degeneration. A general feature of these approaches is their reliance on the optical isolation of defined neurons in toto by genetically expressing markers in one or few cells. Here we use the afferent neurons of the lateral line as an example to describe a simple method for the dynamic neuroanatomical study of axon terminals in the zebrafish by laser-scanning confocal microscopy. PMID- 24048936 TI - Anatomical dissection of zebrafish brain development. AB - Zebrafishbrain.org is an online neuroanatomical atlas of the embryonic zebrafish. The atlas uses high-resolution confocal images and movies of transgenic lines to describe different brain structures. This chapter covers detail of materials and protocols that we employ to generate data for the atlas. PMID- 24048937 TI - Immunohistochemistry and in situ hybridization in the developing chicken brain. AB - One of the first steps in studies of gene function is the spatiotemporal analysis of patterns of gene expression. Indirect immunohistochemistry is a method that allows the detection of a protein of interest by incubating a histological section with an antibody or antiserum raised against the protein and then localizing this primary antibody with a tagged secondary antibody. To determine the cellular source of a protein of interest, or if a specific antibody is not available, specific transcripts can be localized using in situ hybridization. A histological section is incubated with a labeled RNA probe that is complementary to the target transcript; after hybridization with the target transcript, the labeled RNA probe can be identified with an antibody. Here we describe materials and methods used to perform basic indirect immunohistochemistry and in situ hybridization on frozen sections through the developing chicken brain, emphasizing controls and potential problems that may be encountered. PMID- 24048938 TI - Transplantation of neural tissue: quail-chick chimeras. AB - Tissue transplantation is an important approach in developmental neurobiology to determine cell fate, to uncover inductive interactions required for tissue specification and patterning as well as to establish tissue competence and commitment. Avian species are among the favorite model systems for these approaches because of their accessibility and relatively large size. Here we describe two culture techniques used to generate quail-chick chimeras at different embryonic stages and methods to distinguish graft and donor tissue. PMID- 24048939 TI - RNAi-based gene silencing in chicken brain development. AB - The mouse is the most commonly used vertebrate model for the analysis of gene function because of the well-established genetic tools that are available for loss-of-function studies. However, studies of gene function during development can be problematic in mammals. Many genes are active during different stages of development. Absence of gene function during early development may cause embryonic lethality and thus prevent analysis of later stages of development. To avoid these problems, precise temporal control of gene silencing is required. In contrast to mammals, oviparous animals are accessible for experimental manipulations during embryonic development. The combination of accessibility and RNAi-based gene silencing makes the chicken embryo a powerful model for developmental studies. Depending on the time window during which gene silencing is attempted, chicken embryos can be used for RNAi in ovo or cultured in a domed dish for easier access during ex ovo RNAi. Both techniques allow for precise temporal control of gene silencing during embryonic development. PMID- 24048940 TI - Immunohistochemistry and RNA in situ hybridization in mouse brain development. AB - During development, the mouse brain is progressively divided into functionally distinct compartments. Numerous neuronal and glial cell types are subsequently generated in response to various inductive signals. Each cell expresses a unique combination of genes encoding proteins from transcription factors to neurotransmitters that define its role in brain function. To understand these important and highly sophisticated processes, it is critical to accurately locate the various proteins and cells that produce them. In this chapter, we introduce the techniques of immunohistochemistry, which detects the localization of specific proteins, and RNA in situ hybridization, which enables the visualization of specific mRNAs. PMID- 24048941 TI - In utero electroporation to study mouse brain development. AB - In utero electroporation is a rapid and powerful technique to study the development of many brain regions. This approach presents several advantages over other methods to study specific steps of brain development in vivo, from proliferation to synaptic integration. Here, we describe in detail the individual steps necessary to carry out the technique. We also highlight the variations that can be implemented to target different cerebral structures and to study specific steps of development. PMID- 24048942 TI - The Cre/Lox system to assess the development of the mouse brain. AB - Cre-mediated recombination has become a powerful tool to confine gene deletions (conditional knockouts) or overexpression of genes (conditional knockin/overexpression). By spatiotemporal restriction of genetic manipulations, major problems of classical knockouts such as embryonic lethality can be circumvented. Furthermore Cre-mediated recombination has broad applicability in the analysis of the cellular behavior of subpopulations and cell types as well as for genetic fate mapping. This chapter will give an overview about applications for the Cre/LoxP system and their execution. PMID- 24048944 TI - NTS AT1a receptor on long-term arterial pressure regulation: putative mechanism. PMID- 24048945 TI - Failing mouse hearts utilize energy inefficiently and benefit from improved coupling of glycolysis and glucose oxidation. AB - AIMS: To determine whether post-infarction LV dysfunction is due to low energy availability or inefficient energy utilization, we compared energy metabolism in normal and failing hearts. We also studied whether improved coupling of glycolysis and glucose oxidation by knockout of malonyl CoA decarboxylase (MCD KO) would have beneficial effects on LV function and efficiency. METHODS AND RESULTS: Male C57BL/6 mice were subjected to coronary artery ligation (CAL) or sham operation (SHAM) procedure. After 4 weeks and echocardiographic evaluation, hearts were perfused (working mode) to measure LV function and rates of energy metabolism. Similar protocols using MCD-KO mice and wild-type (WT) littermates were used to assess consequences of MCD deficiency. Relative to SHAM, CAL hearts had impaired LV function [lower % ejection fraction (%EF, 49%) and LV work (46%)]. CAL hearts had higher rates (expressed per LV work) of glycolysis, glucose oxidation, and proton production. LV work per ATP production from exogenous sources was lower in CAL hearts, indicative of inefficient exogenous energy substrate utilization. Fatty acid oxidation rates, ATP, creatine, and creatine phosphate contents were unaffected. Utilization of endogenous substrates, triacylglycerol and glycogen, was similar in CAL and SHAM hearts. MCD KO CAL hearts had 31% higher %EF compared with that of WT-CAL, and lower rates of glycolysis, glucose oxidation, proton production, and ATP production, indicative of improved efficiency. CONCLUSION: CAL hearts are inefficient in utilizing energy for mechanical function, possibly due to higher proton production arising from mismatched glycolysis and glucose oxidation. MCD deficiency lessens proton production, LV dysfunction, and inefficiency of exogenous energy substrate utilization. PMID- 24048943 TI - Improvement of NADPH bioavailability in Escherichia coli by replacing NAD(+) dependent glyceraldehyde-3-phosphate dehydrogenase GapA with NADP (+)-dependent GapB from Bacillus subtilis and addition of NAD kinase. AB - Enzymatic synthesis of some industrially important compounds depends heavily on cofactor NADPH as the reducing agent. This is especially true in the synthesis of chiral compounds that are often used as pharmaceutical intermediates to generate the correct stereochemistry in bioactive products. The high cost and technical difficulty of cofactor regeneration often pose a challenge for such biocatalytic reactions. In this study, to increase NADPH bioavailability, the native NAD(+) dependent glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gapA gene in Escherichia coli was replaced with a NADP(+)-dependent gapB from Bacillus subtilis. To overcome the limitation of NADP(+) availability, E. coli NAD kinase, nadK was also coexpressed with gapB. The recombinant strains were then tested in three reporting systems: biosynthesis of lycopene, oxidation of cyclohexanone with cyclohexanone monooxygenase (CHMO), and an anaerobic system utilizing 2 haloacrylate reductase (CAA43). In all the reporting systems, replacing NAD(+) dependent GapA activity with NADP(+)-dependent GapB activity increased the synthesis of NADPH-dependent compounds. The increase was more pronounced when NAD kinase was also overexpressed in the case of the one-step reaction catalyzed by CAA43 which approximately doubled the product yield. These results validate this novel approach to improve NADPH bioavailability in E. coli and suggest that the strategy can be applied in E. coli or other bacterium-based production of NADPH dependent compounds. PMID- 24048947 TI - Spinal cord stimulation: Subjective pain intensity and presurgical correlates in chronic pain patients. AB - OBJECTIVES: This study determined the changes in pain intensity prior to and after permanent placement of spinal cord stimulation (SCS), as measured by the Visual Analog Scale (VAS) and, examined associations of presurgical characteristics to both pre- and post-SCS VAS scores. MATERIALS AND METHODS: Demographic, disease, and psychological data were extracted from the medical charts of chronic pain patients (N = 58) being treated at a Hospital in IL, USA. Most patients were diagnosed with complex regional pain syndrome (51.9%) and low back pain (33.3%). The majority were White (72.5%), male (60%), married (72%), and temporary disabled or receiving worker's compensation (40%). Study objectives were tested with correlational and univariate analysis. RESULTS: A significant reduction between pre (M = 6.87; SD = 1.38) and Post-(M = 4.11; SD = 1.54) SCS pain intensity scores was observed (p < .000). Pre-SCS pain intensity scores were associated with medical diagnosis (p < .01), marital status (p < .05), and catastrophizing (p < .05). Post-SCS pain intensity scores were associated with body mass index (p < .05), medical diagnosis (p < .05), employment status (p < .05), bodily concern (p < .05), marital status (p < .05), and race (p < .05). CONCLUSIONS: Results strengthen support for the short-term effectiveness of SCS and demonstrate the differential associations of presurgical factors on pain intensity. PMID- 24048948 TI - Effect of the treatment of root surface-adhered necrotic periodontal ligament with propolis or fluoride in delayed rat tooth replantation. AB - OBJECTIVES: The purpose of this study was to evaluate the application of 15 % propolis and 2 % acidulated-phosphate sodium fluoride solutions on the root surface-adhered necrotic cemental periodontal ligament in delayed tooth replantation. MATERIALS AND METHODS: Thirty Wistar rats (Rattus norvegicus, albinus) had their right upper incisor extracted and maintained in dry storage for 60 min. After this period, the dental papilla, enamel organ, and pulp tissue were removed, and the animals were randomly assigned to three groups: group I = immersion in saline for 10 min; group II = immersion in a 2 % acidulated phosphate sodium fluoride solution for 10 min; and group III = immersion in a 15 % propolis and propylene glycol solution for 10 min. The root canals were filled with a calcium hydroxide paste and the teeth were replanted. RESULTS: Inflammatory resorption, replacement resorption, and ankylosis were observed in all groups without a statistically significant difference (p > 0.05) among them. CONCLUSIONS: Under the tested conditions, the application of fluoride or propolis on root surface-adhered necrotic periodontal ligament did not favor the healing process in delayed tooth replantation. PMID- 24048949 TI - Diagnostic accuracy of CBCT for periodontal lesions. AB - OBJECTIVES: The present study compares the diagnostic value of periodontal bone defect images using conventional two-dimensional single-tooth radiographs and three-dimensional cone beam computed tomography (CBCT) images. MATERIALS AND METHODS: Classified periodontal bone defects were prepared on pig mandibles and presented radiographically. Fifteen dentists were instructed to make a diagnosis based on these x-rays, regarding the type and the extent of the bone defects. Subsequently, the results were evaluated and compared to the morphology of the surgically prepared defects as the gold standard. RESULTS: On average, the diagnosis of infrabony defects were 21 %, dehiscence 25 %, and fenestration 33 % more accurate using the three-dimensional projection than with the single-tooth radiograph. Furthermore, the CBCT allows grade II furcation to be captured more accurately. CONCLUSIONS: The results of this study indicate that a considerably more precise analysis of periodontal defects is possible due to the third dimension. Particularly, in the oro-vestibular orientation, defects could be detected significantly more accurate. CLINICAL RELEVANCE: CBCT images offer an advantageous alternative to the conventional single-tooth radiograph while taking the higher exposure of radiation into account. PMID- 24048950 TI - Bioequivalence study of two oral formulations of irbesartan 300 mg in healthy volunteers. AB - A bioequivalence study of 2 irbesartan (CAS 138402-11-6) film-coated tablet formulations was carried out in 40 healthy volunteers according to an open label, randomized, 2-period, 2-sequence, crossover, single dose and fasting conditions design. The test and reference formulations were administered in 2 treatment days, separated by a washout period of 7 days. Blood samples were drawn up to 96 h following drug administration. Plasma concentrations of irbesartan were obtained by a validated HPLC method using MS/MS detection. Log-transformed AUC0-t and Cmax values were tested for bioequivalence based on the ratios of the geometric LSmeans (test/reference). tmax was analysed nonparametrically. The 90% confidence intervals of the geometric LSmean values for the test/reference ratios for AUC0-t (98.06-109.48%, point estimator 103.61%) and Cmax (88.93-100.87%, point estimator 94.72%) were within the bioequivalence acceptance range of 80 125%. According to the European Guideline on the Investigation of Bioequivalence it may be therefore concluded that test formulation of irbesartan 300 mg film coated tablet is bioequivalent to the reference formulation. Overall, it was judged that the study was conducted with a good tolerance of the subjects to both study drugs. PMID- 24048951 TI - Study of stress degradation behavior of rasagiline mesylate under hydrolytic conditions by high performance liquid chromatography. AB - A precise and rapid reverse phase HPLC method has been developed for the estimation of Rasagiline Mesylate in bulk drug under stressed hydrolytic conditions according to ICH guidelines Q1(A)R2. The stressed samples of Rasagiline Mesylate were analyzed using Prontosil ODS column. The mobile phase consists of methanol and Phosphate buffer. The pH of the phosphate buffer was adjusted to 3.0 using orthophosphoric acid. The composition of mobile phase Methanol: Phosphate buffer (75:25 v/v) was kept constant up to 1 minute and then changed to 90:10 v/v in next 9 min by HPLC gradient programming. The flow rate was maintained at 1.0 ml/min and detection was carried out at 210 nm using 996 PDA detector. The method was validated in terms of linearity, accuracy, precision specificity and selectivity. The method was found to be linear in the range of 5 15 ug/ml with a correlation coefficient of 0.993. PMID- 24048952 TI - Impact of baseline weight on smoking cessation and weight gain in quitlines. AB - BACKGROUND: The use and effectiveness of tobacco quitlines by weight is still unknown. PURPOSE: This study aims to determine if baseline weight is associated with treatment engagement, cessation, or weight gain following quitline treatment. METHODS: Quitline participants (n = 595) were surveyed at baseline, 3 and 6 months. RESULTS: Baseline weight was not associated with treatment engagement. In unadjusted analyses, overweight smokers reported higher quit rates and were more likely to gain weight after quitting than obese or normal weight smokers. At 3 months, 40 % of overweight vs. 25 % of normal weight or obese smokers quit smoking (p = 0.01); 42 % of overweight, 32 % of normal weight, and 33 % of obese quitters gained weight (p = 0.05). After adjusting for covariates, weight was not significantly related to cessation (approaching significance at 6 months, p = 0.06) or weight gain. CONCLUSIONS: In the first quitline study of this kind, we found no consistent patterns of association between baseline weight and treatment engagement, cessation, or weight gain. PMID- 24048954 TI - Disruptive behavior disorders: taking an RDoC(ish) approach. AB - The disruptive behavior disorders include Conduct Disorder (CD), Oppositional Defiant Disorder (ODD), and Attention Deficit Hyperactivity Disorder (ADHD). These disorders are highly comorbid with each other as well as with mood and anxiety disorders and personality disorders (particularly borderline personality disorder). The goal of this chapter is to consider these disorders from an RDoC(ish) approach. In other words, we will outline four functional processes and the behavioral implications of dysfunction within these processes. Moreover, we will briefly consider how dysfunction in one might increase the risk for the development of rather different behavioral problems that have been previously associated with rather different disorders. Our goal is to identify neurocognitive-based functional targets for treatment. PMID- 24048953 TI - Large Animal Models of Huntington's Disease. AB - Huntington's disease is caused by the expansion of a polyglutamine repeat (>37 glutamines) in the disease protein huntingtin, which results in preferential neuronal loss in distinct brain regions. Mutant huntingtin causes late-onset neurological symptoms in patients in middle life, though the expression of mutant huntingtin is ubiquitous from early life. Thus, it is important to understand why mutant huntingtin selectively causes neuronal loss in an age-dependent manner. Transgenic animal models have been essential tools for uncovering the pathogenesis and therapeutic targets of neurodegenerative diseases. Genetic mouse models have been investigated extensively and have revealed the common pathological hallmark of age-dependent formation of aggregates or inclusions consisting of misfolded proteins. However, most genetic mouse models lack striking neurodegeneration that has been found in patient brains. Since there are considerable species differences between small and large animals, large animal models of Huntington's disease may allow one to identify the pathological features that are more similar to those in patients and also help uncover more effective therapeutic targets. This chapter will focus on the important findings from large animal models of Huntington's disease and discusses the use of large animal models to investigate the pathogenesis of Huntington's disease and develop new therapeutic strategies. PMID- 24048955 TI - CD28 signaling in primary CD4(+) T cells: identification of both tyrosine phosphorylation-dependent and phosphorylation-independent pathways. AB - In addition to TCR signaling, the activation and proliferation of naive T cells require CD28-mediated co-stimulation. Once engaged, CD28 is phosphorylated and can then activate signaling pathways by recruiting molecules to its YMNM motif and two PxxP motifs. In this study, we analyzed the relationship between tyrosine phosphorylation and the co-stimulatory function of CD28 in murine primary CD4(+) T cells. Tyrosine phosphorylation is decreased in CD28 where the N-terminal PxxP motif is mutated (nPA). In cells expressing nPA, activation of Akt and functional co-stimulation were decreased. In contrast, where the C-terminal PxxP motif is mutated, tyrosine phosphorylation and activation of the ERK, Akt and NF-kappaB were intact, but proliferation and IL-2 production were decreased. Using the Y(189) to F mutant, we also demonstrated that in naive CD4(+) T cells, tyrosine at position 189 in the YMNM motif is critical for both tyrosine phosphorylation and the functional co-stimulatory effects of CD28. This mutation did not affect unfractionated T-cell populations. Overall, our data suggest that CD28 signaling uses tyrosine phosphorylation-dependent and phosphorylation-independent pathways. PMID- 24048956 TI - Uptake and subcellular partitioning of trivalent metals in a green alga: comparison between Al and Sc. AB - Despite 40+ years of research on aluminum (Al) toxicity in aquatic organisms, Al transport mechanisms through biological membranes, and the intracellular fate of Al once assimilated, remain poorly understood. The trivalent metal scandium shares chemical similarities with Al and, unlike Al, it has a convenient radioactive tracer (Sc-46) allowing for relatively simple measurements at environmentally relevant concentrations. Thus, we investigated the potential of Sc to substitute for Al in uptake and intracellular fate studies with the green alga Chlamydomonas reinhardtii. Short-term (<60 min) competitive uptake experiments indicated that Al does not inhibit Sc influx, implying that these metals do not share a common transport mechanism. Also, internalized Al concentrations were ~4 times higher than Sc concentrations after long-term (72 h) exposures under similar conditions (4.5 MUM AlT or ScT, 380 MUM FT, pH 7.0, 3.8 pM Al calc (3+) and 1.0 pM Sc calc (3+) ). However, interesting similarities were observed in their relative subcellular distributions, suggesting possible common toxicity/tolerance mechanisms. Both metals mostly distributed to the organelles fraction and almost no association was found with the cytosolic proteins. The greatest difference was observed in the cellular debris fraction (membranes and nucleus) where Al was much more concentrated than Sc. However, it is not clear whether or not this fraction contained extracellular metal associated with the algal surface. To summarize, Sc does not seem to be an adequate substitute of Al for transport/uptake studies, but could be for investigations of toxicity/tolerance mechanisms in C. reinhardtii. Further work is needed to verify this latter suggestion. PMID- 24048957 TI - A psychological approach to learning causal networks. AB - We examine the role of a common cognitive heuristic in unsupervised learning of Bayesian probability networks from data. Human beings perceive a larger association between causal than diagnostic relationships. This psychological principal can be used to orient the arcs within Bayesian networks by prohibiting the direction that is less predictive. The heuristic increased predictive accuracy by an average of 0.51 % percent, a small amount. It also increased total agreement between different network learning algorithms (Max Spanning Tree, Taboo, EQ, SopLeq, and Taboo Order) by 25 %. Prior to use of the heuristic, the multiple raters Kappa between the algorithms was 0.60 (95 % confidence interval, CI, from 0.53 to 0.67) indicating moderate agreement among the networks learned through different algorithms. After the use of the heuristic, the multiple raters Kappa was 0.85 (95 % CI from 0.78 to 0.92). There was a statistically significant increase in agreement between the five algorithms (alpha < 0.05). These data suggest that the heuristic increased agreement between networks learned through use of different algorithms, without loss of predictive accuracy. Additional research is needed to see if findings persist in other data sets and to explain why a heuristic used by humans could improve construct validity of mathematical algorithms. PMID- 24048958 TI - Denoising performance of modified dual-tree complex wavelet transform for processing quadrature embolic Doppler signals. AB - Quadrature signals are dual-channel signals obtained from the systems employing quadrature demodulation. Embolic Doppler ultrasound signals obtained from stroke prone patients by using Doppler ultrasound systems are quadrature signals caused by emboli, which are particles bigger than red blood cells within circulatory system. Detection of emboli is an important step in diagnosing stroke. Most widely used parameter in detection of emboli is embolic signal-to-background signal ratio. Therefore, in order to increase this ratio, denoising techniques are employed in detection systems. Discrete wavelet transform has been used for denoising of embolic signals, but it lacks shift invariance property. Instead, dual-tree complex wavelet transform having near-shift invariance property can be used. However, it is computationally expensive as two wavelet trees are required. Recently proposed modified dual-tree complex wavelet transform, which reduces the computational complexity, can also be used. In this study, the denoising performance of this method is extensively evaluated and compared with the others by using simulated and real quadrature signals. The quantitative results demonstrated that the modified dual-tree-complex-wavelet-transform-based denoising outperforms the conventional discrete wavelet transform with the same level of computational complexity and exhibits almost equal performance to the dual-tree complex wavelet transform with almost half computational cost. PMID- 24048960 TI - Proteomic analysis in usual and nonspecific interstitial pneumonia. AB - Differentiating nonspecific interstitial pneumonia (NSIP) from usual interstitial pneumonia (UIP) is important for the determination of both treatment and prognosis. Using two-dimensional fluorescence difference gel electrophoresis (2D DIGE), we examined 8 UIPs, 8 NSIPs, and 30 normal lung tissues. Comparisons with control in 2D-DIGE showed that (a) in UIP, nine protein spots were significantly upregulated and seven were significantly downregulated, (b) in NSIP, four protein spots were significantly upregulated and nine were significantly downregulated. The detected proteins were analyzed by MALDI-TOF mass spectrometry, allowing qualitative differences in vimentin subtypes to be characterized. One vimentin subtype was upregulated in UIP, while another one was downregulated in NSIP (vs. control). These different characteristics were partially supported by the results of Western blot analysis. Our immunohistochemistry revealed vimentin expression within fibroblasts (a) in fibroblastic foci in UIP and (b) in fibrotic alveolar walls in NSIP. Differences in vimentin subtypes may provide useful biomarkers for separating NSIP from UIP, alongside differences in histological characteristics. PMID- 24048959 TI - Treatment of brain metastases in lung cancer: strategies to avoid/reduce late complications of whole brain radiation therapy. AB - OPINION STATEMENT: Brain metastases occur in 20-40 % of lung cancer patients. The use of whole brain radiation therapy (WBRT) has been shown to ameliorate many neurological symptoms, facilitate corticosteroid reduction, enhance quality of life (QOL), and prolong survival. The acute and early delayed side effects of WBRT are generally mild and inconsequential, whereas late complications often are progressive, irreversible, and may have a profound effect on neurocognitive function and QOL. Nevertheless, WBRT remains the cornerstone for treatment of multiple brain metastases due to its efficacy and the paucity of other treatment options. In avoidance of WBRT and its potential toxicity, patients of good performance status and <=3 metastases may be treated reasonably with focal therapy alone (surgery or radiosurgery) without a compromise in survival. In patients with multiple brain metastases and those undergoing prophylactic cranial irradiation (PCI), established methods to mitigate the late complications of WBRT include total dose observation, dose per fraction restrictions, and avoidance of concomitant chemotherapy. Current areas of active research that hold great potential for benefit include hippocampal-sparing radiotherapy and the use of neuroprotective agents. PMID- 24048961 TI - Immobilization and kinetics of catalase on calcium carbonate nanoparticles attached epoxy support. AB - A novel hybrid epoxy/nano CaCO3 composite matrix for catalase immobilization was prepared by polymerizing epoxy resin in the presence of CaCO3 nanoparticles. The hybrid support was characterized using scanning electron microscopy and Fourier transform infrared spectroscopy. Catalase was successfully immobilized onto epoxy/nano CaCO3 support with a conjugation yield of 0.67 +/- 0.01 mg/cm(2) and 92.63 +/- 0.80 % retention of activity. Optimum pH and optimum temperature of free and immobilized catalases were found to be 7.0 and 35 degrees C. The value of Km for H2O2 was higher for immobilized enzyme (31.42 mM) than native enzyme (27.73 mM). A decrease in Vmax value from 1,500 to 421.10 MUmol (min mg protein)( 1) was observed after immobilization. Thermal and storage stabilities of catalase improved immensely after immobilization. Immobilized enzyme retained three times than the activity of free enzyme when kept at 75 degrees C for 1 h and the half life of enzyme increased five times when stored in phosphate buffer (0.01 M, pH 7.0) at 5 degrees C. The enzyme could be reused 30 times without any significant loss of its initial activity. Desorption of catalase from the hybrid support was minimum at pH 7.0. PMID- 24048962 TI - Enhancement of adaptive immunity to Neisseria gonorrhoeae by local intravaginal administration of microencapsulated interleukin 12. AB - Gonorrhea remains one of the most frequent infectious diseases, and Neisseria gonorrhoeae is emerging as resistant to most available antibiotics, yet it does not induce a state of specific protective immunity against reinfection. Our recent studies have demonstrated that N. gonorrhoeae proactively suppresses host T-helper (Th) 1/Th2-mediated adaptive immune responses, which can be manipulated to generate protective immunity. Here we show that intravaginally administered interleukin 12 (IL-12) encapsulated in sustained-release polymer microspheres significantly enhanced both Th1 and humoral immune responses in a mouse model of genital gonococcal infection. Treatment of mice with IL-12 microspheres during gonococcal challenge led to faster clearance of infection and induced resistance to reinfection, with the generation of gonococcus-specific circulating immunoglobulin G and vaginal immunoglobulin A and G antibodies. These results suggest that local administration of microencapsulated IL-12 can serve as a novel therapeutic and prophylactic strategy against gonorrhea, with implications for the development of an effective vaccine. PMID- 24048963 TI - Persistent endothelial activation and inflammation after Plasmodium falciparum Infection in Malawian children. AB - Endothelial dysregulation is central to the pathogenesis of acute Plasmodium falciparum infection. It has been assumed that this dysregulation resolves rapidly after treatment, but this return to normality has been neither demonstrated nor quantified. We therefore measured a panel of plasma endothelial markers acutely and in convalescence in Malawian children with uncomplicated or cerebral malaria. Evidence of persistent endothelial activation and inflammation, indicated by increased plasma levels of soluble intracellular adhesion molecule 1, angiopoetin 2, and C-reactive protein, were observed at 1 month follow-up visits. These vascular changes may represent a previously unrecognized contributor to ongoing malaria-associated morbidity and mortality. PMID- 24048965 TI - Heterozygous Mutations in the ADCK3 Gene in Siblings with Cerebellar Atrophy and Extreme Phenotypic Variability. AB - We describe a highly variable clinical presentation of cerebellar ataxia in two sisters. The younger sister demonstrates early onset rapidly progressive cerebellar ataxia accompanied by motor and nonmotor cerebellar features, as well as cognitive decline and psychiatric problems. Mitochondrial respiratory chain enzyme analysis in muscle showed a decrease in complex I + III. Progressive cerebellar atrophy was demonstrated on serial brain MR imaging. Coenzyme Q10 (CoQ10) supplementation, started at the age of 5 years, led to a significant improvement in motor and cognitive abilities with partial amelioration of the cerebellar signs. Discontinuation of this treatment resulted in worsening of the ataxia, cognitive decline, and severe depression.The older sister, who is 32 years old, has nonprogressive dysarthria and clumsiness from the age of 10 years and MRI reveals cerebellar atrophy.Exome sequencing identified compound heterozygosity for a known (p. Thr584delACC (c.1750_1752delACC)) and a novel (p.P502R) mutation in the ACDK3 gene. CONCLUSIONS: Patients with primary CoQ10 deficiency due to ADCK3 mutations can demonstrate a wide spectrum of clinical presentations even in the same family. It is difficult to diagnose CoQ10 deficiency based solely on the clinical presentation.Exome sequencing can provide the molecular diagnosis but since it is expensive and not readily available, we recommend a trial of CoQ10 treatment in patients with ataxia and cerebellar atrophy even before confirmation of the molecular diagnosis. PMID- 24048964 TI - Factors related to non-recovery from whiplash. The Nord-Trondelag Health Study (HUNT). AB - BACKGROUND: Whiplash injuries show a variable prognosis which is difficult to predict. Most individuals experiencing whiplash injuries rapidly recover but a significant proportion develop chronic symptoms and ongoing disability. PURPOSE: By employing longitudinal data, we investigated how psychological and physical symptoms, self-rated health, use of health services and medications, health behavior and demographic factors predict recovery from whiplash. METHOD: Data from two waves of a large, Norwegian, population-based study (The Nord-Trondelag Health Study: HUNT2 and HUNT3) were used. Individuals reporting whiplash in HUNT2 (baseline) were identified in HUNT3 11 years later. The characteristics of individuals still suffering from whiplash in HUNT3 were compared with the characteristics of individuals who had recovered using Pearson's chi-squared test, independent sample t-tests and logistic regression. RESULTS: At follow-up, 31.6 % of those reporting whiplash at baseline had not recovered. These individuals (n = 199) reported worse health at baseline than recovered individuals (n = 431); they reported poorer self-rated health (odds ratio [OR] = 3.12; 95 % confidence interval [CI], 2.20-4.43), more symptoms of anxiety (OR = 1.70; 95 % CI, 1.15-2.50), more diffuse somatic symptoms (OR = 2.38; 95 % CI, 1.61-3.51) and more musculoskeletal symptoms (OR = 1.21; 95 % CI, 1.13-1.29). Individuals still suffering from whiplash also visited more health practitioners at baseline (OR = 1.18; 95 % CI, 1.06-1.32) and used more medications (OR = 1.24; 95 % CI, 1.09-1.40). CONCLUSION: Poor self-rated health seems to be a strong risk factor for whiplash injuries becoming chronic. Diffuse somatic symptoms, musculoskeletal symptoms and symptoms of anxiety at baseline are important prognostic risk factors. Knowledge of these maintaining risk factors enables identification of individuals at risk of non-recovery, facilitating adequate treatment for this vulnerable group. PMID- 24048966 TI - Corticosteroid-binding globulin contributes to the neuroendocrine phenotype of mice selected for extremes in stress reactivity. AB - Increasing evidence indicates an important role of steroid-binding proteins in endocrine functions, including hypothalamic-pituitary-adrenal (HPA) axis activity and regulation, as they influence bioavailability, local delivery, and cellular signal transduction of steroid hormones. In the plasma, glucocorticoids (GCs) are mainly bound to the corticosteroid-binding globulin (CBG) and to a lesser extend to albumin. Plasma CBG levels are therefore involved in the adaptive stress response, as they determine the concentration of free, biologically active GCs. In this study, we investigated whether male mice with a genetic predisposition for high-reactivity (HR), intermediate-reactivity (IR), or low-reactivity (LR) stress-induced corticosterone (CORT) secretion present different levels of free CORT and CORT-binding proteins, basally and in response to stressors of different intensity. Our results suggest a fine control interaction between plasma CBG expression and stress-induced CORT release. Although plasma CBG levels, and therefore CBG binding capacity, were higher in HR animals, CORT secretion overloaded the CBG buffering function in response to stressors, resulting in clearly higher free CORT levels in HR compared with IR and LR mice (HR>IR>LR), resembling the pattern of total CORT increase in all three lines. Both stressors, restraint or forced swimming, did not evoke fast CBG release from the liver into the bloodstream and therefore CBG binding capacity was not altered in our three mouse lines. Thus, we confirm CBG functions in maintaining a dynamic equilibrium between CBG-bound and unbound CORT, but could not verify its role in delaying the rise of plasma free CORT immediately after stress exposure. PMID- 24048967 TI - beta-Cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome. AB - Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 MUg/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into beta cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease. PMID- 24048968 TI - Nrf2 expression participates in growth and differentiation of endometrial carcinoma cells in vitro and in vivo. AB - The expression level of Nrf2 is increased in series of tumors and it plays a vital role in proliferation of cancer cells. However, little is known about the clinical implications and biological functions of Nrf2 in endometrial carcinoma. The aim of this study is to study whether up-regulation of Nrf2 expression can promote growth of endometrial carcinoma cells. Using immunohistochemistry, Nrf2 protein expression was analyzed in endometrial carcinoma patients. A series of assays was performed to elucidate the role of Nrf2 in growth of endometrial carcinoma. Positive rate of Nrf2 was 64.3 % (45/70) in endometrial carcinoma patients, and it was associated with FIGO stage and histological grade (P < 0.05). In addition, ectopic overexpression of Nrf2 promoted the growth of endometrial carcinoma cells in vitro and in vivo. Interestingly, Nrf2 protein translocation from cytoplasm to nucleus may influence differentiation of endometrial carcinoma cells. These results suggest that Nrf2 participates in progression of endometrial carcinoma by influencing the growth and differentiation of endometrial carcinoma cells, and it could be used as a novel and potential therapeutic target for endometrial carcinoma. PMID- 24048969 TI - Lifetime body size and prostate cancer risk in a population-based case-control study in Sweden. AB - PURPOSE: The role of body size in prostate cancer etiology is unclear and potentially varies by age and disease subtype. We investigated whether body size in childhood and adulthood, including adult weight change, is related to total, low-intermediate-risk, high-risk, and fatal prostate cancer. METHODS: We used data on 1,499 incident prostate cancer cases and 1,118 population controls in Sweden. Body figure at age 10 was assessed by silhouette drawings. Adult body mass index (BMI) and weight change were based on self-reported height and weight between ages 20 and 70. We estimated odds ratios (ORs) with 95 % confidence intervals (CIs) by unconditional logistic regression. RESULTS: Height was positively associated with prostate cancer. Overweight/obesity in childhood was associated with a 54 % increased risk of dying from prostate cancer compared to normal weight, whereas a 27 % lower risk was seen in men who were moderately thin (drawing 2) in childhood (P trend = 0.01). Using BMI <22.5 as a reference, we observed inverse associations between BMI 22.5 to <25 at age 20 and all prostate cancer subtypes (ORs in the range 0.72-0.82), and between mean adult BMI 25 to <27.5 and low-intermediate-risk disease (OR 0.75, 95 % CI 0.55-1.02). Moderate adult weight gain increased the risk of disease in men with low BMI at start and in short men. CONCLUSIONS: Our comprehensive life-course approach revealed no convincing associations between anthropometric measures and prostate cancer risk. However, we found some leads that deserve further investigation, particularly for early-life body size. Our study highlights the importance of the time window of exposure in prostate cancer development. PMID- 24048970 TI - Using culpability analysis to infer crash risk requires unrealistic assumptions: author's response to: culpability analysis is still a valuable technique. PMID- 24048971 TI - Core-shell noble metal nanostructures templated by gold nanorods. AB - The main research progress in core-shell noble metal nanostructures templated by gold nanorods (Au NRs) is summarized regarding synthesis, optical, and catalytic properties. Design and fabrication of core-shell hybrid nanostructures are demonstrated to be effective not only for optimizing and expanding intrinsic properties but also for creating novel localized surface plasmon enhanced optical and catalytic functionalities, thus providing great prospects in both fundamental research and potential applications. PMID- 24048972 TI - Strongly coupled nanorod vertical arrays for plasmonic sensing. AB - Due to their unique optical properties and facile processability, nanorods of noble metals are promising for highly effective nanoscale optical devices. Specifically, the local electric field enhancement brought about by plasmon coupling between nanorods in an array configuration shows great potential for optical sensing. Recent results demonstrate that vertical arrays of noble metal nanorods, used as substrates for surface enhanced Raman scattering, can achieve the sensitivity levels required for presymptomatic detection. Meanwhile, advancements in controlled fabrication methods can provide nanorod arrays with well-defined structures and properties, which lays the foundation for highly sensitive and reliable sensing. This research news focuses on this rapidly developing field by introducing the mechanisms, characteristics, and preparation methods of nanorod arrays used in plasmonic sensing, along with a perspective for future development and technical requirements. PMID- 24048973 TI - Near-infrared light-mediated nanoplatforms for cancer thermo-chemotherapy and optical imaging. AB - While thermo-chemotherapy has proved to be effective in optimizing the efficacies of cancer treatments, traditional chemotherapy is subject to adverse side effects and heat delivery is often challenging in operation. Some photothermal inorganic nanoparticles responsive to near infrared light provide new opportunities for simultaneous and targeted delivery of heat and chemotherapeutics to the tumor sites in pursuit of synergistic effects for efficacy enhancement. The state of the art of nanoparticle-induced thermo-chemotherapy is summarized and the advantages and challenges of the major nanoplatforms based on gold nanoparticles, carbon nanomaterials, palladium nanosheets, and copper-based nanocrystals are highlighted. In addition, the optical-imaging potentials of the nanoplatforms that may endow them with imaging-guided therapy and therapeutic-result-monitoring capabilities are also briefly discussed. PMID- 24048974 TI - Nanodevices for cellular interfaces and electrophysiological recording. AB - Advances in nanomaterials and nanotechnologies offer important opportunities for cellular interfaces. This Research News highlights some recent progress on cellular electrophysiology enabled by using nanostructures as active elements of bioelectronic devices. We begin with a brief description of signal transduction mechanism at device-cell interfaces and then explain the challenges of currently available techniques. Next, specific examples with substantial potential in both extracellular and intracellular electrophysiological recording are given to illustrate the remarkable power of nanostructures and their devices. We will conclude with a discussion of some exciting directions that are currently being pursued in flexible, 3D bioelectronics. PMID- 24048975 TI - Host-guest supramolecular nanosystems for cancer diagnostics and therapeutics. AB - Extensive efforts have been devoted to the construction of functional supramolecular nanosystems for applications in catalysis, energy conversion, sensing and biomedicine. The applications of supramolecular nanosystems such as liposomes, micelles, inorganic nanoparticles, carbon materials for cancer diagnostics and therapeutics have been reviewed by other groups. Here, we will focus on the recent momentous advances in the implementation of typical supramolecular hosts (i.e., cyclodextrins, calixarenes, cucurbiturils and metallo hosts) and their nanosystems in cancer diagnostics and therapeutics. We discuss the evolutive process of supramolecular nanosystems from the structural control and characterization to their diagnostic and therapeutic function exploitation and even the future potentials for clinical translation. PMID- 24048976 TI - Carbonaceous electrode materials for supercapacitors. AB - Supercapacitors have been widely studied around the world in recent years, due to their excellent power density and long cycle life. As the most frequently used electrode materials for supercapacitors, carbonaceous materials attract more and more attention. However, their relatively low energy density still holds back the widespread application. Up to now, various strategies have been developed to figure out this problem. This research news summarizes the recent advances in improving the supercapacitor performance of carbonaceous materials, including the incorporation of heteroatoms and the pore size effect (subnanopores' contribution). In addition, a new class of carbonaceous materials, porous organic networks (PONs) has been managed into the supercapacitor field, which promises great potential in not only improving the supercapacitor performances, but also unraveling the related mechanisms. PMID- 24048977 TI - DNA-based self-assembly for functional nanomaterials. AB - The unprecedented development of DNA nanotechnology has caused DNA self-assembly to attract close attention in many disciplines. In this research news article, the employment of DNA self-assembly in the fields of materials science and nanotechnology is described. DNA self-assembly can be used to prepare bulk-scale hydrogels and 3D macroscopic crystals with nanoscale internal structures, to induce the crystallization of nanoparticles, to template the fabrication of organic conductive nanomaterials, and to act as drug delivery vehicles for therapeutic agents. The properties and functions are fully tunable because of the designability and specificity of DNA assembly. Moreover, because of the intrinsic dynamics, DNA self-assembly can act as a program switch and can efficiently control stimuli responsiveness. We highlight the power of DNA self-assembly in the preparation and function regulation of materials, aiming to motivate future multidisciplinary and interdisciplinary research. Finally, we describe some of the challenges currently faced by DNA assembly that may affect the functional evolution of such materials, and we provide our insights into the future directions of several DNA self-assembly-based nanomaterials. PMID- 24048978 TI - Low-dimensional Te-based nanostructures. AB - Low-dimensional Te-based nanomaterials have attracted intense attention in recent years due to their novel physical properties including surface-state effects, photoelectricity, phase changes, and thermoelectricity. The recent development of synthesis methods of low-dimensional Te-based nanostructures is reviewed, such as van der Waals expitaxial growth and template-assisted solution-phase deposition. In addition, the unique properties of these materials, such as tunable surface states, high photoresponsivity, fast phase change, and high thermoelectricity figure of merit, are reviewed. The potential applications of low-dimensional Te based nanostructures are broad but particularly promising for nanoscale electronic and photoelectronic devices. PMID- 24048979 TI - Free associate norms for 139 European Portuguese words for children from different age groups. AB - In the present study, we present normative ratings of free association for 139 European Portuguese (EP) words among 7- to 8-, 9- to 10-, and 11- to 12-year-old children attending the 3rd, 5th, and 7th grades of elementary and middle school in Portugal. For each word, five indices are presented: (a) the percentage of associates, (b) the strength of the first associate, (c) the strength of the second associate, (d) the distance between the first and second associates, and (e) the percentage of idiosyncratic responses. Additionally, grade-level frequency values for each word from the ESCOLEX database (Soares et al., in press) are also provided. As expected, the results revealed developmental changes in the knowledge organization of the children, which occurred at the ages of 9-10 (5th grade) and remained stable in the 11- to 12-year-old children (7th grade). Specifically, we observed a decrease in the percentages of associates and idiosyncratic responses, as well as an increase in the strengths of the first and second associates from the 3rd to the 5th grade. Moreover, a comparative analysis with the previous work of Carneiro, Albuquerque, Fernandez, and Esteves (2004) on EP and Macizo, Gomez-Ariza, and Bajo (2000) on Spanish, for the subsets of common words (16 and 58, respectively), showed that the present norms fit well with previous EP data, but differ from the Spanish data. PMID- 24048980 TI - Biokinetically-based in vitro cardiotoxicity of residual oil fly ash: hazard identification and mechanisms of injury. AB - Epidemiological studies have associated air pollution particulate matter (PM) exposure with adverse cardiovascular effects. Identification of causal PM sources is critically needed to support regulatory decisions to protect public health. This research examines the in vitro cardiotoxicity of bioavailable constituents of residual oil fly ash (ROFA) employing in vivo, biokinetically-based, concentrations determined from their pulmonary deposition. Pulmonary deposition of ROFA led to a rapid increase in plasma vanadium (V) levels that were prolonged in hypertensive animals without systemic inflammation. ROFA cardiotoxicity was evaluated using neonatal rat cardiomyocyte (RCM) cultures exposed to particle free leachates of ROFA (ROFA-L) at levels present in exposed rat plasma. Cardiotoxicity was observed at low levels (3.13 MUg/mL) of ROFA-L 24 h post exposure. Dimethylthiourea (28 mM) inhibited ROFA-L-induced cytotoxicity at high (25-12.5 MUg/mL) doses, suggesting that oxidative stress is responsible at high ROFA-L doses. Cardiotoxicity could not be reproduced using a V + Ni + Fe mixture or a ROFA-L depleted of these metals, suggesting that ROFA-L cardiotoxicity requires the full complement of bioavailable constituents. Susceptibility of RCMs to ROFA-L-induced cytotoxicity was increased following tyrosine phosphorylation inhibition, suggesting that phosphotyrosine signaling pathways play a critical role in regulating ROFA-L-induced cardiotoxicity. These data demonstrate that bioavailable constituents of ROFA are capable of direct adverse cardiac effects. PMID- 24048981 TI - Catechin averts experimental diabetes mellitus-induced vascular endothelial structural and functional abnormalities. AB - Diabetes mellitus is associated with an induction of vascular endothelial dysfunction (VED), an initial event that could lead to the pathogenesis of atherosclerosis and hypertension. Previous studies showed that catechin, a key component of green tea, possesses vascular beneficial effects. We investigated the effect of catechin hydrate in diabetes mellitus-induced experimental vascular endothelial abnormalities (VEA). Streptozotocin (50 mg/kg, i.p., once) administration to rats produced diabetes mellitus, which subsequently induced VEA in 8 weeks by markedly attenuating acetylcholine-induced endothelium-dependent relaxation in the isolated aortic ring preparation, decreasing aortic and serum nitrite/nitrate concentrations and impairing aortic endothelial integrity. These abnormalities in diabetic rats were accompanied with elevated aortic superoxide anion generation and serum lipid peroxidation in addition to hyperglycemia. Catechin hydrate treatment (50 mg/kg/day p.o., 3 weeks) markedly prevented diabetes mellitus-induced VEA and vascular oxidative stress. Intriguingly, in vitro incubation of L-NAME (100 MUM), an inhibitor of nitric oxide synthase, or Wortmannin (100 nM), a selective inhibitor of phosphatidylinositol 3-kinase (PI3K), markedly prevented catechin hydrate-induced improvement in acetylcholine provoked endothelium-dependent relaxation in the diabetic rat aorta. Moreover, catechin hydrate treatment considerably reduced the elevated level of serum glucose in diabetic rats. In conclusion, catechin hydrate treatment prevents diabetes mellitus-induced VED through the activation of endothelial PI3K signal and subsequent activation of eNOS and generation of nitric oxide. In addition, reduction in high glucose, vascular oxidative stress, and lipid peroxidation might additionally contribute to catechin hydrate-associated prevention of diabetic VEA. PMID- 24048982 TI - Abdominal aortic tourniquet controls junctional hemorrhage from a gunshot wound of the axilla. AB - Junctional hemorrhage, bleeding from the areas at the junction of the trunk and its appendages, is a difficult problem in trauma. These areas are not amenable to regular tourniquets as they cannot fit to give circumferential pressure around the extremity. Junctional arterial injuries can rapidly lead to death by exsanguination, and out-of-hospital control of junctional bleeding can be lifesaving. The present case report describes an off-label use of the Abdominal Aortic TourniquetTM in the axilla and demonstrates its safety and effectiveness of stopping hemorrhage from a challenging wound. To our knowledge, the present report is the first human use of a junctional tourniquet to control an upper extremity junctional hemorrhage. PMID- 24048983 TI - Tragedy into drama: an american history of tourniquet use in the current war. AB - BACKGROUND: Although the scientific results of recent tourniquet advances in first aid are well recorded, the process by which tourniquet use advances were made is not. The purpose of the present report is to distill historical aspects of this tourniquet story during the current wars in Afghanistan and Iraq to aid scientists, leaders, and clinicians in the process of development of future improvements in first aid. METHODS: The process of how developments of this tourniquet story happened recently is detailed chronologically and thematically in a ?who did what, when, where, why, and how? way. RESULTS: Initially in these wars, tourniquets were used rarely or were used as a means of last resort. Such delay in tourniquet use was often lethal; subsequently, use was improved incrementally over time by many people at several organizations. Three sequential keys to success were (1) unlocking the impasse of enacting doctrinal ideas already approved, (2) reaching a critical density of both tourniquets and trained users on the battlefield, and (3) capturing their experience with tourniquets. Other keys included translating needs among stakeholders (such as casualties, combat medics, providers, trainers, and decision-makers) and problem-solving logistic snags and other issues. Eventually, refined care was shown to improve survival rates. From all medical interventions evidenced in the current wars, the tourniquet broke rank and moved to the forefront as the prehospital medical breakthrough of the war. CONCLUSION: The recorded process of how tourniquet developments in prehospital care occurred may be used as a reference for parallel efforts in first aid such as attempts to improve care for airway and breathing problems. PMID- 24048984 TI - Rigid eye shields: a critical gap in the individual first aid kit. AB - From 5% to 22% of all U.S. Department of Defense combat casualties between 2001 and 2010 suffered some form of ocular trauma. Ocular injuries have an inordinately dramatic impact on return to duty, retention, and reintegration; only 25% of warfighters with severe ocular trauma return to duty. After a traumatic ocular event, the likelihood of saving an eye and preserving vision depends on several factors, especially the treatment quality at the point of injury. Every major organization associated with combat casualty care (e.g., the U.S. Army Institute of Surgical Research, the Committee on Tactical Combat Casualty Care, and the Department of Defense/VA Vision Center of Excellence) emphasizes the importance of placing a rigid eye shield on known/suspected eye injuries at point of injury. On the battlefield, there is no better way to protect an injured eye from further damage than with an eye shield, but shields are not readily available in individual first aid kits. Therefore, it is highly recommended that each Service rapidly integrate at least one rigid eye shield into every individual first aid kit, making them immediately available to every warfighter. PMID- 24048985 TI - Rigid eye shields: a critical gap in the individual first aid kit commentary. PMID- 24048986 TI - Design and demonstration of a battery-less fluid warmer for combat. AB - BACKGROUND: Prehospital battlefield hypothermia remains an issue, with cold fluid resuscitation likely being a significant contributor. Currently, no prehospital battlefield technology exists to warm intravenous resuscitation fluids. Existing commercial fluid-warming technologies are either inadequate or unreliable or have an unacceptable weight and size, making them inappropriate for the austere combat environment. We propose the creation of a battery-less, flameless, portable, lowweight, small, chemically powered fluid warmer for the battlefield. METHODS: A magnesium-based exothermic chemical reaction was used as the sole heating source. A low-weight, small insulated container was created to contain the reaction. The chemical reaction was manipulated to sustain fluid heating as long as required. RESULTS: The exothermic reaction was used to boil a Fluorinert TM liquid within an insulated container that heats resuscitation fluid passing through the heat exchanger. A working prototype device, 9 inches in length and 4 inches in diameter, was engineered and tested. Warming was maintained over a variety of clinically relevant flow rates. CONCLUSION: A chemically based, safe, battery less, flameless, lightweight fluid warmer was created. This technology could represent a significant remote capability currently unavailable on the battlefield. PMID- 24048987 TI - MEDEVAC Use of Ketamine for Postintubation Transport. AB - The use of traditional sedatives and analgesics in intubated patients can have undesired hemodynamic consequences with increases in sedation exacerbating hypotension and potentially avoidable morbidity and mortality. This project compared 50 intubated patients using traditional analgesics and sedatives to 20 intubated patients using ketamine with the hypothesis that there would be a significant difference in subsequent blood pressure drop between the two groups. Though the results did not prove to be statistically significant within this small study, the authors did observe a trend toward significance. Additionally, some hypotensive patients had traditional analgesics and sedatives withheld altogether, which did not occur within the ketamine group. Due to the reduced side-effect profile, deployed medical providers should have increased training with and use of ketamine in the pre-hospital setting. PMID- 24048988 TI - Digital intubation: the two-fingered solution to securing an airway. AB - Digital intubation is a useful technique that is rarely taught in conventional airway management courses. With limited equipment and minimal training, a Special Operations Forces (SOF) medic can use this technique to intubate an unconscious patient with a high degree of success. The objectives of this report are to (1) learn the sequence of events for successful digital intubation, (2) recognize and appreciate the advantages and limitations of this technique, and (3) appreciate the requirements for establishing a unit-level training program. PMID- 24048989 TI - Traumatic brain injury ? What do we know? AB - Traumatic brain injury (TBI) is a significant problem in both the civilian and military worlds. Although much is understood about the effects of TBI, relatively few diagnostic or therapeutic modalities are available. Currently, TBI treatment is in a primitive phase and other than acute lifesaving interventions, is largely relegated to rehabilitation efforts. This article discusses known aspects of neuronal injury related to blast TBI, as well as a review of the current state of diagnostic and therapeutic interventions. PMID- 24048990 TI - Deployed Assessment and Management of mTBI Casualties. AB - The wars in Afghanistan and Iraq have placed a spotlight on screening, evaluation, and treatment of mild traumatic brain injury, otherwise known as concussion. The author presents a mass casualty case in which a Ranger company medical section assessed and managed 30 Servicemembers (SM) diagnosed with concussion. Through the process of treating these Servicemembers, a consolidated checklist was created based on existing Department of Defense, United States Special Operations Command (USSOCOM), and United States Army Special Operations Command (USASOC) guidelines. During this and subsequent clinical encounters, utilization of this checklist resulted in efficient identification of concussed personnel, appropriate treatment, and documentation. PMID- 24048991 TI - Traumatic brain injury: analysis of functional deficits and posthospital rehabilitation outcomes. AB - BACKGROUND: Advances in emergency medicine, both in the field and in trauma centers, have dramatically increased survival rates of persons sustaining traumatic brain injury (TBI). However, these advances have come with the realization that many survivors are living with significant residual deficits in multiple areas of functioning, which make the resumption of a quality lifestyle extremely difficult. To this point, TBI has recently been characterized as a chronic disease. As with other chronic diseases, TBI is often causative of persistent disabling symptoms in multiple organ systems. Therefore, posthospital residential rehabilitation programs have emerged to treat these symptoms with the goal of helping these individuals regain function and live more productive and independent lives. PURPOSE: This study examined the nature and severity of residual deficits experienced by a group of 285 brain-injured individuals and evaluate the efficacy of posthospital residential rehabilitation programs in treating those deficits. METHOD: Participants consisted of 285 individuals who had sustained a TBI and, due to multiple residual deficits, were unable to care for themselves, necessitating admission to residential posthospital rehabilitation programs. All participants were evaluated at admission and discharge on the Mayo-Portland Adaptability Inventory?Version 4 (MPAI-4). The MPAI-4, developed specifically for persons with acquired brain injury, measures 29 areas of function often affected by TBI. RESULTS: From the 29 skills evaluated, the 12 most often rated as causing the greatest interference with function were identified. Of these skills, the cognitive deficits including memory, attention/concentration, novel problem solving, and awareness of deficits were highly correlated with disruption in performing everyday societal roles. The impact of treatment for reducing the level of disability in these areas was statistically significant, t(284) = 17.43, p < .0001. Improvement was significant even for participants admitted more than 1 year postinjury, t(78) = 8.05, p < .0001. CONCLUSIONS: Skill deficits interfering with reintegration into home and community are highly interrelated and should be treated with the understanding that progress in one area may be dependent on change in another area. Cognitive skills including memory, attention/ concentration, novel problem solving, and awareness of deficits were highly correlated with measures of overall functional outcome. Posthospital programs using a multidisciplinary treatment approach achieved significant reduction in disability from program admission to discharge. The benefits of these programs were realized even for the most chronically impaired participants. PMID- 24048992 TI - Cultural self-awareness as a crucial component of military cross-cultural competence. AB - The military forces in the United States represent a unique culture that includes many subcultures within their own military society. Acculturation into the military often deemphasizes the influence of personal narrative and thereby establishes the primacy of military culture over personal cultural influences. The authors make the argument that military personnel need to further develop an understanding and appreciation of personal cultural narrative as well as organizational culture. The increased integration of military personnel with interagency partners, along with cooperative efforts between relief organizations, and nongovernmental organizations in politically/economically unstable areas around the globe serves to make cross-cultural interaction unavoidable in the future. Military medical personnel are especially likely to interact with others who have culturally different values. These interactions can occur between organizations as easily as they can during patient care. They must be able to step outside of their military culture and develop cross-cultural competence that is grounded in cultural self-awareness. Without an appropriate level of cultural self-awareness, military and medical personnel run the risk of being unable to communicate across dissimilar cultures or worse, alienating key stakeholders in collaborative operations between military services, coalition partners, and nonmilitary organizations. It is the authors? contention that unless military personnel, especially those in the medical arena, are able to appropriately self-assess situations that are impacted by culture, both their own and the other personnel involved, the resulting cultural dissonance is more likely to derail any significant positive effect of such collaborations. PMID- 24048993 TI - Cultural competency and patient-centered communication: a study of an isolated outbreak of urinary tract infections in afghanistan. AB - BACKGROUND: Personal hygiene is strongly associated with disease prevention and is especially important during prolonged patrol or combat operations. Understanding cultural variances associated with personal hygiene is critical for Special Operation Forces (SOF) medics to prevent, monitor, and treat acquired and transmitted infections while working with host nation personnel. CASE PRESENTATION: During a multiday, long-range patrol, approximately 40 male Afghan National Army troops between the ages of 22 and 49 presented for treatment of burning or pain while urinating. All patients were empirically diagnosed with urinary tract infections. Methods and Discussion: The high attack rate and isolated nature of the outbreak suggested that personal hygiene or sexual intercourse was the most likely cause of the isolated outbreak. However, the cultural sensitivity of both topics made social history gathering a difficult task. After participating in a detailed medical interview, one patient revealed that he and his comrades were blocking their urethras with clay plugs after voiding to prevent residual urine from dripping onto their clothes. CONCLUSIONS: This case study presents what might be an undocumented practice carried throughout many ethnic cultures endogenous to Afghanistan and discusses how cultural barriers can impact effective health care delivery. PMID- 24048994 TI - Preparing for Operations in a Resource-Depleted and/or Extended Evacuation Environment. AB - The wars in Afghanistan and Iraq are the only conflicts to which many medics have ever been exposed. These mature theaters have robust medical systems that ensure rapid access to full-spectrum medical care for all combat-wounded and medically injured personnel. As current conflicts draw to a close, U.S. medics may be deployed to environments that will require the ability to stabilize casualties for longer than 1 hour. Historical mission analysis reveals the need to review skills that have not been emphasized during upgrade and predeployment training. This unit?s preparation for the extended care environment can be accomplished using a 4-point approach: (1) review of specific long-term skills training, (2) an extended care lab that reviews extended care skills and then lets the medic practice in a real-time scenario, (3) introduction to the HITMAN mnemonic tool, which helps identify and address patient needs, and (4) teleconsultation. PMID- 24048995 TI - Management of Open Pneumothorax in Tactical Combat Casualty Care: TCCC Guidelines Change 13-02. AB - During the recent United States Central Command (USCENTCOM) and Joint Trauma System (JTS) assessment of prehospital trauma care in Afghanistan, the deployed director of the Joint Theater Trauma System (JTTS), CAPT Donald R. Bennett, questioned why TCCC recommends treating a nonlethal injury (open pneumothorax) with an intervention (a nonvented chest seal) that could produce a lethal condition (tension pneumothorax). New research from the U.S. Army Institute of Surgical Research (USAISR) has found that, in a model of open pneumothorax treated with a chest seal in which increments of air were added to the pleural space to simulate an air leak from an injured lung, use of a vented chest seal prevented the subsequent development of a tension pneumothorax, whereas use of a nonvented chest seal did not. The updated TCCC Guideline for the battlefield management of open pneumothorax is: ?All open and/ or sucking chest wounds should be treated by immediately applying a vented chest seal to cover the defect. If a vente chest seal is not available, use a non-vented chest seal. Monitor the casualty for the potential development of a subsequent tension pneumothorax. If the casualty develops increasing hypoxia, respiratory distress, or hypotension and a tension pneumothorax is suspected, treat by burping or removing the dressing or by needle decompression.? This recommendation was approved by the required two-thirds majority of the Committee on TCCC in June 2013. PMID- 24048996 TI - The agitated patient. AB - Caring for an agitated patient can be a daunting task for the tactical emergency medical support (TEMS) or Special Operations Forces (SOF) medic. The cause, degree, and duration of agitation can vary among such individuals. These patients create a high-stress and disruptive environment, needing numerous people involved to control. One agitated patient can disrupt an entire tactical team or casualty evacuation. The patient?s history and physical examination can give important clues to the cause, thereby directing treatment and leading to a quick and safe resolution. The variety of treatments for the agitated patient are just as numerous as the causes and range from verbal deescalation to medications and physical restraint, all of which have a risk-benefit profile to consider. PMID- 24048998 TI - Certified tactical paramedic: a benchmark for competency in austere and hostile environments. PMID- 24048997 TI - Operator Training and TEMS Support: A Survey of Unit Leaders in Northern and Central California. AB - BACKGROUND: Members of Special Weapons and Tactics (SWAT) teams routinely work in high-risk tactical situations. Awareness of the benefit of Tactical Emergency Medical Support (TEMS) is increasing but not uniformly emphasized. OBJECTIVES: To characterize the current regional state of tactical medicine and identify potential barriers to more widespread implementation. METHODS: A multiple-choice survey was administered to SWAT team leaders of 22 regional agencies in northern and central California. Questions focused on individual officer self-aid and buddy care training, the use and content of individual first aid kits (IFAKs), and the operational inclusion of a dedicated TEMS provider. RESULTS: Respondents included city police (54%), local county sheriff (36%), state law enforcement (5%), and federal law enforcement (5%). RESULTS showed that 100% of respondents thought it was ?Very Important? for SWAT officers to understand the basics of self-aid and buddy care and to carry an IFAK, while only 71% of respondents indicated that team members actually carried an IFAK. In addition, 67% indicated that tourniquets were part of the IFAK, and 91% of surveyed team leaders thought it was ?Very Important? for teams to have a trained medic available onsite at callouts or high-risk warrant searches. Also, 59% of teams used an organic TEMS element. CONCLUSION: The majority of SWAT team leaders recognize the benefit of basic Operator medical training and the importance of a TEMS program. Despite near 100% endorsement by unit-level leadership, a significant proportion of teams are lacking one of the key components including Operator IFAKs and/or tourniquets. Tactical team leaders, administrators, and providers should continue to promote adequate Operator training and equipment as well as formal TEMS support. PMID- 24048999 TI - Endovascular resuscitation techniques for severe hemorrhagic shock and traumatic arrest in the presurgical setting. PMID- 24049000 TI - Rabies. AB - Rabies has been a scourge of mankind since antiquity. The name itself, ?rabies? is derived from the ancient Sanskrit rabhas meaning ?to do violence? and has been found described in medical writings several thousand years old. The rabies virus is an RNA virus of the family Rhabdoviridae (Greek for ?rod-shaped virus?), genus Lyssavirus (Lyssa being the Greek God of frenzy and rage). Rabies infections have a worldwide spread, with only a few, mostly island nations laying claim to being ?rabies free.? PMID- 24049001 TI - Sarcoidosis. AB - An active duty male presents to your clinic with concerns of an increasing number of enlarging papules on his neck. How would you describe the morphology of these lesions? What questions should be included in your history? What would you include in your examination? What would you include in your differential diagnosis? What labs and/or tests would you order? This report discusses cutaneous sarcoidosis and its diagnosis and treatment. PMID- 24049002 TI - I remember nothing more: a doctor?s powerfully moving memoir of her struggle to save the children of the warsaw ghetto. PMID- 24049003 TI - Letter from the NATO Surgeon. PMID- 24049004 TI - Who Owns Battlefield Medicine? Bob Mabry on being SOMA President and Being and Black Hawk Down. PMID- 24049005 TI - [The prevalence of eating disorders and comorbid psychiatric disorders in the Sivas Province]. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of eating disorders (EDs) in the Sivas province, and to identify the sociodemographic characteristics and co-morbid axis-I and axis-II diagnoses in EDs. METHOD: 1122 people between 18-44 years of age were enrolled in the study after completing the eating attitude test (EAT), and people who had points around the cut-off score had clinical interviews. The control group included subjects that were age- and sex-matched with the ED group, were not diagnosed with an ED, and had an EAT score <30. In order to determine the following as axis I or axis II, SCID-I (Structured Clinical Interview for DSM-IV Axis-I Disorders) and SCID-II (Structured Clinical Interview for DSM-III-R Personality Disorders) were performed on both the eating disorder and control groups. RESULTS: As a result of the scanning done with EAT, we observed that 5.25% of this population might have an eating behavior disorder. The prevalence of the eating disorders was found to be 1.52% by the structured clinical interview in the second step of the study. While the prevalence of bulimia nervosa was determined to be 0.63%, that of binge eating disorder was 0.81%. The diagnosis of ED is common and statistically significant among women (88.2%). According to the study, persons diagnosed with ED were more likely to have a moderate income as compared with those who were not diagnosed with an ED. Also, people with ED had been exposed to more traumas, and it was more likely that someone in their family had a psychiatric diagnosis. Among the patient group, the axis I and axis II co-morbidity rates were significantly higher than those of the control group. 47% (8/17) of the patients were determined to have a co-morbid axis I diagnosis. The most frequently diagnosed co-morbidity was major depressive disorder. 41% of the patients were determined to have an axis II diagnosis. The most common rate of diagnosis was 11.8% for both obsessive-compulsive personality disorder and avoidant personality disorder. CONCLUSION: The results of this study show that the point prevalence rate for EDs among all the participants was 1.52%, with binge eating disorder being the most prevalent ED. Psychiatric co-morbidity is common in patients with eating disorders. An ED is a disease that can be seen in different age groups and socioeconomic levels. Studies with larger samples, including different regions of the country and different age groups, and with diagnoses that have been confirmed by clinical interviews, are required. PMID- 24049006 TI - [Sociodemographic/Clinical characteristics and risk factors associated with chronic tic disorders]. AB - OBJECTIVE: This study aimed to investigate comorbidity, and sociodemographic and clinical characteristics in children and adolescents with Tourette's syndrome (TS) and chronic motor or vocal tic disorder (CMVTD), and to determine the predictors of tic disorders. MATERIALS AND METHODS: In all, 57 children and adolescents with TS and CMVTD were compared with a control group. Data were obtained using the Yale Global Tic Severity Scale (YGTSS), Turgay DSM-IV-Based Disruptive Behavioral Disorders Screening and Rating Scale (T-DSM-IV-S), Children's Depression Inventory (CDI), Screen for Child Anxiety-Related Disorders (SCARED), Maudsley Obsessive-Compulsive Inventory (MOCI), and Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version (K-SADS-PL). RESULTS: Mean age of the patients was 10.5 +/- 2.4 years. In all, 56 (98.2%) of the patients had simple motor tics, 50 (87.7%) had complex motor tics, and 43 (75.4%) had vocal tics. Self-injurious behavior was observed in 24 (42.1%) patients. In total, 46 (80.7%) of the patients had >=1 comorbid disorder. Among the observed comorbid disorders, attention deficit hyperactivity disorder (ADHD) was the most common (observed in 40.4% of the patients), followed by obsessive-compulsive disorder (OCD) (19.3%). A higher level of maternal education and absence of ADHD were associated with a reduction in the risk of a tic disorder. A family history of psychiatric disorder increased the risk of a tic disorder 5.61-fold, and nail biting increased the risk of a tic disorder 8.2-fold. Every 1-unit increase in CDI score increased the risk of a tic disorder by 12%. CONCLUSION: Chronic tic disorders (CTDs) are often accompanied by other psychiatric disorders. Both child- and family-related factors are associated with the risk of developing a tic disorder. Determination of both the protective and risk factors would be beneficial for improving the mental health of the general public. PMID- 24049007 TI - [Human rights violations among people with mental illness; rural vs. urban comparison]. AB - BACKGROUND: Human rights violations are commonly reported against people with mental illness and have remained a major research issue in recent times. OBJECTIVE: The present study was aimed to compare psychiatric patients' perceptions of human rights needs between rural and urban settings. METHODOLOGY: A descriptive study design was carried out among 100 recovered psychiatric patients based on the Clinical Global Impression-Improvement Scale (CGI-I scale), at a tertiary care center. Participants were selected through a random sampling method. Data was collected through face to face interviews, using a structured questionnaire. Data was analyzed and interpreted using descriptive and inferential statistics. FINDINGS: The present study highlighted the significant differences in meeting their basic human rights needs in a physical needs dimension i.e. availability of hot water for bathing (c2=8.305, p<0.40) and provision of clean clothes to wear (c2=8.229, p<0.42) were rated higher in rural participants than participants from those in an urban setting. Similarly, in the ethical needs dimension, merely 13% of the rural participants reported that they never/rarely experienced sexual advances by family members (c2=9.949, p> .019). CONCLUSION: Our findings revealed that human rights violations among mentally ill are evident across rural and urban environments. Thus, there is an urgent need to change the attitude of the general population towards people with mental illness through awareness campaign. In addition, educating the public about the human rights of mentally ill is also essential. PMID- 24049008 TI - [The impact of compulsory health service on physicians and burnout in a province in Eastern Anatolia]. AB - OBJECTIVE: The Compulsory Health Service (CHS) for physicians has been in place since 2005. The aim of this study was to investigate the impact of the CHS on physicians and the factors associated with burnout. METHOD: The sample group consisted of all physicians working within the province of Mus in this cross sectional, descriptive, epidemiological study. All participants were assessed using the Maslach Burnout Inventory (MBI), the Beck Depression Inventory, the Job Satisfaction Scale (JSS), the Satisfaction with Life Scale, the Professional Quality of Life Scale (ProQOL) and the General Health Questiannaire-12, along with a detailed sociodemographic and professional data form. RESULTS: A total of 139 physicians participated in this study, and 100 of them (71%) were fulfilling the CHS. Physicians who fulfilled the CHS were found to have lower levels of job satisfaction and professional quality of life. They also had higher levels of depression, general psychiatric symptoms, and psychological stress. The relationships between the level of burnout in physicians fulfilling the CHS and the scores from the scales used in the study were statistically significant except those between MBI-Personal Accomplishment, JSS, and ProQOL-Compassion Fatigue subscales. The extent of depressive symptoms and the daily number of patients were predictors of all three subscales of burnout. Job satisfaction was a predictor of both emotional exhaustion and depersonalization, while life satisfaction was a predictor of emotional exhaustion, and gender was a predictor of personal accomplishment. CONCLUSION: The level of burnout among physicians who had fulfilled the CHS was high. The factors and predictors associated with burnout were discussed. PMID- 24049009 TI - [Turkish expressive and receptive language test: I. Standardization, reliability and validity study of the receptive vocabulary sub-scale]. AB - OBJECTIVE: A reliable, valid and original test to assess the receptive vocabulary skills of children in Turkey was not available. Thus, the purpose of the current study was to develop a receptive vocabulary test for Turkish children based on the Turkish language. MATERIALS AND METHODS: For the Receptive Vocabulary Sub Scale (TIFALDI-RT) 242 concrete and abstract words were chosen from word frequency lists and a comprehensive Turkish Dictionary. Pilot data were collected from 648 children aged 2 to 13 from Ankara, and norm data were collected from a nationally representative sample of 3755 children. RESULTS: Item analysis (item difficulty, discrimination and distractor) was carried out on the pilot data and based on the results, the total item number was reduced to 157. Further, three parameter item analyses (IRT) were carried out on the norm data by using BILOG-MG (SSI, 2002), and the results indicated that the TIFALDI Receptive Vocabulary Sub Scale could be reduced to 104 items to assess 2 to 12 year-old children's receptive vocabulary. Test-retest and internal consistency reliabilities were calculated for the whole sample and age groups separately, and all the coefficients were high. For the validity, the relationship between the WISC-R and Ankara Developmental Screening Inventory (AGTE) and Receptive Vocabulary Sub Scale were investigated. Once again, the TIFALDI Receptive Vocabulary Sub-Scale scores were found to be significantly related to WISC-R and AGTE scores. CONCLUSION: The TIFALDI Receptive Vocabulary Sub-Scale was developed on the basis of the Turkish Language and norm data were collected from a nationally representative sample. The TIFALDI-RT also had a high reliability and validity. Thus, the TIFALDI-RT can be used to assess 2 to 12 year-old children's receptive vocabulary skills. PMID- 24049010 TI - [Science, Psychiatry, and the DSM]. AB - The upcoming publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), provides an opportunity to revisit the seldom addressed methodological issues in contemporary psychiatry. We think that DSM widely determines the scientific and clinical orientation of the discipline, and therefore provides a good vantage point to critique the current psychiatric methodology. The main scientific problem is a perseverative attempt at validating descriptively defined disorders that are standardized and simplified to achieve diagnostic reliability. Lack of a single psychiatric phenomenon that is valid, i.e. natural, for initiating any reduction limits research to inductive probabilistic methods, basically correlational analyses. Furthermore, reduction in psychiatry is typically directed at basic sciences, neglecting general medical diagnoses as possible intermediary correlates. The subcategory "Due to a General Medical Condition" is elusive, and the biopsychosocial approach does no more than strengthen the brain-disease illusion surrounding DSM definitions by justifying psychiatry as a branch of medicine while failing to stipulate detailed medical assessment and discouraging psychopathology-based clinical reasoning. It is therefore no surprise that, although our understanding of the neural basis and mechanisms of behavior has improved along with advances in the neurosciences, not a single DSM disorder has been validated by the discovery of a specific cause, pathophysiology, or structural abnormality since the adoption of the descriptive approach in 1980. New knowledge involves single traits or dimensions of mood, thought, or behavior, none of which are specific to any disorder. The optimum approach today would be to redefine the discipline as neuropsychiatry. PMID- 24049011 TI - [Polycystic kidney disease in a patient using lithium chronically]. AB - Lithium remains to be the gold standard in the treatment of mood disorders. This study presents a case treated with lithium for an extended period with a good response. Following an increase in creatinine levels, further investigation of renal dysfunction revealed polycystic kidney disease. Lithium was used prior to the diagnosis of polycystic kidney disease, resulting in the unique opportunity to examine the effects of lithium on kidneys with polycystic kidney disease. Within this context, this study also discusses the pharmacokinetics of lithium, and its possible relation to cyst formation in polycystic kidney disease. PMID- 24049014 TI - Combined effects of polymorphisms of DNA-repair protein genes and metabolic enzyme genes on the risk of cholangiocarcinoma. AB - OBJECTIVE: Although Opisthorchis viverrini is a risk factor for cholangiocarcinoma, not all the infected individuals develop cholangiocarcinoma. We investigated whether the base excision repair enzyme gene polymorphisms with differentiated repair capacities of inflammation-related deoxyribonucleic acid damage may play a key role and such possible effects from those genes may be increased or diminished in co-existence of polymorphisms of metabolic enzymes, including glutathione-S-transferases mu 1 and glutathione-S-transferases theta1. METHODS: We genotyped five non-synonymous single-nucleotide polymorphisms of three genes, including the human homolog of the 8-oxoguanine glycosylase 1 Ser326Cys, X-ray repair cross-complementing protein 1 Arg194Trp, Arg280His and Arg399Gln and poly (adenosine diphosphate ribose) polymerase 1 Val762Ala in 87-94 matched case-control pairs, and examined relations between those polymorphisms and the risk of cholangiocarcinoma. RESULTS: Any single polymorphism did not have a measurable association with the risk of cholangiocarcinoma. However, when considering glutathione-S-transferases mu 1 polymorphism together, the human homolog of the 8-oxoguanine glycosylase 1 codon 326 polymorphism was related to the decreased risk; odds ratios were 1.00 (reference), 0.06 (95% confidence interval 0.01-0.53), 0.06 (0.01-0.54) and 0.14 (0.02-1.08) for persons with human homolog of the 8-oxoguanine glycosylase 1 Ser/Ser and glutathione-S-transferases mu 1 wild, ones with Ser/Ser and glutathione-S-transferases mu 1 null, ones with Ser/Cys or Cys/Cys and glutathione-S-transferases mu 1 wild and ones with Ser/Cys or Cys/Cys and glutathione-S-transferases mu 1 null, respectively (P for interaction <0.01). Further adjustment for the presence of anti-Opisthorchis viverrini antibody, smoking and alcohol drinking did not change the decreased risk. Other combinations of deoxyribonucleic acid-repair gene polymorphism and glutathione-S-transferases were not associated with the risk of cholangiocarcinoma. CONCLUSIONS: The present findings suggested that decreased capacity of deoxyribonucleic acid-repair gene, human homolog of the 8-oxoguanine glycosylase 1, may be related to decreased risk if much damaged cells die before malignant transformation. PMID- 24049015 TI - The effects of intestinal LPS exposure on inflammatory responses in a porcine enterohepatic co-culture system. AB - A porcine enterohepatic co-culture system, with primary hepatocytes as bottom layer and IPEC-J2 epithelial cells as upper layer, was developed to study the effects of lipopolysaccharides (LPS) on the gene expression profile of pro inflammatory cytokines (interleukin-8 (IL-8) and tumor necrosis factor-alpha) and CYP enzymes (CYP1A1, CYP1A2, CYP3A29). The barrier integrity of IPEC-J2 cells was investigated by transepithelial electrical resistance measurements and by fluorescein isothiocyanate-dextran-based test. Basolateral IL-8 production was significantly elevated in LPS-treated IPEC-J2 and primary hepatocyte mono cultures as well as in the co-culture system, in a dose-independent manner. The LPS-induced changes in the expression of the CYP1A2 and CYP3A29 genes in hepatocyte mono-cultures differed from those in co-culture after LPS treatment on the apical side of the IPEC-J2 cell layer. CYP1A2 was downregulated by the LPS treatment in mono-cultures but upregulated at 10 MUg/ml LPS in co-culture; gene expression of CYP3A29 showed no significant LPS-induced change in the hepatocyte mono-culture but was significantly downregulated in co-culture. The newly established co-culture system capable of mimicking enterohepatic interplay in LPS induced inflammatory responses in vitro can be used in the future for reliable screening of potential anti-inflammatory compounds. PMID- 24049016 TI - Effects of a selective sigma 1 antagonist compound on inflammatory pain. AB - The compound (-)-MRV3 [(-)-Methyl (1S,2R)-2-[(4-Hydroxy-4-phenylpiperidin-1-yl) methyl]-1-phenylcyclopropanecarboxylate] has an assessed antagonistsigma 1 (sigma1) profile and showed improved sigma1/sigma2 selectivity with respect to the parent compound(+)-MR200. The sigma1 receptor is reported to play arole in both central sensitization and pain hypersensitivity,which suggests a potential use of sigma1 antagonists forthe treatment of persistent pain conditions. The present study was performed to assess the effects of theselective sigma1 antagonist (-)-MRV3, in carrageenan-inducedinflammatory hyperalgesia, allodynia and edema.Mechanical allodynia with a series of calibratedvon Frey's filaments, thermal hyperalgesia with plantartest and edema evaluation with a plethysmometerwere measured. Subcutaneous (s.c.) treatment with(-)-MRV3 (1, 2, 3, 4, 5 mg/kg) dose-dependentlyreduced allodynia and hyperalgesia induced byintraplantar carageenan. Furthermore, treatment with(-)-MRV3 (3 mg/kg s.c.) also inhibited paw edemawith a significant inhibition of 61.53 % 3 h aftercarrageenan treatment [corrected]. These results provide a strongbasis for the use of sigma1 receptor antagonists in thetreatment of inflammatory pain. PMID- 24049017 TI - Prognosis in patients with left main coronary artery disease managed surgically, percutaneously or medically: a long-term follow-up. AB - BACKGROUND: Left main stenosis (LMS) occurs in 5-7% of patients with coronary artery disease. Half of patients with left main coronary artery (LMCA) disease die within few years after the diagnosis. AIM: To evaluate survival of patients with LMCA disease treated with coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or managed medically due to lack of consent for CABG or being considered unsuitable candidatesfor CABG/PCI. METHODS: In 2006-2008, a significant LMS was found in 257 (5.14%) patients, and 98.44% of these patients were followed upfor on average 15.1 months. The patients were divided into 5 groups according to the treatment used. CABG was performedin 67% of patients, PCI of an unprotected LMS in 8% of patients, and 12% of patients were treated with PCI after a previous CABG (protected LMS). The remaining patients were managed medically: 4% were not considered suitable for CABG, and9% did not give their consent for CABG. RESULTS: Total mortality in the overall study group (n = 253) was 14.6%. Multivessel disease was more frequent in the CABG group (60.9% vs. 15.8%, p < 0.001). Mortality in CABG and PCI groups was comparable (11.4% vs. 15.8%). Patients in the PCI group were more frequently hospitalised due to recurrent angina (21.1% vs. 3.0%, p < 0.001) and the need for repeated revascularisation (15.8% vs. 1.2%, p < 0.001). Compared to the CABG group, patients considered not suitable for CABG hadlower left ventricular ejection fraction (LVEF) (36.55% vs. 51.04%, p < 0.001) and a higher mortality risk as estimated by the EuroScore. Mortality among patients deemed unsuitable for CABG was 54.6% (p < 0.001) and myocardial infarctions were observed more frequently in this group (18.2% vs. 2.4%, p < 0.01). In comparison to the CABG group, patients who did not consent to CABG were older (71.04 vs. 65.99 years, p = 0.027), had lower LVEF (44.05% vs. 51.04%, p = 0.004), were less frequently hospitalised due to acute coronary syndromes (17.4% vs. 40.8%, p = 0.03), and had a smaller degree of LMS (63%vs. 71%, p = 0.027). Mortality in this group was comparable to the CABG group (17.4% vs. 11.4%). The majority of patients who underwent previous CABG needed repeated revascularisation: PCI of a protected LMS was performed in 27% of patients,PCI of other native coronary arteries in 39% of patients, and PCI of a bypass graft in 7% of patients. CONCLUSIONS: PCI of unprotected LMCA may be an equally effective revascularisation method as CABG. High mortality (55%) due to concomitant diseases was observed among patients with LMS who were deemed unsuitable candidates for CABG. Prognosis among patients who declined CABG was relatively good and might have been related to the small number of patients and different patient characteristics in this group. PMID- 24049018 TI - Left main coronary disease: improved early outcomes after off-pump coronary artery bypass grafting in high-risk patients. AB - BACKGROUND: Left main coronary artery (LMCA) stenosis is a risk factor in coronary artery bypass grafting (CABG). Although improved outcomes of off-pump CABG have been well documented, LMCA stenosis is often perceived as a contraindicationfor off-pump CABG. In this study, we compared on-pump and off pump techniques in high-risk patients with LMCA disease. AIM: Documentation of safety and feasibility of off-pump CABG in patients with LMCA disease. METHODS: One hundred ninty nine patients with LMCA disease and a EuroScore >= 5 were operated upon between 2007 and 2010. One hundred patients (Group I) were operated upon using off-pump techniques, while 99 (Group II) were operated upon using conventional on-pump techniques. Perioperative variables and outcomes at first six months were compared. RESULTS: Despite higher mean age and EuroScore (70.9 +/ 4.8 vs. 65.6 +/- 7.9, p < 0.001, and 6.09 +/- 0.8 vs. 5.31 +/- 0.68,p < 0.001, respectively), and lower ejection fraction (41.4 +/- 7.3 vs. 49.0 +/- 6.2, p < 0.001), hospital mortality (1% vs. 6.1%,p = 0.065), postoperative inotropic support (9% vs. 48.4%, p < 0.001), blood loss (680.6 +/- 265.0 vs. 847.2 +/- 382, p < 0.001) and transfusions of blood (0.57 +/- 0.79 U vs. 1.49 +/- 0.82 U, p < 0.001), and hospital stay (6.57 +/- 2.04 vs. 7.68 +/- 3.44,p = 0.006) were lower in Group I. In both groups, mean number of distal anastomoses and completeness of revascularisation were similar. CONCLUSIONS: Using the off-pump technique is safe and improves postoperative early outcomes in high-risk patients with LMCA disease. PMID- 24049019 TI - Can we improve the accuracy of risk assessment in patients with non ST-segment elevation acute coronary syndromes? AB - BACKGROUND: In patients with non-ST segment elevation acute coronary syndromes (NSTE-ACS), the long-term risk of deathand myocardial infarction (MI) is estimated by scores based on noninvasively derived variables. Much less is known about the relation between the degree of atherosclerotic burden in the coronary tree and the long-term risk of patients with NSTE-ACS. AIM: To evaluate the accuracy of a wide spectrum of coronary angiographic and clinical data in predicting outcomes ina long-term follow-up of patients successfully treated invasively for NSTE-ACS. METHODS: The study group consisted of 112 consecutive patients (age 62 +/- 10 years; 76 men) treated invasively for NSTE-ACS.27 (24%) patients had a history of diabetes mellitus (DM) and 37 (33%) patients a history of MI. The coronary angiograms priorto intervention were evaluated blindly for the four angiographic scores: (1) Stenosis score derived from the assessment of thedegree of stenosis in 15 segments of the coronary tree; (2) Vessel score showing the number of main vessels stenosed > 70%; (3) Extensity score assessing the proportion of lumen length irregularity in 15 segments; and (4) Complexity score describingthe number of complex plaques. The angiographic analysis also focused on the flow, presence of thrombus and collateralsupply prior to intervention (according to TIMI) and the size of the culprit lesion vessel. The intervention was successful in 95% of cases. All patients were followed-up for 6 24 months for the occurrence of death or MI. RESULTS: In the follow-up period, the composite end point of death or MI occurred in 20 (17%) patients. In order to indicate therisk predictors from the group of clinical and angiographic variables (age, sex, history of DM, history of MI, four angiographicscores and culprit lesion vessel characterisation), logistic regression analysis was performed. The independent angiographic predictors of composite end point (selected by forward conditional selection) were stenosis score (OR 1.13; 95% CI 1.05-1.2;p < 0.001) and size of the vessel (OR 0.08; 95% CI 0.01-0.6; p = 0.02). CONCLUSIONS: Our preliminary data shows that attempting to add angiographic variables into the risk assessment scoring systems in order to strengthen their predictive accuracy is justified. PMID- 24049020 TI - Is the lumen diameter of peripheral arteries a good marker of the extent of coronary atherosclerosis? AB - BACKGROUND: The lumen diameter (LD) of the extracranial carotid arteries determined by B-mode ultrasound has been provedto be associated with most atherosclerotic risk factors and cardiovascular events. This raises the question as to whether LDmay also predict coronary artery disease. AIM: To elucidate whether LD of the common carotid and/or femoral artery could be a clinically useful marker of the extentof coronary atherosclerosis. METHODS: A duplex ultrasonography and a quantitative coronary angiography were used to assess carotid, femoral and coronary atherosclerosis for 204 patients with angina pectoris. Intima-media thickness (IMT) and LD assessments were performed in peripheral arteries. We used three coronary angiographic scores: Vessel, Gensini and Extent. The following parameterswere recorded: gender, age, diagnoses of arterial hypertension and diabetes, history of myocardial infarction (MI) and stroke, smoking status, body mass index (BMI) and body surface area (BSA). RESULTS: Significant correlations between LD, IMT and coronary scores were found, but the strongest correlations were betweenLD of the common carotid arteries and angiographic scores. In the case of LD in all investigated arteries, and IMT ofthe right carotid and left femoral arteries, significantly higher values were observed for patients with three-vessel disease (3VD) than for patients without it. Univariate analysis showed the important role played by LD of the carotid arteries in predicting 3VD (OR = 2.7). We obtained two multivariate logistic regression models which could estimate the probability P of 3VD. The first model:logit P = 0.05 age + 0.94 RCCALD + 0.70 MI - 9.1; AUC=0.80 (0.03) is based on the value of the right common carotid artery lumen diameter (RCCALD), age and history of MI; the second oneis based on LD of the left common carotid artery, gender, age and previous MI. ROC analysis indicated the optimal cut-offvalue for prediction of 3VD (P = 0.36), with high sensitivity (80%) and specificity (70%) for the first model. CONCLUSIONS: According to our results, LD of the common carotid artery appears to be an independent predictor of 3VD. RCCLD turned out to be a basic prognostic variable (called 'risk variable') of the extent of coronary atherosclerosis afteradjustment for age and prior MI. Measurements of common carotid artery LD, together with age, history of MI (and gender in the case of the left common carotid artery LD), could estimate the probability of 3VD. Other studies will be necessary to confirm our results before the obtained method can be used in clinical practice as a simple non-invasive diagnostic tool for a specific group of patients. PMID- 24049021 TI - Catheter ablation of complex left atrial arrhythmias in patients after percutaneous or surgical mitral valve procedures. AB - BACKGROUND: Mitral valve defects are frequently associated with atrial arrhythmias. Percutaneous or surgical mitral valveprocedures may reverse adverse haemodynamic consequences of the valvular defect but have little effect on the arrhythmiaitself. With safety concerns and few outcome data, the role of catheter ablation in these patients has not been established yet. AIM: To assess safety and efficacy of catheter ablation of complex left atrial arrhythmias in patients after percutaneous orsurgical mitral valve procedures. METHODS: We studied 14 patients (mean age 55 +/- 11 years; 9 females) with a history of percutaneous mitral commissurotomy (PMC; n = 5), surgical valvuloplasty (n = 3), or mitral valve replacement (n = 6) due to mitral stenosis (MS; n = 8) or mitral regurgitation (MR; n = 6). In surgically treated patients, concomitant pulmonary vein isolation was performed in 6 patients and tricuspid valvuloplasty in 4 patients. Atrial fibrillation (AF) was the only arrhythmia in 7 patients, including all 5 patients after PMC (paroxysmal AF in 2 patients, persistent AF in 4 patients, long-persistent AF in 1 patient). Left atrial tachycardia (AT) was the prevailing arrhythmia in 7 of 9 patients after surgical procedures (median of 2 morphologies per patient), lasting uninterrupted for 1 to 48 months before the ablation procedure. The ablation scheme was adjusted to the clinical and electrophysiological status and included pulmonary vein isolation, linear lesions and ablation of fragmented potentials. Atrial tachycardias were mapped and ablated using activation and entrainment mapping. RESULTS: Efficacy of ablation after a single procedure was 36%. A total of 25 ablations were ultimately performed in the study group. During 23 +/- 13 months of follow-up, stable sinus rhythm (SR) was present in 10 (71.4%) patients, including 4 on antiarrhythmic drugs. No differences in the efficacy of ablation were seen between patients with MS and MR, with SR obtained in5 of 8 patients and 5 of 6 patients, respectively (p = 0.57). Similarly, no differences in regard to SR maintenance were noted between patients previously treated by a percutaneous or surgical procedure (percutaneous treatment: SR in 3 of 5 patients; surgical treatment: SR in 7 of 9 patients, p = 0.58). SR was obtained in 5 of 7 patients in whom the original arrhythmia was AF and in 5 of 7 patients who had AT (p = 1.00). Patients in whom stable SR was obtained showed a significantly better functional status as assessed by the New York Heart Association classification, accompanied by a reduction of the left atrial dimension and an increase in the left ventricular ejection fraction. CONCLUSIONS: Catheter ablation of complex left atrial arrhythmias in patients after percutaneous or surgical mitral valve proceduresis an effective and safe therapeutic option. Recurrences after the first ablation are frequent and patients may require repeat ablations. Achieving stable SR significantly reduces complaints related to the arrhythmia and improves patient clinical status. PMID- 24049022 TI - Hepatocyte growth factor - the earliest marker of myocardial injury in ST-segment elevation myocardial infarction. AB - BACKGROUND: Hepatocyte growth factor (HGF) concentration increases in the first few hours of myocardial infarction (MI). AIM: (1) To illustrate human HGF (hHGF) plasma concentration during the first 24 h of ST segment elevation myocardialinfarction (STEMI); (2) To estimate the odds ratio of STEMI in the context of hHGF measurements; (3) To describe the normalconcentration of hHGF in healthy subjects. METHODS: The study groups consisted of 73 STEMI patients and 11 healthy volunteers. In all the patients, we took bloodsamples for hHGF twice, i.e. on admission to hospital and 24 h later. RESULTS: The median value of hHGF in healthy volunteers was 666 pg/mL (576; 760 pg/mL). In STEMI, the highest values of hHGF were observed in the first measurement. An increase of 1 pg/mL in hHGF level increased STEMI odds ratio by 0.2%. CONCLUSIONS: In acute MI, of the known biomarkers, hHGF rises the earliest and very promptly returns to normal values. PMID- 24049023 TI - Is mean platelet volume associated with the angiographic severity of coronary artery disease? AB - BACKGROUND: Platelet activation and aggregation play key roles both in the pathogenesis of atherosclerosis and in the developmentof acute thrombotic events. Platelet volume is a marker of platelet activation and function, and is measured usingmean platelet volume (MPV). AIM: To determine the relationship between MPV and angiographic Gensini and SYNTAX scores, which give information about the severity and complexity of coronary artery disease (CAD). METHODS: This study included 435 consecutive patients undergoing elective coronary angiography. The complete blood countand biochemical examination of blood were obtained after 12 h of fasting. The independent association between MPV andthe severity of CAD was statistically evaluated using PASW Statistics 18 for Windows. RESULTS: Mean age of the study population was 58.4 +/- 9.3 years, of whom 196 were female (45.1%) and 239 male (54.9%). Of the patients, 63.2% had CAD, 31.7% had diabetes mellitus, 61.8% had hypertension, 56.6% had hyperlipidaemia, and 38.6% were smokers. Mean Gensini score was 20.7 +/- 31.1. According to Gensini scores, 160 of the patients (36.8%) hadnormal coronary arteries (Gensini score: 0), 134 of the patients (30.8%) had minimal CAD (Gensini score: 1-19), and 141 ofthem (32.4%) had severe CAD (Gensini score >= 20). Mean MPV values were 8.4 +/- 1.0 fL in the group that had no CAD,8.7 +/- 1.0 fL in the group with minimal CAD, and 9.3 +/- 1.5 fL in the group with severe CAD. According to Spearman correlationanalysis, the positive relationship found between MPV and Gensini score was statistically significant (p < 0.001,r = 0.290). Likewise, SYNTAX score was also associated with MPV (p < 0.001, r = 0.504). CONCLUSIONS: We determined a positive correlation between MPV and Gensini and SYNTAX scores. Therefore, this simple haematology test can be used in determining cardiovascular disease burden besides other risk factors during routine clinical practice. For further information about this topic, large-scale studies are needed. PMID- 24049024 TI - Ischaemic heart preconditioning in rats with adjuvant-induced arthritis. AB - BACKGROUND: Adjuvant-induced arthritis (AIA) in rats is a model of chronic systemic inflammation and a model of rheumatoidarthritis in humans. AIM: To investigate effectiveness of ischaemic preconditioning (IPC) in reducing the area of myocardial infarction in rats with AIA. METHODS: The study was performed in vivo in male SPRD/Mol/Lod rats. Animals were assigned to the experimental group (n = 15) or the control group (n = 14). In the experimental group, AIA was induced by subcutaneous administration of 1 mLof Freund's complete adjuvant, and the experiment was performed after 14 days. In control (healthy) animals, no procedures were performed prior to the proper experiment. Animals were anaesthesized (by intraperitoneal administration of ketamineand xylazine) and put on a ventilator. Then, myocardial infarction was induced, preceded by IPC in some animals. To induceinfarction, left main coronary artery (LMCA) was occluded for 30 min, followed by 60 min of reperfusion. IPC protocol consisted of LMCA occlusion for 3 min, followed by 5 min of reperfusion and a second LMCA occlusion for 7 min. Weevaluated a percentage ratio of the infarct size to the risk area (IS/RA). Necrosis area was stained with tetrazolium, and thearea supplied by LMCA was determined using Evans blue. All areas were determined by planimetry. We used nonparametric Kruskal-Wallis rank ANOVA with multiple comparisons, and the results were shown as median values and 25th and 75th percentiles. P < 0.05 was considered statistically significant. RESULTS: In the control group with IPC (n = 7), the IS/RA ratio of 25% (23-38) was significantly reduced compared to thecontrol group without IPC (n = 7) (58% [57-63], p < 0.05). In the AIA group with IPC (n = 7), the IS/RA ratio of 58% (51-65)did not differ significantly compared to the AIA group without IPC (n = 8) (65% [62-71]). CONCLUSIONS: Our findings indicate that IPC in rats with AIA does not result in a significant reduction of myocardial necrosisarea induced by 30 min of ischaemia and 60 min of reperfusion. This effect might have been related to the presence ofchronic systemic inflammation. Absent or reduced benefits of IPC may be one reason for an increased cardiovascular risk inpatients with rheumatoid arthritis. PMID- 24049025 TI - [Should cardiologist routinely screen and evaluate patients for sleep disordered breathing?]. AB - We report a case of a 61-year-old male patient who presented with reduced exercise capacity, dyspnea, lower limbs oedema,irregular heart rhythm, loud, irregular snoring, history of poorly controlled hypertension, nocturnal hypertension spikes, andmorning headaches. Patient underwent ECG Holter monitoring and polygraphy, which revealed severe obstructive sleepapnea. In ECG Holter monitoring atrial fibrillation with pauses to 6.5 s were observed. Patient was referred for continuouspositive airway pressure (CPAP) treatment. Three months of CPAP therapy resulted in significant decrease in apnea-hypopneaindex (31.6/h vs. 5.1/h) and better control of hypertension and heart failure. CPAP treatment allowed us to reduce patient's cardiovascular risk. Cardiologist should routinely screen and evaluate patients for sleep disordered breathing, especially when patients are obese, have hypertension and/or arrhythmias. PMID- 24049026 TI - Functional mitral stenosis, atrial fibrillation and heart failure secondary to left atrial compression by the formation of a localised periatrial haematoma after cardiac resuscitation. AB - A 53-year-old male patient was diagnosed with progressive dyspnoea after primary coronary intervention of circumflex lesion. Resuscitation was performed in the follow-up period due to the development of asystole. Control angiography showed patentstent without perforation signs and echocardiography revealed prominent compression of the left atrium by a periatrialmass. Magnetic resonance imaging (MRI) was performed for differential diagnosis. The MRI revealed an isolated periatrial haematoma compressing the left atrium and obliterating the mitral valve orifice. Haematoma formation had most probably occurred after resuscitation, since the initial echocardiogram was normal. After a one week follow-up, there had been no decrease in the size of the haematoma, and surgery was proposed. Left atrial compression by the formation of a periatrial haematoma related to resuscitation has not been reported before. It can cause atrial fibrillation and rapidly progressive heart failure. A more accurate diagnosis could be made using an MRI study. PMID- 24049027 TI - [Acute aortic syndrome mimicking anterior wall ST-elevation myocardial infarction]. AB - We present a case of a 58-year-old man presenting with chest pain irradiating to the back and left arm, history of smoking and untreated hypertension. The anamnesis, symptoms and ECG findings consisting of ST elevation in leads aVR and V1-V2 suggested ST segment elevated myocardial infarction. Performed ECHO examination revealed possible acute aortic dissection. Considering haemodynamic instability, augmentation of chest pain and passing time which was obviously worsening the prognosis patient was submitted to aortography which finally proofed acute aortic dissection. Patient was subsequently transferred to cardiac surgery unit and successfully treated. PMID- 24049028 TI - [Cardiac involvement in neuronal ceroid lipofuscinosis]. AB - We present a case of a 58-year-old female with neuropsychiatric symptoms, followed by recurrent episodes of atrial flagellation and symptoms of heart failure. Based on intraoperative myocardial biopsy, neuronal ceroid lipofuscinosis was diagnosed. PMID- 24049029 TI - [Primary pulmonary artery sarcoma in 36-year-old women: 3-years follow-up after partial resection and radiotherapy]. AB - Intimal sarcoma of the heart and pulmonary artery is a very rare, malignant, primary tumour. The prognosis in patients with primary sarcoma of the pulmonary artery, including intimal sarcoma, is poor. We present the case and 3-years follow-up of 36-year-old woman who was successfully treated with surgical, partial resection of the tumour followed by radiotherapy. PMID- 24049030 TI - [A 67-year-old men with not corrected tetralogy of Fallot]. AB - Tetralogy of Fallot is the most common cyanotic congenital heart disease. Total surgical correction of this defect during infancyallows for long-term survival in most of the patients. The long-term prognosis for untreated tetralogy of Fallot is poor and patients who have not undergone total surgical repair rarely live to old age. We present a case of 67-year-old man with not corrected tetralogy of Fallot diagnosed at the age of 44 years without typical clinical symptoms. PMID- 24049031 TI - [Atypical form of tako-tsubo cardiomyopathy in a patient with atrial fibrillation in Wolff-Parkinson-White syndrome complicated with ventricular fibrillation: the diagnostic problems]. AB - Atypical form of tako-tsubo cardiomyopathy (TTC) is associated with regional wall motion abnormalities in basal and/or middle segments or only middle segments with sparing of apical segments or apical and basal segments. We described a case of47 year-old female with atypical form of TTC due to fast atrial fibrillation that converted into ventricular fibrillation in WPW syndrome. The echocardiogram made after direct current cardioversion revealed decreased left ventricular ejection fraction (LVEF 35%) with akinesis of inferior and posterior walls and anterior part of interventricular septum in the middle and the basal segments with hyperkinesis of apical segments. The biochemistry blood samples revealed elevated both troponin T- 0.35 ng/mL and NT-proBNP - 3550 pg/mL plasma level. The ECG showed sinus rhythm 62 bpm, shortened PQ interval 100 ms, widened QRS duration - 115 ms with delta wave, prolonged QT interval - 520 ms, QS in leads: II, III, aVF. NegativeT waves in leads: I, aVL and positive, symmetrical T waves in leads V1-V6. The coronarography revealed normal coronaryarteries. The control echocardiography after 10 days showed normal LVEF 70%, without any wall motion abnormalities. TTC was recognised based on: history of sudden stress situation before, ischaemic ECG changes, positive markers of myocardial injury, transient segmental wall motion abnormalities and normal coronary arteries. The ablation of right postero-septal accessory pathway was successfully performed. PMID- 24049032 TI - [Hypotensive therapy in patients with primary open-angle glaucoma]. PMID- 24049033 TI - [Hypercalcemia mimicking acute coronary syndrome]. AB - We described 2 patients (28-year-old and 69-year-old females) with hypercalcemia (4.47 mmol/L and 4.8 mmol/L), chest painand electrocardiogram with ST-T segment changes mimicking acute coronary syndrome. One patient presented ST segment elevation in right precordial leads V1-V3 max. 4 mm, the second one presented negative T waves in V1-V6 leads. Troponin level was normal in both cases. Additionally, corrected QT apex was shortened in both cases, 250 ms and 206 ms respectively and T wave humps in lateral leads was observed. PMID- 24049034 TI - [Editorial comment]. PMID- 24049035 TI - Real-time three-dimensional transoesophageal echocardiographic imaging of an aorto-left atrial fistula. PMID- 24049036 TI - A case of carcinoid pericardial metastases and massive effusion. PMID- 24049037 TI - Interrupted aortic arch: late diagnosis of congenital malformation. PMID- 24049038 TI - Multimodality imaging of a hiatal hernia compressing the left atrium. PMID- 24049039 TI - Young woman with idiopathic supradiaphragmatic mid-aortic syndrome and hypertension successfully controlled with a beta-blocker-calcium antagonist fixed dose combination. PMID- 24049040 TI - Giant aneurysms of coronary arteries accidentally discovered following out of hospital cardiac arrest. PMID- 24049042 TI - Through the eyes of a medical student. AB - As a medical student, I have come to appreciate the generosity of the patient time that I experience. This places me in a unique position as I can become truly immersed in the perspective of the patients I see. I have the time to engage and understand how they see their illness, their social barriers and many other factors that affect their overall wellbeing. In this particular encounter, I discuss one of the more memorable interviews I've had with a patient. We shared a connection that I hope will influence my interactions with patients in the future. PMID- 24049043 TI - Bedside teaching in medical education: a literature review. AB - Bedside teaching is seen as one of the most important modalities in teaching a variety of skills important for the medical profession, but its use is declining. A literature review was conducted to reveal its strengths, the causes of its decline and future perspectives, the evidence with regard to learning clinical skills and patient/student/teacher satisfaction. PubMed, Embase and the Cochrane library were systematically searched with regard to terms related to bedside teaching. Articles regarding the above-mentioned subjects were included. Bedside teaching has shown to improve certain clinical diagnostic skills in medical students and residents. Patients, students/residents and teachers all seem to favour bedside teaching, for varying reasons. Despite this, the practice of bedside teaching is declining. Reasons to explain this decline include the increased patient turnover in hospitals, the assumed violation of patients' privacy and an increased reliance on technology in the diagnostic process. Solutions vary from increasingly using residents and interns as bedside teachers to actively educating staff members regarding the importance of bedside teaching and providing them with practical essentials. Impediments to bedside teaching need to be overcome if this teaching modality is to remain a valuable educational method for durable clinical skills. PMID- 24049044 TI - Achieving research competences through medical education. PMID- 24049046 TI - Benzodiazepines for psychosis-induced aggression or agitation. AB - BACKGROUND: Acute psychotic illness, especially when associated with agitated or violent behaviour, can require urgent pharmacological tranquillisation or sedation. In several countries, clinicians often use benzodiazepines (either alone or in combination with antipsychotics) for this outcome. OBJECTIVES: To estimate the effects of benzodiazepines, alone or in combination with antipsychotics, when compared with placebo or antipsychotics, alone or in combination with antihistamines, to control disturbed behaviour and reduce psychotic symptoms. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's register (January 2012), inspected reference lists of included and excluded studies and contacted authors of relevant studies. SELECTION CRITERIA: We included all randomised clinical trials (RCTs) comparing benzodiazepines alone or in combination with any antipsychotics, versus antipsychotics alone or in combination with any other antipsychotics, benzodiazepines or antihistamines, for people with acute psychotic illnesses. DATA COLLECTION AND ANALYSIS: We reliably selected studies, quality assessed them and extracted data. For binary outcomes, we calculated standard estimates of relative risk (RR) and their 95% confidence intervals (CI) using a fixed-effect model. For continuous outcomes, we calculated the mean difference (MD) between groups. If heterogeneity was identified, this was explored using a random-effects model. MAIN RESULTS: We included 21 trials with a total of n = 1968 participants. There was no significant difference for most outcomes in the one trial that compared benzodiazepines with placebo, although there was a higher risk of no improvement in people receiving placebo in the medium term (one to 48 hours) (n = 102, 1 RCT, RR 0.62, 95% CI 0.40 to 0.97, very low quality evidence). There was no difference in the number of participants who had not improved in the medium term when benzodiazepines were compared with antipsychotics (n = 308, 5 RCTs, RR 1.10, 95% CI 0.85 to 1.42, low quality evidence); however, people receiving benzodiazepines were less likely to experience extrapyramidal effects (EPS) in the medium term (n = 536, 8 RCTs, RR 0.15, 95% CI 0.06 to 0.39, moderate quality of evidence). Data comparing combined benzodiazepines and antipsychotics versus benzodiazepines alone did not yield any significant results. When comparing combined benzodiazepines/antipsychotics (all studies compared haloperidol) with the same antipsychotics alone (haloperidol), there was no difference between groups in improvement in the medium term (n = 155, 3 RCTs, RR 1.27, 95% CI 0.94 to 1.70, very low quality evidence) but sedation was more likely in people who received the combination therapy (n = 172, 3 RCTs, RR 1.75, 95% CI 1.14 to 2.67, very low quality evidence). However, more participants receiving combined benzodiazepines and haloperidol had not improved by medium term when compared to participants receiving olanzapine (n = 60,1 RCT, RR 25.00, 95% CI 1.55 to 403.99, very low quality evidence) or ziprasidone (n = 60, 1 RCT, RR 4.00, 95% CI 1.25 to 12.75very low quality evidence). When haloperidol and midazolam were compared with olanzapine, there was some evidence the combination was superior in terms of improvement, sedation and behaviour. AUTHORS' CONCLUSIONS: The evidence from trials for the use of benzodiazepines alone is not good. There were relatively little good data and most trials are too small to highlight differences in either positive or negative effects. Adding a benzodiazepine to other drugs does not seem to confer clear advantage and has potential for adding unnecessary adverse effects. Sole use of older antipsychotics unaccompanied by anticholinergic drugs seems difficult to justify. Much more high quality research is needed in this area. PMID- 24049045 TI - Timing of saccadic eye movements during visual search for multiple targets. AB - Visual search requires sequences of saccades. Many studies have focused on spatial aspects of saccadic decisions, while relatively few (e.g., Hooge & Erkelens, 1999) consider timing. We studied saccadic timing during search for targets (thin circles containing tilted lines) located among nontargets (thicker circles). Tasks required either (a) estimating the mean tilt of the lines, or (b) looking at targets without a concurrent psychophysical task. The visual similarity of targets and nontargets affected both the probability of hitting a target and the saccade rate in both tasks. Saccadic timing also depended on immediate conditions, specifically, (a) the type of currently fixated location (dwell time was longer on targets than nontargets), (b) the type of goal (dwell time was shorter prior to saccades that hit targets), and (c) the ordinal position of the saccade in the sequence. The results show that timing decisions take into account the difficulty of finding targets, as well as the cost of delays. Timing strategies may be a compromise between the attempt to find and locate targets, or other suitable landing locations, using eccentric vision (at the cost of increased dwell times) versus a strategy of exploring less selectively at a rapid rate. PMID- 24049047 TI - Coenzyme Q10 for heart failure. AB - BACKGROUND: Coenzyme Q10, or ubiquinone, is a non-prescription nutritional supplement. It is a fat-soluble molecule that acts as an electron carrier in mitochondria and as a coenzyme for mitochondrial enzymes. Coenzyme Q10 deficiency may be associated with a multitude of diseases including heart failure. The severity of heart failure correlates with the severity of coenzyme Q10 deficiency. Emerging data suggest that the harmful effects of reactive oxygen species are increased in patients with heart failure and coenzyme Q10 may help to reduce these toxic effects because of its antioxidant activity. Coenzyme Q10 may also have a role in stabilising myocardial calcium-dependent ion channels and preventing the consumption of metabolites essential for adenosine-5'-triphosphate (ATP) synthesis. Coenzyme Q10, although not a primary recommended treatment, could be beneficial to patients with heart failure. Several randomised controlled trials have compared coenzyme Q10 to other therapeutic modalities, but no systematic review of existing randomised trials has been conducted. OBJECTIVES: To review the safety and efficacy of coenzyme Q10 in heart failure. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12); MEDLINE OVID (1950 to January Week 3 2013) and EMBASE OVID (1980 to 2013 Week 03) on 24 January 2013; Web of Science with Conference Proceedings (1970 to January 2013) and CINAHL Plus (1981 to January 2013) on 25 January 2013; and AMED (Allied and Complementary Medicine) (1985 to January 2013) on 28 January 2013. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials of either parallel or cross-over design that assessed the beneficial and harmful effects of coenzyme Q10 in patients with heart failure. When cross-over studies were identified, we considered data only from the first phase. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from the included studies onto a pre-designed data extraction form. We then entered the data into Review Manager 5.2 for analysis. We assessed study risk of bias using the Cochrane 'Risk of bias' tool. For dichotomous data, we calculated the risk ratio and for continuous data the mean difference (MD). Where appropriate data were available, we performed meta-analysis. For this review we prioritised data from pooled analyses only. Where meta-analysis was not possible, we wrote a narrative synthesis. We provided a QUOROM flow chart to show the flow of papers. MAIN RESULTS: We included seven studies with 914 participants comparing conenzyme Q10 versus placebo. There were no data on clinical events from published randomised trials. The included studies had small sample sizes. Meta-analysis was only possible for a few physiological measures and there was substantial heterogeneity.Only one study reported on total mortality, major cardiovascular events and hospitalisation. Five trials reported on the New York Heart Association (NYHA) classification of clinical status, but it was impossible to pool data due to heterogeneity. None of the included trials considered quality of life, exercise variables, adverse events or cost-effectiveness as outcome measures. Pooled analysis suggests that the use of coenzyme Q10 has no clear effect on left ventricular ejection fraction (MD -2.26; 95% confidence interval (CI) -15.49 to 10.97, n = 60) or exercise capacity (MD 12.79; 95% CI -140.12 to 165.70, n = 85). Pooled data did indicate that supplementation increased blood levels of coenzyme Q10 (MD 1.46; 95% CI 1.19 to 1.72, n = 112). However, there are only a small number of small studies with a risk of bias, so these results should be interpreted with caution. AUTHORS' CONCLUSIONS: No conclusions can be drawn on the benefits or harms of coenzyme Q10 in heart failure at this time as trials published to date lack information on clinically relevant endpoints. Furthermore, the existing data are derived from small, heterogeneous trials that concentrate on physiological measures: their results are inconclusive. Until further evidence emerges to support the use of coenzyme Q10 in heart failure, there might be a need to re-evaluate whether further trials testing coenzyme Q10 in heart failure are desirable. PMID- 24049051 TI - Predictive genetic testing for complex diseases: a public health perspective. AB - From a public health perspective, systematic, evidence-based technology assessments and economic evaluations are needed to guide the incorporation of genomics into clinical and public health practice. However, scientific evidence on the effectiveness of predictive genetic tests is difficult to obtain. This review first highlights the similarities and differences between traditional screening tests and predictive genetic testing for complex diseases and goes on to describe frameworks for the evaluation of genetic testing that have been developed in recent years providing some evidence that currently genetic tests are not used in an appropriate way. Nevertheless, evidence-based recommendations are already available for some genomic applications that can reduce morbidity and mortality and many more are expected to emerge over the next decade. The time is now ripe for the introduction of a range of genetic tests into healthcare practice, but this will require the development of specific health policies, proper public health evaluations, organizational changes within the healthcare systems, capacity building among the healthcare workforce and the education of the public. PMID- 24049052 TI - Monitoring trends in recreational drug use from the analysis of the contents of amnesty bins in gay dance clubs. AB - BACKGROUND: In 2011/12, 8.9% of the UK population reported use of recreational drugs. Problems related to drug use is a major financial burden to society and a common reason for attendance to hospital. AIM: The aim of this study was to establish current trends in recreational drug use amongst individuals attending gay-friendly nightclubs in South London. METHOD: Contents of drug amnesty bins located at two night clubs were documented and categorized into powders, herbal products, liquids, tablets and capsules. These were then sent to a Home Office licensed laboratory for identification through a pre-existing database of almost 25 000 substances. If required, further qualitative analysis was performed. RESULTS: A total of 544 samples were obtained. Of them, 240 (44.1%) were liquids, 220 (40.4%) powders, 42 (7.7%) herbal and 41 (7.5%) tablets or capsules. Gamma butyrolactone (GBL) was the most common liquid drug (n = 160, 66.7%) followed by poppers (n = 72, 30.0%). Powders provided the widest range of drugs with mephedrone being the most common (n = 105, 47.7%) followed by ketamine (n = 28, 12.7%), 3,4-methylenedioxy-N-methylamphetamine (MDMA) (n = 26, 11.8%), and cocaine (n = 21, 9.5%). Tablets and capsules included medicinal drugs, recreational drugs and plaster of Paris tablets that mimicked the appearance of 'ecstasy' tablets. CONCLUSION: This study has provided a snapshot of the pattern of drug use in the gay community which compliments findings of the self-reported surveys and other studies from the same population. The information obtained will be helpful in guiding in designing harm reduction interventions in this community and for monitoring the impact of changes in legislation. PMID- 24049053 TI - Increased aryl hydrocarbon receptor expression in patients with allergic rhinitis. AB - BACKGROUND: A predominant Th17 population is a marker of allergic rhinitis (AR). As a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR) plays a vital role in promoting or inhibiting the development of specific Th cells. However, its role in AR remains undefined. OBJECTIVE: To analyze the potential role of AhR in the pathogenesis of AR. METHODS: In total, 30 AR patients and 13 healthy controls were recruited for this study and AR patients had clinical features, as demonstrated by rhinoconjunctivitis quality of life questionnaires, total symptom scores and visual analog scale scores. The expression of AhR, IL-17 and IL-22 and the presence of Th17 cells in peripheral blood mononuclear cells were measured before and after treatment with the nontoxic AhR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). RESULTS: Pretreatment ITE studies revealed that all AR patients had a significant increase in AhR expression compared with controls and AhR expression positively correlated with clinical parameters. After ITE intervention, a severe reduction in the differentiation of Th17 cells and the production of IL-17 and IL-22 was noted in both AR patients and normal subjects. Simultaneously, a dramatic enhancement of AhR expression was also observed in all healthy controls, but not in AR patients. CONCLUSION: The results suggested that the AhR may be one of the mechanisms underlying the Th17 response during the pathogenesis of AR and AhR levels were closely related to clinical severity in all AR patients. Additionally, ITE may represent a new drug candidate in the treatment of AR. PMID- 24049054 TI - Angina caused by a giant coronary artery fistula. PMID- 24049055 TI - A narrow complex tachycardia for the broad minded. PMID- 24049056 TI - Acute transverse myelitis associated with human parvovirus b19 infection. AB - We describe severe acute transverse myelitis in a previously healthy 9-year-old boy in whom primary human parvovirus B19 infection was confirmed serologically and B19 DNA was detected in his serum and cerebrospinal fluid. Besides erythema infectiosum, parvovirus B19 infection has various clinical manifestations; however, central nervous system involvement is rare. Even more unusual is parvovirus B19-associated acute transverse myelitis. PMID- 24049057 TI - Feasibility of transcranial direct current stimulation use in children aged 5 to 12 years. AB - Transcranial direct current stimulation is a noninvasive brain stimulation technique that has been studied for the treatment of neuropsychiatric disorders in adults, with minimal side effects. The objective of this study is to report the feasibility, tolerability, and the short-term adverse effects of transcranial direct current stimulation in children from 5 to 12 years of age. It is a naturalistic study of 14 children who underwent 10 sessions of transcranial direct current stimulation as an alternative, off-label, and open-label treatment for various languages disorders. Frequency, intensity, adverse effects, and perception of improvement reported by parents were collected. The main side effects detected were tingling (28.6%) and itching (28.6%), acute mood changes (42.9%), and irritability (35.7%). Transcranial direct current stimulation is a feasible and tolerable technique in children, although studies regarding plastic and cognitive changes in children are needed to confirm its safety. In conclusion, this is a naturalistic report in which we considered transcranial direct current stimulation as feasible in children. PMID- 24049058 TI - Role of angiotensin-(1-7) in gastroprotection against stress-induced ulcerogenesis. The involvement of mas receptor, nitric oxide, prostaglandins, and sensory neuropeptides. AB - Angiotensin-(1-7) [Ang-(1-7)] is a major vasoactive metabolite of angiotensin I (Ang I), both being important components of the renin-angiotensin system (RAS). Ang-(1-7) acting via Mas receptor was documented in kidneys, heart, brain, and gastrointestinal (GI)-tract. We studied the gastroprotective activity of exogenous Ang-(1-7) in rats exposed to water immersion and restraint stress (WRS) without or with A-779 [d-Ala7-Ang-(1-7), an antagonist of Ang-(1-7) Mas receptors], AVE 0991 (5-formyl-4-methoxy-2-phenyl-1[[4-[2 (ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]-phenyl]-methyl]-imidazole), the agonist of Ang-(1-7) receptor, as well as the inhibition of nitric-oxide (NO) synthase, the suppression of cyclo-oxygenase (COX)-1 (indomethacin, SC-560 [5-(4 chloro-phenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl-pyrazole]), the activity COX 2 (rofecoxib), and denervation with capsaicin. The mRNA expression of constitutively expressed nitric-oxide synthase (cNOS), inducible nitric-oxide synthase (iNOS), interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha was analyzed by reverse transcription polymerase chain reaction. The WRS lesions were dose-dependently reduced by pretreatment with Ang-(1-7), which also caused an increase in gastric blood flow (GBF) and luminal content of NO. COX-1 and COX 2 inhibitors or L-NNA (N5-[imino(nitroamino)methyl]-L-ornithine) reversed the reduction in lesion number and the rise in GBF evoked by Ang-(1-7). Ang II augmented the WRS lesions, decreased GBF and increased the plasma IL-1beta and TNF-alpha levels. Capsaicin denervation attenuated the reduction of Ang-(1-7) induced gastric lesions and the rise in GBF; these effects were restored by supplementation with calcitonin gene-related peptide (CGRP). The cNOS mRNA was upregulated while iNOS, IL-1beta and TNF-alpha mRNAs were downregulated in Ang-(1 7)-pretreated rats. We conclude that Ang-(1-7), in contrast to Ang II, which worsened WRS ulcerogenesis, affords potent gastroprotection against WRS ulcerogenesis via an increase in GBF mediated by NO, endogenous prostaglandins, sensory neuropeptides, and anti-inflammatory action involving the inhibition of proinflammatory markers iNOS, IL-1beta, and TNF-alpha. PMID- 24049060 TI - Combined analysis of pharmacokinetic and efficacy data of preclinical studies with statins markedly improves translation of drug efficacy to human trials. AB - Correct prediction of human pharmacokinetics (PK) and the safety and efficacy of novel compounds based on preclinical data, is essential but often fails. In the current study, we aimed to improve the predictive value of ApoE*3Leiden (E3L) transgenic mice regarding the cholesterol-lowering efficacy of various statins in humans by combining pharmacokinetic with efficacy data. The efficacy of five currently marketed statins (atorvastatin, simvastatin, lovastatin, pravastatin, and rosuvastatin) in hypercholesterolemic patients (low-density lipoprotein >= 160 mg/dl) was ranked based on meta-analysis of published human trials. Additionally, a preclinical combined PK efficacy data set for these five statins was established in E3L mice that were fed a high-cholesterol diet for 4 weeks, followed by 6 weeks of drug intervention in which statins were supplemented to the diet. Plasma and tissue levels of the statins were determined on administration of (radiolabeled) drugs (10 mg/kg p.o.). As expected, all statins reduced plasma cholesterol in the preclinical model, but a direct correlation between cholesterol lowering efficacy of the different statins in mice and in humans did not reach statistical significance (R(2) = 0.11, P < 0.57). It is noteworthy that, when murine data were corrected for effective liver uptake of the different statins, the correlation markedly increased (R(2) = 0.89, P < 0.05). Here we show for the first time that hepatic uptake of statins is related to their cholesterol-lowering efficacy and provide evidence that combined PK and efficacy studies can substantially improve the translational value of the E3L mouse model in the case of statin treatment. This strategy may also be applicable for other classes of drugs and other preclinical models. PMID- 24049059 TI - Effect of nitric oxide on the anticancer activity of the topoisomerase-active drugs etoposide and adriamycin in human melanoma cells. AB - Nitric oxide (.NO) was originally identified as an innate cytotoxin. However, in tumors it can enhance resistance to chemotherapy and exacerbate cancer progression. Our previous studies indicated that (.NO/.NO-derived species react with etoposide (VP-16) in vitro and form products that show significantly reduced activity toward HL60 cells and lipopolysaccharide (LPS)-induced macrophages. Here, we further confirm the hypothesis that (/)NO generation contributes to VP 16 resistance by examining interactions of .NO with VP-16 in inducible nitric oxide synthase (iNOS)-expressing human melanoma A375 cells. Inhibition of iNOS catalysis by N(6)-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL) in human melanoma A375 cells reversed VP-16 resistance, leading to increased DNA damage and apoptosis. Furthermore, we found that coculturing A375 melanoma cells with LPS-induced macrophage RAW cells also significantly reduced VP-16 cytotoxicity and DNA damage in A375 cells. We also examined the interactions of (.)NO with another topoisomerase active drug, Adriamycin, in A375 cells. In contrast, to VP 16, (.)NO caused no significant modulation of cytotoxicity or Adriamycin dependent apoptosis, suggesting that (?)NO does not interact with Adriamycin. Our studies support the hypothesis that (.)NO oxidative chemistry can detoxify VP-16 through direct nitrogen oxide radical attack. Our results provide insights into the pharmacology and anticancer mechanisms of VP-16 that may ultimately contribute to increased resistance, treatment failure, and induction of secondary leukemia in VP-16-treated patients. PMID- 24049061 TI - Kinetics of 5-HT2B receptor signaling: profound agonist-dependent effects on signaling onset and duration. AB - The kinetics of drug-receptor interactions can profoundly influence in vivo and in vitro pharmacology. In vitro, the potencies of slowly associating agonists may be underestimated in assays capturing transient signaling events. When divergent receptor-mediated signaling pathways are evaluated using combinations of equilibrium and transient assays, potency differences driven by kinetics may be erroneously interpreted as biased signaling. In vivo, drugs with slow dissociation rates may display prolonged physiologic effects inconsistent with their pharmacokinetic profiles. We evaluated a panel of 5-hydroxytryptamine2B (5 HT2B) receptor agonists in kinetic radioligand binding assays and in transient, calcium flux assays, and inositol phosphate accumulation assays; two functional readouts emanating from Galphaq-mediated activation of phospholipase C. In binding studies, ergot derivatives demonstrated slow receptor association and dissociation rates, resulting in significantly reduced potency in calcium assays relative to inositol phosphate accumulation assays. Ergot potencies for activation of extracellular signal-regulated kinases 1 and 2 were also highly time-dependent. A number of ergots produced wash-resistant 5-HT2B signaling that persisted for many hours without appreciable loss of potency, which was not explained simply by slow receptor-dissociation kinetics. Mechanistic studies indicated that persistent signaling originated from internalized or sequestered receptors. This study provides a mechanistic basis for the long durations of action in vivo and wash-resistant effects in ex vivo tissue models often observed for ergots. The 5-HT2B agonist activity of a number of ergot-derived therapeutics has been implicated in development of cardiac valvulopathy in man. The novel, sustained nature of ergot signaling reported here may represent an additional mechanism contributing to the valvulopathic potential of these compounds. PMID- 24049062 TI - Linking phenotype to kinase: identification of a novel benzoxaborole hinge binding motif for kinase inhibition and development of high-potency rho kinase inhibitors. AB - Benzoxaboroles are a novel class of drug-like compounds that have been rich sources of novel inhibitors for various enzymes and of new drugs. While examining benzoxaborole activity in phenotypic screens, our attention was attracted by the (aminomethylphenoxy)benzoxaborole family, which potently inhibited Toll-like receptor-stimulated cytokine secretion from leukocytes. After considering their structure-activity relationships and the central role of kinases in leukocyte biology, we performed a kinome-wide screen to investigate the members of the (aminomethylphenoxy)benzoxaborole family. This technique identified Rho-activated kinase (ROCK) as a target. We showed competitive behavior, with respect to ATP, and then determined the ROCK2-drug cocrystal structure. The drug occupies the ATP site in which the oxaborole moiety provides hydrogen bond donors and acceptors to the hinge, and the aminomethyl group interacts with the magnesium/ATP-interacting aspartic acid common to protein kinases. The series exhibits excellent selectivity against most of the kinome, with greater than 15-fold selectivity against the next best member of the AGC protein kinase subfamily. Medicinal chemistry efforts with structure-based design resulted in a compound with a Ki of 170 nM. Cellular studies revealed strong enzyme inhibition rank correlation with suppression of intracellular phosphorylation of a ROCK substrate. The biochemical potencies of these compounds also translated to functional activity, causing smooth muscle relaxation in rat aorta and guinea pig trachea. The series exhibited oral availability and one member reduced rat blood pressure, consistent with ROCK's role in smooth muscle contraction. Thus, the benzoxaborole moiety represents a novel hinge-binding kinase scaffold that may have potential for therapeutic use. PMID- 24049063 TI - Carbimazole is an inhibitor of protein synthesis and protects from neuronal hypoxic damage in vitro. AB - Oxygen deprivation during ischemic or hemorrhagic stroke results in ATP depletion, loss of ion homeostasis, membrane depolarization, and excitotoxicity. Pharmacologic restoration of cellular energy supply may offer a promising concept to reduce hypoxic cell injury. In this study, we investigated whether carbimazole, a thionamide used to treat hyperthyroidism, reduces neuronal cell damage in oxygen-deprived human SK-N-SH cells or primary cortical neurons. Our results revealed that carbimazole induces an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) that was associated with a marked inhibition of global protein synthesis. Translational inhibition resulted in significant bioenergetic savings, preserving intracellular ATP content in oxygen deprived neuronal cells and diminishing hypoxic cellular damage. Phosphorylation of eEF2 was mediated by AMP-activated protein kinase and eEF2 kinase. Carbimazole also induced a moderate calcium influx and a transient cAMP increase. To test whether translational inhibition generally diminishes hypoxic cell damage when ATP availability is limiting, the translational repressors cycloheximide and anisomycin were used. Cycloheximide and anisomycin also preserved ATP content in hypoxic SK-N-SH cells and significantly reduced hypoxic neuronal cell damage. Taken together, these data support a causal relation between the pharmacologic inhibition of global protein synthesis and efficient protection of neurons from ischemic damage by preservation of high-energy metabolites in oxygen-deprived cells. Furthermore, our results indicate that carbimazole or other translational inhibitors may be interesting candidates for the development of new organ protective compounds. Their chemical structure may be used for computer-assisted drug design or screening of compounds to find new agents with the potential to diminish neuronal damage under ATP-limited conditions. PMID- 24049064 TI - FOXL2: a central transcription factor of the ovary. AB - Forkhead box L2 (FOXL2) is a gene encoding a forkhead transcription factor preferentially expressed in the ovary, the eyelids and the pituitary gland. Its germline mutations are responsible for the blepharophimosis ptosis epicanthus inversus syndrome, which includes eyelid and mild craniofacial defects associated with primary ovarian insufficiency. Recent studies have shown the involvement of FOXL2 in virtually all stages of ovarian development and function, as well as in granulosa cell (GC)-related pathologies. A central role of FOXL2 is the lifetime maintenance of GC identity through the repression of testis-specific genes. Recently, a highly recurrent somatic FOXL2 mutation leading to the p.C134W subtitution has been linked to the development of GC tumours in the adult, which account for up to 5% of ovarian malignancies. In this review, we summarise data on FOXL2 modulators, targets, partners and post-translational modifications. Despite the progresses made thus far, a better understanding of the impact of FOXL2 mutations and of the molecular aspects of its function is required to rationalise its implication in various pathophysiological processes. PMID- 24049065 TI - The islet ghrelin cell. AB - The islets of Langerhans are key regulators of glucose homeostasis and have been known as a structure for almost one and a half centuries. During the twentieth century several different cell types were described in the islets of different species and at different developmental stages. Six cell types with identified hormonal product have been described so far by the use of histochemical staining methods, transmission electron microscopy, and immunohistochemistry. Thus, glucagon-producing alpha-cells, insulin-producing beta-cells, somatostatin producing delta-cells, pancreatic polypeptide-producing PP-cells, serotonin producing enterochromaffin-cells, and gastrin-producing G-cells have all been found in the mammalian pancreas at least at some developmental stage. Species differences are at hand and age-related differences are also to be considered. Eleven years ago a novel cell type, the ghrelin cell, was discovered in the human islets. Subsequent studies have shown the presence of islet ghrelin cells in several animals, including mouse, rat, gerbils, and fish. The developmental regulation of ghrelin cells in the islets of mice has gained a lot of interest and several studies have added important pieces to the puzzle of molecular mechanisms and the genetic regulation that lead to differentiation into mature ghrelin cells. A body of evidence has shown that ghrelin is an insulinostatic hormone, and the potential for blockade of ghrelin signalling as a therapeutic avenue for type 2 diabetes is intriguing. Furthermore, ghrelin-expressing pancreatic tumours have been reported and ghrelin needs to be taken into account when diagnosing pancreatic tumours. In this review article, we summarise the knowledge about islet ghrelin cells obtained so far. PMID- 24049066 TI - Functional characteristics of neonatal rat beta cells with distinct markers. AB - Neonatal beta cells are considered developmentally immature and hence less glucose responsive. To study the acquisition of mature glucose responsiveness, we compared glucose-regulated redox state, insulin synthesis, and secretion of beta cells purified from neonatal or 10-week-old rats with their transcriptomes and proteomes measured by oligonucleotide and LC-MS/MS profiling. Lower glucose responsiveness of neonatal beta cells was explained by two distinct properties: higher activity at low glucose and lower activity at high glucose. Basal hyperactivity was associated with higher NAD(P)H, a higher fraction of neonatal beta cells actively incorporating (3)H-tyrosine, and persistently increased insulin secretion below 5 mM glucose. Neonatal beta cells lacked the steep glucose-responsive NAD(P)H rise between 5 and 10 mM glucose characteristic for adult beta cells and accumulated less NAD(P)H at high glucose. They had twofold lower expression of malate/aspartate-NADH shuttle and most glycolytic enzymes. Genome-wide profiling situated neonatal beta cells at a developmental crossroad: they showed advanced endocrine differentiation when specifically analyzed for their mRNA/protein level of classical neuroendocrine markers. On the other hand, discrete neonatal beta cell subpopulations still expressed mRNAs/proteins typical for developing/proliferating tissues. One example, delta-like 1 homolog (DLK1) was used to investigate whether neonatal beta cells with basal hyperactivity corresponded to a more immature subset with high DLK1, but no association was found. In conclusion, the current study supports the importance of glycolytic NADH-shuttling in stimulus function coupling, presents basal hyperactivity as novel property of neonatal beta cells, and provides potential markers to recognize intercellular developmental differences in the endocrine pancreas. PMID- 24049067 TI - A new link between diabetes and cancer: enhanced WNT/beta-catenin signaling by high glucose. AB - Extensive epidemiological studies suggest that the diabetic population is at higher risk of site-specific cancers. The diabetes-cancer link has been hypothesized to rely on various hormonal (insulin, IGF1, adipokines), immunological (inflammation), or metabolic (hyperglycemia) characteristics of the disease and even on certain treatments. Inflammation may have an important but incompletely understood role. As a growth factor, insulin directly, or indirectly through IGF1, has been considered the major link between diabetes and cancer, while high glucose has been considered as a subordinate cause. Here we discuss the evidence that supports a role for insulin/IGF1 in general in cancer, and the mechanism by which hyperglycemia may enhance the appearance, growth and survival of diabetes-associated cancers. High glucose triggers several direct and indirect mechanisms that cooperate to promote cancer cell proliferation, migration, invasion and immunological escape. In particular, high glucose enhancement of WNT/beta-catenin signaling in cancer cells promotes proliferation, survival and senescence bypass, and represents a previously unrecognized direct mechanism linking diabetes-associated hyperglycemia to cancer. Increased glucose uptake is a hallmark of tumor cells and may ensure enhanced WNT signaling for continuous proliferation. Mechanistically, high glucose unbalances acetylation through increased p300 acetyl transferase and decreased sirtuin 1 deacetylase activity, leading to beta-catenin acetylation at lysine K354, a requirement for nuclear accumulation and transcriptional activation of WNT-target genes. The impact of high glucose on beta-catenin illustrates the remodeling of cancer-associated signaling pathways by metabolites. Metabolic remodeling of cancer-associated signaling will receive much research attention in the coming years. Future epidemiological studies may be guided and complemented by the identification of these metabolic interplays. Together, these studies should lead to the development of new preventive strategies for diabetes-associated cancers. PMID- 24049068 TI - cAMP in the pituitary: an old messenger for multiple signals. AB - The cyclic nucleotide cAMP is a universal regulator of a variety of cell functions in response to activated G-protein coupled receptors. In particular, cAMP exerts positive or negative effects on cell proliferation in different cell types. As demonstrated by several in vitro studies, in somatotrophs and in other endocrine cells, cAMP is a mitogenic factor. In agreement with this notion, it has been found that the mutations of genes coding for proteins that contribute to increases in the cAMP signaling cascade may cause endocrine tumor development. This review will discuss the central role of cAMP signaling in the pituitary, focusing on the cAMP pathway alterations involved in pituitary tumorigenesis, as well as on poorly investigated the aspects of cAMP cascade, such as crosstalk with the ERK signaling pathway and new cAMP effectors. PMID- 24049069 TI - End-to-end crosstalk within the hepatitis C virus genome mediates the conformational switch of the 3'X-tail region. AB - The hepatitis C virus (HCV) RNA genome contains multiple structurally conserved domains that make long-distance RNA-RNA contacts important in the establishment of viral infection. Microarray antisense oligonucleotide assays, improved dimethyl sulfate probing methods and 2' acylation chemistry (selective 2' hydroxyl acylation and primer extension, SHAPE) showed the folding of the genomic RNA 3' end to be regulated by the internal ribosome entry site (IRES) element via direct RNA-RNA interactions. The essential cis-acting replicating element (CRE) and the 3'X-tail region adopted different 3D conformations in the presence and absence of the genomic RNA 5' terminus. Further, the structural transition in the 3'X-tail from the replication-competent conformer (consisting of three stem loops) to the dimerizable form (with two stem-loops), was found to depend on the presence of both the IRES and the CRE elements. Complex interplay between the IRES, the CRE and the 3'X-tail region would therefore appear to occur. The preservation of this RNA-RNA interacting network, and the maintenance of the proper balance between different contacts, may play a crucial role in the switch between different steps of the HCV cycle. PMID- 24049070 TI - The telomere resolvase of the Lyme disease spirochete, Borrelia burgdorferi, promotes DNA single-strand annealing and strand exchange. AB - Spirochetes of the genus Borrelia include the tick-transmitted causative agents of Lyme disease and relapsing fever. They possess unusual genomes composed mainly of linear replicons terminated by closed DNA hairpin telomeres. Hairpin telomeres present an uninterrupted DNA chain to the replication machinery overcoming the 'end-replication problem' for the linear replicons. Hairpin telomeres are formed from inverted repeat replicated telomere junctions by the telomere resolvase, ResT. ResT uses a reaction mechanism similar to that of the type IB topoisomerases and tyrosine recombinases. We report here that ResT also possesses single-strand annealing activity and a limited ability to promote DNA strand exchange reactions on partial duplex substrates. This combination of activities suggests ResT is a nexus between the seemingly distinct processes of telomere resolution and homologous recombination. Implications for hairpin telomere replication and linear plasmid recombination, including antigenic variation, are discussed. PMID- 24049071 TI - DEXUS: identifying differential expression in RNA-Seq studies with unknown conditions. AB - Detection of differential expression in RNA-Seq data is currently limited to studies in which two or more sample conditions are known a priori. However, these biological conditions are typically unknown in cohort, cross-sectional and nonrandomized controlled studies such as the HapMap, the ENCODE or the 1000 Genomes project. We present DEXUS for detecting differential expression in RNA Seq data for which the sample conditions are unknown. DEXUS models read counts as a finite mixture of negative binomial distributions in which each mixture component corresponds to a condition. A transcript is considered differentially expressed if modeling of its read counts requires more than one condition. DEXUS decomposes read count variation into variation due to noise and variation due to differential expression. Evidence of differential expression is measured by the informative/noninformative (I/NI) value, which allows differentially expressed transcripts to be extracted at a desired specificity (significance level) or sensitivity (power). DEXUS performed excellently in identifying differentially expressed transcripts in data with unknown conditions. On 2400 simulated data sets, I/NI value thresholds of 0.025, 0.05 and 0.1 yielded average specificities of 92, 97 and 99% at sensitivities of 76, 61 and 38%, respectively. On real-world data sets, DEXUS was able to detect differentially expressed transcripts related to sex, species, tissue, structural variants or quantitative trait loci. The DEXUS R package is publicly available from Bioconductor and the scripts for all experiments are available at http://www.bioinf.jku.at/software/dexus/. PMID- 24049072 TI - Natural reassignment of CUU and CUA sense codons to alanine in Ashbya mitochondria. AB - The discovery of diverse codon reassignment events has demonstrated that the canonical genetic code is not universal. Studying coding reassignment at the molecular level is critical for understanding genetic code evolution, and provides clues to genetic code manipulation in synthetic biology. Here we report a novel reassignment event in the mitochondria of Ashbya (Eremothecium) gossypii, a filamentous-growing plant pathogen related to yeast (Saccharomycetaceae). Bioinformatics studies of conserved positions in mitochondrial DNA-encoded proteins suggest that CUU and CUA codons correspond to alanine in A. gossypii, instead of leucine in the standard code or threonine in yeast mitochondria. Reassignment of CUA to Ala was confirmed at the protein level by mass spectrometry. We further demonstrate that a predicted tRNA(Ala)UAG is transcribed and accurately processed in vivo, and is responsible for Ala reassignment. Enzymatic studies reveal that tRNA(Ala)UAG is efficiently recognized by A. gossypii mitochondrial alanyl-tRNA synthetase (AgAlaRS). AlaRS typically recognizes the G3:U70 base pair of tRNA(Ala); a G3A change in Ashbya tRNA(Ala)UAG abolishes its recognition by AgAlaRS. Conversely, an A3G mutation in Saccharomyces cerevisiae tRNA(Thr)UAG confers tRNA recognition by AgAlaRS. Our work highlights the dynamic feature of natural genetic codes in mitochondria, and the relative simplicity by which tRNA identity may be switched. PMID- 24049073 TI - Intracellular dynamics of archaeal FANCM homologue Hef in response to halted DNA replication. AB - Hef is an archaeal member of the DNA repair endonuclease XPF (XPF)/Crossover junction endonuclease MUS81 (MUS81)/Fanconi anemia, complementation group M (FANCM) protein family that in eukaryotes participates in the restart of stalled DNA replication forks. To investigate the physiological roles of Hef in maintaining genome stability in living archaeal cells, we studied the localization of Hef-green fluorescent protein fusions by fluorescence microscopy. Our studies revealed that Haloferax volcanii Hef proteins formed specific localization foci under regular growth conditions, the number of which specifically increased in response to replication arrest. Purification of the full-length Hef protein from its native host revealed that it forms a stable homodimer in solution, with a peculiar elongated configuration. Altogether our data indicate that the shape of Hef, significant physicochemical constraints and/or interactions with DNA limit the apparent cytosolic diffusion of halophilic DNA replication/repair complexes, and demonstrate that Hef proteins are dynamically recruited to archaeal eukaryotic-like chromatin to counteract DNA replication stress. We suggest that the evolutionary conserved function of Hef/FANCM proteins is to enhance replication fork stability by directly interacting with collapsed replication forks. PMID- 24049074 TI - DHX9 helicase is involved in preventing genomic instability induced by alternatively structured DNA in human cells. AB - Sequences that have the capacity to adopt alternative (i.e. non-B) DNA structures in the human genome have been implicated in stimulating genomic instability. Previously, we found that a naturally occurring intra-molecular triplex (H-DNA) caused genetic instability in mammals largely in the form of DNA double-strand breaks. Thus, it is of interest to determine the mechanism(s) involved in processing H-DNA. Recently, we demonstrated that human DHX9 helicase preferentially unwinds inter-molecular triplex DNA in vitro. Herein, we used a mutation-reporter system containing H-DNA to examine the relevance of DHX9 activity on naturally occurring H-DNA structures in human cells. We found that H DNA significantly increased mutagenesis in small-interfering siRNA-treated, DHX9 depleted cells, affecting mostly deletions. Moreover, DHX9 associated with H-DNA in the context of supercoiled plasmids. To further investigate the role of DHX9 in the recognition/processing of H-DNA, we performed binding assays in vitro and chromatin immunoprecipitation assays in U2OS cells. DHX9 recognized H-DNA, as evidenced by its binding to the H-DNA structure and enrichment at the H-DNA region compared with a control region in human cells. These composite data implicate DHX9 in processing H-DNA structures in vivo and support its role in the overall maintenance of genomic stability at sites of alternatively structured DNA. PMID- 24049075 TI - ERK phosphorylation of MED14 in promoter complexes during mitogen-induced gene activation by Elk-1. AB - The ETS domain transcription factor Elk-1 stimulates expression of immediate early genes (IEGs) in response to mitogens. These events require phosphorylation of Elk-1 by extracellular signal-regulated kinase (ERK) and phosphorylation dependent interaction of Elk-1 with co-activators, including histone acetyltransferases and the Mediator complex. Elk-1 also recruits ERK to the promoters of its target genes, suggesting that ERK phosphorylates additional substrates in transcription complexes at mitogen-responsive promoters. Here we report that MED14, a core subunit of the Mediator, is a bona fide ERK substrate and identify serine 986 (S986) within a serine-proline rich region of MED14 as the major ERK phosphorylation site. Mitogens induced phosphorylation of MED14 on S986 at IEG promoters; RNAi knockdown of MED14 reduced CDK8 and RNA polymerase II (RNAPII) recruitment, RNAPII C-terminal domain phosphorylation and impaired activation of IEG transcription. A single alanine substitution at S986 reduced activation of an E26 (ETS)-responsive reporter by oncogenic Ras and mitogen induced, Elk-1-dependent transcription, whereas activities of other transcriptional activators were unaffected. We also demonstrate that Elk-1 can associate with MED14 independently of MED23, which may facilitate phosphorylation of MED14 by ERK to impart a positive and selective impact on mitogen-responsive gene expression. PMID- 24049076 TI - Pre-activation of the genome integrity checkpoint increases DNA damage tolerance. AB - The genome integrity checkpoint is a conserved signaling pathway that is regulated in yeast by the Mec1 (homologous to human ATR) and Rad53 (homologous to human Chk1) kinases. The pathway coordinates a multifaceted response that allows cells to cope with DNA damage and DNA replication stress. The full activation of the checkpoint blocks origin firing, stabilizes replication forks, activates DNA repair proteins and may lead to senescence or apoptosisin higher eukaryotes. We have recently demonstrated that endogenous replication stress can activate the genome integrity checkpoint in budding yeast at a low level that does not go so far as to interfere with cell cycle progression, but it does activate DNA damage inducible proteins. Here we demonstrate that the low level pre-activation of the checkpoint, either by endogenous replication stress or by the nucleotide depleting drug hydroxyurea, can increase damage tolerance to multiple DNA damaging agents. These results may provide new strategies for using the checkpoint to protect normal cells from genotoxic stress. PMID- 24049077 TI - Robust RNAi enhancement via human Argonaute-2 overexpression from plasmids, viral vectors and cell lines. AB - As the only mammalian Argonaute protein capable of directly cleaving mRNAs in a small RNA-guided manner, Argonaute-2 (Ago2) is a keyplayer in RNA interference (RNAi) silencing via small interfering (si) or short hairpin (sh) RNAs. It is also a rate-limiting factor whose saturation by si/shRNAs limits RNAi efficiency and causes numerous adverse side effects. Here, we report a set of versatile tools and widely applicable strategies for transient or stable Ago2 co expression, which overcome these concerns. Specifically, we engineered plasmids and viral vectors to co-encode a codon-optimized human Ago2 cDNA along with custom shRNAs. Furthermore, we stably integrated this Ago2 cDNA into a panel of standard human cell lines via plasmid transfection or lentiviral transduction. Using various endo- or exogenous targets, we demonstrate the potential of all three strategies to boost mRNA silencing efficiencies in cell culture by up to 10 fold, and to facilitate combinatorial knockdowns. Importantly, these robust improvements were reflected by augmented RNAi phenotypes and accompanied by reduced off-targeting effects. We moreover show that Ago2/shRNA-co-encoding vectors can enhance and prolong transgene silencing in livers of adult mice, while concurrently alleviating hepatotoxicity. Our customizable reagents and avenues should broadly improve future in vitro and in vivo RNAi experiments in mammalian systems. PMID- 24049079 TI - DNA polymerases zeta and Rev1 mediate error-prone bypass of non-B DNA structures. AB - DNA polymerase zeta (Pol zeta) and Rev1 are key players in translesion DNA synthesis. The error-prone Pol zeta can also participate in replication of undamaged DNA when the normal replisome is impaired. Here we define the nature of the replication disturbances that trigger the recruitment of error-prone polymerases in the absence of DNA damage and describe the specific roles of Rev1 and Pol zeta in handling these disturbances. We show that Pol zeta/Rev1-dependent mutations occur at sites of replication stalling at short repeated sequences capable of forming hairpin structures. The Rev1 deoxycytidyl transferase can take over the stalled replicative polymerase and incorporate an additional 'C' at the hairpin base. Full hairpin bypass often involves template-switching DNA synthesis, subsequent realignment generating multiply mismatched primer termini and extension of these termini by Pol zeta. The postreplicative pathway dependent on polyubiquitylation of proliferating cell nuclear antigen provides a backup mechanism for accurate bypass of these sequences that is primarily used when the Pol zeta/Rev1-dependent pathway is inactive. The results emphasize the pivotal role of noncanonical DNA structures in mutagenesis and reveal the long-sought after mechanism of complex mutations that represent a unique signature of Pol zeta. PMID- 24049080 TI - A novel route to product specificity in the Suv4-20 family of histone H4K20 methyltransferases. AB - The delivery of site-specific post-translational modifications to histones generates an epigenetic regulatory network that directs fundamental DNA-mediated processes and governs key stages in development. Methylation of histone H4 lysine 20 has been implicated in DNA repair, transcriptional silencing, genomic stability and regulation of replication. We present the structure of the histone H4K20 methyltransferase Suv4-20h2 in complex with its histone H4 peptide substrate and S-adenosyl methionine cofactor. Analysis of the structure reveals that the Suv4-20h2 active site diverges from the canonical SET domain configuration and generates a high degree of both substrate and product specificity. Together with supporting biochemical data comparing Suv4-20h1 and Suv4-20h2, we demonstrate that the Suv4-20 family enzymes take a previously mono methylated H4K20 substrate and generate an exclusively di-methylated product. We therefore predict that other enzymes are responsible for the tri-methylation of histone H4K20 that marks silenced heterochromatin. PMID- 24049078 TI - Co-regulated gene expression by oestrogen receptor alpha and liver receptor homolog-1 is a feature of the oestrogen response in breast cancer cells. AB - Oestrogen receptor alpha (ERalpha) is a nuclear receptor that is the driving transcription factor expressed in the majority of breast cancers. Recent studies have demonstrated that the liver receptor homolog-1 (LRH-1), another nuclear receptor, regulates breast cancer cell proliferation and promotes motility and invasion. To determine the mechanisms of LRH-1 action in breast cancer, we performed gene expression microarray analysis following RNA interference for LRH 1. Interestingly, gene ontology (GO) category enrichment analysis of LRH-1 regulated genes identified oestrogen-responsive genes as the most highly enriched GO categories. Remarkably, chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) to identify genomic targets of LRH-1 showed LRH-1 binding at many ERalpha binding sites. Analysis of select binding sites confirmed regulation of ERalpha-regulated genes by LRH-1 through binding to oestrogen response elements, as exemplified by the TFF1/pS2 gene. Finally, LRH-1 overexpression stimulated ERalpha recruitment, while LRH-1 knockdown reduced ERalpha recruitment to ERalpha binding sites. Taken together, our findings establish a key role for LRH-1 in the regulation of ERalpha target genes in breast cancer cells and identify a mechanism in which co-operative binding of LRH 1 and ERalpha at oestrogen response elements controls the expression of oestrogen responsive genes. PMID- 24049081 TI - siRNA enhances DNA-mediated interferon lambda-1 response through crosstalk between RIG-I and IFI16 signalling pathway. AB - In addition to silencing specific genes, small interfering RNA (siRNA) transfection is also associated with the non-specific induction of inflammatory cytokines and type I interferon. Those so-called "off-target" effects have considerable implications for the interpretation of in vitro studies and clinical application of siRNA. The present study attempted to develop a better understanding of the mechanism involved in these off target effects. Synthesized siRNA significantly enhances DNA-mediated interferon lambda-1 response (IFN lambda1/IL-29), a newly characterized antiviral interferon in non-immune or primary immune cells. This enhancement was most pronounced by double-stranded siRNA with at least a 2-nucleotide overhang at one 3' terminus in a dose dependent manner, while the presence of DNA was indispensable. A pull-down assay using biotinylated siRNA- or DNA-conjugated beads indicated that retinoic acid inducible gene I (RIG-I) and interferon gamma-inducible protein 16 (IFI16) were involved in the sensing of siRNA and DNA, respectively. Co-immunoprecipitation analysis further revealed that RIG-I and IFI16 formed a complex via siRNA, and the dissociation of IFI16 from this complex in the presence of DNA activated the downstream STING-TBK1-IRF3 (stimulator of interferon genes - tank-binding kinase 1 - interferon regulatory factor 3) pathway, shedding light on a new physiological signalling pathway to activate innate immunity. Collectively, these findings may provide rational information for siRNA-induced innate immunity, with important implications for developing siRNA-based reagents to control human diseases. PMID- 24049082 TI - PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage. AB - Amyotrophic lateral sclerosis (ALS) is associated with progressive degeneration of motor neurons. Several of the genes associated with this disease encode proteins involved in RNA processing, including fused-in-sarcoma/translocated-in sarcoma (FUS/TLS). FUS is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that bind thousands of pre-mRNAs and can regulate their splicing. Here, we have examined the possibility that FUS is also a component of the cellular response to DNA damage. We show that both GFP-tagged and endogenous FUS re-localize to sites of oxidative DNA damage induced by UVA laser, and that FUS recruitment is greatly reduced or ablated by an inhibitor of poly (ADP-ribose) polymerase activity. Consistent with this, we show that recombinant FUS binds directly to poly (ADP-ribose) in vitro, and that both GFP tagged and endogenous FUS fail to accumulate at sites of UVA laser induced damage in cells lacking poly (ADP-ribose) polymerase-1. Finally, we show that GFP FUS(R521G), harbouring a mutation that is associated with ALS, exhibits reduced ability to accumulate at sites of UVA laser-induced DNA damage. Together, these data suggest that FUS is a component of the cellular response to DNA damage, and that defects in this response may contribute to ALS. PMID- 24049085 TI - Disseminated solitary fibrous tumour of the lung and pleura. AB - Solitary fibrous tumours (SFTs) are a heterogeneous group of rare spindle-cell tumours. Classically they presented as a solitary pleural-based mass. Pulmonary parenchymal SFT is rare and multiple bilateral lesions are extremely rare. We present the clinical, imaging and histological features of SFT which are presented as multiple nodular lesions of the lung and pleura with probable distant metastasis. PMID- 24049083 TI - A regulatory circuit comprising GATA1/2 switch and microRNA-27a/24 promotes erythropoiesis. AB - Transcriptional networks orchestrate complex developmental processes, and such networks are commonly instigated by master regulators for development. By now, considerable progress has been made in elucidating GATA factor-dependent genetic networks that control red blood cell development. Here we reported that GATA-1 and GATA-2 co-regulated the expression of two microRNA genes, microRNA-27a and microRNA-24, with critical roles in regulating erythroid differentiation. In general, GATA-2 occupied the miR-27a~24 promoter and repressed their transcription in immature erythroid progenitor cells. As erythropoiesis proceeded, GATA-1 directly activated miR-27a~24 transcription, and this involved a GATA-1-mediated displacement of GATA-2 from chromatin, a process termed 'GATA switch'. Furthermore, the mature miR-27a and miR-24 cooperatively inhibited GATA 2 translation and favoured the occupancy switch from GATA-2 to GATA-1, thus completing a positive feedback loop to promote erythroid maturation. In line with the essential role of GATA factors, ectopic expression of miR-27a or miR-24 promoted erythropoiesis in human primary CD34+ haematopoietic progenitor cells and mice, whereas attenuated miR-27 or miR-24 level led to impaired erythroid phenotypes in haematopoietic progenitor cells and zebrafish. Taken together, these data integrated micro RNA expression and function into GATA factor coordinated networks and provided mechanistic insight into a regulatory circuit that comprised GATA1/2 switch and miR-27a/24 in erythropoiesis. PMID- 24049086 TI - Hypertrophic osteoarthropathy and congenital heart disease: this is not casual. AB - This case presents a patient with congenital cyanotic heart disease in whom secondary hypertrophic osteoarthropathy was diagnosed. The symptoms of severe bilateral leg pain started 2 months before hospital admission. The presence of clubbing, painful swelling of the lower limbs and his comorbid condition roused the suspicion of hypertrophic osteoarthropathy and a skeleton radiograph of the lower limbs was performed. The last showed changes consistent with periosteal new bone formation, so a non-steroid anti-inflammatory drug was started with complete resolution of the debilitating pain. Hypertrophic osteoarthropathy is an uncommon disease that may be genetically acquired or secondary to other conditions affecting lungs, heart, liver or bowel. Considering it elusive pathogenesis, treatment options are scarce and symptomatic relief is still the main objective. PMID- 24049087 TI - An unexpected positive hypersensitive reaction to eugenol. AB - Eugenol is an active, principal aromatic liquid responsible for several pharmacological activities. It is widely used in dental practice to relieve pain arising from various sources, such as pulpitis and dentinal hypersensitivity. As a primary irritant and sensitiser, it is known to cause contact urticaria as well as chronic urticaria. However, eugenol causes allergic contact dermatitis, possibly because it can react directly with proteins to form conjugate and reactive haptens. It is found that eugenol in various dental preparations especially in the case of some zinc oxide-contains preparations such as periodontal dressings and root canal cements. This can cause hypersensitivity when it comes in contact with gingiva or teeth. This article presents a case of immediate allergic contact urticaria to eugenol during dental treatment. PMID- 24049088 TI - Pramipexole induced psychosis in a patient with restless legs syndrome. AB - In the last few years, dopamine agonists (DA) have been used as first-line treatment for restless legs syndrome (RLS), a disabling sensorimotor disorder. Only recently have they reported some possible iatrogenic side effects, as shown below. The following case presents a RLS patient who developed hallucinatory and delusional symptoms with paranoid ideation after pramipexole assumption; these symptoms gradually decreased after pramipexole suspension and treatment by an oral antipsychotic therapy (quetiapine XR). Correlation between DAs assumption and psychotic symptoms is still not clear. The development of these side effects might be related to many risk factors such as genetic susceptibility, premorbid personality and psychosocial stressor; in order to minimise the risk of iatrogenic psychosis it could be useful to assess patients' vulnerability factors selecting an alternative medication regime. PMID- 24049089 TI - Lung adenocarcinoma: a new bipolar masquerader. PMID- 24049090 TI - Delayed ischemic stroke following spontaneous thrombosis of an arteriovenous malformation. AB - Spontaneous obliteration of an arteriovenous malformation (SOAVM) is a rare event that is not completely understood. Less than 100 cases of SOAVMs have been reported in the literature. We present a unique case of a middle-aged patient with spontaneous obliteration of a cerebral arteriovenous malformation (AVM) who developed an ischemic stroke due to thrombosis of the stagnant proximal segment of the inferior branch of the middle cerebral artery feeder. Although the pathophysiology is not well understood, the arterial feeder hemodynamic changes post SOAVM may behave similarly to what occurs in rare cases after surgical resection of AVMs. Our case raises the hypothesis that stagnation of flow in spontaneous AVM obliteration may lead to delayed ischemic stroke in the territory of the feeding artery. PMID- 24049091 TI - Renal infarction due to spontaneous dissection of the renal artery: an unusual cause of non-visceral type abdominal pain. AB - A 44-year-old man presented with very severe right upper quadrant pain of sudden onset. This was exacerbated by movement but unaffected by food or defaecation. It was continuous-day and night -but resolved over a 1-week period. The physical examination was normal at presentation, by which time the pain had resolved. His white cell count, alanine transaminase and C reactive protein were elevated but normalised after 10 days. An abdominal CT showed low density lesions in the right kidney consistent with segmental infarcts. CT angiogram showed a dissection of the right renal artery. The patient remained asymptomatic and normotensive when reviewed 1 month later. PMID- 24049092 TI - Red herring vaginal discharge. AB - Labial hair tourniquet syndrome is a rare condition that can be easily misdiagnosed and ultimately lead to irreversible damage. An 11-year-old premenarche girl presented with a 5-day history of pain and swelling in the labia with associated vaginal discharge. The general practitioner treated her with clotrimazole without improvement. On examination, there was an oedematous swelling of the right labia with a proximal hair tourniquet. Local anaesthetic was applied and the hair removed with forceps. There was instant relief of pain and the discharge stopped within 24 h. The patient was sent home with a course of antibiotics. PMID- 24049093 TI - Accidental finger ischaemia induced by epinephrine autoinjector. PMID- 24049094 TI - Giant thoracic mass: an unusual presentation of primary pulmonary Hodgkin's lymphoma. AB - Primary pulmonary Hodgkin's lymphoma (PPHL) is rare. PPHL without peripheral lymphadenopathy or hepatosplenomegaly is exceptionally uncommon. We present a 61 year-old woman believed to have a solitary intrapulmonary fibrous tumour on a CT and a CT-guided biopsy, until surgical excision. Histopathology and immunohistochemistry of the excised mass confirmed PPHL. PPHL is a very rare differential diagnosis of large solitary intrapulmonary masses. A CT-guided biopsy is recommended, as it can be diagnostic, reserving excision for cases where the diagnosis remains in doubt. PMID- 24049095 TI - Genome-wide association study of sex hormones, gonadotropins and sex hormone binding protein in Chinese men. AB - BACKGROUND: Sex hormones and gonadotropins exert a wide variety of effects in physiological and pathological processes. Accumulated evidence shows a strong heritable component of circulating concentrations of these hormones. Recently, several genome-wide association studies (GWASs) conducted in Caucasians have identified multiple loci that influence serum levels of sex hormones. However, the genetic determinants remain unknown in Chinese populations. In this study, we aimed to identify genetic variants associated with major sex hormones, gonadotropins, including testosterone, oestradiol, follicle-stimulating hormone (FSH), luteinising hormone (LH) and sex hormone binding globulin (SHBG) in a Chinese population. METHODS: A two-stage GWAS was conducted in a total of 3495 healthy Chinese men (1999 subjects in the GWAS discovery stage and 1496 in the confirmation stage). RESULTS: We identified a novel genetic region at 15q21.2 (rs2414095 in CYP19A1), which was significantly associated with oestradiol and FSH in the Chinese population at a genome-wide significant level (p=6.54*10(-31) and 1.59*10(-16), respectively). Another single nucleotide polymorphism in CYP19A1 gene was significantly associated with oestradiol level (rs2445762, p=7.75*10(-28)). In addition, we confirmed the previous GWAS-identified locus at 17p13.1 for testosterone (rs2075230, p=1.13*10(-8)) and SHBG level (rs2075230, p=4.75*10(-19)) in the Chinese population. CONCLUSIONS: This study is the first GWAS investigation of genetic determinants of FSH and LH. The identification of novel susceptibility loci may provide more biological implications for the synthesis and metabolism of these hormones. More importantly, the confirmation of the genetic loci for testosterone and SHBG suggests common genetic components shared among different ethnicities. PMID- 24049096 TI - Novel cases of D-2-hydroxyglutaric aciduria with IDH1 or IDH2 mosaic mutations identified by amplicon deep sequencing. AB - BACKGROUND: Mosaic IDH1 mutations are described as the cause of metaphyseal chondromatosis with increased urinary excretion of D-2-hydroxyglutarate (MC-HGA), and mutations in IDH2 as the cause of D-2-hydroxyglutaric aciduria (D-2HGA) type II. Mosaicism for IDH2 mutations has not previously been reported as a cause of D 2HGA. Here we describe three cases: one MC-HGA case with IDH1 mosaic mutations, and two D-2HGA type II cases. In one D-2HGA case we identified mosaicism for an IDH2 mutation as the genetic cause of this disorder; the other D-2HGA case was caused by a heterozygous IDH2 mutation, while the unaffected mother was a mosaic carrier. METHODS: We performed amplicon deep sequencing using the 454 GS Junior platform, next to Sanger sequencing, to identify and confirm mosaicism of IDH1 or IDH2 mutations in MC-HGA or D-2HGA, respectively. RESULTS AND CONCLUSIONS: We identified different mutant allele percentages in DNA samples derived from different tissues (blood vs fibroblasts). Furthermore, we found that mutant allele percentages of IDH1 decreased after more passages had occurred in fibroblast cell cultures. We describe a method for the detection and validation of mosaic mutations in IDH1 and IDH2, making quantification with laborious cloning techniques obsolete. PMID- 24049097 TI - Sonographic synovial vascularity of synovitis in rheumatoid arthritis. AB - RA is a condition of multiple synovitis. Abnormal synovial vascularity (SV) is evident with the onset of joint inflammation. The idea of estimating the level of joint inflammation by sonographic SV was conceived with the advancement of US. The ideal treatment strategy, called treat to target (T2T), requires early diagnosis and assessment of RA. Detection of positive SV can be useful for proving the presence of synovitis and finally diagnosing RA. In the assessment of RA, US-based global scores aimed at assessing overall disease activity have the potential to be useful for the achievement of T2T because US can directly detect changes in synovitis. Remaining SV in local joints increases the risk of structural deterioration. RA requires both improvement of overall disease activity and the disappearance of local SV for remission. The evaluation of SV provides various information and contributes to the clinical treatment of RA. PMID- 24049098 TI - The Spanish version of the Fibromyalgia Rapid Screening Tool: translation, validity and reliability. AB - OBJECTIVE: Despite showing acceptable psychometric properties, the criterion validity of the original Fibromyalgia Rapid Screening Tool (FiRST) has been called into question for including insufficiently challenging comparison groups. Consequently our objective was to validate a Spanish version of the FiRST including pain disorders more analogous to fibromyalgia. METHODS: The FiRST was translated following international standards. Internal consistency and temporal stability were assessed. The ability of the FiRST global score as a screening tool for fibromyalgia (criterion validity) was assessed by logistic regression analysis. To determine the degree to which potential confounders might affect the criterion validity of the FiRST (divergent validity), it was reassessed by hierarchical multivariate logistic regression, entering demographics in a first step, followed by pain, anxiety and depression, catastrophizing, disability and the FiRST global score in a last step. RESULTS: The final sample comprised 257 patients (67% cases of fibromyalgia). The Spanish version of the FiRST showed acceptable internal consistency, reliability and criterion validity. The FiRST was able to discriminate between fibromyalgia and non-fibromyalgia patients even after controlling for the effect of potential confounders. However, both criterion and divergent validity were challenged by a moderate specificity. CONCLUSION: The Spanish version of the FiRST may be used as a screening tool for fibromyalgia even in those patients whose cognitive style is characterized by catastrophizing about pain and high levels of functional disability, anxiety and depression. The clinical consequences of the moderate specificity shown by this Spanish version of the FiRST are discussed. PMID- 24049099 TI - In search of nucleus pulposus-specific molecular markers. AB - Intervertebral disc degeneration usually starts from the inner nucleus pulposus (NP). The majority of previous NP-related studies assessed the outcome by the expression of chondrogenic markers since NP cells are chondrocyte like. However, NP cells are unique from chondrocytes and such assessments may be inappropriate. Very recently, several investigators published their findings about the transcriptional differences between NP cells and other related cell types on a genomic scale. In this review we discuss these recent findings and summarize the molecules that may be utilized as NP-specific markers to distinguish normal NP cells from several cell types and as markers that indicate its degeneration. We will revisit markers that distinguish NP cells from the outer surrounding annulus fibrosus (AF) cells and articular chondrocytes so as to facilitate authentic NP cell engineering from stem cells. Our review indicated that N-cadherin and keratin 19 have the potential to serve as common NP markers, as they distinguish healthy NP cells from AF cells, articular cartilage cells and degenerated NP cells. PMID- 24049100 TI - The genetics of juvenile idiopathic arthritis: current understanding and future prospects. AB - Understanding the genetic risk of JIA, a relatively rare chronic disease, is a challenging task, but recent research in this field has shown great advances. This review summarizes the current understanding of the genetic architecture of JIA susceptibility and proposes where this work is heading in the coming years. Insights into how we might progress this relatively understudied field will be provided, highlighting how the field will move towards the ultimate goals of predicting long-term disease outcomes at onset, predicting drug response, and move towards more targeted treatment options for children with JIA. PMID- 24049101 TI - The substantial burden of systemic lupus erythematosus on the productivity and careers of patients: a European patient-driven online survey. AB - OBJECTIVE: The objective of this study was to explore the burden of SLE and its effect on patients' lives. METHODS: The Lupus European Online (LEO) survey included patient-designed questions on demographics, SLE diagnosis, and the impact of SLE on careers. Three SLE-specific patient-reported outcome (PRO) questionnaires were also completed: the Lupus Quality of Life (LupusQoL), the Fatigue Severity Scale (FSS), and the Work Productivity and Activity Impairment (WPAI)-Lupus v2.0. The survey was available online in five languages from May through August 2010. All self-identified SLE participants were eligible to respond. Survey results were analysed using descriptive statistics. Multivariate linear regression explored factors contributing to impaired productivity. RESULTS: Of the 2070 European SLE patients completing the survey, 93.1% were women, 86.7% were aged <50 years and 71.8% had a college or university education. More than two-thirds of respondents (69.5%) reported that SLE affected their careers; 27.7% changed careers within a year of diagnosis. All LupusQoL domains (score range 0-100) were impaired, with fatigue (median domain score 43.8) being the most affected and intimate relationships (median domain score 75.0) the least. Most patients (82.5%) reported fatigue (FSS score >=4). Productivity was impaired across all WPAI domains, both at work and in general activities. Fatigue, an inability to plan and reduced physical health were significantly associated with impaired productivity. Patients whose careers were affected by SLE had worse health-related quality of life, more fatigue and worse productivity than patients whose careers were not affected. CONCLUSION: LEO survey respondents reported that SLE negatively affects their daily lives, productivity and career choices. PMID- 24049102 TI - Pas de quatre: an interaction of HLA-B*27:05 and KIR3DL2 homodimers in spondyloarthropathies. PMID- 24049103 TI - Foot posture, foot function and low back pain: the Framingham Foot Study. AB - OBJECTIVE: Abnormal foot posture and function have been proposed as possible risk factors for low back pain, but this has not been examined in detail. The objective of this study was to explore the associations of foot posture and foot function with low back pain in 1930 members of the Framingham Study (2002-05). METHODS: Low back pain, aching or stiffness on most days was documented on a body chart. Foot posture was categorized as normal, planus or cavus using static weight-bearing measurements of the arch index. Foot function was categorized as normal, pronated or supinated using the centre of pressure excursion index derived from dynamic foot pressure measurements. Sex-specific multivariate logistic regression models were used to examine the associations of foot posture, foot function and asymmetry with low back pain, adjusting for confounding variables. RESULTS: Foot posture showed no association with low back pain. However, pronated foot function was associated with low back pain in women [odds ratio (OR) = 1.51, 95% CI 1.1, 2.07, P = 0.011] and this remained significant after adjusting for age, weight, smoking and depressive symptoms (OR = 1.48, 95% CI 1.07, 2.05, P = 0.018). CONCLUSION: These findings suggest that pronated foot function may contribute to low back symptoms in women. Interventions that modify foot function, such as orthoses, may therefore have a role in the prevention and treatment of low back pain. PMID- 24049105 TI - Orlistat, an under-recognised cause of progressive renal impairment. AB - Obesity is an emerging risk factor for chronic kidney disease (CKD) in the developed world. Orlistat, an intestinal lipase inhibitor, used in the treatment of obesity is available as an over-the-counter medication across the European union and in many countries worldwide. It is associated with acute kidney injury (AKI). We present three adults, followed up from 1 to 6 years, who developed de novo or worsening renal impairment while on orlistat. Stopping the drug halted progression, but did not reverse the degree of renal impairment at presentation. PMID- 24049104 TI - Longitudinal association of body mass index and waist circumference with left ventricular mass in hypertensive predialysis chronic kidney disease patients. AB - BACKGROUND: This study aimed to investigate the association of both body mass index (BMI) and waist circumference (WC) with left ventricular mass (LVM) in hypertensive predialysis chronic kidney disease (CKD) patients. METHODS: From 2004 to 2005, 206 consecutive incident adult patients from the outpatient CKD clinics of two hospitals in Greece were included. Inclusion criteria were the presence of CKD and hypertension. BMI (kg/m(2)), WC (cm) and LVM (g) were assessed annually for 3 years. RESULTS: The mean age was 68.1 years, mean BMI 29.1 kg/m(2) and mean WC was 103.7 cm. The median LVM was 245.7 g (n = 179). In the cross-sectional data, linear regression models showed that WC {beta = 1.2 [95% confidence interval (CI) 0.15; 2.3]}, and not BMI [beta = 2.1 (95% CI: 0.70; 4.8)], was significantly associated with LVM. After adjustment for age, sex, primary renal disease, smoking and history of cardiovascular disease, both BMI [beta = 4.7 (95% CI: 2.0; 7.4] and WC [beta = 1.2 (95% CI: 0.14; 2.3)] were significantly associated with LVM. These associations were pronounced in CKD stage 1-3, but not in CKD stage 4-5. In the longitudinal analysis, linear mixed models adjusting for confounders showed that both an increase in BMI [beta = 2.9 (95% CI: 0.74; 5.1)] and an increase in WC [beta = 1.1 (95% CI: 0.28; 1.8)] were significantly associated with an increase in LVM. CONCLUSIONS: In hypertensive predialysis CKD patients, both BMI and WC were associated with LVM in CKD stage 1 3, but not in CKD stage 4-5. In the longitudinal analysis, both an increase in BMI and WC were associated with an increase in LVM. Future studies should focus on mechanisms responsible for the associations between anthropometric variables and LVM. PMID- 24049106 TI - The obese uremic patient: a newcomer in the nephrology clinic? PMID- 24049107 TI - Interlaboratory optimization and evaluation of a serological assay for diagnosis of human baylisascariasis. AB - A Western blot assay using a recombinant protein, recombinant Baylisascaris procyonis RAG1 protein (rBpRAG1), was developed for the diagnosis of human baylisascariasis concurrently by the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and the National Reference Centre for Parasitology (NRCP) in Montreal, Canada. Assay performance was assessed by testing 275 specimens at the CDC and 405 specimens at the NRCP. Twenty specimens from 16 cases of baylisascariasis were evaluated. Eighteen were positive, with the assay correctly identifying 14 of 16 patients. The rBpRAG1 Western blot assay showed no cross-reactivity with Toxocara-positive serum and had an overall sensitivity of 88% and a specificity of 98%. PMID- 24049108 TI - Serum antibodies from a subset of horses positive for Babesia caballi by competitive enzyme-linked immunosorbent assay demonstrate a protein recognition pattern that is not consistent with infection. AB - Tick-borne pathogens that cause persistent infection are of major concern to the livestock industry because of transmission risk from persistently infected animals and the potential economic losses they pose. The recent reemergence of Theileria equi in the United States prompted a widespread national survey resulting in identification of limited distribution of equine piroplasmosis (EP) in the U.S. horse population. This program identified Babesia caballi seropositive horses using rhoptry-associated protein 1 (RAP-1)-competitive enzyme linked immunosorbent assay (cELISA), despite B. caballi being considered nonendemic on the U.S. mainland. The purpose of the present study was to evaluate the suitability of RAP-1-cELISA as a single serological test to determine the infection status of B. caballi in U.S. horses. Immunoblotting indicated that sera from U.S. horses reacted with B. caballi lysate and purified B. caballi RAP-1 protein. Antibody reactivity to B. caballi lysate was exclusively directed against a single ~50-kDa band corresponding to a native B. caballi RAP-1 protein. In contrast, sera from experimentally and naturally infected horses from regions where B. caballi is endemic bound multiple proteins ranging from 30 to 50 kDa. Dilutions of sera from U.S. horses positive by cELISA revealed low levels of antibodies, while sera from horses experimentally infected with B. caballi and from areas where B. caballi is endemic had comparatively high antibody levels. Finally, blood transfer from seropositive U.S. horses into naive horses demonstrated no evidence of B. caballi transmission, confirming that antibody reactivity in cELISA-positive U.S. horses was not consistent with infection. Therefore, we conclude that a combination of cELISA and immunoblotting is required for the accurate serodiagnosis of B. caballi. PMID- 24049109 TI - Safety and immunogenicity of a single oral dose of recombinant double mutant heat labile toxin derived from enterotoxigenic Escherichia coli. AB - Enterotoxigenic Escherichia coli (ETEC) is a primary cause of traveler's diarrhea for which there is no licensed vaccine. This phase 1 trial determined the safety and immunogenicity of a recombinantly produced double mutant heat-labile enterotoxin (dmLT) of ETEC. It was administered as a single oral dose of dmLT in escalating doses of 5 MUg, 25 MUg, 50 MUg, and 100 MUg, followed by a 72-h inpatient observation, outpatient visits at 8, 14, and 28 days, and telephone calls at 2 and 6 months postvaccination. Safety was assessed by frequency of adverse events, and immune responses determined after immunization included dmLT specific serum IgA and IgG, fecal IgA, antibody-secreting cells (ASC), and antibodies in lymphocyte supernatant (ALS) responses. All doses were well tolerated by the 36 healthy adults enrolled. Immune responses were limited in the 5- and 25-MUg dose recipients. The 50-MUg dose recipients trended toward stronger responses than the 100-MUg dose recipients by serum IgA (67% versus 33%, P = 0.22), serum IgG (58% versus 33%, P = 0.41), and fecal IgA (58% versus 33%, P = 0.41). By day 14 postvaccination, there were significantly more positive responders (>=4-fold increase from baseline) among the 50- versus 100-MUg dose recipients for serum IgA (P = 0.036) but not serum IgG (P = 0.21). In conclusion, a single oral dose of dmLT was well tolerated and immunogenic, with immune responses plateauing at the 50-MUg dose. (This clinical trial is registered at www.clinicaltrials.gov, registration number NCT01147445.). PMID- 24049110 TI - The co-chaperones Fkbp4/5 control Argonaute2 expression and facilitate RISC assembly. AB - Argonaute2 (Ago2) protein and associated microRNAs (miRNAs) or small interfering RNAs (siRNAs) form the RNA-induced silencing complex (RISC) for target messenger RNA cleavage and post-transcriptional gene silencing. Although Ago2 is essential for RISC activity, the mechanism of RISC assembly is not well understood, and factors controlling Ago2 protein expression are largely unknown. A role for the Hsc70/Hsp90 chaperone complex in loading small RNA duplexes into the RISC has been demonstrated in cell extracts, and unloaded Ago2 is unstable and degraded by the lysosome in mammalian cells. Here we identify the co-chaperones Fkbp4 and Fkbp5 as Ago2-associated proteins in mouse embryonic stem cells. Pharmacological inhibition of this interaction using FK506 or siRNA-mediated Fkbp4/5 depletion leads to decreased Ago2 protein levels. We find FK506 treatment inhibits, whereas Fkbp4/5 overexpression promotes, miRNA-mediated stabilization of Ago2 expression. Simultaneous treatment with a lysosome inhibitor revealed the accumulation of unloaded Ago2 complexes in FK506-treated cells. We find that, consistent with unloaded miRNAs being unstable, FK506 treatment also affects miRNA abundance, particularly nascent miRNAs. Our results support a role for Fkbp4/5 in RISC assembly. PMID- 24049111 TI - New validated prognostic models and prognostic calculators in patients with low grade gliomas diagnosed by central pathology review: a pooled analysis of EORTC/RTOG/NCCTG phase III clinical trials. AB - BACKGROUND: In a previous study, the European Organisation for Research and Treatment of Cancer (EORTC) reported a scoring system to predict survival of patients with low-grade gliomas (LGGs). A major issue in the diagnosis of brain tumors is the lack of agreement among pathologists. New models in patients with LGGs diagnosed by central pathology review are needed. METHODS: Data from 339 EORTC patients with LGGs diagnosed by central pathology review were used to develop new prognostic models for progression-free survival (PFS) and overall survival (OS). Data from 450 patients with centrally diagnosed LGGs recruited into 2 large studies conducted by North American cooperative groups were used to validate the models. RESULTS: Both PFS and OS were negatively influenced by the presence of baseline neurological deficits, a shorter time since first symptoms (<30 wk), an astrocytic tumor type, and tumors larger than 5 cm in diameter. Early irradiation improved PFS but not OS. Three risk groups have been identified (low, intermediate, and high) and validated. CONCLUSIONS: We have developed new prognostic models in a more homogeneous LGG population diagnosed by central pathology review. This population better fits with modern practice, where patients are enrolled in clinical trials based on central or panel pathology review. We could validate the models in a large, external, and independent dataset. The models can divide LGG patients into 3 risk groups and provide reliable individual survival predictions. Inclusion of other clinical and molecular factors might still improve models' predictions. PMID- 24049112 TI - Successful treatment of extensive cerebral venous sinus thrombosis using a combined approach with Penumbra aspiration system and Solitaire FR retrieval device. AB - We present a young woman with rapidly progressive neurologic decline in the setting of malignant cerebral edema due to extensive superior sagittal sinus thrombosis and cortical venous thrombosis despite intravenous heparin administration. Complete revascularization of the occluded sinus was achieved using suction thrombectomy with the 5 max Penumbra catheter in combination with the Solitaire FR clot retrieval device. The successful endovascular treatment halted the progression of her cerebral edema, and the patient eventually had an excellent recovery after prolonged intensive medical therapy. To our knowledge, this is the first reported case describing such a combined mechanical approach for cerebral venous sinus thrombosis. The clot retrieval properties of the Solitaire device combined with direct aspiration via the newest generation Penumbra catheters may allow more rapid, safe and efficient revascularization than all previously reported endovascular treatments for this potentially devastating condition. PMID- 24049114 TI - Exercise alters the regulation of myocardial Na(+)/H(+) exchanger-1 activity. AB - The myocardial Na(+)/H(+) exchanger-1 (NHE1) plays a major role in regulation of intracellular pH, and its upregulation has been implicated in increased ischemia reperfusion injury and other pathologies. Hydrogen peroxide (H2O2) increases NHE1 activity acutely via ERK1/2 signaling. Chronic strenuous exercise upregulates NHE1 in skeletal muscle, but we hypothesize this will not occur in the heart, because exercise creates a cardioprotective phenotype. NHE1 activity and its regulation by H2O2 were examined at physiological pH using isolated cardiomyocytes from female Sprague-Dawley rats exercised on a treadmill for 5 wk (E; n = 11). Compared with sedentary (S; n = 15), E displayed increases (P < 0.05) in heart-to-body weight ratio (6.8%) and plantaris mitochondria content (89%). NHE1 activity (acid efflux rate following an acid load) was 209% greater in E (0.65 +/- 0.12 vs. 2.01 +/- 0.29 fmol/min). The difference was attributed primarily to greater cell volume (22.2 +/- 0.6 vs. 34.3 +/- 1.1 pl) and intracellular pH-buffering capacity (33.94 +/- 1.59 vs. 65.82 +/- 5.20 mM/pH unit) of E myocytes. H2O2 stimulation (100 MUM) raised NHE1 activity significantly less in E (45%) than S (167%); however, activity remained 185% greater in E. ERK1/2 inhibition abrogated the increases. H2O2-stimulated ERK1/2 phosphorylation levels normalized to total ERK1/2 were similar between groups. Content of NHE1 and activities of H2O2 scavengers were also similar. We observed that intracellular pH-buffering capacity differences between groups became progressively less with declining pH, which may be an exercise-induced cardioprotective adaptation to lower NHE1 activity during certain pathological situations. We conclude that strenuous endurance exercise increases myocardial NHE1 activity at physiological pH, which would likely enhance cardiac performance under physiological conditions. PMID- 24049113 TI - Mg supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress, and cardiac dysfunction in rats. AB - Use of protease inhibitors (PI) in HIV patients is associated with hyperlipidemia and increased risk of coronary heart disease. Chronic systemic and cardiac effects of ritonavir (RTV), a universal PI booster, and Mg supplementation were examined. RTV was administered (75 mg.kg(-1).day(-1) po) to Lewis * Brown-Norway hybrid (LBNF1) rats for up to 8 wk; significant increases in plasma triglyceride and cholesterol occurred from 8 days to 8 wk. At 5 wk, the expression of selected hepatic genes (CYP7A1, CITED2, G6PC, and ME-1), which are key to lipid catabolism/synthesis, were altered toward lipogenesis. Dietary Mg supplementation (six-fold higher) completely reversed the altered expression of these genes and attenuated both hypertriglyceridemia and hypercholesterolemia. Neutrophils isolated from the RTV-treated rats displayed a three-fold higher basal and a twofold higher stimulated superoxide production; plasma isoprostane and red blood cell (RBC) GSSG levels were elevated two- to three-fold. All oxidative indices were normalized by Mg supplementation. After 5 wk, RTV caused significant decreases in cardiac left ventricular (LV) shortening fraction and LV ejection fraction; mitral valve early/late atrial ventricular filling (E/A) ratio was reduced accompanied by LV posterior wall thinning. Immunohistochemical staining revealed significant white blood cell (WBC) infiltration (5 wk) and prominent fibrosis (8 wk) in the RTV hearts. Mg supplementation attenuated RTV-induced declines in systolic and diastolic (improved mitral valve E/A ratio) function (>70%), lessened LV posterior wall thinning (by 75%), and substantially decreased the pathological markers. The known clinical hyperlipidemia effects of RTV can be mimicked in the LBNF1 rats; in association, systemic oxidative stress and progressive cardiac dysfunction occurred. Remarkably, Mg supplementation alone suppressed RTV-mediated hyperlipidemia, oxidative stress, and cardiac dysfunction. PMID- 24049115 TI - ENaC-expressing neurons in the sensory circumventricular organs become c-Fos activated following systemic sodium changes. AB - The sensory circumventricular organs (CVOs) are specialized collections of neurons and glia that lie in the midline of the third and fourth ventricles of the brain, lack a blood-brain barrier, and function as chemosensors, sampling both the cerebrospinal fluid and plasma. These structures, which include the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and area postrema (AP), are sensitive to changes in sodium concentration but the cellular mechanisms involved remain unknown. Epithelial sodium channel (ENaC) expressing neurons of the CVOs may be involved in this process. Here we demonstrate with immunohistochemical and in situ hybridization methods that ENaC expressing neurons are densely concentrated in the sensory CVOs. These neurons become c-Fos activated, a marker for neuronal activity, after various manipulations of peripheral levels of sodium including systemic injections with hypertonic saline, dietary sodium deprivation, and sodium repletion after prolonged sodium deprivation. The increases seen c-Fos activity in the CVOs were correlated with parallel increases in plasma sodium levels. Since ENaCs play a central role in sodium reabsorption in kidney and other epithelia, we present a hypothesis here suggesting that these channels may also serve a related function in the CVOs. ENaCs could be a significant factor in modulating CVO neuronal activity by controlling the magnitude of sodium permeability in neurons. Hence, some of the same circulating hormones controlling ENaC expression in kidney, such as angiotensin II and atrial natriuretic peptide, may coordinate ENaC expression in sensory CVO neurons and could potentially orchestrate sodium appetite, osmoregulation, and vasomotor sympathetic drive. PMID- 24049116 TI - Effect of hypercapnic hypoxia and bacterial infection (Vibrio campbellii) on protein synthesis rates in the Pacific whiteleg shrimp, Litopenaeus vannamei. AB - Estuarine species frequently encounter areas of simultaneously low dissolved O2 (hypoxia) and high CO2 (hypercapnia). Organisms exposed to hypoxia experience a metabolic depression that serves to decrease ATP utilization and O2 demand during stress. This downregulation is typically facilitated by a reduction in protein synthesis, a process that can be responsible for up to 60% of basal metabolism. The added effects of hypercapnia, however, are unclear. Certain decapods also exhibit a metabolic depression in response to bacterial challenges, leading us to hypothesize that protein synthesis may also be reduced during infection. In the present study, we examined the effects of hypoxia (H), hypercapnic hypoxia (HH), and bacterial infection (Vibrio campbellii) on tissue-specific (muscle and hepatopancreas) fractional protein synthesis rates (ks) in Litopenaeus vannamei. We observed a significant decrease in ks in muscle after 24 h exposure to both H and HH, and in hepatopancreas after 24 h exposure to HH. Thus ks is responsive to changes in O2, and the combined effect of hypercapnic hypoxia on ks is more severe than hypoxia alone. These reductions in ks appear to be driven by changes in RNA translational efficiency (kRNA), and not RNA capacity (Cs). Bacterial infection, however, had no significant effect on ks in either tissue. These results suggest that crustaceans reduce metabolic demand during environmental hypoxia by reducing global protein synthesis, and that this effect is magnified when hypercapnia is concomitantly present. Conversely, an immune-mediated metabolic depression is not associated with a decrease in overall protein production. PMID- 24049117 TI - Knockdown of tyrosine hydroxylase in the nucleus of the solitary tract reduces elevated blood pressure during chronic intermittent hypoxia. AB - Noradrenergic A2 neurons in nucleus tractus solitarius (NTS) respond to stressors such as hypoxia. We hypothesize that tyrosine hydroxylase (TH) knockdown in NTS reduces cardiovascular responses to chronic intermittent hypoxia (CIH), a model of the arterial hypoxemia observed during sleep apnea in humans. Adult male Sprague-Dawley rats were implanted with radiotelemetry transmitters and adeno associated viral constructs with green fluorescent protein (GFP) reporter having either short hairpin RNA (shRNA) for TH or scrambled virus (scRNA) were injected into caudal NTS. Virus-injected rats were exposed to 7 days of CIH (alternating periods of 10% O2 and of 21% O2 from 8 AM to 4 PM; from 4 PM to 8 AM rats were exposed to 21% O2). CIH increased mean arterial pressure (MAP) and heart rate (HR) during the day in both the scRNA (n = 14, P < 0.001 MAP and HR) and shRNA (n = 13, P < 0.001 MAP and HR) groups. During the night, MAP and HR remained elevated in the scRNA rats (P < 0.001 MAP and HR) but not in the shRNA group. TH immunoreactivity and protein were reduced in the shRNA group. FosB/DeltaFosB immunoreactivity was decreased in paraventricular nucleus (PVN) of shRNA group (P < 0.001). However, the shRNA group did not show any change in the FosB/DeltaFosB immunoreactivity in the rostral ventrolateral medulla. Exposure to CIH increased MAP which persisted beyond the period of exposure to CIH. Knockdown of TH in the NTS reduced this CIH-induced persistent increase in MAP and reduced the transcriptional activation of PVN. This indicates that NTS A2 neurons play a role in the cardiovascular responses to CIH. PMID- 24049119 TI - Phylogenetic, expression, and functional analyses of anoctamin homologs in Caenorhabditis elegans. AB - Ca(2+)-activated Cl(-) channels (CaCCs) are critical to processes such as epithelial transport, membrane excitability, and signal transduction. Anoctamin, or TMEM16, is a family of 10 mammalian transmembrane proteins, 2 of which were recently shown to function as CaCCs. The functions of other family members have not been firmly established, and almost nothing is known about anoctamins in invertebrates. Therefore, we performed a phylogenetic analysis of anoctamins across the animal kingdom and examined the expression and function of anoctamins in the genetically tractable nematode Caenorhabditis elegans. Phylogenetic analyses support five anoctamin clades that are at least as old as the deuterostome/protosome ancestor. This includes a branch containing two Drosophila paralogs that group with mammalian ANO1 and ANO2, the two best characterized CaCCs. We identify two anoctamins in C. elegans (ANOH-1 and ANOH-2) that are also present in basal metazoans. The anoh-1 promoter is active in amphid sensory neurons that detect external chemical and nociceptive cues. Within amphid neurons, ANOH-1::GFP fusion protein is enriched within sensory cilia. RNA interference silencing of anoh-1 reduced avoidance of steep osmotic gradients without disrupting amphid cilia development, chemotaxis, or withdrawal from noxious stimuli, suggesting that ANOH-1 functions in a sensory mode-specific manner. The anoh-2 promoter is active in mechanoreceptive neurons and the spermatheca, but loss of anoh-2 had no effect on motility or brood size. Our study indicates that at least five anoctamin duplicates are evolutionarily ancient and suggests that sensory signaling may be a basal function of the anoctamin protein family. PMID- 24049118 TI - Acute systemic hypoxia activates hypothalamic paraventricular nucleus-projecting catecholaminergic neurons in the caudal ventrolateral medulla. AB - Hypoxia activates catecholamine neurons in the caudal ventrolateral medulla (CVLM). The hypothalamic paraventricular nucleus (PVN) modulates arterial chemoreflex responses and receives catecholaminergic projections from the CVLM, but it is not known whether the CVLM-PVN projection is activated by chemoreflex stimulation. We hypothesized that acute hypoxia (AH) activates PVN-projecting catecholaminergic neurons in the CVLM. Fluoro-Gold (2%, 60-90 nl) was microinjected into the PVN of rats to retrogradely label CVLM neurons. After recovery, conscious rats underwent 3 h of normoxia (21% O2, n = 4) or AH (12, 10, or 8% O2; n = 5 each group). We used Fos immunoreactivity as an index of CVLM neuronal activation and tyrosine hydroxylase (TH) immunoreactivity to identify catecholaminergic neurons. Positively labeled neurons were counted in six caudal rostral sections containing CVLM. Hypoxia progressively increased the number of Fos-immunoreactive CVLM cells (21%, 19 +/- 6; 12%, 49 +/- 2; 10%, 117 +/- 8; 8%, 179 +/- 7; P < 0.001). Catecholaminergic cells colabeled with Fos immunoreactivity in the CVLM were observed following 12% O2, and further increases in hypoxia severity caused markedly more activation. PVN-projecting CVLM cells were activated following more severe hypoxia (10% and 8% O2). A large proportion (89 +/- 3%) of all activated PVN-projecting CVLM neurons were catecholaminergic, regardless of hypoxia intensity. Data suggest that catecholaminergic, PVN-projecting CVLM neurons are particularly hypoxia sensitive, and these neurons may be important in the cardiorespiratory and/or neuroendocrine responses elicited by the chemoreflex. PMID- 24049121 TI - Paediatric keratoplasty: choices and conundrums. PMID- 24049120 TI - Spectrum of myelinated pulmonary afferents (II). AB - Recently, it has been recognized that a single airway sensory unit may contain multiple receptive fields and that each field houses at least one encoder. Since some units respond to both lung inflation and deflation, we hypothesized that these units contain heterogeneous encoders for sensing inflation and deflation, respectively. Single unit activities were recorded from the cervical vagus nerve in anesthetized, open chest, and mechanically ventilated rabbits. Fifty-two airway sensory units with multiple receptive fields that responded to both lung inflation and deflation were identified. Among them, 13 units had separate receptive fields for inflation and deflation, where one of the fields could be blocked by local injection of 2% lidocaine (10 MUl). In 8 of the 13 units, the deflation response was blocked without affecting the unit's response to inflation, whereas in the remaining five units, the inflation response was blocked without affecting the deflation response. Our results support the hypothesis that a single mechanosensory unit may contain heterogeneous encoders that can respond to either inflation or deflation. PMID- 24049122 TI - There has to be a better way: evolution of internal filtration glaucoma surgeries. PMID- 24049126 TI - Hormonal determinants of nipple aspirate fluid yield among breast cancer cases and screening controls. AB - BACKGROUND: Nipple aspiration fluid (NAF) use as a biosample is limited by the variable yield across studies. We investigated the endocrine determinants of yield in an ongoing breast cancer case-control study. METHODS: One-hundred and eighteen women yielding >=2 MUL NAF and 120 non-yielders were included; serum hormones were measured; differences in median hormones were assessed using the Wilcoxon rank-sum test. ORs and 95% confidence intervals (95% CI) for yielder status relative to hormone levels were estimated using logistic regression, adjusting for parity and lactation, and, in premenopausal women, menstrual cycle phase (MCP). RESULTS: Prolactin concentrations were higher in yielders than non yielders (premenopausal: 7.6 and 2.5 ng/mL, P < 0.01; postmenopausal 5.3 and 2.2 ng/mL; P < 0.01). Among premenopausal-yielders, estradiol was lower (64.3 vs. 90.5 pg/mL, MCP-adjusted P = 0.02). In separate menopausal status and parity adjusted models, significant case-control differences persisted in prolactin: case OR 1.93 (95% CI, 1.35-2.77), control OR 1.64 (95% CI, 1.17-2.29). Premenopausal control yielders had higher progesterone (OR, 1.70; 95% CI, 1.18 2.46) and sex-hormone binding-globulin (OR, 2.09; 95% CI, 1.08-4.05) than non yielders. Among parous women, further adjustment for lactation suggested a stronger positive association of serum prolactin with yield in cases than controls. CONCLUSION: NAF-yielders show higher prolactin than non-yielders, regardless of menopause and parity; implications of this and other endocrine differences on NAF biomarkers of breast cancer risk deserve further study. IMPACT: NAF yield is associated with a distinct endocrine environment that must be considered in studies of NAF-based breast cancer risk markers. PMID- 24049127 TI - Risk of colorectal cancer in patients with acute myocardial infarction and stroke: a nationwide cohort study. AB - BACKGROUND: An association between colorectal cancer and acute myocardial infarction (AMI) and stroke has been suggested, but evidence is conflicting. METHOD: We conducted a population-based cohort study (1978-2010) of the association between AMI/stroke and colorectal cancer by linking nationwide Danish registries. We calculated standardized incidence ratios (SIR) of colorectal cancer after AMI/stroke as the ratios of observed to expected incidence. RESULTS: A total of 297,523 patients with AMI (median age, 69.4 years; 64% men) were followed for a median of 3.1 years (range, 0-33 years) and 4,387 developed colorectal cancer [SIR, 1.08; 95% confidence interval (CI), 1.05-1.11; P < 0.001]. In the first year of follow-up, the SIR was 1.85 (95% CI, 1.73-1.98; P < 0.001), whereas it was 0.98 (95% CI, 0.95-1.02; P = 0.318) in the second and subsequent years. We followed 246,998 patients with stroke (median age, 72.4 years; 52% men) for a median of 2.9 years (range, 0-33 years) and 3,035 developed colorectal cancer (SIR, 1.04; 95% CI, 1.00-1.07; P = 0.053). In the first year of follow-up, the SIR was 1.42 (95% CI, 1.31-1.53; P < 0.001), whereas it was 0.96 (95% CI, 0.93-1.00; P = 0.072) thereafter. We found no difference between the SIRs for ischemic and hemorrhagic stroke. The increased one-year relative risks for AMI and stroke corresponded to a 0.3% absolute risk. CONCLUSIONS: Our findings reflect detection of occult cancer at the time of the vascular event. The lack of increased risk after one year suggests that an association based on shared risk factors or chronic inflammation is unlikely. IMPACT: In patients with AMI/stroke, the diagnostic workup including screening for colorectal cancer should follow that of the general population. PMID- 24049128 TI - Six iterative reconstruction algorithms in brain CT: a phantom study on image quality at different radiation dose levels. AB - OBJECTIVE: To evaluate the image quality produced by six different iterative reconstruction (IR) algorithms in four CT systems in the setting of brain CT, using different radiation dose levels and iterative image optimisation levels. METHODS: An image quality phantom, supplied with a bone mimicking annulus, was examined using four CT systems from different vendors and four radiation dose levels. Acquisitions were reconstructed using conventional filtered back projection (FBP), three levels of statistical IR and, when available, a model based IR algorithm. The evaluated image quality parameters were CT numbers, uniformity, noise, noise-power spectra, low-contrast resolution and spatial resolution. RESULTS: Compared with FBP, noise reduction was achieved by all six IR algorithms at all radiation dose levels, with further improvement seen at higher IR levels. Noise-power spectra revealed changes in noise distribution relative to the FBP for most statistical IR algorithms, especially the two model based IR algorithms. Compared with FBP, variable degrees of improvements were seen in both objective and subjective low-contrast resolutions for all IR algorithms. Spatial resolution was improved with both model-based IR algorithms and one of the statistical IR algorithms. CONCLUSION: The four statistical IR algorithms evaluated in the study all improved the general image quality compared with FBP, with improvement seen for most or all evaluated quality criteria. Further improvement was achieved with one of the model-based IR algorithms. ADVANCES IN KNOWLEDGE: The six evaluated IR algorithms all improve the image quality in brain CT but show different strengths and weaknesses. PMID- 24049129 TI - Quality assurance evaluation of spot scanning beam proton therapy with an anthropomorphic prostate phantom. AB - OBJECTIVE: The purpose of this study was to evaluate spot scanning proton therapy with an anthropomorphic prostate phantom at the Proton Therapy Center of The University of Texas MD Anderson Cancer Center at Houston, TX (PTCH). METHODS: An anthropomorphic prostate phantom from the Radiological Physics Center (RPC), The University of Texas MD Anderson Cancer Center, Houston, TX, was used, which contained thermoluminescent dosemeters and GAFCHROMIC((r)) EBT2 film (ISP Technologies, Wayne, NJ). The phantom was irradiated by the Hitachi synchrotron (Hitachi America, Ltd, Tarrytown, NY), and the results were compared between the treatment planning system (TPS) and RPC measurements. RESULTS: RPC results show that the right/left, inferior/superior and posterior/anterior aspects of the coronal/sagittal and EBT2 film measurements were within +/-7%/+/-4 mm of the TPS. The RPC thermoluminescent dosemeter measurements of the prostate and femoral heads were within 3% of the TPS. CONCLUSION: The RPC prostate phantom is a useful mechanism to evaluate spot scanning beam proton therapy within certain confidence levels. ADVANCES IN KNOWLEDGE: The RPC anthropomorphic prostate phantom could be used to establish quality assurance of spot scanning proton beam for patients with prostate cancer. PMID- 24049130 TI - How experienced community neurologists make diagnoses during clinical encounters. AB - Study of diagnostic practice is necessary to optimize neurologists' clinical performance and ensure patient safety. To our knowledge, this report is the first set of systematic observations of diagnostic practices of community neurologists in their clinics. The study consisted of six 2-week periods of in situ observations and interviews of 6 experienced community neurologists in Northern California. We describe 3 core domains of diagnosis: 1) clinical (C), 2) laboratory and electrodiagnostics (L), and 3) neuroimaging (N). Neurologists were uniform in their practices across these domains except within the clinical domain, where the physical examination varied considerably among clinicians. All neurologists coordinated findings from the 3 domains to arrive at a final diagnosis. This practice of coordination varied across common disease categories (e.g., meningitis vs dementia). To codify this variance, we developed a provisional model of diagnostic practice derived from the data consisting of a 3 point coordinate shorthand (Cx Lx Nx) and a graphic. This model shows the relative emphasis of each of the 3 core domains for 9 common diagnoses (e.g., stroke is C4 L1 N4 with "4" as the highest priority per domain). The data reveal a heavy emphasis on the clinical domain for most diagnoses. The model may be useful for trainees to learn how to allocate time to make a diagnosis. It may help educators build curricula and evaluation systems that emphasize concrete activities of diagnostic practice. Lastly, our model provides a structure to teach resource utilization and cost containment relating to neurologic diagnoses. PMID- 24049131 TI - Vitamin B6-responsive epilepsy due to inherited GPI deficiency. PMID- 24049132 TI - Limbic hyperconnectivity in the vegetative state. AB - OBJECTIVE: To investigate functional connectivity between the default mode network (DMN) and other networks in disorders of consciousness. METHODS: We analyzed MRI data from 11 patients in a vegetative state and 7 patients in a minimally conscious state along with age- and sex-matched healthy control subjects. MRI data analysis included nonlinear spatial normalization to compensate for disease-related anatomical distortions. We studied brain connectivity data from resting-state MRI temporal series, combining noninferential (independent component analysis) and inferential (seed-based general linear model) methods. RESULTS: In DMN hypoconnectivity conditions, a patient's DMN functional connectivity shifts and paradoxically increases in limbic structures, including the orbitofrontal cortex, insula, hypothalamus, and the ventral tegmental area. CONCLUSIONS: Concurrently with DMN hypoconnectivity, we report limbic hyperconnectivity in patients in vegetative and minimally conscious states. This hyperconnectivity may reflect the persistent engagement of residual neural activity in self-reinforcing neural loops, which, in turn, could disrupt normal patterns of connectivity. PMID- 24049133 TI - Duplications of 17q12 can cause familial fever-related epilepsy syndromes. AB - OBJECTIVES: After we identified a 17q12 duplication cosegregating in a 4 generation family with genetic or generalized epilepsy with febrile seizures plus (GEFS+), we aimed to determine the frequency of 17q12 genomic rearrangements in GEFS+ and a wide spectrum of other epilepsy phenotypes. We furthermore describe seizure prevalence in previously reported patients with a 17q12 duplication or deletion. METHODS: We analyzed 433 patients with a broad range of epilepsy phenotypes. The 180k Cytosure ISCA v2 array was used for copy number variation screening in the index patient. Segregation analysis and follow-up studies were performed with the multiplex amplicon quantification technique. RESULTS: We identified 2 families in which a 17q12 duplication segregated with febrile sensitive epilepsy. In the follow-up study, the mutation rate in familial febrile seizures (FS) and GEFS+ phenotypes was 1/222. No 17q12 deletions were detected. Two of the 6 mutation carriers in the initial GEFS+ family had mild intellectual disability, whereas all family members of the second family were of normal intelligence. In the literature, 4 of 43 individuals with a 17q12 duplication and 4 of 55 with the reciprocal deletion were described to have had seizures. CONCLUSIONS: Our study shows that 17q12 duplications are a rare cause of familial FS and GEFS+. Although some family members might have intellectual disability, seizures can be the sole clinical symptom. This is the first report on an inherited copy number variation in these self-limiting fever-sensitive epilepsy syndromes, potentially revealing a novel pathomechanism involved in familial FS and GEFS+. PMID- 24049134 TI - Preclinical AD predicts decline in memory and executive functions in subjective complaints. AB - OBJECTIVE: We assessed whether preclinical Alzheimer disease (AD) based on CSF biomarkers at baseline predicts decline in cognitive functioning as measured by repeated neuropsychological tests for 4 cognitive domains in patients with subjective complaints. METHODS: We included 132 patients with subjective complaints from our memory clinic-based Amsterdam Dementia Cohort, who underwent lumbar puncture and had repeated (range 2-7) neuropsychological evaluations. Follow-up was 2 +/- 1 years. CSF biomarkers amyloid-beta (Abeta42), total tau (Tau), and hyperphosphorylated tau-181 were used to define National Institute on Aging-Alzheimer's Association (NIA-AA) preclinical AD stages. Predictive value of preclinical AD stages as defined by CSF biomarkers, individual biomarkers, and Abeta42/tau ratio was assessed using linear mixed models. Outcome measures were compound z scores for memory, attention, executive functioning, language, and global cognition. Analyses were adjusted for age, sex, and education. RESULTS: Patients were 61 +/- 8 years old; 56 (42%) were women. Average baseline Mini Mental State Examination score was 28.3 +/- 1.5. Patients who fulfilled criteria for preclinical AD (stage 1: n = 11 + stage 2: n = 10) showed decline over time in memory (beta +/- SE -0.41 +/- 0.14, p < 0.01), executive functions (-0.21 +/- 0.08, p < 0.01), and global cognition (-0.29 +/- 0.10, p < 0.01). There were no differences in cognitive decline between NIA-AA preclinical AD stages 1 and 2. In patients with normal CSF biomarkers, we observed memory improvement (0.19 +/- 0.07, p < 0.01) and stable performance in all other domains. CONCLUSIONS: CSF evidence of preclinical AD in patients with subjective complaints predicted cognitive decline over time, encompassing more than memory alone. Executive functioning and global cognitive functioning also deteriorated. On the other hand, 2-year prognosis for patients without evidence of AD pathophysiology was good. PMID- 24049135 TI - Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: a meta-analysis. AB - OBJECTIVE: To perform a meta-analysis on the effect of lowering homocysteine levels via B vitamin supplementation on cerebrovascular disease risk. METHODS: Using clinical trials published before August 2012 to assess stroke events, we used relative risks (RRs) with 95% confidence intervals (95% CIs) to measure the association between B vitamin supplementation and endpoint events using a fixed effects model and chi(2) tests. We included 14 randomized controlled trials with 54,913 participants in this analysis. RESULTS: We observed a reduction in overall stroke events resulting from reduction in homocysteine levels following B vitamin supplementation (RR 0.93; 95% CI 0.86-1.00; p = 0.04) but not in subgroups divided according to primary or secondary prevention measures, ischemic vs hemorrhagic stroke, or occurrence of fatal stroke. There were beneficial effects in reducing stroke events in subgroups with >=3 years follow-up time, and without background of cereal folate fortification or chronic kidney disease (CKD). Some trials that included CKD patients reported decreased glomerular filtration rate with B vitamin supplementation. We conducted detailed subgroup analyses for cyanocobalamin (vitamin B12) but did not find a significant benefit regarding intervention dose of vitamin B12 or baseline blood B12 concentration. Stratified analysis for blood pressure and baseline participant medication use showed benefits with >130 mm Hg systolic blood pressure and lower antiplatelet drug use in reducing stroke risk. CONCLUSIONS: B vitamin supplementation for homocysteine reduction significantly reduced stroke events, especially in subjects with certain characteristics who received appropriate intervention measures. PMID- 24049136 TI - Natalizumab affects the T-cell receptor repertoire in patients with multiple sclerosis. AB - OBJECTIVE: To assess changes in the T-cell receptor (TCR) repertoire in peripheral venous blood and CSF of patients with multiple sclerosis (MS) treated with natalizumab and the potential implication for developing progressive multifocal leukoencephalopathy (PML) and PML-immune reconstitution inflammatory syndrome (IRIS). METHODS: The TCR repertoire in blood and CSF was assessed by complementarity determining region 3 spectratyping in 59 patients with MS treated with natalizumab for at least 18 months, 5 cases of natalizumab-associated PML, 17 age- and sex-matched patients with MS not treated with natalizumab, and 12 healthy controls. RESULTS: Patients with MS presented with peripheral TCR repertoire expansions in blood, which appeared less prominent during therapy with natalizumab. TCR repertoire restrictions observed in CSF were most pronounced in patients with MS treated with natalizumab. In patients who developed PML with longitudinal samples available, new identical TCR receptor length expansions in blood and CSF were observed following plasma exchange, and preceded the development of IRIS. CONCLUSIONS: Profound TCR repertoire restrictions in CSF of patients treated with natalizumab reflect an altered immune surveillance of the CNS, which may contribute to an increased risk of developing PML. Natalizumab seems to prompt an impaired or delayed peripheral expansion of antigen-specific T cells, whereas increased reconstitution of peripheral T-cell expansion following plasma exchange may trigger PML-IRIS. Our data suggest that treatment with natalizumab results in broader changes in the T-cell immune repertoire beyond lymphocyte migration. PMID- 24049137 TI - A bird's-eye view of T cells during natalizumab therapy. PMID- 24049138 TI - Comment: The tribe in white coats. PMID- 24049139 TI - The pattern of atrophy in familial Alzheimer disease: volumetric MRI results from the DIAN study. AB - OBJECTIVE: To assess regional patterns of gray and white matter atrophy in familial Alzheimer disease (FAD) mutation carriers. METHODS: A total of 192 participants with volumetric T1-weighted MRI, genotyping, and clinical diagnosis were available from the Dominantly Inherited Alzheimer Network. Of these, 69 were presymptomatic mutation carriers, 50 were symptomatic carriers (31 with Clinical Dementia Rating [CDR] = 0.5, 19 with CDR > 0.5), and 73 were noncarriers from the same families. Voxel-based morphometry was used to identify cross-sectional group differences in gray matter and white matter volume. RESULTS: Significant differences in gray matter (p < 0.05, family-wise error-corrected) were observed between noncarriers and mildly symptomatic (CDR = 0.5) carriers in the thalamus and putamen, as well as in the temporal lobe, precuneus, and cingulate gyrus; the same pattern, but with more extensive changes, was seen in those with CDR > 0.5. Significant white matter differences between noncarriers and symptomatic carriers were observed in the cingulum and fornix; these form input and output connections to the medial temporal lobe, cingulate, and precuneus. No differences between noncarriers and presymptomatic carriers survived correction for multiple comparisons, but there was a trend for decreased gray matter in the thalamus for carriers closer to their estimated age at onset. There were no significant increases of gray or white matter in asymptomatic or symptomatic carriers compared to noncarriers. CONCLUSIONS: Atrophy in FAD is observed early, both in areas commonly associated with sporadic Alzheimer disease and also in the putamen and thalamus, 2 regions associated with early amyloid deposition in FAD mutation carriers. PMID- 24049140 TI - The effect of surgical approach on the histologyof the femoral head following resurfacing of the hip: Analysis of retrieval specimens. AB - OBJECTIVES: We aimed to determine the effect of surgical approach on the histology of the femoral head following resurfacing of the hip. METHODS: We performed a histological assessment of the bone under the femoral component taken from retrieval specimens of patients having revision surgery following resurfacing of the hip. We compared the number of empty lacunae in specimens from patients who had originally had a posterior surgical approach with the number in patients having alternative surgical approaches. RESULTS: We found a statistically significant increase in the percentage of empty lacunae in retrieval specimens from patients who had the posterior approach compared with other surgical approaches (p < 0.001). CONCLUSIONS: This indicates that the vascular compromise that occurs during the posterior surgical approach does have long-term effects on the bone of the femoral head, even if it does not cause overt avascular necrosis. Cite this article: Bone Joint Res 2013;2:200-5. PMID- 24049141 TI - Decrease in neuronal nicotinic acetylcholine receptor subunit and PSD-93 transcript levels in the male mouse MPG after cavernous nerve injury or explant culture. AB - Quantitative real-time PCR was used to test whether cavernous nerve injury leads to a decrease in major pelvic ganglia (MPG) neuronal nicotinic ACh receptor (nAChR) subunit and postsynaptic density (PSD)-93 transcript levels. Subunits alpha3, beta4, and alpha7, commonly expressed in the MPG, were selected for analysis. After 72 h in explant culture, MPG transcript levels for alpha3, beta4, alpha7, and PSD-93 were significantly depressed. Three days after cavernous nerve axotomy or crush in vivo, transcript levels for alpha3, beta4, and PSD-93, but not for alpha7, were significantly depressed. Three days after dissection of the cavernous nerve free of underlying tissue and application of a 5-mm lateral stretch (manipulation), transcript levels for alpha3 and PSD-93 were also significantly decreased. Seven days after all three surgical procedures, alpha3 transcript levels remained depressed, but PSD-93 transcript levels were still decreased only after axotomy or nerve crush. At 30 days postsurgery, transcript levels for the nAChR subunits and PSD-93 had recovered. ACh-induced currents were significantly smaller in MPG neurons dissociated from 3-day explant cultured ganglia than from those recorded in neurons dissociated from acutely isolated ganglia; this observation provides direct evidence showing that a decrease in nAChR function was coincident with a decrease in nAChR subunit transcript levels. We conclude that a downregulation of nAChR subunit and PSD-93 expression after cavernous nerve injury, or even manipulation, could interrupt synaptic transmission within the MPG and thus contribute to the loss of neural control of urogenital organs after pelvic surgeries. PMID- 24049142 TI - TGF-beta1 stimulates mitochondrial oxidative phosphorylation and generation of reactive oxygen species in cultured mouse podocytes, mediated in part by the mTOR pathway. AB - Transforming growth factor (TGF)-beta has been associated with podocyte injury; we have examined its effect on podocyte bioenergetics. We studied transformed mouse podocytes, exposed to TGF-beta1, using a label-free assay system, Seahorse XF24, which measures oxygen consumption rates (OCR) and extracellular acidification rates (ECAR). Both basal OCR and ATP generation-coupled OCR were significantly higher in podocytes exposed to 0.3-10 ng/ml of TGF-beta1 for 24, 48, and 72 h. TGF-beta1 (3 ng/ml) increased oxidative capacity 75%, and 96% relative to control after 48 and 72 h, respectively. ATP content was increased 19% and 30% relative to control after a 48- and 72-h exposure, respectively. Under conditions of maximal mitochondrial function, TGF-beta1 increased palmitate driven OCR by 49%. Thus, TGF-beta1 increases mitochondrial oxygen consumption and ATP generation in the presence of diverse energy substrates. TGF-beta1 did not increase cell number or mitochondrial DNA copy number but did increase mitochondrial membrane potential (MMP), which could explain the OCR increase. Reactive oxygen species (ROS) increased by 32% after TGF-beta1 exposure for 48 h. TGF-beta activated the mammalian target of rapamycin (mTOR) pathway, and rapamycin reduced the TGF-beta1-stimulated increases in OCR, ECAR, ATP generation, cellular metabolic activity, and protein generation. Our data suggest that TGF-beta1, acting, in part, via mTOR, increases mitochondrial MMP and OCR, resulting in increased ROS generation and that this may contribute to podocyte injury. PMID- 24049143 TI - From TOR and SMAD, why HIF-1alpha can be bad. PMID- 24049144 TI - Effects of high-fat diet and losartan on renal cortical blood flow using contrast ultrasound imaging. AB - Obesity-related kidney disease occurs as a result of complex interactions between metabolic and hemodynamic effects. Changes in microvascular perfusion may play a major role in kidney disease; however, these changes are difficult to assess in vivo. Here, we used perfusion ultrasound imaging to evaluate cortical blood flow in a mouse model of high-fat diet-induced kidney disease. C57BL/6J mice were randomized to a standard diet (STD) or a high-fat diet (HFD) for 30 wk and then treated either with losartan or a placebo for an additional 6 wk. Noninvasive ultrasound perfusion imaging of the kidney was performed during infusion of a microbubble contrast agent. Blood flow within the microvasculature of the renal cortex and medulla was derived from imaging data. An increase in the time required to achieve full cortical perfusion was observed for HFD mice relative to STD. This was reversed following treatment with losartan. These data were concurrent with an increased glomerular filtration rate in HFD mice compared with STD- or HFD-losartan-treated mice. Losartan treatment also abrogated fibro inflammatory disease, assessed by markers at the protein and messenger level. Finally, a reduction in capillary density was found in HFD mice, and this was reversed upon losartan treatment. This suggests that alterations in vascular density may be responsible for the elevated perfusion time observed by imaging. These data demonstrate that ultrasound contrast imaging is a robust and sensitive method for evaluating changes in renal microvascular perfusion and that cortical perfusion time may be a useful parameter for evaluating obesity-related renal disease. PMID- 24049145 TI - Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1. AB - Deletions of claudin-2 (Cldn2) and aquaporin1 (AQP1) reduce proximal fluid reabsorption (PFR) by about 30% and 50%, respectively. Experiments were done to replicate these observations and to determine in AQP1/claudin-2 double knockout mice (DKO) if the effects of deletions of these established water pores are additive. PFR was determined in inactin/ketamine-anesthetized mice by free-flow micropuncture using single-nephron I(125)-iothalamate (io) clearance. Animal means of PFR [% of glomerular filtration rate (GFR)] derived from TF/Piothalamate ratios in 12 mice in each of four groups [wild type (WT), Cldn2(-/-), AQP1(-/-), and DKO) were 45.8 +/- 0.85 (51 tubules), 35.4 +/- 1 (54 tubules; P < 0.01 vs. WT), 36.8 +/- 1 (63 tubules; P < 0.05 vs. WT), and 33.9 +/- 1.4 (69 tubules; P < 0.01 vs. WT). Kidney and single-nephron GFRs (SNGFR) were significantly reduced in all mutant strains. The direct relationship between PFR and SNGFR was maintained in mutant mice, but the slope of this relationship was reduced in the absence of Cldn2 and/or AQP1. Transtubular osmotic pressure differences were not different between WT and Cldn2(-/-) mice, but markedly increased in DKO. In conclusion, the deletion of Cldn2, AQP1, or of both Cldn2 and AQP1 reduces PFR by 22.7%, 19.6%, and 26%, respectively. Our data are consistent with an up to 25% paracellular contribution to PFR. The reduced osmotic water permeability caused by absence of AQP1 augments luminal hypotonicity. Aided by a fall in filtered load, the capacity of non-AQP1-dependent transcellular reabsorption is sufficient to maintain PFR without AQP1 and claudin-2 at 75% of control. PMID- 24049146 TI - Sexually dimorphic urethral activity in response to pharmacological activation of 5-HT1A receptors in the rat. AB - In this study, we examined the possibility that 5-HT1A receptors may underlie sexually dimorphic mechanisms affecting the regulation of urethral functions in anesthetized rats. Simultaneous recordings of intravesical pressure under isovolumetric conditions, external urethral sphincter-electromyography, and urethral perfusion pressure were used to examine the effects of a 5-HT1A receptor agonist [8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)] and antagonist (WAY 100635) on bladder and urethral functions. This research also evaluated the effects of 8-OH-DPAT and alpha-bungarotoxin (a neuromuscular blockade agent) on urethral continence using leak point pressure testing, and the distribution of 5 HT1A receptors in the lower urinary tract was assessed by immunohistochemistry. The serotonergic mechanism that controls the urinary bladder and external urethral sphincter-electromyography activity showed no significant sexual differences, but urethral activity in urethral perfusion pressure and leak point pressure values exhibited some sexual differences. 8-OH-DPAT enhanced urethral pressure during continence in rats of both sexes, but the drug elevated the pressure during voiding in male rats and reduced it in female rats. The distribution of 5-HT1A receptors in the spinal cord also showed some sexual differences. The present study contributes to our understanding of the role of 5 HT1A receptors in physiological and immunohistochemical properties of urethral smooth muscle in rats of different sexes. These findings may be a basis for the future development of pharmacotherapies for stress urinary incontinence in men. PMID- 24049147 TI - The receptor antagonist picotamide inhibits adrenergic and thromboxane-induced contraction of hyperplastic human prostate smooth muscle. AB - Inhibition of prostate smooth muscle contraction is an important strategy for medical treatment of lower urinary tract symptoms (LUTS). Besides alpha1 adrenoceptors, prostate smooth muscle contraction is induced by activation of thromboxane (TXA2) receptors (TXA2-R). Here, we examined the effects of the TXA2 R antagonist picotamide on contraction of human prostate tissue. Prostate tissues were obtained from radical prostatectomy. The effects of picotamide (300 MUM), L 665,240 (3 MUM), and seratrodast (3 MUM) on U46619-, electric field stimulation- (EFS-), phenylephrine-, and norepinephrine-induced contractions were studied in organ baths. Expression of TXA2-R and TXA2 synthase (TXS) was examined by fluorescence stainings. Picotamide, seratrodast, and L-655,240 inhibited concentration-dependent contractions induced by the TXA2 analog U46619. Picotamide, but not seratrodast or L-655,240, inhibited frequency-dependent contractions induced by EFS. Picotamide inhibited concentration-dependent contractions induced by norepinephrine or by the selective alpha1-adrenoceptor agonist phenylephrine. In prostate strips, where only submaximal contraction by a low dose of phenylephrine was induced, application of U46619 raised tone to maximum phenylephrine-induced tension. Immunoreactivity for TXA2-R and TXS was observed in the stroma and in epithelial cells of glands. Colocalization of both immunoreactivites was observed with the smooth muscle markers calponin and alpha smooth muscle actin, with the epithelial marker pan-cytokeratin, and with prostate-specific antigen in the stroma and glands. The receptor antagonist picotamide inhibits alpha1-adrenergic, TXA2-mediated, and EFS-induced contractions in the human prostate. To the best of our knowledge, this is the first antagonist able to inhibit two different contraction systems in the prostate. PMID- 24049149 TI - Nitro-oleic acid is a novel anti-oxidative therapy for diabetic kidney disease. PMID- 24049148 TI - Renal adaptation during hibernation. AB - Hibernators periodically undergo profound physiological changes including dramatic reductions in metabolic, heart, and respiratory rates and core body temperature. This review discusses the effect of hypoperfusion and hypothermia observed during hibernation on glomerular filtration and renal plasma flow, as well as specific adaptations in renal architecture, vasculature, the renin angiotensin system, and upregulation of possible protective mechanisms during the extreme conditions endured by hibernating mammals. Understanding the mechanisms of protection against organ injury during hibernation may provide insights into potential therapies for organ injury during cold storage and reimplantation during transplantation. PMID- 24049150 TI - Increased tubulointerstitial recruitment of human CD141(hi) CLEC9A(+) and CD1c(+) myeloid dendritic cell subsets in renal fibrosis and chronic kidney disease. AB - Dendritic cells (DCs) play critical roles in immune-mediated kidney diseases. Little is known, however, about DC subsets in human chronic kidney disease, with previous studies restricted to a limited set of pathologies and to using immunohistochemical methods. In this study, we developed novel protocols for extracting renal DC subsets from diseased human kidneys and identified, enumerated, and phenotyped them by multicolor flow cytometry. We detected significantly greater numbers of total DCs as well as CD141(hi) and CD1c(+) myeloid DC (mDCs) subsets in diseased biopsies with interstitial fibrosis than diseased biopsies without fibrosis or healthy kidney tissue. In contrast, plasmacytoid DC numbers were significantly higher in the fibrotic group compared with healthy tissue only. Numbers of all DC subsets correlated with loss of kidney function, recorded as estimated glomerular filtration rate. CD141(hi) DCs expressed C-type lectin domain family 9 member A (CLEC9A), whereas the majority of CD1c(+) DCs lacked the expression of CD1a and DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), suggesting these mDC subsets may be circulating CD141(hi) and CD1c(+) blood DCs infiltrating kidney tissue. Our analysis revealed CLEC9A(+) and CD1c(+) cells were restricted to the tubulointerstitium. Notably, DC expression of the costimulatory and maturation molecule CD86 was significantly increased in both diseased cohorts compared with healthy tissue. Transforming growth factor-beta levels in dissociated tissue supernatants were significantly elevated in diseased biopsies with fibrosis compared with nonfibrotic biopsies, with mDCs identified as a major source of this profibrotic cytokine. Collectively, our data indicate that activated mDC subsets, likely recruited into the tubulointerstitium, are positioned to play a role in the development of fibrosis and, thus, progression to chronic kidney disease. PMID- 24049151 TI - Two oldies join forces to guard homeostasis. PMID- 24049152 TI - Alcohol 'pre-loading': a review of the literature. AB - AIM: To review the international literature concerning pre-loading (PL); this is drinking before going out to pubs and bars. METHOD: A literature review conducted in May 2013 using the EBSCO database entering the following search terms 'pre loading', 'front-loading', 'pre-partying' and 'pre-drinking'. Thereafter, the reference lists were checked for further relevant articles. The review consisted of 40 articles of which 11 were excluded because PL was not the primary unit of analysis or they did not fulfil a quality assurance criterion. RESULTS: Despite being an internationally widespread development to date, most of the research on this has been from the USA and UK. The majority of US studies have been concerned with PL in a college and high school setting, while the research in the UK has mainly concentrated on the correlation/relationship between PL and what takes place when drinkers enter pubs and bars later in the evening. A consistent finding was that PL is associated with greater alcohol consumption, intoxication and alcohol-related risks. The price of alcohol and achieving intoxication were the main motivations for PL. However, other reasons included a chance to meet members of the opposite sex or own friends in surroundings that encouraged interaction rather than intoxication. CONCLUSION: PL should be regarded as part of a wider drinking culture and understood within the context of what individuals require from a night out or staying in when drinking. There is little evidence to suggest that PL is a risk factor for admissions to accident and emergency services. PMID- 24049154 TI - BNF recommendations for the treatment of Wernick's encephalopathy: lost in translation? PMID- 24049153 TI - The relationship between midlife and late life alcohol consumption, APOE e4 and the decline in learning and memory among older adults. AB - AIMS: The aim of the study was to determine whether the trajectory of learning and memory is modified according to an interaction between midlife or late life alcohol consumption status and the presence of one or more APOE e4 alleles. METHODS: This was a secondary analysis of cognitive, genetic and alcohol consumption data collected from members of the Framingham Heart Study Offspring Cohort. RESULTS: Light and moderate alcohol consumption during late life was associated with greater decline in learning and memory among APOE e4 carriers, whereas light and moderate alcohol consumption was associated with an increase in learning and memory among non-APOE e4 carriers. There was not a significant interaction between midlife alcohol consumption status and APOE e4 on the trajectory of learning and memory. CONCLUSION: Light to moderate alcohol consumption during late life may protect against a decline in learning and memory for non-APOE e4 allele carriers, but not for older adults who carry one or more APOE e4 alleles. PMID- 24049156 TI - Disability and chronic disease among older adults in India: detecting vulnerable populations through the WHO SAGE Study. AB - Chronic noncommunicable diseases (NCDs) are now prevalent in many low- and middle income countries and confer a heightened risk of disability. It is unclear how public health programs can identify the older adults at highest risk of disability related to NCDs within diverse developing country populations. We studied nationally representative survey data from 7,150 Indian adults older than 50 years of age who participated in the World Health Organization Study on Global Aging and Adult Health (2007-2010) to identify population subgroups who are highly disabled. Using machine-learning algorithms, we identified sociodemographic correlates of disability. Although having 2 or more symptomatic NCDs was a key correlate of disability, the prevalence of symptomatic, undiagnosed NCDs was highest among the lowest 2 wealth quintiles of Indian adults, contrary to prior hypotheses of increased NCDs with wealth. Women and persons from rural populations were also disproportionately affected by nondiagnosed NCDs, with high out-of-pocket health care expenditures increasing the probability of remaining symptomatic from NCDs. These findings also indicate that NCD prevalence surveillance studies in low- and middle-income countries should expand beyond self-reported diagnoses to include more extensive symptom- and examination-based surveys, given the likely high rate of surveillance bias due to barriers to diagnosis among vulnerable populations. PMID- 24049157 TI - Characteristics of males infected with common Neisseria gonorrhoeae sequence types in the Gonococcal Isolate Surveillance Project, San Francisco, California, 2009. AB - We analyzed 265 urethral Neisseria gonorrhoeae specimens collected from symptomatic males at San Francisco's municipal sexually transmitted disease clinic, a participant in the Gonococcal Isolate Surveillance Project, during 2009. We used N. gonorrhoeae multiantigen sequence typing to describe characteristics of patients infected with common sequence type families. Specimens were classified into 6 homology-based families and 1 additional family of all other identified strains. Strain family results were combined with results of culture-based antibiotic sensitivity minimum inhibitory concentration, sociodemographic and behavioral risk data collected at the clinic, and presence or absence of the mosaic penicillin-binding protein 2 (penA) allele. Characteristics of patients were compared across strain families through the use of chi(2) statistics. Among men who have sex with men, strain distribution differed by those reporting receptive oral sex as their only urethral exposure (P = 0.04), by number of sex partners (P = 0.03), and by race/ethnicity (P < 0.001); there were no differences by age or human immunodeficiency virus status. Also, among men who have sex with men, strain family distributions differed for culture specimens with reduced susceptibility to a range of antibiotics, as well as with presence of the mosaic penA allele (all P < 0.001). The combination of molecular, phenotypic, and epidemiologic data on N. gonorrhoeae infection could help develop a more complete epidemiology of gonorrhea in the United States. PMID- 24049158 TI - Rotating night-shift work and lung cancer risk among female nurses in the United States. AB - The risk of lung cancer among night-shift workers is unknown. Over 20 years of follow-up (1988-2008), we documented 1,455 incident lung cancers among 78,612 women in the Nurses' Health Study. To examine the relationship between rotating night-shift work and lung cancer risk, we used multivariate Cox proportional hazard models adjusted for detailed smoking characteristics and other risk factors. We observed a 28% increased risk of lung cancer among women with 15 or more years spent working rotating night shifts (multivariate relative risk (RR) = 1.28, 95% confidence interval (CI): 1.07, 1.53; Ptrend = 0.03) compared with women who did not work any night shifts. This association was strongest for small cell lung carcinomas (multivariate RR = 1.56, 95% CI: 0.99, 2.47; Ptrend = 0.03) and was not observed for adenocarcinomas of the lung (multivariate RR = 0.91, 95% CI: 0.67, 1.24; Ptrend = 0.40). Further, the increased risk associated with 15 or more years of rotating night-shift work was limited to current smokers (RR = 1.61, 95% CI: 1.21, 2.13; Ptrend < 0.001), with no association seen in nonsmokers (Pinteraction = 0.03). These results suggest that there are modestly increased risks of lung cancer associated with extended periods of night-shift work among smokers but not among nonsmokers. Though it is possible that this observation was residually confounded by smoking, our findings could also provide evidence of circadian disruption as a "second hit" in the etiology of smoking-related lung tumors. PMID- 24049160 TI - A large prospective investigation of sleep duration, weight change, and obesity in the NIH-AARP Diet and Health Study cohort. AB - The relationship between sleep and obesity or weight gain in adults, particularly older populations, remains unclear. In a cohort of 83,377 US men and women aged 51-72 years, we prospectively investigated the association between self-reported sleep duration and weight change over an average of 7.5 years of follow-up (1995 2004). Participants were free of cancer, heart disease, and stroke at baseline and throughout the follow-up. We observed an inverse association between sleep duration per night and weight gain in both men (P for trend = 0.02) and women (P for trend < 0.001). Compared with 7-8 hours of sleep, shorter sleep (<5 hours or 5-6 hours) was associated with more weight gain (in kilograms; men: for <5 hours, beta = 0.66, 95% confidence interval (CI): 0.19, 1.13, and for 5-6 hours, beta = 0.12, 95% CI: -0.02, 0.26; women: for <5 hours, beta = 0.43, 95% CI: 0.00, 0.86, and for 5-6 hours, beta = 0.23, 95% CI: 0.08, 0.37). Among men and women who were not obese at baseline, participants who reported less than 5 hours of sleep per night had an approximately 40% higher risk of developing obesity than did those who reported 7-8 hours of sleep (for men, odds ratio = 1.45, 95% CI: 1.06, 1.99; for women, odds ratio = 1.37, 95% CI: 1.04, 1.79). The association between short sleep and excess weight gain was generally consistent across different categories of age, educational level, smoking status, baseline body mass index, and physical activity level. PMID- 24049161 TI - Association of low to moderate levels of arsenic exposure with risk of type 2 diabetes in Bangladesh. AB - Chronic exposure to high levels of arsenic in drinking water is associated with increased risk of type 2 diabetes mellitus (T2DM), but the association between lower levels of arsenic and T2DM is more controversial. Therefore, this study evaluated the association between low to moderate arsenic exposure and T2DM. In 2009-2011, we conducted a study of 957 Bangladeshi adults who participated in a case-control study of skin lesions in 2001-2003. The odds ratio of T2DM was evaluated in relationship to arsenic exposure measured in drinking water and in subjects' toenails (in 2001-2003) prior to the diagnosis of T2DM (in 2009-2011). Compared with those exposed to the lowest quartile of arsenic in water (<= 1.7 ug/L), the adjusted odds ratio for T2DM was 1.92 (95% confidence interval (CI): 0.82, 4.35) for those in the second quartile, 3.07 (95% CI: 1.38, 6.85) for those in the third quartile, and 4.51 (95% CI: 2.01, 10.09) for those in the fourth quartile. The relative excess risk of T2DM was 4.78 for individuals who smoked and 8.93 for people who had a body mass index (weight (kg)/height (m)(2)) greater than 25. These findings suggest that exposure to modest levels of arsenic in drinking water was associated with increased risk of T2DM in Bangladesh. Being overweight or smoking was also associated with increased risk of T2DM. PMID- 24049162 TI - Associations of personal and family preeclampsia history with the risk of early-, intermediate- and late-onset preeclampsia. AB - Preeclampsia encompasses multiple conditions of varying severity. We examined the recurrence and familial aggregation of preeclampsia by timing of onset, which is a marker for severity. We ascertained personal and family histories of preeclampsia for women who delivered live singletons in Denmark in 1978-2008 (almost 1.4 million pregnancies). Using log-linear binomial regression, we estimated risk ratios for the associations between personal and family histories of preeclampsia and the risk of early-onset (before 34 weeks of gestation, which is typically the most severe), intermediate-onset (at 34-36 weeks of gestation), and late-onset (after 36 weeks of gestation) preeclampsia. Previous early-, intermediate-, or late-onset preeclampsia increased the risk of recurrent preeclampsia with the same timing of onset 25.2 times (95% confidence interval (CI): 21.8, 29.1), 19.7 times (95% CI: 17.0, 22.8), and 10.3 times (95% CI: 9.85, 10.9), respectively, compared with having no such history. Preeclampsia in a woman's family was associated with a 24%-163% increase in preeclampsia risk, with the strongest associations for early- and intermediate-onset preeclampsia in female relatives. Preeclampsia in the man's family did not affect a woman's risk of early-onset preeclampsia and was only weakly associated with her risks of intermediate- and late-onset preeclampsia. Early-onset preeclampsia appears to have the largest genetic component, whereas environmental factors likely contribute most to late-onset preeclampsia. The role of paternal genes in the etiology of preeclampsia appears to be limited. PMID- 24049163 TI - Murine norovirus transcytosis across an in vitro polarized murine intestinal epithelial monolayer is mediated by M-like cells. AB - Noroviruses (NoVs) are the causative agent of the vast majority of nonbacterial gastroenteritis worldwide. Due to the inability to culture human NoVs and the inability to orally infect a small animal model, little is known about the initial steps of viral entry. One particular step that is not understood is how NoVs breach the intestinal epithelial barrier. Murine NoV (MNV) is the only NoV that can be propagated in vitro by infecting murine macrophages and dendritic cells, making this virus an attractive model for studies of different aspects of NoV biology. Polarized murine intestinal epithelial mICcl2 cells were used to investigate how MNV interacts with and crosses the intestinal epithelium. In this in vitro model of the follicle-associated epithelium (FAE), MNV is transported across the polarized cell monolayer in the absence of viral replication or disruption of tight junctions by a distinct epithelial cell with microfold (M) cell properties. In addition to transporting MNV, these M-like cells also transcytose microbeads and express an IgA receptor. Interestingly, B myeloma cells cultured in the basolateral compartment underlying the epithelial monolayer did not alter the number of M-like cells but increased their transcytotic activity. Our data demonstrate that MNV can cross an intact intestinal epithelial monolayer in vitro by hijacking the M-like cells' intrinsic transcytotic pathway and suggest a potential mechanism for MNV entry into the host. PMID- 24049164 TI - A simplified positive-sense-RNA virus construction approach that enhances analysis throughput. AB - Here we present an approach that advances the throughput of a genetic analysis of a positive-sense RNA virus by simplifying virus construction. It enabled comprehensive dissection of a complex, multigene phenotype through rapid derivation of a large number of chimeric viruses and construction of a mutant library directly from a virus pool. The versatility of the approach described here expands the applicability of diverse genetic approaches to study these viruses. PMID- 24049165 TI - Displacement of the C terminus of herpes simplex virus gD is sufficient to expose the fusion-activating interfaces on gD. AB - Viral entry by herpes simplex virus (HSV) is executed and tightly regulated by four glycoproteins. While several viral glycoproteins can mediate viral adhesion to host cells, only binding of gD to cellular receptor can activate core fusion proteins gB and gH/gL to execute membrane fusion and viral entry. Atomic structures of gD bound to receptor indicate that the C terminus of the gD ectodomain must be displaced before receptor can bind to gD, but it is unclear which conformational changes in gD activate membrane fusion. We rationally designed mutations in gD to displace the C terminus and observe if fusion could be activated without receptor binding. Using a cell-based fusion assay, we found that gD V231W induced cell-cell fusion in the absence of receptor. Using recombinant gD V231W protein, we observed binding to conformationally sensitive antibodies or HSV receptor and concluded that there were changes proximal to the receptor binding interface, while the tertiary structure of gD V231W was similar to that of wild-type gD. We used a biosensor to analyze the kinetics of receptor binding and the extent to which the C terminus blocks binding to receptor. We found that the C terminus of gD V231W was enriched in the open or displaced conformation, indicating a mechanism for its function. We conclude that gD V231W triggers fusion through displacement of its C terminus and that this motion is indicative of how gD links receptor binding to exposure of interfaces on gD that activate fusion via gH/gL and gB. PMID- 24049166 TI - Dynamics of viral evolution and neutralizing antibody response after HIV-1 superinfection. AB - Investigating the incidence and prevalence of HIV-1 superinfection is challenging due to the complex dynamics of two infecting strains. The superinfecting strain can replace the initial strain, be transiently expressed, or persist along with the initial strain in distinct or in recombined forms. Various selective pressures influence these alternative scenarios in different HIV-1 coding regions. We hypothesized that the potency of the neutralizing antibody (NAb) response to autologous viruses would modulate viral dynamics in env following superinfection in a limited set of superinfection cases. HIV-1 env pyrosequencing data were generated from blood plasma collected from 7 individuals with evidence of superinfection. Viral variants within each patient were screened for recombination, and viral dynamics were evaluated using nucleotide diversity. NAb responses to autologous viruses were evaluated before and after superinfection. In 4 individuals, the superinfecting strain replaced the original strain. In 2 individuals, both initial and superinfecting strains continued to cocirculate. In the final individual, the surviving lineage was the product of interstrain recombination. NAb responses to autologous viruses that were detected within the first 2 years of HIV-1 infection were weak or absent for 6 of the 7 recently infected individuals at the time of and shortly following superinfection. These 6 individuals had detectable on-going viral replication of distinct superinfecting virus in the env coding region. In the remaining case, there was an early and strong autologous NAb response, which was associated with extensive recombination in env between initial and superinfecting strains. This extensive recombination made superinfection more difficult to identify and may explain why the detection of superinfection has typically been associated with low autologous NAb titers. PMID- 24049168 TI - Epstein-Barr virus and human herpesvirus 6 detection in a non-Hodgkin's diffuse large B-cell lymphoma cohort by using RNA sequencing. AB - Comprehensive virome analysis of RNA sequence (RNA-seq) data sets from 118 non Hodgkin's B-cell lymphomas revealed a small subset that is positive for Epstein Barr virus (EBV) or human herpesvirus 6B (HHV-6B), with one coinfection. EBV transcriptome analysis revealed expression of the latency genes RPMS1, LMP1, and LMP2, with one sample additionally showing a high level of early lytic expression and another sample showing a high level of EBNA2 expression. HHV-6B transcriptome analysis revealed that the majority of genes were transcribed. PMID- 24049170 TI - The human interferon-induced MxA protein inhibits early stages of influenza A virus infection by retaining the incoming viral genome in the cytoplasm. AB - The induction of an interferon-induced antiviral state is a powerful cellular response against viral infection that limits viral spread. Here, we show that a preexisting antiviral state inhibits the replication of influenza A viruses in human A549 cells by preventing transport of the viral genome to the nucleus and that the interferon-induced MxA protein is necessary but not sufficient for this process. This represents a previously unreported antiviral function of MxA against influenza A virus infection. PMID- 24049167 TI - An HIV-1 replication pathway utilizing reverse transcription products that fail to integrate. AB - Integration is a central event in the replication of retroviruses, yet >= 90% of HIV-1 reverse transcripts fail to integrate, resulting in accumulation of unintegrated viral DNA in cells. However, understanding what role, if any, unintegrated viral DNA plays in the natural history of HIV-1 has remained elusive. Unintegrated HIV-1 DNA is reported to possess a limited capacity for gene expression restricted to early gene products and is considered a replicative dead end. Although the majority of peripheral blood CD4(+) T cells are refractory to infection, nonactivated CD4 T cells present in lymphoid and mucosal tissues are major targets for infection. Treatment with cytokine interleukin-2 (IL-2), IL 4, IL-7, or IL-15 renders CD4(+) T cells permissive to HIV-1 infection in the absence of cell activation and proliferation and provides a useful model for infection of resting CD4(+) T cells. We found that infection of cytokine-treated resting CD4(+) T cells in the presence of raltegravir or with integrase active site mutant HIV-1 yielded de novo virus production following subsequent T cell activation. Infection with integration-competent HIV-1 naturally generated a population of cells generating virus from unintegrated DNA. Latent infection persisted for several weeks and could be activated to virus production by a combination of a histone deacetylase inhibitor and a protein kinase C activator or by T cell activation. HIV-1 Vpr was essential for unintegrated HIV-1 gene expression and de novo virus production in this system. Bypassing integration by this mechanism may allow the preservation of genetic information that otherwise would be lost. PMID- 24049169 TI - A unique and conserved neutralization epitope in H5N1 influenza viruses identified by an antibody against the A/Goose/Guangdong/1/96 hemagglutinin. AB - Despite substantial efforts to control and contain H5N1 influenza viruses, bird flu viruses continue to spread and evolve. Neutralizing antibodies against conserved epitopes on the viral hemagglutinin (HA) could confer immunity to the diverse H5N1 virus strains and provide information for effective vaccine design. Here, we report the characterization of a broadly neutralizing murine monoclonal antibody, H5M9, to most H5N1 clades and subclades that was elicited by immunization with viral HA of A/Goose/Guangdong/1/96 (H5N1), the immediate precursor of the current dominant strains of H5N1 viruses. The crystal structures of the Fab' fragment of H5M9 in complexes with H5 HAs of A/Vietnam/1203/2004 and A/Goose/Guangdong/1/96 reveal a conserved epitope in the HA1 vestigial esterase subdomain that is some distance from the receptor binding site and partially overlaps antigenic site C of H3 HA. Further epitope characterization by selection of escape mutants and epitope mapping by flow cytometry analysis of site-directed mutagenesis of HA with a yeast cell surface display identified four residues that are critical for H5M9 binding. D53, Y274, E83a, and N276 are all conserved in H5N1 HAs and are not in H5 epitopes identified by other mouse or human antibodies. Antibody H5M9 is effective in protection of H5N1 virus both prophylactically and therapeutically and appears to neutralize by blocking both virus receptor binding and postattachment steps. Thus, the H5M9 epitope identified here should provide valuable insights into H5N1 vaccine design and improvement, as well as antibody-based therapies for treatment of H5N1 infection. PMID- 24049171 TI - Aged mice exhibit a severely diminished CD8 T cell response following respiratory syncytial virus infection. AB - Respiratory virus infections in the elderly result in increased rates of hospitalization and death. Respiratory syncytial virus (RSV) is a leading cause of severe virus-induced respiratory disease in individuals over the age of 65. CD8 T cells play a critical role in mediating RSV clearance. While it is clear that T cell immunity declines with age, it is not clear to what extent the CD8 T cell response to RSV is altered. Using aged BALB/c mice, we demonstrated that RSV specific CD8 T cell responses were significantly reduced in the lungs of aged mice at the peak of the T cell response and that this decrease correlated with delayed viral clearance. Despite a decrease in the overall numbers of RSV specific CD8 T cells during acute infection, their capacity to produce effector cytokines was not impaired. Following viral clearance, the RSV-specific memory CD8 T cells were similar in total number and phenotype in young and aged mice. Furthermore, following infection with a heterologous pathogen expressing an RSV epitope, RSV-specific memory CD8 T cells exhibited similar activation and ability to provide early control of the infection in young and aged mice. These data demonstrate a decrease in the capacity of aged mice to induce a high-magnitude acute CD8 T cell response, leading to prolonged viral replication, which may contribute to the increased disease severity of RSV infection observed for aged individuals. PMID- 24049172 TI - Retrovirus glycoprotein functionality requires proper alignment of the ectodomain and the membrane-proximal cytoplasmic tail. AB - Nonnative viral glycoproteins, including Friend murine leukemia virus envelope (F MLV Env) are actively recruited to HIV-1 assembly sites by an unknown mechanism. Because interactions with the lipid microenvironment at budding sites could contribute to recruitment, we examined the contribution of the hydrophobicity of the F-MLV Env membrane-spanning domain (MSD) to its incorporation into HIV-1 particles. A series of F-MLV Env mutants that added or deleted one, two, or three leucines in the MSD were constructed. All six mutants retained the ability to be incorporated into HIV-1 particles, but the -1L, -2L, -3L, +1L, and +2L mutants were not capable of producing infectious particles. Surprisingly, the +3L Env glycoprotein was able to produce infectious particles and was constitutively fusogenic. However, when the cytoplasmic tail domains (CTDs) in the Env constructs were deleted, all six of the MSD mutants were able to produce infectious particles. Further mutational analyses revealed that the first 10 amino acids of the CTD is a critical regulator of infectivity. A similar phenotype was observed in HIV-1 Env upon addition of leucines in the MSD, with +1 and +2 leucine mutations greatly reducing Env activity, but +3 leucine mutations behaving similar to the wild type. Unlike F-MLV Env (+1L and +2L), HIV-1 Env (+1L and +2L) infectivity was not restored by deletion of the CTD. We hypothesize that the CTD forms a coiled-coil that disrupts the protein's functionality if it is not in phase with the trimer interface of the ectodomain. PMID- 24049173 TI - Prohibitin Interacts with envelope proteins of white spot syndrome virus and prevents infection in the red swamp crayfish, Procambarus clarkii. AB - Prohibitins (PHBs) are ubiquitously expressed conserved proteins in eukaryotes that are associated with apoptosis, cancer formation, aging, stress responses, cell proliferation, and immune regulation. However, the function of PHBs in crustacean immunity remains largely unknown. In the present study, we identified a PHB in Procambarus clarkii red swamp crayfish, which was designated PcPHB1. PcPHB1 was widely distributed in several tissues, and its expression was significantly upregulated by white spot syndrome virus (WSSV) challenge at the mRNA level and the protein level. These observations prompted us to investigate the role of PcPHB1 in the crayfish antiviral response. Recombinant PcPHB1 (rPcPHB1) significantly reduced the amount of WSSV in crayfish and the mortality of WSSV-infected crayfish. The quantity of WSSV in PcPHB1 knockdown crayfish was increased compared with that in the controls. The effects of RNA silencing were rescued by rPcPHB1 reinjection. We further confirmed the interaction of PcPHB1 with the WSSV envelope proteins VP28, VP26, and VP24 using pulldown and far Western overlay assays. Finally, we observed that the colloidal gold-labeled PcPHB1 was located on the outer surface of the WSSV, which suggests that PcPHB1 specifically binds to the envelope proteins of WSSV. VP28, VP26, and VP24 are structural envelope proteins and are essential for attachment and entry into crayfish cells. Therefore, PcPHB1 exerts its anti-WSSV effect by binding to VP28, VP26, and VP24, preventing viral infection. This study is the first report on the antiviral function of PHB in the innate immune system of crustaceans. PMID- 24049174 TI - Determining the cellular diversity of hepatitis C virus quasispecies by single cell viral sequencing. AB - Single-cell genomics is emerging as an important tool in cellular biology. We describe for the first time a system to investigate RNA virus quasispecies diversity at the cellular level utilizing hepatitis C virus (HCV) replicons. A high-fidelity nested reverse transcription (RT)-PCR assay was developed, and validation using control transcripts of known copy number indicated a detection limit of 3 copies of viral RNA/reaction. This system was used to determine the cellular diversity of subgenomic JFH-1 HCV replicons constitutively expressed in Huh7 cells. Each cell contained a unique quasispecies that was much less diverse than the quasispecies of the bulk cell population from which the single cells were derived, suggesting the occurrence of independent evolution at the cellular level. An assessment of the replicative fitness of the predominant single-cell quasispecies variants indicated a modest reduction in fitness compared to the wild type. Real-time RT-PCR methods capable of determining single-cell viral loads were developed and indicated an average of 113 copies of replicon RNA per cell, correlating with calculated RNA copy numbers in the bulk cell population. This study introduces a single-cell RNA viral-sequencing method with numerous potential applications to explore host-virus interactions during infection. HCV quasispecies diversity varied greatly between cells in vitro, suggesting different within-cell evolutionary pathways. Such divergent trajectories in vivo could have implications for the evolution and establishment of antiviral resistant variants and host immune escape mutants. PMID- 24049175 TI - The protein interaction network of bacteriophage lambda with its host, Escherichia coli. AB - Although most of the 73 open reading frames (ORFs) in bacteriophage lambda have been investigated intensively, the function of many genes in host-phage interactions remains poorly understood. Using yeast two-hybrid screens of all lambda ORFs for interactions with its host Escherichia coli, we determined a raw data set of 631 host-phage interactions resulting in a set of 62 high-confidence interactions after multiple rounds of retesting. These links suggest novel regulatory interactions between the E. coli transcriptional network and lambda proteins. Targeted host proteins and genes required for lambda infection are enriched among highly connected proteins, suggesting that bacteriophages resemble interaction patterns of human viruses. Lambda tail proteins interact with both bacterial fimbrial proteins and E. coli proteins homologous to other phage proteins. Lambda appears to dramatically differ from other phages, such as T7, because of its unusually large number of modified and processed proteins, which reduces the number of host-virus interactions detectable by yeast two-hybrid screens. PMID- 24049176 TI - Identification of alpha interferon-induced envelope mutations of hepatitis C virus in vitro associated with increased viral fitness and interferon resistance. AB - Alpha interferon (IFN-alpha) is an essential component of innate antiviral immunity and of treatment regimens for chronic hepatitis C virus (HCV) infection. Resistance to IFN might be important for HCV persistence and failure of IFN-based therapies. Evidence for HCV genetic correlates of IFN resistance is limited. Experimental studies were hampered by lack of HCV culture systems. Using genotype (strain) 1a(H77) and 3a(S52) Core-NS2 JFH1-based recombinants, we aimed at identifying viral correlates of IFN-alpha resistance in vitro. Long-term culture with IFN-alpha2b in Huh7.5 cells resulted in viral spread with acquisition of putative escape mutations in HCV structural and nonstructural proteins. Reverse genetic studies showed that primarily amino acid changes I348T in 1a(H77) E1 and F345V/V414A in 3a(S52) E1/E2 increased viral fitness. Single-cycle assays revealed that I348T and F345V/V414A enhanced viral entry and release, respectively. In assays allowing viral spread, these mutations conferred a level of IFN-alpha resistance exceeding the observed fitness effect. The identified mutations acted in a subtype-specific manner but were not found in genotype 1a and 3a patients, who failed IFN-alpha therapy. Studies with HCV recombinants with different degrees of culture adaptation confirmed the correlation between viral fitness and IFN-alpha resistance. In conclusion, in vitro escape experiments led to identification of HCV envelope mutations resulting in increased viral fitness and conferring IFN-alpha resistance. While we established a close link between viral fitness and IFN-alpha resistance, identified mutations acted via different mechanisms and appeared to be relatively specific to the infecting virus, possibly explaining difficulties in identifying signature mutations for IFN resistance. PMID- 24049177 TI - Human parvovirus B19 infection causes cell cycle arrest of human erythroid progenitors at late S phase that favors viral DNA replication. AB - Human parvovirus B19 (B19V) infection has a unique tropism to human erythroid progenitor cells (EPCs) in human bone marrow and the fetal liver. It has been reported that both B19V infection and expression of the large nonstructural protein NS1 arrested EPCs at a cell cycle status with a 4 N DNA content, which was previously claimed to be "G2/M arrest." However, a B19V mutant infectious DNA (M20(mTAD2)) replicated well in B19V-semipermissive UT7/Epo-S1 cells but did not induce G2/M arrest (S. Lou, Y. Luo, F. Cheng, Q. Huang, W. Shen, S. Kleiboeker, J. F. Tisdale, Z. Liu, and J. Qiu, J. Virol. 86:10748-10758, 2012). To further characterize cell cycle arrest during B19V infection of EPCs, we analyzed the cell cycle change using 5-bromo-2'-deoxyuridine (BrdU) pulse-labeling and DAPI (4',6-diamidino-2-phenylindole) staining, which precisely establishes the cell cycle pattern based on both cellular DNA replication and nuclear DNA content. We found that although both B19V NS1 transduction and infection immediately arrested cells at a status of 4 N DNA content, B19V-infected 4 N cells still incorporated BrdU, indicating active DNA synthesis. Notably, the BrdU incorporation was caused neither by viral DNA replication nor by cellular DNA repair that could be initiated by B19V infection-induced cellular DNA damage. Moreover, several S phase regulators were abundantly expressed and colocalized within the B19V replication centers. More importantly, replication of the B19V wild-type infectious DNA, as well as the M20(mTAD2) mutant, arrested cells at S phase. Taken together, our results confirmed that B19V infection triggers late S phase arrest, which presumably provides cellular S phase factors for viral DNA replication. PMID- 24049178 TI - Highly divergent type 2 and 3 vaccine-derived polioviruses isolated from sewage in Tallinn, Estonia. AB - Highly divergent vaccine-derived polioviruses (VDPVs) have been isolated from sewage in Tallinn, Estonia, since 2002. Sequence analysis of VDPVs of serotypes 2 and 3 showed that they shared common noncapsid region recombination sites, indicating origination from a single trivalent oral polio vaccine dose, estimated to have been given between 1986 and 1998. The sewage isolates closely resemble VDPVs chronically excreted by persons with common variable immunodeficiency, but no chronic excretors have yet been identified in Estonia. PMID- 24049179 TI - Herpes simplex virus 1 serine/threonine kinase US3 hyperphosphorylates IRF3 and inhibits beta interferon production. AB - Viral infection initiates a series of signaling cascades that lead to the transcription of interferons (IFNs), finally inducing interferon-stimulated genes (ISGs) to eliminate viruses. Viruses have evolved a variety of strategies to modulate host IFN-mediated immune responses. Herpes simplex virus 1 (HSV-1) US3, a Ser/Thr kinase conserved in alphaherpesviruses, was previously reported to counteract host innate immunity; however, the molecular mechanism is elusive. In this study, we report that US3 blocks IFN-beta production by hyperphosphorylating IFN regulatory factor 3 (IRF3). Ectopic expression of US3 protein significantly inhibited Sendai virus (SeV)-mediated activation of IFN-beta and IFN-stimulated response element (ISRE) promoters and the transcription of IFN-beta, ISG54, and ISG56. US3 was also shown to block SeV-induced dimerization and nuclear translocation of IRF3. The kinase activity was indispensable for its inhibitory function, as kinase-dead (KD) US3 mutants K220M and D305A could not inhibit IFN beta production. Furthermore, US3 interacted with and hyperphosphorylated IRF3 at Ser175 to prevent IRF3 activation. Finally, the US3 KD mutant viruses were constructed and denoted K220M or D305A HSV-1, respectively. Cells and mice infected with both mutant viruses produced remarkably larger amounts of IFN-beta than those infected with wild-type HSV-1. For the first time, these findings provide convincing evidence that US3 hyperphosphorylates IRF3, blocks the production of IFN-beta, and subverts host innate immunity. PMID- 24049180 TI - PC61 (anti-CD25) treatment inhibits influenza A virus-expanded regulatory T cells and severe lung pathology during a subsequent heterologous lymphocytic choriomeningitis virus infection. AB - Prior immunity to influenza A virus (IAV) in mice changes the outcome to a subsequent lymphocytic choriomeningitis virus (LCMV) infection and can result in severe lung pathology, similar to that observed in patients that died of the 1918 H1N1 pandemic. This pathology is induced by IAV-specific memory CD8(+) T cells cross-reactive with LCMV. Here, we discovered that IAV-immune mice have enhanced CD4(+) Foxp3(+) T-regulatory (Treg) cells in their lungs, leading us to question whether a modulation in the normal balance of Treg and effector T-cell responses also contributes to enhancing lung pathology upon LCMV infection of IAV-immune mice. Treg cell and interleukin-10 (IL-10) levels remained elevated in the lungs and mediastinal lymph nodes (mLNs) throughout the acute LCMV response of IAV immune mice. PC61 treatment, used to decrease Treg cell levels, did not change LCMV titers but resulted in a surprising decrease in lung pathology upon LCMV infection in IAV-immune but not in naive mice. Associated with this decrease in pathology was a retention of Treg in the mLN and an unexpected partial clonal exhaustion of LCMV-specific CD8(+) T-cell responses only in IAV-immune mice. PC61 treatment did not affect cross-reactive memory CD8(+) T-cell proliferation. These results suggest that in the absence of IAV-expanded Treg cells and in the presence of cross-reactive memory, the LCMV-specific response was overstimulated and became partially exhausted, resulting in a decreased effector response. These studies suggest that Treg cells generated during past infections can influence the characteristics of effector T-cell responses and immunopathology during subsequent heterologous infections. Thus, in humans with complex infection histories, PC61 treatment may lead to unexpected results. PMID- 24049181 TI - Zinc-dependent interaction between JAB1 and pre-S2 mutant large surface antigen of hepatitis B virus and its implications for viral hepatocarcinogenesis. AB - Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) worldwide. The pre-S2 mutant large HBV surface protein (Delta2 LHBS), which contains an in-frame deletion of approximately 17 amino acids in LHBS, is highly associated with risks and prognoses of HBV-induced HCC. It was previously reported that Delta2 LHBS interacts with the Jun activation domain binding protein 1 (JAB1), a zinc metalloprotease. This promotes the degradation of the cell cycle regulator p27(Kip1) and is believed to be the major mechanism for Delta2 LHBS-induced HCC. In this study, it was found that the interaction between JAB1 and Delta2 LHBS is facilitated by divalent metal Zn(2+) ions. The binding of JAB1 to Delta2 LHBS requires the JAB1/CSN5 MPN metalloenzyme (JAMM) motif and residue H138 that binds to Zn(2+) ions in JAB1. Isothermal titration calorimetry showed that Delta2 LHBS binds directly to Zn(2+) ions in a two-site binding mode. Residues H71 and H116 in Delta2 LHBS, which also contact Zn(2+) ions, are also indispensable for Delta2 LHBS-mediated p27(Kip1) degradation in human HuH7 cells. These results suggest that developing drugs that interrupt interactions between Delta2 LHBS and JAB1 can be used to mitigate Delta2 LHBS associated risks for HCC. PMID- 24049183 TI - Yellow fever vaccination elicits broad functional CD4+ T cell responses that recognize structural and nonstructural proteins. AB - Yellow fever virus (YFV) can induce acute, life-threatening disease that is a significant health burden in areas where yellow fever is endemic, but it is preventable through vaccination. The live attenuated 17D YFV strain induces responses characterized by neutralizing antibodies and strong T cell responses. This vaccine provides an excellent model for studying human immunity. While several studies have characterized YFV-specific antibody and CD8(+) T cell responses, less is known about YFV-specific CD4(+) T cells. Here we characterize the epitope specificity, functional attributes, and dynamics of YFV-specific T cell responses in vaccinated subjects by investigating peripheral blood mononuclear cells by using HLA-DR tetramers. A total of 112 epitopes restricted by seven common HLA-DRB1 alleles were identified. Epitopes were present within all YFV proteins, but the capsid, envelope, NS2a, and NS3 proteins had the highest epitope density. Antibody blocking demonstrated that the majority of YFV specific T cells were HLA-DR restricted. Therefore, CD4(+) T cell responses could be effectively characterized with HLA-DR tetramers. Ex vivo tetramer analysis revealed that YFV-specific T cells persisted at frequencies ranging from 0 to 100 cells per million that are detectable years after vaccination. Longitudinal analysis indicated that YFV-specific CD4(+) T cells reached peak frequencies, often exceeding 250 cells per million, approximately 2 weeks after vaccination. As frequencies subsequently declined, YFV-specific cells regained CCR7 expression, indicating a shift from effector to central memory. Cells were typically CXCR3 positive, suggesting Th1 polarization, and produced gamma interferon and other cytokines after reactivation in vitro. Therefore, YFV elicits robust early effector CD4(+) T cell responses that contract, forming a detectable memory population. PMID- 24049182 TI - Crystal structure of Venezuelan hemorrhagic fever virus fusion glycoprotein reveals a class 1 postfusion architecture with extensive glycosylation. AB - Guanarito virus (GTOV) is an emergent and deadly pathogen. We present the crystal structure of the glycosylated GTOV fusion glycoprotein to 4.1-A resolution in the postfusion conformation. Our structure reveals a classical six-helix bundle and presents direct verification that New World arenaviruses exhibit class I viral membrane fusion machinery. The structure provides visualization of an N-linked glycocalyx coat, and consideration of glycan dynamics reveals extensive coverage of the underlying protein surface, following virus-host membrane fusion. PMID- 24049184 TI - West Nile virus genome with glycosylated envelope protein and deletion of alpha helices 1, 2, and 4 in the capsid protein is noninfectious and efficiently secretes subviral particles. AB - Flavivirus genomes with deletions in the capsid (C) gene are attractive vaccine candidates, as they secrete highly immunogenic subviral particles (SVPs) without generating infectious virus. Here, we report that cytomegalovirus promoter-driven cDNA of West Nile virus Kunjin (KUNV) containing a glycosylation motif in the envelope (E) gene and a combined deletion of alpha helices 1, 2, and 4 in C produces significantly more SVPs than KUNV cDNAs with nonglycosylated E and various other deletions in C. PMID- 24049185 TI - A mouse monoclonal antibody against dengue virus type 1 Mochizuki strain targeting envelope protein domain II and displaying strongly neutralizing but not enhancing activity. AB - Dengue fever and its more severe form, dengue hemorrhagic fever, are major global concerns. Infection-enhancing antibodies are major factors hypothetically contributing to increased disease severity. In this study, we generated 26 monoclonal antibodies (MAbs) against the dengue virus type 1 Mochizuki strain. We selected this strain because a relatively large number of unique and rare amino acids were found on its envelope protein. Although most MAbs showing neutralizing activities exhibited enhancing activities at subneutralizing doses, one MAb (D1 IV-7F4 [7F4]) displayed neutralizing activities without showing enhancing activities at lower concentrations. In contrast, another MAb (D1-V-3H12 [3H12]) exhibited only enhancing activities, which were suppressed by pretreatment of cells with anti-FcgammaRIIa. Although antibody engineering revealed that antibody subclass significantly affected 7F4 (IgG3) and 3H12 (IgG1) activities, neutralizing/enhancing activities were also dependent on the epitope targeted by the antibody. 7F4 recognized an epitope on the envelope protein containing E118 (domain II) and had a neutralizing activity 10- to 1,000-fold stronger than the neutralizing activity of previously reported human or humanized neutralizing MAbs targeting domain I and/or domain II. An epitope-blocking enzyme-linked immunosorbent assay (ELISA) indicated that a dengue virus-immune population possessed antibodies sharing an epitope with 7F4. Our results demonstrating induction of these antibody species (7F4 and 3H12) in Mochizuki-immunized mice may have implications for dengue vaccine strategies designed to minimize induction of enhancing antibodies in vaccinated humans. PMID- 24049188 TI - Understanding cognitive deficits in Parkinson's disease: lessons from preclinical animal models. AB - Parkinson's disease (PD) has been, until recently, mainly defined by the presence of characteristic motor symptoms, such as rigidity, tremor, bradykinesia/akinesia, and postural instability. Accordingly, pharmacological and surgical treatments have so far addressed these motor disturbances, leaving nonmotor, cognitive deficits an unmet clinical condition. At the preclinical level, the large majority of studies aiming at defining mechanisms and testing novel therapies have similarly focused on the motor aspects of PD. Unfortunately, deterioration of the executive functions, such as attention, recognition, working memory, and problem solving, often appear in an early, premotor phase of the disease and progressively increase in intensity, negatively affecting the quality of life of ~50%-60% of PD patients. At present, the cellular mechanisms underlying cognitive impairments in PD patients are largely unknown and an adequate treatment is still missing. The preclinical research has recently developed new animal models that may open new perspectives for a more integrated approach to the treatment of both motor and cognitive symptoms of the disease. This review will provide an overview on the cognitive symptoms occurring in early PD patients and then focus on the rodent and nonhuman primate models so far available for the study of discriminative and spatial memory attention and learning abilities related to this pathological condition. PMID- 24049186 TI - Bromo- and extraterminal domain chromatin regulators serve as cofactors for murine leukemia virus integration. AB - Retroviral integrase (IN) proteins catalyze the permanent integration of proviral genomes into host DNA with the help of cellular cofactors. Lens epithelium derived growth factor (LEDGF) is a cofactor for lentiviruses, including human immunodeficiency virus type 1 (HIV-1), and targets lentiviral integration toward active transcription units in the host genome. In contrast to lentiviruses, murine leukemia virus (MLV), a gammaretrovirus, tends to integrate near transcription start sites. Here, we show that the bromodomain and extraterminal domain (BET) proteins BRD2, BRD3, and BRD4 interact with gammaretroviral INs and stimulate the catalytic activity of MLV IN in vitro. We mapped the interaction site to a characteristic structural feature within the BET protein extraterminal (ET) domain and to three amino acids in MLV IN. The ET domains of different BET proteins stimulate MLV integration in vitro and, in the case of BRD2, also in vivo. Furthermore, two small-molecule BET inhibitors, JQ1 and I-BET, decrease MLV integration and shift it away from transcription start sites. Our data suggest that BET proteins might act as chromatin-bound acceptors for the MLV preintegration complex. These results could pave a way to redirecting MLV DNA integration as a basis for creating safer retroviral vectors. PMID- 24049189 TI - Population structure influences sexual conflict in wild populations of water striders. AB - In sexual conflict, aggressive males frequently diminish the long-term reproductive success of females in efforts to gain a short-term advantage over rival males. This short-term advantage can selectively favour high-exploitation males. However, just as the over-exploitation of resources can lead to local extinction, the over-exploitation of females in the form of harassment by aggressive males can yield similar consequences resulting in reduced female fecundity, increased female mortality and overall decline in mating activity. This outcome may often be prevented by selection acting at multiple levels of biological organization. Directional selection favouring aggressive exploitation within groups can be balanced by directional selection amongst groups opposing exploitation. Such between-group selection has recently been demonstrated in laboratory studies of water striders, where the conditional dispersal of individuals increased variation amongst groups and influenced the balance of selection toward reduced male aggression. This multilevel selection (MLS) framework also provides predictive value when investigating natural populations differing in their relative strength of selection within versus among groups. For water striders, the consequences of local exploitation cause fitness differences between groups, favouring less aggressive males. Inconsistently flowing ephemeral streams consist of isolated pools that prevent aggressive male water striders from escaping the consequences of local exploitation. We, therefore, predicted that inconsistently flowing ephemeral streams would favour the evolution of less aggressive males than would perennial streams, which allow aggressive males to move more freely and to escape the group-level costs of their aggression. Comparing two neighbouring streams during the mating season, we found that males dispersed naturally between pools at much higher rates in the perennial stream than in the ephemeral stream. As predicted, we found that males from the perennial stream were significantly more aggressive than those from the ephemeral stream. We also found that dispersers were significantly more aggressive than non dispersers within each stream. These field results illustrate the relevance of the MLS framework in our understanding of the evolution of sexual conflict. PMID- 24049190 TI - The Neurobiology of Attachment to Nurturing and Abusive Caregivers. AB - Decades of research have shown that childhood experiences interact with our genetics to change the structure and function of the brain. Within the range of normal experiences, this system enables the brain to be modified during development to adapt to various environments and cultures. Experiences with and attachment to the caregiver appear particularly important, and recent research suggests this may be due, in part, to the attachment circuitry within the brain. Children have brain circuitry to ensure attachment to their caregivers. Attachment depends on the offspring learning about the caregiver in a process that begins prenatally and continues through most of early life. This attachment serves two basic functions. First, attachment ensures the infant remain in the proximity of the caregiver to procure resources for survival and protection. Second, attachment "quality programs" the brain. This programming impacts immediate behaviors, as well as behaviors that emerge later in development. Animal research has uncovered segments of the attachment circuitry within the brain and has highlighted rapid, robust learning to support this attachment. A child attaches to the caregiver regardless of the quality of care received, even if the caregiver is abusive and neglectful. While a neural system that ensures attachment regardless of the quality of care has immediate benefits, this attachment comes with a high cost. Traumatic experiences interact with genetics to change the structure and function of the brain, compromising emotional and cognitive development and initiating a pathway to pathology. Neurobiological research on animals suggests that trauma during attachment is processed differently by the brain, with maternal presence dramatically attenuating the fear center of the brain (amygdala). Thus, the immaturity of the brain combined with the unique processing of trauma may underlie the enduring effects of abuse, which remain largely hidden in early life but emerge as mental health issues in periadolescence. PMID- 24049191 TI - Regularized Fully 5D Reconstruction of Cardiac Gated Dynamic SPECT Images. AB - In our recent work, we proposed an image reconstruction procedure aimed to unify gated imaging and dynamic imaging in nuclear cardiac imaging. With this procedure the goal is to obtain an image sequence from a single acquisition which shows simultaneously both cardiac motion and tracer distribution change over the course of imaging. In this work, we further develop and demonstrate this procedure for fully 5D (3D space plus time plus gate) reconstruction in gated, dynamic cardiac SPECT imaging, where the challenge is even greater without the use of multiple fast camera rotations. For 5D reconstruction, we develop and compare two iterative algorithms: one is based on the modified block sequential regularized EM (BSREM-II) algorithm, and the other is based on the one-step late (OSL) algorithm. In our experiments, we simulated gated cardiac imaging with the NURBS based cardiac-torso (NCAT) phantom and Tc99m-Teboroxime as the imaging agent, where acquisition with the equivalent of only three full camera rotations was used during the course of a 12-minute postinjection period. We conducted a thorough evaluation of the reconstruction results using a number of quantitative measures. Our results demonstrate that the 5D reconstruction procedure can yield gated dynamic images which show quantitative information for both perfusion defect detection and cardiac motion. PMID- 24049193 TI - Yoga and neurobehavioral sciences: Indian perspective. PMID- 24049192 TI - Yoga and mental health: Promising road ahead, but proceed with caution. PMID- 24049187 TI - Possible contributions of a novel form of synaptic plasticity in Aplysia to reward, memory, and their dysfunctions in mammalian brain. AB - Recent studies in Aplysia have identified a new variation of synaptic plasticity in which modulatory transmitters enhance spontaneous release of glutamate, which then acts on postsynaptic receptors to recruit mechanisms of intermediate- and long-term plasticity. In this review I suggest the hypothesis that similar plasticity occurs in mammals, where it may contribute to reward, memory, and their dysfunctions in several psychiatric disorders. In Aplysia, spontaneous release is enhanced by activation of presynaptic serotonin receptors, but presynaptic D1 dopamine receptors or nicotinic acetylcholine receptors could play a similar role in mammals. Those receptors enhance spontaneous release of glutamate in hippocampus, entorhinal cortex, prefrontal cortex, ventral tegmental area, and nucleus accumbens. In all of those brain areas, glutamate can activate postsynaptic receptors to elevate Ca(2+) and engage mechanisms of early-phase long-term potentiation (LTP), including AMPA receptor insertion, and of late phase LTP, including protein synthesis and growth. Thus, presynaptic receptors and spontaneous release may contribute to postsynaptic mechanisms of plasticity in brain regions involved in reward and memory, and could play roles in disorders that affect plasticity in those regions, including addiction, Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder (ADHD). PMID- 24049195 TI - Integrated Yoga Therapy for mental Illness. PMID- 24049194 TI - Yoga for psychiatry and mental health: an ancient practice with modern relevance. PMID- 24049196 TI - Yogic intervention for mental disorders. PMID- 24049197 TI - Designing, validation and feasibility of a yoga-based intervention for elderly. AB - CONTEXT: Ageing is an unavoidable facet of life. Yogic practices have been reported to promote healthy aging. Previous studies have used either yoga therapy interventions derived from a particular school of yoga or have tested specific yogic practices like meditation. AIMS: This study reports the development, validation and feasibility of a yoga-based intervention for elderly with or without mild cognitive impairment. SETTINGS AND DESIGN: The study was conducted at the Advanced Centre for Yoga, National Institute for Mental Health and Neurosciences, Bangalore. The module was developed, validated, and then pilot tested on volunteers. MATERIALS AND METHODS: The first part of the study consisted of designing of a yoga module based on traditional and contemporary yogic literature. This yoga module along with the three case vignettes of elderly with cognitive impairment were sent to 10 yoga experts to help develop the intended yoga-based intervention. In the second part, the feasibility of the developed yoga-based intervention was tested. RESULTS: Experts (n=10) opined the yoga-based intervention will be useful in improving cognition in elderly, but with some modifications. Frequent supervised yoga sessions, regular follow-ups, addition/deletion/modifications of yoga postures were some of the suggestions. Ten elderly consented and eight completed the pilot testing of the intervention. All of them were able to perform most of the Suksmavyayama, Pranayama and Nadanusandhana (meditation) technique without difficulty. Some of the participants (n=3) experienced difficulty in performing postures seated on the ground. Most of the older adults experienced difficulty in remembering and completing entire sequence of yoga-based intervention independently. CONCLUSIONS: The yoga based intervention is feasible in the elderly with cognitive impairment. Testing with a larger sample of older adults is warranted. PMID- 24049198 TI - Development and feasibility of yoga therapy module for out-patients with depression in India. AB - CONTEXT: Evidence suggests that certain yoga practices are useful in the management of depression. To the best of our knowledge, there has been no study that deals with the formulation of a yoga module for the particular clinical features of depression. AIM: The main aim of our study was to develop a comprehensive yoga therapy module targeting specific clinical features of depression. SETTINGS AND DESIGN: Specific yoga practices were matched for clinical features of depression based on a thorough literature review. A yoga program was developed, which consisted of Suksmavyayama, (loosening exercises), asanas (postures), relaxation techniques, Pranayama (breathing exercises) and chanting meditation to be taught in a 2 week period. MATERIALS AND METHODS: A structured questionnaire was developed for validation from nine experienced yoga professionals. The final version of yoga therapy module was pilot-tested on seven patients (five females) with depression recruited from outpatient service of National Institute of Mental Health and Neuro Sciences, Bangalore. RESULTS: The final yoga therapy module had those practices that received a score of three or more (moderately/very much/extremely useful) from all responders. Six out of nine (>65%) experts suggested Suksmavyayama should be included. Five out of nine experts opined that training with 10 sessions (over 2 weeks) is rather short. All experts opined that the module is easy to teach, learn and practice. At the pilot stage, the five patients who completed the module reported more than 80% satisfaction about the yoga practices and how the yoga was taught. Severity of depression substantially reduced at both 1 and 3 months follow-up. CONCLUSION: The developed comprehensive yoga therapy module was validated by experts in the field and was found to be feasible and useful in patients with depression. PMID- 24049199 TI - Randomized clinical trial of yoga-based intervention in residents from elderly homes: Effects on cognitive function. AB - CONTEXT: Elderly have increased risk for cognitive impairment and dementia. Yoga therapy may be helpful in elderly to improve cognitive function. AIMS: We examined the benefits of yoga-based intervention compared with waitlist control group on cognitive function in the residents of elderly homes. SETTINGS AND DESIGN: Single blind controlled study with block randomization of elderly homes. MATERIALS AND METHODS: Study sample included yoga group (n=62) and waitlist group (n=58). A total of 87 subjects (yoga=44, waitlist=43) completed the study period of 6 months. Yoga group received daily yoga sessions for 1 month, weekly until 3(rd) month and encouraged to continue unsupervised until 6 months. They were assessed on Rey's Auditory Verbal Learning Test (RAVLT), Rey's complex figure test (CFT), Wechsler's Memory Scale (WMS)-digit and spatial span, Controlled Oral Word Association (COWA) test, Stroop Color Word Interference Test and Trail Making Test A and B at baseline and at the end of 6(th) month. STATISTICAL ANALYSIS: Paired t-test and analysis of covariance (ANCOVA) to compare the difference in neuropsychological test scores. RESULTS: Yoga group showed significant improvement in immediate and delayed recall of verbal (RAVLT) and visual memory (CFT), attention and working memory (WMS-spatial span), verbal fluency (COWA), executive function (Stroop interference) and processing speed (Trail Making Test-A) than waitlist group at the end of 6 months after correcting for corresponding baseline score and education. CONCLUSION: Yoga based intervention appears beneficial to improve several domains of cognitive function in elderly living in residential care homes. Study findings need to be interpreted after considering methodological limitations like lack of active comparison group. PMID- 24049200 TI - Effects of yoga intervention on sleep and quality-of-life in elderly: A randomized controlled trial. AB - CONTEXT: Yoga as a life-style practice has demonstrated beneficial effects. The role of yoga in the elderly for such benefits merits investigation. AIMS: The aim of this study is to examine the effects of yoga intervention on quality-of-life (QOL) and sleep quality in the elderly living in old age homes. SETTINGS AND DESIGN: Single blind controlled study with block randomization of elderly homes. MATERIALS AND METHODS: A total of 120 subjects from nine elderly homes were randomized in to yoga group (n=62) and waitlist group (n=58). Subjects in the yoga group were given yoga intervention daily for 1 month and weekly until 3 months and were encouraged to practice yoga without supervision until for 6 months. Subjects in waitlist group received no intervention during this period. Subjects were evaluated with World Health Organization Quality of Life (WHOQOL) BREF for measuring QOL and Pittsburgh Sleep Quality Index for sleep quality in the baseline and after 6 months. STATISTICAL ANALYSIS: Independent t-test and repeated measures analysis of covariance respectively was used to measure the difference in outcome measures between the two groups at baseline and after the study period. RESULTS: Subjects in the yoga group had significantly higher number of years of formal education. Subjects in the yoga group had significant improvement in all the domains of QOL and total sleep quality after controlling for the effect of baseline difference in education between the two groups. CONCLUSION: Yoga intervention appears to improve the QOL and sleep quality of elderly living in old age homes. There is a need for further studies overcoming the limitations in this study to confirm the benefits of yoga for elderly in QOL and sleep quality. PMID- 24049201 TI - Positive antidepressant effects of generic yoga in depressive out-patients: A comparative study. AB - CONTEXT: Therapeutic effects in depression of yoga adopted from different schools have been demonstrated. The efficacy of a generic module of yoga on depressed patients has not yet been tested in the literature. AIMS: The study was aimed to compare the therapeutic effect of a generic yoga module with antidepressant drugs in non-suicidal out-patients of major depression attending a psychiatric hospital. SETTINGS AND DESIGN: The study was outpatient-based using an open labeled design. MATERIALS AND METHODS: A total of 137 out-patients of depressive disorders received one of the three treatments as they chose - yoga-only, drugs only or both. The yoga was taught by a trained yoga physician for over a month in spaced sessions totaling at least 12. Patients were assessed before treatment, after 1 and 3 months on depression and Clinical Global Impression Scales. Out of 137, 58 patients completed the study period with all assessments. RESULTS: Patients in the three arms of treatment were comparable on demographic and clinical variables. Patients in all three arms of treatment obtained a reduction in depression scores as well as clinical severity. However, both yoga groups (with or without drugs) were significantly better than the drugs-only group. Higher proportion of patients remitted in the yoga groups compared with the drugs only group. No untoward events were spontaneously reported in the yoga-treated patients. CONCLUSION: Within the limitations of this study, it can be concluded that the findings support a case for prescribing yoga as taught in the study in depressive non-suicidal out-patients. PMID- 24049202 TI - Efficacy of yoga as an add-on treatment for in-patients with functional psychotic disorder. AB - CONTEXT: The efficacy of yoga as an intervention for in-patients with psychosis is as yet unknown; although, previous studies have shown efficacy in stabilized out-patients with schizophrenia. AIM: This study aimed to compare the effect of add-on yoga therapy or physical exercise along with standard pharmacotherapy in the treatment of in-patients with psychosis. SETTINGS AND DESIGN: This study was performed in an in-patient setting using a randomized controlled single blind design. MATERIALS AND METHODS: A total of 88 consenting in-patients with psychosis were randomized into yoga therapy group (n=44) and physical exercise group (n=44). Sixty patients completed the study period of 11/2 months. Patients who completed in the yoga group (n=35) and in the exercise group (n=25) were similar on the demographic profile, illness parameters and psychopathology scores at baseline. RESULTS: The two treatment groups were not different on the clinical syndrome scores at the end of 2 weeks. At the end of 6 weeks, patients in the yoga group however had lower mean scores on Clinical Global Impression Severity (CGIS), Positive and Negative Syndrome Scale (total and general psychopathology subscale) and Hamilton Depression Rating Scale (HDRS) (P<0.05). Repeated measure analysis of variance detected an advantage for yoga over exercise in reducing the clinical CGIS and HDRS scores. CONCLUSION: Adding yoga intervention to standard pharmacological treatment is feasible and may be beneficial even in the early and acute stage of psychosis. PMID- 24049203 TI - Feasibility and efficacy of yoga as an add-on intervention in attention deficit hyperactivity disorder: An exploratory study. AB - CONTEXT: Attention deficit-hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders. Stimulant medication is frequently used in management, with significant adverse effects. There is a growing interest in complementary treatments like yoga. AIMS: To study the effects of yoga as a complementary therapy in children with moderate to severe ADHD. SETTINGS AND DESIGN: The study was performed on children (consent was taken from parents) admitted in a child psychiatry unit using an open-label exploratory study. MATERIALS AND METHODS: Children between 5 and 16 years of age diagnosed with ADHD and co-operative for yoga were included. Subjects with other serious psychiatric and medical illnesses were excluded. The participants were given yoga training daily during their in-patient stay. They were rated on Conners' abbreviated rating scale - (CARS), ADHD-rating scale-IV (ADHD - RS IV) and clinical global impression (CGI)-Severity, at the beginning of study, at discharge and subsequently at the end of 1(st), 2(nd) and 3(rd) month by a research associate not involved in yoga instruction. Paired t-test was employed to compare the means of scores between baseline and follow-ups. RESULTS: A total of 9 children (8 males, 1 female) were recruited into the study. All, but one were on medications. An average of 8 yoga training sessions was given to subjects. They were able to learn yoga reasonably well. There was a significant improvement in the ADHD symptoms as assessed on CARS (P-0.014), ADHD-RS IV (P=0.021) and CGI- S scales (P=0.004) at the time of discharge. PMID- 24049204 TI - Effect of yoga therapy on anxiety and depressive symptoms and quality-of-life among caregivers of in-patients with neurological disorders at a tertiary care center in India: A randomized controlled trial. AB - CONTEXT: The concerns of caregivers of patients with neurological disorders have been a felt need for a long time, with many of them experiencing significant psychiatric morbidity. AIMS: This study aimed to find the effect of yoga in reducing anxiety and depression, as well as improving quality-of-life in caregivers of patients with neurological disorders. SETTINGS AND DESIGN: The study was conducted using a randomized controlled design, with yoga intervention and waitlisted controls. METHODOLOGY: SIXTY CONSENTING CAREGIVERS OF INPATIENTS IN NEUROLOGY WARDS WERE RANDOMIZED INTO TWO GROUPS: Yoga and control. Demographic variables except years of education and length of caretaking were comparable in the two groups, as also baseline scores of anxiety, depression and quality-of life. A specific yoga module comprising yogasanas, pranayama, and chanting was taught to the participants in the yoga group by the researcher. At follow-up 43 patients (yoga n=20 and control group n=23) were available. Two-way repeated measures analysis of variance was used to test the change from pre-test to post test scores within and between groups. Analysis of covariance was performed to compare the post-test scores between the groups adjusting for education and length of caretaking. RESULTS: Following one month intervention of yoga therapy, there was a significant (P<0.001) decrease in anxiety and depression scores, as well as improved quality-of-life among the participants in the yoga group as compared with the control group. CONCLUSION: This study highlights the usefulness of a yoga intervention for caregivers of inpatients with neurological problems. The small sample size and lack of blinding were some of the limitations of this study. PMID- 24049205 TI - Yoga and epilepsy: What do patients perceive? AB - CONTEXT: Benefit of yoga therapy in the management of epilepsy is emerging. However, there is no data available about the knowledge, attitude and practice (KAP) of yoga amongst people living with epilepsy (PLWE). AIMS: This study was designed to explore the KAP about yoga among PLWE. SETTINGS AND DESIGN: The study was conducted on 300 PLWE attending the neurology out-patient services of a tertiary care hospital. METHODOLOGY: Three hundred PLWE (male:female=173:127; age: 31.6+/-12.4 years) attending the neurology out-patient services of a neuropsychiatry hospital were administered a pre-tested KAP questionnaire. RESULTS: About 87.4% were on regular anti-epileptic drugs and half (50.3%) on monotherapy. Use of complementary and alternative medicine by the respondents included: Ayurveda (26.7%), yoga (25.6%) and homeopathy (16.3%) or folk medicine (29.1%). Nearly 33.7% of the respondents reported that yoga is beneficial in managing epilepsy. More than half the respondents (54.8%) were willing to practice yoga. Those who practiced yoga opined that regular practice of yoga might reduce dosage of medication (62.8%), their side effects (51.3%) and frequency of seizures (54.5%). Majority of the patients were willing to practice yoga, if yoga services were offered. CONCLUSION: The gaps in KAP identified in this study point to the need for more systematic effort to bring about awareness of yoga in patients with epilepsy. PMID- 24049206 TI - Yoga increases the volume of the hippocampus in elderly subjects. AB - CONTEXT: The neurobiological effect of yoga on the cortical structures in the elderly is as yet unknown. MATERIALS AND METHODS: Seven healthy elderly subjects received yoga intervention as an add-on life-style practice. Magnetic resonance imaging scans were obtained before and 6 months later. Voxel-based-morphometric analyses compared the brains before and after the yoga. RESULTS: Yoga group was found to have increases in hippocampal, but not in occipital gray matter. CONCLUSION: Yoga has potential to reduce neuro-senescence. Small sample size and absence of the control group prevent generalization of the findings limiting its translational value. PMID- 24049207 TI - Low serum brain derived neurotrophic factor in non-suicidal out-patients with depression: Relation to depression scores. AB - CONTEXT: Low brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression. The relation between BDNF and severity of depression has been investigated. AIMS: In this study, we aimed to measured serum BDNF levels in never-treated non-suicidal out-patients with depression and relate this to the severity of depression. SETTINGS AND DESIGN: This study was conducted in an out-patient setting in a tertiary care psychiatric hospital on consenting depressed patients. MATERIALS AND METHODS: Forty three (19 females) antidepressant-naive out-patients with depression, aged between 18 and 55 years and 24 (13 females) age-matched healthy volunteers gave consent for the study. Serum BDNF levels were assayed by using the sandwich enzyme-linked immunosorbent assay method on morning serum samples before starting treatment. These were compared between patients and controls using independent sample t-test. Pearson's correlation coefficient was used to assess the association between baseline BDNF and Hamilton depression rating scale (HDRS). RESULTS: Serum BDNF was significantly lower in patients with depression (mean+/-standard deviation (SD)=18.59+/-4.9 ng/ml) than in healthy volunteers (mean+/-SD=23.6+/-5.6 ng/ml; P=0.001). There was a significant negative correlation between the HDRS total scores and BDNF levels (P=0.04), indicating that more severely depressed patients had lower BDNF scores. CONCLUSIONS: Serum BDNF level is lower in non-suicidal out patients with depression. The inverse correlation between ratings of depression and BDNF levels suggests possible relationship between depression, (role of illness on) BDNF levels and neuroplasticity thereof. PMID- 24049208 TI - Positive therapeutic and neurotropic effects of yoga in depression: A comparative study. AB - CONTEXT: Therapeutic effect of yoga in depression is recognized. Neuroplastic effects of antidepressant therapies are inferred by elevations in brain-derived neurotrophic factor (BDNF). Role of yoga in both these effects has not been studied. MATERIALS AND METHODS: Non-suicidal, consecutive out-patients of depression were offered yoga either alone or with antidepressants. The depression severity was rated on Hamilton Depression Rating Scale (HDRS) before and at 3 months. Serum BDNF levels were measured at the same time points. Repeated measures analysis of variance was performed to look at change across groups with respect to HDRS scores and BDNF levels over 3 months of follow-up. Relationship between change in serum BDNF levels and change in HDRS scores was assessed using the Pearson's correlation coefficient. RESULTS: Both yoga groups were better than drugs-only group with respect to reduction in HDRS scores. Serum BDNF rose in the total sample in the 3-month period. This was not, however, different across treatment groups. There was a significant positive correlation between fall in HDRS and rise in serum BDNF levels in yoga-only group (r=0.702; P=0.001), but not in those receiving yoga and antidepressants or antidepressants-alone. CONCLUSIONS: Neuroplastic mechanisms may be related to the therapeutic mechanisms of yoga in depression. PMID- 24049209 TI - Cortisol and antidepressant effects of yoga. AB - CONTEXT: Hypercortisolemia is well-known in depression and yoga has been demonstrated earlier to reduce the parameters of stress, including cortisol levels. AIM: We aimed to find the role of yoga as an antidepressant as well as its action on lowering the serum cortisol levels. SETTINGS AND DESIGN: An open labeled study consisting of three groups (yoga alone, yoga along with antidepressant medication and antidepressant medication alone) was conducted at a tertiary care psychiatry hospital. METHODOLOGY: Out-patient depressives who were not suicidal were offered yoga as a possible antidepressant therapy. A validated yoga module was used as therapy taught over a month and to be practiced at home daily. Patients were free to choose the drugs if their psychiatrist advised. Patients (n=54) were rated on Hamilton Depression Rating Scale (HDRS) with serum cortisol measurements at baseline and after 3 months. In 54 patients, assessments and blood test results were both available. 19 each received yoga alone or with drugs and 16 received drugs only. Healthy comparison subjects (n=18) too underwent morning cortisol measurements once. RESULTS: Serum cortisol was higher in depressives compared with controls. In the total sample, the cortisol level dropped significantly at the end of treatment. More patients in the yoga groups had a drop in cortisol levels as compared to drug-only group. In the yoga-only group, the cortisol drop correlated with the drop in HDRS score (antidepressant effect). CONCLUSION: The findings support that yoga may act at the level of the hypothalamus by its 'anti-stress' effects (reducing the cortisol), to bring about relief in depression. PMID- 24049210 TI - Effect of yoga therapy on plasma oxytocin and facial emotion recognition deficits in patients of schizophrenia. AB - CONTEXT: Yoga therapy has been demonstrated to be useful in treatment of negative symptoms and improving the socio-occupational functioning and emotion recognition deficits in antipsychotic-stabilized schizophrenia patients. Oxytocin has been recently implicated in social cognition deficits in schizophrenia. The effect of yoga therapy on oxytocin levels in schizophrenia has not been studied. AIMS: This study aimed to assess the effect of yoga therapy on symptoms, socio-occupational functioning, facial emotion recognition deficits and plasma oxytocin levels in antipsychotic stabilized schizophrenia patients. SETTINGS AND DESIGN: Randomized controlled study on 43 consenting, medication stabilized patients with schizophrenia in a tertiary psychiatric center using yoga intervention and waitlisted groups. MATERIALS AND METHODS: A total of 43 schizophrenia patients were randomized to yoga group (n=15) or waitlist group (n=28). Patients in the yoga group received training in a specific yoga therapy module for schizophrenia. Patients in both groups were continued on stable antipsychotic medication. Assessments included scale for assessment of positive symptoms, scale for assessment of negative symptoms, socio-occupational functioning scale and tool for recognition of emotions in neuropsychiatric disorders (TRENDS) and plasma oxytocin levels; performed at baseline and at the end of 1 month. RESULTS: A total of 15 patients in the yoga group and 12 in waitlist group completed the study. The yoga therapy group showed a significant improvement in socio occupational functioning, performance on TRENDS (P<0.001) and plasma increase in oxytocin levels (P=0.01) as compared with the waitlist group. CONCLUSION: The study supported the role of add-on yoga therapy in management of schizophrenia and demonstrated an improvement in endogenous plasma oxytocin levels in schizophrenia patients receiving yoga therapy. PMID- 24049211 TI - A micromorphic model for steel fiber reinforced concrete. AB - A new formulation to model the mechanical behavior of high performance fiber reinforced cement composites with arbitrarily oriented short fibers is presented. The formulation can be considered as a two scale approach, in which the macroscopic model, at the structural level, takes into account the mesostructural phenomenon associated with the fiber-matrix interface bond/slip process. This phenomenon is contemplated by including, in the macroscopic description, a micromorphic field representing the relative fiber-cement displacement. Then, the theoretical framework, from which the governing equations of the problem are derived, can be assimilated to a specific case of the material multifield theory. The balance equation derived for this model, connecting the micro stresses with the micromorphic forces, has a physical meaning related with the fiber-matrix bond slip mechanism. Differently to previous procedures in the literature, addressed to model fiber reinforced composites, where this equation has been added as an additional independent ingredient of the methodology, in the present approach it arises as a natural result derived from the multifield theory. Every component of the composite is defined with a specific free energy and constitutive relation. The mixture theory is adopted to define the overall free energy of the composite, which is assumed to be homogeneously constituted, in the sense that every infinitesimal volume is occupied by all the components in a proportion given by the corresponding volume fraction. The numerical model is assessed by means of a selected set of experiments that prove the viability of the present approach. PMID- 24049212 TI - Children's welfare and short term migration from rural India. AB - Few papers in the literature provide quantitative analysis of the difficult circumstances faced by children of short-term labour migrants. This paper uses new survey data from rural northwest India to study both children who migrate and those left behind. It finds that, unlike in other contexts, children who migrate rarely work when they accompany adult migrants. Additionally, this paper reports a robust, previously unquantified negative relationship between children's migration and educational outcomes and investments. It calls for further research about externalities of migration for children and suggests that expansion of a large public employment program might help these children. PMID- 24049213 TI - Explanation of Two Anomalous Results in Statistical Mediation Analysis. AB - Previous studies of different methods of testing mediation models have consistently found two anomalous results. The first result is elevated Type I error rates for the bias-corrected and accelerated bias-corrected bootstrap tests not found in nonresampling tests or in resampling tests that did not include a bias correction. This is of special concern as the bias-corrected bootstrap is often recommended and used due to its higher statistical power compared with other tests. The second result is statistical power reaching an asymptote far below 1.0 and in some conditions even declining slightly as the size of the relationship between X and M, a, increased. Two computer simulations were conducted to examine these findings in greater detail. Results from the first simulation found that the increased Type I error rates for the bias-corrected and accelerated bias-corrected bootstrap are a function of an interaction between the size of the individual paths making up the mediated effect and the sample size, such that elevated Type I error rates occur when the sample size is small and the effect size of the nonzero path is medium or larger. Results from the second simulation found that stagnation and decreases in statistical power as a function of the effect size of the a path occurred primarily when the path between M and Y, b, was small. Two empirical mediation examples are provided using data from a steroid prevention and health promotion program aimed at high school football players (Athletes Training and Learning to Avoid Steroids; Goldberg et al., 1996), one to illustrate a possible Type I error for the bias-corrected bootstrap test and a second to illustrate a loss in power related to the size of a. Implications of these findings are discussed. PMID- 24049214 TI - Invited Paper: The Rediscovery of Bifactor Measurement Models. AB - Bifactor latent structures were introduced over 70 years ago, but only recently has bifactor modeling been rediscovered as an effective approach to modeling construct-relevant multidimensionality in a set of ordered categorical item responses. I begin by describing the Schmid-Leiman bifactor procedure (Schmid & Leiman, 1957), and highlight its relations with correlated-factors and second order exploratory factor models. After describing limitations of the Schmid Leiman, two newer methods of exploratory bifactor modeling are considered, namely, analytic bifactor (Jennrich & Bentler, 2011) and target bifactor rotations (Reise, Moore, & Maydeu-Olivares, 2011). In section two, I discuss limited and full-information estimation approaches to confirmatory bifactor models that have emerged from the item response theory and factor analysis traditions, respectively. Comparison of the confirmatory bifactor model to alternative nested confirmatory models and establishing parameter invariance for the general factor also are discussed. In the final section, important applications of bifactor models are reviewed. These applications demonstrate that bifactor modeling potentially provides a solid foundation for conceptualizing psychological constructs, constructing measures, and evaluating a measure's psychometric properties. However, some applications of the bifactor model may be limited due to its restrictive assumptions. PMID- 24049215 TI - A Comparison of Factor Score Estimation Methods in the Presence of Missing Data: Reliability and an Application to Nicotine Dependence. AB - Factor score estimation is a controversial topic in psychometrics, and the estimation of factor scores from exploratory factor models has historically received a great deal of attention. However, both confirmatory factor models and the existence of missing data have generally been ignored in this debate. This article presents a simulation study that compares the reliability of sum scores, regression-based and expected posterior methods for factor score estimation for confirmatory factor models in the presence of missing data. Although all methods perform reasonably well with complete data, expected posterior-weighted (full) maximum likelihood methods are significantly more reliable than sum scores and regression estimators in the presence of missing data. Factor score reliability for complete data can be predicted by Guttman's 1955 formula for factor communality. Furthermore, factor score reliability for incomplete data can be reasonably approximated by communality raised to the [Formula: see text] power. An empirical demonstration shows that the full maximum likelihood method best preserves the relationship between nicotine dependence and a genetic predictor under missing data. Implications and recommendations for applied research are discussed. PMID- 24049216 TI - LONGITUDINAL RELATIONSHIPS BETWEEN NEIGHBORING BEHAVIOR AND DEPRESSIVE SYMPTOMS IN HISPANIC OLDER ADULTS IN MIAMI, FLORIDA. AB - This study examines the relationship between neighboring behavior and depressive symptoms across 3 years in a prospective study of 273 community-dwelling, Hispanic older adults in Miami, Florida. The analyses extend the literature by testing for a bidirectional or reciprocal relationship between neighboring behavior and depressive symptoms over time and examining the relationship between these variables in Hispanic older adults, a group at risk of developing depressive symptoms. Structural Equation Modeling with a cross-lagged panel design showed that depressive symptoms were unrelated to subsequent neighboring behavior. However, neighboring behavior was related to subsequent depressive symptoms at every time point, such that higher levels of neighboring behavior were related to lower levels of depressive symptoms. Findings suggest that neighboring behavior may be a protective factor against depressive symptoms in community-dwelling Hispanic older adults. PMID- 24049218 TI - Pathways From School Suspension to Adolescent Nonviolent Antisocial Behavior in Students in Victoria, Australia and Washington State, United States. AB - School suspension is associated with school drop-out, crime, delinquency, and alcohol and other drug use for the suspended student. Important research questions are how academic and related factors are relevant to the school suspension process and the generality of the process in different sites. State representative samples of Grade 7 students (N = 1,945) in Washington State, United States and Victoria, Australia were followed from 2002 to 2004. In both states, Grade 7 school suspension was associated with higher rates of nonviolent antisocial behavior and suspension 24 months later, before Grade 8 factors were entered into the model. Relevant factors were Grade 8 low school grades and association with antisocial peers, as well as Grade 8 antisocial behavior in Washington State only. The implications of these findings for the ways in which suspension is used in schools are outlined. PMID- 24049217 TI - USING SOCIAL NETWORK ANALYSIS TO EVALUATE COMMUNITY CAPACITY BUILDING OF A REGIONAL COMMUNITY CANCER NETWORK. AB - The Tampa Bay Community Cancer Network (TBCCN) is one of 25 Community Network Programs funded by the National Cancer Institute's (NCI's) Center to Reduce Cancer Health Disparities with the objectives to create a collaborative infrastructure of academic and community based organizations and to develop effective and sustainable interventions to reduce cancer health disparities. In order to describe the network characteristics of the TBCCN as part of our ongoing evaluation efforts, we conducted social network analysis surveys with our community partners in 2007 and 2008. One key finding showed that the mean trust value for the 20 community partners in the study increased from 1.8 to 2.1 (p<0.01), suggesting a trend toward increased trust in the network. These preliminary results suggest that TBCCN has led to greater collaboration among the community partners that were formed through its capacity-building and evidence based dissemination activities for impacting cancer health disparities at the community level. PMID- 24049219 TI - Minding the Baby: Enhancing reflectiveness to improve early health and relationship outcomes in an interdisciplinary home visiting program. AB - In this paper we focus on the first wave of outcomes in a pilot phase randomized control trial of a home-based intervention for infants and their families, Minding the Baby(r) (MTB), an interdisciplinary, mentalization-based intervention in which home visiting services are provided by a team that includes a nurse practitioner and a clinical social worker. Families are recruited during mother's pregnancy and continue through the child's second birthday. Analyses revealed that intervention families were more likely to be on track with immunization schedules at 12 months, had lower rates of rapid subsequent childbearing, and were less likely to be referred to child protective services. In addition, mother infant interactions were less likely to be disrupted at 4 months when mothers were teenagers, and all intervention infants were more likely to be securely attached, and less likely to be disorganized in relation to attachment at one year. Finally, mothers' capacity to reflect on their own and their child's experience improved over the course of the intervention in the most high-risk mothers. PMID- 24049220 TI - Metabolic syndrome in schizophrenia: theoretical, clinical and translational perspectives. PMID- 24049221 TI - How to calculate sample size for different study designs in medical research? AB - Calculation of exact sample size is an important part of research design. It is very important to understand that different study design need different method of sample size calculation and one formula cannot be used in all designs. In this short review we tried to educate researcher regarding various method of sample size calculation available for different study designs. In this review sample size calculation for most frequently used study designs are mentioned. For genetic and microbiological studies readers are requested to read other sources. PMID- 24049222 TI - A study of profile of disability certificate seeking patients with schizophrenia over a 5 year period. AB - BACKGROUND: Schizophrenia has been identified as one of the most disabling condition known to mankind. Until recently there was no published literature on disability certification seeking behavior of patients diagnosed with schizophrenia. The current study aimed at understanding the profile of patients diagnosed with schizophrenia seeking disability certification for a tertiary level multispecialty hospital in India. MATERIALS AND METHODS: The study was carried out at the Psychiatry department for a tertiary care hospital in India. The evaluation of the subjects was carried out in the presence of a primary care giver. First, the diagnosis was established using International Statistical Classification of Diseases and Related Health Conditions (ICD)-10. Subsequently, the disability was assessed using Indian Disability Evaluation Assessment Scale (IDEAS). Data were analyzed using SPSS (Statistical Package for Social Sciences) software version 17. RESULTS: A total of 169 subjects seeking disability certification over the study period of 5 years were diagnosed with schizophrenia. Out of 169 subjects 132 (78.1%) were male and 37 (21.9%) were female. There was a statistically significant difference in the marital status of the male and female study subjects. Family history of psychiatric illness was positive in 9.8% of male subjects and 10.8% of female subjects. There was no significant difference between male and female subjects for the duration of illness and duration of being on treatment. Male and female subjects did not differ significantly on the IDEAS global score, personal care, interpersonal interaction, and understanding and communication domains of IDEAS. The two groups differed significantly on the work domain. CONCLUSIONS: Majority of patients with schizophrenia seeking disability certificate continue to be male. However, male and female subjects tend to differ very little on various socio-demographic and illness related variables. The levels of disability are also comparable among males and females. However, the work related disability is relatively higher among males and females continue to be financially dependent on the family members. PMID- 24049223 TI - Effects of Psychopathology, Functioning and Anti-psychotic Medication Adherence on Caregivers' Burden in Schizophrenia. AB - BACKGROUND: The aim of the study was to determine the effects of the level of psychopathology and anti-psychotic medication adherence on caregivers' burden in schizophrenia. MATERIALS AND METHODS: Three hundred and sixty-seven schizophrenia patient/caregiver dyads were interviewed. Caregiver's burden was assessed using the Yoruba version of the Family Burden Interview Schedule (FBIS) and 12-Item General Health Questionnaire (GHQ-12). Patients were assessed using the Global Assessment of Functioning (GAF) scale, Positive and Negative Symptoms Scale (PANSS), and medication compliance questionnaire. RESULTS: Mean age of the patients was 29.7 SD (8.6) years. About 82% of the 368 caregivers were parents of the patients with mean age of 58.1 years (SD 19.6). Total mean objective FBIS score was 22.69 (6.21), with 324 caregivers (85.3%) reporting total objective burden and 310 (84.2%) reporting subjective burden. FBIS scores were positively associated with PANSS scores but negatively with GAF P<0.001, respectively. Mean FBIS reduced with medication compliance categories A and B, P<0.01, respectively, but increased in category F, P<0.001. In all, 51.1% scored >=3 on GHQ. CONCLUSION: Caregivers of schizophrenia patients experience enormous burden and are at risk for mental disorders. The severity of this burden is related to the level of psychopathology and medication adeherence, thereby adding to the available evidence pointing to the need for clinicians to optimize patients' management to prevent psychological distress in carers of such patients. PMID- 24049224 TI - A psychological study of stress, personality and coping in police personnel. AB - CONTEXT: There have been few studies focusing on occupational/organizational causes of stress in police. Hardly any studies exist on personality traits and coping methods in this group of individuals. AIMS: To study the association of personality traits and coping methods to psychological stress in police personnel. SETTINGS AND DESIGN: This cross-sectional study was conducted among the constables and head constables working in the Police Department, Vizianagram town, Andhra Pradesh. MATERIALS AND METHODS: The study sample consisted of 150 police persons. The socio-demographic data was individually collected from them. General Health Questionnaire-28 (GHQ-28) was used for assessing psychological stress, Eysenck's Personality Questionnaire (EPQ) for personality traits, and Coping Checklist-1 (CCL-1) for eliciting coping methods. The statistical analysis was done using SPSS v 10 software. RESULTS: On screening by GHQ-28, 35.33% of the police were found to be having psychological distress. The socio-demographic variables showed no significant association to psychological stress. Personality traits such as neuroticism, psychoticism, and extroversion and coping methods like negative distraction and denial/blame showed statistically significant association (P<0.05) with psychological stress. The most commonly used coping methods across the sample were social support (72.55%), acceptance/redefinition (64.72%), and problem solving (60.46%). As measured by Pearson's correlation coefficient (r), there was evidence of linear association between certain personality traits and coping methods as well. CONCLUSIONS: The personality traits and coping methods have significant independent and interactive role in the development of high psychological stress in police persons, thus placing them at a high risk of developing psychiatric disorders. PMID- 24049225 TI - Growing Up with a Parent having Schizophrenia: Experiences and Resilience in the Offsprings. AB - BACKGROUND: Parental mental illness has been found to have an impact on offsprings in their emotional, social, and behavioral aspects of life. AIMS: To examine the experiences of offsprings of a parent having schizophrenia and to study their resilience. MATERIALS AND METHODS: A sample of 45 adults with one parent diagnosed with schizophrenia was selected using purposive sampling. Subjects were assessed using socio-demographic data sheet, semi-structured interview schedule, and Connor-Davidson Resilience Scale. RESULTS: The experiences perceived by them as different from children of healthy parents included negative experiences in social (49%) and emotional aspects (40%), lack of support from the parent who is ill (40%), and burden (66%) in various areas. Majority of the offsprings were satisfied with the parenting received (70%). About 60% of them reported medium resilience, and 24% and 15% reported high and low resilience, respectively. Majority of those with medium and high resilience had supportive relationship with other family members. Social support was the most frequently reported factor that helped them to cope with difficulties. CONCLUSIONS: Growing up with a parent having mental illness can have negative impact on offsprings. However, it can also have positive effects in terms of developing resilience in the presence of good support system. PMID- 24049226 TI - Perception and Attitude towards Mental Illness in an Urban Community in South Delhi - A Community Based Study. AB - BACKGROUND: Mental illness have been largely ignored or neglected because of a community's perception and attached social stigma. MATERIALS AND METHODS: A community based cross-sectional study was conducted in an urban community in South Delhi to study perception and attitude of the community about towards mental illness. An adult member in household selected by systematic random sampling was interviewed using semi-structured interview schedule for perception about mental illness and 34 item Opinion about Mental Illness for Chinese Community (OMICC) scale. RESULTS: A total of 100 adults were interviewed. Mean age of the participants was 35.8 (SD: 12.6) years. Living without tension and satisfaction in routine life were identified as indicators of healthy mental status. Change in the behavior was perceived as the most common symptom of mental illness. Although mental stress was identified as the most common cause of mental illness, 25% attributed it to evil spirits. Keeping surroundings friendly and sharing problems with others were identified as - important preventive measures against mental illness. Mental illness was perceived as treatable; 12% preferred treatment from Tantric/Ojha. Community showed negative attitude for stereotyping, restrictiveness, and pessimistic prediction domains of OMICC scale with mean score of 4.5 (SD: 0.2), 3.9 (SD: 0.9), and 3.8 (SD: 0.4), respectively, with no statistically significant difference across age, sex, and literacy. CONCLUSION: Study observed lack of awareness regarding bio-medical concept of mental illness with socially restrictive, stereotyping, pessimistic, and non-stigmatizing attitude toward mental illness in the capital city. PMID- 24049227 TI - A comparative study of attitudes toward psychiatry among nursing students across successive training years. AB - CONTEXT: Psychiatry nurses are an integral component of a multidisciplinary mental health-care team. AIM: The current study aimed at understanding the attitude of undergraduate nursing students toward psychiatry. Additionally, the attitudes toward psychiatry have been compared across the training years among these students. MATERIALS AND METHODS: The study was carried out at a tertiary care nurse-training institute. All the nursing students enrolled with the institute at the time of the study constituted the sample frame. The study questionnaire used in the current study was a 29-item questionnaire that assessed attitudes toward psychiatry. STATISTICAL ANALYSIS: The data were analyzed using SPSS ver 17. RESULTS: Overall, the majority of the nursing students from all four groups had a favorable response to the statements of the Likert scale. Most of the significantly positive responses (as assessed by the Kruskal-Wallis analysis of variance of the rank order) were from the third-year and internship students. These findings were supported by the significant correlation between these statements and ranked order of the nurse-training years. CONCLUSIONS: The findings of the current study present some interesting insights into the attitude of nursing students toward psychiatry. PMID- 24049228 TI - Metabolic Syndrome in Drug-naive Patients with Depressive Disorders. AB - BACKGROUND: The prevalence of metabolic syndrome (MS) is found to be higher in patients with depression than in the general population. As there is lack of data from India, this study aimed to assess the prevalence of MS in patients with depression who had never been treated with antidepressants for their depressive disorder and compare the same with a matched group of healthy controls. MATERIALS AND METHODS: Forty-three drug-naive patients with depressive disorders and 43 age and gender-matched healthy controls were assessed for the prevalence of MS as per the consensus definition. RESULTS: The prevalence of MS in patients with depression was 37.2% and was significantly higher than that seen in the healthy controls (16.3%). Increased waist circumference was the most common abnormality in both the study groups. Compared to healthy controls, a significantly higher proportion of patients with depression had abnormal waist circumference, systolic blood pressure, or high blood pressure. Besides 16 patients with depressive disorders having MS, another 53.5% of patients fulfilled one or two criteria of MS. None of the sociodemographic variables was associated with development of MS in patients with depression. CONCLUSIONS: Slightly more than one-third of depressed patients who are drug-naive have MS and this prevalence rate is significantly higher than in healthy controls. PMID- 24049229 TI - A descriptive study of clinical, hematological, and biochemical parameters of inhalant users seeking treatment at a tertiary care center in India. AB - BACKGROUND: Inhalant (or solvent) abuse is the purposeful inhalation of vapors or gases, intended to produce pleasurable psychoactive effects. There is a dearth of Indian studies on inhalant users. AIM: The present study aimed to describe the socio-demographic, clinical, and psychosocial characteristics of inhalant users visiting a Tertiary Care Center in North India. MATERIALS AND METHODS: The study was a retrospective chart review for 50 inhalant users who sought treatment for the first time from the center over a period of 2 years. All patients seeking treatment for inhalant use at the center were evaluated by a psychiatrist. RESULTS: Mean age of the sample was 17.16+/-4.09 years and majority comprised of children and adolescents (72.2%). There were only three girls (6%). Majority comprised of school drop-outs (82%), from lower socio-economic status (80%). Mean age of initiation of first substance was 14.13+/-4.27 years and inhalants were first drugs for 38%. Duration of inhalant use ranged between 1 month and 7.5 years. Use was mostly uninterrupted, and 88% were dependent users. Correction fluid was the commonest product, used by huffing or sniffing. A large majority (86%) had used at least one other substance besides inhalants, and 8% reported involvement in high-risk sexual behaviors. Comorbid psychiatric disorder was seen in 8% of sample. Positive family history was observed in 30% of the sample. The mean hemoglobin of the sample was 11.88+/-0.60, with low hemoglobin in 25% of users. Neutrophils, lymphocytes, eosinophils, and monocytes were elevated beyond normal in 10.8%, 6.5%, 15.2%, and 7.5%, respectively. There was no evidence of leucopenia. Bilirubin and serum glutamic pyruvic transaminase was elevated in 6.6% and 13% of inhalant users, respectively. CONCLUSION: The study adds to the limited date available on the treatment-seeking inhalant users from Indian settings. There is a need to examine the pattern of inhalant use in larger samples, across multiple sites in a prospective manner. PMID- 24049230 TI - A computerized stroop test for the evaluation of psychotropic drugs in healthy participants. AB - BACKGROUND: The Stroop paradigm evaluates susceptibility to interference and is sensitive to dysfunction in frontal lobes and drug effects. The aim of the present study was to establish a simple and reliable computerized version of Stroop color-word test, which can be used for screening of various psychotropic drugs. MATERIALS AND METHODS: The standardized method was followed in all cases, by recording the reaction time (RT) in msec in 24 healthy participants using computerized version of Stroop color-word test. Reproducibility of the test procedure was evaluated by recording the RTs by a single experimenter on two sessions (interday reproducibility). Validity of the model was further tested by evaluating the psychotropic effect of Zolpidem 5 mg, Caffeine 500 mg, or Placebo on 24 healthy subjects in a randomized, double blind three-way crossover design. RESULTS: The method was found to produce low variability with coefficient of variation less than 10%. Interday reproducibility was very good as shown by Bland Altman plot with most of the values within +/-2SD. There was a significant increase in RTs in Stroop performance with Zolpidem at 1 hr and 2 hrs; in contrast, caffeine significantly decreased RTs in Stroop performance at 1 hr only compared to placebo. CONCLUSION: The Stroop color-word recording and analysis system is simple, sensitive to centrally acting drug effects, and has potential for future experimental psychomotor assessment studies. PMID- 24049231 TI - Metabolic syndrome in alcohol-dependent men: a cross-sectional study. AB - BACKGROUND: In the context to mental illness metabolic syndrome (MS) has gained significant attention in the last decade. The present research aimed to study the prevalence of MS and its correlates among the alcohol-dependent men at a deaddiction center in Northern India. MATERIALS AND METHODS: A cross-sectional analysis was done for consecutive male subjects who met the diagnosis of alcohol dependence syndrome currently using alcohol according to the International Clinical Diagnostic criteria- tenth revision mental and behavioral disorder- Clinical description and diagnostic guidelines criteria (ICD-10). The subjects were evaluated for alcohol consumption and the components of MS as per the International Diabetic Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel-III (NCEP ATP-III). RESULTS: A total of 200 male subjects were studied: 100 subjects meeting ICD-10 criteria for alcohol dependence currently using alcohol; 50 each of genetically related controls and nongenetically related healthy controls. As per the IDF (with ethnicity specific modifications for waist circumference) and NCEP ATP- III definitions, respectively, MS was found to be less prevalent in alcohol-dependent subjects (27% and 18%) in comparison the healthy controls (30% and 20%). CONCLUSION: Findings of the study suggest that irrespective of the amount the current alcohol intake is associated with a lower prevalence of MS and a favorable effect on serum high density lipoproteins and waist circumference. However, the cross sectional nature of our study does not allow any definitive causal inference. PMID- 24049232 TI - Relationship of personality dimensions and aggression in romantic relationship among youth. AB - BACKGROUND: Aggression in romantic relationships is a continuing factor for breakups, physical assault, kidnapping, rape and even murder. It is also associated with adjustment difficulties including peer rejection, depression and maladaptive personality features. The present study aims to explore the personality correlates of aggression in romantic relationship. MATERIALS AND METHODS: The sample consisted of 110 male and female participants in the age range of 18-32 years. The Socio-demographic schedule, General Health Questionnaire Relationship Satisfaction Scale NEO Five Factor Inventory, The Revised Conflict Tactics Scale and Checklist for Psychological Aggression were administered. RESULTS: Personality characteristics like openness, agreeableness and conscientiousness were negatively correlated with all forms of aggression. Men and women had significant differences with respect to aggression in romantic relationships. The relationship satisfaction has negative association with neuroticism. CONCLUSIONS: It has implications in understanding pattern of aggression in romantic relationships and thus may help in developing intervention programs for the same. PMID- 24049233 TI - Sexual Abuse in 8-year-old Child: Where Do We Stand Legally? AB - We have reporting herein two cases of victims of sexual abuse, both 8 years old girls, both presented with symptoms of irritability, withdrawn behavior, fearfulness, anxiety, and abusive language toward family members. These symptoms appeared following sexual abuse. We are highlighting early identifications of child sex abuse and discussed the legal aspects of child abuse and "protection of children from sexual offences act" 2012. Finally, we have discussed how to prevent such incidences including incorporating school awareness programs in targeted girls' group. PMID- 24049234 TI - Electro Convulsive Therapy in Psychiatric Manifestations in Wilson's Disease. AB - Wilson's disease occurs due to an inborn error of metabolism. Psychiatric symptoms are often the first manifestation of the disease and can obscure the diagnosis. There are five neuropsychiatric symptoms clusters established for Wilson's disease patients: Behavior and/or personality disorders, mood disorders, cognitive deficits, psychotic manifestations, and others. The frequency with which psychiatric manifestations appears in Wilson's disease remains vague. However, whenever they occur, they need to be correctly identified and treated. Though encouraging results have been obtained in controlling psychiatric manifestations of Wilson's with psychotropic medications, some sub-group of patients fail to respond to any therapy. We aim at finding options for controlling psychosis in these patients with electro convulsive therapy (ECT). A patient exhibiting rare neuropsychiatric manifestations of Wilson's and who is not responding to psychotropic medication was considered for ECT. Considerable control over psychiatric manifestations with ECT was observed and later treated with maintenance ECTs for relapse control. PMID- 24049235 TI - Wires in the body: a case of factitious disorder. AB - Factitious disorder can present with a wide variety of symptomatology. We present a case of a young girl presenting with spontaneous extrusion of wires from her limbs. These metallic wires were present in both her upper and lower limbs in the muscle bulk and were visible on X-ray. She sought repeated surgical removal of these wires, but the wires would invariably reappear. The patient could not be engaged in a therapeutic relationship and the family took premature discharge against medical advice, as they believed in supernatural causation for the phenomenon and were afraid that medical intervention might bring further ill fortune. The case highlights the importance of belief systems of family members as a barrier in managing such cases. PMID- 24049236 TI - Zolpidem-induced Hallucinations: A Brief Case Report from the Indian Subcontinent. AB - We are reporting a case of zolpidem-induced hallucinations in a 20-year-old patient. The duration of this phenomenon was brief, 15-20 minutes. Our case suggests that clinicians must be aware of this phenomenon while prescribing zolpidem. PMID- 24049237 TI - Delusional Procreation Syndrome: Report from TURUVECARE Community Intervention Program. AB - New insights on Delusional Procreation Syndrome (DPS), a sequence of delusions in the cycle of human procreation are emerging in recent times. Till date, most of the data on DPS are reported from the clinical samples. Authors report case series of having delusions related to DPS from a rural community sample of schizophrenia patients. Delusion of having spouse, delusion of delivery, and delusion of being a parent are reported in this case-series. This evidence is a forward step towards the validity of DPS as a syndrome. PMID- 24049238 TI - Disulfiram induced reversible hypertension: a prospective case study and brief review. AB - Disulfiram (DSF) is one of the recommended aids in the management of alcohol dependence. Hypertension may be a clinically significant, dose-dependent, and usually reversible adverse event of DSF therapy. We report 6 month prospective study of normotensive case of comorbid alcohol and tobacco dependence that developed reversible stage-II hypertension within 2-4 weeks of DSF therapy. We suggest that regular monitoring of blood pressure at least fortnightly for 1(st) 3 months, followed by monthly for next 3 months, and later once in 3 months, may possibly detect "silent" adverse event of DSF - hypertension. PMID- 24049239 TI - Chronic subdural hematoma following electroconvulsive therapy. PMID- 24049240 TI - Perspectives in pediatric psychopharmacology. PMID- 24049241 TI - Psychological Manifestation in Dengue: Did it Really exist? PMID- 24049242 TI - Emerging influenza and psychosis: an important story in psychological medicine. PMID- 24049243 TI - Relationship between schizophrenia and diabetes mellitus: consideration based on physiogenomics data. PMID- 24049244 TI - Batch Mode Reinforcement Learning based on the Synthesis of Artificial Trajectories. AB - In this paper, we consider the batch mode reinforcement learning setting, where the central problem is to learn from a sample of trajectories a policy that satisfies or optimizes a performance criterion. We focus on the continuous state space case for which usual resolution schemes rely on function approximators either to represent the underlying control problem or to represent its value function. As an alternative to the use of function approximators, we rely on the synthesis of "artificial trajectories" from the given sample of trajectories, and show that this idea opens new avenues for designing and analyzing algorithms for batch mode reinforcement learning. PMID- 24049245 TI - Factors influencing infants' ability to update object representations in memory. AB - Remembering persisting objects over occlusion is critical to representing a stable environment. Infants remember hidden objects at multiple locations and can update their representation of a hidden array when an object is added or subtracted. However, the factors influencing these updating abilities have received little systematic exploration. Here we examined the flexibility of infants' ability to update object representations. We tested 11-month-olds in a looking-time task in which objects were added to or subtracted from two hidden arrays. Across five experiments, infants successfully updated their representations of hidden arrays when the updating occurred successively at one array before beginning at the other. But when updating required alternating between two arrays, infants failed. However, simply connecting the two arrays with a thin strip of foam-core led infants to succeed. Our results suggest that infants' construal of an event strongly affects their ability to update memory representations of hidden objects. When construing an event as containing multiple updates to the same array, infants succeed, but when construing the event as requiring the revisiting and updating of previously attended arrays, infants fail. PMID- 24049246 TI - Developmental Origins of the Other-Race Effect. AB - The other-race effect (ORE) in face recognition refers to better recognition memory for faces of one's own race than faces of another race-a common phenomenon among individuals living in primarily mono-racial societies. In this article, we review findings suggesting that early visual and sociocultural experiences shape one's processing of familiar and unfamiliar race classes and give rise to the ORE within the 1st year of life. However, despite its early development, the ORE can be prevented, attenuated, and even reversed given experience with a novel race class. Social implications of the ORE are discussed in relation to development of race-based preferences for social partners and racial prejudices. PMID- 24049247 TI - Moving beyond the gang-drug-violence connection. AB - The aim of this article is to reflect on the conceptual and methodological developments of our gang research over the past 20 years. We have conducted a large number of consecutive qualitative studies on youth gangs, drugs and alcohol in one urban locale for over two decades and have amassed a data set of over 2000 qualitative interviews. We have kept pace with the social changes in San Francisco as they have impacted and shaped youth gangs and their members' lives. However, these changes have not only occurred in the social context of gang members' lives, but have also occurred in our own thinking about how to conceptualize research on gangs. We have broadened our analysis of gang members' lives and incorporated new theoretical developments from research outside of the gang field. In addition to this shift in emphasis, our overall aim has been to redirect the research focus on youth gangs from a social problem and criminological perspective to a more sociological approach in which these youth are situated within an everyday perspective. With these overall issues in mind, we see this discussion as taking stock of the nature of gang research in the past, present and future. PMID- 24049248 TI - Optimizing the management of lung cancer: Role of the pulmonologist in India. PMID- 24049249 TI - Chronic obstructive pulmonary disease: Indian guidelines and the road ahead. PMID- 24049250 TI - Predictors of requirement of mechanical ventilation in patients with chronic obstructive pulmonary disease with acute respiratory failure. AB - BACKGROUND AND OBJECTIVE: Acute exacerbation of chronic obstructive pulmonary disease (COPD) leads to increased morbidity, mortality and requirement of invasive mechanical ventilation (MV). The aim of this study was to identify predictors of need of MV in these patients. MATERIALS AND METHODS: Clinical symptomatology, demographic profile, biochemical parameters including renal functions, liver functions and acid base parameters, and acute physiology and chronic health evaluation II (APACHE II) score at the time of admission were recorded in 100 patients of COPD exacerbation. Various parameters were compared between patients in whom MV was required with those managed with medical therapy. RESULTS: MV was required in 73% of the patients. Parameters found to be independent predictors of need of MV were: Admission APACHE-II score >= 11.5 {adjusted odds ratio (OR) [95% confidence interval (CI)]: 1.42 [1.08-1.86]; P = 0.012}, first day pH <= 7.28 (adjusted OR [95% CI]: 1.09 [1.02-1.15]; P = 0.008), first day PaCO2 >= 68.6 mmHg (adjusted OR [95% CI]: 1.09 [1.02-1.15]; P = 0.004) and worse premorbid functional status (adjusted OR [95% CI]: 17.01 [1.95-148.68]; P = 0.01). CONCLUSIONS: Underlying disease severity as assessed by premorbid functional status and APACHE-II score, and the acuity of respiratory system decompensation as assessed by the admitting arterial pH and PaCO2, are independent predictors of need of MV in patients with exacerbation of COPD. PMID- 24049251 TI - Regression equations for peak expiratory flow in healthy children aged 7 to 14 years from Punjab, India. AB - BACKGROUND: Measurement of peak expiratory flow (PEF) is imperative for management and evaluation of asthmatic children. It is well-known that lung function parameters show wide variations with respect to regional, racial, and genetic factors. AIM: This study was conducted to measure PEF in healthy Punjabi children aged 7-14 years as only a few studies have evaluated the lung functions in North Indian children. MATERIALS AND METHODS: A cross-sectional study was conducted in which PEF was measured in 366 healthy schoolchildren (186 boys and 180 girls) of Patiala district, using the Mini Wright Peak Flow Meter. Best of the three trials was recorded. All the subjects were tested in standing position after recording their age, height, and weight. SPSS v. 13 was used for the statistical analysis. RESULTS: The present study showed that all the three independent variables (age, height, and weight) had a significant positive correlation with PEF, in both genders. Furthermore, height was maximally correlated with PEF in both boys (r = 0.970) and girls (r = 0.964). The mean PEF value in boys (249.34 +/- 81.36 L/min) was significantly higher than girls (233.31 +/- 67.06 L/min). Regression equations for PEF were also determined using age, height, and weight, separately for the genders. CONCLUSION: Equations derived from this study for estimation of expected PEF values would help the clinicians in assessing the airway obstruction in this population subset. PMID- 24049252 TI - Outcomes of patients with unresected stage III and stage IV non-small cell lung cancer: A single institution experience. AB - INTRODUCTION: To report on the demographic profile and survival outcomes of North Indian population affected with stage III and stage IV non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: From November 2008 to January 2012, 138 consecutively diagnosed NSCLC patients were included in this study. The patient, tumor and treatment related factors were analyzed. Median overall survival (OS), Kaplan-Meier survival plots, t-test, Cox proportional hazards models were generated by multivariate analysis [MVA]) and analyzed on SPSS software (version 19.0; SPSS, Inc., Chicago, IL). RESULTS: Median OS of stage III patients was 9.26 +/- 1.85 months and 2-year survival rate of 13% while stage IV patients had median OS of 5 +/- 1.5 months with a 2-year survival rate of 8%. Cox regression modeling for MVA demonstrated higher biologically equivalent dose (BED) (P = 0.01) in stage III while in stage IV non-squamous histology (P = 0.01), administration of chemotherapy (P = 0.02), partial responders to chemotherapy (P = 0.001), higher BED (P = 0.02), and those with skeletal metastasis alone (P = 0.17) showed a better OS. CONCLUSION: Our data showed that a higher BED is associated with favorable outcomes, indicating a role of dose escalated radiation therapy to the primary lesion in both stage III and essentially in stage IV NSCLC. Additionally, optimal use of chemotherapy relates to better survival. The developing, resource restrained nations need to follow an economically feasible multimodality approach. PMID- 24049253 TI - High altitude pulmonary edema among "Amarnath Yatris". AB - BACKGROUND: Annual pilgrimage (Yatra) to the cave shrine of Shri Amarnath Ji' is a holy ritual among the Hindu devotees of Lord Shiva. Located in the Himalayan Mountain Range (altitude 13,000 ft) in south Kashmir, the shrine is visited by thousands of devotees and altitude sickness is reportedly common. MATERIALS AND METHODS: More than 600,000 pilgrims visited the cave shrine in 2011 and 2012 with 239 recorded deaths. Thirty one patients with suspected altitude sickness were referred from medical centers en-route the cave to Sher-i-Kashmir Institute of Medical Sciences, a tertiary-care center in capital Srinagar (5,000 ft). The clinical features and the response to treatment were recorded. RESULTS: Thirty one patients (all lowlanders, 19 male; age 18-60 years, median 41) had presented with acute onset breathlessness of 1-4 days (median 1.9 d) starting within 12-24 h of a rapid ascent; accompanied by cough (68%), headache (8%), dizziness and nausea (65%). Sixteen patients had associated encephalopathy. Clinical features on admission included tachypnea (n = 31), tachycardia (n = 23), bilateral chest rales (n = 29), cyanosis (n = 22) and grade 2-4 encephalopathy. Hypoxemia was demonstrable in 24 cases and bilateral infiltrates on radiologic imaging in 29. Ten patients had evidence of high-altitude cerebral edema. All patients were managed with oxygen, steroids, nifedipine, sildenafil and other supportive measures including invasive ventilation (n = 3). Three patients died due to multiorgan dysfunction. CONCLUSIONS: Altitude sickness is common among Amaranath Yatris from the plains and appropriate educational strategies should be invoked for prevention and prompt treatment. PMID- 24049254 TI - The role of induced sputum in the diagnosis of pulmonary tuberculosis. AB - BACKGROUND: Microbiological confirmation of pulmonary tuberculosis (TB) is of paramount importance in the era of immunocompromised host and emergence of multi drug resistance. OBJECTIVES: To assess the value of sputum induction (SI) with hypertonic saline nebulization as a diagnostic tool in patients with suspected pulmonary TB who have no/inadequate sputum or have a sputum smear negative for acid fast bacillus (AFB). MATERIALS AND METHODS: One hundred patients with clinical and radiological evidence of pulmonary TB with no/inadequate sputum or smear negative with spontaneous sputum were studied. Sputum was induced with 20 mL of 3% hypertonic saline solution delivered through ultrasonic nebulizer. The specimens were subjected to Ziehl Neelsen staining and were examined under oil immersion lens for the presence of AFB. The specimens were also subjected to mycobacterial culture in BACTEC 460 TB system. RESULTS: Ninety five patients could produce adequate sputum after SI. Sputum from thirty two patients were found to be positive both in smear and culture while sputum from another three patients were smear negative, but culture positive. CONCLUSION: SI is a safe, cheap and non-invasive procedure and provides significant yield in the diagnosis of pulmonary TB; thus, increasing the case detection rate of smear positive pulmonary TB. PMID- 24049255 TI - Spontaneous resolution of post-traumatic pulmonary artery pseudoaneurysm: Report of two cases. AB - Pulmonary artery aneurysm is a rare clinical entity with congenital or mycotic origin being most common causes. Post-traumatic pulmonary pseudoaneurysms are extremely rare. Unless diagnosed early and properly managed, these can be fatal. Only few cases have been reported in the literature with most (except the one) being diagnosed much later after the initial injury and managed surgically. Only one case has been reported following blunt trauma injury, which was diagnosed immediately using computed tomography scan and managed conservatively. Here, we report two cases of pulmonary artery pseudoaneurysm one following gunshot injury and other following blunt injury which was diagnosed on contrast enhanced computed tomography chest and managed conservatively. PMID- 24049256 TI - Plastic bronchitis in beta thalassemia minor. AB - Plastic bronchitis is a rare pulmonary disorder associated with various conditions like cystic fibrosis, asthma, pulmonary infection and characterized by formation and expectoration of cast which assumes the shape of the bronchial tree. We report a case of a 33-year-old woman with beta thalassemia minor who developed plastic bronchitis. PMID- 24049257 TI - Pancoast syndrome: A rare presentation of non-Hodgkin's lymphoma. AB - Pancoast syndrome is a common presentation of bronchogenic carcinoma, but other malignancies are rarely cited as its cause. Pancoast syndrome due to non Hodgkin's lymphoma is rarely described in the literature. Here, we report a case of Pancoast syndrome due to non-Hodgkin's lymphoma to increase the awareness of the clinicians regarding essentiality of tissue diagnosis of Pancoast tumor before starting the treatment. PMID- 24049258 TI - Reversible interstitial lung disease with prolonged use of nitrofurantoin: Do the benefits outweigh the risks? AB - We describe the case summary of a 70-year-old man diagnosed with interstitial lung disease due to prolonged nitrofurantoin therapy. Despite honeycombing confirmed by computed tomography of the thorax, symptoms and radiographic findings disappeared within 1 month after withdrawal of nitrofurantoin. The case highlights the fact that nitrofurantoin-induced lung disease may run a benign course and respond favorably despite radiographic evidence of established lung fibrosis (honey combing). PMID- 24049259 TI - Congenital cystic adenomatoid malformation of lung: Report of two cases with review of literature. AB - Congenital cystic adenomatoid malformations (CCAM) also known as congenital pulmonary airway malformation is a developmental, non-hereditary, hamartomatous abnormality of lung with unknown etiology. It is a rare disease with an incidence of 1 in 25,000 to 1 in 35,000. It is a disease of infancy with most of the cases diagnosed within first 2 years of life. We report autopsy findings of two fetuses with congenital cystic adenomatoid malformation (Stocker Type II and I) with brief review of literature. PMID- 24049260 TI - Potato swelling of sternum. PMID- 24049261 TI - A rare case of interaorticobronchial diverticulum of esophagus in a case of scleroderma. PMID- 24049262 TI - Comments on editorial - Test of reversibility of airway obstruction: Time for review. PMID- 24049263 TI - Author's Response. PMID- 24049264 TI - Same-day sputum microscopy: The road ahead in tuberculosis diagnosis. PMID- 24049266 TI - A 2-year follow-up study of patients on automated peritoneal dialysis. AB - Automated peritoneal dialysis (APD) is increasingly being used for the treatment of end stage renal disease. We present our experience of APD at a government run tertiary care institute. APD was initiated for 22 patients between 2002 and 2010. On comparing APD and continuous ambulatory peritoneal dialysis (CAPD) patients, no difference in patient survival and technique survival was observed. CAPD patients had higher number of peritonitis episodes, greater decline in the serum albumin and a greater number of patients failed to achieve adequacy targets compared to APD. PMID- 24049268 TI - Atherosclerosis in chronic kidney disease: Striking while the Iron is labile. PMID- 24049267 TI - Serum catalytic Iron: A novel biomarker for coronary artery disease in patients on maintenance hemodialysis. AB - Cardiovascular disease is the leading cause of morbidity and mortality in maintenance hemodialysis (MHD) patients. We evaluated the role of serum catalytic iron (SCI) as a biomarker for coronary artery disease (CAD) in patients on MHD. SCI was measured in 59 stable MHD patients. All patients underwent coronary angiography. Significant CAD was defined as a > 70% narrowing in at least one epicardial coronary artery. Levels of SCI were compared with a group of healthy controls. Significant CAD was detected in 22 (37.3%) patients, with one vessel disease in 14 (63.63%) and multi-vessel disease in eight (36.36%) patients. The MHD patients had elevated levels of SCI (4.70 +/- 1.79 MUmol/L) compared with normal health survey participants (0.11 +/- 0.01 MUmol/L) (P < 0.0001). MHD patients who had no CAD had SCI levels of 1.36 +/- 0.34 MUmol/L compared with those having significant CAD (8.92 +/- 4.12 MUmol/L) (P < 0.0001). Patients on MHD and diabetes had stronger correlation between SCI and prevalence of CAD compared with non-diabetics. Patients having one vessel disease had SCI of 8.85 +/- 4.67 MUmol/L versus multi-vessel disease with SCI of 9.05 +/- 8.34 MUmol/L, P = 0.48. In multivariate analysis, SCI and diabetes mellitus were independently associated with significant CAD. We confirm the high prevalence of significant CAD in MHD patients. Elevated SCI levels are associated with presence of significant coronary disease in such patients. The association of SCI is higher in diabetic versus the non-diabetic subgroup. This is an important potentially modifiable biomarker of CAD in MHD patients. PMID- 24049269 TI - Tuberculosis in haemodialysis patients: A single centre experience. AB - We prospectively followed-up new patients of tuberculosis while on maintenance hemodialysis at a State Government-run tertiary care institute. Between 2000 and 2010, 1237 new patients were initiated on maintainence hemodialysis. The number of patients diagnosed with tuberculosis after initiation of hemodialysis was 131 (10.5% of 1237). The age was 46.4 +/- 10.4 (range 8-85) years and there were 90 (68.7%) males. The number of patients diagnosed with tuberculosis on the basis of organ involvement were: Pulmonary-60, pleural effusion-31, lymph node-21, meningitis-8, pericardial effusion-7, peritoneum-2, latent tuberculosis-2. The incidence of tuberculosis in hemodialysis was found to be 105.9 per 1000 patient years. Male gender, diabetes mellitus, past history of tuberculosis, mining as an occupation, low serum albumin, and duration of hemodialysis more than 24 months, and unemployment were found to be significant risk-factors on univariate analysis. PMID- 24049270 TI - Comparison of peritoneal transport characteristics at the second week and at six months of peritoneal dialysis commencement. AB - Peritoneal equilibration test (PET) is an important tool for managing peritoneal dialysis (PD) prescription. The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines suggest that the first PET be performed 4-8 weeks after PD commencement. The main reason for this delay is because of the peritoneal membrane might change its character once it is exposed to the glucose based dialysate. In this study, we compared PET 2 weeks after PD commencement to PET after 6 months to evaluate the changes in the peritoneal membrane character with time. This study included 126 patients who underwent PD initiation between March 2007 and December 2011. The PET was performed as per the standard protocol at 2(nd) week and 6(th) month after PD initiation. Transport status was categorized as low, low average, high average, and high as per the standard definition. There was no change in transport character in 115 patients (91.2%) between the two PET measurements. When the Early PET at 2(nd) week and 6(th) month PET data were analyzed, no significant changes were observed in measured D/P creatinine (0.59 +/- 0.14 vs. 0.62 +/- 0.14 respectively P = 0.26) and D/D0 Glucose (0.46 +/- 0.12 vs. 0.46 +/- 0.11, P = 0.65). Using the Bland-Altman analysis the repeatability coefficients were 0.27 and 0.25 for creatinine and glucose values respectively. In our study, the PET performed at the 2(nd) week are similar to that of the 6(th) month PET in 91.2% of our patients and the test did not significantly change with time. In conclusion, we could do PET early at 2(nd) week to assess the peritoneal membrane character and this would help in proper dialysis prescription to the patients. PMID- 24049271 TI - Significance of pre-transplant anti-HLA antibodies detected on an ELISA mixed antigen tray platform. AB - This study aims at examining the clinical impact, of antibodies detected on an ELISA mixed antigen tray format (LATM, One Lambda) in the absence of complement dependent cytotoxicity (CDC) positivity. All patients who underwent renal transplantation in 2007 and 2008 had their final pre-transplant sera retrospectively analyzed by the LATM assay. These patients were then followed-up with clinical, biochemical, and histopathological end points defined by elevation of serum creatinine and/or histopathological criteria. Among 164 patients who were studied, 149 received grafts from live related donors and 15, from deceased donors. 31 (19%) of the transplanted patients demonstrated pre-transplant anti HLA IgG antibodies on the assay. Totally, 15 were positive for class I antibodies, 4 for class II antibodies, and 12 for both class I and class II antibodies. 44 patients (36%) experienced rejection. 8 out of 31 (26%) ELISA positive patients and 36 out of 133 (27%) ELISA negative patients experienced rejection. Among 15 patients who received deceased donor transplants, 4 were positive for ELISA, and 11 were negative. All 4 (100%) of the ELISA positive patients experienced rejection as compared to 3 out of 11 (27%) ELISA negative patients (P = 0.01). The ELISA LATM assay did not show any predictive value for rejection in our overall patient population; however, results in the specific setting of deceased donor transplants merit further exploration. PMID- 24049272 TI - Effect of sickle cell crises on glomerular filtration rate in children with sickle cell disease in Ilorin, Nigeria. AB - Children with sickle cell disease (SCD) are plagued with incessant crises. There are few studies on the effect of sickle cell crises on renal function as determined by the glomerular filtration rate (GFR). This study was done to assess the effect of sickle cell crises on GFR during crises and after recovery into the steady state. GFR was assessed using the formula derived by Schwartz et al., for consecutive SCD patients aged between 3 and 18 years who came in crises and after recovery into the steady state. A total of 81 patients with a mean age of 9.95 +/ 4.15 years in 81 episodes of crises met the inclusion criteria. Majority of the children (47) had vasooclusive crises, 19 had hyperhaemolytic crises, and 15 had features of both vasooclusive and hyperhaemolytic crises. The means value of GFR in ml/min/1.73 m(2) rose from 81.09 +/- 22.92 to 116.24 +/- 22.11 subsequent to recovery from vasooclusive crises into the steady state, from 77.45 +/- 18.48 to 99.54 +/- 17.71 following recovery from hyperhaemolytic crises into the steady state and from 90.95 +/- 17.53 to 114.01 +/- 22.44 following recovery from crises with features of both vasooclusive and hyperhaemolytic crises with corresponding significant P values of 0.000, 0.001, and 0.004 respectively. The reduced GFR observed during vasooclusive and hyperhaemolytic crises improved significantly following recovery into the steady state. PMID- 24049273 TI - A comparative study of the effect of icodextrin based peritoneal dialysis and hemodialysis on lipid metabolism. AB - Dyslipidemia is frequent in patients with end stage renal disease. Excessive peritoneal glucose absorption from high glucose-containing peritoneal dialysis solutions may enhance disturbances on the lipid metabolism of patients on peritoneal dialysis. We compared the effect of icodextrin-based peritoneal dialysis therapy with hemodialysis (HD) therapy on lipid metabolism. A total of 157 non-diabetic patients on dialysis at least for 3 months; 78 patients on Icodextrin-based continuous ambulatory peritoneal dialysis (CAPD) (44 M, 34 F) and 79 patients in HD group (47M, 32F) were included into the study. After 12 h of fasting and before the dialysis session, serum urea, creatinin, glucose, Sodium, potasium, and albumin, total cholesterol (TC), triglycerides (TG), very low density lipoprotein (VLDL), low density lipoprotein (LDL)-C, high-density lipoprotein (HDL)-C, apolipoprotein A (Apo A), apolipoprotein B, and lipoprotein a were measured. TG (P = 0018) and VLDL (P = 0.022) were lower in CAPD group than HD group, HDL-C (P < 0.001) and Apo A (P = 0.001) were higher in CAPD group than in HD group. A total of 24.4% in CAPD group and 11.4% in HD group (P < 0.034) had normal serum levels of TG, LDL-C, and HDL-C. More patients in CAPD group (47.4%) had high serum Apo A levels than in HD group (21.5%) (P = 0.001). We suggest that patients receiving icodextrin-based CAPD may have better TG, HDL-C, and Apo A levels than patients on HD. PMID- 24049274 TI - Successful treatment of verruca vulgaris with Thuja occidentalis in a renal allograft recipient. AB - Human papillomavirus-driven verruca vulgaris infection is common in solid organ transplant recipients and increases the risk for squamous cell carcinoma. The available treatment modalities have limited response. We report a renal allograft recipient who presented with multiple warts not responding to cryotherapy and radiosurgery with one turning malignant, needing amputation of the finger. An extract from Thuja occidentalis (White cedar tree) cured the resistant warts on the other fingers, leaving only superficial scars and without affecting allograft function. We have reviewed the pharmacological and clinical properties of T. occidentalis. PMID- 24049265 TI - Guidelines for diagnosis and management of chronic obstructive pulmonary disease: Joint ICS/NCCP (I) recommendations. AB - Chronic obstructive pulmonary disease (COPD) is a major public health problem in India. Although several International guidelines for diagnosis and management of COPD are available, yet there are lot of gaps in recognition and management of COPD in India due to vast differences in availability and affordability of healthcare facilities across the country. The Indian Chest Society (ICS) and the National College of Chest Physicians (NCCP) of India have joined hands to come out with these evidence-based guidelines to help the physicians at all levels of healthcare to diagnose and manage COPD in a scientific manner. Besides the International literature, the Indian studies were specifically analyzed to arrive at simple and practical recommendations. The evidence is presented under these five headings: (a) definitions, epidemiology, and disease burden; (b) disease assessment and diagnosis; (c) pharmacologic management of stable COPD; (d) management of acute exacerbations; and (e) nonpharmacologic and preventive measures. The modified grade system was used for classifying the quality of evidence as 1, 2, 3, or usual practice point (UPP). The strength of recommendation was graded as A or B depending upon the level of evidence. PMID- 24049275 TI - Percutaneous stent-in-stent placement for renal artery stenosis of a solitary functioning kidney. AB - Renal artery stenosis is an important cause of secondary hypertension in young, which can be treated effectively with endovascular interventions including stenting. In-stent thrombosis is an infrequent complication and necessitates the need to follow-up these patients with renal artery stents. We present here a young individual who presented with in-stent thrombosis in a solitary functioning kidney and was successfully treated with stent-in-stent placement. PMID- 24049276 TI - Post-infectious glomerulonephritis following infective endocarditis: Amenable to immunosuppression. AB - Glomerulonephritis develops in about 20% patients with infective endocarditis (IE), but is mostly asymptomatic. Heavy proteinuria or derangement of kidney functions is uncommon. We report here a child with IE and proliferative glomerulonephritis who manifested as significant proteinuria that recovered on treatment with immunosupressants. PMID- 24049277 TI - An unusual cause of gross hematuria and renal dysfunction in a young male. AB - Monoclonal immunoglobulin deposition disease (MIDD) is an uncommon disease with a peak incidence between the 5(th) and 6(th) decades of life. It is characterized by non-fibrillar, Congo red negative deposition of monoclonal immunoglobulins in various organs, including in the kidneys. MIDD can be of three types depending on the composition of the deposits, and includes light chain deposition disease (LCDD), heavy chain deposition disease and light and heavy chain deposition disease, of which LCDD is the most common. Renal involvement is a universal finding in MIDD, and is in the form of renal insufficiency, microscopic hematuria and nephrotic range proteinuria. Gross hematuria is a rare occurrence. Renal biopsy usually shows nodular sclerosing glomerulopathy on light microscopy and diffuse linear staining of glomerular and tubular basement membrane on immunofluorescence microscopy. We report a young male who presented with rapidly progressive renal failure and gross hematuria and was diagnosed as LCDD with nodular glomerulopathy and crescents on renal biopsy. PMID- 24049278 TI - Severe hypercalcemia unmasked by Vitamin D in a patient with sarcoidosis. AB - Severe hypercalcemia is uncommon in clinical practice and is usually due to primary hperparathyroidism or malignancy. We present a patient who presented with severe hypercalcemia with renal failure; further evaluation of which revealed the diagnosis of sarcoidosis. This case is presented in view of the rarity of presentation of sarcoidosis with hypercalcemic crisis. PMID- 24049279 TI - Non-O1, non-O139 Vibrio cholerae sepsis in a patient with nephrotic syndrome. AB - Non-O1, non-O139 Vibrio cholerae is an encapsulated bacterium, ubiquitous in the marine environment and generally considered to be non-pathogenic. However, it is known to cause diarrheal illness, wound infection, and bacteremia in immunocompromised hosts. Here we have describe non-O1, non-O139 V. cholerae sepsis in a patient with nephrotic syndrome following exposure to sea-water. Interestingly, the exposure occurred remotely 4 months prior to the onset of nephrotic syndrome. The occurrence of florid sepsis after a prolonged interval from the time of exposure is peculiar and raises the possibility of an association between occult Vibrio sepsis and nephrotic syndrome. PMID- 24049280 TI - Isolated cavitary lung disease in a renal allograft recipient: A rare manifestation of cryptococcus. AB - Although lungs are the portal of entry for cryptococcus, pulmonary disease is relatively uncommon. Cavitary pulmonary disease is even less common. We report a rare case of cryptococcosis with an isolated cavitary lung lesion in a renal allograft recipient. PMID- 24049281 TI - Fulminant hepatic failure following marijuana drug abuse: Molecular adsorbent recirculation system therapy. AB - Marijuana is used for psychoactive and recreational purpose. We report a case of fulminant hepatic failure following marijuana drug abuse who recovered following artificial support systems for acute liver failure. There is no published literature of management of marijuana intoxication with molecular adsorbent recirculation system (MARS). MARS is effective and safe in patients with fulminant hepatic failure following marijuana intoxication. PMID- 24049282 TI - Polycystic horseshoe kidney. PMID- 24049283 TI - Unilateral xanthogranulomatous pyelouretritis with a functioning kidney. PMID- 24049284 TI - Catheter related septic inferior vena cava thrombosis. PMID- 24049285 TI - Malignant hypertension and nephrotic range proteinuria without hematuria: IgA nephropathy. PMID- 24049286 TI - Extended spectrum beta lactamase peritonitis: Our experience. PMID- 24049287 TI - Meningioma in long-term survivor after renal transplantation. PMID- 24049288 TI - Cat on a hot tin roof.... PMID- 24049289 TI - Papillary squamotransitional cell carcinoma of the uterine cervix: A histomorphological and immunohistochemical study of nine cases. AB - BACKGROUND: Papillary squamotransitional cell carcinoma (PSCC) is a distinctive subcategory of squamous cell carcinoma of the uterine cervix. It has a propensity for local recurrence and late metastasis. Histologically, it can be misinterpreted as transitional cell carcinoma, or other papillary lesions of the cervix including squamous papilloma, verrucous carcinoma or cervical intraepithelial neoplasia grade 3 with papillary configuration. MATERIALS AND METHODS: Nine cases of PSCC of the uterine cervix were diagnosed on a cervical biopsy specimen on routine hematoxylin and eosin (H and E) stained sections. Their clinic-morphological features were analyzed. The cases were further evaluated immunohistochemically by cytokeratin 7 (CK7), cytokeratin 20 (CK20), p53 and Ki-67. RESULTS: The patients ranged in age from 35 years to 75 years; with abnormal uterine bleeding being the most common clinical presentation. All the cases showed papillary architecture with fibrovascular cores lined by multilayered atypical epithelium. Three cell types were observed: Clear, intermediate and basaloid. Stromal invasion was seen in five cases, whereas in the remaining four cases, the biopsy specimen was too superficial to definitely assess invasion. Immunohistochemically, eight cases were CK7(+)/CK20(-) and one case was CK7(-)/CK20(-). All nine cases showed nuclear accumulation of mutant p53. Moderate and high proliferative activity was observed in two and seven cases, respectively. Five of patients for whom follow-up information was available underwent radical hysterectomy and two of them were disease free 18 months following treatment. CONCLUSION: PSCC of the uterine cervix are a clinicomorphologically distinct group of cervical lesions that display a morphologic spectrum. They are potentially aggressive malignant tumors that should be distinguished from transitional cell carcinoma and other papillary lesions of the uterine cervix. PMID- 24049290 TI - CA-125 and risk of malignancy index for screening for malignancy in fertile aged females with ovarian cyst, which is more cost effectiveness? AB - BACKGROUND: Ovarian tumor is a cause of infertility in the fertile-aged women. Also, it can also turns into malignancy and causes deadly outcome. Screening for malignancy is an important management. AIMS: The available screening methods that are widely used at present include CA-125 determination and the risk of malignancy index (RMX), which is a combined CA-125 with ultrasonography, determination. MATERIALS AND METHODS: Here, the author tries to assess cost effectiveness of both alternative in screening by basic medical economics technique. STATISTICS: Classical descriptive analysis was used for cost effectiveness calculation. RESULTS: In this work, from the cost-effectiveness analysis, the CA-125 test is more cost-effectiveness than RMX. CONCLUSION: This reflects that the usage of additional ultrasonography test for increasing the diagnostic activity in screening for ovarian cyst in the fertile aged females in Thailand is still not appropriate. PMID- 24049291 TI - Serum galactomannan assay for diagnosis of probable invasive Aspergillosis in acute leukemia and hematopoietic stem cell transplantation. AB - BACKGROUND: Invasive aspergillosis (IA) is a leading cause of mortality in acute leukemia and hematopoietic stem cell transplantation (HSCT). AIMS: To determine the yield of galactomannan (GM) assay for the diagnosis of probable IA, its temporal relationship with the computed tomography (CT) scans and correlation with mortality in AL and HSCT. PATIENTS AND METHODS: Consecutive neutropenic episodes (n=150) among inpatients aged >=15 years with AL or recipients of HSCT were prospectively evaluated over 11/2 years. All patients underwent weekly serum GM assay and optical density index >0.5 for >=2 samples was defined as positive. IA was diagnosed according to EORTC 2008 guidelines. RESULTS: Of the 150 episodes enrolled, 43 (28.7%) were diagnosed with IA: possible 25 (16.7%), probable 17 (11.3%) and proven 1 (0.7%). The yield of GM assay in diagnosing probable IA was 17/42 (40.5%). In 88.2% of probable IA episodes, GM was positive before high resolution CT at a median of 10 days (range 1-16). In the episodes with >=2 samples tested, fatality was higher in those >=2 values positive for GM, compared to the rest (31% vs. 13.2%, odd ratio 2.96, 95% CI 1.09-8.00; P=0.04). CONCLUSIONS: In AL and HSCT, GM assay could identify patients with probable IA earlier than CT chest and also predicted a higher risk of death. PMID- 24049292 TI - Clinico-immunological response to intratumoral versus intravenous neoadjuvant chemotherapy in advanced pediatric solid malignancies. AB - BACKGROUND: There is minimal literature on the use of intralesional chemotherapy in the pediatric age group. We undertook this present study to evaluate the two modalities (intratumoral and intravenous) of giving chemotherapy in terms of toxicity of chemotherapy, hematological parameters, efficacy of chemotherapy in reduction in volume of the tumor as well as resectability of tumor with special emphasis on immunological parameters. MATERIALS AND METHODS: Advanced cases of Wilms' tumor and Neuroblastoma were included in the study. Intratumoral chemotherapy was given through 25 G spinal needle under aseptic precautions and ultrasound guidance in the same dose as in systemic chemotherapy. Intravenous group was given chemotherapy in the usual way. Reassessment was carried out after every course of chemotherapy. RESULTS: Group A included 16 cases of Wilms' tumor and 6 cases of neuroblastoma. In group B, there were 14 cases of Wilms' tumor and 8 of neuroblastoma. Vomiting, diarrhea, mucositis, and thrombophlebitis were more common in the intravenous group (P<0.05). The fall in Immunoglobulin A, Immunogloblulin G, Immunoglobulin M, and T-cell rosetting was more common in the intravenous group (P<0.05). Seventy percent of patients had completely resectable tumor at the end of 6 doses of intratumoral chemotherapy as compared to 50% resectability in the intravenous group (P<0.05). CONCLUSION: Intratumoral chemotherapy, besides causing less of the adverse effects and increasing the resecability rate, also causes less suppression of the immune system. This may be offered as an alternative safe and effective modality of treatment for advanced solid tumors. PMID- 24049293 TI - Review of clinical profile and bacterial spectrum and sensitivity patterns of pathogens in febrile neutropenic patients in hematological malignancies: A retrospective analysis from a single center. AB - BACKGROUND: The aim of this study was to study clinical profile with bacterial spectrum and susceptibility patterns of pathogens in culture positive febrile neutropenic (FN) patients of hematological malignancies. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 23 hematological malignancy patients admitted with chemotherapy induced febrile neutropenia with culture positive results, at our institute between June 2011 and December 2011. RESULTS: A total of 23 patients were studied 12 males and 11 females, with a median age of 35 years. Most common diagnosis was acute leukemia (78%) with the majority of patients developing febrile neutropenia during the induction phase of treatment. Most common presenting symptoms were fever, cough, dyspnea, and diarrhea. Primary site of infection was not found in 47% of patients while the rest had lung, gastro-intestinal and skin/soft-tissue infection. Overall 23 organisms were isolated during the study period, from blood (56%), sputum (46%), stool (23%), and nasal swab from one patient. Gram negative bacteria accounted for 78% of organisms while gram positive organisms accounted for 22% of the total isolates. The most common organisms were: Escherichia coli (43%), Staphylococcus aureus (22%), Pseudomonas aeruginosa (17.4%) and Klebsiella pneumonia (17.4%). Antibiotic sensitivity patterns of these bacteria were studied. Gram negative bacterial infections were associated with higher mortality (89%). CONCLUSIONS: Induction phase of treatment in acute leukemia is the major cause of FN in hematological malignancies at our institute and gram negative organisms are the predominant organisms with E. coli as major isolate while S. aureus represents the most common gram positive organism. Amikacin and cefoperazone/sulbactum appears to be initial antibiotic appropriate to cover most gram negative pathogens while vancomycin to be added for suspected gram positive infections. FN represents a major cause of morbidity and mortality in hematological malignancy patients, high index of suspicion and early empirical antibiotics with supportive care are main interventions to reduce high mortality for these patients. Antibiotics should be modified according to culture sensitive report as soon as possible. PMID- 24049294 TI - Epidemiological and clinical profile of triple negative breast cancer at a cancer hospital in North India. AB - BACKGROUND: Triple negative breast cancer (TNBC) is a recent concept and the burning topic of research today. Various studies have been reported in western literature on TNBCs or the similar group of basal like cancers, all highlighting the poor prognostic features of this molecular subtype in comparison to the other types of breast cancers. However extensive data from India is lacking. The aim of this study was to analyze the epidemiological and clinical profile of TNBcs at our institute. MATERIALS AND METHODS: Data on 171 patients of TNBCs registered at this hospital between 2005 and 2008 and followed up until December 2010 was collected and reviewed for epidemiological and clinical features. RESULTS: The median age at presentation was 49 years (22-75 years). Sixty eight patients (40%) had lump in the breast of less than 1 month duration. Fourteen (8%) were nulliparous and 10 (7%) patients had crossed the age of 30 years at first full term pregnancy, 89 (52%) were pre or peri-menopausal at presentation. Only 8 (5%) patients had a family history of breast or ovarian cancer. One hundred and six (62%) patients were stage II, 26 (15%) stage III, 21 (12%) stage I and 18 (10%) stage IV at presentation. One hundred and twenty eight patients (75%) had early breast cancer eligible for surgery at presentation, 25 (15%) were locally advanced and received neoadjuvant chemotherapy (NACT) and 18 (10%) were found to be metastatic. Modified radical mastectomy was the preferred surgical option by most patients (76%) who underwent upfront surgery in our study. The pathological overall response rates (complete and partial response) after NACT was 75% with complete response rate of 25% and there were no relapses in the complete responders. The median follow-up was 30 months (9-70 months). One hundred and twenty two patients (71%) were alive at last follow-up, 34 (22%) had relapsed, 18 (11%) had died due to progressive disease. Thirty one patients (18%) were lost to follow-up. Most of the relapses were systemic and rarely preceded by local relapses. CONCLUSIONS: TNBCs are aggressive cancers with high rates of systemic relapses within the first 3 years of presentation. Longer follow-up of these patients is required for more mature data on these cancers. PMID- 24049295 TI - Long-term survivor of human immunodeficiency virus-associated plasmablastic lymphoma. AB - Plasmablastic lymphoma (PL) is a type of non-Hodgkin's lymphoma (NHL) having a strong association with immunosuppression, especially, human immunodeficiency virus (HIV) infection. It generally has a poor prognosis with most patients dying within 2 years from initial presentation, and long-term survivors are very few. We report the case of a 10-years-old child, presenting in 2003 with swelling on the right side of the face and fever of 2 months. Evaluation revealed a mass in the right palatal and upper alveolar region with extensive spread and bone destruction, regional adenopathy, mass lesion in the liver and hepatosplenomegaly without bone marrow involvement. Histopathology was suggestive of the PL and patient tested positive for HIV. He was started on high grade NHL chemotherapy protocol along with highly-active anti-retroviral therapy HAART. He responded well and is in complete remission since 8 years of completion of treatment and is on HAART. PMID- 24049296 TI - Acute visual loss as the initial presentation in a child with systemic Burkitt lymphoma. AB - Non-Hodgkin lymphoma (NHL) accounts for 10% of pediatric malignancies and is the third most common malignancy in childhood. We report a previous healthy 3-year old boy with stage IV Burkitt lymphoma presenting with acute visual loss. In funduscopy his pupils were fixed at 6 mm in diameter without light perception. He started therapy according to the UKCCSG 9003 protocol. The boy didn't show any visual improvement but some slight light perception despite his partial remission after CYVE II. He died of neutropenic septicemia before his scheduled radiotherapy. In conclusion, loss of vision is a rare presenting sign in NHL. Differential diagnosis is crucial as early diagnosis and effective treatment are important for survival as well as for visual restoration. PMID- 24049297 TI - Four rare extranodal sites seen on FDG PET/CT in a single patient of disseminated lymphoma. AB - Extranodal disease refers to lymphomatous infiltration of anatomic sites other than lymph nodes. With the advent of FDG PET/CT for staging, rare sites of extranodal disease have been documented. We report a case of Non- Hodgkin's lymphoma with four rare extranodal sites, namely adrenal, peripheral nerves, pancreas and prostate, in the same patient, detected on FDG PET/CT imaging. PMID- 24049298 TI - Subcutaneous panniculitis-like T-cell lymphoma in a case of carcinoma cervix. AB - Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon extra nodal non-Hodgkin lymphoma accounting for less than 1% of all NHLs known to have an aggressive course, with no well-defined treatment protocols. A 42-year-old lady, operated five months earlier for a squamous cell carcinoma of the cervix presented with pain and induration of the lower part of the anterior abdominal wall; 3 months after completing chemotherapy and radiotherapy. FNAC done, yielded scanty material and was inconclusive. The biopsy showed features of a subcutaneous panniculitis-like T-cell lymphoma. While on chemotherapy she developed a vault recurrence and extensive intra-abdominal spread of the squamous cell carcinoma and succumbed. SPTCL is a rare entity and has been reported in renal and cardiac allograft recipients and in one case of ovarian carcinoma. Its occurrence in the setting of carcinoma cervix is unusual, hence is being reported. PMID- 24049299 TI - Oral submucous fibrosis at pediatric age, now time to think: Series of two cases. AB - The younger generation is consuming areca nut and areca nut products, which is coming in the market with different multicolored attractive pouches and easily available in each and every corner of the road. For the children from the lower socioeconomic strata, areca nut use is rampant. Alarmingly, it has been seen that the highest period of risk for engaging in areca nut alone is between the ages of 5 and 12. Oral submucous fibrosis associated with areca nut in children is a great concern for the Society and the Government. Factors associated with this report for consuming areca nut are levels of awareness, household environment, peer pressure, low cost, easy availability etc. PMID- 24049300 TI - Management of isolated recurrence of extramedullary myeloid tumor at a single site. AB - Extramedullary myeloid tumors (EMMT) can precede, occur with or follow AML. Rarely, they can present as isolated relapses. We present a 9-year-old child with t (8, 21) positive AML who was treated with induction regimen and achieved remission. While on high-dose cytarabine consolidation, he had isolated relapse in a single cervical lymph node with uninvolved marrow. He was treated with salvage chemotherapy alone. There are no clear guidelines for treatment of isolated extramedullary relapse. Chemotherapy, radiotherapy followed by stem cell transplant is the usual option. Our patient is unique for the unusual site of relapse and prolonged remission with cladribine-based chemotherapy, mitoxantrone based consolidation, and oral maintenance therapy. PMID- 24049301 TI - A diagnostic dilemma in a patient with lymphoma. AB - We report the case of a 49-year-old man with a diagnosis of gastric diffuse large B cell non-Hodgkin's lymphoma, treated with two lines of chemotherapy followed by radiotherapy, and presented about 3 months after completing therapy with recurrent episodes of epigastric pain, gastrointestinal (GI) bleeding. Computed tomography scan, positron emission tomography scan, and upper GI endoscopy revealed gastric wall thickening and lymphadenopathy. Biopsy and histopathology ultimately revealed Strongyloides stercoralis infection that was mimicking disease recurrence. Opportunistic parasitic infections represent one of the major challenges in the management of cancer patients. PMID- 24049302 TI - Oesophageal carcinoma presenting with a synchronous asymptomatic colon carcinoma. AB - The advancement in diagnostic techniques has resulted in increased incidence of occult second primary in cancer patients. Here, we report a case of symptomatic oesophageal carcinoma and synchronous asymptomatic colon carcinoma diagnosed through Positron Emission Tomography-Computed Tomography imaging. PMID- 24049303 TI - Stage IV lung cancer: Is cure possible? AB - Reporting a case, 53 years old male with stage IV Nonsamall cell lung cancer in view of cytologically proven malignant pleural effusion. Usually the management of stage IV lung cancer is with palliative intent where the patient receives palliative chemotherapy along with palliative radiotherapy and surgery if required. Most of the data on curative management of oligometastatic non-small cell lung cancer includes patient with adrenal metastasis and some reports with brain metastasis. There is scarce literature on the surgical management of stage IV lung cancer with pleural effusion. PMID- 24049304 TI - Primary granulocytic sarcoma of lip - A rare extramedullary presentation of myeloid leukemia. AB - A sixty year old male presented with a swelling in the upper lip. On cytopathology, the patient was diagnosed as a case of granulocytic sarcoma. His bone marrow examination was unremarkable. Patient was then treated by radiotherapy alone 30 Gray in 15 fractions and achieved complete response. Eighteen months after follow up the patient is absolutely normal. To our knowledge this is the first ever reported case of granulocytic sarcoma of lip. PMID- 24049305 TI - Stomach metastasis of breast carcinoma mimicking primary gastric neoplasm on fluorodeoxy glucose-positron emission tomography-computed tomography. AB - We present fluorodeoxy glucose positron emission tomography-computed tomography (FDG-PET/CT) findings in a case of breast carcinoma. The PET/CT findings in this case were suspicious of second primary neoplasm in the stomach. However, on endoscopic biopsy, the lesion was found to be stomach metastasis of breast carcinoma with estrogen receptor positivity. Stomach is a rare site of breast carcinoma metastasis. Our case suggests that it is difficult to distinguish a stomach metastasis of breast cancer from a primary gastric cancer on the basis of clinical and imaging features. However, this differential diagnosis must be kept in mind and it is important to make such distinction because of its implications on patient management. PMID- 24049306 TI - Mediastinal ganglioneuroma: An incidentaloma of childhood. AB - Ganglioneuroma is a rare benign neurogenic tumor which represents the final maturation stage of neuroblast tumors. Here, we are discussing an interesting case of incidentally detected posterior mediastinal ganglioneuroma which should be kept in mind when dealing with any child with respiratory distress. PMID- 24049307 TI - Orbital and infratemporal fossa metastasis: An unusual initial presentation of adenocarcinoma of lung. AB - Orbital metastasis as initial presentation of adenocarcinoma of lung is an extremely rare phenomenon. Here, we report a 46-year-old non-smoker Asian woman, who presented with right eye proptosis due to right orbital and infratemporal fossa metastasis, as the first presentation of adenocarcinoma of right lung. PMID- 24049308 TI - Fatal hematogenous relapse of mucinous borderline ovarian tumor of intestinal type. AB - We describe an unusual case of fatal hematogenous relapse of borderline mucinous ovarian tumour of intestinal type after three years of primary optimal cytoreduction with dissemination to liver, bones and lymphangitic pattern of spread in lungs with resistance to standard chemotherapy. PMID- 24049309 TI - Transformation of follicular lymphoma to high-grade Burkitt's like lymphoma and acute lymphoblastic leukemia-L3 type. PMID- 24049310 TI - Use of nimotuzumab in the patient with G-6-PD deficiency: The first world report. PMID- 24049311 TI - Remission of lung metastasis due to single nimotuzumab treatment: A preliminary observation and the first world report. PMID- 24049312 TI - Is it time to reconsider indications for post-mastectomy chest wall irradiation? PMID- 24049313 TI - Celiac disease presented after autologous bone marrow transplantation for acute myelogenous leukemia. PMID- 24049314 TI - Alopecia due to cancer. PMID- 24049315 TI - Sudden increased blood pressure and flu like symptom: An acute adverse reaction to nimotuzumab administration. PMID- 24049316 TI - The role of medical physicists in clinical trials: More than quality assurance. PMID- 24049317 TI - Improvement of dose distribution with irregular surface compensator in whole breast radiotherapy. AB - Aim of this study was to compare the dosimetric aspects of whole breast radiotherapy (WBRT) between an irregular surface compensator (ISC) and a conventional tangential field technique using physical wedges. Treatment plans were produced for 20 patients. The Eclipse treatment planning system (Varian Medical Systems) was used for the dose calculation: For the physical wedge technique, the wedge angle was selected to provide the best dose homogeneity; for the ISC technique, the fluence editor application was used to extend the optimal fluence. These two treatment plans were compared in terms of doses in the planning target volume, the dose homogeneity index, the maximum dose, ipsilateral lung and heart doses for left breast irradiation, and the monitor unit counts required for treatment. Compared with the physical wedge technique, the ISC technique significantly reduced the dose homogeneity index, the maximum dose, the volumes received at 105% of the prescription dose, as well as reducing both the ipsilateral lung and heart doses (P < 0.01 for all comparisons). However, the monitor unit counts were not significantly different between the techniques (P > 0.05). Thus, the ISC technique for WBRT enables significantly better dose distribution in the planning target volume. PMID- 24049318 TI - Comparative analysis between 5 mm and 7.5 mm collimators in CyberKnife radiosurgery for trigeminal neuralgia. AB - Trigeminal neuralgia (TN) is treated in CyberKnife (Accuray Inc, Sunnyvale, USA) with the 5 mm collimator whose dosimetric inaccuracy is higher than the other available collimators. The 7.5 mm collimator which is having less dosimetric uncertainty can be an alternative for 5 mm collimator provided the dose distribution with 7.5 mm collimator is acceptable. Aim of this study is to analyze the role of 7.5 mm collimator in CyberKnife treatment plans of TN. The treatment plans with 5 mm collimators were re-optimized with 7.5 mm collimator and a bi-collimator system (5 mm and 7.5 mm). The treatment plans were compared for target coverage, brainstem doses, and the dose to normal tissues. The target and brainstem doses were comparable. However, the conformity indices were 2.31 +/ 0.52, 2.40 +/- 0.87 and 2.82 +/- 0.51 for 5 mm, bi-collimator (5mm and 7.5 mm), 7.5 mm collimator plans respectively. This shows the level of dose spillage in 7.5 mm collimator plans. The 6 Gy dose volumes in 7.5 mm plans were 1.53 and 1.34 times higher than the 5 mm plan and the bi-collimator plans respectively. The treatment time parameters were lesser for 7.5 mm collimators. Since, the normal tissue dose is pretty high in 7.5 mm collimator plans, the use of it in TN plans can be ruled out though the treatment time is lesser for these 7.5 mm collimator plans. PMID- 24049319 TI - Forward-planned intensity modulated radiation therapy using a cobalt source: A dosimetric study in breast cancer. AB - This analysis evaluates the feasibility and dosimetric results of a simplified intensity-modulated radiotherapy (IMRT) treatment using a cobalt-therapy unit for post-operative breast cancer. Fourteen patients were included. Three plans per patient were produced by a cobalt-60 source: A standard plan with two wedged tangential beams, a standard tangential plan optimized without the use of wedges and a plan based on the forward-planned "field-in-field" IMRT technique (Co-FinF) where the dose on each of the two tangential beams was split into two different segments and the two segments weight was determined with an iterative process. For comparison purposes, a 6-MV photon standard wedged tangential treatment plan was generated. Dmean, D98%, D2%, V95%, V107%, homogeneity, and conformity indices were chosen as parameters for comparison. Co-FinF technique improved the planning target volume dose homogeneity compared to other cobalt-based techniques and reduced maximum doses (D2%) and high-dose volume (V110%). Moreover, it showed a better lung and heart dose sparing with respect to the standard approach. The higher dose homogeneity may encourage the adoption of accelerated hypofractionated treatments also with the cobalt sources. This approach can promote the spread of breast conservative treatment in developing countries. PMID- 24049320 TI - A study on rectal dose measurement in phantom and in vivo using Gafchromic EBT3 film in IMRT and CyberKnife treatments of carcinoma of prostate. AB - The objective of this study is to check the feasibility of in vivo rectal dose measurement in intensity-modulated radiotherapy (IMRT) and CyberKnife treatments for carcinoma prostate. An in-house pelvis phantom made with bee's wax was used in this study. Two cylindrical bone equivalent materials were used to simulate the femur. Target and other critical structures associated with carcinoma prostate were delineated on the treatment planning images by the radiation oncologist. IMRT treatment plan was generated in Oncentra Master Plan treatment planning system and CyberKnife treatment plan was generated in Multiplan treatment planning system. Dose measurements were carried out in phantom and in patient using Gafchromic EBT3 films. RIT software was used to analyze the dose measured by EBT3 films. The measured doses using EBT3 films were compared with the TPS-calculated dose along the anterior rectal wall at multiple points. From the in-phantom measurements, it is observed that the difference between calculated and measured dose was mostly within 5%, except for a few measurement points. The difference between calculated and measured dose in the in-patient measurements was higher than 5% in regions which were away from the target. Gafchromic EBT3 film is a suitable detector for in vivo rectal dose measurements as it offers the possibility of analyzing the dose at multiple points. In addition, the method of extending this in vivo rectal dose measurement technique as a tool for patient-specific quality assurance check is also analyzed. PMID- 24049321 TI - Investigation on the effect of sharp phantom edges on point dose measurement during patient-specific dosimetry with Rapid Arc. AB - The objective of this work was to investigate and quantify the effect of sharp edges of the phantom on the point dose measurement during patient-specific dosimetry with Rapid Arc (RA). Ten patients with carcinoma of prostate were randomly selected for this dosimetric study. Rapid Arc plans were generated with 6 MV X-rays in the Eclipse (v 8.6.14) with single arc (clockwise). Dosimetry verification plans were generated for two phantoms (cylindrical and rectangular). The cylindrical phantom was solid water (diameter 34 cm) and the rectangular phantom was a water phantom (25 cm * 25 cm * 10 cm). These phantoms were pre scanned in computed tomography (CT) machine with cylindrical ionization chamber (FC65) in place. The plans were delivered with Novalis Tx linear accelerator with 6 MV X-rays for both the phantoms separately. The measured dose was compared with the planned dose for both the phantoms. Mean percentage deviation between measured and planned doses was found to be 4.19 (SD 0.82) and 3.63 (SD 0.89) for cylindrical and rectangular phantoms, respectively. No significant dosimetric variation was found due to the geometry (sharp edges) of the phantom. The sharp edges of the phantom do not perturb the patient specific Rapid Arc dosimetry significantly. PMID- 24049322 TI - Commissioning and quality assurance of Calypso four-dimensional target localization system in linear accelerator facility. AB - Four dimensional (4D) target localization system (Calypso System) was installed at our hospital, which is equipped with Beacon Transponders, Console, Electromagnetic Array, Optical System, Tracking Station, Treatment table overlay, and Calypso kVue Couch top. The objective of this presentation is to describe the results of commissioning measurements carried out on the Calypso System to verify the manufacturer specifications and also to evolve a quality assurance (QA) procedure which can be used to test its performance routinely. The QA program consists of a series of tests (QA for checking the calibration or system accuracy, Camera Calibration with L-frame fixture, Camera Calibration with T frame fixture, System calibration Fixture targets test, Localization, and Tracking). These tests were found to be useful to assess the performance of the Calypso System. PMID- 24049323 TI - Role of step size and max dwell time in anatomy based inverse optimization for prostate implants. AB - In high dose rate (HDR) brachytherapy, the source dwell times and dwell positions are vital parameters in achieving a desirable implant dose distribution. Inverse treatment planning requires an optimal choice of these parameters to achieve the desired target coverage with the lowest achievable dose to the organs at risk (OAR). This study was designed to evaluate the optimum source step size and maximum source dwell time for prostate brachytherapy implants using an Ir-192 source. In total, one hundred inverse treatment plans were generated for the four patients included in this study. Twenty-five treatment plans were created for each patient by varying the step size and maximum source dwell time during anatomy-based, inverse-planned optimization. Other relevant treatment planning parameters were kept constant, including the dose constraints and source dwell positions. Each plan was evaluated for target coverage, urethral and rectal dose sparing, treatment time, relative target dose homogeneity, and nonuniformity ratio. The plans with 0.5 cm step size were seen to have clinically acceptable tumor coverage, minimal normal structure doses, and minimum treatment time as compared with the other step sizes. The target coverage for this step size is 87% of the prescription dose, while the urethral and maximum rectal doses were 107.3 and 68.7%, respectively. No appreciable difference in plan quality was observed with variation in maximum source dwell time. The step size plays a significant role in plan optimization for prostate implants. Our study supports use of a 0.5 cm step size for prostate implants. PMID- 24049324 TI - Whose manuscript is it anyway? The 'Write' position and number of authors.... PMID- 24049325 TI - Growing from strength to strength. PMID- 24049326 TI - An innovative cosmetic technique called lip repositioning: A less invasive treatment possibility for dentists and surgeons. PMID- 24049327 TI - Plasticity of T helper cell subsets: Implications in periodontal disease. AB - T helper (Th) cells have an important role in host defence as well in the pathogenesis of periodontal disease. Th cells differentiate from naive cells into various subsets, each of which is associated with a set of inducing and effector cytokines. Previously, it was thought that this differentiation was an irreversible event. Recent evidence suggest that even differentiated Th cells, retain the flexibility to transform from one lineage to another, a phenomenon referred to as plasticity. This plasticity is thought to be brought about by epigenetic modifications that are regulated by external and internal signals in the micro-environment of these cells. The factors and mechanisms which affect the plasticity of these cells and their potential role in the etio-pathogenesis of periodontal disease has been described in this article. PMID- 24049329 TI - Vitamin D and periodontal health: Current concepts. AB - Vitamin D is crucial for a wide variety of organ systems; nevertheless, its deficiency is highly prevalent, present in 30-50% of the general population. Evidence has demonstrated that vitamin D deficiency may place subjects at risk for not only low mineral bone density/osteoporosis and osteopenia, but also infectious and chronic inflammatory diseases. Through its effect on bone and mineral metabolism, innate immunity, and several vitamin D receptor gene polymorphisms, vitamin D has been reported to be associated with the periodontal disease. PMID- 24049328 TI - Molecular mechanisms involved in the bidirectional relationship between diabetes mellitus and periodontal disease. AB - Both diabetes and periodontitis are chronic diseases. Diabetes has many adverse effects on the periodontium, and conversely periodontitis may have deleterious effects further aggravating the condition in diabetics. The potential common pathophysiologic pathways include those associated with inflammation, altered host responses, altered tissue homeostasis, and insulin resistance. This review examines the relationship that exists between periodontal diseases and diabetes mellitus with a focus on potential common pathophysiologic mechanisms. PMID- 24049331 TI - Enzymatic evaluation of gingival crevicular fluid in cleft palate patients during orthodontic treatment: A clinico-biochemical study. AB - BACKGROUND: Therapeutic goal in patients with cleft lip and palate is esthetics and long-term health of the stomatognathic system. Patients with cleft lip and palate routinely require extensive and prolonged orthodontic treatment. The osseous structures are absent or poorly developed in the osseous clefts and may be traumatized in the course of orthodontic therapy; hence require constant monitoring during orthodontic treatment. The aim of the study was to evaluate the tissue response of cleft palate patients by quantitative analysis of enzyme activity during orthodontic treatment and assess any difference in the tissue response with that of noncleft patients undergoing orthodontic treatment. MATERIALS AND METHODS: 20 patients requiring orthodontic treatment agedbetween 15 to 25 years were included to participate in the studyof which ten were cleft palate patients (group I) and ten noncleft patients (group II). The GCF samples were collected at incisor and molar sites during orthodontic treatment on days as per the study design in both the groups. The GCF enzymatic levels were estimated and compared. RESULTS: Both groups showed significant increased enzyme activity at the incisor site compared to molar site corresponding to the phases of tooth movement. CONCLUSION: There was significant difference in enzyme activity between the incisor adjacent to the cleft site and molar site. There was no difference in the tissue response between cleft palate patients and noncleft patients during orthodontic treatment. PMID- 24049330 TI - Understanding the advances in biology of orthodontic tooth movement for improved ortho-perio interdisciplinary approach. AB - This article provides an insight on detailed current advances in molecular understandings of periodontal ligament cells and the influence of orthodontic force on them in the light of recent advances in molecular and genetic sciences. It sequentially unfolds the cellular events beginning from the mechanical force initiated events of cellular responses to bone remodeling. It also highlights the risks and limitations of orthodontic treatment in certain periodontal conditions, the important areas of team work, orthodontic expectations from periodontal treatment and the possibility of much more future combined research to improve the best possible periodontal health and esthetic outcome of the patient. PMID- 24049332 TI - Effect of surgical and non-surgical periodontal debridement on vascular thrombotic markers in hypertensives. AB - BACKGROUND: Periodontal debridement has an impact on the vascular thrombotic markers in healthy individuals. This study aimed to investigate changes in several vascular thrombotic markers after surgical and non-surgical periodontal debridement in hypertensives with periodontitis. MATERIALS AND METHODS: 40 hypertensives, 27 males and 13 females, 37-68 year old, mean 51.2 years, with moderate to severe periodontitis, were divided into two groups, (n = 20 for each); the first received comprehensive one session non-surgical periodontal debridement, (pockets 4-6 mm), while the second received comprehensive supragingival scaling with surgical debridement at one quadrant, (Pockets > 6 mm). Periodontal parameters included; plaque index (PI), gingival inflammation (GI), bleeding on probing (BOP), pocket probing depth (PPD). Vascular thrombotic tests included; platelets count (Plt), fibrinogen (Fib), Von Willebrand factor antigen activity (vWF:Ag), and D-dimers (DD). RESULTS: PI, GI, BOP, PPD, decreased significantly (P = 0.001) after 6 weeks of periodontal debridement in both groups, while BOP and PPD remained higher in the surgical one (P < 0.05). Thrombotic vascular markers changes through the three-time intervals were significant in each group (P = 0.001), and time-group interception effect was significant for vWF:Ag (P = 0.005), while no significant differences between groups after treatment (P > 0.05). CONCLUSION: Periodontal debridement, surgical and non-surgical, improved the periodontal status in hypertensives. Periodontal treatment activated the coagulation system in hypertensives and recessed later while the treatment modality did not affect the degree of activation. PMID- 24049333 TI - Comparative evaluation of levels of C-reactive protein and PMN in periodontitis patients related to cardiovascular disease. AB - BACKGROUND: Numerous cross-sectional studies have suggested that chronic periodontitis is a risk factor for cardiovascular diseases. There is evidence that periodontitis and cardiovascular diseases are linked by inflammatory factors including C-reactive protein. The purpose of the study was to investigate the levels of CRP and PNM cells as a marker of inflammatory host response in the serum of chronic periodontitis patients and in patients with CVD. MATERIALS AND METHODS: Study population included 75 patients; both male and female above 35 years were included for the study. The patients were divided into three groups of 25 each - Group I: Chronic periodontitis patients with CVD, Group II: Chronic periodontitis patients without CVD and Group III: Control subjects (without chronic periodontitis and CVD). Patients with chronic periodontitis had >=8 teeth involved with probing depth (PD) >=5 mm involved. The control group had PD <= 3 mm and no CVD. Venous blood was collected from the patients and C-reactive protein levels were analyzed by immunoturbidimetry. PMN was recorded by differential count method. RESULTS: On comparison, OHI-S Index, GI, mean PD, CRP and PMN values showed significant difference from Group I to III. CRP level was highly significant in Group I when compared with Group II and Group III. PMN level was highly significant in Group I when compared with Group III PMN level which was not significant. CONCLUSION: This study indicated that periodontitis may add the inflammation burden of the individual and may result in increased levels of CVD based on serum CRP levels. Thus, controlled prospective trials with large sample size should be carried out to know the true nature of the relationship if indeed one exists. PMID- 24049334 TI - Evaluation of serum ceruloplasmin in aggressive and chronic periodontitis patients. AB - BACKGROUND: Pro-inflammatory markers are seen to increase in inflammatory diseases like periodontitis. Detecting an increase in these markers is one of the diagnostic modality. One such marker, which can be detected, is the ceruloplasmin. Ceruloplasmin induces hypoxia and generates oxygen radicals at the site of aggressive periodontitis. It also causes a state of hypoferremia leading to increase in the natural resistance of the body. The aim of this study was to evaluate the serum levels of cerruloplasmin in both aggressive and chronic periodontitis patients. MATERIALS AND METHODS: Blood samples were collected from aggressive periodontitis patients (n = 20), chronic periodontitis patients (n = 20) and periodontally healthy patients (n = 20). The serum was extracted from all the blood samples and ceruloplasmin levels were spectroscopically evaluated through a new kinetic method, which used a norfloxacin based reagent. RESULTS: Serum ceruloplasmin levels were found to be significantly higher in aggressive periodontitis patients (P > 0.05) than in chronic periodontitis patients (P > 0.05) even though increase in the level of ceruloplasmin was found in chronic periodontitis. Periodontally healthy patients did not show increase in the levels of serum ceruloplasmin. The levels of serum ceruloplasmin also increased with the disease severity whose manifestations were increased bleeding on probing, increased pocket depth and increased attachment loss. CONCLUSION: Serum ceruloplasmin levels increased in both aggressive and chronic periodontitis patients, but more in aggressive periodontitis patients making it a potential marker for diagnosis of periodontitis. PMID- 24049335 TI - Periodontitis, diabetes mellitus, and the lopsided redox balance: A unifying axis. AB - AIM: The aim of present study was to evaluate and compare the total antioxidant capacity in the saliva of type 2 diabetes mellitus (DM) patients and healthy subjects, with and without periodontal disease. MATERIALS AND METHODS: The study was designed as a case-control study, comprising of 120 male subjects, who were divided into four groups of 30 patients each. Group I: Thirty type 2 diabetic males with periodontal disease; Group II: Thirty type 2 diabetic males without periodontal disease; Group III: Thirty healthy males with periodontal disease; Group IV: Thirty healthy males without periodontal disease. After clinical measurement and sampling, the total antioxidant capacities in the saliva of type 2 diabetic and healthy men were determined, and the data were tested by non parametric tests. The total antioxidant capacity of the clinical samples was determined spectrophotometrically. RESULTS: The total antioxidant capacity in the saliva was the lowest in type 2 diabetic males with periodontal disease. The results were statistically significant. CONCLUSION: The findings of our study finally conclude that the salivary total antioxidant capacity is affected in type 2 diabetic males, in addition to the impact of periodontal disease, and hence, can be used as a useful marker of periodontitis in healthy and diabetic patients. PMID- 24049336 TI - Use of autologous platelet rich plasma to treat gingival recession in esthetic periodontal surgery. AB - BACKGROUND: Multiple approaches have been used to replace lost, damaged or diseased gingival tissues. Coronally advanced flap (CAF) and the use of guided tissue regeneration are among the successfully used surgical techniques to treat gingival recession. Platelet rich plasma (PRP), containing autologous growth factors, has been shown to promote soft-tissue healing. Therefore, the purpose of this study was to evaluate the efficacy of PRP in combination with CAF in the treatment of gingival recession. MATERIALS AND METHODS: A total of 15 systemically healthy patients with buccal Miller's class I and class II gingival recession in cuspids or premolars participated in the study. CAF procedure was performed and PRP with collagen sponge was placed over the defect. Clinical parameters such as recession depth, recession width, surface area, width of keratinized gingival (KG), clinical attachment level (CAL), probing depth, plaque index and gingival index were evaluated at 3, 6 and 9 months post-surgery. The percentage of root coverage was calculated. RESULTS: The results of this study suggest that the CAF procedure provides a predictable and simple technique in the treatment of localized Class I and Class II gingival recession. The additional application of PRP does significantly increase the width of KG and gain in clinical attachment. CONCLUSION: CAF procedure is a predictable and simple technique in the treatment of gingival recession and the additional application of PRP does significantly increase the width of KG and gain in CAL. The long-term benefits following surgical treatment of such defects needs to be determined further. PMID- 24049337 TI - Evaluation of single-tooth replacement by an immediate implant covered with connective tissue graft as a biologic barrier. AB - BACKGROUND AND OBJECTIVES: The aim of the present study was to evaluate the survival rate of Screw-Vent((r)) immediate implants augmented with sub epithelial connective tissue graft for single-tooth replacement for 1 year. MATERIALS AND METHODS: Ten patients (five men and five women), with the mean age of 25.3 years, were consecutively treated on the out-patient basis by the placement of Screw Vent((r)) dental implants in to the fresh extraction sockets in association of augmentation with sub epithelial connective tissue graft harvested from the palate, supporting single crowns. The clinical and radiographic parameters were recorded to evaluate the peri-implant soft tissue health and marginal bone loss, respectively, for each patient at baseline and at every 3 months interval for 1 year. RESULTS: The 1 year cumulative survival rate of Screw-Vent((r)) dental implants was 100% for all 10 patients. Statistical analysis demonstrated highly significant values indicating an improvement in peri-implant soft tissue parameters in terms of peri-implant aesthetic parameters, which estimated the keratinized mucosa width. Statistically, non-significant marginal bone loss or gain indicated stable condition in hard tissue parameters. INTERPRETATION AND CONCLUSION: Single-tooth replacement by Screw-Vent((r)) dental implants in to a fresh extraction socket, in association with guided bone regeneration using autologous connective tissue graft is a predictable treatment as demonstrated by the 100% implant survival rates and appreciable increase in the width of the keratinized mucosa at 1 year follow up. PMID- 24049338 TI - Evaluation of efficacy of autologous platelet-rich fibrin with demineralized freeze dried bone allograft in the treatment of periodontal intrabony defects. AB - BACKGROUND: Platelet-rich fibrin (PRF), an intimate assembly of cytokines, glycan chains, and structural glycoproteins enmeshed within a slowly polymerized fibrin network, has the potential to accelerate soft and hard tissue healing. The purpose of the study was to clinically evaluate and compare the efficacy of autologous PRF combined with demineralized freeze-dried bone allograft (DFDBA) to DFDBA alone in the treatment of periodontal intrabony defects. MATERIALS AND METHODS: In a split mouth study design, 10 patients having two almost identical intrabony defects with clinical probing depth of at least 6 mm were selected for the study. Selected sites were randomly divided into two groups. In Group I, mucoperiosteal flap elevation followed by the placement of DFDBA was done. In Group II, mucoperiosteal flap elevation followed by the placement of homogeneous mixture of PRF with DFDBA was done. Clinical and radiographic parameters were recorded at baseline and at 6 months post-operatively. RESULTS: Both treatment groups showed a significant probing pocket depth reduction, clinical attachment gain, defect fill, and defect resolution 6 months after surgery compared to baseline. However, there was a significantly greater probing pocket depth reduction and clinical attachment gain when PRF was added to DFDBA. CONCLUSION: Within limits of the study it may be concluded that a combination of PRF with DFDBA demonstrated better results in probing pocket depth reduction and clinical attachment level gain as compared to DFDBA alone in the treatment of periodontal intrabony defects. PMID- 24049339 TI - Evaluation of bioactive glass and demineralized freeze dried bone allograft in the treatment of periodontal intraosseous defects: A comparative clinico radiographic study. AB - AIM: The purpose of this study was to evaluate the efficacy of demineralized freeze dried bone allograft (DFDBA) and bioactive glass by clinically and radiographically in periodontal intrabony defects for a period of 12 months. MATERIALS AND METHODS: Ten systemically healthy patients diagnosed with chronic periodontitis, with radiographic evidence of at least a pair of contralateral vertical osseous defects were included in this study. Defect on one-side is treated with DFDBA and the other side with bioactive glass. Clinical and radiographic measurements were made at baseline 6 month and 12 month after the surgery. RESULTS: Compared to baseline, the 12 month results indicated that both treatment modalities resulted in significant changes in all clinical parameters (gingival index, probing depth, clinical attachment level (CAL) and radiographic parameters (bone fill); P < 0.001*). However, sites treated with DFDBA exhibited statistically significantly more changes compared to the bioactive glass in probing depth reduction (2.5 +/- 0.1 mm vs. 1.8 +/- 0.1 mm) CAL gain 2.4 +/- 0.1 mm versus 1.7 +/- 0.2 mm; (P < 0.001*). At 12 months, sites treated with bioactive glass exhibited 56.99% bone fill and 64.76% bone fill for DFDBA sites, which is statistically significant (P < 0.05*). CONCLUSION: After 12 months, there was a significant difference between the two materials with sites grafted with DFDBA showing better reduction in probing pocket depth, gain in CAL and a greater percentage of bone fill when compared to that of bioactive glass. PMID- 24049340 TI - Papillon-Lefevre syndrome: A case report of 2 affected siblings. AB - Papillon-Lefevre syndrome (PLS) is a very rare syndrome of autosomal recessive inheritance characterized by palmar-plantar hyperkeratosis and early onset periodontitis, leading to premature loss of both primary and permanent dentitions. Various etiopathogenic factors are associated with the syndrome, but a recent report has suggested that the condition is linked to x mutations of the cathepsin C gene. The purpose of this report is to describe two cases of PLS in the same family who presented to the Department of Dentistry of Dr. R. P. Government Medical College at Tanda, Kangra (Himachal Pradesh) with a chief complaint of mobility and rapid loss of teeth. Hyperkeratosis of palms and soles was present. On intraoral examination, there was severe gingival inflammation, abscess formation, and deep periodontal pockets with mobility of teeth. Histopathological examination of the specimen taken from the thickened skin was reported to be consistent with PLS. The dental treatment comprised oral prophylaxis, scaling and root planning, antibiotic therapy, instructions on oral hygiene, restorations, extraction of hopelessly affected teeth, and prosthetic rehabilitation. PMID- 24049342 TI - Paramolar concrescence and periodontitis. AB - Concrescence is a developmental anomaly of dental hard tissues. It is a condition showing union of adjacent teeth by cementum. The concrescence leads to a loss of gingival architecture leading to the development of funnels, which may cause plaque accumulation thus, resulting in periodontal tissue destruction. There is a slight predilection for the mandible especially in the premolar area followed by the molar and anterior regions. Awareness of these developmental disturbances with proper diagnosis and treatment is very essential because it can compromise the periodontal attachment and can lead to the tooth loss. This article highlights the presence of a concrescence between mandibular second molar and the supernumerary fused teeth with their clinical and radiographic findings, along with its management. PMID- 24049341 TI - Orthodontic-periodontic intervention of pathological migration of maxillary anterior teeth in advanced periodontal disease. AB - This case report presents a female patient whose chief complaint was of mobile and palatally drifted upper left central incisor which led to malalignment of upper anterior teeth. Orthodontic treatment of upper left central incisor was done with the help of 'Z' spring for the alignment of the upper anterior teeth. It was followed by splinting of upper anterior teeth to improve the stability and masticatory comfort. Regenerative periodontal surgery with Decalcified freeze dried bone allograft was done in relation to upper left central incisor. PMID- 24049343 TI - Ipsilateral idiopathic gingival enlargement and it's management using conventional gingivectomy and diode laser: A recurrent case after 15 years. AB - Idiopathic gingival fibromatosis is a relatively rare condition characterized by the proliferation of the gingival tissues resulting in masticatory, esthetics, phonetics and psychological disturbances. The severity of the overgrowth can range from a solitary isolated mass to a more generalized and diffused enlargement. The etiopathogenesis of this bizarre condition is poorly understood and has been attributed to various factors. It can present as a single disorder or may manifest as part of a syndrome. This case reports an ipsilateral diffused idiopathic gingival enlargement in a middle aged adult recurring after a gap of 15 years. External bevel gingivectomy on the buccal aspects of maxillary and mandibular gingiva and diode laser for excision of the enlarged tissue on the lingual/palatal aspect was carried out to eliminate the excessive tissue. Periodic recalls showed maintenance of good oral hygiene and 1 year follow-up revealed no recurrence. PMID- 24049344 TI - Multiple myeloma presenting as gingival hyperplasia. AB - Multiple myeloma is a malignant neoplasm that is characterized by a monoclonal proliferation of plasma cells. Oral and maxillofacial manifestations as an initial sign or symptom of multiple myeloma are rare. A 58-year-old male patient presented with generalized gingival enlargement for last 6 months. Based on clinical presentation, a diagnosis of gingival hyperplasia was made. After Phase I therapy, excisional biopsy was taken in anterior mandibular region and excised tissue was sent for histopathological examination. The histopathology report revealed a lining of stratified squamous epithelium with foci of ulceration. The subepithelial zone showed infiltration by sheets of mainly binucleate and multinucleate plasma cells, few cells being less differentiated. Rounded cytoplasmic inclusion bodies were identified in many of these cells. After a series of clinical investigations, a case of "multiple myeloma" was diagnosed. Patient presenting with generalized gingival hyperplasia should be worked up for systemic disease like multiple myeloma. PMID- 24049345 TI - On the minimally invasive approach to the gingival recession. AB - Some aspects of pathogenesis and therapeutic approach to the gingival recession are discussed in this short communication with the example of a typical case from Russia, where excessive socket curettage after a tooth extraction resulted in a marked gingival recession. Subgingival plaque and calculus can be secondary to recession. An argument about plaque as a source of microorganisms might be plausible in case of inflammation, although various microorganisms are normal for the oral cavity. From the viewpoint of general pathology, being an atrophic condition, recession can progress due to repeated damage. On the author's opinion, calculus removal is not indicated at least for aged patients with marked gingival recession, having modest esthetic demands. Socket curettage after exodontia should be gentle. Surgical treatment of the gingival recession is beyond the scope of this communication. PMID- 24049346 TI - Who is Really Afraid of Death? PMID- 24049347 TI - Perceptions and attitudes towards organ donation among people seeking healthcare in tertiary care centers of coastal South India. AB - BACKGROUND: Organ transplantation is the most preferred treatment modality for end-stage organ diseases. The need for the transplants is higher than the availability. Prerequisites for the success of transplantation program include awareness and positive attitudes. AIM: To assess the perceptions and attitudes of the people seeking health care in tertiary care centers towards organ donation in Mangalore, India. SETTINGS AND DESIGN: This cross-sectional study included 863 people seeking general healthcare as outpatients. MATERIALS AND METHODS: Face to face interviews were carried out using pretested tools which included the socio demographic data. Data was analyzed using Statistical Package for Social Sciences version 11.5. RESULTS: Overall, 59.6% participants showed the willingness to donate organs. Females (64.1%) and participants from upper socio economic status (62.7%) had higher willingness rates for organ donations. Hindus (63.6%) and Christians (63.3%) had higher willingness rates for organ donations than Muslims (38.2%). Also, 23.7% participants showed willingness to donate eyes and 33.6% wished to donate any organ after death. Most of the participants (67%) were aware that money should not be accepted for donating organs, and 58.1% were aware that it is an offence to accept any benefit for organ donations. Forty percent participants had perceived risks associated with organ donation. Regarding donor cards, 42.3% of the participants knew about it and 3.7% already possessed it. CONCLUSION: It is apparent from the study that though there was high level of awareness about organ donation, a high proportion of the participants did not have positive attitudes towards organ donation. PMID- 24049348 TI - Distress screening using distress thermometer in head and neck cancer patients undergoing radiotherapy and evaluation of causal factors predicting occurrence of distress. AB - INTRODUCTION: Distress is commonly seen in head and neck cancer patients undergoing radiotherapy. Causal factors of distress are multifactorial; which encompasses physical, psychological, spiritual, and existential factors with complex interrelationship among the factors. MATERIALS AND METHODS: Thirty patients undergoing head and neck radiotherapy were included in the study. Patients were screened for pain scores, distress scores, physical and psychological symptoms, and spiritual and emotional distress. RESULTS: Significant increasing trend seen for pain score, distress score, and total number of symptoms during 2(nd) week, 4(th) week, and on completion of radiotherapy treatment (all P's < 0.001) compared to pretreatment. Those who had chemotherapy (CT) along with radiation had significantly greater pain score (t = 5.54, P = 0.03) and distress score (t = 3.9, P = 0.05) at 2 weeks into radiotherapy compared to those who did not receive CT. There was significantly higher grade of skin toxicity in those with spiritual distress (Somers' d = 0.36, P = 0.02) and higher grade of mucositis in those with existential distress (d = 0.34, P = 0.02) at 4 weeks into radiotherapy. CONCLUSION: Positive correlation between distress score and pain score and occurrence of physical symptoms. Increasing trend seen for pain score, distress score, and total number of symptoms during 2(nd) week, 4(th) week, and completion of radiotherapy treatment compared to pretreatment. Increase in distress score in those with existential and spiritual distress. PMID- 24049349 TI - Hypofractionated Palliative Radiotherapy in Locally Advanced Inoperable Head and Neck Cancer: CMC Vellore Experience. AB - BACKGROUND: A novel, short duration, palliative radiotherapy schedule for inoperable head and neck cancer was evaluated in terms of palliation of cancer related symptoms and acute toxicities. MATERIALS AND METHODS: Thirty-six patients with inoperable head and neck cancer were included in the study (2010-2012). All patients received 40 Gy in 10 fractions (equivalent dose: 49.8 Gy in conventional fractionation) with 2 fractions per week. Treatment-related toxicity was assessed using Radiation Therapy Oncology Group criteria. Functional Assessment of Cancer Therapy (Head and Neck, FACT H and N) quality of life (QOL) tool was administered before starting and at the completion of radiotherapy. Mean value before and after treatment was compared (paired t-test, P = 0.05, two-tailed for significance). RESULTS: Thirty-three patients (male: 29, female: 4, mean age: 57.8 +/- 9.7 years) were included in the analysis (three patients discontinued treatment due to socioeconomic reasons). All patients had advanced inoperable head and neck cancers (27% IVA, 61% IVB, 9% IVC, TNM stage and 3% recurrent disease). Distressing pain at primary site (42%), dysphagia (18%), neck swelling (30%), and hoarseness (10%) were common presentations. Incidence of grade III mucositis and dermatitis and pain was 18%, 3%, and 24%, respectively. Planned radiotherapy without any interruptions was completed by 73% patients. QOL assessment showed improvement in social well-being (17.4 vs. 20.01, P = 0.03), but no significant change was observed in head and neck specific score (25.1 vs. 25.0, P = NS) after treatment. Reduction of pain was observed in 88% patients and 60% patients had improvement of performance status. Median overall survival of the cohort was 7 months. CONCLUSIONS: The study shows that this short duration palliative radiotherapy schedule is a clinically viable option for advanced inoperable head and neck cancer to achieve significant palliation of the main presenting symptoms like pain, dysphagia, and throat pain. PMID- 24049351 TI - Commentary. PMID- 24049350 TI - Spiritual concerns in hindu cancer patients undergoing palliative care: a qualitative study. AB - AIMS: Spiritual concerns are being identified as important components of palliative care. The aim of this study was to explore the nature of spiritual concerns in cancer patients undergoing palliative care in a hospice in India. MATERIALS AND METHODS: THE METHODOLOGY USED WAS A QUALITATIVE METHOD: Interpretive phenomenological analysis. A semi-structured interview guide was used to collect data, based on Indian and western literature reports. Certain aspects like karma and pooja, relevant to Hindus, were included. Theme saturation was achieved on interviewing 10 participants. RESULTS: The seven most common spiritual concerns reported were benefit of pooja, faith in God, concern about the future, concept of rebirth, acceptance of one's situation, belief in karma, and the question Why me? No participant expressed four of the concerns studied: Loneliness, need of seeking forgiveness from others, not being remembered later, and religious struggle. CONCLUSIONS: This study confirms that there are spiritual concerns reported by patients receiving palliative care. The qualitative descriptions give a good idea about these experiences, and how patients deal with them. The study indicates the need for adequate attention to spiritual aspects during palliative care. PMID- 24049352 TI - Tracheobronchomalacia post-pneumonectomy: a late complication. AB - An 83-year-old male presented with dyspnoea and stridor. He had undergone pneumonectomy 40 years ago. CT scan revealed gross shift of mediastinum (post pneumonectomy syndrome) with tortuous trachea kinked at the thoracic inlet. Fibre optic bronchoscopy showed a near total expiratory closure of trachea, right main bronchus, and segmental bronchi confirming tracheobronchomalacia. He was managed with long length, low tracheostomy in view of his poor general condition of permitting more invasive procedures. He showed adequate clinical improvement and was discharged home. Tracheobronchomalacia in post-pneumonectomy syndrome requires emergent management. Its occurrence after 40 years is very rare and may be easily missed. It can be diagnosed with dynamic CT and FOB. Although invasive management with stenting or surgical methods is routinely advised, conservative care can be effective in selected cases. PMID- 24049353 TI - Persistent hiccups in cancer patient: a presentation of syndrome of inappropriate antidiuretic hormone induced hyponatremia. AB - Hyponatremia is quite common in cancer patients, but the presentation as persistent hiccups is not common. Literature over hiccups development due to hyponatremia is quite scant. Hiccups are of various types, persistent hiccups are those that last more than 48 h and remains less than 1 month. Hiccups lasting more than 24 h require investigation for an underlying organic etiology, with hyponatremia included in the differential diagnosis. This paper discusses a carcinoma lip patient presented with the persistent hiccups and unconsciousness post-operatively. The patient was initially responded with trials of both metoclopramide and Ryle's tube insertion, but eventually, his hiccups resolved only after treatment of hyponatremia. Patient's clinical course and investigations suggest an etiology of syndrome of inappropriate antidiuretic hormone (SIADH) secretion behind the hyponatremia. Study suggested that SIADH linked hyponatremia should be considered in the differential diagnosis of cancer patients with refractory hiccups. PMID- 24049354 TI - Gall bladder carcinoma presenting with spinal metastasis: a rare phenomenon. AB - Skeletal metastasis as a primary presentation of gall bladder carcinoma is rare. A 50-year-old lady presented with neck pain and weakness in her right upper limb of 3 months duration. Clinical and imaging work-up suggested locally advanced gall bladder carcinoma with metastasis to cervical vertebra and sternum. Only one case till date has been reported where the patient presented with neurological symptoms due to pathological fracture secondary to metastasis from an occult gall bladder carcinoma. Although rare, an occult gall bladder cancer may present with neurological symptoms due to pathological fracture of spine secondary to metastasis. We present a brief review of literature of patients who presented with skeletal metastases in clinically silent gall bladder malignancy. Palliative care issues in advanced gall bladder carcinoma have also been discussed. PMID- 24049355 TI - Pericardial-peritoneal window: a novel palliative treatment for malignant and recurrent cardiac tamponade. AB - Transdiaphragmatic approach to the pericardium through a subxiphoid incision is a safe, rapid, and effective way to obtain drainage of the pericardium fluid in patient of disseminated malignancy with recurrent cardiac tamponade. No drainage tubes are needed; pericardial fluid is absorbed by the peritoneum; there is no need for double lumen tubes for single lung ventilation and the subxiphoid incisions are small and almost painless. PMID- 24049356 TI - Type 2 (impending) carotid blow out syndrome. PMID- 24049357 TI - Curative to palliative care-transition and communication issues: surgeons perspective. AB - Transition of a cancer patient from curative to palliative stage is one of the most difficult and challenging phases of cancer care both from patient and physician point of view. Most of the time the treating surgeons are expected to facilitate this transition but due to a number of reasons surgeons often fail to fulfill this crucial responsibility. This article highlights the various issues involved in the transition phase from a surgeons perspective. PMID- 24049358 TI - Effective palliative care in head and neck cancer: need of the hour. PMID- 24049359 TI - Guided/Graded Motor Imagery for Cancer Pain: Exploring the Mind-Brain Inter relationship. PMID- 24049360 TI - Evidence-based Practice in Chronic Pain: A Multidimensional Biopsychosocial Paradigm is the "Need of the Hour" in Palliative Care. PMID- 24049361 TI - State of the Globe: The H1N1 Threat Continues to Loom the Planet. PMID- 24049362 TI - Clinical Outcome of Novel H1N1 (Swine Flu)-Infected Patients During 2009 Pandemic at Tertiary Referral Hospital in Western India. AB - BACKGROUND: The first case of 2009 pandemic influenza A (H1N1) virus in Gujarat, India, was reported in August 2009. Oseltamivir was used for treatment of pandemic influenza in India. We discuss the clinical characteristics and outcome of the hospitalized patients with H1N1 infection during 2009 pandemic influenza season. MATERIALS AND METHODS: Hospitalized patient with laboratory-confirmed H1N1 flu during August 2009 to February 2010 were included in this retrospective study. Data were collected from hospital ICU charts. Patients discharged from hospital were considered cured from swine flu. Data analysis was performed using CDC software EPI Info v3.5.3. Both univariate and multivariate analyses were conducted. RESULTS: A total of 63 patients were included in the study, of them 41 (65%) males and 22 (35%) females. Median age was 34 (3-69) years and median duration of symptoms before hospitalization was 5 (2-20) days. Common presenting symptoms include fever 58 (92.06%), cough 58 (92.06%), breathlessness 38 (60.31%), common cold 14 (22.22%), vomiting 12 (19.04%), weakness 9 (14.28%), throat pain 7 (11.11%), body ache 5 (7.93%), and chest pain 4 (6.34%). Co morbidities were seen in 13 (20.63%) patients. Steroids were used in 39 (61.90%) patients, and ventilatory support was required in 17 (26.98%) patients. On presentation chest x-ray was normal in 20 (31.74%) patients, while pulmonary opacities were seen in 43 (68.26%) patients. Forty-seven (74.60%) patients were cured and discharged from hospital, 14 (22.22%) patients died, and 2 (3.17%) patients were shifted to other hospital. Ventilatory requirement, pneumonia, and co-morbidities were the independent predictors of mortality, while age, sex, and steroid use were not associated with increased mortality. CONCLUSION: 2009 pandemic influenza A had the same clinical features as seasonal influenza except vomiting. Mortality rate was high in 2009 H1N1-infected patients with pneumonia, co-morbid conditions, and patients who required ventilatory support. PMID- 24049363 TI - Clinical manifestations and prognostic factor of iliopsoas abscess. AB - INTRODUCTION: Iliopsoas abscess (IPA) is a collection of pus in the iliopsoas compartment, which is considered rare in Japan. However, the number of patients with IPA has recently increased among the elderly or compromised hosts. SUBJECTS AND METHODS: This retrospective study aims to examine the clinical pictures, pathological findings, and the prognostic factor of IPA. We analyzed all patients with IPA who were admitted to our hospital from April 2006 to July 2011. Patients' characteristics, treatment, clinical outcome, radiological findings, bacteria isolated, and comorbidities were evaluated. The comorbidities were evaluated by the Charlson comorbidity index (CCI). We compared the survival and non-survival groups to assess the prognostic factors of IPA. RESULTS: A total of 33 patients were enrolled in this study, which included 14 males and 19 females. The mean age of the patients was 71.5 years (range 32-92 years). The most common underlying disease was spinal disease (16 of 33, 48.5%). Twenty-nine patients (87.9%) were cured and four patients (12.1%) died. While 12 patients (36.4%) were initially treated conservatively with antibiotics alone, percutaneous drainage was performed initially in 19 patients (57.6%). Two patients (6%) directly underwent exploratory surgery and open drainage. In terms of patients' characteristics, there were no significant differences in either group. The score of CCI in non-survivors was higher than that in survivors (1.38 vs. 5.5, P < 0.001). CONCLUSIONS: The epidemiology of IPA is quite different from what it used to be. CCI appears to be useful in evaluating the patients' prognosis with IPA. PMID- 24049364 TI - Assessment of quality of life in a cohort of newly diagnosed patients on HAART regimen, in resource restricted tribal region of chhattisgarh, India: a prospective study. AB - BACKGROUND: Highly active antiretroviral therapy regimens have resulted in the systemic/clinical healing for human immune deficiency virus-infected patients but the consequence of antiretroviral therapy on the whole quality of life has become a major concern. The current study correlates the relationship of quality of life with successful highly active antiretroviral therapy. AIM: To determine the health-related quality of life in human immune deficiency virus-infected patients on highly active anti-retroviral therapy regimen in tribal region of Chhattisgarh. DESIGN: An open label prospective study. MATERIALS AND METHODS: Health-related quality of life was assessed using a standardized questionnaire, the Medical Outcomes Survey Short Form 36. Physical health summary scores and mental health summary scores were compared of pre-Highly Active Anti-Retroviral Therapy (at baseline) and post 12 months of therapy. RESULTS: The increase in CD4 cell counts was extremely significant (P < 0.0001). The Physical Composite Summary (P value = 0.0003) improved significantly, whereas the Mental Composite Summary (with a baseline value of 40.7), post 12 months, was calculated as 42.8 (P value = 0.2371) and was statistically not significant. CONCLUSION: Efficacy measurement is the key ingredient of highly active anti-retroviral therapy, which must also include assessment of health-related quality of life to maximize the holistic approach towards disease. PMID- 24049365 TI - HIV-2 Infection: Where Are We Today? AB - CONTEXT: The choice of antiretroviral therapy for HIV-2 differs from that for HIV 1, underscoring the importance of differentiating between the two. AIMS: The current study was planned to find out the prevalence of HIV-2 infection at our center and to find out the utility of the current diagnostic algorithm in identifying the type of HIV infection. SETTING AND DESIGN: Retrospective analysis in a tertiary care teaching institute over a period of three years. MATERIALS AND METHODS: All patients diagnosed as HIV infected using NACO/WHO HIV testing strategy III were included in the study. They were classified as HIV-1 infected, HIV-2 infected and HIV-1 and HIV-2 co-infected based on their test results. For discordant samples, immunoblotting result from National Reference Laboratory was considered as final. STATISTICAL ANALYSIS USED: Comparison between HIV-1, HIV-2 and HIV-1+2 positive groups for age, gender, route of transmission was made using chi squared test. P value < 0.05 was considered as significant. RESULTS: Of the total of 66,708 patients tested, 5,238 (7.9%) were positive for HIV antibodies. 7.62%, 0.14%, 0.08% and 0.004% were HIV-1, HIV-2, HIV-1 and HIV-2 co-infected and HIV type indeterminate (HIV-1 Indeterminate, 2+) respectively. The current algorithm could not differentiate between the types of HIV infection (as HIV-1 or HIV-2) in 63 (1.2%) cases. CONCLUSION: In areas like the Indian subcontinent, where epidemic of both HIV-1 and HIV-2 infections are ongoing, it is important to modify the current diagnostic algorithms to diagnose and confirm HIV-2 infections. PMID- 24049366 TI - Persistent pediatric gastro-intestinal myiasis: a case report of fly larval infestation with Musca domestica with review of literature. AB - The occurrence of dipterous fly larvae in human is termed as human myiasis. Human myiasis can be classified based on clinical condition it causes like cutaneous myiasis, ocular myiasis, urogenital myiasis and intestinal myiasis. Based on the need for a particular host, myiasis can be divided as specific myiasis, semi specific myiasis. Accidental myiasis results when the fly larvae are deposited/ingested by human resulting in infestation, which is also called as pseudomyiasis. Fly larvae may be present on the dead and decaying organic matter and domestic animals like dog and cats which are naturally infested with fly larvae and can be source for infection in children. Very few cases have been retrieved from literature on the occurrence of intestinal myiasis in children throughout the world. We report a case of two siblings in the same family infested with dipterous fly larvae. PMID- 24049367 TI - Case report of Aspergillus osteomyelitis of the ribs in an immunocompetent patient. AB - Aspergillus is a saprophytic fungus which is universally found in the environment. Most people breathe in the spores of Aspergillus every day without development of disease. It commonly affects immunocompromised hosts. There are only few reported cases in an immunocompetent host. It most commonly affects the respiratory system, causing superficial or invasive disease. It also affects the skin, brain and eye in severely immunocompromised patients. Aspergillosis of the bone is extremely rare. Amongst all the reported cases of invasive aspergillosis the incidence of osteomyelitis is less than three percent. In these cases commonly of the spine is reported. We present a case of Aspergillus osteomyelitis of the ribs in an immunocompetent host. PMID- 24049368 TI - Serological evaluation of leptospirosis: a report from Western India. PMID- 24049369 TI - Leptospirosis coexistent with dengue Fever: a diagnostic dilemma. PMID- 24049370 TI - Epidemiological Investigation on Subcutaneous Nodule Containing a Live Worm Suspected to be Dirofilaria Repens Infection in a Woman from Rural Kerala, India. PMID- 24049371 TI - Parvovirus b19 infection in pediatric patients with hematological disorders. PMID- 24049372 TI - Surgical management of adolescent varicocele: Systematic review of the world literature. AB - Historically, idiopathic varicocele is the most commonly diagnosed pre-pubertal andrological condition. The clinical presentation of varicocele may vary from dull and dragging unilateral or bilateral testicular pain to visible varicose veins lying over the hemiscrotum. Over the last decade, significant strides were made in managing symptomatic varicoceles, particularly minimal invasive procedures and surgeries. We sought to review the published literature in a systematic manner to gain an overview and streamline the presentations and main treatment modalities. PMID- 24049374 TI - Commentary on "Large impacted upper ureteral calculi: A comparative study between retrograde ureterolithotripsy and percutaneous antegrade ureterolithotripsy in the modified lateral position". PMID- 24049373 TI - Large impacted upper ureteral calculi: A comparative study between retrograde ureterolithotripsy and percutaneous antegrade ureterolithotripsy in the modified lateral position. AB - CONTEXT: The treatment for patients with large impacted proximal ureteral stone remains controversial, especially at institutions with limited resources. AIM: The aim of this study is to compare and to evaluate the outcome and complications of two main treatment procedures for impacted proximal ureteral calculi, retrograde ureterolithotripsy (URS), and percutaneous antegrade ureterolithotripsy (Perc-URS). SETTINGS AND DESIGN: Our inclusion criteria were solitary, radiopaque calculi, >15 mm in size in a functioning renal unit. Only those patients in whom the attempt at passing a guidewire or catheter beyond the calculus failed were included in this study. PATIENTS AND METHODS: Between January 2007 and July 2011, a total of 52 patients (13 women and 39 men) with large impacted upper-ureteral calculi >15 mm and meeting the inclusion criteria were selected. Of these, Perc-URS was done in 22 patients (group 1) while retrograde ureteroscopy was performed in 30 patients (group 2). We analyzed operative time, incidence of complications during and after surgery, the number of postoperative recovery days, median total costs associated per patient per procedure, and the stone-free rate immediately after 5 days and after 1 month. STATISTICAL ANALYSIS USED: Bivariate analysis used the Student t-test and the Mann-Whitney test to compare two means and Chi-square and Fisher's exact tests to compare two percentages. The significance level was set at 0.05. RESULTS: The mean age was 42.3 years (range 22-69). The mean stone sizes (mm) were 34 +/- 1.2 and 29.3 +/- 1.8 mm in group 1 and 2, respectively. In the Perc-URS group, 21 patients (95.45%) had complete calculus clearance through a single tract in one session of percutaneous surgery, whereas in the URS group, only 20 patients (66.7%) had complete stone clearance (P = 0.007). The mean operative time was higher in the Perc-URS group compared to group 2 (66.5 +/- 21.7 vs. 52.13 +/- 17.3 min, respectively; P = 0.013). Complications encountered in group 1 included transient postoperative fever (2 pts) and simple urine outflow (2 pts). Ten patients (33%) of group 2 experienced failure: Migration to the kidney (3 pts), ureteral perforation (2 pts), tortuosity of the ureter (2 pts), and epithelial polyps (2 patients). Group 1 patients had an average visual analog (VAS) pain score of 47 mm compared with 31 mm in group 2 patients. The mean hospital stay (days) in group 1 was higher than the group 2 (2.27 +/- 0.8 vs. 1.67 +/- 0.6, respectively; P = 0.01). The mean analgesia requirement for group 1 (paracetamol chlorhydrate + codeine 12 +/- 3 g) was significantly more compared with group B (6.8 +/- 2 g) (P < 0.01). The difference in average blood loss between the two groups was not statistically significant. Total costs was slightly higher in group 1 but the difference was not statistically significant between the two groups (15000 vs. 13400 MDH respectively; P > 0.05). After 1 month, the stone free-rate remained higher in group 1 (95.5% vs. 66.7%, respectively; P = 0.012). CONCLUSIONS: In our series, Perc-URS is a safe and efficient treatment option for proximal ureteral stone, especially when the stone size is superior to 15 mm with the presence of moderate or severe hydronephrosis. PMID- 24049375 TI - Role of ureteric stents in relieving obstruction in patients with obstructive uropathy. AB - PURPOSE: The aim of this study is to evaluate the role of ureteric stents in relieving obstruction and improvement of kidney function in patients with obstructive uropathy. MATERIALS AND METHODS: This study involved 138 patients with obstructive uropathy with age ranged from 2 months to 73 years. Patients classified into two groups: Group (I): Includes 57 patients (41.3%), ureteric stents fixed to them; and Group (II): Includes 81 patients (58.6%) managed by other treatment modalities. All patients underwent clinical assessment, Laboratory and radiologic investigations: At presentation and postoperative. These included: Complete urine analysis, urine culture and sensitivity, serum creatinine, serum urea nitrogen, serum uric acid, serum sodium (Na), serum potassium (K), Fasting blood glucose level and blood picture and plain X-ray (KUB), abdominal ultrasonography (US), diuretic renography and retrograde pyelography. RESULTS: Renal glomerular filtration rate (GFR) was used as an indicator for improvement of renal function after fixation of ureteric stent. In group I: 56 (71.8%) kidneys showed significant recovery compared to 61 kidneys (66.3%). In group II, there is statistically significant relation between renal perfusion and renal recovery (P < 0.004), statistically significant relation between parenchymal thickness and recovery in both groups (P < 0.0002), statistically significant relation between degree of corticomedullary differentiation and recovery (P < 0.0003) and statistically significant relationship between hemoglobin levels at presentation and the recoverability (P < 0.002). CONCLUSION: The predictors of renal recoverability revealed that ureteral stents alone can help in regaining renal function and significant improvement of clinical condition in patients with obstructive uropathy. PMID- 24049376 TI - Is periprostatic nerve block a gold standard in case of transrectal ultrasound guided prostate biopsy? AB - INTRODUCTION: Controversy exists over the pain during prostate biopsy. Periprostatic nerve block (PNB) is a gold standard anesthetic technique during transrectal ultrasound (TRUS)-guided prostate biopsy. Recent studies showed that PNB alone is insufficient as analgesic. We compared the efficacy of tramadol and intraprostatic nerve block (INB) in addition to PNB. MATERIALS AND METHODS: We conducted a prospective double blinded placebo controlled study at our institute in 150 consecutive patients. Patients were randomized into three groups. Group A received PNB with INB with 1% lignocaine. Group B received oral tramadol with PNB. Group C patients were administered PNB only with 1% lignocaine. Patients were asked to grade the pain level using 11 point linear visual analog scale (VAS) at the time of ultrasound probe insertion, at time of anesthesia, during biopsy, and 30 min after biopsy. RESULTS: The study groups were comparable in demographic profile, prostate-specific antigen (PSA) levels, and prostate size. Group A recorded the minimum mean pain score of 2.66 during prostate biopsy which was significantly lower than group 3 (P < 0.001). Group B recorded significantly lower pain score at time of probe insertion and at anesthetic needle insertion than other two groups. CONCLUSIONS: PNB provides better pain control in TRUS guided prostate biopsy but still there is need of additional analgesic in the form of tramadol or INB. Tramadol has advantage of oral intake and analgesic effect at time of probe insertion and at nerve block. Both tramadol and INB may be used in combination along with PNB. PMID- 24049377 TI - Emphysematous pyelonephritis: Our experience with conservative management in 14 cases. AB - CONTEXT: Emphysematous pyelonephritis (EPN) is a rare, severe, acute, necrotizing infection of the kidney. In this study, we present the clinical details, the management strategies, and the outcome of fourteen patients of EPN managed at our center. MATERIALS AND METHODS: A retrospective analysis of the hospital records was done. A total of fourteen patients with EPN were admitted in our hospital from August 2007 to February 2011. All the patients were managed conservatively. Follow-up ranged from six months to one year. RESULTS: Of the fourteen patients, four belonged to class I, five to class II, four to class IIIA and one to class IIIB. All the patients had history of fever, 43% had localized flank pain while 36% had vague abdominal discomfort. Renal angle tenderness was the most common sign, seen in 86% of the patients. E. coli was the most common bacteria, which was isolated from urine in 57% of the patients. On the risk factor stratification, three patients had simultaneous presence of 2 or more risk factors (thrombocytopenia-2 patients; renal function impairment-7 patients; shock 1 patient). All the patients were initially managed with aggressive fluid and electrolyte resuscitation, control of blood sugar levels, and broad spectrum antibiotics. Intervention, in the form of percutaneous drainage or DJ stenting, was done in six patients. One patient failed to respond to this minimally invasive modality of treatment and had to undergo an open drainage. Thus, the acute episode was managed with conservative management strategies in all the patients; however, three patients underwent nephrectomy due to poorly-functioning kidney during follow-up. CONCLUSIONS: EPN is now being more readily diagnosed, at an early stage, making conservative management of EPN a safe, effective, and feasible option. PMID- 24049378 TI - Long anterior urethral stricture: Reconstruction by dorsally quilted penile skin flap. AB - OBJECTIVES: We'd like to present our experience in treating long (>5 cm) anterior urethral stricture by penile skin flap as dorsal on-lay in one-stage procedure. PATIENT AND METHODS: Between January 1998 and December 2010, 18 patients (aged from 28-65 years) presented with long urethral stricture, 5.6-13.2 cm, (penile in 6, bulbar in 2, and combined in 10 cases), those were repaired utilizing long penile skin flaps placed as dorsal on-lay flap in one-stage (Orandi flap 6 cm in 6 cases, circular flaps 7-10 cm in 8, and spiral flaps 10-15 cm in 4). Uroflowmetry and RUG were done following catheter removal and at 6 and 12 months. RESULTS: The urethral patency was achieved in 77% of patients. The complications were fistula in 1 patient (5.5%), re-stricture occurred in 3 patients (16.6%) that required visual internal urethrotomy (VIU), and 2 patients (11%) showed curvature on erection that did not interfere with sexual intercourse. Diverticulum (penile urethra) was seen in 1 patient (5.5%) containing stones and was excised surgically. There was penile skin loss in 3 patients (16.6%). All patients completed at least one year follow-up period. CONCLUSION: Free penile skin flaps offer good results (functional and cosmetic) in long anterior urethral stricture. Meticulously fashioned longitudinal, circular or spiral penile skin flaps could bridge urethral defects up to 15 cm long. PMID- 24049379 TI - Penile corporoplasty with Yachia's technique for Peyronie's disease: Single center experience with 117 patients. AB - INTRODUCTION: Peyronie's disease is an acquired penile deformity with a variety of presentations, caused by the formation of fibrous plaques within the tunica albuginea, leading to bio-mechanical and vascular abnormalities. The objective is to investigate the 18 years outcome of patients with Peyronie's disease treated with penile corporoplasty (Yachia technique) in our department. MATERIALS AND METHODS: One hundred and seventeen patients underwent surgical treatment for PD between 1991 and 2009 and were retrospectively evaluated. We used the Levine and Lenting's algorithm for surgical treatment. Data was obtained from medical records, clinical evaluation, and telephone interview. Post-operative follow-up was at 6 weeks and 12 months. The mean time of follow-up was 14 months (12-19 months). MAIN OUTCOME MEASURES: Patient demographic, co-morbidities, erectile function, penile curvature, and surgical intervention were documented. The main outcome measures of this study are postoperative complications, surgical purpose, and patients and partner's satisfaction rates. RESULTS: Surgical aim was obtained in 106 patients (success rate of 94.6%). Complications occurred in 4.5% of patients, but most of these were mild. At 6 weeks, complete straightening of the penis was achieved in 57 patients (50.9%), and partial straightening which allow sexual intercourse in 49 patients (43.7%). Nine patients report gland hypoesthesia and almost all report subjective perception of penis shortening (0.5 cm to 5 cm). Twenty-two patients developed recurrent deformity at 12 months follow-up, with compromise of sexual intercourse in 7 patients. Patients' responses to our questionnaire showed that overall 88.4% of the patients and partners were satisfied with the surgical results. CONCLUSION: According to the results of this long-term, retrospective study, surgical correction, using the Yachia technique, is an excellent option for patients with functional impairment from their Peyronie's disease, especially. PMID- 24049380 TI - Endorectal coil MRI and MR-spectroscopic imaging in patients with elevated serum prostate specific antigen with negative trus transrectal ultrasound guided biopsy. AB - BACKGROUND: The aim of this study was to see the efficacy of endorectal coil MRI and MR spectroscopic imaging in patients with elevated serum PSA and negative transrectal ultrasonography (TRUS)-guided biopsy. MATERIALS AND METHODS: This study was conducted on 87 patients presented with: * Elevated prostatic specific antigen levels >5 ng/ml * Symptoms and signs of prostatic carcinoma * Patients with negative TRUS-guided biopsy * Suspicious lesion on TRU. All the patients were subjected to TRUS and followed by TRUS-guided biopsy of the lesion identified on endorectal coil MRI and MR-Spectroscopy. TRUS-guided biopsy of prostate was done with a Siemens Sonoline Adana Scanner. The scanning was performed by mechanical probe 5-7.5 MHz. RESULTS: Out of 87 patients, 43 (49.4%) had hypointense lesion, 11 (12.6%) had hyperintense lesion. Out of 87 patients, MR-spectroscopy showed peak choline-creatine in 74 patients. Normal citrate peak was seen in 13 patients. Patients who had choline-creatine peak, among them 28 (37.8%) had peak in left peripheral zone, 23 (31.1%) had peak in the right peripheral zone, 2 (2.7%) had peak in the central zone, 17 had (23%) peak bilaterally. Four patients (5.4%) had peaks in right and central zones. The difference was statistically significant (P < 0.001). CONCLUSION: Prostatic biopsy directed with endorectal coil MRI and MR-spectroscopic imaging findings in patients with elevated serum PSA and prior negative biopsy, improves the early diagnosis of prostatic carcinoma and accurate localization of prostate cancer within the gland. PMID- 24049381 TI - Role of primary chemotherapy in management of large tumors of undescended testis: Our experience. AB - OBJECTIVE: This study aimed to share our experience with tumors of undescended testis (UDT) and to assess the impact of primary cisplatin-based chemotherapy on such tumors. MATERIALS AND METHODS: This study included the cases of tumor in UDT from February 2005 to December 2011. Evaluation of the cases was done with proper clinical examination and laboratory investigations along with tumor markers (alfa feto protein, beta-human chorionic gonadotropin, lactate dehydrogenase) and contrast-enhanced computed tomography abdomen. Fine needle aspiration cytologywas done in all cases. Primary chemotherapy with three cycles of bleomycin, etoposide, and cisplatin regimen at three weekly intervals started in all cases. Response to treatment was seen after four weeks of the third cycle. RESULTS: Fourteen cases (12.5%) of germ cell tumor in UDT out of 112 cases of germ cell tumor of the testis were included. The age ranged from 16-60 years. Histological diagnosis was pure seminoma in all cases. After three cycles of BEP regime, complete response was seen in 11 cases and partial response in three cases where the residual tumor was excised along with retroperitoneal lymph node dissection RPLND. Of the 14 cases, 13 were in regular follow-up and one was lost to follow up. All on follow-up were doing well without recurrence till now. CONCLUSION: Surgical removal of the primary tumor in UDT with or without bulky metastasis is complicated. Primary chemotherapy with cisplatin-based regimen is a good option in such cases. PMID- 24049382 TI - Primary chemotherapy in management of tumors of undescended testis: Where it stands? PMID- 24049383 TI - Mitomycin C instillation following ureterorenoscopic laser ablation of upper urinary tract carcinoma. AB - INTRODUCTION: Instillation of Mitomycin C (MMC) should prevent implantation of cancer cells released during endoscopic treatment and prevent recurrences as seen in carcinoma of the bladder. AIM: TO DEVELOP AND EVALUATE A PROTOCOL FOR A SINGLE DOSE MMC INSTILLATION FOLLOWING HOLMIUM: YAG laser ablation of upper urinary tract transitional cell carcinoma (UUT-TCC). SETTING AND DESIGN: A single institute prospective study. MATERIALS AND METHODS: MMC instillations protocol was designed and offered to patients between August 2005 and April 2011. Following tumor ablation, MMC was instilled into upper urinary tract (UUT) over 40 minutes. All the patients were regularly followed up. RESULTS: Twenty UUT units (19 patients) were managed for UUT-TCCs using our MMC protocol. Two UUT units had G1pTa tumors, 14 had G2pTa, 2 had G3pTa, and 2 had G3pT1. At a mean follow-up of 24 months (range 1-72 months), 13/20 (65%) of the UUT units remained cancer-free, 3 (15%) UUT units developed stricture and were treated with endoscopic dilatation, only 1 (5%) of these developed long-term complications. None of the patients developed postoperative renal impairment or systemic side effects. CONCLUSIONS: Using a set standard protocol, MMC can safely be instilled into the UUT after TCC ablation with minimal complications or side effects, good preservation of renal function, and with a low recurrences rate comparable to the literature. PMID- 24049384 TI - Quality of life after radical cystectomy for bladder cancer in men with an ileal conduit or continent urinary diversion: A comparative study. AB - AIM: To investigate quality of life (QoL) domains with three forms of urinary diversions, including ileal conduit, MAINZ pouch, and orthotopic ileal neobladder after radical cystectomy in men with muscle-invasive bladder cancer. MATERIALS AND METHODS: In a prospective study, 149 men underwent radical cystectomy and urinary diversion (70 ileal conduit, 16 MAINZ pouch, and 63 orthotopic ileal neobladder). Different domains of QoL, including general and physical conditions, psychological status, social status, sexual life, diversion-related symptoms, and satisfaction with the treatment were assessed using an author constructed questionnaire. Assessment was performed at three months postoperatively. RESULTS: In questions addressing psychological status, social status, and sexual life, patients with continent diversion had a more favorable outcome (P = 0.002, P = 0.01, and P = 0.002, respectively). The rate of erectile dysfunction did not differ significantly between the three groups (P = 0.21). The rate and global satisfaction was higher with the MAINZ pouch (68.7%) and ileal neobladder (76.2%) as compared with the ileal conduit group (52.8%) (P = 0.002). CONCLUSION: Continent urinary diversion after radical cystectomy provides better results in terms of QoL as compared with ileal conduit diversion. PMID- 24049385 TI - Challenges on percutaneous nephrolithotomy in pregnancy: Supine position approach through ultrasound guidance. AB - Urolithiasis in pregnancy represents a major diagnostic and therapeutic challenge to the obstetrician, urologist, radiologist and anesthetist. It is a cause of major concern, considering the potential adverse effects of radiation exposure and of any invasive surgical procedure and anesthesia on the mother and fetus. Fortunately, with conservative management, 70-80% of symptomatic calculi pass spontaneously with no sequel. However, fever, infection, uncontrolled pain and progressive hydronephrosis are indications for surgical intervention when retrograde placements of a ureteral stent or a percutaneous nephrostomy tube are the most traditional options. The recent technological advances in stone fragmentation devices and the administration of safe anesthesia have forced clinicians to embark on more definitive stone management techniques in pregnancy. Ureteroscopy is considered the first definitive treatment of obstructive ureteral calculi during all trimesters of pregnancy, but also has limitations. Although generally avoided during pregnancy, percutaneous nephrolithotomy can be a good treatment choice in selected patients. PMID- 24049386 TI - Angiomatous leiomyoma of the urachus: A rare entity masquerading as extraluminal gastrointestinal stromal tumor. AB - The urachus is a vestigial structure located between the dome of the bladder and the umbilicus, which results from the involution of the allantoic duct and the cloaca. Persistence of an embryonic urachal remnant can cause various problems during childhood and young adulthood. Urachal leiomyoma is a rare entity with very few cases being reported in literature. It can be misdiagnosed and confused with a wide spectrum of intra-abdominal or pelvic disorders. We hereby report a case of angiomatous leiomyoma originating from the urachal remnant in a 45-year old lady, masquerading as extraluminal gastrointestinal stromal tumor. Understanding the embryological basis of these urachal disorders and their imaging features coupled with histopathological examination is crucial for the correct diagnosis and management. Pathological diagnosis is required to optimize the surgical approach and preclude unnecessary radical surgery. PMID- 24049387 TI - Paraurethral Skene's duct cyst in a newborn. AB - Paraurethral or Skene's duct cysts are rare causes of interlabial masses in neonates. The diagnosis of Skene's duct cysts in the neonatal period is based on its location, in relation to the urethra, and the demonstration of transitional epithelium in the cyst wall. The distinguishing features of paraurethral cysts are the displacement of urethral meatus by the mass and a cyst containing milky fluid. Thus, we report a case of a Skene's duct cyst in a newborn which was treated by incision and drainage. PMID- 24049388 TI - Feasibility of renal transplantation after unroofing of a large renal cyst in an expanded criteria donor. AB - We present a case in which a deceased donor kidney with a large simple cyst was successfully unroofed and transplanted to a 61-year-old male. The donor was a 62 year-old male with a history of hypertension for 2 years; cerebral vascular accident was the cause of death. A large 8-cm cyst distorting the renal hilum was identified upon the procurement of the deceased donor kidney. Prior to transplantation, the large cyst was unroofed from the allograft; the frozen section confirmed a benign cyst and the transplant was performed. Postoperatively, the serum creatinine level was 1.4 mg/ml at 22-month follow-up and the patient was normotensive. Deceased donor kidneys with giant cysts distorting the renal hilum can be effectively transplanted. PMID- 24049389 TI - Pure primary small cell carcinoma of urinary bladder: A rare diagnostic entity. AB - Small cell carcinoma of the bladder is a rare, aggressive, poorly differentiated neuroendocrine neoplasm accounting for only 0.3-0.7% of all bladder tumors. Since the tumor is very rare, pathogenesis is uncertain. Small cell carcinomas of the urinary bladder are mixed with classic urothelial carcinomas or adenocarcinomas of the bladder in 68% cases, making pure primary small cell carcinoma even a rarer entity. The unknown etiology and natural history of small cell carcinoma of the urinary bladder represent a challenge both to the pathologist and urologists for its diagnosis and treatment, respectively. PMID- 24049391 TI - Anterior bladder flap neo urethra as treatment for stress urinary incontinence due to developmental urogenital anomaly. AB - Congenital anomalies that involve the distal segment of urogenital sinus (giving rise to female urethra and vagina) may lead to abnormal urethral development ranging from absent to markedly deficient urethra. The abnormal division may also cause a short and patulous urethra. Sphincteric defects are likely to be associated and when combined with the short urethral length is a cause for severe urinary incontinence. Urinary incontinence due to a congenital cause requiring repeated urethral reconstruction to relieve symptoms is presented. A 15 year old girl was referred for bothersome urinary incontinence due to a short, wide, patulous urethra with defective sphincteric mechanism as part of urogenital sinus developmental anomaly. She was initially managed by reconstruction of bladder neck and proximal urethra with sphincter augmentation using autologous pubovaginal sling. Persistent urinary incontinence demanded a second urethral reconstruction using tubularised anterior bladder flap (modified Tanagho). Surgical reconstruction of the urethra achieved socially acceptable continence. PMID- 24049390 TI - Holmium:YAG laser ablation of upper urinary tract transitional cell carcinoma with new Olympus digital flexible ureteroscope. AB - Upper urinary tract transitional (UUTT) cell carcinoma is a relatively uncommon urologic tumor. The traditional treatment approach for them is radical nephroureterectomy. However, in recent years, less-invasive treatments, including different nephron-sparing procedures, have become increasingly popular. We report a case of laser ablation of UUTT cell carcinoma using new Olympus digital flexible ureteroscope (URF-V). PMID- 24049393 TI - Metastatic tumors to testis. PMID- 24049392 TI - Urothelial carcinoma of the bladder with asynchronous metastases to both testes. AB - Urothelial carcinoma (UC) or transitional cell carcinoma (TCC) of the bladder has a high likelihood of metastasis, and the more common sites of distant metastasis are bone, liver and lung. Metastasis to the testis is extremely rare. We identified five cases of bladder UC metastasing to the testis in the literature, none of which occurred bilaterally. We present this case of asynchronous UC metastases to both testes as the first report in the literature. Metastatic disease should be considered as a potential differential diagnosis for testicular tumors arising in patients with a history of UC. PMID- 24049394 TI - Histopathological patterns of testicular biopsy in male infertility: A retrospective study from a tertiary care center in the western part of Saudi Arabia. PMID- 24049395 TI - Herbal research vis a vis Ayurvedic clinical research. PMID- 24049396 TI - Proposed ban on mercury may hit Ayurveda adversely. PMID- 24049397 TI - Safeguarding Ayurvedic therapeutics: Need of the hour. PMID- 24049398 TI - Critical review on Bhaishajya Kaala (time of drug administration) in Ayurveda. AB - Bhaishajya Kaala (time of drug administration) is an important principle to be considered while treating a disease. Still hardly a handful of physicians are seen, who account for this. To highlight its imperial role in Chikitsa, there is an immense necessity to analyze this concept, which is the need of the hour. Bhaishajya Kaala is mainly explained in relation with Bala of Roga, Rogi, particular Dosha, Dooshya, and various other factors. The comprehensive understanding of this concept involves so many questions as, why there is a difference in the number of Aushdha Kaala? What is the logic behind their indications as well as contraindications? The present paper focuses on the above points to find out the convincing answers. PMID- 24049399 TI - Medohara and Lekhaniya dravyas (anti-obesity and hypolipidemic drugs) in Ayurvedic classics: A critical review. AB - Santarpanottha Vikaras (diseases due to excessive nutrition) are increasing during current times. Medodushti (disorders of fat metabolism) serves as one of the important etiological factor in most of these disorders including Ischemic Heart Disease (IHD). IHD is identified as one of the leading cause of morbidity and mortality worldwide in both developing and developed countries. Retention and deposition of serum lipids resulting in decreased flow of blood in coronary arteries being the underlying cause. Conventional and herbal drugs are being used to lower levels of serum cholesterol to prevent this menace. In this regard, an attempt has been made to critically review the Medohara and Lekhaniya (Anti obesity and Hypolipidemic) drugs mentioned in Ganas (group of drugs) of Ayurvedic classical texts which may abet our understanding of prevention and management of conditions like Dyslipidemia and its complications. Administration of drugs possessing Tikta Rasa (bitter taste), Ushna Veerya (hot in potency), Laghu and Ruksha Guna (light and dry qualities), Katu Vipaka and Vata Kaphahara actions were noted during the analysis. PMID- 24049400 TI - A review through Charaka Uttara-Tantra. AB - In the present scenario, the available editions of Charaka Samhita contain eight Sthanas only. Charaka Samhita does not contain Uttara-Tantra like Sushruta Samhita and Samhitas of Vagbhata. On contrary, in the 12(th) chapter of Siddhi Sthana, Charaka has mentioned about Uttara-Tantra of Charaka Samhita. So, it is essential to emphasize on this issue, which was not explained in length by commentators of Charaka Samhita. Many controversies raised on the existence and recognition of Uttara-Tantra of Charaka Samhita. On the other hand, some scholars who belong to a later period have been mentioned certain references in their work, which are claimed to be from Uttara-Tantra of Charaka Samhita. After a thorough study and scanning of available literature, it is concluded that, Charaka Uttara-Tantra was existing up to the time of Nishchalakara (13(th) century AD). Nishchalakara has quoted a number of references in Ratnaprabha, which are from Uttara-Tantra of Charaka Samhita. Furthermore, there is a need to discuss about the existence of Uttara-Tantra of Charaka Samhita by further more detailed study and scanning of literatures of Ayurveda and allied literatures. PMID- 24049401 TI - Review of research works done on Tamra Bhasma [Incinerated Copper] at Institute for Post-Graduate Teaching and Research in Ayurveda, Jamnagar. AB - The metal, Tamra though mentioned in Ayurveda with a wide range of therapeutic utilities; is attributed with Ashta Maha Dosha. Hence, one should be cautious while using Tamra Bhasma. Considering the significance of Tamra in therapeutics, many studies have been carried out at different centers of India. Aim of the present study was to compile such available research works done on Tamra in the Department of Rasa Shastra and Bhaishajya Kalpana (RS and BK), IPGT and RA, Jamnagar and provide brief information about pharmaceutical, analytical, and pharmacological studies. Total eleven studies on Tamra Bhasma, which revalidated the impact of classical guidelines, safety issues, and therapeutic utilities, were screened from PG Department of RS and BK, Institute for Post-Graduate Teaching and Research in Ayurveda, Gujarat Ayurved University, Jamnagar. All studies revealed that Tamra Bhasma is safe clinically, experimentally at Therapeutic Equivalent Dose (TED) levels as no toxic hazards were reported during the treatment period. In all aspects (pharmaceutical, pharmacological, and clinical) Somnathi Tamra Bhasma has proven to be better than Tamra Bhasma. The clinical efficacy of Tamra Bhasma has been evaluated in Shvasa, Kasa, Yakrit Pliha Vriddhi, Grahani, etc. conditions. Satisfactory responses with a decrease in the intensity of signs and symptoms were reported in all the studies. Though certain limitations were observed in these researches, the results can be considered as a lead for further well stratified studies covering larger population. No adverse effects were reported in any of these studies. PMID- 24049402 TI - Inter relationship of Ayurveda and Astrology. AB - In the universe all the creatures are related to Adhivyadhi, which indicates mental agony or bodily pain. Acharyas of Ayurveda like Charaka, Sushruta and Kashyap have classified diseases into various categories like Agantuja, Sharirika, Manasika, Swabhavika, etc. Charaka classified diseases based on the prognosis like Sadhya, Asadhya, Mrudu and Daruna. Ayurveda also suggested Daiva Vyapashraya Chikitsa which includes of Manidharana and chanting Mantras. Astrological sciences suggest 10 types of remedial measures in the treatment of diseases. This science considers that causative factors of various disorders are the Navagrahas (nine planets). The influence of the planets on various procedures like drug processing, bath taking, performing Yajna, wearing Ratna, etc. are well documented in Jyotishashastra. Drugs processed in Chandra Nakshatra acts as ambrosia and subdues Tridoshajanya Vyadhi. Medicated baths are suggested for diseases engendered due to involvement of different planet effects viz. Sarshpa for Shukra, Haridra and Daruharidra for Shani Lodhra for Ketu, Sharpunkha for Rahu, etc. In a close scrutiny it appears that Jyotishashastra Siddhanta can play crucial role in the management of chronic diseases. PMID- 24049403 TI - Clinical efficacy of Eranda Muladi Yapana Basti in the management of Kati Graha (Lumbar spondylosis). AB - Low back pain affects approximately 60.85% of adults during some point of their life and 10% of this is because of Lumbar Spondylosis (LS). Kati Graha which is correlated with LS is a degenerative condition affecting the discs, vertebral bodies, and/or associated joints of the lumbar spine. In current study, assessment of Eranda Muladi Yapana Basti in the management of Kati Graha with special reference to LS has been attempted. 23 patients of either sex in the age between 20 to 65 years having signs and symptoms of LS were selected and were administered Yapana Basti for a period of 15 days. Highly significant results were observed and improvement in cardinal symptoms of Kati Graha was observed. It also provided highly significant results in improving Oswestry Disability Index Scale, range of movements and pain intensity This procedure appears to provide good clinical improvement in pacifying pure Vataja or Vata Kaphaja type of Kati Graha. PMID- 24049404 TI - Evaluation of Stambhanakaraka Yoga and counseling in the management of Shukragata Vata (premature ejaculation). AB - Premature Ejaculation (PE) is a very common male sexual problem. Anxiety, stress, fear etc., are the main predisposing factors of PE. In Ayurveda, this condition can be correlated with Shukragata Vata. In the present study, fifty five patients with PE were grouped into two and were treated with Stambhanakaraka Yoga (n = 30) and Placebo (n = 20) for a duration of two months, with luke warm water as anupana. Psychological counseling was given to the patients in both the groups. After completion of treatment, Stambhanakaraka Yoga showed significant results against placebo in all parameters, namely Intravaginal Ejaculation Latency Time (IELT), voluntary control over ejaculation, patient and partner's satisfaction, performance anxiety. PMID- 24049405 TI - Multimodal Ayurvedic management for Sandhigatavata (Osteoarthritis of knee joints). AB - Vata is the governing factor in the maintenance of equilibrium in the universe as well as in the body. As age advances, the influence of Vata Dosha progresses, resulting in the process of gradual degeneration of the body. Sandhigatavata (osteoarthritis) is one of the consequences of this process, which is common in the elderly people. This is one of the major causes of chronic disability, affecting the quality of life. Prevalence of osteoarthritis in India is more among menopausal women. This study has been conducted to evaluate the efficacy of Ayurvedic multimodal management in Sandhigatavata and to provide better options to Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). In present clinical trial, 50 patients of Sandhigatavata have been registered and have been given Snehana, Svedana, Mriduvirechana, Matrabasti, and Jalaukavacharana, along with oral medications like Yogaraja Guggulu and Ashvagandha Churna. This multimodal therapy is being used in P.D. Patel Ayurved Hospital, Nadiad, since years, providing good relief to patients with Sandhigatavata. The results have been analyzed statistically by using the Student paired't' test. The therapy showed highly significant (P < 0.001) beneficial effect on the clinical features of Sandhigatavata. On overall effect of therapy, 4% of the patients were relieved completely, while 24% have shown marked improvement, 50% moderate improvement, and 22% mild improvement. Results of follow-up showed that marked improvement decreased, but moderate improvement was steady. Continuing the study on a larger number of patients, with inclusion of more objective parameters to get better conclusions is suggested at the end of the study. PMID- 24049406 TI - Etiopathological study on cerebral palsy and its management by Shashtika Shali Pinda Sweda and Samvardhana Ghrita. AB - According to World Health Organization (WHO) estimation, 10% of the global population has some form of disability due to different causes; in India, it is 3.8% of the population. Nearly 15-20% of the total physically handicapped children suffer from Cerebral Palsy (CP). For India, the estimated incidence is around 3/1000 live births; however, being a developing country, the expected actual figure may be much higher. Despite the advancement in modern technology and improved neonatal care, stagnant or increasing incidence of CP has been observed, which is of great concern. As far as management or preventive aspect is concerned, no satisfactory criteria have been developed to date. The present study is based on a positive hypothesis for the efficacy of Ayurvedic treatment. The study was carried out in 16 patients, 8 in each group, namely group A (Shashtika Shali Pinda Sweda externally and Samvardhana Ghrita internally) and group B (Samvardhana Ghrita internally) for 35 days duration. In group A, moderate improvement, mild improvement, and no improvement were observed in 50%, 37.5% and 12.5% of patients respectively. In group B, moderate improvement and mild improvement were observed in 75% and 25% of the patients respectively. Statistical significance of results on selected criteria showed the efficacy of the selected Ayurvedic treatment modality in relieving the signs and symptoms of CP. Although it is incurable, Ayurvedic science can provide a better direction by improving the quality of life of children with CP with better life expectancy. PMID- 24049407 TI - A comparative study of Dashana Samskara Choorna Pratisarana and Dashana Samskara paste application in the management of Sheetada (Gingivitis). AB - Sheetada is the early stage of periodontal diseases. This occurs due to negligence of oral hygiene, changing life-style, habits, and addictions. It is Kapha Rakta Pradhana Vyadhi. In modern dentistry papillary or marginal gingivitis can be correlated with Sheetada, on the basis of similarities in symptoms, involvement of anatomical structure, etiology and prognosis. The epidemiological studies conducted by American Academy of Periodontology shows that gingivitis of varying severities is nearly universal. It is estimated that over 80% of the world's population suffers from gingivitis. In this clinical study, 106 patients were registered among them 103 completed the treatment and were randomly divided by lottery method into two groups. In Group-A, Dashana Samskara paste local application on gums and in Group-B, Dashana Samskara Choorna Pratisarana on gums was given. After enrollment of the patients in the study cardinal symptoms of Sheetada (gingivitis) such as, Raktasrava, Krishnata, Prakledata, Mriduta, Mukhadaurgandhya, and also the objective criteria such as oral hygiene index, Gingival Index (GI-S), and Gingival Bleeding Index (GBI-S) were studied before and after the treatment. While considering comparative effect on subjective parameters such as Raktasrava, Dantamamsa Shiryamanata, Shotha and Chalata statistically significant results were obtained in Group-A than Group-B. In objective parameters such as, GI-S and GBI-S also showed statistically significant results in Group-A. Observations in follow-up study confirmed that the recurrence rate in the Group-Awas significantly lesser than the Group-B. PMID- 24049408 TI - Efficacy of Virechana and Basti Karma with Shamana therapy in the management of essential hypertension: A comparative study. AB - Considering high prevalence and the need to look for alternative medicine, essential hypertension was screened in light of Vata-Pitta Pradhana Rakta Pradoshaja Vikara as mentioned by Acharya Charaka. Comparing the etiological factors, symptomatology, and complications with Rakta Pradoshaja Vikara with that of essential hypertension, a striking similarity was revealed. To prove the practical approach of management of Vata-Pitta Pradhana Rakta Pradoshaja Vikara, a randomized open clinical trial on 33 uncomplicated subjects of essential hypertension was conducted. The subjects were allotted in two groups, viz. (Group A) Virechana group having 16 cases who underwent Virechana Karma by Trivrita, Aragvadha, Eranda Taila, and Draksha Kwatha as Sahapana; and (Group B) Basti group consisting of 17 cases who were administered Dashmoola Kala Basti in which Niruha with Dashmoola Kwatha and Anuvasana with Dashmoola Taila was done. Patients of both the groups were followed by Shamana Chikitsa (Arjunadi Ghanavati). The overall effect of the therapies on systolic and diastolic blood pressure showed that Virechana proved better relief (43.75%) as compared to Basti (29.41%). The response was encouraging and has created scope for further studies. PMID- 24049409 TI - Impact of season and constitution on lipid parameters. AB - Ayurveda prescribes daily and seasonal regimen in maintaining good health. Measures in the preservation of health have been described considering one's own Prakriti, Satva, Vayas, Bala, Agni, Ojus, season, and so on. Depending on the relative predominance of Doshas in various constitutions and seasons, certain regimens have been prescribed. The present study was done to assess the lipid profile in 54 healthy volunteers. It was observed from the present data that winter month is one of the potential risk factors for cardiovascular diseases because more lipid profile level was observed during winter. Among the constitutions, Kapha and Pitta Prakriti are more vulnerable for cardiovascular diseases because more lipid profile level is observed in these constitutions during winter. PMID- 24049410 TI - Role of Nasya and Matra Basti with Narayana Taila on anovulatory factor. AB - Description of Vandhyatva is available in most of the Ayurvedic classics, including Nidana (diagnosis), Samprapti (etiopathogenesis), Lakshana (symptomatology), Bheda (types) and Chikitsa (treatment). In current study, efforts have been made to study the effect of Nasya and Matra Basti on anovulation (Beeja Dushti). Ovulation is under the control of Vata. Narayana Taila is attributed for its effect in Vandhyatva. 24 patients of female infertility having anovulatory factor, being diagnosed by Trans-Vaginal Sonography (TVS) for 2 consecutive cycles were divided in two groups. Patients in Group A (n = 12) administered the drug through Nasya and in Group B (n = 12) through Matra Basti. Ovulation occurred 36.36% of patients in group A and 66.16% of patients group B. Matra Basti showed better results than Nasya group on anovulation. PMID- 24049411 TI - Efficacy of traditional treatment regimen on Kati Shoola with special reference to lumbar spondylolisthesis. AB - According to Ayurveda, Kati Shoola is a disease with pain in lumbar region. Lumbar spondylolisthesis, anterior displacement of a vertebra or the vertebral column in relation to the vertebrae below, is one of the common causes. Current case study was carried out at Ayurveda Teaching hospital, Borella, to evaluate the efficacy of a treatment regimen used by Sri Lankan traditional physician family "Weerasinghe." A 59-year-old female with a 9-month history of lumbar spondylolisthesis was treated with this regimen. The patient had progressive pain in left lower back, right and left buttocks, and difficulty in bending forward over 5 degrees . X-ray of lumbo sacral region indicated that patient was suffering from Grade 3 lumbar spondylolisthesis. She was treated for 65 days with four treatment packages consisting of 13 prepared medicines. The response to the treatment was recorded and therapeutic effects were evaluated through symptomatic relief. Clinical symptoms were significantly reduced and degree of anterior flexion increased from 5 degrees to 90 degrees . However, X-rays indicated that the patient was still suffering from Grade 3 lumbar spondylolisthesis. This regimen is effective in successfully treating Kati Shoola (lumbar spondylolisthesis) by helping to reduce the symptoms and improving the degree of anterior flexion. PMID- 24049412 TI - Pharmacognostical evaluation of Launaea sarmentosa (Willd.) schultz-bip.ex Kuntze root. AB - Launaea sarmentosa (Willd) Schultz-Bip.ex Kuntze (Asteraceae), locally known as Kulhafila in the Maldives, is a creeping herb, native to tropical Indian coastlines. According to anecdotal evidence from locals in the Maldives, the roots of this plant are used as an ingredient of a popular medicinal preparation (Hilibeys) taken by mothers after childbirth. It is also used in various other ailments in different parts of the Maldives, as well as in India. So far, there has been no scientific documentation of this plant. The only source of information available is held by natives and traditional medical practitioners. The present study was conducted on the root of L. sarmentosa for its pharmacognostical and phytochemical characteristics as per Ayurvedic Pharmacopoea of India (API) parameters. The microscopic characteristics of the root show prismatic crystals, multiseriate medullary rays, laticiferous cells, and pitted parenchyma. Qualitative analyses, such as loss on drying, ash value, pH, etc., were conducted. Preliminary phytochemical screening shows the presence of alkaloids, tannin, steroids, etc. PMID- 24049413 TI - A comparative pharmacognostical and preliminary physico-chemical analysis of stem and leaf of Bacopa monnieri (L.) Pennel and Bacopa floribunda (R.BR.) Wettst. AB - Brahmi is a well-known herbal drug having an effect on brain as a memory enhancer. Bacopa monnieri (L.) Pennel and Bacopa floribunda (R.Br.) Wettst are both marketed in the name of Brahmi. The present study differentiates Bacopa monnieri and Bacopa floribunda in morphology, transverse section (T.S.) of root and leaf, powder microscopy, and chemical constituents. Morphological characters show color difference in flower, stem and leaf and differences in microscopic study, organoleptic study, and powder characteristics. Morphologically, Bacopa monnieri leaf is fleshy and more succulent than Bacopa floribunda leaf. There is also a difference in the interval of the stem internodes of the two. Physico chemical analysis revealed presence of 26% bacoside A in Bacopa floribunda leaf and 27% in Bacopa floribunda stem, which is higher than the bacoside A content in leaf (22%) and stem (18%) of Bacopa monnieri. However due to the hemolytic action of bacoside A, which is the toxic effect of the chemical constituent, it seems likely that Bacopa monnieri is more popular in regular use than Bacopa floribunda. PMID- 24049414 TI - Standardization of Shadbindu Taila: An Ayurvedic oil based medicine. AB - Shadbindu Taila (ST) is an Ayurvedic formulation used as a remedy for loosening of tooth, weakness of the eyesight, loss of hair, diseases of head, etc., Present study is an attempt to develop some newer approaches for the quality control and standardization of ST. Standardized operating procedure for the preparation of ST was developed in accordance with Ayurvedic Formulary of India. Preliminary phytochemical, physicochemical, and chromatographic evaluation of ST was carried out. Safety of ST was evaluated in terms of skin irritation test and presence of heavy metals. Chemical characterization of ST was done on the basis of kaempferol using validated -High Performance Thin Layer Chromatographic (HPTLC) method. ST did not show presence of any of the heavy metals analyzed and was found non irritant on rabbit skin. The quality control parameters resulted after scientific evaluation of ST can be used as reference standard for quality control/assurance laboratory of a pharmaceutical firm in order to have a proper quality check over its preparation and processing. PMID- 24049415 TI - In vitro alpha -amylase and alpha-glucosidase inhibitory potential of Trigonella foenum-graecum leaves extract. AB - Trigonella foenum-graecum is one of the widely used herbs in food and medicine. The seeds of the plants are investigated for antidiabetic potential; however, no efforts have been done to explore the potential of leaves to modify carbohydrate metabolizing enzymes viz. alpha-amylase and alpha-glucosidase. The present work was designed to investigate the inhibitory potential of ethyl acetate and water extract of T. foenum-graecum on enzymes alpha-amylase and alpha-glucosidase. Different concentrations of extracts were used to study inhibition of enzymatic activity of alpha-amylase and alpha-glucosidase. A dose dependent inhibitory effect on enzymes was observed. The current study, for the first time, revealed alpha-amylase and alpha-glucosidase inhibitory potential of T. foenum-graecum and the study could be helpful to isolate and characterize compounds responsible for it. PMID- 24049416 TI - Anti depressant activity of Mamsyadi Kwatha: An Ayurvedic compound formulation. AB - Depression is a psychiatric condition in which there is loss of interest in all pleasurable outlets, viz. food, sex, work, friends, hobbies and entertainment. The prevalence rate of the disease is 6-8% in women and 3-5% in men. Ayurveda, the science of life, provides systematic management principles for depression. Mamsyadi Kwatha is one such formulation stated by Yadavji Trikamji Acharya in Siddha Yoga Sangraha and Bheshaja Samhita, which is said to be effective in psychiatric conditions. The ingredients are Jatamansi (Nardostachys jatamansi), Ashwagandh (Withania somnifera) and Parasika Yavani (Hyocymus niger) in an 8:4:1 ratio, respectively. The test drug was subjected for antidepressant activity in experimental models. The models selected for anti depressant activity were behavioral despair test, anti-reserpine test and Chronic Fatigue Syndrome (CFS) test in albino mice. The test formulation showed significant inhibition of behavioural despair (P < 0.05), weak to moderate anti-reserpine activity - ptosis (P < 0.001), catatonia (P < 0.01), sedation (P < 0.01) and moderate effect in CFS test (P < 0.050). These effects clearly show that Mamsyadi Kwatha has an anti depressant activity. PMID- 24049417 TI - Repeated dose oral toxicity of Trivanga Bhasma in Swiss albino mice. AB - Trivanga Bhasma, a metallic preparation containing Bhasmas of Naga (lead), Vanga (tin) and Yashada (zinc), was studied for repeated dose toxicity in Swiss albino mice to estimate No Observed Effect Level (NOEL) or No Observed Adverse Effect Level (NOAEL). A total of 80 Swiss albino mice of either sex with an average body weight of 28-30 g were equally divided into four groups (Group I, II, III, and IV). Group I served as control and was given vehicle (honey: water in 2:3 ratio) Group II, III, and IV received Trivanga Bhasma @ 7.8, 39.5,and 78 mg/kg body weight for 90 consecutive days. The effect of drug was assessed on body weight, feed and water consumption changes, hematological, and histopathological parameters. At the end of the study, all animals were sacrificed and examined for gross pathological changes. Histopathological evaluation was performed for control and high dose group. Trivanga Bhasma was found to be safe. No significant clinical signs were noted in all groups studied. No major alterations were observed during histopathological evaluation. Hence, dose rate of 78 mg/kg body weight was established as NOAEL. It is suggested to carry out a toxicity study at possible higher doses and in a different species so as to establish target organ of toxicity. PMID- 24049418 TI - In vitro evaluation of antioxidant activity of Cordia dichotoma (Forst f.) bark. AB - Cordia dichotoma Forst. f. bark, identified as botanical source of Shleshmataka in Ayurvedic pharmacopoeia. Present investigation was undertaken to evaluate possible antioxidant potential of methanolic and butanol extract of C. dichotoma bark. In vitro antioxidant activity of methanolic and butanol extract was determined by 1,1, diphenyl-2, picrylhydrazyl (DPPH) free radical scavenging assay. The extracts were also evaluated for their phenolic contents and antioxidant activity. Phenolic content was measured using Folin-Ciocalteu reagent and was calculated as Gallic acid equivalents. Antiradical activity of methanolic extract was measured by DPPH assay and was compared to ascorbic acid and ferric reducing power of the extract was evaluated by Oyaizu method. In the present study three in vitro models were used to evaluate antioxidant activity. The first two methods were for direct measurement of radical scavenging activity and remaining one method evaluated the reducing power. The present study revealed that the C. dichotoma bark has significant radical scavenging activity. PMID- 24049419 TI - Ayurvedic PG education and Panchakarma. PMID- 24049420 TI - Ayurveda for the management of dyslexia in children: Some caution required. PMID- 24049421 TI - Hyponatremia and death in Healthy children From plain dextrose and Hypotonic Saline Solutions after Surgery. AB - Preventing acute hyponatremia in hospitalized children. PMID- 24049422 TI - Congress Moves on Drug Track-and-Trace Bill: Hospital Pharmacies Will Need to Read 2D Bar Codes. AB - Congress finally addresses track-and-trace technology. PMID- 24049424 TI - Pharmaceutical approval update. AB - Fluticasone furoate/vilanterol inhalation powder (Breo Ellipta) for chronic obstructive pulmonary disease; atorvastatin/ezetimibe tablets (Liptruzet) for reducing low-density lipoproteincholesterol; and radium 223 dichloride (Xofigo) injection for late-stage, castrationresistant prostate cancer. PMID- 24049425 TI - Aclidinium bromide inhalation powder (tudorza): a long-acting anticholinergic for the management of chronic obstructive pulmonary disease. AB - Aclidinium bromide inhalation powder (Tudorza) for COPD. PMID- 24049426 TI - Linaclotide pharmacodynamics. PMID- 24049427 TI - Key Senator Scrutinizes Pharmacy 340B Selling Practices: Federal Office in Charge of Drug Discounts Begins to Feel the Heat. AB - Upselling takes place when a safety-net hospital increases its profits by selling discounted drugs to privately insured patients at full price. Senator Charles Grassley is on the case to increase transparency and to curtail the misuse of 340B purchases. PMID- 24049428 TI - Drug shortages pose problems for p&t committees in accountable care organizations. AB - Drugs in short supply, especially those needed in oncology, can create legal and patient-safety problems for risk-bearing providers. PMID- 24049429 TI - Phosphodiesterase-5 (PDE5) Inhibitors In the Management of Erectile Dysfunction. PMID- 24049430 TI - 2013 american society of clinical oncology. AB - Therapies for pancreatic, breast, lung, and skin cancers were some of the hot topics at this year's ASCO meeting. PMID- 24049431 TI - New York State Council of Health-system Pharmacists: 2013 52nd Annual Assembly: Medication Safety. AB - The Emily Jerry Foundation was instrumental in requiring training and certification for pharmacy technicians; and a representative from the institute for Safe Medication Practices discusses "off-the-beaten-track" areas of medication use. PMID- 24049432 TI - A Multi-Level Approach to Investigating Neighborhood Effects on Physical Aggression among Urban Chicago Youth. AB - The current study evaluates neighborhood effects, individual-level effects, and demographic characteristics that influence physically aggressive behavior among urban youth. Using data derived from 5,812 adolescents from Project Northland Chicago (PNC) and Heirarchical Linear Modeling (HLM) techniques, the results suggested that neighborhood problems significantly predicted physical aggression, before and after adjustment for individual-level risk factors (alcohol use, peer alcohol use, lack of adult supervision, and depression) and demographics. After accounting for baseline physical aggression, however, neighborhood problems were no longer a significant predictor of physical aggression. Implications for intervention at both the neighborhood and individual-level and study limitations are also discussed. PMID- 24049433 TI - Racial Disparities in Mental Health Outcomes After Psychiatric Hospital Discharge Among Individuals With Severe Mental Illness. AB - Racial disparities in mental health outcomes have been widely documented in non institutionalized community psychiatric samples, but few studies have specifically examined the effects of race among individuals with the most severe mental illnesses. A sample of 925 individuals hospitalized for severe mental illness were followed for a year after hospital discharge to examine the presence of disparities in mental health outcomes between African American and White individuals diagnosed with a severe psychiatric condition. Results from a series of individual growth curve models indicated that African American individuals with severe mental illness experienced significantly less improvement in global functioning, activation and anergia symptoms, and were less likely to return to work in the year following hospitalization. Racial disparities persisted after adjustment for sociodemographic and diagnostic confounders, and were largely consistent across gender, socioeconomic status, and psychiatric diagnosis. Implications for social work research and practice with minorities with severe mental illness are discussed. PMID- 24049434 TI - Novel ALMS1 mutations in Chinese patients with Alstrom syndrome. AB - PURPOSE: Alstrom syndrome (AS) is a rare monogenic autosomal recessively inherited disorder characterized by cone rod dystrophy and multiple organ dysfunction. Mutations in the Alstrom syndrome 1 (ALMS1) gene have been found to be causative for AS. The purpose of this study was to identify ALMS1 mutations and to assess the clinical features of Chinese patients with AS. METHODS: Detailed ocular and laboratory examinations were performed. Peripheral blood samples were collected from patients and their parents. Genomic DNA was extracted with a Qiagen kit. Exons and exon/intron junctions of ALMS1 were amplified with polymerase chain reaction (PCR) and screened for mutations with Sanger sequencing. The results were compared with the ALMS1 transcript to exclude polymorphisms and confirm pathogenic mutations. RESULTS: Seven patients from five unrelated non-consanguineous families were diagnosed with AS. All patients had cone rod dystrophy with impaired visual acuity, photophobia, and nystagmus. Other clinical features, including sensorineural hearing loss, truncal obesity, insulin resistance, type 2 diabetes mellitus, renal and hepatic dysfunction, hyperlipidemia, hypothyroidism, mental retardation, acanthosis nigricans, and scoliosis, were present. Sequencing revealed two novel mutations, p.N3150Kfs2X and p.V3154Xfs, in patient 1; one novel mutation, p.N3672Ifs11X, and one previously reported nonsense mutation, p.R3703X, in patient 2; novel mutations p.S2479X and p.R3611Efs7X in patient 3; one novel homozygous mutation, p.S695X, in patients 4 and 5; and two novel mutations, p.H688HfsX and p.Q3147Qfs2X, in patients 6 and 7. These mutations were not present in 100 unrelated healthy Chinese control subjects. The patients' parents were heterozygous carriers of the mutant allele. CONCLUSIONS: Seven Chinese patients with AS showed typical ophthalmic features and multiple organ dysfunction. Novel loss of function mutations in the ALMS1 gene are the underlying genetic defects. PMID- 24049435 TI - Heterogeneity of monosomy 3 in fine needle aspiration biopsy of choroidal melanoma. AB - PURPOSE: To report on the heterogeneity of monosomy 3 in a fine needle aspiration biopsy obtained transsclerally from choroidal melanoma for prognosis. METHODS: All clinical records for patients who had been diagnosed with choroidal melanoma and underwent iodine-125 plaque brachytherapy with intraoperative transscleral fine needle aspiration biopsy from January 2005 to August 20, 2011, and who had a positive result for monosomy 3 according to fluorescence in situ hybridization as reported by clinical cytogenetics testing were collected. Patient age and sex, total number of cells evaluated and number of cells positive for monosomy 3, tumor size, and metastatic outcome were recorded for each patient. RESULTS: A positive result for monosomy 3 was reported in 93 patients who underwent transscleral fine needle aspiration biopsy. Two patients were lost to follow-up immediately post-operatively, and the remaining 91 patients were included in this study. The mean number of cells evaluated in the biopsy was 273 (range 28 to 520). The mean percentage of cells positive for monosomy 3 was 62.9% (range 4.7% 100%). The mean tumor height was 5.91 mm (range 1.99 to 10.85 mm). Larger tumors were associated with a higher percentage of cells positive for monosomy 3. During the average follow-up interval of 28.9 months (range 3-76 months), choroidal melanoma metastasis developed in 18 (20%) patients. Patients whose tumors had 1% 33% of cells positive for monosomy 3 had a significantly lower risk of metastasis related death compared to patients whose tumors harbored a higher percentage of monosomy 3 (p = 0.04). CONCLUSIONS: Cytogenetic heterogeneity of fluorescent in situ hybridization for monosomy 3 exists in a biopsy sample. Larger tumors were more likely to have a higher percentage of monosomy 3 positive cells in the sample. Furthermore, patients whose tumors had more than 33% of cells positive for monosomy 3 had a poorer prognosis than patients whose tumors had lower percentages of monosomy 3. PMID- 24049436 TI - IGF-1 protects retinal ganglion cells from hypoxia-induced apoptosis by activating the Erk-1/2 and Akt pathways. AB - PURPOSE: Hypoxia-induced retinal ganglion cell (RGC) apoptosis has been implicated in many optic neuropathies. Insulin-like growth factor-1 (IGF-1) is important in maintaining neuronal survival, proliferation, and differentiation. The purpose of this study is to explore whether IGF-1 can protect RGCs from hypoxia-induced apoptosis and to determine the precise mechanisms that regulate this process. METHODS: Purified RGC cultures were obtained from the retinas of neonatal Sprague Dawley (SD) rats using a two-step panning method. Primary cultured RGCs were cultured in a closed hypoxic chamber (5% O2, 5% CO2, and 90% N2) for 12 h with or without IGF-1. The degree of apoptosis in the RGCs was detected by caspase-3 expression and TUNEL and JC-1 staining assays. The expression and phosphorylation of protein kinase B (Akt), p44/42 mitogen activated protein kinase (MAPK) (extracellular signal-regulated kinase-1/2 [Erk 1/2]), Bad, and caspase-3 was investigated with immunoblot analysis. RESULTS: Hypoxia induces apoptosis in primary Sprague Dawley rat RGCs, as detected by caspase-3 expression and TUNEL and JC-1 staining assays, and that IGF-1 treatment could significantly reduce this effect in RGCs. Interestingly, pretreatment of RGCs with AG1024 (an IGF-1 inhibitor), U0126 (an Erk-1/2 inhibitor), and LY294002 (an Akt inhibitor) markedly attenuated the effects of IGF-1 treatment. Furthermore, western blot analysis suggested that the Erk-1/2 and Akt signaling pathways play a role in the protective effects of IGF-1 on RGCs exposed to hypoxia. CONCLUSIONS: These data indicate that IGF-1 can protect primary cultured RGCs against hypoxia-induced apoptosis via the Erk-1/2 and Akt signaling pathways, suggesting that IGF-1 treatment is a potential therapeutic approach for treating hypoxia-induced neurodegeneration in the retina. PMID- 24049437 TI - Polymorphisms in the tumor necrosis factor gene and susceptibility to Behcet's disease: an updated meta-analysis. AB - PURPOSE: Studies investigating the association between the tumor necrosis factor (TNF) gene polymorphisms and Behcet's disease (BD) report conflicting results. The aim of this meta-analysis was to assess the association between TNF gene polymorphisms and BD. METHODS: A systematic literature search was conducted to identify all relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of the association. RESULTS: A total of 16 articles, involving 1,708 patients with BD and 1,910 healthy controls, were included in the meta-analysis. Overall, a significant association was found between BD and the TNF -308A/G polymorphism (OR = 0.730, 95% CI = 0.608 0.877, p = 0.001). Meta-analysis of TNF -238A/G showed significant association with BD (OR = 1.512, 95% CI = 1.155-1.979, p = 0.003). The TNF -1031C allele showed significant association with BD (OR = 1.549, 95% CI = 1.190-2.015, p = 0.001). Similarly, the meta-analysis showed a significant association of the TNF 857T/C polymorphism with BD (OR = 0.758, 95% CI = 0.593-0.968, p = 0.027). Stratification by ethnicity revealed that the -308A/G and -857T/C polymorphisms were associated with BD in the Asian group, while the -238A/G and -1031C/T polymorphisms were associated with BD in the Caucasian population. CONCLUSIONS: The results of our meta-analysis suggest that TNF (-308A/G, -238A/G, -1031C/T, and -857T/C) polymorphisms are associated with susceptibility to BD. PMID- 24049439 TI - All-laser bladeless cataract surgery, combining femtosecond and nanosecond lasers: a novel surgical technique. AB - PURPOSE: To report the safety and efficacy of a novel surgical technique using two lasers in cataract surgery. METHODS: In this contralateral eye report, a 57 year-old female underwent cataract extraction. Two laser devices and a standard phacoemulsification, platform were used to conduct the procedures. First, a femtosecond laser was used to perform the corneal incision, capsulorhexis, and initial lens fragmentation in each eye. Following this, a nanosecond laser was used to enter the 2.8 mm incision, uni-axially, and complete the viscoelastic divided nucleus fragment emulsification and removal in one eye. Standard phacoemulsification was used in the completion of the other eye. Posterior chamber foldable acrylic intraocular lenses were implanted in both cases. We evaluated perioperative acuity, refraction, keratometry, Scheimpflug tomography, intraocular pressure, endothelial cell counts, and total energy used with each laser in each case. RESULTS: Corrected distance visual acuity improved from preoperative 20/60 and 20/70 to postoperative 20/20 in both eyes, with 6-month follow-up. In the right eye, the total intraocular energy used was 2 J by the femtosecond laser and 6 J by the phacoemulsification device. In the left eye, the nanosecond laser utilized the same energy of 2 J and the nanosecond laser 2.4 J (80 pulses of 30 mJ each). There were no other differences noted in intraocular pressure or endothelial cell counts. CONCLUSION: In this report, we introduce a bladeless all-laser cataract surgery extraction alternative technique, with several potential novel advantages: enhanced incision and capsulorhexis reproducibility, reduction in intraocular energy used, and elimination of the potential of thermal corneal injury. PMID- 24049438 TI - Acquisition of RGC phenotype in human Muller glia with stem cell characteristics is accompanied by upregulation of functional nicotinic acetylcholine receptors. AB - PURPOSE: Human Muller glia with stem cell characteristics (hMGSCs) can be induced to express genes and proteins of retinal ganglion cells (RGCs) upon in vitro inhibition of Notch-1 activity. However, it is not known whether expression of these markers is accompanied by acquisition of RGC function. This study investigated whether hMGSCs that express RGC markers also display neural functionality, as measured by their intracellular calcium concentration ([Ca(2+)]i) responsiveness following neurotransmitter stimulation in vitro. METHODS: Changes in mRNA expression of RGC markers and neurotransmitter receptors were assessed either by conventional or quantitative reverse transcription PCR (RT-PCR), while changes in protein levels were confirmed by immunocytochemistry. The [Ca(2+)]i levels were estimated by fluorescence microscopy. RESULTS: We showed that while undifferentiated hMGSCs displayed a profound elevation of [Ca(2+)]i after stimulation with N-methyl-D-aspartate (NMDA), this was lost following Notch-1 inhibition. Conversely, untreated hMGSCs did not respond to muscarinic receptor stimulation, whereas [Ca(2+)]i was increased in differentiated hMGSCs that expressed RGC precursor markers. Differentiated hMGSC derived RGCs, but not undifferentiated hMGSCs, responded to stimulation by nicotine with a substantial rise in [Ca(2+)]i, which was inhibited by the alpha4beta2 and alpha6beta2 nicotinic receptor antagonist methyllycaconitine. Notch-1 attenuation not only caused a decrease in the gene expression of the Notch effector HES1 and increased expression of RGC markers, but also an increase in the gene and protein expression of alpha4 and alpha6 nicotinic receptor subunits. CONCLUSIONS: These observations suggest that in response to Notch-1 inhibition, hMGSCs differentiate into a population of RGCs that exhibit some of the functionality observed in differentiated RGCs. PMID- 24049440 TI - Risk factors for suboptimal antiretroviral therapy adherence in HIV-infected adolescents in Gaborone, Botswana: a pilot cross-sectional study. AB - OBJECTIVE: Little is known about factors associated with suboptimal antiretroviral treatment (ART) adherence among adolescents in Sub-Saharan Africa. Our objective was to determine the level of ART adherence and predictors of non adherence among human immunodeficiency virus (HIV)-infected adolescents at the Botswana-Baylor Children's Clinical Centre of Excellence in Gaborone, Botswana. METHODS: In a cross-sectional study, 82 HIV-infected adolescents receiving ART and their caregivers were administered a structured questionnaire. The patient's clinical information was retrieved from medical records. Outcome measures included excellent pill count ART adherence (>95%) and virologic suppression (HIV viral load <400 copies/mL). Multivariate logistic regression analysis was performed to identify independent predictors of ART non-adherence. RESULTS: The overall median (interquartile range) ART adherence was 99% (96.5-100) (N = 82). Seventy-six percent of adolescents had excellent pill count ART adherence levels and 94% achieved virologic suppression. Male adolescents made up 65% of the non adherent group (P = 0.02). Those who displayed suboptimal ART adherence were more likely to report having ever missed ART doses due to failure to pick up medication at the pharmacy (30.0% versus 9.7%, P = 0.03). In the multivariate logistic regression model, male sex (odds ratio [OR] 3.29, 95% confidence interval [CI] 1.13-9.54; P = 0.03) was the only factor which was independently associated with suboptimal ART adherence. CONCLUSIONS: A high proportion of HIV infected adolescents studied had excellent ART adherence and virologic suppression, with male adolescents at higher risk of suboptimal adherence than females. Further research to investigate how sex relates to suboptimal adherence may aid in the design of targeted intervention strategies. PMID- 24049441 TI - Effects of an animated diagram and video-based online breathing program for dyspnea in patients with stable COPD. AB - BACKGROUND: Breathing programs have been reported to have positive effects in alleviating symptoms and optimizing pulmonary function in patients with chronic obstructive pulmonary disease (COPD). However, patients with stable disease may drop out of such programs if they are not modified to the individual's exercise tolerance level, or if they are not easy to perform in the home. Little is known about the effectiveness of web-based home breathing programs for dyspnea. The purpose of this study was to evaluate the effectiveness of an online breathing program which included an animated diagram and video-guided instruction on pulmonary function, exercise capacity, and health-related quality of life in patients with COPD. METHODS: Sixty patients with stable COPD were randomized 1:1 to an experimental group (n = 30) or a control group (n = 30). Subjects in the experimental group trained for four months using an online program which included an animated diagram and video-guided instruction while the control group received conventional patient education on discharge from hospital. Forced expiratory volume, forced expiratory volume in one second (FEV1)/forced vital capacity (%), peak expiratory volume, six-minute walking distance test, and responses to the St George's Respiratory Questionnaire were assessed before and after the intervention. RESULTS: Patients in the two groups were well matched for demographic and clinical characteristics at baseline. All outcome measures showed significant improvement in the experimental group but not in the control group. CONCLUSION: The online training program resulted in improved pulmonary function, exercise capacity, and health status. Therefore, it is strongly recommended that patients with stable COPD be trained with such programs. PMID- 24049443 TI - Errorless learning of everyday tasks in people with dementia. AB - Errorless learning (EL) is a principle used to teach new information or skills to people with cognitive impairment. In people with dementia, EL principles have mostly been studied in laboratory tasks that have little practical relevance for the participants concerned, yet show positive effects. This is the first paper to exclusively review the literature concerning the effects of EL on the performance of useful everyday tasks in people with dementia. The role of factors such as type of dementia, type of task, training intensity, EL elements, outcome measures, quality of experimental design, and follow-up are discussed. The results indicate that, compared with errorful learning (EF) or no treatment, EL is more effective in teaching adults with dementia a variety of meaningful daily tasks or skills, with gains being generally maintained at follow-up. The effectiveness of EL is highly relevant for clinical practice because it shows that individuals with dementia are still able to acquire meaningful skills and engage in worthwhile activities, which may potentially increase their autonomy and independence, and ultimately their quality of life, as well as reduce caregiver burden and professional dependency. Suggestions for future research are given, along with recommendations for effective EL-based training programs, with the aim of developing a clinical manual for professionals working in dementia care. PMID- 24049444 TI - Coronary anomaly: anomalous right coronary artery originates from the left sinus of Valsalva and coursing between the pulmonary artery and aorta. AB - Coronary artery anomalies (CAAs) are present at birth, but are usually asymptomatic and are found during coronary angiography or multi-slice computed tomography (MSCT) detection. The most common coronary anomaly is the separating origin of left anterior descending coronary artery (LAD) and left circumflex artery (LCX) from the left sinus of Valsalva, and this variant is benign. Herein, we present three extremely rare cases of anomalous right coronary artery (RCA) detected incidentally during routine coronary angiography and confirmed by multi slice computed tomography (MSCT) technique. All the anomalous right coronary artery coursed between the pulmonary artery and aorta. We discuss how to make an accurate diagnosis for appropriate management. PMID- 24049445 TI - Development and characterization of dilutable self-microemulsifying premicroemulsion systems (SMEPMS) as templates for preparation of nanosized particulates. AB - The utilization of self-microemulsifying premicroemulsion systems (SMEPMS) as templates for preparing poorly water-soluble compounds in the nanosized range represents a promising strategy. Fenofibrate was formulated with n-butyl L lactate, Tween 80, and a number of cosurfactants (ethanol, 1-propanol, and PEG 600), diluted with the water phase (either water or saccharide solution) and then subjected to a freeze-drying (FD) process to obtain SMEPMS nanosized particulates. Results demonstrated that the particle size after resuspension of these FD SMEPMS nanosized particulates in water was too large, so the addition of saccharide solutions (lactose, mannitol, glucose, sucrose, and trehalose) as the solid carrier to prevent particles from aggregating seemed to be necessary and workable due to steric hindrance and repulsion. However, instability of these resuspended FD nanosized particulates after 30-90 minutes still occurred, and the addition of 0.5% sodium lauryl sulfate in the resuspending medium was able to retard the aggregation and maintain the particle size within the nano-range. Evaluation by scanning electron microscopy and X-ray powder diffraction also confirmed the results. It was concluded that using an SMEPMS formulation with PEG 600 as the cosurfactant, and in the presence of a suitable saccharide as an anticaking agent and FD process were able to produce fenofibrate nanoparticles. PMID- 24049442 TI - Promoting physical activity for elders with compromised function: the lifestyle interventions and independence for elders (LIFE) study physical activity intervention. AB - The Lifestyle Interventions and Independence for Elders (LIFE) Study is a Phase III randomized controlled clinical trial (Clinicaltrials.gov identifier: NCT01072500) that will provide definitive evidence regarding the effect of physical activity (PA) on major mobility disability in older adults (70-89 years old) who have compromised physical function. This paper describes the methods employed in the delivery of the LIFE Study PA intervention, providing insight into how we promoted adherence and monitored the fidelity of treatment. Data are presented on participants' motives and self-perceptions at the onset of the trial along with accelerometry data on patterns of PA during exercise training. Prior to the onset of training, 31.4% of participants noted slight conflict with being able to meet the demands of the program and 6.4% indicated that the degree of conflict would be moderate. Accelerometry data collected during PA training revealed that the average intensity - 1,555 counts/minute for men and 1,237 counts/minute for women - was well below the cutoff point used to classify exercise as being of moderate intensity or higher for adults. Also, a sizable subgroup required one or more rest stops. These data illustrate that it is not feasible to have a single exercise prescription for older adults with compromised function. Moreover, the concept of what constitutes "moderate" exercise or an appropriate volume of work is dictated by the physical capacities of each individual and the level of comfort/stability in actually executing a specific prescription. PMID- 24049446 TI - Current approaches to treatments for schizophrenia spectrum disorders, part I: an overview and medical treatments. AB - During the last three decades, an increasing understanding of the etiology, psychopathology, and clinical manifestations of schizophrenia spectrum disorders, in addition to the introduction of second-generation antipsychotics, has optimized the potential for recovery from the illness. Continued development of various models of psychosocial intervention promotes the goal of schizophrenia treatment from one of symptom control and social adaptation to an optimal restoration of functioning and/or recovery. However, it is still questionable whether these new treatment approaches can address the patients' needs for treatment and services and contribute to better patient outcomes. This article provides an overview of different treatment approaches currently used in schizophrenia spectrum disorders to address complex health problems and a wide range of abnormalities and impairments resulting from the illness. There are different treatment strategies and targets for patients at different stages of the illness, ranging from prophylactic antipsychotics and cognitive-behavioral therapy in the premorbid stage to various psychosocial interventions in addition to antipsychotics for relapse prevention and rehabilitation in the later stages of the illness. The use of antipsychotics alone as the main treatment modality may be limited not only in being unable to tackle the frequently occurring negative symptoms and cognitive impairments but also in producing a wide variety of adverse effects to the body or organ functioning. Because of varied pharmacokinetics and treatment responsiveness across agents, the medication regimen should be determined on an individual basis to ensure an optimal effect in its long-term use. This review also highlights that the recent practice guidelines and standards have recommended that a combination of treatment modalities be adopted to meet the complex health needs of people with schizophrenia spectrum disorders. In view of the heterogeneity of the risk factors and the illness progression of individual patients, the use of multifaceted illness management programs consisting of different combinations of physical, psychological, and social interventions might be efficient and effective in improving recovery. PMID- 24049447 TI - Maternal personality profile of children affected by migraine. AB - BACKGROUND: Empirical evidence of the important role of the family in primary pediatric headache has grown significantly in the last few years, although the interconnections between the dysfunctional process and the family interaction are still unclear. Even though the role of parenting in childhood migraine is well known, no studies about the personality of parents of migraine children have been conducted. The aim of the present study was to assess, using an objective measure, the personality profile of mothers of children affected by migraine without aura (MoA). MATERIALS AND METHODS: A total of 269 mothers of MoA children (153 male, 116 female, aged between 6 and 12 years; mean 8.93 +/- 3.57 years) were compared with the findings obtained from a sample of mothers of 587 healthy children (316 male, 271 female, mean age 8.74 +/- 3.57 years) randomly selected from schools in the Campania, Umbria, Calabria, and Sicily regions. Each mother filled out the Minnesota Multiphasic Personality Inventory - second edition (MMPI 2), widely used to diagnose personality and psychological disorders. The t-test was used to compare age and MMPI-2 clinical basic and content scales between mothers of MoA and typical developing children, and Pearson's correlation test was used to evaluate the relation between MMPI-2 scores of mothers of MoA children and frequency, intensity, and duration of migraine attacks of their children. RESULTS: Mothers of MoA children showed significantly higher scores in the paranoia and social introversion clinical basic subscales, and in the anxiety, obsessiveness, depression, health concerns, bizarre mentation, cynicism, type A, low self-esteem, work interference, and negative treatment indicator clinical content subscales (P < 0.001 for all variables). Moreover, Pearson's correlation analysis showed a significant relationship between MoA frequency of children and anxiety (r = 0.4903, P = 0.024) and low self-esteem (r = 0.5130, P = 0.017), while the MoA duration of children was related with hypochondriasis (r = 0.6155, P = 0.003), hysteria (r = 0.6235, P = 0.003), paranoia (r = 0.5102, P = 0.018), psychasthenia (r = 0.4806, P = 0.027), schizophrenia (r = 0.4350, P = 0.049), anxiety (r = 0.4332, P = 0.050), and health concerns (r = 0.7039, P < 0.001) MMPI-2 scores of their mothers. CONCLUSION: This could be considered a preliminary study that indicates the potential value of maternal personality assessment for better comprehension and clinical management of children affected by migraine, though further studies on the other primary headaches are necessary. PMID- 24049448 TI - Evaluating nicotine levels selection and patterns of electronic cigarette use in a group of "vapers" who had achieved complete substitution of smoking. AB - BACKGROUND: Electronic cigarettes (ECs) are alternative-to-smoking nicotine delivery devices; consumers (commonly called vapers) use them in order to reduce or completely substitute smoking. The European Commission has released a proposal for a new Tobacco Product Directive that might reduce availability of nicotine containing products, including ECs. In this study, the EC use patterns in subjects who have completely substituted smoking with EC use were examined by personal interviews. The study focused on nicotine levels used in order to achieve smoking cessation, reported benefits, associated side effects, and estimation of EC dependence compared with smoking. METHODS: Participants were 111 subjects who had completely substituted smoking with EC use for at least 1 month. Smoking abstinence was validated by measuring blood carboxyhemoglobin levels. Nicotine levels at initiation of EC use, at time of smoking cessation, and at time of interview were recorded. Dependence potential was assessed by asking the first question of the Fagerstrom Test for Cigarette Dependence (time until smoking the first cigarette and until first use of EC in the morning) and questions about perceived past dependence on tobacco cigarettes and present dependence on EC. RESULTS: Forty-two percent of participants reported quitting smoking during the first month of EC use. Liquids with nicotine concentration >15 mg/mL were used by 74% of users at initiation of EC use, while 16.2% had to increase the initial nicotine levels in order to achieve complete smoking abstinence. Seventy-two participants (64.9%) reported that from the time of smoking cessation to the time of the interview (8 months median duration of EC use) they reduced the nicotine concentration they were consuming; however, only 12% of the total sample was using <=5 mg/mL nicotine concentration at the time of the interview. Side effects were mild and temporary. The vast majority of participants reported better exercise capacity and improved olfactory and gustatory senses. Perceived EC dependenct was significantly lower compared to smoking. CONCLUSIONS: Nicotine levels appear to play an important role in achieving and maintaining smoking cessation in the group of motivated subjects studied. High nicotine-containing liquids were used while few mild and temporary side effects were reported. Proposals about regulation should consider the pragmatic use patterns of ECs, especially in consumers who have completely substituted smoking. PMID- 24049449 TI - What constitutes an excellent allied health care professional? A multidisciplinary focus group study. AB - BACKGROUND: Determining what constitutes an excellent allied health care professional (AHCP) is important, since this is what will guide the development of curricula for training future physical therapists, oral hygienists, speech therapists, diagnostic radiographers, and dietitians. This also determines the quality of care. AIM: To describe perspectives of AHCPs on which characteristics are commonly associated with an excellent AHCP. METHODS: AHCPs' perspectives were derived from three focus group discussions. Twenty-one health care professionals participated. The final analysis of the focus group discussions produced eight domains, in which content validity was obtained through a Delphi panel survey of 27 contributing experts. RESULTS: ACCORDING TO THE SURVEY, A COMBINATION OF THE FOLLOWING CHARACTERISTICS DEFINES AN EXCELLENT AHCP: (1) cognizance, to obtain and to apply knowledge in a broad multidisciplinary health care field; (2) cooperativity, to effectively work with others in a multidisciplinary context; (3) communicative, to communicate effectively at different levels in complex situations; (4) initiative, to initiate new ideas, to act proactively, and to follow them through; (5) innovative, to devise new ideas and to implement alternatives beyond current practices; (6) introspective, to self-examine and to reflect; (7) broad perspective, to capture the big picture; and (8) evidence driven, to find and to use scientific evidence to guide one's decisions. CONCLUSION: The AHCPs perspectives can be used as a reference for personal improvement for supervisors and professionals in clinical practice and for educational purposes. These perspectives may serve as a guide against which talented students can evaluate themselves. PMID- 24049450 TI - Kynurenic Acid in the digestive system-new facts, new challenges. AB - This review provides information on the most recent findings concerning presence, origin, and role of kynurenic acid (KYNA), a tryptophan metabolite, in the digestive system. KYNA is an antagonist of both the ionotropic glutamate receptors and the alpha7 nicotinic acetylcholine receptor, as well as an agonist of G-protein coupled GPR35 receptor. Since the GPR35 receptor is mainly present in the gastrointestinal tract, researchers have concentrated on the digestive system in recent years. They have found that KYNA content increases gradually and significantly along the gastrointestinal tract. Interestingly, the concentration of KYNA in the lumen is much higher than in the wall of intestine. It has been documented that KYNA may have a positive influence on the number of pathologies in the gastrointestinal tract, in particular ulcers, colon obstruction, or colitis. Future studies might determine whether it is advisable to supplement KYNA to a human organism. PMID- 24049451 TI - Emerging targets in pancreatic cancer: epithelial-mesenchymal transition and cancer stem cells. AB - Pancreatic ductal adenocarcinoma is one of the most aggressive solid malignancies and is characterized by poor response to current therapy and a dismal survival rate. Recent insights regarding the role of cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) in tumorigenesis have brought further understanding to the field and have highlighted new therapeutic targets. CSCs are a distinct subset of cancer cells, with the ability to differentiate into other cell types and self-renew in order to fuel the maintenance of tumor amplification. Transition of a cancer cell from an EMT leads to increased migratory and invasive properties, and thus facilitates initiation of metastasis. EMT is regulated by a complex network of factors that includes cytokines, growth factors, aberrant signaling pathways, transcription factors, and the tumor microenvironment. There is emerging evidence that the EMT process may give rise to CSCs, or at least cells with stem cell-like properties. We review the key pathways involved in both of these processes, the biomarkers used to identify CSCs, and new therapeutic approaches targeting CSCs and EMT in pancreatic ductal adenocarcinoma. PMID- 24049453 TI - Facial fat grafting with a prototype injection control device. AB - OBJECTIVE: To evaluate the initial clinical performance of a prototype injection control device (ICD) to facilitate fat grafting by injection. METHODS: An ICD, which mechanically couples the act of withdrawing the cannula with the act of depressing the plunger, was fabricated for the purpose of facial fat grafting. The action of the device results in deposition of consistent threads of fat having a volume of approximately 33 uL per cm that the cannula is withdrawn, which is slightly less than the internal volume of a 12-gauge cannula. A total of 26 patients underwent 30 procedures, and the results were subjectively evaluated using pre- and postoperative photographs, with a minimum follow-up of 4 months. RESULTS: The desired degree of correction was more consistent, recovery was faster, and procedural efficiency was improved when performing the procedure with the ICD compared to historical use of the manual method of injection. Minor irregularities were the only complications encountered. CONCLUSION: The ICD optimally distributes fat as a uniform thread along the withdrawal tract of the cannula, thereby eliminating clumping and minimizing tissue trauma, resulting in reduced recovery time as well as more consistent and predictable clinical results. Since the ICD automates the injection process, it provides a notable and easily attainable efficiency in procedural time and minimal learning curve for the user. PMID- 24049452 TI - Long-term cost-effectiveness of atypical antipsychotics in the treatment of adults with schizophrenia in the US. AB - BACKGROUND: The purpose of this study was to evaluate the long-term cost effectiveness (including hospitalizations and cardiometabolic consequences) of atypical antipsychotics among adults with schizophrenia. METHODS: A 5-year Markov cohort cost-effectiveness model, from a US payer perspective, was developed to compare lurasidone, generic risperidone, generic olanzapine, generic ziprasidone, aripiprazole, and quetiapine extended-release. Health states included in the model were patients: on an initial atypical antipsychotic; switched to a second atypical antipsychotic; and on clozapine after failing a second atypical antipsychotic. Incremental cost-effectiveness ratios (ICERs) assessed incremental cost/hospitalization avoided. Effectiveness inputs included discontinuations, hospitalizations, weight change, and cholesterol change from comparative clinical trials for lurasidone and for aripiprazole, and the Clinical Antipsychotic Trials of Intervention Effectiveness for other comparators. Atypical antipsychotic specific relative risk of diabetes obtained from a retrospective analysis was used to predict cardiometabolic events per Framingham body mass index risk equation. Mental health costs (relapsing versus nonrelapsing patients) and medical costs associated with cardiometabolic consequences (cardiovascular events and diabetes management) were obtained from published sources. Atypical antipsychotic costs were estimated from Red Book(r) prices at dose(s) reported in clinical data sources used in the model (weighted average dose of lurasidone and average dose for all other comparators). Costs and outcomes were discounted at 3%, and model robustness was tested using one-way and probabilistic sensitivity analyses. RESULTS: Ziprasidone, olanzapine, quetiapine extended-release, and aripiprazole were dominated by other comparators and removed from the comparative analysis. ICER for lurasidone versus risperidone was $25,884/relapse-related hospitalization avoided. At a $50,000 willingness-to-pay threshold, lurasidone has an 86.5% probability of being cost-effective, followed by a 7.2% probability for olanzapine, and 6.3% for risperidone. One-way sensitivity analysis showed the model is sensitive to lurasidone and generic risperidone hospitalization rates. CONCLUSION: Generic risperidone is the least costly atypical antipsychotic. Lurasidone is more costly and more effective than risperidone and is cost effective at willingness-to-pay thresholds of greater than $25,844 per hospitalization avoided. The favorable cost-effectiveness of lurasidone is driven by its clinical benefits (eg, efficacy in preventing hospitalizations in patients with schizophrenia) and its minimal cardiometabolic adverse effect profile. PMID- 24049454 TI - Vaccination against pneumococcus in West Africa: perspectives and prospects. AB - BACKGROUND: Pneumococcal vaccination has become obligatory due to the enormous burden of pneumococcal diseases. Quite recently, pneumococcal conjugate vaccines have been developed, and have been shown to be superior to the previous polyvalent polysaccharide vaccine of the organism. Pneumococcal conjugate vaccines (PCVs) are being introduced in many West African countries and it is important to understand the expected performance, relevance, and limitations of these vaccines in the subregion. AIM: The objective of the study presented here was to provide epidemiological insights into PCVs in West Africa based on the prevailing pneumococcal serotypes in the subregion. METHODS: A systematic review was carried out on pneumococcal serotypes causing invasive and noninvasive diseases in West Africa. Studies included in the review were those that reported at least 20 serotyped pneumococcal isolates and which were conducted prior to the introduction of PCVs in the region in 2009. The proportion of pneumococcal disease associated with each serotype as well as the serotype coverage of various PCVs (PCV7, PCV10, and PCV13) were calculated. RESULTS: The data covered 718 serotyped pneumococcal isolates from six West African countries: Burkina Faso, Ghana, Nigeria, Mali, Senegal, and The Gambia. The 718 isolates covered more than 20 serotypes. Serotype 1 was the most prevalent serotype (32%), followed by serotype 5 (15%), serotype 6 (7%), serotype 2 (6%), serotype 3 (6%), and serotype 12 (5%). The estimated serotype coverage of PCVs among the West African countries was 2%-36% for PCV7, 39%-80% for PCV10, and 65%-87% for PCV13. CONCLUSION: A pneumococcal capsular vaccine for use in West Africa must contain serotypes 1 and 5, the most important serotypes responsible for pneumococcal disease in the region. Consequently, while PCV10 and PCV13 are generally suitable for use in West Africa, PCV7 is unsuitable. PMID- 24049455 TI - Meningitis and stridor in advanced Human immunodeficiency virus/acquired immune deficiency syndrome. AB - A 37-year-old female presented confused with a preceding history of severe headache. After clinical examination and investigations, she was diagnosed with disseminated tuberculosis (including central nervous system involvement), and Human immunodeficiency virus/acquired immune deficiency syndrome. Her hospital stay was complicated. She developed stridor and a cerebrovascular accident with left hemiplegia. She died approximately 2 weeks after admission. The potential causes of her stridor included a mediastinal mass or a central mechanism secondary to tuberculosis meningitis. Limited resources precluded definitive imaging of the chest to rule out a mediastinal mass. Further, an autopsy was not done. Despite these limitations, this case is unique because it reports the presence of both stridor and tuberculosis meningitis in an adult patient. PMID- 24049456 TI - Development and validation of the Patient Opioid Education Measure. AB - BACKGROUND: Although there are screening tools to aid clinicians in assessing the risk of opioid misuse, an instrument to assess opioid-related knowledge is not currently available. The purpose of this study was to develop a content-valid, understandable, readable, and reliable Patient Opioid Education Measure (POEM). METHODS: Using concept mapping, clinicians caring for patients with chronic pain participated in brainstorming, sorting, and rating need-to-know information for patients prescribed opioids. Concept mapping analyses identified seven clusters addressing knowledge and expectations associated with opioid use, including medicolegal issues, prescribing policies, safe use and handling, expected outcomes, side effects, pharmacology, and warnings. RESULTS: The 49-item POEM was verbally administered to 83 patients (average age 51.3 +/- 9.8 years, 77.1% female, 47.1% African American) taking opioids for chronic nonmalignant pain. Patients averaged in total 63.9% +/- 14.3% (range 23%-91%) correct responses on the POEM. The POEM demonstrated substantial test-retest reliability (interclass correlation coefficient 0.87). The POEM had a mean readability Lexile (L) score of 805.9 +/- 257.3 L (equivalent to approximately a US fifth grade reading level), with individual items ranging from 280 L to 1370 L. CONCLUSION: The POEM shows promise for rapidly identifying patients' opioid-related knowledge gaps and expectations. Correcting misunderstandings and gaps could result in safer use of opioids in a clinical care setting. PMID- 24049457 TI - Assessing the relationship between the level of pain control and patient satisfaction. AB - PURPOSE: The primary assessment tool used by hospitals to measure the outcomes of pain management programs is the 0-10 numerical pain rating scale. However, it is unclear if this assessment should be used as the sole indicator of positive outcomes by pain management programs. Although it is assumed that pain intensity scores would be correlated with patient satisfaction, few studies have evaluated the association between pain intensity scores and patient satisfaction. METHODS: In this pilot study, we investigated the relationship between pain intensity and patient satisfaction by evaluating 88 patients who received opioid analgesics at a 1018-bed acute care institution. A 14-question survey was adapted from a questionnaire developed by the American Pain Society to assess patient pain control and overall satisfaction with our institution's pain management strategies. RESULTS: This study found no association between pain intensity score and patient satisfaction with overall pain management (Spearman's rank correlation coefficient = -0.31; 95% confidence interval = -0.79 to 0.39). The majority of the surveyed patients were satisfied or very satisfied with their overall pain management, regardless of their pain intensity score. CONCLUSION: These findings contribute to the general understanding that institutions should use pain intensity scores together with a measure of patient pain satisfaction when assessing regulatory and quality control programs. PMID- 24049458 TI - Treatment challenges in the management of relapsed or refractory non-Hodgkin's lymphoma - novel and emerging therapies. AB - Over the last few decades, advances in immunochemotherapy have led to dramatic improvement in the prognosis of non-Hodgkin's lymphoma (NHL). Despite these advances, relapsed and refractory disease represents a major treatment challenge. For both aggressive and indolent subtypes of NHL, there is no standard of care for salvage regimens, with prognosis after relapse remaining relatively poor. Nevertheless, there are multiple emerging classes of targeted therapies for relapsed/refractory disease, including monoclonal antibodies, antibody- drug conjugates, radioimmunotherapy, small-molecule inhibitors of cell-growth pathways, and novel chemotherapy agents. This review will discuss treatment challenges of NHL, current available salvage regimens for relapsed/refractory NHL, and the safety and efficacy of novel emerging therapies. PMID- 24049459 TI - Focal low-dose rate brachytherapy for the treatment of prostate cancer. AB - Whole-gland low-dose rate (LDR) brachytherapy has been a well-established modality of treating low-risk prostate cancer. Treatment in a focal manner has the advantages of reduced toxicity to surrounding organs. Focal treatment using LDR brachytherapy has been relatively unexplored, but it may offer advantages over other modalities that have established experiences with a focal approach. This is particularly true as prostate cancer is being detected at an earlier and more localized stage with the advent of better detection methods and newer imaging modalities. PMID- 24049461 TI - Chronic idiopathic axonal neuropathy and pain, treated with the endogenous lipid mediator palmitoylethanolamide: a case collection. AB - Chronic idiopathic axonal polyneuropathy is a frequent diagnosis in patients suffering from idiopathic polyneuropathy and neuropathic pain. No guidelines exist on how to treat these patients. To date, there are no results available from randomized clinical trials, and mostly classical neuropathic analgesics are prescribed, such as amitriptyline and gabapentine. However, the usefulness of these drugs is limited, as many patients remain in pain despite treatment, or suffer debilitating side effects. Palmitoylethanolamide (PEA) is a new analgesic compound, tested in more than 4,000 patients in various clinical trials in a variety of patients suffering from various neuropathic pain states. It is available in Europe and the USA as a food supplement under the brand name PeaPure, and it is available for medical purposes in Italy and Spain under brand names Normast and Pelvilen. We present a case series of seven patients with an electrophysiological confirmed diagnosis of chronic idiopathic axonal polyneuropathy, suffering from neuropathic pains, mostly refractory to previous analgesics. In all these patients, PEA reduced pain significantly, without side effects. PEA can be administered in addition to other analgesics, without negative drug-drug interactions, or can be used as a stand-alone analgesic. Due to a favorable ratio between efficacy and safety, PEA should be considered more often as a treatment for neuropathic pain. PMID- 24049460 TI - HIV-related neuropathy: current perspectives. AB - Distal symmetric polyneuropathy (DSP) related to human immunodeficiency virus (HIV) is one of the most common neurologic complications of HIV, possibly affecting as many as 50% of all individuals infected with HIV. Two potentially neurotoxic mechanisms have been proposed to play a crucial role in the pathogenesis of HIV DSP: neurotoxicity resulting from the virus and its products; as well as adverse neurotoxic effects of medications used in the treatment of HIV. Clinically, HIV DSP is characterized by a combination of signs and symptoms that include decreased deep tendon reflexes at the ankles and decreased sensation in the distal extremities as well as paresthesias, dysesthesias, and pain in a symmetric stocking-glove distribution. These symptoms are generally static or slowly progressive over time, and depending on the severity, may interfere significantly with the patient's daily activities. In addition to the clinical picture, nerve conduction studies and skin biopsies are often pursued to support the diagnosis of HIV DSP. Anticonvulsants, antidepressants, topical agents, and nonspecific analgesics may help relieve neuropathic pain. Specifically, gabapentin, lamotrigine, pregabalin, amitriptyline, duloxetine, and high-dose topical capsaicin patches have been used in research and clinical practice. Further research is needed to elucidate the pathogenesis of HIV DSP, thus facilitating the development of novel treatment strategies. This review discusses the epidemiology, pathophysiology, clinical findings, diagnosis, and management of DSP in the setting of HIV. PMID- 24049463 TI - New treatment of iliac artery disease: focus on the Absolute Pro(r) Vascular Self Expanding Stent System. AB - Management of iliac artery disease has evolved over the years, from a surgical only approach to a primarily endovascular-only approach as the first line treatment option. This has been continuously improved upon with the advent of new devices and applied technologies. Most recently in particular, the literature has shown good, reliable outcomes with the use of self-expandable stents in iliac artery atherosclerotic lesions. Nevertheless, no device is without its limitations, and the Absolute Pro(r) Vascular Self-Expanding Stent System was designed with the intent of overcoming some of the shortcomings of other available stents while maintaining acceptable postprocedural outcomes. Based on preliminary industry-acquired data, it has achieved these goals and appears to be an emergent competitor for the treatment of both focal and complex iliac artery lesions. PMID- 24049462 TI - Role of Cartilage Forming Cells in Regenerative Medicine for Cartilage Repair. AB - Currently, cartilage repair remains a major challenge for researchers and physicians due to its limited healing capacity. Cartilage regeneration requires suitable cells; these must be easily obtained and expanded, able to produce hyaline matrix with proper mechanical properties, and demonstrate sustained integration with native tissue. At present, there is a wide variety of possible cell sources for cartilage regeneration; this review explores the diversity of sources for cartilage forming cells and the distinctive characteristics, advantages, limitations, and potential applications of each cell source. We place emphasis on cell sources used for in vitro and clinical studies. PMID- 24049464 TI - The medication process in a psychiatric hospital: are errors a potential threat to patient safety? AB - PURPOSE: To investigate the frequency, type, and potential severity of errors in several stages of the medication process in an inpatient psychiatric setting. METHODS: A cross-sectional study using three methods for detecting errors: (1) direct observation; (2) unannounced control visits in the wards collecting dispensed drugs; and (3) chart reviews. All errors, except errors in discharge summaries, were assessed for potential consequences by two clinical pharmacologists. SETTING: Three psychiatric wards with adult patients at Aalborg University Hospital, Denmark, from January 2010-April 2010. THE OBSERVATIONAL UNIT: The individual handling of medication (prescribing, dispensing, and administering). RESULTS: In total, 189 errors were detected in 1,082 opportunities for error (17%) of which 84/998 (8%) were assessed as potentially harmful. The frequency of errors was: prescribing, 10/189 (5%); dispensing, 18/189 (10%); administration, 142/189 (75%); and discharge summaries, 19/189 (10%). The most common errors were omission of pro re nata dosing regime in computerized physician order entry, omission of dose, lack of identity control, and omission of drug. CONCLUSION: Errors throughout the medication process are common in psychiatric wards to an extent which resembles error rates in somatic care. Despite a substantial proportion of errors with potential to harm patients, very few errors were considered potentially fatal. Medical staff needs greater awareness of medication safety and guidelines related to the medication process. Many errors in this study might potentially be prevented by nursing staff when handling medication and observing patients for effect and side effects of medication. The nurses' role in psychiatric medication safety should be further explored as nurses appear to be in the unique position to intercept errors before they reach the patient. PMID- 24049465 TI - Morphological Characteristics of Hyphal Interaction between Grifola umbellata and its Companion Fungus. AB - Morphological characteristics of hyphal interaction between Grifola umbellata (Pers. Ex Fr.) Pilat and its companion fungus which related to sclerotia formation from hyphae were investigated by external observations, light microscopy and transmission electron microscopy (TEM). External observations showed that a dense antagonism line was formed by both G. umbellata and companion fungus after their hyphae contacted each other in dual culture. Many hyphal strands emerged on the colony of G. umbellata and differentiated to sclerotia from where hyphal strands crossed. Light microscope observations revealed the process of antagonism line formation. Mature antagonism with structural differentiation, was composed of three main layers: the rind, the rind underlayer and the hypha layer. TEM observations showed that after colonies hyphal contact, a series of reactions always occurred in both G. umbellata and companion fungus. Cells in the center of antagonism line were dead. Cells of G. umbellata adjacent to the antagonism line were usually large and hollow, with unilateral thickened wall, whereas those of companion fungus were empty, with thin or thick wall. Both hyphal interaction at the antagonism line may be one of the main reasons for sclerotia of G. umbellata differentiation from hypha. PMID- 24049466 TI - Induction of Sexual Stage and Colony Morphology of Some Isolates of Sclerotium rolfsii Causing Spotted Leaf Rot in Plants. AB - Twenty-two isolates of Sclerotium rolfsii causing spotted leaf rot from Varanasi, India were grown on 6% Cyperus rotundus rhizome meal agar (CRMA) medium for the induction of athelial stage (Athelia rolfsii). Only one isolate obtained from Sphaeranthus indicus formed basidial stage on CRMA medium while the other 21 isolates did not. Basidial stage was also produced in S. indicus isolate at different concentrations (5.5, 6.0 and 6.5% w/v) of CRMA medium. Size of basidia, sterigmata and basidiospores of this isolate was measured. Basidia clavate, hyaline and measured 10~12 * 4~5 um in size, basidiospores hyaline, unicellular, subglobose to ellipsoid produced on sterigmata and measured 3~5 * 2~4um in size, sterigmata hyaline and measured 4~5 * 1.5~2 um in size. The results of the present study revealed wide variation in spotted leaf rot isolates of S. rolfsii. A reddish zone around the colony of S. rolfsii isolate from Vernonia sp. was observed on CRMA medium. HPLC analysis of the zone revealed the presence of gallic and ferulic acid which were also thought to be responsible for reduced mycelial growth of the isolate on CRMA medium. PMID- 24049467 TI - Cultural Characteristics for the Enhanced Mycelial Growth of Ramaria botrytis. AB - The culture conditions for the enhanced mycelial growth of Ramaria botrytis was investigated. The optimal temperature and pH for the mycelial growth were 24C and 5.0, respectively. It was shown that starch was best of several carbon sources in Czapek-Dox medium as a minimal medium for the enhanced mycelial growth. Organic nitrogen sources were better than inorganic ones for mycelial growth. The appropriate vitamin and mineral salt were biotin and FeCl3, respectively. When this strain was cultured with FeCl3 for 30 days, 19.23 g/l of dry mycelium of R. botrytis was obtained. PMID- 24049468 TI - The Characteristics of Cultural Conditions for the Mycelial Growth of Macrolepiota procera. AB - Macrolepiota procera, one of edible mushrooms belongs to Agaricaceae of Basidiomycota, has a good taste and good medicinal value. As a preliminary study for the development of artificial cultivation method of edible mushroom, cultural characteristics of M. procera was investigated on various culture media under different environmental conditions. Mycelial growth was compared on culture media composed of various carbon and nitrogen sources, and C/N ratios. The optimal conditions for the mycelial growth were 30C and pH 7. M. procera showed the rapid mycelial growth in the PDA media. The optimal carbon and nitrogen sources were maltose and glycine, respectively. The optimum C/N ratio was about 10 : 1 in case that 1% glucose was supplemented to the basal media as carbon source. PMID- 24049469 TI - Effect of 'Azotobacter' Bioinoculant on the Growth and Substrate Utilization Potential of Pleurotus eous Seed Spawn. AB - We investigated the effect of nitrogen fixing Azotobacter bioinoculant on the mycelial growth and the rate of substrate utilization by Pleurotus eous. The synergistic or antagonistic role of the microorganism during dual culturing with the mushroom or the competitor molds Trichoderma viride, and Trichoderma reesi was studied. Azotobacter was inhibitory to the molds, which are competitive to the mushroom in the seed spawn substrate, but was synergistic towards the mushroom. The growth, substrate utilization potential as total nitrogen content and cellulase enzyme activities of the mushroom in the seed spawn substrate were also enhanced in the presence of the bioinoculant at lower inoculum concentrations, upto 5 ml broth culture per spawn bottle. PMID- 24049470 TI - Effects of Some Amino Acids on Ammonia Secretion and Extracellular Protease Activity by Three Oomycetes in Synthetic Medium with or without Glucose. AB - The effects of different concentrations of three amino acids as carbon and or nitrogen sources on mycelial dry weights, changes in pH values of synthetic medium, ammonia secretion and extracellular protease activity by three zoosporic fungi, pathogens of fish and shellfish, were studied. As compared with the control, the addition of isoleucine and aspartic acid as nitrogen sources were generally stimulative for mycelial dry weight production whereas phenylalanine was inhibitory irrespective to the tested fungal species. When amino acids served as carbon and nitrogen sources, the mycelial dry weights of the three fungi were increased (mostly non-significantly) relative to untreated control but weights were decreased as the concentrations of the three amino acids raised. The addition of individual amino acids as carbon and nitrogen sources to the medium significantly increased pH values of the medium comparable to the control. The addition of each of the three amino acids as carbon and nitrogen sources to the medium significantly induced ammonia secretion by the three species of zoosporic fungi. Ammonia secretion in synthetic medium amended with amino acids as nitrogen source raised by the three zoosporic fungi relative to untreated control except in case of Achlya racemosa treated with isoleucine. Extracellular protease activity was almost promoted in case of Achlya proliferoides and Saprolegnia furcata cultures treated with isoleucine and aspartic acid individually in presence of glucose and vice versa in case of phenylalanine. However, extracellular protease activity of A. racemosa decreased compared with the control at various concentrations of isoleucine and both phenylalanine and aspartic acid assumed inconsistent effects. Extracellular protease activity of the three zoosporic fungi in the medium devoid of glucose varied depending upon zoosporic fungal species, the tested amino acid and the applied concentrations. The values of protease activity were approximately less two folds than that obtained in presence of glucose. PMID- 24049471 TI - Changes of Enzyme Activities and Compositions of Abnormal Fruiting Bodies Grown under Artificial Environmental Conditions in Pleurotus ostreatus. AB - This study investigated the biochemical changes of abnormal fruiting bodies grown under artificial environmental conditions in P. ostreatus. Abnormal mushroom growth during cultivation damages the production of good quality mushroom. This study showed that different environmental conditions produced morphological changes in the fruiting bodies of P. ostreatus. The fruiting bodies with morphological changes were collected and examined for differences in biochemical properties, enzyme activities, and carbohydrates composition. The enzyme activities assay showed that glucanase and chitinase activities decreased when the temperature was below or above the optimum cultivation temperature for P. ostreatus. The biochemical compositions of the abnormal mushroom were significantly different from the normal fruiting bodies. It was suggested that the changes in the biochemical composition of abnormal mushroom were caused by the unfavorable environmental conditions during mushroom cultivation. PMID- 24049472 TI - Effect of Iron Availability on Induction of Systemic Resistance to Fusarium Wilt of Chickpea by Pseudomonas spp. AB - Selected isolates of Pseudomonas fluorescens (Pf4-92 and PfRsC5) and P. aeruginosa (PaRsG18 and PaRsG27) were examined for growth promotion and induced systemic resistance against Fusarium wilt of chickpea. Significant increase in plant height was observed in Pseudomonas treated plants. However, plant growth was inhibited when isolates of Pseudomonas were used in combination with Fusarium oxysporum f. sp. ciceri (FocRs1). It was also observed that the Pseudomonas spp. was colonized in root of chickpea and significantly suppressed the disease in greenhouse condition. Rock wool bioassay technique was used to study the effect of iron availability on the induction of systemic resistance to Fusarium wilt of chickpea mediated by the Pseudomonas spp. All the isolates of Pseudomonas spp. showed greater disease control in the induced systemic resistance (ISR) bioassay when iron availability in the nutrient solution was low. High performance liquid chromatography (HPLC) analysis indicated that all the bacterial isolates produced more salicylic acid (SA) at low iron (10uM EDDHA) than high iron availability (10uFe(3+) EDDHA). Except PaRsG27, all the three isolates produced more pseudobactin at low iron than high iron availability. PMID- 24049473 TI - Role of arbuscular mycorrhizal fungi in phytoremediation of soil rhizosphere spiked with poly aromatic hydrocarbons. AB - Results from an innovative approach to improve remediation in the rhizosphere by encouraging healthy plant growth and thus enhancing microbial activity are reported. The effect of arbuscular mycorrhizal fungi (Am) on remediation efficacy of wheat, mungbean and eggplant grown in soil spiked with polyaromatic hydrocarbons (PAH) was assessed in a pot experiment. The results of this study showed that Am inoculation enhanced dissipation amount of PAHs in planted soil, plant uptake PAHs, dissipation amount of PAHs in planted versus unplanted spiked soil and loss of PAHs by the plant-promoted biodegradation. A number of parameters were monitored including plant shoot and root dry weight, plant tissue water content, plant chlorophyll, root lipid content, oxido-reductase enzyme activities in plant and soil rhizosphere and total microbial count in the rhizospheric soil. The observed physiological data indicate that plant growth and tolerance increased with Am, but reduced by PAH. This was reflected by levels of mycorrhizal root colonization which were higher for mungbean, moderate for wheat and low for eggplant. Levels of Am colonization increased on mungbean > wheat > eggplant. This is consistent with the efficacy of plant in dissipation of PAHs in spiked soil. Highly significant positive correlations were shown between of arbuscular formation in root segments (A)) and plant water content, root lipids, peroxidase, catalase polyphenol oxidase and total microbial count in soil rhizosphere as well as PAH dissipation in spiked soil. As consequence of the treatment with Am, the plants provide a greater sink for the contaminants since they are better able to survive and grow. PMID- 24049474 TI - Increased Salinity Tolerance of Cowpea Plants by Dual Inoculation of an Arbuscular Mycorrhizal Fungus Glomus clarum and a Nitrogen-fixer Azospirillum brasilense. AB - Pot greenhouse experiments were carried out to attempt to increase the salinity tolerance of one of the most popular legume of the world; cowpea; by using dual inoculation of an Am fungus Glomus clarum and a nitrogen-fixer Azospirillum brasilense. The effect of these beneficial microbes, as single- or dual inoculation-treatments, was assessed in sterilized loamy sand soil at five NaCl levels (0.0~7.2 ds/m) in irrigating water. The results of this study revealed that percentage of mycorrhizal infection, plant height, dry weight, nodule number, protein content, nitrogenase and phosphatase activities, as well as nutrient elements N, P, K, Ca, Mg were significantly decreased by increasing salinity level in non-mycorrhized plants in absence of NFB. Plants inoculated with NFB showed higher nodule numbers, protein content, nitrogen concentration and nitrogenase activities than those of non-inoculated at all salinity levels. Mycorrhized plants exhibited better improvement in all measurements than that of non-mycorrhized ones at all salinity levels, especially, in the presence of NFB. The concentration of Na(+) was significantly accumulated in cowpea plants by rising salinity except in shoots of mycorrhizal plants which had K(+)/Na(+) ratios higher than other treatments. This study indicated that dual inoculation with Am fungi and N-fixer Azospirillum can support both needs for N and P, excess of NaCl and will be useful in terms of soil recovery in saline area. PMID- 24049475 TI - Notes on three species of the laboulbeniales newly collected in Korea (2005). AB - Three species of the Laboubeniales from Korea are described. They are new to the mycological flora of Korea. Corethromyces purpurascens on several parts of Ochthephilum densipenne, Laboulbenia barbara on the metasternum of Philonthus longicornis and L. compressa on the elytra of Harpalus tinctulus were found. PMID- 24049476 TI - Culture Conditions Affecting the Optimal Mycelial Growth of Cystoderma amianthinum. AB - Cystoderma amianthinum, one of edible fungi belongs to Agaricaceae of Basidiomycota, has a good taste and flavor. This study was carried out to obtain the basic informations for the optimum mycelial growth of C. amianthinum. The optimal conditions for the mycelial growth were 25C and pH 5 in potato dextrose agar (PDA). C. amianthinum showed the favorable growth in the PDA and yeast malt extract agar (YMA). The favorable carbon and nitrogen sources promoting mycelial growth were fructose and histidine, respectively. The optimum C/N ratio was about 30 : 1 in case that 1% glucose was supplemented to the basal medium as a carbon source. PMID- 24049477 TI - Morphological Characteristics of Conidiogenesis in Cordyceps militaris. AB - Conidial development of Cordyceps militaris was observed from germinating ascospores and vegetative hyphae through light and scanning electron microscopy (SEM). Ascospores were discharged from fresh specimens of C. militaris in sterile water as well as Sabouraud Dextrose agar plus Yeast Extract (SDAY) plates. We observed ascospore germination and conidial formation periodically. Under submerged condition in sterile water, most part-spores germinated unidirectionally and conidia were developed directly from the tips of germinating hyphae of part-spores within 36 h after ascospore discharge, showing microcyclic conidiation. First-formed conidia were cylindrical or clavate followed by globose and ellipsoidal ones. Germination of ascospores and conidial development were observed on SDAY agar by SEM. Slimy heads of conidia on variously arranged phialides, from solitary to whorl, developed 5 days after ascospore discharge. Besides, two distinct types of conidia, elongated pyriform or cylindrical and globose, were observed in the same slimy heads by SEM. Conidia were shown to be uninucleate with 4,6-diamidino-2-phenylindole staining. Conidiogenous cells were more slender than vegetative hyphae, having attenuated tips. Microcyclic conidiation, undifferentiated conidiogenous hyphae (phialides), polymorphic conidia and solitary, opposite to whorled type of phialidic arrangement are reported here as the characteristic features of asexual stage of C. militaris, which can be distinguished from other Cordyceps species. PMID- 24049478 TI - Occurrence of Fungal Species and Mycotoxins from Decayed Sugarcane (Saccharrum officinarum) in Egypt. AB - Seventy-three fungal species belonging to forty-three genera were isolated from 40 samples of Saccharrum officinarum (collected from Naage-Hamadi canal in Qena Governorate, Egypt). Aspergillus, Trichoderma, Mucor and Pythium were the most common genera on the two isolation media. The dominant species of Aspergillus were A. niger, A. flavus, A. ustus, A. terreus and A. wentii. Some species were dominant on 40 g/l sucrose such as Aspergillus niger, A. flavus, Emericella nidulans, Trichoderma viride, Torula herbarum and Mamaria echinoeotryoides, while the dominant species on 10 g/l glucose were Mucor circinelloides, Aspergillus niger, Torula herbarum and Trichoderma viride. Mycotoxins including aflatoxins B1, B2, G1 and G2, zearalenone and diacetoxyscirpenol were detected in the examined samples of Saccharrum officinarum. The mycelial growth of A. flavus, A. niger, Fusarium moniliforme and Torula herbarum decreased with the increase in Dimethoate concentrations, although 25 ppm was less effective than the higher levels of the insecticide (75~200 ppm). Dimethoate stimulated the activity of Go T in A. niger, F. moniliforme and T. harbarum, while the Go-T activity was inhibited in A. flavus with the Dimethoate treatments. PMID- 24049479 TI - Production of Xylanolytic Enzyme Complex from Aspergillus flavus using Agricultural Wastes. AB - Five types of agricultural wastes were used for the production of xylanolytic enzyme by Aspergillus flavus K-03. All wastes materials supported high levels of xylanase and beta-xylosidase production. A high level of proteolytic activity was observed in barley and rice bran cultures, while only a weak proteolytic activity was detected in corn cob, barley and rice straw cultures. Maximum production of xylanase was achieved in basal liquid medium containing rice barn as carbon source for 5 days of culture at pH 6.5 and 25C. The xylanolytic enzyme of A. flavus K-03 showed low thermostability. The times required for 50% reduction of the initial enzyme activity were 90 min at 40C, 13 min at 50C, and 3 min at 60C. Xylanolytic activity showed the highest level at pH 5.5~10.5 and more than 70% of the original activity was retained at pH 6.5 and 7.0. The higher stability of xylanolytic enzymes in the broad range of alkaline pH is useful for utilization of the enzymes in industrial process requiring in alkaline conditions. Moreover, the highest production of xylanolytic enzyme was obtained when 0.5% of rice bran was supplied in basal liquid medium. SDS-PAGE analysis revealed a single xylanase band of approximately 28.5 kDa from the culture filtrates. PMID- 24049480 TI - Bioconversion of straw into improved fodder: mycoprotein production and cellulolytic acivity of rice straw decomposing fungi. AB - Sixty two out of the sixty four species of fungal isolates tested could produce both exo-beta1,4-gluconase (C1) and endo-beta1,4-gluconase (Cx) on pure cellulose and rice straw as carbon source in Czapek's medium. Fifty-eight and fifteen species were able to grow at 25C and at 45C, respectively. Eleven species could grow at both 25C and 45C while, four species appeared only at 45C. The most cellulolytic species at 25C was Trichoderma koningii producing 1.164 C1 (mg glucose/1 ml culture filtrate/1 hr) and 2.690 Cx on pure cellulose, and 0.889 C1 and 1.810 Cx on rice straw, respectively. At 45C, the most active thermotolerant species were Aspergillus terreus, followed by A. fumigatus. Talaromyces thermophilus was the highest active thermophilic species followed by Malbranchea sulfurea. Most of these species were also active in fermentation of rice straw at 25 and 45C (P<0.05). The most active ones were T. koningii, A. ochraceus and A. terreus, which produced 201.5, 193.1 and 188.1 mg crude protein/g dry straw, respectively. PMID- 24049481 TI - Antifungal Activity of Nor-securinine Against Some Phytopathogenic Fungi. AB - Crude extracts and active principles from medicinal plants have shown potential role in controlling plant diseases in glasshouses as well as in fields as one of the safest and ecofriendly methods. The effect of nor-securinine (an alkaloid) isolated from Phyllanthus amarus has been seen against spore germination of some fungi (Alternaria brassicae, A. solani, Curvularia pennisetti, Curvularia sp., Erysiphe pisi, Helminthosporium frumentacei) as well as pea powdery mildew (Erysiphe pisi) under glasshouse conditions. The sensitivity of fungi to nor securinine varied considerably. Nor-securinine was effective against most of the fungi. H. frumentacei was more sensitive even at the lowest concentration (1,000 ug/ml). Likewise conidia of E. pisi were also inhibited in partially or completely appressorium formation. Pre-inoculation treatment showed greater efficacy than post-inoculation in inhibiting powdery mildew development on pea plants in a glasshouse. Maximum inhibition occurred at 2000 ug/ml. PMID- 24049482 TI - Development of Species-specific Primers for Rapid Detection of Phellinus linteus and P. baumii. AB - Genus Phellinus taxonomically belongs to Aphyllophorales and some species of this genus have been used as a medicinal ingredients and Indian folk medicines. Especially, P. linteus and morphological-related species are well-known medicinal fungi that have various biological activities such as humoral and cell-mediated, anti-mutagenic, and anti-cancer activities. However, little is known about the rapid detection for complex Phellinus species. Therefore, this study was carried out to develop specific primers for the rapid detection of P. linteus and other related species. Designing the species-specific primers was done based on internal transcribed spacer sequence data. Each primer set detected specifically P. linteus (PL2/PL5R) and P. baumii (PB1/PB4R). These primer sets could be useful for the rapid detection of specific-species among unidentified Phellinus species. Moreover, restriction fragment length polymorphism analysis of the ITS region with HaeIII was also useful for clarifying the relationship between each 5 Phellinus species. PMID- 24049483 TI - Sequence analysis of the internal transcribed spacer of ribosomal DNA in the genus rhizopus. AB - The internal transcribed spacer (ITS) regions including the 3'-end of 18S rRNA gene, 5.8S rRNA gene and the 5'-end of the 28S rRNA gene of Rhizopus spp. were amplified by PCR and analyzed by DNASIS program. Length polymorphism of these region ranged from 564 bp in R. oryzae to 789bp in R. stolonifer. The length and sequence of 5.8S was very conserved with 154~155 bp. The sequence of ITS2 was more variable than that of ITS1. The base substitution rates were ranged from 0 to 0.6069 per site, and higher rate was found in R. stolonifer. In general, transition was usually more frequent than transversion. On the basis of sequencing results, four groups were clustered with value of 61.9% similarity; R. oryzae, R. microspores, R. homothallicus, and R. stolonifer groups. PMID- 24049484 TI - First Report of Penicillium brasilianum and P. daleae Isolated from Soil in Korea. AB - In this study, a total of 300 isolates of Penicillium and related teleomorphic genera were collected from soils of 17 locations in Korea from April to May, 2004. Ninety four isolates were identified as the species of Penicillium subgenus Furcatum based on cultural and morphological characteristics and beta-tubulin gene sequences. Among the species, Korean isolates of P. brasilianum Bat. and P. daleae K. M. Zalessky were phylogenetically identical to the reference species based on DNA sequence of the beta-tubulin gene. Here we described and illustrated P. brasilianum and P. daleae that are new in Korea. PMID- 24049485 TI - Morphological Variations in Conidia of Arthrobotrys oligospora on Different Media. AB - Most commonly occurring predacious fungus Arthrobotrys oligospora showed great variation in size and shape of conidia on some media. The formation of larger conidia was recorded on beef extract and nutrient agar media. The length of conidia in Richard's YPSS, Sabouraud's, PDA and corn meal agar media was of medium size while smaller conidia were produced on Czapek's, Jensen's, Martin's medium. Maximum width of conidia was recorded on YPSS medium followed by Sabouraud's medium. The average size of spores on nematode infested corn meal agar medium was slightly increased than those on corn meal agar medium. PMID- 24049486 TI - Immobilization of Keratinase from Aspergillus flavus K-03 for Degradation of Feather Keratin. AB - Extracellular keratinase isolated from Aspergillus flavus K-03 was immobilized on calcium alginate. The properties and reaction activities of free and immobilized keratinase with calcium alginate were characterized. The immobilized keratinase showed proteolytic activity against soluble azo-casein and azo-keratin, and insoluble feather keratin. Heat stability and pH tolerance of keratinase were greatly enhanced by immobilization. It also displayed a higher level of heat stability and an increased tolerance toward alkaline pHs compared with free keratinase. During the durability test at 40C, 48% of the original enzyme activity of the immobilized keratinase was remained after 7 days of incubation. The immobilized keratinase exhibited better stability, thus increasing its potential for use in industrial application. PMID- 24049487 TI - Genetic Analysis of Pigmentation in Cordyceps militaris. AB - Pigmentation of ascospore-derived isolates from seven different natural specimens of Cordyceps militaris EFCC C-5888, EFCC C-7159, EFCC C-7833, EFCC C-7991, EFCC C 8021, EFCC C-8023 and EFCC C-8179 was observed on the plates of Sabouraud Dextrose agar plus Yeast Extract at 25C under continuous illumination (500 lux). Pigmentation of the wild-type isolates of C. militaris was diverse ranging from yellowish white to orange, while white color was believed as a mutant. Inheritance of pigmentation was found to be controlled by both parental isolates when F1 progeny were analyzed. Pigmentation and mating type were shown to be either independent or distantly linked each other due to the high percentage of non-parental phenotypes among F1 progeny. Crosses between white mutant isolates of C. militaris yielded progeny with wild type pigmentations, indicating that the albino mutations in the parents were unlinked to each other. PMID- 24049488 TI - Observations of Infection Structures after Inoculation with Colletotrichum orbiculare on the Leaves of Cucumber Plants Pre-inoculated with Two Bacterial Strains Pseudomonas putida or Micrococcus luteus. AB - Infection structures were observed at the penetration sites on the leaves of cucumber plants inoculated with Colletotrichum orbiculare using a fluorescence microscope. The cucumber plants were previously drenched with suspension of bacterial strains Pseudomonas putida or Micrococcus luteus. The plants pre inoculated with both bacterial strains were resistant against anthracnose after inoculation with C. orbiculare. To investigate the resistance mechanism by both bacterial strains, the surface of infected leaves was observed at the different time after challenge inoculation. At 3 days after inoculation there were no differences in the germination and appressorium formation of conidia of C. orbiculare as well as in the callose formation of the plants between both bacteria pre-inoculated and non-treated. At 5 days, the germination and appressorium formation of the fungal conidia were, however, significantly decreased on the leaves of plants pre-inoculated with M. luteus at the concentration with 1.0 * 10(7) cfu/ml. Furthermore, callose formation of plants cells at the penetration sites was apparently increased. In contrast, there were no defense reactions of the plants at the concentration with 1.0 * 10(6) cfu/ml of M. luteus. Similarly, inoculation P. putida caused no plant resistance at the low concentration, whereas increase of callose formation was observed at the higher concentration. The results of this study suggest that the resistant mechanisms might be differently expressed by the concentration of pre-treatment with bacterial suspension. PMID- 24049489 TI - Phenolic Acid Changes in Mycelia of Sclerotium rolfsii After Garlic and Onion Supplementation in a Broth Medium. AB - High performance liquid chromatographic (HPLC) analysis of mycelia of Sclerotium rolfsii grown in broth medium supplemented with garlic (Allium sativum) and onion (Allium cepa) was carried out to estimate qualitative and quantitative changes in phenolic acids. Several phenolic acids, such as gallic, chlorogenic, ferulic, o coumaric and cinnamic acids were detected in varied amounts in mycelia grown on such media as compared to control. Phenolic acids represents a wide range of secondary metabolite found in the cells of plants and microbes including fungi. The growth characters of S. rolfsii in various supplements also varied from thin and transparent to thick and opaque. PMID- 24049490 TI - Production of Antihypertensive Angiotensin I-Converting Enzyme Inhibitor from Malassezia pachydermatis G-14. AB - To produce a novel antihypertensive angiotensin I-converting enzyme (ACE) inhibitor from yeast, a yeast isolate, designated G-14 showing the highest ACE inhibitory activity was obtained and identified as Malassezia pachydermatis based on morphological, biochemical and cultural characteristics. The maximal extracellular ACE inhibitor production was obtained from M. pachydermatis G-14 when the strain was cultured in YEPD medium containing 0.5% yeast extract, 3.0% peptone and 2.0% glucose at 30C for 24 h and the final ACE inhibitory activity was 48.9% under the above condition. PMID- 24049491 TI - Production of Soluble Crude Protein Using Cellulolytic Fungi on Rice Stubble as Substrate under Waste Program Management. AB - The investigation was undertaken to enhance the decomposition process by pre treatment of rice stubble, having higher concentration of lignin. Air-dried rice stubble was treated with 1.8 liter of 1% NaOH and autoclaved. Six cellulolytic fungi, Trichoderma harzianum, Penicillium citrinum, Curvularia lunata, Aspergillus flavus and Alternaria alternata were grown in basal synthetic medium along with delignified rice-residue as carbon source for production of soluble crude protein. Though the loss of cellulose has been observed by all of them but having a considerable status in the presence of T. harzianum and T. harzianum yielded highest percentage of crude protein (27.99%) with biomass of 375 mg, whereas the lowest protein value (17.91%) was recorded in case of A. niger with biomass of 422 mg. Among the imperfect fungi, T. harzianum was the most potent. Effects of incubation period and nitrogen sources on soluble crude protein production by T. harzianum were also undertaken in this study. Fifth day of incubation period and potassium nitrate as nitrogen source among other nitrogen sources was found most appropriate for soluble crude protein production by the mentioned organism. PMID- 24049492 TI - Bioconversion of straw into improved fodder: fungal flora decomposing rice straw. AB - The fungal flora decomposing rice straw were investigated all over the soil of Sharkia Province, east of Nile Delta, Egypt, using the nylon net bag technique. Sixty-four straw-decomposing species belonging to 30 genera were isolated by the dilution plate method in ground rice straw-Czapek's agar medium at pH 6. The plates were incubated separately at 5C, 25C and 45C, respectively. Twenty nine species belonging to 14 genera were isolated at 5C. The most frequent genus was Penicillium (seven species), and the next frequent genera were Acremonium (three species), Fusarium (three species), Alternaria, Chaetomium, Cladosporium, Mucor, Stachybotrys (two species) and Rhizopus stolonifer. At 25C, 47 species belonging to 24 genera were isolated. The most frequent genus was Aspergillus (nine species), and the next frequent genera were ranked by Penicillium (five species), Chaetomium (three species), Fusarium (three species). Each of Alternaria, Cladosporium, Mucor, Myrothecium and Trichoderma was represented by two species. At 45C, 15 species belonging to seven genera were isolated. These were seven species of Aspergillus, two species of Chaetomium and two species of Emericella, while Humicola, Malbranchea, Rhizomucor and Talaromyces were represented by one species respectively. The total counts of fungi the genera, and species per gram of dry straw were significantly affected by incubation temperature and soil analysis (P < 0.05). PMID- 24049493 TI - Immunomodulatory Activity of the Water Extract from Medicinal Mushroom Inonotus obliquus. AB - The immunomodulatory effect of aqueous extract of Inonotus obliquus, called as Chaga, was tested on bone marrow cells from chemically immunosuppressed mice. The Chaga water extract was daily administered for 24 days to mice that had been treated with cyclophosphamide (400 mg/kg body weight), immunosuppressive alkylating agent. The number of colony-forming unit (CFU) granulocytes/macrophages (GM) and erythroid burst-forming unit (BFU-E), increased almost to the levels seen in non-treated control as early as 8 days after treatment. Oral administration of the extract highly increased serum levels of IL 6. Also, the level of TNF-alpha was elevated by the chemical treatment in control mice, whereas was maintained at the background level in the extract-treated mice, indicating that the extract might effectively suppress TNF-alpha related pathologic conditions. These results strongly suggest the great potential of the aqueous extract from Inonotus obliquus as immune enhancer during chemotherapy. PMID- 24049494 TI - Soft Rot of Eggplant (Solanum melongena) Caused by Choanephora cucurbitarum in Korea. AB - In April 2002 and 2003, soft rot on fruit of eggplant (Solanum melongena) caused by Choanephora cucurbitarum was observed in the experimental fields at Gyeongnam Agricultural Research and Extension Services in Korea. The disease began with water-soaking and dark-green lesions, and then the infected tissues were rapidly rotten. Sporangium was subglobose in shape and sized 40~130 um. Monosporous sporangiola were elliptic, fusiform or ovoid, brown in color, and measured as 12~20 * 6~14 um. Sporangiospores having three or more appendages were elliptic, fusiform or ovoid in shape, dark brown or brown in color, and sized 14~20 * 7~16 um. The fungus grew well on potato dextrose agar between 15 and 40C and its optimum growth temperature was 30C. Based on morphological characteristics, the causal fungus of the fruit soft rot of eggplant was identified as C. cucurbitarum. This is the first report on the soft rot of S. melongena caused by C. cucurbitarum in Korea. PMID- 24049495 TI - Wood-rotting Fungal Flora of Kanghwa Island. AB - Through ten field surveys in Kanghwa Island from August of 1997 to March of 2002, total 107 specimens of wood-rotting fungi belonging to the Aphyllophorales were collected and identified to the species. They taxonomically amounted to 10 families, 31 genera, and 48 species. Among them, one family, Steccherinaceae, and four genera, Australohydnum, Castanoporus, Dacryobolus and Haplotrichum were confirmed as new to Korea. Five unrecorded species, Australohydnum dregeanum, Castanoporus castaneus, Dacryobolus karstenii, Haplotrichum conspersum and Hyphoderma odontiiforme were registered here with descriptions. PMID- 24049496 TI - Two species of bryoria (lichenized ascomycota, parmeliaceae) from the sino himalayas. AB - We performed a taxonomic study on two species of the genus Bryoria from the Sino Himalayas, SW-China. B. nadvornikiana is new to China and B. furcellata is new to Yunnan and Sichuan provinces in the Sino-Himalayas. Morphology, habitat, distributions and chemistry of the two species are discussed. PMID- 24049497 TI - Distribution and in vitro Fruiting of Cordyceps militaris in Korea. AB - Cordyceps militaris specimens were continuously collected by Entomopathogenic Fungal Culture Collection (EFCC), Kangwon National University from different mountains, national parks and recreation parks of Korea from 1986 to 2002, mainly from late May to October of each year. Dry specimens of C. militaris along with their isolates have been preserved in EFCC. Fruiting of C. militaris was induced from single ascospore isolates as well as their combinations in brown rice medium. Fruiting experiments showed that combinations of single ascospore isolates produced fertile fruiting bodies, but single isolates could not produce any fruiting bodies. It was shown that two isolates of the opposite mating types were required to produce fertile stromata. However, combinations of the same mating type isolates produced no fruiting body, showing that C. militaris is a bipolar, heterothallic fungus. PMID- 24049498 TI - Taxonomic study on some unrecorded species of korean hydropus. AB - Specimens belonging to the genera Mycena and Collybia which have been preserved in the herbarium of National Institute of Agricultural Sciences and Technology, Suwon, Korea were investigated. Among them, four species were confirmed to be Hydropus species viz Hydropus marginellus, H. nitrata, H. erinensis, and H. floccipes. Authors registered them to the Korean mycoflora with full descriptions, illustrations and Korean names. PMID- 24049500 TI - Effect of Fertilizers and Neem Cake Amendment in Soil on Spore Germination of Arthrobotrys dactyloides. AB - Application of fertilizers such as urea, diammonium phosphate (DAP) and muriate of potash in soil adversely affected the spore germination of Arthrobotrys dactyloides. Amendment of soil with urea at the concentrations of 1.0%, 0.5% and 0.1% completely inhibited spore germination and direct trap formation on the conidium, whereas muriate of potash delayed and reduced the spore germination even at the lowest concentration. DAP also inhibited spore germination at 1.0% concentration, while at lower concentration the percentage of spore germination was reduced. Application of neem cake at the concentration of 0.5% also inhibited spore germination after 24 h of amendment. The inhibitory effect of neem cake was reduced after 15 days of amendment, while after 30 days after amendment the inhibitory effect was completely lost and the spore germinated by direct trap as in unamended soil. Nematodes were not attracted to ungerminated spores after 24 h of amendment. After 15 days of amendment nematodes were attracted to agar blocks containing fewer germinated spores after 24 h of incubation but after 48 h of incubation large number of nematodes were attracted and trapped by the germinated spores with direct traps. After 30 days of amendment, larger number of nematodes were attracted and trapped by direct traps. PMID- 24049499 TI - Isolation and Characterization of Cryptococcus neoformans from Environmental Sources in Busan. AB - Twenty nine samples of pigeon droppings (n = 12) and soil contaminated with avian excreta (n = 19), collected from different sites in Busan, were examined for isolation and characterization of Cryptococcus neoformans. Of these samples, 5 strains of C. neoformans were recovered from pigeon droppings (5/12 : 41.7%). All isolates were belonged to C. neoformans var. grubii (serotype A). The extracellular enzyme activities of the strains by using the API-ZYM system showed two different enzymatic patterns. The genetic variability among C. neoformans isolates was analyzed by random amplified polymorphic DNA (RAPD) using three 10 mer primers. Two different RAPD patterns, which clearly distinguished the isolates, were identified. Analysis of RAPD patterns provided a good characterization of environmental strains of C. neoformans serotype A as a heterogeneous group and were in good agreement with enzymatic profiles. PMID- 24049501 TI - Effect of Fungicides and Plant Extracts on the Conidial Germination of Colletotrichum gloeosporioides Causing Mango Anthracnose. AB - In Northern Bangladesh, generally mango trees are planted as agroforest that gives higher Net Present Value (NPV) than traditional agriculture. Mango anthracnose caused by Colletotrichum gloeosporioides Penz. is seen as a very destructive and widely distributed disease, which results in poor market value. Five fungicides such as Cupravit, Bavistin, Dithane M-45, Thiovit and Redomil were tested against conidial germination of C. gloeosporioides. Dithane M-45 and Redomil were the most effective when the conidia were immersed for 10~20 minutes at 500~1000 ppm concentrations. Antifungal activities of 13 plant extracts were tested against conidial germination of C. gloeosporioides. Conidial germination of C. gloeosporioides was completely inhibited in Curcuma longa (leaf and rhizome), Tagetes erecta (leaf) and Zingiber officinales (rhizome) after 15 minutes of incubation respectively. PMID- 24049502 TI - Antifungal Activity of Narceine Methyl Ester and Narceine Isolated from Corydalis longipes Against Some Phytopathogenic Fungi. AB - Narceine methyl ester and narceine are potent alkaloids which were isolated from Corydalis longipes were found effective in vitro at very low concentration, i.e., 100~500 ppm against spore germination of some test plant pathogenic fungi (Alternaria solani, A. tagetica, Cercospora abelmoschi, Curvularia maculans, Erysiphe cichoracearum, E. pisi, Fusarium udum, Helminthosporium oryzae, H. penniseti, Ustilago cynodontis). Among the test, phytopathogens the spores of F. udum, C. maculans and H. penniseti were highly sensitive at 200 ppm. However, spores of E. pisi, A. solani and A. tagetica were less sensitive at low concentration followed by other test fungi. Most of the fungi showed zero or nearly zero percent spore germination at 400 and 500 ppm. PMID- 24049503 TI - Antifungal Activity of Lactic Acid Bacteria Isolated from Kimchi Against Aspergillus fumigatus. AB - More than 120 isolates of lactic acid bacteria obtained from Kimchi was screened for antifungal activity against Aspergillus fumigatus. Approximately 10% of the isolates showed inhibitory activity and only 4.16% (five isolates) exhibited strong activity against the indicator fungus A. fumigatus. The five isolates showed a wide rang of antifungal activity against A. flavus, Fusarium moniliforme, Penicillium commune, and Rhizopus oryzae. They were identified by 16S rDNA sequencing as Lactobacillus cruvatus, L. lactis subsp. lactis, L. casei, L. pentosus, and L. sakei. The effect of Lactobacillus on mycelial growth and fungal biomass as well as its ability to produce toxic compounds were determined. The results indicate that the three species, Lactobacillus casei, L. lactis subsp. lactis, and L. pentosus, are active against A. fumigatus. PMID- 24049504 TI - Screening of Different Media and Substrates for Cultural Variability and Mass Culture of Arthrobotrys dactyloides Drechsler. AB - Variability in growth and sporulation of five isolates of Arthrobotrys dactyloides was studied on five agar, 6 bran and 5 grain media. Potato dextrose agar (PDA) supported maximum growth of isolate A, C and E, while growth of isolate B and D was significantly lower on this medium. On Czapek's agar and yeast glucose agar media the differentiation in the isolates in relation to growth was poor than PDA. The other two media showed much poorer differentiation. On Czapek's agar medium, sporulation was recorded in isolate B only, whereas other isolates showed rare sporulation. Among the bran media, pea bran agar medium supported maximum growth of all the isolates except isolate B. Gram and rice bran agar media were next best. However, the growth of isolate B on the gram bran agar medium was more or less equal as other isolates. On pigeon pea bran agar medium, isolate E failed to grow while other isolates recorded poor growth. On lentil bran agar medium, only isolate B and D recorded little growth, whereas other isolates failed to grow. All the isolates recorded good sporulation on bran agar media except pigeon pea and lentil bran agar media. The grain agar media supported moderate to very good growth of all the isolates. In general isolate B remained slow growing on these media except gram grain and sorghum grain agar media on which growth of this isolate was comparable to other isolates. Sporulation in general, was good on all the grain agar media. Among different substrates screened, barley grain and pea bran were found superior to others for mass culture of isolate A of A. dactyloides. PMID- 24049505 TI - Culture Conditions and Characterizations of a New Phytase-Producing Fungal Isolate, Aspergillus sp. L117. AB - A novel fungal strain Aspergillus sp. L117 that produced acid-stable and thermostable phytase was isolated on basis of the clearing zone on PSM plate and the ability of Na-phytate hydrolysis. The phytase of isolate showed a 3-fold higher activity than that of A. ficuun NRRL3135. The Aspergillus sp. L117 produced maximal level of phytase at initial pH of 5.0 and 30C. The optimal pH and temperature for phytase activity were 5.5 and 50C, respectively. The phytase showed totally stable activity after 20 min of exposure between 30 and 90C, and even at 100C. The highest level of residual phytase activity was obtained at pH 5.5, and still retained the stability at the broadest pH ranges (2.0 to 7.0) of all the aforementioned phytases. Storage stability of phytase was preserved over 96% of initial activities for 60 days at 4, -20, and -70C and to retain even 70% of the initial activity at room temperature. PMID- 24049506 TI - The Optimal Culture Conditions for the Mycelial Growth of Oudemansiella radicata. AB - Oudemansiella radicata, one of edible mushrooms belonging to Tricholomataceae of Basidiomycota, has been known to exhibit outstanding therapeutic effects on the hypertension caused by high blood pressure and inhibitory effects on the sarcoma 180 and Erhrlich carcinoma of mice. As one of preliminary experiments for producing fruiting-body of O. radicata, this study was carried out to obtain the basic information for culture conditions of mycelial growth of the fungus. The optimal temperature and pH for the mycelial growth were 25C and pH 6, respectively. The medium for favorable mycelial growth of O. radicata was shown in the Lilly medium, whereas compact mycelial density was found in Hamada medium. The carbon and nitrogen sources promoting for mycelial growth of O. radicata were xylose and alanine, respectively. The optimum C/N ratio was about 20 : 1 in case that 3% glucose was supplimented to the basal medium as a carbon source. PMID- 24049507 TI - Notes on Cordyceps species Collected from the Central Region of Nepal. AB - The present study was carried out to explore the Cordyceps species and other entomopathogenic fungal flora around Kathmandu Valley and a few high altitude locations of Nepal. In this paper, we report eight Cordyceps species as new to Nepal: C. gracilis, C. ishikariensis, C. liangshanensis, C. martialis, C. militaris, C. pruinosa, C. sphecocephala and C. tricentri. We also mention a few allied genera such as Beauveria, Hirsutella and Paecilomyces from Nepal. Further collections from different ecological regions of Nepal will show the richness of entomopathogenic fungal floral diversity of Nepal. PMID- 24049508 TI - Soft Rot of Tomato Caused by Mucor racemosus in Korea. AB - A soft rot of fruits caused by Mucor racemosus occurred on cherry tomato collected in Agricultural Products Wholesale Market in Jinju, Korea. The disease infection usually occurred wounded areas after cracking of fruits. At first, the lesions started with water soaked and rapidly softened and diseased lesion gradually expanded. Colonies were white to brownish to gray in color. Sporangia were 32~54 um in size and globose in shape. Sporangiophores were 8~14 um in width. Sporangiospores were 5~12 * 4~8 um in size, ellipsoidal to subglobose in shape. Columella was 27~42 um in size, obovoid, ellipsoidal, cylindrical ellipsoidal, slightly pyriform in shape. Chlamydospores were numerous in sporangiophores and barrelshaped when young, subglobose in old cultures. Optimum growth temperature was about 25C. The fungus was identified as M. racemosus Fres. This is the first report of soft rot on cherry tomato caused by M. racemosus in Korea. PMID- 24049509 TI - Identification of three fungi newly intercepted from importing plants in Korea. AB - Three fungi newly intercepted from importing plants were identified in 2004. They were Ascochyta chrysanthemi on Lactuca sativa from China, A. spinaciicola on Spinacia oleracea from Denmark, and Leptosphaerulina australis on Brassica oleracea var. capitata from China. The characters of these fungi were described and illustrated. PMID- 24049510 TI - Laws and policies to support the wellbeing of children: an international comparative analysis. AB - The international community has raised concerns regarding the extent to which countries have implemented laws and policies to support the rights and wellbeing of children. This study evaluates the progress of least-developed countries (LDCs) and middle-income countries (MICs) in developing such legislation. Surveys were sent to 131 UNICEF country offices. Items included efforts to promote family preservation and family ties, family-based care over institutionalization, and child participation in placement decisions. A total of 68 surveys were returned, reflecting a 52 percent response rate (LDC, n = 25; MIC, n = 43). Legislation that addressed abuse and neglect of children, maternity leave, removal of children from the family, family care, adoption, and guardianship was widespread. Chi-square tests indicated that MICs had a substantially higher number of laws and policies related to child allowances, school feeding programs, maternity leave, and day care. PMID- 24049511 TI - Role of Spirituality in Coping with Breast Cancer: A Qualitative Study of Samoan Breast Cancer Survivors and their Supporters. AB - The use of spirituality for guidance and coping affects the quality of life in many cancer survivors and their supporters. Previous research has focused on coping strategies among cancer and terminally ill survivors, primarily among White and African American women. However, the length and extent to which these strategies have been researched in a cultural and communal context, such as Pacific Islanders, is not documented. The purpose of this qualitative study was to explore spiritual coping among a cross-sectional sample of 20 Samoan women diagnosed with breast cancer and 40 of their supporters (family and/or friends) in Southern California. In-depth interviews were conducted retrospectively with survivors and their supporters by trained bilingual/bicultural interviewers. The interviews were recorded, transcribed (and translated where applicable), and analyzed using the grounded theory approach to identify major themes for each group. Results illustrated that spirituality provided considerable emotional and logistical assistance to both survivors and their supporters, with particularly churches playing a potentially important role in the development of social support programs for both groups. This study supports the use of faith-based communities as forums to increase health education and understanding the further use of spiritual coping for cancer survivors, family, and friends. PMID- 24049512 TI - Medical Expenditure Measures in the Health and Retirement Study. AB - This paper reviews out-of-pocket (OOP) medical expenditure measures collected in the Health and Retirement Study (HRS). Medical expenditures are an important cost of poor health. Medical expenditure measures are important for understanding retirement decisions, financial preparation for retirement, and predicting the consequences of health care reform, particularly Medicare reform. Despite the comprehensiveness of the HRS, there are always limitations to what can be learned from population interviews. To assess the quality of current HRS measures of OOP spending, we compare various measures of OOP spending across survey waves to the Medical Expenditure Panel Survey (MEPS) and Medicare Current Beneficiary Survey (MCBS), two surveys that expend considerable resources on measuring both OOP spending and total medical expenditures. Such comparisons make it possible to identify potential bias in the HRS data and to improve HRS measures of OOP. We find that the HRS produces good quality and useful data on OOP spending. PMID- 24049513 TI - Management of Dementia and Depression Utilizing In- Home Passive Sensor Data. AB - PURPOSE: This study investigates whether motion density maps based on passive infrared (PIR) motion sensors and the average time out and average density per hour measures of the density map are sensitive enough to detect changes in mental health over time. METHOD: Within the sensor network, data are logged from PIR motion sensors which capture motion events as people move around the home. If there is continuous motion, the sensor will generate events at 7 second intervals. If the resident is less active, events will be generated less frequently. A web application displays the data as activity density maps showing events per hour with hours on the vertical axis and progressive days on the horizontal axis. Color and intensity provide textural indications of time spent away from home and activity level. Texture features from the co-occurrence matrix are used to capture the periodicity pattern of the activity (including homogeneity, local variation, and entropy) and are combined with the average motion density per hour and the average time away from home. The similarity of two different density maps is represented by a number that is computed in feature space as the distance from one map to the other, or a measure of dis-similarity. Employing a retrospective approach, density maps were compared with health assessment information (Geriatric Depression Scale, Mini Mental State Exam, and Short Form Health Survey -12) to determine congruence between activity pattern changes and the health information20. A case by case study method, analyzed the density maps of 5 individuals with identified mental health issues. These density maps were reviewed along with the averages of time out of apartment per day per hour and average density per hour for hours at home and mental health assessment scores to determine if there were activity changes and if activity patterns reflected changes in mental health conditions. RESULTS & DISCUSSION: The motion density maps show visual changes in the client's activity, including circadian rhythm, time away from home, and general activity level (sedentary vs. puttering). The measures are sensitive enough, yielding averages of time out of apartment and average density per hour for hours at home that indicate significant change. There is evidence of congruence with health assessment scores. This pilot study demonstrates that density maps can be used as a tool for early illness detection. The results indicate that sensor technology has the potential to augment traditional health care assessments and care coordination. PMID- 24049514 TI - Statin treatment in the elderly: how much do we know? PMID- 24049515 TI - Function and expression of prolyl hydroxylase 3 in cancers. AB - Hypoxia inducible factor (HIF) is a product of tumor cells that plays an important role in protecting tumor cells and adjusting to low oxygen tension through driving the progression and aggressiveness of tumors and changing the growth, angiogenesis, differentiation and metastasis of tumors. Prolyl hydroxylase 3 (PHD3) is a member of PHDs that are induced in hypoxia. Many studies have shown that PHD3 not only can hydroxylate HIF-1alpha, but also has various other biological functions. Thus PHD3 plays significant roles in suppressing the growth, angiogenesis, differentiation and metastasis of tumors and promoting apoptosis of tumors under hypoxic conditions. It may become a new tumor suppressor gene and also may become a new approach to investigate tumors. PMID- 24049516 TI - Contemporary role of medical genetics in internal medicine. AB - Molecular biology and medical genetics, one of the most dynamically developing fields of medicine, nowadays is also a base for development of basic and clinical research in internal medicine. Understanding of crucial genetic pathomechanisms of many common diseases was possible due to the newest and modern molecular methods and tools. Moreover, development of genetics also made possible the discovery and understanding of the pathogenesis of many different diseases. However, not so long ago, we discovered precise pathomechanisms leading from damage of a single gene to a related pathological phenotype. Now, we have just started to explain molecular mechanisms of complex, multifactorial diseases. To achieve these goals, we need permanent development of genetic tests, genomics and proteomics. After fulfilling these conditions, we will get a chance to implement all molecular and genetic hopes, particularly their practical application in the clinic. PMID- 24049517 TI - Diagnostic accuracy of adenosine deaminase for tuberculous peritonitis: a meta analysis. AB - INTRODUCTION: Tuberculous peritonitis remains a diagnostic challenge for clinicians. Many studies have investigated the usefulness of adenosine deaminase (ADA) in ascites for the diagnosis of tuberculous peritonitis; however, the overall diagnostic accuracy of ADA for tuberculous peritonitis remains unclear. The aim of the present meta-analysis was to determine the overall accuracy of ADA measurements in the diagnosis of tuberculous peritonitis. MATERIAL AND METHODS: We performed a systematic search in PubMed and Embase to identify published studies that evaluated the diagnostic role of ADA for tuberculous peritonitis. Quality was assessed according to standardized Quality Assessment of Diagnostic Accuracy Studies criteria. Sensitivity, specificity and other measures of accuracy of ADA assay in order to diagnose tuberculous peritonitis were pooled using random effects models. Summary receiver operating characteristic curve (SROC) was used to summarize overall test performance. RESULTS: Sixteen studies met inclusion criteria for the present meta-analysis. The pooled sensitivity and specificity for diagnosing tuberculous peritonitis were 0.93 (95% CI: 0.89-0.95) and 0.96 (95% CI: 0.94-0.97), respectively. The positive likelihood ratio was 15.80 (95% CI: 10.87-22.95), negative likelihood ratio was 0.09 (95% CI: 0.05 0.16) and diagnostic odds ratio was 249.28 (95% CI: 113.11-549.39). The area under the SROC was 0.98. CONCLUSIONS: Ascitic ADA determination is a relatively sensitive and specific test for the diagnosis of tuberculous peritonitis. Measurement of ADA in ascites is thus likely to be a useful diagnostic method for tuberculous peritonitis. PMID- 24049518 TI - Contrast-enhanced ultrasonography follow-up after radiofrequency ablation in normal rabbit kidney. AB - INTRODUCTION: The aim of this study was to evaluate the diagnostic performance of SonoVue-enhanced ultrasonography in the follow-up of rabbit kidney lesions induced by percutaneous radiofrequency ablation. MATERIAL AND METHODS: New Zealand rabbits (28) underwent percutaneous radiofrequency ablation (RFA) to generate renal lesions. Lesions were evaluated by conventional 2D ultrasound and contrast-enhanced ultrasonography (CEUS) at 1 day, 1 week, 1 month and 3 months after RFA, and the results were compared to gross pathology. RESULTS: One day and 1 week after RFA, renal lesions were wedge-shaped in the gross dissection cross sectional profiles. Conventional ultrasound could not indicate the extent of the lesions; however, CEUS could exactly delineate the lesion shape and size. At 1 and 3 months, lesions were observed as hyperechogenic areas on conventional ultrasound, and as small perfusion defects on CEUS. The differences in the lesion measurements obtained by CEUS and in pathological specimens were not statistically significant (p > 0.05). CONCLUSIONS: The conclusion could be deduced from the study that SonoVue-enhanced ultrasonography was effective for the follow-up of normal rabbit kidney percutaneous radiofrequency ablation. PMID- 24049519 TI - A novel ropivacaine-loaded in situ forming implant prolongs the effect of local analgesia in rats. AB - INTRODUCTION: Prolonged postoperative analgesia cannot be achieved by a single injection of local anesthetic solution. The objective of this study was to optimize the formulation of a ropivacaine hydrochloride (Ropi-HCl) loaded in situ forming implant (ISI) by addition of different co-solvents, and evaluate the in vitro release of Ropi-HCl, and the analgesic effect and toxicity of the optimized formulation in rats. MATERIAL AND METHODS: Triacetin (TA), benzyl benzoate (BB) and polyethylene glycol 400 (PEG 400) were used as additives and added to the solvent of N-methyl-2-pyrrolidone (NMP). Drug release to the surface and inner structural properties of the formed implant were evaluated by scanning electron microscopy (SEM). The analgesic effect was determined by injection near the rat sciatic nerve. RESULTS: The solvent system added with TA or BB significantly decreased the burst release, whereas PEG 400 increased the Ropi-HCl burst release from the formulation. Over 70% of the incorporated Ropi-HCl was released from all formulations in 14 days in the in vitro assay. The SEM showed that the surface of NMP-BB formulation was less porous and more homogeneous, compared with the other formulations. Compared with Ropi-HCl injection, the optimized formulation (NMP BB) significantly prolonged the analgesic effect in 48 h (p < 0.05), with a mild degree of motor block from 3 h to 12 h. Histological evaluation of the injection site revealed only mild inflammatory infiltration without obvious pathological nerve alterations. CONCLUSIONS: The biodegradable Ropi-HCl-loaded ISI system with NMP-BB may prove to be an attractive and safe alternative for the delivery of parenteral local anesthetics to prolong pain relief. PMID- 24049520 TI - Effect of statins on platelet function in patients with hyperlipidemia. AB - INTRODUCTION: It is generally assumed that cholesterol reduction by statins is the predominant therapeutic result underlying their beneficial effects in cardiovascular disease. However, the action of statins may be partially independent of their effects on plasma cholesterol levels, as they combine lipid lowering with positive effects on hemorheological conditions and endothelial function. We evaluated the impact of statin treatment on platelet adhesion to fibrinogen (spontaneous and ADP-activated), along with ADP, collagen or ristocetin-induced aggregation in type II hyperlipidemic patients. MATERIAL AND METHODS: The study group included 70 persons: 50 patients affected by type II hyperlipidemia without concomitant diseases and 20 healthy volunteers. The effects of 8-week statin treatment (atorvastatin 10 mg/day, simvastatin 20 mg/day, or pravastatin 20 mg/day) on platelet activation were evaluated. RESULTS: Regardless of the type of statin, a significant decrease in ADP-induced platelet aggregation was observed: for atorvastatin 50.6 +/-12.8% vs. 41.1 +/-15.8% (p < 0.05), for simvastatin 57.2 +/-18.0% vs. 44.7 +/-22.1% (p = 0.05), and for pravastatin 55.8 +/-19.5% vs. 38.8 +/-23.3% (p < 0.05). There was no significant effect of statins on collagen or ristocetin-induced platelet aggregation and adhesion. CONCLUSIONS: Therapy with statins beneficially modifies ADP-induced platelet aggregation in patients with hyperlipidemia and does not affect spontaneous or ADP-induced platelet adhesion to fibrinogen and platelet aggregation induced by collagen or ristocetin. PMID- 24049521 TI - Life satisfaction and cardiovascular disease risk in Poland. AB - INTRODUCTION: Cardiovascular disease is the most common cause of death. Life satisfaction is a predictor of morbidity and mortality, irrespectively of objective measures of health status. The aim of the study was to evaluate the relationship between life satisfaction (LS) and cardiovascular disease risk (CVD) assessed with the Framingham Risk Score (FRS) in Polish adults. MATERIAL AND METHODS: Past, present and projected LS were estimated. The FRS reflecting 10 year CVD risk was calculated from health indices and lifestyle parameters. Relationships between LS and FRS were tested by two-way analysis of variance in 489 men and 591 women, 40-50 years of age. RESULTS: Subjects with a reduction in LS over time had a higher FRS compared to peers with an improvement in LS. The relationship between current LS and FRS had a J-shape in men; FRS was lowest in men with an LS of 5-7 (average LS), slightly higher in men with an LS of 8-10 (highest LS), and highest in men with an LS of 1-4 (lowest LS). Among women, there was an inverse linear relationship between LS and FRS: the higher the LS, the lower FRS. There was a strong linear relationship between predicted LS and CVD risk. Highest risk was evident in subjects with low LS in whom low LS was predicted over the next five years. CONCLUSIONS: Low LS (dissatisfaction) thus has a long-term negative effect on CVD risk in Polish adults of both sexes. PMID- 24049522 TI - Cardiotrophin-1 is not associated with carotid or coronary disease and is inversely associated with obesity in patients undergoing coronary angiography. AB - INTRODUCTION: Cardiotrophin-1 (CT-1) is a member of the interleukin-6 superfamily with known hypertrophic and protective actions upon cardiac myocytes. Although its effects on myocardial tissue and its role in hypertensive heart disease are well documented, there are no studies on CT-1 blood levels in patients with coronary artery disease. In this study we aimed to verify the relationships of serum CT-1 with vascular disease and metabolic parameters in a population of patients undergoing coronary angiography due to clinical indications. MATERIAL AND METHODS: Serum levels of CT-1 were investigated in a cohort of 81 consecutive patients (median age 68 years (95% CI: 64-71), 59 males) undergoing coronary angiography and carotid Doppler ultrasound. Exclusion criteria were: acute coronary syndrome, already-established ischemic cardiopathy, chronic inflammatory diseases and presence or past history of cancer. RESULTS: Levels of CT-1 were inversely correlated with body mass index (BMI) and waist circumference (WC) (rho = -0.261, p = 0.02; rho = -0.224, p = 0.05, respectively). Moreover, obese patients showed significantly lower CT-1 concentrations than non-obese ones (1.18 (0.64-1.64) ng/ml vs. 1.56 (1.37-2.04) ng/ml, p = 0.013), and serum CT-1 was significantly reduced in patients with elevated compared to those with normal WC (1.43 (0.94-1.60) ng/ml vs. 1.64 (1.39-2.49) ng/ml, p = 0.047). Concentrations of CT-1 did not correlate either with the other parameters of metabolic syndrome or with markers of cardiovascular disease (carotid intima-media thickness, presence of carotid or coronary artery plaques). CONCLUSIONS: Our results failed to demonstrate any association between CT-1 and carotid or coronary disease. The inverse association with BMI and WC fits with the latest experimental data on the role of CT-1 in dysmetabolic conditions and could help to further clarify the role of CT-1 in obesity and diabetes. PMID- 24049523 TI - Association of CD36 gene polymorphisms with echo- and electrocardiographic parameters in patients with early onset coronary artery disease. AB - INTRODUCTION: CD36 plays an important role in long-chain fatty acid homeostasis in skeletal muscle and the myocardium. CD36 deficiency may lead to reduced myocardial uptake of long-chain fatty acid. Therefore, different mutations of the CD36 gene may contribute to the clinical heterogeneity of cardiac hypertrophy. MATERIAL AND METHODS: The objective of the study was to investigate whether there is an association between the sequence changes in CD36 and echocardiographic and electrocardiographic parameters in Caucasian patients with early onset coronary artery disease. The study group comprised 100 patients. Electrocardiography and echocardiography were performed in all patients. Amplicons of exons 4 to 6 including fragments of introns were studied using the denaturing high-performance liquid chromatography technique. RESULTS: IVS3-6TC (rs3173798) heterozygotes had impaired left ventricle diastolic function. 573GA heterozygotes (rs5956) had higher frequency of pseudonormal left ventricular diastolic function and it was confirmed by the increase in wave A' in the tissue Doppler. 591AT genotype was associated with borderline higher posterior wall end-diastolic thickness and lower E/A ratio. These results are consistent with electrocardiography parameters which could reflect left ventricular hypertrophy (higher RV5(6) and RV5(6) + SV1(2) parameters, depressed ST segments and tendency to longer Qtc II interval) in 591AT heterozygotes. CONCLUSIONS: Detected variant alleles of CD36 may be associated with features of left ventricular hypertrophy and impaired diastolic function. PMID- 24049524 TI - Analysis of heart rate variability in individuals subjected to different positive end expiratory pressure levels using expiratory positive airway pressure. AB - INTRODUCTION: The increase in the number of studies has led to greater security in the application of this method and the determination of its effectiveness in adults.. The purpose of the present study was to evaluate heart rate variability in healthy individuals submitted to different levels of positive expiratory pressure using an expiratory positive airway pressure (EPAP) device. MATERIAL AND METHODS: The study involved 27 healthy male individuals ranging in age from 20 to 35 years. Patient histories were taken and the subjects were submitted to a physical examination. The volunteers were monitored using the Polar 810s((r)) and submitted to the EPAP experiment. Analyses were performed on variables of the frequency domain. Sympathetic and parasympathetic bands and their relationship with sympathovagal response were also analyzed. RESULTS: The mean value of this variable was 526.89 (55.50) ms(2) in the first period, 2811.0 (721.10) ms(2) in the fourth period and 726.52 (123.41) ms(2) in the fifth period. Regarding the parasympathetic area, significant differences were detected when Periods 1 and 5 (no load) were compared with periods in which the individuals were subjected to the use of the therapy. Sympathetic and parasympathetic areas together, a significant difference was detected regarding the sympathetic/parasympathetic ratio in the comparison between Periods 1 and 4 (p < 0.01) as well as Periods 2 and 4 (p < 0.05). CONCLUSIONS: The findings of the present study suggest that the therapeutic use of EPAP significantly alters the parameters of heart rate variability in the frequency domain, highlighting the importance of monitoring and care during the practice of EPAP. PMID- 24049525 TI - Distinctive biochemical changes in pulmonary tuberculosis and pneumonia. AB - INTRODUCTION: We aimed to investigate the relationship between radiological extent and serum biochemical changes and body mass index (BMI) in patients with pulmonary tuberculosis (PTB) and pneumonia and to determine the usefulness of C reactive protein (CRP) in clinical discriminative diagnosis. MATERIAL AND METHODS: One hundred fifteen patients with tuberculosis (group 1), 70 patients with pneumonia (group 2) and 30 healthy controls (group 3) were included in this case-control study. RESULTS: Total cholesterol (TC, p < 0.001 in group 1; p = 0.011 in group 2), high-density lipoprotein (HDL, p < 0.001), albumin (ALB, p < 0.001) and BMI (p < 0.001) values were significantly lower group 1 and group 2 than group 3. Erythrocyte sedimentation rate (ESR), leucocyte (LEU) and CRP were higher in group 2 than group 1 and group 3 (p < 0.001). As important point; triglyceride (TG) and BMI were significantly lower in group 1 than group 2 (p < 0.001). In group 1; BMI, HDL, TG, total protein (TP) and albumin were found to decrease, while CRP and ESR increased as the radiological stage increased (p < 0.05). But no significant difference was found in levels of TC and LDL (p > 0.05). In group 2; BMI, TC, HDL, LDL, TP and ALB were observed to decrease, while LEU, CRP and ESR increased as the radiological stage increased (p < 0.05). But no significant difference was found in levels of TG (p > 0.05). The best serum CRP cut-off value in differential diagnosis of tuberculosis and pneumonia was defined as 9.4. CONCLUSIONS: The acute phase response occurring in tuberculosis and pneumonia determines the severity of the disease, leads to a decrease of serum levels of lipoproteins and BMI, and is correlated with the radiological extent. The CRP and ESR were found to be useful in differential diagnosis of tuberculosis and pneumonia. PMID- 24049526 TI - Serum p-cresyl sulfate predicts cardiovascular disease and mortality in elderly hemodialysis patients. AB - INTRODUCTION: Previous studies have shown that serum p-cresyl sulfate (PCS) and indoxyl sulfate (IS) were significantly related to clinical outcomes in patients on hemodialysis (HD). However, evidence for the relationship in elderly HD patients remains scarce. We explore whether the two toxins can predict clinical outcomes in elderly HD patients. MATERIAL AND METHODS: Fifty stable HD patients more than 65 years old were enrolled from a single medical center. Serum total and free PCS, IS levels and biochemistry were measured concurrently. The clinical outcomes including cardiovascular events and all-cause mortality were analyzed after 38-month follow-up. RESULTS: Univariate Cox proportional hazard ratio analysis revealed that cardiovascular events were associated with gender (p = 0.02), diabetes (p < 0.01), calcium (p = 0.01), total PCS (p < 0.01), free PCS (p < 0.01) and total IS (p = 0.05). Multivariate analysis showed that diabetes (p = 0.01), total PCS (p = 0.01) and free PCS (p = 0.04) were related to cardiovascular events. For all-cause mortality, only total PCS (p = 0.01) reached significance after adjusting other confounding factors. However, Kaplan-Meier analysis indicated that free PCS (p = 0.02) and total PCS (p < 0.01) were significantly associated with cardiovascular events and total PCS (p = 0.048) was related to all-cause mortality during 38-month follow-up. CONCLUSIONS: Our results indicate that total PCS is a valuable marker in predicting cardiovascular event and all-cause mortality in elderly HD patients. PMID- 24049527 TI - Validation of Mini Nutritional Assessment Scale in peritoneal dialysis patients. AB - INTRODUCTION: Malnutrition is a negative predictive factor for survival in end stage renal disease (ESRD) patients. Coincidence of malnutrition, inflammation and atherosclerosis (MIA syndrome) in the dialysis population is an exceptionally poor outcome event. Due to flexibility, ease of performance and reproducibility, clinical scales are of particular value in assessment of nutritional status in ESRD patients. The aim of the present study was to evaluate the clinical value of Mini Nutritional Assessment (MNA) in peritoneal dialysis (PD) patients. MATERIAL AND METHODS: Nutritional status was assessed in 41 peritoneal dialysis patients by means of the MNA scale and malnutrition inflammation score (MIS). Some other clinical and laboratory parameters associated with nutritional status were analyzed. Patients were followed up for 30 months. RESULTS: In the analyzed group of patients a good nutritional state was diagnosed in 22 patients (54%), risk of malnutrition in 17 (41%) and malnutrition in 2 patients (5%) based on the MNA scale. A strong correlation between MNA based nutritional status and MIS was found (r = -0.85, p < 0.01, ANOVA, p < 0.01). Differences in time on dialysis, body mass index, concentration of albumin, cholesterol and triglycerides were noted between at risk/malnourished and well-nourished (according to MNA) patients. Statistically significant factors determining survival of patients by Cox proportional hazard analysis were age (HR 1.07), being at risk/malnourished according to MNA (HR 5.7), MIS (HR 1.2), and albumin (HR 0.13). CONCLUSIONS: The MNA scale is a valuable, clinically suitable tool for assessment of nutritional status in peritoneal dialysis patients. Risk of malnutrition and malnutrition diagnosed by MNA identifies patients at high mortality risk. PMID- 24049528 TI - Application of biochemical markers CA 19-9, CEA and C-reactive protein in diagnosis of malicious and benign pancreatic tumors. AB - INTRODUCTION: We would save many lives and spare a lot of suffering if we could only detect and accurately determine the character and TMN staging of pancreatic tumors (PTs). With improved diagnosis, we could offer specific treatment that would result in better treatment outcome. The aim of study was to determine the significance of neoplastic markers CA 19-9 and CEA for prognosis in inflammatory and carcinomatous PTs. MATERIAL AND METHODS: We based our research upon a group of 170 patients. The patients were treated in our Oncologic Surgery Department from January 2007 to December 2010 for PTs. The patients were divided into four groups depending on the character of the tumor and underwent the following treatments: group 1 - 34 patients with carcinoma of the ampulla of Vater, group 2 - 64 patients with PTs at different stages (1, 2, 3) according to TMN classification, group 3 - 62 patients with PTs at stage 4 on the TMN scale (unresectable tumors), group 4 - 28 patients with inflammatory PTs. RESULTS: The results of Ca 19-9 in group 2 were 736.00 (25-75% 220.40-4285.00) ng/ml before surgery, 53.00 (25-75% 12.60-84.00) ng/ml in the 7 days after surgery, 29.4 (25 75% 7.90-113.00) ng/ml at day 30, and 119.00 (25-75% 96.30-621.00) ng/ml 3 months after the operation. These results were significantly higher than the control group but were significantly lower than the results for group 3 (unresectable tumors). The highest average concentration and median for CA 19-9 and CEA were noted in patients with unresectable PTs (the 3(rd) group). The average concentration for CEA was lowest in group 4, but much higher than the lab limits. CONCLUSIONS: The sensitivity of the CA 19-9 marker may be as high as 88%. Values of CA 19-9 above 852 U/ml may indicate TNM stage 4, consistent with an unresectable PT. In the cases where CA 19-9 is within normal limits but C reactive protein is above normal limits (often thirty times the upper limit), in comparison to the control group and to patients with pancreatic neoplasms, strong consideration should be given towards the inflammatory characteristics of the pancreatic changes and conservative treatment should be applied. PMID- 24049529 TI - Predictive factors for preeclampsia in pregnant women: a Receiver Operation Character approach. AB - INTRODUCTION: Preeclampsia is a major cause of maternal and prenatal mortality and morbidity worldwide. There are some risk factors that are of great value for prediction of preeclampsia by which the practitioners can counsel women regarding this disease. The aim of this study was to analyze the role of such risk factors as the predictors associated with preeclampsia among Iranian women using logistic regression. MATERIAL AND METHODS: The role of some risk factors such as demographic, anthropometric, medical and obstetrics variables in preeclampsia among 610 women attending the obstetric ward of Mustafa hospital in Ilam in the west of Iran was analyzed from May to September 2010. All the pregnant women referred to this hospital participated in the study except those cases that had abortion. Unvaried and Multiple logistic regression analyses were used to find the predictive factors behind preeclampsia. Standard errors of area compute using nonparametric methods. A p-value of 0.05 was considered statistically significant. RESULTS: Prevalence of preeclampsia was 9.5% (95% CI 7.4-11.6%). Predictive model build using history of preeclampsia, history of hypertension, and history of infertility. Area Under the Receiver Operation Character (AUROC) was estimated 0.67 (95% CI 0.59-0.67, p < 0.01) that showed that using the model is much better than having a guess. CONCLUSIONS: The odd of preeclampsia increased in women with a history of preeclampsia, hypertension and infertility. Recognition of these predictor factors would improve the ability to diagnose and monitor women likely to develop preeclampsia before the onset of disease for timely interventions. PMID- 24049530 TI - High temperature requirement A1 in placental tissues and serum from pre-eclamptic pregnancies with or without fetal growth restriction. AB - INTRODUCTION: Pre-eclampsia (PE) is the most serious syndrome of human pregnancy and it is potentially life-threatening for both mother and fetus. The aim of the study was to identify the role of high temperature requirement A1 (HtrA1) in pre eclampsia. MATERIAL AND METHODS: One hundred consecutive pregnancies complicated by PE and 100 normal controls were included in our study. The changes in serum HtrA1 and fetal growth restriction were recorded. The placentae after delivery was also obtained for laboratory analyses. RESULTS: High temperature requirement A1 expressed positively in all placenta tissues, but showed higher expression from control, PE with AGA (pre-eclamptic pregnancies with appropriate-for gestational-age newborns) to PE with fetal growth restriction (FGR) groups. Early onset PE happened more frequently while in PE with AGA, late-onset PE was more common. Additionally, we found that only during ~28-32 gestational weeks, sera HtrA1 level of PE with AGA and PE with FGR was increased significantly compared with the control group (p < 0.05). In contrast, there was no significant difference between groups in other gestational ages in the third trimester (p > 0.05). CONCLUSIONS: HtrA1 could potentially affect trophoblast migration and invasion during placentation, resulting in the shallow invasion noted in pre eclampsia. HtrA1 may play an important role in the etiology and severity of PE and FGR. But the actual mechanism still needs deep research. PMID- 24049531 TI - Remifentanil patient-controlled analgesia for labor - monitoring of newborn heart rate, blood pressure and oxygen saturation during the first 24 hours after delivery. AB - INTRODUCTION: There is no available information about the effects of remifentanil labor analgesia on newborns' vital signs in the first hours after delivery. The aim of the study was to assess changes in the heart rate, blood pressure and oxygen saturation during the first 24 h of neonatal life after using remifentanil patient-controlled analgesia (PCA) for labor analgesia. MATERIAL AND METHODS: Forty-four full-term neonates, 23 from intravenous PCA remifentanil labor anesthesia 0.2 ug/kg, repeated not more frequently than every 2 min, and 21 born to mothers without any pharmacological forms of analgesia, were studied. Heart rate, oxygen saturation, and systolic (SBP) and diastolic blood pressure (DBP) were monitored using a Nellcor Oxi Max monitor N5500 (Tyco Healthcare), and recorded at 1 h, 6 h, 12 h and 24 h. RESULTS: No significant differences in heart rate (p = 0.54; p = 0.26; p = 0.60; p = 0.83), oxygen saturation (p = 0.21; p = 0.27; p = 0.61; p = 0.9) and DBP (p = 0.98; p = 0.31; p = 0.83; p = 0.58) between the groups at 1 h, 6 h, 12 h and 24 h. Newborns from the remifentanil group had lower SBP at 1 h of life (59 mm Hg vs. 68.5 mm Hg) but the difference was just on the borderline of statistical significance (p > 0.06). There were no significant differences in SBP between the groups at 6 h (p = 0.65), 12 h (p = 0.11), and 24 h (p = 0.89) of life. CONCLUSIONS: Remifentanil PCA analgesia during labor does not significantly modify the oxygen saturation, heart rate and blood pressure in infants during the first day of their life. Therefore, further studies are needed to explain the observed trend for arterial hypotension in the first hour of life in infants born to mothers treated with remifentanil. PMID- 24049532 TI - Increased bone mineral density is associated with breastfeeding history in premenopausal Spanish women. AB - INTRODUCTION: During lactation abundant calcium is lost from the mother as a result of the amount of breast milk produced. Lactation leads to transient fragility, with some women experiencing even fragility fractures, but nearly all of these women subsequently undergo a large increase in bone mineral density (BMD), confirming that the BMD must have declined during lactation but it increases after weaning. We have retrospectively examined the relationship between the duration of breastfeeding and bone properties in Spanish premenopausal healthy women, to identify the site-specific changes in BMD. MATERIAL AND METHODS: Four hundred and thirty-three premenopausal healthy women, 295 with a mean of 7.82 +/-6.68 months of exclusive breastfeeding and 138 control women, were studied. We examined total, trabecular and cortical volumetric BMD (mg/mm(3)) at the distal radius using peripheral quantitative computed tomography. Areal BMD (g/cm(2)) was measured using dual energy X-ray absorptiometry at the femoral neck, lumbar spine, trochanter and Ward's triangle. Phalangeal bone ultrasound was measured by amplitude-dependent speed of sound. RESULTS: Areal BMD analysis at L2-L4 revealed significant intergroup differences (p < 0.05). There were significant intergroup differences in the volumetric BMD in both total and cortical bone (p < 0.05). The observed BMD of breast-feeders was higher than the BMD in non-breast-feeding women. Additionally, the lactation subgroup analysis revealed significant differences in the areal BMD at trochanter and L2-L4 (p < 0.05) and in the cortical volumetric BMD (p < 0.05). CONCLUSIONS: This study adds to the growing evidence that breastfeeding has no deleterious effects and may confer an additional advantage for BMD in premenopausal women. PMID- 24049533 TI - Circulating vascular endothelial growth factor concentrations in patients with postmenopausal osteoporosis. AB - INTRODUCTION: The role of vascular endothelial growth factor (VEGF) in osteoporosis has not yet been clearly established. Vascular endothelial growth factor is an important part of bone formation. In the literature, although the effects of VEGF on bone metabolism were investigated by different studies, there are very rare studies analysing the association between osteoporosis and VEGF. In the present study, our objective was to investigate serum VEGF concentrations in patients with postmenopausal osteoporosis (PMO) and the correlation of serum VEGF levels and bone mineral density (BMD). MATERIAL AND METHODS: This study was performed on 35 PMO patients, and 30 age-matched healthy controls. Serum VEGF concentrations were measured using a quantitative sandwich enzyme immunoassay technique according to the manufacturer's instructions. Bone mineral density values were determined by dual energy X-ray absorptiometry (DEXA). RESULTS: Serum VEGF concentrations were statistically significantly lower in PMO patients than in controls (150 +/-65 pg/ml, 260 +/-135 pg/ml respectively; p = 0.005). A positive correlation was found between serum VEGF concentrations and BMD values (r = 0.63, p = 0.001). CONCLUSIONS: Vascular endothelial growth factor concentrations were decreased in PMO patients and VEGF may play an important role in bone health. PMID- 24049534 TI - Intravenous lidocaine does not affect the anesthetic depth during rapid sequence induction and intubation as assessed by Bispectral Index monitoring: a randomized double blind study. AB - INTRODUCTION: We investigated the impact of intravenous lidocaine on anesthetic depth, as assessed by Bispectral Index score (BIS), and hemodynamic responses to rapid sequence induction/intubation. MATERIAL AND METHODS: Eighty-four surgical patients with risk factors for regurgitation/aspiration were randomized to receive either lidocaine 1.5 mg/kg or normal saline in a double-blind fashion. Propofol 2 mg/kg, lidocaine or normal saline, followed by rocuronium 1 mg/kg were administered intravenously and trachea was intubated under cricoid pressure application. The BIS scores were recorded before induction of anesthesia, immediately after, at 30 s and 1 min after rocuronium injection and every 30 s after intubation, for 10 min. Systolic/diastolic blood pressure and heart rate were measured before induction, immediately after and at 1 min following rocuronium administration, and every minute for 10 min after intubation. RESULTS: Data from 78 patients were analyzed. Demograpic characteristics did not differ between the study groups. A total of 24 BIS scores were recorded for each patient. No difference was found in BIS values between lidocaine and control groups at any time point (F = 2.936, p = 0.91). Also no difference was detected in heart rate, systolic and diastolic blood pressure at any time point of the study period between the two groups (F = 0.063, p = 0.80, F = 0.007, p = 0.93, F = 0.435, p = 0.51 respectively). No episodes of significant bradycardia occurred and none of the patients reported awareness/recall of the procedure. CONCLUSIONS: Lidocaine 1.5 mg/kg given intravenously during rapid sequence induction does not affect BIS values, or blunt the hemodymanic response to laryngoscopy and intubation. PMID- 24049535 TI - Influence of L-arginine on expression of HSP70 and p-53 proteins - early biomarkers of cellular danger in renal tubular cells. Immunohistochemical assessment. AB - INTRODUCTION: The aim of the present study was to investigate expression of HSP70 and p-53 proteins as mechanisms of protection of the renal tubular epithelial cells from l-arginine that induces cellular stress. MATERIAL AND METHODS: The study material consisted of 16 white Wistar female rats. The rats were divided into 2 equal groups. The rats in the experimental group received L-arginine 40 mg/kg body weight per capita every other day for 2 weeks and were decapitated after 3 weeks of the experiment. After decapitation, specimens from the kidney were collected, fixed in 10% formalin, and then embedded in paraffin blocks. Proteins HSP70 and p-53 on slides were detected using the standard three-step immunohistochemical method. RESULTS: The quantitative evaluation of HSP70 and p 53 expression showed that the area occupied with positive HSP70 and p-53 reaction in the rat renal tubular cells of the experimental group (p-53: 2835.44 +/-254.72 um(2); HSP70: 24111.42 +/-4290.88 um(2)) was more statistically significant than the control group (p-53: 1882.05 +/-466.43 um(2); HSP70: 11388.63 +/-1455.24 um(2)). In the present study, the dose of L-arginine was similar to the one that was used in the gestosis treatment of pregnant women. CONCLUSIONS: The renal epithelial cells responded to L-arginine therapy, increasing expression of HSP70 and p-53 proteins. The study showed that L-arginine as a donor of exogenous nitric oxide has a disruptive effect on the renal tubular cells of rat kidneys. Thus it is going to be a subject of the author's future investigations. PMID- 24049536 TI - Genistein ameliorates parathyroid hormone-induced epithelial-to-mesenchymal transition and inhibits expression of connective tissue growth factor in human renal proximal tubular cells. AB - INTRODUCTION: Genistein, a soybean and soy-based product, has been reported to inhibit the growth of a wide range of cancer cells, but there is no evidence concerning its treatment of chronic kidney disease. The aim was to investigate whether genistein has potential to inhibit parathyroid hormone (PTH)-induced renal interstitial fibrosis. MATERIAL AND METHODS: Using human renal tubular epithelial HK-2 cells, alpha-smooth muscle actin (alpha-SMA) was assessed by using immunofluorescence detection. alpha-Smooth muscle actin, E-cadherin and connective tissue growth factor (CTGF) were measured by Western blot analysis. The promoter activity of the CTGF gene was examined by the luciferase reporter assay. RESULTS: When cells were treated with PTH (0.1 nM) for 48 h, alpha-SMA protein expression was induced significantly, the protein expression of E cadherin decreased substantially, and the promoter activity of the CTGF gene as well as its mRNA and protein expression levels increased (p < 0.01). Interestingly, genistein effectively inhibited PTH-induced alpha-SMA expression, restored E-cadherin expression, decreased mRNA and protein expression of CTGF, and suppressed the promoter activity of CTGF in a dose-dependent manner. CONCLUSIONS: Genistein has the ability to block the biomarker for renal transdifferentiation and epithelial-to-mesenchymal transition, alpha-SMA, following PTH treatment and inhibit CTGF expression in human renal tubular epithelial cells; these might be important modes of actions that contribute to genistein anti-fibrogenic effects and may have great implications for its potential in clinical treatment of renal interstitial fibrosis. PMID- 24049537 TI - Distribution of selected gene polymorphisms of UGT1A1 in a Saudi population. AB - INTRODUCTION: Glucuronidation is an important phase II pathway responsible for the metabolism of many endogenous substances and drugs to less toxic metabolites, which undergo renal excretion. The aim of the current work was to evaluate genotype and allele frequencies of certain UDP-glucuronosyltransferase 1A1 (UGT1A1) variants in an Arab population. MATERIAL AND METHODS: Genomic DNA was isolated from 192 healthy unrelated Saudi males of various geographic regions and genotyping of UGT1A1*6, *27, *36, *28, *37, and *60 was carried out using polymerase chain reaction (PCR) amplification followed by direct sequencing. RESULTS: The most common allele for (TA) repeats was the wild type (TA)6 with a frequency of 74.3% followed by the mutant (TA)7 (i.e., UGT1A1*28) with a frequency of 25.7%. The distribution of UGT1A1*60 allele was 62.4% among subjects with the homozygous mutant genotype of 35.4%, while the wild type variant represents 10.6% only. Both UGT1A1*6 and *27 were not detected as all screened subjects showed a homozygous wild type pattern. Similarly, UGT1A1*36* and *37 were either not present or rarely found, respectively. In comparison to other populations, the frequency of UGT1A1*60 and *28 in the studied population was less than that of African Americans but higher than Asians. The geographical origin of the study subjects also implied some differences in genotype distribution of (TA) repeats and UGT1A1*60. CONCLUSIONS: Our data indicate that Saudis harbor some important UGT1A1 mutations known to affect enzyme activity. Additional studies are warranted to assess the clinical implications of these gene polymorphisms in this ethnic group. PMID- 24049538 TI - Effect of an angiotensin II type 1 receptor blocker on caveolin-1 expression in prostate cancer cells. AB - INTRODUCTION: Caveolin-1, the major structural protein of caveolae, interacts directly with the AT1 receptor. The biological functions of caveolin-1 in cancer are compound, multifaceted, and depend on cell type, tumour grade and cancer stage. The AT1-R-caveolin complex in caveolae may coordinate angiotensin II (Ang II) induced signalling. The aim of this study was to determine the effect of the angiotensin II receptor type 1 blocker candesartan on caveolin expression in human metastatic prostate adenocarcinoma cells PC-3. MATERIAL AND METHODS: WST-1 and BrdU assays were used as indicators of cell viability and proliferation after angiotensin II and/or candesartan stimulation. Real-time RT-PCR and western blot were used to study the effect of Ang II and/or candesartan on the expression of Cav-1 and AT1-R in PC-3 cells. RESULTS: We found that the expression of caveolin 1 mRNA in the PC-3 cells treated with CV was significantly decreased in comparison with the control (2.9 +/-0.17, 4.7 +/-0.6, p < 0.05), whereas a higher caveolin-1 mRNA expression was observed in those after Ang II treatment (6.0 +/ 0.43, 4.7 +/-0.6, p < 0.05). Protein analysis indicate that the expression of caveolin-1 protein in the PC-3 cells treated with candesartan was significantly decreased when compared with the control (0.69 +/-0.05, 1.6 +/-0.12, p < 0.05), whereas higher caveolin-1 protein expression was observed after Ang II treatment (2.5 +/-0.20, 1.6 +/-0.12, p < 0.05). CONCLUSIONS: These results provide new information on the action of candesartan and may improve the knowledge about AT1 receptor inhibitors, which can be potentially useful in prostate cancer therapy. PMID- 24049539 TI - Association of Epstein-Barr virus infection and breast carcinoma. AB - INTRODUCTION: A controversy regarding the association of Epstein-Barr virus (EBV) with breast carcinomas has recently been reported in the literature. The present study was carried out in an attempt to determine whether there is a relationship between latent infection with EBV and breast carcinomas in Jordanian females. MATERIAL AND METHODS: Extraction of DNA from the archive samples of breast carcinoma cases embedded in paraffin wax was performed and the extracted DNA was subjected to polymerase chain reaction amplification to detect the EBV genome using four sets of primers for EBER 2, BNLF-1, EBNA 2, and Gp220. Immunohistochemistry study was performed on sections of 4 um which were cut from paraffin blocks of tumor and control groups. Monoclonal antibody against EBNA-1 was applied to all slides to identify the EBV-infected tumor cells. Detection was performed using the Dako envision dual link system. RESULTS: DNA was successfully extracted from 92 paraffin embedded samples of breast carcinoma patients, and from 49 normal samples. The extracted DNA was confirmed by using glyceraldehyde-3 phosphate-dehydrogenase (GAPDH) primers. Twenty-four out of 92 breast carcinoma specimens was found to be infected with EBV as compared to 3 out of 49 control group specimens, which represented a statistically significant difference (p value using chi(2) = 0.008). Immunohistochemically, 24 (26%) of the 92 studied samples were found to be positive, showing EBNA-1 granular nuclear staining in tumor epithelial cells. CONCLUSIONS: These findings suggest an association between EBV infection and breast carcinoma development. PMID- 24049540 TI - A curious case of hypoglycaemia. PMID- 24049541 TI - Unexpected cause of syncope in a young woman. PMID- 24049542 TI - The effects of a first-aid education program for middle school students in a Greek urban area. PMID- 24049543 TI - Adrenal function and MC1R gene analysis in a prepubertal girl with generalized hyperpigmentation: case report. PMID- 24049544 TI - A simple approach to characterizing block copolymer assemblies: graphene oxide supports for high contrast multi-technique imaging. AB - Block copolymers are well-known to self-assemble into a range of 3-dimensional morphologies. However, due to their nanoscale dimensions, resolving their exact structure can be a challenge. Transmission electron microscopy (TEM) is a powerful technique for achieving this, but for polymeric assemblies chemical fixing/staining techniques are usually required to increase image contrast and protect specimens from electron beam damage. Graphene oxide (GO) is a robust, water-dispersable, and nearly electron transparent membrane: an ideal support for TEM. We show that when using GO supports no stains are required to acquire high contrast TEM images and that the specimens remain stable under the electron beam for long periods, allowing sample analysis by a range of electron microscopy techniques. GO supports are also used for further characterization of assemblies by atomic force microscopy. The simplicity of sample preparation and analysis, as well as the potential for significantly increased contrast background, make GO supports an attractive alternative for the analysis of block copolymer assemblies. PMID- 24049545 TI - Force spectroscopy of complex biopolymers with heterogeneous elasticity. AB - Cellular biopolymers can exhibit significant compositional heterogeneities as a result of the non-uniform binding of associated proteins, the formation of microstructural defects during filament assembly, or the imperfect bundling of filaments into composite structures of variable diameter. These can lead to significant variations in the local mechanical properties of biopolymers along their length. Existing spectral analysis methods assume filament homogeneity and therefore report only a single average stiffness for the entire filament. However, understanding how local effects modulate biopolymer mechanics in a spatially resolved manner is essential to understanding how binding and bundling proteins regulate biopolymer stiffness and function in cellular contexts. Here, we present a new method to determine the spatially varying material properties of individual complex biopolymers from the observation of passive thermal fluctuations of the filament conformation. We develop new statistical mechanics based approaches for heterogeneous filaments that estimate local bending elasticities as a function of the filament arc-length. We validate this methodology using simulated polymers with known stiffness distributions, and find excellent agreement between derived and expected values. We then determine the bending elasticity of microtubule filaments of variable composition generated by repeated rounds of tubulin polymerization using either GTP or GMPCPP, a nonhydrolyzable GTP analog. Again, we find excellent agreement between mechanical and compositional heterogeneities. PMID- 24049546 TI - 9(th) Meeting of Asian Congress of Neurological Surgeons. PMID- 24049547 TI - Role of stereotactic biopsy in histological diagnosis of multiple brain lesions. AB - BACKGROUND AND AIM: The current advances in diagnostic and therapeutic modalities and increasing in survival of patients with systemic diseases and immunosuppressive cases have caused to increasing frequency and variety of Central Nervous System neuropathologic processes indicating the necessary need for accurate localization of space-occupying lesions by cytology and histology. This study was aimed to evaluate the usefulness and safety of stereotactic biopsy in histological diagnosis of such lesions. MATERIALS AND METHODS: Of 2081 patients underwent stereotactic biopsy of brain lesions using Riechert-Mundinger system, 158 had multifocal brain lesions, and were enrolled. RESULTS: The ages of studied cases were ranged from 2 years to 75 years (Mean age: 41.3 year), 114 were male and 44 were females. Incidence of histopathologic diagnosis of multifocal brain lesions included Astrocytoma grade II (41.3%), Astrocytoma grade I (12.9%), glioblastoma multiform (11.1%), Astrocytoma grade III (10.2%), malignant lymphoma (10.2%), metastasis (4.6%), pilocytic Astrocytoma (2.7%), abscess (2.7%), craniopharyngioma (1.8%) vascular malformations (0.9%), and tuberculosis (0.9%). Mortality due to operation is none. CONCLUSIONS: Histopathologic diagnosis of multiple brain lesions is necessary for decision of appropriate management and stereotactic biopsy of brain lesion is a useful and safe method for histological diagnosis. PMID- 24049548 TI - Automated end-to-side anastomosis to the middle cerebral artery with C-Port xA: A feasibility study on human cadavers. AB - BACKGROUND: Anastomosis to the superficial temporal artery is suitable in patients with functional and structural impairment of the middle cerebral artery (i.e., complex aneurysms and skull base tumors), as either definitive treatment or an additional safety measure. A shorter occlusion time or a non-occlusive technique is expected to reduce the risk of cerebral ischemia following the procedure. In this cadaver study, we assessed the fitness of C-Port xA((r)) device for use in superficial temporal artery (STA)-middle cerebral artery (MCA) bypass. MATERIALS AND METHODS: Seven fixed human head specimens were prepared through eight pterional craniotomies. The superficial temporal artery was dissected and the sylvian fissure was opened to access the MCA. The C-Port xA was tested on each of the eight exposures. We recorded the lengths of both donor and recipient vessel, the durations of the procedure and the craniotomy, and sylvian scissure opening sizes. The bypass was then assessed by pressure injection of methylene blue in the donor vessel. RESULTS: C-Port xA-assisted STA-MCA anastomosis was successfully accomplished in seven dissections. A minimum STA length of 7 cm, a sylvian scissure opening larger than 5 cm, and a craniotomy size of at least 6 * 6 cm appeared to be the requisites for a safe maneuverability of the device. The MCA occlusion time lasted in all cases less than 4.5 min, and we observed a clear improvement in time performance with growing experience. CONCLUSIONS: The results suggest that the C-Port xA device is suitable for STA-MCA bypass. We experienced a shorter occlusion time and a shorter learning curve compared to conventional techniques. Further miniaturization and special adaptation of this device may allow a future application even to deeper intracranial vessels. Clinical trials will have to assess the long-term results and benefits of this minimal occlusive technique. PMID- 24049549 TI - Prognostic factors in acute stroke, regarding to stroke severity by Canadian Neurological Stroke Scale: A hospital-based study. AB - INTRODUCTION: Stroke is an acute vascular disease and the second leading cause of death in the world. We have assessed the patients on hospital admission with some other prognostic factors besides the preliminary neurological examinations in order to estimate their clinical status in the future. MATERIALS AND METHODS: The present study was performed on the patients admitted to Valiasr Hospital of Arak within 72 h of stroke onset from April to October 2011. Diagnosis of stroke in the suspected patients was done by a neurologist and verified by the findings of the computed tomography scans. For each patient, a specific questionnaire, which described its stroke severity according to canadian neurological scale of stroke (CNSS), was prepared in order to define the severity of the stroke. Systolic as well as diastolic blood pressure of the patients was measured at the admission and their level of blood sugar, cholesterol, and triglyceride was also determined. RESULTS: Out of 62 patients under study (mean age, 66.14 +/- 10.9 years), 36 (58.1%) were males and 26 (41.9%) were females. Overall, 66.1% of the patients were diagnosed with the ischemic stroke, while 33.9% were diagnosed with the hemorrhagic stroke. Regression analysis showed that cholesterol and diastolic blood pressure were the most important prognostic factors of the severity of stroke (CNSS). CONCLUSION: Diastolic blood pressure and serum cholesterol level have the potential to be used for assessing the stroke outcome as well as to improve the stroke rehabilitation. PMID- 24049550 TI - The increase of serum Bcl-2 concentration in moderate head injury outcome: The role of ACTH4-10Pro(8)-Gly(9)-Pro(10.). AB - BACKGROUND: Traumatic brain injury (TBI) is one of the major causes of death and disability. Apoptosis after TBI contributes significantly to the final extent of tissue damage. The Bcl-2 family proteins are important apoptosis modulators which increased in injured neurons. Bcl-2 has shown an antiapoptotic effect in rats and mice. ACTH4-10Pro(8)-Gly(9)-Pro(10) is a synthetic short fragment of ACTH devoid of hormonal effects and has neuromodulatory properties. ACTH4-10Pro8-Gly9-Pro10 has been shown to increase levels of Bcl-2 and BDNF in vitro as well as in vivo. It has been postulated that ACTH4-10Pro(8)-Gly(9)-Pro(10) will result in improved clinical outcome and reduce hospital length of stay. The goal of this study is to compare the effect of standard therapy only with standard therapy and ACTH4 10Pro(8)-Gly(9)-Pro(10), the increase of Bcl-2, and clinical outcome with reduction of hospital stay. MATERIALS AND METHODS: Subjects of moderate head injury (MHI) with no indication of surgery were taken consecutively (n = 40) and separated into two groups: standard treatment only and standard treatment combined with ACTH4-10Pro(8)-Gly(9)-Pro(10). Blood samples were taken on day 1 and day 5 from each subject for measurements of Bcl-2 concentration. Barthel Index and MMSE were measured, at discharge and hospital length of stay was noted. RESULTS: Forty subjects have been involved in this study, three subjects died in the standard therapy group, and one subject in ACTH4-10Pro(8)-Gly(9)-Pro(10) group. Bcl-2 serum level in standard therapy was 1.39 +/- 0.75 ng/mL on day 1 and 1.48 +/- 0.77 ng/mL on day 5. After treatment with ACTH4-10Pro(8)-Gly(9)-Pro(10), Bcl-2 level was 1.39 +/- 0.70 ng/mL on day 1 and 3.70 +/- 1.02 ng/mL on day 5. The serum Bcl-2 concentration was significantly increased with ACTH4-10Pro(8) Gly(9)-Pro(10) therapy with shorter hospital length of stay (P < 0.05). CONCLUSION: ACTH4-10Pro(8)-Gly(9)-Pro(10) increased serum Bcl-2 levels and reduced hospital length of stay significantly compared with standard therapy alone. PMID- 24049551 TI - Silicone injected cadaveric head for neurosurgical dissection: Prepared from defrosted cadaver. AB - BACKGROUND: Most reports of cadaveric specimen preparation for neurosurgical dissection describe methods using fresh cadavers. Our cultural limitations prevent us from obtaining fresh cadaveric heads. OBJECTIVE: To study and report on an alternative method of preparation of head specimens for neurosurgical dissection using defrosted cadavers. MATERIALS AND METHODS: Twenty-four head specimens were procured through the Department of Anatomy, received by donation three to seven days after funeral activity. The specimens were sectioned through the neck, and preserved by refrigeration at a temperature of -10 degrees C for a period of one week to three months prior to preparation. The process began with defrosting the frozen head specimens for 48 hours in a refrigerator, in which the temperature was controlled within the range of -2 degrees to -8 degrees C. The great vessels were identified and cannulated. These were then irrigated with tap water until clear, following which colored silicone was injected. The specimens were preserved in 95% ethyl alcohol, and were assessed for quality one week after the preparation process. They were then re-assessed at monthly intervals for 12 months. RESULTS: When compared with specimens prepared from fresh cadavers, our method provided similar quality specimens for dissection. The scalp and muscles of all specimens remained soft. The vasculature was good, and the colored silicone made identification easy. The brain tissues were soft and easily retracted, and still in good condition for dissection after a long preparation period (12 months). CONCLUSION: The head specimens prepared with this method were of good quality for dissection, and were comparable in quality to those prepared from fresh cadavers as in published methods. We were thus able to provide a suitable substitute to fresh head specimens in situations where access to fresh cadavers is unavailable. PMID- 24049552 TI - Risk factors of recurrent lumbar disk herniation. AB - BACKGROUND: Recurrent lumbar disc herniation (LDH) is a common cause of poor outcomes after lumbar discectomy surgery. Studies focused on risk factors of true recurrent disk herniation at the same level and side, are few. The aim of current study is to evaluate risk factors of recurrent disc herniation in Iranian population. MATERIALS AND METHODS: We retrospectively reviewed 40 patients with recurrent disc herniation and 120 patients without recurrence to evaluate possible risk factors for herniation recurrence. A clinically significant recurrent herniation was defined as a disc herniation causing leg pain with radiographic (MRI) evidence of disc material at the same side and level of the index surgery causing impingement, compression, or deviation of nerve tissue. A series of patients without recurrence was used for comparison to identify possible risk factors for recurrent LDH. RESULTS: There was significant difference between groups with and without LDH in sex (P = 0.003), smoking habit (P = 0.004), height (P = 0.04), weight (P = 0.006) and occupational characteristic (P < 0.001). By putting these differences in logistic regression analysis, it showed that gender (male), taller height, heavy works and being smoker could predict lumbar disc herniation recurrence. CONCLUSION: Considering sex, smoking and heavy works as predictors of recurrent LDH, surgeons should advice their patients to limit hard work and put away smoking especially in tall and male ones to prevent LDH recurrence. PMID- 24049553 TI - Idiopathic spinal cord herniation: Clinical review and report of three cases. AB - Idiopathic spinal cord herniation (ISCH) is a rare condition, of unknown pathogenesis, that primarily affects the thoracic spinal cord. It is characterized by ventral displacement of the spinal cord through a dural defect. The aim of this study was to review the literature and to present a retrospective single center experience with three cases of ISCH. The literature review analyzed a total of 78 relevant publications on ISCH, which included a total of 171 patients, supplemented with 3 patients treated at our institution. Numerous case reports have demonstrated improvement in clinical outcomes after surgery; however, follow-up is predominantly short, data are incomplete, the condition is frequently misdiagnosed, and it is difficult to predict which patients will benefit from surgery. We identified 159 cases treated with surgical management. The mean symptom duration was 54 months, and the mean follow-up 33 months. The result at follow-up was improved neurological outcome in 74%, unchanged result in 18%, and worse outcome in 8%. There were 15 cases of conservative management, with mean symptom duration 52 months and mean follow-up 33 months. The neurological outcome was unchanged in 100%. ISCH is a rare condition causing progressive thoracic myelopathy, and the natural history is unknown. There is a lack of evidence-based treatment strategies, and the majority of cases are treated with surgical management at diagnosis. Management of ISCH needs to be individualized for each patient, and clinicians should be encouraged to report new cases, standardize case reports, and ensure long-term follow-up. PMID- 24049555 TI - Brain herniation induced by drainage of subdural hematoma in spontaneous intracranial hypotension. AB - Spontaneous intracranial hypotension (SIH), typically presents with orthostatic headache, low pressure on lumbar tapping, and diffuse pachymeningeal enhancement on magnetic resonance imaging. SIH is often accompanied by subdural fluid collections, which in most cases responds to conservative treatment or spinal epidural blood patch. Several authors advocate that large subdural hematoma with acute deterioration merits surgical drainage; however, few have reported complications following craniotomy. We describe a complicated case of SIH, which was initially diagnosed as acute subarachnoid hemorrhage with bilateral chronic subdural hematoma (SDH), due to unusual presentation. Burr hole drainage of subdural hematoma was performed due to progressive decrease of consciousness, which then resulted in a huge postoperative epidural hematoma collection. Prompt hematoma evacuation did not restore the patient's consciousness but aggravated downward brain herniation. Trendelenburg position and spinal epidural blood patch achieved a rapid improvement in patient's consciousness. This case indicates that the surgical drainage for chronic SDH in SIH can lead to serious complications and it should be cautiously considered. PMID- 24049554 TI - Interference of apoptosis in the pathophysiology of subarachnoid hemorrhage. AB - Programmed cell death is crucial for the correct development of the organism and the clearance of harmful cells like tumor cells or autoreactive immune cells. Apoptosis is initiated by the activation of cell death receptors and in most cases it is associated with the activation of the cysteine proteases, which lead to apoptotic cell death. Cells shrink, chromatin clumps and forms a large, sharply demarcated, crescent-shaped or round mass; the nucleus condenses, apoptotic bodies are formed and eventually dead cells are engulfed by a neighboring cell or cleared by phagocytosis. The authors have summarized the most important data concerning apoptosis in subarachnoid hemorrhage that have been issued in the medical literature in the last 20 years. PMID- 24049556 TI - "Barriers to Cognitive Behavioral Therapy Homework Completion Scale- Depression Version": Development and Psychometric Evaluation. AB - We conducted a two-phase study to develop and evaluate the psychometric properties of an instrument to identify barriers to Cognitive Behavioral Therapy (CBT) homework completion in a depressed sample. In Phase I, we developed an item pool by interviewing 20 depressed patients and 20 CBT therapists. In Phase II, we created and administered a draft instrument to 56 people with depression. Exploratory Factor Analysis revealed a 2-factor oblique solution of "Patient Factors" and "Therapy/Task Factors." Internal consistency coefficients ranged from .80 to .95. Temporal stability was demonstrated through Pearson correlations of .72 (for the therapist/task subscale) to .95 (for the patient subscale) over periods of time that ranged from 2 days to 3 weeks. The patient subscale was able to satisfactorily classify patients (75 to 79 %) with low and high adherence at both sessions. Specificity was .66 at both time points. Sensitivity was .80 at sessions B and .77 at session C. There were no consistent predictors of assignment compliance when measured by the Assignment Compliance Rating Scale (Primakoff, Epstein, & Covi, 1986). The Rating Scale and subscale scores did, however, correlate significantly with assignment non-compliance (.32 to .46). PMID- 24049557 TI - Positive Affect Enhances the Association of Hypomanic Personality and Cognitive Flexibility. AB - Several lines of research have suggested a link between mania and creativity, The goal of the present study was to test whether positive affect moderated the relationship between risk for mania (assessed with the Hypomanic Personality Scale [HPS]) and a variable postulated to be a cognitive component of creativity: cognitive flexibility. Fifty-three undergraduate students were randomly assigned to either a neutral or positive mood induction condition. They then completed the Delis-Kaplan Executive Function System (DKEFS) Sorting Test as a measure of cognitive flexibility. Consistent with our hypothesis, higher HPS scores were associated with greater cognitive flexibility among participants in the positive mood induction condition. Covariate analyses revealed that results were not confounded by verbal intelligence or the presence of current depression symptoms. Our findings suggest a mood-dependent link between hypomanic personality and one potential component of creative cognition. PMID- 24049558 TI - Binding properties of Treponema denticola lipooligosaccharide. AB - BACKGROUND AND OBJECTIVE: The cell-surface lipooligosaccharide (LOS) of Treponema denticola possesses several biological properties. The aim of this study was to investigate the binding properties of T. denticola LOS to extracellular matrix (ECM) proteins, mucosal cells, and oral bacteria. DESIGN: LOS was isolated from T. denticola and labeled with tritium. Tritium-labeled LOS was placed in ECM protein-, epithelial cell-, fibroblast-, or bacterium-coated wells of a 96-well microplate. Following incubation, unattached LOS was removed by extensive washing, and the amount of bound LOS was determined by measuring the radioactivity in the wells. Peptostreptococcus micros coated with LOS was used to stimulate fibroblasts, and the secretion of interleukin-6 (IL-6) and interleukin 8 (IL-8) by the fibroblasts was determined by ELISA. RESULTS: T. denticola LOS had a high affinity for laminin. It also bound to gingival epithelial cells and fibroblasts. Soluble CD14 significantly increased the binding of LOS to fibroblasts. More LOS bound to P. micros than the other oral bacterial species tested. Stimulating fibroblasts with LOS-coated P. micros induced the secretion of IL-6 and IL-8. CONCLUSIONS: Our study provided evidence that T. denticola LOS possesses the capacity to bind to ECM proteins, mucosal cells, and oral bacteria. In addition, LOS binding to bacteria may increase their pro-inflammatory potential. PMID- 24049560 TI - Relative sensory sparing in the diabetic foot implied through vibration testing. AB - BACKGROUND: The dorsal aspect of the hallux is often cited as the anatomic location of choice for vibration testing in the feet of diabetic patients. To validate this preference, vibration tests were performed and compared at the hallux and 5th metatarsal head in diabetic patients with established neuropathy. METHODS: Twenty-eight neuropathic, diabetic patients and 17 non-neuropathic, non diabetic patients underwent timed vibration testing (TVT) with a novel 128 Hz electronic tuning fork (ETF) at the hallux and 5th metatarsal head. RESULTS: TVT values in the feet of diabetic patients were found to be reduced at both locations compared to controls. Unexpectedly, these values were significantly lower at the hallux (P<0.001) compared to the 5th metatarsal head. CONCLUSION: This study confirms the hallux as the most appropriate location for vibration testing and implies relative sensory sparing at the 5th metatarsal head, a finding not previously reported in diabetic patients. PMID- 24049559 TI - Electrical stimulation to accelerate wound healing. AB - BACKGROUND: There are several applications of electrical stimulation described in medical literature to accelerate wound healing and improve cutaneous perfusion. This is a simple technique that could be incorporated as an adjunctive therapy in plastic surgery. The objective of this review was to evaluate the results of randomized clinical trials that use electrical stimulation for wound healing. METHOD: We identified 21 randomized clinical trials that used electrical stimulation for wound healing. We did not include five studies with treatment groups with less than eight subjects. RESULTS: Electrical stimulation was associated with faster wound area reduction or a higher proportion of wounds that healed in 14 out of 16 wound randomized clinical trials. The type of electrical stimulation, waveform, and duration of therapy vary in the literature. CONCLUSION: Electrical stimulation has been shown to accelerate wound healing and increase cutaneous perfusion in human studies. Electrical stimulation is an adjunctive therapy that is underutilized in plastic surgery and could improve flap and graft survival, accelerate postoperative recovery, and decrease necrosis following foot reconstruction. PMID- 24049561 TI - Marginal fit of anterior 3-unit fixed partial zirconia restorations using different CAD/CAM systems. AB - PURPOSE: Few studies have investigated the marginal accuracy of 3-unit zirconia fixed partial dentures (FPDs) fabricated by computer-aided design/computer-aided manufacturing (CAD/CAM) system. The purpose of this study was to compare the marginal fit of zirconia FPDs made using two CAD/CAM systems with that of metal ceramic FPDs. MATERIALS AND METHODS: Artificial resin maxillary central and lateral incisors were prepared for 3-unit FPDs and fixed in yellow stone. This model was duplicated to epoxy resin die. On the resin die, 15 three-unit FPDs were fabricated per group (45 in total): Group A, zirconia 3-unit FPDs made with the Everest system; Group B, zirconia 3-unit FPDs made with the Lava system; and Group C, metal-ceramic 3-unit FPDs. They were cemented to resin dies with resin cement. After removal of pontic, each retainer was separated and observed under a microscope (Presize 440C). Marginal gaps of experimental groups were analyzed using one-way ANOVA and Duncan test. RESULTS: Mean marginal gaps of 3-unit FPDs were 60.46 um for the Everest group, 78.71 um for the Lava group, and 81.32 um for the metal-ceramic group. The Everest group demonstrated significantly smaller marginal gap than the Lava and the metal-ceramic groups (P<.05). The marginal gap did not significantly differ between the Lava and the metal-ceramic groups (P>.05). CONCLUSION: The marginal gaps of anterior 3-unit zirconia FPD differed according to CAD/CAM systems, but still fell within clinically acceptable ranges compared with conventional metal-ceramic restoration. PMID- 24049562 TI - Adhesion of 10-MDP containing resin cements to dentin with and without the etch and-rinse technique. AB - PURPOSE: This study evaluated the adhesion of 10-MDP containing self-etch and self-adhesive resin cements to dentin with and without the use of etch-and-rinse technique. MATERIALS AND METHODS: Human third molars (N=180) were randomly divided into 6 groups (n=30 per group). Conventional (Panavia F2.0, Kuraray-PAN) and self-adhesive resin cements (Clearfil SA, Kuraray-CSA) were bonded to dentin surfaces either after application of 3-step etch-and-rinse (35% H3PO4 + ED Primer) or two-step self-etch adhesive resin (Clearfil SE Bond). Specimens were subjected to shear bond strength test using the universal testing machine (0.5 mm/min). The failure types were analyzed using a stereomicroscope and quality of hybrid layer was observed under a scanning electron microscope. The data (MPa) were analyzed using two-way ANOVA and Tukey's tests (alpha=.05). RESULTS: Overall, PAN adhesive cement showed significantly higher mean bond strength (12.5 +/- 2.3 - 14.1 +/- 2.4 MPa) than CSA cement (9.3 +/- 1.4 - 13.9 +/- 1.9 MPa) (P<.001). Adhesive failures were more frequent in CSA cement groups when used in conjunction with two-step self-adhesive (68%) or no adhesive at all (66%). Hybrid layer quality was inferior in CSA compared to PAN cement in all conditions. CONCLUSION: In clinical situations where bonding to dentin substrate is crucial, both conventional and self-adhesive resin cements based on 10-MDP can benefit from etch-and-rinse technique to achieve better quality of adhesion in the early clinical period. PMID- 24049563 TI - A comparison of retentive strength of implant cement depending on various methods of removing provisional cement from implant abutment. AB - PURPOSE: This study evaluated the effectiveness of various methods for removing provisional cement from implant abutments, and what effect these methods have on the retention of prosthesis during the definitive cementation. MATERIALS AND METHODS: Forty implant fixture analogues and abutments were embedded in resin blocks. Forty cast crowns were fabricated and divided into 4 groups each containing 10 implants. Group A was cemented directly with the definitive cement (Cem-Implant). The remainder were cemented with provisional cement (Temp-Bond NE), and classified according to the method for cleaning the abutments. Group B used a plastic curette and wet gauze, Group C used a rubber cup and pumice, and Group D used an airborne particle abrasion technique. The abutments were observed using a stereomicroscope after removing the provisional cement. The tensile bond strength was measured after the definitive cementation. Statistical analysis was performed using one-way analysis of variance test (alpha=.05). RESULTS: Group B clearly showed provisional cement remaining, whereas the other groups showed almost no cement. Groups A and B showed a relatively smooth surface. More roughness was observed in Group C, and apparent roughness was noted in Group D. The tensile bond strength tests revealed Group D to have significantly the highest tensile bond strength followed in order by Groups C, A and B. CONCLUSION: A plastic curette and wet gauze alone cannot effectively remove the residual provisional cement on the abutment. The definitive retention increased when the abutments were treated with rubber cup/pumice or airborne particle abraded to remove the provisional cement. PMID- 24049564 TI - Influence of various metal oxides on mechanical and physical properties of heat cured polymethyl methacrylate denture base resins. AB - PURPOSE: To evaluate the effect of various metal oxides on impact strength (IS), fracture toughness (FT), water sorption (WSP) and solubility (WSL) of heat-cured acrylic resin. MATERIALS AND METHODS: Fifty acrylic resin specimens were fabricated for each test and divided into five groups. Group 1 was the control group and Group 2, 3, 4 and 5 (test groups) included a mixture of 1% TiO2 and 1% ZrO2, 2% Al2O3, 2% TiO2, and 2% ZrO2 by volume, respectively. Rectangular unnotched specimens (50 mm * 6.0 mm * 4.0 mm) were fabricated and droptower impact testing machine was used to determine IS. For FT, compact test specimens were fabricated and tests were done with a universal testing machine with a cross head speed of 5 mm/min. For WSP and WSL, discshaped specimens were fabricated and tests were performed in accordance to ISO 1567. ANOVA and Kruskal-Wallis tests were used for statistical analyses. RESULTS: IS and FT values were significantly higher and WSP and WSL values were significantly lower in test groups than in control group (P<.05). Group 5 had significantly higher IS and FT values and significantly lower WSP values than other groups (P<.05) and provided 40% and 30% increase in IS and FT, respectively, compared to control group. Significantly lower WSL values were detected for Group 2 and 5 (P<.05). CONCLUSION: Modification of heat-cured acrylic resin with metal oxides, especially with ZrO2, may be useful in preventing denture fractures and undesirable physical changes resulting from oral fluids clinically. PMID- 24049565 TI - Effect of various intraoral repair systems on the shear bond strength of composite resin to zirconia. AB - PURPOSE: This study compared the effect of three intraoral repair systems on the bond strength between composite resin and zirconia core. MATERIALS AND METHODS: THIRTY ZIRCONIA SPECIMENS WERE DIVIDED INTO THREE GROUPS ACCORDING TO THE REPAIR METHOD: Group I- CoJetTM Repair System (3M ESPE) [chairside silica coating with 30 um SiO2 + silanization + adhesive]; Group II- Ceramic Repair System (Ivoclar Vivadent) [etching with 37% phosphoric acid + Zirconia primer + adhesive]; Group III- Signum Zirconia Bond (Heraus) [Signum Zirconia Bond I + Signum Zirconia Bond II]. Composite resin was polymerized on each conditioned specimen. The shear bond strength was tested using a universal testing machine, and fracture sites were examined with FE-SEM. Surface morphology and wettability after surface treatments were examined additionally. The data of bond strengths were statistically analyzed with one-way ANOVA and Tamhane post hoc test (alpha=.05). RESULTS: Increased surface roughness and the highest wettability value were observed in the CoJet sand treated specimens. The specimens treated with 37% phosphoric acid and Signum Zirconia Bond I did not show any improvement of surface irregularity, and the lowest wettability value were found in 37% phosphoric acid treated specimens. There was no significant difference in the bond strengths between Group I (7.80 +/- 0.76 MPa) and III (8.98 +/- 1.39 MPa). Group II (3.21 +/- 0.78 MPa) showed a significant difference from other groups (P<.05). CONCLUSION: The use of Intraoral silica coating system and the application of Signum Zirconia Bond are effective for increasing the bond strength of composite resin to zirconia. PMID- 24049566 TI - Computerized analysis of occlusal contacts in bruxism patients treated with occlusal splint therapy. AB - PURPOSE: Occlusal splints are commonly used to prevent tooth wear caused by bruxism. However, the effects of splints on occlusion are still unclear. Although it is rarely alluded in literature, splints can provoke severe occlusal alterations and other complications. This study was aimed to identify differences in the responses of individuals with bruxism and healthy individuals to a full arch maxillary stabilization splint in terms of occlusal changes. MATERIALS AND METHODS: Occlusal contacts in 20 (5 male, 15 female) bruxism patients and 20 (5 male, 15 female) controls with normal occlusion were evaluated before and after occlusal splint therapy. T-Scan III, a computerized occlusal analysis system, was used to simultaneously measure occlusion and disclusion times as well as left right and anterior-posterior contact distributions before splint therapy and 3 months after therapy. Wilcoxon and Mann-Whitney U tests were used for statistical analyses (alpha=.05). RESULTS: No differences were found in the posterior contact of bruxism patients before and after stabilization splint treatment. However, differences in posterior contact were observed between bruxists and normal individuals prior to treatment, and this difference disappeared following treatment. CONCLUSION: The results of this study showed the use of a stabilization splint may not have an effect on occlusion. However, the area of posterior occlusal contact among bruxists was found to be greater than that of normal individuals. According to this study, the clinical use of splints may be harmless. PMID- 24049567 TI - Perceived color shift of ceramics according to the change of illuminating light with spectroradiometer. AB - PURPOSE: Perceived color of ceramics changes by the spectral power distribution of ambient light. This study aimed to quantify the amount of shifts in color and color coordinates of clinically simulated seven all-ceramics due to the switch of three ambient light sources using a human vision simulating spectroradiometer. MATERIALS AND METHODS: CIE color coordinates, such as L*, a* and b*,of ceramic specimens were measured under three light sources, which simulate the CIE standard illuminant D65 (daylight), A (incandescent lamp), and F9 (fluorescent lamp). Shifts in color and color coordinate by the switch of lights were determined. Influence of the switched light (D65 to A, or D65 to F9), shade of veneer ceramics (A2 or A3), and brand of ceramics on the shifts was analyzed by a three-way ANOVA. RESULTS: Shifts in color and color coordinates were influenced by three factors (P<.05). Color shifts by the switch to A were in the range of 5.9 to 7.7 DeltaE*ab units, and those by the switch to F9 were 7.7 to 10.2; all of which were unacceptable (DeltaE*ab > 5.5). When switched to A, CIE a* increased (Deltaa*: 5.6 to 7.6), however, CIE b* increased (Deltab*: 4.9 to 7.8) when switched to F9. CONCLUSION: Clinically simulated ceramics demonstrated clinically unacceptable color shifts according to the switches in ambient lights based on spectroradiometric readings. Therefore, shade matching and compatibility evaluation should be performed considering ambient lighting conditions and should be done under most relevant lighting condition. PMID- 24049568 TI - Effect of denture cleansers on surface hardness of resilient denture liners at various time intervals- an in vitro study. AB - PURPOSE: This study was aimed to determine the effect of two chemically distinct denture cleansers and water on the surface hardness of acrylic and silicone based soft denture liners at various time intervals. MATERIALS AND METHODS: Two commonly used commercial resilient liner material were selected based on their chemical composition (silicone- and acrylic-based soft liners) for this investigation. 120 cylindrical specimens were made of 15 mm * 10 mm dimensions (according to ASTM: D-2240-64T) in a custom made metal mold. All specimens were stored in artificial saliva throughout the study. Forty specimens were cleansed daily in 0.5% sodium hypochlorite solution; forty were cleansed in sodium perborate and remaining forty specimens were daily rinsed in water. Testing was done at 1 week, 1 month, 3 months and 6 months for surface hardness using a Shore A Durometer. A mean of 3 reading for each sample was subjected to one-way ANOVA, Post Hoc test and pair-t test for statistical analysis. P values of less than 0.05 were taken as statistically significant. RESULTS: Surface hardness of all the samples was significantly higher after a period of 6 months irrespective of the cleansing treatment. Minor changes were observed between control, sodium hypochlorite and sodium perborate groups with time. Greater change was observed in surface hardness of acrylic-based soft denture liners as compared to silicone based soft liners for all groups, as time progressed. CONCLUSION: Silicone-based soft denture liners performed significantly better in all cleansing treatments than acrylic-based soft denture liners. PMID- 24049569 TI - Push-out bond strengths of fiber-reinforced composite posts with various resin cements according to the root level. AB - PURPOSE: The aim of this study was to determine whether the push-out bond strengths between the radicular dentin and fiber reinforced-composite (FRC) posts with various resin cements decreased or not, according to the coronal, middle or apical level of the root. MATERIALS AND METHODS: FRC POSTS WERE CEMENTED WITH ONE OF FIVE RESIN CEMENT GROUPS (RELYX UNICEM: Uni, Contax with activator & LuxaCore Dual: LuA, Contax & LuxaCore-Dual: Lu, Panavia F 2.0: PA, Super-Bond C&B: SB) into extracted human mandibular premolars. The roots were sliced into discs at the coronal, middle and apical levels. Push-out bond strength tests were performed with a universal testing machine at a crosshead speed of 0.5 mm/min, and the failure aspect was analyzed. RESULTS: There were no significant differences (P>.05) in the bond strengths of the different resin cements at the coronal level, but there were significant differences in the bond strengths at the middle and apical levels (P<.05). Only the Uni and LuA cements did not show any significant decrease in their bond strengths at all the root levels (P>.05); all other groups had a significant decrease in bond strength at the middle or apical level (P<.05). The failure aspect was dominantly cohesive at the coronal level of all resin cements (P<.05), whereas it was dominantly adhesive at the apical level. CONCLUSION: All resin cement groups showed decreases in bond strengths at the middle or apical level except LuA and Uni. PMID- 24049570 TI - Peel strength of denture liner to PMMA and polyamide: laser versus air-abrasion. AB - PURPOSE: This study investigated the effect of laser parameters and air-abrasion on the peel strength of silicon-based soft denture liner to different denture resins. MATERIALS AND METHODS: Specimens (N=180) were prepared out of three different denture base resins (Rodex, cross-linked denture base acrylic resin; Paladent, heat-cured acrylic resin; Deflex, Polyamide resin) (75 mm * 25 mm * 3 mm). A silicon-based soft denture liner (Molloplast B) was applied to the denture resins after the following conditioning methods: a) Air-abrasion (50 um), b) Er,Cr:YSGG laser (Waterlase MD Turbo, Biolase Technology) at 2 W-20 Hz, c) Er,Cr:YSGG laser at 2 W-30 Hz, d) Er,Cr:YSGG laser at 3 W-20 Hz, e) Er,Cr:YSGG laser at 3 W-30 Hz. Non-conditioned group acted as the control group. Peel test was performed in a universal testing machine. Failure modes were evaluated visually. Data were analyzed using two-way ANOVA and Tukey's test (alpha=.05). RESULTS: Denture liner tested showed increased peel strength after laser treatment with different parameters (3.9+/-0.4 - 5.58+/-0.6 MPa) compared to the control (3.64+/-0.5 - 4.58+/-0.5 MPa) and air-abraded groups (3.1+/-0.6 - 4.46+/ 0.3 MPa), but the results were not statistically significant except for Paladent, with the pretreatment of Er,Cr:YSGG laser at 3 W-20 Hz. Polyamide resin after air abrasion showed significantly lower peel strength than those of other groups (3.1+/-0.6 MPa). CONCLUSION: Heat-cured acrylic resin, PMMA, may benefit from Er,Cr:YSGG laser treatment at 3 W-20 Hz irradiation. Air-abrasion of polyamide resins should be avoided not to impair their peel bond strengths to silicon-based soft denture liners. PMID- 24049571 TI - Effect of polishing and glazing on the color and spectral distribution of monolithic zirconia. AB - PURPOSE: The aim of this study was to evaluate the effect of polishing and glazing on the color and spectral distribution of monolithic zirconia. MATERIALS AND METHODS: Forty-five monolithic zirconia specimens (16.3 mm * 16.4 mm * 2.0 mm) were fabricated and divided into 5 groups according to the number of A2 coloring liquid applications (Group I to V). Each group was divided into 3 subgroups according to the method of surface treatments (n=3): N: no treatment; P: polishing; G: glazing. Color and spectral distribution of five different areas of each specimen were measured according to CIELAB color space in the reflectance mode relative to the standard illuminant D65 on a reflection spectrophotometer. Data were analyzed using one-way ANOVA followed by Tukey's HSD test, Pearson correlation and regression analysis (alpha=.05). RESULTS: There was a significant difference in CIE L (*) between Subgroup N and P, and in CIE b (*) between Subgroup P and G in each group. Spectral reflectance generally decreased in Subgroup P and G in comparison with Subgroup N. Color differences between Subgroup P and G were within the perceptibility threshold (DeltaE (*) ab< 3.7) in most groups. Highly significant correlation was found between CIE b (*)and each subgroups as the number of coloring liquid applications increased (R (2)>0.88, P<.001). CONCLUSION: A perceptible color difference can be detected after polishing of monolithic zirconia. Polishing decreases the lightness, and glazing also decreases the lightness, but increases the yellowness of monolithic zirconia. PMID- 24049572 TI - The effect of different adhesive system applications on push-out bond strengths of glass fiber posts. AB - PURPOSE: Over the past years, the adhesion of fiber posts luted with simplified adhesive systems has been a matter of great interest. The aim of this study was to assess the post retentive potential of a self-adhesive resin cement using different adhesive systems to compare the push-out bond strengths of fiber posts. MATERIALS AND METHODS: The post spaces of 56 mandibular premolar roots were prepared and divided into 4 experimental groups and further divided into 2 subgroups according to testing time (n=7). The fiber posts (Rely X Fiber Post) were luted with a self-adhesive resin cement (RelyX Unicem) and one of the following adhesive systems: no adhesive, a total-etch adhesive resin (Single Bond), a two-step self-etch adhesive resin (Clearfil SE Bond) and a one-step self etch adhesive resin (Clearfil S3 Bond). Each root was cut horizontally, and 1.5 mm thick six root segments were prepared. Push-out tests were performed after one week or three months (0.5 mm/min). Statistical analysis were performed with three way ANOVA (alpha=.05). RESULTS: Cervical root segments showed higher bond strength values than middle segments. Adhesive application increased the bond strength. For one week group, the total-etch adhesive resin Single Bond showed higher bond strength than the self-adhesive resin cement RelyX Unicem applied without adhesive resin at middle region. For 3 months group, the two-step self etch adhesive resin Clearfil SE Bond showed the highest bond strength for both regions. Regarding the time considered, Clearfil SE Bond 3 months group showed higher bond strength values than one week group. CONCLUSION: Using the adhesive resins in combination with the self-adhesive resin cement improves the bond strengths. The bond strength values of two-step self-etch adhesive resin Clearfil SE Bond improved as time passes. PMID- 24049573 TI - Comparative study on stress distribution around internal tapered connection implants according to fit of cement- and screw-retained prostheses. AB - PURPOSE: The aim of this study was to compare the passivity of implant superstructures by assessing the strain development around the internal tapered connection implants with strain gauges. MATERIALS AND METHODS: A polyurethane resin block in which two implants were embedded served as a measurement model. Two groups of implant restorations utilized cement-retained design and internal surface of the first group was adjusted until premature contact between the restoration and the abutment completely disappeared. In the second group, only nodules detectable to the naked eye were removed. The third group employed screw retained design and specimens were generated by computer-aided design/computer aided manufacturing system (n=10). Four strain gauges were fixed on the measurement model mesially and distally to the implants. The strains developed in each strain gauge were recorded during fixation of specimens. To compare the difference among groups, repeated measures 2-factor analysis was performed at a level of significance of alpha=.05. RESULTS: The absolute strain values were measured to analyze the magnitude of strain. The mean absolute strain value ranged from 29.53 to 412.94 um/m at the different strain gauge locations. According to the result of overall comparison, the cement-retained prosthesis groups exhibited significant difference. No significant difference was detected between milled screw-retained prostheses group and cement-retained prosthesis groups. CONCLUSION: Within the limitations of the study, it was concluded that the cement-retained designs do not always exhibit lower levels of stress than screw-retained designs. The internal adjustment of a cement-retained implant restoration is essential to achieve passive fit. PMID- 24049574 TI - Effect of the shades of background substructures on the overall color of zirconia based all-ceramic crowns. AB - PURPOSE: The objective of this study was to determine the effect of the color of a background substructure on the overall color of a zirconia-based all-ceramic crown. MATERIALS AND METHODS: Twenty one posterior zirconia crowns were made for twenty subjects. Seven premolar crowns and six molar crowns were cemented onto abutments with metal post and core in the first and second group. In the third group, eight molar crowns were cemented onto abutments with a prefabricated post and composite core build-up. The color measurements of all-ceramic crowns were made before try-in, before and after cementation. A repeated measure ANOVA was used for a statistical analysis of a color change of all-ceramic crowns at alpha=.05. Twenty four zirconia specimens, with different core thicknesses (0.4-1 mm) were also prepared to obtain the contrast ratio of zirconia materials after veneering. RESULTS: L(*) , a(*) , and b(*) values of all-ceramic crowns cemented either on a metal cast post and core or on a prefabricated post did not show significant changes (P>.05). However, the slight color changes of zirconia crowns were detected and represented by DeltaE(*) ab values, ranging from 1.2 to 3.1. The contrast ratios of zirconia specimens were 0.92-0.95 after veneering. CONCLUSION: No significant differences were observed between the L(*) , a(*) , and b(*) values of zirconia crowns cemented either on a metal cast post and core or a prefabricated post and composite core. However, the color of a background substructure could affect the overall color of posterior zirconia restorations with clinically recommended core thickness according to DeltaE(*) ab values. PMID- 24049575 TI - Three-dimensional finite element analysis of implant-supported crown in fibula bone model. AB - PURPOSE: The purpose of this study was to compare stress distributions of implant supported crown placed in fibula bone model with those in intact mandible model using three-dimensional finite element analysis. MATERIALS AND METHODS: Two three dimensional finite element models were created to analyze biomechanical behaviors of implant-supported crowns placed in intact mandible and fibula model. The finite element models were generated from patient's computed tomography data. The model for grafted fibula was composed of fibula block, dental implant system, and implant-supported crown. In the mandible model, same components with identical geometries with the fibula model were used except that the mandible replaced the fibula. Vertical and oblique loadings were applied on the crowns. The highest von Mises stresses were investigated and stress distributions of the two models were analyzed. RESULTS: Overall stress distributions in the two models were similar. The highest von Mises stress values were higher in the mandible model than in the fibula model. In the individual prosthodontic components there was no prominent difference between models. The stress concentrations occurred in cortical bones in both models and the effect of bicortical anchorage could be found in the fibula model. CONCLUSION: Using finite element analysis it was shown that the implant-supported crown placed in free fibula graft might function successfully in terms of biomechanical behavior. PMID- 24049576 TI - Stress-strain distribution at bone-implant interface of two splinted overdenture systems using 3D finite element analysis. AB - PURPOSE: This study was accomplished to assess the biomechanical state of different retaining methods of bar implant-overdenture. MATERIALS AND METHODS: Two 3D finite element models were designed. The first model included implant overdenture retained by Hader-clip attachment, while the second model included two extracoronal resilient attachment (ERA) studs added distally to Hader splint bar. A non-linear frictional contact type was assumed between overdentures and mucosa to represent sliding and rotational movements among different attachment components. A 200 N was applied at the molar region unilaterally and perpendicular to the occlusal plane. Additionally, the mandible was restrained at their ramus ends. The maximum equivalent stress and strain (von Mises) were recorded and analyzed at the bone-implant interface level. RESULTS: The values of von Mises stress and strain of the first model at bone-implant interface were higher than their counterparts of the second model. Stress concentration and high value of strain were recognized surrounding implant of the unloaded side in both models. CONCLUSION: There were different patterns of stress-strain distribution at bone-implant interface between the studied attachment designs. Hader bar-clip attachment showed better biomechanical behavior than adding ERA studs distal to hader bar. PMID- 24049577 TI - Focal adhesion linker proteins expression of fibroblast related to adhesion in response to different transmucosal abutment surfaces. AB - PURPOSE: To evaluate adherence of human gingival fibroblasts (HGFs) to transmucosal abutment of dental implant with different surface conditions with time and to investigate the roles of focal adhesion linker proteins (FALPs) involved in HGFs adhesion to abutment surfaces. MATERIALS AND METHODS: Morphologies of cultured HGFs on titanium and ceramic discs with different surface were observed by scanning electron microscopy. Biocompatibility and focal adhesion were evaluated by ultrasonic wave application and cell viability assay. FALPs expression levels were assessed by RT-PCR and western blot. RESULTS: There seemed to be little difference in biocompatibility and adhesion strength of HGFs depending on the surface conditions and materials. In all experimental groups, the number of cells remaining on the disc surface after ultrasonic wave application increased more than 2 times at 3 days after seeding compared to 1-day cultured cells and this continued until 7 days of culture. FALPs expression levels, especially of vinculin and paxillin, also increased in 5-day cultured cells compared to 1-day cultured fibroblasts on the disc surface. CONCLUSION: These results might suggest that the strength of adhesion of fibroblasts to transmucosal abutment surfaces increases with time and it seemed to be related to expressions of FALPs. PMID- 24049578 TI - Assessment of demographic and clinical data related to dental implants in a group of Turkish patients treated at a university clinic. AB - PURPOSE: This retrospective study analyzed the distribution of the dental implants with regards to age and gender of the patients and type of indication for the implant therapy, as well as the location, dimension and type of the implants. MATERIALS AND METHODS: The data of demographics (age and gender), type of indication for implant therapy, anatomical location, dimensions (length and diameter) and type (bone and tissue level) of 1616 implants were recorded from patient charts between January 2000 and January 2010. Descriptive statistics were analyzed using a chi-squared test for demographic parameters, type of indication, tooth position, anatomical location, implant dimensions and type (alpha=.05). RESULTS: The patient pool comprised of 350 women and 266 men, with a mean age of 52.12 +/- 13.79 years. The difference in n% of the implants of the age groups was statistically significant between the types of indications. The difference in the position of the implants was statistically significant between the n% of the implants of all age groups. Gender did not significantly vary, except that the diameter of the implants was significantly higher for the standard diameter implants in males. The difference between the implant positions was statistically significant when considered according to indication. The relationship between implant length and anatomical location was statistically significant. CONCLUSION: The indication for dental implant use is age dependent and the type and size of the implant seems to be strongly related to the location of the implant. PMID- 24049579 TI - Minimally invasive treatment for esthetic enhancement of white spot lesion in adjacent tooth. AB - This article describes the treatment provided to a patient with the maxillary anterior teeth exhibiting severe secondary caries beneath the previous restoration and a white spot lesion on the adjacent incisor. Two implants were placed after extraction of hopeless teeth with the guided bone regeneration technique. A white spot lesion of the adjacent incisor was treated with minimally invasive treatment. This clinical report describes the multidisciplinary treatment for the white spot lesion and esthetic restoration of missing anterior teeth. PMID- 24049580 TI - The evaluation of maximum bite force in the occlusal rehabilitation of patient with Angle Class III malocclusion: a case report. AB - The case report describes the occlusal rehabilitation of a male patient with Angle Class III malocclusion and its effect on maximum bite force. The main complaints of patient were masticatory difficulty and poor esthetic. The patient's expectations from the treatment were a good esthetic and function with a less invasive and relatively promptly way. Therefore, increasing of the occlusal vertical dimension (OVD) and then restoring the maxillary and mandibular teeth was chosen by the patient among the treatment options. At the beginning of treatment maximum bite force of patient was measured. Then an occlusal splint was provided to evaluate the adaptation of the patient to the altered OVD. Full mouth rehabilitation with metal ceramic restorations was made. After the completion of full mouth restoration, bite force measurement was repeated and patient exhibited increased maximum bite force. Full mouth restorative treatment in a patient with Class III malocclusion could be an effective treatment approach to resolve esthetic concern and to improve masticatory function related to maximum bite force. PMID- 24049581 TI - Knee osteoarthritis diagnosis, treatment and associated factors of progression: part II. AB - Diagnosis of knee osteoarthritis can be confirmed based on clinical and/or radiological features. The potential of a progressive disease can be prevented or decreased by earlier recognition and correction of associated factors. Obesity and alignment especially varus malalignment are recognized factors of a progressive disease. Both nonpharmalogical as well as pharmacological modalities of treatment are useful in managing the symptoms of knee osteoarthritis. Surgery should be considered only in patients who do not respond to medical therapy. The prevalence and risk factors of knee osteoarthritis have been described in the first part of this review. In this issue, the diagnosis progressive factors and management of knee osteoarthritis are discussed. PMID- 24049582 TI - Seroprevalence of anti-Hp and anti-cagA antibodies among healthy persons in Golestan province, northeast of Iran (2010). AB - Background : The major cause of peptic ulcer disease is helicobacter pylori (Hp), and it is also implicated in the pathogenesis of adenocarcinoma of the distal stomach and gastric lymphoma. The incidence of peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma are more common in people infected of cagA positive strains of Hp. The aim of this study was to determine the prevalence of the anti-Hp and anti-cagA antibodies among healthy persons in Golestan province North of Iran. Methods : The blood samples of 1028 healthy people were collected all over Golestan province by cluster sampling. A demographic questionnaire was completed and body mass index (BMI) was calculated for each case. Hp-IgG (Pishtaz teb Co. Iran) and anti- cagA (DIA.PRO Italy) titer were evaluated by Elisa method. Data were collected and analyzed. Results : Six hundred-eighty three individuals (66.4%) were positive for Hp and 395 (57.8%) of them were cagA positive. Hp positive cases were (66.3%) and (66.6%) in male and female, respectively. Prevalence of cagA was 56.3% and 58.9%, respectively. The most seropositivity of Helicobacter Pylori (75.4%) was in 55-64 years old (p<0.001). Prevalence of cagA (63.4%) was more in age between 15-24 years. CONCLUSION: Prevalence of anti-Hp antibody and strains of cagA seropositive in healthy persons of this province of Iran were relatively high. Preventive protocol for reducing of the infection is recommended. PMID- 24049583 TI - Circulating basic fibroblast growth factor in serum of gastric ulcers patient as a biomarker of wound severity. AB - Background : Basic fibroblast growth factor (bFGF) is a glycoprotein with stimulating ability of angiogenesis. In addition, bFGF plays an important role in wound healing process in some tissues for example gastrointestinal tract, but its ability for discrimination of various stages of wound severity in these diseases was not reported. Therefore, we aimed to determine the bFGF levels in gastric ulcer patients compared with healthy controls as a biomarker for staging the severity of wound. METHODS: The study group consisted of 33 patients with gastric ulcer and 27 healthy controls. The diagnosis of patients was based on standard clinical, endoscopic, and histological criteria. Serum levels of bFGF were analyzed by an Elisa kit. Results : According to the histological findings, 19 (57.6%) patients were in moderate stage of ulcer and 14 (42.4%) were in the severe stage of gastric ulcer. The mean bFGF serum levels in patients group (7.8+/-1.3pg/ml) were lower than the healthy group (8.2+/-1.4pg/ml) in crude data, but in statistical analysis the differences were not significant (p=0.082). The mean bFGF serum levels in patients with severe stage of gastric ulcer were greater than the patients with moderate gastric ulcer (8.4+/-1.3 vs. 7.4+/-1.2 pg) and the differences were statistically significant (p<0.05). CONCLUSION: The differences in serum bFGF levels in patients with severe stage of gastric ulcer vs. moderate gastric ulcer was significant. Therefore, serum bFGF level measurements can be used as a useful clinical tool for discrimination of patients with severe stage of gastric ulcer vs. moderate gastric ulcer, when endoscopic and histological examination are not possible to perform. PMID- 24049584 TI - Association between helicobacter pylori infection and serum iron profile. AB - BACKGROUND: It is clear that Helicobacter pylori (H. pylori) is a spiral bacterium that infects human and causes gastritis and peptic ulcer. The aim of this study was to determine the relationship between H .pylori infection and the iron status of the body. METHODS: This study was conducted in Shahid Beheshti Hospital of Babol University of Medical Sciences, Babol, Iran from August 2007 to July 2008. The study group consisted of 35 patients with H. pylori and 35 matched healthy subjects as the control group. The members of both groups were enrolled in the study voluntarily. Serum iron and total iron- binding capacity were measured by Darman-kav Standard kit. Ferritin was measured by Padtan-e-Elm Standard kit. The Collected data were analyzed by SPSS version 16. p-value of <0.05 was considered significant. RESULTS: The serum iron and total iron-binding capacity in H. pylori positive group were lower than in the control group (108.67+/-31.26 vs. 110.92+/-28.45 ug/dL, p=0.578) and (327.88+/-81.39 vs. 342.51+/-79.45 ug/dL, p=0.153) respectively. The mean of ferritin was significantly lower in H.pylori positive group (210.51+/-132.01 ng/ml, p=0.047) than H.pylori negative group (265.03+/-170.79 ng/mL, p=0.047). CONCLUSION: The results of the present study show that serum iron and total iron binding capacity in H.pylori infected group was lower than the control group. H.pylori may impair iron metabolism. It is possible that H.pylori may both directly compete with the host for available iron by impairing its uptake. PMID- 24049585 TI - Comparison of parenteral promethazine versus midazolam effect as a preoperative medication on postoperative nausea and vomiting after appendectomy. AB - BACKGROUND: Postoperative nausea and vomiting is a high unpleasant symptom in surgical procedures. This study compares the effectiveness of midazolam with promethazine as multipurpose drug in postoperative nausea and vomiting as a preoperative and anesthetic medication after appendectomy. Methods : This randomized, double - blind clinical trial study was performed in patients who underwent appendectomy. These patients randomly received either placebo or midazolam or promethazine 5 minutes before appendectomy. All episodes of vomiting and nausea within 24 hours after surgery were recorded. The study population (N=75) comprised 3 comparable subgroups (N=25 in each group). A standard general anesthetic technique and postoperative analgesia were used. The data were collected and analyzed. RESULTS: Vomiting and nausea occurred in 19.20%, 0% and 81.80% of the patients in the midazolam, promethazine and placebo groups, respectively. The frequency of postoperative nausea and vomiting was as follows: the first 6 hours after surgery 0%, 0% and 50%, during the second 6 hours after surgery 19%, 0% and 19%, during the third 6 hours after surgery 0%, 0% and 7%, during the fourth 6 hours after surgery 0%, 0% and 4% in the midazolam, promethazine and placebo groups, respectively. There were no significant differences between promethazine with midazolam in reduction of postoperative nausea and vomiting. CONCLUSION: Our study suggests that midazolam can be used as multipurpose drugs in postoperative nausea and vomiting as a preoperative medication after appendectomy and treatment using midazolam for anti-emetic, prophylaxis provide a similar effect compared to promethazine in the present study. PMID- 24049586 TI - Bleomycin in the treatment of 50 cases with malignant pleural effusion. AB - BACKGROUND: Patients with symptomatic malignant pleural effusion (MPE) may gain profit from pleurodesis for relief of dyspnea and in preventing the accumulation of fluid or air in the pleural space. Pleurodesis methods are palliative and regard the patient's symptoms and underlying disease condition that are different. The purpose of this study was to assess the efficacy of bleomycin in the treatment of malignant pleural effusion. METHODS: From March 2003 to August 2009, 50 cases of malignant pleural effusion referred for chemical pleurodesis. Malignant pleural effusion was diagnosed by cytotogical examination of pleural fluid after thoracosynthesis. Pleurodesis was done by pleural fluid instillation of bleomycin. The severity of effusion with response to treatment was compared. RESULTS: Nineteen (38%) cases were males and 31 (62%) were females. The mean age of these patients was 60.3+/-15.8 years (range=31 to 85 years). The majority of patients had breast cancer and lung adenocarcinoma. The mean volume of pleural fluid drained was 2282+/-848.69(cc) (range 800-4500 (cc)). Pleural effusion was mild in 2 (4%) patients, moderate in 25 (50%) and severe in 23 (46%). There was no statistically significant difference between the response to treatment and the amount of effusion (p=.087). Complete response was seen in 33 (66%) patients, partial response in 11 (22%) and failure to treatment in 6 (12%). There was no relationship between the response to treatment and tumor type. There was not any complication in 33 (66%) patients, but fever was seen in 2 (4%) and chest pain in 7 (14%) and both of them in 8 (16%). CONCLUSION: The results show that pleurodesis with bleomycin has improved the symptoms of 88 percent of patients without causing any significant complications. Although pleurodesis does not have any effect on patients' survival, it has positive impact on their lives continuously by enhancing the quality of life. PMID- 24049587 TI - Comparison of the effect of fish oil and ibuprofen on treatment of severe pain in primary dysmenorrhea. AB - Background : Primary dysmenorrhea is common among young girls and child-bearing women. The purpose of this study was to compare the efficacy of fish oil and Ibuprofen on the treatment of primary dysmenorrhea. METHODS: This clinical trial study was done on students of Babol University of Medical Sciences in 2010. One hundred- twenty students who had moderate and severe dysmenorrhea were randomly divided in two groups. The first group (0 girls) received 1000 mg/day fish oil capsule in all her cycle days and the second group received mg ibuprofen when their pain started (duration of this study was months). Student t-test, Mann Whitney and Freidman tests were used when appropriate. This clinical trial was registered in the Iranian Registry of clinical Trials (www.IRCT.Ir) (IR21101133004N4). RESULTS: There was a significant difference between the intensity of pain before and after treatment by ibuprofen (p=1) and fish oil (p=1). Furthermore, the reduction of pain in fish oil recipient was higher than the IBV prefer group (p=0001). CONCLUSION: The results show that the efficacy of fish oil is better than ibuprofen on treatment of severe pain in primary dysmenorrhea. PMID- 24049588 TI - Takayasu arteritis in a young female. AB - BACKGROUND: Takayasu arteritis is a granulomatous vasculitis which mainly involves the large arterial vessels. The disease is rare and it is more common in females aged between 15-30 years old. In this paper, we report a case of takayasu arteritis in Babol, north of Iran. CASE PRESENTATION: A 22 - year old female was admitted to the Department of Infectious Diseases of Rouhani Teaching Hospital due to anemia, high erythrocyte sedimentation rate (ESR), low grade fever and weight loss in the early summer of 2011. Her problems started four years ago and was hospitalized in another hospital and after full investigation, no diagnosis was found. Physical exam showed a vascular problem, then MRI angiography was done and showed an involvement of right carotid, abdominal aorta and right iliac arteries and the diagnosis of Takayasu Arthritis was confirmed. Prednisolone was administered, her fever subsided and ESR, CRP and hemoglobin were normalized. CONCLUSION: Takayasu arteritis should be considered in the differential diagnosis of patient with protracted low grade fever, anemia and dramatically elevated ESR in young female in order to prevent late complications of the disease. PMID- 24049589 TI - A successful management of aluminum phosphide intoxication. AB - BACKGROUND: Aluminum Phosphide or rice tablet is one of the most common pesticides which leads to accidental or intentional acute intoxication and finally death. In this paper, we describe a successful management of intoxication with rice tablet in a young girl. CASE PRESENTATION: A 14-year-old girl was admitted due to consumption of rice tablet. Gastric washing with two vials of sodium bicarbonate and discharge suction was done. In the first 24 hours, the patient underwent recurrent hydration, dopamine infusion with sodium bicarbonate, calcium, magnesium and amiodarone. On the second day of admission, the patient was transferred to intensive care unit (ICU) and five days later, she was discharged without liver or renal complications. CONCLUSION: Short interval between consumption of this tablet and start of the treatment and on time rescue to the patient can be some of the important factors to prevent early death in intoxication with this tablet. PMID- 24049590 TI - Mental health literacy in iran: an urgent need for a remedy. PMID- 24049591 TI - Effect of 50% hydro-ethanolic leaf extracts of ruellia tuberosa L. And dipteracanthus patulus (jacq.) on lipid profile in alloxan induced diabetic rats. AB - BACKGROUND: The study was undertaken to investigate the effect of 50% hydro ethanolic leaf extracts of Ruellia tuberosa L. and Dipteracanthus patulus (Jacq.) on lipid profile in alloxan induced diabetic rats. METHOD: In lipid profile the parameters studied were serum total cholesterol, phospholipids, triglycerides, HDL-c, LDL-c and VLDL-c level. Extracts were orally administered daily for 30 days at a dosage of 250 and 500 mg/kg bodyweight to alloxan induced diabetic rats. RESULTS: The levels of phospholipids, triglycerides, LDL-c and VLDL-c were significantly (P < 0.05) reduced. The HDL-c level was found to be increased in the treatment groups. Total cholesterol level was found to be significantly (P < 0.05) decreased at 500 mg/kg bodyweight of both the plant extracts treated groups. CONCLUSION: The results further suggests that the effect of plant extract treated groups was found to be lower in reducing the lipid levels in serum when compared to the drug (Glibenclamide 600 MUg/kg body weight) treated group. PMID- 24049592 TI - The Direct Medical Costs of Breast Cancer in Iran: Analyzing the Patient's Level Data from a Cancer Specific Hospital in Isfahan. AB - BACKGROUND: Breast cancer is one of the main causes of mortality and morbidity world-wide. The estimation of the direct medical costs of breast cancer can help payers of the cost to understand the burden of breast cancer on their limited financial resources as well as the society. METHODS: We used a cross-sectional study to calculate the direct medical costs of breast cancer among women in Isfahan, Iran. The medical records of all patients which were registered in Seyed Al-Shohada Hospital between March 2005 and March 2010 were reviewed. The relevant data from patients' profiles extracted. The direct medical costs of received services were calculated with both public and private tariffs. RESULTS: The total numbers of 467 patients in various disease stages were included into the study. The average age of patients was 49 years. The average direct cost per patient per month in stages I to IV were 222.17, 224.61, 316.51 and 828.52 US$, respectively. The surgery cost was the main cost driver for stages I and II with private tariffs. However for stages III and IV, the medication cost was the main cost component for managing breast cancer. CONCLUSIONS: The direct economic cost of breast cancer in Iran is very high; nonetheless, as the age of breast cancer in Iran is nearly 10 years lower than Western countries, the burden of the disease in Iran is expected to be significantly high. Medication therapy is the main cost component of the breast cancer. PMID- 24049593 TI - A report of high triglyceride level in cord blood of Iranian newborns. AB - BACKGROUND: Since cord blood triglyceride level have been reported very different in recent articles, the purpose of this study is determination of triglyceride level in cord blood of Iranian newborns and compare it with other reports. METHODS: In this study, cord blood of 174 healthy term newborn infants (97 girls, 77 boys) born from healthy mothers have been used. Triglyceride level has been measured by calorie metric method Statistical analysis was performed by independent t test, Mann-Whitney regression test and Spearman correlation coefficient method using SPSS 16 .0 software (SPSS, USA). RESULTS: The mean of cord blood triglyceride was 1.37 +/- 4.81 mg /dl and there was no statistical difference between two sexes. There was not exist linear relationship between triglyceride and weight, height, head circumference, body mass index and sex of the babies. In 8.6% of our new born infants, triglyceride levels were more than 95th percentile of triglyceride level reported in Iranian population. In 33.9% of our cases, triglyceride levels were more than 95(th) percentile of triglyceride level reported in the Nelson text book of Pediatrics. In this study, the 95th percentile of triglyceride level in cord blood was 132.5 mg /dl. CONCLUSION: The mean and 95(th) percentiles of triglyceride levels in cord blood of our newborn infants were higher than other reports. We recommend that larger studies should be conducted in this area to establish preventive ways for increasing epidemic of the metabolic syndrome. PMID- 24049594 TI - Analysis of the thermal comfort and impact properties of the neoprene-spacer fabric structure for preventing the joint damages. AB - BACKGROUND: Frequent moves at the joint, plus external factors such as trauma, aging, and etc., are all reasons for joint damages. In order to protect and care of joints, the orthopedic textiles are used. To protect the joints, these textiles keep muscles warm to prevent shock. To produce orthopedic textiles, Neoprene foams have been traditionally used. These foams are flexible and resist impact, but are not comfortable enough and might cause problems for the consumer. This study introduces a new structure consisting of perforated Neoprene foam attached to the spacer fabric and also compares the properties of thermal and moisture comfort and impact properties of this structure in comparison with Neoprene foam. METHODS: In order to measure the factors related to the samples lateral pressure behavior, a tensile tester was used. A uniform pressure is applied to the samples and a force - displacement curve is obtained. The test continues until the maximum compression force is reached to 50 N. The area under the curve is much greater; more energy is absorbed during the impact. In order to investigate the dynamic heat and moisture transfer of fabrics, an experimental apparatus was developed. This device made the simulation of sweating of human body possible and consisted of a controlled environmental chamber, sweating guarded hot plate, and data acquisition system. RESULTS: The findings show that the Neoprene-spacer fabric structure represents higher toughness values compared to other samples (P <= 0.001). Neoprene-spacer fabric structure (A3) has higher rate of moisture transport than conventional Neoprene foam; because of undesirable comfort characteristics in Neoprene. CONCLUSIONS: Results of the tests indicate full advantage of the new structure compared with the Neoprene foam for use in orthopedic textiles (P <= 0.001). PMID- 24049595 TI - Residential segregation of socioeconomic variables and health indices in iran. AB - BACKGROUND: Measures of segregation are essential tools for evaluation of social equality. They describe complex structural patterns by single quantities and allow the comparison of inequalities over time or between residential places. In many countries, patterns of residential segregation are well described (e.g., South Africa, Great Britain, United States of America). In this study, for the first time in Iran, we measured residential segregation for some socioeconomic and health variables and described their pair wise correlation. METHODS: We measured evenness dimension of segregation by generalized dissimilarity segregation index and information theory index and its ordinal equivalent for some determinants of socioeconomic status and health variables using data of last national census in Iran. Segregation indices were computed for 31 socioeconomic variables and four health indices. RESULTS: All the provinces were in the category of low segregation for individual and family disability and death of at least one offspring of mother, but for infant mortality half of the provinces were moderately or highly segregated. For some of socioeconomic variables, many provinces were in the category of moderate, high, or extreme segregation. There was significant correlation between segregation of heath indices and some socioeconomic variables. CONCLUSIONS: Correlation of segregation of determinants of socioeconomic status with segregation of health indices is an indicator of existence of hot zones of health problems across some provinces. Further studies using multilevel modeling and individual data in health outcomes at individual level and segregation measures at appropriate geographic levels are required to confirm these relations. PMID- 24049596 TI - Does Quercetin Improve Cardiovascular Risk factors and Inflammatory Biomarkers in Women with Type 2 Diabetes: A Double-blind Randomized Controlled Clinical Trial. AB - BACKGROUND: Quercetin has been distributed in a wide range of foods, but some of its known effects in vitro, are not proven in human studies. Therefore, the aim of this study was evaluation of the effects of quercetin intake on cardiovascular risk factors and inflammatory biomarkers in women with type 2 diabetes. METHODS: This double-blind randomized clinical trial was carried out on 72 women for 10 weeks. Subjects were assigned to quercetin and placebo groups using a permutated block randomization of size two. Quercetin was given to participants as a 500 mg capsule daily. Biochemical variables were measured at baseline and at the end of the study, and changes were compared using appropriate statistical methods. RESULTS: Compared with placebo, quercetin intake decreased systolic blood pressure significantly (-8.8 +/- 9.3 vs. -3.5 +/- 11.7, P = 0.04). Although changes in diastolic blood pressure between the groups was not significant (P = 0.19), high-density lipoprotein cholesterol (HDL-C) was significantly decreased in both groups while changes in total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and ratio of TG/HDL-C and LDL-C/HDL-C were not significant between and within groups. Quercetin supplementation significantly reduced the serum concentration of tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) (P = 0.01 and P < 0.0001, respectively); however, the mean changes in serum levels of IL-6, TNF-alpha, and high-sensitivity C reactive protein were not significant between the groups. CONCLUSIONS: Quercetin supplementation reduced systolic blood pressure significantly but had no effect on other cardiovascular risk factors and inflammatory biomarkers. Considering the biological effects of quercetin in vitro, we need more studies with a stronger design and sample size with different doses of quercetin. PMID- 24049597 TI - Waist Circumference and Waist-to-Height Ratio Distributions in Polish and German Schoolchildren: Comparative Analysis. AB - BACKGROUND: To analyze differences in the distributions of waist circumference (WC) and waist-to-height ratio (WHtR) between Polish (PL) and German (GE) children and adolescents. METHODS: Two samples of children and adolescents aged 7 18 y: From PL (n = 11,326) GE (n = 8,218) participated. The two WC cut-off points (WC1 as central fat distribution and WC2 as central obesity) corresponding at age 18 to the adult criteria were determined. Furthermore, the mean WC cut-off points (WC1m, WC2m) for boys and girls aged 14-18 from both countries were evaluated. For the WHtR, values over 0.5 were used as a definition of central fat distribution. The effect of different WC and WHtR criteria on the prevalence of abdominal obesity in both study groups was evaluated. RESULTS: The mean and percentile values of WC and WHtR were generally higher in all German children as compared to their peers from Poland. When WC1m is used, the mean (95% CI) prevalence of central fat distribution in the 14-18 y Polish groups was lower (P < 0.05) than those from Germany (boys: 4.4% (3.6-5.2) vs. 8.9% (7.3-10.5); girls: 10.7% (9.0-12.3) vs. 26.4% (23.2-29.6)), whereas, using the WHtR > 0.5, the results were similar for boys - 6.7% (5.9-7.5) vs. 8.5% (8.1-8.9); they were significantly (P < 0.05) lower for Polish and German girls: 5.3% (5.0-5.6) vs. 12.7% (9.7-16.4). The prevalence of central obesity using WC2m as a criterion in the Polish vs. German groups was as follows: (boys - 1.1% (0.8-1.4) vs. 3.1% (2.2 4.0), P < 0.05; girls - 3.1% (2.5-3.7) vs. 10.2% (8.4-12.0), P < 0.05). CONCLUSIONS: The results highlight the greater central obesity associated with the German children, both in terms of WC and WHtR, in comparison to their peers from Poland. The prevalence of AO is significantly associated with the criteria used. The results demonstrate the need for the development of international WC references for pediatric subjects. PMID- 24049598 TI - Group education and nurse-telephone follow-up effects on blood glucose control and adherence to treatment in type 2 diabetes patients. AB - BACKGROUND: Training and continuous dynamic communication between patients and health professionals in chronic diseases like diabetes, is important. The aim of this study is to evaluate the effects of diabetes self-care group education and nurse- telephone follow-up on glycemic control and compliance with treatment orders in patients with type 2 diabetes attending to diabetes clinic in khomein. METHODS: In this clinical trial, 62 patients with type 2 diabetes who attending to the diabetes clinic selected and were randomly assigned to experiment and control groups. Self-care group education was applied for case group (n = 31) and they were followed up using telephone calls for 12 weeks by a nurse. The control group (n = 31) received the conventional management. Demographic characteristics, compliance with treatment recommendations (diet, drug use, exercise) and blood glucose control indices were recorded before and after interventions. Data were analyzed by SPSS software version 16 using independent t-test, paired t-test, Chi square test, non-parametric tests, mixed model (ANOVA + repeated measure) and ANCOVA. RESULTS: The mean age of intervention and control groups was 50.9 +/- 7.3 and 55.1 +/- 10.1 years, respectively. Blood glucose indices (FBS, 2 hpp BS, Hb A1C) were improved in both case and control group after intervention but it was only statistically significant in case group P > 0.0001. During study, percentage of patients with very good compliance in control group decrease from 12.5% to zero (0%), whereas in experiment group these amounts increase from 6.5% to 90.3% P > 0.0001. CONCLUSIONS: According to the results of the current study self-care group education and 12 weeks follow-up by a nurse using telephone causes significant improvement in metabolic parameters and adherence to treatment recommendations in diabetic patients. PMID- 24049599 TI - Occupational stress among male employees of esfahan steel company, iran: prevalence and associated factors. AB - BACKGROUND: Lack of data on occupational stress among Iranian industrial employees persuaded us to design and conduct this study to evaluate the prevalence and associated parameters of occupational stress among male employees of the Esfahan Steel Company (ESCO), one of the biggest industrial units in Iran. METHODS: In this cross-sectional study, 400 male employees were sampled from the operational divisions of the company. Socio-demographic data and stress-related variables were entered into a logistic regression to determine significant associated factors of occupational stress among the participants. RESULTS: From all samples, 53% were found as stressful. A monthly salary of less than $600 (OR = 1.88, 95% confidence interval [CI] = 1.21-2.94), family-related problems (OR = 2.75, 95% CI = 1.22-6.21), work environment (OR = 3.09, 95% CI = 1.78-5.33) and having a second job (OR = 2.68, 95% CI = 1.78-6.78) were significantly associated with the outcome. CONCLUSIONS: Attention to some variables, especially economic problems and the work environment of employees, might play a protective role against the prevalence of occupational stress, not only among the employees of ESCO but also among all industrial employees in Iran. PMID- 24049600 TI - Application of WHOQOL-BREF in Measuring Quality of Life in Health-Care Staff. AB - BACKGROUND: The objective of this study was to evaluate the quality of life of Neyshabur health-care staff and some factors associated with it with use of WHOQOL-BREF scale. METHODS: This cross-sectional study was conducted on 522 staff of Neyshabur health-care centers from May to July 2011. Cronbach's alpha coefficient was applied to examine the internal consistency of WHOQOL-BREF scale; Pearson's correlation coefficient was used to determine the level of agreement between different domains of WHOQOL-BREF. Paired t-test was used to compare difference between score means of different domains. T-independent test was performed for group analysis and Multiple Linear Regression was used to control confounding effects. RESULTS: In this study, a good internal consistency (alpha = 0.925) for WHOQOL-BREF and its four domains was observed. The highest and the lowest mean scores of WHOQOL-BREF domains was found for physical health domain (Mean = 15.26) and environmental health domain (Mean = 13.09) respectively. Backward multiple linear regression revealed that existence chronic disease in staff was significantly associated with four domains of WHOQOL-BREF, education years was associated with two domains (Psychological and Environmental) and sex was associated with psychological domain (P < 0.05). CONCLUSIONS: The findings from this study confirm that the WHOQOL-BREF questionnaire is a reliable instrument to measure quality of life in health-care staff. From the data, it appears that Neyshabur health-care staff has WHOQOL-BREF scores that might be considered to indicate a relatively moderate quality of life. PMID- 24049601 TI - Dexamethasone for prevention of postoperative shivering: a randomized double blind comparison with pethidine. AB - BACKGROUND: Postoperative shivering is very common and followed by many problems such as increasing oxygen consumption, blood pressure, intracranial and intraocular pressure, and postoperative pain. Therefore, prevention of shivering is important, especially in elderly and ischemic heart disease patients. The goal of this study was to compare the effect of pethidine (meperidine), dexamethasone, and placebo on prevention of shivering. METHODS: This double-blind clinical trial study was carried out on 120 patients who were candidates for surgery under general anesthesia. The patients were randomly divided into three groups. Induction and maintenance of anesthesia for all patients were similar. Temperature of patients was measured every 5 min interval. After induction, saline 0.9%, dexamethasone and pethidine were injected to groups a, b, and c, respectively. In recovery, patients were controlled for visible shivering. All data were statistically analyzed by analysis of variance (ANOVA) and Chi-square tests. RESULTS: There were no significant differences among three mentioned groups regarding gender, age, duration of surgery and anesthesia, extubation time, duration of recovery, and basic clinical characteristics. Nineteen cases (47.5%) of placebo group had postoperative shivering, whereas in dexamethasone group only four cases (10%) had shivering and the difference between the two groups was significant. Also in pethidine group, 15 cases (37.5%) had shivering and the difference with placebo group was significant (P value = 0.001). CONCLUSION: The present study showed that pethidine and dexamethasone are effective drugs for prevention of postoperative shivering in elective surgery and the effect of dexamethasone in preventing the postoperative shivering is better than pethidine. PMID- 24049602 TI - Outline of changes in cortisol and melatonin circadian rhythms in the security guards of shiraz university of medical sciences. AB - BACKGROUND: According to the literature, a large number of people working in industries and service providing personnel, such as firefighters, physicians, and nurses are shift workers. The spread of shift working in industrial societies and the incidence of the problems resulting from shift working have caused the researchers to conduct studies on this issue. The present study also aimed to investigate melatonin and cortisol circadian rhythms in the security guards of Shiraz University of Medical Sciences, Shiraz, Iran. METHODS: The present study was conducted on 20 security guards of Shiraz University of Medical Sciences. In order to collect the study data, blood samples were taken from the study subjects in different times of the day (1, 4, 7, 10, 13, 16, 19, and 22) and cortisol and melatonin levels were determined using the radioimmunoassay and enzyme immunoassay techniques, respectively. RESULTS: The results showed that as the intensity of light increased at night, the plasma cortisol level increased, as well. Besides, no statistically significant difference was found between the plasma cortisol levels in natural light and 4500-lux light. On the other hand, a significant difference was observed between the plasma cortisol levels in natural light and 9000-lux light as well as 4500- and 9000-lux lights. The study findings also showed that as the intensity of light increased at night, the plasma melatonin level decreased. In addition, a statistically significant difference was found between the plasma melatonin levels in natural light and 4500-lux light. Nevertheless, no significant difference was observed between the plasma melatonin levels in the natural light and 9000-lux light as well as 4500- and 9000-lux lights. CONCLUSIONS: The present study aimed to investigate the subsequences of shift working in the security guards of Shiraz University of Medical Sciences and showed that occupational exposure to bright light could affect some biological markers, such as melatonin and cortisol secretion. PMID- 24049603 TI - Demographic and socioeconomic differences in fruit and vegetables consumption, 2007-2009: a province-level study in iran. AB - BACKGROUND: High daily intake of fruit and vegetables promotes population health and is inversely associated with morbidity and mortality. Demographic and socioeconomic characteristics are among main predictors of fruit and vegetables consumption. The current study aimed to evaluate these associations using province-level data in Iran during the years 2007-2009. METHODS: Data on the mean number of fruit and vegetables consumption per day in age and sex stratum at the province level from three consecutive stepwise non-communicable diseases risk factors surveys were obtained. Data about provinces' socioeconomic status (SES) were obtained from the Statistical Centre of Iran and published reports. One-way repeated measures ANOVA and random effect linear regression models were applied for non-stratified and stratified analyses, respectively. RESULTS: There were substantial variations in the fruit and vegetables consumption across the country. Consumption of vegetables was higher than fruit over the study period. There were no statistically significant differences in fruit (P = 0.52) and vegetables (P = 0.14) intake among men and women. Older age was associated with lower consumption of fruit. People in the provinces with better SES consumed higher amounts of combined fruit and vegetables and this association was more profound among females. CONCLUSIONS: The results suggest that policies and interventions to improve the intake of fruit and vegetables in the country may be significantly beneficial, especially for older people and women in low socioeconomic groups. PMID- 24049604 TI - Reactive arthritis induced by bacterial vaginosis: prevention with an effective treatment. AB - We report a 42-year-old woman with reactive arthritis induced by bacterial vaginosis who presented with oligoarthritis with an additive form, arthralgia, and enthesitis. She hasn't had a history of diarrhea or dysuria or vaginal secretion, or sexually transmitted infections (STIs). The laboratory tests were normal except for a high erythrocyte sedimentation rate (ESR). Her pelvic examination revealed homogeneous white grey and malodorous vaginal discharge on the vaginal wall and Pap smear and Gram-stained smear of vaginal swab was consistent with bacterial vaginosis. She responded to metronidazole therapy and her six-month follow up hasn't shown recurrence of arthritis. As reactive arthritis (ReA) is a paradigm of a rheumatic disease in which the initiating infectious cause is known, so early use of antimicrobial drugs may prevent the development of musculoskeletal symptoms which are triggered by infections. PMID- 24049605 TI - A rare clinicopathological presentation of the breast carcinoma; implications and outcome. AB - In females, the most common cancer is breast carcinoma in which squamous cell carcinoma (SCC) is a rare type of malignancy. Histologically, infiltrating ductal carcinoma is the most common type and lobular, mucinous, and medullary types have lower incidence. Pure SCC of the breast can originate from the skin, nipple, or epithelium of a deep-seated dermoid cyst or squamous metaplasia on chronic inflammation background. We are reporting a rare case of primary SCC of the breast in a 45-year-old female. In follow-up of 8 months, patient is doing well. We discussed our approach for treatment with review of the literature. We have treated this patient successfully with surgical and adjuvant chemotherapy. PMID- 24049606 TI - Does the health of individuals have a mathematical code? AB - The definition of health of individuals is well described by the World Health Organization (WHO) and other International Health Organizations. Many studies have also been carried out in order to survey the health conditions in different countries based on this definition, therefore, the health condition of every country analyzed by the WHO. In this hypothesis, I would like to explain "whether the health of individuals has a mathematical code or not? If so, the discovery is on the way to examine each individual based on a health profile as well as every nation in the world to find out, what must be carried out on an individual, national, and international level to increase the health rank? The aim of this hypothesis is to bring to your attention and all of the WHO directors and specialist to ask" whether the health of individuals has a mathematical code or not?" If so, the new view must be considered in regard with the health of the world population, which will be discussed in this hypothesis. PMID- 24049607 TI - Is Being a Health-care Worker a Risk Factor for Women's Reproductive System? AB - BACKGROUND: Occupational exposures to workplace hazards in health-care workers can affect on their health including the reproductive system. Some exposures cause reproductive system disorders. Objective of this study was to compare reproductive system disorders between hospital personnel who work in clinical and administrative setting. METHODS: This is a historical cohort study on clinical and administrative workers of hospitals. The study tool was flexible interview and questionnaire. Pregnant personnel had been followed until the end of pregnancy. Frequency of reproductive disorders was compared between two groups. Data were analyzed with SPSS 16, t-test, and chi(2) were calculated considering P < 0.05 as significant level. Odds ratio had been calculated with a confidence interval 95%. RESULTS: Frequency of menses disorders in clinical personnel especially, personnel of emergency departments were the highest and showed a significant difference between two groups (P = 0.042). The odds ratio for menses disorders in clinical personnel was 1.362 (1.008-1.84) and in administrative personnel was 0.653 (0.368-1.159). CONCLUSIONS: Clinical personnel are at higher risk for menses disorders compared with administrative personnel. Assessing the health of these personnel may help to improve future generation's health. PMID- 24049608 TI - Do you intend to use results of occupational medicine surveillances as database of your research? Be careful; it may be achilles heel of your study. PMID- 24049609 TI - Integration of defensins: a promising clinical tool. PMID- 24049610 TI - Prevention of hepatitis a virus infection, need to vaccinate or not? PMID- 24049611 TI - Potential health impacts of hard water. AB - In the past five decades or so evidence has been accumulating about an environmental factor, which appears to be influencing mortality, in particular, cardiovascular mortality, and this is the hardness of the drinking water. In addition, several epidemiological investigations have demonstrated the relation between risk for cardiovascular disease, growth retardation, reproductive failure, and other health problems and hardness of drinking water or its content of magnesium and calcium. In addition, the acidity of the water influences the reabsorption of calcium and magnesium in the renal tubule. Not only, calcium and magnesium, but other constituents also affect different health aspects. Thus, the present review attempts to explore the health effects of hard water and its constituents. PMID- 24049612 TI - Education achievements and goiter size ten years after iodized salt consuming. AB - BACKGROUND: Approximately 2.2 billion (2200 million) of the world population are living in the area with Iodine deficiency (ID), most of them in the developing countries. In IRAN about 2 million are exposed to Iodine deficiency. Most of the complications of ID are not curable, especially brain damage. On the other hand, adding iodine to daily salt is a suitable program for decreasing iodine deficiency. This has been the main aim of IDD National committee since 1986. This study is a before-after preventive trial, and was conducted to determine the effect of iodized salt in preventing the disorders of Iodine deficiency. METHODS: This study was a preventive field trial in 2 stages before and after prevention. Since 1995, Iodized salt has been distributed in Tabas in Yazd province. Sample of 2,150 students aged 6-18 years were chosen by stratified cluster random sampling method from 24 schools, 12 schools from rural and 12 from urban areas. Goiter frequency and educational status were determined using WHO criteria and mean scored, respectively. RESULTS: Prevalence of goiter has decreased from 34 to 25 percent after 10 years (P < 0.001). The prevalence in urban areas has decreased from 35.8 to 23.5 percent and in rural from 35.6 to 28.5 percent (P = 0.02). Prevalence of Goiter has changed from 32.8 to 20 percent and from 39.5 to 31.5 in boys and girls, respectively (P < 0.001). There was a statistically significant relation between educational status and goiter frequency before and after prevention (P = 0.01). There was also a statistically significant relation between educational status in 2 stages, before and after intervention (P < 0.001). CONCLUSIONS: ALTHOUGH, THERE ARE SOME CONFOUNDING VARIABLES, SUCH AS: educational resources development, improved educational methods, and enhanced family emphasis on extracurricular education, increased frequency of students in higher education after intervention shows the iodine effects on mental function. PMID- 24049613 TI - Comparison between the effects of continuous and intermittent aerobic exercise on weight loss and body fat percentage in overweight and obese women: a randomized controlled trial. AB - BACKGROUND: Prevalence of obesity and overweightness in different societies is increasing. Role of physical activity in weight loss and also prevention from some chronic diseases has been discussed previously. The objective of this study was to compare the effect of two different aerobic exercises (intermittent and continuous exercises) while prescribed with concurrent calorie-restrict diet on the weight loss and body fat of overweight and obese females. METHODS: Fifteen individuals in intermittent group performed 40 min moderate Intensity exercise in 3 bouts per day for 5 days per week; the 15 participants of continuous group exercised a single 40 min bout per day, 5 days per week. Also, 15 participants were included in control group without exercise program. A self-monitoring calorie-restrict diet was recommended to all participants. The body fat percentage, waist circumference, and also skin fold thickness of all participants were assessed at baseline and 12(th) weeks. RESULTS: The reduction of weight and BMI of participants in intermittent group (-3.33 +/- 1.80 and -1.34 +/- 0.70, respectively) was significantly more than comparable changes in continuous group (-1.23 +/- 1.60 and 0.49 +/- 0.65, respectively) (P = 0.048 and 0.041, respectively). After the intervention, there was no significant difference between case and controls in terms of body fat percentage, waist circumference, and sum of skin fold thickness. CONCLUSIONS: It seems that moderate intensity intermittent exercise for more than 150 min/ week is more efficient than continuous exercise in weight loss of obese and overweight women. PMID- 24049614 TI - Suppressive impact of anethum graveolens consumption on biochemical risk factors of atherosclerosis in hypercholesterolemic rabbits. AB - BACKGROUND: We aimed to determine the effects of Anethum graveolens (Dill) powder on postprandial lipid profile, markers of oxidation and endothelial activation when added to a fatty meal. METHODS: In an experimental study, 32 rabbits were randomly designated into four diet groups: normal diet, high cholesterol diet (1%), high cholesterol diet plus 5% (w/w) dill powder and high cholesterol diet plus lovastatin (10 mg/kg, bw). The concentrations of glucose, total cholesterol (TC), low-density lipoproteins-cholesterol (LDL-C), alanine aminotransferase (alt), aspartate aminotransferase (ast), fibrinogen, factor VII, apolipoprotein B (ApoB), nitrite and nitrate were measured in blood samples following 15 h of fasting and 3 h after feeding. RESULTS: Concurrent use of A. graveolens powder or lovastatin significantly decreased ALT, TC, glucose, fibrinogen and LDL-C values in comparison with hypercholesterolemic diet group (P < 0.05). Consumption of A. graveolens or lovastatin did not change factor VII, ApoB, nitrite and nitrate levels significantly in comparison with hypercholesterolemic diet group. Intake of A. graveolens significantly decreased serum AST compared to hypercholesterolemic diet. CONCLUSIONS: A. graveolens might have some protective values against atherosclerosis and that it significantly affects some biochemical risk factors of this disease. Our findings also confirm the potential harmful effects of oxidized fats and the importance of dietary polyphenols in the meal. PMID- 24049615 TI - Analysis of Relationship between Tumor Necrosis Factor Alpha Gene (G308A Polymorphism) with Preterm Labor. AB - BACKGROUND: Increased concentrations of tumor necrosis factor alpha (TNF-alpha) in blood and amniotic fluid are observed in women with preterm delivery (PTD) and TNF-alpha mutations at -308 position are associated with higher expression of this gene. Therefore, we compared the frequency of G308A transition in the promoter region of TNF-alpha gene of women and neonates delivered preterm with the normal subjects. METHODS: This cross-sectional study was performed on 135 mothers who were referred for delivery. According to the gestational age, mothers and their neonates were allocated to the case (preterm, 64 subjects) and control (term, 71 subjects) groups. Using the polymerase chain reaction, restrictive fragment length polymorphism (RFLP), genotyping was performed on both maternal peripheral blood and cord blood samples to determine single nucleotide polymorphism in the promoter region of TNF-alpha gene at -308. RESULTS: Two mothers in the case group, one mother in the control group and one neonate in the case group had genotyping assays (GA) mutation. All other subjects had normal GG genotype. Frequency of GA mutation was not significantly different between two groups (P = 0.47). CONCLUSIONS: There is no significant association between PTD and either maternal or fetal TNF-alpha -308 polymorphism and frequency ofGAmutation is not significantly increased in mothers and neonates delivered preterm. It means that the presence of this mutation by itself does not modify the overall risk of PTD. Investigations on the combination of various polymorphisms indifferent genes are recommended to achieve more accurate results. PMID- 24049616 TI - Prophylactic Add-on Antiplatelet Therapy in Chronic Kidney Disease With Type 2 Diabetes Mellitus: Comparison Between Clopidogrel and Low-dose Aspirin. AB - BACKGROUND: Chronic kidney disease (CKD) coexisting with type 2 diabetes mellitus (DM) leads to coronary artery disease. The present study compares clopidogrel and low-dose aspirin as prophylactic therapy against coronary events in patients with CKD with diabetes. METHODS: Total 80 patients of CKD with type 2 DM were randomized and allocated to clopidogrel and aspirin groups to receive the drug at a dose of 75 mg and 150 mg once daily respectively for 8 weeks as add-on therapy. Main outcome was change in blood pressure, metabolic parameters, renal function, inflammatory biomarkers, platelet aggregability and (UKPDS) United Kingdom Prospective Diabetes Study risk scoring. RESULTS: Significant decrease in blood pressure (P < 0.01), total cholesterol (P = 0.02), LDL (P < 0.01), triglyceride (P < 0.01) and a better glycemic control (P < 0.01) was found in clopidogrel group. Renal markers and electrolytes have been improved in clopidogrel group but in aspirin group there was deterioration (2.5%) of creatinine clearance. Clopidogrel group has shown a significant decrease in hsCRP (P < 0.01), UKPDS risk scoring (P < 0.01) and better anti-aggregatory effect. CONCLUSIONS: Clopidogrel has prophylactic role in CKD with type 2 DM due to better control of metabolic parameters, renal function and inflammatory burden in comparison to aspirin. PMID- 24049618 TI - Evaluation of rubella IgG antibodies among women at marriage in kermanshah city, before and after mass vaccination. AB - BACKGROUND: Rubella is a mild viral infectious disease, usually occurs subclinically without a serious complication. But if occurs during pregnancy, specially the first trimester, it can transmit and invade to fetus causing congenital rubella syndrome or fetal death. In 2003, nearly all Iranians at the age of 5 to 25 years old were vaccinated against rubella and the vaccine was included in the compulsory immunization, MMR afterwards. METHODS: This study was carried out on girls attended at a marriage consultancy center in Kermanshah city (West of Iran) in 2006. Considering 95% of confidence, the sample size was estimated at 140. All samples were tested using ELISA serologic method and compared with similar study conducted on 240 unvaccinated girls at the same place in 1999. RESULTS: Antibody positivity was observed in 99.3%, compared to 79.58% of the previous study. A rise of 19.72% (95% CI 12.7%-26.7%) of seropositivity was observed in vaccinated girls versus unvaccinated ones (P < 0.001). CONCLUSION: In our previous study, we had recommended to screen for susceptibility to rubella before marriage, which is no longer required since more than 99% of vaccinated girls showed immunity at the time of marriage. However, as sustainability of immunity after rubella vaccination is usually less than immunity due to illness, we recommend screening for rubella protective antibody every few years. PMID- 24049617 TI - Relation between Body Iron Status and Cardiovascular Risk Factors in Patients with Cardiovascular Disease. AB - BACKGROUND: There is conflicting evidence regarding the relationship between iron stores and cardiovascular disease (CVD). The present study aimed to investigate the association between body iron indices and some cardiovascular risk factors. METHODS: In a case-control study conducted in the south of Shiraz, Iran, we determined ferritin, iron, total iron binding capacity (TIBC), metabolic risk factors, C-reactive protein (CRP), and anthropometric measurements in 100 men aged 45 years and higher with newly diagnosed CVD and 100 adjusted controls without evidence for CVD. RESULTS: The mean of low density lipoprotein (LDL-c), CRP, and ferritin concentrations were significantly higher in cases than controls, and high density lipoprotein (HDL-c) was significantly lower in cases than controls. Pearson correlation coefficient between CRP and the other risk factors in case group showed that only ferritin, serum iron, waist circumference, and LDL-c significantly correlated with CRP (r = 0.32 with P < 0.001, r = 0.29 with P < 0.05, r = 0.41 with P < 0.01, and r = 0.36 with P < 0.001, respectively). CONCLUSIONS: This study indicated an association between a positive balance of body iron and CVD. Hence, caution should be exercised in administration of iron supplements to patients with CVD and in consumption of food rich in iron by them. PMID- 24049619 TI - Effects of pure eicosapentaenoic and docosahexaenoic acids on oxidative stress, inflammation and body fat mass in patients with type 2 diabetes. AB - BACKGROUND: N-3 Fatty acids reduce the risk of cardiovascular disease. Previous studies have shown that they may reduce inflammation, oxidative stress, and fat mass in patients with type 2 diabetes, but the results are inconclusive, due, in part, to type of omega-3 fatty acids used. The aim of this study was to determine the effects of pure eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), the two major omega-3 fatty acids, on inflammation, oxidative stress, and fat mass in patients with type 2 diabetes. METHODS: Sixty patients with DM-II were randomly allocated to receive daily either ~1 gr EPA or ~1 gr DHA, or a canola oil as placebo for 12 weeks in a randomized triple-blind, placebo-controlled trial. Serum MDA, CRP, body weight, BMI, and fat mass were measured at baseline and after intervention. RESULTS: Forty-five patients with a mean (+/-SD) age of 54.9 +/- 8.2 years with BMI of 27.6 +/- 4.1 kg/m(2) and fasting blood glucose 96.0 +/- 16.2 mg/dl completed the intervention. Neither EPA nor DHA had significant effects on serum FBS, C-reactive protein, body weight, BMI, and fat mass after intervention (P > 0.05). In addition, while MDA increased 18% in the placebo group (P = 0.009), it did not change in the EPA or DHA group (P > 0.05). CONCLUSIONS: Twelve weeks of supplementation with 1gr/d EPA or DHA prevent increasing oxidative stress without changing marker of inflammation. This study is the first report demonstrating that neither EPA nor DHA have effects on body fat mass in type 2 diabetic patients. PMID- 24049620 TI - Facilitators and Inhibitors of Health-promoting Behaviors: The Experience of Iranian Women of Reproductive Age. AB - BACKGROUND: There is scant information on the facilitators and inhibitors of health-promoting behaviors among reproductive-aged Iranian women. This study aims to explore the experience of factors influencing health-promoting behaviors among Iranian women of reproductive age from a qualitative perspective. METHODS: This study was performed in Tehran in 2011, over about 8 months. Qualitative methods, specifically in-depth interviews, were used to gather data on 15 women of reproductive age. Data continued to be collected until introduction of new information ceased. The interviews were recorded, transcribed verbatim, and analyzed by conventional content analysis. RESULTS: The reported factors were categorized into four main groups and 12 subgroups: (1) personal barriers (lack of time, school or work duties, lack of preparation or motivation, physical disability); (2) socio-environmental barriers (family responsibilities, environmental pressures, high-costs and financial pressures); (3) personal facilitators (personal interest and motivation, experience of disease); and (4) socio-environmental facilitators (family and social support networks, encouraging and motivating environment, media, and public education). CONCLUSIONS: In these women's experience, factors influencing health-promoting behaviors were either facilitators or inhibitors; most were inhibitors. The findings of this study show that, in addition to personal factors, the pursuit of health-promoting behaviors is affected by socio-environmental factors. These results will be useful in designing interventions and plans for women's health promotion that focus on the improvement of their environment and the modification of social factors. PMID- 24049621 TI - Body image and body change: predictive factors in an Iranian population. AB - BACKGROUND: Body concerns and its health consequences such as eating disorders and harmful body change activities are mentioned in Asian countries. This study evaluates factors contributing to body image/shape changes in an Iranian population. METHODS: In this cross-sectional study we focused on four main body change activity (diet, exercise, substance use, and surgery) and their risk factors such as demographic variables, Body Mass Index (BMI), Media, Body-Esteem, Perceived Socio-cultural Pressure, Body dissatisfaction and, Self-Esteem. Approximately, 1,200 individuals between 14-55 years old participated in this study. We used a multistage sampling method. In each region, the first household was selected at random. The probability of outcomes was estimated from logistic models. RESULTS: About 54.3% of respondents were females. The mean (SD) of age was 31.06 (10.24) years. Variables such as gender, age, BMI, use of media and socio cultural factors as, body dissatisfaction, body-esteem and pressure by relatives were the main factors that influenced body change methods. In particular we have seen that male are 53% less likely to follow surgical treatments, but 125% were more likely to use substances. CONCLUSIONS: Investigation of body concern and its health related problem should be assessed in cultural context. For effectiveness of interventional programs and reducing harmful body image/shape changes activities, socio-cultural background should be noted. PMID- 24049622 TI - Effect of daily consumption of probiotic yoghurt on serum levels of calcium, iron and liver enzymes in pregnant women. AB - BACKGROUND: To reach fetal appropriate growth during the third trimester, the requirements for dietary calcium and iron intakes during the pregnancy increases. This study was carried out to determine the effects of daily consumption of probiotic yoghurt on serum calcium and iron levels and liver enzymes among Iranian healthy pregnant women. METHODS: In this controlled clinical trial, 70 primigravida pregnant women carrying singleton pregnancy at their third trimester were participated. Participants were randomly divided into two groups of consuming 200 g/d of conventional (n = 33) or probiotic yogurts (n = 37) for 9 weeks. The probiotic yogurt contained Lactobacillus acidophilus and Bifidobacterium lactis with a total of min 1 * 10(7) CFU. To measure serum calcium, iron, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, blood samples were drawn in a fasting state at baseline and after 9 weeks intervention. RESULTS: Consumption of probiotic yogurt resulted in maintaining serum calcium levels compared with the conventional yogurt (P = 0.01). Within-group differences in the conventional yogurt group revealed a significant reduction of serum calcium levels (-1.7 mg/dL, P < 0.0001). No significant differences were found between the two yogurts in terms of their effects on serum iron, AST and ALT levels. CONCLUSIONS: Consumption of probiotic yogurt among pregnant women resulted in maintaining serum calcium levels compared with the conventional yogurt; however, it could not affect serum iron, ALT and AST levels. PMID- 24049623 TI - Association of neutrophil gelatinase associated lipocalin and cystatin-C with kidney function in children with nephrotic syndrome. AB - BACKGROUND: Nephrotic syndrome (NS) is a major clinical concern in human health, especially in children. Despite of the etiology, the prediction of remission in different treatment regimens based on suitable biomarkers is under development. The goal of this evaluation was the demonstration of correlation between serum level of Neutrophil gelatinase associated lipocalin (NGAL) and cystatin-C with kidney function in patients with NS. METHODS: During the period between September 2008 and December 2011, 52 patients admitted to St. Al Zahra University Hospital were selected for evaluation. The measured parameters consisted of NGAL, cystatin C, creatinine, albumin, blood urea nitrogen, urine protein, glomerular filtration rate. Demographic data were collected and considered in comparisons. Comparison between variables and their correlations were examined. RESULTS: Means of serum NGAL and cystatin-C were significantly higher in case than the control group, P < 0.05. The mean of serum NGAL in patients without remission and who achieved remission were 23.09 (standard deviation [SD] +/-10.11) and 36.26 (SD +/- 20.10) ng/ml respectively; P < 0.05. Serum NGAL levels had a correlation with the following factors: Systolic blood pressure, diastolic blood pressure (DBP), cystatin-C, remission. Linear regression analysis showed a significant correlation between cystatin-C and systolic and DBP. CONCLUSIONS: Based on the results, serum NGAL can be used as a prognostic marker for remission. In addition, NGAL and cystatin-C are biomarkers of kidney injury in NS. PMID- 24049624 TI - Kikuchi-fujimoto disease in 21-year-old man. AB - Kikuchi-Fujimoto disease also known as histiocytic necrotizing lymphadenitis is a benign disorder characterized histologically by necrotic foci surrounded by histiocytic aggregates, and with the absence of neutrophils. The patient was a 21 year-old man with chills, fever and cervical lymphadenopathy. He had swelling and tenderness of cervical area. Multiple enlarged lymph nodes were palpable. Cervical lymph node excisional biopsy was performed. Microscopic examination showed reactive follicular hyperplasia with vast areas of necrosis without neutrophilic infiltration. No sign of malignancy was seen. Final diagnosis was Kikuchi-Fujimoto necrotizing lymphadenitis. Kikuchi-Fujimoto disease should be considered as one of the differential diagnoses in patients with prolonged fever and cervical lymphadenopathy. It should be differentiated from tuberculous lymphadenitis in regions where tuberculosis is prevalent. PMID- 24049625 TI - Kerathocyst Odontogenic Tumor: Importance of Selection the Best Treatment Modality and A Periodical Follow-up to Prevent from Recurrence: A Case Report and Literature Review. AB - The keratocystic odontogenic tumor (KCOT) is a relatively common oral and maxillofacial lesion with specific characteristics such us rapid growth, extension into the surrounding tissues and high rates of recurrence. Various treatment modalities have been reported. Due to the very thin and friable lining characteristic of the tumor, enucleation can be difficult undertaken and for this reason it is associated with the highest recurrence rates. A 22-year-old male referred to our clinic due to a slight expansion in the right mandible from 2 years ago. He has a history of occurrence of KCOT in this region that was treated surgically by enucleation and curettage 5 years ago. Cone beam computed tomography showed a multilocular radiolucent lesion that extended from the angle of the mandible to the symphysis. Incisional biopsy showed a KCOT recurrence that surgically treated with resection of the right mandible by continuity preservation. Selection of the best treatment modality and also a periodical lifelong follow-up is very important to reduce the rate of recurrence and morbidity of the patient. PMID- 24049626 TI - Socio-demographic Predictors of Depression among the Elderly Patients Attending Out Patient Departments of a Tertiary Hospital in North India. AB - BACKGROUND: Depression is the most common geriatric psychiatric disorder. Other than organic, socio-demographic factors, have been found to play an important role in mental health. In this study we evaluated the association of some socio demographic factors with geriatric depression. METHODS: A cross-sectional study was carried out in the Out Patient Department registration area of a tertiary care teaching hospital in Delhi. Questionnaire based interviews were conducted among the elderly people visiting the hospital. A 15-item geriatric depression scale-Hindi was used to assess depression. RESULTS: Six hundred and seventy eight subjects were interviewed. The age of the subjects ranged from 65 to 85 years. About three-fourth of the study population were males. About 61.4% scored positive for depression. Multiple logistic regression analysis revealed that the following were significant (P<0.05) independent predictors of depression: Higher age, low educational status, financial dependence and presence of any chronic health problem. CONCLUSIONS: The present study found that the prevalence of depression among the study subjects was high. Also the independent risk factors found in this study need to be targeted in formulating mental health policy for geriatrics. PMID- 24049627 TI - Evaluation of chronic arsenic poisoning due to consumption of contaminated ground water in West Bengal, India. AB - BACKGROUND: Chronic arsenic poisoning is an important public health problem and most notable in West Bengal and Bangladesh. In this study different systemic manifestations in chronic arsenic poisoning were evaluated. METHODS: A nonrandomized, controlled, cross-sectional, observational study was carried out in Arsenic Clinic, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, over a period of 1 year 4 months. Seventy-three cases diagnosed clinically, consuming water containing arsenic >=50 MUg/L and having hair and nail arsenic level >0.6 MUg/L, were included. Special investigations included routine parameters and organ-specific tests. Arsenic levels in the drinking water, hair, and nail were measured in all. Twenty-five nonsmoker healthy controls were evaluated. RESULTS: Murshidabad and districts adjacent to Kolkata, West Bengal, were mostly affected. Middle-aged males were the common sufferers. Skin involvement was the commonest manifestation (100%), followed by hepatomegaly [23 (31.5%)] with or without transaminitis [7 (9.58%)]/portal hypertension [9 (12.33%)]. Restrictive abnormality in spirometry [11 (15.06%)], bronchiectasis [4 (5.47%)], interstitial fibrosis [2 (2.73%)], bronchogenic carcinoma [2 (2.73%)], oromucosal plaque [7 (9.58%)], nail hypertrophy [10 (13.69%)], alopecia [8 (10.95%)], neuropathy [5 (6.84%)], and Electrocardiography abnormalities [5 (6.84%)] were also observed. CONCLUSIONS: Mucocutaneous and nail lesions, hepatomegaly, and restrictive change in spirometry were the common and significant findings. Other manifestations were characteristic but insignificant. PMID- 24049628 TI - Curricular reforms in undergraduate medical education: an indispensable need. PMID- 24049629 TI - Prevention of hypomagnesemia in diabetes patients. PMID- 24049631 TI - Genetic biomarkers of placebo response: what could it mean for future trial design? PMID- 24049632 TI - Sost, ECR5, Mef2C and van Buchem disease. PMID- 24049630 TI - Rhodium-catalyzed enantioselective cyclopropanation of electron deficient alkenes. AB - The rhodium-catalyzed reaction of electron-deficient alkenes with substituted aryldiazoacetates and vinyldiazoacetates results in highly stereoselective cyclopropanations. With adamantylglycine derived catalyst Rh2(S-TCPTAD)4, high asymmetric induction (up to 98% ee) can be obtained with a range of substrates. Computational studies suggest that the reaction is facilitated by weak interaction between the carbenoid and the substrate carbonyl but subsequently proceeds via different pathways depending on the nature of the carbonyl.. Acrylates and acrylamides result in the formation of cyclopropanation products while the use of unsaturated aldehydes and ketones results in the formation of epoxides. PMID- 24049633 TI - BMD change predicts bone fracture risk due to zoledronate treatment. PMID- 24049634 TI - Bone loss after ovariectomy: the role of RANKL production by B cells. PMID- 24049636 TI - Wnt signaling balance regulates hematopoietic stem cell homeostasis. PMID- 24049635 TI - Sclerostin antibody: a promising treatment of osteogenesis imperfecta? PMID- 24049637 TI - Reshaping the brain: direct lineage conversion in the nervous system. AB - During embryonic development, cells in an uncommitted pluripotent state undergo progressive epigenetic changes that lock them into a final restrictive differentiated state. However, recent advances have shown that not only is it possible for a fully differentiated cell to revert back to a pluripotent state, a process called nuclear reprogramming, but also that differentiated cells can be directly converted from one class into another without generating progenitor intermediates, a process known as direct lineage conversion. In this review, we discuss recent progress made in direct lineage reprogramming of differentiated cells into neurons and discuss some of the therapeutic implications of the findings. PMID- 24049639 TI - A mechanobiological perspective on cadherins and the actin-myosin cytoskeleton. AB - Classical cadherin receptors mediate morphogenetic cell-cell interactions within many tissues of the body. Their biological impact often entails cooperation between cadherin adhesion and the actin cytoskeleton, but how this may occur and even more urgently - how this leads to morphogenetic outcomes are questions that remain poorly understood. Here, we suggest that the emerging field of cadherin mechanobiology provides a useful new perspective from which to revisit these issues. We propose that the actin cytoskeleton can be considered as an active agent that mediates how cadherin junctions resist, sense and transduce forces between cells. PMID- 24049640 TI - Paraphilias: definition, diagnosis and treatment. AB - There is a great deal of controversy concerning paraphilia, and defining what is normal versus deviant or disordered, given that this is to some degree dependent on cultural views of acceptability. In this article, we outline these issues and describe recent progress in diagnosing and treating paraphilias. PMID- 24049641 TI - Origins of fibrosis: pericytes take centre stage. AB - Pericytes are ubiquitous perivascular cells that have recently attracted interest as potential myofibroblast precursors. In turn, myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis. Given the worldwide burden of fibrotic disease and paucity of therapeutic options available to halt its progression, elucidating the origins of myofibroblasts is of prime importance. The advent of genetic strategies that permit fate-mapping of specific cell populations through permanent and heritable expression of reporter proteins has begun to shed light on the source of the fibrogenic myofibroblast. Here we discuss recent studies in multiple organs that highlight the central role of pericytes in the origins of fibrosis. PMID- 24049638 TI - DNA sequencing methods in human genetics and disease research. AB - DNA sequencing has revolutionized biological and medical research, and is poised to have a similar impact in medicine. This tool is just one of a number of developments in our capability to identify, quantitate and functionally characterize the components of the biological networks keeping us healthy or making us sick, but in many respects it has played the leading role in this process. The new technologies do, however, also provide a bridge between genotype and phenotype, both in man and model (as well as all other) organisms, revolutionize the identification of elements involved in a multitude of human diseases or other phenotypes, and generate a wealth of medically relevant information on every single person, as the basis of a truly personalized medicine of the future. PMID- 24049642 TI - Novel endoscopic approaches in the diagnosis and management of biliary strictures. AB - Indeterminate bilary strictures present the clinician with a wide differential diagnosis. Histological confirmation is usually required for treatment, but tissue acquisition remains challenging. Novel developments in endoscopic technology, such as single operator cholangioscopy and confocal endomicroscopy, have led to improvements in diagnostic accuracy in recent years. In patients with non-resectable malignant biliary obstruction, effective biliary decompression improves symptoms and enables patients to undergo palliative therapies. Improvements in endoscopic techniques, biliary stents and the development of local ablative techniques have led to further improvements in stent patency and survival in these patients. In this article, we review emerging diagnostic and therapeutic techniques for the endoscopic management of indeterminate biliary strictures. PMID- 24049643 TI - The importance of myeloperoxidase in apocynin-mediated NADPH oxidase inhibition. AB - Apocynin is widely used as an inhibitor of the NADPH oxidase. Since myeloperoxidase (MPO) has been considered as essential for the mechanism of action of apocynin, here we used cells with different levels of MPO and compared their sensitivity to apocynin. HL-60 cells were differentiated with DMSO or IFN gamma /TNF alpha and compared with peripheral mononuclear (PBMC) and polymorphonuclear cells (PMN). The relative MPO activity was PBMC = HL60 DMSO < HL60 IFN gamma < PMN. Apocynin inhibited the intracellular reactive oxygen species production by PMN (80%) and IFN gamma /TNF alpha -differentiated HL-60 cells (45%) but showed a minor effect in PBMC and DMSO differentiated HL-60 cells (20%). The addition of azide decreased the efficiency of apocynin in PMN and the addition of peroxidase increased the inhibition in PBMC. We also determined the gene expression of the components gp91phox, p47phox, p22phox and p67phox in the resting cells. Apocynin did not change gp91phox, p47phox or p22phox gene expression in nonstimulated PBMC, HL60 DMSO, HL60 IFN gamma /TNF alpha , and PMN and has a subtle increase in p67phox in HL60 IFN gamma /TNF alpha . The results from this work suggest that a rational search for better inhibitors of NADPH oxidase in leukocytes should include a correlation with their affinity as substrates for MPO. PMID- 24049645 TI - Angiotensin type 1a receptor signaling is not necessary for the production of reactive oxygen species in polymorphonuclear leukocytes. AB - Background. Although angiotensin II (Ang II) has inflammatory effects, little is known about its role in polymorphonuclear leucocytes (PMLs). To elucidate the role of Ang II in PMLs ROS production, we examined hydrogen peroxide (H2O2), one of the ROS, and NO production in AT1a receptor knockout (AT1KO) mice. Methods and Results. PMLs were analyzed from Ang II type 1a receptor knockout mice (AT1KO) and C57BL/6 wild type mice. Using flow cytometry, we studied hydrogen peroxide (H2O2) production from PMLs after Staphylococcus aureus phagocytosis or phorbol myristate acetate (PMA) stimulation. Nitric oxide (NO) production in the AT1KO was low at basal and after phagocytosis. In the AT1KO, basal H2O2 production was low. After PMA or phagocytosis stimulation, however, H2O2 production was comparable to wild type mice. Next we studied the H2O2 production in C57BL/6 mice exposed to Ang II or saline. H2O2 production stimulated by PMA or phagocytosis did not differ between the two groups. Conclusions. AT1a pathway is not necessary for PMLs H2O2 production but for NO production. There was a compensatory pathway for H2O2 production other than the AT1a receptor. PMID- 24049646 TI - sTREM-1 as a Prognostic Marker of Postoperative Complications in Cardiac Surgery. AB - Cell-activating receptor TREM-1 (triggering receptor expressed on myeloid cells 1) regulates congenital immune response and contributes to systemic inflammatory response syndrome (SIRS) development. It is able to multiply cytokine production while stimulated together with the main receptors of the congenital immune system. The purpose of the paper is to study the potential use of soluble TREM-1 (sTREM-1) as a marker of intensive SIRS and a criterion for postoperative complications prediction following on-pump coronary artery bypass surgery (CABG). Results show that early postoperative sTREM-1 concentrations demonstrate their potential prognostic value regarding SIRS-associated complications. PMID- 24049644 TI - Modulation of bacterial pathogenesis by oppressive aging factors: insights into host-pneumococcal interaction strategies. AB - Streptococcus pneumonia, (Spn, the pneumococcus), is the leading cause of community-acquired pneumonia (CAP) and is responsible for 15-40% deaths in the elderly worldwide. A primed inflammatory status is a significant risk factor for the increased severity of infectious diseases among the elderly (>=65 years of age). Studies have shown that expression of host receptors that the pneumococci bind to invade the tissues are increased thereby increasing the susceptibility to pneumococcal challenge in aged mice. Cellular senescence, an age-related phenomenon that leads to cell cycle arrest may also contribute to increased inflammation in aged mice. Evidence of cellular senescence in aged lungs of humans and mice adds credits to the concept of inflammaging and enhanced bacterial ligands expression during aging. Furthermore, cell senescence has been shown to occur in age-associated lung pathologies such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) that may predispose the elderly to pathogenic assaults, including S. pneumoniae. This review highlights the aspects of: chronic inflammation in the aged population; contribution of cellular senescence to age-associated inflammation and their impact on host receptor expression; and, increased susceptibility of fibrosis and emphysematous lesions-bearing lungs to microbial infections. PMID- 24049647 TI - Gadolinium chloride attenuates sepsis-induced pulmonary apoptosis and acute lung injury. AB - Gadolinium chloride (GdCl3), a Kupffer cells inhibitor, attenuates acute lung injury; however, the mechanisms behind this effect are not completely elucidated. We tested the hypothesis that GdCl3 acts through the inhibition of lung parenchymal cellular apoptosis. Two groups of rats were injected intraperitoneally with saline or E. coli lipopolysaccharide. In two additional groups, rats were injected with GdCl3 24 hrs prior to saline or LPS administration. At 12 hrs, lung injury, inflammation, and apoptosis were studied. Lung water content, myeloperoxidase activity, pulmonary apoptosis and mRNA levels of interleukin-1 beta , -2, -5, -6, -10 and TNF- alpha rose significantly in LPS injected animals. Pretreatment with GdCl3 significantly reduced LPS-induced elevation of pulmonary water content, myeloperoxidase activity, cleaved caspase-3 intensity, and attenuated pulmonary TUNEL-positive cells. GdCl3 pre-treatment upregulated IL-1 beta , -2 and -10 pulmonary gene expression without significantly affecting the others. These results suggest that GdCl3 attenuates acute lung injury through its effects on pulmonary parenchymal apoptosis. PMID- 24049648 TI - Expression Analysis of Cytokine and Chemokine Genes during the Natural Course of Murine Experimental Autoimmune Uveoretinitis. AB - C57BL/6 mice were immunized with human interphotoreceptor retinoid-binding protein peptides to induce experimental autoimmune uveoretinitis (EAU). From the day of immunization to 30 days later, RNA was isolated daily from the mouse eyes. Dynamic changes in gene expression during the pathogenesis of EAU were analyzed by TaqMan gene expression assay that contained most chemokines/cytokines and their receptors, and signal transducer and activator of transcription (STAT) family genes, using beta-actin as the endogenous control. Gene clusters based on their expression profiles were analyzed to determine the candidate genes for the pathogenesis of inflammation. Hierarchical cluster analysis showed gene expression during EAU development in seven clustering patterns. Hierarchical cluster analysis also identified four distinct phases in daily expression: entrance, acceleration, deceleration, and remission. Gene expression changes in the EAU active phase showed synergetic upregulation of Th1-type genes (IFN-gamma and CXCL10/IP-10) with elevated Th2-type genes (CCL17/TARC and IL-5). Sequential expression changes of STAT1, STAT6, and STAT3 genes represented the dynamic changes of Th1, Th2, and Th17-type inflammatory genes, respectively. The expression pattern of STAT1 was representative of many gene movements. Our results suggested that coordinated action of Th1, Th2, and Th17 genes and STAT family genes are involved in EAU development and resolution. PMID- 24049649 TI - Implication of NADPH oxidases in the early inflammation process generated by cystic fibrosis cells. AB - In cystic fibrosis (CF) patients, pulmonary inflammation is a major cause of morbidity and mortality. The aim of this study was to further investigate whether oxidative stress could be involved in the early inflammatory process associated with CF pathogenesis. We used a model of CFTR defective epithelial cell line (IB3 1) and its reconstituted CFTR control (S9) cell line cultured in various ionic conditions. This study showed that IB3-1 and S9 cells expressed the NADPH oxidases (NOXs) DUOX1/2 and NOX2 at the same level. Nevertheless, several parameters participating in oxidative stress (increased ROS production and apoptosis, decreased total thiol content) were observed in IB3-1 cells cultured in hypertonic environment as compared to S9 cells and were inhibited by diphenyleneiodonium (DPI), a well-known inhibitor of NOXs; besides, increased production of the proinflammatory cytokines IL-6 and IL-8 by IB3-1 cells was also inhibited by DPI as compared to S9 cells. Furthermore, calcium ionophore (A23187), which upregulates DUOX and NOX2 activities, strongly induced oxidative stress and IL-8 and IL-6 overexpression in IB3-1 cells. All these events were suppressed by DPI, supporting the involvement of NOXs in the oxidative stress, which can upregulate proinflammatory cytokine production by the airway CFTR deficient cells and trigger early pulmonary inflammation in CF patients. PMID- 24049650 TI - Interleukin-17 Expression in the Barrett's Metaplasia-Dysplasia-Adenocarcinoma Sequence. AB - Introduction. This pilot study evaluated the expression of the proinflammatory cytokine IL-17 along the Barrett's metaplasia-dysplasia-adenocarcinoma sequence by establishing the expression levels of IL-17 in columnar epithelium, intestinal metaplastic cells, and dysplastic/glandular neoplastic cells. Immunohistochemical techniques were used to examine the accumulation of the proinflammatory cytokine IL-17 in forty (n = 40) formalin-fixed, paraffin-embedded oesophageal archived specimens across a range of endoscopic diagnostic categories, and a highly significant difference was found, where P <= 0.001, in IL-17 expression (Kruskall Wallis and Mann-Whitney U) between all the cell types examined. There was also a strong positive correlation (Spearman's rank correlation) between disease progression and IL-17 expression (r s = 0.883, P < 0.001, n = 29), IL-17 expression was absent or absent/weak in columnar epithelium, weak to moderate in columnar metaplastic cells, and moderate to strong in dysplastic/neoplastic cells, which demonstrated that the elevation of IL-17 expression occurs in the progression of the disease. Understanding the differential expression of IL-17 between benign and malignant tissue potentially has a significant diagnostic, prognostic, and therapeutic value. Ultimately, this selective biomarker may be employed in routine clinical practice for the screening of oesophageal adenocarcinoma. PMID- 24049651 TI - Cytokines and growth factors promote airway smooth muscle cell proliferation. AB - Chronic airway diseases, such as asthma or chronic obstructive pulmonary disease, are characterized by the presence in the airways of inflammation factors, growth factors and cytokines, which promote airway wall remodelling. The aim of this study was to investigate the effect of cytokines and growth factors on airway smooth muscle cell (ASMC) proliferation, phenotype and responsiveness. Incubation of serum starved human bronchial ASMCs with TNF- alpha , TGF, bFGF, and PDGF, but not IL-1 beta , increased methyl-[(3)H]thymidine incorporation and cell number, mediated by the PI3K and MAPK signalling pathways. Regarding rabbit tracheal ASMC proliferation, TNF- alpha , IL-1 beta , TGF, and PDGF increased methyl [(3)H]thymidine incorporation in a PI3K- and MAPK-dependent manner. bFGF increased both methyl-[(3)H]thymidine incorporation and cell number. Moreover, incubation with TGF, bFGF and PDGF appears to drive human ASMCs towards a synthetic phenotype, as shown by the reduction of the percentage of cells expressing SM- alpha actin. In addition, the responsiveness of epithelium-denuded rabbit tracheal strips to carbachol was not significantly altered after 3-day treatment with bFGF. In conclusion, all the tested cytokines and growth factors increased ASMC proliferation to a different degree, depending on the specific cell type, with bronchial ASMCs being more prone to proliferation than tracheal ASMCs. PMID- 24049652 TI - Anti-inflammatory effects of urocanic Acid derivatives in models ex vivo and in vivo of inflammatory bowel disease. AB - Urocanic acid (UCA) derivatives were tested for their anti-inflammatory activity in inflammatory bowel disease (IBD) in two models: ex vivo and an experimental mouse model. Ex vivo: inflamed colonic tissue was incubated in culture medium with or without the UCA derivatives. Biopsies, incubated with UCA derivatives, produced lower levels of proinflammatory cytokines IL-6 and IL-8 as compared to control biopsies. The same compounds also showed increased levels of IL-10, providing an additional indication for anti-inflammatory properties. In vivo: a combination of two imidazoles and a combination of two of their ethyl esters were administered to mice while colitis was induced by oral administration of dextran sodium sulfate (DSS). Some parameters did not show conclusive effects, but the imidazoles and their ethyl esters reduced the area of inflammation and the number of infiltrating neutrophils. Fibrosis and the sum of all histological aspects were reduced by the imidazoles, whereas the ethyl esters reduced the colon weight to length ratio. These results suggest that the UCA derivatives have anti inflammatory effect on IBD. In addition, fine tuning of the ex vivo model may provide an elegant way to predict anti-inflammatory effects of potential drugs in humans, which may decrease the need for animal experiments. PMID- 24049654 TI - Immunomodulatory Effects of Danshen (Salvia miltiorrhiza) in BALB/c Mice. AB - Danshen, the root and rhizome of Salvia miltiorrhiza Bge, a Traditional Chinese Medicine, especially for cardiovascular and cerebrovascular diseases, has unique immunomodulatory effects. Danshen is capable of anti-inflammation and antiallergy, which are immunosuppressive activities, whereas it is also able to promote immunity against cancer, viruses, and bacteria. Most previous reports were performed with use of a purified compound or compounds of Danshen. Since there are more than twenty active compounds in Danshen, it is very difficult to predict that one compound will act the same way when it is combined with other compounds. In order to overcome this limitation, we used the crude form of Danshen to study its immunomodulatory effects in a mouse model. The mice were fed daily diet supplements of Danshen for three months and then tested for their immunity, including leukocyte subsets in peripheral blood, humoral and cell mediated immune responses, and host defenses against a Listeria monocytogenes (LM) infection. Different doses of Danshen caused different immunomodulatory effects. Danshen at 0.5% decreased serum IgE production in BALB/c mice; 1% Danshen promoted cell-mediated immunity; Danshen at 0.5 and 1% inhibited the production of oxygen free radicals in liver and spleen and NO production in liver; 2% Danshen enhanced the host resistance against LM with increased numbers of peripheral monocytes and natural killer (NK) cells and decreased production of IL-1 beta and NO. PMID- 24049655 TI - Lysophosphatidic Acid Stimulates MCP-1 Secretion from C2C12 Myoblast. AB - Chemokines are regulatory proteins that play an important role in muscle cell migration and proliferation. In this study, C2C12 cells treated with lysophosphatidic acid (LPA) showed an increase in endogenous monocyte chemotactic protein-1 (MCP-1) expression and secretion. LPA is a naturally occurring bioactive lysophospholipid with hormone- and growth-factor-like activities. LPA is produced by activated platelets, cytokine-stimulated leukocytes, and possibly by other cell types. However, the LPA analog cyclic phosphatidic acid (cPA) had no effect on the expression and secretion of MCP-1. LPA, although similar in structure to cPA, had potent inducing effects on MCP-1 expression in C2C12 cells. In this study, we showed that LPA enhanced MCP-1 mRNA expression and protein secretion in a dose-dependent manner. Taken together, these results suggest that LPA enhances MCP-1 secretion in C2C12 cells and thus may play an important role in cell proliferation. PMID- 24049653 TI - Acute phase reactants as novel predictors of cardiovascular disease. AB - Acute phase reaction is a systemic response which usually follows a physiological condition that takes place in the beginning of an inflammatory process. This physiological change usually lasts 1-2 days. However, the systemic acute phase response usually lasts longer. The aim of this systemic response is to restore homeostasis. These events are accompanied by upregulation of some proteins (positive acute phase reactants) and downregulation of others (negative acute phase reactants) during inflammatory reactions. Cardiovascular diseases are accompanied by the elevation of several positive acute phase reactants such as C reactive protein (CRP), serum amyloid A (SAA), fibrinogen, white blood cell count, secretory nonpancreatic phospholipase 2-II (sPLA2-II), ferritin, and ceruloplasmin. Cardiovascular disease is also accompanied by the reduction of negative acute phase reactants such as albumin, transferrin, transthyretin, retinol-binding protein, antithrombin, and transcortin. In this paper, we will be discussing the biological activity and diagnostic and prognostic values of acute phase reactants with cardiovascular importance. The potential therapeutic targets of these reactants will be also discussed. PMID- 24049657 TI - Monocyte Migration Driven by Galectin-3 Occurs through Distinct Mechanisms Involving Selective Interactions with the Extracellular Matrix. AB - Monocyte migration into tissues, an important event in inflammation, requires an intricate interplay between determinants on cell surfaces and extracellular matrix (ECM). Galectin-3 is able to modulate cell-ECM interactions and is an important mediator of inflammation. In this study, we sought to investigate whether interactions established between galectin-3 and ECM glycoproteins are involved in monocyte migration, given that the mechanisms by which monocytes move across the endothelium and through the extravascular tissue are poorly understood. Using the in vitro transwell system, we demonstrated that monocyte migration was potentiated in the presence of galectin-3 plus laminin or fibronectin, but not vitronectin, and was dependent on the carbohydrate recognition domain of the lectin. Only galectin-3-fibronectin combinations potentiated the migration of monocyte-derived macrophages. In binding assays, galectin-3 did not bind to fibronectin, whereas both the full-length and the truncated forms of the lectin, which retains carbohydrate binding ability, were able to bind to laminin. Our results show that monocytes migrate through distinct mechanisms and selective interactions with the extracellular matrix driven by galectin-3. We suggest that the lectin may bridge monocytes to laminin and may also activate these cells, resulting in the positive regulation of other adhesion molecules and cell adhesion to fibronectin. PMID- 24049658 TI - High-fat fish oil diet prevents hypothalamic inflammatory profile in rats. AB - Whether PUFA diets affect inflammatory mediators in central and peripheral sites is not clear. We investigated the effect of high-fat PUFA diets on the expression of proteins involved in inflammatory pathways in hypothalamus, muscle, and liver. Male rats were fed for 2 months with either chow or high-fat diets enriched with either soy (n-6 PUFAs) or fish oil (n-3 PUFAs). The fish group had normal body weight, low serum NEFA, reduced hypothalamic levels of TNF- alpha , IL-6, and TRAF6, and increased levels of IL-10 receptor. In contrast, the soy group had increased body weight and hypothalamic levels of TRAF6 and NF kappa Bp65. In muscle, the fish diet reduced TNF- alpha and IL-6 levels. Both PUFA diets increased muscle IL-10 levels and reduced liver TNF- alpha and IL-6 levels. The data showed that the high-fat soy diet induced activation of the hypothalamic NF kappa B inflammatory pathway, a feature predisposing to feeding and energy expenditure disturbances associated with the development of obesity. On the other hand, the high-fat fish diet improved the central and the peripheral inflammatory profile via reduction of intracellular inflammatory mediators, suggesting a protection against obesity. PMID- 24049656 TI - Atherosclerosis, dyslipidemia, and inflammation: the significant role of polyunsaturated Fatty acids. AB - Phospholipids play an essential role in cell membrane structure and function. The length and number of double bonds of fatty acids in membrane phospholipids are main determinants of fluidity, transport systems, activity of membrane-bound enzymes, and susceptibility to lipid peroxidation. The fatty acid profile of serum lipids, especially the phospholipids, reflects the fatty acid composition of cell membranes. Moreover, long-chain n-3 polyunsatured fatty acids decrease very-low-density lipoprotein assembly and secretion reducing triacylglycerol production. N-6 and n-3 polyunsatured fatty acids are the precursors of signalling molecules, termed "eicosanoids," which play an important role in the regulation of inflammation. Eicosanoids derived from n-6 polyunsatured fatty acids have proinflammatory actions, while eicosanoids derived from n-3 polyunsatured fatty acids have anti-inflammatory ones. Previous studies showed that inflammation contributes to both the onset and progression of atherosclerosis: actually, atherosclerosis is predominantly a chronic low-grade inflammatory disease of the vessel wall. Several studies suggested the relationship between long-chain n-3 polyunsaturated fatty acids and inflammation, showing that fatty acids may decrease endothelial activation and affect eicosanoid metabolism. PMID- 24049659 TI - A TREM-1 Polymorphism A/T within the Exon 2 Is Associated with Pneumonia in Burn Injured Patients. AB - Background. The triggering receptor expressed in myeloid cells (TREM-1) is a key mediator in the activation of the local inflammatory response during lung infections. We aimed to evaluate the effect of a functionally relevant TREM-1 single nucleotide polymorphism within the exon 2 (A->T) on the development of pneumonia in burn patients. Objective. To determine whether a single nucleotide polymorphism (SNP) within the exon 2 (A->T) in the TREM-1 gene is associated with ventilator-associated pneumonia (VAP) in burn-injured patients. Methods. 540 patients with >=10% total body surface area (TBSA) burn injuries or inhalation injury were prospectively enrolled. The influence of a polymorphism (A->T) in exon 2 of the TREM-1 gene was evaluated for association with increased risk of pneumonia by logistic regression analysis. Measurements and Main Results. 209 patients met criteria for VAP. Multivariate regression analysis showed that, after adjustment for potential confounders, we found that carriage of the TREM-1 T allele is associated with more than a 3-fold increased risk of VAP (OR 6.3, 95% CI 4-9). Conclusions. A TREM-1 single nucleotide polymorphism within the exon 2 (A->T) is associated with the development of pneumonia in burn patients. PMID- 24049660 TI - Delayed asthmatic response to allergen challenge and cytokines released by nonspecifically stimulated blood cells. AB - Background. Bronchial asthma patients can develop various asthmatic response types following bronchial allergen challenge, such as immediate (IAR), late (LAR), dual late (DLAR), or delayed (DYAR), due to different immunologic mechanisms. The DYAR, recorded in 24 patients, beginning between 26 and 32 hrs and lasting up to 56 hrs after the bronchial allergen challenge, differs from the IAR, LAR, and DLAR in clinical, diagnostic, and immunologic aspects. Objective. To investigate amounts of particular cytokines released by the blood cells after an additional nonspecific stimulation with Phorbol 12-myristate 13-acetate (PMA) during the DYAR. Methods. In 24 patients, the repeated DYAR was supplemented with determination of cytokines both in the nonstimulated plasma and in the supernatants of the blood cells stimulated with PMA before and up to 72 hours after the bronchial challenge, by means of enzyme-linked immunoassay. Results. No significant changes of the prechallenge cytokine concentrations in the non stimulated serum were recorded in the DYAR patients as compared with the healthy subjects. The DYAR was accompanied by significantly increased postchallenge concentrations (P < 0.05) of IL-2, IL-8, IL-12p70, IL-13, IL-18, IFN- gamma , G CSF, TNF- alpha , and TGF- beta , while decreased concentration of IL-7 (P < 0.05) in the nonstimulated plasma. The significantly increased postchallenge concentrations of IL-2, IL-8, IL-12p70, IL-13, IL-18, IFN- gamma , TNF- alpha , and TGF- beta were released by peripheral blood cells after stimulation with PMA, as compared with both their prechallenge concentrations and with the PBS control values. Conclusions. These results would support evidence for an important role of the Th1 cells, neutrophils, monocytes, and probably also NK cells in the immunologic mechanism(s) leading to the development of the clinical DYAR. Nevertheless, an additional role of macrophages, endothelial and epithelial cells in these mechanisms cannot be even excluded. PMID- 24049661 TI - Nitric Oxide-Dependent Regulation of Cytokines Release in Type-II Diabetes Mellitus. AB - The mechanism of release of proinflammatory cytokines by blood granulocytes in diabetes is unknown. We investigated whether diabetes mellitus affects the production of cytokines by granulocytes (PMN) and mononuclear cells (PBMCs) and whether this is modulated by NO. Isolated PMN and PBMC from with or without type II diabetes mellitus were incubated at 37 degrees C for 6 h with S-nitroso-N acetylpenicillamine (SNAP) at 0, 1, and 100 MU M with or without lipopolysaccharides (LPS) stimulation (1 MU g/mL). Supernatants were assayed for tumor necrosis factor- alpha (TNF- alpha ) and interleukin-8 (IL-8) by sandwich ELISA. Significant increases in TNF- alpha and IL-8 were observed only in PMN from diabetic subjects with or without LPS stimulation and that exogenous NO inhibited further production of cytokines in a concentration-dependent manner. However, activity of PBMC when stimulated with LPS was greatly enhanced by diabetes, but not affected by NO production. Hence, suggesting that granulocytes activation and participation in diabetes related complications is modulated by NO bioavailability. PMID- 24049663 TI - Effect of L. usitatissimum (Flaxseed/Linseed) Fixed Oil against Distinct Phases of Inflammation. AB - The present investigation summarizes the effect of Linum usitatissimum fixed oil against different phases of acute inflammatory reaction, namely, protein exudation, peritoneal capillary permeability, and leukocyte migration. The fixed oil exhibited dose-dependent inhibition of protein exudation vascular permeability, comparable to standard aspirin. The oil also inhibited the leukocyte migration in pleural exudates in a dose-dependent manner. Production of less vasodilatory (PGE3) and chemotactic (LTB5) eicosanoids through EPA (derived from linolenic acid) metabolism could account for the above observations. PMID- 24049662 TI - Adipocytokines in thyroid dysfunction. AB - Adipocytokines are important mediators of interorgan crosstalk in metabolic regulation. Thyroid diseases have effects on metabolism and inflammation. The mechanism of these effects is not clear. Recently, there are several reports suggesting this interrelation between adipocytokines and thyroid dysfunction. In this review, we summarize this relation according to the literature. PMID- 24049664 TI - Paprika Pigments Attenuate Obesity-Induced Inflammation in 3T3-L1 Adipocytes. AB - Obesity is related to various diseases, such as diabetes, hyperlipidemia, and hypertension. Adipocytokine, which is released from adipocyte cells, affects insulin resistance and blood lipid level disorders. Further, adipocytokine is related to chronic inflammation in obesity condition adipocyte cells. Paprika pigments (PPs) contain large amounts of capsanthin and capsorubin. These carotenoids affect the liver and improve lipid disorders of the blood. However, how these carotenoids affect adipocyte cells remains unknown. Present study examined the effects of PP on adipocytokine secretion, which is related to improvement of metabolic syndrome. In addition, suppressive effects of PP on chronic inflammation in adipocyte cells were analyzed using 3T3-L1 adipocyte cells and macrophage cell coculture experiments. PP promoted 3T3-L1 adipocyte cells differentiation upregulated adiponectin mRNA expression and secretion. Further, coculture of adipocyte and macrophage cells treated with PP showed suppressed interleukin-6 (IL-6), tumor necrosis factor- alpha (TNF- alpha ), monocyte chemotactic protein-1 (MCP-1), and resistin mRNA expression, similarly to treatment with troglitazone, which is a PPAR gamma ligand medicine. Conclusion. These results suggest that PP ameliorates chronic inflammation in adipocytes caused by obesity. PP adjusts adipocytokine secretion and might, therefore, affect antimetabolic syndrome diseases. PMID- 24049665 TI - Perioperative Dynamics of TLR2, TLR4, and TREM-1 Expression in Monocyte Subpopulations in the Setting of On-Pump Coronary Artery Bypass Surgery. AB - Hypercytokinemia plays a key role in the pathogenesis of systemic inflammatory response syndrome (SIRS). Monocytes are the main source of cytokines in the early inflammatory phase. Simultaneous stimulation of toll-like receptors (TLRs) and triggering receptor expressed on myeloid cells (TREM-1) activating receptor on monocytes results in the amplification of the inflammatory signal and multiple increase in proinflammatory cytokine production. The dynamics of those receptors expression on monocyte surface of patients with uncomplicated SIRS course followed coronary artery bypass surgery (CABG) was studied. The increase in TLR2 and TREM-1 expression on the first day after CABG induces proinflammatory and amplification potentials of monocytes in that period. The decrease in TLR2 surface expression on the seventh day compared to the preoperative values can be regarded as a mechanism limiting inflammatory response. The highest level of TLR2, TLR4, and TREM-1 surface expression was observed in CD14(hi)CD16(+) monocyte subpopulation, confirming its proinflammatory profile. PMID- 24049666 TI - Marked Effects of Tachykinin in Myositis Both in the Experimental Side and Contralaterally: Studies on NK-1 Receptor Expressions in an Animal Model. AB - Muscle injury and inflammation (myositis) in a rabbit model of an unilateral muscle overuse were examined. It is unknown if the tachykinin system has a functional role in this situation. In this study, therefore, the neurokinin-1 receptor (NK-1R) expression patterns were evaluated. White blood cells, nerve fascicles, fine nerve fibers, and blood vessel walls in myositis areas showed NK 1R immunoreaction. NK-1R mRNA reactions were observable for white blood cells and blood vessel walls of these areas. NK-1R immunoreaction and NK-1R mRNA reactions were also seen for muscle fibers showing degenerative and regenerative features. There were almost no NK-1R immunoreactions in normal muscle tissue. Interestingly, marked NK-1R expressions were seen for myositis areas of both the experimental side and the contralateral nonexperimental side. EIA analyses showed that the concentration of substance P in the muscle tissue was clearly increased bilaterally at the experimental end stage, as compared to the situation for normal muscle tissue. These observations show that the tachykinin system is very much involved in the processes that occur in muscle injury/myositis. The effects can be related to proinflammatory effects and/or tissue repair. The fact that there are also marked NK-1R expressions contralaterally indicate that the tachykinin system has crossover effects. PMID- 24049667 TI - Lactoperoxidase: structural insights into the function,ligand binding and inhibition. AB - Lactoperoxidase (LPO) is a member of a large group of mammalian heme peroxidases that include myeloperoxidase (MPO), eosinophil peroxidase (EPO) and thyroid peroxidase (TPO). The LPO is found in exocrine secretions including milk. It is responsible for the inactivation of a wide range of micro-organisms and hence, is an important component of defense mechanism in the body. With the help of hydrogen peroxide, it catalyzes the oxidation of halides, pseudohalides and organic aromatic molecules. Historically, LPO was isolated in 1943, nearly seventy years ago but its three-dimensional crystal structure has been elucidated only recently. This review provides various details of this protein from its discovery to understanding its structure, function and applications. In order to highlight species dependent variations in the structure and function of LPO, a detailed comparison of sequence, structure and function of LPO from various species have been made. The structural basis of ligand binding and distinctions in the modes of binding of substrates and inhibitors have been analyzed extensively. PMID- 24049668 TI - Biochemical and structural insights into mesotrypsin: an unusual human trypsin. AB - Thirty five years ago mesotrypsin was first isolated from the human pancreas. It was described as a minor trypsin isoform with the remarkable property of near total resistance to biological trypsin inhibitors. Another unusual feature of mesotrypsin was discovered later, when it was found that mesotrypsin has defective affinity toward many protein substrates of other trypsins. As the younger sibling of the two major trypsins secreted by the pancreas, cationic and the anionic trypsin, it has been speculated to represent an evolutionary waste with no apparent function. We know now that mesotrypsin is functionally very different from the other trypsins, with novel substrate specificity that hints at distinct physiological functions. Recently, evidence has begun to emerge implicating mesotrypsin in direct involvement in cancer progression. This review will explore the biochemical characteristics of mesotrypsin and structural insights into its specificity, function, and inhibition. PMID- 24049669 TI - Redundancy or specificity? The role of the CDK Pho85 in cell cycle control. AB - It is generally accepted that progression through the eukaryotic cell cycle is driven by cyclin-dependent kinases (CDKs), which are regulated by interaction with oscillatory expressed proteins called cyclins. CDKs may be separated into 2 categories: essential and non-essential. Understandably, more attention has been focused on essential CDKs because they are shown to control cell cycle progression to a greater degree. After clearly determining the basic and "core" mechanisms of essential CDKs, several questions arise. What role do non-essential CDKs play? Are these CDKs functionally redundant and do they serve as a mere backup? Or might they be responsible for some accessory tasks in cell cycle progression or control? In the present review we will try to answer these questions based on recent findings on the involvement of non-essential CDKs in cell cycle progression. We will analyse the most recent information with regard to these questions in the yeast Saccharomyces cerevisiae, a well-established eukaryotic model, and in its unique non-essential CDK involved in the cell cycle, Pho85. We will also briefly extend our discussion to higher eukaryotic systems. PMID- 24049670 TI - The role of calcium, NF-kappaB and NFAT in the regulation of CXCL8 and IL-6 expression in Jurkat T-cells. AB - T-cells play an important role in host immunity against invading pathogens. Determining the underlying regulatory mechanisms will provide a better understanding of T-cell-derived immune responses. In this study, we have shown the differential regulation of IL-6 and CXCL8 by NF-kappaB and NFAT in Jurkat T cells, in response to PMA, heat killed Escherichia coli and calcium. CXCL8 was closely associated with the activation pattern of NFAT, while IL-6 expression was associated with NF-kappaB. Furthermore, increasing the intracellular Ca(2+) concentration by calcium ionophore treatment of the cells resulted in NFAT induction without affecting the NF-kappaB activity. Interestingly, NF-kappaB activation by heat killed E. coli, as well as CXCL8 and IL-6 expression was significantly suppressed following addition of the calcium ionophore. This indicates that calcium plays an important role in regulating protein trafficking and T-cell signalling, and the subsequent inflammatory gene expression infers an involvement of NFAT in CXCL8 regulation.Understanding these regulatory patterns provide clarification of conditions that involve altered intracellular signalling leading to T-cell-derived cytokine expression. PMID- 24049671 TI - Dual modality endomicroscope with optical zoom capability. AB - We present a miniature endomicroscope that combines large field-of-view (FOV) (1.15 mm) reflectance imaging with high-resolution (~0.5 MUm) multiphoton intrinsic fluorescence imaging. We acquired in vivo and ex vivo images of unstained normal and tumor-laden tissues by using the large-FOV mode to navigate to the site of interest and then switching to the high-resolution modality to resolve cellular details. PMID- 24049672 TI - Observing single protein binding by optical transmission through a double nanohole aperture in a metal film. AB - We experimentally demonstrate protein binding at the single particle level. A double nanohole (DNH) optical trap was used to hold onto a 20 nm biotin-coated polystyrene (PS) particle which subsequently is bound to streptavidin. Biotin streptavidin binding has been detected by an increase in the optical transmission through the DNH. Similar optical transmission behavior was not observed when streptavidin binding sites where blocked by mixing streptavidin with excess biotin. Furthermore, interaction of non-functionalized PS particles with streptavidin did not induce a change in the optical transmission through the DNH. These results are promising as the DNH trap can make an excellent single molecule resolution sensor which would enable studying biomolecular interactions and dynamics at a single particle/molecule level. PMID- 24049673 TI - On the possibility of quantitative refractive-index tomography of large biomedical samples with hard X-rays. AB - One of the most promising applications of the X-ray phase-contrast imaging is the three dimensional tomographic reconstruction of the index of refraction. However, results reported so far are limited to relatively small samples. We present here the tomographic reconstruction of the index of refraction distribution of a large biomedical sample (> 10 cm diameter). A quantitative study comparing the absorption and phase contrast (analyzer-based) tomography images shows that the distribution of the index of refraction obtained with the phase contrast method provides a more accurate depiction (3-10 times larger signal to noise ratio values) of the sample internal structure. Thanks to the higher sensitivity of this method, the improved precision was obtained using an incoming photon fluence on the sample several times smaller than in the case of absorption imaging. PMID- 24049674 TI - Compressive sensing with dispersion compensation on non-linear wavenumber sampled spectral domain optical coherence tomography. AB - We propose a novel compressive sensing (CS) method on spectral domain optical coherence tomography (SDOCT). By replacing the widely used uniform discrete Fourier transform (UDFT) matrix with a new sensing matrix which is a modification of the non-uniform discrete Fourier transform (NUDFT) matrix, it is shown that undersampled non-linear wavenumber spectral data can be used directly in the CS reconstruction. Thus k-space grid filling and k-linear mask calibration which were proposed to obtain linear wavenumber sampling from the non-linear wavenumber interferometric spectra in previous studies of CS in SDOCT (CS-SDOCT) are no longer needed. The NUDFT matrix is modified to promote the sparsity of reconstructed A-scans by making them symmetric while preserving the value of the desired half. In addition, we show that dispersion compensation can be implemented by multiplying the frequency-dependent correcting phase directly to the real spectra, eliminating the need for constructing complex component of the real spectra. This enables the incorporation of dispersion compensation into the CS reconstruction by adding the correcting term to the modified NUDFT matrix. With this new sensing matrix, A-scan with dispersion compensation can be reconstructed from undersampled non-linear wavenumber spectral data by CS reconstruction. Experimental results show that proposed method can achieve high quality imaging with dispersion compensation. PMID- 24049675 TI - Single-cell optoporation and transfection using femtosecond laser and optical tweezers. AB - In this paper, we demonstrate a new single-cell optoporation and transfection technique using a femtosecond Gaussian laser beam and optical tweezers. Tightly focused near-infrared (NIR) femtosecond laser pulse was employed to transiently perforate the cellular membrane at a single point in MCF-7 cancer cells. A distinct technique was developed by trapping the microparticle using optical tweezers to focus the femtosecond laser precisely on the cell membrane to puncture it. Subsequently, an external gene was introduced in the cell by trapping and inserting the same plasmid-coated microparticle into the optoporated cell using optical tweezers. Various experimental parameters such as femtosecond laser exposure power, exposure time, puncture hole size, exact focusing of the femtosecond laser on the cell membrane, and cell healing time were closely analyzed to create the optimal conditions for cell viability. Following the insertion of plasmid-coated microparticles in the cell, the targeted cells exhibited green fluorescent protein (GFP) under the fluorescent microscope, hence confirming successful transfection into the cell. This new optoporation and transfection technique maximizes the level of selectivity and control over the targeted cell, and this may be a breakthrough method through which to induce controllable genetic changes in the cell. PMID- 24049676 TI - Simultaneous imaging of two-photon absorption and stimulated Raman scattering by spatial overlap modulation nonlinear optical microscopy. AB - Imaging of simultaneous two-photon absorption and stimulated Raman scattering is accomplished by detecting the intensity changes of the two-color pulses simultaneously and the mathematical operations of addition and subtraction. The stimulated Raman scattering is quantitatively separated from the two-photon absorption, generated in a mixed solution in which a glycerin solution is miscible in various proportions with a quantum dot solution. Our technique is applied to simultaneous two-photon absorption and stimulated Raman scattering imaging. PMID- 24049677 TI - An optical system for detecting 3D high-speed oscillation of a single ultrasound microbubble. AB - As contrast agents, microbubbles have been playing significant roles in ultrasound imaging. Investigation of microbubble oscillation is crucial for microbubble characterization and detection. Unfortunately, 3-dimensional (3D) observation of microbubble oscillation is challenging and costly because of the bubble size-a few microns in diameter-and the high-speed dynamics under MHz ultrasound pressure waves. In this study, a cost-efficient optical confocal microscopic system combined with a gated and intensified charge-coupled device (ICCD) camera were developed to detect 3D microbubble oscillation. The capability of imaging microbubble high-speed oscillation with much lower costs than with an ultra-fast framing or streak camera system was demonstrated. In addition, microbubble oscillations along both lateral (x and y) and axial (z) directions were demonstrated. Accordingly, this system is an excellent alternative for 3D investigation of microbubble high-speed oscillation, especially when budgets are limited. PMID- 24049678 TI - Spatial Light Interference Microscopy (SLIM) using twisted-nematic liquid-crystal modulation. AB - We report the use of a twisted nematic liquid-crystal spatial light modulator (TNLC-SLM) for quantitative phase imaging. The experimental setup is a new implementation of the SLIM principle, which is a phase shifting, white light method for quantitative phase imaging. The approach is based on switching between the phase and amplitude modulation modes of the SLM. Our system is able to deliver a 0.99 nm spatial and 1.33 nm temporal pathlength sensitivity while retaining the optical transverse resolution. The system is implemented as an additional module mounted to a conventional microscope, which makes the system very easy to deploy and integrate with other imaging modalities. PMID- 24049679 TI - Tri-modal microscopy with multiphoton and optical coherence microscopy/tomography for multi-scale and multi-contrast imaging. AB - Multi-scale multimodal microscopy is a very useful technique by providing multiple imaging contrasts with adjustable field of views and spatial resolutions. Here, we present a tri-modal microscope combining multiphoton microscopy (MPM), optical coherence microscopy (OCM) and optical coherence tomography (OCT) for subsurface visualization of biological tissues. The advantages of the tri-modal system are demonstrated on various biological samples. It enables the visualization of multiple intrinsic contrasts including scattering, two-photon excitation fluorescence (TPEF), and second harmonic generation (SHG). It also enables a rapid scanning over a large tissue area and a high resolution zoom-in for cellular-level structures on regions of interest. The tri-modal microscope can be important for label-free imaging to obtain a sufficient set of parameters for reliable sample analysis. PMID- 24049681 TI - Optical theorem for acoustic non-diffracting beams and application to radiation force and torque. AB - Acoustical and optical non-diffracting beams are potentially useful for manipulating particles and larger objects. An extended optical theorem for a non diffracting beam was given recently in the context of acoustics. The theorem relates the extinction by an object to the scattering at the forward direction of the beam's plane wave components. Here we use this theorem to examine the extinction cross section of a sphere centered on the axis of the beam, with a non diffracting Bessel beam as an example. The results are applied to recover the axial radiation force and torque on the sphere by the Bessel beam. PMID- 24049680 TI - Static and dynamic crystalline lens accommodation evaluated using quantitative 3 D OCT. AB - Custom high-resolution high-speed anterior segment spectral domain Optical Coherence Tomography (OCT) provided with automatic quantification and distortion correction algorithms was used to characterize three-dimensionally (3-D) the human crystalline lens in vivo in four subjects, for accommodative demands between 0 to 6 D in 1 D steps. Anterior and posterior lens radii of curvature decreased with accommodative demand at rates of 0.73 and 0.20 mm/D, resulting in an increase of the estimated optical power of the eye of 0.62 D per diopter of accommodative demand. Dynamic fluctuations in crystalline lens radii of curvature, anterior chamber depth and lens thickness were also estimated from dynamic 2-D OCT images (14 Hz), acquired during 5-s of steady fixation, for different accommodative demands. Estimates of the eye power from dynamical geometrical measurements revealed an increase of the fluctuations of the accommodative response from 0.07 D to 0.47 D between 0 and 6 D (0.044 D per D of accommodative demand). A sensitivity analysis showed that the fluctuations of accommodation were driven by dynamic changes in the lens surfaces, particularly in the posterior lens surface. PMID- 24049682 TI - Label-free high-throughput cell screening in flow. AB - Flow cytometry is a powerful tool for cell counting and biomarker detection in biotechnology and medicine especially with regards to blood analysis. Standard flow cytometers perform cell type classification both by estimating size and granularity of cells using forward- and side-scattered light signals and through the collection of emission spectra of fluorescently-labeled cells. However, cell surface labeling as a means of marking cells is often undesirable as many reagents negatively impact cellular viability or provide activating/inhibitory signals, which can alter the behavior of the desired cellular subtypes for downstream applications or analysis. To eliminate the need for labeling, we introduce a label-free imaging-based flow cytometer that measures size and cell protein concentration simultaneously either as a stand-alone instrument or as an add-on to conventional flow cytometers. Cell protein concentration adds a parameter to cell classification, which improves the specificity and sensitivity of flow cytometers without the requirement of cell labeling. This system uses coherent dispersive Fourier transform to perform phase imaging at flow speeds as high as a few meters per second. PMID- 24049683 TI - Optical pacing of the adult rabbit heart. AB - Optical pacing has been demonstrated to be a viable alternative to electrical pacing in embryonic hearts. In this study, the feasibility of optically pacing an adult rabbit heart was explored. Hearts from adult New Zealand White rabbits (n = 9) were excised, cannulated and perfused on a modified Langendorff apparatus. Pulsed laser light (lambda = 1851 nm) was directed to either the left or right atrium through a multimode optical fiber. An ECG signal from the left ventricle and a trigger pulse from the laser were recorded simultaneously to determine when capture was achieved. Successful optical pacing was demonstrated by obtaining pacing capture, stopping, then recapturing as well as by varying the pacing frequency. Stimulation thresholds measured at various pulse durations suggested that longer pulses (8 ms) had a lower energy capture threshold. To determine whether optical pacing caused damage, two hearts were perfused with 30 uM of propidium iodide and analyzed histologically. A small number of cells near the stimulation site had compromised cell membranes, which probably limited the time duration over which pacing was maintained. Here, short-term optical pacing (few minutes duration) is demonstrated in the adult rabbit heart for the first time. Future studies will be directed to optimize optical pacing parameters to decrease stimulation thresholds and may enable longer-term pacing. PMID- 24049684 TI - Spectrally encoded confocal microscopy of esophageal tissues at 100 kHz line rate. AB - Spectrally encoded confocal microscopy (SECM) is a reflectance confocal microscopy technology that uses a diffraction grating to illuminate different locations on the sample with distinct wavelengths. SECM can obtain line images without any beam scanning devices, which opens up the possibility of high-speed imaging with relatively simple probe optics. This feature makes SECM a promising technology for rapid endoscopic imaging of internal organs, such as the esophagus, at microscopic resolution. SECM imaging of the esophagus has been previously demonstrated at relatively low line rates (5 kHz). In this paper, we demonstrate SECM imaging of large regions of esophageal tissues at a high line imaging rate of 100 kHz. The SECM system comprises a wavelength-swept source with a fast sweep rate (100 kHz), high output power (80 mW), and a detector unit with a large bandwidth (100 MHz). The sensitivity of the 100-kHz SECM system was measured to be 60 dB and the transverse resolution was 1.6 um. Excised swine and human esophageal tissues were imaged with the 100-kHz SECM system at a rate of 6.6 mm(2)/sec. Architectural and cellular features of esophageal tissues could be clearly visualized in the SECM images, including papillae, glands, and nuclei. These results demonstrate that large-area SECM imaging of esophageal tissues can be successfully conducted at a high line imaging rate of 100 kHz, which will enable whole-organ SECM imaging in vivo. PMID- 24049685 TI - Enumerating virus-like particles in an optically concentrated suspension by fluorescence correlation spectroscopy. AB - Fluorescence correlation spectroscopy (FCS) is one of the most sensitive methods for enumerating low concentration nanoparticles in a suspension. However, biological nanoparticles such as viruses often exist at a concentration much lower than the FCS detection limit. While optically generated trapping potentials are shown to effectively enhance the concentration of nanoparticles, feasibility of FCS for enumerating field-enriched nanoparticles requires understanding of the nanoparticle behavior in the external field. This paper reports an experimental study that combines optical trapping and FCS to examine existing theoretical predictions of particle concentration. Colloidal suspensions of polystyrene (PS) nanospheres and HIV-1 virus-like particles are used as model systems. Optical trapping energies and statistical analysis are used to discuss the applicability of FCS for enumerating nanoparticles in a potential well produced by a force field. PMID- 24049686 TI - Aberrations and their correction in light-sheet microscopy: a low-dimensional parametrization. AB - Light sheet microscopy allows rapid imaging of three-dimensional fluorescent samples, using illumination and detection axes that are orthogonal. For imaging large samples, this often forces the objective to be tilted relative to the sample's surface; for samples that are not precisely matched to the immersion medium index, this tilt introduces aberrations. Here we calculate the nature of these aberrations for a simple tissue model, and show that a low-dimensional parametrization of these aberrations facilitates online correction via a deformable mirror without introduction of beads or other fiducial markers. We use this approach to demonstrate improved image quality in living tissue. PMID- 24049687 TI - Calibration of a prototype NIRS oximeter against two commercial devices on a blood-lipid phantom. AB - In a blood-lipid liquid phantom the prototype near-infrared spectroscopy oximeter OxyPrem was calibrated against the INVOS(r) 5100c adult sensor in respect to values of regional tissue oxygen haemoglobin saturation (rStO2) for possible inclusion in the randomised clinical trial - SafeBoosC. In addition different commercial NIRS oximeters were compared on changing haemoglobin oxygen saturation and compared against co-oximetry. The best calibration was achieved with a simple offset and a linear scaling of the OxyPrem rStO2 values. The INVOS adult and pediatric sensor gave systematically different values, while the difference between the NIRO(r) 300 and the two INVOS sensors were magnitude dependent. The co-oximetry proved unreliable on such low haemoglobin and high Intralipid levels. PMID- 24049688 TI - Super-resolution scanning laser microscopy through virtually structured detection. AB - High resolution microscopy is essential for advanced study of biological structures and accurate diagnosis of medical diseases. The spatial resolution of conventional microscopes is light diffraction limited. Structured illumination has been extensively explored to break the diffraction limit in wide field light microscopy. However, deployable application of the structured illumination in scanning laser microscopy is challenging due to the complexity of the illumination system and possible phase errors in sequential illumination patterns required for super-resolution reconstruction. We report here a super-resolution scanning laser imaging system which employs virtually structured detection (VSD) to break the diffraction limit. Without the complexity of structured illumination, VSD provides an easy, low-cost and phase-artifact free strategy to achieve super-resolution in scanning laser microscopy. PMID- 24049689 TI - Dark-field circular depolarization optical coherence microscopy. AB - Optical coherence microscopy (OCM) is a widely used structural imaging modality. To extend its application in molecular imaging, gold nanorods are widely used as contrast agents for OCM. However, they very often offer limited sensitivity as a result of poor signal to background ratio. Here we experimentally demonstrate that a novel OCM implementation based on dark-field circular depolarization detection can efficiently detect circularly depolarized signal from gold nanorods and at the same time efficiently suppress the background signals. This results into a significant improvement in signal to background ratio. PMID- 24049690 TI - Automated bacterial identification by angle resolved dark-field imaging. AB - We propose and demonstrate a dark-field imaging technique capable of automated identification of individual bacteria. An 87-channel multispectral system capable of angular and spectral resolution was used to measure the scattering spectrum of various bacteria in culture smears. Spectra were compared between various species and between various preparations of the same species. A 15-channel system was then used to prove the viability of bacterial identification with a relatively simple microscope system. A simple classifier was able to identify four of six bacterial species with greater than 90% accuracy in bacteria-by-bacteria testing. PMID- 24049691 TI - Real time in vivo investigation of superoxide dynamics in zebrafish liver using a single-fiber fluorescent probe. AB - Superoxide anion is the key radical that causes intracellular oxidative stress. The lack of a method to directly monitor superoxide concentration in vivo in real time has severely hindered our understanding on its pathophysiology. We made transgenic zebrafish to specifically express yellow fluorescent proteins, a reversible superoxide-specific indicator, in the liver and used a fiber-optic fluorescent probe to noninvasively monitor the superoxide concentration in real time. Several superoxide-inducing and scavenging reagents were administrated onto the fish to alter superoxide concentrations. The distinct biochemical pathways of the reagents can be discerned from the transient behaviors of fluorescence time courses. These results demonstrate the feasibility of this method for analyzing superoxide dynamics and its potential as an in vivo pharmaceutical screening platform. PMID- 24049692 TI - In vivo dark-field imaging of the retinal pigment epithelium cell mosaic. AB - Non-invasive reflectance imaging of the human RPE cell mosaic is demonstrated using a modified confocal adaptive optics scanning light ophthalmoscope (AOSLO). The confocal circular aperture in front of the imaging detector was replaced with a combination of a circular aperture 4 to 16 Airy disks in diameter and an opaque filament, 1 or 3 Airy disks thick. This arrangement reveals the RPE cell mosaic by dramatically attenuating the light backscattered by the photoreceptors. The RPE cell mosaic was visualized in all 7 recruited subjects at multiple retinal locations with varying degrees of contrast and cross-talk from the photoreceptors. Various experimental settings were explored for improving the visualization of the RPE cell boundaries including: pinhole diameter, filament thickness, illumination and imaging pupil apodization, unmatched imaging and illumination focus, wavelength and polarization. None of these offered an obvious path for enhancing image contrast. The demonstrated implementation of dark-field AOSLO imaging using 790 nm light requires low light exposures relative to light safety standards and it is more comfortable for the subject than the traditional autofluorescence RPE imaging with visible light. Both these factors make RPE dark field imaging appealing for studying mechanisms of eye disease, as well as a clinical tool for screening and monitoring disease progression. PMID- 24049694 TI - A scattering phantom for observing long range order with two-dimensional angle resolved Low-Coherence Interferometry. AB - Angle-resolved low coherence interferometry (a/LCI) is an approach for assessing tissue structure based on light scattering data. Recent advances in a/LCI have extended the analysis to study scattering distributions in two dimensions. In order to provide suitable scattering phantoms for 2D a/LCI, we have developed phantoms based on soft lithography which can provide a range of structures including long range order. Here we characterize these phantoms and demonstrate their utility for providing standardized multi-scale structural information for light scattering measurements. PMID- 24049693 TI - Multimodal in vivo imaging of oral cancer using fluorescence lifetime, photoacoustic and ultrasound techniques. AB - This work reports a multimodal system for label-free tissue diagnosis combining fluorescence lifetime imaging (FLIm), ultrasound backscatter microscopy (UBM), and photoacoustic imaging (PAI). This system provides complementary biochemical, structural and functional features allowing for enhanced in vivo detection of oral carcinoma. Results from a hamster oral carcinoma model (normal, precancer and carcinoma) are presented demonstrating the ability of FLIm to delineate biochemical composition at the tissue surface, UBM and related radiofrequency parameters to identify disruptions in the tissue microarchitecture and PAI to map optical absorption associated with specific tissue morphology and physiology. PMID- 24049695 TI - Real-time optical pH measurement in a standard microfluidic cell culture system. AB - The rapid growth of microfluidic cell culturing in biological and biomedical research and industry calls for fast, non-invasive and reliable methods of evaluating conditions such as pH inside a microfluidic system. We show that by careful calibration it is possible to measure pH within microfluidic chambers with high accuracy and precision, using a direct single-pass measurement of light absorption in a commercially available phenol-red-containing cell culture medium. The measurement is carried out using a standard laboratory microscope and, contrary to previously reported methods, requires no modification of the microfluidic device design. We demonstrate the validity of this method by measuring absorption of light transmitted through 30-micrometer thick microfluidic chambers, using an inverted microscope fitted with a scientific grade digital camera and two bandpass filters. In the pH range of 7-8, our measurements have a standard deviation and absolute error below 0.05 for a measurement volume smaller than 4 nL. PMID- 24049696 TI - Optimal control of light propagation through multiple-scattering media in the presence of noise. AB - We study the control of coherent light propagation through multiple-scattering media in the presence of measurement noise. In our experiments, we use a two-step optimization procedure to find the optimal incident wavefront that generates a bright focal spot behind the medium. We conclude that the control of coherent light propagation through a multiple-scattering medium is only determined by the number of photoelectrons detected per optimized segment. The prediction of our model agrees well with the experimental results. Our results offer opportunities for imaging applications through scattering media such as biological tissue in the shot noise limit. PMID- 24049698 TI - Welcome to Translational Vision Science and Technology. PMID- 24049697 TI - Stochastic speckle noise compensation in optical coherence tomography using non stationary spline-based speckle noise modelling. AB - Optical coherence tomography (OCT) allows for non-invasive 3D visualization of biological tissue at cellular level resolution. Often hindered by speckle noise, the visualization of important biological tissue details in OCT that can aid disease diagnosis can be improved by speckle noise compensation. A challenge with handling speckle noise is its inherent non-stationary nature, where the underlying noise characteristics vary with the spatial location. In this study, an innovative speckle noise compensation method is presented for handling the non stationary traits of speckle noise in OCT imagery. The proposed approach centers on a non-stationary spline-based speckle noise modeling strategy to characterize the speckle noise. The novel method was applied to ultra high-resolution OCT (UHROCT) images of the human retina and corneo-scleral limbus acquired in-vivo that vary in tissue structure and optical properties. Test results showed improved performance of the proposed novel algorithm compared to a number of previously published speckle noise compensation approaches in terms of higher signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and better overall visual assessment. PMID- 24049699 TI - Joanne Angle: 1941-2012. PMID- 24049700 TI - Antioxidants Protect Trabecular Meshwork Cells From Hydrogen Peroxide-Induced Cell Death. AB - PURPOSE: To examine the protective effects of antioxidants in cultured trabecular meshwork (TM) cells exposed to oxidative stress. METHODS: Primary porcine TM cells were pretreated with 50 MUM resveratrol, 0.2 mM urate, 1 mM ascorbate, 1 mM reduced glutathione (rGSH), or 1 mM rho-coumarate followed by exposure to hydrogen peroxide (0.5-4 mM). Cell metabolism was determined by mitochondrial enzyme activity and cell viability by uptake of the vital dye calcein, a fluorescent calcium binding dye. Reactive oxygen species (ROS), which may reflex oxidative damage, were determined by 2'7'-dichlorofluorescein diacetate. RESULTS: Trabecular meshwork cell metabolism was reduced to 72 +/- 5% of control levels with 1 mM hydrogen peroxide (H2O2) treatment. TM cells that co-incubated with ascorbate (85% +/- 5%), rho-coumarate (98 +/- 11%) or rGSH (103 +/- 17%) had significantly increased metabolism compared to 1 mM H2O2 treatment. Resveratrol significantly increased TM cell metabolism at both 2 mM (102 +/- 14% live) and 4 mM H2O2 (27 +/- 12% live), with H2O2-treated cultures containing mostly metabolically inactive cells (3% at 2 mM; 2% at 4 mM). Similar results were obtained in cell viability assays. Ascorbate and resveratrol, but not rho coumarate or rGSH, decreased ROS levels in TM cells exposed to a sublethal dose of H2O2 (0.5 mM). Urate had no protective effect against H2O2 damage in any of the assays. CONCLUSIONS: Increased oxidative damage was demonstrated in the TM of patients with primary open angle glaucoma. The antioxidants (resveratrol, ascorbate, rho-coumarate) and the antioxidant enzyme cofactor (rGSH) protected TM cells from H2O2-induced damage. TRANSLATIONAL RELEVANCE: Future experiments are needed to determine whether addition of antioxidants may maintain TM cell viability in vivo. Antioxidants could be applied either topically or coupled with extended-release vehicles for intraocular injection to reduce free radical formation leading to enhanced therapeutic outcomes. Ultimately, studies using animal models could determine whether application of antioxidants can ameliorate progression in diseases such as glaucoma and macular degeneration. PMID- 24049701 TI - Translational Epidemiology in Ophthalmology: From Etiologic Research to Personalized Health Impact. PMID- 24049702 TI - Optimization of Fibrin Glue Spray Systems for Ophthalmic Surgery. AB - PURPOSE: To optimize fibrin glue (FG) spray for ophthalmic surgery using two spray applicators, EasySpray and DuploSpray systems, by varying the distance from point of application and the pressure/flow rate, and to compare the adhesive strength of sutured and sutureless (FG sprayed) conjunctival graft surgery in a rabbit model. METHODS: FG was sprayed on a 0.2 mm-thick sheet of paper using EasySpray by variously combining application distances of 2.5, 5, 7.5, and 10 cm with pressures of 10, 15, and 20 psi. DuploSpray was used at the same distances but with varying flow rates of 1 and 2 L/min. Subsequently, FG was sprayed on porcine corneas and FG thickness was analyzed by histology. In addition, adhesive strength of the conjunctival graft (0.5 * 0.5 cm) attached to the rabbit cornea by sutured and sutureless surgery (FG spray) was compared using a tension meter. RESULTS: Histology measurements revealed that the FG thickness decreased with increases in distance and pressure of spray using the EasySpray applicator on paper and porcine corneal sections. The adhesive strength of the sutured conjunctival graft (41 +/- 4.85 [kilopascal] KPa) was found to be higher than the graft attached by spraying (10 +/- 2.3 KPa) and the sequential addition of FG (6 +/- 0.714 KPa). CONCLUSIONS: The EasySpray applicator formed a uniform spread of FG at a distance-pressure combination of 5 cm and 20 psi. The conjunctival graft attached with sutures had higher adhesive strength compared with grafts glued with a spray applicator. Although the adhesive strength of FG applied through the applicator was similar to the drop-wise sequential technique, the former was more cost effective because more samples could be sprayed compared with the sequential manual technique. TRANSLATIONAL RELEVANCE: The standardization of the spray system for the application of FG in ophthalmology will provide an economical method for delivering consistent healing results after surgery. PMID- 24049704 TI - Cellular Resolution Panretinal Imaging of Optogenetic Probes Using a Simple Funduscope. AB - PURPOSE: To acquire and characterize cellular-resolved in vivo fluorescence images of optogenetic probes expressed in rodent retinal ganglion cells, by adapting a low-cost and simple fundus system based on a topical endoscope. METHODS: A custom endoscope-based fundus system was constructed (adapted from the design of Paques and colleagues). Bright field and fluorescence images were acquired from head-fixed transgenic mice expressing Channelrhodopsin2-eYFP, and Sprague Dawley rats virally transfected with the optogenetic probe GCaMP3. Images were compared to in vitro images of the same structures and were analyzed. RESULTS: The fundus system provides high-quality, high-resolution fluorescence images of the eye fundus that span the whole retina. The images allow resolving individual cells and axon bundles in the Channelrhodopsin2-eYFP mice and cellular scale structures in the GCaMP3 expressing rats. The resolution in mouse eyes was estimated to be better than 20 MUm (full width at half maximum) and is only marginally dependent on movement-related blurring. CONCLUSIONS: The fluorescence endoscopy fundus system provides a powerful yet simple and widely accessible tool for obtaining cellular resolved fluorescent images of optogenetic and other fluorescent probes. TRANSLATIONAL RELEVANCE: The new system could prove to be a basic tool for non-invasive in vivo small animal retinal imaging in a wide array of translational vision applications, including the tracking of fluorescently tagged cells and the expression of gene-therapy and optogenetic vectors. PMID- 24049703 TI - Olfactory Ensheathing Cells Rescue Optic Nerve Fibers in a Rat Glaucoma Model. AB - PURPOSE: To determine if transplantation of olfactory ensheathing cells (OECs) can reduce loss of optic nerve axons after raised intraocular pressure (IOP) in the rat. METHODS: OECs cultured from the adult olfactory mucosa were transplanted into the region of the optic disc. The IOP was raised by injection of magnetic microspheres into the anterior chamber. RESULTS: At 4 weeks after raising the IOP, the transplanted OECs had migrated into the dorsal area of the optic nerve head (ONH) where they surrounded the optic nerve fibers with a non-myelinated ensheathment. The mean amount of damage to the ONH astrocytic area in rats was 51.0% compared with 85.8% in those without OEC transplants (P < 0.02) and the mean loss of axons in the optic nerve was 51.0% compared with 80.3% in the absence of OECs (P < 0.01). CONCLUSIONS: OECs transplanted into the region of the ONH of the rat can reduce the loss of axons and the damage to ONH astrocytes caused by raised IOP. TRANSLATIONAL RELEVANCE: Confirmation of these preliminary experimental data, further understanding of possible mechanisms of axonal protection by OECs, and the longer-term time course of protection could provide a basis for future human clinical trials of autografted OECs, which would be available from autologous nasal epithelial biopsies. PMID- 24049705 TI - Imaging Retinal Vascular Changes in the Mouse Model of Oxygen-Induced Retinopathy. AB - PURPOSE: Oxygen-induced retinopathy in the mouse is the standard experimental model of retinopathy of prematurity. Assessment of the pathology involves in vitro analysis of retinal vaso-obliteration and retinal neovascularization. The authors studied the clinical features of oxygen-induced retinopathy in vivo using topical endoscopy fundus imaging (TEFI), in comparison to standard investigations, and evaluated a system for grading these features. METHODS: Postnatal day (P)7 mice were exposed to 75% oxygen for five days to induce retinopathy or maintained in room air as controls. Retinal vascular competence was graded against standard photographs by three masked graders. Retinal photographs were obtained at predetermined ages using TEFI. Postmortem, retinal vaso-obliteration was measured in whole mounts with labeled vasculature, and retinal neovascularization was quantified in hematoxylin- and eosin-stained ocular cross sections. RESULTS: Fundus photography by TEFI was possible from P15, when retinal vascular incompetence, including dilatation and tortuosity, was significant in mice with oxygen-induced retinopathy in comparison to controls. Vascular incompetence peaked in severity at P17 and persisted through P25. Comparison with in vitro analyses indicated that vascular changes were most severe after retinal avascularity had begun to decrease in area, and coincident with the maximum of retinal neovascularization. A weighted Fleiss-Cohen kappa indicated good intra- and interobserver agreement for a 5-point grading system. CONCLUSIONS: Topical endoscopy fundus imaging demonstrates retinal vascular incompetence in mice with oxygen-induced retinopathy. The technique complements standard postmortem analysis for following the course of the model. TRANSLATIONAL RELEVANCE: Topical endoscopy fundus imaging has application in the evaluation of novel biologic drugs for retinopathy of prematurity. PMID- 24049706 TI - Safety of Tumor Necrosis Factor Inhibitors during Pregnancy and Breastfeeding. AB - PURPOSE: Tumor necrosis factor (TNF) inhibitors are useful in the treatment of numerous inflammatory and immunologic disorders. Since many of these conditions occur in women of childbearing age, safety during pregnancy and breastfeeding is of considerable importance. METHODS: This paper is a review of the literature on the safety of TNF inhibitors during pregnancy and breastfeeding published between 2001 and 2011. CONCLUSIONS: TNF inhibitors do not appear to be associated with a high risk of teratogenicity or intrauterine death. However, a small magnitude increase in risk cannot be ruled out given the paucity of data on the subject. Although TNF inhibitor use may be associated with a higher rate of preterm delivery, this may in fact be due to an active, underlying disease. Therefore, the decision to use these medications should be made on a case-by-case basis. If the disease cannot be managed with first line agents, TNF inhibitors may be helpful in reducing the number of disease exacerbations. Nevertheless, when using TNF inhibitors, it is prudent to discontinue treatment around the third trimester when transfer across the placenta is greatest and to restart postpartum. PMID- 24049707 TI - The Oral Iron Chelator Deferiprone Protects Against Retinal Degeneration Induced through Diverse Mechanisms. AB - PURPOSE: To investigate the effect of the iron chelator deferiprone (DFP) on sodium iodate (NaIO3)-induced retinal degeneration and on the hereditary retinal degeneration caused by the rd6 mutation. METHODS: Retinas from NaIO3-treated C57BL/6J mice, with or without DFP cotreatment, were analyzed by histology, immunofluorescence, and quantitative PCR to investigate the effect of DFP on retinal degeneration. To facilitate photoreceptor quantification, we developed a new function of MATLAB to perform this task in a semiautomated fashion. Additionally, rd6 mice treated with or without DFP were analyzed by histology to assess possible protection. RESULTS: In NaIO3-treated mice, DFP protected against retinal degeneration and significantly decreased expression of the oxidative stress-related gene heme oxygenase-1 and the complement gene C3. DFP treatment partially protected against NaIO3-induced reduction in the levels of mRNAs encoded by visual cycle genes rhodopsin (Rho) and retinal pigment epithelium specific 65 kDa protein (Rpe65), consistent with the morphological data indicating preservation of photoreceptors and RPE, respectively. DFP treatment also protected photoreceptors in rd6 mice. CONCLUSIONS: The oral iron chelator DFP provides significant protection against retinal degeneration induced through different modalities. This suggests that iron chelation could be useful as a treatment for retinal degeneration even when the main etiology does not appear to be iron dysregulation. TRANSLATIONAL RELEVANCE: These data provide proof of principle that the oral iron chelator DFP can protect the retina against diverse insults. Further testing of DFP in additional animal retinal degeneration models at a range of doses is warranted. PMID- 24049708 TI - Efficacy and Complications of Intravitreal Rituximab Injection for Treating Primary Vitreoretinal Lymphoma. AB - PURPOSE: To assess the long-term clinical outcomes of intravitreal injections of rituximab (IVR), an anti-CD20 monoclonal antibody, to treat CD20-positive primary vitreoretinal lymphoma (PVRL). METHODS: Twenty eyes of 13 women (mean age, 66.2 +/- 9.9 years) with CD20-positive PVRL were included in this prospective, interventional case series. All patients had discontinued previous intravitreal methotrexate (IVM) treatment because of severe corneal epitheliopathy. Weekly IVR injections (1 mg/0.1 ml) for 4 weeks were administered as a one-course protocol. Additional injections were administered when the PVRL recurred. The effects and the adverse events associated with IVR injections were evaluated. RESULTS: All patients completed a 1-year follow-up (mean observation after IVR injections, 24.7 +/- 6.3 months). Before treatment, diffuse keratic precipitates (KPs), anterior vitreous cells, or both were observed in 18 (90%) eyes of 11 patients, and typical subretinal infiltrates were seen in eight (40%) eyes of six patients; all improved with one treatment course. The anterior segment lesions recurred in 11 (55%) eyes of nine patients and resolved with another course of injections. Transient IOP elevations occurred in 12 (60%) eyes of 10 patients within 3.8 +/- 1.9 weeks after the first treatment course; iridocyclitis with mutton-fat KPs developed in seven (35%) eyes of six patients with elevated IOP and resolved with topical treatment. No other significant ocular complications or systemic side effects developed. CONCLUSIONS: Injections of IVR were shown to be an efficacious alternative treatment for PVRL, although the disease recurred in approximately half of the eyes. Complications included transient IOP elevations and iridocyclitis with mutton-fat KPs that were managed topically. TRANSLATIONAL RELEVANCE: The results of this trial support IVR as one element of combined modality therapy for treating PVRL patients without CNS involvement, particularly for those who respond poorly and have side effects with IVM. (http://www.umin.ac.jp/ctr/ number, UMIN000005604). PMID- 24049710 TI - Take Two Iron Chelators and Call Me in the Morning. PMID- 24049709 TI - The Oral Iron Chelator Deferiprone Protects Against Retinal Degeneration Induced through Diverse Mechanisms. AB - PURPOSE: To investigate the effect of the iron chelator deferiprone (DFP) on sodium iodate (NaIO3)-induced retinal degeneration and on the hereditary retinal degeneration caused by the rd6 mutation. METHODS: Retinas from NaIO3-treated C57BL/6J mice, with or without DFP cotreatment, were analyzed by histology, immunofluorescence, and quantitative PCR to investigate the effect of DFP on retinal degeneration. To facilitate photoreceptor quantification, we developed a new function of MATLAB to perform this task in a semiautomated fashion. Additionally, rd6 mice treated with or without DFP were analyzed by histology to assess possible protection. RESULTS: In NaIO3-treated mice, DFP protected against retinal degeneration and significantly decreased expression of the oxidative stress-related gene heme oxygenase-1 and the complement gene C3. DFP treatment partially protected against NaIO3-induced reduction in the levels of mRNAs encoded by visual cycle genes rhodopsin (Rho) and retinal pigment epithelium specific 65 kDa protein (Rpe65), consistent with the morphological data indicating preservation of photoreceptors and RPE, respectively. DFP treatment also protected photoreceptors in rd6 mice. CONCLUSIONS: The oral iron chelator DFP provides significant protection against retinal degeneration induced through different modalities. This suggests that iron chelation could be useful as a treatment for retinal degeneration even when the main etiology does not appear to be iron dysregulation. TRANSLATIONAL RELEVANCE: These data provide proof of principle that the oral iron chelator DFP can protect the retina against diverse insults. Further testing of DFP in additional animal retinal degeneration models at a range of doses is warranted. PMID- 24049711 TI - Neural Stem Cells Derived by Small Molecules Preserve Vision. AB - PURPOSE: The advances in stem cell biology hold a great potential to treat retinal degeneration. Importantly, specific cell types can be generated efficiently with small molecules and maintained stably over numerous passages. Here, we investigated whether neural stem cell (NSC) derived from human embryonic stem cells (hESC) by small molecules can preserve vision following grafting into the Royal College Surgeon (RCS) rats; a model for retinal degeneration. METHODS: A cell suspension containing 3 * 104 NSCs or NSCs labeled with green fluorescent protein (GFP) was injected into the subretinal space or the vitreous cavity of RCS rats at postnatal day (P) 22; animals injected with cell-carry medium and those left untreated were used as controls. The efficacy of treatment was evaluated by testing optokinetic response, recording luminance threshold, and examining retinal histology. RESULTS: NSCs offered significant preservation of both photoreceptors and visual function. The grafted NSCs survived for long term without evidence of tumor formation. Functionally, NSC treated eyes had significantly better visual acuity and lower luminance threshold than controls. Morphologically, photoreceptors and retinal connections were well preserved. There was an increase in expression of cillary neurotrophic factor (CNTF) in Muller cells in the graft-protected retina. CONCLUSIONS: This study reveals that NSCs derived from hESC by small molecules can survive and preserve vision for long term following subretinal transplantation in the RCS rats. These cells migrate extensively in the subretinal space and inner retina; there is no evidence of tumor formation or unwanted changes after grafting into the eyes. TRANSLATIONAL RELEVANCE: The NSCs derived from hESC by small molecules can be generated efficiently and provide an unlimited supply of cells for the treatment of some forms of human outer retinal degenerative diseases. The capacity of NSCs migrating into inner retina offers a potential as a vehicle to delivery drugs/factors to treat inner retinal disorders. PMID- 24049712 TI - Effective Arrestin-Specific Immunotherapy of Experimental Autoimmune Uveitis with RTL: A Prospect for Treatment of Human Uveitis. AB - PURPOSE: To evaluate the immunotherapeutic efficacy of recombinant T cell receptor ligands (RTLs) specific for arrestin immunity in treatment of experimental autoimmune uveitis (EAU) in humanized leukocyte antigen (HLA-DR3) transgenic (Tg) mice. METHODS: We generated de novo recombinant human DR3-derived RTLs bearing covalently tethered arrestin peptides 291-310 (RTL351) or 305-324 (RTL352). EAU was induced by immunization of HLA-DR3 mice with arrestin or arrestin peptide and treated with RTLs by subcutaneous delivery. T cell proliferation and cytokine expression was measured in RTL-treated and control mice. RESULTS: RTL351 prevented the migration of cells outside of the spleen and the recruitment of inflammatory cells into the eye, and provided full protection against inflammation from EAU induced with arrestin or arrestin peptides. RTL351 significantly inhibited T cell proliferation and secretion of inflammatory cytokines interleukin 2 (IL-2), interferon gamma (IFN-gamma), IL-6, and IL-17 and chemokines (macrophage inflammatory proteins [MIP-1a] and regulated and normal T cell expressed and secreted [RANTES]), which is in agreement with the suppression of intraocular inflammation. RTL350 ("empty," no peptide) and RTL352 were not effective. CONCLUSIONS: Immunotherapy with a single RTL351 successfully prevented and treated arrestin-induced EAU in HLA-DR3 mice and provided proof of concept for therapy of autoimmune uveitis in human patients. The beneficial effects of RTL351 should be attributed to a significant decrease in Th1/Th17 mediated inflammation. TRANSLATIONAL RELEVANCE: Successful therapies for autoimmune uveitis must specifically inhibit pathogenic inflammation without inducing generalized immunosuppression. RTLs can offer such an option. The single retina specific RTLs may have a value as potential immunotherapeutic drug for human autoimmune uveitis because they effectively prevent disease induced by multiple T cell specificities. PMID- 24049713 TI - Antenatal Mental Health and Retinal Vascular Caliber in Pregnant Women. AB - PURPOSE: Depression, anxiety, and poor sleep are associated with increased risks of cardiovascular diseases. Previous studies have demonstrated the relationship between negative emotion and retinal microvascular changes among adults, yet no study has been done in pregnant women so far. This study aims to examine the association of antenatal mental health and retinal vascular caliber among Asian pregnant women. METHODS: Nine hundred and fifty two Asian pregnant women aged 18 to 46 years were included in this study, who were recruited from two Singapore cohort studies, the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) study and the In Vitro Fertilization (IVF) study conducted from 2009 onwards. A total of 835 Asian pregnant women underwent retinal photography at 26 weeks follow up, of whom 800 had gradable photographs. Symptoms of depression, anxiety, and sleep quality were assessed with self-administered questionnaires. RESULTS: In multiple linear regression models adjusted for age, ethnicity, household income, pregnancy outcome history, means of conception, hypertension history, diabetes history, cigarette smoking history, mean arterial blood pressure, body mass index, and spherical equivalent, each standard deviation (SD) increase in the Edinburgh Postnatal Depression Scale (EPDS) (4.49 scores) and in the Pittsburgh Sleep Quality Index (PSQI) (2.90 scores) was associated with a 0.80 MUm (P = 0.03) and a 1.22 MUm (P = 0.01) widening in retinal arteriolar caliber, respectively. CONCLUSIONS: Our study demonstrates relationships of antenatal depressive symptoms and poor sleep quality with retinal arteriolar widening in pregnant women. TRANSLATIONAL RELEVANCE: We speculate that this might possibly indicate an effect of antenatal depression and poor sleep on the microcirculation during pregnancy. PMID- 24049714 TI - Multimodal Highlighting of Structural Abnormalities in Diabetic Rat and Human Corneas. AB - PURPOSE: This study aimed to highlight structural corneal changes in a model of type 2 diabetes, using in vivo corneal confocal microscopy (CCM). The abnormalities were also characterized by transmission electron microscopy (TEM) and second harmonic generation (SHG) microscopy in rat and human corneas. METHODS: Goto-Kakizaki (GK) rats were observed at age 12 weeks (n = 3) and 1 year (n = 6), and compared to age-matched controls. After in vivo CCM examination, TEM and SHG microscopy were used to characterize the ultrastructure and the three dimensional organization of the abnormalities. Human corneas from diabetic (n = 3) and nondiabetic (n = 3) patients were also included in the study. RESULTS: In the basal epithelium of GK rats, CCM revealed focal hyper-reflective areas, and histology showed proliferative cells with irregular basement membrane. In the anterior stroma, extracellular matrix modifications were detected by CCM and confirmed in histology. In the Descemet's membrane periphery of all the diabetic corneas, hyper-reflective deposits were highlighted using CCM and characterized as long-spacing collagen fibrils by TEM. SHG microscopy revealed these deposits with high contrast, allowing specific detection in diabetic human and rat corneas without preparation and characterization of their three-dimensional organization. CONCLUSION: Pathologic findings were observed early in the development of diabetes in GK rats. Similar abnormalities have been found in corneas from diabetic patients. TRANSLATIONAL RELEVANCE: This multidisciplinary study highlights diabetes-induced corneal abnormalities in an animal model, but also in diabetic donors. This could constitute a potential early marker for diagnosis of hyperglycemia-induced tissue changes. PMID- 24049715 TI - Rhodopsin F45L Allele Does Not Cause Autosomal Dominant Retinitis Pigmentosa in a Large Caucasian Family. AB - PURPOSE: To ascertain the potential pathogenicity of a retinitis pigmentosa (RP) causing RHO F45L allele in a family affected by congenital achromatopsia (ACHM). METHODS: Case series/observational study that included two patients with ACHM and 24 extended family members. Molecular genetic analysis was performed to identify RHO F45L carrier status in the family and a control population. An adaptive optics scanning light ophthalmoscope (AOSLO) was used to image the photoreceptor mosaic and assess rod and cone structure. Spectral domain optical coherence tomography (SD-OCT) was used to examine retinal lamination. Comprehensive clinical testing included acuity, color vision, and dilated fundus examination. Electroretinography was used to assess rod and cone function. RESULTS: Five carriers of the RHO F45L allele alone (24-80 years) and three carriers in combination with a heterozygous CNGA3 mutant allele (10-64 years) were all free of the classic symptoms and signs of RP. In heterozygous carriers of both mutations, SD-OCT showed normal retinal thickness and intact outer retinal layers; rod and cone densities were within normal limits on AOSLO. The phenotype in two individuals affected with ACHM and harboring the RHO F45L allele was indistinguishable from that previously reported for ACHM. CONCLUSIONS: The RHO F45L allele is not pathogenic in this large family; hence, the two ACHM patients would unlikely develop RP in the future. TRANSLATIONAL RELEVANCE: The combined approach of comprehensive molecular analysis of individual genomes and noninvasive cellular resolution retinal imaging enhances the current repertoire of clinical diagnostic tools, giving a substantial impetus to personalized medicine. PMID- 24049716 TI - Clinical Tests of Ultra-Low Vision Used to Evaluate Rudimentary Visual Perceptions Enabled by the BrainPort Vision Device. AB - PURPOSE: We evaluated whether existing ultra-low vision tests are suitable for measuring outcomes using sensory substitution. The BrainPort is a vision assist device coupling a live video feed with an electrotactile tongue display, allowing a user to gain information about their surroundings. METHODS: We enrolled 30 adult subjects (age range 22-74) divided into two groups. Our blind group included 24 subjects (n = 16 males and n = 8 females, average age 50) with light perception or worse vision. Our control group consisted of six subjects (n = 3 males, n = 3 females, average age 43) with healthy ocular status. All subjects performed 11 computer-based psychophysical tests from three programs: Basic Assessment of Light Motion, Basic Assessment of Grating Acuity, and the Freiburg Vision Test as well as a modified Tangent Screen. Assessments were performed at baseline and again using the BrainPort after 15 hours of training. RESULTS: Most tests could be used with the BrainPort. Mean success scores increased for all of our tests except contrast sensitivity. Increases were statistically significant for tests of light perception (8.27 +/- 3.95 SE), time resolution (61.4% +/- 3.14 SE), light localization (44.57% +/- 3.58 SE), grating orientation (70.27% +/- 4.64 SE), and white Tumbling E on a black background (2.49 logMAR +/- 0.39 SE). Motion tests were limited by BrainPort resolution. CONCLUSIONS: Tactile-based sensory substitution devices are amenable to psychophysical assessments of vision, even though traditional visual pathways are circumvented. TRANSLATIONAL RELEVANCE: This study is one of many that will need to be undertaken to achieve a common outcomes infrastructure for the field of artificial vision. PMID- 24049717 TI - Accelerated In Vitro Degradation of Optically Clear Low beta-Sheet Silk Films by Enzyme-Mediated Pretreatment. AB - PURPOSE: To design patterned, transparent silk films with fast degradation rates for the purpose of tissue engineering corneal stroma. METHODS: beta-sheet (crystalline) content of silk films was decreased significantly by using a short water annealing time. Additionally, a protocol combining short water annealing time with enzymatic pretreatment of silk films with protease XIV was developed. RESULTS: Low beta-sheet content (17%-18%) and enzymatic pretreatment provided film stability in aqueous environments and accelerated degradation of the silk films in the presence of human corneal fibroblasts in vitro. The results demonstrate a direct relationship between reduced beta-sheet content and enzymatic pretreatment, and overall degradation rate of the protein films. CONCLUSIONS: The novel protocol developed here provides new approaches to modulate the regeneration rate of silk biomaterials for corneal tissue regeneration needs. TRANSLATIONAL RELEVANCE: Patterned silk protein films possess desirable characteristics for corneal tissue engineering, including optical transparency, biocompatibility, cell alignment, and tunable mechanical properties, but current fabrication protocols do not provide adequate degradation rates to match the regeneration properties of the human cornea. This novel processing protocol makes silk films more suitable for the construction of human corneal stroma tissue and a promising way to tune silk film degradation properties to match corneal tissue regeneration. PMID- 24049718 TI - Factors Affecting Perceptual Threshold in Argus II Retinal Prosthesis Subjects. AB - PURPOSE: The Argus II epiretinal prosthesis has been developed to provide partial restoration of vision to subjects blinded from outer retinal degenerative disease. Participants were surgically implanted with the system in the United States and Europe in a single arm, prospective, multicenter clinical trial. The purpose of this investigation was to determine which factors affect electrical thresholds in order to inform surgical placement of the device. METHODS: Electrode-retina and electrode-fovea distances were determined using SD-OCT and fundus photography, respectively. Perceptual threshold to electrical stimulation of electrodes was measured using custom developed software, in which current amplitude was varied until the threshold was found. Full field stimulus light threshold was measured using the Espion D-FST test. Relationships between electrical threshold and these three explanatory variables (electrode-retina distance, electrode-fovea distance, and monocular light threshold) were quantified using regression. RESULTS: Regression analysis showed a significant correlation between electrical threshold and electrode-retina distance (R2 = 0.50, P = 0.0002; n = 703 electrodes). 90.3% of electrodes in contact with the macula (n = 207) elicited percepts at charge densities less than 1 mC/cm2/phase. These threshold data also correlated well with ganglion cell density profile (P = 0.03). A weaker, but still significant, inverse correlation was found between light threshold and electrical threshold (R2 < 0.52, P = 0.01). Multivariate modeling indicated that electrode-retina distance and light threshold are highly predictive of electrode threshold (R2 = 0.87; P < 0.0005). CONCLUSIONS: Taken together, these results suggest that while light threshold should be used to inform patient selection, macular contact of the array is paramount. TRANSLATIONAL RELEVANCE: Reported Argus II clinical study results are in good agreement with prior in vitro and in vivo studies, and support the development of higher-density systems that employ smaller diameter electrodes. (clinicaltrials.gov identifier: NCT00407602). PMID- 24049719 TI - Considering Apical Scotomas, Confusion, and Diplopia When Prescribing Prisms for Homonymous Hemianopia. AB - PURPOSE: While prisms are commonly prescribed for homonymous hemianopia to extend or expand the visual field, they cause potentially troubling visual side effects, including nonveridical location of perceived images, diplopia, and visual confusion. In addition, the field behind a prism at its apex is lost to an apical scotoma equal in magnitude to the amount of prism shift. The perceptual consequences of apical scotomas and the other effects of various designs were examined to consider parameters and designs that can mitigate the impact of these effects. METHODS: Various configurations of sector and peripheral prisms were analyzed, in various directions of gaze, and their visual effects were illustrated using simulated perimetry. A novel "percept" diagram was developed that yielded insights into the patient's view through the prisms. The predictions were verified perimetrically with patients. RESULTS: The diagrams distinguish between potentially beneficial field expansion via visual confusion and the pericentrally disturbing and useless effect of diplopia, and their relationship to prism power and gaze direction. They also illustrate the nonexpanding substitution of field segments of some popular prism designs. CONCLUSIONS: Yoked sector prisms have no effect at primary gaze or when gaze is directed toward the seeing hemifield, and they introduce pericentral field loss when gaze is shifted into them. When fitted unilaterally, sector prisms also have an effect only when the gaze is directed into the prism and may cause a pericentral scotoma and/or central diplopia. Peripheral prisms are effective at essentially all gaze angles. Since gaze is not directed into them, they avoid problematic pericentral effects. We derive useful recommendations for prism power and position parameters, including novel ways of fitting prisms asymmetrically. TRANSLATIONAL RELEVANCE: Clinicians will find these novel diagrams, diagramming techniques, and analyses valuable when prescribing prismatic aids for hemianopia and when designing new prism devices for patients with various types of field loss. PMID- 24049720 TI - Towards Patient-Tailored Perimetry: Automated Perimetry Can Be Improved by Seeding Procedures With Patient-Specific Structural Information. AB - PURPOSE: To explore the performance of patient-specific prior information, for example, from structural imaging, in improving perimetric procedures. METHODS: Computer simulation was used to determine the error distribution and presentation count for Structure-Zippy Estimation by Sequential Testing (ZEST), a Bayesian procedure with prior distribution centered on a threshold prediction from structure. Structure-ZEST (SZEST) was trialled for single locations with combinations of true and predicted thresholds between 1 to 35 dB, and compared with a standard procedure with variability similar to Swedish Interactive Thresholding Algorithm (SITA) (Full-Threshold, FT). Clinical tests of glaucomatous visual fields (n = 163, median mean deviation -1.8 dB, 90% range +2.1 to -22.6 dB) were also compared between techniques. RESULTS: For single locations, SZEST typically outperformed FT when structural predictions were within +/- 9 dB of true sensitivity, depending on response errors. In damaged locations, mean absolute error was 0.5 to 1.8 dB lower, SD of threshold estimates was 1.2 to 1.5 dB lower, and 2 to 4 (29%-41%) fewer presentations were made for SZEST. Gains were smaller across whole visual fields (SZEST, mean absolute error: 0.5 to 1.2 dB lower, threshold estimate SD: 0.3 to 0.8 dB lower, 1 [17%] fewer presentation). The 90% retest limits of SZEST were median 1 to 3 dB narrower and more consistent (interquartile range 2-8 dB narrower) across the dynamic range than those for FT. CONCLUSION: Seeding Bayesian perimetric procedures with structural measurements can reduce test variability of perimetry in glaucoma, despite imprecise structural predictions of threshold. TRANSLATIONAL RELEVANCE: Structural data can reduce the variability of current perimetric techniques. A strong structure-function relationship is not necessary, however, structure must predict function within +/-9 dB for gains to be realized. PMID- 24049721 TI - P-glycoprotein Blockers Augment the Effect of Mitomycin C on Human Tenon's Fibroblasts. AB - PURPOSE: Mitomycin C (MMC), which induces apoptosis in human Tenon's fibroblasts (HTF), is frequently used to retard wound healing after glaucoma surgery. The aim of this in vitro study was to examine whether adjunctive Verapamil and Cyclosporine could augment the cytotoxic effect of MMC on HTF. METHODS: Fibroblast cell lines were established by explant culture from human tissue biopsy samples obtained during trabeculectomy procedures. Cells were exposed to MMC at varying concentrations (0.01-0.4 mg/ml) for 3 minutes, prior to washing in the presence or absence of the following drugs: Staurosporine (0.003mg/ml), Verapamil (2.5-0.25 mg/ml), or Cyclosporine (50-0.5 mg/ml). Following exposure, cells were cultured for 6 hours and surviving cells quantitated by haemocytometer counts. RESULTS: Both Verapamil and Staurosporine exhibited mild toxic effects on their own, but greatly enhanced the apoptotic effect of MMC. Staurosporine is too toxic to be considered clinically, so its augmentive effect on the activity of MMC was not studied further here. Doses as low as 0.25 mg/ml of Verapamil continued to show significant augmentation of the apoptotic effect of MMC Cyclosporine at a clinically used concentration (5 mg/ml) exhibited modest augmentation of the effect of MMC. CONCLUSIONS: Verapamil and Cyclosporine in clinically acceptable concentrations potentiate the effect of MMC and may obviate the need for high dose antimetabolites in trabeculectomy; however, further preclinical study is required. TRANSLATIONAL RELEVANCE: Adjunctive Verapamil or Cyclosporine may allow lower dose MMC to be used in glaucoma filtration surgery while maintaining the same antifibrotic effects. PMID- 24049722 TI - Diagnostic Performance of the ISNT Rule for Glaucoma Based on the Heidelberg Retinal Tomograph. AB - PURPOSE: We determined the accuracy of the inferior > superior > nasal > temporal (ISNT) neuroretinal rim area rule and its variants in adult Asian populations, and evaluated whether disc area impacts its performance characteristics. METHODS: Participants in the Singapore Malay Eye Study (SiMES) and Singapore Indian Eye Study (SINDI) underwent standardized ocular examinations, including optic disc imaging with the Heidelberg retinal tomograph (HRT). Glaucoma was defined using the ISGEO criteria. HRT rim areas in the superior, inferior, nasal, and temporal quadrants were quantified. We determined sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values of violating the ISNT rule and 4 variants (I > S > T, I > S, I > T, and combined I > T and S > T). The influence of disc area was analyzed with multivariate marginal logistic regression. RESULTS: There were 6112 participants (mean age: 57.6 +/- 10.3 years). Glaucoma was present in 194 individuals (3.2%). Among 11,840 eyes, 232 (93.2%) of 249 glaucomatous eyes and 9768 (84.3%) of 11,591 nonglaucomatous eyes, violated the ISNT rule. The ISNT rule had highest sensitivity (93.5%), but lowest specificity (15.7%); I > T had highest specificity (98.2%), but low sensitivity (7.4%). For all variants, PPVs were low (2.1%-8.4%) and NPVs were high (97.9-99.1%). Larger disc area was associated with reduced specificity for the ISNT rule (P < 0.001), and reduced sensitivity (P = 0.01) and increased specificity for I > S > T (P < 0.05). PPV increased (P < 0.05) and NPV decreased (P < 0.001) with increasing disc area. CONCLUSIONS: The ISNT rule based on HRT has high sensitivity, and the I > T, S > T, and combined I > T and S > T variants have high specificity. Disc area influences sensitivity, specificity, PPV, and NPV of the ISNT rule and its variants. TRANSLATIONAL RELEVANCE: The high sensitivity of the ISNT rule, and high specificities of its variants, may have potential utility when used in combination with other HRT algorithms for glaucoma assessment. PMID- 24049723 TI - Latanoprost Stimulates Ocular Lymphatic Drainage: An In Vivo Nanotracer Study. AB - PURPOSE: Ocular lymphatics have been recently shown to contribute to aqueous humor outflow. It is not yet known whether lymphatic outflow can be stimulated by pharmacological agents. Here we determine whether latanoprost, a prostaglandin F2 alpha analog commonly used to lower IOP to treat glaucoma, increases lymphatic drainage from the eye. METHODS: Lymphatic drainage in mice was assessed in vivo, in 11 latanoprost-treated and 11 control animals using hyperspectral imaging at multiple times following quantum dot (QD) injection into the eye. QD signal intensity was also measured in tissue sections using hyperspectral imaging. RESULTS: In the latanoprost-treated group, lymphatic drainage rate into the submandibular lymph node was increased compared with controls (1.23 +/- 1.06 hours-1 vs. 0.30 +/- 0.17 hours-1, mean +/- SD, P < 0.02). Total QD signal intensity in the submandibular lymph node was greater in the latanoprost-treated group compared with controls (10.55 +/- 1.12 vs. 9.48 +/- 1.24, log scale, P < 0.05). CONCLUSIONS: This is the first evidence that latanoprost increases lymphatic drainage from the eye. The pharmacological manipulation of this newly identified lymphatic outflow pathway may be relevant to treatments aimed at lowering intraocular pressure in glaucoma. TRANSLATIONAL RELEVANCE: This is the first evidence that a prostaglandin drug widely prescribed for glaucoma, enhances lymphatic drainage from the eye. The pharmacological stimulation of this newly identified outflow pathway may be highly relevant to treatments aimed at lowering IOP to prevent blindness from glaucoma. PMID- 24049724 TI - A role for PYY3-36 in GLP1-induced insulin secretion. PMID- 24049725 TI - Visualizing browning in vivo. PMID- 24049726 TI - Boosting mitochondrial biogenesis in white adipocytes: A route towards improved insulin sensitivity? PMID- 24049727 TI - Importance of estrogen receptors in adipose tissue function. PMID- 24049728 TI - Adiponectin, driver or passenger on the road to insulin sensitivity? AB - Almost 20 years have passed since the first laboratory evidence emerged that an abundant message encoding a protein with homology to the C1q superfamily is highly specifically expressed in adipocytes. At this stage, we refer to this protein as adiponectin. Despite more than 10,000 reports in the literature since its initial description, we seem to have written only the first chapter in the textbook on adiponectin physiology. With every new aspect we learn about adiponectin, a host of new questions arise with respect to the underlying molecular mechanisms. Here, we aim to summarize recent findings in the field and bring the rodent studies that suggest a causal relationship between adiponectin levels in plasma and systemic insulin sensitivity in perspective with the currently available data on the clinical side. PMID- 24049730 TI - (11)C-meta-hydroxyephedrine PET/CT imaging allows in vivo study of adaptive thermogenesis and white-to-brown fat conversion. AB - Several lines of evidence suggest that novel pharmacological approaches aimed at converting white adipose tissue (WAT) into brown adipose tissue (BAT) may represent an effective therapeutic strategy for obesity and related disorders. ((18))F-fluorodeoxyglucose ((18)F-FDG) is the only positron emission tomography (PET) tracer commonly used to study BAT function, and so far no functional tools have been described to investigate in vivo white-to-brown fat conversion. In this report, we show that the PET tracer (11)C-meta-hydroxyephedrine ((11)C-MHED, a norepinephrine analogue) is a useful tool to investigate the sympathetic nervous system (SNS) activity in BAT of lean and dietary obese mice. Moreover, we demonstrate that (11)C-MHED is a specific marker of the SNS-mediated thermogenesis in typical BAT depots, and that this tracer can detect in vivo WAT to BAT conversion. PMID- 24049729 TI - Peripheral activation of the Y2-receptor promotes secretion of GLP-1 and improves glucose tolerance. AB - The effect of peptide tyrosine-tyrosine (PYY) on feeding is well established but currently its role in glucose homeostasis is poorly defined. Here we show in mice, that intraperitoneal (ip) injection of PYY3-36 or Y2R agonist improves nutrient-stimulated glucose tolerance and enhances insulin secretion; an effect blocked by peripheral, but not central, Y2R antagonist administration. Studies on isolated mouse islets revealed no direct effect of PYY3-36 on insulin secretion. Bariatric surgery in mice, enterogastric anastomosis (EGA), improved glucose tolerance in wild-type mice and increased circulating PYY and active GLP-1. In contrast, in Pyy-null mice, post-operative glucose tolerance and active GLP-1 levels were similar in EGA and sham-operated groups. PYY3-36 ip increased hepato portal active GLP-1 plasma levels, an effect blocked by ip Y2R antagonist. Collectively, these data suggest that PYY3-36 therefore acting via peripheral Y2R increases hepato-portal active GLP-1 plasma levels and improves nutrient stimulated glucose tolerance. PMID- 24049731 TI - STAT1, NF-kappaB and ERKs play a role in the induction of lipocalin-2 expression in adipocytes. AB - Lipocalin-2 (LCN2) is induced in conditions of obesity and Type 2 diabetes (T2DM). IFNgamma and TNFalpha induce LCN2 expression in adipocytes in a manner that is dependent on transcription. The effects of these cytokines are additive. IFNgamma induced STAT1 and TNFalpha induced NF-kappaB play a role in the induction of LCN2. In the LCN2 promoter, one NF-kappaB binding site and four STAT1 binding sites were identified by in silico and in vitro approaches. MAPK (ERKs 1 and 2) activation was required for the IFNgamma and TNFalpha induction of LCN2 expression, but did not affect the nuclear translocation or DNA binding activity of STAT1 or NF-kappaB. The NF-kappaB binding site and the STAT1 binding sites we identified in vitro were confirmed by in vivo studies. Transfection of a LCN2 promoter/luciferase reporter construct confirmed acute activation by IFNgamma and TNFalpha. Our studies identify mechanisms involved in the actions of cytokines secreted from immune cells in adipose tissue that induce LCN2 expression in conditions of obesity and T2DM. PMID- 24049732 TI - Differential colonization with segmented filamentous bacteria and Lactobacillus murinus do not drive divergent development of diet-induced obesity in C57BL/6 mice. AB - Alterations in the gut microbiota have been proposed to modify the development and maintenance of obesity and its sequelae. Definition of underlying mechanisms has lagged, although the ability of commensal gut microbes to drive pathways involved in inflammation and metabolism has generated compelling, testable hypotheses. We studied C57BL/6 mice from two vendors that differ in their obesogenic response and in their colonization by specific members of the gut microbiota having well-described roles in regulating gut immune responses. We confirmed the presence of robust differences in weight gain in mice from these different vendors during high fat diet stress. However, neither specific, highly divergent members of the gut microbiota (Lactobacillus murinus, segmented filamentous bacteria) nor the horizontally transmissible gut microbiota were found to be responsible. Constitutive differences in locomotor activity were observed, however. These data underscore the importance of selecting appropriate controls in this widely used model of human obesity. PMID- 24049733 TI - Role of the circadian clock gene Per2 in adaptation to cold temperature. AB - Adaptive thermogenesis allows mammals to resist to cold. For instance, in brown adipose tissue (BAT) the facultative uncoupling of the proton gradient from ATP synthesis in mitochondria is used to generate systemic heat. However, this system necessitates an increase of the Uncoupling protein 1 (Ucp1) and its activation by free fatty acids. Here we show that mice without functional Period2 (Per2) were cold sensitive because their adaptive thermogenesis system was less efficient. Upon cold-exposure, Heat shock factor 1 (HSF1) induced Per2 in the BAT. Subsequently, PER2 as a co-activator of PPARalpha increased expression of Ucp1. PER2 also increased Fatty acid binding protein 3 (Fabp3), a protein important to transport free fatty acids from the plasma to mitochondria to activate UCP1. Hence, in BAT PER2 is important for the coordination of the molecular response of mice exposed to cold by synchronizing UCP1 expression and its activation. PMID- 24049734 TI - PGC-1beta and ChREBP partner to cooperatively regulate hepatic lipogenesis in a glucose concentration-dependent manner. AB - Peroxisome proliferator-activated receptorgamma coactivators (PGC-1alpha and PGC 1beta) play important roles in the transcriptional regulation of intermediary metabolism. To evaluate the effects of overexpressing PGC-1alpha or PGC-1beta at physiologic levels in liver, we generated transgenic mice with inducible overexpression of PGC-1alpha or PGC-1beta. Gene expression array profiling revealed that whereas both PGC-1 family proteins induced mitochondrial oxidative enzymes, the expression of several genes involved in converting glucose to fatty acid was induced by PGC-1beta, but not PGC-1alpha. The increased expression of enzymes involved in carbohydrate utilization and de novo lipogenesis by PGC-1beta required carbohydrate response element binding protein (ChREBP). The interaction between PGC-1beta and ChREBP, as well as PGC-1beta occupancy of the liver-type pyruvate kinase promoter, was influenced by glucose concentration and liver specific PGC-1beta(-/-) hepatocytes were refractory to the lipogenic response to high glucose conditions. These data suggest that PGC-1beta-mediated coactivation of ChREBP is involved in the lipogenic response to hyperglycemia. PMID- 24049735 TI - Fibroblast growth factor 21 is not required for the antidiabetic actions of the thiazoladinediones. AB - Fibroblast growth factor 21 is an emerging metabolic regulator that was recently proposed to be a fed-state inducible factor in adipose tissue. As mice lacking FGF21 were refractory to treatment with rosiglitazone, FGF21 was suggested to underlie PPARgamma-driven pharmacology and side effect profile (Dutchak et al., 2012 [12]). To evaluate FGF21/PPARgamma cross-talk we conducted experiments in control and FGF21 null animals and found that rosiglitazone was equally efficacious in both strains. Specifically, diverse endpoints ranging from enhanced glycemic control, improved lipid homeostasis and side effects such as adipose accumulation were evident in both genotypes. Furthermore, the transcriptional signature and cytokine secretion profile of rosiglitazone action were maintained in our FGF21KO animals. Finally, we found that FGF21 in adipose was expressed at comparable levels in fasted and fed states. Thus, our data present a new viewpoint on the FGF21/PPARgamma interplay whereby FGF21 is not necessary for the metabolic events downstream of PPARgamma. PMID- 24049736 TI - Mice lacking PGC-1beta in adipose tissues reveal a dissociation between mitochondrial dysfunction and insulin resistance. AB - Proper development and function of white adipose tissue (WAT), which are regulated by multiple transcription factors and coregulators, are crucial for glucose homeostasis. WAT is also the main target of thiazolidinediones, which are thought to exert their insulin-sensitizing effects by promoting mitochondrial biogenesis in adipocytes. Besides being expressed in WAT, the role of the coactivator PGC-1beta in this tissue has not been addressed. To study its function in WAT, we have generated mice that lack PGC-1beta in adipose tissues. Gene expression profiling analysis of WAT reveals that PGC-1beta regulates mitochondrial genes involved in oxidative metabolism. Furthermore, lack of PGC 1beta prevents the induction of mitochondrial genes by rosiglitazone in WAT without affecting the capacity of thiazolidinediones to enhance insulin sensitivity. Our findings indicate that PGC-1beta is important for basal and rosiglitazone-induced mitochondrial function in WAT, and that induction of mitochondrial oxidative capacity is not essential for the insulin-sensitizing effects of thiazolidinediones. PMID- 24049737 TI - The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis. AB - Our data demonstrate that estrogens, estrogen receptor-alpha (ERalpha), and estrogen receptor-beta (ERbeta) regulate adipose tissue distribution, inflammation, fibrosis, and glucose homeostasis, by determining that alphaERKO mice have increased adipose tissue inflammation and fibrosis prior to obesity onset. Selective deletion of adipose tissue ERalpha in adult mice using a novel viral vector technology recapitulated the findings in the total body ERalpha null mice. Generation of a novel mouse model, lacking ERalpha specifically from adipocytes (AdipoERalpha), demonstrated increased markers of fibrosis and inflammation, especially in the males. Additionally, we found that the beneficial effects of estrogens on adipose tissue require adipocyte ERalpha. Lastly, we determined the role of ERbeta in regulating inflammation and fibrosis, by breeding the AdipoERalpha into the betaERKO background and found that in the absence of adipocyte ERalpha, ERbeta has a protective role. These data suggest that adipose tissue and adipocyte ERalpha protects against adiposity, inflammation, and fibrosis in both males and females. PMID- 24049738 TI - Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques. AB - Oxidation of LDL (oxLDL) is a crucial step in the development of cardiovascular disease. Treatment with antibodies directed against oxLDL can reduce atherosclerosis in rodent models through unknown mechanisms. We demonstrate that through a novel mechanism of immune complex formation and Fc-gamma receptor (FcgammaR) engagement, antibodies targeting oxLDL (MLDL1278a) are anti inflammatory on innate immune cells via modulation of Syk, p38 MAPK phosphorylation and NFkappaB activity. Subsequent administration of MLDL1278a in diet-induced obese (DIO) nonhuman primates (NHP) resulted in a significant decrease in pro-inflammatory cytokines and improved overall immune cell function. Importantly, MLDL1278a treatment improved insulin sensitivity independent of body weight change. This study demonstrates a novel mechanism by which an anti-oxLDL antibody improves immune function and insulin sensitivity independent of internalization of oxLDL. This identifies MLDL1278a as a potential therapy for reducing vascular inflammation in diabetic conditions. PMID- 24049739 TI - Verbal descriptors influence hypothalamic response to low-calorie drinks. AB - Messages describing foods constitute a pervasive form of reward cueing. Different descriptions may produce particular appeal depending upon the individual. To examine the extent to which verbal descriptors and individual differences interact to influence food preferences, we used functional magnetic resonance imaging to measure brain responses to the same low-calorie drinks preceded by the spoken verbal descriptor "treat" or "healthy" in 27 subjects varying in BMI, eating style and reward sensitivity. Subjects also sampled a prototypical milkshake treat. Despite the fact that the verbal descriptor had no influence on pleasantness ratings, preferential responses to the low-calorie drinks labeled "treat" vs. "healthy" were observed in the midbrain and hypothalamus. These same regions were also preferentially responsive to the prototypical treat. These results reveal a previously undocumented influence of verbal descriptors on brain circuits regulating energy homeostasis. PMID- 24049740 TI - Metabolic endotoxemia directly increases the proliferation of adipocyte precursors at the onset of metabolic diseases through a CD14-dependent mechanism. AB - Metabolic endotoxemia triggers inflammation, targets cells from the stroma vascular fraction of adipose depots, and metabolic disease. To identify these cells we here infused mice with lipopolysaccharides and showed by FACS analyses and BrdU staining that the number of small subcutaneous adipocytes, preadipocytes and macrophages increased in wild type but not in CD14-knockout (KO) mice. This mechanism was direct since in CD14KO mice grafted subcutaneously and simultaneously with fat pads from CD14KO and wild-type mice the concentration of cytokine mRNA was increased in the wild-type fat pad only. Conversely, the mRNA concentration of genes involved in glucose and lipid metabolism and the number of large adipocytes was reduced. Eventually, a pretreatment with LPS enhanced HFD induced metabolic diseases. Altogether, these results show that metabolic endotoxemia increases the proliferation of preadipocytes through a CD14-dependent mechanism directly, without recruiting CD14-positive cells from non-adipose depot origin. This mechanism could precede the onset of metabolic diseases. PMID- 24049741 TI - PER2 promotes glucose storage to liver glycogen during feeding and acute fasting by inducing Gys2 PTG and G L expression. AB - The interplay between hepatic glycogen metabolism and blood glucose levels is a paradigm of the rhythmic nature of metabolic homeostasis. Here we show that mice lacking a functional PER2 protein (Per2 (Brdm1) ) display reduced fasting glycemia, altered rhythms of hepatic glycogen accumulation, and altered rhythms of food intake. Per2 (Brdm1) mice show reduced hepatic glycogen content and altered circadian expression during controlled fasting and refeeding. Livers from Per2 (Brdm1) mice display reduced glycogen synthase protein levels during refeeding, and increased glycogen phosphorylase activity during fasting. The latter is explained by PER2 action on the expression of the adapter proteins PTG and GL, which target the protein phosphatase-1 to glycogen to decrease glycogen phosphorylase activity. Finally, PER2 interacts with genomic regions of Gys2, PTG, and G L . These results indicate an important role for PER2 in the hepatic transcriptional response to feeding and acute fasting that promotes glucose storage to liver glycogen. PMID- 24049742 TI - Methionine and choline regulate the metabolic phenotype of a ketogenic diet. AB - Low-carbohydrate ketogenic diets are commonly used as weight loss alternatives to low-fat diets, however the physiological and molecular adaptations to these diets are not completely understood. It is assumed that the metabolic phenotype of the ketogenic diet (KD) is caused by the absence of carbohydrate and high fat content, however in rodents the protein content of KD affects weight gain and ketosis. In this study we examined the role of methionine and choline in mediating the metabolic effects of KD. We have found that choline was more effective than methionine in decreasing the liver steatosis of KD-fed mice. On the other hand, methionine supplementation was more effective than choline in restoring weight gain and normalizing the expression of several fatty acid and inflammatory genes in the liver of KD-fed mice. Our results indicate that choline and methionine restriction rather than carbohydrate restriction underlies many of the metabolic effects of KD. PMID- 24049743 TI - Transcriptional regulation of adipocyte formation by the liver receptor homologue 1 (Lrh1)-Small hetero-dimerization partner (Shp) network. AB - Altered adipose tissue formation is a well-known effectors of obesity and T2D. Here, we describe the role of Lrh1 and its co-repressor Shp in the control of adipocyte formation. Expression of Lrh1 in the pre-adipocyte containing SVF is induced in obese mice models and humans while Shp expression is reduced. We demonstrate, that Lrh1 is an inhibitor of adipogenesis while Shp acts functions as an activator through repression of Lrh1 activity. This regulation is at least in part modulated by estradiol conversion through the regulation of Cyp19a1 gene expression. In vivo, loss of Lrh1 leads to induced adipogenesis, while loss of Shp causes uncontrolled activation of Lrh1 and reduced adipogenesis. As Shp expression has been linked to the development of obesity and metabolic disorders, it is possible that alterations of the Shp/Lrh1 network lead to changes in adipocyte formation, which might contribute to the development of obesity associated T2D. PMID- 24049744 TI - Quantified MRI and cognition in TBI with diffuse and focal damage? AB - In patients with chronic-phase traumatic brain injury (TBI), structural MRI is readily attainable and provides rich anatomical information, yet the relationship between whole-brain structural MRI measures and neurocognitive outcome is relatively unexplored and can be complicated by the presence of combined focal and diffuse injury. In this study, sixty-three patients spanning the full range of TBI severity received high-resolution structural MRI concurrent with neuropsychological testing. Multivariate statistical analysis assessed covariance patterns between volumes of grey matter, white matter, and sulcal/subdural and ventricular CSF across 38 brain regions and neuropsychological test performance. Patients with diffuse and diffuse + focal injury were analyzed both separately and together. Tests of speeded attention, working memory, and verbal learning and memory robustly covaried with a distributed pattern of volume loss over temporal, ventromedial prefrontal, right parietal regions, and cingulate regions. This pattern was modulated by the presence of large focal lesions, but held even when analyses were restricted to those with diffuse injury. Effects were most consistently observed within grey matter. Relative to regional brain volumetric data, clinically defined injury severity (depth of coma at time of injury) showed only weak relation to neuropsychological outcome. The results showed that neuropsychological test performance in patients with TBI is related to a distributed pattern of volume loss in regions mediating mnemonic and attentional processing. This relationship holds for patients with and without focal lesions, indicating that diffuse injury alone is sufficient to cause significant neuropsychological disability in relation to regional volume loss. Quantified structural brain imaging data provides a highly sensitive index of brain integrity that is related to cognitive functioning in chronic phase TBI. PMID- 24049745 TI - Bilirubin neurotoxicity in preterm infants: risk and prevention. AB - Hemolytic conditions in preterm neonates, including Rhesus (Rh) disease, can lead to mortality and long-term impairments due to bilirubin neurotoxicity. Universal access to Rh immunoprophylaxis, coordinated perinatal-neonatal care, and effective phototherapy has virtually eliminated the risk of kernicterus in many countries. In the absence of jaundice due to isoimmunization and without access to phototherapy or exchange transfusion (in 1955), kernicterus was reported at 10.1%, 5.5%, and 1.2% in babies <30, 31-32, and 33-34 wks gestational age, respectively. Phototherapy initiated at 24+/-12 hr effectively prevented hyperbilirubinemia in infants <2,000 g even in the presence of hemolysis. This approach (in 1985) reduced exchange transfusions from 23.9% to 4.8%. Now with 3 decades of experience in implementing effective phototherapy, the need for exchange transfusions has virtually been eliminated. However, bilirubin neurotoxicity continues to be associated with prematurity alone. The ability to better predict this risk, other than birthweight and gestation, has been elusive. Objective tests such as total bilirubin, unbound or free bilirubin, albumin levels, and albumin-bilirubin binding, together with observations of concurrent hemolysis, sepsis, and rapid rate of bilirubin rise have been considered, but their individual or combined predictive utility has yet to be refined. The disruptive effects of immaturity, concurrent neonatal disease, cholestasis, use of total parenteral nutrition or drugs that alter bilirubin-binding abilities augment the clinical risk of neurotoxicity. Current management options rely on the "fine-tuning" of each infant's exposure to beneficial antioxidants and avoidance of silent neurotoxic properties of bilirubin navigated within the safe spectrum of operational thresholds demarcated by experts. PMID- 24049746 TI - Effects of Targeting Higher VS Lower Arterial Oxygen Saturations on Death or Disability in Extremely Preterm Infants: The Canadian Oxygen Trial. PMID- 24049747 TI - Oxygen Saturation and Outcomes in Preterm Infants The BOOST II United Kingdom, Australia, and New Zealand Collaborative Groups. PMID- 24049748 TI - A randomized controlled trial to compare heated humidified high-flow nasal cannulae with nasal continuous positive airway pressure postextubation in premature infants. PMID- 24049749 TI - Risk factors and outcomes of persistent pulmonary hypertension of the newborn in neonatal intensive care unit of Al-minya university hospital in egypt. AB - BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) result from the failure of the normal fetal-to-neonatal circulatory transition is associated with substantial infant mortality and morbidity. OBJECTIVE: To estimate the possible risk factors and assess the outcome of these cases. MATERIALS AND METHODS: Prospective study was performed enrolling all full-term and post-term newborn admitted to the NICU from January 2009 to April 2012, All neonates were subjected to complete history and physical examination, laboratory data including a complete blood count, arterial blood gases, blood glucose, serum electrolytes, and blood culture to exclude sepsis. Cases with PPHN had a continuous pulse oximeter, blood pressure and electrocardiography monitoring. Chest X-ray and echocardiogarphy were carried out to verify shunt and exclude structural congenital heart disease. RESULTS: Out of the studied 640 infants, 32 infants (5%) developed PPHN, Meconium aspiration, birth asphyxia, hyaline membrane diseases, neonatal septicemia, post-term birth being large for gestational age, cesarean section, maternal overweight, and diabetes mellitus were associated with an elevated risk for PPHN. All neonates treated with O2, 10 neonates with Mg sulphate, 16 with oral sildenafil and 12 with mechanical ventilation. After 6 months follow-up, 12 (37.54%) improved and followed-up without sequelae, 4 (12.5%) developed some neurodevelopmental impairment, 8 (25%) died, 3 (9.3%) developed chronic lungs diseases, 2 (6.2%) developed hearing defects and another 3 (9.3%) missed follow-up. CONCLUSION: PPHN was found in 5% of the studied population. Meconium aspiration, birth asphyxia, neonatal septicemia, post-term were associated with an elevated risk for PPHN. As this is a unit based study, a comprehensive countrywide survey on PPHN in Egypt is recommended to determine any regional differences in disease incidence. PMID- 24049750 TI - Importance of obtaining lumbar puncture in neonates with late onset septicemia a hospital based observational study from north-west India. AB - OBJECTIVES: The objective of this study was to estimate the prevalence of meningitis in cases with late onset septicemia (LOS). MATERIALS AND METHODS: A prospective study was carried out for a period of 1 year in a tertiary care hospital in North West India to estimate the prevalence of meningitis in cases of LOS. In all the admitted neonates with features of sepsis with a positive C reactive protein, a lumbar puncture (LP) was carried out and results interpreted on the basis of cerebrospinal fluid (CSF) cytology and biochemistry. Simultaneous blood and CSF cultures were also taken. All other baseline investigations were performed and in those diagnosed as meningitis an ultrasound head was carried out prior to discharge. No urine cultures were obtained. RESULTS: The study showed the prevalence of meningitis as 22.5% in neonates with LOS with statistically significant implications of meningitis versus gestation, sex, acquired the place of infection, and outcome in terms of sequelae/mortality. CONCLUSIONS: Meningitis is commonly associated with late onset sepsis hence LP should be the standard of care in such neonates as the treatment protocol and the outcome is directly proportional to the diagnosis at initial presentation. PMID- 24049751 TI - Oral Nystatin Versus Intravenous Fluconazole as Neonatal Antifungal Prophylaxis: Non-inferiority Trial. AB - BACKGROUND: Fluconazole has shown to be effective in reducing both colonization and invasive Candida infection (ICI) in ELBW neonates; we conducted a randomized trial to compare oral nystatin with intravenous fluconazole for prophylaxis against invasive Candidiasis in high risk neonates. MATERIALS AND METHODS: By using SPSS, preterm less than 30 weeks gestation and/or birth weight 1200 grams or less assigned to receive either intravenous Fluconazole (6 mg/kg q72 hr for 1(st) week then q48 h for 6 wks) or oral Nystatin (100,000 unit q8 hr for 6 wks). The medications commenced at one week of age after obtaining the base line investigations and check for Candida colonization by urine culture and rectal swab; subsequently all lab work and the clinical data were monitered regularly. Risk factors were assessed. The data collected prospectively looking for primary end point the invasive Candida infection (ICI) and 2 ndry outcomes include medication safety, tolerance and cost. RESULTS: 65 neonate randomly assigned however only 57 neonates comleted the study 33/57 (57%) to intravenous fluconazole group and 24/57 (42%) to oral nystatin group. No differences in birth weights Nystatin (1.15 Kg) Fluconazole (1.01 Kg), gender males (26/57), female (32/57), Gestational age (29.28 vs l28.22) or risk factors between the two groups. Rectal swab Colonization occurred in 2/24 (8%) in Nystatin group and 4/33 (12%) in the Fluconazole group, but none of the neonates developed ICI or side effects, although in the Fluconazole group transient transaminase elevation 2SD standard deviation above the mean was observed. Central line duration was 2 SD above the mean for fluconazole group, The cost of the Fluconazole treated group (7,581 SAR) 106.4 US/pt double the cost of Nystatin treated group (3,375 SAR) 50 US/pt. CONCLUSION: Intravenous Fluconazole and oral Nystatin at the prophylactic doses are equally effective and safe in preventing (ICI) in preterm neonates, however oral Nystatin is readily available, easily administered with lower cost per neonate. PMID- 24049752 TI - Salmonella Paratyphi B septicemia in a Neonate. AB - Septicemia is a major cause of death in neonates especially in developing countries. We report a case of septicemia in a neonate due to Salmonella Paratyphi B. The baby responded well to therapy and recovered completely. PMID- 24049753 TI - Pentalogy of cantrell: an extremely rare congenital anomaly. AB - A baby with the complete form of pentalogy of Cantrell was delivered at 33 weeks of gestation. The hallmark of this syndrome is ectopia cordis (EC) with omphalocele. Even though a fetal diagnosis was made at 14 weeks, parents have decided to continue with the pregnancy. Early antenatal ultrasonographic diagnosis is essential as survival depends mostly on the EC, associated cardiac anomalies and degree of thoraco-abdominal defect. Fetal diagnosis of this lethal anomaly before viability gives the parents an option of termination. PMID- 24049754 TI - Imaging in classic form of maple syrup urine disease: a rare metabolic central nervous system. AB - Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid metabolism. The condition gets its name from the distinctive sweet odour of affected infants' urine. MSUD is caused by a deficiency of the branched-chain alpha-ketoacid dehydrogenase enzyme complex, leading to accumulation of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products (ketoacids) in the blood and urine. Imaging is characterestized by MSUD oedema affecting the myelinated white matter. We present a neonate with classic type of MSUD and its imaging features on computed tomography, conventional magnetic resonance imaging, diffusion-weighted imaging, and magnetic resonance spectroscopy. PMID- 24049755 TI - Caudal duplication syndrome. AB - Caudal duplication syndrome is a rare entity in which structures derived from the embryonic cloaca and notochord are duplicated to various extents. Its prevalence at birth is less than 1 per 100,000. The term caudal duplication encompasses a spectrum of anomalies and is often used to describe incomplete separation of monovular twins or referred to as part of the spectrum of anomalies associated with conjoined twinning. It usually includes multiple rare malformations and duplications of distal organs derived from the hindgut, neural tube, and caudal mesoderm. It was postulated that the disorder is related to misexpression of one or more of the distal HOX genes, potentially HOX10 or HOX11, leading to abnormal proliferation of caudal mesenchyme. The malformations are usually diagnosed by anomaly scan in the second trimester. Here we report the case of a baby presenting on the first day of life with complete duplication of caudal structures below the dorsolumbar level. PMID- 24049756 TI - Near total jejuno-ileal atresia: a management challenge. AB - A 2-day-old female neonate with the clinical picture of proximal small bowel atresia, on exploration, turned out to have intestinal atresia of a rare variety, i.e., a near-total jejuno-ileal atresia. The baby had total small bowel length of less than 10 cm. She survived for 3 months on enteral feeding after end-to-back duodeno-ileal anastomosis and thereafter succumbed to septicemia. The case is presented for it's extreme rarity and consideration of this extreme form of small bowel atresia as an offshoot of the existing classifications of jejuno-ileal atresia since it has dismal prognosis and presents as a management challenge even today. PMID- 24049757 TI - A Typical Manifestation of Birthmark-Becker's Nevus Syndrome. AB - Full born term male baby having hyperpigmentation over back of neck and back of chest. The colour of nevus is black coloured. Hyperpigmented area is slightly hypertrophy. Imaging, X-ray spine, X-ray fingers and toes, X-ray chest, ultrasound of abdomen, CT scan of brain-normal. Treatment advised: Pigmentation can be reduced by pigment laser. PMID- 24049758 TI - An Atypical form Rhizomelic Chondrodysplasia Punctata in a Newborn. AB - Rhizomelic Chondrodysplasia punctata (RCDP) is an autosomal recessive metabolic disorder affecting mainly peroxisomal function. We describe a case of RCDP in a 12 days old newborn based on the clinical and radiological ground without any major systemic structural or functional abnormalities. PMID- 24049759 TI - Neonatal early onset sepsis due to anaerobies: myth or realities: a review of medical record in one neonatal centre. PMID- 24049766 TI - Optimization of Fe3O4@Ag nanoshells in magnetic field-enriched surface-enhanced resonance Raman scattering for malaria diagnosis. AB - The great potential of magnetic field enriched surface enhanced resonance Raman spectroscopy (SERRS) for early malaria diagnosis has been demonstrated previously. This technique is able to detect beta-hematin, which is equivalent to a malaria biomarker (hemozoin) in Raman features, at a concentration of 5 nM. In this study, we present the optimization of nanoparticles used in the magnetic field enriched SERRS by tuning the core size and shell thickness of nanoparticles with an iron oxide core and a silver shell (Fe3O4@Ag). The discrete dipole approximation (DDA) model was introduced to investigate the localized electromagnetic field distributions and extinction efficiencies of the aggregate of Fe3O4@Ag and beta-hematin, in correlation with their magnetic field enriched SERRS performance. We find that the optimal core-shell size of Fe3O4@Ag leading to the effective aggregation of Fe3O4@Ag and beta-hematin under an external magnetic field with superior extinction efficiencies is the key to realize highly augmented Raman signals in this strategy. Furthermore, it is noted that the optimized result differs from the case without the external magnetic field to that with the external magnetic field. Therefore, this work demonstrates experimentally and theoretically the potential of tuning the core-shell Fe3O4@Ag for achieving the efficient magnetic field-enriched SERRS detection of beta hematin for early malaria diagnosis. PMID- 24049767 TI - Fluorescent silica nanoparticle-based probe for the detection of ozone via fluorescence resonance energy transfer. AB - A fluorescence resonance energy transfer (FRET) platform for the detection of ozone was developed by combining the overlap of the fluorescence spectrum of Ru(bpy)3(2+)-doped silica nanoparticles with the absorption spectrum of indigo carmine at around 600 nm. This FRET system can be used to detect ozone simply within 10 min. Simple qualitative ozone detection methods using cotton swabs or paper were also developed. PMID- 24049768 TI - High sensitivity liquid phase measurements using broadband cavity enhanced absorption spectroscopy (BBCEAS) featuring a low cost webcam based prism spectrometer. AB - Cavity enhanced techniques enable high sensitivity absorption measurements in the liquid phase but are typically more complex, and much more expensive, to perform than conventional absorption methods. The latter attributes have so far prevented a wide spread use of these methods in the analytical sciences. In this study we demonstrate a novel BBCEAS instrument that is sensitive, yet simple and economical to set up and operate. We use a prism spectrometer with a low cost webcam as the detector in conjunction with an optical cavity consisting of two R = 0.99 dielectric mirrors and a white light LED source for illumination. High sensitivity liquid phase measurements were made on samples contained in 1 cm quartz cuvettes placed at normal incidence to the light beam in the optical cavity. The cavity enhancement factor (CEF) with water as the solvent was determined directly by phase shift cavity ring down spectroscopy (PS-CRDS) and also by calibration with Rhodamine 6G solutions. Both methods yielded closely matching CEF values of ~60. The minimum detectable change in absorption (alphamin) was determined to be 6.5 * 10(-5) cm(-1) at 527 nm and was limited only by the 8 bit resolution of the particular webcam detector used, thus offering scope for further improvement. The instrument was used to make representative measurements on dye solutions and in the determination of nitrite concentrations in a variation of the widely used Griess Assay. Limits of detection (LOD) were ~850 pM for Rhodamine 6G and 3.7 nM for nitrite, respectively. The sensitivity of the instrument compares favourably with previous cavity based liquid phase studies whilst being achieved at a small fraction of the cost hitherto reported, thus opening the door to widespread use in the community. Further means of improving sensitivity are discussed in the paper. PMID- 24049769 TI - An IMPLICATION logic gate based on citrate-capped gold nanoparticles with thiocyanate and iodide as inputs. AB - Herein we developed an IMPLICATION logic gate based on citrate-capped AuNPs by employing thiocyanate (SCN(-)) and iodide (I(-)) as inputs, and devised a colorimetric sensor for the determination of I(-) with good selectivity and sensitivity. To the best of our knowledge, this is the first example in which two species of anions serve as inputs to obtain visually observed Boolean outputs. Under the optimum conditions, 0.8 MUM I(-) could induce a significant color change and be recognized by the naked eye. The detection limit is 50 nM by using UV-vis spectroscopy. PMID- 24049770 TI - Multicellular aggregation of maltol-modified cells triggered by Fe(3+) ions. AB - The synthesis of a maltol-derived hydrazide is described which, once attached to a cell surface, induces rapid multicellular aggregation selectively in the presence of Fe(3+) ions. Heterocellular aggregates are also reported. PMID- 24049771 TI - Copper mediated stereoselective synthesis of C-glycosides from unactivated alkynes. AB - A highly stereoselective rapid C-glycosylation reaction has been developed between glycal and unactivated alkynes in the presence of coppertriflate and ascorbic acid at low catalyst loading and at room temperature. A wide variety of glycals and aryl acetylenes participate in the reaction smoothly. TfOH generated during the reduction of Cu(OTf)2 by ascorbic acid may be the active catalyst for the glycosylation. PMID- 24049772 TI - Deracemization and the first CD spectrum of a 3(10)-helical peptide made of achiral alpha-amino-isobutyric acid residues in a chiral membrane mimetic environment. AB - Interaction of the racemic helical homo-octapeptide made by the achiral C(alpha) methyl alanine (Aib) amino acid with a chiral enantiopure micellar aggregate made of N-dodecylproline led to the deracemization of the helical Aib sequence thus allowing us to obtain for the first time the CD signature in water of a 310 helix devoid of the contribution of any chiral amino acid. PMID- 24049773 TI - Controlled homopolymerization of multi-vinyl monomers: dendritic polymers synthesized via an optimized ATRA reaction. AB - In this study, we have managed to find the optimal ATRA system that can obtain the highest mono-adduct yields with the purpose of minimizing the chain growth of divinyl monomers. The most highly hyperbranched polymers have been synthesized by the homopolymerization of multi-vinyl monomers via ATRA reaction. PMID- 24049774 TI - Smudge cells following treatment with pentostatin in a patient with B-cell prolymphocytic leukemia. PMID- 24049775 TI - Sea-blue-colored histiocytes associated with bone marrow granulomas. PMID- 24049776 TI - Authors' reply. PMID- 24049777 TI - Special issue dedicated to the founding editor, Dr. Waclaw Szybalski. PMID- 24049778 TI - Special issue and workshop honoring Professor Stuart E. Reynolds. PMID- 24049779 TI - Proceedings of the Eleventh International Symposium on Applied Bioinorganic Chemistry, December 2-5, 2011, Barcelona, Spain. PMID- 24049780 TI - Calls get louder for global action on silent hepatitis crisis. PMID- 24049781 TI - Highlights from the seventh IAS Conference. PMID- 24049782 TI - Patients have undetectable HIV after coming off treatment. PMID- 24049783 TI - Highlights from the second ICPIC. PMID- 24049784 TI - Proceedings of the International Symposium on the Natural Radiation Exposures and Low Dose Radiation, February 29-March 2, 2012, Hirosaki, Japan. PMID- 24049785 TI - Authors' response: a second-person neuroscience in interaction. AB - In this response we address additions to as well as criticisms and possible misinterpretations of our proposal for a second-person neuroscience. We map out the most crucial aspects of our approach by (1) acknowledging that second-person engaged interaction is not the only way to understand others, although we claim that it is ontogenetically prior; (2) claiming that spectatorial paradigms need to be complemented in order to enable a full understanding of social interactions; and (3) restating that our theoretical proposal not only questions the mechanism by which a cognitive process comes into being, but asks whether it is at all meaningful to speak of a mechanism and a cognitive process when it is confined to intra-agent space. We address theoretical criticisms of our approach by pointing out that while a second-person social understanding may not be the only mechanism, alternative approaches cannot hold their ground without resorting to second-person concepts, if not in the expression, certainly in the development of social understanding. In this context, we also address issues of agency and intentionality, theoretical alternatives, and clinical implications of our approach. PMID- 24049786 TI - Authors' response: forward models and their implications for production, comprehension, and dialogue. AB - Our target article proposed that language production and comprehension are interwoven, with speakers making predictions of their own utterances and comprehenders making predictions of other people's utterances at different linguistic levels. Here, we respond to comments about such issues as cognitive architecture and its neural basis, learning and development, monitoring, the nature of forward models, communicative intentions, and dialogue. PMID- 24049788 TI - Retraction notice to "Renaturation and one step purification of the chicken GIIA secreted phospholipase A2 from inclusion bodies". PMID- 24049787 TI - Detecting differential gene expression in subgroups of a disease population. AB - In many disease settings, it is likely that only a subset of the disease population will exhibit certain genetic or phenotypic differences from the healthy population. Therefore, when seeking to identify genes or other explanatory factors that might be related to the disease state, we might expect a mixture distribution of the variable of interest in the disease group. A number of methods have been proposed for performing tests to identify situations for which only a subgroup of samples or patients exhibit differential expression levels. Our discussion here focuses on how inattention to standard statistical theory can lead to approaches that exhibit some serious drawbacks. We present and discuss several approaches motivated by theoretical derivations and compare to an ad hoc approach based upon identification of outliers. We find that the outlier sum statistic proposed by Tibshirani and Hastie offers little benefit over a t test even in the most idealized scenarios and suffers from a number of limitations including difficulty of calibration, lack of robustness to underlying distributions, high false positive rates owing to its asymmetric treatment of groups, and poor power or discriminatory ability under many alternatives. PMID- 24049789 TI - Re: the "keystone concept': time for some science. PMID- 24049790 TI - Reducing the ecological footprint of surgical hand scrub: it is time to act! PMID- 24049791 TI - The foundation and the specialty: bringing science and clinicians together in otorhinolaryngology. PMID- 24049792 TI - Ethical tensions in surgery: who is doing my operation? PMID- 24049793 TI - Medicine in small doses: robotic surgery - where to from here? PMID- 24049794 TI - In reply. PMID- 24049795 TI - PCSK9 and the road less traveled: how an unconventional approach led to a major discovery. PMID- 24049796 TI - Australia-wide antimicrobial resistance surveillance. PMID- 24049797 TI - Guide to living with aphasia. PMID- 24049798 TI - Education policy--from tamper to tempers! PMID- 24049799 TI - Australia benefits from real-time FMD training courses. PMID- 24049800 TI - First hand: 50-year anniversary of the successful forearm replantation. PMID- 24049801 TI - Hands on stamps: China 1985--United Nations decade for women. PMID- 24049802 TI - Workplace health and safety issues and impacts on productivity in veterinary business. PMID- 24049803 TI - Pet insurance: better care, happier clients. PMID- 24049804 TI - Animals are an essential part of any disaster plan. PMID- 24049805 TI - Ixodes holocyclus in cooler climate regions. PMID- 24049806 TI - Low-concentration topical tacrolimus for the treatment of anogenital lichen sclerosus in childhood: maintenance treatment to reduce recurrence. AB - BACKGROUND: Lichen sclerosus (LS) is a chronic inflammatory skin disorder that is commonly found in the anogenital area, especially in females. Ultra-potent topical corticosteroids are first line for the treatment of LS, but their atrophic side effects and the recurrence of the disease restrict their use. An equally effective, safer, tolerant therapeutic option is required, especially in the treatment and preventing relapse of children. METHODS: Fourteen prepubertal girls (range of age: 4 to 11 years) with anogenital lichen sclerosus were treated with 0.03% tacrolimus ointment twice daily for 16 weeks, then 9 of the 14 patients adhered to 2 times weekly for further 6 months (a total of 10 months). The therapeutic effects were evaluated according to 3 grades: complete response (O75% improvement, partial response (30%-75% improvement),or no response (!30% improvement). RESULTS: Clinical improvement occurred in all patients (100%). Complete response of symptoms and signs was achieved in 5 (36%), 9 (64%) and 11 (79%) patients at week 8, week 16, and month 10 respectively. During the follow up period of 1 year, 4 patients (4/5, 80%) who treated with tacrolimus ointment for 16 weeks had a recurrence of symptoms, while only 2 of 9 (22%) patients who insisted on maintenance therapy developed recurrence of disease. No severe side effects were observed. CONCLUSIONS: Low-concentration topical tacrolimus appears to be an effective and safe treatment for children with anogenital lichen sclerosus. Maintenance therapy (2 times a week for 6 months) can reduce the relapse of the disease. PMID- 24049807 TI - Counseling about the HPV vaccine: desexualize, educate, and advocate. AB - Information is provided for clinicians who treat adolescents and adult women to use when counseling patients about human papillomavirus (HPV) vaccine. A literature search was done to determine: (1) reasons for refusal of the vaccine, including cost and concerns that immunization against HPV will lead to promiscuity; (2) potential for non-sexual transmission of HPV; (3) non-genital locations of HPV; (4) non-genital cancers associated with HPV. Vaccines for Children Program and the Affordable Care Act eliminate many costs.Neither biological nor behavioral evidence supports the idea that sexual behavior changes after immunization. HPV is transmitted from person to person by non-sexual routes including mother to child at birth and apparently by touch after birth. HPV is persistent in the environment, including medical environments. It has been found on apparently sterilized instruments used in vaginal exams. Pathogenic HPV has been recovered from breast tissue, sinonasal areas, and nipples as well as from hair follicles on arms, legs, scalps, eyebrows, and pubic hair. Pathogenic HPV was found in 6.5% of the oral cavities of a random sample of Americans. HPV is known to cause anal and oral cancers. It has also been associated with skin cancers, breast tumors, and prostate cancers. It is not known if the vaccine is protective against these cancers, but it is useful to educate about these other routes of transmission and non-genital HPV linked cancers so that patients/parents do not just focus on the sexual nature of the human papillomavirus. PMID- 24049808 TI - Ischemia-reperfusion injury accelerates human antibody-mediated transplant vasculopathy. AB - Background. The pathogenesis of transplant vasculopathy (TV) is a multifactorial process. We hypothesized that ischemia-reperfusion injury and antibody-mediated damage contribute to the development of TV.Methods. Human vessels were procured from nine separate donors undergoing cardiac surgery and stored in saline solution on ice until transplantation. BALB/c Rag2-/-IL-2Rgamma-/- mice were transplanted with a human vessel graft on day 0. Purified anti-human leukocyte antigen class I antibody (W6/32), isotype control antibody, or saline was injected into recipient mice weekly until day 42, at which point the degree of intimal expansion (IE) of vessels was assessed by histologic analysis.Results. We found that a prolonged cold ischemia time (6-12 hr) alone did not induce IE. In mice that received antibody where vessels were transplanted within 6 hr of procurement, no IE was observed. By contrast, in vessels exposed to more than 6 hr cold ischemia, both W6/32 antibody (30.4%T6.9%) and isotype control antibody(39.5%T6.0%) promoted significant IE (P<0.05 vs. saline [12.4%T1.7%]). Importantly, the isotype control antibody did not cross-react with human tissue. Interestingly, the number of mouse Fc-receptor-positive cells was significantly increased in human vessels exposed to more than 6 hr cold ischemia but only in the presence of antibody (P<0.05).Conclusions. Antibody, regardless of its specificity, may promote IE in human vessels that are injured through cold ischemia via interaction with Fc-receptor-positive cells. This highlights the importance of controlling the degree of cold ischemia in clinical transplantation in an effort to reduce the risk of TV development. PMID- 24049809 TI - [The artificial pancreas. When mathematical equations resolve problems]. PMID- 24049810 TI - Defining 'appropriate'. PMID- 24049811 TI - Sterile-water negative pressure instillation therapy for complex wounds and NPWT failures. AB - OBJECTIVE: To investigate use of negative pressure wound therapy (NPWT) combined with instillation for patients either presenting with a complex wound or after failure of classic NPWT. METHOD: A retrospective case series study conducted on patients treated using an NPWT instillation system (V.A.C. Instill; KCI Inc.) from January to December 2012. The instillation machine was used with pure saline so as not to interfere with local antibacterial solutions. Two clinical indications-patients presenting either large undermining, deep inaccessible wounds or infected wounds and those for whom conventional NPWT had proved ineffective, were analysed-with efficacy of the promotion of granulation tissue as the primary outcome. Length of instillation time, the rhythm and the amount of liquid to be injected compared with the estimated volume of the cavity were also evaluated. RESULTS: Twenty-four patients were included in this series--12 post NPWT failures and 12 complex wounds-with positive outcomes in 23 cases. Surgical closure was realised after promotion of granulation tissue, using either flaps or skin grafts alone, or combined with previous application of a dermal substitute. No complications linked to instillation were observed during the period of use. CONCLUSION: The results of this case series suggests that use of NPWT combined with pure saline instillation could have a positive impact on the healing trajectory of patients with complex wounds or after failure of classic NPWT. PMID- 24049812 TI - Feelings of powerlessness and hope for cure in patients with chronic lower-limb ulcers. AB - OBJECTIVE: To assess feelings of powerlessness and hope for cure in patients with chronic venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs). METHOD: A clinical, analytical, descriptive study was conducted from April to September 2012 in a wound-care clinic in Brazil, on consecutive patients presenting withVLUs and DFUs. The Powerlessness AssessmentTool for Adult Patients (PAT) and the Herth Hope Index (HHI) were used.Total PAT scores range 12-60 and the higher the score, the stronger the feelings of powerlessness. The HHI ranges 12-48, with higher scores indicating higher levels of hope RESULTS: In total, 80 consecutive patients were recruited (40 VLU and 40 DFU). Mean PAT score was 53.3 +/- 9.6 (range 21-60) for DFU patients and 34.3 +/- 7.7 (range 21-60; p = 0.001) forVLU patients, suggesting these individuals had strong feelings of powerlessness. The mean HHI was 16.5 +/- 16.5 (range 12-40) for DFU patients and 27.5 +/- 27.5 (range 12-40; p = 0.001) for patients with VLUs, indicating low levels of hope. CONCLUSION: The results suggest that patients with DFUs had stronger feelings of powerlessness regarding their condition and less hope of recovery compared with patients with VLUs. PMID- 24049814 TI - Global phenomena that require a global perspective. PMID- 24049813 TI - The prevalence of pressure ulceration among Jordanian hospitalised patients. AB - OBJECTIVE: To measure the prevalence rate of pressure ulcers (PUs) among hospitalised patients and to assess the adequacy of preventative care provided to patients at-risk for PUs. METHOD: A cross-sectional survey was conducted by inspecting the skin of each patient included; if a PU was noted, it was classified according to the European Pressure Ulcer Advisory Panel grading system. Risk was assessed using the Braden scale and the use of preventative interventions was also documented. RESULTS: The sample included was 295 patients; mean age of the patients was 49.1 +/- 18.6 years (range 18-87 years) and 55% (n = 162) were male. The prevalence rate was 16% (8.8% excluding category I). Category I was the most common grade of PU (n = 22; 46%). The heels were the most commonly affected sites (n = 23; 49%). Only 19% of patients in need of prevention actually received proper adequate prevention. CONCLUSION: PU prevalence rate was lower than published rates in studies that employed the same method. The young age and general health of our sample could be the best explanation. A very small percentage of at-risk patients receive adequate prevention. This should open the door to scrutinising the provision of PU prevention in Jordan. PMID- 24049815 TI - Difficult leg wounds successfully closed with decortication, bioresorbable ECM and NPWT. AB - Complications of a missed compartment syndrome are severe. This case demonstrates the difficulty in dealing with such complications, including the difficult situation of being faced with limb salvage when amputation is the best option. Through a short case description and several images, it is demonstrated how even the most difficult wounds in cases like this can be dealt with and achieve a non painful limb salvage. In particular, an extreme technique of decorticating the bone and applying bioresorbable extracellular matrix with negative pressure wound therapy was applied in order to achieve final wound closure and pain relief. This case demonstrates integration of multiple modalities for complex wound closure. PMID- 24049816 TI - Pedal osteomyelitis in patients with diabetes: a retrospective audit from Saudi Arabia. AB - OBJECTIVE: To examine the characteristics of patients presenting to the emergency room and the specialist diabetes foot clinic with pedal osteomyelitis (PO). METHOD: A retrospective study was conducted at a regional hospital. The charts of patients with suspected PO who presented during the period 1 January to 31 December 2011 were analysed. Demographics, biochemistry and microbiological data were obtained. Bone biopsies were performed by the attending clinician either during surgical removal of infected bone, or percutaneously under guided fluoroscopy through non-infected tissue. RESULTS: Sixty-six cases of osteomyelitis affecting 102 joints were noted. The study population consisted of 44 men, mean age 62.9 +/- 1.3 years, and 22 women, mean age of 57.6 +/- 10.6 years. Gram-positive bacteria were the predominating pathogens (p < 0.05). Staphylococcus aureus was cultured in 36% of all bone biopsy cases. A predictive trend in HbA1c was observed,where every increase of 1% from the recommended level of 7% was associated with a 10% increase in the likelihood of receiving surgical intervention. CONCLUSION: S. aureus infection is a major cause of osteomyelitis in interphalangeal joints of the feet of diabetic patients.There is an apparent association with patients who present with diabetic foot osteomyelitis and sub optimal glycaemic control, requiring surgical intervention. PMID- 24049817 TI - Treatment of chronic sternal fistulae following cardiac surgery with a bone substitute. AB - Chronic sternal infection is a relatively rare complication following cardiac surgery that can cause high morbidity and mortality and can require repeated surgical procedures, including sternal resection, to resolve. However, preserving sternal integrity is essential, particularly in children. A variety of conservative treatments for this complication of cardiac surgery have been reported. Here, we report three cases of children in whom a bone substitute containing tricalcium phosphate and hydroxyapatite was used to fill sternal defects. After extensive surgical debridement, this method yielded primary wound closure with good resolution, preventing the recurrence of sternal infection. PMID- 24049818 TI - Patient access schemes: making them work in practice. PMID- 24049819 TI - The Fifth National Audit Project: implications for hospital doctors. PMID- 24049820 TI - Preconception care for healthy women and those with medical conditions. PMID- 24049821 TI - Preconception care for women with mental health conditions. PMID- 24049822 TI - Peripartum management of the pre-eclamptic patient. PMID- 24049823 TI - Managing trauma in the pregnant woman. PMID- 24049824 TI - Death certification: a practical guide. PMID- 24049826 TI - Postoperative management after hepatic surgery. PMID- 24049827 TI - A practical approach to thrombophilia testing. PMID- 24049825 TI - Spider naevi. PMID- 24049828 TI - How to appraise a systematic review. PMID- 24049829 TI - Personality, self development the compassionate leader. PMID- 24049830 TI - Cutaneous drug reactions in intensive care. PMID- 24049831 TI - Oxygen therapy in patients with chest pain of acute onset: single centre audit experience. AB - INTRODUCTION: Although oxygen therapy has been commonly used in the treatment of acute coronary syndromes, evidence shows that oxygen administration is not always beneficial to patients with acute chest pain and in certain circumstances may, in fact, be harmful. Hence, several national and international organizations have issued guidelines restricting its use to hypoxic patients only. AIM: To audit and change the inappropriate practice of administering oxygen therapy indiscriminately to patients with acute chest pain. SETTING: Emergency department, coronary care unit and heart assessment centre in a large teaching hospital. METHODS: The authors identified 100 patients who presented with acute chest pain and collected data on oxygen prescription, administration and documentation from clinical notes and observation charts. RESULTS: Only 71% of patients in a hospital setting were correctly assessed for requiring oxygen therapy. After introducing local guidelines and a series of lectures, this rose to 94%. A third audit showed sustained change, with 96% of patients being appropriately assessed for needing oxygen therapy. DISCUSSION: The introduction of local guidelines and a series of lectures improved handling of oxygen in patients presenting with acute chest pain. PMID- 24049832 TI - Giant Meckel's diverticulum causing small bowel obstruction. PMID- 24049833 TI - Neonatal varicella infection: are we being falsely reassured by a maternal history of chickenpox? PMID- 24049834 TI - Two cases of tuberculous meningitis with stroke sequelae. PMID- 24049835 TI - The battle of Gettysburg: the dawn of the modern military hospital system. PMID- 24049836 TI - Anomalies in criteria for heart failure with preserved ejection fraction. PMID- 24049837 TI - Author's reply: To PMID 23411911. PMID- 24049838 TI - Countdown to retirement. PMID- 24049839 TI - Does regional anaesthesia in trauma patients lead to delayed recognition of compartment syndrome? PMID- 24049869 TI - [Comparison between tomosynthesis and CT]. PMID- 24049870 TI - [Dual energy subtraction applied to the evaluation of callus: application of tomosynthesis]. PMID- 24049840 TI - Hydatid cyst presenting as a breast lump in a male patient. AB - The breast is a rare primary site of hydatid disease and accounts for only 0.27% of cases. Mammary hydatidosis generally occurs in females and has never been described in male patients. In this paper, the authors report a new case of isolated hydatid cyst of the breast in a 35-year-old previously healthy man, who presented with a left breast painless lump of one year duration. Physical examination showed a non-tender and immobile mass in the upper lateral quadrant of the left breast, with normal overlying skin and nipple. There was no palpable lymph node in the left axilla and the contralateral breast was normal. Ultrasonography showed a 2.7 x 1.5 cm cystic lesion in the left breast. The patient underwent total excision of the mass, and histopathological examination confirmed the diagnosis of hydatid cyst. The authors conclude that although hydatid cyst of the breast is rare, it should be considered in the differential diagnosis of breast lumps especially in endemic areas. PMID- 24049871 TI - [Statistics necessary in radiological technology. Comparisons of two groups (4)]. PMID- 24049872 TI - [Three-dimensional computer graphics. 6. Image analysis]. PMID- 24049873 TI - [From diagnosis to treatment of heart diseases (with special difference to ischemic heart disease). 1. Heart diseases (on medical information)]. PMID- 24049874 TI - Body tattooing: efficacy of a "new" practice. PMID- 24049875 TI - Massive protein plug in intraductal papillary mucinous neoplasm. PMID- 24049876 TI - Enrichment of vitronectin- and fibronectin-like proteins in NaCI-adapted plant cells and evidence for their involvement in plasma membrane-cell wall adhesion. AB - Cells of tobacco adapted to grow in high concentrations of NaCl develop tight zones of adhesion between the plasma membrane and cell wall, revealed by concave plasmolysis in osmotic solutions. Unadapted cells exhibit mostly convex plasmolysis and exhibit little or no adhesive character. Wall-less protoplasts isolated from the adapted cells retain the complementary adhesive character and adhere tightly to each other, whereas protoplasts from unadapted cells do not. The hexapeptide gly-arg-gly-asp-ser-pro, in which the arg-gly-asp represents the integrin-binding domain of several animal extracellular matrix proteins,specifically blocks adhesion of the protoplasts. A control hexapeptide, gly-arg-gly-glu-ser-pro, is ineffective in blocking adhesion. Tobacco proteins immunologically related to human vitronectin were found in cell walls and membranes of unadapted and NaCI adapted cells, but the total extractable vitronectin-like protein was enriched in the adapted cells. Tobacco proteins immunologically related to human fibronectin were found in membranes and cell walls of NaCI adapted cells but not in those from unadapted cells.Our observations indicate that plant cells possess cell-matrix adhesion complexes similar to animal cells, and these adhesion complexes accumulate ingrowth-limited cells adapted to saline stress. PMID- 24049877 TI - Eligibility of disabled veterans and members of the armed forces with severe burn injuries for financial assistance in the purchase of an automobile or other conveyance and adaptive equipment. Final rule. AB - The Department of Veterans Affairs (VA) adopts as a final rule its proposal to amend its adjudication regulation concerning a certificate of eligibility for financial assistance in the purchase of an automobile or other conveyance and adaptive equipment, which was published in the Federal Register on November 5, 2012, and republished for minor technical corrections on November 26, 2012. The amendment is necessary to incorporate statutory changes made by the Veterans' Benefits Act of 2010. PMID- 24049878 TI - Medicare Advantage update: benefits, enrollment, and payments after the ACA. AB - In 2012, the Medicare program paid private health plans $136 billion to cover about 13 million beneficiaries who received Part A and B benefits through the Medicare Advantage (MA) program rather than traditional fee-for-service (FFS) Medicare. Private plans have been a part of the program since the 1970s. Debate about the policy goals--Should they cost less per beneficiary than FFS Medicare? Should they be available to all beneficiaries? Should they be able to offer additional benefits?--has long accompanied Medicare's private plan option.This debate is reflected in the history of Medicare payment policy,and policy decisions over the years have affected plans' willingness to participate and beneficiaries' enrollment at different periods of the program. Recently, evidence that the Medicare program was paying more per beneficiary in MA relative to what would have been spent under FFS Medicare prompted policymakers to reduce MA payments in the Patient Protection and Affordable Care Act of 2010 (ACA). So far, plans continue to participate in MA and enrollment continues to grow, but payment reductions in 2012 through 2014 have been partially offset by payments made to plans through the quality bonus payment demonstration.This brief contains recent data on plan enrollment, availability, and benefits and discusses MA plan payment policy, including changes to MA payment made in the ACA and their actual and projected effects. PMID- 24049879 TI - The home care industry in California is growing and largely unregulated. AB - The home care industry is growing rapidly and coincides with increases in the growth of the elderly population, who are more frequently chronically ill and disabled and need assistance. This policy brief provides a profile of the home care industry and patients/consumers of these services in California, assessing available data on licensure and certification as a mechanism for promoting safety and quality of care. The findings indicate a dearth of information on the characteristics and care delivery of home care agencies and individual providers of nonmedical home care. The findings also illustrate that licensure and certification of home health agencies may enhance the capacity for improvements in quality of care. Establishing licensure and basic safety standards for home care agencies is a reasonable public health policy for reducing the potential for adverse consequences among the growing aging and disabled populations. PMID- 24049880 TI - [We will not survive without impact factor]. PMID- 24049881 TI - Preliminary study of the ultrasonographic diagnosis of pregnancy and fetal development in the dog. AB - A total of 18 dogs were examined by ultrasound during their gestation period. At gestational day 7, a uterus indicative of possible pregnancy was observed. At gestational day 10, the embryo was observed. Fetal and cardiac activities appeared at 28 days. Rapid increases of the crown-rump length and biparietal diameter occurred between the 5th and the 6th weeks of gestation and of the body diameter between the 4th and 5th weeks and again between the 6th and the 7th weeks of gestation. PMID- 24049882 TI - Effect of acetohydroxamic acid on dissolution of canine struvite uroliths. AB - Long-term administration of acetohydroxamic acid to dogs with experimentally induced urease-positive staphylococcal urinary tract infections and struvite urolithiasis resulted in dose-dependent inhibition of urolith growth or urolith dissolution. Inhibition of urolith growth was associated with drug dose-dependent reduction of urine urease activity, urine pH, crystalluria, pyuria, hematuria, and proteinuria. Lesions of the urinary tract of dogs treated with acetohydroxamic acid were less severe than those of control dogs. Dose-dependent adverse drug reactions included reversible hemolytic anemia, abnormal red cell morphology, and abnormalities of bilirubin metabolism. PMID- 24049883 TI - Effect of acetohydroxamic acid on prevention of canine struvite uroliths. AB - Long-term administration of acetohydroxamic acid (AHA) to dogs with experimentally induced urease-positive staphylococcal urinary tract infections, and bladder zinc disk foreign bodies inhibited urolith growth in 2 dogs and prevented urolith growth in 4 dogs. Inhibition and prevention of urolith growth were associated with reduction in urine urease activity, crystalluria, pyuria, hematuria, and proteinuria. Lesions in the urinary tract of AHA-treated dogs were less severe than those of infected control dogs. Administration of AHA for 6 months induced mild morphologic abnormalities in RBC, but did not cause hemolytic anemia. PMID- 24049884 TI - Pharmacokinetics of phenobarbital in dogs after multiple oral administration. AB - Sodium phenobarbital (PHB) was administered orally as tablets 3 times a day to 6 healthy mature dogs of mixed breeding for 5 days at a dose of 2 mg/kg of body weight. On the 6th day, PHB was administered at 9 AM and venous blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 23, 35, 47, 59, 71, 83, 95, 107, 119, and 131 hours. Additional PHB was not given on day 6. Drug serum concentrations were described by a 1-compartment model with first-order absorption and elimination with fitted correlation coefficients of 0.991 +/- 0.007 (mean +/- SD). The observed PHB half-lives were between 37.3 and 74.6 hours with a mean of 53.0 +/- 15 hours. The calculated volume of distribution (Vd/F) was 743.6 +/- 69.8 ml/kg, and the total body clearance (ClT/F) was 0.173 +/- 0.053 ml/min/ kg. The absorption half-life was 1.27 +/- 0.21 hours. Based on the observed biological half-life after 5 days of dosing, approximately 11 days (8 to 15.5 days) of multiple dosing would be required to achieve steady-state serum concentrations. From average values, predicted maintenance doses of 1.8 mg/kg of body weight 3 times a day or 5.5 mg/kg once daily would be required to achieve average serum concentrations of 20 microg/ml. Due to intersubject variations in ClT/F, these doses would result in subtherapeutic or toxic serum concentrations in 2 of the 6 dogs. Further disposition and dosing regimen studies need to be performed during chronic PHB administration in dogs to evaluate autoinduction and intersubject differences in disposition kinetics. PMID- 24049885 TI - Vascular pathways of the anterior segment of the canine eye. AB - The vasculature of the anterior segment of the canine eye was studied by preparing intravascular casts with a methyl methacrylate resin. Specimens were examined and results were recorded with the aid of stereoscopic dissecting and scanning electron microscopes. The arterial supply was via anterior ciliary and long posterior ciliary arteries. An arterial circle derived from dorsal and ventral anterior ciliary arteries was identified in the anterior sclera. The long posterior ciliary artery contributed branches to the choroid, anterior sclera, and anterior border of the ciliary processes. Radial iris arterioles arose from the major arterial circle of the iris and ended blindly at the pupillary margin. Radial ciliary arteries arose from the major arterial circle of the iris and ran posteriorly and supplied the ciliary processes and muscle and fused with the choroidal vasculature. Each ciliary process was supplied by an afferent arteriole from the radial ciliary artery. Sphincters could be seen at branch points within the vascular net of the ciliary processes. PMID- 24049886 TI - Induction of abortion in the bitch with a synthetic prostaglandin analog. AB - Eight mixed-breed bitches in the middle (30 to 35 days) and late 3rd (53 to 56 days) of gestation were given 20 microg of synthetic prostaglandin analog/kg of body weight, IM (4 bitches) or the polyethylene glycol vehicle, IM (4 bitches). Bitches treated with prostaglandin aborted 2 days after treatment, whereas bitches given the vehicle delivered live pups at term. Luteolysis occurred within 24 hours of treatment, as shown by rapidly declining plasma progesterone concentrations. Microscopic signs of luteal degeneration were seen in ovaries removed 5 days after treatment. Three bitches erroneously designated as pregnant were treated during anestrus and had no marked changes in plasma progesterone or in gross and microscopic appearance of the reproductive tract. Serum alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase activities were increased slightly in 4 bitches on the day after treatment, but values declined to base-line values 24 hours later. Treatment side effects included panting, salivation, vomiting, repeated defecation, and transient pain at the injection site. PMID- 24049888 TI - Identification of the major coagulase-positive Staphylococcus sp of dogs as Staphylococcus intermedius. AB - Specimens obtained from the skin of healthy dogs and from various surgical and pyogenic lesions were culturally examined for coagulase-positive staphylococci. The isolates of Staphylococcus were biotyped, using hemolysin production, coagulase production, and the biochemical tests contained in a commercial Staphylococcus identification system. A total of 72 coagulase-positive isolates were biotyped, with 70/72 identified as S intermedius and 2/72, as S aureus. All of the S intermedius isolates were coagulase-positive with canine plasma. PMID- 24049887 TI - Clinical models for anaerobic bacterial infections in dogs and their use in testing the efficacy of clindamycin and lincomycin. AB - Two canine models of clinical anaerobic bacterial infections were developed for the study of the clinical parameters associated with these infections and for evaluation of antimicrobial agents that might be useful in therapy. In model I, a mixed culture of Bacteroides fragilis, B melaninogenicus, and Fusobacterium necrophorum was used as the inoculum. In model II, a mixed culture of B fragilis and Clostridium perfringens combined with an infection enhancer (sterile cinder dust) was used as the inoculum. In both models, reproducible localized pyogenic or gangrenous infections were induced. Clinical signs of fever, depression, and leukocytosis with a left shift were present. A depression in the nonspecific cell mediated immune response was noticed. The 2 models were used to evaluate clindamycin and lincomycin for therapy of anaerobic bacterial infections, using a subjective scoring system for severity of lesions and general clinical appearance. Clindamycin at dosage levels of 5.5 mg or 11 mg/kg of body weight, twice a day was highly efficacious in the treatment of anaerobic bacterial infections in both models. Dogs given lincomycin (22 mg/kg twice a day) responded to the treatment, but the response was less than that seen with clindamycin. PMID- 24049889 TI - Essential fatty acid requirements of cats: pathology of essential fatty acid deficiency. AB - The pathologic changes of essential fatty acid (EFA) deficiency were studied in specific-pathogen-free, domestic shorthair cats which were fed purified diets for 1.5 to 2.5 years. Cats fed an EFA-deficient diet exhibited signs of deficiency: severe fatty degeneration of the liver, excessive fat in the kidneys, dystrophic mineralization of the adrenal glands, degeneration of the testes, and hyperkeratosis of the skin. Minor clinical pathologic changes were consistent with liver damage. Fatty acid analyses of plasma lipids revealed low concentrations of linoleate and other n6-fatty acids, and high concentrations of n7- and n9-fatty acids, consistent with EFA deficiency. These signs of deficiency were prevented by including safflower seed oil in the diet at a concentration to supply linoleate at 6.7% of dietary energy. Therefore, linoleate is an EFA for the cat, despite negligible conversion of linoleate to arachidonate in cat liver. However, in cats fed a diet containing linoleate, but lacking arachidonate, there was mild mineralization of the kidneys, and the neutral fat content of the liver was slightly higher than that of cats fed a diet containing arachidonate and other long-chain polyunsaturated fatty acids. Also, 2 of the 19 cats fed arachidonate-deficient diets developed unusual inflammatory skin lesions. In cats fed a diet containing hydrogenated coconut oil, safflower seed oil, and chicken fat, fatty livers developed despite the presence of high levels of linoleate. The fatty livers appeared to result from a specific deleterious effect of the medium chain triglycerides in hydrogenated coconut oil. Most of the organ pathologic changes of EFA deficiency in the cat can be prevented by feeding dietary linoleate. Linoleate meets the EFA requirement for functions which depend on proper membrane structure: growth, lipid transport, normal skin and coat condition, and maintenance of the epidermal permeability barrier. However, dietary arachidonate is required by the cat for functions which depend on eicosanoid formation, such as reproduction and blood platelet aggregation. PMID- 24049890 TI - Electromyographic and urethral pressure profilometry: long-term assessment of urethral function after perineal urethrostomy in cats. AB - Urethral pressure and electromyographic profiles were recorded in 18 adult male cats about 61 months after perineal urethrostomy was done. The loss of striated sphincter function postoperatively was reversible in some cats. The increased frequency of bacterial urinary tract infection seen in cats postoperatively after perineal urethrostomy cannot be explained by compromised urethral sphincter function alone. PMID- 24049891 TI - Hematologic values in healthy neonatal, weanling, and juvenile kittens. AB - Blood samples were taken by jugular venipuncture from healthy kittens ranging in age from birth to 17 weeks. Complete blood cell counts, including RBC indices, provided data on reference blood values in kittens. Age-dependent RBC changes observed were decreases in PCV and hemoglobin (Hb) and mean cell Hb concentrations in neonatal kittens and a subsequent increase in PCV, Hb concentration, and RBC count in juvenile kittens. Leukocyte changes included an increasing WBC count from birth through the weanling period, increases in lymphocyte numbers in the neonatal and juvenile age groups, and increases in eosinophil numbers in the juvenile period. PMID- 24049892 TI - Spermatozoa and testes in the boar: correlative analysis of sperm morphologic features, seminiferous epithelial area, and testes weight. AB - Testicular tissue and sperm from the cauda epididymidis of 300 boars were obtained in 6 collections during 1 year at a Chicago abattoir. Seventy-five boars (25%) had - 1 sperm abnormality present at rates that could result in infertility. These abnormalities and their frequency criteria were: proximal droplets > or = 15%, loose heads > or = 10%, abnormal middle pieces > or = 10%, abnormal acrosomes > or = 10%, bent tails > or = 15%, coiled tails > or = 15%, and abnormal head shapes > 5%. These 75 abnormal boars were then compared with a control group of 75 boars selected at random from the remaining 225 boars. Frequency of sperm abnormalities, testicular and epididymal weights, relative seminiferous epithelial areas (SEA), and the degree of testicular lesions were used in making comparisons. Testicular lesions were scored on a scale of 1 (normal) to 5. The SEA was measured and was expressed as the mean area of 50 tubules. The SEA was negatively correlated with proximal droplets and abnormal middle pieces in abnormal boars and abnormal head shapes in control boars. The mean SEA was 8.71 and 5.60 cm2 for control and abnormal boars, respectively. The overall mean score for testicular lesions was 1.72 and 3.17 for control and abnormal boars, respectively. PMID- 24049893 TI - Pharmacokinetics of 4-aminopyridine in horses. AB - The pharmacokinetics of 4-aminopyridine (4-AP), a drug capable of antagonizing nondepolarizing neuromuscular blocking drugs, as well as several classes of injectable sedative and anesthetic agents, were studied in 6 intact, awake horses. Plasma samples were assayed for 4-AP over a frequent sampling schedule for 8 hours after IV administration. The plasma 4-AP vs time data best fit a 2 compartment pharmacokinetic model. Distribution half-life was 7.4 minutes, elimination half-life was 259 minutes, volume of the central compartment was 0.89 L/kg, volume of distribution (area) was 1.98 L/kg, volume of distribution at steady state was 1.9 L/kg, and total clearance was 5.3 ml min(-1) kg(-1). The 259 minute elimination halflife observed in the present study is consistent with prolonged clinical effectiveness observed in a previous study of antagonism of xylazine/ketamine anesthesia by 4-AP in horses. PMID- 24049894 TI - Effects of cyclophosphamide on the immune response of pigs to Salmonella cholerae suis var kunzendorf. AB - The effects of the immunosuppressive agent cyclophosphamide (CY) on the immune response of pigs given IM challenge inoculations of a moderately virulent strain of Salmonella cholerae-suis var kunzendorf were examined. Five groups of Yorkshire-cross pigs (approx 6 kg) were given Salmonella, CY, or both at various times after the 1st of a series of doses of CY was given. The drug was administered subcutaneously in 3 doses, 2 days between doses, at a rate of 20 mg/kg of body weight. Cyclophosphamide was observed to produce significant numerical decrease of circulating leukocytes, especially the polymorphonuclear neutrophils. Circulating lymphocyte numbers were reduced to 40% to 60% of base line values. Pigs (group 4) given 3 x 10(6) S cholerae-suis IM at the time the initial CY dose was given were clinically ill during days 6 to 12; 2 of the 5 pigs died. In contrast, pigs (group 5) given 3 x 10(6) S cholerae-suis at the time of the 3rd dosing with CY did not become clinically ill until 10 days later. A significant increase in antibody titer to S cholerae-suis was delayed in this latter group beyond that of the groups of pigs (group 4) inoculated on the 1st dosing with CY and of pigs (group 6) not given CY. A significant and prolonged increase in mean rectal temperature was observed in those pigs challenge inoculated at the time of the initial CY dose. Pigs also were sensitized to Mycobacterium avium 2 weeks before CY administration. Delayed hypersensitivity reactions were depressed in pigs treated with CY at the time of testing. PMID- 24049895 TI - Relationship between the antibody-complement susceptibility of smooth Salmonella cholerae-suis var kunzendorf strains and their virulence for mice and pigs. AB - In the present work, we attempted to characterize 4 field strains of Salmonella cholerae-suis var kunzendorf susceptible to antibody and complement (Ab-C), and 4 strains not susceptible to Ab-C, with respect to their virulence for mice and pigs. In vivo growth of an Ab-C-susceptible, mouse-virulent strain in the spleens of mice exceeded that of 2 Ab-C-susceptible, but mouse-avirulent strains by at least 10(4) organisms. Comparison of Ab-C susceptibility with virulence for pigs seemed to indicate that parallelism existed between Ab-C susceptibility and avirulence, except for strain 38, which was Ab-C susceptible yet virulent. There was agreement between virulence for mice and pigs, except for strains 10 and 61, which were avirulent for mice but relatively virulent for pigs. The 3 strain criteria under comparison (ie, Ab-C susceptibility, virulence for mice, and virulence for pigs) suggested only partial relatedness. Vaccination of pigs with the least virulent strain was found to protect them against challenge exposure with the most virulent strain, indicating that virulence factors may not be associated with immunogenicity. PMID- 24049896 TI - Diagnosis of mycoplasmal pneumonia of swine: sequential study by direct immunofluorescence. AB - An improved direct fluorescent antibody test was evaluated for specificity and efficacy in diagnosing mycoplasmal pneumonia of swine. A sequential study was carried out in which pigs inoculated with a pneumonic lung suspension containing Mycoplasma hyopneumoniae strain 11 were euthanatized at postinoculation (PI) weeks 2 to 12. Fluorescent coating of M hyopneumoniae was detected primarily on bronchial and bronchiolar epithelial surfaces of lungs with gross lesions of pneumonia. Fluorescence was observed to be most intense at PI weeks 4 to 6, with a tendency to decrease in intensity from PI weeks 8 to 12. This indicated that there may be a decrease in number of M hyopneumoniae cells in the more advanced stages of the disease. The use of a counterstain (chelated azo-dye) provided an excellent color contrast and permitted making unambiguous interpretation of results. PMID- 24049897 TI - Abortion in sows experimentally infected with African swine fever virus: clinical features. AB - Thirteen sows between 38 and 92 days of pregnancy were exposed oronasally to African swine fever virus (1979 Dominican Republic isolate) to determine whether infection would affect their reproductive performance. Abortions occurred in sows in all stages of pregnancy. Of 11 sows, 7 aborted 5 to 8 (6.1 +/- 0.90) days after inoculation or 0 to 3 (1.4 +/- 0.98) days after fever development. Abortions occurred soon after clinical signs of infection first developed and viremia titers peaked. Swelling of the vulva and treading preceded abortion in some sows. Ecchymotic placental and petechial cutaneous hemorrhages were present in 6 of 13 and 9 of 13 litters, respectively. African swine fever was transmitted to 2 healthy barrows by feeding fetal tissues collected from 1 inoculated sow. All inoculated sows not killed, died, precluding further study of neonates from infected sows. PMID- 24049898 TI - African swine fever convalescent sows: subsequent pregnancy and the effect of colostral antibody on challenge inoculation of their pigs. AB - The effect of African swine fever (ASF) virus infection on reproductive performance of recovered sows and their pigs was investigated. Six sows were inoculated with a 1979 ASF isolate from the Dominican Republic. One sow was bred on postinoculation day (PID) 58 and killed on PID 148. Four sows were bred between PID 368 and 419 and were allowed to farrow. One sow did not conceive. Samples collected during pregnancy, at farrowing, and during lactation were tested for virus by tissue culture and animal inoculations to determine whether ASF virus recrudesced during these natural stresses. Virus was recovered only from tissues of the sow killed on PID 148. Virus was not detected in tissue samples from the 4 other sows or from any fetus or neonate. Sow and neonatal pig sera, colostral whey, and milk whey were assayed for antibodies against ASF viral antigens, using an enzyme-linked immunosorbent assay. Antibody values in sows' sera did not change appreciably during pregnancy, farrowing, or lactation. One litter of pigs was raised with their sow. Weekly serum samples were tested for passively acquired antibodies. At 7 weeks of age, the litter was challenge inoculated with the same virus as that used initially to infect their dam. Viremia titers, duration of viremias, and clinical course were reduced. One young pig did not develop fever, viremia, clinical disease, or antibody response to virus challenge exposure. The altered course of infection was attributed to protective effect of passively acquired antibodies. PMID- 24049899 TI - African swine fever in neonatal pigs: passively acquired protection from colostrum or serum of recovered pigs. AB - The effect of passively acquired antibodies on the course of African swine fever (ASF) virus infection was investigated in hysterotomy-derived neonatal pigs fed colostrum from an ASF-recovered sow or given ASF virus antiserum. Thirty neonatal pigs were assigned to 5 study groups: (i) colostrum-deprived, (ii) fed colostrum from a normal sow, (iii) fed colostrum from an ASF-recovered sow, (iv) given ASF virus antiserum, and (v) noninoculated controls. Pigs were inoculated oronasally with 10(6.1) median hemadsorption units (HAd50) of a Dominican Republic ASF virus isolate. The progression of ASF infection was monitored by measure of rectal temperature, viremia titers, antibody response, and observation of attitude. The clinical course of ASF infection was markedly different in young pigs in the various study groups. On postinoculation day (PID) 4, ASF viremia titers for pigs receiving colostrum from an ASF-recovered sow or ASF virus antiserum (mean = 3.2 +/- 1.88 log10 HAd50, n = 10 pigs) were significantly lower (P < 0.001) than viremia titers of colostrum-deprived pigs or of those fed normal colostrum (mean viremia titer = 7.8 +/- 0.55 log10 HAd50, n = 14 pigs). All pigs not given colostrum or serum (n = 15 pigs) from swine recovered from ASF were dead by PID 16. By PID 30, only 1 pig that received colostrum or antiserum (n = 10 pigs) from the sow recovered from ASF had died. To determine whether the protective effect of ASF antiserum resided within the immunoglobulin (Ig) fraction, 4 pigs that had acted as noninoculated controls for the 1st experiment were given 125 mg of ammonium sulfate precipitated Ig from the ASF virus antiserum used in the initial study (intraperitoneally). The 5th pig was not given Ig (nontreated-inoculated control). All 5 pigs were inoculated oronasally with 10(6.1) HAd50 of Dominican Republic ASF virus. The nontreated control pig died on PID 10 and 3 Ig-treated pigs died on PID 17, 23, and 24. The 4th Ig-treated pig survived. Although administration of precipitated ASF Ig did not completely protect against clinical ASF infection or death, the course of infection was markedly altered. PMID- 24049900 TI - Campylobacter microagglutination tests of swine with proliferative enteritis. AB - A microagglutination test was developed to determine campylobacter titers in swine with proliferative enteritis. Formalinized whole cell antigens from 24 Campylobacter isolates, including C hyointestinalis (CHI), C sputorum ss mucosalis (CSM), C jejuni/coli (CJC), C fetus ss fetus (CFF), and C fecalis (CF), were tested with 9 rabbit antisera prepared against each of 3 strains of CHI, CSM, and CJC. The CHI appeared to be antigenically homogeneous. All 6 isolates of CHI agglutinated with homologous antisera at high dilutions and did not react with CSM antisera. Five of 6 isolates of CSM agglutinated with homologous antisera, whereas 1 isolate did not. Seven strains of CJC autoagglutinated in saline solution and various antisera. One of 3 CJC antisera, however, cross reacted with CHI and CSM antigens at high dilutions. The antigens from 5 strains of CFF and CF did not react with CHI, CSM, and CJC antisera. A survey of sera from 1,052 adult pigs from production herds indicated that the majority had high titers to CHI and CSM (mean, in log2: CHI = 5.57, CSM = 6.05). Similar titers were found in weaned pigs from 3 herds with the disease and 2 of 3 herds without the disease. Pigs with confirmed lesions of proliferative enteritis, however, had low titers (mean in log2: CHI = 2.44, CSM = 3.11). Agglutinating antibodies to CHI and CSM were transmitted from farrowing gilts to neonatal pigs via colostrum. The acquired antibodies decayed to low levels in pigs at 4 weeks of age (mean in log2: CHI = 1.09, CSM = 1.27). PMID- 24049901 TI - Anatomy of the tarsal tendons of the equine tibialis cranialis and peroneus tertius muscles. AB - Tendons of insertion of the equine tibialis cranialis muscle and peroneus tertius muscle (PT) were dissected grossly. Precise areas of tendon attachment and fiber arrangements within the tendons were described for the dorsal and medial tendons of the tibialis cranialis, and for the superficial lateral, deep lateral, dorsal, and medial tendons of the PT. Direct attachment of the dorsal and medial tendons of the PT into the periosteum of the central and 3rd tarsal bones and the 3rd metatarsal bone indicates that the PT may be involved in the pathogenesis of hock lamenesses. PMID- 24049902 TI - Effect of flunixin meglumine on prostacyclin accumulation in the equine eye. AB - A study was performed to identify prostacyclin (PGI2) in equine aqueous humor, demonstrate an increase in PGI2 following anterior chamber paracentesis, and determine the effects of subconjunctival injection of flunixin meglumine on PGI2 accumulation. Twenty ponies were found to be normal upon ocular examination and were placed under general anesthesia. Anterior chamber paracentesis was performed in both eyes (right and left); immediately afterward, 25 mg of flunixin meglumine was injected (subconjunctivally) in the left eye. Aqueous paracentesis was performed 1.5 hours later (both eyes). Aqueous humor samples were assayed for 6 keto PGF1alpha, the stable, inactive metabolite of PGI2. Eyes treated with flunixin meglumine contained less 6-keto PGF1alpha than did control eyes. PMID- 24049903 TI - Transmission of bluetongue virus by intrauterine inoculation or insemination of virus-containing bovine semen. AB - Bluetongue virus was inoculated transcervically into the uterine body of estrous heifers to determine whether infection could be readily established by this route of exposure. Two strains of the virus were transmitted by intrauterine deposition. Nine heifers were inseminated at estrus with 0.5 ml of processed, frozen-thawed semen that had been collected during the course of viremia in an experimentally infected bull. This semen contained titratable quantities of bluetongue virus. Of 9 inseminated heifers, 6 became pregnant and 3 became viremic and developed antibody to bluetongue virus. An additional heifer seroconverted, but did not become detectably viremic. Evidence of fetal infection was not present in the heifer that became infected and pregnant or in the 5 heifers that became pregnant, but were not infected. PMID- 24049904 TI - Effect of energy or protein supplements containing monensin on ruminal 3 methylindole formation in pastured cattle. AB - The metabolism of 3-methylindole (3MI), a ruminal degradation product of L tryptophan, results in acute bovine pulmonary edema and emphysema. The effect of feeding an energy or protein supplement containing monensin on ruminal 3MI formation in pastured beef cattle was investigated. A luxuriant pasture of orchard grass was established in a field that was seeded 1 year before the start of the grazing period. This 4-ha pasture was cut, fertilized, divided into 2 equal plots, and then irrigated during a 22-day growth period. All cows were fed a restricted quantity of low-quality alfalfa hay for 33 days before the grazing period. Two experiments were conducted, using 38 cows (30 of the cows were used in experiment I and all 38 cows were used in experiment II). Cows in each experiment were randomly allotted to 2 groups. One group was designated in each experiment as the control group. The control group for experiment I was fed an energy supplement. The control group for experiment II was fed a protein supplement. The 2nd group in each experiment was given the same supplement as the respective control group with 200 mg of monensin added/! kg of feed. Supplements were fed on days - 1, 0, 1, 2, 3, 4, 5, 6, and 7 of each experimental period. Supplements were fed twice daily to provide 1 kg of supplement/cow. Cows were given access to orchard grass pasture on day 0 of each experiment. Ruminal fluid was collected daily for analysis of 3MI, indole, and volatile fatty acids. Ruminal fluid pH was recorded immediately after collection. Ruminal pH of all cows decreased from 7.3 to 6.2 during the first few days of grazing the orchard grass. Ruminal pH then gradually increased toward neutrality by experimental day 10. Significantly (P < 0.01) higher molar percentages of pro-pionate and lower (P < 0.01) molar percentages of acetate and butyrate were observed in the 2 groups fed the supplements with added monensin. These changes in propionate and acetate remained different (P < 0.01) from those of the controls for 10 days (or 3 days after the last monensin feeding). Compared with pregrazing ruminal concentrations of 3MI, the 3MI values were elevated (P < 0.01) by day 1 in all groups, except in the monensin-treated cows of experiment I. In experiment I, 3MI concentrations were highest on experimental days 5 and 10 in control and monensin-treated cows, respectively. In experiment II, 3MI concentrations peaked on day 4 for the control cows and day 6 for the monensin-treated cows. Monensin supplementation reduced (P < 0.05) 3MI formation on days 1 through 5 in experiment I and on days 1 through 3 in experiment II. Formation of 3MI was increased in ruminal fluid of all cows after an abrupt change to the pasture forage, but the rate of 3MI production was slower, and a lower peak concentration of 3MI was reached in cows fed monensin than was observed in the controls. These results indicate that monensin administration in either an energy or protein supplement effectively reduced ruminal 3MI formation in pasture-fed cattle. PMID- 24049905 TI - Seasonal occurrence of infective nematode larvae in California high Sierra pastures grazed by cattle. AB - Worm-free Holstein calves were used to assess the seasonal variation in numbers of nematode infective larvae on herbage at 2 commercial cow-calf ranches in the Sierra Nevada mountains. Both ranches used Herefords as their basic breed. One ranch near Sattley, California, is at an elevation of approximately 1,500 m above sea level, whereas the study area on the 2nd ranch near Susanville is at an elevation of approximately 1,250 m above sea level. Worm-free tracer calves were allowed to graze for approximately 30 days and were then kept free of further nematode infection until euthanasia and necropsy approximately 30 days after removal from the pastures. At necropsy, the number, species, and stages of development of nematodes in the gastrointestinal tract were determined. The most common species of nematode in the abomasum was Ostertagia ostertagi and in the small intestine Cooperia oncophora. Infection levels decreased during early summer and were low in midsummer to early fall. In late fall and winter, infection levels began to increase, and highest infection levels were obtained during the spring. A low level of inhibited development (up to 18%) of 4th-stage O ostertagi occurred in November and December. Considerably higher levels of inhibition (up to 61%) were observed in March, April, and May. Inhibition of development in Cooperia spp was not noticed. Other nematodes seen were O lyrata, C mcmasteri, C punctata, Trichostrongylus axei, Haemonchus sp, and Nematodirus helvetianus. PMID- 24049906 TI - Effect of procaine benzylpenicillin alone or in combination with dihydrostreptomycin on udder pathogens in vitro and in experimentally infected bovine udders. AB - Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of benzylpenicillin (PEN) and dihydrostreptomycinsulfate (DHS) were determined for freshly isolated bovine udder pathogens. Killing curves were determined to study synergism of PEN and DHS on Staphylococcus aureus and Streptococcus uberis. Healthy udder quarters of cows in their first lactation were inoculated with Str dysgalactiae or Str uberis strains. After development of acute mastitis, procaine PEN alone or combined with DHS were given IM, and the concentrations of PEN and DHS in plasma and normal and mastitic milk were determined. Twenty-four hours after 10 mg of procaine PEN/kg of body weight (IM), concentrations in mastitic milk equal to MIC or MBC were maintained only for Str dysgalactiae. Twenty-four hours after 20 mg of procaine PEN/kg (IM), MBC in mastitic milk was maintained for Str uberis and 50% of the S aureus. When concentrations equal to MIC or MBC Of PEN were combined with a sub-MIC amount of DHS, the in vitro synergistic killing of Str uberis was not observed in vivo. In agreement with in vitro killing effect at PEN concentrations equal to MBC, Str dysgalactiae was 100% eliminated in 5 cows when MBC of PEN in mastitic milk was maintained for 24 to 36 hours. On the contrary, only 2 of 6 cows inoculated with Str uberis were free of this pathogen, although MBC of PEN was maintained for 24 to 36 hours in mastitic milk. PMID- 24049907 TI - Restricted dietary chloride and sodium bicarbonate supplementation in early lactation Holstein cows: cerebrospinal fluid electrolyte alterations. AB - As part of an experiment designed to study the acute and chronic metabolic changes associated with dietary chloride (Cl) restriction and sodium bicarbonate (NaHCO3) supplementation in cows in early lactation, base-line and final experimental CSF specimens were collected to evaluate the relative effects of a nutritional Cl deficiency on serum and CSF electrolyte concentrations. Attention was paid to the comparative alterations in serum and CSF Cl concentrations as an indication of the potential for the choroid plexus active Cl transport mechanism to conserve CSF Cl concentrations in the face of total body Cl depletion. Serum Cl values in cows fed the restricted Cl diets decreased from 96.4 +/- 3.5 mEq/L to 83.4 +/- 4.5 mEq/L in a 2-week trial and from 106.0 +/- 2.8 mEq/L to 75.5 +/- 6.7 mEq/L in an 8-week trial, as an indication of a nutritional Cl deficiency. Healthy cows maintained CSF Cl concentrations approximately 20% higher than the serum values, whereas cows fed a diet containing 0.10% Cl and 0.70% NaHCO3 for 2 weeks maintained CSF Cl values at 134.8% of the serum Cl concentrations, and CSF Cl concentrations in cows given a diet with 0.10% Cl and 0.80% NaHCO3 for 8 weeks increased to 137.2% of the serum Cl values. PMID- 24049908 TI - Enhanced uptake of liposomes by bovine macrophages after opsonization with antibodies to Brucella abortus. AB - Phosphatidylcholine:cholesterol liposomes containing 4(5) carboxyfluorescein were modified by incorporation of Brucella abortus lipopolysaccharide. These vesicles were opsonized with bovine anti-B abortus or anti-B abortus plus complement. The fluorescent marker entrapped in antibody-opsonized liposomes was taken up by cultured bovine macrophages more effectively than was the same compound which had been loaded into nonopsonized liposomes. The addition of bovine complement to antibody-opsonized liposomes did not increase the extent of 4(5) carboxyfluorescein uptake over that caused by antibodies alone. The system, described in this report, could be used as a model for evaluation of the efficacy of selectively directing liposomes containing antibiotics to macrophages infected with intracellular B abortus, since macrophages possess Fc receptors capable of binding antibody-opsonized liposomes. PMID- 24049909 TI - Transruminal and transreticular palpation of abdominal viscera of the permanently fistulated dairy cow. AB - A detailed description is given of the abdominal viscera which are palpated through the walls of the rumen and reticulum of the live dairy cow surgically prepared with a permanent fistula. Transruminal and transreticular palpation can be complementary to transrectal and transcolonic examination in gaining detailed knowledge of the topography of abdominal viscera in the live dairy cow. PMID- 24049910 TI - Effects of social stress on response to ketamine anesthesia in chickens. AB - Chickens were housed in low, high, and optimal social stress environments for 16 weeks before they were given ketamine IV. The sleep time was significantly (P < 0.01) longer in the groups exposed to the low (n = 14) and high (n = 30) social stress environments than in the group exposed to optimal-stress environment (n = 12) or controls (n = 12). Birds (n = 12) removed from optimal-stress environment and exposed to high-stress environment for 48 hours did not exhibit longer sleep time than the group in the optimal-stress environment. Long-term exposure to different social stress environments markedly altered ketamine-induced sleep time in chickens. PMID- 24049911 TI - Adverse effects of antibiotics on the development of gut-associated lymphoid tissues and the serum immunoglobulins in chickens. AB - Study was done of the distribution and relative densities of immunoglobulin (Ig)M , IgG-, and IgA-producing cells in the gut-associated lymphoid tissues and the spleen (SP) of control and antibiotic-treated chickens between 3 and 28 days of age. Specific Ig in the serum also were quantitated simultaneously. Antibiotic treatment included preincubation dipping of fertile eggs in gentamicin solution (500 mg/L), injection of chicks with gentamicin (0.2 mg/chick, subcutaneously), and inclusion of chlortetracycline in the diet (200 mg/kg). At 3 days, the gut associated lymphoid tissues of control chicks carried few Ig-positive cells, except the bursa of Fabricius in which all 3 classes of Ig-bearing cells were present in relatively large numbers. The SP had few,but equal, numbers of IgM- and IgA-positive cells at this age. As control birds grew older, IgM-positive cells dominated in the SP, followed by the IgA cells. Cell populations fluctuated in the bursa of Fabricius of chicks until 21 days of age when IgM and IgA cells stabilized at a higher density than the IgG-positive cells. The cecal tonsils had no Ig-positive cells at 3 days, mostly IgM cells by 7 days, but equal numbers of the 3 types of cells by 28 days. The large intestines had few IgM-positive cells at 3 days and no IgG cells at 3 or 7 days. The numbers of IgM and IgA cells were approximately equal in the large intestine of the chicks from 7 days until 28 days. Maternally acquired IgG predominated in sera of chicks until 14 days of age, followed by the IgM. At 28 days, 'there was more IgM in the serum than IgG. Serum IgA was not detectable until 14 days of age, and its concentration remained at a lower level than IgM or IgG values. Antibiotic-treated chickens generally carried lower densities of Ig cells than did the respective controls. However, statistically significant (P < 0.05) differences were apparent only with respect to Ig cell populations in the cecal tonsils and the large intestines. The treated chickens also had significantly lower serum IgM concentrations at 28 days of age. PMID- 24049912 TI - Effects of benzimidazole anthelmintics on the survival and migratory behavior of Toxocara canis larvae in the mouse. AB - Nine benzimidazole anthelmintics-thiabendazole, mebendazole, fenbendazole, cambendazole, flubendazole, albendazole, parbendazole, oxibendazole, and oxfendazole--were tested for their larvicidal effects and capabilities to inhibit migration of larval Toxocara canis in mice. The drugs were administered in medicated diets containing 0.1% (w/w) of the pure compounds (130 to 160 mg/kg each day), starting 24 hours after oral inoculation with 500 infective eggs. Groups of mice were continued on medicated diets until day 8 after inoculation when half of the mice were killed; the other half were placed on normal diet and killed on day 22 after inoculation. Control groups were killed at the same times and the numbers of larvae recovered in pepsin digests of the liver, lungs, and carcass, as well as in press preparations of brain, were recorded. In mice killed after 8 days of treatment, all of the compounds except thiabendazole produced significant arrest of the migrating larvae in the liver. In mice given the normal diet for 2 weeks after termination of treatment with the different drugs, the percentages of larvae that remained in the liver showed wide variation. Significant larvicidal effects were observed only in mice treated with albendazole, oxfendazole, and cambendazole. PMID- 24049913 TI - Morphology of colonies of Anaplasma marginale in nymphal Dermacentor andersoni. AB - Colonies of Anaplasma marginale Theiler were studied in midgut epithelial cells of nymphal Dermacentor andersoni Stiles that had become infected by feeding on splenectomized calves with anaplasmosis. Colonies of A marginale were not observed in nymphal ticks killed during the 6-day feeding period, but were present in sections of midgut epithelial cells of ticks killed as early as 5 days after repletion. Colonies of A marginale also were present in ticks examined throughout development to the adult stage. Two distinct morphologic types of colonies were observed and categorized by light microscopy as nymphal types 1 and 2. Colonies that were morphologically indistinct with characteristics common in both types were termed transitional nymphal (TsN) colonies. Nymphal type 1 (Ny1) colonies were observed at 5 days after repletion and nymphal type 2 (Ny2) colonies were first observed at 20 days after feeding. Representatives of each colony type were selected by light microscopy and were sectioned for electron microscopy. The Ny1 contained small particles and large, round reticulated forms, some of which appeared to be dividing by binary fission. The Ny2 also contained reticulated organisms, but they were rod-like in shape, and there was no morphologic evidence of binary fission. Organisms within Ny2 appeared to be surrounded by 2 double-layered membranes. Electron-dense forms, commonly observed in adult ticks, were not seen in colonies (Ny1, Ny2, or TsN) from nymphal ticks. PMID- 24049914 TI - Immunoperoxidase localization of papillomaviruses in hyperplastic and neoplastic epithelial lesions of animals. AB - In a retrospective study of selected hyperplastic and neoplastic epithelial lesions of wild, exotic, and domestic animals, paraffin sections from 438 biopsies and 15 necropsies were screened for the presence of papillomavirus structural antigens, using the peroxidase-antiperoxidase technique. Viral antigens were detected in tissues from 9 of 21 different mammalian, 1 of 5 avian, and 0 of 2 reptilian species. The latter tissues were histopathologically classified as papillomas, fibropapillomas, and fibromas and of canine origin (n = 6), squamous cell carcinoma. Virus could be readily detected by transmission electron microscopy in lesions that contained numerous nuclei which stained positively by the peroxidase-antiperoxidase technique. PMID- 24049915 TI - Measurement of functional residual capacity and pulmonary carbon monoxide uptake in conscious Greyhounds. AB - A simplified rebreathing method was developed for measurement of functional residual capacity (FRC) and pulmonary diffusing capacity for CO in nonanesthetized standing Greyhounds. The FRC was related to body weight according to the equation: FRC = 0.04 (body weight in kg)1.22 whereas pulmonary diffusing capacity for CO in nonanesthetized standing Greyhounds (ml/min/mm of Hg) = 2.34 (body weight in kg).0.66 The large FRC per unit of body weight in the Greyhound emphasizes the need for breed specific prediction equations in veterinary respiratory physiologic studies and may reflect selection for exercise performance in the development of the Greyhound breed. PMID- 24049916 TI - In vitro action of combinations of antimicrobial agents with EDTA-tromethamine on Proteus vulgaris of a canine origin. AB - Combinations of EDTA-tromethamine and 7 antimicrobial agents (chloramphenicol, nalidixic acid, oxytetracycline, penicillin, polymyxin-B, streptomycin, or a combination of sulfamethazine, sulfapyridine, and sulfathiazole) were tested for synergistic activities against Proteus vulgaris of canine origin. Three in vitro tests were used, including minimal inhibitory concentrations of the drugs, a 2 dimensional microtiter checkerboard technique, and bacterial inhibition studies. A synergistic inhibitory action was observed with combinations of EDTA tromethamine plus penicillin, oxytetracycline, nalidixic acid, chloramphenicol, polymyxin-B, or sulfamethazine-sulfapyridine-sulfathiazole by at least one test system. A synergistic effect was not recorded with combinations of EDTA tromethamine and streptomycin. Poor correlation between data from the 3 test systems was noticed, despite the fact that each monitors bacteriostatic end points. PMID- 24049917 TI - Morbidity and mortality in neonatal kittens. AB - The mortality patterns of 294 Domestic Shorthair kittens indicated that birth weight was closely related to survivability. Slightly over half of the nonsurviving kittens lost at 0 to 3 days of life were stillborn. Abnormal gross anatomy did not appear to be a major factor in neonatal kitten death. Mortality was lowest at the 5th parity and in litters of 5 kittens. Litters of 1 kitten experienced high mortality. Smaller queens tended to deliver fewer kittens per litter, but with improved kitten viability. Overweight queens experienced increased mortality of kittens. Further examination of mortality by litter size also revealed that low birth weight kittens tended to survive less often than normal birth weight kittens, even within the same litter. PMID- 24049918 TI - Analytical evaluation of urinary excretion of furosemide in barrows. AB - Market weight barrows were dosed with furosemide IM or orally, and urine (5 barrows) and blood (1 barrow) samples were collected. Extraction procedures and high-performance liquid chromatographic conditions were modified and adapted for analysis of porcine samples. Furosemide was cleared rapidly from plasma, but could be detected in urine 4 to 5 days after administration, using fluorescent or ultraviolet detection. Fluorescent detection was the preferred method for screening for furosemide. Approximately 12% of furosemide was excreted as the glucuronide conjugate. PMID- 24049919 TI - Angiography of the corpus cavernosum penis in the pony stallion during erection and quiescence. AB - Serial arteriography was used to determine the vascular pattern and blood flow in the penis of the pony stallion. Ponies were anesthetized with pentobarbital sodium, and catheters were surgically introduced into the internal pudendal and obturator arteries. The vascular anatomy was visualized by angiography via image intensified fluoroscopy and was recorded on 70-mm film at 3 frames/s or by direct radiography. Blood flow into the corpus cavernosum penis (CCP) was limited during quiescence because the blood was immediately shunted into the venous system. After vasodilation with mild stimulation from an electroejaculator, there was increased filling of the CCP and corpus spongiosum penis. Contrast medium injected into the internal pudendal artery entered the bulb of the penis during peak erection, but medium injected into the obturator artery could not enter the crus penis during peak erection. The contrast medium stopped in the obturator artery at the edge of the ischiocavernous muscles due to the occlusion of the deep arteries of the penis by contraction of these muscles. When contrast medium was injected directly into the CCP near the glans to outline the body of the penis, there was no evidence of venous outlets along the body. PMID- 24049920 TI - Antiviral responses of bluetongue virus-inoculated bovine fetuses and their dams. AB - Antiviral responses of bovine fetuses to bluetongue virus (BTV) infection were determined. Fetuses inoculated with BTV at 125 days of gestation apparently had cleared all virus by the time of birth; however, the mechanism responsible for virus clearance was not determined. Interferon production and virus clearance were temporally unrelated. Cell-mediated responses to BTV antigens were not detected by the lymphocyte stimulation test using lymphocytes from infected fetuses or cows. Although virus clearance and fetal production of high titers of neutralizing antibody did coincide, it was considered unlikely that antibody alone was responsible for virus clearance. As congenital BTV infection did not lead to specific immunologic tolerance or postnatal persistance of virus, such animals would not be expected to have a major role in the dissemination of BTV. PMID- 24049921 TI - Location of cryptosporidia: review of the literature and experimental infections in calves. AB - Cryptosporidium, a protozoan, was present in the gastrointestinal tract of calves, lambs, goats, deer, foals, cats, rats, mice, guinea pigs, rabbits, monkeys, human beings, birds, reptiles, and fish. The usual location was the gastrointestinal tract with emphasis on the lower portion of the small intestine. In birds, cryptosporidia were also present in the respiratory tract and conjunctiva. In human beings, cryptosporidia were present in specimens from the respiratory tract. Immunologic impairment may allow a more widespread distribution of the parasite in a given animal and may be related to increased susceptibility. Experimental cryptosporidial infections in newborn calves resulted in the establishment of the organisms in jejunum, ileum, cecum, and colon. Middle and lower portions of the jejunum and ileum appeared to have the largest numbers of organisms at 5 to 7 days after inoculation, as determined by histologic examinations. PMID- 24049922 TI - Noninvasive procedural dermatology. PMID- 24049923 TI - Treatment of hyperhidrosis with microwave technology. AB - Hyperhidrosis is the production of sweat above and beyond normal physiological needs, regardless of the ambient temperature, and it affects > 4% of the population. In addition, a poll showed up to 21% of the population is bothered on a daily basis by their amount of underarm sweating. Despite the large number of patients who suffer from hyperhidrosis, there are relatively few effective nonsurgical treatment options. A new, nonsurgical, lasting treatment for axillary hyperhidrosis has now been developed using microwave technology to eliminate sweat glands. PMID- 24049924 TI - Noninvasive radio frequency for skin tightening and body contouring. AB - The medical use of radio frequency (RF) is based on an oscillating electrical current forcing collisions between charged molecules and ions, which are then transformed into heat. RF heating occurs irrespective of chromophore or skin type and is not dependent on selective photothermolysis. RF can be delivered using monopolar, bipolar, and unipolar devices, and each method has theoretical limits of depth penetration. A variant of bipolar delivery is fractional RF delivery. In monopolar configurations, RF will penetrate deeply and return via a grounding electrode. Multiple devices are available and are detailed later in the text. RF thermal stimulation is believed to result in a microinflammatory process that promotes new collagen. By manipulating skin cooling, RF can also be used for heating and reduction of fat. Currently, the most common uses of RF-based devices are to noninvasively manage and treat skin tightening of lax skin (including sagging jowls, abdomen, thighs, and arms), as well as wrinkle reduction, cellulite improvement, and body contouring. PMID- 24049925 TI - Microfocused ultrasound for skin tightening. AB - The demand for noninvasive skin tightening procedures is increasing as patients seek safe and effective alternatives to aesthetic surgical procedures of the face, neck, and body. Over the past decade, radiofrequency and infrared laser devices have been popularized owing to their ability to deliver controlled heat to the dermis, stimulate neocollagenesis, and effect modest tissue tightening with minimal recovery. However, these less invasive approaches are historically associated with inferior efficacy so that surgery still remains the treatment of choice to address moderate to severe tissue laxity. Microfocused ultrasound was recently introduced as a novel energy modality for transcutaneous heat delivery that reaches the deeper subdermal connective tissue in tightly focused zones at consistent programmed depths. The goal is to produce a deeper wound healing response at multiple levels with robust collagen remodeling and a more durable clinical response. The Ulthera device (Ulthera, Inc, Meza, AZ), with refined microfocused ultrasound technology, has been adapted specifically for skin tightening and lifting with little recovery or risk of complications since its introduction in 2009. As clinical parameters are studied and optimized, enhanced efficacy and consistency of clinical improvement is expected. PMID- 24049926 TI - New waves for fat reduction: high-intensity focused ultrasound. AB - With the rising demand for body contouring, noninvasive devices for fat reduction have become increasingly popular and have grown dramatically over the past decade. High-intensity focused ultrasound (HIFU) has been used for nearly half a century for the noninvasive treatment of tumors of various organs, but has only recently been evaluated as a method for the selective destruction of adipose tissue. HIFU works by ablating subcutaneous adipose tissue and causing molecular vibrations that increase the temperature of local tissue and induce rapid cell necrosis. Several studies reveal the safety and efficacy of HIFU for fat reduction in the abdomen and the flanks. These studies indicate consistent reduction in abdominal circumference > 2 cm after a single treatment. The adverse events are limited to transient tenderness, bruising, and edema. Increased utility of HIFU for fat reduction will likely increase over time. PMID- 24049927 TI - Cryolipolysis: a historical perspective and current clinical practice. AB - Dermatologists have long used cold-based therapeutic approaches for a variety of applications. Based on the differences in chemical composition, it is possible to selectively target certain tissues rich with lipid, while sparing the surrounding tissue predominantly containing water. With historical observations of cold induced panniculitis suggesting the feasibility of this strategy, cryolipolysis has emerged as a new methodology using controlled cooling to selectively target fat. Both preclinical and clinical studies have established the safety and efficacy of cryolipolysis for noninvasive body contouring. This review will focus on the evolution of cryolipolysis from initial case reports of cold-induced panniculitis, to preclinical and clinical studies, and the current clinical practice. PMID- 24049928 TI - Body contouring using 635-nm low level laser therapy. AB - Noninvasive body contouring has become one of the fastest-growing areas of esthetic medicine. Many patients appear to prefer nonsurgical less-invasive procedures owing to the benefits of fewer side effects and shorter recovery times. Increasingly, 635-nm low-level laser therapy (LLLT) has been used in the treatment of a variety of medical conditions and has been shown to improve wound healing, reduce edema, and relieve acute pain. Within the past decade, LLLT has also emerged as a new modality for noninvasive body contouring. Research has shown that LLLT is effective in reducing overall body circumference measurements of specifically treated regions, including the hips, waist, thighs, and upper arms, with recent studies demonstrating the long-term effectiveness of results. The treatment is painless, and there appears to be no adverse events associated with LLLT. The mechanism of action of LLLT in body contouring is believed to stem from photoactivation of cytochrome c oxidase within hypertrophic adipocytes, which, in turn, affects intracellular secondary cascades, resulting in the formation of transitory pores within the adipocytes' membrane. The secondary cascades involved may include, but are not limited to, activation of cytosolic lipase and nitric oxide. Newly formed pores release intracellular lipids, which are further metabolized. Future studies need to fully outline the cellular and systemic effects of LLLT as well as determine optimal treatment protocols. PMID- 24049931 TI - The future of noninvasive procedural dermatology. AB - Noninvasive procedural dermatology has evolved rapidly during the past decade. An array of skin tightening, resurfacing, and fat-reducing energy devices can now be combined with filler and neurotoxin injectables to reduce the visible signs of aging with minimal downtime and risk. In the future, such advances will likely continue, although the pace of technological breakthroughs is difficult to predict. Complex feedback devices, nanotechnology, and cell-based therapies will eventually begin to fulfill the promise of scar removal, pigmentation correction, and replacement of aged skin with skin that is new and completely functional. Dermatologists are well equipped to retain their leadership in noninvasive esthetic medicine, and they will, to the extent that they continue to pioneer outstanding therapies that are effective, affordable, and safe. PMID- 24049930 TI - The new age of noninvasive facial rejuvenation. AB - The techniques of noninvasive facial rejuvenation are forever being redefined and improved. This article will review historical as well as present approaches to resurfacing, discussing the nonablative tools that can complement resurfacing procedures. Current thoughts on the pre- and postoperative care of resurfacing patients are also considered. PMID- 24049929 TI - Low-level laser (light) therapy (LLLT) in skin: stimulating, healing, restoring. AB - Low-level laser (light) therapy (LLLT) is a fast-growing technology used to treat a multitude of conditions that require stimulation of healing, relief of pain and inflammation, and restoration of function. Although skin is naturally exposed to light more than any other organ, it still responds well to red and near-infrared wavelengths. The photons are absorbed by mitochondrial chromophores in skin cells. Consequently, electron transport, adenosine triphosphate nitric oxide release, blood flow, reactive oxygen species increase, and diverse signaling pathways are activated. Stem cells can be activated, allowing increased tissue repair and healing. In dermatology, LLLT has beneficial effects on wrinkles, acne scars, hypertrophic scars, and healing of burns. LLLT can reduce UV damage both as a treatment and as a prophylactic measure. In pigmentary disorders such as vitiligo, LLLT can increase pigmentation by stimulating melanocyte proliferation and reduce depigmentation by inhibiting autoimmunity. Inflammatory diseases such as psoriasis and acne can also be managed. The noninvasive nature and almost complete absence of side effects encourage further testing in dermatology. PMID- 24049932 TI - Healthcare is a numbers game. PMID- 24049933 TI - How physician assistants can help Americans get affordable health insurance. PMID- 24049934 TI - Should beta-blockers be used in patients with acute decompensated heart failure? AB - In the absence of contraindications, beta-blockers are the standard of care for treating patients with chronic heart failure due to systolic dysfunction. Guidelines recommend that beta-blocker therapy be continued for patients hospitalized with acute decompensated heart failure due to left ventricular systolic dysfunction. PMID- 24049935 TI - A persistent discoloration of the neck sparing the submental area. PMID- 24049936 TI - Rethinking osteoporosis: balancing risk and benefit in diagnosis, prevention, and treatment. AB - The standard of care for osteoporosis is changing amid questions about the long term safety and efficacy of curren drugs for preventing and treating osteoporosis. This article provides a guide for evidence-based treatment, but not over-treatment, as well as the selection and duration of available drug therapies. PMID- 24049937 TI - Sickle cell disease: taking a multidisciplinary approach. AB - A costly major public health concern, sickle cell disease (SCD) affects up to 100,000 Americans and can cause life-threatening complications. This article reviews the pathophysiology, signs and symptoms, diagnostic testing, management, and treatment of patients with SCD. PMID- 24049938 TI - Slipped capital femoral epiphysis and hypothyroidism in a patient with Down syndrome. AB - Early screening is key for patients, such as those with Down syndrome, at high risk for associated diseases. Slipped capital femoral epiphysis and hypothyroidism require a high level of suspicion, screening, and early referral to avoid long-term complications. PMID- 24049939 TI - An unusual case of sudden hearing loss in a young man. AB - Acute-onset hearing loss of unknown cause may be the result of a tranverse temporal bone fracture. CT imaging is indicated for patients with acute focal neurologic deficits of uncertain cause. PMID- 24049940 TI - Fecal microbiota transplantation: an innovative approach to treating Clostridium difficile disease. AB - Normal gut flora or microbiota, which is key to a healthy digestive tract, can be disrupted by antibiotic therapy, potentially leading to Clostridium difficile associated disease (CDAD). Fecal microbiota transplant has shown promise in quickly and safely eradicating CDAD at low cost. PMID- 24049941 TI - Assessment of single-item literacy questions, age, and education level in the prediction of low health numeracy. AB - OBJECTIVE: Determining a patient's health literacy is important to optimum patient care. Single-item questions exist for screening written health literacy. We sought to assess the predictive potential of three common screening questions, along with patient age and education level, in the prediction of low health numerical literacy (numeracy). METHODS: After demographic and educational information was obtained, 441 patients were administered three health literacy screening questions. The three-item Schwartz-Woloshin Numeracy Scale was then administered to assess for low health numeracy (score of 0 out of 3). This score served as the reference standard for Receiver Operating Characteristics (ROC) curve analysis. ROC curves were constructed and used to determine the area under the curve (AUC); a higher AUC suggests increased statistical significance. RESULTS: None of the three screening questions were significant predictors of low health numeracy. However, education level was a significant predictor of low health numeracy, with an AUC (95% CI) of 0.811 (0.720-0.902). This measure had a specificity of 95.3% at the cutoff of 12 years of education (<12 versus > or = 12 years of education) but was non-sensitive. CONCLUSION: Common single-item questions used to screen for written health literacy are ineffective screening tools for health numeracy. However, low education level is a specific predictor of low health numeracy. PMID- 24049942 TI - Aneurysmal bone cysts. PMID- 24049943 TI - Voiding dysfunction in young men. PMID- 24049944 TI - An approach to managing HPV-associated anal dysplasia. AB - Although anal cancer is rare, incidence rates are rising in the United States. Recognizing and screening high-risk patients can improve management. Vaccination may also play a role in the prevention of HPV-related anal cancer, but more research is needed. PMID- 24049945 TI - Debating the duration of bisphosphonate therapy. PMID- 24049946 TI - Seizures in an immunocompromised patient. PMID- 24049947 TI - Empathetic medicine: what's bred in the bone. PMID- 24049948 TI - Resource guide categorizes vendors across labyrinthine landscape. PMID- 24049949 TI - Accountable care organizations help to coordinate care. The goal of ACOs is to avoid duplication of services, prevent errors and reduce costs, experts say. PMID- 24049950 TI - Making the switch to vendor-neutral archiving. How to optimize comprehensive data storage for healthcare's new age. PMID- 24049951 TI - Don't ask, don't tell. How the Omnibus Final Rule assigns responsibility for safeguarding protected health information (PHI). PMID- 24049952 TI - The endless potential of RTLS. Asset management and real-time location systems save money, time and equipment. PMID- 24049954 TI - Early surfactant for respiratory distress syndrome in premature infants. AB - Effects of early surfactant administration to premature newborns have been widely investigated in several RCTs. Furthermore, recent studies and metanalysis have compared early with delayed administration as well as selective and prophylactic use of surfactant. These data from the literature are discussed in the present review together with the factors that may argue against the standardization of respiratory care at birth. A tailored approach based on the stratification of risk factors may be appropriate in the so heterogeneous population of premature newborns. PMID- 24049955 TI - Which clinical markers for appropriate timing of surfactant therapy? AB - Preterm infants with RDS need adequate resuscitation maneuvers and appropriate timing of surfactant replacement but about the latter there is not an universal consensus. A correct evaluation should consider at the same time the administration of antenatal steroids, the radiological criteria, the clinical presentation, the FiO2 level, OI and a/ApO2. PMID- 24049956 TI - Surfactant therapy for acute respiratory distress in children. AB - In children with acute lung injury the endogenous surfactant system is altered via a variety of different mechanisms, including inflammation, vascular dysfunction, oxidant injury, cellular injury and oedema. This article examines the pathophysiology of acute lung injury and surfactant use for treatment of acute respiratory failure in infants and children. PMID- 24049957 TI - Surfactant administration during spontaneous breathing via a thin endotracheal catheter. AB - In the past two decades exogenous surfactant administration has been a cornerstone of therapy for preterm infants and is known to be effective either given prophylactically in the delivery room or later as selective therapy to infants with estabilished respiratory distress syndrome. Its introduction in neonatal practice in the early 90s was followed by a significant decrease in overall neonatal mortality. With the evolution and refinement of intensive care for preterm infants, the role of exogenous surfactant therapy is changing. The more widespread use of nasal continuous positive airway pressure (n-CPAP) as a primary mode of respiratory support means that many preterm infants now avoid intubation in the delivery room or in early post-natal life. Still, about 50% of them, will require intubation for surfactant delivery for evolving respiratory distress syndrome (RDS) during the course of hospitalization. In view of the difficulties and side effects that may be associated with intubation for surfactant delivery, less invasive ways of surfactant administration have been pursued. The rationale and the available evidences inherent the administration of surfactant via a thin endotracheal catheter during spontaneous breathing will be discussed. PMID- 24049958 TI - Efficacy of exogenous surfactant during conventional and high-frequency oscillatory ventilation in preterm infants with RDS. AB - INTRODUCTION: The immediate effects of exogenous surfactant on lung volume and hemodynamics in preterm infants have been poorly studied. MATERIALS AND METHODS: Lung volume, SpO2, perfusion index, regional SO2, transcutaneous partial pressure of CO2 were simultaneously monitored and recorded ten minutes after surfactant tracheal instillation in elective HFOV ventilated preterm infants with RDS. OUTCOMES: Despite a reduction in gas exchange during the first 5 minutes post surfactant instillation, most likely dependent on airway obstruction, lung volume increases rapidly in HFOV preterm infants with RDS. After 5 minutes from administration of surfactant, lung volume, gas exchange and PI reach stable values and CDP can be safely reduced. PMID- 24049959 TI - Minimally invasive approaches for surfactant administration. AB - Respiratory distress syndrome (RDS) is the most common respiratory morbidity in preterm infants. In addition to respiratory support, the current clinical treatment includes endotracheal intubation and rapid instillation of exogenous surfactant. However, this approach needs skilled operators and has been associated with complications such as hemodynamic instability and electroencephalogram abnormalities. New, less invasive methods for surfactant administration are needed. In this article, we reviewed the available noninvasive procedures for surfactant administration. In particular, we focused on aerosolized surfactant and surfactant administration through LMA. PMID- 24049953 TI - Survey of neonatal respiratory care and surfactant administration in very preterm infants in the Italian Neonatal Network. AB - INTRODUCTION: Variation of respiratory care is described between centers around the world. The Italian Neonatal Network (INN), as a national group of the Vermont Oxford Network (VON) allows to perform a wide analysis of respiratory care in very low birth weight infants. METHODS: We analyzed the dataset of infants enrolled in the INN in 2009 and 2010 and, for surfactant administration only, from 2006 to 2010 from 83 participating centers. All definitions are those of the (VON). A questionnaire analysis was also performed with a questionnaire on centers practices. RESULTS: We report data for 8297 infants. Data on ventilator practices and outcomes are outlined. Variation for both practices and outcome is found. Trend in surfactant administration is also analyzed. CONCLUSIONS. The great variation across hospitals in all the surveyed techniques points to the possibility of implementing potentially better practices with the aim of reducing unwanted variation. These data also show the power of large neonatal networks in identifying areas for potential improvement. PMID- 24049960 TI - Psychodermatology. PMID- 24049961 TI - Psychodermatology: an overview. AB - Psychodermatology is an interface between dermatology and psychiatry. The different disorders within psychodermatology can be categorized in 2 ways: by the type of psychodermatologic disorder or by the underlying psychiatric disorder. The types of psychodermatologic disorders include psychophysiological, primary psychiatric, secondary psychiatric, and cutaneous sensory disorder. The psychiatric disorders include anxiety, depression, obsessive-compulsive disorder, and psychosis. This manuscript gives an overview of the different psychodermatologic disorders, underlying psychiatric disorders, and how to manage psychodermatology cases. PMID- 24049962 TI - Emotional stress as a trigger for inflammatory skin disorders. AB - Dermatologic disorders comprise 15% to 20% of complaints seen in general practice. Skin disorders result in a negative impact to the patient not only physically but also psychologically, socially, and occupationally. The most common trigger for several inflammatory skin disorders, including psoriasis, is emotional stress. Understanding the significance of emotional triggers to common inflammatory dermatologic disorders is critical to the optimal management of these conditions. This article will provide an overview of the effects of emotional stress on skin disorders and psychotherapeutic options. PMID- 24049963 TI - Delusions of parasitosis. AB - The most common monosymptomatic hypochondriacal psychosis encountered by a dermatologist is delusions of parasitosis. In this condition, patients have an "encapsulated" fixed, false belief that they are infested with parasites or have foreign objects extruding from their skin. The patient will often experience feelings of biting, crawling and stinging related to the delusion. Most patients do not have other major psychiatric problems outside of their encapsulated delusion. The patient usually presents with a long history of symptoms and multiple visits to physicians in more than one specialty. Without an informed approach to these patients that focuses on the development of therapeutic alliance, clinical interactions can become very unpleasant. However, when treated with pimozide, risperidone, or other antipsychotic medications, patients have a very high response rate. Therefore, it is important for dermatologists to be able to handle these cases and know that the development of the therapeutic alliance is the key step to successful management. PMID- 24049964 TI - Body dysmorphic disorder. AB - Body dysmorphic disorder (BDD) is a DSM-IV disorder that is characterized by a distressing and excessive preoccupation with a slight or imagined defect of a physical feature. BDD causes significant impairment of psychosocial functioning and a decreased quality of life for patients. Though the disorder is commonly seen in the dermatology setting, the disease remains under recognized and under treated. It is important for dermatologists to be aware of BDD as patients suffer greatly from the disease. In this review, we provide an update on the epidemiology, clinical features, and treatment options for BDD. PMID- 24049965 TI - Obsessive-compulsive disorder in dermatology. AB - Obsessive-compulsive disorder (OCD) is a very common disorder affecting 2% to 3% of the general population. Up to 25% of patients presenting to physicians with skin disease suffer from OCD. Only 20% of all patients with OCD are receiving treatment. Unfortunately, those few receiving treatment remained undiagnosed for many years. Standard treatment includes behavioral therapy and psychotropic drugs (ie, selective serotonin re-uptake inhibitors and clomipramine). The highest dosages of these medications must be used for at least 3 months to see proper effectiveness and maintained for lengthy periods of time. Not only are there abnormalities in the serotonin pathway of patients with OCD but also the glutamate pathway is abnormal, leading to possible new treatment strategies. PMID- 24049966 TI - Trichotillomania. AB - Trichotillomania (TTM) is an impulse disorder in which patients chronically pull out hair resulting in noticeable hair loss. TTM is reported to affect as much as 4% of the population with the highest incidence in childhood and adolescence. The diagnostic criteria for TTM is likely to be revised in the planned fifth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-V) to remove the requirement that the patient has "tension" followed by "relief" or "gratification" after hair pulling. First-line therapy is cognitive behavioral therapy, with strongest support for the subtype habit reversal training. Among pharmacologic therapy, clomipramine has been most effective in clinical trials. However, selective serotonin reuptake inhibitors are most commonly prescribed despite the lack of data supporting their efficacy. This article reviews the clinical features and treatment options for TTM to enhance knowledge and clinical management of TTM. PMID- 24049967 TI - Neurotic excoriations and dermatitis artefacta. AB - Neurotic Excoriations is a psychocutaneous disorder that is characterized by an uncontrollable urge to pick at normal skin or skin with mild irregularities. Dermatitis Artefacta is another psychocutaneous disorder that consists of self induced skin lesions often involving a more elaborate method for damaging the skin, such as the use of a sharp instrument. Both neurotic excoriations and dermatitis artefacta cause significant disfigurement and anxiety for the patient. Since patients often present to dermatologists first, it is important for dermatologists to be aware of the nature of each condition and the available treatment options. This article provides an update on the clinical features, diagnosis, and treatment options for neurotic excoriations and dermatitis artefacta. PMID- 24049968 TI - Quality-of-life effects of common dermatological diseases. AB - Chronic skin conditions can impact a patient's quality of life beyond the skin. This manuscript gives an overview of the negative impact of common chronic skin conditions, such as psoriasis, vitiligo, acne, and eczema measured by the validated quality of life instruments. Literature has shown that patients with vitiligo and acne are mostly affected by their psychosocial wellbeing, whereas psoriasis and atopic dermatitis patients are affected by both physical and psychosocial well-being. Effective treatments of the above skin conditions correlate with positive quality of life outcomes. Further studies are recommended to better understand factors affecting quality of life. PMID- 24049969 TI - Cutaneous sensory disorder. AB - Cutaneous sensory disorder (CSD) represents a heterogeneous clinical situation where the patient presents with either disagreeable skin sensations (ie, itching, burning, stinging) or pain (ie, allodynia) and/or negative sensory symptoms (ie, numbness, hypoaesthesia). These patients have no apparent diagnosable dermatologic or medical condition that explains the cutaneous symptom, and typically have negative findings upon medical workup. Skin regions that normally have a greater density of epidermal innervation tend to be more susceptible to the development of CSD. CSDs can affect any body region but generally tend to be confined to the face, scalp and perineum, and have been referred to in the literature with region-specific terms such as burning mouth syndrome, glossodynia and vulvodynia. Symptoms such as pruritus with unexplained hyperhidrosis may occur during sleep, as a result of heightened sympathetic tone. Sleep deprivation and insomnia can play a moderating role in CSD. Somatization and dissociation can play a central role in the pathogenesis of CSDs. A review of the literature suggests that CSDs represent a complex, and often poorly understood interplay between neurobiological factors associated with neuropathic pain, neuropathic itch and neurologic/neuropsychiatric states (eg, radiculopathies, stroke, depression and posttraumatic stress disorder). These neurologic/neuropsychiatric states can modulate pain and itch perception by potentially affecting the pain and itch pathways at a structural and/or functional level. PMID- 24049970 TI - Nonpharmacologic management of psychodermatologic conditions. AB - Nonpharmacologic management of psychodermatologic conditions includes both structured and unstructured interventions that may ameliorate skin disorders, reduce psychological distress, and improve the functional status of the affected individual. Nonpharmacologic techniques are often referred to as psychocutaneous interventions. This article will review the data on psychocutaneous conditions that have been shown to improve with nonpharmacologic interventions. Suggested clinical approaches to facilitate the implementation of these modalities will be discussed. PMID- 24049971 TI - Psychotropic medications in dermatology. AB - Psychotropic medications are an essential piece to the treatment of psychodermatologic disorders. Patients often refuse psychiatric evaluation, and thus dermatologists are often required to prescribe these medications. Comfort and knowledge of their indications and uses can help dermatologists combat both primary and secondary psychodermatologic pathology. PMID- 24049972 TI - [Obstetric hemorrhage control Bakri balloon]. AB - BACKGROUND: Obstetric hemorrhage is the second leading cause of maternal death in Mexico. Intrauterine tamponades are a valuable resource for the limitation of bleeding. OBJECTIVE: Analyze the success rate of the Bakri balloon in the control of obstetric hemorrhage and calculate the fill volume with clinical parameters. MATERIAL AND METHODS: Descriptive, retrospective and observational study Subjects were included who presented refractory hemorrhage on administration of uterotonics (postpartum, caesarean section, post-caesarean section, and post miscarriage); a Bakri balloon was inserted with epidural anesthesia. The procedure was considered successful where there was immediate cessation of hemorrhage without recurrence. The fill volume in milliliters (FV) was analyzed with a linear regression that included gestational age in weeks (GA) and neonatal weight in grams (NW). RESULTS: The study included 35 subjects: 20 postpartum (57.1%), 10 caesarean and post-caesarean section (28.5%), and 5 post-miscarriage (14.2%). Use of the Bakri balloon was successful in 33 cases (94.2%). Unsuccessful cases involved subinvolution of the placental site and placenta accreta. Fill volume correlated with gestational age (r=0.50, p=0.001) and with neonatal weight (r=0.47, p=0.002). The linear regression equation for calculation of the fill volume is FV = 150 + (4.3 x GA) + (0.03 x NW), (p = 0.003). CONCLUSION: Use of the Bakri balloon is safe, simple, and effective; we encountered no adverse reactions in this study. The procedure can be carried out after delivery or miscarriage or during or after a caesarean section. PMID- 24049973 TI - [Effect of administration of recombinant LH on the 5th day versus the 8th day in ovarian stimulation cycles]. AB - BACKGROUND: Ovarian stimulation is a key component in assisted reproduction techniques. Supraphysiologic levels secondary to hormonal stimulation with high doses of exogenous hormones affect endometrial receptivity, the function of the corpus luteum, ovulation and embryo quality. The use of stimulation protocols called "minimal stimulation" may have a beneficial effect in achieving pregnancy. OBJECTIVES: To evaluate the clinical efficacy (pregnancy rate) of rLH treatment on Day 5 (minimum group "A") vs. Day 8 (minimum group "B") of the ovarian stimulation cycle. MATERIAL AND METHODS: Cohort, retrospective, pilot study. Two groups of 22 patients each who received minimal stimulation "A" or "B" (control group) in the period from April to August 2010. RESULTS: No statistically significant difference in the following variables: age, FSH, estradiol and basal follicles. The median of mature follicles at the shooting day, the minimum group "A" was 3 vs. 2 for low B, the number of oocytes at metaphase II: Minimum group "A" 37/65 (57%) vs. 24/38 (63 %) at minimal group "B". Patients with grade 1+ quality embryos were 7 in minimal group "A" vs. 6 in the minimal group "B". In the minimal group "A", the pregnancy rate per started cycle was 27.3% and 37.5% for transfer, in the minimal group "B", the pregnancy rate per started cycle was 22.7% and per patient transfer which underwent 25%. CONCLUSIONS: Receiving the minimal stimulation protocol "A" has a 15% higher risk of becoming pregnant, compared with minimal group "B" based on pregnancy rate per transfer, for the sample size, the p value was 0.32. PMID- 24049974 TI - [Laparoscopic hysterectomy as first-line procedure in the treatment of women with benign uterine pathology]. AB - BACKGROUND: It is estimated that a total of 600,000 abdominal hysterectomies, vaginal and laparoscopic there are performed in USA, these figures make the hysterectomy the first ranked surgery. In our country, since the first description of the technique in 1989, laparoscopic hysterectomy (HL) has developed and evolved. However, the learning curve for mastering this procedure results in larger and more complex complications than other approaches. MATERIAL AND METHOD: Retrospective, longitudinal and descriptive study were carried out, the collection of data took place from the clinical records of patients who underwent total laparoscopic hysterectomy during January 1, 2007 through December 31 of the same year. It was performed in women older than 18 years with benign uterine pathology. Body mass index greater than 30 Kg/m2, uterus greater than 16 weeks of gestational age or more than 500 grams, illnesses than compromise life of patients o women that did not return to post-surgical evaluation were excluded. RESULTS: There were performe 75 laparoscopic hysterectonies, 72 underwent without any complication. The average hospital stay was 3 days. We founded 3 major surgical complications, a case of bleeding from the surgical area that was immediately attended by laparoscopic Vicril-00 single stitching. Also were founded 2 urinary lesions: 1 complex lesion of the trigonous. The follow up of this case was torpid it were needed to derivate for 15 day with a latex foley catheter after the secondary repair and was unsuccessfully. Thereafter a urogynecological team programed laparotomy for the final fistulectomy. And the third case of accident was referred to a ureteral section, was diagnosed by the leaking at opaquedye from the abdominal x ray, and the patient was programed to laparotomy to performed a termino-terminal anastomosis. CONCLUSIONS: Laparoscopic hysterectomy is a reliable treatment option for benign uterine pathology. We believe that this surgical technique should be offered as the regular way to perform the hysterectomy. PMID- 24049975 TI - [Current indications for invasive prenatal diagnosis. New proposals based on the experience of Institute Nacional de Perinatologia]. AB - BACKGROUND: Invasive prenatal diagnosis (IPD) allows identification of fetal diseases, mainly aneuploidy. With the addition of first-trimester prenatal screening and structural ultrasound, IPD indications have changed. OBJECTIVE: To describe the current indications for IPD in pregnant patients at INPer. METHODS: Descriptive and retrospective study. We reviewed medical records of patients in which IPD was performed during a period of 2.5 years. RESULTS: A total of 339 studies were performed: 81% by amniocentesis (AC), 13% by chorionic villus sampling (CVS) and 6% by cordocentesis or somatocentesis. The most common indications for AC were: advanced maternal age (AMA) (43%), fetuses with multiple defects by ultrasonido (23%) and presence of soft markers for aneuploidies (9%). For CVS were: cystic hygroma (24%). Increased nuchal translucency (NT) (24%), and AMA (18%). When the indication was only AMA, 1.5% of fetus presented aneuploidy. In women under 38 years and normal ultrasoud, chromosomal abnormalities were not detected. The increased NT in women <35 years had a 21% detection and in patients > 35 years it increased to 33%. CONCLUSIONS: We observed that the group who had normal translucencia nucal and AMA presented a low risk of chromosomal abnormalities. In the presence of an increased NT, 33% of fetuses were affected, so that measuring TN is considered the best non invasive PD tool. The average age with cytogenetic abnormalities was above 38 years, so we suggest to offer IPD in women above 38 years-old. PMID- 24049976 TI - [Occupational disability during pregnancy and lactation]. AB - Historically, women have been known for their role as housewives and were held responsible for children's education. This has changed throughout the years, and they have modified their role in our society. Nowadays, in developed countries, 50% of the working population is represented by women of reproductive age. An important number of these women end up pregnant, and most of them are willing to keep theirjobs after delivery. This is the main reason why pregnancy should not compromise their employment or economic stability. Several international treaties have been signed to defend women, improve their health and reduce child mortality. Even when most countries have developed measures to protect and defend maternity, there is still, a strong difference comparing legislations in this matter, between developed and non-developed countries like Mexico. This is why it is essential to get to know and analyze the main legal dispositions and regulations about maternity issues and protection. We must be aware of the differences in legislation between Mexico and other countries that might influence our own country secondary to sociocultural, commercial and financial exchange. There have been clear and evident improvements related to women's health and maternity matters in the past 15 years. These include longer periods of rest after delivery and making the employer responsible for financing maternity leave. PMID- 24049977 TI - [Varix of intra-abdominal umbilical vein: report of two cases]. AB - Varix of the intra-abdominal portion of the umbilical vein is an uncommon sonographic diagnosis, which may be increasing in the coming years for the improvement of ultrasound equipment and the advances in knowledge of fetal anatomy. It has been reported in the literature in many cases associated with chromosomal defects, additional sonographic abnormalities and poor fetal outcome, but, in contrary to earlier reports, especially in cases in which it appears isolated, a good fetal outcome is expected. We report two cases of umbilical vein varix diagnosed in our department at 20 and 33 weeks, both with good perinatal outcome. PMID- 24049978 TI - [Prenatal diagnosis of cardiac rhabdomyoma. Case report]. AB - A case is described of a cardiac tumor diagnosed by ultrasound in a fetus of 28 weeks and presumed as a probable cardiac rhabdomyoma. Labor is concluded vaginally on 36 weeks and in the evaluation of the new born the diagnosis is confirmed via an ecocardiogrphy test. In MRI is performed six months after birth and the subject is diagnosed with tuberous sclerosis. A report of the subject is described emphasizing the prenatal follow up of the fetal cardiac function. PMID- 24049979 TI - [Rudimentary horn pregnancy: first trimester ultrasound diagnosis and laparoscopic confirmation]. AB - Case report of rudimentary uterine horn on first trimester pregnancy that was diagnosed by sonographic images and laparoscopically confirmed. We suggest a set of criteria for early diagnosis of this rare condition using sonographic with 3D endovaginal ultrasound. We present a first trimester extrauterine pregnancy that was diagnosed in rutinary sonographic analisys. A rudimentary horn pregnancy was detected by sonographic with 3D endovaginal ultrasound, that was confirmed laparoscopically. Rudimentary horn pregnancy was right sided without endometrial communication with the uterine body. The rudimentary horn pregnancy was laparoscopically resected, a fibrous bridge between horn and uterus is confirmed, also a normal aspect tube was observed, wich was underwent to fimbriectomy. We suggest to consider this rare posibility on extrauterine pregnancy diagnosis, and also apply 3D technology under endovaginal route to achieve an early diagnosis and avoid rupture. PMID- 24049980 TI - [Placenta percreta with invasion of the bladder, ureter and abdominal wall. Case report]. AB - Placental acretism is the abnormal adherence beyond the underlying of the uterine muscle. The penetration of the serous is known as placenta percreta. The following is a clinical study of a 28 year old woman, who had undergone 2 previous C-Sections, who had been admitted to the hospital previously with ultrasounds suggestive of placental acretism. The magnetic resonance show with severe infiltration of the myometrium in the anterior and lateral right, extending until the mesentery of the abdomen, top of the bladder and the proximal portion of the urethra as well as the soft tissue of the perinea. Cesarean section was performed at 35 weeks of gestation, once the complete protocol of the placenta previa, had been completed. The placentary tissue invaded the bladder, wide ligament along the entire right side and the posterior pelvis. A hysterectomy was performed in the fundic region, resulting in a live birth, and no complications for the patients. Later an obstetric hysterectomy was performed. It is important to note the exemplary work of the gynecologist, surgeon, urologist, anesthesiologist, neonatal specialist, hematologist and intensive care workers, working together for a common goal: avoiding the morbidity and mortality of the mother and child. PMID- 24049981 TI - [The psychological aspect of dysmenorrhea. 1958]. PMID- 24049982 TI - Retention and success of culturally diverse nursing students. AB - One of the major issues facing the future of the nursing profession is to increase the ethnic diversity of the nursing workforce (Institute of Medicine, 2010). The United States population is quickly becoming a nation of minorities (Sullivan Commission, 2004) and the nursing population must adapt in order to provide high quality, culturally competent care. Oklahoma's most recent population statistics indicate a dire need to focus on increasing the Black, Hispanic, and multiracial registered nurse populations. Nursing programs are challenged with this recommendation because culturally diverse students have lower retention rates and higher academic failure rates than Caucasian students. The purpose of this systematic review was to describe common barriers for culturally diverse nursing students and discover best practices to promote retention and success. The findings may be used to encourage further development of beneficial practices and programs within Oklahoma, as well as stimulate additional nursing research on cultural diversity. PMID- 24049983 TI - Nursing education: the new era of healthcare. PMID- 24049984 TI - Nursing work + humor =s happiness. PMID- 24049985 TI - The state of mental health care revisited. ANA, nursing organizations call for improving access to care, better funding. PMID- 24049987 TI - 2013 Nightingale Luminary Awards. PMID- 24049986 TI - Reflections. PMID- 24049988 TI - Moving forward together. PMID- 24049989 TI - Traumatic brain injury vs. post-traumatic stress disorder. PMID- 24049990 TI - Childrens and backpack safety. PMID- 24049991 TI - ASEAN: insights and considerations toward nutrition programs. PMID- 24049992 TI - Key strategies to further reduce stunting in Southeast Asia: lessons from the ASEAN countries workshop. AB - BACKGROUND: To further reduce stunting in Southeast Asia, a rapidly changing region, its main causes need to be identified. OBJECTIVE: Assess the relationship between different causes of stunting and stunting prevalence over time in Southeast Asia. METHODS: Review trends in mortality, stunting, economic development, and access to nutritious foods over time and among different subgroups in Southeast Asian countries. RESULTS: Between 1990-2011, mortality among under-five children declined from 69/1,000 to 29/1,000 live births. Although disease reduction, one of two direct causes of stunting, has played an important role which should be maintained, improvement in meeting nutrient requirements, the other direct cause, is necessary to reduce stunting further. This requires dietary diversity, which is affected by rapidly changing factors: economic development; urbanization, giving greater access to larger variety of foods, including processed and fortified foods; parental education; and modernizing food systems, with increased distance between food producers and consumers. Wealthier consumers are increasingly able to access a more nutritious diet, while poorer consumers need support to improve access, and may also still need better hygiene and sanitation. CONCLUSIONS: In order to accelerate stunting reduction in Southeast Asia, availability and access to nutritious foods should be increased by collaboration between private and public sectors, and the Association of Southeast Asian Nations (ASEAN) can play a facilitating role. The private sector can produce and market nutritious foods, while the public sector sets standards, promotes healthy food choices, and ensures access to nutritious foods for the poorest, e.g, through social safety net programs. PMID- 24049993 TI - Infant and young child feeding practices in urban Philippines and their associations with stunting, anemia, and deficiencies of iron and vitamin A. AB - BACKGROUND: The prevalence of stunting, underweight, and micronutrient deficiencies are persistently high in young children in the Philippines, and among other factors, suboptimal infant and young child feeding behavior may contribute to these forms of malnutrition. OBJECTIVE: To improve the understanding of contributors associated with the nutritional status of children 6 to 23 months of age living in urban areas of the Philippines. METHODS: A cross sectional survey was conducted covering five urban centers in the Philippines. Data on infant and young child feeding and nutritional status (including wasting, stunting, underweight, anemia, iron deficiency, and vitamin A deficiency) were collected for 1,784 children. RESULTS: Among children from urban and predominantly poor and very poor households, 26% were stunted, 18% were underweight, and 5% were wasted. Forty-two percent were anemic, 28% were iron deficient, and 3% were vitamin A deficient. About half of the children were breastfed within an hour after birth, were breastfed at the time of the survey, and had been continuously breastfed up to 1 year of age. Of the factors investigated, low socioeconomic status, use of cheaper cooking fuel, and nonuse of multivitamins were all independently associated with stunting. The prevalence of anemia, iron deficiency, and vitamin A deficiency were independently associated with the same factors and poorer sanitation facilities, lower maternal education, current unemployment, and inflammation. CONCLUSIONS: These factors merit attention in future programming and interventions may include promotion of the timely introduction of appropriate fortified complementary foods, the use of affordable multiple micronutrient preparations, and measures to reduce infections. PMID- 24049994 TI - Cost of the Diet (CoD) tool: first results from Indonesia and applications for policy discussion on food and nutrition security. AB - BACKGROUND: The Minimum Cost of a Nutritious Diet (MCNut) is the cost of a theoretical diet satisfying all nutrient requirements of a family at the lowest possible cost, based on availability, price, and nutrient content of local foods. A comparison with household expenditure shows the proportion of households that would be able to afford a nutritious diet. OBJECTIVE: To explore using the Cost of Diet (CoD) tool for policy dialogue on food and nutrition security in Indonesia. METHODS: From October 2011 to June 2012, market surveys collected data on food commodity availability and pricing in four provinces. Household composition and expenditure data were obtained from secondary data (SUSENAS 2010). Focus group discussions were conducted to better understand food consumption practices. Different types of fortified foods and distribution mechanisms were also modeled. RESULTS: Stark differences were found among the four areas: in Timor Tengah Selatan, only 25% of households could afford to meet the nutrient requirements, whereas in urban Surabaya, 80% could. The prevalence rates of underweight and stunting among children under 5 years of age in the four areas were inversely correlated with the proportion of households that could afford a nutritious diet. The highest reduction in the cost of the child's diet was achieved by modeling provision of fortified blended food through Social Safety Nets. Rice fortification, subsidized or at commercial price, can greatly improve nutrient affordability for households. CONCLUSIONS: The CoD analysis is a useful entry point for discussions on constraints on achieving adequate nutrition in different areas and on possible ways to improve nutrition, including the use of special foods and different distribution strategies. PMID- 24049995 TI - The global, centralized approach of the GAIN Premix Facility has made oil fortification in Indonesia more affordable. AB - BACKGROUND: Access to high-grade micronutrients is a recurring challenge that often threatens the long-term sustainability of food fortification programs. OBJECTIVE: To assess the efficiency of the Global Alliance for Improved Nutrition (GAIN) Premix Facility in procuring quality, affordable vitamin A for fortification of edible oil in Indonesia. METHODS: A global approach to procurement of standard items was used by combining volumes across various demand streams in order to reduce the total cost of acquisition through economies of scale. The GAIN Premix Facility undertook a detailed analysis of vitamin A requirements across its existing customer base, which served as a basis for developing a reliable demand forecast. A consolidated, competitive tender was launched that resulted in the setting up of a long-term commercial agreement with the selected supplier to lock in the most competitive price for a given period of time. RESULTS: The direct benefit to oil manufacturers of fortifying with vitamin A is that the cost of fortification went down significantly compared with prices they would have been offered had they ordered vitamin A individually. In Indonesia, this consolidated procurement approach has allowed a 14.5% decrease in the unit price of vitamin A. CONCLUSIONS: The GAIN Premix Facility demonstrated its effectiveness in acting as a global procurement platform by aggregating demand across different customers and leveraging improved prices through increased volumes. Building on the success of this effort, the GAIN Premix Facility is replicating this global approach for procurement of other standard items being procured across fortification programs worldwide. PMID- 24049996 TI - The growing importance of staple foods and condiments used as ingredients in the food industry and implications for large-scale food fortification programs in Southeast Asia. AB - BACKGROUND: Food fortification is a viable strategy to improve the nutritional status of populations. In Southeast Asia, recent growth and consolidation of the food industry provides an opportunity to explore whether certain widely consumed processed foods could contribute to micronutrient status if they are made with adequately fortified staples and condiments. OBJECTIVE: To estimate the potential contribution certain processed foods can make to micronutrient intake in Southeast Asia if they are made with fortified staples and condiments; e.g., via the inclusion of iodized salt in various processed foods in the Philippines, fortified wheat flour in instant noodles in Indonesia, and fortified vegetable oil in biscuits in Vietnam. METHODS: For Indonesia, the Philippines, and Vietnam, a review of consumption trends, relevant policies, and industry practices was conducted using publicly available sources,food industry market data and research reports, and oral communication. These informed the estimates of the proportion of the Recommended Nutrient Intake (RNI) that could be delivered via select processed foods. RESULTS: In the Philippines, Indonesia, and Vietnam, the processed food industry is not always required to use fortified staples and condiments. In the Philippines, dried salted fish with iodized salt would provide 64% to 85% of the iodine RNI for women of reproductive age and 107% to 141% of the iodine RNI for children 1 to 6 years of age. In Indonesia, a 75-g pack of instant noodles (a highly consumed product) with fortified wheat flour would provide 45% to 51% of the iron RNI for children 4 to 6 years of age and 10% to 11% of the iron RNI for women of reproductive age. In Vietnam, biscuits containing vegetable oil are increasingly popular. One 35-g biscuit serving with fortified vegetable oil would provide 13% to 18% of the vitamin A RNI for children 4 to 6 years of age and 12% to 17% of the vitamin A RNI for women of reproductive age. CONCLUSIONS: Ensuring that fortified staples and condiments such as flour, salt, and vegetable oil are used in widely consumed processed foods would ensure that these foods contribute to improvement in micronutrient intake among populations in Southeast Asia, particularly as the consumption of these foods is increasing. Policymakers and nutrition program managers should consider the contribution to nutritional intake that fortified staples and condiments can provide through processed foods, in addition to being used for cooking in the home, and ensure that the food industry is required to use these fortified staples and condiments rather than nonfortified foods. PMID- 24049997 TI - Fish sauce, soy sauce, and vegetable oil fortification in Cambodia: where do we stand to date? AB - BACKGROUND: The prevalence of micronutrient deficiencies in Cambodia is among the highest in Southeast Asia. Fortification of staple foods and condiments is considered to be one of the most cost-effective strategies for addressing micronutrient deficiencies at the population level. The Government of Cambodia has recognized the importance of food fortification as one strategy for improving the nutrition security of its population. OBJECTIVE: This paper describes efforts under way in Cambodia for the fortification of fish sauce, soy sauce, and vegetable oil. METHODS: Data were compiled from a stability test of Cambodian fish sauces fortified with sodium iron ethylenediaminetetraacetate (NaFeEDTA); analysis of fortified vegetable oils in the Cambodian market; a Knowledge, Attitudes, and Practices (KAP) study of fortified products; and food fortification program monitoring documents. RESULTS: At different levels of fortification of fish sauce with NaFeEDTA, sedimentation and precipitation were observed. This was taken into consideration in the government-issued standards for the fortification of fish sauce. All major brands of vegetable oil found in markets at the village and provincial levels are imported, and most are nonfortified. CONCLUSIONS: Fish sauce, soy sauce, and vegetable oil are widely consumed throughout Cambodia and are readily available in provincial and village markets. Together with an effective regulatory monitoring system, the government can guarantee that these commodities, whether locally produced or imported, are adequately fortified. A communications campaign would be worthwhile, once fortified commodities are available, as the KAP study found that Cambodians had a positive perception of fortified sauces. PMID- 24049998 TI - Vitamin A--fortified vegetable oil exported from Malaysia and Indonesia can significantly contribute to vitamin A intake worldwide. AB - BACKGROUND: Vitamin A deficiency is a public health problem worldwide, affecting approximately 190 million preschool-aged children and 19.1 million pregnant women. Fortification of vegetable oils with vitamin A is an effective, low-cost technology to improve vitamin A intake. OBJECTIVE: To examine the potential contribution of fortification of vegetable oils with vitamin A in Indonesia and Malaysia to increasing vitamin A consumption in these two countries and in countries to which oil is exported. METHODS: Detailed interviews were administered and a desk review was conducted. We also estimated potential vitamin A intakes from fortified vegetable oil. RESULTS: Malaysia and Indonesia are two of the largest producers and exporters of vegetable oil. Fortification of vegetable oil in both countries has the potential to be used as a tool for control of vitamin A deficiency. Both countries have the capacity to export fortified vegetable oil. Vegetable oil fortified at a level of 45 IU/g could provide 18.8% of the Estimated Average Requirement (EAR) for an Ethiopian woman, 30.9% and 46.9% of the EAR for a Bangladeshi child and woman, respectively, and 17.5% of the EAR for a Cambodian woman. Although concerns about obesity are valid, fortification of existing vegetable oil supplies does not promote overconsumption of oil but rather promotes consumption of vegetable oil of higher nutrient quality. CONCLUSIONS: Fortifying vegetable oil on a large scale in Malaysia and Indonesia can reach millions of people globally, including children less than 5 years old. The levels of fortification used are far from reaching the Tolerable Upper Intake Level (UL). Vegetable oil fortification has the potential to become a global public health intervention strategy. PMID- 24049999 TI - A review of vitamin D fortification: implications for nutrition programming in Southeast Asia. AB - BACKGROUND: Vitamin D is vital for bone health and has important roles in nonskeletal health and organ function. Most vitamin D is generated in the body by exposure to sunlight, with limited amounts added by the diet. Despite the presence of regular sunshine in Southeast Asia, vitamin D deficiency or insufficiency is being found there more commonly, primarily due to reduction of sunlight exposure as a result of lifestyle changes. Some of these lifestyle changes are unlikely to be reversed, and foods naturally containing vitamin D are not widely consumed, so fortification of foods with vitamin D may raise vitamin D status. METHODS: The literature database was searched for studies of vitamin D fortification, and we estimated potential vitamin D intakes from fortified vegetable oil. RESULTS: Almost all of the studies showed that circulating vitamin D (25-hydroxyvitamin D [(25OHD]) increased in a dose-dependent manner with increased intake of vitamin D-fortified foods. However, in a number of studies the additional intake was insufficient to increase vitamin D levels to 50 nmol/L. Vegetable oil fortified with vitamin D at a level of 10 microg/100 g could provide 3.9% to 21% of the Institute of Medicine Estimated Average Requirement (EAR) of vitamin D for adults in Southeast Asia. CONCLUSIONS: Fortification of widely consumed foods, such as edible oil, with vitamin D could contribute to improved vitamin D status in Southeast Asian countries. Intake modeling studies should be conducted to calculate the resulting additional intakes, and fortification of additional foods should be considered. More nationally representative studies of vitamin D status in the region are urgently needed. PMID- 24050000 TI - Absorption studies show that phytase from Aspergillus niger significantly increases iron and zinc bioavailability from phytate-rich foods. AB - BACKGROUND: Iron and zinc deficiency are major public health problems affecting many parts of the world, including Southeast Asia. Infants, young children, and women of reproductive age are particularly vulnerable due to their high requirements. Even though iron and zinc are present in significant amounts in the plant-based diets typically consumed in developing countries, their bioavailability is low due to high levels of absorption inhibitors such as phytate. Phytase has been used in animal nutrition for decades to improve the bioavailability of certain minerals in feed. OBJECTIVE: To show the effect of phytase in human nutrition based on evidence from human studies. Phytase can be used either during processing or as an active food ingredient degrading dietary phytate during stomach transit time. METHODS: Evidence from human studies testing the effect of phytase on iron and zinc bioavailability using stable isotopes was reviewed. RESULTS: Twelve studies tested the effect of phytase on iron and five tested its effect on zinc bioavailability. Most of these studies used a phytase derived from Aspergillus niger. They found a beneficial effect unless phytate concentrations were too low or levels of inhibitors or enhancers of iron absorption were too high. Twenty to 320 phytase units per 100 g of flour significantly improved iron absorption, even though higher levels might further increase iron bioavailability. For zinc, not enough information is available to determine optimal activities. CONCLUSIONS: Phytase clearly has a beneficial effect on iron and zinc absorption from phytate-rich foods. It also has the potential to increase the absorption of magnesium, calcium, and phosphorus in areas such as Southeast Asia where mineral deficiencies are widespread. PMID- 24050001 TI - Regulatory monitoring systems of fortified salt and wheat flour in selected ASEAN countries. AB - BACKGROUND: Considerable efforts have been made over the past decade to address vitamin and mineral deficiencies. An increasing number of countries in the Association of Southeast Asian Nations (ASEAN) are adopting mandatory food fortification as one of the primary strategies to overcome these deficiencies. Experience shows that fortified foods can reach large parts of the population, including the poor, if the fortification is done on a mandatory rather than a voluntary basis and if the food vehicle is widely consumed. OBJECTIVE: To review the importance of regulatory monitoring as an essential component of food fortification efforts in selected ASEAN countries, with special focus on the available information on regulatory monitoring systems for iodized salt and fortified wheat flour. METHODS: The role of regulatory monitoring in strengthening food fortification programs was discussed during a joint regional meeting of the World Health Organization, UNICEF, the Flour Fortification Initiative, the Global Alliance for Improved Nutrition, the Micronutrient Initiative, and the World Bank on regulatory monitoring of salt and wheat flour fortification programs in Asia, which took place in Manila, Philippines, on 27-29 September 2011. This paper reviews the regulatory monitoring systems of selected ASEAN countries that participated in this meeting. RESULTS: Problems and challenges in regulatory monitoring systems for iodized salt and fortified wheat flour in selected ASEAN countries are identified, and a description of the role of regulatory monitoring in strengthening food fortification initiatives, particularly of salt and flour, and highlights of areas for improvement are presented. CONCLUSIONS: Regulatory monitoring consists of monitoring activities conducted at the production level, at customs warehouses, and at retail stores by concerned regulatory authorities, and at the production level by producers themselves, as part of quality control and assurance efforts. Unless there are appropriate enforcement and quality assurance mechanisms in place to stimulate compliance by food producers, i.e., regulatory monitoring, having national legislation will not necessarily lead to increased coverage of fortified products and associated outcomes. PMID- 24050002 TI - Legal framework for food fortification: examples from Vietnam and Indonesia. AB - BACKGROUND: Food fortification is a cost-effective, powerful, and sustainable strategy to combat micronutrient deficiency, with the potential to reach large sections of the population with minimal cost and effort. However, the implementation of food fortification on a systematic and large scale, for instance in national programs, has often been challenging. OBJECTIVE: This paper takes a closer look at food fortification efforts and legislation mechanisms in Vietnam and Indonesia in order to determine specific factors and components in the legal framework that are crucial to the success of fortification programs. METHODS: Fortification efforts in Indonesia and Vietnam are evaluated using published data as well as unpublished data from detailed evaluation reports, and compared with respect to the specific circumstances, constraints, objectives and results in each country. RESULTS: The legal framework is a crucial factor for the success of food fortification programs, as it shapes to a large extent the implementation of food fortification. The legal framework is instrumental to ensure the quality, safety, availability, cost-effectiveness, and sustainability of food fortification. In the first place, the legal framework should specify the fortificants and fortification levels, as well as the food vehicles and the fortification procedures. In addition, it should ensure the commitment of policy makers and producers to fortification, regulate the costing, describe and ensure information and communication such as product labeling integrate social marketing into the implementation, and provide the means to monitor and enforce fortification. A clear public health objective, together with careful consideration of the choices and restrictions dictated by the specific national environments, will help to develop legal frameworks that optimize the potential success of food fortification strategies. CONCLUSIONS: The lessons from these experiences show that a mandatory approach to fortification, with costing, monitoring and enforcement, and social marketing clearly defined and well embedded in the legal framework and in the implementation structures, is the best foundation for an effective, sustainable, and feasible food fortification program. PMID- 24050003 TI - Rapid quantification of iron content in fish sauce and soy sauce: a promising tool for monitoring fortification programs. AB - BACKGROUND: In a number of Southeast Asian countries and China, fish sauce and soy sauce produced at the industrial level are fortified with iron. Unfortunately, the food producers and regulatory agencies implementing fortification programs do not always have the capacity to monitor the programs on an ongoing basis. OBJECTIVE: To assess a new portable device for the quantitative measurement of iron content of fortified sauces that could be used to control fortification levels. METHODS: The linearity, detection limits, and inter- and intraassay variability of this device were assessed on fish sauce and soy sauce fortified with ferrous sulfate, ferrous fumarate, and sodium iron ethylenediaminetetraacetate (NaFeEDTA); the accuracy of the results was determined by comparing them with the results obtained by atomic absorption spectrophotometry. RESULTS: Measurements required a minimum incubation time of 1 hour for iron sulfate or iron fumarate and 24 hours for NaFeEDTA. Linearity of the results ranged from 2 to 10 mg iron/L for ferrous sulfate or ferrous fumarate and from 1 to 10 mg iron/L for NaFeEDTA, implying the need for proper dilution, as the iron contents of fortified sauce are usually in the range of 150 to 1,000 mg/L. Depending on incubation time, iron compounds, and sauces, the coefficient of variation (CV) of intraassay precision was between 1.5% and 7.6% and the CV of interassay precision was between 2.9% and 7.4%. Comparison with results from atomic absorption spectrophotometry showed high agreement between both methods, with R = 0.926 and R = 0.935 for incubation times of 1 hour and 24 hours, respectively. The Bland-Altman plots showed limits of agreement between the two methods of +/- 70 mg/L in the range of fortification levels tested (100 to 500 mg/L). CONCLUSIONS; This device offers a viable method for field monitoring of iron fortification of soy and fish sauces after incubation times of 1 hour for ferrous sulfate or ferrous fumarate and 24 hours for NaFeEDTA. PMID- 24050004 TI - The SMILING project: a North-South-South collaborative action to prevent micronutrient deficiencies in women and young children in Southeast Asia. AB - BACKGROUND: The "Sustainable Micronutrient Interventions to Control Deficiencies and Improve Nutritional Status and General Health in Asia" project (SMILING), funded by the European Commission, is a transnational collaboration of research institutions and implementation agencies in five Southeast Asian countries- Cambodia, Indonesia, Laos PDR, Thailand, and Vietnam--with European partners, to support the application of state-of-the art knowledge to alleviate micronutrient malnutrition in Southeast Asia. OBJECTIVE: The major expected outcomes are to improve micronutrient status on a large scale, to identify priority interventions in each Southeast Asian country, and to develop a road map for decision makers and donors for inclusion of these priority interventions into the national policy. METHODS: SMILING has been built around a strong project consortium that works on a constant and proactive exchange of data and analyses between partners and allows for the differences in contexts and development stages of the countries, as well as a strong North-South-South collaboration and colearning. RESULTS: The selection of Southeast Asian countries considered the range of social and economic development, the extent of micronutrient malnutrition, and capacity and past success in nutrition improvement efforts. SMILING is applying innovative tools that support nutrition policy-making and programming. The mathematical modeling technique combined with linear programming will provide insight into which food-based strategies have the potential to provide essential (micro) nutrients for women and young children. Multicriteria mapping will offer a flexible decision-aiding tool taking into account the variability and uncertainty of opinions from key stakeholders. The lessons learned throughout the project will be widely disseminated. PMID- 24050005 TI - [Structure and function of Mad2/Mad2L2 (Rev7)]. PMID- 24050006 TI - [Dynamical aspects of protein structures revealed by newly established NMR approaches]. PMID- 24050007 TI - [Combinatorial approach of molecular dynamics simulations and database analyses for the studies of protein structure and function]. PMID- 24050008 TI - [Molecular dynamics simulation, ion channel, dynamic structure, bioinformatics]. PMID- 24050009 TI - [Structure function relatioship of Keap1 as chemical sensor]. PMID- 24050010 TI - [Study of protein ligand variety based on database analyses]. PMID- 24050011 TI - [NMR methods for observing protein-ligand interaction]. PMID- 24050012 TI - [Regulation of actin dynamics under physical stress: rapid actin filament regeneration by formin homology proteins and F- and G-actin homeostasis]. PMID- 24050013 TI - [Structure and conformational change of collagenase as multi-domain protein]. PMID- 24050014 TI - [Rethinking the theory of melancholia (Tellenbach): its construction process and theoretical significance]. AB - In 1961, Tellenbach published the concept of "Typus melancholicus" (melancholic type) to illustrate the complementary relationship between premelancholic (predepressive) situations and a premorbid personality. The melancholic type is often considered to be a non-universal type that is localized in Germany and Japan; however, this belief is increasingly considered to be incorrect. When referring to papers written in the United States around the time that Tellenbach's monograph was published, it is now possible to identify some personalities corresponding to the melancholic type. In the early 20th century in Germany, the precipitating events and premorbid personalities of manic-depressive illness were frequently reported by Kraepelin and other researchers. They identified a conscientious, punctual, and orderly character that is analogous to the melancholic type. However, they ignored the relationships between events and personality. For them, the etiologies of endogenous psychoses, such as schizophrenia and manic-depressive illness, should not be sought from exogenous factors, such as precipitating events and environmental factors, but from endogenous and constitutional factors. After the end of the Second World War, the traditional view of a reactive (exogenous)-endogenous dichotomy of depression increasingly began to be deemed no longer valid. Consequently, it gradually became clear that many patients develop endogenous and autonomous depression after a psychological precipitating event. Tellenbach tried to resolve the impasse in the reactive-endogenous dichotomy of depression through creation of the concept of the "endon" in place of the "endogenous" concept. Tellenbach considered the endon not as cryptogenic but as transcending the dichotomy between the somatogenic and psychogenic. The endon is represented phenomenologically as transformations of arising rhythms, transformations of form of movement, the globalism of transformations, binding to a maturing process, and reversibility. According to Goethe's morphology. Tellenbach placed the endon in the ideal and phenomenological (empirical) realms simultaneously. The essential feature of the melancholic type is orderliness, which manifests in the following three areas: work, behavior, and conscientiousness. The interpersonal relationships of people with the melancholic type are described as "Being-for-others", which is analogous to altruism. People with the melancholic type think highly of common sense and duty. Furthermore, they cannot lower their level of aspiration even if the quality and quantity of their work is beyond their abilities or their capacities are weakened. In these premelancholic situations, pre-melancholic persons are forced to choose either quality or quantity and are plunged into the depths of despair, which means a hiatus or onset of melancholia. Thus, Tellenbach analyzed the complementary relationship between premelancholic situations and a premorbid personality at the beginning of melancholia. However, Tellenbach failed to explain why people with the melancholic type do not develop any illnesses other than melancholia or contradict the possibility that people with non-melancholic type personalities could have melancholia. In Japan, the melancholic type originated from Hirasawa's viewpoint that he had shifted the essential feature of Shimoda's Immodithymie (Shuuchaku Seikaku) from enthusiasm to orderliness. Subsequently, Kasahara developed the Japanese concept of the melancholic type, which remains in the empirical and descriptive realm and its essential feature is "orderliness underlying the altruism." In the United States, although the melancholic type probably existed, the concept was infrequently discussed because there were few psychiatrists who knew the concept of endogenous depression very well. Moreover, in DSM-III, the difference between endogenous and reactive depression was eliminated according to the "atheoretical" policy. Consequently, Tellenbach's theory of melancholia lost significance. The value of the theory of endon, which constitutes Tellenbach's theory of melancholia in empirical medicine, is considered to be restrictive. However, the discovery of the melancholic type concurrently in Germany, the United States, and Japan is of marked significance. It is now possible to reappraise the importance of the melancholic type and premelancholic situations. PMID- 24050015 TI - [A case of anorexia nervosa with severe physical complications resulting in long term hospitalization]. AB - We report the case of a woman in her late twenties with anorexia nervosa who was difficult to treat both psychologically and physically because she resisted being treated despite presenting with various and severe physical complications, such as a refractory tracheoesophageal fistula. On admission, she weighed 24.8 kg and her body mass index was 9.6 kg/m2. Treatment on a medical ward was not possible due to her resistance to being fed and repeated secretive and deviant behaviors. Therefore, she was treated mainly on a psychiatric ward, with a psychiatrist as the attending doctor. After hospitalization for more than 3 years, she had sufficiently recovered to leave the hospital. She was discharged weighing 37.7 kg and her body mass index was 14.5 kg/m2. As physical complications, the patient manifested with a tracheoesophageal fistula, duodenal bulb perforation, and tension pneumothorax, which were considered to reflect the vulnerability of the intrapleural and intraperitoneal soft tissue. She also manifested with lower limb edema, pulmonary edema, pleural effusion, overreaction to a diuretic, dehydration, and hypernatremia, which were considered to reflect the disturbances of water balance. As seen in this case, a patient with anorexia nervosa who resists being fed, even though treatment of the physical complications requires an improved nutritional status above all, may require treatment on a psychiatric ward even at the risk of providing less than ideal care for the physical complications. We discuss "medical psychiatry" as a model for treating anorexia nervosa patients with severe physical complications. In this concept of "medical psychiatry", it is the most important that staff on the psychiatric ward take an interest in and have concerns about the patient's physical complications. If the psychiatrist as the attending doctor actively and continuously participates in the treatment of physical complications, it should be possible to create a treatment plan that, although complex due to its multidisciplinary nature, is followed smoothly and consistently, and, therefore, provide patients with trustworthy and appropriate medical treatment. PMID- 24050016 TI - [Toward reconsideration of involuntary treatment system in psychiatry]. AB - The guardian system depending on families in the mental health and welfare act is expected to be revised in the near future. Our special articles, based on the present situation, widely discuss the problems with the involuntary treatment system in psychiatry from the viewpoint of ideal and practical aspects. The panel members were selected from the fields of admission psychiatry, community psychiatry, foreign systems, and advocacy. PMID- 24050017 TI - [Forced medical intervention in psychiatric inpatient treatment]. AB - In anticipation of ratification of the Convention on the Rights of Persons with Disabilities, the Japanese Government made a Cabinet decision to promote institutional reforms concerning disabled persons, in which involuntary hospitalization and medical intervention for persons with mental disabilities would be reviewed. In response to the decision, the Cabinet launched the Council to Promote Reform for "Promotion Council reform Persons with Disabilities" in the Cabinet Office, and the Ministry of Health, Labour and Welfare set up a task force aimed to build systems of community mental health care. Although the activities have been progressing, according to published documents, the effectiveness and efficacy of the countermeasures presented in the documents seem insufficient. Fundamental reforms of systems for the treatment and support of persons with mental disabilities are needed. PMID- 24050018 TI - [Involuntary psychiatric intervention in community mental health]. AB - In Japan, the involuntary outpatient treatment system like the Community Treatment Order is defined only in the Medical Treatment and Supervision Act 2005. However, in our outreach approach activities in the community, our treatment may seem to be involuntary intervention for some patients, and, occasionally, we actually have to perform involuntary intervention in certain cases. Some patients do not even agree with our visit, and some agree with our visit but not with medication. Some patients do not take medication in spite of their agreement In this paper, I introduce some cases of our outreach approach activities and discuss the merit and demerit of involuntary intervention in community psychiatric care. The involuntary hospitalization system is being assessed, but involuntary intervention with an outreach approach has not been assessed or discussed well so far. We should discuss and try to develop rules for involuntary psychiatric intervention with an outreach approach. PMID- 24050019 TI - [Involuntary placement and treatment of persons with mental health problems]. AB - Involuntary placement and treatment of persons with mental health problems were initially discussed from the perspective of personal liberty. However, the autonomy of persons with mental health problems has been growing in importance as an issue of involuntary placement and treatment since the last part of the twentieth century, because the purpose of involuntary placement is not the deprivation of liberty but to provide adequate treatment under medical supervision. The UN Convention on the Rights of Persons with Disabilities (CRPD) adds a new perspective from non-discrimination and equality. Article 14 of CRPD states that "the existence of a disability shall in no case justify a deprivation of liberty." This provision should be construed from a perspective of non discrimination. Conventional types of involuntary placement mainly based on dangerousness (UN-MI Principle 16-1a) and incompetency (UN-MI Principle16-1b) are not allowed by Article 14. There is a discussion on the difference between "mental disability" and "mental illness". Some people argue that CRPD should apply not to persons with mental illness, but to those with mental disabilities. However, CRPD does not provide a definition of "disability". It states that its definition is developing. ICF also mentions that ICD-10 and ICF should complement each other. Thus, CRPD should apply to the involuntary placement and treatment of persons with mental illness as well. It is clear that Article 14 intends to change the situation whereby persons who have been described using various terms, such as madness, lunacy, insanity, mental illness, mental disability, mental health problems, and users, are involuntarily hospitalized/placed. The significance of Article 14 will be lost if it cannot be applied to psychiatric hospitalization. From the perspective of non-discrimination, we have to universalize involuntary placement and treatment or completely abolish them. We cannot tolerate a situation where a type of dangerousness is applied to anyone who is a danger and who can be managed by involuntary placement and treatment. However, it will be acceptable to establish strict rules of involuntary placement and treatment in a case where a person loses his/her capacity to provide consent and certain placement and treatment will be helpful to recover his/her autonomy. Such rules are necessary not only for persons with mental disabilities, but also for other patients such as those in a coma. We have to devise new rules on types of incompetency. However, we must consider some other issues. Article 12 of CRPD provides a non-discriminatory view on the legal capacity. It is based on the so called "Social Model". The human capacity to understand and judge is supported by education, social experiences, as well as human and social networks. However, persons with disabilities have far less of these resources than others because of social exclusion. It is essential to overcome such social deficits before we judge one's capacity. Treatability and a less restrictive alternative are also important rules of involuntary placement and treatment. Finally, there is controversy regarding the consent of a family member to involuntary placement with regard to the ongoing discussion on the amendment of the Mental Health Act. It is impossible to regard the consent of a family member as a patient's will. It is unreasonable to grant priority to a family member who gives consent and ignore another family member's opinion against hospitalization, since their legal status is the same. The proposed amendment will cause a serious conflict among the hospital, a family member who gives consent, other family members, and the patient. Consent from a family member is not necessary and detrimental. PMID- 24050020 TI - [Lessons from addiction psychiatry]. AB - In this paper, I would like to share my experience of helping to establish treatment systems for alcohol dependence in hospital and community settings during the period of relatively inadequate alcohol-dependence care in the 1970s. In the hospital-based treatment system, it was important to ensure that information on the patient's condition and course of treatment was shared with colleagues. It was also important to nurture the patient's compliance with treatment decisions, and involve family members in the treatment process. To promote the rehabilitation of the patient back into the community, it was vital to develop a network of staff in relevant hospitals, clinics, health centers, and welfare offices. Self-help groups also played an important role in rehabilitation. The systems we developed for the treatment of alcoholics offer many instructive lessons for the care of patients with other psychiatric disorders. Alcohol dependence and depression share many common symptoms and biological mechanisms. In consequence, studies on the biological basis of alcohol dependence can provide insights into biological mechanisms underlying other psychiatric disorders. PMID- 24050021 TI - [Pharmacotherapy for schizophrenia: are newer drugs truly superior?]. AB - There is an argument that the superiority of second-generation antipsychotics (SGA) over first-generation antipsychotics (FGA) was established in part by the inappropriate use of FGA. When comparison was made with a proper FGA other than haloperidol or a low dose of FGA, the superiority of SGA disappeared in some studies. It would be too optimistic to regard the use of SGA itself as providing substantial progress in the level of treatment. However, with the introduction of SGA, the more effective and proper use of antipsychotics has prevailed. It is of clinical significance to pay more attention to the quality of life and rehabilitation of patients. At present, evidence indicates that clozapine is the most efficacious in treatment-resistant patients, despite its high-risk profile. The proper use of the drug is an important clinical issue. PMID- 24050022 TI - [Sleep psychiatry]. AB - Sleep disorders are serious issues in modern society. There has been marked scientific interest in sleep for a century, with the discoveries of the electrical activity of the brain (EEG), sleep-wake system, rapid eye movement (REM) sleep, and circadian rhythm system. Additionally, the advent of video polysomnography in clinical research has revealed some of the consequences of disrupted sleep and sleep deprivation in psychiatric disorders. Decades of clinical research have demonstrated that sleep disorders are intimately tied to not only physical disease (e. g., lifestyle-related disease) but psychiatric illness. According to The International Classification of Sleep Disorders (2005), sleep disorders are classified into 8 major categories: 1) insomnia, 2) sleep related breathing disorders, 3) hypersomnias of central origin, 4) circadian rhythm sleep disorders, 5) parasomnias, 6) sleep-related movement disorders, 7) isolated symptoms, and 8) other sleep disorders. Several sleep disorders, including obstructive sleep apnea syndrome, restless legs syndrome, periodic limb movement disorder, sleepwalking, REM sleep behavior disorder, and narcolepsy, may be comorbid or possibly mimic numerous psychiatric disorders, and can even occur due to psychiatric pharmacotherapy. Moreover, sleep disorders may exacerbate underlying psychiatric disorders when left untreated. Therefore, psychiatrists should pay attention to the intimate relationship between sleep disorders and psychiatric symptoms. Sleep psychiatry is an academic field focusing on interrelations between sleep medicine and psychiatry. This mini-review summarizes recent findings in sleep psychiatry. Future research on the bidirectional relation between sleep disturbance and psychiatric symptoms will shed light on the pathophysiological view of psychiatric disorders and sleep disorders. PMID- 24050023 TI - [The activities of Mental Health First Aid-Japan Team]. AB - The Mental Health First Aid (MHFA) program is a training program for non-health professionals that deals with persons with a mental health crisis (Kitchener & Jorm, 2006). The MHFA-Japan team was established in 2007, and a founding member completed a MHFA training program in Melbourne, University of Australia. We consulted with Jorm and Kitchener, and started a Japanese study of the program. Providing the MHFA program for gatekeepers in Japan could help them assess risk factors and refer patients for professional care, and contribute to suicide prevention. Our team cooperated with the gatekeeper training program of the cabinet office of the Japanese government. In addition, this program is applied in instructional activities in the area of the Great East Japan Earthquake. PMID- 24050024 TI - Implementing a teaching service for voluntary faculty in obstetrics and gynecology: long-term results. AB - OBJECTIVE: To ensure the highest quality of resident training, by engaging community private physicians (PMDs) as voluntary faculty, through implementing teaching services in both obstetrics (OB) and gynecology (Gyn) in July 2003. We now report on the long-term success and challenges of the strategy. STUDY DESIGN: The case volume performed by residents was analyzed using the Accreditation Council for Graduate Medical Education self-reported resident statistics log, while resident educational satisfaction was analyzed using an anonymous survey. RESULTS: Approximately 90% and 60% of eligible PMDs participated in the Gyn and OB teaching services, respectively. Following implementation of teaching services, resident vaginal delivery volume increased from 859 cases in 2003 to 1,750 in 2004 (104% increase). Gynecologic surgery volume increased from 2,397 cases in 2003 to 3,436 in 2004 (43% increase). Survey of the residents in 2009, 5 years after implementation, indicated that 61% felt the teaching services improved their training experience, 47% that it improved resident-nurse interaction, and 72% that it improved resident-medical staff interaction. However, 28% also felt that the presence of the teaching services frequently caused confusion regarding residents' roles and responsibilities. CONCLUSION: The implementation of voluntary faculty teaching services in a residency training program enhanced the volume of cases available for training, with residents perceiving an improvement in their training and their interactions with attending staff. However, of concern was continued confusion regarding residents' patient care responsibilities. PMID- 24050025 TI - Safety of conservative management of ovarian masses during pregnancy. AB - OBJECTIVE: To determine the clinical outcomes and risk factors for persistence of ovarian cysts in pregnant women. With the increased use of ultrasound in pregnancy, the identification of incidental ovarian masses is becoming more common. STUDY DESIGN: An observational study of women with ovarian masses identified before 24 weeks of pregnancy was performed. Only women who underwent follow-up imaging or surgery were included. Factors associated with persistence and outcomes of women who underwent surgery were analyzed. RESULTS: Of the 803 women with available follow-up, the cysts resolved in 707 (88.1%) patients. Fifty (6.2%) women underwent surgical intervention. Women with persistent cysts were younger, more often Hispanic, detected at a later gestational age, had larger cysts, and more often had complex or solid components (p < 0.05 for all). Overall, 1 (0.1%) malignancy was diagnosed (a patient with a B-cell lymphoma), while 3 (0.4%) women had borderline epithelial ovarian tumors. CONCLUSION: Ovarian masses identified during pregnancy have a low risk of malignancy. The majority of women can be serially monitored without intervention. PMID- 24050026 TI - Perceptions and acceptance of immunization during pregnancy. AB - OBJECTIVE: To estimate patients' perceptions of the need, safety and acceptability of vaccination during pregnancy. STUDY DESIGN: An office-based survey was offered to patients presenting for obstetric and gynecologic care from December 2007 to July 2008 at an academic women's hospital. The anonymous questionnaire assessed demographics, medical and vaccination history, interest in receiving vaccines, and beliefs about vaccination safety. Data were evaluated using descriptive statistics and chi2 analyses. RESULTS: A total of 1,436 completed surveys were available for analysis, including 573 from pregnant women. Pregnant women were less likely than non-pregnant women to report perceived risks from vaccine-preventable illness (22.8% vs. 34.5%, p < 0.001) and to believe that their doctor thinks they should get vaccines (42.6% vs. 49.7%, p < 0.027). Nearly two-thirds (61%) reported concern about possible vaccine effects on their pregnancy. However, the overwhelming majority (89%) of pregnant women surveyed reported willingness to accept vaccination during pregnancy if recommended by their obstetrician. CONCLUSION: Despite concerns about vaccine safety and a low perceived need for immunization, most pregnant respondents endorse acceptance of vaccination when recommended by their obstetrician. These findings suggest that obstetric providers should maximize opportunities for uptake of appropriate immunizations during pregnancy. PMID- 24050027 TI - Relationship between parity and bone mass in postmenopausal women according to number of parities and age. AB - OBJECTIVE: To investigate the impact of multiple pregnancies on postmenopausal bone mineral density (BMD). STUDY DESIGN: BMD at the femoral neck (FN) and lumbar spine (LS) was measured by dual energy X-ray absorptiometry (DXA) method. Diagnosis of osteoporosis (OP) was confirmed by World Health Organization criteria. Women were stratified according to number of parity as < 3, 4-7, and > 7 parity groups as well as in age groups of < 65 and 65 in age groups of < 65 and > or = 65 years. BMD values and frequency of OP were compared across the groups according to age. Multiple logistic regression analysis with calculation of adjusted odds ratio (OR) was used for association. RESULTS: A total of 264 women with mean age of 63 +/- 8.7 and mean menopausal duration of 15.8 +/- 10.2 years were studied. LS-OP and FN-OP were observed in 28% and 58.3% of women, respectively. There were significant differences in BMD values across different parity groups at both sites of LS and FN (p = 0.011 and p = 0.036, respectively). Parity 4-7 (vs. < or = 3) increased BMD nonsignificantly, but > 7 significantly decreased LS-BMD and FN-BMD as compared with 0-7 parity (p = 0.006 and p = 0.009, respectively). Parity > 7 increased the risk of LS-OP by OR = 1.81 (95% CI 1.03 3.1, p = 0.037) and FN-OP by OR = 1.67 (95% CI 0.97-2.8, p = 0.063). In addition, women with high parity had lower BMD decline at LS and FN by age (> or = 65 vs. < 65 years) by 1.3% (p = 0.77) and -10.1% (p = 0.009) as compared with 0-7 parity group by -9.5% (p = 0.001) and -15% (p = 0.0001), respectively. CONCLUSION: Parity > 7 is associated with spinal trabecular bone loss in younger postmenopausal women as well as an osteoprotective effect against age-related bone loss, which counteracts the early negative effect. Therefore, parity should not be considered as a risk factor for postmenopausal osteoporosis. PMID- 24050028 TI - Influence of FSHR diplotypes on ovarian response to standard gonadotropin stimulation for IVF/ICSI. AB - OBJECTIVE: To explore the association of FSHR 307 (T/A)/FSHR 680(N/S) diplotypes with ovarian response to follicle stimulating hormone (FSH) stimulation of women undergoing medically assisted reproduction (in vitro fertilization [IVF] or intracytoplasmic sperm injection [ICSI]). STUDY DESIGN: The study population consisted of 304 women undergoing IVF/ICSI and 300 women with at least 1 spontaneous pregnancy as controls. FSHR polymorphisms were genotyped. Controlled ovarian stimulation and IVF/ICSI were performed in the 304 couples. During oocyte retrieval the follicular size, the follicle and oocyte numbers were recorded. Serum FSH, luteinizing hormone and estradiol were determined at the third day of the menstrual cycle. RESULTS: The FSHR 307(T/A)/FSHR 680(N/S) diplotype analysis revealed lower serum FSH levels, higher follicle and oocyte numbers, increased numbers of large follicles as well as decreased empty follicle numbers in Thr307Thr/Asn680Asn women as compared to Thr307 Ala/Asn680Ser and Ala307Ala/Ser680Ser women (p < 0.006, p < 0.01, p < 0.008, p < 0.01, p < 0.005, respectively). CONCLUSION: FSHR diplotypes were significantly associated with ovarian response to gonadotropin stimulation. FSHR diplotype analysis could be informative for ovarian stimulation outcome and the selection of the proper stimulation protocol, which would ensure a sufficient number of mature oocytes for IVF/ICSI. PMID- 24050029 TI - Does enhanced "bundling" criteria improve outcomes? A comparative study of elective inductions. AB - OBJECTIVE: To assess outcomes and costs of dyads achieving elective induction bundle criteria with a favorable Bishop score. STUDY DESIGN: In a historical automated records-based cohort study, 180 dyads undergoing elective induction bundling at a single institution from 2009 to 2010 were compared to a pre introduction of bundling cohort. The bundled cohort was then compared by Bishop score. RESULTS: The bundled cohort (n = 180) had a lower cesarean delivery rate (12% vs. 21%, p = 0.01), but neonatal special or intensive care admissions were not statistically significant compared to the pre-introduction of bundling cohort (n = 473). Ninety-six percent (n = 173) of the bundled cohort achieved bundle criteria. Those with a Bishop score > 6 (52%, n = 90) had fewer cesarean deliveries (4% vs. 19%, p = 0.003), fewer neonatal special or intensive care admissions (1% vs. 10%, p = 0.015), shorter induction time to vaginal delivery (8.8 vs. 17 hrs, p < 0.001), fewer cesareans for dystocia (75% vs. 94%, p = 0.002) or fetal heart rate abnormalities (25% vs. 50%, p = 0.015), and had one sixth the average net income lost ($423 vs. $2,600, p < 0.001) compared to bundle achievers with a Bishop score of < or = 6. CONCLUSION: The elective induction bundle does not guarantee quality and should require favorable cervix instead of documented Bishop score to proceed with induction. PMID- 24050030 TI - Measurement of serum and peritoneal levels of amyloid protein A and their importance in the diagnosis of pelvic endometriosis. AB - OBJECTIVE: To evaluate serum and peritoneal concentrations of amyloid protein A in women with endometriosis and to compare them with those of women without endometriosis. STUDY DESIGN: A prospective study evaluated 76 women suspected of having pelvic endometriosis. Fifty-seven women (group A) were confirmed by videolaparoscopy and had their serum and peritoneal amyloid A concentrations measured by ELISA. The average levels from group A were compared to those obtained in group B. Group B was composed of 13 women without endometriosis, submitted to elective laparoscopy for tubal ligation. RESULTS: Peritoneal amyloid A concentrations in group A (310.3 +/- 97.8 ng/mL) were higher than those of group B (53.4 +/- 58.2 ng/mL); p = 0.0. However, serum concentrations in groups A (14.01 +/- 32.3 ng/mL) and B (9.5 +/- 15.9 ng/mL) did not differ significantly; p = 0.35. CONCLUSION: The peritoneal amyloid A protein concentration in pelvic endometriosis was higher when compared to normal controls, corroborating the inflammatory nature of the disease. This finding suggests that the procedure of evaluating the peritoneal amyloid A concentration in endometriosis merits further investigation. PMID- 24050031 TI - Do women with deep infiltrating endometriosis have more tubal alterations? Objective evaluation of 473 patients. AB - OBJECTIVE: To evaluate whether deep infiltrating endometriosis (DIE) is associated with tubal alterations. STUDY DESIGN: This was a retrospective study. Our study included 335 women with ovarian endometriosis (Group A), 66 women with DIE (Group B), and 72 women presenting with both conditions (Group C). We evaluated tubal morphology and patency during laparoscopic excision of endometriosis. Tubal patency was assessed by tubal dye test. Tubal morphology was determined using the tubal morphology score (TMS), obtained by a total grade of 4 parameters: tubal caliber, course, surface and fimbrial morphology. RESULTS: There was no significant difference in the 3 groups regarding the presence of tubal occlusion (p = 0.23). Total TMS was not significantly different in the 3 groups (p = 0.13). A history of surgical treatment for endometriosis was associated with higher rate of tubal occlusion (p < 0.0005) and more severe morphological alterations (p < 0.0005). There was a positive correlation between number of previous surgical interventions and worse TMS (rho = 0.197, p < 0.0005). CONCLUSION: Alterations in tubal patency and morphology were not significantly different in patients with DIE as compared to women with ovarian endometriosis. History of surgical interventions for endometriosis was related with the presence of tubal alterations. PMID- 24050032 TI - Can the impact of pelvic inflammatory disease on fertility be prevented? Epidemiology, clinical features and surgical treatment: evolution over 8 years. AB - OBJECTIVE: To assess the epidemiological features and the trend of care of patients diagnosed with pelvic inflammatory disease (PID) and to assess most predictive parameters of severe disease, for which surgical management is warranted, in particular when surgery is certain to cause permanent infertility. STUDY DESIGN: The study population was divided into 3 groups: medical therapy only, conservative surgery, and destructive surgery (surgical procedures that impaired fertility). Data from the 3 groups were compared with respect to general and medical history data, clinical signs on admission, laboratory tests, and ultrasound findings. The p value was considered significant when < 0.05. RESULTS: The non-Italian women in the study appeared to be more at risk of developing PID and were overrepresented in the surgically treated groups. C-reactive protein (CRP) and D-dimer values most likely correlated with disease severity. Ultrasound evidence of ovaritis generally led to medical therapy. Conversely, when sonography revealed pyosalpinx or tuboovarian abscesses, surgery was performed. CONCLUSION: Clinical presentation is fundamental in diagnostic counseling but should be supplemented with further laboratory tests to detect inflammation and sonograms. The latter, along with CRP and D-dimer assays, may represent useful parameters to consider when planning patient management because they appear indicative of the need for surgical treatment. PMID- 24050033 TI - Short cervix and vaginal progesterone: a model on how to tackle the problem of idiopathic preterm labor. AB - Preterm deliveries continue to be a major problem in obstetrics and pediatrics. Short cervical length has been identified as the most accurate way to predict preterm delivery. Recently, vaginally administered progesterone has been shown in separate studies to dramatically decrease the prematurity rate in patients with a short cervix. The research that came to this conclusion is a good model to be used to approach other etiologies of preterm labor and delivery. PMID- 24050034 TI - Laparoscopic myomectomy for hemoperitoneum from a uterine leiomyoma with concomitant tubal abortion: a case report. AB - BACKGROUND: Ruptured ectopic pregnancy accounts for more cases of spontaneous hemoperitoneum than does the less frequently described acute bleeding from pedunculated uterine leiomyomata. When the latter does occur, management has consisted of laparotomy and either hemostatic suture or cauterization, myomectomy, or hysterectomy. CASE: We report a case of hemoperitoneum secondary to active bleeding from a pedunculated uterine fibroid notable for the presence of a concomitant tubal abortion as well as for the minimally invasive, fertility sparing management approach. The patient underwent an uncomplicated laparoscopic myomectomy and was discharged home on the first postoperative day. CONCLUSION: Laparoscopic myomectomy is a safe, feasible alternative in the management of hemoperitoneum from pedunculated leiomyomata. PMID- 24050035 TI - Vaginoplasty: a modern approach: a report of 2 cases. AB - BACKGROUND: Split-thickness skin graft vaginoplasty is one of many methods for vaginal reconstruction. In its 130-year history it has been modified by numerous authors in attempts to improve graft viability and neovaginal function. We describe a modern approach that aims to improve outcomes and reduce complications. CASES: Two cases of split-thickness skin graft vaginoplasty are presented in which the traditional Abbe-McIndoe technique was supplemented by the combined use of vacuum-assisted closure and fibrin tissue sealant. In both cases 100% graft survival and normal neovaginal function were observed, with no recipient site complications. Both patients mobilized on postoperative day 3, and both were sexually active 4 months postoperatively. CONCLUSION: This approach has not been described previously in the literature. The impressive results seen in these cases suggest that the use of vacuum-assisted closure and fibrin tissue sealant in combination may improve graft survival and resulting neovaginal function. PMID- 24050036 TI - Monochorionic diamniotic twin cervical ectopic pregnancy following assisted conception: a case report. AB - BACKGROUND: Ectopic pregnancy is a leading cause of maternal mortality. Its incidence has progressively increased in recent years. Assisted conception techniques are associated with a significantly higher rate of ectopic pregnancies. Cervical ectopic pregnancies are very rare, accounting for < 1% of all ectopic pregnancies. CASE: A 41-year-old, Caucasian woman presented for routine transvaginal scan at 6 weeks' gestation following a single embryo transfer as part of in vitro fertilization (IVF) follow-up. This revealed a monochorionic diamniotic twin pregnancy within the cervix. Serum beta-hCG concentration was 18,470 IU/L, and she reported only a mild brown-stained vaginal discharge. She was counseled regarding the risks of this pregnancy and was managed medically, receiving oral mifepristone and systemic methotrexate. She was subsequently monitored with serial serum beta-hCG measurements and transvaginal ultrasonography. After 6 weeks, due to the slow serum beta-hCG decline and lack of spontaneous menstruation, she was counseled regarding the potential risks of the persistent pregnancy and underwent suction evacuation. CONCLUSION: This case is an example of a complication of LVF. To the best of our knowledge and following a search of the Medline database, this is the only case of monochorionic twin pregnancy located within the cervical canal. PMID- 24050037 TI - Exaggerated placental site leading to postpartum hemorrhage: a case report. AB - BACKGROUND: Exaggerated placental site (EPS) reaction is defined as exuberant infiltration of the endometrium and myometrium at the implantation site by intermediate trophoblastic cells. It is a relatively rare, benign lesion related to pregnancy. The diagnosis of EPS depends mainly on pathologic findings, and it should be distinguished from placental site trophoblastic tumor, placental site nodule and choriocarcinoma. CASE: We present a case of EPS which led clinically to postpartum hemorrhage. During cesarean delivery uterine atony persisted despite pharmacological and surgical intervention. Finally, supracervical hysterectomy was performed due to severe postpartum hemorrhage. CONCLUSION: When postpartum hemorrhage caused by uterine inertia is unresponsive to conventional management, EPS should be considered. Besides timely recognition and intervention with appropriate maneuvers, hysterectomy should be performed as soon as possible to avoid further obstetrical shock and disseminated intravascular coagulation. PMID- 24050038 TI - Conservative management of cervical pregnancy: a report of two cases. AB - BACKGROUND: Cervical ectopic pregnancy is a rare form of ectopic pregnancy. Treatment of this clinical condition is controversial. Previously, hysterectomy was the mainstay of treatment, but in the recent past various conservative management approaches have been applied to preserve fertility. We report 2 such cases in which conservative approach was implemented. CASES: Case 1 was an early, nonviable cervical pregnancy in which systemic methotrexate was used with success. Case 2 was a viable, advanced cervical pregnancy (at 11 weeks) in which a combination of uterine artery embolization and systemic methotrexate was used. Ultimately this patient required hysterectomy due to sudden massive hemorrhage on day 22 of intervention. CONCLUSION: On reviewing our results and the literature, we conclude that uterine artery embolization with methotrexate is effective in reducing the ectopic cervical mass. However, there is always a risk of hemorrhage, which can be treated by either repeat uterine artery embolization alone or uterine artery embolization followed by curettage. Hysterectomy should be the last resort if all conservative methods fail. PMID- 24050039 TI - Teratoma in pregnancy: a case report. AB - BACKGROUND: Mature teratoma is a common complication of pregnancy. To the best of the authors' knowledge this is the largest teratoma in pregnancy documented in the literature. CASE: A 19-year-old woman, gravida 1, at 14 weeks' gestational age with a 37-cm fundal height, was found to have a 30 x 28 x 17 cm mass on ultrasound. She underwent an exploratory laparotomy, and a teratoma was excised. CONCLUSION: A teratoma that could limit the growth of an intrauterine pregnancy, is suspected for rupture or torsion, is causing severe pain, and/or may be suspicious for malignancy should be excised. PMID- 24050040 TI - School nurses setting the stage for wellness and success. PMID- 24050041 TI - Encopresis: Not just an accident. AB - Encopresis is a medical condition that can be seen in the school setting with children of all ages, though primarily at the early childhood and elementary level. This condition can cause a great amount of frustration with the student, family, and teachers due to the child's inability to control elimination patterns. The school nurse must be aware of the warning signs that a student may be experiencing encopresis in order to promote treatment. This article will assist the school nurse in understanding typical causes for functional encopresis, knowing how to help a student who soils, and developing an individualized healthcare plan that assists a student to become continent of stool again. Encopresis is not just an accident. PMID- 24050042 TI - Reducing the risks of delegation: use of procedure skills checklists for unlicensed assistive personnel in schools, Part 2. AB - School nurses are challenged by Federal Civil Rights Laws and the Standards of School Nursing Practice to care for a burgeoning population of students with special healthcare needs. Due to the realities of current school nurse-to-student ratios, school nurses are frequently responsible for directing unlicensed assistive personnel (UAPs) to support the health and safety needs of students, where State Nurse Practice Acts, state legislation, and local policy mandates allow. The delegation of health care tasks to UAPs poses many professional, ethical, and legal dilemmas for school nurses. One strategy to reduce the risks of delegation is through the use of procedure skills checklists, as highlighted by the experience of one large urban school district. Part 1 of this two-part article (Shannon & Kubelka, 2013) explored the scope of the problem and the principles of delegation, including legal and ethical considerations. Part 2 discusses the use of procedure skills checklists by school nurses as a strategy to reduce the risks of delegation of student special health care tasks to UAPs. PMID- 24050043 TI - The unique needs of the preschool and early elementary school-age child with type 1 diabetes. PMID- 24050044 TI - Preventing vision loss among students through eye safety and early detection. AB - Childhood vision problems that are detected and treated early can, in many cases, see improved outcomes compared with those detected late. Untreated, these problems can diminish the learning potential of the student and have long-term health and vision implications. School nurses can play a critical role in improving student outcomes by bringing vision screenings and eye health education to their schools. NASN and the National Eye Institute are working together to elevate awareness in schools about the importance of early detection and eye health and safety. While vision screenings can catch potentially worsening issues early, eye health education can teach children to adopt safe practices at a younger age and recognize changes in their vision. There may be barriers, but nurses can find support from those in their schools and the surrounding communities. PMID- 24050045 TI - Demystifying the differences in using data to improve individual practice versus publishing research findings. PMID- 24050046 TI - The interactive health room: supporting educational goals with elementary students. PMID- 24050047 TI - First steps: making the transition to preschool. AB - The transition from home or daycare to preschool can be a stressful time for both parent and child. Through advance planning and preparation, the school nurse can begin to establish a trusting relationship with the family and provide the educational team with critical information that will shape school programming for the child with disabilities. This investment will ease family stress and facilitate a successful launch to preschool. PMID- 24050048 TI - Health literacy. Part 1. Practical techniques for getting your message home. AB - Health literacy promotion techniques are important for the school nurse's toolkit. Health literacy, an Institute of Medicine objective, is "the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions." Forty-three percent of the adult population has difficulty understanding basic health information. This article is the first of two articles that will describe techniques for improving verbal (part 1) and written (part 2) health communication. PMID- 24050049 TI - Talking out loud in class: utilizing discussion as an effective teaching strategy with adult learners. AB - Staff development is an important role of the school nurse, yet little is written to assist the nurse in this role. Though some obtain advanced degrees in education, most school nurses are not prepared for the staff development role without further education in pedagogy, teaching strategies, and evaluation methods. This article presents discussion as one of many active teaching strategies that can engage learners and promote critical thinking. More work is needed in the area of course design and implementation, as well as additional research to help identify the most effective teaching strategies for school employees. PMID- 24050051 TI - The "readiness" debate. PMID- 24050050 TI - For your information. Management in the school setting: position statement. AB - It is the position of the National Association of School Nurses (NASN) that the safe and effective management of allergies and anaphylaxis in schools requires a collaborative, multidisciplinary team approach. The registered professional school nurse (hereinafter referred to as the school nurse) is the leader in a comprehensive management approach that includes planning and coordination of care, educating staff, providing a safe environment, and ensuring prompt emergency response should exposure to a life-threatening allergen occur. Furthermore, NASN supports, in states where laws and regulations allow, the maintenance of stock nonpatient-specific epinephrine and physician-standing orders for school nurses to administer epinephrine in life-threatening situations in the school setting. School districts must have a clear, concise, all-inclusive policy in place to address the management of allergies in the school setting that should be reviewed annually (National School Boards Association [NSBA], 2012). This policy shall be consistent with federal and state laws, nursing practice standards, and established safe practices in accordance with evidence-based information and include development of a developmentally appropriate Individualized Healthcare Plan (IHP) and Emergency Care Plan (ECP). PMID- 24050052 TI - 5 ways to drive value. PMID- 24050053 TI - From medical home to ACO: a physician group's journey. AB - The Medical Clinic of North Texas (MCNT) launched a population health initiative in 2010 that has involved working with self-insured companies to manage the health of their employee populations. To achieve the goals of providing high quality care at a low cost, MCNT uses historical electronic health record and claims data to calculate state-of-health (SOH) scores for a company's individual employees and for the entire employee population. SOH scores reflect risks related to chronic conditions for each patient, thereby providing clinical teams and care coordinators with the information they need to design and execute patient-specific care plans. PMID- 24050054 TI - Understanding the business of employed physician practices. AB - Health system leaders should understand issues related to finance, compliance, human resources, quality, and safety in their employed physician practices to better support the success of these practices. New business and payment models are driving operational changes in physician offices. Catholic Health Initiatives (CHI) has added new system roles and responsibilities to oversee physician practices. PMID- 24050055 TI - 6 essential elements for physician revenue cycle management. AB - To be effective, a professional fee billing operation requires the following elements: Capable management. An appropriate organizational model. Consolidated practice management systems. Transparency, standards, and controls. An appropriate coding and compliance model. ICD-10 preparedness. PMID- 24050056 TI - Using data analytics to identify revenue at risk. AB - Key factors for successfully using data analytics to improve revenue cycle performance include the following: Senior leaders who engage physicians and work with business unit owners to gain ground-level insights. Communication and learning. Embedded analytics. Transparency related to what the data show, how the data will be used, and what items have been brought to light via data analysis. Real-time monitoring of data. Incorporation of staff feedback in continually improving analytical modeling capabilities. PMID- 24050057 TI - Strategies for successful revenue cycle outsourcing. AB - Revenue cycle outsourcing can offer hospitals and health systems many advantages, including cost savings and revenue gains, but it also carries risks. Some organizations may choose to outsource revenue cycle to third-party service providers; others may opt to develop internal centers of excellence. Hospitals and health systems should consider IT system compatibility, payment arrangements, and incentive and value alignment when selecting an outsourcing partner. PMID- 24050058 TI - Doing well by doing good: patient financial advocacy in action. AB - UPMC has improved its patient financial advocacy by: Establishing a patient financial services center. Developing processes and tools to identify uninsured and underinsured patients across the continuum of care. Positioning itself for changes resulting from Medicaid expansion, insurance exchanges, and the growing self-pay population. PMID- 24050059 TI - Improving pharmacy revenue integrity. AB - Billings Clinic learned the following important lessons in implementing a pharmacy revenue integrity initiative: Integrate pharmacy data as fully as possible. Audit and review pharmacy data regularly to validate the data and identify key areas where education can be provided to support accuracy and compliance. Use technology to bridge gaps between pharmacy data, such as gaps in billable units and billed units. Establish data governance workflows. PMID- 24050060 TI - Creating a positive culture for collections. AB - At OhioHealth, three factors for success have supported the organization's ability to increase collections while easing the transition to consumer-directed health care for patients and staff alike: Establishing internal transparency for collections efforts. Setting target goals for collections by facility and department and regularly sharing the results with leaders and staff. Monitoring patient complaints, sharing them with revenue cycle staff, and using them to identify areas where process improvements are needed. PMID- 24050061 TI - Internal audits can safeguard hospital revenue. AB - Hospitals should routinely perform internal audits of all functions affecting billing accuracy to mitigate the effects of payer audits and to protect revenue by improving billing processes. A primary focus for internal audits should be on coding accuracy, because coding errors leading to denials often reflect gaps in coders' knowledge or training. Effective communication between coding and denials management professionals is a critical success factor. Audits should support appeals processes, and audit findings should be used in educational initiatives aimed at improving coding accuracy. PMID- 24050062 TI - Keeping step with IRS guidance on requirements for tax-exempt hospitals. AB - Section 501(r) of the Internal Revenue Code, enacted as part of the Affordable Care Act, requires that section 501(c)(3) hospitals conduct community health needs assessments (CHNAs) every three years. Proposed regulations issued in April 2013 provide guidance on the CHNA requirement and other issues arising under section 501(r). The proposed regulations generally supersede the guidance provided in Notice 2011-52, although a transition period is provided. Hospitals can generally rely on the proposed regulations until final regulations are issued. PMID- 24050063 TI - Achieving value with physician employment. PMID- 24050064 TI - Why pricing transparency will not reduce costs. PMID- 24050065 TI - Thinking flexibly about fixed income. PMID- 24050066 TI - The quality of antimalarial medicines in western Cambodia: a case study along the Thai-Cambodian border. AB - The prevalence, availability, and use of antimalarial medicines (AMLs) were studied in six Cambodian provinces along the Thai-Cambodian border. The study was divided into two parts: the first looked at the quality of AMLs available in Pursat, Pailin, Battambang, Bantey Meanchey, Oddar Meanchey, and Preah Vihear and the second obtained information about the availability and use of AMLs. A randomized sampling methodology was used to select locations and collect samples, which were screened using Global Pharma Health Fund (GPHF) Minilabs. A subset of samples was sent to quality control laboratories for confirmatory testing. For the second part of the study, face-to-face interviews were conducted using standardized surveys with members of randomly selected households and staff of health facilities in the villages with highest malaria incidence to find out where they acquired their AMLs and which were most frequently used. The results showed an overall failure rate of 12.3% (n = 46 of 374 total AML samples). The causes of medication sample failure were low active pharmaceutical ingredient (API) content, failed dissolution properties, and unacceptably high levels of impurities. A total of 86.2% of survey respondents (n = 1,648 of 1,912) reported a member of their household having malaria in the previous year. The most commonly used medicines were paracetamol (67.1% of respondents), Malarine (A+M co blistered, 28.6%), artesunate + mefloquine co-blistered (public sector product, 17.3%), quinine (16.7%), and artesunate monotherapy (11.9%). Health staff typically prescribed co-blistered artesunate plus mefloquine in the public sector (67.8%), the artesunate plus mefloquine "social marketing" product from Population Services International (PSI), Malarine (50.3%) in the private sector, artemether (49.7%), chloroquine (39%) and paracetamol (72.9%) to reduce fever. PMID- 24050067 TI - The quality of antimalarial medicines in eastern Thailand: a case study along the Thai-Cambodian border. AB - This study examined the prevalence, availability, and use of antimalarial medicines (AMLs) along the Thai-Cambodian border. The study was divided into two parts: the first looked at the quality of AMLs available in six Thai provinces and the second obtained information about the availability and use of AMLs. A randomized sampling methodology was used to select locations and collect samples, which were screened using Global Pharma Health Fund (GPHF) Minilabs. A subset of samples was sent to quality control laboratories for verification testing. For the second part of the study, face-to-face interviews were conducted with members of randomly selected households and the staff of health facilities in villages with the highest malaria incidence to find out where they acquired their AMLs and which were used most frequently. The results of quality testing showed an overall failure rate of 1% (7 of 709 samples) for active pharmaceutical ingredients (API); however, the API failure rate varied from 0.0% to 2.2% by location and the overall failure rates of samples by province varied from 0.0% to 3.4%. A total of 97.9% (n = 272) of respondents had taken AMLS. The most commonly used medicines were primaquine (30% of respondents), chloroquine (15.8%), artesunate+mefloquine (12%), and quinine (10%). Most respondents (97.9%) had received medications from public hospitals or malaria clinics. PMID- 24050068 TI - Hypoalbuminemia as a predictor of diarrhea caused by blastocystis hominis. AB - Blastocystis hominis is an intestinal protozoan found worldwide, particularly in developing countries, that may cause gastrointestinal symptoms, including diarrhea. We conducted a hospital-based study to identify clinical factors predictive of diarrhea caused by B. hominis. We studied patients with positive stool samples for B. hominis by formalin ethyl acetate concentration technique at Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand between 2003 and 2010. Patients were divided into diarrhea and non-diarrhea groups. Diarrhea patients were categorized if the diarrhea was associated with B. hominis only. In total, 81 patients with isolated B. hominis infection were studied. Of those, 17 patients (21%) had diarrhea associated with B. hominis infection. Eight variables were included in the final model predicting diarrhea caused by B. hominis on multiple logistic regression analysis. Only serum albumin level was significantly associated with diarrhea cases in this study with an adjusted OR of 0.162 and a 95% CI of 0.027- 0.957. Hypoalbuminemia is associated with diarrhea associated with blastocystosis. PMID- 24050069 TI - In vivo activity of dihydroartemisinin against Schistosoma mansoni schistosomula in mice. AB - Dihydroartemisinin, an anti-malarial agent, has been shown to exhibit activity against Schistosoma japonicum and S. mansoni. The purpose of the present study was to investigate the in vivo activity of dihydroartemisinin against juvenile S. mansoni and the changes to the genital system among worms surviving drug treatment. Mice were infected with 200 S. mansoni cercariae each and randomly assigned to groups. Dihydroartemisinin at a single oral dose of 300 mg/kg was given to mice on Days 14 or 16, 18, 20, 21, 22, 24, 26 or 28 post-infection, to assess the efficacy of dihydroartemisinin against juvenile S. mansoni. Mice were treated with dihydroartemisinin using various protocols with the total drug dose of 900 mg/kg, to investigate the efficacy of dihydroartemisinin against the schistosomula of S. mansoni. In addition, changes to the genital system among worms surviving dihydroartemisinin treatment, were recorded. An oral dose of dihydroartemisinin of 300 mg/kg was given to mice on Days 14, 16, 18, 20, 21, 22, 24, 26 or 28 days post-infection; this resulted in a 65.0-82.4% reduction in total worm burden and a 70.9-83.0% female worm burden. Better results were seen when treatment was given 20-24 days post-infection. Administration of multiple dose and low-oral-dose dihydroarteminisinin (at doses of 90, 180, 300 and 450 mg/kg) at different times, reduced total worm burdens by 88.7-99.1% and female worm burdens by 93.2-99.5%. The egg tubercles in mice livers were significantly reduced following treatment; in some mice no egg tubercles were found. These findings indicate dihydroartemisinin exhibits high in vivo activity against the schistosomula of S. mansoni. It causes damage to the genital system of worms, influences the development of of S. mansoni worms, reduces the oviposition of surviving worms and enhances the formation of granulomas around tissue-trapped eggs, thereby reducing damage to the infected mammalian host. PMID- 24050070 TI - Attitudes about the 2009 H1N1 influenza pandemic among pregnant Japanese women and the use of the Japanese municipality as a source of information. AB - We conducted this study to determine the use of Japanese municipal information sources about the 2009 H1N1 influenza pandemic among 109 pregnant Japanese women during October and November 2009 and to determine their attitudes regarding the pandemic. During November 2009, the number of municipality information users increased significantly, however, the percentage of public magazine users remained under 40% and the percentage of municipality website users remained significantly lower than other website users. The accession of municipality information did not alleviate the anxiety of subjects caused by inaccurate information, such as mortality due to the virus infection and the safety of oseltamivir use. Those who obtained information about the pandemic from the municipality were more willing to receive the influenza vaccine than non-users. The results show the municipality information system needs to be improved to ameliorate anxiety and more effectively convey health information for future pandemics. Other Japanese public health service information systems shoud be assessed as well to determine their efficacy in delivering information regarding the 2009 H1N1 influenza pandemic. PMID- 24050071 TI - Dengue hemorrhagic fever presenting with hemorrhagic pancreatitis and an intramural hematoma of the duodenal wall: a case report and review of the literature. AB - Dengue fever may present with atypical manifestations. Here we report a 47 year old male presenting with fever and sore throat for 2 days, followed by epigastric pain and tarry stool for 4 days. The esophagogastroduodenoscopy revealed multiple ulcers with a nodular margin in the duodenal bulb and second portion of the duodenum. A MRI of the abdomen revealed hemorrhagic pancreatitis, with a large intramural hematoma in the second portion of duodenum. The final diagnosis was dengue hemorrhagic fever, grade II, complicated with hemorrhagic pancreatitis and an intramural hematoma of the duodenal wall. Physicians should be aware of the atypical abdominal presentations of dengue fever. PMID- 24050072 TI - Outbreak of norovirus gastroenteritis infection, Thailand. AB - Norovirus is a leading cause of gastrointestinal illness worldwide. We investigated an outbreak of gastrointestinal illness in Pattaya, Thailand, among participants of a course. We asked participants and family members to complete a questionnaire asking about symptoms, meals eaten, and foods consumed during the course. We collected stool samples from persons reporting illness and analyzed specimens for several viruses and enteropathogenic bacteria. We defined a case as a person having one or more episodes of diarrhea, with onset between 30 August and 1 September 2010, in a participant or family member who attended the course. Of 56 people who attended, 95% completed the questionnaire: nine met the case definition (attack rate, 17%). Common symptoms included abdominal cramps, nausea, fatigue, headache, and vomiting. Food items with elevated risk ratios included: crispy fish maw, dried squid, and cashew nut salad [risk ratio (RR) 5.1; 95% confidence interval (CI) 0.7-37]; assorted salad bar with dressing (RR 3.0; 95% CI 0.9-11); and seafood kebab (RR 5.8; 95% CI 0.8-43). Among ill persons, four (44%) provided stool samples and two (50%) were positive for norovirus. Our data suggest a foodborne outbreak of norovirus. Increased use of norovirus diagnostics as well as measures to prevent transmission may help identify additional outbreaks and improve control measures to limit the spread of outbreaks. PMID- 24050073 TI - An outcome based nutrition curriculum for counselors at HIV voluntary counseling and testing facilities in Vietnam. AB - We developed, monitored and evaluated an outcome based nutrition curriculum for counselors at HIV voluntary counseling and testing (VCT) facilities in Can Tho City, Vietnam. This outcome based education (OBE) focused on expected competencies appropriate to the local context. The curriculum was designed to train 37 counselors working in HIV VCT centers in Can Tho City, Vietnam regarding nutrition. Lectures and learning activities were developed and assessment criteria were determined. The curriculum content was evaluated and modified by feedback from reviewers. During training, the HIV VCT counselors gave the curriculum a satisfactory rating. More than 80% of HIV VCT counselors stated the subject matter was easily or very easily understand. Testing revealed a significant mean increase in the HIV VCT counselor's competency by the end of training (p = 0.001). More than 89% of HIV VCT counselors felt confident in performing nutritional counseling. These findings suggest the usefulness of this OBE nutrition curriculum for training HIV VCT counselors. PMID- 24050074 TI - Congenital rubella syndrome: a review of laboratory data from 2002 to 2011. AB - Rubella infection in pregnant women during the first trimester of pregnancy can lead to fetal anomalies, commonly known as congenital rubella syndrome (CRS). The objective of our study was to analyze the serological test results among infants suspected of having CRS aged < or = 12 months compared with their clinical status. Between January 2002 and December 2011, 3,279 serum samples from infants aged < or = 12 months from government hospitals in Malaysia were examined for rubella specific IgM and IgG antibodies using a Axsym, automated analyzer (Abbott Laboratories). Forty-eight samples were positive for rubella specific IgM antibodies and 494 samples were positive for rubella specific IgG antibodies. These were then age stratified and their clinical history reviewed for any CRS symptoms. Fifteen of 38 rubella IgM positive infants (39.5%) aged < 3 months, had a clinical appearance compatible with CRS. However, only 1 IgM positive infant aged 3 to 6 months and one infant aged 7 to 11 months had clinical appearance compatible with CRS. The most common abnormal findings in these cases were congenital heart defects and cataracts. Forty-eight point eight percent of IgM positive cases and 53.1% of IgG positive cases, had inadequate information in the chart to determine the presence of CRS. Clinical findings and timely laboratory diagnosis to determine the presence of CRS are important in infants born with congenital defects. Physicians should also be aware of the appropriate interpretation of these findings. PMID- 24050075 TI - Sexually transmitted infections among male highway coach drivers in Myanmar. AB - A cross sectional descriptive study was conducted from February 2008 to December 2009 at the largest Highway Terminal, Yangon, Myanmar to determine the prevalence of curable STIs (syphilis, gonorrhea, chlamydial infections, and trichomoniasis), to find out the associated factors for STIs, and to determine the antibiotic susceptibility pattern of gonococcal infection among highway drivers. Urine and blood specimens were collected from 601 male highway coach drivers after an interview about their behavior. Standard laboratory tests were carried out to detect STIs. Multivariate analysis was used to ascertain potential risk factors for STIs. The prevalence rates of syphilis, gonorrhea, chlamydial infections, and trichomoniasis were 4.8, 4.3, 5.7, and 9.8%, respectively. One hundred and two (17.0%) were infected with at least one of the tested four STIs, and 34 (5.7%) had STI co-infections (2STIs). Those who had multiple sexual contacts were likely to be infected with at least one STI, and those who had a history of inconsistent condom use within past two weeks and multiple sexual contacts were more likely to have STI co-infections (p < 0.05). Antimicrobial susceptibility of 21 Neisseria gonorrhoeae isolates showed that 85.7% were susceptible to azithromycin, 80.9% to spectinomycin, 66.7% to cefixime, 61.9% to ceftriaxone, and 38.1% to ciprofloxacin. The high prevalence of STIs in this study and the decreased susceptibility of Neisseria gonorrhoeae to cephalosporin and fluoroquinolone highlighted the role of periodic screening in early diagnosis and effective treatment of STIs among high-risk populations. PMID- 24050076 TI - Development of a 5-minute rapid test for detecting Vibrio cholerae O139. AB - Vibrio cholerae O139 is an etiology of cholera in Thailand. We determined to prepare a rapid test to detect V cholerae O139 using an immunochromatographic method to be used for surveillance and use in community laboratories. We conjugated murine monoclonal antibodies specific to the lipopolysaccharide of V. cholerae O139 with colloidal gold particles. The sensitivity of the test was determined using 10-fold dilutions of V. cholerae O139. The lowest number of bacterial cells detected by the test was 10(6) cfu/ml. The specificity was determined using 51 isolates of pure cultures, including V. cholerae serogroups O1, O139, and non-O1/non-O139 and other enteric bacteria; 27 rectal swab specimens and 100 specimens of enriched alkaline peptone water, 50 of which contained V. cholerae O1 and the other did not contain V. cholerae O1. The rapid test showed specificity to V cholerae O139 and no cross reaction with V cholerae O1, V. cholerae non-O1/ non-O139, and other enteric bacteria. The test is rapid, simple and easy to use. PMID- 24050077 TI - Salmonella enteritidis ventriculitis. AB - Salmonella sp are important causes of meningitis among neonates and young children in Malaysia. We present a case of Salmonella enteritidis meningitis in a six week old female who presented with a one week history of fever, diarrhea and seizures which was unsuccessfully treated with a third generation cephalosporin. She had a relapse of meningitis complicated with ventriculitis and hydrocephalus, requiring an eleven week course of meropenem. She improved clinically, but did not have improvement in the cerebrospinal fluid (CSF) glucose level despite prolonged antibiotic use. This case illustrates the dilemma in determining the duration of antibiotic needed to successfully treat Salmonella enteritidis ventriculitis. PMID- 24050078 TI - Disseminated Mycobacterium avium and recurrent Salmonella group D infection in a patient with autoantibodies to interferon-gamma. AB - We reported a case of a 40-year-old woman who presented with prolonged fever for 1 month, left sternoclavicular arthritis, anemia, multiple cervical lymphadenopathy and hepatosplenomegaly. She had a previous history of recurrent Salmonella group D septicemia. Computed tomography of her chest and abdomen revealed left sternoclavicular (SC) arthritis, left subscapular collections, hepatosplenomegaly, and multiple hypodensed lesions in the spleen. Blood, synovial fluid and bone marrow for mycobacterial cultures identified Mycobacterium avium by real-time PCR and reverse hybridization. Cell mediated immunodeficiency investigations were strongly positive for autoantibodies to interferon-gamma (IFN-gamma) by ELISA technique. During the third week of antimycobacterial therapy, she developed an acute generalized pustular eruption. Skin biopsy showed leukocytoclastic vasculitis; drug allergy was suspected. The pustular eruption resolved with steroid treatment and discontinuation of levofloxacin and clarithromycin. She was discharged home after 8 weeks of hospitalization with azithromycin, rifampicin and ethambutol. PMID- 24050079 TI - Listeria monocytogenes brain abscess: two cases and review of the literature. AB - Listeria monocytogenes is a gram-positive bacillus that exhibits predilection to infect the central nervous system in immunocompromised individuals; the most common manifestations are meningitis and rhombencephalitis. Listerial brain abscesses are rare. We report here two brain abscess cases caused by L. monocytogenes in patients receiving immunosuppressive agents. The first patient presented with left hemiparesis mimicking stroke and the second patient presented with neurological symptoms without fever, which was indistinguishable from brain tumor. In both cases, magnetic resonance spectroscopy (MRS) was performed to differentiate infectious processes from other causes. Diagnosis was made with a positive blood culture in both cases. Listerial DNA was detected in the pus aspirated from the abscess in the first case. Both patients were successfully treated with intravenous ampicillin followed by oral amoxicillin. MRS was useful in differentiating infectious processes from non-infectious causes. PMID- 24050080 TI - Prevalence of toenail onychomycosis among diabetics at a primary care facility in Malaysia. AB - Onychomycosis increases the risk of developing secondary bacterial infection and cellulitis if left untreated. The aim of this study was to determine the prevalence of onychomycosis among diabetics and its associated factors. A cross sectional study using universal sampling of all type 1 and 2 diabetic patients attending a primary care facility of the Universiti Kebangsaan Malaysia (UKM) from January to March 2011 was conducted. Samples were taken from clinically abnormal nails and from the first right toenail in the absence of nail abnormalities and cultured for fungal elements. A total of 151 diabetics participated in the study. The mean patient age was 60.7 +/- 9.1 years. A total of 123 nail samples (81.5%) were culture positive for fungal elements. A positive correlation was found between onychomycosis and increasing age (p = 0.011) and clinically abnormal nails (p < 0.05). There were no significant correlations with gender, ethnic group, duration of diabetes, types of diabetes or glycemic control. The prevalence of onychomycosis among diabetics in our study was high. PMID- 24050081 TI - Treatment of a brain abscess caused by Scedosporium apiospermum and Phaeoacremonium parasiticum in a renal transplant recipient. AB - Cerebral mycosis is a significant cause of morbidity among immunocompromised populations. We present here a case of cerebral infection with Scedosporium apiospermum and Phaeoacremonium parasiticum in a 49-year-old renal transplant recipient. Fourteen years after renal transplantation, the patient presented with invasive pulmonary aspergillosis treated with intravenous liposomal amphotericin B. The patient had clinical and radiographic improvement. However, 6 weeks later, the patient presented with cerebral infection. Magnetic resonance imaging revealed multiple rim enhancing brain abscesses. Brain and cerebrospinal fluid cultures ultimately grew Scedosporium apiospermum and Phaeoacremonium parasiticum. The patient was treated with voriconazole for 6 months and had clinical and radiologic improvement. We believe this is the first reported case of co-infection of the brain with scedosporiosis and phaeohyphomycosis in a renal transplant recipient, who had received intravenous liposomal amphotericin B. Voriconazole may represent a new therapeutic option for these simultaneous infections in the brain. PMID- 24050082 TI - Causative agents and resistance among hospital-acquired and ventilator-associated pneumonia patients at Srinagarind Hospital, northeastern Thailand. AB - Abstract. Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) have an impact on health care costs and mortality. The aim of this study was to identify the causative agents, antibiotics prescribed, cost of treatment and drug resistance trends among HAP and VAP patients at a tertiary-care hospital in northeastern Thailand during 2008 and 2009. The incidences of HAP in 2008 and 2009 were 0.7/1,000 and 0.55/1,000 hospital days, respectively. The incidences of VAP in 2008 and 2009 were 13.6/1,000 and 12.6/1,000 ventilator days, respectively. About 70% of HAP were caused by Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae; and 70% of VAP were caused by A. baumannii, P. aeruginosa, and K. pneumoniae. The ranking in the causative agents of HAP and VAP was not different, but more antimicrobial resistant organisms were seen in 2009. More than half of the costs of nosocomial infection treatment in 2008 and 2009 were the costs for HAP and VAP, 16.8 and 17.5 million Baht, respectively. Fewer A. baumannii and P. aeruginosa isolates were sensitive to carbapenems. Only one-fifth of A. baumannii isolates were sensitive to cefoperazone/sulbactam. The only two antimicrobial agents with consistently good activity against A. baumannii were tigecycline (approximately 85%) and colistin (approximately 99%). Fifty-seven point six percent of P. aeruginosa isolates were sensitive to ceftazidime, 72.4% were sensitive to piperacillin/tazobactam, 95.9% were sensitive to netilmycin and 99.2% were sensitive to colistin. Forty-seven percent of K. pneumoniae isolates were extended spectrum beta-lactamase and sensitive to carbapenems. Methicillin-resistant S. aureus was the cause of 6-7% of HAP/VAP cases in our study. PMID- 24050083 TI - Fever of unknown origin at a teritiary care teaching hospital in Pakistan. AB - The aim of this study was to determine the causes of fever of unknown origin (FUO) at a tertiary care teaching hospital in Pakistan. We conducted this cross sectional descriptive study at the Department of Medicine, Civil Hospital Karachi, from January 2006 to December 2011. We reviewed the medical records of all patients aged > 12 years with a primary diagnosis of FUO. We excluded those who did not meet inclusion criteria. Two hundred five patients were analyzed, 111 (54%) were male. The mean age of patients was 38 +/-14 years. The mean duration of fever prior to hospitalization was 37 +/- 16 days and the mean time taken to reach a final diagnosis was 19 +/- 14 days. A diagnosis was established in 171 patients. Infections, especially tuberculosis, were the most common cause of FUO, followed by connective tissue diseases and malignancies. Causes of FUO and their frequencies in the population should be known because FUO is most often caused by an unusual presentation of a common disease, but may also be caused by a rare condition. Common diseases should be suspected first when investigating FUO. Factors causing delay in diagnosis should be identified and overcome to improve outcomes. PMID- 24050084 TI - Prevalence of metabolic syndrome and its association with serum uric acid levels in Bangkok Thailand. AB - Metabolic syndrome (MetS) and hyperuricemia are important risk factors for cardiovascular disease, hypertension and renal disease. The relationship between serum uric acid (UA) levels and MetS remains unclear. In the present study we determined the presence of MetS and measured UA levels among personnel at the Thai Red Cross Society and Chulalongkorn University to evaluate the possible presence of an association between the two. We conducted this cross sectional study in 2009. A total of 2,804 persons, aged 35-60 years (628 men and 2176 women) filled out questionnaires, had laboratory testing and were included in the study. MetS was defined by criteria harmonized from six international expert groups. The association between MetS and UA levels was determined using multivariable logistic regression. The overall prevalences of MetS were 25.1, 21.1, and 18.2% when a BMI > or = 23 kg/m2, a BMI > or = 25 kg/m2 or waist circumference were used to classify abdominal obesity, respectively. Body mass index, waist circumference, blood pressure, and triglycerides significantly elevated in both men and women with elevated UA levels (all a p-value < 0.005). After adjustment for potential confounders, the odds ratio of having MetS in the fourth quartile compared with the first quartile of a UA level was 2.77 times for men (95% CI 1.60-4.79) and 8.04 times for women (95% CI 5.43-11.91). There wes a stronger association between the presence of MetS and UA in women than men. UA levels were associated with the presence of MetS. PMID- 24050085 TI - Prevalence of dental caries and periodontal diseases, and their association with socio-demographic risk factors among older persons in Delhi, India: a community based study. AB - Dental health is often neglected in the older persons, and dental conditions associated with aging are complex, adversely affecting the quality of life. The present study was undertaken to estimate the prevalence of dental caries and periodontal diseases among older persons from Delhi, India, and to study their association with selected socio-behavioral risk factors. We conducted a community based cross sectional study among persons aged > or = 60 years from Delhi during 2009-2010. A questionnaire was used to interview elderly regarding dental health. The World Health Organization (WHO) oral health assessment form was used for examining the study participants. A total of 448 participants were examined and included in the study. Of the dentate, 47.1% had active dental caries. The mean decayed, missing and filled teeth (DMFT) score for the study population was 14.4. The prevalence of gingival bleeding, periodontal pockets and loss of attachment was 96.6, 89.1, and 80.3%, respectively. The prevalence of tobacco use was 47.9%. Age, frequency of teeth cleaning, and method used for teeth cleaning were statistically associated with the DMFT score. The prevalence of dental caries and periodontal disease was high in the study population, and warrants intervention. PMID- 24050086 TI - Risk factors of shock in severe falciparum malaria. AB - The objective of this study was to determine the risk factors for the development of shock in adult patients admitted with severe falciparum malaria. As an unmatched case-control study, the records of patients who were admitted to the Bangkok Hospital for Tropical Diseases, Thailand, between the years 2000-2010, were reviewed. One hundred patients with severe falciparum malaria and shock, and another 100 patients with severe malaria but without shock were studied. Demographics, presenting symptoms, physical observations, and laboratory data of these patients were analyzed. Five risk factors for the development of shock were identified: female gender (OR 6.16; 95% CI 3.17-11.97), red cell distribution width (RDW) >15% (adjusted OR 2.90; 95% CI 1.11-7.57), anorexia (adjusted OR 2.76; 95% CI 1.03-7.39), hypoalbuminemia (adjusted OR 2.19; 95% CI 1.10-4.34), and BUN-creatinine ratio >20 (adjusted OR 2.38; 95% CI 1.22-4.64). Diarrhea was found to be a protective factor (adjusted OR 0.33; 95% CI 0.14-0.78). Metabolic acidosis was only weakly correlated to mean arterial blood pressure on admission (r(s) = 0.23). Female gender was the strongest risk factor for the development of shock. We concluded that female gender, RDW >15%, anorexia, hypoalbuminemia, and BUN-creatinine ratio >20 were risk factors of shock development in severe falciparum malaria. PMID- 24050087 TI - Toxocara egg soil contamination and its seroprevalence among public school children in Los Banos, Laguna, Philippines. AB - The soil-transmitted nematode Toxocara sp has little epidemiological information in the Philippines. In this study, we studied the extent of soil contamination with Toxocara eggs and the seroprevalence of Toxocara infection among public school children in Los Banos, Laguna, Philippines. Soil samples were obtained from public schools, backyards, and empty lots in Los Banos to examine for the presence of Toxocara eggs using the modified sucrose flotation technique. Serum samples were obtained from public school children in Los Banos and examined for Toxocara infection using an ELISA test. Of the 200 soil samples, 85 (43%) were positive for Toxocara eggs at a concentration of 1 egg/g of soil. Forty-two percent of soil samples obtained from the public school, 45% of backyard samples, and 40% of empty lot samples were positive. Of the 75 serum samples from children, 37 (49%) were positive for Toxocara infection. There was a positive correlation between Toxocara egg concentration and seroprevalence of Toxocara infection. Results showed a high prevalence of soil contamination and a high seroprevalence of Toxocara infection among children in Los Banos, Laguna, Philippines. PMID- 24050088 TI - The vasculature of nurse cells infected with non-encapsulated Trichinella species. AB - The vasculature surrounding the nurse cells of encapsulated Trichinella spiralis has been described previously. It has been postulated the function of these vessels is to support the growth of the parasite. We describe here for the first time the vasculature surrounding the nurse cells of non-encapsulated T. pseudospiralis and T. papuae. Similar to the vasculature of uninfected muscle cells, the vessels surrounding non-encapsulated Trichinella nurse cells are dense and branched longitudinally along the long axis of the muscle cells; they also appear to be similar in diameter. The netting pattern of enlarged vessels found around T. spiralis (encapsulated) nurse cells is not present in non-encapsulated Trichinella infections. The vessels surrounding non-encapsulated Trichinella nurse cells seem to exist prior to parasite invasion of the muscle cell. PMID- 24050089 TI - Prostatic Schistosoma japonicum with atypical immunophenotyping of individual glandular tubes: a case report and review of the literature. AB - There are few cases of prostatic schistosomiasis. Here we report a case of Schistosoma japonicum of the prostate, in which the immunophenotyping of individual glandular tubes was atypical. Whether the S. japonicum infection contributed to the lesion or not is unknown. We suspect the lesion was a sign of early precancerous hyperplasia. Follow-up of this patient may give clues about the relationship between schistosomiasis and prostate cancer. This is the first case report of prostatic S. japonicum in the English literatures. A review of the literature is carried out. PMID- 24050090 TI - The Mosquito Online Advanced Analytic Service: a case study for school research projects in Thailand. AB - The Mosquito Online Advanced Analytic Service (MOAAS) provides an essential tool for querying, analyzing, and visualizing patterns of mosquito larval distribution in Thailand. The MOAAS was developed using Structured Query Language (SQL) technology as a web-based tool for data entry and data access, webMathematica technology for data analysis and data visualization, and Google Earth and Google Maps for Geographic Information System (GIS) visualization. Fifteen selected schools in Thailand provided test data for MOAAS. Users performed data entry using the web-service, data analysis, and data visualization tools with webMathematica, data visualization with bar charts, mosquito larval indices, and three-dimensional (3D) bar charts overlaying on the Google Earth and Google Maps. The 3D bar charts of the number of mosquito larvae were displayed along with spatial information. The mosquito larvae information may be useful for dengue control efforts and health service communities for planning and operational activities. PMID- 24050091 TI - Comparison of mosquito densoviruses: two clades of viruses isolated from indigenous mosquitoes. AB - We analyzed the phylogenetic tree of densoviruses isolated from indigenous mosquitoes and mosquito cell lines. Our findings suggest two distinct clades of densovirus. The viruses in the first clade were isolated from an indigenous mosquito which had the Aedes aegypti densovirus (AaeDNV) as a representative virus. The other clade of viruses was isolated from mosquito indigenous cell line which had the Aedes albopictus densovirus (AalDNV) as the representative virus. The origin of the two clades of DNVs is unclear but the phylogenetic trees were significantly different from each other. The two major densoviruses, AaeDNV and AalDNV, that infect mosquitoes that are known to carry viruses responsible for dengue hemorrhagic fever and yellow fever. Understanding the evolution of these two clades of densoviruses is important for studying the distribution of these viruses in mosquito cell lines and the information gained may be applied to understanding other viruses in various mosquito cell lines. PMID- 24050092 TI - The prevalence of dengue virus in Brunei Darussalam during January-November 2010. AB - The aim of this study was to retrospectively determine the prevalence of dengue virus from April 2010 to November 2010 in Brunei Darussalam. A total of 250 serum samples from dengue diagnosed patients were examined. All serum samples were tested for dengue IgM and IgG antibodies and dengue NS1 antigen using the PanBio dengue ELISA commercial kit. To determine the prevalence of dengue virus serotype in the country, serotyping was performed for the 14 samples that were positive for NS1 antigen. Dengue virus serotyping was carried out using the conventional reverse transcriptase-polymerase chain reaction (RT-PCR). Of the 250 serum samples included in the study, 196 were laboratory dengue confirmed cases. Dengue virus serotype 1 (DENV-1) was the predominant circulating serotype, followed by DENV-3 and DENV-2. This is the first report of DENV-3 isolation in Brunei Darussalam. PMID- 24050093 TI - Factors associated with severe clinical manifestation of dengue among adults in Thailand. AB - A retrospective study was conducted by reviewing medical records of 323 adult patients hospitalized with dengue infection at the Hospital for Tropical Diseases, Bangkok, Thailand between 2006 and 2010 in order to determine factors associated with severe clinical manifestations of dengue. Of 323 patients, 95 (29.4%) had dengue fever (DF) and 228 (70.6%) had DHF, which were categorized as grade I (67 patients, 29.4%), grade II (62 patients, 27.2%), grade III (95 patients, 41.7%) and grade IV (4 patients, 1.8%) following 1997 WHO definitions. Using the revised 2009 WHO definitions, 233 patients (72.1%) had non-severe dengue infection and 90 patients (27.9%) had severe dengue infection. Of the 233 patients with non-severe dengue infection, 193 (82.8%) were classified as having non-severe dengue infection with warning signs and 40 (17.2%) were classified as having non-severe dengue infection without warning signs. Using stepwise multivariate logistic regression analysis, having a hematocrit >2% above the reference range [odds ratio (OR) 3.235; 95% confidence interval (CI) 1.807-5.793] or having an alanine aminotransferase level >120 IU/l (OR 1.896; 95% CI 1.018 3.531) were associated with having DHF grades II-IV, whereas female gender (OR 2.042; 95% CI 1.143-3.648) or having a mean arterial pressure <80 mmHg (OR 2.275; 95% CI 1.302-3.975) were associated with severe dengue. These findings may help clinicians to determine patients at risk for severe manifestations of dengue infection, which could lead to proper management of these cases. PMID- 24050094 TI - The effects of climate variables on the outbreak of dengue in Queensland 2008 2009. AB - Outbreaks of dengue occur in Queensland, Australia nearly every summer. In 2008 2009, there was an unusually large, protracted outbreak of dengue, comprised of 1,200 cases. We investigated the weather variables and their contribution to the 2008-2009 dengue outbreak in Queensland. Case data were obtained from the Communicable Disease Branch of Queensland Health for 2000-2010 for the towns of Cairns and Townsville. Monthly weather data (rainfall, maximum temperature, minimum temperature) and Southern Oscillation Index (SOI) was obtained from the Bureau of Meteorology (BOM). We used a negative binomial model to test associations between these variables and dengue. Lagged models were also created for one, two and three months. Our models suggest all weather variables but not the SOI were associated with dengue in both Cairns and Townsville, without a lag (p<0.01). No significant lag was seen with the weather variables. Rainfall and temperature preceding the 2008-2009 outbreak were also not significantly different (p<0.01) from other years. Short-term (non-lagged) weather variables were associated with the number of dengue cases in Cairns and Townsville. No lag was seen and no association was seen between the SOI and the number of dengue cases, which suggests there may be limited potential to predict large dengue outbreaks using climate variability. The large outbreak in 2008-2009 may have been driven by other, non-weather factors in addition to the immediate weather effect. PMID- 24050095 TI - Mortality from septic shock in a dengue infected patient: a case report. AB - Dengue infection can be associated with secondary infections which may be challenging to recognize due to the overlap with the symptoms of dengue infection. We report here the case of a 48 year old Chinese female with dengue fever with a fatal secondary bacterial infection due to Enterococcus faecium. PMID- 24050096 TI - Effects of an influenza prevention program using non-pharmaceutical prevention measures to improve the knowledge, attitudes and practices of elementary school students in Nakhon Phanom province, Thailand. AB - We evaluated an influenza prevention educational program using educational media, e-books and cartoons conducted among students in grades 4 through 6. The course was 8 hours long. The study was conducted at 4 schools; 230 students at each school were in the experimental group and 224 students at each school were in the control group (no educational intervention). The data were analyzed using the Wilcoxon matched-pair signed-rank test. The students in the experimental group had significantly greater knowledge (p<0.001), attitudes (p<0.001) and practices (p<0.001) scores after the intervention. However, the control group also had significantly greater knowledge (p<0.001) and attitudes (p<0.001) scores but not practices scores (p = 0.326). Further studies are needed to determine the factors that influenced these differences. PMID- 24050097 TI - Human cytomegalovirus gB1 genotypes among children who live at the Phayathai Babies' home in Nonthaburi, Thailand. AB - We conducted a survey of human cytomegalovirus (HCMV) genotypes among 176 children aged 1 month to 5 years living at Phayathai Babies' Home in Nonthaburi Province, Thailand to determine the prevalence of HCMV glycoprotein B (gB) genotype. The study was conducted on urine samples using nested polymerase chain reaction and restriction fragment length polymorphism; the HCMV gB1 genotype was found in 89% of subjects, much higher than previous reports. Our results show a high proportion of HCMV gB1 infected children in this population. PMID- 24050098 TI - Mortality among HIV/AIDS patients coinfected with Mycobacterium tuberculosis in southern Thailand. AB - The purpose of this study was to investigate the mortality rate among HIV/AIDS patients coinfected with Mycobacterium tuberculosis in southern Thailand. A prospective, hospital-based cohort study was conducted among 52,459 HIV/AIDS patients registered at hospitals in 14 provinces of southern Thailand between January 1990 and April 2010. Twenty-seven point nine percent of the subjects were coinfected with Mycobacterium tuberculosis. Coinfection with Mycobacterium tuberculosis was not significantly associated with an increased mortality among subjects (HR 1.01; 95%CI 0.96-1.05). Subjects with pulmonary tuberculosis infection were 19% more likely to have a longer life (HR 0.81, 95%CI 0.73-0.91) and subjects with extrapulmonary tuberculosis were 31% more likely to have a longer life (HR 0.69; 95%CI 0.57-0.83). Early treatment of tuberculosis in HIV/AIDS patients can decrease mortality rates in southern Thailand. PMID- 24050099 TI - Ecthyma gangrenosum-like lesions associated with disseminated nontuberculous mycobacterial infection in an HIV-infected patient. AB - Ecthyma gangrenosum typically occurs in patients who are immunocompromised. It is most often associated with a Pseudomonas aeruginosa bacteremia but other pathogens can be found. We report an HIV-infected patient with disseminated nontuberculous mycobacterial infection who presented with fever, mucous bloody diarrhea and cutaneous lesions on both legs. The cutaneous lesions had ecthyma gangrenosum feature and the histopathology was compatible with erythema induratum. Hemoculture was positive for nonchromogen slowly growing mycobacteria. PMID- 24050100 TI - Adenosine deaminase activity level as a tool for diagnosing tuberculous pleural effusion. AB - The yield for using a pleural fluid culture to diagnose tuberculous pleural effusion (TPE) is low. Adenosine deaminase activity (ADA) has been shown to have good diagnostic value for TPE. The ADA cutoff point for the diagnosis of TPE is unclear. We attempted to determine the ADA level cutoff point for diagnosing of TPE in Thailand, where tuberculosis is endemic. We reviewed the medical records of patients with newly diagnosed pleural effusion aged >15 years who had a pleural fluid ADAlevel and who underwent a pleural biopsy. The study period was from March 1, 2010 to January 31, 2011. The diagnoses of TPE and malignant pleural effusion (MPE) were based on pathological findings. The diagnostic cutoff level for using ADA to diagnose TPE was determined. Forty-eight patients met study criteria. Of those, 18 patients (37.5%) were diagnosed with TPE. The mean ADA level was significantly higher among patients in the TPE group than in the MPE group (38.2 vs 14.8 U/l, p < 0.001). The cutoff level of 17.5 U/l gave sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 88.9%, 73.3%, 3.33, and 0.15, respectively. An ADA level >17.5 U/l had good diagnostic values among TPE patients in our study. PMID- 24050101 TI - Multiplex PCR for detection of superantigenic toxin genes in methicillin sensitive and methicillin-resistant Staphylococcus aureus isolated from patients and carriers of a hospital in northeast Thailand. AB - The aims of this study were to develop multiplex PCR for simultaneous detection of five superantigenic toxin genes (sea, seb, sec, sed and tst-1) in Staphylococcus aureus isolated from 149 clinical samples and nasal swabs from 201 healthy subjects in Thailand, and to compare prevalence and expression of those genes between methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA). The sensitivity of multiplex PCR was 10(3) CFU/ml (60 CFU/PCR reaction) for DNA templates extracted by both boiling and extraction methods. S. aureus strains from patients (65%) harbored more superantigenic toxin genes than healthy subjects (54%). MRSA (80%) isolated from patients harbored more superantigenic toxin genes than MSSA (52%). Sea was the most frequently found gene in S. aureus strains from patients and carriers. MRSAisolates harbored sea and produced SEA more frequently than MSSA isolates (p <0.05) and MRSA isolates (59%) from blood samples consisted of a higher number of superantigenic toxin producers than MSSA (9%) (p < 0.05). More S. aureus strains isolated from patients with severe septicemia contained superantigenic toxin genes (94%) and produced toxins (82%) than those from non-severe patients (64% and 57%, respectively). The multiplex PCR method described here offers a reliable tool for simultaneous detection of various staphylococcal toxin genes. PMID- 24050102 TI - A peptide ELISA to detect antibodies against Pythium insidiosum based on predicted antigenic determinants of exo-1,3-beta-glucanase. AB - Human pythiosis is a life-threatening infectious disease caused by the oomycete Pythium insidiosum. Diagnosis of pythiosis relies on culture identification, serodiagnosis, and molecular-based assay. Preparation of a serodiagnostic test requires culture filtrate antigen (CFA) extracted from the live pathogen. A 74 kDa immunoreactive protein of P. insidiosum, is encoded by the exo-1,3-beta glucanase gene (PinsEXO1). PinsEXO1 protein is recognized by sera from pythiosis patients but not by sera from uninfected patients; therefore, this protein could be used to detect anti-P. insidiosum antibodies. In this study we aimed to: identify, synthesize, and evaluate an antigenic determinant (epitope) of PinsEXO1 to be used to serodiagnose pythiosis based on peptide ELISA, and to compare the diagnostic performance of that test with the current CFA-based ELISA. Two antigenic determinants of PinsEXO1 (Peptide-A and -B) were predicted using the PREDITOP program. The sera from 34 pythiosis patients and 92 control subjects were evaluated. Peptide-A, Peptide-B, and CFA-based ELISAs all had a specificity of 100%. Peptide-B ELISA had a sensitivity of 91% and an accuracy of 98% and both Peptide-A and CFA-based ELISAs had a sensitivity of 100% and an accuracy of 100%. Peptide-A is a more efficient epitope than Peptide-B, and can be used as an alternative antigen to develop a serodiagnostic assay for pythiosis. PMID- 24050103 TI - Fungal appendicitis: a case series and review of the literature. AB - Appendicitis is a condition characterized by inflammation of the vermiform appendix, which is commonly caused by bacterial infections and rarely caused by fungal organisms. In the present study, we reviewed the prevalence, clinicopathological features, and therapeutic management of fungal appendicitis. During July 2010 to June 2011, the pathology of 262 resected vermiform appendices was reviewed. Fungal appendicitis occurred in 1.15%, including two cases of Candida spp and one case of Aspergillus spp infection. All patients were immunocompromised and presented with the classical signs and symptoms of appendicitis with the onset of illness less than two days. They were considered for acute appendicitis and underwent appendectomy. The histopathology of the resected vermiform appendix showed fungal organisms with suppurative inflammation and secondary periappendiceal peritonitis. The curative treatment was presented in 1-out-of-3 cases. One patient was alive during a follow-up of eight months. Two patients died, and an autopsy was performed in one case. Although fungal appendicitis was uncommon, the disease might occur among immunosuppressed patients who have developed classical signs and symptoms of appendicitis. Early diagnosis and prompt surgery with medical treatment are associated with a survival advantage. PMID- 24050104 TI - Sexual behavior of foreign backpackers in the Khao San Road area, Bangkok. AB - Travelers play a role in the spread of sexually transmitted diseases, including HIV because of having unprotected sex. We studied the incidence of casual sex among foreign backpack tourists in the Khao San Road area of Bangkok, Thailand. We also evaluated their attitudes about sexual health and their actual practices. A cross sectional study was conducted using a self-administered, anonymous questionnaire. The target population was backpackers aged > or =18 years, from Europe, North America and Australia. In total, 415 questionnaires were filled out and analyzed. Sixty-four percent of participants were male, the overall median age was 27 years and the mean duration of stay was 14.6 days. One hundred seven respondents (25%) had casual sex while staying in Thailand; of these, 55% always used condoms. The selection of sex partner influenced the use of condoms. The highest rate of condom use was among backpackers who had sex with sex workers (63%), while those who had sex with their travel partners had the lowest rate of condom use (35.6%). One-fourth of backpackers in our study had casual sex during their trip. Their attitudes towards safe sex practices were not ideal. Methods to change attitudes and behavior about unprotected sex need to be explored in this population. PMID- 24050105 TI - Growth retardation due to panhypopituitarism and central diabetes insipidus following Russell's viper bite. AB - Russell's viper envenomation and its related complications, especially acute kidney injury, is an important cause of morbidity and mortality in tropical developing countries of South Asia. Unusual complications, especially hypopituitarism, are rare and probably missed due to lack of clinical suspicion and diagnostic facilities. We report a rare presentation of growth retardation resulting from hypopituitarism due to Russell's viper envenomation along with central diabetes insipidus. Awareness of the fact that hypopituitarism may occur in this clinical setting is necessary for early diagnosis and treatment, especially among general care practitioners taking care of these patients. PMID- 24050106 TI - Radial artery injury by a cat fish (Pangasius sutchi) spine sting. AB - Peripheral vascular injuries result from penetrating or blunt trauma to the extremities. We describe here an unusual cause of a radial artery injury by the spine from the pectoral fin of Pangasius sutchi in a 51 year-old man and we review the literature. PMID- 24050107 TI - Comparison of hematocrit/hemoglobin ratios in subjects with alpha-thalassemia, with subjects having chronic kidney disease and normal subjects. AB - The ratio of hematocrit (Hct) to hemoglobin (Hb) in the people with normal red blood cell (RBC) morphology is generally three to one. We studied Hct/Hb ratios among patients with alpha-thalassemias (Hb H, H-CS, AEBart, AEBart-CS, EFBart and EFBart-CS diseases) diagnosed by high performance liquid chromatography, and compared them with normal subjects and with patients having anemia due to chronic kidney disease (CKD). The Hct and Hb levels were derived by automated analyzer. The means +/- SD of the Hct/Hb ratios were 3.5 +/- 0.2 (range 3.3 - 4.1), 3.0 +/- 0.1 (range 2.9 - 3.2) and 3.0 +/- 0.1 (range 2.8 - 3.2) in the alpha-thalassemia, normal and CKD groups, respectively. The mean Hct/Hb ratio in subjects with alpha thalassemia was higher than the mean in normal subjects and in those with CKD. The Hct/Hb ratios for each genotype of the alpha-thalassemia were not different from each other. The underlying mechanisms for the higher Hct/Hb ratio among those with alpha-thalassemia are theorized to be less density and/or more hydration of a-thalassemia RBCs, more entrapment of plasma in the spun RBC, the high percent of nucleated RBC and WBC interference. A ratio of 3.5 +/- 0.2 may be helpful in cases of moderate anemia when typing only shows Hb A and E, to consider investigation for alpha-thalassemia, or in cases of alpha-thalassemia with acute blood loss, if the Hct is less than 35%, in the decision to transfuse. PMID- 24050108 TI - The relationship between smoking and exercise among physical education teachers in Turkey. AB - We studied the relationship between smoking and exercise among physical education teachers in Turkey. An online questionnaire was used to collect data. The responses of 1,995 teachers who completed the questionnaire were evaluated. The mean age of the participants was 31.0 +/- 4.7 years; 67.4% of the participants were male. The smoking rate was 65.2%. The mean age of onset of smoking was 16.6 +/- 2.6 years. The age of starting smoking increased with higher parental education level. There were no differences between smokers and nonsmokers with respect to gender. Of smokers, 51.2% were married; 52.4% were in the 30-39 year old age group. The most common reasons for starting smoking were the influence of friends and emulation. The most common reason for trying to quit smoking among men was future health concerns and among women was current health concerns. We found smoking was less common among participants who exercised regularly. The level of nicotine dependence was significantly lower among participants who exercised regularly compared to those who did not. This study suggests physical education teachers, who are role models for their students, have a high smoking rate. We believe urgent action is needed to reduce the smoking rate and increase the quit rate among physical education teachers. PMID- 24050109 TI - Effects of school, family and alcohol marketing communication on alcohol use and intentions to drink among Thai students. AB - This study explored effects of family, school, and marketing communications on alcohol use and intention to drink of Thai students. We conducted a survey in which 5,184 students participated. Respondents were selected randomly from school districts throughout Thailand. In this survey we measured the exposure to, reception of, and perceptions concerning alcohol marketing communication, school absenteeism and achievement, family alcohol use, students' alcohol use, and drinking intentions. Findings indicated students' low alcohol use, moderate intention to drink, and high prevalence of family drinking. The levels of exposure and also the information receptivity to alcohol media marketing of Thai students were low. The respondents had a high level of media literacy on alcohol marketing communication. Multiple regression and focus group discussions provided support for the contention that there were significant effects of school achievement, absenteeism and media marketing communication on alcohol use (R2 = 14%) and intention to drink (R2 = 11%). Therefore, consideration of relevant school and alcohol policies, including monitoring of media marketing communication, will be needed. PMID- 24050110 TI - Electro-thermal vaporization direct analysis in real time-mass spectrometry for water contaminant analysis during space missions. AB - The development of a direct analysis in real time-mass spectrometry (DART-MS) method and first prototype vaporizer for the detection of low molecular weight (~30-100 Da) contaminants representative of those detected in water samples from the International Space Station is reported. A temperature-programmable, electro thermal vaporizer (ETV) was designed, constructed, and evaluated as a sampling interface for DART-MS. The ETV facilitates analysis of water samples with minimum user intervention while maximizing analytical sensitivity and sample throughput. The integrated DART-ETV-MS methodology was evaluated in both positive and negative ion modes to (1) determine experimental conditions suitable for coupling DART with ETV as a sample inlet and ionization platform for time-of-flight MS, (2) to identify analyte response ions, (3) to determine the detection limit and dynamic range for target analyte measurement, and (4) to determine the reproducibility of measurements made with the method when using manual sample introduction into the vaporizer. Nitrogen was used as the DART working gas, and the target analytes chosen for the study were ethyl acetate, acetone, acetaldehyde, ethanol, ethylene glycol, dimethylsilanediol, formaldehyde, isopropanol, methanol, methylethyl ketone, methylsulfone, propylene glycol, and trimethylsilanol. PMID- 24050111 TI - Copper-promoted cyanation of a boron cluster: synthesis, X-ray structure, and reactivity of 12-CN-closo-CHB11H10-. AB - Microwave-assisted cross-coupling reactions of boron-iodinated derivatives of 1 carba-closo-dodecaborate(1-) (1) with CuCN is shown to cyanate boron vertices of this anion. Clusters with one or two CN groups can be prepared: syntheses of 12 CN-CHB11H10(-) (3) and 7,12-(CN)2-CHB11H9(-) (6) gave yields of 80% and 81%, respectively. The [Et4N](+) salts of 3 and 6 were characterized by NMR, IR, and mass spectroscopies, and the crystal structure of [Et4N]3 was determined by single-crystal X-ray diffraction. Hydrolysis of 3 gave the carboxylic acid 12 COOH-CHB11H10(-) (7). PMID- 24050112 TI - New serotonin 5-HT1A receptor agonists endowed with antinociceptive activity in vivo. AB - We report the synthesis of new compounds 4-35 based on two different openings (A and B) of the chromane ring present in the previously identified 5-HT1A receptor (5-HT1AR) ligand 3. The synthesized compounds were assessed for binding affinity, selectivity, and functional activity at the 5-HT1AR. Selected candidates resulting from B opening were also evaluated for their potential antinociceptive effect in vivo and pharmacokinetic properties in vitro. Analogue 19 [2-(4-{[2-(2 ethoxyphenoxy)ethyl]amino}butyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H) dione] has been characterized as a high-affinity and potent 5-HT1AR agonist (Ki = 2.3 nM; EC50 = 19 nM). Pharmacokinetic studies indicated that compound 19 displays a good metabolic stability in human liver microsomes (t1/2 ~ 3 h and CLint = 3.5 mL/min/kg, at 5 MUM), and a low level of protein binding (25%, at 5 MUM). Interestingly, 19 (3 mg/kg, ip, and 30 mg/kg, po) caused significant attenuation of formalin-induced behavior in early and late phases of the mouse intradermal formalin test of pain, and this in vivo effect was reversed by the selective 5-HT1AR antagonist WAY-100635. Thus, the new 5-HT1AR agonist identified in this work, 19, exhibits oral analgesic activity, and the results herein represent a step toward identifying new therapeutics for the control of pain. PMID- 24050113 TI - Vibrio cholerae O1 El Tor and O139 Bengal strains carrying ctxB(ET), Bangladesh. PMID- 24050115 TI - Notch signaling induces retinal stem-like properties in perinatal neural retina progenitors and promotes symmetric divisions in adult retinal stem cells. AB - Understanding the mechanisms regulating retinal stem cell (RSC) activity is fundamental for future stem cell-based therapeutic purposes. By combining gain and loss of function approaches, we addressed whether Notch signaling may play a selective role in retinal stem versus retinal progenitor cells in both developing and adult eyes. Inhibition of either Notch or fibroblast growth factor signaling reduced proliferation of retinal stem and retinal progenitor cells, and inhibited RSC self-renewal. Conversely, exogenous Delta-like 3 and direct intrinsic Notch activation stimulated expansionary symmetric divisions in adult RSCs with the concomitant upregulation of Hes5. Knocking down Hes5 expression specifically decreased the numbers, but not the diameters, of adult RSC primary spheres, indicating that HES5 is the downstream effector of Notch receptor in controlling adult RSC proliferation. In addition, constitutive Notch activation induced retinal stem-like asymmetric self-renewal properties, with no expansion (no symmetrical division) in perinatal neural retina progenitor cells. These findings highlight central roles of Notch signaling activity in regulating the modes of division of retinal stem and retinal progenitor cells. PMID- 24050114 TI - Metagenomics for pathogen detection in public health. AB - Traditional pathogen detection methods in public health infectious disease surveillance rely upon the identification of agents that are already known to be associated with a particular clinical syndrome. The emerging field of metagenomics has the potential to revolutionize pathogen detection in public health laboratories by allowing the simultaneous detection of all microorganisms in a clinical sample, without a priori knowledge of their identities, through the use of next-generation DNA sequencing. A single metagenomics analysis has the potential to detect rare and novel pathogens, and to uncover the role of dysbiotic microbiomes in infectious and chronic human disease. Making use of advances in sequencing platforms and bioinformatics tools, recent studies have shown that metagenomics can even determine the whole-genome sequences of pathogens, allowing inferences about antibiotic resistance, virulence, evolution and transmission to be made. We are entering an era in which more novel infectious diseases will be identified through metagenomics-based methods than through traditional laboratory methods. The impetus is now on public health laboratories to integrate metagenomics techniques into their diagnostic arsenals. PMID- 24050116 TI - The brain networks encoding visceral sensation in patients with gastrointestinal symptoms due to diabetic neuropathy. AB - BACKGROUND: Increasing evidence points to association between long-term diabetes mellitus and abnormal brain processing. The aim of this study was to investigate central changes due to electrical stimulation in esophagus in patients with upper gastrointestinal (GI) symptoms due to diabetic neuropathy. METHODS: Twenty-three diabetes patients with upper GI symptoms and 27 healthy controls were included. A standard ambulatory 24-h electrocardiography was carried out. 122-channel esophageal evoked brain potentials to electrical stimulation were acquired. Brain source/network analysis was performed. Gastroparesis Cardinal Symptom Index was used to evaluate upper GI symptoms and SF-36 questionnaire was utilized to assess patients' quality of life (QOL). KEY RESULTS: Diabetes patients with GI symptoms showed modifications in three brain networks: (i) brainstem/operculum/frontal cortex, (ii) operculum/cingulate, and (iii) mid-cingulate/anterior cingulate/operculum/deep limbic structures. Operculum brain source in patients was localized deeper and more anterior in all three networks. The shift of operculum source was correlated with the severity of upper GI symptoms, decreased heart beat-to-beat interval, and decreased SD of the intervals. The activation of the first network was delayed in patients. Operculum source had higher activity than cingulate in the second network in patients, and this was correlated with decreased physical QOL. Deep limbic source was localized deeper in patients, which also correlated with decreased physical QOL. CONCLUSIONS & INFERENCES: This study indicates involvement of central nervous system in diabetes. Reorganization within opercular cortex was correlated with GI symptoms suggesting that operculo cingulate cortex could contribute to development and maintenance of GI symptoms in diabetes patients. PMID- 24050117 TI - Anilinomethylrhodamines: pH sensitive probes with tunable photophysical properties by substituent effect. AB - A series of pH dependent rhodamine analogues possessing an anilino-methyl moiety was developed and shown to exhibit a unique photophysical response to pH. These anilinomethylrhodamines (AnMR) maintain a colorless, nonfluorescent spirocyclic structure at high pH. The spirocyclic structures open in mildly acidic conditions and are weakly fluorescent; however, at very low pH, the fluorescence is greatly enhanced. The equilibrium constants of these processes show a linear response to substituent effects, which was demonstrated by the Hammett equation. PMID- 24050118 TI - Cage size effects on the rotation of molecular gyrotops with 1,4-naphthalenediyl rotor in solution. AB - 1,4-Naphthalenediyl-bridged macrocages (2, 3, and 4) were synthesized as novel molecular gyrotops. Compound 2 (C14 chains) does not show rotation of the naphthalene ring about an axis in solution. The 1,4-naphthalenediyl moieties of compounds 3 (C16 chains) and 4 (C18 chains) show restricted and rapid rotation inside the cage in solution, respectively. Therefore, steric protective effects on the rotation of the rotor in molecular gyrotops can be controlled by changing the size of the cage. PMID- 24050119 TI - Postpartum breast abscess caused by community-acquired methicillin-resistant Staphylococcus aureus in Japan. PMID- 24050120 TI - Factors associated with maternal infant feeding attitudes in Mumbai, India. PMID- 24050122 TI - Psychomotor and cognitive deficits as predictors of 5-year outcome in first episode schizophrenia. AB - BACKGROUND: Cognitive deficits are common in schizophrenia but the predictive value of these deficits for long-term outcome in first-episode patients is unclear. AIMS: We aimed to investigate associations of performance in psychomotor and cognitive tests with a 5-year functional and symptomatic outcome. METHODS: After clinical stabilization, patients with a first schizophrenia spectrum diagnosis (n = 46) were assessed for global cognitive function [Synonyms, Reasoning, and Block Design (SRB)], psychomotor speed [Trail Making Test (TMT) and finger tapping] and verbal learning (Claeson-Dahl Verbal Learning Test). The subsequent 5-year outcome regarding independent living, occupational and social function, and symptomatic remission status was assessed. RESULTS: Low psychomotor speed was associated with poor social function 5 years later, with an odds ratio (OR) of 3.37 and a 95% confidence interval (CI) of 1.08-10.51, adjusted for antipsychotic drug use. Better performance on finger tapping with the non dominant hand was associated with an increased risk of a 5-year symptomatic non remission (adjusted OR = 0.42, CI 0.19-0.96). Occupational function and independent living were not significantly associated with any of the investigated tests. CONCLUSIONS: Psychomotor speed is associated with a long-term outcome regarding social function and symptom remission in patients with first-episode schizophrenia. PMID- 24050121 TI - Oestrogen levels in serum and urine of premenopausal women eating low and high amounts of meat. AB - OBJECTIVE: Based on the hypothesis that high-meat diets may increase breast cancer risk through hormonal pathways, the present analysis compared oestrogens in serum and urine by meat-eating status. DESIGN: Intervention with repeated measures. SETTING: Two randomized soya trials (BEAN1 and BEAN2) among premenopausal healthy women. SUBJECTS: BEAN1 participants completed seven unannounced 24 h dietary recalls and donated five blood and urine samples over 2 years. BEAN2 women provided seven recalls and three samples over 13 months. Serum samples were analysed for oestrone (E1) and oestradiol (E2) using RIA. Nine oestrogen metabolites were measured in urine by LC-MS. Semi-vegetarians included women who reported consuming <30 g of red meat, poultry and fish daily, and pescatarians those who reported consuming <20 g of meat/poultry but >10 g of fish daily. All other women were classified as non-vegetarians. We applied mixed models to compute least-square means by vegetarian status adjusted for potential confounders. RESULTS: The mean age of the 272 participants was 41.9 (SD 4.5) years. Serum E1 (85 v. 100 pg/ml, P = 0.04) and E2 (140 v. 154 pg/ml, P = 0.04) levels were lower in the thirty-seven semi-vegetarians than in the 235 non vegetarians. The sum of the nine urinary oestrogen metabolites (183 v. 200 pmol/mg creatinine, P = 0.27) and the proportions of individual oestrogens and pathways did not differ by meat-eating status. Restricting the models to the samples collected during the luteal phase strengthened the associations. CONCLUSIONS: Given the limitations of the study, the lower levels of serum oestrogens in semi-vegetarians than non-vegetarians need confirmation in larger populations. PMID- 24050123 TI - Antiangiogenesis therapy in second line metastatic colorectal cancer: similar but different. AB - Recent updates in the second-line treatment of patients with metastatic colorectal cancer (mCRC) have indicated the benefit of adding aflibercept (plus FOLFIRI) after an oxaliplatin-containing regimen (with or without bevacizumab) or a bevacizumab-containing regimen after progression on a different bevacizumab containing regimen. This has led some oncologists to compare the trials and equate the drugs, with the assumption that they confer equal efficacy, but the background of this must be adequately assessed before reaching this conclusion. In fact, the publication of these trial results has left oncologists with much to consider for their mCRC patients who will eventually progress on a first-line chemotherapy/bevacizumab regimen. The author comments on this issue and emphasizes the need for additional research into antiangiogenic biomarkers to identify patients who are likely to respond to one drug more than another. PMID- 24050124 TI - Mass transfer in the dissolution of a multicomponent liquid droplet in an immiscible liquid environment. AB - The Epstein-Plesset equation has recently been shown to predict accurately the dissolution of a pure liquid microdroplet into a second immiscible solvent, such as oil into water. Here, we present a series of new experiments and a modification to this equation to model the dissolution of a two-component oil mixture microdroplet into a second immiscible solvent in which the two materials of the droplet have different solubilities. The model is based on a reduced surface area approximation and the assumption of ideal homogeneous mixing [mass flux d(m(i))/dt = A(frac(i))D(i)(c(i) - c(s)){(1/R) + (1/(piD(i)t)(1/2)}] where A(frac(i)) is the area fraction of component i, c(i) and c(s) are the initial and saturation concentrations of the droplet material in the surrounding medium, R is the radius of the droplet, t is time, and D(i) is the coefficient of diffusion of component i in the surrounding medium. This new model has been tested by the use of a two-chamber micropipet-based method, which measured the dissolution of single individual microdroplets of mutually miscible liquid mixtures (ethyl acetate/butyl acetate and butyl acetate/amyl acetate) in water. We additionally measured the diffusion coefficient of the pure materials-ethyl acetate, butyl acetate, and amyl acetate-in water at 22 degrees C. Diffusion coefficients for the pure acetates in water were 8.65 * 10(-6), 7.61 * 10(-6), and 9.14 * 10(-6) cm(2)/s, respectively. This model accurately predicts the dissolution of microdroplets for the ethyl acetate/butyl acetate and butyl acetate/amyl acetate systems given the solubility and diffusion coefficients of each of the individual components in water as well as the initial droplet radius. The average mean squared error was 8.96%. The dissolution of a spherical ideally mixed multicomponent droplet closely follows the modified Epstein-Plesset model presented here. PMID- 24050125 TI - Practical skills examiner training programme: a novel approach to recruiting assessors. PMID- 24050126 TI - Hypoxia induces abnormal larval development and affects biofilm-larval interaction in the serpulid polychaete Hydroides elegans. AB - Hydroides elegans, a worldwide fouling polychaete, can spawn throughout the year, but its recruitment drops during summer when hypoxia prevails. Here, the influence of hypoxia on larval development and settlement of H. elegans was investigated. Results showed that larval development was compromised at 1mg O2 l( 1) with a lower proportion of competent larvae and a higher proportion of malformed larvae, probably due to reduction in clearance rate. Regarding larval settlement, although most of the larvae were reluctant to settle at 1mg O2 l(-1), regardless of the biofilm nature, they settled quickly within 24h in response to the resumption of dissolved oxygen. Furthermore, only about 5% of the larvae settled on the biofilms developed under hypoxia, regardless of dissolved oxygen levels of the seawater. The delayed larval development and potential alteration of biofilm nature owing to hypoxia explained why the recruitment of H. elegans declines during summer. PMID- 24050127 TI - Culturable populations of Acinetobacter can promptly respond to contamination by alkanes in mangrove sediments. AB - This study evaluated the potential of bacterial isolates from mangrove sediments to degrade hexadecane, an paraffin hydrocarbon that is a large constituent of diesel and automobile lubricants. From a total of 18 oil-degrading isolates obtained by an enrichment technique, four isolates showed a great potential to degrade hexadecane. The strain MSIC01, which was identified by 16S rRNA gene sequencing as Acinetobacter sp., showed the best performance in degrading this hydrocarbon, being capable of completely degrading 1% (v/v) hexadecane within 48 h without releasing biosurfactants. Its hydrophobic surface probably justifies its potential to degrade high concentrations of hexadecane. Thus, the sediments from the studied mangrove harbour bacterial communities that are able to use oil as a carbon source, which is a particularly interesting feature due to the risk of oil spills in coastal areas. Moreover, Acinetobacter sp. MSIC01 emerged as a promising candidate for applications in bioremediation of contaminated mangrove sediments. PMID- 24050128 TI - Indicators of microbial beach water quality: preliminary findings from Teluk Kemang beach, Port Dickson (Malaysia). AB - This study aims to determine the concentrations of total coliforms and Escherichia coli (E. coli) in beach water, Teluk Kemang beach. This study was also aimed to determine relationship between total coliforms, E. coli and physicochemical parameters. As perceived health symptoms among beach visitors are rarely incorporated in beach water studies, this element was also assessed in this study. A total of eight water sampling points were selected randomly along Teluk Kemang beach. Total coliforms concentrations were found between 20 and 1940 cfu/100ml. E. coli concentrations were between 0 and 90 cfu/100ml. Significant correlations were found between total coliforms and E. coli with pH, temperature and oxidation reduction potential. Skin and eyes symptoms were the highest reported though in small numbers. Microbiological water quality in Teluk Kemang public beach was generally safe for recreational activities except sampling location near with sewage outfall. PMID- 24050129 TI - Animal models of Alzheimer's disease and drug development. AB - Animal disease models are considered important in the development of drugs for Alzheimer's disease. This brief review will discuss possible reasons why their success in identifying efficacious treatments has been limited, and will provide some thoughts on the role of animal experimentation in drug development. Specifically, none of the current models of Alzheimer's disease have either construct or predictive validity, and no model probably ever will. Clearly, specific animal experiments contribute to our understanding of the disease and generate hypotheses. Ultimately, however, the hypothesis can only be tested in human patients and only with the proper tools. These tools are a pharmacologically active intervention (in humans) and a clinical trial suited to evaluate the mechanism of action. Integration of knowledge in quantitative (sub) models is considered important if not essential in this process. PMID- 24050130 TI - Technologies: preclinical imaging for drug development. AB - Preclinical imaging with magnetic resonance imaging (MRI), computerised tomography (CT), ultrasound (US), positron emission tomography (PET) or single photon emission computed tomography (SPECT) enable non-invasive measures of tissue structure, function or metabolism in vivo. The technologies can add value to preclinical studies by enabling dynamic pharmacological observations on the same animal and because of possibilities for relatively direct clinical translation. Potential benefits from the application of preclinical imaging should be considered routinely in drug development. PMID- 24050131 TI - Humanised models of infection in the evaluation of anti-malarial drugs. AB - Humanised mice have a crucial role for drug discovery in malaria, which is the most important parasitic disease in the world and is caused by protozoa of the genus Plasmodium that selectively infect human hepatocytes and erythrocytes. There are currently reliable humanised murine models for hepatic and erythrocytic stages of Plasmodium falciparum, which is the most pathogenic malarial species. These models are useful in the evaluation of drugs for malaria prevention and treatment, notably in exploiting the thousands of antimalarial hits discovered. The development of a humanised model for Plasmodium vivax and the validation of the P. falciparum models to inform optimal clinical studies are the next key goals to be achieved. PMID- 24050132 TI - Bridging the gap in the fight against tuberculosis. AB - Identifying the most effective new drugs for tuberculosis will depend on developing systems for preclinical testing that better reflect conditions in the diseased host and the characteristics of persistent M tuberculosis. Integrating information from these diverse new technologies using a model-based approach to antituberculosis drug development could facilitate more effective use of this information in transitioning novel compounds successfully to the clinical phase. PMID- 24050133 TI - Modeling of human tumor xenografts and dose rationale in oncology. AB - Xenograft models are commonly used in oncology drug development. Although there are discussions about their ability to generate meaningful data for the translation from animal to humans, it appears that better data quality and better design of the preclinical experiments, together with appropriate data analysis approaches could make these data more informative for clinical development. An approach based on mathematical modeling is necessary to derive experiment independent parameters which can be linked with clinically relevant endpoints. Moreover, the inclusion of biomarkers as predictors of efficacy is a key step towards a more general mechanism-based strategy. PMID- 24050134 TI - Establishing in vitro to clinical correlations in the evaluation of cardiovascular safety pharmacology. AB - Preclinical studies are vital in establishing the efficacy and safety of a new chemical entity (NCE) in humans. To deliver meaningful information, experiments have to be well defined and provide outcome that is relevant and translatable to humans. This review briefly surveys the various preclinical experiments that are frequently conducted to assess drug effects on cardiac conductivity in early drug development. We examine the different approaches used to establish correlations between non-clinical and clinical settings and discuss their value in the evaluation of cardiovascular risk. PMID- 24050135 TI - Very large virtual compound spaces: construction, storage and utility in drug discovery. AB - Recent activities in the construction, storage and exploration of very large virtual compound spaces are reviewed by this report. As expected, the systematic exploration of compound spaces at the highest resolution (individual atoms and bonds) is intrinsically intractable. By contrast, by staying within a finite number of reactions and a finite number of reactants or fragments, several virtual compound spaces have been constructed in a combinatorial fashion with sizes ranging from 10(11)11 to 10(20)20 compounds. Multiple search methods have been developed to perform searches (e.g. similarity, exact and substructure) into those compound spaces without the need for full enumeration. The up-front investment spent on synthetic feasibility during the construction of some of those virtual compound spaces enables a wider adoption by medicinal chemists to design and synthesize important compounds for drug discovery. Recent activities in the area of exploring virtual compound spaces via the evolutionary approach based on Genetic Algorithm also suggests a positive shift of focus from method development to workflow, integration and ease of use, all of which are required for this approach to be widely adopted by medicinal chemists. PMID- 24050136 TI - Combination of ligand- and structure-based methods in virtual screening. AB - The combination of ligand- and structure-based molecular modelling methods has become a common approach in virtual screening. This review describes different strategies for integration of ligand- and structure-based methods which can be divided into sequential, parallel or hybrid approaches. Although no thorough performance comparisons between combined approaches are available, examples of successful applications in prospective and retrospective virtual screening are discussed. Most published studies use a sequential approach, utilising well documented single methods successfully. PMID- 24050137 TI - Proteome-scale docking: myth and reality. AB - Docking is the computational method of choice to quickly predict how a low molecular-weight ligand binds to its macromolecular target. Despite persistent problems in predicting binding free energies, docking has undergone significant advances in numerous topics (throughput, target flexibility). The ever increasing availability of high-resolution X-ray structures and the development of more reliable comparative models for proteins of pharmacological interest paved the way to apply protein-ligand docking to multiple targets to predict main and off targets for bioactive compounds and even to repurpose existing drugs. Applying docking to multiple targets brings an additional level of complexity in scoring numerous and heterogeneous docking poses. Despite undeniable successes, proteomewide docking should, however, be considered with caution with regard to recall and precision of the predictions. PMID- 24050138 TI - Induced fit docking, and the use of QM/MM methods in docking. AB - Docking methods are popular computational techniques in drug discovery to identify new active molecules that bind to a given biological target. Although widely used, the predictive reliability of docking methods is often limited by the inability to accurately and efficiently model protein flexibility and quantify binding strength. We highlight several emerging concepts that address those methodological issues including a discussion on the incorporation of QM/MM methodologies in the scoring process. PMID- 24050139 TI - Large-scale SAR analysis. AB - The analysis of structure-activity relationships (SARs) is a central task in medicinal chemistry. Traditionally, SAR exploration has concentrated on individual compound series. This conventional approach is complemented by large scale SAR analysis, which puts strong emphasis on data mining and SAR visualization. This contribution reviews recent concepts for large-scale SAR analysis including numerical functions to characterize global and local SAR information content of compound data sets, alternative activity landscape representations and data mining strategies. PMID- 24050140 TI - Multi-objective optimization methods in drug design. AB - Drug discovery is a challenging multi-objective problem where numerous pharmaceutically important objectives need to be adequately satisfied for a solution to be found. The problem is characterized by vast, complex solution spaces further perplexed by the presence of conflicting objectives. Multi objective optimization methods, designed specifically to address such problems, have been introduced to the drug discovery field over a decade ago and have steadily gained in acceptance ever since. This paper reviews the latest multi objective methods and applications reported in the literature, specifically in quantitative structure-activity modeling, docking, de novo design and library design. Further, the paper reports on related developments in drug discovery research and advances in the multi-objective optimization field. PMID- 24050141 TI - Data-driven computer aided synthesis design. AB - Enabled by an increasing body of electronically available experimental data and by advances in computer hardware and software, new technologies are emerging that are designed to support the creativity of chemists during synthesis planning. Leading this development are innovative synthetic route prediction tools that are designed to suggest new reactions and paths to target molecules as an idea generating engine. Other tools are using known reactions in a combinatorial fashion to suggest new routes that are cost-optimized or satisfy some other global criteria. We review the latest developments and the main tools in this domain. PMID- 24050143 TI - Abstracts of the 5th International Conference on NeuroEndocrine Immunology in Rheumatic Diseases. Santa Margherita Ligure, Genova, Italy. October 1-3, 2013. PMID- 24050142 TI - Ultrasound imaging for the rheumatologist. XLVII. Ultrasound of the shoulder in patients with gout and calcium pyrophosphate deposition disease. AB - OBJECTIVES: This study was aimed at determining the prevalence of ultrasound (US) morpho-structural changes in the shoulders of patients with crystal-related arthropathies, and at investigating the relationship between them and the clinical findings. METHODS: Eighty-eight patients with a crystal proven diagnosis of gout or calcium pyrophosphate dihydrate (CPPD) disease attending the in patient and the out-patient clinics of four Italian Rheumatology Departments were consecutively enrolled in this multi-centre study. All patients were clinically examined by an expert rheumatologist who recorded clinical and laboratory data in addition to the presence/absence of spontaneous shoulder pain and performed the Hawkins, Jobe, Patte, Gerber, and Speed tests. In each centre, US examinations were carried out by a rheumatologist expert in musculoskeletal US blinded to clinical data, using a MyLab TWICE XVG machine (Esaote SpA, Genoa, Italy) equipped with a linear probe operating at 4-13 MHz, and a Logiq 9 machine (General Electrics Medical Systems, Milwaukee, WI, USA) with a linear probe operating at 9-14 MHz. Shoulders were scanned to detect peri-articular inflammation, rotator cuff pathology and joint involvement, and to reveal US signs indicative of crystal deposits. RESULTS: A total of 88 patients, 39 with gout, 46 with CPPD disease, and 3 with both gout and CPPD disease, were enrolled. In total, 176 shoulders were clinically assessed, of which 54/176 (30%) were painful and 74/176 (42%) were clinically normal shoulders. All US findings indicative of peri-articular synovial inflammation were more frequently detected in patients with CPPD disease than in gouty patients. In 50 out of 176 (28.4%) shoulders, US allowed the detection of at least one finding indicative of synovial inflammation. Chronic tendinopathy was a frequent US finding both in gout patients and in patients with CPPD disease and the supraspinatus tendon was the most frequently involved one. In CPPD disease the supraspinatus tendon was found ruptured in a number of shoulders seven times higher than in gouty patients. The osteophytes were found at acromion-clavicular joint in nearly 80% of the shoulders in CPPD disease and in 60% in the gouty patients. CONCLUSIONS: The results of this study confirm the high specificity of US findings indicative of crystal deposits at hyaline cartilage level and indicate that the supraspinatus tendon and the fibrocartilage of the acromion-clavicular joint are the most frequently affected structures of the shoulders in patients with crystal related arthropathies. PMID- 24050144 TI - Novel bat coronaviruses, Brazil and Mexico. PMID- 24050145 TI - The genetic and environmental structure of reproduction-related variables: the case of fertility and breastfeeding. AB - Life history theory studies the evolution of traits related to reproductive fitness. Fertility and parental investment are key life history traits which, from an evolutionary standpoint, appear strongly interrelated. The aim of this work was to analyze the genetic and environmental structure and relationship of two behaviors associated with reproductive fitness: total number of offspring and mean duration of breastfeeding. A total of 1,347 women distributed in 239 monozygotic pairs, 236 dizygotic pairs, and 393 individual twins from opposite sex pairs provided information about their reproductive history. We conducted separate univariate analyses to study the sources of variance of both variables; and a bivariate analysis, with threshold liability models. The sources of variance for number of children and breastfeeding were best explained by a model including familial and unique environmental factors, being E = 0.54 (CI 95%: 0.44, 0.66) and E = 0.46 (CI 95%: 0.34, 0.61), respectively. The phenotypic correlation between number of children and breastfeeding was low but significant (r = 0.16, CI 95%: 0.07, 0.25). Familial correlation between these variables did not reach significance, but unique environmental correlation did (re = 0.20, CI 95%: 0.02, 0.37). In conclusion, results do not support the existence of a clear common structure for the number of children a woman has and the time she spends breastfeeding them, at least in modern societies. The relationship found was mainly due to unique environmental factors. More research on these and related phenotypes is needed to better understand women's reproductive decisions and how natural selection acts on the life history traits. PMID- 24050148 TI - One-step cloning and chromosomal integration of DNA. AB - We describe "clonetegration", a method for integrating DNA into prokaryotic chromosomes that approaches the simplicity of cloning DNA within extrachromosomal vectors. Compared to existing techniques, clonetegration drastically decreases the time and effort needed for integration of single or multiple DNA fragments. Additionally, clonetegration facilitates cloning and expression of genetic elements that are impossible to propagate within typical multicopy plasmids. PMID- 24050149 TI - Pickering emulsions stabilized by soft microgels: influence of the emulsification process on particle interfacial organization and emulsion properties. AB - This work reports a new evidence of the versatility of soft responsive microgels as stabilizers for Pickering emulsions. The organization of microgels at the oil water interface is a function of the preparation pathway. The present results show that emulsification energy can be used as a trigger to modify microgel deformation at the oil-water interface and their packing density: high shear rates bring strong flattening of the microgels, whereas low shear rates lead to dense monolayers, where the microgels are laterally compressed. As a consequence, the resulting emulsions have opposite behavior in terms of flocculation, which arises from bridging between neighboring drops and is strongly dependent on their surface coverage. This strategy can be applied to any microgel which can sufficiently adsorb at low shear rates, i.e. small microgels or lightly cross linked ones. The control of the organization of microgels at the interface does not only modify emulsion end-use properties but also constitutes a new tool for the development of Janus-type microgels, obtained by chemical modification of the adsorbed microgels. PMID- 24050150 TI - A chiral bisthiourea as a chiral solvating agent for carboxylic acids in the presence of DMAP. AB - A simple chiral bisthiourea has been used as a highly effective and practical chemical solvating agent (CSA) for diverse alpha-carboxylic acids in the presence of DMAP. Excellent enantiodiscrimination based on well-resolved alpha-H NMR signals of the enantiomers of carboxylic acids can be obtained without interference from the chiral bisthiourea and DMAP. To check the practicality of the chiral bisthiourea/DMAP for enantiomeric determination, the ee values of mandelic acid (MA) samples over a wide ee range were determined by integration of the alpha-H signal of MA in (1)H NMR. A discrimination mechanism is proposed, that the formation of two diasteromeric ternary complexes between the chiral bisthiourea and two in situ formed enantiomeric carboxylate-DMAPH(+) ion pairs discriminates the enantiomers of carboxylic acids. Computational modeling studies show that the chemical shift value of alpha-H of (S)-MA is greater than that of (R)-MA in ternary complexes, which is consistent with experimental observation. 1D and 2D NOESY spectra demonstrate the intermolecular noncovalent interactions between the protons on the aromatic rings of chiral bisthiourea and alpha-H of the enantiomers of racemic alpha-methoxy phenylacetic acids in the complexes. PMID- 24050151 TI - Photochromic properties of polyoxotungstates with grafted spiropyran molecules. AB - The first systems associating in a single molecule polyoxotungstates (POTs) and photochromic organic groups have been elaborated. Using the (TBA)4[PW11O39{Sn(C6H4I)}] precursor, two hybrid organic-inorganic species where a spiropyran derivative (SP) has been covalently grafted onto a {PW11Sn} fragment via a Sonogashira coupling have been successfully obtained. Alternatively, a complex containing a silicotungstate {PW11Si2} unit connected to two spiropyran entities has been characterized. The purity of these species has been assessed using several techniques, including (1)H and (31)P NMR spectroscopy, mass spectrometry, and electrochemical measurements. The optical properties of the hybrid materials have been investigated both in solution and in the solid state. These studies reveal that the grafting of SPs onto POTs does not significantly alter the photochromic behavior of the organic chromophore in solution. In contrast, these novel hybrid SP-POT materials display highly effective solid state photochromism from neutral SP molecules initially nonphotochromic in the crystalline state. The photoresponses of the SP-POT systems in the solid state strongly depend on the nature and the number of grafted SP groups. PMID- 24050152 TI - Folding dynamics of the Trp-cage miniprotein: evidence for a native-like intermediate from combined time-resolved vibrational spectroscopy and molecular dynamics simulations. AB - Trp-cage is a synthetic 20-residue miniprotein which folds rapidly and spontaneously to a well-defined globular structure more typical of larger proteins. Due to its small size and fast folding, it is an ideal model system for experimental and theoretical investigations of protein folding mechanisms. However, Trp-cage's exact folding mechanism is still a matter of debate. Here we investigate Trp-cage's relaxation dynamics in the amide I' spectral region (1530 1700 cm(-1)) using time-resolved infrared spectroscopy. Residue-specific information was obtained by incorporating an isotopic label ((13)C?(18)O) into the amide carbonyl group of residue Gly11, thereby spectrally isolating an individual 310-helical residue. The folding-unfolding equilibrium is perturbed using a nanosecond temperature-jump (T-jump), and the subsequent re-equilibration is probed by observing the time-dependent vibrational response in the amide I' region. We observe bimodal relaxation kinetics with time constants of 100 +/- 10 and 770 +/- 40 ns at 322 K, suggesting that the folding involves an intermediate state, the character of which can be determined from the time- and frequency resolved data. We find that the relaxation dynamics close to the melting temperature involve fast fluctuations in the polyproline II region, whereas the slower process can be attributed to conformational rearrangements due to the global (un)folding transition of the protein. Combined analysis of our T-jump data and molecular dynamics simulations indicates that the formation of a well defined alpha-helix precedes the rapid formation of the hydrophobic cage structure, implying a native-like folding intermediate, that mainly differs from the folded conformation in the orientation of the C-terminal polyproline II helix relative to the N-terminal part of the backbone. We find that the main free energy barrier is positioned between the folding intermediate and the unfolded state ensemble, and that it involves the formation of the alpha-helix, the 310 helix, and the Asp9-Arg16 salt bridge. Our results suggest that at low temperature (T ? Tm) a folding path via formation of alpha-helical contacts followed by hydrophobic clustering becomes more important. PMID- 24050153 TI - Highly efficient synthesis of (R)-3-quinuclidinol in a space-time yield of 916 g L(-1) d(-1) using a new bacterial reductase ArQR. AB - A new keto reductase (ArQR), identified from Agrobacterium radiobacter ECU2556, can efficiently reduce 3-quinuclidinone in excellent enantioselectivity and high space-time yield for the synthesis of (R)-3-quinuclidinol, a chiral building block of many antimuscarinic agents. This is the first time that a high yield of (R)-3-quinuclidinol up to 916 g L(-1) d(-1) using a bioreduction approach is reported. PMID- 24050154 TI - Mechanism of action of dextromethorphan/quinidine:comparison with ketamine. AB - Reports of rapid-onset but short-duration antidepressant effects in patients with treatment-resistant mood disorders after intravenous administration of ketamine have prompted efforts to find an agent with ketamine's properties that can be administered orally in repeated doses in order to sustain that action. One candidate for this dextromethorphan, and here the pharmacologic mechanism of action is compared and contrasted with that of ketamine. PMID- 24050155 TI - Pharmacogenetics of mood disorders: what clinicians need to know. AB - Pharmacogenetics brought the promise of matching individuals with treatments that would be efficacious while minimizing adverse events. This has been long needed in psychiatry, where treatment options have been empirical and treatment choices have been made largely based on clinical judgment. The efficacy and tolerability of antidepressants, the most common drugs used in mood disorders, have been widely studied in pharmacogenetics. Genetic association studies have been reported for pharmacokinetic genes such as the CYP450 isoenzymes or MDR1, and pharmacodynamic genes such as the serotonin transporter (SLC6A4) or the serotonin 2A receptor (HTR2A). However, despite the large number of reports, clinically useful predictors are still scarce for antidepressant monotherapy. Pharmacogenetic predictors of efficacy for mood stabilizers such as lithium and anticonvulsants have not had a dissimilar fate, and clinically meaningful markers are yet to emerge. The lack of consistent results may be in part due to small samples of heterogeneous populations and lack of consensus on phenotype definitions. Current pharmacogenetic recommendations include testing for HLA B*1502 when using carbamazepine in Asian ancestry populations to prevent Stevens Johnson syndrome, CYP2D6 genotypes when using pimozide, and CYP2D6 in polypharmacy to minimize drug interactions. This review, which is aimed at clinicians, lays the basis for understanding strengths and weaknesses of pharmacogenetic studies and outlines current clinical uses of these biomarkers. PMID- 24050156 TI - Copper ferrite nanoparticles: an efficient and reusable nanocatalyst for a green one-pot, three-component synthesis of spirooxindoles in water. AB - A green reaction of isatins, active cyanomethanes, and cyclic 1,3-dicarbonyl derivatives for the efficient and simple one-pot three-component synthesis of spirooxindole fused heterocycles in refluxing water by use of magnetically recoverable and reusable catalyst is reported. The features of this procedure are, the use of magnetically recoverable and reusable catalyst, mild reaction conditions, high to excellent product yields, operational simplicity, and easy workup procedures. Most importantly of all, easy magnetic separation of the catalyst eliminates the requirement of catalyst filtration after completion of the reaction. Furthermore, the catalyst remained highly active even after 5 repeated uses. PMID- 24050157 TI - Synthesis and in vitro pharmacological behavior of platinum(II) complexes containing 1,2-diamino-1-(4-fluorophenyl)-2-alkanol ligands. AB - In continuation of our effort to optimize the pharmacological profile of [1,2 diamino-1,2-bis(4-fluorophenyl)ethane]dichloridoplatinum(II) complexes, we synthesized [1,2-diamino-1-(4-fluorophenyl)alkanol]dichloridoplatinum(II) analogs. The aim of this study was to evaluate the influence of hydroxyl groups at the C2 moiety on aqueous solubility, lipophilicity, cellular platinum accumulation, and cytotoxicity against MDA-MB-231, U-937, RAJI, and SC-1 cells as well as against cisplatin-sensitive and cisplatin-resistant A2780 and A2780cisR ovarian carcinoma cells. As expected, the OH groups improved the water solubility and decreased the lipophilicity of the neutral ligands, resulting in complexes with favorable pharmacokinetic properties. The cellular uptake of the compounds in MDA-MB-231 and U-937 cells proved to depend on the configuration and showed only a slight correlation with lipophilicity. The most active complexes were R,R/S,S configured, which points to a carrier-mediated mode of action. [threo-1,2 Diamino-1-(4-fluorophenyl)propan]dichloridoplatinum(II) and [threo-2,3-diamino-3 (4-fluorophenyl)propan-1-ol]dichloridoplatinum(II) possessed only low cross resistance to cisplatin and were up to 10-fold more active in lymphoma cell lines. PMID- 24050159 TI - Biological markers in older people at risk of mobility limitations. AB - Due to the progressive ageing of the worldwide population, prevention and treatment of late-life dysfunctions, including functional decline and mobility limitations, represent leading targets of scientists and clinicians, but are also receiving growing attention from governments and healthcare systems. The early identification of elderly patients more prone to physical decline represents a crucial step for establishing preventive measures. Although functional capacity can easily be assessed, the use of additional criteria that anticipate the onset of mobility limitations seems much more advantageous. The most challenging issues in the identification of biological markers for assessing the risk of functional decline in the elderly originates from the complex and multifaceted pathogenesis of sarcopenia and the resulting physiological decrement, so that bridging the gap between basic research and clinical practice may appear intricate. Nevertheless, several lines of evidence now confirm the existence of negative associations between functional mobility and values of hemoglobin, total and HDL-cholesterol, vitamin D, testosterone, adiponectin and antioxidants such carotenoids, vitamin C and E, selenium and magnesium, whereas positive associations have been reported with the values of uric acid, white blood cells, plasma and blood viscosity, erythrocyte sedimentation rate (ESR), triglycerides, homocysteine, plasma glucose, glycated hemoglobin (HbA1c), markers of renal functions (i.e., creatine and cystatin C), insulin-like growth factor-1 (IGF-1), as well as several inflammatory (e.g., C reactive protein, Intereleukin-6, Interleukin- 1 receptor antagonist), hemostatic (e.g., fibrinogen, Von Willebrand Factor, factors VIII and IX) and oxidative (oxidized lipoproteins, 8-oxo-7,8-2'-deoxyguanosine, protein carbonylation) biomarkers. In the foreseeable future, proteomic studies might predictably help identify novel associations between putative biomarkers and functional decline. PMID- 24050158 TI - Immunogenic Mycobacterium africanum strains associated with ongoing transmission in The Gambia. AB - In West Africa, Mycobacterium tuberculosis strains co-circulate with M. africanum, and both pathogens cause pulmonary tuberculosis in humans. Given recent findings that M. tuberculosis T-cell epitopes are hyperconserved, we hypothesized that more immunogenic strains have increased capacity to spread within the human host population. We investigated the relationship between the composition of the mycobacterial population in The Gambia, as measured by spoligotype analysis, and the immunogenicity of these strains as measured by purified protein derivative-induced interferon-gamma release in ELISPOT assays of peripheral blood mononuclear cells. We found a positive correlation between strains with superior spreading capacity and their relative immunogenicity. Although our observation is true for M. tuberculosis and M. africanum strains, the association was especially pronounced in 1 M. africanum sublineage, characterized by spoligotype shared international type 181, which is responsible for 20% of all tuberculosis cases in the region and therefore poses a major public health threat in The Gambia. PMID- 24050160 TI - Editorial: The multidomain mobility lab in older persons: from bench to bedside. PMID- 24050161 TI - Medications affecting functional status in older persons. AB - Current evidence suggests that functional status is an important outcome of pharmacologic treatments in older people. At the moment, studies have shown diverse effects of medications on functional status. For example, some have shown potentially detrimental effects, while others have found improvements on physical function in elders. Overall, suboptimal prescribing and the occurrence of adverse drug reactions (ADRs) may negatively affect functional status. The use of selected drugs acting on central nervous system (CNS), e.g. benzodiazepines and antipsychotics, is generally associated with an increased risk of functional decline. The greater sensitivity of older people to these drugs, together with age-related changes in pharmacokinetics and pharmacodynamics, account for the observed detrimental effect and suggests a cautious approach to older and frail patients when prescribing CNS agents. On the other hand, selected drugs may slow or delay functional decline in older people. In particular, drugs aimed at targeting sarcopenia (loss in muscle mass and strength), such as testosterone in androgen deficiency, ACE-inhibitors, vitamin D and beta-hydroxy beta-methyl butyrate (HMB), as well as the recently developed selective androgen receptor modulators (SARMs) may hold extreme importance. This review will provide available evidence of the diverse impacts of drug medications on functional status in older persons. PMID- 24050163 TI - Recovery of muscular performance after surgical stress in elderly patients. AB - INTRODUCTION: Inflammation is related to muscle wasting in elderly persons. Since surgery is accompanied by an important inflammatory response, the degree of muscle wasting and related symptoms such as weakness and tiredness might exacerbate very rapidly in elderly surgery patients. METHODS: PubMed and Web of Science were systematically screened for articles reporting the influence of surgery-induced inflammation on muscle performance and/or fatigue in elderly patients. Studies reporting surgery-induced inflammation and changes in muscle performance and/or fatigue, but without analyzing their association were excluded. Although 5 relevant articles were identified including older patients (highest ages reported were 71-92 years), none focused exclusively on elderly patients. Only 2 studies assessed muscle performance, and in none muscle mass was evaluated. Overall, we found evidence that in elderly patients higher surgery induced inflammation was significantly related to worse muscle performance and fatigue in the first postoperative days as well as after more than one month (especially for fatigue) following the intervention. Pre-operative anti inflammatory treatment using steroids or glucocorticoids can reduce the surgery induced inflammatory response and improve the recovery of muscle performance and postoperative fatigue in elderly elective abdominal surgery or arthroplasty patients. CONCLUSION: We can conclude that to date, only few studies have investigated the association between surgery-induced inflammation and changes in postoperative muscle performance and fatigue in elderly patients. More research is warranted focusing on both the short -and long-term effects of surgical stress on muscle performance in elderly patients as well as the on risks and benefits of peri-operative anti-inflammatory treatment. PMID- 24050162 TI - The multidomain mobility lab in older persons: from bench to bedside. The assessment of body composition in older persons at risk of mobility limitations. AB - With body composition it is possible to divide human body in compartments on the basis of different physical properties. The two level body composition model subdividing the whole body in fat mass and fat free mass is the most used in epidemiological and clinical studies in the elderly. Body composition techniques may be used to study ageing process. Changes in body composition occur as part of the normal ageing process and are associated with important effects on health and function. It has been shown that body composition changes with aging, with an increase in fat mass and a decrease in muscle mass, have important consequences on health and physical disability. Moreover body fat distribution changes with adverse metabolic profiles and increased cardiovascular risk. The purpose of this review is to describe the basic principles and techniques for fat free mass and fat mass evaluation, highlighting the advantages and limitations of different available body composition methods. PMID- 24050164 TI - Physical function and exercise in older patients with cardiovascular and respiratory conditions. AB - The increase of life expectancy together with the decline of birth rates implies a global aging of populations living in industrialized countries. Since advanced age is associated with an exponential consumption of health care resources, this phenomenon is likely to pose a substantial threat to the stability of public health systems. Prevention of physical disability represents a major public health priority. Since disability is considered an irreversible condition, every effort should be made to prevent the onset of the disabling cascade and/or delay the physical function decline. The need for strategies against disability has led researchers to look for the most relevant risk factors potentially determining or accelerating the disabling cascade. In this context, cardiovascular and respiratory conditions have been indicated as playing prominent roles in the determination of frailty. Moreover, the high prevalence of these conditions among older persons makes them particularly amenable to targeting for preventive interventions. The aim of the present review is to show the impact of cardiovascular and respiratory conditions on physical function. Moreover, we will discuss the relationship of these conditions with the disabling process, and the importance of their assessment in the design of preventive interventions against disability in older persons. PMID- 24050166 TI - The role of malnutrition in older persons with mobility limitations. AB - Movement disability has a high prevalence in elderly population, either healthy or with chronic disease. Impaired nutritional status is a very common condition in geriatric patients too, especially if we consider elderly subjects admitted to hospital. There are growing evidences that nutrition and disability are strictly interconnected. On the one side, nutritional status is one of the multiple elements that influence the onset and the course of a functional disability; on the other side, disability itself may contribute to malnutrition onset and worsening. Nutrition may not be the sole factor involved in movement impairment in the elderly, but consciousness of its importance in frail elderly population is growing among clinicians and scientific community. In this paper we review the existing knowledge of these complex relationships, discussing the main observational and interventional studies that explored the role of nutrition in movement disability onset and recovery. We also point out how specific kinds of diet, such as Mediterranean diet or high-protein diet, are involved in disability prevention. Finally, we take a look at the existing evidence of the role of single nutrient dietary intake, such as carotenoids, selenium or vitamin D, in mobility impairment in the elderly population. PMID- 24050167 TI - Quantitative gait disturbances in older adults with cognitive impairments. AB - Gait is a complex motor task, initiated and governed by different areas of the brain. Studies have shown a clear association between gait and cognition. Impairments in both gait and cognition are prevalent in older adults. Older adults with gait impairment have an increased risk of developing cognitive impairments. Those with cognitive impairment often have gait impairments and more falls than cognitively healthy older adults. Recent studies have shown that quantitative gait analysis, particularly performed during dual task conditions, can detect gait deficits that cannot yet be seen by the naked eye, even to a trained specialist. Some studies have shown that such gait disturbances were measurable years before mild cognitive impairment or dementia or walking difficulties were clinically manifest. Quantitative gait analysis can provide early detection of gait and cognitive impairments as well as fall risk. Future quantitative gait studies may help distinguish dementia subtypes in early stages of the diseases. Early detection of gait and cognitive impairments would provide a better understanding of disease pathophysiology and progression. Early detection also allows the timely implementation of interventions with the ultimate goal of improving or maintaining mobility and functional independence for as long as possible. Quantitative gait analysis should be viewed as a clinical tool to aid diagnoses and treatment planning. This review examines the current literature on quantitatively measured gait impairment in older adults with mild cognitive impairment or a dementia subtype. PMID- 24050168 TI - Approaching neurological diseases to reduce mobility limitations in older persons. AB - The rapidly increasing elderly population poses a major challenge for future health-care systems. Neurological diseases in older persons are particularly common and coexist with other clinical conditions. This is not surprising given that, for example, even patients with Alzheimer Disease (AD) could have relevant extrapyramidal signs at the moment of the diagnosis with motor signs having more negative prognostic value. Longitudinal studies conducted on Parkinson Disease (PD) showed that, after 20 years, dementia is not only present in almost all survivors but is also the main factor influencing nursing home admission. Recently, it has been reported the importance of Comprehensive Geriatric Assessment (CGA: comprehensive evaluation of cognition, depressive symptoms, mobility and functional assessment) as a tool reducing morbidity in frail older patients admitted to any acute hospital unit. The CGA should be considered as a technological device, for physicians who take care of older persons affected by overlapping neurological diseases. CGA is an extraordinary and cost effective instrument even in patients with advanced neurological diseases where allows to collect valuable information for an effective plan of management. PMID- 24050170 TI - Depression in older persons with mobility limitations. AB - The impact of depression on physical disability is undisputed. There is convincing evidence that depression increases the subsequent risk for physical disability and, in turn, physical disability results in increased depressive symptoms. Moreover, depression affects also the earlier stages of the disablement process (including functional limitation in mobility) and may accelerate the transitioning along the pathway to disability. Greater knowledge of the structure of this detrimental relationship and the underlying mechanisms should inform the clinical management of older persons at risk of physical decline and the development of effective interventions that break this downward spiral. PMID- 24050171 TI - Assessment of mobility status and risk of mobility disability in older persons. AB - The ability to remain mobile is an essential aspect of quality of life and is critical for the preservation of independence in old age. One of the cornerstones of comprehensive geriatric assessment is the evaluation of functional and mobility status, because it provides clinicians pivotal information on overall health status, quality of life, needs for formal and informal care, and short and long term prognosis. As a consequence, many assessment tools have been developed and proposed for clinical use, including simple self-report measures assessing basic abilities and more complex and challenging performance-based objective tools. Both self-report and objective measures might be used to investigate specific steps of the age-related disablement process. In general, self-report and performance based instruments should not be used interchangeably, since they provide different and complementary information. Selection of the more appropriate tool strongly depends on clinical setting, patient characteristics, and clinical or research objective. PMID- 24050165 TI - Interaction between bone and muscle in older persons with mobility limitations. AB - Aging is associated with a progressive loss of bone-muscle mass and strength. When the decline in mass and strength reaches critical thresholds associated with adverse health outcomes, they are operationally considered geriatric conditions and named, respectively, osteoporosis and sarcopenia. Osteoporosis and sarcopenia share many of the same risk factors and both directly or indirectly cause higher risk of mobility limitations, falls, fractures and disability in activities of daily living. This is not surprising since bones adapt their morphology and strength to the long-term loads exerted by muscle during anti-gravitational and physical activities. Non-mechanical systemic and local factors also modulate the mechanostat effect of muscle on bone by affecting the bidirectional osteocyte muscle crosstalk, but the specific pathways that regulate these homeostatic mechanisms are not fully understood. More research is required to reach a consensus on cut points in bone and muscle parameters that identify individuals at high risk for adverse health outcomes, including falls, fractures and disability. A better understanding of the muscle-bone physiological interaction may help to develop preventive strategies that reduce the burden of musculoskeletal diseases, the consequent disability in older persons and to limit the financial burden associated with such conditions. In this review, we summarize age-related bone-muscle changes focusing on the biomechanical and homeostatic mechanisms that explain bone-muscle interaction and we speculate about possible pathological events that occur when these mechanisms become impaired. We also report some recent definitions of osteoporosis and sarcopenia that have emerged in the literature and their implications in clinical practice. Finally, we outline the current evidence for the efficacy of available anti osteoporotic and proposed antisarcopenic interventions in older persons. PMID- 24050172 TI - The link between insulin resistance and mobility limitation in older persons. AB - In this report we will provide additional insight on the individual features of age-related causes of mobility limitation, explaining why insulin resistance, related to lower muscle functioning, sub-inflammation and hormonal changes, may contribute to its onset and sustain it. According to the recent literature, the same factors playing a role in the onset and maintenance of insulin resistance are related to mobility limitation. Thus, the presence of insulin resistance can be considered a biomarker of susceptibility to mobility limitation among older persons. All described factors related to both conditions are strictly intertwined. Therefore, the identification and correction of a single factor is difficult to convert into clinical practice. Instead, insulin resistance may be considered not only an early biological marker, but also a predictive and modifiable marker of mobility limitation. Thus, interventions aimed at correcting insulin resistance may have a potential role in preventing or at least slowing down functional decline in the elderly population, promoting a better quality of life and potentially extending the "healthspan". PMID- 24050173 TI - The emergence of commercial genomics: analysis of the rise of a biotechnology subsector during the Human Genome Project, 1990 to 2004. AB - BACKGROUND: Development of the commercial genomics sector within the biotechnology industry relied heavily on the scientific commons, public funding, and technology transfer between academic and industrial research. This study tracks financial and intellectual property data on genomics firms from 1990 through 2004, thus following these firms as they emerged in the era of the Human Genome Project and through the 2000 to 2001 market bubble. METHODS: A database was created based on an early survey of genomics firms, which was expanded using three web-based biotechnology services, scientific journals, and biotechnology trade and technical publications. Financial data for publicly traded firms was collected through the use of four databases specializing in firm financials. Patent searches were conducted using firm names in the US Patent and Trademark Office website search engine and the DNA Patent Database. RESULTS: A biotechnology subsector of genomics firms emerged in parallel to the publicly funded Human Genome Project. Trends among top firms show that hiring, capital improvement, and research and development expenditures continued to grow after a 2000 to 2001 bubble. The majority of firms are small businesses with great diversity in type of research and development, products, and services provided. Over half the public firms holding patents have the majority of their intellectual property portfolio in DNA-based patents. CONCLUSIONS: These data allow estimates of investment, research and development expenditures, and jobs that paralleled the rise of genomics as a sector within biotechnology between 1990 and 2004. PMID- 24050169 TI - Multiple hormonal dysregulation as determinant of low physical performance and mobility in older persons. AB - Mobility-disability is a common condition in older individuals. Many factors, including the age-related hormonal dysregulation, may concur to the development of disability in the elderly. In fact, during the aging process it is observed an imbalance between anabolic hormones that decrease (testosterone, dehydroepiandrosterone sulphate (DHEAS), estradiol, insulin like growth factor-1 (IGF-1) and Vitamin D) and catabolic hormones (cortisol, thyroid hormones) that increase. We start this review focusing on the mechanisms by which anabolic and catabolic hormones may affect physical performance and mobility. To address the role of the hormonal dysregulation to mobility-disability, we start to discuss the contribution of the single hormonal derangement. The studies used in this review were selected according to the period of time of publication, ranging from 2002 to 2013, and the age of the participants (>=65 years). We devoted particular attention to the effects of anabolic hormones (DHEAS, testosterone, estradiol, Vitamin D and IGF-1) on both skeletal muscle mass and strength, as well as other objective indicators of physical performance. We also analyzed the reasons beyond the inconclusive data coming from RCTs using sex hormones, thyroid hormones, and vitamin D (dosage, duration of treatment, baseline hormonal values and reached hormonal levels). We finally hypothesized that the parallel decline of anabolic hormones has a higher impact than a single hormonal derangement on adverse mobility outcomes in older population. Given the multifactorial origin of low mobility, we underlined the need of future synergistic optional treatments (micronutrients and exercise) to improve the effectiveness of hormonal treatment and to safely ameliorate the anabolic hormonal status and mobility in older individuals. PMID- 24050174 TI - The genomic and cellular foundations of animal origins. AB - The first animals arose more than six hundred million years ago, yet they left little impression in the fossil record. Nonetheless, the cell biology and genome composition of the first animal, the Urmetazoan, can be reconstructed through the study of phylogenetically relevant living organisms. Comparisons among animals and their unicellular and colonial relatives reveal that the Urmetazoan likely possessed a layer of epithelium-like collar cells, preyed on bacteria, reproduced by sperm and egg, and developed through cell division, cell differentiation, and invagination. Although many genes involved in development, body patterning, immunity, and cell-type specification evolved in the animal stem lineage or after animal origins, several gene families critical for cell adhesion, signaling, and gene regulation predate the origin of animals. The ancestral functions of these and other genes may eventually be revealed through studies of gene and genome function in early-branching animals and their closest non-animal relatives. PMID- 24050175 TI - Genetic techniques for the archaea. AB - Genetic techniques for the Archaea have undergone a rapid expansion in complexity, resulting in increased exploration of the role of Archaea in the environment and detailed analyses of the molecular physiology and information processing systems in the third domain of life. Complementary gains in describing the ever-increasing diversity of archaeal organisms have allowed these techniques to be leveraged in new and imaginative ways to elucidate shared and unique aspects of archaeal diversity and metabolism. In this review, we introduce the four archaeal clades for which advanced genetic techniques are available--the methanogens, halophiles, Sulfolobales, and Thermococcales--with the aim of providing an overall profile of the advantages and disadvantages of working within each clade, as essentially all of the genetically accessible archaeal organisms require unique culturing techniques that present real challenges. We discuss the full repertoire of techniques possible within these clades while highlighting the recent advances that have been made by taking advantage of the most prominent techniques and approaches. PMID- 24050176 TI - Initiation of meiotic recombination: how and where? Conservation and specificities among eukaryotes. AB - Meiotic recombination is essential for fertility in most sexually reproducing species. This process also creates new combinations of alleles and has important consequences for genome evolution. Meiotic recombination is initiated by the formation of DNA double-strand breaks (DSBs), which are repaired by homologous recombination. DSBs are catalyzed by the evolutionarily conserved SPO11 protein, assisted by several other factors. Some of them are absolutely required, whereas others are needed only for full levels of DSB formation and may participate in the regulation of DSB timing and frequency as well as the coordination between DSB formation and repair. The sites where DSBs occur are not randomly distributed in the genome, and remarkably distinct strategies have emerged to control their localization in different species. Here, I review the recent advances in the components required for DSB formation and localization in the various model organisms in which these studies have been performed. PMID- 24050179 TI - Enterococcal sex pheromones: signaling, social behavior, and evolution. AB - In Enterococcus faecalis, lateral transfer of conjugative plasmids that encode antibiotic resistance and virulence determinants can be induced by peptide sex pheromones. The tetracycline-resistance plasmid pCF10 represents a paradigm for illustrating important conserved features of a large family of pheromone responsive enterococcal plasmids. The pheromone is released into the growth medium by plasmid-free recipient cells and sensed by plasmid-containing donors. The activity of the pheromone is antagonized by a plasmid-encoded inhibitor peptide that prevents conjugation in the absence of an inducing signal and is also required to return the system to the ground state following an induction cycle. The pheromone response involves multiple transcriptional and posttranscriptional mechanisms as well as bi-stable biological switch behavior. Multiple layers of regulation are essential for proper function, and evolution of this tight control system may have been favored by reduction of the fitness cost of plasmid maintenance to the host cell. PMID- 24050180 TI - Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage. AB - DNA double-strand breaks (DSBs) are common lesions that continually threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including cell death. Misrepair is also fraught with danger, especially inappropriate end-joining events, which commonly underlie oncogenic transformation and can scramble the genome. Canonically, cells employ two basic mechanisms to repair DSBs: homologous recombination (HR) and the classical nonhomologous end-joining pathway (cNHEJ). More recent experiments identified a highly error-prone NHEJ pathway, termed alternative NHEJ (aNHEJ), which operates in both cNHEJ-proficient and cNHEJ-deficient cells. aNHEJ is now recognized to catalyze many genome rearrangements, some leading to oncogenic transformation. Here, we review the mechanisms of cNHEJ and aNHEJ, their interconnections with the DNA damage response (DDR), and the mechanisms used to determine which of the three DSB repair pathways is used to heal a particular DSB. We briefly review recent clinical applications involving NHEJ and NHEJ inhibitors. PMID- 24050177 TI - New gene evolution: little did we know. AB - Genes are perpetually added to and deleted from genomes during evolution. Thus, it is important to understand how new genes are formed and how they evolve to be critical components of the genetic systems that determine the biological diversity of life. Two decades of effort have shed light on the process of new gene origination and have contributed to an emerging comprehensive picture of how new genes are added to genomes, ranging from the mechanisms that generate new gene structures to the presence of new genes in different organisms to the rates and patterns of new gene origination and the roles of new genes in phenotypic evolution. We review each of these aspects of new gene evolution, summarizing the main evidence for the origination and importance of new genes in evolution. We highlight findings showing that new genes rapidly change existing genetic systems that govern various molecular, cellular, and phenotypic functions. PMID- 24050178 TI - Control of transcriptional elongation. AB - Elongation is becoming increasingly recognized as a critical step in eukaryotic transcriptional regulation. Although traditional genetic and biochemical studies have identified major players of transcriptional elongation, our understanding of the importance and roles of these factors is evolving rapidly through the recent advances in genome-wide and single-molecule technologies. Here, we focus on how elongation can modulate the transcriptional outcome through the rate-liming step of RNA polymerase II (Pol II) pausing near promoters and how the participating factors were identified. Among the factors we describe are the pausing factors- NELF (negative elongation factor) and DSIF (DRB sensitivity-inducing factor)--and P-TEFb (positive elongation factor b), which is the key player in pause release. We also describe the high-resolution view of Pol II pausing and propose nonexclusive models for how pausing is achieved. We then discuss Pol II elongation through the bodies of genes and the roles of FACT and SPT6, factors that allow Pol II to move through nucleosomes. PMID- 24050181 TI - First trimester maternal serum vitamin D and markers of preeclampsia. AB - OBJECTIVE: There is evidence that vitamin D deficiency is associated with preeclampsia. The aim of the study was to determine if maternal levels of vitamin D at 1st trimester were related to markers of preeclampsia. MATERIAL: Serum levels of 25-hydroxy-vitamin D (25OHD), PAPP-A, PlGF, uterine artery pulsatility index and mean arterial pressure were measured in 280 pregnant women. RESULTS: Preeclampsia markers were not related to 25OHD concentration. CONCLUSION: First trimester maternal serum concentration of vitamin D does not seem to be connected with markers of preeclampsia. PMID- 24050182 TI - Novel approaches to anticonvulsant drug discovery. AB - INTRODUCTION: The history of epilepsy dates back to 2000 BC. Yet, it was not until 1912 that the activity of the first antiepileptic, phenobarbital was discovered by accident. After this discovery, the next antiepileptic drugs to be discovered (phenytoin and primidone) were based on the phenobarbital's structure. Then, in 1960, carbamazepine was developed empirically, while in 1962, valproate demonstrated anticonvulsant activity against experimental seizures. The next antiepileptic drugs synthesized were either modifications of the existing drugs (such as oxcarbazepine and pregabalin) or completely novel chemical structures (lacosamide, perampanel and retigabine). AREAS COVERED: The present paper briefly refers to the history of epilepsy and development of antiepileptic drugs. Further, the paper provides a discussion on the antiepileptogenic effects of antiepileptic drugs in terms of the constant percentage of epileptic patients with refractory seizures. The authors also review the likely factors involved in the false refractoriness (such as through the use of caffeine-containing beverages and smoking). Finally, the authors consider future directions in the search of novel antiepileptic drugs. EXPERT OPINION: In spite of the considerable number of newer antiepileptic drugs, the number of drug-resistant epileptic patients remains unchanged. This may be rather an indication of the suitability of the currently available discovery procedures for effective antiepileptic drugs in the whole population of epileptic patients. The authors, however, believe that it is likely that models of mimic chronic epilepsy will help bridge the gaps and aid in the discovery of novel antiepileptic drugs - ones that can effectively modify the course of the disease. PMID- 24050184 TI - A phenotypic null hypothesis for the genetics of personality. AB - We review the genetically informed literature on the genetics of personality. Over the past century, quantitative genetic studies, using identical and fraternal twins, have demonstrated that differences in human personality are substantially heritable. We focus on more contemporary questions to which that basic observation has led. We examine whether differences in the heritability of personality are replicable across different traits, samples, and studies; how the heritability of personality relates to its reliability; and how behavior genetics can be employed in studies of validity, and we discuss the stability of personality in genetic and environmental variance. The appropriate null hypothesis in behavior genetics is not that genetic or environmental influence on personality is zero. Instead, we offer a phenotypic null hypothesis, which states that genetic variance is not an independent mechanism of individual differences in personality but rather a reflection of processes that are best conceptualized at the phenotypic level. PMID- 24050183 TI - Oxytocin pathways and the evolution of human behavior. AB - This review examines the hypothesis that oxytocin pathways--which include the neuropeptide oxytocin, the related peptide vasopressin, and their receptors--are at the center of physiological and genetic systems that permitted the evolution of the human nervous system and allowed the expression of contemporary human sociality. Unique actions of oxytocin, including the facilitation of birth, lactation, maternal behavior, genetic regulation of the growth of the neocortex, and the maintenance of the blood supply to the cortex, may have been necessary for encephalization. Peptide-facilitated attachment also allows the extended periods of nurture necessary for the emergence of human intellectual development. In general, oxytocin acts to allow the high levels of social sensitivity and attunement necessary for human sociality and for rearing a human child. Under optimal conditions oxytocin may create an emotional sense of safety. Oxytocin dynamically moderates the autonomic nervous system, and effects of oxytocin on vagal pathways, as well as the antioxidant and anti-inflammatory effects of this peptide, help to explain the pervasive adaptive consequences of social behavior for emotional and physical health. PMID- 24050185 TI - I study what I stink at: lessons learned from a career in psychology. AB - I describe what I have learned from a rather long career in psychology. My goal is to aid those younger than I to learn from my experience and avoid my mistakes. I discuss topics such as the damage that self-fulfilling prophecies can do, the importance of resilience, the need to overcome fear of failure, the importance of being flexible in one's goals and changing them as needed, the relevance of professional ethics, and the need to be wise and not just smart. In the end, we and our work are forgotten very quickly and one should realize that, after retirement, it likely will be one's family, not one's professional network, that provides one's main source of support and comfort. PMID- 24050187 TI - Properties of the internal clock: first- and second-order principles of subjective time. AB - Humans share with other animals an ability to measure the passage of physical time and subjectively experience a sense of time passing. Subjective time has hallmark qualities, akin to other senses, which can be accounted for by formal, psychological, and neurobiological models of the internal clock. These include first-order principles, such as changes in clock speed and how temporal memories are stored, and second-order principles, including timescale invariance, multisensory integration, rhythmical structure, and attentional time-sharing. Within these principles there are both typical individual differences--influences of emotionality, thought speed, and psychoactive drugs--and atypical differences in individuals affected with certain clinical disorders (e.g., autism, Parkinson's disease, and schizophrenia). This review summarizes recent behavioral and neurobiological findings and provides a theoretical framework for considering how changes in the properties of the internal clock impact time perception and other psychological domains. PMID- 24050186 TI - Cultural neuroscience: biology of the mind in cultural contexts. AB - This article provides a review of how cultural contexts shape and are shaped by psychological and neurobiological processes. We propose a framework that aims to culturally contextualize behavioral, genetic, neural, and physiological processes. Empirical evidence is presented to offer concrete examples of how neurobiological processes underlie social behaviors, and how these components are interconnected in larger cultural contexts. These findings provide some understanding of how the meanings shared by cultural experiences trigger a neurobiological, psychological, and behavioral chain of events, and how these events may be coordinated and maintained within a person. The review concludes with a reflection on the current state of cultural neuroscience and questions for the field to address. PMID- 24050188 TI - A century of selection. AB - Over 100 years of psychological research on employee selection has yielded many advances, but the field continues to tackle controversies and challenging problems, revisit once-settled topics, and expand its borders. This review discusses recent advances in designing, implementing, and evaluating selection systems. Key trends such as expanding the criterion space, improving situational judgment tests, and tackling socially desirable responding are discussed. Particular attention is paid to the ways in which technology has substantially altered the selection research and practice landscape. Other areas where practice lacks a research base are noted, and directions for future research are discussed. PMID- 24050189 TI - Environmental psychology matters. AB - Environmental psychology examines transactions between individuals and their built and natural environments. This includes investigating behaviors that inhibit or foster sustainable, climate-healthy, and nature-enhancing choices, the antecedents and correlates of those behaviors, and interventions to increase proenvironmental behavior. It also includes transactions in which nature provides restoration or inflicts stress, and transactions that are more mutual, such as the development of place attachment and identity and the impacts on and from important physical settings such as home, workplaces, schools, and public spaces. As people spend more time in virtual environments, online transactions are coming under increasing research attention. Every aspect of human existence occurs in one environment or another, and the transactions with and within them have important consequences both for people and their natural and built worlds. Environmental psychology matters. PMID- 24050191 TI - Effects of exercise and poor indoor air quality on learning, memory and blood IGF 1 in adolescent mice. AB - It is known that regular aerobic exercise enhances cognitive functions and increases blood insulin-like growth factor 1 (IGF-1) levels. People living in urban areas spend most of their time indoors and indoor air quality can affect health. We investigated the effects of aerobic exercise in poor and good air quality environments on hippocampus and prefrontal cortex (PFC) neurons, anxiety, and spatial learning and memory in adolescent mice. Poor air quality impaired spatial learning and memory; exercise did not affect learning or memory impairment. Exercise in a good air quality environment improved spatial learning and memory. Poor air quality increased apoptosis in the hippocampus and PFC. Both exercised and sedentary groups living in a poor air quality environment had lower serum IGF-1 levels than those living in a good air quality environment. Living in a poor air quality environment has negative effects on the hippocampus, PFC and blood IGF-1 levels in adolescent mice, but exercise did not alter the negative effects of poor air quality. PMID- 24050190 TI - LPS-stimulated inflammatory environment inhibits BMP-2-induced osteoblastic differentiation through crosstalk between TLR4/MyD88/NF-kappaB and BMP/Smad signaling. AB - Bone morphogenetic protein-2 (BMP-2) is a novel differentiation factor that is capable of inducing osteoblast differentiation and bone formation, making it an attractive option in treatment of bone defects, fractures, and spine fusions. Inflammation, which was a common situation during bone healing, is recognized to inhibit osteogenic differentiation and bone formation. However, the effect of inflammation on BMP-2-induced osteoblastic differentiation remains ambiguous. In this study, we showed that an inflammatory environment triggered by lipopolysaccharide (LPS) in vitro would suppress BMP-2-induced osteogenic differentiation of bone marrow mesenchymal stem cells, which represented by decreased alkaline phosphatase (ALPase) activity and down-regulated osteogenic genes. In addition, LPS activated nuclear factor-kappaB (NF-kappaB) via a TLR4/MyD88-dependent manner and inhibited BMP-2-induced phosphorylation and nuclear translocation of Smad1/5/8. The blocking of NF-kappaB signaling by pretreatment with specific inhibitors such as BAY-11-7082, TPCK and PDTC, or by transfection with plasmids encoding p65 siRNA or IkappaBalpha siRNA could significantly reverse the inhibitory effect of LPS on BMP-2-induced BMP/Smad signaling and osteogenic differentiation. By contrast, even without stimulation of LPS, overexpression of p65 gene showed obvious inhibitory effects on BMP-2 induced BMP/Smad signaling and ALPase activity. These data indicate that the LPS mediated inflammatory environment inhibits BMP-2-induced osteogenic differentiation, and that the crosstalk between TLR4/MyD88/NF-kappaB and BMP/Smad signaling negatively modulates the osteoinductive capacity of BMP-2. PMID- 24050192 TI - Modulation of CEST images in vivo by T1 relaxation: a new approach in the design of responsive PARACEST agents. AB - A novel approach for the design of responsive paramagnetic chemical exchange saturation transfer (PARACEST) magnetic resonance imaging (MRI) agents has been developed where the signal is "turned on" by altering the longitudinal relaxation time (T1) of bulk water protons. To demonstrate this approach, a model Eu(DOTA tetraamide) complex (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) containing two nitroxide free radical units was synthesized. The nitroxide groups substantially shortened the T1 of the bulk water protons which, in turn, resulted in quenching of the CEST signal. Reduction of paramagnetic nitroxide moieties to a diamagnetic species resulted in the appearance of CEST. The modulation of CEST by T1 relaxation provides a new platform for designing biologically responsive MRI agents. PMID- 24050193 TI - Mechanistic studies on the reaction of nitroxylcobalamin with dioxygen: evidence for formation of a peroxynitritocob(III)alamin intermediate. AB - Studies by others suggest that the reduced vitamin B12 complex, cob(II)alamin, scavenges nitric oxide to form air-sensitive nitroxylcobalamin (NO(-)-Cbl(III); NOCbl) in vivo. The fate of newly formed NOCbl is not known. A detailed mechanistic investigation of the oxidation of NOCbl by oxygen is presented. Only base-on NOCbl reacts with O2, and the reaction proceeds via an associative mechanism involving a peroxynitritocob(III)alamin intermediate, Co(III)-N(O)OO( ). The intermediate undergoes O-O bond homolysis and ligand isomerization to ultimately yield NO2Cbl and H2OCbl(+)/HOCbl, respectively. Ligand isomerization may potentially occur independent of O-O bond homolysis. Formation of (*)OH and (*)NO2 intermediates from O-O bond homolysis is demonstrated using phenol and tyrosine radical traps and the characterization of small amounts of a corrinoid product with minor modifications to the corrin ring. PMID- 24050194 TI - Aerobic oxidation of diverse primary alcohols to methyl esters with a readily accessible heterogeneous Pd/Bi/Te catalyst. AB - Efficient aerobic oxidative methyl esterification of primary alcohols has been achieved with a heterogeneous catalyst consisting of 1 mol % Pd/charcoal (5 wt %) in combination with bismuth(III) nitrate and tellurium metal. The Bi and Te additives significantly increase the reaction rate, selectivity, and overall product yields. This readily accessible catalyst system exhibits a broad substrate scope and is effective with both activated (benzylic) and unactivated (aliphatic) alcohols bearing diverse functional groups. PMID- 24050195 TI - Introducing problem-based learning to Malawi. PMID- 24050196 TI - A pre-matriculation learning program that enables medical students with low prerequisite scores to succeed. PMID- 24050197 TI - Health literacy objective structured clinical exam for family medicine residents. PMID- 24050198 TI - In-flight medical emergencies: creation of a novel simulation based medical student curriculum. PMID- 24050199 TI - Professional identity formation amongst medical specialists. PMID- 24050200 TI - In the driver's seat: students' perspectives on a formative OSCE in a multisite OB/GYN clerkship. PMID- 24050202 TI - Structural and functional studies on three alginate lyases from Vibrio alginolyticus. AB - To date, several microorganisms that can metabolize alginate have been characterized. In these microorganisms, a class of enzymes called alginate lyases (Alys) catalyze the depolymerization of alginate into oligomers via an endolytic beta-elimination reaction. But it is not clear how these lyases differ on their enzymological functions or their divisions of labor. We focused on three extracellular secretory alginate lyases in the Gram-negative marine bacterium V.alginolyticus (ATCC 17749). We found differences in lyase function and catalytic specificity, depending on substrates. These properties apparently derived from demonstrable changes to the protein sequences. We found shared structural domains in alginate lyases specific to the pM and pG substrates through the measurements on enzyme activities and kinetic parameters. Substitution of hydrophobic amino acids in the isoleucine site of domain QIH could have an enormous influence on the high-affinity to pM or pG. This isoleucine was reconfirmed to be indispensable for recognition of the pG or G-G bond. We identified key amino acids located in the catalytic center by means of protein site-directed mutagenesis, and found specific amino acid fragments with exclusive recognitional and catalytic activity effects for different substrates. We reconstructed a series of proteins through splicing, with the goal of producing an engineered protein with the ability to degrade alginate on a variety of substrates and with high enzyme activity as well as temperature stability. Our study provides the theoretical basis for future work on alginate oligosaccharide, transport mechanisms, an area of research with potentially large ramifications for the chemical, medical, textile, printing and agricultural industries. PMID- 24050203 TI - Specificity of proteinase K at P2 to P3' sub-sites and its comparison to other serine proteases. AB - Specificity of the commercially important serine protease, proteinase K, has been investigated by measuring free energies of association of proteinase K with turkey ovomucoid third domain inhibitor variants at contact positions P2, P1, P1', P2', and P3'. Correlations of these values were run with similar values that have been obtained for six other serine proteases. Among the six proteases, subtilisin Carlsberg shows a near perfect correlation (Pearson Product correlation coefficient = 0.93 to 0.99) with proteinase K at all of these positions. Proteinase K has only 35% sequence identity with subtilisin Carlsberg, yet, the two enzymes are nearly identical in their specificity at P2 to P3' positions. With other serine proteases such as bovine chymotrypsin, human leukocyte elastase, porcine pancreatic elastase, Streptomyces griseus protease A and B, proteinase K showed relatively poor or no correlation. PMID- 24050204 TI - Leporizines A-C: epithiodiketopiperazines isolated from an Aspergillus species. AB - Three new compounds named leporizines A-C have been isolated from an Aspergillus sp. strain. Their structures were elucidated by analysis of 1D and 2D NMR spectra. Leporizines A and B were isolated during dereplication of hits from a high-throughput screening campaign for correctors of the cystic fibrosis transmembrane conductance regulator (CFTR), and leporizine C was isolated while preparing additional material for characterization of leporizines A and B. CFTR activity observed for leporizines A and B was highly correlated with cell toxicity and was determined to be a nonspecific effect. Leporizine C was not cytotoxic to cells and did not elicit a response in the CFTR assays. To the best of our knowledge, leporizines A-C represent the first examples of this unusual epithiodiketopiperazine skeleton. PMID- 24050205 TI - Kinetic stabilization of N,N-dimethyl-2-propyn-1-amine N-oxide by encapsulation. AB - Thermally and in nonprotic media N,N-dimethyl-2-propyn-1-amine N-oxide undergoes two consecutive sigmatropic rearrangements affording propenal. Two molecular containers capable of the quantitative inclusion/encapsulation of the N-oxide are described. The N-oxide becomes kinetically stabilized when included in the containers. The relationship between the observed kinetic stabilization of the N oxide and the thermodynamic and kinetic stability of its inclusion complexes is explained and modeled. PMID- 24050206 TI - Non-innocence of 1,4-dicyanamidobenzene bridging ligands in dinuclear ruthenium complexes. AB - Four dinuclear complexes, [{Ru(II)(ttpy)(bpy)}2(MU-L)][PF6]2, where bpy is 2,2' bipyridine, ttpy is 4-(tert-butylphenyl)-2,2':6',2"-terpyridine, and L is 2,5 dimethyl-, 2,5-dichloro-, 2,3,4,5-tetrachloro- and unsubstituted 1,4 dicyanamidebenzene dianion have been synthesized and characterized. Electron paramagnetic resonance (EPR) spectroscopy of electrogenerated [{Ru(ttpy)(bpy)}2(MU-L)](3+) ions shows largely ligand centered spin and thus the complexes' oxidation states are best formulated as [Ru(II), L(*-), Ru(II)](3+). Visible-NIR and IR spectra of [{Ru(ttpy)(bpy)}2(MU-L)](3+,4+) ions were also obtained by spectroelectrochemical methods. For the [{Ru(ttpy)(bpy)}2(MU-L)](3+) ions, the significant variations in the spectra were rationalized in terms of an increased ruthenium contribution to the singly occupied molecular orbital with increasing number of chloro substituents on the bridging ligand L. PMID- 24050207 TI - Electroluminescent, polycrystalline cadmium selenide nanowire arrays. AB - Electroluminescence (EL) from nanocrystalline CdSe (nc-CdSe) nanowire arrays is reported. The n-type, nc-CdSe nanowires, 400-450 nm in width and 60 nm in thickness, were synthesized using lithographically patterned nanowire electrodeposition, and metal-semiconductor-metal (M-S-M) devices were prepared by the evaporation of two gold contacts spaced by either 0.6 or 5 MUm. These M-S-M devices showed symmetrical current voltage curves characterized by currents that increased exponentially with applied voltage bias. As the applied biased was increased, an increasing number of nanowires within the array "turned on", culminating in EL emission from 30 to 50% of these nanowires at applied voltages of 25-30 V. The spectrum of the emitted light was broad and centered at 770 nm, close to the 1.74 eV (712 nm) band gap of CdSe. EL light emission occurred with an external quantum efficiency of 4 * 10(-6) for devices with a 0.60 MUm gap between the gold contacts and 0.5 * 10(-6) for a 5 MUm gap-values similar to those reported for M-S-M devices constructed from single-crystalline CdSe nanowires. Kelvin probe force microscopy of 5 MUm nc-CdSe nanowire arrays showed pronounced electric fields at the gold electrical contacts, coinciding with the location of strongest EL light emission in these devices. This electric field is implicated in the Poole-Frenkel minority carrier emission and recombination mechanism proposed to account for EL light emission in most of the devices that were investigated. PMID- 24050208 TI - Trigeminal schwannoma of the sphenoid sinus--report of a rare entity. AB - Schwannomas are common slow growing benign tumors. About 25-45% of all schwannomas arise in the head and neck region. Less than 4% of these tumors are found in sinonasal regions and usually affect nasal ethmoid. There are very few case reports of a schwannoma arising from the sphenoid sinus. We report a case of sphenoid sinus schwannoma treated by microscopic decompression and review the relevant literature. PMID- 24050209 TI - Anthocyanin evolution and color changes in red grapes during their chamber drying. AB - In this work, the effects of chamber drying under controlled temperature and moisture conditions on three varieties of red grapes (Merlot, Tempranillo, and Syrah) cultivated in warm areas in southern Spain were studied. This drying was made with a view to their use in the production of sweet red wines. Analyses included color parameters, browning index, and anthocyanin concentrations measured by HPLC-DAD/MS. Based on the results, drying increases color and the concentration of these phenolic compounds by the effect of dehydration of the berries and diffusion of the colored compounds from the skin to the pulp due to the structural alterations in their skin. In addition, drying increased the browning index (OD 420), although less markedly than OD 520, as well as decreased the hue (OD 420/OD 520). The musts exhibited the typical color of red wines and a marked darkness by the effect of their low lightness (L* < 20 CIELAB units). Although the sugar content of the musts obtained at 24 h of drying was less, these musts were better to use in the vinification process, even without the maceration step as a result of their higher anthocyanin content, less browning, and darker color. To increase the content of the high-molecular weight compounds and anthocyanin derivatives, more raisining time could be required. PMID- 24050211 TI - A new indole alkaloidal glucoside from the aerial parts of Clematis terniflora DC. AB - A new indole alkaloidal glucoside together with three known compounds aurantiamide acetate (2), eleutheroside E (3) and 1-O-caffeoyl-beta-D glucopyranoside (4) has been isolated from ethanol extract of the aerial parts of Clematis terniflora DC. On the basis of their spectroscopic and chemical evidence, the new compound was elucidated as (6-O-beta-D-glucopyranosyl-1H-indol 3-yl) carboxylic acid methyl ester (1). Compounds 1 and 3 showed significant cytotoxicity against human ECA-109. PMID- 24050210 TI - Genetic recombination and Cryptosporidium hominis virulent subtype IbA10G2. AB - Little is known about the emergence and spread of virulent subtypes of Cryptosporidium hominis, the predominant species responsible for human cryptosporidiosis. We conducted sequence analyses of 32 genetic loci of 53 C. hominis specimens isolated from a longitudinally followed cohort of children living in a small community. We identified by linkage disequilibrium and recombination analyses only limited genetic recombination, which occurred exclusively within the 60-kDa glycoprotein gene subtype IbA10G2, a predominant subtype for outbreaks in industrialized nations and a virulent subtype in the study community. Intensive transmission of virulent subtype IbA10G2 in the study area might have resulted in genetic recombination with other subtypes. Moreover, we identified selection for IbA10G2 at a 129-kb region around the 60-kDa glycoprotein gene in chromosome 6. These findings improve our understanding of the origin and evolution of C. hominis subtypes and the spread of virulent subtypes. PMID- 24050213 TI - Metabolic engineering of monoclonal antibody carbohydrates for antibody-drug conjugation. AB - The role that carbohydrates play in antibody function and pharmacokinetics has made them important targets for modification. The terminal fucose of the N-linked glycan structure, which has been shown to be involved in modulation of antibody directed cellular cytotoxicity, is a particularly interesting location for potential modification through incorporation of alternative sugar structures. A library of fucose analogues was evaluated for their ability to incorporate into antibody carbohydrates in place of the native fucose. A number of efficiently incorporated molecules were identified, demonstrating the ability of fucosyltransferase VIII to utilize a variety of non-natural sugars as substrates. Among these structures was a thiolated analogue, 6-thiofucose, which was incorporated into the antibody carbohydrate with good efficiency. This unnatural thio-sugar could then be used for conjugation using maleimide chemistry to produce antibody-drug conjugates with pronounced cytotoxic activities and improved homogeneity compared to drug attachment through hinge disulfides. PMID- 24050215 TI - Type of congenital uterine anomaly and adverse pregnancy outcomes. AB - OBJECTIVE: To estimate whether the severity of uterine anomaly is associated with the risk of adverse pregnancy outcomes. METHODS: Retrospective cohort study of patients delivered by one maternal fetal medicine group from 2005 to 2012. We included 158 patients with a singleton pregnancy and a uterine anomaly, as well as an equal number of randomly selected unexposed singleton pregnancies delivered by the same group. Patients with uterine anomalies were subdivided into those with major fusion defects (unicornuate, bicornuate and didelphys) and minor fusion defects (arcuate, septate and t-shaped). RESULTS: The incidence of adverse pregnancy outcomes increased across unexposed patients, patients with minor fusion defects and patients with major fusion defects. These included preterm birth < 37 weeks, preterm birth < 35 weeks, birth weight < 10th percentile, birth weight < 5th percentile, preeclampsia, malpresentation and cesarean delivery. CONCLUSION: The incidence of adverse pregnancy outcomes and cesarean delivery is increased in patients with minor fusion defects and is further increased in patients with major fusion defects. PMID- 24050216 TI - Facet-selective adsorption on noble metal crystals guided by electrostatic potential surfaces of aromatic molecules. AB - We aim to provide a model platform composed of aromatic molecules and noble metal surfaces to study the molecular facet-selective adsorption and employ the discoveries to design surfactants for predictable shape-controlled syntheses of nanocrystals. Starting from Pt, it is demonstrated that negative electrostatic potential on the aromatic ring is the prerequisite to display binding selectivity to Pt(111), while a neutral to positive one prefers Pt(100). The geometric matching between molecular binding sites and surface lattices plays a role as well in facet selectivity. Significantly, Raman spectroscopy has been employed to probe the interactions between aromatic molecules and metal surfaces, providing direct evidence of their binding mechanisms. These discoveries are further exploited to design and identify Pd(111) and Pd(100) facet-specific surfactants. These results represent a step forward in achieving predictable and programmable nanostructures through better understanding of organic-inorganic interfaces. PMID- 24050217 TI - The importance of synthetic drugs for type 2 diabetes drug discovery. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a major metabolic, multi-causal and heterogeneous disorder which causes significant morbidity and mortality with considerable burden to healthcare resources. The number of deaths due to T2DM highlights the insufficiency of the currently available drugs for controlling the disease and its complications and more needs to be done. AREAS COVERED: This paper reviews the updated pathobiology of T2DM that should be targeted in drug discovery. Further, the article provides discussion on the mechanism of action, side effects and structure of the currently available synthetic drugs. The authors specifically evaluate two newer classes of anti-diabetic agents: dipeptidyl peptidase IV (DPP-4) and sodium-glucose transporter-2 (SGLT2). They also present information on newer synthetic compounds. The article also highlights the key interactions between synthetic compounds and DPP-4 active site residues for rational drug design. EXPERT OPINION: Numerous anti-hyperglycaemic drugs are currently available but many are limited by their adverse effects. The identification of the 3D structure of DPP-4 has opened new avenues for design, thus aiming to produce drugs that directly exploit the structural characteristics of this binding site. Further, structural- and ligand-based screening techniques have been developed for designing novel DPP-4 and SGLT2 inhibitors. There has also been progress with the design and development of novel T2DM therapeutics including: PPARalpha/ dual agonists, Sirtuin 1 activators, glycogen phosphorylase inhibitors and protein tyrosine phosphatase 1B inhibitors. Finding new targets and synthesis methods is still essential but it is becoming accepted that no diabetic therapy is 'best suited' with each patient responding differently. PMID- 24050218 TI - The huge plastic potential of adult brain and the role of connectomics: new insights provided by serial mappings in glioma surgery. AB - While prominent in the traditional literature, the localizationist and static view of brain processing does not explain numerous observations of functional recovery following cerebral damages. Here, the goal is to revisit this classical modular and inflexible model by proposing a dynamic organization of brain circuits, which allows postlesional cerebral adaptative phenomena able to maintain neurological and cognitive functions, even in adults. In this state of mind, recent data provided by serial mappings performed in patients who underwent awake surgery for diffuse glioma infiltrating eloquent structures will be reviewed. Firstly, the use of intraoperative electrical mapping enables the realization of on-line anatomo-functional correlations both at cortical and subcortical levels, supporting a network distribution of the brain, and resulting in the reappraisal of cognitive models - notably regarding language. Secondly, combination of neuropsychological assessments and functional neuroimaging before and after operation demonstrates that it is possible to achieve massive resections of "critical" regions without eliciting permanent sequelae, thanks to reorganization of cerebral circuits. Thirdly, repeated surgeries in cases of tumor relapse show functional remapping in the same patients over time. Taken together, these findings open the window toward a huge plastic potential of human central nervous system (CNS) in adults. However, a better understanding of cerebral connectomics leads to the conclusion that the white matter connectivity constitutes a main limitation of such brain plasticity, explaining the lack of recovery in patients with extensive subcortical damages. PMID- 24050219 TI - Is the right frontal cortex really crucial in the mentalizing network? A longitudinal study in patients with a slow-growing lesion. AB - Assessing the subjective experience of others in terms of mental states, a brain function referred to as mentalizing, is achieved in the brain through a set of low-level perceptual and high-level inference-based processes. Because of its recurrent implication in fMRI studies, the right frontal cortex, especially in its inferolateral and dorsomesial parts, is posited to be a "core system" in the sustenance of these neurocognitive mechanisms. In this context, we reasoned that if the right frontal cortex is really crucial for mentalizing, its surgical resection, following diffuse low-grade glioma invasion, should induce irreversible impairments. To test this hypothesis, we designed a longitudinal experimental setup in which ten patients harboring a low-grade glioma in right frontal areas were assessed just before, immediately after and three months after a brain surgery. Two well-validated behavioral tasks, thought to evaluate both aspects of mentalizing, were administered. The results obtained provide evidence that widespread surgical excisions of the right prefrontal cortex do not induce a long-term worsening of both aspects of mentalizing, although some transitory effects are observed immediately after the surgery. They suggest also for the first time in the same sample of patients a possible double functional dissociation between low-level perceptual (posterior inferolateral prefrontal) and high-level inference-based (dorsomesial prefrontal) mentalizing processes. This overall finding challenges the traditional view according to which the right frontal cortex is an "essential cortical node" in the mentalizing network since it might be expected that massive surgical excisions of this brain area would have induced more definitive impairments. PMID- 24050220 TI - Cortical control of Inhibition of Return: exploring the causal contributions of the left parietal cortex. AB - Inhibition of Return (IOR) refers to longer response times (RTs) when processing information from an already inspected spatial location. This effect encourages orienting towards novel locations and may be hence adaptive to efficiently explore our environment. In a previous study (Bourgeois, Chica, Valero-Cabre, & Bartolomeo, 2013), we demonstrated that repetitive Transcranial Magnetic Stimulation (rTMS) over right hemisphere parietal sites, such as the intra parietal sulcus (IPS), or the temporo-parietal junction (TPJ), lastingly interfered with manual but not saccadic IOR, for ipsilateral right-sided targets. For contralateral left-sided targets, rTMS over the right IPS, but not over the right TPJ, impaired both manual and saccadic IOR. In the present study, we investigated hemispheric differences in the cortical control of IOR by stimulating left parietal sites with the same design. Contrary to the stimulation of the right hemisphere, rTMS over the left IPS or TPJ did not produce significant modulations of either manual or saccadic IOR. This evidence extends to IOR the validity of current models of hemispheric asymmetries in the control of visuospatial attention. PMID- 24050221 TI - Self-tensioning aquatic caddisfly silk: Ca2+-dependent structure, strength, and load cycle hysteresis. AB - Caddisflies are aquatic relatives of silk-spinning terrestrial moths and butterflies. Casemaker larvae spin adhesive silk fibers for underwater construction of protective composite cases. The central region of Hesperophylax sp. H-fibroin contains a repeating pattern of three conserved subrepeats, all of which contain one or more (SX)n motifs with extensively phosphorylated serines. Native silk fibers were highly extensible and displayed a distinct yield point, force plateau, and load cycle hysteresis. FTIR spectroscopy of native silk showed a conformational mix of random coil, beta-sheet, and turns. Exchanging multivalent ions with Na(+) EDTA disrupted fiber mechanics, shifted the secondary structure ratios from antiparallel beta-sheet toward random coil and turns, and caused the fibers to shorten, swell in diameter, and disrupted fiber birefringence. The EDTA effects were reversed by restoring Ca(2+). Molecular dynamic simulations provided theoretical support for a hypothetical structure in which the (pSX)n motifs may assemble into two- and three-stranded, Ca(2+) stabilized beta-sheets. PMID- 24050222 TI - Osmotic second virial coefficient of methane in water. AB - A correlation-function-based scheme is proposed for calculating the osmotic second virial coefficient B for solutes that dissolve very little in a solvent. The short-distance contribution to B, a volume integral of the solute-solute pair correlation function h(r) from 0 to some finite distance rc, is evaluated with h(r) obtained by molecular simulation. The remaining contribution to B from rc to infinity is calculated with an asymptotic form of h(r) (Evans, R.; et al. J. Chem. Phys. 1994, 100, 591). It is shown here that B for a model system of methane in water is obtained accurately in the temperature range between 238 and 373 K at 1 bar, with a result that B is a monotonically decreasing function of temperature, and the hydrophobic interaction between methane molecules measured by B is repulsive (B > 0) in supercooled water, virtually null (B ? 0) at around 0 degrees C, and attractive (B < 0) at higher temperatures. It is also remarked that a nearly linear relation holds between B and the first-peak height of the solute-solute radial distribution function. PMID- 24050223 TI - New synthetic technologies. PMID- 24050224 TI - Gold-catalyzed formation of heterocycles - an enabling new technology for medicinal chemistry. AB - Gold-catalyzed transformations allow efficient access to a wide scope of heterocyclic structures that serve as building blocks and pharmacophores in medicinal chemistry. Compared with other transition metal and Lewis acid catalysis, gold catalysis presents mechanistic divergence, excellent functional group tolerance and/or operational advantages. Emergent applications of gold catalysis have played a key role in the synthesis of biologically active molecules including a drug candidate. PMID- 24050225 TI - Multicomponent reactions - opportunities for the pharmaceutical industry. AB - Multicomponent reactions - reactions that combine three or more starting materials in one pot to give a single product that contains essentially all of the atoms of the reactants - offer many exciting opportunities for medicinal chemistry. Their most obvious application is in the drug discovery phase, where they can provide efficient access to large numbers of analogs for lead discovery or optimization. By contrast, the inherent 'greenness' of multicomponent reactions makes them of increasing importance in the sustainable production of pharmaceuticals. We will discuss recent advances in both fields as well as general drivers and barriers for the application of multicomponent reactions in a medicinal chemistry context. PMID- 24050226 TI - Catalytic asymmetric alkylation of ketones using organometallic reagents. AB - The catalytic asymmetric synthesis of tertiary alcohols by the addition of organometallic reagents to ketones is of central importance in organic chemistry. The resulting quaternary stereocentres are difficult to prepare selectively by other means despite their widespread occurrence in natural products and pharmaceuticals. Over the past few years, several seminal reports on the formation of chiral tertiary alcohols with excellent selectivities have appeared in the literature. This review records the major strategies and current status of the catalytic enantioselective synthesis of chiral tertiary alcohols using alkylation/ arylation reactions with highly reactive organometallic reagents derived from Zn, Al, Mg and Li. PMID- 24050227 TI - Organocatalytic methods for C-C bond formation. AB - Beyond doubt organocatalysis belongs to the most exciting and innovative chapters of organic chemistry today. Organocatalysis has emerged not only as a complement to metal-catalyzed reactions or to biocatalysis over the past decade, but also new asymmetric organocatalyzed reactions have been discovered that could not be accomplished by metal- or biocatalyzed reactions so far. This review gives a brief overview of organocatalyzed asymmetric C-C bond formation processes currently available. PMID- 24050228 TI - Biocatalytic synthesis of enantiopure building blocks for pharmaceuticals. AB - Biocatalytic transformations have emerged as a viable alternative to other asymmetric chemical methods due to the intrinsic high stereoselectivity of the enzymes and the mild reaction conditions. Just a decade ago, the reaction scope of applicable biotransformations for organic synthesis was limited to a handful of reaction types. Tremendous progress has been made in the meantime so that this review presents only a small selection of the broad range of possible biotransfromations for organic synthesis available today. Lyases (hydroxynitrile lyase, aldolases) and redox enzymes like alcohol dehydrogenases, Baeyer-Villiger monooxygenase, dioxygenases, ene reductases, berberine bridge enzyme and v transaminases are discussed besides hydrolases. PMID- 24050229 TI - Metal-free bioconjugation reactions. AB - The recent strategy to apply chemical reactions to address fundamental biological questions has led to the emergence of entirely new conjugation reactions that are fast and irreversible, yet so mild and selective that they can be performed even in living cells or organisms. These so-called bioorthogonal reactions open novel avenues, not only in chemical biology research, but also in many other life sciences applications, including the modulation of biopharmaceuticals by site specific modification approaches. PMID- 24050230 TI - Continuous flow synthesis. AB - This article provides a brief outline of continuous flow synthesis including the advantages of the flow method, serial combinatorial synthesis in flow, space integration of reactions, and reactions that cannot be done in batch to show that continuous flow synthesis will be a powerful and indispensable technology for pharmaceutical research and production. PMID- 24050231 TI - Model organisms offer new possibilities for discovery of therapeutics. PMID- 24050233 TI - Modeling colorectal cancer as a 3-dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies. AB - This review discusses recent shifts in the understanding of colorectal cancer as a stem cell based disease, based on findings that tie patient prognosis to the presence of cancer stem cells in colorectal tumors. Currently no drugs specifically target CSCs in colorectal tumors. However, recent advances in the culturing of colorectal stem cells using mammalian organoids, zebrafish, and Drosophila offer promising avenues for anti-CSC drug discovery. PMID- 24050232 TI - A Drosophila approach to thyroid cancer therapeutics. AB - Thyroid neoplasias represent among the fastest growing cancers. While surgery has become the treatment of choice for most thyroid tumors, many require chemotherapy. In this review, we examine the contributions of work in the fruit fly Drosophila toward multiple endocrine neoplasia type 2 (MEN2), a Ret-based disease to which recent Drosophila models have proven useful both for understanding disease mechanism as well as helping identify new generation therapeutics. PMID- 24050234 TI - Zebrafish cancer and metastasis models for in vivo drug discovery. AB - There is a great need for more efficient methods to discover new cancer therapeutics, as traditional drug development processes are slow and expensive. The use of zebrafish as a whole-organism screen is a time and cost-effective means of improving the efficiency and efficacy of drug development. This review features zebrafish genetic and cell transplantation models of cancer and metastasis, and current imaging and automation technologies that, together, will significantly advance the field of anti-cancer drug discovery. PMID- 24050235 TI - Zebrafish based small molecule screens for novel DMD drugs. AB - Recently, a number of chemical and drug screens using zebrafish embryos have been published. Using zebrafish dystrophin mutants, we screened a chemical library for small molecules that modulate the muscle phenotype and identified seven small molecules that influence muscle pathology in dystrophin-null zebrafish. One chemical, aminophylline, which is known to be a non-selective phosphodiesterase (PDE) inhibitor, had the greatest ability to restore normal muscle structure and to up-regulate cAMP-dependent protein kinase (PKA) in treated dystrophin deficient fish. Our methodologies, which combine drug screening with assessment of the chemical effects by genotyping and staining with anti-dystrophin, provide a powerful means to identify template structures potentially relevant to the development of novel human muscular dystrophies therapeutics. PMID- 24050236 TI - In vivo strategies for drug discovery in myotonic dystrophy disorders. AB - Myotonic dystrophy (DM) is a complex neuromuscular genetic disease for which there is currently no valid therapy. The recent development of non-mammal animal models opened up the possibility of performing drug discovery in vivo, using as screening readout phenotypes with underlying molecular parallels to the disease. In this review we discuss the state of the art technologies already used in large scale drug screening and provide guidance for further development of novel technologies. PMID- 24050237 TI - Animal models in therapeutic drug discovery for oculopharyngeal muscular dystrophy. AB - Oculopharyngeal muscular dystrophy (OPMD) is a late onset disease which affects specific muscles. No pharmacological treatments are currently available for OPMD. In recent years, genetically tractable models of OPMD - Drosophila and Caenorhabditis elegans - have been generated. Although these models have not yet been used for large-scale primary drug screening, they have been very useful in candidate approaches for the identification of potential therapeutic compounds for OPMD. In this brief review, we summarize the data that validated active molecules for OPMD in animal models including Drosophila, C. elegans and mouse. PMID- 24050238 TI - Zebrafish-based small molecule screens for novel cardiovascular drugs. AB - The zebrafish is increasingly being adopted as an in vivo model of high throughput drug screening. In this brief review we outline the advantages and disadvantages of this approach and summarize recent screens that have attempted to identify novel small molecules with activity on the cardiovascular system. PMID- 24050239 TI - Alzheimer's disease drug discovery: in vivo screening using Caenorhabditis elegans as a model for beta-amyloid peptide-induced toxicity. AB - Alzheimer's disease (AD) is a complex human neurodegenerative disease. Currently the therapeutics for AD only treats the symptoms. While numbers of excellent studies have used mammalian models to discover new compounds, the time and effort involved with screening large numbers of candidates is prohibitive. Cultured mammalian neurons are often used to perform high-throughput screens (HTS); however, cell culture lacks the organismal complexity involved in AD. To address these issues several researchers are turning to the roundworm, Caenorhabditis elegans. C. elegans has numerous models of both Tau and Ab induced toxicity, the two prime components observed to correlate with AD pathology. These models have led to the discovery of numerous AD modulating candidates. Further, the ease of performing RNA interference for any gene in the C. elegans genome allows for identification of proteins involved in the mechanism of drug action. These attributes make C. elegans well positioned to aid in the discovery of new AD therapies. PMID- 24050241 TI - Using Drosophila as a tool to identify pharmacological therapies for fragile X syndrome. AB - Despite obvious differences such as the ability to fly, the fruit fly Drosophila melanogaster is similar to humans at many different levels of complexity. Studies of development, cell growth and division, metabolism and even cognition, have borne out these similarities. For example, Drosophila bearing mutations in the fly gene homologue of the known human disease fragile X are affected in fundamentally similar ways as affected humans. The ramification of this degree of similarity is that Drosophila, as a model organism, is a rich resource for learning about human cells, development and even human cognition and behavior. Drosophila has a short generation time of ten days, is cheap to propagate and maintain and has a vast array of genetic tools available to it; making Drosophila an extremely attractive organism for the study of human disease. Here, we summarize research from our lab and others using Drosophila to understand the human neurological disease, called fragile X. We focus on the Drosophila model of fragile X, its characterization, and use as a tool to identify potential drugs for the treatment of fragile X. Several clinical trials are in progress now that were motivated by this research. PMID- 24050240 TI - Phenotypic screens for compounds that target the cellular pathologies underlying Parkinson's disease. AB - Parkinson's disease (PD) is a devastating neurodegenerative disease that affects over one million patients in the US. Yet, no disease modifying drugs exist, only those that temporarily alleviate symptoms. Because of its poorly defined and highly complex disease etiology, it is essential to embrace unbiased and innovative approaches for identifying new chemical entities that target the underlying toxicities associated with PD. Traditional target-based drug discovery paradigm can suffer from a bias toward a small number of potential targets. Phenotypic screening of both genetic and pharmacological PD models offers an alternative approach to discover compounds that target the initiating causes and effectors of cellular toxicity. The relative paucity of reported phenotypic screens illustrates the intrinsic difficulty in establishing model systems that are both biologically meaningful and adaptable to high-throughput screening. Parallel advances in PD models and in vivo screening technologies will help create opportunities for identifying new therapeutic leads with unanticipated, breakthrough mechanisms of action. PMID- 24050242 TI - Chemical screening platforms for autophagy drug discovery to identify therapeutic candidates for Huntington's disease and other neurodegenerative disorders. AB - Autophagy is a cellular degradation process involved in the clearance of aggregate-prone proteins associated with neurodegenerative diseases. While the mTOR pathway has been known to be the major regulator of autophagy, recent advancements into the regulation of autophagy have identified mTOR-independent autophagy pathways that are amenable to chemical perturbations. Several chemical and genetic screens have been undertaken to identify small molecule and genetic regulators of autophagy, respectively. The small molecule autophagy enhancers offer great potential as therapeutic candidates not only for neurodegenerative diseases, but also for diverse human diseases where autophagy acts as a protective pathway. This review highlights the various chemical screening platforms for autophagy drug discovery pertinent for the treatment of neurodegenerative diseases. PMID- 24050243 TI - Metabolites: structure determination and prediction. PMID- 24050244 TI - Drug metabolism in silico - the knowledge-based expert system approach. Historical perspectives and current strategies. AB - Drug metabolism in silico is briefly discussed in terms of the importance of understanding the mechanistic basis of drug molecule biotransformation in vivo and its consequences in terms of changes in the properties of metabolites relative to those of the parent compound. A basic overview of an expert system is presented, along with how these general principles apply to expert systems for the prediction of xenobiotic metabolism. A brief history of the development of these systems is also presented. Methods for increasing both the sensitivity and selectivity of prediction are outlined and the benefits of using complementary prediction systems in a conjoint manner are proposed. PMID- 24050245 TI - Exposition and reactivity optimization to predict sites of metabolism in chemicals. AB - Chemical modifications of drugs induced by phase I biotransformations significantly affect their pharmacokinetic properties. Because the metabolites produced can themselves have a pharmacological effect and an intrinsic toxicity, medicinal chemists need to accurately predict the sites of metabolism (SoM) of drugs as early as possible. However, site of metabolism prediction is rarely accompanied by a prediction of the relative abundance of the various metabolites. Such a prediction would be a great help in the study of drug- drug interactions and in the process of reducing the toxicity of potential drug candidates. The aim of this paper is to present recent developments in the prediction of xenobiotic metabolism and to use concrete examples to explain the computational mechanism employed. PMID- 24050246 TI - Modelling cytochromes P450 binding modes to predict P450 inhibition, metabolic stability and isoform selectivity. AB - The cytochromes P450 (P450) superfamily is a diverse group of enzymes involved in the metabolism of xenobiotics, whose orientations within the catalytic site can lead to different binding modes, namely productive, nonproductive, and inhibitory. This article collects the most recent approaches that individually study P450- ligand interactions, including a novel in silico technology, developed in the framework of the Human Cytochrome P450 Consortium initiative, that provides reliable in silico predictions of P450 inhibition, metabolic stability and isoform selectivity. PMID- 24050247 TI - Inhibition of cytochrome P450 enzymes and biochemical aspects of mechanism-based inactivation (MBI). AB - Mechanism-based inactivation (MBI) often involves metabolic bioactivation of the xenobiotic by cytochrome P450s (CYPs) to an electrophilic reactive intermediate and results in quasi-irreversible or irreversible inactivation. Such reactive intermediate can cause quasi-irreversible inhibition through coordination to the ferrous state, Fe(II), of the P450 enzyme forming a tight noncovalent bond leading to the formation of metabolic-intermediate complex (MIC). By contrast, irreversible inactivation is one of the most common causes for the observed drug drug interaction (DDI) and usually implies the formation of a covalent bond between the metabolite and the enzyme via alkylation of either the heme or the P450 apoprotein. Here we illustrate the important points of the current literature understanding of the mechanisms of inhibition of CYP enzymes with emphasis on general mechanistic aspects of MBI for some drugs/moieties associated with the phenomenon. Additionally, the utility of computational and in silico approaches to address bioactivation issues will be briefly discussed. PMID- 24050248 TI - High-throughput, computer assisted, specific MetID. A revolution for drug discovery. AB - One of the key factors in drug discovery is related to the metabolic properties of the lead compound, which may influence the bioavailability of the drug, its therapeutic window, and unwanted side-effects of its metabolites. Therefore, it is of critical importance to enable the fast translation of the experimentally determined metabolic information into design knowledge. The elucidation of the metabolite structure is the most structurally rich and informative end-point in the available range of metabolic assays. A methodology is presented to partially automate the analysis of this experimental information, making the process more efficient. The computer assisted method helps in the chromatographic peak selection and the metabolite structure assignment, enabling automatic data comparison for qualitative applications (kinetic analysis, cross species comparison). PMID- 24050249 TI - Software aided approaches to structure-based metabolite identification in drug discovery and development. AB - Technological advances in mass spectrometry (MS) such as accurate mass high resolution instrumentation have fundamentally changed the approach to systematic metabolite identification over the past decade. Despite technological break through on the instrumental side, metabolite identification still requires tedious manual data inspection and interpretation of huge analytical datasets. The process of metabolite identification has become largely facilitated and partly automated by cheminformatics approaches such as knowledge base metabolite prediction using, for example, Meteor, MetaDrug, MetaSite and StarDrop that are typically applied pre-acquisition. Likewise, emerging new technologies in postacquisition data analysis like mass defect filtering (MDF) have moved the technology driven analytical methodology to metabolite identification toward generic, structure-based workflows. The biggest challenge for automation however remains the structural assignment of drug metabolites. Software-guided approaches for the unsupervised metabolite identification still cannot compete with expert user manual data interpretation yet. Recently MassMetaSite has been introduced for the automated ranked output of metabolite structures based on the combination of metabolite prediction and interrogation of analytical mass spectrometric data. This approach and others are promising milestones toward an unsupervised process to metabolite identification and structural characterization moving away from a sample focused per-compound approach to a structure-driven generic workflow. PMID- 24050250 TI - An ion channel chip for diagnosis and prognosis of autoimmune neurological disorders. AB - Autoantibodies directed against ion channels and ionotropic receptors are associated with neuromuscular and neurological disorders. Their detection has proven to be useful for diagnosis, prognosis and treatment of these autoimmune syndromes. We have designed an ion channel chip for the systematic and rapid screening of antibodies directed against tens of different ion channels. The chip has been validated by confirming the presence of autoantibodies in patients with anti-NMDA receptor encephalitis. Such a chip will be useful for the diagnosis of already documented disorders, but also to identify new targets of autoimmunity and classification of the corresponding diseases. The article presents some promising patents on the Ion Channel Chip. PMID- 24050251 TI - Enantioselective syntheses of FR901464 and spliceostatin A: potent inhibitors of spliceosome. AB - Enantioselective syntheses of FR901464 and spliceostatin A, potent spliceosome inhibitors, are described. The synthesis of FR901464 has been accomplished in a convergent manner in 10 linear steps (20 total steps). The A-tetrahydropyran ring was constructed from (R)-isopropylidene glyceraldehyde. The functionalized tetrahydropyran B-ring was synthesized utilizing a Corey-Bakshi-Shibata reduction, an Achmatowicz reaction, and a stereoselective Michael addition as the key steps. Coupling of A- and B-ring fragments was accomplished via cross metathesis. PMID- 24050252 TI - Development of a rapid cell-fusion-based phenotypic HIV-1 tropism assay. AB - INTRODUCTION: A dual split reporter protein system (DSP), recombining Renilla luciferase (RL) and green fluorescent protein (GFP) split into two different constructs (DSP1-7 and DSP8-11), was adapted to create a novel rapid phenotypic tropism assay (PTA) for HIV-1 infection (DSP-Pheno). METHODS: DSP1-7 was stably expressed in the glioma-derived NP-2 cell lines, which expressed CD4/CXCR4 (N4X4) or CD4/CCR5 (N4R5), respectively. An expression vector with DSP8-11 (pRE11) was constructed. The HIV-1 envelope genes were subcloned in pRE11 (pRE11-env) and transfected into 293FT cells. Transfected 293FT cells were incubated with the indicator cell lines independently. In developing the assay, we selected the DSP1 7-positive clones that showed the highest GFP activity after complementation with DSP8-11. These cell lines, designated N4R5-DSP1-7, N4X4-DSP1-7 were used for subsequent assays. RESULTS: The env gene from the reference strains (BaL for R5 virus, NL4-3 for X4 virus, SF2 for dual tropic virus) subcloned in pRE11 and tested, was concordant with the expected co-receptor usage. Assay results were available in two ways (RL or GFP). The assay sensitivity by RL activity was comparable with those of the published phenotypic assays using pseudovirus. The shortest turnaround time was 5 days after obtaining the patient's plasma. All clinical samples gave positive RL signals on R5 indicator cells in the fusion assay. Median RLU value of the low CD4 group was significantly higher on X4 indicator cells and suggested the presence of more dual or X4 tropic viruses in this group of patients. Comparison of representative samples with Geno2Pheno [co receptor] assay was concordant. CONCLUSIONS: A new cell-fusion-based, high throughput PTA for HIV-1, which would be suitable for in-house studies, was developed. Equipped with two-way reporter system, RL and GFP, DSP-Pheno is a sensitive test with short turnaround time. Although maintenance of cell lines and laboratory equipment is necessary, it provides a safe assay system without infectious viruses. With further validation against other conventional analyses, DSP-Pheno may prove to be a useful laboratory tool. The assay may be useful especially for the research on non-B subtype HIV-1 whose co-receptor usage has not been studied much. PMID- 24050253 TI - Magnetic fluid hyperthermia for bladder cancer: a preclinical dosimetry study. AB - PURPOSE: This paper describes a preclinical investigation of the feasibility of thermotherapy treatment of bladder cancer with magnetic fluid hyperthermia (MFH), performed by analysing the thermal dosimetry of nanoparticle heating in a rat bladder model. MATERIALS AND METHODS: The bladders of 25 female rats were instilled with magnetite-based nanoparticles, and hyperthermia was induced using a novel small animal magnetic field applicator (Actium Biosystems, Boulder, CO). We aimed to increase the bladder lumen temperature to 42 degrees C in <10 min and maintain that temperature for 60 min. Temperatures were measured within the bladder lumen and throughout the rat with seven fibre-optic probes (OpSens Technologies, Quebec, Canada). An MRI analysis was used to confirm the effectiveness of the catheterisation method to deliver and maintain various nanoparticle volumes within the bladder. Thermal dosimetry measurements recorded the temperature rise of rat tissues for a variety of nanoparticle exposure conditions. RESULTS: Thermal dosimetry data demonstrated our ability to raise and control the temperature of rat bladder lumen >=1 degrees C/min to a steady state of 42 degrees C with minimal heating of surrounding normal tissues. MRI scans confirmed the homogenous nanoparticle distribution throughout the bladder. CONCLUSION: These data demonstrate that our MFH system with magnetite-based nanoparticles provides well-localised heating of rat bladder lumen with effective control of temperature in the bladder and minimal heating of surrounding tissues. PMID- 24050254 TI - C23 steroids from the venom of Bufo bufo gargarizans. AB - Five new C23 steroids (1-5) together with five known bufadienolides (6-10) were isolated from the venom of Bufo bufo gargarizans (ChanSu in Chinese). The structures of the new steroids were elucidated by extensive spectroscopic methods in combination with X-ray diffraction analysis. Among these C23 steroids, only compound 3 showed cytotoxicities against HepG2 and A549 cancer cells, with respective IC50 values of 26.8 +/- 8.3 and 45.6 +/- 2.5 MUM. In contrast, the bufadienolides (7-10) displayed potent inhibitory activities against these cancer cells, with respective IC50 values in the ranges 0.5-5.5 and 0.6-6.5 MUM, but relatively less cytotoxicity on normal mouse spleen cells. In addition, the Na(+)/K(+)-ATPase inhibitory activities of 2, 5, and 7 revealed that the lactone moiety of a bufadienolide was important for the inhibitory activity. PMID- 24050255 TI - Effect of N4-substituent choice on spin crossover in dinuclear iron(II) complexes of bis-terdentate 1,2,4-triazole-based ligands. AB - Seven new dinuclear iron(II) complexes of the general formula [Fe(II)2(PMRT)2](BF4)4.solvent, where PMRT is a 4-substituted-3,5-bis{[(2 pyridylmethyl)-amino]methyl}-4H-1,2,4-triazole, have been prepared in order to investigate the substituent effect on the spin crossover event. Variable temperature magnetic susceptibility and (57)Fe Mossbauer spectroscopy studies show that two of the complexes, [Fe(II)2(PMPT)2](BF4)4.H2O (N(4) substituent is pyrrolyl) and [Fe(II)2(PM(Ph)AT)2](BF4)4 (N(4) is N,N-diphenylamine), are stabilized in the [HS-HS] state between 300 and 2 K with weak antiferromagnetic interactions between the iron(II) centers. Five of the complexes showed gradual half spin crossover, from [HS-HS] to [HS-LS], with the following T(1/2) (K) values: 234 for [Fe(II)2(PMibT)2](BF4)4.3H2O (N(4) is isobutyl), 147 for [Fe(II)2(PMBzT)2](BF4)4 (N(4) is benzyl), 133 for [Fe(II)2(PM(CF3)PhT)2](BF4)4.DMF.H2O (N(4) is 3,5-bis(trifluoromethyl)phenyl), 187 for [Fe(II)2(PMPhT)2](BF4)4 (N(4) is phenyl), and 224 for [Fe(II)2(PMC16T)2](BF4)4 (N(4) is hexadecyl). Structure determinations carried out for three complexes, [Fe(II)2(PMPT)2](BF4)4.4DMF, [Fe(II)2(PMBzT)2](BF4)4.CH3CN, and [Fe(II)2(PM(Ph)AT)2](BF4)4.solvent, revealed that in all three complexes both iron(II) centers are stabilized in the high spin state at 90 K. A general and reliable 4-step route to PMRT ligands is also detailed. PMID- 24050256 TI - Nematicidal activity of mint aqueous extracts against the root-knot nematode Meloidogyne incognita. AB - The nematicidal activity and chemical characterization of aqueous extracts and essential oils of three mint species, namely, Mentha * piperita , Mentha spicata , and Mentha pulegium , were investigated. The phytochemical analysis of the essential oils was performed by means of GC-MS, whereas the aqueous extracts were analyzed by LC-MS. The most abundant terpenes were isomenthone, menthone, menthol, pulegone, and carvone, and the water extracts yielded mainly chlorogenic acid, salvianolic acid B, luteolin-7-O-rutinoside, and rosmarinic acid. The water extracts exhibited significant nematicidal activity against Meloidogyne incognita , and the EC50/72h values were calculated at 1005, 745, and 300 mg/L for M. * piperita, M. pulegium, and M. spicata, respectively. Only the essential oil from M. spicata showed a nematicidal activity with an EC50/72h of 358 mg/L. Interestingly, menthofuran and carvone showed EC50/48h values of 127 and 730 mg/L, respectively. On the other hand, salicylic acid, isolated in the aqueous extracts, exhibited EC50 values at 24 and 48 h of 298 +/- 92 and 288 +/- 79 mg/L, respectively. PMID- 24050257 TI - Chagas disease and breast-feeding. AB - Chagas disease (infection by the protozoan Trypanosoma cruzi) is a major parasitic disease of the Americas and one of the main neglected tropical diseases. Although various routes of transmission sre recognized, the risk for transmission of the infection through breast-feeding has not clearly been established. We reviewed the literature on transmission of T. cruzi through breast-feeding to provide breast-feeding mothers with Chagas disease with medical guidance. Although data from animal studies and human studies are scarce, we do not recommend that mothers with Chagas disease discontinue breast-feeding, unless they are experiencing the acute phase of the disease, reactivated disease resulting from immunosuppression, or bleeding nipples. In these cases, thermal treatment of milk before feeding the infant may be considered. PMID- 24050259 TI - Advanced cardiovascular stent coated with nanofiber. AB - Nanofiber was explored as a stent surface coating substance for the treatment of coronary artery diseases (CAD). Nanofibers loaded with nanoparticles containing beta-estradiol were developed and exploited to prevent stent-induced restenosis through regulation of the reactive oxygen species (ROS). Eudragit S-100 (ES), a versatile polymer, was used as a nanoparticle (NP) base, and the mixtures of hexafluoro-2-propanol (HFIP), PLGA and PLA at varying ratios were used as a nanofiber base. beta-Estradiol was used as a primary compound to alleviate the ROS activity at the subcellular level. Nile-Red was used as a visual marker. Stent was coated with nanofibers produced by electrospinning technique comprising the two-step process. Eudragit nanoparticles (ES-NP) as well as 4 modified types of NP-W (ES-NP were dispersed in H2O, which was mixed with HFIP (1:1 (v/v) and then subsequently added with 15% PLGA), NP-HW (ES-NP were dispersed in H2O, which was mixed with HFIP (1:1 (v/v)) already containing 15% PLGA), NP-CHA (ES-NP with a chitosan layer were added in H2O, which was mixed with HFIP (1:1 (v/v)) containing 15% PLGA), and NP-CHB (ES-NP with a chitosan layer were added in H2O, which was mixed with HFIP (1:1 (v/v)) containing the mixture of PLGA and PLA at a ratio of 4:1) were developed, and their properties, such as the loading capacity of beta-estradiol, the release profiles of beta-estradiol, cell cytotoxicity and antioxidant responses to ROS, were characterized and compared. Among composite nanofibers loaded with nanoparticles, NP-CHB had the maximal yield and drug loading amount of 66.5 +/- 3.7% and 147.9 +/- 10.1 MUg, respectively. The nanofibers of NP-CHB coated on metallic mandrel offered the most sustained release profile of beta-estradiol. In the confocal microscopy study, NP-W exhibited a low fluorescent intensity of Nile-Red as compared with NP-HW, indicating that the stability of nanoparticles decreased, as the percentage volume of the organic solvent increased. Nanofibers incorporated with beta estradiol yielded a high endothelial proliferation rate, which was about 3-fold greater than the control (without beta-estradiol). The cells treated with the enhanced level of H2O2 (>1 mM: as ROS source) were mostly nonviable (81.1 +/- 12.4%, p < 0.01), indicating that ROS induce cell apoptosis and trigger the rupture of atheroma thin layer in a concentration dependent manner. Nanofibers containing beta-estradiol (0.5 mM) lowered cellular cytotoxicity from 25.2 +/- 4.9% to 8.1 +/- 1.4% in the presence of 600 MUM H2O2, and from 86.8 +/- 8.4% to 59.4 +/- 8.7% in the presence of 1.0 mM H2O2, suggesting that beta-estradiol efficiently protected hPCECs from ROS induced cytotoxicity. The level of NO production in hPCECs in the presence of beta-estradiol after 6 days of incubation was much greater than that of the control without beta-estradiol. In summary, nanofibers loaded with nanoparticles containing beta-estradiol could be used as a suitable platform for the surface coating of a cardiovascular stent, achieving enhanced endothelialization at the implanted sites of blood vessels. PMID- 24050258 TI - Mitochondrial protein acetylation as a cell-intrinsic, evolutionary driver of fat storage: chemical and metabolic logic of acetyl-lysine modifications. AB - Hormone systems evolved over 500 million years of animal natural history to motivate feeding behavior and convert excess calories to fat. These systems produced vertebrates, including humans, who are famine-resistant but sensitive to obesity in environments of persistent overnutrition. We looked for cell-intrinsic metabolic features, which might have been subject to an evolutionary drive favoring lipogenesis. Mitochondrial protein acetylation appears to be such a system. Because mitochondrial acetyl-coA is the central mediator of fuel oxidation and is saturable, this metabolite is postulated to be the fundamental indicator of energy excess, which imprints a memory of nutritional imbalances by covalent modification. Fungal and invertebrate mitochondria have highly acetylated mitochondrial proteomes without an apparent mitochondrially targeted protein lysine acetyltransferase. Thus, mitochondrial acetylation is hypothesized to have evolved as a nonenzymatic phenomenon. Because the pKa of a nonperturbed Lys is 10.4 and linkage of a carbonyl carbon to an epsilon amino group cannot be formed with a protonated Lys, we hypothesize that acetylation occurs on residues with depressed pKa values, accounting for the propensity of acetylation to hit active sites and suggesting that regulatory Lys residues may have been under selective pressure to avoid or attract acetylation throughout animal evolution. In addition, a shortage of mitochondrial oxaloacetate under ketotic conditions can explain why macronutrient insufficiency also produces mitochondrial hyperacetylation. Reduced mitochondrial activity during times of overnutrition and undernutrition would improve fitness by virtue of resource conservation. Micronutrient insufficiency is predicted to exacerbate mitochondrial hyperacetylation. Nicotinamide riboside and Sirt3 activity are predicted to relieve mitochondrial inhibition. PMID- 24050260 TI - Linear versus dendritic molecular binders for hydrogel network formation with clay nanosheets: studies with ABA triblock copolyethers carrying guanidinium ion pendants. AB - ABA-triblock copolyethers 1a-1c as linear polymeric binders, in combination with clay nanosheets (CNSs), afford high-water-content moldable supramolecular hydrogels with excellent mechanical properties by constructing a well-developed crosslinked network in water. The linear binders carry in their terminal A blocks guanidinium ion (Gu(+)) pendants for adhesion to the CNS surface, while their central B block comprises poly(ethylene oxide) (PEO) that serves as a flexible linker for adhered CNSs. Although previously reported dendritic binder 2 requires multistep synthesis and purification, the linear binders can be obtained in sizable quantities from readily available starting materials by controlled polymerization. Together with dendritic reference 2, the modular nature of compounds 1a-1c with different numbers of Gu(+) pendants and PEO linker lengths allowed for investigating how their structural parameters affect the gel network formation and hydrogel properties. The newly obtained hydrogels are mechanically as tough as that with 2, although the hydrogelation takes place more slowly. Irrespective of which binder is used, the supramolecular gel network has a shape memory feature upon drying followed by rewetting, and the gelling water can be freely replaced with ionic liquids and organic fluids, affording novel clay reinforced iono- and organogels, respectively. PMID- 24050261 TI - From missing source to missing sink: long-term changes in the nitrogen budget of a northern hardwood forest. AB - Biogeochemical monitoring for 45 years at the Hubbard Brook Experimental Forest in New Hampshire has revealed multiple surprises, seeming contradictions, and unresolved questions in the long-term record of ecosystem nitrogen dynamics. From 1965 to 1977, more N was accumulating in living biomass than was deposited from the atmosphere; the "missing" N source was attributed to biological fixation. Since 1992, biomass accumulation has been negligible or even negative, and streamwater export of dissolved inorganic N has decreased from ~4 to ~1 kg of N ha(-1) year(-1), despite chronically elevated atmospheric N deposition (~7 kg of N ha(-1) year(-1)) and predictions of N saturation. Here we show that the ecosystem has shifted to a net N sink, either storing or denitrifying ~8 kg of N ha(-1) year(-1). Repeated sampling over 25 years shows that the forest floor is not detectably accumulating N, but the C:N ratio is increasing. Mineral soil N has decreased nonsignificantly in recent decades, but the variability of these measurements prevents detection of a change of <700 kg of N ha(-1). Whether the excess N is accumulating in the ecosystem or lost through denitrification will be difficult to determine, but the distinction has important implications for the local ecosystem and global climate. PMID- 24050262 TI - Expanding the Metchnikoff postulate: oral health is crucial in a successful global aging management strategy. AB - The mouth offers a unique opportunity for the physician and dental hygienist to evaluate and monitor a number of early nutritional-related diseases and vitamin deficiencies in still-healthy people. Increasing evidence suggests that periodontal disease might be associated with several systemic diseases (diabetes, immunosuppression, obesity, hormonal changes). Conversely, oral/periodontal disease might be the perpetuating factor or possibly the trigger of chronic illnesses via the activation of pro-inflammatory cytokines from monocytes and polymorphonuclear leukocytes in the sub-gingival biofilm and oral microbiome unbalance. Office-based microbiological and susceptibility genomic testing in the oral cavity (e.g., BACTOdent-DENTYgen, 4P-Genomics, Luxembourg) are expected to be widespread tools in a global approach for an age-management strategy connecting oral health and personalized solutions. PMID- 24050263 TI - Delivery of therapeutic nucleic acids via transferrin and transferrin receptors: lipoplexes and other carriers. AB - INTRODUCTION: The overexpression of transferrin (Tf) receptors on cancer cells renders them a useful target for the delivery of small-molecule drugs and nucleic acid therapeutics to these cells. This approach could alleviate the non-target effects of the drugs. AREAS COVERED: The function of the Tf receptor, the development of Tf-lipid-DNA complexes (Tf lipoplexes), therapeutic use of lipoplexes and polymer-DNA complexes (poylplexes), and the therapeutic use of Tf lipoplexes and anti-Tf-receptor antibody-lipoplexes are outlined. The literature search for this review was based primarily on the terms 'lipoplexes,' 'lipopolyplexes' 'transferrin,' 'transferrin receptor,' and 'gene therapy.' However, the review was not intended to be comprehensive. EXPERT OPINION: Complexes of Tf with cationic liposomes and nucleic acids, or liposomes with covalently attached Tf or anti-transferrin receptor antibodies have been used for the delivery of therapeutic genes, antisense oligodeoxynucleotides, and short interfering RNA. Although such targeted nonviral delivery vehicles may benefit from further enhancement of their efficacy, current achievements at the cell culture and animal model level should be translated into clinical applications, restricted initially to localized delivery into accessible tissues to avoid potential systemic side-effects and non-target delivery. PMID- 24050264 TI - Critical role of water in the binding of volatile anesthetics to proteins. AB - Numerous small molecules exhibit drug-like properties by low-affinity binding to proteins. Such binding is known to be influenced by water, the detailed picture of which, however, remains unclear. One particular example is the controversial role of water in the binding of general anesthetics to proteins as an essential step in general anesthesia. Here we demonstrate that a critical amount of hydration water is a prerequisite for anesthetic-protein binding. Using nuclear magnetic resonance, the concurrent adsorption of hydration water and bound anesthetics on model proteins are simultaneously measured. Halothane binding on proteins can only take place after protein hydration reaches a threshold hydration level of ~0.31 g of water/g of proteins at the relative water vapor pressure of ~0.95. Similar dependence on hydration is also observed for several other anesthetics. The ratio of anesthetic partial pressures at which two different anesthetics reach the same fractional load is correlated with the anesthetic potency. The binding of nonimmobilizers, which are structurally similar to known anesthetics but unable to produce anesthesia, does not occur even after the proteins are fully hydrated. Our results provide the first unambiguous experimental evidence that water is absolutely required to enable anesthetic-protein interactions, shedding new light on the general mechanism of molecular recognition and binding. PMID- 24050265 TI - Evaluation of doxorubicin-loaded 3-helix micelles as nanocarriers. AB - Designing stable drug nanocarriers, 10-30 nm in size, would have significant impact on their transport in circulation, tumor penetration, and therapeutic efficacy. In the present study, biological properties of 3-helix micelles loaded with 8 wt % doxorubicin (DOX), ~15 nm in size, were characterized to validate their potential as a nanocarrier platform. DOX-loaded micelles exhibited high stability in terms of size and drug retention in concentrated protein environments similar to conditions after intravenous injections. DOX-loaded micelles were cytotoxic to PPC-1 and 4T1 cancer cells at levels comparable to free DOX. 3-Helix micelles can be disassembled by proteolytic degradation of peptide shell to enable drug release and clearance to minimize long-term accumulation. Local administration to normal rat striatum by convection enhanced delivery (CED) showed greater extent of drug distribution and reduced toxicity relative to free drug. Intravenous administration of DOX-loaded 3-helix micelles demonstrated improved tumor half-life and reduced toxicity to healthy tissues in comparison to free DOX. In vivo delivery of DOX-loaded 3-helix micelles through two different routes clearly indicates the potential of 3-helix micelles as safe and effective nanocarriers for cancer therapeutics. PMID- 24050266 TI - Molecular interactions of Bcl-2 and Bcl-xL with mortalin: identification and functional characterization. AB - Bcl-2 family of proteins consists of both pro-apoptotic and anti-apoptotic members that control cellular apoptosis. They predominantly reside in the mitochondria and control the release of apoptotic factors from the mitochondria to the cytosol by regulating its membrane potential and opening the PT (permeability transition) pore. Here we report bioinformatics and biochemical evidence to demonstrate the interaction between Bcl-2 and Bcl-xL with a stress chaperone, mortalin. We demonstrate that such interaction results in the abrogation of mortalin-p53 interaction leading to nuclear translocation and transcriptional reactivation of p53 function that results in an induction of senescence in cancer cells. PMID- 24050267 TI - Evidence for impaired plasticity after traumatic brain injury in the developing brain. AB - The robustness of plasticity mechanisms during brain development is essential for synaptic formation and has a beneficial outcome after sensory deprivation. However, the role of plasticity in recovery after acute brain injury in children has not been well defined. Traumatic brain injury (TBI) is the leading cause of death and disability among children, and long-term disability from pediatric TBI can be particularly devastating. We investigated the altered cortical plasticity 2-3 weeks after injury in a pediatric rat model of TBI. Significant decreases in neurophysiological responses across the depth of the noninjured, primary somatosensory cortex (S1) in TBI rats, compared to age-matched controls, were detected with electrophysiological measurements of multi-unit activity (86.4% decrease), local field potential (75.3% decrease), and functional magnetic resonance imaging (77.6% decrease). Because the corpus callosum is a clinically important white matter tract that was shown to be consistently involved in post traumatic axonal injury, we investigated its anatomical and functional characteristics after TBI. Indeed, corpus callosum abnormalities in TBI rats were detected with diffusion tensor imaging (9.3% decrease in fractional anisotropy) and histopathological analysis (14% myelination volume decreases). Whole-cell patch clamp recordings further revealed that TBI results in significant decreases in spontaneous firing rate (57% decrease) and the potential to induce long-term potentiation in neurons located in layer V of the noninjured S1 by stimulation of the corpus callosum (82% decrease). The results suggest that post-TBI plasticity can translate into inappropriate neuronal connections and dramatic changes in the function of neuronal networks. PMID- 24050268 TI - beta-Amyloid-induced cognitive dysfunction impairs glucose homeostasis by increasing insulin resistance and decreasing beta-cell mass in non-diabetic and diabetic rats. AB - OBJECTIVE: beta-Amyloid accumulation in the brain may impair glucose homeostasis in both the brain and peripheral tissues. The present study investigated whether beta-amyloid deposition in the hippocampus impairs glucose homeostasis by altering insulin sensitivity, glucose-stimulated insulin secretion or beta-cell mass. METHODS: Male rats were divided into two groups: a non-diabetic sham group and a diabetic partial pancreatectomized (Px) group. Each group was then subdivided into three treatment groups that received intra-CA1 infusions of beta amyloid (25-35; AMY), beta-amyloid (35-25; RAMY; non-plaque forming), or saline at a rate of 3.6 nmol/day for 14 days. RESULTS: After 4weeks, cognitive function measured by passive avoidance and water maze tests was impaired in non-diabetic rats that received AMY compared with rats that received saline or RAMY. Furthermore, diabetes exacerbated cognitive dysfunction in AMY-infused rats. This was associated with the hyperphosphorylation of tau as a result of attenuated insulin signaling (pAkt->pGSK) through decreased phosphorylation of cAMP responding element binding protein in the hippocampus of non-diabetic and diabetic rats. AMY exacerbated whole-body and hepatic insulin resistance in non diabetic and diabetic rats. However, AMY potentiated glucose-stimulated insulin secretion in non-diabetic and diabetic rats, but caused decreased beta-cell mass via increased beta-cell apoptosis and decreased beta-cell proliferation. As a result, glucose homeostasis was maintained by potentiating insulin secretion in diabetic rats, but may not be sustainable with further decreases in beta-cell mass. CONCLUSION: Cognitive dysfunction attributable to beta-amyloid accumulation in the hippocampus might be related to disturbed glucose homeostasis due to increased insulin resistance and decreased beta-cell mass. PMID- 24050269 TI - Vitamin D and cardio-metabolic disease. PMID- 24050271 TI - Allosteric approaches to GPCR drug discovery. PMID- 24050270 TI - A meta-analysis of the effect of angiotensin receptor blockers and calcium channel blockers on blood pressure, glycemia and the HOMA-IR index in non diabetic patients. AB - OBJECTIVE: This study compared the efficacy of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) in the effect of insulin resistance (IR) as assessed using the homeostasis model assessment of insulin resistance (HOMA-IR) in non-diabetic patients. METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched to identify studies published before December 2012 that investigated the use of ARBs and CCBs to determine the effect on the HOMA-IR index in non-diabetics. Parameters on IR and blood pressure were collected. Review Manager 5.2 and Stata 12.0 were used to perform the meta analysis. Fixed and random effects models were applied to various aspects of the meta-analysis, which assessed the therapeutic effects of the two types of drug using the HOMA-IR index in non-diabetic patients. RESULTS: The meta-analysis included five clinical trials. Patient comparisons before and after treatment with ARBs and CCBs revealed that ARBs reduced the HOMA-IR index (weighted mean difference (WMD) -0.65, 95% confidence interval (CI) -0.93 to -0.38) and fasting plasma insulin (FPI) (WMD -2.01, 95% CI -3.27 to -0.74) significantly more than CCBs. No significant differences in the therapeutic effects of these two types of drug on blood pressure were observed. CONCLUSION: Given that there are no significant differences in the therapeutic effects of ARBs and CCBs on blood pressure, as ARBs are superior to CCBs in their effect on the HOMA-IR index in non-diabetics, they might be a better choice in hypertension patients without diabetes. PMID- 24050272 TI - The concept of allosteric modulation: an overview. AB - A brief historical overview of the concept of allosteric interaction is presented together with the different kinds of allosteric control recognized, in the past decades, with the model system of pentameric ligandgated ion channels. Multiple levels of allosteric modulation are identified that include sites distributed in the extracellular ligand binding domain (e.g. Ca2+ or benzodiazepines), the transmembrane domain (e.g. general anesthetic and various allosteric modulators) and the cytoplasmic domain, as potential targets for drug design. The new opportunities offered by the recent technological developments are discussed. PMID- 24050273 TI - Analytical pharmacology and allosterism: the importance of quantifying drug parameters in drug discovery. AB - Allosteric ligands bind to receptors at sites separate from those binding endogenous ligands; this allows for a wide range of effects from antagonism to potentiation to direct agonism. This paper discusses techniques to quantify complex allosteric behaviors that yield parameters to characterize direct effects (tB, the efficacy of allosteric agonists), a and b (the effect of the allosteric ligand on endogenous ligand affinity and efficacy respectively). These parameters are independent of the system used to determine them and thus can be used to predict allosteric effects in all systems. PMID- 24050275 TI - Dualsteric GPCR targeting and functional selectivity: the paradigmatic M(2) muscarinic acetylcholine receptor. AB - Muscarinic acetylcholine receptors belong to Class Aseven transmembrane helical receptors and serve as important drug targets in the treatment of various diseases such as chronic obstructive pulmonary disease, overactive bladder, bronchial asthma and glaucoma. Despite intensive research the discovery of experimental ligands which activate or block specific muscarinic receptor subtypes has only been successful for the M1 and M4 subtypes but remains a challenging task at the other subtypes. In recent years, ligands have been introduced which bind simultaneously to the acetylcholine binding site, that is, the orthosteric site, and to an allosteric binding site. These so-called dualsteric ligands display M2 subtype preference due to the addressing of the allosteric binding site. As proven recently, dualsteric receptor activation goes along with a pronounced signaling bias which follows clear structure-bias relationships. Dualsteric receptor targeting might represent a common strategy to generate functional selectivity. PMID- 24050274 TI - Allosteric modulation and functional selectivity of G protein-coupled receptors. AB - Agonists of a single G protein-coupled receptor (GPCR) may activate distinct signaling pathways. Functional selectivity, an emerging concept with therapeutic relevance for GPCRs, may be due to conformational selection or stabilization with respect to particular agonists, receptor dimerization, variable expression levels of GPCRs and downstream signaling molecules, and allosteric modulation. Allosteric modulators may have potential advantages over orthosteric ligands, including greater selectivity and safety. This review focuses on functional selectivity resulting from allosteric modulation. PMID- 24050276 TI - New technologies enabling the industrialization of allosteric modulator discovery. AB - Allosteric modulators (AMs) are a promising avenue towards safe and selective drugs. AMs can interact selectively with unique domains distinct from the endogenous ligand binding site of receptors, up- or downregulating the response to receptor activation. Emphasis is placed in this article on the latest development in high-sensitivity technologies designed to identify AMs of G protein coupled receptors. In addition to new pharmacological approaches, encouraging results in the crystal resolution of these targets enable use of more rational approaches to identification and optimization of AMs. PMID- 24050277 TI - Technology combination to address GPCR allosteric modulator drug-discovery pitfalls. AB - Allosteric modulators (AMs) represent a novel paradigm to therapeutically target G-protein-coupled receptors (GPCRs). However, their identification and characterization using standard functional assays remain elusive due to the 'context-dependent phenomena'. Novel technological approaches such as combining a Fluorescence Resonance Energy Transfer (FRET)-based library filtering with a Bioluminescence Resonance Energy Transfer (BRET)-based multiparametric compound profiling can circumvent the limitations of current GPCR screening processes and simplify the discovery of biased AMs. PMID- 24050279 TI - Allosteric modulators of the extracellular calcium receptor. AB - The extracellular calcium receptor (CaR) is a Family C G protein-coupled receptor that controls systemic Ca2+ homeostasis, largely by regulating the secretion of parathyroid hormone (PTH). Ligands that activate the CaR have been termed calcimimetics and are classified as either Type I (agonists) or Type II (allosteric activators) and effectively inhibit the secretion of PTH. CaR antagonists have been termed calcilytics and all act allosterically to stimulate secretion of PTH. The calcimimetic cinacalcet has been approved for treating parathyroid cancer and secondary hyperparathyroidism in patients on renal replacement therapy. Cinacalcet was the first allosteric modulator of a G proteincoupled receptor to achieve regulatory approval. This review will focus on the technologies used to discover and develop allosterically acting calcimimetics and calcilytics as novel therapies for bone and mineral-related disorders. PMID- 24050278 TI - Allosteric modulation of Class C GPCRs: a novel approach for the treatment of CNS disorders. AB - Allosteric modulation has emerged as an innovative pharmacological approach to selectively activate or inhibit several Class C GPCRs. Of the Class C GPCRs, metabotropic glutamate (mGlu) receptors represent the most promising candidates for clinical success, and both positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) of mGluRs have demonstrated therapeutic potential for a range of psychiatric and neurological disorders such as pain, depression, anxiety, cognition, Fragile X syndrome, Parkinson's disease and schizophrenia. PMID- 24050280 TI - Allosteric modulation of A1-adenosine receptor: a review. AB - Allosteric modulators of adenosine receptors represent an alternative to direct acting adenosine agonists and nucleoside uptake blockers, preferably those can selectively modulate the response to adenosine in only those organs or localized areas of a given organ in which production of adenosine is increased. Allosteric enhancers at the adenosine A1 receptor have received attention as anti-arrhythmic cardiac agents, and, more recently, as anti-lipolytic agents. In addition, this class of compounds has therapeutic potential as analgesics and neuroprotective agents. PMID- 24050281 TI - Modeling the allosteric modulation of CCR5 function by Maraviroc. AB - Maraviroc is a non-peptidic, low molecular weight CC chemokine receptor 5 (CCR5) ligand that has recently been marketed for the treatment of HIV infected individuals. This review discusses recent molecular modeling studies of CCR5 by homology to CXC chemokine receptor 4, their contribution to the understanding of the allosteric mode of action of the inhibitor and their potential for the development of future drugs with improved efficiency and preservation of CCR5 biological functions. PMID- 24050282 TI - Chemogenomics of allosteric binding sites in GPCRs. AB - Chemogenomic techniques connect the chemical and biological domains to establish ligand and target relationships not evident from the individual disciplines. Chemogenomics has been applied in lead generation, target classification, focused library design as well as selectivity and polypharmacology profiling. This review describes recent developments structured into ligand-, target- and combined chemogenomic techniques and applications to allosteric GPCR ligands. It also outlines relative strengths and limitations of these techniques and the impact of the increasing crystallographic data. PMID- 24050283 TI - Exploring the experience of clients with tetraplegia utilizing assistive technology for computer access. AB - PURPOSE: Assistive technology for computer access can be used to facilitate people with a spinal cord injury to utilize mainstream computer applications, thereby enabling participation in a variety of meaningful occupations. The aim of this study was to gain an understanding of the experiences of clients with tetraplegia trialing assistive technologies for computer access during different stages in a public rehabilitation service. METHOD: In order to explore the experiences of clients with tetraplegia trialing assistive technologies for computer use, qualitative methodology was selected. Data were collected from seven participants using semi-structured interviews, which were audio-taped, transcribed and analyzed thematically. RESULTS: Three main themes were identified. These were: getting back into life, assisting in adjusting to injury and learning new skills. CONCLUSIONS: The findings from this study demonstrated that people with tetraplegia can be assisted to return to previous life roles or engage in new roles, through developing skills in the use of assistive technology for computer access. Being able to use computers for meaningful activities contributed to the participants gaining an enhanced sense of self-efficacy, and thereby quality of life. Implications for Rehabilitation Findings from this pilot study indicate that people with tetraplegia can be assisted to return to previous life roles, and develop new roles that have meaning to them through the use of assistive technologies for computer use. Being able to use the internet to socialize, and complete daily tasks, contributed to the participants gaining a sense of control over their lives. Early introduction to assistive technology is important to ensure sufficient time for newly injured people to feel comfortable enough with the assistive technology to use the computers productively by the time of discharge. Further research into this important and expanding area is indicated. PMID- 24050284 TI - Mycobacterium poriferae infection in a psoriasis patient on anti-TNF-alpha therapy. AB - Psoriasis is a chronic, auto-inflammatory disease affecting millions of individuals worldwide. In addition to classic cutaneous manifestations, the condition is linked to significant co-morbidities including cardiovascular disease, metabolic syndrome, melanoma and non-melanoma skin cancer, and psychiatric disease. Therefore, more aggressive treatment and multi-disciplinary care is critical. Measures of disease burden (quantified by anatomic location, body surface area (BSA) of involvement, and impact on daily life) assist in determining the severity of disease and have been integral in objective assessment of treatment regimens and new drug therapies. Biologic agents have entered the clinical armamentarium as treatment options for patients with moderate-to-severe psoriasis who have failed traditional systemic therapies. Three of the four FDA-approved biologic agents for psoriasis suppress TNF-alpha mediated pathways, which are essential for granuloma formation and maintenance, key components of host defenses against intracellular pathogens. Subsequently, the increased use of these agents is accompanied by increased reporting of granulomatous infectious diseases such as tuberculosis, histoplasmosis, nocardia, and nontuberculous mycobacteria. Report of any unusual infection is therefore vitally important in the care of this immune suppressed patient population. PMID- 24050285 TI - Malignant combined squamomelanocytic tumor: a clinical case. AB - A combined squamomelanocytic tumor is an exceedingly rare occurrence; little is known about its pathogenesis. A definitive diagnosis can only be made via histological examination. We describe herein an 83 year-old man who was discovered to have this combined tumor and recommend the appropriate management for such a lesion. PMID- 24050286 TI - Lasers and photodynamic therapy in the treatment of onychomycosis: a review of the literature. AB - Onychomycosis is a widespread problem. Oral antifungal medications are currently the gold standard of care, but treatment failure is common and oral therapy is contraindicated in many cases. There is a need for effective treatment without the systemic complications posed by oral therapy. Laser and photodynamic therapy may have the potential to treat onychomycosis locally without adverse systemic effects; some small studies have even reported achieving clinical and mycologic cure. However, there is reason for restraint; these therapies are expensive and time-consuming. Furthermore, they may not be covered by insurance and have not been proven effective with randomized, controlled clinical trials. This paper will review current literature regarding the use of laser and photodynamic therapy as potential treatments for onychomycosis. PMID- 24050287 TI - A bruise-like patch in a 4-year-old girl. AB - Dermatofibrosarcoma protuberans (DFSP), a rare medium grade sarcoma, occasionally occurs in childhood and is even more rarely present at birth. In children, the clinical appearance may be mistaken for a vascular malformation and so delayed diagnosis is not uncommon. Dermatofibrosarcoma protuberans is locally invasive and notorious for its high recurrence rate even after attempted wide local excision owing to extensive subclinical and asymmetrical extensions. In adult DFSP, Mohs Micrographic Surgery (MMS) is the treatment of choice because it offers a higher clearance rate compared to wide local excision. However, MMS may result in extended operating times owing to tissue processing and multiple stages. In children, this means a prolonged period under general anesthetic, which may be undesirable. We describe an interesting case of a 4- year-old girl diagnosed with DFSP. She underwent a modified MMS procedure in which she had two short general anesthetics. The advantage of MMS technique in which the full peripheral and deep margin of the specimen was examined. PMID- 24050288 TI - Generalized acanthosis nigricans without systemic disease associated. AB - Acanthosis nigricans (OMIM ID % 100600) is a dermatosis characterized by velvety hyperpigmentation, skin thickening, and papillomatosis. It mainly affects flexural areas. In most cases, the generalized form is related to malignancy in adults; it is rarely reported in the absence of systemic disease in children and adolescents. The present report is aimed at describing an unusual case of generalized acanthosis nigricans in a 17 year-old patient, in which, after extensive investigation (clinical, laboratorial and by imaging methods) no association with systemic disease was found. PMID- 24050289 TI - Uncorrectable ptosis: primary cutaneous signet-ring cell carcinoma. AB - Primary cutaneous signet-ring cell carcinoma (PCSRCC) is a rare but aggressive tumor. Our case highlights a 60-year-old man who presented with eyelid ptosis, for which he underwent multiple surgical procedures over a 3-year period prior to referral to our clinic. These procedures were complicated by scarring, delayed healing, and poor cosmetic outcome. In addition, the patient was noted to develop progressive enophthalmos. These concerning signs led to a CT scan and subsequent eyelid biopsy, which revealed a diagnosis of PCSRCC. Further management has involved an MRI and orbitotomy with biopsy revealing widespread extension of the carcinoma. Exenteration was performed to reduce the likelihood of metastasis. There are few documented case reports of PCSRCC of the eyelid in the literature. Of the 33 published cases of PCSRCC, 27 cases involve the eyelids and the other 6 cases involve the axilla. The unique clinical features of this case will be discussed, in particular the presentation as ptosis, an otherwise commonplace complaint in the oculoplastics clinic. The surgical course and histopathologic findings will be presented. The literature regarding PCSRCC will be reviewed including demographics, management, and prognosis. Although rare, PCSRCC follows an aggressive course with characteristically delayed diagnosis. Early identification and treatment likely offer a better prognosis. Thus, description of the clinical presentation of this rare tumor may aid in recognition and earlier treatment. PMID- 24050290 TI - Calciphylaxis treated with sodium thiosulfate: report of two cases. AB - Although traditionally observed in patients with end-stage renal disease and secondary hyperparathyroidism, calciphylaxis has been reported in patients with normal renal and parathyroid function. There is no evidence-based therapy available. The use of sodium thiosulfate (STS) has been increasingly described. Herein we describe two patients who responded well to this treatment. PMID- 24050291 TI - Solitary erythematous, tender plaque of the heel in a young infant. AB - Calcinosis cutis is a rare disorder resulting from the precipitation and deposition of insoluble calcium and phosphate salts (hydroxyapatite crystals) in the dermis and subcutaneous tissue. It is generally divided into four main groups on the basis of etiology and pathogenesis. Clinical presentation of cutaneous calcinosis cutis varies according to the diagnosis and the underlying process. We report a case of calcinosis cutis of the heel in which both the extravasation of a calcium gluconate infusion and renal failure could have promoted the development of calcinosis cutis. PMID- 24050292 TI - Preterm infant with a late presentation of blueberry muffin lesions secondary to recombinant erythropoietin. AB - Our patient is a 26-week-old preterm female infant delivered by caesarean section secondary to severe maternal preeclampsia who had been receiving subcutaneous recombinant erythropoietin (r-EPO) for anemia of prematurity. At 8 weeks of age after 8 doses of r-EPO, the infant developed numerous non-blanching erythematous macules and patches located on the back, posterior shoulder, and posterior arms, concerning for late-onset blueberry muffin lesions. Biopsy of the lesions confirmed dermal hematopoiesis. After r-EPO was discontinued all skin lesions gradually resolved over a period of 2 weeks and never recurred. PMID- 24050293 TI - A case of glyburide-induced leukocytoclastic vasculitis. AB - INTRODUCTION: Medication-induced leukocytoclastic vasculitis is a small-vessel vasculitis that most commonly manifests with palpable purpuric lesions on gravity dependent areas. Development of the vasculitis occurs within weeks after the initial administration of the medication, with clearance upon withdrawal of the medication. Glyburide, a sulfonylurea medication, is used to treat non-insulin dependent diabetes mellitus. We report a rare case of glyburide-associated leukocytoclastic vasculitis. OBSERVATION: We report a 71-year-old man with type 2 diabetes mellitus who presented with palpable purpura on the lower extremities. Cutaneous biopsy revealed superficial small vessel vasculitis with IgA perivascular deposits. Further questioning revealed three prior episodes of palpable purpura after restarting the glyburide medication, with clearance upon discontinuation. We diagnosed drug-induced vasculitis related to the glyburide. CONCLUSIONS: This case highlights a rarely reported cutaneous adverse reaction to the commonly used diabetic medication, glyburide. Physicians should consider cutaneous vasculitis as a potential side effect of glyburide. PMID- 24050294 TI - Syringocystadenocarcinoma papilliferum: a rare tumor with a favorable prognosis. AB - Syringocystadenocarcinoma papilliferum (SCACP) is a rare adenexal carcinoma with only 21 cases reported in the literature. Most patients describe a long-standing mass with recent change, supporting the idea that SCACP arises from malignant transformation of pre-existing syringocystadenoma papilliferum (SCAP). Syringocystadenocarcinoma papilliferum is generally treated with wide surgical excision of the lesion and patients do exceeding well and require no systemic therapy. PMID- 24050295 TI - Umbilicated nodule over eyebrow. AB - Trichofolliculoma is a pilosebaceous follicle hamartoma in which several hairs are formed within single pilosebaceous unit and protrude out of single orifice. Herein we report a 45-year-old woman with a trichofolliculoma of the eyebrow. PMID- 24050296 TI - Clinical characteristics and awareness of skin cancer in Hispanic patients. AB - Skin cancer in darker skin is associated with considerable morbidity and mortality. We sought to assess the clinical characteristics of cutaneous malignancy amongst Hispanic skin cancer patients and compare them to age-matched non-Hispanic Caucasians. In this retrospective study, 150 Hispanic skin cancer patients were identified from electronic medical records and age-matched to 150 non-Hispanic Caucasian controls with skin cancer. The incidence of actinic keratoses (AKs) in Hispanic skin cancer patients (34.0%) was statistically lower than age-matched non-Hispanic Caucasian skin cancer controls (61.3%, P <0.001; odds ratio, 3.08; 95% confidence interval, 1.92 - 4.93). Moreover, non-Hispanic Caucasian SCC (squamous cell cancer) controls were much more likely to report AKs (36.1%, P = 0.003) than Hispanic SCC patients (25.0%, P = 0.19). This study illustrates a lower incidence of AKs in Hispanic skin cancer patients as compared to their age-matched non-Hispanic Caucasians. The Hispanic skin malignancies present at a more advanced state and there is usually a lack of awareness in such cases. Therefore, patient knowledge and education is crucial for early detection and prevention of skin cancer in the Hispanic population. PMID- 24050297 TI - A case of microscopic polyangiitis with skin manifestations in a seven-year-old girl. AB - A case of a 7-year-old girl with microscopic polyangiitis (MPA) with a skin eruption characterized by maculopapular, erythematous and purpuric lesions on the face, elbows, and knees is presented. Anti-neutrophil cytoplasmic autoantibodies (ANCA) with myeloperoxidase specificity (MPO-ANCA) were identified. Chest X-ray and computed tomography scan revealed diffuse infiltrates in both lung fields, suggesting alveolar hemorrhage. Microscopic hematuria was detected but a renal biopsy showed no abnormalities. Histological examination of a skin biopsy from a purpuric papule showed leukocytoclastic vasculitis of the small vessels in the entire dermis. The patient was treated with prednisolone and mizoribine, resulting in an improvement in the skin lesions except for those on the knee. PMID- 24050298 TI - Bilateral and symmetrical tinea mammae. AB - Tinea corporis has rarely been reported in some locations such as on the breast skin as unilaterally. Herein, we present a case of bilateral tinea mammae, which has not been reported before in English language literature to our knowledge. PMID- 24050299 TI - Congenital agminated segmental nevi of the chest. AB - Grouped patterns of pigmented lesions are infrequent. Of the several reports of agminated nevi, most have been Spitz nevi or blue nevi. The distribution of these nevi is often segmental, following a dermatome or the lines of Blaschko. Most segmental nevi are not agminated and develop early in childhood [1]. We describe a rare case of congenital agminated segmental nevi on the chest. PMID- 24050300 TI - Examination of the phenolic profile and antioxidant activity of the leaves of the Australian native plant Smilax glyciphylla. AB - Together with the sweet principle component glycyphyllin A (3), seven phenolic compounds including two new dihydrochalcone rhamnopyranosides, glycyphyllin B (1) and glycyphyllin C (2), and five known flavonoids, catechin (4), kaempferol-3-O beta-D-glucopyranoside (5), quercetin-3-O-beta-D-glucopyranoside (6), kaempferol 3-O-beta-neohesperidoside (7), and 2R,3R-dihydrokaempferol-3-O-beta-D glucopyranoside (8), have been isolated from the ethanolic extract of the leaves of Smilax glyciphylla for the first time. The structures of these compounds were characterized by spectroscopic methods including UV, MS, and 1D and 2D NMR. In vitro antioxidant capacity tests employing FRAP and DPPH assays indicated that 1, 4, and 6 exhibited potent antioxidant activity and are the key phenolics responsible for the antioxidant activity of the leaf extract of S. glyciphylla. PMID- 24050301 TI - Mulberry 1-deoxynojirimycin pleiotropically inhibits glucose-stimulated vascular smooth muscle cell migration by activation of AMPK/RhoB and down-regulation of FAK. AB - Mulberry 1-deoxynojirimycin (DNJ), an inhibitor of alpha-glucosidase, has been reported to help prevent diabetes mellitus and suppress lipid accumulation. The aim of this study was to determine whether mulberry DNJ has pleiotropic effects on the development of atherosclerosis. The mechanisms by which mulberry DNJ might inhibit migration of A7r5 vascular smooth muscle cells (VSMCs) under hyperglycemic conditions mimicking diabetes were investigated. The antimigratory effects of DNJ on VSMCs were assessed by Western blot analysis of migration related proteins and by electric cell-substrate impedance sensing (ECIS) and visualization of F-actin cytoskeleton. Two pathways of DNJ-mediated inhibition of VSMC migration were identified. The first involved AMPK activation to inhibit fatty acid synthase (FASN) and Akt activity and then RhoB activation to inhibit nuclear factor-kappaB (NF-kappaB) and matrix metalloproteinase-2 (MMP) activity. The second involved inhibition of focal adhesion kinase (FAK), Ras, and RhoA activity leading to inhibition of F-actin activity. PMID- 24050302 TI - Plasmodium vivax malaria during pregnancy, Bolivia. AB - Plasmodium vivax is a major cause of illness in areas with low transmission of malaria in Latin America, Asia, and the Horn of Africa. However, pregnancy associated malaria remains poorly characterized in such areas. Using a hospital based survey of women giving birth and an antenatal survey, we assessed the prevalence rates of Plasmodium spp. infections in pregnant women in Bolivia, and evaluated the consequences of malaria during pregnancy on the health of mothers and newborns. P. vivax infection was detected in 7.9% of pregnant women attending antenatal visits, and placental infection occurred in 2.8% of deliveries; these rates did not vary with parity. Forty-two percent of all P. vivax malaria episodes were symptomatic. P. vivax-infected pregnant women were frequently anemic (6.5%) and delivered babies of reduced birthweight. P. vivax infections during pregnancy are clearly associated with serious adverse outcomes and should be considered in prevention strategies of pregnancy-associated malaria. PMID- 24050303 TI - Cytokine-induced changes in the gene expression profile of a human cerebral microvascular endothelial cell-line, hCMEC/D3. AB - BACKGROUND: The human cerebral microvascular endothelial cell line, hCMEC/D3, has been used extensively to model the blood-brain barrier (BBB) in vitro. Recently, we reported that cytokine-treatment induced loss of brain endothelial barrier properties. In this study, we further determined the gene expression pattern of hCMEC/D3 cells in response to activation with TNFalpha and IFNgamma. FINDINGS: Using a microarray approach, we observed that expression of genes involved in the control of barrier permeability, including inter-brain endothelial junctions (e.g. claudin-5, MARVELD-2), integrin-focal adhesions complexes (e.g. integrin beta1, ELMO-1) and transporter systems (e.g. ABCB1, SLC2A1), are altered by pro inflammatory cytokines. CONCLUSIONS: Our study shows that previously-described cytokine-induced changes in the pattern of gene expression of endothelium are reproduced in hCMEC/D3 cells, suggesting that this model is suitable to study inflammation at the BBB, while at the same time it has provided insights into novel key molecular processes that are altered in brain endothelium during neuroinflammation, such as modulation of cell-to-matrix contacts. PMID- 24050304 TI - Controlling carrier densities in photochemically reduced colloidal ZnO nanocrystals: size dependence and role of the hole quencher. AB - Photodoped colloidal ZnO nanocrystals are model systems for understanding the generation and physical or chemical properties of excess delocalized charge carriers in semiconductor nanocrystals. Typically, ZnO photodoping is achieved photochemically using ethanol (EtOH) as a sacrificial reductant. Curiously, different studies have reported over an order of magnitude spread in the maximum number of conduction-band electrons that can be accumulated by photochemical oxidation of EtOH. Here, we demonstrate that this apparent discrepancy results from a strong size dependence of the average maximum number of excess electrons per nanocrystal, . We demonstrate that increases in proportion to nanocrystal volume, such that the maximum carrier density remains constant for all nanocrystal sizes. is found to be largely insensitive to precise experimental conditions such as solvent, ligands, protons or other cations, photolysis conditions, and nanocrystal or EtOH concentrations. These results reconcile the broad range of literature results obtained with EtOH as the hole quencher. Furthermore, we demonstrate that depends on the identity of the hole quencher, and is thus not an intrinsic property of the multiply reduced ZnO nanocrystals themselves. Using a series of substituted borohydride hole quenchers, we show that it is possible to increase the nanocrystal carrier densities over 4-fold relative to previous photodoping reports. When excess lithium and potassium triethylborohydrides are used in the photodoping, formation of Zn(0) is observed. The relationship between metallic Zn(0) formation and ZnO surface electron traps is discussed. PMID- 24050305 TI - Confocal UV and resonance Raman microscopic imaging of pharmaceutical products. AB - Chemical imaging using confocal Raman microscopy is a useful analytical tool in drug development because of its ability to spatially image active ingredients and excipients in dosage forms and relate their distribution to product performance. While Raman spectra are highly specific for individual components of a formulation, most Raman microscopic mapping experiments require extensive experimental time. Laser wavelengths in the near-infrared range are used to suppress fluorescence but reduce sensitivity because of the inverse quadratic dependence of Raman scattering on laser wavelength. Compact, simple ultraviolet (UV) laser designs now allow for confocal UV Raman microscopy to be performed using a versatile instrument also capable of conventional Raman microscopy and epifluorescence imaging analyses. This study presents the results of UV Raman microscopy analyses using 266 nm laser irradiation of four pharmaceutical compositions of interest, including two types of tablets containing low doses of active ingredients (in the 0.2% w/w range), an amorphous dispersion containing 1% w/w of a small molecule drug, and an enteric coated layered peptide formulation. Resonance Raman enhancements are observed for four of the active ingredients studied in these formulations. The spectroscopic properties of the materials used in this study are also assessed by diffuse reflectance UV-visible spectroscopy, fluorescence spectroscopy, and conventional bulk Fourier transform Raman spectroscopy using 1064 nm laser irradiation. Confocal UV Raman microscopy was found to offer good sensitivity and allowed for rapid microscopic mapping of drugs and excipients at low concentrations in pharmaceutical formulations. PMID- 24050306 TI - Cell-based therapies for ocular disease. AB - Cell therapy for ocular disease has made significant progress within the last decade. Stem and progenitor populations for many ocular cell types have been identified, and their behavior is now understood well enough to enable clinical application. Corneal epithelial progenitor cell therapy has benefited many patients and is now transitioning from a research technique to established clinical therapy. The application of embryonic stem cell-based therapy is in clinical development for Stargardt's macular dystrophy and dry age-related macular degeneration. These advances have been made possible, in part, by the inherent advantages of the eye as a place to develop and apply cell therapies and the foundation built on transplantation studies. Despite these advances, there are still areas of high unmet need that could benefit from cell therapy when further research identifies methods to identify, generate, and manipulate the progenitor populations. This review discusses, in practical terms, the application of cell therapies to the eye, progress that has been made and progress which remains to be made in the application of cell therapy to ocular disease. PMID- 24050307 TI - Anti-inflammatory and anti-mutagenic effect of the YHK phytocompound in hepatocytes: in view of an age-management liver-protecting approach. AB - The receptor for advanced glycation end products (RAGE) regulates cellular proliferation in hepatocellular carcinoma (HCC). The aim of this study was to test the in vitro effect of Yo Jyo Hen Shi Ko (YHK), a nutraceutical with prior data suggesting its hepatocyte-protecting role, in regulating RAGE in the proliferation of the HCC cell line HuH7 as well checking also its potential modulation in the expression of the transcriptional factor nuclear factor-kappaB (NF-kappaB) p65. Our study showed that YHK significantly reduced cellular growth in the HuH7 cell line (p<0.05). Moreover, this phytocompound partly reduced gene expression of NF-kappaB p65 (by 35%, p<0.05). These data suggest that YHK has a potential role as a modulator of RAGE and RAGE ligands for potential healthy liver intervention in HCC prevention strategies. PMID- 24050309 TI - Polypoid lymphoid hyperplasia of the terminal ileum. PMID- 24050310 TI - Trimming a covered metal stent during hepaticogastrostomy by using argon plasma coagulation. PMID- 24050308 TI - Human cell toxicogenomic analysis linking reactive oxygen species to the toxicity of monohaloacetic acid drinking water disinfection byproducts. AB - Chronic exposure to drinking water disinfection byproducts has been linked to adverse health risks. The monohaloacetic acids (monoHAAs) are generated as byproducts during the disinfection of drinking water and are cytotoxic, genotoxic, mutagenic, and teratogenic. Iodoacetic acid toxicity was mitigated by antioxidants, suggesting the involvement of oxidative stress. Other monoHAAs may share a similar mode of action. Each monoHAA generated a significant concentration-response increase in the expression of a beta-lactamase reporter under the control of the antioxidant response element (ARE). The monoHAAs generated oxidative stress with a rank order of iodoacetic acid (IAA) > bromoacetic acid (BAA) ? chloroacetic acid (CAA); this rank order was observed with other toxicological end points. Toxicogenomic analysis was conducted with a nontransformed human intestinal epithelial cell line (FHs 74 Int). Exposure to the monoHAAs altered the transcription levels of multiple oxidative stress responsive genes, indicating that each exposure generated oxidative stress. The transcriptome profiles showed an increase in thioredoxin reductase 1 (TXNRD1) and sulfiredoxin (SRXN1), suggesting peroxiredoxin proteins had been oxidized during monoHAA exposures. Three possible sources of reactive oxygen species were identified, the hypohalous acid generating peroxidase enzymes lactoperoxidase (LPO) and myeloperoxidase (MPO), nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase 5 (NOX5), and PTGS2 (COX-2) mediated arachidonic acid metabolism. Each monoHAA exposure caused an increase in COX-2 mRNA levels. These data provide a functional association between monoHAA exposure and adverse health outcomes such as oxidative stress, inflammation, and cancer. PMID- 24050311 TI - A novel basket catheter to facilitate endoscopic removal of pancreatic stones (with video). AB - BACKGROUND: Endoscopic removal of pancreatic stones in patients with chronic pancreatitis is still challenging. With a conventional basket catheter, introduction to the target area or catching pancreatic stones is sometimes difficult. OBJECTIVE: To evaluate a novel double-lumen basket catheter composed of nitinol wires with fine reticular structures in the distal end and loose mesh in the proximal part. DESIGN: A prospective feasibility study. SETTING: Tertiary care center. PATIENTS: This study involved 10 patients with main pancreatic duct stones of 5 mm or less in the shorter diameter of the largest stone. INTERVENTION: In the first 5 cases, a nitinol basket catheter was used as salvage after stone extraction with a conventional basket catheter and retrieval balloon (salvage group). In the following 5 cases, stones were initially removed by using a nitinol basket catheter, and the presence of residual stones was evaluated by pancreatogram along with balloon sweep (initial group). MAIN OUTCOME MEASUREMENTS: Success rate of removal of the target stones and procedure-related adverse events. RESULTS: A nitinol basket catheter was easily introduced to the target stone in all patients. In the salvage group, additional stones were retrieved with a nitinol basket catheter in 3 of 5 patients. In the initial group, stone extraction by a nitinol basket catheter was successful, and no residual stones were extracted by additional balloon cleaning in any patients. Basket impaction or after-ERCP pancreatitis was not observed. LIMITATIONS: A small sample size without a control group. CONCLUSION: This novel nitinol basket catheter is useful for the extraction of small pancreatic stones. A randomized, controlled trial is warranted to confirm its efficacy. PMID- 24050315 TI - Exclusion from hexagonal mesophase surfactant domains drives end-to-end enchainment of rod-like particles. AB - Anisotropic rod-like particles assemble end-to-end when the surfactant/water matrix in which they are dispersed is cooled from the isotropic to the lyotropic hexagonal phase. We demonstrate the formation of such end-to-end assemblies for gold nanorods, which are tens of nanometers in size, as well as for micrometer sized ellipsoidal polystyrene particles. In both cases, the particles are well dispersed in the low-viscosity surfactant/water phase above the isotropic-H1 transition temperature. On cooling into the H1 phase, mesophase domains form and the particles are expelled to the isotropic phase. As the H1 domains grow and finally impinge, the particles are localized at the domain boundaries where they reorient and assemble end-to-end. Remarkably, we observe the formation of end-to end assemblies of gold nanorods even for volume fractions as low as 2 * 10(-6) in the initially dispersed state. The extent of particle "enchainment" increases with the particle concentration and with the aspect ratio of the particles. PMID- 24050312 TI - A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma. AB - BACKGROUND: Preclinical studies suggest that interleukin-9 may be a central mediator in the development and maintenance of airway inflammation in asthma. The aim of this study was therefore to evaluate the effects of MEDI-528, an anti interleukin-9 monoclonal antibody, in adults with confirmed uncontrolled moderate to-severe asthma. METHODS: In this prospective double-blind, multicenter, parallel-group study, 329 subjects were randomized (1:1:1:1) to subcutaneous placebo or MEDI-528 (30, 100, 300 mg) every 2 weeks for 24 weeks, in addition to their usual asthma medications. The primary endpoint was change in mean Asthma Control Questionnaire-6 (ACQ-6) score at week 13. Secondary endpoints included weighted asthma exacerbation rates and pre-bronchodilator forced expiratory volume in 1 second (FEV1) at weeks 13 and 25, as well as Asthma Quality of Life Questionnaire scores at weeks 12 and 25 and the safety of MEDI-528 throughout the study period. The primary endpoint was analyzed using analysis of covariance. RESULTS: The study population (n = 327) was predominantly female (69%) with a mean age of 43 years (range 18-65). The mean (SD) baseline ACQ-6 score for placebo (n = 82) and combined MEDI-528 (n = 245) was 2.8 (0.7) and 2.8 (0.8); FEV1 % predicted was 70.7% (15.9) and 71.5% (16.7). Mean (SD) change from baseline to week 13 in ACQ-6 scores for placebo vs combined MEDI-528 groups was 1.2 (1.0) vs -1.2 (1.1) (p = 0.86). Asthma exacerbation rates (95% CI) at week 25 for placebo vs MEDI-528 were 0.58 (0.36-0.88) vs 0.49 (0.37-0.64) exacerbations/subject/year (p = 0.52). No significant improvements in FEV1 % predicted were observed between the placebo and MEDI-528 groups. Adverse events were comparable for placebo (82.9%) and MEDI-528 groups (30 mg, 76.5%; 100 mg, 81.9%; 300 mg, 85.2%). The most frequent were asthma (placebo vs MEDI-528, 30.5% vs 33.5%), upper respiratory tract infection (14.6% vs 17.1%), and headache (9.8% vs 9.8%). CONCLUSIONS: The addition of MEDI-528 to existing asthma controller medications was not associated with any improvement in ACQ-6 scores, asthma exacerbation rates, or FEV1 values, nor was it associated with any major safety concerns. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00968669. PMID- 24050317 TI - Rapid characterization of chemical compounds in liquid and solid states using thermal desorption electrospray ionization mass spectrometry. AB - Rapid characterization of thermally stable chemical compounds in solid or liquid states is achieved through thermal desorption electrospray ionization mass spectrometry (TD-ESI/MS). A feature of this technique is that sampling, desorption, ionization, and mass spectrometric detection are four separate events with respect to time and location. A metal probe was used to sample analytes in their solid or liquid states. The probe was then inserted in a preheated oven to thermally desorb the analytes on the probe. The desorbed analytes were carried by a nitrogen gas stream into an ESI plume, where analyte ions were formed via interactions with charged solvent species generated in the ESI plume. The analyte ions were subsequently detected by a mass analyzer attached to the TD-ESI source. Quantification of acetaminophen in aqueous solutions using TD-ESI/MS was also performed in which a linear response for acetaminophen was obtained between 25 and 500 ppb (R(2) = 0.9978). The standard deviation for a reproducibility test for ten liquid samples was 9.6%. Since sample preparation for TD-ESI/MS is unnecessary, a typical analysis can be completed in less than 10 s. Analytes such as the active ingredients in over-the-counter drugs were rapidly characterized regardless of the different physical properties of said drugs, which included liquid eye drops, viscous cold syrup solution, ointment cream, and a drug tablet. This approach was also used to detect trace chemical compounds in illicit drugs and explosives, in which samples were obtained from the surfaces of a cell phone, piece of luggage made from hard plastic, business card, and wooden desk. PMID- 24050316 TI - Experimental traumatic brain injury induces rapid aggregation and oligomerization of amyloid-beta in an Alzheimer's disease mouse model. AB - Soluble amyloid-beta (Abeta) oligomers are hypothesized to be the pathogenic species in Alzheimer's disease (AD), and increased levels of oligomers in the brain subsequent to traumatic brain injury (TBI) may exacerbate secondary injury pathways and underlie increased risk of developing AD in later life. To determine whether TBI causes Abeta aggregation and oligomerization in the brain, we exposed triple transgenic AD model mice to controlled cortical impact injury and measured levels of soluble, insoluble, and oligomeric Abeta by enzyme-linked immunosorbent assay (ELISA) at 1, 3, and 7 days postinjury. TBI rapidly increased levels of both soluble and insoluble Abeta40 and Abeta42 in the injured cortex at 1 day postinjury. We confirmed previous findings that identified damaged axons as a major site of Abeta accumulation using both immunohistochemistry and biochemistry. We also report that soluble Abeta oligomers were significantly increased in the injured cortex, as demonstrated by both ELISA and Western blot. Interestingly, the mouse brain is able to rapidly clear trauma-induced Abeta, with both soluble and insoluble Abeta species returning to sham levels by 7 days postinjury. In conclusion, we demonstrate that TBI causes acute accumulation and aggregation of Abeta in the brain, including the formation of low- and high molecular-weight Abeta oligomers. The formation and aggregation of Abeta into toxic species acutely after injury may play a role in secondary injury cascades after trauma and, chronically, may contribute to increased risk of developing AD in later life. PMID- 24050319 TI - Communication: Two measures of isochronal superposition. AB - A liquid obeys isochronal superposition if its dynamics is invariant along the isochrones in the thermodynamic phase diagram (the curves of constant relaxation time). This paper introduces two quantitative measures of isochronal superposition. The measures are used to test the following six liquids for isochronal superposition: 1,2,6 hexanetriol, glycerol, polyphenyl ether, diethyl phthalate, tetramethyl tetraphenyl trisiloxane, and dibutyl phthalate. The latter four van der Waals liquids obey isochronal superposition to a higher degree than the two hydrogen-bonded liquids. This is a prediction of the isomorph theory, and it confirms findings by other groups. PMID- 24050318 TI - Increased incidence of invasive fusariosis with cutaneous portal of entry, Brazil. AB - Invasive fusariosis (IF) is an infection with Fusarium spp. fungi that primarily affects patients with hematologic malignancies and hematopoietic cell transplant recipients. A cutaneous portal of entry is occasionally reported. We reviewed all cases of IF in Brazil during 2000-2010, divided into 2 periods: 2000-2005 (period 1) and 2006-2010 (period 2). We calculated incidence rates of IF and of superficial infections with Fusarium spp. fungi identified in patients at a dermatology outpatient unit. IF incidence for periods 1 and 2 was 0.86 cases versus 10.23 cases per 1,000 admissions (p<0.001), respectively; superficial fusarial infection incidence was 7.23 versus 16.26 positive cultures per 1,000 superficial cultures (p<0.001), respectively. Of 21 cases of IF, 14 showed a primary cutaneous portal of entry. Further studies are needed to identify reservoirs of these fungi in the community and to implement preventive measures for patients at risk. PMID- 24050320 TI - Communication: Trapping upconverted energy in neat platinum porphyrin films via an unexpected fusion mechanism. AB - Direct observation of an unexpected product from excited state fusion of two excited triplet states in platinum octaethylporphyrin is reported. Transient spectroscopy was used to identify the product as a metal centered (d, d) state that decays slowly compared with the rate of fusion. The reaction was demonstrated to be second order with a rate coefficient of k(TTF) = (5.4 +/- 0.4) * 10(-10) cm(3) . s(-1). The results contrast with the common assumption that fusion proceeds directly to annihilation via rapid non-radiative deactivation of the products. Following visible photo-excitation, the fusion process results in energetic upconversion of the incident photons stored in the higher energy (d, d) state at irradiances below the threshold for multi-photon absorption. PMID- 24050321 TI - Communication: Determination of the molecular structure of the simplest Criegee intermediate CH2OO. AB - The simplest Criegee intermediate CH2OO was detected in a discharged supersonic jet of a CH2Br2 and O2 gas mixture by Fourier-transform microwave spectroscopy. The experimentally determined rotational constants of CH2OO and its isotopologues enabled us to derive the geometrical structure. The determined OO and CO bond lengths, which are relevant to a discussion on its electronic structure, are 1.345(3) and 1.272(3) A, respectively. The CO bond length is close to that of a typical double bond and is shorter than that of the OO bond by 0.07 A, indicating that CH2OO has a more zwitterionic character H2C = O(?)-O(?) than biradical H2C-O O. PMID- 24050322 TI - Development of open-boundary cluster model approach for electrochemical systems and its application to Ag+ adsorption on Au(111) and Ag(111) electrodes. AB - We present a theoretical method to investigate electrochemical processes on the basis of a finite-temperature density functional theory (FT-DFT) approach combined with our recently developed open-boundary cluster model (OCM). A semi infinite electrode is well mimicked by a finite-sized simple cluster with an open quantum boundary condition rationalized by OCM. An equilibrium state between adsorbates and an electrode is described by the grand canonical formulation of FT DFT. These implements allow us to calculate electronic properties of an adsorbate and electrode system at a constant chemical potential MU, i.e., electrode potential. A solvation effect is approximated by a conductor-like polarized continuum model. The method is applied to the electrochemical processes of Ag(+) adsorption on Au(111) and Ag(111). The present constant MU approach has proved essential to electrochemical systems, demonstrating that the method qualitatively reproduces the experimental evidence that Ag(+) adsorbs more on the Au electrode than the Ag one, while the conventional quantum chemistry approach with a constant number of electrons incorrectly gives exactly the opposite result. PMID- 24050323 TI - Direct calculation of the solid-liquid Gibbs free energy difference in a single equilibrium simulation. AB - Computing phase diagrams of model systems is an essential part of computational condensed matter physics. In this paper, we discuss in detail the interface pinning (IP) method for calculation of the Gibbs free energy difference between a solid and a liquid. This is done in a single equilibrium simulation by applying a harmonic field that biases the system towards two-phase configurations. The Gibbs free energy difference between the phases is determined from the average force that the applied field exerts on the system. As a test system, we study the Lennard-Jones model. It is shown that the coexistence line can be computed efficiently to a high precision when the IP method is combined with the Newton Raphson method for finding roots. Statistical and systematic errors are investigated. Advantages and drawbacks of the IP method are discussed. The high pressure part of the temperature-density coexistence region is outlined by isomorphs. PMID- 24050324 TI - Polaron dynamics in two-dimensional photon-echo spectroscopy of molecular rings. AB - We have developed a new approach to the computation of third-order spectroscopic signals of molecular rings, by incorporating the Davydov soliton theory into the nonlinear response function formalism. The Davydov D1 and D Ansatze have been employed to treat the interactions between the excitons and the primary phonons, allowing for a full description of arbitrary exciton-phonon coupling strengths. As an illustration, we have simulated a series of optical 2D spectra for two models of molecular rings. PMID- 24050325 TI - The role of available sites in the activity of lattice gases with geometric constraints. AB - The activity in lattice-gas systems with geometric constraints is shown to be the ratio of the number of particles to the number of available sites. The key role of sites available for occupation is emphasized. Available sites may be different for different species and are not necessarily just unoccupied sites. Location specific or non-local constraints are allowed. An analytical expression for the number of available sites is given for the hard-hexagon model. The utility of an expression for available sites is illustrated for the non-trivial case of a mixed Langmuir/hard-hexagon adsorption system, where the influence of the Langmuir adsorbates on the hard-hexagon phase transition is investigated. The dependence on available sites indicates how to extend these results to the kinetic regime and simulations of kinetic voltammograms for the hard-hexagon model are given as an example. PMID- 24050326 TI - Role of sampling in evaluating classical time autocorrelation functions. AB - We analyze how the choice of the sampling weight affects efficiency of the Monte Carlo evaluation of classical time autocorrelation functions. Assuming uncorrelated sampling or sampling with constant correlation length, we propose a sampling weight for which the number of trajectories needed for convergence is independent of the correlated quantity, dimensionality, dynamics, and phase-space density. By contrast, it is shown that the computational cost of the "standard" algorithm sampling from the phase-space density may scale exponentially with the number of degrees of freedom. Yet, for the stationary Gaussian distribution of harmonic systems and for the autocorrelation function of a linear function of phase-space coordinates, the computational cost of this standard algorithm is also independent of dimensionality. PMID- 24050327 TI - Solvatochromic shifts from coupled-cluster theory embedded in density functional theory. AB - Building on the framework recently reported for determining general response properties for frozen-density embedding [S. Hofener, A. S. P. Gomes, and L. Visscher, J. Chem. Phys. 136, 044104 (2012)], in this work we report a first implementation of an embedded coupled-cluster in density-functional theory (CC-in DFT) scheme for electronic excitations, where only the response of the active subsystem is taken into account. The formalism is applied to the calculation of coupled-cluster excitation energies of water and uracil in aqueous solution. We find that the CC-in-DFT results are in good agreement with reference calculations and experimental results. The accuracy of calculations is mainly sensitive to factors influencing the correlation treatment (basis set quality, truncation of the cluster operator) and to the embedding treatment of the ground-state (choice of density functionals). This allows for efficient approximations at the excited state calculation step without compromising the accuracy. This approximate scheme makes it possible to use a first principles approach to investigate environment effects with specific interactions at coupled-cluster level of theory at a cost comparable to that of calculations of the individual subsystems in vacuum. PMID- 24050328 TI - Path integral density matrix dynamics: a method for calculating time-dependent properties in thermal adiabatic and non-adiabatic systems. AB - We introduce a new approach for calculating quantum time-correlation functions and time-dependent expectation values in many-body thermal systems; both electronically adiabatic and non-adiabatic cases can be treated. Our approach uses a path integral simulation to sample an initial thermal density matrix; subsequent evolution of this density matrix is equivalent to solution of the time dependent Schrodinger equation, which we perform using a linear expansion of Gaussian wavepacket basis functions which evolve according to simple classical like trajectories. Overall, this methodology represents a formally exact approach for calculating time-dependent quantum properties; by introducing approximations into both the imaginary-time and real-time propagations, this approach can be adapted for complex many-particle systems interacting through arbitrary potentials. We demonstrate this method for the spin Boson model, where we find good agreement with numerically exact calculations. We also discuss future directions of improvement for our approach with a view to improving accuracy and efficiency. PMID- 24050329 TI - Nonequilibrium Ornstein-Zernike relation for Brownian many-body dynamics. AB - We derive a dynamic Ornstein-Zernike equation for classical fluids undergoing overdamped Brownian motion and driven out of equilibrium. Inhomogeneous two-time correlation functions are obtained from functional differentiation of the one body density and current with respect to an appropriately chosen external field. Functional calculus leads naturally to non-Markovian equations of motion for the two-time correlators. Memory functions are identified as functional derivatives of a space- and time-nonlocal power dissipation functional. We propose an excess (over ideal gas) dissipation functional that both generates mode-coupling theory for the two-body correlations and extends dynamical density functional theory for the one-body fields, thus unifying the two approaches. PMID- 24050330 TI - Natural occupation numbers: when do they vanish? AB - The non-vanishing of the natural orbital (NO) occupation numbers of the one particle density matrix of many-body systems has important consequences for the existence of a density matrix-potential mapping for nonlocal potentials in reduced density matrix functional theory and for the validity of the extended Koopmans' theorem. On the basis of Weyl's theorem we give a connection between the differentiability properties of the ground state wavefunction and the rate at which the natural occupations approach zero when ordered as a descending series. We show, in particular, that the presence of a Coulomb cusp in the wavefunction leads, in general, to a power law decay of the natural occupations, whereas infinitely differentiable wavefunctions typically have natural occupations that decay exponentially. We analyze for a number of explicit examples of two-particle systems that in case the wavefunction is non-analytic at its spatial diagonal (for instance, due to the presence of a Coulomb cusp) the natural orbital occupations are non-vanishing. We further derive a more general criterium for the non-vanishing of NO occupations for two-particle wavefunctions with a certain separability structure. On the basis of this criterium we show that for a two particle system of harmonically confined electrons with a Coulombic interaction (the so-called Hookium) the natural orbital occupations never vanish. PMID- 24050331 TI - Long-range interactions and the sign of natural amplitudes in two-electron systems. AB - In singlet two-electron systems, the natural occupation numbers of the one particle reduced density matrix are given as squares of the natural amplitudes which are defined as the expansion coefficients of the two-electron wave function in a natural orbital basis. In this work, we relate the sign of the natural amplitudes to the nature of the two-body interaction. We show that long-range Coulomb-type interactions are responsible for the appearance of positive amplitudes and give both analytical and numerical examples that illustrate how the long-distance structure of the wave function affects these amplitudes. We further demonstrate that the amplitudes show an avoided crossing behavior as function of a parameter in the Hamiltonian and use this feature to show that these amplitudes never become zero, except for special interactions in which infinitely many of them can become zero simultaneously when changing the interaction strength. This mechanism of avoided crossings provides an alternative argument for the non-vanishing of the natural occupation numbers in Coulomb systems. PMID- 24050332 TI - Description of electronic excited states using electron correlation operator. AB - The electron correlation energy in a chemical system is defined as a difference between the energy of an exact energy for a given Hamiltonian, and a mean-field, or single determinant, approximation to it. A promising way to model electron correlation is through the expectation value of a linear two-electron operator for the Kohn-Sham single determinant wavefunction. For practical reasons, it is desirable for such an operator to be universal, i.e., independent of the positions and types of nuclei in a molecule. The correlation operator models the effect of electron correlation on the interaction energy in a electron pair. We choose an operator expanded in a small number of Gaussians as a model for electron correlation, and test it by computing atomic and molecular adiabatic excited states. The computations are performed within the Delta Self-Consistent Field (DeltaSCF) formalism, and are compared to the time-dependent density functional theory model with popular density functionals. The simplest form of the correlation operator contains only one parameter derived from the helium atom ground state correlation energy. The correlation operator approach significantly outperforms other methods in computation of atomic excitation energies. The accuracy of molecular excitation energies computed with the correlation operator is limited by the shortcomings of the DeltaSCF methodology in describing excited states. PMID- 24050333 TI - Equivalence of particle-particle random phase approximation correlation energy and ladder-coupled-cluster doubles. AB - The recent proposal to determine the (exact) correlation energy based on pairing matrix fluctuations by van Aggelen et al. ["Exchange-correlation energy from pairing matrix fluctuation and the particle-particle random phase approximation," preprint arXiv:1306.4957 (2013)] revived the interest in the simplest approximation along this path: the particle-particle random phase approximation (pp-RPA). In this paper, we present an analytical connection and numerical demonstrations of the equivalence of the correlation energy from pp-RPA and ladder-coupled-cluster doubles. These two theories reduce to identical algebraic matrix equations and correlation energy expressions. The numerical examples illustrate that the correlation energy missed by pp-RPA in comparison with coupled-cluster singles and doubles is largely canceled out when considering reaction energies. This theoretical connection will be beneficial to design density functionals with strong ties to coupled-cluster theories and to study molecular properties at the pp-RPA level relying on well established coupled cluster techniques. PMID- 24050334 TI - Particle-particle and quasiparticle random phase approximations: connections to coupled cluster theory. AB - We establish a formal connection between the particle-particle (pp) random phase approximation (RPA) and the ladder channel of the coupled cluster doubles (CCD) equations. The relationship between RPA and CCD is best understood within a Bogoliubov quasiparticle (qp) RPA formalism. This work is a follow-up to our previous formal proof on the connection between particle-hole (ph) RPA and ring CCD. Whereas RPA is a quasibosonic approximation, CC theory is a "correct bosonization" in the sense that the wavefunction and Hilbert space are exactly fermionic, yet the amplitude equations can be interpreted as adding different quasibosonic RPA channels together. Coupled cluster theory achieves this goal by interacting the ph (ring) and pp (ladder) diagrams via a third channel that we here call "crossed-ring" whose presence allows for full fermionic antisymmetry. Additionally, coupled cluster incorporates what we call "mosaic" terms which can be absorbed into defining a new effective one-body Hamiltonian. The inclusion of these mosaic terms seems to be quite important. The pp-RPA and qp-RPA equations are textbook material in nuclear structure physics but are largely unknown in quantum chemistry, where particle number fluctuations and Bogoliubov determinants are rarely used. We believe that the ideas and connections discussed in this paper may help design improved ways of incorporating RPA correlation into density functionals based on a CC perspective. PMID- 24050335 TI - Extension of many-body theory and approximate density functionals to fractional charges and fractional spins. AB - The exact conditions for density functionals and density matrix functionals in terms of fractional charges and fractional spins are known, and their violation in commonly used functionals has been shown to be the root of many major failures in practical applications. However, approximate functionals are designed for physical systems with integer charges and spins, not in terms of the fractional variables. Here we develop a general framework for extending approximate density functionals and many-electron theory to fractional-charge and fractional-spin systems. Our development allows for the fractional extension of any approximate theory that is a functional of G(0), the one-electron Green's function of the non interacting reference system. The extension to fractional charge and fractional spin systems is based on the ensemble average of the basic variable, G(0). We demonstrate the fractional extension for the following theories: (1) any explicit functional of the one-electron density, such as the local density approximation and generalized gradient approximations; (2) any explicit functional of the one electron density matrix of the non-interacting reference system, such as the exact exchange functional (or Hartree-Fock theory) and hybrid functionals; (3) many-body perturbation theory; and (4) random-phase approximations. A general rule for such an extension has also been derived through scaling the orbitals and should be useful for functionals where the link to the Green's function is not obvious. The development thus enables the examination of approximate theories against known exact conditions on the fractional variables and the analysis of their failures in chemical and physical applications in terms of violations of exact conditions of the energy functionals. The present work should facilitate the calculation of chemical potentials and fundamental bandgaps with approximate functionals and many-electron theories through the energy derivatives with respect to the fractional charge. It should play an important role in developing accurate approximate density functionals and many-body theory. PMID- 24050336 TI - Hyperfine interactions in a gadolinium-based MRI contrast agent: high-frequency modulations from ab initio simulations. AB - Hyperfine coupling tensors of the water molecule coordinated to the Prohance contrast agent in liquid water were calculated within and beyond the point dipole approximation along an ab initio molecular dynamics trajectory. We observe the non-equivalence at short time scales on structural as well as magnetodynamical properties of inner sphere water protons due to hydrogen bonds formation with the solvent. In addition, the influence of ultrafast internal motions on the anisotropic, dipolar, contribution to hyperfine couplings was probed thanks to a decomposition of its fluctuations in terms of a small set of meaningful collective variables. PMID- 24050337 TI - Analytic energy gradients for the orbital-optimized third-order Moller-Plesset perturbation theory. AB - Analytic energy gradients for the orbital-optimized third-order Moller-Plesset perturbation theory (OMP3) [U. Bozkaya, J. Chem. Phys. 135, 224103 (2011)] are presented. The OMP3 method is applied to problematic chemical systems with challenging electronic structures. The performance of the OMP3 method is compared with those of canonical second-order Moller-Plesset perturbation theory (MP2), third-order Moller-Plesset perturbation theory (MP3), coupled-cluster singles and doubles (CCSD), and coupled-cluster singles and doubles with perturbative triples [CCSD(T)] for investigating equilibrium geometries, vibrational frequencies, and open-shell reaction energies. For bond lengths, the performance of OMP3 is in between those of MP3 and CCSD. For harmonic vibrational frequencies, the OMP3 method significantly eliminates the singularities arising from the abnormal response contributions observed for MP3 in case of symmetry-breaking problems, and provides noticeably improved vibrational frequencies for open-shell molecules. For open-shell reaction energies, OMP3 exhibits a better performance than MP3 and CCSD as in case of barrier heights and radical stabilization energies. As discussed in previous studies, the OMP3 method is several times faster than CCSD in energy computations. Further, in analytic gradient computations for the CCSD method one needs to solve lambda-amplitude equations, however for OMP3 one does not since lambda(ab)(ij(1))=t(ij)(ab(1)) and lambda(ab)(ij(2))=t(ij)(ab(2)). Additionally, one needs to solve orbital Z-vector equations for CCSD, but for OMP3 orbital response contributions are zero owing to the stationary property of OMP3. Overall, for analytic gradient computations the OMP3 method is several times less expensive than CCSD (roughly ~4-6 times). Considering the balance of computational cost and accuracy we conclude that the OMP3 method emerges as a very useful tool for the study of electronically challenging chemical systems. PMID- 24050338 TI - Slow photoelectron velocity-map imaging spectroscopy of the C9H7 (indenyl) and C13H9 (fluorenyl) anions. AB - High-resolution photoelectron spectra are reported of the cryogenically cooled indenyl and fluorenyl anions, C9H7(-) and C13H9(-), obtained with slow electron velocity-map imaging. The spectra show well-resolved transitions to the neutral ground states, giving electron affinities of 1.8019(6) eV for indenyl and 1.8751(3) eV for fluorenyl. Numerous vibrations are observed and assigned for the first time in the radical ground states, including several transitions that are allowed only through vibronic coupling. The fluorenyl spectra can be interpreted with a Franck-Condon simulation, but explaining the indenyl spectra requires careful consideration of vibronic coupling and photodetachment threshold effects. Comparison of high- and low-resolution spectra along with measurements of photoelectron angular distributions provide further insights into the interplay between vibronic coupling and the photodetachment dynamics. Transitions to the neutral first excited states are also seen, with term energies of 0.95(5) eV and 1.257(4) eV for indenyl and fluorenyl, respectively. Those peaks are much wider than the experimental resolution, suggesting that nearby conical intersections must be considered to fully understand the vibronic structure of the neutral radicals. PMID- 24050339 TI - Structural and vibrational properties of phenanthrene under pressure. AB - The structural and vibrational properties of phenanthrene are measured at high pressures up to 30.2 GPa by Raman spectroscopy and synchrotron X-ray diffraction techniques. Two phase transitions are observed in the Raman spectra at pressures of 2.3 GPa and 5.4 GPa which correspond to significant changes of intermolecular and intramolecular vibrational modes. Above 10.2 GPa, all the Raman peaks are lost within the fluorescence background; however, upon further compression above 20.0 GPa, three broad peaks are observed at 1600, 2993, and 3181 cm(-1), indicating that phenanthrene has transformed into amorphous phase. Using X-ray diffraction, the structures of corresponding phases observed from Raman spectra are indexed with space groups of P2(1) for phase I (0-2.2 GPa), P2/m for phase II (2.2-5.6 GPa), P2/m+Pmmm for phase III (5.6-11.4 GPa) which has a coexistence of structures, and above 11.4 GPa the structure is indexed with space group of Pmmm. Although phenanthrene has transformed to a hydrogenated amorphous carbon structure above 20.0 GPa, these amorphous clusters still show characteristic crystalline behavior based on our X-ray diffraction patterns. Our results suggest that the long-range periodicity and the local disorder state coexist in phenanthrene at high pressures. PMID- 24050340 TI - Microwave, infrared-microwave double resonance, and theoretical studies of C2H4...H2S complex. AB - In this manuscript, rotational spectra of four new isotopologues of the S-H...pi bonded C2H4...H2S complex, i.e., C2D4...H2S, C2D4...D2S, C2D4...HDS, and (13)CCH4...H2S have been reported and analyzed. All isotopologues except C2D4...HDS show a four line pattern whereas a doubling of the transition frequencies was observed for C2D4...HDS. These results together with our previous report on the title complex [M. Goswami, P. K. Mandal, D. J. Ramdass, and E. Arunan, Chem. Phys. Lett. 393(1-3), 22-27 (2004)] confirm that both subunits (C2H4 and H2S) are involved in large amplitude motions leading to a splitting of each rotational transition to a quartet. Further, the results also confirm that the motions which are responsible for the observed splittings involve both monomers. Molecular symmetry group analysis, considering the interchange of equivalent H atoms in H2S and C2H4 could explain the observed four line pattern and their intensities in the microwave spectrum. In addition, hydride stretching fundamentals of the complex were measured using coherence-converted population transfer Fourier Transform Microwave-infrared (IR-MW double resonance) experiments in the S-H and C-H stretch regions. Changes in the tunneling splittings upon vibrational excitation are consistent with the isotopic dependence of pure rotational transitions. A complexation shift of 2.7-6.5 cm(-1) has been observed in the two fundamental S-H stretching modes of the H2S monomer in the complex. Vibrational pre-dissociation in the bound S-H stretch has been detected whereas the instrument-limited line-shapes in other S-H and C-H stretches indicate slower pre-dissociation rate. Some local perturbations in the vibrational spectra have been observed. Two combination bands have been observed corresponding to both the S-H stretching fundamentals and what appears to be the intermolecular stretching mode at 55 cm(-1). The tunneling splitting involved in the rotation of C2H4 unit has been deduced to be 1.5 GHz from the IR-MW results. In addition, ab initio barrier heights derived for different motions of the monomers support the experimental results and provide further insight into the motions causing the splitting. PMID- 24050341 TI - Formation and properties of iron-based magnetic superhalogens: a theoretical study. AB - In order to explore new magnetic superhalogens, we have systematically investigated the structures, electrophilic properties, stabilities, magnetic properties, and fragmentation channels of neutral and anionic Fe(m)F(n) (m = 1, 2; n = 1-7) clusters using density functional theory. Our results show that a maximum of six F atoms can be bound atomically to one Fe atom, and the Fe-Fe bonding is not preferred in Fe2F(n)(0/-) clusters. The computed electron affinities (EAs) indicate that FeF(n) with n >= 3 are superhalogens, while Fe2F(n) can be classified as superhalogens for n >= 5. To further understand their superhalogen characteristic, the natural population analysis charge distribution and the HOMOs of anionic clusters were also analyzed. When the extra negative charge and the content of HOMO are mainly located on F atoms, the clusters could be classified as superhalogens with EAs substantially surpass that of Cl. By calculating the binding energies per atom and the HOMO-LUMO gaps, FeF3, FeF4(-), Fe2F4, Fe2F5(-), and Fe2F7(-) clusters were found to have higher stabilities, corresponding to the Fe atoms that are attained at their favorite +2 and +3 oxidation states. Furthermore, we also predicted the most preferred fragmentation channel and product for all the ground state clusters. Even more striking is the fact that both neutral and anionic Fe(m)F(n) (m = 1, 2; n = 1-7) clusters carry large magnetic moments which mainly come from 3d orbital of iron atom. PMID- 24050342 TI - Photochromic cycle of 2'-hydroxyacetophenone azine studied by absorption and emission spectroscopy in different solvents. AB - This paper reports on the investigations of the synthesized di-(o-hydroxyaryl ketoimine) compound by the steady state absorption and emission techniques as well as picosecond time resolved emission and femtosecond transient absorption methods in different solvents. The results of the experimental observation have been supported by the theoretical DFT and TD-DFT calculations. The theoretical data have revealed the completed influence of the environmental polarity on particular conformers of studied compound. Dependencies between the activation rate constant and polarizability function as well as Kamlet-Abbond-Taft hydrogen bonding parameter have been obtained in different solvent. The mechanism of photodynamic changes of di-(o-hydroxyaryl ketoimine) is presented. PMID- 24050343 TI - Oscillatory and fluctuating terms in energies of assemblies of equicharged particles subject to spherically symmetric power-law confining potentials. AB - Energies E(N) of assemblies of equicharged particles subject to spherically symmetric power-law confining potentials vary in a convoluted fashion with the particle totalities N. Accurate rigorous upper bounds to these energies, which are amenable to detailed mathematical analysis, are found to comprise terms with smooth, oscillatory, and fluctuating dependences on N. The smooth energy component is obtained as a power series in N(-2/3) with the first two terms corresponding to the bulk and Madelung energies. The oscillatory component possesses the large-N asymptotics given by a product of N(1/(lambda + 1)), where lambda is the power-law exponent, and a function periodic in N(1/3). The amplitude of the fluctuating component, which originates mostly from the irregular dependence of the Thomson energy E(Th)(n) on n, also scales like N(1/(lambda + 1)). PMID- 24050344 TI - Spectroscopy of gold atoms isolated in liquid and solid 4He matrices. AB - We present a systematic experimental study of absorption and fluorescence spectra of Au atoms in bulk liquid and solid helium matrices. The results are compared to the spectra of Cu atoms studied earlier. We investigate the dependence of the observed spectral lineshapes on the helium pressure. The observed splitting of the 5d(10)6p - 5d(9)6s(2) transitions of Au in hcp solid He gives evidence for an anisotropic trapping site structure formed either by a non-spherical atomic bubble or a four-vacancy center. PMID- 24050345 TI - Stable negative ions and shape resonances in a series of organic molecules. AB - We report on the theoretical determination of low-lying shape resonances in a selected set of seven molecules. The finite element discrete model method is used and the absolute differences between calculated and experimental values, where known, are ?0.15 eV for the resonances lowest in energy. Difficulties expected with the higher calculated values are discussed. This article reports results for ortho-benzyne, benzene, naphthalene, anthracene, styrene, formamide, and acetamide. Comparisons are made with a few other calculations, again where available. PMID- 24050346 TI - Ab initio ground-state potential energy functions of beryllium monohydride ions: BeH+ and BeH-. AB - The accurate ground-state potential energy functions of beryllium monohydride (BeH) cation and anion have been determined from ab initio calculations using the multi-reference averaged coupled-pair functional (MR-ACPF) method in conjunction with the correlation-consistent core-valence basis sets up to septuple-zeta quality. The effects of electron correlation beyond the MR-ACPF level of approximation, as well as the scalar relativistic and adiabatic corrections were taken into account. The vibration-rotation energy levels of the BeH, BeD, and BeT isotopologues of both ions were predicted to near "spectroscopic" accuracy. The results can be useful in a future experimental detection of the BeH anion by high resolution vibration-rotation spectroscopy. PMID- 24050347 TI - Biomass pyrolysis: thermal decomposition mechanisms of furfural and benzaldehyde. AB - The thermal decompositions of furfural and benzaldehyde have been studied in a heated microtubular flow reactor. The pyrolysis experiments were carried out by passing a dilute mixture of the aromatic aldehydes (roughly 0.1%-1%) entrained in a stream of buffer gas (either He or Ar) through a pulsed, heated SiC reactor that is 2-3 cm long and 1 mm in diameter. Typical pressures in the reactor are 75 150 Torr with the SiC tube wall temperature in the range of 1200-1800 K. Characteristic residence times in the reactor are 100-200 MUsec after which the gas mixture emerges as a skimmed molecular beam at a pressure of approximately 10 MUTorr. Products were detected using matrix infrared absorption spectroscopy, 118.2 nm (10.487 eV) photoionization mass spectroscopy and resonance enhanced multiphoton ionization. The initial steps in the thermal decomposition of furfural and benzaldehyde have been identified. Furfural undergoes unimolecular decomposition to furan + CO: C4H3O-CHO (+ M) -> CO + C4H4O. Sequential decomposition of furan leads to the production of HC=CH, CH2CO, CH3C=CH, CO, HCCCH2, and H atoms. In contrast, benzaldehyde resists decomposition until higher temperatures when it fragments to phenyl radical plus H atoms and CO: C6H5CHO (+ M) -> C6H5CO + H -> C6H5 + CO + H. The H atoms trigger a chain reaction by attacking C6H5CHO: H + C6H5CHO -> [C6H6CHO]* -> C6H6 + CO + H. The net result is the decomposition of benzaldehyde to produce benzene and CO. PMID- 24050349 TI - On the way to the highest coordination number in the planar metal-centred aromatic Ta(c)B10- cluster: evolution of the structures of TaB(n)- (n = 3-8). AB - The structures and chemical bonding of TaB(n)(-) (n = 3-8) clusters are investigated systematically to elucidate the formation of the planar metal centred aromatic borometallic cluster, Ta(c)B10(-) (the (c) sign is used to designate the central position of the doped atom in monocyclic structures in M(c)B(n)-type planar clusters), which was found previously to have the highest coordination number for a metal atom in a planar geometry. Photoelectron spectroscopy is combined with ab initio calculations to determine the global minima of the TaB(n)(-) clusters. We find that from TaB3(-) to TaB5(-) the boron atoms nucleate around the central Ta atom to form fan-like structures. A structural transition occurs at TaB6(-), which is found to have a hexagonal structure, but with a boron atom in the centre and the Ta atom on the periphery. TaB7(-) is shown to have a three-dimensional boat-like structure, which can be viewed as a Ta atom coordinated to an elongated B7 cluster from above. The global minimum of the TaB8(-) cluster is found to be pyramidal with the Ta atom interacting with a B8 monocyclic ring. Starting from this structure, additional boron atoms simply enlarge the boron ring to form the slightly pyramidal TaB9(-) cluster and eventually the perfectly planar Ta-centred B10-ring aromatic cluster, Ta(c)B10(-). It is shown that boron atoms do not nucleate smoothly around a Ta atom on the way to the decacoordinated Ta(c)B10 (-) molecular wheel, but rather the competition between B-B interactions and Ta-B interactions determines the most stable structures of the smaller TaB(n)(-) (n = 3-8) clusters. PMID- 24050348 TI - Observation of exclusively pi-stacked heterodimer of indole and hexafluorobenzene in the gas phase. AB - In this study, the structure of the indole...hexafluorobenzene dimer has been investigated in the gas phase by using resonant two photon ionzation (R2PI) and IR-UV double resonance spectroscopy combined with quantum chemistry calculations. We have confirmed the presence of exclusively pi-stacked structure of the dimer from both experimental and theoretical IR spectra in the N-H stretching region. Observation of a single stable structure of the dimer has also been verified through 3D potential energy surface scan of the pi-stacked dimer by varying the parallel displacement of the hexafluorobenzene unit simultaneously along the major and minor axes of the indole moiety. pi-stacking interaction is present very often between the tryptophan and phenylalanine residues in proteins. But this interaction has not been observed earlier in the gas phase experiment by studying indole...benzene dimer because the N-H group of indole predominately directs towards the N-H...pi hydrogen bonded T-shaped structure. The chosen molecular systems in this study not only rule out the possibility of the formation of the N-H...pi bound T-shaped dimer but also enable the determination of the structure by probing the N-H group. The pi-stacked indole...hexafluorobenzene dimer has a unique structure where the center of the hexafluorobenznene ring is aligned with the center of the shared bond of the indole ring. Our work provides useful insight in designing unnatural proteins having strong pi-stacking interaction between the tryptophan and phenylalanine residues. PMID- 24050350 TI - Selective ionization/dissociation of oriented N2O molecules by asymmetric fs laser field. AB - We report on the selective ionization of oriented nitrous oxide (N2O) molecules in gas phase by the use of an intense asymmetric two-color omega/2omega 40 fs laser field. By means of a time-of-flight mass spectrometer the induced N2O mass spectra have been recorded as a function of the relative phase of the two-color laser fields. It is found that the applied method facilitates the distinction of different dissociation channels that result in fragments with the same mass and kinetic energy. Thus, the potential of the employed technique for phase control of the molecular excitation for the case of N2O is explored. PMID- 24050351 TI - Excitation of helium Rydberg states and doubly excited resonances in strong extreme ultraviolet fields: full-dimensional quantum dynamics using exponentially tempered Gaussian basis sets. AB - Recently optimized exponentially tempered Gaussian basis sets [P. R. Kapralova Zdanska and J. Smydke, J. Chem. Phys. 138, 024105 (2013)] are employed in quantitative simulations of helium absorption cross-sections and two-photon excitation yields of doubly excited resonances. Linearly polarized half-infinite and Gaussian laser pulses at wavelengths 38-58 nm and large intensities up to 100 TW/cm(2) are considered. The emphasis is laid on convergence of the results with respect to the quality of the Gaussian basis sets (typically limited by a number of partial waves, density, and spatial extent of the basis functions) as well as to the quality of the basis set of field-free states (typically limited by the maximum rotational quantum number and maximum excitation of the lower electron). Particular attention is paid to stability of the results with respect to varying complex scaling parameter. Moreover, the study of the dynamics is preceded by a thorough check of helium energies and oscillator strengths as they are obtained with the exponentially tempered Gaussian basis sets, being also compared with yet unpublished emission wavelengths measured in electric discharge experiments. PMID- 24050352 TI - Reactive scattering dynamics of rotational wavepackets: a case study using the model H+H2 and F+H2 reactions with aligned and anti-aligned H2. AB - We propose a method to steer the outcome of reactive atom-diatom scattering, using rotational wavepackets excited by strong non-resonant laser pulses. Full close-coupled quantum mechanical scattering calculations of the D+H2 and F+H2 reactions are presented, where the H2 molecule exists as a coherent superposition of rotational states. The nuclear spin selective control over the molecular bond axis alignment afforded by the creation of rotational wavepackets is applied to reactive scattering systems, enabling a nuclear spin selective influence to be exerted over the reactive dynamics. The extension of the conventional eigenstate to-eigenstate scattering problem to the case in which the initial state is composed of a coherent superposition of rotational states is detailed, and a selection of example calculations are discussed, along with their mechanistic implications. The feasibility of the corresponding experiments is considered, and a suitable simple two pulse laser scheme is shown to strongly differentiate the reactivities of o-H2 and p-H2. PMID- 24050353 TI - Interplay between crystallization and glass transition in binary Lennard-Jones mixtures. AB - In this work we explore the interplay between crystallization and glass transition in different binary mixtures by changing their inter-species interaction length and also the composition. We find that only those systems which form bcc crystal in the equimolar mixture and whose global structure for larger x(A) (x(A) = 0.6, where x(A) is the mole fraction of the bigger particles) is a mixed fcc + bcc phase, do not crystallize at this higher composition. However, the systems whose equimolar structure is a variant of fcc (NaCl type crystal) and whose global structure at larger x(A) is a mixed NaCl + fcc phase, crystallize easily to this mixed structure. We find that the stability against crystallization of this "bcc zone" is due to the frustration between the locally preferred structure (LPS) and the mixed bcc + fcc crystal. Our study suggests that when the global structure is a mixed crystal where a single species contributes to both the crystal forms and where the two crystal forms have large difference in some order parameter related to that species then this induces frustration between the LPS and the global structure. This frustration makes the systems good glass former. When x(A) is further increased (0.70 <= x(A) < 0.90) the systems show a tendency towards mixed fcc crystal formation. However, the "bcc zone" even for this higher composition is found to be sitting at the bottom of a V shaped phase diagram formed by two different variants of the fcc crystal structure, leading to its stability against crystallization. PMID- 24050354 TI - Evidence of nanostructuration from the heat capacities of the 1,3 dialkylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquid series. AB - In the present work, the heat capacities at T = 298.15 K of 1,3 dialkylimidazolium bis(trifluoromethylsulfonyl)imide, [C(N/2)C(N/2)im][NTf2], were measured, for the first time, using a high-precision heat capacity drop calorimeter, with an uncertainty of less than 0.15%. Based on the obtained results, it was possible to evaluate the effect of the cation symmetry on the heat capacity data through a comparative analysis with the [C(N-1)C1im][NTf2] ionic liquid series. The molar heat capacities of the [C(N/2)C(N/2)im][NTf2] ionic liquids series present a less pronounced deviation from the linearity along the alkyl chain length than the asymmetric based ionic liquids series. Lower molar heat capacities for the symmetric than the asymmetric series were observed, being this difference more evident for the specific and volumic heat capacities. As observed for the [C(N-1)C1im][NTf2] series, a trend shift in the heat capacities at [C6C6im][NTf2] was found that reflects the impact of nonpolar region nanostructuration on the thermophysical properties of the ionic liquids. The profile of the two regions is in agreement with the expected effect arising from the nanostructuration in ionic liquids. The results obtained in the present work show a clear indication that for the symmetric series, [C(N/2)C(N/2)im][NTf2], the starting of the liquid phase nanostructuration/alkyl chain segregation occurs around [C6C6im][NTf2]. PMID- 24050355 TI - Thermophysical properties of energetic ionic liquids/nitric acid mixtures: insights from molecular dynamics simulations. AB - Molecular dynamics (MD) simulations of mixtures of the room temperature ionic liquids (ILs) 1-butyl-4-methyl imidazolium [BMIM]/dicyanoamide [DCA] and [BMIM][NO3(-)] with HNO3 have been performed utilizing the polarizable, quantum chemistry based APPLE&P((r)) potential. Experimentally it has been observed that [BMIM][DCA] exhibits hypergolic behavior when mixed with HNO3 while [BMIM][NO3( )] does not. The structural, thermodynamic, and transport properties of the IL/HNO3 mixtures have been determined from equilibrium MD simulations over the entire composition range (pure IL to pure HNO3) based on bulk simulations. Additional (non-equilibrium) simulations of the composition profile for IL/HNO3 interfaces as a function of time have been utilized to estimate the composition dependent mutual diffusion coefficients for the mixtures. The latter have been employed in continuum-level simulations in order to examine the nature (composition and width) of the IL/HNO3 interfaces on the millisecond time scale. PMID- 24050356 TI - Phase changes of filled ice Ih methane hydrate under low temperature and high pressure. AB - Low-temperature and high-pressure experiments were performed with filled ice Ih structure of methane hydrate under 2.0-77.0 GPa and 30-300 K using diamond anvil cells and a helium-refrigeration cryostat. In situ X-ray diffractometry revealed distinct changes in the compressibility of the axial ratios of the host framework with pressure. Raman spectroscopy showed a split in the C-H vibration modes of the guest methane molecules, which was previously explained by the orientational ordering of the guest molecules. The pressure and temperature conditions at the split of the vibration modes agreed well with those of the compressibility change. The results indicate the following: (i) the orientational ordering of the guest methane molecules from an orientationally disordered state occurred at high pressures and low temperatures; and (ii) this guest ordering led to anisotropic contraction in the host framework. Such guest orientational ordering and subsequent anisotropic contraction of the host framework were similar to that reported previously for filled ice Ic hydrogen hydrate. Since phases with different guest-ordering manners were regarded as different phases, existing regions of the guest disordered-phase and the guest ordered-phase were roughly estimated by the X-ray study. In addition, above the pressure of the guest ordered phase, another high-pressure phase developed in the low-temperature region. The deuterated-water host samples were also examined, and the influence of isotopic effects on guest ordering and phase transformation was observed. PMID- 24050357 TI - Pathways and kinetics of methane and ethane C-H bond cleavage on PdO(101). AB - We used conventional density functional theory (DFT) and dispersion-corrected DFT (DFT-D3) calculations to investigate C-H bond activation pathways for methane and ethane sigma-complexes adsorbed on the PdO(101) surface. The DFT-D3 calculations predict lower and more physically realistic values of the apparent C-H bond cleavage barriers, which are defined relative to the gas-phase energy level, while giving nearly the same energy differences between stationary states as predicted by conventional DFT for a given reaction pathway. For the stable CH4 eta(2) complex on PdO(101), DFT-D3 predicts that the C-H bond cleavage barriers are 55.2 and 16.1 kJ/mol relative to the initial molecularly adsorbed and gaseous states, respectively. We also predict that dehydrogenation of the resulting CH3 groups and conversion to CH3O species are significantly more energetically demanding than the initial C-H bond activation of CH4 on PdO(101). Using DFT-D3, we find that an eta(2) and an eta(1) ethane complex can undergo C-H bond cleavage on PdO(101) with intrinsic energy barriers that are similar to that of the methane complex, but with apparent barriers that are close to zero. We also investigated the dissociation kinetics of methane and ethane on PdO(101) using microkinetic models, with parameters derived from the DFT-D3 relaxed structures. We find that a so-called 3N - 2 model, in which two frustrated adsorbate motions are treated as free motions, predicts desorption pre-factors and alkane dissociation probabilities that agree well with estimates obtained from the literature. The microkinetic simulations demonstrate the importance of accurately describing entropic contributions in kinetic simulations of alkane dissociative chemisorption. PMID- 24050358 TI - A new (2 * 1) reconstructed edge structure of zigzag Si nanoribbon: first principles study. AB - Based upon the first principles calculations, a new (2 * 1) reconstructed edge structure (edge-4) with a triangle-pentagon pair topological defect at its edges is found for the zigzag Si nanoribbon, which is different from the previously found ones (edge-2 and edge-3) and more stable in energy than them. More interestingly, it is found that the edge-2 and edge-3 can transform into the new edge-4 under a little bit compression force along the ribbon edge, and the edge-4 could also be transformed into the edge-3 by a tensile strain larger than 9%. The calculated vibrational modes of the edge-4 show that two new characteristic vibrational edge defect modes appear at 434 cm(-1) and 515 cm(-1), which could be used in experiment to distinguish easily the new edge-4 from the edge-2 and edge 3. Finally, a sharp peak near the Fermi level is found to exist in the projected density of states from the edge's pz orbital of edge-4, making its energy bands spin-split and the antiferromagnetic state to be its ground state. PMID- 24050359 TI - Ordered structures of diblock nanorods induced by diblock copolymers. AB - The self-assembly of diblock copolymer (DBCP)/diblock nanorod (DBNR) mixtures are studied by using a dissipative particle dynamics simulation method. The microstructures of DBCP/DBNR blends depend on the type of DBCPs as well as the number of DBNRs. For the asymmetric DBCPs of A3B7, the morphological transition of DBCP/DBNR blends from cylinder phase to lamellar phase is observed for the DBNRs with suitable length and component. Meanwhile, for the symmetric DBCPs of A5B5, the lamellar morphologies of DBCP/DBNR blends can always maintain during the process of adding DBNRs to the blends except for the case of component length mismatch between the DBCPs and the DBNRs. On the other hand, DBCPs can also affect the orientation and the spatial distributions of DBNRs deeply, and the ordered structures of DBNRs are formed for the DBCP/DBNR blends with a large number of DBNRs. Comparisons with homopolymer/DBNR blends are made, and only the aggregation structures are observed in homopolymer/DBNR blends. This investigation can provide valuable assistance in exploring and designing complicated polymer/nanoparticle composites with the desired properties. PMID- 24050360 TI - Dissipative particle dynamics study of translational diffusion of rigid-chain rodlike polymer in nematic phase. AB - In this study, dissipative particle dynamics (DPD) method was employed to investigate the translational diffusion of rodlike polymer in its nematic phase. The polymer chain was modeled by a rigid rod composed of consecutive DPD particles and solvent was represented by independent DPD particles. To fully understand the translational motion of the rods in the anisotropic phase, four diffusion coefficients, D?(u), D?(u), D?(n), D?(n) were obtained from the DPD simulation. By definition, D?(n) and D?(n) denote the diffusion coefficients parallel and perpendicular to the nematic director, while D?(u) and D?(u) denote the diffusion coefficients parallel and perpendicular to the long axis of a rigid rod u. In the simulation, the velocity auto-correlation functions were used to calculate the corresponding diffusion coefficients from the simulated velocity of the rods. Simulation results show that the variation of orientational order caused by concentration and temperature changes has substantial influences on D?(u) and D?(u). In the nematic phase, the changes of concentration and temperature will result in a change of local environment of rods, which directly influence D?(u) and D?(u). Both D?(n) and D?(n) can be represented as averages of D?(u) and D?(u), and the weighted factors are functions of the orientational order parameter S2. The effect of concentration and temperature on D?(n) and D?(n) demonstrated by the DPD simulation can be rationally interpreted by considering their influences on D?(u), D?(u) and the order parameter S2. PMID- 24050361 TI - Investigation of Fickian diffusion in the ternary mixture of 1,2,3,4 tetrahydronaphthalene, isobutylbenzene, and dodecane. AB - We present a comprehensive analysis of experimental results obtained for Fickian diffusion in the benchmark ternary liquid mixture of 1,2,3,4 tetrahydronaphthalene, isobutylbenzene, and dodecane (nC12) with equal mass fractions. Isothermal diffusion coefficients have been measured by two independent experimental methods: by Taylor dispersion technique, and by a counter flow cell fitted with an optical interferometry device. The experimental diffusion matrices have been critically analyzed regarding the Onsager reciprocal relations, for which we introduce a matrix asymmetry index s(2) that is independent of the frame of reference and the component order. PMID- 24050362 TI - Molecular theory for self assembling mixtures of patchy colloids and colloids with spherically symmetric attractions: the single patch case. AB - In this work we develop a new theory to model self assembling mixtures of single patch colloids and colloids with spherically symmetric attractions. In the development of the theory we restrict the interactions such that there are short ranged attractions between patchy and spherically symmetric colloids, but patchy colloids do not attract patchy colloids and spherically symmetric colloids do not attract spherically symmetric colloids. This results in the temperature, density, and composition dependent reversible self assembly of the mixture into colloidal star molecules. This type of mixture has been recently synthesized by grafting of complimentary single stranded DNA [L. Feng, R. Dreyfus, R. Sha, N. C. Seeman, and P. M. Chaikin, Adv. Mater. 25(20), 2779-2783 (2013)]. As a quantitative test of the theory, we perform new monte carlo simulations to study the self assembly of these mixtures; theory and simulation are found to be in excellent agreement. PMID- 24050363 TI - Two-patch colloidal model with re-entrant phase behaviour. AB - We propose a second-order thermodynamic perturbation theory for a hard-sphere patchy colloidal model with two doubly bondable patches of type A and B. AB bonding results in the formation of a three-dimensional network of the particles and AA and BB bonding promotes chain formation. The theory is applied to study the phase behaviour of the model at different values of the potential model parameters. Competition between network and chain formation gives rise to a re entrant phase behaviour with upper and lower critical points. The model with an additional van der Waals type of interaction may have a re-entrant phase diagram with three critical points and two separate regions of the liquid-gas phase coexistence. We analyze our results in terms of the fractions of the particles in different bonding states and conclude that re-entrant phase coexistence can be seen as a coexistence between a gas phase rich in chain ends and a liquid phase rich in branch points. PMID- 24050364 TI - Dynamics of a deformable active particle under shear flow. AB - The motion of a deformable active particle in linear shear flow is explored theoretically. Based on symmetry considerations, we propose coupled nonlinear dynamical equations for the particle position, velocity, deformation, and rotation. In our model, both, passive rotations induced by the shear flow as well as active spinning motions, are taken into account. Our equations reduce to known models in the two limits of vanishing shear flow and vanishing particle deformability. For varied shear rate and particle propulsion speed, we solve the equations numerically in two spatial dimensions and obtain a manifold of different dynamical modes including active straight motion, periodic motions, motions on undulated cycloids, winding motions, as well as quasi-periodic and chaotic motions induced at high shear rates. The types of motion are distinguished by different characteristics in the real-space trajectories and in the dynamical behavior of the particle orientation and its deformation. Our predictions can be verified in experiments on self-propelled droplets exposed to a linear shear flow. PMID- 24050365 TI - Study of the structure dependent behavior of polyelectrolyte in water. AB - We examine the effect of pendant architecture on linear polyelectrolytes in solution using molecular dynamics simulations. A comparison is done between the standard bead-spring polyelectrolyte system and a system which has the charged beads pendant to neutral backbone beads. Recent simulations of ionomer melts have found significant differences in the structure between the two architectures, but we find the structure is not dramatically affected by the different geometry. In general, the backbone architecture is slightly more compact than the pendant architecture. The counterion condensation is typically larger for the backbone systems, which yields the more compact structures. Only when both the Bjerrum length is much larger than the spacing between charges and the spacing between pendants is twice the backbone bead spacing, is the peak in the monomer counterion radial distribution function larger for the pendant architecture. The radius of gyration for the pendant remains larger than backbone architecture because of the extra excluded volume of the pendant. PMID- 24050366 TI - Demixing transition, structure, and depletion forces in binary mixtures of hard spheres: the role of bridge functions. AB - Asymmetric binary mixtures of hard-spheres exhibit several interesting thermodynamic phenomena, such as multiple kinds of glassy states. When the degrees of freedom of the small spheres are integrated out from the description, their effects are incorporated into an effective pair interaction between large spheres known as the depletion potential. The latter has been widely used to study both the phase behavior and dynamic arrest of the big particles. Depletion forces can be accounted for by a contraction of the description in the multicomponent Ornstein-Zernike equation [R. Castaneda-Priego, A. Rodriguez Lopez, and J. M. Mendez-Alcaraz, Phys. Rev. E 73, 051404 (2006)]. Within this theoretical scheme, an approximation for the difference between the effective and bare bridge functions is needed. In the limit of infinite dilution, this difference is irrelevant and the typical Asakura-Osawa depletion potential is recovered. At higher particle concentrations, however, this difference becomes important, especially where the shell of first neighbors is formed, and, as shown here, cannot be simply neglected. In this work, we use a variant of the Verlet expression for the bridge functions to highlight their importance in the calculation of the depletion potential at high densities and close to the spinodal decomposition. We demonstrate that the modified Verlet closure predicts demixing in binary mixtures of hard spheres for different size ratios and compare its predictions with both liquid state and density functional theories, computer simulations, and experiments. We also show that it provides accurate correlation functions even near the thermodynamic instability; this is explicitly corroborated with results of molecular dynamics simulations of the whole mixture. Particularly, our findings point toward a possible universal behavior of the depletion potential around the spinodal line. PMID- 24050367 TI - Size of a crystal nucleus in the isothermal crystallization of supercooled liquid. AB - We present an alternative to classical nucleation theory (CNT). We introduce a size-dependent surface energy into the total Gibbs free-energy of formation of a crystal (DeltaG). We consider the free-energy in the core part of the total volume of crystal and the free-energy in the surface-layer part of it, separately, for the evaluation of DeltaG. As a result, we present an explicit model to evaluate a characteristic size of an initial nucleus that differs from the critical nucleus of CNT, but whose temperature dependence agrees well with that reported for the temperature dependency initial fold length of isotactic polystyrene and polyethylene in the literature. Our model has fitted the experimental data in the literature with only one adjustable parameter that is defined as nucleation constant. The nucleation constant is the Gibbs free-energy difference between the crystal and supercooled liquid phases for the volume of initial nucleus. We also present an expression to approximate the evolution of free-energy in the surface-layer part of crystal during the crystal growth. PMID- 24050368 TI - Theoretical models for electrochemical impedance spectroscopy and local zeta potential of unfolded proteins in nanopores. AB - Single solid-state nanopores find increasing use for electrical detection and/or manipulation of macromolecules. These applications exploit the changes in signals due to the geometry and electrical properties of the molecular species found within the nanopore. The sensitivity and resolution of such measurements are also influenced by the geometric and electrical properties of the nanopore. This paper continues the development of an analytical theory to predict the electrochemical impedance spectra of nanopores by including the influence of the presence of an unfolded protein using the variable topology finite Warburg impedance model previously published by the authors. The local excluded volume of, and charges present on, the segment of protein sampled by the nanopore are shown to influence the shape and peak frequency of the electrochemical impedance spectrum. An analytical theory is used to relate the capacitive response of the electrical double layer at the surface of the protein to both the charge density at the protein surface and the more commonly measured zeta potential. Illustrative examples show how the theory predicts that the varying sequential regions of surface charge density and excluded volume dictated by the protein primary structure may allow for an impedance-based approach to identifying unfolded proteins. PMID- 24050369 TI - Specific heat of hydrated lysozyme, water's contribution to its dynamics, and criteria for glass formation of biomaterials. AB - Previous studies of the dynamics of hydrated proteins had shown a feature resembling an exceptionally broad glass-softening endotherm. Its onset temperature, denoted as T(g), was indefinable in one calorimetric study of hydrated lysozyme and was in the 148-218 K range in another study, depending upon hydration. Other methods reported this T(g) as ~170 K. We argue that glass formation of biomaterials should be studied by measuring a property on both the cooling and heating paths and it should be ascertained (i) that there is thermal hysteresis of the measured property, (ii) that the real and imaginary components of a dynamic property obey the Kramers-Kronig relations, and (iii) that there is an effect of annealing that is consistent with the glass phenomenology. We report the real and imaginary components of the dynamic specific heat, C(p)' and C(p)", of dry and two hydrated lysozyme samples on the cooling and the heating paths as well as the effects of annealing and changing the frequency. For the most hydrated (34.6 g water per 100 g lysozyme) sample, C(p,app) does not show thermal hysteresis in the 160-230 K range, C(p)' varies in a sigmoid-shape manner with T while C(p)" remains close to zero, and there is no effect of annealing. We interpret these findings in terms of continuous development of ice-like aggregates of immobile H2O as more H-bonds form on cooling, and continuous deterioration of the aggregates on heating. As the equilibrium constant between the aggregates and mobile H2O increases on cooling, configurational degrees of freedom of H2O molecules and lysozyme segments decrease. Consequently, the net change in enthalpy is small but the change in C(p) is large. Mobility of the lysozyme segments still depends upon the mobility of H2O molecules. PMID- 24050370 TI - Protein fibrillation due to elongation and fragmentation of initially appeared fibrils: a simple kinetic model. AB - The assembly of various proteins into fibrillar aggregates is an important phenomenon with wide implications ranging from human disease to nanoscience. Employing a new model, we analyze the kinetics of protein fibrillation in the case when the process occurs by elongation of initially appeared fibrils which multiply solely by fragmentation, because fibril nucleation is negligible. Owing to its simplicity, our model leads to mathematically friendly and physically clear formulas for the time dependence of the fibrillation degree and for a number of experimental observables such as the maximum fibrillation rate, the fibrillation lag time, and the half-fibrillation time. These formulas provide a mechanistic insight into the kinetics of fragmentation-affected fibrillation of proteins. We confront theory with experiment and find that our model allows a good global description of a large dataset [W.-F. Xue, S. W. Homans, and S. E. Radford, Proc. Natl. Acad. Sci. U.S.A. 105, 8926 (2008)] for the fibrillation kinetics of beta-2 microglobulin. Our analysis leads to new methods for experimental determination of the fibril solubility, elongation rate constant, and nucleation rate from data for the time course of protein fibrillation. PMID- 24050374 TI - Heat-tolerant versus heat-sensitive Bos taurus cattle: influence of air temperature and breed on the acute phase response to a provocative immune challenge. AB - The difference in the acute phase response of a heat-tolerant and a heat sensitive Bos taurus breed to a lipopolysaccharide (LPS) challenge when housed at different air temperatures (Ta) was studied. Angus (ANG; heat-sensitive; n = 11; 306 +/- 26 kg BW) and Romosinuano (RO; heat-tolerant; n = 10; 313 +/- 32 kg BW) heifers were transported from the USDA Agricultural Research Service SubTropical Agricultural Research Station in Florida to the Brody Environmental Chambers at the University of Missouri, Columbia. Heifers were housed in stanchions in 4 temperature-controlled environmental chambers. Initially, Ta in the 4 chambers was cycling at thermoneutrality (TN; 18.5 degrees C-23.5 degrees C) for a 1-wk adjustment period, followed by an increase in 2 of the 4 chambers to cycling heat stress (HS; 24 degrees C-38 degrees C) for 2 wk. On day 19, heifers were fitted with jugular catheters and rectal temperature (RT) recording devices. On day 20, heifers were challenged with LPS (0.5 MUg/kg BW; 0 h), sickness behavior scores (SBSs) were recorded, and blood samples were collected at 0.5-h intervals from -2 to 8 h and again at 24 h relative to LPS challenge at 0 h. Serum was isolated and stored at -80 degrees C until analyzed for cortisol and cytokine concentrations. A breed by Ta interaction (P < 0.001) was observed for RT such that the post-LPS average RT in RO heifers housed at TN was lower than the RT of all other treatment groups (P < 0.001), whereas ANG heifers housed at HS had greater post LPS average RT than all other treatment groups (P < 0.001). In response to LPS, HS increased SBS after LPS in RO heifers compared to RO heifers housed at TN (P < 0.001), whereas HS decreased SBS after LPS in ANG heifers compared to ANG heifers housed at TN (P = 0.014). The cortisol response to LPS was greater in TN than in HS heifers (P < 0.01) and was also greater in RO than in ANG heifers (P = 0.03). A breed by Ta interaction (P < 0.01) was observed for tumor necrosis factor-alpha (TNF-alpha) concentration such that HS increased post-LPS serum concentrations of TNF-alpha in ANG heifers compared to ANG heifers housed at TN (P = 0.041), whereas HS decreased post-LPS concentrations of TNF-alpha in RO heifers compared to RO heifers housed at TN (P = 0.008). A tendency (P < 0.06) was observed for a breed by Ta interaction for IL-6 concentrations such that RO heifers had greater post-LPS concentrations of IL-6 than ANG heifers when housed at HS (P = 0.020). A breed by Ta interaction was observed for interferon-gamma (IFN-gamma; P < 0.01) concentrations such that HS decreased post-LPS concentrations of IFN-gamma in ANG heifers compared to ANG heifers housed at TN (P < 0.001), and HS increased post LPS concentrations of IFN-gamma in RO heifers compared to RO heifers housed at TN (P = 0.017). These data indicate differences in the acute phase response between the heat-tolerant RO and heat-sensitive ANG heifers under different Ta which may aid in elucidating differences in productivity, disease resistance, and longevity among cattle breeds. PMID- 24050375 TI - Selection of patients for prophylactic treatment with implantable cardioverter defibrillator. PMID- 24050376 TI - The Wedensky test predicts malignant ventricular arrhythmias after myocardial infarction. AB - OBJECTIVES: Better tools are needed for detection of future malignant ventricular arrhythmias post myocardial infarct (MI). Wedensky Modulation (WM) is a new semi invasive method: A short low-amplitude electrical impulse is applied synchronized to the QRS between a precordial and dorsal thoracic patch, and changes in the following QRS-T are registered. DESIGN: A total of 357 (MI) ICD patients underwent WM testing. QRS-T wavelet analysis provided WM Indexes for the QRS complex (WMI-R) and T wave (WMI-T). Outcome was the time to first occurrence of appropriate device therapy for ventricular arrhythmia. Patients were followed at 6-month intervals for 2 years. RESULTS: No arrhythmia was induced by the testing. Two-year appropriate arrhythmia treatment occurred in 35% (WMI-R positive) versus 25% (WMI-R negative, p = 0.014), and. 45% versus 26% (p = 0.001) for WMI-T positive versus negative. Two-year event rates of WMI-R or WMI-T positive versus WMI-R and WMI-T negative were 36% versus 22% (p = 0.004). In Cox proportional hazard model, the combination of WMI-R and WMI-T was the only statistically significant event predictor (p = 0.003). CONCLUSION: Potentially life-threatening ventricular arrhythmic events could be predicted by the WM test. In combination with other risk factors WMI may be useful in these patients. PMID- 24050377 TI - Lack of long-term effects from a pedagogical intervention upon blood pressure control--a randomized primary care study. AB - OBJECTIVE: The primary aim was to evaluate the effect on blood pressure (BP) levels of a previously developed pedagogically structured BP card introduced to patients with inadequately controlled hypertension in primary care. The evaluation was based on the results of a pilot study which is briefly presented. The aim of the study was to validate the positive results from a pilot study in a different, larger setting, for a longer time, and to study the effects of a nurse led individual health counseling strategy. DESIGN: A "BP card" that summarized the essential targets of hypertension treatment was presented to patients with a small set of questions. An open, randomized, controlled study was performed testing the effect of the BP card: BP card with an added semi-structured nurse counseling versus usual care (3 groups) during 12 months. RESULTS: The effects on BP levels differed greatly from results seen in the pilot study where BP fell significantly in the intervention group as compared with that in the control group. In the main study, however, BP levels declined more than 25/8.5 mmHg in all three groups, with no significant differences between the groups. CONCLUSION: The positive results in the pilot study could not be confirmed in the main study. Furthermore, the nurse-led individual health counseling strategy did not show any additive effects. The reasons for these discrepant findings may be external such as increased awareness of hypertension, and internal factors such as contamination and non-biased recruitment. PMID- 24050378 TI - Heparin does not seem to improve the function of pulmonary grafts for lung transplantation. AB - BACKGROUND: It has been debated whether or not heparin infusion before or after non-heart-beating donors are declared dead improves the quality of pulmonary grafts. In clinical lung transplantation with heart-beating donors (HBDs) heparin is routinely infused prior to organ harvesting since it is believed to improve pulmonary grafts by minimizing thrombosis formation in the pulmonary grafts. Here, we raise the question of whether or not the use of heparin in HBDs improves the quality of the pulmonary grafts. METHODS: Twelve landrace pigs were divided into two groups of six animals; heparin was given prior to lung harvesting in one group, while the other group did not receive any heparin. The lungs were evaluated using an ex vivo lung perfusion (EVLP) method. RESULTS: No significant difference in arterial oxygen partial pressure (PaO2) was observed between the two groups at an inspired oxygen fraction (FiO2) of 1.0 (mean 69.2 kPa, range 46.1-77.0 in the non-heparin group, and 61.6 kPa, range 47.9-71.4 in the heparin group, p = 0.44), neither in pulmonary vascular resistance: mean 543 ((dyne * s)/cm(5)) (range 280-615) in the non-heparin group and 533 ((dyne * s)/cm(5)) (320-762) in the heparin group (p = 0.99). CONCLUSIONS: Heparin did not seem to improve pulmonary graft function in our animal model using conventional HBDs. PMID- 24050379 TI - Rickettsia slovaca infection in humans, Portugal. AB - Fifteen years after the initial detection of Rickettsia slovaca in ticks in Portugal, 3 autochthonous cases of R. slovaca infection were diagnosed in humans. All patients had an eschar on the scalp and lymphadenopathy; 2 patients had facial edema. R. slovaca infection was confirmed by serologic testing, culture, and PCR. PMID- 24050380 TI - Chemiluminescence evidence supporting the selective role of ligands in the permanganate oxidation of micropollutants. AB - The selective increase in the oxidation rate of certain organic compounds with permanganate in the presence of environmental "ligands" and reduced species has been ascribed to the different reactivity of the target compounds toward Mn(III), which bears striking similarities to recent independent investigations into the use of permanganate as a chemiluminescence reagent. In spite of the importance of Mn(III) in the light-producing pathway, the dependence of the oxidation mechanism for any given compound on this intermediate could not be determined solely through the emission intensity. However, target compounds susceptible to single electron oxidation by Mn(III) (such as bisphenol A and triclosan) can be easily distinguished by the dramatic increase in chemiluminescence intensity when a permanganate reagent containing high, stable concentrations of Mn(III) is used. The differences are accentuated under the low pH conditions that favor the chemiluminescence emission due to the greater reactivity of Mn(III) and the greater influence of complexing agents. This study supports the previously postulated selective role of ligands and reducing agents in permanganate oxidations and demonstrates a new approach to explore the chemistry of environmental manganese redox processes. PMID- 24050381 TI - Cochrane methods--twenty years experience in developing systematic review methods. AB - This year, The Cochrane Collaboration reached its 20th anniversary. It has played a pivotal role in the scientific development of systematic reviewing and in the development of review methods to synthesize research evidence, primarily from randomized trials, to answer questions about the effects of healthcare interventions. We introduce a series of articles, which form this special issue describing the development of systematic review methods within The Cochrane Collaboration. We also discuss the impact of Cochrane Review methods, and acknowledge the breadth and depth of methods development within The Cochrane Collaboration as part of the wider context of evidence synthesis. We conclude by considering the future development of methods for Cochrane Reviews. PMID- 24050382 TI - Characterization of conformation and interaction of gene delivery vector polyethylenimine with phospholipid bilayer at different protonation state. AB - Polyethylenimine (PEI) is a pH sensitive polymer possessing stretched and coiled conformation at low and high pH, respectively. It is an efficient gene delivery agent. Thus, the interaction of PEI with the biomembrane is very crucial to understand the gene delivery mechanism. In this report, we have investigated the structural properties of PEI and bilayer due to the interaction of PEI with lipid molecules. PEI has coil structure at high pH while at low pH it is elongated. The neutral PEI chain predominately settles itself at the bilayer water interface. We do not find any disruption or pore formation on the bilayer due to interaction of neutral PEI chain. PEI at low pH gets elongated due to electrostatic interaction between charges of the protonated sites. This protonated PEI chain interacts with bilayer membrane, which leads to formation of water/ion channel through the membrane. We have analyzed the structure of the channel and water dynamics along the channel. PMID- 24050384 TI - 1,6-Carbene transfer: gold-catalyzed oxidative diyne cyclizations. AB - In the presence of a gold catalyst an unprecedented oxidative cyclization of diynes takes place. The reaction cascade is initiated by an oxygen transfer from a N-oxide onto a gold-activated alkyne. The formed alpha-oxo carbene is transferred across the second alkyne yielding a stabilized vinyl carbene/cation. Alkyl migration or sp(3)-CH insertion then terminates the catalytic cycle by formation of highly substituted functionalized indenones. A 1,6-carbene shift could be supported by the oxidation of the vinyl carbene. This protocol represents an attractive alternative to procedures which are based on the metal catalyzed decomposition of hazardous, not easily accessible, diazo compounds. PMID- 24050383 TI - Ligand and structure-based classification models for prediction of P-glycoprotein inhibitors. AB - The ABC transporter P-glycoprotein (P-gp) actively transports a wide range of drugs and toxins out of cells, and is therefore related to multidrug resistance and the ADME profile of therapeutics. Thus, development of predictive in silico models for the identification of P-gp inhibitors is of great interest in the field of drug discovery and development. So far in silico P-gp inhibitor prediction was dominated by ligand-based approaches because of the lack of high quality structural information about P-gp. The present study aims at comparing the P-gp inhibitor/noninhibitor classification performance obtained by docking into a homology model of P-gp, to supervised machine learning methods, such as Kappa nearest neighbor, support vector machine (SVM), random fores,t and binary QSAR, by using a large, structurally diverse data set. In addition, the applicability domain of the models was assessed using an algorithm based on Euclidean distance. Results show that random forest and SVM performed best for classification of P-gp inhibitors and noninhibitors, correctly predicting 73/75% of the external test set compounds. Classification based on the docking experiments using the scoring function ChemScore resulted in the correct prediction of 61% of the external test set. This demonstrates that ligand-based models currently remain the methods of choice for accurately predicting P-gp inhibitors. However, structure-based classification offers information about possible drug/protein interactions, which helps in understanding the molecular basis of ligand-transporter interaction and could therefore also support lead optimization. PMID- 24050385 TI - A comparison between oxazoline-imidazolinylidene, -imidazolylidine, benzimidazolylidene hydrogenation catalysts. AB - Imidazolinylidene, imidazolylidine, benzimidazolylidene complexes 1a-c were prepared and tested in asymmetric hydrogenations of a series of largely unfunctionalized alkenes. Similarities and differences in the catalytic performance of these complexes were rationalized in terms of the predicted mechanisms of these reactions, and their relative tendencies to generate protons under the hydrogenation conditions. PMID- 24050386 TI - Potential markers of cisplatin treatment response unveiled by NMR metabolomics of human lung cells. AB - In this work, (1)H high resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy was used to characterize the variations in the metabolome (small metabolites and mobile lipids) of A549 human lung cells in response to exposure to the alkylating drug cisplatin. Multivariate analysis and signal integration of spectral data were carried out to unveil exposure-induced effects and follow their time course. Parallel and strongly correlated increases in lipids (particularly unsaturated triglycerides) and nucleotide sugars (particularly uridine diphosphate N-acetylglucosamine) were found in cisplatin treated cells, highlighting these compounds as potential biomarkers of treatment response. Other significant changes upon drug exposure comprised an increase in sorbitol and decreases in niacinamide and several amino acids (glutamine, alanine, lysine, methionine, citrulline, phenylalanine and tyrosine). These results show that in vitro NMR metabolomics is a powerful tool for detecting variations in a range of intracellular compounds upon drug exposure, thus offering the possibility of identifying candidate metabolite markers for in vivo monitoring of tumor responsiveness to treatment. PMID- 24050387 TI - Malignant H1299 tumour cells preferentially internalize iron-bound inositol hexakisphosphate. AB - In colon enterocytes and in well-differentiated colon cancer CaCo-2 cells, InsP6 (inositol hexakisphosphate) inhibits iron uptake by forming extracellular insoluble iron/InsP6 complexes. In this study, we confirmed that CaCo-2 cells are not able to take up iron/InsP6 but, interestingly, found that the cells are able to internalize metal-free and Cr3+-bound InsP6. Thus, the inability of CaCo-2 cells to take up iron/InsP6 complexes seems to be due to the iron-bound state of InsP6. Since recently we demonstrated that the highly malignant bronchial carcinoma H1299 cells internalize and process InsP6, we examined whether these cells may be able to take up iron/InsP6 complexes. Indeed, we found that InsP6 dose-dependently increased uptake of iron and demonstrated that in the iron-bound state InsP6 is more effectively internalized than in the metal-free or Cr3+-bound state, indicating that H1299 cells preferentially take up iron/InsP6 complexes. Electron microscope and cell fraction assays indicate that after uptake H1299 cells mainly stored InsP6/iron in lysosomes as large aggregates, of which about 10% have been released to the cytosol. However, this InsP6-mediated iron transport had no significant effects on cell viability. This result together with our finding that the well-differentiated CaCo-2 cells did not, but the malignant H1299 cells preferentially took up iron/InsP6, may offer the possibility to selectively transport cytotoxic substances into tumour cells. PMID- 24050388 TI - Levels and spatial distribution of persistent organic pollutants in the environment: a case study of German forest soils. AB - The Of/Oh-horizons of 447 forest stands in Germany were evaluated for concentrations and spatial distribution of selected polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs). While concentrations of dichlorodiphenyltrichloroethane (DDT) and PCBs show similar spatial distribution patterns for all measured compounds within each compound class, significantly different distributions were identified for concentrations of low-molecular-weight PAHs [2- and 3-ring PAHs plus fluoranthene (FLA) and pyrene (PYR)] in contrast to high-molecular-weight PAHs (4 6-ring PAHs without FLA and PYR). Maxima of persistent organic pollutant (POP) concentrations could be mostly explained by specific locatable sources. Because of the slow degradation rates of these target substances, this is especially relevant for historic contamination sources, such as extensive 1980s DDT usage in the former German Democratic Republic and industrial facilities that produced hexachlorobenzene (HCB) or PCBs. A contribution of ubiquitous background pollution derived from long-range atmospheric transport is likely for some compounds in the studied area, e.g., DDT in the western part of Germany and dieldrin. However, most target compounds appear to be mainly sourced from local or regional emissions. This is supported by the absence of clear dependencies between POP concentrations and most evaluated environmental and local parameters. We suggest that these results generally reflect the distribution of POPs in densely populated and industrialized countries located in temperate regions. PMID- 24050389 TI - Protective effect of a fish egg homogenate marine compound on arterial ultrastructure in spontaneous hypertensive rats. AB - We assessed the effect of a sturgeon eggs-based nutraceutical (LD-1227) versus eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) on the ultrastructure of spontaneously hypertensive rat (SHR) aortas. Sixty SHR were randomly divided into three groups that were fed (1) rat chow, (2) rat chow plus 10 mg of EPA/DHA, or (3) rat chow plus 10 mg of LD-1227, for 18 weeks. Afterward, aortas of these rats were used for blind measurements of the thickened intima area and examination by electron microscopy. Control SHR showed an expanded subendothelial space and leukocyte infiltration of the intima that were reduced in LD-1227-fed rats (p<0.05) and less in EPA/DHA group. Transmission electron microscopy showed endothelial alteration with severe subcellular injury and, unlike the EPA/DHA group, LD-1227-treated rats displayed a significant reduction in endothelial alteration with severe subcellular injury (p<0.05). These data suggest that LD 1227 has stronger arterial protective properties and deserves further investigation in view of a preventive medicine strategy. PMID- 24050391 TI - Suffering compounded: the relationship between abuse history and distress in five palliative care domains. AB - BACKGROUND: Research with breast cancer patients suggests that abuse survivors experience more psychological distress and disorders, particularly depression and anxiety, than patients without abuse histories. However, we do not yet understand the impact of abuse on other palliative care domains for individuals with other cancer types. OBJECTIVES: This study explores the relationship between past abuse and distress in a group of cancer patients referred for palliative care. This study also explores differences in distress level and likelihood of meeting diagnostic criteria for major depression and generalized anxiety disorder between patients with and without abuse histories. SETTING/SUBJECTS: Data were from 164 new, palliative care outpatients who completed an initial clinician-administered assessment and the James Supportive Care Screening patient self-report. DESIGN: Multivariate analyses of variance were conducted to explore differences between patients who reported an abuse history and those who did not on the number of items endorsed and associated distress on five palliative care domains. Chi square tests were conducted to identify differences in diagnosis of depression and anxiety between patients with and without abuse histories. RESULTS: Twenty eight percent reported abuse histories. Patients with abuse histories endorsed more physical problems, psychological concerns, and spiritual concerns and greater distress related to psychological and spiritual concerns than patients without abuse histories. Patients with abuse histories more frequently received diagnoses of major depression disorder and generalized anxiety disorder. CONCLUSIONS: These differences underscore the impact of abuse on the adjustment of cancer patients referred for palliative care. Assessment of patient abuse history by palliative care teams and referral for psychological treatment may help reduce patient distress. PMID- 24050392 TI - The potential role of sunitinib targeting melanomas. AB - INTRODUCTION: Metastatic melanoma - independently of its cutaneous, uveal or mucosal origin - represents an exceptionally aggressive tumor with poor prognosis. Molecular and genetics investigations permitted to identify several important driver mutations: BRAF, NRAS, c-Kit, GNA11 and GNAQ. Additionally, hypervascular and immunlogenic characteristics of metastatic melanoma make in this tumor a unique therapeutic target. In this regard, the antiangiogenic, antiproliferative and immunomodulator properties of sunitinib make it an attractive drug to explore in melanoma. AREAS COVERED: In this article, the currently available data on sunitinib in terms of its pharmacokinetics and mechanisms of action is summarized. The reader will also be updated on current clinical experience using this drug in the treatment of cutaneous, mucosal and uveal melanomas. Special attention is placed on the scientific rationales behind its development in melanoma including the potentiality to broadly attack receptor tyrosine kinases as well as its remarkable but certainly still unexplored immunomodulatory qualities. EXPERT OPINION: Given its wide spectrum of actions and the encouraging results obtained from the limited clinical experience, sunitinib remains as a promising drug, especially for mucosal and uveal melanoma, that deserves further exploration in properly designed clinical trials. PMID- 24050390 TI - Phylogeographic evidence of cognate recognition site patterns and transformation efficiency differences in H. pylori: theory of strain dominance. AB - BACKGROUND: Helicobacter pylori has diverged in parallel to its human host, leading to distinct phylogeographic populations. Recent evidence suggests that in the current human mixing in Latin America, European H. pylori (hpEurope) are increasingly dominant at the expense of Amerindian haplotypes (hspAmerind). This phenomenon might occur via DNA recombination, modulated by restriction modification systems (RMS), in which differences in cognate recognition sites (CRS) and in active methylases will determine direction and frequency of gene flow. We hypothesized that genomes from hspAmerind strains that evolved from a small founder population have lost CRS for RMS and active methylases, promoting hpEurope's DNA invasion. We determined the observed and expected frequencies of CRS for RMS in DNA from 7 H. pylori whole genomes and 110 multilocus sequences. We also measured the number of active methylases by resistance to in vitro digestion by 16 restriction enzymes of genomic DNA from 9 hpEurope and 9 hspAmerind strains, and determined the direction of DNA uptake in co-culture experiments of hspAmerind and hpEurope strains. RESULTS: Most of the CRS were underrepresented with consistency between whole genomes and multilocus sequences. Although neither the frequency of CRS nor the number of active methylases differ among the bacterial populations (average 8.6 +/- 2.6), hspAmerind strains had a restriction profile distinct from that in hpEurope strains, with 15 recognition sites accounting for the differences. Amerindians strains also exhibited higher transformation rates than European strains, and were more susceptible to be subverted by larger DNA hpEurope-fragments than vice versa. CONCLUSIONS: The geographical variation in the pattern of CRS provides evidence for ancestral differences in RMS representation and function, and the transformation findings support the hypothesis of Europeanization of the Amerindian strains in Latin America via DNA recombination. PMID- 24050393 TI - Dental morphology of early Holocene foragers of North India: non-metric trait frequencies and biological affinities. AB - The biological affinities of semi-nomadic, early to mid-Holocene foragers of the mid-Ganga Plain, North India are undetermined, yet understanding their place in the population history of South Asia is important. Non-metric tooth trait frequencies are reported for three broadly contemporary, bio-culturally similar, and geographically proximate samples, collectively known as Mesolithic Lake Culture (MLC). The Arizona State University - Dental Anthropology System was used to score 43 tooth-trait combinations (23 maxillary; 21 mandibular). Non-metric trait frequencies are used to determine biological affinities of MLC to a global sample of living populations and to prehistoric and living groups of South Asia. The MLC dental pattern includes lightly sculpted upper incisors in which labial curvature, lingual shoveling, and tuberculum dentale exhibit low grades of expression and low-moderate frequencies. First molars have full-sized hypocones with slight reduction in M2 and M3. Accessory cusps are infrequent and small. Mandibular teeth are morphologically simple and retain conservative attributes. Incisors and canines exhibit weak shoveling. Molar accessory cusps are infrequent, though C-6 attains moderate grades in M3. The molar series (M1:M2:M3) has an Y:X:X groove pattern and 5:4:4 cusp number. Upper M3 agenesis (5%) is less common than lower M3 agenesis (10.0%). Smith's Mean Measure of Divergence (MMD) and Ward's minimum variance cluster methods are used to assess inter-group bio distance in global and regional South Asian settings. In the global comparison, multi-dimensionally scaled MMD values reveal three groups: African, Asian, and a third group composed of MLC, prehistoric South Asians, and European samples. Within South Asia, MMD and cluster analysis find MLC's closest affinities to the Chenchu, a living tribal group of Andhra Pradesh. This result contradicts earlier assertions based on osteological assessment that descendants of Mesolithic foragers of North India (MLC) cannot be identified in the Indian subcontinent. The next closest affinity is with Chalcolithic and Neolithic groups of Pakistan and with a late Chalcolithic group (INM) of west central India. As knowledge of the dental morphology of living and prehistoric South Asians increases, the population history of the subcontinent and its role in understanding world-wide patterns of migration will be clarified. PMID- 24050394 TI - Imaging tau deposits in vivo: progress in viewing more of the proteopathy picture. AB - In this issue of Neuron, Maruyama et al. (2013) demonstrate the binding of a new class of selective tau ligands, termed PBBs, to tau deposits in transgenic mice and in human subjects with normal cognition, Alzheimer's disease, or a corticobasal syndrome. PMID- 24050395 TI - Balancing survival: the role of CTGF in controlling experience-modulated olfactory circuitry. AB - The subventricular zone (SVZ) continuously supplies new interneurons that incorporate into pre-existing olfactory bulb circuitry. Khodosevich et al. (2013) show that connective tissue growth factor (CTGF) regulates a multicellular signaling cascade determining the number of postnatally born inhibitory interneurons in odor-activated glomeruli. PMID- 24050396 TI - The where and when of "what if". AB - In this issue of Neuron, Fischer and Ullsperger (2013) demonstrate that EEG signatures of real and fictive learning differ early in processing, but the latent information in each event converges at the temporospatial nexus commonly associated with the P3b component. PMID- 24050398 TI - Nanoscale-targeted patch-clamp recordings of functional presynaptic ion channels. AB - Direct electrical access to presynaptic ion channels has hitherto been limited to large specialized terminals such as the calyx of Held or hippocampal mossy fiber bouton. The electrophysiology and ion-channel complement of far more abundant small synaptic terminals (<= 1 MUm) remain poorly understood. Here we report a method based on superresolution scanning ion conductance imaging of small synapses in culture at approximately 100-150 nm 3D resolution, which allows presynaptic patch-clamp recordings in all four configurations (cell-attached, inside-out, outside-out, and whole-cell). Using this technique, we report presynaptic recordings of K(+), Na(+), Cl(-), and Ca(2+) channels. This semiautomated approach allows direct investigation of the distribution and properties of presynaptic ion channels at small central synapses. PMID- 24050399 TI - TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. AB - Dynamic changes in 5-methylcytosine (5mC) have been implicated in the regulation of gene expression critical for consolidation of memory. However, little is known about how these changes in 5mC are regulated in the adult brain. The enzyme methylcytosine dioxygenase TET1 (TET1) has been shown to promote active DNA demethylation in the nervous system. Therefore, we took a viral-mediated approach to overexpress the protein in the hippocampus and examine its potential involvement in memory formation. We found that Tet1 is a neuronal activity regulated gene and that its overexpression leads to global changes in modified cytosine levels. Furthermore, expression of TET1 or a catalytically inactive mutant (TET1m) resulted in the upregulation of several neuronal memory-associated genes and impaired contextual fear memory. In summary, we show that neuronal Tet1 regulates DNA methylation levels and that its expression, independent of its catalytic activity, regulates the expression of CNS activity-dependent genes and memory formation. PMID- 24050397 TI - The function of alpha-synuclein. AB - Human genetics has indicated a causal role for the protein alpha-synuclein in the pathogenesis of familial Parkinson's disease (PD), and the aggregation of synuclein in essentially all patients with PD suggests a central role for this protein in the sporadic disorder. Indeed, the accumulation of misfolded alpha synuclein now defines multiple forms of neural degeneration. Like many of the proteins that accumulate in other neurodegenerative disorders, however, the normal function of synuclein remains poorly understood. In this article, we review the role of synuclein at the nerve terminal and in membrane remodeling. We also consider the prion-like propagation of misfolded synuclein as a mechanism for the spread of degeneration through the neuraxis. PMID- 24050400 TI - Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. AB - Accumulation of intracellular tau fibrils has been the focus of research on the mechanisms of neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Here, we have developed a class of tau ligands, phenyl/pyridinyl butadienyl-benzothiazoles/benzothiazoliums (PBBs), for visualizing diverse tau inclusions in brains of living patients with AD or non-AD tauopathies and animal models of these disorders. In vivo optical and positron emission tomographic (PET) imaging of a transgenic mouse model demonstrated sensitive detection of tau inclusions by PBBs. A pyridinated PBB, [(11)C]PBB3, was next applied in a clinical PET study, and its robust signal in the AD hippocampus wherein tau pathology is enriched contrasted strikingly with that of a senile plaque radioligand, [(11)C]Pittsburgh Compound-B ([(11)C]PIB). [(11)C]PBB3-PET data were also consistent with the spreading of tau pathology with AD progression. Furthermore, increased [(11)C]PBB3 signals were found in a corticobasal syndrome patient negative for [(11)C]PIB-PET. PMID- 24050401 TI - Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. AB - The ten-eleven translocation (Tet) family of methylcytosine dioxygenases catalyze oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and promote DNA demethylation. Despite the abundance of 5hmC and Tet proteins in the brain, little is known about the functions of the neuronal Tet enzymes. Here, we analyzed Tet1 knockout mice (Tet1KO) and found downregulation of multiple neuronal activity-regulated genes, including Npas4, c-Fos, and Arc. Furthermore, Tet1KO animals exhibited abnormal hippocampal long-term depression and impaired memory extinction. Analysis of the key regulatory gene, Npas4, indicated that its promoter region, containing multiple CpG dinucleotides, is hypermethylated in both naive Tet1KO mice and after extinction training. Such hypermethylation may account for the diminished expression of Npas4 itself and its downstream targets, impairing transcriptional programs underlying cognitive processes. In summary, we show that neuronal Tet1 regulates normal DNA methylation levels, expression of activity-regulated genes, synaptic plasticity, and memory extinction. PMID- 24050402 TI - Ephrin-B1 controls the columnar distribution of cortical pyramidal neurons by restricting their tangential migration. AB - Neurons of the cerebral cortex are organized in layers and columns. Unlike laminar patterning, the mechanisms underlying columnar organization remain largely unexplored. Here, we show that ephrin-B1 plays a key role in this process through the control of nonradial steps of migration of pyramidal neurons. In vivo gain of function of ephrin-B1 resulted in a reduction of tangential motility of pyramidal neurons, leading to abnormal neuronal clustering. Conversely, following genetic disruption of ephrin-B1, cortical neurons displayed a wider lateral dispersion, resulting in enlarged ontogenic columns. Dynamic analyses revealed that ephrin-B1 controls the lateral spread of pyramidal neurons by limiting neurite extension and tangential migration during the multipolar phase. Furthermore, we identified P-Rex1, a guanine-exchange factor for Rac3, as a downstream ephrin-B1 effector required to control migration during the multipolar phase. Our results demonstrate that ephrin-B1 inhibits nonradial migration of pyramidal neurons, thereby controlling the pattern of cortical columns. PMID- 24050403 TI - Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes. AB - Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia. PMID- 24050405 TI - Inhibitory gradient along the dorsoventral axis in the medial entorhinal cortex. AB - Local inhibitory microcircuits in the medial entorhinal cortex (MEC) and their role in network activity are little investigated. Using a combination of electrophysiological, optical, and morphological circuit analysis tools, we find that layer II stellate cells are embedded in a dense local inhibitory microcircuit. Specifically, we report a gradient of inhibitory inputs along the dorsoventral axis of the MEC, with the majority of this local inhibition arising from parvalbumin positive (PV+) interneurons. Finally, the gradient of PV+ fibers is accompanied by a gradient in the power of extracellular network oscillations in the gamma range, measured both in vitro and in vivo. The reported differences in the inhibitory microcircuitry in layer II of the MEC may therefore have a profound functional impact on the computational working principles at different locations of the entorhinal network and influence the input pathways to the hippocampus. PMID- 24050404 TI - CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. AB - The CYFIP1/SRA1 gene is located in a chromosomal region linked to various neurological disorders, including intellectual disability, autism, and schizophrenia. CYFIP1 plays a dual role in two apparently unrelated processes, inhibiting local protein synthesis and favoring actin remodeling. Here, we show that brain-derived neurotrophic factor (BDNF)-driven synaptic signaling releases CYFIP1 from the translational inhibitory complex, triggering translation of target mRNAs and shifting CYFIP1 into the WAVE regulatory complex. Active Rac1 alters the CYFIP1 conformation, as demonstrated by intramolecular FRET, and is key in changing the equilibrium of the two complexes. CYFIP1 thus orchestrates the two molecular cascades, protein translation and actin polymerization, each of which is necessary for correct spine morphology in neurons. The CYFIP1 interactome reveals many interactors associated with brain disorders, opening new perspectives to define regulatory pathways shared by neurological disabilities characterized by spine dysmorphogenesis. PMID- 24050406 TI - A cortico-hippocampal learning rule shapes inhibitory microcircuit activity to enhance hippocampal information flow. AB - How does coordinated activity between distinct brain regions implement a set of learning rules to sculpt information processing in a given neural circuit? Using interneuron cell-type-specific optical activation and pharmacogenetic silencing in vitro, we show that temporally precise pairing of direct entorhinal perforant path (PP) and hippocampal Schaffer collateral (SC) inputs to CA1 pyramidal cells selectively suppresses SC-associated perisomatic inhibition from cholecystokinin (CCK)-expressing interneurons. The CCK interneurons provide a surprisingly strong feedforward inhibitory drive to effectively control the coincident excitation of CA1 pyramidal neurons by convergent inputs. Thus, in-phase cortico-hippocampal activity provides a powerful heterosynaptic learning rule for long-term gating of information flow through the hippocampal excitatory macrocircuit by the silencing of the CCK inhibitory microcircuit. PMID- 24050407 TI - In the mind of the market: theory of mind biases value computation during financial bubbles. AB - The ability to infer intentions of other agents, called theory of mind (ToM), confers strong advantages for individuals in social situations. Here, we show that ToM can also be maladaptive when people interact with complex modern institutions like financial markets. We tested participants who were investing in an experimental bubble market, a situation in which the price of an asset is much higher than its underlying fundamental value. We describe a mechanism by which social signals computed in the dorsomedial prefrontal cortex affect value computations in ventromedial prefrontal cortex, thereby increasing an individual's propensity to 'ride' financial bubbles and lose money. These regions compute a financial metric that signals variations in order flow intensity, prompting inference about other traders' intentions. Our results suggest that incorporating inferences about the intentions of others when making value judgments in a complex financial market could lead to the formation of market bubbles. PMID- 24050408 TI - Real and fictive outcomes are processed differently but converge on a common adaptive mechanism. AB - The ability to learn not only from experienced but also from merely fictive outcomes without direct rewarding or punishing consequences should improve learning and resulting value-guided choice. Using an instrumental learning task in combination with multiple single-trial regression of predictions derived from a computational reinforcement-learning model on human EEG, we found an early temporospatial double dissociation in the processing of fictive and real feedback. Thereafter, real and fictive feedback processing converged at a common final path, reflected in parietal EEG activity that was predictive of future choices. In the choice phase, similar parietal EEG activity related to certainty of the impending response was predictive for the decision on the next trial as well. These parietal EEG effects may reflect a common adaptive cortical mechanism of updating or strengthening of stimulus values by integrating outcomes, learning rate, and certainty, which is active during both decision making and evaluation. Neuronal processing of real (rewarding, punishing) and fictive action outcomes (which would have happened had one acted differently) differs for 400 ms and then converges on a common adaptive mechanism driving future decision making and learning. PMID- 24050409 TI - Heart failure is associated with impaired anti-inflammatory and antioxidant properties of high-density lipoproteins. AB - Oxidative stress and inflammation are hallmarks of the heart failure (HF) disease state. In the present study, we investigated the inflammatory/anti-inflammatory characteristics of high-density lipoproteins (HDL) in patients with HF. Ninety six consecutive patients with systolic HF were followed in an advanced HF center, and 21 healthy subjects were recruited. Plasma was tested for HDL inflammatory index (HII) using a monocyte chemotactic activity assay, with HII >1.0 indicating proinflammatory HDL. We found significantly increased inflammatory properties of HDL in patients with HF (median HII 1.56 vs 0.59 in controls; p <0.0001). Serum amyloid A level was markedly elevated and the activity of paraoxonase-1, an HDL antioxidant enzyme, was significantly reduced in patients versus controls. HDL and albumin from patients with HF contained markedly elevated levels of oxidized products of arachidonic and linoleic acids. HDL function improved when plasma was treated in vitro with 4F, an apolipoprotein A-I mimetic peptide (40% reduction in HII, p <0.0001). There was no correlation found between HII level and ejection fraction or New York Heart Association functional class. In conclusion, HDL function is significantly impaired and oxidation products of arachidonic and linoleic acids are markedly elevated in patients with HF compared with non-HF controls. PMID- 24050410 TI - Cryptococcus gattii infections in multiple states outside the US Pacific Northwest. AB - Clonal VGII subtypes (outbreak strains) of Cryptococcus gattii have caused an outbreak in the US Pacific Northwest since 2004. Outbreak-associated infections occur equally in male and female patients (median age 56 years) and usually cause pulmonary disease in persons with underlying medical conditions. Since 2009, a total of 25 C. gattii infections, 23 (92%) caused by non-outbreak strain C. gattii, have been reported from 8 non-Pacific Northwest states. Sixteen (64%) patients were previously healthy, and 21 (84%) were male; median age was 43 years (range 15-83 years). Ten patients who provided information reported no past-year travel to areas where C. gattii is known to be endemic. Nineteen (76%) patients had central nervous system infections; 6 (24%) died. C. gattii infection in persons without exposure to known disease-endemic areas suggests possible endemicity in the United States outside the outbreak-affected region; these infections appear to differ in clinical and demographic characteristics from outbreak-associated C. gattii. Clinicians outside the outbreak-affected areas should be aware of locally acquired C. gattii infection and its varied signs and symptoms. PMID- 24050411 TI - Acute alcohol intoxication prolongs neuroinflammation without exacerbating neurobehavioral dysfunction following mild traumatic brain injury. AB - Traumatic brain injury (TBI) represents a leading cause of death and disability among young persons with ~1.7 million reported cases in the United States annually. Although acute alcohol intoxication (AAI) is frequently present at the time of TBI, conflicting animal and clinical reports have failed to establish whether AAI significantly impacts short-term outcomes after TBI. The objective of this study was to determine whether AAI at the time of TBI aggravates neurobehavioral outcomes and neuroinflammatory sequelae post-TBI. Adult male Sprague-Dawley rats were surgically instrumented with gastric and vascular catheters before a left lateral craniotomy. After recovery, rats received either a primed constant intragastric alcohol infusion (2.5 g/kg+0.3 g/kg/h for 15 h) or isocaloric/isovolumic dextrose infusion followed by a lateral fluid percussion TBI (~1.4 J, ~30 ms). TBI induced apnea and a delay in righting reflex. AAI at the time of injury increased the TBI induced delay in righting reflex without altering apnea duration. Neurological and behavioral dysfunction was observed at 6 h and 24 h post-TBI, and this was not exacerbated by AAI. TBI induced a transient upregulation of cortical interleukin (IL)-6 and monocyte chemotactic protein (MCP)-1 mRNA expression at 6 h, which was resolved at 24 h. AAI did not modulate the inflammatory response at 6 h but prevented resolution of inflammation (IL-1, IL-6, tumor necrosis factor-alpha, and MCP-1 expression) at 24 h post-TBI. AAI at the time of TBI did not delay the recovery of neurological and neurobehavioral function but prevented the resolution of neuroinflammation post-TBI. PMID- 24050412 TI - Geospatial exposure to point-of-sale tobacco: real-time craving and smoking cessation outcomes. AB - BACKGROUND: Little is known about the factors that drive the association between point-of-sale marketing and behavior, because methods that directly link individual-level use outcomes to real-world point-of-sale exposure are only now beginning to be developed. PURPOSE: Daily outcomes during smoking cessation were examined as a function of both real-time geospatial exposure to point-of-sale tobacco (POST) and subjective craving to smoke. METHODS: Continuous individual geospatial location data collected over the first month of a smoking-cessation attempt in 2010-2012 (N=475) were overlaid on a POST outlet geodatabase (N=1060). Participants' mobility data were used to quantify the number of times they came into contact with a POST outlet. Participants recorded real-time craving levels and smoking status via ecological momentary assessment (EMA) on cellular telephones. RESULTS: The final data set spanned a total of 12,871 days of EMA and geospatial tracking. Lapsing was significantly more likely on days with any POST contact (OR=1.19, 95% CI=1.18, 1.20), and increasingly likely as the number of daily POST contacts increased (OR=1.07, 95% CI=1.06, 1.08). Overall, daily POST exposure was significantly associated with lapsing when craving was low (OR=1.22, 95% CI=1.20, 1.23); high levels of craving were more directly associated with lapse outcomes. CONCLUSIONS: These data shed light on the way mobility patterns drive a dynamic interaction between individuals and the POST environment, demonstrating that quantification of individuals' exposure to POST marketing can be used to identify previously unrecognized patterns of association among individual mobility, the built environment, and behavioral outcomes. PMID- 24050413 TI - Smart growth community design and physical activity in children. AB - BACKGROUND: Physical inactivity is a leading cause of death and disease globally. Research suggests physical inactivity might be linked to community designs that discourage active living. A "smart growth" community contains features likely to promote active living (walkability, green space, mixed land use), but objective evidence on the potential benefits of smart growth communities is limited. PURPOSE: To assess whether living in a smart growth community was associated with increased neighborhood-centered leisure-time physical activity in children aged 8 14 years, compared to residing in a conventional community (i.e., one not designed according to smart growth principles). METHODS: Participants were recruited from a smart growth community, "The Preserve," located in Chino, California, and eight conventional communities within a 30-minute drive of The Preserve. The analytic sample included 147 children. During 2009-2010, each child carried an accelerometer and a GPS for 7 days to ascertain physical activity and location information. Negative binomial models were used to assess the association between residence in the smart growth community and physical activity. Analyses were conducted in 2012. RESULTS: Smart growth community residence was associated with a 46% increase in the proportion of neighborhood moderate-to-vigorous physical activity (MVPA) as compared to conventional community residence. This analysis included neighborhood activity data collected during the school season and outside of school hours and home. Counterfactual simulations with model parameters suggested that smart growth community residence could add 10 minutes per day of neighborhood MVPA. CONCLUSIONS: Living in a smart growth community may increase local physical activity in children as compared to residence in conventionally designed communities. PMID- 24050414 TI - Neighborhood perceptions and active school commuting in low-income cities. AB - BACKGROUND: Few children accumulate the recommended >=60 minutes of physical activity each day. Active travel to and from school (ATS) is a potential source of increased activity for children, accounting for 22% of total trips and time spent traveling by school-aged children. PURPOSE: This study identifies the association of parents' perceptions of the neighborhood, geospatial variables, and demographic characteristics with ATS among students in four low-income, densely populated urban communities with predominantly minority populations. METHODS: Data were collected in 2009-2010 from households with school-attending children in four low-income New Jersey cities. Multivariate logistic regression analyses (n=765) identified predictors of ATS. Analyses were conducted in 2012. RESULTS: In all, 54% of students actively commuted to school. Students whose parents perceived the neighborhood as very unpleasant for activity were less likely (OR=0.39) to actively commute, as were students living farther from school, with a 6% reduction in ATS for every 0.10 mile increase in distance to school. Perceptions of crime, traffic, and sidewalk conditions were not predictors of ATS. CONCLUSIONS: Parents' perceptions of the pleasantness of the neighborhood, independent of the effects of distance from school, may outweigh concerns about crime, traffic, or conditions of sidewalks in predicting active commuting to school in the low-income urban communities studied. Efforts such as cleaning up graffiti, taking care of abandoned buildings, and providing shade trees to improve neighborhood environments are likely to increase ATS, as are efforts that encourage locating schools closer to the populations they serve. PMID- 24050415 TI - Assessing the distribution of safe routes to school program funds, 2005-2012. AB - BACKGROUND: The federal Safe Routes to School (SRTS) program was launched in 2005 to increase the safety of, and participation in, walking and biking to school. PURPOSE: This study assesses how SRTS funds were allocated to public and private schools and communities and whether there were demographic or locational differences between schools that benefited from SRTS funding and those that did not receive SRTS awards. METHODS: The study analyzes all SRTS projects awarded between 2005 and 2012 (N=5532) by using descriptive statistics to profile SRTS funding amounts and purposes, and to compare demographic and neighborhood characteristics of schools with and without SRTS programs. Analysis was conducted in 2013. RESULTS: The average SRTS award was $158,930 and most funding was spent on infrastructure (62.8%) or combined infrastructure and non-infrastructure (23.5%) projects. Schools benefiting from the SRTS program served higher proportions of Latino students and were more likely to be in higher-density areas. Few differences existed in neighborhood demographics, particularly educational attainment, work-trip commute mode, and median household income. CONCLUSIONS: Schools benefiting from the SRTS program are more urban and have higher Latino populations but are otherwise comparable to U.S. public schools. This suggests that disadvantaged areas have had access to the SRTS program. PMID- 24050416 TI - Promoting healthy lifestyles in high school adolescents: a randomized controlled trial. AB - BACKGROUND: Although obesity and mental health disorders are two major public health problems in adolescents that affect academic performance, few rigorously designed experimental studies have been conducted in high schools. PURPOSE: The goal of the study was to test the efficacy of the COPE (Creating Opportunities for Personal Empowerment) Healthy Lifestyles TEEN (Thinking, Emotions, Exercise, Nutrition) Program, versus an attention control program (Healthy Teens) on: healthy lifestyle behaviors, BMI, mental health, social skills, and academic performance of high school adolescents immediately after and at 6 months post intervention. DESIGN: A cluster RCT was conducted. Data were collected from January 2010 to May of 2012 and analyzed in 2012-2013. SETTING/PARTICIPANTS: A total of 779 culturally diverse adolescents in the U.S. Southwest participated in the trial. INTERVENTION: COPE was a cognitive-behavioral skills-building intervention with 20 minutes of physical activity integrated into a health course, taught by teachers once a week for 15 weeks. The attention control program was a 15-session, 15-week program that covered common health topics. MAIN OUTCOME MEASURES: Primary outcomes assessed immediately after and 6 months post intervention were healthy lifestyle behaviors and BMI. Secondary outcomes included mental health, alcohol and drug use, social skills, and academic performance. RESULTS: Post-intervention, COPE teens had a greater number of steps per day (p=0.03) and a lower BMI (p=0.01) than did those in Healthy Teens, and higher average scores on all Social Skills Rating System subscales (p-values <0.05). Teens in the COPE group with extremely elevated depression scores at pre intervention had significantly lower depression scores than the Healthy Teens group (p=0.02). Alcohol use was 12.96% in the COPE group and 19.94% in the Healthy Teens group (p=0.04). COPE teens had higher health course grades than did control teens. At 6 months post-intervention, COPE teens had a lower mean BMI than teens in Healthy Teens (COPE=24.72, Healthy Teens=25.05, adjusted M=-0.34, 95% CI=-0.56, -0.11). The proportion of those overweight was significantly different from pre-intervention to 6-month follow-up (chi-square=4.69, p=0.03), with COPE decreasing the proportion of overweight teens, versus an increase in overweight in control adolescents. There also was a trend for COPE Teens to report less alcohol use at 6 months (p=0.06). CONCLUSIONS: COPE can improve short and more long-term outcomes in high school teens. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT01704768. PMID- 24050417 TI - Sugar-sweetened beverage consumption in the U.S.: novel assessment methodology. AB - BACKGROUND: Sugar-sweetened beverage (SSB) consumption has been linked with poor diet quality, weight gain, and increased risk for obesity, diabetes, and cardiovascular disease. Previous studies have been hampered by inconsistent definitions and a failure to capture all types of SSBs. PURPOSE: To comprehensively examine total SSB consumption in the U.S. using an all encompassing definition that includes beverages calorically sweetened after purchase in addition to presweetened beverages. METHODS: Data from the 2005-2008 National Health and Nutrition Examination Survey (N=17,078) were analyzed in September 2012 and used to estimate calories (kilocalories) of added sugars from SSBs and to identify top sources of SSBs. RESULTS: On average, Americans aged >=2 years consumed 171 kcal (8% of total kcal) per day from added sugars in SSBs; the top sources were soda, fruit drinks, tea, coffee, energy/sports drinks, and flavored milks. Male adolescents (aged 12-19 years) had the highest mean intakes (293 kcal/day; 12% of total kcal). CONCLUSIONS: Americans consume more calories from added sugars in beverages than previously reported. The methodology presented in this paper allows for more-comprehensive estimates than those previously used regarding the extent to which SSBs provide calories from added sugars. PMID- 24050418 TI - Federal food package revisions: effects on purchases of whole-grain products. AB - BACKGROUND: In 2009, the U.S. Department of Agriculture's Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) implemented revisions to the composition and quantities of WIC-provided foods. New whole-grain products such as whole-wheat bread and allowable substitutes were added to encourage increased intake of whole grains and fiber among WIC participants. PURPOSE: This paper assesses how the WIC revisions affected purchases of bread and rice among WIC-participating households in Connecticut and Massachusetts. METHODS: Scanner data from a regional supermarket chain were used to examine bread and rice purchases of 2137 WIC households. Purchased volume of bread and rice was compared before and after implementation of the WIC revisions (2009-2010) using generalized estimating equation models. Data were analyzed in 2013. RESULTS: Before the WIC revisions, when no bread or rice was provided through WIC, white bread dominated bread purchases among WIC households (78% of volume), and almost all rice purchased was white (94%). As a result of the WIC revisions, the share of 100% whole-grain bread in total bread purchases tripled (from 8% to 24%), replacing purchases of white bread; the share of brown rice rose to 30% of rice purchases. WIC households used WIC benefits to change some of their bread purchases, rather than to buy more bread overall, whereas total rice purchases increased. CONCLUSIONS: The 2009 WIC revisions significantly increased purchases of whole-grain bread and rice among WIC-participating families. The likely increase in whole-grain and fiber intake among low-income communities could have important public health implications. PMID- 24050420 TI - Medicaid home visitation and maternal and infant healthcare utilization. AB - BACKGROUND: The Michigan Maternal and Infant Health Program (MIHP) is a population-based home-visitation program providing care coordination, referrals, and visits based on a plan of care. MIHP is available to all Medicaid-eligible pregnant women and infants aged <=1 year in Michigan. PURPOSE: To assess the effects of MIHP participation on maternal and infant healthcare utilization. METHODS: Propensity-score matching methods were used to assess differences in healthcare utilization between MIHP participants and nonparticipants using 2009 2010 Medicaid claims and administrative data obtained from the Michigan Department of Community Health. Data were analyzed between October 2011 and March 2013. RESULTS: MIHP participants had higher odds of receiving any prenatal care compared to matched women not participating in MIHP (OR=2.94, 95% CI=2.43, 3.60) and higher odds of receiving adequate prenatal care (OR=1.06, 95% CI=1.01, 1.11). MIHP participants had higher odds of receiving an appropriately timed postnatal visit (OR=1.50, 95% CI=1.43, 1.57). Infants participating in MIHP had higher odds of receiving any well-child visits over the first year of life (OR=1.70, 95% CI=1.51, 1.93) and higher odds of receiving the appropriate number of well-child visits over their first year of life (OR=1.47, 95% CI=1.35, 1.60) compared to matched nonparticipant infants. CONCLUSIONS: The results from Michigan provide strong evidence for the effectiveness of a Medicaid-sponsored population-based home-visitation program in improving maternal prenatal and postnatal care and infant care. This evidence is important to consider as the federal healthcare reform is implemented and states are making decisions on the expansion of the Medicaid program. PMID- 24050421 TI - Desk-based occupational sitting patterns: weight-related health outcomes. AB - BACKGROUND: Prolonged, uninterrupted sitting time is associated with poor health outcomes. As most sitting time occurs at work, accurate, objective measurement of occupational sitting patterns is required to fully understand its effects on employee health. PURPOSE: The purpose of this study was to examine associations of desk-based sitting patterns with waist circumference (WC) and BMI. METHODS: Participants were full-time, office-based employees (N=105; mean age 40.9+/-11.5 years; BMI 26.1+/-3.9; 65% women). Sitting patterns (total desk-based sitting time and number of times employees got up from their desk) were assessed for 5 days using an objective measure of desk-based sitting: the sitting pad. WC, height, and weight were measured, and BMI was calculated. Associations of sitting patterns with WC and BMI were tested using logistic regression models. Data were collected and analyzed in 2011-2012. RESULTS: Those with high levels of sitting time at their desk were 2.7 times (95% CI=1.3, 6.3) more likely to have WC >=94 cm (men) and >=80 cm (women), and 9.0 times (95% CI=1.9, 41.9) more likely to have BMI >=30 than those with lower sitting time. There were no associations between the number of times employees got up from sitting at their desk and WC or BMI. CONCLUSIONS: High levels of desk-based sitting time were associated with an increased likelihood of negative weight-related health outcomes, whereas frequency of getting up from sitting at the desk was not. PMID- 24050419 TI - C-reactive protein levels in African Americans: a diet and lifestyle randomized community trial. AB - BACKGROUND: Chronic inflammation is linked to poor lifestyle behaviors and a variety of chronic diseases that are prevalent among African Americans, especially in the southeastern U.S. PURPOSE: The goal of the study was to test the effect of a community-based diet, physical activity, and stress reduction intervention conducted in 2009-2012 on reducing serum C-reactive protein (CRP) in overweight and obese African-American adults. METHODS: An RCT intervention was designed jointly by members of African-American churches and academic researchers. In late 2012, regression (i.e., mixed) models were fit that included both intention-to-treat and post hoc analyses conducted to identify important predictors of intervention success. Outcomes were assessed at 3 months and 1 year. RESULTS: At baseline, the 159 individuals who were recruited in 13 churches and had evaluable outcome data were, on average, obese (BMI=33.1 [+/-7.1]) and had a mean CRP level of 3.7 (+/-3.9) mg/L. Reductions were observed in waist-to hip ratio at 3 months (2%, p=0.03) and 1 year (5%, p<0.01). In female participants attending >=60% of intervention classes, there was a significant decrease in CRP at 3 months of 0.8 mg/L (p=0.05), but no change after 1 year. No differences were noted in BMI or interleukin-6. CONCLUSIONS: In overweight/obese, but otherwise "healthy," African-American church members with very high baseline CRP levels, this intervention produced significant reductions in CRP at 3 and 12 months, and in waist-to-hip ratio, which is an important anthropometric predictor of overall risk of inflammation and downstream health effects. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT01760902. PMID- 24050422 TI - Food marketing expenditures aimed at youth: putting the numbers in context. AB - In response to concerns about childhood obesity, the Federal Trade Commission (FTC) released two reports documenting food and beverage marketing expenditures to children and adolescents. The recently released 2012 report found an inflation adjusted 19.5% reduction in marketing expenditures targeted to youth from $2.1 billion in 2006 to $1.8 billion in 2009. The current article highlights features of the FTC's analysis, examines how expenditures relate to youth exposure to food marketing, and assesses changes in the nutritional content of marketed products. Of the $304.0 million decline in expenditures, $117.8 million (38.7%) was from a decline in premium (i.e., restaurant children's meal toys) expenditures rather than direct marketing. Although inflation-adjusted TV expenditures fell by 19.4%, children and teens still see 12-16 TV advertisements (ads)/day for products generally high in saturated fat, sugar, or sodium. In addition, newer digital forms of unhealthy food and beverage marketing to youths are increasing; the FTC reported an inflation-adjusted 50.7% increase in new media marketing expenditures. The self-regulatory Children's Food and Beverage Advertising Initiative (CFBAI) is limited in scope and effectiveness: expenditures increased for many noncovered marketing techniques (i.e., product placement, movie/video, cross-promotion licenses, athletic sponsorship, celebrity fees, events, philanthropy, and other); only two restaurants are members of CFBAI, and nonpremium restaurant marketing expenditures were up by $86.0 million (22.5% inflation-adjusted increase); industry pledges do not protect children aged >11 years, and some marketing appears to have shifted to older children; and, nutritional content remains poor. Continued monitoring of and improvements to food marketing to youth are needed. PMID- 24050423 TI - Validity of secondary retail food outlet data: a systematic review. AB - CONTEXT: Improving access to healthy foods is a promising strategy to prevent nutrition-related chronic diseases. To characterize retail food environments and identify areas with limited retail access, researchers, government programs, and community advocates have primarily used secondary retail food outlet data sources (e.g., InfoUSA or government food registries). To advance the state of the science on measuring retail food environments, this systematic review examined the evidence for validity reported for secondary retail food outlet data sources for characterizing retail food environments. EVIDENCE ACQUISITION: A literature search was conducted through December 31, 2012, to identify peer-reviewed published literature that compared secondary retail food outlet data sources to primary data sources (i.e., field observations) for accuracy of identifying the type and location of retail food outlets. Data were analyzed in 2013. EVIDENCE SYNTHESIS: Nineteen studies met the inclusion criteria. The evidence for validity reported varied by secondary data sources examined, primary data-gathering approaches, retail food outlets examined, and geographic and sociodemographic characteristics. More than half of the studies (53%) did not report evidence for validity by type of food outlet examined and by a particular secondary data source. CONCLUSIONS: Researchers should strive to gather primary data but if relying on secondary data sources, InfoUSA and government food registries had higher levels of agreement than reported by other secondary data sources and may provide sufficient accuracy for exploring these associations in large study areas. PMID- 24050424 TI - State costs of excessive alcohol consumption, 2006. AB - BACKGROUND: Excessive alcohol consumption is responsible for an average of 80,000 deaths in the U.S. each year and cost $223.5 billion ($1.90/drink) in 2006. Comparable state estimates of this cost are needed to help inform prevention strategies. PURPOSE: The goal of the study was to estimate the economic cost of excessive drinking by state for 2006. METHODS: From December 2011 to November 2012, an expert panel developed methods to allocate component costs from the 2006 national estimate to states for (1) total; (2) government; (3) binge drinking; and (4) underage drinking costs. Differences in average state wages were used to adjust productivity losses. RESULTS: In 2006, the median state cost of excessive drinking was $2.9 billion (range: $31.9 billion [California] to $419.6 million [North Dakota]); the median cost per drink, $1.91 (range: $2.74 [Utah] to $0.88 [New Hampshire]); and the median per capita cost, $703 (range: $1662 [District of Columbia] to $578 [Utah]). A median of 42% of state costs were paid by government (range: 45.0% [Utah] to 37.0% [Mississippi]). Binge drinking was responsible for a median of 76.6% of state costs (range: 83.1% [Louisiana] to 71.6% [Massachusetts]); underage drinking, a median of 11.2% of state costs (range: 20.0% [Wyoming] to 5.5% [District of Columbia]). CONCLUSIONS: Excessive drinking cost states a median of $2.9 billion in 2006. Most of the costs were due to binge drinking and about $2 of every $5 were paid by government. The Guide to Community Preventive Services has recommended several evidence-based strategies-including increasing alcohol excise taxes, limiting alcohol outlet density, and commercial host liability-that can help reduce excessive alcohol use and the associated economic costs. PMID- 24050425 TI - Law, public health, and the diabetes epidemic. AB - The prevalence of new cases of diabetes continues to increase, and the health burden for those with diabetes remains high. This is attributable, in part, to low adoption of evidence-based interventions for diabetes prevention and control. Law is a critical tool for health improvement, yet assessments reported in this paper indicate that federal, state, and local laws give only partial support to guidelines and evidence-based interventions relevant to diabetes prevention and control. Public health practitioners and policymakers who are concerned with the human, fiscal, and economic costs of the epidemic can explore new ways to translate the evidence base for diabetes prevention and control into effective laws and policies. PMID- 24050426 TI - Using electronic health records to address overweight and obesity: a systematic review. AB - CONTEXT: Overweight and obesity are problems of tremendous public health importance, but clinicians often fail to discuss weight management with their patients. Electronic health records (EHRs) have improved quality of care for some conditions and could be an effective mechanism for helping clinicians address overweight and obesity. This review sought to summarize current evidence on the use of EHRs for assessment and management of overweight and obesity. EVIDENCE ACQUISITION: The authors searched PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Web of Science, CINAHL, INSPEC, IEEE Explore, and the ACM Digital Library from their inception through August 15, 2012; analyses were conducted between September 2012 and March 2013. Eligible studies had to involve a new feature or a change in an existing feature within an EHR related to the identification, evaluation, or management of overweight and obesity. Included in the review were RCTs and nonrandomized controlled trials, pre-post studies with a historical control group, and descriptive studies. One reviewer screened all of the titles and abstracts. Citations that were potentially eligible were independently reviewed by two reviewers. Disagreements were resolved by consensus. EVIDENCE SYNTHESIS: Of the 1188 unique citations identified, 11 met the inclusion criteria. Seven of these studies were conducted in children and adolescents, and four were conducted in adults. Most of the studies were pre-post studies with a historical control group, and only three were RCTs. Most of the interventions included calculation, display, or plotting of BMI or BMI percentiles; fewer included other features. The majority of studies examined clinician performance outcomes; only two studies examined patient outcomes. CONCLUSIONS: Few studies have examined whether EHR-based tools can help clinicians address overweight and obesity, and further studies are needed to examine the effects of EHR features on weight-related outcomes in patients. PMID- 24050427 TI - Current mHealth technologies for physical activity assessment and promotion. AB - CONTEXT: Novel mobile assessment and intervention capabilities are changing the face of physical activity (PA) research. A comprehensive systematic review of how mobile technology has been used for measuring PA and promoting PA behavior change is needed. EVIDENCE ACQUISITION: Article collection was conducted using six databases from February to June 2012 with search terms related to mobile technology and PA. Articles that described the use of mobile technologies for PA assessment, sedentary behavior assessment, and/or interventions for PA behavior change were included. Articles were screened for inclusion and study information was extracted. EVIDENCE SYNTHESIS: Analyses were conducted from June to September 2012. Mobile phone-based journals and questionnaires, short message service (SMS) prompts, and on-body PA sensing systems were the mobile technologies most utilized. Results indicate that mobile journals and questionnaires are effective PA self-report measurement tools. Intervention studies that reported successful promotion of PA behavior change employed SMS communication, mobile journaling, or both SMS and mobile journaling. CONCLUSIONS: mHealth technologies are increasingly being employed to assess and intervene on PA in clinical, epidemiologic, and intervention research. The wide variations in technologies used and outcomes measured limit comparability across studies, and hamper identification of the most promising technologies. Further, the pace of technologic advancement currently outstrips that of scientific inquiry. New adaptive, sequential research designs that take advantage of ongoing technology development are needed. At the same time, scientific norms must shift to accept "smart," adaptive, iterative, evidence-based assessment and intervention technologies that will, by nature, improve during implementation. PMID- 24050428 TI - Clinical and community delivery systems for preventive care: an integration framework. AB - Although clinical preventive services (CPS)-screening tests, immunizations, health behavior counseling, and preventive medications-can save lives, Americans receive only half of recommended services. This "prevention gap," if closed, could substantially reduce morbidity and mortality. Opportunities to improve delivery of CPS exist in both clinical and community settings, but these activities are rarely coordinated across these settings, resulting in inefficiencies and attenuated benefits. Through a literature review, semi structured interviews with 50 national experts, field observations of 53 successful programs, and a national stakeholder meeting, a framework to fully integrate CPS delivery across clinical and community care delivery systems was developed. The framework identifies the necessary participants, their role in care delivery, and the infrastructure, support, and policies necessary to ensure success. Essential stakeholders in integration include clinicians; community members and organizations; spanning personnel and infrastructure; national, state, and local leadership; and funders and purchasers. Spanning personnel and infrastructure are essential to bring clinicians and communities together and to help patients navigate across care settings. The specifics of clinical-community integrations vary depending on the services addressed and the local context. Although broad establishment of effective clinical-community integrations will require substantial changes, existing clinical and community models provide an important starting point. The key policies and elements of the framework are often already in place or easily identified. The larger challenge is for stakeholders to recognize how integration serves their mutual interests and how it can be financed and sustained over time. PMID- 24050429 TI - Continuous evaluation of evolving behavioral intervention technologies. AB - Behavioral intervention technologies (BITs) are web-based and mobile interventions intended to support patients and consumers in changing behaviors related to health, mental health, and well-being. BITs are provided to patients and consumers in clinical care settings and commercial marketplaces, frequently with little or no evaluation. Current evaluation methods, including RCTs and implementation studies, can require years to validate an intervention. This timeline is fundamentally incompatible with the BIT environment, where technology advancement and changes in consumer expectations occur quickly, necessitating rapidly evolving interventions. However, BITs can routinely and iteratively collect data in a planned and strategic manner and generate evidence through systematic prospective analyses, thereby creating a system that can "learn." A methodologic framework, Continuous Evaluation of Evolving Behavioral Intervention Technologies (CEEBIT), is proposed that can support the evaluation of multiple BITs or evolving versions, eliminating those that demonstrate poorer outcomes, while allowing new BITs to be entered at any time. CEEBIT could be used to ensure the effectiveness of BITs provided through deployment platforms in clinical care organizations or BIT marketplaces. The features of CEEBIT are described, including criteria for the determination of inferiority, determination of BIT inclusion, methods of assigning consumers to BITs, definition of outcomes, and evaluation of the usefulness of the system. CEEBIT offers the potential to collapse initial evaluation and postmarketing surveillance, providing ongoing assurance of safety and efficacy to patients and consumers, payers, and policymakers. PMID- 24050430 TI - Exposure exposed. PMID- 24050431 TI - Bridging the why and the how of clinical-community integration. PMID- 24050433 TI - Assessment of mealtime environments and nutrition practices in child care centers in Georgia. AB - BACKGROUND: The amount of time children spend in child care each week has increased in recent years. The aim of this cross-sectional study was to describe the nutritional quality of foods served and the mealtime environment in 24 child care centers in Georgia. METHODS: Data were collected between April 2010 and September 2010. Each child care center provided a sample 5-day menu (breakfast, lunch, and an afternoon snack) at baseline. Energy and nutrient contents of the menus were analyzed using NutriKids Menu Planning & Nutritional Analysis software (LunchByte Systems, Inc., Rochester, NY). Foods and beverages on the menus were compared to MyPlate food group standards for preschoolers. The child care environment was assessed in each center over 1 full day using the Environment and Policy Assessment and Observation instrument. RESULTS: Menus met one half to two thirds of the recommended levels for energy, carbohydrate, protein, and vitamins A and C. However, the menus were high in saturated fat and sodium content and did not meet the recommendations for iron or fiber. The majority of the centers did not meet the recommendations for MyPlate food group standards for preschoolers. On the day of the observation, seven centers did not serve a vegetable and more than half of the centers (n=13) did not serve any whole grains. Nineteen centers served high-sugar and/or high-fat foods and 11 did not have visible water indoors. CONCLUSIONS: This study identified determinants of the child care environment and nutritional characteristics of the combined meals and snacks offered to children. Findings from this study could inform child care centers how to provide healthier nutrition environments to preschool children. PMID- 24050434 TI - From polling schools to planning policy: the role of the kids' safe and healthful foods project in school nutrition. PMID- 24050436 TI - Self-supported fibrin-polyvinyl alcohol interpenetrating polymer networks: an easily handled and rehydratable biomaterial. AB - A fibrin hydrogel at physiological concentration (5 mg/mL) was associated with polyvinyl alcohol (PVA) inside an interpenetrating polymer networks (IPN) architecture. Previously, PVA has been modified with methacrylate functions in order to cross-link it by free-radical polymerization. The fibrin network was synthesized by the enzymatic hydrolysis of fibrinogen by thrombin. The resulting self-supported materials simultaneously exhibit the properties of the fibrin hydrogel and those of the synthetic polymer network. Their storage modulus is 50 fold higher than that of the fibrin hydrogel and they are completely rehydratable. These materials are noncytotoxic toward human fibroblast and the fibrin present on the surface of PVAm-based IPNs favors cell development. PMID- 24050437 TI - A neoteric neodymium model: ground and excited electronic state analysis of NdF2+. AB - Neodymium monofluoride dication was studied as a model of the Nd-F bond in NdFx. Multiconfigurational self-consistent field (MCSCF) and second order multireference quasi-degenerate perturbation theory (MCQDPT2) methods were used with a variety of active spaces to elucidate the roles of the Nd 4f, 5d, and 6s orbitals. Spin-orbit coupling calculations were performed at the SO-MCQDPT2 level, and potential energy curves were obtained for the four lowest energy quartet states as well as for the four lowest doublet states and the lowest sextet state. Inclusion of spin-orbit coupling splits these states into 30 levels. Equilibrium bond lengths, dissociation energies, transition energies, and crossing points were determined. PMID- 24050438 TI - Coccidioidomycosis-associated hospitalizations, California, USA, 2000-2011. AB - In the past decade, state-specific increases in the number of reported cases of coccidioidomycosis have been observed in areas of California and Arizona where the disease is endemic. Although most coccidioidomycosis is asymptomatic or mild, infection can lead to severe pulmonary or disseminated disease requiring hospitalization and costly disease management. To determine the epidemiology of cases and toll of coccidioidomycosis-associated hospitalizations in California, we reviewed hospital discharge data for 2000-2011. During this period, there were 25,217 coccidioidomycosis-associated hospitalizations for 15,747 patients and >$2 billion US in total hospital charges. Annual initial hospitalization rates increased from 2.3 initial hospitalizations/100,000 population in 2000 to 5.0 initial hospitalizations/100,000 population in 2011. During this period, initial hospitalization rates were higher for men than women, African Americans and Hispanics than Whites, and older persons than younger persons. In California, the increasing health- and cost-related effects of coccidioidomycosis-associated hospitalizations are a major public health challenge. PMID- 24050439 TI - Helping people make well-informed decisions about health care: old and new challenges to achieving the aim of the Cochrane Collaboration. AB - The aim of the Cochrane Collaboration is to help people make well-informed decisions about health care by preparing, maintaining and promoting the accessibility of systematic reviews of the effects of health care interventions. This aim is as relevant now as it was 20 years ago, when the Cochrane Collaboration was established. Substantial progress has been made toward addressing challenges to achieving the Collaboration's aim. At the same time, a huge amount of work remains to be done. Current challenges include improving the quality of reviews, methodological challenges, meeting the needs of contributors and users and taking on new challenges while staying focused on the Collaboration's aim. Radical thinking and substantial change may be needed to identify and implement pragmatic strategies to ensure that reviews are up-to-date and informative. Methodological challenges include the development and application of better methods for addressing explanatory factors, incorporating non-randomized evidence and making comparisons across multiple interventions. Innovations in editorial processes and strategies to meet the needs of low- and middle-income countries and diverse users of Cochrane reviews are needed. Finally, although it is important to consider broadening the aims of the Collaboration to include types of questions other than the effects of interventions and types of products other than the Cochrane Library, we should not lose sight of the aim of the Cochrane Collaboration. Addressing that aim is still a major challenge that requires the collaboration of thousands of people around the world and continuing improvements in the methods used to achieve that aim. PMID- 24050440 TI - New energy storage option: toward ZnCo2O4 nanorods/nickel foam architectures for high-performance supercapacitors. AB - Hierarchical ZnCo2O4/nickel foam architectures were first fabricated from a simple scalable solution approach, exhibiting outstanding electrochemical performance in supercapacitors with high specific capacitance (~1400 F g(-1) at 1 A g(-1)), excellent rate capability (72.5% capacity retention at 20 A g(-1)), and good cycling stability (only 3% loss after 1000 cycles at 6 A g(-1)). All-solid state supercapacitors were also fabricated by assembling two pieces of the ZnCo2O4-based electrodes, showing superior performance in terms of high specific capacitance and long cycling stability. Our work confirms that the as-prepared architectures can not only be applied in high energy density fields, but also be used in high power density applications, such as electric vehicles, flexible electronics, and energy storage devices. PMID- 24050441 TI - Tissue deposition and residue depletion of cyadox and its three major metabolites in pigs after oral administration. AB - Tissue deposition and residue depletion profiles of cyadox (Cyx) and its three major metabolites, including 1,4-bisdesoxycyadox (Cy1), 4-desoxycyadox (Cy2), and quinoxaline-2-carboxylic acid (QCA), in pigs after multiple oral administrations were determined. Thirty-five healthy adult pigs were randomly divided into seven groups and orally treated with Cyx at a dosage of 20 mg/kg of body weight for five consecutive days. Each group of five pigs was randomly slaughtered 12, 24, 72, 120, 168, 216, and 264 h after the last dosing, and tissue samples, including muscle, liver, kidney, and fat, were collected and analyzed via the liquid chromatography-tandem mass spectrometry method. The concentration-time data of Cyx and its three metabolites (Cy1, Cy2, and QCA) were analyzed with WinNonlin. Results showed that metabolites of Cyx were quickly generated in swine tissues and the concentrations of QCA in kidney were higher than those of Cyx and other metabolites in all edible tissues. These results provide further insight into the metabolism of Cyx and confirmation of the residue marker and target tissue of Cyx in pigs. PMID- 24050442 TI - Effective screening strategy using ensembled pharmacophore models combined with cascade docking: application to p53-MDM2 interaction inhibitors. AB - Protein-protein interactions (PPIs) play a crucial role in cellular function and form the backbone of almost all biochemical processes. In recent years, protein protein interaction inhibitors (PPIIs) have represented a treasure trove of potential new drug targets. Unfortunately, there are few successful drugs of PPIIs on the market. Structure-based pharmacophore (SBP) combined with docking has been demonstrated as a useful Virtual Screening (VS) strategy in drug development projects. However, the combination of target complexity and poor binding affinity prediction has thwarted the application of this strategy in the discovery of PPIIs. Here we report an effective VS strategy on p53-MDM2 PPI. First, we built a SBP model based on p53-MDM2 complex cocrystal structures. The model was then simplified by using a Receptor-Ligand complex-based pharmacophore model considering the critical binding features between MDM2 and its small molecular inhibitors. Cascade docking was subsequently applied to improve the hit rate. Based on this strategy, we performed VS on NCI and SPECS databases and successfully discovered 6 novel compounds from 15 hits with the best, compound 1 (NSC 5359), K(i) = 180 +/- 50 nM. These compounds can serve as lead compounds for further optimization. PMID- 24050443 TI - [Diabetic muscle infarction]. AB - BACKGROUND: Diabetic muscle infarction is a rare complication of diabetes mellitus that typically presents in the thigh; microvascular abnormalities may play a role. CASE DESCRIPTION: A 32-year-old female presented at the outpatient clinic with a painful, swollen thigh. She had suffered from type 1 diabetes for 22 years. The patient was admitted to the nephrology ward for further evaluation. Deep-venous thrombosis and abscess were excluded with echography. After additional investigations - MRI and a biopsy of skin, muscle and fascia - the diagnosis diabetic muscle infarction was made. The patient was treated with bed rest and analgesics. With hindsight, the muscle biopsy was not actually required in reaching a diagnosis. CONCLUSION: The diagnosis 'diabetic muscle infarction' is made on the basis of clinical presentation in combination with MRI findings. The treatment consists of bed rest and analgesics. PMID- 24050444 TI - [Diagnosis and treatment of uveitis; not restricted to the ophthalmologist]. AB - Visual symptoms due to uveitis involve a wide range of possible causes. Familiarity with its clinical manifestations, referral indications and treatment strategies is required for the optimal use of current therapeutic options. Uveitis can be caused by infectious and non-infectious factors, resulting in differing prognoses and treatments. The treatment of chronic, non-infectious uveitis has profoundly changed in the last years due to the advent of biological therapies. In severe uveitis, treatment of the underlying cause is required for the prevention of the loss of vision; multidisciplinary team collaboration is therefore important. PMID- 24050445 TI - [SGLT-2 inhibitors: diabetes treatment by glycosuria; literature review on the effect of dapagliflozin]. AB - OBJECTIVE: To describe the efficacy and safety of dapagliflozin, the first sodium glucose co-transporter-2 (SGLT-2) inhibitor for the treatment of diabetes mellitus type 2 (DM2) to be registered in the Netherlands. DESIGN: Literature review. METHOD: We searched the Medline database for articles on the use of dapagliflozin in patients with DM2. We included randomised studies with a minimum duration of 12 weeks and systematic reviews published up to 19 October 2012. Two assessors selected the articles on the basis of title, abstract and if necessary, the complete text. RESULTS: Eleven articles were suitable for analysis. On comparison with placebo, the use of dapagliflozin gave a drop in HbA1c-value of approximately 0.5-0.8 percentage points (6-9 mmol/mol). The body weight of patients who used dapagliflozin dropped between 1.0-2.4 kg on comparison with the placebo and metformin control groups. Urinary tract infections occurred twice as often and genital infections three to four times more often. There were no data on the effect on micro- and macrovascular complications or on mortality. CONCLUSION: Dapagliflozin regulates the blood glucose levels less effectively than currently used medications, although the small number of studies that compare dapagliflozin with metformin or glipizide show no differences in the drop in HbA1c between the study groups. Dapagliflozin use leads to minor, clinically non-relevant weight loss. There are as yet no data on its long term efficacy and safety. PMID- 24050446 TI - [Treatment of patients with severe glucocorticoid-refractory ulcerative colitis: cyclosporine or infliximab?]. AB - Cyclosporine and infliximab are so-called 'rescue-therapies' as last resort for the treatment of patients with severe glucocorticoid-refractory ulcerative colitis. A recent study found that cyclosporine and infliximab are similar in terms of efficacy in the treatment of patients with severe ulcerative colitis. Cyclosporine may be prescribed as a bridge to treatment with thiopurines; infliximab may be prescribed when a patient is intolerant or refractory to thiopurines. Preoperative treatment with cyclosporine or infliximab does not affect the number of postoperative complications. PMID- 24050447 TI - [One guideline for diagnosing cow milk allergy; for primary, secondary and tertiary care in the Netherlands]. AB - The aims of the new Dutch guideline 'Diagnosing Cow Milk Allergy in Children in the Netherlands' are to provide an evidence-based instrument for the reliable and safe diagnosis of cow milk allergy and to improve the collaboration between health care professionals at well-baby clinics, general practices and hospitals. The double-blind, placebo-controlled cow-milk provocation test is the only test available for establishing an allergy to cows' milk. The double-blind provocation test in children at a low risk of severe reactions may be performed at the better equipped well-baby clinics and at all general practices, thereby shifting care from secondary to primary care. The use of extensively hydrolysed formulas based on whey protein as well as on casein can be advised for a cow-milk-free diet. The general practitioner and well-baby physician should collaborate in designating responsibilities during the diagnostic phase of cow milk allergy in primary care. PMID- 24050448 TI - [Perinatal policy in cases of extreme prematurity; an investigation into the implementation of the guidelines]. AB - OBJECTIVE: To determine to what extent the recommendations to actively treat preterm infants with a gestational age of 24 weeks upwards laid down in the guidelines 'Perinatal policy in cases of extreme prematurity' have influenced policy in Dutch perinatal centres in the first year after publication, and what the health outcomes were. DESIGN: Retrospective, descriptive study. METHOD: Our study population included all pregnant women who were admitted to a perinatal centre at 23 5/7 to 26 weeks gestation with a diagnosis of 'threatened preterm labour', and their preterm infants. We collected both obstetric data and data on survival and morbidity of the infants from the medical files. RESULTS: Of a total of 192 preterm infants 185 (96%) were born alive; 92% of these infants were admitted to the neonatal intensive care unit. Survival rates were 43% and 61% at 24 weeks and 25 weeks gestation, respectively. Short-term morbidity (bronchopulmonary dysplasia, retinopathy of the newborn, severe intraventricular haemorrhage, necrotising enterocolitis and persistent ductus arteriosus) occurred in 79% and 71% of the infants born at 24 weeks and 25 weeks gestation, respectively. CONCLUSIONS: The recommendations from these guidelines have been implemented swiftly in Dutch perinatal centres, and survival of extremely preterm infants has increased. This has imposed a considerable burden on the capacity of these centres. Little is yet known about the long-term (up to school-age) health and survival of these infants. PMID- 24050449 TI - [A woman with paraneoplastic dermatoses; signs of recurrent malignancy]. AB - BACKGROUND: Paraneoplastic dermatoses may be the first manifestation of a malignancy. Rapid recognition is therefore important. CASE DESCRIPTION: A 72-year old woman who had been treated in the past for metastasised neuroendocrine carcinoma and had undergone curative treatment for stage-1c endometrial carcinoma developed three paraneoplastic dermatoses over a 2-year period: acanthosis nigricans, tripe palms and acquired hypertrichosis lanuginosa. Half a year later, cutaneous metastases derived from the endometrial carcinoma treated 12 years prior were discovered. CONCLUSION: The development of three paraneoplastic dermatoses in a short period of time is rare. Acanthosis nigricans, tripe palms and acquired hypertrichosis lanuginosa can develop in association with both neuroendocrine and endometrial carcinoma. The sudden development of paraneoplastic dermatoses is frequently a forewarning of progression of the malignancy. PMID- 24050451 TI - [Stopping smoking preoperatively: the surgeon's role]. AB - Recently a systemic review and meta-analysis of studies on preoperative smoking and postoperative complications was published. The meta-analysis showed that wound healing is better if patients do not smoke before surgery. Also, in major surgery there were fewer postoperative pulmonary complications, wound healing was better and patients who did not smoke stayed fewer days on Intensive Care. In bone surgery the consolidation process was better in non-smoking patients. We suggest that every surgeon should give well-founded and motivational advice on stopping smoking before every operation. If there is time to postpone the operation, as is the case in gastric bypass surgery for obesity, stopping smoking should generally be a conditio sine quanon for surgery. We require surgeons to be fit to operate. Likewise, for improvement of short term and long term results we should require patients to be as fit as possible to be operated on. PMID- 24050453 TI - 1,5-disubstituted 1,2,3-triazolylation at C1, C2, C3, C4, and C6 of pyranosides: a metal-free route to triazolylated monosaccharides and triazole-linked disaccharides. AB - A pair of easily accessible vinyl sulfones derived from styrene epoxide and monotosylated glycerol were reacted with six different azidopyranosides having an azido group at C1, C2, C3, C4, C6, and at the terminal position of an exocylic chain attached to C1. The reaction was performed mostly in water at elevated temperature without any metal catalyst to afford regioselectively 1,5 disubstituted triazolylated pyranosides in high yields. Another set of exocyclic vinyl sulfones prepared from 3-O-methylated- and 3-O-benzylated glucofuranosides as well as 3-O-benzylated allofuranoside were also subjected to 1,3-dipolar cycloaddition reactions with six azidopyranosides under similar reaction conditions to generate a series of 1,5-disubstituted triazole-linked disaccharides. The synthesis of all 1,5-disubstituted triazolylated monosaccharides as well as all 1,5-disubstituted triazole linked disaccharides are reported for the first time. Steric bulk around the azido and vinyl sulfone groups plays a significant role in deciding the outcome of the reactions. This powerful and practical route has the potential to be exploited for the synthesis of complex 1,5-disubstituted 1,2,3-triazolylated carbohydrates. PMID- 24050452 TI - Modified trastuzumab and cetuximab mediate efficient toxin delivery while retaining antibody-dependent cell-mediated cytotoxicity in target cells. AB - Monoclonal antibody-based therapy is one of the most successful strategies for treatment of cancer. However, the insufficient cell killing activity of monoclonal antibodies limits their therapeutic potential. These limitations can be overcome by the application of immunotoxins, which consist of a monoclonal antibody that specifically delivers a toxin into the cancer cell. An ideal immunotoxin combines the functionality of the monoclonal antibody (antagonistic binding to targeted receptors and interaction with the innate immune system) with the cell-killing activity of the toxic moiety. In addition, it should be sensitive for certain triterpenoid saponins that are known to lead to a tremendous augmentation of the antitumoral efficacy of the immunotoxin. In this study, the monoclonal antibodies trastuzumab (Herceptin) and cetuximab (Erbitux) were conjugated via cleavable disulfide bonds to the plant derived toxin saporin. The ability of the modified tumor-specific therapeutic antibodies to deliver their toxic payload into the target cells was investigated by impedance-based real-time viability assays and confocal live cell imaging. We further provide evidence that the immunotoxins retained their ability to trigger antibody dependent cell-mediated cytotoxicity. They specifically bound to their target cell receptor, and their cell-killing activity was drastically augmented in the presence of triterpenoid saponins. Further mechanistic studies indicated a specific saponin-mediated endo/lysosomal release of the toxin moiety. These results open a promising avenue to overcome the present limitations of therapeutic antibodies and to achieve a higher antitumoral efficacy in cancer therapy. PMID- 24050454 TI - Turning for Ulcer ReductioN: a multisite randomized clinical trial in nursing homes. AB - OBJECTIVES: To determine optimal repositioning frequency of nursing home (NH) residents at risk for pressure ulcers (PrUs) when cared for on high-density foam mattresses. DESIGN: Multisite, randomized, clinical trial, known as Turning for Ulcer ReductioN (TURN Study). SETTINGS: NHs in the United States (n = 20) and Canada (n = 7) using high-density foam mattresses. PARTICIPANTS: Consenting residents (N = 942) aged 65 and older without PrUs at moderate (scores 13-14) or high (scores 10-12) risk of PrUs according to the Braden Scale. INTERVENTION: Participants were randomly allocated using risk stratification (moderate vs high) to a repositioning schedule (2, 3, or 4 hour) for 3 weeks. Blinded assessors assessed skin weekly. MEASUREMENTS: PrU incidence (coccyx or sacrum, trochanter, heels). RESULTS: Participants were mostly female (77.6%) and Caucasian (80.5%) and had a mean age of 85.1 +/- 7.7. The most common diagnoses were cardiovascular (76.9%) and dementia (72.5%). Nineteen (2.0%) participants developed superficial PrUs. There was no significant difference (Wilcoxon test for ordered categories) in PrU incidence (P = .68) according to repositioning group (2 hour, 8/321, 2.5%; 3 hour, 2/326, 0.6%; 4 hour, 9/295, 3.1%), nor was there a statistically significant difference in the incidence of PrU between the high and moderate-risk groups (P = .79). Also, PrU incidence was not statistically significantly different between high-risk participants based on repositioning schedule (6/325, 1.8%, P = .90) or between moderate-risk participants based on repositioning schedule (13/617, 2.1%, P = .68). CONCLUSION: There was no difference in PrU incidence over 3 weeks of observation between those turned at 2-, 3-, or 4-hour intervals in this population of residents using high-density foam mattresses at moderate and high risk of developing PrUs when they were repositioned consistently and skin was monitored. This finding has major implications for use of nursing staff and cost of NH care. PMID- 24050456 TI - Global versus local hubs in human protein-protein interaction network. AB - In this study, we have constructed tissue-specific protein-protein interaction networks for 70 human tissues and have identified three types of hubs based on their expression breadths: (a) tissue-specific hubs (TSHs) (proteins that are expressed in <= 10 tissues and also form hubs in <= 10 tissues), (b) tissue preferred hubs (TPHs) (proteins expressed in >= 60 tissues but are highly connected in <= 10 tissues), and (c) housekeeping hubs (HKHs) (proteins that are expressed in >= 60 tissues and also form hubs in >= 60 tissues). Comparative analyses revealed significant differences between TSHs and HKHs and also revealed that TPHs behave more like HKHs. TSHs are lengthier, more disordered, and also quickly evolving proteins as compared with HKHs. Despite having a similar number of binding surfaces and interacting domains, TSHs are associated with a lower degree of centrality as compared with HKHs, suggesting that TSHs are "unsaturated" with regard to their binding capability and are perhaps evolving with regard to their interactions. TSHs are less abundantly expressed as compared with HKHs and are enriched with PEST motifs, indicating their tight regulation. All of these properties of TSHs and HKHs correlate with their distinct functional roles; TSHs are involved in tissue-specific functional roles, viz., secretors, receptors, and signaling proteins, whereas HKHs are involved in core-cellular functions such as transcription, translation, and so on. Our study, therefore, brings forth a clear and distinct classification of hubs simply based on their expression breadth and further assumes significance in the light of the highly debated dichotomy of date and party hubs, which is based on the coexpression pattern of hubs with their partners. PMID- 24050455 TI - Abnormal uterine bleeding, health status, and usual source of medical care: analyses using the Medical Expenditures Panel Survey. AB - BACKGROUND: Traditionally, research on abnormal uterine bleeding (AUB) focused on measured menstrual blood loss. However, the main burden of this symptom from the patient perspective is its impact on quality of life. Better describing the demographic characteristics, quality of life, and utilization of medical care of women with AUB could assist with health resource planning for this population. METHODS: We analyzed data from the Medical Expenditures Panel Survey from 2002 to 2010. AUB was identified by International Classification of Diseases, ninth edition (ICD-9) code group 626, disorders of menstruation and other abnormal bleeding from the female genital tract. Health-related quality of life was assessed by the Short-form 12 Health Survey (SF-12, QualityMetric) physical and mental component summary scores (PCS and MCS). Poorer health-related quality of life was defined as PCS or MCS <50. Odds ratios (OR) and 95% confidence intervals (CI) for the association of AUB with poorer SF-12 scores and having a usual source of care were estimated by multivariable logistic regression models. RESULTS: Data analyzed represented an annual average of 56.2 million nonpregnant women between ages 18 and 50 years. We estimate that 1.4 million women per year (95% CI: 1.3-1.5 million) reported AUB. Women with AUB were more likely to be younger, Caucasian, and obese than women without AUB. Compared to women without AUB, women with AUB had greater odds of a poorer PCS score (OR=1.30, 95% CI: 1.10 1.55), a poorer MCS score (OR=1.28, 95% CI: 1.10-1.51), and a usual source of care (OR=1.85, 95% CI: 1.44-2.38). CONCLUSIONS: AUB is associated with diminished physical and mental health status and having a usual source of medical care. PMID- 24050457 TI - Special infinity1[OPb2] chains and infinity1[O2Pb3] ribbons based on OPb4 anion centered tetrahedra in Pb2(O4Pb8)(BO3)3Br3 and Pb2(O8Pb12)(BO3)2Br6. AB - The structures of two new lead-containing oxyborate bromines, Pb2(O4Pb8)(BO3)3Br3 (1) and Pb2(O8Pb12)(BO3)2Br6 (2), are determined by single-crystal X-ray diffraction for the first time. Both of them crystallize in the space group C2/c of the monoclinic crystal system. Although the two compounds have the same type of fundmental building units (FBUs), the OPb4 anion-centered tetrahedra and BO3 triangles, they exhibit different connection modes. Compound 1 consists of single infinity(1)[OPb2] chains, while compound 2 possesses infinity(1)[O2Pb3] ribbons. Interestingly, large Br atoms profoundly influence the conformation of polyions based on the OPb4 anion-centered tetrahedra, resulting in single infinity(1)[OPb2] chains linked up by finite zweier chains with four OPb4 tetrahedra via the opposite edges in compound 1 and infinity(1)[O2Pb3] ribbons with sequential condensation of OPb2 chains in compound 2. A detailed description of the effect of large Br atoms on the conformation of polyions is discussed. IR spectroscopy, UV-vis-NIR diffuse reflectance spectroscopy, and thermal analysis are also performed on the reported materials. PMID- 24050458 TI - Reaction time and anticipatory skill of athletes in open and closed skill dominated sport. AB - In sports, reaction time and anticipatory skill are critical aspects of perceptual abilities. To date, no study has compared reaction time and anticipatory skill of athletes from open and closed skill-dominated sport. Accordingly, the present study investigated whether a difference exists in sensory-cognitive skills between these two different sport domains. Eleven volleyball players and 11 sprinters participated in this experiment. Reaction time and anticipatory skill of both groups were recorded by a custom-made software called SART (speed anticipation and reaction time test). This software consists of six sensory-cognitive tests that evaluate visual choice reaction time, visual complex choice reaction time, auditory choice reaction time, auditory complex choice reaction time, and anticipatory skill of the high speed and low speed of the ball. For each variable, an independent t-test was performed. Results suggested that sprinters were better in both auditory reaction times (P<0.001 for both tests) and volleyball players were better in both anticipatory skill tests (P = 0.007 and P = 0.04 for anticipatory skill of the high speed and low speed of the ball, respectively). However, no significant differences were found in both visual choice reaction time tests (P > 0.05 for both visual reaction time tests). It is concluded that athletes have greater sensory-cognitive skills related to their specific sport domain either open or closed. PMID- 24050459 TI - The relative age effect among elite youth competitive swimmers. AB - The aim of this study was to analyse the relative age effect (RAE) in competitive swimming. The best 50 Portuguese swimmers (12- to 18-year-olds) for the main individual swimming pool events of both genders were considered. Analysis was conducted on 7813 swimming event participants, taking account of respective swimmer birth dates and the Federation Internationale de Natation points gained. Differences in the distribution of birth dates by quarter year were determined using the Chi-square. A one-way analysis of variance ANOVA was used to test for differences measured in points between individuals by quarterly birth year intervals. A two-way analysis of variance ANOVA was also conducted to test the interaction between gender and seasonal birth date with regard to performance. The results show an inequitable distribution (p<0.01) of birth dates by quarter for almost all age groups and both genders. However, the distribution of birth dates by quarter for each considered swim event shows that RAE seems to exist only for 12-year-old females and 12- to 15-year-old males. Analysing mean swimming performance, post-hoc results (p<0.01) show no consistency in RAE. Higher performance occurs among older swimmers only in 100 m butterfly (female 1998, 1st?2nd quarter, p=0.003). The results also show no interaction between gender and seasonal birth date (p<0.01). Findings of this study show that a higher number of swimmers, particular males, are born in the first two quarters of the year, although there is mostly no effect of seasonal birth date on performance differences within the top 50 swimmers. PMID- 24050460 TI - Influence of a 2-year strength training programme on power performance in elite youth soccer players. AB - In soccer, strength, power and speed are very important because of the large number of power actions performed during the game. Therefore, the aim of this study was to examine the influence of periodised strength training for power performance more than 2 years. In this study, 134 elite youth soccer players were recruited from two youth training centres. The cohorts were arranged as follows: A (under 19 years), B (under 17 years) and C (under 15 years). The participants in each cohort were divided into two groups. One group (Strength training group [STG]) was subjected to regular soccer training in addition to strength training twice a week for 2 years. The other group (Control group [CG]) completed only the regular soccer training. The strength training was periodised with hypertrophy and intramuscular coordination blocks. For strength training, both the front squat and the back squat were performed once a week. The subjects were tested on the one-repetition maximum (1RM) of the front and back squat and a linear sprint over 30 m. There was significantly better performance from the STG on 1RM (p <0.001). In the sprint, the STG displayed significantly better improvements (p <0.05 to p <0.001) of up to 6%. The effects of strength training are reflected in the sprint performance. Therefore, it seems beneficial for youth to perform strength training to exploit the reserve capacity in sprint performances. PMID- 24050461 TI - The role of specialisation in the promotion of young football talents: a person oriented study. AB - This paper investigates the controversial question whether it is more effective to promote specialisation in a specific sport at the beginning of a career or whether to encourage a broad range of sports when promoting competitive sports talents in order for them to achieve a high level of performance in adulthood. The issue of promoting talents depends on human developmental processes and therefore raises developmental scientific questions. Based on recent, dynamic interactionist concepts of development, we assume a person-oriented approach focussing on the person as a whole rather than individual features. Theoretical considerations lead to four interacting factors being summarised to form a subsystem: childhood training. The relative weights of these factors lead to patterns. By relating these to a performance criterion at the age of peak performance, particularly promising developmental patterns may be identified. One hundred fifty-nine former Swiss football talents were retrospectively interviewed about their career and the data analysed using the LICUR method. Two early career patterns were identified as having a favourable influence on adult performance. Both are characterised by an above-average amount of in-club training. One pattern also exhibits an above-average amount of informal football played outside the club, the other above-average scores for activity in other sports. Hence, comprehensive training and practice inside and outside the club form the basis for subsequent football expertise. PMID- 24050462 TI - The effect of morphological and functional variables on ranking position of professional junior Basque surfers. AB - The aim of this study was to analyse the association of morphology as well as functional outcomes during a paddling test with ranking position (RP) of competitive junior surfers. Ten male surfers (age, mean 17.60, s=2.06 years) performed a maximum incremental test on a modified ergometer (Ergo Vasa Swim, USA) to determine, per unit of weight, the relative heart rate at lactate threshold (RHRLT) and at onset of blood lactate accumulation (RHROBLA) and the relative power output at LT (RWLT) and at OBLA (RWOBLA). Anthropometrics were weight, height and sum of six skinfolds (subscapular, triceps, supraspinal, abdominal, anterior thigh and calf) and Heath-Carter anthropometric somatotypes. A stepwise multiple regression was constructed to model and predict RP. Surfers shared a relative short stature and light weight, with a broader range of skinfold thickness (174.30, s=0.07 cm; 66.73, s=5.91 kg; 57.03, s=12.29 mm) and mean somatotype was ectomorphic-mesomorph: 2.20-4.36-3.09 (Category 2). Two model equations were possible: (A) RP = - 244.550 RWOBLA+262.787; (B) RP = - 217.028.RWOBLA+31.21.endomorphy + 169.16 with 63.1% and 83% of variance explained, respectively. A hierarchical cluster analysis on the Euclidean distances of the variables in model B also distinguished between upper and lower ranking groups. RWOBLA was more useful than endomorphy, anthropometric measures and also than the other functional outcomes to predict RPs. RWOBLA and endomorphy should be considered important variables that may influence the success of these young competitive surfers. PMID- 24050463 TI - Effect of using poles on foot-ground kinetics during stance phase in trail running. AB - The aim of this study was to investigate the effect of using poles on foot-ground interaction during trail running with slopes of varying incline. Ten runners ran on a loop track representative of a trail running field situation with uphill (+9 degrees ), level and downhill (-6 degrees ) sections at fixed speed (3.2 m.s( 1)). Experimental conditions included running with (WP) and without (NP) the use of poles for each of the three slopes. Several quantitative and temporal foot ground interaction parameters were calculated from plantar pressure data measured with a portable device. Using poles induced a decrease in plantar pressure intensity even when the running velocity stayed constant. However, the localisation and the magnitude of this decrease depended on the slope situations. During WP level running, regional analysis of the foot highlighted a decrease of the force time integral (FTI) for absolute (FTIabs; -12.6%; P<0.05) and relative values (FTIrel; -14.3%; P<0.05) in the medial forefoot region. FTIabs (-14.2%; P<0.05) and duration of force application (Deltat; -13.5%; P<0.05) also decreased in the medial heel region when WP downhill running. These results support a facilitating effect of pole use for propulsion during level running and for the absorption phase during downhill running. PMID- 24050464 TI - Knee loading patterns in a simulated netball landing task. AB - The knee is a common site of injury in netball players. In this study, 10 high performance netball players underwent a biomechanical assessment of their single leg landing technique whilst receiving a pass. Three-dimensional video and ground reaction force data were recorded using a motion analysis system. Net internal knee joint moments were calculated using a rigid body analysis and inverse dynamics. The kinematics of the support leg and front-on video footage was used to investigate whether players adhered to guidelines on safe and effective landing strategies. Results indicated that for most players the internal valgus moment was the largest frontal plane knee moment during the landing phase. This may reflect a relatively greater need to resist varus knee excursion or may be related to the kinematics of the hip. For 6 of the 10 players the rapid change to an internal knee valgus moment coincided with hip adduction. Since an increase in the magnitude of the internal valgus moment may increase the compressive forces in the medial compartment of the knee, further work should be undertaken to determine if a neuromuscular training intervention to improve the strength of the hip musculature may be beneficial for these players. A large relative excursion of the knee compared to the hip may indicate that these players had a greater reliance on the more distal segments of the lower extremity for the attenuation of the ground reaction forces. This information may be used to better understand potential knee injury mechanisms in netball players. PMID- 24050465 TI - Effects of stance angle on postural stability and performance with national standard air pistol competitors. AB - The effects of stance angle on postural stability and shooting processes were studied using eight national-standard male air-pistol shooters. Each shooter performed 60 shots each in four stance angles (0 degrees , 15 degrees , 30 degrees and 45 degrees from the line of fire). Postural stability was determined by measuring change in centre of pressure with a dual-force platform system assessing centre-of-pressure (COP) excursion (average difference of the centre of pressure from the mean) and COP speed (total COP path divided by time). Shooting process measures were determined by using a NOPTEL ST-2000 optoelectronic system. Score was assessed with a Sius Ascor S10 electronic scoring system. The results revealed no significant difference among the various stance angles; COP excursion or COP speed, p>0.05. Results indicated a significant stance angle effect with the shooting process measure, hit fine (percentage of hold within an area the size of the 10-ring when centred over the actual shot; p = 0.025) and the shooting performance measure adjusted score (raw score adjusted for true zero; p=0.008). Moreover, best overall performance was with a stance angle of 15 degrees . These findings suggest that stance angle may affect pistol stability and performance in air-pistol athletes. PMID- 24050466 TI - Agonist-antagonist muscle activation during drop jumps. AB - Pre-programmed and stretch-induced muscle activities of agonist muscles can play important roles during stretch-shortening cycle exercises. It is still not clear how the antagonist muscles function when the drop and rebound intensities are varied during drop jump (DJ) exercises. The purpose of the present study was to examine the regulation of agonist-antagonist muscle activation during DJ with different drop and rebound heights. The subjects performed DJs with two drop heights (0.2 and 0.4 m) and three different efforts (maximal rebound height, 50% effort of maximal rebound height and landing without rebound). Ankle and knee joint angles, and vertical ground reaction force together with an electromyogram of the lower leg muscles (medial gastrocnemius [MG], soleus [SOL] and tibialis anterior [TA]) were measured simultaneously during DJ. Our results clearly showed that the pre-activation of the antagonist TA was increased with increasing rebound height. Our results further showed that the coactivations of agonist and antagonist muscles during the post-impact 30-ms phase were increased with increasing rebound height. These results suggested that not only the pre programmed agonist MG muscle activation, but also the pre-programmed antagonist TA activation and the coactivation of the post-impact 30-ms phase may play important roles in the control of rebound height. PMID- 24050467 TI - Eating disorders in athletes: overview of prevalence, risk factors and recommendations for prevention and treatment. AB - The prevalence of disordered eating and eating disorders vary from 0-19% in male athletes and 6-45% in female athletes. The objective of this paper is to present an overview of eating disorders in adolescent and adult athletes including: (1) prevalence data; (2) suggested sport- and gender-specific risk factors and (3) importance of early detection, management and prevention of eating disorders. Additionally, this paper presents suggestions for future research which includes: (1) the need for knowledge regarding possible gender-specific risk factors and sport- and gender-specific prevention programmes for eating disorders in sports; (2) suggestions for long-term follow-up for female and male athletes with eating disorders and (3) exploration of a possible male athlete triad. PMID- 24050468 TI - Indirect measures of substrate utilisation following exercise-induced muscle damage. AB - This study investigated whether exercise-induced muscle damage (EIMD) resulted in changes to whole-body substrate utilisation during exercise performed during the subsequent 48 hours. Eight males (31 +/- 6 years) performed 30 minutes of bench stepping exercise. One leg performed eccentric contractions (Ecc) by lowering the body whilst the control leg performed concentric contractions (Con) by raising the body. On the two days following bench-stepping exercise participants performed measures of muscle function on an isokinetic dynamometer and undertook a bout of one leg cycling exercise, at two differing workloads, with the first workload (WL1) at 1.5 +/- 0.25 W/kg and the second workload (WL2) at 1.8 +/- 0.25 W/kg with each leg. Expired respiratory gases were collected during cycling to estimate whole body substrate utilisation. There were significant decrements in measures of muscular performance (isometric force, concentric and eccentric torque) and increased perception of soreness in Ecc compared with Con (P < 0.05). The effect of the Ecc treatment on substrate utilisation during one-legged cycling revealed a significant trial * time interaction with higher rates of CHO oxidation in the Ecc condition compared with Con that were further increased 48 hours later (P = 0.02). A significant treatment * time * effort interaction (P < 0.01) indicated the effect of the treatment altered as workload increased with higher rates of CHO oxidation occurring in WL2. This is consistent with greater reliance upon muscle glycogen. Suggesting that in EIMD, reductions in strength and increased feelings of soreness can be associated with greater reliance upon intramuscular CHO oxidation, than lipid, during subsequent concentric work. PMID- 24050469 TI - Effects of age, sex and activity level on counter-movement jump performance in children and adolescents. AB - The aim of this study was to investigate counter-movement jump performance and its reliability in children and adolescents with respect to age, sex and activity level. We tested 1835 children and adolescents aged between 4 and 17 years. All participants performed three counter-movement jumps on a force platform with arms akimbo. The participants were divided into six age groups and subdivided by sex within each group, to analyse age and sex effects. Subsequently, jumping performance of active and sedentary participants was compared. Jump height was calculated and the highest jump out of three was used for the calculations of peak force and peak rate of force development. Variability of all parameters was quantified using the coefficient of variation over all jumps. Jump height increased significantly with increasing age while peak rate of force development decreased. Peak force was similar for all age groups. Jump height was significantly higher in male participants and peak force and peak rate of force development was significantly lower in male participants. Variability of jump height and peak force decreased significantly with increasing age leading to reliable data above the age of 10 years. Peak rate of force development showed a high variability and, therefore, should be interpreted with caution. This could be useful information for coaches as they need to know from which age onwards the counter-movement jump is applicable in performance diagnostics and which parameters are sensible for interpretation. Finally, the present study provides data to be used as normative references. PMID- 24050470 TI - Determination of thigh volume in youth with anthropometry and DXA: agreement between estimates. AB - This study examined the agreement between estimates of thigh volume (TV) with anthropometry and dual-energy x-ray absorptiometry (DXA) in healthy school children. Participants (n=168, 83 boys and 85 girls) were school children 10.0 13.9 years of age. In addition to body mass, height and sitting height, anthropometric dimensions included those needed to estimate TV using the equation of Jones & Pearson. Total TV was also estimated with DXA. Agreement between protocols was examined using linear least products regression (Deming regressions). Stepwise regression of log-transformed variables identified variables that best predicted TV estimated by DXA. The regression models were then internally validated using the predicted residual sum of squares method. Correlation between estimates of TV was 0.846 (95%CI: 0.796-0.884, Sy.x=0.152 L). It was possible to obtain an anthropometry-based model to improve the prediction of TVs in youth. The total volume by DXA was best predicted by adding body mass and sum of skinfolds to volume estimated with the equation of Jones & Pearson (R=0.972; 95%CI: 0.962-0.979; R (2)=0.945). PMID- 24050471 TI - The impact of breathing on HRV measurements: implications for the longitudinal follow-up of athletes. AB - The purpose of the present work was to compare daily variations of heart rate variability (HRV) parameters between controlled breathing (CB) and spontaneous breathing (SB) sessions during a longitudinal follow-up of athletes. HRV measurements were performed daily on 10 healthy male runners for 21 consecutive days. The signals were recorded during two successive randomised 5-minutes sessions. One session was performed in CB and the other in SB. The results showed significant differences between the two respiration methods in the temporal, nonlinear and frequency domains. However, significant correlations were observed between CB and SB (higher than 0.70 for RMSSD and SD1), demonstrating that during a longitudinal follow-up, these markers provide the same HRV variations regardless of breathing pattern. By contrast, independent day-to-day variations were observed with HF and LF/HF frequency markers, indicating no significant relationship between SB and CB data over time. Therefore, we consider that SB and CB may be used for HRV longitudinal follow-ups only for temporal and nonlinear markers. Indeed, the same daily increases and decreases were observed whatever the breathing method employed. Conversely, frequency markers did not provide the same variations between SB and CB and we propose that these indicators are not reliable enough to be used for day-to-day HRV monitoring. PMID- 24050472 TI - Effects of confidence and anxiety on flow state in competition. AB - Confidence and anxiety are important variables that underlie the experience of flow in sport. Specifically, research has indicated that confidence displays a positive relationship and anxiety a negative relationship with flow. The aim of this study was to assess potential direct and indirect effects of confidence and anxiety dimensions on flow state in tennis competition. A sample of 59 junior tennis players completed measures of Competitive State Anxiety Inventory-2d and Flow State Scale-2. Following predictive analysis, results showed significant positive correlations between confidence (intensity and direction) and anxiety symptoms (only directional perceptions) with flow state. Standard multiple regression analysis indicated confidence as the only significant predictor of flow. The results confirmed a protective function of confidence against debilitating anxiety interpretations, but there were no significant interaction effects between confidence and anxiety on flow state. PMID- 24050473 TI - A cross-cultural study of adolescents' physical activity levels in France and Spain. AB - The goals of this study were (1) to describe and compare levels of physical activity (PA), assessed by accelerometry, of adolescents in two close Spanish and French cities according to gender and period of the week and (2) to assess, with reference to country and gender, the extent to which international PA guidelines were fulfilled. The PA of 401 adolescents (53.37% females) from France and Spain (55.72% French) aged 14.45 +/- 0.67 years was assessed with GT3X accelerometers for seven consecutive days to evaluate their habitual levels of moderate to vigorous physical activity (MVPA). Data collection took place from September to December 2010 in six public and state schools in France and Spain. There were significant differences in MVPA in terms of country, gender and period of the week. Spanish adolescents were more active than French adolescents, boys were more active than girls and MVPA was higher on weekdays than at weekends. French girls showed the lowest level of PA. Only 35.9% of the whole sample met the guidelines for PA in both countries. Governments of relevant countries, especially France, should adopt PA promotion policies targeted at adolescents in order to enhance their compliance with PA guidelines. PMID- 24050474 TI - The effect of exercise intensity on coincidence anticipation performance at different stimulus speeds. AB - The aim of this study was to examine the effect of exercise intensity on coincidence anticipation timing [CAT] performance at different stimulus speeds. Fourteen young adults (11 males and 3 females) volunteered to participate in the study following ethical approval. After familiarisation, coincidence anticipation was measured using the Bassin Anticipation Timer under three conditions: rest, moderate-intensity and high-intensity exercise with stimulus speeds of 3, 5 and 8 mph, set using an incremental running protocol until the participants reached a steady state of 70% and 90% of heart rate reserve (HRR), respectively. Results indicated a significant exercise intensity * stimulus speed interaction (p=0.0001) for absolute error (AE). There were no significant differences in AE across exercise intensities at a stimulus speed of 3 mph (p>0.05). AE was poorer during high-intensity exercise (90% HRR) compared to rest (p=0.022), and moderate intensity (70% HRR) exercise (all, p=0.004 or better) at 5 and 8 mph. Variable error (VE) was similar across exercise intensities at stimulus speeds of both 3 and 5 mph (p>0.05). At a stimulus speed of 8 mph, VE was significantly poorer during high-intensity exercise compared to rest (p=0.006) and moderate-intensity exercise (p=0.008). There were no significant differences for constant error (p>0.05) across exercise intensities or stimulus speeds. High-intensity exercise is associated with poorer CAT performance. However, stimulus speed plays a key role within this association where faster stimulus speeds were associated with a more marked decrease in coincidence anticipation performance. PMID- 24050475 TI - Meeting needs of Muslim girls in school sport: case studies exploring cultural and religious diversity. AB - This paper contains a sociocultural analysis of school sport experiences of Muslim girls in two countries with different gender policies in physical education (PE) classes: England and Denmark. In Denmark, PE lessons take place in co-educative classes, in England schools are more diverse, with predominantly co educational but also single-sex and faith schools offering different learning contexts. Two case studies from Denmark and England are used to explore the experiences of migrant Muslim girls in these different settings. A social constructionist approach to gender underpins the interpretation of stakeholders' voices on the inclusion of Muslim girls and the analysis of PE discourses in these countries. Findings illustrate similarities and differences at the interface of cultural diversity, political rhetoric of inclusion and realities of sport experiences for Muslim girls in both countries. Complex influences on PE experiences include gender stereotypes, cultural and religious orientations and practices, as well as actions and expectations of parents, communities and coaches/teachers. The studies provide insights into the ways participants managed their identities as Muslim girls in different sport environments to enable participation and retention of their cultural identities. Highlighted throughout the paper are the ways in which school sport policy and practice, providers and gatekeepers, can include or exclude groups, in this case Muslim girls. Too often coaches and teachers are unaware of crucial facts about their learners, not only in terms of their physical development and capabilities but also in terms of their cultural needs. Mistakes in creating conducive learning environments leave young people to negotiate a way to participate or refrain from participation. PMID- 24050476 TI - Stresses in the plantar region for long- and short-range throws in women basketball players. AB - This study aimed to assess plantar pressure pattern modifications caused by short and long-distance shots in women basketball players. To this end, 24 experienced national- and regional-level basketball players performed 3 trials of 4 technical gestures (free throw, jump stop shot, three-point shot and lay-up) barefoot on a pressure platform placed in fixed positions on the court. Raw data were processed to calculate location and magnitude of pressure peaks in three sub-regions (forefoot, midfoot and rearfoot), and the increase ratio was calculated relative to plantar pressure measured during a static bipedal and unipedal upright stance. The results showed significant increases (p<0.001) in plantar pressure peaks in forefoot (but not midfoot and rearfoot) for all the gestures that involved the use of both legs. Particularly large increases were detected for the three-point shot. All three sub-regions underwent significant changes of the pressure peak in the case of lay-up (forefoot and rearfoot: p<0.001, midfoot: p=0.002). The high levels of contact stress detected for routinely performed technical gestures suggest that a detailed knowledge of changes in the physiological patterns of plantar stresses that take place during play is crucial in reducing the risk of foot injuries and establishing proper training and rehabilitation protocols. PMID- 24050477 TI - Effectiveness of professionally-guided physical education on fitness outcomes of primary school children. AB - Physical education (PE) at school is an important starting point for long-term interventions improving quality of life in elderly. To evaluate the effectiveness of professionally led PE on motor and health-related abilities of Italian primary schoolchildren (3rd-5th graders), three schools were assigned to the experimental groups "A" (38 pupils, 17 M, 21 F) and "B" (37 pupils, 16 M, 21 F), and to control group "C" (26 pupils, 18 M, 8 F). All groups underwent a six-month, twice a-week (60 min each session) PE intervention. The PE program of the EGs was age tailored, included strength training and was administered by specialised teachers. Group A and B programs differed in the strength training devices used, while they were identical in terms of training load. The control group program was not structured and administered by generalist teachers. At baseline and follow-up, children underwent a motor and health-related abilities test battery. At follow-up, children in group C gained significantly more weight than children in the EGs and scored significantly less than the children in the EGs in the following assessments: counter movement jump (C:+0.15% vs. A:+4.1% and B:+6.99%), plate tapping (C:+13.56% vs. A:+19.37% and B:+36.12%), sit-and-reach (C:-311.15% vs. B:+409.57%), pinch strength (C:+2.39% vs. B:+10.83, on average) and sit-up (C:+29.69% vs. A:+72.61%). In conclusion, specialist-led pupils demonstrated greater increases in some motor and health-related abilities tests compared to generalist-led peers, while different strength training devices produced comparable increases of strength in both EGs. PMID- 24050478 TI - Recurrent pain and discomfort in relation to fitness and physical activity among young school children. AB - As an increase in pain symptoms among children has been shown in the last decades, the aim of this study was to describe perceptions of recurrent pain, measured physical fitness and levels of reported physical activity (PA) in children, and to investigate if any associations between PA, fitness and recurrent pain could be identified. A school-based study comprised 206 Swedish children 8-12 years old, 114 boys, 92 girls. A questionnaire with questions about perceived pain, self-reported PA and lifestyle factors was used. Health-related fitness was assessed by 11 physical tests. A physical index was calculated from these tests as a z score. High physical index indicated high fitness and low physical index indicated low fitness. ANOVA test, chi-square test and logistic regression analysis were used to compare active and inactive children. The prevalence of one pain location (head, abdomen or back) was 26%, two 11% and three 4% (n=206). Female gender, living in single-parent families, low PA and low subjective health were associated with reported recurrent pain. Children reporting high levels of PA had high physical index and reported low prevalence of pain symptoms. The physical index and level of self-reported PA decreased gradually the more pain locations. Physically active children had higher fitness levels and reported less pain symptoms than inactive peers. Coping with pain is an integral part of PA, and active children learn to cope with unpleasant body sensations which together with high fitness may reduce the perception of pain. PMID- 24050479 TI - Endometrial polyp size and polyp hyperplasia. AB - OBJECTIVE: To assess the correlation between the size of endometrial polyps and the histopathologic diagnosis of hyperplasia or cancer. METHODS: A retrospective study was conducted using databases of the outpatient clinic at Antonio Pedro University Hospital in Niteroi, Brazil, and of a private hysteroscopy service. The analysis included 1136 asymptomatic patients with an endometrial polyp identified on hysteroscopy, with pathologic examination, during the period 1999 2012. The polyp size, the patients' age, the indication for hysteroscopic examination, and the use of hormone medication were compared with the finding of hyperplasia in the pathologic examination. RESULTS: Only polyp size showed statistical significance among the variables analyzed (P<0.05). Endometrial polyps greater than 15mm showed a hyperplasia rate of 14.8%, compared with 7.7% in the group with smaller polyps (P<0.05). CONCLUSION: Endometrial polyps measuring more than 15mm were associated with hyperplasia. PMID- 24050480 TI - Stillbirths and neonatal mortality as outcomes. AB - Several recent studies in low-resource countries have claimed that training in and increased use of-newborn resuscitation resulted in reduced stillbirth rates. In the present article, we explore the ability of various types of birth attendant in some low-resource country locations to gather data that accurately differentiate a stillbirth from a live birth/early neonatal death. We conclude that, in many situations, it cannot be determined whether the infant was a stillbirth or a live birth/early neonatal death, and therefore the least-biased description of study outcomes includes a combined stillbirth and live birth/neonatal death outcome. However, because defining the burden of stillbirth and neonatal death is important from a public health perspective, every effort should be made, in low-income countries and elsewhere, to distinguish between stillbirths and live births/neonatal deaths and to report the results independently. PMID- 24050481 TI - A latent class approach for sepsis diagnosis supports use of procalcitonin in the emergency room for diagnosis of severe sepsis. AB - BACKGROUND: Given the acknowledged problems in sepsis diagnosis, we use a novel way with the application of the latent class analysis (LCA) to determine the operative characteristics of C-reactive protein (CRP), D-dimer (DD) and Procalcitonin (PCT) as diagnostic tests for sepsis in patients admitted to hospital care with a presumptive infection. METHODS: Cross-sectional study to determine the diagnostic accuracy of three biological markers against the gold standard of clinical definition of sepsis provided by an expert committee, and also against the likelihood of sepsis according to LCA. Patients were recruited in the emergency room within 24 hours of hospitalization and were follow-up daily until discharge. RESULTS: Among 765 patients, the expert committee classified 505 patients (66%) with sepsis, 112 (15%) with infection but without sepsis and 148 (19%) without infection. The best cut-offs points for CRP, DD, and PCT were 7.8 mg/dl, 1616 ng/ml and 0.3 ng/ml, respectively; but, neither sensitivity nor specificity reach 70% for any biomarker. The LCA analysis with the same three tests identified a "cluster" of 187 patients with several characteristics suggesting a more severe condition as well as better microbiological confirmation. Assuming this subset of patients as the new prevalence of sepsis, the ROC curve analysis identified new cut-off points for the tests and suggesting a better discriminatory ability for PCT with a value of 2 ng/ml. CONCLUSIONS: Under a "classical" definition of sepsis three typical biomarkers (CRP, PCT and DD) are not capable enough to differentiate septic from non-septic patients in the ER. However, a higher level of PCT discriminates a selected group of patients with severe sepsis. PMID- 24050482 TI - Nutraceuticals for prostate cancer chemoprevention: from molecular mechanisms to clinical application. AB - INTRODUCTION: Nutraceutical is a food, or part of a food, used for the prevention and/or treatment of diseases. A number of nutraceuticals serve as candidates for development of prostate cancer chemopreventive agents because of promising epidemiological, preclinical and pilot clinical findings. Their mechanisms of action may involve an ability to target multiple molecular pathways in carcinogenesis without eliciting toxic side effects. AREAS COVERED: This review provides an overview of several nutraceuticals, including green tea polyphenol, omega-3 fatty acids, vitamin D, lycopene, genistein, quercetin, resveratrol and sulforaphane, for the clinical relevance to chemoprevention of prostate cancer. Their mechanisms of action on regulating key processes of carcinogenesis are also discussed. For each of these agents, a brief summary of completed or currently ongoing clinical trials related to the chemopreventive efficacy on prostate cancer is given. EXPERT OPINION: Even though a few clinical trials have been conducted, review of these results indicate that further studies are required to confirm the clinical efficacy and safety, and to provide a guidance on how to use nutraceuticals for optimal effect. Future cancer prevention clinical trials for the nutraceuticals should recruit men with an increased risk of prostate cancer. PMID- 24050483 TI - The not-so-naked eye: phthiriasis palpebrarum. PMID- 24050484 TI - Significant aspirations: recurrent pneumonia. PMID- 24050485 TI - Commonly used data-collection approaches in clinical research. AB - We provide an overview of the different data-collection approaches that are commonly used in carrying out clinical, public health, and translational research. We discuss several of the factors that researchers need to consider in using data collected in questionnaire surveys, from proxy informants, through the review of medical records, and in the collection of biologic samples. We hope that the points raised in this overview will lead to the collection of rich and high-quality data in observational studies and randomized controlled trials. PMID- 24050486 TI - Mobile health messages help sustain recent weight loss. AB - BACKGROUND: Using regulatory focus theory, an intervention of daily weight loss sustaining messages was developed and tested for acceptability, feasibility, and efficacy on helping people sustain weight loss. METHODS: Participants (n = 120) were randomized to a promotion, prevention, or an attention-control text message group after completion of a weight loss program. Participants completed baseline assessments, and reported their weight at 1 and 3 months postbaseline. RESULTS: Participants found the message content and intervention acceptable and valuable. A minimum of one message per day delivered at approximately 8:00 am was deemed the optimal delivery time and frequency. The sustained weight loss rate at month 3 for the control, promotion, and prevention groups was 90%, 95%, and 100%, respectively. Medium-to-large effects were observed for the promotion and prevention groups at month 1 and for prevention at month 3 relative to controls. The mean weight loss for promotion and prevention was 15 pounds, compared with 10 in the controls at month 3. CONCLUSION: A clinically significant decrease in mean weight, higher rate of sustained weight loss, and medium-to-large effects on sustained weight loss occurred in the promotion and prevention interventions. Tools such as this text message-based intervention that are constructed and guided by evidence-based content and theoretical constructs show promise in helping people sustain healthy behaviors that can lead to improved health outcomes. PMID- 24050487 TI - Health consequences among subjects involved in Gulf oil spill clean-up activities. AB - BACKGROUND: Oil spills are known to affect human health through the exposure of inherent hazardous chemicals such as para-phenols and volatile benzene. This study assessed the adverse health effects of the Gulf oil spill exposure in subjects participating in the clean-up activity along the coast of Louisiana. METHODS: This retrospective study included subjects that had been exposed and unexposed to the oil spill and dispersant. Using medical charts, clinical data including white blood cell count, platelets count, hemoglobin, hematocrit, blood urea nitrogen, creatinine, alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine amino transferase (ALT), and somatic symptom complaints by the subjects were reviewed and analyzed. RESULTS: A total of 247 subjects (oil spill exposed, n = 117 and unexposed, n = 130) were included. Hematologic analysis showed that platelet counts (* 10(3) per MUL) were significantly decreased in the exposed group compared with those in the group unexposed to the oil spill (252.1 +/- 51.8 vs 269.6 +/- 77.3, P = .024). Conversely, the hemoglobin (g per dL) and hematocrit (%) levels were significantly increased among oil spill-exposed subjects compared with the unexposed subjects (P = .000). Similarly, oil spill-exposed subjects had significantly higher levels of ALP (76.3 +/- 21.3 vs 61.2 +/- 26.9 IU/L, P = .000), AST (31.0 +/- 26.3 vs 22.8 +/- 11.8 IU/L, P = .004), and ALT (34.8 +/- 26.6 vs 29.8 +/- 27 IU/L, P = .054) compared with the unexposed subjects. CONCLUSION: The results of this study indicate that clean-up workers exposed to the oil spill and dispersant experienced significantly altered blood profiles, liver enzymes, and somatic symptoms. PMID- 24050488 TI - The long and short of it: Ashman's phenomenon. PMID- 24050492 TI - The hidden phenomenon of oxidative stress during treatment of subclinical-mild hypothyroidism: a protective nutraceutical intervention. AB - Recent studies suggest that subjects with hypothyroidism under therapy with levothyroxine (L-T4) might develop oxidative stress. The aim of this study was to test a redox-balance modulator, fermented papaya-based nutraceutical (FPP), together with subclinical (SH) or mild hypothyroidism (MH) treatment in view of biochemical changes. A total of 60 females treated for SH-MH were divided into two matched groups and received either FPP 3 grams 1 sachet three times a day (t.i.d.) or placebo for 3 months. A significant baseline increase of all oxidative markers was observed in SH-MH (p<0.05 vs. control) and even more under T4 treatment (p<0.05). FPP caused a normalization of redox markers (p<0.01 vs. placebo). Thyroid supplementation accelerates mitochondrial oxygen consumption and oxidative stress, whereas a redox-modulator therapy is advisable, given the long-lasting treatment in such cases. PMID- 24050493 TI - Leprosy in pregnant woman, United States. PMID- 24050494 TI - Instructional insights: continuing professional education to enhance therapeutic relationships in occupational therapy. AB - Occupational therapists view the quality of their relationships with clients as an important factor in client outcomes but may feel ill prepared to use themselves as therapeutic agents. This column offers suggestions for providing professional education to support practitioners in reflecting on their relationships with clients and developing new perspectives on their interactions with clients during the occupational therapy process. PMID- 24050495 TI - Evolution of influenza A virus H7 and N9 subtypes, Eastern Asia. AB - Influenza A viruses are a threat to poultry and human health. We investigated evolution of influenza A virus H7 and N9 subtypes in wild and domestic birds. Influenza A(H7N9) virus probably emerged after a long silent circulation in live poultry markets in eastern Asia. PMID- 24050496 TI - Factors associated with ambulatory status 6 months after total hip arthroplasty. AB - OBJECTIVE: To identify an assessment tool and its cut-off point for indicating ambulatory status 6 months after total hip arthroplasty (THA). DESIGN: Cross sectional study. SETTING: Kyoto University Hospital. PARTICIPANTS: Eighty-eight patients who underwent unilateral THA. MAIN OUTCOME MEASURE: Lower-extremity muscle strength, hip range of motion and hip pain were measured 6 months after THA. The patients were divided into two groups according to their ability to walk 6 months after THA: an independent ambulation group and a cane-assisted ambulation group. RESULTS: A stepwise multiple logistic regression analysis indicated that age and lower-extremity maximal load were significant variables affecting mid-term ambulatory status following THA. Receiver operating characteristic curve analyses revealed that ambulatory status following THA was indicated more accurately by leg extension strength (cut-off point=8.24N/kg, sensitivity=92%, specificity=82%, area under the curve=0.93) than age. CONCLUSION: Lower-limb load force with a cut-off point of 8.24N/kg is a reliable assessment tool for indicating ambulatory status 6 months after primary THA. PMID- 24050497 TI - Role of physiotherapy in the rehabilitation of survivors of the Kiss nightclub tragedy in Santa Maria, Brazil. PMID- 24050498 TI - Detecting non-uniform clusters in large-scale interaction graphs. AB - Graph clustering becomes difficult as the graph size and complexity increase. In particular, in interaction graphs, the clusters are small and the data on the underlying interaction are not only complex, but also noisy due to the lack of information and experimental errors. The graphs representing such data consist of (possibly overlapping) clusters of non-uniform size with some false positive and false negative links. In this article, we propose a new approach, assuming that clusters in the graphs of protein-protein interaction (PPI) networks resemble corrupted cliques. Therefore, the problem can be reduced to looking for clusters only among nodes of approximately similar degrees. This idea was implemented using a soft version of the Farthest-Point-First (FPF) clustering algorithm with the Jaccard distance function modified to perform on slightly overlapping clusters. The StripClust program developed by us was tested on a synthetic network and on the yeast PPI network. PMID- 24050499 TI - Heterogeneous substitution effects in chlorocyanomethyl radical and chlorocyanocarbene. AB - We report a photoelectron-imaging investigation of the chlorocyanomethyl radical (CHClCN) and the corresponding carbene (CClCN). The results are discussed in comparison with the corresponding dichloro- and dicyano-substituted species, focusing on the divergent effects of the halogen and pseudohalogen (CN) substitutions. A cooperative (captodative) interaction of the pi-donor Cl and pi acceptor cyano groups favors the increased stability of the CHClCN radical, but a competition of the two substituents is observed in the singlet-triplet splitting of the carbene. The vertical detachment energy (VDE) of CHClCN(-) is determined to be 2.39 +/- 0.04 eV, with the broad photoelectron band consistent with the significant geometry change predicted by theory for the detachment transition. The adiabatic electron affinity of CHClCN, EA = 1.86 +/- 0.08 eV, is estimated on the basis of the experimental VDE and the computed difference between the VDE and EA values. This result allows the calculation of the bond dissociation energy of chloroacetonitrile, DH298(H-CHClCN) = 87.0 +/- 2.7 kcal/mol. Photoelectron imaging of CClCN(-) reveals two main transitions, assigned to the singlet ((1)A') and triplet ((3)A") states of the CClCN carbene. The respective VDEs are 2.76 +/- 0.05 and 3.25 +/- 0.05 eV. The experimental results are in good agreement with the theoretically predicted singlet-triplet vertical energy gap at the anion geometry, but inconclusive with regard to the adiabatic singlet-triplet splitting in CClCN. Consistent with the experimental findings, ab initio calculations using the spin-flip approach in combination with the coupled-cluster theory, indicate that the (1)A' and (3)A" states are nearly degenerate, with the singlet state lying adiabatically only ~0.01 eV below the triplet. PMID- 24050501 TI - Capturing a sulfenic acid with arylboronic acids and benzoxaborole. AB - Post-translational redox generation of cysteine-sulfenic acids (Cys-SOH) functions as an important reversible regulatory mechanism for many biological functions, such as signal transduction, balancing cellular redox states, catalysis, and gene transcription. Herein we show that arylboronic acids and cyclic benzoxaboroles can form adducts with sulfenic acids in aqueous medium and that these boron-based compounds can potentially be used to trap biologically significant sulfenic acids. As proof of principle we demonstrate that a benzoxaborole can inhibit the enzyme activity of an iron-containing nitrile hydratase, which requires a catalytic alphaCys114-SOH in the active site. The nature of the adduct and the effect of the boronic acid's pK(a)(B) on the stability constant of the adduct are discussed within. PMID- 24050500 TI - Peptide-functionalized oxime hydrogels with tunable mechanical properties and gelation behavior. AB - We demonstrate the formation of polyethylene glycol (PEG) based hydrogels via oxime ligation and the photoinitiated thiol-ene 3D patterning of peptides within the hydrogel matrix postgelation. The gelation process and final mechanical strength of the hydrogels can be tuned using pH and the catalyst concentration. The time scale to reach the gel point and complete gelation can be shortened from hours to seconds using both pH and aniline catalyst, which facilitates the tuning of the storage modulus from 0.3 to over 15 kPa. Azide- and alkene-functionalized hydrogels were also synthesized, and we have shown the post gelation "click"-type Huisgen 1,3 cycloaddition and thiolene-based radical reactions for spatially defined peptide incorporation. These materials are the initial demonstration for translationally relevant hydrogel materials that possess tunable mechanical regimes attractive to soft tissue engineering and possess atom neutral chemistries attractive for post gelation patterning in the presence or absence of cells. PMID- 24050502 TI - Elaborate ligand-based modeling coupled with multiple linear regression and k nearest neighbor QSAR analyses unveiled new nanomolar mTOR inhibitors. AB - The mammalian target of rapamycin (mTOR) has an important role in cell growth, proliferation, and survival. mTOR is frequently hyperactivated in cancer, and therefore, it is a clinically validated target for cancer therapy. In this study, we combined exhaustive pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent mTOR inhibitors employing 210 known mTOR ligands. Genetic function algorithm (GFA) coupled with k nearest neighbor (kNN) and multiple linear regression (MLR) analyses were employed to build self-consistent and predictive QSAR models based on optimal combinations of pharmacophores and physicochemical descriptors. Successful pharmacophores were complemented with exclusion spheres to optimize their receiver operating characteristic curve (ROC) profiles. Optimal QSAR models and their associated pharmacophore hypotheses were validated by identification and experimental evaluation of several new promising mTOR inhibitory leads retrieved from the National Cancer Institute (NCI) structural database. The most potent hit illustrated an IC50 value of 48 nM. PMID- 24050503 TI - Fruit and vegetable intake and risk of cardiovascular disease. AB - A high intake of fruit and vegetables (FV) has been shown to be associated with reduced risk of a number of chronic diseases, including CVD. This review aims to provide an overview of the evidence that increased FV intake reduces risk of CVD, focusing on studies examining total FV intake. This evidence so far available is largely based on prospective cohort studies, with meta-analyses demonstrating an association between increased FV intake and reduced risk of both CHD and stroke. Controlled intervention trials examining either clinical or cardiovascular risk factor endpoints are scarce. However, such trials have shown that an increase in FV consumption can lower blood pressure and also improve microvascular function, both of which are commensurate with a reduced risk of CVD. The effects of increased FV consumption on plasma lipid levels, risk of diabetes and body weight have yet to be firmly established. In conclusion, evidence that FV consumption reduces the risk of CVD is so far largely confined to observational epidemiology, with further intervention studies required. PMID- 24050504 TI - Issues in the incorporation of economic perspectives and evidence into Cochrane reviews. AB - BACKGROUND: Methods for systematic reviews of the effects of health interventions have focused mainly on addressing the question of 'What works?' or 'Is this intervention effective in achieving one or more specific outcomes?' Addressing the question 'Is it worth it given the resources available?' has received less attention. This latter question can be addressed by applying an economic lens to the systematic review process.This paper reflects on the value and desire for the consideration by end users for coverage of an economic perspective in a Cochrane review and outlines two potential approaches and future directions. METHODS: Two frameworks to guide review authors who are seeking to include an economic perspective are outlined. The first involves conducting a full systematic review of economic evaluations that is integrated into a review of intervention effects. The second involves developing a brief economic commentary. The two approaches share a set of common stages but allow the tailoring of the economic component of the Cochrane review to the skills and resources available to the review team. RESULTS: The number of studies using the methods outlined in the paper is limited, and further examples are needed both to explore the value of these approaches and to further develop them. The rate of progress will hinge on the organisational leadership, capacity and resources available to the CCEMG, author teams and other Cochrane entities. Particular methodological challenges to overcome relate to understanding the key economic trade-offs and casual relationships for a given decision problem and informing the development of evaluations designed to support local decision-makers. CONCLUSIONS: Methods for incorporating economic perspectives and evidence into Cochrane intervention reviews are established. Their role is not to provide a precise estimate of 'cost effectiveness' but rather to help end-users of Cochrane reviews to determine the implications of the economic components of reviews for their own specific decisions. PMID- 24050505 TI - Cost-effective reduced graphene oxide-coated polyurethane sponge as a highly efficient and reusable oil-absorbent. AB - Reduced graphene oxide coated polyurethane (rGPU) sponges were fabricated by a facile method. The structure and properties of these rGPU sponges were characterized by Fourier transform infrared spectroscopy, thermal gravimetric analysis, X-ray diffraction, and scanning electron microscopy. The rGPU sponges are hydrophobic and oleophilic and show extremely high absorption for organic liquids. For all the organic liquids tested, the absorption capacities were higher than 80 g g(-1) and 160 g g(-1) (the highest value) was achieved for chloroform. In addition, the absorption capacity of the rGPU sponge did not deteriorate after it was reused 50 times, so the rGPU sponge has excellent recyclability. PMID- 24050506 TI - Treatment of splenic marginal zone lymphoma: should splenectomy be abandoned? AB - Splenic marginal zone lymphoma (SMZL) is a rare chronic B-cell lymphoproliferative disorder recognized as a distinct entity in the World Health Organization (WHO) classification. SMZL usually runs an indolent clinical course with a median survival of more than 10 years. However, in a proportion of patients (10-20%) SMZL behaves more aggressively, with a median survival of less than 4 years. Many efforts are ongoing to establish commonly accepted prognostic factors as a guide to therapy for this disorder. Data on the treatment of SMZL come from reported retrospective series including relatively limited numbers of patients. Despite these limitations, much progress has recently been made in the management of patients with SMZL. The oldest and most commonly used first-line therapeutic modality is splenectomy, which offers rapid alleviation of splenomegaly-related symptoms along with an improvement of cytopenias in the majority of patients, with a median PFS of 5 years. However, SMZL is a systemic disease, and splenectomy is not carried out with eradicative intent. Furthermore, splenectomy is a major surgical procedure with significant morbidity or even mortality, especially in older patients. Chemotherapy has only moderate activity in this form of MZL. Recent data suggest that rituximab is a very effective therapy with minimal toxicity and could replace splenectomy as first-line treatment. The overall response rate is > 90%, with almost half of responses being complete, while the 5-year progression-free survival is approximately 70%. The combination of rituximab with chemotherapy requires further evaluation. Based on the current data, splenectomy could be abandoned as first-line treatment for patients with SMZL. PMID- 24050508 TI - Chronic myelomonocytic leukemia associated with generalized myasthenia gravis. PMID- 24050509 TI - Synthesis and characterization of molecular hexagons and rhomboids and subsequent encapsulation of Keggin-type polyoxometalates by molecular hexagons. AB - Structural control among hexagonal (trimer), rhomboidal (dimer), and infinite chain supramolecular complexes with three different supporting ligands of ethylenediamine (en), N,N,N',N'-tetramethylethylenediamine (en*), and 1,2 bis(diphenyl)phosphinoethane (dppe) [(en)Pd(L)]3(OTf)6 1t.OTf, [(en*)Pd(L)]2(PF6)4 2d.PF6, and [(dppe)Pd(L)(OTf)2]infinity 3.OTf (OTf = trifluoromethane sulfonate; L = 1,3-bis(4-pyridylethynyl)benzene) in the solid and solution states was investigated. The encapsulation of a large Keggin-type polyoxometalate [alpha-PW12O40](3-) by these complexes was also examined. As the steric bulkiness of the supporting ligands increased in the order of en < en* < dppe, the hexagonal, rhomboidal, and infinite-chain structures were obtained, as confirmed by X-ray crystallography. In solution, equilibrium between the molecular hexagon (1t.OTf/2t.PF6) and the molecular rhomboid (1d.OTf/2d.PF6) was observed in the en/en* ligand systems, whereas 3.OTf with the dppe ligand did not exhibit equilibrium and instead existed as a single species. These phenomena were established by cold-spray ionization mass spectroscopy (CSI-MS) and (1)H diffusion ordered NMR spectroscopy (DOSY). The addition of the highly negatively charged Keggin-type phosphododecatungstate [alpha-PW12O40](3-) to a solution of 2t/2d.PF6 resulted in the encapsulation of the tungstate species in the cavity of the molecular hexagon to form {[(en*)Pd(L)]3[?alpha-PW12O40]}(PF6)3 2t.[alpha PW12O40](3-), as confirmed by a combination of (1)H and (31)P DOSY and CSI-MS spectral data. PMID- 24050507 TI - Potential mechanisms of disease progression and management of advanced-phase chronic myeloid leukemia. AB - Despite vast improvements in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) in chronic phase (CP), advanced stages of CML, accelerated phase or blast crisis, remain notoriously difficult to treat. Treatments that are highly effective against CML-CP produce disappointing results against advanced disease. Therefore, a primary goal of therapy should be to maintain patients in CP for as long as possible, by (1) striving for deep, early molecular response to treatment; (2) using tyrosine kinase inhibitors that lower risk of disease progression; and (3) more closely observing patients who demonstrate cytogenetic risk factors at diagnosis or during treatment. PMID- 24050510 TI - In-situ characterization of the uncrimping process of arterial collagen fibers using two-photon confocal microscopy and digital image correlation. AB - Uncrimping of collagen fibers in the arterial wall is an integral process in regulating the macro-level mechanical response of arteries. Uncrimping of collagen fibers leads to a gradual, but significant strain-stiffening response of the artery at physiological pressures and prevents overdistention at elevated pressures. In this study, we imaged adventitial collagen fibers from fresh primate arteries using two-photon excitation microscopy while subjecting the arteries to physiological inflation pressures and axial stretches. The imaging focal plane was fixed at a constant radial location in the adventitial wall by adjusting the focal distance as the arteries inflated, allowing for the continuously monitoring of the uncrimping process of a single region of collagen fibers. Digital image correlation was then applied to the sequential images to assess and correlate the local displacements to manual traces of selected reference fibers and their engagements. We found that the collagen fibers of interest became fully engaged at a luminal pressure of 20mmHg, this was then followed by rotation of these fibers as the bulk artery continued to dilate. This technique helps to further the understanding of the uncrimping process of collagen fibers under physiological loads, which can aid in the development of more accurate microstructural constitutive models. PMID- 24050511 TI - Instrumented hip implants: electric supply systems. AB - Instrumented hip implants were proposed as a method to monitor and predict the biomechanical and thermal environment surrounding such implants. Nowadays, they are being developed as active implants with the ability to prevent failures by loosening. The generation of electric energy to power active mechanisms of instrumented hip implants remains a question. Instrumented implants cannot be implemented without effective electric power systems. This paper surveys the power supply systems of seventeen implant architectures already implanted in vivo, namely from instrumented hip joint replacements and instrumented fracture stabilizers. Only inductive power links and batteries were used in-vivo to power the implants. The energy harvesting systems, which were already designed to power instrumented hip implants, were also analyzed focusing their potential to overcome the disadvantages of both inductive-based and battery-based power supply systems. From comparative and critical analyses of the methods to power instrumented implants, one can conclude that: inductive powering and batteries constrain the full operation of instrumented implants; motion-driven electromagnetic energy harvesting is a promising method to power instrumented passive and active hip implants. PMID- 24050513 TI - Lipid-like properties and pharmacology of the anthelmintic macrocyclic lactones. AB - INTRODUCTION: Broad-spectrum antiparasitic macrocyclic lactones (MLs) are the principal nematicides used today, but drug resistance compromises the efficiency of ML-based therapy. Drug action in the parasite is essential for the effectiveness. Thus, to meet the needs of sustainable control of nematodes, the challenge is to maintain an effective drug concentration in the host tissues where parasites locate. This requires knowledge of the site of action of the drug, and processes that govern the pharmacokinetics of MLs in the host and in the parasites. These processes are primarily biotransformation, distribution, storage in fat, and elimination via ATP-binding cassette (ABC) transporters. AREAS COVERED: This article describes how MLs are lipid-like compounds that differ in chemical substituents and in physicochemical properties. Furthermore, the degree of drug lipophilicity influences affinity for fat tissues and for transporters and possibly for target receptors. This opinion highlights how the structural particularities of widely used representative MLs impact on drug kinetics. EXPERT OPINION: Optimizing the efficacy of MLs relies on the choice of the drug on the degree of lipophilicity, taking into account the host species, the location of the parasites, and alterations in lipid status. Furthermore, lipid-based formulations can be used to improve intestinal drug absorption. Inhibiting ABC transporter offers an additional option for increasing ML bioavailability. PMID- 24050512 TI - Long-term follow up Helicobacter Pylori reinfection rate after second-line treatment: bismuth-containing quadruple therapy versus moxifloxacin-based triple therapy. AB - BACKGROUND: The increasing trend of antibiotic resistance requires effective second-line Helicobacter pylori (H. pylori) treatment in high prevalence area of H. pylori. The aim of our study was to evaluate the reinfection rate of H. pylori after second-line treatment that would determine the long-term follow up effect of the rescue therapy. METHODS: A total of 648 patients who had failed previous H. pylori eradication on standard triple therapy were randomized into two regimens: 1, esomeprazole (20 mg b.i.d), tripotassium dicitrate bismuthate (300 mg q.i.d), metronidazole (500 mg t.i.d), and tetracycline (500 mg q.i.d) (EBMT) or 2, moxifloxacin (400 mg q.d.), esomeprazole (20 mg b.i.d), and amoxicillin (1000 mg b.i.d.) (MEA). At four weeks after completion of eradication therapy, H. pylori tests were performed with 13C urea breath test or invasive tests. In patients who maintained continuous H. pylori negativity for the first year after eradication therapy, H. pylori status was assessed every year. For the evaluation of risk factors of reinfection, gender, age, clinical diagnosis, histological atrophic gastritis or intestinal metaplasia were analyzed. RESULTS: The recrudescence rate of the EBMT was 1.7% and of the MEA group 3.3% (p = 0.67). The annual reinfection rate of H. pylori of EBMT was found to be 4.45% and the MEA group 6.46%. Univariate analysis (Log-rank test) showed no association with any clinical risk factor for reinfection. CONCLUSIONS: The long-term reinfection rate of H. pylori stayed low in both of bismuth-containing quadruple therapy and moxifloxacin-based triple therapy; thus reinfection cannot affect the choice of second-line treatment. TRIAL REGISTRATION: Clinical Trial Registration Number NCT01792700. PMID- 24050514 TI - Defensive strategies in Geranium sylvaticum, Part 2: Roles of water-soluble tannins, flavonoids and phenolic acids against natural enemies. AB - Geranium sylvaticum is a common herbaceous plant in Fennoscandia, which has a unique phenolic composition. Ellagitannins, proanthocyanidins, galloylglucoses, gallotannins, galloyl quinic acids and flavonoids possess variable distribution in its different organs. These phenolic compounds are thought to have an important role in plant-herbivore interactions. The aim of this study was to quantify these different water-soluble phenolic compounds and measure the biological activity of the eight organs of G. sylvaticum. Compounds were characterized and quantified using HPLC-DAD/MS, in addition, total proanthocyanidins were determined by BuOH-HCl assay and total phenolics by the Folin-Ciocalteau method. Two in vitro biological activity measurements were used: the prooxidant activity was measured by the browning assay and antioxidant activity by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Organ extracts were fractionated using column chromatography on Sephadex LH-20 and the activities of fractions was similarly measured to evaluate which polyphenol groups contributed the most to the biological activity of each organ. The data on the activity of fractions were examined by multivariate data analysis. The water-soluble extracts of leaves and pistils, which contained over 30% of the dry weight as ellagitannins, showed the highest pro-oxidant activity among the organ extracts. Fraction analysis revealed that flavonoids and galloyl quinic acids also exhibited high pro-oxidant activity. In contrast, the most antioxidant active organ extracts were those of the main roots and hairy roots that contained high amounts of proanthocyanidins in addition to ellagitannins. Analysis of the fractions showed that especially ellagitannins and galloyl quinic acids have high antioxidant activity. We conclude that G. sylvaticum allocates a significant amount of tannins in those plant parts that are important to the fitness of the plant and susceptible to natural enemies, i.e. pistil and leaf tannins protect against insect herbivores and root tannins against soil pathogens. PMID- 24050515 TI - Haemophilus parahaemolyticus septic shock after aspiration pneumonia, France. PMID- 24050516 TI - Adjuvant volumetric-modulated arc therapy with simultaneous integrated boost in endometrial cancer. Planning and toxicity comparison. AB - OBJECTIVE: To report dosimetric and acute toxicity data in prospectively enrolled high-intermediate risk endometrial cancer (HIR-EC) patients postoperatively irradiated by simultaneous integrated boost volumetric modulated arc therapy (SIB VMAT). METHODS: Thirty prospectively enrolled HIR-EC patients were postoperatively treated by SIB-VMAT. Target coverage, dose homogeneity, and sparing of organs at risk (OARs) were compared with corresponding data retrieved from an historical control (30 consecutive selected matched patients) treated by concomitant boost three-dimensional conformal radiotherapy (3D CRT CB) from a previously published study (ADA-I trial). All patients received 45 Gy on pelvic lymph nodes plus 10 Gy boost on the vaginal vault. RESULTS: The SIB-VMAT technique produced more inhomogeneous plans than 3D CRT CB, but showed significantly better conformity index (CIs) for both PTVs. SIB-VMAT was associated with significant reduction in the irradiated small bowel (SB) volume compared with 3D CRT CB for all dose range > 10 Gy (e.g. V15: 163.5 cm(3) vs. 341.3 cm(3), p = 0.001 and V40: 43.8 cm(3) vs. 85.2 cm(3), p = 0.008). With regard to bladder and rectum, SIB-VMAT showed a significant sparing advantage at all dose levels with respect to 3D CRT CB retrieved plans. Moreover, overall OARs Dmean were significantly reduced by the SIB-VMAT (p = 0.001). According to CTCAE v.4.0, acute (within three months) GI toxicities were more frequent in 3D CRT CB versus SIB-VMAT (90.0% vs. 66.7%; p-value 0.028). CONCLUSIONS: Compared to data from a historical database of patients administered 3D CRT CB, SIB-VMAT significantly improves the dose conformity and sparing of OARs in HIR-EC patients undergoing postoperative radiotherapy. The improvement in terms of acute toxicity justifies further prospective clinical evaluation. PMID- 24050517 TI - The epidemiology of long- and short-term cancer survivors. A population-based cohort study exploring denominators for rehabilitation and palliative care programs. AB - INTRODUCTION: In this study, we present data from a population-based cohort of incident cancer patients separated in long- and short-term survivors. Our aim was to procure denominators for use in the planning of rehabilitation and palliative care programs. MATERIAL AND METHODS: A registry-linkage cohort study. All cancer patients, diagnosed from 1993 to 2003 from a 470 000 large population, were followed individually from diagnosis to death or until 31 December 2008. Long term survivors lived five years or more after the time of the cancer diagnosis (TOCD). Short-term survivors died less than five years after TOCD. RESULTS: The cohort comprised 24 162 incident cancer patients with 41% long-term survivors (N = 9813). Seventy percent of the cohort was 60 + years at TOCD. The 14 349 short term survivors' median survival was 0.6 year, and 78% died less than two years after TOCD. A 12 years' difference in age at TOCD was seen between long- and short-term survivors, with median ages of 60 versus 72 years, respectively. Females comprised 64% of long-term, and 46% of short-term survivors. The proportion of breast and lung cancers differed between the groups: Long-term survivors: 31% breast cancer, 2.4% lung cancer. Short-term survivors: 21% lung cancer, 7.2% breast cancer. Chemotherapy was provided to 15% of all patients, and to 10% of the 60 + year olds. DISCUSSION: The epidemiology of long- and short term survivors shows significant differences with regard to age at TOCD, cancer types and sex. Two-year crude cancer survival seems as a clinically relevant cut point for characterizing potential "denominators" for rehabilitation or palliative care programs. From this cohort of incident cancer patients, and using two-year survival as a cut point, it could be estimated that 54% would candidate to a "care trajectory" focusing on rehabilitation and 46% a "care trajectory" focusing on palliative care at TOCD. PMID- 24050519 TI - A detailed analysis of treatment delay from the onset of symptoms in early rheumatoid arthritis patients. AB - OBJECTIVES: A treatment delay of more than 12 weeks can negatively affect treatment response in rheumatoid arthritis (RA). Our aim was to quantify the different stages of delay before RA treatment in different rheumatology centres and to explore influencing factors. METHOD: A total of 156 disease-modifying anti rheumatic drug (DMARD)-naive early RA patients were included from eight practices: one academic hospital, five general hospitals, and two private practices. Eight different types of delay were defined from symptom onset until treatment initiation. Information on the duration of each stage of delay was collected from the patient, their general practitioner (GP), and patient files at the rheumatology practice. Patient/GP demographics and disease activity/severity parameters were recorded. RESULTS: The median total delay from symptom onset until treatment initiation was 23 weeks whereas patient-, GP- and rheumatologist related median delay was 10, 4, and 7 weeks, respectively. Only 21.6% of the patients had a total delay of less than 12 weeks. The total median delay in private rheumatology practices was less than in academic and general hospitals (p < 0.001). Furthermore, RA patients treated within 12 weeks of symptom onset showed a higher level of disease activity. The duration of rheumatologist-related delay was inversely correlated with disease activity parameters. Patients with morning stiffness were treated, on average, 3 weeks sooner than those without morning stiffness (p < 0.006). CONCLUSIONS: In only one out of five early RA patients was treatment initiated within 12 weeks of symptom onset, as recommended. Patient-related delay contributed most to overall delay. Disease activity and type of rheumatology centre are pivotal determinants of delay. PMID- 24050520 TI - Proton-bound 3-cyanophenylalanine trimethylamine clusters: isomer-specific fragmentation pathways and evidence of gas-phase zwitterions. AB - The structures and dissociation pathways of the proton-bound 3 cyanophenylalanine.trimethylamine cluster have been studied using a combination of infrared multiple photon dissociation (IRMPD) spectroscopy and density functional theory calculations. Three isomer motifs are identified: charge solvated, zwitterionic, and trimethylamine (TMA)-bridged. While the TMA-bridged structures fragment to yield protonated TMA (channel 1) and protonated 3 cyanophenylalanine (channel 2), charge-solvated species exclusively fragment via channel 1 and zwitterionic species exclusively fragment via channel 2. Mechanisms are proposed. PMID- 24050521 TI - Human infections with new subspecies of Campylobacter fetus. AB - Campylobacter fetus subsp. testudinum subsp. nov. is a newly proposed subspecies of C. fetus with markers of reptile origin. We summarize epidemiologic information for 9 humans infected with this bacterium. All cases were in men, most of whom were of Asian origin. Infection might have been related to exposure to Asian foods or reptiles. PMID- 24050522 TI - Fundamental aspects of energy dissipation in friction. PMID- 24050523 TI - Types, frequency and impact of asthma triggers on patients' lives: a quantitative study in five European countries. AB - OBJECTIVE: To identify the types, frequency and impact of asthma triggers and the relationship to asthma control among adults with asthma in Europe. METHODS: Adults with self-reported physician-diagnosed asthma receiving maintenance asthma treatment and self-reported exposure to known asthma triggers completed an online questionnaire; a subset completed a diary over 3-4 weeks. Information on asthma control (Asthma Control TestTM [ACT]), asthma triggers, frequency of exposure and behaviours in response or to avoid asthma triggers and the perceived impact on daily life was captured. A post-hoc analysis evaluated the impact of high trigger burden on the frequency of severe asthma exacerbations, hospitalisations and days lost at work/study. RESULTS: A total of 1202 adults participated and 177 completed the diary. Asthma was uncontrolled for the majority (76%) of participants and most (52%) reported exposure to 6-15 asthma triggers. As trigger burden increased, behavioural changes to manage trigger exposure had a significantly increased impact on daily life (p < 0.0001) and job choice (p = 0.002). Participants reporting a high trigger burden (>16) were more likely to report uncontrolled asthma than those with a low trigger burden (1-5). Participants with a high trigger burden had previously experienced on average two more severe asthma attacks during a lifetime (p < 0.001), two more hospitalisations (p < 0.001) and 3.5 more missed days at work or study in the last year due to their asthma (p < 0.001) than those with a low trigger burden. CONCLUSIONS: Adults with asthma reporting a high trigger burden (>16 different triggers) experience more severe asthma attacks than those reporting lower trigger burdens. PMID- 24050524 TI - Asthma screening of inner city and urban elementary school-aged children. AB - OBJECTIVE: Currently, in the United States there is a lack of a standardized method to effectively screen school children with undiagnosed or poorly controlled asthma. The purpose of this proof-of-concept study was to assess the use of the American College of Allergy, Asthma, and Immunology's (ACAAI) Asthma Screening Questionnaire to identify elementary school-age children at risk for asthma (undiagnosed) or poorly controlled asthma. METHODS: Children in grades 3-5 from one urban and two suburban schools completed ACAAI's 14 question asthma screening questionnaire and had their peak expiratory flow (PEF) measured. Children were considered to have a positive asthma screen and be at risk for having undiagnosed or poorly controlled asthma if they answered 'yes' to more than three questions. Children were referred to a physician if they had a positive asthma screen, a previous history of asthma, or a low PEF. RESULTS: Of the 86 participants, 52 were identified as being at risk for asthma. The number was higher among children attending an urban versus suburban school (p = 0.04). The sensitivity and specificity of the screening questionnaire for identifying asthma risk were 90% and 66%, respectively, when the number of 'yes' responses for a positive screen was increased from three to five of 14 questions. CONCLUSIONS: The ACAAI's Asthma Screening Questionnaire identified 52 children at risk for undiagnosed or poorly controlled asthma. Our findings support the need to validate this questionnaire to be used in conjunction with PEFR for identifying elementary school children at risk for asthma. PMID- 24050526 TI - Gestational age, infant birth weight, and subsequent risk of type 2 diabetes in mothers: Nurses' Health Study II. AB - INTRODUCTION: Women with a history of gestational diabetes mellitus (GDM) are at higher risk of developing type 2 diabetes (T2DM); however, little is known about the association between other common pregnancy complications (eg, preterm birth, macrosomia) and T2DM risk. We examined the associations between first-pregnancy preterm, postterm birth, low birth weight, and macrosomia with subsequent risk of T2DM. METHODS: We conducted a prospective cohort study of Nurses' Health Study II (NHSII) participants; 51,728 women in the study had a single live birth and complete pregnancy history. NHSII confirmed incident diabetes mellitus through supplemental questionnaires. Participants were followed from year of first birth until 2005. We defined gestational age as very preterm (20 to <=32 weeks), moderate preterm (33 to <=37 weeks), term (38 to <=42 weeks), and postterm (>=43 weeks). We defined low birth weight as an infant born at term weighing less than 5.5 pounds, and we defined macrosomia as an infant born at term weighing 10 pounds or more. We used Cox proportional hazards models, adjusting for potential confounders. RESULTS: Women with a very preterm birth (2%) had an increased T2DM risk (adjusted hazard ratio, 1.34; 95% confidence interval [CI], 1.05-1.71). This increased risk emerged in the decade following pregnancy. Macrosomia (1.5%) was associated with a 1.61 increased T2DM risk, after adjusting for risk factors, including GDM (95% CI, 1.24-2.08). This association was apparent within the first 5 years after pregnancy. Moderate preterm and term low birth weight did not significantly increase the risk of T2DM over the 35-year follow-up time. CONCLUSION: Women who experienced a very preterm birth or had an infant that weighed 10 pounds or more may benefit from lifestyle intervention to reduce T2DM risk. If replicated, these findings could lead to a reduced risk of T2DM through improved primary care for women experiencing a preterm birth or an infant of nonnormal birth weight. PMID- 24050527 TI - Disability, health, and multiple chronic conditions among people eligible for both Medicare and Medicaid, 2005-2010. AB - INTRODUCTION: People who are eligible for both Medicare and Medicaid (dual eligibles) and who have disabilities and multiple chronic conditions (MCC) present challenges for treatment, preventive services, and cost-effective access to care within the US health system. We sought to better understand dual eligibles and their association with MCC, accounting for sociodemographic factors inclusive of functional disability category. METHODS: Medical Expenditure Panel Survey (MEPS) data for 2005 through 2010 were stratified by ages 18 to 64 and 65 or older to account for unique subsets of dual eligibles. Prevalence of MCC was calculated for those with physical disabilities, physical plus cognitive disabilities, and all others, accounting for sociodemographic and health-related factors. Adjusted odds for having MCC were calculated by using logistic regression. RESULTS: Of dual eligibles aged 18 to 64, 53% had MCC compared with 73.5% of those aged 65 or older. Sixty-five percent of all dual eligibles had 2 or more chronic conditions, and among dual eligibles aged 65 or older with physical disabilities and cognitive limitations, 35% had 4 or more, with hypertension and arthritis the most common conditions. Dual eligibles aged 18 to 64 who had a usual source of medical care had a 127% increased likelihood of having MCC compared with those who did not have a usual source of care. CONCLUSION: Attention to disability can be a component to helping further understand the relationship between health and chronic conditions for dual eligible populations and other segments of our society with complex health and medical needs. PMID- 24050525 TI - Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torpedo postsynaptic membranes. AB - The nicotinic acetylcholine (ACh) receptor, at the neuromuscular junction, is a neurotransmitter-gated ion channel that has been fine-tuned through evolution to transduce a chemical signal into an electrical signal with maximum efficiency and speed. It is composed from three similar and two identical polypeptide chains, arranged in a ring around a narrow membrane pore. Central to the design of this assembly is a hydrophobic gate in the pore, more than 50 A away from sites in the extracellular domain where ACh binds. Although the molecular properties of the receptor have been explored intensively over the last few decades, only recently have structures emerged revealing its complex architecture and illuminating how ACh entering the binding sites opens the distant gate. Postsynaptic membranes isolated from the (muscle-derived) electric organ of the Torpedo ray have underpinned most of the structural studies: the membranes form tubular vesicles having receptors arranged on a regular surface lattice, which can be imaged directly in frozen physiological solutions. Advances in electron crystallographic techniques have also been important, enabling analysis of the closed- and open channel forms of the receptor in unreacted tubes or tubes reacted briefly with ACh. The structural differences between these two forms show that all five subunits participate in a concerted conformational change communicating the effect of ACh binding to the gate, but that three of them (alphagamma, beta and delta) play a dominant role. Flexing of oppositely facing pore-lining alpha helices is the principal motion determining the closed/open state of the gate. These results together with the findings of biochemical, biophysical and other structural studies allow an integrated description of the receptor and of its mode of action at the synapse. PMID- 24050528 TI - Tobacco treatment outcomes in patients with and without a history of depression, Czech Republic, 2005-2010. AB - INTRODUCTION: Higher prevalence of smoking among depressed patients, as well as the risk of depression in smokers, is well documented. The proportion of patients with a history of depression among those seeking intensive treatment of tobacco dependence is also high. In contrast, evidence of treatment success in this subgroup of patients is controversial. The aim of this study was to compare smoking abstinence rates after tobacco treatment in smokers with and without a history of depression. METHODS: We reviewed retrospective data from 1,730 smokers seeking treatment in Prague, Czech Republic. History of depression was defined as past diagnosis of depression or current treatment of depression. After a 1-year, self-reported smoking status was validated by expired-air carbon monoxide. We used logistic regression to analyze associations between abstinence rates, history of depression, and other factors (eg, age, sex, tobacco dependence). RESULTS: Of 1,730 smokers treated, 289 (16.7%) had a history of depression. The smoking abstinence rate at 1 year was 32.5% for smokers with a history of depression and 38.7% for those with no history (P = .048). Among women, abstinence did not differ between groups (35.0% vs 35.7%; P = .86). However, among men, those with a history of depression had lower rates of abstinence (27.4% vs 41.3%; P = .009). After adjustment for baseline covariates, history of depression was not significantly associated with smoking abstinence in men or women. CONCLUSION: Intensive outpatient tobacco treatment programs can achieve abstinence rates among smokers with a history of depression similar to rates among the general population. PMID- 24050529 TI - Adverse childhood experiences and adult smoking, Nebraska, 2011. AB - INTRODUCTION: Smoking is a public health risk; the prevalence of smoking among adults in Nebraska is 18.4%. Studies indicate that maltreatment of children alters their brain development, possibly increasing risk for tobacco use. Previous studies have documented associations between childhood maltreatment and adult health behaviors, demonstrating the influence of adverse experiences on tobacco use. We examined prevalence and associations between adverse childhood experiences and smoking among Nebraskans. METHODS: We analyzed 2011 Nebraska Behavioral Risk Factor Surveillance System (Adverse Childhood Experience module) data, defining adverse childhood experience exposures as physical, sexual, and verbal abuse (ie, direct exposures), and household dysfunction associated with mental illness, substance abuse, divorce, domestic violence, and living with persons with incarceration histories (ie, environmental exposures). We estimated prevalence of exposures, taking into account the complex survey design. We used logistic regression with predicted margins to estimate adjusted relative risk for smoking by direct or environmental exposure. RESULTS: Approximately 51% of Nebraskans experienced 1 or more adverse childhood events; 7% experienced 5 or more. Prevalence of environmental exposures (42%) was significantly higher than that of direct exposures (31%). Prevalence of individual exposures ranged from 6% (incarceration of a household member) to 25% (verbal abuse). Adjusted relative risks of smoking for direct and environmental exposures were 1.5 and 1.8, respectively. CONCLUSION: We present a new method of evaluating adverse childhood experience data. Prevalence of adverse childhood experiences is high among Nebraskans, and these exposures are associated with smoking. State-specific strategies to monitor adverse events among children and provide interventions might help to decrease the smoking rate in this population. PMID- 24050530 TI - Trends in cigarette smoking rates and quit attempts among adults with and without diagnosed diabetes, United States, 2001-2010. AB - INTRODUCTION: Quitting smoking is a critical step toward diabetes control. It is not known whether smoking rates in adults with diabetes are similar to rates among adults who do not have the disease or whether people with diabetes have increased motivation to quit. We examined prevalence trends of current smoking and quit attempts among US adults with and without diagnosed diabetes from 2001 through 2010. METHODS: We used data from the 2001 through 2010 Behavioral Risk Factor Surveillance System, a state-based telephone survey of noninstitutionalized US adults, and conducted linear trend analysis and log linear regression. RESULTS: The adjusted prevalence of cigarette smoking among adults with diagnosed diabetes was 9% less than adults without diagnosed diabetes (adjusted prevalence ratio [APR], 0.91; 99% confidence interval [CI], 0.89-0.93). Declines in smoking prevalence were greater among adults without diabetes than adults with diagnosed diabetes (P < .001). Among smokers, the adjusted prevalence of quit attempts among adults with diagnosed diabetes was 13% higher than among adults without diagnosed diabetes (APR, 1.13; 99% CI, 1.11-1.15). Among adult smokers with diagnosed diabetes, quit attempts were stable over time for those aged 18 to 44 years and those with a high school education or less. Quit attempts were also stable for older smokers, non-Hispanic African Americans, and Hispanic smokers, regardless of diagnosed diabetes status. CONCLUSION: A large proportion of smokers with diagnosed diabetes seemed to have quit smoking, but more research is needed to confirm success and how difficult it was to achieve. PMID- 24050531 TI - Lipid geometrical isomerism: from chemistry to biology and diagnostics. PMID- 24050532 TI - Laparoscopic versus open upper pole heminephroureterectomy for the treatment of duplex kidneys in children. AB - AIM: To evaluate the safety and feasibility of laparoscopic upper pole heminephroureterectomy (HNU) in pediatric patients with duplex kidneys in comparison with open surgery. PATIENTS AND METHODS: From 2007 to 2011, 27 patients underwent HNU. A dimercaptosuccinic acid (DMSA) isotope scan revealed hypofunctioning of ipsilateral moieties in all cases. The patients were divided randomly into laparoscopic HNU (LHNU) and open surgery HNU (OHNU) groups. LHNU was performed by the transperitoneal approach in 10 girls and 5 boys with a mean age of 33 months (range, 9-108 months). All procedures were performed using three or four ports. Open surgery was performed in 10 girls and 2 boys with a mean age of 29 months (range, 7-174 months) by the retroperitoneal approach in all cases. Follow-up included ultrasound and DMSA. RESULTS: Mean operative time in the LHNU and OHNU groups was 148 minutes (range, 100-220 minutes; 95% confidence interval [CI] 129-167 minutes) and 124 minutes (range, 100-150 minutes; 95% CI 115-133 minutes), respectively. In the LHNU and OHNU groups, mean analgesic requirement was 2.8 days (range, 2-4 days; 95% CI 2.4-3.2 days) and 3.7 days (range, 3-5 days; 95% CI 3.3-4.1 days), and mean hospital stay was 4.0 days (range, 2-8 days; 95% CI 3.2-4.8 days) and 5.1 days (range, 3-8 days; 95% CI 4.3-5.9 days), respectively. No intraoperative or major postoperative complications occurred. No conversion to open surgery was necessary in the LHNU group. Statistical analysis showed no statistical significant difference (P>.05) in the operating time between groups, whereas differences in the mean hospital stay (P=.048) and analgesic requirements (P=.005) were significant. The function of the remnant pole was preserved in all patients. Follow-up ultrasound showed asymptomatic cystic structures in 1 patient. CONCLUSIONS: The laparoscopic upper pole HNU is a safe and feasible procedure, even in infants. It is associated with minimal morbidity, and the operative time is acceptable and not significantly longer in comparison with the open approach. LHNU reduces analgesic requirements and hospital stay. In our opinion it should be the preferred option for HNU in children. PMID- 24050533 TI - Circular magnetoplasmonic modes in gold nanoparticles. AB - The quest for efficient ways of modulating localized surface plasmon resonance is one of the frontiers in current research in plasmonics; the use of a magnetic field as a source of modulation is among the most promising candidates for active plasmonics. Here we report the observation of magnetoplasmonic modes on colloidal gold nanoparticles detected by means of magnetic circular dichroism (MCD) spectroscopy and provide a model that is able to rationalize and reproduce the experiment with unprecedented qualitative and quantitative accuracy. We believe that the steep slope observed at the plasmon resonance in the MCD spectrum can be very efficient in detecting changes in the refractive index of the surrounding medium, and we give a simple proof of principle of its possible implementation for magnetoplasmonic refractometric sensing. PMID- 24050534 TI - 3C protein of feline coronavirus inhibits viral replication independently of the autophagy pathway. AB - Feline coronavirus (FCoV) can cause either asymptomatic enteric infection or fatal peritonitis in cats. Although the mutation of FCoV accessory gene 3c has been suggested to be related to the occurrence of feline infectious peritonitis (FIP), how the 3C protein is involved in this phenomenon remains unknown. To investigate the role of the 3C protein, a full-length 3c gene was transiently expressed and the cytoplasmic distribution of the protein was found to be primarily in the perinuclear region. Using 3c-stable expression cells, the replication of a 3c-defective FCoV strain was titrated and a significant decrease in replication (p<0.05) was observed. The mechanism underlying the decreased FIPV replication caused by the 3C protein was further investigated; neither the induction nor inhibition of autophagy rescued the viral replication. Taken together, our data suggest that the 3C protein might have a virulence-suppressing effect in FCoV-infected cats. Deletion of the 3c gene could therefore cause more efficient viral replication, which leads to a fatal infection. PMID- 24050535 TI - Increased arterial stiffness is independently associated with metabolic syndrome and damage index in systemic lupus erythematosus patients. AB - OBJECTIVES: We evaluated whether traditional or non-traditional cardiovascular (CV) risk factors and systemic lupus erythematosus (SLE)-related risk factors were associated with pathological arterial stiffness measured by pulse wave velocity (PWV) adjusted for patients' age and blood pressure. METHOD: CV risk factors were measured in the 46 SLE female patients studied. Activity and organ damage were assessed by the SLE Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) Damage Index, respectively. Other lupus-related parameters and information concerning treatment were recorded. Subclinical atherosclerosis was assessed by PWV calculated from pulse wave recording by Doppler, a non-invasive method to measure arterial stiffness. Multivariate logistic regression analysis was used to identify independent determinants of increased PWV. RESULTS: PWV was categorized as normal or pathological arterial stiffness following the reference values adjusted by age and blood pressure recently published by the European Society of Cardiology. Pathological PWV was associated with CV risk factors including homocysteine (p = 0.01), high-sensitivity C-reactive protein (hs-CRP; p = 0.03), uric acid (p = 0.01), and metabolic syndrome (p = 0.007). With regard to SLE-specific risk factors, a significant association was found between PWV and SLICC/ACR score (p = 0.006). Multivariate analysis showed that increased PWV was independently associated with metabolic syndrome [odds ratio (OR) 6.6, 95% confidence interval (CI) 1.2-38, p = 0.03] and SLICC/ACR score (OR 1.5, 95% CI 1 2.32, p = 0.05). CONCLUSIONS: We have found a close link between metabolic syndrome and SLICC/ACR score with increased aortic stiffness. These variables might be an indicator of subclinical atherosclerosis in SLE women without clinical evidence of atherosclerotic cardiovascular disease (CVD). PMID- 24050536 TI - Centennial of Hashimoto's disease. PMID- 24050537 TI - Emptying the beta-cyclodextrin cavity by light: photochemical removal of the trans-chalcone of 4',7-dihydroxyflavylium. AB - The interaction between the network of chemical reactions of the compound 4',7 dihydroxyflavylium and beta-cyclodextrin was studied by means of pH jumps, followed by UV-vis absorption, flash photolysis, stopped flow, and NMR. The trans chalcone is the network species exhibiting the strongest interaction with the host. In moderately acidic medium, 95% of the trans-chalcone, 2.5 * 10(-5) M, in the presence of beta-cyclodextrin, 9 * 10(-3) M, is expected to fill the host cavity (association constant 2.2 * 10(3) M(-1)). In contrast, flavylium cation does not interact (association constant ~ 0). Irradiation of the trans-chalcone in the presence of beta-cyclodextrin 9 mM leads to the flavylium cation appearance. Light is thus capable of removing the trans-chalcone from the beta cyclodextrin, leaving the cavity empty. The system is reversible and trans chalcone goes back to the initial state upon switching off the light due to the thermodynamic favorable conversion of flavylium cation to trans-chalcone in the presence of beta-cyclodextrin. PMID- 24050538 TI - Computation of binding energies including their enthalpy and entropy components for protein-ligand complexes using support vector machines. AB - Computing binding energies of protein-ligand complexes including their enthalpy and entropy terms by means of computational methods is an appealing approach for selecting initial hits and for further optimization in early stages of drug discovery. Despite the importance, computational predictions of thermodynamic components have evaded attention and reasonable solutions. In this study, support vector machines are used for developing scoring functions to compute binding energies and their enthalpy and entropy components of protein-ligand complexes. The binding energies computed from our newly derived scoring functions have better Pearson's correlation coefficients with experimental data than previously reported scoring functions in benchmarks for protein-ligand complexes from the PDBBind database. The protein-ligand complexes with binding energies dominated by enthalpy or entropy term could be qualitatively classified by the newly derived scoring functions with high accuracy. Furthermore, it is found that the inclusion of comprehensive descriptors based on ligand properties in the scoring functions improved the accuracy of classification as well as the prediction of binding energies including their thermodynamic components. The prediction of binding energies including the enthalpy and entropy components using the support vector machine based scoring functions should be of value in the drug discovery process. PMID- 24050539 TI - How do motorcyclists manage mental tensions of risky riding? AB - BACKGROUND: Road traffic injuries, especially those involving motorcycles, are a particular concern in Iran. We aimed to identify the specific cognitive dissonances and consonances associated with risky riding among Iranian motorcyclists. METHODS: This was a grounded theory qualitative study of male motorcyclists who were >= 18 and were living in one of the three cities of Tehran, Isfahan and Ahwaz. Thirty four (n = 34) motorcyclists participated in 19 in-depth interviews and 5 focus-groups between January 2007 and February 2008. RESULTS: We identified four categories of motorcycle riders each endorsing a unique risk bias they employed to justify their risky ridings. The categories included: (1) Risk Managers who justified risky riding by doubting that it would result in negative outcomes if they are competent riders. (2) Risk Utilizers who justified risky riding as functional and practical that would enable them to handle daily chores and responsibilities more efficiently. (3) Risk Calculators who justified risky riding by believing that it will help them to avoid road crashes. (4) Risk Takers who justified risky riding by arguing that risky riding is thrilling and brings them peer recognition. CONCLUSION: Our findings reveal different groups of motorcyclists according to their different rationalizations for risky riding. Road safety advocates can benefit from our findings by matching relevant and appropriate interventions and incentives to these specific groups. PMID- 24050540 TI - Incidence, risk factors, and outcomes of perioperative acute kidney injury in noncardiac and nonvascular surgery. AB - BACKGROUND: The aim of this study was to determine the incidence rate, identify the risk factors, and describe the clinical outcome of perioperative acute kidney injury (AKI) in patients undergoing noncardiac, nonvascular surgery (NCS). METHODS: A total of 1,200 adult consecutive patients undergoing NCS were prospectively evaluated. Patients with pre-existing renal dysfunction were excluded. The primary outcome of this study was perioperative AKI defined by the RIFLE (risk, injury, failure, loss of function, and end-stage kidney disease) criteria. RESULTS: Eighty-one patients (6.7%) met the AKI criteria. Multivariate analysis identified age, diabetes, revised cardiac risk index, and American Society of Anesthesiologists physical status as independent predictors of AKI. Patients with AKI had more cardiovascular (33.3% vs 11.3%, P < .001) complications and a higher in-hospital mortality rate (6.1% vs 0.9%, P = .003) compared with patients without AKI. CONCLUSIONS: Several preoperative predictors are found to be associated with AKI after NCS. Perioperative AKI is an independent risk factor for outcome after NCS. PMID- 24050541 TI - 5-S-lipoylhydroxytyrosol, a multidefense antioxidant featuring a solvent-tunable peroxyl radical-scavenging 3-thio-1,2-dihydroxybenzene motif. AB - 5-S-Lipoylhydroxytyrosol (1), the parent member of a novel group of bioinspired multidefense antioxidants, is shown herein to exhibit potent peroxyl radical scavenging properties that are controlled in a solvent-dependent manner by the sulfur center adjacent to the active o-diphenol moiety. With respect to the parent hydroxytyrosol (HTy), 1 proved to be a more potent inhibitor of model autoxidation processes in a polar solvent (acetonitrile), due to a lower susceptibility to the adverse effects of hydrogen bonding with the solvent. Determination of O-H bond dissociation enthalpies (BDE) in t-butanol by EPR radical equilibration technique consistently indicated a ca. 1.5 kcal/mol lower value for 1 relative to HTy. In good agreement, DFT calculations of the BDEOH using an explicit methanol molecule to mimic solvent effects predicted a 1.2 kcal/mol lower value for 1 relative to HTy. Forcing the geometry of the -S-R group to coplanarity with the aromatic ring resulted in a dramatic decrease in the computed BDEOH values suggesting a potentially higher activity than the reference antioxidant alpha-tocopherol, depending on geometrical constrains in microheterogeneous environments. These results point to sulfur substitution as an expedient tool to tailor the chain-breaking antioxidant properties of catechol derivatives in a rational and predictable fashion. PMID- 24050557 TI - Mycobacterium iranicum infection in HIV-infected patient, Iran. PMID- 24050559 TI - The profession takes a new look at why more women don't hold leadership positions and what can- and should - be done about it. PMID- 24050560 TI - Should the veterinary profession invest in developing methods to assess quality of life in healthy dogs and cats? PMID- 24050561 TI - What is your diagnosis? Extruded intervertebral disk. PMID- 24050562 TI - What is your diagnosis? Thyroid carcinomas. PMID- 24050563 TI - Pathology in practice. Pancreatolithiasis. PMID- 24050564 TI - Veterinary internship survey, 2012. PMID- 24050565 TI - Employment, starting salaries, and educational indebtedness of year-2013 graduates of US veterinary medical colleges. PMID- 24050566 TI - Acquisition and persistence of antimicrobial-resistant bacteria isolated from dogs and cats admitted to a veterinary teaching hospital. AB - OBJECTIVE: To assess antimicrobial resistance among bacteria isolated from dogs and cats admitted to a veterinary teaching hospital (VTH), determine the incidence of acquisition of and frequency of persistent colonization by antimicrobial-resistant organisms among these animals, and identify risk factors associated with these variables. DESIGN: Prospective longitudinal study. ANIMALS: 622 dogs and 92 cats admitted to a VTH and expected to stay >= 48 hours. PROCEDURES: Samples were collected with rectal and nasal or oropharyngeal swabs at admission and discharge. Isolates of enterococci, staphylococci, and Escherichia coli were tested for antimicrobial resistance via microbroth dilution methods. A subset of isolates was analyzed with pulsed-field gel electrophoresis and multilocus sequence typing. Significant trends in proportions of organisms with antimicrobial resistance over the 3-year study period were assessed. RESULTS: The proportion of staphylococci with antimicrobial resistance increased, whereas the proportion of E coli with resistance decreased, over time; resistance among enterococci was more variable. For 506 dogs with paired admission and discharge samples, multidrug-resistant (MDR) E coli was acquired by 40 (8%) and methicillin-resistant Staphylococcus aureus (MRSA) was acquired by 7 (1.4%); hospitalization for > 3 days was significantly associated with both variables. Most (5/7 isolates) acquired MRSA was of sequence type (ST) 5. CONCLUSIONS AND CLINICAL RELEVANCE: Extended hospitalization was associated with increased risk of acquiring MDR E coli or MRSA, although few animals acquired MRSA. It is unclear whether associations were confounded by illness severity or use of infection control measures. Additionally, MRSA of ST5, which has been associated with small animal medicine, was the most commonly acquired MRSA in this study. PMID- 24050567 TI - Phenotype, inheritance characteristics, and risk factors for idiopathic epilepsy in Finnish Spitz dogs. AB - OBJECTIVE: To determine the phenotype, inheritance characteristics, and risk factors for idiopathic epilepsy (IE) in Finnish Spitz dogs (FSDs). DESIGN: Prospective epidemiological study. ANIMALS: 2,141 FSDs. PROCEDURES: From 2003 to 2004, questionnaires (n = 5,960) were sent to all owners of 1-to 10-year-old FSDs in Finland. Phone interviews were performed 1 to 2 years later. RESULTS: Estimated prevalence of IE was 5.36% (111/2,069 of FSDs that were still alive). Males were predisposed to IE. The median age of onset was 3 years (range, 0.6 to 10 years). The median seizure frequency was 2 seizures/y (range, 0.5 to 48 seizures/y), and the median duration of the seizure episode was 11.75 minutes (range, 1.5 to 90 minutes). The majority (85%) of the seizures had a focal onset, and 54% were characterized as generalized secondary. A generalized seizure phase was determined to be a risk factor for development of progressive disease. Factors associated with the occurrence of a generalized phase were the age of onset, duration of the seizure, number of feeding times per day, and whether the dog was used for hunting. The seizures were not progressing in 678% of the dogs and were easily controlled by antiepileptic treatment in 78.9% of the dogs. The heritability estimate of IE in FSDs was 0.22; IE was best explained as a polygenic trait. CONCLUSIONS AND CLINICAL RELEVANCE: In the present study conducted in Finland, complex focal seizures were the most common seizure type for FSDs with IE, and a generalized seizure phase was a risk factor for progression of the disease. Results suggested a benign course of epilepsy in FSDs. PMID- 24050568 TI - Internet-based survey of the nature and perceived causes of injury to dogs participating in agility training and competition events. AB - OBJECTIVE: To characterize injuries (on the basis of type and severity of injury and affected region of the body) among dogs participating in agility training and competition events and examine associations between injury characteristics and perceived causes of injury. DESIGN: Internet-based, retrospective, cross sectional survey. ANIMALS: 3,801 privately owned dogs participating in agility training or trials. PROCEDURES: A retrospective electronic survey was developed to investigate demographic factors for dogs and handlers, frequency of participation in agility training and competition, and perceived causes and characteristics of injuries acquired by dogs during agility-related activities. Respondents were handlers recruited through member lists of large canine agility associations in Canada and the United Kingdom and through promotion on an agility blog site. Associations between cause and anatomic site or type of injury and between injury severity (mild vs severe) and setting (competition vs practice) were investigated. RESULTS: Surveys were received from 1,669 handlers of 3,801 agility dogs internationally. Handler-reported data indicated 1,209 of 3,801 (32%) dogs had >= 1 injury; of 1,523 analyzed injuries, the shoulder (349 injuries), back (282), and neck (189) regions and phalanges (202) were predominantly affected. Soft tissue injuries (eg, strain [muscle or tendon injury; 807], sprain [ligament injury; 312], and contusion [200]) were common. Injuries were most commonly incurred during interactions with bar jumps, A frames, and dog walk obstacles (260, 235, and 177 of 1,602 injuries, respectively). Anatomic site and type of injury were significantly associated with perceived cause of injury. CONCLUSIONS AND CLINICAL RELEVANCE: These findings provided a basis for further experimental studies to identify specific mechanisms of various types of injury in dogs that participate in agility activities. PMID- 24050569 TI - Survey-based analysis of risk factors for injury among dogs participating in agility training and competition events. AB - OBJECTIVE: To identify potential risk factors for agility-related injuries among dogs. DESIGN: Internet-based, retrospective, cross-sectional survey. ANIMALS: 3,801 privately owned dogs participating in agility training or trials. PROCEDURES: A retrospective electronic survey was used to investigate potential risk factors for injury among dogs participating in agility-related activities. Respondents were handlers recruited through member lists of large canine agility associations in Canada and the United Kingdom and through promotion on an agility blog site. Variables evaluated included demographic information for handlers and dogs, exposure variables (eg, frequency of agility practice and competition in the past year), and use of preventive measures intended to keep dogs fit for agility (warmup, cooldown, or conditioning exercises; alternative therapeutic treatments [eg, acupuncture, massage, or chiropractic care]; or dietary supplement products). RESULTS: Data were collected from 1,669 handlers of 3,801 agility dogs internationally; 1,209 (32%) dogs incurred >= 1 injury. Previous injury (OR, 100.5), <= 4 years of agility experience for dogs (OR, 1.5), use of alternative therapeutic treatments (OR, 1.5), and Border Collie breed (OR, 1.7) were associated with increased odds of injury. Handlers having 5 to 10 or > 10 years of experience (OR, 0.8 and 0.6, respectively) and dogs having > 4 years of experience in the sport (OR, 0.6) were associated with decreased odds of injury. CONCLUSIONS AND CLINICAL RELEVANCE: Specific factors were associated with agility related injuries in dogs. Educational prevention strategies should target at-risk populations in an effort to reduce potential injuries. Future research should focus on the biomechanical factors associated with agility-related injuries. PMID- 24050571 TI - Chronic dermatitis caused by Lactobacillus jensenii infection in a blue and gold macaw (Ara ararauna). AB - CASE DESCRIPTION: A 5-year-old sexually intact female blue and gold macaw (Ara ararauna) was evaluated because of a swelling on the right side of the face and irritated area on the ventral aspect of the keel. CLINICAL FINDINGS: Clinical findings were consistent with dermatitis (right facial lesion) and a coalescing subdermal granuloma (ventral keel lesion). Hematologic analysis revealed monocytosis and mild anemia. Histologic evaluation of the ventral keel lesion revealed evidence of chronic heterophilic dermatitis with multinucleated giant cells and bacterial rods and cocci. An unspeciated gram-positive rod-shaped bacterium was isolated via aerobic bacterial culture. Results of bacterial biochemical tests suggested the organism was a type of Actinomyces. A 16S rRNA gene sequence analysis was performed; results indicated the organism was Lactobacillus jensenii. TREATMENT AND OUTCOME: Extensive surgical debridement of the branching granuloma, which extended throughout the length of the keel, followed by long-term treatment with ciprofloxacin and clindamycin provided full resolution of clinical signs. No recrudescence of clinical signs was evident for up to 18 months after the initial evaluation. CLINICAL RELEVANCE: To the authors' knowledge, this is the first report of Lactobacillus-associated dermatitis or subdermal granuloma in the scientific literature and the second report of L jensenii in avian species. Use of 16S rRNA gene sequence analysis was instrumental in the identification of this fastidious organism, indicating the method's usefulness as a diagnostic tool. PMID- 24050570 TI - Incidence of sterile hemorrhagic cystitis in dogs receiving cyclophosphamide orally for three days without concurrent furosemide as part of a chemotherapeutic treatment for lymphoma: 57 cases (2007-2012). AB - OBJECTIVE: To evaluate the incidence of sterile hemorrhagic cystitis (SHC) and other adverse effects in dogs following oral administration of the single-day, maximum-tolerated dose (MTD) of cyclophosphamide divided over 3 days as part of a multiagent chemotherapy protocol for treatment of lymphoma without concurrent administration of furosemide. DESIGN: Retrospective case series. ANIMALS: 57 dogs. PROCEDURES: Medical records were reviewed to identify dogs with lymphoma that underwent the described cyclophosphamide treatment. Information was obtained regarding signalment, lymphoma stage, concurrent diseases, cyclophosphamide doses administered, adverse effects (including SHC), remission rates, and outcomes. The incidence of SHC was compared with that of literature-derived historical control groups that received the MTD of cyclophosphamide as a single, 1-day dose with or without furosemide treatment. RESULTS: None of the 57 dogs developed SHC during the study period. Forty-seven of 57 (82%) dogs had complete remission of lymphoma. Other adverse effects were uncommon and self-limiting; no dogs had myelosuppression, and only 5 had mild gastrointestinal effects. Incidence of SHC was significantly lower than that reported for historical control dogs that received cyclophosphamide as a single dose without furosemide (24/219) and was not significantly different from that for historical control dogs that received cyclophosphamide as a single dose with furosemide (2/139). CONCLUSIONS AND CLINICAL RELEVANCE: No dogs in this study had SHC following oral administration of the single-day MTD of cyclophosphamide divided over a 3-day period without furosemide administration. Further research is needed to confirm whether this method of cyclophosphamide administration is equivalent or superior to the current single-dose administration method. PMID- 24050572 TI - Association of hematologic variables and castration status at the time of arrival at a research facility with the risk of bovine respiratory disease in beef calves. AB - OBJECTIVE: To determine the association of CBC variables and castration status at the time of arrival at a research facility with the risk of development of bovine respiratory disease (BRD). DESIGN: Retrospective cohort study. ANIMALS: 1,179 crossbred beef bull (n = 588) and steer (591) calves included in 4 experiments at 2 University of Arkansas research facilities. PROCEDURES: Calves underwent processing and treatments in accordance with the experiment in which they were enrolled. Castration status and values of CBC variables were determined at the time of arrival at the facilities. Calves were monitored to detect signs of BRD during a 42-day period. RESULTS: The areas under the receiving operator characteristic curves for CBC variables with significant contrast test results ranged from 0.51 (neutrophil count) to 0.67 (eosinophil count), indicating they were limited predictors of BRD in calves. The only CBC variables that had significant associations with BRD in calves as determined via multivariable logistic regression analysis were eosinophil and RBC counts. The odds of BRD for bulls were 3.32 times the odds of BRD for steers. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study indicated that low eosinophil and high RBC counts in blood samples may be useful for identification of calves with a high risk for development of BRD. Further research may be warranted to validate these variables for prediction of BRD in calves. Calves that were bulls at the time of arrival had a higher risk of BRD, versus calves that were steers at that time. PMID- 24050573 TI - Multimodal evaluation of the effectiveness of a hand hygiene educational campaign at a small animal veterinary teaching hospital. AB - OBJECTIVE: To determine the effect of an intervention (educational campaign) on hand hygiene (HH) and health-care workers' (HCWs') perceptions of HH. DESIGN: Prospective observational study and cross-sectional survey. SAMPLE: Observed opportunities for HH performed by HCWs before (n = 222) and after (249) intervention, measures of HH product usage, and surveys distributed to 300 HCWs. PROCEDURES: Data were collected by means of direct observation, measurement of HH product consumption, and surveys of HCWs. RESULTS: Adherence rates of HCWs for HH practices before and after the intervention were 27% (61/222 observations) and 29% (73/249 observations), respectively. Combined HH and glove use adherence rates before and after the intervention were 84% (186/222 observations) and 81% (201/249 observations), respectively. Before intervention, the highest combined HH and glove use adherence rate was detected for technicians (90% [57/63 observations]) and for opportunities after exposure to a patient's bodily fluids (100% [5/5 opportunities]). Rate of use of alcohol-based antimicrobial hand rubs (AHRs) and amount of HH products used did not significantly change during the study. Survey response rates were 41% (122) and 21% (62) before and after the intervention, respectively. Availability of AHRs and role modeling of HH (performance of HH each time it is warranted) were considered the factors most likely to increase HH adherence rates by survey respondents. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated the intervention did not increase HH adherence or use of AHRs. High rates of glove use before the start of the study may have been a confounding factor. Future educational campaigns should indicate that glove use should not supersede HH. PMID- 24050574 TI - Investigating strategies to reduce toxicity in stereotactic ablative radiotherapy for central lung tumors. AB - BACKGROUND: [corrected] Stereotactic radiotherapy for central lung tumors has a narrower therapeutic index than that for peripheral tumors. Tumor tracking strategies have been proposed to reduce treatment volumes and toxicity, however they need to consider uncertainties in tumor size and shape change throughout respiration to ensure optimal local control. We quantified these uncertainties and explored strategies to account for them. MATERIAL AND METHODS: Ten patients with central tumors, PTV > 100 cm(3), motion > 5 mm and a 10-phase 4DCT without significant artifact in the tumor region were evaluated. Uncertainties were quantified using GTV size in different phases, and the Hausdorff distance (HD) between the phase 50% GTV and other phases after soft-tissue rigid registration. An individualized internal target volume for tracking (ITV(T)) was generated from the union of the GTVs in all phases after rigid registration. This was compared to ITVs generated for tracking based on the phase 50% GTV alone or with isotropic margins of 3 or 5 mm for size and volume overlap. RESULTS: Median free-breathing PTV size and motion were 162.1 cm(3) (110-210) and 8.9 mm (6.1-14.1). Overall, median GTV size variation and HD were 4.7% (0.2-22.3) and 6.3 mm (3.9-17.6). Tracking using GTV 50% alone resulted in median volume overlap with ITV(T) of 71.7% (range 56.8-85.1). Isotropic margins of 3 or 5mm always resulted in a volume overlap less than 95% or a volume larger than the ITV(T). CONCLUSIONS: Changes in size and shape of central lung tumors are substantial during respiration. These limit the ability to reduce treatment volumes with tracking, especially if isotropic margins are used. An individualized ITV for tracking, such as the ITV(T) is preferred. PMID- 24050575 TI - Monte Carlo simulations of new 2D ripple filters for particle therapy facilities. AB - At particle therapy facilities with pencil beam scanning, the implementation of a ripple filter (RiFi) broadens the Bragg peak (BP), which leads to fewer energy steps from the accelerator required to obtain an homogeneous dose coverage of the planned target volume (PTV). At the Universitatsklinikum Giebetaen und Marburg, Germany, a new second generation RiFi has been developed with two-dimensional groove structures. In this work we evaluate this new RiFi design. METHODS: The Monte Carlo (MC) code SHIELD-HIT12A is used to determine the RiFi-induced inhomogeneities in the dose distribution for various ion types, initial particle energies and distances from the RiFi to the phantom surface as well as in the depth of the phantom. The beam delivery and monitor system (BAMS) used at Marburg, the Heidelberg Ionentherapiezentrum (HIT), Universitatsklinikum Heidelberg, Germany and the GSI Helmholtzzentrum fur Schwerionenforschung, Darmstadt, Germany is modeled and simulated. To evaluate the PTV dose coverage performance of the new RiFi design, the heavy ion treatment planning system TRiP98 is used for dose optimization. SHIELD-HIT12A is used to prepare the facility-specific physical dose kernels needed by TRiP, and for recalculating the physical dose distribution after TRiP optimization. RESULTS: At short distances from the RiFi to the phantom surface fine structures in the dose distribution are observed. For various RiFis, ion types and initial particle energies the distance dmax at which maximum dose inhomogeneity occurs is found and an expression for dmax is deduced. The distance d0.01 at which the dose inhomogeneity is less than 1% is estimated and used as a threshold distance at which dose distributions are considered homogeneous. The MC data are found to agree with analytical expressions for dmax and d0.01; both are inversely related to the angular distribution. Increasing scatter from the beam delivery and monitoring system results in reduced dmax and d0.01. Furthermore, dmax and d0.01 are found to be proportional to the RiFi period lambda. CONCLUSION: Our findings clearly indicate that the dose inhomogeneity induced by RiFis does not add uncertainties to the dose distribution in the clinical setting. The new RiFi design can be used in treatments to obtain homogeneous PTV dose coverage with fewer energy steps while improving lateral penumbra, thereby reducing the required treatment time. PMID- 24050576 TI - Pure platinum nanostructures grown by electron beam induced deposition. AB - Platinum has numerous applications in catalysis, nanoelectronics, and sensing devices. Here we report a method for localized, mask-free deposition of high purity platinum that employs a combination of room-temperature, direct-write electron beam induced deposition (EBID) using the precursor Pt(PF3)4, and low temperature (<=400 degrees C) postgrowth annealing in H2O. The annealing treatment removes phosphorus contaminants through a thermally activated pathway involving dissociation of H2O and the subsequent formation of volatile phosphorus oxides and hydrides that desorb during annealing. The resulting Pt is indistinguishable from pure Pt films by wavelength dispersive X-ray spectroscopy (WDS). PMID- 24050577 TI - Improved glycemic control and lipid profile in hyperlipidemic type 2 diabetic patients consuming Salvia officinalis L. leaf extract: a randomized placebo. Controlled clinical trial. AB - OBJECTIVES: Evaluation of the efficacy and safety of Salvia officinalis L. (S. officinalis) leaf extract in the treatment of hyperlipidemic type 2 diabetic patients. DESIGN: Randomized placebo-controlled parallel group study. SETTING: Diabetes Clinic (Karaj City, Alborz Province of Iran). INTERVENTIONS: The efficacy and safety of taking S. officinalis leaf extract (one 500 mg capsule t.i.d. for 3 months) in treatment of 40 hyperlipidemic (hypercholesterolemic and/or hypertriglyceridemic) type 2 diabetic patients were evaluated and compared with the placebo group (n=40). MAIN OUTCOME MEASURES: Fasting blood levels of glucose, glycosylated hemoglobin (HbA1c), total cholesterol, triglyceride, LDL-C (low density lipoprotein cholesterol), HDL-C (high density lipoprotein cholesterol), SGOT (serum glutamic-oxaloacetic transaminase), SGPT (serum glutamic-pyruvic transaminase) and creatinine. RESULTS: The extract lowered fasting glucose, HbA1c, total cholesterol, triglyceride and LDL-C but increased HDL-C compared to baseline at endpoint. Percent difference mean (95% confidence interval) between the extract and placebo groups in terms of effects on fasting glucose, HbA1c, total cholesterol, triglyceride, LDL-C and HDL-C at endpoint were 32.2 (26.5, 37.9), 22.7 (16.8, 28.6), 16.9 (9.7, 24.1), 56.4 (36.1, 76.7), 35.6 (29.9, 41.3) and 27.6 (15.8, 39.4) (P=0.001, P=0.01, P=0.01, P=0.009, P<0.001 and P=0.008), respectively. Moreover, the extract did not have any significant effects on the other parameters compared to the placebo group at endpoint (P>0.05). No adverse effects were reported. CONCLUSIONS: S. officinalis leaves may be safe and have anti-hyperglycemic and lipid profile improving effects in hyperlipidemic type 2 diabetic patients. PMID- 24050578 TI - Capparis spinosa L. (Caper) fruit extract in treatment of type 2 diabetic patients: a randomized double-blind placebo-controlled clinical trial. AB - OBJECTIVES: Capparis spinosa L. (Caper) fruit is traditionally used as an anti hyperglycemic food by Iranian diabetic patients. But yet, no controlled human study has determined its efficacy in treatment of hyperglycemia in type 2 diabetic patients. DESIGN: The present study was undertaken to explore the possible anti-hyperglycemic effects of the caper fruit extract in type 2 diabetic patients. A randomized clinical trial was conducted in 54 type 2 diabetic patients. Two groups 28 and 26 patients on standard anti-diabetic therapy, received 400mg caper fruit extract and placebo capsules three times a day respectively for two months. MAIN OUTCOME MEASURES: The patients fasting blood glucose, glycosylated hemoglobin, lipids levels, liver and renal function tests were determined at baseline and endpoint. RESULTS: Results showed significant decrease in fasting blood glucose levels (p=0.037) and glycosylated hemoglobin (p=0.043) in caper treated patients compared to control group at the end of the study. Triglyceride level also decreased significantly (p=0.29) in caper treated group at the end of the study compared to baseline. No liver, kidney and other side effects were observed in these two groups. CONCLUSIONS: Caper fruit extract may be a safe anti-hyperglycemic and anti-hypertriglyceridemic agent for type 2 diabetic patients. PMID- 24050579 TI - Plant-based ointments versus usual care in the management of chronic skin diseases: a comparative analysis on outcome and safety. AB - OBJECTIVES: To assess the outcome and safety of plant-based ointments versus usual care in the management of chronic skin diseases. METHODS: Prospective mono centric comparative analysis. Patients were recruited at an outpatient dermatology clinic and treated with plant-based ointments or care as usual. Main outcome criterion was the response rate, defined as the proportion of patients experiencing 'complete recovery' or 'major improvement' at 6, 12 and 24 months. Secondary outcome criteria were quality of life (SF-12 and EQ-5D), patient satisfaction and safety of treatment. RESULTS: A total of 112 patients with chronic skin diseases were evaluated of which 44 were treated with plant-based ointments (PO) and 68 received usual care (UC). The majority of patients suffered from psoriasis (PO: 50%; UC: 56%) or eczema (PO: 41%; UC: 32%) and were treated with homoeopathic topical ointments containing mahonia or cardiospermum or usual care creams containing calcipotriene and corticosteroids. The only significant difference in baseline status between the two groups was in disease severity score (PO: 1.8+/-0.7 versus UC: 2.4+/-0.8, p=0.0004). After two years, the main outcome of responders to treatment was 52.3% (95%-CI: 36.1-64.9) in the ointment and 41.2% (95%-CI: 20.4-42.2) in the UC group. Change in SF-12 (2 years compared to baseline), adjusted for baseline disease severity, was not significantly different between both groups; PO: 5.4 (95%-CI: 3.4-7.3) versus UC: 3.2 (95%-CI: 1.5-4.9). The adjusted EQ-5D was found to be significantly different between the two groups after two years, in favour of the ointment group; PO: 0.113 (95%-CI: 0.052-0.174) and UC: -0.008 (95%-CI: -0.055-0.038). Other secondary outcome parameters such as patient satisfaction and number of adverse drug reactions were comparable. CONCLUSIONS: The outcome of this study suggests at least therapeutic equivalence between plant-based ointments and usual care management of chronic skin diseases. As this non-randomised study was open to selection and other bias, further rigorous studies are needed to demonstrate the effectiveness of these topical products. PMID- 24050580 TI - Quality of life improvements among cancer patients in remission following the consumption of Agaricus blazei Murill mushroom extract. AB - OBJECTIVES: The aim of this preliminary clinical study was to assess if the daily intake of Agaricus blazei Murill (ABM) granulated powder (SSI Co., Ltd., Tokyo, Japan) for 6 months improved the quality of life (QOL) in cancer patients in remission. DESIGN: Open study. SETTING: Subjects diurnally took 1 (1.8 g; N=23), 2 (3.6 g; N=22), or 3 (5.4 g; N=22) packs/day orally for 6 months. MAIN OUTCOME MEASURES: The SF-8 Health Survey questionnaire was used to evaluate the QOL. The differences between the SF-8 baseline scores at the time of entry and 6-months after ABM treatment were evaluated. RESULTS: The results showed a significant improvement in QOL in both physical and mental components. More specifically, QOL effects of ABM in different genders showed males improved physical components, while females improved only mental components. QOL effects in the different age groups showed that ages 65 and under improved mental components, while ages 66 and older improved physical components. Furthermore, with respect to optimal dose effects of ABM with respect to QOL improvement, two packs per day for 6 months showed improvements in both physical and mental components. CONCLUSION: This preliminary longitudinal clinical study demonstrated that daily intake of ABM appears to improve both physical and mental components based on SF-8 qualimetric analysis. PMID- 24050581 TI - The impact of kangaroo care and music on maternal state anxiety. AB - OBJECTIVE: The effect of kangaroo care (KC) has not been adequately studied in mothers. This present study was undertaken to determine if music during KC has a greater effect than KC alone, on maternal state anxiety (MSA) in the early postpartum period. DESIGN AND SETTING: In a randomized controlled trial, 90 Iranian women who were scheduled for a repeat Cesarean-section, were randomized into three groups: KC, music during KC, and a control group. Mothers' pain scores were evaluated using a visual analog scale (VAS). If the VAS score was <=3, then MSA was measured by using the State-Trait Anxiety Inventory (STAI) Scale (Spielberg). Interventions were 30 min KC for mother-infant dyads, or playing music for the mothers during KC. Six hours later, in cases where the VAS was <=3, the MSA was re-measured using Spielberg's scale for all mothers. RESULTS: Six hours post intervention, there was no significant difference in the overall mean scores of MSA between the groups, but the severity of MSA in the two experimental groups was less than in the control group (P=0.02), although not between the two experimental groups. CONCLUSIONS: The findings of this study provide evidence that KC has an effect on the severity of MSA in mothers who were delivered by C section, however, music during KC had no more effect than KC alone. More research is needed to document the effectiveness of selected or familiar music during KC on state anxiety in early postpartum. PMID- 24050583 TI - Characteristics of patients with internal diseases who use relaxation techniques as a coping strategy. AB - OBJECTIVES: To assess sociodemographic, clinical, and psychological characteristics of patients with internal diseases who use relaxation techniques as a coping strategy. DESIGN: Cross-sectional analysis among patients with internal diseases. SETTING: Department of Internal and Integrative Medicine at an academic teaching hospital in Germany. MAIN OUTCOME MEASURES: Prior use of relaxation techniques (e.g. meditation, autogenic training), perceived benefit, and perceived harm. Potential predictors of relaxation techniques use (sociodemographic characteristics, health behavior, internal medicine diagnosis, general health status, mental health, satisfaction, and health locus of control) were tested using multiple logistic regression analysis. RESULTS: Of 2486 participants, 1075 (43.2%) reported to have used relaxation techniques, 648 (60.3%) reported benefits, and 11 (1.0%) reported harms. Use of relaxation techniques was independently associated with female gender (Odds ratio [OR]=1.43; 95% confidence interval [CI]=1.08-1.89), higher education (OR=1.32; 95%CI=1.03 1.71), fibromyalgia (OR=1.78; 95%CI=1.22-2.61), and internal health locus of control (OR=1.27; 95%CI=1.01-1.60). Use of relaxation techniques was negatively associated with age below 30 (OR=0.32; 95%CI=0.20-0.52) or above 64 (OR=0.65; 95%CI=0.49-0.88), full-time employment (OR=0.75; 95%CI=0.57-0.98), current smoking (OR=0.72; 95%CI=0.54-0.95), osteoarthritis (OR=0.51; 95%CI=0.34-0.77), rheumatic arthritis (OR=0.59; 95%CI=0.37-0.93), good to excellent health status (OR=0.70; 95%CI=0.52-0.96), and high life satisfaction (OR=0.78; 95%CI=0.62 0.98). CONCLUSION: In a German sample of patients with internal diseases, relaxation techniques were used as a coping strategy by about 43%. Users were more likely to be middle-aged, female, well-educated, diagnosed with fibromyalgia, not smoking, not full-time employed, and not to have a good health status or high life satisfaction. A high internal health locus of control predicted relaxation techniques use. Considering health locus of control might improve adherence to relaxation techniques in internal medicine patients. PMID- 24050582 TI - Immunomodulatory and therapeutic effects of Hot-nature diet and co-supplemented hemp seed, evening primrose oils intervention in multiple sclerosis patients. AB - BACKGROUND: Multiple sclerosis (MS) is the most chronic and inflammatory disorder. Because of limited efficacy and adverse side effects, identifying novel therapeutic and protective agents is important. This study was aimed to assess the potential therapeutic effects of hemp seed and evening primrose oils as well as Hot-nature dietary intervention on RRMS patients. METHODS AND MATERIALS: In this double blind, randomized trial, 100 MS patients with EDSS<6 were allocated into 3 groups: "Group A" who received co-supplemented hemp seed and evening primrose oils with advised Hot-nature diet, "Group B" who received olive oil, "Group C" who received the co-supplemented oils. Mizadj, clinically EDSS and relapse rate as well as immunological factors (IL-4, IFN-gamma and IL-17) were assessed at baseline and after 6 months. RESULTS: Mean follow-up was 180+/-2.9 SD days (N=65, 23 M and 42 F aged 34.25+/-8.07 years with disease duration 6.80+/ 4.33 years). There was no significant difference in studies parameters at baseline. After 6 months, significant improvements in Mizadj, EDSS and relapse rate were found in the groups A and C, while the group B showed a border significant decrease in relapse rate. Immunological parameters showed improvement in groups A and C, whereas there was worsening condition for group B after the intervention. CONCLUSION: The co-supplemented hemp seed and evening primrose oils with Hot-nature diet have beneficial effects in improving of clinical score in RRMS patients which were confirmed by immunological findings. PMID- 24050584 TI - Public perceptions of the risks, benefits and use of natural remedies, pharmaceutical medicines and personalised medicines. AB - OBJECTIVE: To investigate public perceptions of the benefits, risks and use of a natural remedy, a pharmaceutical medicine and a personalised medicine, tailored to a person's genetic-makeup, to treat illness. DESIGN AND OUTCOME MEASURES: In a case-based scenario, groups of participants individually rated the three different treatments of an illness in terms of their perceived benefits, risks and willingness to use, and completed a questionnaire on beliefs about medicines in general. RESULTS: Our study (n=158 adults) revealed a similar perception of a pharmaceutical medicine and a personalised medicine relative to a natural remedy. Contrary to expectation, personalised medicine was rated as no more beneficial and no less risky than a pharmaceutical medicine and was less likely to be used. However, willingness to use each medicine was differentially predicted by general beliefs about medicine. Avoidance of harm predicted willingness to use a natural remedy whereas the beneficial effects of medicines predicted use of a personalised medicine. By contrast, willingness to use a pharmaceutical medicine was predicted by a trade-off between perceived harm, risk of overuse and benefit. CONCLUSION: Personalised medicine, in the form of a pharmacogenetic approach, has the potential to improve drug efficacy and reduce adverse drug reactions but remains closely allied to public perceptions of pharmaceutical medicine. Nonetheless our data indicate some differentiation with respect to background beliefs on the beneficial effects of personalised medicine. PMID- 24050585 TI - The value of complementary and alternative medicine in the treatment of climacteric symptoms: results of a survey among German gynecologists. AB - OBJECTIVES: The present study aims to detect the attitude and experience towards complementary and alternative medicine (CAM) in the treatment of climacteric disorders among gynecologists in Germany. STUDY DESIGN: A self-administered questionnaire, containing 15 questions, was sent to all gynecologists in private practice in Germany (n=9589). MAIN OUTCOME MEASURES: Gynecologists were asked about their experience with several forms of CAM. They were asked to rate different procedures as "effective", "sometimes effective" or "unimportant". RESULTS: The response rate was 33.7% (n=3227). We report on 2549 (26.6%) eligible questionnaires. Well-known therapies were black cohosh (Cimicifuga racemosa), chaste tree (Vitex agnus castus) and St. John's wort. More than 98% had had experiences with these therapies. Fewer experiences were stated with hormone-yoga (42.9%), acupuncture (29.1%) and homeopathy (21.6%). The most effective alternative therapy rated was an alteration of lifestyle with 54.4% (n=1325) stating it was effective and 35.7% (n=871) stating it was sometimes effective. Only 3.9% (n=96) prescribed no efficacy to a change of lifestyle. Other treatments rated as effective were St. John's wort (25.0%, n=606) and Black cohosh (21.1%, n=527). Agents regarded most ineffective were hormone-yoga (4.7%, n=109), acupuncture (10.3%, n=243) and homeopathy (10.6%, n=250). Female gynecologists were more likely to vote for a therapy to be effective compared to their male colleagues. CONCLUSIONS: German gynecologists seem to have made positive experiences with CAM when observing their patients, in general. An alteration of lifestyle is seen as the most effective alternative therapy in menopause. Due to their widespread use, possible side effect of natural agents should be excluded. PMID- 24050586 TI - Use of complementary and alternative medicine for children: a parents' perspective. AB - OBJECTIVES: The present study aims to detect the frequency and types of complementary and alternative medicine (CAM) therapies used for children and to explore parental motivating factors for using CAM for their children in Riyadh, Saudi Arabia. PARTICIPANTS AND METHODS: This is a cross-sectional study that involved 462 families selected through a multistage cluster-sampling technique covering Riyadh region, Saudi Arabia. The sample was selected from 40 clusters, distributed proportionally according to the size of the population in the catchment area of primary health care centres (PHCCs). A structured questionnaire that contains items fulfilling the research objectives was used to collect data by research assistants. RESULTS: The study included 926 parents, comprising 351 fathers and 575 mothers; 37.3% of them reported the use of CAM for their children including reciting the Quran, honey and Ferula asafoetida (26.1%, 21.5% and 18.8%, respectively). CAM was used six times higher for children of parents using CAM for themselves than children of parents who did not use CAM themselves (odds ratio (OR)=6.03, 3.9-9.37). Multivariate logistic regression showed that parental use of CAM (OR=3.0, 2.2-4.0), keeping CAM remedies at home (OR=2.3, 1.8-3.1), perceived success of CAM in practice (OR=1.8, 1.3-2.4) and preference of use of natural materials (OR=1.7, 1.2-2.5) were independent predictors of use of CAM for children. CONCLUSIONS: In this study, around one-third of the parents used CAM for their children. Quran (Muslims' holy book) was the most common CAM type used for children. Parents' use of CAM for themselves is the most important predictor of its use for children. An in-depth study to investigate CAM use for specific diseases in children is recommended. PMID- 24050587 TI - Examining CAM use disclosure using the Behavioral Model of Health Services Use. AB - OBJECTIVES: To improve understanding of factors that may influence disclosure of complementary and alternative medicine (CAM) use in the U.S. DESIGN: Cross sectional survey. METHODS: Data are from the 2001 Health Care Quality Survey (HCQS), a nationally representative study of adults aged 18 and older living in the continental United States. Using the Behavioral Model of Health Services Use, we conducted multivariate logistic regressions to identify factors associated with disclosing CAM use among the sub-sample of recent CAM users (n=1995). MAIN OUTCOME MEASURE: Disclosure of CAM use. RESULTS: Most CAM users (71.0%) disclosed their use of CAM to their doctors. Contextual, individual, and health behavior factors were associated with CAM use disclosure. Of particular interest, disclosure was significantly more likely among those who perceived high quality relationships with their providers (AOR=1.59, CI: 1.01, 2.49) and among those who had a regular source of medical care (AOR=1.54, CI: 1.03, 2.29). The odds of disclosure were also higher among those who used practitioner-provided CAM, with (AOR=2.02, CI: 1.34, 3.06) or without (AOR=1.52, CI: 1.05, 2.20) concurrent herbal medicine use, compared to those who used herbal medicines only. CONCLUSIONS: The Behavioral Model of Health Services Use is a useful framework for examining factors that may influence disclosure of CAM use. Further research should examine these relationships using more comprehensive measures. PMID- 24050588 TI - A novel taping therapy for chronic insomnia: a report on two cases. AB - OBJECTIVES: Here, we report two cases of chronic insomnia treated satisfactorily by re-using of patients' bioelectricity. PATIENTS: First was a 46 years old male who had taken drugs for several years and depression drug for one year. He had heart beat and felt pressure pain on almost of chest. Second was a 64 years old male who had taken drugs for one year. In spite of the medication, he could not sleep at all and had glint eyes. INTERVENTIONS: Method of treatment is to put the medical tape (Chimsband) on acupoints and pressure pain points in the chest, which can be traced down by finger pressing examination. RESULTS: In the first case, the patient escaped from the medications after three weeks. Following seven weeks, depression was reduced remarkably. In the second case, the glint of eyes returned to normal after two treatments. After three treatments, the sleeping time was lengthened to 4h. CONCLUSIONS: First, pressing chest can be used for tracing neurological symptoms; second, when the bioelectricity of the patient reacts to Chimsband, the symptoms could be ameliorated; third, there is a relationship between treating the neurological symptoms such as insomnia and attenuating pressure pain. PMID- 24050589 TI - Three cases of atopic dermatitis in pregnant women successfully treated with Korean medicine. AB - BACKGROUND: Korean medicine (KM) is used in many patients with atopic dermatitis (AD), which is commonly aggravated during pregnancy. However, to date, no previous studies have reported the safety and efficacy of complementary and alternative medicine (CAM) therapy for pregnant patients with AD and their fetus in clinical practice. SUBJECTS: Three pregnant women were suffering from AD that first appeared or was aggravated during pregnancy. They would not have received conventional treatments for AD during their pregnancy. INTERVENTIONS AND OUTCOME MEASURES: They were treated with KM, including acupuncture, herbal medicine, and herbal wet dressing. The severity of AD was assessed with the SCORAD (Severity Scoring Atopic Dermatitis) index. Liver and renal function tests were performed. We noted adverse events on maternity, fetus or neonate and evaluated the side effects of KM therapy. RESULTS: AD symptoms improved after treatment. There was no hepatic or renal toxicity, nor were there any adverse maternal, fetal or neonatal effects. CONCLUSIONS: This study is meaningful as the first case series of AD in pregnant women successfully treated with KM therapy including herbal medicine, acupuncture, and herbal wet dressings. PMID- 24050590 TI - Use of unconventional therapies by primary care patients--religious resources vs. complementary or alternative medicine services. AB - OBJECTIVES: The study examines the difference in characteristics between primary care patients who turn to "religious resources for medical purposes" (RRMP) and those who turn to "complementary or alternative medicine" (CAM) services to cope with a physical or mental health problem. DESIGN AND SETTING: Data were collected from eight primary care clinics in Israel and included 905 Jewish patients aged 25-75. MAIN OUTCOME MEASURE: A self-report questionnaire with a battery of validated mental health assessment instruments and two questionnaires regarding use of unconventional therapies (RRMP and CAM services) were administered to the participants. The association of various variables with type of 'service use' was examined through logistic regression analysis. RESULTS: Primary care patients suffering from emotional problems have a propensity to utilize unconventional therapies in addition to conventional medical treatment. However, differences exist between patients who turn to RRMP and to CAM. The risk factors for turning to RRMP are North African, Middle Eastern or Israeli origin, low SES, religious observance, and high use of primary care clinics. For using CAM services the risk factor is high SES. CONCLUSIONS: In the present study, a quarter of primary care patients also use additional resources for their medical problems. While all segments of the population use unconventional resources, our study reveals that two types of unconventional therapies - RRMP and CAM - tend to be used by two different population sectors. It is noteworthy that those suffering from mental health problems are more likely to utilize unconventional resources. PMID- 24050591 TI - Alternative therapy for persistent childhood immune thrombocytopenic purpura unresponsive to intravenous immunoglobulin. AB - OBJECTIVE: Presentation of a case illustrating the benefits of traditional Chinese herbal granules for treatment of immune thrombocytopenic purpura in children. CLINICAL FEATURES: A 4-year-old girl presented with persistent immune thrombocytopenic purpura refractory to the first-line conventional treatment of steroids and intravenous immunoglobulin over 7 months. She was brought to the traditional Chinese medical clinic at the Chang Gung Memorial Hospital in 2011 for alternative therapy. She received a modified Chinese herbal formula, Zi-Ying Jiang-Huo-Tang (Phellodendri Combination), for 6 months and was followed clinically by both a pediatrician and a traditional Chinese medical doctor. The patient had a dramatic improvement in platelet count and entered complete remission after treatment with the traditional Chinese medicine. There was no recurrence of disease or side effects of treatment noted during the 12-month follow-up period. CONCLUSIONS: Our case report suggests that collaborative monitoring of treatments with traditional Chinese medicine may prove beneficial in the management of childhood persistent immune thrombocytopenic purpura. A larger clinical study is warranted for further evaluation of the role of Zi-Ying Jiang-Huo-Tang in treating immune thrombocytopenic purpura. PMID- 24050592 TI - The effect of complementary therapies on post-operative pain control in ambulatory knee surgery: a systematic review. AB - Ambulatory knee surgery is a common procedure with over 100,000 knee arthroscopies performed in the U.K. in 2010-2011. Pain after surgery can decrease patient satisfaction, delay discharge, and decrease cost effectiveness. Multi modal therapies, including complementary therapies, to improve pain control after surgery have been recommended. However, a comprehensive review of the literature regarding the use of complementary therapies to enhance pain control after ambulatory knee surgery is lacking, and this article aims to address this deficit. CINHAL, EMBASE, MEDLINE, AMED and CENTRAL databases were searched. Only Randomised Controlled Trials were included. All eligible papers were quality assessed using the Jadad system, and data was extracted using piloted forms. Two independent reviewers performed each stage of the review. Full details of the study methodology can be found on Prospero, a systematic review register. Five studies satisfied our eligibility criteria: three reporting on acupuncture, one on homeopathy, and one on acupoints. Acupoint pressure was the only study that demonstrated reduced pain compared with placebo. This study was the least methodologically robust. Arnica, although demonstrating a significant reduction in swelling, did not affect post-operative pain. Acupuncture did not affect post operative pain; however, a reduction in ibuprofen use was demonstrated in two studies. Before recommending complementary therapy for routine use in ambulatory knee surgery, further work is required. Two areas of future research likely to bear fruit are demonstrating robust evidence for the effect of acupoint pressure on post-operative pain, and quantifying the positive effect of homeopathic arnica on post-operative swelling. PMID- 24050593 TI - Acupuncture for lumbar spinal stenosis: a systematic review and meta-analysis. AB - OBJECTIVES: Lumbar spinal stenosis (LSS) negatively affects patients' quality of life. No systematic review evaluating the effects and safety of acupuncture for this population is available. We aimed to evaluate evidence indicating the effectiveness and safety of acupuncture for LSS. METHODS: We searched five English-language databases (EMBASE, MEDLINE, CENTRAL, CINAHL, and AMED) and one Chinese database (CAJ) for randomised controlled trials (RCTs) and non-randomised controlled clinical trials (CCTs) of needle acupuncture for LSS. CCTs were analyzed only in terms of safety and intervention-related information. RESULTS: Six RCTs (n=582) and six CCTs, which were all from China and reported in Chinese, were included. High or uncertain risk of bias and clinical heterogeneity due to different acupuncture techniques were observed. All RCTs compared different combinations or techniques of acupuncture. None of the included studies mentioned safety issues. Acupuncture combined with other interventions and/or with additional stimulation increased the number of improved patients compared with acupuncture alone or relatively simpler stimulation (n=582; relative risk, 1.16; 95% confidence interval 1.08-1.25). Pain intensity, overall symptoms, and functional outcomes related to LSS and quality of life showed significantly favourable improvement in the treatment group compared with the control group, which lasted for up to 6 months post-treatment. CONCLUSIONS: We found no conclusive evidence of the effectiveness and safety of acupuncture for LSS because of high or uncertain risk of bias and the limited generalisability of the included studies. Future trials using rigorous methodology, appropriate comparisons and clinically relevant outcomes should be conducted. PMID- 24050594 TI - An overview of the evidences of herbals for smoking cessation. AB - BACKGROUND: Despite availability of several therapeutic options for smoking cessation, their usages are limited due to high cost and adverse effect profiles. Recently, more attention has been paid to investigating herbals for smoking cessation. OBJECTIVES: To review relevant evidences on the efficacy and safety of herbals for smoking cessation. METHODS: We searched clinical studies evaluating herbals use for smoking cessation from Medline, EMBASE, CINAHL, Cochrane CENTRAL, PsychINFO, AMED, WHO Trial registry, Thai dissertation database, and other databases from its inception to October 2012. Studies are restricted to only English or Thai. RESULTS: A total of 7 studies met inclusion criteria; 6 studies were randomized trial (RCT) evaluating variety of herbals. Three RCTs evaluated oral St. John's wort (SJW) extract (N=289), 2 RCTs evaluated oral mix-herbal tea (N=164), and 1 RCT evaluated inhaled aromatic black pepper (N=48). The other study was a non-randomized controlled trial evaluating oral SJW extract among 24 smokers. All interventions were given in a range of 1 week before starting the study and continued up to 14 weeks. Smoking cessation was measured with various methods including the number of cigarettes per day, abstinence rate, expired CO level, and urine cotinine level. Follow-up duration ranged from 3-h session to 6 months period. Evidences of SJW indicated low percentage in abstinence rate for smoking and its effectiveness was not significantly different from placebo. Studies of mix herbal tea showed a statistically significant effectiveness, compared to placebo, in reducing the number of cigarettes per day, craving scale, and total withdrawal scale but not urinary cotinine excretion. Essential oil of black pepper with a hollow plastic tube significantly reduced craving at 3-h session. CONCLUSION: Evidence supporting the role of complementary medicines as an anti-smoking is limited. Further research in this field would benefit from the standardization of herbals products to implement on standard interventions and outcome measurement for smoking cessation. PMID- 24050595 TI - Characterization of complexes of nucleoside-5'-phosphorothioate analogues with zinc ions. AB - On the basis of the high affinity of Zn(2+) to sulfur and imidazole, we targeted nucleotides such as GDP-beta-S, ADP-beta-S, and AP3(beta-S)A, as potential biocompatible Zn(2+)-chelators. The thiophosphate moiety enhanced the stability of the Zn(2+)-nucleotide complex by about 0.7 log units. ATP-alpha,beta-CH2-gamma S formed the most stable Zn(2+)-complex studied here, log K 6.50, being ~0.8 and ~1.1 log units more stable than ATP-gamma-S-Zn(2+) and ATP-Zn(2+) complexes, and was the major species, 84%, under physiological pH. Guanine nucleotides Zn(2+) complexes were more stable by 0.3-0.4 log units than the corresponding adenine nucleotide complexes. Likewise, AP3(beta-S)A-zinc complex was ~0.5 log units more stable than AP3A complex. (1)H- and (31)P NMR monitored Zn(2+) titration showed that Zn(2+) coordinates with the purine nucleotide N7-nitrogen atom, the terminal phosphate, and the adjacent phosphate. In conclusion, replacement of a terminal phosphate by a thiophosphate group resulted in decrease of the acidity of the phosphate moiety by approximately one log unit, and increase of stability of Zn(2+)-complexes of the latter analogues by up to 0.7 log units. A terminal phosphorothioate contributed more to the stability of nucleotide-Zn(2+) complexes than a bridging phosphorothioate. PMID- 24050596 TI - Decision aids for breast cancer chemoprevention. AB - The article by Korfage and colleagues in this issue of Breast Cancer Research highlights the importance of enabling women to make informed choices about breast cancer chemoprevention. Decision aids have the potential to improve knowledge and decision-making in this context, but they do not guarantee increased uptake of chemoprevention amongst high-risk women if this option is inconsistent with women's values. Important avenues for further research in this area include evaluating: decision aids with explicit values clarification exercises and with comparison between chemoprevention and nonpharmacological options to reduce breast cancer risk, the influence of mediating factors such as anxiety and risk perception, and the role of clinicians and family members in decision-making. PMID- 24050597 TI - Fast estimation of adsorption isotherm parameters in gradient elution preparative liquid chromatography II: the competitive case. AB - Experimental competitive adsorption isotherms were successfully determined directly from overloaded elution profiles in gradient elution mode using an extended inverse method. This approach differs from the existing methods in one important aspect - no isocratic experiments are necessary which makes it possible to study adsorption of substances whose retention factors vary strongly with the mobile-phase composition. The approach was verified with simulated binary data and with experimental data from gradient separations of a cyclohexanone/cycloheptanone mixture. For the synthetic data, the original adsorption isotherm parameters were found using a two-step estimation procedure. In the first step analytical peaks were used to estimate the "analytical" part of the Langmuir equation and in the second step the association equilibrium parameters were estimated from two simulated overloaded elution profiles. For the experimental data, a three-step approach was used. The two first steps were used to reduce the calculation time so that parameter estimation could be performed on an ordinary computer. In the first step, analytical peaks were used to estimate the "analytical" part of the bi-Langmuir equation. In the second step, initial guesses for all other parameters were determined separately for each solute using the faster Rouchon algorithm. In the final and third step, the more accurate orthogonal collocation on finite elements algorithm, was used to fine-tune the isotherm parameters. The model could accurately predict the shape of overloaded elution profiles. The shape of the adsorption isotherms agreed well with those determined with the standard isocratic method, although the numerical values were not the same. The extended inverse method is well suited for process optimization where few experiments and accurate predictions are important. PMID- 24050598 TI - Effect of parallel segmented flow chromatography on the height equivalent to a theoretical plate II - performances of 4.6mm*30mm columns packed with 2.6MUm Accucore-C18 superficially porous particles. AB - The reduced trans-column (or long-range eddy dispersion) height equivalent to a theoretical plate (HETP) of short and wide 4.6mm*30mm columns packed with 2.6MUm Accucore-C18 superficially porous particles was measured under conventional (no split flow) and parallel segmented (outlet and inlet) flow chromatography. The overall reduced HETP was derived from the true moments of the recorded concentration profiles. The longitudinal diffusion HETP term was measured at a very small flow rate (0.05mL/min). The solid-liquid mass transfer resistance was derived from the shell diffusivity, using the composite Garnett-Torquato model of effective diffusion in a heterogeneous system made of a dense packing of core shell particles immersed in a continuous matrix (the eluent). The trans-channel and short-range interchannel eddy dispersion HETP terms were assumed to be equal to the calculated h data after solving the Navier-Stokes equation and simulating the advection-diffusion transport process. Experimental results confirmed that the optimum efficiency of these short columns was increased by a factor of about two. The ratio of the detection sensitivities on the PSFC stream and on a regular stream increased from 1 to 1.45 when the retention factor decreases from about 10 to 0.5. These phenomena are due to a strong reduction of the trans-column eddy dispersion HETP term. The system loses about 60% of the sample mass when only outlet skimming is carried out when the flow rate ratio of 55% is applied, as was done in this work. It loses about 50% of the sample when inlet/outlet segmentation is applied. In gradient elution, the peak capacity is increased by only 15%, due to post-column band spreading, which should imperatively be minimized when the outlet flow is split. PMID- 24050600 TI - Everolimus: a new hope for patients with breast cancer. AB - BACKGROUND: Breast cancer cells can develop resistance to standard hormonal treatment and chemotherapy with the activation of the mTOR pathway; this is supported by results of preclinical and clinical studies. In clinical trials, the addition of everolimus to hormonal treatment or anti-HER2 treatment improved the outcomes of breast cancer patients. The aim of this review is to discuss the efficacy and safety data of everolimus in all categories of breast cancer in recent published studies. SCOPE: Everolimus showed positive results in clinical studies. A literature search was made from PubMed, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts by using the following search key words: 'everolimus', 'RAD001', 'mTOR inhibitor', 'breast cancer' 'endocrine therapy resistance' and 'HER-2 targeted therapies'. The last search was on June 10, 2013. The most important limitation of our review is that most of the data on everolimus rely on phase I and II trials. FINDINGS: Preclinical studies showed that mTOR activation can be the responsible mechanism in all subgroups of breast cancer. Results of both the TAMRAD and BOLERO-2 studies have showed that mTOR inhibition in combination with endocrine therapy can be a new treatment strategy for MBC patients who are resistant to aromatase inhibitors. In the BOLERO-2 study, time to deterioration in health-related quality of life was also significantly higher in the everolimus and exemestane arm compared to the exemestane plus placebo arm. The recently completed BOLERO-3 study showed that mTOR inhibition in combination with trastuzumab plus vinorelbine treatment significantly improved PFS compared to trastuzumab plus vinorelbine alone in trastuzumab-resistant MBC patients. CONCLUSION: Recent trials have shown that everolimus has produced promising anti-tumor activity in combination with trastuzumab in HER2-positive metastatic breast cancer and in combination with exemestane in patients with hormone-receptor-positive metastatic breast cancer who had recurrence or progression while receiving a nonsteroidal aromatase inhibitor. Results of ongoing studies with everolimus show evidence that using everolimus in earlier stages of the disease, namely in the adjuvant and neoadjuvant settings, could be benefical. PMID- 24050601 TI - Autobiographical memory in children with temporal lobe epilepsy. AB - Autobiographical memory involves the recall of personal facts (semantic memory) and re-experiencing of specific personal events (episodic memory). Although impairments in autobiographical memory have been found in adults with unilateral temporal lobe epilepsy (TLE) and attributed to compromised hippocampal integrity, it is not yet known whether this occurs in children with TLE. In the current study, 21 children with TLE and 24 healthy controls of comparable age, sex, and socioeconomic status were administered the Children's Autobiographical Interview. Compared to controls, children with TLE recalled fewer episodic details, but only when no retrieval prompts were provided. There was no difference between the groups for semantic autobiographic details. Interestingly, the number of episodic details recalled increased significantly from 6 to 16 years of age in healthy control children, but not in children with TLE. Exploratory analyses revealed that, within the group of children with TLE, epilepsy factors, including presence or absence of structural hippocampal abnormalities, did not relate to the richness of episodic recall. Our results provide first evidence of autobiographical episodic memory deficits in children with TLE. PMID- 24050602 TI - Limitations of lumbar spine MRI in the diagnosis of ankylosing spondylitis. AB - OBJECTIVES: To assess the value of inflammatory and fatty lesions in the lumbar spine on magnetic resonance imaging (MRI) in differentiating ankylosing spondylitis (AS) from non-inflammatory chronic back pain. METHODS: We reviewed the lumbar spine MR images of 192 consecutive AS patients and 208 non-AS subjects with non-inflammatory chronic back pain. Lesions including vertebral corner inflammatory lesions (CIL), inflammation in posterior elements (PE) of the spine, and fatty deposition lesions (FDL) seen on lumbar spine MRI were scored in a blinded manner. RESULTS: The frequencies of CIL and FDL in AS patients were higher than that in non-AS patients (both p<0.01), but there was no significant difference in the positive rate of inflammation in PE of the spine between two groups. AS patients had higher scores of all three types of lesions than non-AS patients (all p<0.01). Positive likelihood ratio increased as the cut-off score for distinguishing AS from other diseases increased (ranged from 1.14 to 18.42). But the biggest value of area under the receiver operating characteristic curve of all types of lesions was only 62.58%. We also summarised some features of these lesions that may help to distinguish AS from non-inflammatory chronic back pain. CONCLUSIONS: Our study found that the value of inflammatory and fatty lesions (including CIL, inflammation in PE and FDL) seen on lumbar spine MRI in the diagnosis of AS was limited. But the diagnosis of AS would be more convincing if patients had high scores of these three types of lesions (CIL >=16, and/or inflammation in PE of the spine >=5, and/or FDL >=2). PMID- 24050603 TI - The role of B vitamins in marine biogeochemistry. AB - The soluble B vitamins (B1, B7, and B12) have long been recognized as playing a central metabolic role in marine phytoplankton and bacteria; however, the importance of these organic external metabolites in marine ecology has been largely disregarded, as most research has focused on inorganic nutrients and trace metals. Using recently available genomic data combined with culture-based surveys of vitamin auxotrophy (i.e., vitamin requirements), we show that this auxotrophy is widespread in the marine environment and occurs in both autotrophs and heterotrophs residing in oligotrophic and eutrophic environments. Our analysis shows that vitamins originate from the activities of some bacteria and algae and that taxonomic changes observed in marine phytoplankton communities could be the result of their specific vitamin requirements and/or vitamin availability. Dissolved vitamin concentration measurements show that large areas of the world ocean are devoid of B vitamins, suggesting that vitamin limitation could be important for the efficiency of carbon and nitrogen fixation in those regions. PMID- 24050604 TI - Copper redox transformation and complexation by reduced and oxidized soil humic Acid. 2. Potentiometric titrations and dialysis cell experiments. AB - Cation binding and electron transfer reactions of humic substances determine copper speciation in redox-dynamic systems, but quantitative studies for Cu+ binding to humic substances are lacking. We investigated reduction of Cu2+ and binding of Cu+ at pH 7.0 in a dialysis cell experiment using reduced and reoxidized soil humic acid (HA) as reductant and sorbent at copper loadings of 9.5-600 mmol kg(-1). The data were used to quantitatively explain the interaction between cation binding and electron transfer processes that determine copper speciation in the presence of HA under anoxic and oxic conditions. Addition of Cu2+ to reduced HA resulted in almost complete reduction to Cu(I) within 1 h. Reduction was also significant under oxic conditions. The slow decrease of the Cu(I) fraction was attributed to formation of Cu(0) based on thermodynamic consideration. Cu+ binding to HA was found to be strong compared to other chalcophile cations like Ag+ or Cd2+. Our results indicate that Cu+ and Cu2+ isotherms exhibit a redox potential-dependent intersection point. According to the differences in Cu+ and Cu2+ binding, the presence of HA was found to extend the stability field of Cu(II) to moderately reducing conditions and to reduce the stability field of Cu(0) due to the formation of Cu(I) complexes. PMID- 24050605 TI - Palladium-catalyzed asymmetric addition of diarylphosphines to alpha,beta unsaturated sulfonic esters for the synthesis of chiral phosphine sulfonate compounds. AB - Highly stereoselective addition of diarylphosphines to alpha,beta-unsaturated sulfonic esters catalyzed through a PCP pincer-Pd complex is developed to synthesize chiral phosphine sulfonic esters with excellent enantioselectivity (up to 99.5% ee). The transformation of the chiral adduct into a useful palladium phosphine sulfonate complex is also demonstrated. PMID- 24050606 TI - [Cervical spine instability in the surgical patient]. AB - Many congenital and acquired diseases, including trauma, may result in cervical spine instability. Given that airway management is closely related to the movement of the cervical spine, it is important that the anesthesiologist has detailed knowledge of the anatomy, the mechanisms of cervical spine instability, and of the effects that the different airway maneuvers have on the cervical spine. We first review the normal anatomy and biomechanics of the cervical spine in the context of airway management and the concept of cervical spine instability. In the second part, we review the protocols for the management of cervical spine instability in trauma victims and some of the airway management options for these patients. PMID- 24050607 TI - [Contribution of neuromonitoring to the safety of tracheal extubation after total thyroidectomy. Prospective study with needle electrodes]. AB - INTRODUCTION AND OBJECTIVES: Bilateral laryngeal paralysis cause serious respiratory complications. In thyroid surgery, neuromonitoring helps in identifying the recurrent laryngeal nerve, reports on its functioning at the end of surgery, supports decision making, and may reduce the risk of bilateral paralysis. Our objective was to estimate the influence of neuromonitoring in operative strategy and extubation safety in total thyroidectomy. METHODS: A non randomized prospective study was conducted on 210 patients undergoing total thyroidectomy (420 laryngeal nerves stimulated included). We collected qualitative neuromonitoring variables (presence or absence of final signal after stimulation of the vagus nerve), and postoperative indirect laryngoscopy (normal motility or paralysis), performed until 3rd day after the surgery. RESULTS: The accuracy of the test was 99.5% (95% CI 98.3 to 99.9). The positive predictive value was 100% (95% CI 99.1 to 100), which showed the high ability of neuromonitoring to predict paralysis in case of loss of signal, and the negative predictive value was 99.5% (95% CI 98.3 to 99.9), which indicated its predictive capacity for normal motility when there is a normal signal. CONCLUSIONS: In our group of patients, recurrent laryngeal nerve monitoring was useful in total thyroidectomy as it provided information on the prognosis of laryngeal motility, and helped in making decisions during surgery when there was signal loss. Due to the risk of serious respiratory complications due to bilateral recurrent laryngeal nerve paralysis, we opted for the performing of the 2-stage total thyroidectomy in case of signal loss in the first lobectomy. Thereby, neuromonitoring contributed to the safety of the airway in tracheal extubation, aiding in the prevention of a possible bilateral laryngeal paralysis. PMID- 24050608 TI - Parent intention to use a patient portal as related to their children following a facilitated demonstration. AB - OBJECTIVE: To describe parent feedback and intention to use the patient portal related to their children's health records after a facilitated learning session. Patient portals are Internet-based, self-service models for health account information and records that allow patients or parents to be more proactive in their healthcare. MATERIALS AND METHODS: A navigator demonstrated the patient portal to parents using on-site kiosks at a pediatric clinic. Parents >=18 years of age completed an institutional review board-approved survey. RESULTS: Of those approached, 171 (54%) parents participated in the demonstration; 64 (37%) completed surveys. Average age was 28 years (standard deviation 7), and most were white (26, 40%) or Hispanic (14, 22%). Most (46, 72%) did not know about the patient portal prior to demonstration; of those who did, only five (28%) had used it. Following demonstration, the majority (59, 92%) thought the patient portal was easy to use. Parents planned to view medical records and laboratory results but disliked having separate accounts for each child and the lack of a "symptom checker." Many (44, 69%) planned for future use. The majority (62, 97%) found the navigator helpful, and (37, 58%) wanted access to the patient portal via on-site kiosks. CONCLUSIONS: Although most parents had no prior experience with the patient portal, they were satisfied overall with ease of use and offered features. Clinics should consider (1) hands-on demonstrations of the patient portal to encourage understanding and use and (2) alternative access venues if home computers are not available. PMID- 24050609 TI - Walk-in telemental health clinics improve access and efficiency: a 2-year follow up analysis. AB - INTRODUCTION: Telemedicine has demonstrated potential to improve access and quality of mental health services in underserved areas. Use of telemedicine to deliver health services may enable a range of synergistic innovations in care practices, but such innovations will require rigorous evaluation. MATERIALS AND METHODS: We evaluated a telemental health program designed to increase access by eliminating clinician travel time in a multisite rural community mental health center. The program included both traditionally scheduled and "open scheduled" clinics provided via telemedicine. An initial 13-month evaluation showed better access, quality, and sustainability compared with similar services delivered using traditional methods available elsewhere within the organization. A 24-month follow-up analysis was undertaken to determine if initial findings remained consistent. RESULTS: Telemedicine clinics continued to show remarkably consistent advantages in both access and quality compared with traditional services. Cost efficiency gains were also robust, maintaining a 20-percentage-point advantage in conversion of scheduled time to billable time over traditional clinics. Much of this advantage was attributable to the 20% of clinic volume that was open scheduled or "walk-in" in nature. CONCLUSIONS: This study confirms earlier findings that telemedicine technology can support synergistic innovations in service format (such as "open scheduling") and maintain measurable advantages in access and quality along with cost-efficiencies past the initial implementation period. PMID- 24050610 TI - M-HELP: a miniaturized total health examination system launched on a mobile phone platform. AB - BACKGROUND: A timely health examination is of great significance for incipient disease detection and prevention. However, conventional examinations generally rely heavily on bulky and expensive instrumentation, which is not easily available. To address technical barriers, an innovative, highly miniaturized, and integrated health examination system-Mobile Health Examination Launched on the Phone (M-HELP)-was developed. MATERIALS AND METHODS: Based on the design of a multifunctional Android(r) (Google, Mountain View, CA) application and the development of different wireless biomedical sensor modules, a mobile phone was incorporated into a central terminal for personal health examination. More than 12 parameters, including electrocardiogram, heart sound, and eye test, as well as others, covered the majority of the crucial parameters in a total health examination and have been successfully established and incorporated into the system. Unlike the conventional examination, the M-HELP system could generate electronic health records and send them to physicians via e-mails or multimedia messages. This significantly simplifies the general health examination with much lower cost and fewer temporal and spatial restrictions. RESULTS: For proof of concept, a bench-scale test recruiting 11 volunteer subjects showed that the average time spent on a total health examination with M-HELP system was about 28 min. CONCLUSIONS: This article clarifies the basic concept of a total health examination on the platform of a mobile phone, demonstrates the basic features of the M-HELP system with group tests, and suggests the practical future application of the new system and the scientific issues thus raised. PMID- 24050611 TI - Meeting the continuing education needs of rural mental health providers. AB - BACKGROUND: Historically, mental health clinicians at Department of Veterans Affairs (VA) community-based outpatient clinics (CBOCs) have not had the same access to continuing education (CE) as providers at VA medical centers. Mental health clinicians at CBOCs desire an opportunity for VA-sponsored CE, especially on topics and issues pertinent to rural mental healthcare. MATERIALS AND METHODS: Since November 2011, VA CBOC mental health providers in 11 states have been offered a monthly live Web conferencing CE program. This article describes the program's development, implementation, and evaluation. RESULTS: Eleven CE programs have been offered to 397 unique participants. Participants have provided positive feedback about the topics and their impact on job performance. Most negative feedback has been related to technical and logistical problems with the Web conferencing platform. Although providers asked for reportable CE units for licensure, many did not complete the post-test, which is required to receive credit for completing the course. CONCLUSIONS: The Web conferencing format has been well received by participants. Despite technical issues, results show that the participants were satisfied with the content of the trainings and could apply the materials to their job. Although CE units were available, not all participants applied for credit. Efforts to improve technical support and the rate of post-test completion are discussed. Rural mental health providers often have limited access to training opportunities. The VA CBOC Mental Health Rounds, using an interactive Web conferencing platform, has been a successful modality for delivering CE to rural clinicians in the United States. PMID- 24050612 TI - E-learning still increasing--the proportion of Welsh medical students using external Web sites to learn. PMID- 24050613 TI - Accreditation of e-learning. PMID- 24050614 TI - Medication reminder service for mobile phones: an open feasibility study in patients with Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder in which drug dosing regimens become increasingly complicated with the progression of the disease. This poses a significant risk of nonadherence to drug dosing and a failure in treatment response. We hypothesized that a medication reminder delivered by short message service (SMS) could be one way to ameliorate the problem of medication errors. We conducted an open feasibility study in 50 patients with advanced PD. The subjects set up the process to receive reminders by a Web tool, after which they started to receive automatically transmitted text messages as a medication reminder for 4 weeks. In total, 35 of 50 subjects (70.0%) were able to set up the reminder system without any help. The majority (69%) of the subjects rated the set-up process as "very easy" or "easy." Almost all (41 subjects, 91%) felt that SMS reminders worked well for them, and only 4 subjects (9%) felt that SMS texts were totally valueless. Almost half of the subjects (22 of 45, 49%) considered that there were clear benefits, and an additional 17 subjects (38%) enjoyed some benefits in using the medication reminder system. Our results indicate that an SMS medication reminder system is a feasible method, even in subjects with advanced PD. PMID- 24050615 TI - Utilization of the American Telemedicine Association's clinical practice guidelines. AB - BACKGROUND: The American Telemedicine Association (ATA) Standards and Guidelines Committee develops practice standards and guidelines. Key to the Committee's mission is dissemination so the standards can be used in the practice of telemedicine. Over a 2-year period, when a standards document was accessed from the ATA Web site, a short survey was completed, but it did not assess how the documents were used once downloaded. A more formal survey was conducted to determine the impact ATA standards and guidelines are having on healthcare delivery via telemedicine. MATERIALS AND METHODS: A survey was developed and distributed via SurveyMonkey to 13,177 ATA members and nonmembers in November 2011. Results were compiled and analyzed after a 90-day open period for responses to be submitted. RESULTS: The majority of respondents (96%) believe the practice of telemedicine/telehealth should have standards and guidelines and that the ATA and other professional societies/associations should be responsible for developing them. The top uses of guidelines include guidance for clinical practice, training, gaining reimbursement, and research. Respondents indicating a need for standards and guidelines said the ATA (78.7%) and other professional societies/associations (74.5%) should be responsible for development. When asked to list specific practice guidelines or standards they are using for telehealth, the majority (21.5%) are using in-house (e.g., hospital, company)-developed guidelines, followed by those from professional associations/societies (20.4%) and those developed by the ATA (18.2%). CONCLUSIONS: Overall, the survey results indicate guidelines documents developed by the ATA and other professional societies and those developed in-house are being regularly accessed and used in both public and private sectors. Practitioners of telemedicine believe that standards and guidelines are needed for guidance for clinical practice, training, gaining reimbursement, and research, and they are to use those developed by professional organization such as the ATA as well as those developed by their own institutions. PMID- 24050618 TI - Photocatalytic monofluorination of benzene by fluoride via photoinduced electron transfer with 3-cyano-1-methylquinolinium. AB - The photocatalytic fluorination of benzene occurs under photoirradiation of an oxygen-saturated acetonitrile (MeCN) of the 3-cyano-1-methylquinolinium ion (QuCN(+)) containing benzene and tetraethylammonium fluoride tetrahydrofluoride (TEAF.4HF) with a xenon lamp (500 W) attached to a colored-glass filter (lambda < 290 nm) to yield fluorobenzene and hydrogen peroxide. The quantum yield of formation of fluorobenzene was 6%. Nanosecond laser flash photolysis measurements were performed to elucidate the mechanistic details for photocatalytic fluorination. Transient absorption spectra taken after the nanosecond laser excitation at 355 nm of a degassed MeCN solution of QuCN(+) and benzene exhibited absorption bands due to QuCN(*) (lambdamax = 500 nm) and the benzene dimer radical cation (lambdamax = 900 nm), which were generated by photoinduced electron transfer from benzene to the singlet excited state of QuCN(+). The decay rate of the transient absorption band due to the benzene dimer radical cation was accelerated by the addition of TEAF.4HF. The observed rate constant increased with increasing concentration of TEAF.4HF. The rate constant of the electrophilic addition of fluoride to the benzene radical cation was determined to be 9.4 * 10(9) M(-1) s(-1). Thus, the photocatalytic reaction is initiated by intermolecular photoinduced electron transfer from benzene to the single excited state of QuCN(+). The benzene radical cation formed by photoinduced electron transfer reacts with the fluoride anion to yield the F-adducted radical. However, QuCN(*) can reduce O2 to O2(*-), and this is followed by the protonation of O2(* ) to afford HO2(*). The hydrogen abstraction of HO2(*) from the F-adduct radical affords fluorobenzene and H2O2 as the final products. PMID- 24050616 TI - Young women's experience with using videoconferencing for the assessment of sexual behavior and microbicide use. AB - BACKGROUND: Videoconferencing (VC) systems are increasingly recognized as a viable means of enhancing communication across different geographic regions and have been used within multiple settings. Until now, despite increased use and diverse applications, VC has received relatively little attention as a data collection tool in qualitative research. The literature on preferred data collection methods for sensitive topics offers different perspectives, with no clear consensus on the best approach for collecting sensitive data. We sought to determine if VC is a feasible tool for eliciting sexual history from participants in a vaginal microbicide study. SUBJECTS AND METHODS: Fifty-nine young women who participated in a Phase 1 microbicide safety and acceptability study at three sites (Tampa, FL; Pittsburgh, PA; and San Juan, Puerto Rico) were interviewed through VC from New York City. During the third VC session, participants gave feedback on their experience using the method. RESULTS: Most of the participants reported that they preferred VC to phone-only interviews. Participants noted that because of the sensitive nature of the interviews, geographical distance from the interviewer facilitated disclosure. Despite some technical problems, such as the time delay in video transmission and occasional loss of connection, participants expressed a high degree of satisfaction with using VC. CONCLUSIONS: VC seems to be a feasible alternative form of conducting in-depth interviews on sensitive topics. VC enables data collection from geographically dispersed research participants without the cost and time burden of traveling to sites or developing local interviewer capabilities when the number of interviews is small. PMID- 24050619 TI - Pre-processing feature selection for improved C&RT models for oral absorption. AB - There are currently thousands of molecular descriptors that can be calculated to represent a chemical compound. Utilizing all molecular descriptors in Quantitative Structure-Activity Relationships (QSAR) modeling can result in overfitting, decreased interpretability, and thus reduced model performance. Feature selection methods can overcome some of these problems by drastically reducing the number of molecular descriptors and selecting the molecular descriptors relevant to the property being predicted. In particular, decision trees such as C&RT, although they have an embedded feature selection algorithm, can be inadequate since further down the tree there are fewer compounds available for descriptor selection, and therefore descriptors may be selected which are not optimal. In this work we compare two broad approaches for feature selection: (1) a "two-stage" feature selection procedure, where a pre-processing feature selection method selects a subset of descriptors, and then classification and regression trees (C&RT) selects descriptors from this subset to build a decision tree; (2) a "one-stage" approach where C&RT is used as the only feature selection technique. These methods were applied in order to improve prediction accuracy of QSAR models for oral absorption. Additionally, this work utilizes misclassification costs in model building to overcome the problem of the biased oral absorption data sets with more highly absorbed than poorly absorbed compounds. In most cases the two-stage feature selection with pre-processing approach had higher model accuracy compared with the one-stage approach. Using the top 20 molecular descriptors from the random forest predictor importance method gave the most accurate C&RT classification model. The molecular descriptors selected by the five filter feature selection methods have been compared in relation to oral absorption. In conclusion, the use of filter pre processing feature selection methods and misclassification costs produce models with better interpretability and predictability for the prediction of oral absorption. PMID- 24050621 TI - Close relative of human Middle East respiratory syndrome coronavirus in bat, South Africa. PMID- 24050620 TI - Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells. AB - BACKGROUND: Increased levels of the sugar metabolite methylglyoxal (MG) in vivo were shown to participate in the pathophysiology of vascular complications in diabetes. Alterations of endothelial nitric oxide synthase (eNOS) activity by hypophosphorylation of the enzyme and enhanced monomerization are found in the diabetic milieu, and the regulation of this still remains undefined. Using various pharmacological approaches, we elucidate putative mechanisms by which MG modulates eNOS-associated functions of MG-stimulated superoxide O2*- production, phosphorylation status and eNOS uncoupling in EA.hy926 human endothelial cells. METHODS: In cultured EA.hy926 endothelial cells, the effects of MG treatment, tetrahydrobiopterin (BH4; 100 MUM) and sepiapterin (20 MUM) supplementation, NOS inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME; 50 MUM), and inhibition of peroxynitrite (ONOO-) formation (300 MUM Tempol plus 50 MUM L-NAME) on eNOS dimer/monomer ratios, Ser-1177 eNOS phosphorylation and 3-nitrotyrosine (3NT) abundance were quantified using immunoblotting. O2*--dependent fluorescence was determined using a commercially available kit and tissue biopterin levels were measured by fluorometric HPLC analysis. RESULTS: In EA.hy926 cells, MG treatment significantly enhanced O2*- generation and 3NT expression and reduced Ser-1177 eNOS phosphorylation, eNOS dimer/monomer ratio and cellular biopterin levels indicative of eNOS uncoupling. These effects were significantly mitigated by administration of BH4, sepiapterin and suppression of ONOO- formation. L-NAME treatment significantly blunted eNOS-derived O2*- generation but did not modify eNOS phosphorylation or monomerization. CONCLUSION: MG triggers eNOS uncoupling and hypophosphorylation in EA.hy926 endothelial cells associated with O2*- generation and biopterin depletion. The observed effects of the glycolysis metabolite MG presumably account, at least in part, for endothelial dysfunction in diabetes. PMID- 24050622 TI - District specific correlates for hypertension in Kaoma and Kasama rural districts of Zambia. AB - INTRODUCTION: Hypertension a major risk factor for cardiovascular disease and is the most widely recognized modifiable risk factor for this disease. There is little information on the prevalence and risk factors for hypertension in Zambia, and in particular in rural areas of the country. In order to contribute to the existing global literature on hypertension, particularly in rural Zambia, this study was conducted to determine the prevalence of hypertension and its correlates in two rural districts of Zambia, namely Kaoma and Kasama. METHODS: A cross-sectional study using a modified World Health Organization (WHO) global non communicable diseases (NCD) surveillance initiative NCD-STEPwise approach was used. Proportions were compared using the Yates' corrected chi2 test, and a result yielding a p-value of less than 5% was considered significant. Bivariate and multivariate logistic regression analyses were conducted. Factors that were significantly associated with the outcome in bivariate analyses were considered in a multivariate logistic regression analysis using a backward variable selection method. Adjusted odds ratios (AOR) and their 95% confidence intervals (CI) were reported. RESULTS: In total, 895 participants from Kaoma and 1198 participants from Kasama took part in the surveys. Overall, 25.8% participants (27.5% male, 24.6% female; p=0.373) in Kaoma and 30.3% (31.3% male, 29.5% female; p=0.531) in Kasama were hypertensive. In Kaoma, age and BMI were independently associated with hypertension. Compared with participants aged 45 years or older, participants aged 25-34 years were 60% (AOR=0.40, 95% CI [0.21, 0.56]) less likely to be hypertensive. Participants with BMI <18.5 and 18.5-24.9 were 54% (AOR=0.46, 95% CI [0.30, 0.69]) and 31% (AOR=0.69, 95% CI [0.49, 0.98]) less likely to be hypertensive compared with participants with BMI >=30. In Kasama, age, smoking and heart rate were significantly associated with hypertension in multivariate analysis. Participants 25-34 years were 49% (AOR=0.51, 95% CI [0.41, 0.65]) less likely to be hypertensive compared with participants 45 years or older. Compared with participants who were non-smokers, smokers were 21% (AOR=1.21, 95% CI [1.02, 1.45]) more likely to be hypertensive. Participants who had heart rate >90 beats/min were 59% (AOR=1.59, 95% CI [1.17, 2.16]) more likely to be hypertensive compared with participants who had heart rate 60-90 beats/min. CONCLUSIONS: The findings reveal that hypertension is prevalent among rural residents in Kaoma and Kasama, Zambia. The disease is highly associated with age, BMI, smoking and heart rate. Efficient preventive strategies are needed to halt the growing trend of non-communicable diseases through the control of risk factors highlighted in this study. PMID- 24050623 TI - Sjogren's syndrome. AB - Sjogren's syndrome (SS) is a chronic autoimmune disorder that typically affects exocrine glands--mainly labial and lacrimal--leading to complaints of dry mouth and eyes. Given that periepithelial mononuclear cell infiltrates, both in exocrine glands and in other parenchymal organs (kidney, lung, and liver), are the histopathological disease hallmark, the term autoimmune epithelitis has been proposed. B cell hyperactivity is another cardinal SS feature manifested by the presence of autoantibodies and hypergammaglobulinemia, as well as clinical/serological phenotypes mediated by immune complexes, such as peripheral neuropathy, vasculitic lesions, and hypocomplementemia. These have been designated adverse predictors for lymphoma development in approximately 5% to 10% of patients. Activation of the type I interferon/B cell-activating factor axis in SS has recently attracted particular attention. Inappropriate overexpression of endogenous nucleic acids in a genetically susceptible individual might provide a plausible scenario for the immune activation observed in SS. PMID- 24050626 TI - Nox enzymes and new thinking on reactive oxygen: a double-edged sword revisited. AB - Reactive oxygen species (ROS) are a chemical class of molecules that have generally been conceptualized as deleterious entities, albeit ones whose destructive properties could be harnessed as antimicrobial effector functions to benefit the whole organism. This appealingly simplistic notion has been turned on its head in recent years with the discovery of the NADPH oxidases, or Noxes, a family of enzymes dedicated to the production of ROS in a variety of cells and tissues. The Nox-dependent, physiological generation of ROS is highly conserved across virtually all multicellular life, often as a generalized response to microbes and/or other exogenous stressors. This review discusses the current knowledge of the role of physiologically generated ROS and the enzymes that form them in both normal biology and disease. PMID- 24050625 TI - The intracellular life of Cryptococcus neoformans. AB - Cryptococcus neoformans is a fungal pathogen with worldwide distribution. Serological studies of human populations show a high prevalence of human infection, which rarely progresses to disease in immunocompetent hosts. However, decreased host immunity places individuals at high risk for cryptococcal disease. The disease can result from acute infection or reactivation of latent infection, in which yeasts within granulomas and host macrophages emerge to cause disease. In this review, we summarize what is known about the cellular recognition, ingestion, and killing of C. neoformans and discuss the unique and remarkable features of its intracellular life, including the proposed mechanisms for fungal persistence and killing in phagocytic cells. PMID- 24050624 TI - The multifaceted functions of neutrophils. AB - Neutrophils and neutrophil-like cells are the major pathogen-fighting immune cells in organisms ranging from slime molds to mammals. Central to their function is their ability to be recruited to sites of infection, to recognize and phagocytose microbes, and then to kill pathogens through a combination of cytotoxic mechanisms. These include the production of reactive oxygen species, the release of antimicrobial peptides, and the recently discovered expulsion of their nuclear contents to form neutrophil extracellular traps. Here we discuss these primordial neutrophil functions, which also play key roles in tissue injury, by providing details of neutrophil cytotoxic functions and congenital disorders of neutrophils. In addition, we present more recent evidence that interactions between neutrophils and adaptive immune cells establish a feed forward mechanism that amplifies pathologic inflammation. These newly appreciated contributions of neutrophils are described in the setting of several inflammatory and autoimmune diseases. PMID- 24050628 TI - High-performance large-scale flexible dye-sensitized solar cells based on anodic TiO2 nanotube arrays. AB - A simple strategy to fabricate flexible dye-sensitized solar cells involves the use of photoanodes based on TiO2 nanotube (TNT) arrays with rear illumination. The TNT films (tube length ~35 MUm) were produced via anodization, and sensitized with N719 dye for photovoltaic characterization. Pt counter electrodes of two types were used: a conventional FTO/glass substrate for a device of rigid type and an ITO/PEN substrate for a device of flexible type. These DSSC devices were fabricated into either a single-cell structure (active area 3.6*0.5 cm2) or a parallel module containing three single cells (total active area 5.4 cm2). The flexible devices exhibit remarkable performance with efficiencies eta=5.40% (single cell) and 4.77% (parallel module) of power conversion, which outperformed their rigid counterparts with eta=4.87% (single cell) and 4.50% (parallel model) under standard one-sun irradiation. The flexible device had a greater efficiency of conversion of incident photons to current and a broader spectral range than the rigid device; a thinner electrolyte layer for the flexible device than for the rigid device is a key factor to improve the light-harvesting ability for the TNT-DSSC device with rear illumination. Measurements of electrochemical impedance spectra show excellent catalytic activity and superior diffusion characteristics for the flexible device. This technique thus provides a new option to construct flexible photovoltaic devices with large-scale, light-weight, and cost-effective advantages for imminent applications in consumer electronics. PMID- 24050629 TI - Feature: Improving our knowledge of drought-induced forest mortality through experiments, observations, and modeling. PMID- 24050627 TI - Pathogenesis of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated. PMID- 24050630 TI - Thirsty roots and hungry leaves: unravelling the roles of carbon and water dynamics in tree mortality. PMID- 24050631 TI - Our limited ability to predict vegetation dynamics under water stress. PMID- 24050632 TI - Climate-driven tree mortality: insights from the pinon pine die-off in the United States. PMID- 24050633 TI - A novel diiminopyridine ligand containing redox active Co(III) mixed sandwich complexes. AB - The synthesis of a diiminopyridine (DIMPY) ligand containing pendant mixed sandwich cobaltocene functionalities on the imine nitrogens was prepared and characterized (18). Its reactivity with 2 equiv of GeCl2.dioxane and SnCl2 in THF yields the respective Lewis base mediated autoionization products (18Ge and 18Sn). Analogous low-valent complexes utilizing an N,N'- differocenyl diiminopyridine support were also prepared (15Ge and 15Sn). All compounds were characterized by spectroscopic and X-ray crystallographic methods. Electrochemical studies were conducted for both 15Sn and the precursor of 18. PMID- 24050635 TI - Facile synthesis and unique photocatalytic property of niobium pentoxide hollow spheres and the high optoelectronic performance of their nanofilm. AB - In this paper, monodisperse poly(styrene-co-acrylmide) (PSAM)/Nb2O5 hybrid hollow spheres were synthesized using a hollowing mechanism similar to the Kirkendall effect. When these hybrid hollow spheres were calcinated at different temperatures, totally different structures, pseudohexagonal TT phase hollow Nb2O5 spheres, and orthorhombic T phase short rods were obtained. Both of them exhibited stronger photocatalytic activity than the commercial Nb2O5, especially the as-obtained Nb2O5 hollow spheres displayed significantly enhanced photocatalytic property and auto-accelerated photocatalytic kinetics compared to the commercial TiO2 (P25). Moreover, the Nb2O5 hollow sphere-based nanofilm fabricated using oil-water interfacial self-assembly presented excellent UV photodetective performance. PMID- 24050636 TI - Mid- and near-infrared spectroscopic investigation of homogeneous cation distribution in Mg(x)Zn(y)Al(x+y)/2-layered double hydroxide (LDH). AB - In this report, a detailed FTIR fitting analysis was used to recognize Mg, Zn and Al homogeneous distribution in Mg(x)Zn(y)Al(x+y)/2-Layered double hydroxide (LDH) hydroxyl layer. In detail, OH-Mg2Al:OH-Mg3 ratios decreased from 95.2:4.8 (MIR) and 94.2:5.8 (NIR) to 58.9:41.1 (MIR) and 61.8:38.2 (NIR), when Mg:Al increased from 2.2:1.0 to 4.1:1.0 in MgAl-LDHs. These fitting results were similar with theoretical calculations of 94.3:5.7 and 59.0:41.0. In a further analysis of Mg(x)Zn(y)Al(x+y)/2-LDHs, OH bonded Zn2Mg, Zn2Al, MgZnAl, Mg2Al and Mg2Zn peaks were identified at 3420, 3430, 3445-3450, 3454 and 3545 cm(-1), respectively. With the decrease of Mg:Zn from 3:1 to 1:3, metal-hydroxyl bands changed from OH Mg2Al and MgZnAl (with a ratio of 49.4:50.6) to OH-MgZnAl and Zn2Al (with a ratio of 55.0:45.0). They were also similar with theoretical calculations of 47.6:52.4 and 54.6:45.4. As a result, these results show that there is an ordered cation distribution in Mg(x)Zn(y)Al(x+y)/2-LDH, and FTIR is feasible in recognizing this structure. PMID- 24050634 TI - Hypophosphatemia during continuous veno-venous hemofiltration is associated with mortality in critically ill patients with acute kidney injury. AB - INTRODUCTION: The primary aim of this study was to determine whether hypophosphatemia during continuous veno-venous hemofiltration (CVVH) is associated with the global outcome of critically ill patients with acute kidney injury (AKI). METHODS: 760 patients diagnosed with AKI and had received CVVH therapy were retrospectively recruited. Death during the 28-day period and survival at 28 days after initiation of CVVH were used as endpoints. Demographic and clinical data including serum phosphorus levels were recorded along with clinical outcome. Hypophosphatemia was defined according to the colorimetric method as serum phosphorus levels < 0.81 mmol/L (2.5 mg/dL), and severe hypophosphatemia was defined as serum phosphorus levels < 0.32 mmol/L (1 mg/dL). The ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was calculated to reflect the persistence of hypophosphatemia. RESULTS: The Cox proportional hazard survival model analysis indicated that the incidence of hypophosphatemia or even severe hypophosphatemia was not associated with 28-day mortality independently (p = 0.700). Further analysis with the sub-cohort of patients who had developed hypophosphatemia during the CVVH therapy period indicated that the mean ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was 0.58, and the ratio independently associated with the global outcome. Compared with the patients with low ratio (< 0.58), those with high ratio (>= 0.58) conferred a 1.451-fold increase in 28-day mortality rate (95% CI 1.103-1.910, p = 0.008). CONCLUSIONS: Hypophosphatemia during CVVH associated with the global clinical outcome of critically ill patients with AKI. The ratio of CVVH therapy days with hypophosphatemia over total CVVH therapy days was independently associated with the 28-day mortality, and high ratio conferred higher mortality rate. PMID- 24050637 TI - Preparation and rheological characterization of shellac oleogels and oleogel based emulsions. AB - We report the preparation and rheological characterization of oleogels and oleogel-based emulsions prepared using shellac as a structurant. Shellac showed excellent oleogelation properties, resulting in liquid oil gelation at a concentration as low as 2 wt%. Microscopic evaluation of these oleogels indicated that the oil gelation was a result of physical entrapment of liquid oil in crystal networks of shellac formed by cooling the hot oil dispersions of shellac to room temperature. The rheological behaviour of shellac oleogels to varying deformation (% strain) was comparable to oleogels prepared using a commercial crystal starter. The cooling and shear rate showed a significant effects on the rheological properties of formed oleogels. The thermo-reversible, hysteresis, thixotropic and shear thinning properties of oleogels were evaluated by comparing rheological data obtained from rotational and oscillatory measurements. Shellac oleogels were further used as continuous phases to generate emulsifier-free w/o emulsions which surprisingly showed good stability over 4 months of storage. Microscopy and rheological evaluations of these emulsions were carried out to obtain more insight into its microstructures. PMID- 24050638 TI - Effect of glycerol on formation, stability, and properties of vitamin-E enriched nanoemulsions produced using spontaneous emulsification. AB - Oil-in-water nanoemulsions are finding increasing use as delivery systems to encapsulate lipophilic bioactive components in functional food, personal care, and pharmaceutical products. We investigated the influence of a water-soluble cosolvent (glycerol) on the formation, stability, and properties of vitamin E acetate-loaded nanoemulsions (VE-NEs) prepared by spontaneous emulsification. VE NEs were formed by titration of a mixture of vitamin E acetate, carrier oil (MCT) and non-ionic surfactant (Tween 80) into an aqueous glycerol solution with continuous mixing. Cosolvent concentration had an appreciable effect on the particle size produced, with the smallest mean droplet diameters (d<50 nm) being formed at 40 and 50 wt% glycerol. Nanoemulsions (d<100 nm) containing 10% vitamin E acetate could be produced at relatively low surfactant concentrations (5%) using these high glycerol levels. The turbidity of the NEs decreased at high glycerol concentrations due to the reduction in droplet size and refractive index contrast. The long-term stability of the VE-NEs was strongly influenced by glycerol concentration and storage temperature. VE-NEs containing 40% glycerol were relatively stable to droplet growth when stored at 5 and 20 degrees C, but a rapid increase in droplet size and turbidity occurred during storage at 37 degrees C. Temperature scanning experiments (20-80-20 degrees C) indicated that a steep and irreversible increase in turbidity occurred during heating, which was around 70 degrees C in the absence of glycerol and 60 degrees C in the presence of 40% glycerol. Droplet instability was attributed to an increase in the rate of Ostwald ripening and/or coalescence as the temperature was increased, associated with dehydration of the non-ionic surfactant head-group leading to a reduction in phase inversion temperature. Dilution (100*) of VE-NEs containing glycerol with water considerably improved their stability to droplet growth, especially at high storage temperatures. This study provides important information about the effect of glycerol on the formation, stability and physical properties of VE-enriched NEs suitable for food, personal care, and pharmaceutical products. PMID- 24050639 TI - Photocatalytic properties of metal and non-metal doped novel sub 10nm titanium dioxide nanoparticles on methyl orange. AB - This study examines the addition of various dopants to TiO2 nanoparticles for the enhancement of photocatalytic activity. The materials were tested for efficiency on the degradation of methyl orange under UV light. The dopants were added at different molar ratios to find the ideal amount required for optimum results. BET analysis was used to determine surface areas while X-ray diffraction (XRD) analysis was used to study the effect of the dopant on the transformation of the TiO2 structure. The dopants used were Ag, S and Zr and displayed high levels of activity and show some ability to be reused. Decomposition of methyl orange was carried out using a 40 W UV bulb at 365 nm and results were measured by UV-vis spectrometry. It was determined that, overall, Ag doping displayed the best photocatalytic properties but was poor upon reuse. PMID- 24050640 TI - Aminosilane layers on the plasma activated thermoplastics: influence of solvent on its structure and morphology. AB - The chemistry and the structure of aminosilane layer on the plasma activated thermoplastic substrates, e.g., polycarbonate (PC), polystyrene (PS), poly(methyl methacrylate) (PMMA), and cyclic olefin co-polymer (COC) were investigated at the molecular level. The nature of the surface functional groups of the silane layers prepared by solution phase deposition in aqueous and anhydrous solvents were studied using various techniques including ellipsometry, goniometry, atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and attenuated total reflectance infrared spectroscopy (ATR-IR). The XPS analyses revealed the presence of various oxygen functionalities on the plasma activated thermoplastics. Considerable differences were observed for the structure of aminosilane depending on the solvent used for the reaction. Deposition from aqueous solution resulted in relatively flat and smooth surfaces with consistent thickness compared to the anhydrous solution deposition. In the former case, 33% of the total nitrogen accounted for protonated amine and 16% for the free amino groups. In the latter, only 6% accounted for the protonated amine. The point of zero charge (pzc), on the aminosilane modified PC was found to be around 7, indicated that the surface is positively charged below pH 7 and negatively charged above pH 7. The surface analysis data suggested that various interactions are possible between the plasma activated thermoplastic surface and the aminosilane. In general, they are bound to the surface through covalent bond formation between the oxygen functionalities on the thermoplastic surface and the amino or the silanol groups of the aminosilane. PMID- 24050641 TI - Fast assembly of non-thiolated DNA on gold surface at lower pH. AB - In a typical protocol for attaching DNA to a gold electrode, thiolated DNA is incubated with the electrode at neutral pH overnight. Here we report fast adsorption of non-thiolated DNA oligomers on gold electrodes at acidic pH (i.e., pH ~3.0). The peak-to-peak potential difference and the redox peak currents in typical cyclic voltammetry of [Fe(CN)6](3-) are investigated to monitor the attachment. Compared with incubation at neutral pH, the lower pH can significantly promote the adsorption processes, enabling efficient adsorption even in 30 min. The adsorption rate is DNA concentration-dependent, while the ionic strength shows no influence. Moreover, the adsorption is base discriminative, with a preferred order of A>C>>G, T, which is attributed to the protonation of A and C at low pH and their higher binding affinity to gold surface. The immobilized DNA is functional and can hybridize with its complementary DNA but not a random DNA. This work is promising to provide a useful time-saving strategy for DNA assembly on gold electrodes, allowing fast fabrication of DNA-based biosensors and devices. PMID- 24050642 TI - Temperature and pH dual-responsive POEGMA-based coatings for protein adsorption. AB - Poly(oligo(ethylene glycol)ethyl ether methacrylate (POEGMA246) coatings were successfully fabricated using novel approach via polymerization from oligoperoxide grafted to premodified glass substrate. Wettability, content and composition of coatings fabricated with different polymerization times were determined using contact angle measurements, ellipsometry and Time of Flight Secondary Ion Mass Spectrometry (TOF-SIMS). Thermo- and pH-responsive properties of POEGMA246 coatings were found to depend significantly on concentration of the grafted POEGMA246. Coatings fabricated with polymerization time 30 h exhibit not only temperature- but also pH-dependence of wettability. Thermal response of wettability, measured between 20 and 32 degrees C, was prominent at pH 9 and 7 and diminished or was absent at pH 5 and 3, indicating a transition between hydrated loose coils and hydrophobic collapsed chains, blocked at low pH. Protein adsorption, observed by fluorescence microscopy and analyzed semi-quantitatively using integral geometry approach, decreased dramatically for model protein (lentil lectin labeled with fluorescein isothiocyanate) at transition from pH 5 to pH 9, showing only very weak thermal-dependence. Strong protein adsorption response to pH and very weak one to temperature was confirmed by TOF-SIMS and Principal Component Analysis. PMID- 24050643 TI - Usefulness of screening left atrioventricular groove epicardial adipose tissue thickness. PMID- 24050644 TI - From birth to maturity: midline tessier 0-14 craniofacial cleft patients who have completed protocol management at a single craniofacial unit. AB - INTRODUCTION: The rare craniofacial clefts form an important component of craniofacial pathology, but little has been written regarding the definitive management of affected patients. This report describes the presentation, management, and outcomes in a group of patients who have completed their protocol management for treatment of midline Tessier 0-14 clefts. METHODS: A retrospective review of the clinical, photographic, and radiographic records of all midline cleft patients treated at a single center was performed. Data describing each patient's presenting features, surgical management, and final outcomes are presented. RESULTS: Four patients were identified as having completed protocol management for Tessier 0-14 midline clefting at the unit. The age range at the most recent follow-up was 19.3 to 36.3 years. Three patients had entered protocol management during infancy, and the remaining patient presented to the unit at 13.8 years of age. The surgical management regimen is described in detail. Outcomes for development, hearing, speech, and vision at maturity were all acceptable. Three patients attained a respectable educational and social status. With respect to facial aesthetics scores, the only significant difference after management was a significant worsening of deformity in the region of the orbits. The Whitaker grade for repeat surgery improved after management (3.25 before to 2.63 postmanagement), but this improvement was not statistically significant. CONCLUSION: Presented are the results of the first cohort of midline Tessier 0-14 cleft patients to have completed protocol management at a single craniofacial unit. As more patients complete their management in the future, further refinements to the protocol could be made. PMID- 24050645 TI - Comment on: the relationship between statins and depression: a review of the literature. PMID- 24050646 TI - Attention difficulties in a contemporary geographic cohort of adolescents born extremely preterm/extremely low birth weight. AB - The aim of this study was to evaluate attention difficulties in a contemporary geographic cohort of adolescents born extremely preterm (EP, <28 weeks' gestation) or extremely low birth weight (ELBW, birth weight <1000 g). The EP/ELBW group included 228 adolescents (mean age = 17.0 years) born in Victoria, Australia in 1991 and 1992. The control group were 166 adolescents (mean age = 17.4 years) born of normal birth weight (birth weight >2499 g) who were recruited in the newborn period and matched to the EP/ELBW group on date of birth, gender, language spoken and health insurance status. Participants were assessed on measures of selective, sustained, and executive (shift and divided) attention, and parents and participants completed behavioral reports. The EP/ELBW group performed more poorly across tests of selective and executive attention, had greater rates of clinically significant difficulties compared with the control group, and also had greater behavioral attention problems as reported by parents. Neonatal risk factors were weakly associated with attention outcomes. In conclusion, higher rates of attention impairments are observed in individuals born EP/ELBW well into adolescence and may have consequences for their transition to adulthood. PMID- 24050648 TI - Catalytic direct cross-coupling of organolithium compounds with aryl chlorides. AB - Palladium-catalyzed direct cross-coupling of aryl chlorides with a wide range of (hetero)aryl lithium compounds is reported. The use of Pd-PEPPSI-IPent or Pd2(dba)3/XPhos as the catalyst allows for the preparation of biaryl and heterobiaryl compounds in high yields under mild conditions (room temperature to 40 degrees C) with short reaction times. PMID- 24050647 TI - Muscle shortening manoeuvre reduces pain and functional impairment in shoulder impingement syndrome: clinical and ultrasonographic evidence. AB - OBJECTIVES: To evaluate the short-term efficacy of muscle shortening manoeuvre (MSM), by inducing an increase in strength of the shoulder muscles, for the treatment of shoulder impingement syndrome (SIS). METHODS: Sixty subjects (mean age: 58.6 years) with SIS were assigned to one of 3 different treatment interventions: 1) MSM: a series of fast accelerations in the upward direction was applied to the upper limb that was also submitted to forces acting in the opposite direction (added mass); 2) traditional physiotherapeutic technique: scapulothoracic gliding; 3) simple traction: the added mass was applied to the limb without the series of fast accelerations. Pain intensity, Neer's impingement sign, range of motion and muscle strength were assessed. Ultrasound (US) examination was performed before, immediately after and 30 days after each treatment to study the width of the subacromial-subdeltoid bursa, long biceps tendon sheath and acromioclavicular joint. Impingement was evaluated by dynamic examination. RESULTS: After treatment with MSM, pain was significantly reduced (p<0.001), Neer's impingement sign was negative, range of motion and muscle strength were increased. US examination showed that the widths of the subacromial subdeltoid bursa (p<0.001), long biceps tendon sheath (p<0.001) and acromioclavicular joint (p<0.001) were significantly reduced; impingement was no more detected. After 30 days, improvement in clinical and US findings was maintained. In the two control groups, no significant changes were observed after treatment. CONCLUSIONS: Clinical and US findings demonstrate that MSM, by inducing an increase in muscle strength, is effective in the short-term treatment of SIS. PMID- 24050649 TI - Copper redox transformation and complexation by reduced and oxidized soil humic acid. 1. X-ray absorption spectroscopy study. AB - Natural organic matter (NOM) exerts strong influence on copper speciation and bioavailability in soils and aquatic systems. In redox-dynamic environments, electron transfer reactions between copper and redox-active moieties of NOM may trigger Cu(I) and Cu(0) formation. To date, little is known about Cu-NOM redox interactions and Cu(I) binding to NOM. Here, we present X-ray absorption spectroscopy results on copper redox transformations upon addition of Cu(II) or Cu(I) to untreated and electrochemically reduced soil humic acid (HA) under oxic and anoxic conditions. Both untreated and reduced HA mediated copper redox transformations. Under anoxic conditions, Cu(II) and Cu(I) added to reduced HA were primarily complexed and thereby stabilized as Cu(I)-HA at low loadings, whereas high copper loadings resulted in the additional formation of Cu(0) nanoparticles (16-64% of total copper). Cu(I) bound to HA was predominantly 2 fold coordinated and to a lower extent 3- to 4-fold coordinated, with a contribution of at least one nitrogen and/or sulfur ligand group. Under oxic conditions, Cu(II)-HA complexes prevailed, but smaller fractions of copper were also stabilized as Cu(I)-HA in a 3- to 4-fold coordination. Our results show that Cu-HA redox interactions are strongly affected by binding of Cu(II) and Cu(I) to HA and that HA contributes to the stabilization of Cu(I) against disproportionation. PMID- 24050650 TI - Relationship between the relative age effect and anthropometry, maturity and performance in young soccer players. AB - The presence of the relative age effect (RAE) has been widely reported; however, its underlying causes have not yet been determined. With this in mind, the present study examined if anthropometry and performance were different amongst older and younger soccer players born in the same year. Eighty-eight young soccer players participated in the study (age 9.75 +/- 0.30). Anthropometric measurements, physical tests (sprint, agility, endurance test, jump and hand dynamometry) and the estimation of the maturity status were carried out. Most players (65.9%) were born in the first half of the year. Older players were taller (P < 0.05), had longer legs (P < 0.01) and a larger fat-free mass (P < 0.05). Maturity offset was smaller in the older boys (P < 0.05); however, age at peak height velocity was similar. Older boys performed better in velocity and agility (P < 0.05) and particularly in the overall score of performance (P < 0.01). Stepwise regression analysis revealed that chronological age was the most important variable in the agility test and the overall score, after the skinfolds (negative effect). We report differences in anthropometry and physical performance amongst older and younger pre-pubertal soccer players. These differences may underlie the RAE. PMID- 24050651 TI - Changes in the hemagglutinin of H5N1 viruses during human infection--influence on receptor binding. AB - As avian influenza A(H5N1) viruses continue to circulate in Asia and Africa, global concerns of an imminent pandemic persist. Recent experimental studies suggest that efficient transmission between humans of current H5N1 viruses only requires a few genetic changes. An essential step is alteration of the virus hemagglutinin from preferential binding to avian receptors for the recognition of human receptors present in the upper airway. We have identified receptor-binding changes which emerged during H5N1 infection of humans, due to single amino acid substitutions, Ala134Val and Ile151Phe, in the hemagglutinin. Detailed biological, receptor-binding, and structural analyses revealed reduced binding of the mutated viruses to avian-like receptors, but without commensurate increased binding to the human-like receptors investigated, possibly reflecting a receptor binding phenotype intermediate in adaptation to more human-like characteristics. These observations emphasize that evolution in nature of avian H5N1 viruses to efficient binding of human receptors is a complex multistep process. PMID- 24050652 TI - Assessment of quality of life of the children and parents affected by inborn errors of metabolism with restricted diet: preliminary results of a cross sectional study. AB - INTRODUCTION: The development in therapeutic strategies has increased survival of children affected by inborn errors of metabolism with restricted diet (IEMRD). These diseases have mild- and long-term consequences on the health. Little is known about the impact on the quality of life (QoL) of children and their families. The aims of this study were: to compare the QoL of the children and parents affected by IEMRD with the QoL of the general population and one pathology associated with long-term consequences. PATIENTS AND METHODS: This cross-sectional study was performed at the French Reference Center for inborn metabolic disorders (Marseille, France). Inclusion criteria were: a child with a diagnosis of organic aciduria, urea cycle defect, or maple syrups urine disease (MSUD). Socio-demographics, clinical data, and QoL were recorded. RESULTS: Twenty one of 32 eligible families were included during a planned routine visit. Ten (47%, 95% CI 27-69%) children were affected by organic aciduria, six (29%, 95% CI 10-48%) by urea cycle defects, and five (24%, 95% CI 6-42%) by MSUD. Among the younger children, the general well-being was significantly lower in the children with IEMRD than in the leukemia children (58 +/- 16 versus 76 +/- 15, p = 0.012), and among the older children, the leisure activities were significantly lower in the children with IEMRD than in the leukemia children (29 +/- 18 versus 62 +/- 22, p < 10-3), while the relationships with teachers were better (76 +/- 23 versus 60 +/- 23, p = 0.01). The physical QoL score was lower in the parents than in the French norms (66 +/- 21 versus 75 +/- 1, p = 0.05). Factors modulating QoL were: eating and neurologic disorders, enteral nutrition, and feeding modalities. CONCLUSION: The children and the parents of children affected presented altered 'physical' and 'social' QoL scores compared with the norms and patients with leukemia and their families. Future studies based on larger cohort studies should determine the different weights of potential predictive factors of QoL. PMID- 24050654 TI - Development of innovative and versatile polythiol probes for use on ELOSA or electrochemical biosensors: application in hepatitis C virus genotyping. AB - The aim of this study was to develop versatile diagnostic tools based on the use of innovative polythiolated probes for the detection of multiple viruses. This approach is compatible with optical enzyme-linked oligosorbent assay (ELOSA) or electrochemical (biosensors) detection methods. The application targeted here concerns the rapid genotyping of Hepatitis C virus (HCV). HCV genotyping is one of the predictive parameters currently used to define the antiviral treatment strategy and is based on the sequencing of the viral NS5b region. Generic and specific NS5b amplicons were produced by real-time polymease chain reaction (RT PCR) on HCV(+) human plasma. Original NS5b probes were designed for genotypes 1a/1b, 2a/2b/2c, 3a, and 4a/4d. Robust polythiolated probes were anchored with good efficacy on maleimide-activated microplates (MAM) and gold electrodes. Their grafting on MAM greatly increased the sensitivity of the ELOSA test which was able to detect HCV amplicons with good sensitivity (10 nM) and specificity. Moreover, the direct and real-time electrochemical detection by differential pulse voltammetry enabled a detection limit of 10 fM to be reached with good reproducibility. These innovative polythiolated probes have allowed us to envisage developing flexible, highly sensitive, and easy-to-handle platforms dedicated to the rapid screening and genotyping of a wide range of viral agents. PMID- 24050653 TI - Derivatives of dibenzothiophene for positron emission tomography imaging of alpha7-nicotinic acetylcholine receptors. AB - A new series of derivatives of 3-(1,4-diazabicyclo[3.2.2]nonan-4 yl)dibenzo[b,d]thiophene 5,5-dioxide with high binding affinities and selectivity for alpha7-nicotinic acetylcholine receptors (alpha7-nAChRs) (Ki = 0.4-20 nM) has been synthesized for positron emission tomography (PET) imaging of alpha7-nAChRs. Two radiolabeled members of the series [(18)F]7a (Ki = 0.4 nM) and [(18)F]7c (Ki = 1.3 nM) were synthesized. [(18)F]7a and [(18)F]7c readily entered the mouse brain and specifically labeled alpha7-nAChRs. The alpha7-nAChR selective ligand 1 (SSR180711) blocked the binding of [(18)F]7a in the mouse brain in a dose dependent manner. The mouse blocking studies with non-alpha7-nAChR central nervous system drugs demonstrated that [(18)F]7a is highly alpha7-nAChR selective. In agreement with its binding affinity the binding potential of [(18)F]7a (BPND = 5.3-8.0) in control mice is superior to previous alpha7-nAChR PET radioligands. Thus, [(18)F]7a displays excellent imaging properties in mice and has been chosen for further evaluation as a potential PET radioligand for imaging of alpha7-nAChR in non-human primates. PMID- 24050655 TI - Mechanism for the uncatalyzed cyclic acetone-peroxide formation reaction: an experimental and computational study. AB - In this study, a mechanism for the uncatalyzed reaction between acetone and hydrogen peroxide is postulated. The reaction leads to the formation of the important homemade explosives collectively known as cyclic acetone peroxides (CAP). The proposed mechanistic scheme is based on Raman, GC-MS, and nuclear magnetic resonance measurements, and it is supported by ab initio density functional theory (DFT) calculations. The results demonstrate that the proposed mechanism for the uncatalyzed formation reaction of CAP occurs in three steps: monomer formation, polymerization of the 2-hydroperoxipropan-2-ol monomer, and cyclization. The temporal decay of the intensities of important assigned-bands is in excellent agreement with the proposed mechanism. Previous reports also confirm that the polymerization step is favored in comparison to other possible pathways. PMID- 24050656 TI - Multidrug-resistant Escherichia coli bacteremia. PMID- 24050657 TI - Investigating the role of zinc and copper binding motifs of trafficking sites in the cyanobacterium Synechocystis PCC 6803. AB - Although zinc and copper are required by proteins with very different functions, these metals can be delivered to cellular locations by homologous metal transporters within the same organism, as demonstrated by the cyanobacterial ( Synechocystis PCC 6803) zinc exporter ZiaA and thylakoidal copper importer PacS. The N-terminal metal-binding domains of these transporters (ZiaAN and PacSN, respectively) have related ferredoxin folds also found in the metallochaperone Atx1, which delivers copper to PacS, but differ in the residues found in their M/IXCXXC metal-binding motifs. To investigate the role of the nonconserved residues in this region on metal binding, the sequence from ZiaAN has been introduced into Atx1 and PacSN, and the motifs of Atx1 and PacSN swapped. The motif sequence can tune Cu(I) affinity only approximately 3-fold. However, the introduction of the ZiaAN motif (MDCTSC) dramatically increases the Zn(II) affinity of both Atx1 and PacSN by up to 2 orders of magnitude. The Atx1 mutant with the ZiaAN motif crystallizes as a side-to-side homodimer very similar to that found for [Cu(I)2-Atx1]2 ( Badarau et al. Biochemistry 2010 , 49 , 7798 ). In a crystal structure of the PacSN mutant possessing the ZiaAN motif (PacSN(ZiaAN)), the Asp residue from the metal-binding motif coordinates Zn(II). This demonstrates that the increased Zn(II) affinity of this variant and the high Zn(II) affinity of ZiaAN are due to the ability of the carboxylate to ligate this metal ion. Comparison of the Zn(II) sites in PacSN(ZiaAN) structures provides additional insight into Zn(II) trafficking in cyanobacteria. PMID- 24050659 TI - Liver pathology in infantile mitochondrial DNA depletion syndrome. AB - Mitochondrial DNA (mtDNA) depletion syndrome is a relatively novel cause of hepatic dysfunction in the pediatric population. It is caused by mutations in either mtDNA or nuclear DNA (nDNA) that result in a quantitative reduction in mtDNA and, in turn, dysfunctional oxidative phosphorylation. In infants, it results in the hepatocerebral phenotype, characterized by hyperbilirubinemia, coagulopathy, lactic acidosis, hypoglycemia, lethargy, encephalopathy, developmental delay, and hypotonia. Three infants diagnosed with mtDNA depletion syndrome at The Children's Hospital of Philadelphia were identified, and their clinical presentation, disease course, and histologic and ultrastructural features of liver samples (pre- and postmortem) were characterized. While a different mutant gene was identified in each child, they all showed clinical evidence of metabolic dysfunction soon after birth and expired by 1 year of age. Steatosis, cholestasis, and cytoplasmic crowding by atypical mitochondria were consistent pathologic liver findings. Other findings included hepatocyte hypereosinophilia, fibrosis, and hemosiderosis. This analysis provides insight into the important clinical signs/symptoms and histopathologic and ultrastructural features of mtDNA depletion syndrome in infants and young children. Knowledge of these characteristics will facilitate early recognition and appropriate treatment of this rare disorder. Additionally, ultrastructural evaluation of liver samples by electron microscopy is an important diagnostic component of hepatic dysfunction caused by metabolic abnormalities. This type of analysis should be routinely employed in the setting of unexplained cholestasis, especially when accompanied by steatosis and hepatocyte hypereosinophilia. PMID- 24050660 TI - Fabrication of a Cu2ZnSn(S,Se)4 photovoltaic device by a low-toxicity ethanol solution process. AB - Homogeneous molecular precursor solutions are excellent choices for obtaining smooth absorber layers, and they offer the potential to significantly lower the manufacturing cost of solar cells. Here, we present a thermally degradable metal butyldithiocarbamate-based solution approach to fabricate Cu2ZnSn(S,Se)4 solar cells. Low-cost Cu2O, ZnO, and SnO were used as the starting materials and were dissolved in the ethanol solution of butyldithiocarbamic acid. By tuning the composition of the Cu2ZnSn(S,Se)4 thin film, a power conversion efficiency of 6.03% on the basis of the active area has been achieved. PMID- 24050661 TI - The responses of healthcare professionals to the admission of people with cognitive impairment to acute hospital settings: an observational and interview study. AB - AIMS AND OBJECTIVES: To explore the responses of healthcare professionals to the admission of people with cognitive impairment to the acute hospital setting. BACKGROUND: While improving care for people with dementia has been identified as a national priority, providing appropriate care in acute hospitals for people with comorbid cognitive impairment presents challenges to healthcare professionals. DESIGN: Based on the principles of ethnography, this was a qualitative interview and nonparticipation observational study. METHODS: Seventy two hours of nonparticipant observations of care together with semi-structured interviews with family carers of 34 older people who had been admitted to a UK general hospital and had a cognitive impairment. Interviews and observations were conducted in 2009 and 2010. Analysis was undertaken using Strauss and Corbin's framework. RESULTS: The results identified a core problem, 'disruption', and a core process, 'gaining or giving a sense of control to cope with disruption'. Healthcare professionals respond to the disruption in three ways: by acting to preserve the personhood of the individual; by seeking to protect themselves from the stresses associated with caring for the person with cognitive impairment; and by suspending the personhood of the individual. CONCLUSION: Where healthcare professionals acted to suspend the personhood of the patient, they appeared to be demonstrating signs of 'burnout'. RELEVANCE TO CLINICAL PRACTICE: There is a need both to challenge poor practice and for positive development work with healthcare professionals who work in acute hospitals with people with dementia and cognitive impairment so that they are equipped with the skills, emotional resilience and organisational support to be effective in meeting the needs of people with dementia and cognitive impairment. PMID- 24050663 TI - Room-temperature synthesis of flower-like BiOX (X?Cl, Br, I) hierarchical structures and their visible-light photocatalytic activity. AB - A simple method for facile synthesis of three-dimensional (3D) bismuth oxyhalide (BiOX, X?Cl, Br, I) hierarchical structures at room temperature has been developed. Under the influence of L-lysine surfactant, the bismuth and halogen (Cl, Br, I) sources hydrolyze and self-assemble into flower-like hierarchical architectures within 10 min. The resulted materials were characterized by XRD, FESEM, TEM, UV-vis DRS, and N2 adsorption-desorption techniques. We found that l lysine is indispensable for their formation and the amount of HX has great effect on the final morphology. The BiOX (X?Cl, Br, I) hierarchical architectures are composed of single-crystalline nanoplates. We propose an amino-and-carboxyl structure-directing mechanism for the formation of the hierarchical structures. To evaluate the photocatalytic activity of the as-prepared materials, rhodamine-B was employed as a probe dye for degradation under visible light. All of the BiOX (X?Cl, Br, I) with 3D architectures show higher photocatalytic activities than their sheet-like counterparts. The superior activity is ascribed to the better light-harvesting capacity of the 3D hierarchical structures. The adopted method can be applied for large-scale generation of novel structures of similar kinds in a facile manner. PMID- 24050662 TI - Skeletal muscle predicts ventilator-free days, ICU-free days, and mortality in elderly ICU patients. AB - INTRODUCTION: As the population ages, the number of injured elderly is increasing. We sought to determine if low skeletal muscle mass adversely affected outcome in elderly patients following trauma. METHODS: Patients >= 65 years of age with an admission abdominal computed tomography scan and requiring intensive care unit (ICU) stay at a Level I trauma center in 2009-2010 were reviewed. Muscle cross-sectional area at the 3rd lumbar vertebra was quantified and muscle index, a normalized measure of muscle mass, was calculated and related to clinical parameters including ventilator-free days, ICU-free days, and mortality. Using previously established sex-specific, muscle index cut-points, patients were then categorized as sarcopenic or non-sarcopenic and differences in clinical outcomes between these two groups were also compared. We also examined muscle index as a continuous variable relative to the same clinical outcomes. RESULTS: There were 149 severely injured elderly patients (median age 79 years) enrolled in this study of which 71% were sarcopenic. Of the patients who were sarcopenic, 9% were underweight, 44% normal weight, and 47% overweight/obese as per body mass index (BMI) classifications. The overall mortality rate was 27% and univariate analysis demonstrated higher mortality among those who were sarcopenic (32% vs. 14%, P = 0.018). After controlling for age, sex, and injury severity, multiple logistic regression demonstrated that increased muscle index was significantly associated with decreased mortality (OR per unit muscle index = 0.93, 95% CI: 0.875-0.997, P = 0.025). In addition, multivariate linear regression showed that sarcopenia, but not muscle index, was associated with decreased ventilator-free (P = 0.004) and ICU-free days (P = 0.002). Neither BMI, serum albumin nor total adipose tissue on admission were indicative of survival, ventilator-free or ICU free days. CONCLUSIONS: Sarcopenia is highly prevalent in the elderly population with traumatic injuries. Traditional measures of nutritional assessment, such as BMI and serum albumin, do not accurately predict outcome in the injured elderly. Sarcopenia, however, represents a potential new predictor for mortality, discharge disposition, and ICU utilization. Measurement of muscularity allows for the early identification of at-risk patients who may benefit from aggressive and multidisciplinary nutritional and rehabilitative strategies. PMID- 24050664 TI - Utilization of nanoparticle labels for signal amplification in ultrasensitive electrochemical affinity biosensors: a review. AB - Nanoparticles with desirable properties not exhibited by the bulk material can be readily synthesized because of rapid technological developments in the fields of materials science and nanotechnology. In particular their highly attractive electrochemical properties and electrocatalytic activity have facilitated achievement of the high level of signal amplification needed for the development of ultrasensitive electrochemical affinity biosensors for the detection of proteins and DNA. This review article explains the basic principles of nanoparticle based electrochemical biosensors, highlights the recent advances in the development of nanoparticle based signal amplification strategies, and provides a critical assessment of the likely drawbacks associated with each strategy. Finally, future perspectives for achieving advanced signal simplification in nanoparticles based biosensors are considered. PMID- 24050665 TI - Quantitative structure-retention relationships models for prediction of high performance liquid chromatography retention time of small molecules: endogenous metabolites and banned compounds. AB - Quantitative structure-retention relationship (QSRR) is a technique capable of improving the identification of analytes by predicting their retention time on a liquid chromatography column (LC) and/or their properties. This approach is particularly useful when LC is coupled with a high-resolution mass spectrometry (HRMS) platform. The main aim of the present study was to develop and describe appropriate QSRR models that provide usable predictive capability, allowing false positive identification to be removed during the interpretation of metabolomics data, while additionally increasing confidence of experimental results in doping control area. For this purpose, a dataset consisting of 146 drugs, metabolites and banned compounds from World Anti-Doping Agency (WADA) lists, was used. A QSRR study was carried out separately on high quality retention data determined by reversed-phase (RP-LC-HRMS) and hydrophilic interaction chromatography (HILIC-LC HRMS) systems, employing a single protocol for each system. Multiple linear regression (MLR) was applied to construct the linear QSRR models based on a variety of theoretical molecular descriptors. The regression equations included a set of three descriptors for each model: ALogP, BELe6, R2p and ALogP(2), FDI, BLTA96, were used in the analysis of reversed-phase and HILIC column models, respectively. Statistically significant QSRR models (squared correlation coefficient for model fitting, R(2)=0.95 for RP and R(2)=0.84 for HILIC) indicate a strong correlation between retention time and the molecular descriptors. An evaluation of the best correlation models, performed by validation of each model using three tests (leave-one-out, leave-many-out, external tests), demonstrated the reliability of the models. This paper provides a practical and effective method for analytical chemists working with LC/HRMS platforms to improve predictive confidence of studies that seek to identify small molecules. PMID- 24050666 TI - Information fusion via constrained principal component regression for robust quantification with incomplete calibrations. AB - Incomplete calibrations are encountered in many applications and hamper chemometric data analyses. Such situations arise when target analytes are embedded in a chemically complex matrix from which calibration concentrations cannot be determined with reasonable efforts. In other cases, the samples' chemical composition may fluctuate in an unpredictable way and thus cannot be comprehensively covered by calibration samples. The reason for calibration model to fail is the regression principle itself which seeks to explain measured data optimally in terms of the (potentially incomplete) calibration model but does not consider chemical meaningfulness. This study presents a novel chemometric approach which is based on experimentally feasible calibrations, i.e. concentration series of the target analytes outside the chemical matrix ('ex situ calibration'). The inherent lack-of-information is then compensated by incorporating additional knowledge in form of regression constraints. Any outside knowledge can be utilized such as literature values of concentration ranges, concentration ratios implied e.g. by stoichiometry, sum parameters to which multiple analytes need to amount to, and/or reasonable signal reconstructions. The core idea is to mitigate the regression principle's strive for the best possible explanation of measured signals toward the best possible explanation under the condition of chemical meaningfulness. As proof-of-principle application, quantitative analyses of selected compounds in microalgae cells have been chosen. After acquiring FTIR calibration spectra from concentration series of 28 analytes, an ex situ calibration model has been built via principal component regression (PCR). Since microalgae biomass is a very complex matrix, the prediction step based on such an incomplete calibration fails. However, after incorporating several regression constraints into PCR predictions, chemically impossible results are avoided as depicted in the graphical abstract. Equally important are enhancements in concentration reproducibility. For most samples in the chosen application, the errorbars were reduced by one order of magnitude. By means of this novel chemometric method, quantitative analyses have been improved so much that cell responses to chemical shifts in their culturing environment can be studied. PMID- 24050667 TI - Amorphous carbon nitride as an alternative electrode material in electroanalysis: simultaneous determination of dopamine and ascorbic acid. AB - Boron-doped diamond (BDD) films are excellent electrode materials, whose electrochemical activity for some analytes can be tuned by controlling their surface termination, most commonly either to predominantly hydrogen or oxygen. This tuning can be accomplished by e.g. suitable cathodic or anodic electrochemical pretreatments. Recently, it has been shown that amorphous carbon nitride (a-CNx) films may present electrochemical characteristics similar to those of BDD, including the influence of surface termination on their electrochemical activity toward some analytes. In this work, we report for the first time a complete electroanalytical method using an a-CNx electrode. Thus, an a-CNx film deposited on a stainless steel foil by DC magnetron sputtering is proposed as an alternative electrode for the simultaneous determination of dopamine (DA) and ascorbic acid (AA) in synthetic biological samples by square wave voltammetry. The obtained results are compared with those attained using a BDD electrode. For both electrodes, a same anodic pretreatment in 0.1 mol L(-1) KOH was necessary to attain an adequate and equivalent separation of the DA and AA oxidation potential peaks of about 330 mV. The detection limits obtained for the simultaneous determination of these analytes using the a-CNx electrode were 0.0656 MUmol L(-1) for DA and 1.05 MUmol L(-1) for AA, whereas with the BDD electrode these values were 0.283 MUmol L(-1) and 0.968 MUmol L(-1), respectively. Furthermore, the results obtained in the analysis of the analytes in synthetic biological samples were satisfactory, attesting the potential application of the a-CNx electrode in electroanalysis. PMID- 24050668 TI - Development of hyperbranched polymers with non-covalent interactions for extraction and determination of aflatoxins in cereal samples. AB - A novel approach for assembling homogeneous hyperbranched polymers based on non covalent interactions with aflatoxins was developed; the polymers were used to evaluate the extraction of aflatoxins B1, B2, G1 and G2 (AFB1, AFB2, AFG1 and AFG2) in simulant solutions. The results showed that the extraction efficiencies of three kinds of synthesized polymers for the investigated analytes were not statistically different; as a consequence, one of the representative polymers (polymer I) was used as the solid-phase extraction (SPE) sorbent to evaluate the influences of various parameters, such as desorption conditions, pH, ionic strength, concentration of methanol in sample solutions, and the mass of the sorbent on the extraction efficiency. In addition, the extraction efficiencies for these aflatoxins were compared between the investigated polymer and the traditional sorbent C18. The results showed that the investigated polymer had superior extraction efficiencies. Subsequently, the proposed polymer for the SPE packing material was employed to enrich and analyze four aflatoxins in the cereal powder samples. The limits of detection (LODs) at a signal-to-noise (S/N) ratio of 3 were in the range of 0.012-0.120 ng g(-1) for four aflatoxins, and the limits of quantification (LOQs) calculated at S/N=10 were from 0.04 to 0.40 ng g( 1) for four aflatoxins. The recoveries of four aflatoxins from cereal powder samples were in the range of 82.7-103% with relative standard deviations (RSDs) lower than 10%. The results demonstrate the suitability of the SPE approach for the analysis of trace aflatoxins in cereal powder samples. PMID- 24050669 TI - Hyphenation of optimized microfluidic sample preparation with nano liquid chromatography for faster and greener alkaloid analysis. AB - A glass liquid-liquid extraction (LLE) microchip with three parallel 3.5 cm long and 100 MUm wide interconnecting channels was optimized in terms of more environmentally friendly (greener) solvents and extraction efficiency. In addition, the optimized chip was successfully hyphenated with nano-liquid chromatography with ultraviolet and mass spectrometric detection (nanoLC-UV-MS) for on-line analysis. In this system, sample pretreatment, separation and detection are integrated, which significantly shortens the analysis time, saves labor and drastically reduces solvent consumption. Strychnine was used as model analyte to determine the extraction efficiency of the optimized 3-phase chip. Influence of organic solvent, pH of feed phase, type of alkaloid, and flow rates were investigated. The results demonstrated that the 3-phase chip nanoLC-UV/MS hyphenation combines rapid (~25 s) and efficient (extraction efficiency >90%) sample prep, with automated alkaloid analyses. The method was applied to real samples including Strychnos nux-vomica seeds, Cephaelis ipecacuanha roots, Atropa belladonna leaves, and Vinca minor leaves. PMID- 24050670 TI - Biparametric multicommutated flow analysis system for determination of human serum phosphoesterase activity. AB - A multicommutated flow analysis (MCFA) system constructed of microsolenoid valves and pumps offering simultaneous determination of activity of acid phosphatase (ACP) and alkaline phosphatase (ALP) in human serum samples has been developed. The MCFA system is based on optoelectronic flow-through detector made of two light emitting diodes and operating according to paired emitter detector diode (PEDD) principle. This photometric PEDD device has been dedicated for detection of p-nitrophenol (NP) generated in the course of enzymatic hydrolysis of p nitrophenyl phosphate and optimized for the determination of NP in human serum samples. The developed PEDD-based MCFA system allows independent optimization of conditions for reaction and detection steps of photometric ACP and ALP bioassays. Moreover, it allows elimination of photometric interferences from serum matrix components according to two-points kinetic mode of measurement. The single measurement cycle takes 12 min, consists of four measurements (two for each phosphoesterase) and enables determination of serum ACP and ALP activities at physiological and pathological levels. The real analytical utility of the developed MCFA system has been confirmed by analysis of control sera as well as real human serum samples from healthy persons and oncological patients. PMID- 24050671 TI - Alkyd paints in art: characterization using integrated mass spectrometry. AB - Alkyd resins have been commonly used as binders in artist paints since the 1940s. The characterization of alkyds in samples from artworks can help to solve attribution and dating issues, investigate decay processes, and contribute to the planning of conservation strategies. Being able to assess the components of industrially formulated paint materials and to differentiate between different trademarks and producers is extremely interesting and requires multi-analytical approaches. In this paper we describe the characterization of commercial alkyd paint materials using a multi-analytical approach based on the integration of three different mass spectrometric techniques: gas chromatography-mass spectrometry (GC/MS), high performance liquid chromatography coupled with electrospray ionization mass spectrometry with a tandem quadrupole-time of flight mass spectrometer (HPLC-ESI-Q-ToF), and flow injection analysis (FIA) in the ESI Q-ToF mass spectrometer. GC/MS was successful in determining the fatty acid and aromatic fractions of the resins after hydrolysis; HPLC-ESI-Q-ToF analysis enabled us to identify the triglycerides (TAGs) and diglycerides (DAGs) profile of each resin, and FIA analysis was used as a rapid method to evaluate the presence of possible additives such as synthetic polymers. PMID- 24050672 TI - Quantitative analysis of polypeptide antibiotic residues in a variety of food matrices by liquid chromatography coupled to tandem mass spectrometry. AB - A quantitative LC-MS/MS method was developed for the determination of five polypeptide antibiotics (bacitracin, colistin A, colistin B, polymyxin B1 and polymyxin B2) in a variety of food matrices (muscle, liver, kidney, egg and milk). The described method is sufficiently sensitive, selective and provides acceptable recoveries for all compounds. The extraction is based on acidified methanolic solvent. This is followed by a reversed phase solid phase extraction step to clean-up and concentrate the extracts. The use of a modern core shell column in combination with an eluent consisting of trifluoroacetic acid, formic acid and acetonitrile provides chromatographically well resolved analyte peaks The single-step clean-up is fast and produces a sufficiently clean extract in order to control matrix-related signal suppression in the electrospray interface. PMID- 24050673 TI - Sensing of a nucleic acid binding protein via a label-free perylene probe fluorescence recovery assay. AB - A novel label-free fluorescence recovery assay for the sensing of a DNA binding protein has been developed. A transcription factor c-Jun protein, and a 21 base pair duplex DNA containing the c-Jun protein binding site (J-DNA) were selected. J-DNA was mixed with a cationic fluorescent perylene probe (compound 1), and induced aggregation of the probe. Quenching of the probe's fluorescence was observed. However, when c-Jun protein was mixed with the J-DNA, c-Jun bound to the duplex DNA, which reduced the degree of the induced perylene probe aggregation, and a turn on fluorescence signal was observed. The recovered fluorescence intensity was directly related to the amount of c-Jun added. The method is highly selective, six non-DNA binding proteins and one randomly selected 21 base pair duplex DNA (con-1) were tested. No noticeable compound 1 fluorescence recovery was observed. Mutations were also introduced to the c-Jun recognition sequence and much reduced fluorescence recovery was observed. Our assay is label-free, convenient, inexpensive, and fast. It can be used in biomedical research such as high throughput screening of drugs targeted at DNA binding proteins. PMID- 24050674 TI - Cyclically amplified fluorescent detection of theophylline and thiamine pyrophosphate by coupling self-cleaving RNA ribozyme with endonuclease. AB - A structure-switching-based approach for the design of fluorescent biosensors from known RNA aptazymes were demonstrated for the detection of theophylline and thiamine pyrophosphate (TPP). Taking advantages of the ability of graphene oxide (GO) to protect ssDNA from nuclease cleavage and the cyclic amplification induced by deoxyribonuclease I (DNase I), the amplified assay showed high sensitivity. In the presence of target, the target-dependent hammerhead aptazyme cleaves off. The released Shine-Dalgarno (SD) sequence was introduced into the detection system, in which a FAM labeled probe ssDNA was noncovalently assembled on GO, and the fluorescence of the dye was completely quenched. In the presence of the released sequence, the binding between the dye-labeled DNA and the SD sequence alter the conformation of dye-labeled DNA, and disturb the interaction between the dye labeled DNA and GO, liberating dye-labeled DNA from GO. The fluorescent intensity was increased, whereupon the DNase I can cleave the free DNA in the DNA/RNA complex, thereby liberating the fluorophore and ultimately releasing the SD RNA sequence. The released SD RNA sequence then binds another DNA probe, and the cycle starts anew, which leads to significant amplification of the fluorescent signal. The strategy showed good sensitivity and the dynamic ranges were of 0.1 10 MUM and 0.5-100 MUM for theophylline and TPP, respectively. The approach opens up a wide range of possibilities for sensing of other small molecules in biological entities. PMID- 24050675 TI - Recent advances in the treatment of life-threatening, invasive fungal infections. AB - INTRODUCTION: Invasive fungal infections (IFIs) pose significant morbidity and are often life-threatening to many high-risk patients. Timely diagnosis and treatment of these infections with optimal therapy is imperative. AREAS COVERED: Advances have been made in diagnostic biomarkers such as peptide nucleic acid fluorescent in situ hybridization, beta-D-glucan and galactomannan, although more research is needed in this area to assist with both diagnosis and monitoring for improvement of IFI management. Novel antifungal agents (azole antifungals and echinocandins) are being investigated that have activity against Candida spp. and Aspergillus spp. Optimizing the pharmacodynamics (PD) of our current antifungal therapies through such strategies as continuous infusion of amphotericin B and dose escalation of echinocandins and liposomal formulations of amphotericin B have also been investigated with mixed results. Therapeutic drug monitoring (TDM) shows promise as evident from data with such agents as flucytosine, itraconazole, voriconazole and posaconazole. EXPERT OPINION: The goal for the future of biomarkers in IFIs will be to have excellent sensitivity and specificity to ideally identify a particular fungus causing the infection or eliminate its existence to prevent unnecessary costs, resistance and antifungal usage. In addition, further developments of new antifungals are needed and judicious use of the current regimens needs to be optimized through antifungal PD properties and TDM. PMID- 24050676 TI - Rituximab as an effective alternative therapy in refractory idiopathic inflammatory myopathies. AB - OBJECTIVES: To assess the efficacy and safety of B-lymphocyte depletion therapy (BCDT) utilising rituximab in refractory idiopathic inflammatory myositis. METHODS: We retrospectively evaluated 16 adult patients with active dermatomyositis (DM) or polymyositis (PM) who received 1 gram rituximab intravenous infusions two weeks apart after failing to respond to conventional therapy. The clinical and biochemical response were analysed by the Myositis Intention to Treat index (MITAX) and the serum creatine kinase (CK) levels at baseline and 6 and 12 months after treatment. The primary efficacy outcome was 20% improvement in the MITAX index and 30% reduction in CK. RESULTS: Eight patients responded to treatment and achieved both the MITAX and CK levels objectives within 6 months of rituximab therapy. Five out of these 8 responders remained clinically stable at 12 months and CK levels were still reduced or normalised. Of note, 4 patients who did not respond were re-assessed and had their diagnoses corrected. All patients showed adequate B cell depletion (BCD) with re-population occurring for a 15.4 months average (range 3-42 months). Those simultaneously treated with cyclophosphamide achieved more long-lasting depletion (average 18.6 months). CONCLUSIONS: The heterogeneous clinical and serological characteristics of patients diagnosed with IIM probably explain why some, but not all patients respond to rituximab. Myositis overlap and anti-synthetase syndromes seem to respond better than other patient subsets. PMID- 24050677 TI - Electrolyte ion binding at iron oxyhydroxide mineral surfaces. AB - Electrolyte ion loadings at the surfaces of synthetic goethite (alpha-FeOOH) and lepidocrocite (gamma-FeOOH) particles that were pre-equilibrated in aqueous solutions of 10 mM NaCl and NaClO4 at 25 degrees C were investigated by cryogenic X-ray photoelectron spectroscopy (XPS). Atomic concentrations of Cl(-), ClO4(-), and Na(+) were correlated to potential determining ion (pdi; H(+), OH( )) loadings obtained by potentiometric titrations. While Cl(-) promoted more pdi adsorption than ClO4(-), due to its greater charge-to-size ratio, both ions followed the same loading dependence on pdi adsorption, in contrast to previous studies supporting the concept for negligible perchlorate adorption. Lepidocrocite particles exhibited a stronger response of electrolyte adsorption to pdi loadings due electrolyte ion adsorption on the proton inactive (010) plane. These particles also acquired greater sodium loadings than goethite. These loadings were moreover considerably enhanced by perchlorate adsorption, possibly due to a thickening of the interfacial region in NaClO4 on the (010) plane. Finally, goethite particles with rougher surfaces acquired greater pdi and ion loadings than on those with smoother surfaces. No strong differences could be discerned between Cl(-) and ClO4(-) loadings on these materials. This work thus identified key aspects underpinning the relationship between pdi and electrolyte loadings at FeOOH mineral surfaces of environmental and technological importance. PMID- 24050678 TI - Students' motives for using online formative assessments when preparing for summative assessments. AB - BACKGROUND: Formative assessments intend to provide feedback on student performance in order to improve and accelerate learning. Several studies have indicated that students using online formative assessments (OFAs), have better results on their exams. AIMS: The present study aims to provide insight in student reasons for using or not using available OFAs. METHOD: Three OFAs with feedback were available in a second year undergraduate course in physiology for biomedical sciences students (N = 147). First, students received an open questionnaire about why they did (not) complete the first two OFAs. Based on this data, a closed questionnaire was developed and distributed among students. Exploratory factor analysis (EFA) was applied. RESULTS: The results indicate reasons why students do (not) use the OFAs. The EFA for using the OFAs indicated three factors, that were interpreted as collecting (1) feed up, (2) feed forward, and (3) feed back information. The main reasons for not using the OFAs were lack of time and having completed the questions before. CONCLUSIONS: Students' reasons for using OFAs can be described in terms of collecting feed up, forward and back information and students' reasons for not using OFAs can be student-, teacher-, or mode-related. PMID- 24050679 TI - Simultaneous determination of multiple (fluoro)quinolone antibiotics in food samples by a one-step fluorescence polarization immunoassay. AB - This paper describes a rapid one-step fluorescence polarization immunoassay (FPIA) for the simultaneous determination of multiple (fluoro)quinolone antibiotics (FQs) in food samples. Several fluorescent tracers were synthesized and evaluated in the FPIA method based on a broad-specificity of monoclonal antibodies toward FQs. The heterogeneous tracer, SAR-5-FAM, was considered as the optimal choice to prepare the immunocomplex single reagent, which allows a rapid and sensitive displacement reaction by addition of analytes. Optimized single reagent FPIA exhibited broad cross-reactivities in the range of 7.8-172.2% with 16 FQs tested and was capable of determining most FQs at the level of maximum residue limits. Recoveries for spiked milk and chicken muscle samples were from 77.8 to 116%, with relative standard deviation lower than 17.4%. Therefore, this method could be applicable in routine screening analysis of multiple FQ residues in food samples. PMID- 24050680 TI - A selective approach to pyridine appended 1,2,3-triazolium salts. AB - A selective and highly efficient strategy to obtain a library of pyridine appended 1,4-disubstituted-3-methyl-1,2,3-triazolium salts is described. It features pyridine nitrogen protection at click-derived pyridyl-triazoles through N-oxidation with subsequent N3 alkylation of the triazole ring and deprotection. Triazolium salts are obtained in high yield and purity in either a stepwise or one-pot protocol. Preliminary data indicate their remarkable efficiency in palladium-catalyzed Suzuki-Miyaura catalysis in the environmentally benign solvent water. PMID- 24050681 TI - Active cognitive reserve influences the regional atrophy to cognition link in multiple sclerosis. AB - Recent research indicates that cognitive reserve mitigates the clinical expression of neuropsychological impairment in multiple sclerosis (MS). This literature primarily uses premorbid intelligence and lifetime experiences as indicators. However, changes in current recreational activities may also contribute to the maintenance of neural function despite brain atrophy. We examined the moderation effects of current changes in recreational activity on the relationship between brain atrophy and information processing speed in 57 relapsing-remitting MS patients. Current enrichment was assessed using the Recreation and Pastimes subscale from the Sickness Impact Profile. In patients reporting current declines in recreational activities, brain atrophy was negatively associated with cognition, but there was no such association in participants reporting stable participation. The MRI metric-by-recreational activity interaction was significant in separate hierarchical regression analyses conducted using third ventricle width, neocortical volume, T2 lesion volume, and thalamic volume as brain measures. Results suggest that recreational activities protect against brain atrophy's detrimental influence on cognition. PMID- 24050682 TI - Body armour: the effect of load, exercise and distraction on landing forces. AB - We investigated the effect of added load and intense exercise on jump and landing performance and ground reaction force (GRF) during landings where attentional demand was varied. Fifty-two males (37 +/- 9.2 years, 180.7 +/- 6.1 cm, 90.2 +/- 11.6 kg, maximal aerobic fitness (VO(2max)) 50 +/- 8.5 ml (.) kg(-1 .) min(-1), BMI 27.6 +/- 3.1, mean +/- s) completed a VO(2max) test. Experimental sessions were completed (>=4 days in between) in a randomised counterbalanced order, one while wearing body armour and appointments (loaded) and one without load (unloaded). A vertical jump, a drop landing concentrating on safe touchdown, a drop jump and a drop landing with an attentional distraction were performed. These were repeated 1 min after a 5-min treadmill run. Mean jump height decreased by 12% (P < 0.001) with loading and a further by 6% following the running task. Peak GRFs were increased by 13-19% with loading (P < 0.001) depending on the landing task demands and a further by 4-9% following intense exercise. The distracted drop landing had significantly higher GRFs compared to all other landings. Results demonstrate that added load impacts on jumping and landing performance, an effect that is amplified by prior intense exercise, and distraction during landing. Such increases in GRF apply to police officer performance in their duties and may increase the risk of injury. PMID- 24050683 TI - Release of phosphorous impurity from TiO2 anatase and rutile nanoparticles in aquatic environments and its implications. AB - Phosphorus-bearing materials as an additive have been popularly used in nanomaterial synthesis and the residual phosphorus within the nanoparticles (NPs) can be of an environmental concern. For instance, phosphorus within pristine commercial TiO2 NPs greatly influences the surface charge and aggregation behavior of the host TiO2 in aquatic environments; however, it is unknown whether and how fast phosphorus is released. In this study, we focus on the phosphorus release kinetics from five types of TiO2 NPs (i.e., 5, 10, and 50 nm anatase and 10 * 40, 30 * 40 nm rutile) under the influence of varying solution chemistries. The 50 nm anatase has the highest quantity of P (8.05 g/kg) and most leachable P dissolves within the first 2 h (i.e., 5.01 g/kg), which presents a potential pollutant source of P. Higher pH favors the phosphorus release (release order: pH 11.2 > pH 8.2 > pH 2.4), while variations in the environmentally relevant ionic strengths (0.01 M NaCl + 0.01 M NaHCO3 and 0.04 M NaCl + 0.01 M NaHCO3) and the presence of dissolved natural organic matter (10 mg/L) do not affect release rate greatly. X-ray Absorption Near Edge Structure results suggest that phosphate adsorbed on the pristine 50 nm anatase desorbs, and some dissolved phosphate again re-sorbs as a surface precipitate. The findings from this research may have important environmental implications such as accidental release of TiO2 NPs and other nanomaterials that are synthesized using phosphorus containing chemicals as an ingredient. PMID- 24050684 TI - Evaluation of the prediction of trace organic compound removal during ozonation of secondary effluents using tracer substances and second order rate kinetics. AB - The application of the R(CT)-concept for predicting the removal of trace organic compounds (TrOCs) in organic rich WWTP effluents is often problematic due to the fast ozone depletion with instantaneous ozone demand in the range of typically applied ozone dosages. In this study, the determination of OH-radical and ozone exposure from second order rate kinetics with two internal tracer substances was evaluated as alternative approach for these waters. Results from batch and semi batch experiments showed a linear correlation of OH-radical exposure with ozone consumption, characterized by its slope indicating the formation efficiency of OH radicals and a lag ozone consumption without significant formation of OH radicals. Evaluation of data from the project PILOTOX on ozonation of secondary effluent confirmed reasonable prediction of ozone resistant compound removal from relative residual concentration of an internal tracer substance. In contrast, predicting the reduction of TrOCs by direct reactions with ozone from internal tracers was not feasible. Similar removal efficiencies for fast reacting compounds with different rate constants from k(O3) = 10(4) M(-1) s(-1) to k(O3) = 10(6) M(-1) s(-1) were observed indicating a limitation of the reaction by mass transfer. This effect was observed at low ozone dosages in semi-batch and pilot experiments as well as in batch experiments, where mass transfer from gas to liquid phase is not limiting. It is assumed that consumption of low ozone dosages is faster than sample homogenization in the batch reactors used. Thus, prediction of compound removal by direct reaction with ozone always needs to consider reactor design and geometry. PMID- 24050685 TI - Transport of nanoparticles with dispersant through biofilm coated drinking water sand filters. AB - This article characterizes, experimentally and theoretically, the transport and retention of engineered nanoparticles (NP) through sand filters at drinking water treatment plants (DWTPs) under realistic conditions. The transport of four commonly used NPs (ZnO, CeO2, TiO2, and Ag, with bare surfaces and coating agents) through filter beds filled with sands from either acid washed and calcined, freshly acquired filter media, and used filter media from active filter media, were investigated. The study was conducted using water obtained upstream of the sand filter at DWTP. The results have shown that capping agents have a determinant importance in the colloidal stability and transport of NPs through the different filter media. The presence of the biofilm in used filter media increased adsorption of NPs but its effects in retaining capped NPs was less significant. The data was used to build a mathematical model based on the advection-dispersion equation. The model was used to simulate the performance of a scale-up sand filter and the effects on filtration cycle of traditional sand filtration system used in DWTPs. PMID- 24050686 TI - Environmental perceptions as mediators of the relationship between the objective built environment and walking among socio-economically disadvantaged women. AB - BACKGROUND: Women living in socio-economically disadvantaged neighbourhoods are at increased risk for physical inactivity and associated health outcomes and are difficult to reach through personally tailored interventions. Targeting the built environment may be an effective strategy in this population subgroup. The aim of this study was to examine the mediating role of environmental perceptions in the relationship between the objective environment and walking for transportation/recreation among women from socio-economically disadvantaged neighbourhoods. METHODS: Baseline data of the Resilience for Eating and Activity Despite Inequality (READI) study were used. In total, 4139 women (18-46 years) completed a postal survey assessing physical environmental perceptions (aesthetics, neighbourhood physical activity environment, personal safety, neighbourhood social cohesion), physical activity, and socio-demographics. Objectively-assessed data on street connectivity and density of destinations were collected using a Geographic Information System database and based on the objective z-scores, an objective destinations/connectivity score was calculated. This index was positively scored, with higher scores representing a more favourable environment. Two-level mixed models regression analyses were conducted and the MacKinnon product-of-coefficients test was used to examine the mediating effects. RESULTS: The destinations/connectivity score was positively associated with transport-related walking. The perceived physical activity environment mediated 6.1% of this positive association. The destinations/connectivity score was negatively associated with leisure-time walking. Negative perceptions of aesthetics, personal safety and social cohesion of the neighbourhood jointly mediated 24.1% of this negative association. CONCLUSION: For women living in socio-economically disadvantaged neighbourhoods, environmental perceptions were important mediators of the relationship between the objective built environment and walking. To increase both transport-related and leisure-time walking, it is necessary to improve both objective walkability-related characteristics (street connectivity and proximity of destinations), and perceptions of personal safety, favourable aesthetics and neighbourhood social cohesion. PMID- 24050687 TI - Brazilwood reds: the (photo)chemistry of brazilin and brazilein. AB - The ground and excited state (in the singlet state, S1) acid-base equilibria, together with the photophysical properties of the two main constituents of brazilwood, brazilin and brazilein, have been investigated in aqueous solutions in the pH range: -1 < pH < 10. Brazilin is the colorless reduced form of brazilein where three ground and three excited state species (B(red)H(n), with n = 2-4 representing the protonated hydroxyl groups) are observed with two corresponding acidity constants: pKa1 = 6.6 and pKa2 = 9.4 (pKa1* = 4.7 and pKa2* = 9.9, obtained from the Forster cycle). In the case of brazilein, three ground species (pKa1 = 6.5 and pKa2 = 9.5) and four excited state species were identified (again from the Forster cycle: pKa1* = 3.9 and pKa2* = 9.8). The colorless species (brazilin) presents a high fluorescence quantum yield (F = 0.33) and competitive radiative channel (kF = 1.3 * 10(9) s(-1)) over radiationless processes (kNR = 2.6 * 10(9) s(-1)). In contrast to this behavior, brazilein displays a F value 2 orders of magnitude lower and a dominance of the radiationless decay pathways, which is suggested to be linked to an excited state proton transfer leading to a quinoidal-like structure. This is further supported by time-resolved data (obtained in a ps time domain). The overall data indicates that brazilin is more prone to degradation than brazilein, mainly due to the high efficiency of the radiationless decay channel (likely through internal conversion), which confers a stabilizing inherent characteristic to the latter. In the case of brazilein, the efficiency of the radiationless channel is linked to an excited state intramolecular proton transfer resulting from an excited state equilibrium involving neutral and zwitterionic tautomeric species of this compound. Furthermore, a theoretical study has been performed with the determination of the optimized ground-state and excited molecular geometries for the two compounds together with the prediction of the lowest vertical one electron excitation energy and the relevant molecular orbital contours and charge densities changes using density functional theory calculations. These were found to corroborate differences in acidity in the ground and excited states. PMID- 24050688 TI - Transmission of Schmallenberg virus during Winter, Germany. PMID- 24050689 TI - Receptor guided 3D-QSAR analysis of thieno[2,3-b]pyridine-5- carbonitrile inhibitors of protein kinase C theta (PKC-theta). AB - In the present study, receptor induced 3D-QSAR model was developed for a set of 46 thieno[2,3-b]pyridine-5- carbonitrile PKC-theta inhibitors, to explore the structural requirements of the molecules necessary for PKC-theta inhibition. Since the chemical nature of the studied molecules was different from the crystal ligand of the selected protein, induced fit docking (IFD) protocol was employed to induce the conformational changes in the active site of the selected protein. Thereafter, all molecules were docked into the newly generated active site environment of the selected protein using glide docking program, and the 3D-QSAR analysis was performed in PHASE program utilizing the docking based alignment of the molecules. The best 3D-QSAR model was selected on the basis of the highest value of Q(2)test (0.600), and the selected model also showed high values of R(2)train , 0.915, Pearson-r, 0.801 and low value of SD, 0.241. The contour maps corresponding to the selected 3D-QSAR model, in combination with docking analysis, helped to explore the essential amino acid residues involved in binding, and structural requirements of the ligand molecules necessary for complementary fit with the active site of the protein. Therefore, the information revealed from the generated model can further be explored as a novel tool for the designing of new congener molecules that can serve as potential therapeutics for the treatment of various disease conditions associated with abnormal PKC-theta signalling. PMID- 24050690 TI - Scaffold hopping for identification of novel PKCbetaII inhibitors based on ligand and structural approaches, virtual screening and molecular dynamics study. AB - Protein Kinase C betaII (PKCbetaII) overexpression has been linked to various diabetic microvascular complications viz. retinopathy, neuropathy, and cardiomyopathy. Novel and potent small molecules with preferential selective inhibitory property of PKCbetaII will be helpful in treatment as well as understanding insight of PKCbetaII involvement in these complications. Robust 3D hypotheses were developed using both the crystal structure and available PKCbetaII ligands, and were validated by feature mapping and screening in-house database of reported PKCbetaII compounds. The best hypothesis from both methods consists of six features viz. one hydrogen bond donor (D), two hydrogen bond acceptors (A1, A2), two hydrophobic-aromatics (H1, H2) and one ring aromatic (R). A synergistic approach of virtual screening using both ligand and receptor based pharmacophore model was used for the flexible search of ligands from chemical databases. The hits obtained were screened by molecular docking and their binding affinity was predicted using MMPBSA calculations. The first receptor based query of PKCbetaII and new scaffold of its inhibitors with good estimated activities, favorable binding interactions, and high docking score were identified. PMID- 24050691 TI - Identification of potent inhibitors for Salmonella typhimurium quorum sensing via virtual screening and pharmacophore modeling. AB - The quorum sensing (QS) enhanced transcriptional regulator SdiA of S. typhimurium is the best known and potential target and responds to a broad range of AHLs and AHL analogs. On the other hand, in many gram-negative bacteria including S. typhimurium, brominated furanones were reported to have inhibitory activity against the QS phenotypes. Motivated by both, we designed an in silico group of halogenated AHLs by substituting halogen compounds (Br, Cl, F and I) on the lactone ring of AHLs and analyzed their interactions with SdiA. The best analogs based on their docking score and another 18 training sets with inhibitory activity against S. typhimurium QS were used to design the pharmacophore. This pharmacophore model was used as a 3D database query against the MayBridge Database consisting of 56,000 compounds and subsequently, the screened compounds were filtered by Lipinski's rule and ADMET properties. This results in 10 compounds as probable leads to inhibit the SdiA activity and they were docked in the active site of SdiA. Among these, 3 compounds CD01374, RJF00047, and KM10117 exhibited the best docking scores and also favors the necessary hydrogen bond interactions with the essential amino acids in SdiA, and thus identified as novel leads to inhibit Salmonella pathogenicity. PMID- 24050692 TI - A passerini-type condensation: a carboxylic acid-free approach for the synthesis of the alpha-acyloxycarboxamides. AB - A Passerini-type condensation for the synthesis of alpha-acyloxycarboxamides starting from simple and readily available inputs, including an isocyanide, aldehydes and water in the presence of trimethylsilyl azide as a catalyst under reflux conditions in toluene in good yields, is described. PMID- 24050693 TI - Fast and green one-pot multicomponent synthesis of a library of pyrrolo [1,2-c] pyrimidines under microwave irradiation. AB - A simple, clean and rapid one-pot three component, microwave-assisted synthesis of pyrrolo[1,2-c]pyrimidine derivatives starting from various substituted pyrimidines, 2-bromoacetophenones and nonsymmetrical, electron deficient alkynes in 1,2-epoxybutane which acts both as solvent and acid scavenger is reported. This one-pot three component synthesis implies short reaction times being at the same time highly cost-effective and environmental friendly. PMID- 24050694 TI - Insecticidal activity of fatty acid-rich Turkish bryophyte extracts against Sitophilus granarius (Coleoptera: Curculionidae). AB - The composition of fatty acids and insecticidal effects was performed for the Turkish mosses Dicranum scoparium, Hypnum cupressiforme, Polytrichastrum formosum, Homalothecium lutescens and the Turkish liverwort Conocephalum conicum. All structures were determined by means of gas chromatography and gas chromatography-mass spectrometry techniques. The determination of fatty acids was done using a simple and mild method that utilized different solvent extractions ranging from nonpolar to polar solvents (hexane, dichloromethane, chloroform, ethyl acetate and methanol, respectively), and the samples were powdered with and without liquid nitrogen. The correlations between the saturated and unsaturated fatty acid contents depending on the solvent polarity and their crushing process by liquid nitrogen were observed. The insecticidal activity of the bryophytes was analyzed by using the methanol, hexane and esterified methanol extracts. The hexane extracts of Polytrichastrum formosum showed the highest insecticidal activity (70.33%) against Sitophilus granarius. Contact toxicity activities of lauric, myristic and palmitic acids besides single dose studies of the solvent extracts were carried out. The highest mortality rate (53.34%) was obtained from the myristic acid among the tested pure fatty acids. The activities of palmitic and lauric acids were 17.75% and 4.32%, respectively. PMID- 24050695 TI - Density field theory approach to design multi-template imprinted polymers for carcinogenic PAHs sensing. AB - Molecular imprinting is an interesting technique for preparation of molecular recognition materials with discriminating similar molecules from complex systems. In particular, imprinting more than one molecule has immense application in remediation of industrial waste. Major difficulty in molecular imprinting is the selection of suitable polymer precursors. In this article, authors have proposed a new computational approach for combinatorial screening of polymer precursor library to select appropriate polymer precursors to prepare imprinted polymer capable of selectively binding carcinogenic polycyclic aromatic hydrocarbons (PAHs). Molecular Dynamics (MD) and Quantum Mechanics (QM) models were used to compute interaction energy scores between polymer precursors and PAHs in a simulated solvent box. A self-designed virtual library of functional monomers has been prepared, and then used for MD simulations to screen the best functional monomers. Initially, molecules used in the study were geometrically optimized and then interaction energies were computed using density functional theory (DFT) in Becke 3-Parameter Exchange Correlation Function (B3LYP) level with 6-31G*basis set on Gaussian 4.1 Ver. software. Complimentary to theoretical predictions, selected polymers were prepared in laboratory and compared theoretically computed binding score with the binding capacity of the polymer on spectrofluorimetry. The computer simulations used in this research paper are rapid and reliable for the combinatorial screening of polymer precursors in experimental-free way to design of multi-template imprinted polymers. PMID- 24050696 TI - Screening of photosynthetic pigments for herbicidal activity with a new computational molecular approach. AB - There is an immense interest among the researchers to identify new herbicides which are effective against the herbs without affecting the environment. In this work, photosynthetic pigments are used as the ligands to predict their herbicidal activity. The enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase is a good target for the herbicides. Homology modeling of the target enzyme is done using Modeler 9.11 and the model is validated. Docking studies were performed with AutoDock Vina algorithm to predict the binding of the natural pigments such as beta-carotene, chlorophyll a, chlorophyll b, phycoerythrin and phycocyanin to the target. beta-carotene, phycoerythrin and phycocyanin have higher binding energies indicating the herbicidal activity of the pigments. This work reports a procedure to screen herbicides with computational molecular approach. These pigments will serve as potential bioherbicides in the future. PMID- 24050697 TI - Aggregation-induced fluorescence behavior of triphenylamine-based Schiff bases: the combined effect of multiple forces. AB - Eight triphenylamine (TPA)-based Schiff bases that exhibit different aggregation induced emission (AIE) or aggregation-caused quenching (ACQ) behavior in tetrahydrofuran (THF)/water mixtures have been synthesized and characterized. The photophysical properties in solution, aqueous suspension, film, and the crystalline state along with their relationships were comparatively investigated. The single-crystal structures of 1-8 indicate that compact pi...pi stacking or excimers induce fluorescence quenching of 1, 2, 5, and 7. However, the existence of J aggregates or multiple intra- and intermolecular interactions restrict the intramolecular vibration and rotation, enabling compounds 3, 4, 6, and 8 to exhibit good AIE character. The size and growth process of particles with different water fractions were studied using scanning electron microscopy, which demonstrated that smaller uniformly dispersed nanoparticles in the THF/water mixtures favor fluorescence emission. The above results suggest that the combined effects of multiple forces caused by structural variation have a great influence on their molecular packing, electronic structure, and aggregation-induced fluorescence properties. In addition, piezofluorochromic experiments verified the potential applications of 4 and 6. PMID- 24050699 TI - Targeting multidrug resistance protein 1 (MRP1, ABCC1): past, present, and future. AB - The human ATP-binding cassette transporter multidrug resistance protein 1 (MRP1), encoded by ABCC1, was initially identified because of its ability to confer multidrug resistance in lung cancer cells. It is now established that MRP1 plays a role in protecting certain tissues from xenobiotic insults and that it mediates the cellular efflux of the proinflammatory cysteinyl leukotriene C4 as well as a vast array of other endo- and xenobiotic organic anions. Many of these are glutathione (GSH) or glucuronide conjugates, the products of Phase II drug metabolism. MRP1 also plays a role in the cellular efflux of the reduced and oxidized forms of GSH and thus contributes to the many physiological and pathophysiological processes influenced by these small peptides, including oxidative stress. In this review, the pharmacological and physiological aspects of MRP1 are considered in the context of the current status and future prospects of pharmacological and genetic modulation of MRP1 activity. PMID- 24050698 TI - Socioeconomic status and childhood asthma in urban minority youths. The GALA II and SAGE II studies. AB - RATIONALE: The burden of asthma is highest among socioeconomically disadvantaged populations; however, its impact is differentially distributed among racial and ethnic groups. OBJECTIVES: To assess the collective effect of maternal educational attainment, annual household income, and insurance type on childhood asthma among minority, urban youth. METHODS: We included Mexican American (n = 485), other Latino (n = 217), and African American (n = 1,141) children (aged 8 21 yr) with and without asthma from the San Francisco Bay Area. An index was derived from maternal educational attainment, annual household income, and insurance type to assess the collective effect of socioeconomic status on predicting asthma. Logistic regression stratified by racial and ethnic group was used to estimate adjusted odds ratios (aOR) and their 95% confidence intervals (CI). We further examined whether acculturation explained the socioeconomic asthma association in our Latino population. MEASUREMENTS AND MAIN RESULTS: In the adjusted analyses, African American children had 23% greater odds of asthma with each decrease in the socioeconomic index (aOR, 1.23; 95% CI, 1.09-1.38). Conversely, Mexican American children have 17% reduced odds of asthma with each decrease in the socioeconomic index (aOR, 0.83; 95% CI, 0.72-0.96) and this relationship was not fully explained by acculturation. This association was not observed in the other Latino group. CONCLUSIONS: Socioeconomic status plays an important role in predicting asthma, but has different effects depending on race and ethnicity. Further steps are necessary to better understand the risk factors through which socioeconomic status could operate in these populations to prevent asthma. PMID- 24050700 TI - Environmental toxins and Parkinson's disease. AB - Parkinson's disease (PD) is a chronic, progressive, disabling neurodegenerative disorder that begins in mid to late life and is characterized by motor impairment, autonomic dysfunction, and, in many, psychological and cognitive changes. Recent advances have helped delineate pathogenetic mechanisms, yet the cause of PD in most individuals is unknown. Although at least 15 genes and genetic loci have been associated with PD, identified genetic causes are responsible for only a few percent of cases. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, solvents, metals, and other pollutants, and many of these compounds recapitulate PD pathology in animal models. This review summarizes the environmental toxicology of PD, highlighting the consistency of observations across cellular, animal, and human studies of PD pathogenesis. PMID- 24050702 TI - Intense competition between arbuscular mycorrhizal mutualists in an in vitro root microbiome negatively affects total fungal abundance. AB - The root microbiome is composed of an incredibly diverse microbial community that provides services to the plant. A major question in rhizosphere research is how species in root microbiome communities interact with each other and their host. In the nutrient mutualism between host plants and arbuscular mycorrhizal fungi (AMF), competition often leads to certain species dominating host colonization, with the outcome being dependent on environmental conditions. In the past, it has been difficult to quantify the abundance of closely related species and track competitive interactions in different regions of the rhizosphere, specifically within and outside the host. Here, we used an artificial root system (in vitro root organ cultures) to investigate intraradical (within the root) and extraradical (outside the root) competitive interactions between two closely related AMF species, Rhizophagus irregularis and Glomus aggregatum, under different phosphorus availabilities. We found that competitive interactions between AMF species reduced overall fungal abundance. R. irregularis was consistently the most abundant symbiont for both intraradical and extraradical colonization. Competition was the most intense for resources within the host, where both species negatively affected each other's abundance. We found the investment ratio (i.e. extraradical abundance/intraradical abundance) shifted for both species depending on whether competitors were present or not. Phosphorus availability did not change the outcome of these interactions. Our results suggest that studies on competitive interactions should focus on intraradical colonization dynamics and consider how changes in investment ratio are mediated by fungal species interactions. PMID- 24050703 TI - Application of the rotating ring-disc-electrode technique to water oxidation by surface-bound molecular catalysts. AB - We report here the application of a simple hydrodynamic technique, linear sweep voltammetry with a modified rotating-ring-disc electrode, for the study of water oxidation catalysis. With this technique, we have been able to reliably obtain turnover frequencies, overpotentials, Faradaic conversion efficiencies, and mechanistic information from single samples of surface-bound metal complex catalysts. PMID- 24050701 TI - Antiparasitic chemotherapy: from genomes to mechanisms. AB - Owing to the absence of antiparasitic vaccines and the constant threat of drug resistance, the development of novel antiparasitic chemotherapies remains of major importance for disease control. A better understanding of drug transport (uptake and efflux), drug metabolism and the identification of drug targets, and mechanisms of drug resistance would facilitate the development of more effective therapies. Here, we focus on malaria and African trypanosomiasis. We review existing drugs and drug development, emphasizing high-throughput genomic and genetic approaches, which hold great promise for elucidating antiparasitic mechanisms. We describe the approaches and technologies that have been influential for each parasite and develop new ideas for future research directions, including mode-of-action studies for drug target deconvolution. PMID- 24050705 TI - Production of pure indinavir free base nanoparticles by a supercritical anti solvent (SAS) method. AB - CONTEXT: This work investigated the production of pure indinavir free base nanoparticles by a supercritical anti-solvent method to improve the drug dissolution in intestine-like medium. OBJECTIVE: To increase the dissolution of the drug by means of a supercritical fluid processing method. MATERIALS AND METHODS: Acetone was used as solvent and supercritical CO2 as antisolvent. Products were characterized by dynamic light scattering (size, size distribution), scanning electron microscopy (morphology), differential scanning calorimetry (thermal behaviour) and X-rays diffraction (crystallinity). RESULTS AND DISCUSSION: Processed indinavir resulted in particles of significantly smaller size than the original drug. Particles showed at least one dimension at the nanometer scale with needle or rod-like morphology. Results of X-rays powder diffraction suggested the formation of a mixture of polymorphs. Differential scanning calorimetry analysis showed a main melting endotherm at 152 degrees C. Less prominent transitions due to the presence of small amounts of bound water (in the raw drug) or an unstable polymorph (in processed IDV) were also visible. Finally, drug particle size reduction significantly increased the dissolution rate with respect to the raw drug. Conversely, the slight increase of the intrinsic solubility of the nanoparticles was not significant. CONCLUSIONS: A supercritical anti-solvent method enabled the nanonization of indinavir free base in one single step with high yield. The processing led to faster dissolution that would improve the oral bioavailability of the drug. PMID- 24050704 TI - Intraspecific variation of recombination rate in maize. AB - BACKGROUND: In sexually reproducing organisms, meiotic crossovers ensure the proper segregation of chromosomes and contribute to genetic diversity by shuffling allelic combinations. Such genetic reassortment is exploited in breeding to combine favorable alleles, and in genetic research to identify genetic factors underlying traits of interest via linkage or association-based approaches. Crossover numbers and distributions along chromosomes vary between species, but little is known about their intraspecies variation. RESULTS: Here, we report on the variation of recombination rates between 22 European maize inbred lines that belong to the Dent and Flint gene pools. We genotype 23 doubled haploid populations derived from crosses between these lines with a 50 k-SNP array and construct high-density genetic maps, showing good correspondence with the maize B73 genome sequence assembly. By aligning each genetic map to the B73 sequence, we obtain the recombination rates along chromosomes specific to each population. We identify significant differences in recombination rates at the genome-wide, chromosome, and intrachromosomal levels between populations, as well as significant variation for genome-wide recombination rates among maize lines. Crossover interference analysis using a two-pathway modeling framework reveals a negative association between re combination rate and interference strength. CONCLUSIONS: To our knowledge, the present work provides the most comprehensive study on intraspecific variation of recombination rates and crossover interference strength in eukaryotes. Differences found in recombination rates will allow for selection of high or low recombining lines in crossing programs. Our methodology should pave the way for precise identification of genes controlling recombination rates in maize and other organisms. PMID- 24050706 TI - Clinical features and prognosis in 82 patients with adult-onset Still's disease. AB - OBJECTIVES: To assess the clinical features, laboratory findings, and response to therapy according to disease course, and analyse the predictive factors for unfavourable outcomes in patients with adult-onset Still's disease (AOSD). METHODS: We retrospectively reviewed the medical records of 82 patients from January 1992 to December 2010 at a single tertiary hospital. Thirty-three had monocyclic disease, 33 experienced at least one relapse, and 14 had chronic disease. Patients were divided into those with favourable (monocyclic, n=33) and unfavourable (polycyclic or chronic and death, n=49) outcomes. RESULTS: The major clinical features were high spiking fever (96.3%), polyarthralgia (85.4%), skin rash (80.5%), myalgia (70.7%), and sore throat (68.3%). Analysis of prognostic factors for the 2 groups showed that polyarthralgia, elevated erythrocyte sedimentation rate, high serum lactate dehydrogenase, and low dose of initial glucocorticoids were related with unfavourable outcomes. An insufficient starting dosage of prednisolone or its equivalent (<30 mg/day) was the most significant predictive factor (OR 6.476, p=0.007) for chronic and relapsing disease, markedly decreasing response rates. CONCLUSIONS: Although AOSD is a benign disease, relapses are common and a chronic disease requires immunosuppressive therapy, that these unfavourable patients show significantly longer time from initiation of treatment to remission. Hence, it is important to control disease activity at the start of treatment with sufficient glucocorticoids. PMID- 24050707 TI - Chronic rhinosinusitis: an update on current pharmacotherapy. AB - INTRODUCTION: Chronic rhinosinusitis (CRS) is an inflammatory disease of the nasal and paranasal mucosa with great impact on quality of life and a large financial burden on society. This article provides an overview of its current and future pharmacotherapy, the mainstay of CRS treatment. AREAS COVERED: This article reviews the etiology, antibiotic and corticosteroid treatment, nasal irrigation therapy, bacterial lysates, anti-immunoglobulin E and anti-interleukin 5 therapy of CRS. This review highlights articles of interest on these topics in the PubMed database. Studies not in English language were excluded. EXPERT OPINION: CRS is a spectrum of disease characterized by mucosal inflammation. Defining its various subtypes will change its medical treatment from general anti inflammatory medicine towards tailor-made pharmacotherapy. The optimal timing of endoscopic sinus surgery in this treatment process remains to be defined. PMID- 24050708 TI - Influence of arenicin on phase transitions and ordering of lipids in 2D model membranes. AB - Antimicrobial peptides (AMPs) are important effector molecules of the innate immune system of all species. AMPs are highly selective and can be used as lead structures for the development of new drugs complementing standard antibiotic therapies. Understanding the crucial parameters of peptide-membrane interactions is necessary for elucidation of the molecular mechanisms of action. Phospholipid monolayers, as simple 2D models of the membrane surface, can be effectively used for studies of peptide-membrane interactions. The present study is focused on the recently discovered peptide arenicin-1 (Ar-1), which possesses antibacterial and antifungal activities. A linear derivative with serine residues instead of cysteines (C/S-Ar-1) was additionally used to investigate the influence of the AMP on the phase behavior of lipid monolayers at the air/liquid interface. Using the Langmuir balance technique and IRRAS allows us to conclude that both original and modified arenicins reveal a strong influence on the phase transition of anionic phospholipids (fluidization of the lipid hydrocarbon chains), whereas the thermodynamic properties of the zwitterionic phospholipid layers are not affected. A strong effect of the modified peptide on the ordering of negatively charged phospholipids at the air-water interface compared to zwitterionic phospholipids has been observed using GIXD measurements, supported by IRRAS simulations for the spectral range corresponding to the lipid hydrocarbon chains. At lateral pressures above 30 mN/m, both peptides are squeezed out from zwitterionic lipid monolayers, but remains attached to and partly incorporated in anionic lipid monolayers. This study points at the importance of the interplay between hydrophobic and electrostatic interactions for the membrane disruption by AMPs. PMID- 24050709 TI - The Multiple Mini-Interview (MMI) for student selection in health professions training - a systematic review. AB - BACKGROUND: The Multiple Mini-Interview (MMI) has been used increasingly for selection of students to health professions programmes. OBJECTIVES: This paper reports on the evidence base for the feasibility, acceptability, reliability and validity of the MMI. DATA SOURCES: CINAHL and MEDLINE STUDY ELIGIBILITY CRITERIA: All studies testing the MMI on applicants to health professions training. STUDY APPRAISAL AND SYNTHESIS METHODS: Each paper was appraised by two reviewers. Narrative summary findings on feasibility, acceptability, reliability and validity are presented. RESULTS: Of the 64 citations identified, 30 were selected for review. The modal MMI consisted of 10 stations, each lasting eight minutes and assessed by one interviewer. The MMI was feasible, i.e. did not require more examiners, did not cost more, and interviews were completed over a short period of time. It was acceptable, i.e. fair, transparent, free from gender, cultural and socio-economic bias, and did not favour applicants with previous coaching. Its reliability was reported to be moderate to high, with Cronbach's alpha = 0.69 0.98 and G = 0.55-0.72. MMI scores did not correlate to traditional admission tools scores, were not associated with pre-entry academic qualifications, were the best predictor for OSCE performance and statistically predictive of subsequent performance at medical council examinations. CONCLUSIONS: The MMI is reliable, acceptable and feasible. The evidence base for its validity against future medical council exams is growing with reports from longitudinal investigations. However, further research is needed for its acceptability in different cultural context and validity against future clinical behaviours. PMID- 24050710 TI - Self-association of water-soluble peptoids comprising (S)-N-1 (naphthylethyl)glycine residues. AB - Peptoids (N-substituted glycine oligomers) are widely used peptidomimetics, and an enhanced understanding of their structures is needed to expand their utility, particularly in aqueous applications. We report the synthesis and structural study of four water-soluble peptoids that include strongly helix-promoting (S)-N 1-(naphthylethyl)glycine residues. Peptoid structure changes with both peptoid length and solvent composition. Multiple data support the self-association of the longest peptoid studied here, 1, via hydrophobic interactions in aqueous solutions. PMID- 24050711 TI - Inverse relationship between vitamin D status and insulin resistance and the risk of impaired fasting glucose in Korean children and adolescents: the Korean National Health and Nutrition Examination Survey (KNHANES) 2009-2010. AB - OBJECTIVE: To investigate whether low vitamin D status was related to insulin resistance (IR) or impaired fasting glucose (IFG) in Korean adolescents, after adjusting for total body fat mass (FM). DESIGN: A cross-sectional study. SETTING: Korea National Health and Nutrition Examination Survey (KNAHNES) 2009-2010. SUBJECTS: In total, 1466 participants (769 males) aged 10-19 years were assessed for serum 25-hydroxyvitamin D (25(OH)D) levels, for FM by whole-body dual-energy X-ray absorptiometry and for IR by homeostasis model assessment (HOMA-IR) after an 8 h fast. RESULTS: Age-, sex-, season- and physical-activity-adjusted regression models showed that serum 25(OH)D levels were significantly related to markers of adiposity (P = 0.016 for FM (g), P = 0.023 for FM (%) and P = 0.035 for fat mass index). When the participants were stratified into three 25(OH)D categories (<37.5 nmol/l (n 553), 37.5 to < 50 nmol/l (n 543) and >= 50 nmol/l (n 370)), significantly decreasing trends were observed for fasting insulin (all P < 0.001), HOMA-IR (all P < 0.001) and the odds ratios for IFG (all P for trend < 0.05) from the lowest to the highest 25(OH)D category, after adjustments for age, sex, physical activity and all markers of adiposity. In the multivariate logistic regression analysis, the likelihood of participants in the lowest serum 25(OH)D category having IFG was 2.96-3.15 compared with those in the highest 25(OH)D category (all P < 0.05). CONCLUSIONS: There was a significant inverse relationship between vitamin D status and IR and the risk of IFG, independent of adiposity, in Korean adolescents. PMID- 24050712 TI - Effects of short-term exercise training on tissue Doppler indices of left ventricular diastolic function in overweight and obese individuals. AB - Although exercise training is unable to improve obesity-associated decreases in left ventricular (LV) diastolic function, as assessed using chamber function measurements, the effects on LV diastolic myocardial function, as assessed using tissue Doppler imaging (TDI), are uncertain. In 32 overweight (n = 11) or obese (n = 21), sedentary or recreationally active men and women (30-57 years), we assessed the effects of 6 weeks of exercise training either preceded (n = 16) or followed (n = 16) by a 6-week control period on TDI indices of LV diastolic function (e', e'/a' and E/e') (echocardiography). Diastolic function at baseline was comparable to that noted in overweight and obese participants from a community sample (n = 245), and 56% (n = 18) had e' values below the lower 95% CI of a lean and healthy cohort (n = 60) of the community sample. Exercise training increased peak oxygen consumption (27.4 +/- 4.9 to 29.4 +/- 5.8 mL . kg(-1) . min(-1), P = 0.0001), but had no effect on body mass index (P = 0.99). No changes in TDI indices of diastolic function were observed after exercise training in all the participants (e': P = 0.74, a': P = 0.98, e'/a': P = 0.85, E/e': P = 0.26), participants with abnormal e' values (n = 18)(e': P = 0.99, a': P = 0.96, e'/a': P = 0.91, E/e': P = 0.97) or obese participants (n = 21)(e': P = 0.67, a': P = 1.00, e'/a': P = 0.78, E/e': P = 0.11). In conclusion, exercise training, despite increasing cardiorespiratory fitness, is unable to improve obesity-associated decreases in LV diastolic myocardial function. PMID- 24050713 TI - Presence of the Corexit component dioctyl sodium sulfosuccinate in Gulf of Mexico waters after the 2010 Deepwater Horizon oil spill. AB - Between April 22 and July 15, 2010, approximately 4.9 million barrels of oil were released into the Gulf of Mexico from the Deepwater Horizon oil well. Approximately 16% of the oil was chemically dispersed, at the surface and at 1500 m depth, using Corexit 9527 and Corexit 9500, which contain dioctyl sodium sulfosuccinate (DOSS) as a major surfactant component. This was the largest documented release of oil in history at substantial depth, and the first time large quantities of dispersant (0.77 million gallons of approximately 1.9 million gallons total) were applied to a subsurface oil plume. During two cruises in late May and early June, water samples were collected at the surface and at depth for DOSS analysis. Real-time fluorimetry data was used to infer the presence of oil components to select appropriate sampling depths. Samples were stored frozen and in the dark for approximately 6 months prior to analysis by liquid chromatography/tandem mass spectrometry with isotope-dilution quantification. The blank-limited method detection limit (0.25 MUg L(-1)) was substantially less than the U.S. Environmental Protection Agency's (USEPA) aquatic life benchmark of 40 MUg L(-1). Concentrations of DOSS exceeding 200 MUg L(-1) were observed in one surface sample near the well site; in subsurface samples DOSS did not exceed 40 MUg L(-1). Although DOSS was present at high concentration in the immediate vicinity of the well where it was being continuously applied, a combination of biodegradation, photolysis, and dilution likely reduced persistence at concentrations exceeding the USEPA aquatic life benchmark beyond this immediate area. PMID- 24050714 TI - Brief exposure to copper induces apoptosis and alters mediators of olfactory signal transduction in coho salmon. AB - Pacific salmon are particularly susceptible to copper (Cu)-induced olfactory injuries that can ultimately inhibit neurobehaviors critical to survival. However, the molecular mechanisms underlying Cu-mediated olfactory impairment remain poorly understood. In the present study, we conducted a short-term Cu exposure at levels relevant to urban runoff (5, 25 and 50 ppb) , and investigated the roles of impaired olfactory signal transduction and induced apoptosis as underlying mechanisms of olfactory injury. Increased cell death in the olfactory epithelium was evident in coho receiving 4h exposures to 25 and 50 ppb Cu. Expression of olfactory marker protein (omp), a marker of mature olfactory sensory neurons, also decreased at 50 ppb Cu. Immunohistochemical analysis of coho olfactory epithelium demonstrated a loss of type 3 adenylate cyclase (ACIII) in the apical olfactory epithelium cilia at all levels of Cu exposure, suggesting an inhibitory effect of Cu in olfactory signaling. Accompanying the loss of ACIII in Cu-exposed coho were reduced intracellular cyclic guanosine monophosphate (cGMP) levels in the olfactory rosettes. Collectively, these results support a linkage among the initial steps of olfactory signaling in Cu-induced salmon olfactory injury, and suggesting that monitoring olfactory cGMP levels may aid in the assessment of salmon olfactory injury. PMID- 24050715 TI - The aryl receptor inhibitor epigallocatechin-3-gallate protects INS-1E beta-cell line against acute dioxin toxicity. AB - The aim of this research was to investigate the mechanism(s) underlying the acute toxicity of dioxin in pancreatic beta cells and to evaluate the protective effects of epigallocatechin-3-gallate (EGCG), the most abundant of the green tea's catechins and a powerful inhibitor of the aryl hydrocarbon receptor (AhR). Using the insulin-secreting INS-1E cell line we have explored the effect of 1h exposure to different concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), alone or in the presence of EGCG, on: (a) cell survival; (b) cellular ultrastructure; (c) intracellular calcium levels; (d) mitochondrial membrane potential; (e) glucose-stimulated insulin secretion and (f) activation of MAP kinases. Our results demonstrate that TCDD is highly toxic for INS-1E cells, suggesting that pancreatic beta cells should be considered a relevant and sensitive target for dioxin acute toxicity. EGCG significantly protects INS-1E cells against TCDD-induced toxicity in terms of both cell survival and preservation of cellular ultrastructure. The mechanism of this protective effect seems to be related to: (a) the ability of EGCG to preserve the mitochondrial function and thus to prevent the TCDD-induced inhibition of glucose-stimulated insulin secretion and (b) the ability of EGCG to inhibit the TCDD-induced activation of selected kinases, such as e.g. ERK 1/2 and JNK. Our results clearly show that EGCG is able to protect pancreatic beta cells against dioxin acute toxicity and indicate the mitochondrion as the most likely target for this beneficial effect. PMID- 24050716 TI - Elimination kinetics of perfluorohexanoic acid in humans and comparison with mouse, rat and monkey. AB - Major fluorinated chemical manufacturers have developed new short-chain per- and polyfluorinated substances with more favorable environmental, health and safety profiles. This study provides the first evaluation of the elimination half-life of perfluorohexanoic acid (PFHxA) from the blood of humans. PFHxA biomonitoring data were obtained from a recently published study of professional ski wax technicians. These data were analyzed to provide estimates of the apparent half life of PFHxA from humans, and comparisons were made with kinetic studies of PFHxA elimination from mice, rats and monkeys. The apparent elimination half-life of PFHxA in highly exposed humans ranged between 14 and 49 d with a geomean of 32 d. The half-lives of PFHxA in mice, rats, monkeys and humans were proportional to body weight with no differences observed between genders, indicating similar volumes of distribution and similar elimination mechanisms among mammalian species. Compared to long-chain perfluoroalkyl acid analogs, PFHxA is rapidly cleared from biota. The consistent weight-normalized elimination half-lives for PFHxA in mammalian species indicates that results obtained from animal models are suitable for establishment of PFHxA benchmark dose and reference dose hazard endpoints for use in human risk assessments. PMID- 24050717 TI - Comparison of equilibrium and non-equilibrium distribution coefficients for the human drug carbamazepine in soil. AB - The distribution coefficient (KD) for the human drug carbamazepine was measured using a non-equilibrium technique. Repacked soil columns were prepared using an Airport silt loam (Typic Natrustalf) with an average organic matter content of 2.45%. Carbamazepine solutions were then leached through the columns at 0.5, 1.0 and 1.5 mL min(-1) representing average linear velocities of 1.8, 3.5 and 5.3 cm h(-1) respectively. Each flow rate was replicated three times and three carbamazepine pulses were applied to each column resulting in a total of 9 columns with 27 total carbamazepine pulses. Breakthrough curves were used to determine KD using the parameter fitting software CXTFIT. Results indicate that as flow rate decreased from 5.3 to 1.8 cm h(-1), KD increased an average of 21%. Additionally, KD determined by column leaching (14.7-22.7 L kg(-1)) was greater than KD determined by a 2h batch equilibrium adsorption (12.6 L kg(-1)). Based on these KD's carbamazepine would be generally characterized as non-mobile in the soil investigated. However, repeated carbamazepine applications resulted in an average 22% decrease in KD between the first and third applications. Decreasing KD is attributed to differences in sorption site kinetics and carbamazepine residence time in contact with the soil. This would indicate that the repeated use of reclaimed wastewater at high application rates for long-term irrigation or groundwater recharge has the potential to lead to greater transport of carbamazepine than KD determined by batch equilibrium would predict. PMID- 24050718 TI - Enhanced binding of hydrophobic organic contaminants by microwave-assisted humification of soil organic matter. AB - Enhanced binding of hydrophobic organic contaminants (HOCs) with soil organic matter (SOM) by microwave (MW) irradiation was investigated in this study. We used fluorescence excitation emission matrix, humification index (HIX), and organic carbon partitioning coefficient (Koc) to examine characteristic changes in SOM and its sorptive capacity for HOCs. When MW was irradiated to soils, protein-like fluorescence decreased but fulvic- and humic-like fluorescence increased. The addition of activated carbon in the presence of oxygen facilitated the humification-like alteration of SOM more significantly, evidenced by increases in fulvic- and humic-like fluorescence signals. The extent of SOM phenanthrene binding also increased with MW treatment, supported by a notable increase in Koc value from 1.8*10(4) to 7.3*10(5)Lkg(-1). Various descriptors indicating the physical and chemical properties of SOM along with the relative percentage of humic-like fluorescence and HIX values demonstrated strong linear relationships with Koc values. These linear relationships indicated that the increased binding affinity of SOM for phenanthrene was attributed to enhanced SOM humification, which was stimulated by MW irradiation. Thus, our results demonstrate that MW irradiation could be effectively used for remediation or for assessing the environmental risks of HOC-contaminated soils and groundwater. PMID- 24050719 TI - Mobility behavior and environmental implications of trace elements associated with coal gangue: a case study at the Huainan Coalfield in China. AB - The potential environmental hazards posed by trace elements have assumed serious proportions due to their toxicity, bioavailability and geochemical behavior. The toxicity and mobility of trace elements in coal gangue is dependent on the elements' chemical properties, therefore, the quantification of the different forms of trace elements is more significant than the estimation of their total concentrations. In this study, the mobility behavior of trace elements in coal gangue from the Huainan Coalfield was studied to evaluate the potential eco toxicity of the trace elements. Sequential extraction was employed to analyze the fractionation behavior of trace elements in coal gangue. The selected trace elements (As, Co, Cr, Cu, Mn, Ni, Se, Sn, V and Zn) are predominantly found in silicate-bound, sulfide-bound and carbonate-bound fractions. The correlation of the element concentration with ash yield, aluminum, calcium and iron-sulfur indicates that As, Co, Cu, Ni, Se and Zn in coal gangue are mainly associated with sulfide minerals, which could release from coal gangue easily and can disperse into the environment as a result of long-term natural weathering. The Risk Assessment Code reveals that the trace elements (Mn, Cr, Se, Ni, Zn, As and Cu) can pose serious environmental risks to the ecosystem. The fractionation profiles of other elements (Co, Sn and V) indicate no risk or low risk to the environment. PMID- 24050721 TI - Right and left ventricular function and myocardial scarring in adult patients with sickle cell disease: a comprehensive magnetic resonance assessment of hepatic and myocardial iron overload. AB - BACKGROUND: Patients with Sickle cell disease (SCD) who receive regular transfusions are at risk for developing cardiac toxicity from iron overload. The aim of this study was to assess right and left cardiac volumes and function, late gadolinium enhancement (LGE) and iron deposits in patients with SCD using CMR, correlating these values with transfusion burden, ferritin and hemoglobin levels. METHODS: Thirty patients with SCD older than 20 years of age were studied in a 1.5 T scanner and compared to age- and sex-matched normal controls. Patients underwent analysis of biventricular volumes and function, LGE and T2* assessment of the liver and heart. RESULTS: When compared to controls, patients with SCD presented higher left ventricular (LV) volumes with decreased ejection fraction (EF) with an increase in stroke volume (SV) and LV hypertrophy. The right ventricle (RV) also presented with a decreased EF and hypertrophy, with an increased end-systolic volume. Although twenty-six patients had increased liver iron concentrations (median liver iron concentration value was 11.83 +/- 9.66 mg/g), only one patient demonstrated an abnormal heart T2* < 20 msec. Only four patients (13%) LGE, with only one patient with an ischemic pattern. CONCLUSIONS: Abnormal heart iron levels and myocardial scars are not a common finding in SCD despite increased liver iron overload. The significantly different ventricular function seen in SCD compared to normal suggests the changes in RV and LV function may not be due to the anemia alone. Future studies are necessary to confirm this association. PMID- 24050720 TI - Automatic auditory processing deficits in schizophrenia and clinical high-risk patients: forecasting psychosis risk with mismatch negativity. AB - BACKGROUND: Only about one third of patients at high risk for psychosis based on current clinical criteria convert to a psychotic disorder within a 2.5-year follow-up period. Targeting clinical high-risk (CHR) individuals for preventive interventions could expose many to unnecessary treatments, underscoring the need to enhance predictive accuracy with nonclinical measures. Candidate measures include event-related potential components with established sensitivity to schizophrenia. Here, we examined the mismatch negativity (MMN) component of the event-related potential elicited automatically by auditory deviance in CHR and early illness schizophrenia (ESZ) patients. We also examined whether MMN predicted subsequent conversion to psychosis in CHR patients. METHODS: Mismatch negativity to auditory deviants (duration, frequency, and duration + frequency double deviant) was assessed in 44 healthy control subjects, 19 ESZ, and 38 CHR patients. Within CHR patients, 15 converters to psychosis were compared with 16 nonconverters with at least 12 months of clinical follow-up. Hierarchical Cox regression examined the ability of MMN to predict time to psychosis onset in CHR patients. RESULTS: Irrespective of deviant type, MMN was significantly reduced in ESZ and CHR patients relative to healthy control subjects and in CHR converters relative to nonconverters. Mismatch negativity did not significantly differentiate ESZ and CHR patients. The duration + frequency double deviant MMN, but not the single deviant MMNs, significantly predicted the time to psychosis onset in CHR patients. CONCLUSIONS: Neurophysiological mechanisms underlying automatic processing of auditory deviance, as reflected by the duration + frequency double deviant MMN, are compromised before psychosis onset and can enhance the prediction of psychosis risk among CHR patients. PMID- 24050722 TI - Recurrent Bordetella holmesii bacteremia and nasal carriage in a patient receiving rituximab. PMID- 24050724 TI - Comparison of the Isw1a, Isw1b, and Isw2 nucleosome disrupting activities. AB - The three Saccharomyces cerevisiae ISWI chromatin remodeling complexes, Isw1a, Isw1b, and Isw2, are implicated in the regularization of arrayed nucleosomes and regulation of gene activity. Although Isw1a and Isw1b are based on the same catalytic unit, in general, their functions in vivo do not overlap. To better understand the structural consequences of these complexes, we compared the putative nucleosome disrupting activities of the purified Isw1a, Isw1b, and Isw2. To account for the putative effects of nucleosomal environment, we employed reconstituted dinucleosomes in which the histone octamers were specifically positioned by the 146 base pair high-affinity nucleosome sequence "601". We have compared the MNase and deoxyribonuclease I protection patterns of remodeled nucleosome templates and evaluated the nucleosome destabilizing abilities of the Isw1a/b and Isw2 using restriction endonucleases. Although the Isw2 showed little evidence of nucleosome disassembly, the Isw1b remodeled dinucleosomes exhibited some common features with the ySwi-Snf remodeling products. The nuclease digestion data suggest that Isw1a can also promote ATP-dependent distortion of nucleosome structure, although less efficiently than the Isw1b complex. PMID- 24050725 TI - Clickable glycopeptoids for synthesis of glycopeptide mimic. AB - Structurally diverse novel glycopeptoids were synthesized which can be attached to biologically important peptides by click reaction to improve their potential to be used in medicinal chemistry. Triazole-linked alphabeta-hydrid glycopeptoids were synthesized that mimic the conserved linkage region of N-linked glycoproteins in eukaryotes. The amide bonds were replaced with triazole rings, and alphabeta-hybrid peptoids were introduced as the backbone modification in peptidomimetics. In addition to their facile synthesis, these modifications have the possibility of introducing otherwise impossible conformations in the peptide backbone. PMID- 24050723 TI - Autotaxin production of lysophosphatidic acid mediates allergic asthmatic inflammation. AB - RATIONALE: Bioactive lipid mediators, derived from membrane lipid precursors, are released into the airway and airspace where they bind high-affinity cognate receptors and may mediate asthma pathogenesis. Lysophosphatidic acid (LPA), a bioactive lipid mediator generated by the enzymatic activity of extracellular autotaxin (ATX), binds LPA receptors, resulting in an array of biological actions on cell proliferation, migration, survival, differentiation, and motility, and therefore could mediate asthma pathogenesis. OBJECTIVES: To define a role for the ATX-LPA pathway in human asthma pathogenesis and a murine model of allergic lung inflammation. METHODS: We investigated the profiles of LPA molecular species and the level of ATX exoenzyme in bronchoalveolar lavage fluids of human patients with asthma subjected to subsegmental bronchoprovocation with allergen. We interrogated the role of the ATX-LPA pathway in allergic lung inflammation using a murine allergic asthma model in ATX-LPA pathway-specific genetically modified mice. MEASUREMENTS AND MAIN RESULTS: Subsegmental bronchoprovocation with allergen in patients with mild asthma resulted in a remarkable increase in bronchoalveolar lavage fluid levels of LPA enriched in polyunsaturated 22:5 and 22:6 fatty acids in association with increased concentrations of ATX protein. Using a triple-allergen mouse asthma model, we showed that ATX-overexpressing transgenic mice had a more severe asthmatic phenotype, whereas blocking ATX activity and knockdown of the LPA2 receptor in mice produced a marked attenuation of Th2 cytokines and allergic lung inflammation. CONCLUSIONS: The ATX-LPA pathway plays a critical role in the pathogenesis of asthma. These preclinical data indicate that targeting the ATX-LPA pathway could be an effective antiasthma treatment strategy. PMID- 24050726 TI - Lipid profile and hepatic steatosis in hepatitis C infected egyptian survivors of childhood cancer. AB - BACKGOUND/AIM: Studies associating chronic hepatitis C virus (HCV) infection with lipid profile and hepatic steatosis in children and adolescents are scarce. This study investigated lipid profile abnormalities and hepatic steatosis among HCV infected Egyptian children and adolescents who survived leukemia and lymphoma and evaluated impact on response to antiviral therapy. SUBJECTS AND METHODS: Thirty six leukemia/lymphoma cured children and adolescents (mean age: 12.47 +/- 3.56 years) with chronic HCV infection and 30 healthy controls (mean age: 11.64 +/- 3.96 years) were enrolled in this prospective study. Serum lipid profile and abdominal ultrasonography were done for all patients and controls. Guided liver biopsy with histopathological examination was done for 32 (88.9%) patients eligible for antiviral therapy. RESULTS: Total cholesterol, LDL-cholesterol, and apolipoprotein B (apo-B) in patients were significantly lower than in the control group (P <= .01, <= .01, and <= .05, respectively). Among those who underwent liver biopsy (n = 32), macrovesicular hepatic steatosis associated with chronic hepatitis C was documented in 10 children (31.3%). Body mass index was significantly higher (P <= .05) and apo-B was significantly lower in steatotic (P <= .05) than non-steatotic HCV-infected children. Liver span by ultrasound, alanine aminotransferase (ALT), and apo-B were independent predictors for hepatic steatosis (P < .001, <.001, and <.05, respectively). A significantly worse response to interferon alpha 2-b plus ribavrin treatment for HCV was reported among children with steatosis (P < .001). CONCLUSIONS: The study showed low serum lipids in HCV-infected children with cured leukemia/lymphoma. Hepatic steatosis was found in a significant proportion of patients and was associated with a poor response to antiviral treatment. PMID- 24050728 TI - Chemistry of reduced monomeric and dimeric cobalt complexes supported by a PNP pincer ligand. AB - The reduction chemistry of cobalt complexes with HPNP (HPNP = HN(CH2CH2P(i)Pr2)2) as a supporting ligand is described. Reaction of [(HPNP)CoCl2] (1) with n-BuLi generated both the deprotonated Co(II) species [(PNP)CoCl] (2) along with the Co(I) complex [(HPNP)CoCl] (3). Products resulting from reduction of 2 with KC8 vary depending upon the atmosphere under which the reduction is performed. Monomeric square planar [(PNP)CoN2] (4) is obtained under dinitrogen, whereas dimeric [(PNP)Co]2 (5) is formed under argon. Over time, 5 activates a C-H bond in the PNP ligand to form the species [Co(H)(MU-PNP)(MU (i)Pr2PCH2CH2NCHCH2P(i)Pr2)Co] (6). We also observed the oxidative addition of H Si bond to complex 3 to form [(HPNP)CoCl(H)SiH2Ph] (7). (1)H NMR studies showed that species 7 is in equilibrium with 3 and silane in solution. Complex 3 can be oxidized with AgBPh4 to generate {(HPNP)CoCl}BPh4 (8), a square planar species with a formal electron count of 15 electrons. PMID- 24050727 TI - The genetic legacy of the 19th-century decline of the British polecat: evidence for extensive introgression from feral ferrets. AB - In the 19th century, the British polecat suffered a demographic contraction, as a consequence of direct persecution, reaching its lowest population in the years that preceded the First World War. The polecat is now recovering and expanding throughout Britain, but introgressive hybridization with feral ferrets has been reported, which could be masking the true range of the polecat and introducing domestic genes into the species. We used a fragment of the mitochondrial DNA control region and 11 microsatellite loci to characterize the frequency and extent of hybridization and introgression between the two species and assess whether the 19th-century decline corresponded to a genetic bottleneck in the polecat. The proportion of admixture detected in the wild was high (31%) and hybrids were more frequently found outside Wales, suggesting that hybridization is more likely to occur along the eastern edge of the polecat's range expansion. The patterns observed in the mitochondrial and nuclear DNA data show that introgression was mediated by crosses between male polecats and female ferrets, whose offspring backcrossed with polecats. No first-generation (F1 ) hybrids were identified, and the broad range of observed admixture proportions agrees with a scenario of past extensive hybridization between the two species. Using several different methods to investigate demographic history, we did not find consistent evidence for a genetic bottleneck in the British polecat, a result that could be interpreted as a consequence of hybridization with ferrets. Our results highlight the importance of the Welsh polecat population for the conservation and restoration of the genetic identity of the British polecat. PMID- 24050729 TI - Strengthening connections between Down syndrome and AD. PMID- 24050730 TI - Early surgery for Parkinson's disease? Maybe, but not just yet. PMID- 24050731 TI - The promise and perils of ketamine research. PMID- 24050733 TI - Posterior circulation ischaemic stroke and transient ischaemic attack: diagnosis, investigation, and secondary prevention. AB - A fifth of all strokes and transient ischaemic attacks occur in the posterior circulation arterial territory. Diagnosis can be challenging, in part because of substantial overlap in symptoms and signs with ischaemia in the anterior circulation. Improved methods of non-invasive imaging of the vertebrobasilar arterial tree have been used in recent prospective follow-up studies, which have shown a high risk of early recurrent stroke, particularly when there is associated vertebrobasilar stenosis. This finding emphasises the importance of urgent secondary prevention, and the role of stenting for vertebral stenosis is being investigated. PMID- 24050734 TI - Peripheral neuropathy in mitochondrial disorders. AB - Why is peripheral neuropathy common but mild in many mitochondrial disorders, and why is it, in some cases, the predominant or only manifestation? Although this question remains largely unanswered, recent advances in cellular and molecular biology have begun to clarify the importance of mitochondrial functioning and distribution in the peripheral nerve. Mutations in proteins involved in mitochondrial dynamics (ie, fusion and fission) frequently result in a Charcot Marie-Tooth phenotype. Peripheral neuropathies with different phenotypic presentations occur in mitochondrial diseases associated with abnormalities in mitochondrial DNA replication and maintenance, or associated with defects in mitochondrial respiratory chain complex V. Our knowledge of mitochondrial disorders is rapidly growing as new nuclear genes are identified and new phenotypes described. Early diagnosis of mitochondrial disorders, essential to provide appropriate genetic counselling, has become crucial in a few treatable conditions. Recognising and diagnosing an underlying mitochondrial defect in patients presenting with peripheral neuropathy is therefore of paramount importance. PMID- 24050735 TI - Subthalamic neurostimulation for Parkinson's disease with early fluctuations: balancing the risks and benefits. AB - Electrical stimulation of the subthalamic nucleus is an established treatment for patients with advanced Parkinson's disease with pharmacologically unresponsive fluctuations. Compared with pharmacological treatment, subthalamic neurostimulation significantly improves motor symptoms, particularly during the phases of poor response to drug treatment, and reduces the severity of dyskinesias. Importantly, it also significantly improves quality of life and other integral measures of disease severity. The treatment response can last for more than 10 years, although there is no evidence that levodopa-resistant symptoms are delayed by subthalamic neurostimulation. At present, the mean disease duration for patients at the time of implantation is 12 years. In a recent study (EARLYSTIM) in patients with a disease duration of 7.5 years and fluctuations for 1.5 years, similar improvements in clinical outcomes were reported. These findings suggest that neurostimulation of the subthalamic nucleus could be used earlier in the disease course for carefully selected patients if the benefits of the treatment are weighed against the surgical risks and the lifelong need for specialised care by an experienced team. As mobility is consistently improved during the times with poor mobility by reducing fluctuations and delaying levodopa-sensitive complications, we propose that this treatment changes the disease course. PMID- 24050736 TI - What if we had whole-genome sequence data for millions of individuals? PMID- 24050737 TI - A comparative study of the effects of a dipeptidyl peptidase-IV inhibitor and sulfonylurea on glucose variability in patients with type 2 diabetes with inadequate glycemic control on metformin. AB - BACKGROUND: This study aimed to compare the effects of sitagliptin on glycemic change and 24-h blood glucose variability with those of the sulfonylurea glimepiride. SUBJECTS AND METHODS: A 4-week randomized double blind-labeled prospective design was used. We recruited 33 patients who had been treated with metformin for at least 2 months. Each participant prescribed with metformin was randomly assigned to either the sitagliptin (100 mg) or the glimepiride (2 mg) group. Continuous glucose monitoring (CGM) was used to monitor glycemic changes for 3 successive days in both groups at baseline and at the 4-week follow-up. Glycemic changes and glucose variability were obtained using CGM, and these data were averaged over all subjects. RESULTS: The comparison of glycated hemoglobin (HbA1c) between baseline and the 4-week follow-up showed that HbA1c was significantly reduced in the sitagliptin group (7.0 +/- 0.5% to 6.6 +/- 0.4%, P<0.001) and the glimepiride group (7.3 +/- 0.4% to 6.9 +/- 0.4%, P<0.001). The sitagliptin and glimepiride groups had similar HbA1c levels after 4 weeks, and there were no significant differences between the two groups. The mean amplitude of glycemic excursions (MAGE) decreased significantly in the sitagliptin group (4.9 +/- 1.0 to 3.7 +/- 0.9 mmol/L, P<0.001), but no significant difference was observed in the glimepiride group (5.7 +/- 1.5 to 5.0 +/- 1.4 mmol/L, P=0.175). The SD and oxidative stress markers did not differ significantly between the two groups. CONCLUSIONS: When sitagliptin was combined with metformin, the patients showed much more efficient blood glucose controlling effects, not only the three indexes of fasting blood glucose, postprandial blood glucose, and glycated hemoglobin, but also MAGE. PMID- 24050738 TI - The effect of congestive heart failure on sensor accuracy among hospitalized patients with type 2 diabetes. AB - BACKGROUND: Congestive heart failure (CHF) features disturbances in the interstitial environment that may affect the accuracy of subcutaneous continuous glucose monitoring (CGM). SUBJECTS AND METHODS: A pooled analysis of two studies of hospitalized patients with type 2 diabetes randomized to intravenous or subcutaneous insulin was conducted. One study enrolled patients with CHF exacerbation, whereas history of CHF was an exclusion criterion in the other. All patients wore a professional CGM device for at least 24 h. Intravenous insulin was administered according to the institution's nursing-run protocol (duration of 12 and 48 h in non-CHF and CHF protocols, respectively). Subcutaneous insulin was delivered similarly in both groups. RESULTS: Subjects with CHF (n=43) had higher admission glucose and hemoglobin A1c compared with non-CHF subjects (n=32), but the sensor glucose values were similar. Overall mean absolute relative difference (MARD) was similar between CHF and non-CHF subjects (0.11 vs. 0.08, respectively; P=0.12). MARD was higher in the 100-149 mg/dL (P=0.003) and >199 mg/dL (P = 0.02) strata among CHF subjects. Static glucose and continuous glucose error grid analyses favored the non-CHF group. In multivariable analyses, only glucose coefficient of variation and log sensor time were independent predictors of elevated overall MARD >0.10. After adjustment for other factors, only increasing log sensor time was a significant predictor of elevated MARD in the 100-149 mg/dL strata. CONCLUSIONS: Among hospitalized subjects with type 2 diabetes, CHF exacerbation is not associated with lower sensor accuracy after adjustment for other factors, but this requires confirmation over a wider glucose range. PMID- 24050739 TI - OHRP and SUPPORT: lessons in balancing safety and improving the way we care for patients. PMID- 24050740 TI - Dietary interventions in children with autism spectrum disorders - an updated review of the research evidence. AB - Autism Spectrum Disorders (ASD) is a group of life-long neurodevelopmental disorders, with onset before 3 years of age. They are characterized by qualitative impairmentin social interactions, absent or impaired language and communication skills, and present with a wide range of stereotyped, repetitive behaviors. Function and outcome are affected not only by core deficits but by associated behaviors such as hyperactivity, aggression, anxiety, and depression. Increasing evidence indicates that autism is a complex, multifactorial disorder involving the brain and the body, a result of genetic vulnerabilities interacting with environmental factors. Although genetics plays a role, the fact, that the incidence of autism in identical twins is not 100% points to external or environmental factors as contributors. No etiology - based treatment has yet been developed. During the last two decades many educational, psychosocial and pharmacological interventions had been utilized and claimed to be effective and even "curative". The word treatment should be used with caution, and should stand for interventions that are aimed to help people with ASD to adjust more effectively to their environment. Many studies have indicated that behavioral therapy and medication may be at least partially helpful in the treatment of children with ASD particularly on the symptoms of aggression, hyperactivity and attention. In the light of an approved and well established treatment for ASD, over the past two decades research on the effect of diet and nutrition on autism has been increasing. Particular attention has focused on the role of food additives, refined sugar, food allergies, and fatty acid metabolism. However, the results are conflicting and not conclusive. We present here anupdated review summarizing the potentials and limits of the most frequent nutritional and dietary interventions in the treatment of Autism Spectrum Disorders. PMID- 24050741 TI - Second generation antipsychotics in Asperger's Disorder and high functioning autism: a systematic review of the literature and effectiveness of meta-analysis. AB - OBJECTIVE: Second generation antipsychotics (SGA) have gained increased evidence for the treatment of irritability and aggression in children and adolescents with lower functioning autistic disorder. Individuals with Asperger's Disorder (AD) and High Functioning Autism (HFA) experience significant emotional and behavioral problems and psychiatric comorbidity. There is a need to review the published literature on SGA treatment efficacy in the AD and HFA populations to provide more effective treatment choices for these subgroups. METHODS: We conducted a systematic review and meta-analysis of the recent English literature on SGA use in children and adolescents (ages 0-24 years) with AD and HFA using the Medline/PubMed and PsychINFO computerized databases. Key search words were 'Asperger', 'high functioning autism', 'autism spectrum disorders (ASD)', and 'pervasive developmental disorder (PDD)' in combination with 'second generation antipsychotics', 'aripiprazole; 'olanzapine', 'quetiapine', 'risperidone', or 'ziprasidone'. RESULTS: Our search yielded 214 citations, however only open-label or randomized-controlled trials (RCT) with >=25% of their subjects having an IQ>=71 were included in our review. Eleven original studies met our inclusion parameters for review; eight studies for the meta-analysis. These studies, although limited in methodological rigor, and the meta-analytic results suggest that SGAs provide improvement in behavioral symptoms associated with AD and HFA. The majority of the studies reported weight gain as a potentially concerning adverse effect. CONCLUSION: There is a lack of robustly conducted trials on the use of SGAs in the management of AD and HFA. More research in pharmacological and psychosocial treatments is warranted. Clinicians are cautioned to approach pharmacological treatment prudently balancing benefit with potential cardiometabolic risk. PMID- 24050742 TI - Melatonin in autism spectrum disorders. AB - Melatonin is an endogenous neurohormone produced predominantly in the pineal gland. Recent studies have implicated abnormalities in melatonin physiology and the circadian rhythm in individuals with autism spectrum disorders (ASD). These physiological abnormalities include lower nighttime melatonin or melatonin metabolite concentrations in ASD compared to controls. These abnormalities in melatonin concentrations may be directly attributed to variations in melatonin pathway physiology as both functional and genetic variations in this pathway have been reported in children with ASD. Four studies have observed a correlation between abnormal melatonin concentrations and the severity of autistic behaviors. Twenty clinical studies have reported improvements in sleep parameters with exogenous melatonin supplementation in ASD, including longer sleep duration, less nighttime awakenings and quicker sleep onset. A recent meta-analysis of five randomized, double-blind, placebo-controlled crossover trials examining exogenous melatonin supplementation in ASD reported significant improvements with large effect sizes in total sleep duration and sleep onset latency compared to both baseline and placebo. Six studies reported that the nighttime administration of exogenous melatonin was associated with better daytime behaviors. Four studies reported improvements with exogenous melatonin supplementation when other sleep medications had previously failed. Adverse effects of melatonin were minimal to none in the twenty treatment studies. These studies indicate that the administration of exogenous melatonin for abnormal sleep parameters in ASD is evidence-based. Further studies examining optimal effective dosing and timing of dosing are warranted. PMID- 24050743 TI - Non-pharmacological treatments in autism spectrum disorders: an overview on early interventions for pre-schoolers. AB - This paper evaluates the current literature on non-pharmacological early interventions (behavior behavioral, developmental and educational approaches) for pre-schoolers (aged 24-71 months) with autism spectrum disorders. Although there lies a significant heterogeneity among the available studies, the present review emphasizes the importance of considering the wide range of interventions through behavioral (behavioral or developmental interventions) and educational continuum according to the suggestions of the recent literature in this field. Furthermore, the present review: 1) outlines the issues about the scientific validity of the treatment outcome studies; 2) describes the findings of different parent-mediated interventions; 3) highlights the importance to use the same outcome measures through the studies to compare findings of different literature contributions; and 4) focuses on the importance to consider pre-treatment variables to identify children who will have better outcomes. Furthermore, some evidence-based guidelines about clinical management and treatment have also been outlined and summarized in this review. Finally, the review concludes on providing a number of practical recommendations to clinicians working in the field suggesting both the presence of a specialized team and role of an active collaboration of the family to treatment as core milestones for the clinical management. PMID- 24050744 TI - Potential benefits and limits of psychopharmacological therapies in pervasive developmental disorders. AB - The core symptoms of Autistic Spectrum Disorder (ASD) are impairment in reciprocal social interaction, communication, narrow interests, and stereotyped behaviour. These are frequently severe and persistent, although their severity may change over the course of life. Furthermore, the frequently associated symptoms of self-injury, aggressive behaviour, impulsivity, poor attention, anxiety, depression, and sleep disruption, can become a major source of additional distress and interference in functioning. The causes of autism are not yet known, but there is a general consensus that ASDs are highly heritable. Comprehension of the neurobiological basis for autism-spectrum disorders is still in its initial stages: a large body of research, however, has established ASD signs and symptoms are of neurological origin, and suggest that autism is a distributed neural system disorder, which disproportionately impairs many higher order abilities. Currently available medical treatments, primarily address co morbid symptoms, rather than core symptoms. Thus, in spite of recent advances in psychopharmacology, the treatment approach still has important limits and shows poor efficacy on global outcomes. A potential pathway for improving clinical outcomes is that of the personalised treatment for autism, by using therapeutic drug monitoring (TDM) - a valuable tool for drugs with narrow therapeutic index - as well as systematic genetic background assessment, foreseen in future applications. However, it is already possible to implement an active surveillance programme to address safety concerns and to optimise therapeutic drug interventions in ASD. PMID- 24050746 TI - Diagnostic boundaries of autism disorder vs pervasive developmental disorder nos comparative observational study and literature review. AB - Diagnosis of pervasive developmental disorders (PDDs), and above all diagnosis of the different PDD subtypes, is an ongoing challenge in psychopathology. Application of categorical criteria is complex and problematic in the clinical field where the boundaries dividing some of the PDD entities are blurred, creating particular problems for the clinician. A dimensional clinical approach, considering autistic symptom severity, level of functioning, developmental characteristics and symptoms other than the ones typically observed in autism, may be a more suitable approach in the clinical field and could provide the clinician treating these disorders with empirical guidance. To identify the clinical features that might differentiate the PDD subtypes, we conducted a comparative study in a clinical sample of children affected by autism disorder (AD) or pervasive developmental disorders not otherwise specified (PDD-NOS) and a mini critical review of the available literature addressing clinical and psychopathological differences between the two subtypes. The results of both our study and our literature review seem to show little support for the current PDD subtypes. In such a framework, the most significant element in clinical practice appears to be a deep knowledge of the characteristics of the individual in question. By adopting a broad and multi-faceted perspective, it becomes possible to define the most effective rehabilitation treatment. This applies particularly to the pharmacological treatment, since, to date, no specific therapies for PDDs are known and the choice of pharmacotherapy can be decided only on the basis of the patient's general profile and specific features. PMID- 24050747 TI - Integrin modulators: a patent review. AB - INTRODUCTION: Integrins are heterodimeric cell surface receptors, which enable adhesion, proliferation, and migration of cells by recognizing binding motifs in extracellular matrix (ECM) proteins. As transmembrane linkers between the cytoskeleton and the ECM, they are able to recruit a huge variety of proteins and to influence signaling pathways bidirectionally, thereby regulating gene expression and cell survival. Hence, integrins play a key role in various physiological as well as pathological processes, which has turned them into an attractive target for pharmaceutical research. AREAS COVERED: In this review, the latest therapeutic developments of drug candidates and recently patented integrin ligands are summarized. EXPERT OPINION: Integrins have been proven to be valuable therapeutic targets in the treatment of several inflammatory and autoimmune diseases, where leukocyte adhesion processes are regulated by them. Furthermore, they play an important role in pathological angiogenesis and tumor metastasis, being a promising target for cancer therapy. PMID- 24050749 TI - Beyond accreditation: excellence in medical education. AB - Medical school accreditation is a relatively new phenomenon in Korea. The development of an accreditation body and standards for a two-tiered "Must" and "Should" system in 1997 eventually led to the implementation of a third "Excellence" level of attainment. These standards were conceived out of a desire to be able to first recognize and promote outstanding performance of medical schools, second to provide role models in medical education, and furthermore to preview the third level as potential components of the pre-existing second level for the next accreditation cycle. It is a quality-assurance mechanism that, while not required for accreditation itself, pushes medical schools to go beyond the traditional requirements of mere pass-or-fail accreditation adequacy, and encourages schools to deliver an unprecedented level of medical education. The Association for Medical Education in Europe developed its own third-tier system of evaluation under the ASPIRE project, with many similar goals. Due to its advanced nature and global scope, the Korean accreditation body has decided to implement the ASPIRE system in Korea as well. PMID- 24050745 TI - Evaluation of current pharmacological treatment options in the management of Rett syndrome: from the present to future therapeutic alternatives. AB - Neurodevelopmental disorders are a large family of conditions of genetic or environmental origin that are characterized by deficiencies in cognitive and behavioral functions. The therapeutic management of individuals with these disorders is typically complex and is limited to the treatment of specific symptoms that characterize each disorder. The neurodevelopmental disorder Rett syndrome (RTT) is the leading cause of severe intellectual disability in females. Mutations in the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MECP2), located on the X chromosome, have been confirmed in more than 95% of individuals meeting diagnostic criteria for classical RTT. RTT is characterized by an uneventful early infancy followed by stagnation and regression of growth, motor, language, and social skills later in development. This review will discuss the genetics, pathology, and symptoms that distinguish RTT from other neurodevelopmental disorders associated with intellectual disability. Because great progress has been made in the basic and clinical science of RTT, the goal of this review is to provide a thorough assessment of current pharmacotherapeutic options to treat the symptoms associated with this disorder. Furthermore, we will highlight recent discoveries made with novel pharmacological interventions in experimental preclinical phases, and which have reversed pathological phenotypes in mouse and cell culture models of RTT and may result in clinical trials. PMID- 24050750 TI - Synthetic studies toward the citrinadin A and B core architecture. AB - The core architecture of the citrinadin alkaloids has been prepared in racemic form by utilizing a strategy that exploits the alkylation of 2-methoxypyridines. An initially planned indolizidine to quinolizidine transformation to build the D/E rings was unsuccessful. Success was ultimately gained by a direct alkylation to establish the citrinadin core architecture. PMID- 24050751 TI - Diagnostic accuracy of combined tests of anti cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis: a meta-analysis. AB - OBJECTIVES: To evaluate the diagnostic properties of combined tests of anti cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor (RF) in the diagnosis of rheumatoid arthritis (RA). METHODS: We performed an extensive research between January 2000 and January 2013 of the published literature. A random-effects model was used to summarise data from 24 studies that conformed to our inclusion criteria. Heterogeneity among studies was evaluated by threshold effect analysis and meta-regression. RESULTS: The summary estimates for anti-CCP antibody and RF positivity (both serum markers had to be positive) in the diagnosis of RA were: sensitivity 57% (95% confidence interval (CI), 55% to 59%), specificity 96% (CI, 96% to 97%), positive likelihood ratio (LR) 13.84 (CI, 10.56 to 18.12), negative LR 0.46 (CI, 0.40 to 0.52), diagnostic odds ratio (DOR) 33.02 (CI, 23.89 to 45.64). The pooled data for anti-CCP antibody or RF positivity (one serum marker had to be positive) were: sensitivity 78% (CI, 76% to 80%), specificity 82% (CI, 81% to 84%), positive LR 4.24 (CI, 3.61 to 4.97), negative LR 0.27 (CI, 0.22 to 0.34), DOR 16.95 (CI, 12.96 to 22.18). CONCLUSIONS: Both anti-CCP antibody and RF positivity are useful for ruling in the diagnosis of RA, and positivity combined improves the probability of true positivity in the diagnosis. Anti-CCP antibody or RF positivity shows low specificity and positive LR, and should be integrated with other examinations to make a final diagnosis. PMID- 24050752 TI - Enzymatic hydrolysis preparation of mono-O-lauroylsucrose via a mono-O lauroylraffinose intermediate. AB - 1'-O-Lauroylsucrose and 6'-O-lauroylsucrose were formed through hydrolysis of the C-6" galactose group of 1'-O-lauroylraffinose and 6'-O-lauroylraffinose, respectively, in the presence of alpha-galactosidase. The enzymatic hydrolysis of 1'-O-lauroylraffinose and 6'-O-lauroylraffinose is discussed in detail. Acetic acid-sodium acetate was chosen as the buffer solution of the enzymatic hydrolysis reaction. The optimum conditions for the enzymatic hydrolysis reaction were as follows: buffer solution, pH 3.8; enzymatic time, 48 h; and enzymatic temperature, 37 degrees C. Under the optimal process conditions, the efficiency of alpha-galactosidase was ca. 82.6%. The isomers were fully compared in solubility, hydrophile-lipophile balance (HLB) values, critical micelle concentration (CMC), and thermal stability. The results showed that all lauroylsucrose isomers have similar solubilities in polar solvent, HLB values, CMC values, and thermal stabilities. PMID- 24050753 TI - Complementary feeding and attained linear growth among 6-23-month-old children. AB - OBJECTIVE: To examine the association between complementary feeding indicators and attained linear growth at 6-23 months. DESIGN: Secondary analysis of Phase V Demographic and Health Surveys data (2003-2008). Country-specific ANOVA models were used to estimate effects of three complementary feeding indicators (minimum meal frequency, minimum dietary diversity and minimum adequate diet) on length for-age, adjusted for covariates and interactions of interest. SETTING: Twenty one countries (four Asian, twelve African, four from the Americas and one European). SUBJECTS: Sample sizes ranging from 608 to 13 676. RESULTS: Less than half the countries met minimum meal frequency and minimum dietary diversity, and only Peru had a majority of the sample receiving a minimum adequate diet. Minimum dietary diversity was the indicator most consistently associated with attained length, having significant positive effect estimates (ranging from 0.16 to 1.40 for length-for-age Z-score) in twelve out of twenty-one countries. Length-for-age declined with age in all countries, and the greatest declines in its Z-score were seen in countries (Niger, -1.9; Mali, -1.6; Democratic Republic of Congo, -1.4; Ethiopia, -1.3) where dietary diversity was persistently low or increased very little with age. CONCLUSIONS: There is growing recognition that poor complementary feeding contributes to the characteristic negative growth trends observed in developing countries and therefore needs focused attention and its own tailored interventions. Dietary diversity has the potential to improve linear growth. Using four food groups to define minimum dietary diversity appears to capture enough information in a simplified, standard format for multi-country comparisons of the quality of complementary diets. PMID- 24050754 TI - Differences in distal lower extremity tissue masses and mass ratios exist in athletes of sports involving repetitive impacts. AB - This study aimed to examine the effects of sex and sport on the tissue composition of the distal lower extremity of varsity athletes, in sports that involve repetitive-impact loading patterns. Fat mass, lean mass, bone mineral content and wobbling mass were predicted for the leg and leg + foot segments of varsity basketball, cross-country, soccer and volleyball athletes. The absolute masses were normalised to body mass, and also expressed relative to each other as ratios. Females and males differed on most normalised tissue masses and ratios by 11-101%. Characteristic differences were found in the normalised tissue masses across sports, with the lowest and highest values displayed by cross-country and volleyball (female)/basketball (male) athletes, respectively. Conversely, cross country athletes had the highest wobbling mass:bone mineral content and lean mass:bone mineral content ratios for females by 10% and 16%, respectively. The differences between sports may be explained in part by different impact loading patterns characteristic of each sport. Tissue mass ratio differences between sports may suggest that the ratios of soft to rigid tissues are optimised by the body in response to typical loading patterns, and may therefore be useful in investigations of distal lower extremity injury mechanisms in athletes. PMID- 24050756 TI - Rickettsia africae in Amblyomma variegatum ticks, Uganda and Nigeria. PMID- 24050755 TI - Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3 yl)picolinamide (ML254). AB - Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu5 PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu5 PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift ~ 3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu5 PAMs. PMID- 24050757 TI - Feature ranking based on synergy networks to identify prognostic markers in DPT 1. AB - : Interaction among different risk factors plays an important role in the development and progress of complex disease, such as diabetes. However, traditional epidemiological methods often focus on analyzing individual or a few 'essential' risk factors, hopefully to obtain some insights into the etiology of complex disease. In this paper, we propose a systematic framework for risk factor analysis based on a synergy network, which enables better identification of potential risk factors that may serve as prognostic markers for complex disease. A spectral approximate algorithm is derived to solve this network optimization problem, which leads to a new network-based feature ranking method that improves the traditional feature ranking by taking into account the pairwise synergistic interactions among risk factors in addition to their individual predictive power. We first evaluate the performance of our method based on simulated datasets, and then, we use our method to study immunologic and metabolic indices based on the Diabetes Prevention Trial-Type 1 (DPT-1) study that may provide prognostic and diagnostic information regarding the development of type 1 diabetes. The performance comparison based on both simulated and DPT-1 datasets demonstrates that our network-based ranking method provides prognostic markers with higher predictive power than traditional analysis based on individual factors. PMID- 24050759 TI - Novel refractory phase, Ta7Si2(Si(x)B(1-x))2. AB - X-ray single crystal (XSC) and powder diffraction data (XPD) were used to elucidate the crystal structure of a new refractory silicon boride Ta7Si2(Si(x)B(1-x))2 (x = 0.12). Tetragonal Ta7Si2(Si(x)B(1-x))2 (space group P4/mbm; a = 0.62219(2) nm, c = 0.83283(3) nm) with B atoms randomly sharing the 4g site with Si atoms is isotypic with the boride structure of (Re,Co)7B4. The architecture of the structure of Ta7Si2(Si(x)B(1-x))2 combines layers of three capped triangular metal prisms (Si,B)[Ta(6+2)(Si,B)] alternating with double layers of two-capped Si[Ta(8+1)Si] Archimedian metal antiprisms. Consequently, the metal framework contains (B/Si) pairs and Si-Si dumbbells. These two types of coordination figures around the nonmetal atoms are typical for the system inherent structures of Ta2B (or Ta2Si) and Ta3B2. DFT calculations showed strong B(Si)-B(Si) and Si-Si bonding and represent Ta7Si2(Si(x)B(1-x))2 as a covalent ionic compound. This bonding behavior is reflected in the high hardness value of 1750 HV. The Sommerfeld constant, gamma = 7.58 mJ/mol K(2), as derived from the electronic density of states, calculated at the Fermi level, suggests typical metallic behavior. PMID- 24050758 TI - Matrix assisted laser desorption ionization imaging mass spectrometry workflow for spatial profiling analysis of N-linked glycan expression in tissues. AB - A new matrix assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) method to spatially profile the location and distribution of multiple N-linked glycan species in tissues is described. Application of an endoglycosidase, peptide N-glycosidase F (PNGaseF), directly on tissues followed by incubation releases N-linked glycan species amenable to detection by MALDI IMS. The method has been designed to simultaneously profile the multiple glycan species released from intracellular organelle and cell surface glycoproteins, while maintaining histopathology compatible preparation workflows. A recombinant PNGaseF enzyme was sprayed uniformly across mouse brain tissue slides, incubated for 2 h, then sprayed with 2,5-dihydroxybenzoic acid matrix for MALDI-IMS analysis. Using this basic approach, global snapshots of major cellular N-linked glycoforms were detected, including their tissue localization and distribution, structure, and relative abundance. Off-tissue extraction and modification of glycans from similarly processed tissues and further mass spectrometry or HPLC analysis was done to assign structural designations. MALDI-IMS has primarily been utilized to spatially profile proteins, lipids, drug, and small molecule metabolites in tissues, but it has not been previously applied to N-linked glycan analysis. The translatable MALDI-IMS glycan profiling workflow described herein can readily be applied to any tissue type of interest. From a clinical diagnostics perspective, the ability to differentially profile N-glycans and correlate their molecular expression to histopathological changes can offer new approaches to identifying novel disease related targets for biomarker and therapeutic applications. PMID- 24050760 TI - Interferon therapy for Kaposi sarcoma associated with acquired immunodeficiency syndrome: still a valid treatment option? PMID- 24050761 TI - Mapping the pathway toward thiophosphinic pseudopeptides. Synthesis of suitably protected PG-Phe-Psi[P(S)(OX)CH2]-Gly-OY analogues as thiophosphinyl dipeptide isosters (TDI), a comparative study for selective deprotection and further elongation. AB - In the present study, we describe in detail the first synthesis of a new class of phosphorus compounds, thiophosphinyl pseudopeptides. We prepared several fully protected thiophosphinate pseudodipeptides of the general formula PG-Phe Psi[P(S)(OX)CH2]-Gly-OY starting from the corresponding phosphinate pseudodipeptide using Lawesson's reagent. Selective deprotection, further elongation, and stability of these compounds were studied, and the results are disclosed. These compounds can be used as transition-state-mimicking inhibitors for several zinc metalloproteases. PMID- 24050762 TI - Treatment of children with diffuse intrinsic pontine gliomas with chemoradiotherapy followed by a combination of temozolomide, irinotecan, and bevacizumab. AB - BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) are inoperable and highly resistant tumors to chemotherapy and irradiation. DIPG has the worst prognosis among all pediatric brain tumors and the overwhelming majority of patients die within 6-18 months after diagnosis. METHODS: We retrospectively reviewed the charts of six DIPG patients treated with chemoradiotherapy (daily carboplatin and oral etoposide in five patients and temozolomide in one patient) followed by maintenance chemotherapy consisting of irinotecan, temozolomide, and bevacizumab at our institution between January 2007 until December 2007. RESULTS: Event-free survival (EFS) and overall survival (OS) were 10.4 +/- 3.08 and 14.6 +/- 3.55 months, respectively. Side effects in the patients included hypertension in two, abdominal cramping and diarrhea in four, and neutropenia in five patients. CONCLUSIONS: This augmented regimen was associated with increased but tolerable toxicity and a modest increase in EFS and OS when compared with published literature in patients with DIPG (median EFS and OS of 6.1 and 9.6 months, respectively). More effective therapies are desperately needed. PMID- 24050763 TI - Is there a role for FDG-PET for the assessment of treatment efficacy in Wilms' tumor? A case report and literature review. AB - BACKGROUND: The role of FDG-PET in Wilms' tumor has not been well established. The aim of this report is to describe the role of FDG-PET to assess chemotherapy efficacy and to show potential correlations between different Standardized Uptake Values (SUVs) and histopathological features in a patient with persisting metastatic disease. CASE DESCRIPTION: A 3-year-old boy was diagnosed with Wilms' tumor without anaplasia. The patient underwent treatment as according to the AIEOP-TW-2003 protocol, for stage III tumors. Therapy was discontinued with no evidence of disease, yet 9 months later thorax metastases were found. Although second and third line treatments were administered, conventional imaging demonstrated stable disease. Metronomic chemotherapy as well was employed for 44 months and FDG-PET was annually performed basing on responsible local physician choice trying to better describe the disease status. Four months after fourth line treatment was stopped, the patient manifested clinical symptoms; lesions began to increase their metabolic activity inhomogeneously. Therapy was hence restarted and SUVs decreased. Metastasectomies were then performed and histology revealed a correlation between viable disease shown by higher FDG-PET uptake and viable tumor areas. CONCLUSIONS: Our case discussion demonstrates that FDG-PET is potentially valuable in Wilms' tumor correlating SUV values and histological features of the tumor after chemotherapy. This case suggests that FDG-PET is a valid tool to assess chemotherapy response in relapsed Wilms' tumor even in case of no evidence of significant dimensional changes under conventional imaging. PMID- 24050764 TI - Comparison of filgrastim and lenograstim in pediatric solid tumors. AB - PURPOSE: Chemotherapy-induced febrile neutropenia (FEN), which causes treatment delays or chemotherapy dose reductions, is a serious side effect of cancer treatment. In Turkey, recombinant G-CSF (rG-CSF) has been used since 2000 to control neutropenia. The purpose of this prospective randomized study is to compare the effectiveness, toxicities and the cost of these two drugs in children. METHODS: Between April and December 2008, 29 patients were administered 40 courses of chemotherapy in each arm. A randomized crossover study was designed. All patients were administered rG-CSF 24 hours after the last day of chemotherapy as a secondary prophylaxis. Complete blood counts as well as peripheral blood progenitor (CD34+) cell levels were measured before G-CSF treatment and on the fifth and the seventh day of treatment. RESULTS: The median duration of neutropenia, FEN, the length of hospitalization, the incidence of FEN, and documented infection was not different between the two rG-CSF treatment groups. Erythrocyte and platelet transfusion rates were also similar. After 7 days, the mean leukocyte (WBC [white blood cell]) and neutrophil count (ANC [absolute neutrophil count]), hemoglobin and platelet levels were not significantly different. However, the CD34+ cell level was significantly higher in the lenograstim group. Lenograstim was also more expensive than filgrastim. No serious side effects were reported for either rG-CSF treatment. CONCLUSIONS: There is no difference following the administration of either lenograstim or filgrastim for the duration of neutropenia, FEN or hospitalization for pediatric cancer patients. For stem cell mobilization, lenograstim was superior to filgrastim. PMID- 24050765 TI - Urologic outcomes of pediatric pelvic neuroblastoma presenting in acute urinary retention. AB - PURPOSE: To evaluate long-term urologic outcomes of patients with pelvic neuroblastoma (NB) presenting with urinary retention. METHODS: Five cases of pelvic NB presenting with urinary retention were identified between 1971 and 2011. Clinical presentation, treatment, survival and long-term voiding outcomes were analyzed. RESULTS: All five patients presented with acute urinary retention and pelvic outlet dysfunction including bladder perforation (20%), constipation (40%), or fecal incontinence (20%). The presenting age ranged from 7 days to 4 years with female to male ratio of 3:2. Two patients presented with bilateral hydronephrosis and three patients were stage 4 at presentation. All required debulking surgery, four patients required combined anterior and posterior approaches for tumor resection, with two patients requiring concurrent laminectomy. Adjuvant or neoadjuvant chemoradiation was used in four of five cases. Follow-up ranged from 2 to 41 years. Although the long-term oncological outcome is favorable, urologic outcomes of these patients ranged from normal bladder function to the need significant reconstructive procedures. CONCLUSION: Urologic outcomes are related to pelvic nerve and organ preservation during resection more than the severity of urinary symptoms at presentation. PMID- 24050767 TI - Fish farming and immunomodulation. PMID- 24050766 TI - Mechanical performance of novel bioactive glass containing dental restorative composites. AB - OBJECTIVES: Bioactive glass (BAG) is known to possess antimicrobial properties and release ions needed for remineralization of tooth tissue, and therefore may be a strategic additive for dental restorative materials. The objective of this study was to develop BAG containing dental restorative composites with adequate mechanical properties comparable to successful commercially available composites, and to confirm the stability of these materials when exposed to a biologically challenging environment. METHODS: Composites with 72 wt% total filler content were prepared while substituting 0-15% of the filler with ground BAG. Flexural strength, fracture toughness, and fatigue crack growth tests were performed after several different soaking treatments: 24h in DI water (all experiments), two months in brain-heart infusion (BHI) media+Streptococcus mutans bacteria (all experiments) and two months in BHI media (only for flexural strength). Mechanical properties of new BAG composites were compared along with the commercial composite Heliomolar by two-way ANOVA and Tukey's multiple comparison test (p<=0.05). RESULTS: Flexural strength, fracture toughness, and fatigue crack growth resistance for the BAG containing composites were unaffected by increasing BAG content up to 15% and were superior to Heliomolar after all post cure treatments. The flexural strength of the BAG composites was unaffected by two months exposure to aqueous media and a bacterial challenge, while some decreases in fracture toughness and fatigue resistance were observed. The favorable mechanical properties compared to Heliomolar were attributed to higher filler content and a microstructure morphology that better promoted the toughening mechanisms of crack deflection and bridging. SIGNIFICANCE: Overall, the BAG containing composites developed in this study demonstrated adequate and stable mechanical properties relative to three successful commercial composites. PMID- 24050768 TI - Morpho-functional response of Nile tilapia (Oreochromis niloticus) to a homeopathic complex. AB - BACKGROUND: This study evaluated the performance, prevalence of ectoparasites and morpho-functional response of the liver and the branchiae of Nile tilapia (Oreochromis niloticus) raised on fish meal with added of the homeopathic complex Homeopatila 100((r)) at different concentrations. METHODS: Post-reversed juvenile Nile tilapia (O. niloticus) of the GIFT (Genetic Improvement of Farmed Tilapia) strain were used in this study. The performance, ectoparasite prevalence and parasite load in the branchiae and skin as well as the liver and branchial histology. Fish were randomly assigned to receive one of four treatments: control, 20 mL hydroalcoholic solution (alcohol 30 degrees GL); 20 mL Homeopatila 100((r)) per kg of meal; 40 mL Homeopatila 100((r)) per kg of meal; or 60 mL of Homeopatila 100((r)) per kg of meal, compared to control with out the addition of the complex. There were four replications per treatment type (16 experimental units total) at a density of 40 fish per m(3) over a period of 57 days. The Kruskal-Wallis H test (p < 0.05) was employed to analyse the physical and chemical parameters of water as well as for parasite prevalence; whereas analysis of variance was used for liver performance. If the values were significant (p < 0.05), they were compared by Tukey's test. Multiple comparisons of averages were performed using Student's t test (p < 0.05). RESULTS: There were no significant between the physical and chemical parameters of the water between the different groups at the end of the experiment. Significant differences (p < 0.05) in the mixed parasite conditions were found within the different Homeopatila 100((r)) treatments. The hepatosomatic ratio of fish treated with Homeopatila 100((r)) was significantly lower than that of fish from the control group. The best results in the liver and branchiae occurred in fish receiving Homeopatila 100((r)) at 40 mL/kg in terms of the number of hepatocytes/mm(2), the intercellular glycogenic behaviour, the rates of histological changes (hyperplasia, lamella fusion and telangiectasia) and the percentage of neutral and acidic mucin-producing cells. CONCLUSION: The addition of Homeopatila 100((r)) at a concentration 40 mL per kg/meal to the diet of juvenile Nile tilapias resulted in improved hepatocytes and intracellular glycogen levels as well as the lowest mean rate of branchial histological changes with an increase in acidic mucin-producing cells compared to neutral mucin-producing cells, compared to control. PMID- 24050769 TI - Homeopathic prescribing for chronic and acute periodontal conditions in 3 dental practices in the UK. AB - INTRODUCTION: This investigation extends our previous dental data collection pilot study with the following main aims: to gain insight into the periodontal complaints that dentists in the UK treat using individualised homeopathic prescription; to record patient-assessed change in severity of treated complaint (acute or chronic); to determine periodontal pocket depth (PPD). MATERIALS AND METHODS: Three dentists recorded data systematically at 249 homeopathic appointments in 51 patients over a period of 18 months. A spreadsheet enabled the data collection of the following records: date of appointment; anonymised patient identity; main periodontal problem treated; whether the condition was acute or chronic; patient-assessed clinical outcome on a 7-point Likert scale, ranging from -3 to +3, to compare the first and any subsequent appointments; whether any interventional dental surgery (IDS) had been carried out; clinician-assessed PPD measurements. RESULTS: At least one follow-up (FU) appointment was reported for each of 46 patients (22 chronic [6 with IDS, 16 without IDS]; 24 acute [10 with IDS, 14 without IDS]). In chronic cases, strongly positive outcomes (score of +2 or +3) were reported by 2 (33.3%) of 6 IDS patients and by 1 (6.3%) of 16 non-IDS patients. In acute cases, strongly positive outcomes were reported by 7 (70%) of 10 IDS patients and by 8 (57.2%) of 14 non-IDS patients (no statistically significant difference between sub-groups). The FU conditions most frequently treated with homeopathy were chronic periodontitis (19 patients) and acute periodontal abscess (11 patients). Analysis of PPD data was not feasible due to the small numbers of patients involved. CONCLUSION: Limited insight has been gained into the periodontal complaints treated by homeopathy in the UK. Due to small sample size and equivocal results, the interpretation of the patient reported outcomes data is unclear. Positive findings obtained in the acute treatment setting suggest that this may be a promising area for research in periodontal homeopathy. PMID- 24050770 TI - Homeopathic Rhus toxicodendron treatment increased the expression of cyclooxygenase-2 in primary cultured mouse chondrocytes. AB - BACKGROUND: Rhus toxicodendron (Rhus tox) is a homeopathic remedy with anti inflammatory activities used for arthritis pain. METHODS: We studied the effects of 4*, 30*, 30c and 200c homeopathic dilutions of Rhus tox in primary cultured mouse chondrocytes. We examined the expression of collagen type II, a marker protein of chondrocytes, and cyclooxygenase-2 (COX-2), which is responsible for the biosynthesis of prostaglandin E2 (PGE2) and the regulation of the inflammatory response. We assessed the expression of collagen type II and COX-2 using biochemical and immunological methods, such as reverse transcription polymerase chain reaction (RT-PCR), quantitative (or real-time) RT-PCR (qRT-PCR) and immunoblot assays. RESULTS: Stimulation with different concentrations of Rhus tox increased the mRNA expression of COX-2, and stimulation with 30* Rhus tox showed the most prominent mRNA expression in both RT-PCR and qRT-PCR analyses. We also observed that homeopathic dilutions of 4*, 30* and 30c Rhus tox inhibited collagen type II expression, suggesting that Rhus tox induced the dedifferentiation of chondrocytes. In addition, treatment with 30* Rhus tox significantly increased PGE2 release compared with other homeopathic dilutions of Rhus tox. CONCLUSIONS: Taken together, these results suggest that homeopathic treatment with Rhus tox induced chondrocyte dedifferentiation and inflammatory responses, such as COX-2 expression and PGE2 production, in primary cultured chondrocytes. PMID- 24050771 TI - Effect of a homeopathic-complex medicine on state and trait anxiety and sleep disorders: a retrospective observational study. AB - PURPOSE: The primary objective of this open-label, retrospective, observational study was to examine change in indicators of anxiety changed after treatment period of at least 1 month with the homeopathic-complex medicine Datif-PC((r)). A secondary objective was to describe the quantitative changes in the sleep pattern of the subjects included in the study. METHODS: The study population consisted of 71 subjects suffering from mild to moderate anxiety, who were treated with a homeopathic-complex medicine. The subjects had attended at least 2 consultations during the year 2010, with the second visit taking place at least 30 days after the first baseline visit. At both visits, subjects were administered the State Trait Anxiety Inventory (STAI)-Y questionnaire (consisting of trait and state subscales) to assess their level of anxiety. Sleep quality was assessed based on the subjects' self-reported number of hours slept and number of night-time awakenings, before and after treatment. RESULTS: Compared to baseline, the average (STAI)-state score at visit 2 decreased by more than 6 points, while the STAI-trait score decreased by more than 3 points. This was statistically significant (p < 0.0001) for both subscales. These findings were stable in subgroup analyses (gender, age and anxiety level). The average number of hours slept per night increased significantly at visit 2 compared to baseline (from 5.1 +/- 1.1 to 5.56 +/- 0.9 h, p < 0.0001). A marked decrease in the average number of night-time awakenings was also observed at the second visit (-42%, p < 0.0001). CONCLUSIONS: This retrospective observational study suggests that treatment of anxiety and sleep disorders with Datif-PC((r)) can produce notable improvements even in a short period of time. Furthermore, the observed effects were not affected by sex, age or baseline anxiety. Further controlled, randomized studies are justified. PMID- 24050772 TI - Dielectric dispersion studies of some potentised homeopathic medicines reveal structured vehicle. AB - BACKGROUND: Avogadro's Number gives 12c as the limit beyond which no original substance can be present in a highly diluted and succcussed (potentised) homeopathic medicine, implying that chemically such dilutions consist of nothing but the vehicle. But there is evidence that living systems react to homeopathic medicines diluted even above 12c. To explain how such medicines differ from another I hypothesise that altered structure may cause the difference, such as that between diamond and amorphous carbon. Some scientists have argued that dilution followed by succussion may lead to altered structural arrangement of water molecules. This concept may be termed 'Induced Molecular Structure'. METHODS: Dielectric dispersion studies were conducted in a broad range with potencies below and above the Avogadro limit by taking 6c and 30c potencies of Graphites and Cuprum Metallicum in liquid form. Measurements were made with an Anomalous Dielectric Dispersion Detector (A3D), an instrument developed by the author. RESULTS: Experiments were carried out in a frequency range of 100 kHz to 50 MHz. Shifting of resonance frequencies as a function of medicine and potency, with potencies below and above the Avogadro limit, was observed. CONCLUSION: The range of resonance frequencies suggest that the phenomenon might originate from oscillation of dipoles caused by electric field in variously structured and polarised water. Also, there is reasonable evidence that frequencies change with materials and potency. PMID- 24050773 TI - Physiological responses of pacu (Piaractus mesopotamicus) treated with homeopathic product and submitted to transport stress. AB - BACKGROUND: Pacu (Piaractus mesopotamicus) is a species with great potential for Brazilian fish farming and losses through mortality are common after transport as a direct or indirect result of stress. The use of homeopathic complex is a further option to minimize the various stress factors that can interfere negatively in production. METHODS: After feeding for 10 consecutive days with commercial diet; or diet supplemented with sucrose; or commercial diet supplemented with homeopathic complex, juvenile pacu were placed in a polyethylene bags and transported for four hours with the following treatments: commercial diet (control); commercial diet and homeopathic complex dissolved in the transport water (W + HP); commercial diet supplemented with sucrose (D + SU) and commercial diet supplemented with homeopathic complex (D + HP). Blood was collected before transport (basal), after transport (arrival), 24 and 72 h after transport. The physiological indicators of the stress were blood glucose, cortisol and chloride levels, hematocrit, hemoglobin and total protein. Condition factor and mortality were also determined. RESULTS: Blood glucose increased significantly on arrival, returning to the basal values 24 h after, similarly in all treatments. Plasma cortisol levels were elevated on arrival but not significantly compared to the basal values for fish from W + HP and D + SU groups. Increase in hematocrit and hemoglobin and low plasma chloride levels were observed after transport in all treatments. CONCLUSION: Transport resulted in stress responses in juvenile pacu and the homeopathic complex, administered in the water or diet, did not minimize these responses. Sucrose supplementation altered the cortisol and blood glucose levels, suggesting a moderating effect on these stress indicators. PMID- 24050774 TI - Anti-proliferative effects of homeopathic medicines on human kidney, colon and breast cancer cells. AB - OBJECTIVE: Homeopathy is controversial, due to the claims made for very high dilutions. Although several theories are proposed to understand the mechanisms of action, none are scientifically verified. This study aimed to investigate the efficacy of the selected homeopathic medicines in specific in vitro cancer models. METHODS: We assessed the cytotoxic activity of selected homeopathic medicines in mother tincture (MT), and ultramolecular dilution (30C, 200C, 1M and 10M) against cell lines deriving from tumors of particular organs, Sarsaparilla (Sars) on ACHN cells (human renal adenocarcinoma), Ruta graveolens (Ruta) on COLO 205 (human colorectal carcinoma), and Phytolacca decandra (Phyto) on MCF-7 (human breast carcinoma). Sars was also tested against Madin-Darby canine kidney (MDCK) cells (a non-malignant cell line). Cytotoxicity was measured using the 3-(4, 5 dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) method, anti proliferative activity by trypan blue exclusion assay, apoptosis determined by dual staining the cells with ethidium bromide (EB) and acridine orange (AO) dyes. RESULTS: MTs and ultra-diluted preparations of the three homeopathic medicines had highly significant effects in the respective cancer cell lines, producing cytotoxicity and a decrease in cell proliferation. The effects were greatest with the MTs, but in all cases and persisted, although to a lesser degree in the ultra diluted molecular preparations. Sars showed no effect on MDCK cells. In the homeopathic medicine treated cultures, hallmarks of apoptosis were evident including, cell shrinkage, chromatin condensation and DNA fragmentation. CONCLUSION: This study provides preliminary laboratory evidence indicating the ability of homeopathic medicines as anticancer agents. Further studies of the action of these homeopathic remedies are warranted. PMID- 24050775 TI - Reconstitution of R-spondin:LGR4:ZNRF3 adult stem cell growth factor signaling complexes with recombinant proteins produced in Escherichia coli. AB - R-Spondins are secreted glycoproteins (RSPO1-RSPO4) that have proliferative effects on adult stem cells by potentiating Wnt signaling. RSPO actions are mediated by the leucine-rich repeat (LRR)-containing seven-transmembrane receptors LGR4-LGR6 and the transmembrane E3 ubiquitin ligases ZNRF3 and RNF43. Here, we present a methodology for the bacterial expression and purification of the signaling competent, cysteine-rich Fu1-Fu2 domains of the four human RSPOs, a fragment of the human LGR4 extracellular domain (ECD) containing LRR1-14, and the human ZNRF3 ECD. In a cell-based signaling assay, the nonglycosylated RSPOs enhanced low-dose Wnt3a signaling with potencies comparable to those of mammalian cell-produced RSPOs and RSPO2 and -3 were more potent than RSPO1 and -4. LGR4 LRR1-14 and ZNRF3 ECD inhibited RSPO2-enhanced Wnt3a signaling. The RSPOs bound LGR4 LRR1-14 with nanomolar affinities that decreased in the following order in a time-resolved fluorescence resonance energy transfer (TR-FRET) assay: RSPO4 > RSPO2 > RSPO3 > RSPO1. RSPO-receptor interactions were further characterized with a native gel electrophoretic mobility shift assay, which corroborated the RSPO LGR4 TR-FRET results and indicated that RSPOs weakly bound ZNRF3 with affinities that decreased in the following order: RSPO2 > RSPO3 > RSPO1. RSPO4:ZNRF3 complexes were not detected. Lastly, ternary RSPO:LGR4:ZNRF3 complexes were detected for RSPO2 and -3. Our results indicate that RSPO and LGR4 N-glycans are dispensable for function, demonstrate RSPO-mediated ternary complex formation, and suggest that the stronger signaling potencies of RSPO2 and -3 result from their strong binding of both receptors. Our unique protein production methodology may provide a cost-effective source of recombinant RSPOs for regenerative medicine applications. PMID- 24050776 TI - MicroRNA-34a suppresses cell proliferation by targeting LMTK3 in human breast cancer mcf-7 cell line. AB - Breast cancer remains the leading cause of cancer mortality in females, and about 70% of the primary breast cancer patients are diagnosed ERalpha-positive, which is the most common type of breast cancer. MicroRNA-34a (miR-34a) has been shown to be a master regulator of tumor suppression in many types of cancers including breast cancer. However, the role of miR-34a in ERalpha-positive breast cancer has not been elucidated. Here, we find that in MCF-7, which is an ERalpha-positive breast cancer cell line, miR-34a is remarkably downregulated after E2 treatment. Overexpression of miR-34a by lentivirus suppresses cell proliferation, S phase ratio, and tumor formation in an E2-dependent manner in vitro. According to the mRNA sequence, lemur tyrosine kinase 3 (LMTK3), which is an important regulator of estrogen receptor alpha (ERalpha), is a predicted target of miR-34a. This is confirmed by dual luciferase reporter assay and the decrease of LMTK3 mRNA and protein levels after overexpression of miR-34a. Moreover, miR-34a overexpression decreases AKT signaling pathway and increases ERalpha phosphorylation status. Taken together, these results suggest that miR-34a inhibits breast cancer proliferation by targeting LMTK3 and might be used as an anti-ERalpha agent in breast cancer therapy. PMID- 24050777 TI - BDNF Val66Met modifies the risk of childhood trauma on obsessive-compulsive disorder. AB - Childhood trauma has been linked to the development of later psychopathology, including obsessive-compulsive disorder (OCD). Although evidence exists to suggest that genetic and environmental factors are involved in the aetiology of OCD, little attention has been paid to the interactions that exist between genes and environment. The aim of this study was to investigate gene-by-environment interactions between childhood trauma and the BDNF Val66Met variant in patients with OCD. Childhood trauma was assessed in 134 OCD patients and 188 controls using the Childhood Trauma Questionnaire (CTQ). Linear regression models were used for statistical analyses. Gene-environment interactions were estimated by including a combined genotype and CTQ score in the models as interaction terms. All analyses were adjusted for age, gender, CTQ minimisation-denial score and home language by including them in the logistic regression models as covariates. Childhood trauma, specifically emotional abuse and neglect, increased the odds of having OCD significantly (p < 0.001). Although no significant association was observed between BDNF Val66Met and the development of OCD, interaction analysis indicated that the BDNF Met-allele interacted with childhood emotional abuse to increase the risk of OCD significantly in a dose-dependent manner (p = 0.024). To our knowledge, this is one of the first studies to investigate gene-environment interactions in OCD, and the findings indicate the importance of collating genetic and environmental variables in future studies. PMID- 24050778 TI - Electrodermal hyporeactivity as a trait marker for suicidal propensity in uni- and bipolar depression. AB - BACKGROUND: A meta-analysis of studies investigating electrodermal activity in depressed patients, suggested that electrodermal hyporeactivity is sensitive and specific for suicide. AIMS: To confirm this finding and to study electrodermal hyporeactivity relative to type and severity of depression, trait anxiety, its stability and independence of depressive state. METHOD: Depressed inpatients (n = 783) were tested for habituation of electrodermal responses and clinically assessed using the Beck Depression Inventory (BDI) and the STAI-Trait scale for trait anxiety. RESULTS: The high sensitivity and raw specificity of electrodermal hyporeactivity for suicide were confirmed. Its prevalence was highest in bipolar disorders and was independent of severity of depression, trait anxiety, gender and age. Hyporeactivity was stable, while reactivity changed into hyporeactivity in a later depressive episode. CONCLUSIONS: The findings support the hypothesis that electrodermal hyporeactivity is a trait marker for suicidal propensity in depression. PMID- 24050779 TI - Adsorption of a PEO-PPO-PEO triblock copolymer on metal oxide surfaces with a view to reducing protein adsorption and further biofouling. AB - Abstract Biomolecule adsorption is the first stage of biofouling. The aim of this work was to reduce the adsorption of proteins on stainless steel (SS) and titanium surfaces by modifying them with a poly(ethylene oxide) (PEO) poly(propylene oxide) (PPO)-PEO triblock copolymer. Anchoring of the central PPO block of the copolymer is known to be favoured by hydrophobic interaction with the substratum. Therefore, the surfaces of metal oxides were first modified by self-assembly of octadecylphosphonic acid. PEO-PPO-PEO preadsorbed on the hydrophobized surfaces of titanium or SS was shown to prevent the adsorption of bovine serum albumin (BSA), fibrinogen and cytochrome C, as monitored by quartz crystal microbalance (QCM). Moreover, X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry were used to characterize the surfaces of the SS and titanium after competitive adsorption of PEO-PPO-PEO and BSA. The results show that the adsorption of BSA is well prevented on hydrophobized surfaces, in contrast to the surfaces of native metal oxides. PMID- 24050780 TI - Charge-directed fiber surface modification by molecular assemblies of functional polysaccharides. AB - Molecular assemblies, namely, polyelectrolyte complexes (PECs) composed of negatively charged xylan-based derivatives and a novel positively charged cellulose derivative (CN(+)), were used for interfacial modification of wood fibers by charge directed self-assembly. The adsorption process was studied using polyelectrolyte titration and elemental analysis. X-ray spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were used as advanced techniques for the characterization of the modified fiber surfaces. The measurements revealed an intense interaction between the pulp fibers and PECs, and provided essential information for a better understanding of the adsorption process. The information gathered on this paper might contribute to the basis for the development of new value added products by the use of underutilized biomass. PMID- 24050781 TI - The National Student Survey: is it just a bad DREEM? AB - BACKGROUND: In this article, we consider the need for medical schools to improve the overall experience given to students by gaining appropriate feedback and ask whether the UK National Student Survey (NSS) is an appropriate tool. AIMS: We compare the currently used NSS data against data collected via an alternative, well validated, questionnaire - the Dundee Ready Education Environment Measure (DREEM). METHODS: The DREEM data was collected in January to April 2011, from the same cohort of students who were completing the UK online NSS. The NSS results were released into the public domain as frequency tables from which we calculated the standard deviations of each item. The DREEM questionnaire data were rescaled to match the NSS questionnaire data. RESULTS: The results were similar from each questionnaire, with a wide range of responses. Both DREEM and NSS data showed Assessment and Feedback to be the greatest problem, but the DREEM questions were specific, contextualised and could be used for curriculum development. CONCLUSIONS: This comparison shows the benefits of using a medical school specific questionnaire to gain quality feedback in order to precisely alter elements of the course rather than relying on a generic questionnaire to gauge students' opinions. PMID- 24050782 TI - Spatial and temporal interactions between livestock and wildlife in South Central Spain assessed by camera traps. AB - The diversification of livestock farms into hunting estates in South Central Spain (SCS) may impede the success of Mycobacterium bovis eradication programmes by facilitating transmission between wildlife and livestock. In this observational study we aimed to provide information of relevance about the nature and frequency of interactions (observed visits to study points) between livestock (cattle and domestic pigs) and wildlife (wild boar and red deer). The study was conducted in an extensive cattle farm in SCS where the land is also used for game hunting. During a period of one year, camera traps (n=16) were placed at a priori risk points for interspecies interactions: water (natural and artificial troughs), food placed on the ground for baiting wildlife, and pasture. To define indirect interspecies interactions, a critical time window for M. bovis to survive in the environment was selected based on the literature. Results suggest that wildlife frequented food and pasture points more often than water points, and that the number of visits increased through the dry season, peaking during the acorn season (October-January) and the deer breeding season (June-July). Direct interactions were rare (n=10), as opposed to indirect interactions (n=8992). Wildlife-followed-by-livestock interactions (n=7714) occurred much more often than livestock-followed-by-wildlife (n=1278) and were frequent at water points (66% water points, 17% food, 17% pasture). Results also suggest that water points are a hotspot for indirect interactions and might therefore be a source of infection at the wildlife-livestock interface in the territory covered, particularly for M. bovis, as it is around water where the bacteria seem to survive the longest. Preventing aggregation and therefore reducing contact rates between domestic and wild animals especially at water points may be valuable for disease control in South Central Spain. PMID- 24050783 TI - [Interests and potentials of adipose tissue in scleroderma]. AB - Systemic sclerosis is a disorder involving the connective tissue, arterioles and microvessels. It is characterized by skin and visceral fibrosis and ischemic phenomena. Currently, therapy is limited and no antifibrotic treatment has proven its efficacy. Beyond some severe organ lesions (pulmonary arterial hypertension, pulmonary fibrosis, scleroderma renal crisis), which only concern a minority of patients, the skin sclerosis of hands and face and the vasculopathy lead to physical and psychological disability in most patients. Thus, functional improvement of hand motion and face represents a priority for patient therapy. Due to its easy obtention by fat lipopaspirate and adipocytes survival, re injection of adipose tissue is a common therapy used in plastic surgery for its voluming effect. Identification and characterization of the adipose tissue derived stroma vascular fraction, mainly including mesenchymal stem cells, have revolutionized the science showing that adipose tissue is a valuable source of multipotent stem cells, able to migrate to site of injury and to differentiate according to the receiver tissue's needs. Due to easy harvest by liposuction, its abundance in mesenchymal cells far higher that the bone marrow, and stroma vascular fraction's ability to differentiate and secrete growth angiogenic and antiapoptotic factors, the use of adipose tissue is becoming more attractive in regenerative medicine. We here present the interest of adipose tissue use in the treatment of the hands and face in scleroderma. PMID- 24050784 TI - [Unusual cause of neck pain in systemic sclerosis]. PMID- 24050785 TI - [Smoldering multiple myeloma]. AB - Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell neoplasia, characterized by monoclonal plasma cell proliferation in the absence of end-organ damage, but with a high risk of progression to multiple myeloma. It has therefore to be distinguished from monoclonal gammapathy of undetermined significance (MGUS), which has a much lower risk of progression, but also from multiple myeloma, which remains an incurable disease and requires a specific treatment. The critical question in the management of SMM is whether an early therapeutic strategy could help delaying the progression to multiple myeloma, in order to lower the risk of serious complications related to this progression, or even to cure the disease. This early treatment could not be proposed to all SMM patients, who are indeed asymptomatic, and in whom the risk of toxicity could make it difficult to justify the potential benefit obtained. The challenge is to target early at diagnosis SMM patients with a high risk of progression, using available routine tests sufficiently reliable to warrant the therapeutic sanction which relies on it. Today however, apart from randomized studies, recommendations are to maintain therapeutic abstention in SMM patients. PMID- 24050786 TI - [Catheter fracture and pulmonary embolization of the distal fragment: a rare complication of the totally implantable venous access port]. AB - INTRODUCTION: Totally implantable venous access port plays a crucial role in the treatment of patients in oncology. However, its use can result sporadically in catheter fracture with catheter tip embolization into pulmonary arteries. CASE REPORTS: We report this unusual but potentially serious complication in four patients. In these patients, the port had been inserted percutaneously into the subclavian vein using the infra-clavicular approach. This side effect occurred late in three patients. In all patients, the catheter fracture was asymptomatic or pauci-symptomatic and was caused by the pinch-off syndrome. The retrieval of the embolized fragments was successfully performed by transcatheter procedure in the cardiac catheterisation laboratory. CONCLUSION: We reviewed the literature and the newest guidelines and recommendations to detail the clinico-radiological features, the possible causes of this complication and discussed means to recognize, manage and prevent it. PMID- 24050787 TI - Evaluating free school fruit: results from a natural experiment in Norway with representative data. AB - OBJECTIVE: To assess impacts of the nationwide Norwegian School Fruit Scheme (NSFS) using nationally representative data. DESIGN: The NSFS is organized such that primary-school children (grades 1-7) are randomly assigned to one of three school fruit arrangements: (i) the child receives one free fruit or vegetable per day; (ii) the child is given the option to subscribe to one fruit or vegetable per day at a subsidized price; and (iii) the child attends a school that has no school fruit arrangement. SETTING: Data from an Internet survey are used to compare child and parental fruit and vegetable intakes across the three NSFS groups focusing mainly on groups (i) and (iii). The analysis was conducted using multivariate regression techniques. SUBJECTS: Parents of primary-school children (n 1423) who report on behalf of themselves and their children. RESULTS: Children who receive free school fruit eat on average 0.36 more fruit portions daily - or 25.0 % more fruits - than children who attend schools with no fruit arrangement (P < 0.001). Moreover, parents of children who receive free school fruit eat on average 0.19 more fruit portions daily - or 12.5 % more fruits - than parents of children who attend schools with no fruit arrangement (P = 0.040). No significant associations were found between the NSFS and the vegetable intakes of children and their parents. CONCLUSIONS: The study shows, using nationally representative data, that free school fruit is associated with increased child fruit intake and that it may also affect parental fruit intake. PMID- 24050789 TI - Correlation of gene expression and contaminant concentrations in wild largescale suckers: a field-based study. AB - Toxic compounds such as organochlorine pesticides (OCs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ether flame retardants (PBDEs) have been detected in fish, birds, and aquatic mammals that live in the Columbia River or use food resources from within the river. We developed a custom microarray for largescale suckers (Catostomus macrocheilus) and used it to investigate the molecular effects of contaminant exposure on wild fish in the Columbia River. Using Significance Analysis of Microarrays (SAM) we identified 72 probes representing 69 unique genes with expression patterns that correlated with hepatic tissue levels of OCs, PCBs, or PBDEs. These genes were involved in many biological processes previously shown to respond to contaminant exposure, including drug and lipid metabolism, apoptosis, cellular transport, oxidative stress, and cellular chaperone function. The relation between gene expression and contaminant concentration suggests that these genes may respond to environmental contaminant exposure and are promising candidates for further field and laboratory studies to develop biomarkers for monitoring exposure of wild fish to contaminant mixtures found in the Columbia River Basin. The array developed in this study could also be a useful tool for studies involving endangered sucker species and other sucker species used in contaminant research. PMID- 24050790 TI - Identification of a novel benzoxazolone derivative as a selective, orally active 18 kDa translocator protein (TSPO) ligand. AB - Optimization of the pharmacokinetic properties for a series of benzoxazolone derivatives led to the identification of 9b, which showed anxiolytic effect in a rat model. However, 9b, like known benzodiazepines, induced motor impairment. Investigation into the cause of this unexpected side effect and management of 9b off-target binding affinity led to the identification of 10d, which showed oral anxiolytic effect in the rat model with improved safety profile. PMID- 24050791 TI - A critical analysis of the role of testosterone in erectile function: from pathophysiology to treatment-a systematic review. AB - CONTEXT: Androgen modulation of erectile function (EF) is widely accepted. However, the use of testosterone replacement therapy (TRT) in men with erectile dysfunction (ED) has generated an unprecedented debate. OBJECTIVE: To summarize the relevant data on the incidence, diagnosis, and management of ED coexisting with hypogonadism and to develop a pathophysiology-based treatment algorithm. EVIDENCE ACQUISITION: We reviewed the relevant medical literature, with a particular emphasis on original molecular studies, prospective observational data, and randomized controlled trials performed in the past 20 yr. EVIDENCE SYNTHESIS: Testosterone modulates nearly every component involved in EF, from pelvic ganglions to smooth muscle and the endothelial cells of the corpora cavernosa. It also regulates the timing of the erectile process as a function of sexual desire, coordinating penile erection with sex. Epidemiologic studies confirm the significant overlap of hypogonadism and ED; however, most guidelines do not consider the differential diagnosis of hypogonadism or the relevance of subclinical disease. Various clinical tools can help the physician to assess and restore androgen levels in men with ED. Special attention is given to fertility sparing treatments, due to the increasing number of older men desiring fatherhood. The simultaneous use of phosphodiesterase type 5 inhibitors (PDE5-Is) and TRT has recently been questioned. Originally proposed as a salvage therapy for nonresponders to PDE5-Is, this approach has been inappropriately transformed into a combination therapy. Clinical data are consistent when reinterpreted in the proper framework, whereas molecular evidence remains controversial. CONCLUSIONS: A body of molecular and clinical evidence supports the use of TRT in hypogonadal patients with ED, although the benefit-risk ratio is uncertain in advanced age. Critical appraisal of this evidence enabled the development of a pathophysiology-oriented algorithm designed to avoid inappropriate treatments and support whether to start with TRT, PDE5-I only, or both. Apparently divergent findings are reconciled when TRT is correctly indicated. An improved diagnosis and individualized management is desirable in light of the many available options. PMID- 24050792 TI - Can the results of the European Randomized Study of Screening for Prostate Cancer be decontaminated? PMID- 24050788 TI - Seasonal variation in physical activity and sedentary time in different European regions. The HELENA study. AB - This report aims (1) to examine the association between seasonality and physical activity (PA) and sedentary time in European adolescents and (2) to investigate whether this association was influenced by geographical location (Central-North versus South of Europe), which implies more or less extreme weather and daylight hours. Valid data on PA, sedentary time and seasonality were obtained in 2173 adolescents (1175 females; 12.5-17.5 years) included in this study. Physical activity and sedentary time were measured by accelerometers. ANCOVA was conducted to analyse the differences in PA and sedentary time across seasons. Results showed that girls had lower levels of moderate to vigorous PA (MVPA) and average PA, and spent more time in sedentary activities in winter compared with spring (all P < 0.05). Stratified analyses showed differences in PA and sedentary time between winter and spring in European girls from Central-North of Europe (P < 0.05 for sedentary time). There were no differences between PA and sedentary time across seasonality in boys. In conclusion, winter is related with less time spent in MVPA, lower average PA and higher time spent in sedentary activities in European adolescent girls, compared with spring. These differences seem to mainly occur in Central-North Europe. PMID- 24050793 TI - Triple rule-out computed tomographic angiography for chest pain: a diagnostic systematic review and meta-analysis. AB - OBJECTIVES: The objective was to compare the image quality, diagnostic accuracy, radiation exposure, and contrast volume of "triple rule-out" (TRO) computed tomography (CT) to other diagnostic modalities commonly used to evaluate patients with nontraumatic chest pain (dedicated coronary, pulmonary embolism [PE], and aortic dissection CT; invasive coronary angiography; and nuclear stress testing). METHODS: Four electronic databases were searched, along with reference lists and contacted content experts, for relevant studies from inception until October 2012. Eligible studies enrolled patients with nontraumatic chest pain, shortness of breath, suspected acute coronary syndrome (ACS), PE, or aortic dissection; used at least 64-slice CT technology; and compared TRO CT to another diagnostic modality. RESULTS: Eleven studies enrolling 3,539 patients (791 TRO and 2,748 non TRO) were included (one randomized controlled trial and 10 observational). There was no significant difference in image quality between TRO and dedicated CT scans. TRO CT had the following pooled diagnostic accuracy estimates for coronary artery disease: sensitivity of 94.3% (95% confidence interval [CI] = 89.1% to 97.5%), specificity of 97.4% (95% CI = 96.1% to 98.4%), positive likelihood ratio (LR+) of 17.71 (95% CI = 3.92 to 79.96), and negative likelihood ratio (LR-) of 0.08 (95% CI = 0.02 to 0.27). There were insufficient numbers of patients with PE or aortic dissection to generate diagnostic accuracy estimates for these conditions. Use of TRO CT involved greater radiation exposure (mean difference [MD] = 4.84 mSv, 95% CI = 1.65 to 8.04 mSv) and contrast exposure (MD = 38.0 mL, 95% CI = 28.1 to 48.0 mL) compared to non-TRO CT patients. CONCLUSIONS: Triple rule-out CT is highly accurate for detecting coronary artery disease. Given the low (<1%) prevalence of PE and aortic dissection in the included studies, and the increased radiation and contrast exposure, there are insufficient data to recommend use of TRO CT in the diagnosis of these conditions. PMID- 24050794 TI - Effectiveness of booster seats compared with no restraint or seat belt alone for crash injury prevention. AB - OBJECTIVES: The objective was to evaluate the effectiveness of belt-positioning booster seats, compared with no restraint use and with seat belt use only, during motor vehicle crashes among U.S. children. METHODS: This was a retrospective matched cohort study with data from the 1998 through 2009 National Automotive Sampling System (NASS) Crashworthiness Data System (CDS). The study sample consisted of children aged 0 to 10 years who were not seated in the front seat of the vehicle. We used Cox proportional hazards models to estimate the risk of overall, fatal, and regional body injury. RESULTS: Children using seat belts in belt-positioning booster seats experienced less overall injury (Injury Severity Score [ISS] > 0, adjusted risk ratio [RR] = 0.73, 95% confidence interval [CI] = 0.55 to 0.96; Abbreviated Injury Scale [AIS] score of 2 or higher, adjusted RR = 0.30, 95% CI = 0.16 to 0.58; ISS > 8, adjusted RR = 0.19, 95% CI = 0.06 to 0.56), and less injury in most body regions except the neck (adjusted RR = 4.79, 95% CI = 1.43 to 16.00) than did children with no restraint use. Children using seat belts in belt-positioning booster seats had an equal risk of injury but higher risks of neck (adjusted RR = 1.86, 95% CI = 1.02 to 3.40) and thorax (adjusted RR = 2.86, 95% CI = 1.33 to 6.15) injury than did children restrained by seat belts only. CONCLUSIONS: Children using belt-positioning booster seats appear to experience a higher risk of AIS > 0 injury to the neck and thorax than do children using seat belts only. Future research should examine whether the observed increase in neck and thorax injuries can be attributed to improper use of booster seats. PMID- 24050795 TI - A pilot study describing access to emergency care in two states using a model emergency care categorization system. AB - OBJECTIVES: The Institute of Medicine (IOM)'s "Future of Emergency Care" report recommended the categorization and regionalization of emergency care, but no uniform system to categorize hospital emergency care capabilities has been developed. The absence of such a system limits the ability to benchmark outcomes, to develop regional systems of care, and of patients to make informed decisions when seeking emergency care. The authors sought to pilot the deployment of an emergency care categorization system in two states. METHODS: A five-tiered emergency department (ED) categorization system was designed, and a survey of all Pennsylvania and Wisconsin EDs was conducted. This 46-item survey described hospital staffing, characteristics, resources, and practice patterns. Based on responses, EDs were categorized as limited, basic, advanced, comprehensive, and pediatric critical care capable. Prehospital transport times were then used to determine population access to each level of care. RESULTS: A total of 247 surveys were received from the two states (247 of 297, 83%). Of the facilities surveyed, roughly one-quarter of hospitals provided advanced care, 10.5% provided comprehensive care, and 1.6% provided pediatric critical care. Overall, 75.1% of the general population could reach an advanced or comprehensive ED within 60 minutes by ground transportation. Among the pediatric population (age 14 years and younger), 56.2% could reach a pediatric critical care or comprehensive ED, with another 19.5% being able to access an advanced ED within 60 minutes. CONCLUSIONS: Using this categorization system, fewer than half of all EDs provide advanced or comprehensive emergency care. While the majority of the population has access to advanced or comprehensive care within an hour, a significant portion (25%) does not. This article describes how an ED categorization scheme could be developed and deployed across the United States. There are implications for prehospital planning, patient decision-making, outcomes measurement, interfacility transfer coordination, and development of regional emergency care systems. PMID- 24050796 TI - Relationship between body mass index and prognosis of patients presenting with potential acute coronary syndromes. AB - OBJECTIVES: Studies examining the relationship between obesity and acute coronary syndrome (ACS) have been limited to patients with confirmed diagnoses. The authors sought to determine the relationship between body mass index (BMI) and 30 day cardiovascular events in emergency department (ED) patients with potential ACS. METHODS: This was a secondary analysis of a prospective cohort study of patients who presented to the ED with potential ACS. Patients were stratified according to their BMI: underweight (BMI < 18.49 kg/m(2) ), normal weight (BMI = 18.5 to 24.99 kg/m(2) ), overweight (BMI = 25 to 29.99 kg/m(2) ), obese (BMI = 30 to 34.99 kg/m(2) ), and very obese (BMI > 35 kg/m(2) ). The primary outcome was acute myocardial infarction (AMI), death, or revascularization within 30 days of presentation. A logistic regression analysis was used to adjust for confounding variables and adjusted odds ratios (aOR) with 95% confidence intervals (CIs) are presented for cardiac events and readmission outcomes. RESULTS: Of the 3,946 patients included in this study, 73 (1.9%) were underweight, 911 (23%) were normal weight, 1,199 (30.4%) were overweight, 872 (22.1%) were obese, and 891 (22.6%) were very obese. Although increased levels of obesity were associated with a greater number of cardiac risk factors, there was no difference in 30-day cardiovascular events between those of normal weight and underweight (aOR = 1.1; 95% CI = 0.4 to 2.7), overweight (aOR = 1.0; 95% CI = 0.7 to 1.4), obese (aOR = 1.2; 95% CI = 0.8 to1.7), or very obese (aOR = 0.8; 95% CI = 0.5 to 1.3). Those who were underweight were more likely to be readmitted within 30 days (aOR = 1.9; 95% CI = 1.0 to 3.7), and those who were very obese were less likely to be readmitted within 30 days (aOR = 0.7; 95% CI = 0.5 to 0.9). CONCLUSIONS: Among patients who present to the ED with potential ACS, BMI is not associated with higher risk of cardiovascular outcomes at 30 days. PMID- 24050798 TI - Point-of-care ocular ultrasound to detect optic disc swelling. AB - OBJECTIVES: Emergency physicians (EPs) frequently evaluate patients at risk for diseases that cause optic disc swelling, and they may encounter conditions that make traditional fundoscopy difficult or impossible. The objective was to assess whether EP-performed point-of-care (POC) ultrasound (US) could accurately assess swelling of the optic disc. METHODS: This was a blinded, prospective study using a convenience sample of patients presenting to a neuroophthalmology clinic who were thought to be at risk for conditions associated with optic disc edema. Two EPs performed POC US examinations. Patients then underwent standard clinical assessment by a specialist. RESULTS: Fourteen patients were assessed with disc swelling noted on dilated fundoscopic exam in 11 of 28 (39%) eyes. A maximum disc height greater than 0.6 mm as measured by US predicted the presence of optic disc edema noted on fundoscopic exam, with a sensitivity of 82% (95% confidence interval [CI] = 48% to 98%) and a specificity of 76% (95% CI = 50% to 93%). A threshold value of 1.0 mm for disc height yielded a sensitivity of 73% (95% CI = 39% to 94%) and a specificity of 100% (95% CI = 81% to 100%). Measurements of disc height as determined by optical coherence tomography (OCT) exhibited good correlation when compared to US measurements (r = 0.836, p < 0.0001, 95% CI = 0.65 to 0.93). CONCLUSIONS: These data suggest that EP-performed POC US can detect clinically apparent optic disc swelling. Because sonography can be performed readily at the bedside, even in cases where fundoscopy is difficult or impossible, this technique may prove to be a valuable tool for the assessment of optic disc swelling in the emergency department (ED). PMID- 24050797 TI - Patient choice in the selection of hospitals by 9-1-1 emergency medical services providers in trauma systems. AB - OBJECTIVES: Reasons for undertriage (transporting seriously injured patients to nontrauma centers) and the apparent lack of benefit of trauma centers among older adults remain unclear; understanding emergency medical services (EMS) provider reasons for selecting certain hospitals in trauma systems may provide insight to these issues. In this study, the authors evaluated reasons cited by EMS providers for selecting specific hospital destinations for injured patients, stratified by age, injury severity, field triage status, and prognosis. METHODS: This was a retrospective cohort study of injured children and adults transported by 61 EMS agencies to 93 hospitals (trauma and nontrauma centers) in five regions of the western United States from 2006 through 2008. Hospital records were probabilistically linked to EMS records using trauma registries, state discharge data, and emergency department data. The seven standardized reasons cited by EMS providers for selecting hospital destinations included closest facility, ambulance diversion, physician choice, law enforcement choice, patient or family choice, specialty resource center, and other. "Serious injury" was defined as an Injury Severity Score (ISS) >= 16, and unadjusted in-hospital mortality was considered as a marker of prognosis. All analyses were stratified by age in 10 year increments, and descriptive statistics were used to characterize the findings. RESULTS: A total of 176,981 injured patients were evaluated and transported by EMS over the 3-year period, of whom 5,752 (3.3%) had ISS >= 16 and 2,773 (1.6%) died. Patient or family choice (50.6%), closest facility (20.7%), and specialty resource center (15.2%) were the most common reasons indicated by EMS providers for selecting destination hospitals; these frequencies varied substantially by patient age. The frequency of patient or family choice increased with increasing age, from 36.4% among 21- to 30-year-olds to 75.8% among those older than 90 years. This trend paralleled undertriage rates and persisted when restricted to patients with serious injuries. Older patients with the worst prognoses were preferentially transported to major trauma centers, a finding that was not explained by field triage protocols. CONCLUSIONS: Emergency medical services transport patterns among injured patients are not random, even after accounting for field triage protocols. The selection of hospitals appears to be heavily influenced by patient or family choice, which increases with patient age and involves inherent differences in patient prognosis. PMID- 24050800 TI - Triple rule out: why it is not ready to roll out. PMID- 24050799 TI - Characterization of the Council of Emergency Medicine Residency Directors' standardized letter of recommendation in 2011-2012. AB - OBJECTIVES: The Council of Emergency Medicine Residency Directors (CORD) introduced the standardized letter of recommendation (SLOR) in 1997, and it has become a critical tool for assessing candidates for emergency medicine (EM) training. It has not itself been evaluated since the initial studies associated with its introduction. This study characterizes current SLOR use to evaluate whether it serves its intended purpose of being standardized, concise, and discriminating. METHODS: This retrospective, multi-institutional study evaluated letters of recommendation from U.S. allopathic applicants to three EM training programs during the 2011-2012 Electronic Residency Application Service (ERAS) application cycle. Distributions of responses to each question on the SLOR were calculated, and the free-text responses were analyzed. Two pilots, performed on five applicants each, assisted in developing a strategy for limiting interrater reliability. RESULTS: Each of the three geographically diverse programs provided a complete list of U.S. allopathic applicants to their program. Upon randomization, each program received a list of coded applicants unique to their program randomly selected for data collection. The number of applicants was selected to reach a goal of approximately 200 SLORs per site (n = 602). Among this group, comprising 278 of 1,498 applicants (18.6%) from U.S. allopathic schools, a total of 1,037 letters of recommendation were written, with 724 (69.8%) written by emergency physicians. SLORs represented 57.9% (602/1037) of all LORs (by any kind of author) and 83.1% (602/724) of letters written by emergency physicians. Three hundred ninety-two of 602 SLORs had a single author (65.1%). For the question on "global assessment," students were scored in the top 10% in 234 of 583 of applications (40.1%; question not answered by some), and 485 of 583 (83.2%) of the applicants were ranked above the level of their peers. Similarly, >95% of all applicants were ranked in the top third compared to peers, for all but one section under "qualifications for emergency medicine." For 405 of 602 of all SLORs (67.2%), one or more questions were left unanswered, while 76 of all SLORs (12.6%) were "customized" or changed from the standard template. Finally, in 291 of 599 of SLORs (48.6%), the word count was greater than the recommended maximum of 200 words. CONCLUSIONS: Grade inflation is marked throughout the SLOR, limiting its ability to be discriminating. Furthermore, template customization and skipped questions work against the intention to standardize the SLOR. Finally, it is not uncommon for comments to be longer than guideline recommendations. As an assessment tool, the SLOR could be more discerning, concise, and standardized to serve its intended purpose. PMID- 24050801 TI - An emergency department patient flow model based on queueing theory principles. AB - OBJECTIVES: The objective was to derive and validate a novel queuing theory-based model that predicts the effect of various patient crowding scenarios on patient left without being seen (LWBS) rates. METHODS: Retrospective data were collected from all patient presentations to triage at an urban, academic, adult-only emergency department (ED) with 87,705 visits in calendar year 2008. Data from specific time windows during the day were divided into derivation and validation sets based on odd or even days. Patient records with incomplete time data were excluded. With an established call center queueing model, input variables were modified to adapt this model to the ED setting, while satisfying the underlying assumptions of queueing theory. The primary aim was the derivation and validation of an ED flow model. Chi-square and Student's t-tests were used for model derivation and validation. The secondary aim was estimating the effect of varying ED patient arrival and boarding scenarios on LWBS rates using this model. RESULTS: The assumption of stationarity of the model was validated for three time periods (peak arrival rate = 10:00 a.m. to 12:00 p.m.; a moderate arrival rate = 8:00 a.m. to 10:00 a.m.; and lowest arrival rate = 4:00 a.m. to 6:00 a.m.) and for different days of the week and month. Between 10:00 a.m. and 12:00 p.m., defined as the primary study period representing peak arrivals, 3.9% (n = 4,038) of patients LWBS. Using the derived model, the predicted LWBS rate was 4%. LWBS rates increased as the rate of ED patient arrivals, treatment times, and ED boarding times increased. A 10% increase in hourly ED patient arrivals from the observed average arrival rate increased the predicted LWBS rate to 10.8%; a 10% decrease in hourly ED patient arrivals from the observed average arrival rate predicted a 1.6% LWBS rate. A 30-minute decrease in treatment time from the observed average treatment time predicted a 1.4% LWBS. A 1% increase in patient arrivals has the same effect on LWBS rates as a 1% increase in treatment time. Reducing boarding times by 10% is expected to reduce LWBS rates by approximately 0.8%. CONCLUSIONS: This novel queuing theory-based model predicts the effect of patient arrivals, treatment time, and ED boarding on the rate of patients who LWBS at one institution. More studies are needed to validate this model across other institutions. PMID- 24050802 TI - The effect of bundled payment on emergency department use: alternative quality contract effects after year one. AB - OBJECTIVES: The objective was to identify the effect of the Alternative Quality Contract (AQC), a global payment system implemented by Blue Cross Blue Shield (BCBS) of Massachusetts in 2009, on emergency department (ED) presentations. METHODS: Blue Cross Blue Shield of Massachusetts claims from 2006 through 2009 for 332,624 enrollees whose primary care physicians (PCPs) enrolled in the AQC, and 1,296,399 whose PCPs were not enrolled in the AQC, were evaluated. A pre post, intervention-control, propensity-scored difference-in-difference approach was used to isolate the AQC effect on ED visits. The analysis adjusted for age, sex, health status, and secular trends to compare ED use between the treatment and control groups. RESULTS: Overall, secular trends showed that the number of ED visits decreased slightly for both treatment and control groups. The adjusted analysis of the AQC group showed decreases from 0.131 to 0.127 visits per member/quarter, and the control group decreased from 0.157 to 0.152 visits per member/quarter. The difference-in-difference analysis showed the AQC had no statistically significant effect on total ED use compared to the control group. CONCLUSIONS: In the first year of this AQC, we did not find evidence of change in aggregate ED use. Similar global budget programs may not alter ED use in the initial implementation period. PMID- 24050803 TI - Effect of the Mediterranean diet on blood pressure in the PREDIMED trial: results from a randomized controlled trial. AB - BACKGROUND: Hypertension can be prevented by adopting healthy dietary patterns. Our aim was to assess the 4-year effect on blood pressure (BP) control of a randomized feeding trial promoting the traditional Mediterranean dietary pattern. METHODS: The PREDIMED primary prevention trial is a randomized, single-blinded, controlled trial conducted in Spanish primary healthcare centers. We recruited 7,447 men (aged 55 to 80 years) and women (aged 60 to 80 years) who had high risk for cardiovascular disease. Participants were assigned to a control group or to one of two Mediterranean diets. The control group received education on following a low-fat diet, while the groups on Mediterranean diets received nutritional education and also free foods; either extra virgin olive oil, or nuts. Trained personnel measured participants' BP at baseline and once yearly during a 4-year follow-up. We used generalized estimating equations to assess the differences between groups during the follow-up. RESULTS: The percentage of participants with controlled BP increased in all three intervention groups (P-value for within group changes: P<0.001). Participants allocated to either of the two Mediterranean diet groups had significantly lower diastolic BP than the participants in the control group (-1.53 mmHg (95% confidence interval (CI) -2.01 to -1.04) for the Mediterranean diet supplemented with extra virgin olive oil, and -0.65 mmHg (95% CI -1.15 to -0.15) mmHg for the Mediterranean diet supplemented with nuts). No between-group differences in changes of systolic BP were seen. CONCLUSIONS: Both the traditional Mediterranean diet and a low-fat diet exerted beneficial effects on BP and could be part of advice to patients for controlling BP. However, we found lower values of diastolic BP in the two groups promoting the Mediterranean diet with extra virgin olive oil or with nuts than in the control group. TRIAL REGISTRATION: Current Controlled Trials ISRCTN35739639. PMID- 24050804 TI - Ongoing measles outbreak in Orthodox Jewish community, London, UK. PMID- 24050805 TI - Novel alkali earth borohydride Sr(BH4)2 and borohydride-chloride Sr(BH4)Cl. AB - Two novel alkali earth borohydrides, Sr(BH4)2 and Sr(BH4)Cl, have been synthesized and investigated by in-situ synchrotron radiation powder X-ray diffraction (SR-PXD) and Raman spectroscopy. Strontium borohydride, Sr(BH4)2, was synthesized via a metathesis reaction between LiBH4 and SrCl2 by two complementary methods, i.e., solvent-mediated and mechanochemical synthesis, while Sr(BH4)Cl was obtained from mechanochemical synthesis, i.e., ball milling. Sr(BH4)2 crystallizes in the orthorhombic crystal system, a = 6.97833(9) A, b = 8.39651(11) A, and c = 7.55931(10) A (V = 442.927(10) A(3)) at RT with space group symmetry Pbcn. The compound crystallizes in alpha-PbO2 structure type and is built from half-occupied brucite-like layers of slightly distorted [Sr(BH4)6] octahedra stacked in the a-axis direction. Strontium borohydride chloride, Sr(BH4)Cl, is a stoichiometric, ordered compound, which also crystallizes in the orthorhombic crystal system, a = 10.8873(8) A, b = 4.6035(3) A, and c = 7.4398(6) A (V = 372.91(3) A(3)) at RT, with space group symmetry Pnma and structure type Sr(OH)2. Sr(BH4)Cl dissociates into Sr(BH4)2 and SrCl2 at ~170 degrees C, while Sr(BH4)2 is found to decompose in multiple steps between 270 and 465 degrees C with formation of several decomposition products, e.g., SrB6. Furthermore, partly characterized new compounds are also reported here, e.g., a solvate of Sr(BH4)2 and two Li-Sr-BH4 compounds. PMID- 24050806 TI - De novo sequencing of peptides using selective 351 nm ultraviolet photodissociation mass spectrometry. AB - Although in silico database search methods remain more popular for shotgun proteomics methods, de novo sequencing offers the ability to identify peptides derived from proteins lacking sequenced genomes and ones with subtle splice variants or truncations. Ultraviolet photodissociation (UVPD) of peptides derivatized by selective attachment of a chromophore at the N-terminus generates a characteristic series of y ions. The UVPD spectra of the chromophore-labeled peptides are simplified and thus amenable to de novo sequencing. This method resulted in an observed sequence coverage of 79% for cytochrome C (eight peptides), 47% for beta-lactoglobulin (five peptides), 25% for carbonic anhydrase (six peptides), and 51% for bovine serum albumin (33 peptides). This strategy also allowed differentiation of proteins with high sequence homology as evidenced by de novo sequencing of two variants of green fluorescent protein. PMID- 24050807 TI - Synthesis and unexpected oxidization of the tricyclic core of ugibohlin, isophakellin, and styloguanidine. AB - A series of 4-substituted 5,6,7,9-tetrahydropyrrolo[2,3-f]indolizin-9-ones, representing the tricyclic core skeleton of ugibohlin, isophakellin, and styloguanidine, were synthesized via an intramolecular Vilsmeier-Haack reaction. This reaction allows the chemoselective C-C bond formation between the pyrrole C3 and proline C5 of N-[(pyrrol-2-yl)carbonyl]prolinamides to construct the B-ring without the protection of the pyrrole nitrogen. Unexpected oxidizative property of the tricyclic core skeleton was observed, which could illuminate understanding of the biological formation of these marine secondary metabolites. PMID- 24050808 TI - Caseload midwifery care versus standard maternity care for women of any risk: M@NGO, a randomised controlled trial. AB - BACKGROUND: Women at low risk of pregnancy complications benefit from continuity of midwifery care, but no trial evidence exists for women with identified risk factors. We aimed to assess the clinical and cost outcomes of caseload midwifery care for women irrespective of risk factors. METHODS: In this unblinded, randomised, controlled, parallel-group trial, pregnant women at two metropolitan teaching hospitals in Australia were randomly assigned to either caseload midwifery care or standard maternity care by a telephone-based computer randomisation service. Women aged 18 years and older were eligible if they were less than 24 weeks pregnant at the first booking visit. Those who booked with another care provider, had a multiple pregnancy, or planned to have an elective caesarean section were excluded. Women allocated to caseload care received antenatal, intrapartum, and postnatal care from a named caseload midwife (or back up caseload midwife). Controls received standard care with rostered midwives in discrete wards or clinics. The participant and the clinician were not masked to assignment. The main primary outcome was the proportion of women who had a caesarean section. The other primary maternal outcomes were the proportions who had an instrumental or unassisted vaginal birth, and the proportion who had epidural analgesia during labour. Primary neonatal outcomes were Apgar scores, preterm birth, and admission to neonatal intensive care. We analysed all outcomes by intention to treat. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12609000349246. FINDINGS: Publicly insured women were screened at the participating hospitals between Dec 8, 2008, and May 31, 2011. 1748 pregnant women were randomly assigned, 871 to caseload and 877 to standard care. The proportion of caesarean sections did not differ between the groups (183 [21%] in the caseload group vs 204 [23%] in the standard care group; odds ratio [OR] 0.88, 95% CI 0.70-1.10; p=0.26). The proportion of women who had elective caesarean sections (before onset of labour) differed significantly between caseload and standard care (69 [8%] vs 94 [11%]; OR 0.72, 95% CI 0.52 0.99; p=0.05). Proportions of instrumental birth were similar (172 [20%] vs 171 [19%]; p=0.90), as were the proportions of unassisted vaginal births (487 [56%] vs 454 [52%]; p=0.08) and epidural use (314 [36%] vs 304 [35%]; p=0.54). Neonatal outcomes did not differ between the groups. Total cost of care per woman was AUS$566.74 (95% 106.17-1027.30; p=0.02) less for caseload midwifery than for standard maternity care. INTERPRETATION: Our results show that for women of any risk, caseload midwifery is safe and cost effective. FUNDING: National Health and Medical Research Council (Australia). PMID- 24050809 TI - Continuity of maternity carer for all women. PMID- 24050810 TI - Revision of a method quality rating scale for single-case experimental designs and n-of-1 trials: the 15-item Risk of Bias in N-of-1 Trials (RoBiNT) Scale. AB - Recent literature suggests a revival of interest in single-case methodology (e.g., the randomised n-of-1 trial is now considered Level 1 evidence for treatment decision purposes by the Oxford Centre for Evidence-Based Medicine). Consequently, the availability of tools to critically appraise single-case reports is of great importance. We report on a major revision of our method quality instrument, the Single-Case Experimental Design Scale. Three changes resulted in a radically revised instrument, now entitled the Risk of Bias in N-of 1 Trials (RoBiNT) Scale: (i) item content was revised and increased to 15 items, (ii) two subscales were developed for internal validity (IV; 7 items) and external validity and interpretation (EVI; 8 items), and (iii) the scoring system was changed from a 2-point to 3-point scale to accommodate currently accepted standards. Psychometric evaluation indicated that the RoBiNT Scale showed evidence of construct (discriminative) validity. Inter-rater reliability was excellent, for pairs of both experienced and trained novice raters. Intraclass correlation coefficients of summary scores for individual (experienced) raters: ICC(TotalScore) = .90, ICC(IVSubscale) = .88, ICC(EVISubscale) = .87; individual (novice) raters: ICC(TotalScore)= .88, ICC(IVSubscale) = .87, ICC(EVISubscale) = .93; consensus ratings between experienced and novice raters (ICC(TotalScore) = .95, ICC(IVSubscale) = .93, ICC(EVISubscale) = .93. The RoBiNT Scale thus shows sound psychometric properties and provides a comprehensive yet efficient examination of important features of single-case methodology. PMID- 24050812 TI - Evaluation of the mechanical efficiency of knee braces based on computational modeling. AB - Knee orthotic devices are commonly prescribed by physicians and medical practitioners for preventive or therapeutic purposes on account of their claimed effect: joint stabilisation and proprioceptive input. However, the force transfer mechanisms of these devices and their level of action remain controversial. The objectives of this work are to characterise the mechanical performance of conventional knee braces regarding their anti-drawer effect using a finite element model of a braced lower limb. A design of experiment approach was used to quantify meaningful mechanical parameters related to the efficiency and discomfort tolerance of braces. Results show that the best tradeoff between efficiency and discomfort tolerance is obtained by adjusting the brace length or the strap tightening. Thanks to this computational analysis, novel brace designs can be evaluated for an optimal mechanical efficiency and a better compliance of the patient with the treatment. PMID- 24050811 TI - Tribody: robust self-assembled trimeric targeting ligands with high stability and significantly improved target-binding strength. AB - The C-terminal coiled-coil region of mouse and human cartilage matrix protein (CMP) self-assembles into a parallel trimeric complex. Here, we report a general strategy for the development of highly stable trimeric targeting ligands (tribodies), against epidermal growth factor receptor (EGFR) and prostate specific membrane antigen (PSMA) as examples, by fusing a specific target-binding moiety with a trimerization domain derived from CMP. The resulting fusion proteins can efficiently self-assemble into a well-defined parallel homotrimer with high stability. Surface plasmon resonance (SPR) analysis of the trimeric targeting ligands demonstrated significantly enhanced target-binding strength compared with the corresponding monomers. Cellular-binding studies confirmed that the trimeric targeting ligands have superior binding strength toward their respective receptors. Significantly, the EGFR-binding tribody was considerably accumulated in the tumor of mice bearing xenografted EGFR-positive tumors, indicating its effective cancer-targeting feature under in vivo conditions. Our results demonstrate that CMP-based self-assembly of tribodies can be a general strategy for the facile and robust generation of trivalent targeting ligands for a wide variety of in vitro and in vivo applications. PMID- 24050813 TI - Absent median somatosensory evoked potential is a predictor of type I complex regional pain syndrome after stroke. AB - PURPOSE: The objective was to determine whether the abnormal finding of somatosensory evoked potentials (SEPs) associated with the development of type I complex regional pain syndrome (CRPS) after stroke. METHODS: This was a retrospective study conducted from January, 2003, to December, 2007. Seventy patients were confirmed as CRPS type I, and one hundred and eighty-two patients were assigned to the control group. The initial clinical data were reviewed including age, gender, main type of stroke, lateralization and location of the lesion, presence of glenohumeral subluxation, and the development of CRPS. Somatosensory evoked potentials tests (SEP) in median nerve (N20) and posterior tibial nerve (P37) were performed. RESULTS: CRPS groups revealed significantly higher incidence of the absent and abnormal hemiplegic median SEP, hemorrhagic stroke, and glenohumeral subluxation (GHS). Binary logistic regression analysis indicated that GHS (exp.(B)=4.083, p<0.01) with the absent median SEP (exp.(B)=3.246, p<0.01) were significant independent predictors of CRPS onset. CONCLUSIONS: In conclusion, GHS and the absent median SEP at sub-acute phase of stroke were primary predictors of the onset of post-stoke CRPS. Implications for Rehabilitation Recent investigations have suggested that autonomic, motor and somatosensory abnormalities of CRPS are impairments involving the central nervous system (CNS) as well as the peripheral neurogenic inflammatory process. However, the understanding of the pathophysiology of CRPS is still far from complete. The absence of SEP at the sub-acute stage of stroke correlated with the onset of post stroke CRPS type I. The SEP evaluation at the sub-acute period after stroke might be generally used for predicting the concomitant development of post-stroke CRPS type I as well as functional recovery after stroke. PMID- 24050814 TI - The impact of antenatal mental distress on functioning and capabilities: views of health care providers and service users in Cape Town, South Africa. AB - PURPOSE: Antenatal mental distress has disabling consequences. It affects functioning and participation in daily activities and can lead to postnatal depression. This study employs the International Classification of Functioning Disability and Health (ICF), to explore the experiences of pregnant women with mental distress attending the Perinatal Mental Health Project (PMHP). The analysis also adopts Amartya Sen's capabilities approach to provide suggestions for appropriate interventions. METHODS: We conducted in-depth interviews with seven pregnant women experiencing antenatal mental distress, three postnatal women who had experienced antenatal mental distress and seven health care providers all affiliated with the PMHP. We used an open-ended interview guide employing domains from the ICF as well as from the capabilities approach. FINDINGS: Participants attributed their antenatal mental distress to a range of environmental factors. Difficulties in functioning were reported by participants including difficulties at work and caring for children. Participants stated that services provided by the PMHP have a positive impact on functioning and capabilities. CONCLUSION: The study suggests that the ICF is useful for exploring the impact of antenatal mental distress on functioning. It is well complemented by the capabilities approach to inform interventions. Implications for Rehabilitation Antenatal mental distress is a significant public health issue that impacts on women's functioning and participation exacerbated by social factors such as poverty and exposure to violence. This study explored restrictions in functioning and participation faced by women with antenatal mental distress including the ability to care for children, find meaningful employment and sustain relationships. Counselling services can play a role in restoring functioning and capabilities for women experiencing antenatal mental distress. Counselling services have the ability to discuss restrictions in functioning caused by antenatal mental distress with their clients and to offer support for creating capabilities once functioning has improved. PMID- 24050815 TI - Associations between disability prevalence and local-area characteristics in a general community-living population. AB - BACKGROUND: Disability is understood to arise from person-environment interactions. Hence, heterogeneity in local-area characteristics should be associated with local-area variation in disability prevalence. This study evaluated the associations of disability prevalence with local-area socioeconomic status and contextual features. METHODS: Disability prevalence was obtained from the Canada census of 2001 for the entire province of Quebec at the level of dissemination areas (617 individuals on average) based on responses from 20% of the population. Data on local-area characteristics were urban-rural denomination, social and material deprivation, active and collective commuting, residential stability, and housing quality. Associations between local-area characteristics and disability prevalence were assessed using multilevel logistic regressions. RESULTS: Disability was associated with local-area socioeconomic status and contextual characteristics, and heterogeneity in these factors accounted for urban-rural differences in disability prevalence. Associations between contextual features and disability prevalence were confounded by local-area socioeconomic status. Some associations between local-area socioeconomic status and disability prevalence were moderated by contextual characteristics. The importance of this effect modification is greater when expressed in terms of the absolute magnitude of disability than in the relative likelihood of disability. CONCLUSION: Explanation of rural-urban differences by the contribution of other local-area characteristics is consistent with the conceptualization of urban-rural categories as the reflection of spatially varying ensembles of compositional and contextual factors. Although local-area socioeconomic status explains most variability in disability prevalence, this study shows that contextual characteristics are relevant to analyses of the spatial patterning of disability as they predict spatial variations of disability, sometimes in interaction with socioeconomic status. This study demonstrates that absolute and relative perspectives on effect modification may lead to differing conclusions. PMID- 24050816 TI - [Spatiotemporal distribution of tuberculosis cases in the city of Saint-Louis Senegal from 2008-2011]. AB - BACKGROUND: We studied the incidence of tuberculosis in the health district of Saint-Louis, Senegal over a period of 4years (2008-2011). One thousand three hundred and eighty-six cases were identified, producing an annual standardized incidence ratio of 129 cases per 100,000 inhabitants. RESULTS: Men in the 15-24 year old age group were more likely to be affected, and diagnosis was more common in the second half of the year. Treatment compliance was excellent (96%), and the cure rate of patients with a TB-positive microscopic examination was 95%. The overall treatment failure rate was 1% and the 6-month morality was 2%. Seropositivity, measured in volunteer patients (48%) was 3%. CONCLUSION: A spatial and temporal map of tuberculosis in the city of Saint-Louis, Senegal has been established. A cluster appears to be very likely in Guet Ndar, a particularly dense population zone in a fishing area. There is also a possible secondary cluster at Pikine. PMID- 24050817 TI - Development and psychometric evaluation of the Undergraduate Clinical Education Environment Measure (UCEEM). AB - BACKGROUND: There is a paucity of instruments designed to evaluate the multiple dimensions of the workplace as an educational environment for undergraduate medical students. AIM: The aim was to develop and psychometrically evaluate an instrument to measure how undergraduate medical students perceive the clinical workplace environment, based on workplace learning theories and empirical findings. METHOD: Development of the instrument relied on established standards including theoretical and empirical grounding, systematic item development and expert review at various stages to ensure content validity. Qualitative and quantitative methods were employed using a series of steps from conceptualization through psychometric analysis of scores in a Swedish medical student population. RESULTS: The final result was a 25-item instrument with two overarching dimensions, experiential learning and social participation, and four subscales that coincided well with theory and empirical findings: Opportunities to learn in and through work & quality of supervision; Preparedness for student entry; Workplace interaction patterns & student inclusion; and Equal treatment. Evidence from various sources supported content validity, construct validity and reliability of the instrument. CONCLUSION: The Undergraduate Clinical Education Environment Measure represents a valid, reliable and feasible multidimensional instrument for evaluation of the clinical workplace as a learning environment for undergraduate medical students. Further validation in different populations using various psychometric methods is needed. PMID- 24050818 TI - Pathological features of FTLD-FUS in a Japanese population: analyses of nine cases. AB - We investigated the pathological features of frontotemporal lobar degeneration (FTLD) with fused in sarcoma protein (FUS) accumulation (FTLD-FUS) in the Japanese population. Only one out of nine FTLD-FUS cases showed pathology that corresponds to atypical FTLD with ubiquitin-positive inclusions (aFTLD-U). Five were basophilic inclusion body disease (BIBD) and two were neuronal intermediate filament inclusion disease. The last case was unclassifiable and was associated with dystrophic neurites (DNs) as the predominant FUS pathology. The results of this study indicate an ethnic difference from western countries. In Japan, BIBD is the most common subtype of FTLD-FUS and aFTLD-U is rare, a finding which contrasts with aFTLD-U being the most common form in western countries. Immunohistochemical analyses of these FTLD-FUS cases reveal that FUS abnormally accumulated in neuronal cytoplasmic inclusions (NCIs) and DNs has an immunohistochemical profile distinct from that of normal, nuclear FUS. NCIs and DNs are more readily stained than the nuclei by antibodies to the middle portion of FUS. Antibodies to the carboxyl terminal portion, on the other hand, stain the nuclei more readily than NCIs and DNs. Such an immunohistochemical profile of NCIs and DNs was similar to that of cytoplasmic granular FUS staining which we previously reported to be associated with dendrites and synapses. Redistribution of FUS from the nucleus to the cytoplasm could be associated with the formation of abnormal FUS aggregates in FTLD-FUS. PMID- 24050819 TI - Effects of tactile biofeedback by a portable voice accumulator on voice sound level in speakers with Parkinson's disease. AB - OBJECTIVES: To study the effects of biofeedback on voice sound level (SL) in subjects with reduced voice SL, secondary to Parkinson disease (PD), using a portable voice accumulator. STUDY DESIGN: Prospective intervention study. METHODS: Voice SL, phonation time, and level of background noise were registered with a portable voice accumulator during three consecutive registration periods. Six subjects with reduced voice SL secondary to PD participated. Biofeedback, in the form of a vibration signal when voice SL went below an individually set threshold level, was administered during the second registration period only. Mean voice SL was calculated for registration periods with and without feedback. Data on phonation time and level of background noise was also collected. Field registrations with the portable voice accumulator were also compared with registrations made in a recording studio. In addition, subjects were asked about subjective experiences of using the portable voice accumulator for up to 15 days. RESULTS: There was a statistically significant increase in voice SL during the period when biofeedback of voice SL was administered. Subjects reported that using the portable voice accumulator was a positive experience. Several participants wished to continue using the device. In general, subjects handled the device independently with no major problems and did not report any negative experiences. CONCLUSIONS: Although this study was a first trial including six subjects with reduced voice SL secondary to PD, the findings indicate that biofeedback of voice SL administered via a portable voice accumulator may be a useful treatment tool for this group of patients and that further studies are needed. PMID- 24050820 TI - The effect of oral topical anesthesia on the characteristics of voice. AB - OBJECTIVES/HYPOTHESIS: Although oral topical anesthesia is used routinely before rigid laryngeal endoscopy, no study has determined whether oral topical anesthesia changes voice quality. Our goal was to determine the effects of topical anesthesia on voice. STUDY DESIGN: Prospective cohort study. METHODS: Adult patients presenting to a laryngology practice who required rigid laryngeal endoscopy as part of the routine clinical visit were eligible for the study. Voices were recorded before and after oral topical benzocaine (14%)/butamben (2%)/tetracaine (2%) (ie, cetacaine) spray. Consensus auditory perceptual evaluation of voice (CAPE-V) protocol was used for the voice recordings and was the primary outcome measure. Recordings were presented randomly to two blinded speech-language pathologists specialized in voice. Secondary outcome measures were fundamental frequency (F0), jitter, shimmer, and noise-to-harmonics ratio (N/H) on sustained /i/ and speaking F0. RESULTS: One hundred two patients participated in the study. There was no significant difference in CAPE-V measurements before and after topical anesthesia for all six attributes: overall severity (P = 0.145), roughness (P = 0.214), breathiness (P = 0.761), strain (P = 0.053), pitch (P = 0.301), and loudness (P = 0.320). There was no significant difference in jitter (P = 0.315), shimmer (P = 0.942), N/H (P = 0.128), and speaking F0 (P = 0.320). F0 /i/ decreased by a mean of 4.8Hz, which was statistically significant (P = 0.003), but probably not clinically significant. CONCLUSION: There was no clinically significant voice change after oral topical anesthesia. PMID- 24050821 TI - Glucocorticoids for vocal fold disease: a survey of otolaryngologists. AB - OBJECTIVE/HYPOTHESIS: Glucocorticoids (GCs) are commonly used in the treatment of laryngeal disorders despite the absence of clear guidelines regarding their use. We sought to assess clinical practice patterns regarding GC use for various vocal fold diseases and to ascertain factors underlying the selection of particular GCs for different vocal fold pathology. STUDY DESIGN: Prospective, survey. METHODS: A web-based 20-question survey querying clinical indications for GC use and other factors influencing decision making in GC administration was distributed to 5280 otolaryngologists via e-mail using a commercially available database. RESULTS: The overall response rate for the survey was 4% (212/5280). Of the respondents, 99% reported GCs to be valuable in their practice. Previous experience/results, familiarity, and use in practice (68%, 54%, and 37%, respectively) were the most commonly cited reasons for choosing a particular GC; pharmacokinetic profile and academic literature were infrequently cited reasons. Fifty-four percent of respondents were more likely to prescribe GCs for vocal performers compared with other patients. Additionally, most respondents stated that the potential for side effects only occasionally prevented GC utilization. CONCLUSIONS: GC prescription practices vary greatly among otolaryngologists. Drug choice appears to be driven primarily by clinician preference and personal experience rather than by specific pharmacologic or physiologic rationale. These findings likely reflect the current lack of well-constructed studies in the laryngology literature to guide GC selection and administration for benign disorders of the larynx and highlight an important potential area for future studies. PMID- 24050822 TI - Audio-perceptual evaluation of Portuguese voice disorders-an inter- and intrajudge reliability study. AB - OBJECTIVES/HYPOTHESIS: The aim of this article was to describe the results of an audio-perceptual evaluation carried out by 10 judges, on a database comprising 90 voice recordings plus 10 samples repetition, with the purpose of characterizing the intra- and interrater reliability. STUDY DESIGN: Exploratory, transversal. METHODS: The classification of the GRBAS parameters was obtained for each one of the 10 experts, concerning the 90 voice samples. The intraclass correlation coefficient determined the interrater reliability. For the 10 repeated voices, the intrarater reliability was assessed by means of a dispersion analysis. RESULTS: The average judges' classification for each of the GRBAS parameters differs (P < 0.05). The values of the correlations, with confidence intervals of 95%, between the average scores for all components of the GRBAS scale lie, in general, between 0.838 and 0.966. The first three parameters of the scale (G, R, and B) have the higher interrater reliability. Differences were statistically significant (P < 0.05) for experts 1, 6, 9, and 10, which means a poor intrarater reliability for 40% of the judges. CONCLUSIONS: All the experts had similar evaluation criteria for the assessment of the five parameters of the GRBAS scale (the values of the confidence intervals at 95% of the experts average ratings of the GRB were above 0.8). However, its quantification is not statistically similar. Asthenia and Strain have lower reliability. Most experts do not reveal statistically significant differences between the values assigned to the GRB parameters (P > 0.05). PMID- 24050823 TI - A systematic review of anal squamous cell carcinoma in inflammatory bowel disease. AB - AIM: The aim of this systematic review was to determine the incidence, aetiology and clinical characteristics of anal squamous cell carcinomas (SCC) presenting in patients with inflammatory bowel disease. METHOD: A systematic review of the literature was undertaken using Medline, Embase, Cochrane and Web of Science. RESULTS: A total of 33 cases of anal SCC were described, 7 in ulcerative colitis (UC) and 26 in Crohn's disease (CD). The annual incidence of anal SCCs was 0.9/100,000 and 2.0/100,000 in patients with UC and CD respectively. The gender ratio in CD was 3M:17F with a median age of 42 years, the main presenting symptom was anal pain and 85% of CD cases had peri-anal disease. No studies described anal intra-epithelial neoplasia. The human papilloma virus was found to be positive in 2 out of 5 (40%) cases. The majority of patients (73%) with CD received radical surgery as their first line treatment. The cumulative overall and disease free survival in CD was 37 per cent at five years. CONCLUSION: The findings of this review when contrasted with the data from cancer registries suggests that there is a higher incidence of anal SCC, an earlier age of presentation and poorer outcomes in patients with Crohn's disease compared to the general population implying a more aggressive neoplastic process. This review supports the hypothesis that peri-anal disease plays a contributing role in anal SCCs and as such targeted surveillance in patients with longstanding peri-anal disease should be considered. PMID- 24050824 TI - Association of peroxisome proliferator-activated receptors/retinoic acid receptors with renal diseases. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma), belongs to the nuclear receptor superfamily, and is a nuclear transcription receptor involving in the regulation of several biochemical pathways, such as cell growth, differentiation, and apoptosis. The nuclear retinoic acid receptors (RARs) are transcriptional transregulators that control the expression of specific subsets of genes in a ligand-dependent manner, and include three subtypes (RARalpha, RARbeta, and RARgamma). These control the expression of specific gene subsets subsequent to ligand binding and to strictly control phosphorylation processes. The current status of knowledge indicates that there might be inter- or overlapping actions between PPARgamma and RARs, and there might be an association of PPARgamma/RARs with renal diseases. Various agonists of both receptor families seem to prevent or retard the progression of renal disease. Herein, we review if causal relationships can be established between PPARgamma/RARs and renal diseases and its manifestations. PMID- 24050825 TI - Examining local-level factors shaping school nutrition policy implementation in Ontario, Canada. AB - OBJECTIVE: Increasing numbers of overweight and obese youth draw attention to the school as an important setting for targeted nutrition interventions, given that it is where they spend a majority of their waking time. The objective of the present study was to explore local-level factors shaping the implementation of a school nutrition policy. DESIGN: In-depth, semi-structured interviews were conducted in person or via the telephone (a maximum of 60 min). An interview guide was informed by the Analysis Grid for Environments Linked to Obesity (ANGELO) framework, research objectives and literature. Key themes centred on policy implementation, including facilitators and barriers (i.e. resources, capacity), user satisfaction (i.e. students) and communication strategies. SETTING: Secondary schools in Ontario, Canada. SUBJECTS: Twenty-two participants from local agencies supporting school nutrition programming (n 8) and secondary school principals, vice principals and teachers (n 14) from nine schools across three Ontario school boards. RESULTS: Results are organized according to environments outlined in the ANGELO framework. The cost of healthy food for sale, revenue loss (economic), proximity of schools to off-site food outlets (physical), the restrictive nature of policy, the role of key stakeholders (political), the role of stigma and school culture (sociocultural) act as local level barriers to policy implementation. CONCLUSIONS: Gaps in policy implementation include the high cost of food for sale and subsequent revenue generation, the close proximity of internal and external food environments, the need for consultation and communication between stakeholders, and strategies to reduce stigma and improve the school nutrition culture. PMID- 24050826 TI - Non-therapeutic anti-Xa levels in medical patients receiving anticoagulant therapy with enoxaparin. AB - INTRODUCTION: Anticoagulant activity of enoxaparin is not routinely monitored even when previous studies have shown a high pharmacological variability. The aim of this study is to determine the prevalence of non-therapeutic anti-Xa levels among medical patients using enoxaparin as anticoagulant therapy and to point out potential risk factors related to the risk of having a sub-therapeutic level. MATERIALS AND METHODS: Anti-Xa levels were measured in a cohort of sixty patients with medical indication for enoxaparin. Patients were categorized according to anti-Xa levels as follows: suboptimal anticoagulation (<0.5 IU/ml), optimal anticoagulation (between 0.5 and 1.2 IU/ml) or overanticoagulated (>1.2 IU/ml). Demographic and clinical variables and the use of concomitant medications were described for each group. Univariate and multivariate analysis were performed to assess the relationship between sub-optimal anticoagulation and potential predictive variables. A linear regression analysis was done to assess the relationship between anti-Xa activity, age, weight, body mass index, administered dose/weight and creatinine clearance. RESULTS: The mean anti-Xa activity was 0.71+/-0.32 UI/ml. Thirty one percent of patients had anti-Xa levels out of the therapeutic range, most of them (twenty-eight percent of total population) with a sub-therapeutic level. None of the variables were associated with the risk of a sub-therapeutic anti-Xa level. CONCLUSION: Almost one third of patients receiving enoxaparin had anti-Xa levels out of the therapeutic range. We need more studies to determine the clinical relevance of these findings. PMID- 24050827 TI - Recombinant thrombomodulin improved Stevens-Johnson syndrome with high serum high mobility group-B1 DNA-binding protein induced by lenalidomide administered to treat multiple myeloma. PMID- 24050828 TI - The clinical implications of ADAMTS13 function: the perspectives of haemostaseologists. AB - Apart from TTP, ADAMTS13 may be an important player in those conditions where Von Willebrand Factor and the Platelet Glycoprotein GP Ib axis have a part to play in the pathogenesis. This includes stroke, myocardial infarction, sepsis and inflammatory condition. This article reviews the literature in these conditions. PMID- 24050829 TI - Novel homozygous fibrinogen Aalpha chain truncation causes severe afibrinogenemia with life threatening complications in a two-year-old boy. PMID- 24050830 TI - [Non-functioning primary neuroendocrine tumor of the liver with extension to the celiac trunk]. PMID- 24050831 TI - [Influence of the type of thoracic access on postesophagectomy respiratory complications]. AB - INTRODUCTION: A systematic review of the literature was performed with the aim to determine differences in the rate of respiratory complications after esophagectomy for esophageal cancer using minimally invasive access vs traditional thoracic access. METHODS: A literature search was performed using Medline and Cochrane Library, identifying studies that compared the 2 types of thoracic access, regardless of the type of abdominal access (laparotomy/laparoscopy). The studies selected described respiratory complications in absolute numbers and different categories. Studies that considered minithoracotomy as a minimally invasive technique were excluded. Inclusion criteria were: studies decribing the different types of respiratory complications (9 in total), and analysing the most common complications: respiratory infection, respiratory failure and pleural effusion. RESULTS: Nine studies were selected (one prospective randomized trial and 8 case control studies) including 1,190 patients, 1,167 of which were operated on for esophageal cancer: 482 patients by thoracotomy and 708 by thoracoscopy. Three studies included definitions of respiratory complications, and one stratified them. The more frequent complications that allowed a meta-analysis were: respiratory infections, pleural effusion, and respiratory failure. No significant differences were found between the 2 types of access in the global analysis. DISCUSSION: The type of thoracic access (thoracotomy or thoracoscopy) does not seem to influence the development of respiratory complications after esophagectomy for cancer. However, the design of the studies analysed, the absence of clear definitions and stratification of the complications makes this conclusion questionable. A consensus on the definition of complications and further prospective randomized clinical trials are necessary. PMID- 24050832 TI - [Gallstone ileus as a cause of acute abdomen. Importance of early diagnosis for surgical treatment]. AB - Gallstone ileus is an uncommon type of mechanical intestinal obstruction caused by an intraluminal gallstone, and preoperative diagnosis is difficult in the Emergency department. This study is a retrospective analysis of the clinical presentation of 5 patients with gallstone ileus treated between 2000-2010. Clinical features, diagnostic testing, and surgical treatment were analyzed. Five patients were included: 2 cases showed bowel obstruction; 2 patients presented a recurrent gallstone ileus with prior surgical intervention; and one patient presented acute peritonitis due to perforation of an ileal diverticula. In all cases CT confirmed the preoperative diagnosis. In our experience, gallstone ileus may present with clinical features other than intestinal obstruction. In suspicious cases CT may be useful to decrease diagnostic delay, which is associated with more complications. PMID- 24050833 TI - Exciting progresses in stem cell and neural stem cell research. PMID- 24050834 TI - Human infection with Eurasian avian-like influenza A(H1N1) virus, China. PMID- 24050835 TI - Altered inflammatory responsiveness in serotonin transporter mutant rats. AB - BACKGROUND: Growing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of depression. Indeed, depressed patients exhibit increased levels of inflammatory markers in both the periphery and the brain, and high comorbidity exists between major depression and diseases associated with inflammatory alterations. In order to characterize the link between depression and inflammation, we aimed to investigate whether an altered inflammatory system is present in a genetic model of vulnerability for depression, namely rats with partial or total deletion of the serotonin transporter (SERT) gene. METHODS: Wild-type, heterozygous and homozygous SERT rats were analyzed under basal condition or following a challenge with an acute injection of lipopolysaccharide (LPS) and killed 24 h or 5 days later. RESULTS: We found that SERT mutant rats show altered cytokine expression in the dorsal and ventral hippocampus at basal conditions, and they also display an exacerbated cytokine response to the LPS challenge. Moreover, mutant rats exhibit differences in the expression of markers for microglia activation. CONCLUSION: Based on these data, we suggest that basal or functional alterations of immune/inflammatory systems might contribute to the phenotype of SERT rats and to their heightened susceptibility to depressive-like behavior. PMID- 24050836 TI - Effects of ocean acidification and diet on thickness and carbonate elemental composition of the test of juvenile sea urchins. AB - Continuous anthropogenic CO2 emissions to the atmosphere and uptake by the oceans will cause a reduction of seawater pH and saturation state (Omega) of CaCO3 minerals from which marine calcifiers build their shells and skeletons. Sea urchins use the most soluble form of calcium carbonate, high-magnesium calcite, to build their skeleton, spines and grazing apparatus. In order to highlight the effects of increased pCO2 on the test thickness and carbonate elemental composition of juvenile sea urchins and potential differences in their responses linked to the diet, we performed a laboratory experiment on juvenile Paracentrotus lividus, grazing on calcifying (Corallina elongata) and non calcifying (Cystoseira amentacea, Dictyota dichotoma) macroalgae, under different pH (corresponding to pCO2 values of 390, 550, 750 and 1000 MUatm). Results highlighted the importance of the diet in determining sea urchin size irrespectively of the pCO2 level, and the relevance of macroalgal diet in modulating urchin Mg/Ca ratio. The present study provides relevant clues both in terms of the mechanism of mineral incorporation and in terms of bottom-up processes (algal diet) affecting top-down ones (fish predation) in rocky subtidal communities. PMID- 24050837 TI - Quaternary supertetrahedra-layered telluride CsMnInTe3: why does this type of chalcogenide tilt? AB - Dark-red CsMnInTe3 is synthesized by a solid-state approach using CsCl as the reactive flux. This layered compound is constructed by T3 supertetrahedra and crystallizes in the space group C2/c with a = 12.400(7) A, b = 12.400(7) A, c = 24.32(2) A, beta = 97.31(2) degrees , and V = 927.07(6) A(3). The electrostatic interactions cause tilting of the supertetrahedra layers, and the value of the tilting angle is fixed by a structure index, beta' = 180 degrees - arccos(a/4c). Such an index is valid for all of the members in this family known to date. PMID- 24050838 TI - Optimising muscle parameters in musculoskeletal models using Monte Carlo simulation. AB - The use of musculoskeletal simulation software has become a useful tool for modelling joint and muscle forces during human activity, including in reduced gravity because direct experimentation is difficult. Knowledge of muscle and joint loads can better inform the design of exercise protocols and exercise countermeasure equipment. In this study, the LifeModelerTM (San Clemente, CA, USA) biomechanics simulation software was used to model a squat exercise. The initial model using default parameters yielded physiologically reasonable hip joint forces but no activation was predicted in some large muscles such as rectus femoris, which have been shown to be active in 1-g performance of the activity. Parametric testing was conducted using Monte Carlo methods and combinatorial reduction to find a muscle parameter set that more closely matched physiologically observed activation patterns during the squat exercise. The rectus femoris was predicted to peak at 60.1% activation in the same test case compared to 19.2% activation using default parameters. These results indicate the critical role that muscle parameters play in joint force estimation and the need for exploration of the solution space to achieve physiologically realistic muscle activation. PMID- 24050839 TI - Perceived distance during golf putting. AB - This study examined the effect of anxiety states on the relationship between golf putting distance and performance in an environment requiring high movement accuracy. Twenty-three amateur golfers attempted 15 putts at each of three putting distances, 1.25, 1.50, and 1.75m, under conditions characterized by both control demands and pressure. All attempts were recorded, and kinematic features were analyzed. Under conditions involving an audience and a monetary reward, the mean score on the State-Trait Anxiety Inventory Y-1 and the mean heart rate increased by 14 points and 11bpm, respectively. We grouped participants on an a posteriori basis using the median split. The backswing of high-anxiety performers shortened, the downswing speed declined, and the relative time to peak club-head velocity changed when putting under pressure from 1.25m. In contrast, no change in backswing or relative time to peak velocity was observed in low-anxiety performers, although impact velocity increased under this condition. These results indicate that the degree to which both low- and high-anxiety golfers were anxious about failure affected motor control at the 1.25-m distance, suggesting that a distortion in perceived distance may result from the interaction between putting distance and anxiety related to failure during golf putting. PMID- 24050840 TI - "Bridged" n->pi* interactions can stabilize peptoid helices. AB - Peptoids are an increasingly important class of peptidomimetic foldamers comprised of N-alkylglycine units that have been successfully developed as antimicrobial agents, lung surfactant replacements, enzyme inhibitors, and catalysts, among many other applications. Since peptoid secondary structures can be crucial to their desired functions, significant efforts have been devoted to developing means of modularly controlling peptoid backbone amide cis-trans isomerism using side chains. Strategic engineering of interactions between side chain aromatic rings and backbone cis-amides (n->pi*(Ar) interactions) is an attractive strategy for stabilizing helical structures in N-a-chiral aromatic peptoids, which are among the most utilized classes of structured peptoids. Herein, we report the first detailed computational and experimental study of n >pi*(Ar) interactions in models of peptoids containing backbone thioamides, which we term "thiopeptoids". Our work has revealed that these interactions significantly affect amide rotamerism in both peptoid and thiopeptoid models via a newly characterized "bridged" mode of interaction mediated by the N-alpha-C-H sigma orbitals. Overall, this work elucidates new strategies for controlling both peptoid and thiopeptoid folding and suggests that thiopeptoids will be highly structured and therefore potentially useful as therapeutics, biological probes, and nanostructural engineering elements. PMID- 24050841 TI - The changing role of ancillary health care service providers: an evaluation of Health Diagnostic Laboratory, Inc. AB - In an effort to reduce cost and improve quality, health care payers have enacted a number of incentives to motivate providers to focus their efforts on achieving better clinical outcomes and reducing the prevalence and progression of disease. In response to these incentives, providers are entering into new arrangements such as accountable care organizations and patient-centered medical homes to redesign delivery processes and achieve quality and cost objectives. This article reports the results of a study designed to evaluate the impact on cost and quality of care resulting from services provided by Health Diagnostic Laboratory, Inc., a clinical laboratory with a comprehensive care model. The results show that patients who utilized these laboratory services experienced lower total cost of care (23% reduction, P<0.01) and improved lipid profiles during the follow-up period. Total cost reductions were related to cost reductions found in both inpatient and ambulatory care. These findings suggest that accountable care organizations, patient-centered medical homes, and other groups entering shared savings initiatives should consider the potential role ancillary service providers with comprehensive care models can play in the delivery of integrated care. PMID- 24050843 TI - Optimizing nutrition in preterm infants. AB - Extrauterine growth restriction is common in very preterm infants. The incidence in very-low-birth-weight infants ranges between 43% and 97% in various centers, with a wide variability due to the use of different reference growth charts and nonstandard nutritional strategies. Extrauterine growth restriction is associated with an increased risk of poor neurodevelopmental outcome. Inadequate postnatal nutrition is an important factor contributing to growth failure, as most very preterm infants experience major protein and energy deficits during neonatal intensive care unit hospitalization. First-week protein and energy intake are associated with 18-month developmental outcomes in very preterm infants. Early aggressive nutrition, including parenteral and enteral, is well tolerated in the very preterm infant and is effective in improving growth. Continued provision of appropriate nutrition (fortified human milk or premature formula) is important throughout the growing care during the hospitalization. After discharge, exclusively breast-fed infants require additional supplementation. If formula fed, nutrient-enriched postdischarge formula should be continued for approximately 9 months corrected age. Supplementation of the preterm formulas with protein would increase the protein/energy ratio (3 g/100 kcal), leading to increased lean mass with relatively decreased fat deposition. Further research is required to optimize the nutritional needs of preterm infants and to evaluate the effects of nutritional interventions on long-term growth, neurodevelopment, and other health outcomes. PMID- 24050842 TI - Adult patients hospitalized for measles in France, in the 21st century. AB - BACKGROUND: An epidemic of measles broke out in France in 2008. We designed a retrospective study focusing on adults hospitalized for measles in 2010/2011. METHODS: A case was any patient aged more than 15 years, hospitalized (September 2010 to September 2011) with a typical rash or a biological diagnosis. Data was collected with standardized questionnaires in participating hospitals. RESULTS: Four hundred and sixty cases were reported: sex-ratio (M/F) = 0.93, median age 26 years (sigma = 8.8). Twenty-nine cases were severe (6.5%), 27 of which hospitalized in an ICU. Three hundred and twelve (68%) cases had elevated serum transaminases (EST), 155 (34%) cases had pneumonia, 34 (7%) cases had elevated serum creatinine (ESC), four (0.9%) cases had elevated serum amylase and lipase (ESAL), and three (0.7%) cases had neurological symptoms. One hundred and four (23%) patients presented simultaneously with EST and pneumonia. One patient presenting with severe pneumonia died (0.2%). One hundred and ten (24%) patients received antibiotics during a median seven days. CONCLUSION: Measles can present as various syndromes in adults and be responsible for a high burden during outbreaks. The immediate outcome is favorable in most patients. Long-term outcome needs further investigations to identify possible late complications. PMID- 24050844 TI - Role of antineuronal antibodies in children with encephalopathy and febrile status epilepticus. AB - Status epilepticus in childhood is more common, with a different range of causes and a lower risk of death, than convulsive status epilepticus in adults. Acute central nervous system infections appear to be markers for morbidity and mortality. Nevertheless, central nervous infection is usually presumed in these conditions. Many aspects of the pathogenesis of acute encephalitis and acute febrile encephalopathy with status epilepticus have been clarified in the past decade. The pathogenesis is divided into direct pathogens invasion or immune mediated mechanisms. Over the past few decades, the number of antineuronal antibodies to ion channels, receptors, and other synaptic proteins described in association with central nervous system disorders has increased dramatically, especially their role in pediatric encephalitis and status epilepticus. These antineuronal antibodies are divided according to the location of their respective antigens: (1) intracellular antigens, including glutamic acid decarboxylase and classical onconeural antigens such as Hu (antineuronal nuclear antibody 1, ANNA1), Ma2, Yo (Purkinje cell autoantibody, PCA1), Ri (antineuronal nuclear antibody 2, ANNA2), CV2/CRMP5, and amphiphysin; and (2) cell membrane ion channels or surface antigens including voltage-gated potassium channel receptor, N-methyl-d-aspartate receptor, alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor, gamma-aminobutyric acid(B) receptor, leucine rich glioma-inactivated protein 1, and contactin-associated protein-like 2. Identifying the mechanism of the disease may have important therapeutic implications. PMID- 24050845 TI - Consonant and syllable complexity of toddlers with Down syndrome and mixed aetiology developmental delays. AB - This study examines whether speech sound production of toddlers with Down syndrome (DS) is on par with or more severely impaired than that of mental age (MA) peers with developmental delay due to aetiologies other than Down syndrome at two points within an 18-month period near the onset of spoken word production. The utterances of 26 children with DS, aged 24-33 months, with a mean MA of 14.3 months, originally studied by Fey et al. and Warren et al. were compared to those of a group of 22 children with similar intellectual and communication delay but no DS (NDS). Phonological measures included the size of the consonant inventory, syllable shape complexity, and number of communication acts with canonical vocalizations. At Time 1, the DS group performed as well as or better than the NDS group on these measures of speech production. At Time 2, 18 months later, the DS group was behind the NDS group on the same measures. Results extended the pattern of more severe impairment in children with DS than NDS peers commonly noted in expressive language to measures of phonological development. PMID- 24050846 TI - Carotid intima-media thickness and plaque assessment by trained medical residents: validation and preliminary testing of a training protocol. AB - BACKGROUND: Training of nonsonographer physicians or staff members is needed to implement carotid intima-media thickness (CIMT) and plaque screening by ultrasound for the assessment of subclinical atherosclerosis. The purpose of this study was to determine the effect of formal training on CIMT assessment and plaque detection by medical residents. METHODS: A medical resident (R1) was trained using an abbreviated American Society of Echocardiography CIMT protocol. CIMT and plaque assessment by R1 were compared against an expert scanner on 60 subjects using a portable US system. A second medical resident (R2) was then trained on the CIMT protocol focusing on plaque visualization after the results of the first phase of the study were analyzed, and the results were compared against an expert on an additional 10 subjects. RESULTS: In the first phase of the study, a total of 106 images (94% interpretable) were available for CIMT and plaque assessment by both R1 and the expert. CIMT measurements were bioequivalent within the limits of ultrasound resolution, with 88% agreement. Variability on plaque presence was high, with only 53% agreement. R2 and the expert each scanned 10 new subjects twice, from whom 40 images were available for interpretation. R2 demonstrated CIMT agreement (93%) comparable with that observed in phase 1 but with greatly improved plaque agreement (100%). Intraobserver variability during phase 2 for both R2 and the expert was extremely low. CONCLUSIONS: Medical residents can undergo rapid training for CIMT measurement and plaque visualization to detect subclinical atherosclerosis compared with an expert. PMID- 24050847 TI - Nutritional screening tools for hospitalized children: methodological considerations. AB - Children who are admitted to the hospital are at a risk of developing undernutrition, especially children with an underlying disease. High percentages of both acute and chronic undernutrition have been reported in various Western countries for many years. Several nutritional screening tools have been developed for hospitalized children in the last years. This review gives an overview of the nutritional screening tools that are currently available with a focus on their aims, clinical use and validity. PMID- 24050848 TI - Life cycle assessment of biohydrogen production as a transportation fuel in Germany. AB - The goal of this work was to study the assessment of the life cycle of hydrogen production from biomass for transportation purposes concerning greenhouse gas emissions, emissions with an acidification potential and the fossil energy demand. As feedstocks woody biomass from forestry or short rotation coppice, herbaceous biomass (i.e., straw), energy crops (mainly maize and grain), bio waste and organic by-products (e.g., glycerol) were considered and their potential in Germany assessed. The results showed that hydrogen produced from woody biomass emitted the least emissions due to the low emissions caused by the provision of the biomass. Regarding the cumulative fossil energy demand biomass from short rotation coppice showed the lowest values. The highest biomass potential for hydrogen production could be identified for woody biomass from forests as well as from short rotation coppice. PMID- 24050849 TI - Classification of ADHD and BMD patients using visual evoked potential. AB - OBJECTIVES: Children with Bipolar Mood Disorder (BMD) and those with Attention Deficit Hyperactivity Disorder (ADHD) share many clinical signs and symptoms; therefore, achieving an accurate diagnosis is still a challenge, especially in the first interview session. The main focus of this paper is to quantitatively classify the ADHD and BMD patients using their Visual Evoke Potential (VEP) features elicited from their Electroencephalogram (EEG) signals. METHODS AND MATERIALS: In this study, 36 subjects were participated including 12 healthy ones, 12 patients with ADHD and 12 ones with BMD. The age of ADHD patients was 16.92+/-6.29 and for the BMD ones was 17.85+/-3.68. Their scalp EEG signals in the presence of visual stimulus were recorded using 22 silver electrodes located according to the 10-20 international recording protocol. To extract their VEP, first a preprocessing step was executed to remove the power line and movement artifacts. Afterward, the wavelet denoising and synchronous averaging were applied to the preprocessed trials in order to elicit the P100 component. To obtain interpretable features from the evoked patterns, amplitude and latency were extracted and applied to the 1-Nearest Neighbor (1NN) classifier due to the locally scattered distribution of the VEP features. RESULTS: The evaluation was performed according to leave-one(subject)-out method and the experimental results were led to 92.85% classification accuracy which is a fairly promising achievement to distinguish the BMD, ADHD, and healthy subjects from each other. CONCLUSION: From the physiological point of view, this result point out to the existence of significant difference in the neural activities of their visual system in the ADHD, BMD, and healthy subjects in response to a periodic optical stimulus. PMID- 24050850 TI - Strategic use of lamivudine in the management of chronic hepatitis B. AB - Lamivudine is no longer recommended as first-line therapy for chronic hepatitis B. The same advice has been made for adefovir and telbivudine, due to their relatively weak anti-viral activity and low resistance barrier, respectively. Instead, either tenofovir or entecavir is the currently preferred anti-HBV agent, given their potent anti-viral activity and high barrier to resistance. However, these drugs are expensive and their long-term use is often unaffordable for many individuals, including most patients in developing regions, where hepatitis B is generally much more prevalent. Herein, we argue that lack of universal access to the current best anti-viral drugs for hepatitis B should not imply a suboptimal management of chronic hepatitis B which denies therapy to persons who really need it. A wise and strategic use of lamivudine may provide an opportunity to bring the benefit of therapy to large HBV-infected populations, while reducing health care costs. PMID- 24050851 TI - SVM ensemble based transfer learning for large-scale membrane proteins discrimination. AB - Membrane proteins play important roles in molecular trans-membrane transport, ligand-receptor recognition, cell-cell interaction, enzyme catalysis, host immune defense response and infectious disease pathways. Up to present, discriminating membrane proteins remains a challenging problem from the viewpoints of biological experimental determination and computational modeling. This work presents SVM ensemble based transfer learning model for membrane proteins discrimination (SVM TLM). To reduce the data constraints on computational modeling, this method investigates the effectiveness of transferring the homolog knowledge to the target membrane proteins under the framework of probability weighted ensemble learning. As compared to multiple kernel learning based transfer learning model, the method takes the advantages of sparseness based SVM optimization on large data, thus more computationally efficient for large protein data analysis. The experiments on large membrane protein benchmark dataset show that SVM-TLM achieves significantly better cross validation performance than the baseline model. PMID- 24050852 TI - The prognostic role of ephrin A2 and endothelial growth factor receptor pathway mediators in patients with advanced colorectal cancer treated with cetuximab. AB - BACKGROUND: Patients with colorectal cancer (CRC) with wild-type KRAS mutations are often treated with the endothelial growth factor receptor (EGFR) monoclonal antibody cetuximab. Despite the presence of a specific molecular target, most patients still do not derive benefit from this biological treatment. Our study explores the role of ephrin A2 (EphA2) receptor expression and of EGFR pathway mediators as predictors of cetuximab benefit. PATIENTS AND METHODS: Formalin fixed paraffin-embedded (FFPE) tumor biopsy samples from 226 cetuximab-treated patients with CRC were studied for mRNA expression of insulin growth factor binding protein 2 (IGFBP2), insulin growth factor receptor 1 (IGF1R), cMET, EphA2, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 by means of TaqMan reverse-transcribed polymerase chain reaction (RT-PCR). RESULTS: Of the 226 patients evaluable for exploratory analysis, 222 had complete data from follow-up visits. The univariate analysis revealed the following significant adverse prognostic factors for risk of death: high EphA2 mRNA levels (hazard ratio [HR], 1.61; P = .015), high HER2 mRNA levels (HR, 1.51; P = .045), and high IGF1R mRNA levels (HR, 1.56; P = .021). Low EphA2 tumor expression was significantly associated with objective response to cetuximab therapy. In multivariate analysis of a broad biomarker panel, factors with independent prognostic value included EphA2 mRNA levels (HR, 1.67; P = .029), high amphiregulin (AREG) mRNA levels in KRAS wild-type tumors (HR, 0.17; P < .0001), and high epiregulin (EREG) mRNA levels (HR, 0.38; P = .006). CONCLUSION: High EphA2 receptor expression in CRC was associated with a worse outcome in patients treated with cetuximab-based therapy. Prospective validation in treated and control patients is required to dissect the predictive from prognostic role in advanced CRC. PMID- 24050853 TI - Being angry, singing fast? Signalling of aggressive motivation by syllable rate in a songbird with slow song. AB - Syllable rate has been shown to play a role in male-male aggressive interactions and has been proposed to serve as a male quality indicator in several bird species. In those with fast syllable rates, males often increase rates when singing in aggressive context, and respond differently to test stimuli of varying rates. We asked whether the syllable rate fulfils a similar signalling function in the chiffchaff (Phylloscopus collybita), a songbird species with a slow syllable rate. We confronted 36 chiffchaff males with one of three playback types differing in syllable rate: control (non-manipulated rate), fast, or slow (artificially increased and decreased syllable rate, respectively). We recorded tested males' songs and behaviour before and during the experiment. Our results indicate that syllable rate might be an aggressive signal in chiffchaff. Males that physically attacked the loudspeaker during experiments sang faster songs spontaneously, and those that continued singing during the playback responded to fast and non-manipulated stimuli with substantial increase of syllable rate. Indirect evidence further suggests that syllable rate in chiffchaff is unlikely constrained by respiratory demands; thus, we propose that syllable rate in this species functions as a conventional signal of male aggressiveness rather than an index of quality. PMID- 24050854 TI - Invasive renal cell carcinoma with inferior vena cava tumor thrombus: cardiac anesthesia in liver transplant settings. AB - OBJECTIVES: Resection of renal cell carcinomas (RCC) with tumor thrombus invasion into the inferior vena cava (IVC) is associated with significant perioperative morbidity and mortality. This study examined the intra- and inter-departmental collaboration among cardiac, liver transplantation, and urologic surgeons and anesthesiologists in caring for these patients. DESIGN: After IRB approval, medical records of patients who underwent resection of RCC tumor thrombus level III and IV, from 1997 to 2010 in this institution, were reviewed. Data were collected and analyzed by one way-ANOVA and chi-square test. SETTING: Major academic institution, tertiary referral center. PARTICIPANTS: This was a retrospective study based on the medical records of patients who underwent resection of RCC tumor thrombus level III and IV, from 1997 to 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fifty-eight patients (82.9%) with level III thrombus and 12 patients (17.1%) with level IV thrombus were analyzed. Sixty-five (92.9%) did not require any extracorporeal circulatory support; 5 (2 with level III and 3 with level IV; 7.1%) required cardiopulmonary bypass. No patients required veno-venous bypass. Compared to patients with level III thrombus extension, patients with level IV had higher estimated blood loss (6978+/-2968 mL v 1540+/-206, p<0.001) and hospital stays (18.8+/-1.6 days v 8.1+/-0.7, p<0.001). Intraoperative transesophageal echocardiography (TEE) was utilized in 77.6% of patients with level III thrombus extension and in 100% of patients with level IV thrombus extension. Intraoperative TEE guidance resulted in a significant surgical plan modification in 3 cases (5.2%). Short-term mortality was low (n = 3, 4.3%). CONCLUSIONS: Utilization of specialized liver transplantation and cardiac surgical techniques in the resection of RCC with extension into the IVC calls for a close intra-and interdepartmental collaboration between surgeons and anesthesiologists. The transabdominal approach to suprahepatic segments of the IVC allowed avoidance of extracorporeal circulatory support in most of these patients. Perioperative management of these patients reflected the critical importance of TEE-proficient practitioners experienced in liver transplantation and cardiac anesthesia. PMID- 24050855 TI - Comparison of epsilon aminocaproic acid and tranexamic Acid in thoracic aortic surgery: clinical efficacy and safety. AB - OBJECTIVE: To evaluate the efficacy and safety of tranexamic acid (TXA) versus epsilon aminocaproic acid (EACA) in patients undergoing thoracic aortic surgery. DESIGN: A prospective randomized study. SETTING: A tertiary care center. PARTICIPANT: The study was conducted on 64 consecutive adult patients undergoing thoracic aortic surgery with cardiopulmonary bypass (CPB). INTERVENTIONS: Group EACA received a bolus of 50 mg/kg of EACA after induction of anesthesia over 20 minutes followed by maintenance infusion of 25 mg/kg/h until chest closure. Group TXA received a bolus of 10 mg/kg of TXA after induction of anesthesia over 20 minutes followed by maintenance infusion of 1 mg/kg/h until chest closure. MEASUREMENTS AND MAIN RESULTS: Cumulated mean blood loss, total packed red blood cells, and blood product requirement up to 24 h postoperatively were comparable between groups. A significant renal injury (EACA 40% v TXA 16%; p = 0.04) and increased tendency for renal failure (EACA 10% v TXA 0%, p = 0.11; relative risk 2.15) were observed with EACA compared to TXA. There was increased tendency of seizure with TXA (EACA v TXA: 3.3% v 10%; p>0.05, relative risk 1.53). There was significant increase in the D-dimer from preoperative to postoperative values in Group EACA. (p< 0.01). CONCLUSIONS: Both EACA and TXA were equally effective in reducing the perioperative blood loss and transfusion requirement in patients undergoing thoracic aortic surgery. While significant renal injury was observed with EACA, there was a tendency for higher incidence of seizure with TXA. Prospective placebo-controlled trials recruiting larger sample size using sensitive biomarkers are required before any recommendations. PMID- 24050856 TI - Simplified clinical risk score to predict acute kidney injury after aortic surgery. AB - OBJECTIVE: The authors identified risk factors for acute kidney injury (AKI) defined by risk, injury, failure, loss, end-stage (RIFLE) criteria after aortic surgery with cardiopulmonary bypass and constructed a simplified risk score for the prediction of AKI. DESIGN: Retrospective and observational. SETTING: Single large university hospital. PARTICIPANTS: Patients (737) who underwent aortic surgery with cardiopulmonary bypass between 1997 and 2010. MAIN RESULTS: Multivariate logistic regression analysis was used to evaluate risk factors. A scoring model was developed in a randomly selected derivation cohort (n = 417), and was validated on the remaining patients. The scoring model was developed with a score based on regression beta-coefficient, and was compared with previous indices as measured by the area under the receiver operating characteristic curve (AUC). The incidence of AKI was 29.0%, and 5.8% required renal replacement therapy. Independent risk factors for AKI were age older than 60 years, preoperative glomerular filtration rate <60 mL/min/1.73 m(2), left ventricular ejection fraction <55%, operation time >7 hours, intraoperative urine output <0.5 mL/kg/h, and intraoperative furosemide use. The authors made a score by weighting them at 1 point each. The risk score was valid in predicting AKI, and the AUC was 0.74 [95% confidence interval (CI): 0.69 to 0.79], which was similar to that in the validation cohort: 0.74 (95% CI: 0.69 to 0.80; p = 0.97). The risk-scoring model showed a better performance compared with previously reported indices. CONCLUSIONS: The model would provide a simplified clinical score stratifying the risk of postoperative AKI in patients undergoing aortic surgery. PMID- 24050857 TI - Effect of levosimendan on survival and adverse events after cardiac surgery: a meta-analysis. AB - OBJECTIVE: Left ventricular systolic dysfunction is associated with increased morbidity and mortality in patients undergoing cardiac surgery. The authors performed a meta-analysis investigating the effects of levosimendan in cardiac surgery patients with and without preoperative systolic dysfunction. DESIGN: Meta analysis of randomized controlled trials. SETTING: Hospital. PARTICIPANTS: The 1,155 patients who participated in 14 randomized controlled trials of perioperative levosimendan were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PubMed, EMBASE, the Cochrane database of clinical trials, and conference proceedings were searched for clinical trials of perioperative levosimendan in patients undergoing cardiac surgery through May 1, 2012. Studies were grouped by mean ejection fraction (EF). Those with a mean EF <40% were designated as low-EF. Pooled results demonstrated a reduction in mortality with levosimendan (risk difference [RD]-4.2%; 95% CI -7.2%, -1.1%; p = 0.008). Subgroup analysis showed that this benefit was confined to the low-EF studies (RD -7.0%; 95% CI -11.0%, -3.1%; p < 0.001). No benefit was observed in the preserved EF subgroup (RD +1.1%; 95% CI -3.8%, +5.9%; p = 0.66). Significant reductions also were seen in the need for dialysis (RD -4.9%; 95% CI -8.2%, -1.6%; p = 0.003), myocardial injury (RD -5.0%; 95% CI -8.3%, -1.7%; p = 0.003), and postoperative atrial fibrillation (RD -8.1%; 95% CI -13.3%, -3.0%; p = 0.002). CONCLUSIONS: Levosimendan was associated with reduced mortality and other adverse outcomes in patients undergoing cardiac surgery, and these benefits were greatest in patients with reduced EF. These data support the need for adequately powered randomized clinical trials to confirm the benefits of levosimendan in patients with reduced EF undergoing cardiac surgery. PMID- 24050858 TI - An updated bleeding model to predict the risk of post-procedure bleeding among patients undergoing percutaneous coronary intervention: a report using an expanded bleeding definition from the National Cardiovascular Data Registry CathPCI Registry. AB - OBJECTIVES: This study sought to develop a model that predicts bleeding complications using an expanded bleeding definition among patients undergoing percutaneous coronary intervention (PCI) in contemporary clinical practice. BACKGROUND: New knowledge about the importance of periprocedural bleeding combined with techniques to mitigate its occurrence and the inclusion of new data in the updated CathPCI Registry data collection forms encouraged us to develop a new bleeding definition and risk model to improve the monitoring and safety of PCI. METHODS: Detailed clinical data from 1,043,759 PCI procedures at 1,142 centers from February 2008 through April 2011 participating in the CathPCI Registry were used to identify factors associated with major bleeding complications occurring within 72 h post-PCI. Risk models (full and simplified risk scores) were developed in 80% of the cohort and validated in the remaining 20%. Model discrimination and calibration were assessed in the overall population and among the following pre-specified patient subgroups: females, those older than 70 years of age, those with diabetes mellitus, those with ST-segment elevation myocardial infarction, and those who did not undergo in-hospital coronary artery bypass grafting. RESULTS: Using the updated definition, the rate of bleeding was 5.8%. The full model included 31 variables, and the risk score had 10. The full model had similar discriminatory value across pre-specified subgroups and was well calibrated across the PCI risk spectrum. CONCLUSIONS: The updated bleeding definition identifies important post-PCI bleeding events. Risk models that use this expanded definition provide accurate estimates of post-PCI bleeding risk, thereby better informing clinical decision making and facilitating risk-adjusted provider feedback to support quality improvement. PMID- 24050859 TI - Meta-analysis of everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease: final 3-year results of the SPIRIT clinical trials program (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions). AB - OBJECTIVES: This study sought to investigate whether the everolimus-eluting stent (EES) is superior to the paclitaxel-eluting stent (PES) with respect to long-term individual clinical outcomes. BACKGROUND: Individual studies have indicated a clinical advantage of coronary EES compared with PES with respect to restenosis and the composite endpoint of major adverse cardiac events. However, these trials were not powered for superiority in low-frequency event rates and have reported limited data beyond 1-year follow-up. METHODS: We conducted a meta-analysis of the final 3-year results from the international SPIRIT (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) II, III, and IV clinical trials. Individual patient data from 4,989 patients who were prospectively randomized to treatment with EES (n = 3,350) or PES (n = 1,639) were pooled for analysis. RESULTS: At 3-year follow-up, EES was superior to PES in reducing the following event rates: target lesion failure (8.9% vs. 12.5%, hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.59 to 0.85; p = 0.0002), all-cause mortality (3.2% vs 5.1%, HR: 0.65, 95% CI: 0.49 to 0.86; p = 0.003), myocardial infarction (3.2% vs. 5.1%, HR: 0.64, 95% CI: 0.48 to 0.85; p = 0.002), cardiac death or myocardial infarction (4.4% vs. 6.3%, HR: 0.70, 95% CI: 0.54 to 0.90; p = 0.005), ischemia-driven target lesion revascularization (6.0% vs. 8.2%, HR: 0.72, 95% CI: 0.58 to 0.90; p = 0.004), stent thrombosis (0.7% vs. 1.7%, HR: 0.45, 95% CI: 0.26 to 0.78; p = 0.003), and major adverse cardiac events (9.4% vs. 13.0%, HR: 0.71, 95% CI: 0.60 to 0.85; p = 0.0002). No interaction was present between stent type and the 3-year relative rates of target lesion failure across a broad range of subgroups, with the exception of diabetes and vessel (left anterior descending vs. other). CONCLUSIONS: In this large dataset with 3 year follow-up, coronary implantation of EES compared with PES resulted in reduced rates of all-cause mortality, myocardial infarction, ischemia-driven target lesion revascularization, stent thrombosis, and target lesion failure. Further research is warranted to characterize possible interactions between stent type, diabetes, and vessel. PMID- 24050861 TI - Cilostazol--a forgotten antiplatelet agent, but does it even matter? PMID- 24050860 TI - Adjunctive cilostazol versus double-dose clopidogrel after drug-eluting stent implantation: the HOST-ASSURE randomized trial (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Safety & Effectiveness of Drug-Eluting Stents & Anti-platelet Regimen). AB - OBJECTIVES: This study sought to test the noninferiority of triple antiplatelet therapy (TAT) versus double-dose clopidogrel dual antiplatelet therapy (DDAT) in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Antiplatelet regimen is an integral component of medical therapy after PCI. A 1 week duration of doubling the dose of clopidogrel was shown to improve outcome at 1 month compared with the conventional dose in patients with acute coronary syndrome undergoing PCI. Yet in Asia, the addition of cilostazol is used more commonly than DDAT in high-risk patients. METHODS: We randomly assigned 3,755 all comers undergoing PCI to either TAT or DDAT, which was continued for 1 month, to test the noninferiority of TAT versus DDAT. The primary outcome was the cumulative incidence of net clinical outcome at 1 month post-PCI defined as the composite of cardiac death, nonfatal myocardial infarction, stent thrombosis, stroke, and PLATO (Platelet Inhibition and Patient Outcomes) major bleeding. RESULTS: TAT was noninferior to DDAT with respect to the primary outcome, which occurred in 1.2% and 1.4% of patients, respectively (-0.22% absolute difference, 0.34% 1-sided 97.5% confidence interval, p = 0.0007 for noninferiority; hazard ratio: 0.85; 95% confidence interval: 0.49 to 1.48; p = 0.558 for superiority). The individual risks of cardiac death, nonfatal myocardial infarction, stent thrombosis, stroke, and PLATO major bleeding did not differ significantly between the 2 groups. There were no significant between-group differences in the treatment effect with regard to the rate of the primary outcome. CONCLUSIONS: The adjunctive use of cilostazol was noninferior to doubling the dose of clopidogrel for 1 month in all-comers undergoing PCI with exclusively drug-eluting stents. (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-SAfety & EffectiveneSS of Drug-ElUting Stents & Anti-platelet REgimen [HOST-ASSURE]; NCT01267734). PMID- 24050863 TI - To size or not to size--there is no question: balloon sizing for transcatheter aortic valve replacement. PMID- 24050862 TI - Preparatory balloon aortic valvuloplasty during transcatheter aortic valve implantation for improved valve sizing. AB - OBJECTIVES: This study sought to evaluate whether supra-aortic angiography during preparatory balloon aortic valvuloplasty (BAV) improves valve sizing. BACKGROUND: Current recommendations for valve size selection are based on annular measurements by transesophageal echocardiography and computed tomography, but paravalvular aortic regurgitation (PAR) is a frequent problem. METHODS: Data of 270 consecutive patients with either conventional sizing (group 1, n = 167) or balloon aortic valvuloplasty-based sizing (group 2, n = 103) were compared. PAR was graded angiographically and quantitatively using several hemodynamic indices. RESULTS: PAR was observed in 113 patients of group 1 and 41 patients of group 2 (67.7% vs. 39.8%, p < 0.001). More than mild PAR was found in 24 (14.4%) patients of group 1 and 8 (7.8%) patients of group 2. According to pre-interventional imaging, 40 (39%) patients had a borderline annulus size, raising uncertainty regarding valve size selection. Balloon sizing resulted in selection of the bigger prosthesis in 30 (29%) and the smaller prosthesis in the remaining patients, and only 1 of these 40 patients had more than mild PAR. As predicted by the hemodynamic indices of PAR, mortality at 30 days and 1 year was less in group 2 than in group 1 (5.8% vs. 9%, p = 0.2 and 10.6% vs. 20%, p = 0.01). CONCLUSIONS: Preparatory balloon aortic valvuloplasty during transcatheter aortic valve implantation improves valve size selection, reduces the associated PAR, and increases survival in borderline cases. PMID- 24050864 TI - Prospective randomized trial of transthoracic echocardiography versus transesophageal echocardiography for assessment and guidance of transcatheter closure of atrial septal defects in children using the Amplatzer septal occluder. AB - OBJECTIVES: This study sought to determine whether transthoracic echocardiography (TTE) can provide safety and efficacy equivalent to transesophageal echocardiography (TEE) for assessment and guidance of transcatheter atrial septal defect (ASD) closure in pediatric patients. METHODS: We performed a prospective randomized trial of ASD closure using the Amplatzer septal occluder (ASO) from March 2008 to April 2012. Inclusion criteria were isolated secundum ASD, age 2 to 18 years, and adequate TTE windows. Forty patients were enrolled and randomized to either TEE or TTE. In the TEE group, we used "stop flow" balloon sizing to determine device size. In the TTE group, we used the average ASD diameter times 1.2 (scaled). Patients were followed up to 1 year. RESULTS: Patient general and hemodynamic characteristics were similar in both groups. Procedural success was 100% in both groups. The average TEE stop flow diameter was similar to the scaled TTE diameter (15.35 +/- 4.62 mm vs. 16.57 +/- 5.47 mm; p = 0.46). Device size (16.0 +/- 4.94 mm vs. 16.37 +/- 5.05 mm, p = 0.82) and ratio of device to defect size (1.0 +/- 0.06 vs. 0.99 +/- 0.03, p = 0.52) were also similar. Total procedure (70.6 +/- 22.98 min vs. 51.1 +/- 17.61 min, p = 0.005), room (126.8 +/- 28.41 min vs. 95.7 +/- 20.53 min, p = 0.0004), and fluoroscopy (13.6 +/- 6.17 min vs. 8.9 +/- 8.45 min, p = 0.007) times were all significantly shorter in the TTE group. Neither group had significant complications during the procedure nor in follow-up. Rates of shunt resolution were similar between groups. CONCLUSIONS: This study suggests that in selected pediatric patients, use of TTE is as efficacious and safe as TEE for assessment and guidance of ASD occlusion using the ASO. TTE also may offer the additional safety benefit of reduced fluoroscopy exposure. PMID- 24050865 TI - Neurovascular rescue for thrombus-related embolic stroke during transcatheter aortic valve implantation. PMID- 24050866 TI - Is this spontaneous coronary intramural hematoma or fibrotic plaque?: an inconsistent finding between optical coherent tomography and intravascular ultrasound. PMID- 24050867 TI - Visualization of coronary plaque vasa vasorum by intravascular ultrasound. PMID- 24050868 TI - Challenges in retrospective analysis of PCI data in critically ill patients. PMID- 24050869 TI - Reply: Challenges in retrospective analysis of PCI data in critically ill patients. PMID- 24050870 TI - Asymptomatic cerebral lesions after carotid artery stenting may not predict future cerebrovascular events but may be associated with cognitive impairment. PMID- 24050871 TI - Reply: Asymptomatic cerebral lesions after carotid artery stenting may not predict future cerebrovascular events but may be associated with cognitive impairment. PMID- 24050872 TI - How do interventional cardiologists make decisions?: implications for practice and reimbursement. PMID- 24050873 TI - Early osseointegration of a strontium containing glass ceramic in a rabbit model. AB - The most important property of a bone cement or a bone substitute in load bearing orthopaedic implants is good integration with host bone with reduced bone resorption and increased bone regeneration at the implant interface. Long term implantation of metal-based joint replacements often results in corrosion and particle release, initiating chronic inflammation leading onto osteoporosis of host bone. An alternative solution is the coating of metal implants with hydroxyapatite (HA) or bioglass or the use of bulk bioglass or HA-based composites. In the above perspective, the present study reports the in vivo biocompatibility and bone healing of the strontium (Sr)-stabilized bulk glass ceramics with the nominal composition of 4.5SiO2-3Al2O3-1.5P2O5-3SrO-2SrF2 during short term implantation of up to 12 weeks in rabbit animal model. The progression of healing and bone regeneration was qualitatively and quantitatively assessed using fluorescence microscopy, histological analysis and micro-computed tomography. The overall assessment of the present study establishes that the investigated glass ceramic is biocompatible in vivo with regards to local effects after short term implantation in rabbit animal model. Excellent healing was observed, which is comparable to that seen in response to a commercially available implant of HA-based bioglass alone. PMID- 24050874 TI - Self-crosslinked human serum albumin nanocarriers for systemic delivery of polymerized siRNA to tumors. AB - The safe and effective systemic delivery of siRNA is a prerequisite for the successful development of siRNA-based cancer therapeutics. For the enhanced delivery of siRNA, cationic lipids and polymers have been widely used as siRNA carriers to form electrolyte complexes with anionic siRNA. However, the considerable toxicity of strong cationic-charged molecules hampers their clinical use. In this study, we utilized human serum albumin (HSA), which is the most abundant of the plasma proteins, as a siRNA carrier for systemic tumor-targeted siRNA delivery. Both HSA and siRNA molecules were thiol-introduced to improve the binding affinity for each other. The resulting thiolated HSA (tHSA) and polymerized siRNA (psi) formed stable nanosized complexes (psi-tHSAs) by chemical crosslinking and self-crosslinking. After internalization, the psi-tHSAs showed target gene silencing activity in vitro comparable to conventional LipofectamineTM-siRNA complexes, without remarkable cytotoxicity. After intravenous injection in tumor-bearing mice, psi-tHSAs accumulated specifically at the tumor sites, leading to efficient gene silencing in the tumors in a sequential manner. The therapeutic VEGF siRNA was loaded into psi-tHSAs, which significantly inhibited tumor-related angiogenesis in PC-3 tumor xenografts and resulted in retarding the growth of PC-3 tumors. The results showed that self crosslinked psi-tHSA nanocarriers might provide a promising approach for the systemic siRNA therapy of various human cancers. PMID- 24050875 TI - Chitosan tubes of varying degrees of acetylation for bridging peripheral nerve defects. AB - Biosynthetic nerve grafts are desired as alternative to autologous nerve grafts in peripheral nerve reconstruction. Artificial nerve conduits still have their limitations and are not widely accepted in the clinical setting. Here we report an analysis of fine-tuned chitosan tubes used to reconstruct 10 mm nerve defects in the adult rat. The chitosan tubes displayed low, medium and high degrees of acetylation (DAI: ~ 2%, DA: ~ 5%, DAIII: ~ 20%) and therefore different degradability and microenvironments for the regenerating nerve tissue. Short and long term investigations were performed demonstrating that the chitosan tubes allowed functional and morphological nerve regeneration similar to autologous nerve grafts. Irrespective of the DA growth factor regulation demonstrated to be the same as in controls. Analyses of stereological parameters as well as the immunological tissue response at the implantation site and in the regenerated nerves, revealed that DAI and DAIII chitosan tubes displayed some limitations in the support of axonal regeneration and a high speed of degradation accompanied with low mechanical stability, respectively. The chitosan tubes combine several pre-requisites for a clinical acceptance and DAII chitosan tubes have to be judged as the most supportive for peripheral nerve regeneration. PMID- 24050876 TI - Multiplexed in vivo fluorescence optical imaging of the therapeutic efficacy of photodynamic therapy. AB - In our study we wanted to elucidate a time frame for in vivo optical imaging of the therapeutic efficacy of photodynamic therapy (PDT) by using a multiplexed imaging approach for detecting apoptosis and vascularization. The internalization of the photosensitizer Foslip((r)) into tongue-squamous epithelium carcinoma cells (CAL-27) was examined in vitro and in vivo. For detecting apoptosis, annexin V was covalently coupled to the near-infrared dye DY-734 and the spectroscopic properties and binding affinity to apoptotic CAL-27 cells were elucidated. CAL-27 tumor bearing mice were treated with PDT and injected 2 days and 2 weeks thereafter with DY-734-annexin V. PDT-induced changes in tumor vascularization were detected with the contrast agent IRDye((r)) 800CW RGD up to 3 weeks after PDT. A perinuclear enrichment of Foslip((r)) could be seen in vitro which was reflected in an accumulation in CAL-27 tumors in vivo. The DY-734 annexin V (coupling efficiency 30-50%) revealed a high binding affinity to apoptotic compared to non-apoptotic cells (17.2% vs. 1.2%) with a KD-value of 20 nm. After PDT-treatment, the probe showed a significantly higher (p <0.05) contrast in tumors at 2 days compared to 2 weeks after therapy (2-8 h post injection). A reduction of the vascularization could be detected after PDT especially in the central tumor areas. To detect the therapeutic efficacy of PDT, a multiplexed imaging approach is necessary. A detection of apoptotic cells is possible just shortly after therapy, whereas at later time points the efficacy can be verified by investigating the vascularization. PMID- 24050877 TI - An injectable hydrogel incorporating mesenchymal precursor cells and pentosan polysulphate for intervertebral disc regeneration. AB - Intervertebral disc (IVD) degeneration is one of the leading causes of lower back pain and a major health problem worldwide. Current surgical treatments include excision or immobilisation, with neither approach resulting in the repair of the degenerative disc. As such, a tissue engineering-based approach in which stem cells, coupled with an advanced delivery system, could overcome this deficiency and lead to a therapy that encourages functional fibrocartilage generation in the IVD. In this study, we have developed an injectable hydrogel system based on enzymatically-crosslinked polyethylene glycol and hyaluronic acid. We examined the effects of adding pentosan polysulphate (PPS), a synthetic glycosaminoglycan like factor that has previously been shown (in vitro and in vivo) to this gel system in order to induce chondrogenesis in mesenchymal precursor cells (MPCs) when added as a soluble factor, even in the absence of additional growth factors such as TGF-beta. We show that both the gelation rate and mechanical strength of the resulting hydrogels can be tuned in order to optimise the conditions required to produce gels with the desired combination of properties for an IVD scaffold. Human immunoselected STRO-1+ MPCs were then incorporated into the hydrogels. They were shown to retain good viability after both the initial formation of the gel and for longer-term culture periods in vitro. Furthermore, MPC/hydrogel composites formed cartilage-like tissue which was significantly enhanced by the incorporation of PPS into the hydrogels, particularly with respect to the deposition of type-II-collagen. Finally, using a wild-type rat subcutaneous implantation model, we examined the extent of any immune reaction and confirmed that this matrix is well tolerated by the host. Together these data provide evidence that such a system has significant potential as both a delivery vehicle for MPCs and as a matrix for fibrocartilage tissue engineering applications. PMID- 24050878 TI - Attenuation-based automatic kilovolt (kV)-selection in computed tomography of the chest: effects on radiation exposure and image quality. AB - OBJECTIVES: To evaluate an automated attenuation-based kV-selection in computed tomography of the chest in respect to radiation dose and image quality, compared to a standard 120 kV protocol. MATERIALS AND METHODS: 104 patients were examined using a 128-slice scanner. Fifty examinations (58 +/- 15 years, study group) were performed using the automated adaption of tube potential (100-140 kV), based on the attenuation profile of the scout scan, 54 examinations (62 +/- 14 years, control group) with fixed 120 kV. Estimated CT dose index (CTDI) of the software proposed setting was compared with a 120 kV protocol. After the scan CTDI volume (CTDIvol) and dose length product (DLP) were recorded. Image quality was assessed by region of interest (ROI) measurements, subjective image quality by two observers with a 4-point scale (3--excellent, 0--not diagnostic). RESULTS: The algorithm selected 100 kV in 78% and 120 kV in 22%. Overall CTDIvol reduction was 26.6% (34% in 100 kV) overall DLP reduction was 22.8% (32.1% in 100 kV) (all p<0.001). Subjective image quality was excellent in both groups. CONCLUSION: The attenuation based kV-selection algorithm enables relevant dose reduction (~27%) in chest-CT while keeping image quality parameters at high levels. PMID- 24050879 TI - Diagnostic value of real-time elastography in the assessment of hepatic fibrosis in patients with liver iron overload. AB - OBJECTIVE: The objective of our prospective monocentric work was to determine the diagnostic value of real-time elastography (RTE) in the assessment of liver fibrosis in patients with iron overload, using transient elastography (TE) as reference standard. METHODS: Sixty-seven consecutive patients with MRI detectable iron overload (T2*<6.3 ms) were enrolled. TE and RTE were performed on the same day as MRI. Elastograms were acquired by an experienced operator and analyzed by calculating the elastic ratio between perihepatic soft tissues and liver parenchyma. An elliptical ROI of 1cm(2) (Z1) was positioned in the liver parenchyma and a smaller elliptical ROI of 2mm(2) (Z2) was positioned in a homogeneously soft (red) region of the diaphragm, which was considered as internal control to calculate the elastic ratio Z2/Z1. RESULTS: Seven patients were excluded because of invalid TE or RTE examinations. The remaining 60 patients were 57% males and 43% females (mean age: 42 [21-76] years), including 37 homozygous-beta-thalassemics, 13 patients with beta-thalassemia intermedia, 6 with primary hemochromatosis, and 4 with myelodysplastic syndrome. Increasing elastic ratios were significantly correlated with increasing TE values (r=0.645, 95% CI 0.468-0.772, P<0.0001). The mean elastic ratios for each METAVIR group were as follows: F0/1 = 1.9 +/- 0.4; F2 = 2.2 +/- 0.4; F3 = 2.9 +/- 0.5; F4 = 3.2 +/- 0.4. The diagnostic accuracy of RTE for F >= 2 evaluated by AUC-ROC analysis was 0.798 (95% CI 0.674-0.890). The diagnostic accuracy of RTE for F >= 3 was 0.909 (95% CI 0.806-0.968). At a cut-off >= 2.75, RTE showed a sensitivity of 70% (95% CI 45.7-88.1) and a specificity of 97.5% (95% CI 86.8-99.9). CONCLUSIONS: In patients with MRI-detectable liver iron-overload RTE allows to discriminate between F0/1-F2 and F3-F4 with a reasonable diagnostic accuracy. PMID- 24050880 TI - Radiation exposure in CT-guided interventions. AB - PURPOSE: To investigate radiation exposure in computed tomography (CT)-guided interventions, to establish reference levels for exposure, and to discuss strategies for dose reduction. MATERIALS AND METHODS: We analyzed 1576 consecutive CT-guided procedures in 1284 patients performed over 4.5 years, including drainage placements; biopsies of different organs; radiofrequency and microwave ablations (RFA/MWA) of liver, bone, and lung tumors; pain blockages, and vertebroplasties. Data were analyzed with respect to scanner settings, overall radiation doses, and individual doses of planning CT series, CT intervention, and control CT series. RESULTS: Eighty-five percent of the total radiation dose was applied during the pre- and post-interventional CT series, leaving only 15% applied by the CT-guided intervention itself. Single slice acquisition was associated with lower doses than continuous CT-fluoroscopy (37 mGy cm vs. 153 mGy cm, p<0.001). The third quartile of radiation doses varied considerably for different interventions. The highest doses were observed in complex interventions like RFA/MWA of the liver, followed by vertebroplasty and RFA/MWA of the lung. CONCLUSIONS: This paper suggests preliminary reference levels for various intervention types and discusses strategies for dose reduction. A multicenter registry of radiation exposure including a broader spectrum of scanners and intervention types is needed to develop definitive reference levels. PMID- 24050881 TI - Vertebra plana: reappraisal of a contraindication to percutaneous vertebroplasty. AB - PURPOSE: We evaluated the efficacy of percutaneous vertebroplasty (PVP) in treating symptomatic vertebra plana, which is considered a relative contraindication to the procedure. METHODS: Out of 540 levels treated in 260 patients, we treated 40 patients (mean age: 74 years) with vertebra plana between T6 and L3 (37 osteoporotic and 3 metastatic levels). In most cases, the vertebra was accessed with fluoroscopic guidance from a single, transpedicular approach. All patients underwent a preliminary MRI examination, an immediate, post procedure radiological examination, and a follow-up examination (mean duration, 6 months). RESULTS: Both immediate and follow-up examinations showed that the mean pain and physical disability scores were significantly reduced compared to the scores before treatment (p <= 0.001). No complications occurred during the procedures. In 23/40 cases, asymptomatic intradiscal cement leakage occurred. Posterior or perivertebral leakage never occurred. In most cases, an intravertebral cleft was present, and we filled it with polymethylmethacrylate, which healed the pseudarthrosis. Partial vertebral height was restored in 7 cases. In 6 cases, a new fracture occurred between 1 and 3 months at a different level from the treated level. CONCLUSION: Our preliminary results showed that PVP was a safe, effective treatment for symptomatic vertebra plana; thus, it should not be discounted for this group of patients. In most cases, the procedure was favored by the presence of an intravertebral cleft that appeared to contribute to minimizing the risk of posterior cement leakage. Filling the cleft with polymethylmethacrylate allowed intravertebral stabilization. PMID- 24050882 TI - In vivo imaging of intestinal helminths by capsule endoscopy. AB - This review examines the use of digestive endoscopy to visualize intestinal helminths. The infections caused by these parasites are responsible for high levels of morbidity and mortality. These helminths can be visualized using gastroduodenal endoscopy, endoscopic retrograde cholangiopancreatography, and colonoscopy. Endoscopic examination of the small bowel is limited by its considerable length and its distance from the mouth and anus. Since capsule endoscopy (CE) was first reported in 2000, it has been established as a noninvasive modality for the investigation of the gastrointestinal tract. CE is used as a first-line tool for imaging various small-bowel diseases, mainly obscure gastrointestinal bleeding and Crohn's disease. Since the Food and Drug Administration (FDA) approved CE in 2001, the indications for its use have expanded widely. For example, CE can be used to visualize the in vivo kinetics of intestinal helminths. If the current trends in technological development continue, CE will become more widely used to facilitate the diagnosis and treatment of helminth infections in the near future. PMID- 24050883 TI - Tranexamic acid decreases risk of haematomas but not pain after hip arthroplasty. AB - BACKGROUND: Tranexamic acid decreases total blood loss after total hip arthroplasty (THA). Total blood loss is the sum of external bleeding and bleeding into tissues, i.e., haematomas. Haematomas may cause acute or even chronic postoperative pain. HYPOTHESIS: Tranexamic acid decreases haematomas, thereby diminishing postoperative pain after THA. METHODS: In a retrospective matched case-control study, patients receiving tranexamic acid (15 mg/kg, before the incision and again at skin closure) were compared to controls not given tranexamic acid. Matching was on sex, surgeon, and peri-operative analgesics (ketamine, ketoprofen, pregabalin, and nefopam). Standardised protocols were used for anaesthesia, analgesia, and blood sparing. Haematoma volume was computed as the difference between total blood loss (estimated from the erythrocyte counts on days -1 and +5) and measured external blood loss. Patients were monitored from D0 to D7 then interviewed by telephone on D30, D90, and D180. To detect a 30% decrease in the morphine dose at H24 (criterion 1) and D7 (criterion 2) and a 20% decrease in haematoma volume on D5 (criterion 3), the required numbers of patients were 90, 90, and 77, respectively; therefore, 95 patients were included. RESULTS: Tranexamic acid decreased haematoma volume by 30% (351+/-254 mL versus 247+/-189 mL erythrocytes, P=0.002), had no effect on morphine consumption at H24 (12+/-11 mg versus 14+/-12 mg, P=0.346), increased morphine consumption on D7 (26+/-24 mg versus 35+/-36 mg, P=0.029), and had no effect on long-term pain. DISCUSSION: After THA, tranexamic acid decreases haematoma volume without improving analgesia. LEVEL OF EVIDENCE: 3 (case-control study). PMID- 24050884 TI - A local angle compensation method based on kinematics constraints for non invasive vascular axial strain computations on human carotid arteries. AB - Non invasive vascular elastography (NIVE) was developed to highlight atherosclerotic plaque constituents. However, NIVE motion estimates are affected by artifacts, such as an underestimation of deformations due to projected movement angles with respect to the ultrasound beam, movements of the operator or of the patient during image acquisition. The main objective of this work was to propose a local angle compensation method within small measurement windows for the axial strain based on kinematics constraints, and to introduce a filtering process on the strain time-varying curve to reduce as much as possible the impact of motion artifacts. With such preprocessing, we successfully quantified the strain behavior of near and far walls in longitudinal images of internal carotid arteries without (n=30) and with (n=21) significant atherosclerotic disease (greater than 50% stenosis). Maximum strain rates of 4.49% s(-1) for the healthy group and of 2.29% s(-1) for the atherosclerotic group were calculated on the far wall of internal carotid arteries; significant differences were found between these values (p=0.001). The minimum strain rates, also on the far wall of internal carotid arteries, of -3.68% s(-1) for the healthy group and of -1.89% s( 1) for the atherosclerotic group were significantly different as well (p=8*10( 4)). The mean systolic, diastolic and cumulated axial strains could also distinguish the two groups after normalization by the pressure gradient between acquired images. To conclude, the proposed techniques allowed to differentiate healthy and atherosclerotic carotid arteries and may help to diagnose vulnerable plaques. PMID- 24050885 TI - Segmentation of histology slides of cortical bone using pulse coupled neural networks optimized by particle-swarm optimization. AB - The aim of this study is to automatically discern the micro-features in histology slides of cortical bone using pulse coupled neural networks (PCNN). To the best knowledge of the authors, utilizing PCNN in such an application has not been reported in the literature and, as such, constitutes a novel application. The network parameters are optimized using particle swarm optimization (PSO) where the PSO fitness function was introduced as the entropy and energy of the bone micro-constituents extracted from a training image. Another novel contribution is combining the above with the method of adaptive threshold (T) where the PCNN algorithm is repeated until the best threshold T is found corresponding to the maximum variance between two segmented regions. To illustrate the quality of resulting segmentation according to this methodology, a comparison of the entropy/energy obtained of each pulse is reported. Suitable quality metrics (precision rate, sensitivity, specificity, accuracy, and dice) were used to benchmark the resulting segments against those found by a more traditional method namely K-means. The quality of the segments revealed by this methodology was found to be of much superior quality. Another testament to the quality of this methodology was that the images resulting from testing pulses were found to be of similarly good quality to those of the training images. PMID- 24050886 TI - Nitroreductase-activated nitric oxide (NO) prodrugs. AB - Due to the involvement of nitric oxide (NO) in numerous and diverse physiological processes, site-directed delivery of therapeutic NO in order to minimize unwanted side-effects is necessary. O(2)-(4-Nitrobenzyl) diazeniumdiolates are designed as substrates for Escherichia coli nitroreductase (NTR), an enzyme that is frequently used to facilitate directed delivery of cytotoxic species to cancers. O(2)-(4-Nitrobenzyl) diazeniumdiolates are found to be stable in aqueous buffer but are metabolized by NTR to produce NO. A cell viability assay revealed that cytotoxic effects of O(2)-(4-nitrobenzyl)1-(2-methylpiperidin-1-yl)diazen-1-ium 1,2-diolate (4b) towards two cancer cell lines is significantly enhanced in the presence of NTR suggesting the potential for use of this compound in nitric oxide based directed prodrug therapy. PMID- 24050887 TI - Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists. AB - A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9MUMh. PMID- 24050889 TI - Effects of CA1 glutamatergic systems upon memory impairments in cholestatic rats. AB - BACKGROUND: Bile duct ligation (BDL) is shown to induce cholestasis-related liver function impairments as well as consequent cognitive dysfunctions (i.e. impaired learning and memory formation). Glutamatergic neurotransmission plays an important role in hippocampal modulation of learning and memory function. The present study aimed to investigate the possible involvement of dorsal hippocampal (CA1) glutamatergic systems upon cholestasis-induced amnesia. METHOD: Cholestasis was induced in male Wistar rats through double-ligation of the main bile duct (at two points) and transection of the interposed segment. Step-through passive avoidance test was employed to examine rats' learning and memory function. All drugs were injected into CA1 region of the hippocampus. RESULTS: our results indicated a decrease in memory retrieval following cholestasis (11, 17 and 24 days post BDL). Only subthreshold doses of N-methyl-d-aspartate (NMDA; 0.125 and 0.25 MUg/MUl) but not its effective dose (0.5 MUg/MUl), restored the cholestasis induced amnesia in step-through passive avoidance test, 11, 17 and 24 days post BDL. This effect was blocked by the subthreshold dose of D-[1]-2-amino-7 phosphonoheptanoic acid (D-AP7, NMDA receptor antagonist; 0.0625 MUg/MUl, intra CA1) at 0.125 MUg/MUl and 0.25 MUg/MUl doses of NMDA. Moreover, our data revealed that only effective doses of D-AP7 (0.125 and 0.25 MUg/MUl, intra-CA1) potentiate memory impairments in 11 days after BDL. It was noted that none of applied drugs/doses exerted an effect on memory acquisition and locomotors activity, 10 and 12 days post laparotomy, respectively. CONCLUSION: Our findings suggest the potential involvement of CA1 glutamatergic system(s) in cholestasis-induced memory deficits. PMID- 24050888 TI - Environmental manipulations alter age differences in attribution of incentive salience to reward-paired cues. AB - Cues repeatedly paired with rewards often themselves become imbued with enhanced motivational value, or incentive salience. During Pavlovian conditioned approach procedures, a cue repeatedly preceding reward delivery often elicits conditioned responses at either the reward delivery location ("goal-tracking") or the cue itself ("sign-tracking"). Sign-tracking behavior is thought to reflect the individual differences in attribution of incentive salience to reward-paired cues that may contribute to addiction vulnerability. Adolescent rats typically demonstrate less sign-tracking behavior than adult rats, a surprising finding given that adolescence is hypothesized to be a time of heightened addiction vulnerability. Given evidence that adult sign-tracking behavior can be influenced by environmental conditions, the present study compared the effects of isolate housing and food deprivation on expression of sign-tacking and goal-tracking behavior in adolescent and adult male rats across eight days of a Pavlovian conditioned approach procedure. Pair-housed adults exhibited more sign-tracking behavior than pair-housed adolescents; however, this age difference was not apparent in isolate-housed subjects. Adolescents often appeared more sensitive than adults to both food restriction- and isolate housing-induced changes in behavior, with food restriction promoting an increase in sign-tracking among isolate-housed adolescents and an increase in goal-tracking among pair-housed adolescents. For adults, food restriction resulted in a modest increase in overall expression of both sign- and goal-tracking behavior. To the extent that sign-tracking behavior reflects attribution of incentive salience to reward paired cues, results from the present study provide evidence that reactivity to rewards during adolescence is strongly related to the nature of the surrounding environment. PMID- 24050890 TI - Spatial cognition and sexually dimorphic synaptic plasticity balance impairment in rats with chronic prenatal ethanol exposure. AB - Prenatal ethanol exposure can lead to long-lasting impairments in the ability of rats to process spatial information, as well as produce long-lasting deficits in long-term potentiation (LTP), a biological model of learning and memory processing. The present study aimed to examine the sexually dimorphic effects of chronic prenatal ethanol exposure (CPEE) on behavior cognition and synaptic plasticity balance (SPB), and tried to understand a possible mechanism by evaluating the alternation of SPB. The animal model was produced by ethanol exposure throughout gestational period with 4 g/kg bodyweight. Offspring of both male and female were selected and studied on postnatal days 36. Subsequently, the data showed that chronic ethanol exposure resulted in birth weight reduction, losing bodyweight gain, microcephaly and hippocampus weight retardation. In Morris water maze (MWM) test, escape latencies were significantly higher in CPEE treated rats than that in control ones. They also spent much less time in the target quadrant compared to that of control animals in the probe phase. In addition, it was found that there was a more severe impairment in females than that in males after CPEE treatment. Electrophysiological studies showed that CPEE considerably inhibited hippocampal LTP and facilitated depotentiation in males, while significantly enhanced LTP and suppressed depotentiation in females. A novel index, developed by us, showed that the action of CPEE on SPB was more sensitive in females than that in males, suggesting that it might be an effective index to distinguish the difference of SPB impairment between males and females. PMID- 24050891 TI - Brachytherapy practice across Canada: A survey of workforce and barriers. AB - PURPOSE: To determine the current use of brachytherapy, characteristics of the brachytherapy workforce, and barriers to development and maintenance of brachytherapy programs across Canada. METHODS AND MATERIALS: A survey was designed to inquire about the use of brachytherapy and was sent to all Canadian radiation oncologists. RESULTS: Of the 116 respondents, we identified 80 radiation oncologists from 33 of 41 responding centers who currently or in the past have practiced brachytherapy. Responses were received from 30% overall and 80% of provinces. Approximately 58% of the respondents treat in one site with brachytherapy, whereas 12% treat in three or more sites. Gynecologic (GYN) and genitourinary are the most commonly treated sites (49% of respondents). For all sites, there was a large range in the number of patients treated with brachytherapy by each radiation oncologist per year (i.e., cervix: 1-50). Approximately 49% of the respondents have discontinued practicing brachytherapy for a certain site, most commonly head and neck (28%), GYN (25%), and bronchus (24%). The most common reasons include reassignment or lack of a local program. The most common reasons why brachytherapy is not used for sites other than GYN and prostate include lack of infrastructure and insufficient training of radiation oncologists rather than insufficient patient numbers or lack of evidence for a benefit of brachytherapy. CONCLUSIONS: Within its limitations, our study suggests a mismatch between demand and availability of brachytherapy programs across Canada. In light of finite resources, a rational approach to investment in brachytherapy is needed and this must be based on a formal audit of brachytherapy demand and use. PMID- 24050892 TI - Declining use of brachytherapy for the treatment of prostate cancer. AB - PURPOSE: To analyze the recent trends in the utilization of external beam radiation therapy (EBRT) and brachytherapy (BT) for the treatment of prostate cancer. METHODS AND MATERIALS: Using the Surveillance, Epidemiology, and End Results (SEER) database, information was obtained for all patients diagnosed with localized prostate adenocarcinoma between 2004 and 2009 who were treated with radiation as local therapy. We evaluated the utilization of BT, EBRT, and combination BT+EBRT by the year of diagnosis and performed a multivariable analysis to determine the predictors of BT as treatment choice. RESULTS: Between 2004 and 2009, EBRT monotherapy use increased from 55.8% to 62.0%, whereas all BT use correspondingly decreased from 44.2% to 38.0% (BT-only use decreased from 30.4% to 25.6%, whereas BT+EBRT use decreased from 13.8% to 12.3%). The decline of BT utilization differed by patient race, SEER registry, median county income, and National Comprehensive Cancer Network risk categorization (all p<0.001), but not by patient age (p=0.763) or marital status (p=0.193). Multivariable analysis found that age, race, marital status, SEER registry, median county income, and National Comprehensive Cancer Network risk category were independent predictors of BT as treatment choice (all p<0.001). Moreover, after controlling for all available patient and tumor characteristics, there was decreasing utilization of BT with increasing year of diagnosis (odds ratio for BT=0.920, 95% confidence interval: 0.911-0.929, p<0.001). CONCLUSIONS: Our analysis reveals decreasing utilization of BT for prostate cancer. This finding has significant implications in terms of national health care expenditure. PMID- 24050893 TI - Climacturia after definitive treatment of prostate cancer. AB - PURPOSE: Prostate cancer treatment results in several sexually related side effects beyond the well studied erectile dysfunction. Climacturia (leakage of urine during orgasm) has been reported after prostatectomy but studies have been limited by multiple factors. In this study we examine the prevalence, causes and impact on orgasm function of climacturia after definitive treatment of prostate cancer with surgery or radiation. MATERIALS AND METHODS: A total of 906 anonymous surveys were sent to patients with prostate cancer treated with surgery and/or radiation. Respondents were asked about the presence of urinary leakage, climacturia and various elements related to sexual and orgasmic function. We estimated the prevalence of climacturia, evaluated the differences between those with and without climacturia, and assessed the impact of climacturia on orgasmic function. RESULTS: Overall 412 surveys were returned and available for analysis, and of these respondents 75.2% were sexually active or experiencing orgasms. Climacturia was reported by 22.6% of these respondents, and by 28.3%, 5.2% and 28.6% of those treated with surgery, radiation, or both, respectively (p <0.001). The use of aides to obtain an erection (OR 2.24, 95% CI 1.08-4.93, p = 0.035) and the presence of urinary incontinence (OR 3.09, 95% CI 1.66-5.88, p <0.001) were also associated with climacturia in a multivariate logistic regression model. Climacturia had no significant impact on orgasmic function and satisfaction. CONCLUSIONS: Climacturia is experienced by a substantial proportion of men after undergoing definitive treatment of prostate cancer. We found a complex relationship between stress urinary incontinence and climacturia, and noted that the presence of climacturia does not necessarily negatively impact sexual satisfaction. PMID- 24050895 TI - High recurrence rate at 5-year followup in children after upper urinary tract stone surgery. AB - PURPOSE: Pediatric urolithiasis has been treated with shock wave lithotripsy, ureteroscopy and percutaneous nephrolithotomy with high success rates during short-term followup. We studied our success rate and modifiable risk factors in patients with at least 5 years of followup postoperatively. MATERIALS AND METHODS: Retrospective chart review was performed for patients younger than 18 years who underwent upper tract stone surgery between 1999 and 2007, were stone free afterward and had at least 5 years of followup. Recurrence rate, and anatomical and metabolic abnormalities were assessed. RESULTS: Of 60 eligible children 30 (33 kidneys) had at least 5 years of followup. Average patient age at surgery was 10 years, 17 patients were female and 20 kidneys had anatomical abnormalities. Overall recurrence rate at 5 years was 55% (95% CI 38%-70%). Ureteral stones had a lower recurrence rate than renal stones (5 of 19 and 13 of 14, respectively, p <0.001). Patients with abnormal anatomy had a 65% (95% CI 43% 82%) chance of recurrence within 5 years vs 38% (95% CI 18%-65%) in those with normal anatomy (p = 0.17). Of the 18 recurrences 10 required a second operation, 7 demonstrated abnormal anatomy and 14 involved calcium based stones. A 24-hour urine test in 13 children revealed 10 with hypercalciuria and 11 with hypocitraturia, with 9 patients exhibiting both conditions. CONCLUSIONS: We found a high recurrence rate in children with stones requiring surgical intervention, particularly those with abnormal anatomy. This finding should be confirmed in a larger multicenter study of recurrence rates. In the meantime our results suggest a need for aggressive diagnosis and treatment of metabolic abnormalities. PMID- 24050894 TI - The soluble guanylyl cyclase activator BAY 60-2770 ameliorates overactive bladder in obese mice. AB - PURPOSE: Activators of soluble guanylyl cyclase are of potential interest as treatment for cardiovascular diseases but to our knowledge they have never been proposed to treat overactive bladder. We evaluated the effects of the soluble guanylyl cyclase activator BAY 60-2270 on voiding dysfunction and detrusor overactivity in a mouse model of obesity associated overactive bladder. MATERIALS AND METHODS: C57BL/6 male mice fed for 10 weeks with standard chow or a high fat diet were treated with 1 mg/kg BAY 60-2770 per day for 2 weeks via gavage. Cystometric evaluations were done and responses to contractile agents in isolated bladders were determined. RESULTS: Obese mice showed an irregular micturition pattern characterized by significant increases in voiding and nonvoiding contractions, which were normalized by BAY 60-2770. Carbachol, KCl and CaCl2 produced concentration dependent contractions in isolated bladder strips, which were markedly greater in obese than in lean mice. BAY 60-2770 normalized bladder contractions in the obese group. A 78% increase in reactive oxygen species generation in the bladder tissue of obese mice was observed, which was unaffected by BAY 60-2770. Treatment with BAY 60-2770 generated a tenfold increase in cyclic guanosine monophosphate in the bladders of obese mice without affecting the nucleotide level in the lean group. Protein expression of the soluble guanylyl cyclase alpha1 and beta1 subunits was decreased 40% in the bladder tissue of obese mice but restored by BAY 60-2770. CONCLUSIONS: Two-week BAY 60-2770 therapy increased cyclic guanosine monophosphate and rescued expression of the soluble guanylyl cyclase alpha1 and beta1 subunits in bladder tissue, resulting in great amelioration of bladder dysfunction. PMID- 24050896 TI - A relevant experimental model for human bronchiolitis obliterans syndrome. AB - BACKGROUND: The long-term success of human lung transplantation is limited by the development of bronchiolitis obliterans syndrome. Acute rejection episodes and infections are important risk factors and seem to play major pathogenic roles. We established a relevant experimental model that mimics important aspects of human bronchiolitis obliterans syndrome. METHODS: The Fischer 344-to-Lewis rat strain combination was used for orthotopic left lung transplantation. Isogeneic transplantations were performed in the Lewis rat. Recipients were treated with ciclosporin for 10 days. Lipopolysaccharide or vehicle was instilled into the airways 28 days after transplantation. Grafts were monitored by computed tomography, and recipients were euthanized on Days 28-90. The messenger RNA expression of selected chemokines and their receptors was measured on Days 28, 29, 33, 40 after transplantation. Graft histopathology on Day 90 was compared with lungs from patients who underwent re-transplantation due to end-stage allograft dysfunction. RESULTS: Lung allografts treated with ciclosporin and vehicle only sporadically displayed tissue remodeling. In contrast, lipopolysaccharide treatment induced severe inflammation. In the long-term, severe vascular remodeling, lung fibrosis, and fibroproliferative remodeling of airways were found that closely resemble the histopathologic changes in grafts from human patients with bronchiolitis obliterans syndrome. Chronic damage was virtually absent from pulmonary isografts and native right lungs. Chemokine (C-C motif) ligand 5 and chemokine (C-X-C motif) ligand 9-11, and their receptors, were over-expressed in allografts. CONCLUSIONS: Our experimental model mirrors key aspects of human bronchiolitis obliterans syndrome. It will be useful to elucidate its pathogenesis and to develop therapeutic approaches improving the long-term outcome of human lung transplantation. PMID- 24050897 TI - Null genotypes of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms increased susceptibility to type 2 diabetes mellitus, a meta analysis. PMID- 24050898 TI - The HLA class II allele DQB1 0309 is associated with dilated cardiomyopathy. AB - Previous studies have shown weak associations between human dilated cardiomyopathy (DCM) and certain human leucocyte antigen (HLA) class II polymorphisms. Using a sequence-specific primer-PCR (SSP-PCR) technology, we compared the allelic distribution in the HLA-DQ and -DR locus in a cohort of German DCM patients (n=165) and DCM-free controls (n=79). With the exception of HLA-DQB1 0309, we found no significant differences between the two groups, even without adjustment for multiple testing. The HLA-DQB1 0309 allele, however, was detected more frequently in DCM patients as compared to controls (28.5% versus 10.1%, p=0.0010), leading to an odds ratio of 3.5 (95% confidence interval=1.5 9.1). The frequency of this allele was significantly higher in DCM patients without lymphocytic infiltrates in endomyocardial biopsies as compared to patients classified histologically as inflammatory DCM (33.1% versus 14.6%, p=0.028). There was no significant difference in the allelic HLA-DQB1 0309 distribution between DCM patients with and without viral genomes detected in the heart (24.2% versus 29.5%, p=0.668). In summary, the frequency of the HLA-DQB1 0309 allele is overrepresented in DCM patients, suggesting that carriers of this HLA class II variant are associated with an increased risk for developing DCM. Although Bonferroni adjustment was applied, controlled studies in larger samples of DCM patients and in different ethnic populations are warranted to confirm this observation and reveal the pathophysiological mechanisms behind this association. PMID- 24050899 TI - Illumina-based de novo transcriptome sequencing and analysis of Amanita exitialis basidiocarps. AB - Amanita exitialis is a lethal mushroom that was first discovered in Guangdong Province, China. The high content of amanitin in its basidiocarps makes it lethal to humans. To comprehensively characterize the A. exitialis transcriptome and analyze the Amanita toxins as well as their related gene family, transcriptome sequencing of A. exitialis was performed using Illumina HiSeq 2000 technology. A total of 25,563,688 clean reads were collected and assembled into 62,137 cDNA contigs with an average length of 481 bp and N50 length of 788 bp. A total of 27,826 proteins and 39,661 unigenes were identified among the assembled contigs. All of the unigenes were classified into 166 functional categories for understanding the gene functions and regulation pathways. The genes contributing to toxic peptide biosynthesis were analyzed. From this set, eleven gene sequences encoding the toxins or related cyclic peptides were discovered in the transcriptome. Three of these sequences matched the peptide toxins alpha amanitin, beta-amanitin, and phallacidin, while others matched amanexitide and seven matched unknown peptides. All of the genes encoding peptide toxins were confirmed by polymerase chain reaction (PCR) in A. exitialis, and the phylogenetic relationships among these proprotein sequences were discussed. The gene polymorphism and degeneracy of the toxin encoding sequences were found and analyzed. This study provides the first primary transcriptome of A. exitialis, which provided comprehensive gene expression information on the lethal amanitas at the transcriptional level, and could lay a strong foundation for functional genomics studies in those fungi. PMID- 24050900 TI - Fast and high-resolution quantitative mapping of tissue water content with full brain coverage for clinically-driven studies. AB - An efficient method for obtaining longitudinal relaxation time (T1) maps is based on acquiring two spoiled gradient recalled echo (SPGR) images in steady states with different flip angles, which has also been extended, with additional acquisitions, to obtain a tissue water content (M0) map. Several factors, including inhomogeneities of the radio-frequency (RF) fields and low signal-to noise ratios may negatively affect the accuracy of this method and produce systematic errors in T1 and M0 estimations. Thus far, these limitations have been addressed by using additional measurements and applying suitable corrections; however, the concomitant increase in scan time is undesirable for clinical studies. In this note, a modified dual-acquisition SPGR method based on an optimization of the sequence formulism is presented for good and reliable M0 mapping with an isotropic spatial resolution of 1*1*1mm(3) that covers the entire human brain in 6:30min. A combined RF transmit/receive map is estimated from one of the SPGR scans and the optimal flip angles for M0 map are found analytically. The method was successfully evaluated in eight healthy subjects producing mean M0 values of 69.8% (in white matter) and 80.1% (in gray matter) that are in good agreement with those found in the literature and with high reproducibility. The mean value of the resultant voxel-based coefficients-of-variation was 3.6%. PMID- 24050901 TI - Metabolic scaling law for mouse fetal and placental weight. AB - Human birth weight does not scale linearly with the weight of the placenta: placental mass (PM) is proportional to the fetal mass (FM) raised to the scaling exponent of 0.75 (PM ~ FM(0.75)) [1,2]. The mouse is a common model for studying genetic and physiological backgrounds of placental development, function and pathologies. However, to date it has not been known how placental weight scales relative to embryo weight in mice. We analyzed E12.5 litters of CD1 wild-type mice, and found that the mouse placental weight demonstrates a power-law scaling relationship with fetal weight; the value of the scaling exponent is approximately 0.72. PMID- 24050902 TI - Circles of Health: towards an advanced social network about disabilities of neurological origin. AB - OBJECTIVES: This research is concerned with the study of a new social-network platform, which (1) provides people with disabilities of neurological origin, their relatives, health professionals, therapists, carers and institutions with an interoperable platform that supports standard indicators, (2) promotes knowledge democratization and user empowerment, and (3) allows making decisions with a more informed opinion. METHODS: A new social network, Circles of Health, has been designed, developed and tested by end-users. To allow monitoring the evolution of people's health status and comparing it with other users and with their cohort, anonymized data of 2675 people from comprehensive and multidimensional medical evaluations, carried out yearly from 2006 to 2010, have been standardized to the International Classification of Functioning, Disability and Health, integrated into the corresponding medical health records and then used to automatically generate and graphically represent multidimensional indicators. These indicators have been integrated into Circles of Health's social environment, which has been then evaluated via expert and user-experience analyses. RESULTS: Patients used Circles of Health to exchange bio-psycho-social information (medical and otherwise) about their everyday lives. Health professionals remarked that the use of color-coding in graphical representations is useful to quickly diagnose deficiencies, difficulties or barriers in rehabilitation. Most people with disabilities complained about the excessive amount of information and the difficulty in interpreting graphical representations. CONCLUSIONS: Health professionals found Circles of Health useful to generate a more integrative understanding of health based on a comprehensive profile of individuals instead of being focused on patient's diseases and injuries. People with disabilities found enriching personal knowledge with the experiences of other users helpful. The number of descriptors used at the same time in the graphical interface should be reduced in future versions of the social-network platform. PMID- 24050904 TI - Editorial comment. PMID- 24050905 TI - Reply by authors. PMID- 24050903 TI - Methodological aspects of estimating rare cancer prevalence in Europe: the experience of the RARECARE project. AB - This paper describes the usage and the performance evaluation of the completeness index method in the 'Surveillance of Rare Cancers in Europe project' (RARECARE) for estimating rare cancer prevalence in Europe. The 15-year prevalence at 1st January 2003 for 255 cancers is obtained from a pool of 22 RARECARE cancer registries (CRs). Incidence and survival models are applied to the RARECARE database to estimate the parameters from which the completeness indices are calculated. Complete prevalence is obtained adjusting the observed 15-year prevalence by the completeness index, to account for those cancer survivors diagnosed before the CR activity started. Main factors influencing the performance of the completeness index method for rare cancers are the same as for common cancers: age distribution of incidence and lethality of the cancer. For cancers occurring in the elderly, with low survival rates and consequently a restricted number of long-term survivors we obtained completeness indices higher than 0.9. Values lower than 0.7 correspond to those cancers with good prognosis and/or incidence more concentrated at the younger ages, indicating that 15 years of follow up are insufficient to detect all prevalent cases. Validation analysis shows that for a restricted subgroup of rare cancers with very low incidence and low survival, the completeness indices were not able to adequately correct the observed prevalence even considering a registration period of 20 years. On average, sensitivity analyses show a slight overestimation of complete prevalence for rare and common cancers whose increasing incidence is known in literature. RARECARE is the largest project on rare cancers conducted to date. Improving health care programs for cancer survivors is a public health priority and prevalence data which provides important information in this field should be regularly asked to Member States and included in the EU health statistics. PMID- 24050906 TI - Reply by authors. PMID- 24050907 TI - Editorial comment. PMID- 24050908 TI - Editorial comment. PMID- 24050909 TI - Reply by authors. PMID- 24050910 TI - Re: A prospective randomized trial of povidone-iodine prophylactic cleansing of the rectum before transrectal ultrasound guided prostate biopsy: Z. AbuGhosh, J. Margolick, S. L. Goldenberg, S. A. Taylor, K. Afshar, R. Bell, D. Lange, W. R. Bowie, D. Roscoe, L. Machan and P. C. Black J Urol 2013; 189: 1326-1331. PMID- 24050911 TI - Re: Routine flexible nephroscopy for percutaneous nephrolithotomy for renal stones with low density: a prospective, randomized study: A. Gucuk, E. Kemahli, U. Uyeturk, C. Tuygun, M. Yildiz and A. Metin J Urol 2013; 190: 144-148. PMID- 24050912 TI - Editorial comment. PMID- 24050913 TI - Reply by authors. PMID- 24050914 TI - Effectiveness of nursing interventions in heart failure patients in home care using NANDA-I, NIC, and NOC. AB - OBJECTIVE: The objective of the study is to evaluate the effectiveness of nursing interventions (NIC) using nursing outcomes (NOC) and based on NANDA-I nursing diagnoses in patients with heart failure in home care. METHOD: In this longitudinal study, 23 patients with heart failure were followed for 6 months, in four home visits. During the visits, nursing diagnoses were established, outcomes assessed, and interventions implemented. RESULTS: Of the 11 NIC interventions implemented, eight proved effective, that is, showed significant improvement between the first and the fourth visit, according to scores obtained for six outcomes: knowledge: treatment regimen, knowledge: medication, compliance behavior, symptom control, activity tolerance, and energy conservation. CONCLUSION: NIC interventions health education, self-modification assistance, behavior modification, teaching: prescribed medication, teaching: disease process, nutritional counseling, telephone consultation, and energy conservation showed effective outcomes based on NOC scores, suggesting that the NANDA-I, NIC, and NOC linkage is useful in patients with heart failure in home care. PMID- 24050915 TI - Early examination of the middle-range theory of flight nursing expertise. AB - Reliance on expert flight nurses to move critically ill or injured patients generates considerable need for these nurses to obtain advanced education and maintain clinical expertise. The newly proposed middle-range theory of flight nursing expertise provided an initial framework to guide education and training in this rapidly changing specialty, but the framework had yet to be compared to the actual experiences of flight nurses in research. A cooperative inquiry approach was used to guide an investigation into the validity of the theory. The study consisted of two cycles of inquiry. In the first cycle, post-flight questionnaires were administered after patient missions to assess the presence or absence of each concept described in the theory. In the second cycle, individual interviews were used to further explore the flight nurses' decision-making during patient transport missions. Data collected from flight nurses about their decision-making on patient transport missions supported the presence of all the concepts in the newly proposed theory. Another concept, partner cuing, emerged as a concept to be added to the theory, while the concept decision-making, was revised to expanded decision-making. The importance of partner cuing was confirmed by flight nurses as reflecting their expanded decision-making during patient missions. PMID- 24050916 TI - Trying on the professional self: nursing students' perceptions of learning about roles, identity and teamwork in an interprofessional clinical placement. AB - AIM: This study aims to describe how senior nursing students viewed the clinical learning environment and matured their professional identity through interprofessional learning in a student-led hospital 'ward'. BACKGROUND: Undergraduate nursing and medical student teams participated in a trial of ward based interprofessional clinical learning, managing patients over 2 weeks in a rehabilitation ward. METHODS: Qualitative and quantitative program evaluation was conducted using exit student focus groups and a satisfaction survey. RESULTS: Twenty-three nursing and medical students in three placement rounds provided positive feedback. Five main themes emerged describing their engagement in 'trying on' a professional role: 'experiencing independence and autonomy'; 'seeing clearly what nursing's all about'; 'altered images of other professions'; 'ways of communicating and collaborating' and 'becoming a functioning team'. CONCLUSIONS: Ward-based interprofessional clinical placements offer senior students authentic ideal clinical experiences. We consider this essential learning for future interprofessional collaboration which should be included in senior nursing students' education. PMID- 24050917 TI - Treatment adherence of Chinese patients with hypertension: a longitudinal study. AB - BACKGROUND: There is no research concerning treatment adherence and correlated factors using longitudinal design in China. AIM: This article investigated the treatment adherence of patients with hypertension and examined determinants of adherence, with a focus on changes of adherence and psychosocial factors over 1 year. METHODS: A longitudinal design was adopted to facilitate the survey of patients with hypertension across two time points. RESULTS: The results demonstrated that treatment adherence of hypertensive patients improved over 1 year follow-up. The blood pressure values of hypertensive patients decreased at time 2. The regression analysis found that time 1 treatment adherence, social support, education and duration of diagnosis were significant predictors of treatment adherence at time 2, accounting for 26% of the total variance. Time 1 treatment adherence explained 15% of the variance, social support 7%, education 3% and duration of diagnosis 1%. CONCLUSIONS: The effective strategies targeted patients at risk are suggested to be necessary and should be designed according to the factors affecting adherence. PMID- 24050918 TI - Werner complex deficiency in cells disrupts the Nuclear Pore Complex and the distribution of lamin B1. AB - From the surrounding shell to the inner machinery, nuclear proteins provide the functional plasticity of the nucleus. This study highlights the nuclear association of Pore membrane (POM) protein NDC1 and Werner protein (WRN), a RecQ helicase responsible for the DNA instability progeria disorder, Werner Syndrome. In our previous publication, we connected the DNA damage sensor Werner's Helicase Interacting Protein (WHIP), a binding partner of WRN, to the NPC. Here, we confirm the association of the WRN/WHIP complex and NDC1. In established WRN/WHIP knockout cell lines, we further demonstrate the interdependence of WRN/WHIP and Nucleoporins (Nups). These changes do not completely abrogate the barrier of the Nuclear Envelope (NE) but do affect the distribution of FG Nups and the RAN gradient, which are necessary for nuclear transport. Evidence from WRN/WHIP knockout cell lines demonstrates changes in the processing and nucleolar localization of lamin B1. The appearance of "RAN holes" void of RAN corresponds to regions within the nucleolus filled with condensed pools of lamin B1. From WRN/WHIP knockout cell line extracts, we found three forms of lamin B1 that correspond to mature holoprotein and two potential post-translationally modified forms of the protein. Upon treatment with topoisomerase inhibitors lamin B1 cleavage occurs only in WRN/WHIP knockout cells. Our data suggest the link of the NDC1 and WRN as one facet of the network between the nuclear periphery and genome stability. Loss of WRN complex leads to multiple alterations at the NPC and the nucleolus. PMID- 24050919 TI - Intraoperative temporary fixation for primary reconstruction of composite mandibular ablative defects. PMID- 24050920 TI - Surgical treatment of recurring ameloblastoma, are there options? AB - Our aim was to evaluate the treatment given to patients with intraosseus ameloblastomas with special emphasis on recurrence and the outcomes of primary and secondary resection. Forty-eight patients who were treated for intraosseous ameloblastoma at 8 centres across Sweden met the inclusion criteria. They showed typical distribution of age, sex, site of lesion, and characteristic presenting features. Eleven of the 48 were initially treated with radical resection and none recurred. Twenty-two of the remaining 37 who were initially treated by conservative resection presented with recurrences. Sixteen of the 22 then had conservative secondary resections, which resulted in further recurrence in 6 patients. Initial radical resection is therefore superior to conservative management as far as recurrences are concerned. We argue, however, that a conservative surgical approach is adequate for many intraosseous ameloblastomas with limited extension, because relapse can be followed by radical resection if clinically indicated in selected cases. PMID- 24050921 TI - Cutaneous ulcers associated with hydroxyurea therapy. AB - Hydroxyurea is an antitumoral drug mainly used in the treatment of Philadelphia chromosome-negative myeloproliferative syndromes and sickle-cell disease. Ulcers represent a rare but severe long-term adverse effect of hydroxyurea therapy. Hydroxyurea-induced ulcers are often multiple and bilateral, typically developing in the perimalleolar region, although any cutaneous district is potentially affected. They generally look small, well-defined, shallow with an adherent, yellow, fibrinous necrotic base. A constant finding is also an extremely intense, treatment-resistant pain accompanying these ulcerations. Withdrawal of the drug generally leads to spontaneous healing of these lesions. Care providers tend to show insufficient awareness of this highly debilitating cutaneous side effect, and late or missed diagnoses are frequent. Instead, regular dermatologic screening should be performed on hydroxyurea-treated patients. This article will present a comprehensive review of indexed case reports and clinical studies, followed by a discussion about treatment options aiming at increasing knowledge about this specific topic. PMID- 24050922 TI - Screening, purification and characterization of a novel cold-active and organic solvent-tolerant lipase from Stenotrophomonas maltophilia CGMCC 4254. AB - An extracellular organic solvent-tolerant and cold-active lipase producing bacterium was isolated from oil-contaminated soil samples, and identified taxonomically as Stenotrophomonas maltophilia. The lipase from S. maltophilia CGMCC 4254 (SML) was purified 60.5-fold to homogeneity with 38.9 U/mg specific activity. Partially purified SML displayed remarkable stability in 50% and 100% (v/v) hydrophobic organic solvents after incubation for 7 days. The enzyme also retained more than 50% of its residual activity in several pure hydrophilic organic solvents after incubation for 7 days. SML showed 57% maximum activity at 5 degrees C, and had optimal activity at 35 degrees C. These unique properties of SML make it promising as a biocatalyst for industrial processes. PMID- 24050923 TI - Characterization of inulin hydrolyzing enzyme(s) in commercial glucoamylases and its application in lactic acid production from Jerusalem artichoke tubers (Jat). AB - A high inulinase activity was found in three commercially available glucoamylase enzymes. Its origin was investigated and two proteins in the commercial glucoamylases were identified as the potential enzymes showing inulinase activity. One of the commercial glucoamylases, GA-L New from Genencor, was used for Jerusalem artichoke tubers (Jat) hydrolysis and a high hydrolysis yield of fructose was obtained. The simultaneous saccharification and lactic acid fermentation (SSF) of Jat was carried out using GA-L New as the inulinase and Pediococcus acidilactici DQ2 as the fermenting strain. A high lactic acid titer, yield, and productivity of 111.5 g/L, 0.46 g/g DM, and 1.55 g/L/h, respectively, were obtained within 72 h. The enzyme cost using the commercial glucoamylase as inulinase was compared to that using the typical inulinase and a large profit margin was identified. The results provided a practical way of Jat application for lactic acid production using cheap commercial glucoamylase enzyme. PMID- 24050924 TI - Rapid determination of bulk microalgal biochemical composition by Fourier Transform Infrared spectroscopy. AB - Analysis of bulk biochemical composition is a key in fundamental and applied studies of microalgae and is essential to understanding responses to different cultivation scenarios. Traditional biochemical methods for the quantification of lipids, carbohydrates and proteins are often time-consuming, often involve hazardous reagents, require significant amounts of biomass and are highly dependent on practitioner proficiency. This study presents a rapid and non destructive method, utilising Fourier-Transform Infrared (FTIR) spectroscopy for the simultaneous determination of lipid, protein and carbohydrate content in microalgal biomass. A simple univariate regression was applied to sets of reference microalgal spectra of known composition and recognised IR peak integrals. A robust single-species model was constructed, with coefficients of determination r(2)>0.95, high predictive accuracy and relative errors below 5%. The applicability of this methodology is demonstrated by monitoring the time resolved changes in biochemical composition of the marine alga Nannochloropsis sp. grown to nitrogen starvation. PMID- 24050925 TI - Removal of trace organic contaminants by an MBR comprising a mixed culture of bacteria and white-rot fungi. AB - The degradation of 30 trace organic contaminants (TrOC) by a white-rot fungus augmented membrane bioreactor (MBR) was investigated. The results show that white rot fungal enzyme (laccase), coupled with a redox mediator (1-hydroxy benzotriazole, HBT), could degrade TrOC that are resistant to bacterial degradation (e.g. diclofenac, triclosan, naproxen and atrazine) but achieved low removal of compounds (e.g. ibuprofen, gemfibrozil and amitriptyline) that are well removed by conventional activated sludge treatment. Overall, the fungus augmented MBR showed better TrOC removal compared to a system containing conventional activated sludge. The major role of biodegradation in removal by the MBR was noted. Continuous mediator dosing to MBR may potentially enhance its performance, although not as effectively as for mediator-enhanced batch laccase systems. A ToxScreen3 assay revealed no significant increase in the toxicity of the effluent during MBR treatment of the synthetic wastewater comprising TrOC, confirming that no toxic by-products were produced. PMID- 24050926 TI - Potential of ozonolysis as a pretreatment for energy grasses. AB - This study investigated the effect of ozonolysis on Miscanthus * giganteus, Miscanthus sinensis 'Gracillimus', Saccharum arundinaceum and Saccharum ravennae, collectively referred to as 'energy grasses'. Studies were conducted at three different ozone concentrations (40, 50 and 58 mg/l) using two ozone flow configurations - uni-directional and reversed flow. Pretreatment conditions for each variety were optimized based on lignin content and glucan recovery in ozonated solids. Results showed that ozonolysis was effective in removing up to 59.9% lignin without cellulose degradation. However, subsequent hydrolysis of pretreated solids with Cellic(r) CTec2 at 0.06 g/g raw biomass provided glucan conversion lower than untreated samples suggesting enzyme inhibition by lignin degradation products formed during ozonolysis. Future studies investigating hydrolysis efficiency of washed pretreated solids with higher enzyme loadings are therefore warranted to optimize the hydrolysis process and make it functionally feasible. PMID- 24050927 TI - Are prognostic scoring systems of value in patients with follicular thyroid carcinoma? AB - PURPOSE: Most prognostic systems for differentiated carcinoma have been designed for papillary carcinoma. OBJECTIVE: To analyze the value of the existing prognostic systems for evaluating follicular carcinoma and to determine whether any of them have a better predictive effect. METHODS: A total of 66 follicular carcinomas were analyzed. The following prognostic systems were studied: EORTC, AGES, AMES, MACIS, TNM, and NTCTCS. RESULTS: The AGES and AMES systems did not demonstrate a good prognostic correlation. In the EORTC system, the rate of disease-free patients was 89% in group 1, 75% in group 2, 69% in group 3, and 0% in group 4. The MACIS system showed 83, 60, 67, and 0% of disease-free patients respectively. The TNM system showed 81, 71, 50, and 0% of disease-free patients respectively. Finally, the NTCTCS system demonstrated 100, 84, 53, and 0% of disease-free patients respectively. Cox's regression analysis was used to calculate the proportion of variation in survival time explained (PVE). The prognostic classification system with the greatest survival prediction was EORTC at 67.64% of PVE, followed by TNM at 62.5% of PVE, and MACIS at 57.82% of PVE. CONCLUSIONS: MACIS and TNM are good prognostic systems for evaluating follicular thyroid carcinoma, although the one with the most prognostic value was the EORTC system. PMID- 24050928 TI - Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort followed by LOH analysis. AB - OBJECTIVE: The aryl hydrocarbon receptor interacting protein gene (AIP) is associated with pituitary adenoma (PA). AIP has not been sequenced in East Asian PA populations, so we performed this study in a Han Chinese cohort. DESIGN: Our study included six familial PA pedigrees comprising 16 patients and 27 unaffected relatives, as well as 216 sporadic PA (SPA) patients and 100 unrelated healthy controls. METHODS: AIP sequencing was carried out on genomic DNA isolated from blood samples. Multiplex ligation-dependent probe amplification and microsatellite marker analyses on DNA from the paired tumor tissues were performed for loss of heterozygosity analysis. RESULTS: We identified three common and four rare single nucleotide polymorphisms (SNPs), one intron insertion, one novel synonymous variant, four novel missense variants, and a reported nonsense mutation in three familial isolated PA (FIPA) cases from the same family. Large genetic deletions were not observed in the germline but were seen in the sporadic tumor DNA from three missense variant carriers. The prevalence of AIP pathogenic variants in PA patients here was low (3.88%), but was higher in somatotropinoma patients (9.30%), especially in young adults (<=30 years) and pediatric (>=18 years) paients (17.24% and 25.00% respectively). All AIP variant patients suffered from macroadenomas. However, the AIP mutation rate in FIPA families was low in this cohort (16.67%, 1/6 families). CONCLUSION: AIP gene mutation may not be frequent in FIPA or SPA from the Han Chinese population. AIP sequencing and long-term follow-up investigations should be performed for young patients with large PAs and their families with PA predisposition. PMID- 24050929 TI - Membrane protein reconstitution into liposomes guided by dual-color fluorescence cross-correlation spectroscopy. AB - Proteoliposomes represent nanoscale assemblies of indispensable value for studying membrane proteins in general and membrane transporters in particular. Since no universal protocol exists, conditions for proteoliposome formation must be determined on a case-by-case basis. This process will be significantly expedited if the size and composition of the assemblies can be analyzed in a single step using only microliters of sample. Here we show that dual-color fluorescence cross-correlation spectroscopy (FCCS) is of great value for optimizing the reconstitution process, because it distinguishes micelles, liposomes and aggregates in heterogeneous mixtures and permits direct monitoring of the co-localization of proteins and lipids in the diffusing assemblies. As proof-of-principle, liposomes containing the functional multidrug resistance transporter NorA from Staphylococcus aureus were prepared, demonstrating that FCCS is an excellent tool to guide the development of reconstitution protocols. PMID- 24050930 TI - The renin-angiotensin system plays a major role in voiding dysfunction of ovariectomized rats. AB - AIMS: The renin-angiotensin system (RAS) plays a major role in cardiovascular diseases in postmenopausal women, but little is known about its importance to lower urinary tract symptoms. In this study we have used the model of ovariectomized (OVX) estrogen-deficient rats to investigate the role of RAS in functional and molecular alterations in the urethra and bladder. MAIN METHODS: Responses to contractile and relaxant agents in isolated urethra and bladder, as well as cystometry were evaluated in 4-month OVX Sprague-Dawley rats. Angiotensin converting enzyme activity and Western blotting for AT1/AT2 receptors were examined. KEY FINDINGS: Cystometric evaluations in OVX rats showed increases in basal pressure, capacity and micturition frequency, as well as decreased voiding pressure. Angiotensin II and phenylephrine produced greater urethral contractions in OVX compared with Sham group. Carbachol-induced bladder contractions were significantly reduced in OVX group. Relaxations of urethra and bladder to sodium nitroprusside and BAY 41-2272 were unaffected by OVX. Angiotensin-converting enzyme activity was 2.6-fold greater (p<0.05) in urethral tissue of OVX group, whereas enzyme activity in plasma and bladder remained unchanged. Expressions of AT1 and AT2 receptors in the urethra were markedly higher in OVX group. In bladder, AT1 receptors were not detected, whereas AT2 receptor expression was unchanged between groups. 17beta-Estradiol replacement (0.1mg/kg, weekly) or losartan (30 mg/kg/day) largely attenuated most of the alterations seen in OVX group. SIGNIFICANCE: Prolonged estrogen deprivation leads to voiding dysfunction and urethral hypercontractility that are associated with increased ACE activity and up-regulation of angiotensin AT1/AT2 receptor in the urethral tissue. PMID- 24050931 TI - Alpha melanocyte stimulating hormone (alpha-MSH) does not modify pentylenetetrazol- and pilocarpine-induced seizures. AB - AIMS: Alpha-melanocyte stimulating hormone (alpha-MSH) is a pro-opiomelanocortin (POMC)-derived peptide involved in different neurological functions that also exerts anti-inflammatory effects, including in the central nervous system (CNS). Although inflammation has been implicated in seizures and epilepsy, no study has systematically investigated whether alpha-MSH modifies seizures. Therefore, in the current study we determined whether alpha-MSH alters pentylenetetrazol (PTZ)- and pilocarpine-induced seizures. MAIN METHODS: Adult male Swiss mice were injected with alpha-MSH (1.66, 5 or 15 MUg/3 MUL, intracerebroventricular (i.c.v.)) or systemic (0.1, 0.3 or 1 mg/kg, intraperitoneally (i.p.)). Five to sixty minutes after the injection of the peptide, animals were injected with PTZ (60 mg/kg, i.p.) or pilocarpine (370 mg/kg, i.p.). Latency to myoclonic jerks and tonic-clonic seizures, number of seizure episodes, total time spent seizing and seizure intensity, assessed by the Racine and Meurs scales were recorded. Interleukin 1 beta (IL-1beta) levels in the hippocampus were measured by a commercial enzyme-linked immunoabsorbent assay (ELISA). KEY FINDINGS: Neither intracerebroventricular (1.66, 5 or 15 MUg/3 MUL, i.c.v.) nor systemic (0.1, 0.3 or 1 mg/kg, i.p.) administration of alpha-MSH altered PTZ- and pilocarpine induced seizures. IL-1beta levels in the hippocampi were not altered by alpha MSH, PTZ or pilocarpine. SIGNIFICANCE: Although inflammation has been implicated in seizures and epilepsy and alpha-MSH is a potent anti-inflammatory peptide, our results do not support a role for alpha-MSH in seizure control. PMID- 24050932 TI - The Baby Care Questionnaire: a measure of parenting principles and practices during infancy. AB - The current report provides a new framework to explore the role of parenting practices and principles during infancy. We identify structure and attunement as key parenting principles during infancy. Structure represents reliance on regularity and routines in daily life. Attunement represents reliance on infant cues and close physical contact. We suggest parents' relative endorsement of these parenting principles is related to their choices about practices such as feeding, holding and night-time sleeping. We designed the Baby Care Questionnaire to measure parents' endorsement of structure and attunement, as well as their daily parenting practices. We report data demonstrating the factor structure, reliability and validity of the BCQ. The BCQ, to our knowledge, is the first comprehensive measure of parenting practices and principles during infancy. We conclude with a discussion of future directions for the measure. PMID- 24050933 TI - HindII and SduI digests of heat-shock protein 70 PCR for Leishmania typing. AB - Restriction fragment length polymorphisms of the heat-shock protein 70 gene have been used for discriminating Leishmania species. Here, we validated HindII as a much cheaper alternative to EcoRII and SduI for discriminating Leishmania (Viannia) braziliensis from Leishmania (Viannia) naiffi and an atypical Leishmania (V.) braziliensis group, which was previously not possible. PMID- 24050934 TI - Eastern rock sengis as reservoir hosts of Anaplasma bovis in South Africa. AB - Recent work has identified the presence of Anaplasma bovis, a tick-borne pathogen of cattle, in a previously undescribed species of tick collected from eastern rock sengis, Elephantulus myurus, in Limpopo Province, South Africa. These small insectivores are endemic to Africa and are important hosts of immature ticks, however, their role as reservoirs of tick-borne pathogens has not been investigated. In order to elucidate the role of sengis in the epidemiology of A. bovis, we screened the blood of 105 sengis from Limpopo Province, South Africa, for the presence of members of the genera Anaplasma and Ehrlichia by PCR. A total of 30/105 (28.6%) of individuals were infected with A. bovis, and nucleotide sequencing revealed the presence of a novel genetic variant of this pathogen. This represents the first evidence that sengis may be natural reservoir hosts of A. bovis. PMID- 24050935 TI - Nonpolymeric surface-coated iron oxide nanoparticles for in vivo molecular imaging: biodegradation, biocompatibility, and multiplatform. AB - A new approach to the surface engineering of superparamagnetic iron oxide nanoparticles (SPIONs) may encourage their development for clinical use. In this study, we demonstrated that nonpolymeric surface modification of SPIONs has the potential to be an advanced biocompatible contrast agent for biomedical applications, including diagnostic imaging in vivo. METHODS: Adenosine triphosphate (ATP), which is an innate biomaterial derived from the body, was coated onto the surface of SPIONs. An in vivo degradation study of ATP-coated SPIONs (ATP@SPIONs) was performed for 28 d. To diminish phagocytosis, ATP@SPIONs were surface-modified with gluconic acid. We next studied the ability of the SPIONs to serve as a specific targeted contrast agent after conjugation of cMet binding peptide. The SPIONs were conjugated with Cy5.5 and labeled with (125)I for multimodality imaging. In vivo and in vitro tumor-targeted binding studies were performed on U87MG cells or a U87MG tumor model using animal SPECT/CT, an optical imaging system, and a 1.5-T clinical MR scanner. RESULTS: ATP@SPIONs showed rapid degradation in vivo and in vitro, compared with ferumoxides. ATP@SPIONs modified with gluconic acid reduced phagocytic uptake, showed improved biodistribution, and provided good targetability in vivo. The gluconic acid conjugated ATP@SPIONs, when conjugated with cMet-binding peptide, were successfully visualized on the U87MG tumors implanted in mice via multimodality imaging. CONCLUSION: We suggest that ATP@SPIONs can be used as a multiplatform to target a region of interest in molecular imaging. When we consider the biocompatibility of contrast agents in vivo, ATP@SPIONs are superior to polymeric surface-modified SPIONs. PMID- 24050936 TI - Evaluation of the biodistribution of 11C-methionine in children and young adults. AB - The purpose of this study was to evaluate the biodistribution of (11)C-labeled methionine in non-tumor-involved organs in pediatric patients studied for malignant diseases. METHODS: Ninety-three children and young adults with known or suspected malignancies underwent (11)C-methionine PET and CT scans. Imaging began 5-15 min after injection of 740 MBq (20 mCi) per 1.7 m(2) of body surface area. Images were acquired from the top of the head through the mid thighs. Standardized uptake values were determined using regions of interest drawn on the CT image and transferred to the corresponding transverse PET slice. RESULTS: The highest concentrations of (11)C-methionine were found in the pancreas and liver. Less intense uptake was seen in other regions, such as the salivary glands, tonsils, and bone marrow. There was little uptake in the lungs, fat (including brown adipose tissue), and muscle. Uptake in bone marrow, parotid glands, and tonsils was slightly but statistically significantly higher in men than women. Testicular, bone marrow, and left ventricular uptake increased with age. There was little variability statistically between comparisons of uptake change and groupings of age, race, sex, and patients studied at the time of diagnosis versus previously treated patients. CONCLUSION: High uptake of (11)C-methionine is reliably found in the pancreas and liver, consistent with the anabolic functions of these organs. Low uptake in the brain, neck, chest, pelvis, and extremities will facilitate tumor localization in those areas. However, intense uptake in the upper abdomen may limit the diagnostic utility of (11)C-methionine in that area. PMID- 24050937 TI - N-acetylcysteine- and MK-801-induced changes in glutamate levels do not affect in vivo binding of metabotropic glutamate 5 receptor radioligand 11C-ABP688 in rat brain. AB - Abnormal glutamate transmission is involved in various neurologic disorders, such as epilepsy, schizophrenia, and Parkinson disease. At present, no imaging techniques are capable of measuring acute fluctuations in endogenous glutamate levels in vivo. We evaluated the potential of (11)C-ABP688, a PET ligand that binds to an allosteric site of the metabotropic glutamate 5 receptor, in rats by using small-animal PET and beta-microprobes after pharmacologic challenges with N acetylcysteine (NAc) and MK-801. Both compounds are known to induce increases in endogenous glutamate levels. METHODS: Three experiments with (11)C-ABP688 were performed to validate our study setup: first, metabolite analyses during workup (n = 3) and after a selected treatment (n = 3); second, a test-retest (n = 12) small-animal PET experiment (1 h scan; 27.75 MBq of (11)C-ABP688 administered intravenously; <3 nmol/kg); and third, a small-animal PET and beta-microprobe cold blocking study (n = 6/condition) with unlabeled ABP688. After this experimental validation, rats were pretreated with either NAc (intravenous infusion of 50 mg/kg/h) or MK-801 (0.16 mg/kg; given intraperitoneally); this step was followed by small-animal PET with (11)C-ABP688 (n = 12) or beta microprobe measurements (n = 10/condition) of (11)C-ABP688. Time-activity curves were extracted, and the nondisplaceable binding potential (BPND) was calculated by use of the simplified reference tissue model with the cerebellum as a reference region. RESULTS: (11)C-ABP688 BPND measurements were highly reproducible (test-retest), and both small-animal PET and beta-microprobes were able to discriminate changes in (11)C-ABP688 binding (cold blocking). The average small-animal PET BPND measurements in the test experiment for the caudate putamen, frontal cortex, cerebral cortex, hippocampus, and thalamus were 2.58, 1.40, 1.60, 1.86, and 1.09, respectively. However, no significant differences in BPND measurements were observed with small-animal PET in the test and retest conditions on the one hand and the NAc and MK-801 conditions on the other hand for any of these regions. When beta-microprobes were used, the average BPND in the caudate putamen was 0.94, and no significant changes in the test and MK-801 conditions were observed. CONCLUSION: Pharmacologic challenges with NAc and MK 801 did not affect the (11)C-ABP688 BPND in the rat brain. These data suggest that the in vivo affinity of (11)C-ABP688 for binding to an allosteric site of the metabotropic glutamate 5 receptor is not modulated by changes in glutamate levels and that (11)C-ABP688 is not capable of measuring acute fluctuations in endogenous levels of glutamate in vivo in the rat brain. PMID- 24050939 TI - Solitary fibrous tumor of the larynx: case report demonstrating the value of MRI in guiding surgical management. AB - A 74-year-old woman presented with persistent dysphagia, dysphonia, and throat gurgling. Prior intraoperative biopsies were negative, and outside imaging revealed supraglottic swelling. Magnetic resonance imaging (MRI) demonstrated a well-defined T1 and T2 hypointense, avidly enhancing hypopharyngeal mass. Deep intraoperative rebiopsies revealed a tumor with CD34+ tissue, diagnostic of a solitary fibrous tumor. A broad range of nonsquamous cell tumors should be considered when a submucosal laryngeal mass is encountered. MRI may be particularly helpful in guiding appropriate biopsy. PMID- 24050938 TI - Bilateral anterior glenohumeral dislocation and coracoid processes fracture after seizure: acute MRI findings of this rare association. AB - We report a rare case of bilateral anterior shoulder dislocation associated with coracoid processes fracture after a seizure episode in a 37-year-old woman. This combination of findings is rare, especially by the presence of bilateral coracoid processes fracture. Possible mechanisms related are direct trauma of humeral heads over the coracoid processes or sudden pull of biceps short head attachment site during uncontrolled contractures. Few reports published similar combination of injuries, and to our knowledge, this is the first to demonstrate its acute features by magnetic resonance imaging. A review of the literature is also presented. PMID- 24050940 TI - CT findings of synovial sarcomas of the kidney with pathological correlation. AB - PURPOSE: To describe computed tomography (CT) findings of primary synovial sarcoma of the kidney with pathological correlation. METHODS: CT findings of four cases of pathologically confirmed synovial sarcoma of the kidney were retrospectively viewed and correlated with pathologic features. RESULTS: The four synovial sarcomas presented as soft tissue masses with multiple smooth wall cysts. Pathologically, entrapped and dilated renal tubules formed the smooth wall cysts lined by hobnail tubular epithelium. CONCLUSION: Primary renal synovial sarcoma might manifest as a renal mass with multiple smooth wall cysts. The cysts are consistent with entrapped dilated renal tubular and are lined with hobnail tubular epithelium. PMID- 24050941 TI - Bilateral cavitary otosclerosis: a rare presentation of otosclerosis and cause of hearing loss. AB - Cavitary otosclerosis is a rare presentation of otosclerosis, especially when it involves the anterior wall of the internal auditory canal. Recognizing the computed tomographic imaging features of this process is crucial since cavitary otosclerosis may be a cause of a "third window phenomenon", resulting in conductive hearing loss and can cause cerebrospinal fluid leak and electrode misplacement at cochlear implantation. We present a case of bilateral cavitary otosclerosis in a patient with gradual hearing loss followed by a review of literature of this rare but important entity. PMID- 24050942 TI - Adherence and renal biopsy feasibility in the Renin Angiotensin-System Study (RASS) primary prevention diabetes trial. AB - AIMS: Enhancing adherence in research trials is fundamental to the proper testing of treatment hypotheses. METHODS: Regimen and follow-up adherence as well as factors associated with adherence in the Renin Angiotensin-System Study (RASS) diabetic nephropathy primary prevention trial were evaluated. Adherence to medication (i.e., pill count), follow-up visits, and follow-up renal biopsies was evaluated. RESULTS: 89.8% of subjects completed the second renal biopsy. 96% of follow-up visits were attended within prescribed time windows. Mean medication adherence was 85.6%. Subgroup analyses revealed greater declines in the least adherent participants over time. Factors associated with greater adherence levels included older age, type 1 diabetes (TIDM) duration, lower HbA1c and blood pressure, GFR, ethnicity, and participants', principal investigators' (PI), and trial coordinators' (TC) baseline predictions of adherence. CONCLUSIONS: T1DM patients without nephropathy were willing to take experimental medications and undergo repeat renal biopsies. Although overall adherence was excellent, patterns of adherence varied among participants, suggesting the need to better track adherence and to develop customized and targeted approaches for promoting adherence to clinical research regimens. Staff subjective predictions of adherence were imprecise, supporting need for further development of adherence predictors. PMID- 24050943 TI - Seroprevalence and risk factors of Neospora spp. in donkeys from Southern Italy. AB - In some European countries there is an increasing interest on donkey. Despite there are few data regarding the donkey's parasitic diseases especially those with a protozoal etiology as neosporosis. Samples used in the study were collected from 238 domestic donkeys during year 2010 in Southern Italy from 207 females and 31 males of five breeds (Martina-Franca, Amiata, Sicilian-Grey, Ragusano, Sardinian) and crossbreeds with the average age 9 years (1 month - 24 year). Sera were tested by a competitive-inhibition enzyme-linked immunosorbent assay for antibodies against Neospora caninum; the sera were marked positive, if more than 30% inhibition was found. Out of a total 238 donkeys, 28 (11.8%) were found positive for Neospora antibodies with 12% in females and 6% in males. Different seroprevalence 15.4%, 16%, 12% and 8.8% were found in age categories <1 year, 1-4 years, 5-9 years and >=10 years, respectively. The seroprevalence ranged in different breeds from 36% (Sicilian-Grey) to 0% (Sardinian) and in different use from 17% (for breeding) to 0% (for meat production). Logistic regression analysis demonstrated evidence of a significant (P<0.05) association between crossbreed origin of samples and risk of protozoan infection; age of donkeys was also significant risk factor for protozoan infection. No statistical significant difference (P>0.05) was found among genders and use of donkeys and risk of N. caninum infection. This is the first serological survey for Neospora spp. performed in donkeys. PMID- 24050944 TI - Molecular identification of Taenia serialis coenurosis in a wild Ethiopian gelada (Theropithecus gelada). AB - Since morphological identification of a larval Taeniid in geladas (Theropithecus gelada) has produced inconsistent results, genetic information is pivotal for species identification. Nuclear and mitochondrial DNA from a coenurus in a wild gelada were compared to published sequences from multiple Taeniid species, confirming the identification of this parasite as Taenia serialis. A demographic analysis finds age to be a strong predictor of coenuri. Tapeworms rarely employ primates as intermediate hosts, and the presence of T. serialis in a wild gelada population may indicate a substantial ecological shift in this parasite's life cycle. PMID- 24050946 TI - Irradiation capabilities of LR-0 reactor with VVER-1000 Mock-Up core. AB - Even low power reactors, such as zero power reactors, are sufficient for semiconductor radiation hardness effect investigation. This reflects the fact that fluxes necessary for affecting semiconductor electrical resistance are much lower than fluxes necessary to affect material parameters. The paper aims to describe the irradiation possibilities of the LR-0 reactor with a special core arrangement corresponding to VVER-1000 dosimetry Mock-Up. PMID- 24050945 TI - Interactions of PPAR-alpha and adenosine receptors in hypoxia-induced angiogenesis. AB - Hypoxia and adenosine are known to upregulate angiogenesis; however, the role of peroxisome proliferator-activated receptor alpha (PPARalpha) in angiogenesis is controversial. Using transgenic Tg(fli-1:EGFP) zebrafish embryos, interactions of PPARalpha and adenosine receptors in angiogenesis were evaluated under hypoxic conditions. Epifluorescent microscopy was used to assess angiogenesis by counting the number of intersegmental (ISV) and dorsal longitudinal anastomotic vessel (DLAV) at 28 h post-fertilization (hpf). Hypoxia (6h) stimulated angiogenesis as the number of ISV and DLAV increased by 18-fold (p<0.01) and 100 +/- 8% (p<0.001), respectively, at 28 hpf. Under normoxic and hypoxic conditions, WY 14643 (10 MUM), a PPARalpha activator, stimulated angiogenesis at 28 hpf, while MK-886 (0.5 MUM), an antagonist of PPARalpha, attenuated these effects. Compared to normoxic condition, adenosine receptor activation with NECA (10 MUM) promoted angiogenesis more effectively under hypoxic conditions. Involvement of A2B receptor was implied in hypoxia-induced angiogenesis as MRS-1706 (10nM), a selective A2B antagonist attenuated NECA (10 MUM)-induced angiogenesis. NECA- or WY-14643-induced angiogenesis was also inhibited by miconazole (0.1 MUM), an inhibitor of epoxygenase dependent production of eicosatrienoic acid (EET) epoxide. Thus, we conclude that: activation of PPARalpha promoted angiogenesis just as activation of A2B receptors through an epoxide dependent mechanism. PMID- 24050947 TI - A brief review on experimental fluorosis. AB - Fluoride (F) is a naturally occurring contaminant in the water. F is essential for normal maintenance of teeth and bones. However, prolonged exposure to high concentration of F is found to be deleterious to teeth, bones and other organs. Besides drinking water, F can enter the body through food, dental products, drugs and industrial emission. People living in areas where F contamination is much higher than the expected level, are found to suffer from not only teeth and bone problem but also other systems, including brain and its functions. Since animals respond to the toxic effects of F like human beings, the deleterious effects of F have been produced experimentally in animals in order to determine the mechanism involved in the action of F. The reports indicating the chronic harmful effects of F in teeth, bones, heart, liver, kidneys, gastrointestinal tract, lungs, brain, blood, hormones and biochemical parameters of experimental animals and in in vitro studies have been reviewed in this article. The neurotoxic action of F that produces chiefly learning and memory impairment has also been included. The review also points out the harmful effects of F on reproduction, its teratogenic action and in inducing premature ageing. Finally, the reports indicating a reversal of certain toxicities of F in experimental animals after withdrawal of its exposure has been included. PMID- 24050948 TI - Reprint of New opportunities for improved ribotyping of C. difficile clinical isolates by exploring their genomes. AB - Clostridium difficile causes outbreaks of infectious diarrhoea, most commonly occurring in healthcare institutions. Recently, concern has been raised with reports of C. difficile disease in those traditionally thought to be at low risk i.e. community acquired rather than healthcare acquired. This has increased awareness for the need to track outbreaks and PCR-ribotyping has found widespread use to elucidate epidemiologically linked isolates. PCR-ribotyping uses conserved regions of the 16S rRNA gene and 23S rRNA gene as primer binding sites to produce varying PCR products due to the intergenic spacer (ITS1) regions of the multiple operons. With the explosion of whole genome sequence data it became possible to analyse the start of the 23S rRNA gene for a more accurate selection of regions closer to the end of the ITS1. However the following questions must still be asked: (i) Does the chromosomal organisation of the rrn operon vary between C. difficile strains? and (ii) just how conserved are the primer binding regions? Eight published C. difficile genomes have been aligned to produce a detailed database of indels of the ITS1's from the rrn operon sets. An iPad Filemaker Go App has been constructed and named RiboTyping (RT). It contains detail such as sequences, ribotypes, strain numbers, GenBank numbers and genome position numbers. Access to various levels of the database is provided so that details can be printed. There are three main regions of the rrn operon that have been analysed by the database and related to each other by strain, ribotype and operon: (1) 16S gene (2) ITS1 indels (3) 23S gene. This has enabled direct intra- and inter-genomic comparisons at the strain, ribotype and operon (allele) levels in each of the three genomic regions. This is the first time that such an analysis has been done. By using the RT App with search criteria it will be possible to select probe combinations for specific strains/ribotypes/rrn operons for experiments to do with diagnostics, typing and recombination of operons. Many more incomplete C. difficile whole genome sequencing projects are recorded in GenBank as underway and the rrn operon information from these can also be added to the RT App when available. The RT App will help simplify probe selection because of the complexity of the ITS1 in C. difficile even in a single genome and because other allele-specific regions (16S and 23S genes) of variability can be relationally compared to design extra probes to increase sensitivity. PMID- 24050949 TI - Genotyping of outbreak-associated and sporadic Yersinia pseudotuberculosis strains by novel multilocus variable-number tandem repeat analysis (MLVA). AB - Yersinia pseudotuberculosis human infections caused by serotype O:1 and O:3 isolates have been common in Finland and have also caused outbreaks. Epidemiological studies on the outbreaks have been limited by the lack of accurate typing methods. During the recent years, multilocus variable-number tandem repeat analysis (MLVA) has been successfully applied for molecular typing of several bacterial pathogens. We designed an MLVA scheme based on seven loci for Y. pseudotuberculosis. The method was able to discriminate clinical isolates of serotypes O:1 and O:3 into several MLVA types. The MLVA profiles were based on the number of 6 to 9 bp long tandem repeats in each locus. The number of repeats varied from 1 to 23 depending on the locus. The loci were all located in the bacterial chromosome for stability of the markers. The MLVA method developed was serotype-specific and will be a new additional tool for the epidemiological investigations of isolates associated with disease outbreaks and for comparison of sporadic isolates. PMID- 24050950 TI - Agrobacterium-mediated transformation of the white-rot fungus Physisporinus vitreus. AB - The biotechnologically important white-rot fungus Physisporinus vitreus was co cultivated with Agrobacterium tumefaciens AGL-1 carrying plasmids with nourseothricin resistance as the selectable marker gene and red fluorescence protein as a visual marker. Mitotically stable transformed isolates were obtained showing red fluorescence protein activity. PMID- 24050951 TI - Does a trochanteric lag screw improve fixation of vertically oriented femoral neck fractures? A biomechanical analysis in cadaveric bone. AB - BACKGROUND: We assessed the biomechanical performances of a trochanteric lag screw construct and a traditional inverted triangle construct in the treatment of simulated Pauwels type 3 femoral neck fractures. METHODS: An inverted triangle construct (three 7.3-mm cannulated screws placed in inverted triangle orientation) and a trochanteric lag screw construct (two 7.3-mm cannulated screws placed across the superior portion of the femoral neck and one 4.5-mm lag screw placed perpendicular to the fracture in superolateral to inferomedial orientation) were tested in nine matched pairs of non-osteoporotic human cadaveric femora. We used a previously described vertically oriented femoral neck fracture model and testing protocol that incrementally loaded the constructs along the mechanical axis of the femur to 1400 N. Specimens that survived incremental loading underwent cyclic loading. Apparent construct stiffness, force at 3mm of displacement, and survival of incremental loading were recorded. FINDINGS: The trochanteric lag screw group had a 70% increase in stiffness (261 N/mm [29 standard deviation] versus 153 N/mm [16 standard deviation]; P=0.026) and a 43% increase in force required for displacement (620 N versus 435 N; P=0.018) compared with the inverted triangle group. One trochanteric lag screw and no inverted triangle specimen survived incremental loading. INTERPRETATION: A trochanteric lag screw construct applied to vertically oriented femoral neck fractures provides marked improvement in mechanical performance compared with the inverted triangle construct. PMID- 24050952 TI - Inertial sensing algorithms for long-term foot angle monitoring for assessment of idiopathic toe-walking. AB - When children walk on their toes for no known reason, the condition is called Idiopathic Toe Walking (ITW). Assessing the true severity of ITW can be difficult because children can alter their gait while under observation in clinic. The ability to monitor the foot angle during daily life outside of clinic may improve the assessment of ITW. A foot-worn, battery-powered inertial sensing device has been designed to monitor patients' foot angle during daily activities. The monitor includes a 3-axis accelerometer, 2-axis gyroscope, and a low-power microcontroller. The device is necessarily small, with limited battery capacity and processing power. Therefore a high-accuracy but low-complexity inertial sensing algorithm is needed. This paper compares several low-complexity algorithms' aptitude for foot-angle measurement: accelerometer-only measurement, finite impulse response (FIR) and infinite impulse response (IIR) complementary filtering, and a new dynamic predict-correct style algorithm developed using fuzzy c-means clustering. A total of 11 subjects each walked 20 m with the inertial sensing device fixed to one foot; 10 m with normal gait and 10 m simulating toe walking. A cross-validation scheme was used to obtain a low-bias estimate of each algorithm's angle measurement accuracy. The new predict-correct algorithm achieved the lowest angle measurement error: <5 degrees mean error during normal and toe walking. The IIR complementary filtering algorithm achieved almost-as good accuracy with less computational complexity. These two algorithms seem to have good aptitude for the foot-angle measurement problem, and would be good candidates for use in a long-term monitoring device for toe-walking assessment. PMID- 24050954 TI - Gastrointestinal carcinoid: epidemiological and survival evidence from a large population-based study (n = 25 531). AB - BACKGROUND: Owing to its rarity, the published evidence on gastrointestinal (GI) carcinoid is often based on small series of patients or population-based studies regarding all neuroendocrine tumors. Here, we present a comprehensive epidemiological and survival analysis of the largest cohort of patients with GI carcinoid ever reported. PATIENTS AND METHODS: Patients with histological diagnosis of GI carcinoid (n = 25 531) were identified from the Surveillance Epidemiology End Results (SEER) database (including 18 USA cancer registries and spanning the 1973-2009 time frame). Demographic and disease data were used for epidemiological and survival analyses. RESULTS: The incidence of GI carcinoid is steadily increasing over the past three decades at a rate higher than any other cancer [annual percentage change (APC) = 4.4, 95% confidence interval (CI) 4.0 4.8]. These patients have a higher risk of further primary tumor (standardized incidence ratio, SIR = 1.15, 95% CI 1.10-1.21), but also a reduced risk of skin melanoma (SIR = 0.64, 95% CI 0.41-0.95). Despite the overall favorable prognosis (5-year disease-specific and relative survival rate: 91.3% and 87.4%, respectively), the mortality rate is increasing over time (APC = 3.5, 95% CI 3.0 4.0) and the 5-year survival rate of patients dying of GI carcinoid (28.5%), though better than that reported for GI cancers in general (8.4%), cannot be considered satisfactory. Finally, a nomogram is provided to predict patient survival on the basis of clinico-pathological factors independently associated with prognosis at multivariate analysis. CONCLUSIONS: These findings can be clinically useful for the management of patients with GI carcinoid and eagerly prompt the continuous effort to develop more effective therapeutic strategies against this slow-growing but chemoresistant tumor. PMID- 24050953 TI - A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes. AB - BACKGROUND: This phase II study investigated the efficacy and safety of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in locally advanced or metastatic thyroid cancer. PATIENTS AND METHODS: Patients with thyroid cancer of any histology that was resistant or not appropriate for (131)I received everolimus 10 mg daily orally until unacceptable toxicity or disease progression. The primary end point was disease control rate [partial response (PR) + stable response >=12 weeks]. Secondary end points included response rates, clinical benefit (PD + durable stable disease (SD)], progression-free survival (PFS), overall survival, duration of response, and safety. RESULTS: Thirty-eight of 40 enrolled patients were evaluable for efficacy. The disease control rate was 81% and two (5%) patients achieved objective response; their duration of response was 21+ and 24+ weeks. Stable disease (SD) and progressive disease was reported in 76% and 17% of patients, respectively. Seventeen (45%) patients showed durable SD (>=24 weeks) and clinical benefit was reported in 19 (50%) patients. Median PFS was 47 weeks [95% confidence interval (CI) 14.9-78.5]. Calcitonin, CEA, and thyroglobulin concentrations were >=50% lower than baseline in three (30%) and four (44%) patients with medullary thyroid cancer and five (33%) patients with PTC, respectively. The most common treatment-related adverse events were mucositis (84%), anorexia (44%), and aspartate transaminase/alanine transaminase elevation (26%). CONCLUSIONS: Everolimus had a limited activity with low response rate in locally advanced or metastatic thyroid cancer. Reasonable clinical benefit rate and safety profile may warrant further investigation. CLINICALTRIALSGOV NUMBER: NCT01164176. PMID- 24050955 TI - beta-Blocker usage and colorectal cancer mortality: a nested case-control study in the UK Clinical Practice Research Datalink cohort. AB - BACKGROUND: Epidemiological and laboratory studies suggest that beta-blockers may reduce cancer progression in various cancer sites. The aim of this study was to conduct the first epidemiological investigation of the effect of post-diagnostic beta-blocker usage on colorectal cancer-specific mortality in a large population based colorectal cancer patient cohort. PATIENTS AND METHODS: A nested case control analysis was conducted within a cohort of 4794 colorectal cancer patients diagnosed between 1998 and 2007. Patients were identified from the UK Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with a colorectal cancer- specific death (data from the Office of National Statistics death registration system) were matched to five controls. Conditional logistic regression was applied to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) according to beta-blocker usage (data from GP-prescribing records). RESULTS: Post-diagnostic beta-blocker use was identified in 21.4% of 1559 colorectal cancer-specific deaths and 23.7% of their 7531 matched controls, with little evidence of an association (OR = 0.89 95% CI 0.78-1.02). Similar associations were found when analysing drug frequency, beta-blocker type or specific drugs such as propranolol. There was some evidence of a weak reduction in all-cause mortality in beta-blocker users (adjusted OR = 0.88; 95% CI 0.77 1.00; P = 0.04) which was in part due to the marked effect of atenolol on cardiovascular mortality (adjusted OR = 0.62; 95% CI 0.40-0.97; P = 0.04). CONCLUSIONS: In this novel, large UK population-based cohort of colorectal cancer patients, there was no evidence of an association between post-diagnostic beta blocker use and colorectal cancer-specific mortality. CLINICAL TRIALS NUMBER: NCT00888797. PMID- 24050957 TI - Spectrophotometric determination of hydrogen peroxide with osmium(VIII) and m carboxyphenylfluorone. AB - Spectrophotometric determination of hydrogen peroxide was accomplished with osmium(VIII) and m-carboxyphenylfluorone (MCPF) in the presence of cetyltrimethylammonium chloride (CTAC). In the determination of hydrogen peroxide based on the fading of the color of osmium(VIII)-MCPF complex, Beer's law was obeyed in the range 20-406 ng mL(-1), with an effective molar absorption coefficient (at 580 nm) of 5.21*10(4) L mol(-1) cm(-1) and a relative standard deviation of 0.33% (n=6). Further, we performed the characterization of MCPF and obtained the crystal structure. PMID- 24050958 TI - Topographic Distribution of Papillary Thyroid Carcinoma by Mapping in Coronal Sections of 125 Consecutive Thyroidectomy Specimens. AB - INTRODUCTION: Mapping of different foci in multifocal papillary thyroid carcinoma (PTC) has previously not been done as it is difficult to do so when thyroid specimens are serially sectioned transversely (ie, parallel to the horizontal plane). In this study, thyroidectomy specimens were serially sectioned coronally (ie, parallel to the largest surface of the thyroid gland), which allows for panoramic and 3-dimensional visualization of PTC foci and their relationship to one another. MATERIALS AND METHODS: A total of 125 consecutive total thyroidectomies or lobectomies followed by completion thyroidectomies were serially sectioned coronally and reviewed with identification and characterization of PTC foci. PTCs were grouped into either discrete, encapsulated nodule(s) (EN) of both follicular or papillary architecture, usual variant (UV), or tall cell variant (TCV). RESULTS: The predominant tumor masses were identified in the right lobe, isthmus, and left lobe in 52%, 8%, and 40%, respectively. The largest tumor nodules ranged from 3 to 60 mm (18.8 +/- 6.6) with the UV, EN, and TCV groups accounting for 58%, 24%, and 18% of cases, respectively. Three topographic patterns of PTC can be distinguished as follows: (a) single tumor nodule (37 cases), (b) main tumor nodule with satellite nodule(s) displaying no or varying degrees of fusion with the main one (30 cases), and (c) main tumor nodule with either a second large nodule or randomly occurring tumor nodules (58 cases). Bilaterality can be seen in all 3 patterns but was most prevalent in the group comprising the main tumor nodule with either a second large nodule or random tumor nodules. It was least frequent in the EN group without random tumor nodules. The difference in rates of bilaterality between tumors <10 mm and >=10 mm was statistically significant (P < .01). For all 3 groups, satellite nodules displayed histopathological features that were similar or dissimilar to the main tumor mass. They may be of a different variant than that of the main tumor nodule. CONCLUSIONS: With panaromic and 3-dimensional visualization, individual tumors/satellite or random nodules of multifocal PTC were readily identified in serial coronal sections of thyroidectomy specimens. Bilaterality was frequently observed in tumors associated with random PTC foci, whereas, the EN group tended to be unilateral and was not associated with random foci. PMID- 24050959 TI - Localized Intrasplenic Mesothelioma: A Case Report. AB - Malignant mesothelioma is a primary neoplasm of the serosal membranes that usually presents with a diffuse pattern of growth. However, cases of localized mesotheliomas have been described. The predominant localization is the pleura; peritoneum and pericardium being rarer localizations. Only few cases of true intraparenchymal mesothelioma arising in organs such as liver, gonads, lung, and pancreas have been described. We report a case of an otherwise healthy 48-year old man without asbestos exposure with a nodule of 3 cm in diameter, localized in the spleen, discovered incidentally at the ultrasonographic examination, for which histopathological and immunohistochemical findings were consistent with epithelioid mesothelioma: large round cells with eosinophil dense cytoplasm and macronucleoli and with immunohistochemical positivity for pancytokeratins, calretinin, Wilms tumor-1, and others markers of mesothelial differentiation. The diagnosis of localized intrasplenic epithelioid malignant mesothelioma was carried out. To the best of our knowledge, this is the first case of a localized intrasplenic mesothelioma published in the indexed literature. PMID- 24050960 TI - Factors affecting community-agency trust before, during and after a wildfire: an Australian case study. AB - Trust has been identified as a critical relationship component in contexts of high uncertainty and complexity such as wildfire management, and as a primary factor in public support for wildland fire management strategies. However, little attention has been paid to identifying and comparing factors across fire management stages (i.e. before, during, after a fire) that may influence trust between community members and fire management agencies. This paper attempts to address this gap by exploring factors affecting community-agency trusting relationships before, during and after a wildfire event. We draw upon 26 semi structured interviews with 38 residents of a community directly impacted by fires in December 2006 and January 2007 in Victoria, Australia. Communication, cooperation, trustworthiness, and integration of local concerns and knowledge influenced trust in more than one fire management stage. Institutional structures and reduction of uncertainty were particularly strong influences during a fire. After a fire, resolving negative outcomes and immediately meeting perceived needs arising from the fire were factors unique to this stage. PMID- 24050956 TI - Talactoferrin alfa versus placebo in patients with refractory advanced non-small cell lung cancer (FORTIS-M trial). AB - BACKGROUND: Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: An FORTIS-M trial was an international, multicenter, randomized, double-blind comparison of talactoferrin (1.5 g p.o. BID) versus placebo BID, in patients with stage IIIB/IV NSCLC whose disease had failed two or more prior regimens. Treatment was administered for a maximum of five 14-week cycles. The primary efficacy end point was overall survival (OS); secondary end points included 6- and 12-month survival, progression-free survival (PFS), and disease control rate (DCR). RESULTS: Seven hundred and forty-two patients were randomly assigned (2:1) to talactoferrin (497) or placebo (245). The median OS in the intent-to-treat (ITT) population was 7.66 months in the placebo arm and 7.49 months in the talactoferrin arm [hazard ratio (HR), 1.04; 95% CI, 0.873-1.24; P = 0.6602]. The 6-month survival rates were 59.9% (95% CI, 53.4% to 65.8%) and 55.7% (95% CI, 51.1% to 59.9%), respectively. The 12-month survival rates were 32.2% (95% CI, 26.3% to 38.2%) and 30.9% (95% CI, 26.8% to 35%), respectively. The median PFS rates were 1.64 months and 1.68 months, respectively (HR, 0.99; 95% CI, 0.835 1.16; P = 0.8073). The DCRs were 38.4 and 37.6%, respectively [stratified odds ratio (OR), 0.96; 95% CI, 0.698-1.33; P = 0.8336]. The safety profiles were comparable between arms. CONCLUSIONS: There was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens. PMID- 24050961 TI - Intercellular transfer of tau aggregates and spreading of tau pathology: Implications for therapeutic strategies. AB - Filaments made of hyperphosphorylated tau protein are encountered in a group of neurodegenerative disorders termed tauopathies. The most prevalent tauopathy, Alzheimer's disease (AD), additionally presents with extracellular deposits of the amyloid-beta peptide (Abeta). Current symptomatic treatments have shown short term benefits in reducing cognitive symptoms as well as behavioral abnormalities in patients with mild to moderate AD but there is still no effective treatment to prevent or reverse AD. For decades, the amyloid cascade hypothesis of AD dominated basic research and focused pharmaceutical interest on Abeta. However, the existence of tauopathies that are devoid of Abeta deposits, together with the discovery of mutations in the tau gene leading to frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17T), confirmed the importance of tau per se in disease. Tau became an interesting disease target in its own right. We will review here recent research on cell-to-cell propagation of tau pathology, which we believe to be central to disease progression, and discuss tau immunotherapy in the light of these findings. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'. PMID- 24050962 TI - Activation but not blockade of GABAB receptors during early-life alters anxiety in adulthood in BALB/c mice. AB - Although the underlying pathophysiology of anxiety disorders is unknown it is clear that a combination of genetic and environmental factors in early life predispose to disease risk. Preclinical research increasingly suggests an important role for the GABAB receptor in modulating anxiety behaviour, with GABAB receptor deficient mice having increased anxiety behaviour. Previous studies have highlighted critical windows during development where adult anxiety behaviour is primed. However, little is known regarding the role played by the GABAB receptors in the developmental processes that underlie adult anxiety behaviour. To this end, we treated male BALB/c mouse pups with the either the selective GABAB receptor agonist, R-baclofen (2 mg/kg, s.c), the GABAB receptor antagonist CGP 52432 (10 mg/kg and 30 mg/kg) or vehicle from postnatal days (P) 14-28. The anxiety behaviour of these mice was then assessed in adulthood (P62 onwards) in a battery of behavioural tests comprising; the stress induced hyperthermia (SIH) test, defensive marble burying (DMB), elevated-plus maze (EPM) and the forced swim test (FST). Postnatal R-baclofen treatment resulted in increased anxiety like behaviour in the EPM as shown by approach-avoidance and ethological measures. Other behavioural measures were not significantly altered. Interestingly, blockade of GABAB receptors with CGP52432 in early life caused no alterations in emotional behaviour. These data suggest that during early life GABAB receptor signalling can play a functional role in programing anxiety behaviour in adulthood. The underlying neurodevelopmental processes underlying these effects remain to be discovered. PMID- 24050963 TI - Implications of epigenetic modulation for novel treatment approaches in patients with schizophrenia. AB - Schizophrenia is a heterogeneous and complex mental disorder with high rates of disability, non-recovery, and relapse. The primary pharmacological treatments for schizophrenia are antipsychotics. Notwithstanding the efficacy of antipsychotics in ameliorating positive symptoms and reducing relapse rates, cognitive deficits and negative symptoms are not sufficiently treated with available pharmaceutical agents. Moreover, schizophrenia is associated with consistent, replicable, and clinically significant deficits in cognition. The importance of cognitive deficits in schizophrenia is emphasized by reports indicating that the severity of cognitive deficits is predictive of treatment compliance, adherence, and risk of relapse among first-episode individuals. Taken together, this review highlights epigenetic modulations involving histone deacetylase (HDAC) inhibitors as a potential avenue for novel treatment toward improvements in cognition and functional outcomes in patients with schizophrenia. The combination of epigenetic modulation with pharmacological interventions that engage multiple disparate physiological systems implicated in schizophrenia are discussed, and may represent a more effective strategy in ameliorating cognitive deficits and mitigating symptoms for improved functionality. PMID- 24050964 TI - Health care experiences of HIV-infected women with fertility desires in Mexico: a qualitative study. AB - Increased access to antiretroviral therapy has enabled Mexican HIV-infected women to resume healthy sexual and reproductive lives and reduce the risk of mother-to child transmission of HIV infection. However, little information is available on the experiences of HIV-infected women desiring children. In this qualitative study, we conducted in-depth interviews with 31 HIV-infected women in four Mexican cities. The findings indicated that most of the women were given limited information on their pregnancy options. With some exceptions, the women felt they were denied the option to have (or to have more) children and advised to undergo tubal ligations or abortions. The findings of this study indicate that ongoing efforts are needed to promote the reproductive rights of HIV-infected women in Mexico and to ensure that they receive options aligned with their fertility desires. PMID- 24050965 TI - Evidence for cardiac safety and antiarrhythmic potential of chloroquine in systemic lupus erythematosus. AB - AIMS: To perform a comprehensive evaluation of heart rhythm disorders and the influence of disease/therapy factors in a large systemic lupus erythematosus (SLE) cohort. METHODS AND RESULTS: Three hundred and seventeen consecutive patients of an ongoing electronic database protocol were evaluated by resting electrocardiogram and 142 were randomly selected for 24 h Holter monitoring for arrhythmia and conduction disturbances. The mean age was 40.2 +/- 12.1 years and disease duration was 11.4 +/- 8.1 years. Chloroquine (CQ) therapy was identified in 69.7% with a mean use of 8.5 +/- 6.7 years. Electrocardiogram abnormalities were detected in 66 patients (20.8%): prolonged QTc/QTd (14.2%); bundle-branch block (2.5%); and atrioventricular block (AVB) (1.6%). Age was associated with AVB (P = 0.029) and prolonged QTc/QTd (P = 0.039) whereas anti-Ro/SS-A and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were not (P > 0.05). Chloroquine was negatively associated with AVB (P = 0.01) as was its longer use (6.1 +/- 6.9 vs. 1.0 +/- 2.5 years, P = 0.018). Time of CQ use was related with the absence of AVB [odds ratio (OR) = 0.103; 95% confidence interval (CI) = 0.011-0.934, P = 0.043] in multiple logistic regression. Holter monitoring revealed abnormalities in 121 patients (85.2%): supraventricular ectopies (63.4%) and tachyarrhythmia (18.3%); ventricular ectopies (45.8%). Atrial tachycardia/fibrillation (AT/AF) were associated with shorter CQ duration (7.05 +/- 7.99 vs. 3.63 +/- 5.02 years, P = 0.043) with a trend to less CQ use (P = 0.054), and older age (P < 0.001). Predictors of AT/AF in multiple logistic regression were age (OR = 1.115; 95% CI = 1.059-1.174, P < 0.001) and anti-Ro/SS A (OR = 0.172; 95% CI = 0.047-0.629, P = 0.008). CONCLUSIONS: Chloroquine seems to play a protective role in the unexpected high rate of cardiac arrhythmias and conduction disturbances observed in SLE. Further studies are necessary to determine if this antiarrhythmic effect is due to the disease control or a direct effect of the drug. PMID- 24050966 TI - Improving sodium dodecyl sulfate polyacrylamide gel electrophoresis detection of low-abundance protein samples by rapid freeze centrifugation. AB - This work presents a rapid and simple freeze centrifugation method to concentrate dilute protein solutions for detection by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) Coomassie blue staining. Moreover, a simple way to assemble a cryoconcentration device is presented, and its use is discussed. Commercial purified protein standard and an enzyme with high fructosyltransferase (FTase) activity, coming from target fractions obtained by chromatographic separation, were used as an example. FTase, coming directly from the chromatographic fractions, was difficult to view through SDS-PAGE analysis; however, it was easily visualized, and its activity was enhanced, after the application of the freeze centrifugation protocol presented here. PMID- 24050967 TI - Simultaneous quantification of total and conjugated ubiquitin levels in a single immunoblot. AB - Ubiquitin (Ub) is a posttranslational modifier, and total Ub (UbT) is always in dynamic equilibrium among free Ub (UbF), activated Ub (UbA), and conjugated Ub (UbC) in the forms of mono-Ub, thioester-bond-linked Ub, and peptide-bond-linked Ub, respectively. In this study, we developed a simple method to simultaneously determine the levels of UbT, UbF+UbA, and UbC in a single immunoblot and demonstrated its reliability and reproducibility by determining [UbT], [UbF+UbA], and [UbC] in various mouse tissues and cultured cells. PMID- 24050968 TI - Direct detection of rutin-degrading isozymes with polyacrylamide gel electrophoresis. AB - Rutin-degrading enzymes (RDEs) specifically hydrolyze the glycosidic linkages of rutin, producing quercetin and rutinose. Here we report a reliable and sensitive polyacrylamide gel electrophoresis and staining method for the detection of RDE isozymes, which is based on the aqueous solubility difference between rutin and quercetin, as well as the ultraviolet absorbance of quercetin. With this novel method, we achieved a detection limit of 12 ng with 107 U of RDE activity, enabling us to detect at least five RDE isozymes in tartary buckwheat seeds. PMID- 24050969 TI - Single universal primer multiplex ligation-dependent probe amplification with sequencing gel electrophoresis analysis. AB - In this study, a novel single universal primer multiplex ligation-dependent probe amplification (SUP-MLPA) technique that uses only one universal primer to perform multiplex polymerase chain reaction (PCR) was developed. Two reversely complementary common sequences were designed on the 5' or 3' end of the ligation probes (LPs), which allowed the ligation products to be amplified through only a single universal primer (SUP). SUP-MLPA products were analyzed on sequencing gel electrophoresis with extraordinary resolution. This method avoided the high expenses associated with capillary electrophoresis, which was the commonly used detection instrument. In comparison with conventional multiplex PCR, which suffers from low sensitivity, nonspecificity, and amplification disparity, SUP MLPA had higher specificity and sensitivity and a low detection limit of 0.1 ng for detecting single crop species when screening the presence of genetically modified crops. We also studied the effect of different lengths of stuffer sequences on the probes for the first time. Through comparing the results of quantitative PCR, the LPs with different stuffer sequences did not affect the ligation efficiency, which further increased the multiplicity of this assay. The improved SUP-MLPA and sequencing gel electrophoresis method will be useful for food and animal feed identification, bacterial detection, and verification of genetic modification status of crops. PMID- 24050970 TI - Pharmacokinetic interactions between eperisone hydrochloride and aceclofenac: a randomized, open-label, crossover study of healthy Korean men. AB - BACKGROUND: Eperisone hydrochloride, a centrally acting muscle relaxant, is a calcium antagonist that causes vasodilation and antispastic actions. Aceclofenac, an anti-inflammatory analgesic and antipyretic drug, has similar efficacy and improved gastrointestinal tolerance compared with other nonsteroidal anti inflammatory drugs, such as diclofenac. Although eperisone hydrochloride and aceclofenac are frequently coadministered, no published studies have reported on the pharmacokinetic interactions between these 2 drugs. OBJECTIVE: The aim of this study was to investigate any pharmacokinetic interactions between eperisone hydrochloride and aceclofenac in healthy Korean men. METHODS: This was a randomized, open-label, crossover study. Each participant was randomly assigned to 1 of 6 treatment sequences and received eperisone hydrochloride (3 doses of 50 mg each), aceclofenac (2 doses of 100 mg each), or both as a single dose with a 7 day washout period between each dose. Blood samples were collected <= 24 hours after dosing, and plasma eperisone hydrochloride and aceclofenac concentrations were determined using validated LC/MS-MS. Pharmacokinetic analyses were conducted using noncompartmental methods. A safety profile was determined using the measurement of vital signs, ECG, and clinical laboratory tests. RESULTS: A total 24 of men were enrolled, and all completed the study. The geometric mean ratios (90% CIs) of the Cmax and AUC0-infinity values for eperisone were 1.18 (0.828 1.673) and 1.12 (0.836-1.507), respectively. The geometric mean ratios (90% CIs) of the Cmax and AUC0-infinity for aceclofenac were 0.93 (0.847-1.022) and 1.01 (0.979-1.036), respectively. A total of 7 adverse events were reported in 7 men. All adverse events were mild, and no significant differences were found between treatment groups. CONCLUSION: No clinically significant pharmacokinetic differences exist between 150 mg eperisone hydrochloride and 200 mg aceclofenac when administrated as a monotherapy or in combination. PMID- 24050971 TI - The role of NREM sleep micro-arousals in absence epilepsy and in nocturnal frontal lobe epilepsy. AB - The article summarises the role of input and consequent phasic events in the dynamism of non-rapid eye movement (NREM) sleep and in homeostatic slow-wave economy during sleep. Then, an overview of the mechanism of how micro-arousals in NREM sleep gate epileptic events in absence epilepsy (AE) and in sporadic and autosomal dominant nocturnal frontal lobe epilepsy (NFLE/ADNFLE) is presented. The ictal type of generalised spike-wave discharges (SWDs) are associated with a special vigilance level in between NREM, rapid-eye movement (REM) and wake state. This transitional state is characterised by input-driven bidirectional fluctuations. Among them, SWDs are linked to A1 type A phases of CAP and therefore seem to be associated with shifts towards NREM sleep (sleep induction). In ADNFLE (and presumably in NFLE), micro-arousals release epileptic events in NREM sleep probably due to epileptic sensitisation of the cholinergic arousal system by the known acetylcholine (ACh) receptor mutations affecting the arousal system, giving rise to the epileptic (and also parasomniac) episodes. In both kinds of these system epilepsies (AE and NFLE), epileptic events can be released by phasic events during NREM sleep. The difference is that absences are activated in reactive states with a sleep-promoting, antiarousal effect, while in NFLE the epileptic disorder is interwoven with the cholinergic arousal function. The role of arousal/antiarousal in NFLE and AE fits nicely with the hypothesis that these epilepsies are disorders of two antagonistic thalamo-frontal systems involved in functions NREM sleep and wakefulness. PMID- 24050972 TI - Evaluation of cerebral white-matter micro-structural alterations in patients with medically refractory epilepsy using diffusion tensor tractography. AB - INTRODUCTION: Diffusion tensor tractography (DTT) is a newer magnetic resonance imaging (MRI) technique that helps in evaluation of white matter. Presurgical planning with tractography may be valuable for evaluation of white matter tracts and their relationship with epileptogenic focus and for evaluation of cortical fibres around the epileptogenic zone. METHODS: This study was carried out on 33 patients diagnosed with medically refractory epilepsy (males, 27; females, 6) with a mean age of 31.93 (range: 19-50) years. Twenty age and sex matched controls were also included. DTT evaluation was done using a 3.0 TexlaMRI scanner. Single-shot spin-echo echo-planar imaging (with 32-different diffusion gradient directions) was acquired for reconstruction of the white matter tracts. Diffusion metrics within fibre bundles that were reconstructed by a continuous fibre-track algorithm were compared between groups. RESULTS: Patients had either partial seizures (21 patients; simple partial, complex partial or secondarily generalized seizure) or generalized seizures (12 patients; tonic clonic, tonic or myoclonic). Out of the 33 patients, 23 patients were classified into the lesional group and the rest into the non-lesional group. The lesions observed on conventional MRI included focal gliosis, hippocampal sclerosis, post-hypoxic encephalopathy, calcification and post-traumatic cavitation, in various parts of the brain. Significant differences were observed in terms of fractional anisotropy and mean diffusivity values amongst controls and patients, as well as on the lesional and non-lesional side of the brain; patients with a normal conventional imaging showed fractional anisotropy and mean diffusivity changes as well. CONCLUSION: We conclude that widespread diffusion abnormalities occur in the white matter tracts on the side of lesion as well as distant from the epileptic focus. PMID- 24050973 TI - Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: new set of data for predictive in silico ADME models. AB - In silico approaches to predict absorption, distribution, metabolism and excretion (ADME) of new drug candidates are gaining a relevant importance in drug discovery programmes. When considering particularly the pharmacokinetics during the development of oral antiepileptic drugs (AEDs), one of the most prominent goals is designing compounds with good bioavailability and brain penetration. Thus, it is expected that in silico models able to predict these features may be applied during the early stages of AEDs discovery. The present investigation was mainly carried out in order to generate in vivo pharmacokinetic data that can be utilized for development and validation of in silico models. For this purpose, a single dose of each compound (1.4mmol/kg) was orally administered to male CD-1 mice. After quantifying the parent compound and main metabolites in plasma and brain up to 12h post-dosing, a non-compartmental pharmacokinetic analysis was performed and the corresponding brain/plasma ratios were calculated. Moreover the plasma protein binding was estimated in vitro applying the ultrafiltration procedure. The present in vivo pharmacokinetic characterization of the test compounds and corresponding metabolites demonstrated that the metabolism extensively compromised the in vivo activity of CBZ derivatives and their toxicity. Furthermore, it was clearly evidenced that the time to reach maximum peak concentration, bioavailability (given by the area under the curve) and metabolic stability (given by the AUC0-12h ratio of the parent compound and total systemic drug) influenced the in vivo pharmacological activities and must be considered as primary parameters to be investigated. All the test compounds presented brain/plasma ratios lower than 1.0, suggesting that the blood-brain barrier restricts drug entry into the brain. In agreement with in vitro studies already performed within our research group, CBZ, CBZ-10,11-epoxide and oxcarbazepine exhibited the highest brain/plasma ratios (>0.50), followed by eslicarbazepine, R-licarbazepine, trans-diol and BIA 2-024 (ratios within 0.05 0.50). BIA 2-265 was not found in the biophase, probably due to its high plasma protein bound fraction (>90%) herein revealed for the first time. The comparative in vivo pharmacokinetic data obtained in the present work might be usefully applied in the context of discovery of new antiepileptic drugs that are derivatives of CBZ. PMID- 24050974 TI - Noninvasive screening for preclinical atherosclerosis in children on phenytoin or carbamazepine monotherapy: a cross sectional study. AB - PURPOSE: This study was carried out to compare the carotid Intimal Media Thickness (IMT), and endothelial function using brachial flow mediated dilatation (FMD), in Epileptic children (6-12 years) on phenytoin (PHT) or carbamazepine (CBZ) monotherapy for >=18 months with a control group of children. METHODS: In this cross-sectional study 30 children (aged 6-12 years) on PHT monotherapy and 28 children on CBZ monotherapy were compared with an equal number of apparently healthy age and sex matched children unexposed to antiepileptics. Fasting lipids, sugar, Hs-CRP levels and ultrasonographic assessment of carotid IMT and endothelial function using brachial FMD were conducted. RESULTS: The age (years) of the children in the CBZ group (9.1+/-2), PHT group (9.4+/-2) and the controls (9.3+/-2) was comparable. The duration of CBZ therapy was 30.8+/-13.2 months and that of PHT therapy was 29.5+/-13.6 months. The mean dose of CBZ was 18.18+/ 8.5mg/kg and that of PHT was 5.5+/-2.3mg/kg body weight. The time since last seizure was 15.6+/-8.4 months in the CBZ group and 17.3+/-10.4 months in the PHT group. The fasting blood sugar was below 110mg/dl in all children. The height, weight, waist and hip measurements, waist hip ratio and blood pressures were similar in the groups. The total cholesterol levels (161.7+/-24.8 vs 140.2+/ 20.8mg/dl, p=0.001), HDL (53.8+/-10.5 vs 47.1+/-8.8mg/dl, p=0.017) and LDL (85+/ 21.1 vs 70.9+/-19.4mg/dl, p=0.01) were significantly higher in the CBZ group compared to the control group. The HDL levels (54.6+/-9.4 vs 45.8+/-7.7mg/dl, p<0.0001) were significantly higher in the PHT group compared to the control group. The right carotid (0.374+/-0.04 vs 0.339+/-0.05mm, p=0.012), left carotid (0.382+/-0.05 vs 0.351+/-0.05mm, p=0.044) and the overall average carotid intima media thickness (0.378+/-.048 vs 0.345+/-.052mm, p=0.018) of the children on CBZ was significantly higher than the carotid IMT in control group children. The right carotid (0.370+/-0.04 vs 0.342+/-0.05mm, p=0.032) and the overall average carotid IMT (0.374+/-0.04 vs 0.348+/-0.05mm, p=0.035) of the children on PHT was significantly higher than the carotid IMT in controls. The FMD were comparable in the children on CBZ or PHT and the control group. CONCLUSIONS: The results are preliminary but could signal the increased vulnerability of epileptic children on long term antiepileptics to have subclinical atherosclerosis. PMID- 24050975 TI - Withdrawal of antiepileptic drugs improves psychomotor speed after childhood epilepsy surgery. AB - This retrospective study evaluates the impact of postoperative antiepileptic drug (AED) withdrawal on psychomotor speed in seizure-free children, operated for medically refractory epilepsy. Post-surgical medication policy and neuropsychological assessments (performed shortly before and 6, 12 and 24 months after surgery), were evaluated in 57 children (32 female, median age at surgery 13 years). Patients were divided into a withdrawal (n=29) and a no-withdrawal group (n=28). Scores of four psychomotor tests performed at 12 and 24 months after surgery were compared with those of postoperative baseline measurements, performed 6 months after surgery. At 24 months, the withdrawal group had improved significantly more than the no-withdrawal group on three of four tests; reaction time to light (p=0.031), reaction time to sound (p=0.045) and tapping (p=0.003). At 12 months, a non-significant tendency in the same direction was found for both reaction time tests. Drug withdrawal after surgery improves psychomotor speed and may unleash the potential for cognitive improvement. PMID- 24050976 TI - Re: burn care and the Liverpool care pathway. PMID- 24050977 TI - The potential impact of wrong TBSA estimations on fluid resuscitation in patients suffering from burns: things to keep in mind. AB - INTRODUCTION: Accurate estimation of burn size is of critical importance, as it is incorporated in every resuscitation formula. The aim of this study was to investigate total burn surface area (TBSA) accuracy among burn specialists, evaluate the potential impact of incorrect evaluation on variations of resultant fluid resuscitation volumes and to discuss future possibilities to estimate or measure TBSA more precisely. METHODS: In a poll during two international burn meetings in 2010 and 2011 demonstrating three pictures of patients with different burn wound patterns and sizes we asked participants to estimate the total surface area burned in percentages. We then calculated resultant fluid volume differences based on established resuscitation formulas. RESULTS: In the polled 80 participants, the estimations for three patients demonstrated the following differences (DIF=MAX-MIN): for patient 1, 2 and 3 they were 22.5 (25-2.5), 16.5 (20-3.5) and 31.5 (40-8.5) %TBSA, respectively. Based on these differences we calculated the volume differences for patients 1,2 and 3, which were 1080ml (Cincinnati Formula), 5280ml (Parkland Formula) and 2016ml (Cincinnati Formula), respectively. CONCLUSIONS: The analysis showed high deviations of total body surface area among participants, also resulting in large variations of initial fluid resuscitation volumes. One option to address estimation variances is to perform more accurate assessments; also incorporating new technologies aiding to improve the quality of body surface estimations and related decisions. PMID- 24050978 TI - A systematic review on intra-abdominal pressure in severely burned patients. AB - OBJECTIVE: Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are complications that may occur in severely burned patients. Evidenced based medicine for these patients is in its early development. The aim of this study was to provide an overview of literature regarding IAH and ACS in severely burned patients. METHODS: A systematic search was performed in Cochrane Central Register of Controlled Trials, PubMed, Embase, Web of Science and CINAHL on October 1, 2012. These databases were searched on 'burn', 'intra-abdominal hypertension', 'abdominal compartment syndrome', synonyms and abbreviations. Studies reporting original data on mortality, abdominal decompression or abdominal pressure related complications were included. RESULTS: Fifty publications met the criteria, reporting 1616 patients. The prevalence of ACS and IAH in severely burned patients is 4.1-16.6% and 64.7-74.5%, respectively. The mean mortality rate for ACS in burn patients is 74.8%. The use of plasma and hypertonic lactated resuscitation may prevent IAH or ACS. Despite colloids decrease resuscitation volume needs, no benefit in preventing IAH was proven. Escharotomy, peritoneal catheter drainage, and decompression laparotomy are effective intra-abdominal pressure (IAP) diminishing treatments in burn patients. Markers for IAP-related organ damage might be superior to IAP measurement itself. CONCLUSION: ACS and IAH are frequently seen devastating complications in already severely injured burn patients. Prevention is challenging but can be achieved by improving fluid resuscitation strategies. Surgical decompression measures are effective and often unavoidable. Timing is essential since decompression should prevent progression to ACS rather than limit its effects. Prognosis of ACS remains poor, but options for care improvement are available in literature. PMID- 24050979 TI - Adult burn survivors' personal experiences of rehabilitation: an integrative review. AB - Burn rehabilitation is a lengthy process associated with physical and psychosocial problems. As a critical area in burn care, the aim was to systematically synthesise the literature focussing on personal perceptions and experiences of adult burn survivors' rehabilitation and to identify factors that influence their rehabilitation. Studies were identified through an electronic search using the databases: PubMed, CINAHL, EMBASE, Scopus, PsycINFO and Trove of peer reviewed research published between 2002 and 2012 limited to English language research with search terms developed to reflect burn rehabilitation. From the 378 papers identified, 14 research papers met the inclusion criteria. Across all studies, there were 184 participants conducted in eight different countries. The reported mean age was 41 years with a mean total body surface area (TBSA) burn of 34% and the length of stay ranging from one day to 68 months. Significant factors identified as influential in burn rehabilitation were the impact of support, coping and acceptance, the importance of work, physical changes and limitations. This review suggests there is a necessity for appropriate knowledge and education based programmes for burn survivors with consideration given to the timing and delivery of education to facilitate the rehabilitation journey. PMID- 24050980 TI - Effect of phytoestrogens on basal and GnRH-induced gonadotropin secretion. AB - Plant-derived estrogens (phytoestrogens, PEs), like endogenous estrogens, affect a diverse array of tissues, including the bone, uterus, mammary gland, and components of the neural and cardiovascular systems. We hypothesized that PEs act directly at pituitary loci to attenuate basal FSH secretion and increase gonadotrope sensitivity to GnRH. To examine the effect of PEs on basal secretion and total production of FSH, ovine pituitary cells were incubated with PEs for 48 h. Conditioned media and cell extract were collected and assayed for FSH. Estradiol (E2) and some PEs significantly decreased basal secretion of FSH. The most potent PEs in this regard were coumestrol (CM), zearalenone (ZR), and genistein (GN). The specificity of PE-induced suppression of basal FSH was indicated by the absence of suppression in cells coincubated with PEs and an estrogen receptor (ER) blocker (ICI 182 780; ICI). Secretion of LH during stimulation by a GnRH agonist (GnRH-A) was used as a measure of gonadotrope responsiveness. Incubation of cells for 12 h with E2, CM, ZR, GN, or daidzein (DZ) enhanced the magnitude and sensitivity of LH secretion during subsequent exposure to graded levels of a GnRH-A. The E2- and PE-dependent augmentation of gonadotrope responsiveness was nearly fully blocked during coincubation with ICI. Collectively, these data demonstrate that selected PEs (CM, ZR, and GN), like E2, decrease basal secretion of FSH, reduce total FSH production, and enhance GnRH-A induced LH secretion in a manner that is dependent on the ER. PMID- 24050981 TI - Is variation management included in regional healthcare governance systems? Some proposals from Italy. AB - The Italian National Health System, which follows a Beveridge model, provides universal healthcare coverage through general taxation. Universal coverage provides uniform healthcare access to citizens and is the characteristic usually considered the added value of a welfare system financed by tax revenues. Nonetheless, wide differences in practice patterns, health outcomes and regional usages of resources that cannot be justified by differences in patient needs have been demonstrated to exist. Beginning with the experience of the health care system of the Tuscany region (Italy), this study describes the first steps of a long-term approach to proactively address the issue of geographic variation in healthcare. In particular, the study highlights how the unwarranted variation management has been addressed in a region with a high degree of managerial control over the delivery of health care and a consolidated performance evaluation system, by first, considering it a high priority objective and then by actively integrating it into the regional planning and control mechanism. The implications of this study can be useful to policy makers, professionals and managers, and will contribute to the understanding of how the management of variation can be implemented with performance measurements and financial incentives. PMID- 24050982 TI - Interventions to reduce urinary catheter use: it worked for them, but will it work for us? PMID- 24050983 TI - Making improvement interventions happen--the work before the work: four leaders speak. PMID- 24050984 TI - Diagnosis and diagnostic errors: time for a new paradigm. PMID- 24050985 TI - Improving patient waiting times: a simulation study of an obesity care service. AB - BACKGROUND: Obesity care services are often faced with the need to adapt their resources to rising levels of demand. The main focus of this study was to help prioritise planned investments in new capacity allowing the service to improve patient experience and meet future anticipated demand. METHODS: We developed computer models of patient flows in an obesity service in an Academic Health Science Centre that provides lifestyle, pharmacotherapy and surgery treatment options for the UK's National Health Service. Using these models we experiment with different scenarios to investigate the likely impact of alternative resource configurations on patient waiting times. RESULTS: Simulation results show that the timing and combination of adding extra resources (eg, surgeons and physicians) to the service are important. For example, increasing the capacity of the pharmacotherapy clinics equivalent to adding one physician reduced the relevant waiting list size and waiting times, but it then led to increased waiting times for surgical patients. Better service levels were achieved when the service operates with the resource capacity of two physicians and three surgeons. The results obtained from this study had an impact on the planning and organisation of the obesity service. CONCLUSIONS: Resource configuration combined with demand management (reduction in referral rates) along the care service can help improve patient waiting time targets for obesity services, such as the 18 week target of UK's National Health Service. The use of simulation models can help stakeholders understand the interconnectedness of the multiple microsystems (eg, clinics) comprising a complex clinical service for the same patient population, therefore, making stakeholders aware of the likely impact of resourcing decisions on the different microsystems. PMID- 24050986 TI - Characterising the complexity of medication safety using a human factors approach: an observational study in two intensive care units. AB - OBJECTIVE: To examine medication safety in two intensive care units (ICU), and to assess the complexity of medication errors and adverse drug events (ADE) in ICUs across the stages of the medication-management process. METHODS: Four trained nurse data collectors gathered data on medication errors and ADEs between October 2006 and March 2007. Patient care documents (eg, medication order sheets, notes) and incident reports were used to identify medication errors and ADEs in a 24-bed adult medical/surgical ICU and an 18-bed cardiac ICU in a tertiary care, community teaching hospital. In this cross-sectional study, a total of 630 consecutive ICU patient admissions were assessed to produce data on the number, rates and types of potential and preventable ADEs across stages of the medication management process. RESULTS: An average of 2.9 preventable or potential ADEs occurred in each admission, that is, 0.4 events per patient-day. Preventable or potential ADEs occurred in 2.6% of the medication orders. The rate of potential ADEs per 1000 patient-days was 276, whereas the rate of preventable ADEs per 1000 patient-days was 9.2. Most medication errors occur at the ordering (32%) and administration stages (39%). In 16-24% of potential and preventable ADEs, clusters of errors occurred either as a sequence of errors (eg, delay in medication dispensing leading to delay in medication administration) or grouped errors (eg, route and frequency errors in the order for a medication). Many of the sequences led to administration errors that were caused by errors earlier in the medication-management process. CONCLUSIONS: Understanding the complexity of the vulnerabilities of the medication-management process is important to devise solutions to improve patient safety. Electronic health record technology with computerised physician order entry may be one step necessary to improve medication safety in ICUs. Solutions that target multiple stages of the medication-management process are necessary to address sequential errors. PMID- 24050987 TI - Symptomatic pulmonary hypertension with giant left atrial v waves after surgical maze procedures: evaluation by comprehensive hemodynamic catheterization. AB - BACKGROUND: The surgical maze procedure is highly effective in treating symptomatic atrial fibrillation but may have detrimental effects on left atrial (LA) contractile function and compliance. OBJECTIVE: To describe a series of patients presenting with symptomatic pulmonary hypertension due in part to LA dysfunction after surgical maze procedures. METHODS: This report includes 9 patients who (1) presented to Mayo Clinic (Rochester, MN) between 2008 and 2012 with unexplained dyspnea and pulmonary hypertension after the surgical maze procedure, (2) underwent comprehensive hemodynamic catheterization with transseptal measurement of LA pressure, (3) had large v waves on LA pressure waveforms, and (4) did not have significant mitral valve regurgitation or stenosis or pulmonary vein stenosis. RESULTS: Invasive hemodynamic assessment revealed (1) severe pulmonary hypertension (mean pulmonary pressure 47 +/- 6 mm Hg), (2) severe LA hypertension (27 +/- 4 mm Hg), (3) giant LA v waves (to 50 +/- 8 mm Hg), (4) absence of LA or left ventricular a waves, and (5) blunted x descents (2 +/- 1 mm Hg). Left ventricular end-diastolic pressure was also elevated (20 +/- 5 mm Hg). CONCLUSIONS: Abnormalities in LA compliance and contractility may lead to giant LA v waves and symptomatic pulmonary hypertension after surgical maze procedures. This syndrome should be considered in the differential diagnosis for pulmonary hypertension and underscores the importance of comprehensive hemodynamic catheterization. PMID- 24050988 TI - Electrospun drug loaded membranes for sublingual administration of sumatriptan and naproxen. AB - Sublingual administration of active pharmaceutical substances is in principle favourable for rapid onset of drug action, ready accessibility and avoidance of first pass metabolism. This administration could prove very useful in the treatment of migraines, thus two frequently used drugs were selected for our study. Sumatriptan succinate, naproxen, and its salt as well as combinations of these were incorporated into nanofibrous membranes via the electrospinning process. DSC measurements proved that the resulted membranes contained non crystalline drug forms. SEM imaging approved good homogeneity of diameter and shape of the membrane nanofibres. The nanofibrous membranes always showed the rapid and mutually independent release of the tested drugs. The drugs exhibited very high differences in sublingual permeation rates in vitro, but the rates of both substances were increased several times using nanofibrous membranes as the drug carrier in comparison to drug solutions. The released drugs subsequently permeated through sublingual mucosa preferentially as non-ionized moieties. The prepared nanofibrous membranes proved very flexible and mechanically resistant. With their drug load capacity of up to 40% of membrane mass, they could be very advantageous for the formulation of sublingual drug delivery systems. PMID- 24050989 TI - Biorelevant characterisation of amorphous furosemide salt exhibits conversion to a furosemide hydrate during dissolution. AB - Biorelevant dissolution behaviour of the amorphous sodium salt and amorphous acid forms of furosemide was evaluated, together with investigations of the solid state changes during in vitro dissolution in medium simulating the conditions in the small intestine. UV imaging of the two amorphous forms, as well as of crystalline furosemide salt and acid showed a higher rate of dissolution of the salt forms in comparison with the two acid forms. The measured dissolution rates of the four furosemide forms from the UV imaging system and from eluted effluent samples were consistent with dissolution rates obtained from micro dissolution experiments. Partial least squares-discriminant analysis of Raman spectra of the amorphous acid form during flow through dissolution showed that the amorphous acid exhibited a fast conversion to the crystalline acid. Flow through dissolution coupled with Raman spectroscopy showed a conversion of the amorphous furosemide salt to a more stable polymorph. It was found by thermogravimetric analysis and hot stage microscopy that the salt forms of furosemide converted to a trihydrate during dissolution. It can be concluded that during biorelevant dissolution, the amorphous and crystalline furosemide salt converted to a trihydrate, whereas the amorphous acid exhibited fast conversion to the crystalline acid. PMID- 24050991 TI - Interdependence of plant water status with photosynthetic performance and root defense responses in Vigna radiata (L.) Wilczek under progressive drought stress and recovery. AB - The present study investigates the interdependence of plant water status with foliar and root responses in Vigna radiata L.Wilczek under progressive drought. Vegetatively-mature V. radiata plants were subjected to water withdrawal for 3 and 6days (D3 and D6, respectively) and then re-watered subsequently for 6days (6R) for stress-recovery. Changes in plant water status were expressed in terms of leaf and root moisture contents (LMC and RMC, respectively) and leaf relative water content (LRWC). Progressive drought caused apparent decrease in LRWC, LMC and RMC depicting significant level of dehydration of leaf and root tissues. Stomatal limitation alone could not account for the observed decrease in net CO2 assimilation rates (Pn) due to comparatively less decrease in sub-stomatal CO2 (Ci) concentrations with respect to other gas exchange parameters indicating possible involvement of non-stomatal limitations. Analysis of polyphasic chl a fluorescence kinetics during progressive drought showed decreased energy connectivity among PSII units as defined by a positive L-band with highest amplitude during D6. Efficiency of electron flux from OEC towards PSII acceptor side was not significantly affected during drought conditions as evidenced by the absence of a positive K-band. Increasing root-level water-limitation enforced a gradual oxidative stress through H2O2 accumulation and membrane lipid peroxidation in V. radiata roots exhibiting drastic enhancement of proline content and a significant but gradual increase in ascorbic acid content as well as guaiacol peroxidase activity under progressive drought. Expression analysis of Delta(1) pyrroline-5-carboxylate synthetase (P5CS) through real time PCR and enzyme activity studies showed a strong positive correlation between VrP5CS gene expression, enzyme activity and proline accumulation in the roots of V. radiata under progressive drought and recovery. Drought-induced changes in root moisture content (RMC) showed positive linear correlations with leaf water content, stomatal conductance as well as transpirational water loss dynamics and a significant negative correlation with the corresponding drought-induced expression patterns of ascorbate, guaiacol peroxidase and proline in roots of V. radiata. The study provides new insights into the plant water status-dependent interrelationship between photosynthetic performance and major root defense responses of V. radiata under progressive drought conditions. PMID- 24050990 TI - Notch signaling in hematopoietic cell transplantation and T cell alloimmunity. AB - Notch signaling can regulate both hematopoietic progenitors and alloimmune T cells in the setting of allogeneic bone marrow or hematopoietic cell transplantation (allo-HCT). Ex vivo culture of multipotent blood progenitors with immobilized Delta-like ligands induces supraphysiological Notch signals and can markedly enhance progenitor expansion. Infusion of Notch-expanded progenitors shortened myelosuppression in preclinical and early clinical studies, while accelerating T cell reconstitution in preclinical models. Notch also plays an essential role in vivo to regulate pathogenic alloimmune T cells that mediate graft-versus-host disease (GVHD), the most severe complication of allo-HCT. In mouse allo-HCT models, Notch inhibition in donor-derived T cells or transient blockade of Delta-like ligands after transplantation profoundly decreased GVHD incidence and severity, without causing global immunosuppression. These findings identify Notch in T cells as an attractive therapeutic target to control GVHD. In this review, we discuss these contrasting functions of Notch signaling with high translational significance in allo-HCT patients. PMID- 24050992 TI - Comparison between sonodynamic and photodynamic effect on MDA-MB-231 cells. AB - Photodynamic therapy (PDT) and sonodynamic therapy (SDT) are therapeutic modalities for tumors. In this study we investigated the combined cytotoxic effect of 0.36W/cm(2) and 0.72W/cm(2) ultrasound with various Ce6 concentrations (1, 2, 5, 10MUg/ml), and that of 1MUg/ml Ce6 with different laser light dose (650nm; 10.4mW/cm(2); 0.3, 0.6, 1.2 and 2.5J/cm(2)) on MDA-MB-231 cells. Both high reactive oxygen species (ROS) production and a decline in mitochondrial membrane potential (MMP) were detected with high Ce6 concentrations (5 and 10MUg/ml) combined with 0.72W/cm(2) ultrasound and 1.2, 2.5J/cm(2) laser light with 1MUg/ml Ce6. In addition, cell membrane integrity was evaluated by using propidium iodide (PI), revealing membrane damage was aggravated with the increasing ultrasound intensity, but no significant difference on cell membrane integrity could be observed after PDT treatment. These results suggest ROS may play an important role both in SDT and PDT. Besides, mitochondria may be an initial target in PDT while SDT can cause multi-site damages in MDA-MB-231 cells. PMID- 24050993 TI - Needs analysis and development of a tailored mobile message program linked with electronic health records for weight reduction. AB - OBJECTIVE: We developed and pilot-tested a personalized text messaging service program based on data from electronic health records (EHRs) and lifestyle questionnaires for weight control. METHODS: In the health promotion center of a hospital, 340 participants with a body mass index (BMI) greater than 25 were recruited and surveyed for the development of a text messaging program. After developing the interface linking the EHRs with personalized text messages for weight loss, we pilot-tested this program in 102 participants for its feasibility, acceptability and satisfaction. RESULTS: According to the needs analysis, the participants desired additional information about personalized nutrition and exercise. We selected many variables from the EHRs and questionnaires to create text messages with a more personalized program. After a 1-month trial of the text messaging program, the participants' satisfaction score was 7.9 +/- 1.5 and recommendation score was 7.5 +/- 1.8. CONCLUSIONS: A personalized short message service (SMS) linked with EHRs was feasible, and the pilot test showed high satisfaction and recommendation scores. Further evaluation using a well-designed trial will be needed. PMID- 24050994 TI - Assembly and immunological properties of a bivalent virus-like particle (VLP) for avian influenza and Newcastle disease. AB - Avian influenza virus (AIV) and Newcastle disease virus (NDV) are both important pathogens in poultry worldwide. The protection of poultry from avian influenza and Newcastle disease can be achieved through vaccination. We embarked on the development of a bivalent vaccine that would allow for a single immunization against both avian influenza and Newcastle disease. We constructed a chimeric virus-like particle (VLP) that is composed of the M1 protein and HA protein of avian influenza virus and a chimeric protein containing the cytoplasmic and transmembrane domains of AIV neuraminidase protein (NA) and the ectodomain of the NDV hemagglutinin-neuraminidase (HN) protein (NA/HN). The single immunization of chickens with the chimeric VLP vaccine induced both AIV H5- and NDV-specific antibodies. The HI titers and specific antibodies elicited by the chimeric VLPs were statistically similar to those elicited in animals vaccinated with the corresponding commercial monovalent vaccines. Chickens vaccinated with chimeric VLP vaccine and then challenged with the Newcastle disease F48E9 virus displayed complete protection. Overall, the chimeric VLP vaccine elicits strong immunity and can protect against Newcastle disease virus challenge. PMID- 24050995 TI - Phylogeny and evolution of porcine parvovirus. AB - Porcine parvovirus (PPV), a member of the genus Parvovirus, family Parvoviridae, is a significant causative agent in porcine reproductive failure, causing serious economic losses in the swine industry. Previous phylogenetic studies based on the NS1 or VP2 genes indicated that current PPV strains diverged 30 years ago and that VP2 was under neutral or positive selection. Our analysis of NS1, VP2 and complete ORFs indicated that the most recent common ancestor of PPV strains existed about 250 years ago and that the 127-nt repeat in the 3'NTR was present in viruses of some subclades that evolved about 80 years ago. Nucleotide substitution rates of NS1 and VP2 genes were 3.03 * 10(-5) and 1.07 * 10(-4), respectively. Both the NS1 and VP2 proteins were under purifying selection and recombination did not contribute to the genetic diversity of PPV. As expected, surface amino acids are hydrophilic and make up the majority of mutations in the VP2 protein; residues in VP2 interfaces were substituted gradually, often in conjunction with complementary substitutions in the neighboring VP2. PMID- 24050996 TI - Genome exploration of six variants of the Ostreid Herpesvirus 1 and characterization of large deletion in OsHV-1MUVar specimens. AB - The genetic polymorphism of the Ostreid Herpesvirus 1 (OsHV-1) has generally been investigated in three areas: ORFs 4/5, ORFs 42/43, and ORFs 35 to 38. The present study, however, focuses on 40 ORFs, representing 30% of the OsHV-1 genome, encoding four categories of putative proteins: 4 ORFs encoding putative inhibitor of apoptosis proteins; 17 ORFs encoding membrane proteins; 10 ORFs encoding secreted proteins; and 9 ORFs encoding RING finger proteins. The potential role of these proteins in major steps of the life cycle of the OsHV-1 motivated their selection. Seven specimens have been selected in accordance with their nucleotide variations in the C region (area located between the end of the ORF4 and the beginning of ORF 5): 3 OsHV-1MUVar specimens, 2 OsHV-1MUVar Delta9, one specimen of OsHV-1MUVar Delta15, and one OsHV-1 specimen (reference control) close to the reference genome to validate PCRs. The OsHV-1MUVar is mainly characterized by a deletion of 12 consecutive nucleotides followed by a deletion of one adenine in a microsatellite area located in the C region. A representation of nucleotide modifications between the different specimens was performed by building evolutionary trees with respect to the category of ORFs. This phylogenetic analysis revealed two groups: the first one corresponded to the reference control and the reference genome AY509253, and the second one included the 6 OsHV-1 variants. These results suggest that the two main groups come from the same common ancestor, and that the divergence between the reference OsHV-1 and its variants occurred quite far back in time. Moreover, consequences of nucleotide variations in the amino acid sequences, especially the change of the N glycoslyation sites, were investigated. Herein is the first report of four important deletions in these OsHV-1MUVar variants: a deletion of 1385bp in ORF 11; a deletion of 599bp in ORF 48; a deletion of 3549bp in ORFs 61 to 64; and a deletion of 712bp in ORF 114. The size of the deletions differed between OsHV 1MUVar specimens, OsHV-1MUVar Delta9 specimens, and the OsHV-1MUVar Delta15 specimen. These zones seem to correspond to special points of gene rearrangements for producing new proteins. Further investigation necessary proves to link such nucleotide modifications with consequences of protein functions in the OsHV-1 life cycle. PMID- 24050997 TI - Enhanced infectivity of H5N1 highly pathogenic avian influenza (HPAI) virus in pig ex vivo respiratory tract organ cultures following adaptation by in vitro passage. AB - Pigs are thought to play a role in the adaptation of avian influenza (AI) viruses to mammalian hosts. To better understand this mechanism and to identify key mutations two highly pathogenic AI (HPAI) viruses (H5N1 and H7N7) were grown in pig cells, To mimic the pressure of an immune response, these viruses were grown in the presence of antiserum to the homologous virus or porcine IFN-gamma. Mutations were identified in both viruses grown in vitro in the presence and absence of antisera or IFN-gamma and included the PB2 mutations, E627K or 627E,D701N, described previously as requirements for the adaptation of AI viruses to mammalian species. Additional mutations were also identified in PB1, HA, NP and M genes for viruses passaged in the presence of immune pressure. The infectivity of these viruses was then assessed using ex vivo pig bronchi and lung organ cultures. For lung explants, higher levels of virus were detected in organ cultures infected with H5N1 HPAI viruses passaged in pig cell lines regardless of the presence or absence of homologous antisera or IFN-gamma when compared with the wild-type parental viruses. No infection was observed for any of the H7N7 HPAI viruses. These results suggest that the mutations identified in H5N1 HPAI viruses may provide a replication or infection advantage in pigs in vivo and that pigs may continue to play an important role in the ecology of influenza A viruses including those of avian origin. PMID- 24050998 TI - Characterization in vitro and in vivo of a novel porcine parainfluenza virus 5 isolate in Korea. AB - A novel porcine parainfluenza 5 (pPIV5), KNU-11, in the genus Rubulavirus of the subfamily Paramyxovirinae, was isolated from the lung of a piglet in Korea in 2011. To understand the importance of this virus as an infectious agent, in vitro and in vivo characteristics of KNU-11 virus was investigated. KNU-11 was remarkably cytopathogenic, showing distinct cell rounding and clumping evident in porcine alveolar macrophage (PAM), porcine kidney (PK-15), and swine testicle (ST) cells within 12h postinfection and capable of hemagglutinating guinea pig red blood cells. Interestingly, this cytopathology was found to be absent in cell lines from other mammalian species. To evaluate the in vitro immunity of the pPIV5 isolate, we sought to explore alteration of inflammatory cytokine and chemokine expression in PAM cells infected with KNU-11 by using quantitative real time RT-PCR. Most cytokine and chemokine genes including type 1 interferons (IFN alpha/beta) and IFN-related antiviral genes were found to be significantly elevated in KNU-11 virus-infected PAM cells. A serum neutralization test-based serosurvey demonstrated that neutralizing antibodies against KNU-11 are readily detected in domestic swine populations, suggesting high prevalence of pPIV5 in Korean pig farms. Animal studies showed that KNU-11 fails to establish an acute respiratory illness, indicating that pPIV5 is non- or very mildly pathogenic to pigs. PMID- 24050999 TI - Systemically administered DNA and fowlpox recombinants expressing four vaccinia virus genes although immunogenic do not protect mice against the highly pathogenic IHD-J vaccinia strain. AB - The first-generation smallpox vaccine was based on live vaccinia virus (VV) and it successfully eradicated the disease worldwide. Therefore, it was not administered any more after 1980, as smallpox no longer existed as a natural infection. However, emerging threats by terrorist organisations has prompted new programmes for second-generation vaccine development based on attenuated VV strains, which have been shown to cause rare but serious adverse events in immunocompromised patients. Considering the closely related animal poxviruses that might also be used as bioweapons, and the increasing number of unvaccinated young people and AIDS-affected immunocompromised subjects, a safer and more effective smallpox vaccine is still required. New avipoxvirus-based vectors should improve the safety of conventional vaccines, and protect from newly emerging zoonotic orthopoxvirus diseases and from the threat of deliberate release of variola or monkeypox virus in a bioterrorist attack. In this study, DNA and fowlpox recombinants expressing the L1R, A27L, A33R and B5R genes were constructed and evaluated in a pre-clinical trial in mouse, following six prime/boost immunisation regimens, to compare their immunogenicity and protective efficacy against a challenge with the lethal VV IHD-J strain. Although higher numbers of VV-specific IFNgamma-producing T lymphocytes were observed in the protected mice, the cytotoxic T-lymphocyte response and the presence of neutralising antibodies did not always correlate with protection. In spite of previous successful results in mice, rabbits and monkeys, where SIV/HIV transgenes were expressed by the fowlpox vector, the immune response elicited by these recombinants was low, and most of the mice were not protected. PMID- 24051001 TI - New insights in the role of nucleoporins: a bridge leading to concerted steps from HIV-1 nuclear entry until integration. AB - Human Immunodeficiency virus type 1 (HIV-1), as well as many other viruses that depend on nuclear entry for replication, has developed an evolutionary strategy to dock and translocate through the nuclear pore complex (NPC). In particular, the nuclear pore is not a static window but it is a dynamic structure involved in many vital cellular functions, as nuclear import/export, gene regulation, chromatin organization and genome stability. This review aims to shed light on viral mechanisms developed by HIV-1 to usurp cellular machinery to favor viral gene expression and their replication. In particular, it will be reviewed both what is known and what is speculated about the link between HIV translocation through the nuclear pore and the proviral integration in the host chromatin. PMID- 24051000 TI - Beta-defensin 2 enhances immunogenicity and protection of an adenovirus-based H5N1 influenza vaccine at an early time. AB - Reports of human infections with highly pathogenic H5N1 avian influenza viruses in many countries in Asia and Africa with varying case fatality rates highlight the pandemic potential of these viruses. In order to contain a rapidly spreading influenza virus in a pandemic scenario, a vaccine which can induce rapid and robust immune responses, preferably in a single dose, is necessary. Murine beta defensin 2 (Mbd2), a small molecular weight protein expressed by epithelial cells, has been shown to enhance antigen-specific immune responses by recruiting and activating professional antigen presenting cells to the site of vaccination. This study assessed the potential of Mbd2 to enhance the immunogenicity and protective efficacy of a human adenovirus (HAd)-based vaccine expressing the hemagglutinin (HA) and nucleoprotein (NP) [HAd-HA-NP] of an H5N1 influenza virus. A single inoculation of mice with both HAd-HA-NP and a HAd vector expressing Murine beta-defensin 2 (HAd-Mbd2) resulted in significantly higher levels of both humoral and cell-mediated immune responses compared to the groups vaccinated only with HAd-HA-NP. These responses were evident even at day 7 post-immunization. Furthermore, the HAd-HA-NP+HAd-Mbd2-immunized group receiving the lowest vector dose (2 * 10(7)+1 * 10(7)) was completely protected against an rgH5N1 virus challenge on day 7 post-vaccination. These results highlight the potential of Mbd2 as a genetic adjuvant in inducing rapid and robust immune responses to a HAd based vaccine. PMID- 24051002 TI - A novel P450-initiated biphasic process for sustainable biodegradation of benzo[a]pyrene in soil under nutrient-sufficient conditions by the white rot fungus Phanerochaete chrysosporium. AB - High molecular weight polycyclic aromatic hydrocarbons (HMW-PAHs) such as benzo[a]pyrene (BaP) are resistant to biodegradation in soil. Conventionally, white rot fungus Phanerochaete chrysosporium has been investigated for HMW-PAH degradation in soil primarily using nutrient-deficient (ligninolytic) conditions, albeit with limited and non-sustainable biodegradation outcomes. In this study, we report development of an alternative novel biphasic process initiated under nutrient-sufficient (non-ligninolytic) culture conditions, by employing an advanced experimental design strategy. During the initial nutrient-sufficient non ligninolytic phase (16 days), the process showed upregulation (3.6- and 22.3 fold, respectively) of two key PAH-oxidizing P450 monooxygenases pc2 (CYP63A2) and pah4 (CYP5136A3) and formation of typical P450-hydroxylated metabolite. This along with abrogation (84.9%) of BaP degradation activity in response to a P450 specific inhibitor implied key role of these monooxygenases. The subsequent phase triggered on continued incubation (to 25 days) switched the process from non ligninolytic to ligninolytic resulting in a significantly higher net degradation (91.6% as against 67.4% in the control nutrient-limited set) of BaP with concomitant de novo ligninolytic enzyme expression making it a biphasic process yielding improved sustainable bioremediation of PAH-contaminated soil. To our knowledge this is the first report on development of such biphasic process for bioremediation application of a white rot fungus. PMID- 24051003 TI - Native-like brain processing of syntax can be attained by university foreign language learners. AB - Using event-related potentials (ERPs), we examined the neurocognition of late learned second language (L2) Spanish in two groups of typical university foreign language learners (as compared to native (L1) speakers): one group with only one year of college classroom experience, and low-intermediate proficiency (L2 Low), and another group with over three years of college classroom experience as well as 1-2 semesters of immersion experience abroad, and advanced proficiency (L2 Advanced). Semantic violations elicited N400s in all three groups, whereas syntactic word-order violations elicited LAN/P600 responses in the L1 and L2 Advanced groups, but not the L2 Low group. Indeed, the LAN and P600 responses were statistically indistinguishable between the L1 and L2 Advanced groups. The results support and extend previous findings. Consistent with previous research, the results suggest that L2 semantic processing always depends on L1-like neurocognitive mechanisms, whereas L2 syntactic processing initially differs from L1, but can shift to native-like processes with sufficient proficiency or exposure, and perhaps with immersion experience in particular. The findings further demonstrate that substantial native-like brain processing of syntax can be achieved even by typical university foreign-language learners. PMID- 24051004 TI - The unstable bridge from stimulus processing to correct responding in Parkinson's disease. AB - It has been assumed that the basal ganglia implement links between stimulus (S) processing and motor response (R). It has also been proposed that the P3b component of the event-related EEG potential, which is usually as large in R- as in S-locked averages over trials, is a candidate marker to reveal integrity of S R links. Therefore, the P3 complex (consisting of P3a and P3b) was here measured in averages over trials time-locked either to S or to the key-press R. P3b was expected to be equally large in healthy participants' R- and S-locked averages but to be smaller in R-locked than S-locked averages of patients with Parkinson's disease (PD) (n=12 each), reflecting the loss of S-R links in PD. It has been further assumed that the basal ganglia extract unambiguous results from complex signal patterns thereby resolving discrepancies between competing responses. If so, signals arriving at PD patients' cortex may still be discrepant and produce conflicts, as indicated by error-negativity (NE)-type components even with PD patients' correct responses. As expected, healthy persons had equal S- and R- locked P3b amplitudes and topographies, and PD patients had smaller P3b amplitudes in R-locked than S-locked averages. This latter result was due to an R related fronto-central negative shift, overlapping PD patients' P3b in the final 100 ms before overt responding. This negativity might indicate response conflict even with correct responses. In line with this interpretation, PD patients had an N(E)-type signal in error trials not only in R-locked averages, like healthy participants, but in S-locked averages as well. These findings support the discrepancy-resolving hypothesis of the basal ganglia and suggest that the overlap of P3b by N(E)-type components, related both to S and R, may reflect a major pathophysiological feature in Parkinson's disease. PMID- 24051005 TI - You get what you select for: better swarming through more flagella. AB - In a recent Cell Reports paper by van Ditmarsch et al., the authors aim to conduct experimental evolution in Pseudomonas aeruginosa but instead conduct classical forward genetics and select for mutations in a single gene that improves swarming motility at the expense of biofilm formation. PMID- 24051006 TI - The responses of osteoblasts to fluid shear stress depend on substrate chemistries. AB - Natural bone tissue receives chemical and mechanical stimuli in physiological environment. The effects of material chemistry alone and mechanical stimuli alone on osteoblasts have been widely investigated. This study reports the synergistic influences of material chemistry and flow shear stress (FSS) on biological functions of osteoblasts. Self-assembled monolayers (SAMs) on glass slides with functional groups of OH, CH3, and NH2 were employed to provide various material chemistries, while FSS (12 dynes/cm(2)) was produced by a parallel-plate fluid flow system. Material chemistry alone had no obvious effects on the expressions of ATP, nitric oxide (NO), and prostaglandin E2 (PGE2), whereas FSS stimuli alone increased the production of those items. When both material chemistry and FSS were loaded, cell proliferation and the expressions of ATP, NO and PGE2 were highly dependent on the material chemistry. Examination of the focal adhesion (FA) formation and F-actin organization of osteoblasts before FSS exposure indicates that the FA formation and F-actin organization followed similar chemistry-dependence. The inhibition of FAs and/or disruption of F-actins eliminated the material dependence of FSS-induced ATP, PGE2 and NO release. A possible mechanism is proposed: material chemistry controls the F-actin organization and FA formation of osteoblasts, which further modulates FSS-induced cellular responses. PMID- 24051007 TI - Chronic intermittent hypoxia promotes expression of 3-mercaptopyruvate sulfurtransferase in adult rat medulla oblongata. AB - The present experiments were carried out to investigate the expression of 3 mercaptopyruvate sulfurtransferase (3MST) in medulla oblongata of rats and effects of chronic intermittent hypoxia (CIH) on its expression. Sprague Dawley adult rats were randomly divided into two groups, including control (Con) group and CIH group. The endogenous production of hydrogen sulfide (H2S) in medulla oblongata tissue homogenates was measured using the methylene blue assay method, 3MST mRNA and protein expression were analyzed by RT-PCR and Western blotting, respectively, and the expression of 3MST in the neurons of respiratory-related nuclei in medulla oblongata of rats was investigated with immunohistochemical technique. CIH elevated the endogenous H2S production in rat medulla oblongata (P<0.01). The RT-PCR and Western blotting analyses showed that 3MST mRNA and protein were expressed in the medulla oblongata of rats and CIH promoted their expression (P<0.01). Immunohistochemical staining indicated that 3MST existed in the neurons of pre-Botzinger complex (pre-BotC), hypoglossal nucleus (12N), ambiguous nucleus (Amb), facial nucleus (FN) and nucleus tractus solitarius (NTS) in the animals and the mean optical densities of 3MST-positive neurons in the pre BotC, 12N and Amb, but not in FN and NTS, were significantly increased in CIH group (P<0.05). In conclusion, 3MST exists in the neurons of medullary respiratory nuclei and its expression can be up-regulated by CIH in adult rat, suggesting that 3MST-H2S pathway may be involved in regulation of respiration and protection on medullary respiratory centers from injury induced by CIH. PMID- 24051008 TI - How to differentiate spontaneous intramural intestinal hemorrhage from acute mesenteric ischemia. AB - OBJECTS: The purpose of our study was to assess the diagnostic values of laboratory tests to differentiate spontaneous intramural intestinal hemorrhage (SIIH) from acute mesenteric ischemia (AMI) after abdominal computed tomography (CT) survey in the emergency department (ED). METHOD: We retrospectively included 76 patients diagnosed SIIH or AMI after abdominal CT. RESULTS: The mean ages of 28 SIIH patients and 48 AMI patients were 75.9 +/- 13.7 years and 75.8 +/- 11.6 years, respectively. Patients with SIIH had significantly higher rate of Coumadin use (P < .001) and localized tenderness (P < .05). In laboratory findings, SIIH patients had prolonged prothrombin time (PT) (83.6 +/- 30.0 vs. 13.4 +/- 3.2, P < .001), lower blood urea nitrogen (P < .05), lower creatinine (P < .05), and lower creatine kinase (P < .05). Prolonged PT showed good discriminative value to differentiate acute abdomen patients with SIIH from AMI after abdominal CT, with an area under the receiver operating characteristic curve of 0.980 (95% confidence interval, 0.918-0.998; P < .0001). Prolonged PT cut-off value of ?22.5 seconds had a sensitivity of 92.9% and a specificity of 100%. Logistic regression analysis identified prolonged PT as an independent predictor of SIIH (odds ratio, OR, 22.2; P = .007). CONCLUSION: Abdominal pain patients with either SIIH or AMI are rare in the ED, but abdominal CT sometimes cannot help to differentiate them due to similar CT findings. Prolonged PT might help emergency physicians and surgeons differentiate SIIH from AMI in such cases. PMID- 24051009 TI - Diagnosis of testicular cancer with a urine pregnancy test in an austere military medical environment. PMID- 24051010 TI - Acute proximal left anterior descending artery occlusion with de Winter sign. AB - Prompt recognition of electrocardiographic signs of acute coronary occlusion is essential for timely restoration of flow. ST-segment elevation or new onset left bundle-branch block are the most common electrocardiographic changes seen in acute phase of coronary occlusion. However, some patients may present with atypical electrocardiographic signs, and early diagnosis of these patients may constitute a clinical challenge. Here, we report a 41-year-old man presenting with an atypical electrocardiographic manifestation despite angiographically confirmed acute thrombotic occlusion of proximal left anterior descending artery. PMID- 24051011 TI - Competing to the rescue--leveraging social media for cross border collaboration in life-saving rescue operations. PMID- 24051012 TI - Guillain-Barre in a 10-month-old: diagnostic challenges in a pediatric emergency. AB - A 10-month-old male infant presented to the emergency department (ED) with a chief complaint of weakness, decreased mobility, and regression of motor milestones over a period of 6 days. Significant medical history included a Roseola infection 5 weeks before ED presentation. The patient's pediatrician and chiropractor had both previously diagnosed the patient with strains and sprains. After progression of symptoms, the patient presented to the ED and was discharged home to follow up as an outpatient. The patient subsequently returned to the ED and was admitted to neurology with concern for Guillain-Barre syndrome, which was later confirmed after inpatient workup. The patient was successfully treated and released. Guillain-Barre represents a spectrum of acute immune mediated polyneuropathies. There are several variant forms provoked by infection that precedes the onset of symptoms. Diagnosis and management of Guillain-Barre in the ED will be reviewed, along with the importance of early pediatric intensive care involvement for children presenting with signs of flaccid quadriparesis; rapidly progressive weakness; impending respiratory failure; bulbar palsy; and, most importantly, autonomic cardiovascular instability. Guillain-Barre is rare in children younger than 2 years; however, it must be considered in the differential diagnosis of any patient who presents with progressive weakness and history of a recent infection. It is important to recognize the variety and severity of neurologic symptoms associated with Guillain-Barre across a spectrum, especially with the diagnostic difficulties associated with the pediatric population. PMID- 24051013 TI - PPAPDC1B and WHSC1L1 are common drivers of the 8p11-12 amplicon, not only in breast tumors but also in pancreatic adenocarcinomas and lung tumors. AB - Amplification of the 8p11-12 chromosomal region is a common genetic event in many epithelial cancers. In breast cancer, several genes within this region have been shown to display oncogenic activity. Among these genes, the enzyme-encoding genes, PPAPDC1B and WHSC1L1, have been identified as potential therapeutic targets. We investigated whether PPAPDC1B and WHSC1L1 acted as general driver genes, thereby serving as therapeutic targets in other tumors with 8p11-12 amplification. By using publicly available genomic data from a panel of 883 cell lines derived from different cancers, we identified the cell lines presenting amplification of both WHSC1L1 and PPAPDC1B. In particular, we focused on cell lines derived from lung cancer and pancreatic adenocarcinoma and found a correlation between the amplification of PPAPDC1B and WHSC1L1 with their overexpression. Loss-of-function studies based on the use of siRNA and shRNA demonstrated that PPAPDC1B and WHSC1L1 played a major role in regulating the survival of pancreatic adenocarcinoma and small-cell lung cancer-derived cell lines, both in anchorage-dependent and anchorage-independent conditions, displaying amplification and overexpression of these genes. We also demonstrated that PPAPDC1B and WHSC1L1 regulated xenograft growth in these cell lines. Finally, quantitative RT-PCR experiments after PPAPDC1B and WHSC1L1 knockdown revealed exclusive PPAPDC1B and WHSC1L1 gene targets in small-cell lung cancer and pancreatic adenocarcinoma-derived cell lines compared with breast cancer. PMID- 24051014 TI - A simplified method to quantify dysregulated tyrosine transport in schizophrenia. AB - BACKGROUND: Schizophrenia is associated with altered tyrosine transport across plasma membranes. This is typically demonstrated by measuring the uptake of radiolabeled tyrosine in cultured human fibroblasts. Our primary goal was to determine whether tyrosine uptake could be characterized using unlabeled tyrosine. A secondary goal was to assess the effect of antipsychotic drugs added during the incubation. METHOD: Epithelium-derived fibroblast cultures were generated from patients with schizophrenia (n=6) and age-matched controls (n=6). Cells between cycles 8-12 were exposed to an amino acid free medium for 60min and then for 1min to media containing tyrosine (0.008-1.0mM). Amino acid levels were measured and Michaelis-Menten parameters determined. Uptake of tyrosine (0.5mM) was also measured in control cells after antipsychotic drugs were introduced during the depletion or uptake phases. RESULTS: Tyrosine uptake was sodium independent. The maximal transport velocity (Vmax) was significantly lower in patients with schizophrenia than in controls (p<0.01). The transporter affinity (Km) did not differ between the groups. Tyrosine uptake was differentially affected (p<0.001) by inclusion of 10(-4)M haloperidol, chlorpromazine or clozapine during different periods of incubation. CONCLUSION: Dysregulated tyrosine kinetics in schizophrenia can be readily studied without the use of radiolabeled tracers. The data also indicate that tyrosine uptake may be subject to complex pharmacological effects. PMID- 24051015 TI - Working memory and default mode network abnormalities in unaffected siblings of schizophrenia patients. AB - BACKGROUND: Impaired working memory (WM) is a hallmark of schizophrenia. In addition to classical WM regions such as the dorsolateral prefrontal cortex (DLPFC) and the striatum, dysfunctions in the default-mode network (DMN) contribute to these WM deficits. Unaffected siblings of patients also show WM impairments. However, the nature of the functional deficits underlying these impairments is unclear, mainly because of impaired performance confounding neuroimaging results. METHODS: Here, we investigated WM and DMN activity in 23 unaffected siblings of schizophrenia patients and 24 healthy volunteers using fMRI and a Sternberg WM task. WM load was determined prior to scanning to ensure 90% accuracy for all subjects. RESULTS: Siblings showed hyperactivation during the encoding phase of WM in the right medial prefrontal cortex (MPFC) which is the anterior part of the DMN. No differences were found during the maintenance phase. During the retrieval phase, siblings showed hyperactivation in WM regions: DLPFC, inferior parietal cortex and the striatum. Siblings who showed hyperactivity in the MPFC during encoding showed DLPFC and striatum hyperactivation during retrieval. CONCLUSIONS: Our finding of hyperactivation in WM and DMN areas indicates that siblings fail to adequately inhibit DMN activity during demanding cognitive tasks and subsequently hyperactivate WM areas. This failure may reflect dopamine hyperactivity in the striatum which prevents adequate DMN suppression needed for effective WM. This study provides support for the notion that aberrant WM and DMN activation patterns may represent candidate endophenotypes for schizophrenia. PMID- 24051016 TI - Pharmacokinetics of intravenous amiodarone in children. AB - OBJECTIVES: Although amiodarone is an effective treatment for severe paediatric arrhythmias, uncertainties about adverse effects such as hypotension, bradycardia and excessive serum drug concentrations persist. Therefore, the aims of this study were to: (a) determine serum concentrations of intravenous (IV) amiodarone following a widely implemented dosing regimen of 5 mg/kg bolus plus a 10 mg/kg/day continuous infusion and (b) generate descriptive data on safety parameters such as hypotension, bradycardia or corrected QT (QTc) prolongation during this regimen. DESIGN: Prospective observational study. SETTING: Paediatric intensive care unit. PATIENTS: Twenty paediatric patients (median age, 0.23 years; range, 6 days-15.04 years) with arrhythmia secondary to or without cardiac surgery. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Amiodarone serum concentrations, blood pressure, heart rate, QTc intervals. RESULTS: Amiodarone serum concentrations increased markedly during bolus, followed by rapid decreases during maintenance infusion. All patients had serum concentrations regarded as effective in adults (median concentration range: 1.30-2.06 uM/L during maintenance phase). Amiodarone suppressed arrhythmias in 18 (90%) patients. Mean QTc intervals for pretherapy, during and post-therapy periods were 443 ms, 458 ms and 467 ms, respectively. Eight patients had hypotension. CONCLUSIONS: Amiodarone was effective in the majority of children in this small cohort. PMID- 24051017 TI - Rasch analysis of the Spanish version of the Mindful Attention Awareness Scale (MAAS) in a clinical sample. AB - INTRODUCTION: The clinical use of mindfulness has increased recently, and the Mindful Attention Awareness Scale (MAAS) has become one of the most used tools to measure it. The aim of this study was to test the effectiveness of mindfulness training and analyzing the psychometric properties of the MAAS scores in a clinical sample using the Rasch Model. METHODS: One hundred and ninety-nine participants with mood-anxiety clinical symptoms were recruited. The experimental group (n=103) received mindfulness training, and the control group (n=96) a conventional outpatient treatment for the same duration. The pre-post MAAS scores were analyzed to test the effectiveness of training, the psychometric properties of the scores, and differential item functioning (DIF) using the Rating Scale Model (RSM). RESULTS: Misfit in items 9 and 12, DIF in item 9, and Spanish translation problems in the items 5, 9 and 12 were observed. The repetition of the analysis without these items was decided. Appropriate dimensionality, fit and reliability values were obtained with the short version, MAAS-12. CONCLUSIONS: Contrary to previous studies, the MAAS was sensitive to treatment-associated change. However, the commonly used MAAS has some translation and metric problems, and should be revised. MAAS-12 is a better scale than MAAS but suffers from construct under-representation. Constructing tools from a coherent theoretical perspective is suggested, so that all mindfulness facets are represented. PMID- 24051018 TI - Papillomavirus-associated squamous skin cancers following transplant immunosuppression: one Notch closer to control. AB - The frequent occurrence of cutaneous squamous cell carcinomas (SCCs) containing weakly tumorigenic human papillomaviruses (HPVs) following iatrogenic immunosuppression for organ transplantation remains incompletely understood. Here we address this problem in the light of recent insights into (1) the association of low-risk beta-HPVs with skin SCCs in the rare genetic syndromes of epidermodysplasia verruciformis and xeroderma pigmentosum, (2) the frequent recovery of post-transplant tumor control on substituting calcineurin-inhibitory with mTOR-inhibitory immunosuppression, (3) the unexpectedly favorable prognosis of node-positive SCCs containing high-risk alpha-HPVs originating in the activated immune niche of the oropharynx, (4) the rapid occurrence of HPV negative SCCs in ultraviolet (UV)-damaged skin of melanoma patients receiving Raf inhibitory drugs, and (5) the selective ability of beta-HPV E6 oncoproteins to inhibit Notch tumor-suppressive signaling in cutaneous and mesenchymal tissues. The crosstalk so implied between oncogenic UV-induced mutations, defective host immunity, and beta-HPV-dependent stromal-epithelial signaling suggests that immunosuppressants such as calcineurin inhibitors intensify mitogenic signalling in TP53-mutant keratinocytes while also abrogating immune-dependent Notch mediated tumor repression. This emerging interplay between solar damage, viral homeostasis and immune control makes it timely to reappraise strategies for managing skin SCCs in transplant patients. PMID- 24051019 TI - Antihypertensive drugs and the risk of fall injuries: a systematic review and meta-analysis. AB - OBJECTIVE: A meta-analysis of published studies was performed to determine whether administration of any of five antihypertensive drug classes (thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers and beta-blockers) affected the risk of fall injuries in the elderly (aged >=60 years). METHODS: Articles reporting the risk of fall injury in elderly people being treated with the five main classes of antihypertensive drugs were retrieved using MEDLINE(r), EMBASE, SCOPUS(r) and the Cochrane Database. Trial eligibility and methodological quality were assessed before data extraction and analysed using odds ratios with 95% confidence intervals. RESULTS: Sixty-two articles, included in two meta-analyses, were identified. These meta-analyses drew opposite conclusions about the role of antihypertensive drugs in fall injuries in the elderly. However, the present analysis did not reveal a clear association (or the lack of one) between antihypertensive drugs and risk of fall injuries. CONCLUSIONS: There is no clear, statistically significant clinical precedent indicating that the use of any of the antihypertensive drugs considered here increases the risk of fall injuries in the elderly. Nonetheless, in following standard clinical guidelines for hypertension management, physicians need to be aware of the impact of drug therapies on fall injuries. PMID- 24051020 TI - Acute pulmonary embolism following adolescent idiopathic scoliosis correction surgery: case report and review of literature. AB - Pulmonary embolism is a significant complication of surgery. This report presents a case of suspected fatal postoperative acute pulmonary embolism following posterior correction surgery in a 16-year-old female with idiopathic scoliosis. The patient presented with a suspected pulmonary embolism 2 h postoperatively. She lost consciousness quickly, and cardiac respiratory arrest occurred. Cardiopulmonary resuscitation was started immediately. The patient was stabilized but underwent a further suspected pulmonary embolism the following day. Cardiopulmonary resuscitation was performed again, but she lost consciousness and respirator support was required. At 40 days after surgery, a computed tomography scan revealed an area of necrotic brain tissue near the lateral cerebral ventricle. The patient remained in a comatose state for 16 months, after which active management was withdrawn. This case reminds us to be alert to potentially fatal postoperative pulmonary embolism in young patients without any risk factors for thrombosis. PMID- 24051021 TI - High performance computing methods for the integration and analysis of biomedical data using SAS. AB - From microarrays and next generation sequencing to clinical records, the amount of biomedical data is growing at an exponential rate. Handling and analyzing these large amounts of data demands that computing power and methodologies keep pace. The goal of this paper is to illustrate how high performance computing methods in SAS can be easily implemented without the need of extensive computer programming knowledge or access to supercomputing clusters to help address the challenges posed by large biomedical datasets. We illustrate the utility of database connectivity, pipeline parallelism, multi-core parallel process and distributed processing across multiple machines. Simulation results are presented for parallel and distributed processing. Finally, a discussion of the costs and benefits of such methods compared to traditional HPC supercomputing clusters is given. PMID- 24051022 TI - Spinal-supraspinal and intrinsic MU-opioid receptor agonist-norepinephrine reuptake inhibitor (MOR-NRI) synergy of tapentadol in diabetic heat hyperalgesia in mice. AB - Tapentadol is a MU-opioid receptor (MOR) agonist and norepinephrine reuptake inhibitor (NRI) with established efficacy in neuropathic pain in patients and intrinsic synergistic interaction of both mechanisms as demonstrated in rodents. In diabetic mice, we analyzed the central antihyperalgesic activity, the occurrence of site-site interaction, as well as the spinal contribution of opioid and noradrenergic mechanisms in a hotplate test. Tapentadol (0.1-3.16 ug/animal) showed full efficacy after intrathecal as well as after intracerebroventricular administration (ED50 0.42 ug/animal i.t., 0.18 ug/animal i.c.v.). Combined administration of equianalgesic doses revealed spinal-supraspinal synergy (ED50 0.053 ug/animal i.t. + i.c.v.). Morphine (0.001-10 ug/animal) also showed central efficacy and synergy (ED50 0.547 ug/animal i.t., 0.004 ug/animal i.c.v., 0.014 ug/animal i.t. + i.c.v.). Supraspinal potencies of tapentadol and morphine correlated with the 50-fold difference in their MOR affinities. In contrast, spinal potencies of both drugs were similar and correlated with their relative systemic potencies (ED50 0.27 mg/kg i.p. tapentadol, 1.1 mg/kg i.p. morphine). Spinal administration of the opioid antagonist naloxone or the alpha2 adrenoceptor antagonist yohimbine before systemic administration of equianalgesic doses of tapentadol (1 mg/kg i.p.) or morphine (3.16 mg/kg i.p.) revealed pronounced influence on opioidergic and noradrenergic pathways for both compounds. Tapentadol was more sensitive toward both antagonists than was morphine, with median effective dose values of 0.75 and 1.72 ng/animal i.t. naloxone and 1.56 and 2.04 ng/animal i.t. yohimbine, respectively. It is suggested that the antihyperalgesic action of systemically administered tapentadol is based on opioid spinal-supraspinal synergy, as well as intrinsic spinally mediated MOR-NRI synergy. PMID- 24051023 TI - Physalin F from Physalis minima L. triggers apoptosis-based cytotoxic mechanism in T-47D cells through the activation caspase-3- and c-myc-dependent pathways. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Physalin F (a secosteroid derivative), is well recognized as a potent anticancer compound from Physalis minima L., a plant that is traditionally used to treat cancer. However, the exact molecular anticancer mechanism remains to be elucidated. AIM OF THE STUDY: We have recently reported the apoptosis-based cytotoxic effect of the chloroform extract of this plant. Here, we investigated the cytotoxicity and possible cell death mechanism elicited by the active constituent, physalin F on human breast T-47D carcinoma. MATERIALS AND METHODS: Cytotoxic-guided fractionation of the chloroform extract of Physalis minima has led to the isolation of physalin F. The cytotoxicity activity was assayed using MTS assay. The effect of the compound to induce apoptosis was determined by biochemical and morphological observations through DeadEnd Colorimetric and annexin V assays, respectively, and RT-PCR analysis of mRNA expression of the apoptotic-associated genes. RESULTS: Cytotoxicity screening of physalin F displayed a remarkable dose-dependent inhibitory effect on T-47D cells with lower EC50 value (3.60 MUg/ml) than the crude extract. mRNA expression analysis revealed the co-regulation of c-myc- and caspase-3-apoptotic genes in the treated cells with the peak expression at 9 and 12h of treatment, respectively. This apoptotic mechanism is reconfirmed by DNA fragmentation and phosphatidylserine externalization. CONCLUSION: These findings indicate that physalin F may potentially act as a chemopreventive and/or chemotherapeutic agent by triggering apoptosis mechanism via the activation of caspase-3 and c-myc pathways in T-47D cells. PMID- 24051024 TI - Chemical composition and antinociceptive, anti-inflammatory and antiviral activities of Gallesia gorazema (Phytolaccaceae), a potential candidate for novel anti-herpetic phytomedicines. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In traditional medicine, teas made from leaves and bark of Gallesia gorazema are used as antispasmodic, anthelmintic, antihemorrhagic and febrifuge agents. Crude leaves of this plant are also employed as a remedy in the treatment of abscesses, orchitis, gonorrhea and for rheumatic pain relief. this study investigates the presumed antinociceptive and anti-inflammatory activities of leaves and roots Gallesia gorazema (Phytolaccaceae) extracts. The most active extract and its isolated compound, a new natural product, are also evaluated against viruses HSV-1 and HSV-2. MATERIALS AND METHODS: In vivo experiments with mice were used to assess the analgesic and anti-inflammatory activities of Gallesia gorazema extracts. Antiviral activity of extracts and the new natural product was investigated by in vitro experiments. RESULTS: Results show that dichloromethanic root (DRE) and ethanolic leaf (ELE) extracts displayed significant antinociceptive and anti inflammatory activities in in vivo experiments with mice. Both extracts were also assayed against the herpes simplex viruses HSV-1 and HSV-2, but only DRE was highly active, showing a selective antiviral effect against HSV-1. Phytochemical fractionation of DRE led to the isolation of 28-hydroxyoctacosyl ferulate, a novel natural product, which displayed strong antiviral activity against HSV-1 (EC50=21.6 MUg/mL) with a selective index above 9, justifying, at least in part, the high selective antiviral activity observed for DRE. CONCLUSION: These results suggest that the plant Gallesia gorazema is a potential candidate for the development of novel anti-herpetic phytomedicines. PMID- 24051025 TI - Antinociceptive effects of ethanolic extract from the flowers of Acmella oleracea (L.) R.K. Jansen in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Brazil, Acmella oleracea (L.) R.K. Jansen, popularly known as "jambu", has been used by some communities from Amazon region to treat toothache. In this study we examined the antinociceptive effect of the ethanolic extract obtained from the flowers of Acmella oleracea (EEAO) in animal models of nociceptive (chemical and thermal) and neuropathic (partial sciatic nerve ligation) pain. MATERIALS AND METHODS: Adult male mice were treated by intraperitoneal route (i.p.) with EEAO before the induction of nociceptive response by formalin, capsaicin and cinnamaldehyde, thermal heat hyperalgesia (hot plate test) and mechanical allodynia (traumatic sciatic nerve injury). Acute toxicity and non-specific sedative effects were evaluated. RESULTS: EEAO (10, 30 and 100 mg/kg) reduced both neurogenic and inflammatory phases of the formalin- and also capsaicin- and cinnamaldehyde-induced orofacial nociception. Interestingly, EEAO at 100mg/kg (i.p.) also reversed capsaicin-induced heat hyperalgesia assessed as the latency to paw withdrawal in the hot plate test. Also in the hot plate test, paw withdrawal latency was increased by EEAO (100 mg/kg) and this response was only partially reversed by naloxone. Furthermore, EEAO (100 mg/kg) also reduced mechanical allodynia caused by partial sciatic nerve ligation for 3 h. The estimated LD50 value was 889.14 mg/kg and EEAO did not alter the locomotion of animals in the open-field test. CONCLUSION: Taken together, our data show that EEAO produces prevalent antinociceptive effects and does not cause adverse effects. The presence of N-alkylamides, including spilanthol, suggests that the therapeutic effect of EEAO is related to its highest anesthetic activity. PMID- 24051026 TI - Jiawei-Yupingfeng-Tang, a Chinese herbal formula, inhibits respiratory viral infections in vitro and in vivo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Jiawei-Yupingfeng-Tang (JYT) is a Chinese herbal formula that is widely used to treat respiratory tract illness. However, the effect of JYT on respiratory viruses remains unknown. The influenza virus (IFV) and the human respiratory syncytial virus (HRSV) cause millions of cases of severe illness per year, and many of these illnesses develop into lethal pneumonia. The aim of this study is to evaluate whether JYT can be used to treat these infections. MATERIALS AND METHODS: The effect of JYT against IFV and HRSV was tested using a plaque reduction assay in the lower respiratory tract cell line A549. The expression of ICAM-1 was determined by real-time RT-PCR and western blotting. A mouse model infected with lethal influenza developing into interstitial pneumonia was used to evaluate the effect of JYT in vivo. RESULTS: JYT extract inhibited both IFV and HRSV in a dose-dependent manner when given before, during and after a viral infection. JYT was effective in blocking the entry of the virus. Furthermore, pre-treatment with JYT reduced the susceptibility of cells to the invasion of HRSV by inhibiting the expression of ICAM-1. Importantly, JYT extract increased the survival rate of lethal influenza infected mice, prolonged the survival time and alleviated the virus-induced lung lesions, which is comparable with the effects of ribavirin treatment. CONCLUSIONS: These data support JYT as an alternative modality to be used in the treatment of respiratory viral infection induced by HRSV and IFV. PMID- 24051027 TI - Isolation and identification of an anti-hepatitis B virus compound from Hydrocotyle sibthorpioides Lam. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hydrocotyle sibthorpioides (Apiaceae) have been used as a folk remedy for the treatment of fever, edema, detoxication, throat pain, psoriasis and hepatitis B virus infections in China. The aim of this study is to isolate and identify an anti-HBV compound from this herb. MATERIALS AND METHODS: A compound (saponin) was isolated from the active ethanol extract using bioassay-guided screening. The structure of the saponin was elucidated by spectroscopic methods and compared with published data. The anti-HBV activity of the saponin was evaluated by detecting the levels of HBV antigens, extracellular HBV DNA, nuclear covalent closed circular DNA (cccDNA) and five HBV promoters in HepG2.2.15 cells. In addition, the levels of serum HBsAg/HBeAg, DHBV DNA, ALT/AST and hepatic pathological changes were analyzed in DHBV-infected ducks. RESULTS: The chemical analysis indicated that the saponin isolated from Hydrocotyle sibthorpioides is asiaticoside. The pharmacodynamics experimental studies showed that asiaticoside effectively suppressed the levels of HBsAg/HBeAg, extracellular HBV DNA and intracellular cccDNA in a dose-dependent manner. Furthermore, experiments demonstrated that asiaticoside markedly reduced viral DNA transcription and replication by inhibiting the activities of core, s1, s2, and X gene promoters. In addition, asiaticoside markedly reduced DHBV replication without any obvious signs of toxicity. The levels of serum DHBV DNA, HBsAg/HBeAg were increased 3 days after drug withdrawal, but the levels rebounded slightly in the asiaticoside treatment groups compared with the 3TC treatment group. Moreover, analysis of the serum ALT/AST levels and the liver pathological changes indicated that asiaticoside could alleviate liver damage. CONCLUSIONS: Our results show that asiaticoside could efficiently inhibit HBV replication both in vitro and in vivo, and asiaticoside may be a major bioactive ingredient in Hydrocotyle sibthorpioides. PMID- 24051028 TI - Expression of skeletogenic genes during arm regeneration in the brittle star Amphiura filiformis. AB - The brittle star Amphiura filiformis, which regenerates its arms post autotomy, is emerging as a useful model for studying the molecular underpinnings of regeneration, aided by the recent availability of some molecular resources. During regeneration a blastema initially is formed distally to the amputation site, and then a rapid rebuild is obtained by adding metameric units, which will eventually differentiate and become fully functional. In this work we first characterize the developmental process of the regenerating arms using two differentiation markers for muscle and skeletal structures - Afi-trop-1 and Afi alphacoll. Both genes are not expressed in the blastema and newly added undifferentiated metameric units. Their expression at different regenerating stages shows an early segregation of muscle and skeletal cells during the regenerating process, long before the metameric units become functional. We then studied the expression of a set of genes orthologous of the sea urchin transcription factors involved in the development of skeletal and non-skeletal mesoderm: Afi-ets1/2, Afi-alx1, Afi-tbr, Afi-foxB and Afi-gataC. We found that Afi-ets1/2, Afi-alx1, Afi-foxB and Afi-gataC are all expressed at the blastemal stage. As regeneration progresses those genes are expressed in a similar small undifferentiated domain beneath the distal growth cap, while in more advanced metameric units they become restricted to different skeletal domains. Afi-foxB becomes expressed in non-skeletal structures. This suggests that they might play a combinatorial role only in the early cell specification process and that subsequently they function independently in the differentiation of different structures. Afi-tbr is not present in the adult arm tissue at any stage of regeneration. In situ hybridization results have been confirmed with a new strategy for quantitative PCR (QPCR), using a subdivision of the three stages of regeneration into proximal (differentiated) and distal (undifferentiated) arm segments. PMID- 24051029 TI - Psychological trauma symptoms and Type 2 diabetes prevalence, glucose control, and treatment modality among American Indians in the Strong Heart Family Study. AB - AIMS: The aims of this paper are to examine the relationship between psychological trauma symptoms and Type 2 diabetes prevalence, glucose control, and treatment modality among 3776 American Indians in Phase V of the Strong Heart Family Study. METHODS: This cross-sectional analysis measured psychological trauma symptoms using the National Anxiety Disorder Screening Day instrument, diabetes by American Diabetes Association criteria, and treatment modality by four categories: no medication, oral medication only, insulin only, or both oral medication and insulin. We used binary logistic regression to evaluate the association between psychological trauma symptoms and diabetes prevalence. We used ordinary least squares regression to evaluate the association between psychological trauma symptoms and glucose control. We used binary logistic regression to model the association of psychological trauma symptoms with treatment modality. RESULTS: Neither diabetes prevalence (22%-31%; p=0.19) nor control (8.0-8.6; p=0.25) varied significantly by psychological trauma symptoms categories. However, diabetes treatment modality was associated with psychological trauma symptoms categories, as people with greater burden used either no medication, or both oral and insulin medications (odds ratio=3.1, p<0.001). CONCLUSIONS: The positive relationship between treatment modality and psychological trauma symptoms suggests future research investigate patient and provider treatment decision making. PMID- 24051030 TI - STZ treatment induced apoptosis of retinal cells and effect of up-regulation of calcitonin gene related peptide in rats. AB - BACKGROUND: Evidence indicates an early neural injury of the retinal cells in diabetes. The aim of the current study was to investigate the apoptosis of the retinal cells and the relationship with CGRP. MATERIALS AND METHODS: The diabetes was induced by treatment of STZ, using which the apoptosis of retinal cells, the caspase-3 activity and the expression of CGRP in the retina and the serum were examined. Capsaicin (20mg/kg) was given to the animals to induce up-regulation of the CGRP. Apoptosis and CGRP in the retina were also examined in an in vitro study. RESULTS AND CONCLUSION: The apoptosis of the retinal cells was confined to the GCL, in which CGRP was normally located. A significant increase in the apoptosis ratio (P<0.05) was observed in the STZ treated animals and high glucose incubated retina, with reductions of CGRP. The pre-treatment with capsaicin effectively up-regulated CGRP and its encoding mRNA and attenuated the cell apoptosis and caspase-3 activity in the retina. The increases of the cell apoptosis in the retina may be related to the down-regulation of endogenous CGRP in diabetes. Capsaicin may attenuate the apoptosis of the retina cells at early times of diabetes, via up-regulation of CGRP. PMID- 24051031 TI - Comparison of three labeled silica nanoparticles used as tracers in transport experiments in porous media. Part II: transport experiments and modeling. AB - Three types of labeled silica nanoparticles were used in transport experiments in saturated sand. The goal of this study was to evaluate both the efficiency of labeling techniques (fluorescence (FITC), metal (Ag(0) core) and radioactivity ((110m)Ag(0) core)) in realistic transport conditions and the reactive transport of silica nanocolloids of variable size and concentration in porous media. Experimental results obtained under contrasted experimental conditions revealed that deposition in sand is controlled by nanoparticles size and ionic strength of the solution. A mathematical model is proposed to quantitatively describe colloid transport. Fluorescent labeling is widely used to study fate of colloids in soils but was the less sensitive one. Ag(0) labeling with ICP-MS detection was found to be very sensitive to measure deposition profiles. Radiolabeled ((110m)Ag(0)) nanoparticles permitted in situ detection. Results obtained with radiolabeled nanoparticles are wholly original and might be used for improving the modeling of deposition and release dynamics. PMID- 24051032 TI - Monoamine oxidase-A knockdown in human neuroblastoma cells reveals protection against mitochondrial toxins. AB - The study examined how the mitochondrial enzyme monoamine oxidase-A (MAO-A), which produces hydrogen peroxide as a catalytic by-product, influences death and survival mechanisms. Targeted microRNA (miRNA) was used to stably knock down MAO A mRNA, protein, and catalytic activity by 60-70% in SH-SY5Y human neuroblastoma cells. The effects of MAO-A knockdown (KD) on ATP, oxidative stress, electron transport chain, and survival following exposure to mitochondrial toxins were assessed. In control cells, complex I inhibition resulted in caspase-mediated cell death linked with ROS production and reduced ATP, followed by up-regulation of MAO-A mRNA, protein, and enzyme activity levels. Inhibition of complex III and IV resulted in a similar increase in MAO-A expression, while up-regulation of MAO A was lower following complex II inhibition. MAO-A KD decreased basal reactive oxygen species levels by 50% and increased levels of ATP and reduced glutathione and Bcl-2. MAO-A KD specifically increased the activity of complex I but had no effect on complex II-IV activities. Furthermore, MAO-A KD protected against inhibitors of complex I, III, and IV. In summary, endogenous MAO-A levels influence mitochondrial function, notably complex I activity, and MAO-A may be a target for protection against neurodegenerative conditions that involve oxidative stress and mitochondrial dysfunction as underlying pathogenic factors. PMID- 24051033 TI - Endogenous glucocorticoid receptor signaling drives rhythmic changes in human T cell subset numbers and the expression of the chemokine receptor CXCR4. AB - In humans, numbers of circulating naive T cells strongly decline in the morning, which was suggested to be mediated by cortisol, inducing a CXCR4 up-regulation with a subsequent extravasation of the cells. As a systematic evaluation of this assumption is lacking, we investigated in two human placebo-controlled studies the effects of the glucocorticoid receptor (GR) antagonist mifepristone (200 mg orally at 23:00) and of suppressing endogenous cortisol with metyrapone (1 g orally at 04:00) on temporal changes in CXCR4 expression and numbers of different T-cell subsets using flow cytometry. Mifepristone attenuated, and metyrapone completely blocked, the morning increase in CXCR4 expression on naive T cells. In parallel, both substances also hindered the decline in naive T-cell numbers with this effect, however, being less apparent after mifepristone. We identified, and confirmed in additional in vitro studies, a partial agonistic GR effect of mifepristone at night (i.e., between 02:00 and 03:30) that could explain the lower antagonistic efficacy of the substance on CXCR4 expression and naive T-cell counts. CXCR4 expression emerged to be a most sensitive marker of GR signaling. Our studies jointly show that endogenous cortisol, specifically via GR activation, causes the morning increase in CXCR4 expression and the subsequent extravasation of naive T cells, thus revealing an important immunological function of the morning cortisol rise. PMID- 24051034 TI - The role of pathogen-associated molecular patterns in inflammatory responses against alginate based microcapsules. AB - Alginate-based microcapsules are used for immunoisolation of cells to release therapeutics on a minute-to-minute basis. Unfortunately, alginate-based microcapsules are suffering from varying degrees of success, which is usually attributed to differences in tissue responses. This results in failure of the therapeutic cells. In the present study we show that commercial, crude alginates may contain pathogen-associated molecular patterns (PAMPs), which are recognized by the sensors of the innate immune system. Known sensors are Toll-like receptors (TLRs), NOD receptors, and C-type lectins. By using cell-lines with a non functional adaptor molecule essential in Toll-like receptor signaling, i.e. MyD88, we were able to show that alginates signal mainly via MyD88. This was found for low-G, intermediate-G, and high-G alginates applied in calcium-beads, barium-beads as well as in alginate-PLL-alginate capsules. These alginates did stimulate TLRs 2, 5, 8, and 9 but not TLR4 (LPS receptor). Upon implantation in rats these alginates provoked a strong inflammatory response resulting in fibrosis of the capsules. Analysis demonstrated that commercial alginates contain the PAMPs peptidoglycan, lipoteichoic acid, and flagellin. By applying purification procedures, these PAMPs were largely removed. This was associated with deletion of the inflammatory tissue responses as confirmed by an implantation experiment in rats. Our data also show that alginate itself does not provoke TLR mediated responses. We were able to unravel the sensor mechanism by which contaminants in alginates may provoke inflammatory responses. PMID- 24051035 TI - Low prevalence of interleukin-6 haplotypes associated with a decreased risk of type 2 diabetes in Mexican subjects with a family history of type 2 diabetes. AB - BACKGROUND AND AIMS: There is evidence that family history of type 2 diabetes (FHT2D) and single nucleotide polymorphisms (SNP) on the IL-6 gene promoter region are separately associated with the risk of developing type 2 diabetes. However the relationship between adult Mexican subjects with FHT2D and genotypes/haplotypes for IL-6 gene has not been explored. The aim of the present work was to study the prevalence of IL-6 -598G>A-572G>C-174G>C haplotypes among subjects with FHT2D and to determine whether their presence influences the relationship between FHT2D and risk factors for diabetes. METHODS: Two hundred fifty eight nondiabetic subjects participated in this study; 153 with and 105 without FHT2D. Polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) was used for genotyping. Logistic regression analysis was employed to assess the impact of IL-6 haplotypes on FHT2D per se and hyperinsulinemia and insulin resistance as risk factors for diabetes. RESULTS: Subjects with FHT2D showed a higher prevalence of hyperinsulinemia and insulin resistance (IR) than those without FHT2D (14.4 vs. 5.7%, p = 0.029, and 14.2 vs. 7.0% p = 0.050, respectively). Lower prevalence of -598 -572-174 (AGC)-haplotype (19%) in subjects with FHT2D was observed as well as a lower prevalence of hyperinsulinemia and IR among AGC haplotype carriers (12 and 14%, respectively). The relationship between FHT2D and IR was modified by the presence of AGC haplotype (from OR, 2.70; 95% CI, 0.99-7.36; p = 0.050 OR, 30.08; 95% CI, 0.58 1,568.06; p = 0.092). CONCLUSIONS: IL-6 -598/-572/-174 (AGC) haplotype has a low prevalence among first-degree relatives of subjects with type 2 diabetes. Our results suggest that this haplotype is associated with decreased risk of type 2 diabetes in Mexican subjects with FHT2D. PMID- 24051036 TI - Pulmonary arterial hypertension and microRNAs--an ever-growing partnership. AB - Pulmonary arterial hypertension (PAH) is a debilitating condition with progressive remodeling of the pulmonary resistance vessels. PAH is characterized by multifocal, polyclonal lesions inhabited by cells that underwent phenotypic transition, resulting in altered cell proliferation and contractility, ultimately resulting in increased vascular resistance. Diagnosis of PAH is confounded by the fact that it is largely asymptomatic in the initial stages. In fact, idiopathic PAH patients >65 years of age cannot be diagnosed hemodynamically due to high pulmonary capillary wedge pressure. This highlights the need for defining more robust molecular biomarkers for PAH diagnosis and progression. Recent studies have indicated that microRNAs (miRNAs), a class of small noncoding RNAs that regulate gene expression, play a discrete role in vascular inflammation and in the etiology of cardiovascular pathologies inclusive of PAH and can potentially serve as diagnostic biomarkers. However, a cohesive understanding of global miRNA mediated molecular events that control pulmonary vasculature plasticity is lacking which, if addressed systematically, can lead to detailed elucidation of the downstream cellular pathways that are affected by activation/silencing of silenced cognate transcripts. In turn, this can lead to not only robust biomarkers, but also to novel therapeutic strategies targeting more upstream regulators than the existing ones targeting more downstream effectors. The current review aims to provide a summary understanding of PAH, its associated pathophysiology, current knowledge of the role of miRNAs in PAH, and identifies grey areas that need further research for successful bench-to-bedside transition of these exciting new discoveries. PMID- 24051037 TI - Protein restriction in the rat negatively impacts long-chain polyunsaturated fatty acid composition and mammary gland development at the end of gestation. AB - BACKGROUND AND AIMS: Maternal nutrition during gestation is critical for mammary gland cell proliferation and differentiation and development of optimal delta-6 (Delta6D) and delta-5 (Delta5D) desaturase and elongase 2 and 5 (Elovl 2 and 5) activity for synthesis of the long chain polyunsaturated fatty acids (LC-PUFAs), arachidonic (AA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, important for normal fetal and neonatal brain development. We hypothesized that maternal low protein diet (LPD) impairs mammary gland preparation for lactation and PUFA synthesis. The aim of the study was to evaluate consequences of maternal LPD on mammary gland structure and development and expression of enzymes responsible for LC-PUFA production. METHODS: Pregnant rats were assigned to control or protein restricted, isocaloric diet (R). At 19 days gestation, mammary gland tissue was removed for histological analysis and lipid, AA, EPA and DHA determination by gas chromatography. Gene transcription was quantified by RT-PCR and protein by Western blot. RESULTS: In R mothers, mammary gland lobuloalveolar development was decreased and showed fat cell infiltration. Delta6D, Delta5D, and Elovl 5 mRNA were lower in R, whereas protein levels measured by Western blot were unchanged. This is the first report that detects mammary gland desaturase and elongase protein. Although Elovl 2 mRNA was not detectable by RT-PCR, Elovl 2 protein was not different between groups. AA and DHA were lower and EPA undetectable in the mammary gland of R mothers. CONCLUSIONS: Maternal LPD decreased late gestation mammary gland lobuloalveolar development and LC-PUFAs. Protein restriction negatively impacts maternal mammary gland development prior to lactation. PMID- 24051038 TI - Surveillance of methicillin-resistant Staphylococcus aureus causing nosocomial infections in five medical centers of Monterrey, Nuevo Leon, Mexico from 2005 2009. AB - BACKGROUND AND AIMS: Staphylococcus aureus is a principal cause of human bacterial infection worldwide. The dissemination of antibiotic resistance among S. aureus strains is very import in the treatment of Staphylococcal infections. We undertook this study to identify methicillin-resistant Staphylococcus aureus (MRSA) clones responsible for nosocomial infection in five medical centers in Monterrey, Nuevo Leon (N.L.), Mexico from 2005-2009. METHODS: One hundred ninety MRSA strains collected from 2005-2009 from five hospitals affiliated with the Instituto Mexicano del Seguro Social (IMSS) in Monterrey, N.L., Mexico were characterized by antimicrobial susceptibility, pulsed field gel electrophoresis (PFGE) and Staphylococcal Cassette Chromosome mec (SCCmec) typing. RESULTS: Only one clone was present in the five hospitals (clone C); this clone is strongly associated with the New York-Japan clone (SCCmec II) with a broad resistance profile. CONCLUSIONS: This study clearly documented the high ability for dissemination and the persistence of the New York-Japan clone in these centers. PMID- 24051039 TI - Polymorphisms in genes coding for HSP-70 are associated with gastric cancer and duodenal ulcer in a population at high risk of gastric cancer in Costa Rica. AB - BACKGROUND AND AIMS: Costa Rica has among the highest incidence and mortality rates for gastric cancer worldwide. The reasons for this are largely unknown. Polymorphisms of inflammatory response genes including genes encoding heat shock proteins (HSP) have been shown to be associated with the risk of gastric cancer in some populations. This study addresses the possible association between the HSP70-2 +1267 and HSP70-Hom +2437 polymorphisms and the risk of developing gastric cancer in a high-risk population in Costa Rica. METHODS: DNA from 39 individuals diagnosed with gastric cancer, 79 healthy controls, 55 individuals with chronic gastritis and 52 individuals with duodenal ulcer was genotyped for the polymorphisms HSP70-2 +1267 and HSP70-Hom +2437 by RFLP. Logistic regression analysis was used to determine possible associations with the diagnoses and lineal regression analysis to determine associations with blood pepsinogen (PGs) levels as measured by serology. RESULTS: The GA genotype of HSP70-2 was associated with increased risk of gastric cancer (OR = 3.42; 95% CI = 1.27-9.21; p = 0.015) and duodenal ulcer (OR = 2.57; 95% CI = 1.03-6.36; p = 0.042) as compared to the GG genotype. Persons with C carrier genotypes of HSP70-Hom were significantly less susceptible to gastric cancer than those with the TT genotype (OR = 0.29; 95% CI = 0.09-0.87; p = 0.027). The C carrier genotype was associated with lower PGI concentrations but none of the polymorphisms were associated with PGI/PGII. CONCLUSIONS: Polymorphisms of HSP70 genes are associated with the development of gastric cancer and duodenal ulcers in a population at high risk for gastric cancer in Costa Rica. PMID- 24051040 TI - Epidemiological association between body fat percentage and cervical cancer: a cross-sectional population-based survey from Mexico. AB - BACKGROUND AND AIMS: Various studies have reported a direct association of cervical cancer risk with obesity and weight but not with the body fat percentage (BFP). The aim of this study was to analyze various anthropometric measures as potential risk factors for cervical cancer. METHODS: A total of 20,236 women were included in a cross-sectional population-based survey. Obesity was defined according to the World Health Organization criteria, and central obesity was >=80 cm; the BFP was defined using the Deurenberg equation (BFP = 1.2 [BMI] + 0.23 [age] - 10.8 [sex] - 5.4). The odds ratio (OR) was estimated from the chi square test and logistic regression models. RESULTS: The prevalence of cervical cancer increased from 514 (95% confidence interval [CI] 321, 707) and 680 (95% CI 494, 866) to 732 (95% CI 535, 928) per 100,000 inhabitants in subjects with a normal weight, subjects who were overweight and subjects who were obese, respectively. Moreover, an association between cervical cancer and BFP (OR 1.027; CI 95% 1.006, 1.048; p = 0.012) was observed, and the risk increased with a BFP >=45% (OR 2.369; CI 95% 1.284, 4.369; p = 0.006). CONCLUSIONS: These data suggest a trend between the body mass index and the increasing prevalence of cervical cancer. In addition, the data showed a significant association between the BFP and cervical cancer, and this epidemiological association was higher as the BFP increased. PMID- 24051041 TI - Obstructive sleep apnea syndrome, vascular pathology, endothelial function and endothelial cells and circulating microparticles. AB - Accelerated atherosclerosis and increased cardiovascular risk are frequently reported in patients with obstructive sleep apnea (OSA) syndrome. In this article the authors attempt a review of the current understanding of the relationship between vascular risk and OSA syndrome based on large cohort studies that related the disease to several cardiovascular risk factors and vascular pathologies. We also discuss the pathophysiological mechanisms that may be involved in this relationship, starting with endothelial dysfunction and its mediators. These include an increased oxidative stress and inflammation as well as several disorders of coagulation and lipid metabolism. Moreover, circulating microparticles from activated leukocytes (CD62L_MPs) are higher in patients with OSA and there is a positive correlation between circulating levels of CD62L_MPs and nocturnal hypoxemia severity. Finally, circulating level of endothelial microparticles and circulating endothelial cells seem to be increased in patients with OSA. Also, endothelial progenitor cells are reduced and plasma levels of the vascular endothelial growth factor are increased. PMID- 24051042 TI - Re-treatment with highly purified nIFNalpha in Mexican nonresponder patients with chronic genotype 1 hepatitis C. AB - BACKGROUND AND AIMS: We undertook this study to evaluate the virological response to and presence of adverse events to natural interferon alpha (nIFNalpha; Multiferon(r)) treatment in previously nonresponsive Mexican patients chronically infected with genotype 1 hepatitis C. METHODS: Thirty-nine patients received a 4 week induction of 5 days/week of 6 MU nIFNalpha plus weight-based ribavirin followed by 3 MU of nIFNalpha three times a week for 44 weeks. The relationship between viral response and incidence of adverse events was analyzed. RESULTS: Early viral response (EVR) was age- and sex-dependent, with older male patients being less responsive. Sustained viral response (SVR) was evaluated according to: a) intention to treat analysis, b) 48-week treatment and 24-week follow-up (16 patients), and c) patients with EVR (11 patients). None of the factors was significantly different in groups a) and b); however, in group c) there was a better response with a marked viral load decline in younger patients and in patients aged 50 years and older. Five of 39 (13%) patients who completed treatment presented with an SVR. The most common adverse effect was asthenia in 27% of patients. CONCLUSIONS: nIFNalpha could be a useful strategy for re treatment in chronic hepatitis C, genotype 1, in previously nonresponsive patients. Confirmation of these data in a larger population is required. PMID- 24051043 TI - Cervical cancers associated with human papillomavirus types 16, 18 and 45 are diagnosed in younger women than cancers associated with other types: a cross sectional observational study in Wales and Scotland (UK). AB - BACKGROUND: Most cervical cancers are attributable to infection with one of fourteen types of human papillomavirus (HPV), but HPV types differ in oncogenic potential. Characterisation of cancers associated with specific HPV types is required to predict the likely impact of current prophylactic vaccines and the potential benefits of vaccine formulations including additional HPV types. OBJECTIVE: The study aimed to correlate HPV type with histology and age at diagnosis, in Invasive Cervical Cancers (ICCs) from two of the devolved countries of the UK (Wales and Scotland). STUDY DESIGN: Centralised histopathology review and rigorously standardised HPV-DNA typing were applied to 592 ICC diagnosed 2001 2006. HPV status was analysed in relation to histology and age at diagnosis. RESULTS: HPV infection was confirmed in 535/592 cases. Among the 497 tumours infected with single HPV types, the three most common types were HPV16 (62% 95%CI: 57.6-66.1), HPV18 (18.9% 95%CI: 15.7-22.6) and HPV45 (5.4% 95%CI: 3.7 7.8). HPV16 or 18 were present in 80.9% of HPV positive cases. Women with tumours associated with HPV types 16, 18 and 45 were on average 10.5 years younger at diagnosis than women with tumours associated with other HPV types. CONCLUSIONS: Prophylactic vaccines targeting HPV16 and 18 could potentially prevent up to 80.9% of ICC in the populations investigated. Cancers associated with HPV16, 18 and 45 were diagnosed at younger ages, supporting the hypothesis of faster progression than for tumours caused by other HPV types. PMID- 24051044 TI - Recent outbreak of aseptic meningitis in Italy due to Echovirus 30 and phylogenetic relationship with other European circulating strains. AB - BACKGROUND: Enteroviruses (EVs) are common human viral pathogens, causing a variety of diseases, including aseptic meningitis. Recently, EV aseptic meningitis outbreaks have been reported across Europe, but, in Italy, knowledge of recent EV molecular epidemiology is very limited. OBJECTIVES: We report an outbreak of EV aseptic meningitis in 10 adults in North-Western Italy, from October to November 2012. Patients were parents or close relatives of children <5 years old attending the same class of a nursery school, suffering from a mild febrile upper respiratory disease. Phylogenetic relationship with other European circulating strains was analyzed updating E30 circulation in Italy in recent years. STUDY DESIGN: EVs were detected from cerebrospinal fluid (CSF) specimens with a real-time reverse transcription polymerase chain reaction and virus isolation was achieved from rectal and pharyngeal swabs. For cluster definition and phylogenetic studies, viral VP1 region was directly amplified and sequenced from CSF. RESULTS: EVs were identified in CSF from all patients and from rectal and pharyngeal swabs in 7 of them. Direct sequencing of CSF revealed the presence of the same Echovirus 30 (E30) in all patients and phylogenetic analysis identified it as a diverging clade within E30 genotype VII, the most recent strain circulating in UK, Finland and Denmark since 2006. CONCLUSION: Molecular techniques allowed the rapid identification and typing of E30 from CSF. Phylogenetic analysis revealed that the cluster might be due to a new E30 variant within the genotype VII currently circulating in Europe, thus updating the epidemiology of EV circulation in Italy. PMID- 24051045 TI - Converting hazardous organics into clean energy using a solar responsive dual photoelectrode photocatalytic fuel cell. AB - Direct discharging great quantities of organics into water-body not only causes serious environmental pollution but also wastes energy sources. In this paper, a solar responsive dual photoelectrode photocatalytic fuel cell (PFC(2)) based on TiO2/Ti photoanode and Cu2O/Cu photocathode was designed for hazardous organics treatment with simultaneous electricity generation. Under solar irradiation, the interior bias voltage produced for the Fermi level difference between photoelectrodes drives photoelectrons of TiO2/Ti photoanode to combine with photoholes of Cu2O/Cu photocathode through external circuit thus generating electricity. In the meantime, organics are decomposed by photoholes remained at TiO2/Ti photoanode. By using various hazardous organics including azo dyes as model pollutants, the PFC showed high converting performance of organics into electricity. For example, in 0.05 M phenol solution, a short-circuit current density 0.23 mA cm(-2), open-circuit voltage 0.49 V, maximum power output 0.3610( 4)W cm(-2) was achieved. On the other hand, removal rate of chroma reached 67%, 87% and 63% in 8h for methyl orange, methylene blue, Congo red, respectively. PMID- 24051046 TI - Regulated unfolding: a basic principle of intraprotein signaling in modular proteins. AB - Modular proteins possess N-terminal sensor domains connected with different C terminal output domains. Different output domains, for example, phosphodiesterases adenylyl cyclases, are regulated by identical N-terminal domains. Therefore, the mechanisms of intraprotein signaling share properties suitable to regulation of disparate output enzymes, which see the same signal but react differently. The common denominator is a reversible switch of folding/unfolding that connects sensor and output domains. In the inhibited state, output domains are restrained, whereas in the activated state domains are released to assemble according to intrinsic domain properties. We review recent work investigating the mechanism of intraprotein signaling and discuss how this signaling mechanism may have contributed to the evolutionary diversity of specific small molecule-binding domains without loss of regulatory properties. PMID- 24051047 TI - Including physiological variables in studies might confuse more than clarify. PMID- 24051048 TI - Effects of chromatin decondensation on alternative NHEJ. AB - In cells of higher eukaryotes, repair of DNA double strand breaks (DSBs) utilizes different forms of potentially error-prone non-homologous end joining (NHEJ): canonical DNA-PK-dependent (C-NHEJ) and alternative backup pathways (A-NHEJ). In contrast to C-NHEJ, A-NHEJ shows pronounced efficiency fluctuations throughout the cell cycle and is severely compromised as cells cease proliferating and enter the plateau phase (Windhofer et al., 2007 [23]). The molecular mechanisms underpinning this response remain unknown but changes in chromatin structure are prime candidate-A-NHEJ-modulators. Since parameters beyond chromatin acetylation appear to determine A-NHEJ efficiency (Manova et al., 2012 [42,76]), we study here the role of chromatin decondensation mediated either by treatment with 5' aza-2'-deoxycytidine (AzadC) or growth in hypotonic conditions, on A-NHEJ. We report that both treatments have no detectable effect on C-NHEJ but provoke, specifically for A-NHEJ, cell-growth-dependent effects. These results uncover for the first time a link between A-NHEJ and chromatin organization and provide means for understanding the regulatory mechanisms underpinning the growth-state dependency of A-NHEJ. A-NHEJ is implicated in the formation of chromosomal translocations and in chromosome fusions that underlie genomic instability and carcinogenesis. The observations reported here may therefore contribute to the development of drug-based A-NHEJ suppression-strategies aiming at optimizing cancer treatment outcomes and possibly also at suppressing carcinogenesis. PMID- 24051049 TI - Xeroderma pigmentosum complementation group C protein (XPC) serves as a general sensor of damaged DNA. AB - The Xeroderma pigmentosum complementation group C protein (XPC) serves as the primary initiating factor in the global genome nucleotide excision repair pathway (GG-NER). Recent reports suggest XPC also stimulates repair of oxidative lesions by base excision repair. However, whether XPC distinguishes among various types of DNA lesions remains unclear. Although the DNA binding properties of XPC have been studied by several groups, there is a lack of consensus over whether XPC discriminates between DNA damaged by lesions associated with NER activity versus those that are not. In this study we report a high-throughput fluorescence anisotropy assay used to measure the DNA binding affinity of XPC for a panel of DNA substrates containing a range of chemical lesions in a common sequence. Our results demonstrate that while XPC displays a preference for binding damaged DNA, the identity of the lesion has little effect on the binding affinity of XPC. Moreover, XPC was equally capable of binding to DNA substrates containing lesions not repaired by GG-NER. Our results suggest XPC may act as a general sensor of damaged DNA that is capable of recognizing DNA containing lesions not repaired by NER. PMID- 24051050 TI - Contribution of DNA unwrapping from histone octamers to the repair of oxidatively damaged DNA in nucleosomes. AB - Reactive oxygen species generate ~20,000 oxidative lesions in the DNA of every cell, every day. Most of these lesions are located within nucleosomes, which package DNA in chromatin and impede base excision repair (BER). We demonstrated previously that periodic, spontaneous partial unwrapping of DNA from the underlying histone octamer enables BER enzymes to bind to oxidative lesions that would otherwise be sterically inaccessible. In the present study, we asked if these periodic DNA unwrapping events are frequent enough to account for the estimated rates of BER in vivo. We measured rates of excision of oxidative lesions from sites in nucleosomes that are accessible only during unwrapping episodes. Using reaction conditions appropriate for presteady-state kinetic analyses, we derived lesion exposure rates for both 601 and 5S rDNA-based nucleosomes. Although DNA unwrapping-mediated exposure of a lesion ~16NT from the nucleosome edge occurred ~7-8 times per minute, exposure rates fell dramatically for lesions located 10 or more NT further in from the nucleosome edge. The rates likely are too low to account for observed rates of BER in cells. Thus, chromatin remodeling, either BER-specific or that associated with transcription, replication, or other DNA repair processes, probably contributes to efficient BER in vivo. PMID- 24051052 TI - Sleep patterns, diet quality and energy balance. AB - There is increasing evidence showing that sleep has an influence on eating behaviors. Short sleep duration, poor sleep quality, and later bedtimes are all associated with increased food intake, poor diet quality, and excess body weight. Insufficient sleep seems to facilitate the ingestion of calories when exposed to the modern obesogenic environment of readily accessible food. Lack of sleep has been shown to increase snacking, the number of meals consumed per day, and the preference for energy-rich foods. Proposed mechanisms by which insufficient sleep may increase caloric consumption include: (1) more time and opportunities for eating, (2) psychological distress, (3) greater sensitivity to food reward, (4) disinhibited eating, (5) more energy needed to sustain extended wakefulness, and (6) changes in appetite hormones. Globally, excess energy intake associated with not getting adequate sleep seems to be preferentially driven by hedonic rather than homeostatic factors. Moreover, the consumption of certain types of foods which impact the availability of tryptophan as well as the synthesis of serotonin and melatonin may aid in promoting sleep. In summary, multiple connections exist between sleep patterns, eating behavior and energy balance. Sleep should not be overlooked in obesity research and should be included as part of the lifestyle package that traditionally has focused on diet and physical activity. PMID- 24051051 TI - Human Pol epsilon-dependent replication errors and the influence of mismatch repair on their correction. AB - Mutations in human DNA polymerase (Pol) epsilon, one of three eukaryotic Pols required for DNA replication, have recently been found associated with an ultramutator phenotype in tumors from somatic colorectal and endometrial cancers and in a familial colorectal cancer. Possibly, Pol epsilon mutations reduce the accuracy of DNA synthesis, thereby increasing the mutational burden and contributing to tumor development. To test this possibility in vivo, we characterized an active site mutant allele of human Pol epsilon that exhibits a strong mutator phenotype in vitro when the proofreading exonuclease activity of the enzyme is inactive. This mutant has a strong bias toward mispairs opposite template pyrimidine bases, particularly T * dTTP mispairs. Expression of mutant Pol epsilon in human cells lacking functional mismatch repair caused an increase in mutation rate primarily due to T * dTTP mispairs. Functional mismatch repair eliminated the increased mutagenesis. The results indicate that the mutant Pol epsilon causes replication errors in vivo, and is at least partially dominant over the endogenous, wild type Pol epsilon. Since tumors from familial and somatic colorectal patients arise with Pol epsilon mutations in a single allele, are microsatellite stable and have a large increase in base pair substitutions, our data are consistent with a Pol epsilon mutation requiring additional factors to promote tumor development. PMID- 24051053 TI - Expression of maternal behavior and activation of the bed nucleus of the stria terminalis during predatory threat exposure: modulatory effects of transport stress. AB - Past work has established that levels of maternal care provided to rat pups during the postpartum period plays an important role in shaping development of the stress response system, such that high levels of pup licking and grooming and active nursing behaviors are associated with more efficient hypothalamic pituitary-adrenal responses to stressors in adulthood. Furthermore, a prior study from our laboratory has demonstrated facilitation of maternal care for five days following a one-hour predator odor exposure on the day of giving birth. The present study was an investigation of the effects on maternal care during a one hour predator odor exposure administered on the day of giving birth, with or without the addition of transport stress immediately prior to the odor exposure. Stress-induced activation of the medial preoptic area (MPOA) and the bed nucleus of the stria terminalis (BNST), two brain regions involved in regulating maternal behaviors, were also quantified using c-Fos immunohistochemistry. Our results show that predator odor exposure soon after birth does not significantly alter expression of maternal behaviors during the hour-long exposure period, unless the dams are also exposed to transport stress, in which case maternal behaviors are reduced during the first 10min of the exposure but not significantly different during the final 10min. Predator odor exposure (with or without additional transport stress) increased c-Fos immunoreactivity in the BNST, but not the MPOA, relative to control odor exposure, suggesting that the BNST may play an important role in integration of threat cues and transduction of their meaning into long term effects on expression of maternal care. Future experiments should be designed to test the effects of temporary inactivation of the BNST during postpartum predator odor exposure. PMID- 24051054 TI - Deciphering azole resistance mechanisms with a focus on transcription factor encoding genes TAC1, MRR1 and UPC2 in a set of fluconazole-resistant clinical isolates of Candida albicans. AB - Several and often combined mechanisms can lead to acquired azole resistance in Candida albicans and subsequent therapeutic failure. The aim of this study was to provide a complete overview of the molecular basis of azole resistance in a set of six C. albicans clinical isolates recovered from patients who failed azole therapy. For this purpose, expression levels of CDR1, MDR1 and ERG11 were investigated by reverse transcription PCR (RT-PCR) together with amplification and sequencing of the genes encoding their transcription factors TAC1, MRR1 and UPC2. In all, the data underline that azole resistance in this set of clinical isolates results from distinct, often combined, mechanisms, being mostly driven by CDR1 and/or MDR1 active efflux. We show that gain-of-function (GOF) mutations in the transcription-factor-encoding genes TAC1, MRR1 and UPC2 are a common event in azole-resistant C. albicans clinical isolates. In addition, together with the finding that these genes are highly permissive to nucleotide changes, we describe several novel mutations that could act as putative GOF mutations involved in fluconazole resistance. PMID- 24051055 TI - The role of competitive binding to human serum albumin on efavirenz-warfarin interaction: a nuclear magnetic resonance study. AB - The potential for co-prescription of the anti-human immunodeficiency virus (anti HIV) drug efavirenz (EFV) and the oral anticoagulant warfarin (WAR) is currently high as EFV is a drug of choice for HIV type 1 infection and because cardiovascular disease is increasing among HIV-infected individuals. However, clinical reports of EFV-WAR interaction, leading to WAR overdosing, call for elucidation of the mechanisms involved in this drug-drug interaction. Here we present the first report demonstrating competition of the two drugs for the same binding site of human serum albumin. Using ligand-based nuclear magnetic resonance experiments, this study proves that EFV has an effect on the concentration of free WAR. This previously unidentified EFV-WAR interaction represents a potential risk factor that should be taken into account when considering treatment options. PMID- 24051056 TI - Glycerolipids in photosynthesis: composition, synthesis and trafficking. AB - Glycerolipids constituting the matrix of photosynthetic membranes, from cyanobacteria to chloroplasts of eukaryotic cells, comprise monogalactosyldiacylglycerol, digalactosyldiacylglycerol, sulfoquinovosyldiacylglycerol and phosphatidylglycerol. This review covers our current knowledge on the structural and functional features of these lipids in various cellular models, from prokaryotes to eukaryotes. Their relative proportions in thylakoid membranes result from highly regulated and compartmentalized metabolic pathways, with a cooperation, in the case of eukaryotes, of non-plastidic compartments. This review also focuses on the role of each of these thylakoid glycerolipids in stabilizing protein complexes of the photosynthetic machinery, which might be one of the reasons for their fascinating conservation in the course of evolution. This article is part of a Special Issue entitled: Dynamic and ultrastructure of bioenergetic membranes and their components. PMID- 24051057 TI - Mutations and polymorphisms in FSH receptor: functional implications in human reproduction. AB - FSH brings about its physiological actions by activating a specific receptor located on target cells. Normal functioning of the FSH receptor (FSHR) is crucial for follicular development and estradiol production in females and for the regulation of Sertoli cell function and spermatogenesis in males. In the last two decades, the number of inactivating and activating mutations, single nucleotide polymorphisms, and spliced variants of FSHR gene has been identified in selected infertile cases. Information on genotype-phenotype correlation and in vitro functional characterization of the mutants has helped in understanding the possible genetic cause for female infertility in affected individuals. The information is also being used to dissect various extracellular and intracellular events involved in hormone-receptor interaction by studying the differences in the properties of the mutant receptor when compared with WT receptor. Studies on polymorphisms in the FSHR gene have shown variability in clinical outcome among women treated with FSH. These observations are being explored to develop molecular markers to predict the optimum dose of FSH required for controlled ovarian hyperstimulation. Pharmacogenetics is an emerging field in this area that aims at designing individual treatment protocols for reproductive abnormalities based on FSHR gene polymorphisms. The present review discusses the current knowledge of various genetic alterations in FSHR and their impact on receptor function in the female reproductive system. PMID- 24051058 TI - Effects of TET1 knockdown on gene expression and DNA methylation in porcine induced pluripotent stem cells. AB - TET1 is implicated in maintaining the pluripotency of embryonic stem cells. However, its precise effects on induced pluripotent stem cells (iPSCs), and particularly on porcine iPSCs (piPSCs), are not well defined. To investigate the role of TET1 in the pluripotency and differentiation of piPSCs, piPSCs were induced from porcine embryonic fibroblasts by overexpression of POU5F1 (OCT4), SOX2, KLF4, and MYC (C-MYC). siRNAs targeting to TET1 were used to transiently knockdown the expression of TET1 in piPSCs. Morphological abnormalities and loss of the undifferentiated state of piPSCs were observed in the piPSCs after the downregulation of TET1. The effects of TET1 knockdown on the expression of key stem cell factors and differentiation markers were analyzed to gain insights into the molecular mechanisms underlying the phenomenon. The results revealed that knockdown of TET1 resulted in the downregulated expression of pluripotency related genes, such as LEFTY2, KLF2, and SOX2, and the upregulated expression of differentiation-related genes including PITX2, HAND1, GATA6, and LEF1. However, POU5F1, MYC, KLF4, and NANOG were actually not downregulated. Further analysis showed that the methylation levels of the promoters for POU5F1 and MYC increased significantly after TET1 downregulation, whereas there were no obvious changes in the promoters of SOX2, KLF4, and NANOG. The methylation of the whole genome increased, while hydroxymethylation slightly declined. Taken together, these results suggest that TET1 may play important roles in the self-renewal of piPSCs and the maintenance of their characteristics by regulating the expression of genes and the DNA methylation. PMID- 24051059 TI - Prokineticin 1 induces a pro-inflammatory response in murine fetal membranes but does not induce preterm delivery. AB - The mechanisms that regulate the induction of term or preterm delivery (PTD) are not fully understood. Infection is known to play a role in the induction of pro inflammatory cascades in uteroplacental tissues associated with preterm pathological parturition. Similar but not identical cascades are evident in term labour. In the current study, we used a mouse model to evaluate the role of prokineticins in term and preterm parturition. Prokineticins are multi functioning secreted proteins that signal through G-protein-coupled receptors to induce gene expression, including genes important in inflammatory responses. Expression of prokineticins (Prok1 and Prok2) was quantified in murine uteroplacental tissues by QPCR in the days preceding labour (days 16-19). Prok1 mRNA expression increased significantly on D18 in fetal membranes (compared with D16) but not in uterus or placenta. Intrauterine injection of PROK1 on D17 induced fetal membrane mRNA expression of the pro-inflammatory mediators Il6, Il1b, Tnf, Cxcl2 and Cxcl5, which are not normally up-regulated until D19 of pregnancy. However, intrauterine injection of PROK1 did not result in PTD. As expected, injection of lipopolysaccharide (LPS) induced PTD, but this was not associated with changes in expression of Prok1 or its receptor (Prokr1) in fetal membranes. These results suggest that although Prok1 exhibits dynamic mRNA regulation in fetal membranes preceding labour and induces a pro-inflammatory response when injected into the uterus on D17, it is insufficient to induce PTD. Additionally, prokineticin up-regulation appears not to be part of the LPS induced inflammatory response in mouse fetal membranes. PMID- 24051060 TI - Interactive effects of chronic cigarette smoking and age on hippocampal volumes. AB - BACKGROUND: Previous cross-sectional MRI studies with healthy, young-to-middle aged adults reported no significant differences between smokers and non-smokers on total hippocampal volume. However, these studies did not specifically test for greater age-related volume loss in the total hippocampus or hippocampal subregions in smokers, and did they did not examine relationships between hippocampal and subfield volumes and episodic learning and memory performance. METHODS: Healthy, young-to-middle-aged (45 +/- 12 years of age) smokers (n=39) and non-smokers (n=43) were compared on total hippocampal and subfield volumes derived from high-resolution 4 Tesla MRI, emphasizing testing for greater age related volume losses in smokers. Associations between hippocampal volumes and measures of episodic learning and memory were examined. RESULTS: Smokers showed significantly smaller volumes, as well as greater volume loss with increasing age than non-smokers in the bilateral total hippocampus and multiple subfields. In smokers, greater pack-years were associated with smaller volumes of the total hippocampus, presubiculum, and subiculum. In the entire cohort, performance on measures of learning and memory was related to larger total hippocampal and several subfield volumes, predominately in the left hemisphere. CONCLUSIONS: Chronic cigarette smoking in this young-to-middle aged cohort was associated with smaller total hippocampal and subfield volumes, which were exacerbated by advancing age. Findings also indicated an adverse smoking dose/duration response (i.e., pack-years) with total hippocampal and select subfield volumes. These hippocampal volume abnormalities in smokers may be related to the deficiencies in episodic learning and memory in young-to-middle-aged smokers reported in previous studies. PMID- 24051061 TI - Law enforcement attitudes toward overdose prevention and response. AB - BACKGROUND: Law enforcement is often the first to respond to medical emergencies in the community, including overdose. Due to the nature of their job, officers have also witnessed first-hand the changing demographic of drug users and devastating effects on their community associated with the epidemic of nonmedical prescription opioid use in the United States. Despite this seminal role, little data exist on law enforcement attitudes toward overdose prevention and response. METHODS: We conducted key informant interviews as part of a 12-week Rapid Assessment and Response (RAR) process that aimed to better understand and prevent nonmedical prescription opioid use and overdose deaths in locations in Connecticut and Rhode Island experiencing overdose "outbreaks." Interviews with 13 law enforcement officials across three study sites were analyzed to uncover themes on overdose prevention and naloxone. RESULTS: Findings indicated support for law enforcement involvement in overdose prevention. Hesitancy around naloxone administration by laypersons was evident. Interview themes highlighted officers' feelings of futility and frustration with their current overdose response options, the lack of accessible local drug treatment, the cycle of addiction, and the pervasiveness of easily accessible prescription opioid medications in their communities. Overdose prevention and response, which for some officers included law enforcement-administered naloxone, were viewed as components of community policing and good police-community relations. CONCLUSION: Emerging trends, such as existing law enforcement medical interventions and Good Samaritan Laws, suggest the need for broader law enforcement engagement around this pressing public health crisis, even in suburban and small town locations, to promote public safety. PMID- 24051062 TI - A systematic review of evidence on the association between cocaine use and seizures. AB - BACKGROUND: Institutional monographs/medical textbooks mention seizures as a neurological complication of cocaine, but no systematic reviews (SRs) have been published on this issue. We aimed to conduct a SR of the literature on the relationship between cocaine use and seizures and to summarize the biological plausibility of that relationship. METHODS: The pathophysiological mechanisms that may underlie an association between cocaine and seizures were summarized; a SR was then performed using three databases (EMBASE, Medline, PsycINFO) and the Cochrane-library to search for published papers (1980-2012) aimed at quantifying the associations between cocaine use and seizures. The inclusion criteria for selection were: articles based on clinical trials, cohort, case-control (CC) or cross-sectional (CS) studies, participants >= 14 years old and not pregnant, and use of cocaine in the last 72 h. Information was extracted, evaluated and cross checked independently by two researchers. RESULTS: Of the 1243 potentially relevant articles initially identified; one CC and 22 CS studies were finally selected. The CC study did not find cocaine use to be a risk-factor for seizures. In addition to the limitations of the CS design, these studies had important methodological weaknesses and biases. CONCLUSIONS: Despite its biological plausibility, no rigorous scientific evidence supports a causal relationship between cocaine use and seizures. The misinterpretation of the role of cocaine may have important implications in medical services. Well-conducted studies are urgently needed. PMID- 24051064 TI - Prevalence of psychiatric disorders and suicidal ideation in liver transplanted patients: a cross-sectional study. AB - AIM: Liver transplantation is the first choice treatment for terminal liver disease, but its success is strictly related to the adherence to immunosuppressive therapy. Psychiatric disorders can decrease both adherence and quality of life of liver transplanted patients. We aimed to assess prevalence of post-transplant psychiatric disorders in liver transplanted patients and its association with quality of life, adherence, suicidal ideation. METHODS: Psychiatric examination was performed with an internationally validated structured clinical interview: Mini International Neuropsychiatric Interview Plus. Quality of life was assessed using The Short Form (36) Health Survey (SF36). Adherence was established by the Siegal scale, a 7-point self-reported scale, and by collateral reports of relatives and transplant clinicians. The Scale for Suicide Ideation (SSI) was used for suicidal risk assessment. RESULTS: Fifty-one liver transplanted patients (mean age: 60.06 years, SD: 6.49) were enrolled. Thirty patients (58.82%) suffered from one or more psychiatric disease. Patients diagnosed with psychiatric disease displayed worse scores at SSI (P=0.032) and at several SF36 items: physical health (P=0.038), vitality (P=0.012), social activities (P=0.027), emotional state (P=0.031), mental health (P=0.014). Both patients with major depression and patients with two or more psychiatric disorders displayed lower adherence (P<=0.001 and P=0.002). Diagnosis of major depression was associated with female sex (P=0.021), aggressiveness (P=0.042), chronic rejection (P=0.011). CONCLUSIONS: We confirm the high prevalence of psychiatric disease in our cohort of liver transplanted patients. The presence of psychiatric disease is associated with decreased quality of life and increased suicide ideation. Patients with major depression should be considered significantly at risk for non-adherence. PMID- 24051063 TI - Characterizing and improving HIV and hepatitis knowledge among primary prescription opioid abusers. AB - BACKGROUND: The high rates of HIV and Hepatitis C (HCV) infection among opioid abusers is a serious public health problem, and efforts to enhance knowledge regarding risks for HIV/hepatitis infection in this population are important. Abuse of prescription opioids (POs), in particular, has increased substantially in the past decade and is associated with increasing rates of injection drug use and HCV infection. METHODS: This study describes the effects of a brief HIV/HCV educational intervention delivered in the context of a larger randomized, double blind clinical trial evaluating the relative efficacy of 1-, 2-, and 4-week outpatient buprenorphine tapers and subsequent oral naltrexone maintenance for treating PO dependence. HIV- and HCV-related knowledge and risk behaviors were characterized pre- and post-intervention in 54 primary PO abusers. RESULTS: The educational intervention was associated with significant improvements in HIV (p<.001) and HCV (p<.001) knowledge. Significant improvements (p<.001) were observed on all three domains of the HIV questionnaire (i.e., general knowledge, sexual risk behaviors, drug risk behaviors) and on 21 and 11 individual items on the HIV and HCV questionnaires, respectively. Self-reported likelihood of using a condom also increased significantly (p<.05) from pre- to post-intervention. No additional changes in self-reported risk behaviors were observed. CONCLUSION: These results suggest that a brief, easy-to-administer intervention is associated with substantial gains in HIV and HCV knowledge among PO abusers and represents the necessary first step toward the dissemination of a structured prevention HIV and HCV intervention for PO abusers. PMID- 24051065 TI - Experience with an enteral-based nutritional support regimen in critically ill trauma patients. AB - BACKGROUND: Assuring adequate enteral nutritional support in critically ill patients is challenging. By describing our experience, we sought to characterize the challenges, benefits, and complications of an approach that stresses enteral nutrition. STUDY DESIGN: We examined nutritional support received by victims of blunt trauma from 8 trauma centers. We grouped patients according to mean daily enteral caloric intake during the first 7 days. Group 1 received the fewest (0 kcal/kg/d) and group 5 the greatest (16 to 30 kcal/kg/d) number of calories in the first week. We focused our analyses on the patients remaining in the ICU for 8 days or longer and compared clinical outcomes among the groups. RESULTS: There were 1,100 patients in the ICU for 8 days or longer. Patients receiving the greatest number of enteral calories during the first week (group 5) had the highest incidence of ventilator-associated pneumonia (49%) and the lowest incidence of bacteremia (14%). Use of parenteral nutrition was associated with bacteremia (adjusted odds ratio = 2.5; 95% CI, 1.8-3.5), ventilator-associated pneumonia (adjusted odds ratio = 2.4; 95% CI, 1.7-3.3), and death (adjusted odds ratio = 1.9; 95% CI, 1.1-3.1). CONCLUSIONS: Enteral caloric intake during the first week was related to the pattern and severity of injury and was associated with important infectious outcomes. Our observations support moderating enteral intake during the first week after injury and avoiding parenteral nutrition. PMID- 24051066 TI - Laparoscopic pancreaticoduodenectomy: taking advantage of the unique view from the caudal side. PMID- 24051067 TI - Does aptitude influence the rate at which proficiency is achieved for laparoscopic appendectomy? AB - BACKGROUND: The attainment of technical competence for surgical procedures is fundamental to a proficiency-based surgical training program. We hypothesized that aptitude may directly affect one's ability to successfully complete the learning curve for minimally invasive procedures. The aim was to assess whether aptitude has an impact on ability to achieve proficiency in completing a simulated minimally invasive surgical procedure. The index procedure chosen was a laparoscopic appendectomy. STUDY DESIGN: Two groups of medical students with disparate aptitude were selected. Aptitude (visual-spatial, depth perception, and psychomotor ability) was measured by previously validated tests. Indicators of technical proficiency for laparoscopic appendectomy were established by trained surgeons with an individual case volume of more than 150. All subjects were tested consecutively on the ProMIS III (Haptica) until they reached predefined proficiency in this procedure. Simulator metrics, critical error scores, and Objective Structured Assessment of Technical Skills (OSATS) scores were recorded. RESULTS: The mean numbers of attempts to achieve proficiency in performing a laparoscopic appendectomy for group A (high aptitude) and B (low aptitude) were 6 (range 4 to 7) and 14 (range 10 to 18), respectively (p < 0.0001). Significant differences were found between the 2 groups for path length (p = 0.014), error score (p = 0.021), and OSATS score (p < 0.0001) at the initial attempt. CONCLUSIONS: High aptitude is directly related to a rapid attainment of proficiency. These findings suggest that resource allocation for proficiency based technical training in surgery may need to be tailored according to a trainee's natural ability. PMID- 24051068 TI - Development and validation of a risk-stratification score for surgical site occurrence and surgical site infection after open ventral hernia repair. AB - BACKGROUND: Current risk-assessment tools for surgical site occurrence (SSO) and surgical site infection (SSI) are based on expert opinion or are not specific to open ventral hernia repairs. We aimed to develop a risk-assessment tool for SSO and SSI and compare its performance against existing risk-assessment tools in patients with open ventral hernia repair. STUDY DESIGN: A retrospective study of patients undergoing open ventral hernia repair (n = 888) was conducted at a single institution from 2000 through 2010. Rates of SSO and SSI were determined by chart review. Stepwise regression models were built to identify predictors of SSO and SSI and internally validated using bootstrapping. Odds ratios were converted to a point system and summed to create the Ventral Hernia Risk Score (VHRS) for SSO and SSI, respectively. Area under the receiver operating characteristic curve was used to compare the accuracy of the VHRS models against the National Nosocomial Infection Surveillance Risk Index, Ventral Hernia Working Group (VHWG) grade, and VHWG score. RESULTS: The rates of SSO and SSI were 33% and 22%, respectively. Factors associated with SSO included mesh implant, concomitant hernia repair, dissection of skin flaps, and wound class 4. Predictors of SSI included concomitant repair, dissection of skin flaps, American Society of Anesthesiologists class >= 3, wound class 4, and body mass index >= 40. The accuracy of the VHRS in predicting SSO and SSI exceeded National Nosocomial Infection Surveillance and VHWG grade, but was not better than VHWG score. CONCLUSIONS: The VHRS identified patients at increased risk for SSO/SSI more accurately than the National Nosocomial Infection Surveillance scores and VHWG grade, and can be used to guide clinical decisions and patient counseling. PMID- 24051069 TI - Does antiplatelet therapy affect outcomes of patients receiving abdominal laparoscopic surgery? Lessons from more than 1,000 laparoscopic operations in a single tertiary referral hospital. AB - BACKGROUND: The effect of antiplatelet therapy (APT) on surgical blood loss and perioperative complications in patients receiving abdominal laparoscopic surgery still remains unclear. STUDY DESIGN: A total of 1,075 consecutive patients undergoing abdominal laparoscopic surgery between 2005 and 2011 were reviewed. Our perioperative management protocol consisted of interruption of APT 1 week before surgery and early postoperative reinstitution in low thromboembolic risk patients (n = 160, iAPT group). Preoperative APT was maintained in patients with high thromboembolic risk or emergent situation (n = 52, cAPT group). Perioperative and outcomes variables of cAPT and iAPT groups, including bleeding and thromboembolic complications, were compared with those of patients without APT (non-APT group, n = 863). RESULTS: In this cohort, 715 basic and 360 advanced laparoscopic operations were included. No patient suffering excessive intraoperative bleeding due to continuation of APT was observed. There were 10 postoperative bleeding complications (0.9%) and 3 thromboembolic events (0.3%), but the surgery was free of both complications in the cAPT group. No significant differences were found between the groups in operative blood loss, blood transfusion rate, and the occurrence of bleeding and thromboembolic complications. Multivariable analyses showed that multiple antiplatelet agents (p = 0.015) and intraoperative blood transfusion (p = 0.046) were significant prognostic factors for postoperative bleeding complications. Increased thromboembolic complications were independently associated with high New York Heart Association class (p = 0.019) and history of cerebral infarction (p = 0.048), but not associated with APT use. CONCLUSIONS: Abdominal laparoscopic operations were successfully performed without any increase in severe complications in patients with APT compared with the non-APT group under our rigorous perioperative assessment and management. Maintenance of single APT should be considered in patients with high thromboembolic risk, even when an abdominal laparoscopic approach is considered. PMID- 24051070 TI - Reply to: "Controversy on the role of FoxP3+ regulatory T cells in fibrogenesis in chronic hepatitis C virus infections". PMID- 24051071 TI - ALS pathophysiology: insights from the split-hand phenomenon. AB - OBJECTIVE: The aim of the present study was to assess whether peripheral mechanisms, mediated through axonal dysfunction, may contribute to development of the split-hand in amyotrophic lateral sclerosis (ALS). METHODS: Median and ulnar nerve motor axonal excitability studies were undertaken on 21 ALS patients with motor responses recorded over the abductor pollicis brevis (APB), abductor digit minimi (ADM) and first dorsal interosseous (FDI) muscles, and results compared to 24 controls. RESULTS: The split-hand index (SI), an objective biomarker of preferential atrophy of APB and FDI muscles, was significantly reduced in ALS (SI(ALS) 7.8 +/- 1.7, SICONTROLS 13.1 +/- 1.1, P<0.0001). Axonal excitability studies identified significant prolongation of strength-duration time constant in ALS patients when recording over the APB (P<0.05) and ADM axons (P<0.05) but not FDI axons (P=0.22). Greater changes in depolarising threshold electrotonus were also evident across the range of intrinsic hand muscles and were accompanied by increases of superexcitability in APB (P<0.01) and FDI (P<0.05) axons. CONCLUSION: The present study reinforces the significance of the split-hand phenomenon in ALS and argues against a significant peripheral contribution in the underlying development. SIGNIFICANCE: Axonal dysfunction may appear as a downstream process that develops secondary to the intrinsic pathophysiological origins of ALS. PMID- 24051072 TI - Domain-specific suppression of auditory mismatch negativity with transcranial direct current stimulation. AB - OBJECTIVE: To evaluate the influence of frontal transcranial direct current stimulation (tDCS) on auditory mismatch negativity (MMN). METHODS: MMN is an event related potential calculated by subtracting the amplitude of the evoked potentials in response to a "standard" stimulus from the evoked potentials produced by a rare "oddball" stimulus. Here we assessed the influence of anodal tDCS, cathodal tDCS or sham stimulation delivered over the right inferior frontal cortex on MMN in response to duration and frequency auditory deviants in 10 healthy subjects. RESULTS: MMN to frequency deviants was significantly reduced after anodal tDCS compared with sham or cathodal stimulation which did not change MMN to frequency deviants. Neither anodal nor cathodal tDCS had any effect on MMN to duration deviants. CONCLUSIONS: Non-invasive brain stimulation with tDCS can influence MMN. The differing networks known to be activated by duration and frequency deviants could account for the differential effect of tDCS on duration and frequency MMN. SIGNIFICANCE: Non-invasive brain stimulation could be a useful method to manipulate MMN for experimental purposes. PMID- 24051073 TI - Language mapping in healthy volunteers and brain tumor patients with a novel navigated TMS system: evidence of tumor-induced plasticity. AB - OBJECTIVE: This article explores the feasibility of a novel repetitive navigated transcranial magnetic stimulation (rnTMS) system and compares language mapping results obtained by rnTMS in healthy volunteers and brain tumor patients. METHODS: Fifteen right-handed healthy volunteers and 50 right-handed consecutive patients with left-sided gliomas were examined with a picture-naming task combined with time-locked rnTMS (5-10 Hz and 80-120% resting motor threshold) applied over both hemispheres. Induced errors were classified into four psycholinguistic types and assigned to their respective cortical areas according to the coil position during stimulation. RESULTS: In healthy volunteers, language disturbances were almost exclusively induced in the left hemisphere. In patients errors were more frequent and induced at a comparative rate over both hemispheres. Predominantly dysarthric errors were induced in volunteers, whereas semantic errors were most frequent in the patient group. CONCLUSION: The right hemisphere's increased sensitivity to rnTMS suggests reorganization in language representation in brain tumor patients. SIGNIFICANCE: rnTMS is a novel technology for exploring cortical language representation. This study proves the feasibility and safety of rnTMS in patients with brain tumor. PMID- 24051074 TI - Conformational restriction approach to beta-secretase (BACE1) inhibitors III: effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations. AB - For further investigation of BACE1 inhibitors using conformational restriction with sp(3) hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1'R,2'R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach. From the ITC measurement, the binding entropy of 6 was found to be ~0.5kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring. PMID- 24051075 TI - Colorimetric/fluorogenic detection of thiols by N-fused porphyrin in water. AB - A water-soluble derivative of N-fused porphyrin (NFP) possessing four cationic side-arms (pPyNFP) serves as a unique class of colorimetric/fluorogenic reporters that selectively react with biothiols in aquaous media to afford N-confused porphyrin (NCP) derivatives, while other nucleophilic amino acids were inert under a wide range of pH conditions. Owing to the large difference of the optical properties between NCP and NFP, the transformation enabled selective detection of biothiols in colorimetric/fluorogenic manner, especially in the near-infrared region. To the best our knowledge, this is the first example of porphyrin-based thiol detection systems that use the direct attack of thiol group on the optical reporter. PMID- 24051076 TI - Applying technology to the treatment of cannabis use disorder: comparing telephone versus Internet delivery using data from two completed trials. AB - Technology-based interventions such as those delivered by telephone or online may assist in removing significant barriers to treatment seeking for cannabis use disorder. Little research, however, has addressed differing technology-based treatments regarding their comparative effectiveness, and how user profiles may affect compliance and treatment satisfaction. This study addressed this issue by examining these factors in online (N=225) versus telephone (N=160) delivered interventions for cannabis use, using data obtained from two previously published randomized controlled trials conducted by the current authors. Several differences emerged including stronger treatment effects (medium to large effect sizes in the telephone study versus small effect sizes in the Web study) and lower dropout in the telephone intervention (38% vs. 46%). Additionally, around half of the telephone study participants sought concurrent treatment, compared with 2% of participants in the Web study. Demographics and predictors of treatment engagement, retention and satisfaction also varied between the studies. Findings indicate that both telephone and Web-based treatments can be effective in assisting cannabis users to quit or reduce their use; however, participant characteristics may have important implications for treatment preference and outcome, with those who elect telephone-based treatment experiencing stronger outcomes. Thus, participant preference may shape study populations, adherence, and outcome. PMID- 24051078 TI - Effects of sex and postmenopausal estrogen use on serum phosphorus levels: a cross-sectional study of the National Health and Nutrition Examination Survey (NHANES) 2003-2006. AB - BACKGROUND: Elevation of serum phosphorus concentrations has been associated with cardiovascular events in older women and men. Whether age, sex, or estrogen therapy is associated with different phosphorus levels is unknown. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 7,005 participants in the National Health and Nutrition Examination Survey (NHANES) 2003-2006. PREDICTORS: Demographic data; body measurement indexes; dietary intake by 24-hour dietary recall and food-frequency questionnaire; data for reproductive health, prescription medication, cardiovascular disease, osteoporosis, and diabetes mellitus obtained by questionnaire; and blood chemistry indexes. OUTCOMES & MEASUREMENTS: Serum phosphorus concentrations. RESULTS: In both males and premenopausal females, serum phosphorus levels decline progressively with age. In males, the decline continues over the entire age range of 21-85 years. In contrast, in females, serum phosphorus levels increase between ages 46-60 years (sex*age interaction; P<0.001). The increase in serum phosphorus levels in older women is independent of changes in serum parathyroid hormone levels, daily dietary phosphorus intake, and estimated glomerular filtration rate. In analysis of covariance, we show that postmenopausal women receiving estrogen therapy have significantly lower serum phosphorus levels than non-estrogen users after adjusting for age, race, body mass index, daily dietary phosphorus intake, and serum albumin, serum parathyroid hormone, and 25-hydroxyvitamin D levels (3.83 vs 3.98mg/dL; P<0.001). LIMITATIONS: The study was cross-sectional in design and estrogen therapy was not randomly assigned or concealed. Important phosphorus regulatory factors such as serum fibroblast growth factor 23 and klotho were not available in the study. CONCLUSIONS: Estrogen status may account for the difference in serum phosphorus levels in postmenopausal women. PMID- 24051077 TI - Computer-delivered screening and brief intervention (e-SBI) for postpartum drug use: a randomized trial. AB - Electronic screening and brief intervention (e-SBI) approaches for substance use have shown early promise. This trial was designed to replicate previous findings from a single 20-minute e-SBI for drug use among postpartum women. A total of 143 postpartum, primarily low-income African-American women meeting criteria for drug use, were randomly assigned to either a tailored e-SBI or a time-matched control condition. Blinded follow-up evaluation 3- and 6-months following childbirth revealed strong effects for confirmed illicit drug use abstinence at the 3-month observation (OR=3.3, p=.01), as did hair analysis at 6months (OR=4.8, p=.018). Additional primary outcomes suggested small to moderate effect sizes in favor of the e-SBI, but did not reach significance. This result replicates previous findings but fails to show durable effects. Assessment reactivity, e-SBI design, and possible extension of e-SBI via tailored messaging all merit careful consideration. PMID- 24051079 TI - SCr and SCysC concentrations before and after traumatic amputation in male soldiers: a case-control study. PMID- 24051080 TI - Understanding Washington: a nephrologist's perspective from inside the Beltway. AB - The major principles that drive U.S. federal health policy-making are: (1) fixed or reduced costs, (2) ensured outcomes (or no evidence of undertreatment), (3) streamlined administration, and (4) political viability. A corollary is that providers are uniquely sensitive to financial incentives. Understanding these principles is vital to understanding federal health policy. Critically, these principles are nonpartisan and have been supported and used by all administrations since President Reagan. This article examines the end-stage renal disease (ESRD) prospective payment system, colloquially called "The Bundle," in the context of these major principles. Successful health policy, successful legislation, and successful regulation building all require executive leadership, mutual trust, and compromise. This is demonstrated by the events surrounding the passage of the Medicare inpatient prospective payment system, which governs hospital reimbursement for Medicare beneficiaries, including those not covered in the ESRD program. Given that the ESRD benefit consumes 6.3% of the Medicare budget for approximately 2% of Medicare beneficiaries, if nephrology is to experience future success, we must change how both policymakers and the wider field of medicine perceive our specialty. Understanding the major principles behind health care policy may facilitate this goal. PMID- 24051081 TI - Proliferative glomerulonephritis with monoclonal immunoglobulin deposits in a kidney allograft. AB - Paraprotein may accumulate in glomeruli and cause kidney damage associated with variable histopathologic patterns and a characteristic immunofluorescence staining restricted to a single light chain and/or a single heavy chain isotype. Hence, such glomerular injury includes diseases caused by deposition of a monoclonal light chain, heavy chain, or entire immunoglobulin (light and heavy chains), which may manifest as proliferative glomerulonephritis. In this report, we focus on the latter as the least characterized of the 3, particularly in the transplantation setting. We describe a case of late transplant dysfunction associated with glomerular immunoglobulin G1/kappa deposits. We also present our experience with proliferative glomerulonephritis and monoclonal immunoglobulin deposits in transplant and native kidney biopsies, with reference to the literature. PMID- 24051082 TI - Relationships between in vitro lymphoproliferative responses and levels of contaminants in blood of free-ranging adult harbour seals (Phoca vitulina) from the North Sea. AB - In vitro culture of peripheral blood leucocytes (PBLs) is currently used in toxicological studies of marine mammals. However, blood cells of wild individuals are exposed in vivo to environmental contaminants before being isolated and exposed to contaminants in vitro. The aim of this study was to highlight potential relationships between blood contaminant levels and in vitro peripheral blood lymphocyte proliferation in free-ranging adult harbour seals (Phoca vitulina) from the North Sea. Blood samples of 18 individuals were analyzed for trace elements (Fe, Zn, Se, Cu, Hg, Pb, Cd) and persistent organic contaminants and metabolites (SigmaPCBs, SigmaHO-PCBs, SigmaPBDEs, 2-MeO-BDE68 and 6-MeO BDE47, SigmaDDXs, hexachlorobenzene, oxychlordane, trans-nonachlor, pentachlorophenol and tribromoanisole). The same samples were used to determine the haematology profiles, cell numbers and viability, as well as the in vitro ConA-induced lymphocyte proliferation expressed as a stimulation index (SI). Correlation tests (Bravais-Pearson) and Principal Component Analysis with multiple regression revealed no statistically significant relationship between the lymphocyte SI and the contaminants studied. However, the number of lymphocytes per millilitre of whole blood appeared to be negatively correlated to pentachlorophenol (r=-0.63, p=0.005). In adult harbour seals, the interindividual variations of in vitro lymphocyte proliferation did not appear to be directly linked to pollutant levels present in the blood, and it is likely that other factors such as age, life history, or physiological parameters have an influence. In a general manner, experiments with in vitro immune cell cultures of wild marine mammals should be designed so as to minimize confounding factors in which case they remain a valuable tool to study pollutant effects in vitro. PMID- 24051083 TI - Evaluation of the Simplified Comorbidity Score (Colinet) as a prognostic indicator for patients with lung cancer: a cancer registry study. AB - INTRODUCTION: A Simplified Comorbidity Score (SCS) provided additional prognostic information to the established factors in patients with non-small cell lung cancer lung cancer. We undertook this analysis to test the prognostic value of the SCS in a population-based study. PATIENTS AND METHODS: Retrospective survey of all Victorians diagnosed with lung cancer in January-June 2003, identified from the Victorian Cancer Registry. RESULTS: There were 921 patients, with data available for 841 (91.3%). Median age was 72 years (range 30-94) and 63.1% were male. A tissue diagnosis was made for 89.9%, of which 86.6% were non-small cell (NSCLC), and 13.4% small cell carcinoma (SCLC). Comorbidities on which the SCS is based were distributed: cardiovascular 54.6%; respiratory 38.9%; neoplastic 19.9%; renal 4.6%; diabetes 11.7%; alcoholism 5.5%; and tobacco 83.1%. In patients with NSCLC, higher SCS score (>9) was associated with increasing stage, ECOG performance status, male sex, increasing age, tobacco consumption and not receiving treatment. Using Cox regression, survival was analysed by SCS score after adjusting for the effect of age, sex, cell type (NSCLC, SCLC, no histology), ECOG performance status and stage for all patients and then restricted to NSCLC. As a continuous or dichotomous (<= or >9) variable, SCS was not a significant prognostic factor for all patients or when restricted to NSCLC. CONCLUSION: In this retrospective analysis of population based registry patients, SCS did not provide additional prognostic information in patients with lung cancer. ECOG performance status may be a substitute for the effect of comorbidity. PMID- 24051084 TI - Is there an oligometastatic state in non-small cell lung cancer? A systematic review of the literature. AB - OBJECTIVES: Long-term survival has been observed in patients with oligometastatic non-small cell lung cancer (NSCLC) treated with locally ablative therapies to all sites of metastatic disease. We performed a systematic review of the evidence for the oligometastatic state in NSCLC. MATERIALS AND METHODS: A systematic review of MEDLINE, EMBASE and conference abstracts was undertaken to identify survival outcomes and prognostic factors for NSCLC patients with 1-5 metastases treated with surgical metastatectomy, Stereotactic Ablative Radiotherapy (SABR), or Stereotactic Radiosurgery (SRS), according to PRISMA guidelines. RESULTS: Forty nine studies reporting on 2176 patients met eligibility criteria. The majority of patients (82%) had a controlled primary tumor and 60% of studies included patients with brain metastases only. Overall survival (OS) outcomes were heterogeneous: 1 year OS: 15-100%, 2 year OS: 18-90% and 5 year OS: 8.3-86%. The median OS range was 5.9-52 months (overall median 14.8 months; for patients with controlled primary, 19 months). The median time to any progression was 4.5-23.7 months (overall median 12 months). Highly significant prognostic factors on multivariable analyses were: definitive treatment of the primary tumor, N-stage and disease-free interval of at least 6-12 months. CONCLUSIONS: Survival outcomes for patients with oligometastatic NSCLC are highly variable, and half of patients progress within approximately 12 months; however, long-term survivors do exist. Definitive treatment of the primary lung tumor and low-burden thoracic tumors are strongly associated with improved long-term survival. The only randomized data to guide management of oligometastatic NSCLC pertains to patients with brain metastases. For other oligometastatic NSCLC patients, randomized trials are needed, and we propose that these prognostic factors be utilized to guide clinical decision making and design of clinical trials. PMID- 24051085 TI - Potentiation of anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the cyclin-dependent kinase inhibitor P276-00 in human non-small-cell lung cancer cell lines. AB - BACKGROUND: P276-00 is a novel cyclin-dependent kinase (CDK) inhibitor is in Phase II clinical trials. Valproic acid (VPA), an antiepileptic agent has been associated with anticancer activity, through the inhibition of histone deacetylase I. Here we investigate the effect of the combination of VPA and P276 00, in non-small-cell lung cancer (NSCLC) cell lines. MATERIALS AND METHODS: Cell growth inhibition was studied using the Propidium iodide (PI) assay. Cell cycle analysis and recovery were detected by flow cytometry. The expression levels of various proteins were detected by western blot. Inhibition of colony formation in H460 was checked in vitro. In vivo efficacy was studied in H460 xenograft model. RESULTS: The combination of P276-00 and VPA showed synergistic effect on p53+ and p53- NSCLC cell lines in antiproliferative assay at both constant and non constant ratio with marked decrease in colony forming potential. Flow cytometric analysis confirmed a significant time dependent increase in apoptosis with 64% apoptotic population at 96 h compared to VPA (1%) and P276-00 (28%) alone (p < 0.0001). Incubation of the cells after treatment, in fresh medium without drugs, led to the recovery of cells treated with P276-00 alone but not the cells treated with the combination of both the drugs. The combination treatment up-regulated tumor suppressor proteins like p53, p21 and p27 along with down-regulation of proliferation and survival proteins viz. cyclin D1 and Bcl-2. This was also associated with the upregulation of the pro-apoptotic protein Bax and significant accumulation of hyperacetylated histones in the combination treatment. Interestingly, VPA in combination with P276-00 was much more effective as an antitumor agent than alone, in the H460 xenograft tumor model in SCID mice. CONCLUSIONS: This study indicates that the combination of HDAC inhibitor VPA with CDK inhibitor P276-00 is promising novel molecularly targeted therapeutic approach for NSCLC treatment. PMID- 24051086 TI - Development of BMI values of German children and their healthcare costs. AB - The aim of this study is to assess the association between different patterns of Body Mass Index (BMI) development from birth on and later healthcare utilisation and costs in children aged about 10 years based on two birth cohort studies: the GINIplus study (3287 respondents) and the LISAplus study (1762 respondents). Direct costs were estimated using information on healthcare utilisation given by parents in the 10-year follow-up. To meet this aim, we (i) estimate BMI-standard deviation score (BMIZ) trajectories using latent growth mixture models and (ii) examine the correlation between these trajectories and utilisation of healthcare services and resulting costs at the 10-year follow-up. We identified three BMI trajectories: a normative BMIZ growth class (BMI development almost as in the WHO growth standards), a rapid BMIZ growth up to age 2 years class (with a higher BMI in the first two years of life as proposed by the WHO growth standards) and a persistent rapid BMIZ growth up to age 5 years class (with a higher BMI in the first five years of life as proposed by the WHO growth standards). Annual total direct medical costs of healthcare use are estimated to be on average ?368 per child. These costs are doubled, i.e. on average ?722 per child, in the group with the most pronounced growth (persistent rapid BMIZ growth up to age 5 years class). PMID- 24051087 TI - Current and emerging environmentally-friendly systems for fouling control in the marine environment. AB - Following the ban in 2003 on the use of tributyl-tin compounds in antifouling coatings, the search for an environmentally-friendly alternative has accelerated. Biocidal TBT alternatives, such as diuron and Irgarol 1051(r), have proved to be environmentally damaging to marine organisms. The issue regarding the use of biocides is that concerning the half-life of the compounds which allow a perpetuation of the toxic effects into the marine food chain, and initiate changes in the early stages of the organisms' life-cycle. In addition, the break down of biocides can result in metabolites with greater toxicity and longevity than the parent compound. Functionalized coatings have been designed to repel the settlement and permanent attachment of fouling organisms via modification of either or both surface topography and surface chemistry, or by interfering with the natural mechanisms via which fouling organisms settle upon and adhere to surfaces. A large number of technologies are being developed towards producing new coatings that will be able to resist biofouling over a period of years and thus truly replace biocides as antifouling systems. In addition urgent research is directed towards the exploitation of mechanisms used by living organisms designed to repel the settlement of fouling organisms. These biomimetic strategies include the production of antifouling enzymes and novel surface topography that are incompatible with permanent attachment, for example, by mimicking the microstructure of shark skin. Other research seeks to exploit chemical signals and antimicrobial agents produced by diverse living organisms in the environment to prevent settlement and growth of fouling organisms on vulnerable surfaces. Novel polymer-based technologies may prevent fouling by means of unfavourable surface chemical and physical properties or by concentrating antifouling compounds around surfaces. PMID- 24051088 TI - Induction of senescence by adenosine suppressing the growth of lung cancer cells. AB - Extracellular adenosine is well reported to suppress tumor growth by induction of apoptosis. However, in this study we found that adenosine treatment results in cellular senescence in A549 lung cancer cells both in vitro and in vivo; adenosine induces cell cycle arrest and senescence in a p53/p21 dependent manner; adenosine elevates the level of phosphor-gammaH2AX, pCHK2 and pBRCA1, the markers for prolonged DNA damage response which are likely responsible for initiating the cellular senescence. Our study first demonstrates that adenosine suppresses growth of cancer cells by inducing senescence and provides additional evidence that adenosine could act as an effective anticancer agent for targeted cancer therapy. PMID- 24051089 TI - Fine-tuning of xylose metabolism in genetically engineered Saccharomyces cerevisiae by scattered integration of xylose assimilation genes. AB - Manipulation of multiple genes is a common experience in metabolic engineering and synthetic biology studies. Chromosome integration of multiple genes in one single position is always performed, however, there is so far no study on the integration of multiple genes separately in various positions (here in after referred to as "scattered integration") and its effect on fine-tuning of cellular metabolism. In this study, scattered integration of the xylose assimilation genes PsXR, PsXDH and ScXK was investigated in Saccharomyces cerevisiae, and transcription analysis of these genes as well as their enzyme activities were compared with those observed when the genes were integrated into one single site (defined as "tandem integration" here). Not only notable differences in transcription levels and enzyme activities were observed when the genes were integrated by the two strategies, but also change of the cofactor preference of PsXR gene was validated. Xylose fermentation was further studied with the strains developed with these strategies, and elevated xylose utilization rate was obtained in the scattered integration strain. These results proved that by positioning multiple genes on different chromosomes, fine-tuning of cellular metabolism could be achieved in recombinant S. cerevisiae. PMID- 24051090 TI - FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro. AB - FGF1 and FGF2 support hematopoietic stem and progenitor cells (HSPCs) under stress conditions. In this study, we show that fibroblast growth factor (FGF7) may be a novel niche factor for HSPC support and leukemic growth. FGF7 expression was attenuated in mouse embryonic fibroblasts (MEFs) deficient for the MED1 subunit of the Mediator transcriptional coregulator complex. When normal mouse bone marrow (BM) cells were cocultured with Med1(+/+) MEFs or BM stromal cells in the presence of anti-FGF7 antibody, the growth of BM cells and the number of long time culture-initiating cells (LTC-ICs) decreased significantly. Anti-FGF7 antibody also attenuated the proliferation and cobblestone formation of MB1 stromal cell-dependent myeloblastoma cells. The addition of recombinant FGF7 to the coculture of BM cells and Med1(-/-) MEFs increased BM cells and LTC-ICs. FGF7 and its cognate receptor, FGFR2IIIb, were undetectable in BM cells, but MEFs and BM stromal cells expressed both. FGF7 activated downstream targets of FGFR2IIIb in Med1(+/+) and Med1(-/-) MEFs and BM stromal cells. Taken together, we propose that FGF7 supports HSPCs and leukemia-initiating cells indirectly via FGFR2IIIb expressed on stromal cells. PMID- 24051091 TI - ATP-citrate lyase is essential for macrophage inflammatory response. AB - Growing evidence suggests that energy metabolism and inflammation are closely linked and that cross-talk between these processes is fundamental to the pathogenesis of many human diseases. However, the molecular mechanisms underlying these observations are still poorly understood. Here we describe the key role of ATP-citrate lyase (ACLY) in inflammation. We find that ACLY mRNA and protein levels markedly and quickly increase in activated macrophages. Importantly, ACLY activity inhibition as well as ACLY gene silencing lead to reduced nitric oxide, reactive oxygen species and prostaglandin E2 inflammatory mediators. In conclusion, we present a direct role for ACLY in macrophage inflammatory metabolism. PMID- 24051092 TI - The protective effect of trefoil factor 3 on the intestinal tight junction barrier is mediated by toll-like receptor 2 via a PI3K/Akt dependent mechanism. AB - Trefoil factor peptides are highly conserved secreted molecules characterized by heat and enzymatic digestion resistance. Intestinal trefoil factor 3 (TFF3) protects and repairs the gastrointestinal mucosa and restores normal intestinal permeability, which is dependent on the integrity of the tight junction (TJ) barrier and the TJ associated proteins claudin-1, zona occludens-1 (ZO-1) and occludin. Despite the important role of intestinal barrier dysfunction in the pathogenesis of inflammatory bowel diseases, the underlying mechanisms and associated molecules remain unclear. In the present study, we show that TFF3 and toll-like receptor 2 (TLR2) are functionally linked and modulate intestinal epithelial permeability via a mechanism that involves the PI3K/Akt pathway. We used the Caco-2 cell model to show that TLR2 and TFF3 inhibit the IL-1beta induced increase in permeability and release of proinflammatory cytokines, and that this effect is mediated by activation of PI3K/Akt signaling. TLR2 silencing downregulated the expression of TFF3 and overexpression of TLR2 and TFF3 increased the levels of phospho-Akt. TFF3 overexpression significantly upregulated the expression of ZO-1, occludin and claudin-1 and this effect was abrogated by inhibition of the PI3K/Akt pathway. Taken together, our results indicate that TLR2 signaling selectively enhances intestinal TJ barrier integrity through a mechanism involving TFF3 and the activation of the PI3K/Akt pathway. PMID- 24051093 TI - INPP4B-mediated tumor resistance is associated with modulation of glucose metabolism via hexokinase 2 regulation in laryngeal cancer cells. AB - Inositol polyphosphate 4-phosphatase type II (INPP4B) was recently identified as a tumor resistance factor in laryngeal cancer cells. Herein, we show that INPP4B mediated resistance is associated with increased glycolytic phenotype. INPP4B expression was induced by hypoxia and irradiation. Intriguingly, overexpression of INPP4B enhanced aerobic glycolysis. Of the glycolysis-regulatory genes, hexokinase 2 (HK2) was mainly regulated by INPP4B and this regulation was mediated through the Akt-mTOR pathway. Notably, codepletion of INPP4B and HK2 markedly sensitized radioresistant laryngeal cancer cells to irradiation or anticancer drug. Moreover, INPP4B was significantly associated with HK2 in human laryngeal cancer tissues. Therefore, these results suggest that INPP4B modulates aerobic glycolysis via HK2 regulation in radioresistant laryngeal cancer cells. PMID- 24051094 TI - Rck1 up-regulates Hog1 activity by down-regulating Slt2 activity in Saccharomyces cerevisiae. AB - We previously reported that the over-expression of KDX1 up-regulates RCK1 gene expression. To further understand the function of Rck1, microarray analysis was performed using a RCK1 over-expressing strain. Based on microarray and Northern blot analyses, we determined that the expression of KDX1 was down-regulated when RCK1 was over-expressed. Furthermore, we determined that phosphorylated forms of Slt2 and Mkk2 were down-regulated by the over-expression of RCK1. Ptp2, a phosphatase that is regulated by the Slt2 MAP kinase pathway, was down-regulated by the over-expression of RCK1. Ptp2 is a negative regulator of Hog1; thus, the phosphorylated form of Hog1 was up-regulated by RCK1 over-expression. A point mutation of lysine 152 to arginine resulted in a failure to up-regulate Hog1 and the subsequent down-regulation of CTT1, which is a Hog1 pathway target gene. Furthermore, using microarray and Northern blot analyses, we determined that genes that are regulated by Msn2/Msn4 were up-regulated by Rck1 and that this was the result of Hog1 activation by RCK1 over-expression. Together, our results suggest that Rck1 inhibits Slt2 MAP kinase pathway activity and then Ptp2, which subsequently activates Hog1. PMID- 24051095 TI - Characterization of zebrafish mutants with defects in bone calcification during development. AB - Using the fluorescent dyes calcein and alcian blue, we stained the F3 generation of chemically (ENU) mutagenized zebrafish embryos and larvae, and screened for mutants with defects in bone development. We identified a mutant line, bone calcification slow (bcs), which showed delayed axial vertebra calcification during development. Before 4-5 days post-fertilization (dpf), the bcs embryos did not display obvious abnormalities in bone development (i.e., normal number, size and shape of cartilage and vertebrae). At 5-6 dpf, when vertebrae calcification starts, bcs embryos began to show defects. At 7 dpf, for example, in most of the bcs embryos examined, calcein staining revealed no signals of vertebrae mineralization, whereas during the same developmental stages, 2-14 mineralized vertebrae were observed in wild-type animals. Decreases in the number of calcified vertebrae were also observed in bcs mutants when examined at 9 and 11 dpf, respectively. Interestingly, by 13 dpf the defects in bcs mutants were no longer evident. There were no significant differences in the number of calcified vertebrae between wild-type and mutant animals. We examined the expression of bone development marker genes (e.g., Sox9b, Bmp2b, and Cyp26b1, which play important roles in bone formation and calcification). In mutant fish, we observed slight increases in Sox9b expression, no alterations in Bmp2b expression, but significant increases in Cyp26b1 expression. Together, the data suggest that bcs delays axial skeletal calcification, but does not affect bone formation and maturation. PMID- 24051096 TI - Elevated COX2 expression and PGE2 production by downregulation of RXRalpha in senescent macrophages. AB - Increased systemic level of inflammatory cytokines leads to numerous age-related diseases. In senescent macrophages, elevated prostaglandin E2 (PGE2) production contributes to the suppression of T cell function with aging, which increases the susceptibility to infections. However, the regulation of these inflammatory cytokines and PGE2 with aging still remains unclear. We have verified that cyclooxygenase (COX)-2 expression and PGE2 production are higher in LPS stimulated macrophages from old mice than that from young mice. Downregulation of RXRalpha, a nuclear receptor that can suppress NF-kappaB activity, mediates the elevation of COX2 expression and PGE2 production in senescent macrophages. We also have found less induction of ABCA1 and ABCG1 by RXRalpha agonist in senescent macrophages, which partially accounts for high risk of atherosclerosis in aged population. Systemic treatment with RXRalpha antagonist HX531 in young mice increases COX2, TNF-alpha, and IL-6 expression in splenocytes. Our study not only has outlined a mechanism of elevated NF-kappaB activity and PGE2 production in senescent macrophages, but also provides RXRalpha as a potential therapeutic target for treating the age-related diseases. PMID- 24051098 TI - Effect of horizontal magnetization reversal of the tips on magnetic force microscopy images. AB - The effect of magnetization reversal of magnetic force microscope (MFM) tips based on low coercive thin-films on MFM images has been studied both experimentally and theoretically. By analyzing the MFM images obtained on structures with high magnetic stray fields we show that during the imaging process the magnetic state of the probe is modified anisotropically: the horizontal component of the magnetization follows the external field, whereas the vertical component of the magnetization stays almost constant. The observed complex magnetic behavior of the tip is explained theoretically based on the shape anisotropy of the tip. The obtained results are important for interpretation of MFM images of structures with high magnetic moment. Moreover, these results can be used for characterization of both laboratory-made and commercially available MFM tips. PMID- 24051097 TI - Learning and memory ... and the immune system. AB - The nervous system and the immune system are two main regulators of homeostasis in the body. Communication between them ensures normal functioning of the organism. Immune cells and molecules are required for sculpting the circuitry and determining the activity of the nervous system. Within the parenchyma of the central nervous system (CNS), microglia constantly monitor synapses and participate in their pruning during development and possibly also throughout life. Classical inflammatory cytokines, such as interleukin (IL)-1beta and tumor necrosis factor (TNF), are released during neuronal activity and play a crucial role in regulating the strength of synaptic transmission. Systemically, proper functioning of the immune system is critical for maintaining normal nervous system function. Disruption of the immune system functioning leads to impairments in cognition and in neurogenesis. In this review we provide examples of the communication between the nervous and the immune systems in the interest of normal CNS development and function. PMID- 24051099 TI - Psychometric properties of Positive and Negative Affect Schedule (PANAS) original and short forms in an African American community sample. AB - BACKGROUND: The Positive and Negative Affect Schedule (PANAS) has been widely used as a self-report measure of affect in community and clinical contexts. However, evaluations of the psychometric properties of PANAS scores have been limited in diverse ethnic groups. Several short forms of the PANAS have also been proposed, but very little is known about the psychometric properties of these versions. METHODS: The present study investigated the psychometric properties, including the factor structure of the original PANAS and two short forms in an African American community sample (N=239). Descriptive, internal consistency reliability, factorial validity, and measurement invariance analyses were conducted. RESULTS: All PANAS subscales from the original and short forms had adequate internal consistency. For the original PANAS, the model specifying three correlated factors (Positive Affect, Afraid, Upset) with correlated uniquenesses from redundant items provided the best fit to the data. However, the two-factor model (Positive Affect, Negative Affect) with correlated uniquenesses was also supported. For both short forms, the two-factor model with correlated uniquenesses fit the data best. Factors from all forms were generally invariant across age and gender, although there was some minor invariance at the item level. LIMITATIONS: Participants were from a limited geographic area and one ethnic group. Indicators of anxiety, depression, and cultural characteristics were not measured. CONCLUSION: The factor structure was replicated, suggesting no immediate concerns regarding the valid interpretation of PANAS scores. The results support the reliability and validity of the PANAS and its short forms for use among African Americans. PMID- 24051100 TI - Development and preliminary validation of the male depression risk scale: furthering the assessment of depression in men. AB - BACKGROUND: The last decade has seen the burgeoning publication of male-specific depression rating scales designed to assess externalising depression symptoms (e.g., substance use, risk-taking, and aggression). These symptoms are theorised to reflect the behavioural manifestation of depression amongst men who rigidly conform to masculine norms. To date, research findings from these scales have been mixed, and each scale is limited by psychometric shortcomings or constrained assessment of symptom sub-domains. METHODS: The Male Depression Risk Scale (MDRS 22) was developed from online, non-clinical, community samples. Following best practice recommendations, initial scale items were subject to expert review. Study 1 (male n=386) reduced the item pool via exploratory factor analysis while Study 2 (male n=499, female n=291) refined and validated the factor structure using confirmatory factor analysis. Sex and masculinity comparisons were evaluated. RESULTS: Goodness of fit indices validated the six-factor solution with subscales assessing: emotional suppression, drug use, alcohol use, anger and aggression, somatic symptoms and risk-taking. Between-groups analyses indicated higher MDRS-22 scores for males reporting higher conformity to masculine norms. LIMITATIONS: Data were drawn from an online community sample without use of diagnostic interview. Test-retest correlations were not evaluated. Future research should look to examine longitudinal typical-externalising symptom trajectories across a range of clinical and non-clinical settings. CONCLUSIONS: The MDRS-22 reports satisfactory preliminary psychometric properties with validated subscales enabling multidimensional assessment of theorised externalising symptom sub-domains. MDRS-22 scale brevity may facilitate use in primary care settings enabling better identification of at-risk males. PMID- 24051101 TI - Depressive residual symptoms are associated with lower adherence to medication in bipolar patients without substance use disorder: results from the FACE-BD cohort. AB - BACKGROUND: Poor adherence to medication is frequent in Bipolar Disorder (BD). It is associated with illness severity and increases total medical cost. Several factors are associated with poor adherence but previous studies included heterogeneous cohorts of patients with and without current mood episode, with and without SUD. METHODS: We conducted a cross-sectional study, based on the Fondamental Advanced Centers of Expertise in Bipolar Disorders. 382 patients diagnosed with BD (type I, II or NOS) according to DSM-IV, with partial or complete remission and without comorbid SUD, were included. All patients had a large standardized clinical evaluation with structured interview and self reports. Side effects were evaluated with Patient Rated Inventory of Side Effects (PRISE). Adherence behavior was measured by a self reported scale, Medication Adherence Rating Scale (MARS). Univariate analyses and linear regression models were undertaken to determine factors associated with adherence. RESULTS: Residual depressive symptoms (beta=-0.155, p=0.004), and side effects (beta=-0.142, p=0.008) were the main factors associated with adherence behavior in linear regression model. We found no association with residual manic symptoms, age at assessment, marital status, number of past mood episodes as well as past psychotic symptoms. LIMITATION: We used no other assessment than self-rating scale for adherence behavior evaluation. We had no information concerning treatment regimen and patient/family knowledge about BD. CONCLUSIONS: Adherence behavior in bipolar patients appears to be mainly influenced by the presence of residual depressive symptoms in patients without SUD. Improvement in diagnosis and pharmacotherapy of residual depressive symptoms has to be kept in mind to face low adherence to medication. PMID- 24051102 TI - Microparticle-associated tissue factor activity is reduced by inhibition of the complement protein 5 in Neisseria meningitidis-exposed whole blood. AB - Neisseria meningitidis causes fulminant meningococcal sepsis with a massive activation of the coagulation and complement cascades. Bacterial cell envelope molecules from N. meningitidis, particularly lipopolysaccharide (LPS), induce tissue factor (TF) expression. In meningococcal sepsis, TF can be detected on circulating monocytes and microparticles (MPs) within the bloodstream. During infection, Nm activates C5 and C5a, which also is able to induce TF. We evaluated the effect of eculizumab, a C5-blocking monoclonal antibodies (mAb), on cell- and MP-associated TF. Using a lepirudin-anticoagulated whole blood model, we activated the coagulation and complement cascades by N. meningitidis, and investigated the interaction between the cascade systems with special focus on cell-associated TF-expression (mRNA and protein) and MP-associated TF-dependent thrombin and fibrin generation in platelet-free plasma. We also examined the ability of TF-positive MPs to support clot formation in whole blood. In addition, the effect of corn trypsin inhibitor and time-dependent changes on MP-associated functional TF activity was examined. Inhibition of C5 reduced cell-associated TF expression at both gene and protein level, and reduced MP-associated TF-dependent thrombin and fibrin generation in platelet-poor plasma, MP-induced TF-dependent clot formation in whole blood, implying that the complement and coagulation cascades are interplayers in N. meningitidis-mediated activation of these cascades. PMID- 24051103 TI - The cryptic interplay between systemic lupus erythematosus and infections. AB - The underlying trigger for systemic lupus erythematosus (SLE) has remained elusive, and multiple interacting environmental and genetic factors likely contribute to the onset and perpetuation of the disease. Among environmental influences, infectious agents have been suggested to play a pivotal role in driving autoimmunity pathogenesis via structural or functional molecular mimicry, the expression of proteins that induce cross-reactive responses against self antigens, and the aberrant activation or apoptosis of different immune system cells in the context of a peculiar genetic background. The increased viral load and changing subsets of lytic or latent viral proteins observed in selected populations with SLE have indicated that common viruses, such as Epstein-Barr virus, parvovirus B19, cytomegalovirus, retroviruses and transfusion-transmitted viruses, might be triggers for this disease. Alternatively, some infectious agents might exert a protective effect from autoimmunity. Existing achievements have not been fully investigated and clarified. Thus, the aim of this review is to analyze the medical literature within the last 15years regarding the role of infectious agents in the pathogenesis of SLE. PMID- 24051104 TI - Pathogenesis of relapsing polychondritis: a 2013 update. AB - Relapsing polychondritis (RP) is a systemic inflammatory disease primarily affecting not only the cartilaginous structures of the ears, nose and tracheobronchial tree but also the joints, the inner ear, the eyes, and the cardiovascular system. RP is an immune-mediated disease during which target antigens are still unknown, but data from human studies and murine models strongly support a role of both Collagen Type II (CII) and matrilin-1 as potential candidates. RP is likely a Th1-mediated disease as serum levels of interferon (IFN)-gamma, interleukin [IL]-12, and IL-2 parallel changes in disease activity, while the levels of Th2 cytokines do not. Serum levels of sTREM-1, interferon-gamma, CCL4, vascular endothelial growth factor, and matrix metalloproteinases-3 are significantly higher in RP patients than in healthy donors, with sTREM-1 correlating with disease activity. Patients with active RP also have significantly higher levels of MCP-1, MIP-1beta, MIF, and IL-8 than controls. These pro-inflammatory chemokines are involved in the modulation and recruitment of monocytes and neutrophils. Altogether, these data suggest that a complex cytokine network orchestrates the recruitment of infiltrating cells in RP lesions. Cytokine modulation using TNFalpha blockers, rituximab, anakinra, tocilizumab, and abatacept has recently been shown effective in some RP cases but further data are needed. Better understanding of the repertoire of infiltrating cells may provide interesting clues to further define the putative RP auto antigens. Study of circulating mononuclear cells during RP flares may also provide crucial information about the ongoing cellular trafficking and recruitment processes involved in this rare disease. PMID- 24051105 TI - Ligand-induced stabilization of the aptamer terminal helix in the add adenine riboswitch. AB - Riboswitches are structured mRNA elements that modulate gene expression. They undergo conformational changes triggered by highly specific interactions with sensed metabolites. Among the structural rearrangements engaged by riboswitches, the forming and melting of the aptamer terminal helix, the so-called P1 stem, is essential for genetic control. The structural mechanisms by which this conformational change is modulated upon ligand binding mostly remain to be elucidated. Here, we used pulling molecular dynamics simulations to study the thermodynamics of the P1 stem in the add adenine riboswitch. The P1 ligand dependent stabilization was quantified in terms of free energy and compared with thermodynamic data. This comparison suggests a model for the aptamer folding in which direct P1-ligand interactions play a minor role on the conformational switch when compared with those related to the ligand-induced aptamer preorganization. PMID- 24051106 TI - Neck and waist circumference biomarkers of cardiovascular risk in a cohort of predominantly African-American college students: a preliminary study. AB - Receiver operating characteristic curves were constructed to assess the value of measuring neck and waist circumference and waist-to-hip ratio (WHR) as biomarkers of metabolic syndrome in college students (18 to 25 years of age). Participants (n=109) were 92% black, 62.4% female, 45.9% overweight or obese, and 20.2% prehypertensive or hypertensive. Overall, 41 (37.6%) students had one or more risk factors for metabolic syndrome. Percent body fat, assessed using whole-body air-displacement plethysmography, was positively correlated (P<0.0001) with neck and waist circumference (as measured at the midpoint between the right lower rib and suprailiac crest; hereafter "midpoint"). Neck circumference correlated with low-density lipoprotein cholesterol (P <= 0.02) and both neck circumference and waist circumference-midpoint correlated with insulin (P <= 0.001) and triglycerides (P <= 0.002). The best-fit cutoffs were >= 83 cm waist circumference-midpoint and >= 88 cm waist circumference measured at the suprailiac crest for percent body fat in men and >= 75 cm waist circumference midpoint for metabolic syndrome in women. The proportion of overweight and prehypertensive individuals among self-described healthy students underscores the need for screening tools that identify those who might benefit most from health interventions. Waist circumference-midpoint provides a simple yet sensitive method for the estimation of percent body fat and metabolic syndrome risk in primarily African-American college students. The novel use of neck circumference should be further investigated. PMID- 24051107 TI - Comparison of energy assessment methods in overweight individuals. AB - Practical methods of assessing resting energy expenditure (REE) could be useful in large populations of overweight and obese individuals during phases of weight loss and weight-loss maintenance to address weight regain. We compared predicted and measured REE using the MedGem handheld device and a traditional, indirect calorimeter in middle-aged men and women who were overweight and obese (body mass index >= 25.0 and <40.0). Each subject (n=88) completed traditional, indirect calorimetry and handheld calorimetry in random order. A subset of participants (n=10) completed each of these assessments at three different time points to examine their test-retest reliability. We found that MedGem estimates of REE were significantly greater than estimates with the traditional, indirect calorimeter and the predicted REE using the Harris-Benedict equation (P<0.01). Intra-class correlations were .70 (P=0.15) for repeated recordings with the MedGem and .84 (P=0.65) for traditional indirect calorimetry. The MedGem can overestimate REE in middle-aged overweight/obese individuals and has moderate test-retest reliability. Indirect calorimetry is the preferred measurement of REE in this population. PMID- 24051109 TI - The effects of saliva collection, handling and storage on salivary testosterone measurement. AB - Several endocrine parameters commonly measured in plasma, such as steroid hormones, can be measured in the oral fluid. However, there are several technical aspects of saliva sampling and processing that can potentially bias the validity of salivary testosterone measurement. The aim of this study was to evaluate the effects caused by repeated sampling; 5 min centrifugation (at 2000, 6000 or 10,000g); the stimulation of saliva flow by a cotton swab soaked in 2% citric acid touching the tongue; different storage times and conditions as well as the impact of blood contamination on salivary testosterone concentration measured using a commercially available ELISA kit. Fresh, unprocessed, unstimulated saliva samples served as a control. Salivary testosterone concentrations were influenced neither by repeated sampling nor by stimulation of salivary flow. Testosterone levels determined in samples stored in various laboratory conditions for time periods up to 1 month did not differ in comparison with controls. For both genders, salivary testosterone levels were substantially reduced after centrifugation (men F=29.1; women F=56.17, p<0.0001). Blood contamination decreased salivary testosterone levels in a dose-dependent manner (men F=6.54, p<0.01, F=5.01, p<0.05). Salivary testosterone can be considered A robust and stable marker. However, saliva processing and blood leakage can introduce bias into measurements of salivary testosterone using ELISA. Our observations should be considered in studies focusing on salivary testosterone. PMID- 24051110 TI - Linguistic and psychometric validation of the Chinese version of the self efficacy measures for sleep apnea questionnaire. AB - OBJECTIVES: The self-efficacy measure for sleep apnea (SEMSA) questionnaire was shown to be an effective tool to assess adherence-related cognitions on continuous positive airway pressure (CPAP) therapy in obstructive sleep apnea (OSA) subjects. SEMSA helps to solicit fundamental information for formulating strategies to promote CPAP adherence for better treatment outcomes. The objective of our study was to perform a linguistic and psychometric evaluation of a Chinese version of the SEMSA (SEMSA-C). METHODS: Data were obtained from 100 subjects in a randomized controlled trial (RCT) on CPAP education. Subjects were newly diagnosed of OSA and naive to CPAP therapy. RESULTS: A 26-item SEMSA-C was obtained by a rigorous linguistic validation process. Internal consistency was high with Cronbach alpha>0.88. One-week test-retest intraclass correlation coefficient (ICC) ranged from 0.70 to 0.82. Principal component factor analysis identified three of the same hypothesized factors (perceived risks, outcome expectancies, and treatment self-efficacy) as in the original version. CPAP adherence was associated with outcome expectancies and treatment self-efficacy at 3-month assessment. Further, SEMSA-C demonstrated an improvement in self-efficacy after CPAP use. CONCLUSIONS: SEMSA-C shows similar psychometric properties as the original English version. It is a reliable and responsive instrument to measure perceived risks, outcome expectancies, and treatment self-efficacy in Chinese subjects with OSA. PMID- 24051111 TI - Parasomnia overlap disorder: a distinct pathophysiologic entity or a variant of rapid eye movement sleep behavior disorder? A case series. AB - BACKGROUND: Parasomnia overlap disorder (POD) currently is classified by the International Classification of Sleep Disorders, Second Edition (ICSD-2) as a variant of rapid eye movement (REM) sleep behavior disorder (RBD), and therefore its diagnosis also implies counseling the patients on the increased risk for developing neurodegenerative disorders. POD pathophysiology is not clear to date. METHODS: The authors report 5 cases of POD, review the literature, and analyze previously published cases of POD. RESULTS: In all 5 reported cases sleep-related activity was clearly demonstrated, though the RBD component was mild or incidentally discovered. None of the patients had Parkinsonian clinical features. Based on ICSD-2 criteria, there are 139 more POD cases reported in the literature and 69. 2% are idiopathic. The POD patients had an earlier age of onset than the patients with RBD. The RBD component was milder than the disorder of arousal (DOA) in most cases. Recently an updated classification was published, which included new categories of POD. The features mentioned above and the revised classification suggests that POD is not just a subtype of RBD. CONCLUSIONS: We propose that POD is a distinct pathophysiologic parasomnia. Further research to identify the underlying mechanism is needed. Proper counseling is necessary for patients presenting with POD at a young age of onset. PMID- 24051112 TI - Daytime somnolence in adult sleepwalkers. AB - OBJECTIVES: Sleepwalkers often complain of excessive daytime somnolence (EDS). Our retrospective study aimed to document the presence of EDS in a substantial sample of sleepwalkers and to explore the contribution of other sleep disorders, nocturnal sleep disruption, and sleep depth to the alteration of their daytime vigilance. METHODS: Seventy adult sleepwalkers and 70 control subjects completed the Epworth Sleepiness Scale (ESS). Sleepwalkers also were studied for one night in the sleep laboratory. We compared the sleep profiles of 32 somnolent vs 38 nonsomnolent sleepwalkers and investigated the relationship between ESS scores and sleep-related variables. RESULTS: No differences were found in polysomnographic (PSG) parameters. Slow-wave activity (SWA) also was similar in the two subgroups. Sleepwalkers' ESS scores were not correlated with their body mass index (BMI) or periodic limb movements during sleep (PLMS) index, but they tended to be negatively correlated with indices of respiratory events. CONCLUSIONS: The EDS reported by adult sleepwalkers does not appear to be explained by the presence of concomitant sleep disorders or PSG signs of nocturnal sleep disruption. These results raise the possibility that EDS is part of the sleepwalking phenotype and that it is linked to its underlying pathophysiology. PMID- 24051113 TI - Late bedtimes weaken school performance and predispose adolescents to health hazards. AB - STUDY OBJECTIVES: Our study explored if bedtimes influenced school performance and motivation, as well as the odds ratio (OR) for health-related concerns in adolescents. METHODS: The School Health Promotion Study was based on an anonymous self-report questionnaire conducted in 90% of the municipalities in Finland. The study was conducted during 2008 and 2010 in Southern Finland, Eastern Finland, and Lapland, and during 2009 and 2011 in Western Finland, Northern Finland, and Aland. Several indicators were used to measure school performance and motivation. Accidents and health-related complaints, such as depressive symptoms, sleep quality, neck or shoulder pains, lower back pains, stomachaches, anxiety or nervousness, irritation or tantrums, headaches, and tiredness or dizziness were analyzed in relation to the usual bedtime. Our study had a relatively large sample size (N=384,076), consisting of students in the eighth and the ninth grades of secondary schools and the first and the second grades of upper secondary and vocational schools (ages 14-20 years) in Finland. RESULTS: All of the various indicators used to assess school performance and motivation suggest that the later the bedtime of adolescents, the lower their school performance and their motivation. Similarly later bedtimes increase the OR for depressive symptoms and other negative health consequences in adolescents as well as a tendency towards accidents. All of these problems were emphasized in students with bedtimes of 11:30 PM and later. CONCLUSIONS: Late bedtimes, especially those after 11:30 PM, indicate poor sleep which deteriorates school performance and motivation and increases the OR for depressive symptoms and other health-related issues in adolescents. PMID- 24051114 TI - Enhanced cardiorespiratory coupling in patients with obstructive sleep apnea following continuous positive airway pressure treatment. AB - BACKGROUND: Weak cardiorespiratory coupling (CRC) has been suggested in patients with obstructive sleep apnea (OSA), but the effects of continuous positive airway pressure (CPAP) on CRC remain unclear. We investigated the effects of CPAP treatment on CRC in patients with severe OSA to examine possible reversibility of altered CRC. METHODS: High-resolution electrocardiograms (ECGs) and respiratory signals were simultaneously recorded for 13 never-treated OSA patients at baseline and after CPAP treatment. The analyses were performed on a 15-min daytime recording of ECG and respiration. Heart rate variability (HRV) indices were extracted from ECGs. After computing the sample entropy (SampEn) to quantify the regularity of both heart rate (SampEn(RR)) and respiration rhythm (SampEn(resp)), cross-sample entropy (cross-SampEn) was calculated to measure the interaction between the two signals. Cross-SampEn denotes asynchrony between heart rate and respiration, and thus negatively correlates with CRC. RESULTS: Lower SampEn(RR) and higher cross-SampEn as well as a shift toward sympathetic dominance were found in OSA patients compared with age- and gender-matched controls. CPAP treatment was associated with improved sympathovagal balance, increased SampEn(RR), and enhanced CRC, corresponding to a decrease in the cross SampEn value from 0.71+/-0.08 to 0.49+/-0.06 (P<.001). The effect sizes for the CPAP-induced changes in sympathovagal balance, SampEn(RR), and cross-SampEn were medium to large (0.54-0.90). CONCLUSIONS: The findings of our study indicate reduced CRC in untreated OSA patients and suggest that CPAP treatment may reverse this abnormality. PMID- 24051115 TI - Transcranial magnetic stimulation and sleep disorders: pathophysiologic insights. AB - The neural mechanisms underlying the development of the most common intrinsic sleep disorders are not completely known. Therefore, there is a great need for noninvasive tools which can be used to better understand the pathophysiology of these diseases. Transcranial magnetic stimulation (TMS) offers a method to noninvasively investigate the functional integrity of the motor cortex and its corticospinal projections in neurologic and psychiatric diseases. To date, TMS studies have revealed cortical and corticospinal dysfunction in several sleep disorders, with cortical hyperexcitability being a characteristic feature in some disorders (i.e., the restless legs syndrome) and cortical hypoexcitability being a well-established finding in others (i.e., obstructive sleep apnea syndrome narcolepsy). Several research groups also have applied TMS to evaluate the effects of pharmacologic agents, such as dopaminergic agent or wake-promoting substances. Our review will focus on the mechanisms underlying the generation of abnormal TMS measures in the different types of sleep disorders, the contribution of TMS in enhancing the understanding of their pathophysiology, and the potential diagnostic utility of TMS techniques. We also briefly discussed the possible future implications for improving therapeutic approaches. PMID- 24051116 TI - Periodic sighs. PMID- 24051117 TI - Exercise benefits for the aging brain depend on the accompanying cognitive load: insights from sleep electroencephalogram. AB - Although exercise clearly offsets aging effects on the body, its benefits for the aging brain are likely to depend on the extent that physical activity (especially locomotion) facilitates multisensory encounters, curiosity, and interactions with novel environments; this is especially true for exploratory activity, which occupies much of wakefulness for most mammals in the wild. Cognition is inseparable from physical activity, with both interlinked to promote neuroplasticity and more successful brain aging. In these respects and for humans, exercising in a static, featureless, artificially lit indoor setting contrasts with exploratory outdoor walking within a novel environment during daylight. However, little is known about the comparative benefits for the aging brain of longer-term daily regimens of this latter nature including the role of sleep, to the extent that sleep enhances neuroplasticity as shown in short-term laboratory studies. More discerning analyses of sleep electroencephalogram (EEG) slow-wave activity especially 0.5-2-Hz activity would provide greater insights into use-dependent recovery processes during longer-term tracking of these regimens and complement slower changing waking neuropsychologic and resting functional magnetic resonance imaging (fMRI) measures, including those of the brain's default mode network. Although the limited research only points to ephemeral small sleep EEG effects of pure exercise, more enduring effects seem apparent when physical activity incorporates cognitive challenges. In terms of "use it or lose it," curiosity-driven "getting out and about," encountering, interacting with, and enjoying novel situations may well provide the brain with its real exercise, further reflected in changes to the dynamics of sleep. PMID- 24051118 TI - Minimal clinically significant change for the International Restless Legs Syndrome Study Group rating scale in clinical trials is a score of 3. PMID- 24051119 TI - How we fall asleep: regional and temporal differences in electroencephalographic synchronization at sleep onset. AB - OBJECTIVES: We hypothesized that the brain shows specific and predictable patterns of spatial and temporal differences during sleep onset (SO) reflecting a temporal uncoupling of electrical activity between different cortical regions and a dissociated wakelike and sleeplike electrocortical activity in different cortical areas. METHODS: We analyzed full-scalp electroencephalographic (EEG) recordings of 40 healthy subjects to investigate spatial and temporal changes of EEG activity across the wake-sleep transition. We quantified EEG sleep recordings by a fast Fourier transform (FFT) algorithm and by a better oscillation (BOSC) detection method to the EEG signals, which measured oscillatory activity within a signal containing a nonrhythmic portion. RESULTS: The most representative spatial change at SO is the frontalization of slow-wave activity (SWA), while the theta activity, which mostly shares a similar temporal and spatial pattern with SWA, exhibits a temporo-occipital diffusion. The time course of these oscillations confirms that the changes of the dominant waves coexist with topographic changes. The waking occipital prevalence of alpha oscillations is progressively replaced by an occipital prevalence of theta oscillations. On the other hand, more anterior areas show a wide synchronization pattern mainly expressed by slow waves just below 4 Hz and by spindle oscillations. CONCLUSIONS: The whole pattern of results confirms that the centrofrontal areas showed an earlier synchronization (i.e., they fall asleep first). This finding implies a coexistence of wakelike and sleeplike electrical activity during sleep in different cortical areas. It also implies that the process of progressive brain disconnection from the external world as we fall asleep does not necessarily affect primary and higher order cortices at the same time. PMID- 24051120 TI - Polysomnographic abnormalities in patients with vascular cognitive impairment-no dementia. AB - OBJECTIVES: We aimed to investigate subjective sleep quality and polysomnographic sleep structure features in patients with vascular cognitive impairment-no dementia (VCIND). METHODS: Fifty-six patients with VCIND, 48 patients with simple stroke (without cognitive impairment), and 48 control subjects were included. The Pittsburgh Sleep Quality Index (PSQI) and polysomnography (PSG) were used to analyze their sleep characteristics. The Montreal Cognitive Assessment (MoCA) was conducted to assess mental state. RESULTS: Patients with VCIND had higher PSQI scores compared with control subjects and simple stroke patients (P<.01). PSG revealed that patients with VCIND or stroke were more likely to experience prolonged sleep latency (SL), decreased sleep efficiency (SE), increased arousal, and reduced deep sleep and rapid eye movement (REM) sleep than controls. Patients with VCIND had significantly longer SL, increased periodic leg movements in sleep (PLMS), decreased SE, and increased arousal and sleep fragmentation compared to patients with simple stroke (P<.05). In VCIND patients, a significant positive correlation was found between SE and MoCA scores (r=0.632; P<.001), though PSQI, SL, and arousal index were significantly negatively associated with MoCA scores (r=-0.787, -0.740, -0.772, respectively; P<.001 for all). CONCLUSIONS: VCIND patients had different abnormal sleep features, including decreased SE, increased PLMS, and prolonged SL and sleep fragmentation. Abnormal sleep in VCIND may be associated with cognitive impairment. PMID- 24051121 TI - Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations. AB - Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled activation of T cells and macrophages with overproduction of cytokines. Familial HLH type 2 (FHL2) is the most common form of primary HLH and is caused by mutations in PRF1. We have recently described a significant increase in the subpopulation of CD8(+) T cells with clonal expansion and CD5 down-regulation in Epstein-Barr virus associated-HLH, which represented a valuable tool for its diagnosis. However, this unusual phenotype of CD8(+) T cells has not been investigated fully in patients with FHL2. We performed immunophenotypic analysis of peripheral blood and measured serum pro-inflammatory cytokines in five patients with FHL2. All patients showed significantly increased subpopulations of activated CD8(+) T cells with down-regulation of CD5, which were negligible among normal controls. Analysis of T-cell receptor Vbeta repertoire suggested the reactive and oligoclonal expansion of these cells. The proportion of the subset declined after successful treatment concomitant with reduction in the serum levels of cytokines in all patients except one who continued to have a high proportion of the subset and died. These findings suggest that down-regulation of CD5 on activated CD8(+) T cells may serve as a useful marker of dysregulated T cell activation and proliferation in FHL2. PMID- 24051122 TI - Ellagic acid induces a dose- and time-dependent depolarization of mitochondria and activation of caspase-9 and -3 in human neuroblastoma cells. AB - The polyphenol ellagic acid is found in many natural food sources and has been proposed as a candidate compound for clinical applications due to its anti oxidative capacity and as a potential anti-tumorigenic compound. The objective of the present study was to evaluate the sensitivity to and possible apoptosis mechanism induced by ellagic acid in neuronal tumor cells. As a model the human neuroblastoma SH-SY5Y cell line was used. The methods applied were bright field and phase contrast microscopy, XTT- and LDH-assays, western blot, and flow cytometric analysis of DNA degradation and mitochondrial membrane potential. Ellagic acid treatment was found to induce a reduction in cell number preceded by alterations of the mitochondrial membrane potential and activation of caspase-9 and -3, DNA-fragmentation and cell death by apoptosis. The apoptotic cell death studied was not due to anoikis since it was significant in the adherent fraction of the cells. We conclude that ellagic acid induces dose- and time-dependent apoptosis, at least partly by the mitochondrial pathway, in an embryonal neuronal tumor cell system. This finding is in agreement with previously reported data on adult carcinoma cells thus suggesting a more general effect of ellagic acid on tumor cells. PMID- 24051108 TI - Status update and interim results from the asymptomatic carotid surgery trial-2 (ACST-2). AB - OBJECTIVES: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. METHODS: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. RESULTS: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD +/- 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. CONCLUSIONS: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. CLINICAL TRIAL: ISRCTN21144362. PMID- 24051123 TI - Effects of titanium dioxide nanoparticles in human gastric epithelial cells in vitro. AB - Manufacturing or using nanomaterials may result in exposure of workers to nanoparticles. Potential routes of exposure include skin, lung and gastrointestinal tract. The lack of health-based standards for nanomaterials combined with their increasing use in many different workplaces and products emphasize the need for a reliable temporary risk assessment tool. Therefore, the aim of this work was to explore the effects of different doses of titanium dioxide nanoparticles on human gastric epithelial cells in vitro. We analyzed proliferation by MTT assay, apoptosis by Tunel, migration by injury assay, oxidative stress by determining GSH/GSSG ratio and DNA damage by Comet assay on nanoparticle-treated AGS human gastric epithelial cell line in comparison to controls. We show and discuss the tumor-like phenotypes of nanoparticles-exposed AGS cells in vitro, as increased proliferation and decreased apoptosis. Our results demonstrate for the first time that nanoparticles induce tumor-like phenotypes in human gastric epithelial cells. PMID- 24051124 TI - A long acting biodegradable controlled delivery of chitosan microspheres loaded with tetanus toxoide as model antigen. AB - The chitosan microspheres formulated by emulsion cross-linking method were found to be smooth and spherical without aggregation. The particle size range was between 1 and 90MUm. The particle sizes were found to be influenced by the concentration of the chitosan gel. Tetanus toxoide (TT) vaccine was loaded by passive adsorption from an aqueous solution into the preformed chitosan microspheres cross-linked with glutaraldehyde. The loaded TT on to microspheres was estimated by ELISA method. The loading capacity was found to be 40% with microspheres prepared with 1% chitosan gel, 43% for 2% and 46% for the mixed batch of microspheres prepared from 1% and 2% chitosan gel. The loading efficiency was found to decrease with increase in the concentration of chitosan gel. The in vitro release of the antigenic TT into the phosphate buffer at 37 degrees C from different batch of microspheres was studied and release had a remarkable dependence on the size of micropsheres. The percentage release of TT from chitosan microspheres prepared from 1% chitosan gel was 2.7% in 120days and that from 2% chitosan gel was only 2%. The mixed batch of microspheres could release 2.3% in 120days. The antigen integrity was investigated by SDS-PAGE with brilliant blue staining. The SDS-PAGE analysis confirmed that the antigen integrity was not affected by passive adsorption of protein antigen to preformed chitosan microspheres. The study revealed that the cross-linked chitosan microspheres would be an interesting system for long-term delivery of macromolecules drugs. PMID- 24051125 TI - [T plasty for the treatment of skin forehead defects]. AB - INTRODUCTION: The closure of the skin defect of the forehead area with local flap must prevent the distortions of the eyebrow and hairlines and must limit the visibility of the scars. The H plasty is the most common procedure to treat this kind of defect but the scars are extensive and numerous. The H cutaneous flap presents necrosis risks if the skin is thin and the defect important. The H musculocutaneous flap presents sensitive and motors lesions risks. The T cutaneous flap is a good choice because of its excellent cosmetic result and minimized risks. MATERIALS AND METHODS: Twenty-six patients have been treated by the same surgeon between 2006 and 2012 with T cutaneous flap in order to treat forehead and temples' skin defects (the surface goes from 1.5 to 15cm). RESULTS: Excisions were completed in the every 26 cases. We had excellent cosmetic result and no complications such as necrosis, infection, sensitive and motor troubles after the surgery. DISCUSSION: The T plasty is easy for treating skin forehead defects. The scars are 25% less extensive than with a H plasty. The T flap permits to treat important defects without distortion or risks. CONCLUSION: The T cutaneous flap can easily substitute the H plasty for the forehead and temples reconstruction with no risks but good cosmetics results. PMID- 24051126 TI - [Emergency free flap in reconstruction of the lower limb. Thirty-five years of experience]. AB - Authors analyzed 89 cases (86 patients) of lower limb extensive soft tissue defects reconstruction during 1978 to 2013. The mean age is 37 years and 2 months old (range: 5-84 years old). A total of 71 males and 15 female were included. Free flaps were used in emergency in 23 cases for principally covering Gustilo 3B open lower limb fracture and in a later stage for 66 cases all referred from their center for coverage of exposed bone, with frequently osteomyelitis. About the selection of free flaps, in 47 cases we used a latissimus dorsi flaps, 12 cases of epiploon free transfer (in septic area), 10 cases of gracilis transfer and 10 serratus anterior flaps. There are one medial gastrocnemius flap, 2 composite soleus and fibular free flap, 2 antebrachial flap, one inguinal myoosteocutaneous flap, 1 transferred from the other lower limb and one inguinal cutaneous flap. There are 18 free flap losses: one in emergency and 17 after delayed reconstruction. Authors retrospectively analyzed the results (complications, osteomyelitis) according to the timing for lower extremity reconstruction. They found a low infection and flap failure rates (4%) when the coverage is made in the same operating time than initial fracture fixation, they increase to 60% for osteomyelitis and to 23% for flap failure when the reconstruction is delayed. PMID- 24051127 TI - The Italian Hafnia alvei strain LMG 27376 is Hafnia paralvei. PMID- 24051128 TI - Molecular studies on diarrhea-associated Escherichia coli isolated from humans and animals in Egypt. AB - The molecular characteristics of Escherichia coli isolates from Egypt and the relationship of E. coli strains from claves, camels and humans are limited. We analyzed the genetic relationships of 48 diarrhea-associated E. coli strains isolated from sporadic diarrheal cases from humans (n=26), calves (n=14) and camels (n=8) using multilocus sequence type (MLST), virulence genes, and pulsed field gel electrophoresis (PFGE). Enterotoxigenic E. coli (ETEC) accounted for 60.4% of all samples and the rest were Enteropathogenic E. coli (EPEC) 10.4%, Diffuse adhering E. coli (DAEC) 8.3%, Enteroaggreagative E. coli (EAEC) 6.3%, Verotoxigenic E. coli (VTEC) 6.3%, Untypable E. coli. 6.3% and Atypical enteropathogenic E. coli (aEPEC) 2.1%. We identified 17 new sequence types (ST) and 12 new alleles. Generally, strains divided into 6 clonal complexes, and clonal complex (CC) 10 was the major one, detected in (15/48; 31.3%) strains from humans, calves and camels. The close relationship among the strains from different hosts was regarding to mdh, purA, and recA genes which presented a minor variation in relation to other housekeeping genes. CONCLUSION: MLST analysis suggested an endemic prevalence of clonal complex (CC) 10 in Egypt. Same sequencing types (ST) could be detected in human, calf and camel, especially ST10, indicating the ability of E. coli to cross the host barrier. Together with PFGE results and virulence genotypes we conclude that human, calf and camel can be colonized and infected with similar E. coli strains and provide evidence of calves and camels role as a reservoir for similar strains of diarrhea-associated E. coli. PMID- 24051129 TI - Transcriptome alterations in zebrafish embryos after exposure to environmental estrogens and anti-androgens can reveal endocrine disruption. AB - Exposure to environmental chemicals known as endocrine disruptors (EDs) is in many cases associated with an unpredictable hazard for wildlife and human health. The identification of endocrine disruptive properties of chemicals certain to enter the aquatic environment relies on toxicity tests with fish, assessing adverse effects on reproduction and sexual development. The demand for quick, reliable ED assays favored the use of fish embryos as alternative test organisms. We investigated the application of a transcriptomics-based assay for estrogenic and anti-androgenic chemicals with zebrafish embryos. Two reference compounds, 17alpha-ethinylestradiol and flutamide, were tested to evaluate the effects on development and the transcriptome after 48h-exposures. Comparison of the transcriptome response with other estrogenic and anti-androgenic compounds (genistein, bisphenol A, methylparaben, linuron, prochloraz, propanil) showed commonalities and differences in regulated pathways, enabling us to classify the estrogenic and anti-androgenic potencies. This demonstrates that different mechanism of ED can be assessed already in fish embryos. PMID- 24051130 TI - Prepubertal bisphenol A exposure interferes with ovarian follicle development and its relevant gene expression. AB - Bisphenol A (BPA) is recognized as one of several environmental estrogens. Pre puberty is an important part of reproductive system development, and even a short term exposure to BPA during this period may cause serious damage to the reproductive system. In this study, Pre-puberty female Wistar rats were exposed to BPA for one week. The effects of BPA on ovarian structure and function were assessed. The expression levels of follicle development-related genes were analyzed. Our study showed that BPA reduced rat ovarian weights and follicle numbers, and interferes with the constituent ratio of follicles. With increasing doses of BPA, the expression of factor in the germline alpha (FIGLA) and oocyte specific histone H1 variant (H1FOO) genes decreased, and anti-mullerian hormone (AMH) genes expression increased, suggesting that BPA exposure during the pre pubertal period may inhibit the development of ovaries, and follicle development related genes may play certain roles in this process. PMID- 24051131 TI - High levels of heat shock protein 70 are associated with pro-inflammatory cytokines and may differentiate early- from late-onset preeclampsia. AB - Preeclampsia (PE), a specific syndrome of pregnancy, can be classified into early and late onset, depending on whether clinical manifestations occur before or after 34 weeks' gestation. We determined whether plasma concentrations of Hsp60 and Hsp70 were related to circulating cytokine levels, as well as kidney and liver functions, in early- and late-onset PE. Two hundred and thirty-seven preeclamptic women (95 with early- and 142 with late-onset PE) were evaluated. Plasma levels of Hsp60, Hsp70, and their specific antibodies, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-10, IL-12, and soluble TNF-alpha receptor I (sTNFRI) concentrations, were determined by enzyme-linked immunosorbent assay (ELISA). Concentrations of Hsp70, TNF-alpha, IL-1beta, IL-12, and sTNFRI were significantly elevated in patients with early-onset PE compared with women with late-onset PE; IL-10 levels were significantly lower in the early onset PE group. Concentrations of urea, uric acid, proteinuria, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and lactate dehydrogenase (LDH) were also significantly higher in early-onset PE. The percentage of infants with intrauterine growth restriction was also significantly higher in women with early-onset PE. There were positive correlations between Hsp70 levels and TNF-alpha, TNFRI, IL-1beta, IL-12, GOT, GPT, LDH, and uric acid concentrations in early-onset PE group. Thus, early-onset PE was associated with greater maternal and fetal impairment. There are differences in pathophysiology between early- and late-onset PE, highlighting by the difference in Hsp70 levels. PMID- 24051132 TI - Examining the association between statins and lung cancer incidence in patients with type 2 diabetes mellitus. AB - BACKGROUND/PURPOSE: The relationship between statin use and lung cancer remains unclear. Patients with diabetes mellitus, who are at higher risks for both cancer and atherosclerosis, are usually indicated for statin use. The objective was to explore the relationship between statins, lung squamous cell carcinoma (SCC), and lung adenocarcinoma incidence in diabetic patients. METHODS: A cohort of 596,812 type 2 diabetic patients was identified from the Taiwan National Health Insurance claims database in the year 2000, and followed until the earliest of lung cancer diagnosis, death, or December 31, 2007. A Cox regression model with time-varying statin use was applied to estimate the hazard ratio (HR) of lung cancer incidence comparing use and nonuse of statins. A sensitivity analysis was applied to examine the association after adjustment for smoking effect. RESULTS: In the original diabetic cohort, 60,969 statin users and 535,843 statin nonusers were identified. In a median follow-up time of 7.9 years, a total of 1182 incident SCC cases and 2345 adenocarcinoma cases developed. Initial analysis showed a decreased risk of SCC if statins were ever used (HR, 0.69; 95% confidence interval, 0.60-0.81). However, the relative risk would be 0.92 for males and 0.90 for females for statins after adjusting for smoking effect. There was no association between statin use and adenocarcinoma (HR, 0.97; 95% confidence interval, 0.88-1.07), with similar findings after controlling for smoking effect. CONCLUSION: There is no statistically significant association between statin use with lung cancer incidence in diabetic patients after adjustment for the confounding effect attributed to cigarette smoking. PMID- 24051133 TI - Simplifying shared decision-making: physician-patient interactions as negotiations. PMID- 24051134 TI - Ultrastructure of antennal sensilla of a parasitoid fly, Pales pavida Meigen (Diptera: Tachinidae). AB - Pales pavida Meigen is obligated polyparasitic fly and important natural enemy of some most damaging forest or agricultural pests, and thus could contribute to the biological control of them. The external morphology of main olfactory organs in this tachinid was examined using stereopic microscopy and scanning electron microscopy, and types, distribution and density of sensilla were provided. The first two antennal segments, antennal scape and pedicel, are covered by microtrichiae and several mechanoreceptors. A pedicellar button is detected on antennal pedicel as well, after its separation with antennal funiculus. On antennal funiculus, five types of sensillar structures are observed including trichoid, basiconic, coeloconic, clavate sensilla and sensory pit with subtype II basiconic sensilla and a type of rarely described coeloconic-like sensilla in it, respectively. There are two specific sensillar characteristics of Pales pavida, two types of sensory pit on antennal funiculus and lower densities of all sensilla types than relatively monoparasitic species, which may serve as applicable evidence on their adaption to environment and lifestyle. Besides, the morphology of pedicellar button in tachinids is first addressed, armed with a discussion of their possible function. PMID- 24051135 TI - Involvement of the paraventricular (PVN) and arcuate (ARC) nuclei of the hypothalamus in the central noradrenergic regulation of liver cytochrome P450. AB - The present study was aimed at assessing the influence of noradrenergic innervation of the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) of the brain hypothalamus on cytochrome P450 expression in the liver. DSP-4, a neurotoxin specific to noradrenergic nerve terminals, was administrated locally into the PVN or ARC. One week after neurotoxin injection, the levels of neurotansmitters (noradrenaline/dopamine/serotonin) were measured in the middle part of the hypothalamus, hormone concentrations were estimated in blood plasma, and the activity and the protein levels of CYP isoforms were measured in the liver. A significant decrease in noradrenaline level in the hypothalamus was observed after DSP-4 injection into the PVN or ARC. The levels of dopamine or serotonin remained unchanged or slightly lowered. Simultaneously, significant changes in the plasma concentration of growth hormone were found; its elevation in PVN-lesioned rats and a drop in ARC-lesioned ones. There were no changes in the plasma concentration of the thyroid hormones or corticosterone. The activity and protein levels of isoforms CYP2C11, CYP3A and CYP2A rose in the liver of PVN lesioned rats, but the activity and protein level of CYP2C11 fell in ARC-lesioned animals such a tendency being also observed in the case of CYP3A. Our study shows that noradrenergic innervation of the PVN and ARC of the hypothalamus exerts an opposite effect on the regulation of cytochrome P450 in the liver. These findings may be important for pharmacological experiments and pharmacotherapy with neuroactive drugs, since cytochrome P450 is responsible for the metabolism of steroids and the majority of drugs. PMID- 24051137 TI - Impulsivity moderates the association between racial discrimination and alcohol problems. AB - Alcohol use among university students is a serious public health concern, particularly among minority students who may use alcohol to cope with experiences of racial discrimination. Although the impact of racial discrimination on alcohol use has been well-established, individual differences in factors that may act to either attenuate or exacerbate the negative effects of racial discrimination are largely unknown. One potentially fruitful individual differences trait that has repeatedly been found to predict alcohol problems is the multidimensional personality trait of impulsivity. Nonetheless, the ways in which various aspects of impulsivity interact with racial discrimination is yet unknown. The current study, therefore, examined the joint and interactive contribution of racial discrimination and impulsivity in the prediction of alcohol consumption among racial minority university students. Participants included 336 Black/African American and Asian/Asian-American university students. Results revealed both racial discrimination and impulsivity to be significantly associated with alcohol problems. Further, individuals' responses to racial discrimination were not uniform. Specifically, the association between racial discrimination and alcohol problems was moderated by lack of Premeditation; racial discrimination was most strongly predictive of alcohol problems for those who reported low level of premeditation. Findings from the present study highlight the importance of investigating risk factors for alcohol problems across multiple levels of the ecology as individual personality traits appear to relate to how one might respond to the experience of racial discrimination. PMID- 24051136 TI - Selective potentiation of (alpha4)3(beta2)2 nicotinic acetylcholine receptors augments amplitudes of prefrontal acetylcholine- and nicotine-evoked glutamatergic transients in rats. AB - Prefrontal glutamate release evoked through activation of alpha4beta2* nicotinic acetylcholine receptors (nAChRs) situated on thalamic glutamatergic afferents mediates cue detection processes and thus contributes to attentional performance. However, little is known about the respective contributions of the high sensitivity and low sensitivity (LS) stoichiometries of the alpha4beta2 nAChR, (alpha4)2(beta2)3 and (alpha4)3(beta2)2, to these processes. In the present study we employed glutamate-sensitive microelectrodes and the (alpha4)3(beta2)2 selective positive allosteric modulator (PAM) NS9283 to investigate the importance of the LS alpha4beta2 nAChR for glutamate release in the rat medial prefrontal cortex (mPFC). Firstly, the signaling evoked by physiologically relevant ACh concentrations through the (alpha4)3(beta2)2 nAChR in HEK293 cells was potentiated by NS9283, consistent with the classification of NS9283 as a PAM. In urethane-anesthetized rats, intra-prefrontal pressure ejections of NS9283 evoked glutamatergic transients. Importantly, this glutamate release was attenuated by removal of cholinergic projections to the recording area. This finding indicates that the effects of NS9283 depend on endogenous ACh, again consistent with effects of a PAM. We then conducted microdialysis to demonstrate the presence of extracellular ACh in urethane-anesthetized control rats. While detectable, those levels were significantly lower than in awake rats. Finally, the amplitudes of glutamatergic transients evoked by local pressure ejections of a low concentration of nicotine were significantly augmented following systemic administration of NS9283 (3.0mg/kg). In conclusion, our results indicate that a LS alpha4beta2 nAChR PAM such as NS9283 may enhance the cholinergic modulation of glutamatergic neurotransmission in the cortex, thereby perhaps alleviating the attentional impairments common to a range of brain disorders. PMID- 24051138 TI - Reactivity to negative affect in smokers: the role of implicit associations and distress tolerance in smoking cessation. AB - Avoidance of negative affect is one motivational factor that explains smoking cessation relapse during cessation attempts. This negative reinforcement model of smoking cessation and relapse has demonstrated the importance of one's ability to tolerate nicotine withdrawal symptoms, particularly negative affect states, in remaining abstinent from smoking. Distress tolerance and implicit associations are two individual constructs that may influence the strength of this relationship. In this pilot study the authors examined implicit associations related to avoidance and negative affect using a modified Implicit Association Test (IAT), a measure designed to examine implicit associations related to negative affect and avoidance, and the relationship of these associations to distress tolerance and smoking relapse. In total, 40 participants were recruited through community flyers as part of a larger smoking cessation study. Participants completed a brief smoking history, behavioral distress tolerance assessments, and the modified IAT. Smoking status was assessed via phone 3days and 6days post-quit date. Results from a Cox proportional hazard model revealed that implicit associations between avoidance and negative affect were significantly negatively correlated with time to relapse after a smoking cessation attempt, whereas the behavioral distress tolerance assessments did not predict time to relapse. This study provides novel information about the cognitive associations that may underlie avoidant behavior in smokers, and may be important for understanding smoking relapse when negative affect states are particularly difficult to tolerate. Authors discuss the importance of implicit associations in understanding smoking relapse and how they can be targeted in treatment. PMID- 24051139 TI - Surface mapping for visualization of wall stresses during inhalation in a human nasal cavity. AB - Airflow analysis can assist in better understanding the physiology however the human nasal cavity is an extremely complicated geometry that is difficult to visualize in 3D space, let alone in 2D space. In this paper, an anatomically accurate 3D surface of the nasal passages derived from CT data was unwrapped and transformed into a 2D space, into a UV-domain (where u and v are the coordinates) to allow a complete view of the entire wrapped surface. This visualization technique allows surface flow parameters to be analyzed with greater precision. A UV-unwrapping tool is developed and a strategy is presented to allow deeper analysis to be performed. This includes (i) the ability to present instant comparisons of geometry and flow variables between any number of different nasal cavity models through normalization of the 2D unwrapped surface; (ii) visualization of an entire surface in one view and; (iii) a planar surface that allows direct 1D and 2D analytical solutions of diffusion of inhaled vapors and particles through the nasal walls. This work lays a foundation for future investigations that correlates adverse and therapeutic health responses to local inhalation of gases and particles. PMID- 24051140 TI - Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. AB - BACKGROUND: Telomere shortness in human beings is a prognostic marker of ageing, disease, and premature morbidity. We previously found an association between 3 months of comprehensive lifestyle changes and increased telomerase activity in human immune-system cells. We followed up participants to investigate long-term effects. METHODS: This follow-up study compared ten men and 25 external controls who had biopsy-proven low-risk prostate cancer and had chosen to undergo active surveillance. Eligible participants were enrolled between 2003 and 2007 from previous studies and selected according to the same criteria. Men in the intervention group followed a programme of comprehensive lifestyle changes (diet, activity, stress management, and social support), and the men in the control group underwent active surveillance alone. We took blood samples at 5 years and compared relative telomere length and telomerase enzymatic activity per viable cell with those at baseline, and assessed their relation to the degree of lifestyle changes. FINDINGS: Relative telomere length increased from baseline by a median of 0.06 telomere to single-copy gene ratio (T/S)units (IQR-0.05 to 0.11) in the lifestyle intervention group, but decreased in the control group (-0.03 T/S units, -0.05 to 0.03, difference p=0.03). When data from the two groups were combined, adherence to lifestyle changes was significantly associated with relative telomere length after adjustment for age and the length of follow-up (for each percentage point increase in lifestyle adherence score, T/S units increased by 0.07, 95% CI 0.02-0.12, p=0.005). At 5 years, telomerase activity had decreased from baseline by 0.25 (-2.25 to 2.23) units in the lifestyle intervention group, and by 1.08 (-3.25 to 1.86) units in the control group (p=0.64), and was not associated with adherence to lifestyle changes (relative risk 0.93, 95% CI 0.72-1.20, p=0.57). INTERPRETATION: Our comprehensive lifestyle intervention was associated with increases in relative telomere length after 5 years of follow-up, compared with controls, in this small pilot study. Larger randomised controlled trials are warranted to confirm this finding. FUNDING: US Department of Defense, NIH/NCI, Furlotti Family Foundation, Bahna Foundation, DeJoria Foundation, Walton Family Foundation, Resnick Foundation, Greenbaum Foundation, Natwin Foundation, Safeway Foundation, Prostate Cancer Foundation. PMID- 24051141 TI - Targeted gene sequencing identifies variants in the protein C and endothelial protein C receptor genes in patients with unprovoked venous thromboembolism. AB - OBJECTIVE: The interaction of protein C (PC) with the endothelial PC receptor (EPCR) enhances activated PC generation. We performed targeted gene sequencing of the PC gene (PROC) and EPCR genes (PROCR) in patients with unprovoked venous thromboembolism (VTE) to determine whether mutations that impair PC-EPCR interactions are associated with an increased risk of VTE. APPROACH AND RESULTS: We sequenced exon 3 of PROC and exons 2 and 3 of PROCR (the exons that encode the protein-protein binding domains of PC and EPCR) in 653 patients with unprovoked VTE and in 627 healthy controls. Five single nucleotide variants, each in individual patients, were identified that result in abnormal PC (Arg9Cys, Val34Met, and Arg-1Cys) or abnormal EPCR proteins (Arg96Cys and Val170Leu). We did not detect any nonsynonymous coding variants in the controls. When the PC variants were expressed in human embryonic kidney 293 cells, all exhibited decreased synthesis, and 2 of the variants had reduced capacity for activated PC generation. When expressed on the surface of human embryonic kidney 293 cells, the EPCR variants showed reduced affinity for fluorescently labeled PC. In addition, the previously reported EPCR A3 haplotype, which promotes cellular shedding of EPCR, is over-represented in the patient group (P=0.001). CONCLUSIONS: This is the first targeted DNA sequencing analysis of PROC and PROCR in a large group of patients with unprovoked VTE. Our data suggest that mutations that impair PC-EPCR interactions may be associated with an increased risk of VTE. PMID- 24051143 TI - 5'-AMP-activated protein kinase-activating transcription factor 1 cascade modulates human monocyte-derived macrophages to atheroprotective functions in response to heme or metformin. AB - OBJECTIVE: Intraplaque hemorrhage (IPH) is an important driver of the progression of atherosclerotic plaques. Recently, we characterized Mhem as a novel macrophage phenotype that limits the atherogenicity of IPH. Mhem are directed by activating transcription factor 1 (ATF1), which is activated by phosphorylation. A better understanding of the counteratherogenic ATF1-Mhem pathway may facilitate antiatherosclerotic therapies. APPROACH AND RESULTS: We tested the hypothesis that heme in pathologically relevant concentrations activates the ATF1-Mhem pathway via 5'-AMP-activated protein kinase (AMPK) in primary human monocyte derived macrophages and mouse bone marrow macrophages. We found that heme (10 MUmol/L) activates AMPK, and downstream ATF1-mediated coinduction of heme oxygenase and liver X receptor that characterize Mhem. Heme increased macrophage phospho-AMPK, phospho-ATF1, and its target genes, and these effects were inhibited by the AMPK antagonist dorsomorphin, or by AMPK-knockdown with small inhibitory ribonucleic acid. The AMPK-activating oral hypoglycemic agent metformin also induced and phosphorylated ATF1 at a clinically relevant concentration (10 MUmol/L). Functional effects of heme and metformin were inhibited by AMPK-knockdown and included suppression of macrophage oxidative stress; increased cholesterol export; protection from foam-cell formation; and suppression of macrophage inflammatory activation (human leukocyte antigen type DR expression). CONCLUSIONS: Our data indicate that heme activates the ATF1 pathway in human macrophages via AMPK, and that a similar response occurs after treatment of cells with metformin. Our results suggest an in vitro mechanism that may explain the clinical evidence that metformin has vascular protective effects beyond its role in treating hyperglycemia. PMID- 24051142 TI - Role for platelet glycoprotein Ib-IX and effects of its inhibition in endotoxemia induced thrombosis, thrombocytopenia, and mortality. AB - OBJECTIVE: Poor prognosis of sepsis is associated with bacterial lipopolysaccharide (LPS)-induced intravascular inflammation, microvascular thrombosis, thrombocytopenia, and disseminated intravascular coagulation. Platelets are critical for thrombosis, and there has been increasing evidence of the importance of platelets in endotoxemia. The platelet adhesion receptor, the glycoprotein Ib-IX complex (GPIb-IX), mediates platelet adhesion to inflammatory vascular endothelium and exposed subendothelium. Thus, we have investigated the role of GPIb-IX in LPS-induced platelet adhesion, thrombosis, and thrombocytopenia. APPROACH AND RESULTS: LPS-induced mortality is significantly decreased in mice expressing a functionally deficient mutant of GPIbalpha. Furthermore, we have developed a micellar peptide inhibitor, MPalphaC (C13H27CONH SIRYSGHpSL), which selectively inhibits the von Willebrand factor -binding function of GPIb-IX and GPIb-IX-mediated platelet adhesion under flow without affecting GPIb-IX-independent platelet activation. MPalphaC inhibits platelet adhesion to LPS-stimulated endothelial cells in vitro and alleviates LPS-induced thrombosis in glomeruli in mice. Importantly, MPalphaC reduces mortality in LPS challenged mice, suggesting a protective effect of this inhibitor during endotoxemia. Interestingly, MPalphaC, but not the integrin antagonist, Integrilin, alleviated LPS-induced thrombocytopenia. CONCLUSIONS: These data indicate an important role for the platelet adhesion receptor GPIb-IX in LPS induced thrombosis and thrombocytopenia, and suggest the potential of targeting GPIb as an antiplatelet strategy in managing endotoxemia. PMID- 24051144 TI - Radiation-induced intracranial meningioma and multiple cavernomas. AB - Brain irradiation has several well-known long-term side effects, including radiation-induced neoplasms and vasculopathy. In this case report, we describe an extremely rare case of meningioma and 15 cavernomas developing in a 29-year-old man, 19 years after cranial irradiation for posterior cranial fossa medulloblastoma. To our knowledge, this is the first case of a radiation-induced meningioma accompanied by this many radiation-induced cavernous angiomas. PMID- 24051146 TI - What about temperature? Haloperidol-induced hypotermia. AB - The use of treatment with antipsychotic drugs highlights the difficulty of finding the right balance between the benefit on psychotic symptoms and the risk of the occurrence of adverse reactions. There is a strong genetic and pharmacological evidence supporting the hypothesis that activation of D2 receptors could lead to hypothermia and that the treatment haloperidol is capable of inducing hypothermia apomorfino similarily in laboratory animals. It also seems that, haloperidol is not the only antipsychotic able to determine this type of reaction, as some evidence suggests that other drugs such as reserpine, chlorpromazine would be capable of inducing hypothermia. Finally, while some studies suggest the possible occurrence of haloperidol-induced hypothermia only in laboratory animals, other authors argue that this same reaction can occur in humans as well. In this report, we describe the cases, rarely witnessed in the literature, of three patients in whom the administration of haloperidol caused hypothermia. PMID- 24051147 TI - Basaloid squamous cell carcinoma of oral cavity with incongruent clinical course. AB - Basaloid squamous cell carcinoma (BSCC) is a rare variant of SCC having a marked predilection for the upper aerodigestive tract. It is regarded as a high-grade tumour with increased propensity for metastasis to distant sites. The histological hallmark of BSCC is its dimorphic pattern of presentation with a characteristic basal cell component associated with squamous component. We report two cases of BSCC on the buccal mucosa and gingiva, respectively, with the former presenting as a primary lesion in a patient without a positive history of tobacco and alcohol use and the latter present as a seemingly metachronous development from carcinoma lung. The proliferative index of the two diverse yet similar entities was assessed by Ki-67 labelling index (LI) and the association of human papillomavirus (HPV) was detected with p16 monoclonal antibody. The intrinsically aggressive behaviour of BSCC and its association with HPV is highlighted. PMID- 24051148 TI - Angioneurotic oedema secondary to oral thiamine. AB - Although allergic side effects due to parenteral thiamine are well-documented, they are extremely rare when thiamine is used orally. We report a case of a 47 year-old woman who developed angioneurotic oedema secondary to oral ingestion of thiamine at a therapeutic dose. The incident occurred twice with a clear temporal relationship to the initiation on thiamine. PMID- 24051149 TI - A rare association of cerebral dural arteriovenous fistula with venous aneurysm and contralateral flow-related middle cerebral artery aneurysm. AB - The association of cerebral dural arteriovenous fistula (DAVF) and ipsilateral flow related aneurysm has infrequently been reported. We describe a male patient who presented with an acute haemorrhagic stroke and was found to have a large right fronto-parietal intra-parenchymal haemorrhage from the ruptured Borden type II DAVF in addition to a large venous aneurysm and a flow related intraosseous aneurysm of the contralateral middle meningeal artery (MMA) all clearly delineated by CT and DSA. He underwent emergency stereotactic evacuation of the intraparenchymal haemorrhage and successful surgical treatment of all the vascular lesions at the same time with residual neurological deficit. To our knowledge, this is the first such reported case. We discuss the challenging surgical treatment, emphasising the role of CT/DSA in management, and provide a literature review. PMID- 24051150 TI - Lethal liquorice lollies (liquorice abuse causing pseudohyperaldosteronism). AB - A 47-year-old woman was admitted to the emergency department with a history of asthenia, periorbital and lower limbs oedema, associated with hypokalaemia and increased blood pressure levels. Metabolic and renal causes were initially investigated as thyroid disease, Cushing syndrome and tubulopathies were excluded during the first week of admission. However, further questioning of the patient, revealed that she had been consuming several sachets of raw liquorice lollies (ignored amount) obtained from a herbalist a month ago. Based on the history and clinical findings, liquorice poisoning was highly suspected; an apparent mineralocorticoid excess secondary to ingestion of liquorice. Afterwards, levels of aldosterone and plasma renin activity were measured and found low 3 weeks later; therefore, our clinical suspicion was established. During the patient's stay at the hospital, liquorice was stopped and potassium supplements were started. Subsequently, a week after, the patient fully recovered without any significant sequelae. PMID- 24051151 TI - Airway management concerns in patient with gastric banding procedures. AB - Laparoscopic adjustable gastric band (LAGB) is considered a relatively safe and effective treatment for obesity. Even after weight loss patients with LAGB are at increased risk of pulmonary aspiration during induction of general anaesthesia, possibly due to LAGB-induced anatomical and functional changes. We present a case of aspiration in a patient with LAGB following significant weight loss and 14 h of preoperative fasting and review the literature. In the presence of LAGB we propose specific anaesthesia management at least consisting of anti-Trendelenburg positioning; avoidance of mask-ventilation; use of the local rapid sequence induction strategy with endotracheal intubation and fully awake extubation. PMID- 24051152 TI - A heart on the right can be more complex than it first appears. PMID- 24051153 TI - Study in pink...rash! PMID- 24051154 TI - A giant angiokeratoma of Fordyce: an uncommon cause of acute scrotum. PMID- 24051155 TI - Pathways to mental health care in Italy: results from a multicenter study. AB - BACKGROUND AND AIMS: In Italy, the reform of the mental health system in 1978 should have drastically changed the provision of care and pathways of patients seeking to obtain it. The aim of this article is to examine the current pathways to psychiatric care in Italy. METHODS: We used a method developed in the World Health Organization international collaborative studies to investigate pathways to care in 15 Italian mental health centers. We recruited 420 patients with a psychiatric illness and explored the care pathways they took to reach to psychiatric services and the delays from the onset of illness to reaching psychiatric care. RESULTS: The majority of patients (33.8%) had direct access to mental health care, whereas the others arrived to a specialist in psychiatry through general hospitals (20.3%), general practitioners (33.0%) or private practitioners (9.8%). The main diagnosis for referral was neurotic disorder (36.6%), followed by affective disorder (35.4%) and psychotic disorder (11.5%). The delay from onset of illness to psychiatric care was greater for patients with psychotic disorders than for those with affective and neurotic disorders. The most frequently prescribed treatments were pharmacotherapy (56%), psychological support (8%), and psychotherapy (7.0%); 15% of the patients received no treatment. CONCLUSIONS: Our multicenter study shows that although general practitioners and hospital doctors are still the main referral point for mental health care, a greater proportion of patients are first seen in private settings or directly reach mental health centers, compared to previous surveys conducted in Italy. However, a stronger collaboration of psychiatrists with general practitioners and psychologists is still needed. PMID- 24051156 TI - Quantitative proteomics reveals that plasma membrane microdomains from poplar cell suspension cultures are enriched in markers of signal transduction, molecular transport, and callose biosynthesis. AB - The plasma membrane (PM) is a highly dynamic interface that contains detergent resistant microdomains (DRMs). The aim of this work was to determine the main functions of such microdomains in poplar through a proteomic analysis using gel based and solution (iTRAQ) approaches. A total of 80 proteins from a limited number of functional classes were found to be significantly enriched in DRM relative to PM. The enriched proteins are markers of signal transduction, molecular transport at the PM, or cell wall biosynthesis. Their intrinsic properties are presented and discussed together with the biological significance of their enrichment in DRM. Of particular importance is the significant and specific enrichment of several callose [(1 -> 3)-beta-glucan] synthase isoforms, whose catalytic activity represents a final response to stress, leading to the deposition of callose plugs at the surface of the PM. An integrated functional model that connects all DRM-enriched proteins identified is proposed. This report is the only quantitative analysis available to date of the protein composition of membrane microdomains from a tree species. PMID- 24051157 TI - Identification of proteins of Propionibacterium acnes for use as vaccine candidates to prevent infection by the pig pathogen Actinobacillus pleuropneumoniae. AB - Actinobacillus pleuropneumoniae is the causative agent of acute and chronic pleuroneumonia that is responsible for substantial morbidity and mortality in the pig industry. New improved vaccines that can protect against all serotypes and prevent colonization are required. In a previous study we showed that whole cells of Propionibacterium acnes protected pigs from A. pleuropneumoniae serotype 1 and 5 and, therefore, the basis for a promising heterologous vaccine. The aim of this study was to identify those protein antigens of P. acnes responsible for protection against A. pleuropneumoniae infection. Six P. acnes protein antigens that were recognized by sera raised against A. pleuropneumoniae were identified by 2-DE and immunoblotting. Recombinant versions of all P. acnes proteins gave partial protection (10-80%) against A. pleuropneumoniae serotype 1 and/or 5 infection in a mouse challenge model. The best protection (80% serotype 1; 60% serotype 5) was obtained using recombinant P. acnes single-stranded DNA-binding protein. In part, protection against A. pleuropneumoniae infection may be mediated by small peptide sequences present in P. acnes single-stranded DNA binding protein that are cross-reactive with those present in the A. pleuropneumoniae-specific RTX toxin ApxIV and the zinc-binding protein ZnuA. The results suggest that P. acnes may be a useful vaccine to protect against different serotypes of A. pleuropneumoniae. PMID- 24051158 TI - Elicitation of broadly reactive antibodies against glycan-modulated neutralizing V3 epitopes of HIV-1 by immune complex vaccines. AB - HIV-1 envelope gp120 is the target for neutralizing antibodies (NAbs) against the virus. Various approaches have been explored to improve immunogenicity of broadly neutralizing epitopes on this antigen with limited success. We previously demonstrated that immunogenicity of gp120 and especially its V3 epitopes was enhanced when gp120 was co-administered as immune-complex vaccines with monoclonal antibodies (mAb) to the CD4-binding site (CD4bs). To define the mechanisms by which immune complexes influence V3 immunogenicity, we compared gp120 complexed with mAbs specific for the C2 region (1006-30), the V2 loop (2158), or the CD4bs (654), and found that the gp120/654 and gp120/2158 complexes elicited anti-V3 NAbs, but the gp120/654 complex was the most effective. gp120 complexed with 654 F(ab')2 was as potent, indicating that V3 immunogenicity is determined by the specificity of the mAb's Fab fragment used to form the complexes. Importantly, the gp120/654 complex not only induced anti-gp120 antibodies (Abs) to higher titers, but also of greater avidity. The Abs were cross-reactive with V3 peptides from most subtype B and some subtype C isolates. Neutralization was detected only against Tier-1 HIV-1 pseudoviruses, while Tier-2 viruses, including the homologous JRFL strain, were not neutralized. However, JRFL produced in the presence of a mannosidase inhibitor was sensitive to anti-V3 NAbs in the immune sera. These results demonstrate that the gp120/654 complex is a potent immunogen for eliciting cross-reactive functional NAbs against V3 epitopes, of which exposure is determined by the specific compositions of glycans shrouding the HIV-1 envelope glycoproteins. PMID- 24051160 TI - A hepatitis B vaccine with a novel adjuvant. PMID- 24051161 TI - Competing islands limit the rate of adaptation in structured populations. AB - Beneficial mutations can co-occur when population structure slows down adaptation. Here, we consider the process of adaptation in asexual populations distributed over several locations ("islands"). New beneficial mutations arise at constant rate ub, and each mutation has the same selective advantage s>0. We assume that populations evolve within islands according to the successional mutations regime of Desai and Fisher (2007), that is, the time to local fixation of a mutation is short compared to the expected waiting time until the next mutation occurs. To study the rate of adaptation, we introduce an approximate model, the successional mutations (SM) model, which can be simulated efficiently and yields accurate results for a wide range of parameters. In the SM model, mutations fix instantly within islands, and migrants can take over the destination island if they are fitter than the residents. For the special case of a population distributed equally across two islands with population size N, we approximate the model further for small and large migration rates in comparison to the mutation rate. These approximations lead to explicit formulas for the rate of adaptation which fit the original model for a large range of parameter values. For the d island case we provide some heuristics on how to extend the explicit formulas and check these with computer simulations. We conclude that the SM model is a good approximation of the adaptation process in a structured population, at least if mutation or migration is limited. PMID- 24051159 TI - DNA-based adaptive immunity protect host from infection-associated periodontal bone resorption via recognition of Porphyromonas gingivalis virulence component. AB - BACKGROUND: Porphyromonas gingivalis (Pg) is one of a constellation of oral organisms associated with human chronic periodontitis. While adaptive immunity to periodontal pathogen proteins has been investigated and is an important component of periodontal bone resorption, the effect of periodontal pathogen DNA in eliciting systemic and mucosal antibody and modulating immune responses has not been investigated. METHODS: Rowett rats were locally injected with whole genomic Pg DNA in alum. Escherichia coli (Ec) genomic DNA, Fusobacterium nucleatum (Fn) genomic DNA, and saline/alum injected rats served as controls. After various time points, serum IgG and salivary IgA antibody to Ec, Fn or Pg were detected by ELISA. Serum and salivary antibody reactions with Pg surface antigens were determined by Western blot analyses and the specific antigen was identified by mass spectrometry. Effects of genomic DNA immunization on Pg bacterial colonization and experimental periodontal bone resorption were also evaluated. RESULTS: Sera from Pg DNA, Ec DNA and Fn DNA-injected rats did not react with Ec or Fn bacteria. Serum IgG antibody levels to Pg and Pg surface extracts were significantly higher in animals immunized with Pg DNA as compared to the control groups. Rats injected with Pg DNA demonstrated a strong serum IgG and salivary IgA antibody reaction solely to Pg fimbrillin (41kDa), the major protein component of Pg fimbriae. In the Pg DNA-immunized group, the numbers of Pg bacteria in oral cavity and the extent of periodontal bone resorption were significantly reduced after Pg infection. CONCLUSIONS: This study suggests that infected hosts may select specific genes from whole genomic DNA of the periodontal pathogen for transcription and presentation. The results indicate that the unique gene selected can initiate a host protective immune response to the parent bacterium. PMID- 24051162 TI - Proper knowledge on toxicokinetics improves human hazard testing and subsequent health risk characterisation. A case study approach. AB - In the current EU legislative frameworks on chemicals safety, the requirements with respect to information on general kinetic parameters (absorption, distribution, metabolism and excretion or ADME) or integrated toxicokinetic parameters (TK, i.e. plasma concentration-time curve, area under the curve etcetera) in humans and experimental animals vary widely. For agrochemicals and cosmetics, there are regulatory requirements whereas for other frameworks, such as food ingredients, biocides, consumer products and high production volume chemicals (REACH) there are very little or no requirements. This paper presents case studies that illustrate the importance of ADME and TK data in regulatory risk characterisations. The examples were collected by interviewing regulatory risk assessors from various chemicals (non-pharmaceutical) frameworks. The case studies illustrate how (1) applying ADME/TK in an early phase of toxicity testing can be used to improve study design and support the 3R-goals and how (2) increased use of ADME/TK data can improve the final risk assessment. PMID- 24051163 TI - [Vitamin D and autoimmunity]. AB - Vitamin D acts at several levels in the immune systems to maintain immune tolerance. Vitamin D deficiency is a plausible environmental risk factor for autoimmune disease. Basic, genetic and epidemiological studies indicate a potential role of vitamin D in the prevention and the treatment of autoimmune diseases. Most of the epidemiological studies are cross-sectional, so that they are insufficient to establish a direct link between vitamin D deficiency and both disease risk and disease activity. Randomized, controlled trials are necessary. PMID- 24051164 TI - [Vitamin D and cancers]. AB - Low vitamin D plasmatic rates have been correlated to an increased risk of developing cancer. It has been proved that vitamin D could facilitate cell differentiation and have anti-inflammatory, anti-angiogenic and pro-apoptotic effects. Epidemiological studies are likely to show a protective role regarding colon cancer and possibly towards breast cancer. PMID- 24051165 TI - [Vitamin D and infectious diseases]. AB - Vitamin D plays a role in the synthesis of antibacterial peptids and in autophagy. Several studies have shown that low levels of vitamin D are associated with the susceptibility and the severity of acute infections on one hand, and with an unfavorable outcome of some chronic infections (such as HIV infection). Vitamin D supplementation improves response to treatment of some viral (such as chronic hepatitis C infection) or bacterial infections (such as pulmonar tuberculosis). Vitamin D supplementation demonstrated no benefit in reducing the incidence of pulmonary infections. The target level of vitamin D to be reached after supplementation is not known yet. PMID- 24051166 TI - [Metabolism and main effects of vitamin D]. AB - Vitamin D is not a vitamin stricto sensu as its main source does not come from diet. Vitamin D should rather be considered as a prohormone. To become fully active, vitamin D must be hydroxylated into 25(OH)D in the liver and then into 1,25(OH)2D (also called calcitriol) in the kidney, but also in many other tissues. The main classical effects of vitamin D concern bone and calcium/phosphorus metabolism. Many non-classical effects of vitamin D are suggested by the quasi-ubiquitous presence of the vitamin D receptor and by myriads of studies showing an association between vitamin D deficiency/insufficiency and an increased incidence or a poor prognostic of many diseases. The 25(OH)D serum concentration is the biological index that defines vitamin D status. There is currently no absolute consensus on the definition of vitamin D deficiency. Many experts consider that a 25(OH)D level less than 50 nmol/L corresponds to vitamin D deficiency whereas a concentration between 50 and 75 nmol/L corresponds to vitamin D insufficiency. These definitions are mostly based on the musculoskeletal effects of vitamin D. PMID- 24051167 TI - [Vitamin D insufficiency and deficiency: epidemiology, measurement, prevention and treatment]. AB - Vitamin D has been traditionally considered as important for skeletal health. However, during the past decade, numerous research findings have revealed that vitamin D may have beneficial effects on extraskeletal tissues as well. Vitamin D deficiency is now recognized as a worldwide issue. The prevalence of vitamin D deficiency or insufficiency depends on the threshold used to define vitamin D deficiency or insufficiency. However, whatever the threshold (20, 30 or 40 ng/mL), the prevalence is high in France as elsewhere. Vitamin D status is now based on the measurement of 25-hydroxyvitamin D [25(OH)D] concentration. This assay does not seem justified in most situations encountered in clinical practice, and its overprescription generates a significant cost to public health. This is why Official Clinical Societies try to define: (a) target populations for which a determination is required (every situation in which the therapeutic goal requires an optimal serum 25(OH)D level for an appropriate medical care) and which require specific treatment; (b) target populations for which the risk of deficit is important (due to insufficient daily intake) and may benefit from preventive pharmaceutical supplementation without prior testing (infants, pregnant women, patients over 65...). PMID- 24051168 TI - Split weaning increases the incidence of lactation oestrus in boar-exposed sows. AB - This study evaluated the effect of split weaning and fence-line boar exposure during lactation on the incidence of lactation oestrus. Large White and Large White * Landrace sows (parity 2.9 +/- 0.17; mean +/- SEM) were housed in conventional farrowing crates from day -4 to 30 post-parturition. Four treatments (n = 18) were used: control (SPW0): continuous lactation of 10 piglets with all piglets weaned on day 30 of lactation; and three split wean (SPW) treatments with 3 (SPW3), 5 (SPW5) or 7 (SPW7) of the heaviest piglets removed from the sow on day 18 lactation. From day 18 lactation all sows received 15 min daily, fence line boar exposure in a detection mating area. Fewer sows in the SPW0 treatment (56% (10/18)) expressed a lactation oestrus compared to the SPW3, SPW5, and SPW7 treatments (83%; 89%; 94%, respectively). SPW0 sows had a lower subsequent total born compared to SPW5 or SPW7 sows (8.9 +/- 1.1 vs. 12.5 +/- 1.0 and 13.1 +/- 1.1, respectively). Between day 18 and 30 of lactation, sows in SPW5 and SPW7 gained weight (4.5 +/- 1.4 and 1.9 +/- 1.4 kg, respectively) whereas SPW0 and SPW3 sows lost weight (4.9 +/- 1.4 and 2.9 +/- 1.4 kg, respectively) (P<0.05). Split weaned piglets were heavier at day 17 of age by 1.0 kg however by day 40 of age no weight differences were observed between piglets weaned on day 18 compared to day 30 (P<0.05). In conclusion, split weaning coupled with fence-line boar exposure in late lactation induced lactation oestrus in a higher proportion of sows compared to those suckling a normal litter size. PMID- 24051169 TI - Studies on enhancing embryo quantity and quality by immunization against inhibin in repeatedly superovulated Holstein heifers and the associated endocrine mechanisms. AB - To investigate the feasibility of improving embryo production in cattle by immunization against inhibin, both in vivo and in vitro experiments were conducted. In two experiments conducted in two autumns, 14 animals aged 14 months were immunized with a recombinant inhibin alpha subunit protein antigen for four times at monthly intervals, with another 14 animals of the same age served as the controls. Starting from the second immunization, all the heifers received standard superovulation treatment for three sessions, one session per month, each starting 10 days after every antigen administration. Immunization against inhibin increased number of transferable embryos (P<0.05), and high quality Grade A embryos (P<0.01) in each superovulation. Blood concentrations of FSH, estradiol, activin, and also ratio of activin to follistatin concentrations were greater in inhibin immunized than in control animals during the period of superovulatory FSH administration and animal estrous expression. Heifers immunized with inhibin also had greater concentrations of progesterone in the later diestrus period. In the second experiment, the inclusion of anti-inhibin antibody in oocyte IVM medium increased oocyte maturation rate and cleavage rate following IVF (P<0.05). These results demonstrated that inhibition of the adverse effects of inhibin on ovarian follicular development and oocyte maturation improved embryo yield, in both quantity and quality, following superovulation. These results also demonstrate that active immunization against inhibin, in conjunction with the conventional superovulation protocol, can constitute a new technique for consistent improvement of bovine embryo production in vivo; while passive immunization with anti-inhibin antibody can improve embryo production in vitro. PMID- 24051170 TI - Remodeling of bovine endometrium throughout the estrous cycle. AB - The mammalian endometrium changes morphologically and functionally throughout the estrous cycle. In some species, endometrial cells also undergo periodic proliferation and degeneration. However, the remodeling of bovine endometrium throughout the estrous cycle remains unclear. In the present study, we examined how the remodeling of bovine endometrium varied through the estrous cycle by measuring the relative rates of cell proliferation and apoptosis. Cells positive for both KI-67 (a proliferation marker) and cleaved caspase-3 (CCP3: an apoptotic cell marker) were immunohistochemically evaluated throughout the estrous cycle in the luminal and glandular epithelia, and the stroma of bovine endometrium. Percentages of KI-67-positive cells tended to be higher at the early luteal and follicular stages than at the mid and late luteal stages in all cell types. Similarly, percentages of CCP3-positive cells were higher at the early luteal stage than at the mid and late luteal stages in the luminal epithelium and stroma. Furthermore, CCP3 expression levels by Western blot analysis agreed with these immunohistological observations. On the other hand, DNA fragmentation was detected in the bovine endometrium without significant differences during the estrous cycle by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method. Together, these results show that cell proliferation and apoptosis undergo cyclic patterns in the bovine endometrium, and suggest that the bovine endometrium is remodeled in each estrous cycle. PMID- 24051171 TI - Outcome of gestational trophoblastic neoplasia: experience from a tertiary cancer centre in India. AB - AIMS: Gestational trophoblastic neoplasms (GTN) comprise a spectrum of interrelated conditions originating from the placenta. With sensitive assays for human chorionic gonadotropin (beta-hCG) and current approaches to chemotherapy, most women with GTN can be cured with preservation of reproductive potential. The purpose of this analysis was to address the outcome of GTN from a developing country, as data are largely sparse from this region. MATERIALS AND METHODS: We undertook a retrospective review of GTN cases treated at our centre from 2001 to 2008. Patients of GTN were assigned to low-risk (score <= 6) or high-risk (score >= 7) categories as per the modified World Health Organization scoring system. The low-risk group was treated with single-agent methotrexate (MTX) and the high risk group received the EMA/CO regimen. Salvage therapies were EMA/EP or BEP. Treatment was continued until serum beta-hCG values were normal for three consecutive chemotherapy cycles, after which the patients were kept on follow-up. RESULTS: In total, 70 GTN patients were treated at our institution during this period; 48 (68%) were low-risk and 22 (32%) were in the high-risk category. The median beta-hCG level was 50 000 IU/l. The lung was the most common site of metastasis, seen in 15 (21%) patients. Among 48 low-risk patients, 37 (77%) received chemotherapy, of whom 25 (68%) were treated with MTX and 24 (96%) achieved a complete response. Twelve low-risk patients (32%) received EMA/CO therapy; 10 (83%) achieved a complete response. The 22 high-risk patients received EMA/CO and of these 16 (73%) achieved a complete response, two (9%) progressed, two (9%) died of progressive disease and two (9%) were lost to follow up. Grade 3/4 toxicities with MTX included mucositis in two (8%) and neutropenia in five (21%) patients. At a median follow-up of 16.6 months, overall survival in the low- and high-risk groups was 100 and 88.8%, respectively. CONCLUSION: Risk stratified treatment of GTN was associated with acceptable toxicity and resulted in outcome that was comparable with international standards. PMID- 24051172 TI - Trastuzumab retreatment after relapse on adjuvant trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer: final results of the Retreatment after HErceptin Adjuvant trial. AB - AIMS: Trastuzumab, in combination with chemotherapy, is the standard of care for patients with early and metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The Retreatment after HErceptin Adjuvant trial assessed the efficacy and safety of trastuzumab plus a taxane as first-line treatment for patients with metastatic breast cancer (MBC) who had relapsed after adjuvant trastuzumab for HER2-positive early breast cancer. MATERIALS AND METHODS: In total, 43 patients with HER2-positive MBC who had received previous adjuvant trastuzumab for >=10 months, with a relapse-free interval of >=6 months after the last adjuvant trastuzumab dose, were recruited. Eligible patients (n = 41) were assigned to receive trastuzumab, either weekly or every 3 weeks, in combination with docetaxel or paclitaxel until disease progression. RESULTS: At the final analysis, with a median follow-up time of 40 months, a positive response was observed in 25/41 patients (61%; 95% confidence interval: 48.7 80.4%), stable disease in 7/41 (17.1%) and progressive disease in 6/41 (14.6%). Three patients had missing response assessments (one had no measurable lesions at baseline and two had no post-baseline tumour assessments). The median progression free survival (PFS) was 8.0 months (95% confidence interval: 6-11 months) and the median overall survival was 25.0 months (16-33 months). No correlation was found between response rate, PFS or overall survival and the duration of adjuvant trastuzumab treatment, trastuzumab-free interval, relapse-free interval, hormone receptor status or type of pre-metastatic treatment. The most common adverse events (all grades) were alopecia (32%) and diarrhoea (32%). Six patients (14.6%) developed at least one serious adverse event. No congestive heart failure or any unexpected adverse events were reported. CONCLUSION: Trastuzumab, in combination with a taxane, is an effective and well-tolerated first-line treatment for MBC in patients who relapse after trastuzumab-based adjuvant therapy. PMID- 24051173 TI - Malignant mesothelioma, hypoalbuminaemia and the effect of carboplatin/pemetrexed on survival. AB - AIMS: The incidence of malignant mesothelioma in the UK is increasing. The aim of this study was to determine the prognostic factors and assess the effect of carboplatin/pemetrexed chemotherapy on survival. MATERIALS AND METHODS: Cases of malignant mesothelioma diagnosed between 1998 and 2011 were stratified by year of diagnosis. Factors affecting survival were assessed by Cox's proportional hazards regression. RESULTS: In total, there were 202 new cases of malignant mesothelioma between 1998 and 2011. The age-standardised rate (95% confidence interval) increased from 2.84 (2.06-3.60) to 4.44 (3.50-5.4); P = 0.025. Chemotherapy use has increased since 2006: 52% versus 34% (P = 0.007). The median survival (interquartile range) by year diagnosed was 9 (4.0-21.9) versus 10 (3.8-20.1) months for 1998-2005 versus 2006-2011. Independent predictors of survival [hazard ratio (95% confidence interval)] were: histology, sarcomatoid 2.22 (1.49-3.31) and unspecified non-epithelioid 1.50 (1.06-2.14); Eastern Cooperative Oncology Group performance status >=3 2.86 (1.64-5.00); hypoalbuminaemia 2.07 (1.47-2.92), carboplatin/pemetrexed chemotherapy 0.56 (0.38-0.80). CONCLUSION: The incidence of mesothelioma is increasing. Adverse prognostic factors include non-epithelioid histology, performance status and hypoalbuminaemia. Overall survival has not improved significantly, but treatment with carboplatin/pemetrexed chemotherapy is associated with a significant survival benefit. PMID- 24051174 TI - PTB intercomparisons of passive H*(10) area dosemeters for environmental monitoring. AB - For measuring the quantity ambient dose equivalent, H*(10), various passive photon and neutron dosemeters have been newly developed and are used in particular for the monitoring of nuclear facilities in the radiation field of the natural ambient radiation. Since 2005, the Physikalisch-Technische Bundesanstalt (PTB) has been performing intercomparisons to study fundamental properties and the long-term behaviour of area dosemeters under real environmental conditions, i.e. the accuracy of photon and neutron measurements performed in the complex natural radiation field. Measuring bodies from four European countries were the participants, including Germany. The goal was, on the one hand, quality assurance for existing passive dosemeters and measurement procedures and, on the other hand, the experimental investigation of whether the requirements of the appropriate standards and guidelines are met in practical use. PMID- 24051175 TI - Radon levels and doses in dwellings in two villages in Kosovo, affected by depleted uranium. AB - The radon ((222)Rn) activity concentration in 15 dwellings in the Planej village and 10 dwellings in the Gorozhup village has been measured with the aim to complement the national radon survey and to compare the results of two different measurement techniques. The radon concentration has been measured in winter and spring using alpha scintillation cells and in winter, spring and summer by exposing solid-state nuclear track detectors. Both methods gave similar results. Radon concentrations in both villages were similar, ranging from 82 to 432 Bq m( 3); the value of 400 Bq m(-3) was exceeded only in two dwellings. The resulting annual effective doses ranged from 1.78 to 6.40 mSv, with the average values of 3.28 mSv in the Planej village and 3.87 mSv in the Gorozhup village. PMID- 24051176 TI - Isolation and quantification of highly acid resistant variants of Listeria monocytogenes. AB - Heterogeneity in stress response of bacteria is one of the biggest challenges posed by minimal processing, which aims at finding the balance between microbiologically stable foods while maintaining the characteristics of fresh products. In this study, exposure of Listeria monocytogenes LO28 to acid stress, which can be encountered in the food processing environment as well as in the human body upon ingestion, led to inactivation kinetics showing considerable tailing, which was described by a biphasic inactivation model. Stable acid resistant variants of L. monocytogenes LO28 were isolated after exposure of late exponential phase cells to pH 3.5 for 90 min. The resulting 23 stable resistant isolates could be divided in three groups: (a) highly increased acid resistance (<1 log10 reduction, n=16), (b) slightly increased acid resistance (1-3 log10 reduction, n=6), and (c) one isolate showing a variable acid stress response. The highly acid resistant group showed increased resistance to the tested pH range of 2.5 to 3.5 in both late-exponential and stationary phase. Increased acid resistance showed to be significantly correlated to reduced growth rate. The Weibull model was reparameterized, resulting in improved parameter estimation, and was used to estimate the inactivation kinetics at mild pH. Studying the growth boundaries of the wild type and a representative set of variants indicated that the increased resistance of the variants was only related to survival of severe pH stress but did not allow for better growth or survival at mild pH stress. This study shows that acid exposure of late-exponential phase cells reveals the presence of acid resistant subpopulations and that there is a phenotypic diversity amongst them. The occurrence of heterogeneity and stress resistant subpopulations may lead to a higher number of surviving microorganisms than expected. Also, stress resistant subpopulations can become part of the domestic flora in a food production line. The currently isolated acid resistant variants are a new group of stress resistant variants and underline the importance of gaining more insight in the mechanisms underlying this heterogeneity and increased resistance. PMID- 24051177 TI - Elevated homocysteine level in siblings of patients with schizophrenia. AB - Increased homocysteine plasma levels were reported in patients with schizophrenia and Levine et al. (2002) suggested that such increase characterizes mainly males. In the following study we examined whether such increased levels also characterize male siblings of schizophrenia patients. Forty-four pairs of schizophrenia patients and their corresponding healthy male siblings were recruited and sampled for homocysteine. We also had age-matched controls for each of the sibling. The median homocysteine plasma level for patients was 13.0 uMol/L and 11.7 uMol/L for their male siblings compared with a median of 10.9 uMol/L for the siblings' controls. There was no significant difference between homocysteine plasma level in patients and their siblings. Significant difference was found for homocysteine plasma level between the siblings' group and their matched controls. A partial correlation of Ln plasma homocysteine level between patients and their siblings was found to be close to a zero correlation of -0.089, p=0.57 for the whole study group and -0.15, p=0.38 in the male-male patient-sibling pairs. Our results show that elevated homocysteine plasma level may characterize schizophrenia patients' male siblings, a finding that seems to agree with previous studies suggesting elevated homocysteine level as a risk factor for developing schizophrenia. PMID- 24051178 TI - Predicting children's attachment behaviors from the interaction between oxytocin and glucocorticoid receptors polymorphisms. PMID- 24051179 TI - Detection and identification of oxidized insulin-like growth factor-binding proteins and receptors in patients with colorectal carcinoma. AB - Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and also the one with the highest mortality rate. Tumor growth is assisted by various growth factors, and insulin-like growth factors (IGFs) are among the most important. A majority of the IGFs are bound to IGF-binding proteins (IGFBPs) and their release is dependent on the rate of IGFBP proteolysis. The action of free IGFs is exerted and controlled by binding to cell membrane receptors (IGF-Rs). The objective of this work was to connect two determinants of the CRC pathology: oxidation as a process that underlies tumor development and the members of the IGF system that control it. Carbonyl groups (CO) on IGFBP-2, IGFBP-3, IGF-1R, and IGF-2R were determined in samples obtained from patients with CRC, and IGF binding properties of these proteins were analyzed. According to our results, IGFBP-2 and IGFBP-3 in serum had increased content of CO groups due to CRC. Oxidation of IGFBP-2 increased its affinity for IGF molecules, whereas oxidation of IGFBP-3 reduced it. As for receptors, only intact CO-IGF-2R was detected on solubilized colon membranes, whereas CO-IGF-1R was degraded into fragments. Oxidative changes in the IGF axis may be regarded as part of the mechanism of its action. IGFs bound to IGFBP-3 remain in the circulation, whereas those bound to IGFBP-2 freely reach target tissues. Therefore, oxidation supports IGF distribution toward tissues and, consequently, promotes tumor growth. PMID- 24051180 TI - Evaluation of long-term vitamin E insufficiency or excess on bone mass, density, and microarchitecture in rodents. AB - High dietary alpha-tocopherol levels reportedly result in osteopenia in growing rats, whereas alpha-tocopherol deficiency in alpha-tocopherol transfer protein knockout (alpha-TTP-KO) mice results in increased cancellous bone mass. Because osteoporosis is a disease associated primarily with aging, we hypothesized that age-related bone loss would be attenuated in alpha-TTP-KO mice. Cancellous and cortical bone mass and microarchitecture were assessed using dual-energy X-ray absorptiometry and micro-computed tomography in 2-year-old alpha-TTP-KO and wild type (WT) male and female mice fed dl-alpha-tocopherol acetate. In contrast to our expectations, differences in cancellous bone were not detected between WT and alpha-TTP-KO mice of either gender, and alpha-TTP-KO males had lower (p<0.05) cortical bone mass than WT males. We therefore evaluated bone mass, density, and microarchitecture in proximal femur of skeletally mature (8.5-month-old) male Sprague-Dawley rats fed diets containing low (15 IU/kg diet), adequate (75 IU/kg diet), or high (500 IU/kg diet) dl-alpha-tocopherol acetate for 13 weeks. Low dietary alpha-tocopherol did not increase bone mass. Furthermore, no reductions in cancellous or cortical bone mass were detected with high dietary alpha tocopherol. Failure to detect increased bone mass in aged alpha-TTP-KO mice or bone changes in skeletally mature rats fed either low or high levels of alpha tocopherol does not support the hypothesis that alpha-tocopherol has a negative impact on bone mass, density, or microarchitecture in rodents. PMID- 24051181 TI - Nitric oxide scavenging by red cell microparticles. AB - Red cell microparticles form during the storage of red blood cells and in diseases associated with red cell breakdown and asplenia, including hemolytic anemias such as sickle cell disease. These small phospholipid vesicles that are derived from red blood cells have been implicated in the pathogenesis of transfusion of aged stored blood and hemolytic diseases, via activation of the hemostatic system and effects on nitric oxide (NO) bioavailability. Red cell microparticles react with the important signaling molecule NO almost as fast as cell-free hemoglobin, about 1000 times faster than red-cell-encapsulated hemoglobin. The degree to which this fast reaction with NO by red cell microparticles influences NO bioavailability depends on several factors that are explored here. In the context of stored blood preserved in ADSOL, we find that both cell-free hemoglobin and red cell microparticles increase as a function of duration of storage, and the proportion of extra erythrocytic hemoglobin in the red cell microparticle fraction is about 20% throughout storage. Normalized by hemoglobin concentration, the NO-scavenging ability of cell-free hemoglobin is slightly higher than that of red cell microparticles as determined by a chemiluminescence NO-scavenging assay. Computational simulations show that the degree to which red cell microparticles scavenge NO will depend substantially on whether they enter the cell-free zone next to the endothelial cells. Single microvessel myography experiments performed under laminar flow conditions demonstrate that microparticles significantly enter the cell-free zone and inhibit acetylcholine, endothelial-dependent, and NO-dependent vasodilation. Taken together, these data suggest that as little as 5 MUM hemoglobin in red cell microparticles, an amount formed after the infusion of one unit of aged stored packed red blood cells, has the potential to reduce NO bioavailability and impair endothelial-dependent vasodilation. PMID- 24051185 TI - [Severe apparent life-threatening event during "skin-to-skin": treatment with hypothermia]. AB - 'Skin-to-skin' in healthy newborn infants is currently routine practice in Spanish maternity wards. This practice has shown benefits in increasing the duration of breast-feeding and maternal bonding behaviour with no significant adverse events. Early sudden deaths and severe apparent life-threatening events (ALTE) during the first 24 hours of life are infrequent, but well recognised. Risk factors during 'skin to skin' have been established. These events can lead to high neonatal morbidity and mortality. Hypothermia is now the standard of care for moderate to severe hypoxic-ischaemic encephalopathy and has shown to reduce mortality and neurological morbidity in children with hypoxic-ischaemic brain injury. Although there are no clinical trials that evaluate hypothermia after a severe ALTE, neonates who suffer it should be considered for this treatment. We present a case of a healthy newborn who had an ALTE during skin-to-skin with his mother and was treated with hypothermia. PMID- 24051186 TI - [Could pleural aspergillosis happen to be a complication of pleural drainage?]. AB - Four cases of nosocomial aspergillosis are described where the responsibility of pleural drainage is advocated. Infection was pulmonary once, pleural three times. Pleural suction had been long lasting with incomplete re-expansion of the lung and major air leaks. The hypothesis of the responsibility of pleural drainage in the advent of aspergillosis is reinforced by the revision of medical papers, which leads to the conviction that similar cases have been described yet, even though the mechanism of the contamination had not been understood. Prevention needs to limitate the lasting of the suction, especially if there are major air leaks. Cure needs total re-expansion of the lung and suppression of any pleural cavity, even if a thoracoplasty is needed. An anti-fungal therapy is not always needed. PMID- 24051182 TI - Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: a role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation. AB - Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications. PMID- 24051187 TI - [Esophagobronchial fistula as an end complication of esophageal tuberculosis]. PMID- 24051188 TI - [Radiofrequency of lung metastases: should initial pneumothorax predict treatment failure?]. AB - In the management of lung metastases originating from colorectal cancer, RFA is particularly indicated in case of major comorbidities contraindicating thoracic surgery or recurrent disease after previous ipsilateral resection. The most frequent complication of RFA is pneumothorax, requiring chest tube insertion in 5% of cases. Interestingly, this proportion is very close to the rate of local recurrence, suggesting a possible association. We report a case of RFA followed by intractable pneumothorax requiring surgical management, and leading to the diagnosis of residual tumour. This case report illustrates this association and questions its relevance. PMID- 24051189 TI - [Esophageal foreign body revealed by respiratory distress]. AB - Ingestion of a foreign body is usually accidental in children. Respiratory symptoms, often favored by the persistence of the foreign body in the esophagus, can be revealing, but rarely respiratory distress as a method telling. We report a case of unrecognized esophageal foreign body revealed by respiratory distress. PMID- 24051190 TI - Guidance on the use of respiratory and facial protection equipment. AB - Infectious micro-organisms may be transmitted by a variety of routes, and some may be spread by more than one route. Respiratory and facial protection is required for those organisms that are usually transmitted via the droplet/airborne route, or when airborne particles have been artificially created, such as during 'aerosol-generating procedures'. A range of personal protective equipment that provides different degrees of facial and respiratory protection is available. It is apparent from the recent experiences with severe acute respiratory syndrome and pandemic (H1N1) 2009 influenza that healthcare workers may have difficulty in choosing the correct type of facial and respiratory protection in any given clinical situation. To address this issue, the Scientific Development Committee of the Healthcare Infection Society established a short-life working group to develop guidance. The guidance is based upon a review of the literature, which is published separately, and expert consensus. PMID- 24051191 TI - The immunotoxic effects of dual exposure to PCP and TCDD. AB - Pentachlorophenol (PCP) was a commonly used fungicide, herbicide, insecticide, and bactericide in industrial, agricultural, and domestic settings; however, it was also contaminated with polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). It has been reported that technical grade PCP had immunosuppressive effects and that the immune system was the major target of PCDD/PCDFs toxicity. Although the immune response after exposure to PCP or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been studied, the toxic effects of exposure to both PCP and TCDD have not yet been reported. The aim of this study was to evaluate the effects on immune cells from mice intraperitoneally immunized with OVA and subsequently treated with PCP or TCDD alone or in combination by gavage. The animals were terminated on day 7 and 14, and the spleen and plasma samples were collected for immunotoxicity evaluation. The numbers and populations of splenocytes, T cell-derived cytokines produced by splenocytes, splenocyte generated cytotoxicity and OVA-specific antibodies in plasma were investigated. Our results indicate that the spleen/body weight ratio and splenocyte number was reduced by TCDD alone; in addition, this reduction was enhanced when TCDD was combined with PCP. Exposure to TCDD alone or in conjunction with PCP suppressed many ovalbumin (OVA)-stimulated cytokines, including IL-2, IFN-gamma, IL-4, IL-5, and IL-10. Furthermore, the immunoglobulins IgG and IgM were suppressed in mice administered by PCP alone, but the suppressive effects were greater in mice treated with TCDD alone or in combination with PCP. Co-exposure to PCP and TCDD resulted in an antagonistic effect on TCDD-induced suppression of IFN-gamma and IL-10. Our results demonstrate that PCP alone is immunotoxic, regardless of the presence of TCDD. PCP led to mild changes in cytokine secretion, and it compromised splenocyte-generated cytotoxicity and IgM and IgG antibody production on day 7. The finding that PCP antagonizes TCDD-induced IFN-gamma suppression could be due to the competitive binding of PCP to AhR (aryl hydrocarbon receptor). PMID- 24051192 TI - Ursolic acid inhibits tumor angiogenesis and induces apoptosis through mitochondrial-dependent pathway in Ehrlich ascites carcinoma tumor. AB - Ursolic acid (UA) is a pentacyclic triterpene naturally occurring in many plant foods. In the present study, we investigated anti-cancer activity of UA in vivo in Ehrlich ascites carcinoma (EAC) tumor. 15 * 10(6) EAC cells were implanted intraperitoneally (i.p., ascitic tumor) and subcutaneous (s.c., solid tumor) in Swiss albino mice. Mice with established tumors received UA i.p. at 25, 50 and 100mg/kg bw for 14 d in ascitic and 100mg/kg bw in solid tumor for 30 d. On day 15, blood samples were collected for hematological assessment of hemoglobin (Hb%), RBCs, WBCs and PCV. Tumor volume, cell viability, angiogenic, anti angiogenic, anti-inflammatory factors and antioxidant parameters were determined. Immunohistochemistry analysis for VEGF, iNOS, CD31, caspase-3 and Bax were also performed. UA significantly inhibited tumor growth, cell viability, in both ascites and solid tumor model in vivo (p<0.001). The anti-angiogenic effects were accompanied with decreased VEGF, iNOS, TNF-alpha and increased IL-12 levels. UA at 100mg/kg bw dose significantly increased SOD and CAT activity (p<0.01). GSH and TBARS were increased as compared to control group (p<0.001). Furthermore, UA increased total RBCs, WBCs as well as Hb% significantly (p<0.05) compared to cyclophosphamide (CP). Histopathological examination of tumor cells in the treated group demonstrated signs of apoptosis with chromatin condensation and cell shrinkage. Decreased peritoneal angiogenesis showed the anti-angiogenic potential. UA downregulated VEGF & iNOS expression whereas bax and caspase-3 expressions were upregulated suggesting drug induced tumor cell apoptosis through activating the pro-apoptotic bcl-2 family and caspase-3 and downregulation of VEGF. The present study sheds light on the potent antitumor property of the UA and can be extended further to develop therapeutic protocols for treatment of cancer. PMID- 24051193 TI - Orbital lymphomas: clinical and radiological features. AB - The purpose of this prospective study was to evaluate the clinical and radiological features of a consecutive series of orbital lymphomas in two Institutions in the North West of Italy. A prospective study was performed of all cases of diagnosed orbital lymphomas. Data on patient demographics, symptoms and clinical findings, histological type of lymphoma, site of lesion, imaging, and systemic involvement were recorded in each case. The mean age of the enrolled 20 patients was 63.65 years. Most orbital lymphomas were located in the superior lateral quadrant. Superior rectus muscle was the most frequently involved orbital structure. Most patients were affected by extranodal marginal-zone lymphomas. The diagnosis of orbital lymphomas may be challenging, because these neoplasms present few specific features. Although not typically performed by the maxillofacial surgeon, an understanding of the staging process is crucial for multidisciplinary management of orbital lymphomas. PMID- 24051194 TI - Diallyl-disulfide, an organosulfur compound of garlic, attenuates airway inflammation via activation of the Nrf-2/HO-1 pathway and NF-kappaB suppression. AB - Diallyl disulfide (DADS) is a major organosulfur compound found in garlic oil that is widely used as a flavoring agent. In this study, we evaluated the effects of DADS on airway inflammation using an ovalbumin-induced model of allergic asthma and RAW264.7 cells. DADS decreased nitric oxide production with a reduction in the levels of interleukins (IL)-1beta and IL-6 in RAW264.7 cells stimulated with LPS. DADS also reduced the expression of proinflammatory proteins including inducible nitric oxide synthase (iNOS), nuclear factor (NF)-kappaB, and matrix metalloproteinase (MMP)-9, and it enhanced the expression of antioxidant proteins including Nrf-2 and hemeoxygenase (HO)-1. In in vivo experiments, DADS decreased the inflammatory cell count in the bronchoalveolar lavage fluid (BALF) with IL-4, IL-5, IL-13, and immunoglobulin (Ig) E. These results were consistent with the histological analysis. DADS attenuated the airway inflammation and mucus hypersecretion induced by OVA challenge. In addition, DADS induced the activation of Nrf-2 and the expression of HO-1. In contrast, DADS reduced the activation of NF-kappaB, iNOS and MMP-9. In conclusion, DADS reduced the airway inflammation via regulation of Nrf-2/HO-1 and NF-kappaB. These results suggest that DADS might represent a useful new oral therapy to treat allergic asthma. PMID- 24051195 TI - Soy in wheat--contamination levels and food allergy risk assessment. AB - In the United States, packaged food ingredients derived from allergenic sources must be clearly labeled. However, no requirement exists to declare the presence of residues of raw agricultural commodities due to agricultural commodity comingling. Clinical reports of allergic reactions to undeclared soy in wheat based products do not exist suggesting that a rather low degree of risk is posed by wheat-based products that are comingled with soy. Detectable soybean residues (>2.5 ppm soy flour) were found in 62.8% of commercially available wheat flours at concentrations of 3-443 ppm soy flour (1.6-236 ppm soy protein). Conservative probabilistic risk assessments predict a risk of allergic reaction among the most sensitive soy-allergic individuals of 2.8+/-2.0 per 1000 soy-allergic user eating occasions of foods containing wheat flour. However, the predicted reactions occur at exposure levels below the lowest eliciting dose observed to provoke objective reactions in clinical oral soy challenges. Given this low level of predicted risk and the lack of evidence for allergic reactions among soy-allergic consumers to wheat-based products, the avoidance of wheat-based products by soy-allergic consumers does not appear to be necessary. PMID- 24051196 TI - Effects of sleep and endocrine system on health of fragility fracture patients. PMID- 24051197 TI - Canine intracranial gliomas: relationship between magnetic resonance imaging criteria and tumor type and grade. AB - Limited information is available to assist in the ante-mortem prediction of tumor type and grade for dogs with primary brain tumors. The objective of the current study was to identify magnetic resonance imaging (MRI) criteria related to the histopathological type and grade of gliomas in dogs. A convenience sample utilizing client-owned dogs (n=31) with gliomas was used. Medical records of dogs with intracranial lesions admitted to two veterinary referral hospitals were reviewed and cases with a complete brain MRI and definitive histopathological diagnosis were retrieved for analysis. Each MRI was independently interpreted by five investigators who were provided with standardized grading instructions and remained blinded to the histopathological diagnosis. Mild to no contrast enhancement, an absence of cystic structures (single or multiple), and a tumor location other than the thalamo-capsular region were independently associated with grade II tumors compared to higher grade tumors. In comparison to oligodendrogliomas, astrocytomas were independently associated with the presence of moderate to extensive peri-tumoral edema, a lack of ventricular distortion, and an isointense or hyper-intense T1W-signal. When clinical and MRI features indicate that a glioma is most likely, certain MRI criteria can be used to inform the level of suspicion for low tumor grade, particularly poor contrast enhancement. Information obtained from the MRI of such dogs can also assist in predicting an astrocytoma or an oligodendroglioma, but no single imaging characteristic allows for a particular tumor type to be ruled out. PMID- 24051198 TI - Component processes in contour integration: a direct comparison between snakes and ladders in a detection and a shape discrimination task. AB - In contour integration, a relevant question is whether snakes and ladders are processed similarly. Higher presentation time thresholds for ladders in detection tasks indicate this is not the case. However, in a detection task only processing differences at the level of element linking and possibly contour localization might be picked up, while differences at the shape encoding level cannot be noticed. In this study, we make a direct comparison of detection and shape discrimination tasks to investigate if processing differences in the visual system between snakes and ladders are limited to contour detection or extend to higher level contour processing, like shape encoding. Stimuli consisted of elements that were oriented collinearly (snakes) or orthogonally (ladders) to the contour path and were surrounded by randomly oriented background elements. In two tasks, six experienced subjects either detected the contour when presented with a contour and a completely random stimulus or performed a shape discrimination task when presented with two contours with different curvature. Presentation time was varied in 9 steps between 8 and 492 ms. By applying a generalized linear mixed model we found that differences in snake and ladder processing are not limited to a detection stage but are also apparent at a shape encoding stage. PMID- 24051199 TI - The phenotype and genotype of fibrodysplasia ossificans progressiva in China: a report of 72 cases. AB - Fibrodysplasia ossificans progressiva, an ultra-rare and disabling genetic disorder of skeletal malformations and progressive heterotopic ossification (HO), is the most catastrophic condition of skeletal metamorphosis in humans. We studied 72 patients with FOP in China and analyzed their phenotypes and genotypes comprising the world's largest ethnically homogeneous population of FOP patients. Ninety-nine percent of patients (71/72 cases) were of Han nationality; and 1% of patients (1/72 cases) were of Hui nationality. Based on clinical examination, 92% of patients (66/72 cases) had classic FOP; 4% of patients (3/72 cases) were FOP plus; and 4% of patients (3/72) were FOP variants. Importantly, all individuals with FOP had mutations in the protein-coding region of activin A receptor, type I/activin-like kinase 2 (ACVR1/ALK2). Ninety-seven percent of FOP patients (70/72 cases) had the canonical c.617G>A (p.R206H) mutation, while 3% of FOP patients (2/72 cases) had variant mutations in ACVR1/ALK2. Taken together, the genotypes and phenotypes of individuals with FOP from the Han nationality in China are similar to those reported elsewhere and support the fidelity of this ultra-rare disorder in the world's most highly populated nation and across wide racial, ethnic, gender and geographic distributions. PMID- 24051200 TI - Immunoglobulinfree light chains reduce in an antigen-specific manner the rate of rise of action potentials of mouse non-nociceptive dorsal root ganglion neurons. AB - Plasma B cells secrete immunoglobulinfree light chains (IgLC) which by binding to mast cells can mediate hypersensitivity responses and are involved in several immunological disorders. To investigate the effects of antigen-specific IgLC activation, intracellular recordings were made from cultured murine dorsal root ganglion (DRG) neurons, which can specifically bind IgLC. The neurons were sensitized with IgLC for 90min and subsequently activated by application of the corresponding antigen (DNP-HSA). Antigen application induced a decrease in the rate of rise of the action potentials of non-nociceptive neurons (MANOVA, p=2.10( 6)), without affecting the resting membrane potential or firing threshold. The action potentials of the nociceptive neurons (p=0.57) and the electrical excitability of both types of neurons (p>0.35) were not affected. We conclude that IgLC can mediate antigen-specific responses by reducing the rate of rise of action potentials in non-nociceptive murine DRG neurons. We suggest that antigen specific activation of IgLC-sensitized non-nociceptive DRG neurons may contribute to immunological hypersensitivity responses and neuroinflammation. PMID- 24051201 TI - Study of translational dynamics in molten polymer by variation of gradient pulse width of PGSE. AB - Pulsed gradient spin echo is a method of measuring molecular translation. Changing Delta makes it sensitive to diffusion spectrum. Spin translation effects the buildup of phase structure during the application of gradient pulses as well. The time scale of the self-diffusion measurement shortens if this is taken into account. The method of diffusion spectrometry with variable delta is also less sensitive to artifacts caused by spin relaxation and internal gradient fields. Here the method is demonstrated in the case of diffusion spectrometry of molten polyethylene. The results confirm a model of constraint release in a system of entangled polymer chains as a sort of tube Rouse motion. PMID- 24051202 TI - Fast in situ enzymatic gelation of PPO-PEO block copolymer for injectable intraocular lens in vivo. AB - Foldable intraocular lenses (IOLs) have been utilized to substitute natural lens of cataract patients. In this study, we developed a fast, in situ gelable hydrogel requiring no toxic agent as an injectable IOL material. A 4-armed PPO/PEO-phenol conjugate by a non-degradable linker was synthesized to form a hydrogel in situ by horseradish peroxidase. The gelation time and modulus could be controlled, ranging from 20 s to 2 min and from 1 to 43 kPa. The adhesion of human lens epithelial cells on the hydrogel was significantly reduced compared to that on commercial IOLs. The hydrogels were injected into the rabbit eyes to evaluate the in vivo biocompatibility for 8 weeks. Corneal endothelial cell loss and central corneal thickness were comparable with the common IOL implantation procedure. Histologically, the cornea and retina showed the intact structure. The change of refraction after application of pilocarpine was +0.42 D preoperatively and +0.83 D postoperatively, which may indicate the maintenance of accommodation amplitude. PMID- 24051203 TI - March separate, strike together--role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer's disease. AB - The energy demand and calcium buffering requirements of the brain are met by the high number of mitochondria in neurons and in these, especially at the synapses. Mitochondria are the major producer of reactive oxygen species (ROS); at the same time, they are damaged by ROS that are induced by abnormal protein aggregates that characterize human neurodegenerative diseases such as Alzheimer's disease (AD). Because synaptic mitochondria are long-lived, any damage exerted by these aggregates impacts severely on neuronal function. Here we review how increased TAU, a defining feature of AD and related tauopathies, impairs mitochondrial function by following the principle: 'March separate, strike together!' In the presence of amyloid-beta, TAU's toxicity is augmented suggesting synergistic pathomechanisms. In order to restore mitochondrial functions in neurodegeneration as a means of therapeutic intervention it will be important to integrate the various aspects of dysfunction and get a handle on targeting distinct cell types and subcellular compartments. PMID- 24051205 TI - Toll-like receptors in lymphoid malignancies: double-edged sword. AB - Toll-like receptors (TLRs) are the best characterized pattern recognition receptors (PRRs), which play an essential role in the recognition of invading pathogens via specific microbial molecular motifs, comprising a bridge between the innate and adaptive immune responses. Toll-like receptors expression is determined in both normal immune cells and malignant cells, with a distinctive pattern compared to each other, rendering them plausible targets for cancer therapy. Improved molecular profiling of lymphoid malignancies may give new insights into pathogenesis of these cancers and pave the way for novel therapeutic agents, including TLR agonists. In the current review, we summarize the immunopathogenic roles of TLRs in B cell and T cell lymphomas, acute lymphoblastic leukemia, multiple myeloma, and chronic lymphocytic leukemia, as well as the results of studies on TLR ligands and their future implications to manage these hematologic malignancies. PMID- 24051204 TI - Microbiota impact on the epigenetic regulation of colorectal cancer. AB - Mechanisms of colorectal cancer (CRC) development can be generally divided into three categories: genetic, epigenetic, and aberrant immunologic signaling pathways, all of which may be triggered by an imbalanced intestinal microbiota. Aberrant gut microbial composition, termed 'dysbiosis', has been reported in inflammatory bowel disease patients who are at increased risk for CRC development. Recent studies indicate that it is feasible to rescue experimental models of colonic cancer by oral treatment with genetically engineered beneficial bacteria and/or their immune-regulating gene products. Here, we review the mechanisms of epigenetic modulation implicated in the development and progression of CRC, which may be the result of dysbiosis, and therefore may be amenable to therapeutic intervention. PMID- 24051207 TI - Superinfected calcinosis cutis as a presentation of a limited form systemic sclerosis. PMID- 24051206 TI - Aging decreases the contribution of MaxiK channel in regulating vascular tone in mesenteric artery by unparallel downregulation of alpha- and beta1-subunit expression. AB - Vascular disease increases in incidence with age and is the commonest cause of morbidity and mortality among elderly people. Large-conductance Ca(2+)-activated K(+)(MaxiK) channel, with pore-forming alpha-subunit and modulatory beta1 subunit, is a key regulator of vascular tone. This study explored functional and molecular evidence of MaxiK alteration with aging in the mesenteric artery(MA). Young, Middle-aged, and Old male Wistar rats were used. Selective MaxiK channel blocker (Iberiotoxin) induced a significant increase of vascular tension in MA in all three age groups. However, these effects were greatly decreased in Old animals. The amplitude and frequency of spontaneous transient outward currents were significantly decreased with aging. Single channel recording revealed that aging induced a decrease of the open probability and the mean open time, but an increase of the mean closed time of MaxiK channel. The Ca(2+)/voltage sensitivity of MaxiK was also decreased. Western blotting showed that the protein expression of MaxiK beta1- and alpha-subunit was significantly reduced with aging, and the suppression of beta1 subunits was larger than that of alpha subunits. These data suggest that aging decreases capability of MaxiK channel in regulating vascular tone in the MA, which may be partially mediated by unparallel downregulation of alpha- and beta1-subunit expression. PMID- 24051208 TI - Comparing contents of outcome measures in cerebral palsy using the International Classification of Functioning (ICF-CY): a systematic review. AB - The International Classification of Functioning children and youth version (ICF CY) provides a universal framework for defining and classifying functioning and disability in children worldwide. To facilitate the application of the ICF in practice, ICF based-tools like the "ICF Core Sets" are being developed. In the context of the development of the ICF-CY Core Sets for children with Cerebral Palsy (CP), the aims of this study were as follows: to identify and compare the content of outcome measures used in studies of children with CP using the ICF-CY coding system; and to describe the most frequently addressed areas of functioning in those studies. We searched multiple databases likely to capture studies involving children with CP from January 1998 to March 2012. We included all English language articles that studied children aged 2-18 years and described an interventional or observational study. Constructs of the outcome measures identified in studies were linked to the ICF-CY by two trained professionals. We found 231 articles that described 238 outcome measures. The outcome measures contained 2193 concepts that were linked to the ICF-CY and covered 161 independent ICF-CY categories. Out of the 161 categories, 53 (33.5%) were related to body functions, 75 (46%) were related to activities/participation, 26 (16.1%) were related to environmental factors, and 7 (4.3%) were related to body structures. This systematic review provides information about content of measures that may guide researchers and clinicians in their selection of an outcome measure for use in a study and/or clinical practice with children with CP. PMID- 24051209 TI - Chemical constituents from the roots of Cynanchum paniculatum and their cytotoxic activity. AB - Two new steroidal saponins, cynanside A (1) and B (2) were isolated together with three known compounds (3-5) from the roots of Cynanchum paniculatum (Bunge) Kitag. The structures of 1 and 2 were elucidated on the basis of spectroscopic analyses, including extensive 2D NMR and acid hydrolysis. We evaluated the cytotoxicity of isolates (1-5) against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines in vitro using the SRB bioassay. Compounds 1 and 2 showed selective cytotoxicity against SK-MEL-2 cells with IC50 values of 26.55 and 17.36MUM, respectively. PMID- 24051210 TI - Brugada pattern in a patient medicated with lamotrigine. AB - The authors report the case of a 52-year-old woman with depressive syndrome, treated with lamotrigine for about five months, who went to the emergency department for atypical precordial pain. The electrocardiogram (ECG) revealed a 2 mm downsloping ST-segment elevation and negative T waves in V1 and V2. Due to suspicion of ST-elevation acute coronary syndrome, cardiac catheterization was performed, which revealed normal coronary arteries. The initial ECG was suggestive of type 1 Brugada pattern, but subsequent serial ECGs were less typical. A flecainide test showed the same pattern. After discontinuation of lamotrigine reversal of the typical Brugada ECG pattern was observed. Although not currently contraindicated in Brugada syndrome, the antidepressant lamotrigine blocks sodium channels, which are usually inactivated in heart cell membranes in Brugada syndrome, and may be responsible for the expression of type 1 Brugada pattern. PMID- 24051211 TI - Toward patient-centered care: a systematic review of older adults' views of quality emergency care. AB - STUDY OBJECTIVE: Observers have cited a quality gap between the current emergency care and the needs of elderly adults in the emergency setting. The Institute of Medicine identified patient-centeredness as a vital aim of quality health care. To develop a patient-centered approach in the emergency setting, we must first understand the elderly patients' views of their emergency care. Thus, we performed a systematic review to synthesize the current knowledge about the elderly patient's preferences and views of their emergency care. METHODS: Systematic review of qualitative studies and surveys addressing the elderly patients' views of their emergency care using PUBMED and CINAHL. Using meta ethnography, we identified 6 broad themes about the elderly's perspectives of hospital-based emergency care. RESULTS: Of the 81 articles initially identified, our final review included 28 articles. We developed 6 themes of quality emergency care: (1) role of health care providers; (2) content of communication and patient education; (3) barriers to communication; (4) wait times; (5) physical needs in the emergency care setting; and (6) general elder care needs. Key findings were that emergency staff should (1) assume a leadership role with both the medical and social needs; (2) initiate communication frequently; (3) minimize potential barriers to communication; (4) check on patients during prolonged periods of waiting; (5) attend to distress caused by physical discomforts in the emergency care setting; and (6) address general elder care needs, including the care transition and involvement of caregivers when necessary. CONCLUSION: Current qualitative research on the views of the elderly patient to hospital-based emergency care reveals common themes that should be considered in efforts to improve delivery of care to the elderly patient. PMID- 24051212 TI - Pediatric reference values for urine particle quantification by using automated flow cytometer: results of a multicenter study of Italian urinalysis group. AB - OBJECTIVES: The purpose of this Italian multicenter study was to define pediatric upper reference values for urine particle quantification by using automated flow cytometry. DESIGN AND METHODS: Four hospital-based clinical laboratories participated in this multicenter investigation, which included a total study population of 161 Italian children aged from 1 to 12years. Two laboratories used Sysmex UF-100 and analyzed 86 children, whereas the other two used Sysmex UF 1000i and analyzed 75 subjects. Particle quantification included the analysis of white blood cells (WBC), red blood cells (RBC), squamous epithelial cells (EC), transitional epithelial cells (TC), casts (CAST) and bacteria (BACT). RESULTS: The upper reference values in subjects tested with the Sysmex UF-100 were 9.7WBC/MUL, 10.1RBC/MUL, 7.5EC/MUL, 2.5TC/MUL, 0.7CAST/MUL and 3090BACT/MUL, whereas the upper reference values in subjects tested with the Sysmex UF-1000i were 10.5WBC/MUL, 8.3RBC/MUL, 7.2EC/MUL, 2.9TC/MUL, 0.7CAST/MUL and 48BACT/MUL. No statistically significant differences between genders were found in the value distribution of any of the parameters tested. Similarly, no statistically significant differences were observed between the two urine analyzers, except for BACT. CONCLUSIONS: Automated analysis of urine particles appears a suitable means to optimize the workflow of routine urinalysis of children specimens. The upper reference limits for pediatric subjects obtained in this study were comparable to those previously reported in the literature, with no significant differences between genders and analyzers. PMID- 24051214 TI - In vitro endocrine disruption potential of organophosphate flame retardants via human nuclear receptors. AB - Various organophosphate flame retardants (OPFRs) are widely used in building materials, textiles and electric appliances, and have been reported to cause indoor environmental pollution in houses and office buildings. In this study, using cell-based transactivation assays, we characterized the agonistic and/or antagonistic activities of 11 OPFRs against human nuclear receptors; estrogen receptor alpha (ERalpha), ERbeta, androgen receptor (AR), glucocorticoid receptor (GR), thyroid hormone receptor alpha1 (TRalpha1), TRbeta1, retinoic acid receptor alpha (RARalpha), retinoid X receptor alpha (RXRalpha), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARalpha), and PPARgamma. Of the 11 OPFRs tested, triphenyl phosphate (TPhP) and tricrecyl phosphate (TCP) showed ERalpha and/or ERbeta agonistic activity. In addition, tributyl phosphate (TBP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), TPhP and TCP showed AR antagonistic activity, and TBP, tris(2-ethylhexyl) phosphate (TEHP), TDCPP, TPhP and TCP showed GR antagonistic activity. Furthermore, we found that seven compounds, TBP, tris(2-chloro-1-methylethyl) phosphate (TCPP), TEHP, tris(2-butoxyethyl) phosphate (TBEP), TDCPP, TPhP, and TCP, display PXR agonistic activity. However, none of test compounds showed agonistic or antagonistic activity against TRalpha/beta, or agonistic activity against RARalpha, RXRalpha or PPARalpha/gamma. Taken together, these results suggest that several OPFRs may have potential endocrine disrupting effects via ERalpha, ERbeta, AR, GR and PXR. PMID- 24051215 TI - Dragon's blood dropping pills have protective effects on focal cerebral ischemia rats model. AB - Dragon's blood is a bright red resin obtained from Dracaena cochinchinensis (Lour.) S.C.Chen (Yunnan, China). As a traditional Chinese medicinal herb, it has great traditional medicinal value and is used for wound healing and to stop bleeding. Its main biological activity comes from phenolic compounds. In this study, phenolic compounds were made into dropping pills and their protective effects were examined by establishing focal cerebral ischemia rats model used method of Middle Cerebral Artery Occlusion (MCAO), and by investigating indexes of neurological scores, infarct volume, cerebral index, cerebral water content and oxidation stress. Compared to model group, high, middle and low groups of Dragon's blood dropping pills could improve the neurological function significantly (p<0.01) and reduce cerebral infarct volume of focal cerebral ischemia rats remarkably (p<0.05-0.01). Meanwhile, each group could alleviate cerebral water content and cerebral index (p<0.05-0.01) and regulate oxidative stress of focal cerebral ischemia rats obviously (p<0.05-0.01). Activities of middle group corresponded with that treated with positive control drug. The results obtained here showed that Dragon's blood dropping pills had protective effects on focal cerebral ischemia rats. PMID- 24051213 TI - Regulation of the Hippo pathway and implications for anticancer drug development. AB - Research in the past decade has revealed key components of the Hippo tumor suppressor pathway and its critical role in organ size regulation and tumorigenesis. Recent progress has identified a wide range of upstream factors that control the Hippo pathway, which include cell-cell contact, various diffusible signals, and cognate receptors. Dysregulation of the Hippo pathway, caused by gene mutation or aberrant expression, promotes cell proliferation and tumorigenesis. Here, we discuss the current state of Hippo pathway research, primarily focusing on upstream regulators and protein-protein interactions as potential therapeutic targets. Consideration of pharmacological intervention of the Hippo pathway may provide novel avenues for future therapeutic treatment of human diseases, particularly in cancer. PMID- 24051216 TI - Crocin improved locomotor function and mechanical behavior in the rat model of contused spinal cord injury through decreasing calcitonin gene related peptide (CGRP). AB - Various approaches have been offered to alleviate chronic pain resulting from spinal cord injuries (SCIs). Application of herbs and natural products, with potentially lower adverse effects, to cure diseases has been recommended in both traditional and modern medicines. Here, the effect of crocin on chronic pain induced by spinal cord contusion was investigated in an animal model. Female Wistar rats were randomly divided into five groups (5 rats in each); three groups were contused at the L1 level. One group was treated with crocin (150mg/kg) two weeks after spinal cord injury; the second group, control, was treated with vehicle only; and the third group was treated with ketoprofen. Two normal groups were also considered with or without crocin treatment. The mechanical behavioral test, the locomotor recovery test and the thermal behavioral test were applied weekly to evaluate the injury and recovery of rats. Significant improvements (p<0.05) in mechanical behavioral and locomotor recovery tests were seen in the rats treated with crocin. Thermal behavioral test did not show any significant changes due to crocin treatment. Plasma concentration of calcitonin-gene related peptide (CGRP) changed from 780.2+/-2.3 to 1140.3+/-4.5pg/ml due to SCI and reached 789.1+/-2.7pg/ml after crocin treatment. These changes were significant at the level of p<0.05. The present study shows the beneficial effects of crocin treatment on chronic pain induced by SCI, through decreasing CGRP as an important mediator of inflammation and pain. PMID- 24051217 TI - Development of a bio-relevant dissolution test device simulating mechanical aspects present in the fed stomach. AB - A novel bio-relevant in vitro dissolution device was designed to mimic intragastric conditions after food intake paying particular consideration to mechanical aspects: the Fed Stomach Model (FSM). The FSM represents a fully computer-controlled dynamic flow-through system, in which dosage forms are hosted in so-called gastric vessels. Dosage form movement profiles as well as pressures can be simulated in a physiologically relevant manner. This proof-of-concept study aimed at the investigation of the effects of individual parameters and complex test programs on the drug delivery behavior of diclofenac sodium bilayer extended release tablets. Magnetic marker monitoring experiments demonstrated the applicability of the FSM to simulate intragastric movement velocities of solid oral dosage forms equivalent to in vivo data. Dissolution experiments revealed the relevance of all simulated parameters (i.e. pressure, dosage form movement and pump rate). Moreover, three different test scenarios with test programs specific for fundus, antrum and gastric emptying considered the variability of intragastric transit of solid oral dosage forms after food intake and were confirmed to be reasonable. Dissolution rates were low under conditions specific for fundus owing to low shear stresses. In contrast, higher amounts of the drug were released under high stress conditions simulating antral transit and gastric emptying. Concluding, the FSM can be a valuable tool for bio-relevant dissolution testing due to its potential of precise and reproducible simulation of mechanical parameters characteristic for the fed stomach. PMID- 24051218 TI - Molecular pathogenesis in non-Hodgkin lymphoma: implications for therapy. AB - Although Diffuse Large B-Cell lymphoma (DLBCL) represents 30% of all non-Hodgkin lymphomas, there are many different subtypes of DLBCL with various prognostic implications. We are now recognizing that the molecular subtype of the DLBCL may be associated with specific clinical characteristics as well as outcome of the treatment. With this additional information, we may be able to better select a treatment for the patient which will improve the expected response. Only large scale clinical testing will help us with understanding these molecular subtypes and designing therapies for patients with DLBCL. PMID- 24051219 TI - Multimodal surgical guidance towards the sentinel node in vulvar cancer. AB - INTRODUCTION: Conventional sentinel node (SN) mapping is performed by injecting a radiocolloid followed by lymphoscintigraphy (and SPECT/CT imaging). An extra intraoperative injection with blue dye can then allow for optical identification of the SN. In order to improve the current clinical standard, the hybrid tracer indocyanine green (ICG)-(99m)Tc-nanocolloid was introduced, a tracer that is both radioactive and fluorescent. This feasibility study aimed to evaluate the value of a multimodal-based SN biopsy in vulvar cancer. MATERIALS AND METHODS: Fifteen patients with vulvar cancer (29 groins) scheduled for SN biopsy were peritumorally injected with ICG-(99m)Tc-nanocolloid followed by lymphoscintigraphy and SPECT/CT imaging to identify the SNs. In thirteen patients, shortly before the start of the operation, blue dye was intradermally injected around the lesion. SNs were harvested using a combination of radiotracing, fluorescence imaging, and optical blue dye detection. A portable gamma camera was used before and after SN excision to confirm excision of the preoperatively defined SNs. RESULTS: Preoperative lymphoscintigraphy and SPECT/CT imaging visualized drainage to 39 SNs in 28 groins. During the operation, 98% (ex vivo 100%) of the SNs were radioactive. With fluorescence imaging 96% of the SNs (ex vivo 100%) could be visualized. Only 65% of the SNs had stained blue at the time of excision. CONCLUSION: ICG-(99m)Tc-nanocolloid can be used for preoperative SN identification and enables multimodal (radioactive and fluorescent) surgical guidance in patients with vulvar cancer. The addition of fluorescence-based optical guidance offers more effective SN visualization compared to blue dye. PMID- 24051220 TI - Synchronous primary cancers of the endometrium and ovary in young women: a Korean Gynecologic Oncology Group Study. AB - OBJECTIVE: Some authors have recommended the use of diagnostic laparoscopy as a pretreatment assessment step for conservative hormonal treatment in young women with endometrial cancer. The aim of this study was to determine the incidence of synchronous primary cancer of the endometrium and ovary in young women. METHODS: The medical records of 3240 patients with endometrial cancer who underwent primary surgery between 1995 and 2010 were collected from 7 institutions and were retrospectively reviewed. Low-risk endometrial cancer was defined as tumors without myometrial invasion; normal or benign-looking ovaries; normal CA-125; grade 1 endometrioid histology; and early stage endometrial cancer on pretreatment assessment. RESULTS: Fifteen percent (471/3240) were younger than 40 years of age. The incidence of synchronous ovarian cancer in young women with endometrial cancer was 4.5% (21/471). In patients with low-risk endometrial cancer, synchronous cancers were not identified. CONCLUSION: The incidence of synchronous ovarian malignancies in young women with endometrial cancer was quiet low (4.5%), unlike previous studies have revealed (11-29%). Therefore, diagnostic laparoscopy is not mandatory in patients with low-risk early stage endometrial cancer selected for conservative treatment to confirm the absence of ovarian malignancy. PMID- 24051221 TI - p-21-Activated kinase-1, -4 and -6 and estrogen receptor expression pattern in normal placenta and gestational trophoblastic diseases. AB - OBJECTIVES: To delineate the potential role of p21-activated kinases (PAKs) in the pathogenesis of gestational trophoblastic diseases (GTD) by defining the expression pattern of PAK-1, -4 and -6 and their potential implication in estrogen receptor (ER) regulation of normal placental tissue and GTD. METHODS: We evaluated immunohistochemically 10 normal first-trimester placentas (NP), 10 partial moles (PM), 15 complete moles (CM) and 3 choriocarcinomas (CCA) for PAK 1, PAK-4, PAK-6 and ER expression intensity and localization. Staining outcomes were assessed utilizing non-parametric Kruskal-Wallis one-way analysis of variance test followed by pairwise Wilcoxon Rank Sum tests. Statistical significance was determined by two-sided p-value of <0.05. RESULTS: In NP, PAK-6 immunoreactivity was predominantly cytoplasmic. Compared to NP, PM and CM demonstrated significant increase of cytoplasmic PAK-6 in cytotrophoblast (p=0.012, p=0.033 respectively), accompanied by significantly increased nuclear immunoreactivity in cytotrophoblast (p=0.008, p=0.045 respectively) and intermediate trophoblast (p=0.003, p=0.015 respectively). PAK-4 was found significantly upregulated in both cytoplasmic and nuclear compartments of cytotrophoblast and syncytiotrophoblast in PM (p=0.004 and p=0.002 for cytotrophoblast; p=0.018 and p=0.002 for syncytiotrophoblast, respectively) and CM (p=0.001 and p=0.001 for cytotrophoblast; p=0.002 and p=0.001 for syncytiotrophoblast, respectively) when compared to NP, whereas PAK-1 expression was significantly reduced in the syncytiotrophoblast of PM (p=0.025 for cytoplasm and p=0.008 for nucleus). Nuclear expression of ER was undetectable in all stained samples. CONCLUSION: Our results reveal PAK-6 upregulation in GTD compared to NP. The absence of nuclear expression of ER might stem in part from the repressive effect of PAK-6 in trophoblastic tissue. PMID- 24051222 TI - Post treatment surveillance of type II endometrial cancer patients. AB - OBJECTIVE: There are few studies analyzing surveillance for Type II endometrial cancer recurrence. Our objective was to determine the types of post treatment surveillance tests performed in our institution and the efficacy of these tests in detecting recurrence in type II endometrial cancer patients. METHODS: One hundred and thirty six cases of type II endometrial cancers at Cedars-Sinai Medical Center from January of 2000 to August of 2011 were identified and 106 patients met inclusion criteria. Medical charts were reviewed for surveillance methods and number of follow up visits. For patients who underwent a recurrence of disease, the surveillance method utilized for detection was documented. RESULTS: Forty-seven of the 106 (44%) patients developed recurrence with a mean progression free interval of 11 months. All patients had a history and physical at each surveillance visit, 78% had Pap testing, 57% had CA-125 levels drawn, 59% had CT (computed tomography) scans done, 6% had PET (positron emission tomography) scans done for surveillance. In our cohort, recurrence was detected by symptoms in 16, by CA-125 in 11, by physical exam in 7, by CT scan in 12, and by PET scan in one patient. No patients had recurrence detected by vaginal cytology. CONCLUSIONS: Although performed in the majority of patients, Pap testing did not detect any recurrences within this cohort. History and physical exam detected the most recurrences. These findings suggest that educating patients about relevant symptoms and performing thorough follow-up exams may be the most important aspects of detecting type II endometrial cancer recurrence. PMID- 24051223 TI - A multiplex cytokine score for the prediction of disease severity in pediatric hematology/oncology patients with septic shock. AB - Although many inflammatory cytokines are prognostic in sepsis, the utility of cytokines in evaluating disease severity in pediatric hematology/oncology patients with septic shock was rarely studied. On the other hand, a single particular cytokine is far from ideal in guiding therapeutic intervention, but combination of multiple biomarkers improves the accuracy. In this prospective observational study, 111 episodes of septic shock in pediatric hematology/oncology patients were enrolled from 2006 through 2012. Blood samples were taken for inflammatory cytokine measurement by cytometric bead array (CBA) technology at the initial onset of septic shock. Interleukin (IL)-6 and IL-10 were significantly elevated in majority of patients, while tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were markedly increased in patients with high pediatric index of mortality 2 (PIM2) score and non-survivors. All the four cytokines paralleled the PIM2 score and differentially correlated with hemodynamic disorder and fatal outcomes. The pediatric multiplex cytokine score (PMCS), which integrated the four cytokines into one score system, was related to hemodynamic disorder and mortality as well, but showed more powerful prediction ability than each of the four cytokines. PMCS was an independent predictive factor for fatal outcome, presenting similar discriminative power with PIM2, with accuracy of 0.83 (95% CI, 0.71-0.94). In conclusion, this study develops a cytokine scoring system based on CBA technique, which performs well in disease severity and fatality prediction in pediatric hematology/oncology patients with septic shock. PMID- 24051224 TI - Identification of compounds by high-content screening that induce cytoplasmic to nuclear localization of a fluorescent estrogen receptor alpha chimera and exhibit agonist or antagonist activity in vitro. AB - We have completed a robust high-content imaging screen for novel estrogen receptor alpha (ERalpha) agonists and antagonists by quantitation of cytoplasmic to nuclear translocation of an estrogen receptor chimera in 384-well plates. The screen was very robust, with Z' values >0.7 and coefficients of variation (CV) <5%. The screen utilized a stably transfected green fluorescent protein-tagged glucocorticoid/estrogen receptor (GFP-GRER) chimera, which consisted of the N terminus of the glucocorticoid receptor fused to the human ERalpha ligand binding domain. The GFP-GRER exhibited cytoplasmic localization in the absence of ERalpha ligands and translocated to the nucleus in response to stimulation with ERalpha agonists and antagonists. The BD Pathway 435 imaging system was used for image acquisition, analysis of translocation dynamics, and cytotoxicity measurements. We screened 224,891 samples from our synthetic, pure natural product libraries, prefractionated natural product extracts library, and crude natural product extracts library, which produced a 0.003% hit rate. In addition to identifying several known ER ligands, five compounds were discovered that elicited significant activity in the screen. Transactivation potential studies demonstrated that two hit compounds behave as agonists, while three compounds elicited antagonist activity in MCF-7 cells. PMID- 24051225 TI - Good intentions gone awry? Effects of weight-related social control on health and well-being. AB - A negative body image has been associated with a variety of negative health and well-being outcomes. Social pressures from others, in the form of weight-related social control, may serve to exacerbate this effect, especially for college-aged women. Undergraduate students (N=399) completed a variety of questionnaires assessing weight-related social control, well-being, and diet and exercise behaviors. The results suggest that weight is associated with a variety of negative health and well-being outcomes and particularly for women, weight related social control is also associated with these negative effects. In addition, men of higher body mass indexes (BMIs) or higher self-perceived weight did not experience negative health and well-being outcomes to the same degree that overweight women did. Parents in particular seem to instigate weight-related social control to change students' diet and exercise behaviors. These results help clarify the effects of weight-related social control in a college population, where weight may be especially important. PMID- 24051226 TI - Undiagnosed phenylketonuria in parents of phenylketonuric patients, is it worthwhile to be checked? AB - In our phenylketonuria (PKU) cohort of 120 patients, we uncovered a couple of cases of undiagnosed mild phenylketonuria (mPKU)/hyperphenylalaninemia (mHPA) in maternal parents of the PKU cohort. This finding prompted us to evaluate the risk of either mild phenylketonuria or mild hyperphenylalaninemia in the parent population whose children were diagnosed with hyperphenylalaninemia (HPA). Taking into account the phenylalanine hydroxylase (PAH) mutation carrier frequency and the PAH mild mutation rate, we estimated that the prevalence of the parental mPKU/mHPA varied widely, from 1/74 in Turkey to 1/708 in Lithuania. The benefits of the parental detection procedure described here are the prevention of further maternal PKU syndrome, the follow-up of the newly detected patients and the accuracy of the genetic counseling provided to these families. This very simple procedure should be incorporated into neonatal PKU management of the hospitals in countries where a routine systematic neonatal screening is operational. PMID- 24051227 TI - Drosophila Dachsous and Fat polarize actin-based protrusions over a restricted domain of the embryonic denticle field. AB - Atypical cadherins Dachsous (Ds) and Fat coordinate the establishment of planar polarity, essential for the patterning of complex tissues and organs. The precise mechanisms by which this system acts, particularly in cases where Ds and Fat act independently of the 'core' frizzled system, are still the subject of investigation. Examining the deployment of the Ds-Fat system in different tissues of the model organism Drosophila, has provided insights into the general mechanisms by which polarity is established and propagated to coordinate outcomes across a field of cells. The Drosophila embryonic epidermis provides a simple model epithelia where the establishment of polarity can be observed from start to finish, and in the absence of proliferation, over a fixed number of cells. Using the asymmetric placement of f-actin during denticle assembly as a read-out of polarity, we examine the requirement for Ds and Fat in establishing polarity across the denticle field. Comparing detailed phenotypic analysis with steady state protein enrichment revealed a spatially restricted requirement for the Ds Fat system within the posterior denticle field. Ectopic Ds signaling provides evidence for a model whereby Ds acts to asymmetrically enrich Fat in a neighboring cell, in turn polarizing the cell to specify the position of the actin-based protrusions at the cell cortex. PMID- 24051229 TI - The early mortality associated with agitation and sedation in acutely ill medical patients. PMID- 24051228 TI - Ecdysone signaling at metamorphosis triggers apoptosis of Drosophila abdominal muscles. AB - One of the most dramatic examples of programmed cell death occurs during Drosophila metamorphosis, when most of the larval tissues are destroyed in a process termed histolysis. Much of our understanding of this process comes from analyses of salivary gland and midgut cell death. In contrast, relatively little is known about the degradation of the larval musculature. Here, we analyze the programmed destruction of the abdominal dorsal exterior oblique muscle (DEOM) which occurs during the first 24h of metamorphosis. We find that ecdysone signaling through Ecdysone receptor isoform B1 is required cell autonomously for the muscle death. Furthermore, we show that the orphan nuclear receptor FTZ-F1, opposed by another nuclear receptor, HR39, plays a critical role in the timing of DEOM histolysis. Finally, we show that unlike the histolysis of salivary gland and midgut, abdominal muscle death occurs by apoptosis, and does not require autophagy. Thus, there is no set rule as to the role of autophagy and apoptosis during Drosophila histolysis. PMID- 24051230 TI - Cognitive and personality analysis of startle reactivity in a large cohort of healthy males. AB - Subjects with low/undetectable startle are usually excluded from startle studies but few reports not confounded by this factor, show reduced startle in healthy impulsive subjects, or clinical populations with disorders of affect and impulsivity but also in schizophrenia and its prodrome. We examined the relationship of startle reactivity including startle "non-responding" status to cognitive and affective personality traits in a large and ethnically/demographically homogeneous cohort of healthy males from the LOGOS study, Heraklion, Crete. Startle reactivity was monotonically related to sensitivity to reward (higher in "non-responders", lower in strong responders). In addition, "non-responders" had poorer strategy, working memory and sustained attention performance compared to responder tertile groups. More research in clinical and high risk populations is required to examine if low/undetectable startle reactivity is a valuable intermediate phenotype for disorders of affect and impulsivity. It is possible that the "non-responsive" status may capture disease related features such as executive dysfunction. PMID- 24051231 TI - Anti-stress effect of theanine on students during pharmacy practice: positive correlation among salivary alpha-amylase activity, trait anxiety and subjective stress. AB - PURPOSE: Theanine, an amino acid in tea, has significant anti-stress effect on experimental animals under psychosocial stress. Anti-stress effect of theanine on humans was evaluated in 5th-year university students during pharmacy practice. METHOD: The study design was a single-blind group comparison and participants (n=20) were randomly assigned to theanine or placebo groups. Theanine or placebo (lactose) tablets (200 mg, twice a day, after breakfast and lunch) were taken from 1 week prior to the pharmacy practice and continued for 10 days in the practice period. To assess the anxiety of the participants, the state-trait anxiety inventory test was carried out before the pharmacy practice. Salivary alpha-amylase activity (sAA) was measured as a marker of sympathetic nervous system activity. RESULTS: In the placebo-group, sAA in the morning (pre-practice sAA) was higher than in theanine-group during the pharmacy practice (p=0.032). Subjective stress was significantly lower in the theanine-group than in the placebo-group (p=0.020). These results suggest that theanine intake had anti stress effect on students. Furthermore, students with higher pre-practice sAA showed significantly higher trait anxiety in both groups (p=0.015). Similarly, higher pre-practice sAA was correlated to shorter sleeping time in both groups (p=0.41*10(-3)). CONCLUSION: Stressful condition increased the level of sAA that was essentially affected by individual trait anxiety. The low levels of pre practice sAA and subjective stress in the theanine-group suggest that theanine intake suppressed initial stress response of students assigned for a long-term commitment of pharmacy practice. PMID- 24051232 TI - Review of accessory parotid gland tumors: pathologic incidence and surgical management. AB - OBJECTIVE: The current study presents our experience with accessory parotid gland masses and reviews the literature on accessory parotid tumor incidence and surgical management. Based on our results, we advocate a standard parotidectomy approach with routine facial nerve dissection at the time of excision. STUDY DESIGN: We performed a retrospective chart review and comprehensive literature review on incidence of accessory parotid gland neoplasms. METHODS: A retrospective chart review of all patients with mid-cheek masses treated by the senior author was conducted from January 2003 to January 2009. The tumor size at presentation, FNA biopsy, pathologic diagnosis, and surgical treatment were recorded for 13 patients. RESULTS: In the case series, 54% of lesions were benign (n=7) and 46% were malignant (n=6) including benign pathologies of 4 pleomorphic adenomas, 2 lymphadenitis, 1 monomorphic adenoma and malignant pathologies of 2 mucoepidermoid carcinoma, 2 B-cell lymphomas, 1 adenocarcinoma, and 1 myofibrosarcoma. Surgical intervention was performed on all patients with standard parotidectomy incision for accessory parotid mass excision after identification and tracing of facial nerve and its branches. CONCLUSION: The present study provides support for a standard parotid incision with identification of the facial nerve at the time of surgical incision as this resulted in successful excision of accessory parotid tumors with favorable cosmetic results and without facial paralysis or tumor recurrence. Literature review of 152 cases of accessory parotid gland lesions, revealed a pooled incidence of 70% benign and 30% malignant. PMID- 24051233 TI - Time-dependent changes in the obstruction pattern during drug-induced sleep endoscopy. AB - PURPOSE: Drug-induced sleep endoscopy (DISE) is used to identify the site of obstruction causing obstructive sleep apnea (OSA). However, previous studies have reported a wide range of DISE findings, and new patterns of airway obstruction have also been observed during postoperative DISE. Therefore, we aimed to determine the features of changes in obstructive patterns during DISE. MATERIALS AND METHODS: Forty-two patients diagnosed with OSA underwent DISE for 25 min. Sites of obstruction were determined at the levels of the velum, lateral wall of the oropharynx, tongue base, and epiglottis. The velum obstruction configuration was classified as anteroposterior, lateral, or concentric. RESULTS: The obstructive pattern changed in 14 patients (33%). We observed a change in the site of obstruction in 9 patients (21.4%) and in the configuration of velum obstruction in 5 patients (11.9%). The changes occurred between 3 and 22 min after commencing DISE (mean, 10.6 +/- 6.2 min). The proportion of obstructions in the velum, lateral wall of the oropharynx, and tongue base increased with longer DISE durations. The proportion of multiple-level obstructions increased significantly after 15 min (P<0.05). In the velum, anteroposterior obstructions in 2 patients and lateral obstructions in 3 patients changed into concentric obstructions. More configurations were observed with longer procedure durations. CONCLUSIONS: Hence, we assume that it is possible to miss the site of obstruction during DISE if the procedure is too short, which may partly explain the discrepancies between studies. PMID- 24051234 TI - Utility of positron emission tomography/computed tomography for nodal staging of cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia. AB - PURPOSE: Cutaneous squamous cell carcinoma (cSCC) behaves aggressively in patients with chronic lymphocytic leukemia (CLL). Lymphadenopathy due to CLL can obscure the clinical and radiological assessment of nodal involvement by cSCC. This study aimed to evaluate whether functional imaging with positron emission tomography (PET)/computed tomography (CT) may clarify the clinical picture. METHODS: Five consecutive patients with cSCC and CLL who had a PET/CT scan for the purposes of cSCC staging between July 2000 and July 2010 were analyzed. PET/CT findings were compared to histopathology from subsequent neck dissection. RESULTS: PET/CT can distinguish nodal cSCC from leukemic infiltration with high specificity, allowing prompt appropriate management of nodal disease. CONCLUSIONS: PET/CT is a promising modality for nodal staging in patients with cSCC and CLL, with the potential to improve outcomes in this poor prognosis group. Larger confirmatory studies are needed. PMID- 24051235 TI - Methadone-induced bilateral severe sensorineural hearing loss. AB - Methadone, a long-acting opiate agonist, and naltrexone, an opiate receptor antagonist, are both commonly used to treat patients with morphine and heroin addiction. We present a rare case of methadone-induced persistent bilateral sensorineural hearing loss (SNHL) after chronic naltrexone use and review opioid induced hearing loss in the literature. Methadone-induced hearing loss has been described previously described in the literature with all reported cases recovering functional hearing. This is the first description of persistent bilateral severe SNHL following methadone ingestion. We propose opiate receptor sensitization from prolonged naltrexone use as a predisposing factor for methadone-induced irreversible cochlear injury. PMID- 24051236 TI - Nasopharyngeal pleomorphic adenoma presenting as otitis media with effusion: case report and literature review. AB - Most tumors arising in the nasopharynx are malignant and frequently develop otitis media with effusion (OME). On the contrary, benign nasopharyngeal tumors are very rare, and pleomorphic adenoma, which is a benign mixed tumor of the nasopharynx, is also rarely encountered. We herein report a case of nasopharyngeal pleomorphic adenoma which initially presented as OME. This tumor completely blocked the orifice of the Eustachian tube but was removed by a combination of transnasal and transoral endoscopic resection. A defect in the mucous membrane was covered with polyglycolic acid sheet and fibrin glue. Mucous membrane completely covered the exposed tubal cartilage without adhesion near the tubal orifice. OME and hearing loss completely subsided 3 months after the surgery. She was disease-free 2 years after the surgery. Use of polyglycolic acid sheet could be a feasible mesh for closure of surgical defect without scarring, and it also led to healing of OME. PMID- 24051237 TI - Treatment of cervical paragangliomas: is surgery the only way? AB - PURPOSE: To analyze the results after surgery or stereotactic radiotherapy (SRT) in the treatment of cervical paragangliomas. Against this background, the decision-making algorithm used in the treatment of carotid body tumors (CBTs) and vagal paragangliomas (VPs) was reevaluated relative to the existing literature on the topic. MATERIALS AND METHODS: Retrospective study between 2000 and 2012. A total of 27 CBTs and nine VPs in 32 patients were treated. Shamblin class I: 59.3% (n=16); class II: 29.6% (n=8); class III: 11.1% (n=3). Treatment modalities were surgery, radiotherapy, or observation. The end points for analysis were long term tumor control and integrity of the cranial nerves. RESULTS: 21 CBTs and seven VPs underwent surgery; SRT was performed in three CBTs and two VPs. Three CBTs were clinically observed. Permanent nerve paresis followed after surgery for CBTs in five patients (20%) and in all patients with VPs. No impaired cranial nerve function resulted after SRT. The median follow-up period was 4.7 years. The tumor control rate after therapy for CBTs and VPs was 100%. One CBT that received clinical observation showed slow tumor progression. CONCLUSIONS: A surgical procedure should be regarded as the treatment of choice in patients with small CBTs. In larger CBTs, particularly in elderly patients with unimpaired cranial nerves, radical surgery should be regarded critically. As surgery for VPs caused regularly impairment of cranial nerves with functional disturbances of various degrees a comprehensive consultation with the patient is mandatory and nonsurgical strategies should be discussed. PMID- 24051238 TI - Total hip arthroplasty using large-diameter metal-on-metal articulation in patients with neuromuscular weakness. AB - The purpose of this prospective study was to evaluate the clinical and functional outcomes of THA using large-diameter metal-on-metal articulation in patients with neuromuscular weakness. Nineteen consecutive patients (19 hips) with neuromuscular weakness and displaced femoral neck fractures were enrolled. Functional improvement and recovery, radiological evaluation of THA and surgical morbidity were assessed. Mean Harris hip and WOMAC scores at final follow-up were 81.0 and 42.9, respectively. At final follow-up, no dislocation, metal hypersensitivity, or osteolysis was observed and no patient required revision of THA. The findings of this study indicate that the functional results of THA using large-diameter metal-on-metal articulation in patients with neuromuscular weakness can produce satisfactory outcomes with early functional recovery and a low dislocation rate. PMID- 24051239 TI - An in vivo comparison of the orientation of the transverse acetabular ligament and the acetabulum. AB - Aligning the acetabular component with the Transverse Acetabular Ligament (TAL) to ensure optimal anteversion has been reported to reduce dislocation rates. However, to our knowledge in vivo measurement of the TAL angle has not yet been reported in a large cohort of normal hips. CT scans of 218 normal hips were analyzed. The TAL and four acetabular rim anteversion angles were measured (superiorly to inferiorly) relative to the anterior pelvic plane. The mean TAL anteversion angle was 20.5 degrees +/- 7.0 degrees , and the acetabular rim angles from superior to inferior were 11.0 degrees +/- 12.9 degrees , 19.9 degrees +/- 8.8 degrees , 20.9 degrees +/- 6.2 degrees and 25.1 degrees +/- 6.2 degrees respectively. Both the TAL and the acetabular rim were significantly more anteverted in females than in males. The TAL anteversion angle was comparable to the predominant orientation (central rim section) of the native acetabulum while the superior acetabulum was comparatively retroverted and the inferior was relatively more anteverted. PMID- 24051240 TI - Evaluation of the efficacy and safety of tranexamic acid for reducing blood loss in bilateral total knee arthroplasty. AB - Tranexamic acid (TA) has been reported to reduce blood loss after total joint arthroplasty; however, the literature is sparse in evaluating its efficacy in simultaneous bilateral total knee arthroplasty (TKA). In this retrospective study of consecutive patients, TA use in bilateral TKA was associated with a significant reduction in perioperative serum hemoglobin drop, as well as allogeneic blood transfusion needs from 50% to 11% of patients. No autologous blood donation or drains were used. There were no venous thromboembolic events reported. Implementation of a systematic intravenous TA protocol in simultaneous bilateral TKA appears highly effective in reducing transfusion requirements, potentially reducing healthcare resource utilization as well as the morbidity and complications associated with allogeneic blood transfusions. PMID- 24051241 TI - Mixed chimerism induction influences cytokine release from chimeric mice cells. AB - Interest in mixed chimerism has evolved from its role in the induction of alloantigen tolerance. However, its precise impact on the host organism remains to be elucidated. In the present work, we analyzed cytokine secretion from chimeric mice cells to assess the influence of different mixed chimerism induction protocols on immune system function in recipient mice. To our knowledge, there have been no reports on using this parameter for the optimization of the mixed chimerism induction method. B6.SJL-PtprcaPep3b or C57BL/6J mice were used as recipients and Balb/c as donors. We utilized four protocols which consisted of: 3Gy total body irradiation (day -1), the injection of 20-30*10(6) bone marrow cells (day 0), and a combination of CD40L (days 0 and 4), CD8 (day -2), and NK1.1 (day -3) blocking antibodies and cyclophosphamide (175mg/kg - day 2). The concentrations of cytokines (IFN-gamma, IL-2, IL-4, IL-6, IL-10, IL-17A, and TNF) were evaluated in the supernatants of unstimulated or phytohemagglutinin-stimulated chimeric spleen, bone marrow and peripheral blood cells in the 8th week of experiment. The induction of tolerance to Balb/c mouse antigens was initially tested in chimeric mice by assessing the presence of Vbeta5 and Vbeta11 TCR-expressing lymphocytes. The cytokine production was considerably increased, especially in chimeric mice treated by cyclophosphamide. Also the mixed chimerism itself seems to affect IFN-gamma, IL-2, IL-4, IL-6, IL 17A, and TNF secretion. Using the optimized induction protocol, we established that chimeric mice cells secreted lower IFN-gamma, IL-2, IL-4 and higher IL-6, IL 17A, and TNF levels as compared to control animals. We found that both donor and recipient cells markedly participated in the cytokine production. In conclusion, our optimization study based on cytokine assessment contributes to establishing an effective protocol of mixed chimerism induction with no cyclophosphamide use and better understanding of the influence of this phenomenon on the recipient organism. PMID- 24051242 TI - Chiral N-benzyl-N-methyl-1-(naphthalen-1-yl)ethanamines and their in vitro antifungal activity against Cryptococcus neoformans, Trichophyton mentagrophytes and Trichophyton rubrum. AB - In the search for new antifungal compounds and to explore structure activity relationships, a series of 24 chiral benzyl amine type antifungals was synthesised and characterised. In vitro testing against the human pathogen Cryptococcus neoformans revealed that several derivatives had MIC50 values similar to that of the commercial drug Butenafine. All of these contained a bulky group in the para position of the benzyl fragment. Eighteen compounds were also tested for activity against the dermatophytes Trichophyton mentagrophytes and Trichophyton rubrum. Of these (R)-N-(4-tert-butylbenzyl)-N-methyl-1-(naphthalen-1 yl)ethanamine (MIC50: 0.06 MUg/mL) and a para-benzyloxy substituted derivative (MIC50: 0.125 MUg/mL) possessed high activity. Testing of derivatives with a stereocentre at the benzylic carbon, revealed that (S)-stereochemistry was required for potency: a MIC50 value of 1 MUg/mL was obtained for (S)-1-(4-tert butylphenyl)-N-methyl-N-(naphthalen-1-ylmethyl)ethanamine. Preparation of the corresponding fluoromethyl compound was achieved employing lipase B from Candida antarctica as catalyst in the key step. A low antifungal activity was observed for the fluorinated derivative indicating the importance of the amine basicity for the antifungal potency of these compounds. PMID- 24051243 TI - Oxidative stress and apoptosis was induced by bio-insecticide spinosad in the liver of Oreochromis niloticus. AB - This study was conducted to investigate acute toxic effects of spinosad on Glutathione-related oxidative stress markers, lipid peroxidation, heat shock proteins, apoptosis in the liver of Oreochromis niloticus selected as a model organism. The fish were exposed to sublethal spinosad concentrations (25, 50, 75 mg/L) for 24-48-72 h. tGSH, GSH, GSSG, and TBARS contents, GSH/GSSG ratio, and GPx, GR, GST and caspase enzyme activities were measured using spectrophotometrical methods, and Hsp70 content was measured by ELISA technique. The results demonstrated that spinosad exposure caused significant alterations in the GSH-related oxidative stress markers, and also caused increases in lipid peroxidation and stress proteins with inducing ROS generation in the liver. Apoptosis initiated with the induction of caspase-3 and Hsp70 could not protect the liver cells. Our results indicated that GSH-related antioxidant system tried to protect the liver cells from spinosad-induced hepatotoxicity however, the oxidative stress resulting from induction of ROS generation induced apoptosis in the liver of O. niloticus. PMID- 24051244 TI - Nitrogen isotopic composition and density of the Archean atmosphere. AB - Understanding the atmosphere's composition during the Archean eon is fundamental to unraveling ancient environmental conditions. We show from the analysis of nitrogen and argon isotopes in fluid inclusions trapped in 3.0- to 3.5-billion year-old hydrothermal quartz that the partial pressure of N2 of the Archean atmosphere was lower than 1.1 bar, possibly as low as 0.5 bar, and had a nitrogen isotopic composition comparable to the present-day one. These results imply that dinitrogen did not play a significant role in the thermal budget of the ancient Earth and that the Archean partial pressure of CO2 was probably lower than 0.7 bar. PMID- 24051246 TI - Crystal structure of Na+, K(+)-ATPase in the Na(+)-bound state. AB - The Na(+), K(+)-adenosine triphosphatase (ATPase) maintains the electrochemical gradients of Na(+) and K(+) across the plasma membrane--a prerequisite for electrical excitability and secondary transport. Hitherto, structural information has been limited to K(+)-bound or ouabain-blocked forms. We present the crystal structure of a Na(+)-bound Na(+), K(+)-ATPase as determined at 4.3 A resolution. Compared with the K(+)-bound form, large conformational changes are observed in the alpha subunit whereas the beta and gamma subunit structures are maintained. The locations of the three Na(+) sites are indicated with the unique site III at the recently suggested IIIb, as further supported by electrophysiological studies on leak currents. Extracellular release of the third Na(+) from IIIb through IIIa, followed by exchange of Na(+) for K(+) at sites I and II, is suggested. PMID- 24051247 TI - Cell biology. Stalemate in the Golgi battle. PMID- 24051249 TI - Factors predictive of macrosomia in pregnancies with a positive oral glucose challenge test: importance of fasting plasma glucose. AB - AIM: The study aimed to determine the factors associated with fetal macrosomia following a positive oral glucose challenge test (OGCT). METHODS: In this retrospective single-centre study of 1268 pregnancies with positive 50-g OGCTs (plasma glucose>=130mg/dL, or 7.2mmol/L), gestational diabetes mellitus (GDM) was defined as fasting plasma glucose (FPG)>=95mg/dL (5.3mmol/L) and/or postprandial glucose (PPG)>=120mg/dL (6.7mmol/L). RESULTS: In GDM pregnancies, the odds ratios adjusted for confounders (age, BMI, ethnicity, parity and weight gain) were 2.02 for macrosomia (Z score>=1.28) and 2.62 for severe macrosomia (Z score>=1.88). For each 10-mg/dL increase in FPG, the mean birth-weight increase was 60g. Macrosomia risk did not differ between GDM patients with normal FPG (<95mg/dL, or 5.3mmol/L) and non-diabetics, but increased significantly in cases of FPG>=95mg/dL and regardless of the level of PPG. CONCLUSION: In our study population, birth-weight and macrosomia risk were strongly correlated with FPG, suggesting that it is a simple and efficient marker for the risk of macrosomia. PMID- 24051250 TI - Incremental conditions of isolation as a predictor of suicide in prisoners. AB - In a study of the incidence of suicide in jails and prisons under increasing conditions of deprivation in Italy from 2004 to 2008, imprisonment involving greater levels of isolation was found to be associated with a higher rate of suicide. Greater care should be taken to ensure that prisoners in isolation do not commit suicide by limiting this option when possible or providing mental health services when isolation is necessary. PMID- 24051248 TI - Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. AB - Circadian clocks are self-sustained cellular oscillators that synchronize oxidative and reductive cycles in anticipation of the solar cycle. We found that the clock transcription feedback loop produces cycles of nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, adenosine triphosphate production, and mitochondrial respiration through modulation of mitochondrial protein acetylation to synchronize oxidative metabolic pathways with the 24-hour fasting and feeding cycle. Circadian control of the activity of the NAD(+)-dependent deacetylase sirtuin 3 (SIRT3) generated rhythms in the acetylation and activity of oxidative enzymes and respiration in isolated mitochondria, and NAD(+) supplementation restored protein deacetylation and enhanced oxygen consumption in circadian mutant mice. Thus, circadian control of NAD(+) bioavailability modulates mitochondrial oxidative function and organismal metabolism across the daily cycles of fasting and feeding. PMID- 24051251 TI - Interleukin-6 and tumor necrosis factor-alpha gene polymorphisms in chronic idiopathic urticaria. AB - BACKGROUND: This study was performed to evaluate association of gene polymorphisms among proinflammatory cytokines and susceptibility to chronic idiopathic urticaria (CIU). METHODS: Ninety patients with prolonged urticaria more than 6 weeks were included as case group. Single nucleotide polymorphisms (SNPs) of IL-6 (G/C -174, G/A nt565) and TNF-alpha (G/A -308, G/A -238) were evaluated, using polymerase chain reaction (PCR); and the results were compared to the control group. RESULTS: G allele was significantly higher in the patients at locus of -238 of promoter of TNF-alpha gene (p<0.001). Frequency of following genotypes were significantly lower in patients with CIU, compared to controls: AG at -308 and GA at -238 of TNF-alpha gene (p<0.05 and p<0.001, respectively), CG at -174 and GG at +565 of IL-6 gene (p<0.05). Additionally, following genotypes were more common among patients with CIU: GG at -308 and -238 of TNF-alpha gene (p<0.05 and p<0.001, respectively), GG at -174 and GA at +565 of IL-6 gene (p<0.05). CONCLUSIONS: Pro-inflammatory cytokine gene polymorphisms can affect susceptibility to CIU. TNF-alpha promoter polymorphisms as well as IL-6 gene polymorphisms are associated with CIU. PMID- 24051252 TI - Retroperitoneal abscesses in seven dogs. AB - Retroperitoneal abscesses, although uncommon, are clinically important. Medical records of seven dogs with naturally occurring retroperitoneal infections from 1999 to 2011 were reviewed to document historical, examination, clinicopathologic, imaging, and surgical findings; etiologic agents; and outcome. Middle-aged sporting dogs were most commonly affected. Dogs were febrile with evidence of either abdominal or lumbar pain. Although traditional radiography can aid in diagnosis, ultrasound appeared to be a more sensitive indicator of disease within the retroperitoneal space. Numerous bacteria were isolated from the abscesses, with anaerobic and facultative anaerobic bacteria being the most commonly isolated. Etiology was largely unknown, but migrating plant material was often suspected. Resolution of the infection required surgical intervention as well as prolonged antibiotic therapy. Although recurrence is possible, outcome can be favorable with no long-term sequela. PMID- 24051253 TI - Clinicopathologic and MRI characteristics of presumptive hypertensive encephalopathy in two cats and two dogs. AB - Two dogs and two cats were evaluated for the acute-onset of abnormal mentation, recumbency, and blindness. All cases had systemic hypertension, ranging from 180 mm Hg to 260 mm Hg. MRI of the brain disclosed noncontrast-enhancing, ill defined, T2-weighted (T2W) hyperintensities in the white matter of the cerebrum in the areas of the frontal, parietal, temporal, and occipital lobes. Lesions were also observed in the caudate nuclei and thalamus (n = 1 in each). Intracranial hemorrhage was observed in one animal. Diffusion-weighted imaging (DWI) was consistent with vasogenic edema in two animals. Retinal lesions were observed in three animals. Hypertension was secondary to renal disease in three animals. A primary underlying disorder was not identified in one animal. Normalization of blood pressure was achieved with amlodipine either alone or in combination with enalapril. In one cat, hypertension spontaneously resolved. In three cases, neurologic improvement occurred within 24-48 hr of normalization of blood pressure. The presumptive diagnosis of hypertensive encephalopathy was supported by the MRI findings and neurologic dysfunction coincident with systemic hypertension in which the neurologic dysfunction improved with treatment of hypertension. The prognosis appears good for the resolution of neurologic deficits with normalization of blood pressure in animals with hypertensive encephalopathy. PMID- 24051254 TI - Iatrogenic pneumothorax associated with inadvertent intrapleural NGT misplacement in two dogs. AB - This case report presents two cases of inadvertent intrapleural nasogastric tube (NGT) misplacement with consequent creation of a bronchopleural fistula and the development of an iatrogenic pneumothorax in dogs. Due to the simplicity and relative ease of NGT placement and the lack of reported life-threatening complications in the veterinary literature, the serious risks associated with this procedure are often overlooked. Although pulmonary complications with NGT misplacement have been previously reported in the human literature, serious and potentially fatal complications have not been currently described in veterinary patients. Both of the cases described herein were medically managed with successful outcomes; however, one case was associated with significant morbidity. PMID- 24051255 TI - Intermittent single-agent doxorubicin for the treatment of canine B-cell lymphoma. AB - Canine B-cell lymphoma is a highly treatable disease, but cost and logistical factors may hamper an owner's ability to pursue treatment of their pet with this disease. The authors evaluated the use of single-agent doxorubicin in an intermittent fashion for efficacy in the treatment of this disease. Morphologic and clinical data were analyzed for prognostic significance. Eighteen dogs with B cell lymphoma, all with multicentric disease, were enrolled. The overall complete response (CR) rate was 78%, median total doxorubicin remission time (TDR) was 80.5 days, and median overall survival (OS) was 169.5 days. The median number of doxorubicin doses administered was 4.5. First remission times were significantly affected by clinical stage and substage of disease. Outcome for the dogs in this study were similar to those previously reported for single-agent doxorubicin treatment. Additionally, the intermittent nature of the treatments made the described protocol more feasible for the owners who enrolled their pets in this study. Intermittent single-agent doxorubicin is not a substitute for multiagent chemotherapy protocols in the treatment of canine lymphoma; however, it is a reasonable alternative if the cost and time commitments are limiting factors for an owner. PMID- 24051256 TI - Cardiac MRI findings in a dog with a diffuse pericardial mesothelioma and pericardial effusion. AB - Veterinary cardiac MRI (cMRI) is a relatively new technique. A dog with recurrent pericardial effusion and a questionable right atrial mass lesion on echocardiography underwent cMRI. cMRI provided excellent anatomic information about the heart and surrounding structures and helped to rule out the presence of a focal mass. A diffuse thickening and enhancement of the pericardium was detected. Pericardiectomy was performed and histopathology revealed a diffuse pericardial mesothelioma. This case illustrates the potential of cMRI in the management of patients with pericardial effusion when echocardiographic findings are equivocal and illustrates cMRI findings in a case of diffuse pericardial mesothelioma. PMID- 24051258 TI - A prospective evaluation of CT in acutely paraparetic chondrodystrophic dogs. AB - The clinical usefulness of computed tomography (CT) as a sole diagnostic modality in identifying disc lesion(s) in chondrodystrophic breeds presenting with acute signs of intervertebral disc disease (IVDD) is incompletely characterized. CT was used prospectively to determine the validity of this tool. Neurologic examinations and CT scans were performed on all dogs at presentation. Surgical decompression was based on those findings. Clinical follow-up examinations were performed on days 1 and 14 postsurgically. CT detected a lesion consistent with clinical findings in 63 of 69 cases (91%). All 63 dogs with Hansen type I IVDD lesions were identified on CT alone. The surgeon and radiologist agreed on lesion level in 72 of 78 lesions (92%) and lateralization in 71 of 78 lesions (91%). Improvement in neurologic grade was documented in 60 of 69 dogs (87%) by 14 days. CT imaging can be used as a single imaging modality in chondrodystrophic dogs presenting with acute paresis. CT used in this manner is a reliable and noninvasive tool for detecting spinal compression secondary to IVDD in chondrodystrophic dogs. PMID- 24051245 TI - Low upper limit to methane abundance on Mars. AB - By analogy with Earth, methane in the Martian atmosphere is a potential signature of ongoing or past biological activity. During the past decade, Earth-based telescopic observations reported "plumes" of methane of tens of parts per billion by volume (ppbv), and those from Mars orbit showed localized patches, prompting speculation of sources from subsurface bacteria or nonbiological sources. From in situ measurements made with the Tunable Laser Spectrometer (TLS) on Curiosity using a distinctive spectral pattern specific to methane, we report no detection of atmospheric methane with a measured value of 0.18 +/- 0.67 ppbv corresponding to an upper limit of only 1.3 ppbv (95% confidence level), which reduces the probability of current methanogenic microbial activity on Mars and limits the recent contribution from extraplanetary and geologic sources. PMID- 24051257 TI - Canine vaginal leiomyoma diagnosed by CT vaginourethrography. AB - A 13 yr old female spayed Labrador retriever presented for vulvar bleeding. Abdominal radiographs revealed a soft tissue mass in the ventral pelvic canal. A computed tomography (CT) exam and a CT vaginourethrogram localized the mass to the vagina, helped further characterize the mass, and aided in surgical planning. A total vaginectomy was performed and the histologic diagnosis was leiomyoma. Vaginal tumors make up 1.9-3% of all tumors. Seventy-three percent of vaginal tumors are benign, and 83% of those are leiomyomas. Leiomyomas often have a good long-term prognosis with surgical resection. The diagnostic investigation of this case report utilized a multimodal imaging approach to determine the extent and respectability of the vaginal mass. To the best of the authors' knowledge, this is the first report describing a CT vaginourethrogram. PMID- 24051259 TI - GH deficiency in a Dalmatian puppy with megaesophagus. AB - An 8 wk old female Dalmatian weighing .56 kg presented with growth retardation. The puppy exhibited no abnormalities during physical examination other than significantly reduced growth compared with her littermates. Endocrine results suggested pituitary dwarfism. Two wk later, the puppy returned due to the onset of megaesophagus, but the puppy unfortunately died the following morning. This case report describes the diagnosis of dwarfism in a Dalmatian puppy that was caused by growth hormone (GH) deficiency and describes its early clinical manifestations. PMID- 24051260 TI - VAC protocol for treatment of dogs with stage III hemangiosarcoma. AB - Hemangiosarcomas (HSAs) are aggressive tumors with a high rate of metastasis. Clinical stage has been considered a negative prognostic factor for survival. The study authors hypothesized that the median survival time (MST) of dogs with metastatic (stage III) HSA treated with a vincristine, doxorubicin, and cyclophosphamide (VAC) chemotherapy protocol would not be different than those with stage I/II HSA. Sixty-seven dogs with HSA in different anatomic locations were evaluated retrospectively. All dogs received the VAC protocol as an adjuvant to surgery (n = 50), neoadjuvant (n = 3), or as the sole treatment modality (n = 14). There was no significant difference (P = 0.97) between the MST of dogs with stage III and stage I/II HSA. For dogs presenting with splenic HSA alone, there was no significant difference between the MST of dogs with stage III and stage I/II disease (P = 0.12). The overall response rate (complete response [CR] and partial response [PR]) was 86%). No unacceptable toxicities were observed. Dogs with stage III HSA treated with the VAC protocol have a similar prognosis to dogs with stage I/II HSA. Dogs with HSA and evidence of metastases at the time of diagnosis should not be denied treatment. PMID- 24051261 TI - Pituitary metastasis of pancreatic origin in a dog presenting with acute-onset blindness. AB - Pituitary metastases have rarely been recorded in dogs, and to date, none of those reported have been of pancreatic origin. MRI findings are available for only one of those cases. Herein the authors present an 11 yr old English springer spaniel diagnosed with pituitary metastasis of pancreatic origin with a 24 hr history of blindness and only a single lesion on MRI. Neurologic and ophthalmologic examinations localized the lesion to the optic nerves, optic tracts, or optic chiasm. MRI showed a single lesion characterized by a well circumscribed pituitary mass with extrasellar extension, causing compression of the optic chiasm. Signal intensity was unusual as enhancement could not be appreciated after contrast administration. The dog was euthanized without further diagnostic tests. Histopathologic examination revealed a poorly differentiated exocrine pancreatic carcinoma with widespread metastasis involving the pituitary gland. To the authors' knowledge, this is the first such case reported in a dog. Pituitary metastases should be included as a differential diagnosis for dogs presenting with acute-onset blindness and for single brain masses affecting the pituitary gland. PMID- 24051262 TI - Chronic compressive myelopathy and progressive neurologic signs associated with melarsomine dihydrochloride administration in a dog. AB - A 7 yr old castrated male Great Dane presented with a history of progressive myelopathy following the intramuscular injection of melarsomine dihydrochloride 8 wk previously. MRI revealed paraspinal and epidural abscesses at the 13th thoracic (T13) and first lumbar (L1) disc space. The dog's condition worsened despite medical management, necessitating surgical decompression. Surgical decompression resulted in rapid improvement of the patient's clinical signs. Histopathologic evaluation of the lesions revealed pyogranulomatous inflammation. Cultures of fluid and tissue within the lesions were negative for bacterial growth, and no infectious organisms were visualized histologically. Melarsomine associated neurologic signs can be chronic and progressive in nature, presumably secondary to ongoing sterile inflammation that may result in spinal cord compression. PMID- 24051263 TI - Development of antibiotic regimens using graph based evolutionary algorithms. AB - This paper examines the use of evolutionary algorithms in the development of antibiotic regimens given to production animals. A model is constructed that combines the lifespan of the animal and the bacteria living in the animal's gastro-intestinal tract from the early finishing stage until the animal reaches market weight. This model is used as the fitness evaluation for a set of graph based evolutionary algorithms to assess the impact of diversity control on the evolving antibiotic regimens. The graph based evolutionary algorithms have two objectives: to find an antibiotic treatment regimen that maintains the weight gain and health benefits of antibiotic use and to reduce the risk of spreading antibiotic resistant bacteria. This study examines different regimens of tylosin phosphate use on bacteria populations divided into Gram positive and Gram negative types, with a focus on Campylobacter spp. Treatment regimens were found that provided decreased antibiotic resistance relative to conventional methods while providing nearly the same benefits as conventional antibiotic regimes. By using a graph to control the information flow in the evolutionary algorithm, a variety of solutions along the Pareto front can be found automatically for this and other multi-objective problems. PMID- 24051265 TI - Alcohol drinking patterns and health-related quality of life reported in the Spanish adult population. AB - OBJECTIVES: To examine the association between alcohol drinking patterns and health-related quality of life (HRQL). METHODS: Population-based cross-sectional study was conducted in 2008-2010 among 12,715 adult individuals in Spain. HRQL was assessed with the SF-12 questionnaire and alcohol intake with a diet history. The threshold between average moderate drinking and average heavy drinking was >= 40 g/day of alcohol in men and >= 24 g/day in women. Binge drinking was defined as the intake of >= 80 g in men and >= 60 g in women at any drinking session during the preceding 30 days. Analyses were performed with linear regression and adjusted for the main confounders. RESULTS: Compared to non-drinkers, all types of average drinkers reported better scores on the SF-12 physical component: beta=1.42 (95% confidence interval 1.03 to 1.81) in moderate drinkers and beta=1.86 (1.07 to 2.64) in heavy drinkers. In contrast, average alcohol consumption was not associated with the mental component of the SF-12. The number of binge drinking episodes and most types of beverage preference showed no association with physical or mental HRQL. CONCLUSIONS: Alcohol drinkers, including those with heavy drinking, reported better physical HRQL than non drinkers. PMID- 24051264 TI - A prospective study of variability in systolic blood pressure and mortality in a rural Bangladeshi population cohort. AB - OBJECTIVE: Limited studies suggest that blood pressure variability over time is a risk factor of long-term cardiovascular outcomes. However, most of these were in populations with pre-existing cardiovascular diseases (CVD) and studies in general population are lacking. METHODS: The study included 11,153 participants in a population-based, prospective cohort study in Araihazar, Bangladesh. Resting blood pressure was measured at baseline and every two years thereafter. Participants were followed up for an average of 6.5 years (2002-2009). RESULTS: Male gender, older age, baseline systolic blood pressure (SBP), and absence of betel leaf use were independently positively associated with greater SBP variability over time. There was a significant association between SBP variability and the risk of death from overall CVD, especially from major CVD events. The positive association with the risk of death from any cause and stroke in age- and sex-adjusted models was attenuated in fully-adjusted models. In addition, the hazard ratio (HR) of stroke mortality was greater for individuals with both high baseline and high SBP variability. Similar patterns of HRs were observed for all-cause and CVD mortalities. CONCLUSION: In this rural Bangladeshi population, variability in SBP contributes to the risk of death from CVD and may further potentiate the increased mortality risk associated with high SBP. PMID- 24051266 TI - Clusters of AMI risk factors and their association with left ventricular hypertrophy: a population-based study within the Skaraborg Project, Sweden. AB - OBJECTIVES: Risk factors for acute myocardial infarction (AMI) are known to cluster and to be differently distributed in men and women. The aim of this study was to sex-specifically explore clusters of acknowledged AMI risk factors by factor analysis, and to study whether such clusters are associated with left ventricular hypertrophy (LVH), used as a subclinical measure of CHD. METHODS: In 2001-2005, 2328 subjects (30-74 years) were randomly selected from two municipalities in Sweden (participation-rate 76%) and were assessed with regard to cardiovascular risk factors; 852 participants also had an echocardiographic examination performed. RESULTS: Factor analysis identified three identical factors in men and women. WHR, HOMA-ir, systolic blood pressure, and ApoB/ApoA1 loaded significantly on the principal "metabolic factor", leisure-time physical activity and self-rated health loaded significantly on the "vitality factor", and smoking and alcohol consumption loaded significantly on the "addiction factor". The metabolic factor was associated with LVH in both men (P<0.001) and women (P<0.001), whereas the addiction factor was associated with LVH solely in men (P=0.002). CONCLUSIONS: The consistent pattern in the clustering of acknowledged AMI risk factors suggests common underlying mechanisms in both men and women. However, whereas the metabolic factor was paramount in both men and women in the association with LVH, the addiction factor had an impact solely in men. As LVH often precedes AMI, a deeper understanding of risk factors for LVH, including consideration of the supposed sex differences, can be useful in order to explore prevention strategies for AMI. PMID- 24051267 TI - Effects of propofol on GABAergic and glutamatergic transmission in isolated hippocampal single nerve-synapse preparations. AB - We evaluated the effects of propofol on synaptic transmission using a mechanically dissociated preparation of rat hippocampal CA3 neurons to allow assays of single bouton responses evoked from retained functional native nerve endings. We studied synaptic and extrasynaptic GABAA and glutamate receptor responses in a preparation in which experimental solutions rapidly accessed synaptic terminals. Whole-cell responses were evoked by bath application of GABA and glutamate. Synaptic inhibitory and excitatory postsynaptic currents (IPSC and EPSC) were measured as spontaneous and evoked postsynaptic responses. Evoked currents were elicited by focal electrical stimulation. Propofol (1-100 MUM) enhanced extrasynaptic GABAA-receptor mediated responses but the increase at clinically relevant concentrations (1 MUM) were minor. In contrast, 1 MUM propofol significantly increased both the amplitude and frequency of spontaneous IPSCs (sIPSCs) and increased the amplitudes of evoked IPSCs (eIPSCs) while decreasing failure rates (Rf) and paired-pulse ratios (PPR). Decay times of sIPSCs and eIPSCs were significantly prolonged. Although propofol had no effect on extrasynaptic glutamate responses, only supra-clinical propofol concentrations (>= 10 uM) increased the spontaneous EPSCs (sEPSCs, amplitudes and frequencies) but suppressed evoked EPSCs (eEPSCs decreased amplitudes with increased Rf and PPR). The decay phases of sEPSCs and eEPSCs were not changed. The propofol induced changes in sEPSCs and eEPSCs resulted from presynaptic GABAA receptor mediated depolarization, because these actions were blocked by bicuculline. These results suggest that propofol acts at presynaptic and postsynaptic GABAA receptors within GABAergic synapses, but also increases extrasynaptic GABA responses. Our results expand the locus of propofol actions to GABAergic and glutamatergic synapses. PMID- 24051268 TI - A review on antiepileptic drugs-dependent fatigue: pathophysiological mechanisms and incidence. AB - Fatigue represents a common side effect of several drugs, however, the underlying mechanisms have not been well identified. A depression of the central nervous system (CNS) and/or changes in peripheral processes have been associated with the development of fatigue. Antiepileptic drugs (AEDs), generally decreasing CNS excitability, are used in the treatment of seizures as well as other neurological and psychiatric diseases. Fatigue is certainly a common AEDs' side effect, although a high degree of variability exists depending on both patients' characteristics and the drug used. Here, we delineate the pathophysiological central and peripheral mechanisms by which AEDs may cause fatigue also reviewing the available clinical data in order to assess a possible AEDs rank and highlight each AEDs related risk. It appears that drugs acting on the GABAergic system have the highest incidence (with tiagabine exception) of fatigue followed by Gabapentin and Levetiracetam whereas drugs mainly inhibiting sodium channels (Carbamazepine, Eslicarbazepine, Lamotrigine, Phenytoin and Valproate) have the lowest. However, the dose used, AEDs related side effects and patients' characteristics might influence the degree of fatigue observed. PMID- 24051269 TI - The protective and therapeutic effects of alpha-solanine on mice breast cancer. AB - Alpha-solanine, a naturally steroidal glycoalkaloid, is found in leaves and fruits of plants as a defensive agent against fungi, bacteria and insects. Herein, we investigated solanine toxicity in vitro and in vivo, and assessed its protective and the therapeutic effects on a typical animal model of breast cancer. The study conducted in three series of experiments to obtain (i) solanine effects on cell viability of mammary carcinoma cells, (ii) in vivo toxicity of solanine, and (iv) the protective and therapeutic effects of solanine on animal model of breast cancer. Alpha-solanine significantly suppressed proliferation of mouse mammary carcinoma cells both in vitro and in vivo (P<0.05). Under the dosing procedure, 5 mg/kg solanine has been chosen for assessing its protective and therapeutic effects in mice breast cancer. Tumor take rate in the solanine treated group was zero compared with a 75% rate in its respective control group (P<0.05). The average tumor size and weight were significantly lower in solanine treated animals than its respective control ones (P<0.05). Proapoptotic Bax protein expression increased in breast tumor by solanine compared with its respective control group (P<0.05). Antiapoptotic Bcl-2 protein expression found to be lower in solanine-treated animals (P<0.05). Proliferative and angiogenic parameters greatly decreased in solanine-treated mice (P<0.05). Data provide evidence that solanine exerts a significant chemoprotective and chemotherapeutic effects on an animal model of breast cancer through apoptosis induction, cell proliferation and angiogenesis inhibition. These findings reveal a new therapeutic potential for solanine in cancer. PMID- 24051270 TI - Local infiltration of neuropeptide Y as a potential therapeutic agent against apoptosis and fibrosis in a swine model of hypercholesterolemia and chronic myocardial ischemia. AB - While the angiogenic effects of Neuropeptide Y (NPY) in myocardial ischemia and hypercholesterolemia have been studied, its effects on altering oxidative stress, fibrosis and cell death are not known. We hypothesized that local infiltration of NPY in a swine model of chronic myocardial ischemia and hypercholesterolemia will induce nerve growth and cell survival, while reducing oxidative stress and fibrosis. Yorkshire mini-swine (n=15) were fed a high cholesterol diet for 5 weeks. Three weeks after surgical induction of focal myocardial ischemia, an osmotic pump was implanted, which delivered NPY (n=8, high cholesterol treated, HCT) or the vehicle (n=7, high cholesterol control, HCC) for 5 weeks. Then myocardium was harvested for analysis. Assessment of myocardial function and perfusion was made the last intervention. Immunoblotting demonstrated significantly decreased levels of MMP-9 (p=0.001) and TGF-beta (p=0.05) and significantly increased levels of Ang-1 (p=0.002), MnSOD (p=0.006) and NGF (p=0.01) in HCT. Immunohistochemistry results revealed significantly decreased TUNEL staining (p=0.005) and GLUT4 translocation (p=0.004) in HCT. The functional data showed significantly improved blood flow reserve (p=0.02) and improved diastolic function -dP/dt (p=0.009) in the treated animals. Local infiltration of NPY results in positive remodeling in ischemic myocardium in the setting of hypercholesterolemia. By initiating angio and neurogenesis, NPY infiltration improves blood flow reserve and restoration of fatty acid metabolism. The associated increased cell survival and decreased fibrosis result in improved myocardial diastolic function. NPY may have a potential therapeutic role in patients with hypercholesterolemia associated coronary artery disease. PMID- 24051271 TI - Vasorelaxant effect of propentofylline in isolated equine digital veins. AB - We evaluated the vasorelaxant effect of propentofylline (PPF), a methylxanthine derivative, and its mechanism of action in equine digital veins (EDVs). Cumulative concentration-response curves to PPF (1 nM-300 uM) were recorded in phenylephrine-precontracted EDV rings under different experimental conditions. PPF-induced relaxation was partially inhibited by endothelium removal, but was unaltered by CGS-15943 (an adenosine receptor antagonist; 3 uM). PPF-induced relaxation was partially inhibited in the presence of L-NAME (a nitric oxide (NO) synthase inhibitor; 100 uM), ODQ (an inhibitor of soluble guanylyl cyclase; 30 uM) or Rp-8-Br-PET-cGMP-S (a protein kinase G inhibitor; 3 uM). It was not modified by indomethacin (a non-selective cyclooxygenase (COX) inhibitor; 10 uM), and was slightly potentiated by H-89 (a protein kinase A inhibitor; 2 uM). In endothelium-intact EDVs, PPF-induced relaxation was associated with a 2.4- and 24.1-fold increase in the tissue cGMP and cAMP content respectively. PPF (100 MUM) did not shift the concentration-response curve to phenylephrine (1 nM-300 uM) but reduced the maximal effect. To investigate whether PPF can affect cAMP- and cGMP-induced relaxations, relaxation curves to forskolin (an activator of adenylate cyclase) and to sodium nitroprusside (SNP, a NO donor) were recorded in EDV rings pretreated with PPF (100 uM). PPF only slightly potentiated the forskolin-induced relaxation without affecting the SNP-induced relaxation. We demonstrated that PPF-induced relaxation in EDVs is partially endothelium dependent. The PPF-induced relaxation partially occurred via NO release and both cAMP and cGMP generation, through COX-independent mechanisms but could also result from the inhibition of cAMP-phosphodiesterase activity for the highest concentrations. PMID- 24051272 TI - Influence of radiological emphysema on lung function test in idiopathic pulmonary fibrosis. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is one of the most frequent interstitial lung disease. Emphysema can be associated with IPF as described in the "Combined pulmonary fibrosis and emphysema" syndrome. AIM: The primary endpoint of this retrospective cohort study was to evaluate the impact of the association of IPF and emphysema on lung function tests parameters (FVC, TLC, FEV1, FEV1/FVC and DLCO). The secondary endpoint was to assess the impact of the associated radiological emphysema on lung function parameters used in the du Bois prognostic score recently developed by Ron du Bois et al. METHOD: We retrospectively reviewed the medical files of 98 patients with lung fibrosis who were followed in our University Hospital with access to pharmacological studies and lung transplantation from 1981 to 2011. Fifty six patients were considered for analysis. The collected data included gender, age, smoking history and respiratory hospitalizations. We also analysed their pulmonary functional parameters along with radiological characteristics, in particular the presence of emphysema which was assessed on thoracic high resolution CT scan. The du Bois score was retrospectively calculated from these data. RESULTS: TLC and FVC at diagnosis were significantly higher in the IPF-E group compared to the IPF group (respectively 86.6 +/- 17.2% pv versus 72.0 +/- 15.0% pv; p: 0.004 and 86.8 +/- 18.4% pv versus 72.6 +/- 20.6% pv; p: 0.020). The [Formula: see text] used in the calculation of the du Bois prognostic score was significantly higher in the IPF-E group. By cons, [Formula: see text] was not statistically different between the two groups. CONCLUSION: Radiological emphysema associated with IPF had an impact on pulmonary function tests. Despite this difference, the du Bois score was not statistically different between these two groups. Nevertheless, after one year of follow up, the patients with emphysema were in a subclass with a lower mortality rate than those without emphysema. PMID- 24051273 TI - Theophylline and its direct anti-neoplastic effects. PMID- 24051274 TI - Neuroprotective effects of Huang-Lian-Jie-Du-Decoction on ischemic stroke rats revealed by (1)H NMR metabolomics approach. AB - Huang-Lian-Jie-Du-Decoction (HLJDD) is a representative antipyretic and detoxifying recipe in traditional Chinese medicine (TCM). This formula and its component herbs like Radix Scutellariae, Fructus Gardeniae show a variety of neuroprotective activities and have been used for the treatment of nervous system diseases including stroke. To comprehensively and holistically assess its therapeutic effect on ischemic stroke, a novel integrative metabolomics approach was applied. A rat ischemic stroke model was established by introduction of transient middle cerebral artery occlusion (MCAO) followed by reperfusion. The neurological deficit, cerebral infarct size and morphological abnormality were evaluated. An NMR technique combined with appropriate statistical analyses was then performed to explore the metabonomic profiles of serum and brain tissue extracts. Pattern analysis of the (1)H NMR data disclosed that HLJDD could relieve stroke rats suffering from the ischemia/reperfusion (I/R) injury by ameliorating the disturbance in energy metabolism, membrane and mitochondrial metabolism, neurotransmitter and amino acid metabolism, alleviating the oxidative stress from reactive oxygen species (ROS) and the inflammatory damage, and recovering the destructed osmoregulation. PMID- 24051275 TI - Improved detection of variants in recombinant human interferon alpha-2a products by reverse-phase high-performance liquid chromatography on a core-shell stationary phase. AB - The detection of variants is one of the important aspects in quality control of recombinant DNA drugs. In this study, a gradient reverse-phase high-performance liquid chromatography (RP-HPLC) method with fluorescence detection is described for the separation of interferon alpha-2a (rhIFN alpha-2a) from several product related variants. The methodology employed a core-shell C18 column with a linear gradient elution of 0.2% (v/v) trifluoroacetic acid (TFA)-acetonitrile (ACN) at 1.0mL/min, and the temperature of the column was maintained at 60 degrees C. The method was validated in terms of linearity, sensitivity, intra- and inter-day variations. Compared to the European Pharmacopeia RP-HPLC method of rhIFN alpha 2a analysis, this new method can separate N-methionylated variant in both drug substance and finished product, and analyze the variants in untreated, oxidized sample and slightly degraded samples more efficiently. In conclusion the method has an improved capability to detect variants in rhIFN alpha-2a products. PMID- 24051276 TI - Loss of cholecystokinin-containing terminals in temporal lobe epilepsy. AB - Altered GABA-mediated inhibition is proposed to play a role in the pathogenesis of epilepsy. Previous studies have demonstrated a loss of somatostatin-containing GABAergic interneurons innervating granule cells in epileptic animals. However, the reorganization of synapses between interneurons and granule cells has not been investigated. We studied synapse organization in an animal model of temporal lobe epilepsy (TLE) using continuous hippocampal stimulation. The distribution of axon terminals and inhibitory synapses on granule cell dendrites was studied using a combination of immunohistochemistry and pre-embedding electron microscopy techniques. A whole-cell patch-clamp technique was applied to study the functional changes in GABAergic input from different interneurons. In epileptic animals, the density of cholecystokinin (CCK)-immunoreactive (IR) fibers and alpha2 subunit containing GABAA receptors in the inner molecular layer of the dentate gyrus was reduced. Quantitative immuno-electron microscopy study revealed that the ratio of CCK-containing symmetric synapses to the total symmetric synapses was reduced. The frequency of GABAergic synaptic currents (sIPSC) was decreased and their amplitude was increased. The inhibitory effect of the activation of cannabinoid 1 (CB1) receptors was also reduced in epileptic animals. Isolation of CCK- and parvalbumin (PV)-containing GABAergic inputs by N- and P/Q-type calcium channel blockers respectively suggested that GABA release from CCK-containing interneurons was selectively reduced in epileptic rats. This study found that there was a loss of CCK-containing GABAergic synapses to granule cells both morphologically and functionally. These studies add to our understanding of the mechanisms that contribute to altering GABAergic inhibition of granule cells in TLE. PMID- 24051277 TI - Role of the NMDA receptor in cognitive deficits, anxiety and depressive-like behavior in juvenile and adult mice after neonatal dexamethasone exposure. AB - Postnatal dexamethasone (DEX) therapy has been used to treat or prevent chronic lung disease after premature births. However, there are many reports of long-term negative neurodevelopmental sequelae following this treatment. In contrast, hydrocortisone (HYD), which has fewer neurodevelopment adverse effects, is used as an alternative for DEX. In this study, we report that neonatal DEX exposure (days 1-3) caused alterations of amino acids affecting N-methyl-d-aspartate (NMDA) receptor neurotransmission in mouse brains. Neonatal DEX, but not HYD, exposure (days 1-3) significantly decreased the GluN2B subunit of NMDA receptor in the hippocampus at juvenile and adult stages. Mice treated with DEX showed cognitive deficits, as well as anxiety and depressive-like behavior at juvenile and adult stages. In contrast, mice treated with HYD (days 1-3) showed no behavioral abnormalities at these stages. In the DEX suppression test, plasma levels of corticosterone in mice exposed neonatally to DEX and HYD were significantly higher at juvenile, but not adult stages. Pretreatment with Ro 63 1908, an antagonist at GluN2B subunit, 30min before each injection of DEX, prevented cognitive deficits, as well as anxiety and depressive-like behavior in juvenile and adult mice. Interestingly, subsequent repeated (days 29-33) administration of Ro 63-1908 or L701324, an antagonist of the glycine modulatory site on the NMDA receptor, significantly suppressed behavioral abnormalities in juvenile and adult mice after neonatal DEX exposure. These results indicate that neonatal DEX, but not HYD, exposure produced behavioral abnormalities in juvenile and adult mice by altering glutamatergic neurotransmission via the NMDA receptor. The NMDA receptor antagonists may prevent or treat these DEX-induced neonatal behavioral abnormalities in later life. PMID- 24051278 TI - The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy. AB - Pilocarpine-induced status epilepticus (SE), which results in temporal lobe epilepsy (TLE) in rodents, activates the JAK/STAT pathway. In the current study, we evaluate whether brief exposure to a selective inhibitor of the JAK/STAT pathway (WP1066) early after the onset of SE affects the severity of SE or reduces later spontaneous seizure frequency via inhibition of STAT3-regulated gene transcription. Rats that received systemic WP1066 or vehicle at the onset of SE were continuously video-EEG monitored during SE and for one month to assess seizure frequency over time. Protein and/or mRNA levels for pSTAT3, and STAT3 regulated genes including: ICER, Gabra1, c-myc, mcl-1, cyclin D1, and bcl-xl were evaluated in WP1066 and vehicle-treated rats during stages of epileptogenesis to determine the acute effects of WP1066 administration on SE and chronic epilepsy. WP1066 (two 50mg/kg doses) administered within the first hour after onset of SE results in transient inhibition of pSTAT3 and long-term reduction in spontaneous seizure frequency. WP1066 alters the severity of chronic epilepsy without affecting SE or cell death. Early WP1066 administration reduces known downstream targets of STAT3 transcription 24h after SE including cyclin D1 and mcl-1 levels, known for their roles in cell-cycle progression and cell survival, respectively. These findings uncover a potential effect of the JAK/STAT pathway after brain injury that is physiologically important and may provide a new therapeutic target that can be harnessed for the prevention of epilepsy development and/or progression. PMID- 24051279 TI - Axonal and synaptic failure suppress the transfer of firing rate oscillations, synchrony and information during high frequency deep brain stimulation. AB - High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for Parkinson's disease, but its effects on neural activity in basal ganglia circuits are not fully understood. DBS increases the excitation of STN efferents yet decouples STN spiking patterns from the spiking patterns of STN synaptic targets. We propose that this apparent paradox is resolved by recent studies showing an increased rate of axonal and synaptic failures in STN projections during DBS. To investigate this hypothesis, we combine in vitro and in vivo recordings to derive a computational model of axonal and synaptic failure during DBS. Our model shows that these failures induce a short term depression that suppresses the synaptic transfer of firing rate oscillations, synchrony and rate-coded information from STN to its synaptic targets. In particular, our computational model reproduces the widely reported suppression of parkinsonian beta oscillations and synchrony during DBS. Our results support the idea that short term depression is a therapeutic mechanism of STN DBS that works as a functional lesion by decoupling the somatic spiking patterns of STN neurons from spiking activity in basal ganglia output nuclei. PMID- 24051280 TI - Effect of hyperthermia on histamine blood level and convulsive behavior in infant rats. AB - Febrile seizures (FS), which have been extensively studied using animal models, are the most common type of convulsive events in children, but the cellular mechanisms causing FS are still unclear. Histamine has been suggested to participate in seizure control. This study investigated the effect of hyperthermia (HT) on histamine blood level (HBL) and convulsive behavior in prepubertal rats. Forty Wistar rat pups were assigned to 5 groups (n=8), namely, control, HT, cromolyn, chlorpheniramine, and ranitidine. Two groups of adult rats were also used as control and HT adults. The control rats were placed in a hyperthermic chamber, and a room temperature current of air was blown on them. In all other groups, the rats were placed in the chamber for 30 min, and a current of warm air was applied to them. In the pretreatment groups, the rats received an injection of 68-mg/kg cromolyn sodium, 4-mg/kg chlorpheniramine, or 80-mg/kg ranitidine intraperitoneally 30 min prior to HT. Body temperature and convulsive behaviors were recorded. Then, the rats were anesthetized with ether, and their blood sample was obtained through direct heart puncture. Hyperthermia initiated convulsive behaviors in infant rats but not in the adult ones. Pretreatment with chlorpheniramine significantly potentiated convulsive behaviors (p=0.017). Hyperthermia led to a significant decrease in the HBL of both infant (p<0.001) and adult (p=0.003) rats. Pretreatments led to more decrease in the HBL of infant rats (p<0.001). It was concluded that HT could lead to a decrease in HBL, which in turn increases the seizure susceptibility of animals. Histamine may have a pivotal role in hyperthermia-induced seizures. PMID- 24051281 TI - A spectroscopic study of uranyl-cytochrome b5/cytochrome c interactions. AB - Uranium is harmful to human health due to its radiation damage and the ability of uranyl ion (UO2(2+)) to interact with various proteins and disturb their biological functions. Cytochrome b5 (cyt b5) is a highly negatively charged heme protein and plays a key role in mediating cytochrome c (cyt c) signaling in apoptosis by forming a dynamic cyt b5-cyt c complex. In previous molecular modeling study in combination with UV-Vis studies, we found that UO2(2+) is capable of binding to cyt b5 at surface residues, Glu37 and Glu43. In this study, we further investigated the structural consequences of cyt b5 and cyt c, as well as cyt b5-cyt c complex, upon uranyl binding, by fluorescence spectroscopic and circular dichroism techniques. Moreover, we proposed a uranyl binding site for cyt c at surface residues, Glu66 and Glu69, by performing a molecular modeling study. It was shown that uranyl binds to cyt b5 (KD=10 MUM), cyt c (KD=87 MUM), and cyt b5-cyt c complex (KD=30 MUM) with a different affinity, which slightly alters the protein conformation and disturbs the interaction of cyt b5-cyt c complex. Additionally, we investigated the functional consequences of uranyl binding to the protein surface, which decreases the inherent peroxidase activity of cyt c. The information of uranyl-cyt b5/cyt c interactions gained in this study likely provides a clue for the mechanism of uranyl toxicity. PMID- 24051282 TI - Spectral and thermodynamic properties for the exciplexes of N-alkyl carbazoles with dicyanobenzenes in THF. AB - The exciplex emission spectra of N-ethylcarbazole with 1,2-dicyanobenzene (NEC/1,2-DCB), N-methylcarbazole with 1,2-dicyanobenzene (NMC/1,2-DCB), 1,3 dicyanobenzene (NMC/1,3-DCB), and 1,4-dicyanobenzene (NMC/1,4-DCB) are studied in tetrahydrofuran (THF) for the temperature range starting from 253 K to 334 K. Thermochromic shifts along with the spectral properties including change in peak intensities and the ratio of exciplex peak intensity to fluorophore peak intensity are studied. Effect of temperature on the energy of zero-zero transitions hnuo('), Huang-Rhys factor (S), Gauss broadening of vibronic level (sigma) and the dominant high-frequency vibration (hnunu) are also part of investigation. Enthalpy of exciplex formation (DeltaH(EX)(*)) calculated by the model proposed by A. Weller and the Gibb's energy of electron transfer (DeltaG(et)(*)) for all exciplex systems are also discussed in the present paper. All the exciplexes under study were observed to be dipolar in nature. The exciplex of the N-methylcarbazole/1,4-dicyanobenzene was found to be the most stable and the N-methylcarbazole/1,3-dicyanobenzene was the weakest exciplex system. PMID- 24051283 TI - Complex formation equilibria of binary and ternary complexes involving 3,3-bis(1 methylimidazol-2yl)propionic acid and bio-relevant ligands as 1-aminocyclopropane carboxylic acid with reference to plant hormone. AB - The formation equilibria for the binary complexes of Cu(II) with 1 aminocyclopropane carboxylic acid (ACC) and 3,3-bis(1-methylimidazol-2 yl)propionic acid (BIMP) were investigated. ACC and BIMP form the complexes 110, 120 and 11-1. The ternary complexes of Cu(II) with BIMP and biorelevant ligands as some selected amino acids, peptides and DNA constituents are formed in a stepwise mechanism. The stability constants of the complexes formed were determined and their distribution diagrams were evaluated. The kinetics of hydrolysis of glycine methyl ester in presence of [Cu(BIMP)](+) was investigated by pH-stat technique and the mechanism was discussed. PMID- 24051284 TI - Synthesis, spectroscopic characterisation, DNA cleavage, superoxidase dismutase activity and antibacterial properties of some transition metal complexes of a novel bidentate Schiff base derived from isatin and 2-aminopyrimidine. AB - Complexes of manganese(II), cobalt(II), nickel(II), copper(II) and zinc(II) with a Schiff base, formed by the condensation of isatin with 2-aminopyrimidine have been synthesised and characterised through elemental analysis, molar conductance measurements, magnetic susceptibility, IR, UV-Vis, (1)HNMR, FAB mass and EPR spectral studies. The spectral data revealed that the ligand acts as neutral bidentate, coordinating to the metal ion through the carbonyl oxygen and azomethine nitrogen. Molar conductance values adequately support the electrolytic nature of the complexes. On the basis of the above observations the complexes have been formulated as [M(ISAP)2]X2, where M=Mn(II), Co(II), Ni(II), Cu(II) and Zn(II); X=Cl, OAc; ISAP=2-[N-indole-2-one]aminopyrimidine. The ligand and copper(II) complex were subjected to X-ray diffraction studies. The DNA cleavage study was monitored by gel electrophoresis method. The superoxide dismutase (SOD) mimetic activities of the ligand and the metal complexes were checked using NBT assay. The in vitro antibacterial activity of the synthesized compounds has been tested against gram negative and gram positive bacteria. PMID- 24051285 TI - Experimental and DFT studies on the vibrational, electronic spectra and NBO analysis of thiamethoxam. AB - Vibrational and electronic spectral measurements were performed for 3-(2-chloro 1,3-thiazol-5-ylmethyl)-5-methyl-1,3,5-oxadiazinan-4-ylidene(nitro) amine (thiamethoxam). Optimized geometrical structure and harmonic vibrational frequencies were calculated with ab initio RHF and DFT (B3LYP, CAMB3LYP, M06 and PBE1PBE) methods with 6-311++G (d, p) basis set. Complete assignments of the observed spectra were proposed. The absorption spectra of the compound were computed in gas-phase using TD-B3LYP/6-311++G (d, p) approach and H2O solution using PCM-TD-B3LYP/6-311++G (d, p) approach. The calculated results matched well with the experimental values. Temperature dependence of thermodynamic parameters in the range of 100-1000 K were determined. The bond orbital occupancies, contribution from parent natural bond orbital (NBO), the natural atomic hybrids was discussed. PMID- 24051286 TI - Enhanced luminescence and energy transfer study in Tb:Sm codoped lead fluorotellurite glass. AB - Spectroscopic properties of Sm(3+), Tb(3+) doped and Tb(3+):Sm(3+) co-doped lead fluorotellurite glasses have been studied in detail. On the excitation with 355 and 532 nm laser wavelengths, the luminescence properties of the singly and doubly doped glasses have been analyzed. Intensity of characteristic emission bands due to Sm(3+) ions is appreciably enhanced in the presence of Tb(3+) ions. This is due to the energy transfer from Tb(3+) to Sm(3+) ions. Different energy transfer parameters have also been calculated, which affirm an efficient energy transfer from Tb(3+) to Sm(3+) ions. PMID- 24051287 TI - Enhancing photoluminescent behavior of 2-(naphthalen-1-yl)-1,4,5-triphenyl-1H imidazole by ZnO and Bi2O3. AB - A fluorophore 2-(naphthalen-1-yl)-1,4,5-triphenyl-1H-imidazole [NTI] has been designed, synthesized and characterized by (1)H NMR, (13)C NMR, mass and single crystal XRD. Absorption, emission, lifetime and cyclic voltammetry have been made to deduce the interaction between NTI and ZnO and Bi2O3 nanocrystals. NTI act as a new host for ZnO and Bi2O3 nanocrystals that enhance its luminescence. The apparent binding constant has been obtained. Adsorption of the NTI on ZnO and Bi2O3 nanocrystals lowers the HOMO energy level of the NTI. The strong adsorption of the NTI on the surface of ZnO and Bi2O3 nanocrystals is likely due to the chemical affinity of the nitrogen atom of the NTI to the zinc ion on the surface of nanocrystals. SEM and EDS spectra confirmed the adsorption of NTI on the surface of nanocrystals. PMID- 24051288 TI - Vibrational spectroscopic study of the natural layered double hydroxide manasseite now defined as hydrotalcite-2H-Mg6Al2(OH)16[CO3]?4H2O. AB - Raman and thermo-Raman spectroscopy have been applied to study the mineral formerly known as manasseite now simply renamed as hydrotalcite-2H Mg6Al2(OH)16[CO3]?4H2O. The mineral is a member of the homonymous hydrotalcite supergroup. Hydrogen bond distances calculated using a Libowitzky-type empirical function varied between 2.61 and 3.00A. Stronger hydrogen bonds were formed by water units as compared to the hydroxyl units. Raman spectroscopy enabled the identification of bands attributed to the hydroxyl units. Two Raman bands at 1059 and 1064 cm(-1) are assigned to symmetric stretching modes of the carbonate anion. Thermal treatment shifts these bands to higher wavenumbers indicating a change in the strength of the carbonate bonding. PMID- 24051289 TI - Optical transitions of Tm3+ in oxyfluoride glasses and compositional and thermal effect on upconversion luminescence of Tm3+/Yb3+-codoped oxyfluoride glasses. AB - Optical properties of Tm(3+)-doped SiO2-BaF2-ZnF2 glasses have been investigated on the basis of the Judd-Ofelt theory. Judd-Ofelt intensity parameters, radiative transition probabilities, fluorescence branching ratios and radiative lifetimes have been calculated for different glass compositions. Upconversion emissions were observed in Tm(3+)/Yb(3+)-codoped SiO2-BaF2-ZnF2 glasses under 980 nm excitation. The effects of composition, concentration of the doping ions, temperature, and excitation pump power on the upconversion emissions were also systematically studied. PMID- 24051290 TI - Radial integrals 4f and nephelauxetic effect of Nd3+ in crystals. AB - The radial expectation values 4f,k=2, 4, 6, for oxygen- or halogen- coordinated Nd(3+) ions in 25 crystals have been obtained from experimental Slater parameter shifts DeltaFk=Fk (free ion) - Fk (crystal) by means of the dielectric screening model. The 4f values found by this new approach are compatible with those computed by relativistic 4f wave functions. The nephelauxetic ratios betak in respect to the free ion Nd IV have been also determined and related to covalency and bonding parameters. PMID- 24051291 TI - Spectroscopic properties and orientation of molecules in Langmuir-Blodgett layers of selected functionalized fullerenes. AB - Vibrational properties of two fullerene derivatives: C60TZ-OT-5 (1) and C60TH-3HX (2) have been studied using infrared absorption and Raman scattering spectroscopies. Additionally, quantum chemical calculations of the equilibrium geometry and normal mode vibrations of these functionalized fullerenes were performed. It was stated that despite of distinct structural differences between the investigated molecules, their experimental spectra are quite similar and correspond well with the calculated ones. The orientation of the molecules in the Langmuir-Blodgett films was evaluated. PMID- 24051292 TI - Density functional theory and phytochemical study of Pistagremic acid. AB - We report here for the first time a comparative theoretical and experimental study of Pistagremic acid (P.A). We have developed a theoretical model for obtaining the electronic and spectroscopic properties of P.A. The simulated data showed nice correlation with the experimental data. The geometric and electronic properties were simulated at B3LYP/6-31 G (d, p) level of density functional theory (DFT). The optimized geometric parameters of P.A were found consistent with those from X-ray crystal structure. Differences of about 0.01 and 0.15 A in bond length and 0.19-1.30 degrees degree in the angles, respectively; were observed between the experimental and theoretical data. The theoretical vibrational bands of P.A were found to correlate with the experimental IR spectrum after a common scaling factor of 0.963. The experimental and predicted UV-Vis spectra (at B3LYP/6-31+G (d, p)) have 36 nm differences. This difference from experimental results is because of the condensed phase nature of P.A. Electronic properties such as Ionization Potential (I.P), Electron Affinities (E.A), co-efficient of highest occupied molecular orbital (HOMO), co-efficient of lowest unoccupied molecular orbital (LUMO) of P.A were estimated for the first time however, no correlation can be made with experiment. Inter-molecular interaction and its effect on vibrational (IR), electronic and geometric parameters were simulated by using Formic acid as model for hydrogen bonding in P.A. PMID- 24051293 TI - Infrared imaging spectroscopy and chemometric tools for in situ analysis of an imiquimod pharmaceutical preparation presented as cream. AB - In the present work the homogeneity of a pharmaceutical formulation presented as a cream was studied using infrared imaging spectroscopy and chemometric methodologies such as principal component analysis (PCA) and multivariate curve resolution with alternating least squares (MCR-ALS). A cream formulation, presented as an emulsion, was prepared using imiquimod as the active pharmaceutical ingredient (API) and the excipients: water, vaseline, an emulsifier and a carboxylic acid in order to dissolve the API. After exposure at 45 degrees C during 3 months to perform accelerated stability test, the presence of some crystals was observed, indicating homogeneity problems in the formulation. PCA exploratory analysis showed that the crystal composition was different from the composition of the emulsion, since the score maps presented crystal structures in the emulsion. MCR-ALS estimated the spectra of the crystals and the emulsion. The crystals presented amine and C-H bands, suggesting that the precipitate was a salt formed by carboxylic acid and imiquimod. These results indicate the potential of infrared imaging spectroscopy in conjunction with chemometric methodologies as an analytical tool to ensure the quality of cream formulations in the pharmaceutical industry. PMID- 24051294 TI - Ag(I)-mediated homo and hetero pairs of guanosine and cytidine: monitoring by circular dichroism spectroscopy. AB - Ag(I)-containing compounds are attractive as antibacterial and antifungal agents. The renewed interest in the application of silver(I) compounds has led to the need for detailed knowledge of the mechanism of their action. One of the possible ways is the coordination of Ag(I) to G-C pairs of DNA, where Ag(+) ions form Ag(I)-mediated base pairs and inhibit the transcription. Herein, a systematic chiroptical study on silver(I)-mediated homo and mixed pairs of the C-G complementary-base derivatives cytidine(C) and 5'-guanosine monophosphate(G) in water is presented. Ag(I)-mediated homo and hetero pairs of G and C and their self-assembled species were studied under two pH levels (7.0 and 10.0) by vibrational (VCD) and electronic circular dichroism(ECD). VCD was used for the first time in this field and showed itself to be a powerful method for obtaining specific structural information in solution. Based on results of the VCD experiments, the different geometries of the homo pairs were proposed under pH 7.0 and 10.0. ECD was used as a diagnostic tool to characterize the studied systems and as a contact point between the previously defined structures of the metal or proton mediated pairs of nucleobases and the systems studied here. On the basis of the obtained data, the formation of the self-assembled species of cytidine with a structure similar to the i-motif structure in DNA was proposed at pH 10.0. PMID- 24051295 TI - Excited state intramolecular proton transfer (ESIPT) in 2-(2' hydroxyphenyl)benzoxazole and its naphthalene-fused analogs: a TD-DFT quantum chemical study. AB - The intramolecular proton transfer reactions in 2-(2'-hydroxyphenyl)benzoxazole (HBO) and its naphthalene-fused analogs, (HNB1-3) in both S0 and S1 states at the PBE1PBE/6-311++G(2d,2p) level of theory in the gas phase and water have been investigated to find the effects of extension of aromaticity on the intramolecular proton transfer and photophysical properties. The results show that the ground state intramolecular proton transfer (GSIPT) in the studied species is impossible. Excited states potential energy surface calculations support the existence of ESIPT process. Structural parameters, relative energy of isomers, H-bonding energy, adsorption and emission bands, vertical excitation and emission energies, oscillator strength, fluorescence rate constant, dipole moment, atomic charges and electron density at critical points were calculated. Orbital analysis shows that vertical S0->S1 transition in the studied molecules corresponds essentially to the excitation from HOMO (pi) to LUMO (pi(*)). The potential of HNB2 molecule as an emissive and electron transport material in designing improved organic white light emitting diodes is predicted in this work. Our calculations are also supported by the experimental observations. PMID- 24051296 TI - A highly selective colorimetric and ratiometric fluorescent chemodosimeter for detection of fluoride ions based on 1,8-naphthalimide derivatives. AB - A high selective colorimetric and ratiometric fluorescent probe based on 4 hydroxy-1, 8-naphthalimide was designed and synthesized to detect fluoride ions (F(-)). The sensing behavior of this probe was studied by UV-visible and fluorescence spectroscopy. The probe displays an 110 nm red-shift of fluorescence emission and the color changes from colorless to yellow by virtue of the strong affinity of F(-) toward silicon which can act as a new visual sensor for F(-). PMID- 24051297 TI - Spectroscopic and biological approach in the characterization of a novel 14 membered [N4] macrocyclic ligand and its palladium(II), platinum(II), ruthenium(III) and iridium(III) complexes. AB - A novel, tetradentate nitrogen donor [N4] macrocyclic ligand, i.e. 3,5,14,16 tetramethyl-2,6,13,17-tetraazatricyclo[12,0,0(7-12)] cosa 1(22),2,5,7,9,11,13,16,18,20-decaene(L), has been synthesized and characterized by elemental analyses, IR, Mass, and (1)H NMR spectral studies. Complexes of Pd(II), Pt(II), Ru(III) and Ir(III) have been prepared and characterized by elemental analyses, molar conductance measurements, magnetic susceptibility measurements, IR, Mass, electronic spectral and thermal studies. On the basis of molar conductance the complexes may be formulated as [PdL]Cl2, [PtL]Cl2, [Ru(L)Cl2]Cl and [Ir(L)Cl2]Cl. The complexes are insoluble in most common solvents, including water, ethanol, carbon tetrachloride and acetonitrile, but soluble in DMF/DMSO. The value of magnetic moment indicates that all the complexes are diamagnetic except Ru(III) complex which shows magnetic moment corresponding to one unpaired electron. The magnetic moment of Ru(III) complex is 1.73 B.M. at room temperature. The antimicrobial activities of ligand and its complexes have been screened in vitro, as growth inhibiting agents. The antifungal and antibacterial screening were carried out using Food Poison and Disc Diffusion Method against plant pathogenic fungi and bacteria Alternaria porri, Fusarium oxysporum, Xanthomonas compestris and Pseudomonas aeruginosa respectively. The compounds were dissolved in DMSO to get the required solutions. The required medium used for these activities was PDA and nutrient agar. PMID- 24051298 TI - The effect of artificial seawater on SERS spectra of amino acids-Ag colloids: an experiment of prebiotic chemistry. AB - The large enhancement of signal observed in surface enhanced Raman spectroscopy (SERS) could be helpful for identifying amino acids on the surface of other planets, in particular for Mars, as well as in prebiotic chemistry experiments of interaction minerals/amino acids. This paper reports the effect of several substances (NaCl, MgCl2, KBr, CaSO4, K2SO4, MgSO4, KI, NH4Cl, SrCl2, CaCl2, Na2SO4, KOH, NaOH, H3BO3) on the SERS spectra of colloid of sodium citrate-CSC and colloid of sodium borohydride-CSB. The effect of four different artificial seawaters and these artificial seawaters plus amino acids (alpha-Ala-alanine, Gly glycine, Cys-cysteine, AIB-2-aminoisobutiric acid) on SERS spectra using both CSC and CSB was also studied. For CSC, the effect of water, after dilution of the colloid, was the appearance of several absorption bands belonging to sodium citrate in the SERS spectrum. In general, artificial seawaters enhanced several bands in SERS spectra using CSC and CSB and CSC was more sensitive to those artificial seawaters than CSB. The identification of Gly, alpha-Ala and AIB using CSC or CSB was not possible because several bands belonging to artificial seawaters, sodium citrate or sodium borohydride were enhanced. On the other hand, artificial seawaters did not interfere in the SERS spectra of Cys using CSC or CSB, although the interaction of Cys with each colloid was different. For CSC the band at 2568 cm(-1) (S-H stretching) of Cys vanished and for CSB the intensity of this band decreased, indicating the -SH of Cys was bonded to Ag to form -S-Ag. Thus SERS spectroscopy could be used for Cys detection on Mars soils using Mars land rovers as well as to study the interaction between Cys and minerals in prebiotic chemistry experiments. PMID- 24051299 TI - Experimental and theoretical investigation of [Al(PCr)(H2O)] complex in aqueous solution. AB - Phosphocreatine is a phosphorylated creatine molecule synthesized in the liver and transported to muscle cells where it is used for the temporary storage of energy. In Alzheimer's disease, the capture of glucose by cells is impaired, which negatively affects the Krebs cycle, leading to problems with the generation of phosphocreatine. Furthermore, the creatine-phosphocreatine system, regulated by creatine kinase, is affected in the brains of Alzheimer's disease patients. Aluminum ions are associated with Alzheimer's disease. Al(III) decreases cell viability and increases the fluidity of the plasma membrane, profoundly altering cell morphology. In this study, one of the complexes formed by Al(III) and phosphocreatine in aqueous solution was investigated by potentiometry, (31)P and (27)Al NMR, Raman spectroscopy and density functional theory (DFT) calculations. The log KAlPCr value was 11.37+/-0.03. Phosphocreatine should act as a tridentate ligand in this complex. The (27)Al NMR peak at 48.92ppm indicated a tetrahedral molecule. The fourth position in the arrangement was occupied by a coordinated water molecule. Raman spectroscopy, (31)P NMR and DFT calculations (DFT:B3LYP/6 311++G(**)) indicated that the donor atoms are oxygen in the phosphate group, the nitrogen of the guanidine group and the oxygen of the carboxylate group. Mulliken charges, NBO charges, frontier molecular orbitals, electrostatic potential contour surfaces and mapped electrostatic potential were also examined. PMID- 24051300 TI - Structure-based design, synthesis and biological evaluation of novel anthra[1,2 d]imidazole-6,11-dione homologues as potential antitumor agents. AB - By using fragment-based design strategies, a series of 2-thio-substituted anthra[1,2-d]imidazole-6,11-diones were synthesized and evaluated for hTERT repressing activities, cell proliferations, and NCI 60-cell panel assay. Compounds 2, 3, 4, 11, 15 and 35 were selected by the NCI and 3, 4, 11 and 15 represent the GI50, TGI and LC50, respectively. Among them, all were moderate selectivity toward leukemia cancer except for 4 exhibited distinctive selectivity of CNS and renal cancer with 7.403 and 6.475. The overall of test compounds exhibited different cytostatic and cytotoxic activities for further developing potential application as anticancer drugs. PMID- 24051301 TI - The analysis of the human plasma N-glycome in endometriosis patients. AB - OBJECTIVE: Analysis of the plasma N-glycome in endometriosis patients compared with controls. STUDY DESIGN: In a case-control study, blood samples were collected from patients who underwent either diagnostic or operative laparoscopy between 2008 and 2011 in the Semmelweis University, Budapest, I. Department of Obstetrics and Gynaecology. From these patients, 92 with endometriosis (30 stage I-II and 62 stage III-IV, including altogether 18 deep infiltrating cases) and 62 controls were selected for glycan analysis. After release, plasma N-glycans were subjected to hydrophilic interaction high performance liquid chromatography, which resulted in 19 chromatographic glycan peaks (GP). The abundances of the GPs were compared between the study groups. For statistical analysis a non-parametric test, the Mann-Whitney-U test, was used. RESULTS: We found a statistically significant decrease of GP1 and increase of GP14, GP17 and GP18 in endometriosis patients. The latter peaks consist of glycans which play a role in inflammatory processes and malignancy. We also found significant differences in GP2, GP4, GP6, and GP9 between controls and the different endometriosis stage groups. The observed alterations in GP2, GP4 and GP6 may be related to altered glycosylation and remodelling of the glycan branches of the IgG molecule. The alterations of GP9 are presumably associated with changes of transferrin glycosylation. Furthermore we detected a highly significant decrease of GP1 in patients with deep infiltrating endometriosis compared with controls. CONCLUSIONS: This is the first analysis of the plasma N-glycome in endometriosis. The observed changes in GP14, GP17 and GP18 and in GP2, GP4, GP6 and GP9 provide new aspects to the pathophysiology of the disease and the alterations of the GP1 may serve as a new potential marker in the future. PMID- 24051302 TI - Flebogamma((r)) DIF (intravenous immunoglobulin) purification process effectively eliminates procoagulant activities. AB - BACKGROUND: Studies have demonstrated that traces of activated factor XI (FXIa) present in specific brands of intravenous immunoglobulin (IVIG) concentrates may pose a thrombogenic risk. AIM: To characterize procoagulant activity during fractionation and the elimination capacity of the Flebogamma((r)) DIF (Grifols' IVIG) manufacturing process. METHODS: Flebogamma((r)) DIF fractionation steps included cryoprecipitate supernatant (Cryo/S), Fraction (Fr) I supernatant, and Fr II + III suspension. Purification steps included ultrafiltrate I, acid treatment, and pasteurization. Samples were assessed for total protein, IgG, and procoagulant activation markers. RESULTS: Cryo/S showed no procoagulant activity for prekallikrein activator (PKA), kallikrein-like, and non-activated partial thromboplastin time (NaPTT) with normal (-PPP) or FXI-deficient (-FXI) platelet poor plasma. Thrombin generation test (TGT)-PPP and TGT-FXI were <83-148 and <53 197 nM thrombin, respectively. Shortened NaPTTs (100-296 s), high PKA (51-119 IU/mL), kallikrein-like activities (0.043-0.075 DeltaAU/min), positive TGTs (98 298 nM), and FXIa (9.5-14.0 ng/mL) were detected in Fr II + III. After pasteurization, no residual evidence of any procoagulant activity marker was observed, including the final IVIG concentrate at 5% or 10% protein. Results were similar in Fr II + III from different IVIG manufacturing facilities. CONCLUSIONS: The Flebogamma((r)) DIF production process is capable of eliminating procoagulant activity because of its purification steps. PMID- 24051303 TI - Simulation as a methodology for assessing the performance of healthcare professionals working in the delivery room. AB - Formal evaluation of healthcare professionals has been accomplished primarily through assessment of the ability to recall content knowledge despite the fact that cognitive, technical and behavioral skills are all important aspects of human performance in this domain. In addition human performance is also influenced by elements that are extrinsic to the human being including the systems and subsystems with which they must interact. Rigorous assessment of human and system performance in the actual healthcare environment is extremely challenging for a number of reasons. Simulation provides a methodology by which this performance can be objectively assessed, thereby facilitating the delivery of effective, safe and efficient patient care. PMID- 24051304 TI - Quantification of frequency dependence of mechanical effects induced by ultrasound. AB - The physical or mechanical effects induced by ultrasound were investigated through the viscosity change in degradation of polymers. The viscosity change was observed with polyethylene oxide in both aqueous and benzene solution; while polystyrene in only benzene solution. The frequency of ultrasound in these experiments varies from 20 kHz to 1 MHz, under a constant dissipated power. The viscosity ratio and the apparent degradation rate were obtained as a function of the irradiation frequency. From the analysis of these experiments, the mechanical effects are found to slow down above 100 kHz when the frequency increases. In case of the analysis of solution viscosity, since this method yields the same apparent results in both aqueous and benzene solutions, our study propose an alternative simple, cost effective method to quantify the mechanical effects in sonochemistry. PMID- 24051305 TI - Ultrasonically improved galvanochemical technology for the remediation of industrial wastewater. AB - Two general methodologies adopted for the decontamination of industrial wastewater containing oil and metal ions are flocculation and coagulation. Both methods require the addition of chemicals and in the case of electrocoagulation the additional use of electrical power. Another methodology that was developed in Russia some years ago involves the production of Fe2O3 particles as coagulants by a galvanochemical reaction between iron and coke. Both of these materials are inexpensive and generally available in bulk. Ultrasonic processing of the particles generated in this reaction reduces the particle size of the Fe2O3 particles and provides surface cleaning making them more effective. Trials have proved their efficiency for the decontamination of wastewater made up in a laboratory and real wastewater from a carriage cleaning station on the St. Petersburg Metro. A mathematical model for the process has been developed. PMID- 24051306 TI - Clinical relevance of KRAS mutations in codon 13: Where are we? AB - Recent advances in molecular diagnosis and the trend towards personalized medicine have made colorectal cancer one of the tumors where therapies have significantly improved patient survival after metastasis development. KRAS mutations in codon 12 and 13 are recognized biomarkers that are analyzed in clinic previously for anti-EGFR therapies administration. Since originally mutations in both codons were considered as a predictor of lack of response to cetuximab or panitumumab, the European Medicines Agency and the US Food and Drug Administration suggested that patients harboring any of those mutations should be excluded from the treatment. However, subsequent retrospective analysis has shown that mutations in codon 12 and codon 13 of KRAS gene could be different in their biological characteristics and as a result could confer variable effects in patients. In addition and increasing and sometimes contradictory number of solutions have been published demonstrating that patients with mutations in codon 13 could have worse outcome but could obtain a significant clinical benefit from anti-EGFR therapies. Here, we review and update the latest data on the biological role leading to a predictive outcome and benefit from anti-EGFR antibodies in patients with specific KRAS mutations in codon 13. PMID- 24051307 TI - A single extra copy of Dscr1 improves survival of mice developing spontaneous lung tumors through suppression of tumor angiogenesis. AB - The incidence of most solid tumors is remarkably reduced in individuals with Down syndrome. Using mouse models of Down syndrome, we have previously shown that this decrease in tumor incidence is due, in part, to suppression of tumor angiogenesis as a consequence of attenuated calcineurin signaling in endothelial cells. Our prior studies utilized xenografted tumors in a transgenic mouse model with three copies of the Down syndrome critical region-1 (Dscr1) gene, a chromosome 21 encoded endogenous calcineurin inhibitor. These data indicate that upregulated Dscr1 contributes to broad cancer protection by suppressing tumor angiogenesis through inhibiting the calcineurin pathway in the vascular endothelium. However, it still remains to be confirmed whether a single extra copy of Dscr1 is also sufficient to suppress tumor angiogenesis in slow growing spontaneous tumors that more accurately recapitulate molecular features of human malignancies. In this study, utilizing LSL-Kras(G12D) mice, an inducible and autochthonous model of human lung adenocarcinoma, on a Dscr1 transgenic mouse background, we show that a single extra transgenic copy of Dscr1 provides a survival advantage in these mice developing spontaneous lung tumors driven by oncogenic Kras(G12D) without affecting either initiation or progression of spontaneous lung tumors. Furthermore, we show that Dscr1 trisomy significantly reduces microvessel density in lung tumors and thus limits the growth of lung tumors through decreased proliferation and increased apoptosis of lung tumor cells. These data provide evidence that a single extra copy of Dscr1 is sufficient to suppress tumor angiogenesis during spontaneous lung tumorigenesis and further support our hypothesis that suppression of tumor angiogenesis by an additional copy of Dscr1 contributes to the reduced cancer incidence in individuals with Down syndrome and the calcineurin pathway in the tumor vasculature is a potential target for cancer treatment. PMID- 24051308 TI - A personalized view on cancer immunotherapy. AB - Recent progress in cancer immunotherapy has resulted in complete responses in patients refractory to current standard cancer therapies. However, due to tumor heterogeneity and inter-individual variations in anti-tumor immunity, only subsets of patients experience clinical benefit. This review highlights the implementation of a personalized approach to enhance treatment efficacy and reduce side effects, including the identification of tumor-specific antigens for cancer vaccination and adoptive T cell therapies. Furthermore, together with the current advances and promising clinical outcomes of combination cancer (immuno )therapies, the screening for predictive biomarkers in a patient-specific manner is emphasized. PMID- 24051309 TI - Twist1 is essential in maintaining mesenchymal state and tumor-initiating properties in synovial sarcoma. AB - Synovial sarcoma is an aggressive mesenchymal tumor with dual differentiation; epithelial and mesenchymal differentiation. However, the molecular mechanisms behind tumorigenesis and dual differentiation have remained elusive. In this study, we investigated whether Twist1 is an essential transcription factor for maintaining tumor-initiating cell properties in synovial sarcoma. First, we identified that Twist1 is overexpressed in most cases of synovial sarcoma (SS) samples as well as in two synovial sarcoma cell lines (HSSYII, SW982). Additionally, Twist1 depletion led to down-regulation of mesenchymal markers and up-regulation of epithelial markers in SS cell lines. The migratory and invasive abilities of SS cell lines were also significantly reduced following the loss of Twist1. These results indicate that Twist1 plays an essential role in the maintenance of mesenchymal character in SS. Furthermore, knock-down of Twist1 induced G1 cycle arrest and apoptosis as well as remarkable reduction in the sphere-forming cell subpopulation and side population cells. Moreover, Twist1 knock-down profoundly inhibited the growth of synovial sarcoma xenograft in nude mice compared to controls indicating that Twist1 is essential for tumor initiating cell properties. To explore transcriptional regulation by Twist1 at the genomic level, Chromatin immunoprecipiation-solexa whole genome sequencing (ChIP-SEQ) and cDNA microarray analysis were performed. Mesenchymal differentiation/proliferation and PDGF related genes were found to be affected by Twist1. Finally, depletion of SS18-SSX fusion oncoprotein by RNA inference induced down-regulation of Twist1, implying that Twist1 is regulated by SS18-SSX. Hence, our results suggest that Twist1 is an essential transcription factor for the maintenance of mesenchymal characters and tumor initiating properties of synovial sarcoma. PMID- 24051311 TI - Full genome sequence of a Western reference strain of bluetongue virus serotype 16 from Nigeria. AB - The genome of NIG1982/10, a Nigerian bluetongue virus serotype 16 (BTV-16) strain, was sequenced (19,193 bp). Comparisons to BTV strains from other areas of the world show that all 10 genome segments of NIG1982/10 are derived from a western lineage (w), indicating that it represents a suitable reference strain of BTV-16w. PMID- 24051312 TI - Multiple Genome Sequences of Helicobacter pylori Strains of Diverse Disease and Antibiotic Resistance Backgrounds from Malaysia. AB - Helicobacter pylori causes human gastroduodenal diseases, including chronic gastritis and peptic ulcer disease. It is also a major microbial risk factor for the development of gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Twenty-one strains with different ethnicity, disease, and antimicrobial susceptibility backgrounds were sequenced by use of Illumina HiSeq and PacBio RS platforms. PMID- 24051313 TI - Influenza a virus with a human-like n2 gene is circulating in pigs. AB - A novel reassortant influenza A virus, H1avN2hu, has been found in Danish swine. The virus contains an H1 gene similar to the hemagglutinin (HA) gene of H1N1 avian-like swine viruses and an N2 gene most closely related to the neuraminidase (NA) gene of human H3N2 viruses from the mid-1990s. PMID- 24051314 TI - Genome Sequence of Saccharopolyspora erythraea D, a Hyperproducer of Erythromycin. AB - Saccharopolyspora erythraea is a Gram-positive bacterium that can produce antibiotics. However, this microorganism must often be genetically improved for higher production before it can be used in an industrial setting. Here, we report the whole-genome sequence of the industrial hyperproducer strong mutator Saccharopolyspora erythraea strain D. PMID- 24051315 TI - Genome Sequence of Dehalobacter UNSWDHB, a Chloroform-Dechlorinating Bacterium. AB - The chloroform-respiring bacterium Dehalobacter UNSWDHB was isolated from subsurface soil contaminated with a mixture of organohalides, including chloroform. Here, we present its 3.2-Mb genome. PMID- 24051316 TI - Complete Genome Sequence of Antarctic Bacterium Psychrobacter sp. Strain G. AB - Here, we report the complete genome sequence of Psychrobacter sp. strain G, isolated from King George Island, Antarctica, which can produce lipolytic enzymes at low temperatures. The genomics information of this strain will facilitate the study of the physiology, cold adaptation properties, and evolution of this genus. PMID- 24051310 TI - Foreign language training as cognitive therapy for age-related cognitive decline: a hypothesis for future research. AB - Over the next fifty years, the number of older adults is set to reach record levels. Protecting older adults from the age-related effects of cognitive decline is one of the greatest challenges of the next few decades as it places increasing pressure on families, health systems, and economies on a global scale. The disease-state of age-related cognitive decline-Alzheimer's disease and other dementias-hijacks our consciousness and intellectual autonomy. However, there is evidence that cognitively stimulating activities protect against the adverse effects of cognitive decline. Similarly, bilingualism is also considered to be a safeguard. We propose that foreign language learning programs aimed at older populations are an optimal solution for building cognitive reserve because language learning engages an extensive brain network that is known to overlap with the regions negatively affected by the aging process. It is recommended that future research should test this potentially fruitful hypothesis. PMID- 24051317 TI - Whole-Genome Sequence Analysis of Postpandemic Influenza A(H1N1)pdm09 Virus Isolates from India. AB - The pandemic influenza A(H1N1)pdm09 virus was first detected in India in May 2009 and continued to circulate in the postpandemic period. Whole-genome sequence analysis of postpandemic A(H1N1)pdm09 viruses showed the circulation of clade 6 and clade 7 viruses. The hemagglutinin (HA) gene showed increased diversity compared with that in the pandemic phase. PMID- 24051318 TI - Draft Genome Sequences of Helicobacter pylori Strains Isolated from Regions of Low and High Gastric Cancer Risk in Colombia. AB - The draft genome sequences of six Colombian Helicobacter pylori strains are presented. These strains were isolated from patients from regions of high and low gastric cancer risk in Colombia and were characterized by multilocus sequence typing. The data provide insights into differences between H. pylori strains of different phylogeographic origins. PMID- 24051319 TI - Draft Genome Sequences for 10 Isolates of the Swine Pathogen Haemophilus parasuis. AB - Haemophilus parasuis colonizes the upper respiratory tract of swine and can cause a severe systemic disease known as Glasser's disease. We report here the draft genome sequences of 10 isolates from geographically diverse locations representing the full virulence spectrum of the microorganism, which will aid in understanding the pathobiology of H. parasuis. PMID- 24051320 TI - Complete Genome Sequence of the Equol-Producing Bacterium Adlercreutzia equolifaciens DSM 19450T. AB - Adlercreutzia equolifaciens DSM 19450(T) was isolated from human feces and is able to metabolize daidzeins (soybean isoflavonoids) to equol. Here, we report the finished and annotated genome sequence of this organism. PMID- 24051321 TI - Draft Genome Sequence of Sphingobium sp. Strain HDIPO4, an Avid Degrader of Hexachlorocyclohexane. AB - Sphingobium sp. strain HDIPO4 was isolated from a hexachlorocyclohexane (HCH) dumpsite and degraded HCH isomers rapidly. The draft genome sequence of HDIPO4 (~4.7 Mbp) contains 143 contigs and 4,646 coding sequences with a G+C content of 65%. PMID- 24051322 TI - Draft Genome Sequence of a Hexachlorocyclohexane-Degrading Bacterium, Sphingobium baderi Strain LL03T. AB - Sphingobium baderi strain LL03(T) was isolated from hexachlorocyclohexane (HCH) contaminated soil from Spolana, Czech Republic. Strain LL03(T) is a mutant that is deficient in linB and linC (genes that encode hexachlorocyclohexane haloalkane dehalogenase and dehydrogenase, respectively). The draft genome sequence of LL03(T) (~4.85 Mb) consists of 92 contigs and 4,914 coding sequences, with a G+C content of 63.5%. PMID- 24051323 TI - Draft Genome Sequence of Sphingobium lactosutens Strain DS20T, Isolated from a Hexachlorocyclohexane Dumpsite. AB - Sphingobium lactosutens DS20(T) has been isolated from the hexachlorocyclohexane (HCH) dumpsite in Lucknow, India, but does not degrade any of the HCH isomers. Here, we present the ~5.36-Mb draft genome sequence of strain DS20(T), which consists of 110 contigs and 5,288 coding sequences, with a G+C content of 63.1%. PMID- 24051324 TI - Draft Genome Sequence of Methicillin-Resistant Staphylococcus aureus Strain SA16, Representative of an Endemic Clone from a Brazilian Hospital. AB - Here we report the draft genome sequence of a bloodstream isolate of methicillin resistant Staphylococcus aureus strain SA16. Strain SA16 is a sequence type 5 (ST5)-staphylococcal cassette chromosome mec type II (SCCmec II) clone and was the most prevalent isolate at a Brazilian hospital during the second half of 2009. PMID- 24051325 TI - Complete Genome Sequence of a Channel Catfish Epidemic Isolate, Aeromonas hydrophila Strain ML09-119. AB - Aeromonas hydrophila is a Gram-negative, rod-shaped, mesophilic bacterium that infects both aquatic poikilothermic animals and mammals, including humans. Here, we present the complete genome sequence of Aeromonas hydrophila strain ML09-119, which represents a clonal group of A. hydrophila isolates causing outbreaks of bacterial septicemia in channel catfish since 2009. PMID- 24051326 TI - Analysis of the factors involved in the failure of urethroplasty in men. AB - INTRODUCTION: Outcome of urethroplasty techniques in our environment and risk factors for recurrence of stenosis in these patients are studied in this paper. MATERIAL AND METHODS: Retrospective study on men with urethral strictures treated with urethroplasty in the period 2000-2012. Maximum flow (Qmax), post-void residual (PVR) urine and patient perception of voiding were obtained pre- and postoperatively. Complications were recorded according to the Clavien-Dindo scale. Recurrent stricture was defined according to clinical criteria and endoscopic or imaging confirmation (failure of urethroplasty). Univariate analysis (log-rank) and multivariate (Cox regression) were performed to define the variables implied in the recurrence. RESULTS: 82 patients with mean age 55.6 +/- 17.4 (19-84 years) underwent surgery for urethroplasty. 28% of patients showed multiple stricture, 73.2% bulbar stricture, 41.54% penile stricture and 14.6% membranous stricture. End-to-end anastomosis was performed in 26 cases (31.7%), flap urethroplasty in 21 (25.6%), urethroplasty with free graft in 31 (37.8%) and two-time urethroplasty in 4 (4.9%). Graft urethroplasty showed a longer operative time (p = 0.02) and shorter hospital stay (P = 0.0035). The results were: mean DeltaQmax (mean on baseline) 9.1 +/- 7.5 and mean DeltaPVR 65.8 +/- 136 (both P < 0.0001). Minor early complications occurred in 8 (9.8%) and major in 3 (3.6%). Recurrence occurred at a mean time of 39.8 +/- 39.2 months in 18 patients (21.9%). The percentage of recurrence-free patients was: 91.4% (1 year), 82.1% (5-year) and 78.1% (10-year). Univariate analysis assessed technique used (log-rank, P = 0.13), age (P = 0.2), length stricture (P = 0.003), previous Sachse (P = 0.18), associated lichen (P = 0.18), multiplicity (P = 0.36), year of surgery (P = 0.2), Qmax (P = 0.3) and RPM (P = 0.07) preoperative. End to end anastomosis (HR 4.98, P = 0.04) and length > 3 cm (HR 4.6, P = 0.01) were identified by regression analysis as independent variables associated with poor prognosis. CONCLUSION: Length stricture is both prognostic factor and criterion on choosing the type of urethroplasty, and it makes more complicated to compare the success rates of each surgical procedure. Whatever the stricture size is, the results of anastomotic urethroplasty are worse than those of urethroplasty with buccal mucosal-free grafts. PMID- 24051327 TI - Sunitinib objective response in metastatic renal cell carcinoma: analysis of 1059 patients treated on clinical trials. AB - BACKGROUND: Retrospective analyses were performed in patients with metastatic renal cell carcinoma (mRCC) to characterise the objective response (OR) rate to sunitinib and differentiate pretreatment features and outcomes of patients with early (response by <= 12 weeks) versus late response, and responders versus non responders. METHODS: Data were pooled from 1059 patients in six trials. Median progression-free survival (PFS) and overall survival (OS) were estimated by Brookmeyer and Crowley method and compared between groups by log-rank test. Baseline characteristics were compared by Fisher-exact, t-, or Wilcoxon rank-sum tests. Associations between characteristics and survival were investigated by Cox proportional regression analysis. RESULTS: 398 patients (38%) had confirmed OR (12 complete responses); 26%, 61%, 79% and 86% responded by 6, 12, 18 and 24 weeks, respectively. Median (range) time to tumour response (TTR) was 10.6 (2.7 94.4) weeks and was similar in treatment-naive and cytokine-refractory patients. Median response duration in early and late responders was 52.0 and 55.0 weeks, respectively. Median PFS in early versus late responders was 13.8 versus 20.2 months (P=0.001); however, median OS did not significantly differ (37.8 versus 40.8 months; P=0.144). Early responders had more lung metastases (P<0.01), but baseline characteristics were otherwise mostly similar. Median PFS (16.3 versus 5.3 months) and OS (40.1 versus 14.5 months) were longer in responders versus non responders (both P<0.001); responders had more favourable prognostic factors. CONCLUSIONS: OR occurred in 38% of sunitinib-treated mRCC patients. Sixty-one percent of responses occurred by 12 weeks of therapy, and responders had favourable pretreatment features and significantly longer survival. PMID- 24051328 TI - 18F-FDG-PET/CT in predicting pathologic complete response after neoadjuvant chemotherapy: the early metabolic response is the answer. PMID- 24051329 TI - Requirement of B-Raf, C-Raf, and A-Raf for the growth and survival of mouse embryonic stem cells. AB - Extracellular signal-regulated kinases (ERKs) have been implicated to be dispensable for self-renewal of mouse embryonic stem (ES) cells, and simultaneous inhibition of both ERK signaling and glycogen synthase kinase 3 (GSK3) not only allows mouse ES cells to self-renew independent of extracellular stimuli but also enables more efficient derivation of naive ES cells from mouse and rat strains. Interestingly, some ERKs stay active in mouse ES cells which are maintained in regular medium containing leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP). Yet, the upstream signaling for ERK activation and their roles in mouse ES cells, other than promoting or priming differentiation, have not been determined. Here we found that mouse ES cells express three forms of Raf kinases, A-Raf, B-Raf, and C-Raf. Knocking-down each single Raf member failed to affect the sustained ERK activity, neither did A-Raf and B-Raf double knockdown or B-Raf and C-Raf double knockdown change it in ES cells. Interestingly, B-Raf and C-Raf double knockdown, not A-Raf and B-Raf knockdown, inhibited the maximal ERK activation induced by LIF, concomitant with the slower growth of ES cells. On the other hand, A-Raf, B-Raf, and C-Raf triple knockdown markedly inhibited both the maximal and sustained ERK activity in ES cells. Moreover, Raf triple knockdown, similar to the treatment of U-0126, an MEK inhibitor, significantly inhibited the survival and proliferation of ES cells, thereby compromising the colony propagation of mouse ES cells. In summary, our data demonstrate that all three Raf members are required for ERK activation in mouse ES cells and are involved in growth and survival of mouse ES cells. PMID- 24051330 TI - Individualizing breast cancer treatment-The dawn of personalized medicine. AB - Identification of breast cancer not being a single disease but backed by multiple heterogeneous oncogenic subpopulations is of growing interest in developing personalized therapies to provide optimal outcomes. Through this review, we bring attention to evolution of tumor and microenvironment heterogeneity as a predominant challenge in stratifying therapies. Establishment of a 'precancer niche' serves as a prerequisite for genetically initiated cells to survive and promote neoplastic evolution towards clinically established cancer through development of tumor and its microenvironment. Additionally, continuous evolutionary interplay between tumor and recruited stromal cells along with many other components in the tumor microenvironment adds up to further complexity in developing targeted therapies. However, through continued excellence in developing high throughput technologies including the advent of single-nucleus sequencing, which makes it possible to sequence individual tumor cells, leads to improved abilities in decoding the heterogenic perturbations through reconstruction of tumor evolutionary lineages. Furthermore, simple liquid biopsies in form of enumeration/characterization of circulating tumor cells and tumor microvesicles found in peripheral circulation, shed from distinct tumor lesions, show great promise as prospective biomarkers towards better prognosis in tailoring individualized therapies to breast cancer patients. Lastly, by means of network medicinal approaches, it is seemingly possible to develop a map of the cell's intricate wiring network, helping to identify appropriate interconnected protein networks through which the disease spreads, offering a more patient specific outcome. Although these therapeutic interventions through designing personalized oncology-based trials are promising, owing to continuous tumor evolution, targeting genome instability survival pathways might become an economically viable alternative. PMID- 24051331 TI - Spinal hemangioblastoma presenting with low back pain in pregnancy. AB - BACKGROUND CONTEXT: Low back pain (LBP) is a very common complaint in pregnancy. For this reason, it is often considered directly attributable to the pregnancy rather than a medical problem requiring diagnostic workup. Pregnancy-related LBP should be differentiated from the rare cases of LBP associated with serious spinal diseases. Hemangioblastoma is a vascular tumor of the central nervous system that very rarely can involve the spinal cord. Pregnancy can increase the growth of hemangioblastomas, leading to the appearance of neurologic symptoms. PURPOSE: To describe an unusual cause of LBP in pregnancy. STUDY DESIGN: A case report. METHODS: A 38-year-old woman, with a history of surgical resection of a cerebellar hemangioblastoma at the age of 15 years, presented at 38 weeks of gestation with worsening LBP and numbness of the lower limbs. Diagnostic workup led to a diagnosis of spinal hemangioblastoma. The tumor was removed after cesarean section in the 39th week of gestation. RESULTS: The detection of spinal hemangioblastoma resulted in a good outcome for both mother and infant. CONCLUSIONS: This case emphasizes the main role of clinical evaluation in establishing the diagnostic workup, especially in pregnancy. Although LBP is commonly reported, this patient's medical history and the presence of clinical signs on neurologic examination suggested the need for further investigation. PMID- 24051332 TI - Brown-Sequard syndrome after a gun shot wound to the cervical spine: a case report. AB - BACKGROUND CONTEXT: Brown-Sequard syndrome is characterized by a hemisection of the spinal cord most commonly after spinal trauma or neoplastic disease. The injury causes ipsilateral hemiplegia and proprioceptive sensory disturbances with contralateral loss of pain and temperature sensation. Patients with Brown-Sequard syndrome have the best prognosis of all spinal cord injury patterns. At this time, the ideal management for Brown-Sequard syndrome after penetrating trauma has yet to be defined. PURPOSE: To report a case of a gun shot wound to the upper cervical spine that resulted in Brown-Sequard syndrome and was treated effectively with early cervical spine decompression and fusion. STUDY DESIGN: Observational case report. METHODS: A 28-year-old woman presented after sustaining a low-velocity gun shot wound in to the upper cervical spine in a civilian assault. On initial presentation, she had 0/5 motor scores in the left upper and lower extremities and normal motor scores on the right. Sensory examination was limited as she was intubated and sedated on admission due to airway compromise. A computed tomography scan revealed a bullet lodged in the vertebral body of C3 with boney fragments and soft tissue encroaching on the spinal cord. Subsequently, she underwent C3 corpectomy, bulletectomy, and anterior cervical decompression with fusion. RESULTS: Intraoperatively, no dural disruption or cerebral spinal fluid leak was noted, and her posterior longitudinal ligament was intact. One month postoperatively, her left lower extremity motor score was 5/5 with movement of her left thumb and all fingers. Strength in her biceps, triceps, and wrist extensors and flexors was 3/5. Her functional capacity and strength gradually improved. CONCLUSIONS: Reinke et al. support surgical intervention for patients with incomplete paraplegia after the patient is medically stabilized, although their case report discussed lower thoracic injury, which carries a more favorable prognosis. All other prior case reports and prospective studies that reported favorable outcomes after Brown Sequard syndrome involved the midthoracic, low thoracic, or lumbar spinal levels. This report is the first case of Brown-Sequard syndrome after a high cervical gun shot wound, which was managed with immediate decompression and fusion, where near complete recovery was obtained. PMID- 24051333 TI - An unusual case of congenital scoliosis associated with rib agenesis in the upper part of the concavity treated by VEPTR vertebra to vertebra. AB - BACKGROUND CONTEXT: Rib agenesis in congenital scoliosis is rarely encountered, and its disposal in the application area of the proximal vertical expandable prosthetic titanium rib (VEPTR) module is a challenge to the orthopedic surgeon. PURPOSE: To present a case in which known treatment methods in early-onset scoliosis were not possible to apply. STUDY DESIGN: Case report. METHODS: A patient aged 1 year and 10 months, presenting a congenital scoliosis with the following characteristics: left T3 hemisegmented hemivertebra, T5-T6-T7 hemivertebral segment, T9, T10 trapezoidal vertebrae, right side I-IV rib agenesis with T1-T2-T4 hemivertebral hypoplasia (T3 agenesis) and bilateral XIIth rib agenesis, and V-VI and VII-VIII-IX fused ribs on the right side. We applied a standard VEPTR in a new construct, vertebra to vertebra. RESULTS: The VEPTR vertebra to vertebra proved to be an efficient and stabile construct after 1.5 years of follow-up and three device distractions in a row. The curve corrected from 100 to 58 Cobb degrees. CONCLUSIONS: We believe that the vertebra-to vertebra construct with eventual modifications may be a solution in the treatment of early-onset scoliosis needing surgery, which associate rib agenesis in the area where the proximal module has to be applied. PMID- 24051334 TI - Fluorescent detection of copper(II) based on DNA-templated click chemistry and graphene oxide. AB - A novel DNA-templated click chemistry strategy for homogenous fluorescent detection of Cu(2+) has been developed based on click ligation-dependent DNA structure switch and the selective quenching ability of graphene oxide (GO) nanosheet. The clickable duplex probe consists of two DNA strands with alkyne and azide group, respectively, and Cu(+)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction can chemically ligate these two strands. Toehold sequence displacement was consequently exploited to achieve DNA structure transformation bearing fluorescent tag FAM. Cu(2+)-induced chemical ligation caused the probe transfer to hybrid structure with single stranded DNA (ssDNA) tail, while only duplex structure was obtained without Cu(2+). This structural difference can be probed by GO-based fluorescence detection due to the preferential binding of GO to ssDNA. Under the optimum conditions, this sensor can sensitively and specifically detect Cu(2+) with a low detection limit of 58 nM and a linear range of 0.1-10 MUM. This new strategy is highly sensitive and selective for Cu(2+) detection because of the great specificity of click chemistry and super-quenching ability of GO. Moreover, with the aid of high efficient DNA templated synthesis, the detection process requires only about half an hour which is much quicker than previous click-chemistry-based Cu(2+) sensors. PMID- 24051335 TI - Radioactive characterization of phosphogypsum from Imbituba, Brazil. AB - This research aims to characterize the content of natural occurring radionuclides in phosphogypsum stacks at Imbituba, Santa Catarina state, Brazil. (226)Ra, (228)Ra, (40)K, (238)U and (232)Th were determined in PG, soils and sediment samples by gamma spectrometry using the hyper pure germanium detector and neutron activation. The migration of radionuclides in the phosphogypsum profile did not show the same behavior for all sampling sites. The mean activity concentration of (226)Ra was 95 Bq kg(-1), which is far below the limit recommended by the U.S. Environmental Agency (USEPA) for its application in agriculture (370 Bq kg(-1)) and the Brazilian Commission of Nuclear Energy Resolution 113 that established a reference level of 1000 Bq kg(-1) of (226)Ra or (228)Ra for the use of PG in agriculture as well as building materials. PMID- 24051336 TI - Subcutaneous apomorphine and non-motor symptoms in Parkinson's disease. AB - Non-motor symptoms (NMS) are now recognized to occur across all stages of Parkinson's disease (PD) and as a result there has been an increasing focus on their diagnosis, quantification and effective management. While in some subjects, NMS may be present before diagnosis, in advanced PD, NMS can contribute to hospitalization, severe disability and a shortened life expectancy. Strategies for continuous drug delivery have been reported to have a beneficial effect on NMS in PD and while the efficacy of apomorphine on motor function in PD has been confirmed in a number of studies, in addition to its possible anti-dyskinetic effect, a number of reports have also outlined the possible beneficial effect of apomorphine on NMS. This review sets out to examine the efficacy of apomorphine in non-motor aspects of PD, including its effect on neuropsychiatric and gastrointestinal symptoms, sleep (including restless legs syndrome), urinary dysfunction, pain and impulse control disorders. The analysis takes into consideration case reports, and open-label and comparative case-control studies published to date. Results of this review suggest that although data on the effect of apomorphine on NMS in PD patients are limited there is a strong suggestion of a beneficial effect that warrants further investigation in double blind studies. PMID- 24051337 TI - Nonlinear vibrational microscopy applied to lipid biology. AB - Optical microscopy is an indispensable tool that is driving progress in cell biology. It still is the only practical means of obtaining spatial and temporal resolution within living cells and tissues. Most prominently, fluorescence microscopy based on dye-labeling or protein fusions with fluorescent tags is a highly sensitive and specific method of visualizing biomolecules within sub cellular structures. It is however severely limited by labeling artifacts, photo bleaching and cytotoxicity of the labels. Coherent Raman Scattering (CRS) has emerged in the last decade as a new multiphoton microscopy technique suited for imaging unlabeled living cells in real time with high three-dimensional spatial resolution and chemical specificity. This technique has proven to be particularly successful in imaging unstained lipids from artificial membrane model systems, to living cells and tissues to whole organisms. In this article, we will review the experimental implementations of CRS microscopy and their application to imaging lipids. We will cover the theoretical background of linear and non-linear vibrational micro-spectroscopy necessary for the understanding of CRS microscopy. The different experimental implementations of CRS will be compared in terms of sensitivity limits and excitation and detection methods. Finally, we will provide an overview of the applications of CRS microscopy to lipid biology. PMID- 24051339 TI - Effect of decision confidence on the evaluation of conflicting decisions in a social context. AB - Conflicts with others about decisions are reflected in the medial frontal negativity (MFN), which is a component of the event-related brain potential (ERP). The present study examined how decision confidence in a perceptual decision task modulated the ERP components elicited by decision conflicts with others. In a motion discrimination task, participants were randomly assigned to an easy or a difficult group that differed in coherence levels of the moving dots. Participants were paired with a confederate and presented the confederate's decision about the motion direction of the moving dots, which was either congruent or incongruent with the participants' decision. MFN was elicited by the incongruent confederate's decision and its amplitude did not differ between groups. A larger P300 amplitude was elicited by incongruent decisions in the easy group, whereas the P300 amplitude did not differ between congruent and incongruent decisions in the difficult group. These results indicate the functional dissociation between MFN and P300 in the evaluation of social feedback. It is suggested that MFN might reflect automatic detection of conflicts about decisions, whereas the P300 might detect the deviation from internal expectations regarding other's decisions. PMID- 24051340 TI - Word-induced postural changes reflect a tight interaction between motor and lexico-semantic representations. AB - A tight coupling between lexico-semantic access and motor control has been established on the basis of neuropsychological, neurophysiological, and behavioral evidence. For example, sensory and motor cortices have been shown to be active when subjects listen to words denoting bodily actions. Kinematic analyses of subjects' motor actions during the processing of linguistic stimuli provide further insights into the nature and time-course of this relationship. However, such studies have largely focused on individual body parts, in particular the upper limbs, thus neglecting the effect of language processing on lower or whole body representations. The present study bridges this gap by evaluating the interaction between linguistic processing and whole-body postural control during quiet standing. The results reveal a systematic influence of passive listening to action verbs, but not mental-state verbs, on measures of postural control, pointing to a clear and specific neural link between words conveying action concepts and whole-body motor functions. PMID- 24051341 TI - Carvacrol alleviates cerebral edema by modulating AQP4 expression after intracerebral hemorrhage in mice. AB - Carvacrol is a natural compound extracted from many plants of the family Lamiaceae. Previous studies have demonstrated that carvacrol has potential neuroprotective effects in central nervous system diseases such as Alzheimer's disease and cerebral ischemia. In this study, we investigated the preclinical effect of carvacrol on cerebral edema after intracerebral hemorrhage (ICH) using a bacterial collagenase-induced ICH mouse model. Mice were randomly divided into sham (n=43), vehicle-treated (n=51), and carvacrol-treated groups (n=101). In carvacrol-treated group, carvacrol was administrated to mice at 0h, 1h, or 3h after ICH induction. Carvacrol was injected intraperitoneally with single doses of 10, 25, 50, or 100mg/kg. Neurologic dysfunctions, brain water content, aquaporins (AQPs) mRNAs level and AQP4 protein expression in the perihematomal area were evaluated post ICH. Our results showed that carvacrol administration improved neurological deficits after day 3 following ICH (p<0.05). Carvacrol reduced cerebral edema and Evans Blue leakage at day 3 (p<0.05). We also found that carvacrol treatment decreased AQP4 mRNA in a dose-dependent manner at 24h. Furthermore, AQP4 protein expression in the perihematomal area was reduced by carvacrol significantly at day 3 after ICH (p<0.05). Our findings suggest that carvacrol may exert its protective effect on ICH injury by ameliorating AQP4 mediated cerebral edema. PMID- 24051342 TI - Evaluation of the channelized Hotelling observer with an internal-noise model in a train-test paradigm for cardiac SPECT defect detection. AB - The channelized Hotelling observer (CHO) has become a widely used approach for evaluating medical image quality, acting as a surrogate for human observers in early-stage research on assessment and optimization of imaging devices and algorithms. The CHO is typically used to measure lesion detectability. Its popularity stems from experiments showing that the CHO's detection performance can correlate well with that of human observers. In some cases, CHO performance overestimates human performance; to counteract this effect, an internal-noise model is introduced, which allows the CHO to be tuned to match human-observer performance. Typically, this tuning is achieved using example data obtained from human observers. We argue that this internal-noise tuning step is essentially a model training exercise; therefore, just as in supervised learning, it is essential to test the CHO with an internal-noise model on a set of data that is distinct from that used to tune (train) the model. Furthermore, we argue that, if the CHO is to provide useful insights about new imaging algorithms or devices, the test data should reflect such potential differences from the training data; it is not sufficient simply to use new noise realizations of the same imaging method. Motivated by these considerations, the novelty of this paper is the use of new model selection criteria to evaluate ten established internal-noise models, utilizing four different channel models, in a train-test approach. Though not the focus of the paper, a new internal-noise model is also proposed that outperformed the ten established models in the cases tested. The results, using cardiac perfusion SPECT data, show that the proposed train-test approach is necessary, as judged by the newly proposed model selection criteria, to avoid spurious conclusions. The results also demonstrate that, in some models, the optimal internal-noise parameter is very sensitive to the choice of training data; therefore, these models are prone to overfitting, and will not likely generalize well to new data. In addition, we present an alternative interpretation of the CHO as a penalized linear regression wherein the penalization term is defined by the internal-noise model. PMID- 24051343 TI - Prognostic factors in patients undergoing lymphadenectomy for squamous cell carcinoma of the penis. AB - INTRODUCTION: Penile cancer is rare, and data on prognostic factors of the disease are scarce. The aim of the study was to assess prognostic factors in patients undergoing lymphadenectomy for penile cancer. MATERIAL AND METHODS: Ninety-eight men who underwent lymphadenectomy for penile cancer were enrolled in the study. Progression-free survival and overall survival were assessed. RESULTS: Five-year progression-free survival and overall survival were 0.6651 (95% CI: 0.5151-0.7783) and 0.5516 (95% CI: 0.4412-0.6488), respectively. Multivariate analysis showed that the factors that reduce progression-free survival include delay of lymphadenectomy by more than 3 months after diagnosis (p = 0.045) and involvement of non-inguinal lymph nodes (N0 vs. affected lymph nodes other than superficial inguinal, p = 0.0004; superficial inguinal vs. others, p = 0.001). Factors deteriorating overall survival include high grade (G1 vs. G2, p = 0.0072, and G1 vs. G3, p = 0.0347), more than one lymph node affected (p = 0.001) and crossing the lymph node capsule (p = 0.034). CONCLUSIONS: The factors worsening the prognosis in patients with penile cancer after lymphadenectomy include delayed lymphadenectomy, involvement of lymph nodes other than the superficial inguinal, involvement of more than one lymph node, crossing the lymph node capsule, and high grade. PMID- 24051344 TI - Expression of immune relevant genes in rainbow trout following exposure to live Anisakis simplex larvae. AB - Basic immune response mechanisms in vertebrates against helminths are still poorly understood. Fish-nematode models may prove valuable for elucidation of this question. In this study we orally challenged rainbow trout (Oncorhynchus mykiss) with larvae of Anisakis simplex (Nematoda: Anisakidae) and subsequently investigated the expression of 18 immune relevant genes in spleen and liver 1, 4 and 8days post infection (d.p.i.). Gene expression data were analysed with regard to the infection status of the challenged rainbow trout at the time of necropsy; "worms rejected" (/worms), "worms present" (+worms) and a combined group consisting of samples pooled from both previous groups (//+worms). No significant regulation of cytokine genes was recorded but fish which had rejected worms up regulated the CD4 gene (6.1-fold change, 8d.p.i.) in liver. The gene encoding CD8 was significantly down-regulated 24h post challenge in livers in fish still carrying worms (2.7-fold change) but not in the worm-free group. The immunoglobulin gene IgM was significantly down-regulated (2.9-fold change, 8d.p.i.) in liver samples from the +worms group. Complement factor C3 and precerebellin genes were significantly up-regulated twofold in liver samples from infected fish 4d.p.i. Significant up-regulation of the acute-phase protein SAA was observed in all three groups and in both tissues. To our knowledge, this is the first study to describe the expression of immune genes in a fish host challenged with live nematode larvae. PMID- 24051345 TI - Evaluation acaricidal efficacy of botanical extract from Eupatorium adenophorum against the hard tick Haemaphysalis longicornis (Acari: Ixodidae). AB - The aim of this study was to evaluate the acaricidal activity of a botanical extract from Eupatorium adenophorum against the hard tick Haemaphysalis longicornis. This could result in developing effective extracts of E. adenophorum as a source of natural, low-toxicity plant-based acaricidal drugs. Adult engorged females of H. longicornis were collected from naturally infected goats. The engorged females were reared in the laboratory and their offspring (larvae and nymphs) were used as test ectoparasites. The toxic effects of botanical extracts from E. adenophorum against larvae and nymphs of H. longicornis were evaluated. The results showed that the extracts with 1.5 and 1.0g/ml (w/v) concentrations were toxic for H. longicornis, comparable to a toxic effect of 2% chlorpyrifos (positive control). The median lethal time (LT50) for larval and nymphal ticks with 1.5g/ml (w/v) concentration of extract were 0.790 (LT99=1.065) and 1.018 (LT99=10.608) hours, respectively, whereas the LT50 of 1.0g/ml (w/v) concentration were 1.445 (LT99=6.047) and 1.313 (LT99=29.932) hours for larval and nymphal ticks, respectively. At a concentration of 1.5g/ml (w/v), an acaricidal effect of 100% was achieved for both larval and nymphal ticks, while a concentration of 1.0g/ml (w/v) resulted in 100% (for larvae) and 93% (for nymphs) within a 6h period. In additional, we found that the relatively low concentration (0.5g/ml) also obtained a good acaricidal effect during the short experimental period, with 2.22 and 2.651h LT50 for larval and nymphal ticks, respectively. These results indicate that E. adenophorum contains potent acaricidal ingredients against the hard tick H. longicornis. PMID- 24051347 TI - Two unusual cases of haemoglobin Bart's hydrops fetalis due to uniparental disomy or non-paternity. AB - The authors present 2 unusual cases of haemoglobin (Hb) Bart's hydrops fetalis and highlight the problem of a screening system for alpha-thalassaemia which focuses on maternal and paternal mean corpuscular volume (MCV) alone. Normal paternal MCV may not preclude fetal Hb Bart's disease because of the rare occurrence of maternal uniparental disomy or non-paternity. During a mid trimester anomaly scan, with fetal cardiomegaly or hydrops in a woman with low MCV but normal paternal MCV, obstetricians should remain alert for fetal Hb Bart's disease. This is very important and relevant for national screening systems in South-East Asia, where a routine mid-trimester scan may not be available. A routine mid-trimester anomaly scan should therefore be implemented and in high prevalence areas, sonographers should be sensitive to the cardio thoracic ratio even if screening shows that pregnancy is unlikely to be at risk. PMID- 24051346 TI - A clinical frailty index in aging mice: comparisons with frailty index data in humans. AB - We previously quantified frailty in aged mice with frailty index (FI) that used specialized equipment to measure health parameters. Here we developed a simplified, noninvasive method to quantify frailty through clinical assessment of C57BL/6J mice (5-28 months) and compared the relationship between FI scores and age in mice and humans. FIs calculated with the original performance-based eight item FI increased from 0.06 +/- 0.01 at 5 months to 0.36 +/- 0.06 at 19 months and 0.38 +/- 0.04 at 28 months (n = 14). By contrast, the increase was graded with a 31-item clinical FI (0.02 +/- 0.005 at 5 months; 0.12 +/- 0.008 at 19 months; 0.33 +/- 0.02 at 28 months; n = 14). FI scores calculated from 70 self report items from the first wave of the Survey of Health, Ageing and Retirement in Europe were plotted as function of age (n = 30,025 people). The exponential relationship between FI scores and age (normalized to 90% mortality) was similar in mice and humans for the clinical FI but not the eight-item FI. This noninvasive FI based on clinical measures can be used in longitudinal studies to quantify frailty in mice. Unlike the performance-based eight-item mouse FI, the clinical FI exhibits key features of the FI established for use in humans. PMID- 24051348 TI - Fusion of 3D ultrasound images of the fetal femur improves boundary definition and volume measurement. AB - OBJECTIVE: To combine multiple 3D volumes of the same fetal femur into one composite image data set using image registration and wavelet-based fusion. Fused and single data sets were compared in terms of image quality and femur volume (FV) measurement repeatability. METHOD: In healthy pregnant volunteers, six volumes of the same femur were acquired and fused into a composite data set. Image quality scores were given to the fused and single data sets by an independent assessor in a blinded fashion; repeatability of FV measurement was assessed using coefficients of variation (CV), intraclass correlation coefficients (ICC) and Bland-Altman plots. RESULTS: Fusion was successful in 24 out of 25 cases. Median image quality score was 7/10 in fused data sets, compared to 6/10 in single data sets (p = 0.096). Repeatability of FV measurement was better in fused data sets (intraobserver CV 4.6% and ICC 0.987; interobserver CV 4.9%, ICC 0.985) compared to single ones (intraobserver CV 5.8%, ICC 0.977; interobserver CV 10.0%, ICC 0.931). The measured FV was significantly higher in fused data sets (mean FV 1.7 vs. 1.3 ml, p < 0.001). CONCLUSION: Image registration and wavelet-based fusion can improve image quality and FV repeatability; it also results in an increased FV measurement. PMID- 24051349 TI - A new analytical approach for monitoring microplastics in marine sediments. AB - A two-step method was developed to extract microplastics from sediments. First, 1 kg sediments was pre-extracted using the air-induced overflow (AIO) method, based on fluidisation in a sodium chloride (NaCl) solution. The original sediment mass was reduced by up to 80%. As a consequence, it was possible to reduce the volume of sodium iodide (NaI) solution used for the subsequent flotation step. Recoveries of the whole procedure for polyethylene, polypropylene (PP), polyvinyl chloride (PVC), polyethylene terephthalate (PET), polystyrene and polyurethane with sizes of approximately 1 mm were between 91 and 99%. After being stored for one week in a 35% H2O2 solution, 92% of selected biogenic material had dissolved completely or had lost its colour, whereas the tested polymers were resistant. Microplastics were extracted from three sediment samples collected from the North Sea island Norderney. Using pyrolysis gas chromatography/mass spectrometry, these microplastics were identified as PP, PVC and PET. PMID- 24051350 TI - Intravenous immunoglobulins: in-depth review of excipients and acute kidney injury risk. AB - BACKGROUND: Used in a variety of approved and off-label indications, there are several intravenous immunoglobulin (IVIG) preparations available which differ in the excipients (e.g. sucrose, glucose, maltose, D-sorbitol, glycine or L-proline) used to stabilize the protein in the solution. A very rare, but severe adverse drug reaction (ADR) reported with sucrose-stabilized IVIGs, acute renal failure, is well established, but the relative risks with sucrose-free IVIGs are unknown. METHODS: Medline and Embase were searched for published data on ADRs involving the kidney, and DrugCite, a public database of >4,000,000 ADRs from the USA, was also searched. Renal impairment-associated ADRs and categories were summarized. RESULTS: Compared with sucrose-containing IVIGs, reports of ADRs involving the kidney were relatively rare with sucrose-free IVIGs: 12 cases were published prior to February 28, 2012; incidences reported in DrugCite were also relatively low and similar among sucrose-free preparations. The incidence of hemolysis related ADRs, a potential cause of secondary acute renal impairment, was higher with glycine- and L-proline-stabilized IVIGs. Reported incidences of renal impairment with sucrose-free IVIGs are similar between products and much lower than with sucrose-stabilized IVIGs. CONCLUSIONS: It is recommended that the choice of IVIG should be guided by the patient's medical history, present comorbidities and concomitant medications. Prospective studies with inclusion of creatinine values, as well as rigorous reporting of cases in the literature and/or via pharmacovigilance systems, are imperative to better define patient profiles. PMID- 24051351 TI - Reduced olfactory bulb volume in adults with a history of childhood maltreatment. AB - The human olfactory bulb (OB) is the first relay station of the olfactory pathway and may have the potential for postnatal neurogenesis in early childhood. In animals, chronic stress affects the OB and olfactory functioning. For humans, it has been shown that major depressive disorder is accompanied by reduced OB volume and reduced olfactory function. However, it is not clear if major stress in childhood development also affects olfactory functioning and OB volume in humans. OB volume was measured and olfactory function was tested in 17 depressive patients with and 10 without a history of severe childhood maltreatment (CM). CM patients exhibited a significantly reduced olfactory threshold and identification ability. The OB volume of the CM patients was significantly reduced to 80% of the non-CM patients. In conclusion, postnatal neurogenesis might be by reduced in CM, which may affect olfactory function of the brain in later life. Alternatively, a reduced OB volume may enhance psychological vulnerability in the presence of adverse childhood conditions although other areas not analyzed in this study may also be involved. PMID- 24051356 TI - Evaluation of group-specific, whole-brain atlas generation using Volume-based Template Estimation (VTE): application to normal and Alzheimer's populations. AB - MRI-based human brain atlases, which serve as a common coordinate system for image analysis, play an increasingly important role in our understanding of brain anatomy, image registration, and segmentation. Study-specific brain atlases are often obtained from one of the subjects in a study or by averaging the images of all participants after linear or non-linear registration. The latter approach has the advantage of providing an unbiased anatomical representation of the study population. But, the image contrast is influenced by both inherent MR contrasts and residual anatomical variability after the registration; in addition, the topology of the brain structures cannot reliably be preserved. In this study, we demonstrated a population-based template-creation approach, which is based on Bayesian template estimation on a diffeomorphic random orbit model. This approach attempts to define a population-representative template without the cross-subject intensity averaging; thus, the topology of the brain structures is preserved. It has been tested for segmented brain structures, such as the hippocampus, but its validity on whole-brain MR images has not been examined. This paper validates and evaluates this atlas generation approach, i.e., Volume-based Template Estimation (VTE). Using datasets from normal subjects and Alzheimer's patients, quantitative measurements of sub-cortical structural volumes, metric distance, displacement vector, and Jacobian were examined to validate the group-averaged shape features of the VTE. In addition to the volume-based quantitative analysis, the preserved brain topology of the VTE allows surface-based analysis within the same atlas framework. This property was demonstrated by analyzing the registration accuracy of the pre- and post-central gyri. The proposed method achieved registration accuracy within 1mm for these population-preserved cortical structures in an elderly population. PMID- 24051357 TI - Auditory tracts identified with combined fMRI and diffusion tractography. AB - The auditory tracts in the human brain connect the inferior colliculus (IC) and medial geniculate body (MGB) to various components of the auditory cortex (AC). While in non-human primates and in humans, the auditory system is differentiated in core, belt and parabelt areas, the correspondence between these areas and anatomical landmarks on the human superior temporal gyri is not straightforward, and at present not completely understood. However it is not controversial that there is a hierarchical organization of auditory stimuli processing in the auditory system. The aims of this study were to demonstrate that it is possible to non-invasively and robustly identify auditory projections between the auditory thalamus/brainstem and different functional levels of auditory analysis in the cortex of human subjects in vivo combining functional magnetic resonance imaging (fMRI) with diffusion MRI, and to investigate the possibility of differentiating between different components of the auditory pathways (e.g. projections to areas responsible for sound, pitch and melody processing). We hypothesized that the major limitation in the identification of the auditory pathways is the known problem of crossing fibres and addressed this issue acquiring DTI with b-values higher than commonly used and adopting a multi-fibre ball-and-stick analysis model combined with probabilistic tractography. Fourteen healthy subjects were studied. Auditory areas were localized functionally using an established hierarchical pitch processing fMRI paradigm. Together fMRI and diffusion MRI allowed the successful identification of tracts connecting IC with AC in 64 to 86% of hemispheres and left sound areas with homologous areas in the right hemisphere in 86% of hemispheres. The identified tracts corresponded closely with a three-dimensional stereotaxic atlas based on postmortem data. The findings have both neuroscientific and clinical implications for delineation of the human auditory system in vivo. PMID- 24051358 TI - Distribution of MT1 melatonin receptor promoter-driven RFP expression in the brains of BAC C3H/HeN transgenic mice. AB - The pineal hormone melatonin activates two G-protein coupled receptors (MT1 and MT2) to regulate in part biological functions. The MT1 and MT2 melatonin receptors are heterogeneously distributed in the mammalian brain including humans. In the mouse, only a few reports have assessed the expression of the MT1 melatonin receptor expression using 2-iodomelatonin binding, in situ hybridization and/or polymerase chain reaction (PCR). Here, we described a transgenic mouse in which red fluorescence protein (RFP) is expressed under the control of the endogenous MT1 promoter, by inserting RFP cDNA at the start codon of MTNR1a gene within a bacterial artificial chromosome (BAC) and expressing this construct as a transgene. The expression of RFP in the brain of this mouse was examined either directly under a fluorescent microscope or immunohistochemically using an antibody against RFP (RFP-MT1). RFP-MT1 expression was observed in many brain regions including the subcommissural organ, parts of the ependyma lining the lateral and third ventricles, the aqueduct, the hippocampus, the cerebellum, the pars tuberalis, the habenula and the habenula commissure. This RFP-MT1 transgenic model provides a unique tool for studying the distribution of the MT1 receptor in the brain of mice, its cell-specific expression and its function in vivo. PMID- 24051361 TI - Evaluation of progression markers in the premotor phase of Parkinson's disease: the progression markers in the premotor phase study. AB - BACKGROUND: The clinical diagnosis of Parkinson's disease (PD) is proposed to be too late for the application of beneficial neuroprotective treatment. Thus, it is important to identify and follow individuals at risk for PD in order to gain knowledge about the prodromal course of the disease. Substantia nigra hyperechogenicity (SN+) has been confirmed as a risk factor for PD and appears promising as a predictor of PD, particularly in combination with other putative PD markers. We present the design and initial data of a 2-year longitudinal investigation of subjects proposed to be at high risk of developing PD (HRPD), compared to early PD patients and control subjects. The aim of the presented study is to monitor progression of the neurodegenerative process to motor PD. METHODS: In total, 40 HRPD, 16 PD and 41 control individuals were recruited. The HRPD subjects had SN+ and additionally either 1 cardinal PD motor sign or 2 further risk (e.g. positive family history) or prodromal markers (e.g. hyposmia). In this cohort, motor function, olfaction, mood and blood markers will be evaluated every 6 months, complemented by a comprehensive clinical, imaging and electrophysiological assessment. RESULTS: PD, HRPD and control subjects did not differ significantly regarding age, but the HRPD group consisted mainly of males (72.5% of HRPD subjects vs. 43.9% of controls; p = 0.013). Mean disease duration in PD patients was 31 months (range 15-56). HRPD subjects were predominantly recruited according to the occurrence of slight motor signs (HRPD 77.5%, PD 100%, p = 0.05; controls 0%, HRPD vs. controls, p < 0.017). The Unified Parkinson's Disease Rating Scale motor score (mean, range) indicated that the HRPD group (4, 0-12) had values between those of controls (0, 0-2; p < 0.017) and PD subjects (26, 9-55; p < 0.017). Among nonmotor symptoms, hyposmia was more common in both HRPD (47.5%) and PD subjects (75%) than in controls (5.1%; p < 0.017 for both comparisons). CONCLUSIONS: Here, we describe the recruitment of a highly enriched risk cohort and a promising study design to assess progression to motor PD. Whether the HRPD group indeed suffers from early, PD-specific neurodegeneration remains to be verified in the ongoing follow-up examinations. PMID- 24051362 TI - Acute inpatient treatment, hospitalization course and direct costs in bipolar patients with intellectual disability. AB - To explore the impacts of intellectual disability (ID) on psychotropic medication use, length of hospital stay (LOS) and direct hospitalization costs during inpatient treatment for acute bipolar episodes, all 17,899 index hospitalizations due to acute bipolar episodes between 1998 and 2007 in Taiwan were identified from a total population health insurance claims database, amongst which 544 subjects had a concomitant diagnosis of ID. Pattern of psychotropic medication use, LOS, discharge outcome and direct costs during hospitalization were compared between bipolar patients with ID and without ID and multivariate models controlling for major cost confounders were used to explore the impacts of ID on LOS, discharge outcome and inpatient costs. The results indicated that, compared to bipolar patients without ID, bipolar patients with ID were younger, had longer LOS and received significantly lower daily equivalent dosages of antipsychotics, mood stabilizers, lithium and benzodiazepines. Significantly more bipolar patients with ID could not be discharged successfully. The longer LOS possibly reflected slower clinical stabilization, conservative use of medications and difficulty in community placement. The lower average daily reimbursements indicated that treatment of bipolar patients with ID were under-funded, whereas the higher total direct costs resulting from prolonged LOS placed greater economic straint on healthcare system. The findings support that bipolar patients with ID are clinically unique but relatively under-supported during acute hospitalization. Modifying current pharmacological intervention, health care resources allocation and community supporting structure is paramount to reducing LOS and improving hospitalization outcome. PMID- 24051360 TI - ADAMTS-4 and biglycan are expressed at high levels and co-localize to podosomes during endothelial cell tubulogenesis in vitro. AB - Proteolysis of the extracellular matrix influences vascular growth. We examined the expression of ADAMTS-1, -4, and -5 metalloproteinases and their proteoglycan substrates versican, decorin, and biglycan as human umbilical vein endothelial cells (HUVECs) formed tubes within type I collagen gels in vitro. Tubulogenic and control HUVEC cultures expressed low levels of ADAMTS-1 and -5 mRNAs, but ADAMTS 4 mRNA was relatively abundant and was significantly elevated (as was ADAMTS-4 protein) in tubulogenic cultures versus controls. Immunocytochemistry revealed ADAMTS-4 in f-actin- and cortactin-positive podosome-like puncta in single cells and mature tubes. Tubulogenic and control cultures expressed low levels of versican and decorin mRNAs; however, peak levels of biglycan mRNA were 400- and 16,000-fold that of versican and decorin, respectively. Biglycan mRNA was highest at 3 hr, declined steadily through day 7 and, at 12 hr and beyond, was significantly lower in tubulogenic cultures than in controls. Western blots of extracellular matrix from tubulogenic cultures contained bands corresponding to biglycan and its cleavage products. By immunocytochemistry, biglycan was found in the pericellular matrix surrounding endothelial tubes and in cell-associated puncta that co-localized with ADAMTS-4 and cortactin. Collectively, our results suggest that ADAMTS-4 and its substrate biglycan are involved in tubulogenesis by endothelial cells. PMID- 24051359 TI - Histone deacetylases: a saga of perturbed acetylation homeostasis in cancer. AB - In the current era of genomic medicine, diseases are identified as manifestations of anomalous patterns of gene expression. Cancer is the principal example among such maladies. Although remarkable progress has been achieved in the understanding of the molecular mechanisms involved in the genesis and progression of cancer, its epigenetic regulation, particularly histone deacetylation, demands further studies. Histone deacetylases (HDACs) are one of the key players in the gene expression regulation network in cancer because of their repressive role on tumor suppressor genes. Higher expression and function of deacetylases disrupt the finely tuned acetylation homeostasis in both histone and non-histone target proteins. This brings about alterations in the genes implicated in the regulation of cell proliferation, differentiation, apoptosis and other cellular processes. Moreover, the reversible nature of epigenetic modulation by HDACs makes them attractive targets for cancer remedy. This review summarizes the current knowledge of HDACs in tumorigenesis and tumor progression as well as their contribution to the hallmarks of cancer. The present report also describes briefly various assays to detect histone deacetylase activity and discusses the potential role of histone deacetylase inhibitors as emerging epigenetic drugs to cure cancer. PMID- 24051363 TI - Psychological therapies for people with intellectual disabilities: a systematic review and meta-analysis. AB - The aim of this study was to evaluate the efficacy of psychological therapies for people with intellectual disabilities (IDs) through a systematic review and meta analysis of the current literature. A comprehensive literature search identified 143 intervention studies. Twenty-two trials were eligible for review, and 14 of these were subsequently included in the meta-analysis. Many studies did not include adequate information about their participants, especially the nature of their IDs; information about masked assessment, and therapy fidelity was also lacking. The meta-analysis yielded an overall moderate between-group effect size, g=.682, while group-based interventions had a moderate but smaller treatment effect than individual-based interventions. Cognitive-behaviour therapy (CBT) was efficacious for both anger and depression, while interventions aimed at improving interpersonal functioning were not effectual. When CBT was excluded, there was insufficient evidence regarding the efficacy of other psychological therapies, or psychological therapies intended to treat mental health problems in children and young people with IDs. Adults with IDs and concurrent mental health problems appear to benefit from psychological therapies. However, clinical trials need to make use of improved reporting standards and larger samples. PMID- 24051364 TI - Young children with language difficulties: a dimensional approach to subgrouping. AB - A dimensional approach was used to create bottom-up constructed subgroups that captured the behavioral heterogeneity in 36 Dutch-speaking children with language difficulties. Four subgroups were delineated based upon differences in cognitive ability, symbol understanding, joint attention and autism spectrum disorder related characteristics. Children with a different developmental disorder were found within a single cluster. Therefore, the results of this study suggest that bottom-up constructed subgroups might capture the heterogeneous behavioral profiles of young children with developmental difficulties in a more meaningful way. Furthermore, joint attention and symbol understanding seem important skills to assess in young children presenting with language difficulties. PMID- 24051366 TI - A macroscopic view of microstructure: using diffusion-weighted images to infer damage, repair, and plasticity of white matter. AB - Since its introduction in the early 1990s, diffusion-weighted magnetic resonance imaging (MRI) has played a crucial role in the non-invasive evaluation of tissue microstructure of brain parenchyma in vivo. Diffusion anisotropy, in particular, has been extensively used to infer histological changes due to brain maturation and pathology, as it shows a clear dependence on tissue architecture. Although the resolution used in most studies lies in the macroscopic range, the information provided originates at the microscopic level and, as such, diffusion MRI serves as a microscope that can reveal profound details of tissue with direct clinical and research applications. The interpretation of diffusion parameters of white matter rests on what is known to drive diffusion anisotropy, namely axonal membranes, density and coherence, as well as myelin sheaths. However, these factors interact to modulate anisotropy, making interpretations potentially difficult. While there are numerous publications that report diffusion changes in response to particular, histologically confirmed tissue abnormalities in animal models of disease, the microscopic correlates of altered diffusion parameters due to neurological disorders in humans have been difficult to characterize. Animal models may provide insight into the mechanisms involved, but do not necessarily provide accurate representations of the human condition, making human diffusion MRI studies with direct histological confirmation crucial for our understanding of tissue changes secondary to neurodevelopment and disease. This work provides a synopsis of tissue characteristics that give rise to highly informative, specific diffusion patterns, and also of how methodological and artifactual aspects can provide erroneous diffusion measurements that do not accurately reflect tissue and may lead to misinterpretation of results. Examples of diffusion changes due to human conditions are provided to illustrate the wealth of applications of diffusion MRI in clinical and research fields. PMID- 24051365 TI - Visualizing epigenetics: current advances and advantages in HDAC PET imaging techniques. AB - Abnormal gene regulation as a consequence of flawed epigenetic mechanisms may be central to the initiation and persistence of many human diseases. However, the association of epigenetic dysfunction with disease and the development of therapeutic agents for treatment are slow. Developing new methodologies used to visualize chromatin-modifying enzymes and their function in the human brain would be valuable for the diagnosis of brain disorders and drug discovery. We provide an overview of current invasive and noninvasive techniques for measuring expression and functions of chromatin-modifying enzymes in the brain, emphasizing tools applicable to histone deacetylase (HDAC) enzymes as a leading example. The majority of current techniques are invasive and difficult to translate to what is happening within a human brain in vivo. However, recent progress in molecular imaging provides new, noninvasive ways to visualize epigenetics in the human brain. Neuroimaging tool development presents a unique set of challenges in order to identify and validate CNS radiotracers for HDACs and other histone-modifying enzymes. We summarize advances in the effort to image HDACs and HDAC inhibitory effects in the brain using positron emission tomography (PET) and highlight generalizable techniques that can be adapted to investigate other specific components of epigenetic machinery. Translational tools like neuroimaging by PET and magnetic resonance imaging provide the best way to link our current understanding of epigenetic changes with in vivo function in normal and diseased brains. These tools will be a critical addition to ex vivo methods to evaluate - and intervene - in CNS dysfunction. PMID- 24051367 TI - Are economic recessions at the time of leaving school associated with worse physical functioning in later life? AB - PURPOSE: To examine whether economic conditions at the time of leaving school or college are associated with physical functioning in later life among cohorts in 11 European countries. METHODS: Data came from 10,338 participants in the Survey of Health, Ageing and Retirement in Europe (SHARE) aged 50-74 who left school or college between 1956 and 1986. Data on functional limitations, as well as employment, marriage, and fertility retrospective histories were linked to national unemployment rates during the year individuals left school. Models included country-fixed effects and controls for early-life circumstances. RESULTS: Greater unemployment rates during the school-leaving year were associated with fewer functional limitations at ages 50-74 among men (rate ratio 0.63, 95% confidence interval 0.47-0.83), but more physical functioning limitations among women (rate ratio 1.30, 95% confidence interval 1.13-1.50), particularly among those with (post-)secondary education. Economic conditions at the age of leaving school were associated with several labor market, marriage, fertility, and health behavior outcomes, but controlling for these factors did not attenuate associations. Results were similar in models that controlled for selection into higher education due to measured covariates. CONCLUSIONS: Worse economic conditions during the school-leaving year predicted better health at later life among men but worse health among women. Both selection and causation mechanisms may explain this association. PMID- 24051368 TI - Function and regulation of serine/threonine phosphatases in the healthy and diseased heart. AB - Protein phosphorylation is a major control mechanism of a wide range of physiological processes and plays an important role in cardiac pathophysiology. Serine/threonine protein phosphatases control the dephosphorylation of a variety of cardiac proteins, thereby fine-tuning cardiac electrophysiology and function. Specificity of protein phosphatases type-1 and type-2A is achieved by multiprotein complexes that target the catalytic subunits to specific subcellular domains. Here, we describe the composition, regulation and target substrates of serine/threonine phosphatases in the heart. In addition, we provide an overview of pharmacological tools and genetic models to study the role of cardiac phosphatases. Finally, we review the role of protein phosphatases in the diseased heart, particularly in ventricular arrhythmias and atrial fibrillation and discuss their role as potential therapeutic targets. PMID- 24051369 TI - Role of NADPH oxidase isoforms NOX1, NOX2 and NOX4 in myocardial ischemia/reperfusion injury. AB - Myocardial reperfusion injury is mediated by several processes including increase of reactive oxygen species (ROS). The aim of the study is to identify potential sources of ROS contributing to myocardial ischemia-reperfusion injury. For this purpose, we investigated myocardial ischemia/reperfusion pathology in mice deficient in various NADPH oxidase isoforms (Nox1, Nox2, Nox4, as well as Nox1/2 double knockout). Following 30min of ischemia and 24h of reperfusion, a significant decrease in the size of myocardial infarct was observed in Nox1-, Nox2- and Nox1/Nox2-, but not in Nox4-deficient mice. However, no protection was observed in a model of chronic ischemia, suggesting that NOX1 and NOX2-mediated oxidative damage occurs during reperfusion. Cardioprotective effect of Nox1 and Nox2 deficiencies was associated with decrease of neutrophil invasion, but, on the other hand an improved reperfusion injury was also observed in isolated perfused hearts (Langendorff model) suggesting that inflammatory cells were not the major source of oxidative damage. A decrease in global post-reperfusion oxidative stress was clearly detected in Nox2-, but not in Nox1-deficient hearts. Analysis of key signaling pathways during reperfusion suggests distinct cardioprotective patterns: increased phosphorylation was seen for Akt and Erk in Nox1-deficient mice and for Stat3 and Erk in Nox2-deficient mice. Consequently, NOX1 and NOX2 represent interesting drug targets for controlling reperfusion damage associated with revascularization in coronary disease. PMID- 24051370 TI - Preservation of cardiomyocytes from the adult heart. AB - Cardiomyocytes represent one of the most useful models to conduct cardiac research. A single adult heart yields millions of cardiomyocytes, but these cells do not survive for long after isolation. We aimed to determine whether inhibition of myosin II ATPase that is essential for muscle contraction may preserve fully differentiated adult cardiomyocytes. Using inhibitors of the myosin II ATPase, blebbistatin and N-benzyl-p-toluene sulphonamide (BTS), we preserved freshly isolated fully differentiated adult primary cardiomyocytes that were stored at a refrigerated temperature. Specifically, preserved cardiomyocytes stayed viable for a 2-week period with a stable expression of cardiac genes and retained the expression of key markers characteristic of cardiomyocytes. Furthermore, voltage clamp, action potential, calcium transient and contractility studies confirmed that the preserved cardiomyocytes are comparable to freshly isolated cells. Long term exposure of preserved cardiomyocytes to four tyrosine kinase inhibitors, sunitinib malate, dasatinib, sorafenib tosylate and imatinib mesylate, revealed their potential to induce cardiac toxicity that was manifested with a decrease in contractility and induction of cell death, but this toxicity was not observed in acute experiments conducted over the time course amenable to freshly prepared cardiomyocytes. This study introduces the concept that the inhibition of myosin II ATPase safeguards the structure and function of fully differentiated adult cardiomyocytes. The fact that these preserved cardiomyocytes can be used for numerous days after preparation makes them a robust and versatile tool in cardiac research and allows the investigation of long-term exposure to novel drugs on cardiomyocyte function. PMID- 24051371 TI - REEPing the benefits of an animal model of hereditary spastic paraplegia. AB - The hereditary spastic paraplegias (HSPs) are characterized by spasticity of the leg muscles due to axonal degeneration of corticospinal neurons. Beetz et al. report that the core motor phenotype and axonal pathology of HSPs are recapitulated in mice lacking the HSP-associated gene Reep1. REEP1 is shown to regulate ER structure in motor cortex neurons. The Reep1 knockout mouse should be a very useful model in which to study the mechanisms of progressive axon loss in HSPs and other disorders. PMID- 24051372 TI - Common variable immunodeficiency: two mutations are better than one. AB - B cells from common variable immunodeficiency (CVID) patients who have one mutant copy of the gene encoding the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) often display dysfunctional antibody production. Interestingly, some individuals with mutations in both TACI alleles do not present with CVID, suggesting that TACI mutations influence CVID pathogenesis via dominant interference or haploinsufficiency. In this issue of the JCI, Romberg and colleagues report how TACI mutations impact B cell activation, removal of autoreactive B cells, and the development of autoimmune disease in CVID. PMID- 24051373 TI - Zinc, insulin, and the liver: a menage a trois. AB - Insulin and Zn2+ enjoy a multivalent relationship. Zn2+ binds insulin in pancreatic beta cells to form crystalline aggregates in dense core vesicles (DCVs), which are released in response to physiological signals such as increased blood glucose. This transition metal is an essential cofactor in insulin degrading enzyme and several key Zn2+ finger transcription factors that are required for beta cell development and insulin gene expression. Studies are increasingly revealing that fluctuations in Zn2+ concentration can mediate signaling events, including dynamic roles that extend beyond that of a static structural or catalytic cofactor. In this issue of the JCI, Tamaki et al. propose an additional function for Zn2+ in relation to insulin: regulation of insulin clearance from the bloodstream. PMID- 24051374 TI - Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects. AB - Circulating pancreatic glucagon is increased during fasting and maintains glucose balance by stimulating hepatic gluconeogenesis. Glucagon triggering of the cAMP pathway upregulates the gluconeogenic program through the phosphorylation of cAMP response element-binding protein (CREB) and the dephosphorylation of the CREB coactivator CRTC2. Hormonal and nutrient signals are also thought to modulate gluconeogenic gene expression by promoting epigenetic changes that facilitate assembly of the transcriptional machinery. However, the nature of these modifications is unclear. Using mouse models and in vitro assays, we show that histone H3 acetylation at Lys 9 (H3K9Ac) was elevated over gluconeogenic genes and contributed to increased hepatic glucose production during fasting and in diabetes. Dephosphorylation of CRTC2 promoted increased H3K9Ac through recruitment of the lysine acetyltransferase 2B (KAT2B) and WD repeat-containing protein 5 (WDR5), a core subunit of histone methyltransferase (HMT) complexes. KAT2B and WDR5 stimulated the gluconeogenic program through a self-reinforcing cycle, whereby increases in H3K9Ac further potentiated CRTC2 occupancy at CREB binding sites. Depletion of KAT2B or WDR5 decreased gluconeogenic gene expression, consequently breaking the cycle. Administration of a small-molecule KAT2B antagonist lowered circulating blood glucose concentrations in insulin resistance, suggesting that this enzyme may be a useful target for diabetes treatment. PMID- 24051375 TI - A spastic paraplegia mouse model reveals REEP1-dependent ER shaping. AB - Axonopathies are a group of clinically diverse disorders characterized by the progressive degeneration of the axons of specific neurons. In hereditary spastic paraplegia (HSP), the axons of cortical motor neurons degenerate and cause a spastic movement disorder. HSP is linked to mutations in several loci known collectively as the spastic paraplegia genes (SPGs). We identified a heterozygous receptor accessory protein 1 (REEP1) exon 2 deletion in a patient suffering from the autosomal dominantly inherited HSP variant SPG31. We generated the corresponding mouse model to study the underlying cellular pathology. Mice with heterozygous deletion of exon 2 in Reep1 displayed a gait disorder closely resembling SPG31 in humans. Homozygous exon 2 deletion resulted in the complete loss of REEP1 and a more severe phenotype with earlier onset. At the molecular level, we demonstrated that REEP1 is a neuron-specific, membrane-binding, and membrane curvature-inducing protein that resides in the ER. We further show that Reep1 expression was prominent in cortical motor neurons. In REEP1-deficient mice, these neurons showed reduced complexity of the peripheral ER upon ultrastructural analysis. Our study connects proper neuronal ER architecture to long-term axon survival. PMID- 24051376 TI - Renal beta-intercalated cells maintain body fluid and electrolyte balance. AB - Inactivation of the B1 proton pump subunit (ATP6V1B1) in intercalated cells (ICs) leads to type I distal renal tubular acidosis (dRTA), a disease associated with salt- and potassium-losing nephropathy. Here we show that mice deficient in ATP6V1B1 (Atp6v1b1-/- mice) displayed renal loss of NaCl, K+, and water, causing hypovolemia, hypokalemia, and polyuria. We demonstrated that NaCl loss originated from the cortical collecting duct, where activity of both the epithelial sodium channel (ENaC) and the pendrin/Na(+)-driven chloride/bicarbonate exchanger (pendrin/NDCBE) transport system was impaired. ENaC was appropriately increased in the medullary collecting duct, suggesting a localized inhibition in the cortex. We detected high urinary prostaglandin E2 (PGE2) and ATP levels in Atp6v1b1-/- mice. Inhibition of PGE2 synthesis in vivo restored ENaC protein levels specifically in the cortex. It also normalized protein levels of the large conductance calcium-activated potassium channel and the water channel aquaporin 2, and improved polyuria and hypokalemia in mutant mice. Furthermore, pharmacological inactivation of the proton pump in beta-ICs induced release of PGE2 through activation of calcium-coupled purinergic receptors. In the present study, we identified ATP-triggered PGE2 paracrine signaling originating from beta ICs as a mechanism in the development of the hydroelectrolytic imbalance associated with dRTA. Our data indicate that in addition to principal cells, ICs are also critical in maintaining sodium balance and, hence, normal vascular volume and blood pressure. PMID- 24051377 TI - Disruption of CEP290 microtubule/membrane-binding domains causes retinal degeneration. AB - Mutations in the gene centrosomal protein 290 kDa (CEP290) cause an array of debilitating and phenotypically distinct human diseases, ranging from the devastating blinding disease Leber congenital amaurosis (LCA) to Senior-Loken syndrome, Joubert syndrome, and the lethal Meckel-Gruber syndrome. Despite its critical role in biology and disease, very little is known about CEP290's function. Here, we have identified 4 functional domains of the protein. We found that CEP290 directly binds to cellular membranes through an N-terminal domain that includes a highly conserved amphipathic helix motif and to microtubules through a domain located within its myosin-tail homology domain. Furthermore, CEP290 activity was regulated by 2 autoinhibitory domains within its N and C termini, both of which were found to play critical roles in regulating ciliogenesis. Disruption of the microtubule-binding domain in a mouse model of LCA was sufficient to induce significant deficits in cilium formation, which led to retinal degeneration. These data implicate CEP290 as an integral structural and regulatory component of the cilium and provide insight into the pathological mechanisms of LCA and related ciliopathies. Further, these data illustrate that disruption of particular CEP290 functional domains may lead to particular disease phenotypes and suggest innovative strategies for therapeutic intervention. PMID- 24051378 TI - The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. AB - Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive. In this study, we generated mice with beta cell-specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance. The ZnT8KO mice had low peripheral blood insulin levels, despite insulin hypersecretion from pancreatic beta cells. We also demonstrated that a substantial amount of the hypersecreted insulin was degraded during its first passage through the liver. Consistent with these findings, ZnT8KO mice and human individuals carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as assessed by c peptide/insulin ratio. Furthermore, we demonstrated that zinc secreted in concert with insulin suppressed hepatic insulin clearance by inhibiting clathrin dependent insulin endocytosis. Our results indicate that SLC30A8 regulates hepatic insulin clearance and that genetic dysregulation of this system may play a role in the pathogenesis of type 2 diabetes. PMID- 24051379 TI - A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis. AB - The embryonic self-renewal factor SALL4 has been implicated in the development of human acute myeloid leukemia (AML). Transgenic mice expressing the human SALL4B allele develop AML, which indicates that this molecule contributes to leukemia development and maintenance. However, the underlying mechanism of SALL4-dependent AML progression is unknown. Using SALL4B transgenic mice, we observed that HoxA9 was significantly upregulated in SALL4B leukemic cells compared with wild-type controls. Downregulation of HoxA9 in SALL4B leukemic cells led to decreased replating capacity in vitro and delayed AML development in recipient mice. In primary human AML cells, downregulation of SALL4 led to decreased HOXA9 expression and enhanced apoptosis. We found that SALL4 bound a specific region of the HOXA9 promoter in leukemic cells. SALL4 overexpression led to enhanced binding of histone activation markers at the HOXA9 promoter region, as well as increased HOXA9 expression in these cells. Furthermore, we observed that SALL4 interacted with mixed-lineage leukemia (MLL) and co-occupied the HOXA9 promoter region with MLL in AML leukemic cells, which suggests that a SALL4/MLL pathway may control HOXA9 expression. In summary, our findings revealed a molecular mechanism for SALL4 function in leukemogenesis and suggest that targeting of the SALL4/MLL/HOXA9 pathway would be an innovative approach in treating AML. PMID- 24051380 TI - CVID-associated TACI mutations affect autoreactive B cell selection and activation. AB - Common variable immune deficiency (CVID) is an assorted group of primary diseases that clinically manifest with antibody deficiency, infection susceptibility, and autoimmunity. Heterozygous mutations in the gene encoding the tumor necrosis factor receptor superfamily member TACI are associated with CVID and autoimmune manifestations, whereas two mutated alleles prevent autoimmunity. To assess how the number of TACI mutations affects B cell activation and tolerance checkpoints, we analyzed healthy individuals and CVID patients carrying one or two TACI mutations. We found that TACI interacts with the cleaved, mature forms of TLR7 and TLR9 and plays an important role during B cell activation and the central removal of autoreactive B cells in healthy donors and CVID patients. However, only subjects with a single TACI mutation displayed a breached immune tolerance and secreted antinuclear antibodies (ANAs). These antibodies were associated with the presence of circulating B cell lymphoma 6-expressing T follicular helper (Tfh) cells, likely stimulating autoreactive B cells. Thus, TACI mutations may favor CVID by altering B cell activation with coincident impairment of central B cell tolerance, whereas residual B cell responsiveness in patients with one, but not two, TACI mutations enables autoimmune complications. PMID- 24051382 TI - Opening lines of communication in the distal nephron. AB - The distal nephron is composed of two main cell types: principal cells and intercalated cells. These cells have distinct morphologic features that allow them to be readily distinguished by light microscopy, as well as distinct suites of proteins that facilitate cell-specific transport properties. In this issue of the JCI, Gueutin and colleagues describe a new mechanism by which beta intercalated cells, via release of ATP and prostaglandin E2 (PGE2), influence the activity of transporters in principal cells. PMID- 24051383 TI - Multiple chemical sensitivity in pregnancy: an unclassified rare syndrome. PMID- 24051381 TI - Dendritic epidermal T cells regulate skin antimicrobial barrier function. AB - The epidermis, the outer layer of the skin, forms a physical and antimicrobial shield to protect the body from environmental threats. Skin injury severely compromises the epidermal barrier and requires immediate repair. Dendritic epidermal T cells (DETC) reside in the murine epidermis where they sense skin injury and serve as regulators and orchestrators of immune responses. Here, we determined that TCR stimulation and skin injury induces IL-17A production by a subset of DETC. This subset of IL-17A-producing DETC was distinct from IFN-gamma producers, despite similar surface marker profiles. Functionally, blocking IL-17A or genetic deletion of IL-17A resulted in delayed wound closure in animals. Skin organ cultures from Tcrd-/-, which lack DETC, and Il17a-/- mice both exhibited wound-healing defects. Wound healing was fully restored by the addition of WT DETC, but only partially restored by IL-17A-deficient DETC, demonstrating the importance of IL-17A to wound healing. Following skin injury, DETC-derived IL-17A induced expression of multiple host-defense molecules in epidermal keratinocytes to promote healing. Together, these data provide a mechanistic link between IL 17A production by DETC, host-defense, and wound-healing responses in the skin. These findings establish a critical and unique role of IL-17A-producing DETC in epidermal barrier function and wound healing. PMID- 24051384 TI - Effect of an automatic triggering and cycling system on comfort and patient ventilator synchrony during pressure support ventilation. AB - BACKGROUND: The digital Auto-TrakTM system is a technology capable of automatically adjusting the triggering and cycling mechanisms during pressure support ventilation (PSV). OBJECTIVE: To compare Auto-Trak with conventional settings in terms of patient-ventilator synchrony and discomfort. METHODS: Twelve healthy volunteers underwent PSV via the mouth by breathing through an endotracheal tube. In the conventional setting, a pressure support of 8 cm H2O with flow cycling (25% peak inspiratory flow) and a sensitivity of 1 cm H2O was adjusted. In Auto-Trak the triggering and cycling were automatically set. Discomfort, effort of breathing, and the asynchrony index (AI) were assessed. In a complementary bench study, the inspiratory and expiratory time delays were quantified for both settings in three mechanical models: 'normal', obstructive (COPD), and restrictive (ARDS), using the ASL 5000 simulator. RESULTS: In the volunteer study the AI and the discomfort scores did not differ statistically between the two settings. In the bench investigation the use of Auto-Trak was associated with a greater triggering delay in the COPD model and earlier expiratory cycling in the ARDS model but with no asynchronic events. CONCLUSIONS: Use of the Auto-Trak system during PSV showed similar results in comparison to the conventional adjustments with respect to patient-ventilator synchrony and discomfort in simulated conditions of invasive mechanical ventilation. PMID- 24051385 TI - Fetal red blood cell parameters in thalassemia and hemoglobinopathies. AB - INTRODUCTION: With the lack of fetal blood specimens in routine practice, little is known about red blood cell (RBC) parameters of fetuses with various thalassemia syndromes. This study aimed to describe these in various forms of thalassemia. MATERIALS AND METHODS: The study was performed on 93 fetal blood specimens obtained from pregnant women by cordocentesis during 18-24 weeks of gestation. RBC parameters were recorded on automated analyzer. Hemoglobin (Hb) and DNA analyses were performed for definite genotyping. RESULTS: No significant difference in RBC parameters was observed between non-thalassemic fetuses and those with beta-thalassemia trait, Hb E trait, homozygous Hb E and beta thalassemia/Hb E disease. However, in those with alpha(0)-thalassemia trait and double heterozygous alpha(0)-thalassemia/Hb E, slight reduction in mean corpuscular volume (MCV) was noted. Fetuses with the Hb H disease showed significant reductions in Hb, MCV and mean corpuscular Hb (MCH). Marked reductions in Hb, hematocrit, MCH and mean cell Hb concentration and increased RBC distribution width with numerous nucleated RBC were clearly observed in Hb Bart's hydrops fetalis. CONCLUSION: Simple analysis of fetal RBC parameters is useful for making presumptive prenatal diagnosis of alpha-thalassemia syndromes including Hb H disease and Hb Bart's hydrops fetalis which can then be confirmed by Hb and DNA analyses. PMID- 24051386 TI - Dietary folate intake and blood biomarkers reveal high-risk groups in a Mediterranean population of healthy women of childbearing potential. AB - BACKGROUND/AIMS: An important public health issue is monitoring folate inadequacy in women of childbearing potential. The aim of the present study was to investigate associations between folate intake, red blood cell (RBC) folate, total homocysteine (tHcy) and the MTHFR 677T allele. METHODS: A total of 204 women were enrolled in a cross-sectional study. Folate intake was assessed by a food frequency questionnaire, and RBC folate, tHcy and MTHFR C677T genotype were determined. RESULTS: About half of the women had a decreased RBC folate level (<305 nmol/l) and all were <906 nmol/l, even though 51% of the subjects reported use of supplements. Overall 91.5% had a high Hcy concentration. Notably, younger women, and those with a low level of education, were shown to be at higher risk of inadequate RBC folate levels. Additionally, younger women were also at higher risk of carrying the TT genotype, particularly unfavorable in the setting of a low folate status. CONCLUSIONS: Our study revealed significant folate deficiency in our Mediterranean population and higher than ideal Hcy concentrations, thus emphasizing that in these groups an improvement in the folate status is needed via a food-based approach or supplement. Consequently, public health policy strategies aiming at improved supplementation are required. PMID- 24051387 TI - Human vaccines & immunotherapeutics: news. AB - Vaccinating boys against HPV to reduce cancer rates across the sexes: New melanoma vaccine contains natural product from marine sponges: Impact of Hib conjugate vaccines in developing countries: Electronic Health Records to keep track of immunization status: Pregnant women urged to get whooping cough vaccination: New nano-coating developed to preserve vaccines: Alternative approach to creating a universal flu vaccine: New modular vaccine design: MAPS technology. PMID- 24051388 TI - Intrathecal substance P-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation. AB - BACKGROUND: Neurokinin-1 receptors (NK1-rs) located on superficial dorsal horn neurons are essential for integration of nociceptive input. Intrathecal injection of substance P-saporin (SP-SAP) leads to local loss of spinal NK1-r (+) neurons suggesting its potential as a therapeutic agent for chronic pain. The authors determined, in a canine model, effects of lumbar intrathecal SP-SAP. METHODS: Distribution of SP-SAP and Saporin was determined in plasma, lumbar cerebrospinal fluid, and tissue. Safety of intrathecal SP-SAP was determined in four groups (six dogs each) administered 0 (0.9% saline), 1.5, 15, or 150 ug SP-SAP through lumbar intrathecal catheters. Behavioral, physiologic, and biochemical variables were assessed. Spinal tissues were collected at 7 and approximately 90 days, or earlier if significant morbidity developed, and analyzed for NK1-r (+) neuron loss and histopathology. RESULTS: SP-SAP and Saporin were detectable in lumbar cerebrospinal fluid for up to 4 and 24 h, respectively. Animals receiving intrathecal saline, 1.5, or 15 ug of SP-SAP showed no persistent neurologic deficits. Three animals receiving 150 ug of SP-SAP developed pelvic limb paraparesis and were euthanized prematurely. Immunohistochemistry and in situ hybridization cell counts confirmed a significant reduction in NK1-r (+) in superficial dorsal horn neurons from lumbar spinal cord after intrathecal administration of 15 and 150 ug of SP-SAP. A significant loss of NK1-r neurons in the lumbar ventral horn occurred only with 150-ug SP-SAP. CONCLUSION: Intrathecal 15-ug SP-SAP reduced dorsal, but not ventral, NK1-r (+) neurons at the spinal level of delivery with minimal side effects, whereas 150-ug SP-SAP resulted in motor neuron toxicity. PMID- 24051389 TI - Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. PMID- 24051390 TI - Case scenario: residual curarization in diabetic polyneuropathy. PMID- 24051391 TI - Comparison of the potency of different propofol formulations: a randomized, double-blind trial using closed-loop administration. AB - BACKGROUND: Several commercial formulations of propofol are available. The primary outcome of this study was the required dose of propofol alone or combined with lidocaine to achieve induction of general anesthesia. METHODS: This multicenter, double-blinded trial randomized patients (American Society of Anesthesiologists physical status I-III) just before elective surgery with the use of a computer-generated list. Three different propofol 1% formulations Diprivan (Astra-Zeneca, Cheshire, United Kingdom), Propoven (Fresenius-Kabi AG, Bad Homburg, Germany), and Lipuro (B-Braun, Melshungen AG, Germany)-were compared with either placebo (saline solution) or lidocaine 1% mixed to the propofol solution. Depth of anesthesia was automatically guided by bispectral index and by a computerized closed-loop system for induction, thus avoiding dosing bias. The authors recorded the total dose of propofol and duration of induction and the patient's discomfort through a behavioral scale (facial expression, verbal response, and arm withdrawal) ranging from 0 to 6. The authors further evaluated postoperative recall of pain using a Visual Analog Scale. RESULTS: Of the 227 patients enrolled, 217 were available for analysis. Demographic characteristics were similar in each group. Propoven required a higher dose for induction (2.2 +/ 0.1 mg/kg) than Diprivan (1.8 +/- 0.1 mg/kg) or Lipuro (1.7 +/- 0.1 mg/kg; P = 0.02). However, induction doses were similar when propofol formulations were mixed with lidocaine. Patient discomfort during injection was significantly reduced with lidocaine for every formulation: Diprivan (0.5 +/- 0.3 vs. 2.3 +/- 0.3), Propoven (0.4 +/- 0.3 vs. 2.4 +/- 0.3), and Lipuro (1.1 +/- 0.3 vs. 1.4 +/- 0.3), all differences significant, with P < 0.0001. No adverse effect was reported. CONCLUSION: Plain propofol formulations are not equipotent, but comparable doses were required when lidocaine was concomitantly administered. PMID- 24051392 TI - Lung [(18)F]fluorodeoxyglucose uptake and ventilation-perfusion mismatch in the early stage of experimental acute smoke inhalation. AB - BACKGROUND: Acute lung injury occurs in a third of patients with smoke inhalation injury. Its clinical manifestations usually do not appear until 48-72 h after inhalation. Identifying inflammatory changes that occur in pulmonary parenchyma earlier than that could provide insight into the pathogenesis of smoke-induced acute lung injury. Furthermore, noninvasive measurement of such changes might lead to earlier diagnosis and treatment. Because glucose is the main source of energy for pulmonary inflammatory cells, the authors hypothesized that its pulmonary metabolism is increased shortly after smoke inhalation, when classic manifestations of acute lung injury are not yet expected. METHODS: In five sheep, the authors induced unilateral injury with 48 breaths of cotton smoke while the contralateral lung served as control. The authors used positron emission tomography with: (1) [F]fluorodeoxyglucose to measure metabolic activity of pulmonary inflammatory cells; and (2) [N]nitrogen in saline to measure shunt and ventilation-perfusion distributions separately in the smoke-exposed and control lungs. RESULTS: The pulmonary [F]fluorodeoxyglucose uptake rate was increased at 4 h after smoke inhalation (mean +/- SD: 0.0031 +/- 0.0013 vs. 0.0026 +/- 0.0010 min; P < 0.05) mainly as a result of increased glucose phosphorylation. At this stage, there was no worsening in lung aeration or shunt. However, there was a shift of perfusion toward units with lower ventilation-to-perfusion ratio (mean ratio +/- SD: 0.82 +/- 0.10 vs. 1.12 +/- 0.02; P < 0.05) and increased heterogeneity of the ventilation-perfusion distribution (mean +/- SD: 0.21 +/- 0.07 vs. 0.13 +/- 0.01; P < 0 .05). CONCLUSION: Using noninvasive imaging, the authors demonstrated that increased pulmonary [F]fluorodeoxyglucose uptake and ventilation-perfusion mismatch occur early after smoke inhalation. PMID- 24051393 TI - A simple and reliable method for distinguishing danshen in salvia: simultaneous quantification of six active compositions by HPLC. AB - A simple and reliable method for distinguishing Danshen is important to evaluate the quality and clinical efficiency of these species. An HPLC method was developed for the determination of protocatechuic aldehyde, salvianolic acid A, salvianolic acid B, cryptotanshinone, tanshinone I and tanshinone IIA in 23 samples of Salvia. The analytes were separated on an Agilent XDB C18 reversed phase column coupled with a Phenomenex C18 guard column using a gradient elution of acetonitile-0.1% aqueous phosphoric acid as the mobile phase at a flow rate 0.8 mL/min and UV detection at 280 nm. The method allowing the simultaneous quantification of six major active compositions was optimized and validated for linearity, precision, accuracy and limits of detection (LOD) and quantification. The LOD ranged from 0.019 to 0.850 ug/mL (R(2) >= 0.9998). Accuracy, precision and reproducibility were all within the required limits. The average recovery between 96.49 and 102.16% and the relative standard deviations were <3.01%. Based on the six compositions content and clustering result, this research results suggest that these six major active compositions could be distinguishing markers for Danshen and non-Danshen. PMID- 24051394 TI - Comments on a recent article on meteorological and intelligence evidence of long distance transit of chemical weapons fallout from bombing early in the 1991 Persian Gulf War. PMID- 24051395 TI - Modulating GPR40: therapeutic promise and potential in diabetes. AB - The class A G-protein-coupled receptor GPR40 is predominantly expressed in pancreatic beta cells and plays a major part in fatty acid amplification of glucose-induced insulin secretion. GPR40 agonists are being developed for the treatment of type 2 diabetes. Preclinical studies have shown that GPR40 activation improves glucose control, and recent Phase II trials provided proof-of concept for this approach. The pharmacology of GPR40 is only partially understood but recent findings suggest that full agonism of the receptor could, in addition to stimulating insulin release, engage the enteroinsular axis. Much remains to be discovered regarding the biology of the receptor to inform the development of GPR40-based drugs. PMID- 24051396 TI - The development speed paradox: can increasing development speed reduce R&D productivity? AB - In the 1990s the pharmaceutical industry sought to increase R&D productivity by shifting development tasks into parallel to reduce development cycle times and increase development speed. This paper presents a simple model demonstrating that, when attrition rates are high as in pharmaceutical development, such development speed initiatives can increase the expected time for the first successful molecule to complete development. Increasing the development speed of successful molecules could actually reduce R&D productivity - the development speed paradox. PMID- 24051398 TI - Phage display as a technology delivering on the promise of peptide drug discovery. AB - Phage display represents an important approach in the development pipeline for producing peptides and peptidomimetics therapeutics. Using randomly generated DNA sequences and molecular biology techniques, large diverse peptide libraries can be displayed on the phage surface. The phage library can be incubated with a target of interest and the phage which bind can be isolated and sequenced to reveal the displayed peptides' primary structure. In this review, we focus on the 'mechanics' of the phage display process, whilst highlighting many diverse and subtle ways it has been used to further the drug-development process, including the potential for the phage particle itself to be used as a drug carrier targeted to a particular pathogen or cell type in the body. PMID- 24051399 TI - A practical drug discovery project at the undergraduate level. AB - In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kdelta) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and >=tenfold, respectively. PMID- 24051397 TI - Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease. AB - Allosteric modulation of AMPA, NR2B, mGlu2, mGlu5 and M1, targeting glutamatergic dysfunction, represents a significant area of research for the treatment of schizophrenia. Of these targets, clinical promise has been demonstrated using muscarinic activators for the treatment of Alzheimer's disease (AD) and schizophrenia. These diseases have inspired researchers to determine the effects of modulating cholinergic transmission in the forebrain, which is primarily regulated by one of five subtypes of muscarinic acetylcholine receptor (mAChR), a subfamily of G-protein-coupled receptors (GPCRs). Of these five subtypes, M1 is highly expressed in brain regions responsible for learning, cognition and memory. Xanomeline, an orthosteric muscarinic agonist with modest selectivity, was one of the first compounds that displayed improvements in behavioral disturbances in AD patients and efficacy in schizophrenics. Since these initial clinical results, many scientists, including those in our laboratories, have strived to elucidate the role of M1 with compounds that display improved selectivity for this receptor by targeting allosteric modes of receptor activation. A survey of selected compounds in this area will be presented. PMID- 24051400 TI - A phosphonium-type ionic liquid-modified Au electrode: a new platform for entrapping functional molecules on substrate surfaces. AB - The liquid state of a bulky phosphonium-type ionic compound with a disulphide group was used to modify a Au substrate with effective dispersion. The substrate incorporates external compounds into the vacant space formed inside the ionic liquid regardless of the net charge of the compounds without any direct bonding. PMID- 24051401 TI - Involvement of calcium-mediated reactive oxygen species in inductive GRP78 expression by geldanamycin in 9L rat brain tumor cells. AB - Treatment with geldanamycin (GA) leads to an increase in [Ca2+]c and the production of reactive oxygen species (ROS) in rat brain tumor 9L RBT cells. GA exerted calcium signaling was blocked by BAPTA/AM and EGTA. The effect of GA on [Ca2+]c was significantly reduced in the presence of thapsigargin (TG) and ruthenium red (RR). GA-induced GRP78 expression is significantly decreased in the presence of BAPTA/AM, EGTA and RR, suggesting that the calcium influx from the extracellular space and intracellular calcium store oscillations are contributed to by the calcium mobilization and GRP78 expression induced by GA. The induced GRP78 expression is sensitive to added U73122 and Ro-31-8425, pinpointing the involvement of phospholipase C (PLC) and protein kinase C (PKC) in GA-induced endoplasmic reticulum (ER) stress. The antioxidants N-acetylcysteine (NAC), BAPTA/AM, EGTA and H7 also have significant inhibitory effects on ROS generation. Finally, neither H7 nor NAC was able to affect the calcium response elicited by GA. Our results suggest that the causal signaling cascade during GA-inducted GRP78 expression occurs via a pathway that connects PLC to cytoplasmic calcium increase, PKC activation and, then, finally, ROS generation. Our data provides new insights into the influence of GA on ER stress response in 9L RBT cells. PMID- 24051402 TI - Cinnamomum cassia essential oil inhibits alpha-MSH-induced melanin production and oxidative stress in murine B16 melanoma cells. AB - Essential oils extracted from aromatic plants exhibit important biological activities and have become increasingly important for the development of aromatherapy for complementary and alternative medicine. The essential oil extracted from Cinnamomum cassia Presl (CC-EO) has various functional properties; however, little information is available regarding its anti-tyrosinase and anti melanogenic activities. In this study, 16 compounds in the CC-EO have been identified; the major components of this oil are cis-2-methoxycinnamic acid (43.06%) and cinnamaldehyde (42.37%). CC-EO and cinnamaldehyde exhibited anti tyrosinase activities; however, cis-2-methoxycinnamic acid did not demonstrate tyrosinase inhibitory activity. In murine B16 melanoma cells stimulated with alpha-melanocyte-stimulating hormone (alpha-MSH), CC-EO and cinnamaldehyde not only reduced the melanin content and tyrosinase activity of the cells but also down-regulated tyrosinase expression without exhibiting cytotoxicity. Moreover, CC-EO and cinnamaldehyde decreased thiobarbituric acid-reactive substance (TBARS) levels and restored glutathione (GSH) and catalase activity in the alpha-MSH stimulated B16 cells. These results demonstrate that CC-EO and its major component, cinnamaldehyde, possess potent anti-tyrosinase and anti-melanogenic activities that are coupled with antioxidant properties. Therefore, CC-EO may be a good source of skin-whitening agents and may have potential as an antioxidant in the future development of complementary and alternative medicine-based aromatherapy. PMID- 24051404 TI - Analysis of Gln223Agr polymorphism of Leptin Receptor Gene in type II diabetic mellitus subjects among Malaysians. AB - Leptin is known as the adipose peptide hormone. It plays an important role in the regulation of body fat and inhibits food intake by its action. Moreover, it is believed that leptin level deductions might be the cause of obesity and may play an important role in the development of Type 2 Diabetes Mellitus (T2DM), as well as in cardiovascular diseases (CVD). The Leptin Receptor (LEPR) gene and its polymorphisms have not been extensively studied in relation to the T2DM and its complications in various populations. In this study, we have determined the association of Gln223Agr loci of LEPR gene in three ethnic groups of Malaysia, namely: Malays, Chinese and Indians. A total of 284 T2DM subjects and 281 healthy individuals were recruited based on International Diabetes Federation (IDF) criteria. Genomic DNA was extracted from the buccal specimens of the subjects. The commercial polymerase chain reaction (PCR) method was carried out by proper restriction enzyme MSP I to both amplify and digest the Gln223Agr polymorphism. The p-value among the three studied races was 0.057, 0.011 and 0.095, respectively. The values such as age, WHR, FPG, HbA1C, LDL, HDL, Chol and Family History were significantly different among the subjects with Gln223Agr polymorphism of LEPR (p < 0.05). PMID- 24051403 TI - Posttranscriptional regulation of insulin family ligands and receptors. AB - Insulin system including ligands (insulin and IGFs) and their shared receptors (IR and IGFR) are critical regulators of insulin signaling and glucose homeostasis. Altered insulin system is associated with major pathological conditions like diabetes and cancer. The mRNAs encoding for these ligands and their receptors are posttranscriptionally controlled by three major groups of regulators; (i) alternative splicing regulatory factors; (ii) turnover and translation regulator RNA-binding proteins (TTR-RBPs); and (iii) non-coding RNAs including miRNAs and long non-coding RNAs (lncRNAs). In this review, we discuss the influence of these regulators on alternative splicing, mRNA stability and translation. Due to the pathological impacts of insulin system, we also discussed the possibilities of discovering new potential regulators which will improve understanding of insulin system and associated diseases. PMID- 24051405 TI - Comparison of foveal-sparing with foveal-involving photodynamic therapy for myopic choroidal neovascularization. AB - PURPOSE: To evaluate the visual outcomes of choroidal neovascularization (CNV) secondary to pathological myopia in eyes treated with photodynamic therapy (PDT), and to determine the effect of lesion location and foveal involvement on visual prognosis. METHODS: Interventional case series of 24 consecutive patients with myopic CNV treated with PDT. The main outcome measure was final LogMAR visual acuity (VA). RESULTS: Of 24 eyes, the CNV lesion was subfoveal in 11 and extrafoveal in 13. Overall, the mean LogMAR VA at 24 months was 0.72. Extrafoveal CNV lesions achieved significantly better final VA compared with subfoveal CNV (LogMAR 0.45 vs 1.05, P=0.012). Eyes with extrafoveal CNV lesions were subdivided into foveal-sparing PDT (where the PDT laser spot did not involve the foveal center) and foveal-involved PDT (where the PDT laser covered the fovea). At all time points, the group with foveal-sparing PDT had significantly better VA compared with the foveal-involved group. The final LogMAR VA for the foveal sparing PDT group was 0.26 compared with 1.00 for the foveal-involved PDT group (P=0.003). At 24 months, 77.8% of foveal-sparing PDT cases achieved VA of >= 20/40, compared with 25% of foveal-involved PDT cases and 9.1% of subfoveal CNV lesions (P=0.006). CONCLUSION: For patients with myopic CNV, foveal-sparing PDT results in significantly better long-term visual outcomes compared with those with foveal-involved PDT. Foveal-sparing PDT may be of value for treatment of myopic CNV patients who are not suitable for treatment with anti-vascular endothelial growth factor injections. PMID- 24051406 TI - Giant cell arteritis with normal ESR and/or CRP is rare, but not unique! PMID- 24051407 TI - Response to 'Comment on Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm'. PMID- 24051408 TI - Response to Grzybowski and Justynska. PMID- 24051409 TI - Pain score assessment in babies undergoing laser treatment for retinopathy of prematurity under sub-tenon anaesthesia. AB - PURPOSE: To assess the tolerability and outcomes of laser treatment for retinopathy of prematurity (ROP) under sub-tenon anaesthetic with oral or rectal sedation using a reliable, multidimensional, and internationally accepted tool for assessment of neonatal pain. METHODS: Sixty-two babies have had ROP laser treatment in our neonatal unit in the 7-year interval between 1 March 2005 and 28 February 2012; 44% (27 of the 62) were performed using sub-tenon anaesthesia. Pain scores were routinely assessed using the Neonatal Pain Agitation and Sedation Scale (N-PASS) every 10 min during laser treatment. The outcome and requirement for re-treatment in this group was compared with that in the intravenous sedation group. RESULTS: Pain scores were available in 19 of the 27 babies treated under sub-tenon anaesthesia. The mean pain score during treatment was 2.7 (SD +/- 1.7, range 0.5-6.2). There was no statistically significant correlation between the mean pain score and duration of treatment (Spearman correlation coefficient (rho) = 0.31; P = 0.09), number of laser burns (rho = 0.32; P = 0.09), or post-menstrual age of the baby at the time of treatment (rho = 0.38; P = 0.052). Treatments performed under sub-tenon anaesthesia were as successful as those performed under intravenous sedation. The mean pain scores during laser treatment under sub-tenon anaesthesia in our study were lower than those previously reported during ROP screening or heel-stick procedure.Conclusion Our study demonstrated that sub-tenon anaesthesia with oral or rectal sedation provides sufficient pain control for laser treatment for ROP without the need or risks of intravenous sedation and intubation. PMID- 24051410 TI - United Kingdom National Ophthalmology Database Study: Diabetic Retinopathy; Report 1: prevalence of centre-involving diabetic macular oedema and other grades of maculopathy and retinopathy in hospital eye services. AB - AIMS: To report estimates of the prevalence of diabetic retinopathy (DR) and maculopathy grades for a large cohort of patients managed by the UK hospital eye service (HES). METHODS: Anonymised data were extracted from 30 UK NHS hospital trusts using a single ophthalmic electronic medical record (EMR) for the period from April 2000 to November 2010 to create the National Ophthalmology Database (NOD). From 2007, the EMR facilitated capture of a nationally agreed-upon standardised data set (DR Structured Assessment) relating to the presence or absence of clinical signs of DR and maculopathy. An algorithm in the software automatically calculated the Early Treatment of Diabetic Retinopathy Study grades of retinopathy and maculopathy. RESULTS: Between 2007 and 2010, 307,538 patients had data on the NOD, with 76,127 (24.8%) patients having been recorded as having diabetes. The proportion of patients with diabetes who had a structured assessment increased from 50.7% (2007) to 86.8% (2010). In each NHS year, 12.6 20.6% of eyes with structured assessments had no DR; 59.6-67.3% had non proliferative DR; and 18.3-20.9% had active or regressed proliferative DR. Clinically significant macular oedema was present in 15.8-18.1% of eyes, and in 8.7-10.0% of eyes, this involved the central macula. CONCLUSION: This study provides contemporary estimates of the prevalence of retinopathy and maculopathy grades in a large cohort of patients with diabetes managed by the UK HES. Centre involving diabetic macular oedema, potentially amenable to anti-VEGF therapy, is present in the eyes of almost 10% of these patients. This information is useful for clinicians, health-care economists, and commissioners involved in planning and delivering diabetic eye services. PMID- 24051411 TI - The effect of head tilt on keratometric measurement using the IOLMaster. AB - PURPOSE: To investigate the effect of head tilt on keratometric measurement using the IOLMaster. METHODS: Twenty-seven right eyes of 27 volunteers were examined using a manual keratometer (MK), automated keratometer (AK), and an IOLMaster. MK and AK measurements were performed in the upright head position, whereas IOLMaster measurements were performed in five different head positions (upright, 5 degrees or 15 degrees clockwise head tilt, and 5 degrees or 15 degrees counter-clockwise head tilt). The repeatability of IOLMaster was compared with MK and AK. The keratometric measurements (mean keratometric power, magnitude of astigmatism, and steep meridian) in different head positions were compared. RESULTS: The IOLMaster showed good repeatability of keratometric measurement comparable to MK or AK. 15 degrees and 5 degrees clockwise head tilt resulted in 12.09 +/- 9.51 (mean +/- SD) (P<0.001 vs upright) and 5.51 +/- 5.97 (mean +/- SD) degrees (P<0.001) of clockwise rotation of steep meridian, respectively. 15 degrees and 5 degrees counter-clockwise head tilt resulted in 12.49 +/- 7.07 (mean +/- SD) (P<0.001) and 6.08 +/- 5.09 (mean +/- SD) degrees (P<0.001) of counter-clockwise rotation of steep meridian, respectively. CONCLUSIONS: The patient's head tilt (5 degrees or 15 degrees , clockwise or counter-clockwise) significantly changed the steep meridian of astigmatism measured using IOLMaster and the steep meridian generally shifted to the direction of head tilt. The importance of maintaining the upright head posture during IOLMaster measurement is demonstrated. PMID- 24051412 TI - Comment on 'Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm'. PMID- 24051413 TI - A global affair. PMID- 24051416 TI - Structures of a bifunctional cell wall hydrolase CwlT containing a novel bacterial lysozyme and an NlpC/P60 DL-endopeptidase. AB - Tn916-like conjugative transposons carrying antibiotic resistance genes are found in a diverse range of bacteria. Orf14 within the conjugation module encodes a bifunctional cell wall hydrolase CwlT that consists of an N-terminal bacterial lysozyme domain (N-acetylmuramidase, bLysG) and a C-terminal NlpC/P60 domain (gamma-d-glutamyl-l-diamino acid endopeptidase) and is expected to play an important role in the spread of the transposons. We determined the crystal structures of CwlT from two pathogens, Staphylococcus aureus Mu50 (SaCwlT) and Clostridium difficile 630 (CdCwlT). These structures reveal that NlpC/P60 and LysG domains are compact and conserved modules, connected by a short flexible linker. The LysG domain represents a novel family of widely distributed bacterial lysozymes. The overall structure and the active site of bLysG bear significant similarity to other members of the glycoside hydrolase family 23 (GH23), such as the g-type lysozyme (LysG) and Escherichia coli lytic transglycosylase MltE. The active site of bLysG contains a unique structural and sequence signature (DxxQSSES+S) that is important for coordinating a catalytic water. Molecular modeling suggests that the bLysG domain may recognize glycan in a similar manner to MltE. The C-terminal NlpC/P60 domain contains a conserved active site (Cys-His His-Tyr) that appears to be specific to murein tetrapeptide. Access to the active site is likely regulated by isomerism of a side chain atop the catalytic cysteine, allowing substrate entry or product release (open state), or catalysis (closed state). PMID- 24051417 TI - Positional effects of AAN motifs in rpoS regulation by sRNAs and Hfq. AB - The Escherichia coli stationary phase transcription factor RpoS is translated in response to small noncoding RNAs (sRNAs), which base pair with the rpoS mRNA leader. The bacterial Sm-like protein Hfq anneals sRNAs with their mRNA targets by simultaneously binding the mRNA and sRNA. Intriguingly, Hfq is recruited to the rpoS leader via AAN motifs far upstream of the sRNA. SHAPE (selective 2' hydroxyl acylation and primer extension) chemical footprinting showed that the rpoS leader is divided into a far upstream domain, an Hfq binding domain, and a downstream inhibitory stem-loop containing the sRNA and ribosome binding sites. To investigate how Hfq promotes sRNA-mRNA base pairing from a distance, we deleted the natural AAN Hfq binding site, and we inserted artificial AAN binding sites at various positions in the rpoS leader. All the relocated AAN motifs restored tight Hfq binding in vitro, but only insertion at the natural position restored Hfq-dependent sRNA annealing in vitro and sRNA regulation of rpoS translation in vivo. Furthermore, U-rich motifs in the downstream inhibitory domain stabilized the rpoS mRNA-Hfq complex and contributed to regulation of rpoS expression. We propose that the natural Hfq binding domain is optimal for positive regulation because it recruits Hfq to the mRNA and allows it to act on incoming sRNAs without opening the inhibitory stem-loop when sRNA is absent. PMID- 24051418 TI - A novel equation for cooperativity of the allosteric state function. AB - The MWC (Monod-Wyman-Changeux) allosteric model postulates concerted conformational changes between two states: the intrinsically more stable T state with relatively weak ligand binding and the R state with relatively strong ligand binding. The model distinguishes between Y- (the fractional occupation of the binding sites) and R- (the fraction of molecules in the R state). Cooperativity (measured by the Hill coefficient) has strikingly different properties for Y- and R-. For the latter, cooperativity depends only on the relative affinities of the two states, not on their relative intrinsic stabilities, as demonstrated here with a simple new equation relating the Hill coefficient to R-. PMID- 24051420 TI - A limited form of neuromyelitis optica with a lesion of the fourth nerve nucleus. PMID- 24051419 TI - Baseline retinal nerve fiber layer thickness and macular volume quantified by OCT in the North American phase 3 fingolimod trial for relapsing-remitting multiple sclerosis. AB - BACKGROUND: Patients with multiple sclerosis (MS) demonstrate thinning of peripapillary retinal nerve fiber layer (RNFL) and decreased macular volume as measured by optical coherence tomography (OCT). To our knowledge, there are no previous reports from a large MS OCT database with strict quality control measures that quantitate RNFL and macula in patients with relapsing-remitting multiple sclerosis. METHODS: The University of California Davis OCT Reading Center gathered OCT data at baseline as part of the North American phase 3 trial of fingolimod (Gilenya). Average RNFL thickness (RNFLT) and macular volume (TMV) were measured using time domain OCT (TD-OCT). RNFL quadrants, clock hours, and macular subfields were included. With strict quality control and accounting for signal strength differences, scans were categorized as "reduced" or "not reduced" for each field, based on being less than 5th percentile for age-matched controls derived from the normative database in the scanner software. Patients were deemed "abnormal" if at least 1 eye had reduced values for a given parameter. Patients with abnormalities in corresponding RNFL and macular subfields were compared by cross-tabulation. RESULTS: The TD-OCT data were prospectively collected from 939 of the 1,083 trial patients, 712 of whom met all final quality and data inclusion criteria. Of the final cohort, 242 (34.0%) demonstrated reduced (less than 5th percentile) average RNFLT in at least 1 eye. One hundred seventy-eight (25.0%) patients had reduced TMV. One hundred twenty-eight (18.0%) demonstrated both reduced TMV and RNFLT in the same eye, whereas 42 (5.8%) had reduced TMV and RNFLT in both eyes. Of the 242 patients with reduced average RNFL thickness, 128 (52.9%) also had reduced TMV. Fifty patients had reduced TMV in the absence of reduced RNFLT in at least 1 eye, a cohort prevalence of 7.0%. Quadrant and subfield analysis showed a predominance of temporal and inferior RNFL thinning, with inferior macular thinning corresponding best to RNFL thinning. CONCLUSION: RNFL and macular thinning/volume loss is common at baseline in relapsing remitting multiple sclerosis, as measured by TD-OCT. When the RNFL is thin, the macular volume is reduced in more than half of the patients. There is a population of reduced TMV without any reduction in RNFLT. Documenting the prevalence and distribution of these structural abnormalities supports recent reports and suggests new retinal areas to probe for functional vision changes in MS. PMID- 24051421 TI - First cases of dominant optic atrophy in Saudi Arabia: report of two novel OPA1 mutations. AB - BACKGROUND: Fifty to 60% of patients with dominant optic atrophy (DOA) have mutations of the OPA1 gene, which encodes dynamin-related GTPase, a protein of the internal mitochondrial membrane. To date, more than 200 OPA1 mutations in the OPA1 gene have been described. However, DOA is genetically heterogeneous with certain families linked to other chromosomal loci, that is, OPA3, OPA4, OPA5, and OPA7. METHODS: This study describes a clinical series of 40 patients from Saudi Arabia with a positive DOA phenotype (i.e., decreased visual acuity during the first 2 decades of life, temporal or global optic disc pallor, and absence of other neurological or ophthalmological diseases that could explain the optic neuropathy) who underwent molecular genetic testing for OPA1 (and, in some cases, for OPA3). RESULTS: This study describes for the first time 4 OPA1 mutations in DOA patients from Saudi Arabia, including 2 novel OPA1 mutations in 2 different patients. CONCLUSION: The question remains whether certain patients in Saudi Arabia with a clearly defined DOA phenotype may be due to mutations in chromosomal loci other than OPA1 and OPA3. It is likely that genetic alterations associated with different loci will be discovered in the future. PMID- 24051422 TI - Pipeline embolization device: a new source for embolic retinal vascular occlusion. AB - A 57-year-old woman underwent treatment of a left internal carotid artery aneurysm with a Pipeline embolization device. She subsequently experienced multiple branch retinal artery occlusions in her left eye. Although rare, ophthalmic complications may follow this new technique in the treatment of intracranial aneurysms. PMID- 24051423 TI - Sneddon syndrome presenting with unilateral third cranial nerve palsy. AB - Sneddon syndrome is a rare systemic vasculopathy affecting the skin as livedo racemosa and the central nervous system as stroke. A 31-year-old man with a history of livedo racemosa presented with a partial left third nerve palsy. Skin biopsy showed signs of endotheliitis with obliteration of dermal blood vessels due to intimal proliferation and fibrin thrombi consistent with Sneddon syndrome. The patient was treated with platelet antiaggregant therapy with complete resolution of his third nerve palsy. Clinicians should be aware of Sneddon syndrome because prompt diagnosis and treatment may prevent potential morbidity and mortality. PMID- 24051424 TI - Paraneoplastic dermatomyositis related to a chondrosarcoma involving the cavernous sinus. AB - Approximately one third of all cases of dermatomyositis may be associated with malignancy. We describe a patient with unexplained rash, joint pain, and muscle weakness, who subsequently developed a cavernous sinus syndrome due to a central nervous system chondrosarcoma. Discovery of this tumor and further dermatologic evaluation, including skin biopsy, resulted in diagnosis of paraneoplastic dermatomyositis due to cavernous sinus chondrosarcoma. PMID- 24051425 TI - Pseudotumor cerebri syndrome associated with giant arachnoid granulation. PMID- 24051426 TI - Recovery of ocular motor cranial nerve palsy after herpes zoster ophthalmicus. AB - OBJECTIVE: To report the course of ocular motor cranial nerve palsy due to herpes zoster. METHODS: A retrospective chart review identified patients with ocular motor cranial nerve palsy occurring at the time of herpes zoster ophthalmicus. Patients were seen by a single neuro-ophthalmologist from 1994 to 2012. RESULTS: Twenty-one patients were identified; 3 were excluded because of incomplete follow up. Nine (50%) had complete recovery and 8 (44%) had partial recovery but no diplopia in primary gaze (mean time = 10 weeks). One patient with complete ophthalmoplegia had persistent diplopia in primary position for recovery. CONCLUSION: Ophthalmoplegia secondary to herpes zoster ophthalmicus has good long term prognosis for recovery. PMID- 24051427 TI - Molecular cytogenetics in artificial hybrid and highly polyploid sturgeons: An evolutionary story narrated by repetitive sequences. AB - We applied comparative genomic hybridization (CGH) and genomic in situ hybridization (GISH) to examine genomes of artificially produced sturgeon hybrids between sterlet, Acipenser ruthenus female (~120 chromosomes) or Russian sturgeon, A. gueldenstaedtii female (~240 chromosomes) and a spontaneous triploid Siberian sturgeon A. baerii male (~360 chromosomes), respectively. The ploidy levels of progenies were analyzed by karyotyping and flow cytometry. We found that the species-specific regions were surprisingly identifiable only on some micro- and small(er) macrochromosomes in hybrid metaphases. We hypothesize that these distinguishable regions are represented by species-specific repetitive sequences driven by more dynamic molecular evolutionary mechanisms. On larger chromosomes, GISH faintly visualized only blocks of pericentromeric and telomeric repetitive sequences, remaining regions were equally shared by both parental species. We concluded that the interspecies hybridization producing viable and even fertile progeny is enabled by the fact that genomes of the species involved are likely divergent at the level of the repetitive sequences only and probably highly conserved in the coding sequences. These small differences of coding sequences are in concordance with previous estimations of relatedness of examined species producing artificial as well as natural hybrids. CGH and GISH represent a challenge in sturgeon cytogenetics as a valuable though technically not simple tool to discriminate chromosomes of parental species in hybrids. The potentials and drawbacks of CGH and GISH application in sturgeons are discussed and further experimental possibilities are proposed. PMID- 24051428 TI - Differences in geographical distribution and risk factors for urinary incontinence in Turkey: analysis of 6,473 women. AB - OBJECTIVE: To assess the prevalence, types and risk factors for urinary incontinence (UI) and to evaluate the impact of incontinence on quality of life by using validated and objective questionnaires in the western and eastern parts of Turkey. METHODS: In this multicenter observational study, 6,473 women from 38 cities in the western and eastern parts of Turkey were included. UI was assessed by ICIQ-SF (International Consultation on Incontinence Questionnaire Short Form) and IIQ-7 (Incontinence Impact Questionnaire). RESULTS: The UI rate was 20.9% (10% for stress, 8.3% overactive bladder and 2.6% for mixed type). In all, stress incontinence was the most common type. The rate of UI in women residing in the west was higher than in women living in the east (p < 0.001). ICIQ scores were comparable in the two groups but women in the west scored higher in each item of the IIQ. Age >40 years (p < 0.001), number of siblings >5 (p < 0.001) and low educational status (p < 0.001) increased the rate of incontinence. In binary logistic regression analysis menopausal status, age >40 years, number of siblings >5, being overweight, region of residence, and educational status were associated with UI. CONCLUSION: The rate of UI in women residing in the western part of Turkey was higher than women living in the east. Residing in a different geographical region (in our case living either in the western or eastern part of Turkey) seemed to be an independent risk factor for UI. Moreover, UI deteriorates quality of life and more attention should be paid to this vulnerable population. PMID- 24051429 TI - DNA vaccine prime followed by boost with live attenuated virus significantly improves antigen-specific T cell responses against human cytomegalovirus. AB - As a leading cause of congenital infection and a major threat to immunocompromised individuals, human cytomegalovirus (HCMV) is a major global public health concern. Effective HCMV vaccines would need to induce potent and balanced humoral and cellular immune responses. In this pilot study, immunogenicity studies were conducted in mice to examine HCMV antigen-specific antibody and T cell responses when a heterologous prime-boost immunization strategy was tested. DNA vaccines expressing either targets of protective antibody responses (gB and gM/gN) or well characterized T cell immunogens (pp65, pp150, and IE1) were used as the priming immunization while the live attenuated HCMV vaccine Towne strain was used as the boost, which may act like an inactivated vaccine due to the inability of HCMV to replicate in a mouse host. Our data indicate that while DNA vaccines were effective in priming HCMV-specific antibody responses, the final titers of gB- or gM-specific antibodies were not much different from those elicited by using multiple immunizations of HCMV alone. In contrast, DNA priming significantly enhanced T cell responses against gB, pp65, and IE1 as measured by IFN-gamma. However, HCMV alone was not effective in eliciting strong T cell immune responses when used in a mouse host. Our data indicate that the complexity of antigen composition from a large virus, such as HCMV, may affect the profile of immune responses when viral vaccines are used as a boost. PMID- 24051430 TI - Mucosal genetic immunization through microsphere-based oral carriers. AB - Polymeric carriers in the form of cellulose acetate phthalate (CAP) and alginate (ALG) microspheres were used for encapsulation of plasmid DNA for oral mucosal immunization. Access into the intestinal mucosa by pVAX1 eukaryotic expression plasmid vectors carrying gene-coding sequences, either for the cholera enterotoxin B subunit (ctxB) immunostimulatory antigen or the green fluorescent protein (GFP), delivered from both types of microsphere carriers were examined in orally immunized BALB/c mice. Demonstration of transgene protein expression and IgA antibody responses at local mucosal sites suggest immunological response to a potential oral DNA vaccine formulated within the microsphere carriers. PMID- 24051431 TI - Use of Staby((r)) technology for development and production of DNA vaccines free of antibiotic resistance gene. AB - The appearance of new viruses and the cost of developing certain vaccines require that new vaccination strategies now have to be developed. DNA vaccination seems to be a particularly promising method. For this application, plasmid DNA is injected into the subject (man or animal). This plasmid DNA encodes an antigen that will be expressed by the cells of the subject. In addition to the antigen, the plasmid also encodes a resistance to an antibiotic, which is used during the construction and production steps of the plasmid. However, regulatory agencies (FDA, USDA and EMA) recommend to avoid the use of antibiotics resistance genes. Delphi Genetics developed the Staby((r)) technology to replace the antibiotic resistance gene by a selection system that relies on two bacterial genes. These genes are small in size (approximately 200 to 300 bases each) and consequently encode two small proteins. They are naturally present in the genomes of bacteria and on plasmids. The technology is already used successfully for production of recombinant proteins to achieve higher yields and without the need of antibiotics. In the field of DNA vaccines, we have now the first data validating the innocuousness of this Staby((r)) technology for eukaryotic cells and the feasibility of an industrial production of an antibiotic-free DNA vaccine. Moreover, as a proof of concept, mice have been successfully vaccinated with our antibiotic-free DNA vaccine against a deadly disease, pseudorabies (induced by Suid herpesvirus-1). PMID- 24051432 TI - A DNA vaccine targeting p42.3 induces protective antitumor immunity via eliciting cytotoxic CD8+T lymphocytes in a murine melanoma model. AB - The p42.3 gene was recently identified and characterized as having tumor-specific and mitosis phase-dependent expression in many types of cancer. This suggested that p42.3 antigen could be used as a target for vaccines against cancers. In this study, we immunized C57BL/6 mice with a DNA vaccine encoding p42.3. We used intramuscular injection with electroporation, either before or after challenge with tumor B16F10 cells. Vaccination with pcDNA3-p42.3 induced some degree of antitumor effect both therapeutically and prophylactically, as evaluated by the inhibition of tumor growth and decrease in tumor weight. Immunized mice showed a high level of specific cytotoxic activity against the p42.3 protein in vivo and had activated CD8 T cells that secreted IFN-gamma, perforin, and granzyme B in response to stimulation with the antigen in vitro. Thus, this study presents the DNA vaccination against novel tumor target p42.3 as a promising antitumor modality. PMID- 24051433 TI - DNA and protein co-administration induces tolerogenic dendritic cells through DC SIGN mediated negative signals. AB - We previously demonstrated that DNA and protein co-administration induced differentiation of immature dendritic cells (iDCs) into CD11c(+)CD40(low)IL-10(+) regulatory DCs (DCregs) via the caveolin-1 (Cav-1) -mediated signal pathway. Here, we demonstrate that production of IL-10 and the low expression of CD40 play a critical role in the subsequent induction of regulatory T cells (Tregs) by the DCregs. We observed that DNA and protein were co-localized with DC-SIGN in caveolae and early lysosomes in the treated DCs, as indicated by co-localization with Cav-1 and EEA-1 compartment markers. DNA and protein also co-localized with LAMP-2. Gene-array analysis of gene expression showed that more than a thousand genes were significantly changed by the DC co-treatment with DNA + protein compared with controls. Notably, the level of DC-SIGN expression was dramatically upregulated in pOVA + OVA co-treated DCs. The expression levels of Rho and Rho GNEF, the down-stream molecules of DC-SIGN mediated signal pathway, were also greatly upregulated. Further, the level of TLR9, the traditional DNA receptor, was significantly downregulated. These results suggest that DC-SIGN as the potential receptor for DNA and protein might trigger the negative pathway to contribute the induction of DCreg combining with Cav-1 mediated negative signal pathway. PMID- 24051434 TI - Tolerability of intramuscular and intradermal delivery by CELLECTRA((r)) adaptive constant current electroporation device in healthy volunteers. AB - DNA vaccines are being developed as a potentially safe and effective immunization platform. However, translation of DNA vaccines into a clinical setting has produced results that have fallen short of those generated in a preclinical setting. Various strategies are being developed to address this lack of potency, including improvements in delivery methods. Electroporation (EP) creates transient increases in cell membrane permeability, thus enhancing DNA uptake and leading to a more robust immune response. Here, we report on the safety and tolerability of delivering sterile saline via intramuscular (IM) or intradermal (ID) injection followed by in vivo electroporation using the CELLECTRA((r)) adaptive constant current device in healthy adults from two open-label studies. Pain, as assessed by VAS, was highest immediately after EP but diminishes by about 50% within 5 min. Mean VAS scores appear to correlate with the amount of energy delivered and depth of needle insertion, especially for intramuscular EP. Mean scores did not exceed 7 out of 10 or 3 out of 10 for IM and ID EP, respectively. The majority of adverse events included mild to moderate injection site reactions that resolved within one day. No deaths or serious adverse events were reported during the course of either study. Overall, injection followed by EP with the CELLECTRA((r)) device was well-tolerated and no significant safety concerns were identified. These studies support the further development of electroporation as a vaccine delivery method to enhance immunogenicity, particularly for diseases in which traditional vaccination approaches are ineffective. PMID- 24051435 TI - Conductance based sensing and analysis of soluble phosphates in wastewater. AB - The current standard method used for measuring soluble phosphate in environmental water samples is based on a colourimetric approach, developed in the early 1960s. In order to provide an alternative, label free sensing solution, a molecularly imprinted polymer (MIP) was designed to function as a phosphate receptor. A combination of functional monomer (N-allylthiourea), cross-linker and monomer/template ratios were optimised in order to maximise the binding capacity for phosphate. When produced in membrane format, the MIP's ability to produce a reversible change in conductance in the presence of phosphate was explored for fabrication of a sensor which was able to selectively detect the presence of phosphate compared to sulphate, nitrate and chloride. In wastewater samples the sensor had a limit of detection of 0.16 mg P/l, and a linear range between 0.66 and 8 mg P/l. This is below the minimum monitoring level (1 mg P/l) as required by current legislation for wastewater discharges, making the sensor as developed promising for direct quantification of phosphate in environmental monitoring applications. PMID- 24051436 TI - Clinical characteristics and surgical management options for ovarian fibroma/fibrothecoma: a study of 97 cases. AB - AIMS: The aims of this study were to analyze the clinical characteristics, diagnostic features, and operative outcomes of patients with ovarian fibroma/fibrothecoma and to discuss appropriate management options. METHODS: We performed a retrospective comparative analysis of 97 patients with ovarian fibroma/fibrothecoma who underwent laparoscopic and laparotomic procedures, including tumorectomy between January 2008 and December 2011. RESULTS: The mean patient age was 42.5 +/- 11.4 years. Seventy-three patients (75.3%) were premenopausal women. A preoperative diagnosis of benign ovarian tumor or fibroma was made in only 49 cases (50.5%). We found that 42.2% of cases were misdiagnosed as uterine myomas (n = 41) and 6.2% were misdiagnosed as malignant ovarian tumors (n = 6). The presence of ascites was associated with larger tumor size (p < 0.05) but not higher CA125 levels (p = 0.159). Twenty-nine patients (29.9%) underwent laparotomy, and 68 (70.1%), laparoscopic surgery. Laparoscopic surgery facilitated shorter operation times than laparotomy (p < 0.05). Tumorectomy was performed in 40 patients (43.5%), 36 (90%) of whom underwent laparoscopy with operative outcomes comparable to those of patients who underwent laparotomy. CONCLUSIONS: Ovarian fibromas/fibrothecomas are often misdiagnosed as uterine myomas and malignant ovarian tumors. Laparoscopic surgery including tumorectomy may be an effective surgical approach in patients with ovarian fibromas/fibrothecomas. PMID- 24051438 TI - EF1alpha is a suitable housekeeping gene for RT-qPCR analysis during osteogenic differentiation of mouse bone marrow-derived mesenchymal stem cells. AB - The expression of predominant housekeeping genes used in RT-qPCR can vary during development and differentiation. The frequently used housekeeping genes (ACTB, GAPDH, 18S rRNA, EF1alpha and RPL 13a) were evaluated during an early stage of the osteogenic differentiation of mouse bone marrow-derived mesenchymal stem cells (mMSCs) (under normal conditions or treated with CCG-4986) to identify housekeeping genes whose expression remained constant during osteogenic differentiation. When we used RGS4 mRNA, which was determined as copy number per MUg of total RNA, to normalize gene expression, we observed that the relative EF1alpha expression profile was consistent with RGS4 expression after treatment with CCG-4986. All the relative expression profiles of the EF1alpha, 18S rRNA, and RPL13a housekeeping genes were consistent with RGS4 profiles determined by measuring mRNA copies under normal osteogenic differentiation conditions. The expression profiles calibrated by ACTB and GAPDH were not consistent with those determined using mRNA copy number in untreated cells or cells treated with CCG 4986 under osteogenic differentiation conditions. Under normal osteogenic differentiation conditions, EF1alpha, 18S rRNA, and RPL 13a are suitable housekeeping genes for RT-qPCR analysis. However, EF1alpha is the only suitable gene upon CCG-4986 treatment. PMID- 24051437 TI - Targeting BIG3-PHB2 interaction to overcome tamoxifen resistance in breast cancer cells. AB - The acquisition of endocrine resistance is a common obstacle in endocrine therapy of patients with oestrogen receptor-alpha (ERalpha)-positive breast tumours. We previously demonstrated that the BIG3-PHB2 complex has a crucial role in the modulation of oestrogen/ERalpha signalling in breast cancer cells. Here we report a cell-permeable peptide inhibitor, called ERAP, that regulates multiple ERalpha signalling pathways associated with tamoxifen resistance in breast cancer cells by inhibiting the interaction between BIG3 and PHB2. Intrinsic PHB2 released from BIG3 by ERAP directly binds to both nuclear- and membrane-associated ERalpha, which leads to the inhibition of multiple ERalpha-signalling pathways, including genomic and non-genomic ERalpha activation and ERalpha phosphorylation, and the growth of ERalpha-positive breast cancer cells both in vitro and in vivo. More importantly, ERAP treatment suppresses tamoxifen resistance and enhances tamoxifen responsiveness in ERalpha-positive breast cancer cells. These findings suggest inhibiting the interaction between BIG3 and PHB2 may be a new therapeutic strategy for the treatment of luminal-type breast cancer. PMID- 24051439 TI - A simple method for the determination of the cholesterol esterase activity. AB - The proposed method determines the activity of cholesterol esterase (CEH) and takes advantage of its ability to catalyze the hydrolysis of cholesterol esters naturally present in human serum. The assay is based on Allain's method of spectrophotometric determination of cholesterol by means of cholesterol oxidase, peroxidase, but using 3,5-dichloro-dihydroxybenzenesulfonic acid (DHBS) as phenolic chromogen and human serum as a source of substrate for the CEH as a novelty. Furthermore, it is characterized by low costs and high precision. It can be employed to control the activity of CE preparations used for the preparation of enzymatic kits for the determination of cholesterol or for screening of potential bacterial enzyme producers. PMID- 24051440 TI - Matrix metalloproteinase-2 C(-1306)T promoter polymorphism and breast cancer risk in the Saudi population. AB - Matrix metalloproteinase-2 (MMP-2) is an enzyme with proteolytic activity against matrix proteins, particularly basement membrane constituents. A single nucleotide polymorphism (SNP) at -1306, which disrupts a Sp1-type promoter site (CCACC box), displayed a strikingly lower promoter activity with the T allele. In the present study, we investigate whether this MMP-2 SNP is associated with susceptibility to breast cancer in the Saudi population. Ninety breast cancer patients and 92 age matched controls were included in this study. TaqMan Allele Discrimination assay and DNA sequencing techniques were used for genotyping. The results showed that, the frequency of MMP-2 CC wild genotype was lower in breast cancer patients when compared with healthy controls (0.65 versus 0.79). The homozygous CC (OR=2, chi(2)=5.36, p=0.02) and heterozygous CT (OR=1.98, chi(2)=4.1, p=0.04) showing significantly high risk of breast cancer in the investigated group. In conclusion our data suggest that the MMP-2 C(-1306)T polymorphism may be associated with increased breast cancer risk in the Saudi population. PMID- 24051441 TI - Trehalase as a possible marker of intestinal ischemia--reperfusion injury. AB - BACKGROUND: Different pathological affections of the small intestine cause corresponding morphological and functional changes. The present study was aimed to assess intestinal trehalase activities during ischemia and following reperfusion, correlate them with the pathological changes and determine whether trehalase could be used as a biochemical marker of the intestinal ischemia, ischemia - reperfusion injury. MATERIAL AND METHODS: Wistar rats, randomly divided into 5 experimental groups (IR) (each n=15), were subjected to one hour mesenteric ischemia followed by 0, 1, 4, 12 and 24 hours of reperfusion. As a control group sham operated animals were used (n=15). The activity of trehalase was determined using an adapted Dahlqwist method. The range of intestinal injury was determined using histological (histopathological injury index and goblet cell quantification) and immunohistochemical (Ki67, InSitu TUNEL) methods. RESULTS: The highest activities of trehalase were recorded in the control group (C=4.42 +/ 0.373 MUmol/mg/h). The most altered intestinal histology detected in group IR1 was accompanied by the lowest trehalase activity (IR1=0.97 +/- 0.209 MUmol/mg/h; p < 0.001 C vs. IR1). Improved histological structure in the remaining reperfusion periods correlated with increase in trehalase activity. Almost normal mucosal histological architecture and 72% of the enzymatic activity were restored after 24 hours of reperfusion (IR24=3.20 +/- 0.266 MUmol/mg/h; p < 0.01 IR1 vs. IR24). CONCLUSION: The correlation between intestinal histology and trehalase activities during intestinal injury has been shown. Trehalase activity is closely associated with the status of the histological architecture of the small intestine. PMID- 24051442 TI - Congenital disorders of glycosylation. Part II. Defects of protein O glycosylation. AB - Glycosylation is a form of post-translational modification of proteins and occurs in every living cell. The carbohydrate chains attached to the proteins serve various functions. There are two main types of protein glycosylation: N glycosylation and O-glycosylation. In this paper, we describe the O-glycosylation process and currently known congenital disorders of glycosylation associated with defects of protein O-glycosylation. This process takes place in the cis Golgi apparatus after N-glycosylation and folding of the proteins. The O-glycosylation is essential in the biosynthesis of mucins, the formation of proteoglycan core proteins and blood group proteins. Most common forms of O-glycans are the mucin type glycans. There are more than 20 known disorders related to O-glycosylation disturbances. We review 8 of the following diseases linked to defects in the synthesis of O-xylosylglycans, O-N acetylgalactosaminylglycans, O-xylosyl/N acetylglycans, O-mannosylglycans, and O-fucosylglycans: multiple exostoses, progeroid variant of Ehlers-Danlos syndrome, progeria, familial tumoral calcinosis, Schneckenbecken dysplasia, Walker-Warburg syndrome, spondylocostal dysostosis type 3, and Peter's plus syndrome. Causes of these diseases include gene mutations and deficiency of proteins (enzymes). Their diagnosis includes syndromic presentation, organ-specific expression and laboratory findings. PMID- 24051443 TI - Homocysteine thiolactone affects protein ubiquitination in yeast. AB - The formation of homocysteine thiolactone (HcyTl) from homocysteine occurs in all examined so far organisms including bacteria, yeast, and humans. Protein N homocysteinylation at the epsilon-amino group of lysine is an adverse result of HcyTl accumulation. Since tagging of proteins by ubiquitination before their proteasomal degradation takes place at the same residue, we wondered how N homocysteinylation may affect the ubiquitination of proteins. We used different yeast strains carrying mutations in genes involved in the homocysteine metabolism. We found positive correlation between the concentration of endogenous HcyTl and the concentration of ubiquitinated proteins. This suggests that N homocysteinylation of proteins apparently does not preclude but rather promotes their decomposition. PMID- 24051444 TI - The alcohol dehydrogenase isoenzyme (ADH IV) as a candidate tumour marker of esophageal cancer. AB - OBJECTIVE: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are present in esophageal cancer cells. Moreover the total activity of ADH as well as the activity of class IV ADH isoenzyme is significantly higher in cancer tissue than in healthy mucosa. The activity of these enzymes in cancer cells is reflected in the sera and could thus be helpful for diagnostics of esophageal cancer. The aim of this study was to investigate a potential significance of ADH isoenzymes and ALDH as tumour markers of esophageal cancer. We defined diagnostic sensitivity, specificity, predictive value for positive and negative results, and receiver-operating characteristics (ROC) curve for tested enzymes. METHODS: Serum samples were taken for routine biochemical investigation from 180 patients with esophageal cancer before treatment. Total ADH activity was measured by a photometric method with p-nitrosodimethylaniline as a substrate and ALDH activity by a fluorometric method with 6-methoxy-2-naphtaldehyde as a substrate. For the measurement of the activity of class I and II isoenzymes we employed the fluorometric methods, with class-specific fluorogenic substrates. The activity of class III alcohol dehydrogenase was measured by a photometric method with formaldehyde and class IV with m-nitrobenzaldehyde as a substrate. RESULTS: There was a significant increase in the activity of class IV of ADH isoenzyme (7.65 mU/l vs 5.88 mU/l) and total ADH activity (1198 mU/l vs 848 mU/l) in the sera of esophageal cancer patients compared to the control. The diagnostic sensitivity for ADH IV was 72%, the specificity 76%, the positive and negative predictive values were 80% and 72% respectively. The area under the ROC curve for ADH IV was 0.65. CONCLUSION: The results suggest a potential significance of ADH IV as a marker of esophageal cancer. PMID- 24051445 TI - Proposal of an agent-based analytical model to convert industrial areas in industrial eco-systems. AB - The transformation of industrial areas towards greater sustainability results from a strategic objective to address the effects of economic and environmental crisis. Such transformation, however, requires methodologies and tools that support and facilitate the process. This paper proposes an analytical model that favours the redesign of industrial areas based on sustainable strategies for eco industrial parks. The proposed model is enhanced by the definition of building blocks of an agent-based modelling method. The methodology that was followed favours the detailed description of the objectives of the system, with individual elements and adaptation to the surrounding environment, amongst other features. The proposed model integrates a knowledge database that supports the process of identification of cooperative strategies such as material exchange networks in industrial areas. The underlying theory for the assessment of cooperative interactions is game theory, which supports the resolution of problems with strategic choices. This work covers the stage of analytical model formulation that is essential for advancement towards the inference process based on simulation models. PMID- 24051446 TI - Environmental risk assessment for plant pests: a procedure to evaluate their impacts on ecosystem services. AB - The current methods to assess the environmental impacts of plant pests differ in their approaches and there is a lack of the standardized procedures necessary to provide accurate and consistent results, demonstrating the complexity of developing a commonly accepted scheme for this purpose. By including both the structural and functional components of the environment threatened by invasive alien species (IAS), in particular plant pests, we propose an environmental risk assessment scheme that addresses this complexity. Structural components are investigated by evaluating the impacts of the plant pest on genetic, species and landscape diversity. Functional components are evaluated by estimating how plant pests modify ecosystem services in order to determine the extent to which an IAS changes the functional traits that influence ecosystem services. A scenario study at a defined spatial and temporal resolution is then used to explore how an IAS, as an exogenous driving force, may trigger modifications in the target environment. The method presented here provides a standardized approach to generate comparable and reproducible results for environmental risk assessment as a component of Pest Risk Analysis. The method enables the assessment of overall environmental risk which integrates the impacts on different components of the environment and their probabilities of occurrence. The application of the proposed scheme is illustrated by evaluating the environmental impacts of the invasive citrus long-horn beetle, Anoplophora chinensis. PMID- 24051447 TI - Validity of discharge diagnoses in the surveillance of stroke. AB - BACKGROUND: Hospital administrative data have been suggested as a valuable cost effective tool for providing information about the stroke burden. Nevertheless, the choice of the diagnosis codes has been a critical issue in the development of case ascertainment algorithms. METHODS: In this study, the Minimum Basic Data Set administrative database was used to analyze the accuracy of different ICD-9-CM algorithms based on the neurologist's clinical judgement as the 'gold standard'. RESULTS: The most accurate algorithm observed in our study involved the selection of ICD-9-CM codes 430-438 in the primary diagnosis. It yielded a sensitivity of 96.1%, a specificity of 87.5% and a positive predictive value of 82.5%. CONCLUSIONS: The Minimum Basic Data Set is a valuable source to evaluate stroke frequency when using an accurate algorithm to select events. PMID- 24051448 TI - Methylenetetrahydrofolate reductase gene polymorphism and serum homocysteine levels in nonalcoholic fatty liver disease. AB - BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by hepatic fat accumulation in the absence of alcohol consumption. Hyperhomocysteinemia is considered an independent risk factor for liver diseases, and the genetic polymorphisms C677T and A1298C in the MTHFR gene have been linked to hyperhomocysteinemia. The purpose of this study was to investigate serum homocysteine (Hcy) concentrations and the MTHFR C677T and A1298C polymorphisms as risk factors for the development of NAFLD. METHODS: One hundred and thirty-four Brazilian patients with biopsy-proven NAFLD and 134 healthy controls were recruited. The MTHFR C677T and A1298C polymorphisms were detected through polymerase chain reaction restriction fragment length polymorphism. Serum Hcy levels were determined by chemiluminescence. RESULTS: Serum Hcy levels were higher in NAFLD patients as compared to control subjects, but there were no differences between patients with steatosis and nonalcoholic steatohepatitis. The NAFLD and control groups did not differ in genotypic and allelic frequencies of the MTHFR C677T and A1298C polymorphisms, either. Elevated plasma Hcy levels were positively correlated with age in the NAFLD subjects. CONCLUSION: The MTHFR C677T and A1298C polymorphisms are not genetic risk factors for the development of NAFLD. Higher Hcy levels exist in NAFLD subjects, but they are not associated with liver disease severity. PMID- 24051449 TI - MicroRNAs and reactive oxygen species: are they in the same regulatory circuit? AB - Interactions of living organisms with their environment mainly involve modulation of gene expression by stimulation or silencing. One of the epigenetic mechanisms that regulate translation and the levels of transcripts is RNA interference, in which microRNAs (miRNAs) address RNA-induced silencing complexes (RISCs) to degrade specific mRNAs or to silence their translation. In this mechanism, double stranded RNA structure is crucial for miRNA biogenesis and the action of RISCs. RNA molecules can be modified structurally by reactive oxygen and nitrogen species (ROS and RNS) that are produced in cells of all aerobic organisms and may be induced by environmental factors. Here we describe experiments in which changes of ROS and transcript levels are induced by X-irradiation and measured using flow cytometer and the fluorescent dye 2',7'-dichlorofluorescein diacetate and microarray methods in cultured human K562, Me45 and HCT116 cells. Analysis of the nucleotide sequences of mRNAs which are up- or down-regulated after irradiation shows significant differences in the distributions of miRNA-targeted motives between these two groups. Immediately after irradiation most miRNAs behave as "up-regulators", showing more targets in up-than in down-regulated transcripts, and this changes about 12h later when we also observe changes in ROS and miRNA levels. Our results suggest that the changes in the transcriptome could result from changes in RNA interference and that these effects could be related to the changed ROS levels in irradiated cells. We propose that such modulation of gene expression at the mRNA level may be implicated more generally in cellular responses to stresses where ROS levels change. PMID- 24051450 TI - Upper triangular flap method for primary repairs of incomplete unilateral cleft lip patients: minor to two-thirds way defects. AB - Incomplete unilateral cleft lips show a wide range of deformities, ranging from microform to near-complete clefts. Because there are different amounts and qualities of tissue present on the cleft and non-cleft sides, surgical approaches should make distinctions based on the remnant tissue. A new procedure using an upper triangular flap that combines characteristics of both rotation advancement and straight line repair was applied and the surgical results were reviewed. Between June 2007 and April 2011, 28 patients with minor to two-thirds way unilateral cleft lips [minor (n = 12), one-third (n = 2), halfway (n = 11), and two-thirds way (n = 3)] were subjected to the upper triangular flap method. The patients ranged in age from 62 days to 6 years (mean, 9 months). The average follow-up period was 25 months (range, 12-60 months). The repairs were successful in all 28 patients without complications. The scar was acceptable because it ran along the vertical philtral columns. During the follow-up period, long lip deformities and Cupid bow drooping were not observed in any of the patients. However, misalignment of the white skin roll was observed due to insufficient rotation at the cleft side in 1 patient. The repairs of minor to two-thirds way unilateral cleft lips using the upper triangular flap method allowed for a symmetric Cupid bow and philtrum. Moreover, this method allowed for satisfactory nostril sill reconstruction with acceptable scarring. The upper triangular flap method is recommended as an alternative to conventional methods for repair of minor to two-thirds way incomplete unilateral cleft lips. PMID- 24051451 TI - Preparatory intravascular stenting technique: an easier method of supermicrosurgical lymphaticovenular anastomosis. AB - Recent supermicrosurgical techniques have made it possible to anastomose lymph vessels to the subdermal venular system. However, because the lymphatic fluid is clear and the vessel is translucent, soft, and fragile, with a thinner wall than blood vessels, supermicrosurgical lymphaticovenular anastomosis is a demanding technique. One difficulty of lymphaticovenular anastomosis is identification of the lumen to pass the suture into it. This report describes a preparatory intravascular stenting technique to identify the lumen and perform lymphaticovenular anastomosis accurately. In this technique, we placed 9-0 or 10 0 nylon thread into the lymphatic lumen before transecting the lymph vessel. The end of the nylon was pushed through to appear from the lymphatic lumen, then advanced into the vein to stabilize the 2 vessels. This technique allows supermicrosurgical lymphaticovenular anastomosis to be performed quickly and efficiently. PMID- 24051452 TI - The success of free gracilis muscle transfer to restore smile in patients with nonflaccid facial paralysis. AB - BACKGROUND: Development of synkinesis, hypertonicity, and poor smile excursion after facial nerve insult and recovery contribute to disfigurement, psychological difficulties, and an inability to convey emotion via facial expression. Despite treatment with physical therapy and chemodenervation, some patients who recover from transient flaccid facial paralysis never spontaneously regain the ability to perform a meaningful smile. METHODS: Prospective evaluation was performed on 20 patients with nonflaccid facial paralysis who underwent free gracilis muscle transfer. Patients were evaluated using the quality-of-life (QOL) FaCE survey, Facial Nerve Grading Scale, and Facegram to quantify QOL improvement, smile excursion, and symmetry after muscle transfer. RESULTS: A statistically significant increase in the FaCE score was seen after muscle transfer (paired 2 tailed t test, P < 0.039). In addition, there was a statistically significant improvement in the smile score on the Facial Nerve Grading Scale (P < 0.002), in the lower lip length at rest (P = 0.01) and with smile (P = 0.0001), and with smile symmetry (P = 0.0077) after surgery. CONCLUSIONS: Free gracilis muscle transfer has become a mainstay in the management armamentarium for patients who develop severe reduction in oral commissure movement after facial nerve insult and recovery. The operation achieves a high overall success rate, and innovations involving transplanting thinner segments of muscle avoid a cosmetic deformity secondary to excess bulk. This study demonstrates a quantitative improvement in QOL and facial function after free gracilis muscle transfer in patients who failed to achieve a meaningful smile after physical therapy. PMID- 24051453 TI - Effect of fibroblast-seeded artificial dermis on wound healing. AB - In covering wounds, efforts should include use of the safest and least invasive methods with a goal of achieving optimal functional and cosmetic outcome. The recent development of advanced technology in wound healing has triggered the use of cells and/or biological dermis to improve wound healing conditions. The purpose of the study was to evaluate the effects of fibroblast-seeded artificial dermis on wound healing efficacy.Ten nude mice were used in this study. Four full thickness 6-mm punch wounds were created on the dorsal surface of each mouse (total, 40 wounds). The wounds were randomly assigned to one of the following 4 treatments: topical application of Dulbecco phosphate-buffered saline (control), human fibroblasts (FB), artificial dermis (AD), and human fibroblast-seeded artificial dermis (AD with FB). On the 14th day after treatment, wound healing rate and wound contraction, which are the 2 main factors determining wound healing efficacy, were evaluated using a stereoimage optical topometer system, histomorphological analysis, and immunohistochemistry.The results of the stereoimage optical topometer system demonstrated that the FB group did not have significant influence on wound healing rate and wound contraction. The AD group showed reduced wound contraction, but wound healing was delayed. The AD with FB group showed decreased wound contraction without significantly delayed wound healing. Histomorphological analysis exhibited that more normal skin structure was regenerated in the AD with FB group. Immunohistochemistry demonstrated that the AD group and the AD with FB group produced less alpha-smooth muscle actin than the control group, but this was not shown in the FB group.Fibroblast-seeded artificial dermis may minimize wound contraction without significantly delaying wound healing in the treatment of skin and soft tissue defects. PMID- 24051454 TI - Complex ventral hernia repair using components separation with or without biologic mesh: a cost-utility analysis. AB - BACKGROUND: A complex ventral hernia requiring abdominal wall reconstruction presents a challenging scenario to the surgeon. The use of biologic mesh in addition to performing a components separation (CS) is controversial. Our goal was to perform the first cost-utility analysis on the use of biologic mesh in addition to performing CS when performing complex ventral hernia repair. METHODS: A comprehensive literature review was conducted to identify published complication and recurrence rates for ventral hernia repairs requiring CS with or without biologic mesh. The probabilities of the most common complications were combined with Medicare Current Procedural Terminology reimbursement codes, diagnosis related group reimbursement codes, and expert utility estimates to fit into a decision model to evaluate the cost utility of CS with and without biologic mesh in reconstructing ventral hernias. RESULTS: The decision model revealed a baseline cost increase of $775.65 and a 0.0517 increase in the quality adjusted life-years when using biologic mesh yielding an incremental cost-utility ratio of $15,002.90/quality-adjusted life-year. One-way sensitivity analysis revealed that using biologic mesh was cost-effective using Medicare reimbursement rates but not at retail costs. The maximum price of biologic mesh to be cost effective was $1813.53. CONCLUSIONS: The cost utility of biologic mesh when used with CS in ventral hernia repair is dependent on the financial perspective. It is cost-ineffective for hospitals and physicians paying retail costs but cost effective for third-party payers providing Medicare reimbursement. PMID- 24051455 TI - The retrograde limb of internal mammary vessels as reliable recipient vessels in DIEP flap breast reconstruction: a clinical and radiological study. AB - For many microsurgeons, antegrade internal mammary vessels (AIMVs) represent the recipients of choice in autogenous breast reconstruction. For the past few years, the retrograde internal mammary vessels (RIMVs) have been demonstrated to be a further reliable option when needed, according to many papers focusing more on the vein than on the artery. Besides the clinical evidence, the hemodynamic features of the retrograde system have been very seldom analyzed.In this article, we report our clinical experience with deep inferior epigastric perforator (DIEP) flaps anastomosed to RIMVs, along with a perioperative radiological follow-up to study RIMVs' hemodynamics and to further support the reliability of the retrograde system with particular focus on the retrograde internal mammary artery.Prospective, preoperative, and postoperative (3 days, 21 days, and 3 months, respectively) color Doppler sonographies of the internal mammary artery (IMA) and DIEPs have been performed to collect the velocity of flow (v) and resistive index (RI) data. Twenty-two patients agreed to undergo this protocol, of which 10 unipedicle flaps were anastomosed to AIMVs ("control" group), 10 bipedicle DIEPs to both AIMVs and RIMVs ("study" group), and 2 DIEPs anastomosed to retrograde internal mammary artery and antegrade internal mammary vein (not statistically analyzed for their paucity). Student t test was performed to compare the "control" and "study" groups.All the flaps survived, and no re exploration was needed. Internal mammary artery and perforators v showed similar but speculate trend, whereas IMA and perforators RI looked stable during that time. Significant differences have been found in the "study" group for IMA v at 3 day period, for perforator v at 21- and 90-day periods, and for perforator RI at 90-day period, without any clinical implication for flap viability.Retrograde internal mammary vessels can be considered reliable vessels for both arterial flap input and venous flap outflows, either as additional or the sole recipients. However, further and larger studies would be useful to better understand the hemodynamics of the retrograde system. PMID- 24051456 TI - Reverse superior labial artery flap in reconstruction of nose and medial cheek defects. AB - BACKGROUND: Angular artery, lateral nasal artery, and infraorbital artery pedicled nasolabial flaps have been used for reconstruction of lower nose and medial cheek defects. An alternative pedicle to raise a flap in the nasolabial area is the superior labial artery. Superior labial artery is a constant branch of the facial artery, arising above or at the angle of mouth and anastomoses with its counterpart in the middle of the upper lip. This makes a reverse superior labial artery pedicle possible for elevation of a nasolabial flap. PATIENTS AND METHODS: Reverse superior labial artery island flaps were used for reconstruction of lower nose and medial cheek defects in 12 patients. Eleven patients presented with malignant skin lesions and 1 with a traumatic defect of the lower nose. Auricular cartilage graft to support the alar rim and nasal tip was combined to the flap in 3 patients. RESULTS: All flaps survived completely. Temporary venous congestion was observed in 3 flaps in the early postoperative period but this resolved in 3 to 5 days. All patients healed without any postoperative complications and the final results were considered satisfactory. CONCLUSIONS: Reverse superior labial artery pedicled nasolabial island flap proved to be a good choice for reconstruction of the lower nose and moderate sized medial cheek defects. This pedicle should be considered where the defect is located on the course of lateral nasal artery or angular artery. Arc of rotation and reliability of this new flap is considered superior to angular artery and infraorbital artery based nasolabial flaps where these arteries could also be used as pedicle. PMID- 24051457 TI - An atypical presentation of a flexor intratendinous ganglion of the hand. AB - Intratendinous ganglions of the hand are rare. We report an unusual case of a ganglion arising within the flexor tendon in the hand. The intratendinous ganglion arose from the flexor digitorium profundus tendon of the little finger, causing flexion deformity of the finger. PMID- 24051458 TI - Effects of botulinum toxin A injection on healing and tensile strength of ruptured rabbit Achilles tendons. AB - BACKGROUND: Tendon lacerations are most commonly managed with surgical repair. Postoperative complications such as adhesions and ruptures often occur with immobilization. Early postoperative mobilization is therefore advised to minimize complications and time required to return to daily life. The aim of this study was to evaluate whether botulinum neurotoxin type-A (BoNT-A) can be used to enhance healing and prevent rupture in mobilized animals with Achilles tenotomy. METHODS: Twenty-seven rabbits were divided into 3 groups, namely, I, II, and III, after surgical 1-sided Achilles tenotomy and end-to-end repair. The control group for biomechanical comparisons consisted of randomly selected contralateral (unoperated) healthy Achilles tendons. Group I received BoNT-A (4 U/kg) injection into the calf muscles. One week later, electromyographical confirmation was performed to establish the effects of injection. Surgery was then performed. Animals in the second group (n = 9, group II) were immobilized with a cast postoperatively. The third group (n = 9, group III) was mobilized immediately with no cast or BoNT-A. Tendons were harvested and gap formation or ruptures as well as strength of the repaired tendon were assessed 6 weeks after surgery. RESULTS: Achilles tendons healed in all animals injected with BoNT-A, whereas all were ruptured in group III. All Achilles tendons of animals in groups I and II healed. However, group I repaired tendons were biomechanically equivalent to healthy tendons, whereas group II repaired tendons demonstrated significantly decreased tensile strength (P = 0.009). CONCLUSIONS: The present study suggests that local injection of BoNT-A can be used for treatment of tendon rupture and may replace the use of cast for immobilization. However, further studies are needed to determine whether BoNT-A injection can have a beneficial effect on the healing of tendon repairs in humans. PMID- 24051459 TI - Propranolol versus corticosteroids: what should be the treatment of choice in infantile hemangiomas? AB - BACKGROUND: Infantile hemangiomas (IHs) are common and benign vascular tumors and usually involute spontaneously. Nevertheless, in some cases, treatment with systemic corticosteroids or propranolol is required. No randomized controlled studies, in which both treatment options were compared, have been performed. METHODS: A systematic literature review and a retrospective cohort study in the Academic Medical Centre of 56 patients (mean age, 5.5 months; range, 0-40 months; SD, 7.6) with IHs were carried out. These patients were treated with either systemic corticosteroids or propranolol. The outcomes of both treatment options were evaluated and compared. RESULTS: The literature review showed that propranolol resulted in an involution in 100% of the patients, whereas corticosteroids only reached involution in 89%. The mean first response of the IH to propranolol was 3.2 days and of corticosteroids was 8.5 days. In our study sample, the patients treated with propranolol showed a faster and better response than the patients treated with corticosteroids. This is in line with literature findings. CONCLUSIONS: Systemic propranolol treatment is more effective for IHs than systemic corticosteroid treatment. Secondly, propranolol elicits a faster response than corticosteroids. PMID- 24051460 TI - Acquired digital fibrokeratoma: a case report. AB - Acquired digital fibrokeratomas are benign, rare tumors that develop most commonly on the fingers. They can have an appearance of a rudimentary supernumerary digit or be misdiagnosed as a more common condition, such as verruca vulgaris. There are no case reports described in the plastic surgery literature. We are reporting a case that presented to our institution recently. PMID- 24051461 TI - The partial myocutaneous gluteal flap reconstruction of extralevator abdominoperineal defects in irradiated patients. AB - Reconstruction of the irradiated perineum has posed a consistent reconstructive challenge historically. The evolution of reconstructive techniques must mirror advances in neoadjuvant treatment and surgery for low rectal cancer. The purpose of this study was to evaluate the perineal healing in a cohort of patients, of whom a majority had laparoscopic tumor excision and partial myocutaneous gluteal flap reconstruction. There were 11 patients in this cohort; 8 primary reconstructions and 3 salvage cases. Complete healing was measured as the cessation of all dressings. There were no returns to theater for flap-related surgery. Mean postreconstruction inpatient stay was 16.5 days. All patients healed completely. Mean time to healing was 42 days. This method has been successful for primary and salvage reconstruction in patients having laparoscopic or open surgery; thus, averting the major morbidity associated with failed reconstruction as reported for most of other reconstructive modalities in these patients. PMID- 24051462 TI - Expanded indications for the deep plane cervicofacial flap: aesthetic reconstruction of large combined temporofrontal and brow defects. AB - The deep plane cervicofacial (DPCF) rotation advancement flap has been well described for coverage of cheek and lower eyelid defects. The extension of this flap for coverage of complex combined temporofrontal and brow defects has not been previously described. The primary investigator (E.L.C.) performed a chart review of all 7 DPCF flaps performed for reconstructive purposes at the University of Texas Medical Branch, Galveston, Tex, from November 2011 through August 2012. Three patients with complex combined temporal and brow defects were identified. Three patients underwent coverage of complex combined temporofrontal and brow defects using the DPCF flap. Adequate coverage was provided with good skin color match. No flap loss or tip necrosis was seen, despite immediate excision of the resulting cheek standing cone deformity in 2 of the 3 patients at the time of reconstruction. All patients had suture fixation of the DPCF flap to cheek periosteum. All had none or mild lateral canthal distortion, with less than 1 mm of asymptomatic ectropion at a minimum follow-up of 4 months. The DPCF flap is a safe, effective, and reliable means to provide coverage for complex combined temporofrontal and brow defects. The deep plane elevation and musculocutaneous blood supply may improve flap mobility, viability, and resistance to tension. The standing cone deformity resulting from flap advancement can be primarily excised without risking flap necrosis. With further study, indications for the DPCF flap may include adjacent areas of the face currently being reconstructed using other means. PMID- 24051463 TI - A comparison of speech outcomes using radical intravelar veloplasty or furlow palatoplasty for the treatment of velopharyngeal insufficiency associated with occult submucous cleft palate. AB - BACKGROUND: The safety, efficacy, and direct comparison of various surgical treatments for velopharyngeal insufficiency (VPI) associated with occult submucous cleft palate (OSMCP) are poorly characterized. The aim of this study was to report and analyze the safety and efficacy of Furlow palatoplasty (FP) versus radical intravelar veloplasty (IVV) for treatment of VPI associated with OSMCP. METHODS: A retrospective review of one institution's experience treating VPI associated with OSMCP using IVV (group 1) or FP (group 2) during 24 months was performed. Statistical significance was determined by Wilcoxon matched-pair, Independent-Samples Mann-Whitney U, and analysis of variance (SPSS 20.0.0). RESULTS: In group 1 (IVV), 18 patients were identified from August 2010 to 2011 (12 male and 6 female patients; average age, 5.39 years). Seven patients were syndromic and 11 were nonsyndromic. In group 2 (FP), 17 patients were identified from August 2009 to 2011 (8 male and 9 female patients; average age, 8.37 years). Three patients were syndromic and 14 patients were nonsyndromic. There was statistical significance between the average pretreatment Pittsburgh Weighted Speech Score (PWSS) of the 2 groups (group 1 and 2 averages 19.06 and 11.05, respectively, P=0.002), but there was no statistical significance postoperatively (group 1 and 2 averages 4.50 and 4.69, respectively, P=0.405). One patient from each group required secondary speech surgery. Average operative time was greater for FP (140 minutes; range, 93-177 minutes) compared to IVV (95 minutes; range, 58-135 minutes), P<0.001. Average hospital stay was 3.9 days for IVV (range, 2-9 days) and 3.2 days for FP (range, 2-6 days), with no significant difference (P=0.116). There were no postsurgical wound infections, oral-nasal fistulas, postoperative bleeding complications, or mortalities. CONCLUSIONS: Nonsyndromic patients with hypernasal speech are treated effectively and safely with either IVV or FP. Intravelar veloplasty trended toward lower speech scores than FP (76% IVV, 58% FP PWSS absolute reduction). Syndromic patients with OSMCP may be more effectively treated with FP (72% IVV vs 79% FP PWSS absolute reduction). Intravelar veloplasty is associated with shorter operative times. Both techniques are associated with low morbidity, improved speech scores, and low reoperative rates. PMID- 24051464 TI - Safe extensive tumescent liposuction with segmental infiltration of lower concentration lidocaine under monitored anesthesia care. AB - Tumescent anesthesia makes it feasible to perform liposuction in an office setting. There are often patients who desire extensive liposuction on approximately 30% of total body surface area, which means the lidocaine total dose might be over the dosing recommendation. So the segmental infiltration is applied, although the concentration of lidocaine in tumescent fluid is gradually reduced to 0.0252%. Moreover, supplemental intravenous (IV) sedation using monitored anesthesia care is usually applied concurrently to help alleviate discomfort and pain of the patients during tumescent anesthetic infusion and fat extraction which in turn increases the risks of potential lidocaine toxicity due to possible drug interactions. This study was to demonstrate the safety of segmental infiltration of tumescent fluid with lower lidocaine concentration combined with IV sedation in extensive liposuction and determine whether the risk of lidocaine toxicity is increased in this protocol. Ten female patients who requested the extensive liposuction participated in the study. The targeted areas were divided into 2 segments and treated in turn in 1 session. Lidocaine (1600 mg) was infiltrated into the first segment, and approximately 928 mg lidocaine was subsequently infiltrated after accomplishment of the first segment operation. Serum levels of lidocaine were taken every 4 hours during the first 24 hours after the second infiltration. The average time of the procedure is 222 (33) minutes. The dose and total amount of lidocaine injected are 40.7 (5.8) mg/kg and 2528.2 (155.2) mg, respectively. The total volume of the infusates and aspirates are 9918.1 (494) and 6325 (1461.6) mL, respectively, the ratio of total infusates to total aspirates is 1.66 (0.45). The total aspirated fat and fluids are 3280 (1051.8) and 3045 (824.1) mL, respectively. The peak lidocaine levels [2.18 (0.63) MUg/mL] occurred after 12 to 20 hours [16.4 (2.27) hours]. No significant correlation between dose per kilogram body weight or total dose of lidocaine infiltrated and its peak levels or time existed. The extensive liposuction covering the 30% total body surface areas was well tolerated by the patients under tumescent anesthesia in combination with the supplemental IV sedation. Our previous study on the fluid management has demonstrated the risk of hypovolemia or fluid overload is very low with this technique, although the patients who received only maintenance fluid (500 mL) in the operating room and could discharge and resume oral intake after 6 hours of recovery room stay. The adequate anesthesia support is available in our office-based setting with adequate recovery facilities in place. It has a high margin of safety, without increasing of lidocaine toxicity or adverse cardiopulmonary sequelae while using a segmental tumescent infiltration with lower concentration of lidocaine. PMID- 24051465 TI - A new flap alternative for trochanteric pressure sore coverage: distal gluteus maximus musculocutaneous advancement flap. AB - Management of long-term bedridden patients experiencing pressure sores still represents a surgical challenge due to limited flap alternatives and high recurrence rates after the treatment. Fasciocutaneous, musculocutaneous, local perforator-based flaps, and free flaps have all been used for treatment of trochanteric pressure sores. This study presents a new use of distal gluteus maximus (GM) muscle as an advancement musculocutaneous flap for coverage of trochanteric pressure sores in 7 patients. The technique involves design of a long V-shaped skin island over the distal fibers of the GM muscle, beginning from the inferoposterior wound edge and extending inferomedially, almost parallel to the gluteal crease. After its harvest as an island flap on the distal fibers of the GM muscle, the skin paddle can be advanced onto the trochanteric defect, whereas the muscle itself is rotated after severing its insertion to femur. If a second triangular skin island is designed on the proximal fibers of GM muscle to cover an associated sacral defect, 2 coexisting pressure sores can be reconstructed concomitantly with 2 skin paddles on a single muscle belly at 1 surgical setting. Of the 7 patients, 3 had 3 (bilateral trochanteric and sacral), 2 had 2 (sacral and trochanteric), and 2 had 1 (only trochanteric) pressure sores. All ulcers were closed successfully and all of the flaps survived totally without any complication except the one in which we experienced minimal wound dehiscence in the early postoperative period. Conclusively, our current surgical method provided a reliable coverage for trochanteric pressure sores although it was technically straightforward and fast. Additionally, it offers simultaneous closure of 2 pressure ulcers with 2 skin islands on a single muscle flap. PMID- 24051466 TI - Variance in the origin of the pectoralis major muscle: implications for implant based breast reconstruction. AB - BACKGROUND: The pectoralis major muscle plays a crucial role in implant-based breast reconstruction. The goal of this study is to document variations of the origin of the pectoralis major muscle (PM). We hope to understand how many women have anatomy allowing for total submuscular coverage of an implant with the PM alone in immediate breast reconstruction. METHODS: Fifty patients undergoing mastectomy were recruited. Breast width and the costal origin of the natural inframammary fold (IMF) were measured preoperatively and intraoperatively. The PM width at its origin and the rib origin of the PM were measured intraoperatively. A ratio of the PM origin width to breast width was calculated. RESULTS: Forty four percent of breasts studied had the IMF at the level of the seventh rib, 53% at the sixth rib, and 3% at the fifth rib. Twenty percent of PM muscles originated from the seventh rib, 68% from the sixth rib, and 12% from the fifth rib. Thirty-six percent of chests showed a PM originating one rib level above the IMF, 61% at the same level, and 3% one level below the IMF. Seventy-seven percent of chests showed a PM origin width to breast width ratio of <0.8. CONCLUSIONS: Overall, 72% of chests had either a high origin of the PM, a narrow PM relative to the breast width, or both. This anatomy is suboptimal for implant coverage using the PM alone. Surgeons performing implant-based breast reconstruction should be prepared to utilize wide dissection, alternative muscle recruitment, or supplemental acellular dermal matrix. PMID- 24051467 TI - Triangular with Ala Nasi (TAN) II repair of unilateral cleft lips with severe nasal deformity. AB - BACKGROUND/INTRODUCTION: With our previous technique called triangular with ala nasi (TAN) repair, we combined the superiorities of these 2 popular techniques by approaching the skin, as in Tennison-Randall, and the muscle and nose, as in Millard. Although good results have been obtained in most patients, cleft lip nose (CLN) deformity could not entirely be corrected particularly in serious cleft patients. Therefore, we revised the technique, called the TAN II repair, by adding some nasal maneuvers including the bivectoral suspension sutures, alar buckling resection, and alar web resection. METHODS: Forty-two consecutive patients (26 male and 16 female) with unilateral cleft lips were operated on using the TAN II technique in the last 5 years. The mean age at repair was 11.95 months (range, 3 to 120). The postoperative outcomes were assessed subjectively by Williams test and objectively by Lindsay-Farkas method. RESULTS: The mean follow-up time was 16.3 months. No early complication involving hematoma, infection, wound dehiscence, or partial or total flap loss was encountered. The recoveries of 92.42% and 88.89% on average, when compared with the noncleft side, were obtained postoperatively. CONCLUSIONS: With these modifications, the TAN II technique was able to correct the severe unilateral CLN deformities. We obtained good to excellent outcomes in late postoperative follow-up by means of a long term suspension effect. PMID- 24051468 TI - Vascularized sural nerve graft and extracorporeally irradiated osteochondral autograft for oncological reconstruction of wrist sarcoma: case report and review of literature. AB - For tumors that are located beside the main peripheral nerve, combined wide resection of both the tumor and peripheral nerve is mandatory. We here present an interesting case with synovial sarcoma of the wrist. An 8 cm of ulnar nerve defect was reconstructed by vascularized, folded sural nerve graft with the peroneal flap, whereas an 8 cm of distal ulna was reconstructed using extracorporeally irradiated osteochondral autograft. Our case showed excellent nerve regeneration. Extracorporeal irradiated osteochondral graft was a good option for reconstruction of the distal ulna. This procedure should be indicated for the reconstruction of non-weight-bearing joints. These kinds of reconstruction have been addressed in only a few cases of oncological reconstruction. PMID- 24051469 TI - Facelift in a patient with benign symmetric lipomatosis and HIV facial lipoatrophy: a case report. AB - Benign symmetric lipomatosis (BSL) is a rare condition characterized by deposition of unencapsulated adipose tissue at typical sites on the body. Although the pathogenesis is not clearly defined, the disease has been associated with male gender, alcoholism, Mediterranean descent, and highly active antiretroviral therapy. A case study is presented of a facelift performed on a human immunodeficiency virus-positive patient on a highly active antiretroviral therapy with facial lipoatrophy in the anterior cheek region in combination with BSL characterized by excess fat deposits in multiple areas including the posterior cheeks and neck. The resultant peculiar deformity was managed in this case with a modified facelift and fat excision without recurrence. There are few reports in the English literature describing surgical excision using the facelift pattern for treating BSL. PMID- 24051470 TI - Immediate bone grafting and plating of the radial osteocutaneous free flap donor site. AB - BACKGROUND: The primary shortcoming of the osteocutaneous radial forearm flap (ORFF) in head and neck reconstruction is the high incidence of fracture at the donor site. Although several prophylactic measures are reported, combined plating with iliac crest bone graft (ICBG) of the donor site has not been previously described. Outcomes and rationale for this method of radius reconstruction are described. METHODS: Retrospective review of a prospectively maintained database identified 23 consecutive patients who underwent head and neck reconstruction using an ORFF. Flap features, method of donor-site reconstruction, and complications were evaluated. RESULTS: The initial 7 patients from the series had no intervention at the radius donor site. The next 7 patients had ICBG only, whereas the final 9 patients had both plating and ICBG placed at the donor site. The mean cross-sectional diameter and length of radius bone harvested was 30% by 7 cm, 33% by 8 cm, and 53% by 9 cm for the 3 groups, respectively. Fracture rates for the 3 groups were 29%, 14%, and 0%. There were no iliac crest donor-site complications. CONCLUSIONS: Plating combined with ICBG is a safe and effective method for radius donor-site reconstruction. This technique maximizes both early and late strength of the radius while allowing for harvest of greater segments of bone. Decreased donor-site morbidity combined with more bone available for use in oromandibular reconstruction may tip the risk-benefit scale in favor of more widespread ORFF use. PMID- 24051471 TI - Hypertrophy in labial capillary malformations: clinical and pathological findings in 11 patients. AB - Hypertrophy in capillary malformation (CM) may be present at birth or manifest itself later in life. To gain insight into the pathology of hypertrophic CM, we investigated a series of 11 excisional biopsies of hypertrophic lips.All biopsies showed dilated thin-walled microvessels in the superficial dermis without a neural component. However, large multinodular conglomerates of thick-walled vessels with a substantial increase in nerve fibers were found in the deeper parts of the lesions. These veins extended deep into the facial musculature. Hypertrophy in CM is caused by venous malformation underlying the CM. So CM associated with hypertrophy should be considered as Capillary Venous malformations. PMID- 24051472 TI - Anterior-posterior dissociative slide facilitates the second stage of 3-stage forehead flap nasal reconstruction. AB - Pedicle-lining skin grafts contract between the first and second stage in a 3 stage forehead flap nasal reconstruction. The second stage involves an inherent reduction in vascularity due to the soft tissue thinning performed. The Anterior Posterior Dissociative Slide restores first-stage pedicle length at the second stage. Incisions are made at the distal seam between the contracted graft and the pedicle tissue. The flap is then slid caudally relative to the fixed graft, thus relengthening the pedicle. This technique has been performed in 16 patients achieving an average length gain of 0.7 (+0.2) cm. The additional length created with the dissociative slide translates into reduced tension with flap reinset, thus increasing flap workability and overall artistry in the second stage. PMID- 24051473 TI - Digestive disease management in Japan: a report on the 6th diagnostic pathology summer fest in 2012. AB - The 6th Diagnostic Pathology Summer Fest, held in Tokyo on August 25-26, 2012, opened its gates for everyone in the medical profession. Basic pathology training can contribute to the improvement of algorithms for diagnosis and treatment. The 6th Summer Fest with the theme 'Pathology and Clinical Treatment of Gastrointestinal Diseases' was held at the Ito International Research Center, The University of Tokyo. On August 25, 'Treatment of Early Gastrointestinal Cancer and New Guidelines' was discussed in the first session, followed by 'Biopsy Diagnosis of Digestive Tract: Key Points of Pathological Diagnosis for Inflammation and Their Clinical Significance' in the second session. On August 26, cases were discussed in the third session, and issues on pathological diagnosis and classification of neuroendorcrine tumor in the fourth session. The summaries of speeches and discussions are introduced along with the statements of each speaker. This meeting was not a formal evidence-based consensus conference, and 20 experts gave talks on their areas of specialty. Discussion was focused on how the management strategy should be standardized on the algorithm of patient care. PMID- 24051474 TI - Vesical paragonimiasis diagnosed by histopathology: a case report. AB - Vesical paragonimiasis is an extremely rare form of ectopic infestation caused by Paragonimus spp. We reported a case of vesical paragonimiasis associated with urinary symptoms but without history of respiratory symptoms or cercarial dermatitis. The diagnosis was made by histopathological examination of the surgical specimens of the vesical masses. Identification of the species by morphometric analysis of the fluke body sections indicated that the vesical lesion was caused by Paragonimus. Postsurgical medication with the antiparasitic drug praziquantel was applied regularly, and the patient experienced a stable recovery. PMID- 24051475 TI - Solution properties and in vitro anti-tumor activities of polysaccharides from longan pulp. AB - The solution properties of four fractions (LPI-IV) from crude longan pulp polysaccharides (LP3) were analyzed by size-exclusion chromatography combined with laser light scattering, viscometry, complex formation with Congo red, and atomic force microscopy. Their radii of gyration (z)(1/2) were 43.3, 62.6, 43.2 and 77.3 nm, exponents of (z)(1/2) = k M(w)(v) were 0.04, 0.50, 0.52 and 0.02, and intrinsic viscosities ([eta]) were 9.945, 25.38, 308.2 and 452.1 mL/g, respectively. Moreover, the dependence of [eta] on M(w) was established to be [eta] = 5.3 * 10-2M(w)0.61 (mL/g). LPI had both a sphere-like conformation and a triple-helix structure, and LPII-IV existed as flexible chains. LP3, LPI, LPII and LPIII all exhibited direct inhibitory effects on A549, HeLa and HepG2 cells in a positive dose-dependent manner in the range of 50-400 ug/mL. The activities of LPIII, especially the inhibition of HepG2 cell proliferation, were stronger than those of others, which may be partly related to its flexible conformation. The present results support the cancer therapeutic potential of longan polysaccharides. PMID- 24051476 TI - Combined effects of green tea extracts, green tea polyphenols or epigallocatechin gallate with acarbose on inhibition against alpha-amylase and alpha-glucosidase in vitro. AB - Green tea, green tea polyphenols and epigallocatechin gallate (EGCG) are confirmed to have beneficial effects in the treatment of diabetes mellitus, and a possible mechanism can be ascribed to their inhibitory effect against alpha amylase and alpha-glucosidase in the digestive tract. In this paper, we first investigated the combined inhibitory effect of green tea extracts, green tea polyphenols or EGCG with acarbose on alpha-amylase and alpha-glucosidase in vitro. Our results indicated that the interaction between green tea extracts (green tea polyphenols or EGCG) and acarbose was complicated. The combination of green tea extracts, green tea polyphenols or EGCG with acarbose had a synergistic effect on alpha-amylase and alpha-glucosidase at low concentrations and the combined effect turned out to be antagonistic at high concentrations according to the Combination Index (CI) values. These findings not only provided some significant quantitative values, but also provide some valuable implications for the combined use of acarbose and GTE (GTP or EGCG) in the treatment of diabetes mellitus. PMID- 24051477 TI - Corrective distal radius osteotomy following fracture malunion using a fixed angle volar locking plate. AB - Post-traumatic distal radius deformity may cause severe morbidity, and corrective osteotomy is often necessary to realign the functional axis of the wrist to correct symptomatic malunion. The aim of this retrospective study was to review the short-term results of a single surgeon's series of distalradius corrective osteotomies following fracture malunion using a fixed-angle volar locking plate for 20 patients(16 women) of an average age of 57 (range 19-83) years [corrected].At short-term follow up (average 14 months, range 12-15 months), no complications were noted and radiological union was confirmed in all cases at an average of 3 months. The average post-operative Disability of the Arm, Shoulder and Hand score was 13.48 (range 0-48.33) and an objective improvement was noted in movements at the wrist joint. A statistically significant improvement was achieved in ulnar variance, radial inclination, dorsal tilt, and supination. PMID- 24051478 TI - High incidence and treatment of flexor carpi radialis tendinitis after trapeziectomy and abductor pollicis longus suspensionplasty for basal joint arthritis. AB - We reviewed the incidence and treatment of flexor carpi radialis tendinitis in 77 patients (81 thumbs) who had trapeziectomy and abductor pollicis longus suspensionplasty for thumb carpometacarpal joint arthritis. Eighteen patients, 20 wrists (25%) had flexor carpi radialis tendinitis. The onset was 2-10 months (mean 4.7) after surgery. Two cases had preceding trauma. Eight cases (40%) responded to splinting and steroid injection. Ten patients, 12 wrists (60%) underwent surgery after failing non-operative treatment. Eleven wrists had frayed or partially torn flexor carpi radialis tendon and one had a complete tendon rupture with pseudotendon formation. Flexor carpi radialis tenotomy and pseudotendon excision were performed. All operated patients obtained good pain relief initially post-operatively. However, the pain recurred in two patients after 8 months. One required a local steroid injection for localized tenderness at the site of the proximal tendon stump. The other patient required a revision operation for scaphotrapezoid impingement. Both obtained complete pain relief. Our study has shown a high incidence of flexor carpi radialis tendinitis following trapeziectomy and abductor pollicis longus suspensionplasty. Patients should be warned about this potential complication. PMID- 24051480 TI - Elevated C-reactive protein and spontaneous bacterial peritonitis in children with chronic liver disease and ascites. AB - OBJECTIVES: The aims of this study were to compare laboratory indices of spontaneous bacterial peritonitis (SBP) and noninfected ascites in children with chronic liver disease and to determine the infectious agents involved in SBP. METHODS: The medical records of 90 children with chronic liver disease and ascites studied between January 2005 and August 2011 were reviewed for laboratory data of diagnostic significance in SBP. Standard laboratory tests included blood cell count, coagulation indices, liver and renal function tests, C-reactive protein (CRP), serum sodium concentration, serum albumin, and serum cultures. Ascitic fluid obtained from 152 paracentesis procedures was assayed for cytology, Gram stains, neutrophil counts, and bacteriological cultures. RESULTS: The SBP group manifested significantly lower albumin levels and elevated CRP levels, prothrombin times, international normalized ratios, and leukocyte number (P<0.05 in each case). CRP was shown to be an independent variable in the prediction of SBP. Values of serum creatinine, sodium concentration, urea, total bilirubin and differential leukocyte shift were comparable in SBP and noninfected ascites. Streptococcus pneumoniae was the most prevalent infectious agent in the ascitic fluid (44%). CONCLUSIONS: CRP may be useful in early detection and monitoring of SBP in children with liver disease. PMID- 24051479 TI - Opportunities for genomic clinical decision support interventions. PMID- 24051481 TI - Lynch syndrome: a pediatric perspective. AB - Colorectal cancer is a rare disease in the pediatric age group and, when present, suggests an underlying genetic predisposition. The most common hereditary colon cancer susceptibility condition, Lynch syndrome (LS), previously known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant condition caused by a germline mutation in 1 of 4 DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2. The mutation-prone phenotype of this disorder is associated with gastrointestinal, endometrial, and other cancers and is now being identified in both symptomatic adolescents with malignancy as well in asymptomatic mutation carriers who are at risk for a spectrum of gastrointestinal and other cancers later in life. We review the DNA MMR system, our present understanding of LS in the pediatric population, and discuss the newly identified biallelic form of the disease known as constitutional mismatch repair deficiency syndrome. Both family history and tumor characteristics can help to identify patients who should undergo genetic testing for these cancer predisposition syndromes. Patients who carry either single allele (LS) or double allele (constitutional mismatch repair deficiency syndrome) mutations in the MMR genes benefit from cancer surveillance programs that target both the digestive and extraintestinal cancer risk of these diseases. Because spontaneous mutation in any one of the MMR genes is extremely rare, genetic counseling and testing are suggested for all at-risk family members. PMID- 24051482 TI - Rotavirus, intestinal barrier function, and probiotics. PMID- 24051483 TI - Is folic acid supplementation really necessary in preterm infants <= 32 weeks of gestation? AB - OBJECTIVES: The aim of this study was to define whether there was folate deficiency in hospitalized preterm infants, and, second, to define the effect of feeding modalities on serum folate levels. METHODS: Infants born <= 32 weeks of gestation were included in the study. Blood samples for the determination of serum folate levels were obtained on days 14 and 28 postnatally, as well as 36 weeks postconceptionally (or just before discharge if patients are discharged <36 weeks)--samples A, B, and C, respectively. Infants were divided into 3 groups based on mode of feeding; human breast milk (HBM), fortified HBM (fHBM), or preterm formula (PF). RESULTS: A total of 162 preterm infants were enrolled: 17 (10.5%) of whom received HBM alone, 94 (58%) received fHBM, and 51 (31.5%) were fed with PF. None of the preterm infants developed folate deficiency during the study period. Preterm infants in the fHBM and PF groups had significant higher serum folate levels in samples C when compared with those receiving HBM alone (P < 0.001 for both). Multivariate analysis to evaluate the effects of maternal supplementation, smoking habit, gestational age, birth weight, and cumulative folic acid intake in samples A, B, and C suggested that maternal smoking and maternal folic acid supplementation had significant effects on serum folate levels in sample A and B. CONCLUSIONS: Preterm infants receiving parenteral nutrition with high folic acid content have no risk of folate deficiency during the 2 months of age; however, preterm infants fed orally from birth with HBM or PF with a low folic acid content could be at risk for folate deficiency, especially when mothers are smokers and/or do not receive folic acid supplementation during pregnancy. PMID- 24051484 TI - Challenges in meeting fellowship procedural guidelines in pediatric therapeutic endoscopy and liver biopsy. AB - OBJECTIVE: The aims of this study were to assess the opportunities for therapeutic endoscopy, liver biopsies, and percutaneous endoscopic gastrostomy (PEG) placements available to fellows during a 3-year pediatric gastroenterology fellowship, and to evaluate access to ancillary procedural-training opportunities. METHODS: Data were collected from 12 pediatric gastroenterology fellowship programs in the United States. Procedures completed in the years 2009 2011 were queried using CPT codes and endoscopy databases. The maximal opportunity for procedures was based on the total procedures performed by the institution in 3 years divided by the total number of fellows in the program. The centers completed a questionnaire regarding ancillary opportunities for endoscopic training. RESULTS: There is significant variability in pediatric endoscopic training opportunities in specialized gastrointestinal (GI) procedures. Under the 1999 guidelines, no centers were able to meet the thresholds for polypectomy and control of nonvariceal bleeding. The 2013 guidelines allowed the number of programs reaching polypectomy thresholds to increase by 67% but made no difference for control of bleeding despite a decrease in the threshold. Training in PEG placement was not available in 42% of the surveyed centers. Elective ancillary procedural training is offered by 92% of the surveyed centers. CONCLUSIONS: Most training programs do not have the volume of therapeutic endoscopy procedures for all of the fellows to meet the training guidelines. Training in therapeutic endoscopy, PEG placement, and liver biopsy in pediatric GI fellowships should be supplemented using all of the possible options including rotations with adult GI providers and hands-on endoscopy courses. A shift toward evaluating competency via quality measures may be more appropriate. PMID- 24051485 TI - Challenge of meeting fellowship procedural guidelines in therapeutic endoscopy and liver biopsy. PMID- 24051486 TI - Novel methods for training future pediatric gastroenterologists. PMID- 24051491 TI - GM crops and foods: what do consumers want to know? AB - Agricultural biotechnology--GMOs--has a huge positive impact on farming and farmers but remains controversial among the skeptical public. Curious but anxious consumers, driven by scare stories and pseudo-science provided by anti-GMO activists, seek accurate and authoritative answers to their questions. Here, I address a sample of such queries directed to me from the public, including the ubiquitous "Is it safe?" and also discuss some of the shameful tactics used by anti-GM activists in the public debate to garner support at the cost of inciting unnecessary anxiety among the public. PMID- 24051493 TI - Creativity, alcohol and drug abuse: the pop icon Jim Morrison. AB - BACKGROUND: Alcohol and drug abuse is frequent among performers and pop musicians. Many of them hope that alcohol and drugs will enhance their creativity. Scientific studies are scarce and conclusions limited for methodological reasons. Furthermore, extraordinary creativity can hardly be grasped by empirical-statistical methods. Thus, ideographic studies are necessary to learn from extraordinarily creative persons about the relationship of creativity with alcohol and drugs. The pop icon Jim Morrison can serve as an exemplary case to investigate the interrelation between alcohol and drug abuse and creativity. METHODS: Morrison's self-assessments in his works and letters as well as the descriptions by others are analyzed under the perspective of creativity research. RESULTS: In the lyrics of Jim Morrison and in biographical descriptions, we can see how Jim Morrison tried to cope with traumatic events, depressive moods and uncontrolled impulses through creative activities. His talent, skill and motivation to write creatively were independent from taking alcohol and drugs. He used alcohol and drugs to transgress restrictive social norms, to broaden his perceptions and to reinforce his struggle for self actualization. In short, his motivation to create something new and authentic was reinforced by alcohol and drugs. More important was the influence of a supportive group that enabled Morrison's talents to flourish. However, soon the frequent use of high doses of alcohol and drugs weakened his capacity to realize creative motivation. CONCLUSIONS: Jim Morrison is an exemplary case showing that heavy drinking and the abuse of LSD, mescaline and amphetamines damages the capacity to realize creative motivation. Jim Morrison is typical of creative personalities like Amy Winehouse, Janis Joplin, Brian Jones and Jimmy Hendrix who burn their creativity in early adulthood through alcohol and drugs. We suppose that the sacrificial ritual of their decay offers some benefits for the excited spectators. One of these is the illusion that alcohol and drugs can lead to authenticity and creativity. PMID- 24051492 TI - p53 regulates Period2 expression and the circadian clock. AB - The mechanistic interconnectivity between circadian regulation and the genotoxic stress response remains poorly understood. Here we show that the expression of Period 2 (Per2), a circadian regulator, is directly regulated by p53 binding to a response element in the Per2 promoter. This p53 response element is evolutionarily conserved and overlaps with the E-Box element critical for BMAL1/CLOCK binding and its transcriptional activation of Per2 expression. Our studies reveal that p53 blocks BMAL1/CLOCK binding to the Per2 promoter, leading to repression of Per2 expression. In the suprachiasmatic nucleus (SCN), p53 expression and its binding to the Per2 promoter are under circadian control. Per2 expression in the SCN is altered by p53 deficiency or stabilization of p53 by Nutlin-3. Behaviourally, p53-/- mice have a shorter period length that lacks stability, and they exhibit impaired photo-entrainment to a light pulse under a free-running state. Our studies demonstrate that p53 modulates mouse circadian behaviour. PMID- 24051494 TI - Endoscopic laser dichorionization of the placenta in the treatment of severe twin twin transfusion syndrome. AB - OBJECTIVES: To describe the results of a technique of laser ablation of placental vessels in the treatment of severe twin-twin transfusion syndrome (TTTS), which is characterized by separation of the fetoplacental vascular territories and dichorionization of the placenta. PATIENTS AND METHODS: Descriptive analysis of TTTS cases treated with the endoscopic laser dichorionization of the placenta (ELDP) procedure. The variables evaluated were the occurrence of reversal of the donor-recipient phenotype, persistence of TTTS or twin anemia-polycythemia sequence (TAPS); gestational age at delivery; discharge from the hospital of at least 1 or 2 live neonates, and incidence of neurological alterations among survivors. RESULTS: 67 patients were treated with the ELDP procedure. There was no persistence of TTTS, reversal of the donor-recipient phenotype or TAPS. The median gestational age at delivery was 33.0 (23.6-37.7) weeks. The rate of discharge from the hospital of at least 1 or 2 live neonates was 88.2% (67/76) and 71.1% (54/76), respectively. Among survivors, 17 (17/121 = 14.0%) children presented with neurodevelopmental alterations during clinical follow-up. CONCLUSIONS: The major contribution of this study was the demonstration that the ELDP technique appears to be associated with a low risk of persistence or recurrence of TTTS and TAPS. PMID- 24051495 TI - Hydrothermal synthesis of inorganic-organic hybrid gadolinium hydroxide nanoclusters with controlled size and morphology. AB - A series of gadolinium hydroxide [Gd(OH)3] nanoclusters having different morphologies was synthesized in the presence of 3,4-dihydroxy hydrocinnamic acid (DHCA), an organic modifier, under subcritical water conditions. These well shaped Gd(OH)3 clusters are composed of many nanorods in a parallel orientation, rather than a disordered aggregation of nanorods, which are linked together by organic DHCA molecules. Here DHCA works as an inter-linker to form these cluster like structures through coordination bonds. All samples were characterized by X ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy and SQUID magnetometry. We investigated the effect of the concentrations of DHCA and KOH on the size and morphology of the Gd(OH)3 clusters. Their possible formation mechanism is also briefly discussed. PMID- 24051496 TI - Effects of endoscopic mucosal resection in patients with low-grade intraepithelial dysplasia of esophageal squamous cells. AB - BACKGROUND: This study evaluated the effects of endoscopic mucosal resection (EMR) on patients with low-grade intraepithelial dysplasia (LGD) of the esophageal squamous cells. METHODS: A randomized study recruited 128 LGD patients. These patients were randomly divided into treatment and control groups after the preoperative examination. The treatment group was composed of 63 LGD cases who received EMR. The control group included 65 LGD cases that were not treated with EMR. Clinical interviews and endoscopy were conducted after 30 months as postoperative follow-up. RESULTS: Concerning the percentages of esophageal lesions that changed from serious conditions into slight conditions (namely from high-grade intraepithelial dysplasia (HGD) to LGD, basal cell hyperplasia, esophagitis and normal mucosa) there was a significantly linear trend relationship between the treatment group and control group. In downstaging of dysplasia grade, the total percentage for the 52 cases (82.5%) in the treatment group was significantly higher than that for the 32 cases (49.2%) in the control group (Pearson chi(2) = 15.734, p < 0.001). Also, in patients that remained at the LGD grade or had upstaging of their dysplasia grade, the proportions of the change were significantly different between the two groups. CONCLUSION: The percentage rate of regression of LGD was increased in the EMR treatment group as compared to that of the control group. EMR may prevent or delay the progression of LGD to HGD. PMID- 24051497 TI - Disruption of the thymic microenvironment is associated with thymic involution of transitional cell cancer. AB - INTRODUCTION: During bladder tumorigenesis, thymopoiesis is usually downregulated. Considering that the thymus is the site of most T-cell development, this phenomenon may be related to thymic involution. However, the mechanisms involved in this phenomenon remain to be elucidated. MATERIALS AND METHODS: An MB 49 murine bladder tumor model was used to identify mechanisms that might underlie this process. RESULTS: The thymuses of tumor-bearing mice showed less cellularity than those of healthy mice. Involution was found to be associated with less proliferation and more apoptosis of thymic epithelial cells (TEC). Foxn1, KGF, and IL-7, three factors known to be involved in thymic development, were also downregulated in the thymuses of tumor bearers. When these mice were intravenously injected with KGF, the thymic microenvironment, thymopoiesis, and T-cell differentiation all returned to near normal status. CONCLUSIONS: The decreases in thymopoiesis and impaired T-cell differentiation may be attributable to changes in the thymic microenvironment. Improving the function of TEC, rather than T-cell progenitors, should be the focus of therapy. PMID- 24051498 TI - Mandibulectomy and free flap reconstruction for bisphosphonate-related osteonecrosis of the jaws. AB - IMPORTANCE: Bisphosphonate-related osteonecrosis of the jaws is an increasingly recognized complication of intravenous and oral bisphosphonate therapy. Our experience suggests that mandibulectomy and free flap reconstruction is an effective treatment for patients with stage 3 and recalcitrant stage 2 disease. OBJECTIVE: To analyze indications for segmental mandibulectomy and microvascular free flap reconstruction for bisphosphonate-related osteonecrosis of the jaws and surgical outcomes following this procedure. DESIGN, SETTING, AND PARTICIPANTS: In a multi-institutional case series study conducted in academic tertiary care centers, 13 patients underwent segmental mandibulectomy and microvascular free flap reconstruction, including 8 patients with stage 3 disease and 5 patients with recalcitrant stage 2 disease. All patients had persistent or progressive disease despite conservative oral care and antibiotic treatment. INTERVENTIONS: Segmental mandibulectomy and microvascular free flap reconstruction. MAIN OUTCOMES AND MEASURES: Treatment efficacy and postoperative complications. RESULTS There was 1 total flap loss due to infection. The patient with a flap loss ultimately underwent a successful fibula osteocutaneous free flap reconstruction after serial irrigation and debridement. The overall complication rate was 46% (n = 6). All complications occurred in patients with stage 3 disease. Ultimately, all patients achieved a successful reconstruction, with no recurrences. All patients tolerated a soft or regular diet postoperatively. CONCLUSIONS AND RELEVANCE: Bisphosphonate-related osteonecrosis of the jaws is an increasingly recognized complication of intravenous and oral bisphosphonate therapy that can occasionally progress to involve full-thickness mandibular destruction, pathologic fracture, and fistulization, as well as chronic pain and infection. Mandibulectomy and free flap reconstruction is an effective treatment for patients with stage 3 and recalcitrant stage 2 bisphosphonate-related osteonecrosis of the jaws. High rates of chronic infection and underlying medical comorbidities may predispose to a substantial perioperative complication rate. PMID- 24051499 TI - Translational findings on brain-derived neurotrophic factor and anxiety: contributions from basic research to clinical practice. AB - BACKGROUND/AIMS: Anxious responses are evolutionarily adaptive, but excessive fear can become disabling and lead to anxiety disorders. Translational models of anxiety might be useful sources for understanding the neurobiology of fear and anxiety and can contribute to future proposals of therapeutic intervention for the disorders studied. Brain-derived neurotrophic factor (BDNF), which is known for its importance on neuroplasticity and contextual memory, has emerged as a relevant element for emotional memory. Recent studies show that the Val(66)Met BDNF polymorphism correlates with various psychiatric disorders, including anxiety, but there are several differences between experimental and clinical studies. METHODS: In this work, we review the literature focused on the BDNF Val(66)Met polymorphism and anxiety, and discuss biological findings from animal models to clinical studies. RESULTS: As occurs with other psychiatric disorders, anxiety correlates with anatomical, behavioral and physiological changes related to the BDNF polymorphism. In animal studies, it has been shown that a significant decrease in regulated secretion from both BDNFVal/Met and BDNFMet/Met neurons represented a significant decrease in available BDNF. CONCLUSION: These studies suggest that developing pharmacological strategies facilitating the release of BDNF from synapses or prolongation of the half-life of secreted BDNF may improve the therapeutic responses of humans expressing the BDNF polymorphism. PMID- 24051500 TI - Abstracts of the 20th International Congress of Nutrition. Granada, Spain. September 15-20, 2013. PMID- 24051502 TI - Direct access to triazole-olefins through catalytic cycloaddition of azides to unsaturated aldehydes. AB - In situ formed dienamines as HOMO-raising dipolarophiles react with azides to afford the corresponding triazole-olefins in good to excellent yields via a catalytic inverse-electron-demand 1,3-dipolar cycloaddition process. PMID- 24051501 TI - Lycopene supplement and blood pressure: an updated meta-analysis of intervention trials. AB - Epidemiological studies suggested that lycopene supplement could decrease blood pressure, but the results were conflicting. We conducted an updated meta-analysis by screening PubMed databases, and calculated the combined effect size using a random effect model. In addition, subgroup analysis stratified by baseline blood pressure, lycopene dosage, duration, study location and the funding support of the paper was also conducted. Six studies met our inclusion criteria, and the pooled analysis demonstrated a significant reduction of systolic blood pressure (SBP) (mean SBP = -4.953 [-8.820, -1.086], p = 0.012) with obvious heterogeneity (p = 0.034, I2 = 58.5%). Subgroup analysis results showed that higher dosage of lycopene supplement (>12 mg/day) could lower SBP more significantly, especially for participants with baseline SBP >120 mmHg, or Asians, while lycopene intervention had no statistical effect on diastolic blood pressure (DBP) (mean DBP = -3.809 [-8.177, 0.560], p = 0.087), and obvious heterogeneity was also observed (p = 0.074, I2 = 53.1%). Our present study suggests that lycopene supplement >12 mg/day might effectively decrease SBP, particularly among Asians or population with higher baseline SBP. PMID- 24051503 TI - Weight gain, total fat gain and regional fat gain during pregnancy and the association with gestational diabetes: a population-based cohort study. AB - OBJECTIVE: In a multi-ethnic population-based study, we investigate the change in indicators of adiposity (being weight gain and gain of total fat, truncal fat and mean skinfold thickness) from early pregnancy to 28 weeks of gestation overall and across ethnic groups, and explore the association between the change in indicators of adiposity and gestational diabetes (GDM). DESIGN: Weight, skinfold thickness and bioelectrical impedance analysis were performed twice in 728 pregnant women in gestational week 15 (visit 1) and week 28 (visit 2). GDM was defined by the modified International Association of Diabetes in Pregnancy Study Group (IADPSG) criteria (1-hour glucose not available). RESULTS: An increase in all indicators of adiposity gave increased odds ratios (OR) for GDM. After adjusting for pre-pregnant body mass index, a 0.14 kg per week (one standard deviation (s.d.)) increase in truncal fat gave an OR of 1.31 (95% CI 1.10-1.56), while a 0.21 kg per week (one s.d.) weight gain gave an OR of 1.23 (95% CI 1.04 1.46) for GDM. The ORs for the indicators of adiposity remained after additional adjustments for insulin resistance in early pregnancy. When combining the effects of an ethnic origin, 0.14 kg per week (one s.d.) truncal fat gain and 4.7 kg m( 2) (one s.d.) increased pre-pregnant BMI the OR for South Asians was 5.9 (3.5 10.0) versus 2.1 (1.6-2.8) for Europeans. CONCLUSION: Weight gain and gain of total fat mass, mean skinfold thickness and especially truncal fat were all positively associated with GDM. South Asians, in particular, should be encouraged to avoid an excessive weight gain during pregnancy to reduce risk of GDM. PMID- 24051504 TI - Introduction of an enhanced recovery protocol to reduce short-term complications following radical cystectomy and intestinal urinary diversion with vescica ileale Padovana neobladder. AB - OBJECTIVES: To reduce short-term complications of radical cystectomy (RC) and intestinal urinary diversion with vescica ileale Padovana (VIP) neobladder, we described and assessed an enhanced recovery protocol (ERP) in a series of consecutive patients. METHODS: An ERP was introduced focusing on reduced bowel preparation, standardized feeding and analgesic regimens. We analyzed the outcomes with all patients consecutively undergoing RC and VIP neobladder who met the following inclusion criteria: American Society of Anesthesiologists score <3; absence of malnutrition according to the Mini Nutritional Assessment-Short Form criteria; absence of inflammatory bowel diseases. RESULTS: Thirty-one consecutive patients were recruited to undergo our ERP. Mean age of patients was 62.16 years. No patients died due to surgical complications. Nine of 31 patients experienced complications (29.03%), none requiring surgical intervention. According to Clavien grading, all complications were grade <2. CONCLUSION: The application of our ERP to our patients undergoing RC and VIP neobladder contributed to reduce postoperative morbidity. PMID- 24051505 TI - Long-term results after microfracture treatment for full-thickness knee chondral lesions in athletes. AB - PURPOSE: Microfracture is a well-established treatment procedure for chondral defects in high-demand population with good short-term results. The purpose of our study was to evaluate long-term clinical outcome of microfracture treatment in athletes with full-thickness chondral defects. METHODS: Between 1991 and 2001, 170 patients were treated with microfracture for full-thickness knee chondral lesions at our institute and 67 of them were included in this study and prospectively followed up. Sixty-one athletes (91%) were available at final follow-up (average 15.1 years). Average lesion size was 401 +/- 27 mm2. Lysholm, Tegner and International Knee Documentation Committee (IKDC) (subjective objective) scores were utilized pre-operatively and at 2-year, 5-year and final follow-up; Knee injury and Osteoarthritis Outcome Score (KOOS), visual analog scale (VAS) and Marx scores were also collected at final follow-up. RESULTS: IKDC, Lysholm and Tegner scores increased significantly at 2 years, but gradually deteriorated at long term; however, average scores were significantly above baseline at final follow-up. Seven patients (11%) were considered as failures as they underwent another operation because of reinjury or persistent pain during the first 5 years. Pain and swelling during strenuous activities was reported only in nine patients by the end of 2 years and in 35 patients at final follow up. Patients with smaller lesions (<=400 mm2) and younger patients (<=30 years) showed significantly better results in KOOS, VAS and Marx scores. Radiographs performed at final follow-up showed evidence of progression of osteoarthritis changes in 40% of the knees, with higher rate in older patients with large or multiple lesions (p < 0.05). CONCLUSIONS: Microfracture when applied in young patients with smaller lesions can offer good clinical results at short- and long term follow-up; lesion size is more important prognostic factor of outcome than age. Deterioration of the clinical outcome should be expected after 2 and 5 years post-treatment, and degenerative changes are present at long-term follow-up, with higher rate in older athletes with large, multiple lesions. LEVEL OF EVIDENCE: IV. PMID- 24051506 TI - Comparison of anatomic ACL reconstruction between selective bundle reconstruction and double-bundle reconstruction. AB - PURPOSE: The objective of this study was to compare the clinical and radiologic results of preserved ligament remnants in the selective bundle anterior cruciate ligament (ACL) reconstruction and totally sacrificed ligament remnant in the double-bundle ACL reconstruction in order to confirm the evidence of selective bundle reconstruction. METHODS: This retrospective comparative study was conducted for comparison between preserved ligament remnants in the selective bundle ACL reconstruction and totally sacrificed ligament remnant in the double bundle ACL reconstruction. From 2008 to 2010, 16 patients (group I) underwent selective bundle ACL reconstruction and 30 patients (group II) underwent double bundle ACL reconstruction. Clinical, stability and radiologic results (tunnel locations of femoral tunnels using 3-D computed tomography and graft signal intensity using magnetic resonance imaging) were compared. RESULTS: In comparison with functional results, no statistical differences in the Lysholm, Tegner and International Knee Documentation Committee scores were observed between the two groups (n.s.). In comparison with stability results between the two groups, no statistical differences were observed in the Lachman, pivot shift and anterior drawer stress tests using a Telos device at 30 degrees and 90 degrees flexed positions (n.s.). In evaluation of the femoral tunnel location, no statistical significant differences in the tunnel position were observed between the groups (n.s.). No statistically significant differences in signal intensity were observed between the two groups (n.s.). CONCLUSIONS: Compared to the double bundle ACL reconstruction, selective bundle ACL reconstruction produced comparable clinical and radiologic results. Selective bundle ACL reconstruction could be performed instead of double-bundle ACL reconstruction if some intact bundle exists. LEVEL OF EVIDENCE: Comparative study, Level III. PMID- 24051507 TI - The difference between weight-bearing and non-weight-bearing alignment in patient specific instrumentation planning. AB - PURPOSE: Retrospective study to analyse the difference between weight-bearing and non-weight-bearing alignment in osteoarthritic knees planned for patient-specific instrumented (PSI) total knee arthroplasty (TKA). The aim of the study is to observe whether a difference in alignment can be linked to arthritis staging or zone mechanical axis. METHODS: Full-leg standing radiographs and non-weight bearing MRI of the whole leg were compared for hip-knee-ankle (HKA) angle, measured according to Moreland criteria, in seventy osteoarthritic patients. Kellgren-Lawrence (KL) staging and classification according to zone mechanical axis with Kennedy zones was done. RESULTS: A mean preoperative HKA angle on standing radiographs of 176.4 degrees +/- 7.2 degrees was measured compared to 176.4 degrees +/- 6.9 degrees for the MRI whole-leg HKA angle. A difference of 0 degrees -1 degrees was observed in 54% of patients when comparing the weight bearing with the non-weight-bearing HKA angle. Twenty-three per cent had a difference of 2 degrees and another 23 % a difference of 3 degrees or more. In female patients, the dynamic load pattern of weight-bearing increases the HKA angle due to convex side soft tissue laxity both in varus and valgus knees. More important differences were observed in the KL stage 3 and 4 patients (P < 0.05) and with a load-bearing axis outside of the articular surface (P < 0.05). CONCLUSION: Surgeons should be aware that there is a difference between weight bearing and non-weight-bearing alignment in patients with Kellgren-Lawrence 3 and 4 with a load-bearing axis outside of the articular surface (Kennedy 0 or 1 or 5). According to this study, these changes seem related to the amount of articular wear and the load-bearing axis. This is important for the preoperative planning process in PSI-assisted TKA. More concave side ligamentous release or more constraint can be necessary than imagined based on the PSI alignment result. Full-leg standing radiographs should be performed for PSI-assisted TKAs to analyse the position of the load-bearing axis. LEVEL OF EVIDENCE: IV. PMID- 24051508 TI - Reconstruction of the extensor mechanism with fresh-frozen tendon allograft in total knee arthroplasty. AB - PURPOSE: Patellar tendon rupture after total knee replacement is a rare and highly limiting injury with multifactorial aetiology. Many reconstruction techniques have been described with not very predictable results. The use of allografts has been accepted as a suitable solution. METHODS: A series of seven patients with patellar tendon rupture treated with fresh-frozen tendon allograft reconstruction after knee arthroplasty is presented. RESULTS: Median follow-up is 25 months (20-31). Functional assessment improved, and the knee society score and knee functional score improved from 26 and 16 to 82 and 55, respectively. Median extension lag was 5 degrees (0 degrees -20 degrees ), with a median range of motion of 95 degrees (70-100). Radiological study showed a rise of the patella of 22.26 mm. CONCLUSION: The use of fresh-frozen allografts as a solution to patellar tendon ruptures after knee arthroplasty seems to provide acceptable results. Increased patellar height does not seem to affect functionality. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 24051509 TI - Comparative LC-MS/MS analysis of optimal cutting temperature (OCT) compound removal for the study of mammalian proteomes. AB - Primary tissue samples are valuable resources for investigators interested in understanding disease. In order to maximize the information content that can be gained from these precious samples, proper storage, handling, and preparation are essential. Some tissue preservation techniques utilize the cryopreservation medium, optimal cutting temperature (OCT) compound. While this medium provides benefits for traditional molecular studies, certain components can interfere with mass spectrometric analyses. Mass spectrometry based proteomics is a growing field with many applications for disease research. Our goal is to determine a reliable method for separating the proteins from the contaminating species in OCT embedded samples, thus making these samples compatible with mass spectrometric analyses. The novel applications of ether-methanol precipitation, filter-aided sample preparation (FASP), and SDS-PAGE provide researchers with protocols for removing OCT contaminating species from valuable samples. The results presented in this study show that all three methods reproducibly remove OCT; however, precipitation and FASP outperform SDS-PAGE by common proteomic metrics. PMID- 24051510 TI - Molecular and gene network analysis of thyroid transcription factor 1 (TTF1) and enhanced at puberty (EAP1) genes in patients with GnRH-dependent pubertal disorders. AB - BACKGROUND/AIM: TTF1 and EAP1 are transcription factors that modulate gonadotropin-releasing hormone expression. We investigated the contribution of TTF1 and EAP1 genes to central pubertal disorders. PATIENTS AND METHODS: 133 patients with central pubertal disorders were studied: 86 with central precocious puberty and 47 with normosmic isolated hypogonadotropic hypogonadism. The coding region of TTF1 and EAP1 were sequenced. Variations of polyglutamine and polyalanine repeats in EAP1 were analyzed by GeneScan software. Association of TTF1 and EAP1 to genes implicated in timing of puberty was investigated by meta network framework GeneMANIA and Cytoscape software. RESULTS: Direct sequencing of the TTF1 did not reveal any mutation or polymorphisms. Four EAP1 synonymous variants were identified with similar frequencies among groups. The most common EAP1 5'-distal polyalanine genotype was the homozygous 12/12, but the genotype 12/9 was identified in 2 central precocious puberty sisters without functional alteration in EAP1 transcriptional activity. TTF1 and EAP1 were connected, via genetic networks, to genes implicated in the control of menarche. CONCLUSION: No TTF1 or EAP1 germline mutations were associated with central pubertal disorders. TTF1 and EAP1 may affect puberty by changing expression in response to other members of puberty-associated gene networks, or by differentially affecting the expression of gene components of these networks. PMID- 24051511 TI - Glycine 1.5% for irrigation should be abandoned. AB - BACKGROUND: Glycine 1.5% has long maintained a dominating role as an irrigating solution for monopolar transurethral resection of the prostate (TURP), as well as for certain other transurethral procedures. MATERIALS AND METHODS: This review summarizes the findings of systematic experimental and clinical studies in which glycine 1.5% for irrigation was infused/absorbed and the outcome compared to at least one other irrigating fluid, including the isotonic saline used for bipolar TURP. RESULTS: There were 11 studies in animals, 3 in volunteers and 6 in patients undergoing TURP. With only one exception, which is probably due to low power, these studies either show a poorer outcome after administration or absorption of glycine solution or else that glycine 2.2% is more toxic than glycine 1.5%. The poorer outcomes consisted of more tissue damage or higher mortality (animals) or more symptoms (volunteers and patients). CONCLUSION: The safety of monopolar TURP would be improved by replacing glycine 1.5% with some other electrolyte-free fluid. The author argues that glycine 1.5% should be abandoned completely. PMID- 24051512 TI - Consumer choice: Linking consumer intentions to actual purchase of GM labeled food products. AB - With a mandatory labeling scheme for GM food in Europe since 2004 measuring actual consumer choice in practice has become possible. Anticipating Europeans negative attitude toward GM food, the labeling was enforced to allow consumers to make an informed choice. We studied consumers actual purchase behavior of GM food products and compared this with their attitude and behavioral intention for buying GM food. We found that despite a majority of consumers voicing a negative attitude toward GM food over 50% of our European respondents stated that they did not actively avoid the purchase of GM food and 6% actually purchased one of the few available GM labeled food products in the period between September 2006 and October 2007. Our results imply that a voiced negative attitude of consumers in responses to questionnaires about their intentions is not a reliable guide for what they actually do in supermarkets. We conclude that the assumption of a negative attitude with regard to GM food is at least in part construed. PMID- 24051513 TI - Novel p-n heterojunction photocatalyst constructed by porous graphite-like C3N4 and nanostructured BiOI: facile synthesis and enhanced photocatalytic activity. AB - In this work, n-type porous graphite-like C3N4 (denoted as p-g-C3N4) was fabricated and modified with p-type nanostructured BiOI to form a novel BiOI/p-g C3N4 p-n heterojunction photocatalyst for the efficient photocatalytic degradation of methylene blue (MB). The results show that the BiOI/p-g-C3N4 heterojunction photocatalyst exhibits superior photocatalytic activity compared to pure BiOI and p-g-C3N4. The visible-light photocatalytic activity enhancement of BiOI/p-g-C3N4 heterostructures could be attributed to its strong absorption in the visible region and low recombination rate of the electron-hole pairs because of the heterojunction formed between BiOI and p-g-C3N4. It was also found that the photodegradation of MB molecules is mainly attributed to the oxidation action of the generated O2(-) radicals and partly to the action of h(vb)(+)via direct hole oxidation process. PMID- 24051514 TI - Disappearance of nodal gap across the insulator-superconductor transition in a copper-oxide superconductor. AB - The parent compound of the copper-oxide high-temperature superconductors is a Mott insulator. Superconductivity is realized by doping an appropriate amount of charge carriers. How a Mott insulator transforms into a superconductor is crucial in understanding the unusual physical properties of high-temperature superconductors and the superconductivity mechanism. Here we report high resolution angle-resolved photoemission measurement on heavily underdoped Bi2Sr2 xLaxCuO(6+delta) system. The electronic structure of the lightly doped samples exhibit a number of characteristics: existence of an energy gap along the nodal direction, d-wave-like anisotropic energy gap along the underlying Fermi surface, and coexistence of a coherence peak and a broad hump in the photoemission spectra. Our results reveal a clear insulator-superconductor transition at a critical doping level of ~0.10 where the nodal energy gap approaches zero, the three-dimensional antiferromagnetic order disappears, and superconductivity starts to emerge. These observations clearly signal a close connection between the nodal gap, antiferromagnetism and superconductivity. PMID- 24051515 TI - Automated reagent-dispensing system for microfluidic cell biology assays. AB - Microscale systems that enable measurements of oncological phenomena at the single-cell level have a great capacity to improve therapeutic strategies and diagnostics. Such measurements can reveal unprecedented insights into cellular heterogeneity and its implications into the progression and treatment of complicated cellular disease processes such as those found in cancer. We describe a novel fluid-delivery platform to interface with low-cost microfluidic chips containing arrays of microchambers. Using multiple pairs of needles to aspirate and dispense reagents, the platform enables automated coating of chambers, loading of cells, and treatment with growth media or other agents (e.g., drugs, fixatives, membrane permeabilizers, washes, stains, etc.). The chips can be quantitatively assayed using standard fluorescence-based immunocytochemistry, microscopy, and image analysis tools, to determine, for example, drug response based on differences in protein expression and/or activation of cellular targets on an individual-cell level. In general, automation of fluid and cell handling increases repeatability, eliminates human error, and enables increased throughput, especially for sophisticated, multistep assays such as multiparameter quantitative immunocytochemistry. We report the design of the automated platform and compare several aspects of its performance to manually-loaded microfluidic chips. PMID- 24051516 TI - Transfer, imaging, and analysis plate for facile handling of 384 hanging drop 3D tissue spheroids. AB - Three-dimensional culture systems bridge the experimental gap between in vivo and in vitro physiology. However, nonstandardized formation and limited downstream adaptability of 3D cultures have hindered mainstream adoption of these systems for biological applications, especially for low- and moderate-throughput assays commonly used in biomedical research. Here we build on our recent development of a 384-well hanging drop plate for spheroid culture to design a complementary spheroid transfer and imaging (TRIM) plate. The low-aspect ratio wells of the TRIM plate facilitated high-fidelity, user-independent, contact-based collection of hanging drop spheroids. Using the TRIM plate, we demonstrated several downstream analyses, including bulk tissue collection for flow cytometry, high resolution low working-distance immersion imaging, and timely reagent delivery for enzymatic studies. Low working-distance multiphoton imaging revealed a cell type-dependent, macroscopic spheroid structure. Unlike ovarian cancer spheroids, which formed loose, disk-shaped spheroids, human mammary fibroblasts formed tight, spherical, and nutrient-limited spheroids. Beyond the applications we describe here, we expect the hanging drop spheroid plate and complementary TRIM plate to facilitate analyses of spheroids across the spectrum of throughput, particularly for bulk collection of spheroids and high-content imaging. PMID- 24051517 TI - Comment on the article by Droeser et al.: 'Octreotide prophylaxis is not beneficial for biochemical activity and clinical severity of postoperative pancreatic fistula after pancreatic surgery'. PMID- 24051518 TI - Combined modality treatment outcomes for head and neck cancer: comparison of postoperative radiation therapy at academic vs nonacademic medical centers. AB - IMPORTANCE: Patients with head and neck squamous cell carcinoma (HNSCC) who undergo surgical resection in an academic medical center (AC) often receive postoperative adjuvant external beam radiation therapy (RT) at non-ACs closer to home. Few data exist to compare outcomes of these populations. OBJECTIVE: To evaluate treatment metrics and outcomes in patients with HNSCC who underwent surgical resection at an AC and then received postoperative adjuvant external beam RT at an AC vs a non-AC. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study in 1 AC and several community RT non-ACs of patient with primary HNSCC treated with surgery at an AC followed by adjuvant therapy at an AC or a non-AC from January 1, 2002, to January 1, 2012. INTERVENTIONS: We evaluated for between-groups differences in demographics, RT metrics, and survival outcomes. Subgroup analysis by tumor site was then performed. MAIN OUTCOMES AND MEASURES: Overall survival, disease-specific survival, and locoregional control rates. RESULTS: A total of 286 patients underwent surgery at the University of California, San Francisco, followed by adjuvant therapy. A total of 214 patients were analyzed. Significant differences in demographic and oncologic variables emerged, including important differences in RT metrics. Patients treated at a non AC received a lower total RT dose, lower fractional dose, more delays in RT initiation, more breaks in RT, and more early termination of RT. Adjuvant treatment at an AC was associated with improved survival on univariate but not multivariate analysis. Subgroup analysis by SCC tumor site normalized many of the differences between groups, yet still revealed persistent differences in RT metrics. On multivariate analysis, AC treatment was not an independent predictor of survival for any tumor site. CONCLUSIONS AND RELEVANCE: Better oncologic outcomes were seen in the AC group on univariate analysis, but these improved outcomes were not found on multivariate analysis. Important differences in RT metrics were noted for non-AC treatment sites compared with AC sites. Subgroup analysis by tumor site demonstrated persistent differences in treatment metrics. Standardization of adjuvant HNSCC treatment according to national guidelines should be prioritized at non-AC treatment facilities. PMID- 24051519 TI - Inhibition of K+ currents in type I vestibular hair cells by gentamicin and neomycin. AB - Significant ototoxicity limits the use of aminoglycoside (AG) antibiotics. Several mechanisms may contribute to the death of both auditory and vestibular hair cells. In this study the effects of gentamicin and neomycin on K(+) currents in mature and early postnatal type I vestibular hair cells (HCI) were tested directly. The whole-cell patch clamp technique was used to assess the effects of AG and KCNQ channel modulators on K(+) currents (IK) in HCI acutely isolated from gerbil semicircular canals. Extracellular neomycin (1 mM) rapidly reduced peak outward IK by 16 +/- 4% (n = 9) in mature HCI (postnatal days, P, 25-66). Gentamicin (5 mM) reduced outward IK by 16 +/- 3% (n = 8). A similar reduction in outward current was seen in immature HCI (P5-9) that lacked the low-voltage activated component of IK observed in mature cells. Intracellular application of gentamicin and neomycin also reduced IK in mature HCI. Modulators of KCNQ channels were used to probe KCNQ channel involvement. The selective KCNQ antagonist XE991 did not reduce IK and the neomycin-induced reduction in IK was not reversed by the KCNQ agonist flupirtine. Application of intracellular poly-D lysine to sequester PIP2 did not reduce IK. Application of the K(+) channel blocker 4-aminopyridine (4-AP) strongly reduced IK, and extracellular AG in the presence of 4-AP gave no further inhibition of IK. In summary, AG significantly reduce the 4-AP-sensitive IK in early postnatal and mature HCI. K(+) current inhibition differs from that seen in outer hair cells, since it does not appear to involve PIP2 sequestration or KCNQ channels. PMID- 24051520 TI - Effectiveness of bosentan in a case of pulmonary arterial hypertension associated with myelodysplastic syndrome. PMID- 24051521 TI - Experimental investigation on centrifugal compressor blade crack classification using the squared envelope spectrum. AB - Centrifugal compressors are a key piece of equipment for modern production. Among the components of the centrifugal compressor, the impeller is a pivotal part as it is used to transform kinetic energy into pressure energy. Blade crack condition monitoring and classification has been broadly investigated in the industrial and academic area. In this research, a pressure pulsation (PP) sensor arranged in close vicinity to the crack area and the corresponding casing vibration signals are used to monitor blade crack information. As these signals cannot directly demonstrate the blade crack, the method employed in this research is based on the extraction of weak signal characteristics that are induced by blade cracking. A method for blade crack classification based on the signals monitored by using a squared envelope spectrum (SES) is presented. Experimental investigations on blade crack classification are carried out to verify the effectiveness of this method. The results show that it is an effective tool for blade crack classification in centrifugal compressors. PMID- 24051522 TI - Analysis and design of a 3rd order velocity-controlled closed-loop for MEMS vibratory gyroscopes. AB - The time-average method currently available is limited to analyzing the specific performance of the automatic gain control-proportional and integral (AGC-PI) based velocity-controlled closed-loop in a micro-electro-mechanical systems (MEMS) vibratory gyroscope, since it is hard to solve nonlinear functions in the time domain when the control loop reaches to 3rd order. In this paper, we propose a linearization design approach to overcome this limitation by establishing a 3rd order linear model of the control loop and transferring the analysis to the frequency domain. Order reduction is applied on the built linear model's transfer function by constructing a zero-pole doublet, and therefore mathematical expression of each control loop's performance specification is obtained. Then an optimization methodology is summarized, which reveals that a robust, stable and swift control loop can be achieved by carefully selecting the system parameters following a priority order. Closed-loop drive circuits are designed and implemented using 0.35 MUm complementary metal oxide semiconductor (CMOS) process, and experiments carried out on a gyroscope prototype verify the optimization methodology that an optimized stability of the control loop can be achieved by constructing the zero-pole doublet, and disturbance rejection capability (D.R.C) of the control loop can be improved by increasing the integral term. PMID- 24051523 TI - Ontology alignment architecture for semantic sensor Web integration. AB - Sensor networks are a concept that has become very popular in data acquisition and processing for multiple applications in different fields such as industrial, medicine, home automation, environmental detection, etc. Today, with the proliferation of small communication devices with sensors that collect environmental data, semantic Web technologies are becoming closely related with sensor networks. The linking of elements from Semantic Web technologies with sensor networks has been called Semantic Sensor Web and has among its main features the use of ontologies. One of the key challenges of using ontologies in sensor networks is to provide mechanisms to integrate and exchange knowledge from heterogeneous sources (that is, dealing with semantic heterogeneity). Ontology alignment is the process of bringing ontologies into mutual agreement by the automatic discovery of mappings between related concepts. This paper presents a system for ontology alignment in the Semantic Sensor Web which uses fuzzy logic techniques to combine similarity measures between entities of different ontologies. The proposed approach focuses on two key elements: the terminological similarity, which takes into account the linguistic and semantic information of the context of the entity's names, and the structural similarity, based on both the internal and relational structure of the concepts. This work has been validated using sensor network ontologies and the Ontology Alignment Evaluation Initiative (OAEI) tests. The results show that the proposed techniques outperform previous approaches in terms of precision and recall. PMID- 24051524 TI - Detection of upscale-crop and partial manipulation in surveillance video based on sensor pattern noise. AB - In many court cases, surveillance videos are used as significant court evidence. As these surveillance videos can easily be forged, it may cause serious social issues, such as convicting an innocent person. Nevertheless, there is little research being done on forgery of surveillance videos. This paper proposes a forensic technique to detect forgeries of surveillance video based on sensor pattern noise (SPN). We exploit the scaling invariance of the minimum average correlation energy Mellin radial harmonic (MACE-MRH) correlation filter to reliably unveil traces of upscaling in videos. By excluding the high-frequency components of the investigated video and adaptively choosing the size of the local search window, the proposed method effectively localizes partially manipulated regions. Empirical evidence from a large database of test videos, including RGB (Red, Green, Blue)/infrared video, dynamic-/static-scene video and compressed video, indicates the superior performance of the proposed method. PMID- 24051525 TI - Laser doppler blood flow imaging using a CMOS imaging sensor with on-chip signal processing. AB - The first fully integrated 2D CMOS imaging sensor with on-chip signal processing for applications in laser Doppler blood flow (LDBF) imaging has been designed and tested. To obtain a space efficient design over 64 * 64 pixels means that standard processing electronics used off-chip cannot be implemented. Therefore the analog signal processing at each pixel is a tailored design for LDBF signals with balanced optimization for signal-to-noise ratio and silicon area. This custom made sensor offers key advantages over conventional sensors, viz. the analog signal processing at the pixel level carries out signal normalization; the AC amplification in combination with an anti-aliasing filter allows analog-to digital conversion with a low number of bits; low resource implementation of the digital processor enables on-chip processing and the data bottleneck that exists between the detector and processing electronics has been overcome. The sensor demonstrates good agreement with simulation at each design stage. The measured optical performance of the sensor is demonstrated using modulated light signals and in vivo blood flow experiments. Images showing blood flow changes with arterial occlusion and an inflammatory response to a histamine skin-prick demonstrate that the sensor array is capable of detecting blood flow signals from tissue. PMID- 24051526 TI - A 0.0016 mm2 0.64 nJ leakage-based CMOS temperature sensor. AB - This paper presents a CMOS temperature sensor based on the thermal dependencies of the leakage currents targeting the 65 nm node. To compensate for the effect of process fluctuations, the proposed sensor realizes the ratio of two measures of the time it takes a capacitor to discharge through a transistor in the subthreshold regime. Furthermore, a novel charging mechanism for the capacitor is proposed to further increase the robustness against fabrication variability. The sensor, including digitization and interfacing, occupies 0.0016 mm2 and has an energy consumption of 47.7-633 pJ per sample. The resolution of the sensor is 0.28 degrees C, and the 3sigma inaccuracy over the range 40-110 degrees C is 1.17 degrees C. PMID- 24051527 TI - A relevance vector machine-based approach with application to oil sand pump prognostics. AB - Oil sand pumps are widely used in the mining industry for the delivery of mixtures of abrasive solids and liquids. Because they operate under highly adverse conditions, these pumps usually experience significant wear. Consequently, equipment owners are quite often forced to invest substantially in system maintenance to avoid unscheduled downtime. In this study, an approach combining relevance vector machines (RVMs) with a sum of two exponential functions was developed to predict the remaining useful life (RUL) of field pump impellers. To handle field vibration data, a novel feature extracting process was proposed to arrive at a feature varying with the development of damage in the pump impellers. A case study involving two field datasets demonstrated the effectiveness of the developed method. Compared with standalone exponential fitting, the proposed RVM-based model was much better able to predict the remaining useful life of pump impellers. PMID- 24051528 TI - Importance of regulatory T cells in the pathogenesis of psoriasis: review of the literature. AB - Psoriasis is a common chronic relapsing inflammatory cutaneous disease; the main role in the inflammation of this condition is played by lymphocyte Th1, Th17 and their cytokines. The activity of these cells is modulated by a particular kind of T cells recently described: the T regulatory cells (Treg). These are able to inhibit the immunological response and to maintain the cutaneous immunological homeostasis, thus preventing autoimmunity against self antigens. Few data are available in the literature as to Treg in psoriasis; several studies demonstrate that the function of these cells is impaired in this condition and treatments for psoriasis may increase the number and activity of Treg. The role of these cells in the pathogenesis of psoriasis is very important to understand how they may contribute to the development of this cutaneous disorder. In the near future it would be possible to target therapies at these defects, improving the activity of these cells and maintaining cutaneous homeostasis, preventing psoriasis or other inflammatory cutaneous conditions. PMID- 24051540 TI - Interleukin-6-induced Twist and N-cadherin enhance melanoma cell metastasis. AB - Melanoma patients frequently have elevated serum levels of interleukin-6 (IL-6), which is correlated with a poor prognosis. IL-6 activates STAT3 phosphorylation, inducing the transcription of genes that regulate tumor cell proliferation and antiapoptosis. In addition, recent evidence suggests that IL-6 induces the epithelial-to-mesenchymal transition and enhances the invasiveness of tumor cells of epithelial origin. However, it is unknown whether IL-6 affects mesenchymal tumor cells. In this study, we examined the effects of IL-6 on melanoma cells and found that IL-6 can enhance their metastatic potential by regulating the expression of Twist and N-cadherin. First, we confirmed that human melanoma tissues express IL-6 (especially at the lesion site), the IL-6 receptor, N cadherin, and nuclear Twist. Next, we found that IL-6 induces STAT3 phosphorylation in WM-266-4 human melanoma cells, resulting in transient upregulation of Twist, which is a key regulator of metastasis. Importantly, the expression of N-cadherin, a protein downstream of Twist, was also increased on the cell surface after treatment with IL-6. These cells showed enhanced invasiveness, assessed using an invasion assay, and formed more metastatic nodules in the lungs of NOD-SCID mice after an intravenous injection. Importantly, melanoma cells with knocked-down N-cadherin formed less lung nodules compared with control in the NOD-SCID mouse model. Our data suggest that increased serum IL-6 in cancer patients could increase the invasiveness of melanoma cells and accelerate metastasis. Blocking IL-6 in the melanoma microenvironment may therefore inhibit disease progression. PMID- 24051541 TI - Capture and separation of biomolecules using magnetic beads in a simple microfluidic channel without an external flow device. AB - The use of microfluidic devices and magnetic beads for applications in biotechnology has been extensively explored over the past decade. Many elaborate microfluidic chips have been used in efficient systems for biological assays. However most fail to achieve the ideal point of care (POC) status, as they require larger conventional external devices in conjunction with the microchip. This paper presents a simple technique to capture and separate biomolecules using magnetic bead movement on a microchip without the use of an external flow device. This microchip consisted of two well reservoirs (W1 and W2) connected via a tapered microchannel. Beads were dragged through the microchannel between the two wells at an equivalent speed to a permanent magnet that moved alongside the microchip. More than 95% of beads were transferred from W1 to W2 within 2 min at an average velocity of 0.7 mm s(-1). Enzymatic reactions were employed to test our microchip. Specifically, three assays were performed using the streptavidin coated magnetic beads as a solid support to capture and transfer biomolecules: (1) non-specific adsorption of the substrate, 6-8-difluoro-4-methylumbelliferyl phosphate (DiFMUP), (2) capture of the enzyme, biotinylated alkaline phosphatase (AP), and (3) separation of AP from DiFMUP. Our non-specific adsorption assay indicated that the microchip was capable of transferring the beads with less than 0.002% carryover of DiFMUP. Our capture assay indicated efficient capture and transfer of AP with beads to W2 containing DiFMUP, where the transferred AP converted 100% of DiFMUP to DiFMU within 15 minutes. Our separation assay showed effective separation of AP from DiFMUP and elucidated the binding capacity of the beads for AP. The leftover unbound AP in W1 converted 100% of DiFMUP within 10 minutes and samples with less than the full bead capacity of AP (i.e. all AP was transferred) did not convert any of the DiFMUP. The immobilization of AP on the bead surface resulted in 32% reduced enzymatic speed compared to that of free AP in solution, as a result of altered protein conformation and/or steric hindrance of the catalytic site. Overall, this microfluidic platform was established as a simple, efficient and effective approach for separating biomolecules without any flow apparatus. PMID- 24051542 TI - Facial affect recognition performance and event-related potentials in violent and non-violent schizophrenia patients. AB - We investigated whether male inpatients with schizophrenia and a history of hands on violent offences (forensic schizophrenic, FOS) are more impaired in emotion recognition than matched schizophrenia patients without any history of violence (general psychiatric schizophrenic, GPS). This should become apparent in performance in psychometry and in scalp event-related brain potentials (ERPs) evoked by pictures of facial affect. FOS and GPS (each n = 19) were matched concerning age, intelligence, comorbid addiction, medication and illness duration. FOS revealed significantly poorer affect recognition (AR) performance, especially of neutral and fear stimuli. Analysis of ERPs revealed a significant interaction of hemisphere, electrode position and group of the N250 component. Post hoc analysis of group effect showed significantly larger amplitudes in FOS at FC3. These results support the hypothesis that in FOS emotional faces are more salient and evoke higher arousal. Larger impairment in AR performance combined with higher salience and arousal may contribute to the occurrence of violent acts in schizophrenia patients. PMID- 24051543 TI - Detection rate of trisomy 21 in fetuses with isolated and non-isolated aberrant right subclavian artery. AB - OBJECTIVE: The purpose of this study was to determine the frequency of chromosomal anomalies among the fetuses with isolated and non-isolated aberrant right subclavian artery (ARSA), and to evaluate the sonographic findings associated with ARSA. METHODS: This is a retrospective study conducted during the period between January 2008 and December 2012 at the maternal fetal medicine units of three different referral centers. RESULTS: Among the 148 cases of ARSA, 98 were isolated and 50 were associated with cardiac anomalies, extracardiac malformations or soft markers. Trisomy 21 was the only chromosomal anomaly with a prevalence of 6.8% (10/148). The corresponding rate was 6.1% (6/98) and 8% (4/50) for isolated and non-isolated ARSA, respectively. Cardiac anomalies, extracardiac findings and soft markers were detected in 5.4% (8), 10.8% (16) and 24.3% (36) of cases, respectively. Among the 10 fetuses with trisomy 21, 6 were isolated, 4 were associated with soft markers, 2 were associated with fetal growth restriction and 1 was associated with hydrops fetalis. Cardiac anomalies were not observed in any of these fetuses. CONCLUSION: The prenatal diagnosis of ARSA should prompt meticulous anatomic survey, and karyotype analysis might be offered even in the absence of associated findings. PMID- 24051544 TI - Eat and exercise during radiotherapy or chemoradiotherapy for pharyngeal cancers: use it or lose it. AB - IMPORTANCE: Data support proactive swallowing therapy during radiotherapy (RT) or chemoradiotherapy (CRT) for pharyngeal cancers. The benefits of adherence to a regimen of swallowing exercises and maintaining oral intake throughout treatment are reported, but independent effects are unclear. OBJECTIVE: To evaluate the independent effects of maintaining oral intake throughout radiotherapy and adherence to preventive swallowing exercise. DESIGN: Retrospective observational study. SETTING: The University of Texas MD Anderson Cancer Center, Houston. PATIENTS: The study included 497 patients treated with definitive RT or CRT for pharyngeal cancer (458 oropharynx, 39 hypopharynx) between 2002 and 2008. MAIN OUTCOMES AND MEASURES: Swallowing-related end points were final diet after RT or CRT and duration of gastrostomy dependence. Primary independent variables included oral intake status at the end of RT or CRT (no oral intake, partial oral intake, or full oral intake) and adherence to a swallowing exercise regimen. Multiple linear regression and ordered logistic regression models were analyzed. RESULTS: At the conclusion of RT or CRT, 131 patients (26%) had no oral intake and 74% maintained oral intake (167 partial [34%], 199 full [40%]). Fifty-eight percent (286 of 497) reported adherence to swallowing exercises. Maintenance of oral intake during RT or CRT and swallowing exercise adherence were independently associated with better long-term diet after RT or CRT (P = .045 and P < .001, respectively) and shorter duration of gastrostomy dependence (P < .001 and P = .007, respectively) in models adjusted for tumor and treatment burden. CONCLUSIONS AND RELEVANCE: The data indicate independent, positive associations of maintenance of oral intake throughout RT or CRT and swallowing exercise adherence with long-term swallowing outcomes. Patients who either eat or exercise fare better than those who do neither. Patients who both eat and exercise have the highest rate of return to a regular diet and shortest duration of gastrostomy dependence. PMID- 24051545 TI - Nodal quasiparticle dynamics in the heavy fermion superconductor CeCoIn5 revealed by precision microwave spectroscopy. AB - CeCoIn5 is a heavy fermion superconductor with strong similarities to the high-Tc cuprates, including quasi-two-dimensionality, proximity to antiferromagnetism and probable d-wave pairing arising from a non-Fermi-liquid normal state. Experiments allowing detailed comparisons of their electronic properties are of particular interest, but in most cases are difficult to realize, due to their very different transition temperatures. Here we use low-temperature microwave spectroscopy to study the charge dynamics of the CeCoIn5 superconducting state. The similarities to cuprates, in particular to ultra-clean YBa2Cu3O(y), are striking: the frequency and temperature dependence of the quasiparticle conductivity are instantly recognizable, a consequence of rapid suppression of quasiparticle scattering below T(c); and penetration-depth data, when properly treated, reveal a clean, linear temperature dependence of the quasiparticle contribution to superfluid density. The measurements also expose key differences, including prominent multiband effects and a temperature-dependent renormalization of the quasiparticle mass. PMID- 24051546 TI - Therapy by laser equatorial placental dichorionization for early-onset spontaneous twin anemia-polycythemia sequence. AB - We report a case of twin anemia-polycythemia sequence (TAPS) treated by fetoscopic laser equatorial placental dichorionization, also known as the 'Solomon technique', at 24 weeks of gestation. TAPS was present despite the absence of fetoscopically visualized chorionic anastomoses from the donor to the recipient twin. The goal of this procedure was to prevent post-laser TAPS in cases of twin-twin transfusion syndrome. The surgery and subsequent intrauterine blood transfusion to the donor twin could result in the survival of both twins without hematologic or neurological complications. Following the surgery, a placental injection test revealed no residual anastomoses. At present, laser therapy is not always feasible for TAPS, primarily because of its difficulty. However, laser therapy using the Solomon technique could be a viable approach for early-onset TAPS, especially in difficult situations in which undetectable vascular anastomoses related to TAPS are present. PMID- 24051547 TI - Lanthanide(III) complexes of aminoethyl-DO3A as PARACEST contrast agents based on decoordination of the weakly bound amino group. AB - 2-Aminoethyl DOTA analogues with unsubstituted (H3L1), monomethylated (H3L2) and dimethylated (H3L3) amino groups were prepared by improved synthetic procedures. Their solid-state structures exhibit an extensive system of intramolecular hydrogen bonds, which is probably present in solution and leads to the rather high value of the last dissociation constant. The protonation sequence of H3L1 in solution corresponds to that found in the solid state. The stability constants of the H3L1 complexes with La(3+) and Gd(3+) (20.02 and 22.23, respectively) are similar to those of DO3A and the reduction of the pK(A) value of the pendant amino group from 10.51 in the free ligand to 6.06 and 5.83 in the La(3+) and Gd(3+) complexes, respectively, points to coordination of the amino group. It was confirmed in the solid state structure of the [Yb(L1)] complex, where disorder between the SA' and TSA' isomers was found. A similar situation is expected in solution, where a fast equilibration among the isomers hampers the unambiguous determination of the isomer ratio in solution. The PARACEST effect was observed in Eu(III)-H3L1/H3L2 and Yb(III)-H3L1/H3L2 complexes, being dependent on pH in the region of 4.5-7.5 and pH-independent in more alkaline solutions. The decrease of the PARACEST effect parallels with the increasing abundance of the complex protonated species, where the pendant amino group is not coordinating. Surprisingly, a small PARACEST effect was also observed in solutions of Eu(III)/Yb(III)-H3L3 complexes, where the pendant amino group is dimethylated. The effect is detectable in a narrow pH region, where both protonated and deprotonated complex species are present in equilibrium. The data points to the new mechanism of the PARACEST effect, where the slow coordination-decoordination of the pendant amine is coupled with the fast proton exchange between the free amino group and bulk water mediates the magnetization transfer. The pH-dependence of the effect was proved to be measurable by MRI and, thus, the complexes extend the family of pH-sensitive probes. PMID- 24051549 TI - Melanoma-associated retinopathy treated with ipilimumab therapy. AB - Melanoma-associated retinopathy (MAR) is a rare autoimmune syndrome in patients with melanoma characterized by visual disorders. MAR is induced by the degeneration of bipolar cells of the retina and the presence of serum autoantibodies against retina proteins. Ipilimumab, an anti-cytotoxic T lymphocyte-associated antigen 4 antibody, improves survival in previously treated patients with metastatic melanoma, but is responsible for a spectrum of immune related adverse events. Administration of ipilimumab to patients with autoimmune diseases (such as MAR or vitiligo) is actually not recommended. We report a patient presenting with MAR occurring during a melanoma relapse. Surgery and chemotherapy had no effect on visual acuity and melanoma increased. In the absence of alternative antitumoral treatment, we focused on the vital prognosis and treated the patient with ipilimumab. Two years after the treatment the patient is free from new metastasis but has presented with exacerbation of vitiligo and MAR. In the very rare case of melanoma with autoimmune disease without a therapy option, ipilimumab could be discussed, taking into account the fact that it can be effective on tumor burden but can also increase autoimmunity. PMID- 24051548 TI - The statistical-mechanics of chromosome conformation capture. AB - Since Jacob and Monod's characterization of the role of DNA elements in gene control, it has been recognized that the linear organization of genome structure is important for the regulation of gene transcription and hence the manifestation of phenotypes. Similarly, it has long been hypothesized that the spatial organization (in three dimensions evolving through time), as part of the epigenome, makes a significant contribution to the genotype-phenotype transition. Proximity ligation assays commonly known as chromosome conformation capture (3C) and 3C based methodologies (e.g., GCC, HiC and ChIA-Pet) are increasingly being incorporated into empirical studies to investigate the role that three dimensional genome structure plays in the regulation of phenotype. The apparent simplicity of these methodologies-crosslink chromatin, digest, dilute, ligate, detect interactions-belies the complexity of the data and the considerations that should be taken into account to ensure the generation and accurate interpretation of reliable data. Here we discuss the probabilistic nature of these methodologies and how this contributes to their endogenous limitations. PMID- 24051550 TI - Short- and long-term survival of esophageal cancer patients treated at the Cancer Institute of Iran. AB - INTRODUCTION: Little data is available on the prognosis of esophageal cancer (EC) in Iran. We studied the short- and long-term survival of EC patients treated at the Cancer Institute of Iran. METHODS: 619 patients were followed who had been operated in the years 1997-2006. The 1-month to 5-year survival rates of EC and hazard ratios (HR) for different prognostic factors were estimated. RESULTS: Median survival was 11.5 months and 5-year survival was 10%. Patients at the advanced stage had a 2.1-fold higher risk of mortality compared to the early stage (95% CI 1.2-3.4). One-month mortality decreased from 12.2 in 1997-1999 to 9.1% in 2003-2006. In the first month, patients who were diagnosed in 2003-2006 had a significantly (60%) lower HR compared to 1997-1999 (HR = 0.4, 95% CI 0.1 0.9). In addition, patients with cardiopulmonary complications had an 11.7-fold higher HR compared to patients without complications (95% CI 4.7-29.3). CONCLUSIONS: The 5-year survival rate for operated EC patients was considerably low in Iran. Cardiopulmonary complications were the strong prognostic factors for first-month mortality. We suggest improving the pre- and postoperative care of EC to control these complications. Regular monitoring of patient survival is recommended to evaluate the effect of this intervention. PMID- 24051551 TI - Diastolic dysfunction and high levels of new cardiac biomarkers as risk factors for cardiovascular events and mortality in hemodialysis patients. AB - BACKGROUND/AIMS: Cardiovascular events (CVEs) are the most frequent cause of death in hemodialysis (HD). We aim to determine cardiovascular and mortality risk factors. METHODS: A historical cohort study was made of 211 prevalent HD patients [73 (60-80) years, 58% males] between 2005 and 2012. Demographic, laboratory test and echocardiographic values were recorded. During follow-up, CVEs and mortality were documented and analyzed. RESULTS: 94 patients suffered a CVE. Age, history of cardiovascular disease (CVD), peripheral vascular disease, cardiac markers, systolic and diastolic dysfunction (DD) were associated to CVEs. Low albumin (RR 0.414, p = 0.002), DD (1.876, p = 0.038) and previous CVD (3.723, p < 0.001) were identified as independent predictors of CVEs. 98 patients died. Age, a history of CVD, peripheral vascular disease, cardiac markers, DD, dialysis vintage, and a vascular access different from autologous fistulae were associated to mortality. Low albumin (RR 0.499, p = 0.046), DD (RR 2.414, p = 0.017) and a vascular access different from autologous fistulae (RR 2.058, p = 0.034) were independent predictors of mortality. CONCLUSIONS: DD is an emergent risk factor for death and CVEs in dialysis. Low albumin is also a predictor for CVE. Non-autologous fistulae and low albumin are predictors for death. Nt-proBNP and hsTnT offer good information for identifying high-risk patients, but they do not predict events independently as they are only cardiac damage markers. PMID- 24051552 TI - Mutualism between autotrophic ammonia-oxidizing bacteria (AOB) and heterotrophs present in an ammonia-oxidizing colony. AB - Coexistence of an autotrophic ammonia-oxidizing bacterium (Nitrosomonas sp. RA) and heterotrophic bacteria was consistently observed when cultured in an inorganic medium without any external supply of organic carbon. The present study was undertaken to understand the association between autotrophs and the associated heterotrophs for which a system containing active autotrophs and heterotrophs controlled by Hg(2+) addition was developed. The study revealed interdependence of heterotrophs and Nitrosomonas sp. RA for growth under iron limited condition. Growth of Nitrosomonas sp. RA was supported by siderophores produced by the associated heterotroph, Pusillimonas sp., thereby complementing its high iron requirement while the organics (such as pyruvate) excreted by Nitrosomonas sp. RA during its autotrophic growth supported the survival of heterotrophs in the inorganic medium. The study thus sheds light on the nature of the mutual interactions between heterotrophs and autotrophs that play a role in the ammonia-oxidizing system involved in wastewater treatment. PMID- 24051553 TI - AgX/graphite-like C(3)N(4) (X = Br, I) hybrid materials for photoelectrochemical determination of copper(II) ion. AB - A novel photoelectrochemical strategy has been designed for the detection of Cu(2+) with AgX/g-C3N4 (X = Br, I) hybrid materials. The present study can serve as a foundation for the application of AgX/g-C3N4 hybrid materials in photoelectron-chemical ion sensing. It can be successfully applied to the detection of copper in human hair samples. PMID- 24051554 TI - Quantitative mass spectrometric analysis and post-extraction stability assessment of the euglenoid toxin euglenophycin. AB - Euglenophycin is a recently discovered toxin produced by at least one species of euglenoid algae. The toxin has been responsible for several fish mortality events. To facilitate the identification and monitoring of euglenophycin in freshwater ponds, we have developed a specific mass spectrometric method for the identification and quantitation of euglenophycin. The post-extraction stability of the toxin was assessed under various conditions. Euglenophycin was most stable at room temperature. At 8 degrees C there was a small, but statistically significant, loss in toxin after one day. These methods and knowledge of the toxin's stability will facilitate identification of the toxin as a causative agent in fish kills and determination of the toxin's distribution in the organs of exposed fish. PMID- 24051555 TI - Isolation and characterization of marine nonylphenol-degrading bacteria and description of Pseudomaricurvus alkylphenolicus gen. nov., sp. nov. AB - Two novel aerobic p-n-nonylphenol-degrading bacterial strains were isolated from seawater obtained from the coastal region of Ogasawara Islands, Japan. The 16S rRNA gene sequence analysis indicated that the strains are affiliated with the order Alteromonadales within the class Gammaproteobacteria. One isolate, strain KU41G2, is most closely related to Maricurvus nonylphenolicus (99.2 % similarity), and is tentatively identified as M. nonylphenolicus. The other isolate, strain KU41G(T), is also most closely related to M. nonylphenolicus; however, the 16S rRNA gene sequence similarity was only 94.7 %. Cells of strain KU41G(T) are Gram-negative rods with a single polar flagellum. The predominant respiratory lipoquinone was ubiquinone-8, and the major cellular fatty acids were C17:1 omega8c (24.2 %); C15:0 iso 2-OH; and/or C16:1 omega7c (16.3 %), C15:0 (10.3 %), C11:0 3-OH (9.5 %), C9:0 3-OH (6.7 %), C10:0 3-OH (6.4 %), and C18:1 omega7c (5.5 %). The DNA G+C content was 53.3 mol%. On the basis of physiological, chemotaxonomic, and phylogenetic data, strain KU41G(T) is suggested to represent a novel species of a new genus, for which we propose the name Pseudomaricurvus alkylphenolicus gen. nov., sp. nov. The type strain of P. alkylphenolicus is KU41G(T) (=JCM 19135(T) = KCTC 32386(T)). PMID- 24051556 TI - Recent efforts to construct the B-ring of bryostatins. AB - Among macrocyclic natural products, bryostatins have excellent bioactivities and unique structures that make them highly attractive to synthetic chemists. Particularly challenging for the total synthesis of bryostatins is the B-ring, which features a cis-tetrahydropyran containing a geometrically defined exocyclic Z-methyl enoate. Synthetic chemists have recently displayed great prowess in their efforts to construct this ring, and here we summarize the progress towards this goal. PMID- 24051557 TI - Laparoendoscopic single-site retroperitoneoscopic adrenalectomy versus conventional retroperitoneoscopic adrenalectomy: initial experience by the same laparoscopic surgeon. AB - PURPOSE: The purpose of this study was to demonstrate our initial experience with and the feasibility of laparoendoscopic single-site retroperitoneoscopic adrenalectomy (LESS-RA). PATIENTS AND METHODS: 54 patients undergoing conventional retroperitoneoscopic adrenalectomy were compared with 27 patients undergoing LESS-RA. The adrenal tumors were considered to be benign preoperatively and <6 cm. Age, sex, laterality, body mass index, surgical indications, time to resuming oral intake, tumor size, operation time, estimated blood loss, intravenous or intramuscular analgesics (pethidine) and postoperative hospital stay were compared between the two groups. Analysis of covariance was applied to analyze postoperative hospital stay and time to resuming oral intake. RESULTS: The length of postoperative hospital stay was significantly higher in the conventional retroperitoneoscopic adrenalectomy group in the adjusted and unadjusted model. The time to resuming oral intake was significant shorter in the LESS-RA group, but was not significant after adjusting opioid analgesics dosage. No conversions to an open or conventional retroperitoneoscopic approach were necessary. There were neither complications nor blood transfusions in both groups. CONCLUSIONS: LESS-RA for benign adrenal tumors is a feasible surgical procedure when tumors are <6 cm. Further clinical research is warranted to define the role of LESS in adrenal surgery and to prove its efficacy over conventional laparoscopic surgery. PMID- 24051558 TI - Late recovery of cranial diabetes insipidus following pituitary surgery. AB - BACKGROUND: Diabetes insipidus (DI) is common following surgery for a pituitary/sellar lesion. Postoperative DI persisting beyond a few weeks is usually regarded as permanent, requiring lifelong desmopressin therapy. CASE PRESENTATION: A 16-year-old girl underwent pituitary decompression following a pituitary tumour apoplexy. She developed DI with thirst and hypotonic polyuria in the immediate post-operative period, which was controlled with parenteral DDAVP. Her symptoms persisted and she was discharged on oral desmopressin. Subsequently, she commenced growth hormone replacement. A water deprivation test 6 weeks postoperatively confirmed persistent DI with failure to concentrate urine after 8 hours of dehydration. She was maintained on desmopressin and reported intense thirst and polyuria every time she delayed taking the medication up until 1 year postoperatively. After 1 year, she complained of bloating and stopped taking desmopressin but her symptoms did not recur. A repeat water deprivation test confirmed very late resolution of DI with normal urinary concentration. She has remained asymptomatic ever since. CONCLUSION: Delayed recovery of normal posterior pituitary function is exceptionally rare. We hypothesise that the underlying mechanism may be the revascularisation and regeneration of the posterior pituitary tissues or of the axons terminating in the posterior pituitary. PMID- 24051559 TI - Psychiatric classification, stigma, and mental health. PMID- 24051560 TI - Clozapine- induced recurrent and transient parotid gland swelling. PMID- 24051561 TI - Deserves a hearing? A case report of remitting tinnitus with N-acetyl cysteine. PMID- 24051562 TI - Sublingual atropine for the treatment of severe and hyoscine-resistant clozapine induced sialorrhea. PMID- 24051563 TI - The role of spirituality in specialist psychiatry: a review of the medical literature. AB - A review of the international medical literature was undertaken on the role of spirituality in the discipline of psychiatry, within the context that a perceived change is taking place in the health care environment in South Africa. Revitalized interest in spirituality was evident from the literature partly because Western societies have, through the migration of people, become more heterogeneous in recent years. The literature concurred that spirituality must be incorporated into the current approach to the practice and training of psychiatry, but within the professional scope of the discipline, while all faith traditions and belief systems should be regarded equally. Beyond South Africa, it is envisaged that the review has implications for the practice of psychiatry in Africa. PMID- 24051564 TI - Use of interactive teaching techniques to introduce mental health training to medical schools in a resource poor setting. AB - OBJECTIVE: There are currently no practising psychiatrists in Somaliland. In 2007 the first medical students graduated from universities in Somaliland without mental health training. We aimed to pilot an intensive but flexible package of mental health training to all senior medical students and interns using interactive training techniques and to evaluate its effectiveness by assessing knowledge, skills and attitudes. METHODS: Teaching techniques included didactic lectures, case based discussion groups and role playing. Informal feedback informed a flexible teaching package. Assessment tools designed specifically for this course included a pre and post course MCQ exam and an OSCE. Changes in students' attitudes were evaluated using a questionnaire administered before and after the course. In addition, a questionnaire administered following the course evaluated the changes students perceived in their knowledge and attitudes to mental health. RESULTS: The MCQ improved from 50.7% pre course to 64.4% post course (p = 9.73 E-08). Students achieved an average overall OSCE mark of 71%. The pre and post attitudes questionnaire was most significantly different for statements relevant to aetiology, stigma and the overlap between mental and physical health. The statement most strongly agreed with after the course was 'I now understand more about the overlap between mental and physical health'. CONCLUSION: Interactive teaching provided a learning experience for both students and trainers. On site and distance learning based on the teaching described here has widened the scope of the training possible in psychiatry and allowed the provision of regular teaching, supervision and peer support in Somaliland. However, the current lack of local expertise means that important issues of sustainability need to be considered in future work. PMID- 24051565 TI - The role of psycho-education in improving outcome at a general hospital psychiatry clinic in Uganda. AB - OBJECTIVE: While psychoeducation has been shown to positively affect outcomes in psychiatric disorders, its utility has been little studied in developing countries. The current study sought to examine the role of psychoeducation at a general psychiatric outpatient clinic in Kampala, Uganda in improving clinic attendance, treatment adherence, and clinical outcomes. METHOD: A prospective case-control study using a quasi-experimental design was conducted in 117 patients suffering various psychiatric disorders. Participants were recruited for two months and then followed for a further three months after recruitment ended. Participants in the intervention group received formalized psychoeducation sessions at each clinic visit in addition to the usual psychiatric evaluation and care. Participants in the control group received the usual clinical care. Measured outcomes were knowledge of mental illness, compliance with medications and follow-up, and Clinical Global Impression (CGI). RESULTS: The groups did not differ with respect to sociodemographic characteristics or attendance at scheduled follow-up visits. Both groups significantly improved on the CGI, but with no significant difference between the groups. However, the intervention group was more likely to adhere to medication, and their knowledge of mental illness was significantly higher at follow-up. CONCLUSION: These data suggest that psychoeducation is a beneficial mental health intervention in a developing country that may increase compliance with medication and result in greater knowledge of mental illness. However, other factors such as distance from a centralized clinic or cost of treatment may impact outcomes, including attendance at scheduled follow-up visits. PMID- 24051566 TI - The experiences of parents of children with mental disability regarding access to mental health care. AB - OBJECTIVE: The aim of this qualitative study was to describe the problems that parents or caregivers of children with mental health disabilities and disorders in Namibia experience when accessing healthcare resources for their children. METHOD: Data was collected through focus group discussions with the participants and individual interviews with the key informants. Overall, a total of 41 people provided information for this study. Thematic data analysis was used to assess the data. RESULTS: The main barriers experienced by the parents were poor service provision, transport and money, whilst access to education services facilitated access to healthcare services. CONCLUSION: The challenges go beyond commonly reported problems such as sub-optimal service provision and include the basic challenge of lack of transportation to reach healthcare services. Many of the barriers identified in this study have been related to general problems with the healthcare system in Namibia. Therefore there is a need to address general concerns about healthcare provision as well as improve specific services for children with mental health disabilities and disorders in Namibia. PMID- 24051567 TI - Psychosocial rehabilitation in a chronic care hospital in South Africa: views of clinical staff. AB - OBJECTIVE: The study was based at a South African hospital providing inpatient care for people with chronic mental disorders, and aimed at investigating the multidisciplinary team (MDT) members' views, understanding and attitudes towards psychosocial rehabilitation (PSR). METHOD: A survey method was used, with the MDT members completing a questionnaire that tapped, inter alia, their understanding of PSR, perceived aims and goals of PSR, adequacy of their professional training to implement PSR, availability of resources to implement PSR, and their views of chronic mentally ill patients, including their functional skills, needs and prognosis. RESULTS: Of 114 respondents, 19.3% felt they had sufficient knowledge of PSR practice, 53.5% reported that their professional training included teaching on PSR, 90.4% wanted to undertake further training in PSR, 64.9% believed that the hospital environment lends itself to PSR, and 23.7% felt the hospital had sufficient resources to perform PSR. Most (93%) believed that patients with chronic mental disorders can improve their functioning, and 65.8% thought that such patients could make decisions for themselves. CONCLUSION: It is not surprising that most of the clinical staff in this investigation do not feel sufficiently equipped to perform PSR interventions, considering that past mental health policies and training failed to emphasize this component of mental health care. The need for training programmes to address this deficit is evident. PMID- 24051568 TI - Pattern of attendance and predictors of default among Nigerian outpatients with schizophrenia. AB - OBJECTIVE: To assess the pattern of and factors associated with outpatient clinic attendance among patients diagnosed with schizophrenia at a Nigerian psychiatric hospital. METHODS: This was a cross-sectional descriptive study of 313 consecutive outpatients with diagnosis of schizophrenia confirmed with the Structured Clinical Interview for Diagnosis (SCID). Data was collected on sociodemographics, clinic attendance, perceived social support, perceived satisfaction with hospital care and illness severity (assessed using the Brief Psychiatric Rating Scale, BPRS). Logistic regression analysis was used to identify factors associated with outpatient clinic default. RESULTS: Overall, 20.4% respondents were defaulters, with a median duration of clinic non attendance of 8 weeks. Outpatient clinic defaulters had significantly higher BPRS scores and had missed more outpatient clinic appointments compared with non defaulters. A significantly higher proportion of defaulters resided more than 20 km away from the hospital and reported "not satisfied" with their outpatient care. Being financially constrained was the commonest reason given by defaulters for missing their clinic appointments. The significant predictors of outpatient clinic default included residing more than 20 km from the hospital, missing previous appointments and dissatisfaction with outpatient care. CONCLUSION: Outpatient clinic non-attendance is common among patients with schizophrenia, and is significantly associated with demographic, clinical and service related factors. Interventions targeted at addressing the risk factors for defaulting peculiar to developing country settings similar to the location of this study, could significantly improve treatment outcome. PMID- 24051569 TI - Depressive symptoms after a sexual assault among women: understanding victim perpetrator relationships and the role of social perceptions. AB - OBJECTIVES: Although mental health impact of gender based violence has been documented for many decades, the impact of the socio-cultural dimensions and type of perpetrator on mental health outcomes has not been described outside of developed countries. We explore depression symptomatology four to six weeks post rape in South Africa and examine whether this differs according to the circumstances of the rape. METHOD: 140 participants recruited from public hospital services in the Eastern and Western Cape provinces were interviewed within two weeks after completing the post exposure prophylaxis (PEP) medication. A structured questionnaire was used to collect data on socio-demographic and sexual assault characteristics including perpetrator. Depressive symptomatology was measured using the Centre for Epidemiological Studies Depression Scale. RESULTS: 84.3% (95% CI: 78.1-90.3) women were found to have high levels of depressive symptoms, but lower levels were found among women raped in circumstances in which there was a lesser likelihood of blame such as those raped by strangers rather than intimate partners (Odds Ratio: (OR) 0.28 (95% Confidence Intervals (CI): 0.11-0.69) and higher levels were associated with experiencing four or more side effects related to PEP medication (OR: 3.79: CI: 1.03-13.94). Receiving support and severe sexual assaults (involving weapons and multiple perpetrators) were not associated with depression. CONCLUSION: The study does not support the general assumption that more violent rape causes more psychological harm. These results have important implications for individual treatment because it is more generally assumed that multiple perpetrator rapes, stranger rapes and those with weapons would result in more psychological trauma and thus more enduring symptoms. Our findings point to the importance of understanding the socio-cultural dimensions, including dynamics of blame and stigma, of rape on mental health sequelae. PMID- 24051570 TI - Photocopy for your patients. SADAG supporting and guiding your patients when you can't. PMID- 24051571 TI - Photocopy for your patients. Miserable, manic or misdiagnosed? PMID- 24051572 TI - Short stature before puberty: which children should be screened for SHOX deficiency? AB - OBJECTIVE: We studied the prevalence of deficiency in the short stature homeobox containing gene (SHOX) in prepubertal short-statured children and analyzed the clinical and radiological signs. METHODS: Screening for SHOX deficiency was performed in 449 prepubertal short-statured children (54% females, aged 4-10 years) by direct sequencing and multiplex ligation probe-dependent amplification. Children with SHOX deficiency were compared to 1:2 age- and gender-matched prepubertal children without SHOX deficiency with respect to left-hand radiographs and anthropometrics including different ratios to height and proposed scores. RESULTS: We identified 22 (4.9%) patients with SHOX deficiency (64% point mutations). Children with SHOX deficiency demonstrated a mesomelic shortening of extremities. Lower leg lengths but not forearm length was reduced in children <8 years with SHOX deficiency. 36% of all children and none of the children <8 years with SHOX deficiency demonstrated any typical radiologic sign. Increased sitting height-to-height ratio and decreased extremities-to-trunk ratio demonstrated the best positive and negative predictive values to identify SHOX deficiency. CONCLUSIONS: Screening for SHOX deficiency seems rational, especially in children with increased sitting height-to-height ratio or decreased extremities-to-trunk ratio. These criteria were also valid in young children. PMID- 24051573 TI - Serum brain-derived neurotrophic factor levels and cocaine-induced transient psychotic symptoms. AB - BACKGROUND: Cocaine-induced psychosis (CIP) is among the most serious adverse effects of cocaine. Reduced serum brain-derived neurotrophic factor (BDNF) levels have been reported in schizophrenia and psychosis; however, studies assessing the involvement of BDNF in CIP are lacking. METHODS: A total of 22 cocaine-dependent patients (aged 33.65 +/- 6.85) who had never experienced psychotic symptoms under the influence of cocaine (non-CIP) and 18 patients (aged 34.18 +/- 8.54) with a history of CIP completed a 2-week detoxification program in an inpatient facility. Two serum samples were collected from each patient at baseline and at the end of the protocol. Demographic, consumption and clinical data were recorded for all patients. A paired group of healthy controls was also included. RESULTS: At the beginning of the detoxification treatment, serum BDNF levels were similar in both the non-CIP and the CIP groups. During early abstinence, the non-CIP group exhibited a significant increase in serum BDNF levels (p = 0.030), whereas the CIP group exhibited a decrease. Improvements in depression (Beck Depression Inventory, BDI, p = 0.003) and withdrawal symptoms (Cocaine Selective Severity Assessment, CSSA, p = 0.013) show a significant positive correlation with serum BDNF levels in the non-CIP group, whereas no correlation between the same variables was found in the CIP group. CONCLUSIONS: This study suggests that BDNF plays a role in the transient psychotic symptoms associated with cocaine consumption. In the non-CIP group, the increase in serum BDNF appears to be driven by the effects of chronic cocaine consumption and withdrawal. In contrast, patients with CIP share some of the neurotrophic deficiencies that characterize schizophrenia and psychosis. PMID- 24051574 TI - Acidic pH of tumor microenvironment enhances cytotoxicity of the disulfiram/Cu2+ complex to breast and colon cancer cells. AB - BACKGROUND: Resistance of cancer cells to chemotherapeutic agents is a major cause of treatment failure in patients with cancer. The drug resistance of tumor cells can be significantly modified by specific features of tumor microenvironment, such as oxygen depletion (hypoxia), glucose/energy deprivation and acidosis. METHODS: The effects of acidic tumor-like microenvironment on cytotoxicity of antabuse (disulfiram, DSF)/Cu(2+) complexes to MCF-7 breast carcinoma and HT-29 colon carcinoma cells were studied. RESULTS: We show that acidic pH significantly potentiates toxicity of DSF/Cu(2+) complex to breast and colon cancer cells. This phenomenon is associated with changes in cell metabolism, altered Akt kinase and NFkappaB activity and increased reactive oxygen species production. CONCLUSION: Specific pH of tumor microenvironment enhances cytotoxicity of DSF/Cu(2+) to breast and colon cancer cells. PMID- 24051575 TI - A multicenter cohort study of pregnancy outcomes among women with laboratory confirmed H1N1 influenza. AB - OBJECTIVE: To evaluate associations between laboratory-confirmed 2009 H1N1 influenza infection and obstetric and neonatal outcomes. STUDY DESIGN: A multicenter cohort study was performed comparing laboratory-confirmed cases of 2009 H1N1 infection during pregnancy (N=142) with matched controls (N=710). Subanalysis was also performed comparing severely infected (hospitalized) women with controls. RESULT: No outcome differences were noted in comparing all women with H1N1 with controls. Women with severe infection had a higher incidence of delivering a small for gestational age (SGA) infant: 18.8% (6/32) versus 7.4% (52/707), adjusted odds ratio 2.35 (95% confidence interval 1.03, 5.36, P=0.02). Mean birth weight was 3013.0 g among severely infected women and 3223.3 g in controls (P=0.08), and incidence of preterm delivery was 25.0% (8/32) and 11.6% (82/710) (P=0.08), respectively. CONCLUSION: Pregnant women with mild clinical illness secondary to 2009 H1N1 were not at a greater risk of adverse pregnancy outcomes. However, severely infected women were more likely to deliver SGA infants. PMID- 24051576 TI - The impact of growth curve changes in assessing premature infant growth. AB - OBJECTIVE: To assess the impact of using the recently published WHO growth standard, based on healthy, breastfed infants in multiple countries that excluded prematurely born infants, versus the Infant Health Development Program (IHDP) growth reference constructed from premature infants, on the interpretation of the growth of premature infants after hospital discharge. STUDY DESIGN: A retrospective cohort was constructed of infants born at gestational age <=35 weeks who initially presented for care at one of the 32 outpatient sites between 2006 and 2008 (N=2297). Kappa statistics measured overall agreement and agreement in ever classifying infants <5th percentile or >= 95th percentile for age between the WHO and IHDP. Logistic regression models identified factors associated with growth curve disagreement in classifying infants at the extremes of growth. RESULT: The WHO and IHDP growth curves showed moderate agreement for all measurements (kappa=0.40-0.52). When the curves disagreed on whether an infant was <5th percentile for weight (8.3% of cohort) or length (13.6% of cohort), the WHO curve classified the infant in this category over 90% of the time. For head circumference, the IHDP curve classified more infants below the 5th percentile. Gestational age <30 weeks was associated with growth curve disagreement for weight and length <5th percentile. CONCLUSION: Choice of growth curve affects the assessment of growth and the classification of underweight status. Longitudinal studies are needed to determine which assessment identifies the greatest number of premature infants at risk for long-term growth issues. PMID- 24051578 TI - Diagnostic meaning of urodynamic studies in pouch incontinence: results of a small series. AB - INTRODUCTION: To evaluate the meaning of urodynamic parameters in patients with pouch incontinence. MATERIALS AND METHODS: Thirteen urodynamic studies in patients with an ileal nipple as the efferent segment of an ileocecal pouch or ileum/ileocecal-augmented bladder were performed. The recorded parameters included pouch capacity, leak point pressure/volume, maximum pouch pressure, compliance, static and dynamic closure pressure, and functional length. Three patients suffered from urinary incontinence. RESULTS: In all cases of incontinent patients, no functional length or static or dynamic closure pressure could be revealed. In 8 of 10 cases of continent patients, a positive functional length as well as static and/or dynamic closure pressure were measured (mean value in continent patients: 15.9 mm, 14.5 cm H2O and 26.5 cm H2O, respectively). In 2 of 3 cases of incontinent patients, the pouch compliance was restricted (21 and 37 ml/cm H2O). The pouch capacity of continent patients was greater than the capacity of incontinent patients (377.4 vs. 185.7 ml). CONCLUSIONS: Positive functional length, static and dynamic closure pressures, and a high pouch capacity with an unrestricted compliance are predictive for pouch continence. They may individually not determine continence, but combining them can. However, the meaning of urodynamic studies in pouch incontinence is not the same as with the urinary bladder. PMID- 24051577 TI - Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. AB - OBJECTIVE: Compare neurodevelopment after levetiracetam (LEV) and phenobarbital (PB) for neonatal seizures. STUDY DESIGN: Retrospective study of infants who received antiepileptic drugs (AEDs) for neonatal seizures. Effect of cumulative exposure to LEV and PB on outcomes of death, cerebral palsy (CP) and Bayley Scales of Infant Development (BSID) scores were evaluated at 24 months corrected age. Analyses were adjusted for number of electrographic seizures and gestational age. RESULT: In 280 infants with comparable seizure etiology and cranial imaging results, increased exposure to PB was associated with worse BSID cognitive and motor scores (8.1- and 9-point decrease per 100 mg kg(-1); P=0.01). The effect was less with LEV (2.2- and 2.6-point decrease per 300 mg kg(-1) LEV (P=0.01)). CP probability increased by 2.3-fold per 100 mg kg(-1) PB and was not associated with increasing LEV. CONCLUSION: Increased exposure to PB is associated with worse neurodevelopmental outcomes than LEV. Prospective studies of outcomes of neonatal exposure to AEDs are essential. PMID- 24051579 TI - Dependence of fertility on kisspeptin-Gpr54 signaling at the GnRH neuron. AB - Signaling between kisspeptin and its receptor, G-protein-coupled receptor 54 (Gpr54), is now recognized as being essential for normal fertility. However, the key cellular location of kisspeptin-Gpr54 signaling is unknown. Here we create a mouse with a GnRH neuron-specific deletion of Gpr54 to assess the role of gonadotropin-releasing hormone (GnRH) neurons. Mutant mice are infertile, fail to go through puberty and exhibit markedly reduced gonadal size and follicle stimulating hormone levels alongside GnRH neurons that are unresponsive to kisspeptin. In an attempt to rescue the infertile phenotype of global Gpr54-/- mutants, we use BAC transgenesis to target Gpr54 to the GnRH neurons. This results in mice with normal puberty onset, estrous cyclicity, fecundity and a recovery of kisspeptin's stimulatory action upon GnRH neurons. Using complimentary cell-specific knockout and knockin approaches we demonstrate here that the GnRH neuron is the key site of kisspeptin-Gpr54 signaling for fertility. PMID- 24051580 TI - Transoral robotic surgery: simulation-based standardized training. AB - IMPORTANCE: Simulation-based standardized training is important for the clinical training of physicians practicing robotic surgery. OBJECTIVE: To train robotic surgery-naive student volunteers using the da Vinci Skills Simulator (dVSS) for transoral robotic surgery (TORS). DESIGN: Prospective inception cohort in 2012. SETTING: Academic referral center. PARTICIPANTS: Sixteen medical student volunteers lacking experience in robotic surgery. INTERVENTIONS: Participants trained with the dVSS in 12 exercises until competent, defined as an overall score of at least 91%. After a 1-, 3-, 5-, or 7-week postinitial training hiatus (n = 4 per group), participants reachieved competence on follow-up. MAIN OUTCOMES AND MEASURES: Total training time (TTT) to achieve competency, total follow-up time (TFT) to reachieve competency, and performance metrics. RESULTS: All participants became competent. The TTT distribution was normal based on the Anderson-Darling normality test (P > .50), but our sample was divided into a short training time (STT) group (n = 10 [63%]) and long training time (LTT) group (n = 6 [37%]). The mean (SD) TTT was 2.4 (0.6) hours for the STT group and 4.7 (0.5) hours for the LTT group. All participants reachieved competence with a mean TFT that was significantly shorter than TTT. There was no significant difference between STT and LTT in mean TFT at 1 and 3 weeks (P = .79), but the LTT group had a longer TFT at 5 and 7 weeks (P = .04) but with no difference in final follow-up scores (P = .12). CONCLUSIONS AND RELEVANCE: Physicians in training can acquire robotic surgery competency. Participants who acquire skills faster regain robotic skills faster after a training hiatus, but, on retraining, all participants can regain equivalent competence. This information provides a benchmark for a simulator training program. PMID- 24051581 TI - Surgery for colorectal liver metastases. AB - Half of all patients with colorectal cancer develop metastatic disease. The liver is the principal site for metastases, and surgical resection is the only modality that offers the potential for long-term cure. Appropriate patient selection for surgery and improvements in perioperative care have resulted in low morbidity and mortality rates, resulting in this being the therapy of choice for suitable patients. Modern management of colorectal liver metastases is multimodal incorporating open and laparoscopic surgery, ablative therapies such as radiofrequency ablation or microwave ablation and (neo)adjuvant chemotherapy. The majority of patients with hepatic metastases should be considered for resectional surgery, if all disease can be resected, as this offers the only opportunity for prolonged survival. PMID- 24051582 TI - Striving to make a positive difference: school nurses' experiences of promoting the health and well-being of adolescent girls. AB - In Sweden, school nurses are part of the School Health Service with the main objective of health promotion to support students' health and attainment of educational goals. The aim in this phenomenological study was to illuminate the experiences of school nurses in promoting the health and well-being of adolescent girls. Seventeen school nurses were interviewed, both in groups and individually, to facilitate personal disclosure and expressions from their lived experiences. To achieve their goal of improving the health of adolescent girls, school nurses require flexibility in their approach and in endeavoring to make a positive difference they experience many challenges. This study concluded that school nurses can tactfully provide adolescent girls with knowledge and health guidance adjusted to individual needs and empowering the individual girl to participate in her own health process. PMID- 24051583 TI - Risk factors for smoking behaviors among adolescents. AB - Many students in Korea begin to use tobacco and develop a regular smoking habit before they reach adulthood. Yet, little is known about various signs contributing to the transition of the student smoking behaviors. This study used a national sample to explore and compare risk factors for smoking behaviors. Three types of smoking behaviors were defined: never smoking (in their lifetime), history of experimental smoking (ever tried but not within the last 30 days), and current smoking (at least 1 day during the last 30 days). Risk factors for experimentally starting and not continuing smoking were identified as gender, perceived health status, and friend-related stress. School type, academic performance, alcohol use, perception of harm of smoking, and close friends' smoking increased the risk of progressing from never smoking to the history of experimental smoking and current smoking. Our findings may be valuable in school health care settings in planning cessation programs. PMID- 24051584 TI - Alternatives to outpatient commitment. PMID- 24051585 TI - Gun violence: psychiatry, risk assessment, and social policy. PMID- 24051586 TI - A novel approach to training police officers to interact with individuals who may have a psychiatric disorder. AB - Police and law enforcement providers frequently come in contact with individuals who have psychiatric disorders. Repeated studies suggest that greater understanding of psychiatric conditions by police officers would be beneficial. However, few training approaches have been examined. We present a novel approach to training police officers to interact with those who may have a psychiatric disorder. This approach involved development of a program in which police officers interacted with actors highly trained to present one of six realistic psychiatric scenarios. Confidential feedback was given, both by experienced police officers and by the actors, to improve awareness of the officers' behavior. Qualitative feedback from both officers and actors was used to determine the acceptance of role-play training. A total of 663 police officers were trained, with feedback from 381. Results showed that this approach was well accepted by most police officers, and the use of carefully controlled role play in training for police is strongly recommended. Future analysis will determine whether training improves police behavior with respect to interaction with mentally ill individuals. PMID- 24051587 TI - Commentary: Police officers and persons with mental illness. AB - Silverstone et al. present a study outlining the success of a novel training program implemented in Edmonton, Alberta, Canada, to train police officers to interact with persons who may have a psychiatric disorder. The training was well accepted by the participants and was novel in its use of professional actors to portray persons with mental illness across six model scenarios. I outline the need for such training and comment on certain aspects of this particular program, including overall design, usefulness, and limitations. PMID- 24051588 TI - The forensic evaluation and report: an agenda for research. AB - The written report is a central component of forensic psychiatric practice. In the report, an evaluator assembles and organizes data, interprets results of an evaluation, and offers an opinion in response to legal questions. The past 30 years have seen substantial development in principles and practice of forensic report writing. Drawing on recent advances in the psychiatric report, the authors explore topics including narrative, forensic ethics, coercion within the justice system, and implications of limitations on data in forming forensic opinions. They offer an analysis of unanswered questions in these areas, suggesting opportunities for further empirical study and theoretical development. This proposed agenda is important in training, in the development of policy, and in establishing professional guidelines. PMID- 24051589 TI - Commentary: The forensic report--an inevitable nexus for resolving ethics dilemmas. AB - Ethics-related dilemmas arise in forensic psychiatry as in all psychiatric practice. Although most can be resolved by following the AAPL Ethics Guidelines and the AAPL Ethics Questions and Answers, the more complex ones inevitably have no easy solutions. Ethics-based duties can conflict without clear guidance on prioritization. Weighing competing factors necessitates more than merely following a rule, since there are potentially conflicting rules, and ethical practitioners may prioritize them differently. Concerns pertaining to the death penalty and defendants who are victims of discrimination are especially difficult. Such considerations usually are in the realm of aspirational ethics, with conclusions open to debate. They need consideration by most practitioners concerned with determining the most ethical course of action. Much as it is insufficient for an ethical citizen merely to avoid breaking the law, it is not enough to avoid violating any one guideline while remaining blind to context. Most such dilemmas need resolution long before testimony and arise first in the way the forensic assessment is conducted and in decisions on the data to be included in a report and how they are presented. Although there can be legitimate differences of opinion about how to weigh and resolve conflicting considerations, ethics-related dilemmas should not be sidestepped. PMID- 24051590 TI - Updating toxic psychosis into 21st-century Canadian: Bouchard-Lebrun v. R. AB - For centuries, Anglo-Saxon common law tradition has tended to limit voluntary intoxication as a defense on both mens rea (so-called diminished capacity defenses) and insanity. A new decision by the Supreme Court of Canada has clarified for Canadian jurisdictions whether voluntary substance-induced psychosis is a mental disorder for the purposes of determining insanity. In the United States, there is still considerable variation with regard to this question in such settled-insanity cases. This article is a review of Anglo-Saxon, American, and Canadian jurisprudence with regard to intoxication defenses on both mens rea and insanity. The factual and appellate history of Bouchard-Lebrun v. R. and a discussion of the Supreme Court's reasoning and the implications for future forensic practice follow. Potential pitfalls for forensic evaluators are explored, including the lack of scientific evidence available to detect individuals who, while appearing to present with a drug-induced psychosis, prove over time to have an endogenous psychotic illness. PMID- 24051591 TI - Isaac Ray, malpractice defendant. AB - Isaac Ray (1807-1881), founder of American forensic psychiatry, produced his classic Treatise on the Medical Jurisprudence of Insanity in 1838. He did not begin to practice asylum medicine, however, until 1841, when he became superintendent of the Maine Insane Hospital in Augusta. There, he treated a patient, Isaac Hunt, who later sued him for malpractice and then self-published a book, Astounding Disclosures! Three Years in a Mad House, detailing alleged abuses suffered at the doctor's hands. This article recalls the incident and tracks Ray's reactions to it, the public's perception of asylums, and the tension between paternalistic asylum medicine and an emerging consumer-rights movement. PMID- 24051592 TI - Using base rates and correlational data to supplement clinical risk assessments. AB - The current study is a partial replication of previous studies designed to estimate the level of risk posed by capital murder defendants. The study draws on data describing the behavior of nearly 2,000 incarcerated capital murderers to forecast violence propensity among defendants sentenced to life imprisonment. Logistic regression is used to model various violence outcomes, relying on the following predictors: age, educational attainment, prior imprisonment, and gang affiliation. This exercise is designed to illustrate how actuarial data may be used to anchor individualized clinical assessments of risk in capital murder trials. PMID- 24051593 TI - Psychosis-related matricide associated with a lesion of the ventromedial prefrontal cortex. AB - Matricide, the killing of a mother by her biological child, is a rare event. We report a case of matricide associated with a woman who sustained a right ventromedial prefrontal lesion during surgery for nasal polyposis that was performed when she was 40 years old. After her surgery, she developed psychotic symptoms associated with the emergence of antisocial behavior. She committed matricide 22 years later. Neuropsychological evaluation showed decreased frontal executive deficits, and magnetic resonance imaging revealed a lesion in the right gyrus rectus area of the ventromedial prefrontal region. This case suggests that a secondary psychotic syndrome associated with a lesion in the frontal neural network, which is disturbed in psychopathy, could facilitate homicidal behavior. Furthermore, this case has legal implications for the prosecution of murder associated with a brain lesion. PMID- 24051594 TI - No worries, mate: a forensic psychiatry sabbatical in New Zealand. AB - Sabbaticals were initially intended to take place one year of every seven and to provide an opportunity for study or travel. Psychiatrists rarely take sabbaticals, but they can be of tremendous value in widening professional and personal horizons. It is not merely the psychiatrist taking the sabbatical who reaps the benefits, but also the home institution and patients. Sabbatical-takers have an opportunity to learn across cultures, to experience a new system of medical care, and to develop a less provincial view of their work and indeed their place in the world. A sabbatical can be a time of substantial accomplishments, such as writing or reorganizing programs. In this article, the benefits of a forensic psychiatry sabbatical experience in New Zealand are described. PMID- 24051596 TI - For whom the bell tolls: Silver Alerts raise concerns regarding individual rights and governmental interests. AB - The Silver Alert system was initially created to help protect missing persons who have cognitive impairments, particularly the elderly. The Silver Alert is modeled after the Amber Alert, created to help locate and safeguard missing children. Unlike the Amber Alert, however, in most states the Silver Alert applies to the elderly, adults with a mental impairment, or both, depending on the state. The goal of the Silver Alert system is the quick dissemination of information about missing persons to law enforcement personnel as well as to the general public. Previously, states notified law enforcement personnel of missing persons through teletype to other public safety jurisdictions to enlist their assistance in the retrieval of the missing person. Silver Alert programs substantially expand the notification to include the general public, who receive information through radio and television broadcasts as well as highway billboards. The programs serve a legitimate governmental interest by protecting a vulnerable population from possible harm. Yet, the implementation of these alerts can have unintended consequences, including the possible violation of an individual's right to privacy. Such consequences require careful consideration. PMID- 24051595 TI - Sex, lies, and statistics: inferences from the child sexual abuse accommodation syndrome. AB - Victims of child sexual abuse often recant their complaints or do not report incidents, making prosecution of offenders difficult. The child with sexual abuse accommodation syndrome (CSAAS) has been used to explain this phenomenon by identifying common behavioral responses. Unlike PTSD but like rape trauma syndrome, CSAAS is not an official diagnostic term and should not be used as evidence of a defendant's guilt or to imply probative value in prosecutions. Courts have grappled with the ideal use of CSAAS in the evaluation of child witness testimony. Expert testimony should be helpful to the jurors without prejudicing them. The New Jersey Supreme Court ruled recently that statistical evidence about CSAAS implying the probability that a child is truthful runs the risk of confusing jury members and biasing them against the defendant. We review the parameters of expert testimony and its admissibility in this area, concluding that statistics about CSAAS should not be used to draw inferences about the victim's credibility or the defendant's guilt. PMID- 24051597 TI - The National Football League and chronic traumatic encephalopathy: legal implications. AB - The growing awareness of chronic traumatic encephalopathy (CTE) has the potential to change the public perception and on-field rules of the National Football League (NFL). More than 3,000 ex-NFL players or their relatives are engaged in litigation alleging that the NFL failed to acknowledge and address the neuropsychiatric risks associated with brain injuries that result from playing in the NFL. This article explores the intersection between the medical and legal aspects of CTE in the NFL from a forensic psychiatry perspective. PMID- 24051598 TI - Extended suicide with a pet. AB - The combination of the killing of a pet and a suicide is a perplexing scenario that is largely unexplored in the literature. Many forensic psychiatrists and psychologists may be unaccustomed to considering the significance of the killing of a pet. The subject is important, however, because many people regard their pets as members of their family. A case is presented of a woman who killed her pet dog and herself by carbon monoxide poisoning. The purpose of this article is to provide an initial exploration of the topic of extended suicide with a pet. Forensic mental health evaluations may have a role in understanding the etiology of this event and in opining as to the culpability of individuals who attempt to or successfully kill a pet and then commit suicide. Because the scientific literature is lacking, there is a need to understand this act from a variety of perspectives. First, a social and anthropological perspective will be presented that summarizes the history of the practice of killing of one's pet, with a focus on the ancient Egyptians. A clinical context will examine what relationship animals have to mental illness. A vast body of existing scientific data showing the relevance of human attachment to pets suggests that conclusions from the phenomena of homicide-suicide and filicide-suicide are applicable to extended suicide with a pet. Finally, recommendations will be proposed for both clinical and forensic psychiatrists faced with similar cases. PMID- 24051599 TI - From civil war to forensic psychiatry. PMID- 24051600 TI - An improved electrochemical creatinine detection method via a Jaffe-based procedure. AB - The detection of creatinine via an enzymeless electrochemical method is reported through an indirect electrochemical system in which the picrate anion consumed upon the reaction with creatinine is electrochemically measured. After careful optimisation it is found that in pH 13 two linear analytical ranges are possible utilising an Edge Plane Pyrolytic Graphite (EPPG) electrode: 0-6 mM and 7.5-11.5 mM, with a limit of detection (3sigma) corresponding to 0.27 mM; all measurements were taken after a five minute reaction time. Furthermore, screen printed carbon electrodes were applied to the same system and yielded remarkably similar linear ranges to the case of the EPPG electrode: 0-6 mM and 6-11 mM, with a limit of detection (3sigma) of 0.72 mM. These results are critically analysed and contrasted with the previous literature. This electrochemical protocol is applied to the detection of urinary creatinine where we find creatinine content of three samples falling well within our reported linear ranges and more importantly indicating correct kidney function. Additionally our electrochemical results are 'benchmarked' against UV/Vis spectrometry. The devised electroanalytical protocols have the potential to serve as a more solid foundation for electrochemical creatinine testing and have potential to be applied as a point-of care diagnostics system through the use of screen printing technology, especially considering urinary creatinine concentrations fall within our reported linear ranges for both healthy adults and adults with deficient glomerular filtration. PMID- 24051601 TI - Avian influenza virus NS1: A small protein with diverse and versatile functions. PMID- 24051602 TI - The relationship between glycine transporter 1 occupancy and the effects of the glycine transporter 1 inhibitor RG1678 or ORG25935 on object retrieval performance in scopolamine impaired rhesus monkey. AB - Reduced NMDA receptor functioning is hypothesized to underlie the cognitive and negative symptoms associated with schizophrenia. However, because direct activation of the NMDA receptor is accompanied by neurotoxicity, mechanisms that activate the glycine co-agonist site on the NMDA receptor could carry greater therapeutic potential. In the current study, the effects of two glycine transporter 1 (GlyT1) inhibitors, RG1678 and ORG25935, were characterized in the object-retrieval detour (ORD) task in scopolamine-impaired rhesus monkeys and, using positron emission tomography (PET), the GlyT1 occupancy to efficacy relationship of each compound was established. Scopolamine exerted a significant decrease in accuracy in the ORD task. Lower doses of RG1678 (0.3 and 1.0 mg/kg, p.o.) significantly attenuated the impact of scopolamine, whereas the highest dose tested (1.8 mg/kg) did not. The predicted GlyT1 occupancies of RG1678 at the effective doses were ~10 and 30 %. ORG25935 (0.1, 0.3, and 1 mg/kg, p.o.) also significantly attenuated the impact of scopolamine on the ORD task, whereas 3 mg/kg did not. The predicted GlyT1 occupancies of ORG25935 at the effective doses ranged from 16 to 80 %. These data suggest that GlyT1 inhibitors have the potential to improve performance on prefrontal cortex-dependent tests such as the ORD task, but that efficacy is lost when higher occupancies are achieved. Importantly, recent Ph2B data published by Roche suggests that low but not high doses of RG1678 improved negative symptoms in patients with schizophrenia, highlighting the potential translational nature of the current preclinical findings. PMID- 24051603 TI - Molecular and behavioral characterization of adolescent protein kinase C following high dose ethanol exposure. AB - RATIONALE: Ethanol is commonly used and abused during adolescence. Although adolescents display differential behavioral responses to ethanol, the mechanisms by which this occurs are not known. The protein kinase C (PKC) pathway has been implicated in mediating many ethanol-related effects in adults, as well as gamma aminobutyric acid (GABA(A)) receptor regulation. OBJECTIVES: The present study was designed to characterize cortical PKC isoform and GABA(A) receptor subunit expression during adolescence relative to adults as well as assess PKC involvement in ethanol action. RESULTS: Novel PKC isoforms were elevated, while PKCgamma was lower during mid-adolescence relative to adults. Whole-cell lysate and synaptosomal preparations correlated for all isoforms except PKCdelta. In parallel, synaptosomal GABAA receptor subunit expression was also developmentally regulated, with GABA(A)R delta and alpha4 being lower while alpha1 and gamma2 were higher or similar, respectively, in adolescents compared to adults. Following acute ethanol exposure, synaptosomal novel and atypical PKC isoform expression was decreased only in adolescents. Behaviorally, inhibiting PKC with calphostin C, significantly increased ethanol-induced loss of righting reflex (LORR) in adolescents but not adults, whereas activating PKC with phorbol dibutyrate was ineffective in adolescents but decreased LORR duration in adults. Further investigation revealed that inhibiting the cytosolic phospholipase A2/arachidonic acid (cPLA2/AA) pathway increased LORR duration in adolescents, but was ineffective in adults. CONCLUSIONS: These data indicate that PKC isoforms are variably regulated during adolescence and may contribute to adolescent ethanol-related behavior. Furthermore, age-related differences in the cPLA2/AA pathway may contribute to ethanol's age-related effects on novel and atypical PKC isoform expression and behavior. PMID- 24051604 TI - HIV-1 infection of T cells and macrophages are differentially modulated by virion associated Hck: a Nef-dependent phenomenon. AB - The proline repeat motif (PxxP) of Nef is required for interaction with the SH3 domains of macrophage-specific Src kinase Hck. However, the implication of this interaction for viral replication and infectivity in macrophages and T lymphocytes remains unclear. Experiments in HIV-1 infected macrophages confirmed the presence of a Nef:Hck complex which was dependent on the Nef proline repeat motif. The proline repeat motif of Nef also enhanced both HIV-1 infection and replication in macrophages, and was required for incorporation of Hck into viral particles. Unexpectedly, wild-type Hck inhibited infection of macrophages, but Hck was shown to enhance infection of primary T lymphocytes. These results indicate that the interaction between Nef and Hck is important for Nef-dependent modulation of viral infectivity. Hck-dependent enhancement of HIV-1 infection of T cells suggests that Nef-Hck interaction may contribute to the spread of HIV-1 infection from macrophages to T cells by modulating events in the producer cell, virion and target cell. PMID- 24051605 TI - [Basal cell carcinoma of the periocular region]. AB - Basal cell carcinoma is the most common malignant tumor of the periocular region with local aggressive growth and extensive destruction. The histological subtypes of periocular basalioma, the recurrence rates and resection border relationships were analyzed and the results were compared with basaliomas from other body regions. The results of gender and age distribution, histological subtypes, recurrence rates and resection border relationships were evaluated using the chi(2)-test. The results showed a significantly higher recurrence rate (p < 0.01) for the periocular region compared to other body regions and the incidence of periocular basalioma was higher in women (p < 0.05). In addition the rarer histological subtypes were more commonly found in this region compared to other body regions (p < 0.01). PMID- 24051607 TI - Electrochemistry of Au(II) and Au(III) pincer complexes: determination of the Au(II)-Au(II) bond energy. AB - The bond energy of the unsupported Au-Au bond in the Au(ii) dimer [(C(?)N(?)C)Au]2 and the difference between Au(III)-OH and Au(III)-H bond enthalpies have been determined experimentally by electrochemical methods, with Au-OH and Au-H complexes showing unexpected differences in their reduction pathways, supported by DFT modelling. PMID- 24051606 TI - [Self-collection of test material. Supplement to cervical cancer screening]. AB - BACKGROUND: Recent studies have reported high sensitivity of human papillomavirus (HPV) testing from self-collected vaginal specimens. These results suggest the possibility of introducing self-collection of samples for cervical cancer screening to increase overall participation. The current study compared test results from self-collected and physician-collected specimens. PATIENTS AND METHODS: Vaginal samples from patients (n = 102) of a colposcopy clinic were taken by both a physician and themselves. All cell samples were tested using cytological diagnostics with a PAP test and for carcinogenic HPV genotypes (Cervista(r)). Additionally, all patients had a colposcopy (86% with cervical biopsy) and in 40% of patients was carried out a conisation. RESULTS: Of the patients tested 50 had the histological diagnosis of a cervical intraepithelial neoplasia grade 2 (CIN 2+ or 3). Sensitivity of HPV self-collected samples was much lower than that of physician-collected samples (72 % compared to 92 %). The sensitivity of self-collected PAP tests was only 52 % but the positive predictive value of self-collected PAP tests was very high. The cytological diagnosis of high-grade intraepithelial lesion (HSIL) correlated much better with the histological results of conisation (96 %) than with cervical biopsies (76 %). CONCLUSION: The results of this study indicate that self-collection may not provide an adequate collection method for improving efficiency in cervical cancer screening in Germany. PMID- 24051608 TI - From the guest editors: "Palliative medicine: the science of caring". PMID- 24051610 TI - State of art of managing pain in patients with cancer. AB - Pain in cancer patients involves complex interactions between physiological, psychological, sociocultural, sensory, cognitive, and behavioral dimensions. Pain management interventions will be most effective when pharmacological and nonpharmacological treatments are individualized after exploring the various contributors to pain and suffering, and the patient and family are educated and involved in decision making. This entails a systematic multidimensional approach with frequent reassessments of pain and related outcomes. PMID- 24051609 TI - Integrating palliative care in oncology: the oncologist as a primary palliative care provider. AB - The provision of comprehensive cancer care in an increasingly complex landscape necessitates that oncology providers familiarize themselves with the application of palliative care. Palliative care is a learnable skill. Recent endeavors in this arena have demonstrated that providing palliative care is part and parcel with providing compassionate and high-quality cancer care, specifically as it pertains to physical and emotional outcomes for patients and their caregivers alike. The basic tenets of providing palliative care emphasize: frequent and honest communication, routine and systematic symptom assessment, integration of spiritual assessments, and early integration of specialized hospice and palliative care resources as a patient's circumstances evolve. This article will endeavor to review and synthesize recent developments in the palliative care literature, specifically as they pertain to the oncologist as a primary palliative care provider. PMID- 24051611 TI - Interventional treatment of refractory cancer pain. AB - Recent advances in medical science have prolonged the life expectancy for many cancer patients. However, many studies demonstrate that cancer pain is a symptom for two thirds of patients in the advanced stages of the disease and nearly universal in the last 48 hours of life. Whereas most cancer patients can be effectively treated with conventional analgesics, 10% to 15% of patients require additional, and sometimes invasive, therapy. The most commonly used procedures for the treatment of this refractory cancer pain is the topic of review in this paper. Neurolytic blocks, such as celiac plexus and ganglion of impar block, are still used in the management of pain related to abdominal and pelvic cancers. Nondestructive interventional techniques include the use of epidural and intrathecal spinal analgesics. The efficacy, recommended medications, and adverse effect profile of these therapies are reviewed. PMID- 24051613 TI - Symptoms and symptom management in long-term cancer survivors. AB - It is estimated that there are 13 million cancer survivors in the United States, and more than 65% of them are 5 or more years beyond their diagnosis. The majority are "cancer-free and free of cancer," although some survivors have late or long-term effects of treatment or develop second or secondary cancers. Late and long-term effects for survivors of childhood cancers have been well studied, but less is known about the "seasons of survivorship" for adult cancer survivors. Symptoms during diagnosis, treatment, and then extending through the first several years of survivorship were reported in more than half of a large and heterogeneous group of cancer survivors. The incidence of late and/or long-term symptoms and health problems of long-term cancer survivors is less well characterized. These persistent symptoms are related to survivors' cancer diagnosis and the treatment they received, as well as age and other comorbidities. Health-related quality of life generally is stable for many years, although some cancer survivors experience a significant drop in health-related quality of life years after treatment, although the etiology is not clear yet. This article provides an overview of the natural history of cancer survivorship ("The seasons of survivorship"), disease-specific toxicities, and changes in symptoms in cancer survivors over time. Several common symptoms are used as examples including pain, fatigue, and cognitive dysfunction. PMID- 24051612 TI - Treatment of non-pain-related symptoms. AB - Relieving the suffering associated with cancer and its treatment in the physical, emotional, practical, and spiritual domains is impossible without impeccable symptom control. This review summarizes key features essential to the management of: anorexia/cachexia, bowel obstruction, diarrhea, fatigue, mucositis, and nausea/vomiting. Taken together, these are some of the most vexing symptoms for cancer patients. Well-managed symptoms enable the course of overall cancer care to be unimpeded. PMID- 24051614 TI - Palliative care in low- and medium-resource countries. AB - Low- and medium-resource countries are facing a significant increase in the incidence of noncommunicable diseases such as cancer. Unfortunately, the majority of patients with cancer present with advanced disease, and disease-directed treatment may be unlikely to be effective and/or not available. Globally, there will be a growing need for palliative care services. There has been significant progress in the provision and integration of palliative care into the health care policy and systems. Nonetheless, palliative care services vary significantly between regions of the world and also between countries in the same region. Some common barriers to care include the lack of a trained workforce to provide palliative care, lack of availability of opioids or the restriction of their use, cultural attitudes of physicians and patients, and also funding. Despite these challenges, there are examples of low- and medium-resource countries that are providing excellent palliative care that is being integrated into the health care system and the cancer care continuum. This article provides an overview of the progress in providing palliative care in low- and medium-resource countries. In addition, more specific information is provided on palliative care in low resource countries in Latin America, Asia, and Africa. Finally, a more personal perspective is presented on the development of palliative care in Ethiopia, as an example. PMID- 24051615 TI - Role of biopsychosocial screening in cancer care. AB - This review focuses on the aspects of biopsychosocial screening that have specific and significant implications for supportive care related to cancer care and research. There is a robust literature relating to the unmet supportive care needs of cancer patients and their families and the clinical interventions needed to effectively manage many of their problems. The Zeitgeist movement, which promotes the idea that the resources of this planet are the inherent right of all peoples, is also uniquely aligned to see supportive care services in oncology bringing significant value (cost and quality) to a health care system that is experiencing great uncertainty. Overall, there is a broadening of perspective within the supportive care community that there needs to be greater levels of interdisciplinary integration. More significantly, there is a growing realization that for cancer care to be truly patient and family centered and even minimally efficient, disease-directed care and supportive care need to be integrated from the time of diagnosis. The coordination of these services should not be based on the stage of the disease but rather tailored to the needs of the patient, family, and social context. Biopsychosocial screening programs have the potential to be the connective tissue of these patient- and family-centered systems. PMID- 24051616 TI - Personal growth during the experience of advanced cancer: a systematic review. AB - Over the past decade, research has documented the positive consequences individuals attribute to the experience of traumatic, life-threatening events, including enhanced life appreciation, improved social relationships, and a deepened sense of self and meaning. Despite evidence that individuals with cancer frequently perceive growth as a result of their experience, personal growth in the context of advanced cancer has received markedly less attention. In light of the unique challenges accompanying the experience of advanced cancer, the phenomenon of perceiving positive consequences and making meaning of the cancer experience (i.e., personal growth) may be distinct in patients with life-limiting disease as compared with more commonly studied early-stage cancer survivor samples. The purpose of this article was to review studies examining personal growth in adults diagnosed with advanced cancer to encourage medical professionals to consider and respond to their concerns around meaning within palliative care. We conducted a systematic review of the PubMed and PsycINFO electronic databases for studies examining personal growth in patients with advanced cancer published between January 1960 and January 2013. Of the 197 studies reviewed, 12 quantitative studies and 10 qualitative studies met criteria for inclusion. The review revealed that many patients with advanced cancer both cite finding meaning at the end of life as important and perceive positive consequences as a result of their experience. In comparison to early-stage cancer or benign disease, advanced cancer may serve to prompt higher levels of personal growth. However, these findings are mixed and may indicate a complex, nonlinear relationship between cancer prognosis and personal growth. The most promising candidates for promoting personal growth during advanced disease include younger adult age, spirituality, and psychosocial resources (optimism, marriage, and social support from close others and health care providers). Importantly, a co occurrence of personal growth with both distress and well-being in advanced cancer suggests that personal growth in this unique context is characterized by perceived positive consequences in the face of considerable demands, which may be reflected by greater negative and positive markers of adjustment. Understanding and awareness of personal growth in individuals with advanced cancer may facilitate health care providers' ability to consider and respond to concerns around meaning and personal growth within palliative care, given the growing literature on psychosocial interventions for patients with advanced cancer. Integration of the existing research base with intervention development is an opportunity for future research. PMID- 24051617 TI - Spirituality in cancer care at the end of life. AB - There is a compelling need to integrate spirituality into the provision of quality palliative care by oncology professionals. Patients and families report the importance of spiritual, existential, and religious concerns throughout the cancer trajectory. Leading palliative care organizations have developed guidelines that define spiritual care and offer recommendations to guide the delivery of spiritual services. There is growing recognition that all team members require the skills to provide generalist spiritual support. Attention to person-centered, family-focused oncology care requires the development of a health care environment that is prepared to support the religious, spiritual, and cultural practices preferred by patients and their families. These existential concerns become especially critical at end of life and following the death for family survivors. Oncology professionals require education to prepare them to appropriately screen, assess, refer, and/or intervene for spiritual distress. PMID- 24051618 TI - From the Euthanasia Society to physician orders for life-sustaining treatment: end-of-life care in the United States. AB - Advances in medical care and increasing prevalence of noncommunicable illnesses such as cardiovascular disease and cancer had raised concerns about respecting the patients' dying wishes as early as 1938, when the Euthanasia Society of America was formed. Many high-profile cases and landmark court decisions later, there are now several ways in which different states regulate the patients' end of-life wishes. How these laws evolved, how seminal cases and medical and ethical advances helped shape the current state of end-of-life legislation, and how patients-especially those with cancer-began adopting various forms of advance directives will be the topic of this article. PMID- 24051619 TI - Bereavement needs of adults, children, and families after cancer. AB - Many families and close friends are experiencing bereavement due to cancer. A review of recent studies of bereavement outcomes, mainly elevated psychological distress, suggests that bereaved family members, compared with nonbereaved, have poorer quality of life. They display high levels of complicated grief, anxiety, and depression and use bereavement services, but also report finding meaning in the loss, during the first 6 months after death. Similar demographic (e.g., female sex and younger age) and psychological (e.g., premorbid mental health conditions and lack of preparedness for the death) predictors are related to the bereavement outcomes across different familial groups. However, the severity of psychological distress and bereavement needs expressed vary by familial groups. Unrelieved pain and anxiety of the patient before the death and family members being unprepared for the impending death appear to be related to several postdeath psychological and physical morbidities of the surviving family members. Although the number of articles addressing bereavement-related issues associated with cancer has been growing in recent years, more rigorous studies that use longitudinal prospective designs, which bridge cancer survivorship with bereavement research, are needed. PMID- 24051620 TI - Adult height and epigenotype in children with Silver-Russell syndrome treated with GH. AB - AIMS: To compare adult heights of GH-treated and GH-untreated patients with Silver-Russell syndrome (SRS) who were epigenotyped. METHODS: This was a nonrandomized retrospective study with matched controls at a single center. Molecular analysis of 32 out of 37 GH-treated patients (16 females) revealed IGF2 H19 epimutations in 12 and maternal uniparental disomy of chromosome 7 (matUPD7) in 5 patients; 15 were negative. At start of GH, mean age was 7.2 years and mean height -3.34 standard deviation score (SDS). Mean GH dose used was 51 ug/kg.day, mean duration of therapy was 5.6 years. Puberty was blocked by GnRH analogs in 16 patients. The untreated group comprised 13 individuals (5 females, mean age 6.8 years and mean height -3.34 SDS). End points were adult height and overall height gain. RESULTS: GH-treated patients reached an adult height of -2.12 +/- 0.98 SDS gaining 1.22 SDS in comparison to baseline. Adult height SDS of the untreated was -3.13 +/- 1.37 SDS. The matched treated patients were significantly taller than their untreated counterparts. Outcome was dependent on height at start of GH and duration of therapy. Height gain was highest in the shortest patients. CONCLUSIONS: GH improved adult height in SRS to a comparable degree as reported in nonsyndromic SGA children. A trend toward a better outcome in matUPD7 needs confirmation in larger cohorts. PMID- 24051621 TI - Automatic and intentional brain responses during evaluation of face approachability: correlations with trait anxiety. AB - BACKGROUND: The judgment of the approachability of others based on their facial appearance often precedes social interaction. Whether we ultimately approach or avoid others may depend on such judgments. METHOD: We used functional magnetic resonance imaging to determine the neural basis for such approachability judgments and the relationship between these judgments and trait anxiety. Participants viewed ambiguous (i.e. neutral) or relatively unambiguous (i.e. angry, happy) faces, assessing either the approachability or the sex of the person depicted. RESULTS: Neutral faces elicited more inconsistent responses within participants only during approachability judgment, suggesting ambiguous property as signals. The contrast pertaining to the interaction between task and face valence demonstrated activation in several areas, such that the left amygdala and medial, middle and inferior frontal gyri were responsive to angry faces when subjects were asked to recognize the sex (implicit task) and to neutral faces when required to discern the approachability (explicit task). Moreover, the blood oxygenation level-dependent change within the left amygdala in response to neutral faces during the judgment of approachability was positively correlated with participant trait anxiety. CONCLUSIONS: These findings extend a proposed model of social cognition by highlighting the functional engagement of the amygdala in approachability judgments, which underlie an individual's sensitivity to ambiguous sources of probable threat. PMID- 24051622 TI - A multicenter, randomized, open-label, controlled study comparing the efficacy, safety and cost-effectiveness of a sequential therapy with RV4104A ointment, ciclopiroxolamine cream and ciclopirox film-forming solution with amorolfine nail lacquer alone in dermatophytic onychomycosis. AB - BACKGROUND: The efficacy of topical antifungals is controversial. OBJECTIVE: To compare the efficacy and safety of a sequential(SEQ) treatment with chemical nail avulsion and topical antifungals to amorolfine nail lacquer in dermatophytic onychomycosis. METHODS: This was a randomized,parallel-group, controlled study comparing a 36-week SEQ treatment with chemical nail avulsion with RV4104A ointment(class I medical device containing 40% urea) followed by ciclopirox cream for 8 weeks and ciclopirox nail lacquer for 25 weeks (SEQ group) to amorolfine nail lacquer for 36 weeks (AMO group). Patients had to have a big toenail onychomycosis,sparing the matrix. The primary efficacy criterion was complete cure at week 48. A cost-effectiveness analysis was performed. RESULTS: A total of 142 patients were randomized. The complete cure rate at week 48 was significantly higher in the SEQ group than in the AMO group (36.6 vs. 12.7%, p = 0.001). Clinical cure at week 48 was observed in 53.5% of patients in the SEQ group versus 17% in the AMO group (p < 0.01). The cost of cure per patient was 50% lower with SEQ treatment (EUR 33) compared with amorolfine(EUR 76). CONCLUSION: A treatment of onychomycosis comprising chemical avulsion of the pathological nail, ciclopirox cream and nail lacquer is significantly more effective than amorolfine nail lacquer. PMID- 24051625 TI - Genome editing takes off. PMID- 24051626 TI - Frozen frogs spring back to life. PMID- 24051628 TI - Flight of the bumblebee. PMID- 24051629 TI - Alzheimer's disease linked to brain copper buildup. PMID- 24051632 TI - The friendly bottlenose dolphin. PMID- 24051633 TI - A review of USDA's rule on contingency plans. PMID- 24051634 TI - Response to protocol review scenario: kudos to Ayers. PMID- 24051635 TI - Protecting welfare or obstructing research? PMID- 24051636 TI - Response to Protocol Review Scenario: Protecting animal welfare. PMID- 24051637 TI - Response to Protocol Review Scenario: Questioning is appropriate. PMID- 24051638 TI - Techniques for collecting blood from the domestic chicken. AB - As the use of chickens in biomedical research is increasing, demand is growing for technical skills involving poultry, particularly techniques such as venipuncture. Phlebotomy (blood collection) is an important diagnostic tool for determining causes of morbidity and mortality and for collection of other research-relevant data. This column describes four standard methods of blood collection from the domestic chicken. PMID- 24051640 TI - Uterine infection in a cat research colony. PMID- 24051641 TI - Monitoring and mitigating isoflurane emissions during inhalational anesthesia of mice. AB - Establishing a program to monitor waste anesthetic gas (WAG) in order to limit personnel exposure requires measuring the levels of WAG emitted and determining the effectiveness of scavenging methods to reduce such levels. In this study, the authors used infrared spectroscopy to measure levels of WAG emitted while anesthetizing mice with isoflurane for 15 min. They evaluated four different WAG scavenging conditions during induction and maintenance anesthesia: two conditions that used passive techniques and two that used active techniques. Isoflurane concentrations were measured at three different locations: in the operator's vicinity, at the mouse-facemask interface and in the room environment. Passive scavenging of WAG improved when chambers were purged with oxygen after induction and when a diaphragm-sealed facemask delivered a reduced anesthetic flow rate during maintenance anesthesia. Active scavenging of WAG improved when a relief intake opening was provided in the induction chamber's vacuum line, vacuum draw after induction was regulated and the anesthetic flow rate and vacuum scavenging draw were balanced during maintenance anesthesia using a facemask that separated the breathing space from the scavenging zone. Additionally, time-weighted average isoflurane WAG levels detected by personal dosimeters correlated with real-time measurements made using infrared spectroscopy. These observations contribute to the development of a substantiated program for monitoring WAG air quality. PMID- 24051642 TI - Producing timed-pregnant Mongolian gerbils for developmental studies. AB - The developing fetus is differentially susceptible to chemicals and pathogens depending on the stage of its development. In developmental studies, embryos or fetuses therefore must be exposed to experimental interventions at the same gestational stage. Acquiring sufficient numbers of embryos of the same developmental stage requires the use of timed-pregnant animals. Timed-pregnant Mongolian gerbils currently are not available for purchase. The authors developed a novel method for timed mating of virgin female gerbils. Female gerbils were housed in the same cage as males, but physically separated by a partition, for 3 d in order to expose the females to the males' pheromones before they were allowed to interact. Females were monitored for lordosis to determine sexual receptivity. Lordosis was observed in 10 of 15 females (67%), and 9 of these females (90%) became pregnant. When lordosis was not observed, none of the females became pregnant. These results demonstrate that the timed mating method produces a high rate of mating success and indicate that lordosis is a reliable predictor of sexual receptivity and subsequent successful mating in the Mongolian gerbil. PMID- 24051644 TI - What is a knowledge ecosystem? PMID- 24051643 TI - Conditioning laboratory cats to handling and transport. AB - As research subjects, cats have contributed substantially to our understanding of biological systems, from the development of mammalian visual pathways to the pathophysiology of feline immunodeficiency virus as a model for human immunodeficiency virus. Few studies have evaluated humane methods for managing cats in laboratory animal facilities, however, in order to reduce fear responses and improve their welfare. The authors describe a behavioral protocol used in their laboratory to condition cats to handling and transport. Such behavioral conditioning benefits the welfare of the cats, the safety of animal technicians and the quality of feline research data. PMID- 24051645 TI - Do we really need disaster communications plans? PMID- 24051646 TI - Rebuild, restore, renew. Interview with Lynell M. Dupepe. PMID- 24051647 TI - The Safe Harbor Mouse Retreat(TM) is an innovative enrichment shelter that saves mice and money. AB - Environmental enrichment can be defined as altering the living environment of captive animals in order to provide them with opportunities to express their natural behavioral repertoire. As important as offering an enriched environment is assuring lab animals are housed in the safest conditions possible. Cage flooding events are an unfortunate reality; however, technology is advancing to minimize these events. Bio-Serv, in collaboration with Allentown, Inc., has developed an innovative and economical shelter called the Safe Harbor Mouse Retreat (Fig. 1). This shelter offers a life-saving refuge for mice during these occasional, but devastating cage-flooding accidents. Mice will not be lost due to chilling or drowning caused by water exposure. Breeding mice can save their litters by moving their pups to the second level, and all mice can escape to the higher level where they can remain warm and dry until they are rescued. This clever shelter is not only life-saving for mice but offers several other significant benefits as well. PMID- 24051648 TI - Using principles from emergency management to improve emergency response plans for research animals. AB - Animal research regulatory agencies have issued updated requirements for emergency response planning by regulated research institutions. A thorough emergency response plan is an essential component of an institution's animal care and use program, but developing an effective plan can be a daunting task. The author provides basic information drawn from the field of emergency management about best practices for developing emergency response plans. Planners should use the basic principles of emergency management to develop a common-sense approach to managing emergencies in their facilities. PMID- 24051649 TI - Renovating animal facilities to withstand disasters. AB - In the aftermath of Superstorm Sandy, new attention has been drawn to planning for and mitigating the effects of disasters on laboratory animal facilities. A number of design approaches and solutions can be easily incorporated into a new vivarium, enhancing its ability to withstand and recover from a disaster. Renovating a vivarium poses special challenges, however. Existing conditions in the project area may dictate which approaches or solutions are feasible, and retrofitting is often more complex and expensive than incorporating the same features into new construction. The authors explain how project design teams can evaluate the types of disasters that a renovated facility will need to address and develop a design strategy that responds to these disasters in the most effective way. PMID- 24051650 TI - Practical considerations for disaster preparedness and continuity management in research facilities. AB - Many research facility managers, veterinarians and directors are familiar with the principles of Good Laboratory Practice, requirements of the Association for Assessment and Accreditation of Laboratory Animal Care International, tenets of biosecurity and standards of animal welfare and housing but may be less familiar with the ideas of business continuity. But business continuity considerations are as applicable to research facilities as they are to other institutions. The authors discuss how business continuity principles can be applied in the research context and propose that such application, or 'research continuity management,' enables a focused but wide-reaching approach to disaster preparedness. PMID- 24051651 TI - Considerations for the selection of a generator as a back-up power source for an animal facility. AB - Loss of power, whether or not it is related to a disaster, is a potential problem for animal facilities. The lack of light and the inability to operate mechanical systems related to ventilation, security, access, water, sewer and environmental control; to use laboratory instruments and equipment such as cage-washers and automatic watering systems; and to access computers and electronic files, potentially including animal health records and environmental monitoring data, present substantial challenges to facility operation. Therefore, an animal research facility must develop a contingency plan to address loss of power and other potential threats. Use of a back-up power source such as a generator is a common component of such a plan. Here the author discusses factors that should be considered in the selection of a generator as a back-up power source for an animal facility. PMID- 24051652 TI - Planning for the continued humane treatment of animals during disaster response. AB - Responding to a disruptive event is a challenging task for a research facility. One component that must be addressed in a disaster response plan for a facility that houses research animals is the care of those animals during and after a disruptive event. In this article, the author provides recommendations for the preparations, connections and training that are necessary to provide such care. He concludes that the best responses are those that mitigate the unique circumstances involved, which can be developed through practical thinking and problem solving as a community. PMID- 24051653 TI - Impact of earlier ureteral ligation on intravesical recurrence during hand assisted retroperitoneoscopic nephroureterectomy. AB - OBJECTIVE: To determine the impact of earlier ureteral ligation (EUL) during hand assisted retroperitoneoscopic nephroureterectomy (HARN) for primary renal pelvis urothelial cancer. METHODS: We retrospectively reviewed 240 patients with upper urinary tract urothelial cancer who underwent HARN. Only patients with primary renal pelvis urothelial cancer and complete follow-up with a minimum of 1 year after HARN were enrolled into our study. We defined EUL as ligating the ureter prior to pneumoretroperitoneum and mobilizing the kidney during the surgery. Of these 61 patients, 31 (who composed the study group) underwent EUL, while 30 serving as controls were without ureteral ligation during the surgery. We analyzed intravesical recurrence utilizing log rank testing to assess the significance between the two groups. RESULTS: Clinical parameters were similar between the two groups. The median follow-up after HARN was 39.7 months (range 12 96). There was no significant difference in the rate of intravesical recurrence and cancer-specific survival. However, patients without ligation of the ureter had shorter time to first bladder tumor recurrence (11.7 +/- 9.1 months vs. 26.4 +/- 19.1 months, p = 0.03). CONCLUSION: EUL during HARN for primary renal urothelial cancer did not affect intravesical recurrence rate or cancer-specific survival. PMID- 24051654 TI - Synthesis of transparent aminosilane-derived silica based networks for entrapment of sensitive materials. AB - A novel sol-gel synthesis route is reported which results in the formation of optically transparent silica based hydro- and xerogels from an aminosilane precursor in aqueous solutions. These materials can be used for entrapment of microalgae and light-harvesting complex (LHC) samples. PMID- 24051655 TI - Auxin-binding protein 1 is a negative regulator of the SCF(TIR1/AFB) pathway. AB - Auxin is a major plant hormone that controls most aspects of plant growth and development. Auxin is perceived by two distinct classes of receptors: transport inhibitor response 1 (TIR1, or auxin-related F-box (AFB)) and auxin/indole-3 acetic acid (AUX/IAA) coreceptors, that control transcriptional responses to auxin, and the auxin-binding protein 1 (ABP1), that controls a wide variety of growth and developmental processes. To date, the mode of action of ABP1 is still poorly understood and its functional interaction with TIR1/AFB-AUX/IAA coreceptors remains elusive. Here we combine genetic and biochemical approaches to gain insight into the integration of these two pathways. We find that ABP1 is genetically upstream of TIR1/AFBs; ABP1 knockdown leads to an enhanced degradation of AUX/IAA repressors, independently of its effects on endocytosis, through the SCF(TIR1/AFB) E3 ubiquitin ligase pathway. Combining positive and negative regulation of SCF ubiquitin-dependent pathways might be a common mechanism conferring tight control of hormone-mediated responses. PMID- 24051656 TI - Effects of fusaric acid treatment on HEp2 and docetaxel-resistant HEp2 laryngeal squamous cell carcinoma. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) can become resistant to some chemotherapy and becomes a clinical challenge when it recurs. There are few agents identified for second-line treatment of resistant head and neck cancer. Therefore, we evaluated the role of fusaric acid (FA) as a possible agent for treatment for chemotherapy-resistant laryngeal squamous cell carcinoma. METHODS: The HEp2 and docetaxel-resistant HEp2 (HEp-Doc) cell lines were created from human laryngeal cancer. Cell lines were exposed to FA at increasing concentrations (0.1, 0.3, and 0.5 mM) and time intervals of 24, 48, 72, and 96 h. The effects on cell survival, apoptosis, and cytokine and protein expression were analyzed. RESULTS: FA treatment in the HEp-Doc cells showed greater reduction of cell number and colony-forming units and more apoptosis when compared to HEp2 and required less time to reduce cell number. Four cytokines were detected in HEp2 cancer cells that increased with FA treatment. Pro-caspase-9 and -7 and poly (ADP ribose) polymerase also increased with FA treatment. CONCLUSION: FA may be an agent to be considered in cases of HNSCC treatment resistance or post-docetaxel recurrence. Further investigation of FA in vitro and in vivo is indicated. PMID- 24051657 TI - Fosfomycin trometamol (3,000 mg) in perioperative antibiotic prophylaxis of healthcare-associated infections after endourological interventions: a narrative review. AB - INTRODUCTION: Increasing antibiotic resistance also has an impact on perioperative antibiotic prophylaxis (PAP). This narrative review evaluates fosfomycin trometamol (FT) as PAP in endourological interventions. MATERIALS AND METHODS: Nine clinical studies including 4 randomized comparative studies were analyzed. A total of 1,614 patients received FT as PAP for different endourological procedures and extracorporeal shock wave lithotripsy [ESWL; i.e. cystoscopy (n = 498), urodynamic studies (n = 39), ureteropyeloscopy (n = 10), urethrotomy (n = 20), lithotripsy (n = 15), transurethral resection of bladder tumors (n = 139), transurethral resection of the prostate (n = 843), ESWL (n = 20), ureterorenoendoscopic lithotripsy (n = 18), percutaneous nephrostomic lithotripsy (n = 12)]. RESULTS: In 8 clinical studies, FT was shown to be effective in preventing healthcare-associated urinary tract infections (HAUTIs). One study showed no benefit. The usual dosage regimen was oral administration of 3 g of FT 3 h before and 24 h after the procedure. In 1 randomized comparative study investigating HAUTIs after diagnostic cystoscopy, it could also be shown that a single oral dose of 3 g of FT 3 h before cystoscopy was as effective as a double dose. CONCLUSION: According to the published results, for traumatic endourological interventions and surgical procedures, an oral dosage of 3 g of FT 3 h before and 24 h after the procedure and only 1 (prior) oral dosage for diagnostic procedures might be an alternative if PAP is indicated. Limitations of the studies are the low numbers of patients included for most indications. PMID- 24051658 TI - Urban form and psychosocial factors: do they interact for leisure-time walking? AB - INTRODUCTION: This cross-sectional study uses an adaptation of a social ecological model on the hierarchy of walking needs to explore direct associations and interactions of urban-form characteristics and individual psychosocial factors for leisure-time walking. METHODS: Questionnaire data (n = 736) from adults (25-74 yr) and systematic field observations within 14 neighborhoods in Eindhoven (the Netherlands) were used. Multilevel logistic regression models were used to relate the urban-form characteristics (accessibility, safety, comfort, and pleasurability) and individual psychosocial factors (attitude, self-efficacy, social influence, and intention) to two definitions of leisure-time walking, that is, any leisure-time walking and sufficient leisure-time walking according to the Dutch physical activity norm and to explore their interactions. RESULTS: Leisure time walking was associated with psychosocial factors but not with characteristics of the urban environment. For sufficient leisure-time walking, interactions between attitude and several urban-form characteristics were found, indicating that positive urban-form characteristics contributed toward leisure time walking only in residents with a less positive attitude toward physical activity. In contrast, living in a neighborhood that was accessible for walking was stronger associated with leisure-time walking among residents who experienced a positive social influence to engage in physical activity compared with those who reported less social influence. CONCLUSIONS: This study showed some evidence for an interaction between the neighborhood environment and the individual psychosocial factors in explaining leisure-time walking. The specific mechanism of interaction may depend on the specific combination of psychosocial factor and environmental factor. The lack of association between urban form and leisure-time walking could be partly due to the little variation in urban-form characteristics between neighborhoods. PMID- 24051659 TI - Effects of short-term dexamethasone administration on corticospinal excitability. AB - PURPOSE: The short-term administration of glucocorticoids increases maximal voluntary force in healthy humans, but the underlying mechanisms remain poorly understood. The present study investigated the glucocorticoid effects on spinal and corticospinal pathways and on electromechanical properties of the tibialis anterior muscle in response to nerve stimulation. METHODS: Twelve healthy men participated in a single-blind randomized study to receive either dexamethasone (8 mg . d(-1), n = 8 subjects) or placebo (n = 4 subjects) for 7 d. Group Ia afferent and corticospinal pathways were assessed, respectively, by recording the amplitude of the Hoffmann (H) reflex and motor-evoked potential (MEP) by transcranial magnetic stimulation. The ankle dorsiflexor torque and EMG activity during a maximal voluntary contraction (MVC) and muscle twitch evoked by electrical stimulation were also assessed before and after the intervention. RESULTS: The MVC torque (+14%) and the associated tibialis anterior EMG (+16%) increased after glucocorticoid treatment (P < 0.05), whereas muscle twitch parameters did not change (P > 0.05). The H-reflex amplitude did not change (P = 0.58), but the MEP threshold was significantly (P = 0.008) reduced after treatment. Moreover, the slope of the MEP input-output relation and the silent period/MEP ratio increased (P = 0.049) and decreased (P = 0.029), respectively, after treatment. The amount of change in MEP amplitude and MVC torque were positively associated (r(2) = 0.59) for the dexamethasone group. CONCLUSION: This is the first study indicating that short-term glucocorticoid administration in healthy subjects increased corticospinal excitability that contributed to enhance MVC torque. PMID- 24051660 TI - Patient access to care- a need for mental health leadership, and a role for industry. PMID- 24051661 TI - Understanding DSM-5. Advice for South African practitioners. PMID- 24051662 TI - Usage of 'download of psychiatry' in Africa. PMID- 24051663 TI - Mania after termination of epilepsy treatment: a case report. PMID- 24051664 TI - Expressed emotion among schizophrenic patients in Lagos, Nigeria: a pilot study. PMID- 24051665 TI - A review of Quality of Life studies in Nigerian patients with psychiatric disorders. AB - The concept of Quality of Life is becoming an increasingly important measure of the impact of psychiatric disorders and is now recognized as useful in the healthcare evaluation of patients with psychiatric disorders. The aim of this review was to document and analyze the research data on quality of life in Nigerian patients with psychiatric disorders. The electronic databases, Medline and Pubmed were searched for published articles on quality of life in Nigerian patients with psychiatric disorders. A total of 6 studies met the inclusion criteria. All the studies employed the generic World Health Organization Quality of Life Scale - Brief version, which is the only quality of life instrument whose psychometric properties have been evaluated among Nigerian patients with psychiatric disorders. Some of the studies revealed that quality of life was significantly associated with socio demographic factors such marital and employment status and social support. Poor quality of life was reported to be associated with illness related factors such as co morbid medical problems, presence of anxiety and depressive symptoms and non adherence to medications. All the studies with the exception of two were conducted in centers located in South western Nigeria. Quality of life in Nigerian patients suffering from psychiatric disorders is under-researched. There is need for more studies to prospectively investigate quality of life and associated factors among Nigerian patients with psychiatric disorders. PMID- 24051666 TI - Meanings of thinness and dysfunctional eating in black South African females: a qualitative study. AB - OBJECTIVE: This study qualitatively explored local meanings of thinness and dysfunctional eating in black adolescent females in the rapidly westernizing socio-cultural context of post-apartheid South Africa. METHODS: Four (n=4) urban state highschools in KwaZulu-Natal were selected from which 40 subjects were sampled from Grades 9-12. Focus groups were conducted following a semi-structured interview and analysed using Constant Comparative Analysis. RESULTS: Subjects reported a wide range of different meanings for thinness, which included traditional idioms of distress and typically western pressures towards thinness, which was particularly evident in the multicultural schools. Subjects also reported a wide range of dysfunctional eating practices (such as purging) which were underscored by a wide range of motivations, including traditional practices and western body image concern; and which did not tend to follow patterns of 'dieting' that are typical in affluent, western societies. CONCLUSION: Western pressures towards thinness may be blending with traditional idioms of distress and culturally sanctioned rituals of remedial purging and social over-eating, thereby placing this group at particular risk for a range of dysfunctional eating patterns that may not follow typically western paradigms or diagnostic systems. PMID- 24051667 TI - Clinical factors associated with rape victims' ability to testify in court: a records-based study of final psychiatric recommendation to court. AB - OBJECTIVE: A rape victim may encounter professionals in both the health and the legal systems. Unanswered questions remain about clinical factors associated with a rape victim's ability to testify in court, and the quality of care offered to rape victims. The objectives of this study were thus to determine the clinical factors that are associated with a rape victim's ability to testify in court, as well as to undertake a preliminary exploration of the referral system between the court and the mental health services. METHOD: A retrospective study was conducted of rape victims referred by the court (n=70) to be assessed psycho-legally by psychiatrists. Rape victims who were recommended as able and those recommended as unable to testify in court were compared with regard to their clinical characteristics. RESULTS: Thirty-seven (53.6%) victims were recommended as able to testify and 32 (46.4%) victims as unable to testify in court. Victims from rural areas and victims with severe mental retardation were statistically significantly more often found to be unable to testify in court. Almost half (49.2%) of the victims were referred by court for first assessment within six months of being raped. Most (63.5%) victims were assessed for the first time within one month of being referred. CONCLUSION: The decision about a victim's ability to testify should not be based solely on the two statistically significant variables but, rather, individualised. Optimal mental health and legal services should be offered to rape victims. Further studies are required in assessing the collaboration between the health and legal systems. PMID- 24051668 TI - Assessment of the needs of vulnerable youth populations in post-conflict Liberia. AB - OBJECTIVE: The study examined key informants' perceptions of the emotional impact of traumatic events, major problems, functional limitations and appropriate treatment settings for children, adolescents, and young adults in post-conflict Liberia. METHOD: This research is a based on cross-sectional survey conducted between March 30, 2009 and April 30, 2009 in Liberia with 171 local key Liberian informants. Analysis was conducted using mixed methods. The findings we will report were collected in the qualitative portion of the survey. RESULTS: We found that while different interventions were preferred for different types of young people, some interventions were mentioned for all youth and by all age and gender groups of key informants. These included counseling, education, and skills training. Also frequently chosen were housing, community reintegration, recreation, and medical care. In general, key informants reported similar concerns regardless of their ages or genders. Notable exceptions to this were in interventions for youth who joined fighting forces. Men over 50 were the only ones to recommend apology and reparations. Similarly, in recommendations for criminals and violent youth, a number of men mentioned prison, whereas the women did not. CONCLUSION: Our findings suggest that the needs of post-conflict Liberian youth span a variety of domains, including physical, emotional, medical, psychological, and educational. These findings can be used to guide the development of treatment programs for these young people. PMID- 24051669 TI - Clinical and psycho-social profile of child and adolescent mental health care users and services at an urban child mental health clinic in South Africa. AB - OBJECTIVE: National and international child and adolescent mental healthcare policy and action advocate that the health and well being of children should be increasingly given greater attention. The purpose of this study was to describe the demographic, socio economic and clinical profile of the users at the child and adolescent mental health clinic of the Rahima Moosa Mother and Child Hospital (RMMCH). METHOD: A descriptive, retrospective clinical audit from users' clinical files was performed over a one-year period from January to December 2007. Descriptive statistical analyses of demographic and socio-economic variables were made and these variables were compared with the presenting clinical problems. Odds ratios were calculated for variables that showed a statistically significant association (p-value less than 0.05). RESULTS: A total of 303 users attended this clinic. Statistical comparisons between demographic data and disorders revealed that being male increased the likelihood of presenting with AHDH and disruptive behaviour disorders; being female increased the likelihood of being sexually abused. Race showed a significant association with parent-child relationship difficulties. Regarding socio-economic variables, the identity of the caregiver of the child influenced the risk of disruptive behaviour disorders, sexual abuse, neglect and academic problems. Where the child was placed was a risk factor for disruptive behaviour disorders, sexual abuse, neglect and academic problems. Whether the mother of a user was alive or deceased, was found to be related to ADHD and disruptive behaviour and whether the father of a user was alive or deceased, was found to be related to sexual abuse and academic problems. The education level of the caregiver showed a significant association with sexual abuse, neglect and academic problems; the marital status of the parent (widowed mother) showed a significant association with bereavement. Household income was associated with sexual abuse, neglect and academic problems. CONCLUSION: This study demonstrated the impact that socio-economic circumstances have on the prevalence of childhood disorders; hence the urgent need for government and social welfare departments to improve the socio-economic status of communities. There is a need to improve psychiatric services for the population served by this hospital, including more clinics in its catchment area, as well as child psychiatry training posts and extended social work services. PMID- 24051670 TI - Using a treatment partner and text messaging to improve adherence to psychotropic medication: a qualitative formative study of service users and caregivers in Cape Town, South Africa. AB - OBJECTIVE: Poor adherence to medications, including psychotropic medications contributes to the burden of disease. Mental health service users (MHSU) may also not attend follow-up appointments at their health care facilities where they could discuss adherence with their health care provider. This paper reports on preliminary qualitative research preceding a randomised controlled trial that aims to improve adherence to psychotropic medication and to follow up treatment visits. The intervention will entail the support of individuals with serious mental disorder by a treatment partner and short message service (SMS) text messaging. METHODS: The preliminary research reported in this paper aimed to extract views about the intervention from both mental health service users (MHSU) and caregivers through focus group discussions and individual interviews. Data were analysed using ATLAS TI qualitative software. RESULTS: The caregivers interviewed were all mothers of MHSU who took measures to encourage adherence. They held mixed opinions on whether the treatment partner should be a family member. Most participants expressed the view that due to living conditions, family members were natural treatment partners, but others stated that they would prefer a treatment partner who was not a family member. Similarly, while most MHSU supported the idea of a treatment partner, a minority were concerned that a treatment partner may potentially be too controlling and compromise their autonomy. The vast majority of participants supported SMS text messaging as a means of reminding MHSU to take their medication and attend follow-up appointments. One participant mentioned the importance of broader social inclusion issues that should be incorporated in the intervention. CONCLUSION: Qualitative research may provide useful insights for the design of interventions of this nature related to social inclusion randomised control trials with its focus on adherence. PMID- 24051671 TI - The sad truth about depression in the elderly. PMID- 24051673 TI - No association between brain-derived neurotrophic factor G196A polymorphism and clinical features of Parkinson's disease. AB - AIMS: To investigate association of the Val66Met polymorphism in the brain derived neurotrophic factor (BDNF) gene with clinical features in Serbian patients with Parkinson's disease (PD). METHODS: The study comprised 177 consecutive PD patients. A comprehensive set of clinical scales was applied in all patients. The controls (n=366) were recruited among students. Single nucleotide polymorphisms (SNPs; rs6265) were analyzed using TaqMan assays. RESULTS: PD patients (118 males) were aged 58.9+/-10.9 years, with a mean age at onset of 49.0+/-11.2 years. PD patients and controls had a similar distribution of genotypes and allele frequencies. The presence of the Met allele did not influence the clinical characteristics of PD patients (age at onset, family history, gender, disease duration, form of the disease, initial symptoms, cognitive abilities, depression, anxiety, disease severity, severity of motor and prevalence of nonmotor symptoms, and development of motor complications). CONCLUSION: Overall, the Val66Met polymorphism did not modify the clinical features in PD patients. PMID- 24051674 TI - Insulin resistance and cardiovascular risk factors in 3- to 5-year-old overweight or obese children. AB - BACKGROUND/AIMS: The increasing rate of overweight and obesity is alarming. The complications of overweight and obesity at a young age are largely unknown. We aimed to assess the prevalence of insulin resistance (IR) and cardiovascular risk factors among overweight and obese children aged 3-5 years. METHODS: The study population consisted of 75 children (29 overweight, 46 obese). We performed anthropometry and bioelectrical impedance analysis as an indicator of body composition. IR was determined by the updated Homeostasis Model Assessment of Insulin Resistance (HOMA2-IR). Cardiovascular risk factors were defined by the presence of increased serum triglycerides, blood pressure, and HOMA2-IR and by a decreased serum HDL cholesterol. RESULTS: An elevated HOMA2-IR was found in 7.7% of the children. HOMA2-IR was correlated with body mass index (r = 0.63), waist circumference (r = 0.62) and percentage body fat (r = 0.58) (all p < 0.001). Cardiovascular risk factors were present in 6.9% (triglycerides) to 74.3% (hypertension) of the children. CONCLUSION: IR and cardiovascular risk factors are already evident in many 3- to 5-year-old overweight and obese children. IR is strongly related to body composition. PMID- 24051675 TI - Coaxial PANI/TiN/PANI nanotube arrays for high-performance supercapacitor electrodes. AB - Coaxial PANI/TiN/PANI nanotube arrays prepared by electrochemical polymerization of PANI on nanoporous TiN nanotube arrays exhibit a high specific capacitance of 242 mF cm(-2), excellent rate capability with the capacitance remaining at 69% when the current density is increased 50 times from 0.2 to 10 mA cm(-2), and a long cycling life with less than 0.005% decay per cycle. PMID- 24051672 TI - Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2. AB - Mutations in the CACNA1F gene encoding the Cav1.4 Ca (2+) channel are associated with X-linked congenital stationary night blindness type 2 (CSNB2). Despite the increasing knowledge about the functional behavior of mutated channels in heterologous systems, the pathophysiological mechanisms that result in vision impairment remain to be elucidated. This work provides a thorough functional characterization of the novel IT mouse line that harbors the gain-of-function mutation I745T reported in a New Zealand CSNB2 family. (1) Electroretinographic recordings in IT mice permitted a direct comparison with human data. Our data supported the hypothesis that a hyperpolarizing shift in the voltage-dependence of channel activation-as seen in the IT gain-of-function mutant (2)-may reduce the dynamic range of photoreceptor activity. Morphologically, the retinal outer nuclear layer in adult IT mutants was reduced in size and cone outer segments appeared shorter. The organization of the outer plexiform layer was disrupted, and synaptic structures of photoreceptors had a variable, partly immature, appearance. The associated visual deficiency was substantiated in behavioral paradigms. The IT mouse line serves as a specific model for the functional phenotype of human CSNB2 patients with gain-of-function mutations and may help to further understand the dysfunction in CSNB. PMID- 24051676 TI - Performance of gadofosveset-enhanced MRI for staging rectal cancer nodes: can the initial promising results be reproduced? AB - OBJECTIVES: A previous study showed promising results for gadofosveset-trisodium as a lymph node magnetic resonance imaging (MRI) contrast agent in rectal cancer. The aim of this study was to prospectively confirm the diagnostic performance of gadofosveset MRI for nodal (re)staging in rectal cancer in a second patient cohort. METHODS: Seventy-one rectal cancer patients were prospectively included, of whom 13 (group I) underwent a primary staging gadofosveset MRI (1.5-T) followed by surgery (+/- preoperative 5 * 5 Gy) and 58 (group II) underwent both primary staging and restaging gadofosveset MRI after a long course of chemoradiotherapy followed by surgery. Nodal status was scored as (y)cN0 or (y)cN+ by two independent readers (R1, R2) with different experience levels. Results were correlated with histology on a node-by-node basis. RESULTS: Sensitivity, specificity and area under the receiver operating characteristics curve (AUC) were 94%, 79% and 0.89 for the more experienced R1 and 50%, 83% and 0.74 for the non-experienced R2. R2's performance improved considerably after a learning curve, to an AUC of 0.83. Misinterpretations mainly occurred in nodes located in the superior mesorectum, nodes located in between vessels and nodes containing micrometastases. CONCLUSIONS: This prospective study confirms the good diagnostic performance of gadofosveset MRI for nodal (re)staging in rectal cancer. KEY POINTS: * Gadofosveset-enhanced MRI shows high performance for nodal (re)staging in rectal cancer. * Gadofosveset MRI may facilitate better selection of patients for personalised treatment. * Results can be reproduced by non-expert readers. * Experience of 50-60 cases is required to achieve required expertise level. * Main pitfalls are nodes located between vessels and nodes containing micrometastases. PMID- 24051677 TI - Thyroid nodules in Hispanic patients with systemic lupus erythematosus. AB - A thyroid nodule (TN) is a discrete lesion in the thyroid gland radiologically distinct from the adjacent parenchyma, with a prevalence variable depending on the diagnostic method used and the study population. Thyroid disorders have been identified in more than 50% of patients with systemic lupus erythematosus (SLE); however, the prevalence of TN has not been frequently studied. We identified a prevalence of 27% TN in 55 SLE patients > 16 years of age. One-third of TN were >1 cm with radiological features of malignancy. The mean age of patients with TN was 39 +/- 11 years, 93% women, and SLE duration 10 +/- 6 years. Among patients, we reported family history of cancer in three cases (20%), thyroid disease in one (7%), and autoimmune disease in six (40%). Regarding treatment, 50% of patients with TN were treated with azathioprine vs. 23% of patients without TN (p = 0.02), with an OR of 3.94 (95% CI 1.12-13.84, p = 0.03). As a conclusion a high prevalence of TN in SLE patients was found. Prevalence of TN correlated only with history of azathioprine use. We don't know the long-term implications of our findings; however, a functional and morphological evaluation of the thyroid gland is warranted in all patients with SLE. PMID- 24051678 TI - Strongly enhanced flux pinning in one-step deposition of BaFe2(As0.66P0.33)2 superconductor films with uniformly dispersed BaZrO3 nanoparticles. AB - The high upper critical field and low anisotropy of the iron-based superconductor BaFe2As2 make it promising for its use in the construction of superconducting magnets. However, its critical current density in high magnetic fields needs to be improved. Here we demonstrate a simple, one-step and industrially scalable means of achieving just this. We show that introducing controlled amounts of uniformly dispersed BaZrO3 nanoparticles into carrier-doped BaFe2As2 significantly improves its superconducting performance without degrading its structural or superconducting properties. Our BaFe2(As0.66P0.33)2 films also exhibit an increase in both the irreversibility line and critical current density at all magnetic-field orientations. These films exhibit nearly isotropic critical current densities in excess of 1.5 MA cm-2 at 15 K and 1 T--seven times higher than previously reported for BaFe2As2 films. The vortex-pinning force in these films reaches ~59 GN m-3 at 5 K and 3-9 T, substantially higher than that of the conventional Nb3Sn wire. PMID- 24051679 TI - Prognostic impact of anaemia on patients with ST-elevation myocardial infarction treated by primary PCI. AB - AIM: The aim of this study was to investigate the effects of baseline anaemia on the outcome in patients treated by primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction. METHODS: This study was a retrospective cohort study of 2418 patients with ST-elevation myocardial infarction treated by PPCI between January 2004 and August 2010 at a single centre. We investigated the outcome in patients with anaemia compared with that in patients with a normal haemoglobin (Hb) level. Anaemia was defined according to the WHO definition as an Hb level less than 12 g/dl for female individuals and less than 13 g/dl for male individuals. We also calculated hazard ratios using a stratified model according to the Hb level. RESULTS: A total of 471 (19%) patients were anaemic at presentation. The anaemic cohort was older (72.2 vs. 62.4 years, P<0.0001) and had a higher incidence of diabetes (28 vs. 16%, P<0.0001), hypertension (57 vs. 43%, P=0.01), hypercholesterolaemia (48 vs. 40%, P=0.007), previous PCI (15 vs. 9%, P<0.0001), previous myocardial infarction (23 vs. 12%, P=0.002), and cardiogenic shock (12 vs. 5%, P<0.0001). Over a mean follow-up period of 3 years there was significantly higher all-cause mortality in the anaemic group compared with the normal Hb group (20.4 vs. 13.5%, P<0.0001). However, after adjustment for all variables using multivariate analysis, anaemia (on the basis of the WHO definitions) was found not to be an independent predictor of mortality or major adverse cardiac events over the follow-up period. Further, when we used a model stratified by g/dl, we found that there was an increased risk for adverse outcomes among men with low Hb levels. There appeared to be a threshold value of Hb (13 g/dl) associated with increased risk. Although a similar trend was observed among women, no significant difference was observed. CONCLUSION: Patients with anaemia undergoing PPCI are at a higher risk of an adverse outcome. Anaemia is a simple and powerful marker of poor prognosis. Although anaemia (based on the WHO definitions) does not appear to be an independent predictor of all-cause mortality or major adverse cardiac events after PPCI on multivariate analysis, there appears to be a threshold value of Hb among men, below which there is an associated increased risk for PPCI. PMID- 24051680 TI - Adenosine is present in rat brain synaptic vesicles. AB - Evidences in the central nervous system are in favor that adenosine under basal conditions is released by a direct excitation-secretion modality. However, till now, there is no direct evidence that adenosine is contained in synaptic vesicles. Eight synaptic vesicle fractions were recovered on a discontinuous sucrose gradient after ultracentrifugation of the crude synaptosomal fraction (pellet P2) of rat brain. The adenosine content in each fraction was measured by high-performance liquid chromatography coupled to a fluorescence detector (minimum sensitivity 10 femtomoles). The immunoblot analysis, to detect synaptophysin, a molecular marker for the vesicle membrane, showed that fractions from 3 to 8 were rich in synaptophysin. The sum of adenosine found in fractions 3 8 was (mean +/- SEM, n = 4) 3325.6 +/- 94.6 pmol/mg of tissue protein. We proved that adenosine measured in synaptic vesicle fractions was not contaminated by cytosolic adenosine, as adenosine exogenously added to the P2 preferentially distributed in fractions 1 and 2 that are synaptophysin-free and did not contaminate the vesicle pellet P3. Data provide direct demonstration that adenosine is present in rat brain synaptic vesicle fractions. This information is consistent with the notion that adenosine is stored in synaptic vesicles and is released under normoxic physiological conditions by an excitation-secretion mechanism typical of neuronal cells. PMID- 24051681 TI - L-glutamate microinjection in the preoptic area increases brain and body temperature in freely moving rats. AB - The role of the preoptic area (POA) in thermoregulation is well documented. Microinjection of various neurotransmitters into the POA in rats has been shown to influence body temperature. Alhough there are reports showing changes in temperature on administration of L-glutamate into the POA, the role of this excitatory amino acid in thermoregulation has not been studied in unanaesthetized rats. In the present study, brain and body temperatures were recorded in freely moving adult male Wistar rats with K-type thermocouple implanted near the hypothalamus and temperature transmitter implanted inside the peritoneum. Recordings were performed 2 h preinjection and 4 h postinjection. L-glutamate (0.14 nM) microinjection into the POA induced long-lasting hyperthermia and reduced locomotor activity. The rats remained curled up and showed piloerection. L-glutamate-induced hyperthermia was attenuated by previous injection of the ionotropic L-glutamate receptor antagonist, kynurenate (0.11 nM). We propose that L-glutamate in the POA participates not only in heat production and conservation but also plays a role in interlinking sleep and thermoregulation. PMID- 24051684 TI - Local flaps: cheek and lip reconstruction. AB - IMPORTANCE: The reconstruction of cutaneous defects of the cheek and lip is a foundational topic for facial plastic and reconstructive surgeons. Facial defects have a significant impact on patient quality of life that has been well demonstrated. OBJECTIVE: To review new findings that have an impact on the planning and understanding of local flaps for the reconstruction of cutaneous defects of the cheek and upper lip; recent research in facial soft-tissue anatomy and vascular anatomy is integrated into a discussion of local flap reconstruction. EVIDENCE REVIEW: A Medline search of scientific literature was conducted, with an emphasis on 1980 to the present. Search terms included cheek; lip; reconstruction; vascular anatomy, soft-tissue anatomy, aging face, outcomes, and perforator flap. Cadaveric studies were specifically sought for anatomic review, and comparison group outcome studies are preferentially cited over clinical case series. FINDINGS: Reconstruction of large medial defects of the cheek and upper lip is particularly challenging, and the V-Y subcutaneous tissue pedicle island advancement flap is valuable for repair of these defects. Outcomes analyses for local flap reconstruction are in high demand. Pedicled perforator flaps will likely see increased application for facial reconstruction in the near future. CONCLUSION AND RELEVANCE: Detailed knowledge of the soft-tissue anatomy of the cheek and lip is critical to accurate surgical planning in local flap reconstruction. PMID- 24051686 TI - Residual beta-cell mass influences growth of prepubertal children with type 1 diabetes. AB - BACKGROUND: The growth deceleration observed in children with type 1 diabetes (T1D) has been related to poor glycemic control. It is unclear whether growth impairment persists despite the optimization of therapy. We analyzed the effects of intensive insulin treatment on prepubertal growth. METHODS: One hundred and four T1D children were evaluated from T1D diagnosis up to puberty onset. Height, weight, insulin requirement and glycated hemoglobin (HbA1c) were recorded at 3- to 6-month intervals. Residual beta-cell mass was estimated by fasting C-peptide at T1D onset. RESULTS: Age at T1D onset was 5.91 +/- 1.9 years. Follow-up duration was 4.84 +/- 1.58 years. Height velocity standard deviation score (SDS) was -0.14 +/- 1.84. Height SDS changed from 0.52 +/- 1.04 at T1D onset, to 0.36 +/- 1.10 at the end of follow-up (p = 0.04). BMI SDS increased from -0.04 +/- 1.48 to 0.32 +/- 1.03 (p = 0.01). Multivariate analysis showed that height velocity was directly affected by C-peptide (p = 0.03) and insulin requirement (p = 0.004) and inversely related to HbA1c (p = 0.006). BMI gain was negatively influenced by HbA1c (p = 0.01) and positively related to T1D duration (p = 0.01). CONCLUSION: Despite insulin intensive therapy, T1D still negatively affects growth. Residual beta-cell mass has a direct positive impact on growth, independently from the quality of glycemic control. PMID- 24051687 TI - Prenatal diagnosis of common arterial trunk: a single-center's experience. AB - INTRODUCTION: To report our experience in fetuses prenatally diagnosed with common arterial trunk (CAT) and to evaluate the postnatal outcomes. MATERIAL AND METHODS: This was a retrospective study conducted at Asan Medical Center, Seoul, Korea, between 2003 and 2012. Maternal medical and fetal echocardiographic records regarding fetuses were prenatally diagnosed with CAT were reviewed. Postnatal outcomes of survivors were also assessed during the mean follow-up of 36 months. RESULTS: Of the 17 fetuses that were prenatally diagnosed with CAT and had a final diagnosis by postnatal echocardiography or autopsy, 12 were confirmed to have CAT and 5 were incorrectly diagnosed with CAT. Of the latter, 3 had pulmonary atresia and 2 had aortic atresia. The diagnostic accuracy was 71%. The median gestational age at prenatal diagnosis of confirmed CAT was 24.4 weeks (range 21.1-34.3). The truncal valve was prenatally thickened in 8 fetuses. All but 1 of the 12 confirmed CAT cases had associated heart and/or extracardiac anomalies. Of the 8 liveborn cases of postnatally confirmed CAT, 2 died before or after surgery respectively. The remaining 6 remained alive after successful corrective surgery. CONCLUSION: Prenatal diagnosis of CAT can be difficult in some cases and other diseases should be excluded before diagnosing CAT. Isolated CAT can be repaired by postnatal corrective surgery with a good outcome. PMID- 24051688 TI - Tat pathway-mediated translocation of the Sec pathway substrate OprM, an outer membrane subunit of the resistance nodulation division xenobiotic extrusion pumps, in Pseudomonas Aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa produces the Sec and Tat protein secretion machineries. The latter appears to be involved in the secretion of virulence factors, including phospholipase C (PlcH), and hence is a potential target of chemotherapeutic agents. METHODS: The signal sequence of OprM, the outer membrane subunit of the xenobiotic extrusion pumps, was substituted with that of PlcH. The antibiotic susceptibility of oprM-deficient cells expressing the hybrid protein PlcH-OprM was evaluated using the agar dilution method. RESULTS: The PlcH-OprM expressing cells showed resistance to various MexAB-OprM substrate antibiotics. To evaluate the translocation route of PlcH-OprM, tatC encoding an indispensable component of the Tat machinery was knocked out in oprM-deficient cells. The tatC oprM double mutant expressing PlcH-OprM exhibited antibiotic hypersusceptibility like the oprM-deficient cells, indicating that PlcH-OprM was translocated across the inner membrane exclusively through the Tat system. CONCLUSIONS: This system can be used for the screening of Tat system inhibitors and will be an excellent model for the study of secretion and biogenesis of the beta-barrel outer membrane proteins. PMID- 24051689 TI - Increased permeability of cutaneous lymphatic capillaries and enhanced blood flow in psoriatic plaques. AB - INTRODUCTION: Morphological abnormalities of microvessels are described in psoriasis. However, there are conflicting data as to whether their function is also altered. OBJECTIVE: Our aim was to study the morphology and function of the lymphatic capillaries of psoriatic skin. METHODS: Morphology and permeability of initial lymphatics were studied by microlymphography and densitometry in 20 patients. Perfusion was studied by laser Doppler fluxmetry. RESULTS: Permeability of lymphatics in plaques was increased by 7.6% compared to unafflicted skin (p < 0.001). Lymphatic vessel density and the extension of dye in lymphatic networks were not significantly different between involved and uninvolved areas. Both sites showed a wide range of diameters of lymphatics. The median laser Doppler flux in plaques was increased by 144% (91-380%) compared to unaffected skin (p < 0.001). CONCLUSIONS: Increased permeability of lymphatics and increased blood flow was demonstrated in vivo in psoriatic skin lesions. These findings may reflect the local inflammatory process and may be used as markers when studying new therapeutic approaches for psoriasis. PMID- 24051690 TI - The link between high-sensitivity C-reactive protein and orbitofrontal cortex in euthymic bipolar disorder. AB - OBJECTIVE: C-reactive protein (CRP), a marker of underlying low-grade inflammation, has been associated with the pathophysiology of bipolar disorder. Additionally, bipolar disorder may be accompanied by functional or structural cerebral alterations. We attempted to discover whether serum high-sensitivity CRP (hs-CRP) levels are linked to the structural volume change of a specific brain region along with cognitive performance. METHODS: We recruited 17 physically healthy patients with bipolar I disorder (DSM-IV), aged 18-45 years and euthymic, to undergo the Wisconsin Card Sorting Test (WCST) and volumetric magnetic resonance imaging at 1.5 T. The analytic method was based on the hidden Markov random field model with an expectation-maximization algorithm, and the volume of each brain region was presented as a percentage of the total intracranial volume. RESULTS: Among the various regions, only the orbitofrontal cortex had a significantly negative correlation with serum hs-CRP levels after adjustment for age and gender (left and right orbitofrontal cortex: r = -0.62, p < 0.01, and r = -0.67, p < 0.005, respectively). Regarding cognitive function, poor WCST performance was also associated with certain subregions of the orbitofrontal cortex. CONCLUSION: Elevation of serum hs-CRP levels, an indicator of inflammation, may be associated with reduced volume of the orbitofrontal cortex. Persistent inflammation in the euthymic phase of bipolar disorder may involve the pathogenesis or pathophysiology of alteration of the frontal pathway. PMID- 24051691 TI - Baseline inhibin B levels for diagnosis of central precocious puberty in girls. AB - AIM: To evaluate the use of baseline inhibin B (INHB) levels to differentiate the progressive form (PF) from the non-progressive form (NPF) of central precocious puberty (CPP). METHODS: A total of 62 girls were enrolled, 31 with PF and 31 with NPF. Using receiver operating characteristic (ROC) curves, we analysed the diagnostic performance of INHB in addition to other diagnostic tools used to differentiate the 2 forms of CPP. RESULTS: INHB levels were higher in PF versus NPF (29.1 vs. 13.1 pg/ml; p < 0.001). The ROC area under the curve (AUC) was greatest for luteinizing hormone [LH; 0.807, standard error (SE) 0.069], followed by INHB (0.800, SE 0.067), ovarian volume (OV; 0.782, SE 0.070) and uterine volume (0.723, SE 0.076). In ROCs relative to a combination of such parameters, the AUC was greater for LH + INHB (0.972, SE 0.010), followed by OV + LH (0.841, SE 0.084) and OV + INHB (0.836, SE 0.075). The combination of INHB and LH (with cut-offs of 20 pg/ml and 0.2 IU/l, respectively) results in 98% sensitivity and specificity. CONCLUSION: Our results suggest that the addition of basal INHB values to baseline LH levels provides a reliable method to identify PF. Further replication studies are needed to definitively prove or disprove the utility and advantages of INHB levels as part of the work-up of CPP. PMID- 24051692 TI - Migraine headache triggered specifically by sunlight: report of 16 cases. AB - Migraine headaches may take place due to various triggering factors. One or more triggering factors can be detected in a migraine patient. To our knowledge, a factor that is known to trigger migraine attacks in a patient does not cause headache each time the patient is exposed to it. Migraine headaches also can be experienced without these factors. Here, we describe a case series of 16 sunlight induced migraine patients. Records of patients admitted to Firat University Faculty of Medicine Clinic of Neurology with a complaint of headache between January 2001 and June 2010 were scanned. Among those patients, the ones suffering headaches after being exposed to sunlight were examined comprehensively. Nine patients were female and 7 were male. Fourteen patients had the characteristics of migraine without aura, while 2 patients had the characteristics of migraine with aura. The mean times to headache onset after sunlight exposure were 5-10 min in summer and 60 min in winter. Migraine headaches can be triggered by many different causes. We view sunlight as a single triggering factor which should be questioned in migraine patients. PMID- 24051693 TI - Novel specific microRNA biomarkers in idiopathic inflammatory bowel disease unrelated to disease activity. AB - The diagnosis of idiopathic inflammatory bowel disease can be challenging. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate protein synthesis through post-transcriptional suppression. This study is to identify new miRNA markers in inflammatory bowel disease, and to examine whether miRNA biomarkers might assist in the diagnosis of inflammatory bowel disease. Illumina small RNA sequencing was performed on non-dysplastic fresh-frozen colonic mucosa samples of the distalmost colectomy tissue from 19 patients with inflammatory bowel disease (10 ulcerative colitis and 9 Crohn disease) and 18 patients with diverticular disease serving as controls. To determine differentially expressed miRNAs, the USeq software package identified 44 miRNAs with altered expression (fold change >= 2 and false discovery rate <= 0.10) compared with the controls. Among them, a panel of nine miRNAs was aberrantly expressed in both ulcerative colitis and Crohn disease. Validation assays performed using quantitative reverse transcription PCR (qRT-PCR) on additional frozen tissue from ulcerative colitis, Crohn disease, and control groups confirmed specific differential expression in inflammatory bowel disease for miR-31, miR-206, miR-424, and miR-146a (P<0.05). The expression of these four miRNAs was further evaluated on formalin-fixed, paraffin-embedded tissue of the distalmost colectomy mucosa from cohorts of diverticular disease controls (n=29), ulcerative colitis (n=36), Crohn disease (n=26), and the other diseases mimicking inflammatory bowel disease including infectious colitis (n=12) and chronic ischemic colitis (n=19), again confirming increased expression specific to inflammatory bowel disease (P<0.05). In summary, we demonstrate that miR-31, miR-206, miR-424, and miR-146a are novel specific biomarkers of inflammatory bowel disease. Furthermore, miR-31 is universally expressed in both ulcerative colitis and Crohn disease not only in fresh-frozen but also in formalin-fixed, paraffin-embedded tissues. PMID- 24051694 TI - Noncirrhotic hepatocellular carcinoma: derivation from hepatocellular adenoma? Clinicopathologic analysis. AB - The majority of hepatocellular carcinomas arise in background chronic liver disease, particularly cirrhosis. The pathogenesis of noncirrhotic hepatocellular carcinomas remains unclear. While malignant transformation reportedly occurs in <15% of hepatocellular adenoma, the prevalence of noncirrhotic hepatocellular carcinomas arising from a pre-existing adenoma is a challenge to study. Cirrhotic hepatocellular carcinoma and hepatocellular adenoma may be subclassified by molecular pathways, but little is known in noncirrhotic hepatocellular carcinoma. We aim to delineate clinical, morphologic and immunohistochemical features of noncirrhotic hepatocellular carcinoma to evaluate for possible derivation from hepatocellular adenoma. We evaluated the clinicopathologic features of 74 noncirrhotic hepatocellular carcinomas from 72 patients for underlying clinical conditions and immunohistochemical markers known to be associated with hepatocellular adenoma. Men were more commonly affected (59%); however, in the <50-year-old group, women predominated (8:1). The age range was wide: 18-83 years; median-64 years. Underlying liver diseases were identified in only 7%; however, 25% had diabetes mellitus, 69% were overweight or obese and 58% had metabolic syndrome. Only 50% of the noncirrhotic hepatocellular carcinoma were encapsulated. As published in hepatocellular adenoma, multifocality and larger tumor size were more common in liver fatty acid-binding protein-negative noncirrhotic hepatocellular carcinoma. Beta-catenin nuclear positivity was uncommon (5%), and was restricted to hepatocellular carcinomas in older men. Serum amyloid A positivity was not restricted to any subtype. In summary, we present the largest series to date examining noncirrhotic hepatocellular carcinoma. We evaluated these with current hepatocellular adenoma subclassification markers for possible associations. Thirty percent of the 74 noncirrhotic hepatocellular carcinoma had some clinical, morphological or immunophenotypical associations currently described in hepatocellular adenoma. Our data also confirm the association of noncirrhotic hepatocellular carcinoma in middle-aged to elderly men, an association with metabolic syndrome, and, as with hepatocellular adenoma, that women predominated in the noncirrhotic hepatocellular carcinoma subjects <50 years of age. PMID- 24051695 TI - Pediatric autoimmune enteropathy: an entity frequently associated with immunodeficiency disorders. AB - The term pediatric autoimmune enteropathy was originally applied to a form of intractable diarrhea seen in children under the age of 6 months and characterized by male predominance, concurrent autoimmune-associated disorders, circulating gut autoantibodies, a lack of severe immunodeficiency and small bowel atrophy with prominent crypt apoptosis. However, recent studies have cast doubt over the specific clinicopathologic findings associated with this entity. We, therefore, collected 178 gastrointestinal biopsies from 14 patients and examined their clinical, serologic and pathologic findings. Patients at presentation ranged in age from birth to 15.9 years (median, 5.5 months; mean, 4.1 years) and included six males and eight females. All children suffered from chronic watery diarrhea and malnutrition. Concomitant-associated disorders were noted in 11 (79%) cases and included 10 (71%) with an immunodeficiency disorder and/or another autoimmune related disease. Eleven patients (79%) were positive for anti-enterocyte antibodies. The salient findings of autoimmune enteropathy were most prominent in the small intestines and the majority (79%) of patients demonstrated villous blunting, crypt hyperplasia, mononuclear cell inflammatory expansion of the lamina propria and crypt apoptosis. The remaining (21%) patients showed marked intraepithelial lymphocytosis reminiscent of celiac disease. Further, acute cryptitis and crypt abscesses were seen in seven (50%) patients obscuring the presence of apoptosis. The absence of Paneth cells, goblet cells or both was noted in seven (50%) patients. Follow-up information was available for all patients with 13 (93%) receiving immunosuppressant therapy and demonstrating partial-to-complete response. In total, three patients died from continued diarrhea and sepsis with one decedent before treatment could be initiated. In summary, autoimmune enteropathy in children is a heterogenous disease with protean clinical and pathologic findings. Although anti-enterocyte antibodies were identified in the majority of the cases, their presence was variable and insensitive. In addition, pediatric autoimmune enteropathy was frequently encountered in the setting of immunodeficiency disorders. PMID- 24051696 TI - Distinguishing luminal breast cancer subtypes by Ki67, progesterone receptor or TP53 status provides prognostic information. AB - The objectives of this study were to determine the prognostic significance of subgrouping estrogen receptor (ER)-positive breast tumors into low- and high-risk luminal categories using Ki67 index, TP53, or progesterone receptor (PR) status. The study group comprised 540 patients with lymph node negative, invasive breast carcinoma. Luminal A subtype was defined as being ER positive, HER2 negative, and Ki67 low (<14% cells positive) and luminal B subtype as being ER positive, HER2 negative, and Ki67 high (>= 14% cells positive). Luminal tumors were also subgrouped into risk categories based on the PR and TP53 status. Survival analysis was performed. Patients with luminal B tumors (n=173) had significantly worse disease-free survival compared to those with luminal A tumors (n=186) (log rank P-value=0.0164; univariate Cox regression relative risk 2.00; 95% CI, 1.12 3.58; P=0.0187). Luminal subtype remained an independent prognostic indicator on multivariate analysis including traditional prognostic factors (relative risk 2.12; 95% CI, 1.16-3.88; P=0.0151). Using TP53 status or PR negativity rather than Ki67 to classify ER-positive luminal tumors gave similar outcome results to those obtained using the proliferation index. However, it was a combination of the three markers, which proved the most powerful prognostically. Ki67 index, TP53 status, or PR negativity can be used to segregate ER-positive, HER2-negative tumors into prognostically meaningful subgroups with significantly different clinical outcomes. These biomarkers particularly in combination may potentially be used clinically to guide patient management. PMID- 24051697 TI - Keratin 17 in premalignant and malignant squamous lesions of the cervix: proteomic discovery and immunohistochemical validation as a diagnostic and prognostic biomarker. AB - Most previously described immunohistochemical markers of cervical high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma may help to improve diagnostic accuracy but have a minimal prognostic value. The goals of the current study were to identify and validate novel candidate biomarkers that could potentially improve diagnostic and prognostic accuracy for cervical HSIL and squamous cell carcinoma. Microdissected tissue sections from formalin-fixed paraffin-embedded normal ectocervical squamous mucosa, low-grade squamous intraepithelial lesion (LSIL), HSIL and squamous cell carcinoma sections were analyzed by mass spectrometry-based shotgun proteomics for biomarker discovery. The diagnostic specificity of candidate biomarkers was subsequently evaluated by immunohistochemical analysis of tissue microarrays. Among 1750 proteins identified by proteomic analyses, keratin 4 (KRT4) and keratin 17 (KRT17) showed reciprocal patterns of expression in the spectrum of cases ranging from normal ectocervical squamous mucosa to squamous cell carcinoma. Immunohistochemical studies confirmed that KRT4 expression was significantly decreased in squamous cell carcinoma compared with the other diagnostic categories. By contrast, KRT17 expression was significantly increased in HSIL and squamous cell carcinoma compared with normal ectocervical squamous mucosa and LSIL. KRT17 was also highly expressed in immature squamous metaplasia and in endocervical reserve cells but was generally not detected in mature squamous metaplasia. Furthermore, high levels of KRT17 expression were significantly associated with poor survival of squamous cell carcinoma patients (Hazard ratio=14.76, P=0.01). In summary, both KRT4 and KRT17 expressions are related to the histopathology of the cervical squamous mucosa; KRT17 is highly overexpressed in immature squamous metaplasia, in HSIL, and in squamous cell carcinoma and the level of KRT17 in squamous cell carcinoma may help to identify patients who are at greatest risk for cervical cancer mortality. PMID- 24051698 TI - Sacrococcygeal teratomas: clinico-pathological characteristics and isochromosome 12p status. AB - The biological behavior of teratomas is highly variable, and morphologic features alone are insufficient to predict their clinical course. Prognostic factors that influence behavior include the following: patient sex, age, anatomic site, coincident neoplasm, and cytogenetic abnormalities. Gonadal teratomas have been well-characterized; postpubertal testicular teratomas are commonly associated with isochromosome 12p (i12p) and considered to nearly always carry a potential for malignant behavior, whereas ovarian and prepubertal testicular teratomas are i12p negative and predominantly benign in behavior. For extragonadal sites, such as sacrum and coccyx, clinical characteristics and i12p status are yet to be adequately characterized. As part of this study, we identified 19 sacrococcygeal teratomas in our surgical pathology archives from 1990 to 2012. Clinical records and slides were reviewed to confirm the original diagnosis. Gains in chromosome 12p, including i12p status were assessed in representative paraffin sections by fluorescence in situ hybridization. Our cases included 16 mature sacrococcygeal teratomas (11 prepubertal and 5 postpubertal) and three immature saccrococygeal teratomas (all prepubertal). Among mature teratomas, the average tumor size was larger in adults compared with prepubertal patients. A higher number of adult cases were recurrences (80% vs 21%), but only pediatric recurrences were managed with postoperative chemotherapy. All examined tumors were negative for i12p. 100% survival was documented in our cohort with a median follow-up of 6 years. We present a large series of sacrococcygeal teratomas and the first series to examine postpubertal adults at this anatomic site. All tumors lacked chromosome 12p gains, including i12p. Both pre- and postpubertal sacrococcygeal teratomas had a favorable outcome regardless of age or sex. PMID- 24051699 TI - A diagnostic algorithm to distinguish desmoplastic from spindle cell melanoma. AB - Spindle cell melanoma and desmoplastic melanoma differ clinically in prognosis and therapeutic implications; however, because of partially overlapping histopathological features, diagnostic distinction of spindle cell from desmoplastic melanoma is not always straightforward. A direct comparison of diagnostic and therapeutic biomarkers has not been performed. Meta-review of the literature discloses key clinicopathological differences between spindle cell and desmoplastic melanoma, including immunophenotypes. Using 50 biomarkers available in routine diagnostics, we examined 38 archival cases (n=16 spindle, 18 desmoplastic, 4 mixed spindle/desmoplastic melanoma). S100 remains as the most reliable routine marker to reach the diagnosis of melanoma in spindle cell and desmoplastic melanoma. We identified nine distinctly labeling markers with spindle cell melanoma showing positivity for laminin, p75, HMB45, c-kit, and MelanA, and desmoplastic melanoma preferentially labeling with collagen IV, trichrome, CD68, and MDM2. On the basis of comparisons of test performance measures, MelanA and trichrome were used to devise a 94% sensitive diagnostic algorithm for the distinction of desmoplastic from spindle cell melanoma. Gene amplification and expression status was assessed for a set of potentially drugable targets (HER2, EGFR, MET, MDM2, TP53, ALK, MYC, FLI-1, and KIT). Fluorescent in situ hybridizations did not reveal a significant number of gene aberrations/rearrangements; however, protein overexpression for at least one of these markers was identified in 35 of 38 cases (92%). In addition, we found BRAF mutations in 31% of spindle cell and 5% of desmoplastic melanoma, with an overall mutation frequency of 16% (n=6/38). We present the first comprehensive screening study of diagnostic and therapeutic biomarkers in spindle cell and desmoplastic melanoma. The devised algorithm allows diagnostic distinction of desmoplastic from spindle cell melanoma when routine histology is not decisive. PMID- 24051700 TI - The value of mutational profiling of the cytocentrifugation supernatant fluid from fine-needle aspiration of pancreatic solid mass lesions. AB - Fine-needle aspiration (FNA) of pancreatic solid masses can be significantly impacted by sampling variation. Molecular analysis of tumor DNA can be an aid for more definitive diagnosis. The aim of this study was to evaluate how molecular analysis of the cell-free cytocentrifugation supernatant DNA can help reduce sampling variability and increase diagnostic yield. Twenty-three FNA smears from pancreatic solid masses were performed. Remaining aspirates were rinsed for preparation of cytocentrifuged slides or cell blocks. DNA was extracted from supernatant fluid and assessed for DNA quantity spectrophotometrically and for amplifiability by quantitative PCR (qPCR). Supernatants with adequate DNA were analyzed for mutations using PCR/capillary electrophoresis for a broad panel of markers (KRAS point mutation by sequencing, microsatellite fragment analysis for loss of heterozygosity (LOH) of 16 markers at 1p, 3p, 5q, 9p, 10q, 17p, 17q, 21q, and 22q). In selected cases, microdissection of stained cytology smears and/or cytocentrifugation cellular slides were analyzed and compared. In all, 5/23 samples cytologically confirmed as adenocarcinoma showed detectable mutations both in the microdissected slide-based cytology cells and in the cytocentrifugation supernatant. While most mutations detected were present in both microdissected slides and supernatant fluid specimens, the latter showed additional mutations supporting greater sensitivity for detecting relevant DNA damage. Clonality for individual marker mutations was higher in the supernatant fluid than in microdissected cells. Cytocentrifugation supernatant fluid contains levels of amplifiable DNA suitable for mutation detection and characterization. The finding of additional detectable mutations at higher clonality indicates that supernatant fluid may be enriched with tumor DNA. Molecular analysis of the supernatant fluid could serve as an adjunct method to reduce sampling variability and increase diagnostic yield, especially in cases with a high clinical suspicion for malignancy and limited number of atypical cells in the smears. PMID- 24051702 TI - A brassinosteroid-signaling kinase interacts with multiple receptor-like kinases in Arabidopsis. PMID- 24051704 TI - A retrospective analysis of long-term graft survival in 61 pediatric renal transplant recipients: a single-center experience. AB - BACKGROUND: Although short-term renal allograft survival in children has improved over the years, long-term graft outcomes remain unclear. In this study we report the characteristics and other variables that impact long-term kidney graft survival in children. MATERIAL AND METHODS: Records of 61 pediatric kidney transplant recipients (mean age: 14+/-3 years) performed at our institution between 1995 and 2011 were evaluated. Patients were divided into 2 groups (functional and non-functional grafts) to investigate the factors that impact graft survival. The groups were compared in terms of recipient characteristics, underlying disease, HLA status, immunosuppressive therapy, donor characteristics, acute rejection, and delayed graft function (DGF). Statistical significance was detected with the t and chi-squared tests (Pearson and Fisher's exact tests). Kaplan-Meier analysis was performed for graft survival. RESULTS: Overall graft survival at 1, 5, 10, and 15 years were 93%, 66%, 46%, and 41%, respectively. The median graft survival was 128.4 months (range: 3-188 months). Donor age, acute rejection, and DGF strongly predicted the chance of graft survival (p<0.05). CONCLUSIONS: It appears that several modifiable risk factors can partially account for poorer graft survival in pediatric kidney transplant recipients. PMID- 24051701 TI - Socio-cultural, environmental and behavioural determinants of obesity in black South African women. AB - South Africa (SA) is undergoing a rapid epidemiological transition and has the highest prevalence of obesity in sub-Saharan Africa (SSA), with black women being the most affected (obesity prevalence 31.8%). Although genetic factors are important, socio-cultural, environmental and behavioural factors, as well as the influence of socio-economic status, more likely explain the high prevalence of obesity in black SA women. This review examines these determinants in black SA women, and compares them to their white counterparts, black SA men, and where appropriate, to women from SSA. Specifically this review focuses on environmental factors influencing obesity, the influence of urbanisation, as well as the interaction with socio-cultural and socio-economic factors. In addition, the role of maternal and early life factors and cultural aspects relating to body image are discussed. This information can be used to guide public health interventions aimed at reducing obesity in black SA women. PMID- 24051705 TI - Prognostic indicators and treatment outcome in 94 cases of fibrolamellar hepatocellular carcinoma. AB - OBJECTIVE: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of HCC. We report an analysis of the clinicopathologic features, treatment outcomes, and prognostic indicators of 94 cases. METHODS: We retrospectively collected clinicopathologic and treatment outcome data from 94 FLHCC patients (48 males and 46 females). Median overall survival (OS) and recurrence-free survival (RFS) were calculated using Kaplan-Meier curves, and survival rates were compared by the log rank test. The Cox proportional hazard model was used for univariate and multivariate estimation of hazard risk ratios and 95% confidence intervals (CI) for factors that correlated with survival and disease recurrence after resection. RESULTS: Median age was 23 years (14-75); median OS was 57.2 months (95% CI, 36.4 77.9), and median RFS was 13.9 months (95% CI, 8.8-18.9). White race, female gender, early tumor stage, and tumor resection including metastasectomy were positively associated with longer OS, while female gender was the only significant positive predictor of longer RFS. Finally, the 5-fluorouracil interferon combination was the most frequently used systemic therapy. CONCLUSIONS: Our analyses indicate that surgical approaches including metastasectomy as the first-line treatment in FLHCC correlated with better outcome. Multimodality approaches, including neoadjuvant and adjuvant therapies, prolonged patient survival. PMID- 24051710 TI - The quest for precision medicine: towards a "standard model" of aneurysm risk prediction. PMID- 24051711 TI - Bisphosphonate therapy for degenerative disc disease? PMID- 24051706 TI - Neuroprotective maraviroc monotherapy in simian immunodeficiency virus-infected macaques: reduced replicating and latent SIV in the brain. AB - OBJECTIVE: HIV-associated neurocognitive deficits remain a challenge despite suppressive combined antiretroviral therapy. Given the association between HIV induced central nervous system (CNS) disease and replication of HIV in immune activated macrophages, CCR5 antagonists may attenuate CNS disease by modulating inflammatory signaling and by limiting viral replication. DESIGN: To establish whether initiating CCR5 inhibition during early infection altered CNS disease progression, outcomes were compared between simian immunodeficiency virus (SIV) infected macaques treated with maraviroc (MVC) versus untreated SIV-infected macaques. METHODS: Six SIV-infected rhesus macaques were treated with MVC monotherapy for 5 months beginning 24 days postinoculation; 22 SIV-infected animals served as untreated controls. SIV RNA levels in plasma, cerobrospinal fluid, and brain, and CNS expression of TNFalpha and CCL2 were measured by qRT PCR. Immunostaining for CD68 and amyloid precursor protein in the brain was measured by image analysis. Plasma sCD163 was measured by ELISA. RESULTS: SIV RNA and proviral DNA levels in brain were markedly lower with MVC treatment, demonstrating CCR5 inhibition reduces CNS replication of SIV and may reduce the CNS latent viral reservoir. MVC treatment also lowered monocyte and macrophage activation, represented by CNS CD68 immunostaining and plasma sCD163 levels, and reduced both TNFalpha and CCL2 RNA expression in brain. Treatment also reduced axonal amyloid precursor protein immunostaining to levels present in uninfected animals, consistent with neuroprotection. CONCLUSION: CCR5 inhibitors may prevent neurologic disorders in HIV-infected individuals by reducing inflammation and by limiting viral replication in the brain. Furthermore, CCR5 inhibitors may reduce the latent viral reservoir in the CNS. Adding CCR5 inhibitors to combined antiretroviral regimens may offer multiple neuroprotective benefits. PMID- 24051712 TI - A randomized trial of unruptured brain arteriovenous malformations. PMID- 24051713 TI - Hes3 regulates cell number in cultures from glioblastoma multiforme with stem cell characteristics. PMID- 24051714 TI - A BigBrain for all.... PMID- 24051715 TI - Visual screening test for rapid sideline determination of concussive and sub concussive events. PMID- 24051716 TI - Inhibitory neuron therapy for epilepsy. PMID- 24051717 TI - Dopamine as the fountain of youth? Restoring decision making ability in older adults. PMID- 24051719 TI - Roles of dental development and adaptation in rodent evolution. AB - In paleontology, many changes affecting morphology, such as tooth shape in mammals, are interpreted as ecological adaptations that reflect important selective events. Despite continuing studies, the identification of the genetic bases and key ecological drivers of specific mammalian dental morphologies remains elusive. Here we focus on the genetic and functional bases of stephanodonty, a pattern characterized by longitudinal crests on molars that arose in parallel during the diversification of murine rodents. We find that overexpression of Eda or Edar is sufficient to produce the longitudinal crests defining stephanodonty in transgenic laboratory mice. Whereas our dental microwear analyses show that stephanodonty likely represents an adaptation to highly fibrous diet, the initial and parallel appearance of stephanodonty may have been facilitated by developmental processes, without being necessarily under positive selection. This study demonstrates how combining development and function can help to evaluate adaptive scenarios in the evolution of new morphologies. PMID- 24051720 TI - A framework for automatic modeling from point cloud data. AB - We propose a complete framework for the automatic modeling from point cloud data. Initially, the point cloud data are preprocessed into manageable datasets, which are then separated into clusters using a novel two-step, unsupervised clustering algorithm. The boundaries extracted for each cluster are then simplified and refined using a fast energy minimization process. Finally, three-dimensional models are generated based on the roof outlines. The proposed framework has been extensively tested, and the results are reported. PMID- 24051721 TI - A search-and-validate method for face identification from single line drawings. AB - Several studies have been made in finding the faces of an object depicted in a line drawing, but the problem has not been completely solved. Although existing methods can find the correct faces in most cases, there is no mechanism to ascertain that they are indeed correct, leaving the human user to do so. This paper uses a two-stage approach--find potential faces, then validate their correctness--to ensure that only correct faces are delivered ultimately. The face finding itself uses a double breadth-first search algorithm, which yields the shortest path, to find the potential faces. The basic premise is that the smallest faces found are more likely the correct ones. They serve as the "seed" potential faces, from which the algorithm proceeds to search for more faces. If the potential faces found satisfy the validation rules, then they are accepted as correct. Otherwise, the wrong potential faces are identified and removed, and new ones found in their place. The validation process is then repeated. The algorithm is fast and reliable, can deal with planar-faced manifold and nonmanifold objects, and can deliver the different results when a drawing has multiple interpretations. Our extensive tests show that the method can deal with most cases efficiently, including those that previous methods cannot solve. PMID- 24051722 TI - Combining multiple dynamic models and deep learning architectures for tracking the left ventricle endocardium in ultrasound data. AB - We present a new statistical pattern recognition approach for the problem of left ventricle endocardium tracking in ultrasound data. The problem is formulated as a sequential importance resampling algorithm such that the expected segmentation of the current time step is estimated based on the appearance, shape, and motion models that take into account all previous and current images and previous segmentation contours produced by the method. The new appearance and shape models decouple the affine and nonrigid segmentations of the left ventricle to reduce the running time complexity. The proposed motion model combines the systole and diastole motion patterns and an observation distribution built by a deep neural network. The functionality of our approach is evaluated using a dataset of diseased cases containing 16 sequences and another dataset of normal cases comprised of four sequences, where both sets present long axis views of the left ventricle. Using a training set comprised of diseased and healthy cases, we show that our approach produces more accurate results than current state-of-the-art endocardium tracking methods in two test sequences from healthy subjects. Using three test sequences containing different types of cardiopathies, we show that our method correlates well with interuser statistics produced by four cardiologists. PMID- 24051723 TI - Detailed 3D representations for object recognition and modeling. AB - Geometric 3D reasoning at the level of objects has received renewed attention recently in the context of visual scene understanding. The level of geometric detail, however, is typically limited to qualitative representations or coarse boxes. This is linked to the fact that today's object class detectors are tuned toward robust 2D matching rather than accurate 3D geometry, encouraged by bounding-box-based benchmarks such as Pascal VOC. In this paper, we revisit ideas from the early days of computer vision, namely, detailed, 3D geometric object class representations for recognition. These representations can recover geometrically far more accurate object hypotheses than just bounding boxes, including continuous estimates of object pose and 3D wireframes with relative 3D positions of object parts. In combination with robust techniques for shape description and inference, we outperform state-of-the-art results in monocular 3D pose estimation. In a series of experiments, we analyze our approach in detail and demonstrate novel applications enabled by such an object class representation, such as fine-grained categorization of cars and bicycles, according to their 3D geometry, and ultrawide baseline matching. PMID- 24051724 TI - Distance-based image classification: generalizing to new classes at near-zero cost. AB - We study large-scale image classification methods that can incorporate new classes and training images continuously over time at negligible cost. To this end, we consider two distance-based classifiers, the k-nearest neighbor (k-NN) and nearest class mean (NCM) classifiers, and introduce a new metric learning approach for the latter. We also introduce an extension of the NCM classifier to allow for richer class representations. Experiments on the ImageNet 2010 challenge dataset, which contains over 10(6) training images of 1,000 classes, show that, surprisingly, the NCM classifier compares favorably to the more flexible k-NN classifier. Moreover, the NCM performance is comparable to that of linear SVMs which obtain current state-of-the-art performance. Experimentally, we study the generalization performance to classes that were not used to learn the metrics. Using a metric learned on 1,000 classes, we show results for the ImageNet-10K dataset which contains 10,000 classes, and obtain performance that is competitive with the current state-of-the-art while being orders of magnitude faster. Furthermore, we show how a zero-shot class prior based on the ImageNet hierarchy can improve performance when few training images are available. PMID- 24051725 TI - Groupwise elastic registration by a new sparsity-promoting metric: application to the alignment of cardiac magnetic resonance perfusion images. AB - This paper proposes a methodology for the joint alignment of a sequence of images based on a groupwise registration procedure by using a new family of metrics that exploit the expected sparseness of the temporal intensity curves corresponding to the aligned points. Therefore, this methodology is able to tackle the alignment of temporal sequences of images in which the represented phenomenon varies in time. Specifically, we have applied it to the correction of motion in contrast enhanced first-pass perfusion cardiac magnetic resonance images. The time sequence is elastically registered as a whole by using the aforementioned family of multi-image metrics and jointly optimizing the parameters of the transformations involved. The proposed metrics are able to cope with dynamic changes in the intensity content of corresponding points in the sequence guided by the assumption that these changes allow for a sparse representation in a properly selected frame. Results have shown the statistically significant improvement in the performance of the proposed metric with respect to previous groupwise registration metrics for the problem at hand, which is especially relevant to correct for elastic deformations. PMID- 24051726 TI - Label consistent K-SVD: learning a discriminative dictionary for recognition. AB - A label consistent K-SVD (LC-KSVD) algorithm to learn a discriminative dictionary for sparse coding is presented. In addition to using class labels of training data, we also associate label information with each dictionary item (columns of the dictionary matrix) to enforce discriminability in sparse codes during the dictionary learning process. More specifically, we introduce a new label consistency constraint called "discriminative sparse-code error" and combine it with the reconstruction error and the classification error to form a unified objective function. The optimal solution is efficiently obtained using the K-SVD algorithm. Our algorithm learns a single overcomplete dictionary and an optimal linear classifier jointly. The incremental dictionary learning algorithm is presented for the situation of limited memory resources. It yields dictionaries so that feature points with the same class labels have similar sparse codes. Experimental results demonstrate that our algorithm outperforms many recently proposed sparse-coding techniques for face, action, scene, and object category recognition under the same learning conditions. PMID- 24051727 TI - Latent Dirichlet allocation models for image classification. AB - Two new extensions of latent Dirichlet allocation (LDA), denoted topic-supervised LDA (ts-LDA) and class-specific-simplex LDA (css-LDA), are proposed for image classification. An analysis of the supervised LDA models currently used for this task shows that the impact of class information on the topics discovered by these models is very weak in general. This implies that the discovered topics are driven by general image regularities, rather than the semantic regularities of interest for classification. To address this, ts-LDA models are introduced which replace the automated topic discovery of LDA with specified topics, identical to the classes of interest for classification. While this results in improvements in classification accuracy over existing LDA models, it compromises the ability of LDA to discover unanticipated structure of interest. This limitation is addressed by the introduction of css-LDA, an LDA model with class supervision at the level of image features. In css-LDA topics are discovered per class, i.e., a single set of topics shared across classes is replaced by multiple class-specific topic sets. The css-LDA model is shown to combine the labeling strength of topic supervision with the flexibility of topic-discovery. Its effectiveness is demonstrated through an extensive experimental evaluation, involving multiple benchmark datasets, where it is shown to outperform existing LDA-based image classification approaches. PMID- 24051728 TI - Learning with box kernels. AB - Supervised examples and prior knowledge on regions of the input space have been profitably integrated in kernel machines to improve the performance of classifiers in different real-world contexts. The proposed solutions, which rely on the unified supervision of points and sets, have been mostly based on specific optimization schemes in which, as usual, the kernel function operates on points only. In this paper, arguments from variational calculus are used to support the choice of a special class of kernels, referred to as box kernels, which emerges directly from the choice of the kernel function associated with a regularization operator. It is proven that there is no need to search for kernels to incorporate the structure deriving from the supervision of regions of the input space, because the optimal kernel arises as a consequence of the chosen regularization operator. Although most of the given results hold for sets, we focus attention on boxes, whose labeling is associated with their propositional description. Based on different assumptions, some representer theorems are given that dictate the structure of the solution in terms of box kernel expansion. Successful results are given for problems of medical diagnosis, image, and text categorization. PMID- 24051729 TI - Linear latent force models using Gaussian processes. AB - Purely data-driven approaches for machine learning present difficulties when data are scarce relative to the complexity of the model or when the model is forced to extrapolate. On the other hand, purely mechanistic approaches need to identify and specify all the interactions in the problem at hand (which may not be feasible) and still leave the issue of how to parameterize the system. In this paper, we present a hybrid approach using Gaussian processes and differential equations to combine data-driven modeling with a physical model of the system. We show how different, physically inspired, kernel functions can be developed through sensible, simple, mechanistic assumptions about the underlying system. The versatility of our approach is illustrated with three case studies from motion capture, computational biology, and geostatistics. PMID- 24051730 TI - Mapping from frame-driven to frame-free event-driven vision systems by low-rate rate coding and coincidence processing--application to feedforward ConvNets. AB - Event-driven visual sensors have attracted interest from a number of different research communities. They provide visual information in quite a different way from conventional video systems consisting of sequences of still images rendered at a given "frame rate." Event-driven vision sensors take inspiration from biology. Each pixel sends out an event (spike) when it senses something meaningful is happening, without any notion of a frame. A special type of event driven sensor is the so-called dynamic vision sensor (DVS) where each pixel computes relative changes of light or "temporal contrast." The sensor output consists of a continuous flow of pixel events that represent the moving objects in the scene. Pixel events become available with microsecond delays with respect to "reality." These events can be processed "as they flow" by a cascade of event (convolution) processors. As a result, input and output event flows are practically coincident in time, and objects can be recognized as soon as the sensor provides enough meaningful events. In this paper, we present a methodology for mapping from a properly trained neural network in a conventional frame-driven representation to an event-driven representation. The method is illustrated by studying event-driven convolutional neural networks (ConvNet) trained to recognize rotating human silhouettes or high speed poker card symbols. The event driven ConvNet is fed with recordings obtained from a real DVS camera. The event driven ConvNet is simulated with a dedicated event-driven simulator and consists of a number of event-driven processing modules, the characteristics of which are obtained from individually manufactured hardware modules. PMID- 24051731 TI - Markerless motion capture of multiple characters using multiview image segmentation. AB - Capturing the skeleton motion and detailed time-varying surface geometry of multiple, closely interacting peoples is a very challenging task, even in a multicamera setup, due to frequent occlusions and ambiguities in feature-to person assignments. To address this task, we propose a framework that exploits multiview image segmentation. To this end, a probabilistic shape and appearance model is employed to segment the input images and to assign each pixel uniquely to one person. Given the articulated template models of each person and the labeled pixels, a combined optimization scheme, which splits the skeleton pose optimization problem into a local one and a lower dimensional global one, is applied one by one to each individual, followed with surface estimation to capture detailed nonrigid deformations. We show on various sequences that our approach can capture the 3D motion of humans accurately even if they move rapidly, if they wear wide apparel, and if they are engaged in challenging multiperson motions, including dancing, wrestling, and hugging. PMID- 24051732 TI - Multiple hypothesis tracking for cluttered biological image sequences. AB - In this paper, we present a method for simultaneously tracking thousands of targets in biological image sequences, which is of major importance in modern biology. The complexity and inherent randomness of the problem lead us to propose a unified probabilistic framework for tracking biological particles in microscope images. The framework includes realistic models of particle motion and existence and of fluorescence image features. For the track extraction process per se, the very cluttered conditions motivate the adoption of a multiframe approach that enforces tracking decision robustness to poor imaging conditions and to random target movements. We tackle the large-scale nature of the problem by adapting the multiple hypothesis tracking algorithm to the proposed framework, resulting in a method with a favorable tradeoff between the model complexity and the computational cost of the tracking procedure. When compared to the state-of-the art tracking techniques for bioimaging, the proposed algorithm is shown to be the only method providing high-quality results despite the critically poor imaging conditions and the dense target presence. We thus demonstrate the benefits of advanced Bayesian tracking techniques for the accurate computational modeling of dynamical biological processes, which is promising for further developments in this domain. PMID- 24051733 TI - Semi-supervised video segmentation using tree structured graphical models. AB - We present a novel patch-based probabilistic graphical model for semi-supervised video segmentation. At the heart of our model is a temporal tree structure that links patches in adjacent frames through the video sequence. This permits exact inference of pixel labels without resorting to traditional short time window based video processing or instantaneous decision making. The input to our algorithm is labeled key frame(s) of a video sequence and the output is pixel wise labels along with their confidences. We propose an efficient inference scheme that performs exact inference over the temporal tree, and optionally a per frame label smoothing step using loopy BP, to estimate pixel-wise labels and their posteriors. These posteriors are used to learn pixel unaries by training a Random Decision Forest in a semi-supervised manner. These unaries are used in a second iteration of label inference to improve the segmentation quality. We demonstrate the efficacy of our proposed algorithm using several qualitative and quantitative tests on both foreground/background and multiclass video segmentation problems using publicly available and our own datasets. PMID- 24051734 TI - Sparse subspace clustering: algorithm, theory, and applications. AB - Many real-world problems deal with collections of high-dimensional data, such as images, videos, text, and web documents, DNA microarray data, and more. Often, such high-dimensional data lie close to low-dimensional structures corresponding to several classes or categories to which the data belong. In this paper, we propose and study an algorithm, called sparse subspace clustering, to cluster data points that lie in a union of low-dimensional subspaces. The key idea is that, among the infinitely many possible representations of a data point in terms of other points, a sparse representation corresponds to selecting a few points from the same subspace. This motivates solving a sparse optimization program whose solution is used in a spectral clustering framework to infer the clustering of the data into subspaces. Since solving the sparse optimization program is in general NP-hard, we consider a convex relaxation and show that, under appropriate conditions on the arrangement of the subspaces and the distribution of the data, the proposed minimization program succeeds in recovering the desired sparse representations. The proposed algorithm is efficient and can handle data points near the intersections of subspaces. Another key advantage of the proposed algorithm with respect to the state of the art is that it can deal directly with data nuisances, such as noise, sparse outlying entries, and missing entries, by incorporating the model of the data into the sparse optimization program. We demonstrate the effectiveness of the proposed algorithm through experiments on synthetic data as well as the two real-world problems of motion segmentation and face clustering. PMID- 24051735 TI - Temporal localization of actions with actoms. AB - We address the problem of localizing actions, such as opening a door, in hours of challenging video data. We propose a model based on a sequence of atomic action units, termed "actoms," that are semantically meaningful and characteristic for the action. Our actom sequence model (ASM) represents an action as a sequence of histograms of actom-anchored visual features, which can be seen as a temporally structured extension of the bag-of-features. Training requires the annotation of actoms for action examples. At test time, actoms are localized automatically based on a nonparametric model of the distribution of actoms, which also acts as a prior on an action's temporal structure. We present experimental results on two recent benchmarks for action localization "Coffee and Cigarettes" and the "DLSBP" dataset. We also adapt our approach to a classification-by-localization set-up and demonstrate its applicability on the challenging "Hollywood 2" dataset. We show that our ASM method outperforms the current state of the art in temporal action localization, as well as baselines that localize actions with a sliding window method. PMID- 24051736 TI - A bag-of-features framework to classify time series. AB - Time series classification is an important task with many challenging applications. A nearest neighbor (NN) classifier with dynamic time warping (DTW) distance is a strong solution in this context. On the other hand, feature-based approaches have been proposed as both classifiers and to provide insight into the series, but these approaches have problems handling translations and dilations in local patterns. Considering these shortcomings, we present a framework to classify time series based on a bag-of-features representation (TSBF). Multiple subsequences selected from random locations and of random lengths are partitioned into shorter intervals to capture the local information. Consequently, features computed from these subsequences measure properties at different locations and dilations when viewed from the original series. This provides a feature-based approach that can handle warping (although differently from DTW). Moreover, a supervised learner (that handles mixed data types, different units, etc.) integrates location information into a compact codebook through class probability estimates. Additionally, relevant global features can easily supplement the codebook. TSBF is compared to NN classifiers and other alternatives (bag-of-words strategies, sparse spatial sample kernels, shapelets). Our experimental results show that TSBF provides better results than competitive methods on benchmark datasets from the UCR time series database. PMID- 24051737 TI - Conditional alignment random fields for multiple motion sequence alignment. AB - We consider the multiple time-series alignment problem, typically focusing on the task of synchronizing multiple motion videos of the same kind of human activity. Finding an optimal global alignment of multiple sequences is infeasible, while there have been several approximate solutions, including iterative pairwise warping algorithms and variants of hidden Markov models. In this paper, we propose a novel probabilistic model that represents the conditional densities of the latent target sequences which are aligned with the given observed sequences through the hidden alignment variables. By imposing certain constraints on the target sequences at the learning stage, we have a sensible model for multiple alignments that can be learned very efficiently by the EM algorithm. Compared to existing methods, our approach yields more accurate alignment while being more robust to local optima and initial configurations. We demonstrate its efficacy on both synthetic and real-world motion videos including facial emotions and human activities. PMID- 24051738 TI - Low-level spatiochromatic grouping for saliency estimation. AB - We propose a saliency model termed SIM (saliency by induction mechanisms), which is based on a low-level spatiochromatic model that has successfully predicted chromatic induction phenomena. In so doing, we hypothesize that the low-level visual mechanisms that enhance or suppress image detail are also responsible for making some image regions more salient. Moreover, SIM adds geometrical grouplets to enhance complex low-level features such as corners, and suppress relatively simpler features such as edges. Since our model has been fitted on psychophysical chromatic induction data, it is largely nonparametric. SIM outperforms state-of the-art methods in predicting eye fixations on two datasets and using two metrics. PMID- 24051739 TI - Multivalent choline dendrimers increase phagocytosis of Streptococcus pneumoniae R6 by microglial cells. AB - BACKGROUND: Pneumococcal virulence factors common to all serotypes, such as choline-binding proteins (CBPs), are promising therapeutic targets in pneumococcal infections. We studied the effect of a choline dendrimer with maximized binding affinity/specificity for CBPs on microglia-mediated pneumococcal phagocytosis. METHODS: Pneumoccocal cultures were exposed to dendrimers containing 8 choline end groups or amino groups as controls, either from the beginning of bacterial growth or at the late exponential phase. The effect of long/short co-incubation was assessed in terms of bacterial morphological changes and increase in bacterial uptake by primary microglial cultures. RESULTS: Inhibiting CBPs by micromolar concentrations of a choline dendrimer caused the formation of long pneumococcal chains that were readily phagocytosed by microglia. Enhanced phagocytosis was dendrimer dose-dependent. Long bacteria-dendrimer co-incubation (14 h) resulted in a higher bacterial uptake than short co-incubation (2 h; p < 0.001). CONCLUSIONS: Multivalent dendrimers containing choline end groups are promising antimicrobial agents for the management of pneumococcal diseases. PMID- 24051740 TI - Is radical hysterectomy necessary in early cervical cancer? AB - AIMS: To estimate the prevalence of tumor spread to the parametrium, vagina and uterine corpus in radical hysterectomy specimens and define a subgroup of patients with low-risk of extracervical involvement, who may benefit from less radical surgery. METHODS: We retrospectively reviewed 96 patients with stage IA1 IIA cervical cancer who had undergone radical hysterectomy and pelvic lymphadenectomy. RESULTS: Tumor spread beyond the uterine cervix was evident in 45 (47%) patients. Thirteen (13%) of the 96 patients had parametrial tumor spread, 12 (13%) had vaginal tumor extension, and 23 (24%) had uterine corpus involvement. Tumor size >2 cm, stromal invasion to a depth of >=8 mm, and lymph vascular space invasion (LVSI) were significantly associated with extracervical invasion. Twenty-five patients had stromal invasion of <8 mm and no LVSI, of which only 1 (4%) had extracervical involvement. On the contrary, extracervical involvement was evident in 44 patients (63%) among those who had stromal invasion of >=8 mm and/or LVSI (p < 0.001). Among women with LVSI, extracervical tumor spread was seen with any tumor size and any depth of stromal invasion. All patients with stromal invasion to a depth of >15 mm had extracervical invasion. CONCLUSION: Patients with tumor size <2 cm, depth of invasion of <8 mm and no LVSI could be considered for less radical surgery. PMID- 24051741 TI - Aortic Intima-Media Thickness in Newborns with Congenital Hypothyroidism. AB - BACKGROUND/AIMS: Congenital hypothyroidism (CH) in neonates is associated with lipid alterations that might be a risk factor for early cardiovascular disease in adult life. The aim of this study was to investigate the effect of CH on lipid metabolism and aortic intima media thickness (aIMT) as a unique finding of the increased risk of atherogenic risk in neonatal age. METHODS: The study group consisted of 15 newborns with CH who were identified by neonatal mass screening (patient group), and 25 healthy newborns (control group). Serum lipid profiles and aIMT obtained from abdominal aorta were measured in all subjects. RESULTS: The mean aIMT were higher in the patient group (0.46 +/- 0.062 mm) compared with the control group (0.34 +/- 0.035 mm; p = 0.006). The weight-adjusted aIMT of patients (0.13 +/- 0.017 mm/kg) was also significantly greater than that of the controls (0.10 +/- 0.019 mm/kg; p < 0.001). Total serum cholesterol levels were significantly higher in patients than those in healthy controls (130.80 +/- 44.46 vs. 99.96 +/- 18.87 mg/dl). The other lipid levels including triglyceride, low density lipoprotein (LDL), high-density lipoprotein cholesterol and LDL cholesterol levels of the patients were slightly higher than those of the controls, without statistical significance. CONCLUSION: Neonates with CH have significantly higher aIMT with lipid alterations. Hypothyroidism might increase the risk of early atherosclerosis even in the neonatal period. PMID- 24051744 TI - Use of a novel receptor-targeted (CD206) radiotracer, 99mTc-tilmanocept, and SPECT/CT for sentinel lymph node detection in oral cavity squamous cell carcinoma: initial institutional report in an ongoing phase 3 study. AB - IMPORTANCE: Sentinel lymph node biopsy has been proposed as an alternative to up front elective neck dissection (END) for determination of pathologic nodal status in patients undergoing surgical treatment for oral cavity squamous cell carcinoma (OSCC) with clinically negative neck (cN0). Sentinel lymph node biopsy using current standard tracer agents and imaging adjuncts such as radiolabeled sulfur colloid and planar lymphoscintigraphy (LS), however, is associated with several drawbacks. OBJECTIVE: To assess the preliminary utility of technetium Tc 99m (99mTc)-tilmanocept, a novel molecular imaging agent for sentinel lymph node (SLN) mapping, in OSCC. DESIGN, SETTING, AND PARTICIPANTS: Prospective, nonrandomized, single-arm, part of an ongoing phase 3 clinical trial. Patients had previously untreated, clinically and radiographically node-negative OSCC (T1 4aN0M0) at an academic tertiary referral center. INTERVENTIONS: Patients received a single dose of 50 ug 99mTc-tilmanocept injected peritumorally followed by dynamic planar LS and fused single-photon emission computed tomography/computed tomography (SPECT/CT) prior to surgery. Surgical intervention consisted of excision of the primary tumor and radioguided SLN dissection followed by planned END. The excised lymph nodes (SLNs and non-SLNs) underwent histopathologic evaluation for presence of metastatic disease. MAIN OUTCOMES AND MEASURES: False negative rate and negative predictive value of SLNB using 99mTc-tilmanocept and comparison of planar LS with SPECT/CT in SLN localization. RESULTS: Twelve of 20 patients (60%) had metastatic neck disease on pathologic examination. All 12 had at least 1 SLN positive for metastases. No patients had a positive END node who did not have at least 1 positive SLN. These data yield a false-negative rate of 0% and negative predictive value of 100% using 99mTc-tilmanocept in this setting. Dynamic planar LS and SPECT/CT revealed a mean (range) number of hot spots per patient of 2.9 (1-7) and 3.7 (1-12), respectively. Compared with planar LS, SPECT/CT identified additional putative SLNs in 11 of 20 cases (55%). CONCLUSIONS AND RELEVANCE: The high negative predictive value and low false-negative rate in identification of occult metastases shows 99mTc-tilmanocept to be a promising agent in SLN identification in patients with OSCC. Use of SPECT/CT improves preoperative SLN localization including delineation of SLN locations near the primary tumor when compared with planar LS imaging. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00911326. PMID- 24051745 TI - Prevalence of eosinophilic esophagitis in children with refractory aerodigestive symptoms. AB - IMPORTANCE: Eosinophilic esophagitis (EoE) is an increasingly important diagnosis for children; it has a remarkable impact on their quality of life and can present with aerodigestive symptoms commonly evaluated by otolaryngologists. OBJECTIVES: To evaluate the prevalence of EoE in children presenting to a pediatric aerodigestive clinic, to describe their presentation, and to review the role of subsequent food allergy evaluation and treatment. DESIGN: Review of a prospective database. SETTING: Tertiary pediatric multispecialty aerodigestive center. PATIENTS: Children with aerodigestive symptoms refractory to medical treatment who underwent direct laryngoscopy with rigid or flexible bronchoscopy and esophagoscopy with or without pH probe study. MAIN OUTCOMES AND MEASURES: Diagnosis of EoE. RESULTS: Between 2003 and 2012, 376 of 1540 children seen in the center (mean [range] age, 4.54 [0-18.6] years; male to female ratio, 1.72:1) remained symptomatic despite medical therapy and thus underwent triple endoscopic evaluation. Of the 376 children, 14 (3.7%) were eventually diagnosed as having EoE, as defined by 15 or more eosinophils per high-power field on esophageal biopsy and either a negative pH study result or nonresponse to a trial of high dose proton pump inhibitors. The subpopulation with EoE presented with airway symptoms and diagnoses, most commonly cough (n = 6; 42.9%). Inflammatory subglottic stenosis due to EoE was identified in 1 patient. Of the 14 children with EoE, 6 presented with gastrointestinal symptomatology, most commonly choking or gagging. Subsequent treatment including food allergy challenge and elimination diet resulted in a clinical improvement in half of the cases identified. CONCLUSIONS AND RELEVANCE: This represents the largest multispecialty clinic epidemiologic study evaluating the prevalence of EoE in children presenting not strictly with gastrointestinal symptoms but rather with aerodigestive symptoms that are frequently evaluated by pediatric otolaryngologists. Although the prevalence is low, EoE should be considered for children with appropriate symptoms in whom other medical therapies fail. PMID- 24051746 TI - Use of SLC26A4 mutation testing for unilateral enlargement of the vestibular aqueduct. AB - IMPORTANCE: Approximately one-half of all subjects with unilateral or bilateral hearing loss with enlargement of the vestibular aqueduct (EVA) will have SLC26A4 gene mutations. The number (0, 1, or 2) of mutant alleles of SLC26A4 detected in an individual subject with EVA is each associated with a distinct combination of diagnostic and prognostic information as well as probability of recurrence of EVA in siblings. OBJECTIVE: To evaluate the results of SLC26A4 mutation testing in subjects with unilateral EVA. (The study objective was formulated before data were collected.) DESIGN: Prospective cross-sectional study of cohort ascertained between 1998 and 2012. SETTING: National Institutes of Health Clinical Center, a federal biomedical research facility. PARTICIPANTS: Twenty-four subjects (10 males, 14 females) with unilateral EVA, defined as a midpoint diameter greater than 1.5 mm, who were referred or self-referred to participate in a study about the clinical and molecular analysis of EVA. Twenty-one (87.5%) of 24 subjects were white. Mean age was 10.3 years (age range, 5-39 years). INTERVENTION: SLC26A4 mutation analysis. MAIN OUTCOMES AND MEASURES: Audiometric results, the presence or absence of EVA, and the number of mutant alleles of SLC26A4. RESULTS: Approximately 8.3% of the subjects with unilateral EVA had 2 mutant SLC26A4 alleles, 16.7% had 1 mutant allele, and 75.0% had 0 mutant alleles. CONCLUSIONS AND RELEVANCE: Unilateral EVA can be associated with all possible SLC26A4 genotype results. The distinct combination of prognoses and recurrence probability associated with each genotype supports the clinical use of testing for SLC26A4 mutations in subjects with unilateral EVA. PMID- 24051747 TI - Multilayer cell-seeded polymer nanofiber constructs for soft-tissue reconstruction. AB - IMPORTANCE: Cell seeding throughout the thickness of a nanofiber construct allows for patient-specific implant alternatives with long-lasting effects, earlier integration, and reduced inflammation when compared with traditional implants. Cell seeding may improve implant integration with host tissue; however, the effect of cell seeding on thick nanofiber constructs has not been studied. OBJECTIVE: To use a novel cell-preseeded nanofiber tissue engineering technique to create a 3-dimensional biocompatible implant alternative to decellularized extracellular matrix. DESIGN: Animal study with mammalian cell culture to study tissue engineered scaffolds. SETTING: Academic research laboratory. PARTICIPANTS: Thirty-six Sprague-Dawley rats. INTERVENTIONS: The rats each received 4 implant types. The grafts included rat primary (enhanced green fluorescent protein positive [eGFP+]) fibroblast-seeded polycaprolactone (PCL)/collagen nanofiber scaffold, PCL/collagen cell-free nanofiber scaffold, acellular human cadaveric dermis (AlloDerm), and acellular porcine dermis (ENDURAGen). Rats were monitored postoperatively and received enrofloxacin in the drinking water for 4 days prophylactically and buprenorphine (0.2-0.5 mg/kg administered subcutaneously twice a day postoperatively for pain for 48 hours). MAIN OUTCOMES AND MEASURES: The viability of NIH/3T3 fibroblasts cultured on PCL electrospun nanofibers was evaluated using fluorescence microscopy. Soft-tissue remodeling was examined histologically and with novel ex vivo volume determinations of implants using micro-computed tomography of cell-seeded implants relative to nanofibers without cells and commonly used dermal grafts of porcine and human origin (ENDURAGen and AlloDerm, respectively). The fate and distribution of eGFP+ seeded donor fibroblasts were assessed using immunohistochemistry. RESULTS: Fibroblasts migrated across nanofiber layers within 12 hours and remained viable on a single layer for up to 14 days. Scanning electron microscopy confirmed a nanoscale structure with a mean (SD) diameter of 158 (72) nm. Low extrusion rates demonstrated the excellent biocompatibility in vivo. Histological examination of the scaffolds demonstrated minimal inflammation. Cell seeding encouraged rapid vascularization of the nanofiber implants. Cells of donor origin (eGFP+) declined with the duration of implantation. Implant volume was not significantly affected for up to 8 weeks by the preseeding of cells (P > .05). CONCLUSIONS AND RELEVANCE: Polymer nanofiber-based scaffolds mimic natural extracellular matrix. Preseeding the nanofiber construct with cells improved vascularization without notable effects on volume. An effect of cell preseeding on scaffold vascularization was evident beyond the presence of preseeded cells. This 3 dimensional, multilayer method of cell seeding throughout a 1-mm-thick construct is simple and feasible for clinical application. Further development of this technique may affect the clinical practice of facial plastic and reconstructive surgeons. PMID- 24051748 TI - Nasal nitric oxide levels and nasal polyposis in children and adolescents with cystic fibrosis. AB - IMPORTANCE: The counterintuitive decrease of exhaled nitric oxide (NO) levels in a severe inflammatory disorder like cystic fibrosis (CF) is only scarcely understood. Because NO is important in a variety of regulatory processes in the lung, including host defense, inflammation, and bronchomotor control, it is necessary to search for clarifying mechanisms. OBJECTIVES: To explore whether fractional exhaled NO (FENO) and nasal NO (nNO) levels are associated with CF genotype, nutritional status, presence of nasal polyps, pulmonary function, and airway colonization with Staphylococcus aureus and Pseudomonas aeruginosa in children with CF, and to investigate the effect of functional endoscopic sinus surgery (FESS) on FENO and nNO levels in children with CF and persistent sinonasal disease. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study (association with NO) and prospective study (effect of FESS on NO) in a tertiary care referral center. Patients included 95 children with CF in clinically stable condition at routine annual multidisciplinary examination, 13 of whom were referred for a FESS procedure. INTERVENTIONS: Functional endoscopic sinus surgery in children with CF and persistent sinonasal disease. MAIN OUTCOMES AND MEASURES: Body mass index (BMI), FENO and nNO levels, results of flexible nasal endoscopy, pulmonary function tests (forced expiratory volume in 1 second and forced vital capacity), and airway cultures. RESULTS: Children with nasal polyposis have significantly lower nNO levels than those without polyposis (median, 53 vs 140 parts per billion; P = .001); these values are negatively associated with colonization with S aureus (beta = -.22; P = .04). After FESS, nNO values increase significantly, although not to normal levels. CONCLUSIONS AND RELEVANCE: In children with CF, the presence of nasal polyps is associated with significantly lower nNO levels than in children without nasal polyps. After FESS for nasal polyposis, nNO levels increase significantly, but not to normal levels. Low nNO levels are associated with S aureus colonization in the oropharynx and lower airways. PMID- 24051750 TI - Glial choristoma of the temporal bone in a 7-month-old infant. AB - IMPORTANCE: Heterotopic glial tissue is a rare, benign congenital anomaly that can present as a fibrous mass with or without overt signs of neural tissue origin, such as overlying alopecia, pigmentation, or a "hair collar" sign. These lesions are typically found in the midline area, though they have been found laterally involving the mastoid and middle ear regions. As demonstrated by this case report, a lateral scalp lesion may represent glial tissue even if fine needle aspiration does not demonstrate neural findings. OBSERVATIONS: This single case report represents a 7-month-old white infant who presented with a lateral scalp mass over the mastoid area. The mass enlarged as she grew, causing external auditory canal obstruction. Fine-needle aspiration demonstrated fibrovascular tissue, and computed tomographic imaging showed a small bony defect over the mastoid area but no intracranial communication. The final pathologic finding was consistent with glial choristoma, a rare, benign congenital lesion involving heterotopic neural tissue. CONCLUSIONS AND RELEVANCE: Congenital scalp lesions can represent heterotopic neural tissue and warrant complete evaluation prior to treatment; fine-needle aspiration biopsy is not necessarily reliable to rule out neurogenic origin, as demonstrated in this case. The possibility for intracranial extension should always be considered and fully evaluated with computed tomography or magnetic resonance imaging prior to operative intervention. Most prior published case reports of heterotopic glial tissue involving the mastoid and/or middle ear spaces describe adults and suggest that such lesions were acquired later in life. This report of a lateral glial choristoma overlying the mastoid bone in an infant supports a congenital origin of this lesion. PMID- 24051749 TI - Viability and virulence of pneumolysin, pneumococcal surface protein A, and pneumolysin/pneumococcal surface protein A mutants in the ear. AB - IMPORTANCE: Understanding how pneumococcal proteins affect the pathology of the middle ear and inner ear is important for the development of new approaches to prevent otitis media and its complications. OBJECTIVES: To determine the viability and virulence of Streptococcus pneumoniae mutants deficient in pneumolysin (Ply-) and pneumococcal surface protein A (PspA-) in the chinchilla middle ear. DESIGN: Bullae of chinchillas were inoculated bilaterally with wild type (Wt), Ply-, PspA-, and Ply-/PspA- strains. Bacterial colony-forming units (CFUs) in middle ear effusions were counted at 48 hours. The CFUs of the PspA- group were also counted at 6 to 36 hours after inoculation. Temporal bone histopathological results were compared. SETTING AND PARTICIPANTS: Twenty-seven chinchillas in an academic research laboratory. EXPOSURE: Chinchilla middle ears were inoculated with S pneumoniae to produce sufficient volumes of effusions and noticeable histopathological changes in the ears. MAIN OUTCOMES AND MEASURES: The CFU counts in the middle ear effusions and histopathological changes were compared to determine the effect of pneumococcal protein mutations on chinchilla ears. RESULTS: At 48 hours, CFUs in middle ears were increased for the Wt and Ply /PspA- strains, but Ply- remained near inoculum level. No bacteria were detected in the PspA- group. The CFUs of PspA- decreased over time to a low level at 30 to 36 hours. In vitro, PspA- in Todd-Hewitt broth showed an increase in bacterial growth of 2 logs at 43 hours, indicating PspA- susceptibility to host defenses in vivo. The PspA- and Ply- groups had fewer pathologic findings than the Wt or Ply /PspA- groups. Histopathological analysis showed significant differences in the number of bacteria in the scala tympani in the Wt group compared with the Ply-, PspA-, and Ply-/PspA- groups. The PspA- strain was the least virulent. CONCLUSIONS AND RELEVANCE: The PspA- mutant was much less viable and less virulent in the ear than the Wt, Ply-, and Ply-/PspA- strains. There was no significant attenuation in the viability and virulence of the Ply-/PspA- mutant compared with the Wt or single mutants. The viability and virulence of pneumococcal mutants seemed to be protein and organ specific. PMID- 24051751 TI - A patient with nasal valve compromise. PMID- 24051752 TI - A left preauricular mass. PMID- 24051753 TI - Nasal congestion and a rapidly enlarging mass at the nasofacial junction. PMID- 24051754 TI - Progressive left nasal obstruction and intermittent epistaxis. PMID- 24051755 TI - Apneic episodes and sternal retractions in an infant. PMID- 24051756 TI - A paratracheal mass. PMID- 24051758 TI - Wilhelm Erb's years in Leipzig (1880-1883) and their impact on the history of neurology. AB - BACKGROUND: Between 1880 and 1883, the famous German neurologist Wilhelm Erb was appointed Professor of Special Pathology at Leipzig University and Head of the Medical Outpatient Department. SUMMARY: Besides the favourable clinical conditions, it was first and foremost the access to large numbers of patients that enabled him to both establish a new, juvenile form of progressive muscular atrophy and to classify various forms of muscular atrophies already discovered into a new clinical entity which he called dystrophia muscularis progressiva. KEY MESSAGES: His summarising these different forms of muscular atrophies into one group is the most long-lasting outcome of Erb's years in Leipzig. The access to large numbers of different patients at the Medical Outpatient Department, on the one hand, and the dynamics of Leipzig's neurosciences, in particular the so called 'Leipzig Nervous Circle', on the other, had a lasting impact on Erb and definitely gave him other valuable insights, such as the thought that tabes dorsalis must have been caused by a syphilitic infection. PMID- 24051759 TI - [The clinical yield of SPECT/CT for the assessment of lymphatic transport disorders. First experiences]. AB - The aim of this study was to determine whether the additional use of SPECT/CT technique improves the diagnostic value of planar lymphoscintigraphy in patients presenting with lymphatic transport disorders. PATIENTS, METHODS: For a defined period of two years 36 consecutive patients (27 women, 9 men; age 27-87 years) were included in our study. In addition to planar scintigraphy further acquisition of the affected extremities or of the trunk was performed using SPECT/CT-technique. In total, 48 anatomic lymph drainage areas were prospectively analysed by planar scintigraphy and tomographic SPECT/CT. RESULTS: In 28/48 cases (58%) the SPECT/CT-imaging provided relevant additional information before treatment compared to planar technique; among them 27 regarding the exact anatomic localization of lymphatic transport disorders and 8 cases in which the dimension of the lymphatic transport disorders were estimated to a greater extent than in single use of planar lymphoscintigraphy. In 3 cases SPECT/CT provides differential diagnosis of lymph nodes versus lymphoceles. In none of the cases lymph vessels or lymph vessel grafts could be demonstrated by the morphological CT-component. CONCLUSIONS: Additionally to planar lymphoscintigraphy, SPECT/CT specifies anatomical correlation of lymphatic transport disorders and thus the assessment of the extension of the pathology. Furthermore, SPECT/CT dissipates overlapping of anatomic structures by tomographic acquisition and enables differential diagnosis of lymph nodes versus lymphoceles. PMID- 24051760 TI - Changing surgical approaches for laparoscopic adrenalectomy: single-surgeon data of a 6-year experience. AB - AIM: To evaluate outcomes of laparoscopic adrenalectomy (LA) and laparoendoscopic single-site surgery (LESS) for adrenal masses in the light of changing laparoscopic surgical techniques. MATERIALS AND METHODS: Seventy-three patients were analyzed retrospectively. There were 2 groups; group 1 included patients who had conventional transperitoneal LA and transperitoneal LESS, and group 2 included patients who had lateral retroperitoneal LA, retroperitoneal LA in prone position, and retroperitoneal LESS. Demographic data, urine 3-methoxy-4 hydroxymandelic acid, normetanephrine, epinephrine, serum cortisol, aldosterone, adrenocorticotropic hormone, American Society of Anesthesiologists score, side and size of mass, conversion to open surgery, complications, estimated blood loss, operation time, pathological results were recorded and analyzed. RESULTS: There was no difference in demographic data and serum parameters between both groups. Tumor size, estimated blood loss, operation time, transfusion rate and hospital stay were less for group 2 (p < 0.05, p = 0.0001). However, the complication rate was similar in both groups; in retroperitoneal prone position, the complication rate was less than for other surgical approaches, but statistically significant results could not be assessed. CONCLUSIONS: Even if the diameter of adrenal mass is larger than 6 cm, LA may be considered as the gold standard. The retroperitoneal approach especially in prone position may be a promising treatment method in the near future for adrenalectomy in selected patients. PMID- 24051761 TI - Differences in nevirapine biotransformation as a factor for its sex-dependent dimorphic profile of adverse drug reactions. AB - OBJECTIVES: Nevirapine is widely used for the treatment of HIV-1 infection; however, its chronic use has been associated with severe liver and skin toxicity. Women are at increased risk for these toxic events, but the reasons for the sex related differences are unclear. Disparities in the biotransformation of nevirapine and the generation of toxic metabolites between men and women might be the underlying cause. The present work aimed to explore sex differences in nevirapine biotransformation as a potential factor in nevirapine-induced toxicity. METHODS: All included subjects were adults who had been receiving 400 mg of nevirapine once daily for at least 1 month. Blood samples were collected and the levels of nevirapine and its phase I metabolites were quantified by HPLC. Anthropometric and clinical data, and nevirapine metabolite profiles, were assessed for sex-related differences. RESULTS: A total of 52 patients were included (63% were men). Body weight was lower in women (P = 0.028) and female sex was associated with higher alkaline phosphatase (P = 0.036) and lactate dehydrogenase (P = 0.037) levels. The plasma concentrations of nevirapine (P = 0.030) and the metabolite 3-hydroxy-nevirapine (P = 0.035), as well as the proportions of the metabolites 12-hydroxy-nevirapine (P = 0.037) and 3-hydroxy nevirapine (P = 0.001), were higher in women, when adjusted for body weight. CONCLUSIONS: There was a sex-dependent variation in nevirapine biotransformation, particularly in the generation of the 12-hydroxy-nevirapine and 3-hydroxy nevirapine metabolites. These data are consistent with the sex-dependent formation of toxic reactive metabolites, which may contribute to the sex dependent dimorphic profile of nevirapine toxicity. PMID- 24051762 TI - A partition-based framework for building and validating regression models. AB - Regression models play a key role in many application domains for analyzing or predicting a quantitative dependent variable based on one or more independent variables. Automated approaches for building regression models are typically limited with respect to incorporating domain knowledge in the process of selecting input variables (also known as feature subset selection). Other limitations include the identification of local structures, transformations, and interactions between variables. The contribution of this paper is a framework for building regression models addressing these limitations. The framework combines a qualitative analysis of relationship structures by visualization and a quantification of relevance for ranking any number of features and pairs of features which may be categorical or continuous. A central aspect is the local approximation of the conditional target distribution by partitioning 1D and 2D feature domains into disjoint regions. This enables a visual investigation of local patterns and largely avoids structural assumptions for the quantitative ranking. We describe how the framework supports different tasks in model building (e.g., validation and comparison), and we present an interactive workflow for feature subset selection. A real-world case study illustrates the step-wise identification of a five-dimensional model for natural gas consumption. We also report feedback from domain experts after two months of deployment in the energy sector, indicating a significant effort reduction for building and improving regression models. PMID- 24051763 TI - Decision exploration lab: a visual analytics solution for decision management. AB - We present a visual analytics solution designed to address prevalent issues in the area of Operational Decision Management (ODM). In ODM, which has its roots in Artificial Intelligence (Expert Systems) and Management Science, it is increasingly important to align business decisions with business goals. In our work, we consider decision models (executable models of the business domain) as ontologies that describe the business domain, and production rules that describe the business logic of decisions to be made over this ontology. Executing a decision model produces an accumulation of decisions made over time for individual cases. We are interested, first, to get insight in the decision logic and the accumulated facts by themselves. Secondly and more importantly, we want to see how the accumulated facts reveal potential divergences between the reality as captured by the decision model, and the reality as captured by the executed decisions. We illustrate the motivation, added value for visual analytics, and our proposed solution and tooling through a business case from the car insurance industry. PMID- 24051764 TI - Vis4Heritage: visual analytics approach on Grotto wall painting degradations. AB - For preserving the Grotto wall paintings and protecting these historic cultural icons from the damage and deterioration in nature environment, a visual analytics framework and a set of tools are proposed for the discovery of degradation patterns. In comparison with the traditional analysis methods that used restricted scales, our method provides users with multi-scale analytic support to study the problems on site, cave, wall and particular degradation area scales, through the application of multidimensional visualization techniques. Several case studies have been carried out using real-world wall painting data collected from a renowned World Heritage site, to verify the usability and effectiveness of the proposed method. User studies and expert reviews were also conducted through by domain experts ranging from scientists such as microenvironment researchers, archivists, geologists, chemists, to practitioners such as conservators, restorers and curators. PMID- 24051765 TI - UTOPIAN: user-driven topic modeling based on interactive nonnegative matrix factorization. AB - Topic modeling has been widely used for analyzing text document collections. Recently, there have been significant advancements in various topic modeling techniques, particularly in the form of probabilistic graphical modeling. State of-the-art techniques such as Latent Dirichlet Allocation (LDA) have been successfully applied in visual text analytics. However, most of the widely-used methods based on probabilistic modeling have drawbacks in terms of consistency from multiple runs and empirical convergence. Furthermore, due to the complicatedness in the formulation and the algorithm, LDA cannot easily incorporate various types of user feedback. To tackle this problem, we propose a reliable and flexible visual analytics system for topic modeling called UTOPIAN (User-driven Topic modeling based on Interactive Nonnegative Matrix Factorization). Centered around its semi-supervised formulation, UTOPIAN enables users to interact with the topic modeling method and steer the result in a user driven manner. We demonstrate the capability of UTOPIAN via several usage scenarios with real-world document corpuses such as InfoVis/VAST paper data set and product review data sets. PMID- 24051766 TI - HierarchicalTopics: visually exploring large text collections using topic hierarchies. AB - Analyzing large textual collections has become increasingly challenging given the size of the data available and the rate that more data is being generated. Topic based text summarization methods coupled with interactive visualizations have presented promising approaches to address the challenge of analyzing large text corpora. As the text corpora and vocabulary grow larger, more topics need to be generated in order to capture the meaningful latent themes and nuances in the corpora. However, it is difficult for most of current topic-based visualizations to represent large number of topics without being cluttered or illegible. To facilitate the representation and navigation of a large number of topics, we propose a visual analytics system--HierarchicalTopic (HT). HT integrates a computational algorithm, Topic Rose Tree, with an interactive visual interface. The Topic Rose Tree constructs a topic hierarchy based on a list of topics. The interactive visual interface is designed to present the topic content as well as temporal evolution of topics in a hierarchical fashion. User interactions are provided for users to make changes to the topic hierarchy based on their mental model of the topic space. To qualitatively evaluate HT, we present a case study that showcases how HierarchicalTopics aid expert users in making sense of a large number of topics and discovering interesting patterns of topic groups. We have also conducted a user study to quantitatively evaluate the effect of hierarchical topic structure. The study results reveal that the HT leads to faster identification of large number of relevant topics. We have also solicited user feedback during the experiments and incorporated some suggestions into the current version of HierarchicalTopics. PMID- 24051767 TI - Visual analysis of topic competition on social media. AB - How do various topics compete for public attention when they are spreading on social media? What roles do opinion leaders play in the rise and fall of competitiveness of various topics? In this study, we propose an expanded topic competition model to characterize the competition for public attention on multiple topics promoted by various opinion leaders on social media. To allow an intuitive understanding of the estimated measures, we present a timeline visualization through a metaphoric interpretation of the results. The visual design features both topical and social aspects of the information diffusion process by compositing ThemeRiver with storyline style visualization. ThemeRiver shows the increase and decrease of competitiveness of each topic. Opinion leaders are drawn as threads that converge or diverge with regard to their roles in influencing the public agenda change over time. To validate the effectiveness of the visual analysis techniques, we report the insights gained on two collections of Tweets: the 2012 United States presidential election and the Occupy Wall Street movement. PMID- 24051768 TI - ScatterBlogs2: real-time monitoring of microblog messages through user-guided filtering. AB - The number of microblog posts published daily has reached a level that hampers the effective retrieval of relevant messages, and the amount of information conveyed through services such as Twitter is still increasing. Analysts require new methods for monitoring their topic of interest, dealing with the data volume and its dynamic nature. It is of particular importance to provide situational awareness for decision making in time-critical tasks. Current tools for monitoring microblogs typically filter messages based on user-defined keyword queries and metadata restrictions. Used on their own, such methods can have drawbacks with respect to filter accuracy and adaptability to changes in trends and topic structure. We suggest ScatterBlogs2, a new approach to let analysts build task-tailored message filters in an interactive and visual manner based on recorded messages of well-understood previous events. These message filters include supervised classification and query creation backed by the statistical distribution of terms and their co-occurrences. The created filter methods can be orchestrated and adapted afterwards for interactive, visual real-time monitoring and analysis of microblog feeds. We demonstrate the feasibility of our approach for analyzing the Twitter stream in emergency management scenarios. PMID- 24051769 TI - Visual analytics for multimodal social network analysis: a design study with social scientists. AB - Social network analysis (SNA) is becoming increasingly concerned not only with actors and their relations, but also with distinguishing between different types of such entities. For example, social scientists may want to investigate asymmetric relations in organizations with strict chains of command, or incorporate non-actors such as conferences and projects when analyzing coauthorship patterns. Multimodal social networks are those where actors and relations belong to different types, or modes, and multimodal social network analysis (mSNA) is accordingly SNA for such networks. In this paper, we present a design study that we conducted with several social scientist collaborators on how to support mSNA using visual analytics tools. Based on an openended, formative design process, we devised a visual representation called parallel node-link bands (PNLBs) that splits modes into separate bands and renders connections between adjacent ones, similar to the list view in Jigsaw. We then used the tool in a qualitative evaluation involving five social scientists whose feedback informed a second design phase that incorporated additional network metrics. Finally, we conducted a second qualitative evaluation with our social scientist collaborators that provided further insights on the utility of the PNLBs representation and the potential of visual analytics for mSNA. PMID- 24051770 TI - Explainers: expert explorations with crafted projections. AB - This paper introduces an approach to exploration and discovery in high dimensional data that incorporates a user's knowledge and questions to craft sets of projection functions meaningful to them. Unlike most prior work that defines projections based on their statistical properties, our approach creates projection functions that align with user-specified annotations. Therefore, the resulting derived dimensions represent concepts defined by the user's examples. These especially crafted projection functions, or explainers, can help find and explain relationships between the data variables and user-designated concepts. They can organize the data according to these concepts. Sets of explainers can provide multiple perspectives on the data. Our approach considers tradeoffs in choosing these projection functions, including their simplicity, expressive power, alignment with prior knowledge, and diversity. We provide techniques for creating collections of explainers. The methods, based on machine learning optimization frameworks, allow exploring the tradeoffs. We demonstrate our approach on model problems and applications in text analysis. PMID- 24051771 TI - Semantics of directly manipulating spatializations. AB - When high-dimensional data is visualized in a 2D plane by using parametric projection algorithms, users may wish to manipulate the layout of the data points to better reflect their domain knowledge or to explore alternative structures. However, few users are well-versed in the algorithms behind the visualizations, making parameter tweaking more of a guessing game than a series of decisive interactions. Translating user interactions into algorithmic input is a key component of Visual to Parametric Interaction (V2PI) [13]. Instead of adjusting parameters, users directly move data points on the screen, which then updates the underlying statistical model. However, we have found that some data points that are not moved by the user are just as important in the interactions as the data points that are moved. Users frequently move some data points with respect to some other 'unmoved' data points that they consider as spatially contextual. However, in current V2PI interactions, these points are not explicitly identified when directly manipulating the moved points. We design a richer set of interactions that makes this context more explicit, and a new algorithm and sophisticated weighting scheme that incorporates the importance of these unmoved data points into V2PI. PMID- 24051772 TI - SketchPadN-D: WYDIWYG sculpting and editing in high-dimensional space. AB - High-dimensional data visualization has been attracting much attention. To fully test related software and algorithms, researchers require a diverse pool of data with known and desired features. Test data do not always provide this, or only partially. Here we propose the paradigm WYDIWYGS (What You Draw Is What You Get). Its embodiment, SketchPadND, is a tool that allows users to generate high dimensional data in the same interface they also use for visualization. This provides for an immersive and direct data generation activity, and furthermore it also enables users to interactively edit and clean existing high-dimensional data from possible artifacts. SketchPadND offers two visualization paradigms, one based on parallel coordinates and the other based on a relatively new framework using an N-D polygon to navigate in high-dimensional space. The first interface allows users to draw arbitrary profiles of probability density functions along each dimension axis and sketch shapes for data density and connections between adjacent dimensions. The second interface embraces the idea of sculpting. Users can carve data at arbitrary orientations and refine them wherever necessary. This guarantees that the data generated is truly high-dimensional. We demonstrate our tool's usefulness in real data visualization scenarios. PMID- 24051773 TI - Visual analysis of higher-order conjunctive relationships in multidimensional data using a hypergraph query system. AB - Visual exploration and analysis of multidimensional data becomes increasingly difficult with increasing dimensionality. We want to understand the relationships between dimensions of data, but lack flexible techniques for exploration beyond low-order relationships. Current visual techniques for multidimensional data analysis focus on binary conjunctive relationships between dimensions. Recent techniques, such as cross-filtering on an attribute relationship graph, facilitate the exploration of some higher-order conjunctive relationships, but require a great deal of care and precision to do so effectively. This paper provides a detailed analysis of the expressive power of existing visual querying systems and describes a more flexible approach in which users can explore n-ary conjunctive inter- and intra- dimensional relationships by interactively constructing queries as visual hypergraphs. In a hypergraph query, nodes represent subsets of values and hyperedges represent conjunctive relationships. Analysts can dynamically build and modify the query using sequences of simple interactions. The hypergraph serves not only as a query specification, but also as a compact visual representation of the interactive state. Using examples from several domains, focusing on the digital humanities, we describe the design considerations for developing the querying system and incorporating it into visual analysis tools. We analyze query expressiveness with regard to the kinds of questions it can and cannot pose, and describe how it simultaneously expands the expressiveness of and is complemented by cross-filtering. PMID- 24051774 TI - Interactive exploration of implicit and explicit relations in faceted datasets. AB - Many datasets, such as scientific literature collections, contain multiple heterogeneous facets which derive implicit relations, as well as explicit relational references between data items. The exploration of this data is challenging not only because of large data scales but also the complexity of resource structures and semantics. In this paper, we present PivotSlice, an interactive visualization technique which provides efficient faceted browsing as well as flexible capabilities to discover data relationships. With the metaphor of direct manipulation, PivotSlice allows the user to visually and logically construct a series of dynamic queries over the data, based on a multi-focus and multi-scale tabular view that subdivides the entire dataset into several meaningful parts with customized semantics. PivotSlice further facilitates the visual exploration and sensemaking process through features including live search and integration of online data, graphical interaction histories and smoothly animated visual state transitions. We evaluated PivotSlice through a qualitative lab study with university researchers and report the findings from our observations and interviews. We also demonstrate the effectiveness of PivotSlice using a scenario of exploring a repository of information visualization literature. PMID- 24051775 TI - VAICo: visual analysis for image comparison. AB - Scientists, engineers, and analysts are confronted with ever larger and more complex sets of data, whose analysis poses special challenges. In many situations it is necessary to compare two or more datasets. Hence there is a need for comparative visualization tools to help analyze differences or similarities among datasets. In this paper an approach for comparative visualization for sets of images is presented. Well-established techniques for comparing images frequently place them side-by-side. A major drawback of such approaches is that they do not scale well. Other image comparison methods encode differences in images by abstract parameters like color. In this case information about the underlying image data gets lost. This paper introduces a new method for visualizing differences and similarities in large sets of images which preserves contextual information, but also allows the detailed analysis of subtle variations. Our approach identifies local changes and applies cluster analysis techniques to embed them in a hierarchy. The results of this process are then presented in an interactive web application which allows users to rapidly explore the space of differences and drill-down on particular features. We demonstrate the flexibility of our approach by applying it to multiple distinct domains. PMID- 24051776 TI - Open-box spectral clustering: applications to medical image analysis. AB - Spectral clustering is a powerful and versatile technique, whose broad range of applications includes 3D image analysis. However, its practical use often involves a tedious and time-consuming process of tuning parameters and making application-specific choices. In the absence of training data with labeled clusters, help from a human analyst is required to decide the number of clusters, to determine whether hierarchical clustering is needed, and to define the appropriate distance measures, parameters of the underlying graph, and type of graph Laplacian. We propose to simplify this process via an open-box approach, in which an interactive system visualizes the involved mathematical quantities, suggests parameter values, and provides immediate feedback to support the required decisions. Our framework focuses on applications in 3D image analysis, and links the abstract high-dimensional feature space used in spectral clustering to the three-dimensional data space. This provides a better understanding of the technique, and helps the analyst predict how well specific parameter settings will generalize to similar tasks. In addition, our system supports filtering outliers and labeling the final clusters in such a way that user actions can be recorded and transferred to different data in which the same structures are to be found. Our system supports a wide range of inputs, including triangular meshes, regular grids, and point clouds. We use our system to develop segmentation protocols in chest CT and brain MRI that are then successfully applied to other datasets in an automated manner. PMID- 24051777 TI - Transformation of an uncertain video search pipeline to a sketch-based visual analytics loop. AB - Traditional sketch-based image or video search systems rely on machine learning concepts as their core technology. However, in many applications, machine learning alone is impractical since videos may not be semantically annotated sufficiently, there may be a lack of suitable training data, and the search requirements of the user may frequently change for different tasks. In this work, we develop a visual analytics systems that overcomes the shortcomings of the traditional approach. We make use of a sketch-based interface to enable users to specify search requirement in a flexible manner without depending on semantic annotation. We employ active machine learning to train different analytical models for different types of search requirements. We use visualization to facilitate knowledge discovery at the different stages of visual analytics. This includes visualizing the parameter space of the trained model, visualizing the search space to support interactive browsing, visualizing candidature search results to support rapid interaction for active learning while minimizing watching videos, and visualizing aggregated information of the search results. We demonstrate the system for searching spatiotemporal attributes from sports video to identify key instances of the team and player performance. PMID- 24051778 TI - Interactive exploration of surveillance video through action shot summarization and trajectory visualization. AB - We propose a novel video visual analytics system for interactive exploration of surveillance video data. Our approach consists of providing analysts with various views of information related to moving objects in a video. To do this we first extract each object's movement path. We visualize each movement by (a) creating a single action shot image (a still image that coalesces multiple frames), (b) plotting its trajectory in a space-time cube and (c) displaying an overall timeline view of all the movements. The action shots provide a still view of the moving object while the path view presents movement properties such as speed and location. We also provide tools for spatial and temporal filtering based on regions of interest. This allows analysts to filter out large amounts of movement activities while the action shot representation summarizes the content of each movement. We incorporated this multi-part visual representation of moving objects in sViSIT, a tool to facilitate browsing through the video content by interactive querying and retrieval of data. Based on our interaction with security personnel who routinely interact with surveillance video data, we identified some of the most common tasks performed. This resulted in designing a user study to measure time-to-completion of the various tasks. These generally required searching for specific events of interest (targets) in videos. Fourteen different tasks were designed and a total of 120 min of surveillance video were recorded (indoor and outdoor locations recording movements of people and vehicles). The time-to completion of these tasks were compared against a manual fast forward video browsing guided with movement detection. We demonstrate how our system can facilitate lengthy video exploration and significantly reduce browsing time to find events of interest. Reports from expert users identify positive aspects of our approach which we summarize in our recommendations for future video visual analytics systems. PMID- 24051779 TI - Space-time visual analytics of eye-tracking data for dynamic stimuli. AB - We introduce a visual analytics method to analyze eye movement data recorded for dynamic stimuli such as video or animated graphics. The focus lies on the analysis of data of several viewers to identify trends in the general viewing behavior, including time sequences of attentional synchrony and objects with strong attentional focus. By using a space-time cube visualization in combination with clustering, the dynamic stimuli and associated eye gazes can be analyzed in a static 3D representation. Shotbased, spatiotemporal clustering of the data generates potential areas of interest that can be filtered interactively. We also facilitate data drill-down: the gaze points are shown with density-based color mapping and individual scan paths as lines in the space-time cube. The analytical process is supported by multiple coordinated views that allow the user to focus on different aspects of spatial and temporal information in eye gaze data. Common eye-tracking visualization techniques are extended to incorporate the spatiotemporal characteristics of the data. For example, heat maps are extended to motion-compensated heat maps and trajectories of scan paths are included in the space-time visualization. Our visual analytics approach is assessed in a qualitative users study with expert users, which showed the usefulness of the approach and uncovered that the experts applied different analysis strategies supported by the system. PMID- 24051780 TI - An extensible framework for provenance in human terrain visual analytics. AB - We describe and demonstrate an extensible framework that supports data exploration and provenance in the context of Human Terrain Analysis (HTA). Working closely with defence analysts we extract requirements and a list of features that characterise data analysed at the end of the HTA chain. From these, we select an appropriate non-classified data source with analogous features, and model it as a set of facets. We develop ProveML, an XML-based extension of the Open Provenance Model, using these facets and augment it with the structures necessary to record the provenance of data, analytical process and interpretations. Through an iterative process, we develop and refine a prototype system for Human Terrain Visual Analytics (HTVA), and demonstrate means of storing, browsing and recalling analytical provenance and process through analytic bookmarks in ProveML. We show how these bookmarks can be combined to form narratives that link back to the live data. Throughout the process, we demonstrate that through structured workshops, rapid prototyping and structured communication with intelligence analysts we are able to establish requirements, and design schema, techniques and tools that meet the requirements of the intelligence community. We use the needs and reactions of defence analysts in defining and steering the methods to validate the framework. PMID- 24051781 TI - Visual exploration of big spatio-temporal urban data: a study of New York City taxi trips. AB - As increasing volumes of urban data are captured and become available, new opportunities arise for data-driven analysis that can lead to improvements in the lives of citizens through evidence-based decision making and policies. In this paper, we focus on a particularly important urban data set: taxi trips. Taxis are valuable sensors and information associated with taxi trips can provide unprecedented insight into many different aspects of city life, from economic activity and human behavior to mobility patterns. But analyzing these data presents many challenges. The data are complex, containing geographical and temporal components in addition to multiple variables associated with each trip. Consequently, it is hard to specify exploratory queries and to perform comparative analyses (e.g., compare different regions over time). This problem is compounded due to the size of the data-there are on average 500,000 taxi trips each day in NYC. We propose a new model that allows users to visually query taxi trips. Besides standard analytics queries, the model supports origin-destination queries that enable the study of mobility across the city. We show that this model is able to express a wide range of spatio-temporal queries, and it is also flexible in that not only can queries be composed but also different aggregations and visual representations can be applied, allowing users to explore and compare results. We have built a scalable system that implements this model which supports interactive response times; makes use of an adaptive level-of-detail rendering strategy to generate clutter-free visualization for large results; and shows hidden details to the users in a summary through the use of overlay heat maps. We present a series of case studies motivated by traffic engineers and economists that show how our model and system enable domain experts to perform tasks that were previously unattainable for them. PMID- 24051782 TI - Visual traffic jam analysis based on trajectory data. AB - In this work, we present an interactive system for visual analysis of urban traffic congestion based on GPS trajectories. For these trajectories we develop strategies to extract and derive traffic jam information. After cleaning the trajectories, they are matched to a road network. Subsequently, traffic speed on each road segment is computed and traffic jam events are automatically detected. Spatially and temporally related events are concatenated in, so-called, traffic jam propagation graphs. These graphs form a high-level description of a traffic jam and its propagation in time and space. Our system provides multiple views for visually exploring and analyzing the traffic condition of a large city as a whole, on the level of propagation graphs, and on road segment level. Case studies with 24 days of taxi GPS trajectories collected in Beijing demonstrate the effectiveness of our system. PMID- 24051783 TI - Space transformation for understanding group movement. AB - We suggest a methodology for analyzing movement behaviors of individuals moving in a group. Group movement is analyzed at two levels of granularity: the group as a whole and the individuals it comprises. For analyzing the relative positions and movements of the individuals with respect to the rest of the group, we apply space transformation, in which the trajectories of the individuals are converted from geographical space to an abstract 'group space'. The group space reference system is defined by both the position of the group center, which is taken as the coordinate origin, and the direction of the group's movement. Based on the individuals' positions mapped onto the group space, we can compare the behaviors of different individuals, determine their roles and/or ranks within the groups, and, possibly, understand how group movement is organized. The utility of the methodology has been evaluated by applying it to a set of real data concerning movements of wild social animals and discussing the results with experts in animal ethology. PMID- 24051784 TI - Visual analytics for spatial clustering: using a heuristic approach for guided exploration. AB - We propose a novel approach of distance-based spatial clustering and contribute a heuristic computation of input parameters for guiding users in the search of interesting cluster constellations. We thereby combine computational geometry with interactive visualization into one coherent framework. Our approach entails displaying the results of the heuristics to users, as shown in Figure 1, providing a setting from which to start the exploration and data analysis. Addition interaction capabilities are available containing visual feedback for exploring further clustering options and is able to cope with noise in the data. We evaluate, and show the benefits of our approach on a sophisticated artificial dataset and demonstrate its usefulness on real-world data. PMID- 24051785 TI - Supporting awareness through collaborative brushing and linking of tabular data. AB - Maintaining an awareness of collaborators' actions is critical during collaborative work, including during collaborative visualization activities. Particularly when collaborators are located at a distance, it is important to know what everyone is working on in order to avoid duplication of effort, share relevant results in a timely manner and build upon each other's results. Can a person's brushing actions provide an indication of their queries and interests in a data set? Can these actions be revealed to a collaborator without substantially disrupting their own independent work? We designed a study to answer these questions in the context of distributed collaborative visualization of tabular data. Participants in our study worked independently to answer questions about a tabular data set, while simultaneously viewing brushing actions of a fictitious collaborator, shown directly within a shared workspace. We compared three methods of presenting the collaborator's actions: brushing & linking (i.e. highlighting exactly what the collaborator would see), selection (i.e. showing only a selected item), and persistent selection (i.e. showing only selected items but having them persist for some time). Our results demonstrated that persistent selection enabled some awareness of the collaborator's activities while causing minimal interference with independent work. Other techniques were less effective at providing awareness, and brushing & linking caused substantial interference. These findings suggest promise for the idea of exploiting natural brushing actions to provide awareness in collaborative work. PMID- 24051786 TI - Identifying redundancy and exposing provenance in crowdsourced data analysis. AB - We present a system that lets analysts use paid crowd workers to explore data sets and helps analysts interactively examine and build upon workers' insights. We take advantage of the fact that, for many types of data, independent crowd workers can readily perform basic analysis tasks like examining views and generating explanations for trends and patterns. However, workers operating in parallel can often generate redundant explanations. Moreover, because workers have different competencies and domain knowledge, some responses are likely to be more plausible than others. To efficiently utilize the crowd's work, analysts must be able to quickly identify and consolidate redundant responses and determine which explanations are the most plausible. In this paper, we demonstrate several crowd-assisted techniques to help analysts make better use of crowdsourced explanations: (1) We explore crowd-assisted strategies that utilize multiple workers to detect redundant explanations. We introduce color clustering with representative selection--a strategy in which multiple workers cluster explanations and we automatically select the most-representative result--and show that it generates clusterings that are as good as those produced by experts. (2) We capture explanation provenance by introducing highlighting tasks and capturing workers' browsing behavior via an embedded web browser, and refine that provenance information via source-review tasks. We expose this information in an explanation-management interface that allows analysts to interactively filter and sort responses, select the most plausible explanations, and decide which to explore further. PMID- 24051787 TI - The impact of physical navigation on spatial organization for sensemaking. AB - Spatial organization has been proposed as a compelling approach to externalizing the sensemaking process. However, there are two ways in which space can be provided to the user: by creating a physical workspace that the user can interact with directly, such as can be provided by a large, high-resolution display, or through the use of a virtual workspace that the user navigates using virtual navigation techniques such as zoom and pan. In this study we explicitly examined the use of spatial sensemaking techniques within these two environments. The results demonstrate that these two approaches to providing sensemaking space are not equivalent, and that the greater embodiment afforded by the physical workspace changes how the space is perceived and used, leading to increased externalization of the sensemaking process. PMID- 24051788 TI - Using interactive visual reasoning to support sense-making: implications for design. AB - This research aims to develop design guidelines for systems that support investigators and analysts in the exploration and assembly of evidence and inferences. We focus here on the problem of identifying candidate 'influencers' within a community of practice. To better understand this problem and its related cognitive and interaction needs, we conducted a user study using a system called INVISQUE (INteractive Visual Search and QUery Environment) loaded with content from the ACM Digital Library. INVISQUE supports search and manipulation of results over a freeform infinite 'canvas'. The study focuses on the representations user create and their reasoning process. It also draws on some pre-established theories and frameworks related to sense-making and cognitive work in general, which we apply as a 'theoretical lenses' to consider findings and articulate solutions. Analysing the user-study data in the light of these provides some understanding of how the high-level problem of identifying key players within a domain can translate into lower-level questions and interactions. This, in turn, has informed our understanding of representation and functionality needs at a level of description which abstracts away from the specifics of the problem at hand to the class of problems of interest. We consider the study outcomes from the perspective of implications for design. PMID- 24051789 TI - Temporal event sequence simplification. AB - Electronic Health Records (EHRs) have emerged as a cost-effective data source for conducting medical research. The difficulty in using EHRs for research purposes, however, is that both patient selection and record analysis must be conducted across very large, and typically very noisy datasets. Our previous work introduced EventFlow, a visualization tool that transforms an entire dataset of temporal event records into an aggregated display, allowing researchers to analyze population-level patterns and trends. As datasets become larger and more varied, however, it becomes increasingly difficult to provide a succinct, summarizing display. This paper presents a series of user-driven data simplifications that allow researchers to pare event records down to their core elements. Furthermore, we present a novel metric for measuring visual complexity, and a language for codifying disjoint strategies into an overarching simplification framework. These simplifications were used by real-world researchers to gain new and valuable insights from initially overwhelming datasets. PMID- 24051790 TI - Visual analytics for model selection in time series analysis. AB - Model selection in time series analysis is a challenging task for domain experts in many application areas such as epidemiology, economy, or environmental sciences. The methodology used for this task demands a close combination of human judgement and automated computation. However, statistical software tools do not adequately support this combination through interactive visual interfaces. We propose a Visual Analytics process to guide domain experts in this task. For this purpose, we developed the TiMoVA prototype that implements this process based on user stories and iterative expert feedback on user experience. The prototype was evaluated by usage scenarios with an example dataset from epidemiology and interviews with two external domain experts in statistics. The insights from the experts' feedback and the usage scenarios show that TiMoVA is able to support domain experts in model selection tasks through interactive visual interfaces with short feedback cycles. PMID- 24051791 TI - TimeBench: a data model and software library for visual analytics of time oriented data. AB - Time-oriented data play an essential role in many Visual Analytics scenarios such as extracting medical insights from collections of electronic health records or identifying emerging problems and vulnerabilities in network traffic. However, many software libraries for Visual Analytics treat time as a flat numerical data type and insufficiently tackle the complexity of the time domain such as calendar granularities and intervals. Therefore, developers of advanced Visual Analytics designs need to implement temporal foundations in their application code over and over again. We present TimeBench, a software library that provides foundational data structures and algorithms for time-oriented data in Visual Analytics. Its expressiveness and developer accessibility have been evaluated through application examples demonstrating a variety of challenges with time-oriented data and long-term developer studies conducted in the scope of research and student projects. PMID- 24051792 TI - MotionExplorer: exploratory search in human motion capture data based on hierarchical aggregation. AB - We present MotionExplorer, an exploratory search and analysis system for sequences of human motion in large motion capture data collections. This special type of multivariate time series data is relevant in many research fields including medicine, sports and animation. Key tasks in working with motion data include analysis of motion states and transitions, and synthesis of motion vectors by interpolation and combination. In the practice of research and application of human motion data, challenges exist in providing visual summaries and drill-down functionality for handling large motion data collections. We find that this domain can benefit from appropriate visual retrieval and analysis support to handle these tasks in presence of large motion data. To address this need, we developed MotionExplorer together with domain experts as an exploratory search system based on interactive aggregation and visualization of motion states as a basis for data navigation, exploration, and search. Based on an overview first type visualization, users are able to search for interesting sub-sequences of motion based on a query-by-example metaphor, and explore search results by details on demand. We developed MotionExplorer in close collaboration with the targeted users who are researchers working on human motion synthesis and analysis, including a summative field study. Additionally, we conducted a laboratory design study to substantially improve MotionExplorer towards an intuitive, usable and robust design. MotionExplorer enables the search in human motion capture data with only a few mouse clicks. The researchers unanimously confirm that the system can efficiently support their work. PMID- 24051793 TI - Supporting the visual analysis of dynamic networks by clustering associated temporal attributes. AB - The visual analysis of dynamic networks is a challenging task. In this paper, we introduce a new approach supporting the discovery of substructures sharing a similar trend over time by combining computation, visualization and interaction. With existing techniques, their discovery would be a tedious endeavor because of the number of nodes, edges as well as time points to be compared. First, on the basis of the supergraph, we therefore group nodes and edges according to their associated attributes that are changing over time. Second, the supergraph is visualized to provide an overview of the groups of nodes and edges with similar behavior over time in terms of their associated attributes. Third, we provide specific interactions to explore and refine the temporal clustering, allowing the user to further steer the analysis of the dynamic network. We demonstrate our approach by the visual analysis of a large wireless mesh network. PMID- 24051795 TI - A model for structure-based comparison of many categories in small-multiple displays. AB - Many application domains deal with multi-variate data that consist of both categorical and numerical information. Smallmultiple displays are a powerful concept for comparing such data by juxtaposition. For comparison by overlay or by explicit encoding of computed differences, however, a specification of references is necessary. In this paper, we present a formal model for defining semantically meaningful comparisons between many categories in a small-multiple display. Based on pivotized data that are hierarchically partitioned by the categories assigned to the x and y axis of the display, we propose two alternatives for structure based comparison within this hierarchy. With an absolute reference specification, categories are compared to a fixed reference category. With a relative reference specification, in contrast, a semantic ordering of the categories is considered when comparing them either to the previous or subsequent category each. Both reference specifications can be defined at multiple levels of the hierarchy (including aggregated summaries), enabling a multitude of useful comparisons. We demonstrate the general applicability of our model in several application examples using different visualizations that compare data by overlay or explicit encoding of differences. PMID- 24051794 TI - LineUp: visual analysis of multi-attribute rankings. AB - Rankings are a popular and universal approach to structuring otherwise unorganized collections of items by computing a rank for each item based on the value of one or more of its attributes. This allows us, for example, to prioritize tasks or to evaluate the performance of products relative to each other. While the visualization of a ranking itself is straightforward, its interpretation is not, because the rank of an item represents only a summary of a potentially complicated relationship between its attributes and those of the other items. It is also common that alternative rankings exist which need to be compared and analyzed to gain insight into how multiple heterogeneous attributes affect the rankings. Advanced visual exploration tools are needed to make this process efficient. In this paper we present a comprehensive analysis of requirements for the visualization of multi-attribute rankings. Based on these considerations, we propose LineUp--a novel and scalable visualization technique that uses bar charts. This interactive technique supports the ranking of items based on multiple heterogeneous attributes with different scales and semantics. It enables users to interactively combine attributes and flexibly refine parameters to explore the effect of changes in the attribute combination. This process can be employed to derive actionable insights as to which attributes of an item need to be modified in order for its rank to change. Additionally, through integration of slope graphs, LineUp can also be used to compare multiple alternative rankings on the same set of items, for example, over time or across different attribute combinations. We evaluate the effectiveness of the proposed multi-attribute visualization technique in a qualitative study. The study shows that users are able to successfully solve complex ranking tasks in a short period of time. PMID- 24051796 TI - Common angle plots as perception-true visualizations of categorical associations. AB - Visualizations are great tools of communications-they summarize findings and quickly convey main messages to our audience. As designers of charts we have to make sure that information is shown with a minimum of distortion. We have to also consider illusions and other perceptual limitations of our audience. In this paper we discuss the effect and strength of the line width illusion, a Muller Lyer type illusion, on designs related to displaying associations between categorical variables. Parallel sets and hammock plots are both affected by line width illusions. We introduce the common-angle plot as an alternative method for displaying categorical data in a manner that minimizes the effect from perceptual illusions. Results from user studies both highlight the need for addressing line width illusions in displays and provide evidence that common angle charts successfully resolve this issue. PMID- 24051797 TI - What makes a visualization memorable? AB - An ongoing debate in the Visualization community concerns the role that visualization types play in data understanding. In human cognition, understanding and memorability are intertwined. As a first step towards being able to ask questions about impact and effectiveness, here we ask: 'What makes a visualization memorable?' We ran the largest scale visualization study to date using 2,070 single-panel visualizations, categorized with visualization type (e.g., bar chart, line graph, etc.), collected from news media sites, government reports, scientific journals, and infographic sources. Each visualization was annotated with additional attributes, including ratings for data-ink ratios and visual densities. Using Amazon's Mechanical Turk, we collected memorability scores for hundreds of these visualizations, and discovered that observers are consistent in which visualizations they find memorable and forgettable. We find intuitive results (e.g., attributes like color and the inclusion of a human recognizable object enhance memorability) and less intuitive results (e.g., common graphs are less memorable than unique visualization types). Altogether our findings suggest that quantifying memorability is a general metric of the utility of information, an essential step towards determining how to design effective visualizations. PMID- 24051798 TI - Perception of average value in multiclass scatterplots. AB - The visual system can make highly efficient aggregate judgements about a set of objects, with speed roughly independent of the number of objects considered. While there is a rich literature on these mechanisms and their ramifications for visual summarization tasks, this prior work rarely considers more complex tasks requiring multiple judgements over long periods of time, and has not considered certain critical aggregation types, such as the localization of the mean value of a set of points. In this paper, we explore these questions using a common visualization task as a case study: relative mean value judgements within multi class scatterplots. We describe how the perception literature provides a set of expected constraints on the task, and evaluate these predictions with a large scale perceptual study with crowd-sourced participants. Judgements are no harder when each set contains more points, redundant and conflicting encodings, as well as additional sets, do not strongly affect performance, and judgements are harder when using less salient encodings. These results have concrete ramifications for the design of scatterplots. PMID- 24051800 TI - Interactive visualizations on large and small displays: the interrelation of display size, information space, and scale. AB - In controlled experiments on the relation of display size (i.e., the number of pixels) and the usability of visualizations, the size of the information space can either be kept constant or varied relative to display size. Both experimental approaches have limitations. If the information space is kept constant then the scale ratio between an overview of the entire information space and the lowest zoom level varies, which can impact performance; if the information space is varied then the scale ratio is kept constant, but performance cannot be directly compared. In other words, display size, information space, and scale ratio are interrelated variables. We investigate this relation in two experiments with interfaces that implement classic information visualization techniques focus+context, overview+detail, and zooming-for multi-scale navigation in maps. Display size varied between 0.17, 1.5, and 13.8 megapixels. Information space varied relative to display size in one experiment and was constant in the other. Results suggest that for tasks where users navigate targets that are visible at all map scales the interfaces do not benefit from a large display: With a constant map size, a larger display does not improve performance with the interfaces; with map size varied relative to display size, participants found interfaces harder to use with a larger display and task completion times decrease only when they are normalized to compensate for the increase in map size. The two experimental approaches show different interaction effects between display size and interface. In particular, focus+context performs relatively worse at a large display size with variable map size, and relatively worse at a small display size with a fixed map size. Based on a theoretical analysis of the interaction with the visualization techniques, we examine individual task actions empirically so as to understand the relative impact of display size and scale ratio on the visualization techniques' performance and to discuss differences between the two experimental approaches. PMID- 24051799 TI - Selecting the aspect ratio of a scatter plot based on its delaunay triangulation. AB - Scatter plots are diagrams that visualize two-dimensional data as sets of points in the plane. They allow users to detect correlations and clusters in the data. Whether or not a user can accomplish these tasks highly depends on the aspect ratio selected for the plot, i.e., the ratio between the horizontal and the vertical extent of the diagram. We argue that an aspect ratio is good if the Delaunay triangulation of the scatter plot at this aspect ratio has some nice geometric property, e.g., a large minimum angle or a small total edge length. More precisely, we consider the following optimization problem. Given a set Q of points in the plane, find a scale factor s such that scaling the x-coordinates of the points in Q by s and the y-coordinates by 1=s yields a point set P(s) that optimizes a property of the Delaunay triangulation of P(s), over all choices of s. We present an algorithm that solves this problem efficiently and demonstrate its usefulness on real-world instances. Moreover, we discuss an empirical test in which we asked 64 participants to choose the aspect ratios of 18 scatter plots. We tested six different quality measures that our algorithm can optimize. In conclusion, minimizing the total edge length and minimizing what we call the 'uncompactness' of the triangles of the Delaunay triangulation yielded the aspect ratios that were most similar to those chosen by the participants in the test. PMID- 24051801 TI - Hybrid-image visualization for large viewing environments. AB - We present a first investigation into hybrid-image visualization for data analysis in large-scale viewing environments. Hybrid-image visualizations blend two different visual representations into a single static view, such that each representation can be perceived at a different viewing distance. Our work is motivated by data analysis scenarios that incorporate one or more displays with sufficiently large size and resolution to be comfortably viewed by different people from various distances. Hybrid-image visualizations can be used, in particular, to enhance overview tasks from a distance and detail-in-context tasks when standing close to the display. By using a perception-based blending approach, hybrid-image visualizations make two full-screen visualizations accessible without tracking viewers in front of a display. We contribute a design space, discuss the perceptual rationale for our work, provide examples, and introduce a set of techniques and tools to aid the design of hybrid-image visualizations. PMID- 24051802 TI - An empirically-derived taxonomy of interaction primitives for interactive cartography and geovisualization. AB - Proposals to establish a 'science of interaction' have been forwarded from Information Visualization and Visual Analytics, as well as Cartography, Geovisualization, and GIScience. This paper reports on two studies to contribute to this call for an interaction science, with the goal of developing a functional taxonomy of interaction primitives for map-based visualization. A semi-structured interview study first was conducted with 21 expert interactive map users to understand the way in which map-based visualizations currently are employed. The interviews were transcribed and coded to identify statements representative of either the task the user wished to accomplish (i.e., objective primitives) or the interactive functionality included in the visualization to achieve this task (i.e., operator primitives). A card sorting study then was conducted with 15 expert interactive map designers to organize these example statements into logical structures based on their experience translating client requests into interaction designs. Example statements were supplemented with primitive definitions in the literature and were separated into two sorting exercises: objectives and operators. The objective sort suggested five objectives that increase in cognitive sophistication (identify, compare, rank, associate, & delineate), but exhibited a large amount of variation across participants due to consideration of broader user goals (procure, predict, & prescribe) and interaction operands (space-alone, attributes-in-space, & space-in-time; elementary & general). The operator sort suggested five enabling operators (import, export, save, edit, & annotate) and twelve work operators (reexpress, arrange, sequence, resymbolize, overlay, pan, zoom, reproject, search, filter, retrieve, & calculate). This taxonomy offers an empirically-derived and ecologically-valid structure to inform future research and design on interaction. PMID- 24051803 TI - A design space of visualization tasks. AB - Knowledge about visualization tasks plays an important role in choosing or building suitable visual representations to pursue them. Yet, tasks are a multi faceted concept and it is thus not surprising that the many existing task taxonomies and models all describe different aspects of tasks, depending on what these task descriptions aim to capture. This results in a clear need to bring these different aspects together under the common hood of a general design space of visualization tasks, which we propose in this paper. Our design space consists of five design dimensions that characterize the main aspects of tasks and that have so far been distributed across different task descriptions. We exemplify its concrete use by applying our design space in the domain of climate impact research. To this end, we propose interfaces to our design space for different user roles (developers, authors, and end users) that allow users of different levels of expertise to work with it. PMID- 24051804 TI - A multi-level typology of abstract visualization tasks. AB - The considerable previous work characterizing visualization usage has focused on low-level tasks or interactions and high-level tasks, leaving a gap between them that is not addressed. This gap leads to a lack of distinction between the ends and means of a task, limiting the potential for rigorous analysis. We contribute a multi-level typology of visualization tasks to address this gap, distinguishing why and how a visualization task is performed, as well as what the task inputs and outputs are. Our typology allows complex tasks to be expressed as sequences of interdependent simpler tasks, resulting in concise and flexible descriptions for tasks of varying complexity and scope. It provides abstract rather than domain-specific descriptions of tasks, so that useful comparisons can be made between visualization systems targeted at different application domains. This descriptive power supports a level of analysis required for the generation of new designs, by guiding the translation of domain-specific problems into abstract tasks, and for the qualitative evaluation of visualization usage. We demonstrate the benefits of our approach in a detailed case study, comparing task descriptions from our typology to those derived from related work. We also discuss the similarities and differences between our typology and over two dozen extant classification systems and theoretical frameworks from the literatures of visualization, human-computer interaction, information retrieval, communications, and cartography. PMID- 24051805 TI - Information visualization and proxemics: design opportunities and empirical findings. AB - People typically interact with information visualizations using a mouse. Their physical movement, orientation, and distance to visualizations are rarely used as input. We explore how to use such spatial relations among people and visualizations (i.e., proxemics) to drive interaction with visualizations, focusing here on the spatial relations between a single user and visualizations on a large display. We implement interaction techniques that zoom and pan, query and relate, and adapt visualizations based on tracking of users' position in relation to a large high-resolution display. Alternative prototypes are tested in three user studies and compared with baseline conditions that use a mouse. Our aim is to gain empirical data on the usefulness of a range of design possibilities and to generate more ideas. Among other things, the results show promise for changing zoom level or visual representation with the user's physical distance to a large display. We discuss possible benefits and potential issues to avoid when designing information visualizations that use proxemics. PMID- 24051806 TI - An interaction model for visualizations beyond the desktop. AB - We present an interaction model for beyond-desktop visualizations that combines the visualization reference model with the instrumental interaction paradigm. Beyond-desktop visualizations involve a wide range of emerging technologies such as wall-sized displays, 3D and shape-changing displays, touch and tangible input, and physical information visualizations. While these technologies allow for new forms of interaction, they are often studied in isolation. New conceptual models are needed to build a coherent picture of what has been done and what is possible. We describe a modified pipeline model where raw data is processed into a visualization and then rendered into the physical world. Users can explore or change data by directly manipulating visualizations or through the use of instruments. Interactions can also take place in the physical world outside the visualization system, such as when using locomotion to inspect a large scale visualization. Through case studies we illustrate how this model can be used to describe both conventional and unconventional interactive visualization systems, and compare different design alternatives. PMID- 24051808 TI - SketchStory: telling more engaging stories with data through freeform sketching. AB - Presenting and communicating insights to an audience-telling a story-is one of the main goals of data exploration. Even though visualization as a storytelling medium has recently begun to gain attention, storytelling is still underexplored in information visualization and little research has been done to help people tell their stories with data. To create a new, more engaging form of storytelling with data, we leverage and extend the narrative storytelling attributes of whiteboard animation with pen and touch interactions. We present SketchStory, a data-enabled digital whiteboard that facilitates the creation of personalized and expressive data charts quickly and easily. SketchStory recognizes a small set of sketch gestures for chart invocation, and automatically completes charts by synthesizing the visuals from the presenter-provided example icon and binding them to the underlying data. Furthermore, SketchStory allows the presenter to move and resize the completed data charts with touch, and filter the underlying data to facilitate interactive exploration. We conducted a controlled experiment for both audiences and presenters to compare SketchStory with a traditional presentation system, Microsoft PowerPoint. Results show that the audience is more engaged by presentations done with SketchStory than PowerPoint. Eighteen out of 24 audience participants preferred SketchStory to PowerPoint. Four out of five presenter participants also favored SketchStory despite the extra effort required for presentation. PMID- 24051807 TI - A deeper understanding of sequence in narrative visualization. AB - Conveying a narrative with visualizations often requires choosing an order in which to present visualizations. While evidence exists that narrative sequencing in traditional stories can affect comprehension and memory, little is known about how sequencing choices affect narrative visualization. We consider the forms and reactions to sequencing in narrative visualization presentations to provide a deeper understanding with a focus on linear, 'slideshow-style' presentations. We conduct a qualitative analysis of 42 professional narrative visualizations to gain empirical knowledge on the forms that structure and sequence take. Based on the results of this study we propose a graph-driven approach for automatically identifying effective sequences in a set of visualizations to be presented linearly. Our approach identifies possible transitions in a visualization set and prioritizes local (visualization-to-visualization) transitions based on an objective function that minimizes the cost of transitions from the audience perspective. We conduct two studies to validate this function. We also expand the approach with additional knowledge of user preferences for different types of local transitions and the effects of global sequencing strategies on memory, preference, and comprehension. Our results include a relative ranking of types of visualization transitions by the audience perspective and support for memory and subjective rating benefits of visualization sequences that use parallelism as a structural device. We discuss how these insights can guide the design of narrative visualization and systems that support optimization of visualization sequence. PMID- 24051809 TI - Using concrete scales: a practical framework for effective visual depiction of complex measures. AB - From financial statistics to nutritional values, we are frequently exposed to quantitative information expressed in measures of either extreme magnitudes or unfamiliar units, or both. A common practice used to comprehend such complex measures is to relate, re-express, and compare them through visual depictions using magnitudes and units that are easier to grasp. Through this practice, we create a new graphic composition that we refer to as a concrete scale. To the best of our knowledge, there are no design guidelines that exist for concrete scales despite their common use in communication, educational, and decision making settings. We attempt to fill this void by introducing a novel framework that would serve as a practical guide for their analysis and design. Informed by a thorough analysis of graphic compositions involving complex measures and an extensive literature review of scale cognition mechanisms, our framework outlines the design space of various measure relations--specifically relations involving the re-expression of complex measures to more familiar concepts--and their visual representations as graphic compositions. PMID- 24051810 TI - StoryFlow: tracking the evolution of stories. AB - Storyline visualizations, which are useful in many applications, aim to illustrate the dynamic relationships between entities in a story. However, the growing complexity and scalability of stories pose great challenges for existing approaches. In this paper, we propose an efficient optimization approach to generating an aesthetically appealing storyline visualization, which effectively handles the hierarchical relationships between entities over time. The approach formulates the storyline layout as a novel hybrid optimization approach that combines discrete and continuous optimization. The discrete method generates an initial layout through the ordering and alignment of entities, and the continuous method optimizes the initial layout to produce the optimal one. The efficient approach makes real-time interactions (e.g., bundling and straightening) possible, thus enabling users to better understand and track how the story evolves. Experiments and case studies are conducted to demonstrate the effectiveness and usefulness of the optimization approach. PMID- 24051811 TI - Visual sedimentation. AB - We introduce Visual Sedimentation, a novel design metaphor for visualizing data streams directly inspired by the physical process of sedimentation. Visualizing data streams (e. g., Tweets, RSS, Emails) is challenging as incoming data arrive at unpredictable rates and have to remain readable. For data streams, clearly expressing chronological order while avoiding clutter, and keeping aging data visible, are important. The metaphor is drawn from the real-world sedimentation processes: objects fall due to gravity, and aggregate into strata over time. Inspired by this metaphor, data is visually depicted as falling objects using a force model to land on a surface, aggregating into strata over time. In this paper, we discuss how this metaphor addresses the specific challenge of smoothing the transition between incoming and aging data. We describe the metaphor's design space, a toolkit developed to facilitate its implementation, and example applications to a range of case studies. We then explore the generative capabilities of the design space through our toolkit. We finally illustrate creative extensions of the metaphor when applied to real streams of data. PMID- 24051812 TI - Nanocubes for real-time exploration of spatiotemporal datasets. AB - Consider real-time exploration of large multidimensional spatiotemporal datasets with billions of entries, each defined by a location, a time, and other attributes. Are certain attributes correlated spatially or temporally? Are there trends or outliers in the data? Answering these questions requires aggregation over arbitrary regions of the domain and attributes of the data. Many relational databases implement the well-known data cube aggregation operation, which in a sense precomputes every possible aggregate query over the database. Data cubes are sometimes assumed to take a prohibitively large amount of space, and to consequently require disk storage. In contrast, we show how to construct a data cube that fits in a modern laptop's main memory, even for billions of entries; we call this data structure a nanocube. We present algorithms to compute and query a nanocube, and show how it can be used to generate well-known visual encodings such as heatmaps, histograms, and parallel coordinate plots. When compared to exact visualizations created by scanning an entire dataset, nanocube plots have bounded screen error across a variety of scales, thanks to a hierarchical structure in space and time. We demonstrate the effectiveness of our technique on a variety of real-world datasets, and present memory, timing, and network bandwidth measurements. We find that the timings for the queries in our examples are dominated by network and user-interaction latencies. PMID- 24051813 TI - Visualizing request-flow comparison to aid performance diagnosis in distributed systems. AB - Distributed systems are complex to develop and administer, and performance problem diagnosis is particularly challenging. When performance degrades, the problem might be in any of the system's many components or could be a result of poor interactions among them. Recent research efforts have created tools that automatically localize the problem to a small number of potential culprits, but research is needed to understand what visualization techniques work best for helping distributed systems developers understand and explore their results. This paper compares the relative merits of three well-known visualization approaches (side-by-side, diff, and animation) in the context of presenting the results of one proven automated localization technique called request-flow comparison. Via a 26-person user study, which included real distributed systems developers, we identify the unique benefits that each approach provides for different problem types and usage modes. PMID- 24051814 TI - Evaluation of filesystem provenance visualization tools. AB - Having effective visualizations of filesystem provenance data is valuable for understanding its complex hierarchical structure. The most common visual representation of provenance data is the node-link diagram. While effective for understanding local activity, the node-link diagram fails to offer a high-level summary of activity and inter-relationships within the data. We present a new tool, InProv, which displays filesystem provenance with an interactive radial based tree layout. The tool also utilizes a new time-based hierarchical node grouping method for filesystem provenance data we developed to match the user's mental model and make data exploration more intuitive. We compared InProv to a conventional node-link based tool, Orbiter, in a quantitative evaluation with real users of filesystem provenance data including provenance data experts, IT professionals, and computational scientists. We also compared in the evaluation our new node grouping method to a conventional method. The results demonstrate that InProv results in higher accuracy in identifying system activity than Orbiter with large complex data sets. The results also show that our new time based hierarchical node grouping method improves performance in both tools, and participants found both tools significantly easier to use with the new time-based node grouping method. Subjective measures show that participants found InProv to require less mental activity, less physical activity, less work, and is less stressful to use. Our study also reveals one of the first cases of gender differences in visualization; both genders had comparable performance with InProv, but women had a significantly lower average accuracy (56%) compared to men (70%) with Orbiter. PMID- 24051815 TI - Visualizing fuzzy overlapping communities in networks. AB - An important feature of networks for many application domains is their community structure. This is because objects within the same community usually have at least one property in common. The investigation of community structure can therefore support the understanding of object attributes from the network topology alone. In real-world systems, objects may belong to several communities at the same time, i.e., communities can overlap. Analyzing fuzzy community memberships is essential to understand to what extent objects contribute to different communities and whether some communities are highly interconnected. We developed a visualization approach that is based on node-link diagrams and supports the investigation of fuzzy communities in weighted undirected graphs at different levels of detail. Starting with the network of communities, the user can continuously drill down to the network of individual nodes and finally analyze the membership distribution of nodes of interest. Our approach uses layout strategies and further visual mappings to graphically encode the fuzzy community memberships. The usefulness of our approach is illustrated by two case studies analyzing networks of different domains: social networking and biological interactions. The case studies showed that our layout and visualization approach helps investigate fuzzy overlapping communities. Fuzzy vertices as well as the different communities to which they belong can be easily identified based on node color and position. PMID- 24051816 TI - Radial sets: interactive visual analysis of large overlapping sets. AB - In many applications, data tables contain multi-valued attributes that often store the memberships of the table entities to multiple sets such as which languages a person masters, which skills an applicant documents, or which features a product comes with. With a growing number of entities, the resulting element-set membership matrix becomes very rich of information about how these sets overlap. Many analysis tasks targeted at set-typed data are concerned with these overlaps as salient features of such data. This paper presents Radial Sets, a novel visual technique to analyze set memberships for a large number of elements. Our technique uses frequency-based representations to enable quickly finding and analyzing different kinds of overlaps between the sets, and relating these overlaps to other attributes of the table entities. Furthermore, it enables various interactions to select elements of interest, find out if they are over represented in specific sets or overlaps, and if they exhibit a different distribution for a specific attribute compared to the rest of the elements. These interactions allow formulating highly-expressive visual queries on the elements in terms of their set memberships and attribute values. As we demonstrate via two usage scenarios, Radial Sets enable revealing and analyzing a multitude of overlapping patterns between large sets, beyond the limits of state-of-the-art techniques. PMID- 24051817 TI - SoccerStories: a kick-off for visual soccer analysis. AB - This article presents SoccerStories, a visualization interface to support analysts in exploring soccer data and communicating interesting insights. Currently, most analyses on such data relate to statistics on individual players or teams. However, soccer analysts we collaborated with consider that quantitative analysis alone does not convey the right picture of the game, as context, player positions and phases of player actions are the most relevant aspects. We designed SoccerStories to support the current practice of soccer analysts and to enrich it, both in the analysis and communication stages. Our system provides an overview+detail interface of game phases, and their aggregation into a series of connected visualizations, each visualization being tailored for actions such as a series of passes or a goal attempt. To evaluate our tool, we ran two qualitative user studies on recent games using SoccerStories with data from one of the world's leading live sports data providers. The first study resulted in a series of four articles on soccer tactics, by a tactics analyst, who said he would not have been able to write these otherwise. The second study consisted in an exploratory follow-up to investigate design alternatives for embedding soccer phases into word-sized graphics. For both experiments, we received a very enthusiastic feedback and participants consider further use of SoccerStories to enhance their current workflow. PMID- 24051818 TI - Creative user-centered visualization design for energy analysts and modelers. AB - We enhance a user-centered design process with techniques that deliberately promote creativity to identify opportunities for the visualization of data generated by a major energy supplier. Visualization prototypes developed in this way prove effective in a situation whereby data sets are largely unknown and requirements open - enabling successful exploration of possibilities for visualization in Smart Home data analysis. The process gives rise to novel designs and design metaphors including data sculpting. It suggests: that the deliberate use of creativity techniques with data stakeholders is likely to contribute to successful, novel and effective solutions; that being explicit about creativity may contribute to designers developing creative solutions; that using creativity techniques early in the design process may result in a creative approach persisting throughout the process. The work constitutes the first systematic visualization design for a data rich source that will be increasingly important to energy suppliers and consumers as Smart Meter technology is widely deployed. It is novel in explicitly employing creativity techniques at the requirements stage of visualization design and development, paving the way for further use and study of creativity methods in visualization design. PMID- 24051819 TI - Understanding interfirm relationships in business ecosystems with interactive visualization. AB - Business ecosystems are characterized by large, complex, and global networks of firms, often from many different market segments, all collaborating, partnering, and competing to create and deliver new products and services. Given the rapidly increasing scale, complexity, and rate of change of business ecosystems, as well as economic and competitive pressures, analysts are faced with the formidable task of quickly understanding the fundamental characteristics of these interfirm networks. Existing tools, however, are predominantly query- or list-centric with limited interactive, exploratory capabilities. Guided by a field study of corporate analysts, we have designed and implemented dotlink360, an interactive visualization system that provides capabilities to gain systemic insight into the compositional, temporal, and connective characteristics of business ecosystems. dotlink360 consists of novel, multiple connected views enabling the analyst to explore, discover, and understand interfirm networks for a focal firm, specific market segments or countries, and the entire business ecosystem. System evaluation by a small group of prototypical users shows supporting evidence of the benefits of our approach. This design study contributes to the relatively unexplored, but promising area of exploratory information visualization in market research and business strategy. PMID- 24051820 TI - Entourage: visualizing relationships between biological pathways using contextual subsets. AB - Biological pathway maps are highly relevant tools for many tasks in molecular biology. They reduce the complexity of the overall biological network by partitioning it into smaller manageable parts. While this reduction of complexity is their biggest strength, it is, at the same time, their biggest weakness. By removing what is deemed not important for the primary function of the pathway, biologists lose the ability to follow and understand cross-talks between pathways. Considering these cross-talks is, however, critical in many analysis scenarios, such as judging effects of drugs. In this paper we introduce Entourage, a novel visualization technique that provides contextual information lost due to the artificial partitioning of the biological network, but at the same time limits the presented information to what is relevant to the analyst's task. We use one pathway map as the focus of an analysis and allow a larger set of contextual pathways. For these context pathways we only show the contextual subsets, i.e., the parts of the graph that are relevant to a selection. Entourage suggests related pathways based on similarities and highlights parts of a pathway that are interesting in terms of mapped experimental data. We visualize interdependencies between pathways using stubs of visual links, which we found effective yet not obtrusive. By combining this approach with visualization of experimental data, we can provide domain experts with a highly valuable tool. We demonstrate the utility of Entourage with case studies conducted with a biochemist who researches the effects of drugs on pathways. We show that the technique is well suited to investigate interdependencies between pathways and to analyze, understand, and predict the effect that drugs have on different cell types. PMID- 24051822 TI - DiffAni: visualizing dynamic graphs with a hybrid of difference maps and animation. AB - Visualization of dynamically changing networks (graphs) is a significant challenge for researchers. Previous work has experimentally compared animation, small multiples, and other techniques, and found trade-offs between these. One potential way to avoid such trade-offs is to combine previous techniques in a hybrid visualization. We present two taxonomies of visualizations of dynamic graphs: one of non-hybrid techniques, and one of hybrid techniques. We also describe a prototype, called DiffAni, that allows a graph to be visualized as a sequence of three kinds of tiles: diff tiles that show difference maps over some time interval, animation tiles that show the evolution of the graph over some time interval, and small multiple tiles that show the graph state at an individual time slice. This sequence of tiles is ordered by time and covers all time slices in the data. An experimental evaluation of DiffAni shows that our hybrid approach has advantages over non-hybrid techniques in certain cases. PMID- 24051821 TI - Variant view: visualizing sequence variants in their gene context. AB - Scientists use DNA sequence differences between an individual's genome and a standard reference genome to study the genetic basis of disease. Such differences are called sequence variants, and determining their impact in the cell is difficult because it requires reasoning about both the type and location of the variant across several levels of biological context. In this design study, we worked with four analysts to design a visualization tool supporting variant impact assessment for three different tasks. We contribute data and task abstractions for the problem of variant impact assessment, and the carefully justified design and implementation of the Variant View tool. Variant View features an information-dense visual encoding that provides maximal information at the overview level, in contrast to the extensive navigation required by currently-prevalent genome browsers. We provide initial evidence that the tool simplified and accelerated workflows for these three tasks through three case studies. Finally, we reflect on the lessons learned in creating and refining data and task abstractions that allow for concise overviews of sprawling information spaces that can reduce or remove the need for the memory-intensive use of navigation. PMID- 24051823 TI - Visualizing change over time using dynamic hierarchies: TreeVersity2 and the StemView. AB - To analyze data such as the US Federal Budget or characteristics of the student population of a University it is common to look for changes over time. This task can be made easier and more fruitful if the analysis is performed by grouping by attributes, such as by Agencies, Bureaus and Accounts for the Budget, or Ethnicity, Gender and Major in a University. We present TreeVersity2, a web based interactive data visualization tool that allows users to analyze change in datasets by creating dynamic hierarchies based on the data attributes. TreeVersity2 introduces a novel space filling visualization (StemView) to represent change in trees at multiple levels--not just at the leaf level. With this visualization users can explore absolute and relative changes, created and removed nodes, and each node's actual values, while maintaining the context of the tree. In addition, TreeVersity2 provides overviews of change over the entire time period, and a reporting tool that lists outliers in textual form, which helps users identify the major changes in the data without having to manually setup filters. We validated TreeVersity2 with 12 case studies with organizations as diverse as the National Cancer Institute, Federal Drug Administration, Department of Transportation, Office of the Bursar of the University of Maryland, or eBay. Our case studies demonstrated that TreeVersity2 is flexible enough to be used in different domains and provide useful insights for the data owners. A TreeVersity2 demo can be found at https://treeversity.cattlab.umd.edu. PMID- 24051825 TI - Automatic layout of structured hierarchical reports. AB - Domain-specific database applications tend to contain a sizable number of table-, form-, and report-style views that must each be designed and maintained by a software developer. A significant part of this job is the necessary tweaking of low-level presentation details such as label placements, text field dimensions, list or table styles, and so on. In this paper, we present a horizontally constrained layout management algorithm that automates the display of structured hierarchical data using the traditional visual idioms of hand-designed database UIs: tables, multi-column forms, and outline-style indented lists. We compare our system with pure outline and nested table layouts with respect to space efficiency and readability, the latter with an online user study on 27 subjects. Our layouts are 3.9 and 1.6 times more compact on average than outline layouts and horizontally unconstrained table layouts, respectively, and are as readable as table layouts even for large datasets. PMID- 24051824 TI - Visual compression of workflow visualizations with automated detection of macro motifs. AB - This paper is concerned with the creation of 'macros' in workflow visualization as a support tool to increase the efficiency of data curation tasks. We propose computation of candidate macros based on their usage in large collections of workflows in data repositories. We describe an efficient algorithm for extracting macro motifs from workflow graphs. We discovered that the state transition information, used to identify macro candidates, characterizes the structural pattern of the macro and can be harnessed as part of the visual design of the corresponding macro glyph. This facilitates partial automation and consistency in glyph design applicable to a large set of macro glyphs. We tested this approach against a repository of biological data holding some 9,670 workflows and found that the algorithmically generated candidate macros are in keeping with domain expert expectations. PMID- 24051826 TI - Edge compression techniques for visualization of dense directed graphs. AB - We explore the effectiveness of visualizing dense directed graphs by replacing individual edges with edges connected to 'modules'-or groups of nodes-such that the new edges imply aggregate connectivity. We only consider techniques that offer a lossless compression: that is, where the entire graph can still be read from the compressed version. The techniques considered are: a simple grouping of nodes with identical neighbor sets; Modular Decomposition which permits internal structure in modules and allows them to be nested; and Power Graph Analysis which further allows edges to cross module boundaries. These techniques all have the same goal--to compress the set of edges that need to be rendered to fully convey connectivity--but each successive relaxation of the module definition permits fewer edges to be drawn in the rendered graph. Each successive technique also, we hypothesize, requires a higher degree of mental effort to interpret. We test this hypothetical trade-off with two studies involving human participants. For Power Graph Analysis we propose a novel optimal technique based on constraint programming. This enables us to explore the parameter space for the technique more precisely than could be achieved with a heuristic. Although applicable to many domains, we are motivated by--and discuss in particular--the application to software dependency analysis. PMID- 24051827 TI - GPLOM: the generalized plot matrix for visualizing multidimensional multivariate data. AB - Scatterplot matrices (SPLOMs), parallel coordinates, and glyphs can all be used to visualize the multiple continuous variables (i.e., dependent variables or measures) in multidimensional multivariate data. However, these techniques are not well suited to visualizing many categorical variables (i.e., independent variables or dimensions). To visualize multiple categorical variables, 'hierarchical axes' that 'stack dimensions' have been used in systems like Polaris and Tableau. However, this approach does not scale well beyond a small number of categorical variables. Emerson et al. [8] extend the matrix paradigm of the SPLOM to simultaneously visualize several categorical and continuous variables, displaying many kinds of charts in the matrix depending on the kinds of variables involved. We propose a variant of their technique, called the Generalized Plot Matrix (GPLOM). The GPLOM restricts Emerson et al.'s technique to only three kinds of charts (scatterplots for pairs of continuous variables, heatmaps for pairs of categorical variables, and barcharts for pairings of categorical and continuous variable), in an effort to make it easier to understand. At the same time, the GPLOM extends Emerson et al.'s work by demonstrating interactive techniques suited to the matrix of charts. We discuss the visual design and interactive features of our GPLOM prototype, including a textual search feature allowing users to quickly locate values or variables by name. We also present a user study that compared performance with Tableau and our GPLOM prototype, that found that GPLOM is significantly faster in certain cases, and not significantly slower in other cases. PMID- 24051828 TI - Orthographic star coordinates. AB - Star coordinates is a popular projection technique from an nD data space to a 2D/3D visualization domain. It is defined by setting n coordinate axes in the visualization domain. Since it generally defines an affine projection, strong distortions can occur: an nD sphere can be mapped to an ellipse of arbitrary size and aspect ratio. We propose to restrict star coordinates to orthographic projections which map an nD sphere of radius r to a 2D circle of radius r. We achieve this by formulating conditions for the coordinate axes to define orthographic projections, and by running a repeated non-linear optimization in the background of every modification of the coordinate axes. This way, we define a number of orthographic interaction concepts as well as orthographic data tour sequences: a scatterplot tour, a principle component tour, and a grand tour. All concepts are illustrated and evaluated with synthetic and real data. PMID- 24051829 TI - Dimension projection matrix/tree: interactive subspace visual exploration and analysis of high dimensional data. AB - For high-dimensional data, this work proposes two novel visual exploration methods to gain insights into the data aspect and the dimension aspect of the data. The first is a Dimension Projection Matrix, as an extension of a scatterplot matrix. In the matrix, each row or column represents a group of dimensions, and each cell shows a dimension projection (such as MDS) of the data with the corresponding dimensions. The second is a Dimension Projection Tree, where every node is either a dimension projection plot or a Dimension Projection Matrix. Nodes are connected with links and each child node in the tree covers a subset of the parent node's dimensions or a subset of the parent node's data items. While the tree nodes visualize the subspaces of dimensions or subsets of the data items under exploration, the matrix nodes enable cross-comparison between different combinations of subspaces. Both Dimension Projection Matrix and Dimension Project Tree can be constructed algorithmically through automation, or manually through user interaction. Our implementation enables interactions such as drilling down to explore different levels of the data, merging or splitting the subspaces to adjust the matrix, and applying brushing to select data clusters. Our method enables simultaneously exploring data correlation and dimension correlation for data with high dimensions. PMID- 24051830 TI - Empirical guidance on scatterplot and dimension reduction technique choices. AB - To verify cluster separation in high-dimensional data, analysts often reduce the data with a dimension reduction (DR) technique, and then visualize it with 2D Scatterplots, interactive 3D Scatterplots, or Scatterplot Matrices (SPLOMs). With the goal of providing guidance between these visual encoding choices, we conducted an empirical data study in which two human coders manually inspected a broad set of 816 scatterplots derived from 75 datasets, 4 DR techniques, and the 3 previously mentioned scatterplot techniques. Each coder scored all color-coded classes in each scatterplot in terms of their separability from other classes. We analyze the resulting quantitative data with a heatmap approach, and qualitatively discuss interesting scatterplot examples. Our findings reveal that 2D scatterplots are often 'good enough', that is, neither SPLOM nor interactive 3D adds notably more cluster separability with the chosen DR technique. If 2D is not good enough, the most promising approach is to use an alternative DR technique in 2D. Beyond that, SPLOM occasionally adds additional value, and interactive 3D rarely helps but often hurts in terms of poorer class separation and usability. We summarize these results as a workflow model and implications for design. Our results offer guidance to analysts during the DR exploration process. PMID- 24051831 TI - Visualization of shape motions in shape space. AB - Analysis of dynamic object deformations such as cardiac motion is of great importance, especially when there is a necessity to visualize and compare the deformation behavior across subjects. However, there is a lack of effective techniques for comparative visualization and assessment of a collection of motion data due to its 4-dimensional nature, i.e., timely varying three-dimensional shapes. From the geometric point of view, the motion change can be considered as a function defined on the 2D manifold of the surface. This paper presents a novel classification and visualization method based on a medial surface shape space, in which two novel shape descriptors are defined, for discriminating normal and abnormal human heart deformations as well as localizing the abnormal motion regions. In our medial surface shape space, the geodesic distance connecting two points in the space measures the similarity between their corresponding medial surfaces, which can quantify the similarity and disparity of the 3D heart motions. Furthermore, the novel descriptors can effectively localize the inconsistently deforming myopathic regions on the left ventricle. An easy visualization of heart motion sequences on the projected space allows users to distinguish the deformation differences. Our experimental results on both synthetic and real imaging data show that this method can automatically classify the healthy and myopathic subjects and accurately detect myopathic regions on the left ventricle, which outperforms other conventional cardiac diagnostic methods. PMID- 24051833 TI - Detecting symmetry in scalar fields using augmented extremum graphs. AB - Visualizing symmetric patterns in the data often helps the domain scientists make important observations and gain insights about the underlying experiment. Detecting symmetry in scalar fields is a nascent area of research and existing methods that detect symmetry are either not robust in the presence of noise or computationally costly. We propose a data structure called the augmented extremum graph and use it to design a novel symmetry detection method based on robust estimation of distances. The augmented extremum graph captures both topological and geometric information of the scalar field and enables robust and computationally efficient detection of symmetry. We apply the proposed method to detect symmetries in cryo-electron microscopy datasets and the experiments demonstrate that the algorithm is capable of detecting symmetry even in the presence of significant noise. We describe novel applications that use the detected symmetry to enhance visualization of scalar field data and facilitate their exploration. PMID- 24051832 TI - Fast blending scheme for molecular surface representation. AB - Representation of molecular surfaces is a well established way to study the interaction of molecules. The state-of-the-art molecular representation is the SES model, which provides a detailed surface visualization. Nevertheless, it is computationally expensive, so the less accurate Gaussian model is traditionally preferred. We introduce a novel surface representation that resembles the SES and approaches the rendering performance of the Gaussian model. Our technique is based on the iterative blending of implicit functions and avoids any pre computation. Additionally, we propose a GPU-based ray-casting algorithm that efficiently visualize our molecular representation. A qualitative and quantitative comparison of our model with respect to the Gaussian and SES models is presented. As showcased in the paper, our technique is a valid and appealing alternative to the Gaussian representation. This is especially relevant in all the applications where the cost of the SES is prohibitive. PMID- 24051834 TI - Fast generation of virtual X-ray images for reconstruction of 3D anatomy. AB - We propose a novel GPU-based approach to render virtual X-ray projections of deformable tetrahedral meshes. These meshes represent the shape and the internal density distribution of a particular anatomical structure and are derived from statistical shape and intensity models (SSIMs). We apply our method to improve the geometric reconstruction of 3D anatomy (e.g. pelvic bone) from 2D X-ray images. For that purpose, shape and density of a tetrahedral mesh are varied and virtual X-ray projections are generated within an optimization process until the similarity between the computed virtual X-ray and the respective anatomy depicted in a given clinical X-ray is maximized. The OpenGL implementation presented in this work deforms and projects tetrahedral meshes of high resolution (200.000+ tetrahedra) at interactive rates. It generates virtual X-rays that accurately depict the density distribution of an anatomy of interest. Compared to existing methods that accumulate X-ray attenuation in deformable meshes, our novel approach significantly boosts the deformation/projection performance. The proposed projection algorithm scales better with respect to mesh resolution and complexity of the density distribution, and the combined deformation and projection on the GPU scales better with respect to the number of deformation parameters. The gain in performance allows for a larger number of cycles in the optimization process. Consequently, it reduces the risk of being stuck in a local optimum. We believe that our approach will improve treatments in orthopedics, where 3D anatomical information is essential. PMID- 24051835 TI - An information-aware framework for exploring multivariate data sets. AB - Information theory provides a theoretical framework for measuring information content for an observed variable, and has attracted much attention from visualization researchers for its ability to quantify saliency and similarity among variables. In this paper, we present a new approach towards building an exploration framework based on information theory to guide the users through the multivariate data exploration process. In our framework, we compute the total entropy of the multivariate data set and identify the contribution of individual variables to the total entropy. The variables are classified into groups based on a novel graph model where a node represents a variable and the links encode the mutual information shared between the variables. The variables inside the groups are analyzed for their representativeness and an information based importance is assigned. We exploit specific information metrics to analyze the relationship between the variables and use the metrics to choose isocontours of selected variables. For a chosen group of points, parallel coordinates plots (PCP) are used to show the states of the variables and provide an interface for the user to select values of interest. Experiments with different data sets reveal the effectiveness of our proposed framework in depicting the interesting regions of the data sets taking into account the interaction among the variables. PMID- 24051836 TI - Efficient local statistical analysis via integral histograms with discrete wavelet transform. AB - Histograms computed from local regions are commonly used in many visualization applications, and allowing the user to query histograms interactively in regions of arbitrary locations and sizes plays an important role in feature identification and tracking. Computing histograms in regions with arbitrary location and size, nevertheless, can be time consuming for large data sets since it involves expensive I/O and scan of data elements. To achieve both performance- and storage-efficient query of local histograms, we present a new algorithm called WaveletSAT, which utilizes integral histograms, an extension of the summed area tables (SAT), and discrete wavelet transform (DWT). Similar to SAT, an integral histogram is the histogram computed from the area between each grid point and the grid origin, which can be be pre-computed to support fast query. Nevertheless, because one histogram contains multiple bins, it will be very expensive to store one integral histogram at each grid point. To reduce the storage cost for large integral histograms, WaveletSAT treats the integral histograms of all grid points as multiple SATs, each of which can be converted into a sparse representation via DWT, allowing the reconstruction of axis-aligned region histograms of arbitrary sizes from a limited number of wavelet coefficients. Besides, we present an efficient wavelet transform algorithm for SATs that can operate on each grid point separately in logarithmic time complexity, which can be extended to parallel GPU-based implementation. With theoretical and empirical demonstration, we show that WaveletSAT can achieve fast preprocessing and smaller storage overhead than the conventional integral histogram approach with close query performance. PMID- 24051837 TI - Characterizing and visualizing predictive uncertainty in numerical ensembles through Bayesian model averaging. AB - Numerical ensemble forecasting is a powerful tool that drives many risk analysis efforts and decision making tasks. These ensembles are composed of individual simulations that each uniquely model a possible outcome for a common event of interest: e.g., the direction and force of a hurricane, or the path of travel and mortality rate of a pandemic. This paper presents a new visual strategy to help quantify and characterize a numerical ensemble's predictive uncertainty: i.e., the ability for ensemble constituents to accurately and consistently predict an event of interest based on ground truth observations. Our strategy employs a Bayesian framework to first construct a statistical aggregate from the ensemble. We extend the information obtained from the aggregate with a visualization strategy that characterizes predictive uncertainty at two levels: at a global level, which assesses the ensemble as a whole, as well as a local level, which examines each of the ensemble's constituents. Through this approach, modelers are able to better assess the predictive strengths and weaknesses of the ensemble as a whole, as well as individual models. We apply our method to two datasets to demonstrate its broad applicability. PMID- 24051838 TI - Contour boxplots: a method for characterizing uncertainty in feature sets from simulation ensembles. AB - Ensembles of numerical simulations are used in a variety of applications, such as meteorology or computational solid mechanics, in order to quantify the uncertainty or possible error in a model or simulation. Deriving robust statistics and visualizing the variability of an ensemble is a challenging task and is usually accomplished through direct visualization of ensemble members or by providing aggregate representations such as an average or pointwise probabilities. In many cases, the interesting quantities in a simulation are not dense fields, but are sets of features that are often represented as thresholds on physical or derived quantities. In this paper, we introduce a generalization of boxplots, called contour boxplots, for visualization and exploration of ensembles of contours or level sets of functions. Conventional boxplots have been widely used as an exploratory or communicative tool for data analysis, and they typically show the median, mean, confidence intervals, and outliers of a population. The proposed contour boxplots are a generalization of functional boxplots, which build on the notion of data depth. Data depth approximates the extent to which a particular sample is centrally located within its density function. This produces a center-outward ordering that gives rise to the statistical quantities that are essential to boxplots. Here we present a generalization of functional data depth to contours and demonstrate methods for displaying the resulting boxplots for two-dimensional simulation data in weather forecasting and computational fluid dynamics. PMID- 24051839 TI - Uncertainty quantification in linear interpolation for isosurface extraction. AB - We present a study of linear interpolation when applied to uncertain data. Linear interpolation is a key step for isosurface extraction algorithms, and the uncertainties in the data lead to non-linear variations in the geometry of the extracted isosurface. We present an approach for deriving the probability density function of a random variable modeling the positional uncertainty in the isosurface extraction. When the uncertainty is quantified by a uniform distribution, our approach provides a closed-form characterization of the mentioned random variable. This allows us to derive, in closed form, the expected value as well as the variance of the level-crossing position. While the former quantity is used for constructing a stable isosurface for uncertain data, the latter is used for visualizing the positional uncertainties in the expected isosurface level crossings on the underlying grid. PMID- 24051840 TI - Coupled ensemble flow line advection and analysis. AB - Ensemble run simulations are becoming increasingly widespread. In this work, we couple particle advection with pathline analysis to visualize and reveal the differences among the flow fields of ensemble runs. Our method first constructs a variation field using a Lagrangian-based distance metric. The variation field characterizes the variation between vector fields of the ensemble runs, by extracting and visualizing the variation of pathlines within ensemble. Parallelism in a MapReduce style is leveraged to handle data processing and computing at scale. Using our prototype system, we demonstrate how scientists can effectively explore and investigate differences within ensemble simulations. PMID- 24051841 TI - Comparative visual analysis of Lagrangian transport in CFD ensembles. AB - Sets of simulation runs based on parameter and model variation, so-called ensembles, are increasingly used to model physical behaviors whose parameter space is too large or complex to be explored automatically. Visualization plays a key role in conveying important properties in ensembles, such as the degree to which members of the ensemble agree or disagree in their behavior. For ensembles of time-varying vector fields, there are numerous challenges for providing an expressive comparative visualization, among which is the requirement to relate the effect of individual flow divergence to joint transport characteristics of the ensemble. Yet, techniques developed for scalar ensembles are of little use in this context, as the notion of transport induced by a vector field cannot be modeled using such tools. We develop a Lagrangian framework for the comparison of flow fields in an ensemble. Our techniques evaluate individual and joint transport variance and introduce a classification space that facilitates incorporation of these properties into a common ensemble visualization. Variances of Lagrangian neighborhoods are computed using pathline integration and Principal Components Analysis. This allows for an inclusion of uncertainty measurements into the visualization and analysis approach. Our results demonstrate the usefulness and expressiveness of the presented method on several practical examples. PMID- 24051842 TI - Adaptive refinement of the flow map using sparse samples. AB - We present a new efficient and scalable method for the high quality reconstruction of the flow map from sparse samples. The flow map describes the transport of massless particles along the flow. As such, it is a fundamental concept in the analysis of transient flow phenomena and all so-called Lagrangian flow visualization techniques require its approximation. The flow map is generally obtained by integrating a dense 1D, 2D, or 3D set of particles across the domain of definition of the flow. Despite its embarrassingly parallel nature, this computation creates a performance bottleneck in the analysis of large-scale datasets that existing adaptive techniques alleviate only partially. Our iterative approximation method significantly improves upon the state of the art by precisely modeling the flow behavior around automatically detected geometric structures embedded in the flow, thus effectively restricting the sampling effort to interesting regions. Our data reconstruction is based on a modified version of Sibson's scattered data interpolation and allows us at each step to offer an intermediate dense approximation of the flow map and to seamlessly integrate regions that will be further refined in subsequent steps. We present a quantitative and qualitative evaluation of our method on different types of flow datasets and offer a detailed comparison with existing techniques. PMID- 24051843 TI - Visualization of Morse connection graphs for topologically rich 2D vector fields. AB - Recent advances in vector field topologymake it possible to compute its multi scale graph representations for autonomous 2D vector fields in a robust and efficient manner. One of these representations is a Morse Connection Graph (MCG), a directed graph whose nodes correspond to Morse sets, generalizing stationary points and periodic trajectories, and arcs - to trajectories connecting them. While being useful for simple vector fields, the MCG can be hard to comprehend for topologically rich vector fields, containing a large number of features. This paper describes a visual representation of the MCG, inspired by previous work on graph visualization. Our approach aims to preserve the spatial relationships between the MCG arcs and nodes and highlight the coherent behavior of connecting trajectories. Using simulations of ocean flow, we show that it can provide useful information on the flow structure. This paper focuses specifically on MCGs computed for piecewise constant (PC) vector fields. In particular, we describe extensions of the PC framework that make it more flexible and better suited for analysis of data on complex shaped domains with a boundary. We also describe a topology simplification scheme that makes our MCG visualizations less ambiguous. Despite the focus on the PC framework, our approach could also be applied to graph representations or topological skeletons computed using different methods. PMID- 24051844 TI - Semi-automatic vortex extraction in 4D PC-MRI cardiac blood flow data using line predicates. AB - Cardiovascular diseases (CVD) are the leading cause of death worldwide. Their initiation and evolution depends strongly on the blood flow characteristics. In recent years, advances in 4D PC-MRI acquisition enable reliable and time-resolved 3D flow measuring, which allows a qualitative and quantitative analysis of the patient-specific hemodynamics. Currently, medical researchers investigate the relation between characteristic flow patterns like vortices and different pathologies. The manual extraction and evaluation is tedious and requires expert knowledge. Standardized, (semi-)automatic and reliable techniques are necessary to make the analysis of 4D PC-MRI applicable for the clinical routine. In this work, we present an approach for the extraction of vortex flow in the aorta and pulmonary artery incorporating line predicates. We provide an extensive comparison of existent vortex extraction methods to determine the most suitable vortex criterion for cardiac blood flow and apply our approach to ten datasets with different pathologies like coarctations, Tetralogy of Fallot and aneurysms. For two cases we provide a detailed discussion how our results are capable to complement existent diagnosis information. To ensure real-time feedback for the domain experts we implement our method completely on the GPU. PMID- 24051845 TI - Design by dragging: an interface for creative forward and inverse design with simulation ensembles. AB - We present an interface for exploring large design spaces as encountered in simulation-based engineering, design of visual effects, and other tasks that require tuning parameters of computationally-intensive simulations and visually evaluating results. The goal is to enable a style of design with simulations that feels as-direct-as-possible so users can concentrate on creative design tasks. The approach integrates forward design via direct manipulation of simulation inputs (e.g., geometric properties, applied forces) in the same visual space with inverse design via 'tugging' and reshaping simulation outputs (e.g., scalar fields from finite element analysis (FEA) or computational fluid dynamics (CFD)). The interface includes algorithms for interpreting the intent of users' drag operations relative to parameterized models, morphing arbitrary scalar fields output from FEA and CFD simulations, and in-place interactive ensemble visualization. The inverse design strategy can be extended to use multi-touch input in combination with an as-rigid-as-possible shape manipulation to support rich visual queries. The potential of this new design approach is confirmed via two applications: medical device engineering of a vacuum-assisted biopsy device and visual effects design using a physically based flame simulation. PMID- 24051846 TI - A multi-criteria approach to camera motion design for volume data animation. AB - We present an integrated camera motion design and path generation system for building volume data animations. Creating animations is an essential task in presenting complex scientific visualizations. Existing visualization systems use an established animation function based on keyframes selected by the user. This approach is limited in providing the optimal in-between views of the data. Alternatively, computer graphics and virtual reality camera motion planning is frequently focused on collision free movement in a virtual walkthrough. For semi transparent, fuzzy, or blobby volume data the collision free objective becomes insufficient. Here, we provide a set of essential criteria focused on computing camera paths to establish effective animations of volume data. Our dynamic multi criteria solver coupled with a force-directed routing algorithm enables rapid generation of camera paths. Once users review the resulting animation and evaluate the camera motion, they are able to determine how each criterion impacts path generation. In this paper, we demonstrate how incorporating this animation approach with an interactive volume visualization system reduces the effort in creating context-aware and coherent animations. This frees the user to focus on visualization tasks with the objective of gaining additional insight from the volume data. PMID- 24051847 TI - A lightweight tangible 3D interface for interactive visualization of thin fiber structures. AB - We present a prop-based, tangible interface for 3D interactive visualization of thin fiber structures. These data are commonly found in current bioimaging datasets, for example second-harmonic generation microscopy of collagen fibers in tissue. Our approach uses commodity visualization technologies such as a depth sensing camera and low-cost 3D display. Unlike most current uses of these emerging technologies in the games and graphics communities, we employ the depth sensing camera to create a fish-tank stereoscopic virtual reality system at the scientist's desk that supports tracking of small-scale gestures with objects already found in the work space. We apply the new interface to the problem of interactive exploratory visualization of three-dimensional thin fiber data. A critical task for the visual analysis of these data is understanding patterns in fiber orientation throughout a volume.The interface enables a new, fluid style of data exploration and fiber orientation analysis by using props to provide needed passive-haptic feedback, making 3D interactions with these fiber structures more controlled. We also contribute a low-level algorithm for extracting fiber centerlines from volumetric imaging. The system was designed and evaluated with two biophotonic experts who currently use it in their lab. As compared to typical practice within their field, the new visualization system provides a more effective way to examine and understand the 3D bioimaging datasets they collect. PMID- 24051848 TI - Evaluation of static and dynamic visualization training approaches for users with different spatial abilities. AB - Conflicting results are reported in the literature on whether dynamic visualizations are more effective than static visualizations for learning and mastering 3-D tasks, and only a few investigations have considered the influence of the spatial abilities of the learners. In a study with 117 participants, we compared the benefit of static vs. dynamic visualization training tools on learners with different spatial abilities performing a typical 3-D task (specifically, creating orthographic projections of a 3-D object). We measured the spatial abilities of the participants using the Mental Rotation Test (MRT) and classified participants into two groups (high and low abilities) to examine how the participants' abilities predicted change in performance after training with static versus dynamic training tools. Our results indicate that: 1) visualization training programs can help learners to improve 3-D task performance, 2) dynamic visualizations provide no advantages over static visualizations that show intermediate steps, 3) training programs are more beneficial for individuals with low spatial abilities than for individuals with high spatial abilities, and 4) training individuals with high spatial abilities using dynamic visualizations provides little benefit. PMID- 24051849 TI - A systematic review on the practice of evaluating visualization. AB - We present an assessment of the state and historic development of evaluation practices as reported in papers published at the IEEE Visualization conference. Our goal is to reflect on a meta-level about evaluation in our community through a systematic understanding of the characteristics and goals of presented evaluations. For this purpose we conducted a systematic review of ten years of evaluations in the published papers using and extending a coding scheme previously established by Lam et al. [2012]. The results of our review include an overview of the most common evaluation goals in the community, how they evolved over time, and how they contrast or align to those of the IEEE Information Visualization conference. In particular, we found that evaluations specific to assessing resulting images and algorithm performance are the most prevalent (with consistently 80-90% of all papers since 1997). However, especially over the last six years there is a steady increase in evaluation methods that include participants, either by evaluating their performances and subjective feedback or by evaluating their work practices and their improved analysis and reasoning capabilities using visual tools. Up to 2010, this trend in the IEEE Visualization conference was much more pronounced than in the IEEE Information Visualization conference which only showed an increasing percentage of evaluation through user performance and experience testing. Since 2011, however, also papers in IEEE Information Visualization show such an increase of evaluations of work practices and analysis as well as reasoning using visual tools. Further, we found that generally the studies reporting requirements analyses and domain-specific work practices are too informally reported which hinders cross-comparison and lowers external validity. PMID- 24051850 TI - Interactive patient-specific vascular modeling with sweep surfaces. AB - The precise modeling of vascular structures plays a key role in medical imaging applications, such as diagnosis, therapy planning and blood flow simulations. For the simulation of blood flow in particular, high-precision models are required to produce accurate results. It is thus common practice to perform extensive manual data polishing on vascular segmentations prior to simulation. This usually involves a complex tool chain which is highly impractical for clinical on-site application. To close this gap in current blood flow simulation pipelines, we present a novel technique for interactive vascular modeling which is based on implicit sweep surfaces. Our method is able to generate and correct smooth high quality models based on geometric centerline descriptions on the fly. It supports complex vascular free-form contours and consequently allows for an accurate and fast modeling of pathological structures such as aneurysms or stenoses. We extend the concept of implicit sweep surfaces to achieve increased robustness and applicability as required in the medical field. We finally compare our method to existing techniques and provide case studies that confirm its contribution to current simulation pipelines. PMID- 24051851 TI - Area-preservation mapping using optimal mass transport. AB - We present a novel area-preservation mapping/flattening method using the optimal mass transport technique, based on the Monge-Brenier theory. Our optimal transport map approach is rigorous and solid in theory, efficient and parallel in computation, yet general for various applications. By comparison with the conventional Monge-Kantorovich approach, our method reduces the number of variables from O(n2) to O(n), and converts the optimal mass transport problem to a convex optimization problem, which can now be efficiently carried out by Newton's method. Furthermore, our framework includes the area weighting strategy that enables users to completely control and adjust the size of areas everywhere in an accurate and quantitative way. Our method significantly reduces the complexity of the problem, and improves the efficiency, flexibility and scalability during visualization. Our framework, by combining conformal mapping and optimal mass transport mapping, serves as a powerful tool for a broad range of applications in visualization and graphics, especially for medical imaging. We provide a variety of experimental results to demonstrate the efficiency, robustness and efficacy of our novel framework. PMID- 24051852 TI - Colon flattening using heat diffusion Riemannian metric. AB - We propose a new colon flattening algorithm that is efficient, shape-preserving, and robust to topological noise. Unlike previous approaches, which require a mandatory topological denoising to remove fake handles, our algorithm directly flattens the colon surface without any denoising. In our method, we replace the original Euclidean metric of the colon surface with a heat diffusion metric that is insensitive to topological noise. Using this heat diffusion metric, we then solve a Laplacian equation followed by an integration step to compute the final flattening. We demonstrate that our method is shape-preserving and the shape of the polyps are well preserved. The flattened colon also provides an efficient way to enhance the navigation and inspection in virtual colonoscopy. We further show how the existing colon registration pipeline is made more robust by using our colon flattening. We have tested our method on several colon wall surfaces and the experimental results demonstrate the robustness and the efficiency of our method. PMID- 24051853 TI - Vessel visualization using curved surface reformation. AB - Visualizations of vascular structures are frequently used in radiological investigations to detect and analyze vascular diseases. Obstructions of the blood flow through a vessel are one of the main interests of physicians, and several methods have been proposed to aid the visual assessment of calcifications on vessel walls. Curved Planar Reformation (CPR) is a wide-spread method that is designed for peripheral arteries which exhibit one dominant direction. To analyze the lumen of arbitrarily oriented vessels, Centerline Reformation (CR) has been proposed. Both methods project the vascular structures into 2D image space in order to reconstruct the vessel lumen. In this paper, we propose Curved Surface Reformation (CSR), a technique that computes the vessel lumen fully in 3D. This offers high-quality interactive visualizations of vessel lumina and does not suffer from problems of earlier methods such as ambiguous visibility cues or premature discretization of centerline data. Our method maintains exact visibility information until the final query of the 3D lumina data. We also present feedback from several domain experts. PMID- 24051855 TI - ManyVis: multiple applications in an integrated visualization environment. AB - As the visualization field matures, an increasing number of general toolkits are developed to cover a broad range of applications. However, no general tool can incorporate the latest capabilities for all possible applications, nor can the user interfaces and workflows be easily adjusted to accommodate all user communities. As a result, users will often chose either substandard solutions presented in familiar, customized tools or assemble a patchwork of individual applications glued through ad-hoc scripts and extensive, manual intervention. Instead, we need the ability to easily and rapidly assemble the best-in-task tools into custom interfaces and workflows to optimally serve any given application community. Unfortunately, creating such meta-applications at the API or SDK level is difficult, time consuming, and often infeasible due to the sheer variety of data models, design philosophies, limits in functionality, and the use of closed commercial systems. In this paper, we present the ManyVis framework which enables custom solutions to be built both rapidly and simply by allowing coordination and communication across existing unrelated applications. ManyVis allows users to combine software tools with complementary characteristics into one virtual application driven by a single, custom-designed interface. PMID- 24051856 TI - Acuity-driven gigapixel visualization. AB - We present a framework for acuity-driven visualization of super-high resolution image data on gigapixel displays. Tiled display walls offer a large workspace that can be navigated physically by the user. Based on head tracking information, the physical characteristics of the tiled display and the formulation of visual acuity, we guide an out-of-core gigapixel rendering scheme by delivering high levels of detail only in places where it is perceivable to the user. We apply this principle to gigapixel image rendering through adaptive level of detail selection. Additionally, we have developed an acuity-driven tessellation scheme for high-quality Focus-and-Context (F+C) lenses that significantly reduces visual artifacts while accurately capturing the underlying lens function. We demonstrate this framework on the Reality Deck, an immersive gigapixel display. We present the results of a user study designed to quantify the impact of our acuity-driven rendering optimizations in the visual exploration process. We discovered no evidence suggesting a difference in search task performance between our framework and naive rendering of gigapixel resolution data, while realizing significant benefits in terms of data transfer overhead. Additionally, we show that our acuity-driven tessellation scheme offers substantially increased frame rates when compared to naive pre-tessellation, while providing indistinguishable image quality. PMID- 24051854 TI - ConnectomeExplorer: query-guided visual analysis of large volumetric neuroscience data. AB - This paper presents ConnectomeExplorer, an application for the interactive exploration and query-guided visual analysis of large volumetric electron microscopy (EM) data sets in connectomics research. Our system incorporates a knowledge-based query algebra that supports the interactive specification of dynamically evaluated queries, which enable neuroscientists to pose and answer domain-specific questions in an intuitive manner. Queries are built step by step in a visual query builder, building more complex queries from combinations of simpler queries. Our application is based on a scalable volume visualization framework that scales to multiple volumes of several teravoxels each, enabling the concurrent visualization and querying of the original EM volume, additional segmentation volumes, neuronal connectivity, and additional meta data comprising a variety of neuronal data attributes. We evaluate our application on a data set of roughly one terabyte of EM data and 750 GB of segmentation data, containing over 4,000 segmented structures and 1,000 synapses. We demonstrate typical use case scenarios of our collaborators in neuroscience, where our system has enabled them to answer specific scientific questions using interactive querying and analysis on the full-size data for the first time. PMID- 24051857 TI - An exploration framework to identify and track movement of cloud systems. AB - We describe a framework to explore and visualize the movement of cloud systems. Using techniques from computational topology and computer vision, our framework allows the user to study this movement at various scales in space and time. Such movements could have large temporal and spatial scales such as the Madden Julian Oscillation (MJO), which has a spatial scale ranging from 1000 km to 10000 km and time of oscillation of around 40 days. Embedded within these larger scale oscillations are a hierarchy of cloud clusters which could have smaller spatial and temporal scales such as the Nakazawa cloud clusters. These smaller cloud clusters, while being part of the equatorial MJO, sometimes move at speeds different from the larger scale and in a direction opposite to that of the MJO envelope. Hitherto, one could only speculate about such movements by selectively analysing data and a priori knowledge of such systems. Our framework automatically delineates such cloud clusters and does not depend on the prior experience of the user to define cloud clusters. Analysis using our framework also shows that most tropical systems such as cyclones also contain multi-scale interactions between clouds and cloud systems. We show the effectiveness of our framework to track organized cloud system during one such rainfall event which happened at Mumbai, India in July 2005 and for cyclone Aila which occurred in Bay of Bengal during May 2009. PMID- 24051858 TI - MObjects--a novel method for the visualization and interactive exploration of defects in industrial XCT data. AB - This paper describes an advanced visualization method for the analysis of defects in industrial 3D X-Ray Computed Tomography (XCT) data. We present a novel way to explore a high number of individual objects in a dataset, e.g., pores, inclusions, particles, fibers, and cracks demonstrated on the special application area of pore extraction in carbon fiber reinforced polymers (CFRP). After calculating the individual object properties volume, dimensions and shape factors, all objects are clustered into a mean object (MObject). The resulting MObject parameter space can be explored interactively. To do so, we introduce the visualization of mean object sets (MObject Sets) in a radial and a parallel arrangement. Each MObject may be split up into sub-classes by selecting a specific property, e.g., volume or shape factor, and the desired number of classes. Applying this interactive selection iteratively leads to the intended classifications and visualizations of MObjects along the selected analysis path. Hereby the given different scaling factors of the MObjects down the analysis path are visualized through a visual linking approach. Furthermore the representative MObjects are exported as volumetric datasets to serve as input for successive calculations and simulations. In the field of porosity determination in CFRP non destructive testing practitioners use representative MObjects to improve ultrasonic calibration curves. Representative pores also serve as input for heat conduction simulations in active thermography. For a fast overview of the pore properties in a dataset we propose a local MObjects visualization in combination with a color-coded homogeneity visualization of cells. The advantages of our novel approach are demonstrated using real world CFRP specimens. The results were evaluated through a questionnaire in order to determine the practicality of the MObjects visualization as a supportive tool for domain specialists. PMID- 24051860 TI - Noise-based volume rendering for the visualization of multivariate volumetric data. AB - Analysis of multivariate data is of great importance in many scientific disciplines. However, visualization of 3D spatially-fixed multivariate volumetric data is a very challenging task. In this paper we present a method that allows simultaneous real-time visualization of multivariate data. We redistribute the opacity within a voxel to improve the readability of the color defined by a regular transfer function, and to maintain the see-through capabilities of volume rendering. We use predictable procedural noise--random-phase Gabor noise--to generate a high-frequency redistribution pattern and construct an opacity mapping function, which allows to partition the available space among the displayed data attributes. This mapping function is appropriately filtered to avoid aliasing, while maintaining transparent regions. We show the usefulness of our approach on various data sets and with different example applications. Furthermore, we evaluate our method by comparing it to other visualization techniques in a controlled user study. Overall, the results of our study indicate that users are much more accurate in determining exact data values with our novel 3D volume visualization method. Significantly lower error rates for reading data values and high subjective ranking of our method imply that it has a high chance of being adopted for the purpose of visualization of multivariate 3D data. PMID- 24051861 TI - Ambient volume scattering. AB - We present ambient scattering as a preintegration method for scattering on mesoscopic scales in direct volume rendering. Far-range scattering effects usually provide negligible contributions to a given location due to the exponential attenuation with increasing distance. This motivates our approach to preintegrating multiple scattering within a finite spherical region around any given sample point. To this end, we solve the full light transport with a Monte Carlo simulation within a set of spherical regions, where each region may have different material parameters regarding anisotropy and extinction. This precomputation is independent of the data set and the transfer function, and results in a small preintegration table. During rendering, the look-up table is accessed for each ray sample point with respect to the viewing direction, phase function, and material properties in the spherical neighborhood of the sample. Our rendering technique is efficient and versatile because it readily fits in existing ray marching algorithms and can be combined with local illumination and volumetric ambient occlusion. It provides interactive volumetric scattering and soft shadows, with interactive control of the transfer function, anisotropy parameter of the phase function, lighting conditions, and viewpoint. A GPU implementation demonstrates the benefits of ambient scattering for the visualization of different types of data sets, with respect to spatial perception, high-quality illumination, translucency, and rendering speed. PMID- 24051859 TI - GRACE: A visual comparison framework for integrated spatial and non-spatial geriatric data. AB - We present the design of a novel framework for the visual integration, comparison, and exploration of correlations in spatial and non-spatial geriatric research data. These data are in general high-dimensional and span both the spatial, volumetric domain--through magnetic resonance imaging volumes--and the non-spatial domain, through variables such as age, gender, or walking speed. The visual analysis framework blends medical imaging, mathematical analysis and interactive visualization techniques, and includes the adaptation of Sparse Partial Least Squares and iterated Tikhonov Regularization algorithms to quantify potential neurologymobility connections. A linked-view design geared specifically at interactive visual comparison integrates spatial and abstract visual representations to enable the users to effectively generate and refine hypotheses in a large, multidimensional, and fragmented space. In addition to the domain analysis and design description, we demonstrate the usefulness of this approach on two case studies. Last, we report the lessons learned through the iterative design and evaluation of our approach, in particular those relevant to the design of comparative visualization of spatial and non-spatial data. PMID- 24051862 TI - Lighting design for globally illuminated volume rendering. AB - With the evolution of graphics hardware, high quality global illumination becomes available for real-time volume rendering. Compared to local illumination, global illumination can produce realistic shading effects which are closer to real world scenes, and has proven useful for enhancing volume data visualization to enable better depth and shape perception. However, setting up optimal lighting could be a nontrivial task for average users. There were lighting design works for volume visualization but they did not consider global light transportation. In this paper, we present a lighting design method for volume visualization employing global illumination. The resulting system takes into account view and transfer function dependent content of the volume data to automatically generate an optimized three-point lighting environment. Our method fully exploits the back light which is not used by previous volume visualization systems. By also including global shadow and multiple scattering, our lighting system can effectively enhance the depth and shape perception of volumetric features of interest. In addition, we propose an automatic tone mapping operator which recovers visual details from overexposed areas while maintaining sufficient contrast in the dark areas. We show that our method is effective for visualizing volume datasets with complex structures. The structural information is more clearly and correctly presented under the automatically generated light sources. PMID- 24051863 TI - Polymyxin B dosing in obese and underweight adults. PMID- 24051864 TI - Increased risk of cirrhosis and its decompensation in chronic hepatitis B patients with newly diagnosed diabetes: a nationwide cohort study. AB - BACKGROUND: The impact of diabetes on cirrhosis, its decompensation, and their time relationship in patients with chronic hepatitis B (CHB) remain unclear. METHODS: We conducted a nationwide cohort study by using the Taiwanese National Health Insurance Research Database, which was comprised of data from >99% of the entire population. Among 1 million randomly sampled enrollees, 14 523 adult CHB patients were identified from 1997 to 2009. Diabetes was defined as newly diagnosed in CHB patients who were given the diagnosis in the years 1998-2001 but not in 1996-1997 and with physician visits of at least twice per year. The cohorts of CHB with newly diagnosed diabetes (n = 351) and without diabetes (n = 7886) were followed up from the diagnosis of diabetes and from 2000 in the patients without diabetes until development of cirrhosis or its decompensation, withdrawal from insurance, or December 2009. RESULTS: Kaplan-Meier survival analysis showed a significantly higher cumulative incidence of cirrhosis (relative risk [RR] = 3.43; 95% confidence interval [CI], 2.62-4.49; P < .001, log-rank test) and decompensated cirrhosis (RR = 4.11; 95% CI, 2.95-5.70; P < .001, log-rank test) among patients with newly developed diabetes compared with those without diabetes. After adjustment for age, sex, CHB treatment, hepatocellular carcinoma, and comorbidity index by Cox proportional hazards model, diabetes was still an independent predictor for cirrhosis (hazard ratio [HR] = 2.015; 95% CI, 1.393-2.915; P < .001) and its decompensation (HR = 1.792; 95% CI, 1.192-2.695; P = .005). CONCLUSIONS: Patients with CHB who develop diabetes are at an increased risk of liver cirrhosis and its decompensation over time. PMID- 24051865 TI - Reply to Pai. PMID- 24051866 TI - High frequency of false-positive hepatitis C virus enzyme-linked immunosorbent assay in Rakai, Uganda. AB - The prevalence of hepatitis C virus (HCV) infection in sub-Saharan Africa remains unclear. We tested 1000 individuals from Rakai, Uganda, with the Ortho version 3.0 HCV enzyme-linked immunosorbent assay. All serologically positive samples were tested for HCV RNA. Seventy-six of the 1000 (7.6%) participants were HCV antibody positive; none were confirmed by detection of HCV RNA. PMID- 24051867 TI - An easily removable stereo-dictating group for enantioselective synthesis of propargylic amines. AB - We report herein a CuBr-catalyzed three-component coupling of 2-methylbut-3-yn-2 ol, aldehydes and pyrrolidine or 1,2,3,4-tetrahydroisoquinoline leading to the corresponding chiral propargylamines in excellent enantiomeric excess (91 to >99% ee) and high yields (79-95% yield). The dimethylcarbinol unit in 2-methylbut-3-yn 2-ol, which may be easily removed at the later stage to regenerate a terminal alkyne unit for further elaboration, plays a very important role in ensuring high enantioselectivity. This protocol provides easy and very general access to different terminal and non-terminal tertiary propargylic amines. PMID- 24051868 TI - Prognostic value of low and moderately elevated C-reactive protein in acute coronary syndrome: a 2-year follow-up study. AB - BACKGROUND: The main goal of this study was to improve diagnostic and predictive value of low and moderately elevated C-reactive protein (CRP) in patients with acute coronary syndrome (ACS), related to noninvasive clinical parameters, in order to improve and prolong patient life with low or no additional costs. MATERIAL/METHODS: A prospective, open clinical study was conducted at the University Hospital Split, Croatia with 112 patients with ACS and low or moderately elevated CRP (<3.0 mg/L). After diagnosing ACS, data on physical activity, alcohol consumption, and functional status were recorded. Anthropometric measurements were made. Blood and urine samples were taken for analyses. Electrocardiographic, ergometric, and echocardiographic testing was performed. A total of 72 parameters were monitored at the time of hospital admission in ACS patients to analyze which ones could predict disease outcome at the end of follow-up in patients with low or moderately elevated CRP. Patients were followed up for 2 years. RESULTS: The variables that were predictive of major adverse cardiac events (MACE) within 2 years of ACS hospitalization were hemoglobin, fibrinogen, antithrombin III, cholesterol levels, brain natriuretic peptide, and microalbuminuria. ACS patients with CRP<3.0 mg/L had significantly higher risk of developing MACE within 2 years if >=50% of the 8 key parameters were outside the reference values. CONCLUSIONS: Major adverse cardiac events can be predicted in patients with acute coronary syndrome whose CRP values are low or moderately elevated. PMID- 24051870 TI - Simulation in neurosurgery: possibilities and practicalities: foreword. PMID- 24051869 TI - Incidence of brain metastases after trimodality therapy in patients with esophageal or gastroesophageal cancer: implications for screening and surveillance. AB - BACKGROUND: It is unclear whether patients undergoing trimodality therapy (TMT) should be screened or surveyed for brain metastases. METHODS: We retrospectively analyzed esophageal cancer (EC) patients who underwent TMT between the years 2000 and 2010. All were systematically staged and surveyed but none had screening or surveillance brain imaging. RESULTS: The median follow-up time for 518 patients was 29.3 months (range 1-149.2); all patients had adenocarcinoma of the esophagus. Of 188 (36.3%) patients who developed distant metastases, 20 (10.6% of 188 patients or 3.9% of 518 patients) had brain metastases. A higher baseline clinical stage (stage III or IVa) was associated with brain metastases. Most (90%) patients with brain metastases were diagnosed within 24 months of surgery. Sixteen patients had central nervous system symptoms at diagnosis. Twelve (60%) patients had solitary metastasis and 8 (40%) patients had multiple metastases. Although 17 patients received therapy for brain metastases, the median overall survival time of 20 patients was only 10.5 months (95% CI 6.6-14.0). CONCLUSION: After TMT, 3.9% of EC patients developed brain metastases and their prognosis was poor. Our data suggest that screening and/or surveillance for brain metastases in the EC population undergoing TMT is not warranted. PMID- 24051871 TI - Developing an anterior cervical diskectomy and fusion simulator for neurosurgical resident training. AB - BACKGROUND: Surgical simulators are useful in many surgical disciplines to augment residency training. Duty hour restrictions and increasing emphasis on patient safety and attending oversight have changed neurosurgical education from the traditional apprenticeship model. The Congress of Neurological Surgeons Simulation Committee has been developing neurosurgical simulators for the purpose of enhancing resident education and assessing proficiency. OBJECTIVE: To review the initial experience with an anterior cervical diskectomy and fusion (ACDF) simulator. METHODS: The first ACDF training module was implemented at the 2012 Congress of Neurological Surgeons Annual Meeting. The 90-minute curriculum included a written pretest, didactics, a practical pretest on the simulator, hands-on training, a written posttest, a practical posttest, and postcourse feedback. Didactic material covered clinical indications for ACDF, comparison with other cervical procedures, surgical anatomy and approach, principles of arthrodesis and spinal fixation, and complication management. Written pretests and posttests were administered to assess baseline knowledge and evidence of improvement after the module. Qualitative evaluation of individual performance on the practical (simulator) portion was included. RESULTS: Three neurosurgery residents, 2 senior medical students, and 1 attending neurosurgeon participated in the course. The pretest scores were an average 9.2 (range, 6-13). Posttest scores improved to 11.0 (range, 9-13; P = .03). CONCLUSION: Initial experience with the ACDF simulator suggests that it may represent a meaningful training module for residents. Simulation will be an important training modality for residents to practice surgical technique and for teachers to assess competency. Further development of an ACDF simulator and didactic curriculum will require additional verification of simulator validity and reliability. PMID- 24051872 TI - Simulated lumbar minimally invasive surgery educational model with didactic and technical components. AB - BACKGROUND: The learning and development of technical skills are paramount for neurosurgical trainees. External influences and a need for maximizing efficiency and proficiency have encouraged advancements in simulator-based learning models. OBJECTIVE: To confirm the importance of establishing an educational curriculum for teaching minimally invasive techniques of pedicle screw placement using a computer-enhanced physical model of percutaneous pedicle screw placement with simultaneous didactic and technical components. METHODS: A 2-hour educational curriculum was created to educate neurosurgical residents on anatomy, pathophysiology, and technical aspects associated with image-guided pedicle screw placement. Predidactic and postdidactic practical and written scores were analyzed and compared. Scores were calculated for each participant on the basis of the optimal pedicle screw starting point and trajectory for both fluoroscopy and computed tomographic navigation. RESULTS: Eight trainees participated in this module. Average mean scores on the written didactic test improved from 78% to 100%. The technical component scores for fluoroscopic guidance improved from 58.8 to 52.9. Technical score for computed tomography-navigated guidance also improved from 28.3 to 26.6. CONCLUSION: Didactic and technical quantitative scores with a simulator-based educational curriculum improved objectively measured resident performance. A minimally invasive spine simulation model and curriculum may serve a valuable function in the education of neurosurgical residents and outcomes for patients. PMID- 24051873 TI - Simulated spinal cerebrospinal fluid leak repair: an educational model with didactic and technical components. AB - BACKGROUND: In the era of surgical resident work hour restrictions, the traditional apprenticeship model may provide fewer hours for neurosurgical residents to hone technical skills. Spinal dura mater closure or repair is 1 skill that is infrequently encountered, and persistent cerebrospinal fluid leaks are a potential morbidity. OBJECTIVE: To establish an educational curriculum to train residents in spinal dura mater closure with a novel durotomy repair model. METHODS: The Congress of Neurological Surgeons has developed a simulation-based model for durotomy closure with the ongoing efforts of their simulation educational committee. The core curriculum consists of didactic training materials and a technical simulation model of dural repair for the lumbar spine. RESULTS: Didactic pretest scores ranged from 4/11 (36%) to 10/11 (91%). Posttest scores ranged from 8/11 (73%) to 11/11 (100%). Overall, didactic improvements were demonstrated by all participants, with a mean improvement between pre- and posttest scores of 1.17 (18.5%; P = .02). The technical component consisted of 11 durotomy closures by 6 participants, where 4 participants performed multiple durotomies. Mean time to closure of the durotomy ranged from 490 to 546 seconds in the first and second closures, respectively (P = .66), whereby the median leak rate improved from 14 to 7 (P = .34). There were also demonstrative technical improvements by all. CONCLUSION: Simulated spinal dura mater repair appears to be a potentially valuable tool in the education of neurosurgery residents. The combination of a didactic and technical assessment appears to be synergistic in terms of educational development. PMID- 24051874 TI - Sensory and motor skill testing in neurosurgery applicants: a pilot study using a virtual reality haptic neurosurgical simulator. AB - BACKGROUND: Manual skill is important for surgeons, but current methods to evaluate sensory-motor skills in applicants to a surgical residency are limited. OBJECTIVE: To develop a method of testing sensory-motor skill using objective and reproducible virtual reality simulation. METHODS: We designed a set of tests on a 3-dimensional surgical simulator with head and arm tracking, colocalization, and haptic feedback: (1) "trajectory planning in a simulated vertebra," ie, 3 dimensional memory and orientation; "hemostasis in the brain," ie, motor planning, sequence, timing, and precision; and "choose the softest object," ie, haptic perception. We also derived a weighted combined score for all tasks. RESULTS: Of the 55 consecutive applicants to a neurosurgery residency approached, 46 performed at least 1 task, and 36 performed all tasks. For the trajectory planning task, the distance from target ranged from 3 to 30 mm, with 25 of 36 in the 6- to 18-mm range. In the motor planning test, the duration between cauterization attempts ranged between 5 and 22.5 seconds, peaking at 10 to 12.5 seconds in 15 of 36 participants. In the haptic perception test, linear regression demonstrated increased variability in performance with increasing difficulty of task (R = 0.6281). In all tests, performance followed a roughly bell-shaped curve. The combined weighted score of all tests demonstrated a better bell curve distribution, with scores ranging from 0.275 to 0.71 (mean, 0.47; median, 0.4775; SD, 0.1174). CONCLUSION: Our study represents a first step in the direction of an objective, standard, computer-scored test of motor and haptic ability. PMID- 24051875 TI - Surgical rehearsal platform: potential uses in microsurgery. AB - Surgical training has remained remarkably similar in many respects since the early days of halstedian training. Neurosurgery is a demanding field that requires extensive cognitive, perceptive, and technical training. Surgical simulation is a promising approach to facilitate acquiring proficiency in neurosurgical procedures. Simulation can permit mentoring trainees in a "safe" environment. By incorporating images that depict specific abnormalities in actual patients, simulation can provide realistic rehearsal for any given case for both novice and experienced surgeons in much the same way that data acquired from drones can be used to allow pilots to rehearse mission-critical maneuvers in a simulator before taking flight. Most neurosurgical simulators to date have focused on endovascular procedures, spinal procedures, temporal bone dissection, and stereotactic procedures. The use of simulator technology for microsurgery is in its infancy. This article describes a novel simulator technology developed by Surgical Theater LLC (http://www.surgicaltheater.net/home.html) called the Selman Surgical Rehearsal Platform. The platform shows promise for use in intracranial microvascular procedures, which require experience that is becoming increasingly limited for trainees who have to become proficient in more procedures in much less time than ever before. PMID- 24051876 TI - Evolving virtual reality simulation in neurosurgery. AB - BACKGROUND: Virtual reality (VR) applications promise the safe, efficacious, and valid replication of scenarios encountered in modern neurosurgery, and a number of navigation- or dissection-related and endovascular simulators have been successfully deployed in the last 2 decades. Concurrently, neurosurgical training is changing, and VR simulations are expected to play a part in future training. OBJECTIVE: To give an overview of currently available neurosurgical VR applications in the spectrum of desired applications and the outlook of the requirements to be met by future applications. METHODS: The available literature was analyzed using structured Medline and PubMed searches. Relevant articles were retrieved and reviewed. When quantitative results were available, effect sizes were collated or estimated to check for publication bias. RESULTS: There has been a significant increase in publications concerning the use of VR in neurosurgery in the last 22 years (P < .001). Thirty-eight of 117 publications (32%) identified reported data regarding the use of a simulator by practitioners; 35 of these were reported as positive trials (92%). Twenty-two of 38 studies (58%) reported quantitative data with mostly small positive effect sizes (median, 1.41; interquartile range, 1.08-2). The use of VR simulators in endovascular surgery has the most robust basis, with 65% of studies reporting quantitative outcomes. CONCLUSION: Current neurosurgical VR applications focus on basic procedural skill acquisition and are valid and efficacious adjuncts to neurosurgical training. In the future, the development of complex procedural simulators, teamwork, and focus on validated measures will lead to robust framework of the use of VR over the entire career of a neurosurgeon. PMID- 24051877 TI - Mixed-reality simulation for neurosurgical procedures. AB - BACKGROUND: Surgical education is moving rapidly to the use of simulation for technical training of residents and maintenance or upgrading of surgical skills in clinical practice. To optimize the learning exercise, it is essential that both visual and haptic cues are presented to best present a real-world experience. Many systems attempt to achieve this goal through a total virtual interface. OBJECTIVE: To demonstrate that the most critical aspect in optimizing a simulation experience is to provide the visual and haptic cues, allowing the training to fully mimic the real-world environment. METHODS: Our approach has been to create a mixed-reality system consisting of a physical and a virtual component. A physical model of the head or spine is created with a 3-dimensional printer using deidentified patient data. The model is linked to a virtual radiographic system or an image guidance platform. A variety of surgical challenges can be presented in which the trainee must use the same anatomic and radiographic references required during actual surgical procedures. RESULTS: Using the aforementioned techniques, we have created simulators for ventriculostomy, percutaneous stereotactic lesion procedure for trigeminal neuralgia, and spinal instrumentation. The design and implementation of these platforms are presented. CONCLUSION: The system has provided the residents an opportunity to understand and appreciate the complex 3-dimensional anatomy of the 3 neurosurgical procedures simulated. The systems have also provided an opportunity to break procedures down into critical segments, allowing the user to concentrate on specific areas of deficiency. PMID- 24051878 TI - Model-based simulation for early neurosurgical learners. AB - BACKGROUND: Restrictions on duty hours and shift length by the Accreditation Council for Graduate Medical Education and public pressure to reduce complications and to improve outcomes in the clinical educational environment have enhanced interest in the use of procedural and surgical simulation to train neurosurgical residents. OBJECTIVE: To introduce simple, available, and, when possible, inexpensive model-based simulation for early learners into the initial stages of neurosurgical residency training. METHODS: Simulation for early-stage trainees in neurological surgery has taken advantage of model-based systems. The Society of Neurological Surgeons postgraduate year 1 courses have served as one paradigm for designing and using model-based simulators for procedural and surgical skill training as part of a purpose-designed overall curriculum. Ongoing surveys of resident and faculty course participants have supported iterative improvements in simulator models and curriculum from year to year. RESULTS: Simulation for basic neurosurgical and intensive care procedures has been undertaken through the use of available materials, surgical technology, and modifications of related existing model simulators. Simulation of common, standard surgical procedures for early learners may be broken into individual surgical skills and maneuvers to prepare trainees for safe practice of these component skills during live procedures under direct supervision appropriate to their training stage. CONCLUSION: Model-based simulation is particularly effective for early surgical learners as part of a coordinated curriculum. Almost 600 residents have used model-based simulation during the first 3 years of the Society of Neurological Surgeons boot camp courses, with ongoing modification and improvement of individual simulation models. PMID- 24051879 TI - Developing a neurosurgical simulation-based educational curriculum: an overview. AB - BACKGROUND: The science of medicine has undergone rapid advancement and expansion as a result of significant technological innovations, and this has affected the training of neurosurgical residents. OBJECTIVE: To develop a simulation-based neurosurgical educational curriculum to improve resident education. METHODS: The Congress of Neurological Surgeons established a Simulation Committee to explore the use of this technology in maximizing neurosurgical education. Simulators were incorporated into an educational curriculum with both a didactic and a technical component. The simulators and didactic portions were validated with objective pretests and posttests. RESULTS: The Simulator Committee has continued to expand the use of simulators in neurosurgical education and has organized several practical courses. The simulator use continues to expand into vasculature, spinal, and cranial modules. Each module has independently shown improved training scores in both didactic and technical skills. CONCLUSION: The Congress of Neurological Surgeons has successfully incorporated simulation into an educational curriculum with both didactic and technical components. This appears to be a powerful educational tool, and its uses are being further expanded. PMID- 24051880 TI - Surgical expertise in neurosurgery: integrating theory into practice. AB - : The development of technical skills is a major goal of any neurosurgical training program. Residency programs in North America are focused on achieving an adequate level of training to produce technically competent surgeons. The training requirements and educational environments needed to produce expert surgeons are incompletely understood. This review explores the theoretical implications of training technical skills to expertise rather than competency in a complex field such as neurosurgery. First, the terms technical expertise and technical competency are defined. Definitions of these qualities are lacking in all surgical specialties. Second, the assessment of technical skills of neurosurgeons are investigated using an expert performance approach. This approach entails the design of tasks that can capture the level of expertise in a reproducible manner. One method to accomplish this involves the use of novel simulators with validated performance metrics. Third, the training of technical skills using simulation is studied in the optic of developing training curricula that would target the development of expertise rather than simple competency. Such curricula should include objective assessments of technical skills, appropriate feedback, and a distributed schedule of deliberate practice. Implementing a focus on the development of expertise rather than simple competency in surgical performance will lead to innovative developments in the field of neurosurgical education. Novel technologies, such as simulation, will play important roles in the training of future expert surgeons, and focused technical skills curricula with a sound theoretical basis should guide the development of all such programs. PMID- 24051881 TI - Neurosurgery simulation in residency training: feasibility, cost, and educational benefit. AB - BACKGROUND: The effort required to introduce simulation in neurosurgery academic programs and the benefits perceived by residents have not been systematically assessed. OBJECTIVE: To create a neurosurgery simulation curriculum encompassing basic and advanced skills, cadaveric dissection, cranial and spine surgery simulation, and endovascular and computerized haptic training. METHODS: A curriculum with 68 core exercises per academic year was distributed in individualized sets of 30 simulations to 6 neurosurgery residents. The total number of procedures completed during the academic year was set to 180. The curriculum includes 79 simulations with physical models, 57 cadaver dissections, and 44 haptic/computerized sessions. Likert-type evaluations regarding self perceived performance were completed after each exercise. Subject identification was blinded to junior (postgraduate years 1-3) or senior resident (postgraduate years 4-6). Wilcoxon rank testing was used to detect differences within and between groups. RESULTS: One hundred eighty procedures and surveys were analyzed. Junior residents reported proficiency improvements in 82% of simulations performed (P < .001). Senior residents reported improvement in 42.5% of simulations (P < .001). Cadaver simulations accrued the highest reported benefit (71.5%; P < .001), followed by physical simulators (63.8%; P < .001) and haptic/computerized (59.1; P < .001). Initial cost is $341,978.00, with $27,876.36 for annual operational expenses. CONCLUSION: The systematic implementation of a simulation curriculum in a neurosurgery training program is feasible, is favorably regarded, and has a positive impact on trainees of all levels, particularly in junior years. All simulation forms, cadaver, physical, and haptic/computerized, have a role in different stages of learning and should be considered in the development of an educational simulation program. PMID- 24051882 TI - Experience with a simulator-based angiography course for neurosurgical residents: beyond a pilot program. AB - BACKGROUND: Simulation is an increasingly useful means of teaching in the era of duty hour restrictions. Since the completion of our diagnostic cerebral angiography simulator curriculum pilot program, we have performed this resident course at 2 Congress of Neurological Surgeons (CNS) annual meetings with larger participant numbers. OBJECTIVE: To report the ongoing results of these courses. METHODS: A 120-minute simulator-based training course was performed at 2 CNS annual meetings. Precourse written and simulator skills assessments were performed, followed by instructor-guided training on an endovascular simulator. Postcourse written and simulator practical assessments were then performed and compared with precourse scores. RESULTS: Thirty-seven neurosurgery resident participants completed the course module: 16 completed the first course provided and 21 completed the second. Posttest written scores were significantly higher than pretest scores (mean +/- SEM, 8.5 +/- 0.40.3 vs 4.9 +/- 0.3; P < .001). Instructor assessments of practical posttest scores of participants were significantly higher than pretest practical scores for both the CNS 2011 and CNS 2012 groups (P < .001). CONCLUSION: The expansion of a curriculum-based, cerebral angiography simulator pilot program to trainees through courses at national neurosurgical meetings demonstrated excellent results with significant improvements in written test scores and instructor assessments of participant technical skills. With ever-expanding improvements in simulation technology and realism, simulator training for cerebral angiography may become an integral component of resident training in the future. PMID- 24051883 TI - A didactic and hands-on module enhances resident microsurgical knowledge and technical skill. AB - BACKGROUND: Simulation has been adopted as a powerful training tool in many areas of health care. However, it has not yet been systematically embraced in neurosurgery because of the absence of validated tools, assessment scales, and curricula. OBJECTIVE: To use our validated microanastomosis module and scale to evaluate the effects of an educational intervention on the performance of neurosurgery residents at the 2012 Congress of Neurological Surgeons Annual Meeting. METHODS: The module consisted of an end-to-end microanastomosis of a 3 mm vessel and was divided into 3 phases: (1) a cognitive and microsuture prelecture testing phase, (2) a didactic lecture, and (3) a cognitive and microsuture postlecture testing phase. We compared resident knowledge and technical proficiency from the pretesting and posttesting phases. RESULTS: One neurosurgeon and 7 neurosurgery residents participated in the study. None had previous experience in microsurgery. The average score on the microsuture prelecture and postlecture tests, as measured by our assessment scale, was 32.50 and 39.75, respectively (P = .001). The number of completed sutures at the end of each procedure was higher for 75% of participants in the postlecture testing phase (P = .03). The average score on the cognitive postlecture test (12.75) was significantly better than that of the cognitive prelecture test (8.38; P = .001). CONCLUSION: Simulation has the potential to enhance resident education and to elevate proficiency levels. Our data suggest that a focused microsurgical module that incorporates a didactic component and a technical component can enhance resident knowledge and technical proficiency in microsurgical anastomosis. PMID- 24051884 TI - A novel craniotomy simulator provides a validated method to enhance education in the management of traumatic brain injury. AB - BACKGROUND: In a variety of surgical specialties, simulation-based technologies play an important role in resident training. The Congress of Neurological Surgeons (CNS) established an initiative to enhance neurosurgical training by developing a simulation-based curriculum to complement standard didactic and clinical learning. OBJECTIVE: To enhance resident education in the management of traumatic brain injury by the use of simulation-based training. METHODS: A course based neurosurgical simulation curriculum was developed and offered at the 2012 CNS annual meeting. Within this curriculum, a trauma module was developed to teach skills necessary in the management of traumatic brain injury, including the performance of craniotomy for trauma. Didactic and simulator-based instruction were incorporated into the course. Written and practical pre- and posttests, as well as questionnaires, were used to assess the improvement in skill level and to validate the simulator as a teaching tool. RESULTS: Fourteen trainees participated in the didactic section of the trauma module. Average performance improved significantly in written scores from pretest (75%) to posttest (87.5%, P < .05). Eight participants completed the trauma craniotomy simulator. Incision planning, burr hole placement (P < .02), and craniotomy size (P < .05) improved significantly. Junior residents (postgraduate years 1-3) demonstrated the most improvement during the course. CONCLUSION: The CNS simulation trauma module provides a complementary method for residents to acquire necessary skills in the management of traumatic brain injury. Preliminary data indicate improvement in didactic and hands-on knowledge after training. Additional data are needed to confirm the validity of the simulator. PMID- 24051885 TI - Commentary: Simulation training in neurological surgery. PMID- 24051886 TI - Virtual reality-based simulation training for ventriculostomy: an evidence-based approach. AB - BACKGROUND: Virtual reality (VR) simulation-based technologies play an important role in neurosurgical resident training. The Congress of Neurological Surgeons (CNS) Simulation Committee developed a simulation-based curriculum incorporating VR simulators to train residents in the management of common neurosurgical disorders. OBJECTIVE: To enhance neurosurgical resident training for ventriculostomy placement using simulation-based training. METHODS: A course based neurosurgical simulation curriculum was introduced at the Neurosurgical Simulation Symposium at the 2011 and 2012 CNS annual meetings. A trauma module was developed to teach ventriculostomy placement as one of the neurosurgical procedures commonly performed in the management of traumatic brain injury. The course offered both didactic and simulator-based instruction, incorporating written and practical pretests and posttests and questionnaires to assess improvement in skill level and to validate the simulators as teaching tools. RESULTS: Fourteen trainees participated in the didactic component of the trauma module. Written scores improved significantly from pretest (75%) to posttest (87.5%; P < .05). Seven participants completed the ventriculostomy simulation. Significant improvements were observed in anatomy (P < .04), burr hole placement (P < .03), final location of the catheter (P = .05), and procedure completion time (P < .004). Senior residents planned a significantly better trajectory (P < .01); junior participants improved most in terms of identifying the relevant anatomy (P < .03) and the time required to complete the procedure (P < .04). CONCLUSION: VR ventriculostomy placement as part of the CNS simulation trauma module complements standard training techniques for residents in the management of neurosurgical trauma. Improvement in didactic and hands-on knowledge by course participants demonstrates the usefulness of the VR simulator as a training tool. PMID- 24051887 TI - Translating the simulation of procedural drilling techniques for interactive neurosurgical training. AB - BACKGROUND: Through previous efforts we have developed a fully virtual environment to provide procedural training of otologic surgical technique. The virtual environment is based on high-resolution volumetric data of the regional anatomy. These volumetric data help drive an interactive multisensory, ie, visual (stereo), aural (stereo), and tactile, simulation environment. Subsequently, we have extended our efforts to support the training of neurosurgical procedural technique as part of the Congress of Neurological Surgeons simulation initiative. OBJECTIVE: To deliberately study the integration of simulation technologies into the neurosurgical curriculum and to determine their efficacy in teaching minimally invasive cranial and skull base approaches. METHODS: We discuss issues of biofidelity and our methods to provide objective, quantitative and automated assessment for the residents. RESULTS: We conclude with a discussion of our experiences by reporting preliminary formative pilot studies and proposed approaches to take the simulation to the next level through additional validation studies. CONCLUSION: We have presented our efforts to translate an otologic simulation environment for use in the neurosurgical curriculum. We have demonstrated the initial proof of principles and define the steps to integrate and validate the system as an adjuvant to the neurosurgical curriculum. PMID- 24051888 TI - Simulation-based neurosurgical training for the presigmoid approach with a physical model. AB - BACKGROUND: In recent years, there has been growing interest in the use of simulation to supplement conventional surgical training. Simulation remains, however, in its infancy in neurosurgery. OBJECTIVE: To report on and assess the utility of a simulation physical model for the presigmoid approach. METHODS: The Congress of Neurological Surgeons created a Simulation Committee to explore and develop simulation-based models. The current model involves drilling of the presigmoid cranial base under image guidance. Each time the drill touches the dura, facial nerve, or sigmoid sinus, a beeping and a warning sound are emitted. RESULTS: Nine neurosurgery residents participated in and completed the presigmoid approach simulation module. All residents successfully completed the simulation procedure within the allocated time period (20 minutes). The mean number of hits to the dura, facial nerve, and sigmoid sinus decreased from 4.2 in the first test to 3.1 in the second test (P < .05). The facial nerve was the most likely structure to be injured, followed by the sigmoid sinus and finally the dura. All 9 participants had an improvement in their technical scores. CONCLUSION: The presigmoid approach simulation model is a useful tool in resident education that may improve surgical proficiency while minimizing risk to patients. More studies with standardized end points for technical proficiency and clinical outcomes are needed. PMID- 24051889 TI - The development of a virtual simulator for training neurosurgeons to perform and perfect endoscopic endonasal transsphenoidal surgery. AB - BACKGROUND: A virtual reality (VR) neurosurgical simulator with haptic feedback may provide the best model for training and perfecting surgical techniques for transsphenoidal approaches to the sella turcica and cranial base. Currently there are 2 commercially available simulators: NeuroTouch (Cranio and Endo) developed by the National Research Council of Canada in collaboration with surgeons at teaching hospitals in Canada, and the Immersive Touch. Work in progress on other simulators at additional institutions is currently unpublished. OBJECTIVE: This article describes a newly developed application of the NeuroTouch simulator that facilitates the performance and assessment of technical skills for endoscopic endonasal transsphenoidal surgical procedures as well as plans for collecting metrics during its early use. METHODS: The main components of the NeuroTouch-Endo VR neurosurgical simulator are a stereovision system, bimanual haptic tool manipulators, and high-end computers. The software engine continues to evolve, allowing additional surgical tasks to be performed in the VR environment. Device utility for efficient practice and performance metrics continue to be developed by its originators in collaboration with neurosurgeons at several teaching hospitals in the United States. Training tasks are being developed for teaching 1 and 2-nostril endonasal transsphenoidal approaches. Practice sessions benefit from anatomic labeling of normal structures along the surgical approach and inclusion (for avoidance) of critical structures, such as the internal carotid arteries and optic nerves. CONCLUSION: The simulation software for NeuroTouch Endo VR simulation of transsphenoidal surgery provides an opportunity for beta testing, validation, and evaluation of performance metrics for use in neurosurgical residency training. ABBREVIATIONS: CTA, cognitive task analysisVR, virtual reality. PMID- 24051890 TI - History of simulation in medicine: from Resusci Annie to the Ann Myers Medical Center. AB - Medical and surgical graduate medical education has historically used a halstedian approach of "see one, do one, teach one." Increased public demand for safety, quality, and accountability in the setting of regulated resident work hours and limited resources is driving the development of innovative educational tools. The use of simulation in nonmedical, medical, and neurosurgical disciplines is reviewed in this article. Simulation has been validated as an educational tool in nonmedical fields such as aviation and the military. Across most medical and surgical subspecialties, simulation is recognized as a valuable tool that will shape the next era of medical education, postgraduate training, and maintenance of certification. PMID- 24051891 TI - Neurosurgical training with a novel cervical spine simulator: posterior foraminotomy and laminectomy. AB - BACKGROUND: Neurosurgical residents have traditionally been instructed on surgical techniques and procedures through an apprenticeship model. Currently, there has been research and interest in expanding the neurosurgical education model. OBJECTIVE: To establish a posterior cervical decompression educational curriculum with a novel cervical simulation model. METHODS: The Congress of Neurological Surgeons developed a simulation committee to explore and develop simulation-based models. The educational curriculum was developed to have didactic and technical components with the incorporation of simulation models. Through numerous reiterations, a posterior cervical decompression model was developed and a 2-hour education curriculum was established. RESULTS: Individual's level of training varied, with 5 postgraduate year (PGY) 2 participants, 1 PGY-3 participant, 2 PGY-5 participants, and 1 attending, with the majority being international participants (6 of 9, 67%). Didactic scores overall improved (7 of 9, 78%). The technical scores of all participants improved from 11 to 24 (mean, 14.1) to 19 to 25 (mean, 22.4). Overall, in the posterior cervical decompression simulator, there was a significant improvement in the didactic scores (P = .005) and the technical scores (P = .02). CONCLUSION: The posterior cervical decompression simulation model appears to be a valuable tool in educating neurosurgery residents in the aspects of this procedure. The combination of a didactic and technical assessment is a useful teaching strategy in terms of educational development. PMID- 24051892 TI - Acute fatal effects of short-lasting extreme temperatures in Stockholm, Sweden: evidence across a century of change. AB - BACKGROUND: Climate change is projected to increase the frequency of extreme weather events. Short-term effects of extreme hot and cold weather and their effects on mortality have been thoroughly documented, as have epidemiologic and demographic changes throughout the 20th century. We investigated whether sensitivity to episodes of extreme heat and cold has changed in Stockholm, Sweden, from the beginning of the 20th century until the present. METHODS: We collected daily mortality and temperature data for the period 1901-2009 for present-day Stockholm County, Sweden. Heat extremes were defined as days for which the 2-day moving average of mean temperature was above the 98th percentile; cold extremes were defined as days for which the 26-day moving average was below the 2nd percentile. The relationship between extreme hot/cold temperatures and all-cause mortality, stratified by decade, sex, and age, was investigated through time series modeling, adjusting for time trends. RESULTS: Total daily mortality was higher during heat extremes in all decades, with a declining trend over time in the relative risk associated with heat extremes, leveling off during the last three decades. The relative risk of mortality was higher during cold extremes for the entire period, with a more dispersed pattern across decades. Unlike for heat extremes, there was no decline in the mortality with cold extremes over time. CONCLUSIONS: Although the relative risk of mortality during extreme temperature events appears to have fallen, such events still pose a threat to public health. PMID- 24051894 TI - Short-term impact of atmospheric pollution on fecundability. AB - BACKGROUND: Epidemiologic studies have reported associations between air pollution levels and semen characteristics, which might in turn affect a couple's ability to achieve a live birth. Our aim was to characterize short-term effects of atmospheric pollutants on fecundability (the month-specific probability of pregnancy among noncontracepting couples). METHODS: For a cohort of births between 1994 and 1999 in Teplice (Czech Republic), we averaged fine particulate matter (PM2.5), carcinogenic polycyclic aromatic hydrocarbons, ozone, nitrogen dioxide (NO2), and sulfur dioxide levels estimated from a central measurement site over the 60-day period before the end of the first month of unprotected intercourse. We estimated changes in the probability of occurrence of a pregnancy during the first month of unprotected intercourse associated with exposure, using binomial regression and adjusting for maternal behaviors and time trends. RESULTS: Among the 1,916 recruited couples, 486 (25%) conceived during the first month of unprotected intercourse. Each increase of 10 ug/m in PM2.5 levels was associated with an adjusted decrease in fecundability of 22% (95% confidence interval = 6%-35%). NO2 levels were also associated with decreased fecundability. There was no evidence of adverse effects with the other pollutants considered. Biases related to pregnancy planning or temporal trends in air pollution were unlikely to explain the observed associations. CONCLUSIONS: In this polluted area, we highlighted short-term decreases in a couple's ability to conceive in association with PM2.5 and NO2 levels assessed in a central monitoring station. PMID- 24051893 TI - Lipid adjustment for chemical exposures: accounting for concomitant variables. AB - BACKGROUND: Some environmental chemical exposures are lipophilic and need to be adjusted by serum lipid levels before data analyses. There are currently various strategies that attempt to account for this problem, but all have their drawbacks. To address such concerns, we propose a new method that uses Box-Cox transformations and a simple Bayesian hierarchical model to adjust for lipophilic chemical exposures. METHODS: We compared our Box-Cox method to existing methods. We ran simulation studies in which increasing levels of lipid-adjusted chemical exposure did and did not increase the odds of having a disease, and we looked at both single-exposure and multiple-exposure cases. We also analyzed an epidemiology dataset that examined the effects of various chemical exposure on the risk of birth defects. RESULTS: Compared with existing methods, our Box-Cox method produced unbiased estimates, good coverage, similar power, and lower type I error rates. This was the case in both single- and multiple-exposure simulation studies. Results from analysis of the birth-defect data differed from results using existing methods. CONCLUSION: Our Box-Cox method is a novel and intuitive way to account for the lipophilic nature of certain chemical exposures. It addresses some of the problems with existing methods, is easily extendable to multiple exposures, and can be used in any analysis that involves concomitant variables. PMID- 24051895 TI - Pharmacokinetics of daily daptomycin in critically ill patients undergoing continuous renal replacement therapy. AB - BACKGROUND: The optimal daptomycin dosing regimen for critically ill patients undergoing continuous renal replacement therapy (CRRT) has still to be established. METHODS: Daptomycin pharmacokinetics was determined in 9 patients after administration of 6 mg/kg/day over 5 days. RESULTS: At steady state, which was reached by day 3, the area under the curve over 24 h (AUC24h) was 667.4 +/- 356.6 mg.h/l, and the maximum concentration (Cmax) was 66.9 +/-25.3 mg/l. Mean CRRT clearance accounted for 48% (range 32-67%) of total clearance (mean 10.2 ml/min, range 6.1-18 ml/min). Significant correlations were observed between Cmax, minimum concentration (Cmin) and AUC24h (R(2) = 0.91, p < 0.001, and R(2) = 0.94, p < 0.001) and between albumin plasma concentration and free daptomycin (R(2) = 0.7, p = 0.009). CONCLUSION: No significant accumulation occurred with a daily daptomycin dose of 6 mg/kg in patients undergoing CRRT with an effluent flow rate of >30 ml/kg/h. The quantification of trough concentrations (Cmin) appears to be a good surrogate to estimate AUC24h and to monitor daptomycin treatment in patients undergoing CRRT. PMID- 24051896 TI - Effects of prenatal stress on fetal neurodevelopment and responses to maternal neurosteroid treatment in Guinea pigs. AB - BACKGROUND: Maternal psychosocial stress during pregnancy is associated with adverse neonatal outcomes. These outcomes result from changes in fetal brain development and lead to disrupted cognitive, behavioural and emotional development. The neurosteroid allopregnanolone has been shown to reduce neural excitability and aid in protecting the fetal brain from excitotoxic insults. The objectives of this study were to assess the effect of prenatal maternal stress on fetal brain development with and without maternal allopregnanolone treatment. METHODS: Pregnant guinea pigs were subjected to stress induced by exposure to a strobe light at 50, 55, 60 and 65 days gestation. Salivary cortisol levels were measured before and after each exposure. Fetal brains were assessed for markers of brain development using immunohistochemistry and plasma allopregnanolone was measured by radioimmunoassay. RESULTS: Female, but not male prenatal stress exposed fetuses demonstrated higher brain-to-liver ratios (BLR). Male fetuses showed significantly reduced expression of myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and both males and females showed reduced expression of microtubule-associated protein 2 (MAP2). These markers were not affected by maternal allopregnanolone treatment. However, maternal allopregnanolone treatment resulted in an increase in fetal plasma allopregnanolone concentrations in control pregnancies but concentrations were not raised after prenatal stress exposure. CONCLUSIONS: These findings indicate that the effects of prenatal stress on fetal brain development are sexually dimorphic with more pronounced negative effects seen on male neurodevelopment. Allopregnanolone treatment was not effective in raising fetal plasma concentrations after prenatal stress suggesting a stress-induced dysregulation of neurosteroid pathways during gestation. Interestingly, this study directly implicates prenatal stress in the disruption of fetal neurosteroid levels, such that it may mediate some of the deleterious effects on fetal neurodevelopment by facilitating a deficit in normal endogenous neuroprotective mechanisms. PMID- 24051897 TI - Adoption of evidence-based clinical innovations: the case of buprenorphine use by opioid treatment programs. AB - This article examines changes from 2005 to 2011 in the use of an evidence-based clinical innovation, buprenorphine use, among a nationally representative sample of opioid treatment programs and identifies characteristics associated with its adoption. We apply a model of the adoption of clinical innovations that focuses on the work needs and characteristics of staff; organizations' technical and social support for the innovation; local market dynamics and competition; and state policies governing the innovation. Results indicate that buprenorphine use increased 24% for detoxification and 47% for maintenance therapy between 2005 and 2011. Buprenorphine use was positively related to reliance on private insurance and availability of state subsidies to cover its cost and inversely related to the percentage of clients who injected opiates, county size, and local availability of methadone. The results indicate that financial incentives and market factors play important roles in opioid treatment programs' decisions to adopt evidence-based clinical innovations such as buprenorphine use. PMID- 24051898 TI - Strong accumulation of chloroplast DNA in the Y chromosomes of Rumex acetosa and Silene latifolia. AB - Chloroplast DNA (cpDNA) sequences are often found in plant nuclear genomes, but patterns of their chromosomal distribution are not fully understood. The distribution of cpDNA on the sex chromosomes can only be studied in dioecious plant species possessing heteromorphic sex chromosomes. We reconstructed the whole chloroplast genome of Rumex acetosa (sorrel, XY1Y2 system) from next generation sequencing data. We systematically mapped the chromosomal localization of various regions of cpDNA in R. acetosa and in Silene latifolia (white campion, XY system) using fluorescence in situ hybridization. We found that cpDNA was accumulated on the Y chromosomes of both studied species. In R. acetosa, the entire Y chromosome gathered all parts of cpDNA equally. On the contrary, in S. latifolia, the majority of the cpDNA, corresponding to the single copy regions, was localized in the centromere of the Y chromosome, while the inverted repeat region was present also in other loci. We found a stronger accumulation of cpDNA on the more degenerated Y1 and Y2 chromosomes of R. acetosa than in evolutionary younger S. latifolia Y chromosome. Our data stressed the prominent role of the Y chromosome centromere in cpDNA accumulation. PMID- 24051902 TI - In situ growth of NiCo(2)S(4) nanosheets on graphene for high-performance supercapacitors. AB - We demonstrate a facile hydrothermal method for growth of ultrathin NiCo2S4 nanosheets on reduced graphene oxide (RGO), which exhibit remarkable electrochemical performance with higher capacitance and longer cycle life than the bare NiCo2S4 hollow spheres (HSs). PMID- 24051900 TI - Cumulative adversity sensitizes neural response to acute stress: association with health symptoms. AB - Cumulative adversity (CA) increases stress sensitivity and risk of adverse health outcomes. However, neural mechanisms underlying these associations in humans remain unclear. To understand neural responses underlying the link between CA and adverse health symptoms, the current study assessed brain activity during stress and neutral-relaxing states in 75 demographically matched, healthy individuals with high, mid, and low CA (25 in each group), and their health symptoms using the Cornell Medical Index. CA was significantly associated with greater adverse health symptoms (P=0.01) in all participants. Functional magnetic resonance imaging results indicated significant associations between CA scores and increased stress-induced activity in the lateral prefrontal cortex, insula, striatum, right amygdala, hippocampus, and temporal regions in all 75 participants (p<0.05, whole-brain corrected). In addition to these regions, the high vs low CA group comparison revealed decreased stress-induced activity in the medial orbitofrontal cortex (OFC) in the high CA group (p<0.01, whole-brain corrected). Specifically, hypoactive medial OFC and hyperactive right hippocampus responses to stress were each significantly associated with greater adverse health symptoms (p<0.01). Furthermore, an inverse correlation was found between activity in the medial OFC and right hippocampus (p=0.01). These results indicate that high CA sensitizes limbic-striatal responses to acute stress and also identifies an important role for stress-related medial OFC and hippocampus responses in the effects of CA on increasing vulnerability to adverse health consequences. PMID- 24051899 TI - Contribution of a mesocorticolimbic subcircuit to drug context-induced reinstatement of cocaine-seeking behavior in rats. AB - Cocaine-seeking behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)-basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of cocaine-seeking behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose dependently attenuated cocaine-seeking behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced cocaine-seeking behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra- and interhemispheric projections to the OFC, which in turn has reciprocal bi hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC-BLA functional interactions. Thus, a VTA-OFC-BLA neural circuit promotes drug context-induced motivated behavior. PMID- 24051903 TI - Patients' perception of surgical outcomes and quality of life after retroperitoneoscopic and open pyeloplasty. AB - PURPOSE: To report postoperative health-related quality of life (HRQoL) and patients' subjective evaluations of open pyeloplasty (OP) and retroperitoneoscopic pyeloplasty (RP) and influences on preoperative counselling. METHODS: 107 patients (age 16-80 years, mean 31.5) with symptomatic primary ureteropelvic junction obstruction who underwent OP (32) or RP (75) were evaluated prospectively. HRQoL was evaluated using Short Form 36 (SF-36) questionnaires with 1 year follow-up. Operative outcomes were evaluated using a self-designed questionnaire regarding cosmetic outcomes, objective postoperative/current pain, convalescence and return to work. RESULTS: The mean operative time was 174.4 vs. 161.4 min for RP versus OP, respectively, without intraoperative complications/conversions. There was an advantage for RP--except for two domains--without significance in any of the eight SF-36 domain scores. An advantage favouring RP in all aspects of the second questionnaire with significance in four aspects (cosmetic results, scar length, pain and convalescence) was found. Five weeks postoperatively, 58.7% (RP) vs. 25.8% (OP) were fully convalescent compared to 87.0% (RP) vs. 71.0% (OP) at 8 weeks. Similarly, 58.7 vs. 45.1% returned work 5 weeks postoperatively while 93.5 vs. 74.2% did so after 8 weeks, respectively. The small sample size, more questions on satisfaction/regret and mixed design are the main study limitations. CONCLUSION: RP provides the same functional results beside earlier convalescence, better HRQoL and patients' convenience with surgery, which favours its inclusion in preoperative counselling providing patients with realistic postoperative expectations. PMID- 24051904 TI - Rectal cancer: prognostic indicators of long-term outcome in patients considered for surgery. AB - PURPOSE: Patients and clinicians seek an accurate prognosis after resectional surgery for rectal cancer. The aim of this study was to determine long-term outcomes after potentially curative surgery for rectal cancer with particular focus on factors associated with longer-term survival that are available to surgeons in the early post-operative setting. METHODS: We conducted a retrospective review of a prospectively gathered database of all primary rectal adenocarcinomas considered for surgery in the University Hospitals of Leicester National Health Service (NHS) Trust between 1998 and 2007. Survival was calculated using a Kaplan-Meier method. Factors thought to be associated with survival were subjected to univariate analysis followed by Cox proportion regression. RESULTS: One thousand and twelve patients with primary rectal adenocarcinoma diagnosed between 1998 and 2007 were identified. Eight hundred and fifty three patients did not have metastases at the time of presentation and 726 patients underwent major resectional surgery. Five-year survival was 66 %. Patients' age, Dukes' stage, UICC stage, nodal involvement and circumferential resection margin status were independently associated with long-term survival on multivariate analysis. CONCLUSION: This is one of the largest series of rectal cancers from a single NHS trust. We have demonstrated that age, Dukes' stage and CRM status are associated with long-term survival. These clinical factors are readily available to the surgeon at the time of first post-operative review and can provide a good clinical guide to prognosis. PMID- 24051906 TI - New recommendations of the Brazilian Society of Rheumatology: a new strategy. PMID- 24051905 TI - Acute leukemoid reaction associated with liver surgery for metastatic colorectal cancer. PMID- 24051907 TI - Recommendations for the management and treatment of psoriatic arthritis. PMID- 24051908 TI - Recommendations for the management and treatment of ankylosing spondylitis. PMID- 24051909 TI - Recommendations for the management and treatment of systemic sclerosis. PMID- 24051910 TI - Physical activity level and physical performance in the 6-minute walk test in women with fibromyalgia. AB - INTRODUCTION: Fibromyalgia (FM) is a chronic pain condition that causes impaired functional capacity, possibly through the adoption of sedentary behaviour. However, little is known regarding physical activity level and its relationship with physical performance in women with FM. OBJECTIVES: To compare physical activity level, assessed using the International Physical Activity Questionnaire (IPAQ), and physical performance, measured using the six-minute walk test (6MWT), in women with and without FM, and to examine the possible relationships between physical activity level and physical performance in both groups. METHODS: The study included 30 women diagnosed with FM (patients) and 28 healthy women (controls) who answered the IPAQ and performed the 6MWT. RESULTS: Patients and controls self-reported similar physical activity level, considering both the total score and all IPAC subcomponents (P > 0.05). However, the FM patients had worse physical performance in the 6MWT (patients, 441.8 +/- 84.1 m vs. controls, 523.9 +/- 80.3 m; P < 0.01). There were no relationships between the distance walked in the 6MWT and the IPAQ variables for the control group. However, the distance walked by patients in the test showed a significant correlation (P < 0.05) with the total score and the subcomponents transport, household activities, and physical activities of moderate intensity in the IPAQ. CONCLUSIONS: Women with FM had physical activity levels similar to women without FM but exhibited worse physical performance. This functional impairment may be related to lifestyle adopted because there was a relationship between physical activity level and physical performance in those patients. PMID- 24051911 TI - Ultrasonography for the diagnosis of tendinitis and electromyography for the diagnosis of peripheral neuropathy and upper limb radiculopathy: rheumatologists' perspectives. AB - OBJECTIVE: To ascertain the value ascribed by Brazilian rheumatologists to ultrasonography (US) for diagnosing tendinitis and to electromyography (EMG) for diagnosing peripheral neuropathy and upper limb radiculopathy. MATERIAL AND METHODS: In total, 165 rheumatologists answered an anonymous survey (sent via the internet) concerning the two exams, with respect to the following characteristics: reliability, diagnostic accuracy, the importance and necessity of these tests for diagnostic RESULTS: The study revealed that most of the rheumatologists recognised that these exams are operator-dependent, that clinicians do not rely entirely on the results, that these exams are not mandatory for the diagnoses listed, and that professionals who perform these exams should be better trained to provide reliable results. CONCLUSIONS: The Brazilian rheumatologists believe the following: the results of these exams should be interpreted with caution and are not definitive for diagnosis; musculoskeletal US and EMG should be performed by trained professionals; and there must be better preparation of the professionals who perform these exams. PMID- 24051912 TI - Importance of cutaneous silent period in fibromyalgia and its relationship with disease characteristics, psychological disorders and quality of life of patients. AB - INTRODUCTION: Cutaneous silent period (CSP) is an inhibitory spinal protective reflex and its afferents consist of A-delta nerve fibers. We aimed to evaluate patients with fibromyalgia (FM) and healthy controls to determine any differences between the groups in terms of CSP duration and latency, and if present, to determine whether there is any relationship with disease characteristics, psychological disorders and quality of life. MATERIALS AND METHODS: Thirty-two patients with FM and 32 healthy volunteers were included in the study. The patient and control groups were compared in terms of CSP latency and duration in both upper and lower extremities. Disease characteristics, psychological disorders and quality of life of patients were assessed using the Fibromyalgia Impact Questionnaire (FIQ) and Short Form-36 (SF-36). Patients with CSP measurements equal to or lower than those of the control group were compared with those with higher values than controls in terms of disease characteristics, psychological status and quality of life. RESULTS: Significantly prolonged CSP latencies in both upper and lower extremities were determined in patients compared to controls. We found that prolongation of CSP latency in the lower extremity is associated with disease severity and functional disability. CONCLUSIONS: CSP latencies in both upper and lower extremities in patients with FM are longer than in healthy volunteers. Moreover, prolongation of CSP latency in the lower extremity is associated with disease severity and physical functional disability. PMID- 24051913 TI - Gout in the spine. AB - Axial gout can affect all segments of the spine. It is manifested as back pain, as pain associated with neurological symptoms, and as neurological impairment without pain in 17.9%, 75.8% and 4.2% of cases, respectively. These manifestations were the first presentation of gout in many patients. Although x rays as well as computed tomography and especially magnetic resonance scans can be very suggestive, histopathological, cytological and crystal analyses are the diagnostic gold standard. In most cases involving neurological manifestations, the patient underwent surgery, leading to satisfactory results. There are, however, some reports of full recovery following the usual clinical treatment for gout, suggesting that such treatment may be the initial option for those subjects with a history of gout and radiological findings of axial involvement. PMID- 24051914 TI - Variables related to work productivity loss in patients with ankylosing spondylitis. AB - The work productivity loss due to ankylosing spondylitis (AS) has become subject of interest because of its socioeconomic impact. In addition to physical limitations, other variables seem to affect the productivity of those patients, who often withdraw early from the labor force. This review was aimed at identifying articles published in English, from January 2001 to December 2011, which assessed those variables in adult patients of both sexes diagnosed with AS, using standardized instruments to measure disease activity and work productivity. Thirty-three articles meeting the inclusion criteria were identified. The work productivity loss of patients with AS proved to be influenced by demographics, emotional, social, cultural, and occupational factors, and lifestyle. Understanding those potential risk factors may contribute to the development of preventive strategies to maintain patients with AS participating in the labor force. PMID- 24051916 TI - Mucha-Habermann disease. AB - A case of Mucha-Habermann disease (MHD), possibly associated with macrophage activation syndrome (MAS), is reported. The purpose of this paper was to describe the rare MHD (also known as pityriasis lichenoides et varioliformis acuta - PLEVA) in a 28-year-old male, who presented with generalized ulceronecrotic lesions on the skin and mucosae, gastrointestinal involvement, and heart and liver failure, associated with continuous high fever.The patient might have progressed to MAS and eventually died. The MHD is rare, potentially fatal and has severe systemic complications.The importance of early diagnosis and aggressive treatment is emphasized. PMID- 24051915 TI - Erasmus syndrome: silicosis and systemic sclerosis. AB - The silicosis is the pneumoconiosis more frequent, resulting from the inhalation of silica or silicates containing mineral dust, mainly characterized by irreversible lung fibrosis. It is associated with the development of other diseases, including pulmonary tuberculosis, lung cancer and autoimmune diseases. The connective tissue disease after exposure to silica occurs usually after 15 years of initial exposure.The Erasmus syndrome describes the association of systemic sclerosis following exposure to silica with or without silicosis. The authors report two cases of patients with diagnosis of silicosis who developed systemic sclerosis. PMID- 24051919 TI - Motor conduction findings in Fisher syndrome. AB - OBJECTIVE: To report detailed motor conduction findings on Fisher syndrome (FS). METHODS: We retrospectively reviewed motor conduction findings of 55 patients with pure FS and compared them with those obtained from 83 age- and sex-matched healthy volunteers. RESULTS: In the FS group, distal and F-wave latencies of the median, ulnar, peroneal and tibial nerves were all significantly prolonged; motor conduction velocities were slowed in the median, ulnar and peroneal nerves. Conversely, an abnormally low compound muscle action potential amplitude was found only in the median and tibial nerves. Among the four parameters, distal and F-wave latencies were more frequently encountered abnormalities. None of our patients had abnormal temporal dispersion in any motor nerve. Focal involvement of the ulnar nerve across the elbow segment was observed in 6 patients (11%). Of the 55 FS patients, 31 (56%) had abnormal motor conduction results in at least one nerve. Abnormal motor conduction results were noted in 43 and 61% of patients when the tests were performed in the first week and 1 week after onset of FS, respectively (p=0.238). CONCLUSION: Our results confirmed that mild motor conduction abnormalities were noted in pure FS, with a pattern similar to those observed in Guillain-Barre syndrome. PMID- 24051920 TI - Simultaneous inference and clustering of transcriptional dynamics in gene regulatory networks. AB - We present a novel method for simultaneous inference and nonparametric clustering of transcriptional dynamics from gene expression data. The proposed method uses gene expression data to infer time-varying TF profiles and cluster these temporal profiles according to the dynamics they exhibit. We use the latent structure of factorial hidden Markov model to model the transcription factor profiles as Markov chains and cluster these profiles using nonparametric mixture modeling. An efficient Gibbs sampling scheme is proposed for inference of latent variables and grouping of transcriptional dynamics into a priori unknown number of clusters. We test our model on simulated data and analyse its performance on two expression datasets; S. cerevisiae cell cycle data and E. coli oxygen starvation response data. Our results show the applicability of the method for genome wide analysis of expression data. PMID- 24051922 TI - Meta-analysis of the association between the IL-12B +1188 A/C polymorphism and cancer risk. AB - BACKGROUND: Because of inconsistent results from previous studies on the association of IL-12B +1188 A/C polymorphism with cancer risk, a meta-analysis was performed to assess the association. MATERIALS AND METHODS: A literature search was performed to identify all relevant studies to May 31, 2012, with a restriction to English and Chinese publications. Pooled data were estimated using a random-effects model. RESULTS: 17 publications were included in the meta analysis. The results indicated that the polymorphism was significantly associated with a decreased risk for overall cancer (odds ratio (OR), 95% confidence interval (CI): 0.86, 0.76-0.97, p = 0.007; 0.80, 0.68-0.95, p = 0.012; and 0.88, 0.78-0.99, p = 0.032, respectively for dominant model, recessive model, and allele analysis) or nasopharyngeal cancer and hepatocellular carcinoma. This association was also found in Asians (OR, 95% CI: 0.89, 0.80-0.99, p = 0.031; 0.82, 0.68-0.98, p = 0.027; and 0.89, 0.80-1.00, p = 0.047, respectively for dominant model, recessive model, and allele analysis), but not in Europeans and Americans. CONCLUSION: The present study indicates that the IL-12B +1188 A/C polymorphism could play a protective role in the development of cancer. More investigations involving various cancer types among various populations are needed. PMID- 24051923 TI - Outcome of early breast cancer treated in an urban and a rural breast cancer unit in Germany. AB - BACKGROUND: Conflicting evidence has been published concerning survival disadvantages in the outcome of breast cancer patients in relationship to their residency in urban or rural communities. METHODS: The primary aim of this study was to evaluate differences in patients and treatment characteristics between an urban and a rural breast cancer unit. Therefore, all early breast cancer patients treated consecutively between 1999 and 2007 in a rural and an urban breast cancer unit were included. Patient and tumor characteristics, treatment strategies, and guideline adherence were included to evaluate the prognoses of both populations. RESULTS: Overall, data from 2,566 patients were included in this analysis. The 610 patients treated in the rural unit showed significantly more negative prognostic criteria than the 1,956 patients treated in the urban center. No differences were observed with respect to surgical and systemic treatment after adjustment for prognostic parameters. Adherence to national guidelines did not differ significantly between both settings and ranged between 78.0 and 95.6%. Furthermore, no differences regarding recurrence-free and overall survival were observed. CONCLUSIONS: The stage-adjusted pattern of care was similar in 2 German breast care units in a rural region and an urban area. Nevertheless, an earlier diagnosis of breast cancer should be enforced in rural areas to avoid extended treatment burden. PMID- 24051924 TI - Comparison of computed tomography- and positron emission tomography-based radiotherapy planning in cholangiocarcinoma. AB - INTRODUCTION: The aim of this study was to compare computed tomography (CT)- and positron emission tomography (PET)/CT-based gross tumor volume (GTV) delineation and its subsequent expansion to the planning target volume (PTV), and to analyze the resultant doses of 3-dimensional conformal radiotherapy (3D-CRT) to critical organs. METHODS: 15 patients with unresectable extrahepatic cholangiocarcinoma (EHCC) were enrolled into this study. PTVCT-based plans were initially made, and then PTVPET-CT-based plans were created using the same beam angles and isocenter. The dosimetric parameters analyzed included GTVCT, PTVCT, GTVPET-CT and PTVPET CT. Prescribed and delivered radiation doses to target volumes and delineated organs at risk were also compared. RESULTS: Mean GTV and PTV were significantly reduced in the PET/CT-based plan compared to the CT-based plan; the mean reductions of GTV and PTV were 28.7% and 15.2%, respectively. The mean value for GTVPET/GTVCT mismatch was 49.5 +/- 28.9%, and that for GTVCT/GTVPET was 95.9 +/- 19.5%. The mean value for PTVPET-CT/PTVCT mismatch was 21.9 +/- 7.0% and that for PTVCT/PTVPET-CT was 39.1 +/- 9.2%. Liver doses were significantly reduced (17.1%) in the PET/CT-based plan compared to the CT-based plan; the doses received by at least 30% and 50% of the liver were 30.0%, and 27.3%, respectively. CONCLUSION: The potential benefit of PET/CT is the reduction in geographic misses and regional treatment failures associated with CT-based planning. PMID- 24051925 TI - Prognostic significance of the number of removed lymph nodes at lobectomy in patients with positron emission tomography-computed tomography-negative N2 non small cell lung cancer. AB - BACKGROUND: We assessed the relation between the extent of lymph node (LN) dissection and the prognosis for positron emission tomography-computed tomography (PET-CT)-negative patients with clinical early-stage non-small cell lung cancer (NSCLC), undergoing lobectomy and mediastinal LN dissection. METHODS: 277 patients with clinical stage I/II NSCLC who had undergone a preoperative PET-CT scan followed by lobectomy were analysed retrospectively. The prognostic value of age, maximum standardized uptake value (SUVmax) of the tumour, tumour size, carcinoembryonic antigen and number of dissected LNs was assessed to determine any association with overall survival and disease-free survival. RESULTS: 31 patients developed postoperative relapse, and multiple logistic regression revealed that the number of dissected LNs was an independent factor predicting relapse. Patients were categorized into groups according to the number of LNs dissected (group I, < 10; group II, >= 10). There were no statistical differences between 2 groups but group II patients had a lower relapse rate (6.3%, p = 0.003) and better disease-free survival (74.95 months, p = 0.045). CONCLUSIONS: Mediastinal LN dissection is still important for clinical early-stage NSCLC patients undergoing lobectomy even when the preoperative PET-CT is negative, and results in fewer relapses and improved disease-free survival. PMID- 24051926 TI - Letrozole efficacy in the treatment of granulosa cell tumor of the ovary: a case report. AB - BACKGROUND: Granulosa cell tumors (GCT) are malignant tumors of the sex cord stroma representing 5% of all malignant ovarian tumors. Their treatment is surgery, and rarely chemotherapy and radiotherapy. Recently, salvage treatment with aromatase inhibitors was suggested based on few reported clinical cases. CASE REPORT: We present the case of a 61-year-old woman with unresectable recurrent GCT of the right ovary treated with the aromatase inhibitor letrozole. Tumor mass and peritoneal carcinomatosis decreased in size allowing almost complete surgical resection. The patient remained in complete clinical remission for at least 24 months after surgery while under letrozole. CONCLUSION: Aromatase inhibitors represent an innovative treatment for these rare and refractory tumors offering promising results while avoiding toxic and marginally active chemotherapeutic agents. PMID- 24051927 TI - Antitumor effect of everolimus in a patient with type 3 gastric neuroendocrine tumor. AB - BACKGROUND: Gastric neuroendocrine tumors (NET) are rare and are classified into 3 types: type 1 and 2 (characterized by hypergastrinemia), and type 3 (characterized by normal gastrin). Surgery is the standard procedure, and systemic treatment is reserved for unresectable disease. Currently, targeted therapies are being evaluated in NET. The activity of everolimus, an mTOR inhibitor, has been shown in pancreatic NET but not reported in type 3 gastric carcinoid tumors. CASE REPORT: Here we report a case of a patient who, after multiple lines of systemic therapy, had a prolonged disease control of nearly 1 year, significant clinical benefit, and minor tumor shrinkage with oral everolimus 10 mg continuously. CONCLUSION: There is no effective treatment for type 3 gastric carcinoid tumors. The frequency of mTOR expression in these tumors is not known, but the case reported here suggests that inhibition of this pathway may play an important role. PMID- 24051928 TI - A case of positive mixed epithelial/mesenchymal metaplastic breast carcinoma (carcinosarcoma). Towards novel therapeutic targets: case report. AB - BACKGROUND: Metaplastic breast cancer (MeBC) is a rare malignancy, representing less than 1% of all breast cancers. We present a case of triple-negative MeBC with a biphasic growth pattern, including malignant mesenchymal and epithelial components. CASE REPORT: A 45-year-old female patient presented to our hospital with a 1-month history of a lump in her right breast. Upon clinical examination, a mass measuring 24 mm in diameter was revealed at 10-11 o'clock in the outer upper quadrant of the right breast. The patient was submitted for ultrasound scanning, ultrasound-guided core needle biopsy, and excisional biopsy which revealed a mixed epithelial/mesenchymal tumor, 8 cm in diameter. A complete immunohistochemical profile was presented. A right modified radical mastectomy with axillary lymph node dissection was performed and was tolerated well by the patient. The histological diagnosis of the lesion was MeBC with the epithelial component consistent with a grade 3 ductal adenocarcinoma. The 14 dissected axillary nodes were not involved. The patient was later submitted for adjuvant chemotherapy and radiotherapy. To date, 24 months postoperatively, the patient remains without any signs or symptoms of residual disease or recurrence. CONCLUSION: The aggressive behavior and chemoresistance of MeBC warrants early diagnosis and treatment to achieve optimal outcome. PMID- 24051929 TI - Afatinib, erlotinib and gefitinib in the first-line therapy of EGFR mutation positive lung adenocarcinoma: a review. AB - Non-small cell lung cancer (NSCLC) consists of several histomorphologically defined phenotypes that display an enormous genetic variability. In recent years, epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma has emerged as a unique subset of NSCLC in terms of etiopathogenesis and tumor biology. Since the introduction of the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib, patients with metastatic EGFR mutation-positive lung cancer can be offered a therapeutic alternative that has proven its superiority over standard platinum-based chemotherapy. However, primary or acquired resistance limits the therapeutic success of these targeted agents. Irreversible inhibitors targeting all ErbB family receptor tyrosine kinases, such as afatinib and dacomitinib, have been developed to confer sustained disease control in ErbB-dependent cancers. The large LUX-Lung 3 phase III trial recently reported afatinib to be clearly superior over the most effective platinum doublet in patients with EGFR mutation-positive lung cancer. To fully exploit the clinical activity of afatinib, proactive management of its gastrointestinal and dermatologic toxicities is advised. PMID- 24051931 TI - Opportunistic infections due to inflammatory bowel disease therapy. AB - The use of biological agents and immunomodulators for inflammatory bowel disease (IBD) has remarkably improved disease management in the current era but at the same time has increased the risk of infectious complications. Patients with IBD on corticosteroids, immunomodulators, and biological agents are considered immunocompromised and are at risk for opportunistic infections. These are infections caused by organisms that take advantage of a weakened immune system, and cause disease, when they ordinarily would cause mild illness or no disease in an immunocompetent host. Risk factors for opportunistic infections include malnutrition, older age, congenital immunodeficiency, HIV infection, chronic diseases, and use of corticosteroids, immunomodulators, and anti-tumor necrosis factor alpha therapy. Apart from immunosuppressive medications and older age, there is only indirect evidence for above risk factors contributing directly to opportunistic infection risk in patients with IBD. Opportunistic infections in patients with IBD include viral infections (herpes viruses, human papillomavirus, influenza virus, and JC virus), bacterial infections (tuberculosis, nocardiosis, Clostridium difficile infection, pneumococcal infection, legionellosis, and listeriosis), fungal infections (histoplasmosis, cryptococcosis, Pneumocystis jirovecii infection, aspergillosis, and candidiasis), and parasite infections (Strongyloides stercoralis). Although these infections lead to high morbidity and mortality, only a minority of patients with IBD develop opportunistic infections. Currently, we lack a test to accurately predict patients at risk of opportunistic infection, and future research needs to focus on biomarkers or predictive models for risk stratification. Until such a test is developed, we need to screen, prevent, diagnose, and treat opportunistic infections in all patients with IBD in a timely manner. PMID- 24051932 TI - The clinical utility of health-related quality of life screening in a pediatric inflammatory bowel disease clinic. AB - BACKGROUND: Adjusting to symptom flares, treatment regimens, and side effects places youth with inflammatory bowel disease (IBD) at increased risk for emotional and behavioral problems and adverse disease outcomes. Implementation of psychosocial screening into clinical practice remains a challenge. This study examines the clinical utility of health-related quality of life (HRQOL) screening in predicting disease outcome and healthcare utilization. METHODS: One hundred twelve youth of 7 to 18 years diagnosed with IBD and their parents. Youth completed standardized measures of HRQOL and depression. Parents completed a proxy report of HRQOL. Pediatric gastroenterologists provided the Physician Global Assessment. Families were recruited from a pediatric gastroenterology clinic. Retrospective chart reviews examined disease outcome and healthcare utilization for 12 months after baseline measurement. RESULTS: Linear regressions, controlling for demographic and disease parameters, revealed that baseline measurement of youth and parent proxy-reported HRQOL predicted the number of IBD-related hospital admissions, gastroenterology clinic visits, emergency department visits, psychology clinic visits, telephone contacts, and pain management referrals over the next 12 months. Disease outcome was not significant. CONCLUSIONS: Lower HRQOL was predictive of increased healthcare utilization among youth with IBD. Regular HRQOL screening may be the impetus to providing better case management and allocating resources based on ongoing care needs and costs. Proactive interventions focused on patients with poor HRQOL may be an efficient approach to saving on healthcare costs and resource utilization. PMID- 24051933 TI - Increased activation of latent TGF-beta1 by alphaVbeta3 in human Crohn's disease and fibrosis in TNBS colitis can be prevented by cilengitide. AB - BACKGROUND: Strictures develop in >30% of patients affected with Crohn's disease. No available medication prevents stricture development in susceptible patients. In Crohn's strictures, but not adjacent normal intestine, TGF-beta1 increases in muscularis smooth muscle, increasing collagen I production and strictures. Muscle cells express alphaVbeta3 integrin containing an Arg-Gly-Asp (RGD) binding domain. The aim was to determine whether increased TGF-beta1 levels in strictures were the result of latent TGF-beta1, which contains an RGD sequence, binding to and activation by alphaVbeta3; and whether cilengitide, which is an RGD containing alphaVbeta3 integrin inhibitor, decreases TGF-beta1 activation and development of fibrosis in chronic 2,4,6 trinitrobenzene sulfonic acid (TNBS) induced colitis. DESIGN: Muscle cells isolated from Crohn's disease strictures and normal resection margin and from the colon of rats after 42 days of chronic TNBS-induced colitis were used to prepare RNA and protein lysates and to initiate primary cultures. The mechanisms leading to increased TGF-beta1 activation, collagen I production, and fibrosis were examined in human muscle and in rats. Human cultured cells in vitro and rats in vivo were treated with cilengitide to determines it efficacy to decrease TGF-beta1-activation, collagen production, and decrease the development of fibrosis. RESULTS: Latent TGF-beta1 is activated by the alphaVbeta3 RGD domain in human and rat intestinal smooth muscles. Increased activation of TGF-beta1 in Crohn's disease and in TNBS-induced colitis causes increased collagen production, and fibrosis that could be inhibited by cilengitide. CONCLUSIONS: Cilengitide, an alphaVbeta3 integrin RGD inhibitor, could be a novel treatment to diminish excess TGF-beta1 activation, collagen I production, and development of fibrosis in Crohn's disease. PMID- 24051935 TI - Leading the way in women's health...through journalism. PMID- 24051934 TI - Adjuvant versus salvage radiation therapy for prostate cancer patients with adverse pathologic features: comparative analysis of long-term outcomes. AB - OBJECTIVES: To compare long-term outcomes of men with adverse pathologic features after adjuvant radiation therapy (ART) versus salvage radiation therapy (SRT) after radical prostatectomy at our institution. METHODS: Patients treated with postprostatectomy radiation therapy with pT3 tumors, or pT2 with positive surgical margins, were identified. Cumulative freedom from biochemical failure (FFBF), freedom from metastatic failure (FFMF), and overall survival rates were estimated utilizing the Kaplan-Meier method. Multivariate analyses were performed to determine independent prognostic factors correlated with study endpoints. Propensity score analyses were performed to adjust for confounding because of nonrandom treatment allocation. RESULTS: A total of 186 patients with adverse pathologic features treated with ART or SRT were identified. The median follow-up time after radical prostatectomy was 103 and 88 months after completion of radiation therapy. The Kaplan-Meier estimates for 10-year FFBF was 73% and 41% after ART and SRT, respectively (log-rank, P=0.0001). Ten-year FFMF was higher for patients who received ART versus SRT (98.6% vs. 80.9%, P=0.0028). On multivariate analyses there was no significant difference with respect to treatment group in terms of FFBF, FFMF, and overall survival after adjusting for propensity score. CONCLUSIONS: Although unadjusted analyses showed improved FFBF with ART, the propensity score-adjusted analyses demonstrated that long-term outcomes of patients treated with ART and SRT do not differ significantly. These results, with decreased effect size of ART after adjusting for propensity score, demonstrate the potential impact of confounding on observational research. PMID- 24051936 TI - Decreased circulating endothelial progenitor cell levels in patients with heart failure with preserved ejection fraction. AB - OBJECTIVES: The purpose of this study was to explore the relationship between endothelial progenitor cell (EPC) levels, heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). METHODS: A total of 44 HFpEF patients, 40 HFrEF patients and 69 age-, gender- and comorbidity-matched controls were enrolled after evaluating their clinical manifestations and echocardiography findings. Flow cytometry with quantification of three EPC markers in peripheral blood samples was used to assess the number of circulating EPCs. RESULTS: HFpEF and HFrEF patients had significantly decreased circulating EPC levels compared to controls. Among heart failure patients, patients with New York Heart Association functional class (FC) IV had fewer circulating EPCs compared to those with FC II and FC III (p = 0.053). A simple linear regression analysis of data showed that high sensitivity C-reactive protein, left ventricular ejection fraction, left atrium diameter and the ratio of medial early filling to early diastolic mitral annular velocity all correlated with the EPC count. In multivariate Cox regression analyses, both HFpEF and HFrEF were found to be independent predictors of a decreased EPC number. CONCLUSIONS: HFpEF and HFrEF patients have decreased circulating EPC numbers, which is an indication of impaired endothelial turnover. PMID- 24051937 TI - Bernard-Soulier syndrome due to compound heterozygosity for a novel glycoprotein Ibbeta mutation. PMID- 24051938 TI - Surgical impact of new treatments in breast cancer. AB - Local treatment of breast cancer with tumor-free surgical margins is the standard procedure in the treatment of T1 and small T2 breast cancers. Surgery is followed by radiation therapy, and adjuvant systemic therapy is offered depending on primary tumor characteristics, such as tumor size, grade of differentiation, number of involved axillary lymph nodes, the status of estrogen (ER) and progesterone (PR) receptors, and the expression of the human epidermal growth factor 2 (HER2) receptor. Although this approach implies a higher risk of ipsilateral breast tumor recurrence, the total risk of recurrence is low (1% per year), with rates of overall survival similar to that after radical procedures. The most peripheral part of epithelial tumors, the tumor margin, is the part which is most likely to remain in loco after surgical resection. Thus, understanding the biology of the invasion front is important as these tumor cells have been reported to lose epithelial properties, such as cohesiveness and keratin expression, and to acquire features of mesenchymal cells. The parallel appearance of tumor cells in different states of cell dedifferentiation implicates a dynamic equilibrium that is determined by the induction of epithelial-mesenchymal transition (EMT). EMT has been suggested to be of prime importance for tissue and vessel invasion. Furthermore, features of EMT are associated with the activity of tumor stem cells (TSC). TSC exist in breast cancer and their appearance varies depending on the used marker profile. Consequently, intratumoral heterogeneity is reflected by the grade of EMT activation. A specific function at the invasion front is hypothesized but has not yet been proven. Nevertheless, the molecular differentiation between the tumor center and the invasion front enhances the importance of tumor-free surgical margins. PMID- 24051939 TI - Incidence of pre- and postoperative urinary dysfunction associated with deep infiltrating endometriosis: relevance of urodynamic tests and therapeutic implications. AB - Although many series have been published on the management of digestive or urinary deep infiltrating endometriosis (DIE), few data exist on pre- and postoperative urinary dysfunction (UD) and urodynamic tests. Hence, the objective of this review was to evaluate the pre- and postoperative incidence of UD and the contribution of urodynamic tests as well as their therapeutic implications. Studies published between January 1995 and April 2012, available in the databases Medline, Embase or the Cochrane Library and responding to a key word algorithm were selected. Studies were classified according to their level of evidence in the Canadian Task Force classification. Sixty-three studies were included in this review. The incidence of preoperative UD is unknown in patients with DIE without colorectal involvement but ranges from 2% to 48% in patients with colorectal endometriosis. About half of all the patients had abnormal urodynamic test results. DIE surgery is associated with a risk of urinary dysfunction mainly corresponding to de novo voiding dysfunction in 1.4% to 29.2% of cases with a mean value of 4.8%. The rate of persistent voiding dysfunction ranges from 0 to 14.7% with a mean value of 4.6%. Risk factors of postoperative UD are the need for partial colpectomy, parametrectomy and patients requiring colo-anal anastomosis. For patients with urinary tract endometriosis, the incidence of preoperative UD is comprised between 24.4% and 79.2% with a rate of postoperative voiding dysfunction ranging from 0% to 16.9% with a mean value of 11.1%. Prevention of postoperative UD is based on nerve-sparing surgery. Treatment of voiding dysfunction requires self-catheterization. There is a lack of data on medical treatment and surgical techniques to manage postoperative UD. More effort needs to be made to detect preoperative UD associated with DIE. Preoperative evaluation by urodynamic tests and possibly electrophysiology could be of interest especially in patients with risk factors. The current review underlines the difficulties of establishing clear recommendations due to heterogeneity of the studies and the absence of a consensual definition of UD. PMID- 24051940 TI - Patient-tailored conservative surgical treatment of invasive uterine cervical squamous cell carcinoma. A review. AB - The aim of this paper was to review currently available data regarding the results of a more conservative, patient-tailored surgical approach in selected cases of early invasive uterine squamous cell carcinoma (SCC). A PubMed search of investigations in the English language published from January 2000 to September 2012 containing the terms conservative surgery, conservative treatment, trachelectomy, parametrectomy, lymphadenectomy, sentinel lymph node biopsy and fertility sparing surgery in combination with SCC was made. Conization only is optimal for women with stage Ia1 disease mainly in tumors without lymph vascular space involvement (LVSI). In stage Ib1 patients interested to maintain reproductive capacity, vaginal or abdominal radical trachelectomy are the procedures of choice. Patients with small tumors (<2 cm), no deep invasion, no LVSI, and negative pelvic nodes are at very low risk of parametrial involvement and parametrectomy may be omitted in them. Such patients may benefit from less radical surgery and may be candidates for simple hysterectomy, simple trachelectomy, or conization with pelvic lymphadenectomy. Sentinel lymph node (SLN) biopsy is apparently a good predictor of node metastases and allows the performance of lymphadenectomy only in SLN positive cases. Thus lymphadenectomy may also be omitted in some patients. In young women with locally advanced tumors, neoadjuvant chemotherapy followed by fertility-sparing surgery may also be a feasible treatment. A more conservative, patient-tailored surgical approach in selected cases of early SCC is possible resulting in lower morbidity and preservation of fertility without compromising the outcome. PMID- 24051941 TI - Management of occult stress urinary incontinence with prolapse surgery. AB - Pelvic organ prolapse (POP) and stress urinary incontinence (SUI), are two common health-related conditions, each affecting up to 50% women worldwide. Stress urinary incontinence only observed after the reduction of co-existent prolapse is called occult SUI (OSUI), and is found in up to 80% of women with advanced POP. Although there is no consensus on how to diagnose OSUI, there are several reported methods to better diagnose. Counseling symptomatically continent women with POP concerning the potential risk for developing SUI postoperatively cannot be overstated. Evidence suggests that positive OSUI in symptomatically continent women who are planning to have POP repair is associated with a high risk of POSUI, furthermore, adding continence procedure is found to reduce postoperative SUI. Therefore, adding continence surgery at the time of POP surgery in patients who are found to have OSUI preoperatively is advocated. PMID- 24051942 TI - [Evaluation of a new association between insulin-sensitizers and alpha-lipoic acid in obese women affected by PCOS]. AB - AIM: Polycystic ovary syndrome (PCOS) is a multifactorial pathology affecting 7 10% of the female population. Usually occurs with oligo/amenorrhea, anovulation, hirsutism, polycystic ovaries. Hyperinsulinemia associated with insulin resistance has been causally linked to all features of the syndrome. It has been demonstrated that by reducing hyperinsulinemia, in particular with the administration of metformin, insulin-lowering agents might improve endocrine and reproductive abnormalities in PCOS patients. METHODS: Original association between myo-inositol and alpha-lipoic acid, has recently been successfully administered in women with PCOS. The alpha-lipoic acid is a powerful natural antioxidant and an enzyme cofactor of the mitochondrial respiratory chain, is found to be a substance capable of improving glycemic control in patients with type II diabetes. In our study we compared two groups: group A, treated with metformin (3 g) and group B treated with metformin (1.7 g), myo-inositol and alpha-lipoic acid. RESULTS: The results of this study demonstrated a good efficacy of both treatments, although in the group treated with the combination of metformin/myo-inositol/alpha-lipoic acid improvement in hyperandrogenism, BMI and HOMA index were significantly better. CONCLUSION: Thus, the association metformin/myo-inositol/alpha-lipoic acid represents an excellent therapy choice to suggest to those obese women affected by PCOS who do not want to take hormones and neither to have any severe side effect. PMID- 24051943 TI - Lady Prelox(r) improves sexual function in generally healthy women of reproductive age. AB - AIM: This supplement study evaluates the Female Sexual Function Index (FSFI) of 100 healthy women (37 to 45 years) with moderate sexual dysfunction who underwent a management program of lifestyle, diet, exercise, and stress control. In association with the management program a group of these women also used the supplement Lady Prelox(r) in tablets (20 mg Pycnogenol(r) pine bark extract, 200 mg L-arginine, 200 mg L-citrulline and 50 mg Rosvita(r) rose hip extract) for eight weeks. METHODS: One group of women was supplemented with Lady Prelox(r) for 8 weeks. The nine-item FSFI questionnaire was used for evaluation of women's sexual function at inclusion (baseline), after four weeks, and after eight weeks of management and supplementation. Variation in oxidative stress was also evaluated by measuring plasma free radicals. RESULTS: Following supplementation with Lady Prelox(r) the mean total FSFI scores increased from 14.96+/-2.68 to 28.25+/-2.35 after four weeks and 33.91+/-2.7 after eight weeks. Treatment values were significantly higher than in controls (who used only the management plan) with baseline values of 17.92+/-2.32 and scores of 23.45+/-1.82 after four weeks and to 23.52+/-2.20 after eight weeks. Women in the Lady Prelox(r) group had an initial value of plasma free radicals (PFR) of 398+/-29 Carr units: this value decreased to 344:28 at 4 weeks (P<0.05) and 332:31 at 8 weeks (P<0.05). Lower changes were observed in controls with an initial value of 389+/-33, decreasing to 377+/-32 (P<0.05) at 4 weeks and to 365; 33 (P<0.05) at 8 weeks (value significantly higher in controls not using Lady Prelox(r)). The supplementation was well tolerated; no unwanted effects occurred and no women had to stop the supplementation. CONCLUSION: The study suggests that supplementation with Lady Prelox significantly improves sexual function across all domains evaluated by the FSFI in healthy women of late reproductive age. The improvement in FSFI is also associated with a significant decrease in oxidative stress. PMID- 24051944 TI - Effectiveness of sublingual use of 400 mcg prostaglandin E1 for first trimester surgical abortion according to parity: a retrospective study. AB - AIM: The aim of this paper was to evaluate the effectiveness of sublingual use of misoprostol in women undergoing first trimester surgical abortion. Special consideration was given in a sub-group analysis according to parity. METHODS: A retrospective study was conducted, enrolling patients during 2006-2009. Pregnancies less than 12 weeks of gestation were exclusively included. Our sample was divided in: group 1, in which we included women who had received 400 mcg of misoprostol sublingually two hours before surgical abortion and group 2, with no use of misoprostol. Cervical dilatation and estimated blood loss (EBL) were compared between the two groups. Moreover, a sub-group analysis of the former parameters was made separately in nulliparous and multiparous women. RESULTS: Out of 79 patients included, 48 (60.75%) received misoprostol, while 31 (39.25%) did not. Cervical dilatation was significantly higher in group 1 (6.4+/-2.1 mm vs. 4.7+/-1.7 mm in group 2, P=0.001), while EBL was significantly lower in the same group (105.0+/-22.1 mL vs. 120.3+/-24.2 mL for group 2, P=0.005). Concerning the sub-analysis, cervical dilatation was significantly increased and EBL was significantly lower in multiparous receiving misoprostol comparing with those who did not (P=0.001 and P=0.002, respectively). However, the same parameters did not differ significantly between the two sub-groups of nulliparous women. CONCLUSION: Sublingual administration of 400mcg misoprostol is effective concerning cervical ripening and EBL in women undergoing first trimester surgical abortion. According to the results of the present clinical trial prostaglandin E1 is more effective in multiparous group of women. PMID- 24051945 TI - [Administration of micronized palmitoylethanolamide (PEA)-transpolydatin in the treatment of chronic pelvic pain in women affected by endometriosis: preliminary results]. AB - AIM: Aim of the study was to evaluate the effectiveness of micronized palmitoylethanolamide (PEA)-transpolydatin in the treatment of chronic pelvic pain in women affected by endometriosis. METHODS: Twenty-four patients with suspected endometriosis affected by severe pelvic pain were enrolled. All patients received two tablets a day of PEA 400 mg and 40 mg polydatin for 90 days consecutively. A Visual Analogic Scale was used for the assessment of the severity of global pain, dysmenorrhea, dyspareunia, dysuria and dischezia. A second questionnaire was submitted to patients to assess the quality of life. The compilation of a diary lead us to evaluate the monthly assumption of any painkillers. Patients were evaluated at the begin of the treatment and then monthly until the end of the study (90 days). The statistical analysis was performed by using the ANOVA for the analysis of variance. RESULTS: Statistically significant results were found in relation to pelvic pain, dysmenorrhea and dyspareunia compared to the initial evaluation of patients. Results related to dysuria and dischezia were not statistically significant (P>0.05). The decrease in pelvic pain leads to an improvement of the quality of life of patients. A decreased assumption of nonsteroidal anti-inflammatory drugs (NSAIDs) was also observed. CONCLUSION: PEA could be considered an effective supplement to conventional analgesic therapies in the management of pelvic pain related to endometriosis. PMID- 24051946 TI - Effectiveness of vaginal adelmidrol for treating pelvic visceral discomforts and anxiety: a prospective observational study. AB - AIM: The aim of this paper was to show that self-assessed anxiety in patients with pelvic visceral discomforts is reduced after the intravaginal administration of adelmidrol. MATERIAL AND METHODS: Twenty-four patients who described themselves as anxious (scoring 5 or more in a 1 to 10 scale in a self-assessment test) and who suffered from pelvic visceral discomfort (during defecation, urination, sexual intercourse and menstruation) were enrolled in the study. Pelvic visceral discomforts were assessed using a questionnaire in which patients were asked to assign a score between 1 and 10 according to intensity. The patients were offered intravaginal adelmidrol therapy (2%, 4.5 mL twice a day for 30 days). The patients were interviewed again and asked to self-assess anxiety and pelvic visceral discomfort at the end of therapy. RESULTS: 12 patients underwent adelmidrol therapy. With the exception of urinary discomfort, all the median scores of pelvic visceral discomforts had improved after 30 days, with significant values achieved for menstruation (P=0.013) and sexual intercourse (P=0.013). Anxiety had also decreased after 30 days (P=0.025), regardless of changes in discomfort levels. CONCLUSION: Adelmidrol could selectively modulate the visceral nociceptive pathways (interoception), relieving pelvic discomfort. This action should have an independent effect on anxiety responses. PMID- 24051947 TI - Screening for thyroid disease in pregnancy: a review. AB - Screening for thyroid disease in pregnancy remains a contentious issue. This review presents these diverging views and discusses their reasons as well as the relevant facts. The final aim is to establish the information gaps and limitations - technological or otherwise - which still need to be eliminated in order to settle the debate conclusively. The prevalence of the more common thyroid dysfunctions that occur in and after pregnancy is discussed. The subsequent impact of these disorders on mother and offspring is also described. Special focus is placed on the benefits and setbacks of currently available and newly proposed investigations, which assay serum hormone levels, serum autoantibody levels, and/or use clinical data. It is pointed out that the relevance of screening varies from one region of the world to the other, based on the content of iodine and selenium in food and water. The review then discusses the current major arguments for and against screening, as well as recommendations and proposed alternatives. PMID- 24051948 TI - Uterine incisional necrosis after cesarean delivery in a patient with uterine myomas. PMID- 24051950 TI - Accuracy of individual variables in the monitoring of long-term change in pulmonary sarcoidosis as judged by serial high-resolution CT scan data. AB - BACKGROUND: In pulmonary sarcoidosis, the optimal means of quantifying change is uncertain. The comparative usefulness of simple lung function trends and chest radiography remains unclear. We aimed to explore and contrast the disease monitoring strategies of serial pulmonary function tests (PFTs) and chest radiography compared against morphologic change on high-resolution CT (HRCT) scan. METHODS: Seventy-three patients with sarcoidosis were identified who had two HRCT scans with concurrent chest radiography and PFTs. Chest radiography and HRCT scans were assessed by two radiologists for change in disease extent. Concordance between the scoring systems, as well as agreement between PFT trends (% change from baseline in FEV, FVC, and diffusing capacity of the lung for carbon monoxide [Dlco]), chest radiography, and chest HRCT scan change, were examined using the weighted kappa coefficient of variation (Kw). RESULTS: There was fair agreement between change in extent of disease on chest radiograph and significant PFT trends (Kw = 0.35, P < .001) and moderate agreement between change in extent of disease on serial HRCT scan and significant PFT trends (Kw = 0.64, P < .0001). The integration of Dlco trends did not improve concordance between change on HRCT scan and PFT change. Change in gas transfer coefficient (ie, Dlco/alveolar volume) displayed no overall linkage with change in disease extent on chest radiograph (Kw = 0.07, P = .27) and only poor agreement with change in disease extent on HRCT scan (Kw = 0.17, P = .07). CONCLUSIONS: Significant PFT trends correlate better with morphologic change as defined by serial HRCT scan than extent of disease on radiograph. Isolated change in gas transfer coefficient is more frequently discordant with change in disease extent on chest radiograph and HRCT scan and may suggest a pulmonary vascular component. PMID- 24051952 TI - Monitoring oxygen concentration during photodynamic therapy using prompt photosensitizer fluorescence. AB - A novel technique is described that uses either time-resolved or steady state prompt photosensitizer fluorescence to measure local oxygen concentration. Solution experiments conducted with Al(III) phthalocyanine chloride tetrasulfonic acid confirmed that the steady state fluorescence signal is dependent on the oxygen concentration and fluence rate. A relationship between prompt sensitizer fluorescence and sensitizer triplet quenching efficiency is derived which does not require knowledge of the Stern-Volmer constant. Similar relationships are also derived for sensitizer delayed fluorescence and phosphorescence. An explicit photodynamic therapy (PDT) dose metric that incorporates light dosimetry, sensitizer dosimetry, and triplet quenching efficiency is introduced. All components of this metric can be determined by optical measurements. PMID- 24051949 TI - Community-acquired methicillin-resistant Staphylococcus aureus: the new face of an old foe? AB - The burden of infections caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is increasing among different patient populations globally. As CA-MRSA has become established in healthcare facilities, the range of infections caused by them has also increased. Molecular characterization of CA MRSA isolates obtained from different centers has revealed significant diversity in their genetic backgrounds. Although many CA-MRSA strains are still susceptible to non-beta-lactam antibiotics, multiresistance to non-beta-lactam agents has emerged in some clones, posing substantial problems for empirical and directed therapy of infections caused by these strains. Some CA-MRSA clones have acquired the capacity to spread locally and internationally. CA-MRSA belonging to ST80 MRSA-IV and ST30-MRSA-IV appear to be the dominant clones in the countries of the Gulf Cooperation Council (GCC). The emergence of pandemic CA-MRSA clones not only limits therapeutic options but also presents significant challenges for infection control. Continued monitoring of global epidemiology and emerging drug resistance data is critical for the effective management of these infections. PMID- 24051953 TI - Lipoid pneumonia. PMID- 24051954 TI - Acute amiodarone-induced lung toxicity. PMID- 24051955 TI - Efficacy of transthoracic echocardiography for diagnosing heart failure in septic shock. AB - BACKGROUND: Cardiac dysfunction occurs in up to 80% of patients with septic shock. Transthoracic echocardiography (TTE) is an ideal tool for the detailed characterization of cardiac function. Its feasibility is perceived to be poor in critically ill patients, but this has never been studied. To address this question, the authors evaluated the efficacy of TTE to diagnose heart failure in septic shock. METHODS: This was a retrospective study. Patients admitted to the intensive care unit with septic shock and who had a TTE within 72 hours of intensive care unit admission were identified by a computer algorithm and validated by chart review. Echocardiography images were reviewed by a single cardiologist blinded to clinical outcomes. Clinical information was collected from patients' medical record. RESULTS: Seventy-six patients met the studies' inclusion criteria. The feasibility of TTE to calculate left ventricular ejection fraction was 90% and to assess diastolic function was 74%. Significant mitral regurgitation or aortic stenosis was the most frequent impediments for the assessment of diastolic function. Seventy-four percent of all patients showed some type of cardiac dysfunction (left or right ventricular systolic dysfunction and/or left ventricular diastolic dysfunction). In regression analyses, TTE feasibility was not impacted by factors previously associated with poor image acquisition: high body mass index, mechanical ventilation, tachycardia, advanced age or high severity of illness. CONCLUSIONS: This study demonstrated that TTE is a useful tool to assess myocardial function in critically ill patients and suggested its potential to assist in the management of patients with septic shock. PMID- 24051956 TI - Association of indoxyl sulfate with fibroblast growth factor 23 in patients with advanced chronic kidney disease. AB - BACKGROUND: Protein-bound uremic toxins-indoxyl sulfate (IS) and p-cresyl sulfate (PCS)-can not only predict clinical outcomes but also may relate to bone-mineral disorders in patients with chronic kidney disease (CKD). However, the relationship between protein-bound uremic toxins and fibroblast growth factor 23 (FGF23) has not been studied before. The objective of this study was to explore the association of IS and PCS with FGF23 in a CKD-based cohort. METHODS: This is a cross-sectional study that enrolled 80 stable CKD stage 3 to 5 patients who met the inclusion criteria in a single medical center. Serum levels of IS, PCS and FGF23 were measured concurrently. General biochemistry and patient background were also investigated. RESULTS: Serum FGF23 and IS concentrations were elevated commensurately with deteriorating renal function. Pearson's analysis showed that FGF23 levels were significantly associated with blood urea nitrogen (r = 0.381, P < 0.05), creatinine (r = 0.632, P < 0.01), estimated glomerular filtration rate (r = -0.447, P < 0.05), phosphate (r = 0.543, P < 0.01), intact parathyroid hormone (r = 0.543, P < 0.01), IS (r = 0.432, P < 0.01) and PCS (r = 0.318, P < 0.05). After adjusting other confounding factors by stepwise multiple linear regression analysis, only creatinine (beta = 0.82, P < 0.01), phosphate (beta = 0.28, P = 0.02) and IS (beta = 0.39, P = 0.04) retained statistically significant associations with FGF23. Moreover, serum levels of IS were higher in patients with high FGF23 concentration (>90 pg/mL, median value) than those with lower FGF23 (P < 0.01). CONCLUSIONS: Results indicated that only IS but not PCS correlated independently with FGF23 in worsening CKD. IS may be an independent factor involved in regulation of bone-mineral metabolism. PMID- 24051957 TI - The MEK1/2 inhibitor AS703026 circumvents resistance to the BRAF inhibitor PLX4032 in human malignant melanoma cells. AB - BACKGROUND: Although inhibitors of the proto-oncogene BRAF have shown excellent antitumor activity against malignant melanoma, their efficacy is limited by the development of acquired drug resistance, a process in which reactivation of MAP kinase (MEK) is known to play an important role. In this study, we evaluated the efficacy of AS703026, a new MEK inhibitor, in BRAF inhibitor-resistant melanoma cell lines. METHODS: Two melanoma cells lines, RPMI-7951 and SK-MEL5, harboring an activating mutation of BRAF (V600E) were treated with the BRAF inhibitor PLX4032 to select a BRAF inhibitor-resistant cell line for further study. Cell viability assay was determined with MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay and trypan blue exclusion method; apoptosis assay was performed by annexin-V staining. Knockdown of BRAF was investigated by small interfering RNA. RESULTS: RPMI-7951 cells exhibited an increased sensitivity to combined treatment with PLX4032 and AS703026 compared to either drug alone. Consistent with this, the combination of PLX4032 and AS703026 significantly induced apoptosis, whereas each drug used alone did not, as demonstrated by a flow cytometric analysis of annexin V/propidium iodide-stained cells and Western blot analysis of cleaved caspase-3. Notably, immunoblot analyses also showed a depletion of phosphorylated-ERK with combined drug treatment. In addition, AS703026 synergized with small interfering RNA-mediated downregulation of BRAF to produce results similar to those of combined treatment with PLX4032 and AS703026. CONCLUSIONS: Our results suggest that combined treatment with AS703026 and a BRAF inhibitor overcomes the resistance to BRAF inhibitors in malignant melanoma cells harboring a mutant form of BRAF. PMID- 24051958 TI - Large-scale identification of ubiquitination sites by mass spectrometry. AB - Ubiquitination is essential for the regulation of cellular protein homeostasis. It also has a central role in numerous signaling events. Recent advances in the production and availability of antibodies that recognize the Lys-E-Gly-Gly (K-E GG) remnant produced by trypsin digestion of proteins having ubiquitinated lysine side chains have markedly improved the ability to enrich and detect endogenous ubiquitination sites by mass spectrometry (MS). The following protocol describes the steps required to complete a large-scale ubiquitin experiment for the detection of tens of thousands of distinct ubiquitination sites from cell lines or tissue samples. Specifically, we present detailed, step-by-step instructions for sample preparation, off-line fractionation by reversed-phase chromatography at pH 10, immobilization of an antibody specific to K-E-GG to beads by chemical cross-linking, enrichment of ubiquitinated peptides using these antibodies and proteomic analysis of enriched samples by LC-tandem MS (MS/MS). Relative quantification can be achieved by performing stable isotope labeling by amino acids in cell culture (SILAC) labeling of cells. After cell or tissue samples have been prepared for lysis, the described protocol can be completed in ~5 d. PMID- 24051959 TI - The touchscreen operant platform for testing learning and memory in rats and mice. AB - An increasingly popular method of assessing cognitive functions in rodents is the automated touchscreen platform, on which a number of different cognitive tests can be run in a manner very similar to touchscreen methods currently used to test human subjects. This methodology is low stress (using appetitive rather than aversive reinforcement), has high translational potential and lends itself to a high degree of standardization and throughput. Applications include the study of cognition in rodent models of psychiatric and neurodegenerative diseases (e.g., Alzheimer's disease, schizophrenia, Huntington's disease, frontotemporal dementia), as well as the characterization of the role of select brain regions, neurotransmitter systems and genes in rodents. This protocol describes how to perform four touchscreen assays of learning and memory: visual discrimination, object-location paired-associates learning, visuomotor conditional learning and autoshaping. It is accompanied by two further protocols (also published in this issue) that use the touchscreen platform to assess executive function, working memory and pattern separation. PMID- 24051960 TI - The touchscreen operant platform for assessing executive function in rats and mice. AB - This protocol details a subset of assays developed within the touchscreen platform to measure various aspects of executive function in rodents. Three main procedures are included: extinction, measuring the rate and extent of curtailing a response that was previously, but is no longer, associated with reward; reversal learning, measuring the rate and extent of switching a response toward a visual stimulus that was previously not, but has become, associated with reward (and away from a visual stimulus that was previously, but is no longer, rewarded); and the 5-choice serial reaction time (5-CSRT) task, gauging the ability to selectively detect and appropriately respond to briefly presented, spatially unpredictable visual stimuli. These protocols were designed to assess both complementary and overlapping constructs including selective and divided visual attention, inhibitory control, flexibility, impulsivity and compulsivity. The procedures comprise part of a wider touchscreen test battery assessing cognition in rodents with high potential for translation to human studies. PMID- 24051962 TI - Measuring functional health among the elderly: development of the Japanese version of the World Health Organization Disability Assessment Schedule II. AB - The Japanese version of the World Health Organization Disability Assessment Schedule II (WHODAS II-J) was developed and its psychometric properties were evaluated, and then used to determine the influence of disability on quality of life among the elderly in Japan. The study included three phases: qualitative, preliminary and field. For the qualitative portion of the study, six key informants were interviewed before the translation/back-translation procedure. For the preliminary study, 17 healthy elderly individuals were interviewed using the 12-item interview version of the WHODAS II-J. For the field study, different versions of the WHODAS II-J and the Japanese version of the World Health Organization Quality of Life BREF (WHOQOL-BREF) were tested with different participants (the 36-item interview version with 30 participants living in a nursing home, the 36-item proxy version with 30 caregivers working in the nursing home, and the 12-item and 36-item self-report versions with 132 and 129 healthy elderly living in Kanto and Kinki regions, respectively). In total, 321 elderly individuals participated in the field study. Of these participants, physical or mental disabilities were present in 47. Cronbach's alpha scores calculated for each of six domains of the WHODAS II ranged from 0.67 to 0.98. A significant correlation was observed between the results of the WHODAS II-J and the degree of disability (P<0.01), and a negative correlation was observed between WHOQOL-BREF and WHODAS II-J scores (P<0.01). A significant difference was found between healthy elderly individuals and those with disabilities in three domains: getting around, self-care, and life activities (P<0.01). In conclusion, the WHODAS II-J is a reliable and valid instrument for assessment of function in the elderly population in Japan. PMID- 24051961 TI - The touchscreen operant platform for testing working memory and pattern separation in rats and mice. AB - The automated touchscreen operant chamber for rats and mice allows for the assessment of multiple cognitive domains within the same testing environment. This protocol presents the location discrimination (LD) task and the trial-unique delayed nonmatching-to-location (TUNL) task, which both assess memory for location. During these tasks, animals are trained to a predefined criterion during ~20-40 daily sessions. In LD sessions, touching the same location on the screen is rewarded on consecutive trials, followed by a reversal of location reward contingencies. TUNL, a working memory task, requires animals to 'nonmatch' to a sample location after a delay. In both the LD and TUNL tasks, spatial similarity can be varied, allowing assessment of pattern separation ability, a function that is thought to be performed by the dentate gyrus (DG). These tasks are therefore particularly useful in animal models of hippocampal, and specifically DG, function, but they additionally permit discernment of changes in pattern separation from those in working memory. PMID- 24051963 TI - Aortic valve stenosis and atrial fibrillation influence plasma fibulin-1 levels in patients treated with coronary bypass surgery. AB - OBJECTIVES: Aortic valve stenosis (AS) causes cardiac fibrosis and left ventricular hypertrophy, and over time heart failure can occur. To date, a reliable marker to predict progression of AS or the development of heart failure is still lacking. In this study, we addressed the hypothesis that fibulin-1 levels reflect myocardial fibrosis. METHODS: Patients undergoing heart surgery at the Odense University were investigated. By 2012 data on outcome were obtained. RESULTS: In 293 patients, plasma fibulin-1 levels were measured. Patients with AS or atrial fibrillation (AF) had significantly higher fibulin-1 levels compared to those with coronary artery disease only (p = 0.005). Patients with preoperatively diagnosed chronic AF had significantly higher levels of fibulin-1 compared to those without (p = 0.004). Plasma fibulin-1 levels showed no relationship to echocardiographic size and had no impact on outcome, death or other adverse events. CONCLUSION: This study shows that plasma fibulin-1 levels are increased in patients with AS and AF compared to patients with coronary disease only. Our study results suggest fibulin-1, a vascular extracellular matrix (ECM) protein, as a marker of ECM turnover perhaps due to the increased myocardial stretch that is related to pressure overload. PMID- 24051966 TI - Pyeloduodenal fistula due to proximal ureterolithiasis and its successful conservative management. PMID- 24051965 TI - Metformin and survival in pancreatic cancer: a retrospective cohort study. AB - OBJECTIVES: Our aim was to determine the effect of metformin exposure on survival in patients with advanced pancreatic adenocarcinoma (PAC). METHODS: A retrospective cohort study was conducted using The Health Improvement Network, a primary care electronic medical record database from the United Kingdom (2003 2010). The study cohort included all subjects with a diagnostic code for incident PAC and a preexisting diagnosis of type 2 diabetes mellitus. Subjects were classified as exposed if they were prescribed metformin around the time of PAC diagnosis (between 6 months prior and 1 month after). A secondary analysis was performed only on exposed subjects without prior (ie, 6 months before PAC diagnosis) exposure to metformin. The primary outcome was overall survival. The analysis was performed using univariate and multivariable Cox proportional hazards models. RESULTS: The study included 516 subjects with preexisting type 2 diabetes mellitus and PAC, 247 of which were exposed to metformin. In univariate and multivariable analysis, there was no difference in survival between those exposed and those unexposed to metformin in the primary analysis (hazards ratio, 1.11 [0.89-1.38], P = 0.367) or the secondary analysis (hazards ratio, 1.09 [0.80 1.47], P = 0.585). CONCLUSIONS: Metformin use is not associated with improved survival in subjects with advanced PAC. PMID- 24051967 TI - A glyco-gold nanoparticle based assay for alpha-2,8-polysialyltransferase from Neisseria meningitidis. AB - We designed a novel strategy for sensitively detecting the activity of alpha-2,8 polysialyltransferase (PST) by a combination of ganglioside GD3 functionalized gold nanoparticles and inactive endosialidase. We anticipate that this new method will facilitate the search for PST inhibitors as well as for improved mutant forms of PST in directed evolution experiments. PMID- 24051968 TI - Lactobacillus paracasei subsp. paracasei F19 in Bell's stage 2 of necrotizing enterocolitis. AB - AIM: The aim of this trial is to evaluate the role Lactobacillus paracasei in Bell's stage 2 in order to prevent the clinical progression to stage 3. METHODS: A prospective study was approved and started in December 2008. Patients were infants with birth weight 600 to 1500 g. One group received probiotic supplementation (L. paracasei susp.paracasei F-19) and the control group received only standard medical treatment. The primary outcome was the progression to stage 3 as defined by Bell's modified criteria. Inclusion and exclusion criteria were created and discussed with parents before treatment. RESULTS: Thirty-two patients (stage 2 NEC) were considered eligible for the study. Group A: 18 patients and Group B: 14 patients. Three patients in group A and six patients in group B had a clinical history of Bell's stage 3 NEC (P<0.05); oral supplementation of L. paracasei reduced the clinical progression of NEC. It was considered that an improvement in intestinal motility might have contributed to this result. CONCLUSION: The use of Lactobacillus paracasei subsp. paracasei F-19 is safe; the low progression rate to stage 3 NEC suggests that the use of this probiotic in stage 2 NEC could be a valuable therapeutic option. PMID- 24051969 TI - [Review on the use of complementary medicine in pediatrics: an interregional study]. AB - AIM: The use of complementary and alternative medicine (CAM) has not been widely studied among children in Italy. ISTAT-2005 survey showed a prevalence of 10% of children treated with CAM. Most of other contributes were related to Northern populations. The aim of our study was to analyse the rate of CAM use in the children living in Piemonte compared to the children living in Calabria. METHODS: Data were collected through a structural questionnaire administered to the parents of the children admitted to the pediatric department of the Regional Hospital in Torino, Catanzaro and Cosenza. The questionnaire included questions about the use of CAM and the demographic characteristics of the parents and the child responding. RESULTS: For the study 1156 questionnaires were distributed in total and 1,136 were analyzed. Overall the response rate was more than 98%. In Turin 43% of the children were treated also with CAM, in Cosenza and in Catanzaro 38% and 21%, respectively. The parents who used CAM for their children were more aged and with a higher education. In Turin homeopathy was used more, in the south of Italy phytotherapy was preferred. More acute respiratory diseases were the most frequent diseases treated with CAM. In the majority of cases CAM were prescribed by pediatricians. Most of the people preferred CAM for less side effects and the majority of them declared to be satisfied. Furthermore, this survey shows that parents use CAM as complementary rather than alternative to medicine. CONCLUSION: Our study remarks as the use of CAM is dramatically increased among the Italian children in the last years as well as in other countries. Pediatricians need to improve their knowledge about CAM in order to better manage parental attitude. PMID- 24051964 TI - Polymorphisms in metabolism/antioxidant genes may mediate the effect of dietary intake on pancreatic cancer risk. AB - OBJECTIVES: A source of variation for inconsistent dietary-pancreatic cancer associations may be individuals carrying constitutional metabolism/antioxidant gene variants that differentially benefit compared to homozygous individuals. Seventy-six tag single-nucleotide polymorphisms were genotyped in 13 candidate genes to test differential associations with pancreatic adenocarcinoma. METHODS: A clinic-based case-control design was used to rapidly ascertain 251 cases and 970 frequency matched controls who provided blood samples and completed a 144 item food frequency questionnaire. Single-nucleotide polymorphisms were evaluated using a dominant genetic model and dietary categories split on controls' median intake. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusted for potential confounders. RESULTS: Significant increased associations (Bonferroni corrected P <= 0.0007) were observed for carriers of greater than or equal to 1 minor allele for rs3816257 (glucosidase, alpha; acid [GAA]) and lower intake of deep-yellow vegetables (1.90 [1.28-2.83]); and carriers of no minor allele for rs12807961 (catalase [CAT]) and high total grains intake (2.48 [1.50-4.09]), whereas those with greater than or equal to 1 minor allele had a decreasing slope (across grains). The reference group was no minor alleles with low dietary intake. CONCLUSIONS: Interindividual variation in metabolism/antioxidant genes could interact with dietary intake to influence pancreatic cancer risk. PMID- 24051970 TI - [Unidentified bright objects and neuropsychiatric disturbances]. AB - AIM: The neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disease. In 40-70% of cases are described signal hyperintensity on MRI, called unidentified bright objects (UBO). Their correlation with clinical disorders is still debated. The present study investigated the correlation between the UBOs and neuropsychiatric outcomes overall, observes the long-term through the comparison of MRI brain and considers the utility of including MRI early in the investigation of NF1. METHODS: We included 100 patients (age 2-18 years) with NF1. The parents were given a medical questionnaire to fill, a clinical neurologic examination (Touwen) was performed and brain MRI were analyzed during the years. RESULTS: In 72% of cases were detected UBO's last MRI. It was observed that the UBO's tend to shrink over time and in some cases to disappear in pre adolescent. There were significant correlations between UBOs and minor disturbances in motor function (P=0.004) and between UBO's and cognitive deficits (P=0.016). The 79.62% of the patients is followed by a specialist in neuropsychiatry, as correlated significantly (P=0.027) with changes on MRI. CONCLUSIONS: Given the correlation between UBO's, neurological disorders, cognitive and behavioral, suggest be included in the diagnostic protocol MRI brain areas as T2H can be considered predictive for a neuropsychiatric disorder. PMID- 24051971 TI - Predisposing factors, incidence and mortality of pneumothorax in neonates. AB - AIM: Incidence, risk factors, morbidity and mortality of pneumothorax in neonates vary widely. We aimed to evaluate characteristics, predisposing factors and associated primary lung conditions of pneumothorax in neonates. METHODS: Neonates diagnosed to have pneumothoraces in a neonatal unit of university teaching hospital between May 2006 and August 2008 were studied. Pneumothorax was defined as accumulation of air in the pleural cavity as confirmed by chest radiograph. RESULTS: A total of 25 neonates with pneumothorax were studied. Among them, 32% were inborn, 62% were male and 52% were term neonates. Mean birth weight and median gestation were 2336 g and 37 weeks, respectively. Incidence among inborn neonates was 0.27% and among term and preterm, 0.13% and 0.79%, respectively. Incidence among Neonatal Intensive Care Unit admissions was 1.86%. Ten pneumothoraces occurred in neonates receiving ventilation with an incidence of 1.85%. Incidence of pneumothorax among ventilated neonates was not significantly different from nonventilated (P=0.8). About 84% of pneumothorax occurred within 48 hours of life. Pneumothorax was unilateral in 84% and more common on right side. Underlying pulmonary pathology was observed in 72% and included hyaline membrane disease (HMD) in 40%, meconium aspiration syndrome (MAS) in 24% and pneumonia in 8%. Mean intrapleural drainage was 2.5 days and 9 neonates died. CONCLUSION: Incidence of pneumothorax was similar to reports in the literature and higher among preterm than term neonates. HMD and MAS were common underlying lung conditions for neonatal pneumothorax. Incidence among ventilated neonates was lower than other reports. PMID- 24051972 TI - Clinical effects of diet supplementation with DHA in pediatric patients suffering from cystic fibrosis. AB - AIM: Cystic fibrosis (CF) patients present an altered fatty acid (FA) metabolism characterized by imbalance in the arachidonic/docosohexasenoic acid (AA/DHA) ratio in favour of the former which can contribute to the increase in pulmonary inflammation. The present study aims to assess respiratory, nutritional, clinical and laboratory parameters, and inflammatory markers after six months of DHA supplementation in paediatric patients suffering from CF. METHODS: A dose of 1 g/10 kg/die was administered to ten CF patients of paediatric age for the first month and 250 mg/10 kg/die for the remaining 5 months. We carried out follow-ups at T0 (baseline), T6 (after six months of the diet) and T12 (six months after supplementation was interrupted) during which respiratory, nutritional, clinical and laboratory parameters were assessed. RESULTS: After six months of DHA supplementation inflammatory marker levels had diminished: interleukin 8 (IL-8) and Tumour Necrosis Factor Alfa (TNF-alpha) in serum, and calprotectin in stools. In addition, auxometric parameters were improved as was the clinical condition of patients, who tolerated DHA well. CONCLUSION: Dietetic integration with DHA seems to improve clinical condition and the inflammatory pulmonary and intestinal state of pediatric patients suffering from CF. PMID- 24051974 TI - Ileostomy in extremely low birth weight and premature neonates. AB - AIM: The establishment of an ileostomy is a surgical option in the treatment of neonatal intestinal diseases, such as necrotizing enterocolitis (NEC) and meconial disease, in premature or extremely-low-birth-weight (ELBW) infants. METHODS: A prospective study was performed between July 2000-April 2011, with in exam all cases of acute abdomen in newborn premature babies. We perfomed a temporary ileostomy with a skin bridge and resection of the necrotic intestine. The temporary ileostomy was followed by anastomosis and the effect of possible confounding factors were assessed on the intestinal canalization. Data analysis and multiple monovariate were conducted. RESULTS: Thirty-three neonates, 14 males and 19 females, operated for intestinal perforation were identified. They were ELBW or premature neonates. There were 24 neonates with NEC, 4 with meconium peritonitis and 5 with complicated meconium ileus. In 4 cases of meconium ileus we found ileale atresia. Eight patients were excluded from the study because 3 died; 2 had cystic fibrosis and 3 with hydrocephalus. Thirteen patients developed complications: 7 related to ileostomy, 2 cholestasis and 4 recurrent NEC. Patients with meconium ileus gain rcovery of bowel function 4 days or more the others (OR=8.0; P=0.0455). CONCLUSION: In our experience, the establishment of ileostomy for the treatment of acute abdomen in child newborn premature or low birth weight allows optimal management of the child, excluding bowel sick and faster healing with a low rate of morbidity and mortality. PMID- 24051973 TI - [Neonatal asphyxia: neurologic outcome]. AB - AIM: The neonatal asphyxia is recognized as an important cause of morbidity and mortality during the pediatric age. The objective of this study was to evaluate the correlation between some neonatal variables and neurological outcome at two years of life in infants with asphyxia, in order to produce a correct prognosis and to grant a rapid and targeted therapy. METHODS: We have recruited 63 patients whose history and neuroimages suggested a neonatal asphyxia, and we have analysed their clinical- instrumental parameters every three months until two years of life. A correlation study was carried out in order to find a statistical significance indicated by p-value < 0,05. The correlation was made by means of Chi-square and ANOVA (analysis of variance) test. RESULTS: Only one patient developed isolated epilepsy, 17 developed CP associated to epilepsy (14 of them were term infants, 3 were preterm); 25 patients, 13 term and 12 preterm, developed only CP; 20 patients, 11 preterm and 9 term infants, developed a psychomotor delay. The most severe clinical picture (CP associated with epilepsy) appeared in 12 infants of adequate weight and in 5 LBW children; the CP appeared in 14 NW patients, 5 LBW, 4 VLBW and 2 ELBW. Psychomotor delay was developed by 8 NW children, 2 LBW and 10 ELBW. Most patients with severe CP presented severe neurological symptoms at birth. Moderate CP involved those who had a mild neurological or systemic symptoms. Furthermore an association emerged between early epilepsy and CP onset and their severity. CONCLUSION: Neonatal seizures are not related to an increased risk to develop epilepsy. Epilepsy alone is a rare event and it usually complicates CP picture. Most subject with both epilepsy and CP are term infants with adequate weight. Preterm VLBW infants have a greater risk to develop a psychomotor delay. Clinical conditions at birth are related to CP severity (several neonatal neurological signs are the greater risk factors). Severely pathological neonatal EEG (background activity) is related to CP severity and an early symptomatic epilepsy onset is related with both epilepsy and CP severity. PMID- 24051975 TI - Surgical treatment of posthemorrhagic infantile hydrocephalus. AB - The incidence of post-hemorrhagic hydrocephalus (PHH) remains stable over the time since the improvement in the perinatal assistance permits to reduce the risk of preterm brain hemorrhage and, at the same time, to increase the rate of surviving children potentially developing PHH. Children showing symptomatic ventriculomegaly (usually following Papile's grade III or IV hemorrhage) are candidate to treatment. Temporary treatment is based on medical therapy or on transient surgical manoeuvres (lumbar tapping, subcutaneous reservoir, external ventricular drainage, brain wash) with the goal of avoiding or to postponing the definitive surgical operation. Ventriculo-peritoneal shunt still represents the main surgical procedure for PHH. Especially in low-weight babies, however, this procedure is burdened by a high rate of complications as shunt infection or obstruction, skin erosion. PHH is actually one of the types of hydrocephalus more frequently requiring multiple operations (about 30% of the cases). The advent of neuroendoscopy reduced the risk of complications but did not affect the risk of reoperations significantly. Endoscopy is useful in treating the complications of the hemorrhage, for example by aspirating ventricular blood clots, by fenestrating intraventricular cysts or septa, or by treating isolated ventricles (septostomy, aqueductoplasty). These procedures allows the patient to avoid multiple shunts and, therefore, to reduce the risk of complications. However, endoscopic third ventriculostomy, which is the endoscopic definitive option for PHH, is effective in about one third of the cases, thus resulting in the need of reoperation. Immaturity of the CSF re-adsorption pathways, obstruction of the subarachnoid spaces and low intracranial pressure are the main causes of endoscopy failures. PMID- 24051976 TI - [Update on prevention of infections in patients without spleen or with diminished splenic function]. AB - Patients without spleen or with diminished splenic function are at high risk (10 50 times higher than in normal population) of developing life-threatening infections (OPSI). Mortality from OPSI is estimated at 50 to 80% of cases. More frequent causative agents are encapsulated bacteria: Streptococcus Pneumoniae, Haemophilus influenzae type b and Neisseria Meningitidis. The risk of OPSI can be reduced by immunizing patients against these pathogens and by prescribing antibiotic prophylaxis. Continuous antibiotic prophylactic for 2-5 years after splenectomy (longer periods might expose the patients to the risk of antibiotic resistance) with penicillin or amoxicillin/clavulanate acid is mandatory. Asplenic individuals should take empirical antibiotic therapy - so called "self treatment" - and immediate medical consultation in presence of febrile illness. All patients and their parents should be carefully educated about the risk of infections in order to obtain a good long-term compliance with these recommendations. PMID- 24051977 TI - [An unusual case of "complicated" adrenal hemorrhage]. AB - This case report concerns a newborn with bilateral adrenal massive hemorrhage complicated by inferior cava vein thrombosis, hypertension and encephalopathy to elaborate diagnostic and therapeutic problem of neonatal thromboembolic events. Increasing of risk population (extreme prematurity), improvement of imaging, laboratory and neonatologist care enhanced in recent years the diagnosis of this group of diseases. Even if literature about this subject is poor, we remark the significant effort of neonatologist to revise and update neonatal guidelines and the relevance of the institution of the National Registry of Neonatal Thrombosis (RITI). PMID- 24051978 TI - Conservative management of accessory spleen torsion in children. AB - Accessory spleen torsion is very rare condition especially in children. The aim of this study is to report the conservative treatment option. In April 2009 we observed a 10-year-old child affected by hereditary spherocytosis who reported acute abdominal pain without fever or vomiting. At hospitalization all blood tests were within normal value. Abdominal ultrasounds showed an increase in spleen volume and a solid round-shaped hypoechogenic formation with hyperechogenic areas in the lower pole without vascolarisation on color-Doppler scan. These findings suggested torsion of the accessory spleen. We opted for a conservative approach: analgesics on demand and antibiotics. After a week symptoms resolved spontaneously and patient was discharged in good health conditions. Follow-up ultrasound scans were performed at one week, three-six months and one year after hospitalization and showed a progressive reduction of the dimensions of the solid round-shaped formation. Accessory spleen torsion needs to be added to the differential diagnosis of cases of acute abdomen in children. Ultrasounds with eco-color-Doppler scans seem to be the best option for the diagnosis of such condition in the pediatric age since other diagnostic methods are more invasive and require sedation of patients. Once accessory spleen torsion is correctly diagnosed it is possible to opt for its conservative treatment. PMID- 24051979 TI - Sperm parameters: paradigmatic index of good health and longevity. AB - Since the discovery of spermatozoon by Anton van Leeuwenhoek in 1677, there has been an ever increasing understanding of its role in reproduction. Many factors adversely affect sperm quality, including varicocele, accessory gland infection, immunological factors, congenital abnormalities, and iatrogenic systemic and endocrine causes, such as diabetes mellitus, obesity, metabolic syndrome, and smoking. The mechanisms responsible for the association between poor sperm parameters and ill health may include oxidative stress, low-grade inflammation, low testosterone, and low sex-hormone-binding globulin. Oxidative stress in the testicular microenvironment may result in decreased spermatogenesis and sperm DNA damage, loss of sperm motility, and abnormal sperm morphology. Low testosterone caused by advanced age, visceral obesity, and inflammation is associated with the development of cardiovascular disease. Hence, semen analysis has an important role in the routine evaluation of idiopathic male infertility, usually manifested as low sperm counts, impaired sperm motility, or absence of sperm, and remains the most common single diagnostic tool. Several studies have shown an inverse relationship between semen quality and medical disorders. This review elucidates the effect of medical disorders and social habits on sperm quality, the mechanisms that are involved in the impairment of sperm quality, and whether or not sperm quality can be used as an index of good health and longevity in a man. PMID- 24051981 TI - Use of healthy-donor granulocyte transfusions to treat infections in neutropenic patients with myeloid or lymphoid neoplasms: experience in 74 patients treated with 373 granulocyte transfusions. AB - BACKGROUND/AIMS: Despite limited evidence for efficacy, granulocyte transfusions (GTX) are used to prevent and treat opportunistic infections in patients with neutropenia. METHODS: Three hundred and seventy-three GTX given to 74 patients were assessed retrospectively. RESULTS: GTX were discontinued because of clinical improvement more often in patients with severe infections than in patients without severe infections (27 vs. 12%; p <= 0.002), whereas deaths resulted in discontinuation of GTX therapy less often in patients with severe infections than without (8 vs. 39%; p <= 0.002). Patients who died by 12 weeks after GTX initiation were more likely to have leukemia (p = 0.03), not to have recovery of neutrophil counts (p < 0.0001), and to have started GTX during a critical care unit stay (p < 0.001). Uses of granulocyte colony-stimulating factor (p <= 0.02) and interferon-gamma (p <= 0.04) were more common in patients who survived. In patients with comorbidities (31%; odds ratio, OR, 12.6; 95% confidence interval, CI, 2.4-65.7; p <= 0.003), GTX was started in the critical care unit (OR 8.8; 95% CI 2.5-30.9; p < 0.001), and a high total bilirubin level at the end of GTX (OR 2.1; 95% CI 1.1-4.2; p = 0.03) had a higher probability of death 12 weeks after GTX therapy commenced. CONCLUSIONS: The possibility that a niche population may benefit from GTX requires further assessment. PMID- 24051982 TI - Effects of tadalafil on hemorrhagic cystitis and testicular dysfunction induced by cyclophosphamide in rats. AB - INTRODUCTION: The protective and/or therapeutic potential of tadalafil (TDL) on cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) and testicular dysfunction in rats was evaluated. MATERIALS AND METHODS: The animals except from the control group were divided into four groups and treated with saline, or 1, 5 or 10 mg/kg TDL orally (CP, TDL1, TDL5 and TDL10 groups, respectively) before and after CP injection. Body and organ weights, sperm count, cGMP, nitric oxide (NO), IL-6 and IL-10 levels in serum and bladder tissue, and serum testosterone (T), LH and FSH levels were determined. The histological analysis of bladder and testis was performed and the number of apoptotic cells was determined. RESULTS AND CONCLUSION: The CP group had decreased cGMP and NO levels in the bladder, serum T level (p < 0.05) and sperm count (p < 0.001) and higher IL-6 levels in serum and bladder (p < 0.01). Treatment with TDL resulted in increased cGMP (p < 0.001), NO (p < 0.05) and serum T (p < 0.05) levels. Histological analysis of the CP group showed severe HC in bladder and testicular damage. TDL-treated animals showed a dose-dependent improvement in all of these histological impairments. In conclusion, a selective inhibitor of phosphodiesterase-5 enzyme, TDL, showed a protective and/or therapeutic effect on CP-induced HC and testicular dysfunction in rats. PMID- 24051983 TI - Pioneering the concepts of stereognosis and polyradiculoneuritis: Octave Landry (1826-1865). AB - Octave Landry was one of a long list of fine 19th century clinicians who died very young and whose discoveries in physiology and descriptions of new clinical pictures helped found current-day neurology. In 1852, Landry proposed a new take on the physiology of sensation which laid the ground for the concepts of proprioception and stereognosis. He also described the clinical picture of a rapidly progressing ascending paralysis, which in 1859 prefigured Guillain-Barre syndrome. In discussing his very active life, we will mention the hydrotherapies in fashion at the time and the pleasures of Parisian society. Landry's career was also marked by terrible cholera epidemics, one of which killed him at age 39, in the prime of his working life as a devoted physician. PMID- 24051984 TI - Transcriptional and epigenetic regulation of neural crest induction during neurulation. AB - Neurulation is one of the many important events in mammalian development. It is the stage of organogenesis in vertebrate embryos during which the neural tube is transformed into the primitive structures that will later develop into the central nervous system. Recent transcriptome analysis during neurulation and early organogenesis in humans and mice has identified the global dynamics of gene expression changes across developmental time. This has revealed a richer understanding of gene regulation and provides hints at the transcriptional regulatory networks that underlie these processes. Similarly, epigenome analysis, which collectively constitutes histone modifications, transcription factor binding, and other structural features associated with gene regulation, has given a renewed appreciation to the subtle mechanisms involving the process of neurulation. More specifically, the histone demethylases KDM4A and KDM6B have recently been shown to be key histone H3K4 and H3K27 modifiers that regulate neural crest specification and neural tube closure. Additionally, miRNAs have recently been shown to influence transcription of genes directly or by altering the levels of epigenetic modifiers and thus regulate gene expression. This mini review briefly summarizes the literature, highlighting the transcriptional and epigenetic regulation of key genes involved in neural crest induction and neural crest specification by transcription factors and miRNAs. Understanding how these mechanisms work individually and in clusters will shed light on pathways in the context of diseases associated with neural crest cell derivatives such as melanoma, cardiovascular defects and neuronal craniofacial defects. PMID- 24051980 TI - Monocyte chemoattractant protein-1 and the blood-brain barrier. AB - The blood-brain barrier (BBB) is a dynamic structure that maintains the homeostasis of the brain and thus proper neurological functions. BBB compromise has been found in many pathological conditions, including neuroinflammation. Monocyte chemoattractant protein-1 (MCP1), a chemokine that is transiently and significantly up-regulated during inflammation, is able to disrupt the integrity of BBB and modulate the progression of various diseases, including excitotoxic injury and hemorrhage. In this review, we first introduce the biochemistry and biology of MCP1, and then summarize the effects of MCP1 on BBB integrity as well as individual BBB components. PMID- 24051985 TI - Sirolimus decreases circulating lymphangioleiomyomatosis cells in patients with lymphangioleiomyomatosis. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM), sporadic or in women with tuberous sclerosis complex (TSC), is characterized by cystic lung destruction, lymphatic involvement (eg, chylous pleural effusions, lymphangioleiomyomas), and renal angiomyolipomas (AMLs). The multisystem manifestations of LAM appear to result from metastatic dissemination of LAM cells bearing inactivating mutations or having loss of heterozygosity (LOH) of the tumor suppressor genes TSC1 or TSC2, which leads to hyperactivation of the mammalian target of rapamycin. Sirolimus slows the decline of lung function, reduces chylous effusions, and shrinks the size of AMLs. The purpose of this study was to determine the effect of sirolimus on circulating LAM cells. METHODS: Cells from blood were isolated by a density gradient fractionation system and from urine and chylous effusions by centrifugation. Blood cells were incubated with anti-CD45-fluorescein isothiocyanate (FITC) and anti-CD235a-R-phycoerythrin (PE) antibodies, and urine and chylous effusion cells were incubated with anti-CD44v6-FITC and anti-CD9-R-PE antibodies. Cells were sorted and analyzed for TSC2 LOH. RESULTS: LAM cells with TSC2 LOH were identified in 100% of blood specimens and 75% of urine samples from patients before therapy. Over a mean duration of 2.2 +/- 0.4 years of sirolimus therapy, detection rates of LAM cells were significantly decreased to 25% in blood (P < .001) and 8% in urine (P = .003). Following therapy, a greater loss of circulating LAM cells was seen in postmenopausal patients (P = .025). CONCLUSIONS: Patients receiving sirolimus had a progressive loss of circulating LAM cells that depended on time of treatment and menopausal status. PMID- 24051987 TI - Monte Carlo calculated doses to treatment volumes and organs at risk for permanent implant lung brachytherapy. AB - Iodine-125 ((125)I) and Caesium-131 ((131)Cs) brachytherapy have been used with sublobar resection to treat stage I non-small cell lung cancer and other radionuclides, (169)Yb and (103)Pd, are considered for these treatments. This work investigates the dosimetry of permanent implant lung brachytherapy for a range of source energies and various implant sites in the lung. Monte Carlo calculated doses are calculated in a patient CT-derived computational phantom using the EGsnrc user-code BrachyDose. Calculations are performed for (103)Pd, (125)I, (131)Cs seeds and 50 and 100 keV point sources for 17 implant positions. Doses to treatment volumes, ipsilateral lung, aorta, and heart are determined and compared to those determined using the TG-43 approach. Considerable variation with source energy and differences between model-based and TG-43 doses are found for both treatment volumes and organs. Doses to the heart and aorta generally increase with increasing source energy. TG-43 underestimates the dose to the heart and aorta for all implants except those nearest to these organs where the dose is overestimated. Results suggest that model-based dose calculations are crucial for selecting prescription doses, comparing clinical endpoints, and studying radiobiological effects for permanent implant lung brachytherapy. PMID- 24051986 TI - Role of the C-terminal domain in the structure and function of tetrameric sodium channels. AB - Voltage-gated sodium channels have essential roles in electrical signalling. Prokaryotic sodium channels are tetramers consisting of transmembrane (TM) voltage-sensing and pore domains, and a cytoplasmic carboxy-terminal domain. Previous crystal structures of bacterial sodium channels revealed the nature of their TM domains but not their C-terminal domains (CTDs). Here, using electron paramagnetic resonance (EPR) spectroscopy combined with molecular dynamics, we show that the CTD of the NavMs channel from Magnetococcus marinus includes a flexible region linking the TM domains to a four-helix coiled-coil bundle. A 2.9 A resolution crystal structure of the NavMs pore indicates the position of the CTD, which is consistent with the EPR-derived structure. Functional analyses demonstrate that the coiled-coil domain couples inactivation with channel opening, and is enabled by negatively charged residues in the linker region. A mechanism for gating is proposed based on the structure, whereby splaying of the bottom of the pore is possible without requiring unravelling of the coiled-coil. PMID- 24051988 TI - Endocrine-disrupting chemical exposure and the American alligator: a review of the potential role of environmental estrogens on the immune system of a top trophic carnivore. AB - Endocrine-disrupting chemicals (EDCs) alter cellular and organ system homeostasis by interfering with the body's normal physiologic processes. Numerous studies have identified environmental estrogens as modulators of EDC-related processes in crocodilians, notably in sex determination. Other broader studies have shown that environmental estrogens dysregulate normal immune function in mammals, birds, turtles, lizards, fish, and invertebrates; however, the effects of such estrogenic exposures on alligator immune function have not been elucidated. Alligators occupy a top trophic status, which may give them untapped utility as indicators of environmental quality. Environmental estrogens are also prevalent in the waters they occupy. Understanding the effects of these EDCs on alligator immunity is critical for managing and assessing changes in their health and is thus the focus of this review. PMID- 24051989 TI - Serum adiponectin, anemia and left ventricular dimensions in patients with cardiac cachexia. AB - OBJECTIVES: Our study aims to determine the role of serum adiponectin in chronic heart failure (CHF) and cardiac cachexia (CC). METHODS: Ninety consecutive patients were included in the study. Patients were divided into three groups: 30 CHF patients with CC, 30 CHF patients without CC, and 30 healthy individuals. Adiponectin levels were measured through human ELISA kits. RESULTS: Levels of serum adiponectin were significantly higher in the CHF patients with cachexia in comparison with the other groups (CHF with CC: 58.4 +/- 15.5 ng/ml vs. CHF without CC: 24 +/- 6.7 ng/ml and controls: 7.7 +/- 3.4 ng/ml; p = 0.001). Serum adiponectin was negatively correlated with BMI, high-sensitivity C-reactive protein, and hemoglobin (r = -0.37, p = 0.02; r = -0.29, p = 0.02; r = -0.18, p = 0.03, respectively) in the CHF patients with cachexia. Additionally, serum adiponectin levels were positively correlated with B-type natriuretic protein levels, left ventricle end-diastolic and end-systolic diameters (r = 0.36, p = 0.02; r = 0.46, p = 0.01; r = 0.49, p = 0.006, respectively) in the CHF patients with cachexia. CONCLUSION: Our findings suggest that adiponectin may play a critical role in the pathogenesis of cardiac remodeling and anemia in CC. PMID- 24051990 TI - Gated access to alpha-lithiated phenyltetrahydrofuran: functionalisation via direct lithiation of the parent oxygen heterocycle. AB - Cycloreversion of alpha-lithiated phenyltetrahydrofuran was successfully tamed at -78 degrees C in a non-coordinating solvent in the presence of TMEDA. This anion showed excellent nucleophilicity and could be intercepted with a variety of structurally different electrophiles to give 2,2-disubstituted derivatives which can be further elaborated to gamma-butyrolactones. PMID- 24051991 TI - Using biology to define optimal treatments for low back pain: opportunities for physiatrists. PMID- 24051993 TI - Additional virtual reality training using Xbox Kinect in stroke survivors with hemiplegia. AB - OBJECTIVE: The aim of this study was to investigate the effects of additional virtual reality training using Xbox Kinect on upper extremity function, including range of motion, motor function, and gross manual dexterity, in stroke survivors with hemiplegia. DESIGN: This study is a randomized controlled trial. Forty participants were randomly allocated to either the experimental or control groups; the experimental group (n = 20) underwent virtual reality training using Xbox Kinect and conventional occupational therapy, and the control group (n = 20) underwent conventional occupational therapy alone. The mean time since the onset of stroke was 7.22 mos in the experimental group and 8.47 mos in the control group. At baseline and after 6 wks of intervention, range of motion of the upper extremity was measured, and the Fugl-Meyer Assessment and the Box and Block Test were performed. RESULTS: After intervention, significant improvements from baseline values in range of motion of the upper extremity, Fugl-Meyer Assessment scores, and Box and Block Test scores were observed in the experimental and control groups (P < 0.05). At follow-up, there were significant differences between the two groups in range of motion (except for the wrist), Fugl-Meyer Assessment scores, and Box and Block Test scores (P < 0.05). CONCLUSIONS: The hemiplegic stroke survivors who received additional virtual reality training using Xbox Kinect showed significantly improved function of the upper extremity. However, the effects of the virtual reality training using Xbox Kinect may have been a result of the greater total intervention time in the training group compared with the control group. Thus, the potential efficacy of Xbox Kinect in the rehabilitation of post-stroke survivors needs to be investigated in greater depth. PMID- 24051992 TI - New utility for an old tool: can a simple gait speed test predict ambulatory surgical discharge outcomes? AB - OBJECTIVE: The primary aims of this study were to design prediction models based on a functional marker (preoperative gait speed) to predict readiness for home discharge time of 90 mins or less and to identify those at risk for unplanned admissions after elective ambulatory surgery. DESIGN: This prospective observational cohort study evaluated all patients scheduled for elective ambulatory surgery. Home discharge readiness and unplanned admissions were the primary outcomes. Independent variables included preoperative gait speed, heart rate, and total anesthesia time. The relationship between all predictors and each primary outcome was determined in separate multivariable logistic regression models. RESULTS: After adjustment for covariates, gait speed with adjusted odds ratio of 3.71 (95% confidence interval, 1.21-11.26), P = 0.02, was independently associated with early home discharge readiness of 90 mins or less. Importantly, gait speed dichotomized as greater or less than 1 m/sec predicted unplanned admissions, with odds ratio of 0.35 (95% confidence interval, 0.16-0.76, P = 0.008) for those with speeds 1 m/sec or greater in comparison with those with speeds less than 1 m/sec. In a separate model, history of cardiac surgery with adjusted odds ratio of 7.5 (95% confidence interval, 2.34-24.41; P = 0.001) was independently associated with unplanned admissions after elective ambulatory surgery, when other covariates were held constant. CONCLUSIONS: This study demonstrates the use of novel prediction models based on gait speed testing to predict early home discharge and to identify those patients at risk for unplanned admissions after elective ambulatory surgery. PMID- 24051994 TI - Laryngeal response patterns to mechanical insufflation-exsufflation in healthy subjects. AB - OBJECTIVE: Mechanical insufflation-exsufflation (MI-E) is used to assist cough in patients with neuromuscular diseases. Clinically, application may be challenging in some patient groups, possibly related to laryngeal dysfunction. Before launching a study in patients, the authors investigated laryngeal responses to MI E in healthy individuals. DESIGN: Twenty healthy volunteers, aged 21-29 yrs, were studied with video-recorded flexible transnasal fiber-optic laryngoscopy while performing MI-E using the Cough Assist (Respironics, United States) according to a standardized protocol applying pressures of +/-20 to +/-50 cm H2O. RESULTS: An initial abduction of the vocal folds was observed in all subjects, both during the insufflation and exsufflation phases. Nineteen of the 20 subjects adequately coordinated glottic closure when instructed to cough. When instructed simply to exhale during exsufflation, the glottis stayed open in a majority. Subsequent to an initial abduction during exsufflation and cough, various obstructive laryngeal movements were observed in some subjects, such as narrowing of the vocal folds, retroflexion of the epiglottis, hypopharyngeal constriction, and backward movement of the base of the tongue. CONCLUSIONS: The larynx can be studied with transnasal laryngoscopy during MI-E in healthy individuals. Laryngeal responses to MI-E vary, and laryngoscopy may offer valuable clinical information when applying MI-E in patients with bulbar muscle weakness. PMID- 24051995 TI - A historical perspective on expiratory muscle aids and their impact on home care. AB - Mechanically assisted coughing is the combination of mechanical insufflation exsufflation to the airways in conjunction with an exsufflation-timed abdominal thrust. It has permitted in-home long-term survival of respirator-dependent users of continuous noninvasive intermittent positive pressure ventilatory support in the United States since shortly after it became available in 1952. By contrast, the first European patients to benefit from continuous noninvasive intermittent positive pressure ventilatory support were not described until institutionalized continuous noninvasive intermittent positive pressure ventilatory support users with Duchenne muscular dystrophy were described in Belgium in 2006, 2 yrs after mechanically assisted coughing was approved for sale by the European Union. Domiciliary management with continuous noninvasive intermittent positive pressure ventilatory support and mechanically assisted coughing has subsequently been described in Europe. This work describes the historical development of mechanically assisted coughing in the framework of aiding the respiratory muscles to prevent respiratory failure and avoid invasive airway intubation. Some current mechanical in-exsufflators include oscillation as a surrogate for physiologic mucociliary transport along with their assisted coughing function. Noninvasive management prolongs life while promoting cost containment and preserving quality of-life for patients with respiratory muscle impairment. PMID- 24051996 TI - Proximal median nerve entrapment caused by a distal biceps tendon cyst: an ultrasonographic diagnosis. AB - A 60-yr-old woman reported severe pain in the proximal part of her left forearm. The pain was also radiating toward the median nerve-innervated areas of the arm, especially during elbow flexion. Ultrasonographic imaging showed a well defined ganglion cyst around the distal biceps tendon close to the median nerve. Under ultrasound guidance, the cyst was aspirated and corticosteroid injection was performed. The patient's complaint improved 1 wk after the injection, and she started to flex her elbow without any pain. This case highlights the role of ultrasonography as a useful adjunctive tool not only to morphologically confirm a peripheral nerve entrapment but also to uncover the possible underlying etiology and to guide precisely during an intervention. PMID- 24051997 TI - Primary synovial sarcoma of the kidney. AB - Synovial Sarcoma (SS) is a soft tissue neoplasm that occurs generally in the proximity of large joints. Here, we report a case of a 45-year-old man who was diagnosed with Primary SS of the kidney which is an extremely rare tumor that accounts for less than 2% of malignant renal tumors. We also review the literature on primary synovial sarcomas of the kidney and focus especially on the renal tumors' differential diagnosis. PMID- 24051998 TI - Impact and effectiveness of RotaTeq(r) vaccine based on 3 years of surveillance following introduction of a rotavirus immunization program in Finland. AB - BACKGROUND: Finland introduced universal rotavirus (RV) vaccination in September 2009, with exclusive use of the pentavalent human-bovine reassortant RV vaccine RotaTeq(r) and following a vaccination schedule at 2, 3 and 5 months of age. This study monitored the impact of RV vaccination on hospitalizations due to RV acute gastroenteritis (RVGE). The results following the first 3 RV seasons after implementation of universal RV vaccination are presented. METHODS: Prospective hospital-based surveillance identified children with acute gastroenteritis admitted to 2 University Hospitals (Tampere and Oulu, Finland), from December 2009 to August 2012. The surveillance covered a population of approximately 173,000 children from the 2 hospitals' catchment areas. Stool samples were taken and analyzed centrally for RV by enzyme-linked immunosorbent assay, with genotyping by reverse transcription polymerase chain reaction. International Classification of Diseases discharge codes were collected retrospectively pre- and postvaccination. RESULTS: During the 3-year prospective surveillance, 127 RVGE episodes were identified. Of these, 117 were in unvaccinated children and 6 were in fully vaccinated children (RotaTeq, n = 3; Rotarix, n = 3). The vaccine effectiveness against hospitalized RVGE for fully vaccinated children was 92.1% [95% confidence interval (CI): 50.0-98.7] among children eligible for the National Immunization Program. When analyzing retrospectively the Tampere and Oulu hospital databases for all children aged <16 years, hospitalizations for RVGE had decreased by 78% in the postvaccination period (2009-2012) compared with the prevaccination data (2001-2006). CONCLUSIONS: Severe RVGE requiring hospitalization was virtually eliminated in vaccine-eligible children in the 3 years following implementation of universal RotaTeq vaccination in Finland. PMID- 24052000 TI - A pH-triggered bistable copper(II) metallacycle as a reversible emulsion switch for biphasic processes. AB - A unique bistable copper-metallacyclic complex is used as an elegant molecular switch for the reversible formation of emulsions by simple pH variation. This switch may have several exciting applications in biphasic processes such as catalysis and separation science technologies. PMID- 24051999 TI - Diabetes mellitus in neonates and infants: genetic heterogeneity, clinical approach to diagnosis, and therapeutic options. AB - Over the last decade, we have witnessed major advances in the understanding of the molecular basis of neonatal and infancy-onset diabetes. It is now widely accepted that diabetes presenting before 6 months of age is unlikely to be autoimmune type 1 diabetes. The vast majority of such patients will have a monogenic disorder responsible for the disease and, in some of them, also for a number of other associated extrapancreatic clinical features. Reaching a molecular diagnosis will have immediate clinical consequences for about half of affected patients, as identification of a mutation in either of the two genes encoding the ATP-sensitive potassium channel allows switching from insulin injections to oral sulphonylureas. It also facilitates genetic counselling within the affected families and predicts clinical prognosis. Importantly, monogenic diabetes seems not to be limited to the first 6 months but extends to some extent into the second half of the first year of life, when type 1 diabetes is the more common cause of diabetes. From a scientific perspective, the identification of novel genetic aetiologies has provided important new knowledge regarding the development and function of the human pancreas. PMID- 24052002 TI - Clozapine-associated pneumonia and respiratory arrest secondary to severe constipation. AB - Clozapine is often the drug of choice within patients suffering from treatment resistant paranoid schizophrenia. It has a complex side effects profile which includes potentially fatal agranulocytosis. Clozapine has also become increasingly associated with a range of other side effects including constipation and pneumonia. We report on a case of clozapine-induced severe constipation leading to a silent presentation of pneumonia with a subsequent respiratory arrest. To our knowledge, this is the first case report of pneumonia secondary to severe constipation occurring in the absence of respiratory aspiration of feculent vomitus. We suggest a new pathological mechanism by way of severe constipation leading to diaphragmatic dysfunction and subsequent clozapine induced pneumonia. In addition, implications for clinical practice are outlined. PMID- 24052001 TI - Disruption of endogenous purinergic signaling inhibits vascular endothelial growth factor- and glutamate-induced osmotic volume regulation of Muller glial cells in knockout mice. AB - BACKGROUND/AIMS: Osmotic swelling of Muller cells is a common phenomenon in animal models of ischemic and diabetic retinopathies. Muller cells possess a swelling-inhibitory purinergic signaling cascade which can be activated by various receptor ligands including vascular endothelial growth factor (VEGF) and glutamate. Here, we investigated whether deletion of P2Y1 (P2Y1R) and adenosine A1 receptors (A1AR), and of inositol-1,4,5-trisphosphate-receptor type 2 (IP3R2), in mice affects the inhibitory action of VEGF and glutamate on Muller cell swelling. METHODS: The cross-sectional area of Muller cell somata was recorded after a 4-min superfusion of retinal slices with a hypoosmotic solution. RESULTS: Hypoosmolarity induced a swelling of Muller cells from P2Y1R(-/-), A1AR(-/-) and IP3R2(-/-) mice, but not from wild-type mice. Swelling of wild-type Muller cells was induced by hypoosmotic solution containing barium chloride. Whereas VEGF inhibited the swelling of wild-type Muller cells, it had no swelling-inhibitory effect in cells from A1AR(-/-) and IP3R2(-/-) mice. Glutamate inhibited the swelling of wild-type Muller cells but not of cells from P2Y1R(-/-), A1AR(-/-) and IP3R2(-/-) animals. CONCLUSION: The swelling-inhibitory effects of VEGF and glutamate in murine Muller cells is mediated by transactivation of P2Y1R and A1AR, as well as by intracellular calcium signaling via activation of IP3R2. PMID- 24052003 TI - Forensic identification using multiple lot numbers of an implanted device. AB - We report a case in which identification of a deceased individual was established using multiple lot numbers printed on a body implantable device. Autopsy of an unknown woman revealed an intramedullary nail inserted within her right femur. The device manufacturer was identified from the configuration of the intramedullary nail, and the "use history" was traced from lot numbers printed on the device's multiple parts. The deceased individual was thus identified as a woman who had attempted suicide by jumping from a height about a year previously and had been transported to a hospital and undergone surgery that included implantation of the intramedullary nail. The main factor contributing to the rapid identification was the manufacturer's and distributor's record of the use history (traceability) of the product, because of their accountability for purposes of quality control. A second contributing factor was multiple lot numbers, resulting in extremely low probability of the same combination of lot numbers being present in multiple individuals. This case confirmed the utility of multiple lot numbers of body implantable devices in forensic identification. PMID- 24052004 TI - Suicidal strangulation by double ligature: a case report. AB - This article reports a self-strangulation suicide in which a double complex group of ligatures was used. Although similar cases have been referenced in forensic literature, this case is notable because of the unusual method used by the victim. A 61-year-old man was found in a locked room with a double elaborate ligature comprising six wire clothes hangers completely encircling the neck and a black rubber band in a double loop. Autopsy also documented parallel superficial cut lesions in proximal forearm interpreted as hesitation marks. It stresses the importance of characteristics such as analysis of number of ligatures, position of the knots, number of knots and turns of ligature marks and the absence of any defense and relevant internal injuries inherent to suicide ligature strangulation cases. PMID- 24052005 TI - Class IA PI3K inhibition inhibits cell growth and proliferation in mantle cell lymphoma. AB - BACKGROUND/AIMS: Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway preferentially occurs in aggressive blastoid variants of mantle cell lymphoma (MCL) and is implicated in the pathogenesis of this disease. In this study, we investigated the role of PI3K isoforms on proliferation of aggressive MCL cells. METHODS: The changes in cell viability, cell cycle distribution and apoptosis induction by the PI3K isoform-selective inhibitors were evaluated. The molecular basis underlying the effects of the specific inhibition of PI3K isoforms was investigated by Western blot analysis. RESULTS: Our results demonstrated that a class IA PI3K isoform is most commonly involved in the constitutive activation of Akt in aggressive MCL. Treatment with a p110alpha isoform-specific inhibitor induced prominent cell cycle arrest followed by apoptosis through complete abolishment of phosphorylated (p)-Akt and its downstream targets. An inhibitor of isoform p110delta induced moderate cell cycle arrest with downregulation of p-Akt and p-S6K. A dual inhibitor of p110alpha and p110delta GDC-0941 caused more prominent cell growth inhibition compared to selective p110alpha or p110delta inhibitors. Inhibition of the class IB PI3K isoform p110gamma did not cause cell cycle arrest or induce apoptosis in MCL cells. CONCLUSION: These findings suggest that the therapeutic ablation of class IA PI3K may be a promising strategy for the treatment of refractory, aggressive MCL. PMID- 24052006 TI - Pattern of voiding dysfunction after acute brainstem infarction. AB - BACKGROUND: The purpose of this study is to compare the patterns of voiding dysfunction according to the locations of brainstem lesions. METHODS: Between November 2008 and December 2011, a total of 30 patients participated in this study. All 30 subjects, consisting of 16 men and 14 women, aged between 41 and 82 years (mean age, 63.0+/-11.0 years) underwent a urodynamic study within 7 days after the onset of a stroke. RESULTS: Twenty-one (70%) patients had a pontine lesion and 9 (30%) had a medullary lesion. Fourteen of these patients (46.7%) had bladder storage disorder, 7 patients (23.3%) had bladder emptying disorder, and 9 patients (30%) had a normal report. Five of the patients who had a medullary lesion (55.6%) had bladder emptying disorder, whereas only 2 patients who had a pontine lesion (9.5%) had bladder emptying disorder. Thirteen patients who had a pontine lesion (61.9%) showed bladder storage disorder. DISCUSSION: The descending pathway from the midbrain tegmentum is inhibitory, and the pathway from the pontine tegmentum is stimulatory. Because of their location pontine lesions could disrupt the descending fibers of the midbrain tegmentum and medullary lesions could disrupt the descending fibers of the pontine tegmentum. PMID- 24052008 TI - Empowering patients who have specific learning disabilities. PMID- 24052007 TI - Primary cytomegalovirus infection in pregnant Egyptian women confirmed by cytomegalovirus IgG avidity testing. AB - OBJECTIVE: To determine the frequency of primary cytomegalovirus (CMV) infection in pregnant Egyptian women using CMV IgG avidity testing. SUBJECTS AND METHODS: A cross-sectional study was conducted at Suez Canal University Hospital, Ismailia, Egypt. A total of 546 pregnant women, presenting for routine antenatal screening, were tested for CMV IgG and IgM using a commercially available enzyme-linked immunosorbent assay (ELISA). Sera from CMV IgM-positive women were tested by CMV IgG avidity assay. RESULTS: All the 546 pregnant women were seropositive for anti CMV IgG. Of the 546 women, 40 (7.3%) were positive or equivocal for IgM antibodies. All sera from the 40 women (IgG+/IgM+) showed a high or intermediate CMV IgG avidity index. Of the 40 women, 23 (57.5%) were in the second or third trimesters of pregnancy and had their first-trimester blood retrieved, and the tested CMV IgG avidity assay showed a high avidity index. CONCLUSION: Women who were IgM positive had no primary CMV infection in the index pregnancy as evidenced by the high CMV IgG avidity testing. PMID- 24052009 TI - Survival and prognostic factors in non-small cell lung cancer patients with spinal bone metastases: a retrospective analysis of 303 patients. AB - BACKGROUND AND PURPOSE: For palliative care of spinal bone metastases, stability assessment is of crucial importance. Pathological fractures, instability-related patient immobility and the extent of bone metastasis have been reported to affect patient outcome and these parameters have therefore been used for treatment stratification. We report on stability-dependent fracture and survival rates in over 300 non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Data from 303 patients with 868 osteolytic metastases treated with radiotherapy (RT) between 2000 and 2012 were evaluated retrospectively. RESULTS: In NSCLC patients with bone metastases only, the retrospective 6- and 12-month overall survival (OS) rates were 76.7 and 47.2%, respectively. In patients with additional non bone distant metastases, these values were 60.0 and 34.0%, respectively. Survival rates were significantly lower in patients with multiple bone metastases and in those suffering pathological fractures (p=0.017). No significant impact of histological type, location of spinal lesions or treatment regime was detected. Furthermore, stability assessment revealed no influence of vertebral column stability on patient outcome (p=0.739). CONCLUSION: Our analysis demonstrated a correlation between the pathological fractures of bone lesions, the number of bone metastases, additional distant metastases and survival. The results offer a rationale for future prospective investigations. PMID- 24052010 TI - Small bowel toxicity after high dose spot scanning-based proton beam therapy for paraspinal/retroperitoneal neoplasms. AB - PURPOSE: Mesenchymal tumours require high-dose radiation therapy (RT). Small bowel (SB) dose constraints have historically limited dose delivery to paraspinal and retroperitoneal targets. This retrospective study correlated SB dose-volume histograms with side-effects after proton radiation therapy (PT). PATIENTS AND METHODS: Between 1997 and 2008, 31 patients (mean age 52.1 years) underwent spot scanning-based PT for paraspinal/retroperitoneal chordomas (81%), sarcomas (16%) and meningiom (3%). Mean total prescribed dose was 72.3 Gy (relative biologic effectiveness, RBE) delivered in 1.8-2 Gy (RBE) fractions. Mean follow-up was 3.8 years. Based on the pretreatment planning CT, SB dose distributions were reanalysed. RESULTS: Planning target volume (PTV) was defined as gross tumour volume (GTV) plus 5-7 mm margins. Mean PTV was 560.22 cm(3). A mean of 93.2% of the PTV was covered by at least 90% of the prescribed dose. SB volumes (cm(3)) receiving doses of 5, 20, 30, 40, 50, 60, 70, 75 and 80 Gy (RBE) were calculated to give V5, V20, V30, V40, V50, V60, V70, V75 and V80 respectively. In 7/31 patients, PT was accomplished without any significant SB irradiation (V5=0). In 24/31 patients, mean maximum dose (Dmax) to SB was 64.1 Gy (RBE). Despite target doses of >70 Gy (RBE), SB received >50 and >60 Gy (RBE) in only 61 and 54% of patients, respectively. Mean SB volumes (cm(3)) covered by different dose levels (Gy, RBE) were: V20 (n=24): 45.1, V50 (n=19): 17.7, V60 (n=17): 7.6 and V70 (n=12): 2.4. No acute toxicity >= grade 2 or late SB sequelae were observed. CONCLUSION: Small noncircumferential volumes of SB tolerated doses in excess of 60 Gy (RBE) without any clinically-significant late adverse effects. This small retrospective study has limited statistical power but encourages further efforts with higher patient numbers to define and establish high-dose threshold models for SB toxicity in modern radiation oncology. PMID- 24052012 TI - Epidemiology of sexually transmitted infections in global indigenous populations: data availability and gaps. AB - Socioeconomic and health disadvantage is widespread within and across indigenous communities in the world, leading to differentials in morbidity and mortality between indigenous and non-indigenous populations. Sexually transmitted infections (STIs), including HIV/AIDS, among indigenous populations are an emerging public health concern. The focus of this paper is on examining the STI epidemiology in indigenous communities in various parts of the world utilizing a range of data sources. Most of the STI research on global indigenous communities has concentrated on developed countries, neglecting more than half the world's indigenous people in the developing countries. This has resulted in major gaps in data at global level for STIs and HIV/AIDS among indigenous populations. Available data show that the prevalence of STIs is increasing among the indigenous communities and in several instances, the rates of these infections are higher than among non-indigenous populations. However, HIV still remains low when compared with the rates of other STIs. The paper argues that there is an urgent need to collect more comprehensive and reliable data at the global level across various indigenous communities. There is also an opportunity to reverse current trends in STIs through innovative, evidence-based and culturally appropriate targeted sexual health programmes. PMID- 24052011 TI - Definition of stereotactic body radiotherapy: principles and practice for the treatment of stage I non-small cell lung cancer. AB - This report from the Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (Deutschen Gesellschaft fur Radioonkologie, DEGRO) provides a definition of stereotactic body radiotherapy (SBRT) that agrees with that of other international societies. SBRT is defined as a method of external beam radiotherapy (EBRT) that accurately delivers a high irradiation dose to an extracranial target in one or few treatment fractions. Detailed recommendations concerning the principles and practice of SBRT for early stage non-small cell lung cancer (NSCLC) are given. These cover the entire treatment process; from patient selection, staging, treatment planning and delivery to follow-up. SBRT was identified as the method of choice when compared to best supportive care (BSC), conventionally fractionated radiotherapy and radiofrequency ablation. Based on current evidence, SBRT appears to be on a par with sublobar resection and is an effective treatment option in operable patients who refuse lobectomy. PMID- 24052014 TI - Vulvovaginal swabs are the best for chlamydia and gonorrhoea: let's change practice. PMID- 24052013 TI - Failure of moxifloxacin treatment in Mycoplasma genitalium infections due to macrolide and fluoroquinolone resistance. AB - Increasing azithromycin treatment failure in sexually transmitted Mycoplasma genitalium infection, is linked to macrolide resistance and second-line treatment relies on the fluoroquinolone, moxifloxacin. We recently detected fluoroquinolone and macrolide resistance-associated mutations in 15% and 43%, respectively, of 143 initial M. genitalium PCR-positive specimens. For a subset of 33 Western Sydney Sexual Health Centre patients, clinical information and results of sequence analysis of M. genitalium macrolide and fluoroquinolone target genes - the 23S rRNA gene, and parC and gyrA, respectively - were used to examine whether mutations were associated with treatment failure. Macrolide resistance-associated mutations correlated with microbiological (p = 0.013) and clinical (p = 0.024) treatment failure, and fluoroquinolone resistance-associated mutations with microbiological moxifloxacin treatment failure (p = 0.005). We describe the first reported cases of clinical and microbiological moxifloxacin treatment failure. Failure of first- and second-line antibiotic treatment of M. genitalium infection is occurring and likely to increase with current treatment strategies. PMID- 24052015 TI - The interplay between apparent viscosity and wettability in nanoconfined water. AB - Understanding and manipulating fluids at the nanoscale is a matter of growing scientific and technological interest. Here we show that the viscous shear forces in nanoconfined water can be orders of magnitudes larger than in bulk water if the confining surfaces are hydrophilic, whereas they greatly decrease when the surfaces are increasingly hydrophobic. This decrease of viscous forces is quantitatively explained with a simple model that includes the slip velocity at the water surface interface. The same effect is observed in the energy dissipated by a tip vibrating in water perpendicularly to a surface. Comparison of the experimental data with the model shows that interfacial viscous forces and compressive dissipation in nanoconfined water can decrease up to two orders of magnitude due to slippage. These results offer a new understanding of interfacial fluids, which can be used to control flow at the nanoscale. PMID- 24052016 TI - Transient serosal enhancement mimicking pneumoperitoneum. PMID- 24052017 TI - Radium-223 chloride: Extending life in prostate cancer patients by treating bone metastases. AB - The treatment scope for patients with metastatic castrate-resistant prostate cancer (mCRPC) is rapidly expanding. On May 15, 2013, the U.S. Food and Drug Administration (FDA) approved radium-223 chloride ((223)RaCl2) for the treatment of mCRPC patients whose metastases are limited to the bones. Radium-223 is an alpha-emitting alkaline earth metal ion, which, similar to calcium ions, accumulates in the bone. In a phase III study (ALSYMPCA), mCRPC patients with bone metastases received best standard-of-care treatment with placebo or (223)RaCl2. At a prespecified interim analysis, the primary endpoint of median overall survival was significantly extended by 3.6 months in patients treated with radium-223 compared with placebo (P < 0.001). The radioisotope was well tolerated and gave limited bone marrow suppression. (223)RaCl2 is the first bone targeting antitumor therapy that received FDA approval based on a significant extended median overall survival. Further studies are required to optimize its dosing and to confirm its efficacy and safety in cancer patients. PMID- 24052018 TI - Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature. AB - PURPOSE: Cancer-associated fibroblasts (CAF) actively participate in reciprocal communication with tumor cells and with other cell types in the microenvironment, contributing to a tumor-permissive neighborhood and promoting tumor progression. The aim of this study is the characterization of how CAFs from primary human colon tumors promote migration of colon cancer cells. EXPERIMENTAL DESIGN: Primary CAF cultures from 15 primary human colon tumors were established. Their enrichment in CAFs was evaluated by the expression of various epithelial and myofibroblast specific markers. Coculture assays of primary CAFs with different colon tumor cells were performed to evaluate promigratory CAF-derived effects on cancer cells. Gene expression profiles were developed to further investigate CAF characteristics. RESULTS: Coculture assays showed significant differences in fibroblast-derived paracrine promigratory effects on cancer cells. Moreover, the association between CAFs' promigratory effects on cancer cells and classic fibroblast activation or stemness markers was observed. CAF gene expression profiles were analyzed by microarray to identify deregulated genes in different promigratory CAFs. The gene expression signature, derived from the most protumorogenic CAFs, was identified. Interestingly, this "CAF signature" showed a remarkable prognostic value for the clinical outcome of patients with colon cancer. Moreover, this prognostic value was validated in an independent series of 142 patients with colon cancer, by quantitative real-time PCR (qRT-PCR), with a set of four genes included in the "CAF signature." CONCLUSIONS: In summary, these studies show for the first time the heterogeneity of primary CAFs' effect on colon cancer cell migration. A CAF gene expression signature able to classify patients with colon cancer into high- and low-risk groups was identified. PMID- 24052020 TI - End-therapy positron emission tomography for treatment response assessment in follicular lymphoma: a systematic review and meta-analysis. AB - PURPOSE: Use of 2[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in postchemotherapy response assessment in follicular lymphoma is still a controversial issue. Here, we conducted the first systematic review and meta analysis to determine the predictive value of FDG-PET in predicting outcome after chemotherapy of follicular lymphoma. EXPERIMENTAL DESIGN: Comprehensive literature search in Ovid-MEDLINE and EMBASE databases was performed to identify studies which evaluate predictive value of end-therapy PET and/or computed tomography (CT) in patients with follicular lymphoma. To quantitatively compare the predictive value of PET and CT, pooled hazard ratios (HRs) comparing progression-free survival (PFS) between patients with positive and negative results were adopted as the primary indicators for meta-analysis. To explore the efficiency in determining complete remission (CR), pooled CR rates of PET- and CT based response criteria were calculated. Pooling of these parameters was based on the random-effects model. RESULTS: Review of 285 candidate articles identified eight eligible articles with a total of 577 patients for qualitative review and meta-analysis. The pooled HRs of end-therapy PET and CT were 5.1 [95% confidence interval (CI), 3.7-7.2] and 2.6 (95% CI, 1.2-5.8), respectively, which implies that PET is more predictive of PFS after chemotherapy than CT. The pooled CR rates of PET- and CT-based response criteria were 75% (95% CI, 70-79%) and 63% (95% CI, 53-73%), respectively, which implies that PET is more efficient in distinguishing CR (without residual disease) from other states with residual disease. In addition, qualitative systematic review indicates the same findings. CONCLUSIONS: Consistent evidence favoring PET-based treatment assessment should be considered in the management of patients with follicular lymphoma. PMID- 24052019 TI - Targeting fibroblast growth factor pathways in prostate cancer. AB - Advanced prostate cancer carries a poor prognosis and novel therapies are needed. Research has focused on identifying mechanisms that promote angiogenesis and cellular proliferation during prostate cancer progression from the primary tumor to bone-the principal site of prostate cancer metastases. One candidate pathway is the fibroblast growth factor (FGF) axis. Aberrant expression of FGF ligands and FGF receptors leads to constitutive activation of multiple downstream pathways involved in prostate cancer progression including mitogen-activated protein kinase, phosphoinositide 3-kinase, and phospholipase Cgamma. The involvement of FGF pathways in multiple mechanisms relevant to prostate tumorigenesis provides a rationale for the therapeutic blockade of this pathway, and two small-molecule tyrosine kinase inhibitors-dovitinib and nintedanib-are currently in phase II clinical development for advanced prostate cancer. Preliminary results from these trials suggest that FGF pathway inhibition represents a promising new strategy to treat castrate-resistant disease. PMID- 24052021 TI - Influence of the partial volume correction method on (18)F-fluorodeoxyglucose brain kinetic modelling from dynamic PET images reconstructed with resolution model based OSEM. AB - Kinetic parameters estimated from dynamic (18)F-fluorodeoxyglucose ((18)F-FDG) PET acquisitions have been used frequently to assess brain function in humans. Neglecting partial volume correction (PVC) for a dynamic series has been shown to produce significant bias in model estimates. Accurate PVC requires a space variant model describing the reconstructed image spatial point spread function (PSF) that accounts for resolution limitations, including non-uniformities across the field of view due to the parallax effect. For ordered subsets expectation maximization (OSEM), image resolution convergence is local and influenced significantly by the number of iterations, the count density, and background-to target ratio. As both count density and background-to-target values for a brain structure can change during a dynamic scan, the local image resolution may also concurrently vary. When PVC is applied post-reconstruction the kinetic parameter estimates may be biased when neglecting the frame-dependent resolution. We explored the influence of the PVC method and implementation on kinetic parameters estimated by fitting (18)F-FDG dynamic data acquired on a dedicated brain PET scanner and reconstructed with and without PSF modelling in the OSEM algorithm. The performance of several PVC algorithms was quantified with a phantom experiment, an anthropomorphic Monte Carlo simulation, and a patient scan. Using the last frame reconstructed image only for regional spread function (RSF) generation, as opposed to computing RSFs for each frame independently, and applying perturbation geometric transfer matrix PVC with PSF based OSEM produced the lowest magnitude bias kinetic parameter estimates in most instances, although at the cost of increased noise compared to the PVC methods utilizing conventional OSEM. Use of the last frame RSFs for PVC with no PSF modelling in the OSEM algorithm produced the lowest bias in cerebral metabolic rate of glucose estimates, although by less than 5% in most cases compared to the other PVC methods. The results indicate that the PVC implementation and choice of PSF modelling in the reconstruction can significantly impact model parameters. PMID- 24052022 TI - Vitamin K intake, body mass index and warfarin maintenance dose. AB - BACKGROUND: Warfarin inhibits vitamin K-dependent coagulation factors. Being fat soluble, the availability of vitamin K may vary according to body fat. We hypothesized that body mass index (BMI), a proxy of body fat, may interact with vitamin K intake in determining a warfarin maintenance (WM) dose. METHODS: Patients with data on vitamin K intake, potential confounders and WM dose (n = 172) were included in linear regression models to test whether BMI modifies the relation between vitamin K intake and WM dose. RESULTS: Warfarin loading dose correlated with the maintenance dose (r = 0.36, p < 0.0001) but was not significantly associated with WM dose in analyses adjusted for vitamin K epoxide reductase (VKORC1) and cytochrome P450 2C9 (CYP2C9) genotypes. In fully adjusted models, BMI was associated (p = 0.001) with WM dose but vitamin K was only marginally positively associated (p = 0.06) with WM dose. We found no interaction (p > 0.05) between BMI and vitamin K intake with regard to WM dose. Inclusion of vitamin K intake in the model only slightly improved the amount of variance (1.1%) explained by age, gender, BMI, race, physical activity, energy intake and VKORC1 and CYP2C9 genotypes. CONCLUSION: Our data suggest that body fat does not affect the relation between vitamin K intake and WM dose. PMID- 24052024 TI - Human papillomavirus infection and vaginal tape exposure after midurethral sling: a case report. AB - Midurethral tape placement is the gold standard procedure for stress urinary incontinence (SUI). Among reported complications, tape erosion is uncommon. Several risk factors have been postulated as causes of vaginal erosion, but none have been demonstrated. Cases of vaginal erosion caused by tape infections have been described, but none has been associated with human papillomavirus (HPV) infection. We report the first case of vaginal exposure in a woman who underwent a midurethral sling procedure for SUI after HPV colonization. PMID- 24052023 TI - Epigenetics: novel mechanism of pulmonary hypertension. AB - INTRODUCTION: Epigenetics refers to changes in phenotype and gene expression that occur without alterations in DNA sequence. MicroRNAs are relatively recently discovered negative regulators of gene expression and act at the posttranscriptional level. METHODS: This review summarizes epigenetic mechanisms of pulmonary hypertension, focusing on microRNAs related to pulmonary hypertension. RESULTS: There are three major mechanisms of epigenetic regulation, including methylation of CpG islands, modification of histone proteins, and microRNAs. There may be an epigenetic component to pulmonary hypertension. These epigenetic abnormalities can be reversed therapeutically. CONCLUSIONS: By better integrating network biology with evolving technologies in cell culture and in vivo experimentation, we will better understand epigenetic mechanisms of pulmonary hypertension and identify more diagnostic and therapeutic targets in pulmonary hypertension. PMID- 24052026 TI - Influence of psychologic features on rehabilitation outcomes in patients with subacute stroke trained with robotic-aided walking therapy. AB - OBJECTIVE: The aim of this study was to investigate whether the rehabilitation outcomes with robotic-aided gait therapy may be affected by patients' and caregivers' psychologic features after subacute stroke. DESIGN: This is a controlled, longitudinal, observational pilot study conducted on 42 patients divided in robotic-assisted gait training plus conventional physical therapy group, robotic-assisted gait training dropout group, and conventional physical therapy group. The outcome measures were walking ability (Functional Ambulation Category) and independency in activities of daily living (Barthel Index) measured before and after intervention. Psychologic features were measured before intervention using the Hospital Anxiety and Depression Scale, the Eysenck Personality Questionnaire, and recovery locus of control in the patients and the State-Trait Anxiety Inventory and the Beck Depression Inventory in the caregivers. RESULTS: Patient anxiety was significantly higher in those who refused/abandoned robotic therapy (P = 0.002). In the subjects allocated to the robotic group, the recovery of walking ability was significantly affected by the perceived recovery locus of control (P = 0.039, odds ratio = 14); and the recovery of independency in activities of daily living, by anxiety (P = 0.018, odds ratio = 0.042). Conversely, psychologic factors did not significantly affect the outcomes of conventional rehabilitation. CONCLUSIONS: Psychologic features, particularly recovery locus of control and anxiety, affected the rehabilitative outcomes of the patients involved in robotic treatment more than those in conventional rehabilitation. PMID- 24052027 TI - Upper limb robot-assisted therapy in chronic and subacute stroke patients: a kinematic analysis. AB - OBJECTIVE: The aim of this study was to compare motor recovery in subacute and chronic stroke patients through clinical assessment scales and a set of kinematic parameters recorded using a robotic system. DESIGN: Fifty post-stroke patients, 25 subacute and 25 chronic, and 20 healthy subjects participated in this study. The InMotion 2.0 robotic system for shoulder/elbow rehabilitation was used. Clinical outcome measures were used for assessment. Kinematic parameters related to the speed measured at the robot's end effector and to the movement's smoothness were computed. RESULTS: The results of this study show that the robot assisted training can contribute to reduce motor impairment in both subacute and chronic stroke patients. The evaluation of the kinematic parameters and their correlation with the clinical scales highlight some differences in mechanisms of recovery in subacute and chronic stroke patients. CONCLUSIONS: The proposed set of kinematic parameters and the analysis of the reaching movements' onset time, associated with a quantitative evaluation of motor improvement provided by the clinical outcome measures, are also able to quantify the changes in the quality of motion obtained after robot-assisted therapy in stroke patients. The higher gain in the subacute stroke patients suggests that the rehabilitative treatment provided at an earlier stage is able to avoid the development of pathologic patterns, resulting in a better quality of motion. PMID- 24052028 TI - Walking in water and on land after an incomplete spinal cord injury. AB - OBJECTIVE: Although no data are available on the effects of water environment on the gait of subjects with spinal cord injury (SCI), hydrotherapy is used in the rehabilitation protocols of SCI patients. The aim of this study was to characterize gait features of subjects with incomplete SCI walking in water and on land in comparison with healthy controls (CTRLs) to identify the specificity of water environment on influencing gait in SCI subjects. DESIGN: This is a matched case-control study. RESULTS: Kinematic gait parameters and range of motion of joint angles of 15 SCI subjects and 15 CTRLs were analyzed. Compared with gait on land, gait in water of the SCI patients was characterized by speed and stance phase reduction, gait cycle time increment, and invariance of stride length and range of motion values. Comparison with CTRL data remarked that walking in water reduces gait differences between the groups. Furthermore, in water, the SCI subjects presented a reduction in variability of the hip and knee joint angles, whereas in the CTRLs, a larger variability was observed. CONCLUSIONS: Gait in water of the SCI subjects is associated with kinematic parameters more similar to those of the CTRLs, particularly regarding speed, stride length, and stance phase, supporting the idea that walking in a water environment may be of rehabilitative significance for SCI subjects. PMID- 24052029 TI - Impact of airflow communication between nasal cavities on nasal ventilation. AB - OBJECTIVE: To investigate the impact of airflow communication between bilateral nostril sides on nasal ventilation. In addition, we try to validate the efficacy of the Draf III procedure from the aerodynamics perspective. METHODS: One health model and two disease models were constructed. These included 2 patients with nasal septum perforation and 1 patient who received the Draf III procedure. With the computational fluid dynamics method, indices such as airflow velocity and wall shear stress in the nasal cavity were detected and compared among the 3 subjects. RESULTS: The main pathway for airflow in the nasal cavity is the common meatus. Little airflow exchange occurred in the patient who underwent the Draf III procedure, and the wall shear stress around the communication site was as low as in the adjacent areas. However, when airflow communication occurred in the lower part of the nasal cavity, the airflow velocity and wall shear stress were obviously altered, and the ventilation function of the nasal cavity was impaired. CONCLUSION: Airflow communication in the upper part of the nasal cavity has little impact on nasal ventilation. Nonetheless, airflow communication occurring in the lower part of the nasal cavity disturbs the overall airflow distribution and a repair procedure is necessary. PMID- 24052030 TI - Postural effects on intracranial pressure: modeling and clinical evaluation. AB - The physiological effect of posture on intracranial pressure (ICP) is not well described. This study defined and evaluated three mathematical models describing the postural effects on ICP, designed to predict ICP at different head-up tilt angles from the supine ICP value. Model I was based on a hydrostatic indifference point for the cerebrospinal fluid (CSF) system, i.e., the existence of a point in the system where pressure is independent of body position. Models II and III were based on Davson's equation for CSF absorption, which relates ICP to venous pressure, and postulated that gravitational effects within the venous system are transferred to the CSF system. Model II assumed a fully communicating venous system, and model III assumed that collapse of the jugular veins at higher tilt angles creates two separate hydrostatic compartments. Evaluation of the models was based on ICP measurements at seven tilt angles (0-71 degrees ) in 27 normal pressure hydrocephalus patients. ICP decreased with tilt angle (ANOVA: P < 0.01). The reduction was well predicted by model III (ANOVA lack-of-fit: P = 0.65), which showed excellent fit against measured ICP. Neither model I nor II adequately described the reduction in ICP (ANOVA lack-of-fit: P < 0.01). Postural changes in ICP could not be predicted based on the currently accepted theory of a hydrostatic indifference point for the CSF system, but a new model combining Davson's equation for CSF absorption and hydrostatic gradients in a collapsible venous system performed well and can be useful in future research on gravity and CSF physiology. PMID- 24052031 TI - IL-6 and epinephrine have divergent fiber type effects on intramuscular lipolysis. AB - IL-6 is an exercise-regulated myokine that has been suggested to increase lipolysis in fast-twitch skeletal muscle. However, it is not known if a similar effect is present in slow-twitch muscle. Furthermore, epinephrine increases IL-6 secretion from skeletal muscle, suggesting that IL-6 could play a role in mediating the lipolytic effects of catecholamines. The purpose of this study was to determine whether IL-6 stimulates skeletal muscle lipolysis in a fiber type dependent manner and is required for epinephrine-stimulated lipolysis in murine skeletal muscle. Soleus and extensor digitorum longus (EDL) muscles from male C57BL/6J wild-type and IL-6(-/-) mice were incubated with 1 MUM (183 ng/ml) epinephrine or 75 ng/ml recombinant IL-6 (rIL-6) for 60 min. IL-6 treatment increased 5'-AMP-activated protein kinase and signal transducer and activator of transcription 3 phosphorylation and glycerol release in isolated EDL but not soleus muscles from C57BL/6J mice. Conversely, epinephrine increased glycerol release in soleus but not EDL muscles from C57BL/6J mice. Basal lipolysis was elevated in soleus muscle from IL-6(-/-) mice, and this was associated with increases in adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58). The increase in ATGL content does not appear to be due to a loss of IL-6's direct effects, because ex vivo treatment with IL-6 failed to alter the expression of ATGL mRNA in soleus muscle. In summary, IL-6 stimulates lipolysis in glycolytic but not oxidative muscle, whereas the opposite fiber type effect is seen with epinephrine. The absence of IL-6 indirectly upregulates lipolysis, and this is associated with increases in ATGL and its coactivator CGI-58. PMID- 24052034 TI - Left ventricular ejection time, not heart rate, is an independent correlate of aortic pulse wave velocity. AB - Several studies showed a positive association between heart rate and pulse wave velocity, a sensitive marker of arterial stiffness. However, no study involving a large population has specifically addressed the dependence of pulse wave velocity on different components of the cardiac cycle. The aim of this study was to explore in subjects of different age the link between pulse wave velocity with heart period (the reciprocal of heart rate) and the temporal components of the cardiac cycle such as left ventricular ejection time and diastolic time. Carotid femoral pulse wave velocity was assessed in 3,020 untreated subjects (1,107 men). Heart period, left ventricular ejection time, diastolic time, and early-systolic dP/dt were determined by carotid pulse wave analysis with high-fidelity applanation tonometry. An inverse association was found between pulse wave velocity and left ventricular ejection time at all ages (<25 years, r(2) = 0.043; 25-44 years, r(2) = 0.103; 45-64 years, r(2) = 0.079; 65-84 years, r(2) = 0.044; >= 85 years, r(2) = 0.022; P < 0.0001 for all). A significant (P < 0.0001) negative but always weaker correlation between pulse wave velocity and heart period was also found, with the exception of the youngest subjects (P = 0.20). A significant positive correlation was also found between pulse wave velocity and dP/dt (P < 0.0001). With multiple stepwise regression analysis, left ventricular ejection time and dP/dt remained the only determinant of pulse wave velocity at all ages, whereas the contribution of heart period no longer became significant. Our data demonstrate that pulse wave velocity is more closely related to left ventricular systolic function than to heart period. This may have methodological and pathophysiological implications. PMID- 24052033 TI - Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene. AB - Long QT syndrome is the prototypical disorder of ventricular repolarization (VR), and a genotype-phenotype relation is postulated. Furthermore, although increased VR heterogeneity (dispersion) may be important in the arrhythmogenicity in long QT syndrome, this hypothesis has not been evaluated in humans and cannot be tested by conventional electrocardiography. In contrast, vectorcardiography allows assessment of VR heterogeneity and is more sensitive to VR alterations than electrocardiography. Therefore, vectorcardiography was used to compare the electrophysiological phenotypes of two mutations in the LQT1 gene with different in vitro biophysical properties, and with LQT2 mutation carriers and healthy control subjects. We included 99 LQT1 gene mutation carriers (57 Y111C, 42 R518X) and 19 LQT2 gene mutation carriers. Potassium channel function is in vitro most severely impaired in Y111C. The control group consisted of 121 healthy subjects. QRS, QT, and T-peak to T-end (Tp-e) intervals, measures of the QRS vector and T vector and their relationship, and T-loop morphology parameters were compared at rest. Apart from a longer heart rate-corrected QT interval (QT heart rate corrected according to Bazett) in Y111C mutation carriers, there were no significant differences between the two LQT1 mutations. No signs of increased VR heterogeneity were observed among the LQT1 and LQT2 mutation carriers. QT heart rate corrected according to Bazett and Tp-e were longer, and the Tp-e-to-QT ratio greater in LQT2 than in LQT1 and the control group. In conclusion, there was a marked discrepancy between in vitro potassium channel function and in vivo electrophysiological properties in these two LQT1 mutations. Together with previous observations of the relatively low risk for clinical events in Y111C mutation carriers, our results indicate need for cautiousness in predicting in vivo electrophysiological properties and the propensity for clinical events based on in vitro assessment of ion channel function alone. PMID- 24052032 TI - Microparticles generated by decompression stress cause central nervous system injury manifested as neurohypophysial terminal action potential broadening. AB - The study goal was to use membrane voltage changes during neurohypophysial action potential (AP) propagation as an index of nerve function to evaluate the role that circulating microparticles (MPs) play in causing central nervous system injury in response to decompression stress in a murine model. Mice studied 1 h following decompression from 790 kPa air pressure for 2 h exhibit a 45% broadening of the neurohypophysial AP. Broadening did not occur if mice were injected with the MP lytic agent polyethylene glycol telomere B immediately after decompression, were rendered thrombocytopenic, or were treated with an inhibitor of nitric oxide synthase-2 (iNOS) prior to decompression, or in knockout (KO) mice lacking myeloperoxidase or iNOS. If MPs were harvested from control (no decompression) mice and injected into naive mice, no AP broadening occurred, but AP broadening was observed with injections of equal numbers of MPs from either wild-type or iNOS KO mice subjected to decompression stress. Although not required for AP broadening, MPs from decompressed mice, but not control mice, exhibit NADPH oxidase activation. We conclude that inherent differences in MPs from decompressed mice, rather than elevated MPs numbers, mediate neurological injury and that a component of the perivascular response to MPs involves iNOS. Additional study is needed to determine the mechanism of AP broadening and also mechanisms for MP generation associated with exposure to elevated gas pressure. PMID- 24052036 TI - Left ventricular mechanics and arterial-ventricular coupling following high intensity interval exercise. AB - High-intensity exercise induces marked physiological stress affecting the secretion of catecholamines. Sustained elevations in catecholamines are thought to desensitize cardiac beta receptors and may be a possible mechanism in impaired cardiac function following strenuous exercise. In addition, attenuated arterial ventricular coupling may identify vascular mechanisms in connection with postexercise attenuations in ventricular function. Thirty-nine normally active (NA) and endurance-trained (ET) men and women completed an echocardiographic evaluation of left ventricular function before and after an acute bout of high intensity interval exercise (15 bouts of 1:2 min work:recovery cycling: 100% peak power output and 50 W, respectively). Following exercise, time to peak twist and peak untwisting velocity were delayed (P < 0.01) but did not differ by sex or training status. Interactions for sex and condition (rest vs. exercise) were found for longitudinal diastolic strain rate (men, 1.46 +/- 0.19 to 1.28 +/- 0.23 s(-1) vs. women, 1.62 +/- 0.25 to 1.63 +/- 0.26 s(-1); P = 0.01) and arterial elastance (men 2.20 +/- 0.65 to 3.24 +/- 1.02 mmHg . ml(-1) . m(-2) vs. women 2.51 +/- 0.61 to 2.93 +/- 0.68 mmHg . ml(-1) . m(-2); P = 0.04). No cardiac variables were found associated with catecholamine levels. The change in twist mechanics was associated with baseline aortic pulse-wave velocity (r(2) = 0.27, P = 0.001). We conclude that males display greater reductions in contractility in response to high-intensity interval exercise, independent of catecholamine concentrations. Furthermore, a novel association of arterial stiffness and twist mechanics following high-intensity acute exercise illustrates the influence of vascular integrity on cardiac mechanics. PMID- 24052035 TI - Appetite regulation in overweight, sedentary men after different amounts of endurance exercise: a randomized controlled trial. AB - Weight loss induced by endurance exercise is often disappointing, possibly due to an increase in energy intake mediated through greater appetite. The aim of this study was to evaluate fasting, postprandial, and postexercise appetite regulation after an intervention prescribing two amounts of endurance exercise. Sixty-four sedentary, overweight, healthy young men were randomized to control (CON), moderate-dose (MOD: ~ 30 min/day), or high-dose (HIGH: ~ 60 min/day) endurance exercise for 12 wk. Along with subjective appetite ratings, plasma ghrelin, glucagon, insulin, peptide YY3-36, glucose, free fatty acids, and glycerol were measured during fasting and in relation to a breakfast meal and an acute bout of exercise, both at baseline and at follow-up. Ad libitum lunch energy intake was evaluated 3 h after the breakfast meal. Despite different amounts of endurance exercise, the subjects lost similar amounts of fat mass (MOD: 4.2 +/- 0.5 kg; HIGH: 3.7 +/- 0.5 kg). Fasting and postprandial insulin decreased ~ 20% in both exercise groups (P < 0.03 vs. CON). Appetite measurements were not upregulated in the fasting and postprandial states. On the contrary, fasting and postprandial ratings of fullness and postprandial PYY3-36 increased in HIGH (P < 0.001 vs. CON). Ad libitum lunch energy intake remained unchanged over the course of the intervention. In both exercise groups, plasma ghrelin increased in relation to acute exercise after training. Thus neither moderate nor high doses of daily endurance exercise increased fasting and postprandial measures of appetite, but a high dose of exercise was associated with an increase in fasting and meal-related ratings of fullness and satiety. PMID- 24052037 TI - Activated protein C improves macrovascular and microvascular reactivity in human severe sepsis and septic shock. AB - We tested the effects of activated protein C (APC) in macrovascular and microvascular beds within 60 min of treatment. Twelve patients treated with APC for severe sepsis were included. We assessed macrovascular reactivity by phenylephrine arterial dose response. Pharmacological modeling (EC50, Emax, and Hill coefficient) and individual dose-response curve were tested. Microvascular reactivity was tested with skin laser Doppler by using postocclusive reactive hyperemia with measurements of peak, time to peak (Tmax), time to half recovery (T1/2R), and myogenic and sympathetic tones. All measurements were done 30 min before, just before, and 30 and 60 min after APC infusion. Microvascular reactivity was also tested in eight healthy volunteers. In patients, arterial pressure did not increase significantly. However, 60 min after the beginning of APC infusion, reactivity to alpha-1 stimulation was improved: EC50 decreased from 15.3 (0.9-56) to 3.1 (1.0-6.2) (P = 0.04), and 5 of 12 patients improved their dose-response curve. As for microcirculatory parameters, as early as 30 min after the beginning of APC infusion, postocclusive reactive hyperemia peak increased from 102 (40-168) to 162 (35-196) (P = 0.04), Tmax was shorter: 30 s (14-52 s) versus 56 s (22-83 s) (P = 0.03), and the T1/2R also decreased, from 72.4 s (41.9 134.6 s) to 49.8 s (31.0-129.8 s) (P = 0.02). Myogenic tone increased (P = 0.03), whereas sympathetic tone decreased (P = 0.03), and myogenic tone was lower than controls before but not after APC treatment. In conclusion, APC improves vascular reactivity both at macrocirculatory and microcirculatory levels very quickly, suggesting that this is not due to protein synthesis or anticoagulant effect. The myogenic properties of vessels could partly drive this effect. PMID- 24052038 TI - Prolonged induced hypothermia in hemorrhagic shock is associated with decreased muscle metabolism: a nuclear magnetic resonance-based metabolomics study. AB - Hemorrhagic shock is a leading cause of trauma-related death in war and is associated with significant alterations in metabolism. Using archived serum samples from a previous study, the purpose of this work was to identify metabolic changes associated with induced hypothermia in a porcine model of hemorrhagic shock. Twelve Yorkshire pigs underwent a standardized hemorrhagic shock and resuscitation protocol to simulate battlefield injury with prolonged evacuation to definitive care in cold environments. Animals were randomized to receive either hypothermic (33 degrees C) or normothermic (39 degrees C) limited resuscitation for 8 h, followed by standard resuscitation. Proton nuclear magnetic resonance spectroscopy was used to evaluate serum metabolites from these animals at intervals throughout the hypothermic resuscitation period. Animals in the hypothermic group had a significantly higher survival rate (P = 0.02) than normothermic animals. Using random forest analysis, a difference in metabolic response between hypothermic and normothermic animals was identified. Hypothermic resuscitation was characterized by decreased concentrations of several muscle related metabolites including taurine, creatine, creatinine, and amino acids. This study suggests that a decrease in muscle metabolism as a result of induced hypothermia is associated with improved survival. PMID- 24052040 TI - Poly(vinylpyrrolidone)/KF electrolyte membranes for facilitated CO(2) transport. AB - In this study, we show for the first time that potassium fluoride (KF) can be utilized as a carrier for facilitated CO2 transport. A polymer electrolyte membrane was prepared by incorporating KF through coordinate covalent bonding with the amide groups of poly(vinylpyrrolidone) (PVP). The resulting PVP/KF electrolyte membrane showed enhanced CO2 separation performance compared with neat PVP. The selectivity ratio CO2/N2 increased to 4.1 with a CO2 permeance of 28 GPU. This enhanced separation performance was attributable to the reversible interaction of KF with CO2 molecules, resulting in the increase of CO2 transport. The interaction between KF and the amide groups of PVP was confirmed by FT-IR spectroscopy and X-ray photoelectron spectroscopy (XPS). The coordination of potassium ions with the amide groups caused the free ions in KF to be increased, resulting in the favorable interaction with CO2 molecules. PMID- 24052041 TI - Sex-related genomic sequences in cartilaginous fish: an overview. AB - Sex determination and differentiation are key events in the development of either the testis or ovary in fish. Sex determination mechanisms include environmental and genetic regulation. Research on sex determination systems and their related genes have been implemented in the teleost species, but the amount of information about these genes in cartilaginous fish is very scarce. This paper summarizes the few available data on molecular studies and chromosome localization of specific sequences useful to discriminate between various chromosome pairs in the common torpedo, Torpedo torpedo, and in the scyliorhinid coral catshark, Atelomycterus marmoratus, species that do not have morphologically distinct sex chromosomes. In addition, recent results obtained by sequence analysis of foxl2, a female specific gene expressed during early phases of gonadal development in interesting key-species, such as the holocephalian Callorhinchus milii, is discussed. Nevertheless, the mechanism of sex determination in cartilaginous fish remains largely unknown. Further research needs to be carried out regarding the importance of basic and applied sex determination studies in fish, including chromosomal distribution of sex-related sequences. PMID- 24052039 TI - Differential diagnosis of glomerular disease: a systematic and inclusive approach. AB - BACKGROUND: Glomerular disease is a complex and evolving topic. In evaluating a specific case it is not unusual for the clinician to ask: 'Am I missing something? Should I biopsy? When? Should I treat first, then biopsy?' This work, which is both evidence and experience based, is intended to address each of these concerns and many other issues relevant to the differential diagnosis of glomerular disease. SUMMARY: The central approach is the use of diagnostic algorithms that are based on quantitative measures routinely obtained early in the course of the diagnostic evaluation. The algorithms are designed to be easy to navigate, systematic, and inclusive. Also provided is a detailed and prioritized list of recommended diagnostic testing, and the rationale for each test. KEY MESSAGE: This work is intended to facilitate accurate diagnosis in the individual patient presenting with evidence of glomerular disease. PMID- 24052042 TI - Tissue engineering for in vitro analysis of matrix metalloproteinases in the pathogenesis of keloid lesions. AB - IMPORTANCE: Keloid lesions form because of alterations in the mechanisms that govern cutaneous wound healing. Although matrix metalloproteinases (MMPs) have been implicated in keloid pathophysiology, many questions still remain about their involvement. Our incomplete understanding of keloid pathophysiology has led to high recurrence rates in current treatments. No reliable animal model is available for studying keloids. OBJECTIVE: To gain a better understanding of the disease mechanisms involved in keloid lesions in the hopes of identifying therapeutic options. DESIGN: Fibroblasts derived from keloid tissue were incorporated in either Matrigel or polyethylene glycol diacrylate mixed with type I collagen to create 3-dimensional models to investigate the role MMPs play in keloid formation. The MMP gene expressions were also compared between fibroblasts isolated from different sites within the same keloid lesion. SETTING: The Johns Hopkins School of Medicine, Baltimore, Maryland. PARTICIPANTS: Keloid fibroblasts were received from the Baylor College of Medicine, and additional keloid fibroblasts were enzymatically isolated from the dermal layer of lesions removed from consenting patients at The Johns Hopkins Hospital. RESULTS: In the Matrigel system, MMP9 and MMP13 were observed to be significantly upregulated in keloid fibroblasts. The addition of decorin resulted in a significant decrease of type I collagen and MMP1, MMP9, and MMP13 gene expressions from keloid fibroblasts. Higher MMP gene expressions were observed in fibroblasts isolated from the margins of the original keloid wound. CONCLUSIONS AND RELEVANCE: MMP9 and MMP13 are expressed significantly more in keloid-derived cells, thus making them 2 potential targets for disease modification. Molecules that target organization of the lesion's matrix can be beneficial in downregulating increased markers during the disease. In addition, heterogeneity is observed with the varying MMP gene expressions from site-specific fibroblasts within the same keloid lesion. PMID- 24052044 TI - Lung cancer survival in England: trends in non-small-cell lung cancer survival over the duration of the National Lung Cancer Audit. AB - BACKGROUND: In comparison with other European and North American countries, England has poor survival figures for lung cancer. Our aim was to evaluate the changes in survival since the introduction of the National Lung Cancer Audit (NLCA). METHODS: We used data from the NLCA to identify people with non-small cell lung cancer (NSCLC) and stratified people according to their performance status (PS) and clinical stage. Using Cox regression, we calculated hazard ratios (HRs) for death according to the year of diagnosis from 2004/2005 to 2010; adjusted for patient features including age, sex and co-morbidity. We also assessed whether any changes in survival were explained by the changes in surgical resection rates or histological subtype. RESULTS: In this cohort of 120,745 patients, the overall median survival did not change; but there was a 1% annual improvement in survival over the study period (adjusted HR 0.99, 95% confidence interval (CI) 0.98-0.99). Survival improvement was only seen in patients with good PS and early stage (adjusted HR 0.97, 95% CI 0.95-0.99) and this was partly accounted for by changes in resection rates. CONCLUSION: Survival has only improved for a limited group of people with NSCLC and increasing surgical resection rates appeared to explain some of this improvement. PMID- 24052043 TI - The novel toluidine sulphonamide EL102 shows pre-clinical in vitro and in vivo activity against prostate cancer and circumvents MDR1 resistance. AB - BACKGROUND: Taxanes are routinely used for the treatment of prostate cancer, however the majority of patients eventually develop resistance. We investigated the potential efficacy of EL102, a novel toluidine sulphonamide, in pre-clinical models of prostate cancer. METHODS: The effect of EL102 and/or docetaxel on PC-3, DU145, 22Rv1 and CWR22 prostate cancer cells was assessed using cell viability, cell cycle analysis and PARP cleavage assays. Tubulin polymerisation and immunofluorescence assays were used to assess tubulin dynamics. CWR22 xenograft murine model was used to assess effects on tumour proliferation. Multidrug resistant lung cancer DLKPA was used to assess EL102 in a MDR1-mediated drug resistance background. RESULTS: EL102 has in vitro activity against prostate cancer, characterised by accumulation in G2/M, induction of apoptosis, inhibition of Hif1alpha, and inhibition of tubulin polymerisation and decreased microtubule stability. In vivo, a combination of EL102 and docetaxel exhibits superior tumour inhibition. The DLKP cell line and multidrug-resistant DLKPA variant (which exhibits 205 to 691-fold greater resistance to docetaxel, paclitaxel, vincristine and doxorubicin) are equally sensitive to EL102. CONCLUSION: EL102 shows potential as both a single agent and within combination regimens for the treatment of prostate cancer, particularly in the chemoresistance setting. PMID- 24052045 TI - Re-attendance after false-positive screening mammography: a population-based study in the Netherlands. AB - BACKGROUND: In the current study, mammography adherence of women who had experienced a false-positive referral is evaluated, with emphasis on the probability of receiving surveillance mammography outside the national screening programme. METHODS: We included 424,703 consecutive screens and collected imaging, biopsy and surgery reports of 3463 women who experienced a false positive referral. Adherence to screening, both in and outside the screening programme, was evaluated. RESULTS: Two years after the false-positive referral, overall screening adherence was 94.6%, with 64.7% of women returning to the national screening programme, compared with 94.9% of women re-attending the screening programme after a negative screen (P<0.0001). Four years after the false-positive screen, the overall adherence had decreased to 85.2% (P<0.0001) with a similar proportion of the women re-attending the screening programme (64.4%) and a lower proportion (20.8%) having clinical surveillance mammography. Women who had experienced a false-positive screen at their first screening round were less likely to adhere to mammography than women with an abnormal finding at one of the following screening rounds (92.4% vs 95.5%, P<0.0001). CONCLUSION: Overall screening adherence after previous false-positive referral was comparable to the re-attendance rate of women with a negative screen at 2-year follow-up. Overall adherence decreased 4 years after previous false-positive referral from 94.6% to 85.2%, with a relatively high estimate of women who continue with clinical surveillance mammography (20.8%). Women with false-positive screens should be made aware of the importance to re-attend future screening rounds, as a way to improve the effectiveness of the screening programme. PMID- 24052046 TI - Intravenous zoledronic Acid given every 6 months in childhood osteoporosis. AB - AIM: To evaluate the safety and efficacy of 12 months of zoledronic acid (ZA) administered every 6 months to children with osteoporosis. METHODS: Retrospective cohort study of 27 patients (16 male, 11 female) treated with ZA (0.05 mg/kg/dose) every 6 months for 1 year. 20 were immobile, 4 steroid-induced osteoporosis, 2 idiopathic osteoporosis and 1 neurofibromatosis type 1. 16 had long bone fractures and 12 had vertebral wedging at baseline. Mineral homeostasis, bone mineral density (BMD) and vertebral morphometry were evaluated at baseline and 12 months. Results were compared to published data on 3-monthly ZA treatment. RESULTS: Median age at ZA start was 10.5 years (range 6.2-13.3). Following the first infusion, 2 developed asymptomatic hypocalcemic, 14 developed temperature > 38 degrees C, 13 aches/pain and 6 nausea. At 12 months, there was reduction in bone turnover and improvement in BMD and vertebral shape. No patient fractured after starting ZA. Growth was normal. Outcomes were similar to 3 monthly ZA. CONCLUSION: ZA administered 6-monthly was associated with acute phase reaction to the first dose and improvement in BMD, reduction in bone turnover and improved vertebral shape at 12 months. PMID- 24052048 TI - Anticancer drugs: Breaking a cancerous interaction. PMID- 24052049 TI - Biotechnology: Rice-derived rotavirus antibody shows promise. PMID- 24052047 TI - New avenues for anti-epileptic drug discovery and development. AB - Despite the introduction of over 15 third-generation anti-epileptic drugs, current medications fail to control seizures in 20-30% of patients. However, our understanding of the mechanisms mediating the development of epilepsy and the causes of drug resistance has grown substantially over the past decade, providing opportunities for the discovery and development of more efficacious anti epileptic and anti-epileptogenic drugs. In this Review we discuss how previous preclinical models and clinical trial designs may have hampered the discovery of better treatments. We propose that future anti-epileptic drug development may be improved through a new joint endeavour between academia and the industry, through the identification and application of tools for new target-driven approaches, and through comparative preclinical proof-of-concept studies and innovative clinical trials designs. PMID- 24052050 TI - Anticancer drugs: Stapled peptide reactivates p53. PMID- 24052051 TI - [Update on preemptive analgesia : options and limits of preoperative pain therapy]. AB - BACKGROUND: Wall created the term preemptive analgesia in 1988 and in doing so set in motion a movement to prevent acute and chronic postsurgical pain. The concept of preemptive analgesia implies the administration of analgesic drugs or an intervention before a surgical procedure. A preemptive analgesic approach can comprise non-steroidal anti-inflammatory drugs (NSAID) and cyclo-oxygenase-2 inhibitors (coxibs) used to decrease the production of prostaglandins, local anesthetics (e.g. epidural) to reduce nociceptive input to the spinal cord as well as opioids, N-methyl-D-aspartate (NMDA) antagonists, antidepressants and anticonvulsants, all of which have an inhibitory influence on the central nervous system. AIM: The aim of this article is to present the current possibilities and limits of preoperative pain therapy. MATERIAL AND METHODS: Since 2002 several meta-analyses on the effectiveness of preemptive analgesia have been published which came to varying conclusions on the supportive use of preemptive analgesia. The S3 guidelines on current perioperative pain management developed by the German Interdisciplinary Association for Pain Management (DIVS) specify the preemptive analgesic interventions found to be effective and will be discussed in detail in this article. Furthermore, the results of a current meta-analysis which follows the principle of preventive analgesia will be presented and which have not yet been considered in the S3 guidelines. RESULTS: Preemptive analgesia can reduce acute postoperative pain; however, minimizing the development of chronic pain conditions can only be successful in combination with intraoperative and postoperative pain therapy as well as social and psychological support when indicated (preventive analgesia). CONCLUSION: Reduction of chronic postoperative pain is an important medical function which is also justified from socioeconomic perspectives. Future studies should combine several procedures for perioperative pain therapy in order to do justice to the multifactorial aspects of pain chronification and should also be planned over a sufficiently long observation time period. PMID- 24052052 TI - Atomic structure of amorphous shear bands in boron carbide. AB - Amorphous shear bands are the main deformation and failure mode of super-hard boron carbide subjected to shock loading and high pressures at room temperature. Nevertheless, the formation mechanisms of the amorphous shear bands remain a long standing scientific curiosity mainly because of the lack of experimental structure information of the disordered shear bands, comprising light elements of carbon and boron only. Here we report the atomic structure of the amorphous shear bands in boron carbide characterized by state-of-the-art aberration-corrected transmission electron microscopy. Distorted icosahedra, displaced from the crystalline matrix, were observed in nano-sized amorphous bands that produce dislocation-like local shear strains. These experimental results provide direct experimental evidence that the formation of amorphous shear bands in boron carbide results from the disassembly of the icosahedra, driven by shear stresses. PMID- 24052053 TI - Simultaneous energy recovery and autotrophic nitrogen removal from sewage at moderately low temperatures. AB - This study assessed the technical feasibility of treating sewage with a combination of direct anaerobic treatment and autotrophic nitrogen removal, while simultaneously achieving energy recovery and nitrogen removal under moderately low temperatures. The concentrations of ammonia, nitrite, and COD in effluent were below 1, 0.1, and 30 mg/L, respectively. In the up-flow, anaerobic sludge fixed-bed, there was no obvious change observed in the total methane production at temperatures of 35 +/- 1 degrees C, 28 +/- 1 degrees C, 24 +/- 3 degrees C, and 17 +/- 3 degrees C, with the accumulation of volatile fatty acids occurring with decreasing temperatures. The control strategy employed in this study achieved a stable effluent with equimolar concentrations of nitrite and ammonium, coupled with high nitrite accumulation (>97 %) in the partial nitrification sequencing batch reactor system at moderately low temperatures. In the anaerobic ammonium oxidation (anammox) reactor, a short hydraulic retention time of 0.96 h, with a nitrogen removal rate of 0.83 kgN/(m(3)/day) was achieved at 12-15 degrees C. At low temperatures, the corresponding fluorescence in situ hybridization image revealed a high amount of anammox bacteria. This study demonstrates that efficient nitrogen removal and energy recovery from sewage at moderately low temperatures can be achieved by utilizing a combined system. Additionally, this system has the potential to become energy-neutral or even energy-producing. PMID- 24052054 TI - Monte Carlo calculation of dose distributions in oligometastatic patients planned for spine stereotactic ablative radiotherapy. AB - Dosimetric consequences of plans optimized using the analytical anisotropic algorithm (AAA) implemented in the Varian Eclipse treatment planning system for spine stereotactic body radiotherapy were evaluated by re-calculating with BEAMnrc/DOSXYZnrc Monte Carlo. Six patients with spinal vertebral metastases were planned using volumetric modulated arc therapy. The planning goal was to cover at least 80% of the planning target volume with a prescribed dose of 35 Gy in five fractions. Tissue heterogeneity-corrected AAA dose distributions for the planning target volume and spinal canal planning organ-at-risk volume were compared against those obtained from Monte Carlo. The results showed that the AAA overestimated planning target volume coverage with the prescribed dose by up to 13.5% (mean 8.3% +/- 3.2%) when compared to Monte Carlo simulations. Maximum dose to spinal canal planning organ-at-risk volume calculated with Monte Carlo was consistently smaller than calculated with the treatment planning system and remained under spinal cord dose tolerance. Differences in dose distribution appear to be related to the dosimetric effects of accounting for body composition in Monte Carlo simulations. In contrast, the treatment planning system assumes that all tissues are water-equivalent in their composition and only differ in their electron density. PMID- 24052055 TI - Antipsychotic drug use and the risk of venous thromboembolism in elderly patients with dementia. AB - The aim of this study was to investigate the association between the use of antipsychotics and the risk of venous thromboembolism (VTE) in elderly patients with dementia. Based on data from the German Pharmacoepidemiological Research Database, a nested case-control study was conducted within a cohort of 72,591 patients with dementia aged at least 65 years at cohort entry. Cases were patients with a hospitalization due to VTE. Up to 4 controls were matched to each case according to age, sex, health insurance, and calendar time of the VTE. Users of antipsychotics were classified into current or former users, and in addition, all current users were categorized as prevalent or new users. For a further analysis, we distinguished between users of either conventional or atypical antipsychotics or concurrent users of both conventional and atypical antipsychotics. Multivariate conditional logistic regression was applied to calculate odds ratios (ORs) of VTE for all user groups compared with nonusers. The case-control data set comprised 1028 VTE cases and 4109 controls. An increased risk of VTE was found for current users (OR, 1.23; 95% confidence interval [CI], 1.01-1.50) and for users of a combination of atypical and conventional antipsychotics (OR, 1.62; 95% CI, 1.15-2.27). In current users, only new use was associated with an increased risk (OR, 1.63; 95% CI, 1.10-2.40). Increased attention to clinical signs of VTE should be paid during the first 3 months of treatment with antipsychotics and in patients receiving both conventional and atypical agents, especially if other risk factors for VTE exist. PMID- 24052056 TI - Epidemiology, symptoms, and treatment characteristics of hyponatremic psychiatric inpatients. AB - Hyponatremia is a common phenomenon in psychiatry occurring as an adverse effect to drugs or following polydipsia. We performed a retrospective in-depth analysis of hyponatremia cases in a large unselected population of psychiatric inpatients. During a 3-year period, all cases of hyponatremia were identified among patients admitted to a large psychiatric state and university hospital by the institution's electronic laboratory database. Demographic, treatment-related, and laboratory data were obtained by consecutive chart review, respectively. Hyponatremia occurred in 347 (4.9%) of 7113 cases, of which the majority (78%) displayed only a mild manifestation. Symptoms were recorded in 28.8% of cases, already occurred in mild forms, and comprised gait impairment (45%, including falls), confusion (30%), sedation (26%), and dyspepsia (41%). Age, female sex, nonpsychiatric drug polypharmacy-particularly with thiazides and/or angiotensin converting enzyme inhibitors-and diagnosis of a mood disorder were associated with more severe hyponatremia, respectively. The proportion of hyponatremic patients treated with venlafaxine, trazodone, carbamazepine, oxcarbazepine, and first-generation antipsychotics, respectively, was significantly higher in the hyponatremia sample than in the normonatremic population. This was, surprisingly, not the case with selective serotonin reuptake inhibitors or any other antidepressant drug class. We found prescription with second-generation antipsychotics to be significantly associated with less severe hyponatremia.Hyponatremia may be mainly attributed to the syndrome of inappropriate antidiuretic hormone secretion, as indicated by decreased serum osmolarity in our sample. Besides old age and female sex, treatment with certain drugs-rather than whole drug classes-carries a substantially increased risk. PMID- 24052058 TI - Causality of incest: a reply to ten Kate. PMID- 24052059 TI - Body fluid identification by integrated analysis of DNA methylation and body fluid-specific microbial DNA. AB - Identification of body fluids found at crime scenes provides important information that can support a link between sample donors and actual criminal acts. Previous studies have reported that DNA methylation analysis at several tissue-specific differentially methylated regions (tDMRs) enables successful identification of semen, and the detection of certain bacterial DNA can allow for identification of saliva and vaginal fluid. In the present study, a method for detecting bacterial DNA was integrated into a previously reported multiplex methylation-sensitive restriction enzyme-polymerase chain reaction. The developed multiplex PCR was modified by the addition of a new semen-specific marker and by including amplicons for the 16S ribosomal RNA gene of saliva- and vaginal fluid specific bacteria to improve the efficacy to detect a specific type of body fluid. Using the developed multiplex system, semen was distinguishable by unmethylation at the USP49, DACT1, and PFN3 tDMRs and by hypermethylation at L81528, and saliva could be identified by detection of saliva-specific bacteria, Veillonella atypica and/or Streptococcus salivarius. Additionally, vaginal fluid and menstrual blood were differentiated from other body fluids by hypomethylation at the PFN3 tDMR and the presence of vaginal fluid-specific bacteria, Lactobacillus crispatus and/or Lactobacillus gasseri. Because the developed multiplex system uses the same biological source of DNA for individual identification profiling and simultaneously analyses various types of body fluid in one PCR reaction, this method will facilitate more efficient body fluid identification in forensic casework. PMID- 24052061 TI - Acute olanzapine overdose in a toddler: a case report. AB - We describe a 17-month-old female presented with an acute overdose of olanzapine, an atypical antipsychotic. She displayed prolonged extrapyramidal symptoms as compared with that in previous reports and prolactin levels above the upper limits of normal ranges. This is the first report to measure serum prolactin levels in an olanzapine-overdosed toddler and the second to calculate olanzapine's elimination half-life. PMID- 24052062 TI - Clinical pharmacokinetics of tyrosine kinase inhibitors: implications for therapeutic drug monitoring. AB - The treatment of many malignancies has been improved in recent years by the introduction of molecular targeted therapies. These drugs interact preferentially with specific targets that are mutated and/or overexpressed in malignant cells. A group of such targets are the tyrosine kinases, against which a number of inhibitors (tyrosine kinase inhibitors, TKIs) have been developed. Imatinib, a TKI with targets that include the breakpoint cluster region-Abelson (bcr-abl) fusion protein kinase and mast/stem cell growth factor receptor kinase (c-Kit), was the first clinically successful drug of this type and revolutionized the treatment and prognosis of chronic myeloid leukemia and gastrointestinal stromal tumors. This success paved the way for the development of other TKIs for the treatment of a range of hematological malignancies and solid tumors. To date, 14 TKIs have been approved for clinical use and many more are under investigation. All these agents are given orally and are substrates of a range of drug transporters and metabolizing enzymes. In addition, some TKIs are capable of inhibiting their own transporters and metabolizing enzymes, making their disposition and metabolism at steady-state unpredictable. A given dose can therefore give rise to markedly different plasma concentrations in different patients, favoring the selection of resistant clones in the case of subtherapeutic exposure, and increasing the risk of toxicity if dosage is excessive. The aim of this review was to summarize current knowledge of the clinical pharmacokinetics and known adverse effects of the TKIs that are available for clinical use and to provide practical guidance on the implications of these data in patient management, in particular with respect to therapeutic drug monitoring. PMID- 24052063 TI - Hair cortisol as a biomarker of stress among a first nation in Canada. AB - BACKGROUND: Cortisol level in hair is increasingly being used as a biomarker of chronic stress. Members of First Nation communities in Canada are experiencing stress related to a higher incidence of chronic diseases, socioeconomic factors, the state of their environment, and cultural oppression. This study aimed to investigate hair cortisol as a biomarker of stress in this population. MATERIALS AND METHODS: Hair samples were collected from the posterior vertex of 55 Walpole Island First Nation (WIFN) volunteers and compared with white volunteers living in and around London, ON, Canada. An enzyme-linked immunosorbent assay technique was used to measure cortisol content in 1 cm of hair, considered to represent 1 month of growth. In parallel, the Perceived Stress Scale (PSS), which measures short-term stress, was also completed. RESULTS: Median hair cortisol level (range) in WIFN volunteers was 177 (93-273) ng/g, significantly higher than the median hair cortisol in the healthy white controls of 116 (26-204) ng/g (P < 0.0001, Mann-Whitney U test). Hair cortisol correlated positively with gender, smoking status, and self-reported diabetes. Unlike hair cortisol, the Perceived Stress Scale did not differentiate between the First Nation and control population. CONCLUSIONS: The increased hair cortisol concentrations among WIFN volunteers compared with volunteers from a non-First Nation community suggests higher levels of chronic stress. The causes for this apparent increased stress are likely due to factors such as socioeconomic and poorer health and are worthy of further evaluation. The results highlight the difference between acute stress measured for short periods of time compared with chronic stress, measured by hair analysis. PMID- 24052064 TI - Impact of CYP3A4*22 allele on tacrolimus pharmacokinetics in early period after renal transplantation: toward updated genotype-based dosage guidelines. AB - BACKGROUND: Tacrolimus (Tac) metabolism is mainly mediated by the cytochrome P450 3A (CYP3A) subfamily. Recently, it has been reported that kidney transplant recipients carrying the CYP3A4*22 decrease-of-function allele require lower Tac doses and are more at risk of Tac overexposure than CYP3A4*1/*1 patients. This effect was shown to be independent of the CYP3A5*3 allelic status. However, the pharmacokinetic (PK) parameters assessed in previous studies were limited on single time point whole blood trough concentrations (C0) during routine follow-up of the patient after transplantation. METHODS: Our study investigates the impact of the CYP3A4*22 allele on Tac PK [C0, area under the time vs concentration curve (AUC0-12h), apparent clearance (Cl/F), Cmax, and dose requirement], time to achieve target C0, and creatinine clearance (CrCl) in 96 kidney transplant recipients considering the 2 first weeks after the graft. All patients were genotyped for both the CYP3A4*22 and the CYP3A5*3 polymorphisms. RESULTS: CYP3A4*22 carriers had higher Tac C0 during the first week with significant longer exposures to C0 > 15 ng/mL. These patients showed reduced Tac Cl/F but higher dose-adjusted AUC0-12h and Cmax and were at increased risk of C0 > 20 ng/mL. These effects were independent from CYP3A5*3 genotype: clustering patients according to both CYP3A4*22 and CYP3A5*3 allelic status did increase the predictive value of the genotype to explain interindividual differences in Tac PK. During the second week after transplantation, CrCl was on average 9.5 mL/min higher for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (P = 0.007), suggesting that Tac overexposure in CYP3A4*22 carriers might provide a renal function benefit. CONCLUSIONS: Our study confirms the decreased CYP3A4 activity toward Tac for CYP3A4*22 carriers early after transplantation and provides evidence for refining genotype-based dosage by adding the CYP3A4*22 genotype information to the CYP3A5*3 allelic status. PMID- 24052065 TI - Clinical pharmacology quality assurance program: models for longitudinal analysis of antiretroviral proficiency testing for international laboratories. AB - Among National Institutes of Health HIV Research Networks conducting multicenter trials, samples from protocols that span several years are analyzed at multiple clinical pharmacology laboratories (CPLs) for multiple antiretrovirals. Drug assay data are, in turn, entered into study-specific data sets that are used for pharmacokinetic analyses, merged to conduct cross-protocol pharmacokinetic analysis, and integrated with pharmacogenomics research to investigate pharmacokinetic-pharmacogenetic associations. The CPLs participate in a semiannual proficiency testing (PT) program implemented by the Clinical Pharmacology Quality Assurance program. Using results from multiple PT rounds, longitudinal analyses of recovery are reflective of accuracy and precision within/across laboratories. The objectives of this longitudinal analysis of PT across multiple CPLs were to develop and test statistical models that longitudinally: (1) assess the precision and accuracy of concentrations reported by individual CPLs and (2) determine factors associated with round-specific and long-term assay accuracy, precision, and bias using a new regression model. A measure of absolute recovery is explored as a simultaneous measure of accuracy and precision. Overall, the analysis outcomes assured 97% accuracy (+/-20% of the final target concentration of all (21) drug concentration results reported for clinical trial samples by multiple CPLs). Using the Clinical Laboratory Improvement Act acceptance of meeting criteria for >=2/3 consecutive rounds, all 10 laboratories that participated in 3 or more rounds per analyte maintained Clinical Laboratory Improvement Act proficiency. Significant associations were present between magnitude of error and CPL (Kruskal-Wallis P < 0.001) and antiretroviral (Kruskal-Wallis P < 0.001). PMID- 24052066 TI - Interaction between paliperidone and carbamazepine. AB - BACKGROUND: This aim of this study was to determine the impact of carbamazepine on the pharmacokinetics of paliperidone. METHODS: Six schizophrenic patients initially received a 6-12 mg/d dose of paliperidone alone. Subsequently, a 200 mg/d dose of carbamazepine was administered, and the carbamazepine dose was increased to 400 mg/d and then 600 mg/d. Plasma concentrations of paliperidone before and after carbamazepine coadministration were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: Carbamazepine significantly reduced the plasma concentration of paliperidone. The plasma concentration of paliperidone at baseline and with coadministration of 200, 400, and 600 mg/d were 45.8 +/- 11.7, 26.9 +/- 13.7, 17.1 +/- 8.2, and 15.9 +/- 7.6 ng/mL, respectively. The concentration of paliperidone with carbamazepine coadministration at doses of 200, 400, and 600 mg/d were 55.7% +/- 20.7%, 36.1% +/- 12.2%, and 33.6% +/- 10.4%, respectively, of baseline. This effect occurred even at the carbamazepine dose of 200 mg/d and reached a plateau at doses higher than 400 mg/d. However, carbamazepine coadministration exacerbated the psychotic symptoms in some patients. CONCLUSIONS: The results of the present study suggest that adjunctive treatment with carbamazepine reduces the concentration of paliperidone in a dose-dependent manner, most likely because of the induction of several drug-metabolizing enzymes and several drug transporters. PMID- 24052067 TI - Does the endoscopic treatment of lower ureter stones affect uroflowmetric values? A prospective clinical trial. AB - OBJECTIVES: The aim of this study was to document if stones at the lower ureter alter the micturition capability of the patients and to investigate whether endoscopic removal of these stones restores normal urinary flow rates or not in the 3 months of follow-up. METHODS: Forty patients with lower ureteral stone (group 1) and 20 control subjects with proximal ureteral stone (group 2) were enrolled into the study. All patients underwent uroflowmetry testing before and 3 months after the treatment for endoscopic stone removal. The mean average and peak flow rates with a sufficient voided volume (>=150 ml) were evaluated before and after surgery and compared between the groups. RESULTS: Mean values of the peak flow rates before and after surgery were 20.3 and 27.5 ml/s in group 1 and 22.5 and 23.6 ml/s in group 2, and the mean average flow rate values before and after surgery were 10.5 and 13.6 ml/s in group 1 and 11.4 and 12.1 ml/s in group 2. Statistically significant differences were determined between before and after ureteroscopy values were determined in terms of average (p < 0.05) and peak flow rates (p < 0.01) in group I; however, there no significant difference was seen in the control group. CONCLUSION: We document for the first time in the literature that patients with lower ureteric stones have a reduction in their urinary stream which resolves with endoscopic removal of the stones. PMID- 24052068 TI - Psychosomatic assessment and integrative care. Abstracts of the 22nd World Congress on Psychosomatic Medicine. Lisboa, Portugal. September 12-14, 2013. PMID- 24052069 TI - Using the zygomatic root as a reference point in temporal lobe surgery. AB - BACKGROUND: The zygomatic root (ZR) is an anatomic landmark routinely identified during cranial procedures. Traditionally, it has been used for identification of structures other than temporal lobe anatomy. The aim of this study was to define the structural relationship between the ZR and temporal lobe anatomy and provide a consistent landmark to guide surgical dissection. To our knowledge, there have been no studies demonstrating this relationship. METHODS: Eighteen DICOM series were analyzed. 2 mm axial MRI slices were reconstructed with the x-axis centered along the zygoma. The posterior point of the ZR that marks the beginning of the groove between the zygoma and temporal bone was identified on all images. Several measures were taken to quantify the relationship of the zygomatic root to surgical landmarks used during temporal lobe surgery. RESULTS: The inferior temporal gyrus was always found just medial to the ZR. The mean distance between the ZR and temporal pole was 2.75 cm on the right and 2.78 cm on the left. The tip of the temporal horn was located on average 2.4 cm (left) and 2.31 cm (right) medial to the ZR. The tip of the temporal horn was found to be an average distance of 1 mm (left and right) posterior and 1.34 cm (left and right) superior to the ZR. All distances were measured orthogonally for each of the x, y, and z axes. CONCLUSION: The zygomatic root is an easily identifiable and consistent bony landmark that can serve as an adjuvant to neuronavigation for identification of temporal lobe surgical anatomy. PMID- 24052070 TI - Population-based validation of the iScore for predicting mortality and early functional outcome in ischemic stroke patients. AB - BACKGROUND: We aimed to determine the accuracy of the iScore for predicting mortality and early disability following ischemic stroke in a French population based study. METHODS: All patients with acute ischemic stroke were identified among residents of the city of Dijon, France, between 2006 and 2011, using a population-based stroke registry. The 30-day iScore and 1-year iScore were calculated. A logistic regression model was used to assess the performance of the iScore for predicting both 30-day and 1-year mortality, and poor functional outcome at discharge (modified Rankin Scale score of 3-6). The discrimination and calibration of the model were assessed using the c-statistic and the Hosmer Lemeshow goodness-of-fit test, respectively. RESULTS: Among the 1,199 ischemic stroke patients recorded, 107 (8.9%) were excluded because at least one item of data was missing. For the remaining 1,092 patients, the c-statistic was 0.85 (95% CI: 0.82-0.89) for 30-day and 0.84 (0.81-0.87) for 1-year mortality, and calibration was good (p = 0.82 and p = 0.96, respectively, for the Hosmer Lemeshow test). Similar results were found for disability (c-statistic 0.81, 95% CI: 0.79-0.84, and p = 0.45 for the Hosmer-Lemeshow test). CONCLUSION: This is the first population-based study to demonstrate the accuracy of the iScore for predicting mortality and early disability in ischemic stroke patients. PMID- 24052071 TI - Gate control of the electron spin-diffusion length in semiconductor quantum wells. AB - The spin diffusion length is a key parameter to describe the transport properties of spin polarized electrons in solids. Electrical spin injection in semiconductor structures, a major issue in spintronics, critically depends on this spin diffusion length. Gate control of the spin diffusion length could be of great importance for the operation of devices based on the electric field manipulation and transport of electron spin. Here we demonstrate that the spin diffusion length in a GaAs quantum well can be electrically controlled. Through the measurement of the spin diffusion coefficient by spin grating spectroscopy and of the spin relaxation time by time-resolved optical orientation experiments, we show that the diffusion length can be increased by more than 200% with an applied gate voltage of 5 V. These experiments allow at the same time the direct simultaneous measurements of both the Rashba and Dresselhaus spin-orbit splittings. PMID- 24052072 TI - Neoalbaconol induces energy depletion and multiple cell death in cancer cells by targeting PDK1-PI3-K/Akt signaling pathway. AB - Many natural compounds derived from plants or microbes show promising potential for anticancer treatment, but few have been found to target energy-relevant regulators. In this study, we report that neoalbaconol (NA), a novel small molecular compound isolated from the fungus, Albatrellus confluens, could target 3-phosphoinositide-dependent protein kinase 1 (PDK1) and inhibit its downstream phosphoinositide-3 kinase (PI3-K)/Akt-hexokinase 2 (HK2) pathway, which eventually resulted in energy depletion. By targeting PDK1, NA reduced the consumption of glucose and ATP generation, activated autophagy and caused apoptotic and necroptotic death of cancer cells through independent pathway. Necroptosis was remarkably induced, which was confirmed by several necroptosis specific markers: the activation of autophagy, presence of necrotic morphology, increase of receptor-interacting protein 1 (RIP1)/RIP3 colocalization and interaction and rescued by necroptosis inhibitor necrostatin-1. The possibility that Akt overexpression reversed the NA-induced energy crisis confirmed the importance of the PDK1-Akt-energy pathway in NA-mediated cell death. Moreover, NA shows the capability to inhibit PI3-K/Akt signaling and suppress tumor growth in the nasopharyngeal carcinoma (NPC) nude mouse model. These results supported the feasibility of NA in anticancer treatments. PMID- 24052073 TI - Neuronal STAT3 activation is essential for CNTF- and inflammatory stimulation induced CNS axon regeneration. AB - CNS neurons, such as retinal ganglion cells (RGCs), do not normally regenerate injured axons, but instead undergo apoptotic cell death. Regenerative failure is due to inhibitory factors in the myelin and forming glial scar as well as due to an insufficient intrinsic capability of mature neurons to regrow axons. Nevertheless, RGCs can be transformed into an active regenerative state upon inflammatory stimulation (IS) in the inner eye, for instance by lens injury, enabling these RGCs to survive axotomy and to regenerate axons into the lesioned optic nerve. The beneficial effects of IS are mediated by various factors, including CNTF, LIF and IL-6. Consistently, IS activates various signaling pathways, such as JAK/STAT3 and PI3K/AKT/mTOR, in several retinal cell types. Using a conditional knockdown approach to specifically delete STAT3 in adult RGCs, we investigated the role of STAT3 in IS-induced neuroprotection and axon regeneration. Conditional STAT3 knockdown in RGCs did not affect the survival of RGCs after optic nerve injury compared with controls, but significantly reduced the neuroprotective effects of IS. STAT3 depletion significantly compromised CNTF stimulated neurite growth in culture and IS-induced transformation of RGCs into an active regenerative state in vivo. As a consequence, IS-mediated axonal regeneration into the injured optic nerve was almost completely abolished in mice with STAT3 depleted in RGCs. In conclusion, STAT3 activation in RGCs is involved in neuroprotection and is a necessary prerequisite for optic nerve regeneration upon IS. PMID- 24052074 TI - Targeting annexin A7 by a small molecule suppressed the activity of phosphatidylcholine-specific phospholipase C in vascular endothelial cells and inhibited atherosclerosis in apolipoprotein E-/-mice. AB - Phosphatidylcholine-specific phospholipase C (PC-PLC) is a key factor in apoptosis and autophagy of vascular endothelial cells (VECs), and involved in atherosclerosis in apolipoprotein E-/- (apoE-/-) mice. But the endogenous regulators of PC-PLC are not known. We recently found a small chemical molecule (6-amino-2, 3-dihydro-3-hydroxymethyl-1, 4-benzoxazine, ABO) that could inhibit oxidized low-density lipoprotein (oxLDL)-induced apoptosis and promote autophagy in VECs, and further identified ABO as an inhibitor of annexin A7 (ANXA7) GTPase. Based on these findings, we hypothesize that ANXA7 is an endogenous regulator of PC-PLC, and targeting ANXA7 by ABO may inhibit atherosclerosis in apoE-/- mice. In this study, we tested our hypothesis. The results showed that ABO suppressed oxLDL-induced increase of PC-PLC level and activity and promoted the co localization of ANXA7 and PC-PLC in VECs. The experiments of ANXA7 knockdown and overexpression demonstrated that the action of ABO was ANXA7-dependent in cultured VECs. To investigate the relation of ANXA7 with PC-PLC in atherosclerosis, apoE-/- mice fed with a western diet were treated with 50 or 100 mg/kg/day ABO. The results showed that ABO decreased PC-PLC levels in the mouse aortic endothelium and PC-PLC activity in serum, and enhanced the protein levels of ANXA7 in the mouse aortic endothelium. Furthermore, both dosages of ABO significantly enhanced autophagy and reduced apoptosis in the mouse aortic endothelium. As a result, ABO significantly reduced atherosclerotic plaque area and effectively preserved a stable plaques phenotype, including reduced lipid deposition and pro-inflammatory macrophages, increased anti-inflammatory macrophages, collagen content and smooth muscle cells, and less cell death in the plaques. In conclusion, ANXA7 was an endogenous regulator of PC-PLC, and targeting ANXA7 by ABO inhibited atherosclerosis in apoE-/- mice. PMID- 24052075 TI - The sodium/iodide symporter NIS is a transcriptional target of the p53-family members in liver cancer cells. AB - Thyroid iodide accumulation via the sodium/iodide symporter (NIS; SLC5A5) has been the basis for the longtime use of radio-iodide in the diagnosis and treatment of thyroid cancers. NIS is also expressed, but poorly functional, in some non-thyroid human cancers. In particular, it is much more strongly expressed in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) cell lines than in primary human hepatocytes (PHH). The transcription factors and signaling pathways that control NIS overexpression in these cancers is largely unknown. We identified two putative regulatory clusters of p53-responsive elements (p53REs) in the NIS core promoter, and investigated the regulation of NIS transcription by p53-family members in liver cancer cells. NIS promoter activity and endogenous NIS mRNA expression are stimulated by exogenously expressed p53-family members and significantly reduced by member-specific siRNAs. Chromatin immunoprecipitation analysis shows that the p53-REs clusters in the NIS promoter are differentially occupied by the p53-family members to regulate basal and DNA damage-induced NIS transcription. Doxorubicin strongly induces p53 and p73 binding to the NIS promoter, leading to an increased expression of endogenous NIS mRNA and protein in HCC and CCA cells, but not in PHH. Silencing NIS expression reduced doxorubicin-induced apoptosis in HCC cells, pointing to a possible role of a p53-family-dependent expression of NIS in apoptotic cell death. Altogether, these results indicate that the NIS gene is a direct target of the p53 family and suggests that the modulation of NIS by DNA-damaging agents is potentially exploitable to boost NIS upregulation in vivo. PMID- 24052077 TI - VDAC1-based peptides: novel pro-apoptotic agents and potential therapeutics for B cell chronic lymphocytic leukemia. AB - The voltage-dependent anion channel 1 (VDAC1), localized in the outer mitochondrial membrane, mediates metabolic cross-talk between the mitochondrion and the cytoplasm and thus serves a fundamental role in cell energy metabolism. VDAC1 also plays a key role in mitochondria-mediated apoptosis, interacting with anti-apoptotic proteins. Resistance of cancer cells to apoptosis involves quenching the mitochondrial apoptotic pathway by over-expression of anti apoptotic/pro-survival hexokinase (HK) and Bcl-2 family proteins, proteins that mediate their anti-apoptotic activities via interaction with VDAC1. Using specifically designed VDAC1-based cell-penetrating peptides, we targeted these anti-apoptotic proteins to prevent their pro-survival/anti-apoptotic activities. Anti-apoptotic proteins are expressed at high levels in B-cell chronic lymphocytic leukemia (CLL), an incurable disease requiring innovative new approaches to improve therapeutic outcome. CLL is characterized by a clonal accumulation of mature neoplastic B cells that are resistant to apoptosis. Specifically, we demonstrate that the VDAC1-based peptides (Antp-LP4 and N Terminal-Antp) selectively kill peripheral blood mononuclear cells (PBMCs) obtained from CLL patients, yet spare those obtained from healthy donors. The cell death induction competence of the peptides was well correlated with the amount of double positive CD19/CD5 cancerous CLL PBMCs, further illustrating their selectivity toward cancer cells. Moreover, these VDAC1-based peptides induced apoptosis by activating the mitochondria-mediated pathway, reflected in membrane blebbing, condensation of nuclei, DNA fragmentation, release of mitochondrial cytochrome c, loss of mitochondrial membrane potential, decreased cellular ATP levels and detachment of HK, all leading to apoptotic cell death. Thus, the mode of action of the peptides involves decreasing energy production and inducing apoptosis. Over 27 versions of cell-penetrating VDAC1-based peptides were designed and screened to identify the most stable, short and apoptosis inducing peptides toward CLL-derived lymphocytes. In this manner, three optimized peptides suitable for in vivo studies were identified. This study thus reveals the potential of VDAC1-based peptides as an innovative and effective anti-CLL therapy. PMID- 24052076 TI - A novel extracellular role for tissue transglutaminase in matrix-bound VEGF mediated angiogenesis. AB - The importance of tissue transglutaminase (TG2) in angiogenesis is unclear and contradictory. Here we show that inhibition of extracellular TG2 protein crosslinking or downregulation of TG2 expression leads to inhibition of angiogenesis in cell culture, the aorta ring assay and in vivo models. In a human umbilical vein endothelial cell (HUVEC) co-culture model, inhibition of extracellular TG2 activity can halt the progression of angiogenesis, even when introduced after tubule formation has commenced and after addition of excess vascular endothelial growth factor (VEGF). In both cases, this leads to a significant reduction in tubule branching. Knockdown of TG2 by short hairpin (shRNA) results in inhibition of HUVEC migration and tubule formation, which can be restored by add back of wt TG2, but not by the transamidation-defective but GTP-binding mutant W241A. TG2 inhibition results in inhibition of fibronectin deposition in HUVEC monocultures with a parallel reduction in matrix-bound VEGFA, leading to a reduction in phosphorylated VEGF receptor 2 (VEGFR2) at Tyr1214 and its downstream effectors Akt and ERK1/2, and importantly its association with beta1 integrin. We propose a mechanism for the involvement of matrix-bound VEGFA in angiogenesis that is dependent on extracellular TG2-related activity. PMID- 24052078 TI - The HDAC inhibitor, MPT0E028, enhances erlotinib-induced cell death in EGFR-TKI resistant NSCLC cells. AB - Epidermal growth factor receptor (EGFR), which promotes cell survival and division, is found at abnormally high levels on the surface of many cancer cell types, including many cases of non-small cell lung cancer. Erlotinib (Tarceva), an oral small-molecule tyrosine kinase inhibitor, is a so-called targeted drug that inhibits the tyrosine kinase domain of EGFR, and thus targets cancer cells with some specificity while doing less damage to normal cells. However, erlotinib resistance can occur, reducing the efficacy of this treatment. To develop more effective therapeutic interventions by overcoming this resistance problem, we combined the histone deacetylase inhibitor, MPT0E028, with erlotinib in an effort to increase their antitumor effects in erlotinib-resistant lung adenocarcinoma cells. This combined treatment yielded significant growth inhibition, induced the expression of apoptotic proteins (PARP, gammaH2AX, and caspase-3), increased the levels of acetylated histone H3, and showed synergistic effects in vitro and in vivo. These effects were independent of the mutation status of the genes encoding EGFR or K-Ras. MPT0E028 synergistically blocked key regulators of the EGFR/HER2 signaling pathways, attenuating multiple compensatory pathways (e.g., AKT, extracellular signal-regulated kinase, and c-MET). Our results indicate that this combination therapy might be a promising strategy for facilitating the effects of erlotinib monotherapy by activating various networks. Taken together, our data provide compelling evidence that MPT0E028 has the potential to improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents. PMID- 24052080 TI - [Retrovirus superantigen hypothesis of multiple sclerosis]. PMID- 24052081 TI - Renal interstitial fibrosis in 0-hour biopsy as a predictor of post-transplant anemia. AB - BACKGROUND/AIMS: Anemia is common in kidney transplant patients and may cause adverse cardiovascular events. Several studies have reported some predictors of post-transplant anemia. However, associations between the pathological findings in the 0-hour biopsy and anemia have not been well described. METHODS: 258 consecutive kidney transplant patients were enrolled in this retrospective study. The patients were divided into two groups, according to the presence or absence of interstitial fibrosis and tubular atrophy (IF/TA) in the 0-hour biopsy: the IF/TA group with fibrotic area >=5% (n = 131) and the non-IF/TA group with fibrotic area <5% (n = 127). We examined the association between IF/TA and post transplant anemia. RESULTS: Serial changes in hemoglobin levels in the IF/TA group were lower than in the non-IF/TA group (p = 0.007). Anemia at 12 months was found in 53% of the IF/TA group, and 35% of the non-IF/TA group (p = 0.004). Even after adjustment for several confounders including graft function, the presence of IF/TA was independently associated with post-transplant anemia at 12 months (odds ratio 1.88, 95% confidence interval 1.06-3.36, p = 0.031). This association was still significant in a subgroup with normal graft function. CONCLUSIONS: IF/TA in the 0-hour biopsy specimen is one of the predictors for post-transplant anemia and can be used to identify patients who need the treatment with erythropoiesis-stimulating agents. PMID- 24052082 TI - Acute, bilateral, concurrent central retinal artery occlusion in sickle cell disease after use of tadalafil (Cialis). AB - IMPORTANCE: Sickle cell disease (SCD) is characterized by vaso-occlusive crisis. In the eye, central retinal artery occlusion (CRAO) is a rare complication in SCD, with only 1 previous report of bilateral, concurrent CRAO. We report a case of bilateral, concurrent CRAO in a patient with SCD, possibly precipitated by the use of phosphodiesterase 5 inhibitors. OBSERVATIONS: A 37-year-old African American woman with a known medical history significant for SCD and pulmonary arterial hypertension who was receiving treatment with tadalafil, a phosphodiesterase 5 inhibitor, developed bilateral, concurrent CRAO that persisted after exchange transfusion. CONCLUSIONS AND RELEVANCE: Bilateral CRAO secondary to SCD is extremely rare, with only 1 previous case report in the literature. The use of phosphodiesterase 5 inhibitors is an additional risk factor and may have contributed to the development of concurrent CRAO in this patient. PMID- 24052079 TI - PIAS1-modulated Smad2/4 complex activation is involved in zinc-induced cancer cell apoptosis. AB - Prostate cancer is one of the most frequently diagnosed cancers among men. Dietary intake of nutrients is considered crucial for preventing the initiation of events leading to the development of carcinoma. Many dietary compounds have been considered to contribute to cancer prevention including zinc, which has a pivotal role in modulating apoptosis. However, the mechanism for zinc-mediated prostate cancer chemoprevention remains enigmatic. In this study, we investigated the therapeutic effect of zinc in prostate cancer chemoprevention for the first time. Exposure to zinc induced apoptosis and resulted in transactivation of p21(WAF1/Cip1) in a Smad-dependent and p53-independent manner in prostate cancer cells. Smad2 and PIAS1 proteins were significantly upregulated resulting in dramatically increased interactions between Smad2/4 and PIAS1 in the presence of zinc in LNCaP cells. Furthermore, it was found that the zinc-induced Smad4/2/PIAS1 transcriptional complex is responsible for Smad4 binding to SBE1 and SBE3 regions within the p21(WAF1/Cip1) promoter. Exogenous expression of Smad2/4 and PIAS1 promotes zinc-induced apoptosis concomitant with Smad4 nuclear translocation, whereas endogenous Smad2/4 silencing inhibited zinc-induced apoptosis accompanying apparent p21(WAF1/Cip1) reduction. Moreover, the knockdown of PIAS1 expression attenuated the zinc-induced recruitment of Smad4 on the p21(WAF1/Cip1) promoter. The colony formation experiments demonstrate that PIAS1 and Smad2/4 silencing could attenuate zinc apoptotic effects, with a proliferation of promoting effects. We further demonstrate the correlation of apoptotic sensitivity to zinc and Smad4 and PIAS1 in multiple cancer cell lines, demonstrating that the important roles of PIAS1, Smad2, and Smad4 in zinc-induced cell death and p21(WAF1/Cip1) transactivation were common biological events in different cancer cell lines. Our results suggest a new avenue for regulation of zinc-induced apoptosis, and provide a model that demonstrates zinc endorses the Smad2/4/PIAS1 complex to activate the p21(WAF1/Cip1) gene that mediates apoptosis. PMID- 24052083 TI - Lower male genitourinary trauma: a pictorial review. AB - Blunt and penetrating trauma to the male pelvis and external genitalia may result in significant injury to the lower genitourinary system including the bladder, urethra, penis, and scrotum. Emergent imaging plays an important role in identifying these injuries and directing appropriate, timely management. In this article, we review indications for dedicated genitourinary system imaging in trauma and illustrate the imaging features of injuries to the lower male genitourinary system in order to facilitate accurate and rapid diagnosis. PMID- 24052084 TI - Shifting dependence: the influence of partner instrumentality and self-esteem on responses to interpersonal risk. AB - High and low self-esteem people typically have divergent responses to interpersonal risk. Highs draw closer to their partner, whereas lows self protectively distance. However, these responses should be more likely when people are dependent on the rewards their partner offers. Two experiments tested the hypothesis that structural changes in the situation of interdependence lead high and low self-esteem people to reverse their typical responses to risk. When partners were instrumental to a current goal pursuit (and participants were more dependent on the rewards partners could offer), highs drew closer and lows distanced when risk was primed. However, when partners were not instrumental to an active goal (and participants were less dependent on the rewards partners could offer), these responses were reversed. Reducing one's dependence on a partner to attain one's personal goals appears to reduce highs' incentive to connect, whereas it appears to increase lows' incentive to connect. PMID- 24052085 TI - Acculturation attitudes and social adjustment in British South Asian children: a longitudinal study. AB - A 1-year longitudinal study with three testing points was conducted with 215 British Asian children aged 5 to 11 years to test hypotheses from Berry's acculturation framework. Using age-appropriate measures of acculturation attitudes and psychosocial outcomes, it was found that (a) children generally favored an "integrationist" attitude, and this was more pronounced among older (8 10 years) than in younger (5-7 years) children and (b) temporal changes in social self-esteem and peer acceptance were associated with different acculturation attitudes held initially, as shown by latent growth curve analyses. However, a supplementary time-lagged regression analysis revealed that children's earlier "integrationist" attitudes may be associated with more emotional symptoms (based on teachers' ratings) 6 months later. The implications of these different outcomes of children's acculturation attitudes are discussed. PMID- 24052087 TI - Prognostic performance of a high-sensitivity cardiac troponin I assay in patients with non-ST-elevation acute coronary syndrome. AB - BACKGROUND: High-sensitivity assays for cardiac troponin enable more precise measurement of very low concentrations and improved diagnostic accuracy. However, the prognostic value of these measurements, particularly at low concentrations, is less well defined. METHODS: We evaluated the prognostic performance of a new high-sensitivity cardiac troponin I (hs-cTnI) assay (Abbott ARCHITECT) compared with the commercial fourth generation cTnT assay in 4695 patients with non-ST segment elevation acute coronary syndromes (NSTE-ACS) from the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in NSTE-ACS) and SEPIA-ACS1-TIMI 42 (Otamixaban for the Treatment of Patients with NSTE-ACS) trials. The primary endpoint was cardiovascular death or new myocardial infarction (MI) at 30 days. Baseline cardiac troponin was categorized at the 99th percentile reference limit (26 ng/L for hs-cTnI; 10 ng/L for cTnT) and at sex-specific 99th percentiles for hs-cTnI. RESULTS: All patients at baseline had detectable hs-cTnI compared with 94.5% with detectable cTnT. With adjustment for all other elements of the TIMI risk score, patients with hs-cTnI >=99th percentile had a 3.7-fold higher adjusted risk of cardiovascular death or MI at 30 days relative to patients with hs-cTnI <99th percentile (9.7% vs 3.0%; odds ratio, 3.7; 95% CI, 2.3-5.7; P < 0.001). Similarly, when stratified by categories of hs-cTnI, very low concentrations demonstrated a graded association with cardiovascular death or MI (P-trend < 0.001). Use of sex-specific cutpoints did not improve prognostic performance. Patients with negative fourth generation cTnT (<10 ng/L) but hs-cTnI >=26 ng/L were at increased risk of cardiovascular death/MI compared to those with hs-cTnI <26 ng/L (9.2% vs 2.9%, P = 0.002). CONCLUSIONS: Application of this hs-cTnI assay identified a clinically relevant higher risk of recurrent events among patients with NSTE-ACS, even at very low troponin concentrations. PMID- 24052088 TI - Beam controlled arc therapy--a delivery concept for stationary targets. AB - Volumetric modulated arc therapy (VMAT) presupposes that it is beneficial to deliver radiation from all beam angles as the gantry rotates, requiring the multi leaf collimator to maintain continuity in shape from one angle to another. In turn, radiation from undesirable beam angles could compromise the dose distribution. In this work, we challenge the notion that the radiation beam must be held on as the gantry rotates around the patient. We propose a new approach for delivering intensity-modulated arc therapy, beam-controlled arc therapy (BCAT), during which the radiation beam is controlled on or off and the dose rate is modulated while the gantry rotates around the patient. We employ linear programming-based dose optimization to each aperture weight, resulting in some zero weight apertures. During delivery, the radiation beam is held off at control points with zero weights as the MLC shape transits to the next non-zero weight shape. This was tested on ten head and neck cases. Plan quality and delivery efficiency were compared with VMAT. Improvements of up to 17% (p-value 0.001) and 57% (p-value 0.018) in organ-at-risk sparing and target dose uniformity, respectively, were achieved. Compared to the fixed number of apertures used in single-arc and double-arc VMAT, the BCAT used 109 and 175 apertures on average, respectively. The difference in total MUs for VMAT and BCAT plans was less than 4%. Plan quality improvement was confirmed after delivery with gamma analysis resulting in over 99% agreement, or 4 in 1099 points that failed. PMID- 24052086 TI - Recent human adaptation: genomic approaches, interpretation and insights. AB - The recent availability of genomic data has spurred many genome-wide studies of human adaptation in different populations worldwide. Such studies have provided insights into novel candidate genes and pathways that are putatively involved in adaptation to different environments, diets and disease prevalence. However, much work is needed to translate these results into candidate adaptive variants that are biologically interpretable. In this Review, we discuss methods that may help to identify true biological signals of selection and studies that incorporate complementary phenotypic and functional data. We conclude with recommendations for future studies that focus on opportunities to use integrative genomics methodologies in human adaptation studies. PMID- 24052090 TI - Feasibility of [(123)I]-meta-iodobenzylguanidine dynamic 3-D kinetic analysis in vivo using a CZT ultrafast camera: preliminary results. AB - PURPOSE: No data are yet available in the literature concerning 3-D [(123)I]-meta iodobenzylguanidine ([(123)I]-MIBG) kinetics in vivo. In this study we investigated the feasibility of dynamic 3-D [(123)I]-MIBG kinetic analysis using a CZT ultrafast camera. METHODS: The study group comprised 16 patients consecutively scheduled for [(123)I]-MIBG cardiac scintigraphy for clinical purpose who were studied using a CZT camera (NM530c, GE). Dynamic acquisition in list mode was simultaneously started with a bolus injection of the radiotracer (185-370 MBq) for an overall duration of 900 s. A temporal series of 3-D volumes was reconstructed from the first 150 s of dynamic acquisition with a temporal resolution of 5 s. A summed cardiac image was also reconstructed to serve as reference for blood pool (BP) and left ventricle (LV) wall identification. BP and LV volumes of interest (VOIs) were manually drawn to cover the whole heart and automatically reported on the reframed volumes. Time-activity curves (TACs) for the BP and LV were extracted by averaging the signal intensity in the respective VOI in each time frame. BP TACs were fitted to a gamma variate model while LV TACs were fitted to a bicompartmental model. RESULTS: TAC analysis was feasible in all patients with good interobserver reproducibility. BP TACs were well described by a gamma variate model as they represent the first pass of the tracer. The first compartment of LV TACs corresponded to contamination spillover of the LV signal from the BP signal. The LV second compartment characterized the uptake of the tracer in the myocardium quantified in terms of maximum signal intensity value (6.95 +/- 2.76 counts/mm(3)/s(2)), maximum up-slope value (0.36 +/- 0.15 counts/mm(3)/s) and normalized washout of the signal value (7.0 +/- 0.6 %). CONCLUSION: Using CZT technology and dynamic 3-D acquisition, analysis of [(123)I]-MIBG radiotracer kinetics in vivo is feasible and may provide pathophysiological information in addition to that available with standard planar and SPECT imaging. PMID- 24052089 TI - Radiation risk and protection of patients in clinical SPECT/CT. AB - Clinical studies have demonstrated that hybrid single photon emission computed tomography (SPECT)/CT for various diagnostic issues has an added value as compared to SPECT alone. However, the combined acquisition of functional and anatomical images can substantially increase radiation exposure to patients, in particular when using a hybrid system with diagnostic CT capabilities. It is, therefore, essential to carefully balance the diagnostic needs and radiation protection requirements. To this end, the evidence on health effects induced by ionizing radiation is outlined. In addition, the essential concepts for estimating radiation doses and lifetime attributable cancer risks associated with SPECT/CT examinations are presented taking into account both the new recommendations of the International Commission on Radiological Protection (ICRP) as well as the most recent radiation risk models. Representative values of effective dose and lifetime attributable risk are reported for ten frequently used SPECT radiopharmaceuticals and five fully diagnostic partial-body CT examinations. A diagnostic CT scan acquired as part of a combined SPECT/CT examination contributes considerably to, and for some applications even dominates, the total patient exposure. For the common SPECT and CT examinations considered in this study, the lifetime attributable risk of developing a radiation-related cancer is less than 0.27 %/0.37 % for men/women older than 16 years, respectively, and decreases markedly with increasing age at exposure. Since there is no clinical indication for a SPECT/CT examination unless an emission scan has been indicated, the issue on justification comes down to the question of whether it is necessary to additionally acquire a low-dose CT for attenuation correction and anatomical localization of tracer uptake or even a fully diagnostic CT. In any case, SPECT/CT studies have to be optimized, e.g. by adapting dose reduction measures from state-of-the-art CT practice, and exposure levels should not exceed the national diagnostic reference levels for standard situations. PMID- 24052091 TI - The prevalence of vegetative and minimally conscious states: a systematic review and methodological appraisal. AB - OBJECTIVES: To systematically review prevalence studies of vegetative state (VS) and minimally conscious state (MCS) in geographically defined populations, to appraise study methods and assess sources of heterogeneity. METHODS: MEDLINE, EBM Reviews, and EMBASE databases were searched using key terms. Two reviewers independently identified pertinent articles and screened the references for additional studies. Studies measuring the prevalence of VS and/or MCS in a defined population were included, and information on characteristics, methods, and results was extracted. Heterogeneity was quantified through the statistic I. RESULTS: We identified 5 cross-sectional prevalence surveys of VS and 1 of MCS. Prevalence ranged from 0.2 cases per 100,000 inhabitants to 3.4 for VS and was 1.5 per 100,000 for MCS. Relevant heterogeneity (I = 99.0%) prevented us from calculating a summary estimate. The prevalence of trauma cases varied from 21.9% to 53.8%. Variability pertaining to diagnostic criteria, definition of case, and methods of ascertainment was found. CONCLUSION: In the few prevalence studies of VS and MCS that were identified, the estimates showed high variability and could not be pooled. Future studies should consider using comparable methods for the definition, ascertainment, and confirmation of cases. PMID- 24052092 TI - Mindfulness-based cognitive therapy reduces symptoms of depression in people with a traumatic brain injury: results from a randomized controlled trial. AB - OBJECTIVE: We sought to determine if we could reduce symptoms of depression in individuals with a traumatic brain injury using mindfulness-based cognitive therapy. SETTING: The study was conducted in a community setting. PARTICIPANTS: We enrolled adults with symptoms of depression after a traumatic brain injury. DESIGN: We conducted a randomized controlled trial; participants were randomized to the 10-week mindfulness-based cognitive therapy intervention arm or to the wait-list control arm. MAIN MEASURES: The primary outcome measure was symptoms of depression using the Beck Depression Inventory-II. RESULTS: The parallel group analysis revealed a greater reduction in Beck Depression Inventory-II scores for the intervention group (6.63, n = 38,) than the control group (2.13, n = 38, P = .029). A medium effect size was observed (Cohen d = 0.56). The improvement in Beck Depression Inventory-II scores was maintained at the 3-month follow-up. CONCLUSION: These results are consistent with those of other researchers that use mindfulness-based cognitive therapy to reduce symptoms of depression and suggest that further work to replicate these findings and improve upon the efficacy of the intervention is warranted. PMID- 24052093 TI - Comparative effectiveness of traumatic brain injury rehabilitation: differential outcomes across TBI model systems centers. AB - OBJECTIVE: To measure patient functional outcomes across rehabilitation centers. SETTING: Traumatic Brain Injury Model System (TBIMS) centers. PARTICIPANTS: Patients with traumatic brain injury (TBI) admitted to 21 TBIMS rehabilitation centers (N = 6975, during 1999-2008). DESIGN: Retrospective analysis of prospectively collected data. MAIN MEASURES: Center-specific functional outcomes of TBI patients using Functional Independence Measure, Disability Rating Scale, and Glasgow Outcome Scale-Extended. RESULTS: There were large differences in patient characteristics across centers (demographics, TBI severity, and functional deficits at admission to rehabilitation). However, even after taking those factors into account, there were significant differences in functional outcomes of patients treated at different TBIMS centers. CONCLUSION: There are significant differences in functional outcomes of TBI patients across rehabilitation centers. PMID- 24052094 TI - The effect of hyperbaric oxygen on persistent postconcussion symptoms. AB - BACKGROUND: The high incidence of persistent postconcussion symptoms in service members with combat-related mild traumatic brain injury has prompted research in the use of hyperbaric oxygen (HBO2) for management. OBJECTIVE: The effects of HBO2 on persistent postconcussion symptoms in 60 military service members with at least 1 combat-related mild traumatic brain injury were examined in a single center, double-blind, randomized, sham-controlled, prospective trial at the Naval Medicine Operational Training Center at Naval Air Station Pensacola. METHODS: Over a 10-week period, subjects received a series of 40, once-daily, hyperbaric chamber compressions at 2.0 atmospheres absolute (ATA). During each session, subjects breathed 1 of 3 preassigned oxygen fractions (10.5%, 75%, or 100%) for 60 minutes, resulting in an oxygen exposure equivalent to breathing surface air, 100% oxygen at 1.5 ATA, or 100% oxygen at 2.0 ATA, respectively. Individual, subscale and total item responses on the Rivermead Postconcussion Symptom Questionnaire and individual and total Posttraumatic Disorder Checklist-Military Version were measured just prior to intervention and immediately postintervention. RESULTS: Between-group testing of pre- and postintervention means revealed no significant differences on individual or total scores on the Posttraumatic Disorder Checklist-Military Version or Rivermead Postconcussion Symptom Questionnaire, demonstrating a successful randomization and no significant main effect for HBO2 at 1.5 or 2.0 ATA equivalent compared with the sham compression. Within-group testing of pre- and postintervention means revealed significant differences on several individual items for each group and difference in the Posttraumatic Disorder Checklist-Military Version total score for the 2.0 ATA HBO2 group. DISCUSSION: The primary analyses of between group differences found no evidence of efficacy for HBO2. The scattered within group differences are threatened by Type 2 errors and could be explained by nonspecific effects. CONCLUSION: This study demonstrated that HBO2 at either 1.5 or 2.0 ATA equivalent had no effect on postconcussion symptoms after mild traumatic brain injury when compared with sham compression. PMID- 24052095 TI - Disease and civilization: constipation & health since the industrial revolution. PMID- 24052096 TI - Health insurance exchanges: a hospital perspective. PMID- 24052097 TI - Attention employed physicians: keys to protect your interests. PMID- 24052098 TI - Improving patient flow and asset management using real-time location systems. PMID- 24052099 TI - Vaccine-preventable diseases still pose a threat to our communities. PMID- 24052100 TI - Minimally invasive surgery: patient safety & informed consent a discussion with Steven McCarus, MD. Interviewed by Theresa Foy DiGeronimo. PMID- 24052101 TI - Building your MD brand. PMID- 24052102 TI - Legislative brief: hot topic issues in Trenton. PMID- 24052103 TI - Maintenance of certification: an ongoing controversy. PMID- 24052104 TI - Radical cystectomy in the elderly: national trends and disparities in perioperative outcomes and quality of care. AB - INTRODUCTION: To examine national trends of radical cystectomy (RC) for urothelial carcinoma of urinary bladder in octogenarian patients and to assess the rates of adverse outcomes. MATERIALS AND METHODS: Within the Nationwide Inpatient Sample (NIS), we focused on RCs performed between 1998 and 2007. Age was stratified as <80 versus >=80 years. Propensity-based matched analyses were used to account for treatment selection biases. Generalized linear regression analyses were fitted to predict adverse perioperative events according to age. RESULTS: Of 12,274 RC patients, 1,605 were >=80 years (13.1%). The RC rates in octogenarians increased significantly from 9.9% in 1998 to 13.7% in 2007. Most elderly patients were treated at low-/intermediate-volume hospitals (81.7%) and nonacademic centers (60.6%). After propensity score matching, the inpatient mortality rate was higher in octogenarians (4.6 vs. 2.6%, p < 0.001). In multivariable analyses, octogenarians were at increased risk of blood transfusions (OR: 1.30) and postoperative complications (OR: 1.22). CONCLUSIONS: Most octogenarians undergoing RC are treated at low-/intermediate-volume hospitals and at nonacademic centers. The inpatient hospital mortality is about twice as high in these patients, and adverse perioperative outcomes are more frequent. Such patients may benefit from RC at high-volume and/or academic centers to maximally reduce adverse perioperative outcomes. PMID- 24052105 TI - Gosha-jinki-gan reduced oxaliplatin-induced hypersensitivity to cold sensation and its effect would be related to suppression of the expression of TRPM8 and TRPA1 in rats. AB - Peripheral neuropathy is a common side effect of the chemotherapeutic agent oxaliplatin (Oxp), and is associated with hypersensitivity to cold sensation in the acute stage. Recently, gosha-jinki-gan (GJG), a Japanese herbal medicine, was reported to improve Oxp-induced cold hypersensitivity. However, the mechanism for this effect was not elucidated. We hypothesized that the effect of GJG on Oxp induced cold hypersensitivity may be associated with the expression of the transient receptor potential melastatin 8 (TRPM8) and transient receptor potential ankyrin 1 (TRPA1) channels, which are cold-gated ion channels. To assess this hypothesis, we examined alteration of the withdrawal response to cold stimulation following coadministration of GJG and Oxp in rats, and the relationship between this altered withdrawal response and the expression of TRPM8 and TRPA1 mRNA in the dorsal root ganglia (DRG). Assessment of cold hypersensitivity was performed at 4 and 10 degrees C using a cold plate. Compared with Oxp administration alone, coadministration of GJG (oral dose: 1 g/kg/day for 12 days) and Oxp (intraperitoneal dose: 4 mg/kg twice a week) significantly reduced the withdrawal response to cold stimulation. On the 12th day of drug administration, the L4-L6 DRG were removed and the expression of TRPM8 and TRPA1 mRNA was determined using RT-PCR. The expression of TRPM8 and TRPA1 in the DRG of rats that were coadministered GJG and Oxp decreased significantly compared with that in the rats administered Oxp alone. These results suggest that coadministration of GJG may improve Oxp-induced cold hypersensitivity by suppressing the overexpression of TRPM8 and TRPA1 mRNA. PMID- 24052106 TI - Sustained-release protamine sulphate-impregnated microspheres may reduce the frequent administration of recombinant interferon alpha-2b in ovarian cancer: in vitro characterization. AB - Parenteral administration of recombinant interferon-alpha-2b (rINF-alpha-2b) at a dose of 50*10 IU once a week for 8 weeks is recommended for ovarian cancer. However, short half-life, small therapeutic index and proteolytic degradation cause fluctuations in plasma level and pose barriers in the development of a clinically viable dosage form. Therefore, in the present investigation, fluorescein isothiocynate-tagged rINF-alpha-2b was loaded into stearic acid (*rINF-alpha-2b-SMs), pectin (*rINF-alpha-2b-PMs) and gelatin (*rINF-alpha-2b GMs) microspheres. Parameters such as particle size, zeta potential, encapsulation efficiency and in-vitro release were studied to follow the optimization process. The formulation, *rINF-alpha-2b-GMs of particle size 8.3+/ 2.1 MUm with an encapsulation efficiency of 76.0+/-7.4%, offered 97.4% of *rINF alpha-2b release at 288 h. Thus, negatively charged extended-release formulation *rINF-alpha-2b-GMs was then tethered with a gradient concentration (5-20 mg/ml) of a cationic arginine-rich protein stabilizer, protamine sulphate (Pt). The nanoformulation, *rINF-alpha-2b-Pt-GMs-15 superimposed with 15 mg/ml of Pt, released 95.0% of *rINF-alpha-2b at 336 h and was designated as the optimized formulation. The optimized formulation also conserved the primary and secondary structure of *rINF-alpha-2b as analysed by gel electrophoresis and circular dichroism. Moreover, in-vitro cytotoxicity analysis of SKOV3 cells of the optimized nanoformulation reported significantly (one-way analysis of variance test, P<0.05) lower IC50 (414.3 IU/ml) compared with *rINF-alpha-2b-GMs (514.3 IU/ml) and pure rINF-alpha-2b (628.6 IU/ml) at 72 h by offering a prolonged cytotoxic effect. Therefore, *rINF-alpha-2b-Pt-GMs-15, a promising nanomedicine, warrants further in-depth in-vivo study to scale up the technology for clinical translation. PMID- 24052107 TI - Zebularine induces chemosensitization to methotrexate and efficiently decreases AhR gene methylation in childhood acute lymphoblastic leukemia cells. AB - Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in childhood. Despite the advances in treatment, about 20% of patients relapse and/or die, indicating the need for different therapies for this group. Zebularine (ZB) is a potent DNA methyltransferase (DNMT) inhibitor and has been associated with gene demethylation and enhancement of tumor chemosensitivity. This study aimed to evaluate the effects of ZB, alone or combined with chemotherapeutics (methotrexate and vincristine), on childhood ALL cell lines. Cell proliferation, apoptosis, and clonogenic capacity were studied in Jurkat and ReH cell lines. Bisulfite modification, followed by methylation-specific PCR was carried out to evaluate aryl hydrocarbon receptor (AhR) methylation status. Gene expression of DNMT1, DNMT3a, DNMT3b, and AhR was assessed using qRT-PCR. Both cell cultures were sensitive to ZB, showing a dose-dependent and time-dependent response (P<0.05). ZB induced apoptosis and decreased clonogenic capacity in both cell lines. Combination with methotrexate resulted in a strong synergistic effect, whereas combination with vincristine led to an antagonistic response in both cell lines. ZB treatment decreased gene expression of the three DNMTs and induced AhR gene promoter demethylation and its re-expression. These results indicate that ZB may be a promising drug for the adjuvant treatment of ALL, mainly when combined with methotrexate. PMID- 24052108 TI - The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. AB - The amyloid cascade hypothesis is widely accepted as the centerpiece of Alzheimer disease (AD) pathogenesis. It proposes that abnormal production of beta amyloid protein (Abeta) is the cause of AD and that the neurotoxicity is due to Abeta itself or its oligomeric forms. We suggest that this, in itself, cannot be the cause of AD because demonstrating such toxicity requires micromolar concentrations of these Abeta forms, while their levels in brain are a million times lower in the picomolar range. AD probably results from the inflammatory response induced by extracellular Abeta deposits, which later become enhanced by aggregates of tau. The inflammatory response, which is driven by activated microglia, increases over time as the disease progresses. Disease-modifying therapeutic attempts to date have failed and may continue to do so as long as the central role of inflammation is not taken into account. Multiple epidemiological and animal model studies show that NSAIDs, the most widely used antiinflammatory agents, have a substantial sparing effect on AD. These studies provide a proof of concept regarding the anti-inflammatory approach to disease modification. Biomarker studies have indicated that early intervention may be necessary. They have established that disease onset occurs more than a decade before it becomes clinically evident. By combining biomarker and pathological data, it is possible to define six phases of disease development, each separated by about 5 years. Phase one can be identified by decreases in Abeta in the CSF, phase 2 by increases of tau in the CSF plus clear evidence of Abeta brain deposits by PET scanning, phase 3 by slight decreases in brain metabolic rate by PET-FDG scanning, phase 4 by slight decreases in brain volume by MRI scanning plus minimal cognitive impairment, phase 5 by increased scanning abnormalities plus clinical diagnosis of AD, and phase 6 by advanced AD requiring institutional care. Utilization of antiinflammatory agents early in the disease process remains an overlooked therapeutic opportunity. Such agents, while not preventative, have the advantage of being able to inhibit the consequences of both Abeta and tau aggregation. Since there is more than a decade between disease onset and cognitive decline, a window of opportunity exists to introduce truly effective disease-modifying regimens. Taking advantage of this opportunity is the challenge for the future. PMID- 24052109 TI - Onabotulinumtoxin type A (Botox((r))) versus Incobotulinumtoxin type A (Xeomin((r))) in the treatment of focal idiopathic palmar hyperhidrosis: results of a comparative double-blind clinical trial. AB - Focal hyperhidrosis often has a substantial psychological and social impact on quality of life, since it interferes with daily activities. To date, for the treatment of focal hyperhidrosis, the botulinum toxin type A is an effective second line tool. The purpose of this study was to compare Onabotulinumtoxin A (Botox((r))) and Incobotulinumtoxin A (Xeomin((r))) administration in the treatment of palmar hyperhidrosis. In a double-blind clinical trial, 25 patients with moderate or severe palmar hyperhidrosis received in the same session intradermal injections of Onabotulinumtoxin A on one hand and Incobotulinumtoxin A on the other. Several measures of efficacy and safety were evaluated: disease severity improvement, sweat reduction, hand-grip strength decrease, pain/discomfort during the treatment, and patient's global satisfaction. All patients were responsive to the treatments (HDSS at T4 vs HDDs at T0; p < 0.0001), and no significant difference between Onabotulinumtoxin A and Incobotulinumtoxin A in terms of anhidrotic effect (Minor's test at T4; p = 0.51), long-term efficacy (Minor's test at T12; p = 0.76), (Minor's test at T24; p = 0.58), subjective pain related to the injections (p = 0.88), muscle strength reduction after treatment (p = 0.56), and global satisfaction with the treatment (p = 0.26). Onabotulinum toxin A and Incobotulinumtoxin A seem to be comparable in terms of anhidrotic effect (short-term results), duration of benefits (long term efficacy), muscle strength reduction (safety), pain related to injections (tolerability), and treatment satisfaction expressed by patients. PMID- 24052110 TI - Screening of two indel polymorphisms in the 5'UTR of the DJ-1 gene in South African Parkinson's disease patients. AB - Mutations in the DJ-1 gene have been implicated in early-onset Parkinson's disease (PD). Two indel variants (g.168_185del and g.-6_+10del) in the 5'UTR of DJ-1 have been described. Genotyping of both variants in 402 South African PD patients of various ethnicities and 528 ethnically matched controls revealed that they are rare in the South African population. Further studies on these variants in other populations are warranted given their possible role in transcriptional regulation and DJ-1's critical role in alleviating oxidative stress. PMID- 24052112 TI - Impact of impaired insulin secretion and insulin resistance on the incidence of diabetes in a Japanese cohort. Reply to Yamauchi K and Aizawa T [letter]. PMID- 24052111 TI - PREP1 deficiency downregulates hepatic lipogenesis and attenuates steatohepatitis in mice. AB - AIMS/HYPOTHESIS: The aim of this study was to investigate the function of Prep1 (also known as Pknox1) in hepatic lipogenesis. METHODS: The hepatic lipogenesis pathway was evaluated by real-time RT-PCR and Western blot. Biochemical variables were assessed using a clinical chemistry analyser. RESULTS: Serum triacylglycerols and liver expression of fatty acid synthase (FAS) were significantly decreased in Prep1 hypomorphic heterozygous (Prep1 (i/+) ) mice compared with their non-hypomorphic littermates. Upstream FAS expression, phosphorylation of protein kinase C (PKC)zeta, liver kinase B1 (LKB1), AMP activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) increased in Prep1 (i/+) mice, while protein and mRNA levels of the lipid phosphatase inhibitor of PKCzeta, SH2-containing inositol 5'-phosphatase 2 (SHIP2), was more than 60% reduced. Consistent with these findings, HepG2 cells transfected with Prep1 cDNA exhibited increased triacylglycerol accumulation and FAS expression, with strongly reduced PKCzeta, LKB1, AMPK and ACC phosphorylation. Further experiments revealed the presence of both Prep1 and its major partner Pbx1 at the Ship2 (also known as Inppl1) promoter. PBX-regulating protein 1 (PREP1) and pre-B cell leukaemia transcription factor 1 (PBX1) enhanced Ship2 transcription. The PREP1HR mutant, which is unable to bind PBX1, exhibited no effect on Ship2 function, indicating transcriptional activation of Ship2 by the PREP1/PBX1 complex. Treatment with a methionine- and choline-deficient diet (MCDD) induced steatosis in both Prep1 (i/+) and non-hypomorphic control mice. However, alanine aminotransferase increase, intracellular triacylglycerol content and histological evidence of liver steatosis, inflammation and necrosis were significantly less evident in Prep1 (i/+) mice, indicating that Prep1 silencing protects mice from MCDD-induced steatohepatitis. CONCLUSIONS/INTERPRETATION: Our results indicate that Prep1 silencing reduces lipotoxicity by increasing PKCzeta/LKB1/AMPK/ACC signalling, while levels of PREP1 expression may determine the risk of steatohepatitis and its progression. PMID- 24052113 TI - Business oriented EU human cell and tissue product legislation will adversely impact Member States' health care systems. AB - The transplantation of conventional human cell and tissue grafts, such as heart valve replacements and skin for severely burnt patients, has saved many lives over the last decades. The late eighties saw the emergence of tissue engineering with the focus on the development of biological substitutes that restore or improve tissue function. In the nineties, at the height of the tissue engineering hype, industry incited policymakers to create a European regulatory environment, which would facilitate the emergence of a strong single market for tissue engineered products and their starting materials (human cells and tissues). In this paper we analyze the elaboration process of this new European Union (EU) human cell and tissue product regulatory regime-i.e. the EU Cell and Tissue Directives (EUCTDs) and the Advanced Therapy Medicinal Product (ATMP) Regulation and evaluate its impact on Member States' health care systems. We demonstrate that the successful lobbying on key areas of regulatory and policy processes by industry, in congruence with Europe's risk aversion and urge to promote growth and jobs, led to excessively business oriented legislation. Expensive industry oriented requirements were introduced and contentious social and ethical issues were excluded. We found indications that this new EU safety and health legislation will adversely impact Member States' health care systems; since 30 December 2012 (the end of the ATMP transitional period) there is a clear threat to the sustainability of some lifesaving and established ATMPs that were provided by public health institutions and small and medium-sized enterprises under the frame of the EUCTDs. In the light of the current economic crisis it is not clear how social security systems will cope with the inflation of costs associated with this new regulatory regime and how priorities will be set with regard to reimbursement decisions. We argue that the ATMP Regulation should urgently be revised to focus on delivering affordable therapies to all who are in need of them and this without necessarily going to the market. The most rapid and elegant way to achieve this would be for the European Commission to publish an interpretative document on "placing on the market of ATMPs," which keeps tailor made and niche ATMPs outside of the scope of the medicinal product regulation. PMID- 24052116 TI - Acute rhabdomyolysis induced by tonic-clonic epileptic seizures in a patient with glucose-6-phosphate dehydrogenase deficiency. PMID- 24052117 TI - Traumatic brain injury: risk factors and prognostic assessment. PMID- 24052115 TI - The diagnosis of chronic inflammatory demyelinating polyneuropathy: a Delphi method approach. AB - The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) is based on a set of clinical and neurophysiological parameters. However, in clinical practice, CIDP remains difficult to diagnose in atypical cases. In the present study, 32 experts from 22 centers (the French CIDP study group) were asked individually to score four typical, and seven atypical, CIDP observations (TOs and AOs, respectively) reported by other physicians, according to the Delphi method. The diagnoses of CIDP were confirmed by the group in 96.9 % of the TO and 60.1 % of the AO (p < 0.0001). There was a positive correlation between the consensus of CIDP diagnosis and the demyelinating features (r = 0.82, p < 0.004). The European CIDP classification was used in 28.3 % of the TOs and 18.2 % of the AOs (p < 0.002). The French CIDP study group diagnostic strategy was used in 90 % of the TOs and 61 % of the AOs (p < 0.0001). In 3 % of the TOs and 21.6 % of the AOs, the experts had difficulty determining a final diagnosis due to a lack of information. This study shows that a set of criteria and a diagnostic strategy are not sufficient to reach a consensus for the diagnosis of atypical CIDP in clinical practice. PMID- 24052118 TI - Fulminant toxic shock syndrome following rituximab therapy in an 11-year-old boy. PMID- 24052119 TI - Family perceptions of shared decision-making with health care providers: results of the National Survey of Children With Special Health Care Needs, 2009-2010. AB - The Maternal and Child Health Bureau recently revised its measure of family provider shared decision-making (SDM) to better align with parents' views and the intent of SDM. We sought to assess achievements in meeting the revised measure; examine socio-demographic/health correlates; and determine the relationships between SDM and access to quality health care. We analyzed data for 40,242 children with special health care needs (CSHCN) from the 2009-2010 National Survey of CSHCN and assessed the prevalence of SDM and association with other US CSHCN socio-demographic/health characteristics using bivariate and multivariate methods. Logistic regression was used to determine associations between SDM and having a medical home and preventive medical/dental visits. Approximately 70% of families of CSHCN perceived themselves as shared decision-makers in their child's care. Families of CSHCN with greater functional limitations had twice the odds of lacking SDM than those never affected. Disparities in attainment rates were noted for families with low versus high income (61 vs. 77%), less versus more than high school education (59 vs. 73%), privately insured versus uninsured (76 vs. 57%), and minority versus white race (63 vs. 74%). CSHCN with medical homes had 6 times greater odds of perceived SDM and as much as one and a half times the odds of receiving preventive care than CSHCN without a medical home. Major differences in family SDM perceptions are associated with having a medical home, particularly when characterized by family-centered care. Populations of concern are those with more functionally limited children and increased socio-economic challenges. PMID- 24052126 TI - Tailoring deposition and morphology of discharge products towards high-rate and long-life lithium-oxygen batteries. AB - Lithium-oxygen batteries are an attractive technology for electrical energy storage because of their exceptionally high-energy density; however, battery applications still suffer from low rate capability, poor cycle stability and a shortage of stable electrolytes. Here we report design and synthesis of a free standing honeycomb-like palladium-modified hollow spherical carbon deposited onto carbon paper, as a cathode for a lithium-oxygen battery. The battery is capable of operation with high-rate (5,900 mAh g -1 at a current density of 1.5 A g-1) and long-term (100 cycles at a current density of 300 mA g-1 and a specific capacity limit of 1,000 mAh g-1). These properties are explained by the tailored deposition and morphology of the discharge products as well as the alleviated electrolyte decomposition compared with the conventional carbon cathodes. The encouraging performance also offers hope to design more advanced cathode architectures for lithium-oxygen batteries. PMID- 24052128 TI - Human mesenchymal stem cells and their paracrine factors for the treatment of brain tumors. AB - Glioblastoma multiforme (GBM or World Health Organization (WHO) grade IV) is the most malignant tumor of the brain. Despite conventional combination treatment of surgery, radiotherapy and chemotherapy, the survival of patients with GBM is generally <1 year. It is a great challenge to identify an effective drug that could efficiently inhibit (i) the growth of cancer cells; (ii) angiogenesis; (iii) metastasis; (iv) tumor-associated inflammation; (v) inactivate proliferative signal, (vi) induce specific apoptosis, and yet causes minimal harm to normal cells. Mesenchymal stem cells (MSCS) do possess some unique features (inherent tumor tropism; anti-inflammatory and immunosuppressive properties) that are not commonly found in current anticancer agents. These cells are known to secrete a vast array of proteins including growth factors, cytokines, chemokines and so on that regulate their biology in an autocrine or paracrine manner in accordance to the surrounding microenvironment. This review briefly summarizes the biology of MSCs and discusses their properties and new development for brain cancer treatment. PMID- 24052127 TI - Intraprostatic distribution and long-term follow-up after AdV-tk immunotherapy as neoadjuvant to surgery in patients with prostate cancer. AB - A phase I-II study to evaluate gene-mediated cytotoxic immunotherapy in newly diagnosed prostate cancer before radical prostatectomy was conducted in Monterrey, Mexico. First, to investigate delivery of adenovirus to the prostate, fluorescently labeled vector was injected into fresh prostatectomy specimens and distribution was visually analyzed. The optimal volume and site instillation was then used for transrectal ultrasound guided intraprostatic injection in 10 patients with adenocarcinoma scheduled for radical prostatectomy. Each received two apical and two basal 0.5 ml injections of AdV-tk for a total of 1 * 10(11) vp followed by 14 days of prodrug. Nine patients continued to tumor resection: six high risk, one intermediate and two low risk. In vivo vector distribution was analyzed from the resected tissue of four patients. Patients were monitored for tumor progression and acute and long-term safety. For vector delivery, two apical and two basal injections of 0.5 ml led to optimal organ-wide distribution ex vivo and in vivo. Cytotoxicity was evidenced by transient rise in PSA and tumor histology. There were no significant adverse events deemed related to the treatment and no late toxicities after median follow-up of 11.3 years. All six high-risk patients had positive surgical margins and one had seminal vesicle involvement. Despite slow PSA rise post surgery in three of these patients, none developed metastases. The intermediate- and low-risk patients had complete resections and none have progressed. In conclusion, in vivo transrectal ultrasound guided instillation of an adenoviral vector into four sites in the prostate was practical as an outpatient procedure, well tolerated and led to distribution throughout the intraprostatic tumor mass. AdV-tk demonstrated no significant acute or late toxicities. Trends in PSA and disease progression conveyed the possibility of a sustained immune response against residual disease. PMID- 24052129 TI - Potent CD4+ T-cell epitope P30 enhances HER2/neu-engineered dendritic cell induced immunity against Tg1-1 breast cancer in transgenic FVBneuN mice by enhanced CD4+ T-cell-stimulated CTL responses. AB - One of the major obstacles in human epidermal growth factor receptor (HER)-2/neu specific trastuzumab immunotherapy of HER2/neu-positive breast cancer is the development of trastuzumab resistance, warranting the search for other therapeutic strategies. Although dendritic cell (DC) vaccines have been extensively applied in clinical trials for cancer treatment, the vaccination efficacy is still limited, mostly because DC vaccines are not sufficient to break tumor-associated antigen-specific self-immune tolerance in cancer patients. P30 (FNNFTVSFWLRVPKVSASHLE) derived from tetanus toxin is a universally potent CD4(+) T helper epitope capable of enhancing CD8(+) cytotoxic T-lymphocyte (CTL) responses. In this study, we constructed two recombinant adenoviral vectors (AdVs), AdVOVA-P30 and AdVHER2/neu-P30, expressing ovalbumin (OVA)-P30 and HER2/neu-P30. In order to enhance DC vaccine efficacy, we transfected mouse bone marrow (BM)-derived DCs with AdVOVA-P30 and AdVHER2/neu-P30 to generate engineered DCOVA-P30 and DCHER2/neu-P30 vaccines, respectively. We, then, compared CD4(+) and CD8(+) T-cell responses and antitumor immunity derived from DCOVA-P30 and DCHER2/neu-P30 vaccination in wild-type C57BL/6 and transgenic FVBneuN mice, respectively. We demonstrate that engineered DCOVA-P30 vaccine stimulates more efficient CD4(+) and CD8(+) T-cell responses than DCOVA in C57BL/6 mice. Interestingly, the increased DCOVA-P30-induced CTL responses are mainly contributed by enhanced CD4(+) T-cell-stimulated CTL proliferation. We show that DCOVA-P30 vaccine also stimulates more efficient therapeutic immunity against OVA-expressing BL6-10OVA melanoma than DCOVA in C57BL/6 mice. In addition, we demonstrate that DCHER2/neu-P30 vaccine stimulates more efficient CD4(+) and CD8(+) T-cell responses and protective immunity against HER2/neu expressing Tg1-1 breast cancer than DCHER2/neu in transgenic FVBneuN mice with HER2/neu-specific self-immune tolerance. Therefore, the engineered DCHER2/neu-P30 vaccine may provide a new immunotherapy alternative for women with HER2/neu(+) breast cancer, especially for trastuzumab-resistant HER2/neu(+) breast cancer patients. PMID- 24052130 TI - Peripapillary chorioretinal lacunae in a girl with 3q21.3 to 3q22.1 microdeletion with features of Aicardi syndrome. PMID- 24052131 TI - Gain or loss? Sunscreen efficiency after cosmetic pretreatment of the skin. AB - Sunscreens are a key pillar of the multimodal protection strategy against short- and long-term impacts of intermittent and continuous UV exposure. Hitherto, an unanswered part of current scientific discourse is the question whether a cosmetic pretreatment has an impact on distribution and adhesiveness of sunscreens on the skin and therefore affects UV protection. In order to evaluate the homogeneity of sunscreen filter distribution, water resistance as a parameter of adhesiveness and effective UV protection of sunscreens after a pretreatment with cream or lotion was investigated in 18 volunteers who were examined before and after swimming, using the established combination of the tape stripping procedure and UV/VIS spectroscopy. It was shown that a cosmetic skin pretreatment affects neither filter homogeneity nor effective UV protection prior to water contact. However, compared to nonpretreated skin, a considerable loss of water resistance is caused. Therefore, using a cream or lotion before application of sunscreens is not to be recommended. PMID- 24052132 TI - Current chemotherapeutic approaches for hepatoblastoma. AB - Cisplatin-based chemotherapy has markedly improved the survival of patients with standard-risk hepatoblastoma (HB). However, treatment results for patients with metastatic disease remain unsatisfactory. As a result, the current therapeutic strategy for HB is to decrease dose intensity for standard-risk tumors in order to reduce chemotherapy-related toxicity and to intensify chemotherapy in combination with new drugs to develop new therapies and improve the outcome of patients with metastatic disease. Results from various trials of The North American Cooperative Study demonstrated that patients with localized disease achieved long-term survival following treatment with a combination of cisplatin, 5-fluorouracil, and vincristine (C5V). In the ongoing Children's Oncology Group (COG) trial, AHEP0731, patients with stage I pure fetal histology are classified as very low risk and treated with resection only, and patients with any stage IV disease or any stage plus an alpha-fetoprotein level at diagnosis of <100 ng/ml are classified as high risk and receive up-front window therapy followed by C5V + doxorubicin in an attempt to discover novel efficacious agents. The early International Childhood Liver Tumors Strategy Group (SIOPEL) trial, SIOPEL-1, demonstrated that a combination of cisplatin + doxorubicin (PLADO) is effective. In the SIOPEL-3SR trial, cisplatin alone was proved to be non-inferior to PLADO for standard-risk HB. In the SIOPEL-4 trial, intensified preoperative cisplatin was administered on a weekly basis, and this approach achieved the highest survival rate ever reported for patients, even those with metastatic disease. SIOPEL, COG, and the Japanese Study Group for Pediatric Liver Tumor (JPLT) have established the Children's Hepatoma International Collaboration (CHIC) to create a common risk classification and initiate international clinical trials in order to further improve the outcome of children with HB. PMID- 24052133 TI - Changes in hip fracture incidence, mortality and length of stay over the last decade in an Australian major trauma centre. AB - PURPOSE: The aim of this study was to describe the population-based longitudinal trends in incidence, 30-day mortality and length of stay of hip fracture patients in a tertiary referral trauma centre in Newcastle, New South Wales, Australia, and identify the factors associated with increased 30-day mortality. METHODS: A retrospective database and chart review was conducted to patients aged >=65 years with a diagnosis of femoral neck or pertrochanteric fracture admitted to the John Hunter Hospital between 01 January 2002 and 30 December 2011. The main outcome measure was 30-day mortality; secondary outcome was acute length of stay. RESULTS: There were 4,269 eligible patients (427+/-20 per year) with hip fractures over the 10-year study period. The absolute incidence increased slightly (p=0.1) but the age-adjusted rate decreased (p<=0.0001). The average age (83.5+/-7.1 years) and percentage of females (73.7%) did not change. Length of stay increased by a factor of 2.5% per year (p<0.0001). Thirty-day mortality decreased from 12.3% in 2002 to 8.20% in 2011 (p=0.0008). Independent risk factors associated with increased 30-day mortality were longer admissions (p<0.0001), increased age (p=0.005), dementia (p=0.01), male gender (p<0.0001), higher American Society of Anaesthesiologists score (p<0.0001), and longer time to operating theatre (p=0.002). CONCLUSIONS: Despite the relative ageing of our population, a decrease in the age-standardised rate of fractured hip in elderly patients has seen the number of admissions remain unchanged in our institution from 2002 to 2011. There was a decrease in 30-day mortality, while length of stay increased. PMID- 24052134 TI - A content analysis of media coverage of the introduction of a smoke-free bylaw in Vancouver parks and beaches. AB - The Board of Parks and Recreation in Vancouver, BC approved a smoke-free bylaw in the city's parks, beaches and recreational facilities, effective 1 September 2010. We analyzed local news coverage and portrayal of the bylaw to understand the potential influence of news media on public perception of the bylaw in order to inform the media advocacy work of public health interest groups. We compiled a data set of newspaper articles (n = 90) and conducted a quantitative content analysis to examine content related to the outdoor smoke-free policy, including article slant, topics related to smoking and tobacco control, and any equity related concerns raised. Newspaper coverage in Vancouver was largely supportive of the outdoor smoke-free bylaw. However, concerns over rights were frequently discussed in letters to the editor. Such equity concerns were rarely discussed in news articles, showing a potential disconnect between the concerns expressed in the media by members of the public and the coverage provided by print media. PMID- 24052135 TI - Preparation of polymer gel dosimeters based on less toxic monomers and gellan gum. AB - New polymer gel dosimeters consisting of 2-hydroxyethyl methacrylate (HEMA), triethylene glycol monoethyl ether monomethacrylate (TGMEMA), polyethylene glycol 400 dimethacrylate (9G), tetrakis (hydroxymethyl) phosphonium chloride as an antioxidant, and gellan gum as a gel matrix were prepared. They were optically analyzed by measuring absorbance to evaluate a dose response. The absorbance of the polymer gel dosimeters that were exposed to (60)Co gamma-rays increased with increasing dose. The dosimeters comprising HEMA and 9G showed a linear increase in absorbance in the dose range from 0 to 10 Gy. The dose response depended on the 9G concentration. For others comprising HEMA, 9G and TGMEMA, the absorbance of the polymer gel dosimeters drastically increased above a certain dose, and then leveled off up to 10 Gy. The optical variations in these polymer gel dosimeters were also induced by x-irradiation from Cyberknife radiotherapy equipment. Furthermore, the exposed region of the latter polymer gel dosimeter exhibited a thermo-responsive behavior. PMID- 24052136 TI - Antitumor immune responses induced by ionizing irradiation and further immune stimulation. AB - The therapy of cancer emerged as multimodal treatment strategy. The major mode of action of locally applied radiotherapy (RT) is the induction of DNA damage that triggers a network of events that finally leads to tumor cell cycle arrest and cell death. Along with this, RT modifies the phenotype of the tumor cells and their microenvironment. Either may contribute to the induction of specific and systemic antitumor immune responses. The latter are boosted when additional immune therapy (IT) is applied at distinct time points during RT. We will focus on therapy-induced necrotic tumor cell death that is immunogenic due to the release of damage-associated molecular patterns. Immune-mediated distant bystander (abscopal) effects of RT when combined with dendritic cell-based IT and the role of fractionation of radiation in the induction of immunogenic tumor cell death will be discussed. Autologous whole-tumor-cell-based vaccines generated by high hydrostatic pressure technology will be introduced and the influence of cytokines and the immune modulator AnnexinA5 on the ex vivo generated or in situ therapy-induced vaccine efficacy will be outlined. RT should be regarded as immune adjuvant for metastatic disease and as a tool for the generation of an in situ vaccine when applied at distinct fractionation doses or especially in combination with IT to generate immune memory against the tumor. To identify the most beneficial combination and chronology of RT with IT is presumably one of the biggest challenges of innovative tumor research and therapies. PMID- 24052137 TI - Effectiveness of team training on fall prevention. AB - A longitudinal, repeated-measures design with intervention and comparison groups was used to evaluate the effect of a training curriculum based on TeamSTEPPS with video vignettes focusing on fall prevention. Questionnaires, behavioral observations, and fall data were collected over 9 months from both groups located at separate hospitals. The intervention group questionnaire scores improved on all measures except teamwork perception, while observations revealed an improvement in communication compared with the control group. Furthermore, a 60% fall reduction rate was reported in the intervention group. Team training may be a promising intervention to reduce falls. PMID- 24052138 TI - Use of healthcare failure mode and effect analysis (HFMEA) to quantify risks of the human milk feeding process. AB - The complexity of the expressed breast milk feeding process in the neonatal intensive care unit was not fully appreciated until we used a healthcare failure mode and effect analysis. This approach identified latent risks and provided semiquantitative estimates of the effectiveness of recommendations. Findings demonstrated nursing interruptions and multitasking requirements contributed to risk, emphasizing the need for focused and isolated expressed breast milk handling to improve patient safety and outcomes. PMID- 24052139 TI - Using high-performance work practices in health care organizations: a perspective for nursing. AB - Studies suggest that the use of high-performance work practices (HPWPs) may help improve quality in health care. We interviewed 67 administrators and clinicians across 5 health care organizations and found that the use of HPWPs was valued and salient for nurses. Communication appeared particularly important to facilitate HPWP use. Enhancing our understanding of HPWP use may help improve the work environment for nurses while also increasing care quality. PMID- 24052140 TI - Development and pilot testing of a patient-participatory pressure ulcer prevention care bundle. AB - This study developed and piloted a patient-centered pressure ulcer prevention care bundle for adult hospitalized patients to promote patient participation in prevention. The care bundle had 3 core messages: (1) keep moving, (2) care for your skin, and (3) ensure a good diet. A brief video, combined brochure/checklist, and poster were developed as training resources. Patient evaluation identified benefits of the care bundle; however, the combined checklist/brochure was rarely used. PMID- 24052141 TI - Evaluating a breakthrough series collaborative in a Swedish health care context. AB - This study evaluated the use of the Breakthrough Series Collaborative methodology in a Swedish county council improvement program, comparing measurements at the beginning and after 6 months. A questionnaire was used, and improvement processes and outcomes were analyzed. The results showed an overall large engagement in improvements, although the methodology and facilitators were seen as only moderately supportive. PMID- 24052142 TI - Introduction to the special section on 3D representation, compression, and rendering. AB - A new set of three-dimensional (3D) data formats and associated compression technologies are emerging with the aim to achieve more flexible representation and higher compression of 3D and multiview video content. These new tools will facilitate the generation of multiview output (e.g., as needed for multiview auto stereoscopic displays), provide richer immersive multimedia experiences, and allow new interactive applications. This special section includes a timely set of papers covering the most recent technical developments in this area with papers covering topics in the different aspects of 3D systems, from representation and compression algorithms to rendering techniques and quality assessment. This special section includes a good balance on topics that are of interest to academic, industrial, and standardization communities. We believe that this collection of papers represent the most recent advances in representation, compression, rendering, and quality assessment of 3D scenes. PMID- 24052143 TI - The impact of candle burning during All Saints' Day ceremonies on ambient alkyl substituted benzene concentrations. AB - Research findings concerning benzene, toluene, ethylobenzene, meta-, para- and ortho-xylene as well as styrene (BTEXS) emission at public cemeteries during All Saints' Day are presented here. Tests were carried out at town-located cemeteries in Opole and Grodkow (southern Poland) and, as a benchmark, at the centres of those same towns. The purpose of the study was to estimate BTEXS emissions caused by the candle burning and, equally important to examine, whether emissions generated by the tested sources were similar to the BTEXS emissions generated by road transport. During the festive period, significant increases in benzene concentrations, by 200 % and 144 %, were noted at the cemeteries in Opole and Grodkow, as well as in toluene, by 366 % and 342 %, respectively. Styrene concentrations also increased. It was demonstrated that the ratio of toluene to benzene concentrations from emissions caused by the burning candles are comparable to the ratio established for transportation emissions. PMID- 24052144 TI - Phytoremediation of Cu, Cr and Pb mixtures by Lemna minor. AB - The present study reports the capacity of the aquatic macrophyte Lemna minor to remediate combinations of Cu(II), Pb(II) and Cr(III) from a simulated natural environment. The effect of these metal mixtures on the growth of L. minor was also investigated using growth rate and biomass inhibition calculations. L. minor was successful in removing Cr and Pb from the water, and it remained an effective remediation agent when both metals were present in the environment. However, a relatively low absorption capacity was observed for Cu, increasing concentrations of which were associated with significant decreases in growth rate. No statistically significant difference was found between the 24 h and 7 days absorption rates of Cu, Pb and Cr, suggesting that, at the concentrations tested, equilibrium occurs within 24 h of metal exposure. PMID- 24052145 TI - Family-centered care to promote successful community reintegration after war: it takes a nation. AB - The papers in this section focus on public health responses and implementation considerations in addressing the challenges military families confront when parents go to war. While many military families show resilience, the challenges resulting from a decade of war with multiple deployments are detailed, as are innovative military and civilian programs designed to help service members and their families reintegrate successfully into the community. As more and more service members leave active duty, the burden of meeting military families' psychological needs will transition from the Department of Defense (DoD) and into the Veterans Administration (VA) and civilian arenas. While many strategies to support successful readjustment are offered, in this time of dwindling mental health resources and competing needs, it is unclear what priority the broader society places on meeting the needs of returning service members and their families. A growing emphasis on family-centered care in the Veterans Administration may help meet this gap. PMID- 24052146 TI - Thymus involution and regeneration: two sides of the same coin? AB - In vertebrates, the thymus is the main site of T cell development. The thymus reaches its maximum output during adolescence, after which it shrinks and generates fewer and fewer T cells. Physiological age-related involution of the thymus and failure to recover after injury are associated with impaired cellular immunity; hence, there is considerable interest in developing strategies to combat these deficiencies. In this Opinion article, we briefly review the phylogenetic and ontogenetic hallmarks of thymus development and function, and we discuss experimental models of impaired thymopoiesis and the molecular mechanisms of thymopoietic recovery. At each stage of the discussion we highlight the major gaps in our current knowledge. PMID- 24052147 TI - Combination of sulfamethoxazole and selenium in anticancer therapy: a novel approach. AB - Sulfonamides have been reported to possess substantial antitumor activity as they act as carbonic anhydrase inhibitors. In addition, selenium appears to have a protective effect at various stages of cancer due to its antioxidant property, enhanced carcinogen detoxification, inhibition of cell invasion, and by inhibiting angiogenesis. Here, in the present study we aimed to evaluate and synergize the cytotoxic activity of sulfonamide and selenium (SM+SE) as effective therapy in the treatment of DENA-induced HCC. Hepatocarcinogeneis was induced by a single intraperitoneal injection of diethylnitrosamine (DENA) (200 mg/kg) in phosphate buffer. 30 Male Wistar rats used in this study were divided randomly into five equal groups (n = 6). DENA-administered animals showed significant alteration (p < 0.001) in liver-specific enzymes-glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), and Alpha fetoproteins (AFP), and also induced severe histopathological changes in the hepatic tissues. Interestingly, treatment with (SE+SE) (SM 30 mg/kg + SE 3 mg/kg) significantly reduced (P < 0.001, P < 0.001, P < 0.001, P < 0.001) the elevated AFP, SGOT, SGPT, and ALP levels, respectively, suggesting that combination therapy of SM+SE has a potential to treat DENA induced liver damage. PMID- 24052148 TI - Detection of norovirus genogroup IV, klassevirus, and pepper mild mottle virus in sewage samples in South Korea. AB - Norovirus (NoV) genogroup (G) IV has been infrequently isolated from patients suffering from acute gastroenteritis (AGE), although this virus has not been detected in Korea. Klassevirus, a novel virus belonging to the family Picornaviridae and a possible etiologic agent of AGE, and pepper mild mottle virus (PMMoV), which originates from processed pepper products and is shed in human feces, are suggested to be new indicators of fecal pollution. We aimed to investigate the presence of NoV-GIV, klassevirus, and PMMoV in sewage samples collected in Korea. Between December 2010 and February 2012, influent sewage samples were collected every month from a wastewater treatment plant located in the eastern part of Seoul in Korea. The sewage samples were concentrated by the adsorption elution method using an HA (pore size of 0.45 MUm with mixed cellulose ester) electronegative filter with an acid-rinse procedure. RT-PCR was performed using specific primers for the capsid gene of NoV-GII and NoV-GIV, the coat gene of PMMoV, and the VP0/VP1 gene of klassevirus. Among the 14 sewage samples tested, klassevirus was detected in eight (57.1 %), PMMoV in eight (57.1 %), NoV GII in five (35.7 %), and NoV-GIV in three (21.4 %). NoV-GIV was detected in December 2010 and January and March 2011. PMMoV and klassevirus were frequently detected in winter. Phylogenetic analysis revealed that the NoV-GIV detected in this study belonged to G-IV1 lineage. This is the first study to confirm the presence of NoV-GIV, klassevirus, and PMMoV in sewage samples in Korea. PMID- 24052149 TI - Recent evolution of a novel begomovirus causing tomato leaf curl disease in the Al-Batinah region of Oman. AB - For last two decades, begomoviruses (family Geminiviridae) have been a major constraint for tomato production in Oman, particularly in the Al-Batinah region, the major agricultural area of Oman. Farms in the Al-Batinah region were surveyed during January-March and November-December in 2012 and January-February in 2013. Leaf samples of tomato plants showing typical leaf curl disease symptoms were collected and analyzed for begomoviruses. Out of fifteen begomovirus clones sequenced, seven were shown to be tomato yellow leaf curl virus strain Oman (TYLCV-OM); three, chili leaf curl virus strain Oman (ChLCV-OM); and one, tomato leaf curl Oman virus (ToLCOMV) - viruses that have previously been shown to occur in Oman. Four sequences were shown to have relatively low percent identity values to known begomoviruses, with the highest (86 %) to isolates of pepper leaf curl Lahore virus, indicating that these should be included in a new species, for which the name "Tomato leaf curl Al Batinah virus" (ToLCABV) is proposed. Although the betasatellite tomato leaf curl betasatellite (ToLCB; 7 full-length sequences isolated) was identified with some isolates of ChLCV-OM, TYLCV-OM and ToLCOMV, it was not identified in association with any of the ToLCABV isolates. Analysis of the sequences of the TYLCV-OM and ToLCOMV isolates characterized here did not show them to differ significantly from previously characterized isolates of these viruses. The three isolates of ChLCV-OM characterized were shown to have a recombination pattern distinct from earlier characterized isolates. ToLCABV was shown to have resulted from recombination between ChLCV-OM and ToLCOMV. A clone of ToLCABV was infectious by Agrobacterium-mediated inoculation to Nicotiana benthamiana and tomato, inducing symptoms typical of those seen in tomato in the field. Additionally, ToLCABV was shown to be able to interact in planta with ToLCB, resulting in a change in symptom phenotype, although the betasatellite did not appear to affect viral DNA levels. PMID- 24052150 TI - The effect of selected lifestyle factors and diet on mortality of men with documented physical fitness in the city of Lodz. AB - INTRODUCTION: It is still uncertain if having at least moderate physical fitness is a necessary and sufficient condition for lowering the risk of death. The aforementioned statement constituted the basis for undertaking the study concerning the effect of particular health-related behaviours on the likelihood of survival in subjects with a moderate and high physical fitness. MATERIALS AND METHODS: The study sample, i.e. 204 men aged 30-59 years living in Lodz, Poland, was selected within the CINDI WHO Programme and examined over the years 1980-1990 and 2003-2004. In each subject approximate values of one week energy expenditures associated with performing physical exercise of at least moderate intensity (> 1000 kcal/week) were estimated. Physical efficiency in the study group was evaluated basing on the results of the submaximal effort test. Information about selected socio-demographic characteristics, consumption of alcohol, cigarette smoking and diet was gathered. The vital status of the examined sample was checked in 2009. The Cox proportional hazards regression model was used to identify factors which influence the survival of examined population. RESULTS: The probability of death was more than fourfold higher in the case of individuals who eat "beef or pork meat", as compared to those who consumed these products rarely or never. On the other hand, the subjects who declared regular consumption of yellow cheese had nearly fourfold lower death probability. Current smoking was found to be a significant negative risk factor while moderate consumption of beer a protective one. The level of physical fitness (VO2max) did not significantly influence mortality. CONCLUSIONS: The results of the performed analyses indicate negative effect associated with consumption of beef/pork meat and smoking. Furthermore, the data pertaining to the consumption of yellow cheese as a potent protective factor for men's health requires further verification. The possibility that it is some lifestyle proxy rather than a causal factor cannot be excluded. PMID- 24052151 TI - Psychosocial work dimensions, personality, and body mass index: sex differences. AB - OBJECTIVES: The association between psychosocial work dimensions (i.e. demand and control) and obesity has been found to be inconclusive, indicating that individual differences factors might also contribute to explain the variability in BMI. MATERIALS AND METHODS: The interaction between work dimensions and personality variables in a group of male and female workers (N = 506), and its associations with BMI were analyzed with a cross-sectional study with self-report data. Hierarchical regression analyses were used to predict the BMI levels from work and individual differences variables and their interactions for males and females. RESULTS: The main effects of personality variables were not significant, physical workload interacted with neuroticism for males, whereas control interacted with activity for females. CONCLUSIONS: Psychosocial work dimensions and personality traits were related to BMI for men and women. These outcomes reinforce the notion that different models might account for the explanatory mechanisms of BMI in regard to sex. PMID- 24052152 TI - Low back pain among female nurses in Yemen. AB - OBJECTIVES: This study aimed to investigate the prevalence of Low Back Pain (LBP) among female nursing staff and explore the potential risk factors associated with LBP. METHODS: An analytical cross-sectional study was conducted on randomly selected female nurses using payroll as a sampling frame in all public hospitals in Sana'a City, Yemen. Data was collected through face-to-face interview using a structured, pre-coded questionnaire that was available in Arabic and English. Weight and height of the nurses were measured using weight and height scales and body mass index was calculated. Multiple logistic regression was used to identify the factors associated with LBP. RESULTS: Out of 696 female nurses selected, 687 (98.7%) responded. The life-time, the 12-month and one-week prevalence rates of LBP among female nurses were 512 (74.5%; 95% CI: 71.1-77.7%), 411 (59.8%; 95% CI: 56.0-63.5%) and 249 (36.2%; 95% CI: 32.6-39.9%), respectively. The prevalence was significantly lower in Indian nurses compared to other nurses. Three out of every 10 nurses with LBP had sick leave because of LBP in the last 12 months. Factors that showed significant association with LBP among nursing staff in the multivariate analysis were age, nationality, menstrual disorders and stress level at work. CONCLUSION: LBP is common among female nurses in Yemen. The role of menstrual disorders in developing LBP among female nurses seems to be important. Although sharing the same working conditions, Indian nurses were less likely to report LBP, which highlight the importance of cultural differences in willingness to report LBP. PMID- 24052153 TI - An audit on public awareness of depression symptoms in Jordan. AB - OBJECTIVES: Depression is a common mental health disorder. The aim of this study is to determine the level of public awareness regarding this illness, its symptoms, associated factors, available forms of treatment, and the attitude towards depressed people. METHODS: A self administered questionnaire was filled in by approximately 5000 individuals selected from various regions of Jordan. RESULTS: The majority of participants thought that depression is a treatable condition that can affect patient at any age, and may be controlled by the will power. Loss of interest in things and presence of negative feelings were the most commonly recognized symptoms of depression, while, unemployment and poverty were found to be the most recognized risk factors for depression. In addition, most participants considered support from family and friends (93.6%) as well as exercise (80.4%) to be the best available forms of depression treatment. Respondents found it acceptable to work, make friends with, or marry depressed individuals. The first choice persons for seeking help by most participants were family members and friends (49.8%). CONCLUSION: Collectively, the level of awareness of depression was acceptable. However, further efforts are necessary to establish public educational programs related to depression in order to raise awareness regarding the disease. PMID- 24052154 TI - Partial protection from organophosphate-induced cholinesterase inhibition by metyrapone treatment. AB - BACKGROUND: Organophosphates are cholinesterase (ChE) inhibitors with worldwide use as insecticides. Stress response, evidenced by a dramatic and relatively long lasting (several hours) rise in the plasma glucocorticoid concentration is an integral element of the organophosphate (OP) poisoning symptomatology. In rodents, corticosterone (CORT) is the main glucocorticoid. There are several reports suggesting a relationship between the stressor-induced rise in CORT concentration (the CORT response) and the activity of the cerebral and peripheral ChE. Thus, it seems reasonable to presume that, in OP intoxication, the rise in plasma CORT concentration may somehow affect the magnitude of the OP-induced ChE inhibition. Metyrapone (MET) [2-methyl-1,2-di(pyridin-3-yl)propan-1-one] blocks CORT synthesis by inhibiting steroid 11beta-hydroxylase, thereby preventing the CORT response. Chlorfenvinphos (CVP) [2-chloro-1-(2,4-dichlorophenyl) ethenyl diethyl phosphate] is an organophosphate insecticide still in use in some countries. MATERIAL AND METHODS: The purpose of the present work was to compare the CVP-induced effects - the rise of the plasma CORT concentration and the reduction in ChE activity - in MET-treated and MET-untreated rats. Chlorfenvinphos was administered once at 0.0, 0.5, 1.0 and 3.0 mg/kg i.p. Metyrapone, at 100 mg/kg i.p., was administered five times, at 24-h intervals. The first MET dose was given two hours before CVP. CONCLUSION: The following was observed in the MET-treated rats: i) no rise in plasma CORT concentration after the CVP administration, ii) a reduced inhibition and a faster restitution of blood and brain ChE activities. The results suggest that MET treatment may confer significant protection against at least some effects of OP poisoning. The likely mechanism of the protective MET action has been discussed. PMID- 24052155 TI - Estimation of tissue and serum lipocalin-2 in psoriasis vulgaris and its relation to metabolic syndrome. AB - Adipose tissue is now considered an endocrine organ secreting different cytokines known as adipocytokines. Lipocalin-2 has been recently identified as an adipokine present in the circulation, it is related to insulin resistance, obesity, atherosclerotic diseases and type 2 diabetes. Lipocalin-2 and psoriasis are assumed to be closely associated with the metabolic syndrome. The aim of the present study is to estimate the level of lipocalin-2 in the serum and tissue of psoriatic patients and to correlate these levels with markers of metabolic syndrome, CRP and disease severity. This study was done on 30 patients of psoriasis and 30 healthy controls. All patients and controls were subjected to clinical examination. Serum, tissue levels of lipocalin-2 and C-reactive protein (CRP) were measured by enzyme linked immunosorbent assay technique. Metabolic syndrome parameters including anthropometric measures, lipid profiles, blood sugar and blood pressure were studied. Patients with psoriasis showed significant association with metabolic syndrome parameters than controls. Tissue lipocalin-2 was significantly higher than serum levels in psoriasis patients. A significant difference was detected in tissue levels of lipocalin-2 and not in the serum between patients and controls. Both tissue and serum lipocalin-2 correlated with CRP. Although there was a correlation between tissue and serum levels of lipocalin-2 in patients, there was no correlation between both of them with metabolic syndrome and related disorders. Our results revealed that patients with psoriasis are at increased risk of metabolic and cardiovascular complications, tissue lipocalin-2 is more specific to psoriasis than serum lipocalin-2. Lipocalin-2 has no role in determining severity of the disease. Neither tissue nor serum lipocalin-2 conveys cardiovascular risk in psoriasis patients. PMID- 24052156 TI - Biomarkers associated with high-density lipoproteins in atherosclerotic kidney disease. AB - High-density lipoproteins (HDL) originate as discoidal particles that are rapidly converted by lecithin:cholesterol acyltransferase (LCAT) into the spherical particles that predominate in normal human plasma. Spherical HDL consist of multiple populations of particles that vary widely in size, composition and function. Human population studies have established that high plasma HDL cholesterol levels are associated with a reduced incidence of cardiovascular disease. The mechanistic basis of this relationship is not well understood, but most likely involves a number of the cardioprotective functions of HDL. These include the ability of apolipoprotein (apo) A-I, the main apolipoprotein constituent of HDL, to remove cholesterol from macrophages in the artery wall. HDL also have antioxidant and anti-inflammatory properties that are potentially cardioprotective. Evidence that some of these beneficial properties are compromised in people with diabetes and renal disease is emerging. Persistently elevated plasma glucose levels in people with diabetes and poor glycemic control can lead to irreversible, non-enzymatic glycation of plasma proteins, including apoA-I. Non-enzymatically glycated proteins are also prevalent in people with diabetes and end-stage renal disease who are at high cardiovascular risk. Evidence that non-enzymatically glycated apoA-I inhibits the LCAT reaction and impairs some of the cardioprotective properties of HDL is also emerging. This review is concerned with how non-enzymatic glycation of apoA-I affects the ability of LCAT to convert discoidal HDL into spherical HDL, how it affects cholesterol efflux from macrophages and how it affects the anti-inflammatory and antioxidant properties of HDL. PMID- 24052157 TI - Lipoprotein metabolism and CKD: overview. AB - Patients with chronic kidney disease (CKD) frequently display abnormalities of plasma lipids and lipoproteins. These abnormalities include hypertriglyceridemia associated with elevated levels of very low-density lipoproteins (VLDLs) and chylomicrons. There is often also an increase in the concentration of the atherogenic, cholesterol-enriched remnants of VLDLs and chylomicrons. The concentration of low-density lipoprotein cholesterol is usually normal, but there is frequently a decrease in concentration of the cardio-protective high-density lipoproteins. There is also often an increase in the concentration of the atherogenic lipoprotein (a) particles. This article provides an overview of plasma lipoprotein transport and identifies mechanisms responsible for the abnormalities observed in patients with CKD. PMID- 24052158 TI - Estimated glomerular filtration rate and daily amount of urinary protein predict the clinical remission rate of tonsillectomy plus steroid pulse therapy for IgA nephropathy. AB - BACKGROUND: This retrospective study was designed to estimate the clinical remission (CR) rate of tonsillectomy plus steroid pulse (TSP) therapy in patients with IgA nephropathy. METHODS: Based on 292 of 302 patients with IgA nephropathy treated at 11 Japanese hospitals, we constructed heat maps of the CR rate at 1 year after TSP with the estimated glomerular filtration rate (eGFR), grade of hematuria, pathological grade, number of years from diagnosis until TSP, and age at diagnosis on the vertical axis and the daily amount of urinary protein (urinary protein) on the horizontal axis. We compared subgroups usinge Student's t test, the chi-square test with Yates correction, or Fisher's exact probability test. RESULTS: The first heat map of eGFR and urinary protein showed that the CR rate was 71 % (CR vs. non-CR, 96 vs. 40) in patients with eGFR greater than 30 ml/min/1.73 m(2) and 0.3-1.09 g/day of urinary protein. However, the CR rate in patients with more than 1.50 g/day of urinary protein was approximately 30 %. The second heat map of grade of hematuria and urinary protein revealed that the CR rate is 72 % (CR vs. non-CR, 93 vs. 37) in patients with more than 1+ hematuria and 0.3-1.09 g/day of urinary protein; however, it was 28.6 % in patients with no hematuria. The third heat map of pathological grade and urinary protein demonstrated that the highest CR rate was 83 % (CR vs. non-CR, 52 vs. 11) in patients with pathological grade I or II disease and less than 1.09 g/day of urinary protein, as opposed to 22 % (CR vs. non-CR, 9 vs. 32) in patients with pathological grade III or IV disease and more than 2.0 g/day of urinary protein. The fourth heat map of the number of years from diagnosis until TSP and urinary protein revealed that the former did not influence the CR rate in patients with less than 1.09 g/day of urinary protein. However, in patients with more than 1.10 g/day of urinary protein, the CR rate of the subgroup with less than 6 years was 43 % (CR vs. non-CR; 23 vs. 54) compared to 23 % (CR vs. non-CR, 11 vs. 48; P = 0.01) in the subgroup with more than 6 years. The fifth heat map of age at diagnosis and urinary protein showed that the CR rate is approximately 72 % (CR vs. non-CR, 73 vs. 28) in patients older than 19 years at diagnosis with 0.3-1.09 g/day of urinary protein. CONCLUSIONS: The daily amount of urinary protein is an important predictor of the CR rate after TSP in IgA nephropathy patients. Heat maps are useful tools for predicting the CR rate associated with TSP. PMID- 24052159 TI - A molecular dynamics simulation of DNA damage induction by ionizing radiation. AB - We present a multi-scale simulation of the early stage of DNA damages by the indirect action of hydroxyl ((*)OH) free radicals generated by electrons and protons. The computational method comprises of interfacing the Geant4-DNA Monte Carlo with ReaxFF molecular dynamics software. A clustering method was employed to map the coordinates of (*)OH-radicals extracted from the ionization-track structures onto nano-meter simulation voxels filled with DNA and water molecules. The molecular dynamics simulation provides the time-evolution and chemical reactions in individual simulation voxels as well as the energy-landscape accounted for the DNA-(*)OH chemical reaction that is essential for the first principle enumeration of hydrogen abstractions, chemical bond breaks, and DNA lesions induced by collection of ions in clusters less than the critical dimension which is approximately 2-3 A. We show that the formation of broken bonds leads to DNA-base and backbone damages that collectively propagate to DNA single and double-strand breaks. For illustration of the methodology, we focused on particles with an initial energy of 1 MeV. Our studies reveal a qualitative difference in DNA damage induced by low energy electrons and protons. Electrons mainly generate small pockets of (*)OH-radicals, randomly dispersed in the cell volume. In contrast, protons generate larger clusters along a straight-line parallel to the direction of the particle. The ratio of the total DNA double strand breaks induced by a single proton and electron track is determined to be ~4 in the linear scaling limit. In summary, we have developed a multi-scale computational model based on first-principles to study the interaction of ionizing radiation with DNA molecules. The main advantage of our hybrid Monte Carlo approach using Geant4-DNA and ReaxFF is the multi-scale simulation of the cascade of both physical and chemical events which result in the formation of biological damage. The tool developed in this work can be used in the future to investigate the relative biological effectiveness of light and heavy ions that are used in radiotherapy. PMID- 24052160 TI - Functional burden of strabismus: decreased binocular summation and binocular inhibition. AB - IMPORTANCE: Binocular summation (BiS) is defined as the superiority of visual function for binocular over monocular viewing. Binocular summation decreases with age and large interocular differences in visual acuity. To our knowledge, BiS has not heretofore been well studied as a functional measure of binocularity in strabismus. OBJECTIVE: To evaluate the effect of strabismus on BiS using a battery of psychophysical tasks that are clinically relevant and easy to use and to determine whether strabismus is associated with binocular inhibition in extreme cases. DESIGN: Case-control study. SETTING: University-based eye institute. PARTICIPANTS: Strabismic patients recruited during 2010 to 2012 from a preoperative clinic and control participants with no history of eye disease other than refractive error. INTERVENTION: A battery of psychophysical and electrophysiological tests including Early Treatment Diabetic Retinopathy Study visual acuity, Sloan low-contrast acuity (LCA) (2.5% and 1.25%), Pelli-Robson contrast sensitivity, and sweep visual evoked potential contrast sensitivity. MAIN OUTCOME AND MEASURE: Binocular summation was calculated as the ratio between binocular and better-eye individual scores. RESULTS: Sixty strabismic and 80 control participants were prospectively examined (age range, 8-60 years). Mean BiS was significantly lower in the strabismic patients than controls for LCA (2.5% and 1.25%, P = .005 and <.001, respectively). For 1.25% LCA, strabismic patients had a mean BiS score less than 1, indicating binocular inhibition (ie, the binocular score was less than that of the better eye's monocular score). There was no significant difference in BiS for contrast thresholds on Early Treatment Diabetic Retinopathy Study visual acuity, Pelli-Robson contrast sensitivity, or sweep visual evoked potential contrast sensitivity. Regression analysis revealed a significant worsening of BiS with strabismus for 2.5% (P = .009) and 1.25% (P = .002) LCA, after accounting for age. CONCLUSIONS AND RELEVANCE: Strabismic patients demonstrate subnormal BiS and even binocular inhibition for LCA, suggesting that strabismus impairs visual function more than previously appreciated. This may explain why strabismic patients who are not diplopic close 1 eye in visually demanding situations. This finding clarifies the visual deficits impacting quality of life in strabismic patients and may represent a novel measure by which to evaluate and monitor function in strabismus. PMID- 24052161 TI - Acute onset of mediastinal cystic lymphangioma in the puerperium. AB - Lymphangioma is a benign congenital malformation developing from the prenatal lymphatic vessels. Lymphangiomas are typically slow-growing and asymptomatic, but can occur throughout the body; there are few documented cases of either mediastinal or rapid growing lymphangiomas. Here, we report a case of a 27-year old female who experienced sudden-onset nocturnal dyspnea 1 month after delivery. Ultrasound and computed tomography revealed a cystic tumor (diameter, 8 cm), which posteriorly displaced the superior vena cava and trachea. Ultrasound-guided aspiration was performed and the tumor disappeared on chest X-ray, only to return on subsequent chest X-ray performed the following day. Therefore, thoracoscopic excision of the mediastinal tumor was performed, and pathological diagnosis confirmed mediastinal cystic lymphangioma. In this report, we discuss the rare nature of this case and the treatment of lymphangioma in pregnancy. PMID- 24052162 TI - Macular pigment optical density in aging eye. PMID- 24052163 TI - Remission rate of implant-related infections following revision surgery after fractures. AB - PURPOSE: In contrast to a large amount of epidemiological data regarding the incidence of implant infections after fracture management, surprisingly few have been published concerning the success of their treatment. METHODS: This was a single-centre cohort study at Geneva University Hospitals from 2000 to 2012 investigating the remission rates of orthopaedic implant infections after fracture repair and associated variables. RESULTS: A total of 139 episodes were included: There were 51 women (37%) and 28 immunosuppressed (20%) patients with a median age and American Society of Anaesthesiologists (ASA) score of 51 years and 2 points, respectively. The infected implants were plates (n = 75, 54 %), nails (24, 17%), wires (20), screws (10), cerclage cables or wires (3), hip screws (4) or material for spondylodesis (3). A pathogen was identified in 135 (97%) cases, including Staphylococcus aureus (73, 52%), coagulase-negative staphylococci (20), streptococci (7) and 19 Gram-negative rods. All patients underwent antibiotic treatment, and 128 (92%) remained in remission at a median follow-up time of 2.6 years (range one to 13 years). In multivariate logistic regression analysis, the plate infections were significantly associated with lower remission rates [65/75, 87%, odds ratio (OR) 0.1, 95% confidence interval (CI) 0.01-0.90]. No associations were found for gender, age, immune status, ASA score, additional surgical interventions (OR 0.4, 95% CI 0.1-4.1) or duration of antibiotic treatment (OR 1.0, 95% CI 0.98-1.01). CONCLUSIONS: Among all infected and removed orthopaedic implants, plates were associated with slightly lower remission rates, while the overall treatment success exceeded 90%. The duration of antibiotic therapy did not alter the outcome. PMID- 24052164 TI - The natural history of unexplained early poor function following total hip replacement. AB - PURPOSE: The majority of patients experience a significant improvement in quality of life and function after total hip replacement (THR). It has recently been shown that age and good pre-operative function are the best predictors of postoperative function. When patients fail to achieve a satisfactory outcome, a cause is often identified. Where there is no identifiable cause, advice, follow up and management is not clear. The aim of this study was to determine the long term outcome of patients who had early poor function, but no identifiable cause. METHODS: From a regional database, we identified 1,564 patients who underwent unilateral THR between 1998 and 2004 and who were without complication or subsequent bilateral procedure at six months. These patients were divided into two groups according to their Harris hip score (HHS) at this stage: group A consisted of 270 patients with a 'poor' result (HHS less than 70). Group B consisted of 1,294 patients with a 'good' or 'excellent' result (HHS 70 or above). The patients were reviewed at five years. One hundred and ten patients from group A and 980 from group B completed five-year follow-up without further identifiable complication. RESULTS: Those with poor or fair function at six months were at an increased risk of developing an identified complication by five years including dislocation (OR 5.7, 95% CI 1.8-18.2), deep infection (OR 9.8, 95%CI 2.9-37.7) and death (OR 1.6, 95% CI 1.1-2.3). There was a greater rate of revision in group A versus group B (OR 5.7, 95% CI 2.9-11). The overall function measured by the Harris hip score significantly improved in group A, but never reached that of those with good or excellent function at six months (HHS 76.2 versus 90.3, P < 0.001). CONCLUSIONS: Patients with poor function at six months, but no obvious cause, are at higher risk of developing complications by five years. This group may benefit from more regular arthroplasty review and intervention. PMID- 24052165 TI - Reply to comment on Gong et al.: Single-bundle versus double-bundle anterior cruciate ligament reconstruction: an up-to-date meta-analysis. PMID- 24052166 TI - MicroRNAs: their involvement in fibrosis pathogenesis and use as diagnostic biomarkers in scleroderma. AB - miRNAs are important post-transcriptional regulators. The aberrant expression of miRNAs is strongly associated with the initiation and progression of pathophysiologic processes in a wide range of human diseases. Scleroderma (systemic sclerosis; SSc) is a highly heterogeneous autoimmune disease that includes the progressive fibrotic replacement of normal tissue architecture in multiple organs. Our previous studies have suggested that SSc skin tissues display a different miRNA expression signature than that found in normal controls. miRNAs with pro- or antifibrotic properties are found to be dysregulated in SSc skin fibrosis. Serum miRNA levels are associated with SSc activity and severity. miRNAs have the potential to be therapeutic targets and serve as biomarkers for SSc diagnosis and assessment of disease state and severity. This review summarizes the SSc miRNA expression signature and the roles of dysregulation of miRNAs in SSc tissues and serum and examines the future therapeutic potential of targeting miRNAs in the management of SSc patients. PMID- 24052167 TI - U6 is unsuitable for normalization of serum miRNA levels in patients with sepsis or liver fibrosis. AB - MicroRNA (miRNA) levels in serum have recently emerged as potential novel biomarkers for various diseases. miRNAs are routinely measured by standard quantitative real-time PCR (qPCR); however, the high sensitivity of qPCR demands appropriate normalization to correct for nonbiological variation. Presently, RNU6B (U6) is used for data normalization of circulating miRNAs in many studies. However, it was suggested that serum levels of U6 themselves might differ between individuals. Therefore, no consensus has been reached on the best normalization strategy in 'circulating miRNA'. We analyzed U6 levels as well as levels of spiked-in SV40-RNA in sera of 44 healthy volunteers, 203 intensive care unit patients and 64 patients with liver fibrosis. Levels of U6 demonstrated a high variability in sera of healthy donors, patients with critical illness and liver fibrosis. This high variability could also be confirmed in sera of mice after the cecal ligation and puncture procedure. Most importantly, levels of circulating U6 were significantly upregulated in sera of patients with critical illness and sepsis compared with controls and correlated with established markers of inflammation. In patients with liver fibrosis, U6 levels were significantly downregulated. In contrast, levels of spiked-in SV40 displayed a significantly higher stability both in human cohorts (healthy, critical illness, liver fibrosis) and in mice. Thus, we conclude that U6 levels in the serum are dysregulated in a disease-specific manner. Therefore, U6 should not be used for data normalization of circulating miRNAs in inflammatory diseases and previous studies using this approach should be interpreted with caution. Further studies are warranted to identify specific regulatory processes of U6 levels in sepsis and liver fibrosis. PMID- 24052168 TI - Effects of carbon nanotubes in a chitosan/collagen-based composite on mouse fibroblast cell proliferation. AB - This study investigated the in vitro cytocompatibility of carbon nanotubes (CNTs) in a chitosan/collagen-based composite. Mouse fibroblasts were cultured on the surface of a novel material consisting of CNTs in a chitosan/collagen-based composite (chitosan/collagen+CNTs group). Chitosan/collagen composites without CNTs served as the control material (chitosan/collagen group) and cells cultured normally in tissue culture plates served as blank controls (blank control group). Cell adhesion and proliferation were observed, and cell apoptosis was measured. The doubling time (DT1) of cells was significantly shorter in the chitosan/collagen+CNTs group than in the chitosan/collagen group, and that in the chitosan/collagen group was shorter than in the blank control group. The CNTs in the chitosan/collagen-based composites promoted mouse fibroblast adhesion, producing a distinct cytoskeletal structure. At 24 h after culture, the cytoskeleton of the cells in the chitosan/collagen+CNTs group displayed typical fibroblastic morphology, with clear microfilaments. Cells in the chitosan/collagen group were typically round, with an unclear cytoskeleton. The blank control group even had a few unattached cells. At 4 days after incubation, no early apoptosis of cells was detected in the blank control group, whereas early apoptosis of cells was observed in the chitosan/collagen+CNTs and chitosan/collagen groups. No significant difference in the proportion of living cells was detected among the three groups. After entering the plateau stage, the average cell number in the chitosan/collagen+CNTs group was similar to that in the chitosan/collagen group and significantly smaller than that in the blank control group. Early apoptosis of cells in the blank control group was not detectable. There were significant differences in early apoptosis among the three groups. These results suggest that CNTs in a chitosan/collagen-based composite did not cause significant cytotoxic effects on mouse fibroblasts. Compared with chitosan/collagen composites, early adhesion and proliferation of fibroblasts were increased on chitosan/collagen+CNTs. However, at relatively high cell densities, the CNTs in the chitosan/collagen-based composite might exert an inhibitory effect on mouse fibroblast proliferation by inducing apoptosis. PMID- 24052169 TI - The impact of computed tomography slice thickness on the assessment of stereotactic, 3D conformal and intensity-modulated radiotherapy of brain tumors. AB - PURPOSE: To evaluate radiotherapy treatment planning accuracy by varying computed tomography (CT) slice thickness and tumor size. METHODS: CT datasets from patients with primary brain disease and metastatic brain disease were selected. Tumor volumes ranging from about 2.5 to 100 cc and CT scan at different slice thicknesses (1, 2, 4, 6 and 10 mm) were used to perform treatment planning (1-, 2 , 4-, 6- and 10-CT, respectively). For any slice thickness, a conformity index (CI) referring to 100, 98, 95 and 90 % isodoses and tumor size was computed. All the CI and volumes obtained were compared to evaluate the impact of CT slice thickness on treatment plans. RESULTS: The smallest volumes reduce significantly if defined on 1-CT with respect to 4- and 6-CT, while the CT slice thickness does not affect target definition for the largest volumes. The mean CI for all the considered isodoses and CT slice thickness shows no statistical differences when 1-CT is compared to 2-CT. Comparing the mean CI of 1- with 4-CT and 1- with 6-CT, statistical differences appear only for the smallest volumes with respect to 100, 98 and 95 % isodoses-the CI for 90 % isodose being not statistically significant for all the considered PTVs. CONCLUSIONS: The accuracy of radiotherapy tumor volume definition depends on CT slice thickness. To achieve a better tumor definition and dose coverage, 1- and 2-CT would be suitable for small targets, while 4- and 6-CT are suitable for the other volumes. PMID- 24052170 TI - [Acute inpatient conservative multimodal treatment of complex and multifactorial orthopedic diseases in the ANOA concept]. AB - In Germany there is a clear deficit in the non-operative treatment of chronic and complex diseases and pain disorders in acute care hospitals. Only about 20 % of the treatments are carried out in orthopedic hospitals. Hospitals specialized in manual medicine have therefore formed a working group on non-operative orthopedic manual medicine acute care clinics (ANOA). The ANOA has developed a multimodal assessment procedure called the OPS 8-977 which describes the structure and process quality of multimodal and interdisciplinary diagnosis and treatment of the musculoskeletal system. Patients are treated according to clinical pathways oriented on the clinical findings. The increased duration of treatment in the German diagnosis-related groups (DRG) system is compensated for with a supplemental remuneration. Thus, complex and multifactorial orthopedic diseases and pain disorders are conservatively and appropriately treated as inpatient departments of acute care hospitals. PMID- 24052171 TI - Memory: RBAP48 drives age-related memory loss. PMID- 24052176 TI - Genes and circuits of courtship behaviour in Drosophila males. AB - In Drosophila melanogaster, the causal links among a complex behaviour, single neurons and single genes can be demonstrated through experimental manipulations. A key player in establishing the male courtship circuitry is the fruitless (fru) gene, the expression of which yields the FruM proteins in a subset of male but not female neurons. FruM probably regulates chromatin states, leading to single neuron sex differences and, consequently, a sexually dimorphic circuitry. The mutual connections among fru-expressing neurons--including primary sensory afferents, central interneurons such as the P1 neuron cluster that triggers courtship, and courtship motor pattern generators--probably form the core portion of the male courtship circuitry. PMID- 24052180 TI - Issues in the diagnosis and management of disorders of sexual development. AB - Disorders of sexual development (DSD) are a complex group of disorders to manage, not only because the diagnosis is difficult, but also because it involves many factors related to the psychosexual well being, the social stigma associated with the disorder, confusion and reluctance on the part of medical professionals in dealing with this issue, catastrophic experience of parents of these children and difficult interpersonal relationships between parents and children born with this disorder. This brief review attempts to throw light on the recent advances in understanding and management of these disorders to help improve immediate and long term care of these patients and their families. PMID- 24052177 TI - The what, where and how of auditory-object perception. AB - The fundamental perceptual unit in hearing is the 'auditory object'. Similar to visual objects, auditory objects are the computational result of the auditory system's capacity to detect, extract, segregate and group spectrotemporal regularities in the acoustic environment; the multitude of acoustic stimuli around us together form the auditory scene. However, unlike the visual scene, resolving the component objects within the auditory scene crucially depends on their temporal structure. Neural correlates of auditory objects are found throughout the auditory system. However, neural responses do not become correlated with a listener's perceptual reports until the level of the cortex. The roles of different neural structures and the contribution of different cognitive states to the perception of auditory objects are not yet fully understood. PMID- 24052181 TI - ADad 1: rationale and study design for Anxiety Disorders among adolescents in a rural community population in India. AB - OBJECTIVE: The Anxiety Disorders among adolescents (ADad) study aimed to document the prevalence, clinical pattern, co-morbidities, predictive factors, relationship with depression, associated suicidal phenomenon and school phobia of Anxiety Disorders in a rural community population in India. This paper reviews the rationale and study design used as well as discusses the strengths and limitations of the survey. METHODS: The ADad was a cross-sectional study that recruited 537 adolescents, with anganwadi workers, representative of the population aged 11-19 y. Trained raters independently administered the Screen for Child Anxiety Related Emotional Disorders (SCARED), Beck Depression Inventory (BDI), SAD PERSONS scale and Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Version (K-SADS-PL). Appropriate bivariate and multivariate statistical analyses were done. RESULTS: Five hundred adolescents opted to participate and completed the study. About 37% of boys and 63.4% of girls responded to the measures, almost comparable with the gender distribution in the panchayat. CONCLUSIONS: The ADad study creates a comprehensive database on validation of measure, the prevalence, clinical pattern, co-morbidities, predictive factors, relationship with depression, associated outcomes of suicidal phenomenon, school phobia, impairment associated with Anxiety Disorders and policy recommendations in a community population of adolescents in India. These data will enable policy makers to rationally plan clinical services and prevention programs for the target population. PMID- 24052182 TI - 5 alpha-reductase type 2 deficiency - response to dihydrotestosterone gel: correspondence. PMID- 24052178 TI - Choosing an animal model for the study of Huntington's disease. AB - Since the identification of the causative gene in Huntington's disease (HD), a number of animal models of this disorder have been developed. A frequently asked question is: which of these models most closely recapitulates the human disease? In this Review, we provide an overview of the currently available animal models of HD in the context of the clinical features of the disease. In doing so, we highlight their strengths and limitations for modelling specific symptoms of the disease. This should highlight the animal model that is best suited to address a particular question of interest and, ultimately, to expedite the discovery of treatments that will prevent or slow the progression of HD. PMID- 24052183 TI - 5 alpha-reductase type 2 deficiency - response to dihydrotestosterone gel: authors' reply. PMID- 24052185 TI - A bicentennial celebration of the birth of Claude Bernard. PMID- 24052184 TI - BRAF(V600E) mutation analysis in papillary thyroid carcinoma: is it useful for all patients? AB - BACKGROUND: The BRAF(V600E) mutation has been adopted as a prognostic factor in papillary thyroid carcinoma (PTC). However, it remains unclear whether routine BRAF mutation analysis is useful in establishing a prognosis for PTC patients. In the present study we investigated BRAF mutation analysis in a large number of PTC patients with long-term follow-up. PATIENTS AND METHODS: We enrolled 766 patients from our hospital who underwent initial surgery for PTC without distant metastasis at diagnosis between 1996 and 2001, and whose BRAF mutation of primary lesions could be analyzed. The average age and follow-up period were 51 years and 130 months, respectively. RESULTS: To date, 77 (10 %) and 37 (5 %) patients have developed lymph node and distant recurrence, respectively, and 10 (1 %) have died of PTC. The BRAF mutation was positive in 281 patients (37 %), and it had no prognostic impact on lymph node recurrence-free (LNRFS) (p = 0.700), distant recurrence-free (DRFS) (p = 0.696), and cause-specific (CSS) (p = 0.125) survival in our entire series. However, CSS of BRAF mutation-positive high-risk patients based on AMES (p = 0.030), MACIS (score >6) (p = 0.017), the UICC stage (IVa) (p = 0.021), CIH classification (Sugitani et al. Surgery 135:139-148, 2004) (p = 0.015), and our own classification system (Ito et al. World J Surg 34:2570-2580, 2010) (p = 0.010) were significantly poorer than CSS of mutation-negative high risk patients. The BFAF mutation did not affect CSS of non-high-risk patients, although the incidence of the BRAF mutation did not significantly differ between high-risk and non-high-risk groups based on these classification systems. The BRAF mutation was not related to LNRFS and DRFS in the subsets of high-risk and non-high-risk patients. CONCLUSIONS: BRAF mutation analysis is useful in estimating the CSS of high-risk PTC patients based on the representative classification systems. It was not related to the prognosis in non-high-risk patients, at least those living in Japan. PMID- 24052186 TI - Guidewire localization by transthoracic echocardiography during central venous catheter insertion: a periprocedural method to evaluate catheter placement. AB - PURPOSE: To evaluate the feasibility of guidewire detection in right cardiac cavities by transthoracic echocardiography (TTE) in order to detect catheter misplacement and to optimize central venous catheter (CVC) positioning. Ultrasonic control for catheter tip positioning was compared to that by chest X ray (CXR). METHODS: We conducted a monocentric prospective observational study (January-November 2010). All consecutive patients undergoing CVC insertion were included. The puncture was performed using the landmark method or ultrasound guidance. TTE was performed during the procedure to follow the arrival of the guidewire in the right cardiac cavities. Catheter misplacement was defined as an aberrant position on the postprocedural CXR (catheter positioning in ipsilateral or contralateral veins). The primary endpoint was the prediction of catheter misplacement by guidewire detection in the cardiac cavities. The secondary endpoint was the optimization of the catheter tip placement in the superior vena cava. RESULTS: A total of 98 patients received 101 CVC. The guidewire was visualized in 92 cases. In five cases, the guidewire was not seen in the right cardiac cavities and CXR showed catheter misplacement. In four cases, poor echogenicity led to the ultrasound examination being abandoned. Catheter misplacement was detected by TTE with a sensitivity of 96% (CI 90-98%), a specificity of 83% (CI 44-97%), a positive predictive value of 98%, and a negative predictive value of 55%. Likelihood ratios were LR+ 5.7 (CI 0.96-34.4) and LR- 0.05 (CI 0.02-0.14). Guidewire removal under TTE avoided an excessively distal position of the catheter tip in all cases. CONCLUSION: TTE is a reliable tool to detect catheter misplacement and to optimize catheter tip positioning during the procedure of CVC insertion. PMID- 24052187 TI - GPCR: G protein complexes--the fundamental signaling assembly. AB - G protein coupled receptors (GPCR) constitute the largest group of cell surface receptors that transmit various signals across biological membranes through the binding and activation of heterotrimeric G proteins, which amplify the signal and activate downstream effectors leading to the biological responses. Thus, the first critical step in this signaling cascade is the interaction between receptor and its cognate G protein. Understanding this critical event at the molecular level is of high importance because abnormal function of GPCRs is associated with many diseases. Thus, these receptors are targets for drug development. PMID- 24052188 TI - Association of statin use with cataracts: a propensity score-matched analysis. AB - IMPORTANCE: Cataracts are a main cause of low vision; with the growing elderly population, the incidence of cataracts is likely to increase. Investigators have previously hypothesized that statin antioxidant effects may slow the natural aging process of the lens. OBJECTIVE: To compare the risks for development of cataracts between statin users and nonusers. DESIGN: A propensity score-matched cohort analysis using retrospective data from October 1, 2003, to March 1, 2010. A propensity score-matched cohort of statin users and nonusers was created using 44 variables. SETTING: Database of a military health care system. PARTICIPANTS: Based on medication fills during fiscal year 2005, patients were divided into 2 groups: (1) statin users (received at least a 90-day supply of statin) and (2) nonusers (never received a statin throughout the study). Among 46,249 patients meeting study criteria, we identified 13,626 statin users and 32,623 nonusers. EXPOSURE: Use of statin therapy for more than 90 days. MAIN OUTCOMES AND MEASURES: Primary analysis examined the risks for cataract in the propensity score-matched cohort. Secondary analyses examined the risks for cataract in patients with no comorbidities according to the Charlson Comorbidity Index (patients with no Charlson comorbidity). A sensitivity analysis was conducted to repeat the secondary analysis in patients taking statins for durations of 2, 4, and 6 years. RESULTS: For our primary analysis, we matched 6972 pairs of statin users and nonusers. The risk for cataract was higher among statin users in comparison with nonusers in the propensity score-matched cohort (odds ratio, 1.09; 95% CI, 1.02-1.17). In secondary analyses, after adjusting for identified confounders, the incidence of cataract was higher in statin users in comparison with nonusers (odds ratio, 1.27; 95% CI, 1.15-1.40). Sensitivity analysis confirmed this relationship. CONCLUSIONS AND RELEVANCE: The risk for cataract is increased among statin users as compared with nonusers. The risk-benefit ratio of statin use, specifically for primary prevention, should be carefully weighed, and further studies are warranted. PMID- 24052189 TI - The emergence of explicit knowledge from implicit learning. AB - Substantial evidence has highlighted the ability of observers to incidentally extract statistical contingencies present in visual environments. This study examined whether the knowledge extracted regarding statistical contingencies is unconscious initially, even when it becomes fully accessible to conscious awareness after extensive training. Using a "typical" contextual cuing procedure adapted to real-world scenes, we first observed that, after extensive training in searching for a target within repeated scenes, knowledge about regularities was associated with conscious awareness (Experiment 1). However, both subjective and objective measures of consciousness revealed that in the early phase of training, learning of regular structures first takes place at an unconscious level (Experiments 2 and 3). These results are discussed in the light of the causal relationships between learning and consciousness. PMID- 24052190 TI - Recent progress in the development of near-infrared fluorescent probes for bioimaging applications. AB - Near-infrared (NIR) fluorescent dyes have emerged as promising modalities for monitoring the levels of various biologically relevant species in cells and organisms. The use of NIR probes enables deep photon penetration in tissue, minimizes photo-damage to biological samples, and produces low background auto fluorescence from biomolecules present in living systems. The number of new analyte-responsive NIR fluorescent probes has increased substantially in recent years as a consequence of intense research efforts. In this tutorial review, we highlight recent advances (2010-2013) made in the development and applications of NIR fluorescent probes. The review focuses on NIR fluorescent probes that have been devised to sense various biologically important species, including ROS/RNS, metal ions, anions, enzymes and other related species, as well as intracellular pH changes. The basic principles involved in the design of functional NIR fluorescent probes and suggestions about how to expand applications of NIR imaging agents are also described. PMID- 24052191 TI - Ventilatory muscle strength, diaphragm thickness and pulmonary function in world class powerlifters. AB - PURPOSE: Resistance training activates the ventilatory muscles providing a stimulus similar to ventilatory muscle training. We examined the effects of elite powerlifting training upon ventilatory muscle strength, pulmonary function and diaphragm thickness in world-class powerlifters (POWER) and a control group (CON) with no history of endurance or resistance training, matched for age, height and body mass. METHODS: Body composition was assessed using single-frequency bioelectrical impedance. Maximal static volitional inspiratory (P(I,max)) and expiratory (P(E,max)) mouth pressures, diaphragm thickness (T(di)) derived from ultrasound measurements and pulmonary function from maximal flow volume loops were measured. RESULTS: There were no differences in physical characteristics or pulmonary function between groups. P(I,max) (22 %, P < 0.05, effect size d = 1.13), P(E,max) (16 %, P = 0.07, effect size d = 0.86) and T(di) (27 %, P < 0.01, effect size d = 1.59) were greater in POWER than CON. Correlations were observed between both T(di) and P(I,max) (r = 0.518, P < 0.05), T(di) and P(E,max) (r = 0.671, P < 0.01) and T(di) and body mass (r = 0.502, P < 0.05). CONCLUSIONS: We conclude that manoeuvres performed by world-class powerlifters improve ventilatory muscle strength and increases diaphragm size. Whole-body resistance training may be an appropriate training mode to attenuate the effects of ventilatory muscle weakness experienced with ageing and some disease states. PMID- 24052193 TI - Gastric adenoma with low-grade dysplasia: two countries, two outcomes. PMID- 24052194 TI - Are caudal-type homeobox genes causal for gastro-esophageal reflux disease and Barrett's esophagus? PMID- 24052192 TI - Morbidity in survivors of child and adolescent meningioma. AB - BACKGROUND: The extent of initial surgical resection has been identified as the strongest prognostic indicator for survival in child and adolescent meningioma. Given the paucity of data concerning long-term outcome, the authors undertook a meta-analysis to analyze morbidity in survivors of this disease. METHODS: Individual patient data were obtained from 19 case series published over the last 23 years through direct communication with the authors. Ordinal logistic regression models were used to assess the influence of risk factors on morbidity. RESULTS: Of 261 patients, 48% reported a completely normal life with no morbidity, and 25% had moderate/severe meningioma-associated morbidity at last follow-up. Multivariate analysis identified relapse as the only independent variable associated with an increased risk of morbidity (odds ratio, 4.02; 95% confidence interval, 2.11-7.65; P <= .001). Univariate analysis also revealed an increased risk for patients with neurofibromatosis (odds ratio, 1.90; 95% confidence interval, 1.04-3.48; P = .04). Subgroup analysis identified a higher incidence of morbidity among patients who had intracranial tumors with a skull base location compared with a nonskull base location (P <= .001). Timing at which morbidity occurred was available for 70 patients, with persistence of preoperative tumor-related symptoms in 67% and as a result of therapy in 20%. CONCLUSIONS: The majority of survivors of child and adolescent meningioma had no or only mild long-term morbidity, whereas 25% had moderate/severe morbidity, with a significantly increased risk in patients with relapsed disease. In the majority, morbidity occurred as a consequence of the tumor itself, justifying aggressive surgery to achieve gross total resection. However, for patients with neurofibromatosis and skull base meningioma, a more cautious surgical approach should be reserved. PMID- 24052195 TI - Hepatitis B management in vulnerable populations: gaps in disease monitoring and opportunities for improved care. AB - BACKGROUND: Hepatitis B (HBV) is prevalent in certain US populations and regular HBV disease monitoring is critical to reducing associated morbidity and mortality. Adherence to established HBV monitoring guidelines among primary care providers is unknown. AIMS: The purpose of this study was to evaluate HBV disease monitoring patterns and factors associated with adherence to HBV management guidelines in the primary care setting. METHODS: Primary providers within the San Francisco safety net healthcare system were surveyed for HBV management practices, knowledge, attitudes, and barriers to HBV care. Medical records from 1,727 HBV-infected patients were also reviewed retrospectively. RESULTS: Of 148 (45 %) responding providers, 79 % reported ALT and 44 % reported HBV viral load testing every 6-12 months. Most providers were knowledgeable about HBV but 43 % were unfamiliar with HBV management guidelines. Patient characteristics included: mean age 51 years, 54 % male and 67 % Asian. Within the past year, 75 % had ALT, 24 % viral load, 21 % HBeAg tested, and 40 % of at-risk patients had abdominal imaging for HCC. Provider familiarity with guidelines (OR 1.02, 95 % CI 1.00 1.03), Asian patient race (OR 4.18, 95 % CI 2.40-7.27), and patient age were associated with recommended HBV monitoring. Provider HBV knowledge and attitudes were positively associated, while provider age and perceived barriers were negatively associated with HCC surveillance. CONCLUSIONS: Comprehensive HBV disease monitoring including HCC screening with imaging were suboptimal. While familiarity with AASLD guidelines and patient factors were associated with HBV monitoring, only provider and practice factors were associated with HCC surveillance. These findings highlight the importance of targeted provider education to improve HBV care. PMID- 24052196 TI - Granulocytapheresis for the treatment of severe alcoholic hepatitis: a case series and literature review. AB - Severe alcoholic hepatitis has a high mortality rate due to limited therapeutic methods. Although corticosteroids have been used to control the inflammatory response, the outcomes vary and no standardized therapy has been established. Novel therapeutic approaches, such as anti-TNF-alpha, pentoxifilline, and others have been tested clinically on the basis of their cytokinemic pathophysiology with limited success. However, treatment of leukocytosis that causes cytokinemia and hepatic inflammation in patients via granulocytapheresis and leukocytapheresis showed promising results in a number of reports. Here, we report two cases of severe alcoholic hepatitis treated with granulocytapheresis. The liver function and inflammation recovered after the therapy. A review of 35 cases treated with granulocytapheresis and leukocytapheresis demonstrated their efficacy in treating alcoholic hepatitis by controlling leukocytosis as well as cytokines such as IL-8. Multidisciplinary treatment for severe alcoholic hepatitis should be considered case by case on the basis of the complexity and severity of the condition. PMID- 24052197 TI - Prediction of antiprion activity of therapeutic agents with structure-activity models. AB - We have developed computational structure-activity models for the prediction of antiprion activity of compounds with known molecular structure. The aim is to apply the developed classification and predictive models in further drug design of antiprion therapeutics. The neural network models developed on the counter propagation reinforcement learning strategy performed better than the linear regression models. The initial data set was composed of 461 compounds representing diverse groups of chemicals (derivatives of acridine, quinolone, Congo red, 2-aminopyridine-3,5-dicarbonitrile, styrylbenzoazole, 2,5-diamino benzoquinone), which have been tested in comparable cell-screening assay studies for their activity against prion accumulation. Initially, we have designed a classification model for preliminary sorting of compounds into highly active, active, and inactive groups. Further, only the active compounds with IC50 less or equal to 10 MUM were considered as the initial source of data. Altogether, 158 compounds were used to train the artificial neural network model for the estimation of the antiprion activity. The predictive ability of the model was significantly improved after selection of influential variables with genetic algorithm. The root- mean-squared error of the predicted pIC50 values for the external validation set (RMS EV) was slightly above 0.50 log units. A linear regression model, developed for the reasons of comparison, performed with a lower predictive ability (RMS EV 0.92 log units). The applicability domain of the models was assessed by a leverage and distance approach. The set of selected influential structural variables was further studied with the aim to get a better insight into the structural features of compounds potentially involved in disturbing of the prion-prion interactions. PMID- 24052198 TI - Sulfonoketenimides as key intermediates for the synthesis of 2-thioxo-2H-1,3 thiazines and 2-arylimino-2H-1,3-thiazines. AB - The synthesis of a novel class of highly functionalized 1,3-thiazine derivatives via a copper-catalyzed tandem reaction of 1,1,3,3-tetramethylguanidine, [Formula: see text], sulfonyl azides, and terminal alkynes is described. Using isothiocyanates as the heterocumulene component, affords 2-arylimino-1,3-thiazine derivatives in moderate to good yields. PMID- 24052199 TI - The subtalar and talonavicular joints: a way to access the long-term load intake using conventional CT-data. AB - PURPOSE: The aim of this study was to investigate the distribution of density of the subchondral bone plate within the articular surfaces of the subtalar and talonavicular joint regarding to its mineralisation and to verify whether a correlation to the mechanical bone strength exists. METHODS: A total of 21 cadaverous lower leg specimens were investigated. Computed tomography osteo absorptiometry (CT-OAM) was used to display the mineralisation of the subchondral bone plate analysing its density. The mechanical strength was measured by means of indentation testing. The distribution pattern was analysed regarding their dissemination with the main focus on number and location of their maxima. The correlation of both parameters was evaluated by linear regression. RESULTS: The mineralisation and the mechanical strength were not distributed homogenously throughout the articular surfaces but showed unique and reproducible patterns. The range of absolute values for density and strength varied in between the samples and joint surfaces, but the number and location of the maxima evaluated by both methods showed to be concurring. The coefficient of correlation of both datasets ranged from 0.76 to 0.95 (median 0.88) and showed a linear dependency. CONCLUSIONS: Density distribution and mechanical strength of the subchondral bone plate are significantly associated and can be seen as a mirror of the long-term load intake of a joint. It can be concluded that CT-OAM as a tool to visualize subchondral bone plate density distribution regarding to its mineralisation can be used to indirectly gain information about joint biomechanics in vivo by the use of conventional CT-data. PMID- 24052200 TI - Radiological anatomical study of the origin of the uterine artery. AB - PURPOSE: To clarify the origin of the uterine artery and quantify its anatomical variants. MATERIALS AND METHODS: We carried out a study based on dissections, intraoperative findings and retrospective analysis of arteriograms. Thirty female cadavers were dissected and bilaterally observed, with a total of 60 origins visualised. Fifty laparotomies were carried out during the treatment for pelvic neoplasms (100 origins observed) and 34 arteriograms performed for uterine fibroid embolisation were studied (58 origins visualised). RESULTS: In total, 218 origins of the uterine artery were visualised. The uterine artery originated from a common trunk with the umbilical artery in 80.7% of cases. It arose separately from the internal iliac artery in 13.16% of cases and directly from the superior gluteal artery in 3.51% of cases. It branched from a common trunk with the internal pudendal artery in 1.75% of cases, whereas arose separately from the obturator artery in 0.88% of cases. CONCLUSION: The uterine artery arose from a common trunk with the umbilical artery in the majority of the Caucasian population. Surgeons and radiologists should be aware of this mode of branching to facilitate surgery and interventional radiology and improve the safety of these procedures. PMID- 24052201 TI - Reliability and validity of self-care and mobility accommodations measures in the National Health and Aging Trends Study. AB - PURPOSE OF THE STUDY: Comprehensive measures of disability accommodations have been lacking in national health and aging studies. This article introduces measures of accommodations developed for the National Health and Aging Trends Study, evaluates their reliability, and explores the validity and reliability of hierarchical classification schemes derived from these measures. DESIGN AND METHODS: We examined test-retest reliability for questions about assistive device use, doing activities less often, and getting help from another person with both percentage agreement and kappa (N = 111). Summary measures across activities and several hierarchical classification schemes (e.g., no accommodation, devices/activity reductions only, help) were developed. For the latter, we also evaluated validity by examining correlations with measures of capacity and demographic characteristics (N = 326). RESULTS: Items about assistive device use and help in the last month were robust (most kappas 0.7-0.9). Activity reduction measures were moderately reliable (around 0.5) but still showed reasonable agreement. Reliabilities for summary measures were good for device use (0.78 0.89) and help (0.62-0.67) but lower, albeit acceptable, for activity reduction (0.53). Hierarchical classifications had acceptable reliability and levels demonstrated hierarchical properties. IMPLICATIONS: National Health and Aging Trends Study's self-care and mobility accommodation measures offer ample reliability to study adaptation to limitations and can be used to construct a reliable and valid hierarchy. PMID- 24052202 TI - Redirection: an extension of career during retirement. AB - PURPOSE OF THE STUDY: This study explores (a) whether retirees' formal volunteer experiences represent an extension of their career in the paid workforce; and (b) how this integration of life roles affects career self-concept, as interpreted through Donald Super's life-span, life-space theory of career development. DESIGN AND METHODS: A survey was conducted involving a Canadian sample of 214 individuals aged 55-75 years to examine retirees' volunteer activities and their sense of self. RESULTS: The results demonstrate the need to further develop Super's theory with the addition of a new developmental stage, which I am labeling "Redirection" to better reflect postretirement experiences. During "Redirection," retirees develop a "new self." IMPLICATIONS: This study indicates that retirees experienced a new stage of "Redirection" and found new meaning through volunteer work during retirement. The results will be of interest to professionals and researchers focused on career development, older workers, and retirement. PMID- 24052203 TI - Effectiveness of a community health worker-led diabetes self-management education program and implications for CHW involvement in care coordination strategies. AB - PURPOSE: The purpose of this study was to evaluate the effectiveness of a Community Health Worker (CHW)-led diabetes self-management education (DSME) program and to understand how CHWs and primary care providers (PCPs) work together to provide comprehensive diabetes care. METHODS: A quantitative pre- and postassessment of change in patients' blood glucose levels (A1C), blood pressure, and body mass index was performed to determine the clinical effectiveness of the program. Qualitative, semi-structured interviews with 5 CHWs and 7 PCPs were conducted to assess how CHWs were incorporated into clinical teams and their impact on care delivery and diabetes-related outcomes. RESULTS: Patients who participated in the program experienced a statistically significant decrease in mean A1C levels and systolic blood pressure readings 1 year post baseline. CHWs provided high-quality care and bridged the gap between patients and care providers through diabetes management support and education, medication assistance, access to community resources, and social support. CONCLUSIONS: CHWs play a variety of roles in helping patients overcome barriers to diabetes control and can be successfully integrated into a health care system's care coordination strategy. PMID- 24052204 TI - Implementation of a culturally tailored diabetes intervention with community health workers in American Samoa. AB - PURPOSE: The purpose of this article is to answer key implementation questions from our translation research with a primary care-based, nurse-community health worker (CHW) team intervention to support type 2 diabetes self-management. METHODS: Descriptive data are given on intervention delivery, CHW visit content, patient safety, and intervention costs, along with statistical analyses to examine participant characteristics of higher attendance at visits. RESULTS: In the intervention sample (n = 104), 74% (SD = 16%) of planned intervention visits occurred, guided by an algorithm-based protocol. Higher risk participants had a significantly lower dose of their weekly assigned visits (66%) than those at moderate (74%) and lower risk (90%). Twenty-eight percent of participants moved to a lower risk group over the year. Estimated intervention cost was $656 per person. Participants with less education were more likely to attend optimal percentage of visits. CONCLUSIONS: A nurse-CHW team can deliver a culturally adapted diabetes self-management support intervention with excellent fidelity to the algorithm-based protocols. The team accommodated participants' needs by meeting them whenever and wherever they could. This study provides an example of adaptation of an evidence-based model to the Samoan cultural context and its resource-poor setting. PMID- 24052205 TI - Duration of television viewing and bone mineral density in Chinese women. AB - Studies on the relationship between television (TV) viewing and bone mineral density (BMD) in adults are limited. The purpose of this study was to examine whether longer duration of TV viewing increased the risk of lower BMD in Chinese women. A total of 626 female adults were voluntarily recruited into the study. Anthropometric measurements were obtained using standard procedures. Body composition including total body and regional BMD was estimated using dual-energy X-ray absorptiometry. The duration of TV viewing was categorized into 4 groups: <1 h, 1 to <2 h, 2 to <3 h, and >=3 h. Multiple linear regression models were applied to analyze the associations between duration of TV viewing and total and regional BMD in all subjects and in subjects stratified by age of 45 years, respectively. After adjusting for age, BMI, alcohol use, smoking, education, income, urbanicity, leisure time physical activity, occupational physical activity, and menopause, the significant trend of pelvic BMD across categories of TV viewing was observed in all subjects (p < 0.05). Further analysis revealed that women aged <45 years, the 1 to <2 h group, the 2 to <3 h group, and the >=3 h group were significantly associated with lower total body and regional BMD compared to women aged <45 years in the <1 h group. We concluded that the duration of TV viewing was negatively associated with BMD in Chinese women, especially in those aged 18-44 years. It might be sensible to reduce TV viewing time to prevent bone loss in young women. PMID- 24052206 TI - Skipping breakfast and less exercise are risk factors for bone loss in young Japanese adults: a 3-year follow-up study. AB - Although bone loss contributes to osteoporosis (OP) in the elderly, little is known about changes in bone mineral density (BMD) in young adults that lead to bone loss. Here, we evaluated the rate of bone change and risk factors for bone loss in young men and women using data from a 3-year prospective study of Japanese medical students. The study included a self-administrated questionnaire survey, anthropometric measurements, and BMD measurements of the spine (L2-L4) and femoral neck (FN). After 3 years, the BMD of the participants was again measured at the same sites. In all, 458 students (95.4 %; 298 men and 160 women; age range, 18-29 years; mean age, 20.2 years) completed both the baseline and follow-up surveys. The mean L2-L4 BMD value at baseline increased significantly within 3 years. This tendency was also observed for the FN in men but not in women. The annual changes at L2-L4 were 1.78 % in men and 0.97 % in women per year; those for FN were 1.08 % in men and 0.08 % in women per year. However, 20.3 % and 38.5 % of the total freshmen lost BMD in the lumbar spine and FN, respectively. After adjustment for age and body mass index, logistic regression analysis revealed that bone loss in men at L2-L4 at the baseline was affected by skipping breakfast. In contrast, exercise (>2 h/week) increased lumbar spine BMD in both genders. These findings indicate that breakfast and exercise are important for maintaining BMD in young men and women. PMID- 24052207 TI - Relationships between serum adipocyte hormones (adiponectin, leptin, resistin), bone mineral density and bone metabolic markers in osteoporosis patients. AB - The purpose of this study was to investigate the relationship between fasting serum leptin, adiponectin and resistin levels and bone mineral density (BMD) in osteoporosis patients and a non-osteoporosis control group. We studied 81 non diabetic osteoporosis patients (92 % female, 8 % male; mean age 54.5 +/- 15.5 years and body mass index [BMI] 28.2 +/- 4.6) and 120 non-diabetic individuals with normal BMD as controls (86 % female, 14 % male; mean age 39.7 +/- 10.4 years and BMI 28.8 +/- 4.4). BMD was studied by dual-energy X-ray absorptiometry from the lumbar spine (L1-L4) and femoral neck and fasting blood samples were taken for biochemical measurement of fasting blood glucose, leptin, adiponectin and resistin. Fasting levels of plasma adiponectin had a significant negative correlation with BMD of the femoral neck and lumbar spine in the osteoporosis group (r = -0.478, P = 0.003, r = -0.513, P = 0.023) but not in the non osteoporosis group (r = -0.158, P = 0.057, r = -0.23, P = 0.465). Fasting plasma levels of resistin were significantly correlated only with femur BMD in the osteoporosis group, and not significantly correlated with lumbar spine BMD (r = 0.244, P = 0.048 vs r = 0.276, P = 0.56). Leptin did not have a significant correlation with BMD in either the osteoporosis or non-osteoporosis groups (P > 0.05). Adiponectin had a significant negative correlation with BMD of the lumbar spine and femoral neck. The correlation between leptin and resistin are not inconclusive. PMID- 24052208 TI - Familial interactions and physical, lifestyle, and dietary factors to affect bone mineral density of children in the KNHANES 2009-2010. AB - We examined familial bone mineral density (BMD) interactions between parents and children and lifestyle factors affecting BMD in the Korean general population of children under 20 and parents under 50 years of age. This cross-sectional study included 2,453 participants (667 daughters, 705 sons, 719 mothers, and 362 fathers) in the 2009-2010 Korean National Health and Nutrition Examination Survey. We calculated prevalence ratios and 95 % confidence intervals for BMD values of whole femur, femur neck, lumbar spine, and whole body excluding the head being in the low tertile in adolescents according to parental BMD tertile after adjusting for physical, lifestyle, and dietary factors. For daughters and sons, there were significant differences in BMD at the four bone sites according to age group, body fat percentage, regular walking and exercise, and milk consumption compared to the reference value for each classification category. Surprisingly, there were no differences in BMD according to serum 25-OH-D levels. Birth order affected BMD of only whole body except head, but its impact was less than that of lifestyle factors. The mean differences in BMD between daughters and sons in the first and third parental BMD tertiles were statistically significant. Notably, the prevalence ratio of whole body without head BMD being in the low tertile increased eight and ten-folds in adolescent daughters and sons, respectively, when parents were in the low BMD tertile. In specific bone regions, parental BMD had a greater effect on total femur in daughters but in the lumbar spine in sons. In conclusion, parental BMD positively influences BMD in daughters and sons after adjustment for environmental parameters. This suggests that the children from parents with low BMD need to make an extra effort to increase BMD through dietary and lifestyle changes. PMID- 24052209 TI - Phosphate enhances reactive oxygen species production and suppresses osteoblastic differentiation. AB - Phosphate has been shown to work as a signaling molecule in several cells including endothelial cells and chondrocytes. However, it is largely unknown how phosphate affects osteoblastic cells. In the present study, we investigated the effects of phosphate on reactive oxygen species (ROS) production and osteoblastic differentiation in murine osteoblastic MC3T3-E1 cells. Phosphate increased production of ROS in MC3T3-E1 cells and the inhibitors of sodium-phosphate cotransporter and NADPH oxidase suppressed ROS production by phosphate. Silencing Nox1 and Nox4 also inhibited the increase of ROS by phosphate. Phosphate also decreased alkaline phosphatase activity induced by bone morphogenetic protein 2 and this inhibition was abrogated by an inhibitor of NADPH oxidase. Furthermore, phosphate decreased the expression of osteoblastic marker genes in MC3T3-E1 cells. These results indicate that phosphate suppresses osteoblastic differentiation at least in part by enhancing ROS production in MC3T3-E1 cells. PMID- 24052211 TI - Neurogenic and sympathoexcitatory actions of NaCl in hypertension. AB - Excess dietary salt intake is a major contributing factor to the pathogenesis of salt-sensitive hypertension. Strong evidence suggests that salt-sensitive hypertension is attributed to renal dysfunction, vascular abnormalities, and activation of the sympathetic nervous system. Indeed, sympathetic nerve transections or interruption of neurotransmission in various brain centers lowers arterial blood pressure (ABP) in many salt-sensitive models. The purpose of this article is to discuss recent evidence that supports a role of plasma or cerebrospinal fluid hypernatremia as a key mediator of sympathoexcitation and elevated ABP. Both experimental and clinical studies using time-controlled sampling have documented that a diet high in salt increases plasma and cerebrospinal fluid sodium concentration. To the extent it has been tested, acute and chronic elevations in sodium concentration activates the sympathetic nervous system in animals and humans. A further understanding of how the central nervous system detects changes in plasma or cerebrospinal fluid sodium concentration may lead to new therapeutic treatment strategies in salt-sensitive hypertension. PMID- 24052213 TI - Pick up a book or "google it?" a survey of radiologist and trainee-preferred references and resources. AB - The purpose of this study was to investigate radiologist and trainee-preferred sources for solving imaging questions. The institutional review board determined this study to be exempt from informed consent requirements. Web-based surveys were distributed to radiology staff and trainees at 16 academic institutions. Surveys queried ownership and use of tablet computers and habits of utilization of various electronic and hardcopy resources for general reference. For investigating specific cases, respondents identified a single primary resource. Comparisons were performed using Fisher's exact test. For staff, use of Google and online journals was nearly universal for general imaging questions (93 [103/111] and 94 % [104/111], respectively). For trainees, Google and resident generated study materials were commonly utilized for such questions (82 [111/135] and 74 % [100/135], respectively). For specific imaging questions, online journals and PubMed were rarely chosen as a primary resource; the most common primary resources were STATdx for trainees and Google for staff (44 [55/126] and 52 % [51/99], respectively). Use of hard copy journals was nearly absent among trainees. Sixty percent of trainees (78/130) own a tablet computer versus 41 % of staff (46/111; p = 0.005), and 71 % (55/78) of those trainees reported at least weekly use of radiology-specific tablet applications, compared to 48 % (22/46) of staff (p < 0.001). Staff radiologists rely heavily on Google for both general and specific imaging queries, while residents utilize customized, radiology-focused products and apps. Interestingly, residents note continued use of hard copy books but have replaced hard copy journals with online resources. PMID- 24052212 TI - Physical activity and the prevention of hypertension. AB - As the worldwide prevalence of hypertension continues to increase, the primary prevention of hypertension has become an important global public health initiative. Physical activity is commonly recommended as an important lifestyle modification that may aid in the prevention of hypertension. Recent epidemiologic evidence has demonstrated a consistent, temporal, and dose-dependent relationship between physical activity and the development of hypertension. Experimental evidence from interventional studies has further confirmed a relationship between physical activity and hypertension as the favorable effects of exercise on blood pressure reduction have been well characterized in recent years. Despite the available evidence strongly supporting a role for physical activity in the prevention of hypertension, many unanswered questions regarding the protective benefits of physical activity in high-risk individuals, the factors that may moderate the relationship between physical activity and hypertension, and the optimal prescription for hypertension prevention remain. We review the most recent evidence for the role of physical activity in the prevention of hypertension and discuss recent studies that have sought to address these unanswered questions. PMID- 24052214 TI - Foreword for the special issue on lamprey and salamander robots and the central nervous system. PMID- 24052218 TI - CKD-mineral and bone disorder and risk of death and cardiovascular hospitalization in patients on hemodialysis. AB - BACKGROUND AND OBJECTIVES: Parathyroid hormone, calcium, and phosphate have been independently associated with cardiovascular event risk. Because these parameters may be on the same causal pathway and have been proposed as quality measures, an integrated approach to estimating event risks is needed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prevalent dialysis patients were followed from August 31, 2005 to December 31, 2006. A two-stage modeling approach was used. First, the 16-month probabilities of death and composite end point of death or cardiovascular hospitalization were estimated and adjusted for potential confounders. Second, patients were categorized into 1 of 36 possible phenotypes using average parathyroid hormone, calcium, and phosphate values over a 4-month baseline period. Associations among phenotypes and outcomes were estimated and adjusted for the underlying event risk estimated from the first model stage. RESULTS: Of 26,221 patients, 98.5% of patients were in 22 groups with at least 100 patients and 20% of patients were in the reference group defined using guideline-based reference ranges for parathyroid hormone, calcium, and phosphate. Within the 22 most common phenotypes, 20% of patients were in groups with significantly (P<0.05) higher risk of death and 54% of patients were in groups with significantly higher risk of the composite end point relative to the in target reference group. Increased risks ranged from 15% to 47% for death and from 8% to 55% for the composite. More than 40% of all patients were in the three largest groups with elevated composite end point risk (high parathyroid hormone, target calcium, and high phosphate; target high parathyroid hormone, target calcium, and high phosphate; and target high parathyroid hormone, target calcium, and target phosphate). CONCLUSION: After adjusting for baseline risk, phenotypes defined by categories of parathyroid hormone, calcium, and phosphate identify patients at higher risk of death and cardiovascular hospitalization. Identifying common high-risk phenotypes may inform clinical interventions and policies related to quality of care. PMID- 24052219 TI - Dietary acid, age, and serum bicarbonate levels among adults in the United States. AB - BACKGROUND AND OBJECTIVES: Greater dietary acid has been associated with lower serum bicarbonate levels in patients with CKD. Whether this association extends to the general population and if it is modified by age are unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study examined the association of the dietary acid load, estimated by net endogenous acid production, with serum bicarbonate levels in adult participants in the National Health and Nutrition Examination Survey 1999-2004. RESULTS: The mean serum bicarbonate was 24.9 mEq/L (SEM=0.1), and the mean estimated net endogenous acid production was 57.4 mEq/d (SEM=0.4). Serum bicarbonate was linearly associated with age, such that the oldest participants had the highest serum bicarbonate levels. After multivariable adjustment, participants in the highest quartile of net endogenous acid production had 0.40 mEq/L (95% confidence interval, -0.55 to -0.26) lower serum bicarbonate and a 33% (95% confidence interval, 3 to 72) higher likelihood of acidosis compared with those participants in the lowest quartile. There was a significant interaction by age of the association of net endogenous acid production with serum bicarbonate (P=0.005). Among participants 20-39, 40-59, and >=60 years old, those participants in the highest net endogenous acid production quartile had 0.26 (95% confidence interval, -0.49 to -0.03), 0.60 (95% confidence interval, -0.92 to -0.29), and 0.49 (95% confidence interval, -0.84 to -0.14) mEq/L lower serum bicarbonate, respectively, compared with participants in the lowest quartile. CONCLUSION: Greater dietary acid is associated with lower serum bicarbonate in the general US population, and the magnitude of this association is greater among middle-aged and elderly persons than younger adults. PMID- 24052220 TI - Urinary eosinophils in AIN: farewell to an old biomarker? PMID- 24052221 TI - Consideration of ICD-9 code-derived disease-specific safety indicators in CKD. AB - BACKGROUND AND OBJECTIVES: The Agency for Healthcare and Research Quality patient safety indicators track adverse safety events in hospitalized patients but overlook safety incidents specific to CKD. This study considers candidate CKD pertinent patient safety indicators and compares them with the Agency for Healthcare and Research Quality patient safety indicators. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a national Veterans Health Administration database of hospitalized veterans from fiscal year 2005, 247,160 hospitalized veterans with prehospitalization measures of renal function were retrospectively examined for proposed CKD patient safety indicators versus Agency for Healthcare and Research Quality patient safety indicators using International Classification of Diseases, Ninth Revision diagnosis codes. Candidate CKD-pertinent patient safety indicators included in-hospital acute kidney failure; in-hospital congestive heart failure (and related diagnostic codes); electrolyte disturbances; and medication errors, poisoning, and intoxication. Patients with a prehospital estimated GFR<60 ml/min per 1.73 m(2) (CKD group) were compared with a non-CKD group. For CKD patient safety indicators, hospitalizations were excluded if the admitting condition was a potential cause of the secondary condition. Regression methods were used to present adjusted rates in study groups of interest. RESULTS: The CKD patient safety indicators were generally more common than the Agency for Healthcare and Research Quality patient safety indicators in all groups, tended to occur in different patients than those patients who experienced Agency for Healthcare and Research Quality patient safety indicators, and were more common in the CKD group than the non-CKD group, except for hypoglycemia, hypokalemia, and hyponatremia. The adjusted composite CKD patient safety indicators rate (per 1000 patient-hospitalizations) was 398.0 (95% confidence interval, 391.2 to 405.0) for patients in the CKD group and 250.0 (95% confidence interval, 247.4 to 252.7) for patients in the non-CKD group. The prevalence ratio of CKD patient safety indicators to Agency for Healthcare and Research Quality patient safety indicators was 23.4 (95% confidence interval, 21.9 to 25.0). CONCLUSION: The candidate CKD patient safety indicators that occur in hospitalized patients are distinct from the Agency for Healthcare and Research Quality patient safety indicators and tend to be more common in CKD than non-CKD patients. These measures have the potential to serve as sentinel tools for identifying patients with CKD who warrant examination for disease-pertinent safety events. PMID- 24052222 TI - Utility of urine eosinophils in the diagnosis of acute interstitial nephritis. AB - BACKGROUND AND OBJECTIVES: Urine eosinophils (UEs) have been shown to correlate with acute interstitial nephritis (AIN) but the four largest series that investigated the test characteristics did not use kidney biopsy as the gold standard. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective study of adult patients with biopsy-proven diagnoses and UE tests performed from 1994 to 2011. UEs were tested using Hansel's stain. Both 1% and 5% UE cutoffs were compared. RESULTS: This study identified 566 patients with both a UE test and a native kidney biopsy performed within a week of each other. Of these patients, 322 were men and the mean age was 59 years. There were 467 patients with pyuria, defined as at least one white cell per high-power field. There were 91 patients with AIN (80% was drug induced). A variety of kidney diseases had UEs. Using a 1% UE cutoff, the comparison of all patients with AIN to those with all other diagnoses showed 30.8% sensitivity and 68.2% specificity, giving positive and negative likelihood ratios of 0.97 and 1.01, respectively. Given this study's 16% prevalence of AIN, the positive and negative predictive values were 15.6% and 83.7%, respectively. At the 5% UE cutoff, sensitivity declined, but specificity improved. The presence of pyuria improved the sensitivity somewhat, with a decrease in specificity. UEs were no better at distinguishing AIN from acute tubular necrosis compared with other kidney diseases. CONCLUSIONS: UEs were found in a variety of kidney diseases besides AIN. At the commonly used 1% UE cutoff, the test does not shift pretest probability of AIN in any direction. Even at a 5% cutoff, UEs performed poorly in distinguishing AIN from acute tubular necrosis or other kidney diseases. PMID- 24052223 TI - Minimally invasive techniques for female stress urinary incontinence, how, why, when. AB - AIM: The main purpose of this paper is to summarize the recent experience that has been obtained till now in the surgical treatment of urinary stress incontinence with less invasive techniques. MATERIALS AND METHODS: We used current literature and papers published in MEDLINE and Cochrane library. The keywords used for this review were Stress urinary incontinence, Tension-free vaginal tape (TVT), Transobturator tape (TOT, TVT-O), and Single-incision mini slings (SIMS). RESULTS: Tension-free vaginal tape and the transobturator urethral suspension are the most commonly used surgical approach for women who suffer from stress urinary incontinence, with long-term success rates ranging from 84 to 95 %. TVT is shown to be as effective as the older colposuspension, associated with less post-operative complications, shorter hospital stay and shorter recovery period. Bladder perforations that have been mentioned with the TVT inserter apparently do not result in any clinically significant morbidity. Major vascular and bowel injuries have been reported at rates of 0.07 and 0.04 %, respectively. Studies between TVT-O and TOT show equal effectiveness with slightly lower cure rates than TVT group, but TOT had a significant lower risk of bladder and vaginal perforations. There were no significant differences in objective cure rates between 'inside-out' and 'outside-in' transobturator tapes. Very recently a meta analysis does not support routine use of SIMS in clinical practice, moreover suggested the retropubic TVT as the preferred choice for the management of stress urinary incontinence due to familiarity, its effectiveness, minimal invasiveness and low complication and morbidity rates as a primary procedure. Similar results have been announced in a randomized control trial in USA. CONCLUSIONS: Certainly, larger randomized clinical trials with longer follow-up about the mentioned techniques are needed to accurately determine the efficacy and safety of the mentioned minimally invasive techniques. PMID- 24052224 TI - Acquired dyschromatopsia in acute myelocytic leukaemia. AB - BACKGROUND: Patients with haematological malignancy are referred to the ophthalmologist either with visual symptoms or to exclude orbital or intraocular involvement after the diagnosis has been established. This report describes a patient with acute myelocytic leukaemia (AML) whose presenting symptom was dyschromatopsia. METHODS: A 52-year-old female, previously in good health, presented with a disturbance of colour vision. On examination, there was bilateral reduction in visual acuity, impaired colour vision and severely constricted visual fields. Electrophysiological testing and colour contrast sensitivity (CCS) assessment were performed. RESULTS: CCS showed bilateral threshold elevation in the tritan axis of both eyes, right worse than left. Pattern ERG showed marked macular dysfunction in the right eye, but was normal in the left eye. Full-field ERGs fell within the normal range. Pattern VEPs were reduced in the right eye, without peak time shift; flash VEPs showed bilateral delay. Investigation showed severe anaemia, and a bone marrow biopsy confirmed a diagnosis of acute AML. There was symptomatic improvement in visual acuity and colour vision following blood transfusion and initiation of chemotherapy. CONCLUSION: This appears to be the first case report of dyschromatopsia in AML with symptomatic improvement following treatment. The case lends support to previously suggested hypotheses of chromatic visual disturbance in association with presumed hypoxia. PMID- 24052225 TI - Electrooculogram (EOG) findings in a case of acute exudative polymorphous vitelliform maculopathy (AEPVM) detected following trauma. AB - PURPOSE: The purpose of this study was to monitor a case of acute exudative polymorphous vitelliform maculopathy detected following trauma. METHODS: Clinical examination included fundus photographs, optical coherence tomography (OCT) and fluorescein angiography. Pattern and full-field electroretinograms (PERG; ERG) and serial electrooculograms (EOG) were performed, incorporating the international standards. RESULTS: A 45-year-old Caucasian woman developed blurring of vision in both eyes 5 days after a serious road traffic accident. On examination, bilateral serous macular detachments and multiple small yellow subretinal lesions were observed in both eyes associated with areas of serous retinal detachment superior and inferior to the yellow lesions in the left eye. OCT showed retinal elevation with a band of high reflectance on the outer retina but no intra-retinal fluid or elevation of the retinal pigment epithelium (RPE). There was bilateral EOG reduction in keeping with generalised RPE dysfunction and pattern ERG evidence of left macular involvement. After 9 months, the patient reported spontaneous improvement in vision with gravitational settling and coalescence of the subretinal yellow deposits. At 37 months, there was improvement in the EOG and visual acuity. CONCLUSIONS: A rare case of AEPVM is described that was detected following trauma and which gradually improved over 37 months. The EOG showed evidence of generalised RPE dysfunction that resolved and may be useful in the monitoring of AEPVM. PMID- 24052226 TI - Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients (AIONID) study: results of the pilot-feasibility, double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Low serum albumin is common and associated with protein-energy wasting, inflammation, and poor outcomes in maintenance hemodialysis (MHD) patients. We hypothesized that in-center (in dialysis clinic) provision of high protein oral nutrition supplements (ONS) tailored for MHD patients combined with anti-oxidants and anti-inflammatory ingredients with or without an anti inflammatory appetite stimulator (pentoxifylline, PTX) is well tolerated and can improve serum albumin concentration. METHODS: Between January 2008 and June 2010, 84 adult hypoalbuminemic (albumin <4.0 g/dL) MHD outpatients were double-blindly randomized to receive 16 weeks of interventions including ONS, PTX, ONS with PTX, or placebos. Nutritional and inflammatory markers were compared between the four groups. RESULTS: Out of 84 subjects (mean +/- SD; age, 59 +/- 12 years; vintage, 34 +/- 34 months), 32 % were Blacks, 54 % females, and 68 % diabetics. ONS, PTX, ONS plus PTX, and placebo were associated with an average change in serum albumin of +0.21 (P = 0.004), +0.14 (P = 0.008), +0.18 (P = 0.001), and +0.03 g/dL (P = 0.59), respectively. No related serious adverse events were observed. In a predetermined intention-to-treat regression analysis modeling post-trial serum albumin as a function of pre-trial albumin and the three different interventions (ref = placebo), only ONS without PTX was associated with a significant albumin rise (+0.17 +/- 0.07 g/dL, P = 0.018). CONCLUSIONS: In this pilot-feasibility, 2 * 2 factorial, placebo-controlled trial, daily intake of a CKD-specific high protein ONS with anti-inflammatory and anti-oxidative ingredients for up to 16 weeks was well tolerated and associated with slight but significant increase in serum albumin levels. Larger long-term controlled trials to examine hard outcomes are indicated. PMID- 24052227 TI - Enhancing dissolved oxygen control using an on-line hybrid fuzzy-neural soft sensing model-based control system in an anaerobic/anoxic/oxic process. AB - An on-line hybrid fuzzy-neural soft-sensing model-based control system was developed to optimize dissolved oxygen concentration in a bench-scale anaerobic/anoxic/oxic (A(2)/O) process. In order to improve the performance of the control system, a self-adapted fuzzy c-means clustering algorithm and adaptive network-based fuzzy inference system (ANFIS) models were employed. The proposed control system permits the on-line implementation of every operating strategy of the experimental system. A set of experiments involving variable hydraulic retention time (HRT), influent pH (pH), dissolved oxygen in the aerobic reactor (DO), and mixed-liquid return ratio (r) was carried out. Using the proposed system, the amount of COD in the effluent stabilized at the set-point and below. The improvement was achieved with optimum dissolved oxygen concentration because the performance of the treatment process was optimized using operating rules implemented in real time. The system allows various expert operational approaches to be deployed with the goal of minimizing organic substances in the outlet while using the minimum amount of energy. PMID- 24052228 TI - Cloning, expression of a feruloyl esterase from Aspergillus usamii E001 and its applicability in generating ferulic acid from wheat bran. AB - A cDNA gene (AufaeA), which encodes a mature polypeptide of the type-A feruloyl esterase from Aspergillus usamii E001 (abbreviated to AuFaeA), was cloned and heterologously expressed in Pichia pastoris GS115. One transformant, labeled as P. pastoris GSFaeA4-8, expressing the highest recombinant AuFaeA (reAuFaeA) activity of 10.76 U/ml was selected by the flask expression test. The expressed reAuFaeA was purified to homogeneity with an apparent molecular weight of 36.0 kDa by SDS-PAGE analysis, and characterized using the model substrate of methyl ferulate (MFA). The purified reAuFaeA was optimally active at pH 5.0 and 45 degrees C, and highly stable at pH 4.0-6.5 and 45 degrees C or below. Its activity was not significantly affected by metal ions tested and EDTA. The K m and V max of reAuFaeA towards MFA were 4.64 mM and 115.5 U/mg, respectively. High performance liquid chromatography analysis showed that only 9.7 % of total alkali extractable ferulic acid (FA) was released from destarched wheat bran by reAuFaeA alone. The released FA increased to 36.5 % when reAuFaeA was used together with a recombinant Aspergillus usamii GH family 11 xylanase A, indicating a synergistic interaction between them. PMID- 24052229 TI - Butyric acid-induced rat jugular blood cytosolic oxidative stress is associated with SIRT1 decrease. AB - Butyric acid (BA) induces jugular blood mitochondrial oxidative stress, whereas heme-induced oxidative stress was previously reported to inhibit SIRT1 in vitro. This would imply that BA-induced oxidative stress may similarly affect SIRT1. Here, we elucidated the BA effects on jugular blood cytosolic oxidative stress and SIRT1. Jugular blood cytosol was collected 0, 60, and 180 min after BA injection into rat gingival tissues and used throughout the study. Blood cytosolic oxidative stress induction, heme accumulation, NADPH oxidase (NOX) activation, nicotinamide adenine dinucleotide (NAD(+)) and NADP pool levels, NAD kinase (NADK), and SIRT1 amounts were determined. We found that BA retention in the gingival tissue induces blood cytosolic oxidative stress and heme accumulation which we correlated to both NOX activation and NADP pool increase. Moreover, we showed that BA-related NADP pool build-up is associated with NADK increase which we suspect decreased NAD(+) levels and consequentially lowered SIRT1 amounts in the rat blood cytosol. PMID- 24052230 TI - hABCF3, a TPD52L2 interacting partner, enhances the proliferation of human liver cancer cell lines in vitro. AB - In the present study, we characterized an evolutionarily conserved non transmembrane ATP-binding cassette protein: hABCF3. Subcellular immunofluorescence staining demonstrated that hABCF3 localizes preferentially in cytoplasm, unlike its paralog protein hABCF1, which localizes in both cytoplasm and nucleus. Quantitative realtime PCR analysis revealed that hABCF3 is expressed in all tissues examined, with high expression level in heart, liver, and pancreas. Interestingly, ectopic hABCF3 promoted proliferation of human liver cancer cell lines. Moreover, knock down of hABCF3 protein expression by siRNA inhibited cell proliferation. In addition, we identified TPD52L2 (Tumor Protein D52-like 2) as a hABCF3 interacting protein via yeast two-hybrid. This interaction was further confirmed by in vivo co-immunoprecipitation and co localization assays. Furthermore, we identified the interactional region of hABCF3 to be the first 200 amino acids uncharacterized region. Notably, the truncated version of hABCF3, which lacks the TPD52L2 binding region, remarkably impaired hABCF3-mediated cell proliferation. Taken together, these findings suggest that hABCF3 positively regulates cell proliferation, at least partially through the interaction with a tumor protein D52 protein family member: TPD52L2. PMID- 24052231 TI - Construction and application of the vectors to identify genes encoding exported proteins of Escherichia coli. AB - In order to clone genes having signal sequences of Escherichia coli, four vectors with or without Lac or Ara promoter were constructed using a leaderless beta lactamase as reporter. Fragments of tetracycline resistance gene (Tet) with or without promoter were used to confirm the vectors' ability to clone and report signal sequences. The minimum inhibitory concentration of ampicillin of the transformants was measured to detect the expression and secretion efficiency of the vectors. The results showed that the beta-lactamase could be co-expressed and secreted with Tet protein. The Lac or Ara promoter in the vectors could be regulated by different inducers, and the Ara promoter showed higher regulative efficiency than the Lac. The best induction dose of L-arabinose for the Ara promoter is 1.25 %. All the four vectors were stably maintained in host after being inoculated for 20 passages in antibiotics-free media. Genomic library of an avian pathogenic strain, E. coli O2, was constructed using the pMB-Ara-T vector we developed. 318 clones were obtained from the genomic library of E. coli strain O2, and the inserts in these clones represented 276 genes based on sequence analysis. Among the 276 cloned fragments, only 128 had complete promoter sequence. For the 128 fragments with promoter, only 27 could be expressed under LB culture condition without inducer, the other 101 were only expressed under induction. The results showed our constructed vectors could efficiently capture all kinds of exported protein genes in vitro, including the ones without promoter or with inactive promoter. PMID- 24052232 TI - Adenovirus conducted connective tissue growth factor on extracellular matrix in trabecular meshwork and its role on aqueous humor outflow facility. AB - Deposition of extracellular matrix (ECM) in trabecular meshwork, such as fibronectin, collagen IV, elastin. leads to increased resistance of trabecular meshwork in primary open angle glaucoma (POAG). Connective tissue growth factor (CTGF) is known to regulate the ECM deposits. In this study, we detect the effect of adenovirus conducted CTGF (Adv-CTGF) transfection on either the expression of ECM components or aqueous humor outflow facility. Adv-CTGF was used to transfect rat trabecular meshwork cells in vivo and in vitro. Aqueous humor outflow facility was test by microbeads perfusion. Protein expression of CTGF, fibronectin, and collagen IV was determined using Western blot. In the Adv-CTGF group, the outflow facility displayed a significant decrease from baseline. It appears as though the transfection with Adv-CTGF significantly affects the aqueous humor outflow pattern. A negative correlation between IOP and PEFL indicated that a decrease in the area of bead deposition corresponded to an overall decrease of outflow, leading to an elevated IOP. Adv-CTGF can enhance the expression of CTGF, fibronectin and collagen IV. CTGF is the novel target for treatment of POAG. It is necessary to further study to test inhibition of CTGF expression for treatment of POAG. PMID- 24052233 TI - Characterization of microRNA expression profiles in 3T3-L1 adipocytes overexpressing C10orf116. AB - Our data in the previous report demonstrated that C10orf116 (AFRO) is an adipocyte lineage-specific nuclear factor that can modulate the master adipogenesis transcription factors early during differentiation. However, more precise functional properties of this gene need to be clarified and await further investigation. Therefore, in this study, we performed an expression profile of cellular MicroRNAs (miRNAs) in the C10orf116 overexpression 3T3-L1 adipocytes and performed target prediction and functional enrichment of the differentially expressed miRNAs. Our study identified 34 miRNAs up-regulated in the 3T3-L1 adipocytes stably overexpressing C10orf116, whereas 43 miRNAs up-regulated in the control cells. The target genes of differentially expressed miRNAs were found to be involved in multiple signalling pathways, such as Wnt, TGF-beta, MAPK, Jak STAT, insulin signalling pathway, et al. Our data provided novel information for the identification of C10orf116. PMID- 24052234 TI - Efficient growth inhibition of EGFR over-expressing tumor cells by an anti-EGFR nanobody. AB - Epidermal growth factor receptor (EGFR) is deemed to be one of the main molecular targets for diagnosis and treatment of cancer. It has been identified that EGFR involves in pathogenesis of some forms of human cancers. Monoclonal antibodies targeting EGFR could control the tumor cell growth, proliferation, and apoptosis by suppressing the signal transduction pathways. Nanobodies can be regarded as the smallest intact antigen binding fragments, derived from heavy chain-only antibodies existing in camelids. Here, we describe the identification of an EGFR specific nanobody, referred to as OA-cb6, obtained from immunized camel with a cell line expressing high levels of EGFR. Utilizing flow cytometry (FACS) and blotting methods, we demonstrated that OA-cb6 nanobody binds specifically to EGFR expressing on the surface of A431 cells. In addition, OA-cb6 nanobody potently causes the inhibition of EGFR over expression, cell growth and proliferation. The antibody fragments can probably be regarded as worthwhile binding block for further rational design of anti-cancer therapy. PMID- 24052236 TI - Chondroitinase from baculovirus Bombyx mori nucleopolyhedrovirus and chondroitin sulfate from silkworm Bombyx mori. AB - Chondroitin sulfate (CS) is a linear polysaccharide composed of repeating disaccharide units of glucuronic acid (GlcUA) and N-acetyl-d-galactosamine (GalNAc) with sulfate groups at various positions. Baculovirus is an insect pathogenic virus that infects Lepidoptera larvae. Recently, we found that the occlusion-derived virus envelope protein 66 (ODV-E66) from Autographa californica nucleopolyhedrovirus (AcMNPV) exhibits chondroitin (CH)-digesting activity with distinct substrate specificity. Here, we demonstrate that the ODV-E66 protein from Bombyx mori nucleopolyhedrovirus (BmNPV) exhibits 92% homology to the amino acid sequence and 83% of the CH lyase activity of ODV-E66 from AcMNPV. ODV-E66 cleaves glycosyl bonds at nonreducing sides of disaccharide units consisting of nonsulfated and 6-O-sulfated GalNAc residues. We then investigated CS in the silkworm, Bombyx mori, which is the host of BmNPV. CS was present in insect tissues such as the midgut, peritrophic membrane, silk gland and skin. The polysaccharide consisted of a nonsulfated disaccharide unit, mono-sulfated disaccharide at Position 4 of the GalNAc residue and mono-sulfated disaccharide at Position 6 of the GalNAc residue. With regard to immunohistochemical analysis, the staining patterns of the silkworm tissues were different among anti-CS antibodies. Chondroitn sulfate that is digestible by ODV-E66 exists sufficiently in the peritrophic membrane protecting the midgut epithelium from ingested pathogens. Our results suggest that ODV-E66 facilitates the primary infection of the virus by digestion of CS in the peritrophic membrane. PMID- 24052235 TI - Idiopathic osteoporosis in men. AB - Over the last decade, the increasingly significant problem of osteoporosis in men has begun to receive much more attention than in the past. In particular, recent observations from large scale population studies in males led to an advance in the understanding of morphologic basis of growth, maintenance and loss of bone in men, as well as new insights about the pathophysiology and treatment of this disorder. While fracture risk consistently increases after age 65 in men (with up to 50 % of cases due to secondary etiologies), osteoporosis and fractures may also occur in young or middle aged males in the absence of an identifiable etiology. For this category (so called idiopathic osteoporosis), there are still major gaps in knowledge, particularly concerning the etiology and the clinical management. This article provides a summary of recent developments in the acquisition and maintenance of bone strength in men, as well as new insights about the pathogenesis, diagnosis, and treatment of idiopathic osteoporosis. PMID- 24052237 TI - Continuous irrigation around pancreatic remnant decreases pancreatic fistula related intraabdominal complications after distal pancreatectomy. AB - PURPOSE: To evaluate whether the technique of irrigation around pancreatic remnant after distal pancreatectomy (DP) can reduce the incidence of postoperative pancreatic fistula (PF) and its related intraabdominal complications. METHODS: In the retrospective clinical trial, the technique of irrigation around pancreatic remnant after DP was introduced. The clinical data of 60 patients who underwent the irrigation technique (irrigation group) and the other 65 patients who did not undergo the technique (non-irrigation group) were recorded, respectively. Preoperative clinicopathological features, intraoperative parameters, postoperative morbidity, clinically significant PF, and its related intraabdominal complications were compared between the two groups. RESULTS: The patency of irrigation tubes and drains was maintained in 59 patients. The overall incidence of PF was 31.2 %. There was no significant difference in the rate of PF between the two groups (P = 0.781), but the rate of PF-related intraabdominal complications was significantly lower in the irrigation group than that in the non-irrigation group (5 vs. 18, P = 0.005). The overall incidence of intraabdominal complications was significantly lower in the irrigation group than that in the non-irrigation group (23 vs. 39, P = 0.025). CONCLUSION: The technique of irrigation around pancreatic remnant after DP is a simple method for prevention of clinically significant PF and its related intraabdominal complications. PMID- 24052238 TI - Physicochemical quality evaluation of groundwater and development of drinking water quality index for Araniar River Basin, Tamil Nadu, India. AB - Groundwater is the most important natural resource which cannot be optimally used and sustained unless its quality is properly assessed. In the present study, the spatial and temporal variations in physicochemical quality parameters of groundwater of Araniar River Basin, India were analyzed to determine its suitability for drinking purpose through development of drinking water quality index (DWQI) maps of the post- and pre-monsoon periods. The suitability for drinking purpose was evaluated by comparing the physicochemical parameters of groundwater in the study area with drinking water standards prescribed by the World Health Organization (WHO) and Bureau of Indian Standards (BIS). Interpretation of physicochemical data revealed that groundwater in the basin was slightly alkaline. The cations such as sodium (Na(+)) and potassium (K(+)) and anions such as bicarbonate (HCO3 (-)) and chloride (Cl(-)) exceeded the permissible limits of drinking water standards (WHO and BIS) in certain pockets in the northeastern part of the basin during the pre-monsoon period. The higher total dissolved solids (TDS) concentration was observed in the northeastern part of the basin, and the parameters such as calcium (Ca(2+)), magnesium (Mg(2+)), sulfate (SO4 (2-)), nitrate (NO3 (-)), and fluoride (F(-)) were within the limits in both the seasons. The hydrogeochemical evaluation of groundwater of the basin demonstrated with the Piper trilinear diagram indicated that the groundwater samples of the area were of Ca(2+)-Mg(2+)-Cl(-)-SO4 (2-), Ca(2+)-Mg(2+)-HCO3 (-) and Na(+)-K(+)-Cl(-)-SO4 (2-) types during the post-monsoon period and Ca(2+) Mg(2+)-Cl(-)-SO4 (2-), Na(+)-K(+)-Cl(-)-SO4 (2-) and Ca(2+)-Mg(2+)-HCO3 (-) types during the pre-monsoon period. The DWQI maps for the basin revealed that 90.24 and 73.46% of the basin area possess good quality drinking water during the post- and pre-monsoon seasons, respectively. PMID- 24052239 TI - Evaluation of diffusive gradients in thin films technique (DGT) for measuring Al, Cd, Co, Cu, Mn, Ni, and Zn in Amazonian rivers. AB - Studies concerning the lability and bioavailability of trace metals have played a prominent role in the search for contamination of water resources. This work describes the first application yet of the diffusive gradients in thin films technique (DGT) to the determination of the fraction of free plus labile metals in waters from the Amazon Basin. Due to the complexity of the use of DGT for samples with low ionic strength and high organic matter content (characteristic of Amazonian rivers), a new analytical procedure was developed. The method is based on the determinations of apparent diffusion coefficients (Dap) in the laboratory, by performing deployments in samples collected in the corresponding sites of study. The Dap thereby determined is then used for in situ measurements. The suitability of the proposed approach for determination of labile Al, Cd, Co, Cu, Mn, Ni, and Zn in the Amazon River and Rio Negro (English: Black River) was evaluated. Except for Co, Mn (in a deployment at Rio Negro), Ni and Zn (in a deployment at Amazon River), labile in situ measurements were lower or similar to dissolved concentrations, indicating suitability of the proposed approach. PMID- 24052240 TI - Construction of an in vivo human spinal cord atlas based on high-resolution MR images at cervical and thoracic levels: preliminary results. AB - OBJECT: Our goal was to build a probabilistic atlas and anatomical template of the human cervical and thoracic spinal cord (SC) that could be used for segmentation algorithm improvement, parametric group studies, and enrichment of biomechanical modelling. MATERIALS AND METHODS: High-resolution axial T2* weighted images were acquired at 3T on 15 healthy volunteers using a multi-echo gradient-echo sequence (1 slice per vertebral level from C1 to L2). After manual segmentation, linear and affine co-registrations were performed providing either inter-individual morphometric variability maps, or substructure probabilistic maps [CSF, white and grey matter (WM/GM)] and anatomical SC template. RESULTS: The larger inter-individual morphometric variations were observed at the thoraco lumbar levels and in the posterior GM. Mean SC diameters were in agreement with the literature and higher than post-mortem measurements. A representative SC MR template was generated and values up to 90 and 100% were observed on GM and WM probability maps. CONCLUSION: This work provides a probabilistic SC atlas and a template that could offer great potentialities for parametrical MRI analysis (DTI/MTR/fMRI) and group studies, similar to what has already been performed using a brain atlas. It also offers great perspective for biomechanical models usually based on post-mortem or generic data. Further work will consider integration into an automated SC segmentation pipeline. PMID- 24052241 TI - Improved short tau inversion recovery (iSTIR) for increased tumor conspicuity in the abdomen. AB - OBJECT: To develop an improved short tau inversion recovery (iSTIR) technique with simultaneous suppression of fat, blood vessels and fluid to increase tumor conspicuity in the abdomen for cancer screening. MATERIALS AND METHODS: An adiabatic spectrally selective inversion pulse was used for fat suppression to overcome the reduced signal to noise ratio associated with chemically non selective inversion pulse of STIR. A motion-sensitizing driven equilibrium was used for blood vessel suppression and a dual-echo single-shot fast spin echo acquisition was used for fluid suppression. The technique was optimized on four normal subjects and later tested on five patients referred for metastatic tumor evaluation. RESULTS: A velocity encoding of 2 cm/s achieved effective blood suppression even in small vessels. Subtraction of two images (one with 60 ms and the other with 280 ms echo time) acquired in the same echo train achieved excellent fluid suppression (>70% reduction). Simultaneous suppression of fat, blood vessels and fluid improved the tumor conspicuity compared to corresponding fat-suppressed (STIR) image. CONCLUSION: This technique generated two complementary images from a single scan: one that is equivalent to a STIR image and the other that qualitatively resembles a diffusion-weighted image and may have potential for magnetic resonance imaging cancer screening. PMID- 24052242 TI - Pituitary incidentalomas. AB - INTRODUCTION: Incidentally discovered pituitary adenomas are more and more commonly encountered in endocrinology and neurosurgical practices. Often they present as difficult problems in management strategies. This review summarizes the latest evidence and opinions in a variety of settings in which incidental pituitary tumors are discovered, including subclinical pituitary tumor apoplexy. METHODS: A systematic literature review was accomplished using a spectrum of contemporary sources for information regarding pituitary incidentalomas. RESULTS: Up to date findings regarding epidemiology, definition of pituitary incidentaloma, patient evaluation, diagnostic studies, and management are presented. CONCLUSIONS: Current experience from a multidisciplinary pituitary center is presented, with indications for treatment and longitudinal care of these challenging patients. PMID- 24052243 TI - Patient-focussed outcomes in acromegaly. AB - BACKGROUND: Health-related quality of life (QoL) is severely impaired in acromegaly due to the physical and psychological consequences of the disease. Pharmacological and surgical treatments, when available, can improve QoL and life expectancy. CASE DESCRIPTION: A 34-year-old male with uncontrolled acromegaly due to a large and invasive macroadenoma, which could not be resected by transsphenoidal surgery. Over 9 years, he had limited access to pharmacological interventions and persisted with clinically and biochemically active disease, with severe co-morbidities and a poor QoL, which eventually lead to a premature sudden death. CONCLUSION: This case highlights the impact that active acromegaly has when treatment resources are limited. We review the factors contributing to poor QoL in this disease, with special reference to the Latin American scenario. PMID- 24052245 TI - FLAIR fornix hyperintensity in VGKC-related autoimmune encephalitis. PMID- 24052244 TI - Quantitative and qualitative evaluation tool in planning stroke treatment strategies: the "Safe implementation of treatments in stroke Monitoring Study (SITS MOST)" registry. AB - A decade ago, stroke was the first leading cause of morbidity and mortality in Croatia. Nowadays, we record reduction in stroke incidence, as well as stroke consequences-invalidity and mortality. These are due to long-term planned actions in the field of public health as well as actions performed by professional organizations. Today, we can be satisfied with improvement in that field, but there are still things we can improve, at the first place improvement of the emergency medicine network due to Croatian-specific topographical characteristics to reduce onset-to-door time. In this paper, we evaluated results from 11 Croatian hospitals in the period 11/2005-11/2012. To find out about the past and present state in applying thrombolytic therapy in Croatia and to plan further actions in light of new studies and efforts in Europe and in the world, all with the aim of improvement in stroke prevention and acute treatment resulting in reduction of stroke morbidity, mortality and symptomatic intracerebral hemorrhage as well as better functional outcome. Our results have shown that we improved stroke treatment in the last decade, but further actions should be performed to raise public stroke awareness and to improve emergency medicine network as well as in hospital protocols. PMID- 24052246 TI - Spontaneous low cerebrospinal fluid pressure headaches revealed by a unilateral subdural hematoma. PMID- 24052247 TI - Microglial inhibitory effect of ginseng ameliorates cognitive deficits and neuroinflammation following traumatic head injury in rats. AB - Traumatic brain injury produces several neuropathological alterations, some of them are analogous to patients suffering from memory disorders. Role of neuroinflammation and oxidative stress has been suggested in the pathophysiology of brain injury-induced cognitive dysfunction. Therefore, the present study was designed to explore the possible role of ginseng and its interaction with minocycline (microglial inhibitor) against experimental brain trauma-induced behavioral, biochemical and molecular alterations. Wistar rats were exposed to brain traumatic injury using weight-drop method. Following injury and a post injury rehabilitation period of 2 weeks, animals were administered vehicle/drugs for another 2 weeks. Brain injury caused significant memory impairment in Morris water maze task as evident from increase in escape latency and total distance travelled to reach the hidden platform. This was followed by a significant decrease in time spent in target quadrant and frequency of appearance in target quadrant. Further, there was a significant increase in oxidative stress markers, neuroinflammation (TNF-alpha and IL-6) and acetylcholinesterase levels in both cortex and hippocampal regions of traumatized rat brain. Ginseng (100 and 200 mg/kg) and minocycline (50 mg/kg) treatment for 2 weeks significantly attenuated all these behavioral, biochemical and molecular alterations. Further, combination of sub-effective doses of ginseng (50 and 100 mg/kg) and minocycline (25 mg/kg) potentiated their protective effects which was significant as compared to their effects alone. The results of the present study suggest that the therapeutic effects of ginseng might involve inhibition of microglial pathway against head trauma-induced cognitive impairment and neuroinflammation in rats. PMID- 24052248 TI - Relative frequency of chronic postoperative pain in patients operated for chronic otitis media. AB - Chronic postoperative pain may lead to physical disability and psychosocial distress. In this longitudinal observational study, for the first time we evaluated the relative frequency of chronic postoperative pain in patients operated for chronic otitis media (COM) at two university hospitals. Patients were questioned about pain at the site of the surgical incision 3-6 months after the operation, and again 3 months after the first visit. Pain intensity was quantified by visual analogue scale (VAS). T test, Chi-square test, and logistic regression were used for analyzing data and multivariate analysis. In 155 patients (42 male, 113 female, mean age: 38.57 +/- 10.66 years), chronic postoperative pain was observed in 50 cases (32.3 %). A significant decrease in the average score of VAS was observed from 5.18 to 2.64 within 3 months (P = 0.0001). Statistically significant correlation was observed between chronic postoperative pain and age, sex, acute postoperative pain and history of Irritable Bowel Syndrome or migraine, but after multivariate analysis, only the age group and severe acute post-operation pain were effective on incidence of chronic post-operative pain. In conclusion, surgery for COM is followed by chronic pain in about 32 % of patients, and some risk factors for the development of chronic postoperative pain after this surgery exist, including age and severe acute post-operation pain. PMID- 24052249 TI - Hypotensive anaesthesia and bleeding during endoscopic sinus surgery: an observational study. AB - Significant bleeding during functional endoscopic naso-sinusal surgery (FESS) impairs recognition of anatomical references and may negatively affect surgical outcome. Through their hypotensive effect, adjuvant anaesthetic agents may influence intraoperative bleeding. The present study compared intraoperative bleeding in patients undergoing FESS administered a clonidine-based anaesthetic regimen and in patients receiving other an anaesthetic combination with higher acquisition costs. Prospective observational study included 37 subjects undergoing FESS in 2011. Assessment of intraoperative bleeding was according to type of anaesthesia (clonidine vs. opioid derivatives). Patients receiving clonidine (N = 11; 29.7%) presented significantly lower surgical field bleeding scores than those receiving opioid derivatives (N = 26; 70.3%) [mean (SD) Boezaart scores 1.91 (0.53) vs. 2.92 (0.79), p < 0.0001]. The multivariate analysis including baseline characteristics and risk factors related to bleeding intensity showed that the type of drug used for controlled hypotensive anaesthesia was the best predictor of bleeding during FESS, with an OR of 0.03 for clonidine based vs. opioid based anaesthesia (p = 0.014). The anaesthetic combination including clonidine for controlled hypotensive anaesthesia produces lower levels of surgical field bleeding during FESS. Compared with other hypotensive anaesthetics, clonidine is inexpensive and associated with better surgical conditions during FESS. If confirmed through randomized clinical trials, the use of clonidine during FESS can reduce surgical time and improve surgical results through a less bloody field, resulting in lower patient morbidity and improvement of operating room resources. PMID- 24052250 TI - Outcomes of endonasal endoscopic dacryocystorhinostomy after maxillectomy in patients with paranasal sinus and skull base tumors. AB - Maxillectomy followed by radiotherapy and/or chemotherapy can result in lacrimal blockage and the need for subsequent dacryocystorhinostomy (DCR). Endonasal endoscopic DCR, as opposed to external DCR, allows better accuracy and leaves no scar. To date no report was published regarding the results of endoscopic DCR in these patients. The current study presents a retrospective review of all patients with paranasal and skull base tumors who developed nasolacrimal duct blockage after ablative maxillectomy with or without radiotherapy and/or chemotherapy and underwent endonasal endoscopic DCR between January 2006 and October 2012 in a tertiary reference medical center. According to our results, ten patients underwent 11 subsequent endonasal endoscopic DCR. There were 6 men and 4 women with a median age of 55 years (range, 19-81 years); four suffered from benign tumors and six had malignant tumors. All underwent maxillectomy. Six received high-dose radiotherapy. Time interval between primary ablative surgery and endonasal endoscopic DCR was 18 months (range, 7-118 months). Silicone stents were removed after median period of 11 weeks (range, 1-57 weeks). Nine out of ten patients experienced symptomatic improvement following one endonasal endoscopic DCR. One patient had recurrent epiphora and underwent a successful endonasal endoscopic revision DCR. In conclusion, endonasal endoscopic DCR in patients with paranasal and skull base tumors, who previously underwent maxillectomy, is generally successful and not associated with a high rate of complications or failure. Moreover, our findings may suggest that silicone stents can be removed shortly after the operation with high success rate. PMID- 24052251 TI - Idiopathic vs. secondary retroperitoneal fibrosis: a clinicopathological study of 12 cases, with emphasis to possible relationship to IgG4-related disease. AB - Retroperitoneal fibrosis (RF) is a rare disease characterized by inflammation and fibrosis of retroperitoneal soft tissues. It is classified into two types: idiopathic (iRF) and secondary (sRF). The aim of the study was to investigate the relationship between iRF and IgG4-related disease (IgG4-RD) and to eventually extend the clinicopathological features of this condition by analysis of the sample comprising six iRF and six sRF patients. The iRF patients included four males and two females, aged 12-62 years (median 55 years). Two lesions were periaortic, one was periureteral, and three cases showed both periaortic and periureteral localization. Two patients had increased serum levels of IgG4. None of the patients developed any manifestation of IgG4-RD during the follow-up period ranging for 15-133 months (median 43 months). Microscopically, in two iRF cases, fibrosis was highly cellular encircling the vessels, nerves, and paraganglia. Phlebitis was found in all cases and being obliterative in four. Lymphocytic inflammation with formation of follicles and plasma cell infiltration were scored as severe in five iRF cases. The numbers of IgG-positive plasma cells ranged 0-373 per 1 HPF (high power field; median 132) and of IgG4-positive plasma cells 0-238 per 1 HPF (median 91). The IgG4/IgG ratio values ranged 0.38-0.74 (median 0.68). Two of the iRF cases were diagnosed as definite and three cases as probable IgG4-RD. To the contrary, none of the sRF cases met the diagnostic criteria for either definite, probable, or possible IgG4-related disease. Our results indicate that a substantial portion of iRF cases, including some of very rare pediatric cases, is a manifestation of IgG4-RD. PMID- 24052252 TI - Fracture behavior of zirconia implant abutments is influenced by superstructure geometry. AB - OBJECTIVES: The purpose of this in vitro study was to evaluate the influence of the superstructure-geometry on the fracture behavior of zirconia abutments (Compartis, DeguDent GmbH, Hanau, G). MATERIALS AND METHODS: Four different groups (n = 8) representing anterior single crown replacement were prepared. In groups 1 and 2, the implants were restored with customized all-ceramic abutments and anatomically shaped crowns (chromium cobalt alloy). Groups 3 and 4 received crowns with a geometry according to the international standard ISO 14801 (dynamic fatigue test for endosseous dental implants) with a spherical contact area. Groups 2 and 4 were subjected to mechanical aging in a chewing simulator (50 N * 1,200,000 cycles). Static loading until fracture was performed using a universal testing device at an angle of 30 degrees to the implant axis. Fracture patterns were analyzed using SEM. RESULTS: In group 2, only one specimen survived mechanical aging. In group 4, one specimen fractured during the chewing simulation. Groups 1 and 2 showed significantly lower load-bearing capacity than groups 3 and 4. Artificial aging did not influence the fracture resistance. The SEM analysis revealed fatigue-related fracture patterns in those specimens, which failed during artificial aging. CONCLUSIONS: Drawing conclusions from ISO testing concerning clinical performance appears to be critical as anatomic superstructure geometries induce different fracture behaviors. CLINICAL RELEVANCE: ISO testing of zirconia abutments should be accompanied by load-bearing capacity testing under simulated clinical conditions to predict clinical performance. PMID- 24052253 TI - Reproducibility of mandibular third molar assessment comparing two cone beam CT units in a matched pairs design. AB - The aim of this study was to evaluate the reproducibility of the third molar assessment, comparing five observers and two cone beam CT (CBCT) units. 28 patients, each with two impacted mandibular third molars, were included. Each patient was randomly examined with a Scanora((r)) 3D (Soredex, Helsinki, Finland) CBCT unit in one mandibular third molar region and with a Cranex((r)) 3D (Soredex) CBCT unit in the other region. Five observers with varying CBCT experience assessed all third molars and recorded the following variables: number and morphology of the roots, relation to the mandibular canal in two directions, shape of the canal and whether there was a direct contact between the roots of the molar and the mandibular canal. The radiographic assessments were compared pairwise among all observers for all variables. Wilcoxon's signed-rank test was used to test the differences in observer accordance percentages among the recorded variables in the images from the two units, and kappa statistics expressed interobserver reproducibility. The mean percentages for observer accordance ranged from 65.4 to 92.9 for Scanora 3D and 60.3 to 94.8 for Cranex 3D. There was no significant difference between the observer accordance in the two CBCT units (p > 0.05), except for assessing root flex in the mesiodistal direction, for which the observer accordance was higher for Scanora 3D (p < 0.05). Kappa values ranged from 0.1 to 1.0 for Scanora 3D and from 0.2 to 0.9 for Cranex 3D. For the variable "direct contact", the interobserver reproducibility was excellent for the two trained radiologists. The two units had almost similar interobserver reproducibility for mandibular third molar assessment. Observer variation existed, and experienced radiologists demonstrated the highest interobserver reproducibility for canal-related variables. PMID- 24052254 TI - "Black Bone" MRI: a potential non-ionizing method for three-dimensional cephalometric analysis--a preliminary feasibility study. AB - OBJECTIVES: CT offers a three-dimensional solution to the inaccuracies associated with lateral cephalogram-based cephalometric analysis. However, it is associated with significant concerns regarding ionizing radiation exposure. MRI offers a non ionizing alternative, but this has been less well investigated. We present a novel gradient echo MRI sequence ("Black Bone") and highlight the potential of this sequence in cephalometric analysis. METHODS: After regional ethics approval, "Black Bone" imaging was obtained in eight patients in whom lateral cephalograms were available. "Black Bone", T1 and T2 weighted spin echo imaging were obtained in the mid-sagittal plane, and measurements were compared with those obtained on the lateral cephalogram using both the Advantage Windows Workstation (GE Medical Systems, Buckinghamshire, UK) and the Dolphin((r)) cephalometric software (v. 11.5.04.23, Premium; Dolphin Imaging, Chatsworth, CA) by one assessor. Further assessment was made by scoring the ease of landmark identification on a ten-point scale. RESULTS: "Black Bone" imaging surpassed T1 and T2 weighted imaging in terms of cephalometric landmark identification. A number of mid-sagittal cephalometric landmarks could not be clearly identified on T2 weighted imaging, making analysis impossible. Measurements on "Black Bone" demonstrated the smallest discrepancy when compared with those obtained on the lateral cephalogram. The discrepancy seen between measurements completed on mid-sagittal MRI and the lateral cephalogram was compounded by inherent inaccuracies of the lateral cephalogram. The overall mean discrepancy between distance measurements on "Black Bone" imaging and those on the lateral cephalogram was 1-2 mm. CONCLUSIONS: Overall, "Black Bone" MRI offered an improved method of cephalometric landmark identification over routine MRI sequences, and provides a potential non-ionizing alternative to CT for three-dimensional cephalometrics. PMID- 24052255 TI - Reduction of synaptojanin 1 accelerates Abeta clearance and attenuates cognitive deterioration in an Alzheimer mouse model. AB - Recent studies link synaptojanin 1 (synj1), the main phosphoinositol (4,5) biphosphate phosphatase (PI(4,5)P2-degrading enzyme) in the brain and synapses, to Alzheimer disease. Here we report a novel mechanism by which synj1 reversely regulates cellular clearance of amyloid-beta (Abeta). Genetic down-regulation of synj1 reduces both extracellular and intracellular Abeta levels in N2a cells stably expressing the Swedish mutant of amyloid precursor protein (APP). Moreover, synj1 haploinsufficiency in an Alzheimer disease transgenic mouse model expressing the Swedish mutant APP and the presenilin-1 mutant DeltaE9 reduces amyloid plaque load, as well as Abeta40 and Abeta42 levels in hippocampus of 9 month-old animals. Reduced expression of synj1 attenuates cognitive deficits in these transgenic mice. However, reduction of synj1 does not affect levels of full length APP and the C-terminal fragment, suggesting that Abeta generation by beta- and gamma-secretase cleavage is not affected. Instead, synj1 knockdown increases Abeta uptake and cellular degradation through accelerated delivery to lysosomes. These effects are partially dependent upon elevated PI(4,5)P2 with synj1 down regulation. In summary, our data suggest a novel mechanism by which reduction of a PI(4,5)P2-degrading enzyme, synj1, improves amyloid-induced neuropathology and behavior deficits through accelerating cellular Abeta clearance. PMID- 24052256 TI - Protein phosphatase 2A isoforms utilizing Abeta scaffolds regulate differentiation through control of Akt protein. AB - Protein phosphatase 2A (PP2A) regulates almost all cell signaling pathways. It consists of a scaffolding A subunit to which a catalytic C subunit and one of many regulatory B subunits bind. Of the more than 80 PP2A isoforms, 10% use Abeta as a scaffold. This study demonstrates the isoform-specific function of the A scaffold subunits. Polyomaviruses have shown the importance of phosphotyrosine, PI3K, and p53 in transformation. Comparisons of polyoma and SV40 small T antigens implicate Abeta in the control of differentiation. Knockdown of Abeta enhanced differentiation. Akt signaling regulated differentiation; its activation or inhibition promoted or blocked it, respectively. Abeta bound Akt. Enhancement of PP2A Abeta/Akt interaction by polyoma small T antigen increased turnover of Akt Ser-473 phosphorylation. Conversely, knockdown of Abeta promoted Akt activity and reduced turnover of phosphate at Ser-473 of Akt. These data provide new insight into the regulation of Akt, a protein of extreme importance in cancer. Furthermore, our results suggest that the role for Abeta in differentiation and perhaps tumor suppression may lie partly in its ability to negatively regulate Akt. PMID- 24052257 TI - Replacement of the catalytic nucleophile aspartyl residue of dextran glucosidase by cysteine sulfinate enhances transglycosylation activity. AB - Dextran glucosidase from Streptococcus mutans (SmDG) catalyzes the hydrolysis of an alpha-1,6-glucosidic linkage at the nonreducing end of isomaltooligosaccharides and dextran. This enzyme has an Asp-194 catalytic nucleophile and two catalytically unrelated Cys residues, Cys-129 and Cys-532. Cys-free SmDG was constructed by replacement with Ser (C129S/C532S (2CS), the activity of which was the same as that of the wild type, SmDG). The nucleophile mutant of 2CS was generated by substitution of Asp-194 with Cys (D194C-2CS). The hydrolytic activity of D194C-2CS was 8.1 * 10(-4) % of 2CS. KI-associated oxidation of D194C-2CS increased the activity up to 0.27% of 2CS, which was 330 times higher than D194C-2CS. Peptide-mapping mass analysis of the oxidized D194C 2CS (Ox-D194C-2CS) revealed that Cys-194 was converted into cysteine sulfinate. Ox-D194C-2CS and 2CS shared the same properties (optimum pH, pI, and substrate specificity), whereas Ox-D194C-2CS had much higher transglucosylation activity than 2CS. This is the first study indicating that a more acidic nucleophile ( SOO(-)) enhances transglycosylation. The introduction of cysteine sulfinate as a catalytic nucleophile could be a novel approach to enhance transglycosylation. PMID- 24052258 TI - Neutrophil elastase and proteinase-3 trigger G protein-biased signaling through proteinase-activated receptor-1 (PAR1). AB - Neutrophil proteinases released at sites of inflammation can affect tissue function by either activating or disarming signal transduction mediated by proteinase-activated receptors (PARs). Because PAR1 is expressed at sites where abundant neutrophil infiltration occurs, we hypothesized that neutrophil-derived enzymes might also regulate PAR1 signaling. We report here that both neutrophil elastase and proteinase-3 cleave the human PAR1 N terminus at sites distinct from the thrombin cleavage site. This cleavage results in a disarming of thrombin activated calcium signaling through PAR1. However, the distinct non-canonical tethered ligands unmasked by neutrophil elastase and proteinase-3, as well as synthetic peptides with sequences derived from these novel exposed tethered ligands, selectively stimulated PAR1-mediated mitogen-activated protein kinase activation. This signaling was blocked by pertussis toxin, implicating a Galphai triggered signal pathway. We conclude that neutrophil proteinases trigger biased PAR1 signaling and we describe a novel set of tethered ligands that are distinct from the classical tethered ligand revealed by thrombin. We further demonstrate the function of this biased signaling in regulating endothelial cell barrier integrity. PMID- 24052259 TI - Crystal structures of beta-1,4-galactosyltransferase 7 enzyme reveal conformational changes and substrate binding. AB - The beta-1,4-galactosyltransferase 7 (beta4GalT7) enzyme is involved in proteoglycan synthesis. In the presence of a manganese ion, it transfers galactose from UDP-galactose to xylose on a proteoglycan acceptor substrate. We present here the crystal structures of human beta4GalT7 in open and closed conformations. A comparison of these crystal structures shows that, upon manganese and UDP or UDP-Gal binding, the enzyme undergoes conformational changes involving a small and a long loop. We also present the crystal structures of Drosophila wild-type beta4GalT7 and D211N beta4GalT7 mutant enzymes in the closed conformation in the presence of the acceptor substrate xylobiose and the donor substrate UDP-Gal, respectively. To understand the catalytic mechanism, we have crystallized the ternary complex of D211N beta4GalT7 mutant enzyme in the presence of manganese with the donor and the acceptor substrates together in the same crystal structure. The galactose moiety of the bound UDP-Gal molecule forms seven hydrogen bonds with the protein molecule. The nonreducing end of the xylose moiety of xylobiose binds to the hydrophobic acceptor sugar binding pocket created by the conformational changes, whereas its extended xylose moiety forms hydrophobic interactions with a Tyr residue. In the ternary complex crystal structure, the nucleophile O4 oxygen atom of the xylose molecule is found in close proximity to the C1 and O5 atoms of the galactose moiety. This is the first time that a Michaelis complex of a glycosyltransferase has been described, and it clearly suggests an SN2 type catalytic mechanism for the beta4GalT7 enzyme. PMID- 24052260 TI - The amidohydrolases IAR3 and ILL6 contribute to jasmonoyl-isoleucine hormone turnover and generate 12-hydroxyjasmonic acid upon wounding in Arabidopsis leaves. AB - Jasmonates (JAs) are a class of signaling compounds that mediate complex developmental and adaptative responses in plants. JAs derive from jasmonic acid (JA) through various enzymatic modifications, including conjugation to amino acids or oxidation, yielding an array of derivatives. The main hormonal signal, jasmonoyl-L-isoleucine (JA-Ile), has been found recently to undergo catabolic inactivation by cytochrome P450-mediated oxidation. We characterize here two amidohydrolases, IAR3 and ILL6, that define a second pathway for JA-Ile turnover during the wound response in Arabidopsis leaves. Biochemical and genetic evidence indicates that these two enzymes cleave the JA-Ile signal, but act also on the 12OH-JA-Ile conjugate. We also show that unexpectedly, the abundant accumulation of tuberonic acid (12OH-JA) after wounding originates partly through a sequential pathway involving (i) conjugation of JA to Ile, (ii) oxidation of the JA-Ile conjugate, and (iii) cleavage under the action of the amidohydrolases. The coordinated actions of oxidative and hydrolytic branches in the jasmonate pathway highlight novel mechanisms of JA-Ile hormone turnover and redefine the dynamic metabolic grid of jasmonate conversion in the wound response. PMID- 24052261 TI - FAD104, a regulatory factor of adipogenesis, acts as a novel regulator of calvarial bone formation. AB - Osteogenesis is a complex process that is orchestrated by several growth factors, extracellular cues, signaling molecules, and transcriptional factors. Understanding the mechanisms of bone formation is pivotal for clarifying the pathogenesis of bone diseases. Previously, we reported that fad104 (factor for adipocyte differentiation 104), a novel positive regulator of adipocyte differentiation, negatively regulated the differentiation of mouse embryonic fibroblasts into osteocytes. However, the physiological role of fad104 in bone formation has not been elucidated. Here, we clarified the role of fad104 in bone formation in vivo and in vitro. fad104 disruption caused craniosynostosis-like premature ossification of the calvarial bone. Furthermore, analyses using primary calvarial cells revealed that fad104 negatively regulated differentiation and BMP/Smad signaling pathway. FAD104 interacted with Smad1/5/8. The N-terminal region of FAD104, which contains a proline-rich motif, was capable of binding to Smad1/5/8. We demonstrated that down-regulation of Smad1/5/8 phosphorylation by FAD104 is dependent on the N-terminal region of FAD104 and that fad104 functions as a novel negative regulator of BMP/Smad signaling and is required for proper development for calvarial bone. These findings will aid a comprehensive description of the mechanism that controls normal and premature calvarial ossification. PMID- 24052263 TI - Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. AB - Mammalian sirtuins (SIRT1 through SIRT7) are members of a highly conserved family of NAD(+)-dependent protein deacetylases that function in metabolism, genome maintenance, and stress responses. Emerging evidence suggests that some sirtuins display substrate specificity toward other acyl groups attached to the lysine epsilon-amine. SIRT6 was recently reported to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups. Here we investigated the catalytic ability of all sirtuins to hydrolyze 13 different acyl groups from histone H3 peptides, ranging in carbon length, saturation, and chemical diversity. We find that long chain deacylation is a general feature of mammalian sirtuins, that SIRT1 and SIRT2 act as efficient decrotonylases, and that SIRT1, SIRT2, SIRT3, and SIRT4 can remove lipoic acid. These results provide new insight into sirtuin function and a means for cellular removal of an expanding list of endogenous lysine modifications. Given that SIRT6 is a poor deacetylase in vitro, but binds and prefers to hydrolyze long-chain acylated peptides, we hypothesize that binding of certain free fatty acids (FFAs) could stimulate deacetylation activity. Indeed, we demonstrate that several biologically relevant FFAs (including myristic, oleic, and linoleic acids) at physiological concentrations induce up to a 35-fold increase in catalytic efficiency of SIRT6 but not SIRT1. The activation mechanism is consistent with fatty acid inducing a conformation that binds acetylated H3 with greater affinity. Binding of long-chain FFA and myristoylated H3 peptide is mutually exclusive. We discuss the implications of discovering endogenous, small molecule activators of SIRT6. PMID- 24052262 TI - ASB2alpha, an E3 ubiquitin ligase specificity subunit, regulates cell spreading and triggers proteasomal degradation of filamins by targeting the filamin calponin homology 1 domain. AB - Filamins are actin-binding and cross-linking proteins that organize the actin cytoskeleton and anchor transmembrane proteins to the cytoskeleton and scaffold signaling pathways. During hematopoietic cell differentiation, transient expression of ASB2alpha, the specificity subunit of an E3-ubiquitin ligase complex, triggers acute proteasomal degradation of filamins. This led to the proposal that ASB2alpha regulates hematopoietic cell differentiation by modulating cell adhesion, spreading, and actin remodeling through targeted degradation of filamins. Here, we show that the calponin homology domain 1 (CH1), within the filamin A (FLNa) actin-binding domain, is the minimal fragment sufficient for ASB2alpha-mediated degradation. Combining an in-depth flow cytometry analysis with mutagenesis of lysine residues within CH1, we find that arginine substitution at each of a cluster of three lysines (Lys-42, Lys-43, and Lys-135) renders FLNa resistant to ASB2alpha-mediated degradation without altering ASB2alpha binding. These lysines lie within previously predicted actin binding sites, and the ASB2alpha-resistant filamin mutant is defective in targeting to F-actin-rich structures in cells. However, by swapping CH1 with that of alpha-actinin1, which is resistant to ASB2alpha-mediated degradation, we generated an ASB2alpha-resistant chimeric FLNa with normal subcellular localization. Notably, this chimera fully rescues the impaired cell spreading induced by ASB2alpha expression. Our data therefore reveal ubiquitin acceptor sites in FLNa and establish that ASB2alpha-mediated effects on cell spreading are due to loss of filamins. PMID- 24052264 TI - Dragon (repulsive guidance molecule RGMb) inhibits E-cadherin expression and induces apoptosis in renal tubular epithelial cells. AB - Dragon is one of the three members of the repulsive guidance molecule (RGM) family, i.e. RGMa, RGMb (Dragon), and RGMc (hemojuvelin). We previously identified the RGM members as bone morphogenetic protein (BMP) co-receptors that enhance BMP signaling. Our previous studies found that Dragon is highly expressed in the tubular epithelial cells of mouse kidneys. However, the roles of Dragon in renal epithelial cells are yet to be defined. We now show that overexpression of Dragon increased cell death induced by hypoxia in association with increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels in mouse inner medullary collecting duct (IMCD3) cells. Dragon also inhibited E-cadherin expression but did not affect epithelial-to-mesenchymal transition induced by TGF beta in IMCD3 cells. Previous studies suggest that the three RGM members can function as ligands for the receptor neogenin. Interestingly, our present study demonstrates that the Dragon actions on apoptosis and E-cadherin expression in IMCD3 cells were mediated by the neogenin receptor but not through the BMP pathway. Dragon expression in the kidney was up-regulated by unilateral ureteral obstruction in mice. Compared with wild-type mice, heterozygous Dragon knock-out mice exhibited 45-66% reduction in Dragon mRNA expression, decreased epithelial apoptosis, and increased tubular E-cadherin expression and had attenuated tubular injury after unilateral ureteral obstruction. Our results suggest that Dragon may impair tubular epithelial integrity and induce epithelial apoptosis both in vitro and in vivo. PMID- 24052265 TI - Structural analysis of a calmodulin variant from rice: the C-terminal extension of OsCaM61 regulates its calcium binding and enzyme activation properties. AB - OsCaM61 is one of five calmodulins known to be present in Oryza sativa that relays the increase of cytosolic [Ca(2+)] to downstream targets. OsCaM61 bears a unique C-terminal extension with a prenylation site. Using nuclear magnetic resonance (NMR) spectroscopy we studied the behavior of the calmodulin (CaM) domain and the C-terminal extension of OsCaM61 in the absence and presence of Ca(2+). NMR dynamics data for OsCaM61 indicate that the two lobes of the CaM domain act together unlike the independent behavior of the lobes seen in mammalian CaM and soybean CaM4. Also, data demonstrate that the positively charged nuclear localization signal region in the tail in apo-OsCaM61 is helical, whereas it becomes flexible in the Ca(2+)-saturated protein. The extra helix in apo-OsCaM61 provides additional interactions in the C-lobe and increases the structural stability of the closed apo conformation. This leads to a decrease in the Ca(2+) binding affinity of EF-hands III and IV in OsCaM61. In Ca(2+)-OsCaM61, the basic nuclear localization signal cluster adopts an extended conformation, exposing the C-terminal extension for prenylation or enabling OsCaM61 to be transferred to the nucleus. Moreover, Ser(172) and Ala(173), residues in the tail, interact with different regions of the protein. These interactions affect the ability of OsCaM61 to activate different target proteins. Altogether, our data show that the tail is not simply a linker between the prenyl group and the protein but that it also provides a new regulatory mechanism that some plants have developed to fine-tune Ca(2+) signaling events. PMID- 24052266 TI - Using network analysis to explore if professional opinions on Japanese encephalitis risk factors in Nepal reflect a socio-ecological system perspective. AB - Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia and a significant public health problem in Nepal. Its epidemiology is influenced by factors affecting its amplifying hosts (pigs), vectors (mosquitoes), and dead-end hosts (including people). While most control efforts target reduced susceptibility to infection either by vaccination of people or pigs or by reduced exposure to mosquitoes; the economic reality of Nepal makes it challenging to implement standard JE control measures. An ecohealth approach has been nominated as a way to assist in finding and prioritizing locally relevant strategies for JE control that may be viable, feasible, and acceptable. We sought to understand if Nepalese experts responsible for JE management conceived of its epidemiology in terms of a socio-ecological system to determine if they would consider ecohealth approaches. Network analysis suggested that they did not conceive JE risk as a product of a socio-ecological system. Traditional proximal risk factors of pigs, mosquitoes, and vaccination predominated experts' conception of JE risk. People seeking to encourage an ecohealth approach or social change models to JE management in Nepal may benefit from adopting social marketing concepts to encourage and empower local experts to examine JE from a socio-ecological perspective. PMID- 24052267 TI - Antidepressant combinations: cutting edge psychopharmacology or passing fad? AB - This article reviews the rationale for and history of combining antidepressants, as well as the current state of the evidence, in the treatment of major depression. Although it has long been suggested that some individuals may benefit from regimens that combine two dissimilar antidepressants, enthusiasm for this practice has waxed and waned and there was never a strong empirical foundation to support this practice. The tangibly better safety profiles of the newer generation antidepressants, both singly and in combination, have permitted greater use of such combinations in contemporary practice than ever before. Combinations that pair a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) with a dissimilar antidepressant, such as bupropion or mirtazapine, are now widely used for patients who have not responded to trials of first- or second-line antidepressant monotherapies and have been tested as a potential way of speeding the benefits of treatment. However, there still is no strong evidence that even the most widely used combinations have particular merit and clinicians should be mindful that alternatives exist with more established efficacy. Moreover, aside from selected cases of drug-drug interactions, it may take full therapeutic doses of both drugs across a typically adequate duration of exposure to achieve the desired effects of combined treatment. PMID- 24052268 TI - Structure analysis and characterization of the cytochrome c-554 from thermophilic green sulfur photosynthetic bacterium Chlorobaculum tepidum. AB - The cytochrome (Cyt) c-554 in thermophilic green photosynthetic bacterium Chlorobaculum tepidum serves as an intermediate electron carrier, transferring electrons to the membrane-bound Cyt c z from various enzymes involved in the oxidations of sulfide, thiosulfate, and sulfite compounds. Spectroscopically, this protein exhibits an asymmetric alpha-absorption band for the reduced form and particularly large paramagnetic (1)H NMR shifts for the heme methyl groups with an unusual shift pattern in the oxidized form. The crystal structure of the Cyt c-554 has been determined at high resolution. The overall fold consists of four alpha-helices and is characterized by a remarkably long and flexible loop between the alpha3 and alpha4 helices. The axial ligand methionine has S chirality at the sulfur atom with its C(epsilon)H3 group pointing toward the heme pyrrole ring I. This configuration corresponds to an orientation of the lone-pair orbital of the sulfur atom directed at the pyrrole ring II and explains the lowest-field (1)H NMR shift arising from the 18(1) heme methyl protons. Differing from most other class I Cyts c, no hydrogen bond was formed between the methionine sulfur atom and polypeptide chain. Lack of this hydrogen bond may account for the observed large paramagnetic (1)H NMR shifts of the heme methyl protons. The surface-exposed heme pyrrole ring II edge is in a relatively hydrophobic environment surrounded by several electronically neutral residues. This portion is considered as an electron transfer gateway. The structure of the Cyt c-554 is compared with those of other Cyts c, and possible interactions of this protein with its electron transport partners are discussed. PMID- 24052269 TI - Polyhydroxybutyrate particles in Synechocystis sp. PCC 6803: facts and fiction. AB - Transmission electron microscopy has been used to identify poly-3-hydroxybutyrate (PHB) granules in cyanobacteria for over 40 years. Spherical inclusions inside the cell that are electron-transparent and/or slightly electron-dense and that are found in transmission electron micrographs of cyanobacteria are generally assumed to be PHB granules. The aim of this study was to test this assumption in different strains of the cyanobacterium Synechocystis sp. PCC 6803. Inclusions that resemble PHB granules were present in strains lacking a pair of genes essential for PHB synthesis and in wild-type cells under conditions that no PHB granules could be detected by fluorescence staining of PHB. Indeed, in these cells PHB could not be demonstrated chemically by GC/MS either. Based on the results gathered, it is concluded that not all the slightly electron-dense spherical inclusions are PHB granules in Synechocystis sp. PCC 6803. This result is potentially applicable to other cyanobacteria. Alternate assignments for these inclusions are discussed. PMID- 24052270 TI - [Meagre evidence so far for effectiveness of in-home comprehensive geriatric assessment: a literature review]. AB - BACKGROUND: Most elderly people attach great value to staying functionally independent for as long as possible. A targeted detection and treatment of factors that threaten functional independence, through comprehensive geriatric assessment, might promote this. This paper describes a review on the effect of in home comprehensive geriatric assessment. METHODS: A search was carried out in Pubmed (1977-2012) for randomized controlled trials investigating the effectiveness of multidisciplinary multidimensional in-home geriatric assessment. Data was extracted about effectiveness, costs and factors that had a positive or negative influence on the outcome of CGA. RESULTS: Nine RCTs could be included in the study. All studies were of moderate to good quality, except for one study of poor quality. A positive effect was found in three out of six studies on functional status and in two out of four studies on quality of life. No effect was found on number of hospital admissions, nursing home admissions and on mortality. Most studies showed a rise in total health care expenditure. CONCLUSION: In-home CGA has a modest positive effect on functional status and quality of life. Evidence suggest that in-home CGA might be most effective in elderly that have a relatively high level of functioning. PMID- 24052271 TI - [Religious/spiritual well-being in mentally ill persons II: the development of a short scale and comparison scores for clinical psychiatric groups and healthy controls]. AB - OBJECTIVE: The Multidimensional Inventory for Religious/Spiritual Well-Being (MI RSWB) was successfully applied in several clinical as well as non-clinical studies. However, the original version of the scale often showed to be as too comprehensive especially for clinical surroundings. There for the aim of this study is to develop a short version of the scale comprising 12 items. METHOD: Based on a sample representative of the Austrian general population (N = 1,500), a first MI-RSWB short version is developed by means of factor- and reliability analysis. Furthermore the new short version of the scale is initially validated through several indicators of mental illness. RESULTS: The MI-RSWB short version shows convincing psychometric properties. The total scale as well as the sub scales exhibit at least a sufficient internal consistency. A significant negative association with several indicators of psychiatric illness is also confirmed for the short version of the scale. CONCLUSIONS: The MI-RWSB 12 scale is especially recommended for further research focusing on the clinical relevance of religiosity and spirituality. PMID- 24052272 TI - Exonic variants affecting pre-mRNA splicing add to genetic burden in chronic pancreatitis. PMID- 24052274 TI - Oral contraceptives and Crohn's disease. PMID- 24052273 TI - Chloride channel inhibition by a red wine extract and a synthetic small molecule prevents rotaviral secretory diarrhoea in neonatal mice. AB - BACKGROUND: Rotavirus is the most common cause of severe secretory diarrhoea in infants and young children globally. The rotaviral enterotoxin, NSP4, has been proposed to stimulate calcium-activated chloride channels (CaCC) on the apical plasma membrane of intestinal epithelial cells. We previously identified red wine and small molecule CaCC inhibitors. OBJECTIVE: To investigate the efficacy of a red wine extract and a synthetic small molecule, CaCCinh-A01, in inhibiting intestinal CaCCs and rotaviral diarrhoea. DESIGN: Inhibition of CaCC-dependent current was measured in T84 cells and mouse ileum. The effectiveness of an orally administered wine extract and CaCCinh-A01 in inhibiting diarrhoea in vivo was determined in a neonatal mouse model of rotaviral infection. RESULTS: Screening of ~150 red wines revealed a Cabernet Sauvignon that inhibited CaCC current in T84 cells with IC50 at a ~1:200 dilution, and higher concentrations producing 100% inhibition. A >1 kdalton wine extract prepared by dialysis, which retained full inhibition activity, blocked CaCC current in T84 cells and mouse intestine. In rotavirus-inoculated mice, oral administration of the wine extract prevented diarrhoea by inhibition of intestinal fluid secretion without affecting rotaviral infection. The wine extract did not inhibit the cystic fibrosis chloride channel (CFTR) in cell cultures, nor did it prevent watery stools in neonatal mice administered cholera toxin, which activates CFTR-dependent fluid secretion. CaCCinh-A01 also inhibited rotaviral diarrhoea. CONCLUSIONS: Our results support a pathogenic role for enterocyte CaCCs in rotaviral diarrhoea and demonstrate the antidiarrhoeal action of CaCC inhibition by an alcohol-free, red wine extract and by a synthetic small molecule. PMID- 24052276 TI - Standing up for GMOs. PMID- 24052275 TI - Brief report: Pilot single-blind placebo lead-in study of acamprosate in youth with autistic disorder. AB - RATIONALE: An excitatory/inhibitory (E:I) imbalance marked by enhanced glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission may contribute to the pathophysiology of autism spectrum disorders (ASD). OBJECTIVES: We report on the first single-blind placebo lead-in trial of acamprosate, a drug with putative mechanisms restoring E:I imbalance, in twelve youth with ASD. MATERIALS AND METHODS: We conducted a 12-week single-blind, placebo lead-in study of acamprosate in youth age 5-17 years with autistic disorder. RESULTS: Six of nine subjects who received active drug treatment were deemed treatment responders (defined by a score at final visit of "very much improved" or "much improved" on the Clinical Global Impressions Improvement scale) and >=25% improvement on the Aberrant Behavior Checklist Social Withdrawal subscale. CONCLUSION: Future larger scale dose finding studies of acamprosate in ASD may be warranted given this preliminary indication of benefit. PMID- 24052280 TI - Water resources. Kenyan find heralds new era in water prospecting. PMID- 24052281 TI - Space exploration. India aims a probe at Mars--and at earthly prestige. PMID- 24052282 TI - Agriculture. What happens when weed killers stop killing? PMID- 24052283 TI - Biomedical publishing. Secretive and subjective, peer review proves resistant to study. PMID- 24052284 TI - Predators in the 'hood. PMID- 24052285 TI - Man in the middle. PMID- 24052286 TI - Neuroscience. Concentrating on kindness. PMID- 24052287 TI - Putting GenBank data on the map. PMID- 24052288 TI - Beware side effects of research ethics revision. PMID- 24052289 TI - Protecting privacy for dual-use researchers. PMID- 24052290 TI - Comment on "Invasive harlequin ladybird carries biological weapons against native competitors". AB - We comment on the implications that Vilcinskas et al. (Reports, 17 May 2013, p. 862) attach to the finding that the exotic, invasive ladybird Harmonia axyridis carries microsporidia to which this species is insensitive but that is lethal to species that are native to the invaded areas. The authors suggest that these microsporidia might serve as "biological weapons" against the native competitors, but we cast doubt on the importance of this suggestion in the field. PMID- 24052291 TI - Comment on "Invasive harlequin ladybird carries biological weapons against native competitors". AB - Conclusions about the nontarget effects of putatively invasive pathogens should be based on biologically relevant data. We disagree that the research experiments on a microsporidium isolated from Harmonia axyridis conducted by Vilcinskas et al. (Reports, 17 May 2013, p. 862) can explain the decline of native coccinellid species in the absence of such data. PMID- 24052292 TI - Comment on "Invasive harlequin ladybird carries biological weapons against native competitors". AB - Vilcinskas et al. (Reports, 17 May 2013, p. 862) proposed that infectious microsporidia of the invasive ladybird Harmonia axyridis act against intraguild predators, rather than ladybird alkaloid defenses. However, as both microsporidia and the harmonine defense alkaloid were administered to predators by microinjection rather than into the gut, such a conclusion is premature. Alkaloids also provide defense when predation occurs, whereas microsporidia act much later. PMID- 24052293 TI - Response to comments on "Invasive harlequin ladybird carries biological weapons against native competitors". AB - Comments by de Jong et al., Solter et al., and Sloggett question the ecological relevance of the abundant microsporidia found in the invasive ladybird Harmonia axyridis. We contend that there is abundant evidence that native ladybirds feed on H. axyridis eggs and that interspecific microsporidial transfer is a common phenomenon, supporting the proposed role of these parasites as biological weapons. PMID- 24052294 TI - Medicine. Mitochondrial replacement, evolution, and the clinic. PMID- 24052295 TI - Chemistry. Lewis acids with a difference. PMID- 24052296 TI - Cell signaling. Concentrating (on) native proteins to control cell fate. PMID- 24052297 TI - Materials science. Polymers find plenty of wiggle room at the bottom. PMID- 24052298 TI - Immunology. Pasteur approach to a malaria vaccine may take the lead. PMID- 24052299 TI - Neuroscience. Promiscuous Alzheimer's amyloid: yet another partner. PMID- 24052300 TI - Earth science. Causes of the Cambrian explosion. PMID- 24052301 TI - Linear structures in the core of the Coma cluster of galaxies. AB - The hot x-ray-emitting plasma in galaxy clusters is predicted to have turbulent motion, which can contribute around 10% of the cluster's central energy density. We report deep Chandra X-ray Observatory observations of the Coma cluster core, showing the presence of quasi-linear high-density arms spanning 150 kiloparsecs, consisting of low-entropy material that was probably stripped from merging subclusters. Two appear to be connected with a subgroup of galaxies at a 650 kiloparsec radius that is merging into the cluster, implying coherence over several hundred million years. Such a long lifetime implies that strong isotropic turbulence and conduction are suppressed in the core, despite the unrelaxed state of the cluster. Magnetic fields are presumably responsible. The structures seen in Coma present insight into the past billion years of subcluster merger activity. PMID- 24052302 TI - Control of surface charges by radicals as a principle of antistatic polymers protecting electronic circuitry. AB - Even minute quantities of electric charge accumulating on polymer surfaces can cause shocks, explosions, and multibillion-dollar losses to electronic circuitry. This paper demonstrates that to remove static electricity, it is not at all necessary to "target" the charges themselves. Instead, the way to discharge a polymer is to remove radicals from its surface. These radicals colocalize with and stabilize the charges; when they are scavenged, the surfaces discharge rapidly. This radical-charge interplay allows for controlling static electricity by doping common polymers with small amounts of radical-scavenging molecules, including the familiar vitamin E. The effectiveness of this approach is demonstrated by rendering common polymers dust-mitigating and also by using them as coatings that prevent the failure of electronic circuitry. PMID- 24052303 TI - Glassy dynamics in condensed isolated polymer chains. AB - In the course of miniaturization down to the nanometer scale, much remains unknown concerning how and to what extent the properties of materials are changed. To learn more about the dynamics of condensed isolated polymer chains, we used broadband dielectric spectroscopy and a capacitor with nanostructured electrodes separated by 35 nanometers. We measured the dynamic glass transition of poly(2-vinylpyridine) and found it to be bulk-like; only segments closer than 0.5 nanometer to the substrate were weakly slowed. Our approach paves the way for numerous experiments on the dynamics of isolated molecules. PMID- 24052304 TI - Lewis acidity of organofluorophosphonium salts: hydrodefluorination by a saturated acceptor. AB - Prototypical Lewis acids, such as boranes, derive their reactivity from electronic unsaturation. Here, we report the Lewis acidity and catalytic application of electronically saturated phosphorus-centered electrophilic acceptors. Organofluorophosphonium salts of the formula [(C6F5)(3 x)Ph(x)PF][B(C6F5)4] (x = 0 or 1; Ph, phenyl) are shown to form adducts with neutral Lewis bases and to react rapidly with fluoroalkanes to produce difluorophosphoranes. In the presence of hydrosilane, the cation [(C6F5)3PF](+) is shown to catalyze the hydrodefluorination of fluoroalkanes, affording alkanes and fluorosilane. The mechanism demonstrates the impressive fluoride ion affinity of this highly electron-deficient phosphonium center. PMID- 24052305 TI - Deep-focus earthquake analogs recorded at high pressure and temperature in the laboratory. AB - Phase transformations of metastable olivine might trigger deep-focus earthquakes (400 to 700 kilometers) in cold subducting lithosphere. To explore the feasibility of this mechanism, we performed laboratory deformation experiments on germanium olivine (Mg2GeO4) under differential stress at high pressure (P = 2 to 5 gigapascals) and within a narrow temperature range (T = 1000 to 1250 kelvin). We found that fractures nucleate at the onset of the olivine-to-spinel transition. These fractures propagate dynamically (at a nonnegligible fraction of the shear wave velocity) so that intense acoustic emissions are generated. Similar to deep-focus earthquakes, these acoustic emissions arise from pure shear sources and obey the Gutenberg-Richter law without following Omori's law. Microstructural observations prove that dynamic weakening likely involves superplasticity of the nanocrystalline spinel reaction product at seismic strain rates. PMID- 24052306 TI - Energy release of the 2013 M(w) 8.3 Sea of Okhotsk earthquake and deep slab stress heterogeneity. AB - Earth's deepest earthquakes occur in subducting oceanic lithosphere, where temperatures are lower than in ambient mantle. On 24 May 2013, a magnitude 8.3 earthquake ruptured a 180-kilometer-long fault within the subducting Pacific plate about 609 kilometers below the Sea of Okhotsk. Global seismic P wave recordings indicate a radiated seismic energy of ~1.5 * 10(17) joules. A rupture velocity of ~4.0 to 4.5 kilometers/second is determined by back-projection of short-period P waves, and the fault width is constrained to give static stress drop estimates (~12 to 15 megapascals) compatible with theoretical radiation efficiency for crack models. A nearby aftershock had a stress drop one to two orders of magnitude higher, indicating large stress heterogeneity in the deep slab, and plausibly within the rupture process of the great event. PMID- 24052307 TI - Constitutive MU-opioid receptor activity leads to long-term endogenous analgesia and dependence. AB - Opioid receptor antagonists increase hyperalgesia in humans and animals, which indicates that endogenous activation of opioid receptors provides relief from acute pain; however, the mechanisms of long-term opioid inhibition of pathological pain have remained elusive. We found that tissue injury produced MU opioid receptor (MOR) constitutive activity (MOR(CA)) that repressed spinal nociceptive signaling for months. Pharmacological blockade during the posthyperalgesia state with MOR inverse agonists reinstated central pain sensitization and precipitated hallmarks of opioid withdrawal (including adenosine 3',5'-monophosphate overshoot and hyperalgesia) that required N-methyl D-aspartate receptor activation of adenylyl cyclase type 1. Thus, MOR(CA) initiates both analgesic signaling and a compensatory opponent process that generates endogenous opioid dependence. Tonic MOR(CA) suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain. PMID- 24052309 TI - An epidermal microRNA regulates neuronal migration through control of the cellular glycosylation state. AB - An appropriate balance in glycosylation of proteoglycans is crucial for their ability to regulate animal development. Here, we report that the Caenorhabditis elegans microRNA mir-79, an ortholog of mammalian miR-9, controls sugar-chain homeostasis by targeting two proteins in the proteoglycan biosynthetic pathway: a chondroitin synthase (SQV-5; squashed vulva-5) and a uridine 5'-diphosphate-sugar transporter (SQV-7). Loss of mir-79 causes neurodevelopmental defects through SQV 5 and SQV-7 dysregulation in the epidermis. This results in a partial shutdown of heparan sulfate biosynthesis that impinges on a LON-2/glypican pathway and disrupts neuronal migration. Our results identify a regulatory axis controlled by a conserved microRNA that maintains proteoglycan homeostasis in cells. PMID- 24052310 TI - Teaching metathesis "simple" stereochemistry. AB - Applications of metal-catalyzed olefin metathesis reactions manifested dramatic growth during the late 20th and early 21st centuries, culminating in the 2005 Nobel Prize awarded to three of the pioneers. The standard catalysts developed during that time frame and their descendants have profoundly changed the mindset of the synthetic community, even though they do not provide a handle to control selectivity issues as fundamental as the E/Z geometry of the newly formed double bond. With yet another generation of catalysts in the making that are far superior in this regard, a new wave seems to be building up that is expected to have enormous impact, too. The current state of the art is critically assessed, as are possible alternatives such as the metathesis of triple bonds followed by stereoselective semi-reduction. PMID- 24052308 TI - Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. AB - Soluble beta-amyloid (Abeta) oligomers impair synaptic plasticity and cause synaptic loss associated with Alzheimer's disease (AD). We report that murine PirB (paired immunoglobulin-like receptor B) and its human ortholog LilrB2 (leukocyte immunoglobulin-like receptor B2), present in human brain, are receptors for Abeta oligomers, with nanomolar affinity. The first two extracellular immunoglobulin (Ig) domains of PirB and LilrB2 mediate this interaction, leading to enhanced cofilin signaling, also seen in human AD brains. In mice, the deleterious effect of Abeta oligomers on hippocampal long-term potentiation required PirB, and in a transgenic model of AD, PirB not only contributed to memory deficits present in adult mice, but also mediated loss of synaptic plasticity in juvenile visual cortex. These findings imply that LilrB2 contributes to human AD neuropathology and suggest therapeutic uses of blocking LilrB2 function. PMID- 24052311 TI - Acute effects of pelvic irradiation on the adult uterus revealed by dynamic contrast-enhanced MRI. AB - OBJECTIVE: Pelvic radiation therapy (RT) can influence fertility in female rectal cancer survivors. Data regarding its effects on the adult uterus are scant. This study aims to evaluate the uterus before and after RT, using dynamic contrast enhanced MRI. METHODS: Eligible patients (n=10) received RT for rectal cancer, had an intact uterus and underwent dynamic contrast-enhanced MRI before and after RT. Seven patients were pre-menopausal. RESULTS: Patients received pelvic RT (median, 50.2 Gy) with concurrent 5-fluorouracil. Five patients were treated with intensity modulated RT (IMRT) and five with a three-field technique. The median D95 of the uterus was 30 Gy; D05 was 48 Gy; and V95 was 97%. The median cervical D95 was 45 Gy; D05, 50 Gy; and V95, 100%. Cervical dose was higher with IMRT than with three-field plans (p<=0.038). On T2 MRI, the junctional zone was visible in nine patients before and in one after RT (p=0.001). Median cervical length (2.3 vs 3.0 cm) and endometrial thickness (2.6 vs 5.9 mm) were reduced after RT (p<=0.008). In pre-menopausal patients, the volume transfer constant, K(trans), (0.069 vs 0.195, p=0.006) and the extracellular extravascular volume fraction, V(e), (0.217 vs 0.520, p=0.053) decreased. CONCLUSION: Pelvic RT significantly affected uterine anatomy and perfusion. Cervical dose was higher with IMRT than three-field plans, but no attempt was made to constrain the dose. ADVANCES IN KNOWLEDGE: Pelvic RT significantly affects the adult uterus. These findings are crucial to understand the potential consequences of RT on fertility, and they lay the groundwork for further prospective studies. PMID- 24052313 TI - Prognosis of solitary fibrous tumors: a multicenter study. AB - BACKGROUND: Solitary fibrous tumors (SFTs) are rare mesenchymal tumors, and data regarding outcome and prognostic factors are scarce. We report the outcome and analysis of prognostic factors of a retrospective multicenter cohort study for patients treated for SFTs. METHODS: Retrospective analysis was performed of patients treated for SFTs between 1995 and 2012. Clinical and histopathological features were analyzed for prognostic value. Endpoints were set at local recurrence, metastasis formation, or death. Survival was analyzed using Kaplan Meier and Cox proportional hazards analyses. RESULTS: A total of 81 patients underwent surgical resection of a SFT with curative intent. During follow-up, 21 patients developed distant metastases, while 18 patients developed local recurrence. The 5-year overall survival was 84 %. The local recurrence rate and the metastasis rate at 5 years were 29 and 34 %, respectively. Of all factors analyzed, positive resection margin significantly correlated with local recurrence [hazard ratio (HR) 4.8; 95 % confidence interval (95 % CI) 1.5-14.9]. Tumor size >10 cm (HR 4.4; 95 % CI 1.7-11.5) and high mitosis rate (HR 3.3; 95 % CI 1.06-10.3) significantly correlated with higher incidence of metastases. The combination of tumors >10 cm and high mitosis rate significantly correlated with higher incidence of metastases (HR 4.8; 95 % CI 1.4-16.2) and showed a trend toward worse overall survival (HR 5.7; 95 % CI 0.95-34.7). CONCLUSIONS: A substantial portion of patients with a SFT developed local recurrence or metastases. Local recurrence is significantly higher in patients with positive resection margins; metastasis frequency is significantly higher in patients with tumors >10 cm and tumors with a high mitosis rate. PMID- 24052312 TI - Spontaneous regression of primary abdominal wall desmoid tumors: more common than previously thought. AB - PURPOSE: The relevance of the initial observational approach for desmoid tumors (DTs) remains unclear. We investigated a new conservative management treatment for primary abdominal wall DTs. METHODS: Data were collected from 147 patients between 1993 and 2012. The initial therapeutic approaches were categorized as front-line surgery [surgery group (SG), n = 41, 28 %] and initial observation or medical treatment [nonsurgery group (NSG), n = 106, 72 %]. The cumulative incidence of the last strategy modification was estimated using competing risk methods with variable censoring times. RESULTS: Of the 147 patients, 143 were female (97 %). In the SG, 27 patients (66 %) required full-thickness abdominal wall mesh repair. In the NSG, 102 patients (96 %) underwent initial observation and four received medical treatment. In the NSG, the 1- and 3-year incidences of changing to medical treatment (no further changes during the follow-up) were 19 % [95 % confidence interval (CI) 11-28] and 25 % (95 % CI 17-35), respectively, and the 1- and 3-year incidences of a final switch to surgery were 14 % (95 % CI 8 22) and 16 % (95 % CI 9-24), respectively. An initial tumor size of >7 cm was associated with a higher strategy modification risk (p = 0.004). Of the 102 patients initially observed, 29 experienced spontaneous regression over a median follow-up period of 32 months. All second-intent resections were macroscopically completed, with R0 resections achieved in 82 % of patients. CONCLUSIONS: This study supports an initial nonsurgical approach to abdominal wall DTs <=7 cm, followed by surgery based on tumor growth in select cases. PMID- 24052314 TI - Patterns of recurrence and survival after lymphadenectomy in melanoma patients: clarifying the effects of timing of surgery and lymph node tumor burden. AB - BACKGROUND: Melanoma patients with lymph node (LN) metastases have variable survival after lymphadenectomy. This study investigates whether lymphadenectomy at different times in the course of disease progression influences disease-free survival (DFS; time from primary diagnosis to first recurrence after lymphadenectomy), post recurrence survival (PRS; time from first recurrence after lymphadenectomy to death), and overall survival (OS; time from diagnosis to death). METHODS: Between 1992 and 2010, a total of 1,704 patients underwent lymphadenectomy; 502 underwent immediate completion lymphadenectomy (ICL) after positive sentinel node biopsy (SNB), 214 had delayed completion lymphadenectomy (DCL) for regional recurrence after positive SNB with no ICL or after an earlier false-negative SNB, 709 had no SNB and later required delayed therapeutic lymphadenectomy (DTL) for clinically evident metastasis, and 279 had immediate therapeutic lymphadenectomy (ITL) for clinically positive LNs at primary melanoma diagnosis. RESULTS: Median DFS for ICL, DCL, DTL, and ITL was 68, 48, 82, and 16 months, respectively (p < 0.001). Median PRS for ICL, DCL, DTL, and ITL was 14, 8, 9, and 9 months, respectively (p < 0.001). Median OS for ICL was not reached whilst for DCL, DTL, and ITL it was 71, 101, and 29 months, respectively (p < 0.001). Extranodal spread and tumor, node, metastasis classification system N stage were the only significant prognostic factors for OS within each group. ICL patients had significantly improved DFS (p = 0.005) and OS (p = 0.012) beyond 5 years compared to DTL patients. CONCLUSIONS: Variable outcomes after lymphadenectomy were observed with different timing of surgery and LN tumor burden. ICL patients had the best outcome. PMID- 24052316 TI - Reply to "Anti-cytokeratin CAM5.2 recognized CK8 mainly, but not CK18: comment on 'Early assessment of axillary response with 18F-FDG PET/CT during neoadjuvant chemotherapy in stage II-III breast cancer: implications for surgical management of the axilla. Ann Surg Oncol. 2013;20(7):2227-35'". PMID- 24052315 TI - Association between postoperative complications and clinical cancer outcomes. AB - INTRODUCTION: The treatment for a majority of solid organ tumors is surgical resection; 10-20 % of patients suffer a perioperative complication. Perioperative complications may contribute to cancer recurrence. This study examined the relationship between postoperative complications and risk-adjusted patient overall survival. METHODS: Data from 2003 to 2009 were linked from our clinical cancer registry, the National Surgery Quality Improvement Project (NSQIP), and medical records. Patients who had tumor extirpation for cure were included. The NSQIP was used to identify complications. Patients with a complication were matched to patients without a complication. chi (2) tests and Cox proportional hazard regression models were used. RESULTS: A total of 415 patients were included for survival analysis. The hazard ratio (HR) for mortality associated with having a complication was 2.17. The HR for mortality after 200 days postoperatively was 2.47. Infectious complications were associated with the highest association with increased mortality (HR = 3.56). Noninfectious complications were not associated with an increased risk of mortality. CONCLUSIONS: This study investigated the relationship of surgical infectious complications in cancer patients with long-term survival for patients who had a number of different types of cancer. After taking into account the site, histology, and stage of the cancer, we found that patients with infectious complications had earlier death. PMID- 24052317 TI - Peritumoral expression of adipokines and fatty acids in breast cancer. AB - BACKGROUND: Adipokines in the tumor microenvironment may contribute to cancer growth. We hypothesized that peritumoral fat can be a source of lipid-derived energy for tumors by increasing adipose triglyceride lipase (ATGL)-mediated lipolysis and down-regulating a negative regulator of adipogenesis, pigment epithelium-derived factor (PEDF). METHODS: In a pilot study, tissue from mastectomies (n = 19) was collected from sites both adjacent (peritumoral) and distant to the tumor for comparison of ATGL, PEDF, and leptin expression levels using immunohistochemistry. Statistical analysis was performed by Student's t test to determine significance. RESULTS: Mean tumor size was 2.4 cm, and 10 (59 %) patients had tumor-positive nodes. Mean body mass index (BMI) was 28.1 kg/m(2). ATGL expression was significantly increased in obese patients (BMI >= 30 kg/m(2)) compared with the nonobese group (P < 0.04). Leptin expression was increased in the peritumoral stroma of obese patients compared with distant sites (P = 0.03). Peritumoral PEDF and the leptin/PEDF ratio were significantly affected by tumor size and node status. Tumors >= 2 cm had lower peritumoral stromal expression of PEDF than tumors <2 cm (P = 0.01). In node-positive cases, expression of PEDF was significantly decreased in the peritumoral stroma compared with node-negative cases (1.22 vs. 1.80, P < 0.04). The leptin/PEDF ratio was markedly elevated in the peritumoral region of node-positive cases versus node negative cases (2.17 vs. 1.18, P < 0.001). CONCLUSIONS: Peritumoral expression of adipokines was altered in both obesity and more advanced breast tumors, suggesting a role for adipokines in enhancing tumor growth. Future studies should focus on the use of adipokines as biomarkers. PMID- 24052318 TI - Progress in survival outcomes in patients with advanced ovarian cancer treated by neo-adjuvant platinum/taxane-based chemotherapy and late interval debulking surgery. AB - BACKGROUND: Steady progress in outcomes has been observed after standard treatment by surgery and chemotherapy in patients with advanced ovarian cancer (AOC), but little is known about outcomes after alternative neoadjuvant chemotherapy (NAC) proposed to primary inoperable patients. We assessed whether NAC offers comparable survival to standard treatment, whether survival rates have progressed over time, and what the optimal extent of surgery at late interval debulking surgery (IDS) should be. METHODS: This was a retrospective data analysis of prospectively recorded patients with poor prognosis AOC treated by platinum/taxane NAC and late IDS (after six cycles). Independent prognostic factors for surgical morbidity and overall survival (OS) are determined and survival outcomes are compared to survival rates for a similar group of patients treated with platinum protocols. RESULTS: A total of 118 patients with stages IIIC-IV AOC (median age: 64 years, stage IV: 31%) received IDS (46% standard surgery and 54% radical, with 68% obtaining complete resection). Major morbidity was 18%. OS was 42 months across all patients (95% confidence interval 35.3-49.1) and 80 months in stage IIIC. This is higher by 15 months than after platinum based treatment. Higher morbidity was associated with bowel resection. Longer OS was associated with ASA class I, stage IIIC, no bowel surgery, and no residual disease. CONCLUSIONS: The neoadjuvant approach with late IDS offers survival similar to that reported by standard treatment, with progress in outcomes compared with rates after platinum treatment. The goal of IDS surgery is complete resection, while sparing surrounding organs. PMID- 24052319 TI - The effects of surgical cytoreduction prior to imatinib therapy on the prognosis of patients with advanced GIST. AB - BACKGROUND: Baseline tumor size is one of important prognostic factors for imatinib therapy in patients with advanced gastrointestinal stromal tumor (GIST). The purpose of this study was to determine whether surgical cytoreduction before imatinib therapy can improve the prognosis. METHODS: A total of 249 patients with advanced GIST were reviewed retrospectively. Patients were categorized into two groups according to the degree of initial cytoreduction: 35 patients with >=75 % of initial tumor bulk removed (cytoreduction group) and the other 214 patients (no cytoreduction group). The median follow-up was 44.0 months. RESULTS: Patients in the cytoreduction group were younger, in better performance, showed more initially metastatic disease, peritoneal metastases, but fewer liver metastases. The baseline tumor size when starting imatinib became significantly reduced in the cytoreduction group, which made significant difference between the two groups. By multivariate analyses, mutational status, tumor size, and granulocyte count at presentation were associated with progression-free survival. Age and tumor size were associated with overall survival. However, initial cytoreduction was not significantly related to the prognosis. CONCLUSIONS: Cytoreduction before imatinib therapy appears not to improve the prognosis. Imatinib therapy should still represent the initial treatment for advanced GIST. PMID- 24052320 TI - Can prevention classification be improved by considering the function of prevention? AB - Universal, selective and indicated forms of prevention have been adopted as improvements on previous notions of primary and secondary prevention. However, some conceptual confusion remains concerning the placing of environmental, community-based or mass media preventive interventions within this typology. It is suggested that a new dimension of functional types of prevention, namely environmental, developmental and informational prevention should be specified alongside the forms of prevention in a taxonomy matrix. The main advantage of this new taxonomy is that a matrix combining the form and function dimensions of prevention can be used to identify and map out prevention strategies, to consider where research evidence is present and where more is needed, and to evaluate the relative effectiveness of different categories and components of prevention for specific health and social issues. Such evaluations would provide empirical evidence as to whether the different categories of prevention are related to outcomes or processes of prevention in ways that suggest the value of the taxonomy for understanding and increasing the impact of prevention science. This new prevention taxonomy has been useful for conceptualising and planning prevention activities in a case study involving the Swedish National Institute for Public Health. Future work should assess (1) the robustness of this new taxonomy and (2) the theoretical and empirical basis for profiling prevention investments across the various forms and functions of prevention. PMID- 24052321 TI - Predicting automaticity in exercise behaviour: the role of perceived behavioural control, affect, intention, action planning, and behaviour. AB - BACKGROUND: Habit formation has been proposed as a way to maintain behaviour over time. PURPOSE: Recent evidence suggests that constructs additional to repeated performance may predict physical automaticity, but no research has yet explored possible direct impacts of intention, planning, affect, and perceived behavioural control (PBC) on automaticity. METHOD: In a prospective study over a 2-week period amongst 406 undergraduate students (M age = 21.5 years [SD = 2.59], 27.4 % males), we investigated main and interaction effects of past exercise behaviour, PBC, intention, planning, and affect on exercise automaticity. RESULTS: Results showed that - controlling for past behaviour - PBC, affect, and planning were significant and positive predictors of exercise automaticity. Decomposing a significant interaction between PBC and planning when to exercise revealed that planning became less predictive of exercise automaticity at higher levels of PBC. CONCLUSION: Findings show that exercise automaticity is predicted by repeated performance and social-cognitive constructs. Further, interactions between social cognitive predictors may be different for behavioural automaticity than for behavioural frequency. PMID- 24052322 TI - Peritoneal metastases of lower gastrointestinal tract origin:a comparative study of patient outcomes following cytoreduction and intraperitoneal chemotherapy. AB - BACKGROUND: Cytoreductive surgery (CS) combined with intraperitoneal chemotherapy (IPC) is a multimodal approach to the treatment of peritoneal metastases (PM) of lower gastrointestinal origin. This study examines patient outcomes and critically evaluates its patterns of recurrences relative to the site of metastatic origin. METHODS: Patients treated with CS/IPC from 2000 to 2012 where PM arose from a primary tumour of the appendix, colon and rectum were identified from a prospective database for retrospective evaluation. The primary endpoints were survival (overall and disease-free), and secondary end points include patterns of recurrence and prognostic factors associated with overall outcomes. RESULTS: Two hundred and eleven patients were followed up for a median of 23.3 months (range 1-156). Overall median survival was 46.8 months, and the 1-, 3-, 5 year survival rates were 87, 56 and 42 %, respectively. The 5-year survival of patients with appendiceal, colonic and rectal PM was 55, 33 and 20 %, respectively. Tumour origin was the only independent prognostic factor associated with overall survival (p = 0.03). Recurrences were more common in patients of colorectal origin over appendiceal origin (p?0.001) and were more likely to be of a systemic nature (p = 0.05). CONCLUSION: CS/IPC provides an option for improved survival in patients with PM of lower gastrointestinal origin and appears to be most promising in patients with disease of appendiceal origin. PMID- 24052323 TI - Endovascular exclusion of complex postsurgical aortic arch pseudoaneurysm using vascular plug devices and a review of vascular plugs. AB - We report the management of a patient presenting with haemoptysis due to aortobronchial fistula. He had previously undergone emergency exclusion bypass of a ruptured pseudoaneurysm developing post-aortic coarctation repair. Computed tomography scan showed persistent filling of pseudoaneurysm sac from proximal and distal aortic ligature sites tied during previous exclusion bypass surgery. Successful exclusion of aneurysm was achieved by using 3 vascular plug devices (1 Amplatzer plug II and 2 Amender patent ductus arteriosus occluder devices). We also review types of Amplatzer vascular plugs and their use in peripheral vascular interventions. PMID- 24052324 TI - Intent recognition in a powered lower limb prosthesis using time history information. AB - New computerized and powered lower limb prostheses are being developed that enable amputees to perform multiple locomotion modes. However, current lower limb prosthesis controllers are not capable of transitioning these devices automatically and seamlessly between locomotion modes such as level-ground walking, stairs and slopes. The focus of this study was to evaluate different intent recognition interfaces, which if configured properly, may be capable of providing more natural transitions between locomotion modes. Intent recognition can be accomplished using a multitude of different signals from mechanical sensors on the prosthesis. Since these signals are non-stationary over any given stride, and gait is cyclical, time history information may improve locomotion mode recognition. The authors propose a dynamic Bayesian network classification strategy to incorporate prior sensor information over the gait cycle with current sensor information. Six transfemoral amputees performed locomotion circuits comprising level-ground walking and ascending/descending stairs and ramps using a powered knee and ankle prosthesis. Using time history reduced steady-state misclassifications by over half (p < 0.01), when compared to strategies that did not use time history, without reducing intent recognition performance during transitions. These results suggest that including time history information across the gait cycle can enhance locomotion mode intent recognition performance. PMID- 24052325 TI - Preliminary reliability and validity of Persian version of the Family Dermatology Life Quality Index (FDLQI). AB - PURPOSE: Family Dermatology Life Quality Index (FDLQI) is an instrument for assessing the quality of life of family members of dermatologic patients. The aim of this study was to describe the cultural adaptation of this questionnaire and to assess psychometric properties of the Persian version. METHODS: At first, the questionnaire was translated into Persian, and then back-translation was performed. The whole cycle was repeated until a consensus was reached about the optimal translation. In the next step, cognitive debriefing was performed, and after approval of the Persian version by FDLQI developers, it was distributed among 100 family members of dermatological patients in order to evaluate its validity and reliability. RESULTS: Mean age of participants was 37.1 years (+/ 12.3). Mean score of FDLQI was 15.4 (+/-5.5) with maximum and minimum scores of 30 and 6, respectively. The quality of life of studied participants showed no significant difference based on age-group, sex, educational level and the family relationship. Cronbach's alpha was calculated as 0.87. Exploratory factor analysis revealed a one-factor solution that accounted for 40.7 % of the variance. The unidimensional model was supported by confirmatory factor analysis. CONCLUSIONS: The results of the present study showed that the Persian version of FDLQI has acceptable factorial validity and internal consistency reliability. PMID- 24052326 TI - Equivalence and measurement properties of an electronic version of the Psoriasis Symptom Inventory. AB - PURPOSE: To evaluate the equivalence of electronic and paper versions of the Psoriasis Symptom Inventory and to examine measurement properties of the electronic version. METHODS: In a prospective, randomized, crossover, non interventional study in adult subjects (age >=18 years) with plaque psoriasis conducted over a period of 15 days, subjects were randomized to two groups, completing either the paper or electronic Psoriasis Symptom Inventory daily for 7 consecutive days followed by the alternate version. Equivalence was assessed by the intraclass correlation coefficient (ICC) between both administration modes. Differences in scores were also tested using paired Student's t test. Measurement properties included internal consistency reliability, test-retest reliability, and convergent and discriminant validity between the Psoriasis Symptom Inventory and (1) disease-specific (Dermatology Life Quality Index) and (2) general health (SF-36v2) status. RESULTS: Eighty subjects [74 % (59/80) moderate-to-severe psoriasis; 26 % (21/80) mild psoriasis receiving systemic treatment] were enrolled from 8 sites in the USA. The two modes were highly concordant for both total (ICC = 0.97) and individual item scores (ICC range = 0.93-0.97). Response bias testing showed no differences based on completion order with all ICC values >0.91. All mean score differences, except for one item ("flaking"), were non significant (P > 0.05). Minimum values for reliability (>0.70) and validity (convergent, r >= 0.40) were exceeded for the electronic Psoriasis Symptom Inventory. CONCLUSIONS: Equivalence between paper and electronic versions of the Psoriasis Symptom Inventory and strong measurement properties of the electronic mode indicated a successful migration from paper to electronic format of the Psoriasis Symptom Inventory. PMID- 24052327 TI - Mokken scaling of the Chinese version of the Medical Outcomes Study Social Support Survey. AB - PURPOSE: To validate the Chinese Mandarin version of the Medical Outcomes Study Social Support Survey (MOS-SSS-CM) using a model of ordinal unidimensional measurement known as Mokken scaling. METHODS: We administered in face-to-face interviews the MOS-SSS-CM to 200 patients with coronary heart disease. Data were analysed using Mokken scaling. RESULTS: The MOS-SSS-CM contains a set of items which meet the criteria of a reliable (Rho = 0.87) moderate Mokken scale (H = 0.40) with weak invariant item ordering (H = 0.39). CONCLUSIONS: The MOS-SSS-CM has a hierarchy of items which can be interpreted in terms of concerns with the physical aspects of social support through the need for companionship to items related to more personal worries. PMID- 24052328 TI - Laparoscopic cholecystectomy under spinal anesthesia in a patient with limb girdle muscular dystrophy. PMID- 24052329 TI - A sequence of events in the uterus prior to implantation in the mouse. AB - I reviewed a series of events in the mouse uterus before implantation on Day 4 of pregnancy (the sperm positive day is counted as Day 1). Major events are spacing of embryos along the uterine horns, shedding of the zona pellucida, and closure of the uterine lumen. How subtle they may be, there appear to exist interactions between intrauterine blastocysts and the uterus which is regulated by ovarian steroids. Spacing of embryos along the uterine horn is not random, but they are rather evenly distributed along the entire horn. The mechanism of even distribution of embryos needs clarification, although studies indicate that adrenergic nerve activity, prostaglandins, and other molecules appear to be involved. Shedding of the zona pellucida involves trypsin-like proteinase lysis of the zona. Through the opening created by zona lysis, blastocyst gets out of the zona by repeating expansion-collapse movements. Closure of rat uterine lumen is reported to be the result of absorption of uterine fluid through uterine glands. This needs to be confirmed in other species of rodents. Since these events influence blastocyst implantation, we need more detailed information on their regulatory mechanisms in order to improve the rate of healthy implantation of transferred embryo. PMID- 24052331 TI - Dolutegravir: first global approval. AB - Dolutegravir, an orally administered HIV-1 integrase strand transfer inhibitor (INSTI), is under development by ViiV Healthcare. Like other drugs belonging in the INSTI class of antiretroviral agents, dolutegravir binds to the integrase site of HIV-1 and blocks the strand transfer integration step, thereby preventing the replication of HIV-1. Dolutegravir is being developed as an unboosted once daily therapy for use in combination with other antiretroviral agents for the treatment of both treatment-naive and treatment-experienced patients with HIV-1 infection. Dolutegravir has been approved in the USA for the treatment of HIV-1 infection in combination with other antiretroviral agents and has been filed for approval in the EU and Canada. Phase III development is underway in North America, Europe, South Africa, South America, Australia and Taiwan. This article summarizes the milestones in the development of dolutegravir leading to this first approval for the treatment of HIV-1 infection in both therapy-naive and experienced patients. PMID- 24052330 TI - Localization of parathyroid hormone-related protein in the preimplantation mouse embryo is associated with events of blastocyst hatching. AB - PURPOSE: To determine the pattern of expression of parathyroid hormone-related protein (PTHrP) and its receptor, parathyroid hormone receptor 1 (PTHR1), in mouse embryos in different stages of preimplantation development. METHODS: Embryos were cultured from the pronuclear zygote stage and harvested as 2-cell, 4 cell and 8-cell embryos, morulae and blastocysts. RT-PCR was carried out on mRNAs of these and of trophoblast outgrowths for detection of PTHrP and PTHR1. Whole mounted embryos intact or stripped of zonae pellucidae were immunofluorescently stained for PTHrP and PTH receptor and observed with confocal microscopy. RESULTS: PTHrP mRNA was present in the pronuclear zygote, not present in 2-cell, 4-cell and uncompacted 8-cell embryos, present in the 8-cell compacting embryo, and not detected in 16-cell morulae or blastocysts. The mRNA was present in trophoblasts growing on fibronectin beds. mRNA for PTHR1 was detected in the pronuclear zygote, then undetected until the compacted 8-cell stage and thereafter. PTH receptor protein was observed in 2-cell embryos, morulae and in the inner cell mass and trophectoderm of blastocysts. PTHrP was observed dispersed in the cytoplasm of 2-cell, 4-cell and uncompacted 8-cell embryos, and in distinct foci near the nuclei of morulae. In blastocysts, PTHrP appeared on the apical surface of only trophoblast cells which had extruded from the zona pellucida. Fully hatched blastocysts expressed the protein on the apical side of all trophoblasts. When morulae were prematurely stripped of their zonae, PTHrP was observed on the embryos' outer surface. CONCLUSIONS: PTHrP protein is expressed throughout early embryo development, and its receptor PTHR1 is expressed from the morula stage. Embryo hatching is associated with translocation of PTHrP to the apical plasma membrane of trophoblasts. PTHrP may thus have autocrine effects on the developing blastocyst. PMID- 24052332 TI - Differential ecophysiological response of deciduous shrubs and a graminoid to long-term experimental snow reductions and additions in moist acidic tundra, Northern Alaska. AB - Changes in winter precipitation that include both decreases and increases in winter snow are underway across the Arctic. In this study, we used a 14-year experiment that has increased and decreased winter snow in the moist acidic tussock tundra of northern Alaska to understand impacts of variation in winter snow depth on summer leaf-level ecophysiology of two deciduous shrubs and a graminoid species, including: instantaneous rates of leaf gas exchange, and delta(13)C, delta(15)N, and nitrogen (N) concentrations of Betula nana, Salix pulchra, and Eriophorum vaginatum. Leaf-level measurements were complemented by measurements of canopy leaf area index (LAI) and depth of thaw. Reductions in snow lowered summer leaf photosynthesis, conductance, and transpiration rates by up to 40% compared to ambient and deep snow conditions for Eriophorum vaginatum, and reduced Salix pulchra conductance and transpiration by up to 49%. In contrast, Betula nana exhibited no changes in leaf gas exchange in response to lower or deeper snow. Canopy LAI increased with added snow, while reduced winter snow resulted in lower growing season soil temperatures and reduced thaw depths. Our findings indicate that the spatial and temporal variability of future snow depth will have individualistic consequences for leaf-level C fixation and water flux by tundra species, and that these responses will be manifested over the longer term by changes in canopy traits, depth of thaw, soil C and N processes, and trace gas (CO2 and H2O) exchanges between the tundra and the atmosphere. PMID- 24052334 TI - A qualitative study into the development of a physical activity legacy from the London 2012 Olympic Games. AB - Olympic Games have sometimes been considered as public health interventions capable of improving population health by encouraging increased physical activity levels. However, the evidence base does not appear to support this and is of poor quality, focussing on population level outcomes, usually related only to participation in organised sports. A new approach to research into the effects of such events is required focussing on the processes and mechanisms by which population physical activity levels might be increased enabling more effective use of such events in the future. Two separate processes, the 'demonstration effect' and 'festival effect,' have been proposed in Government guidance and are explored using qualitative methods in eight inactive people and four physical activity promotion specialists in Brighton & Hove. The findings appear to support the idea that watching elite athletes compete is unlikely to inspire participation among inactive people and may even discourage it by reducing self efficacy as a result of the perceived competence gap. Despite this, positive attitudes towards the London Olympics were observed among inactive members of the public and a desire to become actively involved in the event. Examples of intention to continue participating in community events and physical activities as a result of positive experiences of Olympic related events were also observed. PMID- 24052335 TI - Effect of microalgae/activated sludge ratio on cooperative treatment of anaerobic effluent of municipal wastewater. AB - In this work, capability of the green microalga (MA), Chlorella vulgaris, in treating synthetic anaerobic effluent of municipal wastewater was investigated. While pure C. vulgaris (100 % MA) provided maximum soluble chemical oxygen demand (sCOD) and N-NH4(+) removal efficiencies of 27 and 72 % respectively, addition of activated sludge (AS) to MA in different mass ratios (91, 80, 66.7, 9 % MA) improved wastewater treatment efficiency. Thus giving maximum sCOD and N-NH4(+) removal efficiencies 85 and 86.3 % (for MA/AS = 10/1), respectively. Utilizing AS without C. vulgaris, for treating the synthetic wastewater resulted in 87 % maximum sCOD and 42 % maximum N-NH4(+) removal efficiencies. Furthermore, algal growth and specific growth rates were measured in the systems with microalga as the dominant cellular population. As a result, faster algal growth was observed in mixed systems. Specific growth rate of C. vulgaris was 0.14 (day(-1)) in 100 % MA and 0.39 (day(-1)) in 80 % MA. Finally, data gathered by online measurement of dissolved oxygen indicate that algae-activated sludge mixture improves photosynthetic activity of examined microalga strain during anaerobic effluent treatment. PMID- 24052336 TI - Highly thermostable and pH-stable cellulases from Aspergillus niger NS-2: properties and application for cellulose hydrolysis. AB - Optimization of cultural conditions for enhanced cellulase production by Aspergillus niger NS-2 were studied under solid-state fermentation. Significant increase in yields (CMCase 463.9 +/- 20.1 U/g, FPase 101.1 +/- 3.5 U/g and beta glucosidase 99 +/- 4.0 U/g) were obtained under optimized conditions. Effect of different nutritional parameters was studied to induce the maximum production of cellulase complex. Scale-up studies for enzyme production process were carried out. Characterization studies showed that enzymes produced by A. niger NS-2 were highly temperature- and pH stable. At 50 degrees C, the half life for CMCase, FPase, beta-glucosidase were approximately 240 h. Cellulases from A. niger NS-2 were stable at 35 degrees C for 24 h over a broader pH range of 3.0-9.0. We examined the feasibility of using steam pretreatment to increase the saccharification yields from various lignocellulosic residues for sugar release which can potentially be used in bioethanol production. Saccharification of pretreated dry potato peels, carrot peels, composite waste mixture, orange peels, onion peels, banana peels, pineapple peels by crude enzyme extract from A. niger NS-2, resulted in very high cellulose conversion efficiencies of 92-98 %. PMID- 24052338 TI - Nutrition & metabolic syndrome. PMID- 24052337 TI - Characteristics of men who have sex with men (MSM) who attend sex parties: results from a national online sample in the USA. AB - OBJECTIVE: To compare three groups of men who have sex with men (MSM)-men who had attended a sex party in the past year (45.2%); men who had been to a sex party more than a year ago (23.3%); and men who had never been to one (31.5%)-on socio demographic and behavioural characteristics. METHOD: In spring 2012, 2063 sexually active MSM in the USA were recruited using banner advertising on a sexual networking website to complete an online survey about their sexual behaviour and attendance at sex parties. RESULTS: A significantly higher proportion of past year attendees were HIV-positive (28.1%), single (31.7%), demonstrated sexual compulsivity symptomology (39.2%), recently used drugs (67.8%), averaged the greatest number of recent male partners (Mdn=15, <90 days), and had greater instances of recent unprotected anal intercourse (UAI) with male partners (median=3, <90 days). Adjusting for covariates, those having been to a sex party in the last year were significantly more likely than others to report UAI. Free lubricant (93.4%) and condoms (81.0%) were the most desirable services/products men wanted at sex parties. More than half of men having been to a sex party expressed interest in free rapid HIV testing at sex parties (52.8%); however, few considered it acceptable to see 'medical providers' (11.7%) and 'peer outreach workers' (9.5%) at sex parties. CONCLUSIONS: MSM who have attended a sex party in the last year are appropriate candidates for targeted HIV and sexually transmitted infection (STI) prevention. Collaborating with event promoters presents valuable opportunities to provide condoms, lubricant and HIV/STI testing. PMID- 24052339 TI - The low prevalence of smoking in the Northern Sweden MONICA study, 2009. AB - AIMS: The purpose of this study was to describe tobacco use in the 2009 Northern Sweden cohort of the World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Diseases (MONICA) study. METHODS: Subjects (N = 1698) were randomly selected from population registers, stratified for age (25 74 years old) and gender, in the two northernmost Swedish counties of Norrbotten and Vasterbotten. Responses from tobacco-related questions were used to develop three mutually exclusive categories of snus use: past, current, or never use; and three comparable categories of smoking that were consistent with previous studies. RESULTS: Among men, the prevalence of smoking (9%) and dual use (2%) remain unchanged from 2004, although the prevalence of snus use declined from 27% in 2004 to 24% in 2009. Among women, the prevalence of all forms of tobacco use declined between 2004 and 2009; smoking dropped from 16% to 11%, dual use from 2% to less than 1%, and snus use from 9% to 8%. Although overall prevalence of tobacco use was similar for younger versus older men and younger versus older women, there were notable differences in specific snus and smoking rates. CONCLUSIONS: This study confirms that use of snus was a significant factor in the low prevalence of smoking, especially among younger men and women in Northern Sweden. Furthermore, it documents that tobacco harm reduction is entirely compatible with a population-level decline in overall tobacco use. PMID- 24052340 TI - A DFT study of the Al2Cl6-catalyzed Friedel-Crafts acylation of phenyl aromatic compounds. AB - The reaction pathways of several Friedel-Crafts acylations involving phenyl aromatic compounds were studied using density functional theory. The reactions were related to the Friedel-Crafts polycondensation of polyaryletherketones. In particular, the acylation of benzene with benzoyl chloride to form benzophenone and variations on this reaction were investigated. The acylation of benzene by one molecule of terephthaloyl chloride or isophthaloyl chloride as well as acylations at the m-, o-, and p-positions of diphenyl ether with one molecule of benzoyl chloride were studied. Adding an additional acyl chloride group to the electrophile appeared to have little influence on the reaction pathway, although the activation energy for the C-C bond-forming steps that occurred when isophthaloyl choride was used was different to the activation energy observed when terephthaloyl chloride was used. Upon changing the nucleophile to diphenyl ether, the reactivity changed according to the trend predicted on based on the o , p-directing effects of the ether group. The deprotonation step that restored aromaticity varied widely according to the reaction. The rate-determining step in all of the studied reactions was the formation of the acylium ion, followed in importance by either the formation of the Wheland intermediate or the abstraction of hydrogen, depending on the reactivity of the nucleophile. PMID- 24052341 TI - The role of caseload in determining outcome following laparoscopic colorectal cancer resection: an observational study. AB - BACKGROUND: This study aimed to evaluate using national data the role of surgeon laparoscopic caseload in determining outcome following elective laparoscopic colorectal cancer resection. METHODS: All patients who underwent an elective laparoscopic primary colorectal cancer resection between 2002 and 2008 were included from the Hospital Episode Statistics database. Surgeon teams were divided into tertiles according to the mean laparoscopic caseload per year. High volume corresponded to more than 12 laparoscopic procedures per year and low volume corresponded to seven or fewer procedures per year. Outcome measures were 30-day in-hospital mortality, return to theatre (RTT), 30-day medical morbidity, 365-day medical morbidity, length of stay (LOS), and unplanned 28-day readmission. RESULTS: There was a significant increase in the number of surgeons selecting patients for the laparoscopic approach between 2002-2003 and 2007-2008. In 2002-2003, a total of 41 surgeon teams performed laparoscopic resections whereas in 2007-2008 there were 398 surgeon teams. The patients of high-volume surgeon teams had a shorter LOS [OR 0.88 (0.85-0.91), p < 0.0001]. Patients of medium-volume surgeon teams had the highest medical morbidity rates [30-day medical morbidity: OR 1.24 (1.04-1.48), p = 0.015; 365-day medical morbidity: OR 1.22 (1.04-1.45), p = 0.018]. There were no differences between the high- and low volume groups in terms of mortality, morbidity, RTT, or readmission. CONCLUSION: Although there has been a significant increase in the number of surgeon teams offering the minimal access approach, this study has not found a consistent relationship between surgeon laparoscopic cancer surgery caseload and outcome. WHAT'S NEW IN THIS MANUSCRIPT: This is the first national study to explore the role of surgical volume in determining outcome following laparoscopic surgery. This study questions the impact of surgeon caseload on laparoscopic surgical outcome. PMID- 24052342 TI - Colorectal anastomosis facilitated by the use of the LigaSure((r)) sealing device: comparative study in an animal model. AB - BACKGROUND: Recently, there has been speculation about the possibility of fusing intestinal tissue using bipolar sealing devices. In this study we compare in a porcine model the anastomoses created using the LigaSure((r)) device with those created with a stapler after section and closure of a rectal stump. METHODS: Thirty pigs underwent laparoscopic colorectal anastomosis. In group A (n = 15), the division of the intestine and distal stump closure were done with a 10-mm LigaSure Atlas((r)) device. In group B, these steps were carried out using an endoscopic stapler. Subsequently, the colorectal anastomosis was performed using circular stapling in both groups. The 4-week follow-up included health status, weight gain, blood tests, X-rays, and colonoscopy. Anastomotic tissue was processed to study the mechanical tensile strength and histopathology. RESULTS: There was no difference in the rate of conversion to open surgery or in average operating time between the groups. In the sealing device group, there was a significantly higher rate of failure in rectal stump closure (p = 0.042). There was one death in group B due to anastomotic leak. There was no difference in adhesion formation or stenosis. Mid-section anastomosis area was 89.7 mm(2) in group A compared with 100 mm(2) in group B (p = 0.52). In tensile strength studies, the maximum load resisted by the sample was 13.8 +/- 4.9 N (group A) versus 15.7 +/- 4.4 N (group B) (p = 0.17). There was no difference between the groups in degree of reepithelialization, number of inflammatory cells, or the presence of microabscesses. CONCLUSIONS: Division and sealing of the rectal stump with the LigaSure((r)) device is feasible in the proposed experimental model, but it is less reliable than conventional closure with a stapler, since it has a significantly greater failure rate. Therefore, The LigaSure((r)) device should not be used for this purpose in the clinical setting as this could lead to serious and dramatic complications. PMID- 24052343 TI - Prediction of protein secondary structure using feature selection and analysis approach. AB - The prediction of the secondary structure of a protein from its amino acid sequence is an important step towards the prediction of its three-dimensional structure. However, the accuracy of ab initio secondary structure prediction from sequence is about 80% currently, which is still far from satisfactory. In this study, we proposed a novel method that uses binomial distribution to optimize tetrapeptide structural words and increment of diversity with quadratic discriminant to perform prediction for protein three-state secondary structure. A benchmark dataset including 2,640 proteins with sequence identity of less than 25% was used to train and test the proposed method. The results indicate that overall accuracy of 87.8% was achieved in secondary structure prediction by using ten-fold cross-validation. Moreover, the accuracy of predicted secondary structures ranges from 84 to 89% at the level of residue. These results suggest that the feature selection technique can detect the optimized tetrapeptide structural words which affect the accuracy of predicted secondary structures. PMID- 24052345 TI - Reflecting on confocal microscopy: a personal perspective. AB - The first practical laser scanning confocal microscopes were introduced to the biomedical community over 30 years ago. Their subsequent development continues to influence the introduction of new methods and applications of optical sectioning microscopy. PMID- 24052344 TI - Hydroxyapatite, fluor-hydroxyapatite and fluorapatite produced via the sol-gel method: dissolution behaviour and biological properties after crystallisation. AB - Hydroxyapatite (HA), fluor-hydroxyapatite (FHA) with varying levels of fluoride ion substitution and fluorapatite (FA) were synthesised by the sol-gel method as possible implant coating or bone-grafting materials. Calcium nitrate and triethyl phosphite were used as precursors under an ethanol-water based solution. Different amounts of ammonium fluoride were incorporated for the preparation of the FHA and FA sol-gels. After heating and powdering the sol-gels, dissolution behaviour was assessed using ion chromatography to measure Ca(2+) and PO4 (3-) ion release. Biological behaviour was assessed using cellular proliferation with human osteosarcoma cells and alamarBlueTM assay. Statistical analysis was performed with a two way analysis of variance and post hoc testing with a Bonferroni correction. Increasing fluoride substitution into an apatite structure decreased the dissolution rate. Increasing the firing temperature of the HA, FHA and FA sol-gels up to 1,000 degrees C decreased the dissolution rate. There was significantly higher cellular proliferation on highly substituted FHA and FA than on HA or Titanium. The properties of an implant coating or bone grafting material can be tailored to meet specific requirements by altering the amount of fluoride that is incorporated into the original apatite structure. The dissolution behaviour can further be altered by the temperature at which the sol-gel is fired. PMID- 24052346 TI - Laser scanning confocal microscopy: history, applications, and related optical sectioning techniques. AB - Confocal microscopy is an established light microscopical technique for imaging fluorescently labeled specimens with significant three-dimensional structure. Applications of confocal microscopy in the biomedical sciences include the imaging of the spatial distribution of macromolecules in either fixed or living cells, the automated collection of 3D data, the imaging of multiple labeled specimens and the measurement of physiological events in living cells. The laser scanning confocal microscope continues to be chosen for most routine work although a number of instruments have been developed for more specific applications. Significant improvements have been made to all areas of the confocal approach, not only to the instruments themselves, but also to the protocols of specimen preparation, to the analysis, the display, the reproduction, sharing and management of confocal images using bioinformatics techniques. PMID- 24052347 TI - Confocal microscopy on the Internet. AB - In a few short years, the Internet (in terms of the World Wide Web) has become a powerful informational resource for the original scientific literature pertaining to biological investigations using the laser scanning confocal microscope. However, there still remains an obvious void in the development of educational Web sites targeted at beginning students and novices in the field. Furthermore, many of the commercial aftermarket manufacturers (for example, those offering live-cell imaging chambers) have Web sites that are not adequately represented in published compilations, and are therefore somewhat difficult to locate. In order to address this issue, several educational sites dedicated to optical microscopy and digital imaging that are being constructed and hosted at The Florida State University are currently turning their attention to the increasing application of confocal microscopy in the biological and materials sciences. The primary focus of this effort is to create new sections on the existing sites that address the important educational issues in confocal microscopy, as well as creating indices of links to both the confocal scientific literature and the Web sites of manufacturers who supply useful accessories. PMID- 24052348 TI - Using Photoshop with images created by a confocal system. AB - Many pure colors and grayscales tones that result from confocal imaging are not reproducible to output devices, such as printing presses, laptop projectors, and laser jet printers. Part of the difficulty in predicting the colors and tones that will reproduce lies in both the computer display, and in the display of unreproducible colors chosen for fluorophores. The use of a grayscale display for confocal channels and a LUT display to show saturated (clipped) tonal values aids visualization in the former instance and image integrity in the latter. Computer monitors used for post-processing in order to conform the image to the output device can be placed in darkened rooms, and the gamma for the display can be set to create darker shadow regions, and to control the display of color. These conditions aid in visualization of images so that blacks are set to grayer values that are more amenable to faithful reproduction. Preferences can be set in Photoshop for consistent display of colors, along with other settings to optimize use of memory. The Info window is opened so that tonal information can be shown via readouts. Images that are saved as indexed color are converted to grayscale or RGB Color, 16-bit is converted to 8-bit when desired, and colorized images from confocal software is returned to grayscale and re-colorized according to presented methods so that reproducible colors are made. Images may also be sharpened and noise may be reduced, or more than one image layered to show colocalization according to specific methods. Images are then converted to CMYK (Cyan, Magenta, Yellow and Black) for consequent assignment of pigment percentages for printing presses. Changes to single images and multiple images from image stacks are automated for efficient and consistent image processing changes. Some additional changes are done to those images destined for 3D visualization to better separate regions of interest from background. Files are returned to image stacks, saved and then printed to best reveal colors, contrast, details and features. PMID- 24052349 TI - Clearing up the signal: spectral imaging and linear unmixing in fluorescence microscopy. AB - The ongoing progress in fluorescence labeling and in microscope instrumentation allows the generation and the imaging of complex biological samples that contain increasing numbers of fluorophores. For the correct quantitative analysis of datasets with multiple fluorescence channels, it is essential that the signals of the different fluorophores are reliably separated. Due to the width of fluorescence spectra, this cannot always be achieved using the fluorescence filters in the microscope. In such cases spectral imaging of the fluorescence data and subsequent linear unmixing allows the separation even of highly overlapping fluorophores into pure signals. In this chapter, the problems of fluorescence cross talk are defined, the concept of spectral imaging and separation by linear unmixing is described, and an overview of the microscope types suitable for spectral imaging are given. PMID- 24052350 TI - Low magnification confocal microscopy of tumor angiogenesis. AB - Blood vessels are critical to normal mammalian development, tissue repair, and growth and treatment of cancer. Mouse research models enable mechanistic studies of blood vessels. We detail how to perfuse mice with fluorescent tomato lectin or the lipophilic fluorophore DiI. We provide details on how to image fluorescently labeled blood vessels. PMID- 24052351 TI - Confocal imaging of butterfly tissue. AB - To understand the molecular events responsible for morphological change requires the ability to examine gene expression in a wide range of organisms in addition to model systems to determine how the differences in gene expression correlate with phenotypic differences. There are approximately 12,000 species of butterflies, most, with distinct patterns on their wings. The most important tool for studying gene expression in butterflies is confocal imaging of butterfly tissue by indirect immunofluorescence using either cross-reactive antibodies from closely related species such as Drosophila or developing butterfly-specific antibodies. In this report, we describe how indirect immunofluorescence protocols can be used to visualize protein expression patterns on the butterfly wing imaginal disc and butterfly embryo. PMID- 24052352 TI - Confocal microscopy of cardiac myocytes. AB - Detailed methods are provided for the preparation and confocal imaging of cardiac myocyte development and differentiation. Examples include protocols for the analysis of cultured myocytes as well as vibratome sections of hearts from embryonic and adult tissue. Techniques include routine labeling of F-actin with phalloidin as well as multiple labeling protocols for colocalization studies and cell volume analysis. PMID- 24052353 TI - Confocal imaging of fluorescently labeled proteins in the Drosophila larval neuromuscular junction. AB - The Drosophila larval neuromuscular junction (NMJ) consists of a presynaptic motor neuron terminal and a postsynaptic muscle cell that offer an accessible and popular model system for the analysis of synaptic growth and function. I describe techniques for visualizing fluorescently labeled proteins within dissected, formaldehyde-fixed second to third instar larval NMJs. In addition, I present two strategies using confocal microscopy to solve a particular problem in NMJ analysis: distinguishing fluorescence in the presynaptic nerve terminal from that in the adjacent postsynaptic muscle cell. This problem arises from the fact that the membrane of the muscle cell envelops the motor neuron terminal with a convoluted process called the subsynaptic reticulum, obscuring the boundary between muscle and nerve. A first strategy entails taking thin optical sections through synaptic boutons to capture a cross section of the nerve terminal, and a second strategy involves visualizing epitope-tagged isoforms of particular proteins that have been transgenically expressed in either the nerve or the muscle. PMID- 24052354 TI - Confocal imaging and three-dimensional visualization of thick autofluorescent specimens. AB - Three-dimensional (3-D) rendering methods (maximum intensity projection, alpha blending, and isosurface rendering) are described for the visualization of thick, autofluorescent, arthropod cuticular structures (e.g., Drosophila melanogaster external genitalic structures) imaged by confocal laser scanning microscopy (CLSM). Additionally, specimen mounting and data collection strategies for thick specimens are described. Axial aberration artifacts are discussed in the context of these methods because of the critical roles they play in the quality of final 3-D images. PMID- 24052355 TI - Vital imaging of multicellular spheroids. AB - Cell behavior is significantly different in two-dimensional and three-dimensional culture conditions, and a number of methods have been developed to establish and study three-dimensional cellular arrays in vitro. When grown under nonadherent conditions, many types of cells form structures called multicellular spheroids (MCSs), which have been popular models to study cell behavior in a three dimensional environment. The histoarchitecture of MCSs derived from malignant cells resembles that of tumors, and there is rapidly increasing interest in using these structures to more accurately understand the dynamics of cancer cells in situ, including their responses to chemotherapeutics. Confocal microscopy is an extremely useful method to investigate cell behavior in MCSs due to its ability to more clearly image fluorescent probes at some depth in three-dimensional structures. This chapter describes some basic approaches toward visualizing a variety of fluorescent probes in MCSs. PMID- 24052356 TI - Live confocal analysis of mutant- and drug-treated Drosophila embryos. AB - The model organism Drosophila melanogaster is particularly well suited for live image analysis. The availability of GFP transgenic flies and a wide array of fluorescent probes, in conjunction with laser scanning confocal microscopy, allow us to image multiple aspects of the cell cycle simultaneously. Confocal microscopy provides the sensitivity and resolution to observe the dynamics of specific cellular events in real time. For example, GFP-histone and rhodamine labeled tubulin enable one to follow specific nuclear and cytoskeletal events including nuclear envelope formation, nuclear envelope breakdown, spindle formation, centrosome duplication, separation and migration, chromosomes condensation, and segregation. This analysis permits a detailed morphological and temporal description of nuclear and cytoskeletal events in normal or drug injected embryos. PMID- 24052357 TI - Confocal imaging of the microtubule cytoskeleton in C. elegans embryos and germ cells. AB - The microtubule cytoskeleton plays important roles in a number of cellular processes including cell division, establishing and maintaining cell architecture and polarity, and intracellular trafficking. The identification and characterization of factors required for the proper functioning of the microtubule cytoskeleton have been aided by approaches that combine sensitive and rapid methods for high-resolution optical imaging, such as confocal microscopy, with the powerful genetics available in model organisms. Here we present methods for confocal imaging of live and fixed tissues of the nematode C. elegans, a model organism that has been employed with great success to study the microtubule cytoskeleton and its roles in cell division and cell polarity. PMID- 24052358 TI - Measurement in the confocal microscope. AB - All measurements require that the microscope must be aligned as accurately as possible, and the gain (or PMT voltage) and black level must be set to avoid any overflow or underflow. Measuring surface profiles and relative depths is straightforward and can be carried out to a higher accuracy than the depth resolution of the microscopes, even though the actual images may look poor. Measuring the thickness of objects which are labeled throughout is less accurate. Length and 2D area measurements are common image analysis problems and easily carried out with image analysis software. Volume measurements are conceptually equally simple but require manual techniques or 3D analysis software. 3D surface area measurements require specialist software, or can be carried out with stereological techniques. Fluorescence intensity measurements require careful calibration. For ratiometric measurements filters and/or laser lines should be chosen to optimize the response and calibration should be done in conditions as close as possible to the experimental ones. FLIM allows exploration of the chemical environment, and multiple labelling even where spectra overlap. When the hardware is available it is also usually the method of choice for measuring FRET, which can measure molecular interactions in the nanometer range. Without FLIM hardware, either intensity measurements with correction for bleed-through and cross talk or acceptor bleaching are the most popular methods of measuring FRET. PMID- 24052359 TI - A method for quantifying blood flow distribution among the alveoli of the lung. AB - This article describes a method for quantifying blood flow distribution among lung alveoli. Our method is based on analysis of trapping patterns of small diameter (4 MUm) fluorescent latex particles infused into lung capillaries. Trapping patterns are imaged using confocal microscopy, and the images are analyzed statistically using SAS subroutines. The resulting plots provide a quantifiable way of assessing interalveolar perfusion distribution in a way that has not previously been possible. Methods for using this technique are described, and the SAS routines are included. This technique can be an important tool for learning how this critical vascular bed performs in health and disease. PMID- 24052360 TI - Imaging tools for analysis of the ureteric tree in the developing mouse kidney. AB - The structure of the ureteric tree in developing mouse and rat kidneys has previously been quantified in two dimensions. While this type of analysis may provide evidence of changes in ureteric growth, these measurements are effectively inaccurate, as the ureteric tree is a three-dimensional (3D) object. Here we describe a method for measuring the ureteric tree in three dimensions. This technique involves (1) culture of the metanephric kidney at embryonic day 12 (mouse) or 14 (rat), (2) whole-mount immunofluorescence to selectively stain ureteric tree epithelium, (3) confocal microscopy to obtain a complete Z series through the ureteric tree, and (4) image analysis algorithms to binarize, skeletonize, and measure individual branch lengths in 3D. This method has been extended to analysis of the same ureteric tree over time (4D). The results obtained provide accurate and precise quantitation of ureteric tree growth in the developing mouse or rat kidney. PMID- 24052361 TI - Evaluating confocal microscopy system performance. AB - A confocal microscope was evaluated with a series of tests that measure field illumination, lens clarity, laser power, laser stability, dichroic functionality, spectral registration, axial resolution, scanning stability, PMT quality, overall machine stability, and system noise. These tests will help investigators measure various parameters on their confocal microscopes to insure that they are working correctly with the necessary resolution, sensitivity, and precision. Utilization of this proposed testing approach will help eliminate some of the subjectivity currently employed in assessing the CLSM performance. PMID- 24052362 TI - Single dose ivabradine versus intravenous metoprolol for heart rate reduction before coronary computed tomography angiography (CCTA) in patients receiving long term calcium channel-blocker therapy. AB - BACKGROUND: In patients with contraindication for beta-blockers who are also under long-term calcium channel-blocker therapy for any reason, ivabradine may be used as an alternative treatment to achieve the target heart rate. PURPOSE: To assess whether single dose oral ivabradine in patients referred for coronary computed tomography angiography (CCTA) is safe and can significantly decrease heart rate compared to intravenous (i.v.) metoprolol in patients receiving long term calcium channel-blocker therapy. MATERIAL AND METHODS: One-hundred and twenty patients who were under calcium channel-blocker therapy referred for CCTA were randomized to premedication with single dose (15 mg) ivabradine (n = 63) or i.v. metoprolol (5-10 mg) (n = 62). Hearth rate (HR) was assessed at admission (HR1), prescan (HR2), and during CCTA scan (HR3) for all patients. Blood pressure (BP) was measured before medication (BP1) and immediately before CCTA scan (BP2). RESULTS: Although the HR averages of two groups were not significantly different before medication (HRIv1 = 80 +/- 7 bpm vs. HRbeta1 = 81 +/- 7 bpm; P = 0.42), significant HR reduction was observed in the ivabradine group (HRIv3 = 62 +/- 7 bpm) when compared to the metoprolol group (HRbeta3 = 66 +/- 6 bpm; P = 0.001). Decreases in HR forivabradine (18 +/- 6 bpm) was significantly higher than for metoprolol (15 +/- 4 bpm; P = 0.003) without relevant side-effects. Ivabradine showed no significant effect on either systolic BP or diastolic BP (siBPIv1, 139 +/- 10; siBPIv2, 138 +/- 10; P = 0.260; diBPIv1, 81 +/- 7; diBPIv2, 81 +/- 6; P = 0.59). Nevertheless, metoprolol group demonstrated significant reduction in both SiBP and DiBP (siBPbeta1, 136 +/- 11; siBPbeta2 130 +/- 11; P < 0.001; diBPbeta1, 81 +/- 6; diBPbeta2, 78 +/- 6; P < 0.001). CONCLUSION: Single dose ivabradine is safe and significantly more effective than i.v. metoprolol in decreasing HR in patients under calcium channel-blocker therapy. PMID- 24052363 TI - Effects of dietary copper on growth, digestive, and brush border enzyme activities and antioxidant defense of hepatopancreas and intestine for young grass carp (Ctenopharyngodon idella). AB - To investigate the effects of dietary copper (Cu) on fish growth, digestive and absorptive enzyme activities, and antioxidant status in the hepatopancreas and intestine, young grass carp (Ctenopharyngodon idella) (282+/-2.8 g) were fed six diets containing 0.74 (basal diet), 2.26, 3.75, 5.25, 6.70, and 8.33 mg Cu /kg diet for 8 weeks. Results showed that percentage weight gain (PWG) and feed intake were increased with dietary Cu levels up to 3.75 mg/kg diet. In addition, the positive effects of dietary Cu at a level 3.75 or 5.25 mg/kg diet on trypsin, chymotrypsin, and lipase activities in the hepatopancreas and of Na(+), K(+) ATPase, alkaline phosphatase, creatine kinase, and gamma-glutamyl transpeptidase activities in three intestine segments produced significantly (P<0.05) better feed efficiency (FE). However, amylase activity in the hepatopancreas was decreased by dietary Cu levels up to 3.75 mg/kg diet (P<0.05). In addition, dietary Cu at 3.75 or 5.25 mg/kg diet decreased malondialdehyde and protein carbonyl content partly by significantly (P<0.05) increasing the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and glutathione content in the hepatopancreas and intestine. Collectively, dietary Cu improved growth and digestive and absorptive capacity and decreased lipid peroxidation and protein oxidation partly by enhancing antioxidant defense in the hepatopancreas and intestine. The dietary Cu requirement for PWG, plasma ceruloplasmin activity, and FE of young grass carp (282-688 g) were 4.78, 4.95, and 4.70 mg/kg diet, respectively. PMID- 24052364 TI - The 1st EMBO workshop on PVC bacteria-Planctomycetes-Verrucomicrobia-Chlamydiae superphylum: exceptions to the bacterial definition? AB - The PVC superphylum is a phylogenetically supported collection of various related bacterial phyla that comprise unusual characteristics and traits. The 'PVC' abbreviation derives from Planctomycetes, Verrucomicrobia and Chlamydiae as members of this superphylum, while additional bacterial phyla are related. There has recently been increasing and exciting interest in the cell biology, physiology and ecology of members of this superphylum, including evolutionary implications of the complex cell organization of some species. It is timely that international researchers in the PVC superphylum field met to discuss these developments. The first meeting entirely dedicated to those bacteria, the EMBO workshop "PVC superphylum: Exceptions to the bacterial definition" was held at the Heidelberg University to catalyze the formation of a vital scientific community supporting PVC-bacterial research. More than 45 investigators from more than 20 countries (PIs, senior scientists and students) attended the meeting and produced a great starting point for future collaborative research. This Special Issue will focus on the EMBO-PVC meeting. This Perspective briefly summarizes the history of PVC-research, focusing on the key findings and provides a brief summary of the meeting with a focus on the major questions that arose during discussion and that might influence the research in the years to come. PMID- 24052365 TI - High ultraviolet C resistance of marine Planctomycetes. AB - Planctomycetes are bacteria with particular characteristics such as internal membrane systems encompassing intracellular compartments, proteinaceous cell walls, cell division by yeast-like budding and large genomes. These bacteria inhabit a wide range of habitats, including marine ecosystems, in which ultra violet radiation has a potential harmful impact in living organisms. To evaluate the effect of ultra-violet C on the genome of several marine strains of Planctomycetes, we developed an easy and fast DNA diffusion assay in which the cell wall was degraded with papain, the wall-free cells were embedded in an agarose microgel and lysed. The presence of double strand breaks and unwinding by single strand breaks allow DNA diffusion, which is visible as a halo upon DNA staining. The number of cells presenting DNA diffusion correlated with the dose of ultra-violet C or hydrogen peroxide. From DNA damage and viability experiments, we found evidence indicating that some strains of Planctomycetes are significantly resistant to ultra-violet C radiation, showing lower sensitivity than the known resistant Arthrobacter sp. The more resistant strains were those phylogenetically closer to Rhodopirellula baltica, suggesting that these species are adapted to habitats under the influence of ultra-violet radiation. Our results provide evidence indicating that the mechanism of resistance involves DNA damage repair and/or other DNA ultra-violet C-protective mechanism. PMID- 24052366 TI - Maricoccus atlantica gen. nov. sp. nov., isolated from deep sea sediment of the Atlantic Ocean. AB - A taxonomic study was carried out on strain 22II-S10r2(T), which was isolated from the deep sea sediment of the Atlantic Ocean using oil-degrading enrichment. The bacterium was Gram-negative, oxidase positive and catalase negative, spherical in shape, and motile by polar flagella. Growth was observed at salinities of 0.5-7 % and at temperatures of 10-41 degrees C. The isolate was capable of aesculin hydrolysis, but unable to reduce nitrate to nitrite or degrade Tween 80 or gelatine. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain 22II-S10r2(T) belonged to the family Ectothiorhodospiraceae, with highest sequence similarity to Thioalkalivibrio sulfidiphilus HL-EbGR7(T) (90.9 % similarity). The principal fatty acids were Sum In Feature 8 (C18:1 omega7c/omega6c (29.9 %), C18:1 omega9c (13.5 %), C16:1 omega5c (12.3 %), C12:03OH (6.8 %), C18:1 omega5c (5.7 %) and C16:0 (5.3 %). The G+C content of the chromosomal DNA was 60.7 mol%. The respiratory quinone was determined to be Q-7 (25 %) and Q-8 (75 %). Phosphatidylethanolamine, phosphatidylglycerol, aminophospholipid, glycolipid, three phospholipids and lipid were present. The strain was aerobic, non-phototrophic and non chemolithoautotrophic. The combined genotypic and phenotypic data show that strain 22II-S10r2(T) represents a novel species within a novel genus, for which the name Maricoccus atlantica gen. nov. sp. nov. is proposed, with the type strain 22II-S10r2(T) (=CGMCC NO.1.12317(T) = LMG 27155(T) = MCCC 1A09384(T)). PMID- 24052367 TI - A phosphoramidon-sensitive metalloprotease induces apoptosis of human endothelial cells by Group B Streptococcus. AB - We explored Group B Streptococcus (GBS)-induced apoptosis in human umbilical vein endothelial cells (HUVEC) and the role of phosphoramidon, a zinc metalloprotease inhibitor, in this process. GBS 90186 strain (serotype V, a blood isolate) and concentrated supernatant (CS) were used to investigate the viability and morphological alterations in HUVEC by Trypan blue uptake, electrophoresis in 2 % agarose gel and scanning electron microscopy assays. Apoptosis before and after phosphoramidon-treatment were verified by flow cytometry using annexin V-FITC labeling. Differences were considered significant when P < 0.05 using unpaired Student's t test. GBS and CS induced HUVEC death by apoptosis (76.5 and 32 %, respectively) with an increasing pro-apoptotic Bax expression and decreasing anti apoptotic Bcl-2 expression. Caspase-3 was activated during GBS-induced endothelial apoptosis. Phosphoramidon reduced 89.3 and 100 % of GBS and CS cell death by apoptosis, respectively. Some GBS strains may induce cell death by apoptosis with involvement of metalloproteases and signaling through the intrinsic pathway of apoptosis, which may contribute to GBS survival during sepsis of adults and neonates. PMID- 24052368 TI - Hyaluronic acid: in vitro and in vivo analysis, biochemical properties and histological and morphological evaluation of injected filler. AB - BACKGROUND: No human model has emerged as an accepted standard to evaluate tissue filler longevity. OBJECTIVES: To validate a human model adequate to compare soft tissue filler degradation and tissue reaction. MATERIALS AND METHODS: We evaluated in 18 patients the persistence of hyaluronic acid (HA) filler injected into labial tissue analyzing hyaluronidase (HYAL) activity by means of in vitro and in vivo tests, MRI and histological and ultra-structural examination at 3 and 6 months postop. RESULTS: MRI examination revealed the presence of HA filler in a clear hyperintense area. Histology demonstrated fibroblast activation. The amount and the degradation rate of HYAL and HA did not show a linear correlation. CONCLUSION: MRI demonstrated the presence of HA in lip tissue even after 6 months. Biopsies at 3 months revealed tissue maturation and at 6 months confirmed the ability of HA to reorganize and integrate the extracellular matrix. The absence of linear correlation between HYAL and HA revealed that the result clinically is probably dependent on systemic factors which can determine HYAL activity and therefore HA longevity. PMID- 24052370 TI - Catalysis-material crosstalk at tailored nano-carbon interfaces. AB - The use of carbon nanomaterials as supports for molecular and nanostructured catalysts is becoming a more and more popular strategy to improve heterogeneous catalysis. Their outstanding electronic and optical properties together with high surface area and thermal and mechanical stabilities make them ideal elements to provide catalysts with additional or improved characteristics. The role of the carbon nanostructures in the different types of catalysis is more intricate and often involves active and strong interactions between the support and the catalytic active species, creating a synergistic effect that in many cases leads to performance enhancement and an expanded range of possible applications. In particular, photocatalysis and electrocatalysis seem to benefit from the features of these types of carbon support, although applicability can be extended to more classic transformations of organic substrates. PMID- 24052369 TI - Role of equine herpesviruses as co-infecting agents in cases of abortion, placental disease and neonatal foal mortality. AB - Herpesviral infections frequently occur in horses. The objective of this study was to investigate the possible association of equine herpesviruses (EHV-1, EHV 2, EHV-3, EHV-4, EHV-5) with other causes of abortion, neonatal mortality or placental disorder. Sixty-seven abortions, 22 stillbirths, 14 cases of neonatal foal mortality and 3 cases of placental disease were investigated for infectious and non-infectious causes. Type-specific nested PCR assays and virus isolation were performed to detect EHV infections. A cause of fetal loss or placental disease was reached in 68 out 116 (58.7%) cases. Twenty-seven cases were positive for EHV, and 22/27 (81.5%) were positive for EHV-1 (16 neuropathogenic and 6 non neuropathogenic strains), 4 (14.8%) for EHV-2 and 3 (11.1%) for EHV-5. The association between EHV infections and other etiological agents was statistically significant (two sided P = 0.002). The odds ratio of EHV DNA associated with other diagnoses, especially with bacterial infection and premature placental separation, was 10.88 (95% confidence interval: 2.15-55.16). EHV-1 was the main viral cause of pregnancy loss in this study, also associated with other etiological agents, including EHV-2 and EHV-5. The latter viruses in particular need to be more fully investigated to elucidate what role either or both may play as co-infecting agents with other established infectious causes of reproductive disease. PMID- 24052371 TI - Risk factors for sports concussion: an evidence-based systematic review. AB - Concussion is a common sports injury with approximately 1.6-3.8 million sport related concussions reported in the USA annually. Identifying risk factors may help in preventing these injuries. This systematic review aims to identify such risk factors. Three electronic databases; ScienceDirect, PubMed and SpringerLink, were searched using the keywords 'RISK FACTORS' or 'PREDISPOSITION' in conjunction with 'SPORT' and 'CONCUSSION'. Based on the inclusion and exclusion criteria, 13 628 identified titles were independently analysed by two of the authors to a final list of 86 articles. Only articles with a level of evidence of I, II and III were included according to robust study design and data analysis. The level of certainty for each risk factor was determined. A high level of certainty for increased risk of a subsequent concussion in athletes sustaining more than one previous concussion was reported in 10 of 13 studies. Further, a high level of certainty was assigned to match play with all 29 studies reporting an increased concussion risk during matches. All other risk factors were evaluated as having a low level of certainty. Although several risk factors were identified from the appraised studies, prospective cohort studies, larger sample sizes, consistent and robust measures of risk should be employed in future research. PMID- 24052372 TI - Percutaneous balloon valvotomy for the treatment of pacemaker lead-induced tricuspid stenosis. PMID- 24052373 TI - Early spontaneous recovery of exocrine pancreatic insufficiency in a 3-year-old child with Shwachman-Diamond syndrome. PMID- 24052374 TI - Johanson-Blizzard syndrome: hepatic and hematological features with novel genotype. AB - Johanson-Blizzard syndrome (JBS); (OMIM: 243800) presents with features of malabsorption and dysmorphic features with onset of symptoms in infantile age group. The disorder was first described in the year 1971 with report of the first Indian case in 2004. We discuss two rare phenotypes (hepatitis and anemia) in a molecularly confirmed case of JBS. PMID- 24052375 TI - Serum HBsAg quantification in treatment-naive Indian patients with chronic hepatitis B. AB - BACKGROUND AND AIMS: There is paucity of Indian data regarding serum HBsAg levels (qHBsAg) in treatment-naive chronic hepatitis B (CHB). This study was done to determine correlation of qHBsAg with hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA levels and its ability to independently categorize subgroups of CHB. METHODS: We studied 131 treatment-naive CHB patients and initially classified them based on HBeAg status. The HBeAg-positive group was further classified into immune tolerance (IT) and immune clearance (IC) phases based on serum alanine aminotransferase. HBeAg-negative patients were classified into low replicators (LR) and HBeAg-negative chronic hepatitis (ENH) based on DNA levels. HBsAg quantification was performed using the Architect chemiluminescence system. RESULTS: HBeAg-positive patients had higher DNA (7.89 vs. 2.69 log10 IU/mL) and higher qHBsAg (4.60 vs. 3.85 log10 IU/mL) compared to the HBeAg-negative group. Good correlation between qHBsAg and DNA was seen in HBeAg-positive (rho = 0.6, p < 0.001) but not in HBeAg-negative CHB (rho = 0.2). A qHBsAg level greater than 4.39 log10 IU/mL predicted HBeAg-positive state with 81 % sensitivity and 85 % specificity. However, among HBeAg-negative CHB, qHBsAg failed to discriminate between LR and ENH. CONCLUSIONS: A single point estimation of qHBsAg in treatment naive patients could predict replicative HBeAg-positive CHB, but was not helpful in defining replicative status in the HBeAg-negative CHB. PMID- 24052377 TI - An introduction to fluorescence imaging techniques geared towards biosensor applications. AB - After providing a brief overview of the basics of fluorescence and FRET, this chapter discusses the most commonly used methods to record FRET. Emphasis is on microscopy methods that are widely used for biosensor imaging. We cover choice of instruments, describe various ways to detect FRET based on intensity as well as on donor lifetime, and provide some guidelines to match particular recording methods with specific scientific experiments. We end with an extensive discussion on further practical considerations that may greatly affect the success of the experiments. PMID- 24052376 TI - The design and application of genetically encodable biosensors based on fluorescent proteins. AB - To track the activity of cellular signaling molecules within the endogenous cellular environment, researchers have developed a diverse set of genetically encodable fluorescent biosensors. These sensors, which can be targeted to specific subcellular regions to monitor specific pools of a given signaling molecule in real time, rely upon conformational changes in a sensor domain to alter the photophysical properties of green fluorescent protein (GFP) family members. In this introductory chapter, we first discuss the properties of GFP family members before turning our attention to the design and application of genetically encodable fluorescent biosensors to live cell imaging. PMID- 24052378 TI - Quantitative measurement of Ca2+ and Zn2+ in mammalian cells using genetically encoded fluorescent biosensors. AB - Genetically encoded, ratiometric, fluorescent biosensors can be used to quantitatively measure intracellular ion concentrations in living cells. We describe important factors to consider when selecting a Ca(2+) or Zn(2+) biosensor, such as the sensor's dissociation constant (K(d')) and its dynamic range. We also discuss the limits of quantitative measurement using these sensors and reasons why a sensor may perform differently in different biological systems or subcellular compartments. We outline protocols for (1) quickly confirming sensor functionality in a new biological system, (2) calibrating a sensor to convert a sensor's FRET ratio to ion concentration, and (3) titrating a sensor in living cells to obtain its K(d') under different experimental conditions. PMID- 24052379 TI - Detecting cAMP with an EPAC-based FRET sensor in single living cells. AB - Cyclic nucleotides such as cGMP and cAMP play pivotal roles as second messengers in many biological processes. Upon stimulation of appropriate signal transduction pathways, the levels of these messengers change rapidly. Such variations in second messenger level may also be spatially restricted within the cell. To detect dynamic and local changes in second messengers, we need to study them in living cells with high spatial and temporal resolution. Focusing on cAMP, here we describe how imaging of an EPAC-based FRET sensor in single cells provides that spatiotemporal resolution. PMID- 24052380 TI - Analysis of compartmentalized cAMP: a method to compare signals from differently targeted FRET reporters. AB - Forster resonance energy transfer (FRET)-based reporters are important tools to study the spatiotemporal compartmentalization of cyclic adenosine monophosphate (cAMP) in living cells. To increase the spatial resolution of cAMP detection, new reporters with specific intracellular targeting have been developed. Therefore it has become critical to be able to appropriately compare the signals revealed by the different sensors. Here we illustrate a protocol to calibrate the response detected by different targeted FRET reporters involving the generation of a dose response curve to the cAMP raising agent forskolin. This method represents a general tool for the accurate analysis and interpretation of intracellular cAMP changes detected at the level of different subcellular compartments. PMID- 24052381 TI - Genetically encoded fluorescent biosensors for live cell imaging of lipid dynamics. AB - Fluorescence imaging provides a powerful technique to visualize spatiotemporal dynamics of biomolecules in living cells, if fluorescent biosensors for the relevant biomolecules become available. Here I describe a fluorescent biosensor for a lipid second messenger, phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3). The biosensor overcomes limitations of existing methods for the lipid analysis and allows us to pinpoint that the PI(3,4,5)P3 concentrations are increasing and/or decreasing not only at the plasma membrane but also at organelle membranes, such as the Golgi apparatus membranes and endoplasmic reticulum membranes. The present biosensor has also been shown to be applicable to a variety of lipid second messengers, including diacylglycerol and phosphatidylinositol 3,4-bisphosphate. PMID- 24052382 TI - Live-cell imaging of cytosolic NADH-NAD+ redox state using a genetically encoded fluorescent biosensor. AB - NADH is an essential redox cofactor in numerous metabolic reactions, and the cytosolic NADH-NAD(+) redox state is a key parameter in glycolysis. Conventional NADH measurements rely on chemical determination or autofluorescence imaging, which cannot assess NADH specifically in the cytosol of individual live cells. By combining a bacterial NADH-binding protein and a fluorescent protein variant, we have created a genetically encoded fluorescent biosensor of the cytosolic NADH NAD(+) redox state, named Peredox (Hung et al., Cell Metab 14:545-554, 2011). Here, we elaborate on imaging methods and technical considerations of using Peredox to measure cytosolic NADH:NAD(+) ratios in individual live cells. PMID- 24052383 TI - Measuring membrane voltage with microbial rhodopsins. AB - Membrane voltage (Vm) is a fundamental biological parameter that is essential for neuronal communication, cardiac activity, transmembrane transport, regulation of signaling, and bacterial motility. Optical measurements of Vm promise new insights into how voltage propagates within and between cells, but effective optical contrast agents have been lacking. Microbial rhodopsin-based fluorescent voltage indicators are exquisitely sensitive and fast, but very dim, necessitating careful attention to experimental procedures. This chapter describes how to make optical voltage measurements with microbial rhodopsins. PMID- 24052384 TI - Imaging the activity of Ras superfamily GTPase proteins in small subcellular compartments in neurons. AB - Resolving the spatiotemporal dynamics of intracellular signaling is important for understanding the molecular mechanisms of various cellular processes induced by extracellular signals. Two-photon fluorescence lifetime imaging microscopy (2pFLIM) in combination with a fluorescence resonance energy transfer (FRET) based signaling sensors allows one to image signaling within small subcellular compartments, such as dendritic spines of neurons, with high sensitivity and spatiotemporal resolution. In this protocol, we describe the procedures and equipment required for imaging intracellular signaling activity, with a particular focus on signaling mediated by the Ras superfamily of small GTPase proteins. PMID- 24052385 TI - Imaging kinase activity at protein scaffolds. AB - Kinase signaling is under tight spatiotemporal control, with signaling hubs within the cell often coordinated by protein scaffolds. Genetically encoded kinase activity reporters afford a unique tool to interrogate the rate, amplitude, and duration of kinase signaling at specific locations throughout the cell. This protocol describes how to assay kinase activity at a protein scaffold in live cells using a fluorescence resonance energy transfer (FRET)-based kinase activity sensor for protein kinase D (PKD) as an example. PMID- 24052386 TI - Using a genetically encoded FRET-based reporter to visualize calcineurin phosphatase activity in living cells. AB - Calcineurin is an evolutionarily conserved, ubiquitously expressed protein phosphatase that serves as a major effector of Ca(2+) signals, regulating diverse biological processes such as gene expression, tissue differentiation, immune responses, and neural plasticity. The following method describes how to monitor real-time calcineurin activity in cultured mammalian cells using a fluorescence resonance energy transfer (FRET)-based activity reporter. PMID- 24052387 TI - Genetically encoded FRET indicators for live-cell imaging of histone acetylation. AB - Histone acetylation is dynamically and reversibly controlled by histone acetyltransferases and deacetylases during cellular events such as cell division and differentiation. However, the dynamics of histone modifications in living cells are poorly understood because of the lack of experimental tools to monitor them in a real-time fashion. Herein, we introduce Forster/fluorescence resonance energy transfer (FRET)-based indicators to visualize acetylation of histone H4, and describe a protocol for live-cell imaging with high spatiotemporal resolution. PMID- 24052388 TI - Genetically encoded fluorescent biosensors for live-cell imaging of MT1-MMP protease activity. AB - The proteolytic activity of Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) is crucial for cancer cell invasion and metastasis. To visualize the protease activity of MT1-MMP with high spatiotemporal resolution at the extracellular plasma membrane surface of live cancer cells, a genetically encoded fluorescent biosensor of MT1-MMP has been developed. Here we describe the design principles of the MT1-MMP biosensor, the characterization of the MT1-MMP biosensor in vitro, and the live-cell imaging protocol used to visualize MT1-MMP activity in mammalian cells. We also provide brief guidelines for observing MT1-MMP subcellular activity by fluorescence resonance energy transfer (FRET) in a cell migration assay. PMID- 24052389 TI - Biosensor imaging in brain slice preparations. AB - Cyclic-AMP dependent protein kinase (PKA) is present in most branches of the animal kingdom, and is an example in the nervous system where a kinase effector integrates the cellular effects of various neuromodulators. The recent development of FRET-based biosensors, such as AKAR, now allows the direct measurement of PKA activation in living cells by simply measuring the ratio between the fluorescence emission at the CFP and YFP wavelengths upon CFP excitation. This novel approach provides data with a temporal resolution of a few seconds at the cellular and even subcellular level, opening a new avenue of understanding the integration processes in space and time. Our protocol has been optimized to study morphologically intact mature neurons and we describe how simple and cheap wide-field imaging, as well as more elaborate two-photon imaging, allows real-time monitoring of PKA activation in pyramidal cortical neurons in neonate rodent brain slices. In addition, many practical details presented here also pertain to image analysis in other cellular preparations, such as cultured cells. Finally, this protocol can also be applied to the various other CFP-YFP-based FRET biosensors that are available for other kinases or other intracellular signals. It is likely that this kind of approach will be generally applicable to a broad range of assays in the near future. PMID- 24052390 TI - Optical calcium imaging using DNA-encoded fluorescence sensors in transgenic fruit flies, Drosophila melanogaster. AB - The invention of protein-based fluorescent biosensors has paved the way to target specific cells with these probes and visualize intracellular processes not only in isolated cells or tissue cultures but also in transgenic animals. In particular, DNA-encoded fluorescence proteins sensitive to Ca(2+) ions are often used to monitor changes in intracellular Ca(2+) concentrations. This is of particular relevance in neuroscience since the dynamics of intracellular Ca(2+) concentrations represents a faithful correlate for neuronal activity, and optical Ca(2+) imaging is commonly used to monitor spatiotemporal activity across populations of neurons. In this respect Drosophila provides a favorable model organism due to the sophisticated genetic tools that facilitate the targeted expression of fluorescent Ca(2+) sensor proteins. Here we describe how optical Ca(2+) imaging of neuronal activity in the Drosophila brain can be carried out in vivo using two-photon microscopy. We exemplify this technique by describing how to monitor odor-evoked Ca(2+) dynamics in the primary olfactory center of the Drosophila brain. PMID- 24052391 TI - A multiparameter live cell imaging approach to monitor cyclic AMP and protein kinase A dynamics in parallel. AB - Parallel detection of signaling activities allows us to correlate activity dynamics between signaling molecules. In this review, we detail a multiparameter live cell imaging method to monitor 3',5'-cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activities in parallel. PMID- 24052392 TI - FRET and BRET-based biosensors in live cell compound screens. AB - Live cell compound screening with genetically encoded fluorescence or bioluminescence-based biosensors offers a potentially powerful approach to identify novel regulators of a signaling event of interest. In particular, compound screening in living cells has the added benefit that the entire signaling network remains intact, and thus the screen is not just against a single molecule of interest but against any molecule within the signaling network that may modulate the distinct signaling event reported by the biosensor in use. Furthermore, only molecules that are cell permeable or act at cell surface receptors will be identified as "hits," thus reducing further optimization of the compound in terms of cell penetration. Here we discuss a detailed protocol for using genetically encoded biosensors in living cells in a 96-well format for the execution of high throughput compound screens and the identification of small molecules which modulate a signaling event of interest. PMID- 24052393 TI - Integrating fluorescent biosensor data using computational models. AB - This book chapter provides a tutorial on how to construct computational models of signaling networks for the integration and interpretation of FRET-based biosensor data. A model of cAMP production and PKA activation is presented to provide an example of the model building process. The computational model is defined using hypothesized signaling network structure and measured kinetic parameters and then simulated in Virtual Cell software. Experimental acquisition and processing of FRET biosensor data is discussed in the context of model validation. This data is then used to fit parameters of the computational model such that the model can more accurately predict experimental data. Finally, this model is used to show how computational experiments can interrogate signaling networks and provide testable hypotheses. This simple, yet detailed, tutorial on how to use computational models provides biologists that use biosensors a powerful tool to further probe and evaluate the underpinnings of a biological response. PMID- 24052394 TI - Antidepressant exposure in utero is associated with an increased risk of cardiovascular malformation. PMID- 24052395 TI - A 5-day course of systemic corticosteroids is adequate to treat acute exacerbations of chronic obstructive pulmonary disease. PMID- 24052396 TI - Does treatment of depression in ageing populations decrease risk of mortality? PMID- 24052397 TI - Aspirin plus clopidogrel in acute minor ischaemic stroke or transient ischaemic attack is superior to aspirin alone for stroke risk reduction: CHANCE trial. PMID- 24052398 TI - Meta-analysis: antidepressant exposure during pregnancy is associated with poor neonatal adaptation. PMID- 24052399 TI - Functional characterization of polyunsaturated fatty acid delta 6-desaturase and elongase genes from the black seabream (Acanthopagrus schlegelii). AB - Fatty acid delta 6-desaturase (D6DES) and elongases are key enzymes in the synthesis of polyunsaturated fatty acids (PUFAs) including arachidonic acid (ARA) and eicosapentaenoic acid (EPA) from microorganisms to higher animals. To identify the genes encoding D6DES and elongases for PUFAs, we isolated each cDNA with a high similarity to the D6DES and ELOVL5-like elongases of mammals and fishes via degenerate PCR and RACE-PCR from Acanthopagrus schlegelii. A recombinant vector expressing AsD6DES was subsequently constructed and transformed into Saccharomyces cerevisiae to test the enzymatic activity toward n 6 and n-3 fatty acids in the PUFA biosynthesis. The heterologously expressed AsD6DES produced gamma-linolenic acid (GLA, C18:3 n-6) and stearidonic acid (STA, C18:4 n-3) at conversion rates of 26.3-35.6% from exogenous linoleic acid (LA, C18:2 n-6) and alpha-linolenic acid (ALA, C18:3 n-3) substrates, respectively. When AsELOVL5 was expressed in yeast, it conferred an ability to elongate GLA to di-homo-gamma-linolenic acid (DGLA, C20:3 n-6). In addition, AsELOVL5 showed an ability to convert ARA (C20:4 n-6) and EPA (C20:5 n-3) to dodecylthioacetic acid (DTA, C22:4 n-6) and docosapentaenoic acid (DPA, C22:5 n-3), respectively. In these results, the AsD6DES encodes a delta 6-fatty acid desaturase and the AsELOVL5 encoding a long-chain fatty acid elongase shows activity to enlongate C18Delta6/C20Delta5, but not C22. PMID- 24052400 TI - Acaricidal properties of an Ailanthus altissima bark extract against Psoroptes cuniculi and Sarcoptes scabiei var. cuniculi in vitro. AB - The potential acaricidal properties of an Ailanthus altissima bark extract were assessed against two common species of animal ectoparasitic mites, Psoroptes cuniculi and Sarcoptes scabiei var. cuniculi, in vitro. A. altissima bark extract was obtained by ethanol thermal circumfluence and tested at four concentrations (1.0, 0.5, 0.25 and 0.125 g/ml) on mites collected from rabbits. Compared to the fenvalerate treatment group, the A. altissima bark exhibited significant acaricidal properties for both mite species treated. The extract of concentrations of 1.0, 0.5 and 0.25 g/ml killed all tested S. scabiei within 7 h, however, only 1.0 and 0.5 g/ml of extract killed all treated P. cuniculi. The median lethal time (LT50) values at 1, 0.5 and 0.25 g/ml were 0.60, 0.78, 1.48 h for S. scabiei and 0.74, 1.29, 3.33 h for P. cuniculi. The median lethal concentration (LC50) for P. cuniculi was approximately 1.6 times that for S. scabiei var. cuniculi at 4 h. The extract showed stronger toxicity against S. scabiei than against P. cuniculi. Mortality rates increased with increasing concentration of extract administered and with increasing time post-treatment, indicating that the acaricidal activity of A. altissima bark extract is both time dependent and dose-dependent. This is the first report on acaricidal activity of A. altissima against P. cuniculi and S. scabiei var. cuniculi. It indicates that A. altissima contain potential acaricidal compounds. Our study is the first step to develop potentially novel compounds from A. altissima for the effective control of mites in livestock. PMID- 24052401 TI - Homozygous dystroglycan mutation associated with a novel muscle-eye-brain disease like phenotype with multicystic leucodystrophy. AB - Defects in dystroglycan post-translational modification result in congenital muscular dystrophy with or without additional eye and brain involvement, are referred to as secondary dystroglycanopathies and have been associated with mutations in 11 different genes encoding glycosyltransferases or associated proteins. However, only one patient with a mutation in the dystroglycan encoding gene DAG1 itself has been described before. We here report a homozygous novel DAG1 missense mutation c.2006G>T predicted to result in the amino acid substitution p.Cys669Phe in the beta-subunit of dystroglycan in two Libyan siblings. The affected girls presented with a severe muscle-eye-brain disease like phenotype with distinct additional findings of macrocephaly and extended bilateral multicystic white matter disease, overlapping with the cerebral findings in patients with megalencephalic leucoencephalopathy with subcortical cysts. This novel clinical phenotype observed in our patients further expands the clinical spectrum of dystroglycanopathies and suggests a role of DAG1 not only for dystroglycanopathies but also for some forms of more extensive and multicystic leucodystrophy. PMID- 24052402 TI - Acute traumatic instability of the coccyx: results in 28 consecutive coccygectomies. AB - INTRODUCTION: Coccygeal instability includes hypermobility, subluxation and fracture-dislocation. Surgical resection is still controversial, with intractable post-traumatic coccygodynia being an indication to surgery. MATERIALS AND METHODS: From 2001 to 2010, we enrolled 31 patients with post-traumatic coccygodynia (19 females, 12 males; mean age 31 years, range 21-47). Conservative treatment failed in 28 patients, who underwent surgical resection of the coccyx. Twenty-one were total, while seven were partial coccygectomies. At follow-up (mean 33 months; range 24-70), clinical outcomes evaluation included measurement of complications rate, pain relief and satisfaction degree. RESULTS: Nineteen patients experienced complete pain relief, while two had incomplete, and four had no relief. Partial coccygectomies were associated with poor results. Twenty-one patients were satisfied, whilst four were not. CONCLUSIONS: Coccygectomy is the treatment of choice for post-traumatic instability. Patients' selection allowed excellent or good results. This study favors a more aggressive approach including total resection of the coccyx. PMID- 24052403 TI - The Universal Clamp hybrid system: a safe technique to correct deformity and restore kyphosis in adolescent idiopathic scoliosis. AB - PURPOSE: Adolescent idiopathic scoliosis (AIS) is a tridimensional deformity characterized by coronal and sagittal profiles changes. We present a series of 62 patients affected by AIS and treated by thoracic Universal Clamps and transpedicular lumbar screws hybrid system. METHODS: Mean age was 13 years. Average pre-operative Cobb angle was 63 degrees +/- 12 degrees . Patients were divided into two groups depending on the kyphosis angle: lower than 45 degrees (51 patients, 82.3 %, mean 21 degrees +/- 3 degrees ) and higher than 45 degrees (11 patients, 17.7 %, mean 62 degrees +/- 6 degrees ). RESULTS: The average percentage of coronal correction was 70 +/- 3 % (mean post-operative Cobb angle 19 degrees +/- 4 degrees , P < 0.001). In patients with pre-operative physiological thoracic kyphosis-hypokyphosis, we observed an increase in the average value (32 degrees +/- 4 degrees , P < 0.001), while in patients with pre operative hyperkyphosis, mean decrease of thoracic kyphosis was 19 degrees +/- 3 degrees (43 degrees +/- 4 degrees , P < 0.001). CONCLUSIONS: This case-series study showed the efficacy and safety of Universal Clamp hybrid system in correcting coronal deformity and restoring physiological thoracic kyphosis in patients affected by AIS. PMID- 24052404 TI - Instrumented fusion surgery in elderly patients (over 75 years old): clinical and radiological results in a series of 53 patients. AB - OBJECTIVE: To evaluate the clinical and radiological outcomes of elderly (>75 years old) patients who underwent spinal instrumented fusion surgery. METHODS: Patients underwent lumbar pedicle screw fixation and fusion for degenerative spondylolisthesis. Clinical and radiological outcomes were assessed. RESULTS: 53 patients were studied. Pre-operative VAS was 7.8, ODI was 47.6 %. 254 screws were placed (36 single level; 13 double levels and 4 cases three-levels). No mortality occurred. At 18 months follow-up VAS was 4.1, ODI was 21.8 %. A stable fusion was observed in 41 patients (78.8 %); in four cases there was minimal sign of instability and seven patients underwent a second surgery due to screw mobilization. CONCLUSION: Spinal fixation and fusion in patients older than 75 years old grants good results in terms of quality of life but the rate of morbidity is higher than standard spine surgery. Rate of fusion especially is still a critical point. PMID- 24052405 TI - Revision of surgical correction of scoliosis in pediatric patients affected by neuromuscular pathology using Unit Rod instrumentation. AB - PURPOSE: The purpose of this study is to present a large consecutive series of pediatric patients affected by neuromuscular scoliosis treated with Unit Rod instrumentation. METHODS: Retrospective review of 160 children treated with Unit Rod instrumentation between 2003 and 2010. This review analyzed complications, radiographic outcome, time surgery, average blood loss, hospital staying and functional outcome of patients and parents after surgery. The follow-up of 80 patients is at more than 5 years. RESULTS: Scoliosis was corrected from a mean of 56 degrees range 21 degrees to 76 degrees Cobb (68 %). Pelvic obliquity was corrected from a mean of 24 degrees to 5 degrees (74 %). Major complications are not related to the technique but to the pathology. CONCLUSION: Unit Rod instrumentation is a common standard technique, is considerably less expensive than the other system, and remains a good indication for the treatment of the spinal deformity in children affected by neuromuscular disease. PMID- 24052406 TI - Compensatory mechanisms contributing to keep the sagittal balance of the spine. AB - INTRODUCTION: Aging spine is characterized by facet joints arthritis, degenerative disc disease, bone remodeling and atrophy of extensor muscles resulting in a progressive kyphosis of the lumbar spine. OBJECTIVE: The aim of this paper is to describe the different compensatory mechanisms for patients with severe degenerative lumbar spine. MATERIAL AND METHODS: According to the severity of the imbalance, three stages are observed: balanced, balanced with compensatory mechanisms and imbalanced. For the two last stages, the compensatory mechanisms permit to limit the consequences of loss of lumbar lordosis on global sagittal alignment and therefore contribute to keep the sagittal balance of the spine. RESULTS: The basic concept is to extend adjacent segments of the kyphotic spine allowing for compensation of the sagittal unbalance but potentially inducing adverse effects. CONCLUSION: Finally, we propose a three-step algorithm to analyze the global balance status and take into consideration the presence of the compensatory mechanisms in the spinal, pelvic and lower limb areas. PMID- 24052407 TI - (E)-2,4-Bis(p-hydroxyphenyl)-2-butenal inhibits tumor growth via suppression of NF-kappaB and induction of death receptor 6. AB - The Maillard reaction products are known to be effective in chemoprevention. Here, we focused on the anti-cancer effects of (E)-2,4-bis(p-hydroxyphenyl)-2 butenal on in vitro and in vivo colon cancer. We analysed the anti-cancer activity of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal on colon cancer cells by using cell cycle and apoptosis analysis. To elucidate it's mechanism, NF-kappaB DNA binding activity, docking model as well as pull-down assay. Further, a xenograft model of colon cancer was studied to test the in vivo effects of (E)-2,4-bis(p hydroxyphenyl)-2-butenal. (E)-2,4-Bis(p-hydroxyphenyl)-2-butenal inhibited colon cancer cells (SW620 and HCT116) growth followed by induction of apoptosis in a concentration-dependent manner via down-regulation of NF-kappaB activity. In docking model as well as pull-down assay, (E)-2,4-bis(p-hydroxyphenyl)-2-butenal directly binds to three amino acid residues of IKKbeta, thereby inhibited IKKbeta activity in addition to induction of death receptor 6 (DR6) as well as their target apoptotic genes. Finally, (E)-2,4-bis(p-hydroxyphenyl)-2-butenal suppressed anchorage-independent cancer cell growth, and tumor growth in xenograft model accompanied with apoptosis through inhibition of IKKbeta/NF kappaB activity, and overexpression of DR6. These results suggest that (E)-2,4 bis(p-hydroxyphenyl)-2-butenal inhibits colon cancer cell growth through inhibition of IKKbeta/NF-kappaB activity and induction of DR6 expression. PMID- 24052408 TI - Superoxide activates mTOR-eIF4E-Bax route to induce enhanced apoptosis in leukemic cells. AB - Mammalian target of rapamycin (mTOR) is a central kinase that regulates cell survival, proliferation and translation. Reactive oxygen species (ROS) are second messengers with potential in manipulating cellular signaling. Here we report that two ROS generating phytochemicals, hydroxychavicol and curcumin synergize in leukemic cells in inducing enhanced apoptosis by independently activating both mitogen activated protein kinase (MAPK) (JNK and P(38)) and mTOR pathways. Low level transient ROS generated after co-treatment with these phytochemicals led to activation of these two pathways. Both mTOR and MAPK pathways played important roles in co-treatment-induced apoptosis, by knocking down either mTOR or MAPKs inhibited apoptosis. Activation of mTOR, as evident from phosphorylation of its downstream effector eukaryotic translation initiation factor 4E-binding protein 1, led to release of eukaryotic translation initiation factor 4E (eIF4E) which was subsequently phosphorylated by JNK leading to translation of pro-apoptotic proteins Bax and Bad without affecting the expression of anti-apoptotic protein Bcl-xl. Our data suggest that mTOR and MAPK pathways converge at eIF4E in co treatment-induced enhanced apoptosis and provide mechanistic insight for the role of mTOR activation in apoptosis. PMID- 24052409 TI - Mahanine synergistically enhances cytotoxicity of 5-fluorouracil through ROS mediated activation of PTEN and p53/p73 in colon carcinoma. AB - 5-Fluorouracil (5-FU) alone or in combination with other drugs is the main basis of chemotherapeutic treatment in colorectal cancer although patients with microsatellite instability generally show resistance to 5-FU treatment. The present investigation is focussed on the mechanistic insight of a pure herbal carbazole alkaloid, mahanine, as a single or in combination with 5-FU in colon cancer. We demonstrated that mahanine-induced apoptosis involved reactive oxygen species (ROS)-mediated nuclear accumulation of PTEN and its interaction with p53/p73. Mahanine and 5-FU in combination exerted synergistic inhibitory effect on cell viability. This combination also enhanced ROS production, increased tumour suppressor proteins and suppressed chemo-migration. Taken together, our results revealed that mahanine can be a potential chemotherapeutic agent with efficacy to reduce the concentration of toxic 5-FU in colon cancer. PMID- 24052410 TI - MicroRNA-29a protects against acute liver injury in a mouse model of obstructive jaundice via inhibition of the extrinsic apoptosis pathway. AB - Recent studies have shown that microRNA-29 (miR-29) is significantly decreased in liver fibrosis, as demonstrated in human liver cirrhosis, and that its downregulation influences the activation of hepatic stellate cells. In addition, both cleaved caspase-3 production and apoptosis play a role in cholestatic liver injury. However, it is unknown if miR-29 is effective in modulating the extent of injury. We employed miR-29a transgenic mice (miR-29aTg mice) and wild-type (WT) littermates to clarify the role of miR-29 in hepatic injury and fibrogenesis, using the bile duct-ligation (BDL) mouse model. After BDL, all three members of the miR-29 family were significantly downregulated in the livers of WT mice, and miR-29b and miR-29c were significantly downregulated in the livers of the miR 29aTg mice. Liver function, as measured by alanine transaminase and aspartate transaminase activity, was significantly improved in the miR-29aTg mice than in the WT littermates, following 1 week of obstructive jaundice. In addition, overexpression of miR-29a was associated with a significant downregulation of the expression of collagen-1alpha1, collagen-4alpha1, phospho-FADD, cleaved caspase 8, cleaved caspase-3, Bax, Bcl-2, PARP, and nuclear factor-kappaB, as well as an upregulation of phospho-AKT expression. In addition, there were significantly fewer TUNEL-positive liver cells in the miR-29aTg group than in the WT littermates after BDL. Our results indicate that miR-29a decreases cholestatic liver injury and fibrosis after BDL, at least partially, by modulating the extrinsic rather than intrinsic pathway of apoptosis. PMID- 24052412 TI - HN(CA)N and HN(COCA)N experiments for assignment of large disordered proteins. AB - Two new 3D HN-based experiments are proposed for backbone assignment of large disordered proteins. The spectra obtained with the new pulse schemes are free of redundant diagonal peaks (HiNi-Ni) and provide sequential correlations (HiNi-Ni+1 and HiNi-Ni-1) not only between adjacent non-proline residues but also between non-proline and proline residues. The experiments have been demonstrated on an intrinsically disordered protein with 306 amino acids including 64 proline residues. Using the two experiments, we obtained nearly complete assignments of backbone amides and proline (15)N spins except for 4 proline and 4 non-proline residues. PMID- 24052411 TI - The osteogenic effect of erythropoietin on human mesenchymal stromal cells is dose-dependent and involves non-hematopoietic receptors and multiple intracellular signaling pathways. AB - Erythropoietin (EPO) is a pleiotropic growth factor. Of interest for skeletal tissue engineering, the non-hematopoietic capabilities of EPO include its osteogenic and angiogenic potencies. The main aim of this study was to investigate the dose-response relationship and determine the lowest effective dose of EPO that reliably increases the osteogenic differentiation of human mesenchymal stromal cells (hMSCs). Additional aims were to elucidate the surface receptors and to investigate the role of the intracellular signaling pathways by blocking the mammalian target of rapamycin (mTOR), Jak-2 protein tyrosine kinase (JAK2), and phosphoinositide 3-kinases (PI3K). The primary outcome measures were two mineralization assays, Arsenazo III and alizarin red, applied after 10, 14, and 21 days. Moreover, alkaline phosphatase activity, cell number, and cell viability were determined after 2 and 7 days. A proportional dose-response relationship was observed. In vivo, the lowest effective dose of 20 IU/ml should be used for further research to accommodate safety concerns about adverse effects. Ex vivo, the most effective dose of 100 IU/ml could facilitate vascularization and bone ingrowth in cell-based scaffolds. The expression of non hematopoietic receptors EPOR and CD131 was documented, and EPO triggered all three examined intracellular pathways. Future studies of the efficacy of EPO in cell-based tissue engineering can benefit from our findings. PMID- 24052414 TI - Clonal immortalized human glial cell lines support varying levels of JC virus infection due to differences in cellular gene expression. AB - JC virus (JCV) is a ubiquitous human polyomavirus that causes the demyelinating disease Progressive Multifocal Leukoencephalopathy (PML). JCV replicates in limited cell types in culture, predominantly in human glial cells. Following introduction of a replication defective SV40 mutant that expressed large T protein into a heterogeneous culture of human fetal brain cells, multiple phenotypes became immortalized (SVG cells). A subset of SVG cells could support JCV replication. In the current study, clonal cell lines were selected from the original SVG cell culture. The 5F4 clone showed low levels of viral growth. The 10B1 clone was highly permissive for JCV DNA replication and gene expression and supported persistent and stable JCV infection over months in culture. Microarray analysis revealed that viral infection did not significantly change gene expression in these cells. More resistant 5F4 cells expressed high levels of transcription factors known to inhibit JCV transcription. Interestingly, 5F4 cells expressed high levels of RNA of markers of radial glia and 10B1 cells had high expression of markers of immature glial cells and activation of transcription regulators important for stem/progenitor cell self-renewal. These SVG-derived clonal cell lines provide a biologically relevant model to investigate cell type differences in JCV host range and pathogenesis, as well as neural development. Several transcription regulators were identified which may be targets for therapeutic modulation of expression to abrogate JCV replication in PML patients. Additionally, these clonal cell lines can provide a consistent culture platform for testing therapies against JCV infection of the central nervous system. PMID- 24052413 TI - Relationship between body composition and both cardiovascular risk factors and lung function in systemic sclerosis. AB - The aims of this study were to evaluate body composition in systemic sclerosis (SSc) and to assess its association with the traditional risk factors for atherosclerosis and parameters of lung function. Eighty-six patients affected by SSc (13 men and 73 women, mean age 58.5 years, mean disease duration 10.7 years, 31 with diffuse form and 55 with limited pattern) underwent evaluation of body composition using a dual-energy X-ray (DXA) fan beam densitometer (GE Lunar iDXA) in order to assess total and regional body fat mass and fat-free mass. Clinical features, pulmonary function parameters, and the concomitant presence of the traditional cardiovascular risk factors were recorded. Android fat resulted to be higher in SSc patients with coexistence of hypercholesterolemia (P = 0.021), hypertension (P = 0.028), and overweight/obesity (P < 0.001) and positively correlated with body mass index (P < 0.001). Forced vital capacity (FVC) was inversely correlated with android fat (P = 0.034) and with the android fat/gynoid fat ratio (P = 0.013) and positively correlated with android lean (P = 0.041); the correlations were improved when FVC data were adjusted for sex, age, disease duration, and smoking habits (P = 0.010 for android fat, P = 0.010 for android fat/gynoid fat ratio, P = 0.011 for android lean). In this study, we showed that visceral abdominal fat, measured by DXA, is correlated with the main cardiovascular risk factors and lung volumes in SSc patients. Longitudinal studies are needed to evaluate if decrease of abdominal fat would improve lung function. PMID- 24052415 TI - Cooperative role between p21cip1/waf1 and p27kip1 in premature senescence in glandular proliferative lesions in mice. AB - Cellular senescence has been considered a novel target for cancer therapy. It has also been pointed out that p21(cip1/waf1) and p27(kip1) cyclin-dependent kinase inhibitors (CKIs) play a role in cellular senescence in some tumor types. Therefore, in order to address the possibility of a cooperative role between p21 and p27 proteins in senescence in vivo we analyzed cellular senescence in spontaneous glandular proliferative lesions (adrenal, thyroid and pituitary glands) in a double-KO mice model, using gammaH2AX, p53, p16, PTEN and Ki67 as senescence markers. The results obtained showed that p21p27 double-null mice had the lowest number of gammaH2AX positive cells in glandular hyperplasias and benign tumors. Also, in this group, Ki67 proliferation index correlated with a lower immunohistochemical expression of gammaH2AX and p53. The expression of p16 and PTEN do not seem to cause synergism of senescence in the benign lesions analyzed in p21p27 double-KO mice. These observations suggest an intrinsic cooperation between p21 and p27 CKIs in the activation of stress-induced cellular senescence and tumor progression in vivo, which would be a physiological mechanism to prevent tumor cell proliferation. PMID- 24052416 TI - Minimally invasive and computer-assisted total knee arthroplasty versus conventional technique: a prospective, randomized study. AB - We conducted a prospective, randomized study to compare the short-term results of minimally invasive and computer-assisted total knee arthroplasty (MICA-TKA) with those of conventional total knee arthroplasty (C-TKA) for 12-month follow-up. A total of 87 subjects who met the inclusion and exclusion criteria of the study were prospectively randomized consecutively into two groups: the C-TKA group (Group A, n = 44) and the MICA-TKA technique (Group B, n = 43). All the operations were performed by the same senior surgeon. Before surgery and at follow-up, patients were evaluated by the same observer. Tourniquet time as well as total blood loss was compared. Knee Society scores (KSSs), Knee Society functional scores (KSFSs), range of motion (ROM), and radiographic results were assessed and reported preoperatively and at 12-month follow-up. Of these patients, 82 (Group A 42; Group B 40) were available for 12-month evaluation. The two groups were found to be similar in terms of coronal mechanical axis. Similarly, the femoral rotational profile revealed that the prosthesis in Group A was implanted with similar internal rotation to Group B. The average blood loss in patients of Group B was significantly reduced as compared to patients of Group A. No significant difference was detected in terms of tourniquet time. Clinical results in Group B, with regard to ROMs and KSSs, as well as KSFSs were significantly superior to that in Group A. Based on the results obtained from this study, it is demonstrated that MICA-TKA leads to a similarly accurate restoration of leg alignment and component orientation compared to the C-TKA. Moreover, MICA-TKA produces superior clinical results to that of C-TKA. However, there is clearly a need for additional high-quality clinical trials with long term follow-up to confirm the clinical benefits of MICA-TKA. PMID- 24052417 TI - Fat dogs and coughing horses: K-12 programming for veterinary workforce development. AB - Workforce development strategies to educate, inform, and diversify the veterinary profession of the future must begin with children in elementary school. This article provides a description of the Fat Dogs and Coughing Horses program, which takes a multifaceted approach toward informing young students, beginning in first grade, about the interesting work and career opportunities available in the field of veterinary medicine. The program, a collaboration among Purdue University and Indiana public schools, is supported by a Science Education Partnership Award from the Office of Research Infrastructure Programs, a component of the National Institutes of Health. The overall goal of the program is to provide formal and informal educational opportunities for students, parents, teachers, and the public about the science involved in keeping people and their animals healthy. Examples of health concerns that impact both people and their pets are used to inform and excite children about careers in the health sciences. The program resulted in (1) curricula for students in Grades 1-3, 6, and 9; (2) four children's books and a set of collectible cards which highlight veterinarians, veterinary technicians, and research scientists who work with animals; and (3) four traveling museum-level quality exhibits. Preliminary assessment data has shown that the implementation of the curricula enhanced student science learning and science attitudes and interests. The program provides evidence that partnerships among professionals in veterinary medicine and K-12 education can result in impactful workforce development programs. PMID- 24052418 TI - Workplace learning in veterinary education: a sociocultural perspective. AB - Veterinary practice is a broad sphere of professional activity encompassing clinical activity and other vocational opportunities conducted in rapidly changing contemporary social conditions. Workplace learning is an important but resource-intensive component of educating students for practice. This conceptual article argues that literature on workplace learning in the veterinary context is dominated by descriptive accounts and that there is a dearth of theoretically informed research on this topic. Framing veterinary practice as a social, relational, and discursive practice supports the use of workplace learning theories developed from a sociocultural perspective. Situated learning theory, with its associated concepts of communities of practice and legitimate peripheral participation, and workplace learning theory focused on workplace affordances and learner agency are discussed. Two composite examples of student feedback from veterinary clinical learning illustrate the concepts, drawing out such themes as the roles of teachers and learners and the assessment of integrated practice. The theoretical perspective described in this article can be used to inform development of models of workplace learning in veterinary clinical settings; relevant examples from medical education are presented. PMID- 24052419 TI - The prevalence of morphological changes in the thoracolumbar spine on whole-spine computed tomographic images. AB - OBJECTIVES: This article reviews the prevalence of lumbarisation, sacralisation and lumbar ribs, and their morphological relevance by evaluating multi-slice computed tomography (MSCT) images. These segment variations can cause miscounting of vertebrae at the lumbar spinal level. METHODS: A retrospective radiographic analysis of 226 cases scanned by MSCT prior to forensic autopsy was undertaken. MSCT scans of the entire spine were obtained. Radiological data were evaluated on a three-dimensional image workstation. Vertebral levels were determined by counting downward from the first cervical vertebra, based on the assumption of seven cervical, 12 thoracic and five lumbar vertebrae. The prevalence of lumbarisation, sacralisation and lumbar ribs was assessed. RESULTS: Lumbar ribs were observed in 13 of the 226 cases (5.8 %). Lumbarisation and sacralisation were observed in 14 cases (6.2 %) and six cases (2.7 %), respectively. Lumbar ribs were present in 11 of the 14 cases with lumbarisation, and in two of the 206 cases with normal lumbar vertebral configuration. Lumbarisation had a statistically significant association with lumbar ribs (p < 0.01). CONCLUSIONS: There was a strong association between lumbar ribs and lumbarisation, with a resulting miscount rate for the lumbar spine of slightly less than 10 %. TEACHING POINTS: * Lumbarisation and sacralisation are observed 6.2 % and 2.7 %, respectively. * Thoracolumbar segment variations can cause a miscount rate for the lumbar spine of less than 10 %. * Lumbar rib is significantly associated to lumbarisation. PMID- 24052422 TI - Circulating cytokines and gastric cancer risk. AB - PURPOSE: Chronic inflammation has been hypothesized to play a significant role in the aetiology of cancer, including gastric cancer. In the present study, we sought to examine pre-diagnostic systemic cytokine levels in plasma, which can be seen as markers of aggregate inflammation, and risk of distal gastric cancer in a case-control study nested within the prospective Shanghai Men's Health Study. METHODS: Circulating levels of eight inflammation-related cytokines were measured in the plasma collected at baseline for 180 incident cases of distal gastric cancer and 358 matched controls. Helicobacter pylori sero-positivity was assessed using multiplex serology. Conditional logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CI). RESULTS: Individuals with IL-8 levels above the lowest quartile were at twofold increased odds of gastric cancer [OR 1.91 (95 % CI 1.05-3.46), OR 2.10 (95 % CI 1.19-3.74), and OR 2.30 (95 % CI 1.26-4.19), for the second through fourth quartiles, respectively]. While there were suggestions of an increase in risk with increased level of many of the other cytokines measured (IL-1beta, IL-2, IL-4, IL-6, IL-10, TNF-alpha, and IFN gamma), no significant associations were found at the p < 0.05 level. Infection with CagA-positive H. pylori did not modify these associations. CONCLUSIONS: In a population with high gastric cancer incidence and high H. pylori prevalence, increased circulating levels of IL-8 may indicate increased risk of gastric cancer. These findings add to our understanding of the disease and further efforts to uncover biomarkers of disease risk. PMID- 24052423 TI - Early changes in membrane potential of Saccharomyces cerevisiae induced by varying extracellular K(+), Na (+) or H (+) concentrations. AB - Recently we introduced a fluorescent probe technique that makes possible to convert changes of equilibrium fluorescence spectra of 3,3' dipropylthiadicarbocyanine, diS-C3(3), measured in yeast cell suspensions under defined conditions into underlying membrane potential differences, scaled in millivolts (Plasek et al. in J Bioenerg Biomembr 44: 559-569, 2012). The results presented in this paper disclose measurements of real early changes of plasma membrane potential induced by the increase of extracellular K(+), Na(+) and H(+) concentration in S. cerevisiae with and without added glucose as energy source. Whereas the wild type and the ?tok1 mutant cells exhibited similar depolarization curves, mutant cells lacking the two Trk1,2 potassium transporters revealed a significantly decreased membrane depolarization by K(+), particularly at lower extracellular potassium concentration [K(+)]out. In the absence of external energy source plasma membrane depolarization by K(+) was almost linear. In the presence of glucose the depolarization curves exhibited an exponential character with increasing [K(+)]out. The plasma membrane depolarization by Na(+) was independent from the presence of Trk1,2 transporters. Contrary to K(+), Na(+) depolarized the plasma membrane stronger in the presence of glucose than in its absence. The pH induced depolarization exhibited a fairly linear relationship between the membrane potential and the pHo of cell suspensions, both in the wild type and the Deltatrk1,2 mutant strains, when cells were energized by glucose. In the absence of glucose the depolarization curves showed a biphasic character with enhanced depolarization at lower pHo values. PMID- 24052421 TI - SUMO: a (oxidative) stressed protein. AB - Redox species are produced during the physiological cellular metabolism of a normal tissue. In turn, their presence is also attributed to pathological conditions including neurodegenerative diseases. Many are the molecular changes that occur during the unbalance of the redox homeostasis. Interestingly, posttranslational protein modifications (PTMs) play a remarkable role. In fact, several target proteins are modified in their activation, localization, aggregation, and expression after the cellular stress. Among PTMs, protein SUMOylation represents a very important molecular modification pathway during "oxidative stress". It has been reported that this ubiquitin-like modification is a fine sensor for redox species. Indeed, SUMOylation pathway efficiency is affected by the exposure to oxidative species in a different manner depending on the concentration and time of application. Thus, we here report updated evidence that states the role of SUMOylation in several pathological conditions, and we also outline the key involvement of c-Jun N-terminal kinase and small ubiquitin modifier pathway cross talk. PMID- 24052424 TI - The use of sonoelastographic elasticity index to differentiate benign and malignant thyroid nodules. AB - PURPOSE: The aim of this study is to evaluate the elasticity index of thyroid nodules by sonoelastographic imaging, and to determine the cut-off value to distinguish malignant nodules from benign nodules with optimum sensitivity and specificity. MATERIALS AND METHODS: Fine needle aspiration biopsy (FNAB) of 84 cases were evaluated with B-mode US and Sonoelastography (USE) preoperatively. The elasticity score (ELX 2/1) index of the nodules were calculated. Seventy three patients with diagnostic biopsy results were included in this study. RESULTS: According to the FNAB results, 9 (12 %) nodules were malignant, 64 (88 %) nodules were benign. All malignant nodules were papillary carcinoma, and their diagnosis was confirmed with thyroidectomy. The ELX 2/1 index of all malignant nodules was higher than 1.65. The ELX 2/1 index of 45 (70.3 %) benign nodules was lower than 1.65 whereas the ELX 2/1 index of 19 (29.7 %) benign nodules was higher than 1.65. Using an ELX 2/1 index cut-off value of 1.65 led to a sensitivity of 100 % and a specificity of 71 % in detecting papillary thyroid carcinomas. CONCLUSIONS: Assessing the ELX 2/1 index as a screening test and deciding on FNAB accordingly, in addition to gray-scale ultrasound findings of the nodules, will be beneficial in order to prevent unnecessary biopsies. PMID- 24052425 TI - Cell-scaffold interactions in the bone tissue engineering triad. AB - Bone tissue engineering has emerged as one of the leading fields in tissue engineering and regenerative medicine. The success of bone tissue engineering relies on understanding the interplay between progenitor cells, regulatory signals, and the biomaterials/scaffolds used to deliver them--otherwise known as the tissue engineering triad. This review will discuss the roles of these fundamental components with a specific focus on the interaction between cell behaviour and scaffold structural properties. In terms of scaffold architecture, recent work has shown that pore size can affect both cell attachment and cellular invasion. Moreover, different materials can exert different biomechanical forces, which can profoundly affect cellular differentiation and migration in a cell type specific manner. Understanding these interactions will be critical for enhancing the progress of bone tissue engineering towards clinical applications. PMID- 24052426 TI - Hyaluronan-based pericellular matrix: substrate electrostatic charges and early cell adhesion events. AB - Cells are surrounded by a hyaluronan-rich coat called 'pericellular matrix' (PCM), mainly constituted by hyaluronan, a long-chain linear polysaccharide which is secreted and resorbed by the cell, depending on its activity. Cell attachment to a surface is mediated by PCM before integrins and focal adhesions are involved. As hyaluronan is known to bear a negative charge at physiological pH, the relevance of its electrical properties in driving the early cell adhesion steps has been studied, exploring how PCM mediates cell adhesion to charged surfaces, such as polyelectrolyte multilayer (PEM) films. Poly(ethylene imine) (PEI) and poly(sodium 4-styrene sulphonate) (PSS), assembled as PEI/PSS and PEI/PSS/PEI layers, were used. The nanoscale morphology of such layers was analysed by atomic force microscopy, and the detailed surface structure was analysed by X-ray photoemission spectroscopy. PCM-coated and PCM-depleted MG63 osteoblast-like cells were used, and cell density, morphology and adhesive structures were analysed during early steps of cell attachment to the PEM surfaces (1-6 h). The present study demonstrates that the pericellular matrix is involved in cell adhesion to material surfaces, and its arrangement depends on the cell interaction with the surface. Moreover, the PCM/surface interaction is not simply driven by electrostatic effects, as the cell response may be affected by specific chemical groups at the material surface. In the development of biomimetic surfaces promoting cell adhesion and function, the role of this unrecognised outer cell structure has to be taken into account. PMID- 24052427 TI - Dronabinol treatment of refractory nausea and vomiting related to peritoneal carcinomatosis. AB - Nausea and vomiting are common and often highly distressing symptoms in advanced cancer and in hospice and palliative medicine practice. Nausea and vomiting generally respond well to correction of the underlying etiology (when possible) and appropriate selection of antiemetic medication, but up to 7% of patients will have refractory symptoms. Dronabinol is extensively studied for chemotherapy related nausea and vomiting, but there are only a few case reports of its use in nausea and vomiting unrelated to chemotherapy. We report a patient with end-stage ovarian cancer with peritoneal carcinomatosis and refractory nausea and vomiting who responded dramatically to addition of dronabinol. Dronabinol is usually well tolerated and may have several novel mechanisms of antiemetic action; further study of its scope of efficacy is warranted. PMID- 24052428 TI - A hierarchy of personal agency for people with life-limiting illness. AB - The purpose of the study was to discover how individuals diagnosed with a life limiting illness experienced themselves as agents, even in the face of death. In this qualitative, multiple case study design, 4 female outpatient hospice patients with terminal illnesses received humanistic counseling to explore their experiences of themselves and their illness. A graded set of 8 levels of personal agency emerged from analyses of the texts of their sessions, ranging from a passive, objectified nonagentic mode to an active, autonomous fully agentic mode, with multiple subcategories representing further gradations within levels. Our results are consistent with guidelines for supportive and palliative care with advanced cancer, which specify that dying patients' needs be assessed and that they be involved in decisions about their care. PMID- 24052430 TI - Preferences of patients with Parkinson's disease for communication about advanced care planning. AB - BACKGROUND: Despite shortening life, Parkinson's disease (PD) is often not considered "terminal." Uncertainty exists about when to discuss end-of-life planning. METHODS: A survey was sent to patients with PD assessing attitudes toward the timing and initiation of discussions regarding their disease. Data were analyzed for patient preferences regarding communication. RESULTS: Of 585 surveys, 267 were returned. Ninety-four percent of patients wanted prognosis and treatment information early. Half of the patients wanted to discuss advanced care documents early. Some wanted early discussions about end-of-life care planning (27%) or end-of-life care options such as hospice (21%). The majority felt shared responsibility for initiating discussions about life expectancy, advance care documents, and end-of-life care planning. CONCLUSIONS: Preferences regarding end of-life discussions vary. Consequently, neurologists should ask patients about their preferences for this information and offer discussion periodically. PMID- 24052429 TI - Strategy of coping with end-stage disease and cancer-related fatigue in terminally ill patients. AB - The aim was to investigate whether there is a relationship between strategy of coping with end-stage disease and cancer-related fatigue. The study was conducted using the Rotterdam Symptom Checklist, Brief Fatigue Inventory, and Mini-Mental Adjustment to Cancer scale to specify patient's strategy of coping. Finally, 51 hospice care patients with cancer were analyzed. MAIN FINDINGS: The majority of responders adopted 1 of the 2 styles; avoidance (belongs to adaptive coping) or anxious preoccupation (destructive or maladaptive). Less often moderate fatalism and helpless/hopeless (H/H) or fighting spirit were observed. Significant correlation has been found between H/H or fatalism strategy and fatigue. CONCLUSIONS: High level of fatigue had a negative impact on almost all aspects of daily living among people with H/H or fatalism strategy. PMID- 24052431 TI - End-of-life care beliefs among Hindu physicians in the United States. AB - Several studies from the United States and Europe showed that physicians' religiosity is associated with their approach to end-of-life care beliefs. No such studies have focused exclusively on Hindu physicians practicing in the United States. A 34-item questionnaire was sent to 293 Hindu physicians in the United States. Most participants believed that their religious beliefs do not influence their practice of medicine and do not interfere with withdrawal of life support. The US practice of discussing end-of-life issues with the patient, rather than primarily with the family, seems to have been adopted by Hindu physicians practicing in the United States. It is likely that the ethical, cultural, and patient-centered environment of US health care has influenced the practice of end-of-life care by Hindu physicians in this country. PMID- 24052432 TI - Perforated gastrointestinal stromal tumor (GIST) in a true jejunal diverticulum in adulthood: report of a case. AB - A 61-year-old man was referred to us for investigation of acute abdominal pain. Computed tomography showed a 5.9 * 5.3 * 5.0 cm lump of food residue in the jejunum, and a large amount of free air and ascites around the liver and right paracolic gutter. He underwent emergency laparotomy for suspected peritonitis from perforation by a foreign body in the small intestine. We identified purulent exudate in the abdominal cavity and perforation of a jejunal cystic mass, attached ~40 cm from Treitz's ligament at the anti-mesenteric side of the jejunum. Based on a diagnosis of jejunal duplication with perforation, we resected that part of the small intestine and performed intra-abdominal drainage. Pathological findings confirmed the diagnosis of a perforated gastrointestinal stromal tumor (GIST) in a true jejunal diverticulum. Histopathological evidence suggests that intestinal pressure and/or hemorrhage can cause perforation in the background of a true jejunal diverticulum. To our knowledge, this is the first case report of a perforated GIST in a true jejunal diverticulum. PMID- 24052433 TI - Hydrophilic polymer gel. PMID- 24052434 TI - Update on clinical and mechanistic aspects of paraneoplastic syndromes. AB - Many patients with cancer are afflicted with an array of severe ailments caused by remote effects of the neoplasm on distant organs, which it has not invaded or colonized. The growing local tumor dominates attention, but invisible chemical and cellular components released by this parasitic neoplastic growth can operate below the threshold of detection to derange feedback loops coordinating essential physiological functions. Ultimately, these changes cause serious signs and symptoms, collectively described as paraneoplastic syndromes (PNSs), which significantly diminish the patient's quality of life. PNS can appear before, or after, detection of the cancer and are sometimes surprising or even bizarre. The patterns of clinical changes seen in these patients are caused by a range of mechanisms that reveal intricate networks of communications between different body systems, normally utilized for healthy function. For example, these disorders demonstrate that (1) hormones, peptides, and other long- and short range signaling molecules produced by the tumor and (2) immune reactions to tumor related antigens, can mediate diverse destabilizing effects. However, comparative analysis of numerous PNS reveals valuable information indicating that the primary pathogenetic events instigating these disturbances are much more fundamental. This article provides an overview of the diverse clinical manifestations of paraneoplastic disorders, with representative examples and presents evidence that inappropriate gene expression in the tumor, caused by loss of regulatory control, is a novel unifying explanation for such wide effects of the neoplasm on the host. It also discusses treatment options and issues relating to conducting randomized clinical trials on these disorders. PMID- 24052435 TI - New synthesis: animal communication mediated by microbes: fact or fantasy? PMID- 24052436 TI - XRCC1 Arg399Gln polymorphism is not associated with oral cancer risk: evidence from a meta-analysis. AB - Previous studies regarding the association between X-ray repair cross complementing group 1 (XRCC1) Arg399Gln polymorphism and oral cancer risk were contradictory. We performed a meta-analysis to derive a more precise estimation of the association. The PubMed and Web of Science were searched for eligible studies. Odds ratio (OR) with its 95% confidence interval (95% CIs) was used to assess the strength of the association. Nine individual studies with a total of 3,244 subjects were finally included into the meta-analysis. Overall, there was no association between XRCC1 Arg399Gln polymorphism and oral cancer risk under all genetic models (Gln versus Arg: OR = 1.09, 95% CI 0.86-1.37, P = 0.46; GlnGln versus ArgArg: OR = 1.11, 95% CI 0.69-1.79, P = 0.66; GlnGln versus ArgArg/ArgGln: OR = 1.04, 95% CI 0.68-1.61, P = 0.84; and GlnGln/ArgGln versus ArgArg: OR = 1.13, 95% CI 0.88-1.44, P = 0.34). After excluding studies on oral leukoplakia, there was still no association between XRCC1 Arg399Gln polymorphism and oral cancer risk under all genetic models. Subgroup analysis by ethnicity suggested that there was no association between XRCC1 Arg399Gln polymorphism and oral cancer risk in both Asians and Caucasians. In conclusion, the data from the meta-analysis suggests that XRCC1 Arg399Gln polymorphism is not associated with oral cancer risk. PMID- 24052437 TI - Clinical significance of the expression of EGFR signaling pathway-related proteins in esophageal squamous cell carcinoma. AB - Epidermal growth factor receptor (EGFR) signaling is an important pathway that is not only involved in the determination of cellular development, but also has significant roles in tumor development and progression. The study aims to examine the expression of EGFR signaling pathway-related proteins (EGFR, c-Fos, and c-erb B2) in esophageal squamous cell carcinoma and to investigate their relationships with clinical significance. Sixty esophageal squamous carcinoma specimens obtained by fiber esophagoscope were subjected to two-step immunohistochemistry to test the expression of EGFR, c-Fos, and c-erb-B2. EGFR expression was observed in 73.3% of tumors (44/60); positive EGFR expression was significantly correlated with tumor-node-metastasis (TNM) staging, lymph node metastasis, and distant metastasis (P < 0.05). c-Fos expression was found in 85% (51/60) of tumors, and its expression was significantly related to tumor depth and TNM staging (P < 0.05). c-erb-B2 expression was 75% (45/60) in esophageal squamous cell carcinoma (ESCC) specimens, and positive-erb-B2 expression had a significant association with the depth of tumor invasion (P < 0.05). c-Fos expression was significantly and positively correlated with c-erb-B2 (P < 0.05). Overexpression of EGFR, c Fos, and c-erb-B2 was associated with tumor progression and development. EGFR and c-Fos expression can predict the tumor stage. c-Fos and c-erb-B2 expression can be used to determine the depth of tumor invasion and can also act as a combined prognostic indicator in ESCC. PMID- 24052438 TI - Applicability of gene expression profile of childhood acute lymphoblastic leukemia at diagnosis and at the end of the induction phase of chemotherapy at a cancer hospital in the state of Goias (Brazil). AB - The present study compared the gene expression pattern of some previously described genes at the time of diagnosis and after induction chemotherapy for childhood acute lymphoblastic leukemia (ALL) in patients submitted to Brazilian Childhood Leukemia Treatment Group (GBTLI) ALL-99 Protocol. Samples were obtained at the time of diagnosis from 16 patients with ALL and on the 28th day of induction chemotherapy the bone marrow samples were obtained from 12 children. The genes expression profiles in diagnostic and induction samples were analyzed by array-based qPCR and then related to the clinical and biological prognostic factors. The results showed significant associations (p <= 0.05) between gender and immunophenotype, immunophenotype and age, immunophenotype and risk group, presence of CD10 and RUNX1 expression, risk group, and immunophenotype. A significant positive correlation was observed between the expression levels of BAX and BCL2. There was a significant difference (p = 0.008) between the gene expression pattern at the time of diagnosis and after induction chemotherapy. The expression pattern of these genes after the induction phase of treatment approached the expression profile of the control group, indicating a good induction response in children treated according to the GBTLI ALL-99 protocol. The findings of the current research could be routinely useful for clinical practice and could assist in the discovery phase of medical applications. PMID- 24052439 TI - [Subjective memory complaints, personality and prefrontal symptomatology in young adults]. AB - INTRODUCTION: This work explores two issues related with the appearance of subjective memory complaints in young adults: on the one hand, the possibility of the complaints being a result of attentional and executive deficits and, on the other, whether certain characteristics of the personality favour and modulate the clinical expression of these complaints. SUBJECTS AND METHODS: The Memory Failures of Everyday questionnaire, Spanish version, the Prefrontal Syndromes Inventory and the Revised Temperament and Character Inventory were administered to a sample of 1132 participants (900 from the general population and 232 on treatment for drug addiction). The correlation among the variables of the memory complaints, of prefrontal functioning in daily life and of the dimensions of personality proposed by Cloninger was explored. The causal relationships among the variables were studied using structural methods. RESULTS: A strong correlation was observed between cognitive complaints and prefrontal symptoms, suggesting that the complaints are, in fact, a result of an inadequate management of the attentional and executive functions that favours daily errors. A relationship with a large effect size is also observed between the cognitive complaints and low self-management. This dimension of the personality offers an important predictive capacity regarding the appearance and the intensity of the complaints, either directly or modulated by other dimensions, especially harm avoidance. CONCLUSIONS: The data back the idea that memory complaints are the result of the self-perception of daily faults and errors that are produced at the attentional and executive level -although they are taken as instances of mnemonic oversight- and that the clinical expression of these complaints is modulated by a profile of the personality. PMID- 24052440 TI - [Analysis of a series of cases with an initial diagnosis of acute disseminated encephalomyelitis over the period 2000-2010]. AB - INTRODUCTION: Acute disseminated encephalomyelitis (ADEM) is a demyelinating disease that essentially affects the white matter of the central nervous system. The diagnosis is based on clinical-imaging and developmental findings. Magnetic resonance imaging of the brain is the most useful diagnostic tool. The disease course is usually monophasic and the preferred initial treatment is with corticoids. PATIENTS AND METHODS: We conducted a retrospective study of 18 patients with a presumptive diagnosis of ADEM. Symptoms, imaging findings, progress and treatment were analysed. The definitive diagnosis was established in 12 patients, excluding one patient with positive polymerase chain reaction for herpes simplex virus in cerebrospinal fluid, one with a clinical picture that was consistent but normal magnetic resonance imaging of the brain, and four with an onset that was similar to ADEM whose definitive diagnoses were: Rassmusen's syndrome, haemophagocytic syndrome, brain tumour, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). RESULTS: The median age was 31 months with no predominance of either sex. Infection of the upper respiratory tract was the most frequent cause in children over 2 years of age and of the gastrointestinal tract in those under the age of 2. All of them presented altered levels of consciousness and multifocal neurological deficits. The most frequent imaging finding was multifocal alteration of the white matter in both hemispheres. Corticoids were the preferred treatment in most cases. Progression was favourable in nearly all patients except for two, who were left with important sequelae. CONCLUSIONS: ADEM may present at any age, including in infants. There are a number of conditions that can mimic ADEM in the early stages. PMID- 24052441 TI - [Aetiology and treatment of epilepsy in a series of 1,557 patients]. AB - INTRODUCTION: The aetiology of epilepsy is an important decisive factor in its treatment and prognosis. Diagnostic and therapeutic advances suggest that the causal distribution, treatment and prognosis of the population with epilepsy may have undergone some modification. AIM: To describe the distribution of syndromes, aetiology and pharmacological treatment in patients with epilepsy. PATIENTS AND METHODS: We conducted a cross-sectional descriptive study of patients with epilepsy who were treated consecutively in our epilepsy department. Demographic data were collected, together with information about syndromes, aetiology and pharmacological treatment at the time of eligibility. The data were analysed jointly and by age groups. RESULTS: Altogether 1,557 patients were included, 54% of them males. Seventy-three per cent of the sample had focal epilepsy, which was secondary to a structural lesion in 56% of patients. Generalised epilepsies accounted for 20%. Five per cent were unclassifiable. By ages, vascular causation predominated in practically all the groups and its prevalence increased with age. The most commonly used antiepileptic drugs were valproic acid (29%), levetiracetam (27%) and carbamazepine (20%). Seventy per cent of the generalised epilepsies and 57% of the focal ones were on monotherapy treatment. CONCLUSIONS: The prevalence by age groups was similar to that reported in developed countries, although a lower prevalence of cryptogenic epilepsies was observed. More than 60% of patients followed monotherapy and valproic acid was the most widely used. PMID- 24052442 TI - [Lacosamide as an alternative in the treatment of post-surgery neuropathic pain in an allergic patient]. AB - INTRODUCTION: Neuropathic pain is a condition that is still not well understood, although it affects a significantly high percentage of the population. The main problem lies in the fact that it can become a fairly disabling pathology. The most frequent treatment is based essentially on two drugs: gabapentin and pregabalin. Other pharmaceuticals, such as antidepressants, opioids or N-methyl-D aspartate receptor antagonists can also be employed in combination with the primary drugs. All the same, treatment remains unsatisfactory. Furthermore, it must be borne in mind that there may be patients who are allergic to the two main drugs. CASE REPORT: We report the case of a 36-year-old female with neuropathic pain secondary to surgery to correct a neurinoma in the brachial plexus, who could not be treated with gabapentin or pregabalin because of a personal history of allergy to these substances. Treatment with another drug (lacosamide), however, was very effective and displayed a very good response. CONCLUSIONS: Lacosamide is a third-generation antiepileptic drug that has been proven to be effective, safe and with few side effects. It has been considered a good therapeutic option for the treatment of neuropathic pain in patients who are allergic to pregabalin. PMID- 24052443 TI - Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (III). AB - The most significant data presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in France in October 2012, have been summarised in the fifth edition of the Post ECTRIMS Experts Meeting, held in Madrid in October 2012. This led to the drafting of this review, which has been published in three parts. This third part of the Post-ECTRIMS review presents the findings from the latest studies conducted with disease-modifying treatments, more specifically with glatiramer acetate, laquinimod, ponesimod, BG-12, teriflunomide, daclizumab, natalizumab and secukinumab (AIN457). Likewise, we also address the reasons that justify the search for innovative treatments for multiple sclerosis, with antigen-specific therapy, cell therapy and therapy aimed at promoting remyelination being highlighted among other future therapeutic strategies. Access to new pharmacological agents and the complexity of the therapy of multiple sclerosis in the future will require new design strategies and directions in clinical trials, including the use of surrogate markers, new statistical applications, superiority, inferiority or equivalence clinical trials and adaptable designs. PMID- 24052445 TI - Foix-Chavany-Marie syndrome caused by bilateral opercular lesions: right side tumor and left side ischemic stroke. PMID- 24052446 TI - [Aphasia and thrombocytopenic thrombotic purpura in a young woman: the platelet count dilemma]. PMID- 24052447 TI - Sequential compression biomechanical device versus primary amputation in patients with critical limb ischemia. AB - INTRODUCTION: Patients with critical limb ischemia (CLI), who are unsuitable for intervention, face the consequence of primary amputation. Sequential compression biomechanical device (SCBD) therapy provides a limb salvage option for these patients. OBJECTIVES: To assess the outcome of SCBD in patients with severe CLI who are unsuitable for revascularization. Primary end points were limb salvage and 30-day mortality. METHODS: From 2005 to 2012, 189 patients with severe CLI were not suitable for revascularization. In all, 171 joined the SCBD program. We match controlled 75 primary amputations. RESULTS: All patients were Rutherford category 4 or higher. Sustained clinical improvement was 68% at 1 year. Mean toe pressure increased from 19.9 to 35.42 mm Hg, P < .0001. Mean popliteal flow increased from 35.44 to 55.91 cm/sec, P < .0001. The 30-day mortality was 0.6%. Limb salvage was 94% at 5 years. Freedom from major adverse clinical events was 62.5%. All-cause survival was 69%. Median cost of managing a primary amputation patient is ?29,815 compared to ?3,985 for SCBD. We treated 171 patients with artassist at a cost of ?681,965. However, primary amputation for 75 patients cost ?2,236,125. CONCLUSION: The SCBD therapy is a cost-effective and clinically effective solution in patients with CLI having no option of revascularization. It provides adequate limb salvage while providing relief of rest pain without any intervention. PMID- 24052448 TI - Stent graft in the treatment of pseudoaneurysms of the hepatic arteries. AB - OBJECTIVE: The purpose of our study was to evaluate the technical feasibility, procedural complications, clinical follow-up, and computed tomography (CT) scan outcomes of hepatic artery pseudoaneurysms (HAPs) treated with stent graft. METHODS: Between October 2004 and October 2009, we treated 8 patients with HAPs with stent graft. RESULTS: Stent graft deployment was technically successful in all the patients. Complete exclusion of the pseudoaneurysm preserving patency of the hepatic artery was achieved in 6 patients. Total occlusion of the common hepatic artery was observed in 1 patient, and vasospasm of proper hepatic artery and endoleak from distal stent margin were observed in another patient. The 2 patient were controlled through occlusion parent artery with coils. After these procedures, symptoms of bleeding and abdominal pain disappeared. Follow-up enhanced CT scan was performed at an average of 14 months (range, 6-26 months), which showed complete disappearance of the HAP and patency of the stent without intrastent stenosis in 6 patients who had successful deployment of the stent. CONCLUSIONS: Endovascular treatment of HAPs using stent graft can maintain the hepatic artery blood flow and could be considered as an alternative to embolization. PMID- 24052449 TI - Neural progenitor cell apoptosis and differentiation were affected by activated microglia in spinal cord slice culture. AB - Neural progenitor cell (NPC) transplantation offers great potential to treat spinal cord injury (SCI). NPCs may replace lost neurons or oligodendrocytes and act as a source of neurotrophic factors to support survival of remaining cells. However, their efficiency was limited by poor survival after transplantation, and they tended more to differentiate into astrocytes, but not neurons and oligodendrocytes. This study investigated whether activated microglia is a factor that contributes to this phenomenon. Organotypic spinal cord slice (SCS) culture was used to mimic the local environment after SCI, and NPCs were co-cultured with them to share the culture medium. After specific depletion of microglia in the SCSs with clodronate loaded liposome, the apoptotic rate of NPCs decreased, more NPCs differentiated into neurons, and glial differentiation was impaired. This suggested that microglia may impair NPC survival, and neuronal differentiation, but improve astrocyte differentiation. In NPC transplantation strategy for SCI, microglia would be manipulated to improve the survival and neuronal differentiation of NPCs. PMID- 24052450 TI - Cocaine-induced cluster-like headache. PMID- 24052451 TI - The MTHFR C677T polymorphism modifies age at onset in Parkinson's disease. AB - Hyperhomocysteinemia is a risk factor for Parkinson's disease (PD) and may result from genetic mutations or/and environmental factors. 5,10 methylenetetrahydrofolate reductase (MTHFR) is a folate-dependent enzyme that catalyzed remethylation of homocysteine (Hcy) and the MTHFR C677T polymorphism makes the MTHFR enzyme thermolabile causing hyperhomocysteinemia. In this study we analyzed whether two functional polymorphisms of MTHFR gene, A1298C and C677T, affect age of onset in PD. We enrolled 120 patients with sporadic PD. Patients were divided into three groups based on MTHFR C677T polymorphisms: (a) homozygotes wild type (CC) (b) heterozygotes (CT) and (c) homozygotes carriers of mutation (TT). MTHFR SNPs were analyzed using High-Resolution Melt analysis and ANOVA was performed to assess whether polymorphisms of MTHFR gene could influence age of onset. The MTHFR A1298C polymorphism had no effect on PD age at onset (p = 1.0) while there was a significant association with MTHFR C677T (p = 0.019 Bonferroni-adjusted post hoc) showing an earlier onset in CC as compared with TT. (p = 0.024). No differences were found for vascular load assessed with magnetic resonance imaging, pharmacological therapy and cognitive state for two MTHFR SNPs. Our results suggest a possible association of MTHFR C677T with age at onset of PD and may have important implications regarding the role of MTHFR. PMID- 24052452 TI - Cortical action myoclonus due to cortical laminar necrosis. PMID- 24052453 TI - A randomized clinical trial of alcohol care management delivered in Department of Veterans Affairs primary care clinics versus specialty addiction treatment. AB - BACKGROUND: Alcohol use disorder is one of the leading causes of disability worldwide. Despite the availability of efficacious treatments, few individuals with an alcohol use disorder are actively engaged in treatment. Available evidence suggests that primary care may play a crucial role in the identification of patients with an alcohol use disorder, delivery of interventions, and the success of treatment. OBJECTIVE: The principal aims of this study were to test the effectiveness of a primary care-based Alcohol Care Management (ACM) program for alcohol use disorder and treatment engagement in veterans. DESIGN: The design of the study was a 26-week single-blind randomized clinical trial. The study was conducted in the primary care practices at three VA medical centers. Participants were randomly assigned to treatment in ACM or standard treatment in a specialty outpatient addiction treatment program. PARTICIPANTS: One hundred and sixty-three alcohol-dependent veterans were randomized. INTERVENTION: ACM focused on the use of pharmacotherapy and psychosocial support. ACM was delivered in-person or by telephone within the primary care clinic. MAIN MEASUREMENTS: Engagement in treatment and heavy alcohol consumption. KEY RESULTS: The ACM condition had a significantly higher proportion of participants engaged in treatment over the 26 weeks [OR = 5.36, 95 % CI = (2.99, 9.59)]. The percentage of heavy drinking days were significantly lower in the ACM condition [OR = 2.16, 95 % CI = (1.27, 3.66)], while overall abstinence did not differ between groups. CONCLUSIONS: Results demonstrate that treatment for an alcohol use disorder can be delivered effectively within primary care, leading to greater rates of engagement in treatment and greater reductions in heavy drinking. PMID- 24052454 TI - Swarm-based medicine. AB - Occasionally, medical decisions have to be taken in the absence of evidence-based guidelines. Other sources can be drawn upon to fill in the gaps, including experience and intuition. Authorities or experts, with their knowledge and experience, may provide further input--known as "eminence-based medicine". Due to the Internet and digital media, interactions among physicians now take place at a higher rate than ever before. With the rising number of interconnected individuals and their communication capabilities, the medical community is obtaining the properties of a swarm. The way individual physicians act depends on other physicians; medical societies act based on their members. Swarm behavior might facilitate the generation and distribution of knowledge as an unconscious process. As such, "swarm-based medicine" may add a further source of information to the classical approaches of evidence- and eminence-based medicine. How to integrate swarm-based medicine into practice is left to the individual physician, but even this decision will be influenced by the swarm. PMID- 24052455 TI - The seamless transfer of care: a pilot study assessing the usability of an electronic transfer of care communication tool. AB - The purpose of this pilot study was to explore the feasibility of implementing a new electronic transfer of care (TOC) tool. The study was conducted in a Canadian tertiary care center. Brief survey instruments were completed by acute care physicians, community-based physicians, and patients to assess providers' perspectives on the usability of the novel electronic tool. The units of analysis were physician and patient perceptions. Mixed methods were used including descriptive statistical analyses and qualitative thematic analysis. Twenty-eight unique acute care physicians completed 100 electronic TOC summaries, and 44 unique community-based physicians rated quality and pertinence of the summaries. Twenty-two patients responded to a follow-up telephone call. The novel TOC communication tool was generally well received by physicians and patients, and it is now being evaluated in a large-scale clinical trial assessing hard clinical outcomes. The information presented herein provides a template for assessment of such information system innovations. PMID- 24052456 TI - Sensitivity of compressed spectral arrays for detecting seizures in acutely ill adults. AB - BACKGROUND: Continuous EEG recordings (cEEGs) are increasingly used in evaluation of acutely ill adults. Pre-screening using compressed data formats, such as compressed spectral array (CSA), may accelerate EEG review. We tested whether screening with CSA can enable detection of seizures and other relevant patterns. METHODS: Two individuals reviewed the CSA displays of 113 cEEGs. While blinded to the raw EEG data, they marked each visually homogeneous CSA segment. An independent experienced electroencephalographer reviewed the raw EEG within 60 s on either side of each mark and recorded any seizures (and isolated epileptiform discharges, periodic epileptiform discharges (PEDs), rhythmic delta activity (RDA), and focal or generalized slowing). Seizures were considered to have been detected if the CSA mark was within 60 s of the seizure. The electroencephalographer then determined the total number of seizures (and other critical findings) for each record by exhaustive, page-by-page review of the entire raw EEG. RESULTS: Within each of the 39 cEEG recordings containing seizures, one CSA reviewer identified at least one seizure, while the second CSA reviewer identified 38/39 patients with seizures. The overall detection rate was 89.0 % of 1,190 total seizures. When present, an average of 87.9 % of seizures were detected per individual patient. Detection rates for other critical findings were as follows: epileptiform discharges, 94.0 %; PEDs, 100 %; RDA, 97.9 %; focal slowing, 100 %; and generalized slowing, 100 %. CONCLUSIONS: CSA-guided review can support sensitive screening of critical pathological information in cEEG recordings. However, some patients with seizures may not be identified. PMID- 24052457 TI - Serotonin syndrome in the intensive care unit: clinical presentations and precipitating medications. AB - BACKGROUND: Serotonin syndrome (SS) is becoming a more frequent diagnosis in the intensive care unit (ICU). We sought to determine the clinical presentation, drug exposures, and outcomes of SS in critically ill patients. METHODS: A retrospective study of 33 consecutive ICU patients with SS between March 2007 and March 2012 in ICUs in a large teaching hospital. SS was defined using the Hunter Serotonin Toxicity Criteria. RESULTS: Seventeen patients (52%) were admitted for mental status changes, including seven patients (21%) with drug overdose and four cases (12%) in which SS was considered the primary admission diagnosis. In 13 patients (39%) the features of SS developed only after a mean of 6.8 +/- 9 days of hospitalization. Most received multiple serotonergic drugs upon diagnosis (median three drugs, range 1-5). Antidepressants were the serotonergic medications most often used before admission, and opioids (principally fentanyl) and antiemetics were the most frequently prescribed new serotonin-enhancing medications. Altered mental status was present in all patients and myoclonus, rigidity, and hyperreflexia were the most prevalent examination signs. All but one patient had documented recovery. The mean time to neurological improvement was 56 +/- 5 h, but ranged from 8 to 288 h. There were no cases of renal failure related to rhabdomyolysis, or death or persistent disability caused by SS. CONCLUSION: SS in the ICU occurs most often because of exposure to multiple serotonergic agents. Continuation of antidepressants plus the addition of opioids and antiemetics during hospitalization are most commonly responsible for this complication. PMID- 24052458 TI - The association of a single-nucleotide polymorphism in CUBN and the risk of albuminuria and cardiovascular disease. AB - BACKGROUND: Albuminuria is an important risk factor for cardiovascular disease (CVD). We have previously identified a missense single-nucleotide polymorphism (rs1801239) in the CUBN gene that is associated with albuminuria. Whether albuminuria is associated with CVD in the presence of the CUBN mutation is unknown. METHODS: We analyzed participants from the Framingham Heart Study (n=6399, mean age 47 years, 53.4% women) who underwent genotyping of rs1801239. Cox proportional hazards models were used to test the association between microalbuminuria [UACR>=17 mg/g (men) and >=25 mg/g (women)] and incident CVD stratified by the presence or absence of the CUBN risk allele. We tested whether the association between microalbuminuria and CVD was altered by the presence of the risk allele with interaction testing. RESULTS: Overall, 21.1% of participants carried the risk allele. As expected, carriers of the risk (C) allele had a higher prevalence of microalbuminuria (10.7 versus 8.9%, P=0.04). During a mean follow-up of 10.4 years, 5.6% (n=346) of participants experienced a CVD event. Microalbuminuria was associated with an increased risk of CVD [hazards ratio (HR) 1.46, 95% confidence interval (CI) 1.14-1.88]. When stratified by risk allele carrier status, the HR for CVD was 1.95 (95% CI 1.15-3.29) among those with compared to 1.33 (95% CI 1.00-1.76) among those without the risk allele. There was no interaction between microalbuminuria and rs1801239 on CVD (Pinteraction=0.49). CONCLUSIONS: MA is associated with CVD irrespective of the presence of the CUBN risk allele. These results challenge the concept that albuminuria in the setting of this mutation is benign. PMID- 24052459 TI - Variation in centre-specific survival in patients starting renal replacement therapy in England is explained by enhanced comorbidity information from hospitalization data. AB - BACKGROUND: Unadjusted survival on renal replacement therapy (RRT) varies widely from centre to centre in England. Until now, missing data on case mix have made it impossible to determine whether this variation reflects genuine differences in the quality of care. Data linkage has the capacity to reduce missing data. METHODS: Modelling of survival using Cox proportional hazards of data returned to the UK Renal Registry on patients starting RRT for established renal failure in England. Data on ethnicity, socioeconomic status and comorbidity were obtained by linkage to the Hospital Episode Statistics database, using data from hospitalizations prior to starting RRT. RESULTS: Patients with missing data were reduced from 61 to 4%. The prevalence of comorbid conditions was remarkably similar across centres. When centre-specific survival was compared after adjustment solely for age, survival was below the 95% limit for 6 of 46 centres. The addition of variables into the multivariable model altered the number of centres that appeared to be 'outliers' with worse than expected survival as follows: ethnic origin four outliers, socioeconomic status eight outliers and year of the start of RRT four outliers. The addition of a combination of 16 comorbid conditions present at the start of RRT reduced the number of centres with worse than expected survival to one. CONCLUSIONS: Linked data between a national registry and hospital admission dramatically reduced missing data, and allowed us to show that nearly all the variation between English renal centres in 3-year survival on RRT was explained by demographic factors and by comorbidity. PMID- 24052461 TI - Proteinuria and VEGF-targeted therapies: ?an underestimated toxicity? AB - Oncologists and nephrologists usually manage proteinuria related to anti-vascular endothelial growth factor (anti-VEGF) treatment only when it is in the nephrotic range or associated with renal insufficiency. This report is based on our personal experience with 78 patients developing renal problems with anti-VEGF therapy. We found that proteinuria induced by anti-VEGF therapy, even if weak and without associated renal insufficiency, may reflect a serious histological renal disease. PMID- 24052460 TI - Synthesis of BODIPY derivatives substituted with various bioconjugatable linker groups: a construction kit for fluorescent labeling of receptor ligands. AB - The goal of the present study was to design small, functionalized green-emitting BODIPY dyes, which can readily be coupled to target molecules such as receptor ligands, or even be integrated into their pharmacophores. A simple two-step one pot procedure starting from 2,4-dimethylpyrrole and omega-bromoalkylcarboxylic acid chlorides was used to obtain new omega-bromoalkyl-substituted BODIPY fluorophores (1a-1f) connected via alkyl spacers of different length to the 8 position of the fluorescent dye. The addition of radical inhibitors reduced the amount of side products. The omega-bromoalkyl-substituted BODIPYs were further converted to introduce various functional groups: iodo-substituted dyes were obtained by Finkelstein reaction in excellent yields; microwave-assisted reaction with methanolic ammonia led to fast and clean conversion to the amino-substituted dyes; a hydroxyl-substituted derivative was prepared by reaction with sodium ethylate, and thiol-substituted BODIPYs were obtained by reaction of 1a-1f with potassium thioacetate followed by alkaline cleavage of the thioesters. Water soluble derivatives were prepared by introducing sulfonate groups into the 2- and 6-position of the BODIPY core. The synthesized BODIPY derivatives showed high fluorescent yields and appeared to be stable under basic, reducing and oxidative conditions. As a proof of concept, 2-thioadenosine was alkylated with bromoethyl BODIPY 1b. The resulting fluorescent 2-substituted adenosine derivative 15 displayed selectivity for the A3 adenosine receptor (ARs) over the other AR subtypes, showed agonistic activity, and may thus become a useful tool for studying A3ARs, or a lead structure for further optimization. The new functionalized dyes may be widely used for fluorescent labeling allowing the investigation of biological targets and processes. PMID- 24052462 TI - Efficacy and safety of once-monthly continuous erythropoietin receptor activator in patients with chronic renal anemia. AB - BACKGROUND: In the management of anemia in patients with chronic kidney disease stage 5 undergoing dialysis (CKD-5D), maintaining hemoglobin (Hb) within the range recommended by the guidelines is challenging. METHODS: The CARISMA study aim was to evaluate the efficacy, safety and tolerability of a once-monthly continuous erythropoietin receptor activator (CERA) for the treatment of anemia in CKD-5D patients. In this single-arm, multicenter, open-label, phase IIIb study, we screened adult patients from 66 centers in Italy receiving intravenous epoetin alfa or beta or darbepoetin alfa. Eligible patients entered the CERA dose titration phase (DTP), followed by an efficacy evaluation period (EEP) and a long term safety period (LTSP). Patients were analyzed by intention-to-treat (ITT), per protocol (PP) and safety populations. RESULTS: The rate of patients maintaining Hb within the range 10.0-12.0 g/dL throughout the EEP was 63.22% (220/348), and concentration from baseline to any postbaseline time point. CERA may thus offer a convenient and effective treatment 73.94% (122/165) in the ITT and PP population, respectively, periods in both populations. The rate of patients requiring a dose change was higher during the DTP (69.2%) and the LTSP (73.0%) than during the EEP (54.5%), as expected. CERA treatment was generally well tolerated. CONCLUSIONS: Once-monthly CERA administered to CKD-5D patients was associated with negligible changes in mean Hb option for these patients. PMID- 24052463 TI - Erythropoietin use in CKD patients with cancer: to tread with caution? AB - Erythropoietin (Epo) has long been known to be the principal hematopoietic growth factor that regulates cellular proliferation and differentiation of the erythroid lineage. Recombinant Epo (rEpo) is frequently used in the prevention and treatment of anemia of chronic kidney disease (CKD) and in the treatment of anemia associated with cancer. The expression of the Epo receptor (EpoR) in certain cancer cells has raised the possibility that exogenous rEpo may have direct effects on tumor cells with potential for stimulation of proliferation and resistance to chemotherapy and possibly metastasis. With recent clinical trials reporting negative outcomes with rEpo in the treatment of cancer-related anemia, with increased ?mortality in those who received rEpo, it has become necessary for nephrologists to analyze and review ?the effect of use of rEpo in treatment of anemia of CKD in patients who may have current or previously treated malignancy. It is known that CKD patients have an increased prevalence of certain malignancies (Wong G et al. Association of CKD and cancer risk in older people. J Am Soc Nephrol. 2009;20(6):1341-1350). If a CKD patient develops cancer or has a previous history of cancer, there is a dilemma which faces the treating nephrologist with respect to the use of rEpo in this situation. So far this issue has been addressed infrequently in the nephrology literature, and the guidelines are unclear. This review describes Epo and EpoR biology, reviews use of rEpo for treatment of cancer-related anemia and makes a case to the nephrology community for the careful use of rEpo in CKD patients with cancer. PMID- 24052464 TI - Pneumonia in hemodialysis patients: a challenging diagnosis in the emergency room. AB - BACKGROUND: Diagnosing pneumonia in hemodialysis patients is challenging. We hypothesized that pulmonary edema, which occurs commonly in hemodialysis patients, may frequently be misdiagnosed as pneumonia. METHODS: We retrospectively reviewed the records of 105 hemodialysis patients admitted with the diagnosis of pneumonia. Two experienced radiologists masked to the clinical course and subsequent imaging, independently interpreted the admission chest radiographs. In 68 of the patients, 2 internists independently reviewed the hospitalization records to diagnose pneumonia and pulmonary edema. The level of agreement among the radiologists was assessed using the kappa test. Using the clinical diagnoses, chest radiograph attributes were calculated. Logistic regression was performed to identify clinical and laboratory markers associated with pneumonia and pulmonary edema. RESULTS: The radiologist showed slight agreement on pneumonia (kappa = 0.32) and pulmonary edema (kappa = 0.28). Using clinical consensus, pneumonia was diagnosed in only 21% (14/68) of patients. Chest radiograph attributes for diagnosing pneumonia included: sensitivity 50%, specificity 58%, positive predictive value 25% and negative predictive value 81%. Pneumonia was associated with presenting temperature (odds ratio [OR] = ?2.01; 95% CI, 1.03-3.93). Pulmonary edema was associated with shortness of breath (SOB) at admission ?(OR = 4.83; 95% CI, 1.25-18.6), presenting temperature (OR = 0.44; 95% CI, 0.21-0.92) and volume removed during hemodialysis (OR = 1.96; 95% CI, 1.16-3.31). CONCLUSIONS: The admission chest radiograph has significant limitations when used to diagnose pneumonia in hemodialysis patients. A high presenting temperature supports the diagnosis of pneumonia, while a low presenting temperature, SOB and large volume ultrafiltration favor the diagnosis of pulmonary edema. PMID- 24052465 TI - Folic acid supplementation in end-stage renal disease patients reduces total mortality rate. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) are at high risk of cardiovascular disease and elevated serum homocysteine levels. Although folic acid supplementation has been documented to reduce serum homocysteine levels in ESRD patients, most trials of folic acid therapy for reducing cardiovascular diseases in ESRD patients have failed, mainly because of limited patient numbers. METHODS: We used the Taiwan National Health Insurance Research Database (NHIRD) to conduct a matched-pair retrospective cohort study to clarify whether folic acid supplementation benefits ESRD patient survival. Patients were divided into a folic acid supplementation group and a control group. All-cause and cardiovascular-related mortality rates between groups were compared. RESULTS: In total, 55,636 stable incident hemodialysis patients were identified from the database. Using a propensity score-matched method and intention-to-treat analysis, the survival rate of 17,000 patients with folic acid supplementation was compared with a 1:1 matched control group. The baseline demographic data and comorbid disease incidence between the 2 groups were comparable. During the study period, the mortality rate in the matched pair cohort was 35.5% (n = 6,030) over a mean follow-up period of 3.0 years, corresponding to a mortality rate of 12.8/100 patient-years. The all-cause mortality rates were 12.3 and 13.4/100 patient-years in the folic acid group and control group, respectively (p = 0.005). CONCLUSIONS: In adult hemodialysis patients, folic acid supplementation improves cardiovascular and all-cause mortality rates. PMID- 24052466 TI - Forewarned is forearmed: erythropoietin use in CKD patients with cancer. AB - Nayak-Rao and McCormick raise important concerns about erythropoietin use in patients with chronic kidney disease and cancer, and appropriately build a case for caution in this setting (J Nephrol. 2013, in press). Their comprehensive and insightful review highlights both the clinical and the basic science considerations that form the basis for this warning. PMID- 24052467 TI - Risk factors for kidney diseases and awareness of blood pressure and proteinuria in general population and in high school students: Italian report for World Kidney Days 2012-2013. PMID- 24052468 TI - Endothelial progenitor cells in systemic lupus erythematosus. AB - BACKGROUND AND AIM: Systemic lupus erythematosus (SLE) is an autoimmune-mediated disease, characterized by inflammation of small arteries and arterioles. Patients with SLE suffer from a 17-fold higher risk for developing atherosclerosis than healthy individuals. Endothelial progenitor cells (EPCs) have been shown to be critically involved in microvascular repair under both physiological and pathological conditions. The aim of the present study was to analyze EPC regeneration and mobilization in SLE patients with variable disease activity and undergoing different treatment regimens. METHODS: Forty-eight patients with SLE were analyzed. Healthy, age- and sex-matched individuals served as controls. Total circulating EPCs were enumerated by FACS analysis, and regenerative activity of the cells was analyzed by a colony-forming assay. Vasomodulatory mediators were quantified by ?ELISA. RESULTS: SLE patients did not show lower or higher percentages of total circulating EPCs, but they displayed significantly lower colony numbers as compared with healthy controls, indicating impaired EPC regeneration and mobilization. Low and high disease activity were associated with decreased EPC regeneration, while moderate disease activity was not. Hypertension and, to some extent, renal involvement were associated with reduced colony formation. Patients not receiving hydroxychloroquine (HCQ) treatment and those undergoing glucocorticoid therapy showed impaired EPC regeneration as well. CONCLUSIONS: SLE patients suffer from both defective regeneration and mobilization of EPCs. Such an impairment of the EPC system, as one key regulatory element in the process of vasorepair, could potentially promote microvascular damage in SLE. Long-term glucocorticoid therapy may further suppress the EPC system, while HCQ may prevent regeneration of the cells. PMID- 24052469 TI - Alterations in tubular epithelial cells in diabetic nephropathy. AB - Renal hypertrophy, matrix protein accumulation and tubulointerstitial fibrosis are major pathological features of diabetic nephropathy (DN) that eventuate in renal failure. Hyperglycemia and high concentration of glucose increase matrix protein expression, but the pathogenic mechanisms are not fully understood. We have previously reported that inactivation of tuberin resulting in activation of the mammalian target of rapamycin (mTOR) pathway and increased matrix protein accumulation in cultured proximal tubular cells exposed to high glucose and in kidney cortex of rats with type 1 diabetes. In this report, we show that kidney sections of diabetic patients express higher levels of phospho-tuberin (inactive form of tuberin), and that is associated with an increase in mTOR activation as measured by phosphorylation level of p70S6K. Inactivation of tuberin and activation of mTOR lead to accumulated cell matrix proteins (fibronectin and collagen IV) mainly in tubular epithelial cells of the kidneys of diabetic patients. In addition, significant staining of vimentin as a marker of cells undergoing an epithelial-to-mesenchymal transition (EMT) was detected in kidney sections of diabetic patients. On the other hand, very weak or nondetectable staining of cell matrix proteins, p-tuberin and P-p70S6K as well as vimentin was found in normal kidney sections of healthy subjects. The morphological changes in kidney sections of diabetic patients showed tubular thickening, glomerular and tubular hypertrophy, compared to normal structure of tubuli and glomeruli in kidney from healthy control subjects. These data suggest that alterations in tubular cells' structure, including tubular thickening and hypertrophy, are major mediators of the fibrotic process in DN. PMID- 24052470 TI - Aortic intimal sarcoma masquerading as bilateral renal artery stenosis. AB - Aortic intimal sarcoma is a rare tumor with poor prognosis. The most common manifestations are thromboembolic phenomena and vascular obstruction. We present a case of aortic intimal sarcoma causing bilateral renal artery stenosis which manifested as resistant hypertension and acute kidney inury. Multiple attempts to stent the renal arteries were unsuccessful. Eventually the patient developed acute limb ischemia and oliguric kidney failure as complications of the primary tumor. PMID- 24052471 TI - Tubular injury marker netrin-1 is elevated early in experimental diabetes. AB - BACKGROUND: Netrin-1 was recently identified as an early diagnostic biomarker of acute kidney injury. However, its usefulness for early diagnosis of chronic kidney disease (CKD) is unknown. The current study evaluated whether these proteins are increased in urine from experimental animals with diabetes. METHODS: The current study evaluated whether netrin-1 is increased in urine from diabetic rats and mice, and whether netrin-1 correlated with development of nephropathy. RESULTS: In rats, urinary netrin-1 excretion was significantly (p<0.001) higher in the diabetic group at 4 and 10 weeks after induction of diabetes as compared with the control group. Similarly, netrin-1 was increased significantly (p<0.001) in urine from hypertensive rats at 4 weeks as compared with controls. Likewise, urinary albumin excretion rates were increased in diabetic rats at 4 and 10 weeks as compared with controls and were increased in hypertensive rats at 4 weeks. Consistent with the diabetic model in rats, netrin-1 excretion was also increased early in diabetic mice's urine, and peak levels correlated with disease severity. CONCLUSION: Netrin-1 can be detected in urine from diabetic and hypertensive rats and may serve as a useful early diagnostic biomarker for development of CKD. PMID- 24052472 TI - Perfusion machines for liver transplantation: technology and multifunctionality. AB - The reliability of machine perfusion (alternative to static cold storage) for the preservation of liver for transplantation has been well investigated in experimental models, by taking into account the temperature, oxygenation, flow, pressure, and settings of the machine or proposed circuit. Machine perfusion is considered by many researchers as a valid method for preserving organs. While circuits or machines for preservation have been described, no agreement has been reached concerning how these devices should be developed. The machines proposed to date are considered here to identify the technical and functional features necessary for a machine to have multifunctionality and adaptability to cater all the needs of preservation, according to the type and features of the liver to be transplanted, including marginal livers. The need to establish a uniform method for the use of this machine is also emphasized, to achieve a clinical protocol for its use. PMID- 24052473 TI - Establishment and characterization of dairy cow growth hormone secreting anterior pituitary cell model. AB - A dairy cow anterior pituitary cell (DCAPC) model was established in vitro for the study of growth hormone (GH) synthesis and secretion in the anterior pituitary gland of the dairy cow. Pituitary glands were obtained from Holstein dairy cows' heads cut by electric saw, and the posterior pituitary glands were removed to obtain integrated anterior pituitary glands. Immunohistochemistry assay of GH in the anterior pituitary glands showed that most somatotrophs were located within the lateral wings of the anterior pituitary. Tissues of the lateral wings of the anterior pituitary were dispersed and cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum. The DCAPCs displayed a monolayer, cobblestone, epithelial-like morphology which are the typical characteristics of the anterior pituitary cells. The DCAPCs were subcultured continuously over ten passages. GH immunoreactivity was present in DCAPCs at passage 10. The transcription of the bovine GH mRNA in DCAPCs at passage 10 was decreased to below 50% compared with the lateral wings of the anterior pituitary tissues. Thus, our DCAPCs model is effective for the in vitro examination of GH synthesis and secretion in the dairy cow anterior pituitary gland. The effects of transforming growth factor beta 1 (TGF-beta1) and interferon-gamma (IFN-gamma) on the expression of GH mRNA in DCAPCs at passage 3 were also investigated. There were no obvious changes in transcription of the GH gene after treatment with TGF-beta1 for 24 h, while IFN-gamma increased transcription of the GH gene in a dose-dependent manner. PMID- 24052474 TI - In vitro hepatic differentiation of human endometrial stromal stem cells. AB - Human endometrial stromal stem cells (hESSCs) can differentiate into mesodermal and ectodermal cellular lineages in the endometrium. However, whether hESSCs can differentiate into functional hepatic-like cells is unknown. In this study, we developed a multiple-step induction protocol to differentiate hESSCs into functional hepatic-like cells in vitro. Endometrial stromal cells were isolated by magnetic affinity sorting using anti-epithelial cell adhesion molecule-coated Dynabeads. The enriched hESSCs were analyzed by flow cytometry and were able to differentiate into osteoblasts or adipocytes under proper induction media. To differentiate into hepatic-like cells, hESSCs were cultured in a stepwise system containing hepatocyte growth factor, fibroblast growth factor-4, oncostatin M, and trichostatin A for a total of 24 d. The hepatic-like cell differentiation was analyzed by confocal microscopy and immunocytochemical staining. Glycogen storage, cellular urea synthesis, and ammonia concentrations were measured. Hepatic-like cells were successfully generated from hESSCs and were identified by their epithelial-like shape characteristics and expression of specific biomarkers albumin and cytokeratin 8 accompanied with a reduction of alpha-fetoprotein and alpha-smooth muscle actin expression. The hepatic-like cells generated were functional as evidenced by urea synthesis and glycogen storage. Our study demonstrated that hESSCs were able to differentiate into hepatic-like cells in vitro. Thus, endometrial stromal cells may be used as an easily accessible alternative source of stem cells for potential therapeutic applications in liver disease. PMID- 24052475 TI - Knockdown of endogenous myostatin promotes sheep myoblast proliferation. AB - Myostatin (MSTN), is a known negative regulator of myogenesis. Silencing of the function of MSTN could result in increasing muscle mass in mice. To determine the function of endogenous MSTN expression on proliferation of sheep myoblasts, a short-hairpin RNA-targeting sheep MSTN was constructed into lentiviral vector to silence endogenous MSTN expression. We demonstrated that silencing of endogenous MSTN gene with up to approximately 73.3% reduction by short hairpin RNA (shRNA) resulted in significant increase (overall 28.3%) of proliferation of primary ovine myoblasts. The upregulation of proliferation was accompanied by the decrease expression of MyoD (-37.6%, p = 0.025), myogenin (-33.1%, p = 0.049), p21 (-49.3%, p = 0.046), and Smad3 (-50.0%, p = 0.007). Silencing of myostatin using shRNA may provide a feasible approach to improve meat productivity in farm animals. PMID- 24052476 TI - Barriers to healthcare access among refugees with disabilities and chronic health conditions resettled in the US Midwest. AB - Chronic conditions and related functional disabilities are highly prevalent among resettled refugees in the United States. There is a need to explore this population's access to appropriate healthcare services in order to identify service disparities and improve interventions. Using a community-based participatory research approach, semi-structured interviews were conducted with key informants to identify healthcare access barriers affecting disabled and chronically ill refugees. Eighteen participants were interviewed, revealing three main barriers: (1) inadequate health insurance, (2) language and communication barriers, and (3) a complex maze of service systems. These barriers were found to operate at systems, provider, and individual levels. Broad-based policy and practice interventions are required to address barriers including: an expanded pool of medical interpreters, peer navigators, innovative health information technologies, and greater collaboration and information-sharing between service systems. Further research is needed to monitor the impact the Affordable Care Act on service access of refugees with disabilities and chronic conditions. PMID- 24052477 TI - Exploring the role of ethnic identity on the attitudes towards HPV vaccine advertising among Puerto Ricans: a qualitative analysis. AB - Despite the existence of guidelines recommending vaccination against the human papillomavirus (HPV) and widespread availability of the vaccine through the Vaccines for Children program, HPV vaccination rates among island Puerto Ricans are suboptimal. Advertising plays a central role in promoting HPV vaccination by increasing awareness of and knowledge about the vaccine; however, little is known about the influence of cultural factors on the impact of HPV messages delivered through the media. The aim of this qualitative study was to explore the role of ethnic identity on the attitudes towards HPV vaccine advertising among island Puerto Ricans. Five focus groups (n = 23) were conducted with parents and non vaccinated females. Our analysis found several themes that may influence attitudes towards HPV vaccine advertising among this population: physical ethnic similarity, relevance of information, and sociocultural congruence. Findings may assist in developing culturally appropriate health promotion programs and media to promote HPV vaccination among Puerto Ricans. PMID- 24052478 TI - Awareness and knowledge of Human papillomavirus (HPV) among ethnically diverse women varying in generation status. AB - Although Human papillomavirus (HPV) is a common sexually transmitted infection, there is limited knowledge of HPV with ethnic/racial minorities experiencing the greatest disparities. This cross-sectional study used the most recent available data from the California Health Interview Survey to assess disparities in awareness and knowledge of HPV among ethnically/racially diverse women varying in generation status (N = 19,928). Generation status emerged as a significant predictor of HPV awareness across ethnic/racial groups, with 1st generation Asian Americans and 1st and 2nd generation Latinas reporting the least awareness when compared to same-generation White counterparts. Also, generation status was a significant predictor of HPV knowledge, but only for Asian-Americans. Regardless of ethnicity/race, 1st generation women reported lowest HPV knowledge when compared to 2nd and 3rd generation women. These findings underscore the importance of looking at differences within and across ethnic/racial groups to identify sub-groups at greatest risk for poor health outcomes. In particular, we found generation status to be an important yet often overlooked factor in the identification of health disparities. PMID- 24052479 TI - Immigrant women's perspective on prenatal and postpartum care: systematic review. AB - Female migration represents a major public health challenge faced today because its heterogeneity and gender issues placing immigrant women among the most vulnerable and at-risk group. To identify and analyze studies dealing with immigrant women's perspectives with prenatal and postpartum health care. A systematic literature review was conducted to assess studies published between 2000 and 2010 using Cumulative Index to Nursing and Allied Health Literature, EMBASE, PubMed and Cochrane Database of Systematic Reviews. The studies explored the relation between socio-demographic characteristics of immigrant women participants and its impact on the main factors identified as influencing prenatal and postpartum care, characterizing the manifested knowledge and behaviors expressed and describing the women's experience with health care services and the incidence of postpartum depression symptoms. The less favorable socio-economic status of migrant women participants seems to have been influential in the quality of health service in prenatal and postpartum periods. The language barrier was the main negative factor interfering with communication between women and health professionals, followed by health care professionals' lack of cultural sensitivity, leading to women's reluctance in using health services. PMID- 24052481 TI - Extrinsic primary afferent neurons projecting to the pylorus in the domestic pig- localization and neurochemical characteristics. AB - The pig, as an omnivorous animal, seems to be especially valuable species in "gastrointestinal" experiments. The importance of the pylorus in the proper functioning of the digestive tract is widely accepted. Although it is commonly known that sensory innervation plays an important role in the regulation of gastric activity and gastrointestinal tissue resistance, there is complete lack of data on the extrinsic afferents projecting to the swine pylorus. The present experiment has been designed to discover the precise localization and neurochemical properties of the primary sensory neurons projecting to the porcine pylorus. Combined retrograde tracing technique and double immunocytochemistry were applied in five piglets. An additional RT-PCR reaction was used to confirm the presence of all investigated neurotransmitters in the studied ganglia. Traced neurons were localized within the bilateral nodose ganglia of the vagus and bilateral dorsal root ganglia spreading from Th4 to L1. Fast Blue-positive afferents expressed immunoreactivity to substance P, calcitonin gene-related peptide, neuronal isoform of nitric oxide synthase, and galanin. In the vagal and spinal ganglia, the percentages of traced neurons immunoreactive to these substances were 54.8, 10.7, 49.6, 7.4 % and 22.2, 75.5, 95.2 %, respectively, and the solitary perikarya were Gal immunoreactive. The presence of all substances studied in the ganglion tissue was confirmed by RT-PCR technique. PMID- 24052480 TI - Perspectives on physical activity among immigrants and refugees to a small urban community in Minnesota. AB - Immigrants and refugees to the United States exhibit relatively low levels of physical activity, but reasons for this disparity are poorly understood. 16 gender and age-stratified focus groups were conducted among 127 participants from heterogenous immigrant and refugee groups (Cambodian, Mexican, Somali, Sudanese) in a small Minnesota urban community. We found many similarities in perceived barriers and facilitators to physical activity between heterogeneous immigrant and refugee groups. While the benefits of physical activity were widely acknowledged, lack of familiarity and comfort with taking the first steps towards being physically active were the most significant barriers to physical activity. Participants described being motivated by social support from family, friends, and communities to be physically active. Our findings suggest that shared experiences of immigration and associated social, economic, and linguistic factors influence how physical activity is understood, conceptualized and practiced. PMID- 24052482 TI - Laparoscopic double-tract proximal gastrectomy for proximal early gastric cancer. AB - BACKGROUND: Proximal gastrectomy is not routinely performed because it is associated with increased reflux symptoms and anastomotic strictures. The purpose of this study is to describe a novel method of laparoscopic proximal gastrectomy (LPG) with double-tract reconstruction (DTR) for proximal early gastric cancer (EGC), and to evaluate the technical feasibility, safety, and short-term surgical outcomes, especially reflux symptoms, after LPG. METHODS: Retrospective review of the prospective cohort data of 43 patients who presented to a single tertiary hospital from June 2009 through April 2012 and underwent LPG with DTR for proximal EGC. The data of this prospective cohort were analyzed, and the reflux symptoms, clinicopathologic characteristics, surgical outcomes, postoperative morbidities and mortalities, and follow-up findings were analyzed. RESULTS: The mean surgical time was 180.7 min; mean estimated blood loss, 120.4 mL; mean length of the proximal resection margin, 4.13 cm; mean number of retrieved lymph nodes, 41.2; and mean postoperative hospital stay, 7.1 days. Early complication rate was 11.6 % (n = 5); major complication (grade higher than Clavien-Dindo IIIa) occurred in 1 patient (2.3 %). Late complication rate was 11.6 % (n = 5): 2 patients had esophagojejunostomy stenosis, which was successfully treated with fluoroscopic balloon dilatations; 1, chylous ascites; and 2 had Visick grade II reflux symptoms (4.6 %), managed by medication during the mean follow-up period of 21.6 months. CONCLUSION: DTR after LPG is a feasible, simple, and novel reconstruction method with excellent postoperative outcomes in terms of preventing reflux symptoms. Its clinical applicability must be validated by prospective randomized trials. PMID- 24052483 TI - Active chest compression-decompression for cardiopulmonary resuscitation. AB - BACKGROUND: Active compression-decompression cardiopulmonary resuscitation (ACDR CPR) uses a hand-held suction device, applied mid-sternum, to compress the chest then actively decompress the chest after each compression. Randomised controlled trials testing this device have shown discordant results. OBJECTIVES: To determine the effect of active chest compression-decompression CPR compared to standard chest compression CPR on mortality and neurological function in adults with cardiac arrest treated either in-hospital or out-of-hospital. SEARCH METHODS: We updated the searches of CENTRAL in The Cochrane Library (Issue 12 of 12, 2012), MEDLINE (OVID, 1946 to January week 1 2013), and EMBASE (OVID, 1980 to week 1 2013) on 14 January 2013. We checked the reference list of retrieved articles, contacted experts in the field, and searched ClinicalTrials.gov. SELECTION CRITERIA: All randomised or quasi-randomised studies comparing active compression-decompression with standard manual chest compression in adults with a cardiac arrest who received cardiopulmonary resuscitation by a trained medical or paramedical team. DATA COLLECTION AND ANALYSIS: We independently extracted data on an intention-to-treat basis. When needed, we contacted the authors of the primary studies. If appropriate, we cumulated studies and pooled relative risk (RR) estimates. We predefined subgroup analyses according to setting (out-of hospital or in-hospital) and attending team composition (with physician or paramedic only). MAIN RESULTS: In this update, 27 new related publications were found, but they did not all fulfil inclusion criteria or concerned participants already reported in previous publications. In the end, we included 10 trials in this review: Eight were in out-of-hospital settings; one was set in-hospital only; and one had both in-hospital and out-of-hospital components. Allocation concealment was adequate in four studies. The two in-hospital studies were different in quality and size (773 and 53 participants). Both found no differences between ACDR CPR and STR in any outcome.Out-of-hospital trials cumulated 4162 participants. There were no differences between ACDR CPR and STR for mortality either immediately (RR 0.98, 95% confidence interval (CI) 0.94 to 1.03) or at hospital discharge (RR 0.99, 95% CI 0.98 to 1.01). The pooled RR of neurological impairment of any severity was 1.71 (95% CI 0.90 to 3.25), with a non-significant trend to more frequent severe neurological damage in survivors of ACDR CPR (RR 3.11, 95% CI 0.98 to 9.83). However, assessment of neurological outcome was limited, and few participants had neurological damage.There was no difference between ACDR CPR and STR with regard to complications such as rib or sternal fractures, pneumothorax, or haemothorax (RR 1.09, 95% CI 0.86 to 1.38). Skin trauma and ecchymosis were more frequent with ACDR CPR. AUTHORS' CONCLUSIONS: Active chest compression-decompression in people with cardiac arrest is not associated with any clear benefit. PMID- 24052489 TI - Feasibility of applying data mining techniques for predicting technical difficulties during laparoscopic cholecystectomy based on routine patient work-up in a small community hospital. AB - BACKGROUND/AIMS: Predicting technical difficulties in laparoscopic cholecystectomy (LC) in a small regional hospital increases efficacy, cost benefit and safety of the procedure. The aim of the study was to assess whether it is possible to accurately predict a difficult LC (DLC) in a small regional hospital based only on the routine available clinical work-up parameters (patient history, ultrasound examination and blood chemistry) and their combinations. METHODOLOGY: A prospective, cohort, of 369 consecutive patients operated by the same surgeon was analyzed. Conversion rate was 10 (2.7%). DLC was registered in 55 (14.90%). Various data mining techniques were applied and assessed. RESULTS: Seven significant predictors of DLC were identified: i) shrunken (fibrotic) gallbladder (GB); ii) ultrasound (US) GB wall thickness >4 mm; iii) >5 attacks of pain lasting >5 hours; iv) WBC >10x109 g/L; v) pericholecystic fluid; vi) urine amylase >380 IU/L, and vii) BMI >30kg/m2. Bayesian network was selected as the best classifier with accuracy of 94.57, specificity 0.98, sensitivity 0.77, AUC 0.96 and F-measure 0.81. CONCLUSION: It is possible to predict a DLC with high accuracy using data mining techniques, based on routine preoperative clinical parameters and their combinations. Use of sophisticated diagnostic equipment is not necessary. PMID- 24052490 TI - Influence of hepatic impairment on the pharmacokinetics of the dopamine agonist rotigotine. AB - The transdermally applied dopamine receptor agonist rotigotine is extensively metabolized in the liver. An open-label, parallel-group study was conducted to evaluate the effects of moderate hepatic impairment on the pharmacokinetics, safety and tolerability of rotigotine. Eight subjects with normal hepatic function and nine with moderate hepatic impairment (Child-Pugh class B) received one rotigotine transdermal patch (providing a dose of 2 mg/24 h) daily for 3 days with a 24-h patch-on period. Blood and urine samples were collected to evaluate pharmacokinetic parameters characterizing drug bioavailability and elimination. Primary variables included plasma and urine concentrations of unconjugated rotigotine (active parent compound) and total rotigotine (unconjugated rotigotine plus sulfate and glucuronide conjugates) under steady-state (SS) conditions. For unconjugated rotigotine, point estimates for the ratios of AUC(0-24)SS and C max,SS between the two groups (normal vs. impaired hepatic function) were near 1: AUC(0-24)SS, 0.90 (90 % CI 0.59, 1.38) and C max,SS, 0.94 (90 % CI 0.66, 1.35); t max,SS and t 1/2 were lower in subjects with hepatic impairment, while renal clearance was unaffected and overall clearance was higher. For total rotigotine, C max,SS was higher in subjects with hepatic impairment compared with those with normal hepatic function (P = 0.0239, ANOVA). A tendency to reduced non-renal clearance was observed in subjects with hepatic impairment, consistent with their higher plasma concentrations of total rotigotine. Thus, moderate hepatic impairment did not influence the pharmacokinetics of unconjugated rotigotine under steady-state conditions suggesting that dose adjustment will not be required for patients with mild or moderate hepatic insufficiency. In addition, the rotigotine patch was well tolerated in subjects with moderate hepatic impairment. PMID- 24052491 TI - n-3 Polyunsaturated fatty acids supplementation in peripheral artery disease: the OMEGA-PAD trial. AB - Despite current consensus guidelines recommending intensive cardiovascular risk factor management for peripheral artery disease (PAD), patients suffering from PAD continue to experience significant morbidity and mortality. This excess morbid burden is at least partially related to impaired vascular function and systemic inflammation. Interventions bridging this gap are critical. Dietary supplementation of n-3 polyunsaturated fatty acids (n-3 PUFA) has been shown to improve endothelial function and reduce inflammation in different cohorts, as well as to decrease cardiovascular events in secondary prevention trials in patients with coronary artery disease. Their effects in the PAD population are, however, less well understood. The OMEGA-PAD trial is a double-blinded, randomized, placebo-controlled trial that examines the impact of a high-dose, short-duration dietary oral supplementation of n-3 PUFA on vascular function and inflammation in patients with established PAD. The purpose of this article is to provide a detailed description of the design and methods of the OMEGA-PAD trial, and a summary of baseline characteristics of the cohort. PMID- 24052492 TI - Quantification of selected endogenous hydroxy-oxylipins from tropical marine macroalgae. AB - The present study investigated the contents of hydroxy-oxylipins hydroxyoctadecadienoic acids (HODEs), hydroxyoctadecatrienoic acids (HOTrEs), and hydroxyeicosatetraenoic acids (HETEs) in 40 macroalgae belonging to the Chlorophyceae, Rhodophyceae and, Phaeophyceae. The hydroxy-oxylipin content was low and ranged from 0.14 +/- 0.012 ng/g (Codium dwarkense) to 8,161.9 +/- 253 ng/g (Chaetomorpha linum) among the Chlorophyceae, 345.4 +/- 56.8 ng/g (Scytosiphon lomentaria) to 2,574.5 +/- 155.5 ng/g (Stoechospermum marginatum) among the Phaeophyceae, and 19.4 +/- 2.2 ng/g (Laurencia cruciata) to 1,753.1 +/- 268.2 ng/g in Gracilaria corticata v. folifera) among the Rhodophyceae on fresh weight basis (p <= 0.01). The concentrations of C18-oxylipins were greater than C20-oxylipins in all the investigated macroalgae, except forUlva linza, Codium sursum, Dictyopteris deliculata, S. marginatum, Sargassum tenerrimum, Gracilaria spp. (except G. textorii), Rhodymenia sonderi, and Odonthalia veravalensis.The macroalgal species rich in HODEs, HOTrEs, and HETEs were segregated using principal component analysis. The red macroalgae showed the highest contents of HETEs, followed by brown and green macroalgae in consistent with their PUFA profiles. The relative contents of isomeric forms of oxylipins displayed the species-specific positional selectivity of lipoxygenase (LOX) enzyme in macroalgae. All the species exhibited 13-LOX specificity for linoleic acid analogous of higher plants, while 21 out of 40 species showed 9-LOX selectivity for the oxygenation of alpha-linolenic acid. No trend was observed for the oxygenation of arachidonic acid in macroalgae, except for in the Halymeniales, Ceramiales (except L. cruciata), and Corallinales. This study infers that LOX products, octadecanoids and eicosanoids, described in macroalgal taxa were similar to those of higher plants and mammals, respectively, and thus can be utilized as an alternative source of chemically synthesized oxylipin analogues in therapeutics, cosmetics, and nutritional oil supplements. PMID- 24052493 TI - Microarray analysis of hepatic gene expression in juvenile Japanese flounder Paralichthys olivaceus fed diets supplemented with fish or vegetable oils. AB - Gene expression profiling was performed in Japanese flounder Paralichthys olivaceus fed diets supplemented with fish oil (FO), linseed oil (LO), or olive oil (OO) for 6 weeks. The LO and OO groups showed significantly retarded growth, lower feed intake, lower protein efficiency ratio, and lower hepatosomatic index (P < 0.05). Liver fatty acid composition reflected the dietary fatty acid composition. Microarray analysis revealed that dietary n - 3 highly unsaturated fatty acid (HUFA) deficiency affected 169 transcripts. In the LO group, 57 genes were up-regulated and 38 genes were down-regulated, whereas in the OO group nine genes were up-regulated and 87 genes were down-regulated. Analysis of the functional annotations suggested that dietary n - 3 HUFA affected genes involved in signal transduction (23.2 %), cellular processes (21.1 %), metabolism (including glucose, lipid, and nucleobase; 15.5 %), transport (11.3 %), regulation of transcription (10.5 %), and immune response (4.2 %). Several genes encoding serine/threonine kinases such as protein kinase C and calmodulin dependent kinase and nuclear hormone receptors such as vitamin D receptor, retinoic acid receptor, and receptors for cytokines (bone morphogenic protein and transforming growth factor beta) were affected. Among 169 transcripts, 22 genes were affected in both LO and OO groups. The present study identified several genes involved in n - 3 HUFA deficiency-sensitive pathways, which will be useful for selective breeding of flounder strains able to adapt to n - 3 HUFA deficiency. PMID- 24052494 TI - Isolation, expression, and characterization of blue light receptor AUREOCHROME gene from Saccharina japonica (Laminariales, Phaeophyceae). AB - Photosynthetic stramenopile have chloroplasts of secondary endosymbiotic origin and are significant as aquatic primary productivity and biomass production. In marine environments, many photosynthetic stramenopiles utilize blue light to regulate growth, development, and organelle movement. Aureochrome (AUREO) is a new type blue light photoreceptor specific in photosynthetic stramenopiles. Previously, several AUREO orthologs were reported in genomes of stramenopile members, but the full-length cDNA sequences were completed only in Vaucheria frigida (Xanthophyceae), Fucus distichus (Phaeophyceae), and Ochromonas danica (Chrysophyceae). In this study, the full-length cDNA of AUREO from Saccharina japonica (designated as SjAUREO) was isolated based on homologous cloning and the rapid amplification of cDNA ends (RACE). It characterized by the full length of 1,013 bp with an open reading frame of 612 bp, which encoded a polypeptide of 203 amino acids with predicted molecular weight of 23.08 kDa and theoretical isoelectric point of 7.63. The deduced amino acid sequence of SjAUREO contained one N-terminal basic region/leucine zipper (bZIP) transcription regulation domain and a single light-, oxygen-, or voltage-sensitive (LOV) domain near the C terminus. Homologous analysis showed that SjAUREO shared 40-92 % similarities with those of other photosynthetic stramenopiles. Phylogenetic analysis revealed close phylogenetic affinity between SjAUREO and AUREO4 of brown alga Ectocarpus siliculosus. Real-time PCR detection revealed that the SjAUREO transcription was markedly increased under BL exposure and dramatically upregulated in the 1-month juvenile sporophyte than those in the 2 and 3-month materials, which indirectly reflected the SjAUREO associated with the BL-mediated photomorphogenesis during the growth and early development of juvenile sporophytes. In vitro expression showed one distinct band existed at ~27 kDa, and western blot detection proved that it was positive to the anti-His antibody with high specificity. Our results enriched the knowledge of AUREO properties in S. japonica and provided clues to explore the mechanisms underlying diverse physiological responses mediated by BL photoreceptors AUREO in the photosynthetic stramenopiles. PMID- 24052495 TI - Identifying delays to mechanical thrombectomy for acute stroke: onset to door and door to clot times. AB - Outcomes from endovascular therapy for acute stroke are time dependent. Delays in the administration of this therapy have not been extensively studied and no performance benchmarks have been established. There are limited data on the complex factors that can affect these delays. In this review, we discuss the existing literature on the delays involved in endovascular therapy and have presented them as prehospital and inhospital factors. Some of these factors are common to intravenous thrombolysis; in addition, there are some that are unique to endovascular therapy. These include the awareness of the first responders, emergency medical services, interhospital transfer and triage systems, activation of the endovascular team, complex imaging decisions, and intraprocedural delays. A thorough understanding of these delays can help identify areas of improvement which may affect clinical outcomes. PMID- 24052496 TI - Prepare to launch: optimizing doctoral education to ensure career success. PMID- 24052497 TI - Inducible overexpression of GLUT1 prevents mitochondrial dysfunction and attenuates structural remodeling in pressure overload but does not prevent left ventricular dysfunction. AB - BACKGROUND: Increased glucose transporter 1 (GLUT1) expression and glucose utilization that accompany pressure overload-induced hypertrophy (POH) are believed to be cardioprotective. Moreover, it has been shown that lifelong transgenic overexpression of GLUT1 in the heart prevents cardiac dysfunction after aortic constriction. The relevance of this model to clinical practice is unclear because of the life-long duration of increased glucose metabolism. Therefore, we sought to determine if a short-term increase in GLUT1-mediated myocardial glucose uptake would still confer cardioprotection if overexpression occurred at the onset of POH. METHODS AND RESULTS: Mice with cardiomyocyte specific inducible overexpression of a hemagglutinin (HA)-tagged GLUT1 transgene (G1HA) and their controls (Cont) were subjected to transverse aortic constriction (TAC) 2 days after transgene induction with doxycycline (DOX). Analysis was performed 4 weeks after TAC. Mitochondrial function, adenosine triphosphate (ATP) synthesis, and mRNA expression of oxidative phosphorylation (OXPHOS) genes were reduced in Cont mice, but were maintained in concert with increased glucose utilization in G1HA following TAC. Despite attenuated adverse remodeling in G1HA relative to control TAC mice, cardiac hypertrophy was exacerbated in these mice, and positive dP/dt (in vivo) and cardiac power (ex vivo) were equivalently decreased in Cont and G1HA TAC mice compared to shams, consistent with left ventricular dysfunction. O-GlcNAcylation of Ca2+ cycling proteins was increased in G1HA TAC hearts. CONCLUSIONS: Short-term cardiac specific induction of GLUT1 at the onset of POH preserves mitochondrial function and attenuates pathological remodeling, but exacerbates the hypertrophic phenotype and is insufficient to prevent POH-induced cardiac contractile dysfunction, possibly due to impaired calcium cycling. PMID- 24052498 TI - Transbaffle mapping and ablation for atrial tachycardias after mustard, senning, or Fontan operations. AB - BACKGROUND: In Fontan and atrial switch patients, transcatheter ablation is limited by difficult access to the pulmonary venous atrium. In recent years, transbaffle access (TBA) has been described, but limited data document its safety and utility. METHODS AND RESULTS: All ablative electrophysiological study cases of this population performed between January 2006 and December 2010 at Boston Children's Hospital were reviewed. Pre-case and follow-up clinical characteristics were documented. Adverse events were classified by severity and attributability to the intervention. We included 118 cases performed in 90 patients. TBA was attempted in 74 cases and was successful in 96%: in 20 via baffle leak or fenestration and in 51 (94%) of 54 using standard or radiofrequency transseptal techniques. There were 10 procedures with adverse events ranked as moderate or more severe. The event rate was similar in both groups (TBA 8% versus non-TBA 9%, P = 1), and no events were directly attributable to TBA. There was a trend to higher proportion of cases having a > 5 point drop in saturations from baseline in the TBA group versus the non-TBA group in Fontan cases (15% vs 0%, P = 0.14). When cases with follow-up > 90 and > 365 days were analyzed, the median initial arrhythmia score of 5 significantly changed--3 points in both time periods (P <= 0.001). CONCLUSIONS: TBA is feasible in this population; its use was not associated with a higher incidence of adverse events; and changes in clinical scores support its efficacy. Desaturation observed in some patients is of uncertain significance but warrants postablation monitoring and prospective study. PMID- 24052499 TI - Adiponectin-mediated modulation of lymphatic vessel formation and lymphedema. AB - BACKGROUND: Obesity is linked with an increased risk of lymphedema, which is a serious clinical problem. Adiponectin is a circulating adipokine that is down regulated in obese states. We investigated the effects of adiponectin on lymphatic vessel formation in a model of lymphedema and dissected its mechanisms. METHODS AND RESULTS: A mouse model of lymphedema was created via ablation of tail surface lymphatic network. Adiponectin-knockout mice showed the greater diameter of the injured tail compared with wild-type mice, which was associated with lower numbers of lymphatic endothelial cells (LECs). Systemic delivery of adiponectin reduced the thickness of the injured tail and enhanced LEC formation in wild-type and adiponectin-knockout mice. Adiponectin administration also improved the edema of injured tails in obese KKAy mice. Treatment with adiponectin protein stimulated the differentiation of human LECs into tubelike structures and increased LEC viability. Adiponectin treatment promoted the phosphorylation of AMP-activated protein kinase (AMPK), Akt, and endothelial nitric oxide synthase n LECs. Blockade of AMPK or Akt activity abolished adiponectin-stimulated increase in LEC differentiation and viability and endothelial nitric oxide synthase phosphorylation. Inhibition of AMPK activation also suppressed adiponectin induced Akt phosphorylation in LECs. In contrast, inactivation of Akt signaling had no effects on adiponectin-mediated AMPK phosphorylation in LECs. Furthermore, adiponectin administration did not affect the thickening of the damaged tail in endothelial nitric oxide synthase-knockout mice. CONCLUSIONS: Adiponectin can promote lymphatic vessel formation via activation of AMPK/Akt/endothelial nitric oxide synthase signaling within LECs, thereby leading to amelioration of lymphedema. PMID- 24052500 TI - Compliance with an EMA monitoring protocol and its relationship with participant and smoking characteristics. AB - INTRODUCTION: Arguably, the greatest advantage of ecological momentary assessment (EMA) studies is that data are collected repeatedly in real-time and real-world situations, which reduces recall and situational biases and thus improves the accuracy and validity of the data collected. However, the validity of EMA data is contingent upon compliance rates. If participant characteristics are related to missing data, analyses should control for these factors, or they should be targeted in EMA training sessions. This study evaluates the impact of demographic and smoking-related participant characteristics on compliance to an EMA smoking study protocol. METHODS: Prequit-day data were taken from the control arm of an ongoing randomized controlled trial of a smoking-cessation program. After training, 119 participants were asked to carry a mobile device with them at all times for ~6 days and to log every cigarette they smoked in addition to completing randomly scheduled assessments. Different types of compliance were assessed: the percentage of completed random prompts (signal-contingent compliance), the percentage of logged cigarettes per day compared to a timeline follow-back measure, and the correlation between logged cigarettes and a carbon monoxide assessment 2 hr later (both event-contingent compliance). RESULTS: Overall compliance rates were 78.48% for event-contingent and 72.17% for signal contingent compliance. None of the demographic or smoking-related participant characteristics predicted signal-contingent compliance; however, female participants showed higher event-contingent compliance than male participants, and Caucasian participants showed higher event-contingent compliance than non Caucasian participants. CONCLUSIONS: Compliance did not depend on smoking-related characteristics. EMA is a valid method for assessing smoking behavior in real time and real-world settings. PMID- 24052501 TI - Effectiveness of nicotinic agonists as desensitizers at presynaptic alpha4beta2- and alpha4alpha5beta2-nicotinic acetylcholine receptors. AB - INTRODUCTION: Nicotine interacts with nicotinic acetylcholine receptors (nAChRs) and modifies neuronal functions. The net result of nicotine exposure is difficult to assess because multiple nAChR subtypes exist and are expressed on multiple classes of neurons. Nicotine, unlike the natural agonist acetylcholine, remains in tissues for hours, and during this extended exposure nAChRs desensitize. Therefore, agonists can block the natural functions of nAChRs. Higher nicotine concentrations are required to desensitize alpha4beta2-nAChRs containing the alpha5 subunit. The aim of these experiments was to determine if this property holds true for compounds other than nicotine. METHODS: [(3)H]-dopamine release from crude mouse striatal synaptosomal preparations was used to measure activation and desensitization of the [(alpha4beta2)2beta2] and [(alpha4beta2)2alpha5] nAChR subtypes. Affinity was measured by competition with [(125)I]-epibatidine. RESULTS: Nine compounds of varying affinity and efficacy were tested. All compounds partially desensitized both subtypes; concentration necessary for desensitization correlated with binding site affinity but not efficacy. All compounds showed a similar, significant shift in concentration necessary for a 50% effect when the alpha5 subunit was included (averaging 8-fold higher). The extent of desensitization produced by a 10-min exposure did not correlate with affinity or efficacy of compound. CONCLUSION: Full or partial nicotinic agonists used as medications may effectively desensitize alpha4beta2 nAChRs. However, significantly higher concentrations of all compounds tested were required to elicit desensitization of alpha4alpha5beta2-nAChRs than alpha4beta2 nAChRs. If desensitization is the important property for a smoking cessation drug, basic screening at both subtypes may provide a mechanistic foundation for effectiveness. PMID- 24052502 TI - Modeling mood variation and covariation among adolescent smokers: application of a bivariate location-scale mixed-effects model. AB - INTRODUCTION: Ecological momentary assessments (EMAs) are useful for understanding both between- and within-subject dynamic changes in smoking and mood. Modeling 2 moods (positive affect [PA] and negative affect [NA], PA and NA) simultaneously will better enable researchers to explore the association between mood variables and what influences them at both the momentary and subject level. METHODS: The EMA component of a natural history study of adolescent smoking was analyzed with a bivariate location-scale mixed-effects model. The proposed model separately estimates the between- and within-subject variances and jointly models the 2 mood constructs. A total of 461 adolescents completed the baseline EMA wave, which resulted in 14,105 random prompts. Smoking level, represented by the number of smoking events on EMA, entered the model as 2 predictors: one that compared nonsmokers during the EMA week to 1-cigarette smokers, and the second one that estimated the effect of smoking level on mood among smokers. RESULTS: Results suggest that nonsmokers had more consistent positive and negative moods compared to 1-cigarette smokers. Among those who smoked, both moods were more consistent at higher smoking levels. The effects of smoking level were greater for NA than for PA. The within-subject association between mood constructs was negative and strongest among 1-cigarette smokers; the within-subject association between positive and negative moods was negatively associated with smoking. CONCLUSIONS: Mood variation and association between mood constructs varied across smoking levels. The most infrequent smokers were characterized with more inconsistent moods, whereas mood was more consistent for subjects with higher smoking levels. PMID- 24052504 TI - Pregnancy loss managed by cervical dilatation and curettage increases the risk of spontaneous preterm birth. AB - STUDY QUESTION: Do women with a previous miscarriage or termination of pregnancy have an increased risk of spontaneous preterm birth and is this related to previous cervical dilatation and curettage? SUMMARY ANSWER: A single previous pregnancy loss (termination or miscarriage) managed by cervical dilatation and curettage is associated with a greater risk of SpPTB. WHAT IS KNOWN ALREADY: Miscarriage affects ~20% of pregnancies and as many as a further 20% of pregnancies undergo termination. STUDY DESIGN, SIZE, DURATION: We utilized data from 5575 healthy nulliparous women with singleton pregnancies recruited to the Screening for Pregnancy Endpoints (SCOPE) study, a prospective cohort study performed between November 2004 and January 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary outcome was spontaneous preterm birth (defined as spontaneous preterm labour or preterm premature rupture of membranes (PPROM) resulting in preterm birth <37 weeks' gestation). Secondary outcomes included PPROM, small for gestational age, birthweight, pre-eclampsia and placental abruption. MAIN RESULTS AND THE ROLE OF CHANCE: Women with previous pregnancy loss (miscarriage or termination) were compared with those with no previous pregnancy loss. There were 4331 (78%) women who had no previous pregnancy loss, 974 (17.5%) who had one early previous pregnancy loss, 249 (4.5%) who had two and 21 (0.5%) who had three or four losses. Women with two to four previous losses, but not those with a single loss, had an increased risk of spontaneous preterm birth (adjusted OR 2.12; 95% CI 1.55, 2.90) and/or placental abruption (adjusted OR 2.30; 95% CI 1.36, 3.89) compared with those with no previous pregnancy. A single previous miscarriage or termination of pregnancy where the management involved cervical dilatation and curettage was associated with an increased risk of spontaneous preterm birth (adjusted OR 1.64; 95% CI 1.08, 2.50; 6% absolute risk and adjusted OR 1.83; 95% CI 1.35, 2.48; 7% absolute risk, respectively) compared with those with no previous pregnancy losses. This is in contrast with women with a single previous miscarriage or termination managed non-surgically who showed no increase risk (adjusted OR 0.86; 95% CI 0.38, 1.94; 3.4% absolute risk and adjusted OR 0.87; 95% CI 0.69, 1.12; 3.8% absolute risk, respectively). LIMITATIONS, REASONS FOR CAUTION: Although every effort was made to record accurate previous pregnancy data, it was not feasible to confirm the history and management of previous pregnancy loss by hospital records. This may have introduced recall bias. WIDER IMPLICATIONS OF THE FINDINGS: This large prospective cohort study of healthy nulliparous women has demonstrated that women with either a previous miscarriage or termination of pregnancy were at increased risk of spontaneous preterm birth if they were managed by procedures involving cervical dilatation and curettage. However, overall, women with a single pregnancy loss did not have an increased risk of having any other of the adverse pregnancy outcomes examined. In contrast, two to four previous pregnancy losses were associated with an increased risk of having a pregnancy complicated by spontaneous preterm birth and/or placental abruption. Research is required to determine whether non-surgical management of miscarriage or termination of pregnancy should be advocated over surgical treatment. STUDY FUNDING/COMPETING INTEREST(S): New Zealand: New Enterprise Research Fund, Foundation for Research Science and Technology; Health Research Council; Evelyn Bond Fund, Auckland District Health Board Charitable Trust. Australia: Premier's Science and Research Fund, South Australian Government. Ireland: Health Research Board. Leeds: Cerebra Charity, Carmarthen. Manchester: National Health Service NEAT Grant; Manchester Biotechnology and Biological Sciences Research Council; University of Manchester Proof of Concept Funding. King's College London: Guy's and St Thomas' Charity. King's College London and Manchester: Tommy's-The Baby Charity. TRIAL REGISTRATION NUMBER: N/A. PMID- 24052503 TI - Premature formation of nucleolar channel systems indicates advanced endometrial maturation following controlled ovarian hyperstimulation. AB - STUDY QUESTION: Is there a shift in the timing of nucleolar channel system (NCS) formation following controlled ovarian hyperstimulation (COH)? SUMMARY ANSWER: NCSs appear prematurely following COH compared with natural cycles. WHAT IS KNOWN ALREADY: During natural cycles, NCSs of endometrial epithelial cell (EEC) nuclei are exclusively present during the window of implantation and are uniformly distributed throughout the upper endometrial cavity. STUDY DESIGN, SIZE, DURATION: Prospective two-cohort study. Cohorts I and II each consisted of seven volunteers for the duration of three menstrual study cycles that were separated by at least one wash-out or rest cycle, between December 2008 and May 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recruited from a pool of healthy oocyte donors. Consecutive endometrial biopsies were obtained during the same luteal phase on cycle days (CD) 16, 20 and 26 for Cohort I, and on CD14, 22 and 24 for Cohort II, following random assignment to a natural cycle group, a COH cycle group (using a GnRH antagonist), or a COH cycle group receiving luteal phase hormonal supplementation (COH + S). The day of oocyte retrieval was designated CD14 in COH cycles and the day of the LH surge was designated CD13 in natural cycles. Prevalence of NCSs in the nuclei of EECs was quantified using indirect immunofluorescence with an antibody directed against a subset of related nuclear pore complex proteins that are major constituents of NCSs. Progesterone and estradiol levels were measured on the day of each endometrial biopsy. MAIN RESULTS AND THE ROLE OF CHANCE: The natural cycle group exhibited peak NCS prevalence on CD20 [53.3%; interquartile range (IQR) 28.5-55.8], which rapidly declined on CD22 (11.8%; IQR 6.3-17.6), CD24 (2.5%; IQR 0.0-9.2) and CD26 (0.3%; IQR 0.0-3.5), and no NCSs on CD14 and 16 defining a short NCS window around CD20. In contrast, in COH and COH + S cycles, NCS prevalence was high already on CD16 (40.4%; IQR 22.6-53.4 and 35.6%; IQR 26.4-44.5, respectively; P = 0.001 compared with CD16 of the natural cycle group, Mann-Whitney), whereas no significant difference in NCS prevalence was detected on any of the other five CDs between the three groups (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: The cohort size was small (n = 7) but was offset by the all-or-none presence of NCSs on CD16 in natural versus COH and COH + S cycles and the fact that each subject served as her own control. WIDER IMPLICATIONS OF THE FINDINGS: Premature appearance of NCSs and hence maturation of the endometrium following COH is consistent with previous studies based on histological dating but contradicts studies based on mRNA expression profiling, which reported a lag in endometrial maturation. However, this is the first study of this kind that is based on consecutive endometrial biopsies within the same cycle and that reports such clear-cut differences: no versus robust NCS presence on CD16. Our observation of advanced endometrial maturation following COH may contribute to the reduced implantation rates seen in fresh compared with frozen and donor IVF-embryo transfer cycles. Therefore, the NCS window could serve as a sensitive guide for timing of embryo transfer in frozen and donor cycles. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the March of Dimes Birth Defects foundation (1-FY09-363 to U.T.M.); Ferring Pharmaceuticals, Parsippany, NJ; East Coast Fertility, Plainview, NY and the CMBG Training Program (T32 GM007491 to M.J.S.). We report no competing interests. PMID- 24052506 TI - Utility of diffusion tensor imaging in evaluation of the peritumoral region in patients with primary and metastatic brain tumors. AB - In the brain, diffusion tensor imaging is a useful tool for defining white matter anatomy, planning a surgical approach to space-occupying lesions, and characterizing tumors, including distinguishing primary tumors from metastases. Recent studies have attempted, with varying success, to use DTI to define the extent of tumor microinfiltration beyond the apparent borders on T2-weighted imaging. In the present review, we discuss the current state of research on the utility of DTI for evaluating the peritumoral region of brain tumors. PMID- 24052505 TI - Role of diffusion tensor imaging as an independent predictor of cognitive and language development in extremely low-birth-weight infants. AB - BACKGROUND AND PURPOSE: Diffusion tensor imaging at term can predict later development of cerebral palsy. Less is known about its ability to independently predict cognitive and language development in extremely preterm infants. The goals of the study were to investigate the following: 1) whether regional DTI measures at term-equivalent age in extremely low-birth-weight infants (birth weight, <=1000 g) are predictive of Bayley III developmental scores at 18- to 22 months' corrected age, and 2) to compare white matter microstructural development at term and neurodevelopmental outcomes of extremely low-birth-weight infants with healthy term controls. MATERIALS AND METHODS: Fractional anisotropy and mean diffusivity in 7 vulnerable cerebral regions were measured in 42 extremely low birth-weight and 16 term infants with high-quality DTI scans. The Bayley mental scale score (average of cognitive and language scale scores) was the primary outcome of interest with individual scores serving as secondary outcomes. Multiple linear regression modeling was used to identify the incremental ability of DTI measures to predict Bayley scores over known predictors. RESULTS: Compared with healthy term infants, extremely low-birth-weight infants exhibited significantly higher mean diffusivity and lower fractional anisotropy in 6 of 7 regions. At 18- to 22-months' corrected age, 39 extremely low-birth-weight infants (93%) and 14 term infants (88%) had undergone neurodevelopmental assessments. Although not statistically significant, extremely low-birth-weight infants averaged 7-9 points lower on Bayley subtests than term controls. In multivariable analyses, centrum semiovale mean diffusivity was a significant predictor of mental and language scale scores, and subventricular zone fractional anisotropy was a significant predictor of cognitive scale scores. A 10% increase in centrum semiovale mean diffusivity was associated with a 4.6 (95% CI, 1.6-7.6) point lower mental scale score (adjusted R(2) = 0.341, P = .001). CONCLUSIONS: In our extremely low-birth-weight cohort, DTI was an independent predictor of later cognitive and language development. PMID- 24052507 TI - Time-dependent structural changes of the dentatothalamic pathway in children treated for posterior fossa tumor. AB - BACKGROUND AND PURPOSE: Injury to the dentatothalamic pathway that originates in the cerebellum has been suggested as a mechanism for neurologic complications in children treated for posterior fossa tumors. We hypothesized that time-dependent changes occur in the dentatothalamic pathway. MATERIALS AND METHODS: Diffusion tensor evaluation was performed in 14 children (median age, 4.1 years; age range, 1-20 years) who underwent serial MR imaging at 3T as part of routine follow-up after posterior fossa tumor resection with or without adjuvant therapy. Tensor metrics were obtained in the acute (<=1 week), subacute (1 to <6 months), and chronic (>=6 months) periods after surgery. We evaluated the following dentatothalamic constituents: bilateral dentate nuclei, cerebellar white matter, and superior cerebellar peduncles. Serial dentate nuclei volumes were also obtained and compared with the patient's baseline. RESULTS: The most significant tensor changes to the superior cerebellar peduncles and cerebellar white matter occurred in the subacute period, regardless of the tumor pathology or therapy regimen, with signs of recovery in the chronic period. However, chronic volume loss and reduced mean diffusivity were observed in the dentate nuclei and did not reverse. This atrophy was associated with radiation therapy and symptoms of ataxia. CONCLUSIONS: Longitudinal diffusion MR imaging in children treated for posterior fossa tumors showed time-dependent tensor changes in components of the dentatothalamic pathway that suggest evolution of structural damage with inflammation and recovery of tissue directionality. However, the dentate nuclei did not show tensor or volumetric recovery, suggesting that the injury may be chronic. PMID- 24052508 TI - Improving the efficiency of stroke trials: feasibility and efficacy of group adjudication of functional end points. AB - BACKGROUND AND PURPOSE: Use of the modified Rankin scale (mRS) in multicenter trials may be limited by interobserver variability. We assessed the effect of this on trial power and developed a novel group adjudication approach. METHODS: We generated power and sample size estimates from simulated trials modeled with varying mRS reliability. We conducted a virtual acute stroke trial across 14 UK sites to develop a group adjudication approach. Traditional mRS interviews, performed at local sites, were digitally recorded and scored by adjudication committee. We assessed the effect of translation by comparing scores in translated mRS interviews, originally conducted in English and Mandarin. Agreement was measured using kappa and weighted kappa (kappaw) statistics and intraclass correlation coefficient. RESULTS: Statistical simulations suggest that improving mRS reliability from kappa=0.25 to kappa=0.5 or 0.7 may allow reductions in sample size of n=386 or 490 in a typical n=2000 study. Our virtual acute stroke trial included 370 participants and 563 mRS video assessments. We adjudicated mRS in 538 of 563 (96%) study visits. At 30 and 90 days, 161 of 280 (57.5%) and 131 of 258 (50.8%) clips showed interobserver disagreement. Agreement within the adjudication committee was good (30-day kappaw=0.85 [95% confidence interval, 0.81-0.86]; 90-day kappaw=0.86 [95% confidence interval, 0.82-0.88]) without significant or systematic bias in mRS scoring compared with the local mRS. Interobserver reliability of translated mRS assessments was similar to native language clips (native [n=69] kappaw=0.91 [95% confidence interval, 0.94 0.99]; translated [n=89] kappaw=0.90 [95% confidence interval, 0.83-0.96]). CONCLUSIONS: Achievable improvements in interobserver reliability may substantially reduce study sample size, with associated financial benefits. Central adjudication of mRS assessments is feasible (including across international centers), valid and reliable despite the challenges of mRS assessment in large clinical trials. PMID- 24052509 TI - Door-to-needle time and the proportion of patients receiving intravenous thrombolysis in acute ischemic stroke: uniform interpretation and reporting. PMID- 24052511 TI - Bigger, faster? Associations between hospital thrombolysis volume and speed of thrombolysis administration in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: There is evidence that high-volume hospitals may produce better patient outcomes. We aimed to identify whether there were any associations between hospital thrombolysis volume and speed of thrombolysis (tissue-type plasminogen activator [tPA]) administration in patients with ischemic stroke. METHODS: Data were drawn from 2 national clinical audits in England: the Stroke Improvement National Audit Program and the 2012 Sentinel Stroke Audit. Hospitals were categorized into 3 groups based on the annualized volume of thrombolysis: 0 to 24, 25 to 49, and >=50 cases per annum. Arrival-brain scan, onset-tPA, and arrival-tPA times were compared across groups and stratified by onset-arrival time. Multilevel logistic models were used to estimate the odds of receiving tPA within 60 minutes of arrival. RESULTS: Of the 42 024 patients with acute ischemic stroke admitted to 80 hospitals, 4347 received tPA (10.3%). Patients admitted to hospitals with an annual thrombolysis volume of >=50 cases per annum had median arrival-tPA times that were 28 and 22 minutes shorter than patients admitted to hospitals with volumes of 0 to 24 and 25 to 49, respectively. Onset-tPA times were shorter by 24 to 32 minutes across strata of onset-arrival times. In multivariable analysis, patients admitted to hospitals with a volume of >=50 cases per annum had 4.33 (2.21-8.50; P<0.0001) the odds of receiving tPA within 60 minutes of arrival. No differences in safety outcomes were observed, with similar 30-day mortality and complication rates across the groups. CONCLUSIONS: Hospitals with higher volumes of thrombolysis activity achieve statistically and clinically significant shorter delays in administering tPA to patients after arrival in hospital. PMID- 24052512 TI - Predicting adult obesity from measures in earlier life. AB - BACKGROUND: As most obese adults were not overweight as children, the prediction of adult obesity from childhood body size alone is limited. We constructed a two way, multifactor risk assessment framework for predicting adult obesity during childhood using the Foresight Obesity System Map and tested it against longitudinal data from the 1958 National Child Development Study. METHODS: The framework divided study participants according to two categories of risk: 'conditioning factors' (past/fixed events and conditions) and 'intervention factors' (present and modifiable). At the age of 11 years, conditioning factors were 'low/high birth weight' and 'absence of breastfeeding', and intervention factors were 'low childhood activity level' and 'having at least one obese parent'. From a composite score of all four variables, study participants were assigned to one of the four risk groups: low risk, past 'conditioning' risk only, present 'intervention' risk only and high combined risk. ORs and relative risks for the development of future overweight/obesity at ages 23, 33 and 42 years were calculated for each risk group. RESULTS: Those identified in the highest risk category at the age of 11 were around twice as likely to become overweight (body mass index (BMI)>=25 kg/m(2)) by the age of 23 years, and obese (BMI>=30 kg/m(2)) by ages 33 and 42 years, in comparison to their low-risk peers (total sample, N=11 752). Increased prevalence of future obesity was also observed for high-risk children who were not already overweight at the age of 11 (filtered sample, N=9549). CONCLUSIONS: This framework identifies a greater proportion of the population that is at risk for future obesity than does childhood weight assessment alone. PMID- 24052510 TI - How well do standard stroke outcome measures reflect quality of life? A retrospective analysis of clinical trial data. AB - BACKGROUND AND PURPOSE: Quality of life (QoL) is important to stroke survivors yet is often recorded as a secondary measure in acute stroke randomized controlled trials. We examined whether commonly used stroke outcome measures captured aspects of QoL. METHODS: We examined primary outcomes by National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI) and modified Rankin Scale (mRS), and QoL by Stroke Impact Scale (SIS) and European Quality of Life Scale (EQ-5D) from the Virtual International Stroke Trials Archive (VISTA). Using Spearman correlations and logistic regression, we described the relationships between QoL mRS, NIHSS, and BI at 3 months, stratified by respondent (patient or proxy). Using chi2 analyses, we examined the mismatch between good primary outcome (mRS <=1, NIHSS <=5, or BI >=95) but poor QoL, and poor primary outcome (mRS >=3, NIHSS >=20, or BI <=60) but good QoL. RESULTS: Patient-assessed QoL had a stronger association with mRS (EQ-5D weighted score n=2987, P<0.0001, r=-0.7, r2=0.53; SIS recovery n=2970, P<0.0001, r=-0.71, r2=0.52). Proxy responses had a stronger association with BI (EQ-5D weighted score n=837, P<0.0001, r=0.78, r2=0.63; SIS recovery n=867, P<0.0001, r=0.68, r2=0.48). mRS explained more of the variation in QoL (EQ-5D weighted score=53%, recovery by SIS v3.0=52%) than NIHSS or BI and resulted in fewer mismatches between good primary outcome and poor QoL (P<0.0001, EQ-5D weighted score=8.5%; SIS recovery=10%; SIS-16=4.4%). CONCLUSIONS: The mRS seemed to align closely with stroke survivors' interests, capturing more information on QoL than either NIHSS or BI. This further supports its recommendation as a primary outcome measure in acute stroke randomized controlled trials. PMID- 24052514 TI - Polypill is not a 'vaccine-like' solution for primary cardiovascular disease prevention in all parts of the world. PMID- 24052513 TI - The second European Perinatal Health Report: documenting changes over 6 years in the health of mothers and babies in Europe. PMID- 24052515 TI - Job strain and depressive symptoms in men and women: a prospective study of the working population in Sweden. AB - BACKGROUND: Several prospective studies have indicated increased risk of developing depressive symptoms in employees who report psychologically demanding and uncontrollable work (job strain). There are diverging findings regarding gender differences in this relationship. The aim was to analyse whether men and women differ with regard to the prospective relationship between adverse psychosocial work environment and depressive symptoms during a 2-year period. METHOD: The Swedish Longitudinal Occupational Survey of Health cohort based on representative recruitment of working men and women in Sweden was used. 2731 men and 3446 women had answered questions regarding work environment and mental health in 2008 and 2010. Psychological demands, decision authority, age and income as well as depressive symptoms in 2008 were used as predictors of depressive symptoms in 2010. RESULTS: Women reported less decision authority at work and their demand level developed more unfavourably than did men's--resulting in increased job strain gap between men and women from 2008 to 2010. The relationship between demand and decision authority (and job strain) on one hand and depressive symptoms on the other hand was not statistically different in men and women. CONCLUSIONS: Overall, women reported higher levels of job strain than men. In Sweden, job strain was as strongly related to depressive symptoms among men as among women. PMID- 24052517 TI - Mean platelet volume and platelet count values in patients with carbon monoxide poisoning. PMID- 24052516 TI - Biomarkers of diabetes risk in the National Diet and Nutrition Survey rolling programme (2008-2011). AB - This study describes the distribution of glycosylated haemoglobin (Hb(A1c)) and glucose concentrations in the combined year 1 (2008-2009), year 2 (2009-2010) and year 3 (2010-2011) of the National Diet and Nutrition Survey (NDNS) rolling programme. The NDNS rolling programme is a nationally representative survey of food consumption, nutrient intakes and nutritional status of people aged 1.5 years and over living in England, Wales, Scotland and Northern Ireland. The study population comprised survey members who completed three or four days of dietary recording and who provided a blood sample. After excluding survey members with self-reported diabetes (n=25), there were 1016 results for HbA1c and 942 for glucose (not the same individuals in each case). Around 5.4% of men and 1.7% of women aged 19-64 years, and 5.1% of men and 5.9% of women aged >=65 years had impaired fasting glucose (glucose concentrations 6.1-6.9 mmol/L). Over 20% of men aged >=65 years had fasting glucose concentrations above the clinical cut-off for diabetes (>=7 mmol/L) compared to 2.1% of women of similar age (p=0.007). Similarly, 16.4% of men had Hb(A1c) concentrations >=6.5%, compared to 1.5% of women (p=0.003). Children and teenagers had fasting glucose and Hb(A1c) values largely within the normal range. To conclude, this is the first study to provide data on the distribution of HbA1c and glucose concentrations in a nationally representative sample of the British population. The high prevalence of men aged >=65 years with Hb(A1c) and glucose concentrations above the clinical cut-off of diabetes warrants further attention. PMID- 24052519 TI - Response to letter regarding "a new parameter predicting chronic total occlusion of coronary arteries: platelet distribution width". PMID- 24052518 TI - Relation of epicardial adipose tissue with arterial compliance and stiffness in patients with hypertension. AB - The main aim of the present study was to investigate the association between epicardial adipose tissue (EAT) and arterial function in patients with asymptomatic hypertension. Patients with hypertension (n = 155) were enrolled consecutively. Patients with decreased arterial compliance (AC) and increased cardioankle vascular index (CAVI) had higher EAT values compared with those with normal AC and CAVI (6.23 +/- 1.67 vs 4.91 +/- 1.40, P < .001 and 6.02 +/- 1.61 vs 4.96 +/- 1.46, P = .01, respectively). Analysis using the receiver-operating characteristics curve demonstrated that EAT 5.5 mm constitutes the cutoff value for the presence of increased CAVI with 67% sensitivity and 62% specificity (area under the curve [AUC]: 0.702, 95% confidence interval [CI] 0.590-0.814) and decreased AC with 77% sensitivity and 65% specificity (AUC: 0.756, 95% CI 0.645 0.867). Assessment of EAT during echocardiography examination may provide information on arterial function in patients with asymptomatic hypertension. The link between EAT and arterial stiffness deserves further investigation. PMID- 24052520 TI - Response to the letter: uric acid levels and atrial fibrillation. PMID- 24052521 TI - Relationship between increased serum resistin level and severity of coronary artery disease. AB - Resistin, which is derived from the gene of RSTN, belongs to a family of cysteine rich secretory proteins called resistin-like molecules (RELMs). Increased serum resistin levels are associated with coronary artery disease (CAD) and the risk of cardiovascular death. Patients (n = 214) with an initial diagnosis of stable angina pectoris, unstable angina pectoris, and myocardial infarction without ST segment elevation and referred to catheter laboratory for coronary angiography were enrolled in the study. We aimed to investigate the relationship between increased serum resistin level and CAD. The severity of CAD was calculated by the Gensini scoring system. In conclusion, we established a significant correlation between serum resistin levels and CAD (P = .010). Also, serum resistin levels correlated with the Gensini score that represents the severity of CAD angiographically (P = .010). PMID- 24052522 TI - Coronary artery ectasia as a histopathological pattern of atherosclerosis. PMID- 24052523 TI - Neutrophil-to-lymphocyte ratio predicts contrast-induced nephropathy in patients undergoing primary percutaneous coronary intervention. PMID- 24052524 TI - Mean platelet volume as an inflammatory indicator in behcet disease. PMID- 24052525 TI - High-density lipoproteins and coronary artery disease: a single-center cohort study. AB - Our goal was to estimate the role of high-density lipoprotein cholesterol (HDL-C) in predicting the prevalence and extent of coronary artery disease (CAD) in 3280 patients undergoing coronary angiography. Predictors of lower HDL levels (<32 mg/dL) were male gender (P < .001), diabetes mellitus (P = .03), renal failure (P = .01), higher low-density lipoprotein and total cholesterol (P < .001, respectively), triglycerides (P < .001), and white blood cells (P < .001), aging (P < .001), previous myocardial infarction (P = .02) and hemoglobin (P < .001), treatment with angiotensin-receptor blockers (P < .001), and statins (P = .002). The HDL-C levels were significantly inversely associated with prevalence of CAD (P < .001, adjusted odds ratio [OR] [95% confidence interval, CI] = 1.35 [1.25 1.45], P < .001), and HDL-C <44 mg/dL was best the predictive value of the risk of CAD, (adjusted OR [95%CI] = 1.61 [1.24-2.1], P < .001). We found significant association between HDL-C and the risk of CAD; a value <44 mg/dL was the best cutoff in the prediction of CAD. PMID- 24052526 TI - STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. AB - Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of STING prevented IRF3 phosphorylation by ethanol or ER stress, and absence of IRF3 prevented hepatocyte apoptosis. The pathogenic role of IRF3 in ALD was independent of inflammation or Type-I interferons. Thus, STING and IRF3 are key determinants of ALD, linking ER stress signaling with the mitochondrial pathway of hepatocyte apoptosis. PMID- 24052527 TI - Nematic phase of achiral dimers spontaneously bends and twists. PMID- 24052528 TI - Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1gamma. AB - Due to a unique pattern of CD8 T-cell response induced by cytomegaloviruses (CMVs), live attenuated CMVs are attractive candidates for vaccine vectors for a number of clinically relevant infections and tumors. NKG2D is one of the most important activating NK cell receptors that plays a role in costimulation of CD8 T cells. Here we demonstrate that the expression of CD8 T-cell epitope of Listeria monocytogenes by a recombinant mouse CMV (MCMV) expressing the NKG2D ligand retinoic acid early-inducible protein 1-gamma (RAE-1gamma) dramatically enhanced the effectiveness and longevity of epitope-specific CD8 T-cell response and conferred protection against a subsequent challenge infection with Listeria monocytogenes. Unexpectedly, the attenuated growth in vivo of the CMV vector expressing RAE-1gamma and its capacity to enhance specific CD8 T-cell response were preserved even in mice lacking NKG2D, implying additional immune function for RAE-1gamma beyond engagement of NKG2D. Thus, vectors expressing RAE-1gamma represent a promising approach in the development of CD8 T-cell-based vaccines. PMID- 24052529 TI - Integrating salience and value in decision making. PMID- 24052530 TI - Neurogenic and myogenic motor activity in the colon of the guinea pig, mouse, rabbit, and rat. AB - Gastrointestinal motility involves interactions between myogenic and neurogenic processes intrinsic to the gut wall. We have compared the presence of propagating myogenic contractions of the isolated colon in four experimental animals (guinea pig, mouse, rabbit, and rat), following blockade of enteric neural activity. Isolated colonic preparations were distended with fluid, with the anal end either closed or open. Spatiotemporal maps of changes in diameter were constructed from video recordings. Distension-induced peristaltic contractions were abolished by tetrodotoxin (TTX; 0.6 MUM) in all animal species. Subsequent addition of carbachol (0.1-1 MUM) did not evoke myogenic motor patterns in the mouse or guinea pig, although some activity was observed in rabbit and rat colon. These myogenic contractions propagated both orally and anally and differed from neurogenic propagating contractions in their frequency, extent of propagation, and polarity. Niflumic acid (300 MUM), used to block myogenic activity, also blocked neural peristalsis and thus cannot be used to discriminate between these mechanisms. In all species, except the mouse colon, small myogenic "ripple" contractions were revealed in TTX, but in both rat and rabbit an additional, higher-frequency ripple-type contraction was superimposed. Following blockade of enteric nerve function, a muscarinic agonist can evoke propulsive myogenic peristaltic contractions in isolated rabbit and rat colon, but not in guinea pig or mouse colon. Marked differences between species exist in the ability of myogenic mechanisms to propel luminal content, but in all species there is normally a complex interplay between neurogenic and myogenic processes. PMID- 24052531 TI - Grain development in Brachypodium and other grasses: possible interactions between cell expansion, starch deposition, and cell-wall synthesis. AB - To explain the low levels of starch, high levels of (1,3;1,4)-beta-glucan, and thick cell walls in grains of Brachypodium distachyon L. relative to those in other Pooideae, aspects of grain development were compared between B. distachyon and barley (Hordeum vulgare L.). Cell proliferation, cell expansion, and endoreduplication were reduced in B. distachyon relative to barley and, consistent with these changes, transcriptional downregulation of the cell-cycle genes CDKB1 and cyclin A3 was observed. Similarly, reduced transcription of starch synthase I and starch-branching enzyme I was observed as well as reduced activity of starch synthase and ADP-glucose pyrophosphorylase, which are consistent with the lowered starch content in B. distachyon grains. No change was detected in transcription of the major gene involved in (1,3;1,4)-beta-glucan synthesis, cellulose synthase-like F6. These results suggest that, while low starch content results from a reduced capacity for starch synthesis, the unusually thick cell walls in B. distachyon endosperm probably result from continuing (1,3;1,4)-beta-glucan deposition in endosperm cells that fail to expand. This raises the possibility that endosperm expansion is linked to starch deposition. PMID- 24052532 TI - AUXIN-BINDING-PROTEIN1 (ABP1) in phytochrome-B-controlled responses. AB - The auxin receptor ABP1 directly regulates plasma membrane activities including the number of PIN-formed (PIN) proteins and auxin efflux transport. Red light (R) mediated by phytochromes regulates the steady-state level of ABP1 and auxin inducible growth capacity in etiolated tissues but, until now, there has been no genetic proof that ABP1 and phytochrome regulation of elongation share a common mechanism for organ elongation. In far red (FR)-enriched light, hypocotyl lengths were larger in the abp1-5 and abp1/ABP1 mutants, but not in tir1-1, a null mutant of the TRANSPORT-INHIBITOR-RESPONSE1 auxin receptor. The polar auxin transport inhibitor naphthylphthalamic acid (NPA) decreased elongation in the low R:FR light-enriched white light (WL) condition more strongly than in the high red:FR light-enriched condition WL suggesting that auxin transport is an important condition for FR-induced elongation. The addition of NPA to hypocotyls grown in R and FR-enriched light inhibited hypocotyl gravitropism to a greater extent in both abp1 mutants and in phyB-9 and phyA-211 than the wild-type hypocotyl, arguing for decreased phytochrome action in conjunction with auxin transport in abp1 mutants. Transcription of FR-enriched light-induced genes, including several genes regulated by auxin and shade, was reduced 3-5-fold in abp1-5 compared with Col and was very low in abp1/ABP1. In the phyB-9 mutant the expression of these reporter genes was 5-15-fold lower than in Col. In tir1-1 and the phyA-211 mutants shade-induced gene expression was greatly attenuated. Thus, ABP1 directly or indirectly participates in auxin and light signalling. PMID- 24052534 TI - An exploration of the alcohol policy environment in post-conflict countries. AB - AIMS: Populations in countries emerging from armed conflict may have elevated levels of harmful alcohol use due to risk factors such as trauma exposure, increased daily stressors, elevated levels of mental health disorders, urbanization, and weak alcohol control policies and institutions. This study explores the challenges and opportunities for strengthening alcohol control policies in post-conflict countries. METHODS: Exploratory qualitative approach: experts (from United Nations agencies, non-governmental organizations, academic institutions and independent consultants) selected on the basis of their experience were interviewed. Thematic analysis identified key emergent themes. RESULTS: Perceived challenges to addressing harmful alcohol use in post-conflict countries included: lack of priority and recognition among key actors; limited resources and capacity, including in policy enforcement; and the role of the alcohol industry. Perceived opportunities included: increasing recognition of the harmful health and social effects of alcohol globally; sharing information, experience, and expertise to more effectively strengthen alcohol control policies; and collecting better data to advocate and inform stronger alcohol policies. CONCLUSION: This exploratory study provides a starting point to better understand the alcohol policy environment in post-conflict settings but considerably more research is required. PMID- 24052533 TI - Alcohol consumption and liver disease in Australia: a time series analysis of the period 1935-2006. AB - AIMS: The aim of the study was to examine for Australia whether the link between population alcohol consumption and liver disease mortality varies over time, using 71 years of data. METHODS: Overall and gender-specific rates of liver disease mortality were analysed in relation to total alcohol consumption as well as for different beverage types by using autoregressive integrated moving average (ARIMA) time series methods. Separate models were developed for the entire time period and for two sub-periods (1935-1975, 1976-2006). RESULTS: A 1-l increase in adult per capita consumption of pure alcohol led to a rise of ~10% in overall liver disease mortality rates and a 11 and 9% increase in female and male liver disease mortality, respectively. The strength of the relationship between per capita consumption and liver disease mortality diminished over time. Spirits consumption was found to be the main driving factor in liver mortality rates between 1935 and 1975, while beer consumption was found to be the most significant predictor in liver diseases in the last three decades. In a comparative perspective, the effect of per capita alcohol consumption on liver disease in Australia is similar to the USA, Southern and Eastern Europe countries, but weaker than in Canada and western European countries. CONCLUSION: An increase in per capita alcohol consumption in Australia is likely to lead to an increase in liver disease. Changes in the most important beverage over the study period suggest substantial shifts in drinking patterns and preferences among the heaviest Australian drinkers. PMID- 24052535 TI - SSR_pipeline: a bioinformatic infrastructure for identifying microsatellites from paired-end Illumina high-throughput DNA sequencing data. AB - SSR_pipeline is a flexible set of programs designed to efficiently identify simple sequence repeats (e.g., microsatellites) from paired-end high-throughput Illumina DNA sequencing data. The program suite contains 3 analysis modules along with a fourth control module that can automate analyses of large volumes of data. The modules are used to 1) identify the subset of paired-end sequences that pass Illumina quality standards, 2) align paired-end reads into a single composite DNA sequence, and 3) identify sequences that possess microsatellites (both simple and compound) conforming to user-specified parameters. The microsatellite search algorithm is extremely efficient, and we have used it to identify repeats with motifs from 2 to 25 bp in length. Each of the 3 analysis modules can also be used independently to provide greater flexibility or to work with FASTQ or FASTA files generated from other sequencing platforms (Roche 454, Ion Torrent, etc.). We demonstrate use of the program with data from the brine fly Ephydra packardi (Diptera: Ephydridae) and provide empirical timing benchmarks to illustrate program performance on a common desktop computer environment. We further show that the Illumina platform is capable of identifying large numbers of microsatellites, even when using unenriched sample libraries and a very small percentage of the sequencing capacity from a single DNA sequencing run. All modules from SSR_pipeline are implemented in the Python programming language and can therefore be used from nearly any computer operating system (Linux, Macintosh, and Windows). PMID- 24052537 TI - Targeting endothelial cells by gene therapy. AB - In this issue of Blood, Abel et al designed lentiviral vectors (LVs) enabling specific gene delivery into endothelial cells in vivo. This opens new perspectives for gene therapy of hereditary disorders, cardiovascular diseases, and cancer. PMID- 24052536 TI - Exploring the sociotechnical intersection of patient safety and electronic health record implementation. AB - OBJECTIVE: The intersection of electronic health records (EHR) and patient safety is complex. To examine the applicability of two previously developed conceptual models comprehensively to understand safety implications of EHR implementation in the English National Health Service (NHS). METHODS: We conducted a secondary analysis of interview data from a 30-month longitudinal, prospective, case study based evaluation of EHR implementation in 12 NHS hospitals. We used a framework analysis approach to apply conceptual models developed by Sittig and Singh to understand better EHR implementation and use: an eight-dimension sociotechnical model and a three-phase patient safety model (safe technology, safe use of technology, and use of technology to improve safety). RESULTS: The intersection of patient safety and EHR implementation and use was characterized by risks involving technology (hardware and software, clinical content, and human-computer interfaces), the interaction of technology with non-technological factors, and improper or unsafe use of technology. Our data support that patient safety improvement activities as well as patient safety hazards change as an organization evolves from concerns about safe EHR functionality, ensuring safe and appropriate EHR use, to using the EHR itself to provide ongoing surveillance and monitoring of patient safety. DISCUSSION: We demonstrate the face validity of two models for understanding the sociotechnical aspects of safe EHR implementation and the complex interactions of technology within a healthcare system evolving from paper to integrated EHR. CONCLUSIONS: Using sociotechnical models, including those presented in this paper, may be beneficial to help stakeholders understand, synthesize, and anticipate risks at the intersection of patient safety and health information technology. PMID- 24052538 TI - MLL1 and menin: not partners in crime? AB - In this issue of Blood, Li et al report an unexpected but clinically relevant finding. They demonstrate that the mixed lineage leukemia (MLL1) gene acts independently from menin (Men1) in the hematopoietic system. PMID- 24052539 TI - The path(way) less traveled. AB - In this issue of Blood, Mathewson et al characterized targeting a novel intracellular pathway with an agent known to induce potent antitumor effects but now also appears to potently suppress inflammatory responses by dendritic cells (DCs) and prevent graft-vs-host disease (GVHD). Identifying agents that can suppress GVHD yet not compromise graft-vs-tumor (GVT) effects remains a paramount goal in allogeneic hematopoietic stem cell transplantation (HSCT). PMID- 24052540 TI - TMA: beware of complements. AB - In this issue of Blood, Jodele and colleagues report that defective complement regulation contributes to the development of thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) with important implications for diagnosis and management of this severe clinical complication. PMID- 24052542 TI - Breast cancer: an increasing public health problem in the Asia Pacific region. PMID- 24052543 TI - Surgical specimens, haemodynamics and long-term outcomes after pulmonary endarterectomy. AB - BACKGROUND: Chronic thromboembolic pulmonary hypertension is surgically curable by pulmonary endarterectomy (PEA). It is unclear whether PEA impacts primarily steady state right ventricular afterload (ie, pulmonary vascular resistance (PVR)) or pulsatile right ventricular afterload (ie, pulmonary arterial compliance (C(PA))). Our objectives were to (1) quantify PEA specimens and measure the impact of PEA on PVR and C(PA) in a structure/function study and (2) analyse the effects of haemodynamic changes on long-term survival/freedom of lung transplantation in an outcome study. METHODS: Thrombi were laid out, weighed, photographed and measured. PVR, C(PA) and resistance times compliance (RC-time) were assessed at baseline, within 4 days after PEA ('immediately postoperative') and 1 year after PEA, in 110 consecutive patients who were followed for 34.5 (11.9; 78.3) months. RESULTS: Lengths and numbers of PEA specimen tails were inversely correlated with immediate postoperative PVR (p<0.0001, r=-0.566; p<0.0001, r=-0.580). PVR and C(PA) normalised immediately postoperatively while RC-time remained unchanged. Immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation (p<0.0001). Patients with immediate postoperative PVR<590 dynes.s.cm(-5) had better long-term outcomes than patients with PVR>=590 dynes.s.cm(-5) (p<0.0001, respectively). CONCLUSIONS: PEA immediately decreased PVR and increased C(PA) under a constant RC-time. However, immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation. Our study confirms the importance of a complete, bilateral surgical endarterectomy. Low PVR measured immediately postoperative predicts excellent long-term outcome. PMID- 24052545 TI - Assessing the generalization of relapse-prevention behaviors of sexual offenders diagnosed with an intellectual disability. AB - The generalization of relapse-prevention skills of 10 males residing at a state facility for sexual offenders diagnosed with an intellectual disability was assessed in the community using three different experimental probes: (a) treatment staff (TS), (b) nontreatment staff (NTS), and (c) community adults (CAs). Results indicated a decrease in compliance from the TS to NTS and CAs, with the lowest levels of generalization displayed by offenders who were older and displayed a wider range of paraphilias. The degree of generalization also varied as a function of the contingencies for prevention-plan noncompliance, with higher rates of generalization occurring for violations that were more severely consequated. The implications of the findings for future research in promoting the generalization of relapse-prevention skills of sexual offenders, in general, and those who also exhibit intellectual disabilities, in particular, are discussed. PMID- 24052544 TI - Welding and lung cancer in a pooled analysis of case-control studies. AB - Several epidemiologic studies have indicated an increased risk of lung cancer among welders. We used the SYNERGY project database to assess welding as a risk factor for developing lung cancer. The database includes data on 15,483 male lung cancer cases and 18,388 male controls from 16 studies in Europe, Canada, China, and New Zealand conducted between 1985 and 2010. Odds ratios and 95% confidence intervals between regular or occasional welding and lung cancer were estimated, with adjustment for smoking, age, study center, and employment in other occupations associated with lung cancer risk. Overall, 568 cases and 427 controls had ever worked as welders and had an odds ratio of developing lung cancer of 1.44 (95% confidence interval: 1.25, 1.67) with the odds ratio increasing for longer duration of welding. In never and light smokers, the odds ratio was 1.96 (95% confidence interval: 1.37, 2.79). The odds ratios were somewhat higher for squamous and small cell lung cancers than for adenocarcinoma. Another 1,994 cases and 1,930 controls had ever worked in occupations with occasional welding. Work in any of these occupations was associated with some elevation of risk, though not as much as observed in regular welders. Our findings lend further support to the hypothesis that welding is associated with an increased risk of lung cancer. PMID- 24052546 TI - Tobacco-free pharmacies: can we extend the ban? PMID- 24052548 TI - Management of the refractory aplastic anemia patient: what are the options? AB - Refractory aplastic anemia (AA) is defined as a lack of response to first-line immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporin and is manifested as persistence of severe cytopenias at 6 months after IST. Although supportive care is critical for AA patients, it is of paramount importance for refractory disease in view of the longer duration of pancytopenia and susceptibility to life-threatening infections due to IST. Improvements in supportive care have largely contributed to better outcome over the past 2 decades, with 5-year overall survival reaching 57% during 2002 to 2008 for patients with AA unresponsive to initial IST. Exclusion of hypocellular myelodysplastic syndrome and constitutional BM failure masquerading as apparent idiopathic AA should be done in conjunction with centers of excellence. Hematopoietic stem cell transplantation is indicated if refractory AA patients are fit and have a suitably matched donor, either a sibling (>40-50 years) or unrelated donor. Patients lacking a fully matched donor should be considered for a second course of antithymocyte globulin plus cyclosporin, although response in the refractory setting is only ~30% to 35%. Response may also occur with alemtuzumab or the thrombopoietin mimetic eltrombopag in refractory AA. The emerging data for alternate donor (cord or haploidentical) transplantation in AA has provided additional therapeutic choices to consider in refractory disease. PMID- 24052547 TI - EZH2 mutations are frequent and represent an early event in follicular lymphoma. AB - Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy. PMID- 24052550 TI - Learning from failings in healthcare: a challenge for all healthcare systems. PMID- 24052549 TI - Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. AB - Recurrent and unpredictable episodes of vaso-occlusion are the hallmark of sickle cell disease. Symptomatic management and prevention of these events using the fetal hemoglobin-reactivating agent hydroxyurea are currently the mainstay of treatment. Discoveries over the past 2 decades have highlighted the important contributions of various cellular and soluble participants in the vaso-occlusive cascade. The role of these elements and the opportunities for therapeutic intervention are summarized in this review. PMID- 24052551 TI - Republished: instigating change: trainee doctors' perspective. AB - In the 21st century, the core skills of trainee doctors are evolving as clinicians, leaders and innovators. Leadership skills are an essential tool for all doctors and need to be an integral part of their training and learning as set out in the General Medical Council's Good Medical Practice. It is essential to develop these skills at an early stage and continually improve them. A group of junior doctors participated in a pilot programme for leadership with the aim of executing a quality improvement (QI) project. This article describes our experiences of both the course itself and the project undertaken by our group. As part of the process of implementing change, we faced a number of challenges which contributed to our learning. These have been explored as well as potential ways to overcome them to enable the swift and smooth development of future QI projects. Using an example of a QI project looking at handover, this article demonstrates how a trainee doctor can implement their project for both professional and institutional improvement. PMID- 24052553 TI - The end of the National Health Service. PMID- 24052552 TI - Republished: going glass to digital: virtual microscopy as a simulation-based revolution in pathology and laboratory science. AB - The recent technological advance of digital high resolution imaging has allowed the field of pathology and medical laboratory science to undergo a dramatic transformation with the incorporation of virtual microscopy as a simulation-based educational and diagnostic tool. This transformation has correlated with an overall increase in the use of simulation in medicine in an effort to address dwindling clinical resource availability and patient safety issues currently facing the modern healthcare system. Virtual microscopy represents one such simulation-based technology that has the potential to enhance student learning and readiness to practice while revolutionising the ability to clinically diagnose pathology collaboratively across the world. While understanding that a substantial amount of literature already exists on virtual microscopy, much more research is still required to elucidate the full capabilities of this technology. This review explores the use of virtual microscopy in medical education and disease diagnosis with a unique focus on key requirements needed to take this technology to the next level in its use in medical education and clinical practice. PMID- 24052554 TI - Floral polymorphism and the fitness implications of attracting pollinating and florivorous insects. AB - BACKGROUND AND AIMS: Floral polymorphism is frequently attributed to pollinator mediated selection. Multiple studies, however, have revealed the importance of non-pollinating visitors in floral evolution. Using the polymorphic annual daisy Ursinia calenduliflora, this study investigated the importance of different insect visitors, and their effects on fitness, in the maintenance of floral polymorphism. METHODS: The spatial structure of a discrete floral polymorphism was characterized based on the presence/absence of anthocyanin floret spots in U. calenduliflora. A 3-year observational study was then conducted in polymorphic populations to investigate differences in visitation rates of dominant visitors to floral morphs. Experiments were performed to explore the floral preference of male and female Megapalpus capensis (the dominant insect visitor) and their effectiveness as pollinators. Next, floral damage by antagonistic florivores and the reproductive success of the two floral morphs were surveyed in multiple populations and years. KEY RESULTS: Floral polymorphism in U. calenduliflora was structured spatially, as were insect visitation patterns. Megapalpus capensis males were the dominant visitors and exhibited strong preference for the spotted morph in natural and experimental observations. While this may indicate potential fitness benefits for the spotted morph, female fitness did not differ between floral morphs. However, as M. capensis males are very efficient at exporting U. calenduliflora pollen, their preference may likely increase the reproductive fitness of the spotted morph through male fitness components. The spotted morph, however, also suffered significantly greater costs due to ovule predation by florivores than the spotless morph. CONCLUSIONS: The results suggest that pollinators and florivores may potentially exert antagonistic selection that could contribute to the maintenance of floral polymorphism across the range of U. calenduliflora. The relative strength of selection imposed by each agent is potentially determined by insect community composition and abundance at each site, highlighting the importance of community context in the evolution of floral phenotypes. PMID- 24052555 TI - Floral odour chemistry defines species boundaries and underpins strong reproductive isolation in sexually deceptive orchids. AB - BACKGROUND AND AIMS: The events leading to speciation are best investigated in systems where speciation is ongoing or incomplete, such as incipient species. By examining reproductive barriers among incipient sister taxa and their congeners we can gain valuable insights into the relative timing and importance of the various barriers involved in the speciation process. The aim of this study was to identify the reproductive barriers among sexually deceptive orchid taxa in the genus Chiloglottis. METHODS: The study targeted four closely related taxa with varying degrees of geographic overlap. Chemical, morphological and genetic evidence was combined to explore the basis of reproductive isolation. Of primary interest was the degree of genetic differentiation among taxa at both nuclear and chloroplast DNA markers. To objectively test whether or not species boundaries are defined by the chemistry that controls pollinator specificity, genetic analysis was restricted to samples of known odour chemistry. KEY RESULTS: Floral odour chemical analysis was performed for 600+ flowers. The three sympatric taxa were defined by their specific chiloglottones, the semiochemicals responsible for pollinator attraction, and were found to be fully cross-compatible. Multivariate morphometric analysis could not reliably distinguish among the four taxa. Although varying from very low to moderate, significant levels of genetic differentiation were detected among all pairwise combinations of taxa at both nuclear and chloroplast loci. However, the levels of genetic differentiation were lower than expected for mature species. Critically, a lack of chloroplast DNA haplotype sharing among the morphologically indistinguishable and most closely related taxon pair confirmed that chemistry alone can define taxon boundaries. CONCLUSIONS: The results confirmed that pollinator isolation, mediated by specific pollinator attraction, underpins strong reproductive isolation in these taxa. A combination of large effective population sizes, initial neutral mutations in the genes controlling floral scent, and a pool of available pollinators likely drives diversity in this system. PMID- 24052557 TI - Matching floral and pollinator traits through guild convergence and pollinator ecotype formation. AB - BACKGROUND AND AIMS: Pollinator landscapes, as determined by pollinator morphology/behaviour, can vary inter- or intraspecifically, imposing divergent selective pressures and leading to geographically divergent floral ecotypes. Assemblages of plants pollinated by the same pollinator (pollinator guilds) should exhibit convergence of floral traits because they are exposed to similar selective pressures. Both convergence and the formation of pollination ecotypes should lead to matching of traits among plants and their pollinators. METHODS: We examined 17 floral guild members pollinated in all or part of their range by Prosoeca longipennis, a long-proboscid fly with geographic variation in tongue length. Attractive floral traits such as colour, and nectar properties were recorded in populations across the range of each species. The length of floral reproductive parts, a mechanical fit trait, was recorded in each population to assess possible correlation with the mouthparts of the local pollinator. A multiple regression analysis was used to determine whether pollinators or abiotic factors provided the best explanation for variation in floral traits, and pollinator shifts were recorded in extralimital guild member populations. KEY RESULTS: Nine of the 17 species were visited by alternative pollinator species in other parts of their ranges, and these displayed differences in mechanical fit and attractive traits, suggesting putative pollination ecotypes. Plants pollinated by P. longipennis were similar in colour throughout the pollinator range. Tube length of floral guild members co-varied with the proboscis length of P. longipennis. CONCLUSIONS: Pollinator shifts have resulted in geographically divergent pollinator ecotypes across the ranges of several guild members. However, within sites, unrelated plants pollinated by P. longipennis are similar in the length of their floral parts, most probably as a result of convergent evolution in response to pollinator morphology. Both of these lines of evidence suggest that pollinators play an important role in selecting for certain floral traits. PMID- 24052556 TI - Characterization of the sequence and expression pattern of LFY homologues from dogwood species (Cornus) with divergent inflorescence architectures. AB - BACKGROUND AND AIMS: LFY homologues encode transcription factors that regulate the transition from vegetative to reproductive growth in flowering plants and have been shown to control inflorescence patterning in model species. This study investigated the expression patterns of LFY homologues within the diverse inflorescence types (head-like, umbel-like and inflorescences with elongated internodes) in closely related lineages in the dogwood genus (Cornus s.l.). The study sought to determine whether LFY homologues in Cornus species are expressed during floral and inflorescence development and if the pattern of expression is consistent with a function in regulating floral development and inflorescence architectures in the genus. METHODS: Total RNAs were extracted using the CTAB method and the first-strand cDNA was synthesized using the SuperScript III first strand synthesis system kit (Invitrogen). Expression of CorLFY was investigated by RT-PCR and RNA in situ hybridization. Phylogenetic analyses were conducted using the maximum likelihood methods implemented in RAxML-HPC v7.2.8. KEY RESULTS: cDNA clones of LFY homologues (designated CorLFY) were isolated from six Cornus species bearing different types of inflorescence. CorLFY cDNAs were predicted to encode proteins of approximately 375 amino acids. The detection of CorLFY expression patterns using in situ RNA hybridization demonstrated the expression of CorLFY within the inflorescence meristems, inflorescence branch meristems, floral meristems and developing floral organ primordia. PCR analyses for cDNA libraries derived from reverse transcription of total RNAs showed that CorLFY was also expressed during the late-stage development of flowers and inflorescences, as well as in bracts and developing leaves. Consistent differences in the CorLFY expression patterns were not detected among the distinct inflorescence types. CONCLUSIONS: The results suggest a role for CorLFY genes during floral and inflorescence development in dogwoods. However, the failure to detect expression differences between the inflorescence types in the Cornus species analysed suggests that the evolutionary shift between major inflorescence types in the genus is not controlled by dramatic alterations in the levels of CorLFY gene transcript accumulation. However, due to spatial, temporal and quantitative limitations of the expression data, it cannot be ruled out that subtle differences in the level or location of CorLFY transcripts may underlie the different inflorescence architectures that are observed across these species. Alternatively, differences in CorLFY protein function or the expression or function of other regulators (e.g. TFL1 and UFO homologues) may support the divergent developmental trajectories. PMID- 24052558 TI - Identification of transcription factors potentially involved in the juvenile to adult phase transition in Citrus. AB - BACKGROUND AND AIMS: The juvenile to adult transition (JAT) in higher plants is required for them to reach reproductive competence. However, it is a poorly understood process in woody plants, where only a few genes have been definitely identified as being involved in this transition. This work aims at increasing our understanding of the mechanisms regulating the JAT in citrus. METHODS: Juvenile and adult plants from Pineapple sweet orange (Citrus sinensis) and Rough lemon (C. jambhiri) were used to screen for differentially expressed transcription factors (TFs) using a 1.15K microarray developed on the basis of the CitrusTF database. Murcott tangor (C. reticulata * C. sinensis) and Duncan grapefruit (C. paradisi) were incorporated into the quantitative real-time reverse transcription PCR validation in order to select those genes whose phase-specific regulation was common to the four species. KEY RESULTS: A browsable web database has been created with information about the structural and functional annotation related to 1152 unigenes of putative citrus TFs (CTFs). This database constitutes a valuable resource for research on transcriptional regulation and comparative genomics. Moreover, a microarray has been developed and used that contains these putative CTFs, in order to identify eight genes that showed differential expression in juvenile and adult meristems of four different species of citrus. Those genes have been characterized, and their expression pattern in vegetative and reproductive tissues has been analysed. Four of them are MADS-box genes, a family of TFs involved in developmental processes, whereas another one resembles MADS-box genes but lacks the MADS box itself. The other three showed high partial sequence similarity restricted to specific Arabidopsis protein domains but negligible outside those domains. CONCLUSIONS: The work presented here indicates that the JAT in citrus could be controlled by mechanisms that are in part common to those of Arabidopsis, but also somehow different, since specific factors without Arabidopsis orthologues have also been characterized. The potential involvement of the genes in the JAT is discussed. PMID- 24052560 TI - Dissimilarity of contemporary and historical gene flow in a wild carrot (Daucus carota) metapopulation under contrasting levels of human disturbance: implications for risk assessment and management of transgene introgression. AB - BACKGROUND AND AIMS: Transgene introgression from crops into wild relatives may increase the resistance of wild plants to herbicides, insects, etc. The chance of transgene introgression depends not only on the rate of hybridization and the establishment of hybrids in local wild populations, but also on the metapopulation dynamics of the wild relative. The aim of the study was to estimate gene flow in a metapopulation for assessing and managing the risks of transgene introgression. METHODS: Wild carrots (Daucus carota) were sampled from 12 patches in a metapopulation. Eleven microsatellites were used to genotype wild carrots. Genetic structure was estimated based on the FST statistic. Contemporary (over the last several generations) and historical (over many generations) gene flow was estimated with assignment and coalescent methods, respectively. KEY RESULTS: The genetic structure in the wild carrot metapopulation was moderate (FST = 0.082) and most of the genetic variation resided within patches. A pattern of isolation by distance was detected, suggesting that most of the gene flow occurred between neighbouring patches (<=1 km). The mean contemporary gene flow was 5 times higher than the historical estimate, and the correlation between them was very low. Moreover, the contemporary gene flow in roadsides was twice that in a nature reserve, and the correlation between contemporary and historical estimates was much higher in the nature reserve. Mowing of roadsides may contribute to the increase in contemporary gene flow. Simulations demonstrated that the higher contemporary gene flow could accelerate the process of transgene introgression in the metapopulation. CONCLUSIONS: Human disturbance such as mowing may alter gene flow patterns in wild populations, affecting the metapopulation dynamics of wild plants and the processes of transgene introgression in the metapopulation. The risk assessment and management of transgene introgression and the control of weeds need to take metapopulation dynamics into consideration. PMID- 24052561 TI - Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. AB - Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are capable of detecting drug-induced clinical arrhythmia, Torsade de Pointes (TdP), and QT prolongation. Efforts herein employ a broad set of structurally diverse drugs to optimize the predictive algorithm for applications in discovery toxicology and cardiac safety screening. The changes in the beat rhythm and rate of a confluent monolayer of hiPS-CMs by 88 marketed and 30 internal discovery compounds were detected with real-time cellular impedance measurement and quantified by measures of arrhythmic beating (IB20, lowest concentration inducing >= 20% arrhythmic [irregular, atypical] beats in 3 consecutive 20-s sweeps, and predicted proarrhythmic score [PPS]-IB20) or changes in beat rate (BR20, the lowest concentration inducing a reduction in beat rate of >= 20% at 3 consecutive sweeps compared with the time-matched vehicle control group, and PPS-BR20). Drug-induced arrhythmic beats and reductions in beat rates are predictive of clinical arrhythmia and QT prolongation, respectively. A threshold of <= 10 MUM for class determination results in 82% in vitro-in vivo concordance for TdP prediction and 91% sensitivity for non-TdP arrhythmia detection, or 83% and 91% if clinically efficacious plasma (effective serum therapeutic concentration [C eff]) values are incorporated. This human cardiomyocyte arrhythmic risk (hCAR) model provides greater predictivity for torsadogenicity in humans compared with either human ether-a-go-go-related gene (hERG) inhibition (75%) or QT prolongation (81%). The concordance of beat rate reductions to predict clinical QT prolongation is 86%, or 87% when C eff is considered, which is greater than a hERG signal (80%). Further, arrhythmic beats resulting from cytotoxicity were identified by a distinct arrhythmic beating pattern, which occurred after the onset of cytolethality. This hCAR assay showed increased performance over existing preclinical tools in predicting clinical QT prolongation, arrhythmia, and TdP. Thus, hiPS-CMs are a relevant cell system to improve evaluating cardiac safety liabilities of drug candidates. PMID- 24052559 TI - A unifying conceptual model for the environmental responses of isoprene emissions from plants. AB - BACKGROUND AND AIMS: Isoprene is the most important volatile organic compound emitted by land plants in terms of abundance and environmental effects. Controls on isoprene emission rates include light, temperature, water supply and CO2 concentration. A need to quantify these controls has long been recognized. There are already models that give realistic results, but they are complex, highly empirical and require separate responses to different drivers. This study sets out to find a simpler, unifying principle. METHODS: A simple model is presented based on the idea of balancing demands for reducing power (derived from photosynthetic electron transport) in primary metabolism versus the secondary pathway that leads to the synthesis of isoprene. This model's ability to account for key features in a variety of experimental data sets is assessed. KEY RESULTS: The model simultaneously predicts the fundamental responses observed in short term experiments, namely: (1) the decoupling between carbon assimilation and isoprene emission; (2) a continued increase in isoprene emission with photosynthetically active radiation (PAR) at high PAR, after carbon assimilation has saturated; (3) a maximum of isoprene emission at low internal CO2 concentration (ci) and an asymptotic decline thereafter with increasing ci; (4) maintenance of high isoprene emissions when carbon assimilation is restricted by drought; and (5) a temperature optimum higher than that of photosynthesis, but lower than that of isoprene synthase activity. CONCLUSIONS: A simple model was used to test the hypothesis that reducing power available to the synthesis pathway for isoprene varies according to the extent to which the needs of carbon assimilation are satisfied. Despite its simplicity the model explains much in terms of the observed response of isoprene to external drivers as well as the observed decoupling between carbon assimilation and isoprene emission. The concept has the potential to improve global-scale modelling of vegetation isoprene emission. PMID- 24052562 TI - Cardiotoxicity of mycotoxin citrinin and involvement of microRNA-138 in zebrafish embryos. AB - Citrinin (CTN) is a fungal secondary metabolite that contaminates various foodstuffs and animal feeds; it also exhibits organotoxicity in several animal models. In this study, the zebrafish was used to elucidate the mechanism of CTN cardiotoxicity in developing embryos. Following CTN administration, the gross morphology of the embryonic heart was apparently altered, including heart malformation, pericardial edema, and red blood accumulation. Whole-mount immunostaining and histological analysis of ventricle and atrium indicated incorrect heart looping and reduced size of heart chambers. From the perspective of cardiac function, the heartbeat and blood flow rate of embryos were significantly decreased in the presence of CTN. CTN also modulated the expression of tbx2a and jun B genes, but not that of bmp4 and nkx2.5. Furthermore, the heart areas of CTN-exposed embryos demonstrated an elevated levels of aldh1a2 and cspg2 messenger RNA; these 2 cardiac-related genes are known to be involved in retinoic acid (RA) pathway as well as downstream targets of microRNA-138 (miR-138) in zebrafish. CTN treatment also downregulated the expression of miR-138. Moreover, overexpression of miR-138 was able to rescue the heart defects generated by CTN. These results support the notion that CTN exposure has a severe impact on heart development, affecting heart morphogenesis through the dysregulation of miR-138, RA signaling, and tbx2a. PMID- 24052563 TI - SOT Symposium Highlight: Translatable Indicators of Testicular Toxicity: Inhibin B, MicroRNAs, and Sperm Signatures. AB - Testicular toxicity is an important safety endpoint in drug development and risk assessment, but reliable and translatable biomarkers for predicting injury have eluded researchers. However, this area shows great potential for improvement, with several avenues currently being pursued. This was the topic of a symposium session during the 2013 Society of Toxicology Annual Meeting in San Antonio, TX, entitled "Translatable Indicators of Testicular Toxicity: Inhibin B, MicroRNAs, and Sperm Signatures." This symposium brought together stakeholders from academia, government, and industry to present the limitations and drawbacks of currently used indicators of injury and discussed the ongoing efforts in developing more predictive biomarkers of injury. The presentations highlighted the early challenges of using circulating inhibin B and microRNA levels, and sperm messenger RNA transcript abundance and DNA methylation profiles, as novel biomarkers of testicular toxicity. PMID- 24052564 TI - A single gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin disrupts the adult uterine response to estradiol in mice. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) given as a cotreatment with estrogen exhibits antiestrogenic properties on the rodent adult uterus, but less is understood regarding hormonal responsiveness of the adult uterus from animals having been exposed to TCDD during critical periods of development. We characterized the inhibitory effects of TCDD (T) exposure at gestational day 15 (GD15), 4 weeks, and 9 weeks of age (TTT) on the adult uterus following hormone treatment. TTT-exposed mice in response to hormone treatment exhibited a blunted weight increase, had fewer uterine glands, displayed morphological anomalies, and had marked decreases in the hormonal regulation of genes involved in fluid transport (Aqp3 and Aqp5), cytoarchitectural (Dsc2 and Sprr2A), and immune (Lcn2 and Ltf) regulation. To determine if the 9-week exposure was responsible for the blunted uterine response, due to the 7- to 11-day half-life of TCDD in mice, a second set of experiments was performed to examine exposure to TCDD given at GD15, GD15 only (cross-fostered at birth), only during lactation (cross-fostered at birth), or at GD15 and 4 weeks of age. Our studies demonstrate that a single developmental TCDD exposure at GD15 is sufficient to elicit a blunted adult uterine response to estradiol and is due in part to fewer gland numbers and the reduced expression of forkhead box A2 (FoxA2), a gene involved in gland development. Together, these results provide insight regarding the critical nature of in utero exposure and the potential impact on ensuing uterine biology and reproductive health later in life. PMID- 24052566 TI - Just a graze? Cephalic tetanus presenting as a stroke mimic. PMID- 24052567 TI - Evaluation of the impact of frost resistances on potential altitudinal limit of trees. AB - Winter physiology of woody plants is a key issue in temperate biomes. Here, we investigated different frost resistance mechanisms on 1-year-old branches of 11 European tree species from November until budburst: (i) frost hardiness of living cells (by electrolyte leakage method), (ii) winter embolism sensitivity (by percentage loss of conductivity: PLC) and (iii) phenological variation of budburst (by thermal time to budburst). These ecophysiological traits were analyzed according to the potential altitudinal limit, which is highly related to frost exposure. Seasonal frost hardiness and PLC changes are relatively different across species. Maximal PLC observed in winter (PLCMax) was the factor most closely related to potential altitudinal limit. Moreover, PLCMax was related to the mean hydraulic diameter of vessels (indicating embolism sensitivity) and to osmotic compounds (indicating ability of living cells to refill xylem conducting elements). Winter embolism formation seems to be counterbalanced by active refilling from living cells. These results enabled us to model potential altitudinal limit according to three of the physiological/anatomical parameters studied. Monitoring different frost resistance strategies brings new insights to our understanding of the altitudinal limits of trees. PMID- 24052565 TI - Reactivation of plasma butyrylcholinesterase by pralidoxime chloride in patients poisoned by WHO class II toxicity organophosphorus insecticides. AB - Some clinicians assess the efficacy of pralidoxime in organophosphorus (OP) poisoned patients by measuring reactivation of butyrylcholinesterase (BuChE). However, the degree of BuChE inhibition varies by OP insecticide, and it is unclear how well oximes reactivate BuChE in vivo. We aimed to assess the usefulness of BuChE activity to monitor pralidoxime treatment by studying its reactivation after pralidoxime administration to patients with laboratory-proven World Health Organization (WHO) class II OP insecticide poisoning. Patient data were derived from 2 studies, a cohort study (using a bolus treatment of 1g pralidoxime chloride) and a randomized controlled trial (RCT) (comparing 2g pralidoxime over 20 min, followed by an infusion of 0.5 g/h, with placebo). Two grams of pralidoxime variably reactivated BuChE in patients poisoned by 2 diethyl OP insecticides, chlorpyrifos and quinalphos; however, unlike acetylcholinesterase reactivation, this reactivation was not sustained. It did not reactivate BuChE inhibited by the dimethyl OPs dimethoate or fenthion. The 1 g dose produced no reactivation. Pralidoxime produced variable reactivation of BuChE in WHO class II OP-poisoned patients according to the pralidoxime dose administered, OP ingested, and individual patient. The use of BuChE assays for monitoring the effect of pralidoxime treatment is unlikely to be clinically useful. PMID- 24052568 TI - Acclimation and soil moisture constrain sugar maple root respiration in experimentally warmed soil. AB - The response of root respiration to warmer soil can affect ecosystem carbon (C) allocation and the strength of positive feedbacks between climatic warming and soil CO2 efflux. This study sought to determine whether fine-root (<1 mm) respiration in a sugar maple (Acer saccharum Marsh.)-dominated northern hardwood forest would adjust to experimentally warmed soil, reducing C return to the atmosphere at the ecosystem scale to levels lower than that would be expected using an exponential temperature response function. Infrared heating lamps were used to warm the soil (+4 to +5 degrees C) in a mature sugar maple forest in a fully factorial design, including water additions used to offset the effects of warming-induced dry soil. Fine-root-specific respiration rates, root biomass, root nitrogen (N) concentration, soil temperature and soil moisture were measured from 2009 to 2011, with experimental treatments conducted from late 2010 to 2011. Partial acclimation of fine-root respiration to soil warming occurred, with soil moisture deficit further constraining specific respiration rates in heated plots. Fine-root biomass and N concentration remained unchanged. Over the 2011 growing season, ecosystem root respiration was not significantly greater in warmed soil. This result would not be predicted by models that allow respiration to increase exponentially with temperature and do not directly reduce root respiration in drier soil. PMID- 24052569 TI - DSM-5. PMID- 24052570 TI - The test of time: Karl Popper. PMID- 24052572 TI - The pan-Bcl-2 blocker obatoclax promotes the expression of Puma, Noxa, and Bim mRNA and induces apoptosis in neoplastic mast cells. AB - Advanced SM is an incurable neoplasm with short survival time. So far, no effective therapy is available for these patients. We and others have shown recently that neoplastic MC in ASM and MCL express antiapoptotic Mcl-1, Bcl-2, and Bcl-xL. In this study, we examined the effects of the pan-Bcl-2 family blocker obatoclax (GX015-070) on primary neoplastic MC, the human MC leukemia cell line HMC-1, and the canine mastocytoma cell line C2. Obatoclax was found to inhibit proliferation in primary human neoplastic MC (IC50: 0.057 MUM), in HMC 1.2 cells expressing KIT D816V (IC50: 0.72 MUM), and in HMC-1.1 cells lacking KIT D816V (IC50: 0.09 MUM), as well as in C2 cells (IC50: 0.74 MUM). The growth inhibitory effects of obatoclax in HMC-1 cells were accompanied by an increase in expression of Puma, Noxa, and Bim mRNA, as well as by apoptosis, as evidenced by microscopy, TUNEL assay, and caspase cleavage. Viral-mediated overexpression of Mcl-1, Bcl-xL, or Bcl-2 in HMC-1 cells was found to introduce partial resistance against apoptosis-inducing effects of obatoclax. We were also able to show that obatoclax synergizes with several other antineoplastic drugs, including dasatinib, midostaurin, and bortezomib, in producing apoptosis and/or growth arrest in neoplastic MC. Together, obatoclax exerts major growth-inhibitory effects on neoplastic MC and potentiates the antineoplastic activity of other targeted drugs. Whether these drug effects can be translated to application in patients with advanced SM remains to be determined. PMID- 24052571 TI - CSF-1 receptor-mediated differentiation of a new type of monocytic cell with B cell-stimulating activity: its selective dependence on IL-34. AB - With the use of a mouse FDC line, FL-Y, we have been analyzing roles for FDCs in controlling B cell fate in GCs. Beside these regulatory functions, we fortuitously found that FL-Y cells induced a new type of CD11b+ monocytic cells (F4/80+, Gr-1-, Ly6C-, I-A/E(-/lo), CD11c-, CD115+, CXCR4+, CCR2+, CX3CR1-) when cultured with a Lin-c-kit+ population from mouse spleen cells. The developed CD11b+ cells shared a similar gene-expression profile to mononuclear phagocytes and were designated as FDMCs. Here, we describe characteristic immunological functions and the induction mechanism of FDMCs. Proliferation of anti-CD40 antibody-stimulated B cells was markedly accelerated in the presence of FDMCs. In addition, the FDMC-activated B cells efficiently acquired GC B cell-associated markers (Fas and GL-7). We observed an increase of FDMC-like cells in mice after immunization. On the other hand, FL-Y cells were found to produce CSF-1 as well as IL-34, both of which are known to induce development of macrophages and monocytes by binding to the common receptor, CSF-1R, expressed on the progenitors. However, we show that FL-Y-derived IL-34, but not CSF-1, was selectively responsible for FDMC generation using neutralizing antibodies and RNAi. We also confirmed that FDMC generation was strictly dependent on CSF-1R. To our knowledge, a CSF-1R-mediated differentiation process that is intrinsically specific for IL-34 has not been reported. Our results provide new insights into understanding the diversity of IL-34 and CSF-1 signaling pathways through CSF-1R. PMID- 24052573 TI - Hypomorphic mutation in the RAG2 gene affects dendritic cell distribution and migration. AB - OS is a severe combined immunodeficiency characterized by erythrodermia and protracted diarrhea as a result of infiltration of oligoclonal-activated T cells, caused by hypomorphic mutations in RAGs. The RAG2(R229Q) mouse model fully recapitulates the clinical OS phenotype. We evaluated whether T and B cell defects, together with the abnormal lymphoid structure, could affect DC homeostasis and function. High density of LCs was observed in skin biopsies of Omenn patients and in the derma of RAG2(R229Q) mice, correlating with the presence of erythrodermia. In vivo models of cutaneous skin painting and CHS demonstrated a decreased migration of RAG2(R229Q) DCs-in particular, LCs-into draining LNs. Interestingly, at steady state, RAG2(R229Q) mice showed a reduction in DC number in all hematopoietic organs except LNs. Analysis of the MHCII marker revealed a diminished expression also upon the LPS-driven inflammatory condition. Despite the decreased number of peripheral DCs, BM pre-cDCs were present in normal number compared with RAG2(+/+) controls, whereas pDCs and monocytes were reduced significantly. Overall, these results point to a secondary defect in the DC compartment, which contributes to clinical manifestations and autoimmunity in OS. PMID- 24052574 TI - Infant overweight as early marker of childhood overweight in Brazil. AB - OBJECTIVE: To investigate infant overweight and rapid weight gain as predictors of overweight and adiposity in childhood. METHODS: Prospective, longitudinal birth cohort following 153 low-income Brazilian children. Weight, length, middle upper arm circumference (MUAC) and triceps skinfold thickness (TSF) were measured on enrolment and 6-monthly for 18 months. Anthropometric z-scores were calculated. RESULTS: Infants with overweight were >5 times likely to have MUAC z score >2, >6 times likely to have weight-for-height/length z-score >2 and >3 times likely to have TSF z-score >2 during childhood. Children with more than two overweight episodes were 27.7 [95% confidence interval (CI) 8.1-87.9] times more likely to have MUAC z-score >2 and 13.8 (95% CI 4.4-43.9) times more likely to have TSF z-score >2 in childhood. Rapid weight gain increased 10.7 (95% CI 2.3 50.0) times the risk of childhood overweight. CONCLUSIONS: Infant overweight and rapid weight gain predict overweight and adiposity in childhood among low-income children. PMID- 24052575 TI - Factors associated with perinatal mortality in Kassala, Eastern Sudan: a community-based study 2010-2011. AB - This study investigated the factors associated with perinatal mortality in eastern Sudan from 2010 to 2011. Among 808 deliveries, there were 15 pairs of twins, giving 823 babies at risk of perinatal deaths. There were 761 live births and 62 perinatal deaths. Of the 62 perinatal deaths, 25 (40.3%) were stillbirths and 37 (59.7%) were early neonatal deaths. The stillbirth risk, early neonatal mortality risk and perinatal mortality rate were 30.9 per 1000 pregnancies, 48.6 per 1000 live births and 75.3 per 1000 births, respectively. In the logistic regression model, home delivery [odds ratio (OR) = 5.1; confidence interval CI = 1.8-14; p = 0.001] and parity >=3 (OR = 4.5; CI = 2.2-8.8; p < 0.001) were predictors for perinatal deaths, whereas use of antenatal care (OR = 0.3; CI = 0.1-0.6; p = 0.002), use of a mosquito net (OR = 0.07; CI = 0.03-0.1; p < 0.001) and antenatal iron supplementation for at least 3 months (OR = 0.06; CI = 0.02 0.1; p < 0.001) were significant protective factors of perinatal deaths. PMID- 24052577 TI - Accuracy of 2 activity monitors in detecting steps in people with stroke and traumatic brain injury. AB - BACKGROUND: Advances in sensor technologies and signal processing techniques provide a method to accurately measure walking activity in the home and community. Activity monitors geared toward consumer or patient use may be an alternative to more expensive monitors designed for research to measure stepping activity. OBJECTIVE: The objective of this study was to examine the accuracy of 2 consumer/patient activity monitors, the Fitbit Ultra and the Nike+ Fuelband, in identifying stepping activity in people with stroke and traumatic brain injury (TBI). Secondarily, the study sought to compare the accuracy of these 2 activity monitors with that of the StepWatch Activity Monitor (SAM) and a pedometer, the Yamax Digi-Walker SW-701 pedometer (YDWP). DESIGN: A cross-sectional design was used for this study. METHOD: People with chronic stroke and TBI wore the 4 activity monitors while they performed the Two-Minute Walk Test (2MWT), during which they were videotaped. Activity monitor estimated steps taken were compared with actual steps taken counted from videotape. Accuracy and agreement between activity monitor estimated steps and actual steps were examined using intraclass correlation coefficients (ICC [2,1]) and the Bland-Altman method. RESULTS: The SAM demonstrated the greatest accuracy (ICC [2,1]=.97, mean difference between actual steps and SAM estimated steps=4.7 steps) followed by the Fitbit Ultra (ICC [2,1]=.73, mean difference between actual steps and Fitbit Ultra estimated steps= 9.7 steps), the YDWP (ICC [2,1]=.42, mean difference between actual steps and YDWP estimated steps=-28.8 steps), and the Nike+ Fuelband (ICC [2,1]=.20, mean difference between actual steps and Nike+ Fuelband estimated steps=-66.2 steps). LIMITATIONS: Walking activity was measured over a short distance in a closed environment, and participants were high functioning ambulators, with a mean gait speed of 0.93 m/s. CONCLUSIONS: The Fitbit Ultra may be a low-cost alternative to measure the stepping activity in level, predictable environments of people with stroke and TBI who can walk at speeds >=0.58 m/s. PMID- 24052576 TI - Inhibition of the HER2 pathway by n-3 polyunsaturated fatty acids prevents breast cancer in fat-1 transgenic mice. AB - Overexpression of the tyrosine kinase receptor, ErbB2/HER2/Neu, occurs in 25-30% of invasive breast cancer (BC) with poor patient prognosis. Due to confounding factors, inconsistencies still remain regarding the protective effects of n-3 polyunsaturated fatty acids (PUFAs) on BC. We therefore evaluated whether fat-1 transgenic mice, endogenously synthesizing n-3 PUFAs from n-6 PUFAs, were protected against BC development, and we then aimed to study in vivo a mechanism potentially involved in such protection. E0771 BC cells were implanted into fat-1 and wild-type (WT) mice. After tumorigenesis examination, we analyzed the expression of proteins involved in the HER2 signaling pathway and lipidomic analyses were performed in tumor tissues and plasma. Our results showed that tumors totally disappeared by day 15 in fat-1 mice but continued to grow in WT mice. This prevention can be related in part to significant repression of the HER2/beta-catenin signaling pathway and formation of significant levels of n-3 PUFA-derived bioactive mediators (particularly 15-hydroxyeicosapentaenoic acid, 17-hydroxydocosahexaenoic acid, and prostaglandin E3) in the tumors of fat-1 mice compared with WT mice. All together these data demonstrate an anti-BC effect of n 3 PUFAs through, at least in part, HER2 signaling pathway downregulation, and highlight the importance of gene-diet interactions in BC. PMID- 24052578 TI - Home palliative care services increase the chance of adults with advanced illness dying at home and reduce symptom burden without impact on caregiver grief. PMID- 24052579 TI - The majority of hospitalised elderly people at high risk of dying have thought about end-of-life care, though documentation of preferences in medical records may be lacking. PMID- 24052580 TI - Acute epiglottitis. PMID- 24052581 TI - An unusual cause of breathlessness. PMID- 24052583 TI - Humanism in the time of metrics--an essay by David Loxterkamp. PMID- 24052582 TI - Type of stress ulcer prophylaxis and risk of nosocomial pneumonia in cardiac surgical patients: cohort study. AB - OBJECTIVE: To examine the relation between the type of stress ulcer prophylaxis administered and the risk of postoperative pneumonia in patients undergoing coronary artery bypass grafting. DESIGN: Retrospective cohort study. SETTING: Premier Research Database. PARTICIPANTS: 21,214 patients undergoing coronary artery bypass graft surgery between 2004 and 2010; 9830 (46.3%) started proton pump inhibitors and 11,384 (53.7%) started H2 receptor antagonists in the immediate postoperative period. MAIN OUTCOME MEASURE: Occurrence of postoperative pneumonia, assessed using appropriate diagnostic codes. RESULTS: Overall, 492 (5.0%) of the 9830 patients receiving a proton pump inhibitor and 487 (4.3%) of the 11,384 patients receiving an H2 receptor antagonist developed postoperative pneumonia during the index hospital admission. After propensity score adjustment, an elevated risk of pneumonia associated with treatment with proton pump inhibitors compared with H2 receptor antagonists remained (relative risk 1.19, 95% confidence interval 1.03 to 1.38). In the instrumental variable analysis, use of a proton pump inhibitor (compared with an H2 receptor antagonist) was associated with an increased risk of pneumonia of 8.2 (95% confidence interval 0.5 to 15.9) cases per 1000 patients. CONCLUSIONS: Patients treated with proton pump inhibitors for stress ulcer had a small increase in the risk of postoperative pneumonia compared with patients treated with H2 receptor antagonists; this risk remained after confounding was accounted for using multiple analytic approaches. PMID- 24052584 TI - Military rather than civil aviation holds the answers for safer healthcare. PMID- 24052586 TI - Make children move. PMID- 24052585 TI - Parking the issue. PMID- 24052587 TI - Perioperative beta blockade. PMID- 24052588 TI - Sharing information on violence saved Cardiff L7m in health, legal, and social costs in 2007. PMID- 24052589 TI - Indian doctors condemn move to fund treatments abroad for civil servants. PMID- 24052591 TI - Doctors urge Syrian government to allow them access to patients. PMID- 24052592 TI - Spending on health in the US is projected to reach almost 20% of GDP by 2022. PMID- 24052593 TI - Fifteen-minute consultation: a structured approach to the management of recurrent oral ulceration in a child. AB - OBJECTIVE: To present a structured approach for an outpatient consultation of a child with recurrent mouth ulcers. METHOD: Review of literature and description of approach followed in our unit. CONCLUSIONS: The literature emphasises the need to consider local and systemic causes for oral ulceration in a child. Focused history and examination are key in establishing the cause and in order to ensure appropriate management. PMID- 24052594 TI - Risk factors for symptomatic and asymptomatic chikungunya infection. AB - BACKGROUND: In 2008, a chikungunya epidemic occurred in Southern Thailand. In many epidemics, there is a sizable number of asymptomatic cases. It is uncertain whether symptomatic and asymptomatic cases share the same risk factors. METHODS: Residents aged 18 years or more from three villages were sampled, their venous blood tested for anti-chikungunya virus IgG (haemagglutination-inhibition [HI] technique), and a face-to-face interview conducted during a home visit. RESULTS: Of 507 subjects selected, 314 (61.9%) were seropositive (HI titre>=1:10), of whom 148 (47.1%) were asymptomatic. Among subjects who reported fever and joint pain during the epidemic, 166 (97.1%) still had a positive titre. Having a garbage pile nearby and spending at least eight hours per day outdoors were associated with an increased risk of both symptomatic and asymptomatic chikungunya infection. Protective factors for symptomatic infection were age more than 58 and having a high level of formal education. CONCLUSIONS: Transmission was determined by environmental conditions whereas symptoms were associated with personal biological factors and social setting. PMID- 24052596 TI - Stability of self-control: Hirschi's redefined self-control. AB - In 2004, Hirschi redefined self-control by using the framework of his social control theory while retaining assumptions of his original self-control theory. A few studies have provided supportive evidence for the relationship between the newly defined self-control and deviant behavior, whereas no study has tested stability hypothesis by using this new self-control. This is the first study that examines whether the stability hypothesis is still valid in the revised self control theory. A recent longitudinal national sample of South Korean youths has been used for this purpose. Correlation analysis revealed moderate relationships among self-control measures for 5 years. Self-control differences across genders and across offenders/nonoffenders were significant and consistent. Finally, the results of growth-mixture modeling indicated that 89.5% of the sample exhibited stable group differences in self-control. These findings provide support for the stability thesis in the new version of self-control theory. The implications of these findings are discussed. PMID- 24052595 TI - Bead capture increases the sensitivity of sputum microscopy for the diagnosis of tuberculosis in Beijing, China. AB - BACKGROUND: A review of the scientific literature concluded that indirect smear can improve detection of TB in sputum compared to direct smear. However few laboratories have access to centrifugation in order to perform indirect smear. This study investigated whether an alternative method of magnetic bead concentration could enhance diagnosis of TB in China in laboratories which only perform direct smear microscopy. METHODS: A total of 129 sputum samples were investigated by direct smear microscopy, microscopy after TB-Bead extraction and by solid and liquid culture. RESULTS: Direct smear had a sensitivity of 40% by Ziehl-Neelsen (ZN) and 45% by auramine compared to combined culture results. After TB-Bead extraction, this increased to 65% for ZN and 70% for auramine. CONCLUSION: Magnetic bead concentration of mycobacteria from sputum led to a significant improvement (p<0.05) in the sensitivity of microscopy compared with direct smear. PMID- 24052597 TI - Examining ethnic differences in self-reported psychopathic traits among Portuguese male juvenile offenders. AB - The aim of the present study was to analyze differences regarding psychopathic traits and related constructs in male youths of diverse ethnic backgrounds. The participants were 216 male youths from the Juvenile Detention Centers of the Portuguese Ministry of Justice (White Europeans group: n = 108; ethnic minorities group: n = 108). Psychopathy was measured by the Antisocial Process Screening Device and the Child and Adolescent Taxon Scale. The results showed that no differences were found between ethnic groups regarding psychopathic traits and psychopathy taxon. Independent of ethnic group membership, psychopathic trait scores were significantly associated with behavioral problems, conduct disorder, self-reported delinquency, seriousness of criminal activity, age of criminal activity onset, and age at first trouble with the law. The present study adds support to the literature regarding youth psychopathic traits and supports the psychopathy construct as universally and interculturally consistent. PMID- 24052598 TI - Criminal recidivism of incarcerated male nonviolent offenders in Hong Kong. AB - Criminal recidivism of the incarcerated population in Hong Kong has rarely been studied. The purpose of this study is to explore the recidivism rates and to identify significant predictors of reoffending among incarcerated male offenders convicted of a nonviolent offense in Hong Kong. Using a self-reported methodological design, 278 offenders were sampled. These offenders' immediate past incarceration is used as the benchmark for this recidivism study. The 1-, 2 , and 3-year recidivism rates are 21%, 68%, and 87%, respectively. The findings denote that offending history, psychological attributes, interpersonal relationships, and environmental influences are significant reoffending risk factors. These findings, especially the alarming failure rates, highlight the need to seriously assess the effectiveness of intervention strategies used by the Hong Kong correctional system in preventing future offending. Implications for intervention strategies with emphasis on the risk factors for recidivism are discussed. PMID- 24052599 TI - Mechanism of bystander-blaming: defensive attribution, counterfactual thinking, and gender. AB - Contemporary victimology recognizes that an understanding of the mechanism of blaming requires a comprehensive approach that includes the victim, the offender, and the bystander. However, most of the existing research on blaming focuses on the victim and the offender, ignoring the issue of bystander-blaming. This study highlights the bystander and investigates bystander-blaming by exploring some theoretical explanations, including counterfactual thinking, defensive attribution, and gender differences. The study included 363 young male and female participants, who read vignettes describing the behavior of the victim and the bystander in a rape scenario and answered questions regarding bystander-blaming. The results show that both counterfactual thinking and defensive attribution play a role in bystander-blaming. This article addresses the theoretical and practical implications of these findings. PMID- 24052602 TI - Near-infrared spectroscopy for cardiovascular risk assessment? Not ready for prime time. PMID- 24052603 TI - Morecambe Bay hospital trust is still not meeting its improvement targets, CQC says. PMID- 24052604 TI - Patients rate hospitals high on cleanliness but low on food. PMID- 24052605 TI - Video-assisted thoracoscopic lobectomy in non-small-cell lung cancer patients with chronic obstructive pulmonary disease is associated with lower pulmonary complications than open lobectomy: a propensity score-matched analysis. AB - OBJECTIVES: Non-small-cell lung cancer (NSCLC) patients with chronic obstructive pulmonary disease (COPD) are at an increased risk of pulmonary complications after pulmonary resection. This study aimed to identify whether video-assisted thoracoscopic (VATS) lobectomy can reduce postoperative pulmonary complications compared with lobectomy by thoracotomy in NSCLC patients with COPD. METHODS: Among a total of 1502 NSCLC patients who underwent lobectomy from April 2005 to June 2012 at the Seoul National University Hospital, 446 (29.7%) were diagnosed with COPD based on the spirometric criteria of the Global Initiative for COPD. Among the 446 patients, 283 presented with stage I NSCLC and were selected for this study. The study patients were divided into two groups: patients undergoing VATS (n = 160) lobectomy and patients undergoing thoracotomy (n = 123) lobectomy. A propensity analysis that incorporated preoperative variables, such as age, sex, Charlson comorbidity index, extent of smoking, preoperative pulmonary function, size of the mass, histological type of the tumour and additional lung resection, was performed, and postoperative outcomes were compared. RESULTS: Matching based on propensity scores produced 91 patients in each group for the analysis of postoperative outcomes. There were only three operative mortalities in the thoracotomy group, and all of these patients died of postoperative pneumonia. The overall incidence of postoperative complications was 32.9% (30 of 91) and 22.0% (20 of 91) in the thoracotomy group and in the VATS group, respectively (P = 0.14). Compared with lobectomy by thoracotomy, VATS lobectomy was associated with a lower incidence of pulmonary complications (1.1 vs 12.1%; P < 0.01), shorter operation time (165 vs 201 min; P < 0.01) and shorter length of stay (6.0 vs 9.0 days; P = 0.04). CONCLUSIONS: VATS lobectomy is associated with a lower incidence of pulmonary complications compared with lobectomy by thoracotomy in stage I NSCLC patients with COPD. VATS lobectomy may be the preferred strategy for appropriately selected NSCLC patients with COPD. PMID- 24052606 TI - Modified valve-sparing reimplantation technique for para-commissural coronary ostia. AB - In some patients undergoing a valve-sparing reimplantation technique, a coronary ostium may be very close to one of the commissures. This condition jeopardizes the coronary ostium patency and valve reimplantation. The authors describe a simple and safe modification of the reimplantation technique, leaving the misplaced coronary ostium attached to the commissure. PMID- 24052607 TI - Predicted postoperative lung function is associated with all-cause long-term mortality after major lung resection for cancer. AB - OBJECTIVES: Preoperative lung function is an independent predictor of long-term survival after lung resection for non-small-cell lung cancer (NSCLC). The extent of resection has an impact on operative mortality, determines postoperative lung function and may influence both overall- and cancer-specific survival. We sought to determine the impact of predicted postoperative (ppo) lung function on long term survival after lung cancer resection. METHODS: We previously reported long term survival analyses for patients who underwent major lung resection for NSCLC 1980-2006. For this study, we calculated ppo spirometry (forced expiratory volume in the first second, FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) in the same cohort using the functional segment technique or quantitative perfusion scans when available, and updated survival data; missing data were imputed. We assessed the relationship of ppoFEV1 and ppoDLCO to long-term survival using Cox regression. RESULTS: Of 854 patients, 471 (55%) were men, the mean age was 63 years and median survival was 42 months. At the time of analysis, 70% of patients had died. On regression analysis, all-cause mortality was related to age, stage, performance status, renal function and prior myocardial infarction. Preoperative lung function was marginally associated with mortality [DLCO (10-percentage point decrease): HR (hazard ratio) 1.04, 95% confidence interval (95% CI) 1.00-1.08, P = 0.056; FEV1 (10-percentage point decrease): HR 1.04, 95% CI 1.00-1.09, P = 0.067]. In contrast, ppo lung function was strongly associated with mortality (ppoDLCO: HR 1.06, 95% CI 1.01-1.12, P = 0.024; ppoFEV1: HR 1.06, 95% CI 1.01-1.12, P = 0.031). CONCLUSIONS: Ppo lung function is strongly associated with long-term survival after major lung resection and is more strongly related to survival than preoperative lung function. Surgeons struggle with challenging decisions about the appropriate extent of resection for early-stage cancer, balancing factors such as operative morbidity/mortality, local recurrence and postoperative quality of life. Ppo lung function and its relation to survival also should be taken into consideration during such deliberations. PMID- 24052608 TI - Reply to Bauer et al. PMID- 24052609 TI - Oestrogen receptor polymorphisms are an associated risk factor for mild cognitive impairment and Alzheimer disease in women APOE {varepsilon}4 carriers: a case control study. AB - OBJECTIVES: Examine the role of single nucleotide polymorphisms (SNPs) in the oestrogen receptor (ER) genes: rs9340799, rs2234693, rs2228480 (in the ESR1 gene) and rs4986938 (in the ESR2 gene) as a risk factor for amnesic mild cognitive impairment (MCIa) and Alzheimer's disease (AD) and its possible association with the apolipoprotein E (APOE) gene. DESIGN: We have investigated the independent and combined association of different alleles of the oestrogen receptor genes and APOE*epsilon4 allele with cognitive impairment using a case-control design. SETTING: Participants were prospectively recruited from the neurology departments of several Basque Country hospitals. PARTICIPANTS: This study comprised 816 Caucasian participants who were aged 50 years and older: 204 MCIa, 350 sporadic patients with AD and 262 healthy controls. PRIMARY AND SECONDARY OUTCOME MEASURES: Clinical criteria and neuropsychological tests were used to establish the diagnostic groups (MCIa, AD and healthy controls). A dichotomous variable was used for each allele and genotype and the association with MCIa and AD was established using Logistic Regression Models. RESULTS: Neither alleles nor genotypes of SNPs rs9340799, rs2234693, rs2228480 and rs4986938 of oestrogen receptor genes (ESR1 and ESR2) are independently associated with the risk of MCIa or AD. However, the genetic profile created with the combination of the less represented alleles of these SNPs (expressed as XPAA) was associated with an increased risk for MCIa (OR=3.30, 95% CI 1.28 to 8.54, p=0.014) and AD (OR=5.16, 95% CI 2.19 to 12.14, p<0.001) in women APOE*epsilon4 allele carriers. CONCLUSIONS: The less represented alleles of SNPs studied are associated with MCIa and AD in APOE*E4 carriers. In particular, the genetic profile created with the less represented alleles of ESR1 and ESR2 SNPs are associated with an increased risk for MCIa and AD in women APOEepsilon4 allele carriers. PMID- 24052610 TI - Poor glycaemic control in Brazilian patients with type 2 diabetes attending the public healthcare system: a cross-sectional study. AB - OBJECTIVES: To describe the clinical profile of Brazilian patients with type 2 diabetes attending the public healthcare system and identify factors associated with poor glycaemic control. DESIGN: Cross-sectional study. SETTING: 14 centres in five regions of Brazil, including primary care units and outpatient clinics of University Hospitals. PARTICIPANTS: Patients with type 2 diabetes attending outpatient clinics of public healthcare system. MAIN OUTCOME MEASURED: Glycated haemoglobin (HbA1c), centrally measured by high-performance liquid chromatography (National Glycohemoglobin Standardization Program certified). RESULTS: A total of 5750 patients aged 61+/-10 years, with 11+/-8 years of diabetes duration (66% women, 56% non-white, body mass index: 28.0+/-5.3 kg/m(2)) were analysed. Mean HbA1c was 8.6+/-2.2%, and median HbA1c was 8.1% (6.9% to 9.9%). HbA1c <7% was observed in only 26% of patients. Mean HbA1c was higher (p < 0.01) in the North (9.0+/-2.6%) and Northeast (8.9+/-2.4%) than in the Midwest (8.1+/-2%), Southeast (8.4+/-2.1%) and South regions (8.3+/-1.9%). Using the cut-off value of HbA1c above the median, age (0.986 (0.983 to 0.989)), white ethnicity (0.931 (0.883 to 0.981)) and being from Midwest region (0.858 (0.745 to 0.989)) were protective factors, while diabetes duration (1.015 (1.012 to 1.018)), use of insulin (1.710 (1.624 to 1.802)) and living in the Northeast region (1.197 (1.085 to 1.321)) were associated with HbA1c >8%. CONCLUSIONS: The majority of Brazilian patients with type 2 diabetes attending the public healthcare system had HbA1c levels above recommended targets. The recognition of Northeast residents and non-white patients as vulnerable populations should guide future policies and actions to prevent and control diabetes. PMID- 24052611 TI - Quality of newborn care: adherence to guidelines for parenteral nutrition in preterm infants in four European countries. AB - OBJECTIVE: The level of adherence to guidelines should be explored particularly in preterm infants for whom poor nutrition has major effects on outcomes in later life. The objective was to evaluate compliance to international guidelines for parenteral nutrition (PN) in preterm infants across neonatal intensive care units (NICUs) of four European countries. DESIGN: Clinical practice survey by means of a questionnaire addressing routine PN protocols, awareness and implementation of guidelines. SETTING: NICUs in the UK, Italy, Germany and France. PARTICIPANTS: One senior physician per unit; 199 units which represent 74% of the NICUs of the four countries. PRIMARY OUTCOME MEASURE: Adherence of unit protocol to international guidelines. SECONDARY OUTCOME MEASURE: Factors that influence adherence to guidelines. RESULTS: 80% of the respondents stated that they were aware of some PN clinical practice guidelines. For amino acid infusion (AA), 63% of the respondents aimed to initiate AA on D0, 38% aimed to administer an initial dose >=1.5 g/kg/day and 91% aimed for a target dose of 3 or 4 g/kg/day, as recommended. For parenteral lipids, 90% of the respondents aimed to initiate parenteral lipids during the first 3 days of life, 39% aimed to use an initial dose >=1.0 g/kg/day and 76% defined the target dose as 3-4 g/kg/day, as recommended. Significant variations in PN protocols were observed among countries, but the type of hospital or the number of admissions per year had only a marginal impact on the PN protocols. CONCLUSIONS: Most respondents indicated that their clinical practice was based on common guidelines. However, the initiation of PN is frequently not compliant with current recommendations, with the main differences being observed during the first days of life. Continuous education focusing on PN practice is needed, and greater efforts are required to disseminate and implement international guidelines. PMID- 24052612 TI - Changes in cardiovascular risk factors in relation to increasing ethnic inequalities in cardiovascular mortality: comparison of cross-sectional data in the Health Surveys for England 1999 and 2004. AB - OBJECTIVES: Reducing disease inequalities requires risk factors to decline quickest in the most disadvantaged populations. Our objective was to assess whether this happened across the UK's ethnic groups. DESIGN: Secondary analysis of repeated but independent cross-sectional studies focusing on Health Surveys for England 1999 and 2004. SETTING: Community-based population level surveys in England. PARTICIPANTS: Seven populations from the major ethnic groups in England (2004 sample sizes): predominantly White general (6704), Irish (1153), Chinese (723), Indian (1184), Pakistani (941), Bangladeshi (899) and Black Caribbean (1067) populations. The numbers were smaller for specific variables, especially blood tests. OUTCOME MEASURES: Data on 10 established cardiovascular risk factors were extracted from published reports. Differences between 1999 and 2004 were defined a priori as occurring when the 95% CI excluded 0 (for prevalence differences), or 1 (for risk ratios) or when there was a 5% or more change (independent of CIs). RESULTS: Generally, there were reductions in smoking and blood pressure and increases in the waist-hip ratio, body mass index and diabetes. Changes between 1999 and 2004 indicated inconsistent progress and increasing inequalities. For example, total cholesterol increased in Pakistani (0.3 mmol/L) and Bangladeshi men (0.3 mmol/L), and in Pakistani (0.3 mmol/L), Bangladeshi (0.4 mmol/L) and Black Caribbean women (0.3 mmol/L). Increases in absolute risk factor levels were common, for example, in Pakistani (five risk factors), Bangladeshi (four factors) and general population women (four factors). For men, Black Caribbeans had the most (five factor) increases. The changes relative to the general population were also adverse for three risk factors in Pakistani and Black Caribbean men, four in Bangladeshi women and three in Pakistani women. CONCLUSIONS: Changes in populations with the most cardiovascular disease and diabetes did not decline the quickest. Cardiovascular screening programmes need more targeting. PMID- 24052615 TI - Stem cell senescence: a double-edged sword? PMID- 24052613 TI - Altered brain activity for phonological manipulation in dyslexic Japanese children. AB - Because of unique linguistic characteristics, the prevalence rate of developmental dyslexia is relatively low in the Japanese language. Paradoxically, Japanese children have serious difficulty analysing phonological processes when they have dyslexia. Neurobiological deficits in Japanese dyslexia remain unclear and need to be identified, and may lead to better understanding of the commonality and diversity in the disorder among different linguistic systems. The present study investigated brain activity that underlies deficits in phonological awareness in Japanese dyslexic children using functional magnetic resonance imaging. We developed and conducted a phonological manipulation task to extract phonological processing skills and to minimize the influence of auditory working memory on healthy adults, typically developing children, and dyslexic children. Current experiments revealed that several brain regions participated in manipulating the phonological information including left inferior and middle frontal gyrus, left superior temporal gyrus, and bilateral basal ganglia. Moreover, dyslexic children showed altered activity in two brain regions. They showed hyperactivity in the basal ganglia compared with the two other groups, which reflects inefficient phonological processing. Hypoactivity in the left superior temporal gyrus was also found, suggesting difficulty in composing and processing phonological information. The altered brain activity shares similarity with those of dyslexic children in countries speaking alphabetical languages, but disparity also occurs between these two populations. These are initial findings concerning the neurobiological impairments in dyslexic Japanese children. PMID- 24052614 TI - Role of type II pneumocyte senescence in radiation-induced lung fibrosis. AB - BACKGROUND: Radiation is a commonly delivered therapeutic modality for cancer. The causes underlying the chronic, progressive nature of radiation injury in the lung are poorly understood. METHODS: C57Bl/6NCr mice were exposed to thoracic irradiation (n = 3 per dose and time point for tissue collection). Microarray analysis of gene expression from irradiated murine lung was performed using one way analysis of variance with post hoc Scheffe analysis. Senescence and type II airway epithelial cell (AECII) count were assayed in irradiated murine lung tissue (n = 3 per condition). Irradiated mice were treated with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase (NOX), and fibrosis was assessed by collagen assays. All statistical tests were two-tailed. RESULTS: Gene expression in lung tissue from mice irradiated to 17.5 Gy clustered with that of aged unirradiated mice. Only fibrogenic exposures led to AECII senescence (0 Gy: 0.66% +/- 0.67%; 5 Gy: 4.5% +/- 1.19%; 17.5 Gy: 18.7% +/- 3.05; P = .007) and depletion (0 Gy: 2.89 per alveolus +/- 0.26; 5 Gy: 2.41 +/- 0.19; 17.5 Gy: 1.6 +/ 0.14; P < .001) at 30 weeks. Treatment of irradiated mice with DPI for 16 weeks markedly reduced collagen accumulation (5*6 Gy: 57.26 MUg/lung +/- 9.91; 5*6 Gy +/- DPI: 36.54MUg/lung +/- 4.39; P = .03) and AECII senescence (5*6 Gy: 37.61% +/ 4.82%; 5*6 Gy +/- DPI: 12.38% +/- 2.78; P < .001). CONCLUSIONS: These studies identify senescence as an important process in AECII in vivo and indicate that NOX is a critical mediator of radiation-induced AECII senescence and pulmonary fibrosis. PMID- 24052617 TI - Tracking chemotherapy's effects on secondary cancers. PMID- 24052619 TI - Re: selective inhibition of Her2-positive breast cancer cells by the HIV protease inhibitor nelfinavir. PMID- 24052620 TI - Use of sentinel node biopsy expands. PMID- 24052622 TI - Acquired mutations that affect pre-mRNA splicing in hematologic malignancies and solid tumors. AB - The application of next-generation sequencing technologies to interrogate the genome of human hematologic malignancies is providing promising insights into their molecular etiology and into the pathogenesis of seemingly unrelated malignancies. Among the somatic mutations identified by this approach are ones that target components of the spliceosome, a ribonucleoprotein complex responsible for the posttranscriptional processing of primary transcripts to form mature messenger RNA species. These mutations were initially detected in patients with chronic lymphocytic leukemia or a myelodysplastic syndrome, but can also occur at relatively high frequency in some solid tumors, including uveal malignant melanoma, adenocarcinoma of the lung, and estrogen receptor-positive breast cancers. Their presence in a variety of malignancies suggests that the spliceosomal mutations may play a fundamental role in defining the malignant phenotype. The development and testing of drugs that eliminate cells bearing a spliceosomal mutation, or normalize their altered transcript splicing patterns, are therefore a priority. Here, we summarize the effects of spliceosome associated mutations on transcript processing in vitro and in vivo, and their impact on disease initiation and/or progression and patient outcome. Moreover, we discuss the therapeutic potential of compounds already known to target splicing factor 3B subunit 1 (SF3B1), an essential component of the spliceosome that is frequently mutated. PMID- 24052618 TI - From bench to bedside: lessons learned in translating preclinical studies in cancer drug development. AB - The development of targeted agents in oncology has rapidly expanded over the past 2 decades and has led to clinically significant improvements in the treatment of numerous cancers. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. As preclinical studies shift toward defining proof of mechanism, patient selection, and rational drug combinations, it is critical to understand the lessons learned from prior translational studies to gain an understanding of prior drug development successes and failures. By learning from prior drug development, future translational studies will provide more clinically relevant data, and the underlying hope is that the clinical success rate will improve and the treatment of patients with ineffective targeted therapy will be limited. PMID- 24052623 TI - From bench to bedside: does preclinical practice in translational oncology need some rebuilding? PMID- 24052624 TI - Targeting amino acid transport in metastatic castration-resistant prostate cancer: effects on cell cycle, cell growth, and tumor development. AB - BACKGROUND: L-type amino acid transporters (LATs) uptake neutral amino acids including L-leucine into cells, stimulating mammalian target of rapamycin complex 1 signaling and protein synthesis. LAT1 and LAT3 are overexpressed at different stages of prostate cancer, and they are responsible for increasing nutrients and stimulating cell growth. METHODS: We examined LAT3 protein expression in human prostate cancer tissue microarrays. LAT function was inhibited using a leucine analog (BCH) in androgen-dependent and -independent environments, with gene expression analyzed by microarray. A PC-3 xenograft mouse model was used to study the effects of inhibiting LAT1 and LAT3 expression. Results were analyzed with the Mann-Whitney U or Fisher exact tests. All statistical tests were two-sided. RESULTS: LAT3 protein was expressed at all stages of prostate cancer, with a statistically significant decrease in expression after 4-7 months of neoadjuvant hormone therapy (4-7 month mean = 1.571; 95% confidence interval = 1.155 to 1.987 vs 0 month = 2.098; 95% confidence interval = 1.962 to 2.235; P = .0187). Inhibition of LAT function led to activating transcription factor 4-mediated upregulation of amino acid transporters including ASCT1, ASCT2, and 4F2hc, all of which were also regulated via the androgen receptor. LAT inhibition suppressed M phase cell cycle genes regulated by E2F family transcription factors including critical castration-resistant prostate cancer regulatory genes UBE2C, CDC20, and CDK1. In silico analysis of BCH-downregulated genes showed that 90.9% are statistically significantly upregulated in metastatic castration-resistant prostate cancer. Finally, LAT1 or LAT3 knockdown in xenografts inhibited tumor growth, cell cycle progression, and spontaneous metastasis in vivo. CONCLUSION: Inhibition of LAT transporters may provide a novel therapeutic target in metastatic castration-resistant prostate cancer, via suppression of mammalian target of rapamycin complex 1 activity and M-phase cell cycle genes. PMID- 24052625 TI - Metastatic castration-resistant prostate cancer hungers for leucine. PMID- 24052626 TI - Nakazawaea siamensis f.a., sp. nov., a yeast species isolated from phylloplane. AB - Strain DMKU-RK467(T), representing a novel yeast species, was isolated from the external surface of sugar cane leaves collected in Thailand. On the basis of morphological, biochemical, physiological and chemotaxonomic characteristics, and sequence analysis of the D1/D2 region of the LSU rRNA gene and the internal transcribed spacer (ITS) region, strain DMKU-RK467(T) was assigned to a novel species of the genus Nakazawaea. The novel species was related most closely to the type strain of Candida wickerhamii but they differed by 1.9 % nucleotide substitutions in the D1/D2 region of the LSU rRNA gene and by 5.2 % nucleotide substitutions in the ITS region. The name Nakazawaea siamensis f.a., sp. nov. is proposed (type strain DMKU-RK467(T) = BCC 50734(T) = NBRC 108903(T) = CBS 12569(T)). PMID- 24052627 TI - Anoxybacillus calidus sp. nov., a thermophilic bacterium isolated from soil near a thermal power plant. AB - A novel thermophilic, Gram-stain-positive, facultatively anaerobic, endospore forming, motile, rod-shaped bacterium, strain C161ab(T), was isolated from a soil sample collected near Kizildere, Saraykoy-Buharkent power plant in Denizli. The isolate could grow at temperatures between 35 and 70 degrees C (optimum 55 degrees C), at pH 6.5-9.0 (optimum pH 8.0-8.5) and with 0-2.5 % NaCl (optimum 0.5 %, w/v). The strain formed cream-coloured, circular colonies and tolerated up to 70 mM boron. Its DNA G+C content was 37.8 mol%. The peptidoglycan contained meso diaminopimelic acid as the diagnostic diamino acid. Strain C161ab(T) contained menaquinones MK-7 (96 %) and MK-6 (4 %). The major cellular fatty acids were iso branched fatty acids: iso-C15 : 0 (52.2 %) and iso-C17 : 0 (28.0 %,) with small amounts of C16 : 0 (7.4 %). Phylogenetic analysis based on the 16S rRNA gene revealed 94.6-96.8 % sequence similarity with all recognized species of the genus Anoxybacillus. Strain C161ab(T) showed the greatest sequence similarity to Anoxybacillus rupiensis DSM 17127(T) and Anoxybacillus voinovskiensis DSM 17075(T), both had 96.8 % similarity to strain C161ab(T), as well as to Anoxybacillus caldiproteolyticus DSM 15730(T) (96.6 %). DNA-DNA hybridization revealed low levels of relatedness with the closest relatives of strain C161ab(T), A. rupiensis (21.2 %) and A. voinovskiensis (16.5 %). On the basis of the results obtained from phenotypic, chemotaxonomic, genomic fingerprinting, phylogenetic and hybridization analyses, the isolate is proposed to represent a novel species, Anoxybacillus calidus sp. nov. (type strain C161ab(T) = DSM 25520(T) = NCIMB 14851(T)). PMID- 24052628 TI - Sphingobacterium arenae sp. nov., isolated from sandy soil. AB - A novel, Gram-stain-negative, non-motile, non-spore-forming, short rod-shaped, aerobic bacterium designated H-12(T) was isolated from a mixed sandy soil sample collected from Xinjiang, China. Strain H-12(T) grew at 20-37 degrees C (optimum, 30 degrees C), pH 7.0-11.0 (optimum, pH 8.5) on TGY medium with 0-5 % NaCl (w/v). 16S rRNA gene sequence analysis indicated that strain H-12(T) shared sequence similarities with Sphingobacterium composti DSM 18850(T) (90.0 %). Strain H-12(T) showed a low level of DNA-DNA relatedness to Sphingobacterium composti DSM 18850(T) (45.5 %). The predominant isoprenoid quinone of strain H 12(T) was MK-7 and the major polar lipid was phosphatidylethanolamine. The predominant cellular fatty acids were C16:1omega7c and/or C16 : 1omega6c, iso-C15 : 0, iso-C17 : 0 3-OH, C16 : 0, C16 : 0 3-OH and iso-C15 : 0 3-OH. DNA G+C content of strain H-12(T) was 44.15 mol%. On the basis of phenotypic, genetic and phylogenetic data, strain H-12(T) is proposed to be a representative of a novel species of the genus Sphingobacterium, for which the name Sphingobacterium arenae sp. nov. is suggested and the type strain is H-12(T) ( = ACCC 05758(T) = KCTC 32294(T)). PMID- 24052629 TI - Pontibacter indicus sp. nov., isolated from hexachlorocyclohexane-contaminated soil. AB - An orange-pigmented bacterial strain, designated LP100(T), was isolated from hexachlorocyclohexane-contaminated soil (Lucknow, India). A neighbour-joining tree based on 16S rRNA gene sequences showed that strain LP100(T) occupied a distinct phylogenetic position in the Pontibacter species cluster, showing highest similarity with Pontibacter lucknowensis DM9(T) (97.4 %). Levels of similarity to strains of other Pontibacter species ranged between 94.0 and 96.8 %. Strain LP100(T) contained MK-7 as the predominant menaquinone and sym homospermidine was the major polyamine in the cell. The major cellular fatty acids of strain LP100(T) were anteiso-C17 : 0 A, iso-C15 : 0 and iso-C18 : 1 H. The polar lipid profile of strain LP100(T) showed the presence of phosphatidylethanolamine, an unidentified aminophospholipid, three unknown aminolipids and two unknown polar lipids. The G+C content of strain LP100(T) was 58.2 mol%. The results of DNA-DNA hybridization, biochemical and physiological tests clearly distinguish the novel strain from closely related species of the genus Pontibacter. Therefore, strain LP100(T) represents a novel species of the genus Pontibacter for which the name Pontibacter indicus is proposed. The type strain is LP100(T) ( = CCM8435(T) = MCC2027(T)). PMID- 24052630 TI - Chitinophaga jiangningensis sp. nov., a mineral-weathering bacterium. AB - A Gram-stain-negative, rod-shaped bacterial strain, JN53(T), was isolated from the surfaces of weathered rock (potassic trachyte) from Nanjing, Jiangsu Province, PR China. Strain JN53(T) grew optimally at 30 degrees C, pH 7.0. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain JN53(T) belonged to the genus Chitinophaga in the family Chitinophagaceae. It was most closely related to Chitinophaga terrae KP01(T) (97.3 % 16S rRNA gene sequence similarity), Chitinophaga eiseniae YC6729(T) (96.3 %). Strain JN53(T) contained MK-7 as the major menaquinone and homospermidine as the major polyamine. The main fatty acids of strain JN53(T) were iso-C15 : 0, C16 : 1omega5c, C16 : 1omega7c and/or C16 : 1omega6c (summed feature 3), iso-C17 : 0 3 OH, C16 : 0, iso-C15 : 0 3-OH and C16 : 0 3-OH. The polar lipid profile contained phosphatidylethanolamine, unknown aminolipids and unknown lipids. The total DNA G+C content of strain JN53(T) was 49.7 mol%. The low level of DNA-DNA relatedness to other species of the genus Chitinophaga and the many phenotypic properties that distinguished strain JN53(T) from recognized species of this genus demonstrated that isolate JN53(T) should be classified as representing a novel species of the genus Chitinophaga, for which the name Chitinophaga jiangningensis sp. nov. is proposed. The type strain is JN53(T) ( = CCTCC AB 2013166(T) = JCM 19354(T)). PMID- 24052631 TI - Effect of paricalcitol on left ventricular mass and function in CKD--the OPERA trial. AB - Vitamin D seems to protect against cardiovascular disease, but the reported effects of vitamin D on patient outcomes in CKD are controversial. We conducted a prospective, double blind, randomized, placebo-controlled trial to determine whether oral activated vitamin D reduces left ventricular (LV) mass in patients with stages 3-5 CKD with LV hypertrophy. Subjects with echocardiographic criteria of LV hypertrophy were randomly assigned to receive either oral paricalcitol (1 MUg) one time daily (n=30) or matching placebo (n=30) for 52 weeks. The primary end point was change in LV mass index over 52 weeks, which was measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volume, echocardiographic measures of systolic and diastolic function, biochemical parameters of mineral bone disease, and measures of renal function. Change in LV mass index did not differ significantly between groups (median [interquartile range], -2.59 [-6.13 to 0.32] g/m(2) with paricalcitol versus 4.85 [-9.89 to 1.10] g/m(2) with placebo). Changes in LV volume, ejection fraction, tissue Doppler-derived measures of early diastolic and systolic mitral annular velocities, and ratio of early mitral inflow velocity to early diastolic mitral annular velocity did not differ between the groups. However, paricalcitol treatment significantly reduced intact parathyroid hormone (P<0.001) and alkaline phosphatase (P=0.001) levels as well as the number of cardiovascular-related hospitalizations compared with placebo. In conclusion, 52 weeks of treatment with oral paricalcitol (1 MUg one time daily) significantly improved secondary hyperparathyroidism but did not alter measures of LV structure and function in patients with severe CKD. PMID- 24052633 TI - Urine podocyte mRNAs, proteinuria, and progression in human glomerular diseases. AB - Model systems demonstrate that progression to ESRD is driven by progressive podocyte depletion (the podocyte depletion hypothesis) and can be noninvasively monitored through measurement of urine pellet podocyte mRNAs. To test these concepts in humans, we analyzed urine pellet mRNAs from 358 adult and pediatric kidney clinic patients and 291 controls (n=1143 samples). Compared with controls, urine podocyte mRNAs increased 79-fold (P<0.001) in patients with biopsy-proven glomerular disease and a 50% decrease in kidney function or progression to ESRD. An independent cohort of patients with Alport syndrome had a 23-fold increase in urinary podocyte mRNAs (P<0.001 compared with controls). Urinary podocyte mRNAs increased during active disease but returned to baseline on disease remission. Furthermore, urine podocyte mRNAs increased in all categories of glomerular disease evaluated, but levels ranged from high to normal, consistent with individual patient variability in the risk for progression. In contrast, urine podocyte mRNAs did not increase in polycystic kidney disease. The association between proteinuria and podocyturia varied markedly by glomerular disease type: a high correlation in minimal-change disease and a low correlation in membranous nephropathy. These data support the podocyte depletion hypothesis as the mechanism driving progression in all human glomerular diseases, suggest that urine pellet podocyte mRNAs could be useful for monitoring risk for progression and response to treatment, and provide novel insights into glomerular disease pathophysiology. PMID- 24052632 TI - Tenofovir effect on the kidneys of HIV-infected patients: a double-edged sword? AB - Tenofovir disoproxil fumarate (TDF), the first nucleotidic inhibitor of HIV reverse transcription, became available in 2001. It has been extensively used worldwide and is now the most prescribed antiretroviral (ARV) drug. Its high antiviral activity and favorable metabolic profile are responsible for its success. Furthermore, TDF has been associated with other ARVs to form new combined antiretroviral treatments in only one tablet once-a-day, which increases treatment adherence. Fears of potential nephrotoxicity that tenofovir would have in common with two other drugs from the same family (adefovir, used to treat hepatitis B, and cidofovir, used to treat cytomegalovirus infections) were alleviated by the early clinical trials. Yet, in 2001, the first case of TDF induced acute nephrotoxicity was published. Numerous cases have been published since then, and it is now established that TDF presents a tubular toxicity risk. Some facilitating factors have been identified, such as co-prescription of didanosine or boosted protease inhibitor, preexisting CKD, low body weight, and associated diabetes mellitus. Conversely, whether TDF is nephrotoxic in the long term is a highly debated question. Some studies suggest a decreased GFR when TDF is prescribed for a long period, while others indicate that TDF is safe for the kidneys even after many years of use. Here we review the differences in patient characteristics, study designs, and measured outcomes that can possibly explain these conflicting findings. We conclude with rational recommendation for appropriate TDF prescription. PMID- 24052634 TI - COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome. AB - Alport syndrome is an inherited disease characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities. Autosomal recessive Alport syndrome is suspected in consanguineous families and when female patients develop renal failure. Fifteen percent of patients with Alport syndrome have autosomal recessive inheritance caused by two pathogenic mutations in either COL4A3 or COL4A4. Here, we describe the mutations and clinical features in 40 individuals including 9 children and 21 female individuals (53%) with autosomal recessive inheritance indicated by the detection of two mutations. The median age was 31 years (range, 6-54 years). The median age at end stage renal failure was 22.5 years (range, 10-38 years), but renal function was normal in nine adults (29%). Hearing loss and ocular abnormalities were common (23 of 35 patients [66%] and 10 of 18 patients [56%], respectively). Twenty mutation pairs (50%) affected COL4A3 and 20 pairs affected COL4A4. Of the 68 variants identified, 39 were novel, 12 were homozygous changes, and 9 were present in multiple individuals, including c.2906C>G (p.(Ser969*)) in COL4A4, which was found in 23% of the patients. Thirty six variants (53%) resulted directly or indirectly in a stop codon, and all 17 individuals with early onset renal failure had at least one such mutation, whereas these mutations were less common in patients with normal renal function or late-onset renal failure. In conclusion, patient phenotypes may vary depending on the underlying mutations, and genetic testing should be considered for the routine diagnosis of autosomal recessive Alport syndrome. PMID- 24052635 TI - Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the General Practice Research Database. AB - OBJECTIVES: To estimate the incidence and prevalence of multiple sclerosis (MS) by age and describe secular trends and geographic variations within the UK over the 20-year period between 1990 and 2010 and hence to provide updated information on the impact of MS throughout the UK. DESIGN: A descriptive study. SETTING: The study was carried out in the General Practice Research Database (GPRD), a primary care database representative of the UK population. MAIN OUTCOME MEASURES: Incidence and prevalence of MS per 100 000 population. Secular and geographical trends in incidence and prevalence of MS. RESULTS: The prevalence of MS recorded in GPRD increased by about 2.4% per year (95% CI 2.3% to 2.6%) reaching 285.8 per 100 000 in women (95% CI 278.7 to 293.1) and 113.1 per 100 000 in men (95% CI 108.6 to 117.7) by 2010. There was a consistent downward trend in incidence of MS reaching 11.52 per 100 000/year (95% CI 10.96 to 12.11) in women and 4.84 per 100 000/year (95% CI 4.54 to 5.16) in men by 2010. Peak incidence occurred between ages 40 and 50 years and maximum prevalence between ages 55 and 60 years. Women accounted for 72% of prevalent and 71% of incident cases. Scotland had the highest incidence and prevalence rates in the UK. CONCLUSIONS: We estimate that 126 669 people were living with MS in the UK in 2010 (203.4 per 100 000 population) and that 6003 new cases were diagnosed that year (9.64 per 100 000/year). There is an increasing population living longer with MS, which has important implications for resource allocation for MS in the UK. PMID- 24052636 TI - Neutralization of ocular surface TNF-alpha reduces ocular surface and lacrimal gland inflammation induced by in vivo dry eye. AB - PURPOSE: The purpose of this study was to investigate the effectiveness of tumor necrosis factor (TNF)-alpha blocker for treatment of dry eye (DE)-induced inflammation and determine a more effective method to suppress lacrimal gland inflammation. Efficacy of topical versus systemic administration of TNF-alpha blockers was determined using a murine dry eye (DE) model. METHODS: The TNF-alpha blocker HL036 was developed by modification of the TNF receptor I. Protein purity, binding affinity, and clearance of TNF-alpha was compared with etanercept. Using DE-induced C57BL/6 mice, corneal erosion and goblet cell counts were measured after subcutaneous or topical treatment with etanercept or HL036. Inflammatory cytokines in cornea and lacrimal glands were determined by quantitative RT-PCR and ELISA. RESULTS: HL036 showed TNF-alpha binding affinity comparable to etanercept, as measured by surface plasmon resonance. HL036 concentration was significantly higher in cornea and anterior segment than etanercept and effectively eliminated TNF-alpha on ocular surfaces. Etanercept was preferentially concentrated in the posterior segment. Corneal erosion and goblet cell counts were improved only with topically applied etanercept and HL036. Ocular surface IFN-gamma, IL-6, and IL-21 were significantly decreased by topical HL036. DE-induced lacrimal gland IFN-gamma and IL-6 expression was effectively suppressed by topical etanercept and HL036. CONCLUSIONS: Topical TNF alpha blockers effectively suppressed lacrimal gland and corneal inflammation by suppressing IFN-gamma, IL-21, and IL-6. Differences in TNF-alpha affinity, clearance, and local concentration of blockers may account for the anti inflammatory effects in different ocular regions. PMID- 24052637 TI - Imaging errors in localization of COMS-type plaques in choroidal melanoma brachytherapy. AB - PURPOSE: To investigate mathematically and experimentally the sources of errors in localization of COMS-type plaques in melanoma brachytherapy when using ultrasound and transillumination and to give recommendations to avoid such errors. METHODS: A computer-aided simulation tool was developed to model the errors seen in the patient images when using ultrasound imaging and transillumination during localization of the COMS-type plaque in melanoma brachytherapy. Several laboratory experiments were performed on sheep eyes to confirm the validity of the error sources and the simulator outputs. Results were compared to the intraoperative ultrasonographic patient images for validation. RESULTS: Based on mathematical modeling and computer simulation results, transillumination provides acceptable accuracy for small to medium tumors with less than 7-mm height but shows poor accuracy as the tumor height increases. In ultrasound imaging, two sources of error are predicted in longitudinal scan using our computer simulation modeling, and the results are supported by the experiments on sheep eyes and patient images taken during the operation. Both errors are related to the lens. The first error is due to attenuation and refraction of the lens causing opaque areas and a change of curvature in the image of the plaque edge that is nearest to the lens. The second type of error is related to the total internal reflection from the lens. CONCLUSIONS: The simulation method presented in this article allows quantitative assessment of the sources, mechanisms, and measures of errors in localization of the CMOS-type plaques by ultrasound and transillumination techniques. Errors predicted by the simulation method are validated by experiments. Error assessment by this method provides guidelines for avoiding such errors. PMID- 24052638 TI - Axial length as a factor associated with visual outcome after vitrectomy for diabetic macular edema. AB - PURPOSE: To investigate whether axial length predicts visual acuity outcome after vitrectomy for diffuse macular edema secondary to diabetic retinopathy. METHODS: Fifty-one eyes of 41 patients with diabetic macular edema (DME) who underwent vitrectomy were reviewed retrospectively. Clinical data, including axial length measured by partial coherence interferometry, postoperative best-corrected visual acuity (BCVA), and postoperative status of integrity of the photoreceptor layer observed by optical coherence tomography, were recorded. The relationship between axial length and postoperative BCVA or visibility of the junction between the inner and outer segment (IS/OS) line at 12 months after surgery were analyzed. Logistic regression analyses were performed to examine predictors related to postoperative BCVA. RESULTS: Median BCVA improved significantly (P < 0.0001) after surgery (0.4 logMAR units; range, 0-1.5) compared to baseline (0.69 logMAR units; range, 0.22-1.22). Median axial length was significantly longer (P = 0.017) when postoperative BCVA was below 0.4 logMAR units (23.51 mm; range, 22.30 26.10) compared to over 0.4 logMAR units (23.02 mm; range, 22.10-24.65). A significant negative correlation was observed between postoperative logMAR and axial length (n = 51, rs = -0.35, P = 0.012). Median axial length was significantly longer (P = 0.039) in eyes with visible IS/OS line (23.54 mm; range, 22.39-26.10) than in those without visible IS/OS line (23.02 mm; range, 22.13-24.65) at 12 months after surgery. Multivariate logistic regression analysis showed that short axial length (odds ratio: 0.3, P = 0.009) increased the risk of poor visual outcome after surgery. CONCLUSIONS: Longer axial length predicts better postoperative BCVA after vitrectomy for diffuse macular edema secondary to diabetic retinopathy. PMID- 24052640 TI - Chemokine receptor CCR7 expression predicts poor outcome in uveal melanoma and relates to liver metastasis whereas expression of CXCR4 is not of clinical relevance. AB - PURPOSE: To examine the prognostic relevance of expression of the chemokine receptors CCR7 and CXCR4 and its ligand CXCL12 in uveal melanoma in nonmetastatic and metastatic patients with correlation to liver metastasis and overall survival. METHODS: Primary uveal melanoma specimens from 19 patients with correlating liver metastasis specimens and 30 primary uveal melanoma specimens of patients without metastasis were collected between the years 1988 and 2008. Expression of CCR7, CXCR4, and CXCL12 were studied using immunohistochemistry. Single nucleotide polymorphism (SNP) arrays were used to examine gains or losses of chromosomes 1, 3, 6, and 8 and the regions of CCR7 (17q12-q21.2), CXCR4 (2q21), and CXCL12 (10q11.1) genes. RESULTS: Strong cytoplasmic staining for CCR7 correlated with the presence of epithelioid cells (P = 0.037), tumor thickness (P = 0.011), lymphocytic infiltration (P = 0.041), and necrosis (P = 0.045). Nuclear staining for CXCR4 correlated with lymphocytic infiltration (P = 0.017). CXCL12 showed no correlation to histologic parameters. Single nucleotide polymorphism analyses showed no copy number variations in the regions of CCR7, CXCR4, or CXCL12. Strong expression of CCR7 was observed in 76% of the metastatic patients and 0% of nonmetastasis patients. In multivariate analysis, CCR7 staining was inversely correlated to overall survival and disease-free survival, whereas CXCR4 nuclear staining was not. CONCLUSIONS: Our data suggest that CCR7 plays a role in uveal melanoma metastasis and is associated with poor survival. CCR7 and its involved related pathways are of prognostic value in uveal melanoma and may prove to be a target for therapeutic intervention. PMID- 24052639 TI - The role of the NFAT signaling pathway in retinal neovascularization. AB - PURPOSE: The purpose of the present study was to investigate the role of nuclear factor of activated T cells (NFAT), a transcription factor downstream of VEGF, in angiogenic cell behaviors of human retinal microvascular endothelial cells (HRMEC), and to assess the efficacy of NFAT signaling inhibitors in a rat model of oxygen-induced retinopathy (OIR). METHODS: Human retinal microvascular endothelial cells were treated with VEGF in the presence or absence of the NFAT inhibitor of NFAT-calcineurin association-6 (INCA-6), and NFAT translocation was evaluated using immunocytochemistry (ICC). Human retinal microvascular endothelial cells were treated with increasing doses of INCA-6, and cell proliferation and tube formation were assessed. Rats subjected to OIR were administered increasing doses of INCA-6 or the CN inhibitor FK-506, and the retinal neovascular area was measured. RESULTS: Nuclear factor of activated T cells c1 was translocated to the nucleus of HRMEC treated with VEGF, and INCA-6 treatment blocked translocation. Inhibitor of NFAT-calcineurin association 6inhibited HRMEC proliferation and tube formation in a dose-dependent manner. Both INCA-6 and FK-506 treatment significantly reduced pathologic neovascularization in OIR. CONCLUSIONS: This investigation has demonstrated that in HRMEC, NFATc1 is activated downstream of VEGF signaling and NFAT signaling plays a key role in angiogenic cell behaviors. In addition, NFAT inhibition is shown to be highly efficacious in an OIR model. These findings indicate that the NFAT signaling pathway may serve as a suitable therapeutic target for the treatment of neovascular eye disease. PMID- 24052642 TI - Transition of pharmacy educators to faculty champions of interprofessional education. PMID- 24052641 TI - In vivo retinal vascular oxygen tension imaging and fluorescein angiography in the mouse model of oxygen-induced retinopathy. AB - PURPOSE: Oxygenation abnormalities are implicated in the development of retinopathy of prematurity (ROP). The purpose of this study is to report in vivo retinal vascular oxygen tension (PO2) measurements and fluorescein angiography (FA) findings in the mouse model of oxygen-induced retinopathy (OIR). METHODS: We exposed 19 neonatal mice to 77% oxygen from postnatal day 7 (P7) to P12 (OIR), while 11 neonatal mice were kept under room air (control). Using phosphorescence lifetime imaging, retinal vascular PO2 was measured followed by FA. Repeated measures ANOVA was performed to determine the effects of blood vessel type (artery and vein) and group (OIR and control) on PO2. Avascular retinal areas were measured from FA images in OIR mice. RESULTS: There was a significant effect of vessel type on PO2 (P < 0.001). The effect of group on PO2 was not significant (P = 0.3), indicating similar PO2 between OIR and control mice. The interaction between group and vessel type was significant (P = 0.03), indicating a larger arteriovenous PO2 difference in OIR mice than control mice. In control mice, FA displayed normal vascularization, while FA of OIR mice showed abnormalities, including dilation and tortuosity of major retinal blood vessels, and avascular regions. In OIR mice, the mean percent avascular retinal area was 33% +/- 18%. CONCLUSIONS: In vivo assessment of retinal vascular oxygen tension and vascularization patterns demonstrated abnormalities in the mouse model of OIR. This approach has the potential to improve understanding of retinal vascular development and oxygenation alterations due to ROP and other ischemic retinal diseases. PMID- 24052643 TI - Opportunities and responsibilities for the academy in the medical home. PMID- 24052644 TI - Reenvisioning assessment for the Academy and the Accreditation Council for Pharmacy Education's standards revision process. AB - Assessment has become a major aspect of accreditation processes across all of higher education. As the Accreditation Council for Pharmacy Education (ACPE) plans a major revision to the standards for doctor of pharmacy (PharmD) education, an in-depth, scholarly review of the approaches and strategies for assessment in the PharmD program accreditation process is warranted. This paper provides 3 goals and 7 recommendations to strengthen assessment in accreditation standards. The goals include: (1) simplified standards with a focus on accountability and improvement, (2) institutionalization of assessment efforts; and (3) innovation in assessment. Evolving and shaping assessment practices is not the sole responsibility of the accreditation standards. Assessment requires commitment and dedication from individual faculty members, colleges and schools, and organizations supporting the college and schools, such as the American Association of Colleges of Pharmacy. Therefore, this paper also challenges the academy and its members to optimize assessment practices. PMID- 24052645 TI - Report of the AACP task force on patient-centered medical homes and accountable care organizations. PMID- 24052646 TI - Characteristics of postgraduate year two pharmacy residency programs with a secondary emphasis on academia. AB - OBJECTIVES: To identify and characterize postgraduate year 2 (PGY2) pharmacy residency programs with a secondary emphasis on academia. METHODS: Residency programs were identified using the American College of Clinical Pharmacy (ACCP) online directory of residencies, fellowships, and graduate programs and cross referenced with the American Society of Health-System Pharmacists (ASHP) residency directory. An electronic questionnaire was developed and sent to residency program directors to collect attributes of each program. Data were analyzed using descriptive statistics. RESULTS: Most programs were initiated during the past decade. More than two-thirds were ASHP-accredited and half had a primary specialty in ambulatory care. The average program structure consisted of clinical practice service (50.4%), experiential teaching (18.5%), classroom-based teaching (16.4%), research (10.7%), and service (3.7%). Most residents (90.0%) accepted an academic appointment upon completion of these programs. CONCLUSIONS: Postgraduate year 2 residency programs with an emphasis on academia provide experiences in clinical practice, experiential and classroom teaching, research, and service. These residency programs result in participants obtaining academic positions after graduation. PMID- 24052647 TI - Preceptor perceptions of the importance of experiential guidelines. AB - OBJECTIVES: To assess preceptors' perceptions of the importance of experiential guidelines and identify and compare differences in perceptions. METHODS: Active advanced and introductory pharmacy practice experience preceptors for the University of New Mexico were invited to participate in an anonymous electronic survey regarding the importance of specific tasks and abilities expected in new pharmacist practitioners as outlined in Appendix C of the Accreditation Council for Pharmacy Education (ACPE) Standards and Guidelines. RESULTS: While the majority of preceptors rated most tasks (eg, communication, patient counseling) as very important or important, emerging tasks (eg, health literacy, public health, physical assessment) were not rated as highly by a majority of preceptors. CONCLUSION: The deficiencies identified in the study suggest potential reductions in the transfer of learning from preceptors to experiential students. Preceptor training programs should be structured to raise the perceived level of importance of these tasks. PMID- 24052648 TI - Pharmacoeconomics education in US colleges and schools of pharmacy. AB - OBJECTIVE: To determine the extent of pharmacoeconomics education in US colleges and schools of pharmacy provided to doctor of pharmacy (PharmD) students in 2011. METHODS: E-mails requesting syllabi and information about courses covering pharmacoeconomic topics were sent to all US colleges and schools of pharmacy from which PharmD students had graduated in 2011 (n=103). RESULTS: Of 87 responding pharmacy colleges and schools, 85 provided pharmacoeconomics education in 2011. The number of hours dedicated to pharmacoeconomic-related topics varied from 2 to 60 per year (mean=20). CONCLUSIONS. Pharmacoeconomics education is provided at almost all US colleges and schools of pharmacy; however, variation in the number of teaching hours and topics covered demonstrates a lack of standardization in the PharmD curriculum. Pharmacy administrators and educators should invest more resources and tools to standardize training in this area. PMID- 24052649 TI - Graduating pharmacy students' perspectives on e-professionalism and social media. AB - OBJECTIVE: To determine the use patterns of social media among graduating pharmacy students, characterize students' views and opinions of professionalism on popular social media sites, and compare responses about social media behavior among students seeking different types of employment. METHODS: All graduating pharmacy students (n=516) at Purdue University, The University of Findlay, Butler University, and Midwestern University were invited to complete a survey instrument during the fall semester of 2011. RESULTS: Of 212 (41%) students who responded to the survey, 93% (194/209) had a social media profile. Seventy-four percent (120/162) of participants felt they should edit their social media profiles prior to applying for a job. CONCLUSIONS: Many graduating pharmacy students use social media; however, there appears to be a growing awareness of the importance of presenting a more professional image online as they near graduation and begin seeking employment as pharmacists. PMID- 24052650 TI - Mental health curricula at schools of pharmacy in the United Kingdom and recent graduates' readiness to practice. AB - OBJECTIVE: To assess mental health education in the undergraduate pharmacy curricula in the United Kingdom and gauge how well prepared graduates are to manage mental health patients. METHOD: The authors conducted semi-structured telephone interviews with pharmacy educators and administered an electronic self administered survey instrument to pharmacy graduates. RESULTS: The mental health conditions of depression, schizophrenia, bipolar disorder, and Parkinson disease were taught, in detail, by all schools, but more specialized areas of mental health (eg, personality disorder, autism) were generally not taught. Just 5 of 19 schools attempted to teach the broader social aspects of mental health. A third of the schools provided experiential learning opportunities. Graduates and recently registered pharmacists stated that undergraduate education had prepared them adequately with regard to knowledge on conditions and treatment options, but that they were not as well prepared to talk with mental health patients and deal with practical drug management-related issues. CONCLUSION: The mental health portion of the undergraduate pharmacy curricula in colleges and schools of pharmacy in the United Kingdom is largely theoretical, and pharmacy students have little exposure to mental health patients. Graduates identified an inability to effectively communicate with these patients and manage common drug management related issues. PMID- 24052651 TI - Academic performance and personal experience of local, international, and collaborative exchange students enrolled in an Australian pharmacy program. AB - OBJECTIVE: To assess the academic performance and experiences of local, international, and collaborative exchange students enrolled in a 4-year Australian bachelor of pharmacy degree program. METHODS: Survey instruments exploring the demographics, background, and academic and cultural experiences of students during the program were administered in 2005 to students in all 4 years. Additionally, grades from each semester of the program for students (406 local, 70 international, 155 exchange) who graduated between 2002 and 2006 were analyzed retrospectively. RESULTS: The main differences found in the survey responses among the 3 groups were in students' motivations for choosing the degree program and school, with international and collaborative exchange students having put more thought into these decisions than local students. The average grades over the duration of the program were similar in all 3 demographic groups. However, local students slightly outperformed international students, particularly at the start of the year, whereas collaborative exchange students' grades mirrored those of local students during the 2 years prior to leaving their home country of Malaysia but more closely mirrored those of international students in the final 2 years after arriving on campus in Australia. CONCLUSION: Despite differences in academic backgrounds and culture, international and exchange students can perform well compared to local students in a bachelor of pharmacy program and were actually more satisfied than local students with the overall experience. Studying in a foreign country can negatively influence academic grades to a small extent and this is probably related to adjusting to the new environment. PMID- 24052652 TI - A tool to assess student performance in a Clostridium difficile infection simulation scenario. AB - OBJECTIVE: To develop and validate an evaluation tool to assess student pharmacists' performance in a simulation scenario involving a patient with Clostridium difficile infection (CDI). METHODS: The authors used an expert panel review process to establish content validity of the tool. Four faculty members used the tool to evaluate student pharmacist groups during 2011 and tested a modified version of the tool in 2012. The authors analyzed the results for each year to determine internal consistency and inter-rater reliability. RESULTS: The 2011 tool demonstrated sound internal consistency, but several items had poor inter-rater agreement. The revised 2012 tool demonstrated acceptable internal consistency and good to excellent inter-rater agreement for all items except one. CONCLUSIONS: The tool facilitated reliable assessment of student pharmacists' clinical decision-making during simulation performance involving a patient with CDI. PMID- 24052653 TI - Peer-led team learning in an online course on controversial medication issues and the US healthcare system. AB - OBJECTIVE: To implement peer-led team learning in an online course on controversial issues surrounding medications and the US healthcare system. DESIGN: The course was delivered completely online using a learning management system. Students participated in weekly small-group discussions in online forums, completed 3 reflective writing assignments, and collaborated on a peer-reviewed grant proposal project. ASSESSMENT: In a post-course survey, students reported that the course was challenging but meaningful. Final projects and peer-reviewed assignments demonstrated that primary learning goals for the course were achieved and students were empowered to engage in the healthcare debate. CONCLUSIONS: A peer-led team-learning is an effective strategy for an online course offered to a wide variety of student learners. By shifting some of the learning and grading responsibility to students, the instructor workload for the course was rendered more manageable. PMID- 24052654 TI - Promotion of self-directed learning using virtual patient cases. AB - OBJECTIVE: To assess the effectiveness of virtual patient cases to promote self directed learning (SDL) in a required advanced therapeutics course. DESIGN: Virtual patient software based on a branched-narrative decision-making model was used to create complex patient case simulations to replace lecture-based instruction. Within each simulation, students used SDL principles to learn course objectives, apply their knowledge through clinical recommendations, and assess their progress through patient outcomes and faculty feedback linked to their individual decisions. Group discussions followed each virtual patient case to provide further interpretation, clarification, and clinical perspective. ASSESSMENTS: Students found the simulated patient cases to be organized (90%), enjoyable (82%), intellectually challenging (97%), and valuable to their understanding of course content (91%). Students further indicated that completion of the virtual patient cases prior to class permitted better use of class time (78%) and promoted SDL (84%). When assessment questions regarding material on postoperative nausea and vomiting were compared, no difference in scores were found between the students who attended the lecture on the material in 2011 (control group) and those who completed the virtual patient case on the material in 2012 (intervention group). CONCLUSION: Completion of virtual patient cases, designed to replace lectures and promote SDL, was overwhelmingly supported by students and proved to be as effective as traditional teaching methods. PMID- 24052656 TI - A training program for pharmacy students on providing diabetes care. AB - OBJECTIVE: To compare second- and third-year pharmacy students' competence, attitudes, and self-confidence in providing diabetes care before and after completing a hand-on diabetes training program and to determine if the program had an impact on students' attitude and self-confidence based on their year in the curriculum. DESIGN: The program included classroom lectures and hands-on learning sessions in 5 facets of diabetes care. Pre- and post-test instruments measured students' competence, attitudes, and confidence in diabetes care. ASSESSMENT: Students' competence and the mean overall confidence score significantly improved after completing the program, while mean overall attitude score did not. Third-year students had significantly higher confidence scores than did second-year students on both pre- and post-program tests. No significant difference was found for attitude scores between second- and third-year students. CONCLUSION: The hands-on learning program was an effective approach to training pharmacy students in diabetes care, improving both their competence and confidence. PMID- 24052655 TI - A standardized patient counseling rubric for a pharmaceutical care and communications course. AB - OBJECTIVE: To restructure a required pharmaceutical care and communications course to place greater emphasis on communication skills and include a high stakes assessment. DESIGN: A standardized counseling rubric was developed for use throughout the pharmacy curriculum and the counseling laboratory practicals were changed to high-stakes assessments. ASSESSMENT: An annual mid-semester and end-of semester high-stakes patient-counseling objective structured clinical examination (OSCE) conducted prior to and after revision of the course and counseling rubric documented improvements in students' scores. Performance on the post-course annual assessment patient counseling OSCE improved compared to that on the pre course (p<0.001). CONCLUSION: The 2010 course revision improved students' medication counseling abilities and readiness to practice. Major course revisions should be undertaken only after input from all stakeholders and with data to support the need for change. PMID- 24052657 TI - A 4-week nutrition and therapeutics course in an undergraduate pharmacy program. AB - OBJECTIVE: To determine the effectiveness of an intensive 4-week nutrition course in increasing the knowledge of undergraduate pharmacy students. DESIGN: A Nutrition and Therapeutics elective course was developed that covered the Australian Guide to Healthy Eating, as well as nutrition labeling, food composition, functional foods, diabetes, cardiovascular disease, nutrition and cancer, osteoporosis, nutrient-drug interactions, nutritional supplements, weight management, and infant feeding. The course was taught using lectures, student focused tutorials featuring evidence-based practice, problem-based learning exercises, case-based scenarios, media examples, video clips from the lay press, and articles from the professional/scientific literature. ASSESSMENT: A self administered, validated questionnaire on dietary recommendations, sources of nutrients, choosing everyday foods, and diet-disease relationship was administered prior to and after completion of the course. Students' scores in all 4 areas improved significantly; however, their knowledge of the national dietary recommendations, sources of nutrients, and everyday foods high in nutrients was below that of members of the community. CONCLUSIONS: Nutritional education courses can increase the nutrition knowledge of undergraduate pharmacy students. The need for pharmacists to advise patients regarding nutritional supplements continues to increase the need for incorporating nutrition courses within curriculum. PMID- 24052658 TI - Best practice strategies for effective use of questions as a teaching tool. AB - Questions have long been used as a teaching tool by teachers and preceptors to assess students' knowledge, promote comprehension, and stimulate critical thinking. Well-crafted questions lead to new insights, generate discussion, and promote the comprehensive exploration of subject matter. Poorly constructed questions can stifle learning by creating confusion, intimidating students, and limiting creative thinking. Teachers most often ask lower-order, convergent questions that rely on students' factual recall of prior knowledge rather than asking higher-order, divergent questions that promote deep thinking, requiring students to analyze and evaluate concepts. This review summarizes the taxonomy of questions, provides strategies for formulating effective questions, and explores practical considerations to enhance student engagement and promote critical thinking. These concepts can be applied in the classroom and in experiential learning environments. PMID- 24052659 TI - A novel question-based framework for writing assessment plans to facilitate their understanding and acceptance in pharmacy education. PMID- 24052661 TI - Council of Deans Business Meeting, February 10, 2013, Rio Mar, Puerto Rico. PMID- 24052660 TI - Curricular conundrum: how specialization cripples adaptability. PMID- 24052662 TI - Council of Faculties Business Meeting, February 10, 2013, Rio Grande, Puerto Rico. PMID- 24052663 TI - Report of the Speaker of the House of Delegates. PMID- 24052664 TI - Council of Faculties Business Meeting, July 15, 2013, Chicago, Illinois. PMID- 24052665 TI - Using Markov chain Monte Carlo (MCMC) to visualize and test the linearity assumption of the Bradley-Terry class of models. AB - The construction of dominance hierarchies for animal societies is an important aspect of understanding the nature of social relationships, and the models to calculate dominance ranks are many. However, choosing the appropriate model for a given data set may appear daunting to the average behaviourist, especially when many of these models assume linearity of dominance. Here, we present a method to test whether or not a data set fits the assumption of linearity using the Bradley Terry model as a representative of the class of models that assume linearity. Our method uses the geometry of a posterior distribution of possible rankings given the data by using a random walk on this distribution. This test is intuitive, efficient, particularly for large number of individuals, and represents an improvement over previous linearity tests because it takes into account all information (i.e. both linear and apparently circular or nonlinear information) from the data with few restrictions due to high dimensionality. Such a test is not only useful in determining whether a linear hierarchy is relevant to a given animal society, but is necessary in justifying the results of any analysis for which the assumption of linearity is made, such as the Bradley-Terry model. If the assumption of linearity is not met, other methods for ranking, such as the beta random field method proposed by Fushing et al. (2011, PLoS One, 6, e17817) should be considered. PMID- 24052666 TI - URBANIZATION, EDUCATION AND RACIAL INTERMARRIAGE IN BRAZIL. AB - Urbanization and education have brought numerous changes in societies around the world. One change is the contact of different groups, often with an attendant increase in intergroup marriage. In this paper we examine the intergroup intermarriage in Brazil in the context of changing urbanization and education. While intergroup marriage has been intensively examined in the United States, the topic has received less attention in Brazil. We use census data from 1991 and 2000, and national survey data from 2001 and 2008 to examine factors predicting intergroup marriage and the trends in intergroup marriage in Brazil. The results show higher rates of intermarriage in urban than in rural areas. Intermarriage is less common among the most educated people. While the rates of intermarriage are increasing substantially, the rates of change are diffuse across urban and rural areas, regions and education groups. PMID- 24052667 TI - Electrical Current Signatures of DNA Base Modifications in Single Molecules Immobilized in the alpha-Hemolysin Ion Channel. AB - Nanopore technology holds high potential for next-generation DNA sequencing. This method operates by drawing an individual single-stranded DNA molecule through a nanoscale pore while monitoring the current deflections that occur as the DNA passes through. Individual current levels for the four DNA nucleotides have been established by immobilization of an end biotinylated strand in the pore in which the nucleotide of interest is suspended at the most sensitive region of the ion channel. Due to the inherent reactivity of the DNA bases, many modified nucleotides in the genome exist resulting from oxidative and UV insults, among others. Herein, the current levels for the common DNA damages 8-oxo-7,8 dihydroguanine (OG), spiroiminodihydantoin (Sp), guanidinohydantoin (Gh), uridine (U), abasic sites (AP), thymine dimers (T=T), thymine glycol (Tg) and 5 iodocytosine (5-I-C) were assessed via immobilization experiments. In some cases, the current difference between the damaged and canonical nucleotides was not well resolved; therefore, we took advantage of the chemical reactivity of the new functional groups present to make amine adducts that shifted the current levels outside the range of the native nucleotides. Among adducts studied, only the 2 aminomethyl-18-crown-6 adduct was able to give a large current shift in the immobilization experiment, as well as to be observed in a translocation experiment. The results show potential in providing current level modulators for identification of some types of DNA damage. In principle, any DNA base modification that can be converted chemically or enzymatically to an abasic site could be identified in this way. PMID- 24052669 TI - Synthesis and characterization of a compact tricyclic resorcinol from (+)- and ( )-3-pinanol. AB - Resorcinol derivatives are important building blocks in the synthesis of natural products and pharmaceutical compounds including cannabinoids. Here we describe the synthesis and the structural characterization of a key resorcinol which carries a fully restricted bridged bicyclic group. We also report a potential mechanism for the acid catalyzed condensation of (+)- or (-)-3-pinanol with 2,6 dimethoxyphenol. The synthesized resorcinol facilitates the development of novel conformationally restricted cannabinoid analogs. PMID- 24052668 TI - Facile Access to Ring-Fused Aminals via Direct alpha-Amination of Secondary Amines with ortho-Aminobenzaldehydes. Synthesis of Vasicine, Deoxyvasicine, Deoxyvasicinone, Mackinazolinone and Ruteacarpine. AB - Secondary amines undergo redox-neutral reactions with aminobenzaldehydes under conventional and microwave heating to furnish polycyclic aminals via amine alpha amination/N-alkylation. This unique alpha-functionalization reaction proceeds without the involvement of transition metals or other additives. The resulting aminal products are precursors for various quinazolinone alkaloids and their analogues. PMID- 24052671 TI - Why are we failing to promote physical activity globally? PMID- 24052672 TI - Independent drug bulletins to promote the prescription of appropriate drugs: a necessary but difficult task. PMID- 24052673 TI - Brazil meeting on HIV treatment access. PMID- 24052674 TI - Syrians flee violence and disrupted health services to Jordan. AB - Half a million Syrian refugees are sheltering in Jordan. Dale Gavlak reports on how United Nations agencies are helping the government respond to their needs, especially those of mothers and young children. PMID- 24052675 TI - Lessons from Fukushima: scientists need to communicate better. AB - Roy Shore was the co-chair of a scientific panel that compiled the WHO Health risk assessment from the nuclear accident after the 2011 great East Japan earthquake and tsunami released in February. He talks to Fiona Fleck about the challenges of producing valid science in a highly charged environment. PMID- 24052676 TI - Breastfeeding policy: a globally comparative analysis. AB - OBJECTIVE: To explore the extent to which national policies guaranteeing breastfeeding breaks to working women may facilitate breastfeeding. METHODS: An analysis was conducted of the number of countries that guarantee breastfeeding breaks, the daily number of hours guaranteed, and the duration of guarantees. To obtain current, detailed information on national policies, original legislation as well as secondary sources on 182 of the 193 Member States of the United Nations were examined. Regression analyses were conducted to test the association between national policy and rates of exclusive breastfeeding while controlling for national income level, level of urbanization, female percentage of the labour force and female literacy rate. FINDINGS: Breastfeeding breaks with pay are guaranteed in 130 countries (71%) and unpaid breaks are guaranteed in seven (4%). No policy on breastfeeding breaks exists in 45 countries (25%). In multivariate models, the guarantee of paid breastfeeding breaks for at least 6 months was associated with an increase of 8.86 percentage points in the rate of exclusive breastfeeding (P < 0.05). CONCLUSION: A greater percentage of women practise exclusive breastfeeding in countries where laws guarantee breastfeeding breaks at work. If these findings are confirmed in longitudinal studies, health outcomes could be improved by passing legislation on breastfeeding breaks in countries that do not yet ensure the right to breastfeed. PMID- 24052677 TI - Public sector services for the prevention of mother-to-child transmission of HIV infection: a micro-costing survey in Namibia and Rwanda. AB - OBJECTIVE: To assess the costs associated with the provision of services for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus in two African countries. METHODS: In 2009, the costs to health-care providers of providing comprehensive PMTCT services were assessed in 20 public health facilities in Namibia and Rwanda. Information on prices and on the total amount of each service provided was collected at the national level. The costs of maternal testing and counselling, male partner testing, CD4+ T-lymphocyte (CD4+ cell) counts, antiretroviral prophylaxis and treatment, community-based activities, contraception for 2 years postpartum and early infant diagnosis were estimated in United States dollars (US$). FINDINGS: The estimated costs to the providers of PMTCT, for each mother-infant pair, were US$202.75-1029.55 in Namibia and US$94.14-342.35 in Rwanda. These costs varied with the drug regimen employed. At 2009 coverage levels, the maximal estimates of the national costs of PMTCT were US$3.15 million in Namibia and US$7.04 million in Rwanda (or < US$0.75 per capita in both countries). Adult testing and counselling accounted for the highest proportions of the national costs (37% and 74% in Namibia and Rwanda, respectively), followed by management and supervision. Treatment and prophylaxis accounted for less than 20% of the costs of PMTCT in both study countries. CONCLUSION: The costs involved in the PMTCT of HIV varied widely between study countries and in accordance with the protocols used. However, since per-capita costs were relatively low, the scaling up of PMTCT services in Namibia and Rwanda should be possible. PMID- 24052678 TI - Use of data from registered clinical trials to identify gaps in health research and development. AB - OBJECTIVE: To explore what can be learnt about the current composition of the "global landscape" of health research and development (R&D) from data on the World Health Organization's International Clinical Trials Registry Platform (ICTRP). METHODS: A random 5% sample of the records of clinical trials that were registered as interventional and actively recruiting was taken from the ICTRP database. FINDINGS: Overall, 2381 records of trials were investigated. Analysis of these records indicated that, for every million disability-adjusted life years (DALYs) caused by communicable, maternal, perinatal and nutritional conditions, by noncommunicable diseases, or by injuries, the ICTRP database contained an estimated 7.4, 52.4 and 6.0 trials in which these causes of burden of disease were being investigated, respectively. For every million DALYs in high-income, upper-middle-income, lower-middle-income and low-income countries, an estimated 292.7, 13.4, 3.0 and 0.8 registered trials, respectively, were recruiting in such countries. CONCLUSION: The ICTRP constitutes a valuable resource for assessing the global distribution of clinical trials and for informing policy development for health R&D. Populations in lower-income countries receive much less attention, in terms of clinical trial research, than populations in higher-income countries. PMID- 24052679 TI - Improved neonatal survival after participatory learning and action with women's groups: a prospective study in rural eastern India. AB - OBJECTIVE: To determine whether a women's group intervention involving participatory learning and action has a sustainable and replicable effect on neonatal survival in rural, eastern India. METHODS: From 2004 to 2011, births and neonatal deaths in 36 geographical clusters in Jharkhand and Odisha were monitored. Between 2005 and 2008, these clusters were part of a randomized controlled trial of how women's group meetings involving participatory learning and action influence maternal and neonatal health. Between 2008 and 2011, groups in the original intervention clusters (zone 1) continued to meet to discuss post neonatal issues and new groups in the original control clusters (zone 2) met to discuss neonatal health. Logistic regression was used to examine neonatal mortality rates after 2008 in the two zones. FINDINGS: Data on 41,191 births were analysed. In zone 1, the intervention's effect was sustained: the cluster-mean neonatal mortality rate was 34.2 per 1000 live births (95% confidence interval, CI: 28.3-40.0) between 2008 and 2011, compared with 41.3 per 1000 live births (95% CI: 35.4-47.1) between 2005 and 2008. The effect of the intervention was replicated in zone 2: the cluster-mean neonatal mortality rate decreased from 61.8 to 40.5 per 1000 live births between two periods: 2006-2008 and 2009-2011 (odds ratio: 0.69, 95% CI: 0.57-0.83). Hygiene during delivery, thermal care of the neonate and exclusive breastfeeding were important factors. CONCLUSION: The effect of participatory women's groups on neonatal survival in rural India, where neonatal mortality is high, was sustainable and replicable. PMID- 24052680 TI - The cost of type 1 diabetes: a nationwide multicentre study in Brazil. AB - OBJECTIVE: To determine the direct medical costs of type 1 diabetes mellitus (T1DM) to the National Brazilian Health-Care System (NBHCS) and quantify the contribution of each individual component to the total cost. METHODS: A retrospective, cross-sectional, nationwide multicentre study was conducted between 2008 and 2010 in 28 public clinics in 20 Brazilian cities. The study included 3180 patients with T1DM (mean age 22 years +/- 11.8) who were surveyed while receiving health care from the NBHCS. The mean duration of their diabetes was 10.3 years (+/- 8.0). The costs of tests and medical procedures, insulin pumps, and supplies for administration, and supplies for self-monitoring of blood glucose (SMBG) were obtained from national and local health system sources for 2010-2011. Annual direct medical costs were derived by adding the costs of medications, supplies, tests, medical consultations, procedures and hospitalizations over the year preceding the interview. FINDINGS: The average annual direct medical cost per capita was 1319.15 United States dollars (US$). Treatment-related expenditure - US$ 1216.33 per patient per year - represented 92.20% of total direct medical costs. Insulin administration supplies and SMBG (US$ 696.78 per patient per year) accounted for 52.82% of these total costs. Together, medical procedures and haemodialysis accounted for 5.73% (US$ 75.64 per patient per year) of direct medical costs. Consultations accounted for 1.94% of direct medical costs (US$ 25.62 per patient per year). CONCLUSION: Health technologies accounted for most direct medical costs of T1DM. These data can serve to reassess the distribution of resources for managing T1DM in Brazil's public health-care system. PMID- 24052681 TI - External quality assessment of Giemsa-stained blood film microscopy for the diagnosis of malaria and sleeping sickness in the Democratic Republic of the Congo. AB - OBJECTIVE: To report the findings of a second external quality assessment of Giemsa-stained blood film microscopy in the Democratic Republic of the Congo, performed one year after the first. METHODS: A panel of four slides was delivered to diagnostic laboratories in all provinces of the country. The slides contained: (i) Plasmodium falciparum gametocytes; (ii) P. falciparum trophozoites (reference density: 113,530 per ul); (iii) Trypanosoma brucei subspecies; and (iv) no parasites. FINDINGS: Of 356 laboratories contacted, 277 (77.8%) responded. Overall, 35.0% of the laboratories reported all four slides correctly but 14.1% reported correct results for 1 or 0 slides. Major errors included not diagnosing trypanosomiasis (50.4%), not recognizing P. falciparum gametocytes (17.5%) and diagnosing malaria from the slide with no parasites (19.0%). The frequency of serious errors in assessing parasite density and in reporting false-positive results was lower than in the previous external quality assessment: 17.2% and 52.3%, respectively, (P < 0.001) for parasite density and 19.0% and 33.3%, respectively, (P < 0.001) for false-positive results. Laboratories that participated in the previous quality assessment performed better than first-time participants and laboratories in provinces with a high number of sleeping sickness cases recognized trypanosomes more frequently (57.0% versus 31.2%, P < 0.001). Malaria rapid diagnostic tests were used by 44.3% of laboratories, almost double the proportion observed in the previous quality assessment. CONCLUSION: The overall quality of blood film microscopy was poor but was improved by participation in external quality assessments. The failure to recognize trypanosomes in a country where sleeping sickness is endemic is a concern. PMID- 24052682 TI - Self-reported illness and household strategies for coping with health-care payments in Bangladesh. AB - OBJECTIVE: To investigate self-reported illness and household strategies for coping with payments for health care in a city in Bangladesh. METHODS: A cluster sampled probability survey of 1593 households in the city of Rajshahi, Bangladesh, was conducted in 2011. Multilevel logistic regression - with adjustment for any clustering within households - was used to examine the risk of self-reported illness in the previous 30 days. A multilevel Poisson regression model, with adjustment for clustering within households and individuals, was used to explore factors potentially associated with the risk of health-care-related "distress" financing (e.g. paying for health care by borrowing, selling, reducing food expenditure, removing children from school or performing additional paid work). FINDINGS: According to the interviewees, about 45% of the surveyed individuals had suffered at least one episode of illness in the previous 30 days. The most frequently reported illnesses among children younger than 5 years and adults were common tropical infections and noncommunicable diseases, respectively. The risks of self-reported illness in the previous 30 days were relatively high for adults older than 44 years, women and members of households in the poorest quintile. Distress financing, which had been implemented to cover health-care payments associated with 13% of the reported episodes, was significantly associated with heart and liver disease, asthma, typhoid, inpatient care, the use of public outpatient facilities, and poverty at the household level. CONCLUSION: Despite the subsidization of public health services in Bangladesh, high prevalences of distress financing - and illness - were detected in the surveyed, urban households. PMID- 24052683 TI - Birth registration and access to health care: an assessment of Ghana's campaign success. AB - PROBLEM: Birth registration remains far from complete in many developing countries. This was true of Ghana before a major registration campaign was undertaken. APPROACH: This study, based on survey data, assesses the results of a registration campaign initiated in 2004-2005 in Ghana. Key strategies included: extending the legal period for free registration of infants; incorporating registration in child health promotion weeks; training community health workers to register births; using community registration volunteers; registering children during celebrations, and piloting community population registers. This paper discusses the contribution of these strategies to the increase in registration rates and shows the degree of association between birth registration and various health-care access indicators and family characteristics. LOCAL SETTING: The Ghana Births and Deaths Registry worked together with international organizations, mainly Plan International and the United Nations Children's Fund, to implement the birth registration campaign. RELEVANT CHANGES: Unlike many other sub-Saharan African countries, Ghana saw a substantial rise in registration rates over the campaign period. Campaign strategies improved accessibility and shortened distance to registration centres. Survey data show that the registration rate for children younger than 5 years rose from 44% in 2003 to 71% in 2008. LESSONS LEARNT: Incorporation of birth registration into community health care, health campaigns and mobile registration activities can reduce the indirect costs of birth registration, especially in poorer communities, and yield substantial increases in registration rates. The link between the health sector and registration activities should be strengthened further and the use of community population registers expanded. PMID- 24052684 TI - Perception of Eligible Black Men as a Context for HIV Risk Behavior Among Black Women. AB - African American women are leading in number of newly diagnosed HIV cases, which is a cause for alarm and has a deleterious impact on families and communities. Research suggests the gender-ratio imbalance as a contextual factor leading to increases in high risk sexual behavior and subsequent increases in the rates of HIV infection among African American women. The current study examines correlates of consistent condom use among 213 single, heterosexual, African American women in the community, on probation, and incarcerated who believe it is difficult to find an eligible Black man. Results of this study reveal that drug using women and incarcerated women were less likely to use condoms consistently. In addition, after controlling for drug use and criminal justice status, age emerged as significant. Specifically, older African American women were less likely to use condoms consistently. Community level implications and targeted prevention efforts are discussed. PMID- 24052685 TI - Statistical Methods for Estimation of Direct and Differential Kinematics of the Vocal Tract. AB - We present and evaluate two statistical methods for estimating kinematic relationships of the speech production system: Artificial Neural Networks and Locally-Weighted Regression. The work is motivated by the need to characterize this motor system, with particular focus on estimating differential aspects of kinematics. Kinematic analysis will facilitate progress in a variety of areas, including the nature of speech production goals, articulatory redundancy and, relatedly, acoustic-to-articulatory inversion. Statistical methods must be used to estimate these relationships from data since they are infeasible to express in closed form. Statistical models are optimized and evaluated - using a heldout data validation procedure - on two sets of synthetic speech data. The theoretical and practical advantages of both methods are also discussed. It is shown that both direct and differential kinematics can be estimated with high accuracy, even for complex, nonlinear relationships. Locally-Weighted Regression displays the best overall performance, which may be due to practical advantages in its training procedure. Moreover, accurate estimation can be achieved using only a modest amount of training data, as judged by convergence of performance. The algorithms are also applied to real-time MRI data, and the results are generally consistent with those obtained from synthetic data. PMID- 24052686 TI - Locomotor performance of sand lizards (Lacerta agilis): effects of predatory pressure and parasite load. AB - Locomotor performance affects foraging efficiency, predator avoidance and consequently fitness. Agility and speed determine the animal's social status and reflect its condition. In this study, we test how predatory pressure and parasite load influences locomotor performance of wild specimens of the sand lizard Lacerta agilis. Animals were chased on a 2-metre racetrack. Lizards with autotomy ran significantly faster than lizards with an intact tail, but there was no significant difference in running speed between individuals with fresh caudal autotomy and regenerated tails. Parasite presence and load, age and sex had no significant effect on speed. Our results indicate that autotomy either alters locomotory behaviour or that individuals with autotomised tails were those that previously survived contact with predators, and therefore represented a subgroup of the fastest individuals. Therefore, in general, predatory pressure but not parasites affected locomotor performance in lizards. PMID- 24052687 TI - Legitimating Racial Discrimination: Emotions, Not Beliefs, Best Predict Discrimination in a Meta-Analysis. AB - Investigations of racial bias have emphasized stereotypes and other beliefs as central explanatory mechanisms and as legitimating discrimination. In recent theory and research, emotional prejudices have emerged as another, more direct predictor of discrimination. A new comprehensive meta-analysis of 57 racial attitude-discrimination studies finds a moderate relationship between overall attitudes and discrimination. Emotional prejudices are twices as closely related to racial discrimination as stereotypes and beliefs are. Moreover, emotional prejudices are closely related to both observed and self-reported discrimination, whereas stereotypes and beliefs are related only to self-reported discrimination. Implications for justifying discrimination are discussed. PMID- 24052688 TI - Polychlorinated biphenyls increase apoptosis in the developing rat brain. AB - While both epidemiological and experimental animal studies have demonstrated that perinatal exposure to polychlorinated biphenyls (PCBs) negatively impacts cognitive and psychomotor function, there remains considerable uncertainty regarding mechanisms by which PCBs cause these functional deficits. In vitro studies have shown that PCBs can trigger apoptosis in cultured neurons and suggest this effect is mediated in part by increased levels of reactive oxygen species (ROS). However, whether PCBs cause similar effects in vivo in the developing brain has yet to be reported. In this study, rat pups were exposed to the commercial PCB mixture Aroclor 1254 (A1254) at 0.1 or 1.0 mg/kg/d in the maternal diet throughout gestation and lactation. Apoptosis and oxidative damage were quantified in three brain regions within several days after birth and at weaning. Caspase-3 activity was significantly increased in the cortex, hippocampus and cerebellum of newborn but not weanling rats exposed to A1254 at 1.0 mg/kg/d in the maternal diet. The most prominent effect was observed in the cerebellum, and PCB-induced apoptosis in this brain region was confirmed by TUNEL. Western blotting revealed that developmental A1254 exposure also increased levels of 3-nitrotyrosine and 4-hydroxynonenal levels in the cerebellum of new born rats, indicating increased oxidative damage of proteins and lipids, respectively. These findings provide the first in vivo data in support of the hypothesis that PCB-induced oxidative stress alters spatiotemporal profiles of apoptosis, and suggest that this is an important mechanism contributing to the developmental neurotoxicity of PCBs. PMID- 24052689 TI - Method for Shipping Live Cultures of Dissociated Rat Hippocampal Neurons. AB - Primary neuronal cell culture is a powerful research tool for studies of cellular and molecular neurobiology, and the development of methods for manipulating DNA expression has provided new opportunities to exploit these in vitro models for mechanistic studies. However, because of the specialized equipment and training required to set up primary neuronal cell cultures of consistently high quality, and the need for multiple cultures to optimize transfection parameters for different experimental applications, this model system is often not practical for non-routine use. One solution is to collaborate with a laboratory that routinely cultures primary neurons, but currently this is not feasible if the collaborating laboratories are distant from each other. We describe a method that allows laboratories with the requisite tissue culture expertise to ship live primary cultures of transfected neuronal cells for subsequent experimentation in the receiving laboratory. PMID- 24052691 TI - Combining an expert-based medical entity recognizer to a machine-learning system: methods and a case study. AB - Medical entity recognition is currently generally performed by data-driven methods based on supervised machine learning. Expert-based systems, where linguistic and domain expertise are directly provided to the system are often combined with data-driven systems. We present here a case study where an existing expert-based medical entity recognition system, Ogmios, is combined with a data driven system, Caramba, based on a linear-chain Conditional Random Field (CRF) classifier. Our case study specifically highlights the risk of overfitting incurred by an expert-based system. We observe that it prevents the combination of the 2 systems from obtaining improvements in precision, recall, or F-measure, and analyze the underlying mechanisms through a post-hoc feature-level analysis. Wrapping the expert-based system alone as attributes input to a CRF classifier does boost its F-measure from 0.603 to 0.710, bringing it on par with the data driven system. The generalization of this method remains to be further investigated. PMID- 24052690 TI - Clickable Poly(ethylene glycol)-Microsphere-Based Cell Scaffolds. AB - Clickable poly(ethylene glycol) (PEG) derivatives are used with two sequential aqueous two-phase systems to produce microsphere-based scaffolds for cell encapsulation. In the first step, sodium sulfate causes phase separation of the clickable PEG precursors and is followed by rapid geleation to form microspheres in the absence of organic solvent or surfactant. The microspheres are washed and then deswollen in dextran solutions in the presence of cells, producing tightly packed scaffolds that can be easily handled while also maintaining porosity. Endothelial cells included during microsphere scaffold formation show high viability. The clickable PEG-microsphere-based cell scaffolds open up new avenues for manipulating scaffold architecture as compared with simple bulk hydrogels. PMID- 24052692 TI - Fate of pathologically bound oxygen resulting from inhalation of labeled ozone in rats. AB - Inhaled ozone (O3) reacts chemically with respiratory tract biomolecules where it forms covalently bound oxygen adducts. We investigated the fate of these adducts following inhalation exposure of rats to labeled ozone ((18)O3, 2 ppm, 6 hr or 5 ppm, 2 hr). Increased (18)O was detected in blood plasma at 7 hr post exposure and was continuously present in urine for 4 days. Total (18)O excreted was ~53% of the estimated amount of (18)O3 retained by the rats during (18)O3 exposure suggesting that only moderate recycling of the adduct material occurs. The time course of excretion, as well as properties of the excreted (18)O were determined to provide guidance to future searches for urinary oxidative stress markers. These results lend plausibility to published findings that O3 inhalation could exert influences outside the lung, such as enhancement of atherosclerotic plaques. PMID- 24052693 TI - Immunotherapy of melanoma with the immune costimulatory monoclonal antibodies targeting CD137. AB - Knowledge of how the immune system recognizes and attempts to control cancer growth and development has improved dramatically. The advent of immunotherapies for cancer has resulted in robust clinical responses and confirmed that the immune system can significantly inhibit tumor progression. Until recently, metastatic melanoma was a disease with limited treatment options and a poor prognosis. CD137 (also known as 4-1BB) a member of the tumor necrosis factor (TNF) receptor superfamily, is an activation-induced T cell costimulator molecule. Growing evidence indicates that anti-CD137 monoclonal antibodies possess strong antitumor properties, the result of their powerful capability to activate CD8+ T cells, to produce interferon (IFN)-gamma, and to induce cytolytic markers. Combination therapy of anti-CD137 with other anticancer agents, such as radiation, has robust tumor-regressing abilities against nonimmunogenic or poorly immunogenic tumors. Of importance, targeting CD137 eliminates established tumors, and the fact that anti-CD137 therapy acts in concert with other anticancer agents and/or radiation therapy to eradicate nonimmunogenic and weakly immunogenic tumors is an additional benefit. Currently, BMS-663513, a humanized anti-CD137 antibody, is in clinical trials in patients with solid tumors, including melanoma, renal carcinoma, ovarian cancer, and B-cell malignancies. In this review, we discuss the basis of the therapeutic potential of targeting CD137 in cancer treatment, focusing in particular, on BMS-663513 as an immune costimulatory monoclonal antibody for melanoma immunotherapy. PMID- 24052694 TI - Correlation of Stroke Volume Measurement between Sonosite Portable Echocardiogram and Edwards Flotrac Sensor-Vigileo Monitor in an Intensive Care Unit. AB - PURPOSE: Stroke volume (SV) is a parameter that is being recognized as an endpoint in fluid resuscitation algorithms. Its role is now being realized as an important variable in hemodynamic assessment in various clinical scenarios such as septic and cardiogenic shocks. Direct measurement of stroke volume (SV) and its novel corollary, stroke volume variation (SVV) derived by proprietary software, are preferred over mean cardiac output (CO) measurements because they render a more accurate reflection of hemodynamic status independent of heart rate. Flotrac-Vigileo monitor (FTV) (Edwards Lifesciences, Irvine, CA, USA) is a system that uses a complex algorithm analyzing arterial waveform to calculate SV, SVV, and CO. We assessed the feasibility of obtaining SV measurements with a portable echocardiogram and validated its accuracy with the FTV system in mechanically ventilated patients in our intensive care unit (ICU). Furthermore, we emphasized the importance of hemodynamic measurements and familiarity with critical care echocardiography for the intensivists. METHODS: Ten patients who were on mechanical ventilation were studied. A femoral arterial line was connected to the FTV system monitoring SV and CO. A portable echocardiogram (M Turbo; Sonosite, Bothell, WA) was used to measure SV. CO was calculated by multiplying SV by heart rate. No patient had arrhythmia. We used biplane Simpson's method of discs to calculate SV in which subtraction of end-systolic volume from end-diastolic volume yields the SV. RESULTS: The comparison of simultaneous SV and CO measurements by echocardiography with FTV showed a strong correlation between the 2. (For SV, y = 0.9545x + 3.3, R (2) = 0.98 and for CO, y = 0.9104x + 7.7074, R (2) = 0.97). CONCLUSIONS: In our small cohort, the SV and CO measured by a portable echocardiogram (Sonosite M-Turbo) appears to be closely correlated with their respective values measured by FTV. Portable echocardiography is a reliable noninvasive tool for the hemodynamic assessment of the critically ill. Its results need further validation with gold standard measures in a larger cohort of patients. However, our results suggest portable echocardiography could be an attractive tool in assessment of different hemodynamic scenarios in the critically ill. PMID- 24052695 TI - Do obese children perceive submaximal and maximal exertion differently? AB - We examined how obese children perceive a maximal cardiorespiratory fitness test compared with a submaximal cardiorespiratory fitness test. Twenty-one obese children (body mass index >=95th percentile, ages 10-17 years) completed maximal and submaximal cardiorespiratory fitness tests on 2 separate occasions. Oxygen consumption (VO2) and overall perceived exertion (Borg 15-category scale) were measured in both fitness tests. At comparable workloads, perceived exertion was rated significantly higher (P < 0.001) in the submaximal cardiorespiratory fitness test compared with the maximal cardiorespiratory fitness test. The submaximal cardiorespiratory fitness test was significantly longer than the maximal test (14:21 +/- 04:04 seconds vs. 12:48 +/- 03:27 seconds, P < 0.001). Our data indicate that at the same relative intensity, obese children report comparable or even higher perceived exertion during submaximal fitness testing than during maximal fitness testing. Perceived exertion in a sample of children and youth with obesity may be influenced by test duration and protocol design. PMID- 24052696 TI - Interleukin-18 Promoter Gene Polymorphisms are not Associated with Myocardial Infarction in Type 2 Diabetes in Slovenia. AB - Type 2 diabetes is a major risk factor for myocardial infarction (MI) and chronic inflammation may play a central role in both diseases. Interleukin (IL)-18 is a potent proinflammatory cytokine, which is considered important in acute coronary syndromes and type 2 diabetes. We investigated the association of the -137 (G>C), polymorphism (rs187238) and the -607 (C>A) polymorphism (rs1946518) of the IL-18 gene promoter region in 495 Caucasians with type 2 diabetes, of whom 169 had MI and 326 subjects had no clinically evident coronary artery disease (controls). We also investigated the impact of these polymorphisms on the serum IL-18 level in subsets of both groups and in a normal group. Genotype distributions of the polymorphisms showed no significant difference between cases and controls. However, IL-18 serum levels were significantly lower in diabetics with the 137 CC genotype than in those with other genotypes (241.5 +/- 132.7 ng/L vs. 340.2 +/- 167.4 ng/L; p <0.05). High sensitivity C-reactive protein and IL-18 serum levels were higher in diabetics in the MI group than in the control group. We conclude that these IL-18 promoter gene polymorphisms are not risk factors for MI in Caucasians with type 2 diabetes. PMID- 24052697 TI - Individual phenotype trait variability as genetic markers of gender susceptibility to spina bifida. AB - We compared individual trait variability in 65 male and 81 female patients with spina bifida occulta (SBO) or spina bifida aperta (SBA) against 170 male and 200 female subjects randomly selected Serbian subjects without these conditions. Variability was evaluated by direct observation of 15 homozygous recessive traits (HRT), while gender was evaluated separately. Individual trait variations between genders in SBO patients (4/15 HRT) and in SBA patients (12/15 HRT) showed remarkable differences. Individual trait variations between the male control group and SBO (9/15 HRT), between the female control group and SBO (5/15 HRT), between the male control group and SBA (8/15 HRT), between the female control group and SBA (9/15 HRT), between male SBO and SBA patients (6/15 HRT), between female SBO and SBA patients (6/15 HRT), also indicated remarkable differences. These differences could be explained by different expression of genes that may contribute to expression of spina bifida (SB). PMID- 24052698 TI - Detection of the GJB2 Mutation in Iranian Children with Hearing Loss Treated with Cochlear Implantation. AB - The 35delG mutation in the gap junction protein, beta2, 26kDa (GJB2) gene is the most common mutation that has been found in children with non syndromic hearing loss. Testing for the GJB2 gene mutation is simple and can directly answer the concerns of the parents about cause of the disorder and prognosis for their children. Cochlear implantation (CI) is one of the methods of hearing rehabilitation in patients with complete hearing loss. The present study was designed for genetic assessment of children who were referred for CI. Connexin 26 (Cx26) gene analyses were performed on 42 children with non syndromic hearing loss who were referred to the Baqiyatallah Hospital, Tehran, Iran for genetic consultation and CI. Clinical history was obtained and an examination conducted on each individual. Genomic DNA was extracted from peripheral blood and mutation identification of the Cx26 gene was performed by polymerase chain reaction (PCR) amplification and direct sequencing of the coding sequence of the gene. Cochlear implantation was performed for all patients and treatment response was assessed for all of them based on speech intelligibility rating (SIR) before and after CI. We found six patients (14.3%) with the 35delG mutation on the Cx26 gene, two homozygotes and four heterozygotes. No other mutation was detected. Treatment response in children with the homozygous 35delG mutation was better than in heterozygous patients, and treatment response in children with the mutation was better than in children with no mutation. Mutation screening for finding deafness causing mutations in the GJB2 gene is a useful predictor of post-implantation speech perception. We suggest microarray or other advanced mutation detection methods for assessment of other genes that might be responsible for non syndromic deafness. PMID- 24052699 TI - RLIP76 Gene Variants are not Associated with Drug Response in Turkish Epilepsy Patients. AB - Approximately 30% of epileptic patients remain untreated, in spite of trials with maximum tolerable doses of more than one drug. The RalA binding protein 1 (RALBP1/RLIP76), a multifunctional, anti-apoptot-ic, multidrug transporter protein, has been proposed as being responsible for the drug resistance mechanism in epilepsy. We have investigated polymorphic differences in the coding regions and exonintron boundaries of the RLIP76 gene, between 146 refractory and 155 non refractory epileptic patients in Turkey, using denaturing high performance liquid chromatography (HPLC) and sequencing analysis techniques. We have detected the following sequence variants: c.160-4G>A, c.187C>G, c.1562-38G>A, c.1670+107G>A, c.1670+93G>A, c.1670+96G>A, c.1670+100C>T, c.1670+130C>T, c.1670+131G>C, c.1670+140 G>C, and found no statistically significant correlation between allele frequencies and drug response status. We conclude that sequence variants of this gene are not involved in drug resistance in epilepsy. PMID- 24052700 TI - Polymorphisms of HPC2/ELAC2 and SRD5A2 (5alpha-Reductase Type II) Genes in Prostate Cancer. AB - Prostate cancer is the proliferation of malignant cells in the prostate gland. The HPC2/ELAC2 gene on chromosome 17p11.2 and SRD5A2 gene on chromosome 2p22-23 are predisposing genetic factors. We examined the relationship between Ser217Leu and Ala541Thr polymorphisms of the former gene, and Ala49Thr and Val89Leu polymorphisms of the latter gene to prostate cancer in Turkish men, using the polymerase chain reaction (PCR) method and appropriate restriction enzymes. The HPC2/ELAC2 gene Ser217-Leu and SRD5A2 gene Ala49Thr polymorphisms were associated with an increased risk of prostate cancer in Turkish men [for the HPC2/ELAC2 gene Ser217Leu polymorphism: odds ratio (OR) 2.7; confidence interval 95% (CI 95%) 1.6 4.8; p 0.000<0.05, and for the SRD5A2 gene Ala49Thr polymorphism: OR 2.4; CI 95% 1.2-4.9; p 0.004<0.05]. PMID- 24052701 TI - Aplasia ras homologous member I gene and development of glial tumors. AB - The ARHI (aplasia Ras homologue member I, also known as DIRAS3) gene shows 60.0% sequence homology to the Ras proto-oncogene and was the first mater-nally imprinted tumor suppressor gene identified in the Ras family. It is constitutively expressed from the paternal allele in normal breast, ovary, heart, liver, pancreas, thyroid and brain tissues, and is lost or markedly down regulated primarily in breast, ovarian, pancreas and thyroid tumor tissues. We have investigated the expression, LOH (loss of heterozygosity) and methylation status of this gene in glial tumors and peripheral blood samples of 21 patients, and in seven normal brain tissue samples. Gene expression by real time reverse transcriptase polymerase chain reaction (RT-PCR) was found to be increased in 14 and decreased in seven of the 21 tumors. The LOH was detected by fragment analysis, using five labeled polymorphic markers specific for the 1p31 region, in two of the tumors. Methylation status of the CpG island I, II and III was evaluated using COBRA (combined bisulfite restriction analysis) and RFLP (restriction fragment length polymorphism) in 21 tumors and also a hypermethylated healthy volunteer as a positive control, revealed that only two tumors had hypermethylation in CpG island I (of which one also had LOH). These results suggest that LOH and hypermethylation may be one mechanism of silencing the ARHI gene expression and development of glial tumor development. PMID- 24052702 TI - Molecular Genetic Characterization of beta-Thalassemia and Sickle Cell Syndrome in the Albanian Population. AB - beta-Thalassemia (beta-thal) is a major public health problem in Albania as it is in many Mediterranean countries. We determined the different beta-thal alleles that are present in the Albanian population by using the temporal temperature gradient electrophoresis (TTGE) method because of its high throughput, cost effectiveness, sensitivity and simplicity. DNA from blood of 68 patients with beta-thal, 26 with sickle cell anemia or sickle cell beta-thal, 54 parents of these patients and 14 heterozygotes related to these families. We found the IVS-I 110 (G>A), codon 39 (C>T), IVS-I-6 (T>C), IVS-I-1 (G>A) and codon 44 (-C) mutations that accounted for nearly 90% of the beta-thal alleles. Their frequencies were similar to those found in other studies in the Albanian population. This method has permitted the detection of heterozygotes for beta thal in this population and offers a prenatal diagnosis with a probability of 90% accuracy. PMID- 24052704 TI - Turner Syndrome with Isochromosome Xq and Familial Reciprocal Translocation t(4;16)(p15.2;p13.1). AB - We present here a 16-year-old Turner syndrome patient with a complex karyotype that includes a maternally-inherited balanced translocation between chromosomes 4 and 16 and mosaicism of the isochromosome Xq10. Her karyotype was 45,X,t(4;16) (p15.2;p13.1)[9]/46,X,i(X) (q10),t(4;16)(p15.2;p13.1) [91]. The karyotype of her father was normal, whereas that of her mother had the same balanced translocation and numerical abnormalities of chromosome X and was designated as 45,X,t(4;16)(p15.2;p13.1) [2]/46,XX,t(4;16)(p15.2;p13.1)[93]/47,XXX,t(4;16) (p15.2; p13.1)[5]. The two siblings of the patient also had the same reciprocal translocation. We consider this to be the first such patient with an inherited reciprocal translocation and structural abnormality of the X chromosome (isochromosome Xq). PMID- 24052703 TI - Pulmonary Thromboembolism Following Radio-Frequency Ablation of the Atrioventricular Node in a Patient Heterozygous for the Factor V Leiden and the Mthfr C677T Mutations. AB - Patients who undergo radiofrequency ablation of the atrioventricular (AV) node rarely develop acute major complications. A 41-year-old Caucasian male smoker, was admitted to the Pulmology Teaching Hospital at Belgrade, Serbia, for sharp persistent chest pain, fever and fatigue following AV node radiofrequency ablation for arrhythmia. Chest X-ray showed obtuse right costo-phrenic angle and laminar atelectasis in the right lower lung lobe. The plasma D-dimer level was elevated. A perfusion lung scan showed multiple bilateral perfusion defects and multislice computed tomography showed thrombotic mass in the right pulmonary artery. Genetic analysis revealed that he was heterozygous for the prothrombin Factor V (FV) Leiden and MTHFR C677T mutations. Therapy started with intravenous heparin, followed by warfarin. He had no other episodes over a 2-year follow-up. Lifelong oral anticoagulant therapy was recommended. PMID- 24052705 TI - Partial Trisomy 9p(p22->pter) from a Maternal Translocation 4q35 and 9p22. AB - We present clinical and cytogenetic data on a 7-year-old female child with partial trisomy for 9p22->9pter as a result of a maternal balanced reciprocal translocation. Her karyotype was ascertained as 46,XX,dec(4)t(4;9)(q35; p22)mat. The father had a normal karyotype, while the mother had an apparently balanced translocation involving chromosomes 4 and 9 [46,XX,t(4;9)(q35;p22)]. This case will be briefly compared with other published cases of a similar translocation. PMID- 24052706 TI - Stem cells: a personal perspective. PMID- 24052707 TI - Evidence for correlation of fragile sites and chromosomal breakpoints in carriers of constitutional balanced chromosomal rearrangements. AB - A molecular cytogenetic study of 251 cases with balanced chromosomal rearrangements detected due to infertility of unclear origin or in prenatal diagnostics with a later normal outcome was done. Balanced translocations (127 cases), inversions (105 cases), insertions (three cases), balanced complex rearrangements (four cases), or derivative chromosomes leading to no imbalance (12 cases), were studied by multicolor banding (MCB) and/or subcentromeric multicolor fluorescence in situ hybridization (subcenM-FISH). Five-hundred and twenty-nine break-events were characterized by molecular cytogenetics. Only 150 of these were unique breakpoints, the remainder were observed between two and 10 times. According to the results obtained, there was cytogenetic co-localization of fragile site (FS) in ~71% of the studied 529 break-events. Nine selected cases with evidence for breakpoints within FS were further analyzed by FS-specific bacterial artificial chromosome (BAC) probes; only one did not show a co localization. Further detailed molecular analysis will be necessary to characterize the mechanisms and genetic basis for this phenomenon. PMID- 24052708 TI - Amplification of c-MYC and MLL Genes as a Marker of Clonal Cell Progression in Patients with Myeloid Malignancy and Trisomy of Chromosomes 8 or 11. AB - Gene amplification (amp) is one of the basic mechanisms connected with overexpression of oncogenes. The c-MYC (located in 8q24) and MLL (located in 11q23) are the most often over represented genes that lead to a rapid proliferation of the affected cell clone in patients with myeloid neoplasms. Assessment of the level of amp c-MYC or amp MLL in the cases with trisomy 8 (+8) or trisomy 11 (+11) and myeloid malignances is necessary for a more precise estimation of the disease progression. A total of 26 patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) were included in the study: 18 with +8, six with +11 and two with complex karyotypes suspected of the partial trisomy. Routine cytogenetic analysis and fluorescent in situ hybridization (FISH) were applied to indicate the chromosome alterations and genes amp in the bone marrow cells. Amp c-MYC was observed in 12 from 18 (66.7%) patients with +8. All the patients with +11 demonstrated a different level of amp MLL. In most of the cases with MDS (9/10), the coincidence of the +8 or +11 with amp c-MYC or amp MLL, respectively, leads to transformation to AML and/or short overall survival. Our data suggest that amp c-MYC and amp MLL develop in conformity with +8 and +11, especially in cases with progressive deviations in the karyotype as an aggressive expansion of an aberrant cell clone and appearance of additional chromosome anomalies. PMID- 24052709 TI - Alterations of copy number of methylation pattern in mismatch repair genes by methylation specific-multiplex ligation-dependent probe amplification in cases of colon cancer. AB - Genetic alterations and changes in genomic DNA cytosine methylation patterns are associated with all types of cancer and are caused by germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1 (MutL homolog 1, 19 exons) and MSH2 (MutS homolog 2, 16 exons). Genomic DNA was extracted from tissue samples embedded in paraffin from 49 patients with adenocarcinoma and from 21 patients with carcinoma for the study group; genomic DNA was extracted from lymphocytes from 10 healthy donors for the control group. We used methylation specific multiplex ligation-dependent probe amplification (MS-ML-PA), which allows the detection of copy number changes and unusual methylation levels of 10 to 50 different sequences in one reaction by use of the methylation-sensitive restriction enzyme HhaI and sequence-specific capillary electrophoresis for the study of 24 genes. We found the mean methylation rates for MLH1 (97.14%), MSH2 (24.28%), MSH6 (MutS homolog 6) (67.14%), MSH3 (MutS homolog 3) (78.57%), MLH3 (MutL homolog 3) (75.71%), PMS2 (postmeiotic segregation increased 2) (65.71%), MGMT(O-6-methylguanine-DNA methyltransferase ) (82.85%). We conclude that the mismatch repair (MMR) system is critical for the maintenance of genomic stability. PMID- 24052710 TI - Role of the APOB Gene Polymorphism (c.12669G>A, p. Gln4154Lys) in Coronary Artery Disease in the Indian Punjabi Population. AB - High concentration of apolipoprotein B (apoB) is a risk factor for coronary artery disease (CAD). The association of the APOB gene polymorphism c.12669G>A, p.Gln4154Lys with the risk of CAD varies considerably in different populations. The present study represents the first investigation regarding the role of this APOB gene polymorphism with CAD in the Indian Punjabi population. We have studied the APOB gene polymorphism c.12669G>A, p.Gln4154Lys and its relationship with lipid, apoB, low-density lipoprotein (LDL) heterogeneity and oxidation in subjects suffering from CAD. The study was conducted on 87 patients with CAD; 75 healthy subjects served as controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the DNA polymorphism in the APOB gene. Frequency of R- (mutant) allele was significantly high (p <0.05) in CAD patients when compared to controls. Variations in serum lipid levels in the R+R+ and R+R- APOB genotypes were insignificant (p >0.05). However, serum apoB levels were significantly raised (p <0.05) in CAD patients with the R+R- genotype as compared to those with the R+R+ APOB genotype. Coronary artery disease patients had raised significantly raised (p <0.01) Log triglyceride/high density lipoprotein-cholesterol (HDL-C) ratio, apoB carbonyl content and increased malondialdehyde-low density lipoprotein (MDA-LDL levels, irrespective of APOB genotype as compared to controls. Carriers of the R- allele are at higher risk of CAD, probably because of elevated serum apoB levels in the Indian Punjabi population. Overall, it may be concluded that the R- allele might be associated with increased susceptibility towards CAD development in the Indian Punjabi population, and one of the linking factor is the elevation in serum apoB levels. However, this association needs further evaluation in a larger population. Secondly, the robust mechanism behind the positive association of the R- allele with raised serum apoB levels needs to be explored, which might be helpful in the strengthening the observed results. PMID- 24052711 TI - IL-18 Gene Promoter Region 607C/A Polymorphism in HIV-1 Infected North Indian Population. AB - Several host genetic factors play an important role in susceptibility to human immunodeficiency virus type 1 (HIV-1) infection and in its progression to acquired immune deficiency syndrome (AIDS). The interleukin-18 (IL-18) is a multifunctional proinflammatory cytokine that regulates immune responses and plays a pathogenic role in HIV-1 infection by enhancing viral replication. Single nucleotide polymorphisms (SNPs) in the IL-18 gene promoter region may lead to altered transcriptional activity and IL-18 production, and may account for variation in the risk of HIV-1 infection. We have investigated the association between IL-18 promoter polymorphism -607C>A and HIV-1 infection through a case control study of 500 patients with HIV-1/AIDS and an equal number of age and sex matched controls in a north Indian population. Genotyping using sequence specific primer-polymerase chain reaction (SSP-PCR) showed a statistically significant reduced risk of HIV-1 infection for the A>A genotype [odds ratio (OR) = 0.57, 95% confidence interval (95% CI) = 0.33-0.98, p = 0.040], but not for the C>A genotype (OR = 0.87, 95% CI = 0.66-1.14, p = 0.321). We concluded that the -607A allele of the IL-18 gene promoter polymorphism may play a protective role against the progression of HIV-1 infection in this population. PMID- 24052712 TI - Metadata management and semantics in microarray repositories. AB - The number of microarray and other high-throughput experiments on primary repositories keeps increasing as do the size and complexity of the results in response to biomedical investigations. Initiatives have been started on standardization of content, object model, exchange format and ontology. However, there are backlogs and inability to exchange data between microarray repositories, which indicate that there is a great need for a standard format and data management. We have introduced a metadata framework that includes a metadata card and semantic nets that make experimental results visible, understandable and usable. These are encoded in syntax encoding schemes and represented in RDF (Resource Description Frame-word), can be integrated with other metadata cards and semantic nets, and can be exchanged, shared and queried. We demonstrated the performance and potential benefits through a case study on a selected microarray repository. We concluded that the backlogs can be reduced and that exchange of information and asking of knowledge discovery questions can become possible with the use of this metadata framework. PMID- 24052713 TI - Diagnosis of Fanconi's Anemia by Diepoxybutane Analysis in Children from Serbia. AB - The high sensitivity of Fanconi's anemia (FA) cells to drug induced DNA interstrand crosslinks (ICL) such as diepoxybutane (DEB) was used as a part of FA screening in the children with clinical suspicion of FA. The study considered a total of 66 children with the hematological and/or congenital phenotypic symptoms reminiscent of FA. Blood samples from patients with clinical suspicion of FA and controls were collected for chromosome fragility evaluation by the DEB test. According to the results of DEB test, the patients were divided into two subgroups: FA displaying typical DEB sensitive cellular response and non FA. In this study, 10 out of 66 patients were found to have a FA cellular phenotype. The percentage of DEB-induced aberrant cells was increased more than 26 times in FA patients (range 22.00-82.00% with a mean of 48.32%) when compared to non FA patients (range 0.00-12.00% with a mean of 1.84%). The number of DEB-induced breaks/cells was more than 68 times higher in FA patients (range 0.26-4.39 with a mean of 1.37 breaks/cell) when compared to non FA patients (range 0.00-0.20 with a mean of 0.02 breaks/cell). The spontaneous chromosome fragility values in FA patients were overlapping those in non FA patients. Our results indicate that the DEB sensitivity test is the most reliable in vitro method for verification of the FA cellular phenotype. PMID- 24052714 TI - Molecular analysis of ring y chromosome in a 10-year-old boy with mixed gonadal dysgenesis and growth hormone deficiency. AB - Ring Y chromosome is a very rare chromosomal aberration. The published mixed gonadal dysgenesis (MGD) patients with a ring Y chromosome are short in stature, but are not growth hormone (GH) deficient. We present the molecular cytogenetic and molecular characterization of ring Y chromosome mosaicism in a 10-year-old boy with MGD whose short stature could be explained by the high percentage of cells monosomic for the X-chromosome, but also by the presence of severe GH deficiency. The ring Y chromosome in our patient is a de novo structural aberration. The father's karyotype was normal. PMID- 24052715 TI - Hypergonadotropic hypogonadism, progressive early-onset spinocerebellar ataxia, and late-onset sensorineural hearing loss: case report and literature review. AB - The association of ataxia, hypergonadotropic hypogonadism and hearing loss is extremely rare. Considerable heterogeneity exists in the literature of the neurological manifestations, age of onset, clinical severity and associated abnormalities. We describe a 24-year-old woman with secondary hypergonadotropic amenorrhea, early-onset progressive spinocerebellar ataxia (SCA), late-onset sensorineural hearing loss and normal intelligence and compare it with reported cases. PMID- 24052716 TI - Cytogenetic and morphological analysis of de novo acute myeloid leukemia in adults: a single center study in jordan. AB - Acute myeloid leukemia (AML) in adults is known to be a heterogeneous disease with diverse chromosomal abnormalities. Some of these abnormalities are found with a high incidence in specific ethnic groups and in certain geographical areas. We report the results of cytogenetic studies of 35 adult Jordanian Arab patients with de novo AML diagnosed according to the French-American-British (FAB) criteria. Four patients did not have meta-phases secondary to hypocellular bone marrow. The most common morphological subtype was M5 (55%) followed by M3 (19%). Cytogenetic abnormalities were present in 20 patients (65%); t(15;17) translocation in six patients (19%), inv(16) in four patients (13%), t(11;17) in two patients (4%), and the t(8;21) translocation was not present in any patient. Trisomy 8 was the most common numerical chromosomal abnormality [four patients (13%)]. There were variations and similarities with similar ethninc Arab populations. The most common chromosomal abnormalities were t(15;17), +8 and inv(16). Further and larger crossborder studies are needed. PMID- 24052717 TI - Rapid detection of fetal aneuploidies by quantitative fluorescent-polymerase chain reaction for prenatal diagnosis in the Turkish population. AB - Prenatal diagnosis is testing for diseases or conditions in a fetus or embryo before it is born. It employs a variety of techniques to determine the health and condition of an unborn fetus. The main goal of this process is to perform prenatal diagnosis at the earliest possible stage of gestation. In this regard, quantitative fluorescent-polymerase chain reaction (QF-PCR), a novel technique that is fast and reliable, was employed to detect aneuploidies (13, 18, 21, X and Y) without the need of the time-consuming culturing process. The QF-PCR method can detect five different chromosome aneuploidies with 98.6% accuracy. In this study, 1874 amniotic fluid samples of pregnant subjects, who were referred to the Department of Medical Biology and Genetics, Adana, Turkey (molecular biology section), were analyzed with the QF-PCR technique by employing 27 short tandem repeat (STR) markers to detect chromosomes 13, 18, 21, X and Y aneuploidies. We detected 31 subjects (1.7%) with aneuploidies or euploidies out of the 1874 subjects. The average age of the pregnant subjects was 32 (range: 14-49). Abnormal karyotypes detected were as follows: 47,XX,+21 (19.4%, 6/31), 47,XY,+21 (48.4%, 15/31), 48,XXX,+21 (3.2%, 1/31), 69,XXX (3.2%, 1/31), 47,XY,+13 (3.2%, 1/31), 47,XXY (9.6%, 3/31), 47,XXX (9.6%, 3/31) and 45,X (3.2%, 1/31). Moreover, some STR markers were found to be more specific to the Turkish population. In conclusion, QF-PCR can be regarded as an alternative method of conventional cytogenetic analysis as it is a rapid and reliable method; however, in most cases it is required to be supported or validated with conventional cytogenetic karyotyping and some STR markers employed for QF-PCR can be more informative for a given population. PMID- 24052718 TI - Influence of the SCN1A IVS5N + 5 G>A Polymorphism on Therapy with Carbamazepine for Epilepsy. AB - Carbamazepine (CBZ) blocks neuronal sodium channels in a voltage- and frequency dependent manner, delaying the recovery of the channels from the inactivated state, reducing the number of action potentials within a burst, and decreasing burst duration. The alpha-subunit of the first neuronal sodium channel (SCN1A) is a major gene in different epilepsies. A synonymous polymorphism (SCN1A IVS5N + 5 G>A or rs3812718) is common in exon 5 of this gene. Mutations in the alpha-unit of this gene are associated with CBZ-resistant epilepsy and a higher maintenance dose of CBZ. We have investigated the association of this single nucleotide polymorphism (SNP) and epilepsy, efficacy and dose-dependence of CBZ therapy in 147 adult Macedonian patients and 137 non epileptic controls. No significant differences in allelic frequencies and genotype distribution were found between patients and controls (p = 0.94278), or between CBZ-responsive and unresponsive patients (p = 0.55449). An association between the A allele and a higher maintenance dose in CBZ-responsive patients was detected. No statistical difference was found between the plasma levels of CBZ and genotype of patients receiving the same dose, indicating that the variant exerts its effect at the level of receptor responsiveness. The predictive value of pretreatment testing showed a minor insignificant difference between patients with different genotypes, primarily due to a small number of patients. PMID- 24052719 TI - Mitochondrial DNA 4977 bp Deletion in Chronic Cervicitis and Cervix Cancers. AB - Mitochondrial DNA (mtDNA) mutations have been implied in many diseases including cancer and inflammatory diseases. The aim of this study is to investigate the relationship between the 4977 bp deletion of the mtDNA and chronic cervicitis or cervix cancer in patients. The study included a group of patients with chronic cervicitis or cervix cancer, and a control group consisting of individuals without any cervical tissue disease. A total of 72 subjects in an East Turkish population were included in the study. Of these, 35 had chronic cervicitis, 21 had cervix cancer and 16 served as the control group. Isolation of mtDNA was performed from the tissues of these patients and then mtDNA deletions were studied using polymerase chain reaction (PCR). In the cancer groups, there were 9.5% heteroplasmic and homoplasmic deletions. There were no homoplasmic deletions in the cervicitis and control groups, but the frequencies of heteroplasmic deletions were 80.0 and 31.2%, respectively. Chronic inflammation leading to increased reactive oxygen species (ROS) may be the cause of the high mtDNA 4977 bp deletion frequencies in cancer and cervicitis. The older age of the cancer patient may suggest that ageing in addition to long time exposure to ROS may lead to deletions and subsequently cancer. This is the first study to investigate the relationship of the mtDNA 4977 bp deletion to chronic cervicitis and cervix cancer. PMID- 24052720 TI - CAG Repeat Number in the Androgen Receptor Gene and Prostate Cancer. AB - Prostate cancer (PC) is the second leading cause of cancer deaths in men. The effects of androgens on prostatic tissue are mediated by the androgen receptor (AR) gene. The 5' end of exon 1 of the AR gene includes a polymorphic CAG triplet repeat that numbers between 10 to 36 in the normal population. The length of the CAG repeats is inversely related to the transactivation function of the AR gene. There is controversy over association between short CAG repeat numbers in the AR gene and PC. This retrospective case-control study evaluates the possible effect of short CAG repeats on the AR gene in prostate cancer risk in Macedonian males. A total of 392 male subjects, 134 PC patients, 106 patients with benign prostatic hyperplasia (BPH) and 152 males from the general Macedonian population were enrolled in this study. The CAG repeat length was determined by fluorescent polymerase chain reaction (PCR) amplification of exon1 of the AR gene followed by capillary electrophoresis (CE) on a genetic analyzer. The mean repeat length in PC patients was 21.5 +/- 2.65, in controls 22.28 +/- 2.86 (p = 0.009) and in BPH patients 22.1 +/- 2.52 (p = 0.038). Short CAG repeats (<19) were found in 21.64% of PC patients vs. 9.43% in BPH patients (p = 0.0154). We also found an association of low Gleason score (<7) with short CAG repeat (<19) in PC patients (p = 0.0306), and no association between the age at diagnosis of PC and BPH and CAG repeat length. These results suggest that reduced CAG repeat length may be associated with increased prostate cancer risk in Macedonian men. PMID- 24052722 TI - Muscle hemangiomatosis presenting as a severe feature in a patient with the pten mutation: expanding the phenotype of vascular malformations in bannayan-riley ruvalcaba syndrome. AB - Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare autosomal, dominantly inherited, hamartoma syndrome with distinct phenotypic features. Mutations in the PTEN gene have been identified in PTEN hamartoma tumor syndromes. Our aim was to determine the correlation of phenotype-genotype relationships in a BRRS case. We have evaluated a PTEN mutation in a patient with vascular anomalies and the phenotypic findings of BRRS. We described an 8-year-old girl with the clinical features of BRRS, specifically with vascular anomalies. The mutation in the PTEN gene was identified by DNA sequencing. In our patient, we defined a de novo nonsense R335X (c.1003 C>T) mutation in exon 8, which results in a premature termination codon. Due to vascular anomalies and hemangioma, the patient's left leg was amputated 1 year after the hemangioma diagnosis. Bannayan - Riley - Ruvalcaba syndrome patients with macrocephaly and vascular anomalies should be considered for PTEN mutation analysis and special medical care. PMID- 24052723 TI - Clouston syndrome: first case in Russia. AB - Hidrotic ectodermal dysplasia type 2 (HED2) or Clouston syndrome (OMIM #129500) is a rare autosomal dominant genetic disorder which affects skin and its derivatives, characterized by the major triad of features: nail dystrophy, generalized hypotrichosis, and palmoplantar hyperkeratosis. Here we describe the first case of Clouston syndrome in Russia and the molecular genetic analysis of this case. PMID- 24052721 TI - The many faces of oral-facial-digital syndrome. AB - The oral-facial-digital (OFD) syndrome is a heterogeneous group of abnormalities that share anomalies of the oral cavity, face and digits of hands and feet. On the basis of other anomalies of brain, kidneys, limbs, eyes and other organs, at least 13 subgroups have been described. We here describe four unrelated patients with this syndrome, who have the typical facial, oral and digital anomalies and also anomalies of other organs and systems. Facial features, digital malformations, as well as the existence of additional malformations all of which can be classified into different subgroups. The report points out the difficulty in delineation of the subtypes of OFD syndrome because of the overlapping features between OFD subgroups. PMID- 24052724 TI - Ring chromosome 22: a review of the literature and first report from India. AB - Ring chromosome 22 [r(22)], a rare cytogenetic finding, has been described in nearly 70 cases to date. Cytogenetic investigations were carried out on a 5-year old male child with microcephaly and intellectual disability. Cytogenetic investigations revealed his karyotype to be 46,XY,r(22). To the best of our knowledge, this is the first report of an r(22) anomaly from India. PMID- 24052725 TI - Mosaic Intrachromosomal Triplication of (12)(p11.2p13) in a Patient with Pallister-Killian Syndrome. AB - Pallister-Killian syndrome (PKS) is a rare genetic disorder usually characterized by mosaic tetrasomy of isochromosome 12p detected in cultured fibroblast cells. We describe here a patient with PKS and intrachromosomal triplication of the short arm of chromosome 12. Her karyotype was mos 46,XX,inv trp(12)(p11.2p13)[34]/ 46,XX[16]de novo by conventional cytogenetics and fluorescent in situ hybridization (FISH) analysis. However, this chromosomal abnormality was not detected from the patient's cultured blood lymphocytes. We report here the third patient with intrachromosomal triplication on the short arm of chromosome 12, presenting a PKS phenotype. PMID- 24052726 TI - Detecting Sex-Biased Gene Flow in African-Americans through the Analysis of Intra and Inter-Population Variation at Mitochondrial DNA and Y- Chromosome Microsatellites. AB - This study reports on variations at the mitochondrial DNA (mtDNA) hypervariable region 1 (HVR-1) and at seven Y-chromosome microsatellites in an African-American population sample from Chicago, IL, USA. Our results support the hypothesis that the population studied had undergone a European male-biased gene flow. We show that comparisons of intra-and inter-population diversity parameters between African-Americans, Europeans and Africans may help detect sex-biased gene flow, providing a complement to quantitative methods to estimate genetic admixture. PMID- 24052727 TI - Clinical impact of proximal autosomal imbalances. AB - Centromere-near gain of copy number can be induced by intra- or inter-chromosomal rearrangements or by the presence of a small supernumerary marker chromosome (sSMC). Interestingly, partial trisomy to hexasomy of euchromatic material may be present in clinically healthy or affected individuals, depending on origin and size of chromosomal material involved. Here we report the known minimal sizes of all centromere-near, i.e., proximal auto-somal regions in humans, which are tolerated; over 100 Mb of coding DNA are comprised in these regions. Additionally, we have summarized the typical symptoms for nine proximal autosomal regions including genes obviously sensitive to copy numbers. Overall, studying the carriers of specific chromosomal imbalances using genomics-based medicine, combined with single cell analysis can provide the genotype-phenotype correlations and can also give hints where copy-number-sensitive genes are located in the human genome. PMID- 24052728 TI - Chromosomal polymorphisms involved in reproductive failure in the romanian population. AB - Cytogenetic heteromorphisms are described as variations at specific chromosomal regions with no impact on phenotype. The purpose of this study was to investigate the effects of these chromosomal polymorphisms involved in reproductive failure in the Romanian population. One thousand eight hundred and nine infertile patients, who were referred to Life Memorial Hospital, Bucharest, Romania, between January 2008 and April 2011, were investigated in this retrospective study. The frequency of chromosomal polymorphic variations was calculated for these patients. The control group is represented by 1116 fetuses investigated by amniocentesis between January 2009 and April 2011. In this study 122 (6.74%) infertile patients and 63 fetuses (5.65%) showed chromosomal polymorphic variations. The differences between the two groups was not statistically significant (p <0.242) but there was statistical significance for some specific chromosomal polymorphisms [inv(9),1qh+, 9qh+, fra(17)]. Some chromosomal polymorphic variations appear to be associated with reproductive failure. The statistically significantly higher incidence of heterochromatic variations found in infertile individuals emphasizes the need to assess their role in infertility and subfertility. PMID- 24052729 TI - Cytogenetic findings in mentally retarded Iranian patients. AB - We conducted a cytogenetic study on 865 individuals with idiopathic mental retardation (MR) who were admitted to the Cytogenetics Department of the Iran Blood Transfusion Organisation (IBTO) Research Centre, Tehran, Iran; these were performed on blood samples using conventional staining methods. Chromosome anomalies were identified in 205 of the patients (23.6%). The majority were Down's syndrome cases (n = 138). In 33 males, a positive fragile X anomaly was found. The remainder (n = 34) had other chromosomal abnormalities including structural chromosome aberrations (n = 23), marker chromosomes with an unknown origin (n = 3), sex chromosome aneuploidy (n = 6) and trisomy 18 (n = 2). The contribution of chromosome aberrations to the cause of MR in this group of patients is discussed. PMID- 24052731 TI - Mitochondrial DNA mutations in two bulgarian children with autistic spectrum disorders. AB - Autism is a neurodevelopmental disorder of unknown origin that manifests in early childhood. Autism spectrum disorders (ASDs) refer to a broader group of neurobiological conditions, pervasive developmental disorders. Despite several arguments for a strong genetic contribution, the molecular basis in most cases remains unexplained. Several studies have reported an association between ASDs and mutations in the mitochondrial DNA (mtDNA) molecule. In order to confirm these causative relationship, we screened 21 individuals with idiopathic ASDs for a number of the most common mtDNA mutations. We identified two patients with candidate mutations: m.6852G>A that produces an amino acid change of glycine to serine in the MT-CO1 gene and m.8033A>G (Ile->Val) in the MT-CO2 gene. Overall, these findings support the notion that mitochondrial mutations are associated with ASDs. Additional studies are needed to further define the role of mitochondrial defects in the pathogenesis of autism. PMID- 24052732 TI - Human leukocyte antigen-b27 and disease susceptibility in vojvodina, serbia. AB - There are numerous studies showing the role of human leukocyte antigens (HLAs) related with susceptibility or resistance to certain diseases. The aim of this study was to determine the association of HLA-B27 with ankylosing spondylitis (AS), polyarthralgia, lumboishialgia, acute anterior uveitis (AAU), psoriatic arthritis (PA), synovitis coxae and rheumatoid arthritis (RA) in patients from Vojvodina, Serbia. An HLA I class typing was performed by the serological immunomagnetic two-color fluorescence method using peripheral blood T lymphocytes in 97 patients and 224 healthy controls from the population of Vojvodina, Serbia. We calculated HLA-B27 frequencies, relative risk (RR), ethiologic fraction (EF), e.g., population attributive risk, when RR was greater than 1, while, preventive fraction (PF) was calculated when RR was lower than 1. This study revealed the strongest association of AS with HLAB27 antigen: RR = 25.0, while the EF was greater than 0.15, respectively. The chi(2) test showed the significant difference (p <0.05) in HLA-B27 in patients with AS in comparison to controls (chi(2) = 52.5). It was concluded that there is a positive association of HLA-B27 with AS and that HLA-B27 can serve as a marker for predisposition to diseases. PMID- 24052730 TI - Ring autosomes: some unexpected findings. AB - Ring chromosomes are rare entities, usually associated with phenotypic abnormalities in correlation with the loss of genetic material. There are various breakpoints and sometimes there is a dynamic mosaicism that is reflected in clinical features. Most of the ring chromosomes are de novo occurrences. Our study reflects the experience of three Romanian cytogenetic laboratories in the field of ring chromosomes. We present six cases with ring chromosomes involving chromosomes 5, 13, 18, and 21. All ring chromosomes were identified after birth in children with plurimalformative syndromes. The ring chromosome was present in mosaic form in three cases, and this feature reflects the ring's instability. In case of ring chromosome 5, we report a possible association with oculo-auriculo vertebral spectrum. PMID- 24052733 TI - Association between Obsessive Compulsive Disorder and Tumor Necrosis Factor-alpha Gene -308 (G>A) and -850 (C>T) Polymorphisms in Turkish Children. AB - Obsessive compulsive disorder (OCD) is a neurobiological disease characterized with obsessions and compulsions. Obsessive compulsive disorder occurs with an autoimmune mechanism after Group A beta hemolytic streptococcus (GABHS) infection. Tumor necrosis factor (TNF) is an important cytokine, as well as having an important role in the apoptosis mechanism of autoimmune diseases. It is expressed by the TNF-alpha gene. The aim of this study was to examine the relationship between the TNF-alpha gene promoter region -308 (G>A) and -850 (C>T) polymorphisms and OCD. In this study, ages of the OCD patients and the control group ranged between 4 and 12 years. We studied two patient groups, one included childhood onset OCD patients (n = 49) and the control group was composed of healthy children (n = 58). Patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria and with Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime (KSAD-S PL) version. For identifying the polymorphisms, polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) and polyacrylamide gel electrophoresis (PAGE) methods were used. For the -308 polymorphism, 45 of 49 OCD patients' results were completed, and for the -850 polymorphism, 47 of 49 OCD patients' results were completed. According to our statistical results, there is a positive relationship between OCD and the -308 polymorphism (p <0.001) but no association between OCD and the -850 polymorphism (p = 0.053). There is no positive relationship between antistreptolysin O (ASO) titers and the -308 polymorphism (p = 0.953) but there is an important significance between the -850 polymorphism and ASO (p = 0.010). There is no positive relationship between gender of patients and OCD (p = 0.180) and no positive association between ASO and gender (p = 0.467). According to our results, we hypothesize that we can propose the mutant AA genotype for the -308 polymorphism, and that the mutant CT genotype for the -850 polymorphism may be used as molecular indicators for OCD. PMID- 24052735 TI - 16p subtelomeric duplication with vascular anomalies: an Albanian case report and literature review. AB - A patient with karyotype 46,XY,der(4) was recognized by standard cytogenetic techniques, and presented with facial features, neurological impairment and pulmonary hypertension. Multiplex ligation-dependent probe amplification (MLPA) demonstrated duplication of the subtelomeric region of chromosome 16p and deletion of the subtelomeric region of chromosome 4q, suggesting a translocation between 4q and 16p. The karyotype of his parents was normal and their MLPA analysis also indicated a de novo imbalance. He had microcephaly, high frontal hairline, thin blond hair, bilateral blepharophimosis and palpebral ptosis, short nose, everted upper lip, cleft palate, micrognathia, cupped anteverted ears, hypoplastic distal phalanges and bilateral inguinal hernia. He also had pulmonary hypertension with tricuspidal regurgitation; cavernous liver hemangioma anomalies have been previously described in association with dup16p. We concluded that pulmonary and other vascular anomalies can be a feature of dup16p. We believe this is the first confirmed case of a 16p subtelomeric duplication with vascular anomalies identified in Albania. PMID- 24052734 TI - The Impact of the D727E Polymorphism has no Significant Role in Multi Nodular Goiter. AB - Interactions between individual genetic and environmental factors determine the onset of the multi nodular goiter (MNG). The thyroid-stimulating hormone receptor (TSHR) gene is a convincing candidate gene in the pathogenesis of certain thyroid diseases including MNG. We investigated the codon 727 polymorphism (p.Asp727Glu, p.D727E) of the human TSHR gene using the polymerase chain reaction-restriction fragment length polymorphim (PCR-RFLP) methods in 31 Turkish patients with MNG and in 30 control subjects, aiming to evaluate the relationship between this polymorphism and MNG. After genomic DNA isolation, PCR amplification was performed using a pair of primers in exon 10 of the TSHR gene that contains the p.D727E polymorphism and digested by theNlaIII (Hin1II) restriction enzyme. We found the CC and CG genotype incidence for the patient group to be 0.71 and 0.29, respectively, and for the control group to be 0.8 and 0.2, respectively. No statistically significant difference was found between the genotype and allele distribution of both groups (p = 0.417 and p = 0.449, respectively). However, the polymorphism is significantly correlated with the low serum level of the TSH (p = 0.047). These results suggest that the p.D727E polymorphism of the TSHR gene may not contribute to the pathogenesis of nontoxic MNG diseases. PMID- 24052736 TI - National Reference Centre for Genomics and Proteomics - MACPROGEN. PMID- 24052737 TI - Renopathological Microstructure Visualization from Formalin Fixed Kidney Tissue by Matrix-Assisted Laser/Desorption Ionization-Time-of-Flight Mass Spectrometry Imaging. AB - Understanding early stage renal malfunctions with regard to the glomerular filtration processes is essential for nephropathological prescreening strategies and intervention at an early stage. Mass spectrometry imaging (MSI) in combination with histopathology can provide an universal analytical approach. Proteomic and lipidomic aspects of glomerular biocompositions were applied for micro-structural differentiation in healthy rat kidney samples. Usability of commonly used tissue embedding media and the compatibility of histological staining and fixation methods were of interest. It was demonstrated that ultra thin tissue samples (500 nm, 1 and 10 MUm) can be used for lipid and peptide based differentiation at the glomerular resolution level in formalin-fixed tissue samples in combination with preceding histological staining for correlating optical and molecular mass images. PMID- 24052739 TI - Proteomics of the spermatozoon. AB - The study of the sperm proteins is crucial for understanding its normal function and alterations in infertile patients. The sperm is a highly specialized cell with a very large flagella, with little cytoplasm and a highly condensed nucleus. The most abundant proteins in the nucleus of mammalian sperm are the protamines. The main functions of the protamines are the condensation of the DNA, possibly contributing to the generation of a more hydrodynamic sperm head and to the protection of the genetic message. However, in addition to protamines, about 5.0 15.0% of the paternal genome is also complexed with histones and histone variants. It has also demonstrated a differential distribution of genes in regions associated with histone and protamine-associated regions, suggesting a potential epigenetic relevance in embryonic development. More recently, detailed lists of proteins have been described corresponding to the different compartments of the sperm cell thanks to the application of recent proteomic techniques based on mass spectrometry (MS). Differential proteomics is also being applied to identify the presence of protein abnormalities found in infertile patients. PMID- 24052738 TI - Non invasive prenatal diagnosis of aneuploidy: next generation sequencing or fetal DNA enrichment? AB - Current invasive procedures [amniocentesis and chorionic villus sampling (CVS)] pose a risk to mother and fetus and such diagnostic procedures are available only to high risk pregnancies limiting aneuploidy detection rate. This review seeks to highlight the necessity of investing in non invasive prenatal diagnosis (NIPD) and how NIPD would improve patient safety and detection rate as well as allowing detection earlier in pregnancy. Non invasive prenatal diagnosis can take either a proteomics approach or nucleic acid-based approach; this review focuses on the latter. Since the discovery of cell free fetal DNA (cffDNA) and fetal RNA in maternal plasma, procedures have been developed for detection for monogenic traits and for some have become well established (e.g., RHD blood group status). However, NIPD of aneuploidies remains technically challenging. This review examines currently published literature evaluating techniques and approaches that have been suggested and developed for aneuploidy detection, highlighting their advantages and limitations and areas for further research. PMID- 24052740 TI - Genetic causes of male infertility. PMID- 24052741 TI - Human seminal plasma proteome study: a search for male infertility biomarkers. AB - Seminal plasma is a potential source of biomarkers for many disorders of the male reproductive system including male infertility. Knowledge of the peptide and protein components of seminal fluid is accumulating especially with the appearance of high-throughput MS-based techniques. Of special interest in the field of male infertility biomarkers, is the identification and characterization of differentially expressed proteins in seminal plasma of men with normal and impaired spermatogenesis. However, the data obtained until now is still quite heterogeneous and with small percentage of overlap between independent studies. Extensive comparative analysis of seminal plasma proteome is still needed in order to establish a potential link between seminal plasma proteins and male infertility. PMID- 24052742 TI - Rapid and non invasive prenatal diagnosis. PMID- 24052743 TI - Integrative 'omic' approach towards understanding the nature of human diseases. AB - The combination of improving technologies for molecular interrogation of global molecular alterations in human diseases along with increases in computational capacity, have enabled unprecedented insight into disease etiology, pathogenesis and have enabled new possibilities for biomarker development. A large body of data has accumulated over recent years, with a most prominent increase in information originating from genomic, transcriptomic and proteomic profiling levels. However, the complexity of the data made discovery of high-order disease mechanisms involving various biological layers, difficult, and therefore required new approaches toward integration of such data into a complete representation of molecular events occurring on cellular level. For this reason, we developed a new mode of integration of results coming from heterogeneous origins, using rank statistics of results from each profiling level. Due to the increased use of next generation sequencing technology, experimental information is becoming increasingly more associated to sequence information, for which reason we have decided to synthesize the heterogeneous results using the information of their genomic position. We therefore propose a novel positional integratomic approach toward studying 'omic' information in human disease. PMID- 24052744 TI - A Preliminary microRNA Analysis of Non Syndromic Thoracic Aortic Aneurysms. AB - The development of thoracic aortic aneurysms (TAAs) involves a multifactorial process resulting in alterations of the structure and composition of the extracellular matrix (ECM). Recently, modifications in microRNA (miRNA) expression were implicated in the pathogenesis of TAA. This study presents a preliminary miRNA microarray analysis conducted on pooled ascending aorta RNAs obtained from non familial non syndromic TAA patients (five males and five females) compared to matched control pools. Ninety-nine differentially expressed miRNAs with >1.5-fold-up- or down-regulation in TAAs compared to controls were identified, 16.0% of which were similarly regulated in the two sexes. Genes putatively targeted by differentially expressed miRNAs belonged preferentially to focal adhesion and adherens junction pathways. The results indicate an altered regulation of miRNA-mediated gene expression in the cellular interactions of aneurysmal aortic wall. PMID- 24052745 TI - Genetics of non syndromic hearing loss in the republic of macedonia. AB - Hearing impairment is the most common sensory deficit in humans affecting 1 in 1000 newborns. When present in an infant, deafness may have dramatic effects on language acquisition, seriously compromising the quality of their life. Deafness is influenced by both genetic and environmental factors, with inherited causes as the most prominent etiological factor in deafness in developed countries. The genetic basis of hearing loss is complex with numerous loci and genes underlying hereditary sensoryneural non syndromic hearing loss (NSHL) in humans. Despite the wide functional heterogeneity of the genes, mutations in the GJB2 gene are found to be the most common cause of sporadic and recessive NSHL in many populations worldwide. Molecular characterization of deafness in the Republic of Macedonia was performed in 130 NSHL profoundly deaf children from different ethnic origins. Molecular studies included direct sequencing of the GJB2 gene and specific polymerase chain reaction (PCR) analyses for the del(GJB6-D13S1830) mutation. Five common mitochondrial DNA (mtDNA) mutations [A1555G, 961delT+ C(n), T1095C, C1494T and A827G] were also analyzed using the SNaPShot method. In preliminary studies, GJB2 gene mutations were found in 36.4% of analyzed patients, with predominance of 35delG in Macedonian and Albanian patients and W24X in Gypsy patients, respectively. No del(GJB6-D13S1830) mutation was found. None of the analyzed deafness-associated mutations in mtDNA were identified in the studied patients. PMID- 24052746 TI - Molecular Diagnostics of beta-Thalassemia. AB - A high-quality hemoglobinopathy diagnosis is based on the results of a number of tests including assays for molecular identification of causative mutations. We describe the current diagnostic strategy for the identification of beta thalassemias and hemoglobin (Hb) variants at the International Reference Laboratory for Haemoglobinopathies, Research Centre for Genetic Engineering and Biotechnology (RCGEB) "Georgi D. Efremov," Skopje, Republic of Macedonia. Our overall approach and most of the methods we use for detection of mutations are designed for the specific target population. We discuss new technical improvements that have allowed us to substantially reduce the average time necessary for reaching a conclusive diagnosis. PMID- 24052747 TI - Study of the hepatitis C virus in the republic of macedonia. AB - Hepatitis C virus (HCV) is a major public health problem. It is a leading cause of chronic liver disease and the most common indication for liver transplantation. The therapy for eradication of HCV infection is successful in only 50.0-80.0% of patients and is highly dependent on the HCV genotype. Molecular detection and characterization of HCV in the Republic of Macedonia started in 1990. Since then, more than 4000 samples have been analyzed at the Research Centre for Genetic Engineering and Biotechnology (RCGEB) "Georgi D. Efremov," Skopje, Republic of Macedonia. The prevalence of HCV infections in the healthy population of the Republic of Macedonia was found to be 0.4%, while it varies between 23.0 and 43.0% in different at-risk groups of patients. The prevalence of HCV genotypes, according to associated risk factors in HCV infected patients from the Republic of Macedonia, was analyzed. We found genotype 1 to be predominant in a group of hemodialysis patients, while genotype 3 was predominant in intravenous (IV) drug users. Association of six polymorphisms in the Oligoadenylate synthetase (OASL)-like interferon-stimulated gene with a sustained virological response was also analyzed. Our preliminary results suggest that non ancestral alleles in four of the six studies polymorphisms in OASL gene are associated with sustained virological response among HCV infected patients in R. Macedonia. PMID- 24052748 TI - Integrated genomic analysis of breast cancers. AB - Breast cancer is the most frequent and the most deadly cancer in women in Western countries. Different classifications of disease (anatomoclinical, pathological, prognostic, genetic) are used for guiding the management of patients. Unfortunately, they fail to reflect the whole clinical heterogeneity of the disease. Consequently, molecularly distinct diseases are grouped in similar clinical classes, likely explaining the different clinical outcome between patients in a given class, and the fact that selection of the most appropriate diagnostic or therapeutic strategy for each patient is not done accurately. Today, treatment is efficient in only 70.0-75.0% of cases overall. Our repertoire of efficient drugs is limited but is being expanded with the discovery of new molecular targets for new drugs, based on the identification of candidate oncogenes and tumor suppressor genes (TSG) functionally relevant in disease. Development of new drugs makes therapeutical decisions even more demanding of reliable classifiers and prognostic/predictive tests. Breast cancer is a complex, heterogeneous disease at the molecular level. The combinatorial molecular origin and the heterogeneity of malignant cells, and the variability of the host background, create distinct subgroups of tumors endowed with different phenotypic features such as response to therapy and clinical outcome. Cellular and molecular analyses can identify new classes biologically and clinically relevant, as well as provide new clinically relevant markers and targets. The various stages of mammary tumorigenesis are not clearly defined and the genetic and epigenetic events critical to the development and aggressiveness of breast cancer are not precisely known. Because the phenotype of tumors is dependent on many genes, a large-scale and integrated molecular characterization of the genetic and epigenetic alterations and gene expression deregulation should allow the identification of new molecular classes clinically relevant, as well as among the altered genes and/or pathways, the identification of more accurate molecular diagnostic, prognostic/predictive factors, and for some of them, after functional validation, the identification of new therapeutic targets. PMID- 24052749 TI - Molecular genetics of breast and ovarian cancer: recent advances and clinical implications. AB - Over the last few years, evidence has been accumulated that several susceptibility genes exist that differentially impact on the lifetime risk for breast or ovarian cancer. High-to-moderate penetrance alleles have been identified in genes involved in DNA double-strand break signaling and repair, and many low-penetrance susceptibility loci have been identified through genome-wide association studies. In this review, we briefly summarize present knowledge about breast and ovarian cancer susceptibility genes and discuss their implications for risk prediction and therapy. PMID- 24052750 TI - Genetic variation of the brca1 and brca2 genes in macedonian patients. AB - The most significant and well characterized genetic risk factors for breast and/or ovarian cancer are germline mutations in the BRCA1 and BRCA2 genes. The BRCA1 and BRCA2 gene mutations strikingly increase breast cancer risk, suggesting that polymorphisms in these genes are logical candidates in seeking to identify low penetrance susceptibility alleles. The aim of this study was to initiate a screen for BRCA1/2 gene mutations in order to identify the genetic variants in the Republic of Macedonia, and to evaluate the association of several single nucleotide polymorphisms (SNPs) in these genes with breast cancer risk. In this study, we included 100 patients with invasive breast cancer from the Republic of Macedonia, classified according to their family history and 100 controls. The methodology included direct sequencing, single nucleotide primer extension method and multiplex ligation probe amplification (MLPA) analysis, all followed by capillary electrophoresis (CE) on an ABI PRISMTM 3130 Genetic Analyzer. We identified a total of seven carriers of mutations in the BRCA1/2 genes. None of the tested polymorphisms was associated with sporadic breast cancer risk, however, polymorphism rs8176267 in BRCA1 and N372H in BRCA2 showed an association with breast cancer risk in patients with at least one family member with breast cancer. PMID- 24052752 TI - From the Editor's Desk. PMID- 24052751 TI - MicroRNAs in Breast Cancer -Our Initial Results. AB - MicroRNAs (miRNAs) are small [~21 nucleotide (nt)] non coding RNAs (ncRNAs) that regulate gene expression posttranscriptionally. About 3.0% of human genes encode for miRNAs, and up to 30.0% of human protein coding genes may be regulated by miRNAs. Currently, more than 2000 unique human mature microRNAs are known. MicroRNAs play a key role in diverse biological processes including development, cell proliferation, differentiation and apoptosis. These processes are commonly dysregulated in cancer, implicating miRNAs in carcinogenesis, where they act as tumor supressors or oncogenes. Several miRNAs are associated with breast cancer. Here we present our initial results of miRNA analyses of breast cancer tissues using quantitative real time-polymerase chain reaction (ReTi-PCR) (qPCR) involving stem-loop reverse transcriptase (RT) primers combined with TaqMan(r) PCR and miRNA microarray analysis. PMID- 24052753 TI - Advancing evidence-based practice - a quarterly compilation of research updates most likely to change clinical practice. PMID- 24052754 TI - Bioethics in practice - a quarterly column about medical ethics: ethics, quality, safety, and a just culture: the link is evident. PMID- 24052755 TI - Clinical images - a quarterly column: transorbital coil embolization of a carotid cavernous fistula. PMID- 24052756 TI - Editorial - can distance learning improve the quality of medical education? PMID- 24052758 TI - Improving Immunization Rates Using Lean Six Sigma Processes: Alliance of Independent Academic Medical Centers National Initiative III Project. AB - BACKGROUND: Quality improvement education and work in interdisciplinary teams is a healthcare priority. Healthcare systems are trying to meet core measures and provide excellent patient care, thus improving their Hospital Consumer Assessment of Healthcare Providers & Systems scores. Crittenton Hospital Medical Center in Rochester Hills, MI, aligned educational and clinical objectives, focusing on improving immunization rates against pneumonia and influenza prior to the rates being implemented as core measures. Improving immunization rates prevents infections, minimizes hospitalizations, and results in overall improved patient care. Teaching hospitals offer an effective way to work on clinical projects by bringing together the skill sets of residents, faculty, and hospital staff to achieve superior results. METHODS: WE DESIGNED AND IMPLEMENTED A STRUCTURED CURRICULUM IN WHICH INTERDISCIPLINARY TEAMS ACQUIRED KNOWLEDGE ON QUALITY IMPROVEMENT AND TEAMWORK, WHILE FOCUSING ON A SPECIFIC CLINICAL PROJECT: improving global immunization rates. We used the Lean Six Sigma process tools to quantify the initial process capability to immunize against pneumococcus and influenza. RESULTS: The hospital's process to vaccinate against pneumonia overall was operating at a Z score of 3.13, and the influenza vaccination Z score was 2.53. However, the process to vaccinate high-risk patients against pneumonia operated at a Z score of 1.96. Improvement in immunization rates of high-risk patients became the focus of the project. After the implementation of solutions, the process to vaccinate high-risk patients against pneumonia operated at a Z score of 3.9 with a defects/million opportunities rate of 9,346 and a yield of 93.5%. Revisions to the adult assessment form fixed 80% of the problems identified. CONCLUSIONS: This process improvement project was not only beneficial in terms of improved quality of patient care but was also a positive learning experience for the interdisciplinary team, particularly for the residents. The hospital has completed quality improvement projects in the past; however, this project was the first in which residents were actively involved. The didactic components and experiential learning were powerfully synergistic. This and similar projects can have far-reaching implications in terms of promoting patient health and improving the quality of care delivered by the healthcare systems and teaching hospitals. PMID- 24052757 TI - Implementation of a surgical safety checklist: impact on surgical team perspectives. AB - BACKGROUND: The World Health Organization (WHO) surgical safety checklist has been shown to decrease mortality and complications and has been adopted worldwide. However, system flaws and human errors persist. Identifying provider perspectives of patient safety initiatives may identify strategies for improvement. The purpose of this study was to determine provider perspectives of surgical safety checklist implementation in an effort to improve initiatives that enhance surgical patients' safety. METHODS: In September 2010, a WHO-adapted surgical safety checklist was implemented at our institution. Surgical teams were invited to complete a checklist-focused questionnaire 1 month before and 1 year after implementation. Baseline and follow-up results were compared. RESULTS: A total of 437 surgical care providers responded to the survey: 45% of providers responded at baseline and 64% of providers responded at follow-up. Of the total respondents, 153 (35%) were nurses, 104 (24%) were anesthesia providers, and 180 (41%) were surgeons. Overall, we found an improvement in the awareness of patient safety and quality of care, with significant improvements in the perception of the value of and participation in the time-out process, in surgical team communication, and in the establishment and clarity of patient care needs. Some discordance was noted between surgeons and other surgical team members, indicating that barriers in communication still exist. Overall, approximately 65% of respondents perceived that the checklist improved patient safety and patient care; however, we found a strong negative perception of operating room efficiency. CONCLUSION: Implementation of a surgical safety checklist improves perceptions of surgical safety. Barriers to implementation exist, but staff feedback may be used to enhance the sustainability and success of patient safety initiatives. PMID- 24052759 TI - Implementation of a faculty development curriculum emphasizing quality improvement and patient safety: results of a qualitative study. AB - BACKGROUND: We developed a faculty development curriculum emphasizing quality improvement and patient safety. Our project focused on developing a learning environment that fosters resident education in quality improvement and patient safety. METHODS: A multidisciplinary team developed a survey to assess baseline perceptions of quality improvement tools and training and resident participation in quality improvement and patient safety programs. We then developed a curriculum to address deficiencies. The curriculum paired residents with faculty. At the completion of the first curriculum cycle, we asked faculty and residents to complete the same survey. RESULTS: Our pilot survey revealed a need for a comprehensive program to teach faculty and residents the art of teaching. Our follow-up study showed an increase in the number of residents and faculty who reported that their programs were extremely or very good at providing tools to develop skills and habits to practice quality improvement. We also had a statistically significant decrease (15.8%, P=0.0128) in faculty who reported their program as not at all effective at providing resident quality improvement tools and skills. Among residents and faculty, we had a 12% (P=0.2422) and a 38.2% (P=0.0010), respectively, improvement in reported monthly resident involvement in quality improvement and patient safety projects. CONCLUSION: We demonstrated that developing a sustainable and practical faculty development program within a large academic medical center is feasible. Our postimplementation survey demonstrated an improvement in perceived participation in quality improvement, patient safety, and faculty development among faculty and residents. Future targets will focus on sustaining and spreading the program to all faculty and residents in the institution. PMID- 24052760 TI - A qualitative study of improving preceptor feedback delivery on professionalism to postgraduate year 1 residents through education, observation, and reflection. AB - BACKGROUND: To better standardize the teaching of professionalism, the American Board of Internal Medicine and the Accreditation Council for Graduate Medical Education established competency-based training milestones for internal medicine residency programs. Accordingly, professionalism milestones served as the basis for a faculty development program centered on providing feedback to postgraduate year 1 residents (interns) on their own professionalism behaviors during preceptor-resident sessions in the internal medicine continuity clinic. METHODS: To determine the level of faculty (n=8) understanding and comfort in providing feedback, surveys listing 12-month professionalism milestones were distributed to core internal medicine teaching faculty. Current interns (n=10) also rated their understanding of the same milestones. The faculty development program included interpersonal communication education, role-plays of difficult situations, and pocket resources, as well as direct feedback on videotaped sessions with residents. At the end of the intervention period, participating faculty completed a postdevelopment survey, and the current 6-month interns completed a follow-up assessment. RESULTS: Average ratings between the pre- and postintervention teaching faculty surveys fell approximately 0.25%-0.50% on all measures of understanding, but increased slightly on measures of comfort. Conversely, average ratings between the pre- and postintervention 6-month intern surveys generally increased 0.25%-0.50% for measures of comfort and understanding. CONCLUSIONS: The faculty perceived the intervention as helpful in teaching them to focus on behaviors that change the context of overall feedback delivery. However, the study results showed that the system in place was not conducive to implementing such a program without modification and the introduction of resources. PMID- 24052761 TI - Insulin administration and meal delivery coordination for hospitalized patients. AB - BACKGROUND: Through efforts to continuously improve the quality of care provided to hospitalized patients with diabetes by evaluation of adherence to standards and performance metrics, we identified an opportunity for improvement. METHODS: A plan-do-study-act cycle was initiated with the goal of enhancing patient satisfaction with the timing of blood glucose monitoring, insulin administration, and meal delivery in the hospital. RESULTS: Despite an educational intervention with the nursing staff, patient satisfaction with mealtime insulin administration decreased from 83% to 78%. CONCLUSION: Education of frontline staff was not adequate to achieve our quality improvement goal. PMID- 24052762 TI - Patient Preferences for Doctor Attire: The White Coat's Place in the Medical Profession. AB - BACKGROUND: The white coat's place in the medical profession is a heavily debated topic. Five years after the bare-below-the-elbow policy took effect in England, we reexamined the evidence about coats' potential to transmit infection, reviewed previous studies, and explored our patients' opinions on doctor attire. METHODS: We administered a survey at 3 locations in the Ochsner Health System (hospital clinic, satellite clinic, and inpatient ward) in 2013. The survey assessed patient preference for doctors to wear white coats and included 4 images of the same doctor in different attire: traditional white coat, bare-below-the-elbow attire, a white coat with scrubs, and scrubs alone. Respondents rated images head to-head for their preferences and individually for their confidence in the physician's skills and for their comfort level with the physician based upon the displayed attire. Participants' attitudes were then reassessed after they were given information about potential disease transmission. RESULTS: Overall, 69.9% of the 153 patients surveyed preferred doctors to wear white coats. When locations were compared, a statistically higher proportion of outpatients preferred coats (P=0.001), a trend most pronounced between hospital clinic (84%) and ward inpatients (51.9%). Patients disliked bare-below-the-elbow attire, scoring it lowest on the comfort and confidence scales (0.05 and 0.09, respectively). Information regarding risks of coat-carried infections did not influence respondents' opinions; 86.9% would still feel comfortable with a doctor who wore one. CONCLUSIONS: These findings suggest patients prefer white coats, and they contribute to greater comfort and confidence in their physicians, despite knowledge of theoretic concerns of disease transmission. PMID- 24052763 TI - Evaluating A Patient-Centered Medical Home From the Patient's Perspective. AB - BACKGROUND: The medical home is an organizational approach for improving care, improving patient experience, and reducing costs. The purpose of this qualitative project was to obtain input from patients that could be used to improve their experiences in the medical home for ongoing disease management and health improvement and to obtain their recommendations for the most effective methods to involve patients in shaping system policies, procedures, and practices consistent with patient- and family-centered care principles. METHODS: We conducted cognitive interviews to complete patient experience surveys, structured focus groups, and exit surveys. A sample of 32 adults participated in cognitive interviews (n=15) and structured focus groups (n=17) using the nominal group technique (NGT). Exit surveys collected demographic information and input from patients about opportunities for their involvement in shaping medical homes. RESULTS: Cognitive interviews, NGT sessions, and exit surveys revealed patient perceived strengths and inadequacies within the medical home. Better access to care, including more efficient appointment scheduling and reduced wait times to see a physician once patients arrived for scheduled appointments, was identified as a necessary improvement. Patients' positive perceptions included how the medical home helps them reach their health goals and their overall satisfaction with the quality of care received. CONCLUSION: The input received from patients through the methods used in this project was useful in revealing needed improvements within a medical home and, if resolved, will ensure that all patients have access to the kind of care that works for them. PMID- 24052764 TI - Bridging the gap: a collaborative to reduce peripherally inserted central catheter infections in the home care environment. AB - BACKGROUND: Ochsner Health System agreed to participate in a nationwide collaboration to reduce central line infections in our intensive care units. Our outpatient peripherally inserted central catheter (PICC) infection rate was unacceptably high, so as an adjunct to the nationwide study we attempted to reduce PICC infections in the home care environment. Typically, home health nurses or outpatient infusion centers care for PICCs per protocol. However, no standardized protocol exists, and each facility may have a different way to care for PICCs, leading to varied and inconsistent maintenance. METHODS: Key members from our hospital, home health agencies, and an infusion company formulated a plan to reduce outpatient PICC infections. We hypothesized that the only way to reduce infections was to standardize line care and maintenance and to empower the patient to be an advocate for his or her care. The best avenue for achieving standardized care across multiple infusion companies and multiple home health agencies was to develop an order set for PICC care and dressing changes. We also developed a checklist for the nurse and the patient to complete together during dressing changes. The checklist and order set were linked to the hospital's home health discharge orders so that they would print automatically when the provider discharged the patient to home health care. RESULTS: Baseline data were collected from July 1, 2010, to June 30, 2011. During that time, the infusion company identified 20 PICC infections. In 20,773 line days, the infection rate was 0.963 per 1,000 line days. The new order sets and checklists were instituted on July 1, 2011. From July 1, 2011 through June 30, 2012, 11 PICC infections were identified with 21,021 line days. The calculated infection rate was 0.52 per 1,000 line days. PICC infections so far have been reduced by 46%. CONCLUSION: By bridging the gap between inpatient and outpatient care, we reduced PICC infections by 46% in our home infusion patients. We accomplished this result through a collaborative partnership among hospital staff, an infusion company, and home health agencies and a standardized process for line care and maintenance using a PICC home care order set and a patient/nursing PICC care checklist. PMID- 24052765 TI - Using quality improvement principles to improve the care of patients with severe sepsis and septic shock. AB - BACKGROUND: Sepsis, an inflammatory response to an infection that may lead to severe organ dysfunction and death, is the leading cause of death in medical intensive care units. The Society of Critical Care Medicine has issued guidelines and promoted protocols to improve the management of patients with severe sepsis and septic shock. Generally, the medical community has been slow to adopt these guidelines because of the system challenges associated with protocol implementation. We describe an interdisciplinary team approach to the development and implementation of management protocols for treating patients with severe sepsis and septic shock. METHODS: To determine the effectiveness of the bundled emergency department and critical care order sets developed by the Sepsis Steering Committee, we performed a case review of 1,105 sequential patients admitted to a large academic tertiary referral hospital with a diagnosis of severe sepsis or septic shock between July 2008 and January 2012. RESULTS: Implementation of the protocol led to improved order set use over time, a significant decrease in the median time to antibiotics of 140 (range 1-820) minutes in 2008 to 72 (range 1-1,020) minutes in 2011 (P<=0.001), and a decrease in median length of stay from 8 days (range 1-54) in 2008 to 7 days (range 1-33) in 2011 (P=0.036). CONCLUSION: A multidisciplinary team approach to sepsis management using protocols and early goal-directed therapy is feasible in a large academic medical center to improve the process of care and outcomes. PMID- 24052766 TI - Patient tobacco use, quit attempts, and perceptions of healthcare provider practices in a safety-net healthcare system. AB - BACKGROUND: Although smoking rates in the United States (US) are high, healthcare systems and clinicians can increase cessation rates through application of the US Public Health Service tobacco treatment guideline (2000, 2008). In primary care settings, however, guideline implementation remains low. This report presents the results from an assessment of patient tobacco use, quit attempts, and perceptions of provider treatment before (2004) and after (2010) guideline implementation. METHODS: By use of a systems approach, the Louisiana Tobacco Control Initiative integrated evidence-based treatment of tobacco use into patient care practices in Louisiana's public hospital system. This prospective study, designed to collect data at 2 time points for the purpose of evaluating the effect of the 5A protocol (ask, advise, assess, assist, and arrange), included 571 and 889 adult patients selected from primary care clinics in 2004 and 2010, respectively. Chi-square analyses determined differences between survey administrations, along with direct standardization of weighted rates to control for confounding factors. RESULTS: Patient reports indicated that provider adherence to the 5A clinical protocol increased from 2004 to 2010. Significant (P<0.001) improvements were observed for the assess (39% vs 72%), assist (24% vs 76%), and arrange (8% vs 31%) treatment variables. Patient-reported quit attempts increased, along with awareness of cessation services (from 19% to 70%, P<0.001), while use of cessation medications decreased (from 23% to 5%, P<0.002). CONCLUSION: Following implementation of the guideline, significant improvements were noted in patient reports of provider treatment and awareness of cessation services. PMID- 24052768 TI - Quality improvement on the acute inpatient psychiatry unit using the model for improvement. AB - BACKGROUND: A need exists for constant evaluation and modification of processes within healthcare systems to achieve quality improvement. One common approach is the Model for Improvement that can be used to clearly define aims, measures, and changes that are then implemented through a plan-do-study-act (PDSA) cycle. This approach is a commonly used method for improving quality in a wide range of fields. The Model for Improvement allows for a systematic process that can be revised at set time intervals to achieve a desired result. METHODS: We used the Model for Improvement in an acute psychiatry unit (APU) to improve the screening incidence of abnormal involuntary movements in eligible patients-those starting or continuing on standing neuroleptics-with the Abnormal Involuntary Movement Scale (AIMS). RESULTS: After 8 weeks of using the Model for Improvement, both of the participating inpatient services in the APU showed substantial overall improvement in screening for abnormal involuntary movements using the AIMS. CONCLUSION: Crucial aspects of a successful quality improvement initiative based on the Model for Improvement are well-defined goals, process measures, and structured PDSA cycles. Success also requires communication, organization, and participation of the entire team. PMID- 24052767 TI - Evaluation of pediatricians' adherence to tobacco prevention, control, and treatment guidelines before and after an educational outreach program. AB - BACKGROUND: Tobacco use is the world's leading single preventable cause of death. Because children exposed to second- and third-hand smoke are at risk for smoke related morbidity, pediatricians have an obligation to address tobacco use in their practices. The purpose of this study was to measure physician adherence to the American Academy of Pediatrics' guidelines on tobacco prevention, control, and treatment before and after the implementation of an educational outreach program. METHODS: Charts were randomly selected from pediatric clinics before and after the educational outreach. The intervention consisted of a review of the guidelines and available tools physicians could implement into their practices. We measured the rates of adherence to the guidelines before and after the educational outreach. RESULTS: We analyzed 213 charts (116 pre- and 97 posteducation). The proportion of families screened for tobacco smoke exposure was comparable between the pre- and postintervention groups (67.2% vs 59.8%, P=0.317). The postintervention group had a higher proportion of counseling compared to the preintervention group (51.5% vs 31.9%, P<0.05). We found no statistically significant change in the rate of screening or referral to smoking cessation services. CONCLUSION: Current guidelines to reduce tobacco use are underutilized. Educational outreach may increase the rate of counseling. Physician acceptance of guidelines is urgently needed to affect the tobacco epidemic. PMID- 24052769 TI - Does integrated practice guideline testing in gastroenterology fellowship training improve fellows' education? AB - BACKGROUND: Multiple professional societies have issued practice guidelines that provide up-to-date evidence-based recommendations and expert opinions on patient care in the field of gastroenterology (GI). While most physicians are aware that formal guidelines exist, these GI guidelines have not been integrated into academic training curricula in most of the top-ranked GI fellowship programs. METHODS: Two fellows in the Ochsner GI fellowship program (the control group) reviewed 14 current American Society of Gastrointestinal Endoscopy guidelines deemed essential for GI fellowship training and wrote 200 questions based on these guidelines. Four additional fellows (the experimental group) had no knowledge of which articles would be tested. A 14-week curriculum focused on reviewing the guidelines. All 6 fellows took a pretest before the guideline review and then took a postreview test. All of the participating GI fellows completed a survey evaluating the perceived effectiveness of the formal guideline testing. RESULTS: The experimental group had a 33% improvement in test scores between the pre- and posttest, while the control group had a 7% improvement. The survey showed that 100% of the fellows felt more secure in their knowledge of the guidelines and would recommend that this learning format be implemented into the annual academic curriculum. All also agreed that this format provided evidence based knowledge to improve patient safety and provide optimal patient care. CONCLUSION: We plan to continue formal practice guideline reviews in our fellowship and believe this format would benefit other medical training programs as well. PMID- 24052771 TI - House Staff Quality Council: One Institution's Experience to Integrate Resident Involvement in Patient Care Improvement Initiatives. AB - BACKGROUND: Residents and fellows perform a large portion of the hands-on patient care in tertiary referral centers. As frontline providers, they are well suited to identify quality and patient safety issues. As payment reform shifts hospitals to a fee-for-value-type system with reimbursement contingent on quality outcomes, preventive health, and patient satisfaction, house staff must be intimately involved in identifying and solving care delivery problems related to quality, outcomes, and patient safety. Many challenges exist in integrating house staff into the quality improvement infrastructure; these challenges may ideally be managed by the development of a house staff quality council (HSQC). METHODS: Residents and fellows at Scott & White Memorial Hospital interested in participating in a quality council submitted an application, curriculum vitae, and letter of support from their program director. Twelve residents and fellows were selected based on their prior quality improvement experience and/or their interest in quality and safety initiatives. RESULTS: In only 1 year, our HSQC, an Alliance of Independent Academic Medical Centers National Initiative III project, initiated 3 quality projects and began development of a fourth project. CONCLUSION: Academic medical centers should consider establishing HSQCs to align institutional quality goals with residency training and medical education. PMID- 24052770 TI - Effective use of bronchial blockers in lung isolation surgery: an analysis of 130 cases. AB - BACKGROUND: One-lung ventilation (OLV) is necessary for selected surgical settings and medical conditions. Different methods have been described and used to isolate 1 lung, including the double-lumen endotracheal tube (DLT) and a variety of bronchial blockers (BBs). This selection is often based on the preferences and experiences of the anesthesiologist and surgeon. Complications associated with OLV isolation tubes have been previously described, but complications specifically associated with the Cohen BB (CBB) (Cook Medical, Bloomington, IN) have not been investigated. The purpose of this retrospective review was to determine the incidence of vocal cord injury, tracheobronchial injury, and hoarseness in adult patients who underwent OLV with the CBB. METHODS: We reviewed electronic anesthesia records, operative dictation, and inpatient progress notes to collect information about vocal cord injury, bronchial injury, hoarseness, and sore throat for adults who underwent surgical and diagnostic procedures requiring OLV. Secondary endpoints were types of surgical procedures, degree of difficulty with orotracheal intubation, ability of the patient to tolerate extubation in the operating room, and whether the thoracic surgeon deemed the lung separation adequate. P<0.05 was considered significant. RESULTS: Of 130 patients, 113 underwent OLV with a CBB, and 17 patients underwent OLV with a DLT. The thoracic surgeon deemed the lung isolation adequate in all cases. Airway injury occurred in 2 patients with a CBB and none with a DLT (P=0.86). Both airway injuries were attributed to surgical technique. Two cases of postoperative hoarseness occurred in the CBB group (P=0.86). One injury was attributed to vagus nerve transection, and the other injury was diagnosed as vocal cord paralysis of unknown etiology. In 1 case, orotracheal intubation with a DLT was unsuccessful because of intubation difficulty and required conversion to a regular endotracheal tube and CBB for successful lung isolation. CONCLUSION: This study demonstrates that the use of CBB can be successful in a wide variety of thoracic operations, has minimal complications, eliminates the need for tracheal tube exchange when postoperative mechanical ventilation is required, and effectively isolates the lungs of critically ill patients. PMID- 24052772 TI - Just culture: a foundation for balanced accountability and patient safety. AB - BACKGROUND: The framework of a just culture ensures balanced accountability for both individuals and the organization responsible for designing and improving systems in the workplace. Engineering principles and human factors analysis influence the design of these systems so they are safe and reliable. METHODS: Approaches for improving patient safety introduced here are (1) analysis of error, (2) specific tools to enhance safety, and (3) outcome engineering. CONCLUSION: The just culture is a learning culture that is constantly improving and oriented toward patient safety. PMID- 24052773 TI - An inpatient hypoglycemia committee: development, successful implementation, and impact on patient safety. AB - BACKGROUND: Hypoglycemia is a major and preventable cause of morbidity and mortality in the hospital setting. Prevention of hypoglycemia in hospitalized patients relates to the practice climates and prescribing patterns of physicians, the development of safe and effective protocols, and the education of providers and nursing staff on hypoglycemia and its consequences. METHODS: Many hospitals use multidisciplinary committees to address issues of healthcare quality and patient safety. This article describes the creation of a subspecialty Hypoglycemia Committee, its design and function, and the steps taken to reduce hypoglycemia in a large, tertiary acute care hospital. RESULTS: The committee's initiatives included a systematic investigation of all severe hypoglycemic events, the development of a standalone hypoglycemia treatment protocol, reduction of sliding scale insulin therapy, revision of insulin order sets, and education of physicians and house staff. Hypoglycemic events have consequently decreased. CONCLUSION: The Hypoglycemia Committee is unique in that every case of severe hypoglycemia is reviewed by physicians, endocrinologists, and diabetes specialists. This multidisciplinary approach can effect measurable decreases in preventable hypoglycemic events. PMID- 24052774 TI - Liver transplantation at the ochsner clinic: quality and outcomes improvement. AB - BACKGROUND: In 2005, the results published by the Scientific Registry of Transplant Recipients showed that Ochsner Clinic Foundation's patient and graft survival rates were statistically lower than expected, and the United Network for Organ Sharing Membership and Professional Standards Committee placed our center under peer review. METHODS: In response, patient outcomes prior to August 2005 were carefully reviewed in a transparent fashion and protocols were written to standardize treatments. We renewed the focus on patient-related outcomes and regulatory adherence and empowered frontline staff to express their views, allowing for real teamwork to develop. Multiple changes were implemented in the everyday running of the program. A quality assurance and performance improvement plan (QAPI) was initiated to improve outcomes. RESULTS: In 2012, the Ochsner liver transplant program became the largest liver transplant program in the United States by volume and in 2013 was awarded the prestigious CareChex award, acknowledging it as the number one program in terms of quality of care and outcomes for liver transplantation. CONCLUSION: The methodical application of this QAPI program achieved a remarkable transformation of the Ochsner liver transplant program and exemplifies what is possible with strong teamwork from dedicated and talented staff. PMID- 24052777 TI - Ochsner research update, 2012-2013. PMID- 24052775 TI - Care transitions in anticoagulation management for patients with atrial fibrillation: an emphasis on safety. AB - BACKGROUND: Thromboprophylaxis with oral anticoagulants is an important but underused element of atrial fibrillation (AF) treatment. Reduction of stroke risk by anticoagulants comes at the price of bleeding risk. Patients with AF receiving anticoagulants require heightened attention with transition from one care setting to another. METHODS: This review of the literature focuses on issues specific to the anticoagulation treatment of patients with AF. RESULTS: Patients presenting for emergency care of anticoagulant-related bleeding should be triaged for the severity and source of the bleeding using appropriate measures, such as discontinuing the oral anticoagulant, administering vitamin K when appropriate to reverse warfarin-induced bleeding, or administering clotting factors for emergent bleeding. Reversal of oral anticoagulants in patients admitted to the hospital for surgery can be managed similarly to patients with bleeding, depending on the urgency of the surgical procedure. Patients with AF who are admitted for conditions unrelated to AF should be assessed for adequacy of stroke risk prophylaxis and bleeding risk. Newly diagnosed AF should be treated in nearly all patients with either warfarin or a newer anticoagulant. CONCLUSIONS: Patient education is critically important with all anticoagulants. Close adherence to the prescribed regimen, regular international normalized ratio testing for warfarin, and understanding the stroke risk conferred by AF and aging are goals for all patients receiving oral anticoagulants. Detailed handoff from the hospitalist to the patient's primary care physician is required for good continuity of care. Monitoring by an anticoagulation clinic is the best arrangement for most patients. The elderly, particularly frail or debilitated patients who are transferring to long-term care, need a detailed transfer of information between settings, education for the patient and family, and medication reconciliation. Communication and coordination of care among outpatient, emergency, inpatient, subacute, and long-term care settings are vital in patients with AF who are receiving anticoagulants to balance stroke prevention and bleeding risk. PMID- 24052776 TI - Letters to the editor. PMID- 24052778 TI - Introduction to Ochsner's Tenth Annual Research Day. PMID- 24052780 TI - CME Upcoming Events/CME Credit Information. PMID- 24052781 TI - CME Test/CME Application Form. PMID- 24052779 TI - Research day 2013 award winners. PMID- 24052782 TI - Ethical issues in pediatric pharmacogenomics. PMID- 24052783 TI - Management strategies for neonatal hypoglycemia. AB - While hypoglycemia occurs commonly among neonates, treatment can be challenging if hypoglycemia persists beyond the first few days of life. This review discusses the available treatment options for both transient and persistent neonatal hypoglycemia. These treatment options include dextrose infusions, glucagon, glucocorticoids, diazoxide, octreotide, and nifedipine. A stepwise, practical approach to the management of these patients is offered. PMID- 24052784 TI - Genetics-based pediatric warfarin dosage regimen derived using pharmacometric bridging. AB - BACKGROUND: Warfarin dosage regimens using CYP2C9 and VKORC1 polymorphisms have been extensively studied in adults and is included in US Food and Drug Administration-approved warfarin labeling. However, no dosage algorithm is available for pediatric patients. OBJECTIVE: To derive a genetics-based pediatric dosge regimen for warfarin, including starting dose and titration scheme. METHODS: A model-based approach was developed based on a previously validated warfarin dosage model in adults, with subsequent comparison to pediatric data from pediatric warfarin dose, genotyping, and international normalized ratio (INR) results. The adult model was based on a previously established model from the CROWN (CReating an Optimal Warfarin dosing Nomogram) trial. Pediatric warfarin data were obtained from a study conducted at the Children's Hospital of Los Angeles with 26 subjects. Variant alleles of CYP2C9 (rs1799853 or *2, and rs1057910 or *3) and the VKORC1 single nucleotide polymorphism (SNP) rs9923231 ( 1639 G>A) were assessed, where the rs numbers are reference SNP identification tags assigned by the National Center for Biotechnology Information. RESULTS: A pediatric warfarin model was derived using the previously validated model and clinical pharmacology considerations. The model was validated, and clinical trial simulation and stochastic modeling were used to optimize pediatric dosage and titration. The final dosage regimen was optimized based on simulations targeting a high (>=60%) proportion of INRs within the therapeutic range by week 2 of warfarin therapy while minimizing INRs >3.5 or <2. CONCLUSIONS: The proposed pediatric warfarin dosage scheme based on individual CYP2C9 (alleles *1,*2,*3) and VKORC1 rs9923231 (-1639 G>A) genotypes may offer improved dosage compared to current treatment strategies, especially in patients with variant CYP2C9 and VKORC1 alleles. This pilot study provides the foundation for a larger prospective evaluation of genetics-based warfarin dosage in pediatric patients. PMID- 24052785 TI - The impact of a pediatric antibiotic standard dosing table on dosing errors. AB - OBJECTIVE: The goal of this study was to compare the rate of dosing errors for antibiotic orders in pediatric patients before and after the implementation of an antibiotic standard dosing table with precalculated dosage for different weight ranges at a tertiary care hospital. METHODS: A retrospective study of 300 antibiotic prescriptions for pediatric patients in three different settings (ambulatory care, inpatient, and emergency department) at a tertiary care hospital assessed the appropriateness of antibiotic dosing. The need for an antibiotic dosing standardization policy was identified after finding that more than 30% of patients experienced a dose variation of +/-10% of the recommended daily dose. An antibiotic dosing standardization policy was implemented with an antibiotic standard dosing table for different weight ranges, and a hospital wide education program was conducted to increase awareness of this new practice and its benefits. Three months after implementation, a random sampling of 300 antibiotic prescriptions collected from the same settings as the pre-intervention period was evaluated for compliance with the new policy and its effect on the number of antibiotic dosing errors. RESULTS: Six hundred prescriptions were included in this study (300 in the pre-implementation phase and 300 in the post implementation phase). Patient characteristics were similar in both groups in terms of sex, age, and weight. Physician compliance with the antibiotic dosing standardization policy after its implementation was 62%. The dosing standardization policy reduced the rate of dosing errors from 34.3% to 5.06% (p=0.0001), and weight documentation on the antibiotic prescription improved from 65.8% to 85.7% (p=0.0001). CONCLUSIONS: Implementation of an antibiotic dosing standardization policy significantly reduced the incidence of dosing errors in antibiotics prescribed for pediatric patients in our hospital. PMID- 24052786 TI - Glycemic control in pediatric patients on extracorporeal membrane oxygenation. AB - OBJECTIVES To determine whether glycemic control has an effect on outcomes for pediatric patients on extracorporeal membrane oxygenation (ECMO) therapy, while controlling for multiple factors. METHODS A single-center retrospective chart review was performed on 82 patients who required ECMO from January 1, 2008, to December 31, 2010. All glucose concentrations collected while patients were on ECMO were analyzed; multiple other factors that may have affected mortality were also recorded. Primary outcome was mortality, and secondary outcomes were length of time on ECMO and length of time until death or discharge from the hospital. RESULTS Of 82 patients, 53 patients survived ECMO (64.6%). Glucose control had no effect on survival of patients on ECMO (p=0.56), even when controlling for multiple factors (p=0.48). Similarly, statistical evaluation showed no differences for hospital mortality in relationship to controlled serum glucose (p=0.50). Patients with controlled glucose spent an average of 31.5% more time on ECMO than non-controlled patients (p=0.048). CONCLUSIONS In this study, glycemic control, defined as serum glucose concentration between 60 mg/dL and 250 mg/dL for >95% of the time on ECMO, had no statistically significant effect on mortality for patients on ECMO. Future studies could focus on tighter glucose control or specific dextrose/glucose protocols to evaluate whether improved glucose control would have an effect on morbidity and mortality. PMID- 24052787 TI - Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) in an Adolescent Treated With Lamotrigine. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) is a hypersensitivity syndrome most commonly associated with antiepileptic agents, allopurinol, and sulfonamides. It is a severe adverse reaction associated with fever, rash, eosinophilia, lymphadenopathy, and internal organ involvement. We present the case of a 17-year-old Caucasian female with bipolar disorder type II and posttraumatic stress disorder treated with lamotrigine for a non-Food and Drug Administration-approved indication that developed DRESS syndrome at an initial dose higher than that recommended. Her symptoms were atypical in that she developed a rash with influenza-like symptoms that resolved after discontinuation of lamotrigine and returned 8 days later. She was hospitalized because of elevated liver enzymes and treated with corticosteroids. In patients presenting with rash and systemic symptoms, DRESS syndrome should be considered and treated appropriately to reduce mortality, which can be as high as 10%. Treatment includes withdrawal of the offending agent and corticosteroids. PMID- 24052788 TI - Ondansetron to treat pruritus due to cholestatic jaundice. AB - Intractable itching is a symptom of cholestatic liver disease of various causes that is bothersome and difficult to manage. Although treatment of the primary cause of cholestasis is paramount in resolving the issue, given the debilitating consequences of pruritus, symptomatic treatment is frequently necessary. Although many medications including cholestyramine, rifampin, opioid antagonists (i.e., naloxone, naltrexone), phenobarbital, and antihistamines have been used to treat cholestatic-induced pruritus, none has resulted in uniform success. We report anecdotal success with the use of ondansetron to treat pruritus associated with cholestasis following prolonged intensive care unit course of a 16-year-old. The theories accounting for pruritus with cholestasis are presented, treatment options are reviewed, and the role of ondansetron in the treatment of pruritus is discussed. PMID- 24052789 TI - Evaluating medication use in pregnancy and lactation: what every pharmacist should know. AB - As a pharmacist, being asked to give advice about medication use during pregnancy or lactation can be daunting. This article reviews the principles of drug transfer across the placenta, into breast milk, and reviews the rating scales and different resources available. The Food and Drug Administration classification scale is reviewed and the upcoming changes are explained, along with recent labeling changes for specific medications or drug classes when appropriate. This article provides the pharmacist with a practical set of tools to review the information available and assess the risks of treating or withholding a medication for mother and infant. PMID- 24052790 TI - Pediatric news. PMID- 24052791 TI - Recurrent Strokes due to Transient Vasospasms of the Extracranial Internal Carotid Artery. AB - Vasospasms of the intracranial arteries are a well-known complication of subarachnoid hemorrhage and are also frequently encountered in other disorders such as migraine, cerebral vasculitis or reversible cerebral vasoconstriction syndrome. In contrast, recurrent spontaneous vasospasms of the extracranial circulation appear to be extremely rare and have most often been associated with migraine. We present a patient with recurrent strokes due to spontaneous transient vasospastic occlusions of the internal carotid artery (ICA) without migraine over a time period of at least 13 years. Initially, the patient had presented with a bilateral ICA occlusion and a cerebral infarct on the right side. While the right ICA remained occluded, a reopening of the left ICA could be detected 3 days after this initial event. In subsequent years, both duplex sonography and magnetic resonance angiography revealed recurrent occlusions of the left ICA, which resolved spontaneously within days. This case and other rare previous reports indicate that recurrent non-migrainous vasospasms of the extracranial carotid artery likely reflect a distinct entity which can cause ischemic strokes. PMID- 24052792 TI - CT and Clinical Predictors of Fatigue at One Month after Stroke. AB - BACKGROUND: Fatigue is a common and distressing consequence of stroke, and the aetiology of post-stroke fatigue (PSF) is poorly understood. It is unclear whether chronic brain changes [cerebral atrophy and white matter lesions (WML)], stroke lesion location or certain clinical features are related to its development. The aim of this study was to identify, in patients with acute stroke, whether features in different brain regions on routine CT imaging or routinely collected clinical features predicted PSF at 1 month. METHODS: In total, 107 patients (62% male) with acute ischaemic or haemorrhagic stroke were assessed for fatigue (Fatigue Assessment Scale), anxiety and depression (Hospital Anxiety and Depression Scale) at 1 month. Admission brain CT was rated using a structured scoring system for (i) severity of atrophy and (ii) severity of WML in different regions of the brain, and (iii) site of acute and previous vascular lesions. RESULTS: Cerebral atrophy of mild or greater severity was present in 84 patients (77.5%) and WML of mild or greater severity was present in 54 patients (50.5%) in at least one of the evaluated brain regions. There was no association between PSF and severity of atrophy or WML, or presence of acute or previous vascular lesions. We used the Oxfordshire Community Stroke Project (OCSP) classification to explore the possible influence of lesion location because a minority of the patients (37.4%) had visible acute lesions. Fatigue scores were higher in patients with clinically diagnosed posterior strokes (p = 0.046), in females (p = 0.05) and in those with higher depression and anxiety scores (rho = 0.52; p < 0.001 and rho = 0.49; p < 0.001, respectively). Structural CT variables were not significant predictors of fatigue (log FAS) in a linear regression which controlled for age, sex, pre-stroke fatigue, OCSP classification, depression and anxiety. The significant predictors of fatigue were depression (beta = 0.30; p = 0.007) and anxiety (beta = 0.28; p = 0.013; adjusted R(2) = 0.254). Stroke subtype (according to the OCSP classification) was marginally predictive (beta = 0.17; p = 0.05) and sex was not statistically significant (beta = 0.15; p = 0.08). CONCLUSIONS: Features on routine post-stroke CT do not appear to associate with fatigue at 1 month. However, clinically diagnosed posterior strokes as well as female gender, anxiety and depression may be linked with fatigue. Therefore, clinical vigilance rather than CT features should be used to predict fatigue early after stroke. Further research is needed in this area to establish whether biological mechanisms underlie the development of PSF. PMID- 24052793 TI - Negative fluid-attenuated inversion recovery-based intravenous thrombolysis using recombinant tissue plasminogen activator in acute stroke patients with unknown onset time. AB - BACKGROUND: Approximately 25% of acute stroke patients were excluded from intravenous thrombolysis using recombinant tissue plasminogen activator (IV-tPA) because of unknown onset time. Recent studies have shown that patients with unknown onset time would be able to receive IV-tPA when showing no ischemia on fluid-attenuated inversion recovery (negative FLAIR). The present study evaluated the safety and feasibility of IV-tPA in patients with unknown onset time and negative FLAIR compared to those with standard IV-tPA. METHODS: Stroke patients with unknown onset time were prospectively enrolled. Only patients with an occlusion of the internal carotid artery (ICA) and/or middle cerebral artery (M1 and M2) with a Diffusion-Weighted Imaging-Alberta Stroke Program Early CT Score (DWI-ASPECTS) >=5 were analyzed. IV-tPA was performed within 3 h from the 'first found abnormal time' if the patient showed negative FLAIR. Standard IV-tPA patients were extracted from our registry as controls after having been matched by age and occluded artery to the negative FLAIR (N-F) group. RESULTS: Twenty patients in the N-F group and 60 in the control group were included. National Institutes of Health Stroke Scale (NIHSS) scores [median 18 (interquartile range 13-20) vs. 17 (12-20), p = 0.609] and DWI-ASPECTS [9 (7-9) vs. 8 (5-9), p = 0.213] were similar between the 2 groups. ICA occlusion was seen in 35%, M1 in 50%, and M2 in 15% in both groups. None of the N-F group and 1 (2%) of the control group experienced symptomatic intracerebral hemorrhage (p = 1.000). Recanalization within 1 h after IV-tPA was achieved in 6 (30%) patients in the N F group and 24 (40%) in the control group (p = 0.595). Recanalization at 24 h after IV-tPA was seen in 13 (65%) patients in the N-F group and 43 (72%) in the control group (p = 0.584). At 7 days, 8 (40%) in the N-F group and 28 (47%) in the control group had a dramatic recovery (defined as a >=10-point reduction in the total NIHSS score or a score of 0 or 1) (p = 0.796). At 3 months, a favorable outcome (modified Rankin scale score, 0-2) was seen in 47% in the N-F group and 33% in the control group (p = 0.365). CONCLUSION: IV-tPA in negative FLAIR patients with unknown onset time appears safe and feasible. PMID- 24052794 TI - Fluid-attenuated inversion recovery hyperintense vessels in posterior cerebral artery infarction. AB - BACKGROUND: Fluid-attenuated inversion recovery hyperintense vessels (FHVs) are known to reflect stagnant or slow blood flow within the cerebral artery. FHVs are frequently observed in patients with acute cerebral infarction accompanied by arterial occlusion or significant stenosis of the anterior cerebral circulation. However, FHVs have not been studied in the context of posterior cerebral circulation. Thus, we investigated the prevalence of FHVs and its clinical significance in patients with acute posterior cerebral artery (PCA) territory infarction. METHODS: In this retrospective study, consecutive patients with PCA territory infarction who underwent MRI within 1 week after symptom onset were enrolled. Two neurologists who were blinded to the angiographic findings read the images and determined the presence of FHVs. Afterwards, FHVs were graded according to the extent (subtle or prominent) and location (proximal or distal) of the hyperintense vessels. Neurologic deficits of the patients were assessed by the National Institutes of Health Stroke Scale (NIHSS) upon admission and after 5 days. The clinical outcome between patient groups based on FHVs grading was compared using the NIHSS. Among the patients with PCA occlusion, infarction volume on the diffusion-weighted image was compared between the two groups with and without distal FHVs. RESULTS: FHVs were observed in 25 of the 87 patients (28.7%) with PCA territory infarction and in 65.7% of the 35 patients with significant arterial stenosis (10 patients) or occlusion (25 patients) in the posterior cerebral circulation. Among the 18 patients with PCA occlusion, the NIHSS score was significantly improved in patients with distal FHVs compared to the others (2.00 +/- 2.18 vs. 0.56 +/- 1.01, p = 0.04). The infarction volume was smaller in the distal FHV group than in the others (8.3 +/- 8.7 vs. 16.8 +/- 17.6 ml), but the difference was not statistically significant. CONCLUSIONS: FHVs are detected in patients with PCA territory infarction, especially in those with an occlusive lesion in the PCA. FHVs can be used as an imaging marker of PCA occlusion. Although this study showed a better clinical improvement in patients with distal FHVs, further study is needed to elucidate the clinical meaning of FHVs in PCA infarction. PMID- 24052795 TI - Vascular steal explains early paradoxical blood oxygen level-dependent cerebrovascular response in brain regions with delayed arterial transit times. AB - INTRODUCTION: Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) during manipulation of inhaled carbon dioxide (CO2) can be used to measure cerebrovascular reactivity (CVR) and map regions of exhausted cerebrovascular reserve. These regions exhibit a reduced or negative BOLD response to inhaled CO2. In this study, we sought to clarify the mechanism behind the negative BOLD response by investigating its time delay (TD). Dynamic susceptibility contrast (DSC) MRI with the injection of a contrast agent was used as the gold standard in order to provide measurement of the blood arrival time to which CVR TD could be compared. We hypothesize that if negative BOLD responses are the result of a steal phenomenon, they should be synchronized with positive BOLD responses from healthy brain tissue, even though the blood arrival time would be delayed. METHODS: On a 3-tesla MRI system, BOLD CVR and DSC images were collected in a group of 19 patients with steno-occlusive cerebrovascular disease. For each patient, we generated a CVR magnitude map by regressing the BOLD signal with the end-tidal partial pressure of CO2 (PETCO2), and a CVR TD map by extracting the time of maximum cross-correlation between the BOLD signal and PETCO2. In addition, a blood arrival time map was generated by fitting the DSC signal with a gamma variate function. ROI masks corresponding to varying degrees of reactivity were constructed. Within these masks, the mean CVR magnitude, CVR TD and DSC blood arrival time were extracted and averaged over the 19 patients. CVR magnitude and CVR TD were then plotted against DSC blood arrival time. RESULTS: The results show that CVR magnitude is highly correlated to DSC blood arrival time. As expected, the most compromised tissues with the longest blood arrival time have the lowest (most negative) CVR magnitude. However, CVR TD shows a noncontinuous relationship with DSC blood arrival time. CVR TD is well correlated to DSC blood arrival time (p < 0.0001) for tissue of positive reactivity, but fails to maintain this trend for tissue of negative reactivity. Regions with negative reactivity have similar CVR TD than healthy regions. CONCLUSION: These results support the hypothesis that negative reactivity is the result of a steal phenomenon, lowering the BOLD signal as soon as healthier parts of the brain start to react and augment their blood flow. BOLD CVR MRI is capable of identifying this steal distribution, which has particular diagnostic significance as it represents an actual reduction in flow to already compromised tissue. PMID- 24052796 TI - Adapting the computed tomography criteria of hemorrhagic transformation to stroke magnetic resonance imaging. AB - BACKGROUND: The main safety aspect in the use of stroke thrombolysis and in clinical trials of new pharmaceutical or interventional stroke therapies is the incidence of hemorrhagic transformation (HT) after treatment. The computed tomography (CT)-based classification of the European Cooperative Acute Stroke Study (ECASS) distinguishes four categories of HTs. An HT can range from a harmless spot of blood accumulation to a symptomatic space-occupying parenchymal bleeding associated with a massive deterioration of symptoms and clinical prognosis. In magnetic resonance imaging (MRI) HTs are often categorized using the ECASS criteria although this classification has not been validated in MRI. We developed MRI-specific criteria for the categorization of HT and sought to assess its diagnostic reliability in a retrospective study. METHODS: Consecutive acute ischemic stroke patients, who had received a 3-tesla MRI before and 12-36 h after thrombolysis, were screened retrospectively for an HT of any kind in post treatment MRI. Intravenous tissue plasminogen activator was given to all patients within 4.5 h. HT categorization was based on a simultaneous read of 3 different MRI sequences (fluid-attenuated inversion recovery, diffusion-weighted imaging and T2* gradient-recalled echo). Categorization of HT in MRI accounted for the various aspects of the imaging pattern as the shape of the bleeding area and signal intensity on each sequence. All data sets were independently categorized in a blinded fashion by 3 expert and 3 resident observers. Interobserver reliability of this classification was determined for all observers together and for each group separately by calculating Kendall's coefficient of concordance (W). RESULTS: Of the 186 patients screened, 39 patients (21%) had an HT in post treatment MRI and were included for the categorization of HT by experts and residents. The overall agreement of HT categorization according to the modified classification was substantial for all observers (W = 0.79). The degrees of agreement between experts (W = 0.81) and between residents (W = 0.87) were almost perfect. For the distinction between parenchymal hematoma and hemorrhagic infarction, the interobserver agreement was almost perfect for all observers taken together (W = 0.82) as well as when experts (W = 0.82) and residents (W = 0.91) were analyzed separately. CONCLUSION: The ECASS CT classification of HT was successfully adapted for usage in MRI. It leads to a substantial to almost perfect interobserver agreement and can be used for safety assessment in clinical trials. PMID- 24052797 TI - Six-minute walking distance correlated with memory and brain volume in older adults with mild cognitive impairment: a voxel-based morphometry study. AB - BACKGROUND/AIMS: High fitness levels play an important role in maintaining memory function and delaying the progression of structural brain changes in older people at risk of developing dementia. However, it is unclear which specific regions of the brain volume are associated with exercise capacity. We investigated whether exercise capacity, determined by a 6-min walking distance (6MWD), is associated with measures of logical and visual memory and where gray matter regions correlate with exercise capacity in older adults with mild cognitive impairment (MCI). METHODS: Ninety-one community-dwelling older adults with MCI completed a 6 min walking test, structural magnetic resonance imaging scanning, and memory tests. The Wechsler Memory Scale-Revised Logical Memory and Rey-Osterrieth Complex Figure Tests were used to assess logical and visual memory, respectively. RESULTS: The logical and visual memory tests were positively correlated with the 6MWD (p < 0.01). Poor performance in the 6MWD was correlated with a reduced cerebral gray matter volume in the left middle temporal gyrus, middle occipital gyrus, and hippocampus in older adults with MCI. CONCLUSIONS: These results suggest that a better 6MWD performance may be related to better memory function and the maintenance of gray matter volume in older adults with MCI. PMID- 24052798 TI - Imaging findings associated with cognitive performance in primary lateral sclerosis and amyotrophic lateral sclerosis. AB - INTRODUCTION: Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes. METHODS: The Delis-Kaplan Executive Function System (D-KEFS), the Mattis Dementia Rating Scale (DRS-2), and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI) and DTI. Atlas based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model. RESULTS: More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores. CONCLUSION: The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment. PMID- 24052799 TI - Clinical Characteristics of C9ORF72-Linked Frontotemporal Lobar Degeneration. AB - BACKGROUND: The most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) has been linked to a hexanucleotide repeat expansion in the C9ORF72 gene. The frequency of the C9ORF72 expansion in Finland is among the highest in the world. METHODS: We assessed 73 Finnish patients with FTLD in order to examine the clinical characteristics associated with the expanded C9ORF72. Demographic and clinical features were evaluated. As a potential disease modifier, the apolipoprotein E (APOE) genotype was also assessed. Neuropathological analysis was available on 2 expansion carriers and 1 non-carrier. RESULTS: The C9ORF72 expansion was present in 20 of 70 (29%) probands. Significant associations with the C9ORF72 expansion were observed for concomitant ALS and positive family history of dementia or ALS. Psychoses were detected in both carriers and non-carriers (21 vs. 10%, p = 0.25). The APOE epsilon4 allele did not cluster among expansion carriers. Numerous p62 positive neuronal inclusions were detected in the cerebellar cortex of the 2 expansion carriers. CONCLUSION: In line with the suggested C9ORF72 core phenotype, we also detected a high frequency of neuropsychiatric symptoms; however, these symptoms seem not be specific to C9ORF72-associated FTLD. FTLD should be considered in cases of middle-age-onset psychosis. PMID- 24052800 TI - Cognitive stimulation in patients with dementia: randomized controlled trial. AB - BACKGROUND/AIMS: This study explores the effective outcomes of a structured cognitive stimulation treatment to improve cognition and behavioral symptoms in people with dementia (PWDs), using a randomized controlled clinical trial. METHODS: THIRTY PWDS WERE DIVIDED INTO THREE GROUPS: experimental (treated with cognitive stimulation), placebo (treated with occupational therapy), and control (continuing with the usual activities of the nursing home). Assessment, at baseline and after a period of 8 weeks, was performed using the Clinical Dementia Rating Scale, activities of daily living, Mini-Mental State Examination, Esame Neuropsicologico Breve 2, Geriatric Depression Scale and Behavioral Pathology in Alzheimer's Disease Scale. RESULTS: Only the experimental group improved its performance in cognitive tests (p < 0.05) and showed a significant decrease in behavioral symptoms (p < 0.01) after the treatment. CONCLUSIONS: The results suggest that a cognitive stimulation treatment for PWDs would improve not only their cognition, but also behavioral symptoms. PMID- 24052801 TI - Variation of urate transport in the nephrons in subtypes of hyperuricemia. AB - BACKGROUND: Hyperuricemia cases (HU) can be classified into four subgroups by combining the two main causes of hyperuricemia, i.e. urate underexcretion and overproduction. These subgroups are as follows: underexcretion-type cases (UE); overproduction-type cases (OP); combined-type cases, and normal-type cases. Since urinary urate excretion (Uua) and urate clearance differ significantly between UE and OP, urate transport in the nephrons and the intratubular urate contents might also differ. Such differences might help clarify the pathophysiology of urate underexcretion in subgroups of hyperuricemia, and thus reveal its underlying mechanisms. METHODS: Urate transport coefficients in each subtype of HU were determined employing the previously reported benzbromarone-loading urate clearance tests. The subtype cases of HU were plotted on a graph of urate transport coefficients versus Uua as coordinates. The characteristic features in the distribution of subtype cases on graphs were analyzed in relation to Uua. RESULTS: The mean (+/-standard error) tubular secretion rate (TSR) in the UE (48.7 +/- 1.7 ml/min) was significantly lower and the postsecretory urate reabsorption rate (R2) in the UE (0.904 +/- 0.004) was significantly higher than those in the normal controls (78.0 +/- 2.1 ml/min and 0.877 +/- 0.003) or the OP (61.1 +/- 3.2 ml/min and 0.861 +/- 0.009). Decrements of TSR and increments of R2 in the UE were largest in the subtypes of the HU, in terms of case numbers and the deviation rate of the group. Conversely, decrements of TSR and increments of R2 were smallest in the OP. A significant correlation was identified between TSR and Uua (r = 0.345, p < 0.0001), and a significant negative correlation was also found between R2 and Uua (r = -0.393, p < 0.0001). CONCLUSION: IN THE UE, HYPERURICEMIA IS INDUCED MAINLY BY URATE UNDEREXCRETION, WHICH RESULTS FROM THE COMBINATION OF TWO MAIN CAUSES IN URATE TRANSPORTERS OF THE NEPHRON: significantly lower TSR and significantly higher R2. Neither of these was observed in OP. Differences in urate transporters in subtypes of the HU might be important not only for understanding the pathophysiology and mechanisms of urate underexcretion and hyperuricemia, but also for providing a strategic therapy for hyperuricemia. PMID- 24052802 TI - When host defense goes awry: Modeling sepsis-induced immunosuppression. AB - Sepsis is associated with an initial hyperinflammatory state; however, therapeutic trials targeting the inflammatory response have yielded disappointing results. It is now appreciated that septic patients often undergo a period of relative immunosuppression, rendering them susceptible to secondary infections. Interest in this phenomenon has led to the development of animal models to study the immune dysfunction of sepsis. In this review, we analyze the available models of sepsis-induced immunosuppression. PMID- 24052803 TI - Using Neuroscience to Broaden Emotion Regulation: Theoretical and Methodological Considerations. AB - Behavioral research on emotion regulation thus far has focused on conscious and deliberative strategies such as reappraisal. Neuroscience investigations into emotion regulation have followed suit. However, neuroimaging tools now open the door to investigate more automatic forms of emotion regulation that take place incidentally and potentially outside of participant awareness that have previously been difficult to examine. The present paper reviews studies on the neuroscience of intentional/deliberate emotion regulation and identifies opportunities for future directions that have not yet been addressed. The authors suggest a broad framework for emotion regulation that includes both deliberative and incidental forms. This framework allows insights from incidental emotion regulation to address open questions about existing work, and vice versa. Several studies relevant to incidental emotion regulation are reviewed with the goal of providing an empirical and methodological groundwork for future research. Finally, several theoretical issues for incidental and intentional emotion regulation are discussed. PMID- 24052804 TI - Improved PET imaging of uPAR expression using new (64)Cu-labeled cross-bridged peptide ligands: comparative in vitro and in vivo studies. AB - The correlation between uPAR expression, cancer cell invasion and metastases is now well-established and has prompted the development of a number of uPAR PET imaging agents, which could potentially identify cancer patients with invasive and metastatic lesions. In the present study, we synthesized and characterized two new cross-bridged (64)Cu-labeled peptide conjugates for PET imaging of uPAR and performed a head-to-head comparison with the corresponding and more conventionally used DOTA conjugate. Based on in-source laser-induced reduction of chelated Cu(II) to Cu(I), we now demonstrate the following ranking with respect to the chemical inertness of their complexed Cu ions: DOTA-AE105 << CB-TE2A-AE105 < CB-TE2A-PA-AE105, which is correlated to their corresponding demetallation rate. No penalty in the uPAR receptor binding affinity of the targeting peptide was encountered by conjugation to either of the macrobicyclic chelators (IC50 ~ 5 10 nM) and high yields and radiochemical purities (>95%) were achieved in all cases by incubation at 95oC. In vivo, they display identical tumor uptake after 1h, but differ significantly after 22 hrs, where the DOTA-AE105 uptake remains surprisingly high. Importantly, the more stable of the new uPAR PET tracers, (64)Cu-CB-TE2A-PA-AE105, exhibits a significantly reduced liver uptake compared to (64)Cu-DOTA-AE105 as well as (64)Cu-CB-TE2A-AE105, (p<0.0001), emphasizing that our new in vitro stability measurements by mass spectrometry predicts in vivo stability in mice. Specificity of the best performing ligand, (64)Cu-CB-TE2A PA-AE105 was finally confirmed in vivo using a non-binding (64)Cu-labeled peptide as control ((64)Cu-CB-TE2A-PA-AE105(mut)). This control PET-tracer revealed significantly reduced tumor uptake (p<0.0001), but identical hepatic uptake compared to its active counterpart ((64)Cu-CB-TE2A-PA-AE105) after 1h. In conclusion, our new approach using in-source laser-induced reduction of Cu(II) chelated PET-ligands provides useful information, which are predictive for the tracer stability in vivo in mice. Furthermore, the increased stability of our new macrobicyclic (64)Cu-CB-TE2A-PA-AE105 PET ligand is paralleled by an excellent imaging contrast during non-invasive PET scanning of uPAR expression in preclinical mouse cancer models. The translational promises displayed by this PET tracer for future clinical cancer patient management remains, however, to be investigated. PMID- 24052805 TI - Label-free luminescent mesoporous silica nanoparticles for imaging and drug delivery. AB - We report herein a straightforward and label-free approach to prepare luminescent mesoporous silica nanoparticles. We found that calcination at 400 degrees C can grant mesoporous organosilica nanoparticles with strong fluorescence of great photo- and chemical stability. The luminescence is found to originate from the carbon dots generated from the calcination, rather than the defects in the silica matrix as was believed previously. The calcination does not impact the particles' abilities to load drugs and conjugate to biomolecules. In a proof-of-concept study, we demonstrated that doxorubicin (Dox) can be efficiently encapsulated into these fluorescent mesoporous silica nanoparticles. After coupled to c(RGDyK), the nanoconjugates can efficiently home to tumors through interactions with integrin alphavbeta3 overexpressed on the tumor vasculature. This calcination-induced luminescence is expected to find wide applications in silica based drug delivery, nanoparticle coating, and immunofluorescence imaging. PMID- 24052806 TI - Multivalent dendritic molecules as broad spectrum bacteria agglutination agents. AB - This study reports the first set of synthetic molecules that act as broad spectrum agglutination agents and thus are complementary to the specific targeting of antibodies. The molecules have dendritic architecture and contain multiple copies of zinc(II)-dipicolylamine (ZnDPA) units that have selective affinity for the bacterial cell envelope. A series of molecular structures were evaluated, with the number of appended ZnDPA units ranging from four to thirty two. Agglutination assays showed that the multivalent probes rapidly cross-linked ten different strains of bacteria, regardless of Gram-type and cell morphology. Fluorescence microscopy studies using probes with four ZnDPA units indicated a high selectivity for bacteria agglutination in the presence of mammalian cells and no measurable effect on the health of the cells. The high bacterial selectivity was confirmed by conducting in vivo optical imaging studies of a mouse leg infection model. The results suggest that multivalent ZnDPA molecular probes with dendritic structures have great promise as selective, broad spectrum bacterial agglutination agents for infection imaging and theranostic applications. PMID- 24052808 TI - Synthesis and in silico evaluation of 1N-methyl-1S-methyl-2-nitroethylene (NMSM) derivatives against Alzheimer disease: to understand their interacting mechanism with acetylcholinesterase. AB - Anomalous action of human acetylcholinesterase (hAChE) in Alzheimer's disease (AD) was restrained by various AChE inhibitors, of which the specific and potent lead candidate Donepezil is used for treating the disease AD. Besides the specificity, the observed undesirable side effects caused by Donepezil invoked the quest for new lead molecules with the increased potency and specificity for AChE. The present study elucidates the potency of six 1N-methyl-1S-methyl-2 nitroethylene (NMSM) derivatives to form a specific interaction with the peripheral anionic site and catalytic anionic subsite residues of hAChE. The NMSMs were prepared in good yield from 1,1-di(methylsulfanyl)-2-nitroethylene and primary amine (or) amino acid esters. In silico interaction analysis reveals specific and potent interactions between hAChE and selected ligand molecules. The site-specific interactions formed between these molecules also results in a conformational change in the orientation of active site residues of hAChE, which prevents them from being accessed by beta-amyloid protein (Abeta), which is a causative agent for amyloid plaque formation and acetylcholine (ACh). In silico interaction analysis between the ligand-bounded hAChE with Abeta and ACh confirms this observation. The variation in the conformation of hAChE associated with the decreased ability of Abeta and ACh to access the respective functional residues of hAChE induced by the novel NMSMs favors their selection for in vivo analysis to present themselves as new members of hAChE inhibitors. PMID- 24052807 TI - Necrosis avidity: a newly discovered feature of hypericin and its preclinical applications in necrosis imaging. AB - Hypericin has been widely studied as a potent photosensitizer for photodynamic therapy in both preclinical and clinical settings. Recently, hypericin has also been discovered to have a specific avidity for necrotic tissue. This affinity is also observed in a series of radiolabeled derivatives of hypericin, including [(123)I]iodohypericin, [(124)I]iodohypericin, and [(131)I]iodohypericin. Hypericin, along with other necrosis-avid contrast agents, has been investigated for use in noninvasively targeting necrotic tissues in numerous disorders. Potential clinical applications of hypericin include the identification of acute myocardial infarction, evaluation of tissue viability, assessment of therapeutic responses to treatments, and interventional procedures for solid tumors. The mechanisms of necrosis avidity in hypericin remain to be fully elucidated, although several hypotheses have been suggested. In particular, it has been proposed that the necrosis avidity of hypericin is compound specific; for instance, cholesterol, phosphatidylserine, or phosphatidylethanolamine components in the phospholipid bilayer of cellular membranes may be the major targets for its observed selectivity. Further investigations are needed to identify the specific binding moiety that is responsible for the necrosis avidity of hypericin. PMID- 24052809 TI - BAYESIAN ALIGNMENT OF SIMILARITY SHAPES. AB - We develop a Bayesian model for the alignment of two point configurations under the full similarity transformations of rotation, translation and scaling. Other work in this area has concentrated on rigid body transformations, where scale information is preserved, motivated by problems involving molecular data; this is known as form analysis. We concentrate on a Bayesian formulation for statistical shape analysis. We generalize the model introduced by Green and Mardia for the pairwise alignment of two unlabeled configurations to full similarity transformations by introducing a scaling factor to the model. The generalization is not straight-forward, since the model needs to be reformulated to give good performance when scaling is included. We illustrate our method on the alignment of rat growth profiles and a novel application to the alignment of protein domains. Here, scaling is applied to secondary structure elements when comparing protein folds; additionally, we find that one global scaling factor is not in general sufficient to model these data and, hence, we develop a model in which multiple scale factors can be included to handle different scalings of shape components. PMID- 24052810 TI - Meta-analysis of neuroimaging data. AB - As the number of neuroimaging studies that investigate psychological phenomena grows, it becomes increasingly difficult to integrate the knowledge that has accrued across studies. Meta-analyses are designed to serve this purpose, as they allow the synthesis of findings not only across studies but also across laboratories and task variants. Meta-analyses are uniquely suited to answer questions about whether brain regions or networks are consistently associated with particular psychological domains, including broad categories such as working memory or more specific categories such as conditioned fear. Meta-analysis can also address questions of specificity, which pertains to whether activation of regions or networks is unique to a particular psychological domain, or is a feature of multiple types of tasks. This review discusses several techniques that have been used to test consistency and specificity in published neuroimaging data, including the kernel density analysis (KDA), activation likelihood estimate (ALE), and the recently developed multilevel kernel density analysis (MKDA). We discuss these techniques in light of current and future directions in the field. Copyright (c) 2010 John Wiley & Sons, Ltd. This article is categorized under: Neuroscience > Cognition. PMID- 24052811 TI - The atrazine metabolite diaminochlorotriazine suppresses LH release from murine LbetaT2 cells by suppressing GnRH-induced intracellular calcium transients. AB - The primary metabolite of the herbicide atrazine (ATRA), diaminochlorotriazine (DACT), has been suggested to cause disruption in the hypothalamic-pituitary gonadal axis leading to inhibition of luteinizing hormone (LH) release. DACT is a reactive electrophile known to form covalent protein adducts both in vitro and in vivo following ATRA exposure and maybe targeting proteins involved in GnRH induced calcium signaling and subsequent LH release. To test this hypothesis, LbetaT2 pituitary cells were exposed to 300 MUM DACT for 24 hrs and examined by fluorescence microscopy for GnRH-induced changes in intracellular calcium and LH release. LbetaT2 cells exposed to DACT had markedly diminished GnRH-induced intracellular calcium transients and a significant decreased LH release in response to GnRH. DACT appeared to cause a selective decrease in caffeine sensitive ryanodine receptor-operated calcium stores in LbetaT2 cells, rather than in thapsigargin-sensitive ER calcium stores. This sensitivity correlated with the formation of covalent protein adducts by DACT, as determined by mass spectrometry. ERp57 was identified by mass spectrometry as a target of DACT adduction in the ER that could potentially mediate the effects of DACT on inhibition of GnRH-induced calcium signaling and inhibition of LH release. Intracellular calcium responses to GnRH and release of LH were restored in DACT treated cells with the addition of a calcium ionophore (A23187). These data suggest that DACT forms adducts on proteins involved in calcium handling within the ER and that dysfunction in this critical signaling system is associated with loss of normal sensitivity to GnRH and subsequent decreased release of LH. PMID- 24052812 TI - Caveolae internalization repairs wounded cells and muscle fibers. AB - Rapid repair of plasma membrane wounds is critical for cellular survival. Muscle fibers are particularly susceptible to injury, and defective sarcolemma resealing causes muscular dystrophy. Caveolae accumulate in dystrophic muscle fibers and caveolin and cavin mutations cause muscle pathology, but the underlying mechanism is unknown. Here we show that muscle fibers and other cell types repair membrane wounds by a mechanism involving Ca(2+)-triggered exocytosis of lysosomes, release of acid sphingomyelinase, and rapid lesion removal by caveolar endocytosis. Wounding or exposure to sphingomyelinase triggered endocytosis and intracellular accumulation of caveolar vesicles, which gradually merged into larger compartments. The pore-forming toxin SLO was directly visualized entering cells within caveolar vesicles, and depletion of caveolin inhibited plasma membrane resealing. Our findings directly link lesion removal by caveolar endocytosis to the maintenance of plasma membrane and muscle fiber integrity, providing a mechanistic explanation for the muscle pathology associated with mutations in caveolae proteins. DOI:http://dx.doi.org/10.7554/eLife.00926.001. PMID- 24052815 TI - Effects of Neighborhood Disadvantage on Problem Gambling and Alcohol Abuse. PMID- 24052814 TI - MEGF8 is a modifier of BMP signaling in trigeminal sensory neurons. AB - Bone morphogenetic protein (BMP) signaling has emerged as an important regulator of sensory neuron development. Using a three-generation forward genetic screen in mice we have identified Megf8 as a novel modifier of BMP4 signaling in trigeminal ganglion (TG) neurons. Loss of Megf8 disrupts axon guidance in the peripheral nervous system and leads to defects in development of the limb, heart, and left right patterning, defects that resemble those observed in Bmp4 loss-of-function mice. Bmp4 is expressed in a pattern that defines the permissive field for the peripheral projections of TG axons and mice lacking BMP signaling in sensory neurons exhibit TG axon defects that resemble those observed in Megf8 (-/-) embryos. Furthermore, TG axon growth is robustly inhibited by BMP4 and this inhibition is dependent on Megf8. Thus, our data suggest that Megf8 is involved in mediating BMP4 signaling and guidance of developing TG axons. DOI:http://dx.doi.org/10.7554/eLife.01160.001. PMID- 24052813 TI - Crystal structures of the CPAP/STIL complex reveal its role in centriole assembly and human microcephaly. AB - Centrioles organise centrosomes and template cilia and flagella. Several centriole and centrosome proteins have been linked to microcephaly (MCPH), a neuro-developmental disease associated with small brain size. CPAP (MCPH6) and STIL (MCPH7) are required for centriole assembly, but it is unclear how mutations in them lead to microcephaly. We show that the TCP domain of CPAP constitutes a novel proline recognition domain that forms a 1:1 complex with a short, highly conserved target motif in STIL. Crystal structures of this complex reveal an unusual, all-beta structure adopted by the TCP domain and explain how a microcephaly mutation in CPAP compromises complex formation. Through point mutations, we demonstrate that complex formation is essential for centriole duplication in vivo. Our studies provide the first structural insight into how the malfunction of centriole proteins results in human disease and also reveal that the CPAP-STIL interaction constitutes a conserved key step in centriole biogenesis. DOI:http://dx.doi.org/10.7554/eLife.01071.001. PMID- 24052816 TI - Synthesis, physiochemical properties, photochemical probe, and antimicrobial effects of novel norfloxacin analogues. AB - The emerging resistance to antimicrobial drugs demands the synthesis of new remedies for microbial infections. Attempts have been made to prepare new compounds by modifications in the quinolone structure. An important method for the synthesis of new quinolone is using Vilsmeier approach but has its own limitations. The present work aimed to synthesize novel norfloxacin analogues using modified Vilsmeier approach and conduct preliminary investigations for the evaluation of their physicochemical properties, photochemical probe, and antimicrobial effects. In an effort to synthesize norfloxacin analogues, only 7 bromo-6-N-benzyl piperazinyl-4-oxoquinoline-3-carboxylic acid was isolated using Vilsmeier approach at high temperature, where N, N'-bis-(4-fluoro-3-nitrophenyl) oxalamide and N, N'-bis-(3-chloro-4-fluorophenyl)-malonamide were obtained at low temperature. Correlation results showed that lipophilicity, molecular mass, and electronic factors might influence the activity. The synthesized compounds were evaluated for their antimicrobial effects against important pathogens, for their potential use in the inhibition of vitiligo. PMID- 24052817 TI - Ferric Hydrogensulfate [Fe(HSO4)3] As a Reusable Heterogeneous Catalyst for the Synthesis of 5-Substituted-1H-Tetrazoles and Amides. AB - Ferric hydrogensulfate catalyzed the synthesis of 5-substituted 1H-tetrazoles via [2 + 3] cycloaddition of nitriles and sodium azide. This method has the advantages of high yields, simple methodology, and easy workup. The catalyst can be recovered by simple filtration and reused delivering good yields. Also, ferric hydrogensulfate catalyzed the hydrolysis of nitriles to primary amides under aqueous conditions. Various aliphatic and aromatic nitriles converted to the corresponding amides in good yields without any contamination with carboxylic acids. PMID- 24052818 TI - Progress in the total synthesis of rocaglamide. AB - The first cyclopenta[b]benzofuran derivative, rocaglamide, from Aglaia elliptifolia, was found to exhibit considerable insecticidal activities and excellent potential as a therapeutic agent candidate in cancer chemotherapy; the genus Aglaia has been subjected to further investigation. Both the structural complexity of rocaglamide and its significant activity make it an attractive synthetic target. Stereoselective synthesis of the dense substitution pattern of these targets is a formidable synthetic challenge: the molecules bear five contiguous stereocenters and cis aryl groups on adjacent carbons. In past years of effort, only a handful of completed total syntheses have been reported, evidence of the difficulties associated with the synthesis of rocaglate natural products. The advance on total synthesis of rocaglamide was mainly reviewed from intramolecular cyclization and biomimetic cycloaddition approach. PMID- 24052819 TI - Surface Modification of PET Fabric by Graft Copolymerization with Acrylic Acid and Its Antibacterial Properties. AB - Graft copolymerization of acrylic acid (AA) onto Poly(ethylene terephthalate) (PET) fabrics with the aid of benzoyl peroxide was carried out. The effect of polymerization parameters on the graft yield was studied. Percent grafting was enhanced significantly by increasing benzoyl peroxide (BP) concentrations up to 3.84 g/lit and then decreased upon further increase in initiator concentration. Preswelling of PET leads to changes in its sorption-diffusion properties and favors an increase in the degree of grafting. The antibiotics treated grafted fabrics showed antibacterial properties towards gram-positive and gram-negative microorganisms. FTIR and SEM were used to characterize AA-grafted polyester fabrics. PMID- 24052820 TI - Ammonium Trifluoroacetate-Mediated Synthesis of 3,4-dihydropyrimidin-2(1H)-ones. AB - A simple and economic synthesis of 3,4-dihydropyrimidin-2(1H)-ones using ammonium trifluoroacetate as catalyst and as solid support is accomplished. Easy workup procedure for the synthesis of title compounds is well arrived at and is well documented. PMID- 24052821 TI - Potassium Hydroxide Impregnated Alumina (KOH-Alumina) as a Recyclable Catalyst for the Solvent-Free Multicomponent Synthesis of Highly Functionalized Substituted Pyridazines and/or Substituted Pyridazin-3(2H)-ones under Microwave Irradiation. AB - The work described herein employs potassium hydroxide impregnated alumina (KOH alumina) as a mild, efficient, and recyclable catalyst for a one-pot solvent-free and environmentally safer synthesis of 3,4,6-triarylpyridazines and some substituted pyridazines from active methylene carbonyl species, 1,2-dicarbonyls, and hydrazine hydrate by microwave (MW) irradiation. The method offers highly convergent, inexpensive, and functionality-tolerable procedure for rapid access to important pyridazine compounds in good yields. PMID- 24052823 TI - New way to substitute tetracyanocyclopropanes: one-pot cascade assembling of carbonyls and malononitrile by the only bromine direct action. AB - THE NEW TYPE OF THE CHEMICAL CASCADE REACTION WAS FOUND: formation of cyclopropanes from carbonyl compounds and CH acid by the only bromine direct action. The action of aqueous bromine on the carbonyl compounds and malononitrile in EtOH-H2O solutions in the presence of NaOAc results in the formation of 3 substituted 1,1,2,2-tetracyanocyclopropanes in 48-93% yields. The latter are well known precursors for the different bicyclic heterosystems, among them those containing cyclopropane ring and those possessing different types of pharmacological activity. PMID- 24052822 TI - A Remarkably High-Speed Solution-Phase Combinatorial Synthesis of 2-Substituted Amino-4-Aryl Thiazoles in Polar Solvents in the Absence of a Catalyst under Ambient Conditions and Study of Their Antimicrobial Activities. AB - Remarkably high-speed synthesis of 2-substituted amino-4-aryl thiazoles in polar solvents with a minimum threshold polarity index of 4.8 was found to proceed to completion in just 30-40 sec. affording excellent yields of thiazoles under ambient temperature conditions without the use of any additional catalyst. The purification-free procedure afforded libraries based around a known pharmacophore, namely, substituted arylthiazoles and generated samples of high purity. In terms of combinatorial synthesis in a single solution phase, our protocol is significantly better than those hitherto reported and is amenable for HTS. The in vitro biological tests of some thiazoles showed good activity towards gram-positive bacteria, gram-negative bacteria and fungi comparable with the standard drugs, nitrofurantoin and griseofulvin, for their antibacterial and antifungal activities, respectively. PMID- 24052824 TI - Spectral Analysis and Crystal Structures of 4-(4-Methylphenyl)-6-Phenyl-2,3,3a, 4 Tetrahydro-1H-Pyrido[3,2,1-jk]Carbazole and 4-(4-Methoxyphenyl)-6-Phenyl-2,3,3a, 4-Tetrahydro-1H-Pyrido[3,2,1-jk]Carbazole. AB - The crystal structures of 4-(4-methylphenyl)-6-phenyl-2,3,3a,4-tetrahydro-1H pyrido[3,2,1-jk]carbazole (IIa) and 4-(4-methoxyphenyl)-6-phenyl-2,3,3a,4 tetrahydro-1H-pyrido[3,2,1-jk]carbazole (IIb) were elucidated by single crystal X ray diffraction. Compound (IIa), C28H25N, crystallizes in the triclinic system, space group P-1, with a = 8.936(2) A, b = 10.490(1) A, c = 11.801(1) A, alpha = 102.69(5) ( degrees ) , beta = 103.27(3) ( degrees ) , gamma = 93.80(1) ( degrees ) , and Z = 2. The compound (IIb), C28H25NO, crystallizes in the monoclinic system, space group P21/a, with a = 11.376(5) A, b = 14.139(3) A, c = 13.237(4) A, beta = 97.41(3) ( degrees ) , and Z = 4. In both the structures, the pyrido ring adopts a twist boat conformation and the carbazole molecule has the twisted envelope structure with C3 and C13 at the flap. No classical hydrogen bonds are observed in the crystal structures. Details of the preparation, structures, and spectroscopic properties of the new compounds are discussed. PMID- 24052825 TI - Linear and angular distyrylpyrazines with terminal donor groups: synthesis, solvatochromism, and acidochromism of the electronic spectra. AB - A series of linear and angular distyrylpyrazines and lateral donor groups has been prepared by aldol condensation between dimethylpyrazines and the appropriate aromatic aldehyde. The optical absorption and emission properties of these systems were studied in different solvents and media. The materials display a strong solvatochromism of the emission that is reflected by large red shifts of their fluorescence emission maxima on increasing the solvent polarity. This behaviour suggests a highly polar emitting state, which is characteristic of compounds that undergo an internal charge transfer upon excitation. Upon protonation, the UV-vis spectra are altered, and the fluorescence intensity of the neutral compound vanishes. These molecules can be used as colorimetric and luminescence polarity and pH sensors. PMID- 24052826 TI - Conformational analysis in 18-membered macrolactones based on molecular modeling. AB - Conformational analysis of 18-ring membered macrolactones has been carried out using molecular mechanics calculations and molecular dynamics. A high conformational flexibility of macrolactones was obtained, and an important stereoselectivity was observed for the complexed macrolides. For 18d macrolactone, which was presented by a most favored conformer with 20.1% without complex, it was populated with 50.1% in presence of Fe(CO)3. PMID- 24052827 TI - Bismuth (III) Salts Promoted and Ionic Liquid Assisted an Efficient and Environmentally Benign One-Pot Synthesis of 1,5-Benzodiazepine Derivatives. AB - 1,5-Benzodiazepine derivatives were synthesized by the condensation reactions of o-phenylenediamine and ketones catalyzed by bismuth (III) salts under mild conditions. This method is easy, efficient, environment and eco-friendly, free of toxic catalysts, and gives good to excellent yields of 1, 5-benzodiazepines. PMID- 24052828 TI - Thio Analogs of Pyrimidine Bases: Synthesis, Spectroscopic Study, and In Silico Biological Activity Evaluation of New 2-o-(m- and p-)Chlorobenzylthio-6-Methyl-5 Piperidino-(Morpholino-)Methyluracils. AB - Six new 2-o-(m- and p-)chlorobenzylthio-6-methyl-5-piperidino-(or morpholino-) methyluracils have been prepared. The structures of these compounds were confirmed by spectroscopic (FT-IR, UV-Vis, (1)H NMR, (13)C NMR, and HMBC) and elemental analyses. Estimation of pharmacotherapeutic potential has been made for synthesized compounds on the basis of prediction of activity spectra for substances (PASS). PMID- 24052829 TI - An efficient and recyclable ionic liquid-supported proline catalyzed knoevenagel condensation. AB - The Knoevenagel condensation reaction of aldehydes with malononitrile was described in this study, which was catalyzed by an efficient and recyclable ionic liquid-supported proline. The method represented an attractive alternative to the classical synthesis strategies and exhibited the advantage of performing homogeneous chemistry on a large scale additionally avoided large excesses of reagents. The products were obtained in good yields and reasonable purities without the need for further chromatographic purification. Moreover, the catalyst could be reused for at least four times. PMID- 24052830 TI - Synthesis, Characterization, and Crystal Structure of a Diorganotin(IV) Complex with 2-Oxo-2-Phenylacetic Acid 4-Hydroxybenzohydrazone. AB - The complex dibutyltin 2-oxo-2-phenylacetic acid 4-hydroxybenzohydrazone has been synthesized and characterized by elemental analysis, IR, (1)H and (13)C NMR, and X-ray single-crystal diffraction studies. The crystal structure belongs to triclinic, space group P-1 with a = 9.3220 (10) A, b = 9.8779 (11) A, c = 15.9401 (17) A, beta = 97.0930 (10) degrees , Z = 2, V = 1427.6(3) A(3), Dc = 1.413 mg/cm(3), MU = 0.936 mm(-1), F(000) = 628, R = 0.1158, and wR = 0.2522. X-ray analysis indicates that O(2), N(2), O(4), and O(4)#1 from the ligand and O(5) from ethanol molecule are in the equatorial positions; the axial positions are occupied by two n-butyl groups. It shows a distorted pentagonal bipyramid configuration with seven-coordination for central tin atom. Fascinatingly, the supramolecular infrastructures are observed, which exist as two-dimensional sheets assembled from the organometallic subunits through intermolecular and intramolecular O-H?X or C-H?X (X = O or N) hydrogen bonds. PMID- 24052831 TI - Synthesis, Characterization, Thermal Properties, and Antimicrobial Activities of 5-(Diethylamino)-2-(5-nitro-1H-benzimidazol-2-yl)phenol and Its Transition Metal Complexes. AB - Synthesis and antimicrobial activities of new metal [Co(II), Cu(II), Ni(II), and Fe(II)] complexes from 5-(diethylamino)-2-(5-nitro-1H-benzimidazol-2-yl)phenol are described. The newly synthesized ligands were characterized by IR, (1)H NMR, and LC-MS analysis, and metal-ligand complex formations were confirmed by using atomic absorption spectroscopy and elemental analysis. All complexes show significant in vitro antibacterial activities against E. coli and S. aureus strains and in vitro antifungal activity against C. albicans and A. niger strains by using serial dilution method. The antibacterial activities were expressed as the minimum inhibitory concentration (MIC) in MUg/mL. Thermal properties and electrochemical behavior of novel transition metal complexes have been studied. PMID- 24052832 TI - Catalytic Reduction of Noble Metal Salts by Sodium Hypophosphite Promoted by the Film Poly-(p-Allyl Ether Benzenesulfonic Acid). AB - Glassy carbon electrodes were coated with the film poly-(p-allyl ether benzenesulfonic acid) by an anodic procedure. Nickel, platinum, and palladium ions were introduced into the film by ion exchange of H(+) with the corresponding salts. These ions were catalytically reduced to their corresponding metals using the known electroless reducing agent sodium hypophosphite. Scanning electron microcopy and energy dispersive X-ray spectroscopy were carried out to demonstrate the occurrence of the catalytic process. To compare this method with another one carried out in our laboratory, the electrocatalytic reduction of H(+) was studied using the same modified electrodes. A suggested mechanism for the catalysis is proposed. PMID- 24052833 TI - General approach to the synthesis of prochiral atropisomeric biaryls. AB - General approach to the synthesis of prochiral precursors of chiral atropisomeric biaryls based on several complementary methods has been developed. Biaryls were obtained in good to excellent yields depending on their structure and selected method of synthesis. Furthermore, we demonstrate a possibility of utilisation of the obtained compounds possessing 2 or 3 ortho substituents around the aryl-aryl bond in direct and directed arylation reaction leading through transition metal mediated C-H bond activation to atropisomeric compounds. PMID- 24052834 TI - Computational Study of Coordinated Ni(II) Complex with High Nitrogen Content Ligands. AB - Density functional computations were performed on two tetracoordinated Ni(II) complexes as high nitrogen content energetic materials (1: dinickel bishydrazine ter[(1H-Tetrazol-3-yl)methan-3yl]-1H-tetrazole and 2: dinickel tetraazide ter[(1H Tetrazol-3-yl)methan-3yl]-1H-tetrazolate). The geometrical structures, relative stabilities and sensitivities, and thermodynamic properties of the complexes were investigated. The energy gaps of frontier molecular orbital (HOMO and LUMO) and vibrational spectroscopies were also examined. There are minor Jahn-Teller distortions in both complexes 1 and 2, with two long Ni-N bond lengths and two short ones. The enthalpies of combustion for both complexes are over 3600 kJ/mol. The N-N bond lengths in the moieties of hydrazine and azide ligands increase in the coordination process compared to those of the isolated molecules. PMID- 24052835 TI - Copper Perchlorate Hexahydrate: An Efficient Catalyst for the Green Synthesis of Polyhydroquinolines under Ultrasonication. AB - Copper perchlorate hexahydrate as an efficient catalyst was used for the synthesis of polyhydroquinolines by four-component condensation reaction of aldehyde, ethyl acetoacetate, dimedone, and ammonium acetate in excellent yields and short reaction times at room temperature under ultrasound irradiation. This novel synthetic method is especially favoured because it provides a synergy between copper perchlorate hexahydrate and ultrasound irradiation which offers the advantages of high yields, short reaction times, simplicity, and easy workup compared to the conventional methods reported in the literature. PMID- 24052836 TI - Microwave-assisted hydrogenation of codeine in aqueous media. AB - An efficient one-pot microwave-assisted hydrogenation of codeine was achieved in aqueous solution. This technique is simple, fast, environmentally friendly, and highly efficient. Structure of produced dihydrocodeine was approved by using FT IR, (1)H NMR, (13)C NMR, EIMS, and elemental analysis technique. Its purity analysis was performed by using HPLC and assay analysis was performed by using potentiometric titration methods. PMID- 24052837 TI - Synthesis of macrocyclic bis-hydrazone and their use in metal cations extraction. AB - Two new macrocyclic hydrazone Schiff bases were synthesized by reaction of succindihydrazide and adipdihydrazide with acetylacetone. Hydrazones have been characterized by elemental analyses and IR, mass, (1)H NMR, and (13)C NMR spectral data. Hydrazones have been studied by liquid-liquid extraction towards the s-metal ions (Li(+), Na(+), and K(+)) and d-metal ions (Cu(2+) and Cr(3+)) from aqueous phase to organic phase. The effect of chloroform and dichloromethane as organic solvents over the metal chlorides extraction was investigated at 25 +/ 0.1 degrees C by using flame atomic absorption. We found differences between the two solvents in extraction selectivity. PMID- 24052838 TI - ZnO Catalyzed Efficient Synthesis of Some New 2-Substituted-4,6 diarylpyrimidines. AB - A simple and efficient protocol is developed for the synthesis of 2-substituted 4,6-diarylpyrimidines from one-pot three-component reaction of 4'-hydroxy-3',5' dinitro substituted chalcones, S-benzylthiouronium chloride (SBT), and heterocyclic secondary amines (morpholine/pyrrolidine/piperidine) in the presence of 15 mol% of ZnO as a heterogeneous catalyst. The present methodology offers several advantages such as being a simple procedure as well as providing excellent yields, and short reaction time. The catalyst is inexpensive, stable, and can be easily recycled and reused for several cycles with consistent activity. PMID- 24052839 TI - Formation of 5-Hydroxy-3-methoxy-1,4-naphthoquinone and 8-Hydroxy-4-methoxy-1,2 naphthoquinone from Juglone. AB - From the treatment of 5-hydroxy-1,4-naphthoquinone (juglone) with acetic anhydride and H2SO4 followed subsequently by treatment with methanolic HCl, 5 hydroxy-3-methoxy-1,4-naphthoquinone (3-methoxy juglone) and 8-hydroxy-4-methoxy 1,2-naphthoquinone were obtained as products rather than the anticipated product 2,5-dihydroxy-1,4-naphthoquinone (2-hydroxy juglone). The reaction and the identification of the products are discussed in terms of NMR and DFT calculations. PMID- 24052840 TI - N-aryl lactams by regioselective ozonation of N-aryl cyclic amines. AB - Ozonation of N-aryl-cyclic amines in organic solvents gave N-aryl-lactams regioselectively. In particular, 4-(4-aminophenyl)-morpolin-3-one, a key intermediate in the preparation of factor Xa inhibitors, was obtained in fair yields. The method represents an alternative approach for the lactamization of tertiary N-arylic substrates and is based on a "metal-free" introduction of the carbonyl function into the heterocyclic ring. PMID- 24052842 TI - N-tert-Butoxycarbonylation of Structurally Diverse Amines and Sulfamides under Water-Mediated Catalyst-Free Conditions. AB - A simple, efficient, and eco-friendly protocol for the N-Boc protection of the amine moiety in a variety of compounds with di-tert-butyl dicarbonate under water acetone catalyst-free conditions is described. The corresponding monocarbamate is obtained in excellent yields on short reaction times. No competitive side reactions such as isocyanate urea and O-Boc were observed. This method represents a reasonable alternative to the previous reported protection procedures. PMID- 24052841 TI - "On-water" catalyst-free ecofriendly synthesis of the hantzsch dihydropyridines. AB - An eco-friendly "on-water" protocol for efficient catalyst-free synthesis of the Hantzsch dihydropyridines from aryl, heteroaryl, alkyl, and vinylogous aldehydes has been developed with minimum auxiliary substances, toxic reagents, organic solvents, and disposal problems. PMID- 24052843 TI - A Green, Expeditious, One-Pot Synthesis of 3, 4-Dihydropyrimidin-2(1H)-ones Using a Mixture of Phosphorus Pentoxide-Methanesulfonic Acid at Ambient Temperature. AB - An expeditious, one-pot method for the synthesis of 3,4-dihydropyrimidin-2(1H) ones using a mixture of phosphorus pentoxide-methanesulfonic acid (Eaton's reagent) at room temperature under solvent-free conditions is described. The salient features of this method include short reaction time, green aspects, high yields, and simple procedure. PMID- 24052844 TI - Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones and Their Corresponding 2(1H)Thiones Using Trichloroacetic Acid as a Catalyst under Solvent-Free Conditions. AB - Trichloroacetic acid was found to be a convenient catalyst for the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and their corresponding 2(1H)-thiones through a one-pot three-component reaction of aldehydes, alkyl acetoacetate, and urea or thiourea at 70 degrees C under solvent-free conditions. PMID- 24052845 TI - An Efficient One-Pot Green Protocol for the Synthesis of 5-Unsubstituted 3,4 Dihydropyrimidin-2(1H)-Ones Using Recyclable Amberlyst 15 DRY as a Heterogeneous Catalyst via Three-Component Biginelli-Like Reaction. AB - An environmentally benign green protocol for the synthesis of 5-unsubstituted 3,4 dihydropyrimidin-2(1H)-ones using Amberlyst 15 DRY as a recyclable catalyst has been developed. The use of resinous, nontoxic, thermally stable, and inexpensive Amberlyst 15 DRY, as a recyclable heterogeneous catalyst, makes the process simple with negligible chemical waste. Among the various solid acid catalysts Amberlyst 15 DRY was found to be the most efficient catalyst with regard to reaction time, yield, and ease of work-up procedure. PMID- 24052846 TI - New way of direct nitrogen atom phenylation in quinoline derivatives. AB - Comparison of ion-molecular reactions of free-phenyl cations generated by tritium beta -decay with 2-methyl- and 2-phenylquinolines has been investigated. The reaction of direct nitrogen atom phenylation with the help of nucleogenic phenyl cations has been fulfilled for the first time and a new one-step synthesis of tritium-labeled N-phenyl-2-phenylquinolinium salt-lipophilic radioactive biological marker has been elaborated. PMID- 24052847 TI - An Efficient Protocol for the Green and Solvent-Free Synthesis of Azine Derivatives at Room Temperature Using BiCl3-Loaded Montmorillonite K10 as a New Recyclable Heterogeneous Catalyst. AB - A new BiCl3-loaded montmorillonite K10 catalyst has been prepared by solid dispersion method and was characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), and cyclic voltammetry (CV) measurements. BiCl3 loaded K10 (BiCl3-K10) has been used as solid acid catalyst for the synthesis of azine derivatives from benzophenone hydrazone and ketones/aldehydes by simple physical grinding. This BiCl3-K10 gives an excellent yield with short reaction time and is an inexpensive, easily recyclable catalyst for this reaction. PMID- 24052849 TI - Facile Iodine-Catalyzed Michael Addition of Indoles to alpha,alpha' Bis(arylmethylene)cyclopentanones: An Efficient Synthesis of E-2-(3 Indolylphenylmethyl)-5-phenylmethylenecyclopentanones. AB - Iodine-catalyzed reaction of indoles with alpha,alpha' bis(arylmethylene)cyclopentanones afforded one diastereomer of the corresponding Michael adducts, namely, E-2-(3-indolylphenylmethyl)-5 phenylmethylenecyclopentanones, in a good yield. The products form a new group of indole derivatives. PMID- 24052848 TI - I2-SDS-H2O System: A highly Efficient Dual Catalytic Green System for Deprotection of Imines and in Situ Preparation of Bis(indolyl)alkanes from Indoles in Water. AB - A novel catalytic system consisting of I2-SDS-H2O has been developed which cleaves 2,3-diaza-1,3-butadiene, 1-aza-1,3-butadienes, oximes and in presence of indoles in the medium uses the corresponding aldehyde products to produce bis(indolyl)alkanes in situ. This one pot simple and mild dual catalytic system works in water at room temperature under neutral conditions. PMID- 24052850 TI - Synthesis and Biological Evaluation of Some Novel 5-[(3-Aralkyl Amido/Imidoalkyl) Phenyl]-1,2,4-Triazolo[3,4-b]-1,3,4-Thiadiazines as Antiviral Agents. AB - A series of novel 4-amino-5-mercapto-3-[(3-aralkyl amido/imidoalkyl) phenyl] 1,2,4-triazoles (5a-d) were obtained by treating m-(aralkyl amido/imidoalkyl) benzoic acid hydrazides (3a-d) with carbon disulphide in alcoholic KOH and hydrazine hydrate, respectively. These triazole derivatives were employed in the synthesis of 5-[(3'-aralkyl amido/imidoalkyl) phenyl]-1,2,4-triazolo[3,4-b]-1,3,4 thiadiazines (6a-d). The newly synthesized compounds were evaluated for their antiviral activity against two animal viruses, namely, Japanese encephalitis virus (JEV) strain P20778 and herpes simplex virus-1 (HSV-1) strain 753166. PMID- 24052852 TI - La2O3 Catalyzed C-C Coupling of Aryl Iodides and Boronic Acids. AB - An efficient La2O3-catalyzed new route for the carbon-carbon bond formation in particular, symmetrical and unsymmetrical biphenyls has been developed, which proceeds through carbon-carbon coupling reaction of aryl iodides with boronic acids. The reaction provided the desired products in moderate-to-good yields with a wide range of functional group tolerance. PMID- 24052851 TI - Synthesis of new fused benzothiadiazepines and macrocyclic sulfamides starting from n,n-disubstituted sulfamides and n(boc)-sulfamides. AB - Herein, we describe an efficient one-step synthesis of new fused benzothiadiazepine-1,1-dioxides and macrocyclic sulfamides. The synthesis of these compounds was achieved in moderate yields starting from previously described N,N'-disubstituted symmetric sulfamides and N-tert-butoxycarbonyl, N' alkyl sulfamide. The chemical structures of all the new compounds reported in this work were confirmed by NMR, IR, and mass spectrometry. These compounds are beneficial building blocks that can be used in deriving new chemical entities that exert a wide spectrum of pharmacological activities. PMID- 24052853 TI - Interaction of 5'-Guanosine Monophosphate with Organotin(IV) Moieties: Synthesis, Structural Characterization, and Anti-Inflammatory Activity. AB - Reaction(s) of 5'-guanosine monophosphate (5'GMP) with di- and triorganotin(IV) chloride(s) led to formation of organotin(IV) derivatives of general formulae, [R2Sn(5'-GMP).H2O] n and [(R'3Sn)2(5'-GMP).H2O] n , where R = Me, n-Bu, and Ph; R' = Me, i-Pr, n-Bu, and Ph; (5'-GMP)(2-) = 5'-guanosine monophosphate. An attempt has been made to prove the structures of the resulting derivatives on the basis of FT-IR, multinuclear (1)H, (13)C, and (119)Sn NMR and (119)Sn Mossbauer spectroscopic studies. These investigations suggest that both di- and triorganotin(IV)-5'-guanosine monophosphates are polymeric in which (5'-GMP)(2-) is bonded through phosphate group resulting in a distorted trigonal bipyramidal geometry around tin. The ribose conformation in all of the derivatives is C3' endo, except diphenyltin(IV) and tri-i-propyltin(IV) derivatives where it is C2' endo. All of the studied derivatives exhibited mild-to-moderate anti-inflammatory activity (~15.64-20.63% inhibition) at 40 mg kg(-1) dose and LD50 values > 400 mg kg(-1) in albino rats. PMID- 24052854 TI - Synthesis of Azidohydrin from Hura crepitans Seed Oil: A Renewable Resource for Oleochemical Industry and Sustainable Development. AB - The replacement of petrochemicals by oleochemical feedstocks in many industrial and domestic applications has resulted in an increase in demand for biobased products and as such recognizing and increasing the benefits of using renewable materials. In line with this, the oil extracted from the seed of Hura crepitans was characterized by an iodine value of 120.10 +/- 0.70 g Iodine/100 g and a saponification number of 210.10 +/- 0.40 mg KOH/g with the dominant fatty acid being C18:2 (52.8 +/- 0.10%). The epoxidised fatty acid methyl esters prepared from the oil were used to synthesise the azidohydrin with a yield of 91.20%. The progress of the reaction was monitored and confirmed using FTIR and NMR. This showed the seed oil of Hura crepitans as a renewable resource that can be used to make valuable industrial and domestic products. PMID- 24052855 TI - Langmuir-blodgett films of supported polyester dendrimers. AB - Amphiphiles with a dendritic structure are attractive materials as they combine the features of dendrimers with the self-assembling properties and interfacial behavior of water-air affinities. We have synthesized three generations of polyester dendrimers and studied their interfacial properties on the Langmuir films. The behavior obtained was, as a rule, the lowest generation dendrimers behaving like traditional amphiphiles and the larger molecules presenting complicated isotherms. The Langmuir films of these compounds have been characterized by their surface pressure versus molecular area (pi/A) and Brewster angle microscopy (BAM) observations. PMID- 24052856 TI - Chitosan as a renewable heterogeneous catalyst for the knoevenagel reaction in ionic liquid as green solvent. AB - The combination of chitosan as a renewable heterogeneous catalyst and ionic liquid as a "green" solvent was employed for the Knoevenagel reaction. The chitosan catalyst was characterized by various techniques, including X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR), and elemental analysis. Excellent conversions were achieved under mild conditions without the need for an inert atmosphere. There was no contribution from leached active species, and conversion was only being possible in the presence of the solid catalyst. The chitosan catalyst as well as the ionic liquid solvent could be recovered in essentially pure form after being used in the reaction, and each of them could be reused several times without a significant degradation in efficiency. PMID- 24052857 TI - Interaction of the O-Benzoyl-beta-aminopropioamidoximes with Lawesson's Reagent and Spectral Characterization of the Products. AB - Interaction of O-benzoyl-beta-aminopropioamidoximes [beta-amino group: pyperidin 1-yl; morpholin-1-yl; thiomorpholin-1-yl; 4-phenylpiperazin-1-yl; benzimidazol-1 yl] with Lawesson's reagent was done in tetrahydrofuran at heating to 70 degrees C during 10 h. New O-thiobenzoyl-beta-aminopropioamidoximes were obtained with the outputs 57-96%; they were characterized with the help of physicochemical, IR, and NMR spectra. PMID- 24052858 TI - A Convenient, TiCl 4 /SnCl 4 -Mediated Synthesis of N-Phenyl or N-Aryl Benzamidines and N-Phenylpicolinamidines. AB - A new, TiCl4-or SnCl4-mediated, solvent-free method was developed for the synthesis of N-Aryl benzamidines and N-phenylpicolinamidines, in moderate-to-good yield, using suitable amines and nitriles as starting materials. PMID- 24052859 TI - Synthesis and optoelectronic characterization of some star-shaped oligomers with benzene and triphenylamine cores. AB - Six star-shaped oligomers containing triphenylamine (D1-D3) and benzene unit (D4 D6) as cores have been synthesized by Wittig condensation or Heck coupling reaction using aromatic aldehydes and triphenylphosphonium salts or aromatic halogenated compounds with vinyl triphenylamine. All oligomers have well-defined molecular structure and high purity. Characterization of the oligomers was made by FT-IR, (1)H-NMR spectroscopy, UV-Vis, and fluorescence spectroscopy. The electrochemical behavior was studied by cyclic voltammetry (CV). The cyclic voltammograms have revealed that oligomers undergo quasireversible or irreversible redox processes. The irreversible process is associated with electrochemical polymerization of oligomers by dimerization of unsubstituted triphenylamine groups. Thermal characterization was accomplished by TGA and DSC methods and evidenced that all oligomers were stable materials until 250 degrees C and have formed stable molecular glasses after first heating scan. PMID- 24052860 TI - Synthesis and in vitro evaluation of novel acyclic and cyclic nucleoside analogs with a thiadiazole ring. AB - THE SYNTHESIS OF SIX THIADIAZOLE NUCLEOSIDE ANALOGS IS REPORTED: 5-diacetylamino 1,2,4-thiadiazol-3-one (1), 5-amino-2- (tetrahydrofuran-2-yl)-1,2,4-thiadiazol-3 one (2), 5-amino-3-[(2'-hydroxyethoxy)methyl]-1,3,4-thiadiazol-2-one (3), 5-amino 3-(4'-hydroxy-2'-hydroxymethyl-butyl)-1,3,4-thiadiazole-2-thione (4), (R)-5-amino 3-(2',3'-dihydroxypropyl)-1,3,4-thiadiazole-2-thione (5), and (S)-5-amino-3 (2',3'-dihydroxypropyl)-1,3,4-thiadiazole-2-thione (6). The synthesis, characterization, and properties of these new synthesized thiadiazole derivatives are discussed. A dimerization of 5-amino-3H-1,3,4-thiadiazole-2-thione (14) by sodium nitrite resulting in di-(5-amino-1,3,4-thiadiazol-2-yl) disulfide (19) is also reported. The preliminary in vitro evaluation of these newly synthesized compounds is discussed. PMID- 24052861 TI - A simple, efficient synthesis of 2-aryl benzimidazoles using silica supported periodic Acid catalyst and evaluation of anticancer activity. AB - A new, efficient method for the synthesis of 2-aryl substituted benzimidazole by using silica supported periodic acid (H5IO6-SiO2) as a catalyst has been developed. The salient feature of the present method includes mild reaction condition, short reaction time, high yield and easy workup procedure. The synthesized benzimidazoles exhibited potent anticancer activity against MCF7 and HL60 cell lines. PMID- 24052862 TI - The Potential of 13C Isotopomers as a Test for the Vibrational Theory of Olfactory Sense Recognition. AB - The continuing debate over the basis of odorant recognition with respect to the molecular shape ("lock and key") theory versus the vibrational theory could potentially be resolved by the testing of (13)C-labeled odorants. The application of (13)C isotopomers is discussed herein by means of DFT-calculated IR vibrations and Gibbs' free energies (DeltaG) for acetophenone and octan-1-ol, two odorants for which the (2)D (deuterium) isotopomers have previously been shown to be discernible from their respective (1)H (normal) counterparts by Drosophila melanogaster. PMID- 24052863 TI - DABCO Catalyzed Synthesis of Xanthene Derivatives in Aqueous Media. AB - The reaction of 5,5-dimethylcyclohexane-1,3-dione with various heteroarylaldehydes afforded the corresponding heteroaryl substituted xanthene derivatives 1(a-f). The reaction proceeds via the initial Knoevenagel, subsequent Michael, and final heterocyclization reactions using 1,4 diazabicyclo[2.2.2]octane (DABCO) as a catalyst in aqueous media. The synthesized heteroaryl substituted xanthenes 1(a-f) reacted with malononitrile to obtain different alkylidenes 2(a-f). Short reaction time, environmentally friendly procedure, avoiding of cumbersome apparatus, and excellent yields are the main advantages of this procedure which makes it more economic than the other conventional methods. PMID- 24052864 TI - An Eco-Friendly Improved Protocol for the Synthesis of Bis(3-indolyl)methanes Using Poly(4-vinylpyridinium)hydrogen Sulfate as Efficient, Heterogeneous, and Recyclable Solid Acid Catalyst. AB - Highly efficient and eco-friendly protocol for the synthesis of bis(3 indolyl)methanes by the electrophilic substitution reaction of indole with aldehydes catalyzed by poly(4-vinylpyridinium)hydrogen sulfate was described. Excellent yields, shorter reaction times, simple work-up procedure, avoiding hazardous organic solvents, and reusability of the catalyst are the most obvious advantages of this method. PMID- 24052865 TI - Synthesis and Antioxidant Activity of 2-Amino-5-methylthiazol Derivatives Containing 1,3,4-Oxadiazole-2-thiol Moiety. AB - A series of new 5-(2-amino-5-methylthiazol-4-yl)-1,3,4-oxadiazole-2-thiol derivatives 6(a-j) were designed and synthesized with various substituted aldehydes. The chemical structures were confirmed by elemental analyses, FT-IR, (1)H NMR, and mass spectral studies. The antioxidant activity of the synthesized compounds was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl, nitric oxide, and superoxide radical scavenging assay methods. Compounds 6a, 6e, and 6c showed significant radical scavenging potential due to the presence of electron donating substituent on substituted aldehydes. PMID- 24052866 TI - Design, Synthesis, and In Vitro Antimicrobial Evaluation of Fused Pyrano[3,2 e]tetrazolo[1,5-c]pyrimidines and Diazepines. AB - A series of novel pyranochromene-containing tetrazoles fused with pyrimidinethiones, pyrimidines, and diazepines 3a-f, 4a-f, and 5a-f were synthesized by condensation of the corresponding tetrazoles 2a-f with carbon disulfide, benzaldehyde, and 4-methoxy phenacyl bromide, respectively. The compound 2a-f was obtained by reaction of pyrano[3,2-c]chromenes 1a-f with sodium azide. The structures of the newly synthesized compounds 2a-f to 5a-f were established on the basis of their elemental analyses, IR, (1)H NMR, (13)C NMR, and mass spectral data. All of the title compounds were subjected to in vitro antibacterial testing against four pathogenic strains and antifungal screening against two fungi. Preliminary results indicate that some of them exhibited promising activities and that they deserve more consideration as potential antimicrobials. PMID- 24052868 TI - Three Component Reaction: An Efficient Synthesis and Reactions of 3,4 Dihydropyrimidin-2(1H)-Ones and Thiones Using New Natural Catalyst. AB - Synthesis of 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidin-2(1H)-thione derivatives from aldehydes, 1,3-dicarbonyl derivatives and urea or thiourea using granite and quartz as new, natural and reusable catalysts. Some of the 3,4 dihydropyrimidin-2(1H)-thione derivatives were used to prepare new heterocyclic compounds. The antimicrobial activity of selected examples of the synthesized compounds was tested and showed moderate activity. PMID- 24052867 TI - Noncovalent functionalization of graphene in suspension. AB - Suspensions of graphene, prepared from graphite foil by sonochemical exfoliation, have been treated with new nonpolar pyrenebutyric amides. The assemblies, in suspension and after deposition on solid supports, were characterized by NMR, absorption, and fluorescence spectroscopy and by transmission electron microscopy, where the well-defined shape and size of an appended [60]fulleropyrrolidine unit facilitates TEM detection of the nonstationary molecules. The accumulated evidence, also including direct comparisons of carbon nanotubes treated with pyrene amides under the same conditions, proves the successful noncovalent functionalization of graphene suspended in non-polar solvent with non-polar pyrene derivatives. PMID- 24052869 TI - Synthesis, Characterization, and BSA Binding Studies of Some New Benzamides Related to Schiff Base. AB - Condensation of amine 1 with aldehyde 2 gives Schiff base, N-(4-((benzofuran-2 ylmethylene) amino)phenyl)acetamide 3. Schiff base on N-acylation with different substituted acid chlorides in the presence of triethylamine gives the corresponding benzamides, N-acetyl-N-(4-((benzofuran-2 ylmethylene)amino)phenyl)substitutedbenzamide (NABP) 5a-j. The structures of newly synthesized compounds were characterized by elemental analysis, (1)H NMR, (13)C NMR FT-IR, and mass spectral studies. Compounds 3 and 5a-j have been screened for their antimicrobial activity using the disc diffusion and minimum inhibitory concentration (MIC) method against the selected bacterial and fungal strain. Compounds 5a, 5e, 5g, and 5h were found to be more active against all tested strains. The antioxidant properties were evaluated by 2,2-diphenyl-1 picrylhydrazyl (DPPH) and superoxide radical scavenging methods. Compounds 5i and 5j showed predominant antioxidant activities among the synthesized analogues. The interaction between NABP and bovine serum albumin (BSA) was investigated using fluorescence and ultraviolet spectroscopic techniques at 298 K under imitated physiological conditions. The results revealed that NABP caused the fluorescence quenching of BSA through a static quenching procedure. The binding constants and the number of binding sites were calculated. The binding distance between the donor (BSA) and acceptor (NABP) was determined based on Forster's theory. PMID- 24052870 TI - Nanorod-Shaped Basic Al2O3 Catalyzed N,N-Diformylation of Bisuracil Derivatives: A Greener "NOSE" Approach. AB - A feasible "NOSE" (nanoparticles-catalyzed organic synthesis enhancement) protocol has been developed for N,N-diformylation of bisuracil derivatives using nano-Al2O3 rods as an efficient, inexpensive, and recyclable catalyst under solvent-free reaction condition at 40 degrees C. The catalyst was reused up to the 4th cycle without affecting the rate and yield of the N,N-diformylation products appreciably. PMID- 24052872 TI - Motivating Factors and Psychosocial Barriers to Condom Use among out-of-School Youths in Dar es Salaam, Tanzania: A Cross Sectional Survey Using the Health Belief Model. AB - Condoms remain a cost-effective and relatively simple intervention to prevent HIV infection. However, condom use is still very low, particularly among youths aged 15 to 24. 348 individuals (186 males and 162 females) completed a pre-tested questionnaire. Logistic regression analysis was used to identify factors associated with condom use. Out of 348 respondents, 296 (85.0%) were sexually experienced, and 260 (87.8%) reported noncondom use in the past 3 months prior to the study. Among men, noncondom use was independently associated with feeling shy to buy condoms (AOR = 1.16; 95% CI 1.12-1.34), condoms reducing sexual pleasure (AOR = 8.19; 95% CI 3.98-17.01), and HIV is a serious and deadly disease (AOR = 0.36; 95% CI 0.28-0.46). Among women, experiencing forced sex (AOR = 1.16; 95% CI 1.10-2.78), condoms reduce sexual pleasure (AOR = 8.29; 95% CI 3.36-20.73), and inability to convince a partner to use condoms (AOR = 1.14; 95% CI 1.04-1.28) were predictors of noncondom use. In conclusion, sexually active youths in this population practice risky sexual behaviours, with low condom use practices. Strategies to improve condom use should address these psychosocial barriers associated with noncondom use. PMID- 24052871 TI - Moderate-Intensity Exercise Improves Body Composition and Improves Physiological Markers of Stress in HIV-Infected Men. AB - HIV/AIDS and its treatment often alter body composition and result in poorer physical functioning. The aim of this study was to determine the effects of a moderate-intensity exercise program on body composition and the hormones and cytokines associated with adverse health outcomes. HIV-infected males (N = 111) were randomized to an exercise group (EX) who completed 6 weeks of moderate intensity exercise training, or to a nonintervention control group (CON). In pre- and postintervention, body composition was estimated via DXA, peak strength was assessed, and resting blood samples were obtained. There was a decrease in salivary cortisol at wake (P = 0.025) in the EX and a trend (P = 0.07) for a decrease 1 hour after waking. The EX had a significant increase in lean tissue mass (LTM) (P < 0.001) following the intervention. Those in the EX below median body fat (20%) increased LTM (P = 0.014) only, while those above 20% decreased fat mass (P = 0.02), total fat (N = 0.009), and trunk fat (P = 0.001), while also increasing LTM (P = 0.027). Peak strength increased between 14% and 28% on all exercises in the EX group. These data indicate that 6 weeks of moderate-intensity exercise training can decrease salivary cortisol levels, improve physical performance, and improve body composition in HIV-infected men. PMID- 24052873 TI - Who Is Going for VCT? A Case Study in Urban Burkina Faso. AB - Introduction. Voluntary HIV counselling and testing (VCT) is a key element of treatment and is essential for prevention of vertical HIV transmission. Little information is available on the uptake of VCT in Burkina Faso. This study aims to assess the prevalence of VCT in urban Burkina Faso, where the epidemic is still highly concentrated. Methods. We conducted a two-stage clustered population-based survey among 1,694 subjects living in Ouagadougou, Burkina Faso. After informed consent was obtained, a behavioural questionnaire was administered to participants. Results. Overall, 10.2% of individuals had used VCT, while 9% were women. Among women who had a child after the launch of the programme to prevent mother-to-child transmission (PMTCT), only 10.4% have been tested for HIV. Almost all participants (99.3%) were aware of HIV/AIDS, and 65% knew the main methods of prevention. In multivariate analysis, older age and being married and better educated were independent factors associated with VCT. Conclusions. Despite high public knowledge and awareness about HIV, VCT uptake was still very low and PMTCT coverage was poor. New strategies are required to increase VCT uptake in urban areas, in particular among the youngest age. PMID- 24052874 TI - Prevalence and Factors Associated with Vitamin D Deficiency and Hyperparathyroidism in HIV-Infected Patients Treated in Barcelona. AB - Vitamin D deficiency is an important problem in patients with chronic conditions including those with human immunodeficiency virus (HIV) infection. The aim of this cross-sectional study was to identify the prevalence and factors associated with vitamin D deficiency and hyperparathyroidism in HIV patients attended in Barcelona. Cholecalciferol (25OH vitamin D3) and PTH levels were measured. Vitamin D insufficiency was defined as 25(OH) D < 20 ng/mL and deficiency as <12 ng/mL. Hyperparathyroidism was defined as PTH levels >65 pg/mL. Cases with chronic kidney failure, liver disease, treatments or conditions potentially affecting bone metabolism were excluded. Among the 566 patients included, 56.4% were exposed to tenofovir. Vitamin D insufficiency was found in 71.2% and 39.6% of those had deficiency. PTH was measured in 228 subjects, and 86 of them (37.7%) showed high levels. Adjusted predictors of vitamin D deficiency were nonwhite race and psychiatric comorbidity, while lipoatrophy was a protective factor. Independent risk factors of hyperparathyroidism were vitamin D < 12 ng/mL (OR: 2.14, CI 95%: 1.19-3.82, P: 0.01) and tenofovir exposure (OR: 3.55, CI 95%: 1.62 7.7, P: 0.002). High prevalence of vitamin deficiency and hyperparathyroidism was found in an area with high annual solar exposure. PMID- 24052875 TI - HIV-Positive Status Disclosure and Associated Factors among Children in North Gondar, Northwest Ethiopia. AB - Introduction. Clinical reports have indicated positive outcomes associated with disclosure of HIV-positive status in children. This study assessed the level and associated factors of HIV-positive status disclosure to HIV-infected children in northwest Ethiopia. Methods. Institution-based cross-sectional study was conducted among HIV-positive children from March to April 2012. Data were collected using a structured questionnaire by face-to-face interview technique. Bivariate and multivariate analyses were performed. Results. Of the 428 children, 169 (39.5%) were disclosed their HIV-positive status. The mean age of HIV positive status disclosure was at 10.7 (+/-2.3) years. Having a nonbiological parent (AOR = 4.14, 95% CI: 1.22, 14.04), child's age older than 10 years (AOR = 8.54, 95% CI: 4.5, 15.53), and death of a family member (AOR = 2.04, 95% CI: 1.16, 3.6) were significantly and independently associated with disclosure of HIV positive status to infected children. Conclusions. The rate of disclosure of HIV positive status to infected children still remains low in North Gondar. Hence, it is important to target children living with their biological parents and having young parents and children younger than 10 years. The guideline for disclosure of children with HIV/AIDS should be established in an Ethiopian context. PMID- 24052876 TI - Anogenital Lesions: Kaposi's Sarcoma and Its Mimicks. AB - Kaposi's sarcoma (KS) is a low-grade vascular neoplasm associated with human herpes virus-8 (HHV-8) infection, and, in the epidemic form, with the human immunodeficiency virus (HIV). Although HHV-8 is present in all body fluids and is sexually transmitted, there are surprisingly few reports of anogenital KS. Clinically, especially in HIV/KS endemic areas, dark stained skin patches or nodules are prone to misdiagnosis, especially in dark-skinned individuals. Therefore, a biopsy is recommended. The histologic appearance spans a broad spectrum of KS and non-KS lesions; therefore, the final diagnosis should be confirmed by HHV-8 immunohistochemistry. We report a series of 36 anogenital biopsies from a group of 16 documented HIV-positive patients; in 20 the HIV serostatus was unknown. There were ten KS (five in HIV-positive patients), and 26 non-KS (11 in HIV-positive subjects) lesions. In the era of HIV/AIDS, anogenital lesions may be the first manifestation of KS in immunocompromised individuals and should be biopsied. The histological diagnosis should be confirmed by HHV-8 immunohistochemistry. PMID- 24052877 TI - Evaluation of a Low-Cost Strategy for Enumerating CD4 Lymphocyte Absolute Count and Percentage Using the FACSCalibur Flow Cytometer in HIV-Infected Patients from a Resource-Limited Setting. AB - Enumeration of CD4 lymphocytes is essential for the clinical management of HIV infected patients, but it can be difficult to afford in developing countries. In this study we evaluated a reagent reduction strategy for reducing the cost of enumerating CD4 cell absolute count and percentage using the FACSCalibur flow cytometer (Becton Dickinson). We compared the protocol recommended by the manufacturer with a protocol that used half of the usual amount of CD3/CD4/CD45 monoclonal antibody reagent in 100 samples from HIV-infected patients in a rural hospital in India. The concordance correlation coefficient between the two protocols was 0.976 for CD4 cell count and 0.984 for CD4 cell percentage. We did not find significant bias when performing Deming regression or Bland-Altman analysis. Sensitivity and specificity were 97% and 98.5% for identifying patients with less than 200 CD4 cells/ MU L, 98.1% and 93.8% for identifying patients with less than 350 CD4 cells/ MU L, and 100% and 94.7% for identifying patients with less than 25% CD4 cells, respectively. This reagent reduction strategy can be used for reducing the cost of enumerating CD4 lymphocytes in high-volume laboratories from resource-limited settings. PMID- 24052878 TI - Clinicopathological Proficiency in the Diagnosis of Kaposi's Sarcoma. AB - Background. The prevalence of Kaposi's sarcoma (KS), an AIDS-defining illness, has increased in parallel with the HIV/AIDS epidemic. The presence of violaceous skin lesions should raise suspicion of KS. However, especially on dark skin, KS mimics a variety of non-KS skin conditions. Histologically, there is a wide range of expressions of KS and a large number of mimickers. For all these reasons, a HHV-8 immunohistochemically biopsy-proven diagnosis of KS should be the gold standard. Methods. Prospective study of 490 consecutive skin biopsies from the general community in the Limpopo Province of South Africa, from April 2010 through December 2011. Results. The clinical discordance rate (over /underdiagnosis of KS) was 30.5%; the histological discordance rate was 9.2%. Conclusion. Because of the magnitude of diagnostic error, both clinical and histological, all clinical lesions suspicious of KS should be biopsied and HHV-8 LAN-1 immunophenotyped. PMID- 24052879 TI - Loss to Followup: A Major Challenge to Successful Implementation of Prevention of Mother-to-Child Transmission of HIV-1 Programs in Sub-Saharan Africa. AB - Purpose. The purpose of this paper was to explore how loss to followup (LFTU) has affected the successful implementation of prevention of mother to child transmission of HIV-1 (PMTCT) programs in sub-Saharan Africa. Methods. We conducted an electronic search from the following databases PubMed, ScienceDirect, Directory of Open Access Journals (DOAJs), and PyscINFO. Additional searches were made in WHO, UNAIDS, UNICEF, Google, and Google scholar websites for (1) peer-reviewed published research, (2) scientific and technical reports, and (3) papers presented on scientific conferences. Results. A total of 678 articles, published from 1990 to 2011, were retrieved. Only 44 articles met our inclusion criteria and were included in the study. The rates of LTFU of mother-child pairs ranged from 19% to 89.4 in the reviewed articles. Health facility factors, fear of HIV-1 test, stigma and discrimination, home deliveries and socioeconomic factors were identified as reasons for LTFU. Conclusion. There is a great loss of mother-child pairs to follow up in PMTCT programs in sub Saharan Africa. There is need for more research studies to develop public health models of care that can help to improve followup of mother-child pairs in PMTCT programs in Sub-Saharan Africa. PMID- 24052880 TI - Diabetes and Hypertension among Patients Receiving Antiretroviral Treatment Since 1998 in Senegal: Prevalence and Associated Factors. AB - Cardiovascular risk factors in people on antiretroviral treatment (ART) are poorly documented in resource-constrained settings. A cross-sectional study was conducted in 2009 to assess prevalence of diabetes and hypertension in a sample of 242 HIV-infected patients who had initiated ART between 1998 and 2002 in Dakar, Senegal (ANRS 1215 observational cohort). World Health Organization (WHO) criteria were applied to diagnose diabetes and hypertension. Multiple logistic regressions were used to identify factors associated with diabetes and hypertension. Patients had a median age of 46 years and had received ART for a median duration of about 9 years. 14.5% had diabetes and 28.1% had hypertension. Long duration of ART (>=119 months), older age, higher body mass index (BMI), and higher levels of total cholesterol were associated with higher risks of diabetes. Older age, higher BMI at ART initiation, and higher levels of triglycerides were associated with higher risk of hypertension. This study shows that diabetes and hypertension were frequent in these Senegalese HIV patients on ART. It confirms the association between duration of ART and diabetes and highlights the need to implement programs for prevention of cardiovascular risk factors in HIV patients from resource-constrained settings. PMID- 24052881 TI - Large epidemiological influenza a outbreak in a teaching hospital from guatemala city. AB - Objective. To describe the characteristics and interventions to control a large epidemiological Influenza A Outbreak. Methods. During the months of February to April 2006, a large outbreak of Influenza A was detected, which affected Health Care Workers and hospitalized patients in a large teaching Hospital in Guatemala City. Interventions to interrupt transmission were implemented and included barrier methods (N95 masks, respiratory isolation measures, etc.) and enhanced hand hygiene, vaccination of healthy Health Care Workers (HCW), restrictions for patient visits. Results. From February to April 2006, 59 hospitalized patients diagnosed with Influenza A. 19 AIDS patients (mortality: 71%) and 5/40 (12.5%) in other diseases: cancer (3), severe cardiac failure (1) and severe malnutrition (1). The attack rate at day 20 in doctors and medical students was 21% while in other HCW it was 10.5%. Within 3 weeks of the beginning of the plan, deaths were stopped and no more cases in HCW were detected after 3 additional weeks. Conclusion. A rapid, comprehensive plan for the control of nosocomial epidemic Influenza A outbreaks is essential to limit severe morbidity and mortality in hospitals who attend large immunocompromised populations, including AIDS patients. HCW regular vaccinations programs are mandatory. PMID- 24052882 TI - Study of Depression and Its Associated Factors among Women Living with HIV/AIDS in Coastal South India. AB - Background. Depression is one of the most prevalent psychiatric diagnoses seen in HIV-positive individuals. Women with HIV are about four times more likely to be depressed than those who are not infected. Aims. To assess the sociodemographic and clinical correlates of depression among women living with HIV/AIDS. Setting and Design. One public and one private hospital in Mangalore, Coastal South India, and cross-sectional design. Methods and Materials. Study constituted of 137 HIV-positive women, depression was assessed using BDI (Beck Depression Inventory), and social support was assessed using Lubben Social Network Scale. Statistical Analysis. All analysis was conducted using SPSS version 11.5. Chi square test with P value less than 0.05 was taken as statistically significant. Results. Among 137 HIV-positive women, 51.1% were depressed. Around 16% were having moderate to high risk for isolation. Depression was statistically significant in rural women, widowed women, and lower socioeconomic class women. Conclusion. Depression is highly prevalent among women living with HIV which is still underdiagnosed and undertreated, and there is a need to incorporate mental health services as an integral component of HIV care. PMID- 24052883 TI - High loss to followup and early mortality create substantial reduction in patient retention at antiretroviral treatment program in north-west ethiopia. AB - Background. There has been a rapid scale up of antiretroviral therapy (ART) in Ethiopia since 2005. We aimed to evaluate mortality, loss to followup, and retention in care at HIV Clinic, University of Gondar Hospital, north-west Ethiopia. Method. A retrospective patient chart record analysis was performed on adult AIDS patients enrolled in the treatment program starting from 1 March 2005. We performed survival analysis to determine, mortality, loss to followup and retention in care. Results. A total of 3012 AIDS patients were enrolled in the ART Program between March 2005 and August 2010. At the end of the 66 months of the program initiation, 61.4% of the patients were retained on treatment, 10.4% died, and 31.4% were lost to followup. Fifty-six percent of the deaths and 46% of those lost to followup occurred in the first year of treatment. Male gender (adjusted hazard ratio (AHR) was 3.26; 95% CI: 2.19-4.88); CD4 count <=200 cells/ MU L (AHR 5.02; 95% CI: 2.03-12.39), tuberculosis (AHR 2.91; 95% CI: 2.11-4.02); bed-ridden functional status (AHR 12.88; 95% CI: 8.19-20.26) were predictors of mortality, whereas only CD4 count <200 cells/ MU L (HR = 1.33; 95% CI: (0.95, 1.88) and ambulatory functional status (HR = 1.65; 95% CI: (1.22, 2.23) were significantly associated with LTF. Conclusion. Loss to followup and mortality in the first year following enrollment remain a challenge for retention of patients in care. Strengthening patient monitoring can improve patient retention AIDS care. PMID- 24052884 TI - Conservation, Compensation, and Evolution of N-Linked Glycans in the HIV-1 Group M Subtypes and Circulating Recombinant Forms. AB - The "glycan shield" exposed on the surface of the HIV-1 gp120 env glycoprotein has been previously proposed as a novel target for anti-HIV treatments. While such targeting of these glycans provides an exciting prospect for HIV treatment, little is known about the conservation and variability of glycosylation patterns within and between the various HIV-1 group M subtypes and circulating recombinant forms. Here, we present evidence of strong strain-specific glycosylation patterns and show that the epitope for the 2G12 neutralising antibody is poorly conserved across HIV-1 group M. The unique glycosylation patterns within the HIV-1 group M subtypes and CRFs appear to explain their varying susceptibility to neutralisation by broadly cross-neutralising (BCN) antibodies. Compensatory glycosylation at linearly distant yet three-dimensionally proximal amino acid positions appears to maintain the integrity of the glycan shield while conveying resistance to neutralisation by BCN antibodies. We find that highly conserved clusters of glycosylated residues do exist on the gp120 trimer surface and suggest that these positions may provide an exciting target for the development of BCN anticarbohydrate therapies. PMID- 24052885 TI - Prevalence of HIV-Associated Metabolic Abnormalities among Patients Taking First Line Antiretroviral Therapy in Uganda. AB - Introduction. While the introduction of highly active antiretroviral therapy decreased HIV-related morbidity and mortality rates in the sub-Saharan Africa, a subsequent increase in metabolic abnormalities has been observed. We sought to determine the prevalence of HIV-associated metabolic abnormalities among patients on first-line antiretroviral therapy (ART) in an ART clinic in Kampala, Uganda. Methods. Four hundred forty-two consecutive patients on first-line ART for at least 12 months were screened for eligibility in a cross-sectional study, and 423 were enrolled. Pre-ART patient characteristics were abstracted from medical charts, examinations included anthropometric measurement and physical assessment for lipodystrophy. Results. The prevalence of hyperglycemia and dyslipidemia was 16.3% (69/423) and 81.5% (345/423), respectively. Prevalence of dyslipidemia between stavudine- and zidovudine-based regimens (91% versus 72%; P < 0.001). Being on stavudine (aOR 4.79, 95%, 2.45-9.38) and peak body weight (aOR 1.44, 95% CI 1.05-1.97) were independent risk factors for dylipidemia. Stavudine (aOR 0.50, 95% CI 0.27-0.93) use was associated with lower risk for hyperglycemia while, and older age (aOR 1.31, 95% CI 1.11-1.56) and having a family history of DM (aOR 2.18, 95% CI 1.10-4.34) were independent risk factors for hyperglycemia. Conclusions. HIV-associated metabolic complications were prevalent among patients on thymidine analogue-containing ART regimens. Screening for lipid and glucose abnormalities should be considered in ART patients because of cardiovascular risks. PMID- 24052886 TI - Missed Doses and Missed Appointments: Adherence to ART among Adult Patients in Uganda. AB - Background. Missed doses and appointments are predictors of incomplete adherence among patients on ART. The AIDSRelief model emphasizes treatment preparation and continuous treatment support for ART patients including community followup. Methods. In August 2008, a survey was conducted among patients on antiretroviral therapy (ART) (interquartile range for duration of ART = 29-46 months, median = 33 months, n = 763, age >16 years), in 15 health facilities in Uganda. Missed doses and appointments among adult patients on ART and the factors most associated with these were identified. Reasons for missed doses were also explored. Results. The survey revealed that 97% of the patients had not missed their doses in the last week while 93% had not missed their appointments in the last three months. For those who had missed their doses, the most common reasons were travel (48%) and forgetfulness (28%). There was a significant association between missing doses and missing appointments (P = 0.0004) and between alcohol use and missed doses (P < 0.005). Conclusions. The level of adherence to medication and clinic appointments for patients on ART in the study population was very high. It is important to strengthen adherence strategies at both facility and community levels to assist patients that are likely to miss their doses or appointments. PMID- 24052887 TI - Rapid Point-of-Care Testing for Detection of HIV and Clinical Monitoring. AB - Reversing and arresting the epidemic of HIV are a challenge for any country. Early diagnosis and rapid initiation of treatment remain a key strategy in the control of HIV. Technological advances in the form of low-cost rapid point-of care tests have completely transformed the diagnosis and management of HIV, especially in resource limited settings, where health infrastructure is poor and timely access to medical care is a challenge. Point-of-care devices have proven to be easy to transport, operate, and maintain, and also lower-skilled staff is equally able to perform these tests as compared to trained laboratory technicians. Point-of-care tests allow rapid detection of HIV allowing for rapid initiation of therapy, monitoring of antiretroviral therapy and drug toxicity, and detection of opportunistic infections and associated illnesses. PMID- 24052888 TI - Prevalence of Intestinal Parasitic Infection among HIV Positive Persons Who Are Naive and on Antiretroviral Treatment in Hiwot Fana Specialized University Hospital, Eastern Ethiopia. AB - Background. Intestinal parasitic infection affects the health and quality of life of people living with HIV. This study was aimed to determine the prevalence of intestinal parasites among HIV positive individuals who are naive and who are on antiretroviral treatment (ART) in Hiwot Fana Specialized University Hospital, Eastern Ethiopia. Methods. A comparative cross-sectional study was conducted on 371 (112 ART-naive group and 259 on ART) HIV positive individuals. Stool specimens were collected and examined by direct wet mount, formol ether concentration technique, and modified ziehl-Neelsen methods. Results. The overall prevalence of intestinal parasitic infections was 33.7%; it was significantly higher among the study participants who were ART-naive group (45.5%) (AOR: 2.60(1.56,4.34)) and diarrheic (53.3%) (AOR: 2.30(1.34,3.96)) and with CD4 count <200 cells/ MU L (46%) (AOR: 2.07(1.06,4.04)). The most commonly identified parasites were Entamoeba histolytica/E. dispar (13.5%), Giardia lamblia (8.1%), Strongyloides stercoralis (4.0%), and Cryptosporidium species (2.2%). Conclusion. HIV positive individuals with diarrhea and low CD4 count and ART naive groups were more infected with intestinal parasites than their counterparts. Early stool examination and treatment of intestinal parasites for HIV/AIDS patients is essential. PMID- 24052890 TI - Determinants of Mortality among HIV Positives after Initiating Antiretroviral Therapy in Western Ethiopia: A Hospital-Based Retrospective Cohort Study. AB - Studies revealed that there are various determinants of mortality among HIV positives after ART initiation. These determinants are so variable with context and dynamic across time with the advancement of cares and treatments. In this study we tried to identify determinants of mortality among HIV positives after initiating ART. A retrospective cohort study was conducted among 416 ART attendees enrolled between July 2005 to January 2012 in Nekemte Referral Hospital, Western Ethiopia. Actuarial table was used to estimate survival of patients after ART initiation and log rank test was used to compare the survival curves. Cox proportional-hazard regression was applied to determine the independent determinants of time to death. The estimated mortality was 4%, 5%, 6%, 7%, and 7% at 6, 12, 24, 36 and 48 months respectively with mortality incidence density of 1.89 deaths per 100 person years (95% CI 1.74, 3.62). Forty years and above AHR = 3.055 (95% CI 1.292, 7.223), low baseline hemoglobin level (AHR = 0.523 (95% CI .335, 0.816)), and poor ART adherence (AHR 27.848 (95% CI 8.928, 86.8)) were found to be an independent determinants of mortality. These determinants of mortality have to be taken into account to enhance better clinical outcomes of ART attendees. PMID- 24052892 TI - Factors affecting adherence to antiretroviral treatment in harari national regional state, eastern ethiopia. AB - Background. The efficacy of antiretroviral treatment (ART) depends on strict adherence to the regimen, but many factors have been identified for nonadherence. Method. To identify the factors for non-adherence to ART, a cross-sectional study was conducted on people living with human immunodeficiency virus (HIV) and attending the ART service at Hiwot Fana and Jugal hospitals; it was done from October to December, 2010. Adherence was defined as taking 95% of the prescribed doses in the week before the survey. Data were collected using a standard interview questionnaire and were analyzed using SPSS Version 16. Result. Among the 239 study participants, the magnitude of adherence to ART in the week before interview was 87%. The main reasons for nonadherence were forgetting (47.2%), traveling (18.9%), and being busy doing other things (15.1%). There was not any independent predicator identified for adherence to ART. Conclusion. Compared to other similar studies in Ethiopia, in this study a high adherence rate was found. Forgetfulness was the most common reason for the nonadherence. Therefore, the ART counseling needs to give emphasis to using memory aids. In addition, a further study on adherence rate and its determinants with multiple adherence measurements is recommended. PMID- 24052889 TI - New Insights into HIV/AIDS-Associated Cryptococcosis. AB - Cryptococcal meningitis is a life-threatening opportunistic fungal infection in both HIV-infected and HIV-uninfected patients. According to the most recent taxonomy, the responsible fungus is classified into a complex that contains two species (Cryptococcus neoformans and C. gattii), with eight major molecular types. HIV infection is recognized worldwide as the main underlying disease responsible for the development of cryptococcal meningitis (accounting for 80-90% of cases). In several areas of sub-Saharan Africa with the highest HIV prevalence despite the recent expansion of antiretroviral (ARV) therapy programme, cryptococcal meningitis is the leading cause of community-acquired meningitis with a high mortality burden. Although cryptococcal meningitis should be considered a neglected disease, a large body of knowledge has been developed by several studies performed in recent years. This paper will focus especially on new clinical aspects such as immune reconstitution inflammatory syndrome, advances on management, and strategies for the prevention of clinical disease. PMID- 24052893 TI - In this issue of Adipocyte. PMID- 24052891 TI - Innate immune evasion strategies by human immunodeficiency virus type 1. AB - Host immune components play both beneficial and pathogenic roles in human immunodeficiency virus type 1 (HIV-1) infection. During the initial stage of viral infection, a complex network of innate immune factors are activated. For instance, the immune cells express a number of inflammatory proteins including cytokines, chemokines, and antiviral restriction factors. These factors, specifically, interferons (IFNs) play a crucial role in antiviral defense system by modulating the downstream signaling events, by inducing maturation of dendritic cells (DCs), and by activation of macrophages, natural killer (NK) cells, and B and T cells. However, HIV-1 has evolved to utilize a number of strategies to overcome the antiviral effects of the host innate immune system. This review discusses the pathways and strategies utilized by HIV-1 to establish latent and persistent infection by defeating host's innate defense system. PMID- 24052894 TI - Brown adipose tissue thermogenesis in the resistance to and reversal of obesity: A potential new mechanism contributing to the metabolic benefits of proglucagon derived peptides. AB - The capacity for increased thermogenesis through brown adipose tissue (BAT) activation is important for body weight homeostasis. Differences in BAT thermogenesis can underlie significant differences in body weight and body composition, as we demonstrate in a rat model of obesity. This mini-review focuses on our current understanding of physiological BAT regulation, with a view to how it may be exploited therapeutically. BAT activation is under central nervous system control, with the most potent activator of BAT being the sympathetic nervous system, although other humoral and hormonal factors also contribute to BAT regulation. The peptide products of the proglucagon gene are important in energy homeostasis, with well-described effects on feeding and body weight. We recently demonstrated that the peptides glucagon-like peptide 1, glucagon, and oxyntomodulin are also able to induce BAT thermogenesis by a central, sympathetic mechanism. Given the wide spread use of GLP-1 receptor based therapies for type 2 diabetes, drugs targeting this system may be useful in a wider energy balance context. PMID- 24052895 TI - Circadian regulation of adipose function. AB - Adipose physiology shows prominent variation over the course of the day, responding to changing demands in energy metabolism. In the last years the tight interaction between the endogenous circadian timing system and metabolic function has been increasingly acknowledged. Recent work suggests that clock and adipose function go hand in hand, regulating each other to ensure optimal adaptation to environmental changes over the 24-h cycle. In this review we describe the current knowledge on the mechanistic basis of this interaction and summarize recent findings on the impact of clock dysfunction on adipose physiology and energy homeostasis. PMID- 24052896 TI - Loss of menin mediated by endothelial cells treated with CoPP is associated with increased maturation of adipocytes. AB - Oxidative stress is caused by an increase in reactive oxygen species (ROS) relative to the antioxidant defense system. An increase in ROS is known to decrease vascular function, increase inflammatory cytokines, and promote adipocyte hypertrophy. A known regulator of the oxidative stress response is the heat shock protein, heme-oxygenase 1 (HO-1), which is induced by cobalt protoporphyrin IX (CoPP). Menin was recently found to promote the sustained expression of heat shock proteins and is implicated in the regulation of oxidative stress. In this study, we investigated how changes in menin expression affected adipogenesis via the interaction between endothelial cells and adipocytes in response to CoPP treatment during oxidative stress. Using angiotensin II (Ang II) to induce oxidative stress in endothelial cells and adipocytes, we observed the induction of various cytokines including EGF, VEGF, angiogenin, IL-6, and MCP-1. Preadipocytes cultured in endothelial cell conditioned media treated with Ang II showed no changes in differentiation markers. Preadipocytes treated with the endothelial cell-conditioned media pretreated with CoPP resulted in an increase in the number of adipocytes, which expressed higher levels of adipocyte differentiation markers in direct correlation with the complete downregulation of the stress response regulator, menin. This change was not detected in adipocytes directly treated with CoPP alone. Therefore, we concluded that loss of menin is associated with the maturation of adipocytes induced by conditioned media from endothelial cells treated with CoPP. PMID- 24052898 TI - Beneficial effects of Brazilian propolis on type 2 diabetes in ob/ob mice: Possible involvement of immune cells in mesenteric adipose tissue. AB - The anti-diabetic effects of Brazilian propolis were examined using ob/ob mice. Although repeated injection of an ethanol extract of Brazilian propolis (100 mg/kg, ip, twice a week for 12 weeks) did not affect body weight gain and food intake of ob/ob mice, blood glucose and plasma cholesterol levels were significantly attenuated. Moreover, the propolis extract partially restored glucose tolerance and insulin resistance, indicating anti-diabetic properties of the extract. The propolis-treated mice exhibited lower weight gain in mesenteric adipose tissue, while weight gains in inguinal and epididymal adipose tissues were not modulated. Flow cytometric and microscopic analyses suggested that the extract promoted accumulation of eosinophils into mesenteric and epididymal adipose tissues. Alternatively, the ratio of M1-like macrophages to M2-like macrophages in mesenteric adipose tissue was reduced by the propolis injection, coincident with the decrement of the number of interleukin-12A(+) cells. Levels of M1 macrophage markers, such as Itgax and Il12b transcripts, were decreased in the vascular stromal fraction of mesenteric adipose tissue, whereas those of pan macrophage markers Emr1 and Cd68 were not influenced. Microarray and subsequent gene ontology term analyses suggested that propolis attenuated immune activation in mesenteric adipose tissues. Taken together, this indicates that Brazilian propolis improves diabetes in ob/ob mice, presumably through modification of immune cells in mesenteric adipose tissues. PMID- 24052897 TI - Adipose tissue depot and cell size dependency of adiponectin synthesis and secretion in human obesity. AB - Adiponectin is an insulin sensitizing fat cell (FC) hormone whose levels are related to adipose tissue (AT) mass and depot distribution. We hypothesized that the nature of AT expansion (hypertrophy vs. hyperplasia) contributes to obesity related reductions in serum adiponectin and that this effect is influenced by the regional distribution of AT to subcutaneous (S) and visceral (V) depots. Thirteen obese subjects provided paired AT biopsies. Serum total and high molecular weight (HMW) adiponectin levels were determined by ELISA. Secretion was quantified following 24-h explant culture. FC size, number, % large, and % small FC were determined by microscopic analysis. Secretion of total adiponectin was highest by SAT (P = 0.008) and correlated more strongly with serum adiponectin (total: P = 0.015, r = 0.77; HMW: P = 0.005, r = 0.83) than did secretion by VAT (P = 0.05, r = 0.66 for both). FC size was greatest in SAT and correlated negatively with both serum (total: P = 0.01, r = -0.74; HMW: P = 0.03, r = -0.69) and secreted (total: P = 0.05, r = -0.72; HMW: P = 0.02, r = -0.87) adiponectin. The % small FC in SAT correlated positively with both serum (total: P = 0.006, r = 0.87; HMW: P = 0.009, r = 0.79) and secreted (total: P = 0.03, r = 0.75; HMW: P = 0.01, r = 0.92) adiponectin. VAT FC size correlated negatively with serum HMW adiponectin (P = 0.01, r = -0.76) but not with any measure of secretion. VAT had the greatest % small FC, which related positively to serum HMW (P = 0.004, r = 0.81) and to secreted total adiponectin (P = 0.02, r = 0.78). These studies indicate that differences in fat cell size and depot distribution of AT expansion are important influences on adiponectin in obesity. PMID- 24052899 TI - Rats perinatally exposed to food restriction and high-fat diet show differences in adipose tissue gene expression under chronic caloric restriction. AB - The aim of this study is to analyze how maternal diet during the lactational period influences the adipose tissue response to chronic caloric restriction in offspring. Lactating dams were subjected to one of three treatments: 50% food restriction (FR), ad lib standard chow (AL), or ad lib high-fat diet (HF). Juveniles were first weaned onto standard chow, then in adulthood 50% calorically restricted and maintained at 90% of normal body weight for 60 d. HF animals showed increased percent body fat compared with AL and FR animals despite equivalent body weights. HF animals showed alterations in the balance of adipose tissue lipogenic (FAS, LPL) and lipolytic (HSL) gene expression that may underlie their propensity to maintain fat stores under caloric restriction. PMID- 24052901 TI - Knockdown of ZBED6 is not associated with changes in murine preadipocyte proliferation or differentiation. AB - ZBED6 was identified as a transcription factor that affects muscle mass and fat deposition in pigs. Mechanisms mediating effects on fat mass are unclear. The objective was to determine the effect of ZBED6 mRNA knockdown on 3T3-L1 preadipocyte differentiation and gene expression. Differentiation was associated with increased mRNA abundance of CEBP/alpha (P < 0.05), CEBP/beta (P < 0.05), CEBP/delta (P < 0.05), FASN (P < 0.05), PPARgamma (P < 0.05), and SREBP-1 (P < 0.05), and decreased abundance of PREF-1 (P < 0.05). Knockdown of ZBED6 was not associated with changes in mRNA abundance of selected genes, lipid accumulation, lipid droplet size, or cell number. These results suggest that ZBED6 does not play a major role in preadipocyte differentiation. PMID- 24052900 TI - Roles of activin receptor-like kinase 7 signaling and its target, peroxisome proliferator-activated receptor gamma, in lean and obese adipocytes. AB - We recently discovered a novel signaling pathway involving activin receptor-like kinase 7 (ALK7), one of the type I transforming growth factor-beta receptors. ALK7 and activated Smads 2, 3, and 4 inhibit the master regulators of adipogenesis, CCAAT/enhancer-binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) specifically in differentiated adipocytes, but surprisingly increase both the adipocyte size and lipid content by suppressing lipolysis. Here, we show that, although both transcription factors are suppressed by ALK7 in either the obese or lean state, PPARgamma, but not C/EBPalpha, is further suppressed under obesity through an ALK7-independent pathway. As a result, PPARgamma and adipose lipolytic activities are severely downregulated in obesity. Reactivation of PPARgamma by ALK7 inactivation leads to downregulation of inflammatory adipocytokines and upregulation of adiponectin. We propose that PPARgamma promotes lipid turnover and remodeling by stimulating both triglyceride synthesis and breakdown in differentiated adipocytes. Finally, we discuss the physiological and evolutionary roles of the ALK7-signaling pathway and consider it as a potential target of therapy for obesity. PMID- 24052902 TI - Mutually exclusive acetylation and ubiquitylation among enzymes involved in glucose metabolism. AB - The posttranslational modification (PTM) in protein occurs in a regiospecific manner. In addition, the most commonly occurring PTMs involve similar residues in proteins such as acetylation, ubiquitylation, methylation and sumoylation at the lysine residue and phosphorylation and O-GlcNAc modification at serine/threonine residues. Thus, the possibility of modification sites where two such PTMs may occur in a mutually exclusive manner (ME-PTM) is much higher than known. A recent surge in the identification and the mapping of the commonly occurring PTMs in proteins has revealed that this is indeed the case. However, in what way such ME PTM sites are regulated and what could be their relevance in the coordinated network of protein function remains to be known. To gain such potential insights in a biological context, we analyzed two most prevalent PTMs on the lysine residue by acetylation and ubiquitylation along with the most abundant PTM in proteins by phosphorylation among enzymes involved in glucose metabolism, a fundamental process in biology. The analysis of the PTM data sets has revealed two important clues that may be intrinsically associated with their regulation and function. First, the most commonly occurring PTMs by phosphorylation, acetylation and ubiquitylation are widespread and clustered in most of the enzymes involved in glucose metabolism; and the prevalence of phosphorylation sites correlates with the number of acetylation and ubiquitylation sites including the ME-modification sites. Second, the prevalence of ME acetylation/ubiquitylation sites is exceptionally high among enzymes involved in glucose metabolism and have distinct pattern among the subset of enzymes of glucose metabolism such as glycolysis, tricarboxylic acid (TCA) cycle, glycogen synthesis, and the irreversible steps of gluconeogenesis. We hypothesize that phosphorylation including tyrosine phosphorylation plays an important role in the regulation of ME-acetylation/ubiquitylation sites and their similar pattern among the subset of functionally related proteins allows their coordinated regulation in the normal physiology. Similarly their coordinated dysregulation may underlie the disease processes such as reprogrammed metabolism in cancer, obesity, type 2 diabetes, and cardiovascular diseases. Our hypothesis provides an opportunity to understand the regulation of ME-PTMs in proteins and their relevance at the network level and is open for experimental validation. PMID- 24052903 TI - A role for 5-lipoxygenase products in obesity-associated inflammation and insulin resistance. AB - There is a growing amount of evidence that obesity-induced low-grade inflammation is an important causative link between obesity and many of its associated pathologies such as type 2 diabetes and atherosclerosis. In the quest to identify the triggers of obesity-associated inflammation of adipose tissue, our laboratory recently demonstrated that adipocytes can secrete leukotrienes, and that these pro-inflammatory lipid mediators contribute to obesity-associated inflammation and insulin resistance in mice. Together with other recent studies, our recent findings identify an important role for the enzyme 5-lipoxygenase and its products in the induction and resolution of adipose tissue inflammation. Therefore, pharmaceutical approaches that target this enzyme or its products should be considered as novel treatments aimed at preventing or resolving obesity induced inflammation and its associated pathologies. PMID- 24052904 TI - Galectin-3 is a regulator of metaflammation in adipose tissue and pancreatic islets. AB - The cells of the innate and adaptive immune systems have been implicated in the development of obesity-induced metaflammation and metabolic disorders including type 2 diabetes. Galectin-3, a beta-galactoside-binding lectin, modulates immune/inflammatory responses and specifically binds to advanced glycation end products (AGE), modified lipoproteins, and endotoxin. In the recently published study we demonstrate proinflammatory changes in the visceral adipose tissue and pancreatic islets in galectin-3-deficient mice fed high-fat diet which also exhibited excess adiposity, hyperglycemia, insulin resistance and systemic inflammation compared with their diet matched wild-type controls. This was associated with the increased incidence of Type-1 T and NKT cells and pro inflammatory CD11c(+)CD11b(+) macrophages in the visceral adipose tissue. Severe insulitis, infiltration of macrophages expressing NLRP3 inflammasome and IL 1beta, and enhanced accumulation of AGE were present within the pancreatic islets in obese LGALS3(-/-) mice. Moreover, increased caspase-1 dependent IL-1beta secretion with increased expression of NLRP3 inflammasome and phospho-NFkappaBp65 were observed in LGALS3(-/-) peritoneal macrophages stimulated in vitro by lipopolysaccharide and/or saturated fatty acid palmitate. The amplified high-fat diet-induced obesity and hyperglycemia and exacerbated inflammation in adipose tissue and pancreatic islets in LGALS3(-/-) mice suggest an important role for galectin-3 in the regulation of adiposity, metaflammation and type 2 diabetes. PMID- 24052905 TI - Preadipocytes proliferate and differentiate under the guidance of Delta-like 1 homolog (DLK1). AB - Obesity occurs when an excessive dietary fat intake leads to expansion of adipose tissue, which mainly consists of adipocytes that arise from proliferating and differentiating adipose stem cells, the preadipocytes. Obesity is a consequence of both adipocyte hypertrophy and hyperplasia. Knowledge about preadipocyte differentiation is relatively well established, whereas the mechanism responsible for preadipocyte proliferation is incompletely understood and only in the early stage of comprehension. In this regard, we have recently identified that Delta like 1 homolog (Dlk1) (also known as Preadipocyte factor 1 [Pref-1]) inhibits preadipocyte proliferation by regulating their entry into G1/S-phase. This novel disclosure, adding to the previous published data on Dlk1 repression of preadipocyte differentiation, has given us the chance to firmly place Dlk1 as a master regulator of preadipocyte homeostasis and adipose tissue expansion. Dlk1 manipulation may, therefore, open new perspectives in obesity treatments. PMID- 24052907 TI - Identification of a novel interorgan mechanism favoring energy storage in overnutrition. AB - While body weight is essentially determined by the balance of energy intake and energy consumption, it is not necessarily the case that changes in daily food intakes and exercise directly reflect changes in body weight. In recent years, it has been revealed that numerous metabolic interactions between organs, which are organized by the brain, function as a feedback mechanism, and are involved in maintaining body weight homeostasis against excess energy intake. On the other hand, since obesity has seen an explosive increase in this age of plenty, there must be other interactions between organs working as feedforward mechanisms favoring weight gain. However, no such interaction has yet been demonstrated. Recently, we discovered a new interorgan neural network, from the liver, which may represent the feedforward mechanism.(1) Under conditions of excessive energy intake, changes in glucose metabolism occur in the liver with increased expression of hepatic glucokinase (GK) and the induction of neuronal signal transmission via the afferent vagus nerve. These signals are received by the medulla and result in inactivation of sympathetic nerve to brown adipose tissue (BAT), thereby suppressing thermogenesis in BAT and promoting adiposity. Furthermore, the efficacy of the liver-to-BAT interaction differs among mouse strains and these differences may contribute to determining the obesity predispositions of various strains. In conclusion, this novel interorgan neuronal relay system functions to suppress energy expenditure when energy intake is increased, and thus, is considered to be a thrifty mechanism operating on the whole body level. During periods when sufficient food was not always available, this system worked in favor of survival. However, in the current age of plenty, it is assumed to work as a mechanism flipping a metabolic switch toward obesity. PMID- 24052906 TI - gamma-synuclein is a novel player in the control of body lipid metabolism. AB - Synucleins are a family of homologous, predominantly neuronal proteins known for their involvement in synaptic transmission and neurodegeneration. gamma-synuclein is predominantly localized in axons and presynaptic terminals of selected populations of peripheral and central neurons but is also highly expressed in human white adipose tissue (WAT) and increased in obesity. We have recently shown that gamma-synuclein is nutritionally regulated in murine adipocytes while its loss protects mice from high fat diet (HFD)-induced obesity and associated metabolic complications. This protection was coupled with increased adipocyte lipolysis, lipid oxidation, and energy expenditure in HFD-fed gamma-synuclein null mutant compared with wild-type mice. Cellular studies suggest that relocalization of ATGL to the lipid droplet in gamma-synuclein-deficient adipocytes may contribute to increased lipolysis in these cells. Loss of gamma synuclein in adipocytes also attenuates the assembly of SNARE complexes, an important component of lipid droplet fusion machinery, possibly due to reduced chaperoning of SNAP-23 to the assembling SNARE complex by gamma-synuclein. Together our data suggests that not only is gamma-synuclein a novel regulator of lipid handling in adipocytes but also that the deficiency of this protein has a significant effect on whole body energy expenditure. PMID- 24052908 TI - Novel insights into histone modifiers in adipogenesis. AB - Recently, it has been progressively recognized that gene expression is regulated by histone methylation status, which is dynamically modulated by histone methyltransferases (HMTs) and histone demethylases (HDMs). In the past decade, many HMTs and HDMs were identified and their biological and biochemical functions have been characterized. As with other cells, several HMTs and HDMs are known to be indispensable for appropriate differentiation of adipocytes from mesenchymal stem cells. Phf2 is a recently identified dimethylated histone H3 lysine 9 (H3K9me2) demethylase that has a significant function in hepatocytes and macrophages in vitro; however, the in vivo significance of Phf2 remains unclear. To determine the physiological role of Phf2, we recently generated Phf2 knockout mice. Our analyses of these mice revealed that Phf2 has a positive role in adipogenesis by coactivating CEBPA, one of the master regulators of adipogenesis, through its demethylation activity toward H3K9me2. In this commentary, we discuss several remaining questions that underlie phenotypic abnormalities seen in our investigations of Phf2 knockout mice. These studies are related to novel functions of histone modifiers and may help identify new therapeutic targets for metabolic syndrome. PMID- 24052909 TI - Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor? AB - FNDC5 (fibronectin domain-containing [protein] 5) was initially discovered and characterized by two groups in 2002. In 2011 FNDC5 burst into prominence as the parent of irisin, a small protein containing the fibronectin type III domain. Irisin was proposed to be secreted by skeletal muscle cells in response to exercise, and to circulate to fat tissue where it induced a transition to brown fat. Since brown fat results in dissipation of energy, this pathway is of considerable interest for metabolism and obesity. Here I review the original discoveries of FNDC5 and the more recent discovery of irisin. I note in particular three problems in the characterization of irisin: the antibodies used to detect irisin in plasma lack validity; the recombinant protein used to demonstrate activity in cell culture was severely truncated; and the degree of shedding of soluble irisin from the cell surface has not been quantitated. The original discovery proposing that FNDC5 may be a transmembrane receptor may deserve a new look. PMID- 24052910 TI - Guest Editors' Message: American College of Physicians, Hawai'i Chapter, Annual Meeting 2013. PMID- 24052911 TI - New triple therapy for chronic hepatitis C: real life clinical experience in a community setting. AB - Recent advances in treatment of chronic hepatitis C virus have improved significantly due to the introduction of two new protease inhibitors-telaprevir and boceprevir. In combination with the previous standard of care, peginterferon and ribavirin, telaprevir and boceprevir have demonstrated improved sustained virologic response rates for HCV genotype 1 patients by approximately 30%. The purpose of this study was to assess the validity of large clinical trial data with respect to efficacy and side effects in a community setting in Honolulu, Hawai'i. This retrospective study was performed by reviewing the charts of 59 chronic HCV patients who were started on triple therapy from July 1, 2011 to July 7, 2012. Sustained virologic response was attained by 73% of patients treated with telaprevir and 46% of patients treated with boceprevir respectively. Our clinical experience with telaprevir demonstrates that SVR rates are compatible with published literature values. Rates of SVR in our cohort were also similar to those reported in cirrhotic patients - about 50%. Due to small number of patients treated with a boceprevir-based regimen, it is difficult to compare our experience with pivotal trial experience. The side effect profiles for the two protease inhibitors were similar to the literature values except for more rectal irritation and a higher incidence and severity of anemia on telaprevir therapy in the clinical setting. While not intended to be conclusive, our study demonstrates that clinical trial data are largely compatible with the outcomes obtained in our community setting. PMID- 24052912 TI - Anti-gliadin antibodies identify celiac patients overlooked by tissue transglutaminase antibodies. AB - For patients with suspected celiac disease, the American Gastroenterological Association recommends initial screening with anti-tissue transglutaminase antibody (tTG) and confirmation testing with small bowel biopsy. However, at Tripler Army Medical Center we routinely screen patients with both tTG and anti gliadin antibodies (AGA) in combination. The purpose of this study was to evaluate whether this dual screening method adds to the evaluation of patients with suspected celiac disease or results in more false-positive results than tTG screening alone. A retrospective chart review of all tTG and AGA screening serologies at Tripler Army Medical Center between September 2008 and March 2012 was performed. For patients with positive serologic testing, small bowel biopsy results or reasoning for deferring biopsy were investigated. tTG was found to have a higher positive predictive value for celiac disease than AGA, however AGA identified 5 patients (19% of biopsy confirmed celiac disease) that had a negative tTG and would not have been identified by tTG screening alone. Using AGA in combination with tTG should be considered if the goal of screening is to identify all patients with celiac disease, with the understanding that this strategy will generate more false positive tests and result in additional patients undergoing small bowel biopsy. PMID- 24052913 TI - Success using tacrolimus in patients with proliferative and membranous lupus nephritis and refractory proteinuria. AB - Standard treatment for class III, IV, and V lupus nephritis (LN) is a combination of oral corticosteroids and mycophenolate mofetil (MMF). There is an estimated failure rate of 16%. Several small studies have looked at the use of tacrolimus in class III, IV, and V LN, both as induction treatment and as maintenance in patients refractory to other treatments. The majority of these studies were conducted in Asian patients. We discuss a cohort of eight female patients of various ethnicities with biopsy proven LN. All patients were evaluated retrospectively. Six were started on tacrolimus after failing to respond to MMF and corticosteroids, and one was started on tacrolimus alone because treatment options were limited by pregnancy. Five were Caucasian, one African American, one Hispanic, and one Vietnamese. Mean tacrolimus dose was 3.3mg daily (range 2-5 mg) titrated to a mean level of 3-6 ng/dl (range 3-6.6 ng/dl) for a mean of duration of 16 months (range 2-54 months). Six patients experienced complete remission (proteinuria <0.33 g/day), and two patients had a partial remission (minimum of 50% reduction in baseline proteinuria). Albumin increased an average of 32%. Average C3/C4 levels were 64/15 mg/dL, respectively, prior to treatment, and 95/25 mg/dL following treatment. No treatment-limiting adverse effects were reported. Our case series supports the growing body of evidence that tacrolimus is an effective therapy in LN patients with refractory proteinuria. Further studies are required to establish the long-term safety and efficacy of tacrolimus. PMID- 24052914 TI - Rapid multiplex PCR assay to identify respiratory viral pathogens: moving forward diagnosing the common cold. AB - Upper respiratory tract infections (URIs) can be a serious burden to the healthcare system. The majority of URIs are viral in etiology, but definitive diagnosis can prove difficult due to frequently overlapping clinical presentations of viral and bacterial infections, and the variable sensitivity, and lengthy turn-around time of viral culture. We tested new automated nested multiplex PCR technology, the FilmArray((r)) system, in the TAMC department of clinical investigations, to determine the feasibility of replacing the standard viral culture with a rapid turn-around system. We conducted a feasibility study using a single-blinded comparison study, comparing PCR results with archived viral culture results from a convenience sample of cryopreserved archived nasopharyngeal swabs from acutely ill ED patients who presented with complaints of URI symptoms. A total of 61 archived samples were processed. Viral culture had previously identified 31 positive specimens from these samples. The automated nested multiplex PCR detected 38 positive samples. In total, PCR was 94.5% concordant with the previously positive viral culture results. However, PCR was only 63.4% concordant with the negative viral culture results, owing to PCR detection of 11 additional viral pathogens not recovered on viral culture. The average time to process a sample was 75 minutes. We determined that an automated nested multiplex PCR is a feasible alternative to viral culture in an acute clinical setting. We were able to detect at least 94.5% as many viral pathogens as viral culture is able to identify, with a faster turn-around time. PMID- 24052915 TI - A comparison of methods for estimating glomerular filtration rate for a population in Hawai'i with non-valvular atrial fibrillation. AB - Warfarin is the primary treatment for those with atrial fibrillation at increased risk for stroke. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RELY) trial demonstrated that dabigatran, a direct thrombin inhibitor, was associated with lower rates of systemic embolism compared to warfarin.1 Although individuals with a creatinine clearance of less than 30 mL/min were excluded from the trial, the FDA approved the use of dabigatran for those with creatinine clearances as low as 15 mL/min, with a lower dose of dabigatran recommended for individuals with creatinine clearances below 30 mL/min. This study calculated Glomerular Filtration Rates (GFR) via three existing formulas with varying levels of accuracy (ie, the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) to evaluate how patient eligibility for the RELY trial may have varied depending upon the formula used. A retrospective study was performed based on a chart review conducted at a private cardiologist's office in Honolulu, Hawai'i using patients with non-valvular atrial fibrillation. Patients included were those with a BUN/Creatinine assessment within 12 months of the chart review and a CHADS2 (Congestive Heart Disease, hypertension, age greater than 75, diabetes mellitus, and stroke or transient ischemic attack) score of 1 or greater. Of 376 subjects assessed, 64 subjects who failed to meet criteria for the RELY trial when using the Cockcroft-Gault formula (ie, GFR estimates were lower than 30 mL/min) met eligibility criteria when the MDRD formula was used (ie, GFR estimates exceeded 30 mL/min). Subgroup analysis of the 64 subjects revealed that subjects were 89 years-old on average, predominantly female (76.5%), and mostly Japanese (62.5%). Nearly one in five individuals (17%) in the studied population would have received a lower dose of dabigatran if the Cockcroft-Gaunt formula was used for estimating GFRs. The authors recommend caution while dosing dabigatran in the Asian population, as the estimates of kidney functioning vary substantially depending on the formula used to estimate GFR, which may in turn lead in some cases of inadequate dosing of dabigatran. PMID- 24052916 TI - Trial and error: investigational drug induced liver injury, a case series report. AB - This is a case report series of four patients who exhibited signs and symptoms of acute liver dysfunction during participation in a Phase I trial of a novel non steroidal anti-inflammatory drug (NSAID) designed to inhibit microsomal prostaglandin synthase 1 (MPGES1). Within one month of trial initiation, all four patients presented with epigastric pain, fatigue, nausea, and increasing liver function tests (LFTs). Two out of four patients required hospitalization, underwent liver biopsies, and were treated with N-acetylcysteine. The remaining two patients were managed as outpatients. Liver biopsies were consistent with drug induced liver injury (DILI). Within three months of stopping the investigational drug, symptoms subsided and LFTs normalized in all patients. This case report series signifies the importance of NSAIDs and novel drug agents in general as potentially hepatotoxic substances, the need for a high level of suspicion of DILI when considering possible etiologies of acute liver failure, and the need for prompt withdrawal of the causative agent in management of patients presenting with DILI. PMID- 24052917 TI - Albuminuria as a marker of cardiovascular risk in HIV-infected individuals receiving stable antiretroviral therapy. AB - Albuminuria (urinary excretion of more than 30 milligram of albumin per gram of creatinine) serves as an indicator of microvascular injury, which has been associated with atherosclerosis and cardiovascular disease in HIV-seronegative individuals. Albuminuria has been reported to be prevalent among HIV-seropositive individuals, however, the relationship between albuminuria and risk for cardiovascular disease in this population has not been well-studied. We examined the relationships between albuminuria and parameters of atherosclerosis including carotid intima-media thickness and traditional cardiovascular risk assessment among HIV-seropositive individuals receiving stable antiretroviral therapy. We utilized a cross-sectional baseline data from the Hawai'i Aging with HIV Cardiovascular Study cohort. RESULTS: Data was available on 111 HIV-infected patients (median age of 52 (Q1,Q3: 46, 57), male 86%; diabetes 6%; hypertension 33%; dyslipidemia 50%; median CD4 count of 489 cells/mm(3) (341, 638); HIV RNA PCR < 48 copies/ml of 85%). Eighteen subjects (16.2%) had microalbuminuria, and two subjects (1.8%) had macroalbuminuria. Albuminuria was significantly associated with increased Framingham Risk Score (P=.002), insulin resistance by HOMA-IR (P=.02), diastolic blood pressure (P=.01), and carotid intima-media thickness (P =.04). The correlation between the amount of albuminuria and carotid intima-media thickness remained significant even after adjusting for age, gender, ethnicity, current smoking status, diabetes mellitus, diastolic blood pressure, fasting insulin level, CD4 count, and HIV-RNA viral load. CONCLUSION: Albuminuria is prevalent among HIV-infected patients receiving stable antiretroviral therapy. It is significantly related to previously defined markers of cardiovascular disease and metabolic syndrome among HIV-infected patients receiving stable antiretroviral therapy. PMID- 24052918 TI - Are you okay? PMID- 24052920 TI - Watermelon smoothie. PMID- 24052919 TI - The importance of empathy--as I have studied and experienced it. PMID- 24052921 TI - The other pain. PMID- 24052922 TI - Medical professionalism: is it on your mind? PMID- 24052923 TI - The youngest member of the old school. PMID- 24052924 TI - Health Disparity and Structural Violence: How Fear Undermines Health Among Immigrants at Risk for Diabetes. AB - Diabetes is a national health problem, and the burden of the disease and its consequences particularly affect Hispanics. While social determinants of health models have improved our conceptualization of how certain contexts and environments influence an individual's ability to make healthy choices, a structural violence framework transcends traditional uni-dimensional analysis. Thus, a structural violence approach is capable of revealing dynamics of social practices that operate across multiple dimensions of people's lives in ways that may not immediately appear related to health. Working with a Hispanic immigrant community in Albuquerque, New Mexico, we demonstrate how structural forces simultaneously directly inhibit access to appropriate healthcare services and create fear among immigrants, acting to further undermine health and nurture disparity. Although fear is not normally directly associated with diabetes health outcomes, in the community where we conducted this study participant narratives discussed fear and health as interconnected. PMID- 24052925 TI - Age-related Differential Item Functioning for the Patient-Reported Outcomes Information System (PROMIS(r)) Physical Functioning Items. AB - PURPOSE: To evaluate the equivalence of the PROMIS(r) wave 1 physical functioning item bank, by age (50 years or older versus 18-49). MATERIALS AND METHODS: A total of 114 physical functioning items with 5 response choices were administered to English- (n=1504) and Spanish-language (n=640) adults. Item frequencies, means and standard deviations, item-scale correlations, and internal consistency reliability were estimated. Differential Item Functioning (DIF) by age was evaluated. RESULTS: Thirty of the 114 items were fagged for DIF based on an R squared of 0.02 or above criterion. The expected total score was higher for those respondents who were 18-49 than those who were 50 or older. CONCLUSIONS: Those who were 50 years or older versus 18-49 years old with the same level of physical functioning responded differently to 30 of the 114 items in the PROMIS(r) physical functioning item bank. This study yields essential information about the equivalence of the physical functioning items in older versus younger individuals. PMID- 24052926 TI - New method to visualize neurons with DAT in slices of rat VTA using fluorescent substrate for DAT, ASP+ AB - The ventral tegmental area (VTA), and in particular dopamine (DA) neurons in this region of midbrain, has been shown to play an important role in motivation (goal directed behavior), reward, and drug addiction. Most evidence that implicates VTA DA neurons in these functions are based on widely accepted but indirect electrophysiological characterization, including the hyperpolarization activated non-specific cation current (Ih), spike frequency, and inhibition by D2 receptor agonists. In this study, we used a known neuronal dopamine transporter (DAT) fluorescent substrate [4-(4- (dimethylamino) styryl)-N-methylpyridinium iodide] (ASP+) to visualize DAT-containing cell bodies of DA neurons in VTA region in rat brain slices. Uptake of 100 nM of ASP+ in brain slices of rat VTA region marked 38% of visible neurons, while other neurons from this region and 100% neurons from hippocampus slices were not fluorescent. Using patch-clamp techniques, we have found that pronounced Ih current was present in all fluorescent neurons from VTA area, also spike frequency was similar to the widely accepted values for DA neurons. Furthermore, additional study has shown that there are 84% coincidence of ASP+ fluorescence in neuronal cell bodies and Falck-Hillarp labeling of DA cells. Electrophysiological recordings during ASP+ application have confirmed that low concentrations (100 nM) of ASP+ have no visible effect on neuronal activity during 1-2 hours after staining. Thus, uptake of fluorescent monoamine analog ASP+ by DAT can be an additional criterion for identification of DAT containing neurons in slices. PMID- 24052927 TI - Comparison of adaptive neuro-fuzzy inference system and artificial neutral networks model to categorize patients in the emergency department. AB - Unexpected disease outbreaks and disasters are becoming primary issues facing our world. The first points of contact either at the disaster scenes or emergency department exposed the frontline workers and medical physicians to the risk of infections. Therefore, there is a persuasive demand for the integration and exploitation of heterogeneous biomedical information to improve clinical practice, medical research and point of care. In this paper, a primary triage model was designed using two different methods: an adaptive neuro-fuzzy inference system (ANFIS) and artificial neural network (ANN).When the patient is presented at the triage counter, the system will capture their vital signs and chief complains beside physiology stat and general appearance of the patient. This data will be managed and analyzed in the data server and the patient's emergency status will be reported immediately. The proposed method will help to reduce the queue time at the triage counter and the emergency physician's burden especially duringdisease outbreak and serious disaster. The models have been built with 2223 data set extracted from the Emergency Department of the Universiti Kebangsaan Malaysia Medical Centre to predict the primary triage category. Multilayer feed forward with one hidden layer having 12 neurons has been used for the ANN architecture. Fuzzy subtractive clustering has been used to find the fuzzy rules for the ANFIS model. The results showed that the RMSE, %RME and the accuracy which evaluated by measuring specificity and sensitivity for binary classificationof the training data were 0.14, 5.7 and 99 respectively for the ANN model and 0.85, 32.00 and 96.00 respectively for the ANFIS model. As for unseen data the root mean square error, percentage the root mean square error and the accuracy for ANN is 0.18, 7.16 and 96.7 respectively, 1.30, 49.84 and 94 respectively for ANFIS model. The ANN model was performed better for both training and unseen data than ANFIS model in term of generalization. It was therefore chosen as the technique to develop the primary triage prediction model. This primary triage model will be combined with the secondary triage prediction model to produce the final triage category as a tool to assist the medical officer in the emergency department. PMID- 24052928 TI - Validation of the Enterococci indicator for bacteriological quality monitoring of beaches in Malaysia using a multivariate approach. AB - There is currently no established bacteriological beach quality monitoring (BQM) program in place in Malaysia. To initiate cost-effective, sustainable bacteriological BQM schemes for the ultimate goal of protecting public health, policy decision makers need to be provided robust, indigenous empirical findings that validate appropriate water quality parameters for inclusion in such monitoring programs. This is the first study that assesses the validity of enterococci as an ideal indicator for bacteriological BQM in Malaysia using a multivariate approach. Beach water and sand samples from 7 beach locations were analyzed for a total of twenty-one microbial and non-microbial water quality parameters. A multivariate approach incorporating cluster analyses (CA), principal component analyses (PCA), and factor analysis (FA) was also adopted. Apart from the weak correlations of Staphylococcus aureus with concentrations of Vibro species (r = 0.302, p = 0.037) and total coliforms (r = 0.392, p = 0.006) in seawater, no correlation existed between S. aureus concentration and other parameters. Faecal coliforms failed to correlate with any of the tested parameters. Enterococci also correlated with more quality parameters than faecal coliforms or any other indicator. Multiple linear regressions highlighted a significant, best fit model that could predict enterococci concentrations in relation to other parameters with a maximum predictive success of 69.64%. PCA/FA clearly delineated enterococci and faecal coliforms as parameters that weighed strongly for BQM while Staphylococcus aureus, faecal coliforms and enterococci weighed strongly for beach sand quality monitoring. On the whole, higher correlations of enterococci levels with other parameters than was observed for faecal coliforms suggest that the former be considered a preferred parameter of choice for BQM in Malaysia. Our findings provide meaningful evidence particularly as it relates to the correlation of Enterococci with pathogens and other non microbial parameters. It also provides empirical data to validate the applicability of the enterococci indicator paradigm for bacteriological beach quality monitoring in Malaysia. The current study thus provides policy decision makers evidenced based approach to parameter streamlining for optimized beach sampling and sustainable bacteriological quality monitoring. PMID- 24052929 TI - Mapping saline water intrusion into the coastal aquifer with geophysical and geochemical techniques: the University of Lagos campus case (Nigeria). AB - Saltwater intrusion into the coastal aquifer, a phenomenon brought by the flow of seawater into freshwater aquifers originally caused by groundwater extraction near the coast, has long been recognised as a major concern around the world. In this study, we employed geophysical and geochemical techniques to map and provide evidences that the coastal aquifers in the study area have been intruded by saltwater from the adjacent Lagos lagoon. The resistivity data were acquired with an electrode spacing (a) that vary between 1.6 to 8 m, and expansion factor n of 30. The depth inverted models obtained from inversion of the fifteen resistivity data obtained in the area revealed significant impact of the lagoon water on the aquifers indicated as low resistivity usually below 7 Omegam. A combination of four different electrode arrays - Schlumberger, Wenner, Dipole-dipole and pole dipole, with at least three deployed at each site ( except for three traverses - traverses 13, 14 and 15), yield better horizontal and vertical resolution, having depth range of 36-226 m with 1.6-8 m electrode spacing used. The delineated geoelectric layers were juxtaposed with logs from both boreholes located within the campus. Evidence from geochemical study of borehole and the lagoon water samples corroborated the ERT result. Progressive decrease in total dissolved solute (TDS) and electrical conductivity (EC) from the lagoon to the coastal aquifer buttresses gradual encroachment of the inland aquifers by the intruding lagoon water. In addition, similar trend was observed in heavy metal distribution Pollution Index (PI) plot suggesting possible underground flow of water from the lagoon to the aquifers. From this study, we deduced that excessive groundwater extraction and possibly the reduction of groundwater gradients which allows saline-water to displace fresh water in the aquifer of the investigated area are responsible for the saline water intrusion observed. PMID- 24052930 TI - A Japanese neonatal case of glucose-6-phosphate dehydrogenase deficiency presenting as severe jaundice and hemolytic anemia without apparent trigger. AB - BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is rare among Japanese ethnicity although it is known as one of the most common hereditary disorders of erythrocytes, causing intravascular hemolysis. It is well-known that G6PD deficiency may cause hemolysis even in the neonatal period. However, most cases are asymptomatic, and the frequency of severe anemia is low. FINDINGS: We describe a Japanese male neonatal case of G6PD deficiency presenting as severe, persistent indirect hyperbilirubinemia on day 2 and hemolytic anemia. He was born to non-consanguineous Japanese parents without any family history. We could not find any triggers that could have induced hemolysis during pregnancy. CONCLUSIONS: This case encouraged us to investigate G6PD deficiency as a differential diagnosis of severe neonatal jaundice and hemolytic anemia despite the low prevalence in Japan. PMID- 24052931 TI - Sociomicrobiome of wood decay in a tropical rain forest: unraveling complexity. AB - Given that microbial interactions in nature are very complex, we propose that quorum-sensing, as well as quorum-quenching, phenazine and secondary metabolite production, resistance and toxin-antitoxin systems within a microbial community should all comprise the battery of processes involving the study of what we would define as the "sociomicrobiome". In the present study the genes/molecules, subsystems and taxonomic breakup of the mentioned processes were identified in decaying tropical wood from the El Yunque rainforest in Puerto Rico, and soil using a shotgun metagenomic approach. The rapid decomposition of wood and litter in tropical regions suggests that processes in these settings are governed by unexplored microbes with the potential of being further studied and exploited for various purposes. Both ecosystems were characterized by the presence of specific genes/molecules, subsystems and microbes associated with the mentioned processes, although the average abundances for specific processes differed. Of the sociomicrobiomes studied, that from El Yunque was found to be the most complex. The approach considered in the present study could also be applied to study the sociomicrobiome of other ecosystems. PMID- 24052932 TI - The political economy of healthcare reform in China: negotiating public and private. AB - China's healthcare system is experiencing significant growth from expanded government-backed insurance, greater public-sector spending on hospitals, and the introduction of private insurance and for-profit clinics. An incremental reform process has sought to develop market incentives for medical innovation and liberalize physician compensation and hospital finance while continuing to keep basic care affordable to a large population that pays for many components of care out-of-pocket. Additional changes presently under consideration by policymakers are likely to further restructure insurance and the delivery of care and will alter competitive dynamics in major healthcare industries, notably pharmaceuticals, medical devices, and diagnostic testing. This article describes the institutional history of China's healthcare system and identifies dilemmas emerging as the country negotiates divisions between public and private in healthcare. Building on this analysis, the article considers opportunities for public-private partnerships and greater systems integration to reconcile otherwise incommensurable approaches to rewarding innovation and improving access. The article concludes with observations on the public function of health insurance and its significance to further development of China's healthcare system. PMID- 24052933 TI - Handgrip and quadriceps muscle endurance testing in young adults. AB - BACKGROUND: Grip strength is widely used for estimating whole body strength but there is a lack of information relating to grip endurance. Comparison between endurance of different muscle groups has received little attention. The main aim of the present study was to determine the endurance characteristics of hand grip and quadriceps muscles in healthy young adults and then to examine the association between fatigability of the two muscle groups. METHODS: Twenty one healthy participants (8 males and 13 females) aged 18-35 years were studied. A maximal intermittent endurance test, consisting of 12 isometric contractions held for 3 seconds separated by 5 second rest periods, was utilised to measure muscle endurance. A Biodex isokinetic dynamometer and Jamar dynamometer were used to assess quadriceps and hand grip respectively. The mean of first (M1) and last (M2) three repetitions was calculated. Fatigue index values were calculated for both muscle groups by the 1st peak torque (PT) minus the last (12th) PT, divided by the 1st PT multiplied by 100. RESULTS: Quadriceps torque (M1:197.3 +/- 65.2 Nm; M2:163.1 +/- 47.6 Nm) and grip strength (M1:33.6 +/- 9.9 Kg; M2:25.2 +/- 8.1 Kg) both declined significantly during the 12 repetitions (p < 0.05). Hand grip showed a significantly higher mean fatigue index of 30% compared to 18% in the quadriceps (p < 0.05). CONCLUSIONS: Quadriceps showed better fatigability than hand grip. The findings therefore indicate caution against using grip endurance as a surrogate measure of quadriceps endurance. Further research is warranted to confirm observed differences between genders and to study endurance in different age groups. PMID- 24052935 TI - Welcome to stem cell reports. PMID- 24052934 TI - In vitro-generated immune complexes containing galactose-deficient IgA1 stimulate proliferation of mesangial cells. AB - IgA nephropathy (IgAN) patients have elevated serum levels of immune complexes consisting of IgA1 with galactose-deficient hinge-region O-glycans (Gd-IgA1) and anti-glycan IgG. These immune complexes deposit in the kidney and activate mesangial cells. To confirm that the activity of these immune complexes depends on the interaction of Gd-IgA1 with anti-glycan IgG, we generated in vitro analogous immune complexes using Gd-IgA1 myeloma protein and anti-glycan IgG from cord blood of healthy women. The Gd-IgA1 and anti-glycan IgG from cord-blood serum formed IgA1-IgG immune complexes that resembled those in sera of patients with IgAN. Furthermore, the ability to activate cellular proliferation was dependent on a heat-sensitive serum factor. In summary, we developed a new protocol for in-vitro formation of IgA1-IgG immune complexes, thus providing a new tool for studies of the pathogenesis of IgAN. PMID- 24052936 TI - Quantum leap year. PMID- 24052937 TI - From stealing fire to cellular reprogramming: a scientific history leading to the 2012 Nobel Prize. AB - Cellular reprogramming was recently "crowned" with the award of the Nobel Prize to two of its groundbreaking researchers, Sir John Gurdon and Shinya Yamanaka. The recent link between reprogramming and stem cells makes this appear almost a new field of research, but its historical roots have actually spanned more than a century. Here, the Nobel Prize in Physiology or Medicine 2012 is placed in its historical context. PMID- 24052938 TI - The interfollicular epidermis of adult mouse tail comprises two distinct cell lineages that are differentially regulated by Wnt, Edaradd, and Lrig1. AB - Current models of how mouse tail interfollicular epidermis (ife) is maintained overlook the coexistence of two distinct terminal differentiation programs: parakeratotic (scale) and orthokeratotic (interscale). lineage tracing and clonal analysis revealed that scale and interscale are maintained by unipotent cells in the underlying basal layer, with scale progenitors dividing more rapidly than interscale progenitors. Although scales are pigmented and precisely aligned with hair follicles, melanocytes and follicles were not necessary for scale differentiation. Epidermal Wnt signaling was required for scale enlargement during development and for postnatal maintenance of scale-interscale boundaries. Loss of Edaradd inhibited ventral scale formation, whereas loss of Lrig1 led to scale enlargement and fusion. In wild-type skin, Lrig1 was not expressed in IFE but was selectively upregulated in dermal fibroblasts underlying the interscale. We conclude that the different IFE differentiation compartments are maintained by distinct stem cell populations and are regulated by epidermal and dermal signals. PMID- 24052939 TI - The luminal progenitor compartment of the normal human mammary gland constitutes a unique site of telomere dysfunction. AB - Telomeres are essential for genomic integrity, but little is known about their regulation in the normal human mammary gland. We now demonstrate that a phenotypically defined cell population enriched in luminal progenitors (LPs) is characterized by unusually short telomeres independently of donor age. Furthermore, we find that multiple DNA damage response proteins colocalize with telomeres in >95% of LPs but in <5% of basal cells. Paradoxically, 25% of LPs are still capable of exhibiting robust clonogenic activity in vitro. This may be partially explained by the elevated telomerase activity that was also seen only in LPs. Interestingly, this potential telomere salvage mechanism declines with age. Our findings thus reveal marked differences in the telomere biology of different subsets of primitive normal human mammary cells. The chronically dysfunctional telomeres unique to LPs have potentially important implications for normal mammary tissue homeostasis as well as the development of certain breast cancers. PMID- 24052940 TI - Sox2-mediated regulation of adult neural crest precursors and skin repair. AB - Nerve-derived neural crest cells are essential for regeneration in certain animals, such as newts. Here, we asked whether they play a similar role during mammalian tissue repair, focusing on Sox2-positive neural crest precursors in skin. In adult skin, Sox2 was expressed in nerve-terminal-associated neural crest precursor cells (NCPCs) around the hair follicle bulge, and following injury was induced in nerve-derived cells, likely dedifferentiated Schwann cell precursors. At later times postinjury, Sox2-positive cells were scattered throughout the regenerating dermis, and lineage tracing showed that these were all neural-crest derived NCPCs. These Sox2-positive NCPCs were functionally important, since acute deletion of Sox2 prior to injury caused a decrease of NCPCs in the wound and aberrant skin repair. These data demonstrate that Sox2 regulates skin repair, likely by controlling NCPCs, and raise the possibility that nerve-derived NCPCs may play a general role in mammalian tissue repair. PMID- 24052941 TI - WNT3 is a biomarker capable of predicting the definitive endoderm differentiation potential of hESCs. AB - Generation of functional cells from human pluripotent stem cells (PSCs) through in vitro differentiation is a promising approach for drug screening and cell therapy. However, the observed large and unavoidable variation in the differentiation potential of different human embryonic stem cell (hESC)/induced PSC (iPSC) lines makes the selection of an appropriate cell line for the differentiation of a particular cell lineage difficult. Here, we report identification of WNT3 as a biomarker capable of predicting definitive endoderm (DE) differentiation potential of hESCs. We show that the mRNA level of WNT3 in hESCs correlates with their DE differentiation efficiency. In addition, manipulations of hESCs through WNT3 knockdown or overexpression can respectively inhibit or promote DE differentiation in a WNT3 level-dependent manner. Finally, analysis of several hESC lines based on their WNT3 expression levels allowed accurate prediction of their DE differentiation potential. Collectively, our study supports the notion that WNT3 can serve as a biomarker for predicting DE differentiation potential of hESCs. PMID- 24052942 TI - WNT3A promotes hematopoietic or mesenchymal differentiation from hESCs depending on the time of exposure. AB - We investigated the role of canonical WNT signaling in mesoderm and hematopoietic development from human embryonic stem cells (hESCs) using a recombinant human protein-based differentiation medium (APEL). In contrast to prior studies using less defined culture conditions, we found that WNT3A alone was a poor inducer of mesoderm. However, WNT3A synergized with BMP4 to accelerate mesoderm formation, increase embryoid body size, and increase the number of hematopoietic blast colonies. Interestingly, inclusion of WNT3A or a GSK3 inhibitor in methylcellulose colony-forming assays at 4 days of differentiation abrogated blast colony formation but supported the generation of mesospheres that expressed genes associated with mesenchymal lineages. Mesospheres differentiated into cells with characteristics of bone, fat, and smooth muscle. These studies identify distinct effects for WNT3A, supporting the formation of hematopoietic or mesenchymal lineages from human embryonic stem cells, depending upon differentiation stage at the time of exposure. PMID- 24052943 TI - Rebuilding pluripotency from primordial germ cells. AB - Mammalian primordial germ cells (PGCs) are unipotent progenitors of the gametes. Nonetheless, they can give rise directly to pluripotent stem cells in vitro or during teratocarcinogenesis. This conversion is inconsistent, however, and has been difficult to study. Here, we delineate requirements for efficient resetting of pluripotency in culture. We demonstrate that in defined conditions, routinely 20% of PGCs become EG cells. Conversion can occur from the earliest specified PGCs. The entire process can be tracked from single cells. It is driven by leukemia inhibitory factor (LIF) and the downstream transcription factor STAT3. In contrast, LIF signaling is not required during germ cell ontogeny. We surmise that ectopic LIF/STAT3 stimulation reconstructs latent pluripotency and self renewal. Notably, STAT3 targets are significantly upregulated in germ cell tumors, suggesting that dysregulation of this pathway may underlie teratocarcinogenesis. These findings demonstrate that EG cell formation is a robust experimental system for exploring mechanisms involved in reprogramming and cancer. PMID- 24052944 TI - Identification of novel imprinted differentially methylated regions by global analysis of human-parthenogenetic-induced pluripotent stem cells. AB - Parental imprinting is an epigenetic phenomenon by which genes are expressed in a monoallelic fashion, according to their parent of origin. DNA methylation is considered the hallmark mechanism regulating parental imprinting. To identify imprinted differentially methylated regions (DMRs), we compared the DNA methylation status between multiple normal and parthenogenetic human pluripotent stem cells (PSCs) by performing reduced representation bisulfite sequencing. Our analysis identified over 20 previously unknown imprinted DMRs in addition to the known DMRs. These include DMRs in loci associated with human disorders, and a class of intergenic DMRs that do not seem to be related to gene expression. Furthermore, the study showed some DMRs to be unstable, liable to differentiation or reprogramming. A comprehensive comparison between mouse and human DMRs identified almost half of the imprinted DMRs to be species specific. Taken together, our data map novel DMRs in the human genome, their evolutionary conservation, and relation to gene expression. PMID- 24052946 TI - Functional vascular endothelium derived from human induced pluripotent stem cells. AB - Vascular endothelium is a dynamic cellular interface that displays a unique phenotypic plasticity. This plasticity is critical for vascular function and when dysregulated is pathogenic in several diseases. Human genotype-phenotype studies of endothelium are limited by the unavailability of patient-specific endothelial cells. To establish a cellular platform for studying endothelial biology, we have generated vascular endothelium from human induced pluripotent stem cells (iPSCs) exhibiting the rich functional phenotypic plasticity of mature primary vascular endothelium. These endothelial cells respond to diverse proinflammatory stimuli, adopting an activated phenotype including leukocyte adhesion molecule expression, cytokine production, and support for leukocyte transmigration. They maintain dynamic barrier properties responsive to multiple vascular permeability factors. Importantly, biomechanical or pharmacological stimuli can induce pathophysiologically relevant atheroprotective or atheroprone phenotypes. Our results demonstrate that iPSC-derived endothelium possesses a repertoire of functional phenotypic plasticity and is amenable to cell-based assays probing endothelial contributions to inflammatory and cardiovascular diseases. PMID- 24052945 TI - Germline transgenic methods for tracking cells and testing gene function during regeneration in the axolotl. AB - The salamander is the only tetrapod that regenerates complex body structures throughout life. Deciphering the underlying molecular processes of regeneration is fundamental for regenerative medicine and developmental biology, but the model organism had limited tools for molecular analysis. We describe a comprehensive set of germline transgenic strains in the laboratory-bred salamander Ambystoma mexicanum (axolotl) that open up the cellular and molecular genetic dissection of regeneration. We demonstrate tissue-dependent control of gene expression in nerve, Schwann cells, oligodendrocytes, muscle, epidermis, and cartilage. Furthermore, we demonstrate the use of tamoxifen-induced Cre/loxP-mediated recombination to indelibly mark different cell types. Finally, we inducibly overexpress the cell-cycle inhibitor p16 (INK4a) , which negatively regulates spinal cord regeneration. These tissue-specific germline axolotl lines and tightly inducible Cre drivers and LoxP reporter lines render this classical regeneration model molecularly accessible. PMID- 24052947 TI - Temporal control of retroviral transgene expression in newborn cells in the adult brain. AB - Neural stem/progenitor cells (NSPCs) generate new neurons throughout life in distinct areas of the adult mammalian brain. Besides classical transgenesis-based approaches, retrovirus-mediated genetic manipulation is frequently used to study mechanisms that regulate neurogenesis in the nervous system. Here, we show that fusion of a tamoxifen-regulatable estrogen receptor (ER(T2)) motif to transcription factors (i.e., ASCL1 and NEUROD1) enables temporal control of transgene expression in adult mouse NSPCs in vitro and in vivo. Thus, the approach described here represents a versatile strategy for regulating gene expression to study gene function in dividing cells and their progeny. PMID- 24052948 TI - DNA damage in mammalian neural stem cells leads to astrocytic differentiation mediated by BMP2 signaling through JAK-STAT. AB - The consequences of DNA damage generation in mammalian somatic stem cells, including neural stem cells (NSCs), are poorly understood despite their potential relevance for tissue homeostasis. Here, we show that, following ionizing radiation-induced DNA damage, NSCs enter irreversible proliferative arrest with features of cellular senescence. This is characterized by increased cytokine secretion, loss of stem cell markers, and astrocytic differentiation. We demonstrate that BMP2 is necessary to induce expression of the astrocyte marker GFAP in irradiated NSCs via a noncanonical signaling pathway engaging JAK-STAT. This is promoted by ATM and antagonized by p53. Using a SOX2-Cre reporter mouse model for cell-lineage tracing, we demonstrate irradiation-induced NSC differentiation in vivo. Furthermore, glioblastoma assays reveal that irradiation therapy affects the tumorigenic potential of cancer stem cells by ablating self renewal and inducing astroglial differentiation. PMID- 24052949 TI - Multipotent human mesenchymal stromal cells mediate expansion of myeloid-derived suppressor cells via hepatocyte growth factor/c-met and STAT3. AB - Mesenchymal stromal cells (MSCs) are multilineage progenitors with immunomodulatory properties, including expansion of immunomodulatory leukocytes such as regulatory T lymphocytes (Tregs) and tolerogenic dendritic cells. We report that human MSCs can expand CD14(-)CD11b(+)CD33(+) human myeloid-derived suppressor cells (MDSCs). MSC-expanded MDSCs suppress allogeneic lymphocyte proliferation, express arginase-1 and inducible nitric oxide synthase, and increase the number of Tregs. This expansion occurs through the secretion of hepatocyte growth factor (HGF), with effects replicated by adding HGF singly and abrogated by HGF knockdown in MSCs. In wild-type mice, the liver, which secretes high levels of HGF, contains high numbers of Gr-1(+)CD11b(+) MDSCs, and injection of HGF into mice significantly increases the number of MDSCs. Expansion of MDSCs by MSC-secreted HGF involves c-Met (its receptor) and downstream phosphorylation of STAT3, a key factor in MDSC expansion. Our data further support the strong immunomodulatory nature of MSCs and demonstrate the role of HGF, a mitogenic molecule, in the expansion of MDSCs. PMID- 24052951 TI - Enhanced hemangioblast generation and improved vascular repair and regeneration from embryonic stem cells by defined transcription factors. AB - The fetal liver kinase 1 (FLK-1)(+) hemangioblast can generate hematopoietic, endothelial, and smooth muscle cells (SMCs). ER71/ETV2, GATA2, and SCL form a core transcriptional network in hemangioblast development. Transient coexpression of these three factors during mesoderm formation stage in mouse embryonic stem cells (ESCs) robustly enhanced hemangioblast generation by activating bone morphogenetic protein (BMP) and FLK-1 signaling while inhibiting phosphatidylinositol 3-kinase, WNT signaling, and cardiac output. Moreover, etsrp, gata2, and scl inhibition converted hematopoietic field of the zebrafish anterior lateral plate mesoderm to cardiac. FLK-1(+) hemangioblasts generated by transient coexpression of the three factors (ER71-GATA2-SCL [EGS]-induced FLK 1(+)) effectively produced hematopoietic, endothelial, and SMCs in culture and in vivo. Importantly, EGS-induced FLK-1(+) hemangioblasts, when codelivered with mesenchymal stem cells as spheroids, were protected from apoptosis and generated functional endothelial cells and SMCs in ischemic mouse hindlimbs, resulting in improved blood perfusion and limb salvage. ESC-derived, EGS-induced FLK-1(+) hemangioblasts could provide an attractive cell source for future hematopoietic and vascular repair and regeneration. PMID- 24052950 TI - LNGFR(+)THY-1(+)VCAM-1(hi+) cells reveal functionally distinct subpopulations in mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSCs), which conventionally are isolated based on their adherence to plastic, are heterogeneous and have poor growth and differentiation, limiting our ability to investigate their intrinsic characteristics. We report an improved prospective clonal isolation technique and reveal that the combination of three cell-surface markers (LNGFR, THY-1, and VCAM 1) allows for the selection of highly enriched clonogenic cells (one out of three isolated cells). Clonal characterization of LNGFR(+)THY-1(+) cells demonstrated cellular heterogeneity among the clones. Rapidly expanding clones (RECs) exhibited robust multilineage differentiation and self-renewal potency, whereas the other clones tended to acquire cellular senescence via P16INK4a and exhibited frequent genomic errors. Furthermore, RECs exhibited unique expression of VCAM-1 and higher cellular motility compared with the other clones. The combination marker LNGFR(+)THY-1(+)VCAM-1(hi+) (LTV) can be used selectively to isolate the most potent and genetically stable MSCs. PMID- 24052954 TI - Progress towards eliminating onchocerciasis in the WHO Region of the Americas: verification by WHO of elimination of transmission in Colombia. PMID- 24052953 TI - Do pluripotent stem cells exist in adult mice as very small embryonic stem cells? AB - Very small embryonic-like stem cells (VSELs) isolated from bone marrow (BM) have been reported to be pluripotent. Given their nonembryonic source, they could replace blastocyst-derived embryonic stem cells in research and medicine. However, their multiple-germ-layer potential has been incompletely studied. Here, we show that we cannot find VSELs in mouse BM with any of the reported stem cell potentials, specifically for hematopoiesis. We found that: (1) most events within the "VSEL" flow-cytometry gate had little DNA and the cells corresponding to these events (2) could not form spheres, (3) did not express Oct4, and (4) could not differentiate into blood cells. These results provide a failure to confirm the existence of pluripotent VSELs. PMID- 24052955 TI - Performance of acute flaccid paralysis (AFP) surveillance and incidence of poliomyelitis,2013. PMID- 24052952 TI - Reprogramming to pluripotency using designer TALE transcription factors targeting enhancers. AB - The modular DNA recognition code of the transcription-activator-like effectors (TALEs) from plant pathogenic bacterial genus Xanthomonas provides a powerful genetic tool to create designer transcription factors (dTFs) targeting specific DNA sequences for manipulating gene expression. Previous studies have suggested critical roles of enhancers in gene regulation and reprogramming. Here, we report dTF activator targeting the distal enhancer of the Pou5f1 (Oct4) locus induces epigenetic changes, reactivates its expression, and substitutes exogenous OCT4 in reprogramming mouse embryonic fibroblast cells (MEFs) to induced pluripotent stem cells (iPSCs). Similarly, dTF activator targeting a Nanog enhancer activates Nanog expression and reprograms epiblast stem cells (EpiSCs) to iPSCs. Conversely, dTF repressors targeting the same genetic elements inhibit expression of these loci, and effectively block reprogramming. This study indicates that dTFs targeting specific enhancers can be used to study other biological processes such as transdifferentiation or directed differentiation of stem cells. PMID- 24052956 TI - Social representations and health. PMID- 24052957 TI - [Attach importance to multidisciplinary combination therapy for primary liver cancer]. PMID- 24052958 TI - [Combined modality therapy for recurrent hepatocellular carcinoma following liver transplantation]. PMID- 24052959 TI - [Comprehensive prevention and treatment of recurrence for hepatocellular carcinoma after hepatectomy]. PMID- 24052960 TI - [Radiotherapy strategies for multimodality treatments of hepatocellular carcinoma]. PMID- 24052961 TI - [Role of anti-viral therapy in survival and quality of life of patients with viral hepatitis-associated hepatocellular carcinoma]. PMID- 24052962 TI - [Congenital intrahepatic bile duct disease cystic expansion: a case report]. PMID- 24052963 TI - [A proposal for redefining and reclassifying cirrhosis]. PMID- 24052964 TI - [Report of the Third Chinese National Symposium on Liver Fibrosis and Cirrhosis]. PMID- 24052965 TI - [Report of the Fourth Symposium on the Hotspots and Challenges in Research of Antiviral Therapy for Chronic Hepatitis B]. PMID- 24052966 TI - [Current perspectives on the research for establishing accurate and efficient mouse models of hepatitis C virus infections]. PMID- 24052967 TI - Assessment of body temperature measurement options. PMID- 24052968 TI - Wound care and word care go hand in hand. PMID- 24052969 TI - [Sensory restoration by using implantable prosthesis--restoration of vision by using an artificial retina]. PMID- 24052970 TI - [Progress in chemotherapy of head and neck cancers]. PMID- 24052971 TI - The impact of a retirement savings account cap. AB - This Issue Brief provides an initial analysis of the potential financial impact on private-sector retirement benefits of the retirement savings account cap included in the Obama administration's FY 2014 budget proposal. It finds that although a very small percentage of current 401(k) participants with IRA accounts have combined balances sufficient to be immediately affected by the proposed limit, over time (and depending on the applicable discount rates, whether a defined benefit pension is involved, and the size of the 401(k) plan) the impact could be much greater. Simulation results for 401(k) participants assuming no defined benefit accruals and no job turnover show that more than 1 in 10 current 401(k) participants are likely to hit the proposed limit sometime prior to age 65, even at the current historically low discount rate of 4 percent. When the simulation is rerun with discount rate assumptions closer to historical averages, the percentage of 401(k) participants likely to be affected by these proposed limits increases substantially: For example, with an 8 percent discount rate, more than 20 percent of the 401(k) participants are simulated to reach the limit prior to retirement. When the impact of stylized, defined benefit account assumptions are added to the analysis, the percentage of 401(k) participants simulated to reach the proposed limits increases even more: In fact, for 401(k) participants assumed to be covered by a 2 percent, three-year, final-average plan with a subsidized early retirement at 62, nearly a third are assumed to be affected by the proposed limit at an 8 percent discount rate. Additional analysis is performed for small plans (those with less than 100 participants) to assess the potential impact of eventual plan terminations if an when the owners and/or key decision makers of the firms reach the cap threshold. Depending on plan size, this may involve as few as 18 percent of the firms (at a 4 percent discount rate) to as many as 75 percent of the firms (at an 8 percent discount rates). PMID- 24052972 TI - Safety and tolerability of the use of atorvastatin 40 mg in common daily practice in short-term observation in 3,227 patients. AB - BACKGROUND: Statins reduce cardiovascular morbidity and mortality but their administration is associated with a broad array of potential adverse effects. The aim of the study was to assess the safety and tolerability of the use of atorvastatin in the dose of 40 mg a day during short-term observation in daily practice--in outpatient clinics, specialized individual practice offices and in patient health care units. MATERIAL AND METHODS: A prospective authorial interviewer questionnaire-based study comprised 3,227 consecutive patients who were already administered 40 mg of atorvastatin a day or just started the therapy. The mean follow-up was 38 +/- 13 days. RESULTS: Fifty two patients (1.6% of all study participants) interrupted atorvastatin therapy due to drug-related adverse effects, which comprised mainly increased liver transaminases (0.4%) and myalgia (0.5%). In many of those patients complex side reactions were observed concerning mostly gastrointestinal disturbances (1.2%). No cases of rhabdomyolysis were reported. As many as 160 individuals (5.0%) did not continue the therapy due to economical issues, personal belief or low awareness of cardiovascular diseases and their potential complications. CONCLUSIONS: Atorvastatin in daily dose of 40 mg is a safe and well tolerable medication for the treatment for dyslipidemic disorders in patients of different clinic profile and cardiovascular risk groups in common medical practice. PMID- 24052973 TI - Medication adherence in hypertensive patients of different cardiovascular risk treated in primary health care. AB - BACKGROUND: The execution of the dosing regimen in Polish primary health care is unknown. The aim of the study was to appraise the medication adherence in patients with hypertension of various cardiovascular risk. MATERIAL AND METHODS: A prospective interviewer questionnaire-based study included 1,467 consecutive patients with arterial hypertension with the pharmacotherapy containing ramipril in the daily dose of 10 mg. The mean observation period was 30.3 +/- 7.0 days (20 56 days). At the followup visit the study participants filled the Morisky-Green test appraising the medication non-adherence. RESULTS: As many as 60.9% of the study participants have ever forgotten to take their medicine, 60.7% are sometimes neglectful in regard to their medicine hours, 32.4% skip their medicine hours when they are feeling well and 37.4% skip the drugs when they feel badly due to the medicine. Drug adherence was observed in 26.0% of patients. The level of adherence varied between different cardiovascular risk groups and was higher in the groups of lower cardiovacular risk. A very weak correlation between cardiovascular risk level and non-adherence to medication assessed with Morisky Green scale was observed (r = 0.078, p = 0.047). No relation of non-compliance to medication to age and gender was noted. CONCLUSIONS: Drug adherence in patients with hypertension treated in Polish primary healthcare is very low regardless of the cardiovascular risk level. PMID- 24052974 TI - Renal replacement therapy in acute poisonings--one center experience. AB - The authors described three groups of patients after acute poisonings. In the first group were 60 patients after carbon tetrachioride poisoning, the second group consisted of 81 patients after mushroom poisoning and 20 patients after ethylene glycol poisoning were in the third group. Besides two patients with rare poisonings after potassium dichromate and after paraquat poisoning were analysed. All groups of patients with the kidney damage were presented from the diagnostic, differential diagnostic, conservative, ntra- and extracorporeal elimination treatment point of view. In the group of patients suffering from acute carbon tetrachloride poisoning and with acute renal failure following therapy was used: conservative treatment, exchange blood transfusion--in 4 patients in hepatic coma, renal replacement therapy (peritoneal dialysis, haemodialysis, plasmapheresis). From the total number of 60 patients 58 survived and 2 patients died in liver coma. Survival of patients after mushroom poisoning depended on amount of oral use of mushroom (Amanita phalloides), on early admission in dialysis centre and on early beginning of renal replacement therapy within 24 hr after acute poisoning. Twenty four patients from 81 patients of this group died. Main clinical signs of ethylene glycol poisoning were various neurological symptoms (cramps, hemiparesis, coma), severe metabolic acidosis (pH = 7.06 +/- 0.14), leucocytosis (26.4 +/- 5.5x 10(9)/L) and the signs of acute toxic hepatitis and of acute renal failure. Calcium oxalic crystals in urine were present in 17 patients and leucocytosis was observed in every patient. In the first 4 patients we administered intravenously ethylalcohol as an antidotum and later in other patients we used ethylalcohol in dialysis solution. The concentration of ethylalcohol in dialysis solution was 100 mg%. Severe metabolic acidosis improved in 17 patients using bicarbonate haemodialysis and 3 patients died before the possibility to use bicarbonate haemodialysis. Eighty-four hours after acute potassium dichromate poisoning and 24 hours after exchange blood transfusion during haemodialysis a 41-year old man died in haemorhagic shock, which developed after the extensive chemical burns of mucous membrane of gastrointestinal tract caused by this poison. Our patient after paraquat poisoning was treated by repeated charcoal haemoperfusion and haemodialysis. Despite of that therapy the patient died in severe respiratory insufficiency. PMID- 24052975 TI - [Beta-cathinone derivatives--a new generation of dangerous psychostimulant "designer drugs"]. AB - Synthetic beta-cathinone derivatives belong to the novel group of psychostimulant "designer drugs". They show significant structural similarity to catecholamines and exogenous central nervous system (CNS) stimulating agents such as amphetamine, methamphetamine, ephedrine, 3,4-methylenedioxy-N-methylamphetamine (MDMA, ecstasy), and act as dopamine, noradrenaline and serotonin reuptake inhibitors. Popular synthetic beta-cathinones include e.g. mephedrone (4 methylmethcathinone, 4-MMC), naphyrone (naphthylpyrovalerone) and MDPV (3,4 methylenedioxypyrovalerone). Ingestion of synthetic cathinones produces effects of CNS stimulation, often comparable to those evoked by cocaine, amphetamine and MDMA. Chronic abuse of beta-cathinone derivatives leads to the development of tolerance, psychic and physical dependence. This paper discusses pharmacological properties of the most commonly used beta-cathinone derivatives as well as risks associated with their abuse. Special emphasis is given to neurological, psychiatric, cardiovascular and hematologic disturbances. Authors also present cases of fatalities caused by acute beta-cathinone intoxication or resulting from the drug-related accidents and crimes. PMID- 24052976 TI - [Analysis of selected inflammatory markers for early prediction of severe clinical course of acute pancreatitis]. AB - Despite new diagnostic methods, including novel laboratory parameters and imaging techniques, and growing knowledge on pathogenesis of acute pancreatitis, early assessment of severity remains the main factor influencing prognosis in the disease. The aim of the study was the evaluation of diagnostic accuracy of interleukins (IL): 6 and 18 and acute phase proteins: C-reactive protein (CRP) and serum amyloid A (SAA), together with Glasgow prognostic score during first 48 hours after diagnosing acute pancreatitis in a group of 40 patients treated in the I-st Department of General and Gastrointestinal Surgery University Hospital in Cracow. All the studied inflammatory markers were significantly higher in patients with moderate and severe acute pancreatitis versus patients with mild form of the disease on the first 48 hours of the disease. Expanding Glasgow score with IL-6, IL-18, SAA or CRP determinations resulted in better accuracy for diagnosing severe clinical course of acute pancreatitis. PMID- 24052977 TI - [Lithium nephropathy]. AB - Lithium salts are the first-line drug therapy in the treatment of uni- and bipolar disorder since the sixties of the twentieth century. In the mid-70s, the first information about their nephrotoxicity appeared. Lithium salts have a narrow therapeutic index. Side effects during treatment are polyuria, polydipsia and nephrogenic diabetes insipidus. Accidental intoxication can cause acute renal failure requiring renal replacement therapy while receiving long-term lithium salt can lead to the development of chronic kidney disease. The renal biopsy changes revealed a type of chronic tubulointerstitial nephropathy. The imaging studies revealed the presence of numerous symmetric microcysts. Care of the patient receiving lithium should include regular determination of serum creatinine, creatinine clearance and monitoring of urine volume. In case of deterioration of renal function reducing the dose should be considered. PMID- 24052978 TI - [Performance neutrophil gelatinase-associated lipocalin in clinical settings]. AB - Acute kidney injury (AKI) is largely asymptomatic, and establishing the diagnosis in thisin creasingly common disorder currently hinges on functional biomarkers such as serum creatinine. Early neutrophil gelatinase-associated lipocalin (NGAL) measurements can identify patients with sub-clinical AKI who have an increased risk of adverse outcomes, even in the absence of diagnostic increases in serum creatinine. NGAL is emerging as an excellent biomarker in the urine and plasma, for the early prediction of AKI, for monitoring clinical trials in AKI, and for the prognosis of AKI in several common clinical scenarios. Also numerous studies have also demonstrated that NGAL may be a potential biomarker for the diagnosis, prediction, prevention, and prognosis of non-AKI diseases such as chronic kidney diseases, vascular disorders, cancer, preeclampsia, and allergies. The current status of the most promising of novel biomarkers in medicin as NGAL is appraised in this review. PMID- 24052979 TI - [Diabetes type 2--criteria concerning the recognition and prevention, as well as therapeutic targets in the light of research results and guidelines formulated by the American Diabetes Association in 2012]. AB - The article summarizes the current state of knowledge on the detection of pre diabetic condition and type 2 diabetes, as well as therapeutic purposes. ADA guidelines published in January 2012, in line with the earlier experts' findings allow the detection of diabetes on the basis of HbA1C (> or = 6.5%) marking. Moreover, there are still applicable criteria that impose the following methods of blood glucose level monitoring: fasted, and 2 hours after a 75 gram of oral glucose intake. Screening for diabetes type 2 is indicated especially in obese patients and patients with arterial hypertension. This includes also those, in whom a prediabetic condition is found, and who would benefit most from their lifestyle modification, or from pharmacological diabetes prevention with the use of metformin. The results of clinical trials and recent meta-analyses indicate that for most patients, the therapeutic goal in the treatment of diabetes may be less precise than it was previously thought, and for HbA1C it is < 7.0%. An individualized approach is, however, advised, as patients with respect to whom a short period of time has elapsed after diabetes was diagnosed in them, young people and those with a high life expectancy and low hypoglycemia risk may benefit from a stricter controlling regime (< 6.5%). PMID- 24052980 TI - [Efficiency of imaging methods (urography, CT contrast-enhanced) in acute stage of ureterolithiasis-interpretation problems based on description case and bibliography review]. AB - An osmotic diuresis phenomenon appearing in renal colic during urography was refered. The pressures occurent in renal pelvis during obstruction of ureter and normal conditions were described. The pressure surge patomechanism in renal collecting system as a cause of renal rupture and retroperitoneal extravasation of urine was discussed. Another causes of extravasation of urine were mentioned. Case description. The patient case with ureterolithiasis (stone placed in ureteric orifice) complicated with spontaneous pelvic rupture. The extravasation of urine and ureterolithiasis were confirmed by ultrasonography and urography. Temporary nephrostomy and antibiotic therapy were performed. The stone underwent spontaneous passage. Absence of characteristic symptoms of urine extravasation makes the diagnosis difficult, requiring additional imaging studys. Proper differentiation of real urine extravasation from diffusion through the renal parenchyma to the perirenal area due to osmotic diuresis is important part of diagnosis. Elevated inflammatory parameters and infection of urinary tract often coexist with peripelvic extravasation. Ureterolithiasis complicated by urinary tract infection requires renal drainage and antibiotic therapy as a first-line treatment. Either nephrostomy or antibiotic therapy are successful treatment of urine extravasation. PMID- 24052981 TI - [Jerzy Fryszman. Member of the Founding Committee of the Polish Urological Association. Biographical note]. PMID- 24052982 TI - [Echocardiographic methods for assessment of left ventricular diastolic dysfunction--state of the art]. AB - The assessment of left ventricle diastolic function is an important part of echocardiographic examination and consists of analysis of mitral inflow, pulmonary vein flow, as well as mitral inflow propagation velocity and diastolic velocities of mitral annulus movement. Diastolic dysfunction is a common cause of heart failure, especially in elderly patients. In this article, various methods of left ventricle diastolic function assessment were presented with reference to current guidelines of diagnosis of diastolic dysfunction and heart failure. PMID- 24052983 TI - [Faulty posture and selected respiratory indicators]. AB - THE AIM OF THE STUDY: Was to diagnose the body posture of physiotherapy students of the Medical University of Lodz and to determine the relationship between selected respiratory indicator and the incidence of faulty posture in the studied group. MATERIAL AND METHODS: 196 students of Medical University of Lodz were included in the study. Posture assessment was conducted using Kasperczyk's points method. In the study authors indicated selected respiratory parameters, incuding: forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and maximum inspiratory and expiratory pressure measured in the mouth (MIP, MEP). RESULTS: The results of the study showed a reduction of the respiratory parameters rates (FVC, FEV1) and respiratory muscle strength (MIP, MEP) in the group of students with a poor posture compared to students with a good posture. Although the statistical analysis showed no significant correlation between the presence of the faulty posture and respiratory parameters, there was a clear tendency for those parameters to decrease in the group of students with a poor posture. CONCLUSIONS: The results of the examined indicators showed a reduction of the respiratory parameters rates (FVC, FEV1) and respiratory muscle strength (MIP, MEP) in the group of students with a poor posture compared to students with a good posture. The posture classified by Kasperczyk as good is prevailing in the studied. The results obtained in this study suggest the need to take action on the prevention and correction of faulty posture. PMID- 24052984 TI - [Serum HCV core antigen concentration in HCV monoinfection and HCV/HIV coinfection]. AB - Currently, in the diagnosis and monitoring of treatment of HCV infection are used molecular biology methods to detect HCV genetic material and which are based on the polymerase chain reaction (PCR). Due to limitations in the application of this method, such as expensiveness and labor intensive, the alternative might be quantification of HCV core antigen (HCVcAg). Aim of the study was an evaluation of HCVcAg concentrations in patients monoinfected with HCV and HCV/HIV coinfected depending on laboratory parameters characterizing HCV and HIV infections, as well as to evaluate the usefulness of HCVcAg concentrations as a predictor of treatment efficacy. MATERIALS AND METHODS: The study was conducted in 31 patients including 12 HCV/HIV coinfected and 19 HCV monoinfected enrolled for treatment with pegylated interferon combined with ribavirin. HCVcAg concentrations were analyzed with regard to HCV RNA level, laboratory indicators of liver function and hematology and additionally in HIV infected to HIV RNA level and immune status. During the treatment the prognostic value of HCVcAg concentrations were analyzed before treatment, at 24 hours, as well as 4 and 12 weeks after initiation of therapy for possible prediction of sustained virologic response (SVR). RESULTS: Among HCV monoinfected patients significant correlation has been shown between HCVcAg concentrations and HCV RNA levels, that was not a case in HCV/HIV co-infection. Significant HCVcAg reduction was demonstrated in both groups during initial 24 hours of treatment, but there were no significant differences between groups at particular time points. Baseline HCVcAg levels were significantly higher in patients without SVR compared to those who achieved SVR and this trend continued throughout the analyzed treatment period. CONCLUSIONS: HCVcAg concentration demonstrate correlation with HCV RNA, and its decrease at the beginning of treatment can predict SVR. HIV coinfection does not affect HCVcAg concentration during therapy. PMID- 24052985 TI - [Serum iron parameters in chronic liver diseses]. AB - Iron is an essential micronutrient of almost all organisms, which is involved in many metabolic processes. Disorders of serum iron balance that relate mainly to its deficiency are frequently observed in patients with liver diseases. The aim of the study was the evaluation of serum iron parameters in patients with different chronic liver diseases and analysis of the relationships between serum level of iron, ferritin and transferrin in women and men in groups examined. MATERIAL AND METHODS: The study includes 424 patients: 151 with alcoholic liver cirrhosis (ALC), 53 with nonalcoholic fatty liver disease (NAFLD), 54 with autoimmune hepatitis (AIH), 19 patients with hepatocellulare cancer (HOC), 34 with primary biliaris cirrhosis (PBC), 39 with chronic HCV hepatitis, 48 with chronic HBV hepatitis, 15 with primary sclerosans cholangitis (PSC) and 11 patients with hemochromatosis. Forty two healthy volunteers were the control group. RESULTS: The highest mean serum level of iron was observed in patients with hemochromatosis and was 278.56 +/- 25.04 mg/dl. The mean level of iron was statistically significant different in patients with HCC in comparison to the patients with ALC (p = 0.0000), with AIH (p = 0.0108) and NAFLD (p = 0.00768). The mean level of ferritin was statistically significantly higher among patients with hemochromatosis (p = 0.0000), with ALC (p = 0.0037) and NAFLD (p = 0.0442) than in the controls. Patients with AIH, HCC, HCV infection, PSC and hemochromatosis showed higher serum level of transferin than the controls (p = 0.0000). The mean level of iron and ferritin was lowerin women than in men in the patients with ALC (p = 0.0088, p = 0.0018 respectively). The mean level of ferritin was significantly lower in men than in women among patients with NAFLD. (p = 0.0065). There were no statistically significant differences in the mean level of examined parameters between the sexes. CONCLUSION: Reduced serum level of iron is observed in chronic liver diseases. Elevated ferritin level is typical for patients with ALC and NAFLD. Differences in the level of iron, ferritin and transferin between men and women concemrn the patients with ALC while among patients with NAFLD only ferritin level differences are found. PMID- 24052986 TI - [Evaluation of COX-2 protein expression in melanocytic nevi in children]. AB - Melanocytic skin tumors can be divided into benign nevi and malignant which take the form of melanoma. Melanocytic nevi are common in both adults and children. It is widely acknowledged that they are one of the risk factors of the formation of melanoma. However, melanoma among children is rare. In addition, differentiation of benign and malignant melanocytic tumors is often challenging. Recent studies suggest that COX-2 protein maybe useful in excluding malignant transformation of melanocytic lesion. The aim of the study was to evaluate the occurrence and differences of reactions with COX-2 in groups of nevi in children and melanoma adults. MATERIAL AND METHODS: The study included 75 common nevi and 43 atypical nevi incised in children and 15 cases of melanoma removed in adults. Paraffin blocks were used to make a preparations with routine hematoxylin and eosin staining (H + E) and immunohistochemistry. The results were statistically analyzed. RESULTS: Positive reactions were observed in both melanocytic nevi and melanoma. Differences between benign and malignant melanocytic tumors were statistically significant. Differences within melanocytic nevi were not statistically significant. CONCLUSIONS: The reactions of COX-2 are present in all nevi and do not allow to differentiate between their various types. COX-2 has potential utility in the differentiation of benign and malignant melanocytic tumors. PMID- 24052987 TI - [Increased level of lipid peroxidation products and disturbances in oxidation reduction balance in erythrocytes from patients suffering from systemic sclerosis, who are chronically treated with vitamin E]. AB - Systemic sclerosis is a chronic connective tissue disease of unknown pathogenesis. In view of the reports of essential role of oxidative stress in development of disease, trials with supportive care with vitamin E are undertaken. The aim of the study was to estimate parameters of oxidation reduction balance in erythrocytes from scleroderma patients, who were chronically treated with vitamin E compared with healthy controls. MATERIAL AND METHODS: In the study there were included 14 women with systemic sclerosis (limited form - ISSc - n = 10, diffuse form - dSsc - n = 4, age 53.8 lat +/- 11.5), who were treated with vitamin E in dose 400 mg/day not shorter than in 6 months period and 23 healthy women (age 52.7 +/- 11.2) as a control group. The following measurements were done: hs CRP (immunoturbidimetic method), glutathione peroxidase activity (Gpx--method of Rice-Evans, 1991), superoxide dismutase activity (SOD--method of Misra, 1972), catalase activity (CAT--method of Aebi H, 1984), free thiol group concentration (SH--method of ElIman, 1959), level of lipid peroxidation products (TBARs--method of Stocks and Dormandy, 1971), total antioxidant capacity (TAC) depended of slow (TAC "slow") and fast (TAC "fast") antioxidants. RESULTS: . In both forms of systemic sclerosis significantly higher TBARs in comparison of healthy controls (5.81 +/- 1.57 vs 4.28 +/- 0.89 nM TBARS/gHb; p < 0.01) was observed. Patients with limited systemic sclerosis have significantly higher activity of Gpx (59.9 +/- 26.11 vs 32.19 +/- 11.67 U/mg Hb; p < 0.01), and no differences in activity of CAT and SOD. In patients with diffuse systemic sclerosis significantly lower activity of CAT (173.06 +/- 60.3 vs 284.47 +/- 43.33 U/mg Hb; p < 0.01) and SOD (2334.95 +/- 193.97 vs 3231.47 +/- 840.21 U/mg Hb; p < 0.05) was observed. There are no differences in TAC and SH between investigated groups. CONCLUSIONS: In scleroderma patients despite chronical treatment with vitamin E, oxidation-reduction balance disturbances are observed in the form of increased level of lipid peroxidation products. Besides, a lower activity of catalase and superoxide dysmutase in patients who suffer from diffuse form of systemic sclerosis is noted. Patients with limited systemic sclerosis have higher glutathione peroxidase activity. PMID- 24052988 TI - [Analysis of current conditions concerning development of palliative care in three selected countries of the former Eastern Bloc]. AB - Palliative care is an active and comprehensive care provided to all patients who no longer react to treatment that would bring recovery. Its main objective is to gradually improve and maintain patients' high quality of life in their end stage of disease. In Europe palliative care has developed since the 1970's, 20th century. The aim of the study was to assess the current conditions concerning development of palliative care in selected countries of the former Eastern Bloc, Belarus, Kazakhstan, Ukraine, by defining the following: recognition of the term "palliative care" in the analyzed countries, the type of palliative care units existing in a given country as well as funding sources, access to opioid drugs and barriers hindering palliative care development. MATERIALS AND METHODS: The analysis included data collected based on survey forms filled in by medical staff from the selected countries of the former Eastern Bloc, as well as data contained in official documents and reports on palliative care development obtained from the three countries. 95 respondents, medical employees from Belarus, Kazakhstan and Ukraine, took part in the survey conducted in the period from January to December 2011. RESULTS: The profession that was most frequently declared by the respondents was a doctor (from Eastern Bloc in Belarus up to 76.7% in Ukraine) or a nurse (from 3.3% in Kazakhstan up to 50.0% in Belarus). 40% of respondents from Belarus were of the opinion that the term "palliative care" was commonly known by a major part of society, and as much as 53.3% of respondents from Kazakhstan believed that it was familiar only to certain social groups. From 93.3% of respondents from Kazakhstan up to 100% of respondents from Ukraine and Belarus regarded full-time hospices and palliative care units to be the main place providing such care. 30% of respondents from Belarus, 46.4% from Kazakhstan and as much as 80% from Ukraine stated that palliative care was publicly funded, however, only in part. CONCLUSIONS: The term 'palliative care' is not commonly known in either of the three countries analyzed. Full-time hospices or palliative care units function in all of these countries, and palliative care services are publicly funded, however, only in part. Patients do not have access to opioids in amounts required for regular daily use. No differences as to the main barriers hindering palliative care development between the analyzed countries were identified. PMID- 24052989 TI - [Burnout symptoms of cardiosurgery nurses]. AB - Changes in society, technological progress and time pressure cause irreversible changes in all health care professionals. Taking care of patient in severe condition can cause burnout syndrome among nurses. The aim of the study was to show the problem of burnout syndrome among nurses working in cardiac surgery ward. Those affect three main areas: psychological burnout syndrome, depersonalization, and job-related dissatisfaction. MATERIAL AND METHODS: The study was conducted among 50 nurses working in The Intensive Cardiac Care Unit at the University Hospital of Lodz. Inquiry form used in the survey created the author. RESULTS: The study showed, that nurses working in specific specialties are affected by burnout syndrome. Despite knowledge of the causes and consequences of this condition majority of nurses fail to recognize symptoms and independently deal with them. In the opinion of the respondents the main factors causing burnout syndrome are: inadequate non-material and material compensation, interpersonal relationships with patients. As a result more than half of the respondents would like to change jobs or consider changing profession. CONCLUSIONS: Burnout syndrome was observed with a different intensivity and covers several areas in almost all surveyed nurses. PMID- 24052990 TI - [Impact of the women's press on the attitudes of readers toward ultraviolet radiation--a survey of law and psychology students]. AB - Excessive exposure to ultraviolet radiation (UVA and UVB) leads to negative consequences including sunburn, carcinogenesis and photoaging. Therefore, educational campaigns promoting safe tanning and sunscreens are necessary. Helpful with this regard might be mass media including women's magazines, which for young people are important source of information on health, beauty and lifestyle. The aim of the study was to examine the influence of women's press in the attitude of non-medical students toward ultraviolet radiation (UV) as well as to analyse articles about tanning and skin protection against UV rays in selected magazines for women. MATERIAL AND METHODS: The study group consisted of 68 psychology students and 60 law students (n = 128). An original author's questionnaire was used in this research, including 22 questions regarding frequency of reading articles about sunbathing, and the impact of women's press on the respondents' attitude toward suntanning. In the second part of the study 13 articles were examined from magazines "Twoj Styl", "ELLE", "PANI" (years 2007 2011), which contained keywords "sun", "tanning bed", "tanning", "UV radiation". Selected articles were assessed whether they were encouraging to, or discouraging from sunbathing. RESULTS: A majority (63%) of respondents declared that after reading the article in women's magazines, they began to apply a sunscreen with higher SPF rate than before. Moreover, 57% refrained from using tanbeds, and 48% began to regularly check melanocytic naevi and monitor their skin after sun exposures. The analysis of the articles showed that majority of articles discouraged from the sunbathing (11 articles discouraging versus and 2 encouraging). CONCLUSIONS: Women's press in Poland generally promotes women's rational behavior against UV radiation and tanning. PMID- 24052991 TI - [Arterial baroreflex--physiological role and assessment of functioning]. AB - Arterial baroreflex is one of the key mechanisms responsible for the homeostasis maintenance within the cardiovascular system. Through the modulation of sympathetic and parasympathetic drive within the autonomic nervous system, baroreflex enables to stabilize arterial blood pressure and maintain perfusion within critical organs (e.g. brain, heart). This review provides the physiological background of the baroreflex functioning and describes the methodology for assessing the arterial baroreflex sensitivity (BRS). Decreased BRS reflects autonomic imbalance and predicts unfavorable outcome in cardiovascular diseases accompanied by the autonomic dysfunction, such as arterial hypertension and heart failure. BRS assessment methods can be divided into those that are performed in resting conditions (the measurements of spontaneous BRS, e.g. the sequence or spectral analysis method) and methods with the application of the external stimuli, which may be either non-invasive (e.g. the controlled breathing method) or invasive (e.g. the phenylephrine method). PMID- 24052992 TI - [Rare solid pancreatic tumors]. AB - The most common tumor of the pancreas is cancer, which constitutes 85% of all pancreatic neoplasms. Cystic pancreatic tumors comprise 10% of malignancies. No more than 5% of pancreatic tumors are rare solid tumors as: neuroendocrine tumors, gastrointestinal stromal tumors, solid pseudopapillary tumors, pecomas, lymphomas, granulocytic sarcomas, schwannomas, lipomas, liposarcomas and metastases to pancreas. Nowadays, these tumors are diagnosed more commonly due to the developement and accessibility of the diagnostic imaging techniques. Moreover, the treatment and management of rare solid pancreatic tumors often differs from the management in pancreatic cancer what makes the differential diagnosis difficult and responsible challenge. The main purpose of this article is to present an actual data of epidemiology, clinical presentation, management and treatment of rare solid pancreatic tumors according to recent literature and self experience. PMID- 24052993 TI - [The role of bioethics committees in the systems protecting scientific biomedical research participants in France and in Poland]. AB - Bioethics committees are along with ethic regulations and rules of law one of three main pillars in the system of protection of scientific biomedical research participants. Although principal directives for bioethics committees are established by international guidelines, detailed regulations may differ in particular states. The aim of this article was to compare two bioethic committees systems: French and Polish one. Historical beginnings of the bioethics committees system in France and in Poland are briefly mentioned, Subsequently, the networks of bioethics committees in both countries are compared. Although the number of bioethics committees (Research Ethic Committees) in both countries is comparable, the procedure of their establishment varies. French committees are based on administrative division of the country and divide on regional and interregional committees. In Poland, bioethics committees are established by medical universities, medical research and development units or regional chambers of physicians and dentists. In France there is no equivalent of Appeal Bioethics Committee, however one could appeal from the negative bioethics committee's opinion. The composition of French bioethics committees is more diverse and half of the members are not related to medical professions. Members of French committees are named on indefinite term by headmaster of Regional Health Agency after having been chosen in competition for the post. In Poland members are called on three-year-term but the rotation of members is not overwhelming since there is no limit of terms for one member. French legal solutions seems more secure for scientific bioethics research participants. For this reason, a detailed research on legislation in other countries is necessary before introducing any new regulations in Polish law. PMID- 24052994 TI - Top standards compliance issues for first half of 2013. PMID- 24052995 TI - APPROVED: optional behavioral health home certification product. PMID- 24052996 TI - APPROVED: revision for laboratory procedure review. PMID- 24052997 TI - Editorial Advisory Boards: what are they and what do they do? PMID- 24052998 TI - On EBP language. PMID- 24053000 TI - Comfort measures: a concept analysis. AB - Reference to the concept of comfort measures is growing in the nursing and medical literature; however, the concept of comfort measures is rarely defined. For the comfort work of nurses to be recognized, nurses must be able to identify and delineate the key attributes of comfort measures. A concept analysis using Rodgers' evolutionary method (2000) was undertaken with the goal of identifying the core attributes of comfort measures and thereby clarifying this concept. Health care literature was accessed from the CINAHL and PubMed databases. No restrictions were placed on publication dates. Four main themes of attributes for comfort measures were identified during the analysis. Comfort measures involve an active, strategic process including elements of "stepping in" and "stepping back," are both simple and complex, move from a physical to a holistic perspective and are a part of supportive care. The antecedents to comfort measures are comfort needs and the most common consequence of comfort measures is enhanced comfort. Although the concept of comfort measures is often associated with end-of-life care, this analysis suggests that comfort measures are appropriate for nursing care in all settings and should be increasingly considered in the clinical management of patients who are living with multiple, chronic comorbidities. PMID- 24052999 TI - Constructivist philosophy and nursing student medication calculations. AB - Prelicensure nursing students often have difficulty performing medication calculations (MCs). Faculty at one baccalaureate nursing program wanted to use nursing theory to guide the development of a teaching-learning approach related to MC's. Finding little theory related to the topic of MCs, a constructivist based teaching-learning approach was used instead. The purpose of the study was to assess whether nursing students who received an MC review class that used a teaching-learning approach based on constructivist philosophy had better results on an MC examination than students who received their review via traditional teaching-learning methods. The study participants consisted of two cohorts of first-semester junior-level nursing students from one university-based school of nursing in the Midwestern United States. The results indicated that students in the simulation review class had higher mean scores on an MC examination than students who received their review via more traditional means. Teaching-learning strategies related to MCs based on constructivist philosophy have the potential to improve student learning outcomes, but more research is needed before middle range theory related to this critically important area of nursing education can be developed. PMID- 24053001 TI - Job embeddedness scoring: measurement equivalence between rural and urban nurses. AB - This study examined the measurement equivalency (ME) of the job embeddedness (JE) instrument for rural and urban registered nurses (RNs) using a secondary analysis of a cross-sectional mailed survey. JE represents the sum of reasons an employee remains at the present job. RNs from both rural and urban areas returned a 40 item JE instrument designed to assess their level of embeddedness. Analysis was performed using a multi-group confirmatory factor analysis for JE ratings of rural and urban RNs. The findings indicated that the original 40-item JE instrument needed to be respecified to achieve adequate fit for the sample of rural and urban RNs. This 32-item respecified instrument demonstrated that rural and urban RNs use the same metric when giving ratings for JE items. The findings of ME across rural and urban RNs facilitate comparisons between the two groups. The implications of these findings are that differences in ratings between rural and urban RNs may be attributed to real differences and not merely measurement artifact. Examination of these differences may lead to real strategies to retain nurses, thus mitigating the impact of the global nursing shortage. PMID- 24053002 TI - Intervention fidelity in a translational study: lessons learned. AB - This article examined the intervention fidelity strategies used and lessons learned in a translational study. In this study, the behavioral intervention was delivered within an existing clinical practice environment, outpatient cardiac rehabilitation (CR). The primary lessons learned were that the fidelity components of design, training, and delivery of the intervention were the most different from fidelity strategies used in typical intervention studies. The design component needed to take into account the unique characteristics of the clinical environments where the study was conducted and build these unique differences into the study design. Training and delivery of the intervention was different because existing CR staff delivered the intervention in this study; which is unlike typical intervention studies where research staff are trained to deliver the intervention. Monitoring receipt and enactment fidelity components were similar to monitoring in usual intervention studies probably because these components focus on monitoring the behaviors of the research participant. Translational research presents unique challenges and requires the development of a flexible and novel intervention fidelity plan tailored to a particular study. PMID- 24053003 TI - Angular cheilitis: a maligned condition. PMID- 24053004 TI - Plantar keratolysis: a casual finding or underdiagnosed illness? PMID- 24053005 TI - Serum levels of interleukins 2, 4, 6, and 10 in veterans with chronic sulfur mustard-induced pruritus: a cross-sectional study. AB - Inflammation is a key component in the pathogenesis of sulfur mustard (SM) induced skin complications. Here, the levels of interleukin (IL) -2, IL-4, IL-6, and IL-10 were evaluated in patients with chronic SM-induced complications. Seventy-four serum samples were collected from SM-injured veterans (SM group; n = 37) and nonchemically injured patients (control group; n = 37) with skin pruritus. The levels of IL-2, IL-4, IL-6, and IL-10 were evaluated by sandwich enzyme-linked immunosorbant assay technique in both nil and mitogen medium. No significant difference was found in pruritus score between SM (74.16 +/- 5.93) and control (74.48 +/- 6.15) groups (P > .05). The mean serum concentrations of IL-2 and IL-6 were found to be significantly elevated in the control compared with the SM group (P < .05). However, no significant difference was observed between the study groups regarding serum levels of IL-4 and IL-10 (P > .05). Serum IL-2 (in both SM and control groups) and IL-6 (in the control group) concentrations were significantly correlated with pruritus score while no significant association was found for IL-4 and IL-10. Serum concentrations of IL 2, IL-6, and IL-10 are significantly decreased in SM-exposed patients with chronic pruritus. Such alterations might represent a plausible mechanism for tissue damage and skin itching following SM exposure. Therefore, variation of ILs may also contribute to skin pruritus induced by SM. PMID- 24053006 TI - Cutaneous malignant and premalignant conditions caused by chronic arsenicosis from contaminated ground water consumption: a profile of patients from eastern India. AB - Natural arsenic pollution is a major global health problem. The two worst affected areas e Bangladesh and West Bengal, India. Arsenic is a well-documented human carcinogen that affects many organs including the skin. The authors sought to find out the clinical patterns of different malignant and premalignant conditions associated with chronic arsenicosis from drinking contaminated ground water in a group of patients from eastern India. This was a clinical observational study. Patients with chronic arsenicoses with suspected cutaneous malignancies for whom dermatology service was sought were enrolled in the study. A total of 24 patients (male to female ratio, 11:1; age range, 32-71 years; mean age, 52.2 years) were evaluated. Squamous cell carcinoma (SCC) was the commonest malignancies in our series, seen in 10 (41.7%) patients. This was followed by Bowen's disease (9 [37.5%]) and basal cell carcinoma (8 [33.3%]). Three patients (12.5%) had > 1 type of cutaneous malignancies. Multicentric lesions were seen in 3 cases. The most common site of involvement was the chest (8 [33.3%]). No statistically significant correlation was found between number of lesions and arsenic content in the hairs and nails of the patients. PMID- 24053007 TI - Nutrition supplementation for diabetic wound healing: a systematic review of current literature. AB - There are 25.8 million people with diabetes in the United States (Centers for Disease Control and Prevention 2011 National Diabetes Fact Sheet). This number is expected to increase by 1 million per year. Diabetic foot ulcers (DFUs) occur in patients with a history of poorly controlled blood glucose. Almost 30% of people with diabetes aged 40 years or older experience DFUs caused by an impaired nerve sensation. It is one of the more persistent types of chronic wounds, which poses an economic burden on individuals and society and reduces the quality of life of patients and their families. This paper reviews the efficacy of nutrition supplementation in diabetic wound healing, including both human and animal studies. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses methods, the search was conducted in PubMed and ISI's Web of Science databases. Studies in which diabetic wounds/foot ulcers were treated with specific nutritional or herbal suplements were selected. This review includes 4 human and 9 animal studies that met the criteria of the search. Positive outcomes in the human studies were not significant while the nutritional supplements used in the animal studies were effective and promoted wound healing. The most notable effect of supplementation with curcumin, L-Arginine, or vitamin E have been shown in animal sudies. More human studies need to be conducted to determine the efficacy of these nutritional supplements in promoting wound healing. PMID- 24053008 TI - Hair biology and its comprehensive sequence in female pattern baldness: clinical connotation diagnosis and differential diagnosis--Part II. AB - Hair can become a source of concern when there is a change in its texture, number, and thinning. Although female pattern baldness is common, it has received little attention compared with male pattern baldness. Thinning that affects the vertex is insidious and progressive. Hair loss in women has accordingly been interpreted and classified differently than that in men. The Ludwig scale is the most accepted classification. The gross anatomy and the general microanatomy of the hair follicle, including that of the anagen, catagen, and telogen phase, are presented. The hair growth cycle, encompassing anagen, catagen, telogen, exogen, and kenogen, is also discussed to address pattern hair loss in women and provide therapeutic options that are currently available. PMID- 24053009 TI - Dendritic melanocytic pseudomelanomas. PMID- 24053011 TI - Imquimod 2.5% cream. PMID- 24053010 TI - Efinaconazole 10% nail solution. PMID- 24053012 TI - A second look at vitamin E. PMID- 24053013 TI - Sneddon's syndrome presenting with neuropathic pain. AB - A 55-year-old man was admitted to us with a sense of numbness, tingling, and burning in his feet and headache, characterized as a feeling of pressure all around his head, for 1 year and aggravated in the past 3 months. The patient's neurologic examination was normal and he had no other known diseases except for hypertension according to his medical history. During the examination, we recognized purplish lesions on the patient's body. His kidney, liver, and thyroid function test results and vitamin B12 levels were all normal. His hematocrit level was 41.8%, platelet value was 234,000 (150,000-500,000); and sedimentation rate was 9 mm/h (0-20). Electromyography was performed and results were found to be normal. The patient was diagnosed as having small fiber neuropathy. Dermatologic examination revealed reddish blue mottling of the skin with fishnet reticular pattern on his back, on the front side of the body, and on both arms and legs, and the lesions were classified as livedo racemosa (Figure 1). Brain magnetic resonance imaging (MRI) showed subcortical hyperintense ischemic-gliotic signal changes on T2-FLAIR in the deep white matter of bilateral frontoparietal vertex, centrum semiovale, and corona radiata (Figure 2). FLAIR sequence axial MRI of the brain of our patient showed subcortical hyperintense lesions in both cerebral hemispheres. His cardiac examination was normal and minimal aortic regurgitation was seen on echocardiography. His cognitive assessment Minimental Test Score was 22, and Montreal Cognitive Assessment score was 18. Laboratory values for inflammatory markers and autoimmune antibodies including syphilis serology, lupus anticoagulants, and anticardiolipin antibodies were negative. Factor V Leiden mutation was not detected in the patient. The patient was diagnosed with Sneddon's syndrome with the above signs and symptoms and small fiber neuropathy. Clopidogrel 75 mg and gabapentin 1200 mg was started once a day and blood pressure regulation was achieved. PMID- 24053014 TI - Mucinous carcinoma: a translucent blue papule on an 89-year-old man. AB - An 89-year-old man with no significant medical history presented with a slow growing, asymptomatic translucent blue mass noticed 1 year prior to evaluation. Review of symptoms was negative for constitutional symptoms, gastrointestinal (GI) disturbance, and visual complaints. Physical evaluation revealed a 4-mm firm light blue translucent papule on the left medial canthus (Figure 1). No cervical or axillary adenopathy was present. No further lesions were identified during full body skin examination, including chest wall masses. A diagnostic study was performed and stained with hematoxylin-eosin (Figure 2) and periodic acid-Schiff (Figure 3). PMID- 24053015 TI - Recombinant thermostable AP exonuclease from Thermoanaerobacter tengcongensis: cloning, expression, purification, properties and PCR application. AB - Apurinic/apyrimidinic (AP) sites in DNA are considered to be highly mutagenic and must be corrected to preserve genetic integrity, especially at high temperatures. The gene encoding a homologue of AP exonuclease was cloned from the thermophilic anaerobic bacterium Thermoanaerobacter tengcongensis and transformed into Escherichia coli. The protein product showed high identity (80%) to human Ape1 nuclease, whereas to E. coli exonuclease III - 78%. This is the first prokaryotic AP nuclease that exhibits such high identity to human Ape1 nuclease. The very high expression level (57% of total soluble proteins) of fully active and soluble His6-tagged Tte AP enzyme with His6-tag on C-terminal end was obtained in Escherichia coli Rosetta (DE3) pLysS. The active enzyme was purified up to 98% homogeneity in one chromatographic step using metal-affinity chromatography on Ni(2+)-IDA-Sepharose resin. The yield was 90 mg (14000 kU) of pure His6-tagged Tte AP (153 kU/mg) from 1 liter of culture. The optimal conditions of Tte AP endo , exonuclease and 3'-nuclease activity were investigated using fluorescein labeled dsDNA with inserted AP sites and ssDNA. Optimal Tte AP endonuclease activity was observed at 70-75 degrees C, pH 8.0 and at low Mg2+ concentration (0.5 mM). Higher Mg2+ concentration (> 1 mM) enhanced 3'-5' exonuclease activity and at Mg2+ concentration > 2.0 mM 3' nuclease activity was observed. Because of the endonuclease activity of Tte AP exonuclease, the enzyme was applied in PCR amplification of long DNA templates. Tte AP exonuclease eliminated AP-sites in DNA template and improved the efficiency of DNA amplification. PMID- 24053016 TI - The effectiveness of photocatalytic ionisation disinfection of filter materials. AB - The purpose of this study was to determine the effectiveness of photocatalytic ionisation as a disinfection method for filter materials contaminated by microorganisms, and to assess how air relative humidity (RH), time and microbe type influence the effectiveness of this disinfection. In the quantitative analysis of a used car air filter, bacterial contamination equalled 1.2 x 10(5) cfu/cm2, fungal contamination was 3.8 x 10(6) cfu/cm2, and the isolated microorganisms were Aspergillus niger, Bacillus megaterium, Cladosporium herbarum, Cryptococcus laurenti, Micrococcus sp., Rhodotorula glutinis and Staphylococcus cohnii. In the model experiment, three isolates (C. herbarum, R. glutinis, S. cohnii) and 3 ATCC species (A. niger, E. coli, S. aureus) were used for photocatalytic ionisation disinfection. The conditions of effective photocatalytic ionisation disinfection (R > or = 99.9%) were established as 2-3 h at RH = 77% (bacteria) and 6-24 h at RH = 53% (fungi). RH has an influence on the effectiveness of the photocatalytic disinfection process; the highest effectiveness was obtained for bacteria at RH = 77%, with results 5% higher than for RH = 49%. The studies show that the sensitivity of microorganisms to photocatalytic ionisation disinfection is ordered as follows: Gram-positive bacteria (S. cohnii, S. aureus), Gram-negative bacteria (E. coli), yeasts (R. glutinis), and moulds (C. herbarum, A. niger). Of all the mathematical models used for the description of death dynamics after photocatalytic ionisation disinfection, the Chick-Watson model is the most useful, but for more resistant microorganisms, the delayed Chick-Watson model is highly recommended. It therefore seems, that the presented disinfection method of photocatalytic ionisation can be successfully used to clean filtration materials. PMID- 24053017 TI - The screening of microorganisms capable of methyl tert-butyl ether (MTBE) biodegradation. AB - As a result of examinations carried out, 16 strains of microorganisms able to grow on mineral media with methyl tert-butyl ether as the sole source of carbon and energy were isolated. Bacteria prevailed among the isolated microorganisms. The growth of microorganisms under laboratory conditions was long and accompanied by low biomass increase. Under the conditions of the experiment, the isolated microorganisms did not show any quantitatively measurable biodegradability of methyl tert-butyl ether (MTBE) under aerobic conditions. This requires far reaching caution with respect to trading in MTBE-modified petrols in order to protect the natural environment in Poland against contamination with that hard-to biodegrade substance. PMID- 24053018 TI - Taxonomic classification of Anoxybacillus isolates from geothermal regions in Turkey by 16S rRNA gene sequences and ARDRA, ITS-PCR, Rep-PCR analyses. AB - A total of 115 endospore-forming bacilli were taken for 16S rRNA gene sequence analyses and clustered among 7 genera. In this paper, the most abundant thermophiles belonging to genus Anoxybacillus with its 53 isolates are presented. The Anoxybacillus species, some of which were producing biotechnologically valuable enzymes, mostly displayed amylolytic and glucosidic activities and the ability of carbohydrate degradation made them superior in number among the other bacilli in these extreme habitats. In comparative sequence analyses, similarities ranged from 91.1% to 99.9% between the isolates and the type strains. Isolates were clustered into eight phylogenetic lineages within the type strains of A. kamchatkensis, A. flavithermus, A. kamchatchensis subsp. asaccharedens, and A. salavatliensis. In addition, C161ab and A321 were proposed as novel species which displayed < 97.0% similarities to their closest relatives. Moreover, their individual AluI, HaeIII, and TaqI ARDRA restriction patterns, ITS-, (GTG)5-, and BOX-PCR fingerprintings generated 27, 28, 31, 35, 40, and 41 clusters, respectively. The twelve type strains and 35 of the isolates showed unique distinctive patterns from all the others at least in two of these analyses. These phenotypic and genomic characters allowed us to differentiate their genotypic diversity from the reference strains. PMID- 24053019 TI - Age as a factor influencing diversity of commensal E. coli microflora in pigs. AB - Commensal, intestinal E. coli microflora plays a role in maintenance of intestinal balance of the host, is responsible for defending against pathogenic E. coli. This study encompasses the analysis of BOX-PCR fingerprinting patterns, phylogenetic grouping and virulence genes prevalence among commensal E. coli isolates derived from healthy pigs. Altogether, 274 unique E. coli isolates were identified, 110 from weaned piglets (Piglets I and Piglets II) and 164 from adult sows (Sows I and Sows II). BOX-PCR analysis distinguished isolates from pigs in different age and indicated that during maturation the changes in E. coli microflora occurred. Phylogenetic grouping revealed significant differences between distribution of four phylogenetic groups among isolates derived from piglets and sows. In phylogenetic structure of isolates from the piglets group B1 prevailed significantly, while among isolates derived from the sows the majority of them were classified into phylogenetic group A. The identification of 17 virulence factors in E. coli isolates derived from healthy pigs was performed. Three of 13 intestinal (escV, ehxA, estII) and four extra-intestinal virulence genes (VGs) (hlyA, fimH, papA, sfaS) were detected in the porcine isolates. The percentage of VGs positive isolates among piglets is higher than among sows, moreover, the VGs occurring in E. coli isolates from piglets revealed greater diversity than that detected among isolates from sows. PMID- 24053020 TI - The phenotypic and genotypic characteristics of antibiotic resistance in Escherichia coli populations isolated from farm animals with different exposure to antimicrobial agents. AB - The aim of the study was to determine the influence of the presence or the absence of antibiotic input on the emergence and maintenance of resistance in commensal bacteria from food producing animals. The research material constituted E. coli isolates from two animal species: swine at different age from one conventional pig farm with antibiotic input in young pigs and from beef and dairy cattle originated from organic breeding farm. The sensitivity to 16 antimicrobial agents was tested, and the presence of 15 resistance genes was examined. In E. coli from swine, the most prevalent resistance was resistance to streptomycin (88.3%), co-trimoxazole (78.8%), tetracycline (57.3%) ampicillin (49.3%) and doxycycline (44.9%) with multiple resistance in the majority. The most commonly observed resistance genes were: bla(TEM) (45.2%), tetA (35.8%), aadA1 (35.0%), sul3 (29.5%), dfrA1 (20.4%). Differences in phenotypes and genotypes of E. coli between young swine undergoing prevention program and the older ones without the antibiotic pressure occurred. A disparate resistance was found in E. coli from cattle: cephalothin (36.9%), cefuroxime (18.9%), doxycycline (8.2%), nitrofurantoin (7.7%), and concerned mainly dairy cows. Among isolates from cattle, multidrug resistance was outnumbered by resistance to one or two antibiotics and the only found gene markers were: bla(SHV), (3.4%), tetA (1.29%), bla(TEM) (0.43%) and tetC (0.43%). The presented outcomes provide evidence that antimicrobial pressure contributes to resistance development, and enteric microflora constitutes an essential reservoir of resistance genes. PMID- 24053021 TI - Bifidogenic and antioxidant activity of exopolysaccharides produced by Lactobacillus rhamnosus E/N cultivated on different carbon sources. AB - Lactobacillus rhamnosus E/N is a probiotic bacterium, which synthesizes exopolysaccharides (EPS) with significant bifidogenic and antioxidant activities. The sugar composition of the EPSs produced depended on carbohydrates used as a carbon source in the growth media. Five Bifidobacterium strains were tested in vitro for their ability to utilize all the EPSs studied. The highest bifidogenic activity was revealed by EPSs obtained from Lactobacillus cultures supplemented with Gal, Lac, and Mal as the only carbon source, while significant antioxidant effects were observed in EPSs isolated from growth media enriched with galactose, lactose, and sucrose. PMID- 24053022 TI - Evaluation of bean and soy tempeh influence on intestinal bacteria and estimation of antibacterial properties of bean tempeh. AB - In this study the effect of bean tempeh on the growth of Bacillus subtilis, Escherichia coli, Lactobacillus acidophilus and Lactobacillus paracasei bacteria was investigated. Antibacterial activity was observed only in relation to the bacteria Bacillus subtilis. The effect of tempeh products on human intestinal microflora was also assessed. Bean and soy tempeh were culinarily processed and next digested in conditions simulating the human digestive tract (one of the digestive tracts was equipped with a mechanism simulating absorption). Soy tempeh stimulated most the growth of bacteria of the genus Bifidobacterium, while bean tempeh that of Escherichia coli. Using simulation of absorption for the digestion of fried soy tempeh resulted in a higher rise in the bacteria count of the genus Lactobacillus, while after digestion of fried bean tempeh the highest increase was recorded for Bifidobacterium and E. coli. PMID- 24053023 TI - Use of real-time PCR technique in determination of major fibrolytic and non fibrolytic bacteria present in Indian Surti buffaloes (Bubalus bubalis). AB - In the milk industry in India, buffalo breeds are most commonly used for milk production. Efficiency of fiber digestion in ruminants is critical for animal productivity. Bacteria play an important role in fiber digestion and utilization. Absolute quantification real-time PCR was used to quantify ten bacterial species in rumen fluid of Surti buffalo fed green fodder, dry roughage and compound concentrate mixture. Abundance of each target taxon was calculated as a fraction of the total 16S rRNA gene copies in the samples, using taxon-specific primers. Bacterial populations showed a clear predominance of Ruminococcus albus, which comprised 5.66% of the bacterial rRNA gene copies in the samples. However, only 0.9% to 4.24% of the bacterial rRNA gene copies were represented by the ruminal Fibrobacter succinogenes, Ruminococcus flavefaciens and Prevotella species. The proportion of rRNA gene copies attributable to Selenomonas ruminantium, Streptococcus bovis, Ruminobacter amylophilus, Treponema bryantii and Anaerovibrio lipolytica was even less abundant, each comprising < 0.11% of the bacterial rRNA gene copies. The data suggest that the aggregate abundance of the most intensively studied ruminal bacterial species is relatively low and that a large fraction of the uncultured population represents a single bacterial genus. PMID- 24053024 TI - IS6110-based differentiation of Mycobacterium tuberculosis strains. AB - In this study, 62 Mycobacterium tuberculosis strains were characterized by fast ligation-mediated PCR (FLiP) and, previously performed, IS6110 restriction fragment length polymorphism (RFLP). FLiP proved a reproducible and specific method for differentiation between M. tuberculosis strains. The discriminatory power of FLiP was close to that of the reference IS6110 RFLP suggesting its usefulness in studying the genetic diversity of M. tuberculosis strains. PMID- 24053025 TI - Tissue tropism of Ornithobacterium rhinotracheale in chickens determined by culture and nucleic acid detection. AB - The aim of the present study was to evaluate the ability of Ornithobacterium rhinotracheale (ORT) to colonize chosen organs of chicks infected intratracheally (group A1), or intravenously (group A2), with the use of bacteriological methods and PCR. The bacteriological methods enabled to reisolate ORT bacteria from trachea and lungs of the birds from group A1 only on day 3 and 6 after infection. The PCR technique additionally detected the bacterial genetic material in these organs on the 9th day after infection, and gave positive results in the samples from air sacs until the 6th day of the experiment. In birds infected intravenously (A2) ORT was reisolated from liver on day 3 and from spleen on day 3 and 6 after infection, whereas the reisolation from the tibiotarsal joint occurred during the entire experimental period. PCR enabled to detect the bacterial DNA in the liver, spleen and lungs of chickens until the 9th day after infection and in case of tibiotarsal joint during the whole time of the study. PMID- 24053026 TI - Serological studies of Proteus penneri strains determining qualification to appropriate O-serogroup. AB - Our Department of General Microbiology created a wide collection of P. penneri isolates and classified most of them into 19 different O-serogroups. This work describes the classification of 12 remaining P. penneri strains. The lipopolysaccharides extracted from P. penneri strains were tested in an enzyme linked immunosorbent assay (ELISA) with selected O-antisera against Proteus sp. strains. Homologous and cross-reacting systems were checked in: passive immunohemolysis (PIH), inhibition of ELISA and PIH and Western blot procedure. These studies led to the qualification of tested P. penneri strains to five Proteus sp. O-serogroups, thus completing the serological classification of the whole collection. PMID- 24053027 TI - Meningitis in a pregnant woman caused by Streptococcus dysgalactiae subspecies equisimilis. AB - Infection of the central nervous system by streptococci is known to result in severe bacterial meningitis, however some strains have low pathogenic potential and affect the brain only in immunocompromised patients. Here we report the first case of an otherwise healthy non immunocompromised young adult woman who developed meningitis caused by Streptococcus dysgalactiae subspecies equisimilis. The patient was in the 17th week of her 3rd pregnancy. The course of the disease was quickly remittent under antibiotic treatment. PMID- 24053028 TI - Application of brain oscillations to neuropsychiatric diseases: a new land? Preface. PMID- 24053029 TI - Neurophysiological techniques in the study of the excitability, connectivity, and plasticity of the human brain. AB - There is increasing evidence to support the concept that brain plasticity involves distinct functional and structural components, each requiring several cellular mechanisms operating at different time scales, synaptic loci, and developmental phases within an extremely complex framework. However, the precise relationship between functional and structural components of brain plasticity/connectivity phenomena is still unclear and its explanation represents a major challenge within modern neuroscience. The key feature of neurophysiological techniques described in this review paper is their pivotal role in tracking temporal dynamics and inner hierarchies of brain functional and effective connectivities, possibly clarifying some crucial issues underlying brain plasticity. Taken together, the findings presented in this review open an intriguing new field in neuroscience investigation and are important for the adoption of neurophysiological techniques as a tool for basic research and, in future, even for clinical diagnostics purposes. PMID- 24053030 TI - Brain's alpha, beta, gamma, delta, and theta oscillations in neuropsychiatric diseases: proposal for biomarker strategies. AB - Brain oscillations have gained tremendous importance in neuroscience during recent decades as functional building blocks of sensory-cognitive processes. Research also shows that event-related oscillations (EROs) in "alpha," "beta," "gamma," "delta," and "theta" frequency windows are highly modified in pathological brains, especially in patients with cognitive impairment. The strategies and methods applied in the present report reflect the innate organization of the brain: "the whole brain work." The present paper is an account of methods such as evoked/event-related spectra, evoked/ERDs, coherence analysis, and phase-locking. The report does not aim to cover all strategies related to the systems theory applied in brain research literature. However, the essential methods and concepts are applied in several examples from Alzheimer's disease (AD), schizophrenia, and bipolar disorder (BD), and such examples lead to fundamental statements in the search for neurophysiological biomarkers in cognitive impairment. An overview of the results clearly demonstrates that it is obligatory to apply the method of oscillations in multiple electroencephalogram frequency windows in search of functional biomarkers and to detect the effects of drug applications. Again, according to the summary of results in AD patients and BD patients, multiple oscillations and selectively distributed recordings must be analyzed and should include multiple locations. Selective connectivity between selectively distributed neural networks has to be computed by means of spatial coherence. Therefore, by designing a strategy for diagnostics, the differential diagnostics, and application of (preventive) drugs, neurophysiological information should be analyzed within a framework including multiple methods and multiple frequency bands. The application of drugs/neurotransmitters gains a new impact with the analysis of oscillations and coherences. A more clear and differentiated analysis of drug effects can be attained in comparison to the application of the conventional wide-band evoked potential and event-related potential applications. PMID- 24053031 TI - Preferred pre-stimulus EEG states affect cognitive event-related potentials. AB - Current views of the genesis of the event-related potential (ERP) emphasize the contribution of ongoing oscillations - the ongoing electroencephalogram (EEG) is recognized as much more than "background noise" to be removed by response averaging to find the ERP. Early work from Basar's group noted that repetitive stimuli led to selective phase re-ordering of activity in the delta and alpha bands, such that enhanced brain negativity occurred at the time of the regular stimulus. Other work related negativity in alpha activity at stimulus onset to improved reaction times and ERP enhancements. These findings led us to begin a program of brain dynamics studies exploring pre-stimulus EEG phase states, their preferential occurrence in paradigms with regularly presented stimuli, and their relation to ERP outcomes. In particular, with very narrow EEG bands, we have repeatedly found that certain phase states preferentially occur at stimulus onset, implying ongoing phase re-ordering driven by stimulus occurrence. Effects are weakened with slightly varying inter-stimulus intervals, but still occur reliably. Further, these preferential phase states are functionally effective in relation to the ERP correlates of efficient stimulus processing. Preferential phase occurrence and their effects were originally reported in auditory oddball tasks, using narrow EEG bands derived by digital filtering. A recent study is presented illustrating generalization of the phenomenon in the auditory Go/NoGo task, using narrow bands derived by FFT techniques. Our current work is extending this research in normal children (to provide a comparative context for research in children with AD/HD), and well-functioning elderly (to provide a context for future work in relation to Alzheimer's disease). PMID- 24053032 TI - The in vivo topography of cortical changes in healthy aging and prodromal Alzheimer's disease. AB - BACKGROUND: Gray matter atrophy is regarded as a valid marker of neurodegeneration in Alzheimer's disease (AD), but few studies have investigated in detail the topographic changes associated with normal aging. In addition, few studies have compared the changes in the earliest clinical stage of AD (prodromal AD (pAD)) with those of healthy aging. Here we aimed to investigate the topographical distribution of age-related cortical atrophy and to compare it with that associated with prodromal and estabilished AD. METHODS: Structural T1 weighted high-resolution brain magnetic resonance imaging scans were acquired from 60 healthy volunteers (20 young adults, YA: age 32.7 +/- 4.5 years; 40 elderly subjects, HE: age 71.3 +/- 6.2 years), 16 mild cognitive impairment subjects who converted to AD within 2 years (prodromal AD, pAD: age 72.8 +/- 5.4), and 20 mild to moderate AD patients (mAD, age 72.5 +/- 10.3). Cortical gray matter differences were investigated using a surface-based anatomical mesh modeling technique (cortical pattern matching) and region-of-interest (ROI) analyses based on hypothesized brain networks taught to have a functional and a structural link to each other. Differences in cortical atrophy were assessed between groups, as well as the effect of age within groups. RESULTS: HE compared to YA showed a 10-30% deficit in cortical gray matter in widespread frontal, temporal, and parietal regions (p = 0.0001 by permutation testing), 6-13% loss in the visual and sensorimotor cortices (p < 0.01) and up to 13% loss in the direct hippocampal pathway ROIs (p < 0.001). pAD patients showed on average 8-9% cortical loss compared to HE (p < 0.0001), mainly in the left (up to 6% loss, p = 0.06) and right polysynaptic hippocampal pathway ROIs (up to 8% loss, p = 0.01), and in the left and right olfactory/orbitofrontal cortex (up to 12-15% loss, p < 0.001). The pattern of cortical atrophy in mAD versus HE was similar to that in pAD, but was more severe in the direct hippocampal pathway ROIs and sensorimotor, visual and temporal cortices (13-15% loss compared with HE, p < 0.0001). CONCLUSION: Gray matter loss occurs during aging with rates of atrophy even more severe than that observed during the course of AD. These changes may be caused by normal mechanisms. In pAD, cortical atrophy due to disease is milder than that due to aging, maybe resulting from a slowed down velocity of cell loss, but affects specific brain areas. These findings are consistent with the view that AD is not merely accelerated aging. PMID- 24053033 TI - The value of spontaneous EEG oscillations in distinguishing patients in vegetative and minimally conscious states. AB - OBJECTIVE: The value of spontaneous electroencephalography (EEG) oscillations in distinguishing patients in vegetative state (VS) and minimally conscious states (MCS) was studied. METHODS: We quantified dynamic repertoire of EEG oscillations in resting condition with closed eyes in patients in VS and MCS. The exact composition of EEG oscillations was assessed by the probability-classification analysis of short-term EEG spectral patterns. RESULTS: The probability of delta, theta, and slow-alpha oscillations occurrence was smaller for patients in MCS than for VS. Additionally, only patients in MCS demonstrated fast-alpha oscillation occurrence. Depending on the type and composition of EEG oscillations, the probability of their occurrence was either etiology dependent or independent. The probability of EEG oscillations occurrence differentiated brain injuries with different etiologies. CONCLUSIONS: Spontaneous EEG oscillations have a potential value in distinguishing patients in VS and MCS. SIGNIFICANCE: This work may have implications for clinical care, rehabilitative programs, and medical-legal decisions in patients with impaired consciousness states following coma due to acute brain injuries. HIGHLIGHTS: The probability of delta, theta, and slow-alpha oscillations occurrence was smaller and the probability of fast-alpha oscillations occurrence was higher for patients in MCS than for patients in VS. The probability of EEG oscillations occurrence differentiated brain injuries with different etiologies. Spontaneous EEG has a potential value in distinguishing patients in VS and MCS. PMID- 24053035 TI - Clinical relevance of animal models of schizophrenia. AB - Animal models and endophenotypes of mental disorders are regarded as preclinical heuristic approaches aiming at understanding the etiopathogenesis of these diseases, and at developing drug treatment strategies. A frequently used translational model of sensorimotor gating and its deficits in some neuropsychiatric disorders is prepulse inhibition (PPI) of startle. PPI is reduced in schizophrenia patients, but the exact relationship between symptoms and reduced PPI is still unclear. Recent findings suggest that the levels of PPI in humans and animals may be predictive of certain cognitive functions. Hence, this simple measure of reflex suppression may be of use for clinical research. PPI is the reduction of the acoustic startle response that occurs when a weak prestimulus is presented shortly prior to a startling noise pulse. It is considered a measure of sensorimotor gating and is regulated by a cortico-limbic striato-pallidal circuit. However, PPI does not only occur in the domain of startle. PPI of alpha, gamma, and theta oscillations at frontal and central locations has been found, suggesting a relationship between PPI and cognitive processes. In fact, levels of PPI in healthy subjects and in animals predict their performance in cognitive tasks mainly mediated by the frontal cortex. Taken together, PPI might reflect a more general filtering performance leading to gating of intrusive sensory, motor, and cognitive input, thereby improving cognitive function. Hence, PPI might be used in clinical settings to predict the impact of drugs or psychotherapy on cognitive performance in neuropsychiatric patients. PMID- 24053034 TI - The auditory steady-state response (ASSR): a translational biomarker for schizophrenia. AB - Electrophysiological methods have demonstrated disturbances of neural synchrony and oscillations in schizophrenia which affect a broad range of sensory and cognitive processes. These disturbances may account for a loss of neural integration and effective connectivity in the disorder. The mechanisms responsible for alterations in synchrony are not well delineated, but may reflect disturbed interactions within GABAergic and glutamatergic circuits, particularly in the gamma range. Auditory steady-state responses (ASSRs) provide a non invasive technique used to assess neural synchrony in schizophrenia and in animal models at specific response frequencies. ASSRs are electrophysiological responses entrained to the frequency and phase of a periodic auditory stimulus generated by auditory pathway and auditory cortex activity. Patients with schizophrenia show reduced ASSR power and phase locking to gamma range stimulation. We review alterations of ASSRs in schizophrenia, schizotypal personality disorder, and first-degree relatives of patients with schizophrenia. In vitro and in vivo approaches have been used to test cellular mechanisms for this pattern of findings. This translational, cross-species approach provides support for the role of N-methyl-D-aspartate and GABAergic dysregulation in the genesis of perturbed ASSRs in schizophrenia and persons at risk. PMID- 24053036 TI - Auditory-evoked alpha oscillations imply reduced anterior and increased posterior amplitudes in schizophrenia. AB - OBJECTIVE: Most of the work on disturbed oscillatory activity during auditory tasks in schizophrenia has focused on reduced gamma oscillations at fronto central sites. Recent studies of our group, however, indicate a more general disturbance affecting the spatial distribution of oscillatory brain activity of gamma as well as slow frequencies, such as alpha oscillations. METHODS: During a passive auditory listening task, electroencephalography was recorded from healthy controls and patients with schizophrenia. Stimulus-locked alpha activity within the first 250 ms after stimulus onset was analyzed from midline electrodes. RESULTS: Healthy controls showed the common fronto-central maximum of the early alpha response, while patients with schizophrenia showed lower fronto-central and larger parieto-occipital alpha activity than controls, leading to a more similar amplitude distribution across the midline electrode sites. CONCLUSIONS: The present results indicate malfunctioning long-range inhibition of task-irrelevant cortical areas in schizophrenia, which may disturb functional integration of perception and attention. We emphasize the importance of the whole-brain network theory for the understanding of schizophrenia since it proposes that integrative brain function is based on the coexistence and cooperative action of many interwoven and interacting sub-mechanisms. SIGNIFICANCE: Neuropsychiatric illnesses such as schizophrenia are marked by communication and coordination failures between different brain regions and different frequency bands. PMID- 24053037 TI - Early auditory gamma band response abnormalities in first hospitalized schizophrenia. AB - BACKGROUND: Abnormalities in coherent cortical circuit functioning, reflected in gamma band activity (to approximately 40 Hz), may be a core deficit in schizophrenia. The early auditory gamma band response (EAGBR) is a neurophysiologically simple probe of circuit functioning in primary auditory cortex. We examined the EAGBR in first hospitalized schizophrenia to assess whether it was reduced at first hospitalization. METHOD: Wavelet evoked power and intertrial phase locking of the EAGBR at Fz to standard tones during an oddball target detection task were examined in 28 first hospitalized schizophrenia patients (10 female) and 44 control subjects (17 female). RESULTS: At first hospitalization EAGBR trial-to-trial phase locking and evoked power were significantly reduced in patients. Although reduced overall in patients, greater total symptoms were significantly associated with greater gamma phase locking and power. Additionally, greater EAGBR power was marginally associated with greater positive factor scores, hallucinations, and thinking disturbance. CONCLUSIONS: Abnormalities of gamma band functioning in local auditory sensory circuits are present in schizophrenia at first hospitalization further evidence that basic sensory processes are impaired in schizophrenia. It remains to be determined whether the EAGBR becomes permanently impaired with disease progression, and if its reduction is specific to schizophrenia. PMID- 24053038 TI - Early auditory gamma-band responses in patients at clinical high risk for schizophrenia. AB - BACKGROUND: Gamma-band oscillations and their synchronization have been implicated in the coordination of activity between distributed neuronal assemblies in the service of sensory registration of stimuli and perceptual binding of their features. Prior electroencephalographic (EEG) studies of chronic schizophrenia patients have documented deficits in the magnitude and/or phase synchrony of stimulus-evoked gamma oscillations, findings that have been linked to neurotransmission abnormalities involving GABA and NMDA-glutamate receptors. However, it remains unclear whether these abnormalities are present at the onset of the illness, or indeed, whether they are present during the prodromal period preceding illness onset. Accordingly, we examined the magnitude and phase synchrony of the transient gamma-band response (GBR) elicited by an auditory stimulus in young patients with schizophrenia and in patients at clinical high risk for psychosis based on their manifestation of putatively prodromal symptoms. METHODS: EEG was recorded during an auditory oddball target detection task in three groups: young schizophrenia patients early in their illness (YSZ; n = 19), patients at clinical high risk for psychosis (CHR; n = 55), and healthy controls (HC; n = 42). Single-trial EEG epochs and the average event-related potential time-locked to standard tones from the oddball task were subjected to time frequency decomposition using Morlet wavelet transformations. The GBR between 50 and 100 ms following the tone onset was quantified in terms of evoked power, total power, and the phase-locking factor (PLF) reflecting cross-trial phase synchrony. RESULTS: GBR evoked power was significantly reduced in YSZ (p < 0.01) and CHR (p < 0.05) patients, relative to HC. Similarly, GBR PLF was significantly reduced in YSZ (p < 0.01) and showed a marginal reduction in CHR patients (p = 0.057), relative to HC. GBR total power was not reduced in CHR patients (p = 0.68) and showed only a trend level reduction in YSZ (p = 0.072). Within the CHR group. there were no significant GBR differences between the patients who converted to a psychotic disorder and those who did not convert to psychosis during a 12-month follow-up period. CONCLUSION: Reductions in the transient auditory GBR, as reflected by evoked power and phase synchrony, are evident in the early stages of schizophrenia and appear to precede psychosis onset. However, the absence of total power GBR abnormalities in CHR patients, with only a trend toward reduction in YSZ patients, suggests that the magnitude of the GBR is intact early in the course PMID- 24053040 TI - Connectivity and local activity within the fronto-posterior brain network in schizophrenia. AB - BACKGROUND: Fronto-posterior networks have been implicated in cognitive control and understanding the detailed functional dynamics within this network is important to understand the pathophysiology of cognitive deficits in schizophrenia. In a previous study (Sharma et al., 2011), we found reduced event related coherence between frontal and posterior electrode sites in delta and theta frequencies during cognitive control in schizophrenia. The current study aimed to look at the relationship between locally evoked frontal and posterior activity (measured by event-related potentials (ERPs)) and long-range coherence within the fronto-posterior network in healthy controls and patients with schizophrenia. METHODS: 16 schizophrenic/schizoaffective patients and 20 age matched healthy controls performing a choice reaction task took part in the study. We examined ERPs occurring at frontal and posterior sites between 100 and 250 ms (overlapping with the time period where coherence deficits were previously found) for differences between patients and controls. ERPs examined were Pla/P2a and N1/N2b components occurring simultaneously during 100-200/200-250 ms post stimulus at the frontal (F5'/F6') and posterior (P7'/P8') sites, respectively. We further looked at group difference in event-related delta and theta fronto posterior coherence in the exact same time windows as the ERPs and calculated the correlation between ERP amplitudes and simultaneous event-related delta and theta coherence for both hemispheres and time periods. Bonferroni correction was applied to correct for multiple correlations. RESULTS: We found a significant reduction in schizophrenia patients of the posterior N2b and a trend for reduction for the frontal P2a which are implicated in target-related information processing while the earlier frontal Pla and posterior N1 associated with more general sensory processing were relatively spared. However, the event-related coherence between the frontal and posterior areas was reduced in patients compared to controls during both the early and late time windows, indicating connectivity deficits to be a more consistent impairment in schizophrenia. There was limited linear correlation between fronto-posterior coherence and frontal and posterior ERP amplitudes but uncorrected correlation coefficients showed coherence in delta frequency to be correlated with P2a amplitude in both hemispheres and with Pla only in the left hemisphere in healthy controls. In the patients, however, this correlation was disrupted in the left hemisphere for both early and later stage evoked activity, whereas they showed a similar degree of correlation as healthy controls between P2a and delta coherence in the right hemisphere. Coherence in theta frequency showed no significant correlation with ERPs nor did N1/N2b show any significant correlation with coherence. CONCLUSIONS: Impaired cognitive control in schizophrenia might be driven by disrupted communication between the frontal and posterior brain areas, long-range connectivity being a more consistent deficit in schizophrenia as compared to locally evoked activity. Event-related fronto-posterior coherence and locally evoked frontal and posterior ERP amplitudes seem to reflect independent aspects of information processing in the brain although some linear relationship may exist between local frontal activity and fronto-posterior coherence in the delta frequency, implicating this frequency in frontal top-down control of information processing. A disruption of this relationship specifically in the left hemisphere is consistent with previously reported disturbances of the left hemisphere in schizophrenia. Connectivity measures may add important information as markers of cognitive pathophysiology in schizophrenia and may represent a fundamental impairment underlying cognitive control deficits in schizophrenia. PMID- 24053041 TI - Neurophysiological findings in patients with bipolar disorder. AB - The present article reviews findings from measuring evoked and event-related responses, neural oscillation and synchronization, and near-infrared spectroscopy (NIRS) studies in patients with bipolar disorder. Studies of evoked responses have indicated that the P50 suppression deficits may be related to the generation of psychosis and may constitute an endophenotype of bipolar disorder patients with psychotic features. The N100 may be intact in patients with bipolar disorder, and the N100 might be a biological index to distinguish bipolar disorder and schizophrenia. In studies of event-related responses, bipolar disorder patients appear to exhibit P300 abnormalities to some extent. In addition, some bipolar disorder patients may have preattentive dysfunction, indexed by abnormal mismatch negativities. Recent studies of neural oscillations suggest that bipolar disorder may be characterized by deficits in the auditory steady-state response. Moreover, bipolar patients may have altered gamma band responses, as well as abnormal beta and alpha activities perhaps related to deficits of fronto-temporal-parietal functional connectivity. NIRS studies of bipolar disorder have indicated hypofrontality during a verbal fluency task, and altered NIRS responses compared with those of patients with major depressive disorder or healthy subjects. In future studies, these techniques may be used to elucidate the neurophysiological abnormalities in patients with bipolar disorder. Moreover, neurophysiological approaches may reveal appropriate biological indices to distinguish bipolar disorder and schizophrenia, aiding the development of more effective medication at the early stages of illness. PMID- 24053042 TI - Brain oscillations in bipolar disorder in search of new biomarkers. AB - This report presents six cardinal results obtained with methods of oscillatory brain dynamics in euthymic and manic bipolar patients in comparison to healthy controls. Measurements include changes in oscillatory response activities in the theta, alpha, beta, and gamma frequency ranges. The analysis shows that spontaneous and response activities in the alpha range are highly reduced in euthymic and manic patients, respectively; conversely, beta responses are increased in euthymic and manic patients. Lithium use seems to be associated with further and significant increase in the beta frequency range in euthymic patients. Theta responses to auditory target stimulus during odd-ball paradigm appeared in two different frequency bands (4-6 and 6-8 Hz) in healthy participants. However, only fast theta responses were highly reduced under cognitive load in drug-free euthymic patients. The analysis of connectivity was performed by assessment of long-distance coherence function in the gamma frequency range. Both manic and euthymic patients presented significantly decreased fronto-temporal coherence function during visual odd-ball task, indicating a selective reduction in connectivity during cognitive processing. The present report also discusses that these six oscillatory parameters may serve as an ensemble of biomarkers for diagnostic purposes and tracking treatment response in bipolar disorder. PMID- 24053039 TI - Converging evidence for gamma synchrony deficits in schizophrenia. AB - BACKGROUND: In electroencephalogram (EEG) studies of auditory steady-state responses (ASSRs), patients with schizophrenia show a deficit in power and/or phase-locking, particularly at the 40 Hz frequency where these responses resonate. In addition, studies of the transient gamma-band response (GBR) elicited by single tones have revealed deficits in gamma power and phase-locking in schizophrenia. We examined the degree to which the 40 Hz ASSR and the transient GBR to single tones are correlated and whether they assess overlapping or distinct gamma-band abnormalities in schizophrenia. METHODS: EEG was recorded during 40 Hz ASSR and auditory oddball paradigms from 28 patients with schizophrenia or schizoaffective disorder (SZ) and 25 age- and gender-matched healthy controls (HC). The ASSR was elicited by 500 ms click trains, and the transient GBR was elicited by the standard tones from the oddball paradigm. Gamma phase and magnitude values, calculated using Morlet wavelet transformations, were used to derive total power and phase-locking measures. RESULTS: Relative to HC, SZ patients had significant deficits in total gamma power and phase-locking for both ASSR- and GBR-based measures. Within both groups, the 40 Hz ASSR and GBR phase-locking measures were significantly correlated, with a similar trend evident for the total power measures. Moreover, co-varying for GBR substantially reduced 40 Hz ASSR power and phase-locking differences between the groups. CONCLUSIONS: 40 Hz ASSR and transient GBR measures provide very similar information about auditory gamma abnormalities in schizophrenia, despite the overall enhancement of 40 Hz ASSR total power and phase-locking values relative to the corresponding GBR values. PMID- 24053043 TI - Resting state cortical EEG rhythms in Alzheimer's disease: toward EEG markers for clinical applications: a review. AB - The human brain contains an intricate network of about 100 billion neurons. Aging of the brain is characterized by a combination of synaptic pruning, loss of cortico-cortical connections, and neuronal apoptosis that provoke an age dependent decline of cognitive functions. Neural/synaptic redundancy and plastic remodeling of brain networking, also secondary to mental and physical training, promote maintenance of brain activity and cognitive status in healthy elderly subjects for everyday life. However, age is the main risk factor for neurodegenerative disorders such as Alzheimer's disease (AD) that impact on cognition. Growing evidence supports the idea that AD targets specific and functionally connected neuronal networks and that oscillatory electromagnetic brain activity might be a hallmark of the disease. In this line, digital electroencephalography (EEG) allows noninvasive analysis of cortical neuronal synchronization, as revealed by resting state brain rhythms. This review provides an overview of the studies on resting state eyes-closed EEG rhythms recorded in amnesic mild cognitive impairment (MCI) and AD subjects. Several studies support the idea that spectral markers of these EEG rhythms, such as power density, spectral coherence, and other quantitative features, differ among normal elderly, MCI, and AD subjects, at least at group level. Regarding the classification of these subjects at individual level, the most previous studies showed a moderate accuracy (70-80%) in the classification of EEG markers relative to normal and AD subjects. In conclusion, resting state EEG makers are promising for large-scale, low-cost, fully noninvasive screening of elderly subjects at risk of AD. PMID- 24053044 TI - Biomarkers in Alzheimer's disease with a special emphasis on event-related oscillatory responses. AB - Alzheimer's disease (AD) is a devastating neurodegenerative dementing illness. Early diagnosis at the prodromal stage is an important topic of current research. Significant advances were recently made in the validation process of several biomarkers, including structural/amyloid imaging, cerebrospinal fluid measurements, and glucose positron emission tomography. Nevertheless, there remains a need to develop an efficient, low cost, potentially portable, noninvasive biomarker in the diagnosis, course, or treatment of AD. There is also a great need for a biomarker that would reflect functional brain dynamic changes within a very short time period, such as milliseconds, to provide information about cognitive deficits. Electrophysiological methods have the highest time resolution for reflecting brain dynamics in cognitive impairments. There are several strategies available for measuring cognitive changes, including spontaneous electroencephalography (EEG), sensory-evoked oscillations (SEOs), and event-related oscillations (EROs). The term "sensory-evoked" (SE) implies responses elicited upon simple sensory stimulation, whereas "event-related" (ER) indicates responses elicited upon a cognitive task, generally an oddball paradigm. Further selective connectivity deficit in sensory or cognitive networks is reflected by coherence measurements. When simple sensory stimulus is used, a sensory network becomes activated, whereas an oddball task initiates an activation in a sensory network and additionally in a related cognitive network. In AD, spontaneous activity reveals a topographically changed pattern of oscillations. In addition, the most common finding in spontaneous EEG of AD is decrease of fast and increase of slow frequencies. The hyperexcitability of motor and sensory cortices in AD has been demonstrated in many studies. The motor cortex hyperexcitability has been shown by transcranial magnetic stimulation studies. Also, the SEOs reflecting sensory network indicate a visual sensory cortex hyperexcitability in AD, as demonstrated by increased responses over posterior regions of the hemispheres. On the other hand, ERO studies reflecting activation of a cognitive network imply decreased responses in fronto-central regions of the brain in delta and theta frequencies. Coherence studies show the connectivity between different parts of the brain. Studies of SE coherence in mild AD subjects imply almost intact connectivity in all frequency ranges, whereas ER coherence is decreased in wide connections in alpha, theta, and delta frequency ranges. Moreover, alpha ER coherence seems to be sensitive to cholinergic treatment in AD. In further research in a search of AD biomarkers, multimodal methods should be introduced to electrophysiology in order to validate these methods. Standardization and harmonization of user-friendly acquisition and analysis protocols in larger cohort populations are also needed in order to incorporate electrophysiology as a part of the clinical criteria of AD. PMID- 24053045 TI - Resting state brain oscillations and symptom profiles in attention deficit/hyperactivity disorder. AB - Our perspective on resting-state electroencephalogram (EEG) is that it provides a window into the substrate of cognitive and perceptual processing, reflecting the dynamic potential of the brain's current functional state. In an extended research program into the electrophysiology of attention deficit/hyperactivity disorder (AD/HD), we have examined resting-state EEG power and coherence, and event-related potentials (ERPs), in children, adolescents, and adults with the disorder. We sought initially to identify consistent AD/HD anomalies in these measures, relative to normal control subjects, and then to understand how these differences related to existing models of AD/HD. An emergent strand in this program has been to clarify the EEG correlates of "arousal" and to understand the role of arousal dysfunction as a core anomaly in AD/HD. To date, findings in this strand serve to rule out a commonly held dictum in the AD/HD field: that elevated theta/beta ratio is an indicator of hypo-arousal. In turn, this requires further work to elucidate the ratio's functional significance in the disorder. Our brain dynamics studies relating prestimulus EEG amplitude and phase states to ERP outcomes are expected to help in this regard, but we are still at a relatively early stage, currently examining these relationships in control children, in order to better understand normal aspects of brain dynamics before turning to children with AD/HD. This range of studies provides a framework for our recent work relating resting-state EEG anomalies, in individuals with AD/HD, to their symptom profile. This has had promising results, indicating links between increased inattention scores and reduced resting EEG gamma power. With resting state EEG coherence, reduced left lateralized coherences across several bands have correlated negatively with inattention scores, while reduced frontal interhemispheric coherence has been correlated negatively with hyperactivity/impulsivity scores. Such linkages appear to provide encouraging leads for future EEG research in AD/HD. PMID- 24053046 TI - Event-related oscillations reflect functional asymmetry in children with attention deficit/hyperactivity disorder. AB - Previous studies have found that event-related theta and gamma oscillations elicited in an auditory selective attention task are deviant in children with attention deficit/hyperactivity disorder (ADHD). It has been suggested that these deviations are associated with deficient motor inhibition in ADHD, which may lead to increased excitability of not only the motor generation networks but also the networks involved in sensory and cognitive processing of the stimulus requiring motor response. Within this suggestion, the present study used the same experimental database to compare the motor cortical activation of healthy controls and children with ADHD during the performance of the auditory selective attention task. Electroencephalography mu (8-12 Hz) activity at C3 and C4 electrodes was used as a measure of motor cortical activation. Mu power was analyzed for four stimulus conditions of the task (attended target, unattended target, attended nontarget, and unattended nontarget). It was found that motor cortical activation as reflected by mu power suppression was not overall greater in ADHD than healthy children. However, stimuli that possessed only partial target features and did not require motor responding (unattended target and attended nontarget) produced a significant reduction of mu activity in ADHD patients. These results suggest that motor cortical excitability is not generally increased in ADHD children. Rather, the co-existence of conflict features in complex stimuli induces task-irrelevant motor activation in these children. The deficient inhibition of motor cortical networks contralateral to the response may therefore be responsible for the functional asymmetry in stimulus processing in ADHD. PMID- 24053047 TI - Review of delta, theta, alpha, beta, and gamma response oscillations in neuropsychiatric disorders. AB - Method and concepts of brain oscillations pervade the neuroscience literature, especially in cognitive processes. Electrophysiological changes in patients with cognitive impairment will provide fundamental knowledge, not only for clinical studies but also, in turn, for understanding cognitive processes in healthy subjects. This review includes description of brain oscillations in schizophrenia, bipolar disorder, mild cognitive impairment, Alzheimer's disease, and attention deficit hyperactivity disorder. The reviewed publications include several methodological approaches: analysis of spontaneous electroencephalogram (EEG) spectra, evoked oscillations, event-related oscillations, and coherences both in spontaneous EEG and event-related oscillations. The review clearly shows that, in cognitive impairment, fundamental changes are observed in all diseases under study. Accordingly, oscillations can most probably be used as biomarkers in clinical studies. The conclusions of this review include several remarks indicating the nature of brain oscillations, their application to cognitive processes, and the usefulness of recording brain oscillations in memory loss, attention deficit, and learning. PMID- 24053048 TI - Brain oscillations as biomarkers in neuropsychiatric disorders: following an interactive panel discussion and synopsis. AB - This survey covers the potential use of neurophysiological changes as a biomarker in four neuropsychiatric diseases (attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), bipolar disorder (BD), and schizophrenia (SZ)). Great developments have been made in the search of biomarkers in these disorders, especially in AD. Nevertheless, there is a tremendous need to develop an efficient, low-cost, potentially portable, non-invasive biomarker in the diagnosis, course, or treatment of the above-mentioned disorders. Electrophysiological methods would provide a tool that would reflect functional brain dynamic changes within milliseconds and also may be used as an ensemble of biomarkers that is greatly needed in the evaluation of cognitive changes seen in these disorders. The strategies for measuring cognitive changes include spontaneous electroencephalography (EEG), sensory evoked oscillation (SEO), and event-related oscillations (ERO). Further selective connectivity deficit in sensory or cognitive networks is reflected by coherence measurements. Possible candidate biomarkers discussed in an interactive panel can be summarized as follows: for ADHD: (a) elevation of delta and theta, (b) diminished alpha and beta responses in spontaneous EEG; for SZ: (a) decrease of ERO gamma responses, (b) decreased ERO in all other frequency ranges, (c) invariant ERO gamma response in relation to working memory demand; for euthymic BD: (a) decreased event related gamma coherence, (b) decreased alpha in ERO and in spontaneous EEG; for manic BD: (a) lower alpha and higher beta in ERO, (b) decreased event-related gamma coherence, (c) lower alpha and beta in ERO after valproate; and for AD: (a) decreased alpha and beta, and increased theta and delta in spontaneous EEG, (b) hyperexcitability of motor cortices as shown by transcortical magnetic stimulation, (c) hyperexcitability of visual sensory cortex as indicated by increased SEO theta responses, (d) lower delta ERO, (e) lower delta, theta, and alpha event-related coherence, (f) higher theta synchrony and higher alpha event related coherence in cholinergically treated AD subjects. In further research in the search for biomarkers, multimodal methods should be introduced to electrophysiology for validation purposes. Also, providing the protocols for standardization and harmonization of user-friendly acquisition or analysis methods that would be applied in larger cohort populations should be used to incorporate these electrophysiologic methods into the clinical criteria. In an extension to conventional anatomical, biochemical and brain imaging biomarkers, the use of neurophysiologic markers may lead to new applications for functional interpretrations and also the possibility to monitor treatments tailored for individuals. PMID- 24053049 TI - Determining "in control" versus "not in control" glucose management of medical/surgical community hospital patients. AB - PURPOSE: To move beyond the correlation analysis between glucose statistics and patient outcome and to benchmark summary statistics calculated on all glucose values taken during an entire individual patient-stay. METHOD: The sample consisted of 141 patient-stays with multiple finger-stick blood glucose (BG) measurements resulting in 5,428 total BGs. Glucose control assessments of the BG profiles for each patient-stay were independently conducted by two endocrinologists. Summary statistics (mean, standard deviation, mean absolute glucose [MAG], percentage of hours of patient-stay with BG over threshold) were calculated for BG using patient-stay as the unit of analysis. RESULTS: Produced numerical benchmarks for the mean (148 mg/dL), SD (40 mg/dL), MAG (6.2), and the percentage of patient-stay hours over 200 mg/dL (10%). Specificity and sensitivity were high, ranging from 91% to 89% for specificity and from 90% to 81% for sensitivity. CONCLUSION: This study demonstrated that benchmarks developed on specific patient populations can be used to evaluate glycemic control in a straightforward, computationally simple system. PMID- 24053050 TI - Clinical performance of infrared consumer-grade thermometers. AB - BACKGROUND AND PURPOSE: Technology of ear infrared (IR) thermometers has improved. This study compared a modern ear thermometer to forehead or temporal artery thermometers. METHODS: Temperatures were measured with a heated-tip ear thermometer, a temporal artery thermometer, 3 forehead thermometers, and a thermistor-based reference thermometer in monitor mode. RESULTS: In 171 subjects, mean bias with the forehead thermometers was significantly higher (p < .001) than with the ear thermometer (0.01 degrees C +/- 0.41 degrees C). In 64 febrile subjects, bias with the ear thermometer was significantly lower than with 3 of the other thermometers. A false-negative reading was less likely with the ear thermometer (8%) versus the others (55%, 56%, 28%, and 47%). CONCLUSIONS: Modem ear thermometry provides more precise measurements closer to those of a reference thermometer and is less likely to give false-negative readings than forehead or temporal artery measurements. PMID- 24053051 TI - Determining left ventricular hypertrophy in overweight-obese youth using electrocardiogram criteria. AB - BACKGROUND AND PURPOSE: There is an escalating prevalence of obesity in youth that increases the risk for cardiovascular alterations such as left ventricular hypertrophy (LVH). The purpose of this study is to identify the most effective electrical voltage measurement for determining LVH in youth who are overweight and obese. METHODS: A retrospective chart review was conducted to determine sensitivity, specificity, and the receiver operator characteristic (ROC) curve of 4 popular electrical voltage measures. RESULTS: Our findings indicated the sensitivity and specificity for Cornell product (50.0%; 96.2%), Cornell voltage (52.9%; 98.0%), Romhilt Estes (50.0%; 100.0%), and Sokolow-Lyon index (60.0%; 86.4%) consecutively. CONCLUSION: The Romhilt-Estes and Cornell voltage measures displayed the highest specificity and could prove to be beneficial as a screening method to rule out LVH in overweight and obese youth. PMID- 24053052 TI - Self-as-doer for diabetes: development and validation of a diabetes-specific measure of doer identification. AB - BACKGROUND: The purpose of this study was to develop and validate a scale to measure the level of self-care behavior "doer identity" in persons with diabetes. METHODS: Persons with diabetes (N = 355) completed questionnaires assessing self as-doer identity and other related constructs. Principle components and parallel analyses and tests of reliability and validity were performed. RESULTS: A 7 factor solution explained 55.24% of the total variance on behaviors. Cronbach's alpha was .93 for the overall scale. Extracted components moderately correlated with one another and theoretically similar constructs. Self-as-doer identity significantly predicted all self-care behaviors (except for blood glucose monitoring) and glycemic control over and above related variables for persons with type 1 diabetes. Self-as-doer identity also predicted diet behaviors for persons with type 2 diabetes. CONCLUSIONS: Evidence for a reliable and valid factor structure of the Self-as-doer-Diabetes measure was demonstrated. PMID- 24053053 TI - Psychometric properties of a prediabetes instrument to assess perceived susceptibility and perceived severity in Appalachians. AB - BACKGROUND AND PURPOSE: The purpose of this study was to develop an instrument that assesses perceived susceptibility and perceived severity for individuals at risk but not yet diagnosed with type 2 diabetes living in Appalachia. METHODS: From 168 surveys, Cronbach's alpha and item-total correlations assessed reliability, confirmatory factor analysis confirmed construct validity (convergent and discriminant), and multiple linear regression determined concurrent criterion-related validity of perceived susceptibility and perceived severity scales. There were 22 in-depth interviews conducted to triangulate meaning of the scales' results. RESULTS: Discriminant validity was demonstrated via low interfactor covariation. Concurrent criterion-related validity was also established via significant regression coefficients and supplemental qualitative data. CONCLUSIONS: This prediabetes screening instrument provides a strong foundation for measuring perceived susceptibility and perceived severity in Appalachian individuals who have prediabetes. PMID- 24053054 TI - Reliability and validity analysis of modified Nursing Stress Scale for Indian population. AB - The original Nursing Stress Scale (NSS) was structurally modified according to results of factorial analysis and a new scale was named as modified nursing stress scale (MNSS). This is the first study to modify and validate NSS for Indian nursing population. Factorial analysis showed different factor loading for two subscales and items were shifted according to their loading to provide a more meaningful structure. After relocation of Items 13, 14, and 15 into first factor, this factor was renamed as "emotional and painful conditions of patients" to provide a more appropriate name to the first factor. Items 24, 25, 26, 27, 28, and 29 were found to be distributed under two different factors; one of these two was renamed as "unpredictable changes" and another retained its original name (i.e., workload). This distribution was also supported by rational analysis. All other items were distributed under factors as in the original scale. Rest of the validity assessment was done with the modified scale. Thus, with minor changes in structure, the scale was found to have better content validity. PMID- 24053055 TI - Occupational stress in remote area nursing: development of the Remote Area Nursing Stress Scale (RANSS). AB - BACKGROUND AND PURPOSE: The purpose of this study was to develop a measure that would adequately and sensitively measure the occupational stress experience of nurses working in very remote health care facilities. Because no existing nursing stress tool is suitable to assess the unique stressors of remote nursing practice, the aim was to address this gap in psychometric measurement capacity and develop the Remote Area Nursing Stress Scale (RANSS). METHOD: A focus group (n = 19) of remote area nurses identified potential questionnaire items through open discussion and by later listing the stressors they experienced individually in their day-to-day functioning. Subsequently, the Delphi method was employed to further refine the questionnaire (n = 12 experts). The RANSS was successfully pilot tested and was afterward administered to nurses working in very remote Australia in 2008 (n = 349) and in 2010 (n = 433). RESULTS: Principal components analysis and confirmatory factor analysis were performed for both waves of survey administration, demonstrating a robust 7-factor structure consistent across samples and accounting for significant variance in dependent measures. CONCLUSION: The development and validation of the RANSS is a significant advancement in remote area nursing research. The RANSS should be administered on an ongoing basis to monitor occupational stress among nurses working in very remote Australia. The RANSS should also be administered internationally in countries that also accommodate remote health care facilities. This would determine whether the RANSS is a psychometrically valid stress measure beyond the context of very remote Australia. PMID- 24053056 TI - Examining the factor structure of the Pain Catastrophizing Scale (PCS) as a measure of victim response to the psychological pain of subtle workplace bullying. AB - BACKGROUND AND PURPOSE: Literature addressing victim-bully dynamics suggests that subtle bullying is prevalent in health care, both in practice and educational settings. The complex dynamics of workplace bullying complicate its assessment. The purpose was to investigate the factor structure of the Pain Catastrophizing Scale (PCS) for modeling victim responses to subtle workplace bullying. METHODS: Nursing faculty members from multiple Midwestern universities (N = 116) completed the PCS online. RESULTS: The 3-factor PCS structure (i.e., Rumination, Helplessness, Magnification) developed to describe victim response to chronic physical pain was useful in describing victim response to the chronic psychological pain of bullying via confirmatory factor analysis (CFA). CONCLUSIONS: With minor modifications, the PCS represented the construct of victim response to bullying's psychological pain. PMID- 24053057 TI - The inter-rater reliability of the incontinence-associated dermatitis intervention tool-D (IADIT-D) between two independent registered nurses of nursing home residents in long-term care facilities. AB - BACKGROUND AND PURPOSE: Incontinence-associated dermatitis (IAD) is the clinical manifestation of moisture related skin damage (Beeckman, Woodward, & Gray, 2011). Valid assessment instruments are needed for risk assessment and classification of IAD. Aim of the quantitative-descriptive cross-sectional study was to determine the inter-rater reliability of the item scores of the German Incontinence Associated Dermatitis Intervention Tool (IADIT-D) between two independent assessors of nursing home residents (n = 381) in long-term care facilities. The 19 pairs of assessors consisted of registered nurses. METHODS: The data analysis was computed first with the calculation of the total percentage of agreement. Because this value is not randomly adjusted, the calculation of the Kappa coefficients and AC1-Statistic was done as well. RESULTS: The total percentage of the inter-rater agreement was 84% (n = 319). In a second step of analysis, the calculation of all items determined high (kappa = .70) and very high agreement (AC1 = .83) levels, respectively. For the risk assessment (kappa = .82; AC1 = .94), the values amounted to very high agreement levels and for the classification (kappa(w) = .70; AC1 = .76) to high agreement levels. CONCLUSIONS: The high to very high agreement values of IADIT-D demonstrate that the items can be regarded as stable in regards to the inter-rater reliability for the use in long-term care facilities. In addition, further validation studies are needed. PMID- 24053058 TI - Meaning-in-life in nursing home patients: a validation study of the Purpose-in Life test. AB - BACKGROUND: The experience of meaning has been found to be a strong individual predictor of life satisfaction and an important psychological variable that promotes well-being. Therefore, a valid and reliable measurement of meaning-in life among nursing home patients is highly warranted. AIMS: This study intended to further investigate (a) the factor structure of the Purpose-in-Life test (PIL), (b) the reliability of PIL scores, and (c) the construct validity of the PIL test in a nursing home population. METHODS: Participants were 202 cognitively intact nursing home patients representing 44 different Norwegian nursing homes. Concerning the dimensionality of the PIL, the following 3 measurement models were tested using confirmatory factor analysis; the original 1-factor, a 2-factor, and a 3-factor model. RESULTS: With the exclusion of 10 items, a previously published and supported 2-factor construct for the PIL by Morgan and Farsides (2007) provided a good fit for older nursing home patients, demonstrating good measurement reliability and construct validity. CONCLUSION: The 2-factor model by Morgan and Farsides, comprising 10 items, is an improvement over the original 20 items PIL, based on these nursing home data. The measure yielded highly significantly factor loadings, good values for average variance extracted and composite reliability, as well as significant correlations in the expected direction for relevant selected measures; all supporting the construct validity. PMID- 24053059 TI - Psychometric analysis of the Patient Assessment of Own Functioning Inventory in women with breast cancer. AB - BACKGROUND AND PURPOSE: The purpose of this secondary analysis was to examine the reliability and validity of the Patient Assessment of Own Functioning Inventory (PAOFI) in postmenopausal women with early-stage breast cancer before adjuvant therapy. METHODS: Data from 259 postmenopausal women with early-stage breast cancer before adjuvant therapy were analyzed. Exploratory factor analysis was used to uncover the PAOFI's underlying factor structure and reliability coefficients were computed for each subscale. RESULTS: 5 factors measuring perceived cognitive functioning had eigenvalues > 1 and accounted for 54% of the extracted variance. Subscale reliability coefficients ranged from .572 to .883. CONCLUSIONS: Psychometric evaluation of the PAOFI provided evidence of reliability and construct validity in this population. Additional studies are needed to confirm the 5-factor structure. PMID- 24053060 TI - Self-esteem among nursing assistants: reliability and validity of the Rosenberg Self-Esteem Scale. AB - PURPOSE: To establish the reliability and validity of the Rosenberg Self-Esteem Scale (RSES) when used with nursing assistants (NAs). METHOD: Testing the RSES used baseline data from a randomized controlled trial testing the Res-Care Intervention. Female NAs were recruited from nursing homes (n = 508). Validity testing for the positive and negative subscales of the RSES was based on confirmatory factor analysis (CFA) using structural equation modeling and Rasch analysis. Estimates of reliability were based on Rasch analysis and the person separation index. RESULTS: Evidence supports the reliability and validity of the RSES in NAs although we recommend minor revisions to the measure for subsequent use. CONCLUSION: Establishing reliable and valid measures of self-esteem in NAs will facilitate testing of interventions to strengthen workplace self-esteem, job satisfaction, and retention. PMID- 24053061 TI - The attitudes of older adults living in institutions and their caregivers to ageing. AB - OBJECTIVES: The aim of this study was to explore the attitudes of older people living in institutions and their caregivers to ageing. Recent outcomes showed prevailing negative social stereotype to ageing in CR. METHODS: The Attitudes to Ageing Questionnaire (AAQ-24) was used in two waves of data collection to measure attitudes of 400 randomly selected residents of 19 Senior Residential Homes. The reduced sample of 220 seniors and 276 professional carers employed at twelve Senior Residential Homes completed 12 items of general form (AAQ-12). All respondents expressed their agreement or disagreement with the statements presented in the questionnaire regarding positive or negative attitudes to ageing. RESULTS: The AAQ total score proved significant influence of gender, having children, self-perceived health, depression, and quality of life. Subscale scores (psychosocial losses, physical changes, psychological growth) were significantly influenced by gender, age, activities limitations, having own children, depression, self-perceived health status, and quality of life. Globally, the attitudes of professional caregivers to ageing were more positive compared to the attitudes of older people living in institutions. Older adults showed higher agreement with negative statements about ageing. There was no difference between professional caregivers and older people in the positive attitudes to ageing expressed as the growth potential. Physical activity, wisdom, better ability to cope with life and contacting young generation were effective in the positive attitudes of both groups. PMID- 24053062 TI - Trends in age-adjusted coronary heart disease mortality rates in Slovakia between 1993 and 2009. AB - Cardiovascular diseases (CVD) and especially coronary heart disease (CHD) are the main causes of death in the Slovak Republic (SR). The aim of this study is to explore trends in age-adjusted coronary heart disease mortality rates in the whole Slovak population and in the population of working age between the years 1993 and 2009. A related indicator - potential years of life lost (PYLL) due to CHD--was calculated in the same period for males and females. Crude CHD mortality rates were age-adjusted using European standard population. The joinpoint Poisson regression was performed in order to find out the annual percentage change in trends. The age-adjusted CHD mortality rates decreased in the Slovak population and also in the population of working age. The change was significant only within the working-age sub-group. We found that partial diagnoses (myocardial infarction and chronic ischaemic heart disease) developed in the mirror-like manner. PYLL per 100,000 decreased during the observed period and the decline was more prominent in males. For further research we recommend to focus on several other issues, namely, to examine the validity of cause of death codes, to examine the development of mortality rates in selected age groups, to find out the cause of differential development of mortality rates in the Slovak Republic in comparison with the Czech Republic and Poland, and to explain the causes of decrease of the age-adjusted CHD mortality rates in younger age groups in Slovakia. PMID- 24053063 TI - Changes and determinants in under-five mortality rate in Turkey since 1988. AB - Child survival is the focus of the fourth Millenium Developmental Goal (MDG4). This paper describes levels, trends, and differentials in Under-Five Mortality Rate (U5MR) and also summarizes state programmes in Turkey between 1988 and 2010. Turkey is among only a few countries that have already surpassed MDG4 and have reduced their under-five mortality rate by more than two-thirds. In 2010, 13 out of every 1,000 children died before their fifth birthday. Low birth weight, high birth order, short birth intervals, rural residence, low level of maternal education and lowest wealth quintile have affected negatively children's chances of survival. Expanding the scope of free vaccination programmes for children, improving screening and disease prevention schemes aimed at children, encouraging breastfeeding, implementing an emergency obstetric care programme, improving the services provided to newborns (a newborn intensive care programme) have brought about a significant decrease in the rate of infant and under-five mortality. The implementation of state and region specific action plans should be necessary to increase the chance of an access to the Continuum of Care for each mother and infant and to surpass MDG4. PMID- 24053064 TI - The association between gene polymorphisms of glutathione S-transferase T1/M1 and type 1 diabetes in Slovak children and adolescents. AB - BACKGROUND: Considering a dramatic increase in the incidence of type 1 diabetes (T1D) worldwide, current research focuses on complex etiology of T1D where immune system, environmental and genetic factors play a significant role. Glutathione S transferase family of enzymes protects tissue from oxidative damage which is discussed in the context of T1D. The aim of the study was to investigate an association of glutathione S-transferase mu 1 (GST M1) and glutathione S transferase theta 1 (GST T1) polymorphisms with type 1 diabetes. METHODS: 163 children, 116 with type 1 diabetes and 47 healthy controls, at the age 6-19 years were enrolled to the study. Basic anthropometric, biochemical parameters and GST T1 diabetes and M1 polymorphisms were established in each subject. RESULTS: Subjects with T1D had significantly lower concentration of uric acid compared to the healthy subjects (212.85 +/- 57.10 micromol/l vs. 269.57 +/- 72.53; p < 0.001). GST T1 null genotype was more frequent in patients with diabetes compared to the healthy controls (36.2% vs. 21.3%) and represented 2.1-fold increased risk of T1D of borderline statistical significance (OR = 2.1; 95% Cl = 0.949-4.648; p = 0.06). GST T1 null/M1 wild genotype combination was more frequent in patients with diabetes (25.9% vs. 10.6%) and represented 2.9-fold increased risk for T1D development (OR = 2.93; 95% CI = 1.061-8.095; p = 0.032). CONCLUSION: The study indicates that GST T1 null genotype and GST T1 null/M1 wild combination could be considered a risk factor for type 1 diabetes development in Slovak children and adolescents. PMID- 24053065 TI - Occupational viral hepatitis in the Slovak and the Czech Republic. AB - BACKGROUND: The proportion of occupational infectious diseases (ID) in the total number of occupational diseases reported in the Slovak Republic (SR) and the Czech Republic (CR) was decreasing from 1973 to 2010. Our study presents a longitudinal analysis of the occurrence of occupational infectious diseases in the Slovak Republic and the Czech Republic in the period from 1973-2010 with special focus on viral hepatitis. METHODS: The sources of data were national health statistics of Czechoslovakia, the Czech Republic and the Slovak Republic. Descriptive statistical methods were used for data analysis. Incidence rate of reported diseases was calculated per 100,000 general population or per 100,000 people insured. RESULTS: During the studied period, a total of 2,931 and 8,318 cases of occupational viral hepatitis (VH) were reported in the Slovak Republic and the Czech Republic, respectively. The incidence culminated in the late 1970s when hepatitis represented almost 50% of all reported occupational infectious diseases. Most cases of occupational hepatitis occurred in health and social services. Since the early 1980s, a steep decrease in the incidence of hepatitis has been observed due to the gradual implementation of mandatory vaccination against hepatitis A and B in risk groups. In SR in 1973, the incidence rate of occupational infectious diseases and that of occupational viral hepatitis was 10.85/100,000 and 1.86/100,000, respectively. In 2010, these rates decreased to 0.74/100,000 and 0.20/100,000, respectively. In CR, the incidence rates of occupational infectious diseases and that of occupational viral hepatitis reported in 1973 were 11.75/100,000 and 3.69/100,000. In 2010, reported incidence rates were 1.71/100,000 and 0.10/100,000, respectively. CONCLUSION: Although the incidence of occupational viral hepatitis has dramatically decreased in the Slovak and the Czech Republic as well as in other Visegrad group countries during the studied period, we emphasize the necessity of continuing epidemiological surveillance of hepatitis, especially with regard to the recent incidence increase of viral hepatitis C. PMID- 24053066 TI - The challenges of tobacco control in Romania. Policy review. AB - This article investigates elements of tobacco control issues in Romania. Using European Union requirements for tobacco control legislation as a backdrop, it examines the key issues of smuggling, taxation, and unemployment in a transitional economy. Romania has made some progress by adding text and pictorial warnings to cigarette packages and offering comprehensive help to quit smoking. Using empirical examples, it is argued that more progress in tobacco control is needed in the area of increased taxation, enforcement of non-smoking bans, and new legislation requiring advertising bans at point of sale, kiosks, and billboards. This article draws wider public attention to the problems that smuggling and taxation present for tobacco control, helps identify other countries confronting similar issues, and stimulates effective interventions. PMID- 24053067 TI - Pediculosis capitis: prevalence and its associated factors in primary school children living in rural and urban areas in Kayseri, Turkey. AB - OBJECTIVE: The aim of this study was to investigate the prevalence and risk factors of pediculosis capitis in schoolchildren living in rural and urban areas in Kayseri, a city located in central Anatolia in Turkey. METHODS: This cross sectional school-based study was performed in 24 randomly selected public schools. A total of 8,122 schoolchildren aged 5-16 years, from kindergarten to eighth grade, were examined for the presence of pediculosis capitis. A child was defined as being infested by the presence of live or dead lice or eggs/nits. The results were analyzed using the chi-squared test and logistic regression analysis. RESULTS: The overall prevalence of head lice infestation was 13.1%. Pediculosis was more frequent in girls (25.2%) than in boys (0.86%) (p < 0.001). The prevalence was lower in children aged 5-8 years than in those aged 9-11 or 12 16 years (p < 0.001). In multiple regression analyses, the variables demonstrating statistically significant association with pediculosis were: being a girl (OR = 40.93; 95% Cl = 29.06-57.66), being 9-11 years old (OR = 1.54; 95% Cl = 1.25-1.89), residing with > or = 3 siblings (OR = 1.98; 95% Cl = 1.57-2.50), having a mother with no education (OR = 1.73; 95% CI = 1.29-2.33), having a father with no education (OR = 1.45; 95% Cl = 1.08-1.94), living in a rural area (OR = 2.34; 95% Cl = 2.02-2.71) and living in a one-room house (OR = 2.39; 95% CI = 1.41-4.08). CONCLUSIONS: Pediculosis capitis remains a health problem in schoolchildren in Kayseri, Turkey. In addition to improvement in socioeconomic status, collaborative and participation efforts among physicians, nurses, teachers, and parents are necessary to maintain effective epidemiological surveillance and provide treatment. PMID- 24053068 TI - The perception of patients' rights among Belgian population. AB - The aim of this study was to explore the knowledge and perception of specific patients' rights and the problems experienced with their fulfilment among the Belgian population. Participants were recruited through patient association groups and health insurance companies. They completed an Internet-based questionnaire with 20 questions concerning patients' rights. In total, 309 persons completed all questions. The mean age of participants was 46 years (SD = 15), 58% of them were women. Participants judged patients' rights concerning the end of life (88%), affordable health care (87%) and information about health status (85%) as the most important issues. Participants particularly showed concern about their legal rights for care offered in the patients' own language (21%), euthanasia (15%) and affordable health care (14%). The most important problems experienced so far were related to care offered in the patients' own language (12%), affordable health care (11%) and access to their medical file (7%). PMID- 24053069 TI - Unemployment and lung cancer incidence in the Province of Opole. Brief report. AB - In this geostatistical analysis we present the results of interrelation between unemployment rate and lung cancer incidence ratios in the Province of Opole, Poland. In the study, unemployment statistics and population data were analyzed together with the registered (histopathologically confirmed) lung cancer cases (C34, ICD10) in sex-stratified working age population (18-65 years). The data were collected in the years 2006-2008 in the Statistical Office in Opole and Opole Cancer Registry, Poland. The statistically significant positive correlation/interrelation between unemployment rate and lung cancer incidence ratios in male population was established; in females, this effect was statistically insignificant. The obtained results are consistent with the most up to-date reports supporting the thesis that a higher burden of disease is observed in more deprived areas. The statistics may have practical relevance in terms of improving health status of the local population following economic reforms. PMID- 24053070 TI - A foxy view of human beauty: implications of the farm fox experiment for understanding the origins of structural and experiential aspects of facial attractiveness. AB - Within 20 years, experimental selection of quantified "not too aggressive, not too fearful" behavior to human approach was shown in silver foxes (Vulpes vulpes) to produce a neotenic package of traits in adults: ability to seek, induce, and sustain contact (called friendly or rapport behavior); relatively short limbs and foreshortened skull/face; and light pigmentation areas. Earlier sexual maturation, prolonged receptivity, and larger litters were also noted. The increased estradiol supporting these changes was apparently also responsible for faster skeletal maturation, including earlier fusion of the basicranium causing tooth crowding, but also paedomorphic craniofacial proportions that we find attractive in our own and other species. In this paper, these important findings of the farm fox experiment are juxtaposed with insights from social psychology, physical anthropology, and neuroscience about facial beauty and reaction to it. Since many unrelated species show some or all of the neotenic package or domestication profile when they have achieved rapport past the juvenile stage, craniofacial proportions considered attractive are discussed as genetically and hormonally linked to the evolution of rapport--social contact, trust, and cooperation--whether by natural, intuitive, intentional, or mixed paths of selection. PMID- 24053071 TI - Life-history evolution and the polyphenic regulation of somatic maintenance and survival. AB - Here we discuss life-history evolution from the perspective of adaptive phenotypic plasticity, with a focus on polyphenisms for somatic maintenance and survival. Polyphenisms are adaptive discrete alternative phenotypes that develop in response to changes in the environment. We suggest that dauer larval diapause and its associated adult phenotypes in the nematode (Caenorhabditis elegans), reproductive dormancy in the fruit fly (Drosophila melanogaster) and other insects, and the worker castes of the honey bee (Apis mellifera) are examples of what may be viewed as the polyphenic regulation of somatic maintenance and survival. In these and other cases, the same genotype can--depending upon its environment--express either of two alternative sets of life-history phenotypes that differ markedly with respect to somatic maintenance, survival ability, and thus life span. This plastic modulation of somatic maintenance and survival has traditionally been underappreciated by researchers working on aging and life history. We review the current evidence for such adaptive life-history switches and their molecular regulation and suggest that they are caused by temporally and/or spatially varying, stressful environments that impose diversifying selection, thereby favoring the evolution of plasticity of somatic maintenance and survival under strong regulatory control. By considering somatic maintenance and survivorship from the perspective of adaptive life-history switches, we may gain novel insights into the mechanisms and evolution of aging. PMID- 24053072 TI - The two faces of Robert Fitzroy, Captain of HMS Beagle and governor of New Zealand. AB - Robert FitzRoy, Captain of HMS Beagle and second governor of New Zealand, has two contradictory reputations among modern academics. Evolutionary biologists and Darwin scholars generally view FitzRoy as a supporter of slavery, famously quarrelling with the abolitionist Darwin over that topic during a Brazilian stopover early in the voyage of HMS Beagle. He is also regarded as a political and religious reactionary, taking a biblically creationist position at the infamous 1860 Oxford meeting of the British Association for the Advancement of Science. New Zealand historians, however, view his record as governor much more positively. They emphasize that FitzRoy was wildly unpopular with the British settlers because of his enlightened insistence that the native Maori should be treated fairly. We outline the history of these seemingly inconsistent views and examine the evidence for each. We conclude by suggesting that a more nuanced account of FitzRoy's career would surely be more thought-provoking as well as respectful of the facts. PMID- 24053073 TI - The influence of psychological state on oral lichen planus. AB - Oral lichen planus (OLP) is a T-cell mediated disease directed to a still unknown antigen, which may affect oral mucosa. The aim of this study was to determine whether differences in anxiety, depression and stress could be seen in patients with OLP in acute stage and in remission, as well as in comparison with healthy control subjects. The study included 50 OLP patients aged 22-79 (mean age 61.04) years and 50 control subjects who had healthy oral mucosa aged 38-80 (mean age 58.70) years. Patients with OLP filled out the State-Trait Anxiety Inventory for Adults and Beck Depression Inventory II test in acute stage and in remission. Control subjects also filled out the same tests. On detailed medical history, study subjects were asked about the possible stressors, which might have happened in the previous year. Statistical analysis was performed by use of descriptive statistics and t-test. There were no differences in the level of anxiety, depression and stress between the two stages of OLP disease (acute vs. remission period). Patients with OLP were significantly more anxious, depressed and stressed in both OLP stages as compared with healthy controls. It might be that psychological disturbances precede OLP development rather than worsening the disease process itself. PMID- 24053075 TI - A ten-year study of depressive symptoms in Serbian medical students. AB - The main objective of this study was to examine the rate of three dimensions of depressive symptoms in medical student population in Serbia, and to find out whether this rate had changed over the period often years. This cross-sectional study included 615 medical students (F = 61% and M = 39%), mean age = 23.60 (SD = 1.541), who were tested in five non-consecutive surveys between 2002 and 2012. Depressive symptoms were measured by the Beck Depression Inventory (BDI). The mean BDI score for the entire sample was 6.26 +/- 6.175. There was no significant difference in total BDI score among the values obtained during the ten years of testing. The greatest portion of the examined sample (77.24%) had no signs of depressive symptoms, and there was no difference in symptom intensity between medical students and other educational profiles. Similar to previous results, females had higher scores on all depressive dimensions except for one tested year, whereas a weak correlation was found between BDI scores and student age (r = 0.104; p = 0.010). Since there are still discrepancies among studies that do (not) report that medical students have typical depressive symptoms, potential explanations for the mentioned discrepancies may be found in individual characteristics of the members of the student population. Our suggestions for future studies are that they should include the stress factor, stress coping strategies, estimated life satisfaction, and the impact of these factors on the potential mental disorders. PMID- 24053074 TI - Serum levels of calcium, selenium, magnesium, phosphorus, chromium, copper and iron--their relation to zinc in rats with induced hypothyroidism. AB - There is an important relation between thyroid hormones and zinc. Establishment of low zinc levels in hypothyroidism and high levels in hyperthyroidism is a significant proof of this relation. The aim of the present study was to explore changes in serum levels of some elements and their relation to zinc in rats with hypothyroidism. Thirty adult male rats of Sprague-Dawley type were divided into 3 equal groups: group 1, control; group 2, sham-hypothyroidism group supplemented with 10 mg/kg serum physiologic i.p. for 4 weeks; and group 3, hypothyroidism group supplemented with 10 mg/kg propylthiouracil i.p. for 4 weeks. Blood samples were collected from all animals by decapitation and serum calcium, phosphorus, chromium, copper, iron, magnesium, selenium and zinc levels were analyzed using an atomic emission apparatus. Group 3 had lower calcium, selenium and zinc levels, and higher chromium, copper, iron and phosphorus levels (p < 0.01 all) relative to groups 1 and 2. Study parameters did not differ between groups 1 and 2. Results obtained in this study indicate that hypothyroidism leads to changes in serum levels of some elements in rats. These changes may be associated with reduced zinc levels in hypothyroidism. PMID- 24053076 TI - Analysis of the key issues in the organization of emergency care for stroke and heart attack patients in Bjelovar-Bilogora County. AB - Emergency care for patients with acute ischemic stroke and acute myocardial infarction according to the principles of evidence-based medicine is a challenge for the healthcare system, as it requires a multidisciplinary approach and good cooperation of all the subjects involved. The time elapsed from symptom onset to patient admission to the hospital, and the period from admission to the hospital to the beginning of therapy play an essential role in the thrombolytic treatment of stroke. For the patient, effective functioning of the system can mean the difference between preserved functional independence and disability. In recent years in Bjelovar-Bilogora County, there has been some development in emergency care of patients with acute heart attack by applying thrombolytic therapy and organizing transfer of indicated cases to the nearest clinical department for invasive cardiologic therapy. In case of acute ischemic stroke, thrombolysis has so far remained the only method of causal treatment. Results of a retrospective study conducted in 2010 in Bjelovar General Hospital on 169 patients with the established time of ischemic stroke symptom onset showed that only 39.64% of patients reached the hospital for treatment within the target time window. The results indicated the need for continuous efforts in preventing cardiovascular and cerebrovascular disease, as well as for education of citizens and healthcare professionals in recognizing the early symptoms of stroke and understanding them as an emergency condition. The present situation calls for permanent education of health workers in first line contact, an increase in the number of neurologists and cardiologists, as well as the introduction of stroke units on the model of coronary units, with constant presence of specialists. The radiology and laboratory services need adjustment to enable performing diagnostic procedures within the given time limit. At the national level, a network of stroke units should be organized, which would eliminate distance to county hospitals as a limiting factor in effective treatment. PMID- 24053077 TI - Time dependent accuracy of dental radiometers. AB - Inadequate intensity of the polymerization light source can compromise the quality and longevity of dental composite restorations. In order to maintain optimal strength of polymerization devices, regular control of polymerization units is necessary. The aim of this study was to compare the accuracy of two radiometers in the measurement of light intensity of photopolymerization devices concerning the time point of measurement. Light intensity measurements of 16 halogen and 8 LED curing lights were performed using three different devices at the beginning as well as 10 and 40 seconds after the start of illumination. Two were handheld radiometers: Bluephase meter (BM) and Cure Rite (CR), while an integrating sphere (IS) represented the reference device. Data were statistically analyzed using Friedman's test and Wilcoxon signed-rank test (p < 0.05). The values at the beginning and after 10 seconds measured by BM were significantly higher than the measurements by IS, whereas CR showed higher values after 10 and 40 seconds. Both commercial radiometers tended to overestimate the light intensity of LED and halogen curing units when compared to the reference device. The time point of measurement influences the output value. The heating of radiometers was proposed as a possible explanation for the inaccuracy. PMID- 24053078 TI - Use of complementary and alternative medicine among patients with chronic diseases. AB - The objective of this study was to evaluate the use of complementary and alternative medicine (CAM) and related factors among patients with chronic diseases. A cross-sectional study was carried out in outpatient clinics of a general hospital using a random sample of 252 adult patients with chronic diseases. Data included information on patient demographics and socioeconomic factors, as well as items to identify CAM use and the reasons for using CAM. Data were evaluated by Pearson's chi2-test and Fisher's exact test. It was found that 55.9% of study patients applied CAM. A significant number of patients (63.8%) were using CAM for hypertension. This study found that CAM use was associated with female gender, married status, housewives, low income and high levels of education. The present study confirmed the high frequency of CAM use among patients with chronic diseases in a Turkish public hospital. PMID- 24053079 TI - Assessment of gender differences in body composition and physical fitness scoring in Saudi adults by bioelectrical impedance analysis. AB - Obesity is a global problem that is reaching epidemic proportions. Body composition is an important parameter for humans because previous studies indicate high values of body fat as a predictor of mortality. The aim of the study was to assess gender differences in body composition and physical fitness in Saudi adult population. This epidemiological cross-sectional study included 411 healthy adult Saudi subjects aged 18-72 years (mean +/- SD, 36.91 +/- 15.22). All participants underwent body composition analysis. Body composition was assessed by bioelectrical impedance analysis, with a commercially available body analyzer (InBody 3.0, Biospace, Seoul, Korea). Measurements included body weight, body mass index (BMI), percent body fat, target weight, fat control, muscle control and fitness scoring based on target values. The mean BMI of the whole study population was 27.22 +/- 5.65 (median = 26.80, range = 15.6-55.4). The mean fitness score was 69.3 +/- 8.48 (median = 71.0, range = 29-99). Significant gender differences were observed in BMI, fitness score, percent body fat, and other parameters of body composition. In conclusion, the prevalence of obesity, percent body fat (%BF) and poor fitness is high in Saudi population with significant gender differences. In this regard, public awareness programs including exercise and diet teaching are required at large scale to cope up with the growing burden of obesity. PMID- 24053080 TI - Peripheral facial weakness (Bell's palsy). AB - Peripheral facial weakness is a facial nerve damage that results in muscle weakness on one side of the face. It may be idiopathic (Bell's palsy) or may have a detectable cause. Almost 80% of peripheral facial weakness cases are primary and the rest of them are secondary. The most frequent causes of secondary peripheral facial weakness are systemic viral infections, trauma, surgery, diabetes, local infections, tumor, immune disorders, drugs, degenerative diseases of the central nervous system, etc. The diagnosis relies upon the presence of typical signs and symptoms, blood chemistry tests, cerebrospinal fluid investigations, nerve conduction studies and neuroimaging methods (cerebral MRI, x-ray of the skull and mastoid). Treatment of secondary peripheral facial weakness is based on therapy for the underlying disorder, unlike the treatment of Bell's palsy that is controversial due to the lack of large, randomized, controlled, prospective studies. There are some indications that steroids or antiviral agents are beneficial but there are also studies that show no beneficial effect. Additional treatments include eye protection, physiotherapy, acupuncture, botulinum toxin, or surgery. Bell's palsy has a benign prognosis with complete recovery in about 80% of patients, 15% experience some mode of permanent nerve damage and severe consequences remain in 5% of patients. PMID- 24053081 TI - Cerebral venous circulatory system evaluation by ultrasonography. AB - Venous system can be classified as pulmonary veins, systemic veins and venous sinuses that are present only within the skull. Cerebral venous system is divided into two main parts, the superficial and the deep system. The main assignment of veins is to carry away deoxygenated blood and other maleficient materials from the tissues towards the heart. Veins have thinner walls and larger lumina than arteries. Between 60% and 70% of the total blood volume is found in veins. The major factors that influence venous function are the respiratory cycle, venous tone, the function of the right heart, gravity, and the muscle pump. Venous system, in general, can be presented by selective venography, Doppler sonography, computed tomography (CT) venography and magnetic resonance (MR) venography, and cerebral venous system can be displayed by selective venography, cerebral CT venography, cerebral MR venography, and specialized extracranial and transcranial Doppler sonography. The aim of this paper is to show the possibilities of intracranial and extracranial ultrasound evaluation of the head and neck venous circulation and chronic cerebrospinal venous insufficiency as one of the most common pathologies evaluated as part of neurodegenerative processes in the central nervous system. PMID- 24053082 TI - Aphthous ulcers as a multifactorial problem. AB - Recurrent aphthous stomatitis (RAS) is a disorder characterized by recurrent ulcerations limited to the oral mucosa. Many specialists and researchers in the domain of oral medicine and other fields do not recognize a single disease in RAS, but several pathologic states with similar clinical characteristics. Even though the real cause is unknown, there are some predisposing factors such as anemia caused by the lack of iron, folic acid and vitamin B, neutropenia, local trauma, emotional stress, metabolic disorders, hormonal disorders and chronic diseases, which cause immunodeficiency. This disease can appear in three clinical forms: small aphthous ulcers, large aphthous ulcers and herpetiform aphthous ulcers. The treatment of this type of disorder involves local or systemic use of corticosteroids, immunostimulants and vitamin therapy. Due to the association of aphthous ulcers with various other diseases, cooperation among multiple fields of medicine and a multidisciplinary approach are necessary. PMID- 24053083 TI - Kidney transplantation from deceased donors with high terminal serum creatinine. AB - The increasing number of possible recipients for kidney transplantation and relatively unchanged number of organ donors has led to consideration of alternative strategies and expansion of deceased donor criteria in order to expand donor pool. Previously, kidneys from expanded criteria donors (ECD) were strongly underestimated because of the conventional opinion suggesting these kidneys to have a higher rate of preservation injury, delayed graft function, rejection and nonfunction. Reducing the difference between graft outcome in patients transplanted from ECD and standard criteria donor (SCD) is one of the goals of many respectable kidney transplantation centers. This assignment includes major concern about reduction of cold ischemia time, recipient selection, novel and adapted immunosuppressive regimens, increased nephron mass by dual kidney transplantation, and using histologic criteria for marginal donor graft selection. There are not many reports on the outcome of kidneys transplanted from donors with acute renal failure and high terminal creatinine. This review presents the exact definition of marginal donor, especially donor with acute renal failure. The management of such grafts during preimplantation and implantation period, outcomes and post-transplantation care are the main assignments for transplantation teams. Recipients of such grafts should be well informed about the possibilities and potential complications and sign their informed consent thereafter. Some respectable studies have shown that under certain, highly controlled conditions, these kidneys can be used safely, with excellent short- and long-term outcomes. PMID- 24053084 TI - Laparoscopic versus open splenectomy: a single center eleven-year experience. AB - The 11-year experience with open (OS) and laparoscopic (LS) splenectomy at a single center is reported. A total of 201 splenectomies were performed and clinical and demographic data were retrospectively analyzed. Patients were classified according to the type of operation as LS or OS. The mean age of patients was 45.1 +/- 17.1, and 141 patients were male. Out of 43 LS, 40 were done for hematologic causes, and they had a significantly shorter hospital stay compared to OS for hematologic causes (6.87 +/- 2.2 vs. 9.84 +/- 2.9 days; p = 0.000003) and significantly less requirement for blood transfusion (26.2 +/- 93.4 vs. 132.4 +/- 252.3 mL; p = 0.0152). In the OS group, comparison of patients with trauma and those with hematologic causes showed that significantly more males underwent surgery for trauma causes (35 of 43 vs. 16 of 21), hospital stay was longer (18.9 +/- 27.4 vs. 9.8 +/- 2.9 days) and blood requirement higher (708.1 +/- 603.7 mL vs. 132.4 +/- 252.3 mL; p = 0.0004, p = 0.047 and p = 0.000001, respectively). Laparoscopic splenectomy is a safe procedure for spleen removal. PMID- 24053085 TI - Expression of growth hormone and growth hormone receptor in fibroadenomas of the breast. AB - Fibroadenoma is the most prevalent benign breast tumor. It consists of epithelial and stromal components. In general, breast tumors are highly hormonally dependent and growth hormone by its physiology may have a possible oncogenic potential. Therefore, the aim of this study was to determine the expression of growth hormone and growth hormone receptor in epithelial and stromal components of fibroadenomas. Study group included 30 randomly chosen fibroadenomas from female patients aged between 18 and 69 years. The expression of growth hormone and growth hormone receptor was defined in both histologic components of fibroadenomas. Growth hormone was expressed in 96.7% of both epithelial and stromal components of fibroadenomas, with stronger expression in the stromal component. The same percentage of positive reaction (96.7%) was obtained in the epithelial component of fibroadenomas for growth hormone receptor expression. Only 6.7% of stromal components tested for growth hormone receptor were positive. The high expression of growth hormone and growth hormone receptor in fibroadenoma tissue indicates their possible role in the pathogenesis of this tumor. Follow up of patients with high expression of growth hormone and growth hormone receptor may be suggested. PMID- 24053086 TI - Is there difference in perinatal outcome of singleton and twin pregnancies after assisted conception: two-year experience. AB - The aim of the study was to compare perinatal outcome of singleton and twin pregnancies conceived after assisted reproductive technologies (ART). This retrospective study included singleton and twin pregnancies conceived after ART in the period from January 1, 2007 until December 31, 2008. The study variables were maternal age (years), parity, body mass index (BMI; kg/m2), week (< or =36 (6/7) and > or = 37) and mode of delivery (vaginal and cesarean section), birth weight (grams) and APGAR score (< or = 7; 8-10). During the study period, there were 195 pregnancies after ART that fulfilled inclusion criteria. We found no between-group difference in parity (chi2 = 0.0133; P = 0.9081), but such difference was found in mean age (t = 2.0486; P = 0.0419) and BMI (chi2 = 31.038; P = 0.001). A statistically significant difference was recorded in preterm delivery rate (chi2 = 25.539; P = 0.001), average duration of pregnancy (t = 12.8591; P = 0.001), average birth weight (t = 10.5446; P = 0.001) and mode of delivery (chi2 = 13,691; P = 0.001). A statistically significant difference was found in low birth weight babies (chi2 = 102.02; P = 0.001) and APGAR score (chi2 = 19.96; P = 0.001), but there was no difference in the prevalence of small for gestational age babies (chi2 = 0.90629; P = 0.635). In conclusion, this study indicated the perinatal outcome after ART to be considerably poorer in twins than in singletons. PMID- 24053087 TI - Dermatitis artefacta: case report. AB - Automutilating behavior is becoming ever more frequent in patients seeking dermatologic care. Psychocutaneous disorders encompass a wide range of dermatologic conditions, all of which have in common the important role of psychological factors. Dermatitis artefacta syndrome is characterized by unconscious self-injury behavior, while dermatitis para-artefacta syndrome is labeled with manipulation of an existing specific dermatosis. Consciously stimulated injuries with the purpose of obtaining material gain is known as malingering. Here we present a 20-year-old female patient with a sudden pain and an oval, yellowish skin defect on her left lower leg, 3 x 3.5 cm in diameter, with an erythematous, clearly defined border, surrounded by erythematous, painful skin resembling pyoderma gangrenosum. The patient had a clinically typical skin presentation but with atypical therapeutic outcome. The diagnosis of dermatitis artefacta was made. Liaison psychiatry can reaffirm the diagnosis of dermatitis artefacta and provide necessary psychopharmacotherapy and psychotherapy. PMID- 24053088 TI - Successful management of the superior mesenteric artery occlusion in 86-year-old female: case report. AB - Chronic superior mesentery ischemia often presents a clinically asymptomatic diffuse atherosclerotic process. There are no compelling recommendations on the benefits of early revascularization strategy besides antithrombotic prophylaxis and statin treatment. Conversely, long-term prevalence of symptomatic cases in surgical patient cohorts is rarely reported in the literature. Acutization of chronic ischemia has a severe clinical course, so timely recognition may be considered lifesaving. We present a case of an 86-year-old woman hospitalized for acutized atherosclerotic narrowing of superior mesenteric artery. The patient was urgently operated on by aorto-mesenteric ring prosthesis revascularization. Postoperative course was uneventful and the patient regained 10 kilograms in the next few months. PMID- 24053089 TI - Liver abscess as a therapeutic and diagnostic challenge. AB - Liver abscess still represents a significant clinical entity with mortality rates of up to 10%. Traditional treatment of liver abscesses is open surgical treatment. Recently, percutaneous and laparoscopic drainage has been increasingly used. Still, in spite of these relatively novel techniques and improved imaging, liver abscess can sometimes be difficult to diagnose or treat. Here we present two cases of chronic liver abscess treated at our department. First patient was twice hospitalized in other hospitals without reaching definitive diagnosis. He was admitted at our department because of clinical presentation of sepsis, and definitive diagnosis of liver abscess was established only during open surgery. Second patient was admitted after laparoscopic drainage and repeated percutaneous drainage had failed to resolve his symptoms. In both cases, liver segment resection led to complete healing. These cases indicate that chronic liver abscess can still present a diagnostic and therapeutic challenge. PMID- 24053090 TI - Intraoperative gamma hand-held probe navigation in resection of osteoid osteoma tumor--report of two cases. AB - Two cases of osteoid osteoma tumor (OO) are presented and our early experience with intraoperative gamma probing to localize OO during surgery is reported. The concept of radioguided surgery was developed 60 years ago and the gamma detection probe technology for radioguided biopsy and/or resection of bone lesions has been applied since the early 1980s. Bone scintigraphy is very important for initial diagnosis of OO with almost 100% sensitivity. The bone scan finding is specific, with so called double density appearance, very intense accumulation of radiopharmaceutical in the nidus and therefore great difference between the nidus and the surrounding healthy bone, thus making possible to treat this lesion with probe guided surgery. Three phase bone scintigraphy and single photon emission computed tomography were conducted in our patients for initial diagnosis of OO. A second bone scintigraphy was performed before surgery. The surgery followed 12-15 hours later by intraoperative nidus detection with a hand-held gamma probe. Gamma hand-held probe is a system that detects gamma photons. The count rate in the nidus area on the day of surgery was 3 to 4 times higher than in the healthy bone area. Drilling was performed until the counts decreased to the level of the surrounding bone counts, thereby confirming complete excision. This is the method of choice for minimizing bone resection, the risk of pathologic fracture, the need of bone grafting, and reducing the period of convalescence. Evidence for the treatment efficiency is pain disappearance after the surgery. PMID- 24053091 TI - Ischemic stroke due to postpartum angiopathy complicated by pulmonary embolism with favorable outcome. AB - Postpartum cerebral angiopathy is a relatively rare condition. It can cause either ischemic or hemorrhagic stroke, or both, and usually occurs within the first week following non-complicated pregnancy and natural delivery. Although its pathophysiology is unclear, the cause of the condition is believed to be prolonged reversible vasospasm. We present an unusual case of a 37-year-old woman who developed right hemiparesis with aphasia on day 8 of natural delivery complicated by pulmonary embolism. Steroids, heparin, and calcium channel blockers were successfully instituted and the patient was discharged from the hospital on day 50. The article presents clinical and imaging characteristics, differential diagnosis, management, and considers the difficulties that occurred during the patient's hospital stay. PMID- 24053092 TI - [Improvised summer travel, illustrative clinical cases]. PMID- 24053093 TI - [Clinical case of the month. Rare case of ureteral endometriosis nine years after hysterectomy]. AB - Ureteral endometriosis is a rare entity, especially when it occurs in the postmenopausal period. In certain circumstances, this severe disease can cause obstruction, leading to ureterohydronephrosis and, finally, to a progressive and often silent loss of renal function. The symptomatology is variable and non specific, making preoperative diagnosis difficult. The treatment is mainly surgical. Its aim is the relief of obstruction to preserve the renal function. We report the case of a 39 year old patient, hysterectomised for endometriosis nine years earlier, who developed a recurrence demonstrated by ureteral endometriosis and revealed by ureterohydronephrosis. Robot-assisted laparoscopic ureterolysis allowed a complete resection of the lesion and resolved the obstruction. No recurrence of ureterohydronephrosis was found at the fifth and ninth postoperative month ultrasonographic controls. PMID- 24053094 TI - [Clinical case of the month. Extended portal vein thrombosis in patient on vitamin K antagonists]. AB - There is a long-recognized association between cancer and venous thromboembolism. Venous thrombosis is the most common paraneoplastic complication. We describe a case of rupture of esophageal varices in a patient with a paraneoplastic portal thrombosis. We highlight the links between venous thromboembolism and cancer and also discuss treatment and prognostic factors. PMID- 24053095 TI - [Clinical case of the month. An unusual sepsis]. AB - Lemierre's syndrome is a rare, but significant pathology to recognize. It most often affects young patients in good health; a late diagnosis can be fatal. It consists in an anaerobic septicemia (usually, Fusobacterium necrophorum) originating from a suppurative thrombophlebitis of the internal jugular vein. Infection occurs during a common sore throat and spreads by contiguity. The clinical presentation is a sepsis with pulmonary embolisations, but other sites of dissemination can also occur. Treatment consists of prolonged intravenous antibiotherapy associated with supportive therapy, if needed. Anticoagulation remains controversial. The outcome is favorable in most cases provided diagnosis and treatment are early; mortality however remains significant, around 5%. PMID- 24053096 TI - [Clinical case of the month. The role of radiotherapy for the treatment of advanced squamous cell carcinoma of the vulva. Case report and review of the literature]. AB - Locally advanced squamous cell carcinoma of the vulva is treated with concomitant chemoradiotherapy if surgery is too mutilating and/or implies the use of stomy. We report in this paper, the unusual case of a young patient treated successfully with this non-surgical approach. PMID- 24053097 TI - [Clinical case of the month: non-familial vitreous amyloidosis]. AB - Vitreous amyloidosis is characterized by the presence of amyloid deposition in the vitreous cavity. It is frequently associated with dominantly inherited familial amyloidosis of the transthyretin mutation. The nonfamilial form is rare, and only a dozen of cases have been reported in the ophthalmological literature. PMID- 24053098 TI - [Clinical case of the month. Ulnar artery aneurysm in a roofer]. AB - A case of ulnar artery aneurysm in an independent roofer is reported. It is a rare disease often associated with the Hammer Hypothenar Syndrome specifically found in manual workers and athletes exposed to repetitive palmar trauma. PMID- 24053099 TI - [Clinical case of the month. Thyrotoxic periodic paralysis. Report of a case in a Somalian male]. AB - We report the case of a man hospitalized for tetraparesis related with hypokalemia due to a potassium shift from the extracellular to the intracellular compartment revealing a hyperthyroidism. We will discuss different physiopathological hypotheses giving relating periodic paralysis and hyperthyroidism. Correction of hypokalemia combined with a synthetic antithyroid agent and a beta blocking drug allowed complete motor fonctional recovery. PMID- 24053100 TI - [Clinical case of the month. Idiopathic mediastinal fibrosis]. AB - Fibrosing mediastinitis is a rare condition characterized by an excessive growth of dense fibrous tissue within the mediastinum. The etiology of the disease is most often a fungal infection and may in some cases be idiopathic. We present the case of a patient with chronic obstructive pulmonary disease (COPD) suffering from fibrosing mediastinitis of undetermined origin and in whom the diagnosis was established by histopathological analysis after mediastinoscopy. PMID- 24053101 TI - [Clinical case of the month. Renovascular arterial hypertension complicated by diabetes insipidus: report of a case and review of the literature]. AB - Mrs. A, a 62 year old patient with a history of hypertension, polyuria and polydipsia is hospitalized after a malaise. A severe hypokalemia, which is the cause of the polyuria and polydipsia, is discovered. The presence of hypertension and hypokalemia arises suspicion of a primary hyperaldosteronism and the plasma levels of renin and aldosterone are measured. Elevated aldosterone levels are combined with high plasma renin concentrations which permits to rule out primary hyperaldosteronism. Further explorations reveal a subocclusive ostial stenosis of the right renal artery. A treatment by sartan is instaured, which allows arterial pressure control and kalemia normalization. Chronic hypokalemia can be the cause of tubular nephropathy manifested by nephrogenic diabetes insipidus. PMID- 24053102 TI - [Clinical case of the month. Chemotherapy, immunodepression and secondary neoplasms: a case report]. AB - We report the case of a multi-metastatic mucinous adenocarcinoma of the colon discovered pre-mortem in a patient with a history of multiple myeloma. This case gives the opportunity to discuss the prognostic value of histological typing of colorectal cancer and secondary neoplasms to chemotherapy and/or immunodepression. PMID- 24053103 TI - [Clinical case of the month. A rare case of arthritis and fever]. AB - We present the case report ofa 28 year old male presenting with recurrent fever episodes and arthralgia. Based on the presence of an inflammatory syndrome, a hyperferritinemia, a salmon-pink rash and recurrent fever episodes, the diagnosis of an adult onset Still's disease (AOSD) was made. A treatment with corticosteroids was started. During the following years, the corticosteroids could not be tapered. Eventually, a treatment with anakinra, an interleukin 1 (IL 1) receptor antagonist was started, allowing tapering of the corticosteroids. This case report supports the possible role of IL-1 in the pathogenesis ofAOSD, possibly through the inflammasome. PMID- 24053104 TI - [Clinical case of the month. Amoebic liver abscess contracted in India with diagnosis confirmed by PCR]. AB - Amoebiasis is a disease of parasitic origin responsible for dysentery and extra intestinal complications. The infection is by Entamoeba histolytica, an amoeba whose geographical distribution is cosmopolitan, but that is more prevalent in tropical areas. Only a few infections are symptomatic and some of them may cause extra-intestinal complications. Hepatic amoebiasis is the most frequently observed. We report the case of a Belgian woman who developed an amoebic liver abscess after returning from a trip to India. The diagnosis was confirmed by PCR detection of E. histolytica DNA performed on the abscess fluid. The epidemiological, diagnosis and treatment aspects are discussed. PMID- 24053105 TI - Inhibition and working memory in young preschool children with symptoms of ADHD and/or oppositional-defiant disorder. AB - BACKGROUND: Early symptoms of attention deficit/hyperactivity disorder (ADHD) and oppositional-defiant disorder (ODD) are associated with deficits in cognitive self-regulatory processes or executive functions (EF)s. However, the hypothesis that neurocognitive deficits underlying the two disorders are already evident during early preschool years still has limited empirical support. The present study investigated associations between symptoms of ADHD and/or ODD and two core EFs, inhibition and working memory, in a large nonclinical sample of 3-year old children. METHOD: Participants were 1045 children (554 boys, age 37-47 months), recruited from the population based Norwegian Mother and Child Cohort Study (MoBa). Relations between behavioral symptoms and measures of inhibition and working memory were studied both categorically and dimensionally. RESULTS: Children with co-occurring symptoms of ADHD and ODD performed at a significantly lower level than typically developing children in 4 out of 5 EF measures. Symptoms of ADHD, both alone and in combination with ODD, were associated with reduced performance on tests of inhibition in the group comparisons. Dimensional analyses showed that performance within both EF domains contributed to variance primarily in ADHD symptom load. The associations between test results and behavioral symptoms remained significant after gender and verbal skills had been controlled. CONCLUSION: Young preschoolers show the same pattern of relations between EF and behavioral symptoms of ADHD and/or ODD as previously described in older children diagnosed with ADHD and/or ODD. Effect sizes were generally small, indicating that measures of EF have limited clinical utility at this stage in development. PMID- 24053106 TI - Should centralized histopathological review in penile cancer be the global standard? AB - OBJECTIVE: To assess the role of centralized pathological review in penile cancer management. MATERIALS AND METHODS: Newly diagnosed squamous cell carcinomas (SCC) of the penis, including squamous cell carcinoma in situ (CIS), from biopsy specimens were referred from 15 centres to the regional supra-network multidisciplinary team (Sn-MDT) between 1 January 2008 and 30 March 2011. Biopsy histology reports and slides from the respective referring hospitals were reviewed by the Sn-MDT pathologists. The biopsy specimens' histological type, grade and stage reported by the Sn-MDT pathologist were compared with those given in the referring hospital pathology report, as well as with definitive surgery histology. Any changes in histological diagnosis were sub-divided into critical changes (i.e. those that could alter management) and non-critical changes (i.e. those that would not affect management). RESULTS: A total of 155 cases of squamous cell carcinoma or CIS of the penis were referred from 15 different centres in North-West England. After review by the Sn-MDT, the histological diagnosis was changed in 31% of cases and this difference was statistically significant. A total of 60.4% of the changes were deemed to be critical changes that resulted in a significant change in management. When comparing the biopsy histology reported by the Sn-MDT with the final histology from the definitive surgical specimens, a good correlation was generally found. CONCLUSIONS: In the present study a significant proportion of penile cancer histology reports were revised after review by the Sn-MDT. Many of these changes altered patient management. The present study shows that accurate pathological diagnosis plays a crucial role in determining the correct treatment and maximizing the potential for good clinical outcomes in penile cancer. In the case of histopathology, centralization has increased exposure to penile cancer and thereby increased diagnostic accuracy, and should therefore be considered the 'gold standard'. PMID- 24053107 TI - Bulk synthesis of exfoliated two-dimensional polymers using hydrazone-linked covalent organic frameworks. AB - Two-dimensional (2D) polymers assemble organic subunits into covalently linked, high-aspect-ratio networks with long-range order. Despite recent advances in 2D polymerization, scalable and general methods to access few- and single-layer materials are limited. Here we exfoliate a hydrazone-linked covalent organic framework (COF) to yield bulk quantities of few-layer two-dimensional (2D) polymers. Immersing the COF powder in several laboratory solvents exfoliates and disperses thin COF-43 samples, which maintain their characteristic periodic hexagonal structure. This phenomenon was characterized using infrared spectroscopy, dynamic light scattering, atomic force microscopy, transmission electron microscopy, and selected area electron diffraction. 2D COFs with reduced interlayer interaction energies offer a new means to access high-aspect-ratio 2D polymers whose structure may be designed using established principles of COF synthesis. PMID- 24053108 TI - Nanoceria particles as catalytic amplifiers for alkaline phosphatase assays. AB - We propose a novel system to enhance detection sensitivity of alkaline phosphatase (ALP) in electrochemical assays by using nanoceria particles as redox active catalytic amplifiers of ALP signals. The catalytic activity of nanoceria particles attributed to their dual oxidation state Ce(4+)/Ce(3+) and high oxygen mobility enabled oxidation of the products of the ALP-catalyzed reaction. A suite of spectroscopic and electrochemical methods, including UV-vis spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS), and cyclic voltammetry (CV) were used to characterize the interaction of nanoceria with the ALP-generated products. Spectrometric experiments demonstrate change in the oxidation state of nanoceria upon exposure to the hydrolytic products of ALP. Three enzymatically generated products of commonly used ALP substrates were detected at a screen printing electrode surface in the presence of nanoceria. Electrochemical experiments demonstrate signal amplification of the ALP activity assay by nanoceria for all three products, demonstrating remarkable sensitivity of this assay. The assay was optimized with respect to pH and buffer composition. Analytical characterization of the nanoceria-based ALP activity assay was established using a 1-naphthyl phosphate substrate. The proposed strategy can find widespread applications in sensing schemes involving ALP. PMID- 24053109 TI - Paradoxical effect of obesity on hemorrhagic transformation after acute ischemic stroke. AB - BACKGROUND: Among the patients with established coronary artery diseases, obese patients tend to have a more favorable prognosis, which is called as obesity paradox. Interestingly, mildly obese patients who underwent coronary revascularization had a lower risk of bleeding. In this context, we have investigated the association between obesity and hemorrhagic transformation (HTf) after acute ischemic stroke. METHODS: A total of 365 patients with first-ever acute ischemic stroke were included in this study. Demographic, clinical and radiological information was collected and HTf was evaluated through follow-up T2*-weighted gradient-recalled echo MRI performed usually within 1 week after occurrence of stroke. Body mass index was calculated, and obesity was defined using the World Health Organization Western Pacific Regional Office criteria. RESULTS: The HTf was identified in 59 patients (16.2%). As the severity of obesity increased, the occurrence of HTf decreased. Compared with the normal weight group and after controlling possible confounders including acute and previous treatment, stroke severity and subtype, the risk of HTf decreased significantly in the obese group (odds ratio, 0.39; 95% confidence interval, 0.17 0.87). CONCLUSIONS: The better outcome for HTf seen in obese patients suggests the existence of a "bleeding-obesity paradox" in acute ischemic stroke. PMID- 24053110 TI - Production of the alkaloid swainsonine by a fungal endophyte in the host Swainsona canescens. AB - Legumes belonging to the Astragalus, Oxytropis, and Swainsona genera have been noted by ranchers in the Americas, Asia, and Australia to cause a neurologic disease often referred to as locoism or peastruck. The toxin in these legumes is swainsonine, an alpha-mannosidase and mannosidase II inhibitor. Recent research has shown that in Astragalus and Oxytropis species swainsonine is produced by a fungal endophyte belonging to the Undifilum genus. Here Swainsona canescens is shown to harbor an endophyte that is closely related to Undifilum species previously cultured from locoweeds of North America and Asia. The endophyte produces swainsonine in vitro and was detected by PCR and culturing in S. canescens. The endophyte isolated from S. canescens was characterized as an Undifilum species using morphological and phylogenetic analyses. PMID- 24053112 TI - Frequent detection of parental consanguinity in children with developmental disorders by a combined CGH and SNP microarray. AB - BACKGROUND: Genomic microarrays have been used as the first-tier cytogenetic diagnostic test for patients with developmental delay/intellectual disability, autism spectrum disorders and/or multiple congenital anomalies. The use of SNP arrays has revealed regions of homozygosity in the genome which can lead to identification of uniparental disomy and parental consanguinity in addition to copy number variations. Consanguinity is associated with an increased risk of birth defects and autosomal recessive disorders. However, the frequency of parental consanguinity in children with developmental disabilities is unknown, and consanguineous couples may not be identified during doctor's visit or genetic counseling without microarray. RESULTS: We studied 607 proband pediatric patients referred for developmental disorders using a 4 * 180 K array containing both CGH and SNP probes. Using 720, 360, 180, and 90 Mb as the expected sizes of homozygosity for an estimated coefficient of inbreeding (F) 1/4, 1/8, 1/16, 1/32, parental consanguinity was detected in 21cases (3.46%). CONCLUSION: Parental consanguinity is not uncommon in children with developmental problems in our study population, and can be identified by use of a combined CGH and SNP chromosome microarray. Identification of parental consanguinity in such cases can be important for further diagnostic testing. PMID- 24053113 TI - What new mothers' favorite web sites and features tell us about designing web based health promotion: a content analysis. AB - OBJECTIVE: Unmet health needs experienced by new mothers may potentially be reduced by the use of Internet-based information, advice, decision support, and social networking. New mothers' Web site preferences must be understood in order to develop successful Internet-delivered healthcare information. The purpose of this study is to determine the Web site preferences of new mothers in order to better design health resources distributed through the Internet. MATERIALS AND METHODS: Data were derived from two open-ended questions in a larger survey of new mothers of varying incomes and racial/ethnic groups (n=145). The questions focused on mothers' favorite Web sites and their favorite aspect of the Web sites. Content analysis was used to condense data into descriptive categories. RESULTS: Mothers most frequently chose commercial search engines, followed by social networking sites, as their favorite Web sites. Mothers' most frequently mentioned favorite attributes of the Web sites were, first, the ability to interact with other users, and then ease of navigation, access, and use. Except for a difference in favorite Web site associated with maternal age, Web sites and their most liked attributes did not differ by demographic characteristics. CONCLUSIONS: New mothers' Web site preferences offer preliminary guidance for designers of e-health resources for this population. An expanded survey with more detailed questions about preferences and devices would further refine this knowledge base. PMID- 24053111 TI - Variants in toll-like receptor 9 gene influence susceptibility to tuberculosis in a Mexican population. AB - BACKGROUND: The control of Mycobacterium tuberculosis (Mtb) infection begins with the recognition of mycobacterial structural components by toll like receptors (TLRs) and other pattern recognition receptors. Our objective was to determine the influence of TLRs polymorphisms in the susceptibility to develop tuberculosis (TB) in Amerindian individuals from a rural area of Oaxaca, Mexico with high TB incidence. METHODS: We carried out a case-control association community based study, genotyping 12 polymorphisms of TLR2, TLR4, TLR6 and TLR9 genes in 90 patients with confirmed pulmonary TB and 90 unrelated exposed but asymptomatic household contacts. RESULTS: We found a significant increase in the frequency of the allele A of the TLR9 gene polymorphism rs352139 (A>G) in the group of TB patients (g.f. = 0.522) when compared with controls (g.f. = 0.383), (Pcorr = 0.01, OR = 1.75). Under the recessive model (A/G + A/A vs G/G) this polymorphism was also significantly associated with TB (Pcorr = 0.01, OR= 2.37). The association of the SNP rs352139 was statistically significant after adjustment by age, gender and comorbidities by regression logistic analysis (Dominant model: p value = 0.016, OR = 2.31; Additive model: p value = 0.023, OR = 1.68). The haplotype GAA of TLR9 SNPs was also associated with TB susceptibility (Pcorr = 0.02). Differences in the genotype or allele frequencies of TLR2, TLR4 and TLR6 polymorphisms between TB patients and healthy contacts were not detected. CONCLUSIONS: Our study suggests that the allele A of the intronic polymorphism rs352139 on TLR9 gene might contribute to the risk of developing TB in Mexican Amerindians. PMID- 24053114 TI - Comparative effectiveness study to assess two examination modalities used to detect dental caries in preschool urban children. AB - BACKGROUND: Dental caries affecting the primary dentition of U.S. children continues to be the most prevalent chronic childhood disease. Preventive screening for dental caries in toddlers by dental professionals is labor intensive and costly. Studies are warranted to examine innovative screening modalities that reduce cost, are less labor-intensive, and have the potential to identify caries in high-risk children. SUBJECTS AND METHODS: Two hundred ninety one children were randomized into two groups: Group 1 received a traditional, visual tactile examination initially and follow up-examinations at 6 and 12 months, and Group 2 received a teledentistry examination initially and follow-up examinations at 6 and 12 months. The mean primary tooth decayed and filled surfaces (dfs) scores were calculated for all children at baseline and 6 and 12 months. RESULTS: At baseline, the mean dfs score for children examined by means of teledentistry was 2.19, and for the children examined by means of the traditional method, the mean was 1.27; the means were not significantly different. At the 12-month examination, the mean dfs score for the children examined by means of teledentistry was 3.02, and for the children examined by means of the clinical method, the mean dfs was 1.70; the means were not significantly different. At 12 months the mean fillings score for the children examined by means of teledentistry was 1.43 and for the children examined by means of the clinical method was 0.51; the means were statistically significantly different (p<0.001). CONCLUSIONS: These results suggest that the teledentistry examinations were comparable to clinical examinations when screening for early childhood caries in preschool children. The data further showed that color printouts of teeth with cavities provided to parents of children who received teledentistry screenings promoted oral healthcare utilization, as children from the teledentistry study group received more dental care than children from the clinical study group. PMID- 24053115 TI - Primary care provider and imaging technician satisfaction with a teledermatology project in rural Veterans Health Administration clinics. AB - OBJECTIVE: Assessment of a multisite rural teledermatology project between 2009 and 2012 in four Pacific Northwest states that trained primary care providers and imaging technicians in state-of-the-art techniques of telemedicine. MATERIALS AND METHODS: In 2012, we assessed provider and imaging technician acceptability and satisfaction with a 32-item survey instrument based on the Patient Satisfaction Questionnaire developed by Ware et al. (Eval Program Plann 1983;6:247-63) and modified for telemedicine by Kraai et al. (J Card Fail 2011;17:684-690). Survey questions covered eight satisfaction domains: interpersonal manner, technical quality, accessibility, finances, efficacy, continuity, physical environment, and availability. RESULTS: Overall, 71% of the primary care providers and 94% of the imaging technicians reported being satisfied or extremely satisfied with the teledermatology project. Most (95%) providers found the continuing education classes on dermatology diagnosis and treatment topics useful, and 86% reported teledermatology was a good addition to regular patient services. Most (97%) of the imaging technicians were satisfied with the ability of teledermatology to improve the description of dermatology conditions using images of the lesions or rashes, and 91% were satisfied with the convenience of teledermatology. Challenges reported by both providers and imaging technicians include an increase in workload due to more patient visits related to dermatology care and limited information technology support. CONCLUSIONS: Given the Veterans Health Administration's initiatives to promote accessible health care to underserved Veterans using telehealth, these findings can inform future program designs for teledermatology. PMID- 24053116 TI - Living in two homes-a Swedish national survey of wellbeing in 12 and 15 year olds with joint physical custody. AB - BACKGROUND: The practice of joint physical custody, where children spend equal time in each parent's home after they separate, is increasing in many countries. It is particularly common in Sweden, where this custody arrangement applies to 30 per cent of children with separated parents. The aim of this study was to examine children's health-related quality of life after parental separation, by comparing children living with both parents in nuclear families to those living in joint physical custody and other forms of domestic arrangements. METHODS: Data from a national Swedish classroom study of 164,580 children aged 12 and 15-years-old were analysed by two-level linear regression modelling. Z-scores were used to equalise scales for ten dimensions of wellbeing from the KIDSCREEN-52 and the KIDSCREEN-10 Index and analysed for children in joint physical custody in comparison with children living in nuclear families and mostly or only with one parent. RESULTS: Living in a nuclear family was positively associated with almost all aspects of wellbeing in comparison to children with separated parents. Children in joint physical custody experienced more positive outcomes, in terms of subjective wellbeing, family life and peer relations, than children living mostly or only with one parent. For the 12-year-olds, beta coefficients for moods and emotions ranged from -0.20 to -0.33 and peer relations from -0.11 to -0.20 for children in joint physical custody and living mostly or only with one parent. The corresponding estimates for the 15-year-olds varied from -0.08 to -0.28 and from -0.03 to -0.13 on these subscales. The 15-year-olds in joint physical custody were more likely than the 12-year-olds to report similar wellbeing levels on most outcomes to the children in nuclear families. CONCLUSIONS: Children who spent equal time living with both parents after a separation reported better wellbeing than children in predominantly single parent care. This was particularly true for the 15-year-olds, while the reported wellbeing of 12-years olds was less satisfactory. There is a need for further studies that can account for the pre and post separation context of individual families and the wellbeing of younger age groups in joint physical custody. PMID- 24053117 TI - Whole genome duplication events in plant evolution reconstructed and predicted using myosin motor proteins. AB - BACKGROUND: The evolution of land plants is characterized by whole genome duplications (WGD), which drove species diversification and evolutionary novelties. Detecting these events is especially difficult if they date back to the origin of the plant kingdom. Established methods for reconstructing WGDs include intra- and inter-genome comparisons, KS age distribution analyses, and phylogenetic tree constructions. RESULTS: By analysing 67 completely sequenced plant genomes 775 myosins were identified and manually assembled. Phylogenetic trees of the myosin motor domains revealed orthologous and paralogous relationships and were consistent with recent species trees. Based on the myosin inventories and the phylogenetic trees, we have identified duplications of the entire myosin motor protein family at timings consistent with 23 WGDs, that had been reported before. We also predict 6 WGDs based on further protein family duplications. Notably, the myosin data support the two recently reported WGDs in the common ancestor of all extant angiosperms. We predict single WGDs in the Manihot esculenta and Nicotiana benthamiana lineages, two WGDs for Linum usitatissimum and Phoenix dactylifera, and a triplication or two WGDs for Gossypium raimondii. Our data show another myosin duplication in the ancestor of the angiosperms that could be either the result of a single gene duplication or a remnant of a WGD. CONCLUSIONS: We have shown that the myosin inventories in angiosperms retain evidence of numerous WGDs that happened throughout plant evolution. In contrast to other protein families, many myosins are still present in extant species. They are closely related and have similar domain architectures, and their phylogenetic grouping follows the genome duplications. Because of its broad taxonomic sampling the dataset provides the basis for reliable future identification of further whole genome duplications. PMID- 24053118 TI - Faces in context: modulation of expression processing by situational information. AB - Numerous studies using the event-related potential (ERP) technique have found that emotional expressions modulate ERP components appearing at different post stimulus onset times and are indicative of different stages of face processing. With the aim of studying the time course of integration of context and facial expression information, we investigated whether these modulations are sensitive to the situational context in which emotional expressions are perceived. Participants were asked to identify the expression of target faces that were presented immediately after reading short sentences that described happy or anger inducing situations. The main manipulation was the congruency between the emotional content of the sentences and the target expression. Context-independent amplitude modulation of the N170 and N400 components by emotional expression was observed. On the other hand, context effects appeared on a later component (late positive potential, or LPP), with enhanced amplitudes on incongruent trials. These results show that the early stages of face processing where emotional expressions are coded are not sensitive to verbal information about the situation in which they appear. The timing of context congruency effects suggests that integration of facial expression with situational information occurs at a later stage, probably related to the detection of affective congruency. PMID- 24053119 TI - Long-chain omega-3 polyunsaturated fatty acid intake and risk of colorectal cancer. AB - Research suggests that long-chain omega-3 polyunsaturated fatty acids (LC-PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have antineoplastic properties, yet evidence for association between LC-PUFAs and colorectal cancer (CRC) remains inconsistent. Using the VITamins And Lifestyle (VITAL) cohort, we evaluated how EPA/DHA intake, and its primary sources, fish oil supplement use and dark fish consumption, relate to CRC risk. A total of 68,109 Washington residents aged 50-76 completed a questionnaire between 2000-2002 and were followed for CRC through 2008 (n = 488). Persons using fish oil supplements on 4+ days/wk for 3+ yr experienced 49% lower CRC risk than nonusers (hazard ratio = 0.51, 95% CI = 0.26-1.00; P trend = 0.06). The association between fish oil use and decreased CRC risk was primarily observed for men (P interaction = 0.02; P trend men = 0.02; P trend women = 0.88) and for colon cancer (P difference = 0.05; P trend colon = 0.03; P trend rectum = 0.87). Although dark fish and total EPA + DHA intake were not associated with CRC risk overall, these associations varied by genetic risk (P interaction = 0.009 and 0.02, respectively), with inverse associations observed among low-moderate genetic risk groups and positive associations observed among high risk groups. Results suggest that associations between LC-PUFA intake and CRC may vary by gender, subsite, and genetic risk, providing additional insight into the potential role of LC-PUFAs in cancer prevention. PMID- 24053120 TI - Mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: predictors, management, and outcomes. AB - OBJECTIVE: To characterise the incidence, onset, management, predictors, and clinical impact of mammalian target of rapamycin (mTOR) inhibitor-associated non infectious pneumonitis (NIP) on patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Retrospective review of 310 patients with mRCC who received temsirolimus and/or everolimus between June 2007 and October 2010. Clinical correlations were made with serial radiological imaging. Fisher's exact, Wilcoxon rank-sum, and logistic regression analyses were used to evaluate the association of NIP with demographic or clinical factors. Log-rank and Cox proportional hazards regression analyses were used for the time-to-event analysis. RESULTS: NIP occurred in 6% of temsirolimus-treated and 23% of everolimus-treated patients. Symptoms included cough, dyspnoea, and fever (median of two and three symptoms per patient, respectively). The median National Cancer Institute Common Toxicity Criteria for Adverse Events pneumonitis grade was 2 for both groups. Older age and everolimus treatment were predictive of NIP. Patients who developed NIP had a significantly longer time on treatment (median 4.1 vs 2 months) and overall survival (OS) (median 15.4 vs 7.4 months). NIP was a predictor of improved OS by multivariate analysis. CONCLUSIONS: There was an increased incidence of NIP in everolimus-treated patients. Improved OS in patients who developed NIP is an intriguing finding and should be further investigated. Given the incidence, morbidity, and outcomes seen in patients on everolimus who develop NIP, management should include proactive monitoring and treatment of NIP with the goal of preserving mTOR inhibitor therapy. PMID- 24053123 TI - Tunable electronic coupling and driving force in structurally well-defined tetracene dimers for molecular singlet fission: a computational exploration using density functional theory. AB - Singlet fission (SF), a process by which two excited states are formed in a chromophoric system following the absorption of a single photon, has the potential to increase the theoretical efficiency of solar energy conversion devices beyond the single-junction Shockley-Quiesser limit. Although SF is observed with high yield in the solid state of certain molecules, linearly linked dimers based on these same constituents exhibit small yields in part due to small interchromophore electronic coupling. Previous work from our group demonstrated enhancement of SF yield in polycrystalline tetracene (Tc) via excitation of intermolecular motions, which increased direct overlap of monomer pi-systems. In this current work, a series of norbornyl-bridged bistetracene (BT) dimers are investigated using DFT and the ability to control SF thermodynamics along with important interchromophore electronic coupling parameters via bridging geometry is shown. Although the electronic coupling of a series of C2v-symmetric dimers (BT1-BT3) that differ in norbornyl bridge length is larger than in previously studied Tc dimers, a key nonhorizontal electron-transfer (ET) matrix element used in determining the SF rate is zero due to symmetry. In these systems, SF may be expected but electronic excitation will require coupling to vibrational modes that break symmetry. Singly bridged dimer isomers BT1-trans and BT1-cis, which break the C2v symmetry of BT1 by exploiting attachment of the norbornyl bridge at the 1,2 instead of the 2,3 Tc positions, are expected to be significantly more favorable for SF due to an exoergic driving force, increased electronic coupling, a lower charge-transfer-state energy (particularly in the case of BT1-cis), and nonhorizontal ET matrix elements that are nonzero. PMID- 24053122 TI - Decreased striatal dopamine in group II metabotropic glutamate receptor (mGlu2/mGlu3) double knockout mice. AB - BACKGROUND: Group II metabotropic glutamate receptors (mGlu2 and mGlu3, encoded by Grm2 and Grm3) have been the focus of attention as treatment targets for a number of psychiatric conditions. Double knockout mice lacking mGlu2 and mGlu3 (mGlu2/3-/-) show a subtle behavioural phenotype, being hypoactive under basal conditions and in response to amphetamine, and with a spatial memory deficit that depends on the arousal properties of the task. The neurochemical correlates of this profile are unknown. Here, we measured tissue levels of dopamine, 5-HT, noradrenaline and their metabolites in the striatum and frontal cortex of mGlu2/3 /- double knockout mice, using high performance liquid chromatography. We also measured the same parameters in mGlu2-/- and mGlu3-/- single knockout mice. RESULTS: mGlu2/3-/-mice had reduced dopamine levels in the striatum but not in frontal cortex, compared to wild-types. In a separate cohort we replicated this deficit and, using tissue punches, found it was more prominent in the nucleus accumbens than in dorsolateral striatum. Noradrenaline, 5-HT and their metabolites were not altered in the striatum of mGlu2/3-/- mice, although the noradrenaline metabolite MHPG was increased in the cortex. In mGlu2-/- and mGlu3 /- single knockout mice we found no difference in any monoamine or metabolite, in either brain region, compared to their wild-type littermates. CONCLUSIONS: Group II metabotropic glutamate receptors impact upon striatal dopamine. The effect may contribute to the behavioural phenotype of mGlu2/3-/- mice. The lack of dopaminergic alterations in mGlu2-/- and mGlu3-/- single knockout mice reveals a degree of redundancy between the two receptors. The findings support the possibility that interactions between mGlu2/3 and dopamine may be relevant to the pathophysiology and therapy of schizophrenia and other disorders. PMID- 24053121 TI - Declining burden of malaria over two decades in a rural community of Muheza district, north-eastern Tanzania. AB - BACKGROUND: The recently reported declining burden of malaria in some African countries has been attributed to scaling-up of different interventions although in some areas, these changes started before implementation of major interventions. This study assessed the long-term trends of malaria burden for 20 years (1992-2012) in Magoda and for 15 years in Mpapayu village of Muheza district, north-eastern Tanzania, in relation to different interventions as well as changing national malaria control policies. METHODS: Repeated cross-sectional surveys recruited individuals aged 0 - 19 years from the two villages whereby blood smears were collected for detection of malaria parasites by microscopy. Prevalence of Plasmodium falciparum infections and other indices of malaria burden (prevalence of anaemia, splenomegaly and gametocytes) were compared across the years and between the study villages. Major interventions deployed including a mobile clinic, bed nets and other research activities, and changes in national malaria control policies were also marked. RESULTS: In Magoda, the prevalence of P. falciparum infections initially decreased between 1992 and 1996 (from 83.5 to 62.0%), stabilized between 1996 and 1997, and further declined to 34.4% in 2004. A temporary increase between 2004 and 2008 was followed by a progressive decline to 7.2% in 2012, which is more than 10-fold decrease since 1992. In Mpapayu (from 1998), the highest prevalence was 81.5% in 1999 and it decreased to 25% in 2004. After a slight increase in 2008, a steady decline followed, reaching <5% from 2011 onwards. Bed net usage was high in both villages from 1999 to 2004 (>=88%) but it decreased between 2008 and 2012 (range, 28% - 68%). After adjusting for the effects of bed nets, age, fever and year of study, the risk of P. falciparum infections decreased significantly by >=97% in both villages between 1999 and 2012 (p < 0.001). The prevalence of splenomegaly (>40% to <1%) and gametocytes (23% to <1%) also decreased in both villages. DISCUSSION AND CONCLUSIONS: A remarkable decline in the burden of malaria occurred between 1992 and 2012 and the initial decline (1992 - 2004) was most likely due to deployment of interventions, such as bed nets, and better services through research activities. Apart from changes of drug policies, the steady decline observed from 2008 occurred when bed net coverage was low suggesting that other factors contributed to the most recent pattern. These results suggest that continued monitoring is required to determine causes of the changing malaria epidemiology and also to monitor the progress towards maintaining low malaria transmission and reaching related millennium development goals. PMID- 24053124 TI - Analysis of oncological outcomes and renal function after laparoendoscopic single site (LESS) partial nephrectomy: a multi-institutional outcome analysis. AB - OBJECTIVE: To report on a large multi-institutional series of laparoendoscopic single-site (LESS) partial nephrectomy (PN) and analyse renal function and short term oncological outcomes. MATERIAL AND METHODS: We conducted a retrospective analysis of consecutive cases of LESS-PN performed between November 2007 and March 2012 at 11 participating institutions. Demographic data and data on the main peri-operative outcomes and complications were gathered and analysed. Kidney function was evaluated by measuring serum creatinine concentration and estimated glomerular filtration rate (eGFR). Chronic kidney disease was defined in stages for each patient according to the National Kidney Foundation, Kidney Disease Outcomes Quality Initiative. RESULTS: A total of 190 cases were included in this analysis. The mean renal tumour size was 2.6 cm, and the mean PADUA score was 7.2. The median operating time was 170 min with a median estimated blood loss of 150 mL. A clampless technique was used in 70 cases (36.8%) and the median warm ischaemia time (WIT) was 16.5 min. PADUA score independently predicted the length of WIT (low vs high score: odds ratio 5.11, CI 1.50-17.41, P = 0.009; intermediate vs high score: odds ratio 5.13, CI 1.56-16.88, P = 0.007). The overall postoperative complication rate was 14.7%. Where a clamping technique was used, a significant increase in serum creatinine concentration and a significant decrease in eGFR were observed postoperatively and at 6 months. On multivariate analysis PADUA score was the only predicting factor. Overall survival rates were 99, 97 and 88% at 12-, 24- and 36-month follow-up, respectively, while disease free survival rates were 98% at 12-month and 97% at 24- and 36-month follow-up. CONCLUSION: The study showed that LESS-PN is effective in terms of renal function preservation and oncological control at short- and intermediate-term follow-up. PMID- 24053125 TI - Dendritic fibromyxolipoma in the right inguinal and perineum regions: a case report and review of the literature. AB - A 32-year-old woman presented with a slow-growing, painless, subcutaneous lesion in the right inguinal and perineum regions. The mass was 24.0 cm * 10.5 cm * 5.0 cm in size, well circumscribed, mobile, and rubbery. Microscopically, the resected mass was mainly composed by a proliferation of small spindle or stellate cells, variably admixed with mature adipose tissue, embedded within an abundant myxoid and collagenized stroma. Immunohistochemically, the spindle and stellate cells were strongly positive for vimentin, CD34, and bcl-2 antibodies but not for smooth muscle actin and desmin. The tumor was diagnosed as dendritic fibromyxolipoma based on the typical findings of histology and immunohistochemistry. Clinical follow-up of 9 months after surgery revealed no evidence of recurrence. We report the first case of dendritic fibromyxolipoma in the right inguinal and perineum regions and discuss the different diagnosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1313680868103019. PMID- 24053128 TI - Population-based analysis of prostate-specific antigen (PSA) screening in younger men (<55 years) in Australia. AB - OBJECTIVE: To analyse the trends in opportunistic PSA screening in Australia, focusing on younger men (<55 years of age), to examine the effects of this screening on transrectal ultrasonography (TRUS)-guided biopsy rates and to determine the nature of prostate cancers (PCas) being detected. SUBJECTS AND METHODS: All men who received an opportunistic screening PSA test and TRUS-guided biopsy between 2001 and 2008 in Australia were analysed using data from the Australian Cancer registry (Australian Institute of Health and Welfare) and Medicare databases. The Victorian cancer registry was used to obtain Gleason scores. Age-standardized and age-specific rates were calculated, along with the incidence of PCa, and correlated with Gleason scores. RESULTS: A total 5 174 031 PSA tests detected 128 167 PCas in the period 2001-2008. During this period, PSA testing increased by 146% (a mean of 4629 tests per 100 000 men annually), with 80 and 59% increases in the rates of TRUS-guided biopsy and incidence of PCa, respectively. The highest increases in PSA screening occurred in men <55 years old and up to 1101 men had to be screened to detect one incident case of PCa (0.01%). Screening resulted in two thirds of men aged <55 years receiving a negative TRUS biopsy. There was no correlation with Gleason >7 tumours in patients aged <55 years. CONCLUSION: Despite the ongoing controversy about the merits of PCa screening, there was an increase in PSA testing, especially in men <55 years old, leading to a modestly higher incidence of PCa in Australia. Overall, PSA screening was associated with high rates of negative TRUS-biopsy and the detection of low/intermediate grade PCa among younger patients. PMID- 24053129 TI - A nationwide survey of nurses' attitudes toward music therapy and their need for education in its application. AB - BACKGROUND: Music therapy is increasingly used to help heal patients. However, there is a significant gap in the literature about nurses' attitudes toward and need for education in music therapy for nursing practice. This cross-sectional study was conducted to describe nurses' attitudes toward music therapy and determine their need for education in music therapy. METHODS: Participants included 1,197 nurses who were recruited from hospitals in different regions of Taiwan. RESULTS: Participants expressed positive attitudes toward music therapy. Most participants were willing to learn about music therapy. "Skill in using musical instruments" was the most frequently identified educational need. Further study of the discrepancy between the attitudes toward "performing music therapy" and "learning music therapy" is needed to clarify why nurses expected that they would receive no support for attending music therapy education. CONCLUSION: Given participants' attitudes toward music therapy and their motivation for learning, nursing administrators and educators may consider developing policies to further the advancement of music therapy in educational programs and practice. PMID- 24053126 TI - HypoxamiR regulation and function in ischemic cardiovascular diseases. AB - SIGNIFICANCE: MicroRNAs (miRNAs) are deregulated and play a causal role in numerous cardiovascular diseases, including myocardial infarction, coronary artery disease, hypertension, heart failure, stroke, peripheral artery disease, kidney ischemia-reperfusion. RECENT ADVANCES: One crucial component of ischemic cardiovascular diseases is represented by hypoxia. Indeed, hypoxia is a powerful stimulus regulating the expression of a specific subset of miRNAs, named hypoxia induced miRNAs (hypoxamiR). These miRNAs are fundamental regulators of the cell responses to decreased oxygen tension. Certain hypoxamiRs seem to have a particularly pervasive role, such as miR-210 that is virtually induced in all ischemic diseases tested so far. However, its specific function may change according to the physiopathological context. CRITICAL ISSUES: The discovery of HypoxamiR dates back 6 years. Thus, despite a rapid growth in knowledge and attention, a deeper insight of the molecular mechanisms underpinning hypoxamiR regulation and function is needed. FUTURE DIRECTIONS: An extended understanding of the function of hypoxamiR in gene regulatory networks associated with cardiovascular diseases will allow the identification of novel molecular mechanisms of disease and indicate the development of innovative therapeutic approaches. PMID- 24053130 TI - Concept mapping in a critical care orientation program: a pilot study to develop critical thinking and decision-making skills in novice nurses. AB - BACKGROUND: Newly graduated registered nurses who were hired into a critical care intensive care unit showed a lack of critical thinking skills to inform their clinical decision-making abilities. METHODS: This study evaluated the effectiveness of concept mapping as a teaching tool to improve critical thinking and clinical decision-making skills in novice nurses. A self-evaluation tool was administered before and after the learning intervention. RESULTS: The 25-item tool measured five key indicators of the development of critical thinking skills: problem recognition, clinical decision-making, prioritization, clinical implementation, and reflection. Statistically significant improvements were seen in 10 items encompassing all five indicators. CONCLUSION: Concept maps are an effective tool for educators to use in assisting novice nurses to develop their critical thinking and clinical decision-making skills. PMID- 24053127 TI - Calcarea carbonica induces apoptosis in cancer cells in p53-dependent manner via an immuno-modulatory circuit. AB - BACKGROUND: Complementary medicines, including homeopathy, are used by many patients with cancer, usually alongside with conventional treatment. However, the molecular mechanisms underneath the anti-cancer effect, if any, of these medicines have still remained unexplored. To this end we attempted to evaluate the efficacy of calcarea carbonica, a homeopathic medicine, as an anti-cancer agent and to delineate the detail molecular mechanism(s) underlying calcerea carbonica-induced tumor regression. METHODS: To investigate and delineate the underlying mechanisms of calcarea carbonica-induced tumor regression, Trypan blue dye-exclusion test, flow cytometric, Western blot and reverse transcriptase-PCR techniques were employed. Further, siRNA transfections and inhibitor studies were used to validate the involvement of p53 pathway in calcarea carbonica-induced apoptosis in cancer cells. RESULTS: Interestingly, although calcarea carbonica administration to Ehrlich's ascites carcinoma (EAC)- and Sarcoma-180 (S-180) bearing Swiss albino mice resulted in 30-35% tumor cell apoptosis, it failed to induce any significant cell death in ex vivo conditions. These results prompted us to examine whether calcarea carbonica employs the immuno-modulatory circuit in asserting its anti-tumor effects. Calcarea carbonica prevented tumor-induced loss of effector T cell repertoire, reversed type-2 cytokine bias and attenuated tumor induced inhibition of T cell proliferation in tumor-bearing host. To confirm the role of immune system in calcarea carbonica-induced cancer cell death, a battery of cancer cells were co-cultured with calcarea carbonica-primed T cells. Our results indicated a "two-step" mechanism of the induction of apoptosis in tumor cells by calcarea carbonica i.e., (1) activation of the immune system of the host; and (2) induction of cancer cell apoptosis via immuno-modulatory circuit in p53-dependent manner by down-regulating Bcl-2:Bax ratio. Bax up-regulation resulted in mitochondrial transmembrane potential loss and cytochrome c release followed by activation of caspase cascade. Knocking out of p53 by RNA interference inhibited calcarea carbonica-induced apoptosis thereby confirming the contribution of p53. CONCLUSION: These observations delineate the significance of immuno-modulatory circuit during calcarea carbonica-mediated tumor apoptosis. The molecular mechanism identified may serve as a platform for involving calcarea carbonica into immunotherapeutic strategies for effective tumor regression. PMID- 24053131 TI - Elucidation of the selectivity of proton-dependent electrocatalytic CO2 reduction by fac-Re(bpy)(CO)3Cl. AB - A complete mechanism for the proton-dependent electrocatalytic reduction of CO2 to CO by fac-Re(bpy)(CO)3Cl that is consistent with experimental observations has been developed using first principles quantum chemistry. Calculated one-electron reduction potentials, nonaqueous pKa's, reaction free energies, and reaction barrier heights provide deep insight into the complex mechanism for CO2 reduction as well as the origin of selectivity for this catalyst. Protonation and then reduction of a metastable Re-CO2 intermediate anion precedes Bronsted-acid catalyzed C-O cleavage and then rapid release of CO at negative applied potentials. Conceptually understanding the mechanism of this rapid catalytic process provides a useful blueprint for future work in artificial photosynthesis. PMID- 24053132 TI - Noninvasive measurement of alkaline phosphatase activity in embryoid bodies and coculture spheroids with scanning electrochemical microscopy. AB - Alkaline phosphatase (ALP) is an enzyme commonly used as an undifferentiated marker of embryonic stem cells (ESCs). Although noninvasive ALP detection has long been desired for stem cell research and in cell transplantation therapy, little progress has been made in developing such techniques. In this study, we propose a noninvasive evaluation method for detecting ALP activity in mouse embryoid bodies (mEBs) using scanning electrochemical microscopy (SECM). SECM has several advantages, including being noninvasive, nonlabeled, quantitative, and highly sensitive. First, we found that SECM-based ALP evaluation permits the comparison of ALP activity among mEBs of different sizes by monitoring the p aminophenol (PAP) production rate in aqueous solution containing p aminophenylphosphate (PAPP) normal to the surface area of each sample. Second, coculture spheroids, consisting of mEB and MCF-7 cells for the core and the concentric outer layer, respectively, were prepared as model samples showing heterogeneous ALP activities. The overall PAP production rate dramatically declined in the presence of the MCF-7 cell outer layer, which blocked the mass transfer of PAPP to inner mEB. This result indicated that the SECM response mainly originated from ALP located at the surface of the cellular aggregate, including mEBs and coculture spheroids. Third, taking advantage of the noninvasive nature of SECM, we examined the relevance of ALP activity and cardiomyocyte differentiation. Collectively, these results suggested that noninvasive SECM-based ALP activity normalized by the sample surface enables the selection of EBs with a higher potential to differentiate into cardiomyocytes, which can contribute toward various types of stem cell research. PMID- 24053133 TI - Infrared multiple photon dissociation action spectroscopy of deprotonated RNA mononucleotides: gas-phase conformations and energetics. AB - The IRMPD action spectra of the deprotonated forms of the four common RNA mononucleotides, adenosine-5'-monophosphate (A5'p), guanosine-5'-monophosphate (G5'p), cytidine-5'-monophosphate (C5'p), and uridine-5'-monophosphate (U5'p), are measured to probe their gas-phase structures. The IRMPD action spectra of all four deprotonated RNA mononucleotides exhibit distinct IR signatures in the frequency region investigated, 570-1900 cm(-1), that allows these deprotonated mononucleotides to be easily differentiated from one other. Comparison of the measured IRMPD action spectra to the linear IR spectra calculated at the B3LYP/6 31+G(d,p) level of theory finds that the most stable conformations of the deprotonated forms of A5'p, C5'p, and U5'p are accessed in the experiments, and these conformers adopt the C3' endo conformation of the ribose moiety and the anti conformation of the nucleobase. In the case of deprotonated G5'p, the most stable conformer is also accessed in the experiments. However, the ground-state conformer differs from the other three deprotonated RNA mononucleotides in that it adopts the syn rather than anti conformation for the nucleobase. Present results are compared to results previously obtained for the deprotonated forms of the four common DNA mononucleotides to examine the fundamental conformational differences between these species, and thus elucidate the effects of the 2' hydroxyl group on their structure, stability, and fragmentation behavior. PMID- 24053134 TI - Mesenchymal glucocorticoid receptor regulates the development of multiple cell layers of the mouse lung. AB - Endogenous glucocorticoid (GC) hormones, signaling via the GC receptor (GR), are essential for normal lung development, and synthetic GCs are routinely used to treat respiratory disorders of very preterm babies. Germline GR knockout (GR(-/ )) mice show immature lung morphology and severe lung cellular hyperplasia during embryogenesis and die at birth due to respiratory failure. Two recent studies have reported contradictory results regarding the necessity for GR expression in specific lung germ layers during respiratory maturation. We further investigate in detail the lung phenotype in mice with a conditional deletion of GR in the endothelium, mesenchyme, and lung epithelium. We show that loss of GR in the mesenchyme alone produces a retarded lung phenotype almost identical to that of germline GR(-/-) mice, including severe postnatal lethality and lung cell hyperplasia. Loss of GR in lung epithelial cells and the endothelium had no gross effect on survival or lung morphology, but loss of epithelial GR caused increased cell proliferation in multiple compartments. Mesenchymal GR loss also produced increased epithelial cell proliferation, implying the existence of GC-regulated germ layer cross-talk. Protein levels of GR-mediated cell cycle regulators, including the cyclin-dependent kinase inhibitor p21(CIP1) and the growth factor midkine, were unaffected by mesenchymal GR deletion, yet expression of the extracellular matrix proteoglycan versican was up-regulated in the distal lung on loss of mesenchymal GR. These results show that GR-mediated signaling from the mesenchyme regulates respiratory maturation and ultimately survival at birth and that a key GR-repressed transcriptional target in lung mesenchymal cells is versican. PMID- 24053136 TI - Taenia ovis infection and its control: a Canadian perspective. AB - Distributed worldwide, Taenia ovis infection is responsible for the condemnation of sheep carcasses in many countries. This review highlights the programme used in New Zealand to successfully control T. ovis in sheep, and discusses how similar approaches may be modified for use in Canada, given what is currently known about the epidemiology of T. ovis. The lifecycle of the parasite is well known, involving dogs as the definitive host and sheep or goats as the intermediate host. An effective vaccine does exist, although it is not presently commercially available. In New Zealand an industry-based, non-regulatory programme was created to educate producers about T. ovis and necessary control strategies, including the need to treat farm dogs with cestocides regularly. This programme resulted in a substantial decrease in the prevalence of T. ovis infections between 1991 and 2012. Historically, T. ovis was not a concern for the Canadian sheep industry, but more recently the percentage of lamb condemnations due to T. ovis has increased from 1.5% in 2006 to 55% in 2012. It has been suggested that coyotes may be transmitting T. ovis, but this has not been confirmed. Recommendation are made for the Canadian sheep industry to adopt a control programme similar to that used in New Zealand in order to reduce the prevalence of T. ovis infection. PMID- 24053135 TI - The male advantage in child facial resemblance detection: behavioral and ERP evidence. AB - Males have been suggested to have advantages over females in reactions to child facial resemblance, which reflects the evolutionary pressure on males to solve the adaptive paternal uncertainty problem and to identify biological offspring. However, previous studies showed inconsistent results and the male advantage in child facial resemblance perception, as a kin detection mechanism, is still unclear. Here, we investigated the behavioral and brain mechanisms underlying the self-resembling faces processing and how it interacts with sex and age using event-related potential (ERP) technique. The results showed a stable male advantage in self-resembling child faces processing, such that males have higher detectability to self-resembling child faces than females. For ERP results, males showed smaller N2 and larger late positive component (LPC) amplitudes for self resembling child faces, which may reflect face-matching and self-referential processing in kin detection, respectively. Further source analysis showed that the N2 component and LPC were originated from the anterior cingulate cortex and medial frontal gyrus, respectively. Our results support the male advantage in self-resembling child detection and further indicate that such distinctions can be found in both early and late processing stages in the brain at different regions. PMID- 24053138 TI - Prediction of chromatographic retention time in high-resolution anti-doping screening data using artificial neural networks. AB - The computational generation of gradient retention time data for retrospective detection of suspected sports doping species in postanalysis human urine sample data is presented herein. Retention data for a selection of 86 compounds included in the London 2012 Olympic and Paralympic Games drug testing schedule were used to train, verify, and test a range of computational models for this purpose. Spiked urine samples were analyzed using solid phase extraction followed by ultrahigh-pressure gradient liquid chromatography coupled to electrospray ionization high-resolution mass spectrometry. Most analyte retention times varied <=0.2 min over the relatively short runtime of 10 min. Predicted retention times were within 0.5 min of experimental values for 12 out of 15 blind test compounds (largest error: 0.97 min). Minimizing the variance in predictive ability across replicate networks of identical architecture is presented for the first time along with a quantitative discussion of the contribution of each selected molecular descriptor toward the overall predicted value. The performance of neural computing predictions for isobaric compound retention time is also discussed. This work presents the application of neural networks to the prediction of gradient retention time in archived high-resolution urine analysis sample data for the first time in the field of anti-doping. PMID- 24053139 TI - Exclusive photothermal heat generation by a gadolinium bis(naphthalocyanine) complex and inclusion into modified high-density lipoprotein nanocarriers for therapeutic applications. AB - A hydrophobic gadolinium bis(naphthalocyanine) sandwich complex (GdSand) possessing several absorbances across visible and infrared wavelengths (up to 2500 nm) was solubilized in aqueous solution by uptake into a nascent mutant high density lipoprotein (HDL) nanocarrier. The HDL nanocarrier was additionally functionalized with a trans-activator of transcription peptide sequence to promote efficient cell penetration of the drug delivery system (cpHDL). The dye loaded nanocarrier (GdSand@cpHDL) exhibited photothermal heat generation properties upon irradiation with near-infrared (NIR) laser light, with controllable heat generation abilities as a function of the incident laser light power. Comparison of the photothermal behavior of the dyes GdSand and the well explored molecular photothermal agent indocyanine green (ICG) in the cpHDL nanocarrier (i.e., ICG@cpHDL) revealed two significant advantages of GdSand@cpHDL: (1) the ability to maintain elevated temperatures upon light absorption for extended periods of time, with a reduced degree of self destruction of the dye, and (2) exclusive photothermal heat generation with no detectable singlet oxygen production leading to improved integrity of the cpHDL nanocarrier after irradiation. Finally, GdSand@cpHDL was successfully subjected to an in vitro study against NCI-H460 human lung cancer cells, demonstrating the proof-of-principle utility of lanthanide sandwich complexes in photothermal therapeutic applications. PMID- 24053141 TI - Influence of lycopene on cell viability, cell cycle, and apoptosis of human prostate cancer and benign hyperplastic cells. AB - Prostate cancer is the most common malignancy in men and the second leading cause of cancer-related mortality in men of the Western world. Lycopene has received attention because of its expcted potential to prevent cancer. In the present study, we evaluated the influence of lycopene on cell viability, cell cycle, and apoptosis of human prostate cancer cells and benign prostate hyperplastic cells. Using MTT assay, we observed a decrease of cell viability in all cancer cell lines after treatment with lycopene, which decreased the percentage of cells in G0/G1 phase and increased in S and G2/M phases after 96 h of treatment in metastatic prostate cancer cell lineages. Flow citometry analysis of cell cycle revealed lycopene promoted cell cycle arrest in G0/G1 phase after 48 and 96 h of treatment in a primary cancer cell line. Using real time PCR assay, lycopene also induced apoptosis in prostate cancer cells with altered gene expression of Bax and Bcl-2. No effect was observed in benign prostate hyperplasia cells. These results suggest an effect of lycopene on activity of human prostate cancer cells. PMID- 24053142 TI - A new strategy and its effect on adherence to intermittent preventive treatment of malaria in pregnancy in Uganda. AB - BACKGROUND: Few women in Uganda access intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP). Previous studies have shown that high costs, frequent stock-out of drugs, supplies and poor quality of care are the greatest hindrance for women to access health services. In order to increase adherence to IPTp, we conceptualised an intervention that offset delivery care costs through providing a mama kit, created awareness on health benefits of IPTp and built trust between the provider and the client. METHODS: The new strategy was conceived along four constructs namely: 1) creating awareness by training midwives to explain the benefits of SP and the importance of adhering to the two doses of SP as IPTp to all pregnant women who attended ANC and consented to the study. Midwives were trained for two days in customer care and to provide a friendly environment. The pregnant women were also informed of the benefits of attending ANC and delivering at health facilities. 2) Each woman was promised a mama kit during ANC; 3) trust was built by showing the mama kit to each woman and branding it with her name; 4) keeping the promise by providing the mama kit when women came to deliver. The strategy to increase adherence to two doses of SP and encourage women to deliver at health facilities was implemented at two health facilities in Mukono district (Kawolo hospital and Mukono health centre IV). The inclusion criteria were women who: i) consented to the study and ii) were in the second trimester of pregnancy. All pregnant women in the second trimester (4-6 months gestation) who attended ANC and consented to participate in the study were informed of the benefits of SP, the importance of delivering at health facilities, were advised to attend the scheduled visits, promised a mama kit and ensured the kit was available at delivery. The primary outcome was the proportion of pregnant women adhering to a two dose SP regimen. RESULTS: A total of 2,276 women received the first dose of SP and 1,656 (72.8%) came back for the second dose. 1,069 women were involved in the evaluation (384 had participated in the intervention while 685 had not). The main reasons that enabled those who participated in the intervention to adhere to the two doses of IPTp and deliver at the study facilities were: an explanation provided on the benefits of IPTp and delivering at health facilities (25.1%), availability of a mama kit at delivery (24.6%), kind midwives (19.8%) and fearing complications of pregnancy (8.5%). Overall, 78.0% of these women reported that they were influenced to adhere to IPTp by the intervention. In a multivariable regression, nearby facility, P = 0. 007, promising a mama kit, P = 0.002, kind midwives, P = 0.0001 and husbands' encouragement, P = 0.0001 were the significant factors influencing adherence to IPTp with SP. CONCLUSION: The new strategy was a good incentive for women to attend scheduled ANC visits, adhere to IPTp and deliver at the study facilities. Policy implications include the urgent need for developing a motivation package based on the Health-Trust Model to increase access and adherence to IPTp. PMID- 24053140 TI - Redox regulation of store-operated Ca2+ entry. AB - SIGNIFICANCE: Store-operated Ca2+ entry (SOCE) is a ubiquitous Ca2+ signaling mechanism triggered by Ca2+ depletion of the endoplasmic reticulum (ER) and by a variety of cellular stresses. Reactive oxygen species (ROS) are often concomitantly produced in response to these stresses, however, the relationship between redox signaling and SOCE is not completely understood. Various cardiovascular, neurological, and immune diseases are associated with alterations in both Ca2+ signaling and ROS production, and thus understanding this relationship has therapeutic implications. RECENT ADVANCES: Several reactive cysteine modifications in stromal interaction molecule (STIM) and Orai proteins comprising the core SOCE machinery were recently shown to modulate SOCE in a redox-dependent manner. Moreover, STIM1 and Orai1 expression levels may reciprocally regulate and be affected by responses to oxidative stress. ER proteins involved in oxidative protein folding have gained increased recognition as important sources of ROS, and the recent discovery of their accumulation in contact sites between the ER and mitochondria provides a further link between ROS production and intracellular Ca2+ handling. CRITICAL ISSUES AND FUTURE DIRECTIONS: Future research should aim to establish the complete set of SOCE controlling molecules, to determine their redox-sensitive residues, and to understand how intracellular Ca2+ stores dynamically respond to different types of stress. Mapping the precise nature and functional consequence of key redox sensitive components of the pre- and post-translational control of SOCE machinery and of proteins regulating ER calcium content will be pivotal in advancing our understanding of the complex cross-talk between redox and Ca2+ signaling. PMID- 24053143 TI - Myeloproliferative neoplasm with ETV6-ABL1 fusion: a case report and literature review. AB - ETV6-ABL1 is a rare gene fusion with oncogenic properties, reported so far in 28 patients presenting a variety of haematological malignancies associated with clinical outcome, including chronic myeloid leukaemia (CML), acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and chronic myeloproliferative neoplasm (cMPN). Here we report on a 46-year-old female who presented with Philadelphia negative CML, positive for the ETV6-ABL1 fusion. Whole genome screening carried out with oligonucleotide arrays showed a subtle loss at 12p13 and cryptic imbalances within the 9q34.3 region in a highly unstable genome. FISH mapping with custom BAC probes identified two breakpoints 5 Mb apart within the 9q34 region, together with a break at 12p13. While FISH with commercial BCR-ABL1 probes failed to detect any ABL1 changes, the ETV6 break apart probe conclusively identified the ETV6-ABL1 fusion thus determining the probe's role as the primary diagnostic FISH test for this chimeric oncogene. In addition, we confirm the association of the ETV6-ABL1 fusion with imatinib resistance reported so far in three other patients, while recording excellent response to the 2nd generation tyrosine kinase inhibitor (TKI) nilotinib. In summary, we highlight the value of ETV6 FISH as a diagnostic test and the therapy resistance of ETV6-ABL1 positive disorders to imatinib. PMID- 24053144 TI - Assessing malaria transmission in a low endemicity area of north-western Peru. AB - BACKGROUND: Where malaria endemicity is low, control programmes need increasingly sensitive tools for monitoring malaria transmission intensity (MTI) and to better define health priorities. A cross-sectional survey was conducted in a low endemicity area of the Peruvian north-western coast to assess the MTI using both molecular and serological tools. METHODS: Epidemiological, parasitological and serological data were collected from 2,667 individuals in three settlements of Bellavista district, in May 2010. Parasite infection was detected using microscopy and polymerase chain reaction (PCR). Antibodies to Plasmodium vivax merozoite surface protein-119 (PvMSP119) and to Plasmodium falciparum glutamate rich protein (PfGLURP) were detected by ELISA. Risk factors for exposure to malaria (seropositivity) were assessed by multivariate survey logistic regression models. Age-specific antibody prevalence of both P. falciparum and P. vivax were analysed using a previously published catalytic conversion model based on maximum likelihood for generating seroconversion rates (SCR). RESULTS: The overall parasite prevalence by microscopy and PCR were extremely low: 0.3 and 0.9%, respectively for P. vivax, and 0 and 0.04%, respectively for P. falciparum, while seroprevalence was much higher, 13.6% for P. vivax and 9.8% for P. falciparum. Settlement, age and occupation as moto-taxi driver during previous year were significantly associated with P. falciparum exposure, while age and distance to the water drain were associated with P. vivax exposure. Likelihood ratio tests supported age seroprevalence curves with two SCR for both P. vivax and P. falciparum indicating significant changes in the MTI over time. The SCR for PfGLURP was 19-fold lower after 2002 as compared to before (lambda1 = 0.022 versus lambda2 = 0.431), and the SCR for PvMSP119 was four-fold higher after 2006 as compared to before (lambda1 = 0.024 versus lambda2 = 0.006). CONCLUSION: Combining molecular and serological tools considerably enhanced the capacity of detecting current and past exposure to malaria infections and related risks factors in this very low endemicity area. This allowed for an improved characterization of the current human reservoir of infections, largely hidden and heterogeneous, as well as providing insights into recent changes in species specific MTIs. This approach will be of key importance for evaluating and monitoring future malaria elimination strategies. PMID- 24053145 TI - A new xinjiangchelyid turtle from the Middle Jurassic of Xinjiang, China and the evolution of the basipterygoid process in Mesozoic turtles. AB - BACKGROUND: Most turtles from the Middle and Late Jurassic of Asia are referred to the newly defined clade Xinjiangchelyidae, a group of mostly shell-based, generalized, small to mid-sized aquatic froms that are widely considered to represent the stem lineage of Cryptodira. Xinjiangchelyids provide us with great insights into the plesiomorphic anatomy of crown-cryptodires, the most diverse group of living turtles, and they are particularly relevant for understanding the origin and early divergence of the primary clades of extant turtles. RESULTS: Exceptionally complete new xinjiangchelyid material from the ?Qigu Formation of the Turpan Basin (Xinjiang Autonomous Province, China) provides new insights into the anatomy of this group and is assigned to Xinjiangchelys wusu n. sp. A phylogenetic analysis places Xinjiangchelys wusu n. sp. in a monophyletic polytomy with other xinjiangchelyids, including Xinjiangchelys junggarensis, X. radiplicatoides, X. levensis and X. latiens. However, the analysis supports the unorthodox, though tentative placement of xinjiangchelyids and sinemydids outside of crown-group Testudines. A particularly interesting new observation is that the skull of this xinjiangchelyid retains such primitive features as a reduced interpterygoid vacuity and basipterygoid processes. CONCLUSIONS: The homology of basipterygoid processes is confidently demonstrated based on a comprehensive review of the basicranial anatomy of Mesozoic turtles and a new nomenclatural system is introduced for the carotid canal system of turtles. The loss of the basipterygoid process and the bony enclosure of the carotid circulation system occurred a number of times independently during turtle evolution suggesting that the reinforcement of the basicranial region was essential for developing a rigid skull, thus paralleling the evolution of other amniote groups with massive skulls. PMID- 24053146 TI - Increased concentration of iodide in airway secretions is associated with reduced respiratory syncytial virus disease severity. AB - Recent studies have revealed that the human and nonrodent mammalian airway mucosa contains an oxidative host defense system. This three-component system consists of the hydrogen peroxide (H2O2)-producing enzymes dual oxidase (Duox)1 and Duox2, thiocyanate (SCN(-)), and secreted lactoperoxidase (LPO). The LPO-catalyzed reaction between H2O2 and SCN(-) yields the bactericidal hypothiocyanite (OSCN( )) in airway surface liquid (ASL). Although SCN(-) is the physiological substrate of LPO, the Duox/LPO/halide system can generate hypoiodous acid when the iodide (I(-)) concentration is elevated in ASL. Because hypoiodous acid, but not OSCN( ), inactivates respiratory syncytial virus (RSV) in cell culture, we used a lamb model of RSV to test whether potassium iodide (KI) could enhance this system in vivo. Newborn lambs received KI by intragastric gavage or were left untreated before intratracheal inoculation of RSV. KI treatment led to a 10-fold increase in ASL I(-) concentration, and this I(-) concentration was approximately 30-fold higher than that measured in the serum. Also, expiratory effort, gross lung lesions, and pulmonary expression of an RSV antigen and IL-8 were reduced in the KI-treated lambs as compared with nontreated control lambs. Inhibition of LPO activity significantly increased lesions, RSV mRNA, and antigen. Similar experiments in 3-week-old lambs demonstrated that KI administration was associated with reduced gross lesions, decreased RSV titers in bronchoalveolar lavage fluid, and reduced RSV antigen expression. Overall, these data indicate that high-dose KI supplementation can be used in vivo to lessen the severity of RSV infections, potentially through the augmentation of mucosal oxidative defenses. PMID- 24053147 TI - Dynamics of bone healing after osteotomy with piezosurgery or conventional drilling - histomorphometrical, immunohistochemical, and molecular analysis. AB - BACKGROUND: Piezosurgery is an osteotomy system used in medical and dental surgery. Many studies have proven clinical advantages of piezosurgery in terms of quality of cut, maneuverability, ease of use, and safety. However, few investigations have tested its superiority over the traditional osteotomy systems in terms of dynamics of bone healing. Therefore, the aim of this study was to evaluate the dynamics of bone healing after osteotomies with piezosurgery and to compare them with those associated to traditional bone drilling. METHODS: One hundred and ten rats were divided into two groups with 55 animals each. The animals were anesthetized and the tibiae were surgically exposed to create defects 2 mm in diameter by using piezosurgery (Piezo group) and conventional drilling (Drill group). Animals were sacrificed at 3, 7, 14, 30 and 60 days post surgery. Bone samples were collected and processed for histological, histomorphometrical, immunohistochemical, and molecular analysis. The histological analysis was performed at all time points (n = 8) whereas the histomorphometrical analysis was performed at 7, 14, 30 and 60 days post-surgery (n = 8). The immunolabeling was performed to detect Vascular Endothelial Growth Factor (VEGF), Caspase-3 (CAS-3), Osteoprotegerin (OPG), Receptor Activator of Nuclear Factor kappa-B Ligand (RANKL), and Osteocalcin (OC) at 3, 7, and 14 days (n = 3). For the molecular analysis, animals were sacrificed at 3, 7 and 14 days, total RNA was collected, and quantification of the expression of 21 genes related to BMP signaling, Wnt signaling, inflammation, osteogenenic and apoptotic pathways was performed by qRT-PCR (n = 5). RESULTS: Histologically and histomorphometrically, bone healing was similar in both groups with the exception of a slightly higher amount of newly formed bone observed at 30 days after piezosurgery (p < 0.05). Immunohistochemical and qRT-PCR analyses didn't detect significant differences in expression of all the proteins and most of the genes tested. CONCLUSIONS: Based on the results of our study we conclude that in a rat tibial bone defect model the bone healing dynamics after piezosurgery are comparable to those observed with conventional drilling. PMID- 24053149 TI - Plant proteolytic enzyme papain abrogates angiogenic activation of human umbilical vein endothelial cells (HUVEC) in vitro. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a key regulator of physiologic and pathogenic angiogenesis in diseases such as cancer and diabetic retinopathy. It is known that cysteine proteases from plants, like bromelain and papain are capable to suppress inflammatory activation. Recent studies have demonstrated that they may interfere with angiogenesis related pathways as well. The aim of this study was to investigate the anti-angiogenic effects of papain on human umbilical vein endothelial cells (HUVEC) in vitro. METHODS: Cell viability after prolonged treatment with papain was investigated by life cell staining and lactate dehydrogenase release assay. Angiogenic activation was assessed by ELISA against phosphorylated proteins AKT, MEK1/2, ERK1/2, SAPK/JNK and p38-MAPK. Growth inhibition was determined by means of an MTT-assay and cell migration by means of a scratch assay. Capability to form a capillary network was investigated using a tube formation assay. RESULTS: Papain did not induce proteolysis or cell detachment of HUVEC in a concentration range between 0 and 25 MUg/mL. Four hours treatment with 10 MUg/mL papain resulted in a reduced susceptibility of endothelial cells to activation by VEGF as determined by phosphorylation levels of Akt, MEK1/2, SAPK/JNK. Papain exerted a distinct inhibitory effect on cell growth, cell migration and tube formation with inhibition of tube formation detectable at concentrations as low as 1 MUg/mL. Bromelain and ficin displayed similar effects with regard to cell growth and tube formation. CONCLUSION: Papain showed a strong anti-angiogenic effect in VEGF activated HUVEC. This effect may be due to interference with AKT, MEK1/2 and SAPK/JNK phosphorylation. Two other plant derived cysteine proteases displayed similar inhibition of HUVEC cell growth and tube formation. These findings indicate that plant proteolytic enzymes may have potential as preventive and therapeutic agents against angiogenesis related human diseases. PMID- 24053148 TI - Effects of simultaneously performed cognitive and physical training in older adults. AB - BACKGROUND: While many studies confirm the positive effect of cognitive and physical training on cognitive performance of older adults, only little is known about the effects of simultaneously performed cognitive and physical training. In the current study, older adults simultaneously performed a verbal working memory and a cardiovascular training to improve cognitive and motor-cognitive dual task performance. Twenty training sessions of 30 minutes each were conducted over a period of ten weeks, with a test session before, in the middle, and after the training. Training gains were tested in measures of selective attention, paired associates learning, executive control, reasoning, memory span, information processing speed, and motor-cognitive dual task performance in the form of walking and simultaneously performing a working memory task. RESULTS: Sixty-three participants with a mean age of 71.8 +/- 4.9 years (range 65 to 84) either performed the simultaneous training (N = 21), performed a single working memory training (N = 16), or attended no training at all (N = 26). The results indicate similar training progress and larger improvements in the executive control task for both training groups when compared to the passive control group. In addition, the simultaneous training resulted in larger improvements compared to the single cognitive training in the paired-associates task and was able to reduce the step to-step variability during the motor-cognitive dual task when compared to the single cognitive training and the passive control group. CONCLUSIONS: The simultaneous training of cognitive and physical abilities presents a promising training concept to improve cognitive and motor-cognitive dual task performance, offering greater potential on daily life functioning, which usually involves the recruitment of multiple abilities and resources rather than a single one. PMID- 24053150 TI - Clinical trial risk in castration-resistant prostate cancer: immunotherapies show promise. AB - OBJECTIVES: To determine the risk of failure during drug development in castration-resistant prostate cancer (CRPC) and to identify factors that could improve outcomes. METHODS: We investigated CRPC by analysing compounds in phase I to phase III clinical trials between 1998 and April 2011. Drug development failures were classified as medical or commercial and were compared with industry expectations. Compounds were excluded from analysis if their phase I occurred before 1998, if they targeted patients that were did not have hormone-refractory prostate cancer, or if they did not assess outcomes such as overall survival, time to disease progression, or prostate-specific antigen levels. RESULTS: Thorough searches of clinicaltrial.gov and other databases yielded 77 compounds that met the inclusion criteria. The cumulative pass rate for first-line compounds in CRPC was 3% and was far below aggregate industry expectations. In total, there were nearly equivalent numbers of commercial and medical failures. Biological products were found to have had greater relative success than small molecule drugs and biotechnology firms had been slightly more successful than pharmaceutical firms in this disease indication. Phase III failures were high, despite equally high failures during phase II. CONCLUSIONS: Currently, one in 33 compounds that enters clinical testing will be awarded US Food and Drug Administration approval. This appears to be the highest risk indication investigated to date, based on clinical trial studies alone, with an average cost of $1.411bn to bring a new drug to market when adjusted for risk. Development of radical therapeutics such as immunotherapies may also be warranted instead of classic antineoplastic therapeutics. Given the high clinical trial risk, efforts may have to shift to biomarker and surrogate endpoints to manage future clinical trial risk in prostate cancer. PMID- 24053151 TI - Epidermal growth factor receptor-targeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis. AB - OBJECTIVE: To evaluate the safety and efficacy of epidermal growth factor receptor (EGFR)-targeted therapy in patients with advanced penile or scrotal cancer. PATIENTS AND METHODS: We retrospectively reviewed the charts of patients with penile or scrotal squamous cell carcinoma who had visited our tertiary cancer centre between 2002 and 2009, including their subsequent treatment and follow-up. We collected details of EGFR-targeted therapy and clinical outcomes. Treatment-associated time-to-disease-progression (TTP), overall survival (OS), responses to therapy and toxicity were evaluated. RESULTS: A total of 24 patients had received EGFR-targeted therapies, including cetuximab, erlotinib and gefitinib. The most common treatment given (to 67% of patients) was cetuximab combined with one or more cytotoxic drugs. The most common adverse effect was skin rash (71%). The median (range) TTP and OS were 11.3 (1-40) and 29.6 (2-205) weeks, respectively. The OS time for patients with visceral or bone metastases was significantly shorter than it was for those without (24.7 vs 49.9 weeks, P = 0.013). Among 17 patients treated with cetuximab alone or in combination with cisplatin, there were four partial responses (23.5%) including two patients with apparently chemotherapy-resistant tumours. CONCLUSIONS: Our results suggest that cetuximab has antitumour activity in metastatic penile cancer, and may enhance the effect of cisplatin-based chemotherapy. Prospective studies of EGFR-targeted therapies in men with these tumours are warranted. PMID- 24053152 TI - One-step conversion of 2-amino-N'-arylbenzamidines into 3-aryl-4-imino-3,4 dihydroquinazoline-2-carbonitriles using 4,5-dichloro-1,2,3-dithiazolium chloride. AB - 2-Amino-N'-arylbenzamidines react with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) in the presence of Hunig's base (2 equiv) to give in one step 3-aryl 4-imino-3,4-dihydroquinazoline-2-carbonitriles in 53-81% yields. Nine examples are presented along with the single-crystal X-ray structure of 4-imino-3-phenyl 3,4-dihydroquinazoline-2-carbonitrile. Furthermore, the behavior of the latter toward both acid and base hydrolysis is investigated. All new compounds are fully characterized, and a mechanistic rationale for the formation of the iminoquinazolines is provided. PMID- 24053153 TI - Prospective randomized trial of hexylaminolevulinate photodynamic-assisted transurethral resection of bladder tumour (TURBT) plus single-shot intravesical mitomycin C vs conventional white-light TURBT plus mitomycin C in newly presenting non-muscle-invasive bladder cancer. AB - OBJECTIVE: To determine if photodynamic 'blue-light'-assisted resection leads to lower recurrence rates in newly presenting non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: We conducted a prospective randomized trial of hexylaminolevulinate (HAL) photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumour (TURBT) plus single-shot intravesical mitomycin C vs standard white-light-assisted TURBT plus single-shot intravesical mitomycin C. A total of 249 patients with newly presenting suspected NMIBC enrolled at Guy's Hospital between March 2005 and April 2010. Patients with a history of bladder cancer were excluded. The surgery was performed by specialist bladder cancer surgical teams. Of the eligible patients, 90% agreed to be randomized. RESULTS: Of the 249 patients, 209 (84%) had cancer and in 185 patients (89%) the cancer was diagnosed as NMIBC. There were no adverse events related to HAL in any of the patients randomized to the intravesical HAL-PDD arm. Single-shot intravesical mitomycin C was administered to 61/97 patients (63%) in the HAL-PDD arm compared with 68/88 patients (77%) in the white-light arm (P = 0.04) Intravesical HAL was an effective diagnostic tool for occult carcinoma in situ (CIS). Secondary CIS was identified in 25/97 patients (26%) in the HAL-PDD arm compared with 12/88 patients (14%) in the white-light arm ((P = 0.04) There was no significant difference in recurrence between the two arms at 3 or 12 months: in the HAL-PDD and the white-light arms recurrence was found in 17/86 and 14/82 patients (20 vs 17%), respectively ((P = 0.7) at 3 months, and in 10/63 and 15/67 patients (16 vs 22%), respectively ((P = 0.4) at 12 months. CONCLUSIONS: Despite HAL-PDD offering a more accurate diagnostic assessment of a bladder tumour, in this trial we did not show that this led to lower recurrence rates of newly presenting NMIBC compared with the best current standard of care. PMID- 24053155 TI - Energy management using virtual reality improves 2000-m rowing performance. AB - Elite-standard rowers tend to use a fast-start strategy followed by an inverted parabolic-shaped speed profile in 2000-m races. This strategy is probably the best to manage energy resources during the race and maximise performance. This study investigated the use of virtual reality (VR) with novice rowers as a means to learn about energy management. Participants from an avatar group (n = 7) were instructed to track a virtual boat on a screen, whose speed was set individually to follow the appropriate to-be-learned speed profile. A control group (n = 8) followed an indoor training programme. In spite of similar physiological characteristics in the groups, the avatar group learned and maintained the required profile, resulting in an improved performance (i.e. a decrease in race duration), whereas the control group did not. These results suggest that VR is a means to learn an energy-related skill and improve performance. PMID- 24053154 TI - A multicomponent theory-based intervention improves uptake of pelvic floor muscle training before radical prostatectomy: a 'before and after' cohort study. AB - OBJECTIVE: To assess the effect of a multicomponent theory-based intervention, incorporating patient information guides, an evidence summary, audit and feedback processes and a provider directory, in the provision/receipt of preoperative pelvic floor muscle training (PFMT) among patients undergoing radical prostatectomy. SUBJECTS AND METHODS: Over an 18-month period (9 months before and 9 months after the intervention), we measured the provision/receipt of preoperative PFMT using surveys of patients undergoing radical prostatectomy at one public hospital (n = 32) and two private hospitals (n = 107) in Western Sydney, Australia, as well as practice audits of associated public sector (n = 4) and private sector (n = 2) providers of PFMT. Self-report urinary incontinence was assessed 3 months after radical prostatectomy using the International Consultation on Incontinence Questionnaire - Urinary Incontinence Form (ICIQ-UI Short Form). RESULTS: There was a significant increase in the proportion of survey respondents receiving preoperative PFMT post-intervention (post intervention: 42/58 respondents, 72% vs pre-intervention: 37/81 respondents, 46%, P = 0.002). There was a corresponding significant increase in provision of preoperative PFMT by private sector providers (mean [sd] post-intervention: 16.7 [3.7] patients/month vs pre-intervention: 12.1 [3.6] patients/month, P = 0.018). Respondents receiving preoperative PFMT had significantly better self-report urinary incontinence at 3 months after radical prostatectomy than those who did not receive preoperative PFMT (mean [sd] ICIQ-UI Short Form sum-scores: 6.2 [5.0] vs 9.2 [5.8], P = 0.002). CONCLUSIONS: The intervention increased the provision/receipt of preoperative PFMT among patients undergoing radical prostatectomy. Additional component strategies aimed at increasing the use of public sector providers may be necessary to further improve PFMT receipt among patients undergoing radical prostatectomy in the public hospital system. PMID- 24053156 TI - Microsurgical denervation of rat spermatic cord: safety and efficacy data. AB - OBJECTIVE: To describe a microsurgical technique for denervation of the spermatic cord and use of multiphoton microscopy (MPM) laser to identify and ablate residual nerves after microsurgical denervation. To evaluate structural and functional changes in the rat testis and vas deferens after denervation. MATERIALS AND METHODS: Nine Sprague-Dawley rats were divided into three experimental groups: sham, microsurgical denervation of the spermatic cord (MDSC), and MDSC immediately followed by laser ablation with MPM. At 2 months after surgery, we assessed testicular volume, functional circulation of the testicular artery with Doppler, patency of the vas deferens, and histology of the testis and vas deferens. RESULTS: There was a significant decrease in the median number of nerves remaining around the vas deferens with MDSC alone (3.5 nerves) or MDSC with MPM (1.5 nerves) compared with sham rats (15.5 nerves) (P = 0.003). Although, MDSC with MPM resulted in the fewest remaining nerves, this result was similar to MDSC alone (P = 0.29). No deleterious effects on spermatogenesis or vas patency were seen in the experimental groups when compared with the sham rats. CONCLUSION: A microsurgical approach can be used to effectively and safely denervate the rat spermatic cord with minimal changes to structure and function of the testis and vas deferens. MPM can be used as an adjunct to identify and ablate residual nerves after MDSC. PMID- 24053157 TI - Job tenure and work injuries: a multivariate analysis of the relation with previous experience and differences by age. AB - BACKGROUND: One of the consequences of the increasing flexibility in contemporary labour markets is that individuals change jobs more frequently than in the past. Indeed, in many cases, through collecting a lot of contracts, individuals work in the same economic sector or even in the same company, doing the same job in the same way as existing colleagues. A very long literature has established that newly hired workers--whatever the contract type--are more likely to be injured than those with longer job tenures. The objectives of this paper are: 1) to study the relationship between job tenure and injury risk taking into account past experience as a possible confounder; and 2) to evaluate how the effects of past experience and job tenure are modified by age. METHODS: Using a longitudinal national database, we considered only job contracts starting in 1998-2003 held by men working as blue collars or apprentices in the non-agricultural private sector. We calculated injury rates stratified by job tenure and age. Multivariate analyses were adjusted for background variables and previous experience accrued in the same economic sector of the current job. RESULTS: In the study period 58,271 workers who had experienced 10,260 injuries were observed. These people worked on 115,277 contracts in the six years observed (1.98 contracts per worker). Injury rates decrease with job tenure; the trend is the same in each age group; young workers have both the highest injury rate (9.20; CI 95%: 8.95-9.45) and the highest decrease with job tenure. Previous experience is associated with a decreasing injury rate in all age groups and for all job tenures. Multivariate analyses show that, even after checking for previous experience, workers with job tenure of less than 6 months show always higher relative risks compared with job tenure > 2 years: relative risk is 41% higher among under-thirty workers; it is 22% higher among people over forty. Previous experience is protective against injury risk in workers over thirty: after checking for all other variables, relative risk is lower in workers who have accumulated more than 5 years of experience. CONCLUSIONS: In a context in which career fragmentation is increasing, workers find themselves more and more in the "high risk" period and only individuals who are able to build their career with similar jobs may mitigate the higher risks thanks to their past experience. If institutions don't adopt appropriate prevention policies, injury risk is likely to increase, especially among young people. PMID- 24053158 TI - Identification of aberrant microRNA expression pattern in pediatric gliomas by microarray. AB - BACKGROUND: Brain tumor remains the leading cause of disease-related death in children. Many studies have focused on the complex biological process involved in pediatric brain tumors but little is know about the possible role of microRNAs in the genesis of these tumors. METHODS: In this study, we used a microRNA microarray assay to study the expression pattern of microRNAs in pediatric gliomas and matched normal tissues. RESULTS: We found 40 differentially expressed microRNAs, among which miR-1321, miR-513b, miR-769-3p were found be related to cancer genesis for the first time. The expression of selected microRNAs were then confirmed by qRT-PCR. Furthermore, GO and pathway analysis showed that the target genes of the 40 differentially expressed microRNAs were significantly enriched in nervous system-related and tumor-related biological processes and signaling pathways. Additionally, an apoptosis-related network of microRNA-mRNA interaction, representing the critical microRNAs and their targets, was constructed based on microRNA status. CONCLUSIONS: In the present study we identified the changed expression pattern of microRNAs in pediatric gliamas. Our study also provides a better understanding of pediatric brain tumor biology and may assist in the development of less toxic therapies and in the search for better markers for disease stratification. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1323049861105720. PMID- 24053159 TI - Design and application of an internal amplification control to improve Dehalococcoides mccartyi 16S rRNA gene enumeration by qPCR. AB - Dehalococcoides mccartyi (Dhc) strains are keystone bacteria for reductive dechlorination of chlorinated ethenes to nontoxic ethene in contaminated aquifers. Enumeration of Dhc biomarker genes using quantitative real-time PCR (qPCR) in groundwater is a key component of site assessment and bioremediation monitoring. Unfortunately, standardized qPCR procedures that recognize impaired measurements due to PCR inhibition, low template DNA concentrations, or analytical error are not available, thus limiting confidence in qPCR data. To improve contemporary approaches for enumerating Dhc in environmental samples, multiplex qPCR assays were designed to quantify the Dhc 16S rRNA gene and one of two different internal amplification controls (IACs): a modified Dhc 16S rRNA gene fragment (Dhc*) and the firefly luciferase gene luc. The Dhc* IAC exhibited competitive inhibition in qPCR with the Dhc 16S rRNA gene template when the ratio of either target was 100-fold greater than the other target. A multiplex qPCR assay with the luc IAC avoided competitive inhibition and accurately quantified Dhc abundances ranging from ~10 to 10(7) 16S rRNA gene copies per reaction. The addition of ~10(6) E. coli luc IAC to simulated groundwater amended with the Dhc containing consortium KB-1 yielded reproducible luc counts after DNA extraction and multiplex qPCR enumeration. The application of the luc IAC assay improved Dhc biomarker gene quantification from simulated groundwater samples and is a valuable approach for "ground truthing" qPCR data obtained in different laboratories, thus reducing ambiguity associated with qPCR enumeration and reproducibility. PMID- 24053160 TI - Finger displacement in Parkinson disease: up? down? sideways? AB - We previously reported that patients with tremor preponderant Parkinson disease (PD) displayed upward or lateral displacement of their more tremulous finger when they pointed both their index fingers at a target and closed their eyes for 15 seconds. In this study, we examined the phenomenon in 104 PD patients: 72 patients without tremor and 32 with minimal tremor to see if the displacement is related to the disease or the tremor. Sixty-eight of the 72 patients without tremor, 94%, exhibited finger displacement suggesting the phenomenon is related to the disease. None of the 104 patients were demented: mini-mental status examination (MMSE) score 29.0 +/- 0. 75. Ninety patients displayed upward displacement (56 patients) or lateral or medial displacement (34 patients). MMSE score of the 90 patients: 29.2 +/- 0.74 with no score < 28. Eight patients (6 without tremor) displayed downward displacement. MMSE score of the 8 patients: 27.5 +/- 0.35 with 5 having MMSE score of 27. Although not significant the results suggest that patients with downward displacement and lower MMSE score may be evolving a dementia. Upward displacement with eyes closed for 15 seconds requires an ability to "remember" the position of the finger in space and to alter tone to overcome gravity. Downward displacement implies an inability to "remember" the position of the finger in space an inability to overcome the effects of gravity. This may be more likely in patients who are evolving a dementia. Two patients, with PD-like symptoms, and specific anatomical abnormalities are also presented as they illustrate the anatomy of finger displacement. PMID- 24053161 TI - An old drug with a new future: bendamustine in multiple myeloma. AB - INTRODUCTION: Bendamustine is a unique bifunctional alkylating agent with promising activity in multiple myeloma (MM). It is currently licensed in Europe for use as frontline treatment with prednisolone for patients with MM who are unsuitable for transplantation and who are contraindicated for thalidomide and bortezomib therapy. AREAS COVERED: Studies evaluating the safety and efficacy of bendamustine administered alone or in combination in both the upfront and relapse settings of MM patients, including those with renal insufficiency, were reviewed. The use of bendamustine as conditioning for autologous stem-cell transplantation and the possibility of stem-cell mobilization after bendamustine therapy are discussed. EXPERT OPINION: Bendamustine seems to be efficacious either in monotherapy or in combination with other drugs in previously treated or untreated patients. This is due to its unique mechanism of action including its ability to activate apoptosis and inhibit mitotic checkpoints, making it potentially more effective than other alkylating agents. Moreover, it has an acceptable toxicity profile and is suitable for patients with renal impairment. Finally, this drug does not seem to compromise the possibility of achieving a stem-cell mobilization. Nonetheless, data from Phase III studies demonstrating its effectiveness in terms of overall survival are not yet available. PMID- 24053163 TI - Interleukin-1 superfamily member, interleukin-33, in periodontal diseases. AB - Interleukin (IL) -33 is a nuclear protein that is released from damaged cells and acts as an alarmin. We investigated the expression of IL-33 in human gingival fibroblasts after stimulation by tumor necrosis factor alpha (TNF-alpha). Human periodontal tissue samples were collected and fixed in phosphate-buffered 4% formalin in saline and processed to paraffin blocks. TNF-alpha was immunostained in samples of ten periodontitis patients and ten controls. Human gingival fibroblasts were isolated using an explant culture technique. The influence of TNF-alpha on IL-33 in gingival fibroblasts was analyzed using enzyme-linked immunosorbent assay (ELISA). The number of TNF-alpha positive cells was significantly greater in periodontitis samples than in controls. TNF-alpha was located mainly in macrophage- and fibroblast-like cells, vascular endothelial cells and epithelial cells. Analysis of IL-33 expression in cell culture lysates showed that TNF-alpha induced IL-33 in cultured gingival fibroblasts. Periodontitis samples are characterized by Th2 cell dominance, which has been linked to anti-inflammatory responses and periodontal repair. TNF-alpha-induced IL-33 may link inflammation directly to the IL-33-dependent stimulation of Th2 cytokine producing cells and participate in the induction of lymphocytes, which results in protective, anti-inflammatory and reparative responses. PMID- 24053164 TI - Role of the ERK signaling pathway in regulating vasopressin secretion in dehydrated rats. AB - Dehydration activates the vasopressinergic system of the hypothalamus. We analyzed the effects of dehydration induced by water deprivation for 3 days on the activities of ERK1/2 and transcription factors, Elk1 and cAMP response element-binding protein (CREB) in vasopressinergic neurons, as well as the distribution and level of the motor protein, kinesin, in the hypothalamo neurohypophyseal system. We showed that dehydration resulted in enhanced vasopressin (VP) expression and activation of CREB, and increased the activity of the MEK/ERK/Elk1 pathway in magnocellular neurons of the supraoptic nucleus. The activation of VP secretion was associated also with accumulation of phospho ERK1/2 in the VP-ergic terminals of the posterior lobe of the pituitary. Analysis of the amount and distribution of kinesin and SNAP25, the proteins associated with transport and secretion, demonstrated that dehydration enhanced kinesin content in the perikarya of magnocellular neurons in the supraoptic nucleus and decreased kinesin and SNAP25 levels in the posterior pituitary. ERK1/2 and ERK1/2 dependent transcription factors, Elk1 and CREB, participate in the regulation of dehydration-evoked VP expression. We propose that ERK1/2 and kinesin participate in regulation of anterograde transport of VP dense core vesicles. PMID- 24053162 TI - Synergistic targeting of cell membrane, cytoplasm, and nucleus of cancer cells using rod-shaped nanoparticles. AB - Design of carriers for effective delivery and targeting of drugs to cellular and subcellular compartments is an unmet need in medicine. Here, we report pure drug nanoparticles comprising camptothecin (CPT), trastuzumab (TTZ), and doxorubicin (DOX) to enable cell-specific interactions, subcellular accumulation, and growth inhibition of breast cancer cells. CPT is formulated in the form of nanorods which are coated with TTZ. DOX is encapsulated in the TTZ corona around the CPT nanoparticle. Our results show that TTZ/DOX-coated CPT nanorods exhibit cell specific internalization in BT-474 breast cancer cells, after which TTZ is recycled to the plasma membrane, leaving CPT nanorods in the perinuclear region and delivering DOX into the nucleus of the cells. The effects of CPT-TTZ-DOX nanoparticles on growth inhibition are synergistic (combination index = 0.17 +/- 0.03) showing 10-10 000-fold lower inhibitory concentrations (IC50) compared to those of individual drugs. The design of antibody-targeted pure drug nanoparticles offers a promising design strategy to facilitate intracellular delivery and therapeutic efficiency of anticancer drugs. PMID- 24053165 TI - Effect of prolonged duration therapy of subclinical mastitis in lactating dairy cows using penethamate hydriodide. AB - AIM: To evaluate the efficacy of nil, three or six treatments of penethamate hydriodide on successive days for treatment of subclinical mastitis on the bacteriological cure proportion and subsequent somatic cell count (SCC). METHODS: Milk samples were collected from all glands of 102 cows with SCC of >200,000 cells/mL, and at least one gland with a rapid mastitis test (RMT) score >0. Cows from which a bacterial pathogen was isolated were treated (Day 0) with either three (3 * PH; n=31 cows), six (6 * PH; n=30) or no (Control; n=31) daily I/M injections of 5 g of penethamate hydriodide. Milk samples were collected on Days 21 and 28 for bacteriology. Bacteriological cure was defined as having occurred when the pathogen isolated pre-treatment was isolated from neither of the post treatment samples. Post-treatment, cow-level composite SCC data were collated. The identity of Staphylococcus aureus isolates was confirmed by PCR and antimicrobial resistance patterns for these isolates were determined by zone diffusion testing. RESULTS: Corynebacterium spp. (40%) and S. aureus (32%) were the most common isolates pre-treatment. The proportion of glands cured increased from 0.16 (SE 0.04) for the Control, to 0.32 (SE 0.06) for the 3 * PH, and 0.56 (SE 0.02) for the 6 * PH groups (p<0.001); decreased with increasing age (p=0.02); and was lower for S. aureus than for other isolates (p<0.001). Of the 60 isolates defined as S. aureus by phenotypic bacteriology, 55 were confirmed as S. aureus by PCR. Of these, 24 (45%) were resistant to penicillin. One of 24 (4%) glands with S. aureus resistant to penicillin was cured compared with 7/29 (24%) sensitive isolates (p=0.04). The geometric mean SCC at the subsequent herd test declined from 481 (95% CI=350-659) * 10(3) cells/mL in Control, to 352 (95% CI=255-486) * 10(3) cells/mL in 3 * PH, and 276 (95% CI=199-383) * 10(3) cells/mL in 6* PH cows (p=0.05). CONCLUSIONS: Increasing the duration of treatment of subclinical mastitis using penethamate hydriodide in dairy cows resulted in a higher bacteriological cure proportion, a lower proportion of glands infected post-treatment, and a reduced SCC. Cure proportion was reduced in older cows, and for glands infected with S. aureus, especially when resistant to penicillin. CLINICAL RELEVANCE: This study demonstrated that bacteriological cure of subclinical intramammary infections can be increased by increasing the duration of therapy, but a number of cow and pathogen factors also affected the probability of cure. PMID- 24053166 TI - A three-dimensional visualisation preoperative treatment planning system in microwave ablation for liver cancer: a preliminary clinical application. AB - OBJECTIVES: The aim of this study was to evaluate the clinical application value of a 3D visualisation preoperative treatment planning system in microwave ablation for liver cancer. METHODS: From December 2011 to November 2012, 94 enrolment patients of liver cancer were divided into two groups. The 3D preoperative planning group included 36 patients with 44 lesions, who underwent microwave ablation with the aid of the self-developed 3D visualisation preoperative treatment planning system. The 2D preoperative planning group included 58 patients with 64 lesions, who underwent microwave ablation according to conventional 2D image preoperative planning methods. After microwave ablation, therapeutic efficacy was assessed by contrast-enhanced imaging during follow-up. RESULTS: The 3D preoperative planning group had a higher success rate of first ablation than the 2D preoperative planning group (p = 0.01). There were more sessions in the 2D preoperative planning group than in the 3D preoperative planning group (p = 0.002). There were no significant differences in technique effectiveness rate between the 2D preoperative planning group (96.55%) and the 3D preoperative planning group (100%) according to the contrast-enhanced imaging follow-up after microwave ablation (p = 0.64). There were no significant differences in the rate of LTP between the 2D preoperative planning group and the 3D preoperative planning group (p = 0.64) during 3-12 months follow up (median 6 months). CONCLUSIONS: Compared with the 2D preoperative planning group, the 3D preoperative planning group had a higher success rate of first ablation and fewer sessions. Therefore, the 3D visualisation preoperative treatment planning system has a relatively high clinical application value. PMID- 24053167 TI - 'Being in a womb' or 'playing musical chairs': the impact of place and space on infant feeding in NICUs. AB - BACKGROUND: Becoming a parent of a preterm baby requiring neonatal care constitutes an extraordinary life situation in which parenting begins and evolves in a medical and unfamiliar setting. Although there is increasing emphasis within maternity and neonatal care on the influence of place and space upon the experiences of staff and service users, there is a lack of research on how space and place influence relationships and care in the neonatal environment. The aim of this study was to explore, in-depth, the impact of place and space on parents' experiences and practices related to feeding their preterm babies in Neonatal Intensive Care Units (NICUs) in Sweden and England. METHODS: An ethnographic approach was utilised in two NICUs in Sweden and two comparable units in England, UK. Over an eleven month period, a total of 52 mothers, 19 fathers and 102 staff were observed and interviewed. A grounded theory approach was utilised throughout data collection and analysis. RESULTS: The core category of 'the room as a conveyance for an attuned feeding' was underpinned by four categories: the level of 'ownership' of space and place; the feeling of 'at-homeness'; the experience of 'the door or a shield' against people entering, for privacy, for enabling a focus within, and for regulating socialising and the; 'window of opportunity'. Findings showed that the construction and design of space and place was strongly influential on the developing parent-infant relationship and for experiencing a sense of connectedness and a shared awareness with the baby during feeding, an attuned feeding. CONCLUSIONS: If our proposed model is valid, it is vital that these findings are considered when developing or reconfiguring NICUs so that account is taken of the influences of spatiality upon parent's experiences. Even without redesign there are measures that may be taken to make a positive difference for parents and their preterm babies. PMID- 24053168 TI - Novel aspects of glutamine synthetase (GS) regulation revealed by a detailed expression analysis of the entire GS gene family of Medicago truncatula under different physiological conditions. AB - BACKGROUND: Glutamine Synthetase (GS, EC 6.3.1.2) is a central enzyme in nitrogen metabolism, and a key component of nitrogen use efficiency (NUE) and plant yield and thus it is extremely important to understand how it is regulated in plants. Medicago truncatula provides an excellent model system to study GS, as it contain a very simple GS gene family comprising only four expressed genes, MtGS1a and MtGS1b encoding cytosolic polypeptides, and MtGS2a and MtGS2b encoding plastid located enzymes. To identify new regulatory mechanisms controlling GS activity, we performed a detailed expression analysis of the entire GS gene family of M. truncatula in the major organs of the plant, over a time course of nodule or seed development and during a diurnal cycle. RESULTS: Individual GS transcripts were quantified by qRT-PCR, and GS polypeptides and holoenzymes were evaluated by western blot and in-gel activity under native electrophoresis. These studies revealed that all four GS genes are differentially regulated in each organ of the plant, in a developmental manner, and identified new regulatory controls, which appear to be specific to certain metabolic contexts. Studies of the protein profiles showed that the GS polypeptides assemble into organ-specific protein complexes and suffer organ-specific post-translational modifications under defined physiological conditions. Our studies also reveal that GS expression and activity are modulated during a diurnal cycle. The biochemical properties of the four isoenzymes were determined and are discussed in relation to their function in the plant. CONCLUSIONS: This work provides a comprehensive overview of GS expression and regulation in the model legume M. truncatula, contributing to a better understanding of the specific function of individual isoenzymes and to the identification of novel organ-specific post-translational mechanisms of GS regulation. We demonstrate that the GS proteins are modified and/or integrated into protein-complexes that assemble into a specific composition in particular organs of the plant. Taken together, the results presented here open new avenues to explore the regulatory mechanisms controlling GS activity in plants, a subject of major importance due to the crucial importance of the enzyme for plant growth and productivity. PMID- 24053170 TI - Transcorporal artificial urinary sphincter implantation as a salvage surgical procedure for challenging cases of male stress urinary incontinence: surgical technique and functional outcomes in a contemporary series. AB - OBJECTIVES: To describe the surgical technique of transcorporal artificial urinary sphincter (AUS) implantation. To assess the efficacy of the AUS on continence and erectile function. PATIENTS AND METHODS: A prospective evaluation was conducted between December 2007 and October 2012 at a tertiary referral centre of all male patients treated by transcorporal AUS (AMS800TM, AmericanMedicalSystems, Minnetonka, MN, USA) implantation for stress urinary incontinence (SUI) recurrence, after failure of previous anti-incontinence surgery. Functional urinary outcomes were assessed according to daily pad use, the Urinary Symptom Profile questionnaire, and International Consultation on Incontinence Questionnaire - Short-Form. Erectile function was evaluated using the five-item International Index of Erectile Function (IIEF-5) questionnaire and patient satisfaction was assessed by Patient Global Impression of Improvement questionnaire. Data were collected by telephone interview. RESULTS: A total of 23 patients were included. Their mean (sd; range) age was 70 (7; 60-85) years. Of these, 18 patients had urethral atrophy and/or erosion after placement of AUS (11 patients), male sling (four patients) or both (three patients), and five patients had severe urethral atrophy after pelvic radiation therapy. The implantation of the AUS with transcorporal cuff placement was successful in all patients, with no peri-operative complications. Follow-up data over 1 year were available for 17 patients. After a median (sd; range) follow-up of 20 (15; 2-59) months, eight patients were perfectly dry (no pad use and no symptoms), five achieved social continence (less than one pad/day), and four still had SUI (required two or more pads/day). Among six patients who had good preoperative erectile function and were sexually active, four had no decrease in their IIEF-5 score. CONCLUSIONS: Transcorporal AUS cuff placement is a useful alternative for challenging cases of male SUI after failure of previous surgical treatment, urethral atrophy or erosion. Erectile function can be maintained despite dissection of the corporal body. PMID- 24053169 TI - An integrated transcriptome and epigenome analysis identifies a novel candidate gene for pancreatic cancer. AB - BACKGROUND: Pancreatic cancer is a highly lethal cancer with limited diagnostic and therapeutic modalities. METHODS: To begin to explore the genomic landscape of pancreatic cancer, we used massively parallel sequencing to catalog and compare transcribed regions and potential regulatory elements in two human cell lines derived from normal and cancerous pancreas. RESULTS: By RNA-sequencing, we identified 2,146 differentially expressed genes in these cell lines that were enriched in cancer related pathways and biological processes that include cell adhesion, growth factor and receptor activity, signaling, transcription and differentiation. Our high throughput Chromatin immunoprecipitation (ChIP) sequence analysis furthermore identified over 100,000 regions enriched in epigenetic marks, showing either positive (H3K4me1, H3K4me3, RNA Pol II) or negative (H3K27me3) correlation with gene expression. Notably, an overall enrichment of RNA Pol II binding and depletion of H3K27me3 binding were seen in the cancer derived cell line as compared to the normal derived cell line. By selecting genes for further assessment based on this difference, we confirmed enhanced expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in two larger sets of pancreatic cancer cell lines and in tumor tissues as compared to normal derived tissues. CONCLUSIONS: As aldehyde dehydrogenase (ALDH) activity is a key feature of cancer stem cells, our results indicate that a member of the ALDH superfamily, ALDH1A3, may be upregulated in pancreatic cancer, where it could mark pancreatic cancer stem cells. PMID- 24053171 TI - Development of an NADPH-dependent homophenylalanine dehydrogenase by protein engineering. AB - l-Homophenylalanine is a nonproteinogenic amino acid and can be used as a versatile pharmaceutical intermediate. Production of l-homophenylalanine involves amination of the keto acid precursor 2-oxo-4-phenylbutyric acid (2-OPBA), which can be accomplished by bioenzymatic processes. Current biocatalysts for this reaction include transaminases and NADH-dependent phenylalanine dehydrogenases, which are not optimal for metabolic engineering of whole-cell biocatalysis. Here, we report the development of an NADPH-dependent homophenylalanine dehydrogenase by engineering the NADPH-dependent glutamate dehydrogenase (GDH) from Escherichia coli, which provides a new tool for in vitro catalysis and in vivo metabolic engineering. We took a stepwise substrate walking strategy: the first round directed evolution switched GDH's substrate specificity from its natural substrate 2-ketoglutarate to the intermediate target phenylpyruvate, which has similar structure as 2-OPBA; and the second round further improved the enzyme's catalytic efficiency toward the final target 2-OPBA. Compared to wild type GDH, the catalytic efficiency (kcat/Km) of the final mutant was ~100 fold higher for 2 OPBA and ~3000 fold lower for the original substrate 2-ketoglutarate. When overexpressed in E. coli, the engineered GDH aminated 2-OPBA to l homophenylalanine more effectively than the transaminases and NADH-dependent phenylalanine dehydrogenase, possibly because it utilizes the strong anabolic driving force NADPH under aerobic condition. PMID- 24053172 TI - Integrated community case management of malaria and pneumonia increases prompt and appropriate treatment for pneumonia symptoms in children under five years in Eastern Uganda. AB - BACKGROUND: Efforts to improve access to treatment for common illnesses in children less than five years initially targeted malaria alone under the home management of malaria strategy. However under this strategy, children with other illnesses were often wrongly treated with anti-malarials. Integrated community case management of common childhood illnesses is now recommended but its effect on promptness of appropriate pneumonia treatment is unclear. OBJECTIVES: To determine the effect of integrated malaria and pneumonia management on receiving prompt and appropriate antibiotics for pneumonia symptoms and treatment outcomes as well as determine associated factors. METHODS: A follow-up study was nested within a cluster-randomized trial that compared under-five mortality in areas where community health workers (CHWs) treated children with malaria and pneumonia (intervention areas) and where they treated children with malaria only (control areas). Children treated by CHWs were enrolled on the day of seeking treatment from CHWs (609 intervention, 667 control) and demographic, illness, and treatment seeking information was collected. Further information on illness and treatment outcomes was collected on day four. The primary outcome was prompt and appropriate antibiotics for pneumonia symptoms and the secondary outcome was treatment outcomes on day four. RESULTS: Children in the intervention areas were more likely to receive prompt and appropriate antibiotics for pneumonia symptoms compared to children in the control areas (RR = 3.51, 95%CI = 1.75-7.03). Children in the intervention areas were also less likely to have temperature >=37.5 degrees C on day four (RR = 0.29, 95%CI = 0.11-0.78). The decrease in fast breathing between day one and four was greater in the intervention (9.2%) compared to the control areas (4.2%, p-value = 0.01). CONCLUSIONS: Integrated community management of malaria and pneumonia increases prompt and appropriate treatment for pneumonia symptoms and improves treatment outcomes. TRIAL REGISTRATION ISRCTN: ISRCTN52966230. PMID- 24053173 TI - Ion-based materials derived from positively and negatively charged chloride complexes of pi-conjugated molecules. AB - Oriented salts from planar charged species were prepared by combining positively and negatively charged receptor-anion complexes with similar geometries using dicationic and electronically neutral pi-conjugated receptors. Phenylene- or pyrimidine-bridged bis(imidazolium) dicationic anion receptors formed monocationic receptor-Cl(-) complexes that were accompanied by a free Cl(-). This free Cl(-) was subsequently captured by pyrrole-based neutral anion receptors to form negatively charged receptor-Cl(-) complexes. The ion pair of the resulting positively and negatively charged planar receptor-Cl(-) complexes could produce a supramolecular octane gel, adopting a lamellar self-organized structure in its xerogel state. On the other hand, the solid-state ion pairs had hexagonal columnar mesophases, which formed via alternate stacking of the positively and negatively charged planar receptor-Cl(-) complexes. By use of the flash photolysis time-resolved microwave conductivity technique, the one-dimensional charge-carrier transporting property, with a mobility of 0.05 cm(2) V(-1) s(-1), was determined for the newly prepared solid-state ion pairs. PMID- 24053174 TI - Laparoendoscopic single-site (LESS) robot-assisted nephroureterectomy: comparison with conventional multiport technique in the management of upper urinary tract urothelial carcinoma. AB - OBJECTIVE: To compare the peri-operative, pathological and oncological outcomes of laparoendoscopic single-site (LESS) robot-assisted nephroureterectomy (LESS RALNU) with those of multiport robot-asssisted nephroureterectomy (M-RALNU). PATIENTS AND METHODS: A total of 38 patients with upper urinary tract urothelial carcinoma underwent LESS-RALNU (n = 17) or M-RALNU (n = 21) by a single surgeon at a tertiary institution. Data were obtained from a prospectively maintained database. RESULTS: Patients' demographics and tumour characteristics were similar between the M-RALNU and LESS-RALNU groups. The mean follow-up was 48.4 months for M-RALNU and 30.9 months for LESS-RALNU (P = 0). The mean operating time, estimated blood loss and length of hospitalization for M-RALNU and LESS-RALNU were 251 min, 192 mL, 6.5 days and 247 min, 376 mL and 5.4 days, respectively (P > 0.05). Overall, there were no significant differences in complication rates, although three patients in the LESS-RALNU group required blood transfusion, whereas no patient in the M-RALNU group did (P = 0.081). The proportion of patients with bladder recurrence, local recurrence and distant metastases was similar between the two groups. There were no significant differences in the recurrence-free survival, cancer-specific survival and overall survival rates between the two groups. CONCLUSIONS: Although the oncological and peri-operative outcomes of patients who underwent LESS-RALNU compared well with those who underwent M-RALNU and with series of other surgical approaches, LESS-RALNU might result in greater intra-operative blood loss. We suggest careful selection of patient for this technique. PMID- 24053175 TI - Dissociation of FK506-binding protein 12.6 kD from ryanodine receptor in bronchial smooth muscle cells in airway hyperresponsiveness in asthma. AB - Airway hyperresponsiveness (AHR) in asthma is predominantly caused by increased sensitivity of bronchial smooth muscle cells (BSMCs) to stimuli. The sarcoplasmic reticulum (SR)-Ca(2+) release channel, known as ryanodine receptor (RyR), mediates the contractive response of BSMCs to stimuli. FK506-binding protein 12.6 kD (FKBP12.6) stabilizes the RyR2 channel in a closed state. However, the interaction of FKBP12.6 with RyR2 in AHR remains unknown. This study examined the interaction of FKBP12.6 with RyR2 in BSMCs in AHR of asthma. The interaction of FKBP12.6 with RyR2 and FKBP12.6 expression was determined in a rat asthma model and in BSMCs treated with inflammatory cytokines. The calcium responses to contractile agonists were determined in BSMCs with overexpression and knockdown of FKBP12.6. Asthmatic serum, IL-5, IL-13, and TNF-alpha enhance the calcium response of BSMCs to contractile agonists and cause dissociation of FKBP12.6 from RyR2 and a decrease in FKBP12.6 gene expression in BSMCs in culture and in ovalbumin (OVA)-sensitized and -challenged rats. Knockdown of FKBP12.6 in BSMCs causes a decrease in the association of RyR2 with FKBP12.6 and an increase in the calcium response of BSMCs. Overexpression of FKBP12.6 increases the association of FKBP12.6 with RyR2, decreases the calcium response of BSMCs, and normalizes airway responsiveness in OVA-sensitized and -challenged rats. Dissociation of FKBP12.6 from RyR2 in BSMCs is responsible for the increased calcium response contributing to AHR in asthma. Manipulating the interaction of FKBP12.6 with RyR2 might be a novel and useful treatment for asthma. PMID- 24053176 TI - Sudden death of an infant with cardiac, nervous system and genetic involvement--a case report. AB - We present a case of sudden death of a 1-month-old male infant with heart, brainstem and genetic polymorphism involvement. Previously considered quite healthy, the child died suddenly and unexpectedly during sleep. The autopsy protocol included an in-depth anatomopathological examination of both the autonomic nervous system and the cardiac conduction system, and molecular analysis of the serotonin transporter gene promoter region, in which a specific genetic condition seems to be associated with sudden infant death. Histological examination revealed the presence of congenital cardiac alterations (hypertrophic cardiomyopathy and an accessory Mahaim fiber in the cardiac conduction system), severe hypodevelopment of all the raphe nuclei and a heterozygous genotype L/S related to the serotonin transporter gene. The sudden death of this infant was the unavoidable outcome of a complex series of congenital anomalies, each predisposing to SIDS. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3480540091031788. PMID- 24053177 TI - Spatial aspects of prebiotic replicator coexistence and community stability in a surface-bound RNA world model. AB - BACKGROUND: The coexistence of macromolecular replicators and thus the stability of presumed prebiotic replicator communities have been shown to critically depend on spatially constrained catalytic cooperation among RNA-like modular replicators. The necessary spatial constraints might have been supplied by mineral surfaces initially, preceding the more effective compartmentalization in membrane vesicles which must have been a later development of chemical evolution. RESULTS: Using our surface-bound RNA world model - the Metabolic Replicator Model (MRM) platform - we show that the mobilities on the mineral substrate surface of both the macromolecular replicators and the small molecules of metabolites they produce catalytically are the key factors determining the stable persistence of an evolvable metabolic replicator community. CONCLUSION: The effects of replicator mobility and metabolite diffusion on different aspects of replicator coexistence in MRM are determined, including the maximum attainable size of the metabolic replicator system and its resistance to the invasion of parasitic replicators. We suggest a chemically plausible hypothetical scenario for the evolution of the first protocell starting from the surface-bound MRM system. PMID- 24053178 TI - Bullying and the older nurse. AB - AIM: The purpose of this article is to discuss bullying from the perspective of the older nurse. BACKGROUND: Inappropriate behaviours, such as bullying, are being scrutinised in health care because of the potential negative impact on patient care and safety and worker wellbeing and satisfaction. Although this phenomenon is often referred to as 'nurses eating their young', the implications for the older nurse cannot be ignored. EVALUATION: The work environment is instrumental in the retention of workers. Older nurses are essential for knowledge transfer. When developing strategies to retain the older worker, issues such as bullying need to be examined. KEY ISSUES: Without proper identification and the willingness of management to acknowledge it, bullying may become a cultural norm. Once this occurs, it is necessary to examine the underlying structures that support its continued presence. Hierarchical and disempowering work environments may be contributors. CONCLUSIONS: Nurses of all ages can be affected by bullying, so empowering initiatives need to be developed to prevent perpetuation and victimisation. IMPLICATIONS FOR NURSING MANAGEMENT: To prevent bullying, initiatives that recognise the skills and knowledge that nurses contribute to patient care need to be developed. PMID- 24053179 TI - Learning curves for urological procedures: a systematic review. AB - OBJECTIVE: To determine the number of cases a urological surgeon must complete to achieve proficiency for various urological procedures. PATIENT AND METHODS: The MEDLINE, EMBASE and PsycINFO databases were systematically searched for studies published up to December 2011. Studies pertaining to learning curves of urological procedures were included. Two reviewers independently identified potentially relevant articles. Procedure name, statistical analysis, procedure setting, number of participants, outcomes and learning curves were analysed. RESULTS: Forty-four studies described the learning curve for different urological procedures. The learning curve for open radical prostatectomy ranged from 250 to 1000 cases and for laparoscopic radical prostatectomy from 200 to 750 cases. The learning curve for robot-assisted laparoscopic prostatectomy (RALP) has been reported to be 40 procedures as a minimum number. Robot-assisted radical cystectomy has a documented learning curve of 16-30 cases, depending on which outcome variable is measured. Irrespective of previous laparoscopic experience, there is a significant reduction in operating time (P = 0.008), estimated blood loss (P = 0.008) and complication rates (P = 0.042) after 100 RALPs. CONCLUSIONS: The available literature can act as a guide to the learning curves of trainee urologists. Although the learning curve may vary among individual surgeons, a consensus should exist for the minimum number of cases to achieve proficiency. The complexities associated with defining procedural competence are vast. The majority of learning curve trials have focused on the latest surgical techniques and there is a paucity of data pertaining to basic urological procedures. PMID- 24053180 TI - Plasma microRNA-133a is a new marker for both acute myocardial infarction and underlying coronary artery stenosis. AB - BACKGROUND: Previous study demonstrated that miR-133a was released into blood from injured myocardium in cardiovascular diseases. However, the dynamic change of circulating miR-133a level in the early phase of acute myocardial infarction (AMI) and the correlation between miR-133a and severity of coronary stenosis in coronary heart disease (CHD) patients are not clear. METHODS AND RESULTS: Three different cohorts (including 13 AMI patients, 176 angina pectoris patients and 127 control subjects) were enrolled to investigate the expression levels of circulating miR-133a in patients with myocardial ischemia and also the relationship between plasma miR-133a and severity of coronary stenosis. Plasma miR-133a levels of participants were examined by real-time quantitative PCR. Simultaneously, plasma cardiac troponin I (cTnI) concentrations were measured by ELISA assays. The results showed that circulating miR-133a level was significantly increased in AMI patients in time-dependent manner, and achieved a 72.1 fold peak at 21.6 +/- 4.5 hours after the onset of AMI symptoms and exhibited a similar trend to plasma cTnI level. We also found that plasma miR 133a levels were higher in CHD patients than control group. Importantly, the levels of circulating miR-133a positively correlated with the severities of the coronary artery stenosis. Receiver operating characteristic (ROC) analysis revealed that circulating miR-133a had considerable diagnostic accuracy for CHD with an AUC of 0.918 (95% confidence interval 0.877-0.960). CONCLUSIONS: Circulating miR-133a may be a new biomarker for AMI and as a potential diagnostic tool. And increased miR-133a level may be used to predict both the presence and severity of coronary lesions in CHD patients. PMID- 24053182 TI - Therapy of Clostridium difficile infection: perspectives on a changing paradigm. AB - INTRODUCTION: Clostridium difficile disease (CDI) have increased in frequency and severity over the past decade and are a leading cause of hospital acquired infections, contributing to increased hospital length of stay and costs, as well as associated increased mortality, especially amongst the elderly. Standard therapy has been associated with 20 - 30% relapse rates. Consequently, new CDI therapeutic approaches have emerged. AREAS COVERED: The role of metronidazole, vancomycin, fidaxomicin, rifaximin, nitizoxanide, tigecycline, fusidic acid, LFF 571, cardazolid, SMT 19969, CamSA and surotomycin were reviewed. EXPERT OPINION: New IDSA/SHEA guidelines are expected within the next year and may impact selection of primary therapy for CDI. Until then, metronidazole will likely remain as first line therapy because of low cost and despite its inferiority compared to vancomycin. Vancomycin will likely see increasing use, especially as generics become available. Fidaxomicin will emerge as an important therapy for relapse patients and perhaps as initial therapy for patients at greatest risk for relapse, with concomitant antibiotics, multiple comorbidities and renal insufficiency, advanced age and hypoalbuminemia. Biotherapeutics such as fecal microbiota transplantation and non-toxogenic C. difficile prevention will emerge as the preferred therapy in multiple relapse patients and the development of an oral formulation will occur within five years. PMID- 24053181 TI - Histone deacetylase (HDAC) inhibitory and antiproliferative activities of phenolic-rich extracts derived from the rhizome of Hydnophytum formicarum Jack.: sinapinic acid acts as HDAC inhibitor. AB - BACKGROUND: The rhizome of Hydnophytum formicarum Jack., a medicinal plant known in Thai as Hua-Roi-Roo, has been used in Thai traditional herbal medicine for treatment of cancer. We assessed the ability of its ethanolic and phenolic-rich extracts and its major phenolic compound, sinapinic acid, possessing histone deacetylase (HDAC) inhibitory activity to inhibit proliferation of 5 human cancer cell lines. METHODS: HeLa cells were used to study HDAC inhibitory activity of the extracts, sinapinic acid, and a well-known HDAC inhibitor sodium butyrate. Five human cancer cell lines and one non-cancer cell line were used to study antiproliferative activities of the plant extracts, sinapinic acid and sodium butyrate, comparatively. RESULTS: Results indicated that ethanolic and phenolic rich extracts of H. formicarum Jack. rhizome possessed both antiproliferative activity and HDAC inhibitory activity in HeLa cells. Sinapinic acid, despite its lower HDAC inhibitory activity than the well-known HDAC inhibitor sodium butyrate, inhibited the growth of HeLa and HT29 cells more effectively than sodium butyrate. However, sinapinic acid inhibited the growth of HCT116 and Jurkat cells less effectively than sodium butyrate. The non-cancer cell line (Vero cells) and breast cancer cell line (MCF-7 cells) appeared to be resistant to both sinapinic acid and sodium butyrate. The growth inhibitory effects of the ethanolic and phenolic-rich extracts and sinapinic acid in HeLa cells were mediated by induction of apoptosis. CONCLUSIONS: The results of this study support the efficacy of H. formicarum Jack. rhizome ethanolic and phenolic-rich extracts for the treatment of cervical cancer, colon cancer, and T- cell leukemia in an alternative medicine. Further studies of other active ingredients from this plant are needed. PMID- 24053183 TI - Recurrent intraventricular thrombus six months after ST-elevation myocardial infarction in a diabetic man: a case report. AB - BACKGROUND: Percutaneous coronary intervention with placement of a drug-eluting stent in a diabetic patient with ST-elevation myocardial infarction is a relatively common procedure, and always requires subsequent treatment with dual antiplatelet therapy. It is sometimes necessary to add oral anticoagulation therapy because of individual clinical circumstances, which further increases the risk of bleeding. CASE PRESENTATION: A 66-year-old hypertensive diabetic man with a history of gastrointestinal bleeding was admitted with an ST-elevation inferior myocardial infarction that had been evolving over 72 h. Electrocardiography showed ST segment elevation in the inferior leads and Q waves in the inferior and anterior leads. He reported a similar episode of chest pain 1 month previously, for which he had not sought medical treatment. Coronary angiography showed chronic occlusion of the mid-left anterior descending coronary artery, and acute occlusion of the mid-right coronary artery. He was treated by percutaneous coronary intervention, with placement of a drug-eluting stent in the right coronary artery. Soon after admission, transthoracic echocardiography showed abnormal left ventricular contractility and a large left intraventricular thrombus. Three weeks after admission, the patient was discharged on dual antiplatelet therapy (clopidogrel and aspirin) and oral anticoagulation therapy (acenocoumarol). Four months after discharge, transthoracic echocardiography showed absence of left ventricular thrombus and resolution of the abnormal contractility in the area supplied by the revascularized right coronary artery. Given the high risk of bleeding, oral anticoagulation therapy was stopped. Six months later, transthoracic echocardiography showed recurrent left ventricular apical thrombus, and an underlying hypercoagulable state was ruled out. Oral anticoagulation therapy was restarted on an indefinite basis, and dual antiplatelet therapy was continued. CONCLUSIONS: The present case illustrates the need for repeat transthoracic echocardiography following the withdrawal of oral anticoagulation therapy in patients with ST-elevation myocardial infarction, both to monitor thrombus status and to assess left ventricular segmental contraction. In patients who require anticoagulation, avoidance of a drug-eluting stent is strongly preferred and second-generation stents are recommended. The alternative regimen of oral anticoagulation and clopidogrel may be considered in this scenario. In patients with recurrent intraventricular thrombus an underlying hypercoagulable state should be ruled out. PMID- 24053184 TI - Prevalence of gestational, placental and congenital malaria in north-west Colombia. AB - BACKGROUND: The frequency of pregnancy-associated malaria is increasingly being documented in American countries. In Colombia, with higher frequency of Plasmodium vivax over Plasmodium falciparum infection, recent reports confirmed gestational malaria as a serious public health problem. Thick smear examination is the gold standard to diagnose malaria in endemic settings, but in recent years, molecular diagnostic methods have contributed to elucidate the dimension of the problem of gestational malaria. The study was aimed at exploring the prevalence of gestational, placental and congenital malaria in women who delivered at the local hospitals of north-west Colombia, between June 2008 and April 2011. METHODS: A group of 129 parturient women was selected to explore the prevalence of gestational, placental and congenital malaria in a descriptive, prospective and transversal (prevalence) design. Diagnosis was based on the simultaneous application of two independent diagnostic tests: microscopy of thick blood smears and a polymerase chain reaction assay (PCR). RESULTS: The prevalence of gestational malaria (thick smear /PCR) was 9.1%/14.0%; placental malaria was 3.3%/16.5% and congenital malaria was absent. A history of gestational malaria during the current pregnancy was significantly associated with gestational malaria at delivery. Plasmodium vivax caused 65% of cases of gestational malaria, whereas P. falciparum caused most cases of placental malaria. CONCLUSIONS: Gestational and placental malaria are a serious problem in the region, but the risk of congenital malaria is low. A history of malaria during pregnancy may be a practical indicator of infection at delivery. PMID- 24053185 TI - Prognostic significance of venous tumour thrombus consistency in patients with renal cell carcinoma (RCC). AB - OBJECTIVES: To identify the prognostic impact of venous tumour thrombus (VTT) in locally advanced renal cell carcinomas (RCCs). To further differentiate the clinical course of patients with VTT who have similar clinicopathological characteristics. PATIENTS AND METHODS: We determined the VTT consistency (solid vs friable) in a retrospective cohort of 200 patients with RCC who had undergone nephrectomy between 1994 and 2011. We examined the correlation of VTT consistency in these patients with clinical and pathological variables. RESULTS: A total of 65% of the patients had solid VTT and 35% had friable VTT, which has a significantly lower amount of cell-cell adhesion molecules and connective tissue than solid VTT. We found that friable VTT was associated with advanced pT stage, higher VTT level, papillary RCC subtype and a lower age. Patients with friable VTT had a significantly shorter median overall survival than those with solid VTT (29 vs 89 months), but VTT consistency was not found to be an independent predictor of patients' survival in the multivariate Cox analysis. We found that VTT consistency was an independent significant predictor of overall survival in patients without evidence of distant and nodal metastases (N = 119). CONCLUSIONS: The VTT consistency is caused by the tumour and not by different surgical handling. Friable VTT is an important adverse prognostic predictor of overall survival in patients with non-metastatic RCC. PMID- 24053186 TI - Mechanical stress induces pre-B-cell colony-enhancing factor/NAMPT expression via epigenetic regulation by miR-374a and miR-568 in human lung endothelium. AB - Increased lung vascular permeability and alveolar edema are cardinal features of inflammatory conditions such as acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). We previously demonstrated that pre-B-cell colony-enhancing factor (PBEF)/NAMPT, the proinflammatory cytokine encoded by NAMPT, participates in ARDS and VILI inflammatory syndromes. The present study evaluated posttranscriptional regulation of PBEF/NAMPT gene expression in human lung endothelium via 3'-untranslated region (UTR) microRNA (miRNA) binding. In silico analysis identified hsa-miR-374a and hsa-miR-568 as potential miRNA candidates. Increased PBEF/NAMPT transcription (by RT-PCR) and expression (by Western blotting) induced by 18% cyclic stretch (CS) (2 h: 3.4 +/- 0.06 mRNA fold increase (FI); 10 h: 1.5 +/- 0.06 protein FI) and by LPS (4 h: 3.8 +/- 0.2 mRNA FI; 48 h: 2.6 +/- 0.2 protein FI) were significantly attenuated by transfection with mimics of hsa-miR-374a or hsa-miR-568 (40-60% reductions each). LPS and 18% CS increased the activity of a PBEF/NAMPT 3'-UTR luciferase reporter (2.4-3.25 FI) with induction reduced by mimics of each miRNA (44-60% reduction). Specific miRNA inhibitors (antagomirs) for each PBEF/NAMPT miRNA significantly increased the endogenous PBEF/NAMPT mRNA (1.4-3.4 +/- 0.1 FI) and protein levels (1.2-1.4 +/- 0.1 FI) and 3'-UTR luciferase activity (1.4-1.7 +/- 0.1 FI) compared with negative antagomir controls. Collectively, these data demonstrate that increased PBEF/NAMPT expression induced by bioactive agonists (i.e., excessive mechanical stress, LPS) involves epigenetic regulation with hsa-miR-374a and hsa-miR-568, representing novel therapeutic strategies to reduce inflammatory lung injury. PMID- 24053187 TI - Multiple sclerosis and risk of Parkinson's disease: a Danish nationwide cohort study. AB - BACKGROUND AND PURPOSE: Case reports have observed a co-occurrence of multiple sclerosis (MS) and Parkinson's disease (PD) and it has been hypothesized that MS lesions could affect dopaminergic pathways causing parkinsonism. Our aim was to examine the association between MS and PD in a historically prospective cohort study using Danish nationwide register data. METHODS: Multiple sclerosis patients identified in the Multiple Sclerosis Registry were followed for PD from 1977 to 2011 in the National Patient Register. As measures of relative risk, ratios of observed to expected incidence rates of first hospitalization for PD amongst persons with MS were used, i.e. standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). RESULTS: Amongst 15,557 MS patients 26 cases of PD were observed versus 26.51 expected, reflecting no overall increased risk of PD (SIR 0.98, 95% CI 0.67-1.44). Similar estimates were seen for female (SIR 0.99, 95% CI 0.58-1.67) and male MS patients (SIR 0.97, 95% CI 0.55-1.72). Likewise, no increased risk of PD amongst MS patients was observed in a robustness analysis backdating the date of diagnosis of PD by 5 years to account for the time lag between disease onset and first hospital contact with PD (SIR 0.57, 95% CI 0.32 1.00). CONCLUSION: Our data do not suggest an increased risk of PD amongst patients with MS. PMID- 24053188 TI - Association between placentome size, measured using transrectal ultrasonography, and gestational age in cattle. AB - AIM: The aim of this study was to estimate whether fetal age could be accurately estimated using placentome size. METHODS: Fifty-eight cows with confirmed conception dates in two herds were used for the study. The length of the long axis and cross-sectional area of placentomes close to the cervix were measured once every 10 days between approximately 60-130 days of gestation and once every 15 days between 130-160 days of gestation. Four to six placentomes were measured using transrectal ultrasonography in each uterine horn. A linear mixed model was used to establish the factors that were significantly associated with log mean placentome length and to create an equation to predict gestational age from mean placentome length. Limits of agreement analysis was then used to evaluate whether the predictions were sufficiently accurate for mean placentome length to be used, in practice, as a method of determining gestational age. RESULTS: Only age of gestation (p<0.001) and uterine horn (p=0.048) were found to have a significant effect on log mean placentome length. From the three models used to predict gestational age the one that used log mean placentome length of all placentomes, adjusting for the effect of horn, had the smallest 95% limits of agreement; +/-33 days. That is, predicted gestational age had a 95% chance of being between 33 days greater and 33.7 days less than actual age. This is approximately twice that reported in studies using measurement of fetal size. CONCLUSIONS: Measurement of placentomes near to the cervix using transrectal ultrasonography was easily achieved. There was a significant association between placentome size and gestational age, but between-cow variation in placentome size and growth resulted in poor agreement between placentome size and gestational age. CLINICAL RELEVANCE: Although placentomes can be easily visualised during diagnosis of pregnancy using transrectal ultrasonography, mean placentome size should not be used to estimate gestational age. PMID- 24053189 TI - Development and evaluation of an air mattress structure and function for reducing discomfort when elevating the head-of-bed. AB - PURPOSE: To develop a new structure and function of alternating pressure air mattress (APAM) which reduces discomfort during head-of-bed (HOB) elevation and evaluate the effectiveness. METHOD: An observational study (Study 1) and randomized crossover experiment (Study 2) were conducted in healthy adult volunteers. External force (interface pressure and shear force), body shift, discomfort (pushing feeling and pulling feeling) and HOB elevation angle were measured in Study 1. We developed a new APAM according to these findings. Study 2 compared the external force and discomfort of the new APAM with a control APAM. The magnitude of the discomfort was measured by visual analogue scale. RESULTS: Study 1 clarified that the external force and discomfort during HOB elevation are positively correlated, and that discomfort can be reduced by decreasing the external force. Thus, we designed an APAM with a low friction layer and a novel mattress air-cell pressure control function to reduce the external force. Study 2 confirmed that the external force and discomfort were significantly decreased in the developed APAM. CONCLUSIONS: In this study, we developed a new APAM to reduce discomfort during HOB elevation and confirmed its effectiveness. Implications for Rehabilitation A positive correlation exists between the external force and the discomfort that arises during head-of-bed (HOB) elevation, and a mattress could be developed to reduce the discomfort by decreasing the external force. A new alternating pressure air mattress (APAM) with a low friction layer structure and novel control of mattress air-cell pressure that responds to HOB elevation angle can reduce discomfort during HOB elevation. This new APAM should allow more comfortable rehabilitation in bed-bound patients with mobility impairments. PMID- 24053190 TI - Samsoeum, a traditional herbal medicine, elicits apoptotic and autophagic cell death by inhibiting Akt/mTOR and activating the JNK pathway in cancer cells. AB - BACKGROUND: Samsoeum (SSE), a traditional herbal formula, has been widely used to treat cough, fever, congestion, and emesis for centuries. Recent studies have demonstrated that SSE retains potent pharmacological efficiency in anti-allergic and anti-inflammatory reactions. However, the anti-cancer activity of SSE and its underlying mechanisms have not been studied. Thus, the present study was designed to determine the effect of SSE on cell death and elucidate its detailed mechanism. METHODS: Following SSE treatment, cell growth and cell death were measured using an MTT assay and trypan blue exclusion assay, respectively. Cell cycle arrest and YO-PRO-1 uptake were assayed using flow cytometry, and LC3 redistribution was observed using confocal microscope. The mechanisms of anti cancer effect of SSE were investigated through western blot analysis. RESULTS: We initially found that SSE caused dose- and time-dependent cell death in cancer cells but not in normal primary hepatocytes. In addition, during early SSE treatment (6-12 h), cells were arrested in G2/M phase concomitant with up regulation of p21 and p27 and down-regulation of cyclin D1 and cyclin B1, followed by an increase in apoptotic YO-PRO-1 (+) cells. SSE also induced autophagy via up-regulation of Beclin-1 expression, conversion of microtubule associated protein light chain 3 (LC3) I to LC3-II, and re-distribution of LC3, indicating autophagosome formation. Moreover, the level of B-cell lymphoma 2 (Bcl 2), which is critical for cross-talk between apoptosis and autophagy, was significantly reduced in SSE-treated cells. Phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) was increased, followed by suppression of the protein kinase B/mammalian target of rapamycin (Akt/mTOR) pathway, and phosphorylation of mitogen-activated protein kinases (MAPKs) in response to SSE treatment. In particular, among MAPKs inhibitors, only the c-Jun N-terminal kinase (JNK)-specific inhibitor SP600125 nearly blocked SSE-induced increases in Beclin-1, LC3-II, and Bax expression and decreases in Bcl-2 expression, indicating that JNK activation plays critical role in cell death caused by SSE. CONCLUSIONS: These findings suggest that SSE efficiently induces cancer cell death via apoptosis as well as autophagy through modification of the Akt/mTOR and JNK signaling pathways. SSE may be as a potent traditional herbal medicine for treating malignancies. PMID- 24053191 TI - Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study. AB - BACKGROUND: Somatostatin analogues (SSAs) are indicated to relieve carcinoid syndrome but seem to have antiproliferative effects on neuroendocrine tumours (NETs). This is the first prospective study investigating tumour stabilisation with the long-acting SSA lanreotide Autogel in patients with progressive NETs. METHODS: This was a multicentre, open-label, phase II trial conducted in 17 Spanish specialist centres. Patients with well-differentiated NETs and radiologically confirmed progression within the previous 6 months received lanreotide Autogel, 120 mg every 28 days over <=92 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, tumour biomarkers, symptom control, quality of life (QoL), and safety. Radiographic imaging was assessed by a blinded central radiologist. RESULTS: Of 30 patients included in the efficacy and safety analyses, 40% had midgut tumours and 27% pancreatic tumours; 63% of tumours were functioning. Median PFS time was 12.9 (95% CI: 7.9, 16.5) months, and most patients achieved disease stabilisation (89%) or partial response (4%). No deterioration in QoL was observed. Nineteen patients (63%) experienced treatment-related adverse events, most frequently diarrhoea and asthenia; only one treatment-related adverse event (aerophagia) was severe. CONCLUSION: Lanreotide Autogel provided effective tumour stabilisation and PFS >12 months in patients with progressive NETs ineligible for surgery or chemotherapy, with a safety profile consistent with the pharmacology of the class. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00326469; EU Clinical Trial Register EudraCT no 2004-002871-18. PMID- 24053193 TI - Genetic variant in fat mass and obesity-associated gene associated with type 2 diabetes risk in Han Chinese. AB - BACKGROUND: Genome-wide association study (GWAS) has identified that rs8050136 C/A polymorphism in fat mass and obesity-associated gene (FTO) was associated with the risk of type 2 diabetes (T2D) in Europeans. But this association was abolished after adjustment for body mass index (BMI), suggesting that the effect of rs8050136 on T2D risk might be mediated by BMI in Europeans. However, the findings in subsequent studies were inconsistent among Asian populations. To determine whether rs8050136 polymorphism in FTO is independently associated with the risk of T2D in Chinese, we conducted a case-control study with 2,925 T2D patients and 3,281 controls in Han Chinese. RESULTS: Logistic regression revealed that the A allele of rs8050136 was significantly associated with an increased risk of T2D, independent of BMI (odds ratio (OR) = 1.17, 95% confidence interval (95% CI) = 1.03-1.32, p = 0.016). Meta-analysis containing 10 reported studies and our data with a total of 15,819 cases and 18,314 controls further confirmed the association between rs8050136 polymorphism and T2D risk in East Asians (OR = 1.13, 95% CI = 1.07-1.19). CONCLUSIONS: Our findings indicate that the genetic variant in FTO may contribute to T2D risk in Han Chinese and rs8050136 polymorphism may be a genetic marker for T2D susceptibility. PMID- 24053192 TI - Ocular and neural distribution of feline herpesvirus-1 during active and latent experimental infection in cats. AB - BACKGROUND: Herpes simplex virus 1 (HSV-1) and varicella zoster virus (VZV) cause extensive intra-ocular and neural infections in humans and are closely related to Felid herpes virus 1 (FeHV-1). We report the extent of intra-ocular replication and the extent and morphological aspects of neural replication during the acute and latent phases of FeHV-1 infection. Juvenile, SPF cats were inoculated with FeHV-1. Additional cats were used as negative controls. Cats were euthanized on days 6, 10, and 30 post-inoculation. RESULTS: FeHV-1 was isolated from the conjunctiva, cornea, uveal tract, retina, optic nerve, ciliary ganglion (CG), pterygopalatine ganglion (PTPG), trigeminal ganglion (TG), brainstem, visual cortex, cerebellum, and olfactory bulb of infected cats during the acute phase, but not the cranial cervical ganglion (CCG) and optic chiasm. Viral DNA was detected in all tissues during acute infection by a real-time quantitative PCR assay. On day 30, viral DNA was detected in all TG, all CCG, and 2 PTPG. Histologically mild inflammation and ganglion cell loss were noted within the TG during acute, but not latent infection. Using linear regression, a strong correlation existed between clinical score and day 30 viral DNA copy number within the TG. CONCLUSIONS: The correlation between clinical score and day 30 viral DNA copy number suggests the severity of the acute clinical infection is related to the quantity of latent viral DNA. The histologic response was similar to that seen during HSV-1 or VZV infection. To the author's knowledge this is the first report of FeHV-1 infection involving intraocular structures and autonomic ganglia. PMID- 24053194 TI - Discrepancies between cardiovascular magnetic resonance and Doppler echocardiography in the measurement of transvalvular gradient in aortic stenosis: the effect of flow vorticity. AB - BACKGROUND: Valve effective orifice area EOA and transvalvular mean pressure gradient (MPG) are the most frequently used parameters to assess aortic stenosis (AS) severity. However, MPG measured by cardiovascular magnetic resonance (CMR) may differ from the one measured by transthoracic Doppler-echocardiography (TTE). The objectives of this study were: 1) to identify the factors responsible for the MPG measurement discrepancies by CMR versus TTE in AS patients; 2) to investigate the effect of flow vorticity on AS severity assessment by CMR; and 3) to evaluate two models reconciling MPG discrepancies between CMR/TTE measurements. METHODS: Eight healthy subjects and 60 patients with AS underwent TTE and CMR. Strouhal number (St), energy loss (EL), and vorticity were computed from CMR. Two correction models were evaluated: 1) based on the Gorlin equation (MPG(CMR Gorlin)); 2) based on a multivariate regression model (MPG(CMR-Predicted)). RESULTS: MPGCMR underestimated MPGTTE (bias = -6.5 mmHg, limits of agreement from -18.3 to 5.2 mmHg). On multivariate regression analysis, St (p = 0.002), EL (p = 0.001), and mean systolic vorticity (p < 0.001) were independently associated with larger MPG discrepancies between CMR and TTE. MPG(CMR-Gorlin) and MPGTTE correlation and agreement were r = 0.7; bias = -2.8 mmHg, limits of agreement from -18.4 to 12.9 mmHg. MPG(CMR-Predicted) model showed better correlation and agreement with MPGTTE (r = 0.82; bias = 0.5 mmHg, limits of agreement from -9.1 to 10.2 mmHg) than measured MPGCMR and MPG(CMR-Gorlin). CONCLUSION: Flow vorticity is one of the main factors responsible for MPG discrepancies between CMR and TTE. PMID- 24053195 TI - "Grafting-from" polymerization of PMMA from stainless steel surfaces by a RAFT mediated polymerization process. AB - The synthesis of grafted PMMA homopolymer films is reported using a surface initiated reversible addition-fragmentation chain transfer (SI-RAFT) polymerization from a RAFT-agent immobilized on a silanized stainless steel surface. Therefore, stainless steel surfaces were hydroxylated with piranha solution followed by silanization with 3-aminopropylsilane (APS). The pendant primary amino groups of the cross-linked polysiloxane layer were reacted with 4 cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid N hydroxysuccinimide ester to produce a surface with covalently immobilized RAFT agents. PMMA homopolymers of different molecular weights between 13 060 and 45 000 g/mol were then prepared by a surface-initiated RAFT polymerization. Molecular weight (MW) and polydispersity index (PDI) were determined from sacrificial polymerization in solution. The different steps of stainless steel surface modification and the ultrathin films were investigated using atomic force microscopy (AFM), static, X-ray photoelectron spectroscopy (XPS), attenuated total reflectance infrared spectroscopy (ATR-IR), and ellipsometry. PMID- 24053196 TI - The forgotten ureteric stent: what next? PMID- 24053197 TI - Effects of double ligation of Stensen's duct on the rabbit parotid gland. AB - Salivary gland duct ligation is an alternative to gland excision for treating sialorrhea or reducing salivary gland size prior to tumor excision. Duct ligation also is used as an approach to study salivary gland aging, regeneration, radiotherapy, sialolithiasis and sialadenitis. Reports conflict about the contribution of each salivary cell population to gland size reduction after ductal ligation. Certain cell populations, especially acini, reportedly undergo atrophy, apoptosis and proliferation during reduction of gland size. Acini also have been reported to de-differentiate into ducts. These contradictory results have been attributed to different animal or salivary gland models, or to methods of ligation. We report here a bilateral double ligature technique for rabbit parotid glands with histologic observations at 1, 7, 14, 30, 60 days after ligation. A large battery of special stains and immunohistochemical procedures was employed to define the cell populations. Four stages with overlapping features were observed that led to progressive shutdown of gland activities: 1) marked atrophy of the acinar cells occurred by 14 days, 2) response to and removal of the secretory material trapped in the acinar and ductal lumens mainly between 30 and 60 days, 3) reduction in the number of parenchymal (mostly acinar) cells by apoptosis that occurred mainly between 14-30 days, and 4) maintenance of steady-state at 60 days with a low rate of fluid, protein, and glycoprotein secretion, which greatly decreased the number of leukocytes engaged in the removal of the luminal contents. The main post- ligation characteristics were dilation of ductal and acinar lumens, massive transient infiltration of mostly heterophils (rabbit polymorphonuclear leukocytes), acinar atrophy, and apoptosis of both acinar and ductal cells. Proliferation was uncommon except in the larger ducts. By 30 days, the distribution of myoepithelial cells had spread from exclusively investing the intercalated ducts pre-ligation to surrounding a majority of the residual duct-like structures, many of which clearly were atrophic acini. Thus, both atrophy and apoptosis made major contributions to the post-ligation reduction in gland size. Structures also occurred with both ductal and acinar markers that suggested acini differentiating into ducts. Overall, the reaction to duct ligation proceeded at a considerably slower pace in the rabbit parotid glands than has been reported for the salivary glands of the rat. PMID- 24053198 TI - Population-based determinants of radical prostatectomy operative time. AB - OBJECTIVES: To determine factors that influence radical prostatectomy (RP) operative times. Operative time assessment is inherent to defining surgeon learning curves and evaluating quality of care. SUBJECTS/PATIENTS AND METHODS: Population-based observational cohort study using USA Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data of men diagnosed with prostate cancer during 2003-2007 who underwent robot-assisted radical prostatectomy (RARP, 3458 men) and retropubic RP (RRP, 6993) through to 2009. We obtained median operative time using anaesthesia administrative data for RP and used median regression to assess the contribution of patient, surgeon, and hospital factors to operative times. RESULTS: The median RARP operative time decreased from 315 to 247 min from 2003 to 2008-2009 (P < 0.001), while the median RRP operative time remained similar (195 vs 197 min, P = 0.90). In adjusted analysis, RARP vs RRP (parameter estimate [PE] 70.9; 95% confidence interval [CI] 58, 84; P < 0.001) and obesity (PE 15; 95% CI 7, 23; P < 0.001) were associated with longer operative times while higher surgeon volumes were associated with shorter operative times (P < 0.001). RPs performed by surgeons employed by group (parameter estimate [PE] 22.76; 95% CI -38, -7.49; P = 0.004) and non-government (PE -35.59; 95% CI 68.15, -3.03; P = 0.032) vs government facilities and non-profit vs government hospital ownership (PE -21.85; 95% CI -32.28, -11.42; P < 0.001) were associated with shorter operative times. CONCLUSIONS: During our study period, RARP operative times decreased by 68 min while RRP operative times remained stagnant. Higher surgeon volume was associated with shorter operative times, and selective referral or improved efficiency to the level of high-volume surgeons would net almost $15 million (USA dollars) in annual savings. PMID- 24053199 TI - Toward a cure for chronic lymphocytic leukemia: an attack on multiple fronts. PMID- 24053200 TI - Combination therapy for older men with colorectal cancer: are two drugs better than one? PMID- 24053202 TI - Treatment of acute promyelocytic leukemia with arsenic trioxide: clinical results and open questions. AB - Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia. The specific translocation t(15;17), which results in the fusion gene PML-RARA is the diagnostic and pathomechanistic hallmark of APL. By combination, treatment consisting of the differentiating agent all-trans retinoic acid (ATRA), which targets this molecular lesion, and cytotoxic chemotherapy, cure can be achieved in over 70% of patients. Recently, arsenic trioxide (ATO) has emerged to be the most active single agent in the treatment of APL. Previous studies employing ATO in relapse settings reported average complete remission rates of 85% and a mean overall survival of over 60%. In recent approaches installing ATO in first-line treatment, ATO-induced response rates comparable to previous combination regimen. The results of these newer studies indicate that the backbone of chemotherapy can be dramatically reduced or completely replaced by ATO and ATRA with similar or even better outcome. PMID- 24053203 TI - Management of premalignant lesions of the larynx. AB - Premalignant lesions of the laryngeal epithelium most commonly involve the glottis. Abnormal appearing mucosal lesions may warrant biopsy for histologic review before an assessment can be made regarding their risk for malignant transformation. Although higher degrees of dysplasia portend a greater chance for malignant transformation, findings of dysplasia or carcinoma in situ should prompt ablative therapy followed by surveillance for recurrence or progression. Risk factor modification remains important not only as a primary prevention strategy, but also to reduce the risk of progression to invasive carcinoma. We review the current evidence pertaining to the work-up and management of premalignant epithelial lesions of the larynx. Surgical excision continues to be the treatment of choice. Alternative therapies like photodynamic therapy and radiation may be employed in selected patients when surgical therapy is not the best option. PMID- 24053205 TI - Concurrent chemoradiotherapy versus induction chemotherapy followed by chemoradiotherapy (sequential approach) in the management of head and neck cancer. AB - Concurrent chemoradiation is considered the standard-of-care for locally advanced head and neck cancer of the hypopharynx, oropharynx and larynx, as well as unresectable disease. This paradigm was challenged by the introduction of induction chemotherapy (IC), which demonstrated non-inferiority in regards of overall survival (OS), along with increased organ preservation, when compared to the surgery and radiotherapy. More recently, IC followed by concurrent chemoradiation, the so-called sequential approach was developed in an attempt to decrease metastatic spread and improve locoregional control (LRC) rates, with much controversy amongst experts. A careful evaluation by a multidisciplinary team is necessary to recognize which patients should be offered this therapeutic approach due to a significantly greater rate of toxicity. Herein, we analyze the most current available evidence regarding the use of sequential therapy versus concurrent chemoradiation. Different factors including toxicity profile, adherence and patient characteristics play a major role in choosing the most appropriate treatment regimen. PMID- 24053204 TI - Chemoselection: a paradigm for optimization of organ preservation in locally advanced larynx cancer. AB - Definitive chemoradiation (CRT) and laryngectomy followed by postoperative radiotherapy (RT) are both considered standard-of-care options for the management of advanced laryngeal cancer. While organ preservation with chemoradiotherapy is often the preferred up-front approach for appropriately selected candidates, the functional benefits of organ preservation must be carefully balanced against the considerable morbidity of salvage laryngectomy in patients who fail primary chemoradiation. Up-front identification of patients who are likely to require surgical salvage, therefore, is an important aim of any organ preserving approach in order to minimize morbidity while maximizing organ preservation. To this end, a strategy of 'chemoselection', using the primary tumor's response after 1 cycle of induction chemotherapy as an in vivo method of selecting responders for definitive chemoradiation while reserving primary surgical management for non responders, has been employed extensively at our institution. The rationale, treatment results and future directions of this approach are discussed. PMID- 24053206 TI - Synoptic pathology reporting for thyroid cancer: a review and institutional experience. AB - Thyroid cancer surgical pathology reports contain information that is critical for diagnosis, determining completeness of resection, staging and guiding postoperative management. Traditional narrative pathology reporting is prone to errors and omissions with variability in content and completeness. The objective of this review was to evaluate the impact of synoptic reporting on thyroid cancer pathology reporting. Our institutional study of pathology reporting of differentiated thyroid cancers at a Canadian tertiary care institution relative to the College of American Pathologists checklists is also presented and critically evaluates deficiencies in the narrative pathology reporting format. PMID- 24053207 TI - Elotuzumab and daratumumab: emerging new monoclonal antibodies for multiple myeloma. AB - Multiple myeloma (MM) has been mostly incurable due to its highly complex and heterogeneous molecular abnormalities and the support from myeloma microenvironment factors. A therapeutic strategy which effectively targets relevant and specific molecule to myeloma cells, and which is potent in overcoming tumor microenvironment-mediated drug resistance needs to be developed. One of the promising fields is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This review focuses on the basic and clinical aspects of two emerging and promising novel MoAbs for MM, elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are relatively specific to myeloma cells and expressed in more than 90% of MM patients, and mediate adhesion of myeloma cells to bone marrow stromal cells. We also discuss the unique characteristics of the two MoAbs by comparing with other MoAbs being developed for MM. PMID- 24053208 TI - Recurrent or refractory primary central nervous lymphoma: therapeutic considerations. AB - Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin lymphoma (NHL) that involves the brain, leptomeninges, eyes or spinal cord without evidence of systemic disease. Despite the high complete remission rate achieved with aggressive first-line therapy, 10-35% of PCNSL are treatment refractory and 35-60% of patients relapse. Standard therapy for recurrent or refractory disease has not yet been established, although retrospective data suggests improvement in survival with salvage therapy. The reported survival after relapse of PCNSL varies between 2 months and 24 months, with most series reporting an average of 4-12 months. The outcomes depend on whether treatment is instituted or not, suggesting a need for treatment guidelines for these patients. We review therapeutic approaches and their outcomes in recurrent or refractory PCNSL. PMID- 24053209 TI - Hematological malignancies: role of miRNAs and their in silico aspects. AB - Hematological malignancies is a broad term that includes blood cell cancers including chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), Myelodysplastic syndrome, acute lymphocytic leukemia (ALL), multiple myelomas (MM) and lymphomas. miRNAs are ~22-nt long non coding RNAs that play a very important role in gene regulation by binding to mRNA at their complementary sequence. These miRNAs are conceptually connected with various signal and pathway networks that make them capable of regulating various diseases including hematological malignancies. These miRNAs are not only playing regulatory roles in hematological malignancies, but are also providing new potent markers for efficient diagnosis and prognosis for hematological malignancies patients. Since the discovery of very first miRNA, the importance and role of miRNAs have been established in various fields, and there is a need to search for new potent miRNAs and their targets. A large amount of sequence data have been generated in last few years, which has further generated the need to develop efficient and reliable computational tools to analyze and extract out relevant information promptly from raw data. Here, we review various possible roles played by miRNA in hematological malignancies, principles involved in miRNA gene identification, target prediction and their preceding role in hematological malignancies research. PMID- 24053210 TI - A follow-up study of neurometabolic alterations in female concussed athletes. AB - Athletes who sustain a concussion demonstrate a variety of symptoms and neuropsychological alterations that could be brought on by neurometabolic abnormalities. However, no study has yet investigated these aspects in female athletes using magnetic resonance spectroscopy. The present study investigated the neurometabolic and -psychological effects of a concussion in the acute (7-10 days postinjury) and chronic (6 months postinjury) phases after injury. Eleven female concussed athletes and 10 female control athletes were scanned at both time points in a 3T magnetic resonance imaging scanner. Neuropsychological and symptomatic evaluations were completed at each time point. Neuropsychological alterations and a higher severity of symptoms were found in the acute phase in concussed athletes, relative to controls, but showed recovery in the chronic phase. Concussed athletes showed neurometabolic impairment in prefrontal and motor cortices characterized by a pathological increase of glutamine/glutamate and creatine (Cr) only in the chronic phase. Also, a significant decrease in N acetyl-aspartate/Cr ratio was observed in control athletes at the second time point. Concussed female athletes showed acute cognitive alterations and higher severity of symptoms that do not appear to be underlied by neurometabolic abnormalities, which are only present in the chronic postinjury phase. PMID- 24053211 TI - Socioeconomic variation in the burden of chronic conditions and health care provision--analyzing administrative individual level data from the Basque Country, Spain. AB - BACKGROUND: Chronic diseases are posing an increasing challenge to society, with the associated burden falling disproportionally on more deprived individuals and geographical areas. Although the existence of a socioeconomic health gradient is one of the main concerns of health policy across the world, health information systems commonly do not have reliable data to detect and monitor health inequalities and inequities. The objectives of this study were to measure the level of socioeconomic-related inequality in prevalence of chronic diseases and to investigate the extent and direction of inequities in health care provision. METHODS: A dataset linking clinical and administrative information of the entire population living in the Basque Country, Spain (over 2 million individuals) was used to measure the prevalence of 52 chronic conditions and to quantify individual health care costs. We used a concentration-index approach to measure the extent and direction of inequality with respect to the deprivation of the area of residence of each individual. RESULTS: Most chronic diseases were found to be disproportionally concentrated among individuals living in more deprived areas, but the extent of the imbalance varies by type of disease and sex. Most of the variation in health care utilization was explained by morbidity burden. However, even after accounting for differences in morbidity, pro-poor horizontal inequity was present in specialized outpatient care, emergency department, prescription, and primary health care costs and this fact was more apparent in females than males; inpatient costs exhibited an equitable distribution in both sexes. CONCLUSIONS: Analyses of comprehensive administrative clinical information at the individual level allow the socioeconomic gradient in chronic diseases and health care provision to be measured to a level of detail not possible using other sources. This frequently updated source of information can be exploited to monitor trends and evaluate the impact of policy reforms. PMID- 24053212 TI - A novel RNA binding protein affects rbcL gene expression and is specific to bundle sheath chloroplasts in C4 plants. AB - BACKGROUND: Plants that utilize the highly efficient C4 pathway of photosynthesis typically possess kranz-type leaf anatomy that consists of two morphologically and functionally distinct photosynthetic cell types, the bundle sheath (BS) and mesophyll (M) cells. These two cell types differentially express many genes that are required for C4 capability and function. In mature C4 leaves, the plastidic rbcL gene, encoding the large subunit of the primary CO2 fixation enzyme Rubisco, is expressed specifically within BS cells. Numerous studies have demonstrated that BS-specific rbcL gene expression is regulated predominantly at post transcriptional levels, through the control of translation and mRNA stability. The identification of regulatory factors associated with C4 patterns of rbcL gene expression has been an elusive goal for many years. RESULTS: RLSB, encoded by the nuclear RLSB gene, is an S1-domain RNA binding protein purified from C4 chloroplasts based on its specific binding to plastid-encoded rbcL mRNA in vitro. Co-localized with LSU to chloroplasts, RLSB is highly conserved across many plant species. Most significantly, RLSB localizes specifically to leaf bundle sheath (BS) cells in C4 plants. Comparative analysis using maize (C4) and Arabidopsis (C3) reveals its tight association with rbcL gene expression in both plants. Reduced RLSB expression (through insertion mutation or RNA silencing, respectively) led to reductions in rbcL mRNA accumulation and LSU production. Additional developmental effects, such as virescent/yellow leaves, were likely associated with decreased photosynthetic function and disruption of associated signaling networks. CONCLUSIONS: Reductions in RLSB expression, due to insertion mutation or gene silencing, are strictly correlated with reductions in rbcL gene expression in both maize and Arabidopsis. In both plants, accumulation of rbcL mRNA as well as synthesis of LSU protein were affected. These findings suggest that specific accumulation and binding of the RLSB binding protein to rbcL mRNA within BS chloroplasts may be one determinant leading to the characteristic cell type-specific localization of Rubisco in C4 plants. Evolutionary modification of RLSB expression, from a C3 "default" state to BS cell-specificity, could represent one mechanism by which rbcL expression has become restricted to only one cell type in C4 plants. PMID- 24053213 TI - A national survey of radiation oncologists and urologists on recommendations of prostate-specific antigen screening for prostate cancer. AB - OBJECTIVE: To assess recommendations for prostate-specific antigen (PSA) screening in a national survey of radiation oncologists and urologists following the recent USA Preventive Services Task Force (USPSTF) grade D recommendation. METHODS: A random sample of 1366 radiation oncologists and urologists were identified from the American Medical Association Physician Masterfile. From November 2011 to April 2012, a mail survey was sent to query PSA screening recommendations for men at average risk of prostate cancer for the following age groups: 40-49, 50-59, 60-69, 70-74, 75-79 and >=80 years. Multivariable logistic regression was used to test for differences in PSA-based screening recommendations by physician characteristics. RESULTS: Response rates were similar at 52% for radiation oncologists and urologists (P = 0.92). Overall, 51.5% of respondents recommended PSA-based screening for men aged 40-49 years, while nearly all endorsed it for those aged 50-74 years (96.1% for 50-59, 97.3% for 60-69, and 87.7% for 70-74 years). However, screening recommendations decreased to 43.9% and 12.8% for men aged 75-79 and >=80 years, respectively. On multivariable analysis, urologists were more likely to recommend screening for men aged 40-49 (odds ratio [OR] 3.09; P < 0.001) and 50-59 years (OR 3.81; P = 0.01), but less likely for men aged 75-79 (OR 0.66; P = 0.01) and >=80 years (OR 0.45; P = 0.002) compared with radiation oncologists. CONCLUSION: While radiation oncologists and urologists recommended PSA screening for men aged 50-69 years, there was less agreement about screening for younger (40-49 years old) and older (>=70 years) men at average risk for prostate cancer. PMID- 24053214 TI - A comparative study of hollow copper sulfide nanoparticles and hollow gold nanospheres on degradability and toxicity. AB - Gold and copper nanoparticles have been widely investigated for photothermal therapy of cancer. However, degradability and toxicity of these nanoparticles remain concerns. Here, we compare hollow CuS nanoparticles (HCuSNPs) with hollow gold nanospheres (HAuNS) in similar particle sizes and morphology following intravenous administration to mice. The injected pegylated HCuSNPs (PEG-HCuSNPs) are eliminated through both hepatobiliary (67 percentage of injected dose, %ID) and renal (23 %ID) excretion within one month postinjection. By contrast, 3.98 %ID of Au is excreted from liver and kidney within one month after iv injection of pegylated HAuNS (PEG-HAuNS). Comparatively, PEG-HAuNS are almost nonmetabolizable, while PEG-HCuSNPs are considered biodegradable nanoparticles. PEG-HCuSNPs do not show significant toxicity by histological or blood chemistry analysis. Principal component analysis and 2-D peak distribution plots of data from matrix-assisted laser desorption ionization-time-of-flight imaging mass spectrometry (MALDI-TOF IMS) of liver tissues demonstrated a reversible change in the proteomic profile in mice receiving PEG-HCuSNPs. This is attributed to slow dissociation of Cu ion from CuS nanoparticles along with effective Cu elimination for maintaining homeostasis. Nonetheless, an irreversible change in the proteomic profile is observed in the liver from mice receiving PEG-HAuNS by analysis of MALDI-TOF IMS data, probably due to the nonmetabolizability of Au. This finding correlates with the elevated serum lactate dehydrogenase at 3 months after PEG HAuNS injection, indicating potential long-term toxicity. The comparative results between the two types of nanoparticles will advance the development of HCuSNPs as a new class of biodegradable inorganic nanomaterials for photothermal therapy. PMID- 24053215 TI - Prevalence and risk factors for resistant hypertension among hypertensive patients from a developing country. AB - BACKGROUND: To study the prevalence and define deferential risk factors for 'Resistant' hypertension (RHT) in a hypertensive population of South Asian origin. METHODS: A descriptive cross-sectional study was carried out among hypertensive patients attending clinics at the Cardiology Unit, Colombo from July October 2009. All the patients with hypertension who provided informed written consent were recruited to the study (n = 277). A pre-tested interviewer administered questionnaire was used for data collection. A binary logistic regression analysis was performed in all patients with 'presence of RHT' as the dichotomous dependent variable and other independent co-variants. RESULTS: Mean age was 61 +/- 10.3 years and 50.2% were males. The mean of average systolic and diastolic blood pressures (BP) were 133.04 +/- 12.91 mmHg and 81.07 +/- 6.41 mmHg respectively. Uncontrolled BP was present in 41.1% (n = 114) of patients, of which RHT was present in 19.1% (n = 53). Uncontrolled BP were due to 'therapeutic inertia' in 27.8% of the study population. Those with diabetes mellitus, obesity (BMI > 27.5 kg/m2) and those who were older than 55 years were significantly higher in the RHT group than in the non-RHT group. In the binary logistic regression analysis older age (OR:1.36), longer duration of hypertension (OR:1.76), presence of diabetes mellitus (OR:1.67) and being obese (OR:1.84) were significantly associated with RHT. CONCLUSION: A significant proportion of the hypertensive patients were having uncontrolled hypertension. Nearly 1/5th of the population was suffering from RHT, which was significantly associated with the presence of obesity and diabetes mellitus. Therapeutic inertia seems to contribute significantly towards the presence of uncontrolled BP. PMID- 24053216 TI - Ergonomics and nursing in hospital environments. AB - This study describes workplace conditions, the environment, and activities that may contribute to musculoskeletal injuries among nurses, as well as identifies solutions to decrease these risks and improve work-related conditions. The study used a mixed-methods design. Participants included nurses and stakeholders from five hospitals. Several focus groups were held with nurses, walk-throughs of clinical units were conducted, and stakeholder interviews with key occupational health and safety personnel were conducted in each of the five hospitals, as well as with representatives from the American Nurses Association, Veterans Health Administration hospital, and National Institute for Occupational Safety and Health. Several key contributing factors, including the physical environment (e.g., layout and organization of work stations), work organization and culture (e.g., heavy workload, inadequate staffing, lack of education), and work activities (e.g., manual lifting of patients, lack of assistive devices), were identified. Recommendations included the need for a multifaceted and comprehensive approach to developing a sound ergonomics program. PMID- 24053217 TI - Exploring workplace violence among home care workers in a consumer-driven home health care program. AB - Nominal research has examined sexual harassment and workplace violence against home care workers within consumer-driven home care models such as those offered in Oregon. This study examined home care workers' experiences of violence while providing care to consumer employers, the patients who hire and manage home care workers. Focus groups and interviews were conducted in Oregon with 83 home care workers, 99 Oregon Department of Human Services (DHS) employees, and 11 consumer employers. Home care workers reported incidents of workplace physical violence (44%), psychological abuse (65%), sexual harassment (41%), and sexual violence (14%). Further, three themes were identified that may increase the risk of workplace violence: (1) real and perceived barriers to reporting violence; (2) tolerance of violence; and (3) limited training to prevent violence. To ensure worker safety while maintaining quality care, safety policies and training for consumer employers, state DHS employees, and home care workers must be developed. PMID- 24053218 TI - The effect of cushioning insoles on back and lower extremity pain in an industrial setting. AB - The purpose of this study was to examine the relationship between low back pain and lower extremity pain in a group of factory workers and determine the effect of cushioning insoles on low back pain and lower extremity pain. Data were gathered via questionnaire from 306 employees of an aircraft engine assembly factory. A subset of 40 workers who had reported significant levels of back or lower extremity pain were sampled for four consecutive 12-hour shifts wearing their normal footwear and then a week later for four consecutive shifts wearing cushioning insoles. High levels of low back pain and lower extremity pain were reported by workers on the plant floor, but low back pain was poorly correlated to lower extremity pain (r = 0.371). The effect of insoles on the subset of 40 workers was to lower low back pain by 38%, foot pain by 37%, and knee pain by 38% (p < .001). The reduction in low back pain, however, was not correlated to the reduction in lower extremity pain; workers reporting a decrease in low back pain differed from those reporting less lower extremity pain. PMID- 24053219 TI - Evaluation of a cardiovascular Risk Reduction Program at a workplace medical clinic. AB - The Cardiovascular Risk Reduction Program (CVRRP) was implemented in the 3M Medical Clinic in December 2009. The goal of the CVRRP was to evaluate 3M employees at risk for developing cardiovascular disease (CVD) and address any related modifiable risk factors with appropriate intervention strategies through clinic visits with a 3M nurse practitioner or physician and, if needed, a registered dietitian and/or exercise professional. Data for the first 100 participants were analyzed to initially assess the effectiveness of the program. Based on this evaluation, the 3M CVRRP and active collaboration between participants and providers in the workplace successfully reduced modifiable CVD risk factors. PMID- 24053220 TI - Urinary tract abnormalities in boys with recurrent urinary tract infections after hypospadias repair. AB - OBJECTIVE: To examine the development of recurrent urinary tract infections (UTIs) in boys who have undergone hypospadias repair. MATERIALS AND METHODS: We retrospectively reviewed the records of all boys who had recurrent UTIs after primary or redo tubularized incised plate (TIP) or transverse island flap (TVIF) repairs, between 1998 and 2009. Data on age, operating details, postoperative complications and imaging studies were collected. We attempted to identify risk factors for recurrent UTIs after hypospadias repair. RESULTS: During the study period, 43/2249 boys (1.91%) were diagnosed with recurrent UTIs after hypospadias repair. The boys' mean (range) age at repair was 14 (6-24) months and the median (range) follow-up was 6.5 (1.5-11) years. Primary TIP and TVIF were performed in 47% (20/43) and 35% (15/43) of the boys, respectively. Redo surgeries were performed in 18% of the boys (8/43). The initial meatal location was proximal in all TVIF and redo repairs, and in one of the TIP repairs. Postoperative voiding cysto-urethrography, ultrasonography and dimercapto-succinic acid (DMSA) scans were performed in 58% (25/43), 90% (39/43) and 19% (8/43) of the boys, respectively. Abnormalities were noted. Of those boys who underwent a TVIF repair, urethral diverticula were seen in 47% (7/15) and urethral fistulae were also seen in 47% (7/15). Conversely, in those who had a TIP repair, an elevated PVR and vesico-ureteric reflux were more common; they were found in 40% (8/20) and 50% (10/20) of patients, respectively. CONCLUSIONS: The pathophysiology of recurrent UTI is multifactorial, but postoperative complications seem to vary with type of procedure. Recurrent UTIs after hypospadias surgery should prompt a specific assessment for potentially functionally relevant and correctable anatomical abnormalities. PMID- 24053221 TI - Food availability of glucose and fat, but not fructose, increased in the U.S. between 1970 and 2009: analysis of the USDA food availability data system. AB - BACKGROUND: Obesity rates in the United States have risen consistently over the last four decades, increasing from about 13% of the population in 1970 to more than 34% in 2009. Dietary fructose has been blamed as a possible contributor to the obesity increase, although the consumption pattern of fructose and other key nutrients during this 40 year period remains a topic of debate. Therefore, we analyzed the USDA Loss-Adjusted Food Availability Database in combination with the USDA Nutrient Database for Standard Reference (Release 24) to determine whether fructose consumption in the US has increased sufficiently to be a casual factor in the rise in obesity prevalence. METHODS: Per capita loss-adjusted food availability data for 132 individual food items were compiled and analyzed. Nutrient profiles for each of these foods were used to determine the availability of energy as well as macronutrients and monosaccharides during the years 1970 2009. The percent change in energy from food groups and individual nutrients was determined by using the year 1970 as the baseline and area-under-the-curve analysis of food trends. RESULTS: Our findings indicate that during this 40 year period the percent change in total energy availability increased 10.7%, but that the net change in total fructose availability was 0%. Energy available from total glucose (from all digestible food sources) increased 13.0%. Furthermore, glucose availability was more than 3-times greater than fructose. Energy available from protein, carbohydrate and fat increased 4.7%, 9.8% and 14.6%, respectively. CONCLUSIONS: These data suggest that total fructose availability in the US did not increase between 1970 and 2009 and, thus, was unlikely to have been a unique causal factor in the increased obesity prevalence. We conclude that increased total energy intake, due to increased availability of foods providing glucose (primarily as starch in grains) and fat, to be a significant contributor to increased obesity in the US. PMID- 24053222 TI - Erectile dysfunction in men treated for testicular cancer. AB - OBJECTIVE: To study the unique characteristics of erectile dysfunction (ED) in a population of men who developed ED after testicular cancer (TC) diagnosis and treatment. PATIENTS AND METHODS: All men treated for TC who presented for sexual function evaluation were included in an institutional database. All men underwent standard evaluation including a history/physical examination, completion of the International Index of Erectile Function (IIEF) questionnaire, testosterone/gonadotropin measurement and penile duplex Doppler ultrasonography (DUS). RESULTS: The study population comprised 76 men whose mean (SD) age was 29 (8) years and of whom 25% were married/had a partner. In all, 39% of the patients had seminoma and 61% had non-seminomatous germ-cell tumour (NSGCT). A total of 66% of patients with seminoma underwent radiation therapy. Of the patients with NSGCT, 79% received chemotherapy, 18% underwent primary retroperitoneal lymph node dissection (RPLND) and 20% underwent post-chemotherapy RPLND. The mean (SD) time before seeking sexual medicine consultation was 12 (7) months after treatment completion, the median (range) number of vascular risk factors was 0 (0 2) and the mean (SD) remaining testis volume was 16 (8) mL. Mean (SD) total testosterone, luteinizing hormone, follicle-stimulating hormone levels were 312 (186) ng/dL, 9 (7) IU/mL, 17 (12) IU/mL. A total of 26% of patients had total testosterone levels <300 ng/dL. In all, 84% of patients complained primarily of loss of erection-sustaining capability and 24% had episodes of transient ED before TC diagnosis. The mean (SD) IIEF erectile function domain score was 16 (7). All the patients (100%) had a normal DUS. Mean (SD) peak systolic and end diastolic velocities were 48 (16) and 1.2 (2.2) cm/s, respectively. A total of 88% of patients responded to phosphodiesterase type 5 inhibitor (PDE5i) use with erections sufficient for penetration, but 12% did not (mean [SD] erectile function domain score 27 [5] vs 17 [6]). There were no differences in haemodynamics between those men with and without hypogonadism. CONCLUSIONS: Men with TC presenting with ED after treatment appear uniformly to have normal erectile haemodynamics, suggesting adrenaline-mediated ED. While the majority of TC survivors with ED respond successfully to PDE5i, a significant minority do not. PMID- 24053223 TI - Increased breast cancer risk for patients with multiple sclerosis: a nationwide population-based cohort study. AB - BACKGROUND AND PURPOSE: Studies have suggested that multiple sclerosis (MS) might be linked to an overall reduced cancer rate, but a positive relationship is also found for several types of cancer. This study determines whether MS is associated with cancer risk in Taiwan. METHODS: Data from the National Health Insurance System of Taiwan were used to assess this issue. The MS cohort included 1292 patients, and each patient was randomly frequency-matched with four participants without MS, based on their age, sex and index year (control cohort). Cox proportional hazards regression analysis was conducted to estimate the influence of MS on cancer risk. RESULTS: A significantly higher risk of developing overall cancer was found amongst the MS cohort compared with the control cohort [adjusted hazard ratio (HR) 1.85, 95% confidence interval (CI) 1.26-2.74], as well as breast cancer (adjusted HR 2.23, 95% CI 1.11-4.46). CONCLUSIONS: The nationwide population-based cohort study revealed that Taiwanese patients with MS have a higher risk of developing overall cancer types and breast cancer in particular. PMID- 24053224 TI - Off-pathway alpha-synuclein oligomers seem to alter alpha-synuclein turnover in a cell model but lack seeding capability in vivo. AB - Aggregated alpha-synuclein is the major component of Lewy bodies, protein inclusions observed in the brain in neurodegenerative disorders such as Parkinson's disease and dementia with Lewy bodies. Experimental evidence indicates that alpha-synuclein potentially can be transferred between cells and act as a seed to accelerate the aggregation process. Here, we investigated in vitro and in vivo seeding effects of alpha-synuclein oligomers induced by the reactive aldehyde 4-oxo-2-nonenal (ONE). As measured by a Thioflavin-T based fibrillization assay, there was an earlier onset of aggregation when alpha synuclein oligomers were added to monomeric alpha-synuclein. In contrast, exogenously added alpha-synuclein oligomers did not induce aggregation in a cell model. However, cells overexpressing alpha-synuclein that were treated with the oligomers displayed reduced alpha-synuclein levels, indicating that internalized oligomers either decreased the expression or accelerated the degradation of transfected alpha-synuclein. Also in vivo there were no clear seeding effects, as intracerebral injections of alpha-synuclein oligomers into the neocortex of alpha synuclein transgenic mice did not induce formation of proteinase K resistant alpha-synuclein pathology. Taken together, we could observe a seeding effect of the ONE-induced alpha-synuclein oligomers in a fibrillization assay, but neither in a cell nor in a mouse model. PMID- 24053225 TI - Discrimination of intonation contours by adolescents with cochlear implants. AB - OBJECTIVE: Differences in fundamental frequency (F0) contour peak alignment contribute to the perception of pitch accents in speech intonation. The present study assessed the discrimination of differences in F0 contour peak alignment by adolescent users of cochlear implants (CIs). DESIGN: In Experiment 1, subjects discriminated between rise-fall F0 contours located early in the syllable and those aligned late. Recorded utterances with manipulated F0 were used as stimuli and all subjects wore a unilateral CI. In Experiment 2, bilaterally-implanted subjects repeated Experiment 1 in the bilateral condition. STUDY SAMPLE: Twenty one CI users aged 12-21 years participated. A normally-hearing control group (n = 20) also completed Experiment 1. RESULTS: Listeners with normal hearing (NH) could discriminate between F0 peaks differing by 80 ms or more. Results varied among the CI users, with only four users displaying a pattern of results similar to that of the NH listeners. Sixteen CI users responded inconsistently or at chance levels (p > 0.05; binomial test). Ten CI users who were bilaterally implanted completed the tests in unilateral and bilateral listening conditions. CONCLUSIONS: Results suggest that CI users may have difficulty discriminating between F0 alignment and that use of bilateral implants did not provide an advantage to discrimination. PMID- 24053226 TI - Using response time to speech as a measure for listening effort. AB - OBJECTIVE: Speech signals that do not differ in intelligibility might differ in listening effort. This study aimed to investigate the effect of background noise on response time to intelligible speech. DESIGN: We added various amounts of stationary noise to spoken digit triplets and measured the influence of noise on the response time for both an identification and an arithmetic task: Task 1 'identify the final digit in a triplet', and Task 2 'calculate the sum of the initial and the final digits in a triplet.' STUDY SAMPLE: Twelve normal-hearing participants with a mean age of 30.6 years (range: 28-44 years). RESULTS: Response time increased with lower (i.e. worse) signal to noise ratios for both tasks, even for signal to noise ratios with almost maximum intelligibility (close to 100%). The response time during the arithmetic task was more affected by the noise than during the identification task, but the arithmetic task demonstrated higher variance. CONCLUSIONS: The response time to digit triplets reduces significantly for increasing signal to noise ratios, even where speech intelligibility is optimal. These differences in response time might be related to listening effort and as such might be used to evaluate hearing-aid signal processing at positive SNRs. PMID- 24053227 TI - A general linear model-based approach for inferring selection to climate. AB - BACKGROUND: Many efforts have been made to detect signatures of positive selection in the human genome, especially those associated with expansion from Africa and subsequent colonization of all other continents. However, most approaches have not directly probed the relationship between the environment and patterns of variation among humans. We have designed a method to identify regions of the genome under selection based on Mantel tests conducted within a general linear model framework, which we call MAntel-GLM to Infer Clinal Selection (MAGICS). MAGICS explicitly incorporates population-specific and genome-wide patterns of background variation as well as information from environmental values to provide an improved picture of selection and its underlying causes in human populations. RESULTS: Our results significantly overlap with those obtained by other published methodologies, but MAGICS has several advantages. These include improvements that: limit false positives by reducing the number of independent tests conducted and by correcting for geographic distance, which we found to be a major contributor to selection signals; yield absolute rather than relative estimates of significance; identify specific geographic regions linked most strongly to particular signals of selection; and detect recent balancing as well as directional selection. CONCLUSIONS: We find evidence of selection associated with climate (P < 10-5) in 354 genes, and among these observe a highly significant enrichment for directional positive selection. Two of our strongest 'hits', however, ADRA2A and ADRA2C, implicated in vasoconstriction in response to cold and pain stimuli, show evidence of balancing selection. Our results clearly demonstrate evidence of climate-related signals of directional and balancing selection. PMID- 24053228 TI - Laser irradiation of ZnO:Al/Ag/ZnO:Al multilayers for electrical isolation in thin film photovoltaics. AB - Laser irradiation of ZnO:Al/Ag/ZnO:Al transparent contacts is investigated for segmentation purposes. The quality of the irradiated areas has been experimentally evaluated by separation resistance measurements, and the results are complemented with a thermal model used for numerical simulations of the laser process. The presence of the Ag interlayer plays two key effects on the laser scribing process by increasing the maximum temperature reached in the structure and accelerating the cool down process. These evidences can promote the use of ultra-thin ZnO:Al/Ag/ZnO:Al electrode in large-area products, such as for solar modules. PMID- 24053229 TI - Intestinal-type of differentiation predicts favourable overall survival: confirmatory clinicopathological analysis of 198 periampullary adenocarcinomas of pancreatic, biliary, ampullary and duodenal origin. AB - BACKGROUND: Periampullary adenocarcinomas comprise pancreatic, distal bile duct, ampullary and duodenal adenocarcinoma. The epithelia of these anatomical structures share a common embryologic origin from the foregut. With steadily increasing numbers of pancreatoduodenectomies over the last decades, pathologists, surgeons and oncologists are more often confronted with the diagnosis of "other than pancreatic" periampullary cancers. The intestinal subtype of ampullary cancer has been shown to correlate with better prognosis. METHODS: Histological subtype and immunohistochemical staining pattern for CK7, CK20 and CDX2 were assessed for n = 198 cases of pancreatic ductal, distal bile duct, ampullary and duodenal adenocarcinoma with clinical follow-up. Routine pathological parameters were included in survival analysis performed with SPSS 20. RESULTS: In univariate analysis, intestinal subtype was associated with better survival in ampullary, pancreatic ductal and duodenal adenocarcinoma. The intestinal type of pancreatic ductal adenocarcinoma was not associated with intraductal papillary mucinous neoplasm and could not be reliably diagnosed by immunohistochemical staining pattern alone. Intestinal differentiation and lymph node ratio, but not tumor location were independent predictors of survival when all significant predictor variables from univariate analysis (grade, TNM stage, presence of precursor lesions, surgical margin status, perineural, vascular and lymphatic vessel invasion, CK7 and CDX2 staining pattern) were included in a Cox proportional hazards model. CONCLUSIONS: Intestinal type differentiation and lymph node ratio but not tumor location are independent prognostic factors in pooled analysis of periampullary adenocarcinomas. We conclude that differentiation is more important than tumor location for prognostic stratification in periampullary adenocarcinomas. PMID- 24053230 TI - Five-year outcomes after iodine-125 seed brachytherapy for low-risk prostate cancer at three cancer centres in the UK. AB - OBJECTIVE: To report the outcomes of >1000 men with low-risk prostate cancer treated with low-dose-rate (LDR) brachytherapy at three large UK cancer centres. PATIENTS AND METHODS: A total of 1038 patients with low-risk prostate cancer (prostate-specific antigen [PSA] <=10 ng/mL, Gleason score 6, <=T2b disease) were treated with LDR iodine 125 (I-125) brachytherapy between 2002 and 2007. Patients were treated at three UK centres. PSA and clinical follow-up was performed at each centre. Biochemical recurrence-free survival was reported for the cohort. RESULTS: The median (range) PSA follow-up for the whole group was 5 years (4 months to 9 years). A total of 79 patients had biochemical failure, defined by a rise in PSA level: 16 patients fulfilled the ASTRO definition of biochemical failure, 25 patients fulfilled the Phoenix definition and 38 patients fulfilled both definitions. The 5-year biochemical relapse-free survival (bRFS) rate was 94.1% by the ASTRO definition and 94.2% by the Phoenix definition. The absence of neoadjuvant hormone therapy was predictive of inferior biochemical control as defined by the Phoenix definition (P = 0.033). CONCLUSIONS: Our prospective multicentre series showed excellent bRFS with LDR I-125 brachytherapy for patients with low-risk prostate cancer. Further work is necessary to define the role of neoadjuvant androgen deprivation therapy in combination with brachytherapy. PMID- 24053231 TI - Subdomain architecture and stability of a giant repeat protein. AB - Tandem repeat proteins, which are widespread in the human genome, tend to exhibit high stability and favorable expression, and hence, they are emerging as promising protein scaffolds in alternative to antibodies in biotechnology. In order to investigate the origin of the stability of these proteins, we dissect the subdomain architecture of the giant repeat protein PR65/A, which comprises 15 alpha-helical HEAT repeats, using a series of truncations and deletions. We find that the N (HEAT 1-2) and the C (HEAT 14-15) subdomains are not capable of independent folding, but the addition of HEAT 13 to HEAT 14-15 results in an independently stable C-terminal subdomain (HEAT 13-15), which is in turn further stabilized by the inclusion of HEAT 12 (HEAT 12-15). We also further show that the stability of HEAT 13-15 is enhanced by its fusion to HEAT 1-2, and the artificial 5-HEAT-repeat protein thereby created (HEAT NC) behaves like a cooperative multidomain protein. We construct further variants, lacking one or both of the terminal subdomains, and find that such subdomains function as stabilizing caps within full-length PR65/A as in their absence, the central subdomain of the protein unfolds to form non-native beta-sheet-like oligomers. Taken together, our results suggest that in full-length PR65/A, the more unstable regions within the central repeats are protected by the adjacent folded repeats, which thus act as gatekeepers by virtue of their greater stability. PMID- 24053232 TI - Viability analysis of oocyte-follicle complexes and gonadal fragments of zebrafish as baseline for toxicity testing. AB - To achieve more information about growth and development of oocytes in teleost fish or concerning toxicity testing, it is necessary to develop adequate in vitro oocyte culture conditions. Herein, initial stages of zebrafish oocytes (I, primary; II, cortical; III, vitellogenic) were analyzed under serum-free medium conditions as gonadal fragments or as separated oocyte-follicle complexes. Two vital dye staining methods (MTT, trypan blue) were applied to assess mitochondrial activity and membrane integrity of the oocytes during 4 days, and compared to morphological alterations studied by transmission electron microscopy. Vital dye staining indicated reduced viability at day 4 for all stages in both in vitro culture methods. Additionally, the viability decreased significantly in gonadal fragments at day 2 for stages III (MTT, TB) and II (TB only). Signs of degradation at the ultrastructural level (vacuoles, disintegration of endoplasmic reticulum and detachment of follicular cell layers) appeared in gonadal fragments at day 4 for stages II and III, and in separated oocyte-follicle complexes both at day 4 for stages I-III, and at day 2 for stage III. In conclusion, zebrafish oocytes at stages I and II seemed viable for 2 days as separated oocyte-follicle complexes considering their mitochondrial activity, membrane integrity and ultrastructural morphology. Cultured as gonadal fragments, the majority of analyses indicated similar results for stages I and II oocytes. In contrast, stage III oocytes seemed viable for not longer than 24 h. Results should be taken into consideration for the experimental design of in vitro assays using teleost fish oocytes. PMID- 24053233 TI - LC-MS/MS of large molecules in a regulated bioanalytical environment - which acceptance criteria to apply? PMID- 24053234 TI - Phase I and beyond - the importance of switching to patient's plasma: considerations and perspectives on bioanalytical procedures. PMID- 24053235 TI - Hydrophilic strong anion exchange chromatography for proteomics: what's the future outlook? PMID- 24053236 TI - Biomarkers of sepsis can predict death. PMID- 24053237 TI - Bioanalysis annual round-up: the bioanalysis editorial team is delighted to welcome you to this mid-year round-up. AB - This year has so far proven to be another eventful one for the journal and its affiliated website Bioanalysis Zone. Key highlights include the unveiling of the finalists for the annual Young Investigator Award [1] , the publication of four exciting special issues and a selection of noteworthy White Papers, as well as the addition of more new features on Bioanalysis Zone. Not only this, but the Impact Factor of Bioanalysis increased to 3.253 (2012), demonstrating the journal's continuing high editorial standards. This mid-year round-up looks at the highlights of the year to date and features a selection of must-read articles from volume 5. Enjoy! PMID- 24053238 TI - Electron paramagnetic resonance in a biomedical laboratory. PMID- 24053239 TI - Metabolomics pilot study to identify volatile organic compound markers of childhood asthma in exhaled breath. AB - BACKGROUND: In-community non-invasive identification of asthma-specific volatile organic compounds (VOCs) in exhaled breath presents opportunities to characterize phenotypes, and monitor disease state and therapies. The feasibility of breath sampling with children and the preliminary identification of childhood asthma markers were studied. METHOD: End-tidal exhaled breath was sampled (2.5 dm3) from 11 children with asthma and 12 healthy children with an adaptive breath sampler. VOCs were collected onto a Tenax(r)/Carbotrap hydrophobic adsorbent trap, and analyzed by GC-MS. Classification was by retention-index and mass spectra in a 'breath matrix' followed by multivariate analysis. RESULTS: A panel of eight candidate markers (1-(methylsulfanyl)propane, ethylbenzene, 1,4-dichlorobenzene, 4-isopropenyl-1-methylcyclohexene, 2-octenal, octadecyne, 1-isopropyl-3 methylbenzene and 1,7-dimethylnaphtalene) were found to differentiate between the asthmatic and healthy children in the test cohort with complete separation by 2D principal components analysis (2D PCA). Furthermore, the breath sampling protocol was found to be acceptable to children and young people. CONCLUSION: This method was found to be acceptable for children, and healthy and asthmatic individuals were distinguished on the basis of eight VOCs at elevated levels in the breath of asthmatic children. PMID- 24053240 TI - Quantification of D-dimer levels in human saliva. AB - BACKGROUND: Plasma D-dimer tests are currently used to exclude deep vein thrombosis and pulmonary embolism. Human saliva has numerous advantages over blood as a diagnostic sample. The aims of our study were to develop a reliable immunoassay to detect D-dimer levels in saliva, and to determine the correlation between salivary and blood D-dimer levels. RESULTS/METHODOLOGY: Saliva and blood samples were collected from 40 healthy volunteers. We developed a AlphaLISA(r) immunoassay with acceptable analytical performances to quantify D-dimer levels in the samples. The median salivary D-dimer levels were 138.1 ng/ml (morning) and 140.7 ng/ml (afternoon), and the plasma levels were 75.0 ng/ml. Salivary D-dimer levels did not correlate with plasma levels (p = 0.61). CONCLUSION: For the first time, we have quantified D-dimer levels and found twofold increase in saliva (p < 0.05) than in plasma. Further studies are required to demonstrate the clinical relevance/utility of salivary D-dimer in patients with confirmed deep vein thrombosis and/or pulmonary embolism. PMID- 24053241 TI - Screening of synthetic cannabinoids in preserved oral fluid by UPLC-MS/MS. AB - BACKGROUND: The abuse of a rapidly changing range of synthetic cannabinoids is increasing worldwide. Oral fluid, which contains the parent compounds and is easily collected, could be a good alternative medium for drug screening for synthetic cannabinoids. RESULTS: A method for screening of 18 synthetic cannabinoids in preserved oral fluid collected with the Intercept(r) collection device, using UPLC-MS/MS, was validated. Limits of quantification ranged from 0.2 to 2 ng/ml in oral fluid. In several real cases, AM-2201 and/or JWH-018 were found. CONCLUSION: The presented method allowed rapid and sensitive screening of synthetic cannabinoids in preserved oral fluid collected with the Intercept collection device. PMID- 24053242 TI - Generation and evaluation of antibodies against human MGF E-peptide by reverse phase protein microarray and reverse competitive ELISA. AB - BACKGROUND: Since 2005, as one of prohibited substances on the Prohibited List of the World Anti-Doping Agency (WADA), the occurence of mechano growth factor (MGF) abuse in sport has likely increased. However, there is still no WADA-validated and -approved method for its detection. RESULTS: Four polyclonal antibodies (Ab K01, Ab-B01, Ab-B02 and Ab-K02) against MGF C-terminal peptides were generated, purified and evaluated by western blot, ELISA and reverse-phase protein microarray, respectively. It was found that all the antibodies could identify their corresponding antigen in mouse serum by reverse-phase protein microarray, in particular, Ab-K01 showed the highest affinity among them and might be a potential tool for the detection of antibody affinity. Furthermore, Ab-B01 and Ab K01 were successfully used for the determination of MGF-40 by reverse competitive ELISA. CONCLUSION: The quantitative measurement of MGF-40 has laid the foundation for doping detection of MGF and further biological research on MGF. PMID- 24053243 TI - Ultrasound assisted dispersive liquid-liquid microextraction followed by injector port silylation: a novel method for rapid determination of quinine in urine by GC MS. AB - BACKGROUND: Silylation is a widely used derivatization method for the analysis of polar analytes by GC-MS. Ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) is an ecofriendly, rapid and simple microextraction method. For the first time, a novel approach has been developed and applied for the analysis of quinine in urine by combining UA-DLLME with injection port silylation. RESULTS: The LOD and LOQ were found to be 5.4 and 18 ng/ml. The intra and inter-day precisions were less than 5 and 8%, respectively. Mean recoveries of quinine were found to be in the range of 87 to 96%. CONCLUSION: Ultrasound assisted dispersive liquid-liquid microextraction is rapid, simple and consumes less reagent for the analysis of polar analytes such as quinine. PMID- 24053244 TI - Detection of volatile organic compounds as biomarkers in breath analysis by different analytical techniques. AB - Breath is a rich mixture containing numerous volatile organic compounds at trace amounts (ppbv-pptv level) such as: hydrocarbons, alcohols, ketones, aldehydes, esters or heterocycles. The presence of some of them depends on health status. Therefore, breath analysis might be useful for clinical diagnostics, therapy monitoring and control of metabolic or biochemical cell cycle products. This Review presents an update on the latest developments in breath analysis applied to diagnosing different diseases with the help of high-quality equipment. Efforts were made to fully and accurately describe traditional and modern techniques used to determine the components of breath. The techniques were compared in terms of design, function and also detection limit of different volatile organic compounds. GC with different detectors, MS, optical sensor and laser spectroscopic detection techniques are also discussed. PMID- 24053245 TI - Determination of pteridines in biological samples with an emphasis on their stability. AB - Pteridines are a group of endogenous heterocyclic compounds whose concentrations in biological fluids may be increased in some disorders, such as infections, autoimmune disorders and cancer. In particular, pteridine concentrations in urine may represent promising noninvasive markers. However, their specificity requires further investigation. Pteridines can occur in three oxidation states with different stability. In order to enable the analysis of the unstable di- and tetra-hydroforms either an oxidation (mainly with iodine) or stabilization by reducing agents is applied. Due to the high polarity of pteridines, many analytical procedures employed ion-pair, ion-exchange or hydrophilic interaction liquid chromatography using mostly fluorescence detection. In the last decade, MS was found to be applicable. The objective of this Review is to show possibilities and different approaches in pteridine analysis in biological samples. PMID- 24053248 TI - The formation of surface multilayers at the air-water interface from sodium diethylene glycol monoalkyl ether sulfate/AlCl3 solutions: the role of the alkyl chain length. AB - The influence of the alkyl chain length on surface multilayer formation at the air-water interface for the anionic surfactant sodium diethylene glycol monoalkyl ether sulfate, SAE2S, in the presence of Al(3+) multivalent counterions, in the form of AlCl3, is described. In the absence of electrolyte, the saturated monolayer adsorption is determined by the headgroup geometry and is independent of the alkyl chain length. In the presence of Al(3+) counterions, surface multilayer formation occurs, due to the strong SAE2S/Al(3+) binding and complexation. The neutron reflection data show that the alkyl chain length of the surfactant has a significant impact upon the evolution of the surface multilayer structure with surfactant and AlCl3 concentration. Increasing the alkyl chain length from decyl to tetradecyl results in the surface multilayer formation occurring at lower surfactant and AlCl3 concentrations. At the short alkyl chain lengths, decyl and dodecyl, the regions of multilayer formation with a small number of bilayers are increasingly extended with decreasing alkyl chain length. For the alkyl chain lengths of tetradecyl and hexadecyl, the surface behavior is further affected by decreases in the surfactant solubility in the presence of AlCl3, and this ultimately dominates the surface behavior at the longer alkyl chain lengths. PMID- 24053249 TI - Microwave imaging: perception and reality. PMID- 24053250 TI - Digital breast tomosynthesis: the future of mammography screening or much ado about nothing? PMID- 24053252 TI - Will biventricular pacing replace right ventricular pacing for antibradycardia therapy? AB - Evaluation of: Curtis AB, Worley SJ, Adamson PB, et al; Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) Trial Investigators. Biventricular pacing for atrioventricular block and systolic dysfunction. N. Engl. J. Med. 368(17), 1585-1593 (2013). Recent trials have shown the benefit of cardiac resynchronization (CRT) in mild or moderate heart failure with a left bundle branch block or intraventricular conduction delay. Randomized trials (including the BLOCK-HF study) have now shown that irrespective of baseline QRS duration, long-term left ventricular (LV) remodeling, dysfunction and heart failure are more common in patients with long term conventional right ventricular (RV) than those with biventricular (BiV) pacing. The detrimental effects of long-term RV pacing may occur in patients with normal and abnormal LV ejection fractions (LVEF). LV dysfunction induced by RV pacing can be improved by upgrading to a BiV system. Possible new indications for CRT (currently under investigation), include heart failure due to diastolic dysfunction (normal LVEF) with left bundle branch block or intraventricular conduction delay in the absence of bradycardia, and conditions not necessarily associated with a wide QRS complex or bradycardia, such as hypertrophic cardiomyopathy and LV non-compaction. The widespread use of CRT will be limited by the greater complications of LV pacing, unfamiliarity with implantation techniques and cost. At first, CRT will be favored in young patients and those with a low LVEF where ventricular pacing is required >40% of the time. PMID- 24053253 TI - Evolving technologies in robotic surgery for minimally invasive treatment of gynecologic cancers. AB - Since the introduction of robotic technology, there have been significant changes to the field of gynecologic oncology. The number of minimally invasive procedures has drastically increased, with robotic procedures rising remarkably. With recent evidence suggesting that minimally invasive techniques should be the standard of care for early endometrial and cervical cancers, the push for new technology and advancements has continued. Several emerging robotic technologies have significant potential in the field of gynecologic oncology. The single-site robotic platform enables robotic surgery through a single incision; the Firefly camera detects the fluorescent dye indocyanine green, which may improve sensitivity in sentinel lymph node biopsy; and a robotic vessel-sealing device and stapler will continue to improve efficiency of the robotic surgeon. PMID- 24053254 TI - Engineering perspective on the evolution of push/pull-based dialysis treatments. AB - The incidence of kidney disease is rapidly increasing worldwide, and techniques and devices for treating end-stage renal disease (ESRD) patients have been evolving. Better outcomes achieved by convective treatment have encouraged the use of synthetic membranes with high water permeability in clinical setups, and high-flux hemodialysis (HD) and hemodiafiltration (HDF) are now preferred forms of convective therapy in ESRD patients. Push/pull-based dialysis strategies have also been examined to increase convective mass transfer in ESRD patients. The push/pull technique uses the entire membrane as a forward filtration domain for a period of time. However, backfiltration must accompany the forward filtration to compensate for the fluid depletion resulting from the forward filtration, making it necessary to switch the membranes to a backfiltration domain. This paper attempts to describe the advancement of push/pull-based renal supportive treatments in terms of their technical description, hemodialytic efficacy including fluid management accuracy and applicability for clinical use. How the optimization of push and pull actions could translate into better convective efficiency will also be discussed in depth. PMID- 24053255 TI - The composite of hydroxyapatite and calcium sulphate: a review of preclinical evaluation and clinical applications. AB - Recent publications have shown that the combination of alpha-calcium sulfate hemihydrate, the densest form of hydrates and hydroxyapatite (HA) particles gives good clinical outcome in various applications. It has large potential as bone substitute since the material transforms to bone throughout the entire volume and not only by creeping substitution, from the surface toward the inside. Release of important proteins for osteogenesis has been observed around implanted material and is speculated to be due to fast dissolution of the calcium sulfate phase in combination with the osteoconductive and bioactive nature of HA. In diabetic foot infection, the osteoconductive HA/calcium sulfate material has been successfully used loaded with antibiotics and since it is injectable, the application is minimally invasive, easy and precise. It is a bone substitute for the future. PMID- 24053256 TI - Selaginella tamariscina extract suppresses TPA-induced invasion and metastasis through inhibition of MMP-9 in human nasopharyngeal carcinoma HONE-1 cells. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is known for its high incidence of neck lymph node metastasis, which represents poor prognosis. The present study aimed to examine the anti-metastatic properties of Selaginella tamariscina extract (STE) in human nasopharyngeal carcinoma HONE-1 cells in vitro. METHODS: Cell viability was examined by MTT assay, whereas cell motility was measured by invasive, migration and would healing assays. Real-time PCR, and promoter assays confirmed the inhibitory effects of STE on matrix metalloproteinase-9 (MMP-9) mRNA level in HONE-1 cells. RESULTS: The STE inhibits 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced HONE-1 cell migration and invasion in a concentration dependent manner. By zymographic and Western blot analyses, STE was shown to inhibit the activities and expression of MMP-9. Treatment of STE on TPA-induced HONE-1 cells inhibited MMP-9 expression and ERK1/2 phosphorylation without affecting JNK and p38 phosphorylation. CONCLUSIONS: STE inhibits MMP-9 expression and HONE-1 cell metastasis. Its inhibitory effects may involve the Src/FAK/ERK 1/2 pathway. STE may have the potential of being an anti-metastatic agent against NPC. PMID- 24053257 TI - Better together? a naturalistic qualitative study of inter-professional working in collaborative care for co-morbid depression and physical health problems. AB - BACKGROUND: Mental-physical multi-morbidities pose challenges for primary care services that traditionally focus on single diseases. Collaborative care models encourage inter-professional working to deliver better care for patients with multiple chronic conditions, such as depression and long-term physical health problems. Successive trials from the United States have shown that collaborative care effectively improves depression outcomes, even in people with long-term conditions (LTCs), but little is known about how to implement collaborative care in the United Kingdom. The aim of the study was to explore the extent to which collaborative care was implemented in a naturalistic National Health Service setting. METHODS: A naturalistic pilot study of collaborative care was undertaken in North West England. Primary care mental health professionals from IAPT (Increasing Access to Psychological Therapies) services and general practice nurses were trained to collaboratively identify and manage patients with co morbid depression and long-term conditions. Qualitative interviews were performed with health professionals at the beginning and end of the pilot phase. Normalization Process Theory guided analysis. RESULTS: Health professionals adopted limited elements of the collaborative care model in practice. Although benefits of co-location in primary care practices were reported, including reduced stigma of accessing mental health treatment and greater ease of disposal for identified patients, existing norms around the division of mental and physical health work in primary care were maintained, limiting integration of the mental health practitioners into the practice setting. Neither the mental health practitioners nor the practice nurses perceived benefits to joint management of patients. CONCLUSIONS: Established divisions between mental and physical health may pose particular challenges for multi-morbidity service delivery models such as collaborative care. Future work should explore patient perspectives about whether greater inter-professional working enhances experiences of care. The study demonstrates that research into implementation of novel treatments must consider how the introduction of innovation can be balanced with the need for integration into existing practice. PMID- 24053258 TI - Problem drinking as a risk factor for tuberculosis: a propensity score matched analysis of a national survey. AB - BACKGROUND: Epidemiological and other evidence strongly supports the hypothesis that problem drinking is causally related to the incidence of active tuberculosis and the worsening of the disease course. The presence of a large number of potential confounders, however, complicates the assessment of the actual size of this causal effect, leaving room for a substantial amount of bias. This study aims to contribute to the understanding of the role of confounding in the observed association between problem drinking and tuberculosis, assessing the effect of the adjustment for a relatively large number of potential confounders on the estimated prevalence odds ratio of tuberculosis among problem drinkers vs. moderate drinkers/abstainers in a cross-sectional, nationally representative sample of the South African adult population. METHODS: A propensity score approach was used to match each problem drinker in the sample with a subset of moderate drinkers/abstainers with similar characteristics in respect to a set of potential confounders. The prevalence odds ratio of tuberculosis between the matched groups was then calculated using conditional logistic regression. Sensitivity analyses were conducted to assess the robustness of the results in respect to misspecification of the model. RESULTS: The prevalence odds ratio of tuberculosis between problem drinkers and moderate drinkers/abstainers was 1.97 (95% CI: 1.40 to 2.77), and the result was robust with respect to the matching procedure as well as to incorrect adjustment for potential mediators and to the possible presence of unmeasured confounders. Sub-population analysis did not provide noteworthy evidence for the presence of interaction between problem drinking and the observed confounders. CONCLUSION: In a cross-sectional national survey of the adult population of a middle income country with high tuberculosis burden, problem drinking was associated with a two fold increase in the odds of past TB diagnosis after controlling for a large number of socio-economic and biological confounders. Within the limitations of a cross-sectional study design with self-reported tuberculosis status, these results adds to previous evidence of a causal link between problem drinking and tuberculosis, and suggest that the observed higher prevalence of tuberculosis among problem drinkers commonly found in population studies cannot be attributed to the confounding effect of the uneven distribution of other risk factors. PMID- 24053259 TI - Foreword. PMID- 24053260 TI - Intimate partner violence: office screening for victims and perpetrators of IPV. AB - Intimate partner violence (IPV) affects more than 12 million individuals annually. Power and control are central concepts underlying abusive relationships. Physicians may see IPV victims, perpetrators, and their children for annual examinations, as well as for injuries and health conditions associated with abuse. In 2013, the US Preventive Services Task Force recommended that women of childbearing age (ie, 14 to 46 years) be screened for IPV. Brief, validated screening tools, such as the 4-item Hurt, Insult, Threaten, and Scream (HITS), can be used to facilitate screening. Physicians should always assess patients whose medical histories or presenting symptoms or injuries are consistent with abuse. Risk factors for IPV and consequences of abuse include general health conditions (eg, asthma, irritable bowel syndrome), reproductive issues (eg, gynecologic disorders, unintended pregnancies), psychological conditions (eg, depression, sleep disturbances), and risky health behaviors (eg, substance use, poor health care adherence). Tools for identifying perpetrators are under investigation. To prepare the practice to address IPV, physicians should educate themselves and staff and learn about community and national resources. By identifying and responding to IPV, clinicians may be able to reduce IPV and interrupt the intergenerational cycle of violence. PMID- 24053261 TI - Intimate partner violence: counseling, community resources, and legal issues for IPV victims and perpetrators. AB - The family physician's office is a potentially safe place to discuss intimate partner violence (IPV). RADAR (Remember to ask routinely, Ask directly [in private], Document findings, Assess safety, Review options) is a tool for identifying and responding to IPV. Physicians should ask permission to document abuse, consider using a body map, and ensure confidentiality. They should also assess immediate safety by asking about weapons in the home, children's safety, and the likelihood that the perpetrator will harm him- or herself or others. Federal privacy laws require physicians to inform patients about health information disclosure. Because mandatory reporting varies by state, physicians should communicate clearly the office's responsibilities. Interventions are based on an advocacy model that requires appropriate training and establishment of links to community-based resources. Brief advocacy includes providing information cards, whereas intensive intervention includes IPV education, danger assessment, prevention options, safety planning, and community referrals. The Stages of Change Model may help physicians understand a patient's readiness and ability to make a change. For the IPV survivor who has left an abusive partner, physicians should be aware of the challenges of safety, health, legal, and financial issues; protection orders are a possible safety strategy. The most common intervention for perpetrators is a batterer intervention program. Couples counseling by family physicians is contraindicated. PMID- 24053262 TI - Intimate partner violence: childhood exposure to domestic violence. AB - Children who are exposed to domestic violence (DV) may experience many short- and long-term negative effects. They are up to 3.8 times more likely to become perpetrators or victims in adulthood than are children not exposed to DV. They also are at high risk of health problems, risky health behaviors, violence, and social functioning problems. Girls who witness intimate partner violence (IPV) are more likely to experience depression, anxiety, and trauma symptoms, and boys exposed to IPV are more likely to exhibit aggression and delinquent behaviors. To prepare the practice to identify and assist children exposed to DV, physicians should undergo training, implement screening protocols, use caution when documenting findings, collaborate with local agencies, and learn about the state's reporting laws. State and local DV service programs or other community resources can provide assessment and intervention assistance. Social workers, mental health professionals, and child and DV advocates can assist in providing treatment for children exposed to violence. Physicians should schedule follow-up appointments for children who need treatment, monitor behavior, and coordinate intervention services. PMID- 24053263 TI - Intimate partner violence: IPV in the LGBT community. AB - Nationally, the rates of intimate partner violence (IPV) among lesbian, gay, bisexual, or transgender (LGBT) individuals are similar to or greater than rates for heterosexuals. Many have experienced psychological and physical abuse as sexual minorities, making it difficult for them to seek help for IPV. Physician behavior, such as not assuming that all patients are heterosexual, being nonjudgmental, and using inclusive language, can empower LGBT patients to disclose IPV. Also, physicians should ascertain the degree to which the patient is out. The threat of being outed can be an aspect of the power and control exerted by an abusive partner and a significant barrier to seeking help. Physicians should screen for IPV and intervene in a similar manner with LGBT and non-LGBT patients, but they should be aware of potential limitations in resources for LGBT patients, such as shelters. As sexual minorities experiencing IPV, LGBT individuals are at greater risk of depression and substance abuse than are non LGBT individuals. Minority stress, resulting from stigmatization and discrimination, can be exacerbated by IPV. Physicians should learn about legal issues for LGBT individuals and the availability of community or advocacy programs for LGBT perpetrators or victims of IPV. PMID- 24053264 TI - Sensorimotor polyneuropathy after hexavalent vaccination. AB - New vaccines in infants are generally well tolerated and serious adverse events are rare. We present a patient who developed severe sensorimotor polyneuropathy 2 weeks after the first immunization with hexavalent routine vaccine (INFANRIX hexa). Through intense physiotherapy the infant made a complete recovery. PMID- 24053265 TI - Bayesian methods for expression-based integration of various types of genomics data. AB - : We propose methods to integrate data across several genomic platforms using a hierarchical Bayesian analysis framework that incorporates the biological relationships among the platforms to identify genes whose expression is related to clinical outcomes in cancer. This integrated approach combines information across all platforms, leading to increased statistical power in finding these predictive genes, and further provides mechanistic information about the manner in which the gene affects the outcome. We demonstrate the advantages of the shrinkage estimation used by this approach through a simulation, and finally, we apply our method to a Glioblastoma Multiforme dataset and identify several genes potentially associated with the patients' survival. We find 12 positive prognostic markers associated with nine genes and 13 negative prognostic markers associated with nine genes. PMID- 24053266 TI - Description of transthyretin S50A, S52P and G47A mutations in familial amyloidosis polyneuropathy. AB - OBJECTIVE: To describe 58 subjects with rare TTR mutations, and to compare the different biomarkers between carriers and patients. METHODS: TTR gene sequence test was performed in 15 suspicious subjects and in their direct family. All positive subjects undertook prospective evaluations in a period of 49 months. RESULTS: Of 95 genetic tests performed, 58 (61%) were positive for TTR mutations, Ser50Arg mutation in 38 (65%), Ser52Pro in 15 (26%) and Gly47Ala in 5 (9%). Initial symptoms were neuropathic in 19 (73%), gastrointestinal in 6 (23%) and autonomic in 1 (4%). CONCLUSIONS: The natural history of Ser50Arg, Ser52Pro and Gly47Ala TTR mutations is similar to the Val30Met mutation described in endemic areas. The small fiber assessments were the initial tests to show abnormalities in asymptomatic subjects. PMID- 24053267 TI - Assessment of Junior Doctor performance: a validation study. AB - BACKGROUND: In recent years, Australia has developed a National Junior Doctor Curriculum Framework that sets out the expected standards and describes areas of performance for junior doctors and through this has allowed a national approach to junior doctor assessment to develop. Given the significance of the judgments made, in terms of patient safety, development of junior doctors, and preventing progression of junior doctors moving to the next stage of training, it is essential to develop and validate assessment tools as rigorously as possible. This paper reports on a validation study of the Junior Doctor Assessment Tool as used for PGY1 doctors to evaluate the psychometric properties of the instrument and to explore the effect of length of experience as a PGY1 on assessment scores. METHODS: This validation study of the Australian developed Junior Doctor Assessment Tool as it was used in three public and other associated hospitals in Western Australia for PGY1 across a two year period addressed two core aims, namely: (1) to evaluate the psychometric properties of the instrument; (2) to explore the effect of length of experience as a PGY1 on assessment scores. RESULTS: The highest mean scores were for professional behaviours, teamwork and interpersonal skills and the lowest were for procedures. Most junior doctors were assessed three or more times and scores were not different in the first rotation compared to subsequent rotations. While statistically significant, there appeared to be little practical influence on scores obtained by the number of times they were assessed. Principal component analysis identified two principal components of junior doctor performance are being assessed rather than the commonly reported three. A Cronbach Alpha of .883 was calculated for the 10 item scale. CONCLUSIONS: Now that the components of the tool have been analysed it will be more meaningful and potentially more influential to consider these factors on the potential educational impact of this assessment process for monitoring junior doctor development and progression. PMID- 24053269 TI - New generation sequencing in pathogen discovery and microbial surveillance. AB - The annual congress of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) is recognized as the largest European congress for the presentation and discussion of the key priorities and more recent scientific developments in the fields of clinical microbiology and infection. This year, it attracted almost 10,000 participants from all over the world. Keynote lectures, symposia, meet-the-expert sessions, educational workshops, poster and oral sessions covered the diagnosis, treatment, epidemiology and prevention of infectious diseases, as well as related basic microbiology. Moreover, interactive sessions addressing specific subjects underlined the important educational aspect of the ECCMID's congress. The scientific program, abstracts, oral presentations are available at their website [101] . This meeting report is focused on one of the several challenging and one of the most transversal topics of the meeting: the application of the next-generation sequencing (NGS) to the microbial world. PMID- 24053270 TI - Is there really no benefit to combination therapy with colistin? AB - Despite many theoretical and in vitro advantages, clinical data comparing combination therapy with colistin + rifampicin to colistin alone for infection due to extremely-drug resistant (XDR) Acinetobacter baumanni are scarce and limited by small numbers and/or low quality evidence. This article represents the first large, randomized, controlled, prospective study comparing colistin monotherapy and combination therapy. The reviewed article found no difference in all cause or infection related mortality, though there was an improved rate of microbiological clearance in the combination therapy arm. This study adds important new data to the literature and sets the stage for future studies that can be designed to overcome the limitations of this study, which are discussed in detail below. Based on this study, we cannot say definitively that combination therapy is not warranted for treatment of invasive infection due to A. baumannii, but the results do suggest that rifampicin is not an ideal agent to be combined with colistin. PMID- 24053271 TI - Epidemiological and behavioral factors associated with Crimean-Congo hemorrhagic fever virus infections in humans. AB - Crimean-Congo hemorrhagic fever (CCHF), a viral disease with high fatality rate, is endemic in many countries in Europe, the Middle East, Asia and Africa. It is transmitted to humans either by tick bite or by direct contact with blood or tissues of viremic patients or livestock. Aim of the present study was to review the main epidemiological characteristics of the disease worldwide, with special attempt to show the epidemiological and behavioral factors that play a role in acquisition of the infection. It is obvious that these factors differ among countries, and the knowledge and understanding of the transmission routes in each region facilitates the implementation of proper control measures, the awareness enhancement and the prevention of the disease. PMID- 24053272 TI - Use of bacteriophages in the treatment of Pseudomonas aeruginosa infections. AB - Phage therapy for Pseudomonas aeruginosa infections has been used for more than 50 years. Controlled investigation into its use dates from the early 1990s when positive laboratory studies of local and systemic infection were followed by clinical studies: symptomatic improvement and phage multiplication were seen in a pet dog with otitis and a human with an infected burn. Antibiotic resistance has renewed interest in this approach. There have been recent positive reports in the treatment of experimental animal infection including systemic and respiratory infections. Phages have shown promise against experimental biofilms. Two small recent clinical trials in otitis, of dogs and of human patients have provided some encouraging results. Phage has potential in the treatment of antibiotic resistant infection by P. aeruginosa. Hence, full scale clinical trials are needed. PMID- 24053273 TI - Prediction of prognosis by markers in community-acquired pneumonia. AB - Early identification of patients with community-acquired pneumonia (CAP) at risk of poor outcome is critical for defining site of care and may impact on hospital resource consumption and prognosis. The Pneumonia Severity Index and CURB-65 are clinical rules that accurately identify individuals at risk of death. However, these scores have some limitations. Therefore in recent years, increasing attention has been being paid to research on biomarkers, since they have the potential to resolve fundamental issues regarding prognostic prediction that cannot be readily addressed using CAP-specific scores. Nevertheless, the use of biomarkers in this context needs to be validated in prospective trials so as to elucidate how they can best be applied in practice. This review examines the usefulness of biomarkers, whether used alone or in conjunction with other clinical severity of illness scores, for identifying CAP patients at risk of short- and long-term mortality and for predicting both the need for intensive care unit admission and the potential for treatment failure. PMID- 24053274 TI - Therapeutic drug monitoring of voriconazole and posaconazole for invasive aspergillosis. AB - Voriconazole and posaconazole are extended-spectrum triazoles recommended for treatment, prophylaxis and salvage therapy of Aspergillus diseases. Over the past decade many papers have emerged supporting the use of therapeutic drug monitoring (TDM) for azole antifungals. TDM is used to tailor the exposure of a specific drug to the individuals to optimize treatment response and minimize side effects. We reviewed the pharmacokinetics and pharmacodynamics (PK-PD) characteristics of voriconazole and posaconazole. We present the available evidence on target concentrations defining maximal efficacy and minimal toxicity. Finally we provide some practical recommendations how to best perform TDM in clinical practice. PMID- 24053275 TI - Human toxoplasmosis: which biological diagnostic tests are best suited to which clinical situations? AB - The Toxoplasma gondii parasite is a worldwide threat most particularly in fetal life and immunosuppression. In most clinical situations (except in some ocular cases), correct detection or identification of toxoplasmosis requires biological analysis. This article considers the laboratory tools that have been developed in this field since the discovery of the pathogen, with emphasis on the most recent tests and how they can or should be used in different clinical situations. The authors also discuss the requirements and pitfalls that one should be aware of when biologically investigating this intriguing parasitosis. PMID- 24053276 TI - Evaluating Chagas disease progression and cure through blood-derived biomarkers: a systematic review. AB - This article reviews the usefulness of various types of blood-derived biomarkers that are currently being studied to predict the progression of Chagas disease in patients with the indeterminate form, to assess the efficacy of antiparasitic drugs and to identify early cardiac and gastrointestinal damage. The authors used a search strategy based on MEDLINE, Cochrane Library Register for systematic review, EmBase, Global Health and LILACS databases. Out of 1716 screened articles, only 166 articles were eligible for final inclusion. The authors classified the biomarkers according to their biochemical structure and primary biological activity in four groups: i) markers of inflammation and cellular injury, ii) metabolic biomakers, iii) prothrombotic biomarkers and iv) markers derived from specific antigens of the parasite. Several potential biomarkers might have clinical potential for the detection of early cardiopathy. Such capacity is imperative in order to detect high-risk patients who require intensive monitoring and earlier therapy. Prospective studies with longer follow ups are needed for the appraisal of biomarkers assessing clinical or microbiological cure after therapy. At the same time, studies evaluating more than one biomarker are useful to compare the efficacy among them given the lack of a recognized gold standard. PMID- 24053278 TI - Combined effects of C225 and 125-iodine seed radiation on colorectal cancer cells. AB - BACKGROUND: To characterize the effect of combined treatment of the anti epidermal growth factor receptor (EGFR) monoclonal antibody C225 and 125-iodine (125I) seed radiation in human colorectal cancer. METHODS: We treated LS180 cells with 125I continuous low dose rate radiation in the presence and absence of 100 nM C225. The clonogenic capacity, cellular proliferation, cell cycle distribution, apoptosis, and molecular pathways of the cells following the treatments were analyzed in vitro. RESULTS: The sensitizer enhancement ratio of C225 was approximately 1.4. Treatment with C225 and radiation alone produced significant inhibition of cell growth, but combination therapy produced greater inhibition than either treatment administered alone. C225 increased the radiation induced apoptosis and the fraction of gamma-H2AX foci positive cells at 48 h after treatment. The Akt phosphorylation level was lower in the cells receiving the combination treatment than in the cells treated with radiation or C225 alone. CONCLUSIONS: These findings indicate that C225 sensitizes LS180 cells to 125I seed radiation. Growth inhibition is mediated by inducing apoptosis and not cell cycle arrest. Additionally, we confirmed that C225 impairs DNA repair by reducing the cellular level of the DNA-PKcs and Ku70 proteins. Furthermore, the inhibition of Akt signaling activation may be responsible for the C225-mediated radiosensitization. PMID- 24053280 TI - Probability mapping of scarred myocardium using texture and intensity features in CMR images. AB - BACKGROUND: The myocardium exhibits heterogeneous nature due to scarring after Myocardial Infarction (MI). In Cardiac Magnetic Resonance (CMR) imaging, Late Gadolinium (LG) contrast agent enhances the intensity of scarred area in the myocardium. METHODS: In this paper, we propose a probability mapping technique using Texture and Intensity features to describe heterogeneous nature of the scarred myocardium in Cardiac Magnetic Resonance (CMR) images after Myocardial Infarction (MI). Scarred tissue and non-scarred tissue are represented with high and low probabilities, respectively. Intermediate values possibly indicate areas where the scarred and healthy tissues are interwoven. The probability map of scarred myocardium is calculated by using a probability function based on Bayes rule. Any set of features can be used in the probability function. RESULTS: In the present study, we demonstrate the use of two different types of features. One is based on the mean intensity of pixel and the other on underlying texture information of the scarred and non-scarred myocardium. Examples of probability maps computed using the mean intensity of pixel and the underlying texture information are presented. We hypothesize that the probability mapping of myocardium offers alternate visualization, possibly showing the details with physiological significance difficult to detect visually in the original CMR image. CONCLUSION: The probability mapping obtained from the two features provides a way to define different cardiac segments which offer a way to identify areas in the myocardium of diagnostic importance (like core and border areas in scarred myocardium). PMID- 24053281 TI - Multiple testing in orthopedic literature: a common problem? AB - BACKGROUND: Performing multiple tests in primary research is a frequent subject of discussion. This discussion originates from the fact that when multiple tests are performed, it becomes more likely to reject one of the null hypotheses, conditional on that these hypotheses are true and thus commit a type one error. Several correction methods for multiple testing are available. The primary aim of this study was to assess the quantity of articles published in two highly esteemed orthopedic journals in which multiple testing was performed. The secondary aims were to determine in which percentage of these studies a correction was performed and to assess the risk of committing a type one error if no correction was applied. METHODS: The 2010 annals of two orthopedic journals (A and B) were systematically hand searched by two independent investigators. All articles on original research in which statistics were applied were considered. Eligible publications were reviewed for the use of multiple testing with respect to predetermined criteria. RESULTS: A total of 763 titles were screened and 127 articles were identified and included in the analysis. A median of 15 statistical inference results were reported per publication in both journal A and B. Correction for multiple testing was performed in 15% of the articles published in journal A and in 6% from journal B. The estimated median risk of obtaining at least one significant result for uncorrected studies was calculated to be 54% for both journals. CONCLUSION: This study shows that the risk of false significant findings is considerable and that correcting for multiple testing is only performed in a small percentage of all articles published in the orthopedic literature reviewed. PMID- 24053279 TI - Single-molecule dynamics and mechanisms of metalloregulators and metallochaperones. AB - Understanding how cells regulate and transport metal ions is an important goal in the field of bioinorganic chemistry, a frontier research area that resides at the interface of chemistry and biology. This Current Topic reviews recent advances from the authors' group in using single-molecule fluorescence imaging techniques to identify the mechanisms of metal homeostatic proteins, including metalloregulators and metallochaperones. It emphasizes the novel mechanistic insights into how dynamic protein-DNA and protein-protein interactions offer efficient pathways via which MerR-family metalloregulators and copper chaperones can fulfill their functions. This work also summarizes other related single molecule studies of bioinorganic systems and provides an outlook toward single molecule imaging of metalloprotein functions in living cells. PMID- 24053308 TI - Role of multiparametric 3.0-Tesla magnetic resonance imaging in patients with prostate cancer eligible for active surveillance. AB - OBJECTIVE: To evaluate predictors of more aggressive disease and the role of multiparametric 3.0-T magnetic resonance imaging (MRI) in selecting patients with prostate cancer for active surveillance (AS). PATIENTS AND METHODS: We retrospectively assessed 298 patients with prostate cancer who met the Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, defined as T1c/T2, PSA level of <=10 ng/mL, PSA density (PSAD) of <0.2 ng/mL(2) , Gleason score <7, and one or two positive biopsy cores. All patients underwent preoperative MRI, including T2-weighted, diffusion-weighted, and dynamic contrast enhanced imaging, as well as radical prostatectomy (RP) between June 2005 and December 2011. Imaging results were correlated with pathological findings to evaluate the ability of MRI to select patients for AS. RESULTS: In 35 (11.7%) patients, no discrete cancer was visible on MRI, while in the remaining 263 (88.3%) patients, a discrete cancer was visible. Pathological examination of RP specimens resulted in upstaging (>T2) in 21 (7%) patients, upgrading (Gleason score >6) in 136 (45.6%), and a diagnosis of unfavourable disease in 142 (47.7%) patients. The 263 patients (88.3%) with visible cancer on imaging were more likely to have their cancer status upgraded (49.8% vs 14.3%) and be diagnosed with unfavourable disease (52.1% vs 14.3%) than the 35 patients (11.7%) with no cancer visible upon imaging, and these differences were statistically significant (P < 0.001 for all). A visible cancer lesion on MRI, PSAD, and patient age were found to be predictors of unfavourable disease in multivariate analysis. CONCLUSION: MRI can predict adverse pathological features and be used to assess the eligibility of patients with prostate cancer for AS. PMID- 24053309 TI - Inflammation and prostate cancer: the role of interleukin 6 (IL-6). AB - Environmental and genetic aspects are reflected in the development of prostate cancer. In this context, there is growing evidence that chronic inflammation is involved in the regulation of cellular events in prostate carcinogenesis, including disruption of the immune response and regulation of the tumour microenvironment. One of the best surrogates of chronic inflammation in prostate cancer is interleukin 6 (IL-6). Serum IL-6 levels are elevated in patients with untreated metastatic or castration-resistant prostate cancer (CRPC) and correlate negatively with tumour survival and response to chemotherapy. Via multiple signal pathways including the Janus tyrosine family kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, the extracellular signal-regulated kinase 1 and 2 (ERK1/2)-mitogen activated protein kinase (MAPK) pathway, and the phosphoinositide 3-kinase (PI3-K) pathway, IL-6 is able to promote prostate cancer cell proliferation and inhibit apoptosis in vitro and in vivo. IL-6 is associated with aggressive prostate cancer phenotype and may be involved in the metastatic process through regulation of epithelial-mesenchymal transition (EMT) and homing of cancer cells to the bone. A substantial body of evidence suggests that IL-6 plays a major role in the transition from hormone-dependent to CRPC, most notably through accessory activation of the androgen receptor. Collectively, these data have stimulated the development of agents targeting IL-6 signalling pathways. A chimeric anti-IL-6 monoclonal antibody has been tested in clinical trials, with mixed results. PMID- 24053310 TI - Comparison of an adjustable anchored single-incision mini-sling, Ajust((r)) , with a standard mid-urethral sling, TVT-O(TM) : a health economic evaluation. AB - OBJECTIVES: To assess the cost, quality of life (QoL) and cost-effectiveness of a single-incision mini-sling (SIMS; Ajust((r)) , C. R. Bard Inc., New Providence, NJ, USA) compared with a standard mid-urethral sling (SMUS; TVT-OTM, Ethicon Inc., Somerville, NJ, USA) in the surgical management of female stress urinary incontinence. PATIENTS AND METHODS: A total of 137 women, in a secondary care setting, were randomized between October 2009 and October 2011 to undergo SIMS placement (n = 69) under local anaesthesia as an opt-out policy or SMUS placement (n = 68) under general anaesthesia. Clinical outcome measures included the patient-reported success rate (Patient Global Impression of Improvement [PGI-I]) and the impact on the patients' QoL (King's Health Questionnaire [KHQ]). Health economic data (cost and quality-adjusted life year [QALY] data) were compared using linear regression models to generate an incremental cost per QALY estimate, in order to determine a measure of cost-effectiveness. Deterministic sensitivity analyses investigated uncertainty in the results, and non-parametric bootstrapping techniques were used to estimate a probability of cost effectiveness. RESULTS: There were no significant differences between the groups in terms of the KHQ total score (P = 0.27) or the patient-reported success rate (P = 1.00, odds ratio: 0.895; 95% confidence interval [CI]: 0.344 to 2.330). There was no significant difference in QALYs for the SIMS group compared with the SMUS group (mean difference: -0.003; 95% CI: -0.008 to +0.002). The SIMS was on average less costly, -L142.41 95% CI: (-316.99 to 32.17) and generated cost savings of L48 419 per QALY loss with 94% probability of cost savings to the health services. Taking a wider perspective on the costing analysis by including the wider community benefit associated with the significantly earlier return to work observed in the SIMS group (P = 0.006, 95% CI: 11.756 to 17.217), there was an increase in cost savings to -L477, (95% CI: -823.65 to -129.63), with a probability of 100% of cost savings to the wider economy. CONCLUSIONS: The adjustable anchored SIMS (Ajust), performed under local anaesthesia as an opt-out policy, delivers cost savings to the health service provider when compared with the SMUS (TVT-O), and is likely to be cost-effective up to 1 year after placement. Further research should be undertaken to confirm the results of our study over longer follow-up and should explore patient preferences alongside an adequately powered non-inferiority randomized controlled trial. PMID- 24053311 TI - Involvement of ethylene biosynthesis and signalling in fruit set and early fruit development in zucchini squash (Cucurbita pepo L.). AB - BACKGROUND: We have identified a kind of parthenocarpy in zucchini squash which is associated with an incomplete andromonoecy, i.e. a partial conversion of female into bisexual flowers. Given that andromonoecy in this and other cucurbit species is caused by a reduction of ethylene production in the female flower, the associated parthenocarpic development of the fruit suggested the involvement of ethylene in fruit set and early fruit development. RESULTS: We have compared the production of ethylene as well as the expression of 13 ethylene biosynthesis and signalling genes in pollinated and unpollinated ovaries/fruits of two cultivars, one of which is parthenocarpic (Cavili), while the other is non-parthenocarpic (Tosca). In the latter, unpollinated ovaries show an induction of ethylene biosynthesis and ethylene signal transduction pathway genes three days after anthesis, which is concomitant with the initiation of fruit abortion and senescence. Fruit set and early fruit development in pollinated flowers of both cultivars and unpollinated flowers of Cavili is coupled with low ethylene biosynthesis and signalling, which would also explain the partial andromonoecy in the parthenocarpic genotype. The reduction of ethylene production in the ovary cosegregates with parthenocarpy and partial andromonoecy in the selfing progeny of Cavili. Moreover, the induction of ethylene in anthesis (by ethephon treatments) reduced the percentage of bisexual parthenocarpic flowers in Cavili, while the inhibition of ethylene biosynthesis or response (by AVG and STS treatments) induces not only andromonoecy but also the parthenocarpic development of the fruit in both cultivars. CONCLUSIONS: Results demonstrate that a reduction of ethylene production or signalling in the zucchini flower is able to induce fruit set and early fruit development, and therefore that ethylene is actively involved in fruit set and early fruit development. Auxin and TIBA treatments, inducing fruit set and early fruit development in this species, also inhibit ethylene production and the expression of ethylene biosynthesis and response genes. A model is presented that discusses the crosstalk between ethylene and auxin in the control of fruit set and early fruit development in zucchini squash. PMID- 24053312 TI - NMR study of histidine metabolism during alcoholic and malolactic fermentations of wine and their influence on histamine production. AB - The metabolic pathways of amino acids play a crucial role in the organoleptic and hygienic quality in wines. In particular, histidine is one of the most studied amino acids of wines due to histamine toxicity in humans, a biogenic amine derived from histidine by enzymatic decarboxylation. The development of new tools to increase knowledge on metabolism that produces histamine in wine is critical. This study investigated by using nuclear magnetic resonance (NMR) spectroscopy the transformation of histidine into histaminol and histamine during alcoholic and malolactic fermentations. The transformations of histidine into histaminol during alcoholic fermentation and into histamine during malolactic fermentation were observed. This paper highlights the importance of selecting lactic acid bacteria for malolactic fermentation to avoid the production of biogenic amines such as histamine. PMID- 24053313 TI - Turning off hydrogen to realize seeded growth of subcentimeter single-crystal graphene grains on copper. AB - Subcentimeter single-crystalline graphene grains, with diameter up to 5.9 mm, have been successfully synthesized by tuning the nucleation density during atmospheric pressure chemical vapor deposition. Morphology studies show the existence of a single large nanoparticle (>~20 nm in diameter) at the geometric center of those graphene grains. Similar size particles were produced by slightly oxidizing the copper surface to obtain oxide nanoparticles in Ar-only environments, followed by reduction into large copper nanoparticles under H2/Ar environment, and are thus explained to be the main constituent nuclei for graphene growth. On this basis, we were able to control the nanoparticle density by adjusting the degree of oxidation and hydrogen annealing duration, thereby controlling nucleation density and consequently controlling graphene grain sizes. In addition, we found that hydrogen plays dual roles on copper morphology during the whole growth process, that is, removing surface irregularities and, at the same time, etching the copper surface to produce small nanoparticles that have only limited effect on nucleation for graphene growth. Our reported approach provides a highly efficient method for production of graphene film with long range electronic connectivity and structure coherence. PMID- 24053314 TI - Proposal for a prospective multi-centre audit of chronic subdural haematoma management in the United Kingdom and Ireland. AB - BACKGROUND. Chronic subdural haematoma (CSDH) is a common condition that increases in incidence with rising age. Evacuation of a CSDH is one of the commonest neurosurgical procedures; however the optimal peri-operative management, surgical technique, post-operative care and the role of adjuvant therapies remain controversial. AIM. We propose a prospective multi-centre audit in order to establish current practices, outcomes and national benchmarks for future studies. METHODS. Neurosurgical units (NSU) in the United Kingdom and Ireland will be invited to enrol patients to this audit. All adult patients aged 16 years and over with a primary or recurrent CSDH will be eligible for inclusion. OUTCOME MEASURES AND ANALYSIS. The proposed outcome measures are (1) clinical recurrence requiring re-operation within 60 days; (2) modified Rankin scale (mRS) score at discharge from NSU; (3) morbidity and mortality in the NSU; (4) destination at discharge from NSU and (5) length of stay in the NSU. Audit standards have been derived from published systematic reviews and a recent randomised trial. The proposed standards are clinical recurrence rate < 20%; unfavourable mRS (4-6) at discharge from NSU < 30%; mortality rate in NSU < 5%; morbidity rate in NSU < 10%. Data will be submitted directly into a secure online database and analysed by the study's management group. CONCLUSIONS. The audit will determine the contemporary management and outcomes of patients with CSDH in the United Kingdom and Ireland. It will inform national guidelines, clinical practice and future studies in order to improve the outcome of patients with CSDH. PMID- 24053315 TI - Boundary lubricant polymer films: effect of cross-linking. AB - We have studied the adsorption and lubricant properties of a multifunctional triblock copolymer poly(L-lysine)-b-poly(acrylic acid)-b-poly(L-lysine). In particular, we investigated the nature of the layer adsorbed under different conditions of polymer and salt concentration and the lubricant properties of the polymer layer before and after its chemical cross-linking by bridging the poly(acrylic acid) blocks. We found that the amount of polymer adsorbed is controlled by the ionic strength and the polymer concentration in the solution. In all cases, the self-assembled polymer layer is a poor lubricant before cross linking, but the cohesion and load-carrying ability of the layer are substantially improved by this reaction. However, the chemically cross-linked coating has a limited deformation capacity as a consequence of its permanent network nature, and irreversible damage is observed after excessive strain of the film. PMID- 24053316 TI - Urinary incontinence as a marker of higher mortality in patients receiving home care services. AB - OBJECTIVE: To evaluate urinary incontinence (UI) as a predictor of nursing home admission, hospitalization or death in patients receiving home care services. SUBJECTS AND METHODS: A total of 699 community-dwelling participants receiving home care services in Geneva were evaluated in Autumn 2004 using the Minimal Data Set-Home Care, a validated instrument that includes grading of UI. Data on death, hospitalization and nursing home admission were collected up until June 2007. The impact of UI on time-dependent outcomes was analysed using survival analysis and multivariate regression Cox models to adjust for age, gender, body mass index, cardiac failure, cognitive impairment, delirium, depression, disability, alcohol and tobacco use, self-rated health, faecal incontinence and number of medications. RESULTS: We found that UI was present in 193 participants (27.8%). After adjustment for confounding factors, UI was associated with a longer length of hospital stay: +36.7 days, (95% confidence interval [CI]: 1.2-72.3) and a higher mortality rate (hazard ratio [HR] 1.6; 95% CI: 1.1-2.6). The HR for death was 1.5 (95% CI: 0.9-2.5) for participants complaining of one episode of urinary leakage per week at most, 2.0 (95% CI: 1.2-3.5) for those presenting with two or more episodes per week and 4.2 (95% CI: 2.3-7.7; P for trend: <0.001) for daily UI compared with participants without UI. Institutionalization (HR 1.1; 95% CI: 0.6-2.2) and hospitalization rates (HR 1.0; 95% CI: 0.7-1.3) were not different between patients with or without UI. CONCLUSION: In a cohort of patients receiving home care services, UI was a strong predictor of length of hospital stay and mortality, increasing with UI severity. PMID- 24053317 TI - Postoperative visual loss after robotic pelvic surgery. PMID- 24053319 TI - Temporal variation of genetic composition in Atlantic salmon populations from the Western White Sea Basin: influence of anthropogenic factors? AB - BACKGROUND: Studies of the temporal patterns of population genetic structure assist in evaluating the consequences of demographic and environmental changes on population stability and persistence. In this study, we evaluated the level of temporal genetic variation in 16 anadromous and 2 freshwater salmon populations from the Western White Sea Basin (Russia) using samples collected between 1995 and 2008. To assess whether the genetic stability was affected by human activity, we also evaluated the effect of fishing pressure on the temporal genetic variation in this region. RESULTS: We found that the genetic structure of salmon populations in this region was relatively stable over a period of 1.5 to 2.5 generations. However, the level of temporal variation varied among geographical regions: anadromous salmon of the Kola Peninsula exhibited a higher stability compared to that of the anadromous and freshwater salmon from the Karelian White Sea coast. This discrepancy was most likely attributed to the higher census, and therefore effective, population sizes of the populations inhabiting the rivers of the Kola Peninsula compared to salmon of the Karelian White Sea coast. Importantly, changes in the genetic diversity observed in a few anadromous populations were best explained by the increased level of fishing pressure in these populations rather than environmental variation or the negative effects of hatchery escapees. The observed population genetic patterns of isolation by distance remained consistent among earlier and more recent samples, which support the stability of the genetic structure over the period studied. CONCLUSIONS: Given the increasing level of fishing pressure in the Western White Sea Basin and the higher level of temporal variation in populations exhibiting small census and effective population sizes, further genetic monitoring in this region is recommended, particularly on populations from the Karelian rivers. PMID- 24053320 TI - Punishing maternal behavior: potential legal consequences for obesity-associated poor fetal outcome in the United States. PMID- 24053321 TI - A cry for help: preventing passive euthanasia decision-making for neonates with non-fatal congenital defects. PMID- 24053318 TI - BMP4 inhibits the proliferation of breast cancer cells and induces an MMP dependent migratory phenotype in MDA-MB-231 cells in 3D environment. AB - BACKGROUND: Bone morphogenetic protein 4 (BMP4) belongs to the transforming growth factor beta (TGF-beta) family of proteins. BMPs regulate cell proliferation, differentiation and motility, and have also been reported to be involved in cancer pathogenesis. We have previously shown that BMP4 reduces breast cancer cell proliferation through G1 cell cycle arrest and simultaneously induces migration in a subset of these cell lines. Here we examined the effects of BMP4 in a more physiological environment, in a 3D culture system. METHODS: We used two different 3D culture systems; Matrigel, a basement membrane extract from mouse sarcoma cells, and a synthetic polyethylene glycol (PEG) gel. AlamarBlue reagent was used for cell proliferation measurements and immunofluorescence was used to determine cell polarity. Expression of cell cycle regulators was examined by Western blot and matrix metalloproteinase (MMP) expression by qRT-PCR. RESULTS: The MCF-10A normal breast epithelial cells formed round acini with correct apicobasal localization of alpha6 integrin in Matrigel whereas irregular structures were seen in PEG gel. The two 3D matrices also supported dissimilar morphology for the breast cancer cells. In PEG gel, BMP4 inhibited the growth of MCF-10A and the three breast cancer cell lines examined, thus closely resembling the 2D culture conditions, but in Matrigel, no growth inhibition was observed in MDA-MB-231 and MDA-MB-361 cells. Furthermore, BMP4 induced the expression of the cell cycle inhibitor p21 both in 2D and 3D culture, thereby partly explaining the growth arrest. Interestingly, MDA-MB-231 cells formed large branching, stellate structures in response to BMP4 treatment in Matrigel, suggestive of increased cell migration or invasion. This effect was reversed by Batimastat, a broad spectrum MMP inhibitor, and subsequent analyses showed BMP4 to induce the expression of MMP3 and MMP14, that are thus likely to be responsible for the stellate phenotype. CONCLUSIONS: Taken together, our results show that Matrigel provides a more physiological environment for breast epithelial cells than PEG gel. Moreover, BMP4 partly recapitulates in 3D culture the growth suppressive abilities previously seen in 2D culture and induces an MMP-dependent migratory phenotype in MDA-MB-231 cells. PMID- 24053322 TI - Accountable care organizations antitrust guidelines will not save rural providers. PMID- 24053325 TI - Clinical and imaging characterization of progressive spastic dysarthria. AB - BACKGROUND AND PURPOSE: To describe speech, neurological and imaging characteristics of a series of patients presenting with progressive spastic dysarthria as the first and predominant sign of a presumed neurodegenerative disease. METHODS: Participants were 25 patients with spastic dysarthria as the only or predominant speech disorder. Clinical features, pattern of MRI volume loss on voxel-based morphometry and pattern of hypometabolism on F18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan are described. RESULTS: All patients demonstrated speech characteristics consistent with spastic dysarthria, including strained voice quality, slow speaking rate, monopitch and monoloudness, and slow and regular speech alternating motion rates. Eight patients did not have additional neurological findings on examination. Pseudobulbar affect, upper motor neuron pattern limb weakness, spasticity, Hoffman sign and positive Babinski reflexes were noted in some of the remaining patients. Twenty-three patients had electromyographic assessment and none had diffuse motor neuron disease or met El Escorial criteria for amyotrophic lateral sclerosis. Voxel-based morphometry revealed striking bilateral white matter volume loss affecting the motor cortex (BA 4), including the frontoparietal operculum (BA 43) with extension into the middle cerebral peduncle. FDG-PET showed subtle hypometabolism affecting the premotor and motor cortices in some patients, particularly in those who had a disease duration longer than 2 years. CONCLUSIONS: A neurodegenerative disorder that begins focally with spastic dysarthria due to involvement of the motor and premotor cortex and descending corticospinal and corticobulbar pathways is characterized. The descriptive label 'progressive spastic dysarthria' to best capture the dominant presenting feature of the syndrome is proposed. PMID- 24053326 TI - Blockade of reactive oxygen species and Akt activation is critical for anti inflammation and growth inhibition of metformin in phosphatase and tensin homolog deficient RAW264.7 cells. AB - CONTEXT: Metformin is widely used for treatment of type 2 diabetes and has a potential application on the treatment of inflammation and cancer. Phosphatase and tensin homolog (PTEN) plays a critical role in cancer cell growth and inflammation; however, precise mechanisms remain unclear. OBJECTIVE: We aimed to investigate the possible mechanisms of how PTEN regulates metformin against cell growth and inflammation. MATERIALS AND METHODS: We established PTEN knockdown in RAW264.7 murine macrophages (shPTEN cells) to detect inflammatory mediators using commercial kits, production of reactive oxygen species (ROS) by flow cytometry, cell growth by MTT assay and phosphorylated levels of signal molecules by western blot. RESULTS: The shPTEN cells had a significant large amount of inflammatory mediators, such as inducible nitric oxide synthase (iNOS)/nitric oxide (NO) and cyclooxygenase-2 (COX-2)/prostaglandin E(2) (PGE(2)); and also elevated the production of ROS and increased cell proliferation. These effects were accompanied with the activation of Akt and p38 mitogen-activated protein kinase (MAPK), and the inactivation of an AMP-activated protein kinase (AMPK) activator and extracellular signal-regulated kinase 1/2. Pretreatment with metformin not only blocked these inflammatory mediators, but also caused growth inhibition induced by significant apoptosis. Furthermore, inactivation of Akt, blockade of ROS generation and independence of activations of AMPK and MAPK by metformin were also observed. CONCLUSION: Macrophages with PTEN deficiency developed a continuous inflammatory microenvironment, which further aggravated tumor cell growth. Moreover, metformin affected PTEN-deficient cells dependent of inhibition of ROS production and Akt activation against enlarged inflammatory mediators and/or cell growth in shPTEN cells. PMID- 24053327 TI - Ginsenoside Rg1 inhibits the TSLP production in allergic rhinitis mice. AB - Recent study reports that Korean red ginseng reduces the nasal allergic inflammatory reaction in an allergic murine model. However, the contribution of ginsenoside Rg1 (RG1) and its mechanisms on allergic rhinitis (AR) have not been elucidated. In this study, we evaluated the important activities of RG1 in the ovalbumin (OVA)-induced AR mice. RG1 significantly reduced the levels of thymic stromal lymphopoietin (TSLP) and interleukin (IL)-1beta compared with the AR control mice. Allergic symptom such as rub scores and biomarkers such as spleen weight, histamine, IgE and IgG(1) in the RG1 group were decreased compared with the AR mice. The levels of interferon-gamma were enhanced while the levels of IL 4 were reduced in the RG1 group. In the RG1 group, the eosinophils and mast cells infiltration increased by OVA were also decreased. RG1 reduced the levels of inflammation-related protein. RG1 inhibited the caspase-1 activity in nasal mucosa tissue. In addition, RG1 inhibited the production of TSLP and IL-1beta and the activations of caspase-1, receptor interacting protein 2, IkappaB kinase-beta and nuclear factor-kappaB/Rel A in activated HMC-1 cells. Our results indicate that RG1 has the inhibitory effect of TSLP production and caspase-1 activity in AR experimental model. PMID- 24053328 TI - Response to letter: identification of patients at risk of anaphylactoid reactions to N-acetylcysteine in the treatment of paracetamol overdose. PMID- 24053329 TI - Response to Letter: Anaphylactoid reactions to NAC. PMID- 24053330 TI - Empathy in Chinese medical students: psychometric characteristics and differences by gender and year of medical education. AB - BACKGROUND: In recent years in China, the tense physician-patient relationship has been an outstanding problem. Empathy is one of the fundamental factors enhancing the therapeutic effects of physician-patient relationships and is significantly associated with clinical and academic performance among students. METHODS: This cross-sectional study used the JSPE-S (The Student Version of the Jefferson Scale of Physician Empathy) to assess 902 medical students from 1st year to 4th year at China Medical University. The reliability of the questionnaire was assessed by Cronbach's alpha coefficient. We performed an exploratory factor analysis to evaluate the construct validity of the JSPE-S. Group comparisons of empathy scores were conducted via the t-test and one-way ANOVA. Statistic analysis was performed by SPSS 13.0. RESULTS: The Cronbach's alpha coefficient was 0.83. The three factors emerging in the factor analysis of the JSPE-S are "perspective taking", "compassionate care" and "ability to stand in patients' shoes", which accounted for 48.00%. The mean empathy score was 109.60. The empathy score of medical students had significant differences between different genders (p < 0.05) and academic year level (p < 0.05). CONCLUSIONS: This study provided support for the validity and reliability of the Chinese translated version of the JSPE-S for medical students. Early exposure to clinical training and a curriculum for professional competencies help to enhance the empathy of medical students. We suggest that the curriculum within Chinese medical schools include more teaching on empathy and communicational skills. PMID- 24053331 TI - Amyloid fibril formation by a normally folded protein in the absence of denaturants and agitation. AB - The conversion of normally folded proteins into amyloid-like fibrils is an important process in protein chemistry, biology, pathology and biotechnology. This process generally requires harsh conditions, such as pH extremes, organic cosolvents, high temperatures, high pressures or shear forces. Such conditions promote aggregation because they partially unfold structured proteins or allow the sampling of locally unfolded native-like states, both of which possibly represent amyloidogenic states. Here we report the formation of amyloid-like fibrils by the lipase from Pseudomonas sp. under conditions that are close to physiological, that is, in the absence of denaturants and agitation. The resulting aggregates bind thioflavin T and Congo red, causing their characteristic spectral changes observed in the presence of amyloid fibrils. They possess a significant quantity of beta-sheet structure, as detected with Fourier transform infrared and far-UV circular dichroism spectroscopies, and appear fibrillar using transmission electron microscopy. These results indicate that the lipase from Pseudomonas sp. can be a useful model system for the characterization of a key process, such as amyloid fibril formation under physiological conditions. PMID- 24053332 TI - Cervical necrosis after chemoradiation for cervical cancer: case series and literature review. AB - BACKGROUND: The aim of this study was to assess the management of cervical necrosis (CN) following radiotherapy (RT) and the impact of smoking status. This rare complication mimics a neoplastic recurrence, and causes concern among attending physicians. METHODS: Between July 2008 and March 2013, 5 women on 285 with localized cervical cancer had a CN following RT. Patients were treated with concomitant chemoradiation. The medical records were reviewed to abstract demographic and clinical information until March 2013. RESULTS: 1.75% (95% confidence interval: 0.23 to 3.28%) developed CN. All patients were smokers with a mean of 19.5 pack-years (range: 7.5-45 pack-years). All patients were treated with weekly Cisplatin chemotherapy and external beam radiation to the pelvis, 45 Gy in 25 fractions. Four patients received an extra boost with a median dose of 7.2 Gy (range: 5.4-10 Gy). All patients had intracavitary brachytherapy (range: 27.9 to 30 Gy). Clinical presentation was similar for all the cases: vaginal discharge associated with pain. Mean time for time post-radiation therapy to necrosis was 9.3 months (range: 2.2-20.5 months). Standard workup was done to exclude cancer recurrence: biopsies and radiologic imaging. Conservative treatment was performed with excellent results. Resolution of the necrosis was complete after a few months (range: 1 to 4 months). Median follow-up until March 2013 was 19 months. All the patients were alive with no clinical evidence of disease. CONCLUSIONS: This study, the largest to date, shows that conservative management of CN after RT is effective, and should be attempted. This complication is more common in smokers, and counseling intervention should result in fewer complications of CN. PMID- 24053333 TI - Mechanisms of nanoparticle-mediated siRNA transfection by melittin-derived peptides. AB - Traditional peptide-mediated siRNA transfection via peptide transduction domains exhibits limited cytoplasmic delivery of siRNA due to endosomal entrapment. This work overcomes these limitations with the use of membrane-destabilizing peptides derived from melittin for the knockdown of NFkB signaling in a model of adult T cell leukemia/lymphoma. While the mechanism of siRNA delivery into the cytoplasmic compartment by peptide transduction domains has not been well studied, our analysis of melittin derivatives indicates that concurrent nanocomplex disassembly and peptide-mediated endosomolysis are crucial to siRNA transfection. Importantly, in the case of the most active derivative, p5RHH, this process is initiated by acidic pH, indicating that endosomal acidification after macropinocytosis can trigger siRNA release into the cytoplasm. These data provide general principles regarding nanocomplex response to endocytosis, which may guide the development of peptide/siRNA nanocomplex-based transfection. PMID- 24053335 TI - Impact of prostate size on urinary quality of life scores after open radical prostatectomy: a single-center experience. AB - OBJECTIVE: The aim of this study was to assess the effects of prostate size on long-term health-related quality of life (HRQoL) and functional outcomes after radical prostatectomy (RP). MATERIAL AND METHODS: A total of 207 consecutive patients who underwent RP for localized prostate cancer was stratified by pathological prostate gland weight into group 1, patients with prostate glands weighing less than 30 g; group 2, those with prostates weighing 30-50 g; and group 3, those with prostates weighing more than 50 g. Urinary HRQoL was assessed before surgery and at 1, 3, 6, 12, 18, 24, 36, 48 and 60 months after RP using a Japanese version of the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. RESULTS: Baseline urinary function was significantly (p < 0.05) reduced in patients with the largest glands (group 3), as demonstrated by EPIC urinary domain summary and subscale scores, including scores for urinary bother, irritation and obstruction, compared with patients with smaller glands (groups 1 and 2). At follow-up ranging from 18 to 36 months, patients in group 3 had improved EPIC urinary domain summary and subscale scores, including scores for urinary irritation and obstruction and urinary bother subscale scores, compared with their baseline scores (p < 0.05). CONCLUSIONS: In patients with large prostate glands, postoperative improvement was observed in HRQoL and functional outcome after RP. Thus, RP may be beneficial in patients with large prostates. PMID- 24053334 TI - Elucidating features that drive the design of selective antifolates using crystal structures of human dihydrofolate reductase. AB - The pursuit of antimicrobial drugs that target dihydrofolate reductase (DHFR) exploits differences in sequence and dynamics between the pathogenic and human enzymes. Here, we present five crystal structures of human DHFR bound to a new class of antimicrobial agents, the propargyl-linked antifolates (PLAs), with a range of potency (IC50 values of 0.045-1.07 MUM) for human DHFR. These structures reveal that interactions between the ligands and Asn 64, Phe 31, and Phe 34 are important for increased affinity for human DHFR and that loop residues 58-64 undergo ligand-induced conformational changes. The utility of these structural studies was demonstrated through the design of three new ligands that reduce the number of contacts with Asn 64, Phe 31, and Phe 34. Synthesis and evaluation show that one of the designed inhibitors exhibits the lowest affinity for human DHFR of any of the PLAs (2.64 MUM). Comparisons of structures of human and Staphylococcus aureus DHFR bound to the same PLA reveal a conformational change in the ligand that enhances interactions with residues Phe 92 (Val 115 in huDHFR) and Ile 50 (Ile 60 in huDHFR) in S. aureus DHFR, yielding selectivity. Likewise, comparisons of human and Candida glabrata DHFR bound to the same ligand show that hydrophobic interactions with residues Ile 121 and Phe 66 (Val 115 and Asn 64 in human DHFR) yield selective inhibitors. The identification of residue substitutions that are important for selectivity and the observation of active site flexibility will help guide antimicrobial antifolate development for the inhibition of pathogenic species. PMID- 24053336 TI - Apparent mineralcorticoid excess syndrome, an often forgotten or unrecognized cause of hypokalemia and hypertension: case report and appraisal of the pathophysiology. AB - The glicyrrhizic acid, contained in licorice, has a mineralcorticoid-like effect. Chronic excess intake of licorice induces the rare syndrome of "apparent mineralcorticoid excess", due to the inhibitory effect of glicyrrhizic acid on 11 beta-hydroxysteroid dehydrogenase type 2 determining clinical/biochemical manifestations as resistant hypertension, metabolic alkalosis and severe hypokalemia. We report a typical clinical case of licorice abuse to emphasize the importance of a detailed anamnesis, which is essential for the diagnosis, avoid unnecessary and expensive investigations, and reduce the duration of hospitalization. We also provide an appraisal of the pathophysiology of "apparent mineralcorticoid excess" syndrome, still an often forgotten or unrecognized cause of hypokalemia and hypertension. PMID- 24053337 TI - The surgical spectacle: a survey of urologists viewing live case demonstrations. AB - OBJECTIVE: To evaluate perspectives of urologists viewing live case demonstrations (LCD) and taped case demonstrations (TCD). METHOD: A 15-question anonymous survey was distributed to attendees of the live surgery session at the American Urological Association 2012 national meeting (Atlanta) and the second International Challenges in Endourology meeting (Paris). RESULTS: Of 1000 surveys distributed, 253 were returned completed (response rate 25%). Nearly half of respondents were in the academic practice setting and nearly 75% were beyond training. Just over 30% had performed a LCD previously. The perceived benefit of an LCD was greater than unedited and edited videos (chi-squared P = 0.014 and P < 0.001, respectively). Nearly no one selected 'not helpful' and a few selected 'minimally helpful' for any of the three forms of demonstration. Most respondents identified that opportunity to ask questions (61%) and having access to the full unedited version (72%), two features inherent to LCD, improved upon the educational benefit of edited videos. Most (78%) identified LCD as ethical. However, those that did not perceived lower educational benefit from LCD (P = 0.019). A slim majority (58%) would allow themselves or a family member to be a patient of a LCD and the vast majority (86%) plan to transfer knowledge gained at the LCD session into their practice. CONCLUSIONS: Urologists who attended these LCD sessions identified LCDs as beneficial and applicable to their practice. LCDs are preferred over videos. The large majority considers LCD ethical, although not as many would volunteer themselves for LCD. Further studies are necessary to determine if there is actual benefit from LCD over TCD to patient care. PMID- 24053338 TI - Suppression of experimental autoimmune encephalomyelitis by interleukin-10 transduced neural stem/progenitor cells. AB - Neural stem/progenitor cells (NSPCs) have the ability to migrate into the central nervous system (CNS) to replace damaged cells. In inflammatory CNS disease, cytokine transduced neural stem cells may be used as vehicles to specifically reduce inflammation and promote cell replacement. In this study, we used NSPCs overexpressing IL-10, an immunomodulatory cytokine, in an animal model for CNS inflammation and multiple sclerosis (MS). Intravenous injection of IL-10 transduced neural stem/progenitor cells (NSPC(IL-10)) suppressed myelin oligodendrocyte glycoprotein aa 35-55 (MOG35-55)- induced experimental autoimmune encephalomyelitis (EAE) and, following intravenous injection, NSPC(IL-10) migrated to peripheral lymphoid organs and into the CNS. NSPC(IL-10 )suppressed antigen-specific proliferation and proinflammatory cytokine production of lymph node cells obtained from MOG35-55 peptide immunized mice. In this model, IL-10 producing NSPCs act via a peripheral immunosuppressive effect to attenuate EAE. PMID- 24053339 TI - Percentage of high-grade tumour volume does not meaningfully improve prediction of early biochemical recurrence after radical prostatectomy compared with Gleason score. AB - OBJECTIVE: To examine whether percentage of tumour volume (%TV) and percentage of high-grade tumour volume (%HGTV) help to better identify men at higher risk of early biochemical recurrence (BCR) after radical prostatectomy (RP) for non metastatic high-risk prostate cancer, as early BCR after RP might be associated with higher risk of metastases and cancer-specific mortality. PATIENTS AND METHODS: We examined the data of 595 men treated with RP for non-metastatic high risk prostate cancer between 1992 and 2011 at two European tertiary care centres. Kaplan-Meier analyses were used to graphically depict 2-year BCR-free survival. Multivariable Cox regression models addressed early BCR. We tested whether addition of %TV and %HGTV to a multivariable Cox regression model helps to increase a model's predictive accuracy (PA) for prediction of early BCR. RESULTS: In all, 32 men (10%) with specimen-confined prostate cancer (pT2-pT3a, negative surgical margin, pN0) and 67 men (24%) with non-specimen-confined prostate cancer had early BCR. After stratification according to %HGTV (%HGTV threshold: <=33.33 vs >33.33%), the 2-year BCR-free survival rates were respectively 93 vs 60% (log rank P < 0.001). In multivariable Cox regression models %HGTV emerged as an independent predictor of early BCR (P < 0.001), whereas %TV did not (P > 0.05). However, adding %HGTV (regardless of its coding) to other covariates in multivariable Cox regression analysis did not increase the model's PA in a meaningful fashion compared with the use of the detailed Gleason grading system (6 vs 7a vs 7b vs 8 vs 9-10). CONCLUSIONS: In a large cohort of patients with high-risk prostate cancer, %HGTV and %TV did not improve prediction of early BCR after RP substantially, although %HGTV was an independent predictor of early BCR. Therefore, sophisticated TV/HGTV measurements do not seem to have additional benefit for early BCR prediction relative to the use of Gleason grading. However, these results need to be confirmed in larger, prospective studies. PMID- 24053341 TI - Current status of safinamide for the drug portfolio of Parkinson's disease therapy. AB - Parkinson's disease (PD) is characterized by a slowly ongoing neuronal death. This alters dopaminergic and glutamatergic neurotransmission and causes a wide variety of motor and non-motor features. Safinamide has a unique pharmacological profile, which combines modulation of dopamine metabolism by reversible, highly specific monoamine oxidase-B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and of glutamate release induced by abnormal neuronal activity. Therefore, safinamide represents an ideal candidate for the treatment of PD. This compound asks for one time daily intake only within an optimum dose range between 50 and 100 mg. In clinical trials, safinamide was well tolerated and safe, improved motor behavior even in combination with dopamine agonist only, ameliorated levodopa-associated motor complications. Safinamide has the potential to become an important compound for the therapy of PD, since its symptomatic efficacy appears to be superior to available monoamine oxidase-B inhibitors or N-methyl-d-aspartate receptor antagonists like amantadine, according to available trial outcomes. PMID- 24053343 TI - Monitoring neuromyelitis optica activity. AB - Neuromyelitis optica (NMO) is a demyelinating and inflammatory disease essentially restricted to the spinal cord and the optic nerves. Emerging evidence indicates that serum antiaquaporin-4 (AQP4) antibodies have a critical role in its pathogenesis. NMO courses with multiple relapses, often leading to severe disability. Management of NMO focuses on the effective treatment of acute attacks and the prevention of relapses. The latter is currently attempted with immunosuppressive drugs. Although several factors have been associated with disease activity, especially serum levels of anti-AQP4 IgG, no single one of them has been proved clinically useful for guiding treatment. New drugs that target specifically AQP4 antibodies and complement activation are being developed; they may prove to be more efficient with fewer side effects. PMID- 24053342 TI - The use of methylphenidate hydrochloride extended-release oral suspension for the treatment of ADHD. AB - More than 50 years ago, methylphenidate immediate-release (MPH-IR) was found to be effective in relieving symptoms of attention-deficit/hyperactivity disorder. Although the exact mechanism of the action is unknown, the efficacy of MPH is thought to be mediated by blocking the reuptake of norepinephrine and dopamine into the presynaptic neuron and increasing the release of these neurotransmitters into the extraneuronal space. Because of its short duration of effect, MPH-IR had to be dosed multiple times daily. In recent years, several methyphenidate extended-release (MPH-ER) formulations have been developed. Methylphenidate hydrochloride for extended-release oral suspension (MEROS or Quillivant(TM) XR) is the first long-acting MPH-ER oral suspension developed to treat attention deficit/hyperactivity disorder. It offers advantages when compared with other MPH ER preparations for patients who cannot or prefer not to swallow or manipulate capsules or wear a transdermal patch, while maintaining comparable efficacy and duration of effect. The pharmacokinetic, efficacy and safety profiles of this controlled substance are reviewed. PMID- 24053344 TI - Recent progress in omics-driven analysis of MS to unravel pathological mechanisms. AB - At present, the pathophysiology and specific biological markers reflecting pathology of multiple sclerosis (MS) remain undetermined. The risk of developing MS is considered to depend on genetic susceptibility and environmental factors. The interaction of environmental factors with epigenetic mechanisms could affect the transcriptional level and therefore also the translational level. In the last decade, growing amount of hypothesis-free 'omics' studies have shed light on the potential MS mechanisms and raised potential biomarker targets. To understand MS pathophysiology and discover a subset of biomarkers, it is becoming essential to take a step forward and integrate the findings of the different fields of 'omics' into a systems biology network. In this review, we will discuss the recent findings of the genomic, transcriptomic and proteomic fields for MS and aim to make a unifying model. PMID- 24053346 TI - Is the migrainous brain normal outside of acute attacks? Lessons learned from psychophysical, neurochemical and functional neuroimaging studies. AB - Migraine is a largely inherited disorder of the brain with recurrent head pain attacks. There is an increasing awareness, however, that the manifestation of migrainous biology is not restricted to such acute head pain attacks, but that migraine is rather a disorder with a continuous complex and broad sensory processing dysfunction in which normal sensory stimuli (somatosensory, visual, auditory and olfactory) are misinterpreted by the brain. This dysfunction is most prominent during attacks, but there are more and more evidences that the processing and perception of stimuli is abnormal also outside of attacks to a varying degree. In this topical review, we will summarize and discuss the current clinical, neurochemical and functional neuroimaging literature on this paradigm shift from a strictly episodic head pain disorder to migraine as a more general dysfunction of sensory processing. PMID- 24053345 TI - Cellular targets and mechanistic strategies of remyelination-promoting IgMs as part of the naturally occurring autoantibody repertoire. AB - Immunoglobulins with germline sequences occur in invertebrates and vertebrates and are named naturally occurring autoantibodies (NAbs). NAbs may target foreign antigens, self- or altered self-components and are part of the normal immunoglobulin repertoire. Accumulating evidence indicates that naturally occurring antibodies can act as systemic surveillance molecules, which tag, damaged or stressed cells, invading pathogens and toxic cellular debris for elimination by the immune system. In addition to acting as detecting molecules, certain types of NAbs actively signal in different cell types with a broad range of responses from induction of apoptosis in cancer cells to stimulation of remyelination in glial cells. This review emphasizes functions and characteristics of NAbs with focus on remyelination-promoting mouse and human antibodies. Human remyelination-promoting NAbs are potential therapeutics to combat a wide spectrum of disease processes including demyelinating diseases like multiple sclerosis. We will highlight the identified glycosphingolipid (SL) antigens of polyreactive remyelination-promoting antibodies and their proposed mechanism(s) of action. The nature of the identified antigens suggests a lipid raft-based mechanism for remyelination-promoting antibodies with SLs as most essential raft components. However, accumulating evidence also suggests involvement of other antigens in stimulation of remyelination, which will be discussed in the text. PMID- 24053347 TI - Curcumin protection activities against gamma-rays-induced molecular and biochemical lesions. AB - BACKGROUND: Curcumin is a yellow-pigment phenolic compound used as a food spice and has a broad spectrum of antioxidant, anti-carcinogenic, anti-mutagenic and anti-inflammatory properties. METHODS: Radio-protective efficacy of curcumin; diferuloylmethane (C21H20O6) was evaluated using molecular and biochemical assays in male mice after exposure to 3 Gy gamma-rays. Curcumin was given at a dose of 400 MUmol/ kg body weight via gastric tubes for 5 following days either pre-, post- or both pre- and post-exposure. RESULTS: The incidence of aberrant cells and aberration types (mostly chromatids, breaks and fragments) was reduced with curcumin dosage as compared to irradiated group. Thiobarbituric acid reactive substances (TBARS), hydroperoxide (HP), xanthine oxidase (XO) and apoptotic markers (DNA- fragmentation and caspase-3 activation) were increased significantly, whereas levels of glutathione (GSH) and the enzymatic antioxidants [Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)] were significantly depleted in gamma-irradiated mice. Curcumin treatments of mice groups including the 5 days pre-irradiation treated group (protected), the 5 days post-irradiation treated group (treated), and the curcumin treated group 5 days pre- and post-irradiation (protracted), have attenuated the liver toxic effects of gamma-rays as manifested by reducing the levels of TBARS, HP, XO and DNA fragmentation. Curcumin has also rescued the depletion of GSH and the enzymatic antioxidant status. CONCLUSIONS: Curcumin has significant radio-protective and radio-recovery activities in gamma-irradiated mice. It has antioxidant potential against gamma-rays-induced cytogenetic, molecular and biochemical lesions in mice. PMID- 24053348 TI - Development of adaptive pneumatic tourniquet systems based on minimal inflation pressure for upper limb surgeries. AB - BACKGROUND: Pneumatic tourniquets are medical devices that occlude blood flow to distal part of extremities and are commonly used in upper limb surgeries to provide a dry, clean and bloodless field. To decrease pressure-related injuries and potential risk of complications subjected to the high inflation pressure of pneumatic tourniquet, minimal inflation pressures are recommended. METHODS: A new occlusion pressure mathematical model for the upper limb was established based on the correlation analysis between several possible influencing parameters and the minimal pneumatic tourniquet pressure at which the peripheral pulse disappeared was recorded using a digital plethysmograph. A prototype of an adaptive pneumatic tourniquet which automatically varies the pressure in the tourniquet cuff according to the above prediction model was developed for the upper limb which used the lowest possible inflation pressure to achieve occlusion. The prototype comprises a blood pressure monitoring module, an inflatable tourniquet cuff, and a pressure relief mechanism to maintain an optimal cuff inflation pressure. Simulation experiments were conducted to verify the function and stability of the designed adaptive pneumatic tourniquet and clinical experiments using volunteers were undertaken to evaluate the performance of the prototype design in achieving adequate haemostasis in the upper limb. RESULTS: Results demonstrated that the mean arterial occlusion pressure was 152.3 +/- 16.7 mmHg, obviously below the 250 to 300 mmHg previously recommended (J Bone Joint Surg Br 68:625-628, 1986 and Arthroscopy 11:307-311, 1995). CONCLUSIONS: In conclusion, this adaptive method and apparatus which can provide minimal inflation pressure may be a clinically practical alternative for upper limb surgery performed with pneumatic tourniquets. PMID- 24053350 TI - A dual functional layer for block copolymer self-assembly and the growth of nanopatterned polymer brushes. AB - We present a versatile method for fabricating nanopatterned polymer brushes using a cross-linked thin film made from a random copolymer consisting of an inimer (p (2-bromoisobutyloylmethyl)styrene), styrene, and glycidyl methacrylate (GMA). The amount of inimer was held constant at 20 or 30% while the relative amount of styrene to GMA was varied to induce perpendicular domain orientation in an overlying P(S-b-MMA) block copolymer (BCP) film for lamellar and cylindrical morphologies. A cylinder forming BCP blend with PMMA homopolymer was assembled to create a perpendicular hexagonal array of cylinders, which allowed access to a nanoporous template without the loss of initiator functionality. Surface initiated ATRP of 2-hydroxyethyl methacrylate was conducted through the pores to generate a dense array of nanopatterned brushes. Alternatively, gold was deposited into the nanopores, and brushes were grown around the dots after removal of the template. This is the first example of combining the chemistry of nonpreferential surfaces with surface-initiated growth of polymer chains. PMID- 24053349 TI - Tuberculosis case finding based on symptom screening among immigrants, refugees and asylum seekers in Rome. AB - BACKGROUND: In Italy the proportion of cases of tuberculosis in persons originating from high-prevalence countries has been increasing in the last decade. We designed a study to assess adherence to and yield of a tuberculosis screening programme based on symptom screening conducted at primary care centres for regular and irregular immigrants and refugees/asylum seekers. METHODS: Presence of symptoms suggestive of active tuberculosis was investigated by verbal screening in migrants presenting for any medical condition to 3 free primary care centres in the province of Rome. Individuals reporting at least one symptom were referred to a tuberculosis clinic for diagnostic workup. RESULTS: Among 2142 migrants enrolled, 254 (11.9%) reported at least one symptom suggestive of active tuberculosis and 176 were referred to the tuberculosis clinic. Of them, 80 (45.4%) did not present for diagnostic evaluation. Tuberculosis was diagnosed in 7 individuals representing 0.33% of those screened and 7.3% of those evaluated for tuberculosis. CONCLUSION: The overall yield of this intervention was in the range reported for other tuberculosis screening programmes for migrants, although we recorded an unsatisfactory adherence to diagnostic workup. Possible advantages of this intervention include low cost and reduced burden of medical procedures for the screened population. Further evaluation of this approach appears to be warranted. PMID- 24053352 TI - Evaluation of suspected malignant hyperthermia events during anesthesia. AB - BACKGROUND: Malignant hyperthermia (MH), a metabolic myopathy triggered by volatile anesthetics and depolarizing muscle relaxants, is a potentially lethal complication of general anesthesia in susceptible patients. The implementation of modern inhalation anesthetics that research indicates as less potent trigger substances and the recommended limitations of succinylcholine use, suggests there may be considerable decline of fulminant MH cases. In the presented study, the authors analyzed suspected MH episodes during general anesthesia of patients that were referred to the Wuerzburg MH unit between 2007 and 2011, assuming that MH is still a relevant anesthetic problem in our days. METHODS: With approval of the local ethics committee data of patients that underwent muscle biopsy and in vitro contracture test (IVCT) between 2007 and 2011 were analyzed. Only patients with a history of suspected MH crisis were included in the study. The incidents were evaluated retrospectively using anesthetic documentation and medical records. RESULTS: Between 2007 and 2011 a total of 124 patients were tested. 19 of them were referred because of suspected MH events; 7 patients were diagnosed MH susceptible, 4 MH-equivocal and 8 MH-non-susceptible by IVCT. In a majority of cases masseter spasm after succinylcholine had been the primary symptom. Cardiac arrhythmias and hypercapnia frequently occurred early in the course of events. Interestingly, dantrolene treatment was initiated in a few cases only. CONCLUSIONS: MH is still an important anesthetic complication. Every anesthetist must be aware of this life-threatening syndrome at any time. The rapid onset of adequate therapy is crucial to avoid major harm and possibly lethal outcome. Dantrolene must be readily available wherever MH triggering agents are used for anesthesia. PMID- 24053353 TI - Can the Leibovich score for clear cell renal cell carcinoma (ccRCC) be accurately reported by a general pathologist? AB - OBJECTIVES: To evaluate the accuracy of reporting of the Leibovich score (LS) by general pathologists at our centre by comparing the LS in their initial reports with the LS in subsequent review reports by our specialist urological pathologists. We also assessed whether a revision in the LS subsequently altered the risk group. PATIENTS AND METHODS: In all, 54 consecutive patients had had their initial histology after nephrectomy reported by a general pathologist between August 2008 and March 2012. The histological slides were subsequently re reviewed by the two specialist urological pathologists and revised LS were given if appropriate. The cases were then discussed at the Uro-oncology Multi disciplinary meeting (MDT) and the reason for the revised LS was discussed with the participating panel and reviewed by the uropathologist. RESULTS: The general pathologists allocated the 54 patients into low- (13 patients), intermediate- (25) and high-risk (16) categories. After a review of the slides by the specialist urological pathologists and discussion at the MDT meeting the LS was revised in 23 patients (42.6%). The 23 patients who had their LS revised were divided into two groups for the purpose of the present study. On revision of the LS a total of eight patients (14.8%) changed their prognostic group. The change in the prognostic group in the eight patients was increased from intermediate- to high-risk in four patients. There was a reduction in the LS in four patients, which was from high- to intermediate-risk category in one patient and intermediate- to low-risk in three patients. CONCLUSION: In the present study, histopathology review by a specialist urological pathologist led to a change in LS in 42.6% of cases leading a change in risk grouping in 14.8% of cases. This level of discrepancy is not insignificant. However, the few cases evaluated in the present study does limit robust conclusions and further studies are needed to investigate this issue, so that recommendations can be made to enhance diagnostic accuracy and reproducibility. PMID- 24053354 TI - Examining long-term outcomes of bladder exstrophy: a 20-year follow-up. AB - OBJECTIVE: To examine long-term quality-of-life, urinary continence and sexual function outcomes in patients diagnosed with bladder exstrophy (BE). PATIENTS AND METHODS: A total of 65 patients with BE and follow-up of at least 20 years were identified. After informed consent for inclusion in the study, the patients were asked to complete three validated questionnaires, the Short-Form 36 quality-of life questionnaire (SF-36), the International Consultation on Incontinence Questionnaire (ICIQ) and the International Index of Erectile Function (IIEF), to assess quality of life, perceived urinary continence and sexual function. RESULTS: In all, 21 patients responded to the questionnaires, yielding a 32% response rate. High scores in each of the eight dimensions of the SF-36 reflected a positive perception of quality of life by respondents; calculated scores were compared with those of a normal control group. The only significant difference found between the groups was that the study population perceived their general health to be poorer than those in the control group. High scores on the ICIQ indicate high levels of subjective incontinence in patients, with scores ranging from 0 to 21. Reporting scores of 0 (continent), 12/21 patients perceived their continence to be normal, 9/21 patients had scores >2 (mild), with one patient scoring a 16, and 11 (severe incontinence), patients reported no identifiable leakage during normal activities. There was a 29% response rate for the IIEF (15 patients completed this). IIEF scores were broken down into five dimensions and mean scores were calculated. The mean scores showed mild to moderate dysfunction in each category, including overall satisfaction with sexual experience. CONCLUSIONS: The patient-reported quality of life in patients with BE was normal in all dimensions, with the exception of perception of general health. Half of the patients reported normal continence and had no complaints of urinary leakage. Sexual function in males was significantly affected across all dimensions, with mild to moderate dysfunction. PMID- 24053355 TI - First three-dimensional structure of Toxoplasma gondii thymidylate synthase dihydrofolate reductase: insights for catalysis, interdomain interactions, and substrate channeling. AB - Most species, such as humans, have monofunctional forms of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) that are key folate metabolism enzymes making critical folate components required for DNA synthesis. In contrast, several parasitic protozoa, including Toxoplasma gondii , contain a unique bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) having the catalytic activities contained on a single polypeptide chain. The prevalence of T. gondii infections across the world, especially for those immunocompromised, underscores the need to understand TS-DHFR enzyme function and to find new avenues to exploit for the design of novel antiparasitic drugs. As a first step, we have solved the first three-dimensional structures of T. gondii TS-DHFR at 3.7 A and of a loop truncated TS-DHFR, removing several flexible surface loops in the DHFR domain, improving resolution to 2.2 A. Distinct structural features of the TS-DHFR homodimer include a junctional region containing a kinked crossover helix between the DHFR domains of the two adjacent monomers, a long linker connecting the TS and DHFR domains, and a DHFR domain that is positively charged. The roles of these unique structural features were probed by site-directed mutagenesis coupled with presteady state and steady state kinetics. Mutational analysis of the crossover helix region combined with kinetic characterization established the importance of this region not only in DHFR catalysis but also in modulating the distal TS activity, suggesting a role for TS-DHFR interdomain interactions. Additional kinetic studies revealed that substrate channeling occurs in which dihydrofolate is directly transferred from the TS to DHFR active site without entering bulk solution. The crystal structure suggests that the positively charged DHFR domain governs this electrostatically mediated movement of dihydrofolate, preventing release from the enzyme. Taken together, these structural and kinetic studies reveal unique, functional regions on the T. gondii TS-DHFR enzyme that may be targeted for inhibition, thus paving the way for designing species specific inhibitors. PMID- 24053356 TI - An expression atlas of human primary cells: inference of gene function from coexpression networks. AB - BACKGROUND: The specialisation of mammalian cells in time and space requires genes associated with specific pathways and functions to be co-ordinately expressed. Here we have combined a large number of publically available microarray datasets derived from human primary cells and analysed large correlation graphs of these data. RESULTS: Using the network analysis tool BioLayout Express3D we identify robust co-associations of genes expressed in a wide variety of cell lineages. We discuss the biological significance of a number of these associations, in particular the coexpression of key transcription factors with the genes that they are likely to control. CONCLUSIONS: We consider the regulation of genes in human primary cells and specifically in the human mononuclear phagocyte system. Of particular note is the fact that these data do not support the identity of putative markers of antigen-presenting dendritic cells, nor classification of M1 and M2 activation states, a current subject of debate within immunological field. We have provided this data resource on the BioGPS web site (http://biogps.org/dataset/2429/primary-cell-atlas/) and on macrophages.com (http://www.macrophages.com/hu-cell-atlas). PMID- 24053358 TI - Small temperature coefficient of resistivity of graphene/graphene oxide hybrid membranes. AB - Materials with low temperature coefficient of resistivity (TCR) are of great importance in some areas, for example, highly accurate electronic measurement instruments and microelectronic integrated circuits. In this work, we demonstrated the ultrathin graphene-graphene oxide (GO) hybrid films prepared by layer-by-layer assembly with very small TCR (30-100 degrees C) in the air. Electrical response of the hybrid films to temperature variation was investigated along with the progressive reduction of GO sheets. The mechanism of electrical response to temperature variation of the hybrid film was discussed, which revealed that the interaction between graphene and GO and the chemical doping effect were responsible for the tunable control of its electrical response to temperature variation. The unique properties of graphene-GO hybrid film made it a promising candidate in many areas, such as high-end film electronic device and sensor applications. PMID- 24053357 TI - Multivariate normal tissue complication probability modeling of gastrointestinal toxicity after external beam radiotherapy for localized prostate cancer. AB - BACKGROUND: The risk of radio-induced gastrointestinal (GI) complications is affected by several factors other than the dose to the rectum such as patient characteristics, hormonal or antihypertensive therapy, and acute rectal toxicity. Purpose of this work is to study clinical and dosimetric parameters impacting on late GI toxicity after prostate external beam radiotherapy (RT) and to establish multivariate normal tissue complication probability (NTCP) model for radiation induced GI complications. METHODS: A total of 57 men who had undergone definitive RT for prostate cancer were evaluated for GI events classified using the RTOG/EORTC scoring system. Their median age was 73 years (range 53-85). The patients were assessed for GI toxicity before, during, and periodically after RT completion. Several clinical variables along with rectum dose-volume parameters (Vx) were collected and their correlation to GI toxicity was analyzed by Spearman's rank correlation coefficient (Rs). Multivariate logistic regression method using resampling techniques was applied to select model order and parameters for NTCP modeling. Model performance was evaluated through the area under the receiver operating characteristic curve (AUC). RESULTS: At a median follow-up of 30 months, 37% (21/57) patients developed G1-2 acute GI events while 33% (19/57) were diagnosed with G1-2 late GI events. An NTCP model for late mild/moderate GI toxicity based on three variables including V65 (OR = 1.03), antihypertensive and/or anticoagulant (AH/AC) drugs (OR = 0.24), and acute GI toxicity (OR = 4.3) was selected as the most predictive model (Rs = 0.47, p < 0.001; AUC = 0.79). This three-variable model outperforms the logistic model based on V65 only (Rs = 0.28, p < 0.001; AUC = 0.69). CONCLUSIONS: We propose a logistic NTCP model for late GI toxicity considering not only rectal irradiation dose but also clinical patient-specific factors. Accordingly, the risk of G1-2 late GI increases as V65 increases, it is higher for patients experiencing previous acute toxicity and it is lower for patients who take AH/AC drugs. The developed NTCP model could represent a potentially useful tool to be used in prospective trial and for comparison among different RT techniques. PMID- 24053359 TI - Non-invasive evaluation of energy loss in the pulmonary arteries using 4D phase contrast MR measurement: a proof of concept. AB - BACKGROUND: The repair surgery of congenital heart disease (CHD) associated with the right ventricular (RV)-pulmonary artery (PA) pathophysiology often left patients with critical post-operative lesions, leading to regurgitation and obstruction in the PAs. These lesions need longitudinal (with time) assessment for monitoring the RV function, in order for patients to have appropriate treatment before irreversible RV dysfunction occurs. In this research, we computed energy loss in the branch PAs using blood flow and pressure drop data obtained from 4D phase contrast (PC) MRI, to non-invasively quantify the RV-PA pathophysiology. METHODS: 4D PC MRI was acquired for a CHD patient with abnormal RV-PA physiology, including pulmonary regurgitation and PA stenosis, and a subject with normal RV-PA physiology. The blood velocity, flow rate, and pressure drop data, obtained from 4D PC MRI, were used to compute and compare the energy loss values between the patient and normal subjects. RESULTS: The pressure drop in the branch PAs for the patient was -1.3 mmHg/s and -0.2 mmHg/s for the RPA and LPA, respectively, and was larger (one order of magnitude) than that for the control. Similarly, the total energy loss in the branch PAs for the patient, 96.9 mJ/s and -16.4 mJ/s, for the RPA and LPA, respectively, was larger than that for the control. CONCLUSIONS: The amount of energy loss in the pulmonary blood flow for the patient was considerably larger than the normal subject due to PA regurgitation and PA stenosis. Thus, we believe that the status of RV-PA pathophysiology for CHD patients can be evaluated non-invasively using energy loss endpoint. PMID- 24053360 TI - Molecular detection of Toxoplasma gondii in water sources of district Nowshehra, Khyber Pakhtunkhwa, Pakistan. AB - Toxoplasmosis is spread through contamination of water sources and results in morbidity globally. In the current study 300 water samples were processed by polymerase chain reaction (PCR) for detection of Toxoplasma gondii. The overall prevalence in different water sources was 6.6% (17/300). Among different water sources the highest prevalence was recorded in drain water at 7% (7/100), followed by tube well water at 7.5% (3/40) and open well water at 5% (5/100) ,and the lowest was recorded in tap water at 3.33% (2/60). The highest prevalence was recorded in summer. Evidence indicates that cleaning and filtration need to be adopted to avoid the health hazards of waterborne zoonotic parasites. PMID- 24053361 TI - Effects of pyrene exposure on sheepshead minnow (Cyprinodon variegatus) reproduction. AB - Polycyclic aromatic hydrocarbons are known to adversely affect survival, growth, and reproduction in many aquatic species. Adult female sheepshead minnow, Cyprinodon varietagus (SHM), were exposed to chronic, low levels of pyrene (12.5, 25, or 50 MUg/L nominal concentrations) and the impact on reproductive ability and larval survival was assessed. Viable egg production was significantly reduced in a dose-dependent manner following a 28-d exposure of SHM to pyrene, confirming reproductive dysfunction. Gonadosomatic index (GSI) values were unchanged with pyrene exposure, but histological assessment of ovarian development showed significant differences in reproductive phases in SHM exposed to pyrene for 28 d, with a greater percentage of prespawning and nonspawning females observed in the two highest pyrene concentrations. The percentage of embryos successfully hatching varied significantly among treatments, with lowest hatch occurring at 25 MUg/L, but survival of larval fish to 14 d was not significantly different. These results suggest that chronic maternal exposure to low concentrations of pyrene has the potential to affect population structures by altering reproductive development and output as well as embryo/larval survival rates. PMID- 24053362 TI - Effects of subchronic exposure to phosalone on oxidative stress and histopathological alterations in common carp (Cyprinus carpio, L., 1758). AB - In this study, possible oxidative stress, biomarkers, and histopathological alterations were investigated in common carp (Cyprinus carpio, L., 1758) that were exposed to various phosalone concentrations in vivo. Fish were exposed to 0.15, 0.3, and 0.6 mg/L phosalone concentrations in a semistatic regime for 14 d. Biomarkers, including Na(+), K(+)-ATPase, reduced glutathione (GSH), thiobarbituric acid-reactive substances (TBARS), and histopathological changes, were determined in gills, liver, and kidney tissues of fish. Sublethal phosalone concentrations produced lipid peroxidation and impairment in the antioxidant defense system by increasing reactive oxygen species (ROS) production. While GSH increased in all groups at d 7 compared to control, GSH fell significantly at medium and high doses at d 14. Reduced GSH levels were diminished in all tissues and a significant induction in lipid peroxidation (TBARS) was observed. Na(+),K(+)-ATPase enzyme activity was significantly inhibited especially in gills. No histopathological effects were observed in the control group. Lamellar aneurysm, lamellar fusion, hyperplasia, epithelial lifting, and hemorrhages were observed in gill tissues exposed to phosalone. Histopathological effects in the liver tissues of fish exposed to phosalone were characterized by cytoplasmic vacuolation, congestion, hypertrophy, and nuclear degeneration. Hypertrophy, tubule degeneration, mononuclear cell infiltration, and dilation of glomerular capillaries were noted in kidney tissues exposed to phosalone. The results indicate that phosalone exposure adversely affected the health of the fish, attributable to oxidative stress. PMID- 24053364 TI - In vitro adverse effects of iron ore dusts on human lymphoblastoid cells in culture. AB - The aim of this study was to investigate the adverse effects produced by four types of iron (Fe) ore dust using cultured human cells. Genotoxicity and cytotoxicity induced by Fe ore dusts were determined by assays including cytokinesis block micronucleus (CBMN), population growth, and methyl tetrazolium (MTT). Four iron ore dusts were tested, namely, 1002 Limonite & Goethite (1002), HG2 hematite (HG2), HG1 Soutlem Pit (HG1), and HG4. WIL2 -NS cells were incubated for 10 h with extracts from a range of concentrations (0, 75, or 150 MUg/ml) of Fe ore dust. Significant decreases in percent cell viability were seen at 150 MUg/ml HG2 and 1002 as measured by MTT, with viability that decreased to 75 and 73%, respectively, compared to untreated controls. The cell population regrew to a different extent after Fe ore dust was removed, except for HG1, where population remained declined. An approximately twofold significant increase in the frequency of micronucleated binucleated cells (MNBNC) was seen with 1002, HG2, and HG1 at 150 MUg/ml. A significant rise in apoptosis induction was observed at 150 MUg/ml HG1. Data indicate that Fe ore dusts at 150 MUg/ml produced cytotoxicity and genotoxicity. PMID- 24053363 TI - Is bisphenol-A exposure during pregnancy associated with blood glucose levels or diagnosis of gestational diabetes? AB - Recent epidemiological studies indicate bisphenol A (BPA), an estrogenic chemical used in production of epoxy, polycarbonate, and plastic may increase risk of insulin resistance and type 2 diabetes. Exposure to BPA during pregnancy may contribute to development of gestational diabetes mellitus (GDM), a precursor to type 2 diabetes in women. This pilot study examined the association between BPA exposure, fasting blood glucose levels (FBG), and GDM diagnosis during pregnancy. Banked urine samples from 22 cases of GDM and 72 controls were analyzed for total (free BPA + conjugates) urinary BPA concentrations (MUg/L). FBG levels (mg/dl) were obtained from 1-h 50-g glucose tolerance tests (GTT) that women underwent for routine GDM screening (mean gestational age = 26.6 weeks, SD = 3.8). Those with an initial screening value >= 135 mg/dl underwent 3-h 100 g oral GTT. GDM diagnoses were made when the initial screening value was >= 200 mg/dl or when values at >= 2 time points exceeded 3-h oral GTT thresholds. Among controls, median FBG levels (mg/dL) did not differ across exposure tertiles, defined according to the distribution of total specific-gravity-adjusted urinary BPA concentrations. Logistic regression models controlling for race/ethnicity did not provide evidence of association between BPA exposure and case status across increasing tertiles of BPA exposure (number of GDM cases/controls in tertile1: 13/24; in tertile 2: 6/24; in tertile 3: 3/24). Findings do not support a relationship between total urinary BPA concentrations and altered glucose metabolism during pregnancy. However, due to study limitations, findings need to be interpreted with caution. PMID- 24053365 TI - The effect of clothing care activities on textile formaldehyde content. AB - Textiles are commonly treated with formaldehyde-based residues that may potentially induce allergic contact dermatitis in sensitive individuals. This study examined the initial formaldehyde content in clothing and resulting changes due to care activities. Twenty clothing articles were examined and 17 of them did not have detectable levels of formaldehyde. One shirt contained a formaldehyde concentration of 3172 ppm, and two pairs of pants had formaldehyde concentrations of 1391 ppm and 86 ppm. The two highest results represent formaldehyde levels that are up to 40-fold greater than international textile regulations. The two items with the greatest formaldehyde content were washed and dried in a manner similar to that used by consumers, including hand and machine washing in hot or cold water followed by air or machine drying. The washing and drying procedures reduced formaldehyde levels to between 26 and 72% of untreated controls. Differences in the temperature or type of washing and drying did not result in a clear trend in the subsequent formaldehyde content. In addition, samples were hot ironed, which did not affect the formaldehyde content as significantly. Understanding the formaldehyde content in clothing and its potential reduction through care activities may be useful for manufacturers and formaldehyde sensitive individuals. PMID- 24053366 TI - Different treatment strategies are applied to patients with the same periodontal status in general dentistry. AB - OBJECTIVE: To analyse how general dental practitioners (GDPs) and dental hygienists judge and plan to treat patients with different periodontal conditions. MATERIALS AND METHODS: Seventy-seven GDPs and 50 dental hygienists in a Swedish county, Halland, participated in a questionnaire study. The response rate was 94%. The questionnaire consisted of four simulated patient cases and an attached answer sheet. The patient cases had different periodontal status, ranging from healthy to moderate bone loss with general inflammation. The clinicians judged the periodontal status as healthy or diseased. If judged as diseased the clinicians suggested a diagnosis, selected treatment options and estimated the number of treatment sessions for each patient case. The clinicians were compared to each other regarding their judgement, as healthy or diseased, diagnostics and treatment. RESULTS: Three out of four patients were judged both as healthy and diseased by different clinicians. If judged as diseased the patients were diagnosed as having gingivitis or periodontitis. Regardless of the clinicians' former judgement and diagnostics there were no differences (p > 0.05) in the selected treatment options but there was a difference (p < 0.05) in the suggested number of treatment sessions. CONCLUSIONS: Clinicians' judgement of the same periodontal condition, as healthy or diseased, varies, which partly results in different treatment decisions considering the number of treatment sessions. The suggested number of treatment sessions varied also between clinicians even if they judged and diagnosed the condition likewise. The willingness to treat and suggested treatment options were not influenced by the variation in judgement and diagnostics. PMID- 24053367 TI - Association between viral hepatitis B infection and halitosis. AB - OBJECTIVE: Oral malodor can be increased in breath of liver patients. However, no study has been performed for the association between volatile sulfur compounds (VSCs) and viral hepatitis. The aim of the present study was to determine the relationship between viral hepatitis and VSCs. METHODS: This study analyzed 182 subjects and measured hydrogen sulfide (H2S), methyl mercaptan (CH3SH) and dimethyl sulfide [(CH3)2S] using the OralChroma((r)). Hepatitis type B was evaluated. Periodontal health was assessed using the Community Periodontal Index (CPI) and bleeding on probing (BOP). Tongue coating score (TCS) was evaluated. Multiple logistic regression analyses were conducted to evaluate the relationship. RESULTS: Viral hepatitis had an elevated odds of dimethyl sulfide defined halitosis (OR = 9.22, 95% CI = 2.08-40.95) after controlling for age, gender, alcohol consumption, current smoking, periodontitis, BOP, TCS and tongue brushing habit. The magnitude of the association between viral hepatitis and VSCs defined halitosis attenuated with adjustment of mediators (alcohol consumption, periodontitis, BOP, TCS and tongue brushing habit for hydrogen sulfide defined halitosis; periodontitis, TCS and tongue brushing habit for methyl mercaptan defined halitosis; tongue brushing habit for dimethyl sulfide defined halitosis). CONCLUSIONS: Findings of this study suggest that viral hepatitis may be associated with methyl mercaptan defined halitosis. PMID- 24053368 TI - Single nucleotide polymorphisms in fibroblast growth factor 23 gene, FGF23, are associated with prostate cancer risk. AB - OBJECTIVE: To determine whether sequence variants within the FGF23 gene are associated with the risk of developing prostate cancer in a Korean population. PATIENTS AND METHODS: Five common single nucleotide polymorphisms (SNPs) in the FGF23 gene were assessed in 272 patients with prostate cancer and 173 control subjects with benign prostatic hyperplasia. Single-locus analyses were conducted using conditional logistic regression. In addition, we performed a haplotype analysis for the five FGF23 SNPs tested. RESULTS: Three SNPs in the FGF23 gene (rs11063118, rs13312789 and rs7955866) were associated with an increased risk of prostate cancer in our study population. Odds ratios for homozygous variants vs wild-type variants ranged from 1.68 (95% confidence interval [CI]: 1.15-2.46) to 1.79 (95% CI: 1.16-2.75). CONCLUSION: This is the first study showing that genetic variations in FGF23 increase prostate cancer susceptibility. PMID- 24053369 TI - Long-term functional outcomes after artificial urinary sphincter implantation in women with stress urinary incontinence. AB - OBJECTIVE: To assess the long-term outcomes obtained after artificial urinary sphincter (AUS) implantation in women with stress urinary incontinence (SUI). MATERIALS AND METHODS: Women with SUI caused by intrinsic sphincter deficiency who underwent an AUS placement between 1984 and 1992 were included. Explantation, revision and deactivation rates of the AUS were reported. Continence, defined as no pad use, was assessed at the end of the follow-up. Kaplan-Meier survival curves were generated to evaluate the survival rate of the device without explantation or revision. RESULTS: A total of 34 patients were included. The median (interquartile range [IQR]) age of the patients at surgery was 56.5 (50 64.7) years and the median (IQR) follow-up was 17 (12-19) years. Overall, 26 women (74%) still had their AUS in place at the end of the follow-up, while eight patients underwent an explantation of the device. The 10-, 15- and 20-year device survival rates without explantation were 80, 80 and 74%, respectively. The 10-, 15- and 20-year survival rates of the device without revision were 79, 65 and 40%, respectively. After 20 years of follow-up, 11 women still had successful outcomes (61%). CONCLUSION: The AUS provided satisfactory very long-term functional results among women with SUI caused by intrinsic sphincter deficiency. PMID- 24053370 TI - The management of secondary pelvi-ureteric junction obstruction - a comparison of pyeloplasty and endopyelotomy. AB - OBJECTIVE: To review our experience in the management of secondary pelvi-ureteric junction obstruction (PUJO) comparing endopyelotomy with pyeloplasty. PATIENTS AND METHODS: We retrospectively analysed our database of 58 patients having undergone operative management of PUJO after failed primary management, including 41 with failed pyeloplasty and 17 failed endopyelotomy. Outcomes included mercapto-acetyltriglycine (MAG3) drainage capacity, symptomatic control and need for further intervention. Success was defined as freedom from failure in all three. RESULTS: Patients undergoing secondary pyeloplasty had better outcomes than endopyelotomy for symptomatic success (87.5% vs 74%), resolution of obstruction on MAG3 renography (96% vs 74%), and no need for further intervention (96% vs 71%). Overall success was 87.5% for pyeloplasty compared with 44% after secondary endopyelotomy. CONCLUSION: Outcomes of pyelopasty for secondary PUJO were superior when compared with endopyelotomy. PMID- 24053371 TI - The usefulness of ICG video angiography in the surgical treatment of superior cluneal nerve entrapment neuropathy: technical note. AB - Superior cluneal nerve (SCN) entrapment neuropathy is a known cause of low back pain. Although surgical release at the entrapment point of the osteofibrous orifice is effective, intraoperative identification of the thin SCN in thick fat tissue and confirmation of sufficient decompression are difficult. Intraoperative indocyanine green video angiography (ICG-VA) is simple, clearly demonstrates the vascular flow dynamics, and provides real-time information on vascular patency and flow. The peripheral nerve is supplied from epineurial vessels around the nerve (vasa nervorum), and the authors now present the first ICG-VA documentation of the technique and usefulness of peripheral nerve neurolysis surgery to treat SCN entrapment neuropathy in 16 locally anesthetized patients. Clinical outcomes were assessed with the Roland-Morris Disability Questionnaire before surgery and at the latest follow-up after surgery. Indocyanine green video angiography was useful for identifying the SCN in fat tissue. It showed that the SCN penetrated and was entrapped by the thoracolumbar fascia through the orifice just before crossing over the iliac crest in all patients. The SCN was decompressed by dissection of the fascia from the orifice. Indocyanine green video angiography visualized the SCN and its termination at the entrapment point. After sufficient decompression, the SCN was clearly visualized on ICG-VA images. Low back pain improved significantly, from a preoperative Roland-Morris Questionnaire score of 13.8 to a postoperative score of 1.3 at the last follow-up visit (p < 0.05). The authors suggest that ICG-VA is useful for the inspection of peripheral nerves such as the SCN and helps to identify the SCN and to confirm sufficient decompression at surgery for SCN entrapment. PMID- 24053372 TI - Malignant transformation of an intramedullary epidermoid cyst in the thoracic region of the spinal cord: case report. AB - Malignant transformation of epidermoid cysts (ECs) to squamous cell carcinomas (SCCs) in the CNS is exceedingly rare and has only been described in intracranial ECs. In this article, the authors describe a 53-year-old man with a history of a previously resected T3-4 EC, who presented with a 2-month history of progressively worsening weakness in the left side of his body. Magnetic resonance imaging revealed an enhancing mass in the T3-4 region, the exact location of the previous cyst. The mass was resected in gross-total fashion, and pathological analysis revealed an SCC. Postoperatively, the patient regained full strength in his lower extremities. After the resection, he received radiotherapy administered at an isodose of 50 Gy. To the authors' knowledge, this is the first reported case of malignant transformation of an intramedullary spinal EC in the literature. PMID- 24053373 TI - Postoperative magnetic resonance imaging artifact with cobalt-chromium versus titanium spinal instrumentation: presented at the 2013 Joint Spine Section Meeting. Clinical article. AB - OBJECT: Cobalt-chromium alloy (CoCr) rods haves some preferred biomechanical properties over titanium rods for spinal fixation. The use of CoCr rods in spinal fusion is relatively new, and there is no study in the existing world literature assessing the artifact caused by these rods in patients undergoing postoperative MRI. The purpose of this study is to compare the amount of imaging artifact caused by these implants and to assess its impact on the visualization of neighboring neural structures. METHODS: This study investigated MR images in patients who underwent implantation of thoracolumbar instrumentation using 5.5-mm diameter CoCr rods between November 2009 and March 2011 and images obtained in a comparison group of patients who had 5.5-mm titanium rods implanted during the same time period. Axial measurements of the artifact created by the rods between the screw heads were compared between the groups. Two blinded board-certified radiologists performed the measurements independently. They scored the visualization of the spinal canal using a subjective scoring system of 1-3, with 1 representing very good visualization and 2 and 3 representing reduced (good or suboptimal, respectively) visualization as a result of rod-related artifact. All measurements and scores were independently provided for T1-weighted and T2 weighted fast spin echo sequences (1.5-T magnet, 5-mm slice thickness). RESULTS: A total of 40 levels from the CoCr group (6 patients) and 30 levels from the titanium group (9 patients) were included in the analysis. Visualization of the canal at all levels was rated a score of 1 (very good) by both evaluators for both the CoCr and titanium groups. The average artifact on T1-weighted images measured 11.8 +/- 1.8 mm for the CoCr group and 8.5 +/- 1.2 mm for the titanium group (p < 0.01). The corresponding measurements on T2-weighted images were 11.0 +/- 2.3 mm and 8.3 +/- 1.7 mm (p < 0.01), respectively. In a mixed regression model, the mean artifact measurement for the CoCr group was, on average, 3.5 mm larger than for the control group. There was no significant difference between the measurements of the 2 evaluators (p = 0.99). CONCLUSIONS: The artifact caused by CoCr rods is approximately 3.5 mm larger than that caused by titanium rods on axial T1- and T2-weighted MRI. However, artifact from either CoCr or titanium was not found to interfere with the evaluation of the spinal canal and surrounding neural elements. PMID- 24053374 TI - Letter to the editor: The O-arm revolution in spine surgery. PMID- 24053375 TI - Civilian gunshot wounds to the atlantoaxial spine: a report of 10 cases treated using a multidisciplinary approach. AB - OBJECT: Gunshot wounds to the atlantoaxial spine are uncommon injuries and rarely require treatment, as a bullet traversing this segment often results in a fatal injury. Additionally, these injuries are typically biomechanically stable. The authors report a series of 10 patients with gunshot wounds involving the lateral mass and/or bodies of the atlantoaxial complex. Their care is discussed and conclusions are drawn from these cases to identify the optimal treatment for these injuries. METHODS: A retrospective review was conducted of patients presenting to the emergency rooms of 3 institutions with gunshot wounds involving the atlantoaxial spine. Mechanism of injury and neurological status were obtained, as was the extent of the osteoligamentous, vascular, and neurological injuries. Nonoperative and operative treatment, complications, and clinical and radiographic outcome were recorded. The data were then analyzed to determine the neurological and biomechanical prognosis of these injuries, the utility of the various diagnostic modalities in the acute management of the injuries, and the nature and effectiveness of the nonoperative and operative treatment modalities. RESULTS: Ten patients with gunshot wounds involving the lateral mass and/or bodies of the atlantoaxial complex were identified. All but 2 patients sustained a vertebral artery injury. Each patient was evaluated using cervical radiographs, CT scans, and vascular imaging, 8 in the form of digital subtraction angiography and 2 with high-resolution CT angiography. Uncomplicated patients were treated conservatively using cervical collar immobilization, local wound care, and antibiotics. One patient was treated using a halo for instability and 1 underwent posterior fusion following a posterolateral decompression for delayed myelopathy. One patient underwent transoral resection of a bullet fragment. One patient underwent embolization for a symptomatic arteriovenous fistula and a second patient underwent a neck exploration and a jugular vein ligation. None of the patients received anticoagulation therapy. The mean follow-up duration was 13 months. All but 2 patients regained their previous functional status and all ultimately attained a mechanically stable spine. CONCLUSIONS: These 10 patients represent a rare form of cervical spine penetrating injury. Unilateral gunshot wounds to the atlantoaxial complex are usually stable and the need for acute surgical intervention is rare. Unilateral vertebral artery injury is well tolerated and any information provided by angiography does not alter the acute management of the patient. Vascular complications from gunshot wounds can be managed effectively by endovascular techniques. PMID- 24053376 TI - Endoscopic transnasal odontoidectomy combined with posterior reduction to treat basilar invagination: technical note. AB - OBJECT: Transoral microscopic odontoidectomy has been accepted as a standard procedure to treat basilar invagination over the past several decades. In recent years the emergence of new technologies, including endoscopic odontoidectomy and posterior reduction, has presented a challenge to the traditional treatment algorithm. In this article, the authors describe 1 patient with basilar invagination who was successfully treated with endoscopic transnasal odontoidectomy combined with posterior reduction. The purpose of this report is to validate the effectiveness of this treatment algorithm in selected cases and describe several operative nuances and pearls based on the authors' experience. METHODS: One patient with basilar invagination caused by a congenital osseous malformation underwent endoscopic transnasal odontoidectomy combined with posterior reduction in a single operative setting. The purely endoscopic transnasal odontoidectomy was first conducted with the patient supine. The favorable anatomical reduction was then achieved through a posterior approach after the patient was moved prone. RESULTS: The patient was extubated after recovery from anesthesia and allowed oral food intake the next day. No complications were noted, and the patient was discharged 4 days after the operation. Postoperative imaging demonstrated excellent decompression of the anterior cervicomedullary junction pathology. The patient was followed up for 12 months and remarkable neurological recovery was observed. CONCLUSIONS: The endoscopic transnasal odontoidectomy is a better minimally invasive approach for anterior decompression and can make the posterior reduction easier because the anterior resistant force is eliminated. The subsequent posterior reduction can make decompression of the ventral side of the cervicomedullary junction more effective because the C-2 vertebral body is pushed forward. A combination of these 2 approaches has the advantages of minimally invasive access and a faster patient recovery, and thus is a valid alternative in selected cases. PMID- 24053377 TI - Delayed postoperative neurological complication in a patient with congenital kyphoscoliosis: recovered by revision of the 4-rod instrumentation technique: case report. AB - The authors report a case of progressive congenital kyphoscoliosis in which the patient, a boy, originally underwent combined anterior and instrumented posterior spinal fusion at the age of 7 years and 3 months. Early proximal junctional kyphosis and implant failure mandated proximal extension of implants with 2 new rods connected to the old caudad short rods. At the 3-year follow-up, clinical and CT assessment revealed a thoracolumbar pseudarthrosis for which the patient underwent a 2-stage procedure without complication. Recordings of somatosensory evoked potentials intraoperatively were normal. Twelve hours after surgery, his neurological status started to progressively deteriorate. The patient was brought to the operating room, and the initially achieved correction was reversed by an apex-only exposure of the 4-rod system. After surgery the patient started to show progressive improvement in his neurological function. A final myelography was performed and showed free passage of the dye without evidence of obstruction. Clinically, the patient continued to improve and at his 3-month follow-up had near-complete resolution of his neurological deficits. Findings on his physical examination were normal at the final 12-year follow-up. Despite normal findings on intraoperative neuromonitoring, a delayed neurological deficit can occur after complex spine reconstruction. Preoperative risk assessment, surgical approach, and instrumentation deserve careful attention. Advantages of a 4-rod construct are discussed in this case. PMID- 24053378 TI - Left-right axial rotation within C1-2 after implant removal. AB - OBJECT: Surgical treatment of atlantoaxial injuries may be performed by a variety of surgical procedures, with each of these having its own specific advantages and disadvantages. To preserve the range of motion within the atlantoaxial joint after surgical treatment, posterior atlantoaxial screw fixation according to the method of Goel and Harms could be beneficial. This technique is not considered to fix the joint permanently if the screws are removed. However, this must not necessarily be true, especially if one notices that cervical joints have a tendency for rapid fusion after surgery. The objective of this study was to analyze left-right axial rotation following implant removal, with the following research questions addressed: 1) is there a relevant rotational left-right mobility in C1-2; 2) is there a difference in mobility depending on sex; 3) is there a correlation of mobility to age; 4) is there a correlation of mobility to the "implant-in-body time"; and 5) is neck pain improved by this method of surgical treatment? METHODS: This is a retrospective study in 10 patients who had received atlantoaxial fixation according to the Harms method following atlantoaxial injury. These patients had undergone implant removal after a mean time of 128 days, followed by functional atlantoaxial CT in left-right rotation. Statistical analysis was performed using the SPSS software package; significance was assumed for p < 0.05. RESULTS: The following findings are reported. 1) Left right axial rotation within the atlantoaxial joint was measured to be 17 degrees (mean value) following implant removal. 2) There was no significant difference between men (20 degrees ) and women (14.8 degrees ) (p = 0.595). 3) Left-right axial rotation negatively correlated to the age of the patient (r = -0.646, p = 0.043). 4) "Implant-in-body time" did not influence left-right axial rotation (r = 0.04, p = 0.907) if the implants are removed within 90-180 days after surgery. 5) Neck pain as assessed by the patients themselves on the visual analog scale was 7.9 +/- 1.1 preoperatively and 3.6 +/- 1.2 (mean +/- SD) after implant removal (p = 0.002). CONCLUSIONS: The authors conclude that removal of the implants 3-6 months after posterior atlantoaxial fixation according to the method of Goel and Harms is beneficial for obtaining some axial rotation within the atlantoaxial joint. The range of motion preserved depends on the age of the patient. PMID- 24053379 TI - Control of oxidative reactions of hemoglobin in the design of blood substitutes: role of the Vc, NAC, TEMPO and their reductant system. AB - Oxidative reactions of hemoglobin (Hb) are still a serious problem for Hb-based blood substitute development. Although varieties of antioxidant strategies have been suggested, this in vitro study examined the ability of the ascorbate, N Acetyl-L-Cysteine (NAC), 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-1-oxygen free radicals (TEMPO) and their reductant system in preventing Hb oxidation. The content of ferric Hb is monitored in the process of vitamin C (Vc), NAC, TEMPO and their reductant system. The results suggest that ascorbate is effective in reducing ferryl Hb, and TEMPO with Vc/NAC could obviously shorten the reaction time, but it does not play the role of Met-Hb reductases. It demonstrates that TEMPO did little to recover Hb under oxidative stress. PMID- 24053380 TI - Suppression of thymosin beta10 increases cell migration and metastasis of cholangiocarcinoma. AB - BACKGROUND: Thymosin beta10 (Tbeta10) expression is associated with malignant phenotypes in many cancers. However, the role and mechanisms of Tbeta10 in liver fluke-associated cholangiocarcinoma (CCA) are not fully understood. In this study, we investigated the expression of Tbeta10 in CCA tumor tissues and cell lines as well as molecular mechanisms of Tbeta10 in tumor metastasis of CCA cell lines. METHODS: Tbeta10 expression was determined by real time RT-PCR or immunocytochemistry. Tbeta10 silence or overexpression in CCA cells was achieved using gene delivery techniques. Cell migration was assessed using modified Boyden chamber and wound healing assay. The effect of silencing Tbeta10 on CCA tumor metastasis was determined in nude mice. Phosphorylation of ERK1/2 and the expression of EGR1, Snail and matrix metalloproteinases (MMPs) were studied. RESULTS: Ten pairs of CCA tissues (primary and metastatic tumors) and 5 CCA cell lines were studied. With real time RT-PCR and immunostaining analysis, Tbeta10 was highly expressed in primary tumors of CCA; while it was relatively low in the metastatic tumors. Five CCA cell lines showed differential expression levels of Tbeta10. Silence of Tbeta10 significantly increased cell migration, invasion and wound healing of CCA cells in vitro; reversely, overexpression of Tbeta10 reduced cell migration compared with control cells (P<0.05). In addition, silence of Tbeta10 in CCA cells increased liver metastasis in a nude mouse model of CCA implantation into the spleen. Furthermore, silence of Tbeta10 activated ERK1/2 and increased the expression of Snail and MMPs in CCA cell lines. Ras-GTPase inhibitor, FPT inhibitor III, effectively blocked Tbeta10 silence-associated ERK1/2 activation, Snail expression and cell migration. CONCLUSIONS: Low expression of Tbeta10 is associated with metastatic phenotype of CCA in vitro and in vivo, which may be mediated by the activation of Ras, ERK1/2 and upregulation of Snail and MMPs. This study suggests a new molecular pathway of CCA pathogenesis and a novel strategy to treat or prevent CCA metastasis. PMID- 24053382 TI - Unpopular, overweight, and socially inept: reconsidering the stereotype of online gamers. AB - Online gaming has become an activity associated with a highly specific, caricatured, and often negative image. This "stereotype" has permeated the collective consciousness, as online gamers have become common caricatures in popular media. A lack of comprehensive demographic inquiries into the online gaming population has made it difficult to dispute these stereotypical characteristics and led to rising concerns about the validity of these stereotypes. The current study aims to clarify the basis of these negative characterizations, and determine whether online video game players display the social, physical, and psychological shortcomings stereotypically attributed them. Sampling and recruiting was conducted using a two-stage approach. First, a representative sample of 50,000 individuals aged 14 and older who were asked about their gaming behavior in an omnibus telephone survey. From this sample, 4,500 video game players were called for a second telephone interview, from which the current data were collected. Only those participants who completed all of the questions relating to video game play were retained for the current analysis (n=2,550). Between- and within-group analyses were enlisted to uncover differences between online, offline, and nongame playing communities across varying degrees of involvement. The results indicate that the stereotype of online gamers is not fully supported empirically. However, a majority of the stereotypical attributes was found to hold a stronger relationship with more involved online players than video game players as a whole, indicating an empirical foundation for the unique stereotypes that have emerged for this particular subgroup of video game players. PMID- 24053381 TI - A school intervention for mental health literacy in adolescents: effects of a non randomized cluster controlled trial. AB - BACKGROUND: "Mental health for everyone" is a school program for mental health literacy and prevention aimed at secondary schools (13-15 yrs). The main aim was to investigate whether mental health literacy, could be improved by a 3-days universal education programme by: a) improving naming of symptom profiles of mental disorder, b) reducing prejudiced beliefs, and c) improving knowledge about where to seek help for mental health problems. A secondary aim was to investigate whether adolescent sex and age influenced the above mentioned variables. A third aim was to investigate whether prejudiced beliefs influenced knowledge about available help. METHOD: This non-randomized cluster controlled trial included 1070 adolescents (53.9% boys, M age 14 yrs) from three schools in a Norwegian town. One school (n = 520) received the intervention, and two schools (n = 550) formed the control group. Pre-test and follow-up were three months apart. Linear mixed models and generalized estimating equations models were employed for analysis. RESULTS: Mental health literacy improved contingent on the intervention, and there was a shift towards suggesting primary health care as a place to seek help. Those with more prejudiced beliefs did not suggest places to seek help for mental health problems. Generally, girls and older adolescents recognized symptom profiles better and had lower levels of prejudiced beliefs. CONCLUSIONS: A low cost general school program may improve mental health literacy in adolescents. Gender specific programs and attention to the age and maturity of the students should be considered when mental health literacy programmes are designed and tried out. Prejudice should be addressed before imparting information about mental health issues. PMID- 24053383 TI - Problematic use of social network sites: the interactive relationship between gratifications sought and privacy concerns. AB - Problematic Internet use has long been a matter of concern; however, few studies extend this line of research from general Internet use to the use of social network sites (SNSs), or explicate the problematic use of SNSs by understanding what factors may enhance or reduce users' compulsive behaviors and excessive form of use on SNSs. Building on literature that found a positive relationship between gratifications sought from the Internet and problematic Internet use, this study first explores the types of gratifications sought from SNSs and examines their relationship with problematic SNS use. It found that three types of gratifications-diversion, self-presentation, and relationship building-were positively related to problematic SNS use. In addition, with a growing body of research on SNS privacy, a moderating role of privacy concerns on SNSs has been proposed to understand how it can influence the relationship between gratifications sought from SNSs and problematic SNS use. The findings suggest that different subdimensions of privacy concerns interact with gratifications sought in different manners. In other words, privacy concerns, including unauthorized secondary use and improper access, play a more influential role in constraining the positive relationship between gratifications sought and problematic SNS use when individuals seek to build relationships on SNSs. However, if individuals seek to have diversion on SNSs, their privacy concerns will be overridden by their gratifications sought, which in turn leads to problematic SNS use. Implications of these findings for future research are discussed. PMID- 24053384 TI - Characterization of immune response to neurofilament light in experimental autoimmune encephalomyelitis. AB - BACKGROUND: Autoimmunity to neuronal proteins occurs in several neurological syndromes, where cellular and humoral responses are directed to surface as well as intracellular antigens. Similar to myelin autoimmunity, pathogenic immune response to neuroaxonal components such as neurofilaments may contribute to neurodegeneration in multiple sclerosis. METHODS: We studied the immune response to the axonal protein neurofilament light (NF-L) in the experimental autoimmune encephalomyelitis animal model of multiple sclerosis. To examine the association between T cells and axonal damage, pathology studies were performed on NF-L immunized mice. The interaction of T cells and axons was analyzed by confocal microscopy of central nervous system tissues and T-cell and antibody responses to immunodominant epitopes identified in ABH (H2-Ag7) and SJL/J (H2-As) mice. These epitopes, algorithm-predicted peptides and encephalitogenic motifs within NF-L were screened for encephalitogenicity. RESULTS: Confocal microscopy revealed both CD4+ and CD8+ T cells alongside damaged axons in the lesions of NF-L immunized mice. CD4+ T cells dominated the areas of axonal injury in the dorsal column of spastic mice in which the expression of granzyme B and perforin was detected. Identified NF-L epitopes induced mild neurological signs similar to the observed with the NF-L protein, yet distinct from those characteristic of neurological disease induced with myelin oligodendrocyte glycoprotein. CONCLUSIONS: Our data suggest that CD4+ T cells are associated with spasticity, axonal damage and neurodegeneration in NF-L immunized mice. In addition, defined T-cell epitopes in the NF-L protein might be involved in the pathogenesis of the disease. PMID- 24053385 TI - "Do your homework...and then hope for the best": the challenges that medical tourism poses to Canadian family physicians' support of patients' informed decision-making. AB - BACKGROUND: Medical tourism-the practice where patients travel internationally to privately access medical care-may limit patients' regular physicians' abilities to contribute to the informed decision-making process. We address this issue by examining ways in which Canadian family doctors' typical involvement in patients' informed decision-making is challenged when their patients engage in medical tourism. METHODS: Focus groups were held with family physicians practicing in British Columbia, Canada. After receiving ethics approval, letters of invitation were faxed to family physicians in six cities. 22 physicians agreed to participate and focus groups ranged from two to six participants. Questions explored participants' perceptions of and experiences with medical tourism. A coding scheme was created using inductive and deductive codes that captured issues central to analytic themes identified by the investigators. Extracts of the coded data that dealt with informed decision-making were shared among the investigators in order to identify themes. Four themes were identified, all of which dealt with the challenges that medical tourism poses to family physicians' abilities to support medical tourists' informed decision-making. Findings relevant to each theme were contrasted against the existing medical tourism literature so as to assist in understanding their significance. RESULTS: Four key challenges were identified: 1) confusion and tensions related to the regular domestic physician's role in decision-making; 2) tendency to shift responsibility related to healthcare outcomes onto the patient because of the regular domestic physician's reduced role in shared decision-making; 3) strains on the patient physician relationship and corresponding concern around the responsibility of the foreign physician; and 4) regular domestic physicians' concerns that treatments sought abroad may not be based on the best available medical evidence on treatment efficacy. CONCLUSIONS: Medical tourism is creating new challenges for Canadian family physicians who now find themselves needing to carefully negotiate their roles and responsibilities in the informed decision-making process of their patients who decide to seek private treatment abroad as medical tourists. These physicians can and should be educated to enable their patients to look critically at the information available about medical tourism providers and to ask critical questions of patients deciding to access care abroad. PMID- 24053386 TI - Modulation of the deswelling temperature of thermoresponsive microgel films. AB - We demonstrate fine-tuning of the deswelling temperatures of thermoresponsive microgels within a biologically relevant range (30-40 degrees C). This was achieved by copolymerizing N-isopropylacrylamide and N-isopropylmethacrylamide (NIPAm and NIPMAm, respectively) in varying ratios; the parent homopolymers are well-known thermoresponsive polymers. Polyelectrolyte layer-by-layer (LbL) assemblies of these microgels retain the temperature response properties as demonstrated by temperature-dependent light scattering. Furthermore, films composed of more than one type of microgel building block were shown to have multiple temperature responses similar to those observed for the individual building blocks, permitting further tailoring of the temperature responsive interface. Additional experiments with mixed composition films, investigating multiple assembly processes, show that the location of the microgels within the film does not interfere with the temperature response. This suggests that microgels within the polyelectrolyte assembly behave independently of neighboring microgels with respect to their thermally induced deswelling. PMID- 24053388 TI - The Tzu Chi nomograms for maximum urinary flow rate (Qmax ) in children: comparison with Miskolc nomogram. AB - OBJECTIVE: To report the first ranking method-based age- and gender-specific nomograms for maximum urinary flow rate (Qmax ) in children. PATIENTS AND METHODS: Healthy children aged 4-12 years were enrolled for two sets of uroflowmetry tests. The first and the higher value of the two consecutive Qmax of each child with a voided volume (VV) of >=50 mL were included for establishing single- and dual-Qmax nomograms. Children with possible urinary tract infection or lower urinary tract dysfunctions were excluded. RESULTS: In all, 1128 children (583 boys and 545 girls) with a mean (sd) age of 7.7 (2.2) years were eligible for analysis and construction of nomograms. Multivariate analysis showed that the Qmax was significantly affected by age, VV and gender (all P < 0.01). The values of the corresponding percentile of the Qmax were significantly higher in the dual Qmax nomogram compared with the single-nomogram. In boys aged 8-12 years, the 5th percentile line of the Miskolc nomogram was significantly lower than that of the present nomograms at all VVs. Minimally acceptable Qmax values, around the 10th percentile of the dual-Qmax nomogram, were >11.5 mL/s in children aged <=6 years and >15.0 mL/s in children aged >=7 years. External validation is required for the present dual-Qmax nomograms. CONCLUSION: We recommend repeating uroflowmetry in cases with a Qmax lower than the minimally acceptable age- and gender-specific Qmax values. PMID- 24053387 TI - Prenatal diagnosis and post-mortem examination in a fetus with thrombocytopenia absent radius (TAR) syndrome due to compound heterozygosity for a 1q21.1 microdeletion and a RBM8A hypomorphic allele: a case report. AB - BACKGROUND: Thrombocytopenia-absent radius syndrome is a rare autosomal recessive disorder characterized by megakaryocytic thrombocytopenia and longitudinal limb deficiencies mostly affecting the radial ray. Most patients are compound heterozygotes for a 200 kb interstitial microdeletion in 1q21.1 and a hypomorphic allele in RBM8A, mapping in the deleted segment. At the moment, the complete molecular characterization of thrombocytopenia-absent radius syndrome is limited to a handful of patients mostly ascertained in the pediatric age CASE PRESENTATION: We report on a fetus with bilateral upper limb deficiency found at standard prenatal ultrasound examination. The fetus had bilateral radial agenesis and humeral hypo/aplasia with intact thumbs, micrognathia and urinary anomalies, indicating thrombocytopenia-absent radius syndrome. Molecular studies demonstrated compound heterozygosity for the 1q21.1 microdeletion and the RBM8A rs139428292 variant at the hemizygous state, inherited from the mother and father, respectively CONCLUSION: The molecular information allowed prenatal diagnosis in the following pregnancy resulting in the birth of a healthy carrier female. A review was carried out with the attempt to the trace the fetal ultrasound presentation of thrombocytopenia-absent radius syndrome and discussing opportunities for second-tier molecular studies within a multidisciplinary setting. PMID- 24053389 TI - A novel multivalent OspA vaccine against Lyme borreliosis shows promise in Phase I/II studies. PMID- 24053390 TI - Is electroporation decisive for the efficacy of DNA vaccine against house dust mite allergy? PMID- 24053391 TI - Potential of the adhesin complex protein of Neisseria meningitidis for next generation meningococcal vaccines. PMID- 24053392 TI - Have you 'herd'? Childhood pneumonia immunization has long-lasting impact on populations. PMID- 24053393 TI - Perspectives on the role of surveillance in eliminating rubella and congenital rubella syndrome in the Americas. AB - Effective management and coordination in regions currently lacking surveillance capacity will require significant increases in existing human resources to manage vitally needed expanded national surveillance systems. An adequate investment in human resources and infrastructure capacity is essential for ensuring surveillance functions well. This was the experience in the Americas, particularly with the recent elimination of rubella and congenital rubella syndrome. By taking this path, other benefits to the overall public health of the nations will occur. The purpose of this paper is to present perspectives on the role of surveillance in the elimination of rubella in the Americas and to share related perspectives on capacity development in developing countries. Hopefully, these perspectives will aid efforts to strengthen surveillance and advance rubella elimination in other regions of the world. PMID- 24053394 TI - Challenges in reducing dengue burden; diagnostics, control measures and vaccines. AB - Dengue is a major public health concern worldwide, with the number of infections increasing globally. The illness imposes the greatest economic and human burden on developing countries that have limited resources to deal with the scale of the problem. No cure for dengue exists; treatment is limited to rehydration therapy, and with vector control strategies proving to be relatively ineffective, a vaccine is an urgent priority. Despite the numerous challenges encountered in the development of a dengue vaccine, several vaccine candidates have shown promise in clinical development and it is believed that a vaccination program would be at least as cost-effective as current vector control programs. The lead candidate vaccine is a tetravalent, live attenuated, recombinant vaccine, which is currently in Phase III clinical trials. Vaccine introduction is a complex process that requires consideration and is discussed here. This review discusses the epidemiology, burden and pathogenesis of dengue, as well as the vaccine candidates currently in clinical development. PMID- 24053395 TI - Future directions for the development of Chlamydomonas-based vaccines. AB - Besides serving as a valuable model in biological sciences, Chamydomonas reinhardtii has been used during the last decade in the biotechnology arena to establish models for the low cost production of vaccines. Antigens from various pathogens including Plasmodium falciparum, foot and mouth disease virus, Staphylococcus aureus, classical swine fever virus (CSFV) as well as some auto antigens, have been produced in C. reinhardtii. Although some of them have been functionally characterized with promising results, this review identifies future directions for the advancement in the exploitation of this robust and safe vaccine production platform. The present analysis reflects that important immunological implications exist for this system and remain unexplored, including the possible adjuvant effects of algae biomolecules, the effect of bioencapsulation on immunogenicity and the possible development of whole-cell vaccines as an approach to trigger cytotoxic immune responses. Recently described molecular strategies that aim to optimize the expression of nuclear-encoded target antigens are also discussed. PMID- 24053396 TI - Increasing rates of Salmonella Paratyphi A and the current status of its vaccine development. AB - Enteric fever caused by Salmonella enterica serovar Typhi and Salmonella enterica serovar Paratyphi is still a major disease burden mainly in developing countries. Previously, S. Typhi was believed to be the major cause of enteric fever. The real situation is now becoming clear with reports emerging from many Asian countries of S. Paratyphi, mostly S. Paratyphi A, causing a substantial number of cases of enteric fever. Although there have been advances in the use of the currently available typhoid vaccines and in the development of newer typhoid vaccines, paratyphoid vaccine development is lagging behind. Since the disease caused by S. Typhi and S. Paratyphi are clinically indistinguishable and are commonly termed 'enteric' fever, it will be necessary to have a vaccine available against both S. Typhi and S. Paratyphi A as a bivalent 'enteric fever vaccine'. PMID- 24053398 TI - Translational sciences approach to RSV vaccine development. AB - Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and the elderly. Despite its relatively low degree of antigenic variation, it causes frequent reinfection throughout life. Clinical manifestations of RSV disease and the immune response to infection differ in infants and the elderly, suggesting that vaccines designed to protect these two populations may require different attributes. Here, the authors describe the translational approach of utilizing data from epidemiology studies performed in these populations, the use of RSV diagnostics in clinical practice, lessons learned from previous vaccine clinical trials and the success of palivizumab in prevention of RSV disease in premature and high-risk infants to aid the development of safe and effective RSV vaccines. PMID- 24053399 TI - Exploitation of physiology and metabolomics to identify pneumococcal vaccine candidates. AB - Streptococcus pneumoniae (the pneumococcus) is the etiologic agent of community acquired pneumonia and invasive pneumococcal diseases such as septicemia and bacterial meningitis. The increasing antibiotic resistance and the suboptimal efficacy or limited serotype coverage of currently available vaccines urgently requires novel approaches in exploring new antimicrobials, therapeutic intervention strategies and vaccines. The current vaccine development strategies rely on the hypothesis that surface-exposed proteins, which are essential for pneumococcal virulence, are the most suitable candidates for future protein-based vaccines. Since virulence is closely linked with bacterial fitness, the potential of a pathogen to colonize and infect the host depends further on its physiology. This review summarizes the application of genome-wide techniques and their exploitation to decipher fundamental insights into bacterial factors associated with fitness, metabolism and virulence, leading to the discovery of vaccine candidates or antimicrobials. PMID- 24053397 TI - Salmonella as a vaccine delivery vehicle. AB - Attenuated Salmonella vaccines can be administered orally to deliver recombinant antigens to mucosal surfaces inducing a protective immune response against a variety of targeted pathogens. A number of exciting new approaches and technologies for attenuated Salmonella vaccines have been developed recently. However, a disconnect remains between results obtained with mice in preclinical studies and results obtained in human clinical trials. This is due to an incomplete understanding of Salmonella Typhi interactions with human hosts and inadequate animal models available for study. In this review, the authors describe recent progress in identifying important differences underlying S. Typhi host interactions, the development of novel approaches to vaccine design and six recent clinical trials evaluating Salmonella-vectored vaccines. PMID- 24053400 TI - Vaccination and the TAP-independent antigen processing pathways. AB - The cytotoxic CD8(+) T lymphocyte-mediated cellular response is important for the elimination of virus-infected cells and requires the prior recognition of short viral peptide antigens previously translocated to the endoplasmic reticulum by the transporter associated with antigen processing (TAP). However, individuals with nonfunctional TAP complexes or infected cells with TAP molecules blocked by specific viral proteins, such as the cowpoxvirus, a component of the first source of early empirical vaccination against smallpox, are still able to present several HLA class I ligands generated by the TAP-independent antigen processing pathways to specific cytotoxic CD8(+) T lymphocytes. Currently, bioterrorism and emerging infectious diseases have renewed interest in poxviruses. Recent works that have identified HLA class I ligands and epitopes in virus-infected TAP deficient cells have implications for the study of both the effectiveness of early empirical vaccination and the analysis of HLA class I antigen processing in TAP-deficient subjects. PMID- 24053401 TI - Adjuvanted influenza vaccines. AB - Influenza is one of the most common causes of human morbidity and mortality that is preventable by vaccination. Immunization with available vaccines provides incomplete protection against illness caused by influenza virus, especially in high-risk groups such as the elderly and young children. Thus, more efficacious vaccines are needed for the entire population, and all the more so for high-risk groups. One way to improve immune responses and protection is to formulate the vaccine with antigen carriers and/or adjuvants, which can play an important role in improving immune responses and delivery to antigen-presenting cells, especially for a vaccine like influenza that is based on protein antigens usually administered without a carrier or adjuvant. In this review, the authors present an overview of available vaccines, focusing on research and development of new adjuvants used in influenza vaccines, as well as adjuvanted influenza vaccines aimed to improve immune responses, protection and breadth of coverage for influenza. PMID- 24053403 TI - Penile cancer: organ-sparing techniques. AB - To compare the oncological safety of treating patients with penile cancer with conservative techniques developed to preserve function, cosmesis and psychological well-being with more radical ablative strategies. We conducted an extensive review of the literature of penile-preserving and ablative techniques and report on the oncological as well as functional outcomes. There were no randomised studies comparing penile-preserving and ablative techniques. Most studies consisted of retrospective cohorts. The quality of evidence was level 3 at best. Cancer-specific survival is similar in penile-preserving and ablative approaches for low-stage disease. Penile preservation is better for functional and cosmetic outcomes and should be offered as a primary treatment method in men with low-stage penile cancer. PMID- 24053402 TI - Hypereosinophilic syndrome masquerading as a myocardial infarction causing decompensated heart failure. AB - BACKGROUND: An 81 year old female patient diagnosed with a chronic low grade hypereosinophilic syndrome presented with angina and dyspnoea. CASE PRESENTATION: She was managed for a non-ST elevated myocardial infarction since her troponin levels were elevated. On day 5, she suffered an acute clinical deterioration with type I respiratory failure and cardiogenic shock, accompanied by deterioration in left ventricular systolic function demonstrated on echocardiography, and this coincided with a marked rise in eosinophil count. Secondary causes of eosinophilia were excluded permitting a diagnosis of Hypereosinophilic Syndrome (HES) to be made. Coronary angiography revealed unobstructed arteries. Supportive treatment for heart failure included diuretic and inotropes but she dramatically improved both clinically and echocardiographically upon commencement of high dose steroids and hydroxycarbamide. Cardiac magnetic resonance imaging (CMR) demonstrated diffuse, shallow endomyocardial enhancement with late gadolinium, consistent with a diagnosis of eosinophilic myocarditis. CONCLUSION: Hypereosinophilic Syndrome can masquerade as a myocardial infarction causing decompensated heart failure. Early recognition and treatment with steroids can improve outcome. PMID- 24053404 TI - Determinants of manganese in prenatal dentin of shed teeth from CHAMACOS children living in an agricultural community. AB - Manganese (Mn) is an essential nutrient, but overexposure can be neurotoxic. Over 800 000 kg of Mn-containing fungicides are applied each year in California. Manganese levels in teeth are a promising biomarker of perinatal exposure. Participants in our analysis included 207 children enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a longitudinal birth cohort study in an agricultural area of California. Mn was measured in teeth using laser-ablation-inductively coupled plasma-mass spectrometry. Our purpose was to determine environmental and lifestyle factors related to prenatal Mn levels in shed teeth. We found that storage of farmworkers' shoes in the home, maternal farm work, agricultural use of Mn-containing fungicides within 3 km of the residence, residence built on Antioch Loam soil and Mn dust loading (MUg/m(2) of floor area) during pregnancy were associated with higher Mn levels in prenatal dentin (p < 0.05). Maternal smoking during pregnancy was inversely related to Mn levels in prenatal dentin (p < 0.01). Multivariable regression models explained 22-29% of the variability of Mn in prenatal dentin. Our results suggest that Mn measured in prenatal dentin provides retrospective and time specific levels of fetal exposure resulting from environmental and occupational sources. PMID- 24053405 TI - Demographics of the injury pattern in severely injured patients with an associated clavicle fracture: a retrospective observational cohort study. AB - BACKGROUND: Despite an increasing interest in the treatment of clavicle fractures, this is still a not yet defined area in severely injured patients as most studies exclude these patients. Analyzing fracture type and evaluate accompanying injuries can provide valuable information in an early stage of trauma care. OBJECTIVE: To identify prevalence, fracture type and accompanying injuries of clavicle fractures in the severely injured patient. METHODS: We included all severely injured patients (ISS >= 16) with a clavicle fracture from January 2007 - December 2011. We prospectively collected data about demographics, injuries, trauma mechanism and mortality. Fractures were classified using the Robinson classification. RESULTS: A total of 1534 patients had an ISS >=16, of which 164 (10.7%) patients had a clavicle fracture. Traffic related accidents were the main cause of injury (65%). Most fractures were midshaft fractures (66.5%) of which 56% were displaced. Seven patients were treated operatively. There was no significant difference in ISS between the three fracture types. 83% of the patients sustained additional injury to the head and neck; the most prevalent injuries were skull or skull base fractures (41.5%) and maxillofacial fractures (29%). Furthermore 77% of the patients had additional thoracic injury; the most prevalent injuries were rib fractures (59%) and a pneumothorax (38%). The mortality rate was 21.4%. CONCLUSION: A clavicle fracture was present in more than 10% of the severely injured patients. Displaced midshaft clavicle fractures were the most common type of fracture. Additional injuries to the head and neck region occurred in 83% of the patients and thoracic injuries occurred in 77% of the patients. PMID- 24053406 TI - Afrobatrachian mitochondrial genomes: genome reorganization, gene rearrangement mechanisms, and evolutionary trends of duplicated and rearranged genes. AB - BACKGROUND: Mitochondrial genomic (mitogenomic) reorganizations are rarely found in closely-related animals, yet drastic reorganizations have been found in the Ranoides frogs. The phylogenetic relationships of the three major ranoid taxa (Natatanura, Microhylidae, and Afrobatrachia) have been problematic, and mitogenomic information for afrobatrachians has not been available. Several molecular models for mitochondrial (mt) gene rearrangements have been proposed, but observational evidence has been insufficient to evaluate them. Furthermore, evolutionary trends in rearranged mt genes have not been well understood. To gain molecular and phylogenetic insights into these issues, we analyzed the mt genomes of four afrobatrachian species (Breviceps adspersus, Hemisus marmoratus, Hyperolius marmoratus, and Trichobatrachus robustus) and performed molecular phylogenetic analyses. Furthermore we searched for two evolutionary patterns expected in the rearranged mt genes of ranoids. RESULTS: Extensively reorganized mt genomes having many duplicated and rearranged genes were found in three of the four afrobatrachians analyzed. In fact, Breviceps has the largest known mt genome among vertebrates. Although the kinds of duplicated and rearranged genes differed among these species, a remarkable gene rearrangement pattern of non-tandemly copied genes situated within tandemly-copied regions was commonly found. Furthermore, the existence of concerted evolution was observed between non neighboring copies of triplicated 12S and 16S ribosomal RNA regions. CONCLUSIONS: Phylogenetic analyses based on mitogenomic data support a close relationship between Afrobatrachia and Microhylidae, with their estimated divergence 100 million years ago consistent with present-day endemism of afrobatrachians on the African continent. The afrobatrachian mt data supported the first tandem and second non-tandem duplication model for mt gene rearrangements and the recombination-based model for concerted evolution of duplicated mt regions. We also showed that specific nucleotide substitution and compositional patterns expected in duplicated and rearranged mt genes did not occur, suggesting no disadvantage in employing these genes for phylogenetic inference. PMID- 24053407 TI - Asymmetric synthesis of beta-hydroxy-alpha-amino phosphonic acid derivatives via organocatalytic direct aldol reaction of alpha-isothiocyanato phosphonates with aldehydes. AB - alpha-Isothiocyanato phosphonates are first used as nucleophiles to react with aldehydes for the asymmetric synthesis of beta-hydroxy-alpha-amino phosphonic acid derivatives. The process is catalyzed by a quinine-derived thiourea via cascade aldol/cyclization reaction, affording a wide range of protected beta hydroxy-alpha-amino phosphonates containing adjacent quaternary-tertiary stereocenters in up to 93% yield, up to 81% ee, and >99:1 dr. This work represents the first example of alpha-isothiocyanato phosphonates serving as nucleophiles that are used in the catalytic asymmetric synthesis. PMID- 24053409 TI - all-trans-retinoic acid improves immunocompetence in a murine model of lipopolysaccharide-induced immunosuppression. AB - Secondary infections due to post-sepsis immunosuppression are a major cause of death in patients with sepsis. Strategies aimed at restoring immune functions offer a new perspective in the treatment of sepsis. In the present study, we used LPS (lipopolysaccharide)-immunosuppressed mice to analyse the effects of ATRA (all-trans retinoic acid) on different immune parameters. The IS (immunocompromised) group had decreased lymphocyte and increased MDSC (myeloid derived suppressor cell) counts in lymph nodes. They also had an impaired in vitro T-cell proliferation, mediated by MDSCs. ATRA administration restored T cell proliferation, which was associated with a decreased number of live MDSCs. The IS group treated with ATRA had an increased number of CD4+ and CD8+ T-cells. ATRA partially improved the primary humoral immune response, even when immunosuppression was established first and ATRA was administered subsequently. Our results demonstrate that ATRA restores immunocompetence by modulating the number of leucocytes and the survival of MDSCs, and thus represents an additional potential strategy in the treatment of the immunosuppressive state of sepsis. PMID- 24053408 TI - Expression profiling of ion channel genes predicts clinical outcome in breast cancer. AB - BACKGROUND: Ion channels play a critical role in a wide variety of biological processes, including the development of human cancer. However, the overall impact of ion channels on tumorigenicity in breast cancer remains controversial. METHODS: We conduct microarray meta-analysis on 280 ion channel genes. We identify candidate ion channels that are implicated in breast cancer based on gene expression profiling. We test the relationship between the expression of ion channel genes and p53 mutation status, ER status, and histological tumor grade in the discovery cohort. A molecular signature consisting of ion channel genes (IC30) is identified by Spearman's rank correlation test conducted between tumor grade and gene expression. A risk scoring system is developed based on IC30. We test the prognostic power of IC30 in the discovery and seven validation cohorts by both Cox proportional hazard regression and log-rank test. RESULTS: 22, 24, and 30 ion channel genes are found to be differentially expressed with a change in p53 mutation status, ER status, and tumor histological grade in the discovery cohort. We assign the 30 tumor grade associated ion channel genes as the IC30 gene signature. We find that IC30 risk score predicts clinical outcome (P < 0.05) in the discovery cohort and 6 out of 7 validation cohorts. Multivariate and univariate tests conducted in two validation cohorts indicate that IC30 is a robust prognostic biomarker, which is independent of standard clinical and pathological prognostic factors including patient age, lymph node status, tumor size, tumor grade, estrogen and progesterone receptor status, and p53 mutation status. CONCLUSIONS: We identified a molecular gene signature IC30, which represents a promising diagnostic and prognostic biomarker in breast cancer. Our results indicate that information regarding the expression of ion channels in tumor pathology could provide new targets for therapy in human cancers. PMID- 24053410 TI - Cholesterol-mediated conformational changes in the steroidogenic acute regulatory protein are essential for steroidogenesis. AB - Although the mechanism by which the steroidogenic acute regulatory protein (StAR) promotes steroidogenesis has been studied extensively, it remains incompletely characterized. Because structural analysis has revealed a hydrophobic sterol binding pocket (SBP) within StAR, this study sought to examine the regulatory role of cholesterol concentrations on protein folding and mitochondrial import. Stopped-flow analyses revealed that at low concentrations, cholesterol promotes StAR folding. With increasing cholesterol concentrations, an intermediate state is reached followed by StAR unfolding. With 5 MUg/mL cholesterol, the apparent binding was 0.011 s(-1), and the unfolding time (t1/2) was 63 s. The apparent binding increased from 0.036 to 0.049 s(-1) when the cholesterol concentration was increased from 50 MUg/mL to 100 MUg/mL while t1/2 decreased from 19 to 14 s. These cholesterol-induced conformational changes were not mediated by chemical chaperones. Protein fingerprinting analysis of StAR in the absence and presence of cholesterol by mass spectrometry revealed that the cholesterol binding region, comprising amino acids 132-188, is protected from proteolysis. In the absence of cholesterol, a longer region of amino acids from position 62 to 188 was protected, which is suggestive of organization into smaller, tightly folded regions with cholesterol. In addition, rapid cholesterol metabolism was required for the import of StAR into the mitochondria, suggesting that the mitochondria have a limited capacity for import and processing of steroidogenic proteins, which is dependent on cholesterol storage. Thus, cholesterol regulates StAR conformation, activating it to an intermediate flexible state for mitochondrial import and its enhanced cholesterol transfer capacity. PMID- 24053411 TI - Resin glycosides from the yellow-skinned variety of sweet potato (Ipomoea batatas). AB - Native to tropical America, Ipomoea batatas has been cultivated for over 5000 years in Mexico. The yellow-skinned tuber crop variety, with an orange flesh, has a higher nutritional value than potato. Raw sweet potato can cause a purge due to its resin glycoside content. Purification of the chloroform-soluble resin glycosides from the roots of this variety was accomplished by preparative-scale HPLC, which allowed for the collection of six oligosaccharides, batatin VII (1) and batatinosides VII-IX (2-4), all of novel structure, together with the known resin glycosides pescaprein I and batatinoside IV. High-field NMR spectroscopy and FAB mass spectrometry were used to characterize each structure, identifying operculinic acid A for compounds 2 and 4, and simonic acid B for 3, as their pentasaccharide glycosidic cores. Batatin VII (1) represents a dimer of the know batatinoside IV, consisting of two units of simonic acid B. PMID- 24053412 TI - National prospective study on the use of local haemostatic agents during partial nephrectomy. AB - OBJECTIVE: To assess the use of local haemostatic agents (HAs) in a prospective multicentre large series of partial nephrectomies (PNs). PATIENTS AND METHODS: Prospective National Observational Registry on the Practices of Haemostasis in Partial Nephrectomy (NEPHRON): the study was conducted in 54 French urological centres from 1 June to 31 December 2010. In all, 570 consecutive patients undergoing a PN were enrolled in this study in a prospective manner. The data was collected prospectively via an electronic case-report form: five different sheets were included for preoperative, perioperative, postoperative and follow-up data respectively. Information related to haemostasis was analysed. RESULTS: The median patient age was 60 years and the mean (range) tumour size was 3.68 (0.19 15) cm. An HA was primarily used in 71.4% of patients, with a statistically significant difference among surgical approaches (P = 0.024). In 91.8% of cases, a single use of a HA was sufficient for achieving haemostasis. The HA was used either alone (13.9%) or in association with sutures (80.3%). One or more additional haemostatic action(s) was needed in 12.3% of the cases. When comparing patients who received a HA with those who did not receive a HA, there was no statistical difference between the groups for tumour size (P = 0.542), collecting system drainage (P = 0.538), hospital stay (P = 0.508), operation time (P = 0.169), blood loss (P = 0.387) or transfusion rate (P = 0.713). CONCLUSION: HAs are widely used by urologists during PN. Progress is needed for standardising HA application, especially for the timing of application. For the time being, the role of the HA in nephron-sparing surgery is still to be evaluated. PMID- 24053413 TI - Single-stage preputial skin flap urethroplasty for long-segment urethral strictures: evaluation and determinants of success. AB - OBJECTIVE: To determine the overall efficacy and predictors of success of the penile preputial flap in the management of complex urethral strictures >2.5 cm in length. PATIENTS AND METHODS: We performed a retrospective and prospective study of 58 patients undergoing single-stage penile preputial flap urethroplasty for complex long-segment urethral strictures, without lichen sclerosus, repaired between May 2005 and April 2012 at our institution. For obvious reasons circumcised patients were excluded from the study. Results were assessed by univariate analysis of various patient characteristics, preoperative and postoperative patient satisfaction (based on symptoms), and urethral ultrasonography, retrograde urethrography and uroflowmetry. RESULTS: The median (range) follow-up was 42 (6-90) months, the median (range) intra-operative stricture length was 48.5 (26-85) mm and the median (range) operating time was 90 (85-125) min. A total of 87.93% of patients had a satisfactory outcome, with an overall success rate of 81.03%. Diabetes mellitus (relative risk [RR] 5.21, confidence interval [CI] 2.31-64.68, P = 0.003) and smoking (RR 4.19, CI 1.54- 45.0, P = 0.01) were predictors of failure, while postinfective aetiology (RR 2.19), panurethral stricture (RR 2.73), stricture length >70 mm (RR 3.25), previous urethroplasty (RR 2.4) and severe peri-urethral fibrosis (RR 2.37) were also associated with a higher risk of failure. CONCLUSIONS: A urologist should try to gain experience of all the methods of urethroplasty as the techniques may vary according to the circumstances. Single-stage preputial skin flap urethroplasty, in experienced and expert hands, has results equivalent to all other methods of urethroplasty in complex urethral strictures. We prefer this technique in this part of the world where buccal mucosa cannot be used because of dyskeratotic changes as a result of consumption of gutkha, tobacco, pan masala, betel nut. PMID- 24053415 TI - Migration speed and directionality switch of normal epithelial cells after TGF beta1-induced EMT (tEMT) on micro-structured polydimethylsiloxane (PDMS) substrates with variations in stiffness and topographic patterning. AB - The epithelial to mesenchymal transition (EMT) involves several physiological and pathological phenomena and endows cells with invasive and migratory properties. However, the effects of substrate stiffness and topography on the migration of cells before or after transforming growth factor-beta1 (TGF-beta1)-induced EMT (tEMT) are unknown. Herein, we seed control or tEMT NMuMG cells on the 2D patterns consisted of 1 MUm or 5 MUm line-widths and groove or cone patterns on either 2 MPa (1.96 +/- 0.48 MPa) or 4 MPa (3.70 +/- 0.74 MPa) polydimethylsiloxane (PDMS) substrates. After tEMT, the increased expression of alpha-SMA with vinculin in focal adhesion (FA) sites led to an acceleration of tEMT cell motility. On the 2 MPa substrate, the most influenced substrate was the 1 MUm, cone-patterned substrate, where the tEMT cells' motility decelerated by 0.13 MUm/min (36% slower than the cells on groove pattern). However, on the 5 MUm, groove-patterned substrate, where the tEMT cells demonstrated the most rapid motility relative to the control cells, with an increment of 0.18 MUm/min (100%). Among the different physical cues from substrate, the cone pattern could impede the migration speed of tEMT cells. Furthermore, we recommend the groove-patterned with a 5 MUm line-width substrate as a useful tool to differentiate control and tEMT cells by migration speed. PMID- 24053416 TI - A longitudinal study evaluating the effect of exacerbations on physical activity in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Physical inactivity is common in stable chronic obstructive pulmonary disease (COPD) and independently predicts poor outcomes. Longitudinal assessments of physical activity in outpatients with COPD, covering periods of stability and exacerbations, have not been evaluated previously. METHODS: Patients with clinically stable COPD and a history of two or more clinical exacerbations in the preceding 12 months were recruited. Physical activity was measured using a triaxial accelerometer worn continuously on the nondominant wrist. Mean minutes per day of higher level physical activity was the primary outcome variable. Symptom-defined exacerbations were assessed using the 14-item Exacerbations of Chronic Pulmonary Disease Tool (EXACT) daily dairy. Clinically reported exacerbations were also captured. Minutes per day of higher level physical activity during exacerbation and nonexacerbation days were compared, using a mixed model analysis. MEASUREMENTS AND MAIN RESULTS: Seventeen patients were monitored for 135 +/- 18 days. Nine were male with a mean age of 63 +/- 12 years and mean FEV1 of 52 +/- 20%. Fifteen patients had 27 symptom (EXACT)-defined exacerbations, including 9 that were also clinically reported. Patients spent fewer minutes per day at a higher level physical activity level during exacerbation days than nonexacerbation days: 131 +/- 14 versus 157 +/- 14 minutes (P < 0.0001). The greatest reduction in physical activity was during the first week of the exacerbation; activity remained low for approximately 2 weeks after exacerbation resolution. CONCLUSIONS: Physical activity decreased significantly during exacerbations. Reduction in activity occurs early during an exacerbation and persists for about 2 weeks after symptomatic recovery. PMID- 24053417 TI - Snapshot of transurethral resection of bladder tumours in the United Kingdom Audit (STUKA). AB - OBJECTIVES: To determine the quality of transurethral resection of bladder tumour (TURBT) in the UK. To evaluate the utility of a novel 'snapshot' methodology in carrying out national audits. PATIENTS AND METHODS: Every consultant Urologist in the UK was asked to contribute details of their first patient with a new bladder cancer treated with TURBT after midnight of 31st January 2010. Responses were received from 192 consultants. RESULTS: The median (range) time from referral to first Urology appointment was 11 (0-161) days, and the median (range) time from first appointment to TURBT was 27 (1-588) days. In all, 12 (6.3%) patients underwent photodynamic diagnosis-assisted TURBT and 119 patients (61%) received a dose of Mitomycin C after TURBT. The rate of major complications was low, with five incidences (2.6%) of bladder perforation. There was no record of muscle present in resected specimens in 40 cases (20.8%) and resection was considered incomplete in 26 cases (13.5%). In all, 31 patients (16.1%) underwent early re resection with residual tumour or carcinoma in situ detected in 17 cases, although no tumour was upstaged. Of the 37 patients classified with intermediate risk non-muscle-invasive bladder cancer (NMIBC), there were nine recurrences (24.3%) at 3 months, and 13 recurrences (35.1%) at 1 year. Newly presenting MIBC managed with currently available treatments has a high mortality rate of 33.3% at 1 year. CONCLUSIONS: The quality of TURBT in the UK is high. Areas for improvement include the timeliness of diagnosis and treatment, and improved care of patients with intermediate-risk NMIBC and MIBC. The 'snapshot' methodology is promising but widening participation is a priority. PMID- 24053418 TI - Development of a nanoemulsion of Phyllanthus emblica L. branch extract. AB - For potential topical administration, we formulated a nanoemulsion containing phenolic constituents of Phyllanthus emblica branch extract. The nanoemulsion has high entrapment efficiency, small particle size, is stable, and can release its main chemical components. Branches of P. emblica were extracted with 50% ethanol (EPE) with 5.4% yield. HPLC analysis indicated several phenolic compounds, including gallic acid, vanillic acid, epigallocatechin (EGC), epigallocatechin gallate (EGCG) and ellagic acid. These were selected as chemical markers of EPE in the nanoemulsion development. The nanoemulsion was prepared by microemulsion techniques with hot high pressure homogenization. A ternary phase diagram was constructed to obtain the optimized nanoemulsion. The obtained transparent EPE nanoemulsion is composed of isopropyl myristate (0.6% w/w), Brij(r) 78 (0.35% w/w), and 0.15% (w/w) EPE. The optimized EPE nanoemulsion had a median particle size of 191.63 +/- 4.07 nm with a narrow particle size distribution, a zeta potential of -10.19 +/- 0.54 mV, high entrapment efficiency at 67.99 +/- 0.87% and good stability at 4 degrees C after 90 d of storage. The release of active ingredients from the EPE nanoemulsion was slower than that of the EPE aqueous formulation. The loading ratios of the five phenolic compounds were high, with relative order of EGC > EGCG > vanillic acid > gallic acid > ellagic acid, resulting in slow release profiles of EGC and EGCG in the EPE nanoemulsion. In conclusion, the obtained EPE nanoemulsion has good characteristics for future clinical trials. PMID- 24053419 TI - Differential effects of ketoconazole, itraconazole and voriconazole on the pharmacokinetics of imatinib and its main metabolite GCP74588 in rat. AB - The aim of the study was to develop a high performance liquid chromatography method for simultaneous determination of imatinib and CGP74588 in rat serum and study the inhibition effects of ketoconazole, itraconazole and voriconazole on pharmacokinetics of imatinib and CGP74588 in rats. In our study, we found that ketoconazole caused a significant increase (63.4%) in the AUC of imainib and a 28.8% increase in Cmax, which was greater than that of itraconazole but lower than that of voriconazole. When co-administered with voriconazole, pharmacokinetic parameters of imatinib were not significantly altered except for a 36.8% increase in the Cmax of imtinib. The Cmax of CGP74588 was decreased by 55.8% and AUC(0-infinity) 49.7%, while the Vz/F and CLz/F values were increased by 1.7-fold and 1.1-fold, respectively. Itraconazole did not significantly influence the pharmacokinetic parameters of imatinib and CGP74588. The difference may be related to the different variation of inhibition sites of the three azole antifungal agents on CYP3A4 and P-gp. In clinical, when imatinib was co administrated with ketoconazole or voriconazole, dose adjustment of imatinib should be taken into account. PMID- 24053420 TI - Condom use and sexuality communication with adults: a study among high school students in South Africa and Tanzania. AB - BACKGROUND: Fostering adolescents' communication on sexuality issues with their parents and other significant adults is often assumed to be an important component of intervention programmes aimed at promoting healthy adolescent sexual practices. However, there are few studies describing the relationship between such communication and sexual practices, particularly in sub-Saharan Africa. This study examined the relationships between adolescents' communication with significant adults and their condom use in three sites in this region. METHODS: Data stem from a multi-site randomized controlled trial of a school-based HIV prevention intervention implemented in Cape Town and Mankweng, South Africa and Dar es Salaam, Tanzania. Only data from comparison schools were used. The design is therefore a prospective panel study with three waves of data collections. Data were collected in 2004 from 6,251 participants in 40 schools. Associations between adolescents' communication with adults about sexuality issues and their use of condoms were analysed cross-sectionally using analysis of variance, as well as prospectively using multiple ordinal logistic regression analysis. RESULTS: Cross-sectional analyses showed that consistent condom users had significantly higher mean scores on communication (across topics and communication partners) than both occasional users and never-users, who had the lowest scores. After controlling for condom use at the first data collection occasion in each model as well as for possible confounders, communication scores significantly predicted consistent condom use prospectively in all three ordinal logistic regression models (Model R(2) = .23 to .31). CONCLUSION: The findings are consistent with the assertion that communication on sexuality issues between adolescents and significant adults results in safer sexual practices, as reflected by condom use, among in-school adolescents. The associations between communication variables and condom use might have been stronger if we had measured additional aspects of communication such as whether or not it was initiated by the adolescents themselves, the quality of advice provided by adults, and if it took place in a context of positive adult-adolescent interaction. Studies with experimental designs are needed in order to provide stronger evidence of causality. PMID- 24053421 TI - Robot-assisted partial nephrectomy (RAPN) for completely endophytic renal masses: a single institution experience. AB - OBJECTIVE: To analyse the outcomes of robot-assisted partial nephrectomy (RAPN) for completely endophytic renal tumours. PATIENTS AND METHODS: Medical records of patients who had undergone RAPN for a completely endophytic (i.e. 3 points for the 'E' domain of the R.E.N.A.L. nephrometry score) enhancing renal mass at our Centre from 2006 to 2012 were retrieved from our prospectively maintained RAPN database and used for this analysis. Demographics, surgical and early postoperative outcomes were compared with those of patients with exophytic masses (i.e. 1 point for the 'E' domain) and those of patients with mesophytic masses (i.e. 2 points for the 'E' domain). RESULTS: In all, 65 patients (mean age 56 years; mean body mass index 29.4 kg/m(2) ; mean Charlson comorbidity index 3.2) were included in the study group, accounting for 16.7% of RAPN cases over the study period. The main surgical outcomes were: mean operative time 175 min, mean estimated blood loss 225 mL, and mean warm ischaemia time 21.7 min. Pathology showed a malignant histology in 48 cases (74%), mostly clear cell renal cell carcinoma. Two positive margins (3%) were found. Patients with a completely endophytic mass had smaller tumours on preoperative imaging (mean 2.6 vs 3.3 for mesophytic vs 3.7 cm for exophytic; P < 0.001), and higher overall R.E.N.A.L. score (mean 8.7 vs 7.6 vs 6.4; P < 0.001). There was a lower rate of unclamped cases in the endophytic group (3.1% vs 4.8% vs 18%; P < 0.001). There were no differences in intraoperative complications, length of hospital stay, positive margin rate, postoperative change in estimated glomerular filtration rate, given a similar length of follow-up (mean 12.6 vs 15.7 vs 14.5 months; P = 0.3). CONCLUSION: RAPN for completely intraparenchymal renal tumours can be safely and effectively performed in centres with significant robotic expertise, with surgical outcomes resembling those obtained in the general RAPN population. PMID- 24053423 TI - Interactions of selected indole derivatives with COX-2 and their in silico structure modifications towards the development of novel NSAIDs. AB - Cyclooxygenase-2 (COX-2) is an important enzyme responsible for the formation of potent inflammatory mediators like prostaglandins, prostacyclin and thromboxane. Hence, inhibition of COX-2 is one of the best ways to control the inflammation. Non-steroidal anti-inflammatory drugs can control inflammation by inhibiting Cyclooxygenase. Selective inhibition of COX-2 is preferable over the inhibition of COX-1 because of the fewer adverse effects produced. Molecular modeling and docking of 134 selected indole compounds were done against COX-2. The pharmacophore-based in silico structural modifications of the best scored compounds were carried out in order to enhance the binding affinity and selectivity. The modification resulted in derivatives with better binding energies than that of known COX-2 inhibitors. The four best derivatives in terms of the binding energies were selected and their binding stabilities were studied by molecular dynamics simulation methods. PMID- 24053422 TI - Class III beta-tubulin is a predictive marker for taxane-based chemotherapy in recurrent and metastatic gastric cancer. AB - BACKGROUND: Class III beta-tubulin (TUBB3) is a prognostic marker in various tumors, but the role of TUBB3 in advanced gastric cancer is not clearly defined. We analyzed the significance of TUBB3 expression, along with that of excision repair cross-complementation group 1 (ERCC1) in recurrent and metastatic gastric cancer patients receiving taxane-based first-line palliative chemotherapy. METHODS: We reviewed the cases of 146 patients with advanced gastric adenocarcinoma who received taxane-based first-line palliative chemotherapy between 2004 and 2010 at Chonnam National University Hwasun Hospital (Gwangju, Korea). Immunohistochemical staining for TUBB3 and ERCC1 was performed using paraffin wax-embedded tumor tissues. We evaluated the patients' response to chemotherapy, progression-free survival (PFS), and overall survival (OS). RESULTS: In total, 146 patients with advanced gastric cancer received docetaxel and cisplatin (n = 15) or paclitaxel and cisplatin (n = 131). The median PFS was significantly shorter for patients with high-level TUBB3 expression than for patients with low-level TUBB3 expression (3.63 vs. 6.67 months, P = 0.001). OS was not associated with TUBB3 expression (13.1 vs. 13.1 months, P = 0.769). By multivariate analysis, only TUBB3 was related to a shorter PFS (HR 2.74, 95% CI 1.91-3.91, P = 0.001). Patients with high-level ERCC1 expression showed a lower response rate than patients with low-level ERCC1 expression (24 vs. 63.2%, P = 0.001); however, ERCC1 had no clinical effect on PFS or OS. CONCLUSIONS: TUBB3 was a strong predictive marker in recurrent and metastatic gastric cancer patients receiving taxane-based first-line palliative chemotherapy. No clinical impact of ERCC1 was evident in this setting. PMID- 24053424 TI - The enigma of eugregarine epicytic folds: where gliding motility originates? AB - BACKGROUND: In the past decades, many studies focused on the cell motility of apicomplexan invasive stages as they represent a potential target for chemotherapeutic intervention. Gregarines (Conoidasida, Gregarinasina) are a heterogeneous group that parasitize invertebrates and urochordates, and are thought to be an early branching lineage of Apicomplexa. As characteristic of apicomplexan zoites, gregarines are covered by a complicated pellicle, consisting of the plasma membrane and the closely apposed inner membrane complex, which is associated with a number of cytoskeletal elements. The cell cortex of eugregarines, the epicyte, is more complicated than that of other apicomplexans, as it forms various superficial structures. RESULTS: The epicyte of the eugregarines, Gregarina cuneata, G. polymorpha and G. steini, analysed in the present study is organised in longitudinal folds covering the entire cell. In mature trophozoites and gamonts, each epicytic fold exhibits similar ectoplasmic structures and is built up from the plasma membrane, inner membrane complex, 12 nm filaments, rippled dense structures and basal lamina. In addition, rib-like myonemes and an ectoplasmic network are frequently observed. Under experimental conditions, eugregarines showed varied speeds and paths of simple linear gliding. In all three species, actin and myosin were associated with the pellicle, and this actomyosin complex appeared to be restricted to the lateral parts of the epicytic folds. Treatment of living gamonts with jasplakinolide and cytochalasin D confirmed that actin actively participates in gregarine gliding. Contributions to gliding of specific subcellular components are discussed. CONCLUSIONS: Cell motility in gregarines and other apicomplexans share features in common, i.e. a three-layered pellicle, an actomyosin complex, and the polymerisation of actin during gliding. Although the general architecture and supramolecular organisation of the pellicle is not correlated with gliding rates of eugregarines, an increase in cytoplasmic mucus concentration is correlated. Furthermore, our data suggest that gregarines utilize several mechanisms of cell motility and that this is influenced by environmental conditions. PMID- 24053425 TI - Implementing computerised Aboriginal and Torres Strait Islander health checks in primary care for clinical care and research: a process evaluation. AB - BACKGROUND: Paper-based Aboriginal and Torres Strait Islander health checks have promoted a preventive approach to primary care and provided data to support research at the Inala Indigenous Health Service, south-west Brisbane, Australia. Concerns about the limitations of paper-based health checks prompted us to change to a computerised system to realise potential benefits for clinical services and research capability. We describe the rationale, implementation and anticipated benefits of computerised Aboriginal and Torres Strait Islander health checks in one primary health care setting. METHODS: In May 2010, the Inala Indigenous Health Service commenced a project to computerise Aboriginal and Torres Strait Islander child, adult, diabetic, and antenatal health checks. The computerised health checks were launched in September 2010 and then evaluated for staff satisfaction, research consent rate and uptake. Ethical approval for health check data to be used for research purposes was granted in December 2010. RESULTS: Three months after the September 2010 launch date, all but two health checks (378 out of 380, 99.5%) had been completed using the computerised system. Staff gave the system a median mark of 8 out of 10 (range 5-9), where 10 represented the highest level of overall satisfaction. By September 2011, 1099 child and adult health checks, 138 annual diabetic checks and 52 of the newly introduced antenatal checks had been completed. These numbers of computerised health checks are greater than for the previous year (2010) of paper-based health checks with a risk difference of 0.07 (95% confidence interval 0.05, 0.10). Additionally, two research projects based on computerised health check data were underway. CONCLUSIONS: The Inala Indigenous Health Service has demonstrated that moving from paper-based Aboriginal and Torres Strait Islander health checks to a system using computerised health checks is feasible and can facilitate research. We expect computerised health checks will improve clinical care and continue to enable research projects using validated data, reflecting the local Aboriginal and Torres Strait Islander community's priorities. PMID- 24053427 TI - Polybromo-1 (PBRM1), a SWI/SNF complex subunit is a prognostic marker in clear cell renal cell carcinoma. AB - OBJECTIVE: To analyse the immunohistochemical and mRNA expression of SWI/SNF (SWItch/Sucrose NonFermentable) complex subunit polybromo-1 (PBRM1) in clear cell renal cell carcinoma (ccRCC) and its impact on clinical outcomes. PATIENTS AND METHODS: In all, 213 consecutive patients treated surgically for renal cell carcinoma (RCC) between 1992 and 2009 were selected. A single pathologist reviewed all cases to effect a uniform reclassification and determined the most representative tumour areas for construction of a tissue microarray. In addition, mRNA expression of PBRM1 was analysed by reverse transcriptase-polymerase chain reaction. RESULTS: Of the 112-immunostained ccRCC specimens, 34 (30.4%) were PBRM1-negative, and 78 (69.6%) were PBRM1-positive. The protein expression of PBRM1 was associated with tumour stage (P < 0.001), clinical stage (P < 0.001), pN stage (P = 0.035) and tumour size (P = 0.002). PBRM1 mRNA expression was associated with clinical stage (P = 0.023), perinephric fat invasion (P = 0.008) and lymphovascular invasion (P = 0.042). PBRM1 significantly influenced tumour recurrence and tumour-related death. Disease-specific survival rates for patients whose specimens showed positive- and negative-PBRM1 expression were 89.7% and 70.6%, respectively (P = 0.017). Recurrence-free survival rates in patients with positive- and negative-expression of PBRM1 were 87.3% and 66.7%, respectively (P = 0.048). CONCLUSIONS: PBRM1-negative expression is a markedly poor prognosis event in ccRCC. We encourage PBRM1 study by other groups in order to validate our findings and confirm its possible role as a useful marker in the management of patients with ccRCC. PMID- 24053426 TI - Microneedle-assisted percutaneous delivery of naltrexone hydrochloride in yucatan minipig: in vitro-in vivo correlation. AB - Although microneedle-assisted transdermal drug delivery has been the subject of multiple scientific investigations, very few attempts have been made to quantitatively relate in vitro and in vivo permeation. The case of naltrexone hydrochloride is not an exception. In the present study, a pharmacokinetic profile obtained following a "poke and patch" microneedle application method in the Yucatan minipig is reported. The profile demonstrates a rapid achievement of maximum naltrexone hydrochloride plasma concentration followed by a relatively abrupt concentration decline. No steady state was achieved in vivo. In an attempt to correlate the present in vivo findings with formerly published in vitro steady state permeation data, a diffusion-compartmental mathematical model was developed. The model incorporates two parallel permeation pathways, barrier thickness-dependent diffusional resistance, microchannel closure kinetics, and a pharmacokinetic module. The regression analysis of the pharmacokinetic data demonstrated good agreement with an independently calculated microchannel closure rate and in vitro permeation data. Interestingly, full-thickness rather than split-thickness skin employed in in vitro diffusion experiments provided the best correlation with the in vivo data. Data analysis carried out with the model presented herein provides new mechanistic insight and permits predictions with respect to pharmacokinetics coupled with altered microchannel closure rates. PMID- 24053428 TI - MicroRNAs and multiple sclerosis: from physiopathology toward therapy. AB - INTRODUCTION: MicroRNAs (miRNAs) are an emerging group of small noncoding RNAs that regulate gene expression posttranscriptionally, by targeting messenger RNAs (mRNAs) for translational repression or degradation. They have roles in multiple facets of immunity, from regulation of cell development to activation and function in immune responses. Recent evidence underlines an involvement of miRNAs in the pathogenesis of autoimmune diseases as well as multiple sclerosis (MS). AREAS COVERED: In this review, the current knowledge of miRNA biogenesis, diverse roles of miRNAs in different cells that could be involved in the process of the disease, and their potential therapeutic applications are summarized. The authors searched MEDLINE and Science direct databases. EXPERT OPINION: The miRNAs in central nervous system lesions and peripheral blood are potential biomarkers for diagnostic and prognostic use. Also, miRNA mimics, small-molecule inhibitors of specific miRNAs, and antisense oligonucleotides could be therapeutic weapons that facilitate us to combat the disease. PMID- 24053430 TI - Molecular dynamics simulations of water sorption in a perfluorosulfonic acid membrane. AB - Atomistic molecular dynamics simulations are reported over a wide range of water contents and temperatures to obtain a better understanding of the structural and transport aspects of water sorption in Nafion, a perfluorosulfonic acid membrane, under equilibrium conditions. For the short Nafion chains studied, good agreement is found between the water sorption isotherms from simulations and experiments at intermediate hydration (2 ? lambda ? 7, where lambda is the number of water molecules per sulfonate group), suggesting that, in that range, the isotherm is insensitive to effects of polymer chain relaxation. If polymer chain relaxation were important for water sorption at these conditions, then the water uptake of experimental membranes, which contain very long chains, might be far from equilibrium, making it difficult to obtain agreement with equilibrated, short chain simulations. At lambda ? 7, strong water-sulfonate interactions, rather than chain relaxation, may control water sorption, despite the fact that chain relaxation time increases dramatically with decreasing hydration. Evidence for strong water-sulfonate interactions is found in the observation that sulfonate groups share water molecules in their first coordination shells at lambda ? 7. Strong water-sulfonate interactions are also observed to influence transport properties like water diffusivity, and are as important for understanding these transport properties as larger-scale phenomena like morphology and percolation transitions. Finally, at low humidity (lambda ~ 1-2), rod-like hydrophilic clusters are observed, as well as a mechanism of water diffusion that differs qualitatively from that of water at high hydration (lambda ? 7) and in the bulk, pure-component phase. PMID- 24053429 TI - Klebsiella pneumoniae bacteremia and renosplenic abscesses without intestinal symptoms as the initial manifestations of non-steroidal anti-inflammatory drug induced colitis: a rare case report. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs), the most widely prescribed drugs in the world, can cause gastrointestinal damage, including colitis. However, the prevalence of NSAID-induced colitis is unknown because the disease is often asymptomatic. CASE PRESENTATION: We report the case of a 64-year old female patient with a history of long-term NSAID use, who was hospitalized with septic shock caused by Klebsiella pneumoniae bacteremia. Computed tomography revealed multiple renal and splenic abscesses with diffuse colon wall thickening. A colonoscopy confirmed colitis with diffuse ulcers. NSAIDs were discontinued after this hospitalization. The abscesses improved after antibiotic treatment. A short course of balsalazide treatment was given under the suspicion of ulcerative colitis. Balsalazide was discontinued four months later due to a non-compatible clinical course. A follow-up colonoscopy two years later revealed a normal colon mucosa, and NSAID-induced colitis was diagnosed. CONCLUSION: This is the first reported case of combined bacterial splenic and renal abscesses without intestinal manifestations as the initial presentation of NSAID-induced colitis. In contrast to cases of K. pneumoniae bacteremia with primary liver abscesses in patients with diabetes mellitus in Taiwan, we presented the first case with abscesses caused by community-acquired K. pneumoniae in the kidneys and spleen without liver invasion. In conclusion, our case report alerts clinicians to the possibility that K. pneumoniae bacteremia combined with multiple abscesses can be associated with severe NSAID-induced colitis. PMID- 24053431 TI - Hyaluronan-mediated motility receptor (RHAMM) immunohistochemical expression and androgen deprivation in normal peritumoral, hyperplasic and neoplastic prostate tissue. AB - OBJECTIVES: To evaluate hyaluronan-mediated motility receptor (RHAMM) expression in normal, hyperplasic and neoplastic prostate tissue after various types and durations of androgen-deprivation therapy (ADT). Clinical and oncological data from men with localised prostate adenocarcinoma were also assessed and compared with RHAMM expression data. PATIENTS AND METHODS: Data from 367 men who underwent histological evaluation of the prostate were retrospectively evaluated under six conditions: (i) benign prostatic hyperplasia (BPH), (ii) BPH treated with finasteride, (iii) prostate cancer without ADT, (iv) prostate cancer treated with neoadjuvant ADT before prostatectomy (cyproterone 200 mg/day), (v) castration resistant prostate cancer (CRPC), and (vi) normal peritumoral prostate tissue. Tissue microarrays were constructed and 1354 cores were evaluated for immunohistochemical RHAMM expression. RESULTS: There was no RHAMM expression in any tissue from normal patients or those with BPH or prostate cancer without ADT. There was RHAMM expression in 39.4% of prostate cancer tissues treated with ADT and in 46.2% of CRPC samples (P = 0.001). There was a significant increase in RHAMM expression with increased ADT duration in group 4, with a marked increase in RHAMM expression after 6-12 months of ADT (P = 0.04). No prognostic or clinical factors related to prostate cancer were associated with RHAMM expression. CONCLUSIONS: RHAMM expression in prostate cancer is directly associated with ADT. Significant RHAMM expression occurs as early as after 1 month of ADT and progressively increases with ADT duration. When prostate cancer becomes CRPC, RHAMM expression is higher. RHAMM expression was not associated with prostate cancer prognostic factors. RHAMM overexpression may contribute to the development of hormonal resistance in prostate cancer. PMID- 24053432 TI - Flexible fixation of syndesmotic diastasis using the assembled bolt-tightrope system. AB - BACKGROUND: Syndesmotic diastasis is a common injury. Syndesmotic bolt and tightrope are two of the commonly used methods for the fixation of syndesmotic diastasis. Syndesmotic bolt can be used to reduce and maintain the syndesmosis. However, it cannot permit the normal range of motion of distal tibiofibular joint, especially the rotation of the fibula. Tightrope technique can be used to provide flexible fixation of the syndesmosis. However, it lacks the ability of reducing the syndesmotic diastasis. To combine the advantages of both syndemostic bolt and tightrope techniques and simultaneously avoid the potential disadvantages of both techniques, we designed the assembled bolt-tightrope system (ABTS). The purpose of this study was to evaluate the primary effectiveness of ABTS in treating syndesmotic diastasis. METHODS: From October 2010 to June 2011, patients with syndesmotic diastasis met the inclusion criteria were enrolled into this study and treated with ABTS. Patients were followed up at 2, 6 weeks and 6, 12 months after operation. The functional outcomes were assessed according to the American Orthopedic Foot and Ankle Society (AOFAS) scores at 12 months follow-up. Patients' satisfaction was evaluated based upon short form-12 (SF-12) health survey questionnaire. The anteroposterior radiographs of the injured ankles were taken, and the medial clear space (MCS), tibiofibular overlap (TFOL), and tibiofibular clear space (TFCS) were measured. All hardwares were routinely removed at 12-month postoperatively. Follow-ups continued. The functional and radiographic assessments were done again at the latest follow-up. RESULTS: Twelve patients were enrolled into this study, including 8 males and 4 females with a mean age of 39.5 years (range, 26 to 56 years). All patients also sustained ankle fractures. At 12 months follow-up, the mean AOFAS score was 95.4 (range, 85 to 100), and all patients were satisfied with the functional recoveries. The radiographic MCS, TFOL, and TFCS were within the normal range in all patients. After hardware removal, follow-up continued. At the latest follow-up (28 months on average, (range, 25 to 33 months) from internal fixation), the mean AOFAS score was 96.3 (range, 85 to 100), without significant difference with those assessed at 12 months after fixation operations. No syndesmotic diastasis reoccurred based upon the latest radiographic assessment. CONCLUSIONS: ABTS can be used to reduce the syndesmotic diastasis and provide flexible fixation in a minimally invasive fashion. It seems to be an effective alternative technique to treat syndesmotic diastasis. PMID- 24053433 TI - Mixed venous O2 saturation and fluid responsiveness after cardiac or major vascular surgery. AB - BACKGROUND: It is unclear if and how SvO2 can serve as an indicator of fluid responsiveness in patients after cardiac or major vascular surgery. METHODS: This was a substudy of a randomized single-blinded clinical trial reported earlier on critically ill patients with clinical hypovolemia after cardiac or major vascular surgery. Colloid fluid loading was done for 90 min, guided by changes in pulmonary artery occlusion pressure (PAOP) or central venous pressure (CVP). Fluid responsiveness was defined as >=15% increase in cardiac index (CI). Hemodynamics, including transpulmonary dilution-derived global end-diastolic volume index (GEDVI) and global ejection fraction (GEF), were measured and blood samples taken. RESULTS: Whereas baseline SvO2 (>70% in 68% of patients) did not differ, the SvO2 increased in patients responding to fluid loading (>=15% in CI in n = 26) versus those not responding (n = 11; P = 0.03). The increase in GEDVI was also greater in responders (P = 0.005). The area under the receiver operating characteristic curve for fluid responsiveness of changes in SvO2 was 0.73 (P = 0.007), with an optimal cutoff of 2%, and of those in GEDVI 0.82 (P < 0.001), while the areas did not differ. However, the value of SvO2 increases to reflect CI increases with fluid loading was greatest when GEF was <=20% (in 53% of patients). CONCLUSIONS: An increase in SvO2 >=2%, irrespective of a relatively high baseline value, can thus be used as a monitor of fluid responsiveness in clinically hypovolemic patients after cardiac or major vascular surgery, particularly in those with systolic cardiac dysfunction. Fluid responsiveness concurs with increased tissue O2 delivery. PMID- 24053434 TI - Enantiospecific total synthesis of (+)-tanikolide via a key [2,3]-Meisenheimer rearrangement with an allylic amine N-oxide-directed epoxidation and a one-pot trichloroisocyanuric acid N-debenzylation and N-chlorination. AB - The enantiospecific total synthesis of the delta-lactonic marine natural product (+)-tanikolide (1), isolated from Lyngbya majuscula , was achieved using a [2,3] Meisenheimer rearrangement as the key reaction. During this rearrangement, we discovered that the allylic amine N-oxide could direct the m-CPBA double-bond epoxidation to the syn position. The resulting syn product 8 underwent epoxide ring opening under the m-CBA conditions to give the five- and six-membered cyclic ether amine N-oxides, which we further treated with Zn and conc. HCl to obtain the reduced bisbenzyl tertiary amines 23 and 22, respectively. When 23 and 22 were treated with trichloroisocyanuric acid (TCCA) in dichloromethane, oxidation at the benzyl position occurred, forming iminium ions. These intermediates were trapped by intramolecular reaction with the hydroxyls, and the resulting intermediates were then oxidized or shifted to afford 25 and 24, respectively. The entire one-pot process involves N-debenzylation, N-chlorination, and hemiacetal oxidation. The amine N-oxide-directed epoxidation complements Davies' ammonium-directed epoxidation. Thus, TCCA N-debenzylation is described for the first time and might be a useful N-debenzylation technique. PMID- 24053435 TI - Introduction. Sources of new teaching techniques. PMID- 24053436 TI - The ventral-hypothalamic input route: a common neural network for abstract cognition and sexuality. AB - Classically, external receptors of the body transmit information from the environment to the cerebral cortex via the thalamus. This review explains and argues that only concrete external information is transmitted from peripheral receptors to the cortex via a thalamic route, while abstract and sexual external information are actually transmitted from peripheral receptors to the cortex through a cognitive hypothalamic route. Sexual function typically implies participation of two distinct partners, ensuring reproduction in many species including humans. Human sexual response involves participation of multiple (environmental, biological, psychological) kinds of stimuli and processing, so the understanding of sexual control and response supposes integration between the classical physiological mechanisms with the more complex processes of our 'mind'. Cognition and sexuality are two relational functions, which are dependent on concrete (colours, sounds, etc.) and/or abstract (gestures, facial expression, how you move, the way you say something seemingly trivial, etc.) environmental cues. Abstract cues are encoded independent of the specific object features of the stimuli, suggesting that such cues should be transmitted and interpreted within the brain through a system different than the classical thalamo-cortical network that operates on concrete (material) information. Indeed, data show that the cerebral cortex is capable of interpreting two distinct (concrete and abstract) formats of information via distinct and non-compatible brain areas. We expand upon this abstract-concrete dichotomy of the brain, positing that the two distinct cortical networks should be uploaded with distinct information from the environment via two distinct informational input routes. These two routes would be represented by the two distinct routes of the ascending reticular activating system (ARAS), namely the classical/dorsal thalamic input route for concrete information and the ventral hypothalamic input route for abstract cognition and sexuality. Physiologically, the hypothalamic (dual-autonomic) route of the ARAS that processes abstract and sexual information is incompatible with the thalamic (somatic) route of the ARAS that processes concrete information, such that the two distinct routes would be needed to support the mind processes (awareness, consciousness, sexuality) through their own informational inputs from the environment. Informationally, the concrete external data are differentiated from abstract and sexual external data, so that they should be transmitted to cortex through distinct input routes. Pathologically, the hardware and/or software impairments of the hypothalamic default-mode network generate disturbed messages within the brain (related to information transmitted on this route), laying at the basis of mental and sexual disorders. The novel conceptualisations presented in the present paper help address issues surrounding the mind-brain dichotomy and, in doing so, suggest new possible avenues for exploration in the treatment and interventions for cognitive and sexual problems. PMID- 24053437 TI - Does co-residence with adult children associate with better psychological well being among the oldest old in China? AB - OBJECTIVES: Embedded in a traditional culture where filial piety was honored, living with adult children once had been the most prevalent living arrangement and the best option for Chinese elderly people. This study examined whether co residence with adult children would be still beneficial to the psychological well being (PWB) among the oldest old (aged 80 and above) in China today. METHOD: Using data from the fifth wave of the Chinese Longitudinal Healthy Longevity Survey conducted in 2008, the authors examined the living arrangements among the total sample (n = 12,213) and the association between living arrangement and PWB among a subsample (n = 7037) of respondents with normal cognition. RESULTS: (1) More than half (67.1%) of the unmarried oldest old reported being co-resided with their children; while for the married oldest old, the majority of the respondents (62.4%) lived with a spouse only. (2) For the widowed, co-residence with adult children was associated with better PWB compared to living alone; but for the married, co-residence did not bring additional benefits to the PWB. (3) Co residence of the widowed and children was associated with better life satisfaction compared to living with a spouse only, while it was associated with lower emotional well-being compared to living with a spouse (with or without a child). CONCLUSION: These findings suggest that living arrangements of Chinese oldest old are partially getting westernized, and a majority of them adapt it well. Government programs need to be developed to assist the Chinese oldest old (especially widowed) to live independently. PMID- 24053438 TI - Long- and short-distance signaling in the regulation of lateral plant growth. AB - Lateral growth of shoot and root axes by the formation of secondary vascular tissues is an instructive example for the plasticity of plant growth processes. Being purely postembryonic, lateral growth strongly depends on environmental input and is tightly regulated by long- and short-distance signaling. In general, plant vasculature represents the main route for long-distance transport of compounds throughout the plant body, thereby providing also a fast and efficient signaling pipeline for the coordination of growth and development. The vasculature consists of three major tissues; the xylem conducts water and nutrients, the phloem transports mainly organic compounds and the vascular cambium is a group of undifferentiated stem cells responsible for the continuous production of secondary vascular tissues. Notably, the close proximity to functional vascular tissues makes the vascular cambium especially accessible for the regulation by long-distance-derived signaling molecules as well as by the physical and physiological properties of transport streams. Thus, the vascular cambium offers unique opportunities for studying the complex regulation of plant growth processes. In this review, we focus on recent findings about long- and short-distance signaling mechanisms regulating cambium activity and, thereby, lateral expansion of plant growth axes by the formation of additional vascular tissues. PMID- 24053439 TI - Model of gene expression in extreme cold - reference transcriptome for the high Antarctic cryopelagic notothenioid fish Pagothenia borchgrevinki. AB - BACKGROUND: Among the cold-adapted Antarctic notothenioid fishes, the high latitude bald notothen Pagothenia borchgrevinki is particularly notable as the sole cryopelagic species, exploiting the coldest and iciest waters of the Southern Ocean. Because P. borchgrevinki is a frequent model for investigating notothenioid cold-adaptation and specialization, it is imperative that "omic" tools be developed for this species. In the absence of a sequenced genome, a well annotated reference transcriptome of the bald notothen will serve as a model of gene expression in the coldest and harshest of all polar marine environments, useful for future comparative studies of cold adaptation and thermal responses in polar teleosts and ectotherms. RESULTS: We sequenced and annotated a reference transcriptome for P. borchgrevinki, with added attention to capturing the transcriptional responses to acute and chronic heat exposures. We sequenced by Roche 454 a normalized cDNA library constructed from pooled mRNA encompassing multiple tissues taken from environmental, warm acclimating, and acute heat stressed specimens. The resulting reads were assembled into 42,620 contigs, 17,951 of which could be annotated. We utilized this annotated portion of the reference transcriptome to map short Illumina reads sequenced from the gill and liver of environmental specimens, and also compared the gene expression profiles of these two tissue transcriptomes with those from the temperate model fish Danio rerio. From this, we identified a conserved group of 58 GO terms, in which terms related to transcription and its regulation, ubiquitin-protein ligase activity, protein ubiquitination, and protein binding among others are more prevalent in the bald notothen, suggesting the pertinent genes play essential roles in cold temperature functioning. CONCLUSION: We sequenced multiple tissue transcriptomes from native and heat-exposed experimental specimens of the high Antarctic, cryopelagic notothenioid P. borchgrevinki to construct a reference transcriptome. In a proof of concept, we utilized the annotated reference transcriptome to profile the gene expression patterns of gill and liver, and identified a suite of over and under-represented GO terms when compared to the tropical water zebrafish suggesting these functions may be important for surviving in freezing waters. The transcriptome resource from this study will aid future investigations of cold adaptation and thermal response of polar ectothermic species. PMID- 24053440 TI - Spirometry use among older adults with chronic obstructive pulmonary disease: 1999-2008. AB - RATIONALE: Clinical practice guidelines recommend spirometry to diagnose chronic obstructive pulmonary disease (COPD) and facilitate management. National trends in spirometry use in older adults with newly diagnosed COPD are not known. OBJECTIVES: To examine the rate and beneficiary characteristics associated with spirometry use in subjects with newly diagnosed COPD between 1999 and 2008. METHODS: We examined newly diagnosed beneficiaries with COPD using a 5% Medicare population from 1999 to 2008. A new COPD diagnosis required two outpatient visits or one hospitalization with primary International Classification of Diseases, 9th edition code 491.xx, 492.xx, or 496 occurring at least 30 days apart with none in the prior 12 months. The primary measurement was spirometry performed within 365 days (+/-) of the first claim with a COPD diagnosis. MEASUREMENTS AND MAIN RESULTS: Between 1999 and 2008, 64,985 subjects were newly diagnosed with COPD. Of these, 35,739 (55%) had spirometry performed within 1 year before or after the initial diagnosis of COPD. Spirometry use increased from 51.3% in 1999 to 58.3% in 2008 (P < 0.001). Subjects with younger age, men, whites, those with higher socioeconomic status, and those with a greater number of comorbidities were more likely to have spirometry. In a multivariable analysis, compared with 1999, subjects diagnosed in 2008 had 10% higher odds (odds ratio, 1.10; 95% confidence interval, 1.06-1.13) of having spirometry performed. CONCLUSIONS: Despite an increase in the use of spirometry over time in newly diagnosed older adults with COPD, spirometry use remains low. Clinical practice guidelines and educational efforts should focus on increasing the use of spirometry to diagnose and manage COPD. PMID- 24053441 TI - Conserved Walker A cysteines 431 and 1074 in human P-glycoprotein are accessible to thiol-specific agents in the apo and ADP-vanadate trapped conformations. AB - P-Glycoprotein (P-gp) is an ATP-binding cassette efflux transporter involved in the development of multidrug resistance in cancer cells. Although the mechanism of P-gp efflux has been extensively studied, aspects of its catalytic and transport cycle are still unclear. In this study, we used conserved C431 and C1074 in the Walker A motif of nucleotide-binding domains (NBDs) as reporter sites to interrogate the interaction between the two NBDs during the catalytic cycle. Disulfide cross-linking of the C431 and C1074 residues in a Cys-less background can be observed in the presence of M14M and M17M cross-linkers, which have spacer arm lengths of 20 and 25 A, respectively. However, cross-linking with both cross-linkers was prevented in the ADP-vanadate trapped (closed) conformation. Both C431 and C1074 alone or together (double mutant) in the apo and closed conformations were found to be accessible to fluorescein 5-maleimide (FM) and methanethiosulfonate derivatives of rhodamine and verapamil. In addition, C1074 showed 1.4- and 2-fold higher degrees of FM labeling than C431 in the apo and closed conformations, respectively, demonstrating that C1074 is more accessible than C431 in both conformations. In the presence of P-gp substrates, cross-linking with M17M is still observed, suggesting that binding of substrate in the transmembrane domains does not change the accessibility of the cysteines in the NBDs. In summary, the cysteines in the Walker A motifs of NBDs of human P gp are differentially accessible to thiol-specific agents in the apo and closed conformations. PMID- 24053442 TI - Induction of apoptosis and cell cycle arrest in A549 human lung adenocarcinoma cells by surface-capping selenium nanoparticles: an effect enhanced by polysaccharide-protein complexes from Polyporus rhinocerus. AB - Surface-capping agents play key roles in cellular uptake and biological activity of functional nanomaterials. In the present study, functionalized selenium nanoparticles (SeNPs) have been successfully synthesized using Polyporus rhinocerus water-soluble polysaccharide-protein complexes (PRW) as the capping agent during the reduction of selenium salts. The acquired monodisperse, spherical PRW-SeNPs presented desirable size distribution and stability in the solution. Moreover, PRW surface decoration significantly enhanced the cellular uptake of SeNPs via endocytosis. Exposure to PRW-SeNPs significantly inhibited the growth of A549 cells through induction of apoptosis and G2/M phase arrest (IC50 = 4.06 +/- 0.25 MUM) supported by an increase of sub-G1 and G2/M phase cell populations, DNA fragmentation, and chromatin condensation. Caspase-3/8 activation induced by PRW-SeNPs indicated that the activation of death receptors was the main cause of PRW-SeNP-induced apoptosis. Collectively, the results suggest that it is highly efficient to use PRW as a surface decorator of SeNPs to enhance cellular uptake and anticancer efficacy, and the PRW-SeNPs are potential chemopreventive agents for lung cancer therapy. PMID- 24053443 TI - Epithelial-mesenchymal transition: focus on metastatic cascade, alternative splicing, non-coding RNAs and modulating compounds. AB - Epithelial-mesenchymal transition (EMT) is a key process in embryonic development and metastases formation during malignant progression. This review focuses on transcriptional regulation, non-coding RNAs, alternative splicing events and cell adhesion molecules regulation during EMT. Additionally, we summarize the knowledge with regard to the small potentially druggable molecules capable of modulating EMT for cancer therapy. PMID- 24053444 TI - Incidence and predictors of understaging in patients with clinical T1 urothelial carcinoma undergoing radical cystectomy. AB - OBJECTIVE: To evaluate predictors of understaging in patients with presumed non muscle-invasive bladder cancer (NMIBC) identified on transurethral resection of bladder tumour (TURBT) who underwent radical cystectomy (RC) with attention to the role of a restaging TURBT. PATIENTS AND METHODS: We retrospectively evaluated 279 consecutive patients with clinically staged T1 (cT1) disease after TURBT who underwent RC at our institution from April 2000 to July 2011. In all, 60 of these cT1 patients had undergone a restaging TURBT before RC. The primary outcome measure was pathological staging of >=T2 disease at the time of RC. RESULTS: In all, 134 (48.0%) patients were understaged. Of the 60 patients who remained cT1 after a restaging TURBT, 28 (46.7%) were understaged. Solitary tumour (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.25-0.76, P = 0.004) and fewer prior TURBTs (OR 0.84, 95% CI 0.71-1.00, P = 0.05) were independent risk factors for understaging. CONCLUSIONS: Despite the overall improvement in staging accuracy linked to restaging TURBTs, the risk of clinical understaging remains high in restaged patients found to have persistent T1 urothelial carcinoma who undergo RC. Solitary tumour and fewer prior TURBTs are independent risk factors for being understaged. Incorporating these predictors into preoperative risk stratification may allow for augmented identification of those patients with clinical NMIBC who stand to benefit most from RC. PMID- 24053445 TI - Measuring stone volume - three-dimensional software reconstruction or an ellipsoid algebra formula? AB - OBJECTIVES: To determine the optimal method for assessing stone volume, and thus stone burden, by comparing the accuracy of scalene, oblate, and prolate ellipsoid volume equations with three-dimensional (3D)-reconstructed stone volume. Kidney stone volume may be helpful in predicting treatment outcome for renal stones. While the precise measurement of stone volume by 3D reconstruction can be accomplished using modern computer tomography (CT) scanning software, this technique is not available in all hospitals or with routine acute colic scanning protocols. Therefore, maximum diameters as measured by either X-ray or CT are used in the calculation of stone volume based on a scalene ellipsoid formula, as recommended by the European Association of Urology. METHODS: In all, 100 stones with both X-ray and CT (1-2-mm slices) were reviewed. Complete and partial staghorn stones were excluded. Stone volume was calculated using software designed to measure tissue density of a certain range within a specified region of interest. Correlation coefficients among all measured outcomes were compared. Stone volumes were analysed to determine the average 'shape' of the stones. RESULTS: The maximum stone diameter on X-ray was 3-25 mm and on CT was 3-36 mm, with a reasonable correlation (r = 0.77). Smaller stones (<9 mm) trended towards prolate ellipsoids ('rugby-ball' shaped), stones of 9-15 mm towards oblate ellipsoids (disc shaped), and stones >15 mm towards scalene ellipsoids. There was no difference in stone shape by location within the kidney. CONCLUSIONS: As the average shape of renal stones changes with diameter, no single equation for estimating stone volume can be recommended. As the maximum diameter increases, calculated stone volume becomes less accurate, suggesting that larger stones have more asymmetric shapes. We recommend that research looking at stone clearance rates should use 3D-reconstructed stone volumes when available, followed by prolate, oblate, or scalene ellipsoid formulas depending on the maximum stone diameter. PMID- 24053446 TI - Urinary 6-sulphatoxymelatonin levels in patients with senile cataracts. AB - BACKGROUND: The antioxidant melatonin effectively scavenges highly toxic hydroxyl radicals. Decreases in circulating melatonin levels have been reported in patients with diseases that become more serious with advancing age. The purpose of the present study was to explore the relationship between circulatory melatonin level and the extent of senile cataracts. To this end, we assessed the urinary excretion levels of 6-sulphatoxymelatonin (aMTS6), a major metabolite of melatonin. METHODS: A total of 22 patients (aged 64 +/- 7 years; 12 males and 10 females) with senile cataracts and 22 healthy controls (aged 61 +/- 8 years, 12 males and 10 females) were studied. aMTS6 urine levels were measured using commercial ELISA kits. Each aMTS6 level was expressed as [aMTS6] (in ng)/[mg] creatinine. As the data were not normally distributed, the Mann-Whitney U-test was employed to assess the statistical validity of the difference observed. RESULTS: The aMT6 level in nocturnal urine was 17.87 +/- 14.43 ng aMTS6/mg creatinine (mean +/- SD) in senile cataract patients; this was 76% of the level measured in age- and gender-matched controls (23.28 +/- 16.27 ng aMTS6/mg creatinine). This difference in nocturnal urine aMTS6 level between senile cataract patients and controls was not statistically significant (p = 0.358). CONCLUSION: The urinary aMTS6 level did not differ between subjects with and without senile cataracts. PMID- 24053447 TI - Flash nanoprecipitation: particle structure and stability. AB - Flash nanoprecipitation (FNP) is a process that, through rapid mixing, stabilizes an insoluble low molecular weight compound in a nanosized, polymer-stabilized delivery vehicle. The polymeric components are typically amphiphilic diblock copolymers (BCPs). In order to fully exploit the potential of FNP, factors affecting particle structure, size, and stability must be understood. Here we show that polymer type, hydrophobicity and crystallinity of the small molecule, and small molecule loading levels all affect particle size and stability. Of the four block copolymers (BCP) that we have studied here, poly(ethylene glycol)-b poly(lactic-co-glycolic acid) (PEG-b-PLGA) was most suitable for potential drug delivery applications due to its ability to give rise to stable nanoparticles, its biocompatibility, and its degradability. We found little difference in particle size when using PLGA block sizes over the range of 5 to 15 kDa. The choice of hydrophobic small molecule was important, as molecules with a calculated water-octanol partition coefficient (clogP) below 6 gave rise to particles that were unstable and underwent rapid Ostwald ripening. Studies probing the internal structure of nanoparticles were also performed. Analysis of differential scanning calorimetry (DSC), cryogenic transmission electron microscopy (cryo-TEM), and (1)H NMR experiments support a three-layer core-shell corona nanoparticle structure. PMID- 24053448 TI - Effects of anti-miR-182 on TSP-1 expression in human colon cancer cells: there is a sense in antisense? AB - OBJECTIVE: miRNAs are attractive molecules for cancer treatment, including colon rectal cancer (CRC). We investigate on the molecular mechanism by which miR-182 could regulate thrombospondin-1 (TSP-1) expression, a protein downregulated in CRC and inversely correlated with tumor vascularity and metastasis. BACKGROUND: MicroRNAs are small non-coding RNAs that regulate the expression of different genes, involved in cancer progression, angiogenesis and metastasis. miR-182, over expressed in colorectal cancer (CRC), has like predictive target thrombospondin-1 (TSP-1), a protein inversely correlated with tumor vascularity and metastasis that results downregulated in different types of cancer including CRC. RESULTS: We found that TSP-1 increased after transfection with anti-miR-182 and we showed that miR-182 targets TSP-1 3'UTR-mRNA in both cells. Moreover, we observed that anti-miR-182 did not induce significant variation of Egr-1 expression, but affected the nuclear translocation and its binding on tsp-1 promoter in HCT-116. Equally, Sp-1 was slightly increased as total protein, rather we found a nuclear accumulation and its loading on the TSP-1 promoter in HT-29 transfected with anti miR-182. CONCLUSION: Our data suggest that miR-182 targets the anti-angiogenic factor TSP-1 and that anti-miR-182 determines an upregulation of TSP-1 expression in colon cancer cells. Moreover, anti-miR-182 exerts a transcriptional regulatory mechanism of tsp-1 modulating Egr-1 and Sp-1 function. Anti-miR-182 could be used to restore TSP-1 expression in order to contrast angiogenic and invasive events in CRC. PMID- 24053449 TI - Cross-protective immunity against influenza A/H1N1 virus challenge in mice immunized with recombinant vaccine expressing HA gene of influenza A/H5N1 virus. AB - BACKGROUND: Influenza virus undergoes constant antigenic evolution, and therefore influenza vaccines must be reformulated each year. Time is necessary to produce a vaccine that is antigenically matched to a pandemic strain. A goal of many research works is to produce universal vaccines that can induce protective immunity to influenza A viruses of various subtypes. Despite intensive studies, the precise mechanisms of heterosubtypic immunity (HSI) remain ambiguous. METHOD: In this study, mice were vaccinated with recombinant virus vaccine (rL H5), in which the hemagglutinin (HA) gene of influenza A/H5N1 virus was inserted into the LaSota Newcastle disease virus (NDV) vaccine strain. Following a challenge with influenza A/H1N1 virus, survival rates and lung index of mice were observed. The antibodies to influenza virus were detected using hemagglutination inhibition (HI). The lung viral loads, lung cytokine levels and the percentages of both IFN gamma+CD4+ and IFN-gamma+CD8+ T cells in spleen were detected using real-time RT PCR, ELISA and flow cytometry respectively. RESULTS: In comparison with the group of mice given phosphate-buffered saline (PBS), the mice vaccinated with rL H5 showed reductions in lung index and viral replication in the lungs after a challenge with influenza A/H1N1 virus. The antibody titer in group 3 (H1N1-H1N1) was significantly higher than that in other groups which only low levels of antibody were detected. IFN-gamma levels increased in both group 1 (rL H5-H1N1) and group 2 (rL H5 + IL-2-H1N1). And the IFN-gamma level of group 2 was significantly higher than that of group 1. The percentages of both IFN-gamma+CD4+ and IFN-gamma+CD8+ T cells in group 1 (rL H5-H1N1) and group 2 (rL H5 + IL-2 H1N1) increased significantly, as measured by flow cytometry. CONCLUSION: After the mice were vaccinated with rL H5, cross-protective immune response was induced, which was against heterosubtypic influenza A/H1N1 virus. To some extent, cross-protective immune response can be enhanced by IL-2 as an adjuvant. Cellular immune responses may play an important role in HSI against influenza virus. PMID- 24053450 TI - Biphasic insulin aspart 30 in insulin-naive people with type 2 diabetes in non western nations: results from a regional comparative multinational observational study (A(1)chieve). AB - BACKGROUND: A1chieve((r)) (Novo Nordisk A/S, Bagsvaerd, Denmark) was a prospective, multicenter, noninterventional study in 66,726 people with type 2 diabetes mellitus (T2DM) in 28 countries beginning biphasic insulin aspart 30 (aspart premix), insulin detemir, or insulin aspart in routine clinical care. SUBJECTS AND METHODS: A subgroup of 27,594 insulin-naive people began therapy with aspart premix with or without oral agents. Safety and effectiveness data were taken from clinic records at baseline and after 24 weeks. Seven regional country groupings were prespecified. RESULTS: Mean final insulin dose ranged from 0.68+/-0.26 U/kg/day (Middle East/Gulf) to 0.38+/-0.14 U/kg/day (South Asia). The baseline glycated hemoglobin (HbA1c) level varied from 10.5+/-2.0% (Latin America) to 9.2+/-1.3% (South Asia), with reductions from -2.9+/-2.1% (Latin America) to -1.9+/-1.3% (South Asia). The proportion of people reaching an HbA1c level of <7.0% was highest in China (56%) and lowest in North Africa (22%). Fasting plasma glucose level reductions were from -6.4+/-5.3 mmol/L (Latin America) to -3.6+/-2.6 mmol/L (South Asia). Most people began aspart premix twice daily, varying from 91% (North Africa) to 70% (Latin America). Improvement in HbA1c increased with baseline dose frequency (once daily, -1.5+/-1.4%; twice daily, -2.2+/-1.6%; three times daily, -2.9+/-2.2%). CONCLUSIONS: Insulin-naive people with T2DM beginning aspart premix insulin in routine clinical practice in non-western nations had clinically useful improvements in blood glucose control after 24 weeks in all seven regions. Improvements from baseline for glucose control variables were greater than cross-regional differences in those variables at 24 weeks. PMID- 24053451 TI - Current methods of analgesia for transrectal ultrasonography (TRUS)-guided prostate biopsy -- a systematic review. AB - Transrectal ultrasonography (TRUS)-guided prostate biopsy is the most commonly used method of sampling prostate tissue for the diagnosis of prostate cancer. The technique is well recognised to potentially cause severe pain and discomfort for patients and this has led to numerous attempts to devise ways to minimise these problems. This systematic review summarises the techniques that have been described to date, with special reference to studies using either a visual analogue or numerical analogue scale to report outcomes. Commonly used approaches that are effective to minimise pain or discomfort include intravenous sedoanalgesia, inhalational agents and periprostatic infiltration of local anaesthetic. Whilst diclofenac suppositories are more effective than placebo, intra-rectal local anaesthetic gels appear to be of no benefit. Performing TRUS guided prostate biopsy without any form analgesia is not appropriate. PMID- 24053452 TI - Polymer-cobalt(III) complexes: structural analysis of metal chelates on DNA interaction and comparative cytotoxic activity. AB - A new series of pendant-type polymer-cobalt(III) complexes, [Co(LL)2(BPEI)Cl](2+), (where BPEI = branched polyethyleneimine, LL = dipyrido[3,2-a:2',3'-c](6,7,8,9-tetrahydro)phenazine (dpqc), dipyrido[3,2-d:2',3' f]quinoxaline (dpq) and imidazo[4,5-f]1,10-phenanthroline (ip)) each with three different degrees of coordination have been synthesized and characterized. Studies to know the mode and strength of interaction between these polymer-metal complexes and calf thymus DNA have been performed by UV-Visible absorption and emission techniques. Among these series, each polymer metal complex having higher binding strength with DNA has been selected to test against human cancer/normal cell lines. On the basis of these spectral studies, it is proposed that our polymer-metal complexes bind with DNA mainly through intercalation along with some electrostatic binding. The order of binding strength for the complexes with ligand, dpqc > dpq > ip. The analysis of the results suggests that polymer cobalt(III) complexes with higher degree of coordination effectively binds with DNA due to the presence of large number of positively charged cobalt(III) chelates in the polymer chain which cooperatively act to increase the overall binding strength. These polymer-cobalt(III) complexes with hydrophobic ligands around the cobalt(III) metal centre favour the base stacking interactions via intercalation. All the complexes show very good anticancer activities and increasing of binding strength results in higher inhibition value. The polymer cobalt(III) complex with dpqc ligand possess two fold increased anticancer activity when compared to complexes with other ligands against MCF-7 cells. Besides, the complexes were insensitive towards the growth of normal cells (HEK 293) at the IC50 concentration. PMID- 24053453 TI - Inflammation and corticosteroid responsiveness in ex-, current- and never-smoking asthmatics. AB - BACKGROUND: It has been suggested that smoking asthmatics benefit less from corticosteroid treatment than never-smoking asthmatics. We investigated differences in blood and sputum inflammatory profiles between ex-, current-, and never-smokers and assessed their ICS treatment response after 2-week and 1-year treatment. METHODS: We analyzed FEV1, PC20 methacholine and PC20 AMP, (differential) cell counts in sputum and blood in ex-, current- and never-smokers at baseline (n=114), after 2-week treatment with fluticasone 500 or 2000 MUg/day (n=76) and after 1-year treatment with fluticasone 500 MUg/day or a variable dose of fluticasone based on a self-management plan (n=64). RESULTS: A total of 114 patients were included (29 ex-, 30 current- and 55 never-smokers. At baseline, ex and current-smokers had less eosinophils in sputum and blood than never-smokers. Blood neutrophil counts were higher in current- than in never-smokers. A higher number of cigarettes smoked daily was associated with lower blood and sputum eosinophils. After 2-week ICS treatment, FEV1 %predicted improved less in current smokers than never-smokers (2.4% versus 8.1%, p=0.010) and ex-smokers tended to improve less than never-smokers (4.1%, p=0.067). In contrast, no differences in ICS treatment response in lung function or inflammatory cells were found between the three groups after 1 year. CONCLUSIONS: Ex- and current-smokers have less eosinophils and more neutrophils in their sputum and blood than never-smokers. Although ex- and current-smokers have a reduced short-term corticosteroid treatment response, we did not find a difference in their long-term treatment response. PMID- 24053454 TI - The role of ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review. AB - BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a condition that occurs during the progression of non-alcoholic fatty liver disease. Effective therapy for NASH is still lacking. In this study, we investigated the effects of Ursodeoxycholic acid (UDCA) in the treatment of NASH. METHODS: Western and Chinese databases were searched by independent investigators using appropriate MESH headings to identify randomized, controlled Western and Chinese clinical trials, published between January 1990 and October 2012, testing the effects of UDCA in patients with NASH. Patient characteristics and trial endpoints were analyzed, with quality assessment according to widely acknowledged criteria. P < 0.05 was defined as statistically significant in all trials. RESULTS: Twelve qualified randomized clinical trials, including six from China and involving 1160 subjects, were selected. Seven of these trials assessed the effects of UDCA Monotherapy, with the other five testing combinations of UDCA with vitamin E, polyene phosphatidylcholine, silymarin, glycyrrhizin and tiopronin. The duration of therapy ranged from 3 to 24 months, with two studies using high doses of UDCA (23-35 mg/kg/d). The average quality point was 2.69, and was significantly lower in articles from China than in those from Western countries (2.2 +/- 0.4 vs. 3.8 +/- 1.1, respectively, p < 0.05). UDCA Monotherapy significantly improved liver function in five studies and improved steatosis and fibrosis in two studies. All five studies assessing UDCA combination therapy showed significant improvements liver function, while two studies also improved steatosis and inflammation. One study of high-dose UDCA showed significant improvements in ALT, gammaGT and liver fibrosis, whereas the other study showed no significant change in ALT and liver pathology. CONCLUSIONS: UDCA therapy is effective in NASH, especially when combined with other drugs. However, the low quality of these studies and the heterogeneity of their results precluded further meta-analysis. Additional carefully designed clinical trials are needed, especially in China. PMID- 24053455 TI - Infrared metrics for fixation-free liver tumor detection. AB - Infrared (IR) spectroscopic imaging of human liver tissue slices has been used to identify and characterize liver tumors. Liver tissue, containing a liver metastasis of breast origin (mucinous carcinoma), was surgically removed from a consenting patient and frozen without formalin fixation or dehydration procedures, so that lipids and water remained in the tissues. A set of IR metrics (ratios of various IR peaks) was determined for tumors in fixation-free liver tissues. K-means cluster analysis was used to tell tumor from nontumor. In this case, there was a large reduction in lipid content upon going from nontumor to tumor tissue, and a well-resolved IR spectrum of nontumor liver lipid was obtained and analyzed. These IR metrics may someday guide work on IR spectroscopic diagnostics on patients in the operating room. This work also suggests utility for these methods beyond the identification of liver tumors, perhaps in the study of liver lipids. PMID- 24053456 TI - Family caregivers' sleep disturbance and its associations with multilevel stressors when caring for patients with dementia. AB - OBJECTIVE: We tested a stress process model of multilevel stressors on sleep disturbance for family caregivers (FCG) of persons with dementia (PWD). METHODS: For this cross-sectional study, trained research assistants collected data from a purposive sample of 180 PWD-FCG dyads at two teaching hospitals, two local hospitals, and two community long-term care service programs in northern Taiwan. PWDs' neuropsychiatric symptoms were assessed using the Chinese Neuropsychiatric Inventory (CNPI), FCGs' distress by CNPI Caregiver Distress Scale, physical fatigue by Visual Analogue for Fatigue Scale, mental fatigue by Attentional Function Index, depressive symptoms by the Center for Epidemiological Studies Depression Scale - Short Form, and sleep disturbance by the General Sleep Disturbance Scale. RESULTS: FCGs' most prevalent sleep disturbance problems were sleep quality problems (99.4%). Hierarchical regression models revealed that FCGs' sleep disturbance was predicted by their physical fatigue, their depressive symptoms, and the synergistic effect of physical fatigue and depressive symptoms in the final model, explaining 57.8% of the variance. CONCLUSIONS: This study supports the model that development of caregivers' sleep problems may depend on their depression, fatigue, and the synergistic effects of these two variables. These findings suggest that clinicians should educate FCGs about self-care and offer strategies for dealing with a cluster of symptoms when maintaining sleep hygiene. PMID- 24053457 TI - STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years. AB - BACKGROUND: The transcription factor STAT6 is crucial for activation of the interleukin (IL)-4/IL-13 pathway and has been linked to regulatory T cells (Tregs). Associations of STAT6 polymorphisms with IgE levels were described; however, their impact on neonatal immune responses and early disease development is unknown. METHODS: STAT6 polymorphisms were genotyped in cord blood mononuclear cells by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Gene expression was assessed by real-time polymerase chain reaction (PCR) and cytokines by Multiplex. At age 3 years, atopic diseases were assessed by questionnaires. RESULTS: STAT6 rs324011 but not rs1059513 polymorphism was associated with significant or borderline significant decreased mRNA expression of Treg-associated genes (FOXP3, GITR, LAG3). Heterozygotes and minor allele homozygotes of rs324011 had low levels of tumor necrosis factor alpha (TNF-alpha) and increased interferon gamma (IFN-gamma) (P <= 0.04), while heterozygotes and minor allele homozygotes of rs1059513 had increased TNF-alpha and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (P <= 0.05). In minor allele homozygotes of rs324011, expression of Treg-associated genes was strongly inverse correlated with IFN-gamma (unstimulated, r = -0.7, P = 0.111; LpA stimulation, r = -0.8, P = 0.011), but not in heterozygotes or major allele homozygotes. Heterozygotes and minor allele homozygotes of rs324011 presented a lower risk of atopic dermatitis and obstructive bronchitis until age 3 years. CONCLUSIONS: Two STAT6 polymorphisms were associated with altered immune responses already at birth. STAT6 rs324011 was associated with lower neonatal Treg and increased Th1 response. Those neonates had a lower risk of atopic dermatitis and obstructive bronchitis until 3 years. Our data suggest a role for STAT6 polymorphisms in early immune regulation and implications on early atopic disease development. PMID- 24053458 TI - A socio-technical assessment of the success of Picture Archiving and Communication Systems: the radiology technologist's perspective. AB - BACKGROUND: With the increasing prevalence of Picture Archiving and Communication Systems (PACS) in healthcare institutions, there is a growing need to measure their success. However, there is a lack of published literature emphasizing the technical and social factors underlying a successful PACS. METHODS: An updated Information Systems Success Model was utilized by radiology technologists (RTs) to evaluate the success of PACS at a large medical center in Taiwan. A survey, consisting of 109 questionnaires, was analyzed by Structural Equation Modeling. RESULTS: Socio-technical factors (including system quality, information quality, service quality, perceived usefulness, user satisfaction, and PACS dependence) were proven to be effective measures of PACS success. Although the relationship between service quality and perceived usefulness was not significant, other proposed relationships amongst the six measurement parameters of success were all confirmed. CONCLUSIONS: Managers have an obligation to improve the attributes of PACS. At the onset of its deployment, RTs will have formed their own subjective opinions with regards to its quality (system quality, information quality, and service quality). As these personal concepts are either refuted or reinforced based on personal experiences, RTs will become either satisfied or dissatisfied with PACS, based on their perception of its usefulness or lack of usefulness. A satisfied RT may play a pivotal role in the implementation of PACS in the future. PMID- 24053460 TI - Closing remarks from associate editor. PMID- 24053459 TI - Effects of moving emergency trauma laparotomies from the ED to a dedicated OR. AB - INTRODUCTION: The trauma room at Oslo University Hospital- Ulleval is fully equipped for major damage control procedures, in order to minimize delay to surgery. Since 2006, patients in need of immediate laparotomy have increasingly been transferred to a dedicated trauma operating room (OR). We wanted to determine the decrease in number of procedures performed in the emergency department (ED), the effect on time from admission to laparotomy, the effect on non-therapeutic laparotomies, and finally to determine whether such a change could be undertaken without an increase in mortality. METHODS: Retrospective evaluation of haemodynamically unstable trauma patients undergoing laparotomy during the period 2002-2009. Based on time for protocol change Period 1 was defined as 2002-2006 and Period 2 as 2007-2009. Significance was set at p < 0.05. RESULTS: A total of 167 consecutive patients were included; 103 patients from Period 1 and 64 from Period 2. We found a 42% decrease in ED laparotomies (p < 0.001). Median time to laparotomy increased from 24.0 to 34.0 minutes from Period 1 to Period 2 (p = 0.029). Crude mortality fell from 57% to 39%. The proportion of non-therapeutic laparotomies in the OR tended to be lower over the whole study period. CONCLUSION: Moving this cohort of haemodynamically compromised trauma patients in need of emergency laparotomy out of the ED to a dedicated OR resulted in longer median time to laparotomy, but did not increase mortality. PMID- 24053461 TI - Destruction of the bladder by single dose Mitomycin C for low-stage transitional cell carcinoma (TCC)--avoidance, recognition, management and consent. AB - OBJECTIVES: To identify a cohort of patients under our care who have had significant and in some cases irreparable damage to their bladders after Mitomycin C (MMC) instillation. To highlight the importance of avoidance and recognition of bladder perforations during transurethral resection of bladder tumour (TURBT) and explore the issue of consent regarding MMC given the serious complications that may occur after its instillation. PATIENTS AND METHODS: Patients referred to our tertiary centre for a second opinion to manage their complications after a suspected MMC leak was identified from the departmental database between January 2000 and December 2010. After collection of all the records, we established a cohort of six patients. All patients had their initial tumour resection elsewhere and were referred for specialist management thereafter. Details of the operating surgeon and cystoscopic findings were known only in half of the cases. Retrospective analysis of their notes including documentation from the referring centre was undertaken. This included a review of all the histology and imaging. RESULTS: All patients had immediate severe pelvic pain on instillation of the MMC. Four of the six continue to have chronic pelvic pain. Two patients had urinary retention and three had severe lower urinary tract symptoms. One patient developed a frozen pelvis. Initial treatment was with an indwelling catheter for a period of 2-52 weeks to aid healing. Two patients had reconstructive surgery, one with success and the other with failure, as an intestinal patch failed to close the fistula and he continues with a catheter. One patient had an ileal conduit. No patient was warned of such complications. CONCLUSIONS: Although rare, prophylactic MMC can have devastating consequences. Patients should be aware of such major risks. Strong emphasis should be placed on the quality of the initial TURBT coupled with the judgement of an experienced surgeon before to MMC instillation. The real clinical benefit could be reviewed and intravesical MMC offered only to patients who have a good chance of benefit. PMID- 24053462 TI - Waist circumference in predicting gestational diabetes mellitus. AB - BACKGROUND: To evaluate waist circumference (WC) measured at 20-24 weeks of gestation as a predictor of gestational diabetes mellitus (GDM). METHODS: This cross-sectional study included 240 women at 20-24 weeks of gestation. At enrollment, WC was measured, and both prepregnancy and gestational body mass index (BMI) were estimated. According to the results of 75-g oral glucose tolerance test (OGTT) performed at 24-28 weeks, subjects were allocated into two groups, non-GDM and GDM. WC sensitivity and specificity, and odds ratios (OR) and 95% confidence intervals for BMI and WC were estimated, and a receiver operating characteristics curve was generated. RESULTS: Of the 240 pregnant women enrolled, 31 (13%) had GDM. Prepregnancy BMI (OR = 4.21), gestational BMI (OR = 3.17) and WC at 20-24 weeks (OR = 4.02) correlated with GDM risk. At 20-24 weeks, a WC of 85.5-88.5 cm was the optimal cutoff point for predicting GDM (Sens/Spec balance between 87.1/41.1% and 77.4/56.9%). CONCLUSION: At 20-24 weeks of gestation, WC values in the range of 86-88 cm showed to be a good performance in predicting GDM. PMID- 24053463 TI - Impact of smoking status and cumulative exposure on intravesical recurrence of upper tract urothelial carcinoma after radical nephroureterectomy. AB - OBJECTIVE: To assess the impact of cigarette smoking status, cumulative smoking exposure, and time from cessation on intravesical recurrence (IVR) outcomes in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: In all, 519 patients underwent RNU at five institutions. Smoking history included smoking status, quantity of cigarettes smoked per day (cpd), duration, and time from cessation. The cumulative smoking exposure was categorised as light-short-term (<=19 cpd and <=19.9 years), moderate (all combinations except light-short-term and heavy-long term), and heavy-long-term (>=20 cpd and >=20 years). Univariable/multivariable cox regression analyses assessed the effects of smoking on IVR. RESULTS: In all, 190 patients (36%) never smoked; 205 (40%) and 125 (24%) were former and current smokers, respectively. Among smokers, 42 (8%), 185 (36%), and 102 (20%) patients were light-short-term, moderate, and heavy-long-term smokers, respectively. Within a median follow-up of 37 months, 152 patients (29%) had IVR. Actuarial IVR free-survival estimates (standard error) at 2, 5, and 10 years were 72 (2)%, 58 (3)%, and 51 (4)%, respectively. In multivariable analyses, current smoking status, smoking intensity (>=20 cpd), smoking duration (>=20 years), and heavy long-term smoking were associated with higher risk of IVR (all P <= 0.01). Patients who quit smoking >=10 years before RNU had better IVR outcomes than current smokers and those patients who quit smoking <10 years before RNU. CONCLUSIONS: Cigarette smoking is significantly associated with IVR in patients treated with RNU for UTUC. Current and heavy-long-term smokers have the highest risk of IVR. Smoking cessation for >10 years before RNU seems to mitigate these detrimental effects. PMID- 24053464 TI - Feasibility study on the use of near-infrared hyperspectral imaging for the screening of anthocyanins in intact grapes during ripening. AB - The potential of near-infrared hyperspectral imaging to determine anthocyanins in intact grape has been evaluated. The hyperspectral images of intact grapes during ripening were recorded using a near-infrared hyperspectral imaging covering the spectral range between 900 and 1700 nm. Reference values of anthocyanins were obtained by HPLC-DAD. A number of spectral pretreatments and different mask development strategies were studied. Calibrations were performed by modified partial least-squares regression (MPLS) and present a good potential (RSQ of 0.86 and SEP values of 2.62 and 3.05 mg g(-1) of grape skin for nonacylated and total anthocyanins, respectively) for a fast and reasonably inexpensive screening of these compounds in intact grapes. PMID- 24053465 TI - Doped lanthanum nickelates with a layered perovskite structure as bifunctional cathode catalysts for rechargeable metal-air batteries. AB - Rechargeable metal-air batteries have attracted a great interest in recent years because of their high energy density. The critical challenges facing these technologies include the sluggish kinetics of the oxygen reduction-evolution reactions on a cathode (air electrode). Here, we report doped lanthanum nickelates (La2NiO4) with a layered perovskite structure that serve as efficient bifunctional electrocatalysts for oxygen reduction and evolution in an aqueous alkaline electrolyte. Rechargeable lithium-air and zinc-air batteries assembled with these catalysts exhibit remarkably reduced discharge-charge voltage gaps (improved round-trip efficiency) as well as high stability during cycling. PMID- 24053467 TI - Single-step Ugi multicomponent reaction for the synthesis of phosphopeptidomimetics. AB - This article describes the design and optimization of an effective microwave assisted multicomponent reaction to produce a novel class of phosphopeptidomimetic compounds. When using aminophosphonic acids (alpha, beta, gamma), aldehydes, and isocyanides as reactants and alcohols as solvents, these building blocks are merged to functionalized amido-aminophosphonate structures in a novel Ugi-type one-pot transformation reaction. A high level of structural diversity can be achieved with this synthetic approach, providing a platform for the production of functionalized building blocks for novel bioactive molecules. The general scope of this multicomponent synthetic protocol is explored by variation of reaction parameters together with an evaluation of a diverse set of reaction substrates. The applicability of this reaction has been demonstrated by the synthesis of 17 distinct compounds giving yields in the range of 20-92%. PMID- 24053466 TI - Role of a guanidinium cation-phosphodianion pair in stabilizing the vinyl carbanion intermediate of orotidine 5'-phosphate decarboxylase-catalyzed reactions. AB - The side chain cation of Arg235 provides a 5.6 and 2.6 kcal/mol stabilization of the transition states for orotidine 5'-monophosphate (OMP) decarboxylase (OMPDC) from Saccharomyces cerevisiae catalyzed reactions of OMP and 5-fluoroorotidine 5' monophosphate (FOMP), respectively, a 7.2 kcal/mol stabilization of the vinyl carbanion-like transition state for enzyme-catalyzed exchange of the C-6 proton of 5-fluorouridine 5'-monophosphate (FUMP), but no stabilization of the transition states for enzyme-catalyzed decarboxylation of truncated substrates 1 (beta-d-erythrofuranosyl)orotic acid and 1-(beta-d-erythrofuranosyl) 5 fluorouracil. These observations show that the transition state stabilization results from formation of a protein cation-phosphodianion pair, and that there is no detectable stabilization from an interaction between the side chain and the pyrimidine ring of substrate. The 5.6 kcal/mol side chain interaction with the transition state for the decarboxylation reaction is 50% of the total 11.2 kcal/mol transition state stabilization by interactions with the phosphodianion of OMP, whereas the 7.2 kcal/mol side chain interaction with the transition state for the deuterium exchange reaction is a larger 78% of the total 9.2 kcal/mol transition state stabilization by interactions with the phosphodianion of FUMP. The effect of the R235A mutation on the enzyme-catalyzed deuterium exchange is expressed predominantly as a change in the turnover number kex, whereas the effect on the enzyme-catalyzed decarboxylation of OMP is expressed predominantly as a change in the Michaelis constant Km. These results are rationalized by a mechanism in which the binding of OMP, compared with that for FUMP, provides a larger driving force for conversion of OMPDC from an inactive open conformation to a productive, active, closed conformation. PMID- 24053469 TI - Microarray gene expression profiling and analysis of bladder cancer supports the sub-classification of T1 tumours into T1a and T1b stages. AB - OBJECTIVE: To try and identify a molecular signature for pathological staging and/or grading. through microarray analysis. PATIENTS AND METHODS: We performed a prospective multicentre study between September 2007 and May 2008 that included 108 bladder tumours (45 pTa, 35 pT1 and 28>pT1). Microarray analysis was performed using Agilent Technologies Human Whole Genome 4 * 44K oligonucleotide microarrays (Agilent, Santa Clara, CA, USA). A 'dual colour' method was used vs a reference pool of tumours. From the lists of genes provided by the Biometric Research Branch class comparison analyses, we validated the microarray results of 38 selected differentially expressed genes using reverse transcriptase quantitative PCR in another bladder tumour cohort (n = 95). RESULTS: The cluster 'superficial vs invasive stage' correctly classified 92.9% of invasive stages and 66.3% of superficial stages. Among the superficial tumours, the cluster analysis showed that pT1b tumours were closer to invasive stages than pT1a tumours. We also found molecular differences between low and high grade superficial tumours, but these differences were less well defined than the difference observed for staging. CONCLUSIONS: We confirmed that the histopathological classification into subgroups pTa, pT1a and pT1b can be translated into a molecular signature with a continuous progression of deregulation (overexpression or repression of these genes) from superficial (pTa) to more invasive (pT1a then b) stages. PMID- 24053470 TI - New side-view imaging technique for observing posterior chamber structures during cataract surgery in porcine eyes. AB - BACKGROUND: To develop a side-view imaging technique for observing the dynamic behavior of posterior chamber structures (PCSs) in porcine eyes which mimics closed-eye cataract surgery in humans. METHODS: Enucleated porcine eyes were placed into liquid nitrogen for 5 seconds and immediately bisected at about a 45 degree angle to the equatorial plane. The anterior portion was attached firmly to a glass slide with superglue and sprinkled with wheat flour. Phacoemulsification and aspiration (PEA) was performed as in humans on 10 consecutive porcine eyes. The movements of the PCSs were monitored through the glass slide with a high resolution video camera set below the cut surface of the eye. The intraocular pressure (IOP) was monitored during the surgery. The highest IOP, operation time, and volume of irrigation fluid of 10 whole eyes were compared to that obtained from the bisected eyes glued to a glass slide. In a second set of experiments, the strength of the seal between the bisected eye and the glass slide was tested in three sets of eyes: 1) frozen eye fixed with superglue with wheat flour for 3 min; 2) frozen eye fixed with superglue for 3 min; and 3) non-frozen eye fixed with superglue for 30 min. The highest IOP that led to a disruption of the seal was compared among the three groups. RESULTS: PEA was successfully performed on 9 of 10 (90%) eyes with the movements of the PCSs clearly observed. The average maximum intraocular pressure of the 9 bisected eyes was 55.8 +/- 4.7 mmHg and that for the 10 unbisected eyes was 55.3 +/- 5.0 mmHg (P = 0.650). The frozen eye fixed with superglue in combination with wheat flour (Group 1) had the strongest sealing strength with an average IOP at the breaking point of 117.3 +/- 36.2 mmHg. CONCLUSIONS: Our side-view imaging technique can be used to evaluate the changes of the PCSs during intraocular surgery and for surgical training of new residents. PMID- 24053471 TI - Numerical model for intraosseous infusion of the human calvarium for hydrocephalus shunting. AB - Hydrocephaly is the defective absorption of cerebrospinal fluid (CSF) into the blood stream. This work is an experimental and computational fluid dynamic modelling study to determine the permeability of the diploe as a potential receptor for CSF. Human calvariae were studied by micro-CT to measure their porosity, the area of flow and develop model geometry. Pressure-flow measurements were conducted on specimens to determine their permeability in the physiological and transverse flow directions to compare with numerical results. The overall porosity and permeability of the calvaria were spatially variable. Results suggest an order of magnitude increase in permeability for a 14% increase in overall porosity based on a small number of samples. Numerical results fell within the experimental infusion tests results. Due to the difficulty and ethical considerations in obtaining adolescent skull samples to perform large-scale testing, the developed model will be invaluable. PMID- 24053468 TI - MYC, FBXW7 and TP53 copy number variation and expression in gastric cancer. AB - BACKGROUND: MYC deregulation is a common event in gastric carcinogenesis, usually as a consequence of gene amplification, chromosomal translocations, or posttranslational mechanisms. FBXW7 is a p53-controlled tumor-suppressor that plays a role in the regulation of cell cycle exit and reentry via MYC degradation. METHODS: We evaluated MYC, FBXW7, and TP53 copy number, mRNA levels, and protein expression in gastric cancer and paired non-neoplastic specimens from 33 patients and also in gastric adenocarcinoma cell lines. We also determined the invasion potential of the gastric cancer cell lines. RESULTS: MYC amplification was observed in 51.5% of gastric tumor samples. Deletion of one copy of FBXW7 and TP53 was observed in 45.5% and 21.2% of gastric tumors, respectively. MYC mRNA expression was significantly higher in tumors than in non-neoplastic samples. FBXW7 and TP53 mRNA expression was markedly lower in tumors than in paired non neoplastic specimens. Moreover, deregulated MYC and FBXW7 mRNA expression was associated with the presence of lymph node metastasis and tumor stage III-IV. Additionally, MYC immunostaining was more frequently observed in intestinal-type than diffuse-type gastric cancers and was associated with MYC mRNA expression. In vitro studies showed that increased MYC and reduced FBXW7 expression is associated with a more invasive phenotype in gastric cancer cell lines. This result encouraged us to investigate the activity of the gelatinases MMP-2 and MMP 9 in both cell lines. Both gelatinases are synthesized predominantly by stromal cells rather than cancer cells, and it has been proposed that both contribute to cancer progression. We observed a significant increase in MMP-9 activity in ACP02 compared with ACP03 cells. These results confirmed that ACP02 cells have greater invasion capability than ACP03 cells. CONCLUSION: In conclusion, FBXW7 and MYC mRNA may play a role in aggressive biologic behavior of gastric cancer cells and may be a useful indicator of poor prognosis. Furthermore, MYC is a candidate target for new therapies against gastric cancer. PMID- 24053472 TI - Preparation and characterisation of vancomycin-impregnated gelatin microspheres/silk fibroin scaffold. AB - A type of antibacterial silk fibroin (SF) scaffold was developed and characterised as a potential functional wound dressing for acute trauma treatment. To achieve this, SF solution was mixed with previously fabricated vancomycin (Vm)-loaded gelatin (G) microspheres, followed by a freeze-drying step. Some physical and antimicrobial properties of the prepared Vm/G/SF scaffolds were investigated and the results demonstrated that the average pore size and porosity of the composite scaffold were 60-80 MUm and 75%, respectively. The compressive stress and compressive modulus of Vm/G/SF scaffold were 140 and 468 KPa, respectively. Compared with Vm/G microspheres and Vm/SF scaffold, the Vm/G/SF scaffold has slower release rate of Vm. In addition, the Vm release rate of Vm/G/SF scaffold matched well with the degradation rate of SF scaffold. With respect to the antimicrobial effect, the results showed that the Vm/G/SF scaffold had good antimicrobial activity against Staphylococcus aureus (gram-positive), which is a gram-positive bacteria commonly found in infected wounds. PMID- 24053473 TI - Robot-assisted partial nephrectomy vs laparoscopic cryoablation for the small renal mass: redefining the minimally invasive 'gold standard'. AB - OBJECTIVE: To identify differences between the ablative and extirpative minimally invasive techniques of laparoscopic cryoablation (LC) and robot-assisted laparoscopic partial nephrectomy (RPN), respectively, in treating small renal tumours in terms of safety, peri-operative morbidity and early oncological outcomes. PATIENTS AND METHODS: Between June 2008 and April 2012 56 patients underwent LC and from October 2010 to April 2012, 47 patients underwent RPN using the Da Vinci robotic platform (Intuitive Surgical, Sunnyvale, CA, USA). Data on intra-operative, postoperative and oncological outcomes were collected prospectively, and were analysed and compared for both groups. RESULTS: The median patient ages were 69 and 60 for the LC and RPN groups, respectively (P < 0.05). There was no significant difference in disease stage, but there was a significant difference in tumour size, with patients in the RPN group having larger tumours. The mean operating times were 146 and 159 min for the LC and RPN groups, respectively (P = 0.094) and the mean blood loss was 47 and 94 mL for the LC and the RPN groups, respectively (P = 0.251). The median length of hospital stay (1 day) was the same for both groups and the mean warm ischaemia time was 23 min in the RPN group. The marginal change in preoperative and 6-week postoperative renal function was recorded: the mean postoperative increase in serum creatinine was 5.4 mmol/L in the LC group and 9.2 mmol/L in the RPN group. Of the 47 patients in the RPN group, two (4.3%) were converted to laparoscopic radical nephrectomy because of difficulty in controlling bleeding during hilar dissection. Only two patients (3.6%) had recurrence in the LC group, both of whom were treated with re-cryoablation. A total of 5.4% of patients in the LC and 4.3% in the RPN group had Clavien grade I postoperative complications, one patient in the LC group had a Clavien grade II complication, while 1.8 and 4.3% of patients had Clavien IIIb in the LC and RPN groups, respectively. CONCLUSION: Our data confirm that LC is a successful, minimally invasive and safe treatment option for the management of small renal tumours, but the apparently similar characteristics of RPN suggest that an increasing proportion of patients, whatever their age or medical comorbidities, may be reasonably offered a robot-assisted extirpative procedure with the likely benefit of lower risk of local recurrence and need for retreatment. PMID- 24053475 TI - Cooling after successful resuscitation in cardiac surgery patients. AB - BACKGROUND: Despite many years of intensive research sudden cardiac death is one of the most common causes of death all over the world. The European Resuscitation Council (ERC) recommends the use of moderate therapeutic hypothermia for 12-24 hours to improve neurological outcome. However, the beneficial effect of this therapy on outcomes for cardiac surgery patients with In- Hospital- Resuscitation (IHR) has not been well studied.The purpose of this single center analysis was to investigate our first experience in a non - selected IHR population, where hypothermia was induced independent from initial heart rhythm disturbance. METHOD: A total of 20 resuscitated patients who were treated in our institution between January 2010 and December 2011 formed the study cohort. RESULTS: In all patients post- resuscitation course was significantly prolonged with severe low cardiac output syndrome in six patients (30%). Overall four patients (20%) sustained septicemia with the need for high dose inotropic support. The 30 day mortality was 30% (six of twenty). However, stroke with severe neurological impairment appeared in only four patients (20%) after resuscitation with subsequent therapeutic hypothermia. CONCLUSION: With our observation study we could demonstrate the benefits for neurological outcome due to therapeutic hypothermia in cardiac surgery patients after successful resuscitation. However post- resuscitation treatment should focus on sufficient therapeutic strategies to avoid the distinctive short term morbidity and mortality. PMID- 24053474 TI - Gene expression modifications in Wharton's Jelly mesenchymal stem cells promoted by prolonged in vitro culturing. AB - BACKGROUND: It has been demonstrated that the umbilical cord matrix, represented by the Wharton's Jelly (WJ), contains a great number of mesenchymal stem cells (MSCs), characterized by the expression of specific MSCs markers, shared by both human and animal models. The easy access to massive WJ amount makes it an attractive source of MSCs for cell-based therapies. However, as in other stem cell models, a deeper investigation of WJ-derived MSCs (WJ-MSCs) biological properties, probably modulated by their prolonged expansion and fast growth abilities, is required before their use in clinical settings. In this context, in order to analyze specific gene expression modifications occurring in WJ-MSCs, along with their culture prolongation, we investigated the transcriptomic profiles of WJ-MSCs after 4 and 12 passages of in vitro expansion by microarray analysis. RESULTS: Hierarchical clustering analysis of the data set originated from a total of 6 experiments revealed that in vitro expansion of WJ-MSCs up to 12 passages promote selective over-expression of 157 genes and down-regulation of 440 genes compared to the 4th passage. IPA software analysis of the biological functions related to the identified sets of genes disclosed several transcripts related to inflammatory and cell stress response, cell proliferation and maturation, and apoptosis. CONCLUSIONS: Taken together, these modifications may lead to an impairment of both cell expansion ability and resistance to apoptosis, two hallmarks of aging cells. In conclusion, results provided by the present study suggest the need to develop novel culture protocols able to preserve stem cell plasticity. PMID- 24053476 TI - Durability of MemokathTM urethral stent for stabilisation of recurrent bulbar urethral strictures -- medium-term results. AB - OBJECTIVE: To examine the durability after 3 months deployment of a urethral (MemokathTM) stent in conjunction with endoscopic treatment of recurrent bulbar urethral strictures, as repeated endoscopic treatment of urethral strictures can cause worsening of underlying spongiofibrosis. PATIENTS AND METHODS: Prospective series of 22 patients with recurrent bulbar strictures requiring repeat endoscopic treatment were included. The median age was 38 years and the mean stricture length was 2.4 cm. The median number of previous dilatation or direct visual internal urethrotomy (DVIU) procedures was three with a mean time to stricture recurrence of 2 months. After endoscopic dilatation or DVIU, the urethral (MemokathTM) stent was deployed and left situ for 3 months. Re-stricture rates were examined with uroflowmetry at 3, 6 and 12 months and confirmed with 17 F cystoscopy at 1 year after stent removal. A telephone survey was conducted at >1-year follow-up. RESULTS: Five of the 22 (22%) patients had stricture recurrence after stent removal. In all, 17/22 (78%) patients remained stricture free at a median (range) follow-up of 23 (9-31) months. Uroflowmetry showed significantly improved flow rates, which were sustained at 12 months after stent removal. On Kaplan-Meier analysis, there was a significant delay (23 vs 2 months) in stricture or symptom recurrence after stent removal. CONCLUSION: The medium term results of temporary urethral stent placement are encouraging with 78% of patients remaining stricture-free at a median follow-up of 23 months. PMID- 24053477 TI - Stability of low back pain reporting over 8 years in a general population aged 40/41 years at base-line: data from three consecutive cross-sectional surveys. AB - BACKGROUND: A recent review on the natural course of low back pain (LBP) in the general population indicated that the LBP reporting pattern is fairly constant over time. Furthermore, the LBP status at baseline (yes/no) seems to be predictive of the future course. When fluctuations occur, they seem most common between the nearest categories. However, in the majority of articles, non responders were not taken into account in the analyses or interpretation of data, meaning that estimates may have been biased. Further, all reviewed studies included study participants of many different age groups. Data from three cross sectional surveys over 8 years of the same cohort made it possible to answer the following questions: 1) Would the prevalence estimates of LBP be stable over time? 2) How would results change when taking into account non-responders? 3) Is the LBP reporting over the three survey periods stable at an individual level, taking into account also the non-responding group? METHODS: Data from three subsequent cross-sectional surveys of a study sample were available and questions about LBP were asked at baseline and also 4 and 8 years later. Study participants were 40/41 years at base-line and initially randomly selected from the general Danish population. Data were analyzed with STATA/IC 12, and presented with percentages and 95% confidence intervals. RESULTS: The majority of participants reported to have had LBP in the preceding year but not having taken sick leave in relation to this pain. LBP was stable or relatively stable for the study participants as they progressed through their fifth decade. This was true on a population basis and also on an individual level. When non-responders were taken into account the results did not change. CONCLUSIONS: This study confirmed the results from our recent review; both presence and absence of LBP seem to be predictive for the future course. The percentage of non-responders in this type of study may not be as important as previously thought in relation to the presence/absence of LBP. PMID- 24053478 TI - Pre-exposure prophylaxis (PrEP) for HIV infection: results of a survey of HIV healthcare providers evaluating their knowledge, attitudes, and prescribing practices. AB - Antiretroviral medications can be taken by HIV-negative persons to prevent HIV infection, also known as pre-exposure prophylaxis (PrEP). PrEP was first shown to be effective during the iPrEX study. We conducted a survey involving HIV healthcare providers to document their attitudes and prescribing practices about PrEP in response to this study. An online survey was completed by 189 members and credentialees of the American Academy of HIV Medicine between April 2011 and September 2011. Ninety percent of respondents were familiar with the results of the iPrEx study, and most (78%) were familiar with CDC's interim guidance regarding the use of PrEP in MSM. Only 19% of respondents had prescribed PrEP. The majority of PrEP prescribers were compliant with CDC interim guidance; however, only 61% screened for hepatitis B. Of PrEP prescribers, 78% prescribed to MSM, 31% to MSW, and 28% to WSM. Greatest concerns about prescribing PrEP included development of antiretroviral resistance (32%), potential increase in high-risk behavior, (22%) and poor medication adherence (21%). Fifty-eight percent stated that HIV serodiscordance within a relationship most influenced their decision to prescribe PrEP to the HIV-seronegative partner. This study demonstrates that, despite awareness of the efficacy of PrEP, its use is limited. Survey participants used PrEP most commonly in MSM; however, a significant percentage also prescribed PrEP to women. The best candidate for PrEP is felt to be individuals in an HIV-serodiscordant relationship. Limitations to our study included a low response rate, changes in the evidence base, and the novelty of PrEP. PMID- 24053479 TI - Hydrogen-bond dynamics of water at the interface with InP/GaP(001) and the implications for photoelectrochemistry. AB - We investigate the structure, topology, and dynamics of liquid water at the interface with natively hydroxylated (001) surfaces of InP and GaP photoelectrodes. Using ab initio molecular dynamics simulations, we show that contact with the semiconductor surface enhances the water hydrogen-bond strength at the interface. This leads to the formation of an ice-like structure, within which dynamically driven water dissociation and local proton hopping are amplified. Nevertheless, the structurally similar and isovalent InP and GaP surfaces generate qualitatively different interfacial water dynamics. This can be traced to slightly more covalent-like character in the binding of surface adsorbates to GaP, which results in a more rigid hydrogen-bond network that limits the explored topological phase space. As a consequence, local proton hopping can give rise to long-range surface proton transport on InP, whereas the process is kinetically limited on GaP. This allows for spatial separation of individual stages of hydrogen-evolving, multistep reactions on InP(001). Possible implications for the mechanisms of cathodic water splitting and photocorrosion on the two surfaces are considered in light of available experimental evidence. PMID- 24053481 TI - Conversational pursuit of medication compliance in a Therapeutic Community for persons diagnosed with mental disorders. AB - PURPOSE: In this article, we contribute to the debate on medication compliance by exploring the conversational "technologies" entailed in the process of promoting clients' adherence to psychopharmacological prescriptions. Using a case study approach, we explore how medication-related problems are dealt with in conversational interaction between the staff members and the clients of a mental health Therapeutic Community (TC) in Italy. METHOD: Four meetings between two staff members (Barbara and Massimo) and the clients of the TC were audio recorded. The data were transcribed and analyzed using the method of Conversation Analysis. RESULTS: Barbara and Massimo recur to practices of topic articulation to promote talk that references the clients' failure to take the medications. Through these practices they deal with the practical problem of mobilizing the clients' cooperation in courses of action that fit into the institutional agenda of fostering medication adherence. CONCLUSIONS: Barbara and Massimo's conversational practices appear to reflect the assumption that medication-related problems can be reduced to compliance problems. This assumption works to make the clients accountable for their failure to take the medications while shaping a conversational environment that is unreceptive to their complaints about side effects. Implications for the understanding of mental health rehabilitation practice in TCs are discussed. Implications of Rehabilitation Therapeutic community staff members should be aware of the challenges and blocks in communicating with their clients. Therapeutic communities can promote staff members' awareness of communication challenges through reflective workshops in which they can jointly view and comment on interaction with their clients. Reflective workshops can be used to raise awareness of the presuppositions underlying therapeutic community staff members' communication practices. PMID- 24053480 TI - Efficacy of combination of Ezetimibe 10 mg and rosuvastatin 2.5 mg versus rosuvastatin 5 mg monotherapy for hypercholesterolemia in patients with type 2 diabetes. AB - BACKGROUND: Statins are used to treat hypercholesterolemia in patients with type 2 diabetes mellitus, but many of these patients fail to achieve the target LDL-C level. Recent reports have suggested that a synergistic effect can be obtained by concomitant administration of the cholesterol absorption inhibitor ezetimibe and a statin. However, in patients with type 2 diabetes who are already being treated with satins, it remains unclear whether it is more effective to add ezetimibe or to increase the statin dose. Therefore, this study was performed to examine the effects of these two regimens on LDL-C and lipoproteins. METHODS: The subjects were type 2 diabetic patients under treatment with rosuvastatin (2.5 mg daily), who had LDL-C levels >=80 mg/dL. They were randomly allocated to a group that received add-on therapy with ezetimibe at 10 mg/day (combination group, n = 40) or an increase of the rosuvastatin dose to 5 mg/day (dose escalation group, n = 39). These two groups were compared at baseline and after 12 weeks of treatment. RESULTS: The percent change of LDL-C was -31% in the combination group and -12% in the dose escalation group. Both groups showed a significant decrease, but the decrease was greater in the combination group. In both groups, there was a significant decrease in the levels of small dense LDL-C, oxidized LDL and remnant like lipoprotein cholesterol. For all of these parameters, the percent changes were greater in the combination group. Only the combination group showed a significant decrease of triglycerides. Multivariate analysis was performed to identify factors associated with reaching an LDL-C level <80 mg/dL. As a result, add-on therapy with ezetimibe was extracted as a factor related to improvement of LDL-C. CONCLUSIONS: Compared with increasing the dose of rosuvastatin, the combination of rosuvastatin and ezetimibe not only achieves quantitative but also qualitative improvement of serum lipid levels in type 2 diabetic patients, suggesting that this combination could suppress the progression of atherosclerosis. TRIAL REGISTRATION: UMIN000011005. PMID- 24053482 TI - Decreased antigenicity profiles of immune-escaped and drug-resistant hepatitis B surface antigen (HBsAg) double mutants. AB - BACKGROUND: Selective pressure from either the immune response or the use of nucleoside analogs in antiviral therapy could be driving the emergence of HBV mutants. Because of the overlap of the open reading frame (ORF) S for the HBsAg and ORF P for viral polymerase, rtM204I and rtM204V mutations in the polymerase would produce sI195M and sW196S in the HBsAg. The combined effects of immune escaped mutations (sT118M, sG145K, sG145R) and drug-resistant mutations (rtM204I, rtM204V) on the antigenicity profiles of HBsAg has not been widely explored. METHODS: To determine the combined effects of immune-escaped and drug-resistant mutants on the antigenicity profiles of HBsAg, recombinant plasmids encoding HBsAg double mutants were constructed using site-directed mutagenesis. The supernatant from each plasmid transfection was analyzed for HBsAg in the western blotting and five of the most commonly used commercial ELISA kits in China. RESULTS: Western-blotting assay showed the successful expression of each HBsAg mutant. All five ELISA kits manifested similar avidity, which were demonstrated by the slope of the curves, for the sT118M mutant, and sT118M-rtM204I (sT118M sI195M) and sT118M-rtM204V (sT118M-sW196S) double mutants, suggesting that drug resistant YMDD mutants caused negligible losses in the antigenicity of immune escaped sT118M HBsAg. In contrast, the presence of the rtM204I (sI195M) mutation, but not rtM204V (sW196S) in combination with the sG145K mutation significantly reduced the avidity of sG145K HBsAg. The rtM204I (sI195M) mutation also decreased the antigenicity profiles for sG145R HBsAg. CONCLUSIONS: Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R, which may hamper HBV diagnosis and disease control from HBV blood-transfusion transmissions in China. The development of ELISA kits with a greater sensitivity for drug resistant and immune-escaped HBsAg warrants further consideration. PMID- 24053483 TI - Soy and soy isoflavones in prostate cancer: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the evidence from randomized controlled trials (RCTs) on the efficacy and safety of soy/isoflavones in men with prostate cancer (PCa) or with a clinically identified risk of PCa. PATIENTS AND METHODS: MEDLINE, EMBASE, the Allied and Complementary Medicine (AMED), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the Cochrane Library databases were searched. We identified RCTs investigating soy/soy isoflavones as dietary supplements or dietary components for the secondary prevention or treatment of PCa in men with PCa or with a clinically identified risk of developing PCa. Studies of multi-component formulations were excluded. Six authors were contacted for further information for the meta-analyses. Methodological quality was assessed using the Cochrane Collaboration's risk-of- bias tool. The PRISMA statement for reporting systematic reviews was followed. RESULTS: Of the eight RCTs that met the inclusion criteria, six restricted recruitment to men diagnosed with PCa, while two included men with clinically identified risk of PCa. A large degree of heterogeneity was found with respect to dosages and preparations of soy/isoflavones administered. Most studies had small sample sizes and were of short duration. The risk of bias was assessed as low in all assessed studies except for one, for which the risk of bias was unclear. Meta-analyses of the two studies including men with identified risk of PCa found a significant reduction in PCa diagnosis after administration of soy/soy isoflavones (risk ratio = 0.49, 95% CI 0.26, 0.95). Meta-analyses indicated no significant differences between groups for prostate-specific antigen (PSA) levels or sex steroid endpoints (sex hormone-binding globulin [SHBG], testosterone, free testosterone, oestradiol and dihydrotestosterone). CONCLUSIONS: The results of a meta-analysis of two studies suggest there may be support for epidemiological findings of a potential role for soy/soy isoflavones in PCa risk reduction; however, a clear understanding of the impact of soy/isoflavones on PSA, total testosterone, free testosterone and SHBG levels in men with, or at identified risk of, PCa could not be derived from these data, given the limitations of sample size and study duration in individual trials. A good safety profile is shown by this meta-analysis for soy/soy isoflavones supplementation. PMID- 24053484 TI - CO2 migration pathways in oxalate decarboxylase and clues about its active site. AB - Oxalate decarboxylase catalyzes the decarboxylation of oxalate to formate and CO2 in the presence of molecular oxygen. This enzyme has two domains, each containing a Mn(II) ion coordinated with three histidine residues. The specific domain in which the decarboxylation process takes place is still a matter of investigation. Herein, the transport of the product, i.e., CO2, from the reaction center to the surface of the enzyme is studied using atomistic molecular dynamics simulations. The specific pathway for the migration of the molecule as well as its microscopic interactions with the amino acid residues lining the path is delineated. Further, the transport of CO2 is shown to occur in a facile manner from only domain I and not from domain II, indicating that the former is likely to be the active site of the enzyme. PMID- 24053485 TI - Nephron-sparing management vs radical nephroureterectomy for low- or moderate grade, low-stage upper tract urothelial carcinoma. AB - OBJECTIVE: To compare overall and cancer-specific outcomes between patients with upper tract urothelial carcinoma (UTUC) managed with either radical nephroureterectomy (RNU) or nephron-sparing measures (NSM) using a large population-based dataset. PATIENTS AND METHODS: Using Surveillance, Epidemiology, and End Results (SEER) data, patients diagnosed with low- or moderate-grade, localised non-invasive UTUC were stratified into two groups: those treated with RNU or NSM (observation, endoscopic ablation, or segmental ureterectomy). Cancer specific mortality (CSM) and other-cause mortality (OCM) rates were determined using cumulative incidence estimators. Adjusting for clinical and pathological characteristics, the associations between surgical type, all-cause mortality and CSM were tested using Cox regressions and Fine and Gray regressions, respectively. RESULTS: Of 1227 patients [mean (sd) age 70.2 (11.00) years, 63.2% male] meeting inclusion criteria, 907 (73.9%) and 320 (26.1%) patients underwent RNU and NSM for low- or moderate-grade, low-stage UTUC from 1992 to 2008. Patients undergoing NSM were older (mean age 71.6 vs 69.7 years, P < 0.01) with a greater proportion of well-differentiated tumours (26.3% vs 18.0%, P = 0.001). While there were differences in OCM between the groups (P < 0.01), CSM trends were equivalent. After adjustment, RNU treatment was associated with improved non cancer cause survival [hazard ratio (HR) 0.78, confidence interval [CI] 0.64 0.94) while no association with CSM was demonstrable (HR 0.89, CI 0.63-1.26). CONCLUSIONS: Patients with low- or moderate-grade, low-stage UTUC managed through NSM are older and are more likely to die of other causes, but they have similar CSM rates to those patients managed with RNU. These data may be useful when counselling patients with UTUC with significant competing comorbidities. PMID- 24053486 TI - How to predict cochlear length before cochlear implantation surgery. AB - CONCLUSIONS: The basal turn diameter of the human cochlea predicts the outer wall length of the basal and two first turns relatively well but there was less correlation for the total cochlear length. The linear regression graph defines the length of the basal turn within an error of +/- 1 mm and could be used clinically to distinguish small and large cochleae. OBJECTIVE: The human cochlea varies in size. The preoperative assessment of cochlear length can be crucial for non-traumatic electrode insertion and hearing preservation. In this study, we estimated the external cochlear wall length by assessing the basal turn diameter. METHODS: A total of 51 non-selected, human inner ear moulds were analysed. A line was drawn from the midpoint of the round window through the cochlear mid-portion to the opposite side (A) and correlated to the cochlear turn lengths. Linear regression analyses were carried out. RESULTS: Mean diameter A was 9.3 mm. The mean basal turn length was 22.8 mm, the two first turns were 35.1 mm and the total length was 41.2 mm. Linear regression analyses indicated a coefficient of determination (R(2)) of 0.74 for diameter A and the basal turn length, R(2) = 0.70 for the two-turn length and R(2) = 0.39 for the total length. PMID- 24053487 TI - Nod-like receptors in head and neck squamous cell carcinoma. AB - CONCLUSION: The capability of Nod1 to recognize bacteria along with its altered expression and ability to cause an immunological response in head and neck cancer suggest a novel pathway for bacteria to interfere with ongoing cancer inflammation. OBJECTIVE: Nucleotide oligomerization domain (Nod)-like receptors (NLRs) comprise a recently discovered family of pattern-recognition receptors. In addition to their protective function against infections, accumulating evidence suggests a role for these receptors in various diseases, including cancer. The present study was designed to explore the presence of NLRs in head and neck squamous cell carcinoma, and to determine if these cells have the ability to respond immunologically to ligand stimulation. METHODS: The pharyngeal squamous cell carcinoma cell lines Detroit-562 and FaDu were used as a model for head and neck cancer, and compared to healthy primary human nasal epithelial cells. Analyses were performed using immunohistochemistry, real-time RT-PCR, Luminex Multiplex Immunoassay, ELISA, and flow cytometry. RESULTS: The expression profile of NLRs in head and neck cancer cells differed from that seen in healthy epithelial cells. Further, Nod1 stimulation induced an immunological response in tumor cells that differed from the response in normal epithelial cells, especially regarding the expression of beta-defensin 2, granulocyte monocyte colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G CSF), intercellular adhesion molecule-1 (ICAM-1), and cell survival. PMID- 24053488 TI - Prevalence and classification of rhinitis in preschool children in Portugal: a nationwide study. AB - BACKGROUND: Information on rhinitis epidemiology in preschool children is scarce. OBJECTIVES: To estimate, in children with 3-5 years of age, current rhinitis prevalence, to describe rhinitis symptoms and associated sociodemographic characteristics, and to report allergic rhinitis and its impact on asthma (ARIA) classification. METHODS: Cross-sectional, nationwide, population-based study including children aged 3-5 years. A multistep selection strategy was used to obtain a representative sample. Data were collected at kindergartens and parish centers by face-to-face interview to caregivers, using an adapted ISAAC questionnaire. 'Current rhinitis' (CR) was defined as the presence of >=1 rhinitis symptom (repeated sneezing and/or itchy nose, blocked nose for >1 h, or runny nose without having a cold/flu) in the last year. Rhinitis lasting >=4 days/week and >=4 consecutive weeks was classified as persistent. Moderate-severe disease interfered 'a moderate amount' or 'a lot' in daily activities. RESULTS: Five thousand and eighteen children were included. CR prevalence was 43.4% [95% CI (42.0-44.8%); n = 2179] and that of physician-diagnosed rhinitis was 11.7% [95% CI (10.8-12.6%); n = 588]. Of children with CR, 67% reported blocked nose, 48% rhinorrhea, and 46% sneezing/itchy nose. Considering ARIA classification, 30% of the population had mild intermittent, 3% mild persistent, 7% moderate-severe intermittent, and 3% moderate-severe persistent rhinitis. Children with CR had more current wheezing, physician-diagnosed asthma, self-reported food allergy, and family history of allergic disease. These characteristics were also associated with persistent and moderate-severe rhinitis. CONCLUSIONS: This is the first nationwide population-based study reporting rhinitis prevalence and ARIA classification in preschool children. In this age-group, rhinitis is frequent and underdiagnosed. About 25% children with rhinitis presented moderate-severe disease. PMID- 24053489 TI - Caring for relatives with chronic obstructive pulmonary disease: how does the disease severity impact on family carers? AB - OBJECTIVES: Chronic Obstructive Pulmonary Disease (COPD) is a major cause of disability, morbidity and mortality in old age, representing a significant burden for families. However, information on the impacts of caring for relatives with COPD on carers' psychological health is limited. This study aimed to analyse the subjective burden of family carers of people with early and advanced COPD and its predictor variables. METHODS: A cross-sectional study was conducted. A structured questionnaire was used to collect socio-demographics and care-giving characteristics. Self-rated physical and mental health were measured by two items from the International Classification of Functioning, Disability and Health checklist. The Hospital Anxiety and Depression Scale was used to assess anxiety and depression. Subjective burden was assessed with the Carers' Assessment of Difficulties Index (CADI). Descriptive and inferential analyses were performed. RESULTS: A total of 167 family carers participated: 113 were caring for people with early and 54 with advanced COPD. Both groups presented anxiety/depression symptoms. Those caring for people with advanced COPD reported higher subjective burden, more depression symptoms and poorer self-rated mental health than those caring for early COPD. Advanced COPD (coefficient 6.7), depression (coefficient 6.3), anxiety (coefficient 5.6), care-giving hours per week (coefficient 3.2) and self-rated mental health (coefficient 2.8) were significant predictors of carers' subjective burden. CONCLUSION: The findings suggest that the gradual course of COPD imposes an increasing physical and emotional burden on carers, with negative impacts on their psychological health. The study highlights the relevance of early interventions in the context of COPD to prevent carers' burden. PMID- 24053490 TI - Bodyweight loss in predicting neonatal hyperbilirubinemia 72 hours after birth in term newborn infants. AB - BACKGROUND: Severe dehydration is generally believed to be a cause of significant hyperbilirubinemia in newborn babies. This study aimed to analyze the weight loss of healthy term newborn infants at 24, 48 and 72 hours after birth to predict significant hyperbilirubinemia at 72 hours. METHODS: From January 2007 to December 2008, we conducted this retrospective chart review by measuring total bilirubin (transcutaneous and serum) in 343 healthy, term newborns with a birth body weight of more than 2500 g. We then analyzed the association between body weight loss (BWL) and significant hyperbilirubinemia (total bilirubin more than 15 mg/dL) 72 hours after birth. Receiver operating characteristic curves were used to evaluate the appropriate cutoff BWL percentages on the first three days after birth for the prediction of neonatal hyperbilirubinemia 72 hours after birth. RESULTS: A total of 115 (33.5%) neonates presented with significant hyperbilirubinemia 72 hours after birth, and the percentages of BWL on the first three days were all higher than those in the non-significant hyperbilirubinemia group (all p < 0.05). Breastfeeding was not statistically correlated with significant hyperbilirubinemia (p=0.86). To predict significant hyperbilirubinemia 72 hours after birth, receiver operating characteristic curve analysis showed that the optimum cutoff BWL percentages were 4.48% on the first day of life (sensitivity: 43%, specificity: 70%, positive likelihood ratio [LR+]: 1.43, and negative likelihood ratio [LR-]: 0.82), 7.60% on day 2 (sensitivity: 47%, specificity: 74%, LR+: 1.81, LR-: 0.72), and 8.15% on day 3 (sensitivity: 57%, specificity: 70%, LR+: 1.92, LR-: 0.61) (all p < 0.05). CONCLUSIONS: BWL on the first three days after birth may be a predisposing factor for neonatal hyperbilirubinemia, and may also serve as a helpful clinical factor to prevent significant hyperbilirubinemia 72 hours after birth. The optimal BWL cutoff percentages on the first three days after birth presented in this study may predict hyperbilirubinemia and indicate the need for supplementary feeding. PMID- 24053491 TI - Multicomponent combinatorial development and conformational analysis of prolyl peptide-peptoid hybrid catalysts: application in the direct asymmetric Michael addition. AB - A solution-phase combinatorial approach based on the Ugi four-component reaction was implemented for the development of new prolyl peptide-peptoid hybrid catalysts. Three different elements of diversity were varied during the creation of the set of catalysts: the amine, oxo, and isocyano components. The multicomponent nature of this process enabled the straightforward generation of a series of peptide-peptoid hybrids having the generic sequence Pro-N-R(1)-Xaa NHR(3), with Xaa being either Gly (R(2) = H) or Aib (R(2) = gem-Me) and R(1) and R(3) either alkyl or amino acid substituents. The catalytic behavior of the peptide-peptoid hybrids was assessed in the asymmetric conjugate addition of aldehydes to nitroolefins, where most of the catalysts showed great efficacy and rendered the Michael adducts with good to excellent enantio- and diastereoselectivity. A molecular modeling study was performed for two distinct catalysts aiming to understand their conformational features. The conformational analysis provided important information for understanding the remarkable stereocontrol achieved during the organocatalytic transformation. PMID- 24053493 TI - Hollow, spherical nitrogen-rich porous carbon shells obtained from a porous organic framework for the supercapacitor. AB - Hollow, spherical nitrogen-rich porous carbon shells were prepared as supercapacitor electrode materials through the carbonization of structure controlled porous organic frameworks at high temperature. The structure and electrochemical properties of the resulting carbonized materials were systematically characterized. Experimental results revealed that the nitrogen rich hollow carbon spheres obtained at 800 degrees C were a kind of amorphous carbon with micropores on the shell frame and with specific surface areas as high as 525 m2 g(-1). The prepared porous carbon possessed a specific capacitance of 230 F g(-1) at a current density of 0.5 A g(-1) and could retain ~98% of the initial capacitance after 1500 successive charge-discharge cycles. Electrochemical impedance spectroscopy indicated that the material has a small equivalent series resistance (0.62 Omega). All of these values demonstrated that the prepared porous carbon is a promising supercapacitor material. The proposed method represents a simple approach towards the preparation of unique structures of nitrogen-containing porous carbon that exhibit the advantages of having a simple preparation process, a wide availability of precursors, flexible control of the structure, and an easier adjustment of the amount of heteroatoms. PMID- 24053492 TI - An easy operating pathogen microarray (EOPM) platform for rapid screening of vertebrate pathogens. AB - BACKGROUND: Infectious diseases emerge frequently in China, partly because of its large and highly mobile population. Therefore, a rapid and cost-effective pathogen screening method with broad coverage is required for prevention and control of infectious diseases. The availability of a large number of microbial genome sequences generated by conventional Sanger sequencing and next generation sequencing has enabled the development of a high-throughput high-density microarray platform for rapid large-scale screening of vertebrate pathogens. METHODS: An easy operating pathogen microarray (EOPM) was designed to detect almost all known pathogens and related species based on their genomic sequences. For effective identification of pathogens from EOPM data, a statistical enrichment algorithm has been proposed, and further implemented in a user friendly web-based interface. RESULTS: Using multiple probes designed to specifically detect a microbial genus or species, EOPM can correctly identify known pathogens at the species or genus level in blinded testing. Despite a lower sensitivity than PCR, EOPM is sufficiently sensitive to detect the predominant pathogens causing clinical symptoms. During application in two recent clinical infectious disease outbreaks in China, EOPM successfully identified the responsible pathogens. CONCLUSIONS: EOPM is an effective surveillance platform for infectious diseases, and can play an important role in infectious disease control. PMID- 24053494 TI - A positive real-time elastography is an independent marker for detection of high risk prostate cancers in the primary biopsy setting. AB - OBJECTIVE: To evaluate the performance of real-time elastography (RTE) in an initial biopsy setting. PATIENTS AND METHODS: In the period from February 2011 to June 2012, 127 consecutive patients were included in the study. We used a Hitachi Preirus with Hi-RTE module, a prostate end-fire transrectal probe was used for RTE and for targeted biopsies, and a simultaneous biplane probe was used for the standard systematic biopsies. The peripheral zone of the prostate was divided into six regions, and each biopsy obtained was referred to a specific region. All patients were first examined with RTE and, if cancer was suspected, targeted biopsies were taken. A standard systematic 10-core biopsy was then taken in all patients. RESULTS: In all, 64 (50%) patients were diagnosed with prostate cancer in the initial biopsy setting. Three patients were diagnosed solely on RTE targeted biopsies, 31 were found only in systematic biopsies, and 30 were correctly diagnosed with both methods. In the RTE-positive group there was a significantly higher frequency of positive cores, a lower prostate volume, a higher Gleason score, and a higher fraction of cancer tissue in each core. In a multiple regression model RTE was an independent marker for high-risk cancer. The sensitivity of 42% for all prostate cancers increased to 60% for high-grade prostate cancers. Similarly, the negative predictive value increased from 79% to 97%. An additional eight patients were diagnosed with prostate cancer during the study period. CONCLUSIONS: A positive RTE is an independent marker for detection of high-risk prostate cancer, and a negative RTE argues against such. RTE with targeted biopsies cannot replace systematic biopsies, but provides valuable additional information about the tumours. PMID- 24053495 TI - Awake craniotomy. PMID- 24053496 TI - Delayed postoperative hyponatremia after transsphenoidal surgery: prevalence and associated factors. AB - OBJECT: Transient delayed postoperative hyponatremia (DPH) after transsphenoidal surgery (TSS) is common and can have potentially devastating consequences. However, the true prevalence of transient symptomatic and asymptomatic DPH has not been studied in a large patient cohort with close and accurate follow-up. METHODS: A retrospective analysis of a single-institution prospective database was conducted; all patients undergoing TSS for lesions involving the pituitary gland were followed up in a multidisciplinary neuroendocrine clinic, and demographic, imaging, and clinical data were prospectively collected. Patients were examined preoperatively and followed up postoperatively in a standardized fashion, and their postoperative sodium levels were measured at Weeks 1 and 2 postoperatively. Levels of hyponatremia were rated as mild (serum sodium concentration 130-134 mEq/L), moderate (125-129 mEq/L), or severe (< 125 mEq/L). Routine clinical questionnaires were administered at all postoperative office visits. Postoperative hyponatremia was analyzed for correlations with demographic and clinical features and with immediate postoperative physiological characteristics. RESULTS: Over a 4-year interval, 373 procedures were performed in 339 patients who underwent TSS for sellar and parasellar lesions involving the pituitary gland. The mean (+/- SD) age of patients was 48 +/- 18 years; 61.3% of the patients were female and 46.1% were obese (defined as a body mass index [BMI] >= 30). The overall prevalence of DPH within the first 30 days postoperatively was 15.0%; 7.2% of the patients had mild, 3.8% moderate, and 3.8% severe hyponatremia. The incidence of symptomatic hyponatremia requiring hospitalization was 6.4%. The Fisher exact test detected a statistically significant association of DPH with female sex (p = 0.027) and a low BMI (p = 0.001). Spearman rank correlation detected a statistically significant association between BMI and nadir serum sodium concentration (r = 0.158, p = 0.002) and an inverse association for age (r = -0.113, p = 0.031). Multivariate analyses revealed a positive correlation between postoperative hyponatremia and a low BMI and a trend toward association with age; there were no associations between other preoperative demographic or perioperative risk factors, including immediate postoperative alterations in serum sodium concentration. Patients were treated with standardized protocols for hyponatremia, and DPH was not associated with permanent morbidity or mortality. CONCLUSIONS: Delayed postoperative hyponatremia was a common result of TSS; a low BMI was the only clear predictor of which patients will develop DPH. Alterations in immediate postoperative sodium levels did not predict DPH. Therefore, an appropriate index of suspicion and close postoperative monitoring of serum sodium concentration should be maintained for these patients, and an appropriate treatment should be undertaken when hyponatremia is identified. PMID- 24053497 TI - Effect of dural detachment on long-term tumor control for meningiomas treated using Simpson grade IV resection. AB - OBJECT: Meningiomas treated by subtotal or partial resection are associated with significantly shorter recurrence-free survival than those treated by gross-total resection. The Simpson grading system classifies incomplete resections into a single category, namely Simpson Grade IV, with wide variations in the volume and location of residual tumors, making it complicated to evaluate the achievement of surgical goals and predict the prognosis of these tumors. Authors of the present study investigated the factors related to necessity of retreatment and tried to identify any surgical nuances achievable with the aid of modern neurosurgical techniques for meningiomas treated using Simpson Grade IV resection. METHODS: This retrospective analysis included patients with WHO Grade I meningiomas treated using Simpson Grade IV resection as the initial therapy at the University of Tokyo Hospital between January 1995 and April 2010. Retreatment was defined as reresection or stereotactic radiosurgery due to postoperative tumor growth. RESULTS: A total of 38 patients were included in this study. Regrowth of residual tumor was observed in 22 patients with a mean follow-up period of 6.1 years. Retreatment was performed for 20 of these 22 tumors with regrowth. Risk factors related to significantly shorter retreatment-free survival were age younger than 50 years (p = 0.006), postresection tumor volume of 4 cm(3) or more (p = 0.016), no dural detachment (p = 0.001), and skull base location (p = 0.016). Multivariate analysis revealed that no dural detachment (hazard ratio [HR] 6.42, 95% CI 1.41-45.0; p = 0.02) and skull base location (HR 11.6, 95% CI 2.18-218; p = 0.002) were independent risk factors for the necessity of early retreatment, whereas postresection tumor volume of 4 cm(3) or more was not a statistically significant risk factor. CONCLUSIONS: Compared with Simpson Grade I, II, and III resections, Simpson Grade IV resection includes highly heterogeneous tumors in terms of resection rate and location of the residual mass. Despite the difficulty in analyzing such diverse data, these results draw attention to the favorable effect of dural detachment (instead of maximizing the resection rate) on long term tumor control. Surgical strategy with an emphasis on detaching the tumor from the affected dura might be another important option in resection of high risk meningiomas not amenable to gross-total resection. PMID- 24053498 TI - Hypertonic saline. PMID- 24053499 TI - Quality of life following endoscopic endonasal resection of anterior skull base cancers. AB - OBJECT: For several decades, the exclusive purpose in the management of anterior skull base malignancies has been to increase survival rates. Recently, given the improved prognosis achieved, more attention has been focused on quality of life (QOL) as well. Producing data on QOL in anterior skull base cancers is hampered by the rarity of the neoplasm and the lack of specific questionnaires. The purpose of this study was to assess health-related QOL in a large and homogeneous cohort of patients affected by anterior skull base cancers who had undergone endoscopic endonasal resection. METHODS: The authors conducted a retrospective review of patients treated for sinonasal and skull base cancers via an endoscopic endonasal approach at two Italian tertiary care referral centers. All patients were asked to complete the Anterior Skull Base Surgery Questionnaire to evaluate their QOL before and 1 month and 1 year after surgical treatment. To assess which parameters affect QOL, the study population was divided into subgroups according to age, sex, stage of disease, surgical approach, and adjuvant therapy. RESULTS: One hundred fifty-three patients were enrolled in this study according to the adopted inclusion criteria. Overall QOL started at a score of 4.68 for the preoperative period, sharply decreased as far as a score of 4.03 during the 1st postoperative month, and rose again to a score of 4.59 over the course of 1 year after treatment, with a significant difference among the 3 values (p < 0.05). The specific symptoms and physical status domains registered poorer results at the 1 year assessment (4.00 and 4.71, respectively) than at the preoperative assessment (both domains 4.86), with a statistically significant reduction in scores (p < 0.05). Worse outcomes were associated with several variables: age > 60 years (difference of 0.21 points between the preoperative and 1-year period, p < 0.05), expanded surgical approaches with transnasal craniectomy (decrease of 0.20 points between the preoperative and 1-year period, p < 0.05), and postoperative radiotherapy (score of 4.53 at the 1-year period vs. 4.70 in patients without any adjuvant treatment, p < 0.05). No statistically significant differences were found when analyzing the study population according to sex (p > 0.1) and T classification of disease at presentation (p > 0.05). CONCLUSIONS: Radical endoscopic endonasal resection led to either complete or at least partial recovery of patient QOL within the 1st postoperative year. PMID- 24053500 TI - Dural detachment and long-term tumor control in unresectable meningiomas. PMID- 24053501 TI - Craniopharyngiomas and the hypothalamus. PMID- 24053502 TI - Individualized surgical strategies for Rathke cleft cyst based on cyst location. AB - OBJECT: An assessment regarding both surgical approaches and the extent of resection for Rathke cleft cysts (RCCs) based on their locations has not been reported. The aim of this study was to report the results of a large series of surgically treated patients with RCCs and to evaluate the feasibility of individualized surgical strategies for different RCCs. METHODS: We retrospectively reviewed 87 cases involving patients with RCCs (16 intrasellar, 50 intra- and suprasellar, and 21 purely suprasellar lesions). Forty-nine patients were treated via a transsphenoidal (TS) approach, and 38 were treated via a transcranial (TC) approach (traditional craniotomy in 21 cases and supraorbital keyhole craniotomy in 17). The extent of resection was classified as gross-total resection (GTR) or subtotal resection (STR) of the cyst wall. Patients were thus divided into 3 groups according to the approach selected and the extent of resection: TS/STR (n = 49), TC/STR (n = 23), and TC/GTR (n = 15). RESULTS: Preoperative headaches, visual dysfunction, hypopituitarism, and diabetes insipidus (DI) resolved in 85%, 95%, 55%, and 65% of patients, respectively. These rates did not differ significantly among the 3 groups. Overall, complications occurred in 8% of patients in TS/STR group, 9% in TC/STR group, and 47% in TC/GTR group, respectively (p = 0.002). Cerebrospinal fluid (CSF) leakage (3%), new hypopituitarism (9%), and DI (6%) were observed after surgery. All CSF leaks occurred in the endonasal group, while the TC/GTR group showed a higher rate of postoperative hypopituitarism (p = 0.7 and p < 0.001, respectively). It should be particularly noted that preoperative hypopituitarism and DI returned to normal, respectively, in 100% and 83% of patients who underwent supraorbital surgery, and with the exception of 1 patient who had transient postoperative DI, there were no complications in patients treated with supraorbital surgery. Kaplan-Meier 3-year recurrence-free rates were 84%, 87%, and 86% in the TS/STR, TC/STR, and TC/GTR groups, respectively (p = 0.9). CONCLUSIONS: It is reasonable to adopt individualized surgical strategies for RCCs based on cyst location. Gross-total resection does not appear to reduce the recurrence rate but increase the risk of postoperative complications. The endonasal approach seems more appropriate for primarily intrasellar RCCs, while the craniotomy is recommended for purely or mainly suprasellar cysts. The supraorbital route appears to be preferred over traditional craniotomy for its minimal invasiveness and favorable outcomes. The endoscopic technique is helpful for either endonasal or supraorbital surgery. PMID- 24053503 TI - Selection of intraoperative tasks for awake mapping based on relationships between tumor location and functional networks. AB - Intraoperative electrical brain mapping is currently the most reliable method to identify eloquent cortical and subcortical structures at the individual level and to optimize the extent of resection of intrinsic brain tumors. The technique allows the preservation of quality of life, not only allowing avoidance of severe neurological deficits but also facilitating preservation of high neurocognitive functions. To accomplish this goal, however, it is crucial to optimize the selection of appropriate intraoperative tasks, given the limited intrasurgical awake time frame. In this review, the authors' aim was to propose specific parameters that could be used to build a personalized protocol for each patient. They have focused on lesion location and relationships with functional networks to guide selection of intrasurgical tasks in an effort to increase reproducibility among neurooncological centers. PMID- 24053504 TI - Safety and efficacy of early thromboembolism chemoprophylaxis after intracranial hemorrhage from traumatic brain injury. AB - OBJECT: Patients with traumatic brain injury (TBI) are at risk for development of thromboembolic disease. The use of chemoprophylaxis in this patient group has not fully been characterized. The authors hypothesize that early chemoprophylaxis in patients with TBI is safe and efficacious. METHODS: In May 2009, a protocol was instituted for patients with TBI where chemoprophylaxis for thromboembolic disease (either 30 mg of Lovenox twice daily or 5000 U of heparin 3 times a day) was initiated 24 hours after an intracranial hemorrhage (ICH) was demonstrated as stable on head CT image. Two cohorts were evaluated: Cohort A included patients from May 2008 through April 2009 who had no routine administration of chemoprophylaxis, and Cohort B included patients from May 2009 through May 2010 after the protocol was instituted. The groups were compared, with the major outcomes being deep venous thrombosis (DVT), pulmonary embolism, and increase in size of ICH. RESULTS: Of the 312 patients with TBI who were seen during the study course, 236 patients met criteria for inclusion in the study: 107 patients in Cohort A and 129 patients in Cohort B. The DVT rate was 6 occurrences (5.61%) in Cohort A and 0 occurrences (0%) in Cohort B, which was a statistically significant difference (p = 0.0080). Pulmonary embolism was found in 4 patients (3.74%) in Cohort A and 1 patient (0.78%) in Cohort B, a difference that did not reach statistical significance (p = 0.18). Three instances (2.8%) in Cohort A and 1 instance (0.7%) in Cohort B of increased ICH occurred after starting anticoagulation for chemoprophylaxis; this was not statistically different (p = 0.33). CONCLUSIONS: Use of chemoprophylaxis in TBI 24 hours after stable head CT is safe and decreases the rate of DVT formation. PMID- 24053505 TI - Rupture of lenticulostriate artery aneurysms. AB - The authors report on 3 rare cases of ruptured lenticulostriate artery (LSA) aneurysms that were heralded by deep cerebral hematomas. The hematomas were unilateral in 2 cases and bilateral in 1; in the bilateral case, only a single LSA aneurysm could be identified on the right side of the brain. Because of their small size (<= 2 mm), fusiform aspect, and deep location within the brain, all of the aneurysms were treated conservatively. There was no hemorrhage recurrence, and follow-up angiography demonstrated spontaneous thrombosis in 2 of the 3 cases. The clinical course was favorable in 2 of the 3 patients. The course in the patient with the bilateral hematoma was marked by an ischemic event after the initial episode, resulting in an aggravation of deficits. The cause of this second event was uncertain. Because our knowledge about the natural history of LSA aneurysms is incomplete, there is no consensus concerning a therapeutic strategy. The authors' experience in 3 reported cases leads them to think that a conservative approach involving close angiographic monitoring may be proposed as first-line treatment. If the monitored aneurysm then persists or grows in size, its occlusion should be considered. Nonetheless, other studies are needed to further strengthen the legitimacy of this strategy. PMID- 24053506 TI - The broad autism phenotype predicts child functioning in autism spectrum disorders. AB - BACKGROUND: Broad autism phenotype (BAP) is a milder expression of the social and communication impairments seen in autism spectrum disorders (ASD). While prior studies characterized the BAP in unaffected family members of probands with ASD, the relationship between parental BAP traits and proband symptomatology remains poorly understood. This study utilizes the Broad Autism Phenotype Questionnaire (BAPQ) in parents and the Social Responsiveness Scale (SRS) in children to examine this connection. We hypothesized that in families affected by ASD, elevated maternal and paternal BAPQ scores would correlate with greater autism symptomatology in diagnosed children. In an extension of prior research, we also explored this relationship in families with typically developing children (TDC). METHODS: Two hundred and forty-five children with ASD, 129 TDC and all parents were recruited as part of a larger study investigating relationships between genes, brain and behavior. The Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS) and expert clinical judgment confirmed ASD diagnoses in children. SRS was collected for all children. Parents completed a self-report BAPQ and an informant report BAPQ for their spouse; an average of self-report and informant report for each parent was used in all analyses. RESULTS: Mothers and fathers of children with ASD had significantly higher rates of BAP traits as compared to parents of TDC. Maternal and paternal BAPQ total scores were not correlated with child IQ in either group. In the ASD group, 10% of mothers and 21% of fathers scored above the established BAP threshold compared to 4% of TDC parents. Crude regression analyses showed that maternal and paternal BAPQ total scores accounted for significant variance in child SRS scores in both ASD (17.1%) and TDC (19.8%) families. CONCLUSIONS: Our results suggest that broad autism symptomatology in parents is moderately associated with their child's autism symptomatology. This result extended to TDC families, suggesting that the BAPQ and SRS capture subtle, subclinical social variation in both children and adults. These findings could help define multi generational social impairments in future phenotypic and genetic studies. PMID- 24053507 TI - Outcomes after recto-anastomosis fistula repair in patients who underwent radical prostatectomy for prostate cancer. AB - OBJECTIVES: To assess fistula recurrence rate and health-related quality of life (HRQL) after repair, as well as the impact on continence and erection in patients with recto-anastomotic fistula after radical prostatectomy (RP). In recent publications, the numbers of cases of recto-urinary fistulae after RP are relatively small. Success rates at fistula closure are good; however, data about functional outcomes and HRQL are more restricted. PATIENTS AND METHODS: A retrospective study of patients treated for recto-urethral fistulae after RP between 1993 and 2008. All 17 patients were assessed for fistula recurrence in 2007 and received a standardised non-validated questionnaire to assess HRQL in 2011; furthermore, a patient's chart review was performed. SURGICAL TECHNIQUE: fistula closure was abdominal in 10 patients, perineal in five and combined abdominal and perineal in two, some with tissue interposition. RESULTS: In 2007, follow-up was available for 14 patients, one was deceased and two were lost to follow-up. The mean follow-up was 73.3 months and the mean patient age was 63 years. In two of the 17 patients, rectal injury during the initial surgery was reported; another three had undergone adjuvant radiation therapy (18%). In 2011, another two patients were deceased; the mean (range) follow-up was 99.5 (44-184) months. There was a great improvement in HRQL as compared with before surgery in seven of the 12 evaluable patients, a slight improvement in one and no change in three. In all, eight of the 12 patients were very satisfied with the surgery and four were satisfied. CONCLUSION: Perineal or abdominal fistula repair yields excellent success rates and high patient satisfaction. However, urinary incontinence can be found in some patients postoperatively, requiring further treatment. PMID- 24053508 TI - The impact of nurse practitioners on care delivery in the emergency department: a multiple perspectives qualitative study. AB - BACKGROUND: Despite well-articulated benefits, the introduction of Nurse Practitioners (NPs) in Australia has been slow. Poorly defined nomenclature relating to advanced practice roles in nursing and variations in such roles both across Australia and worldwide have resulted in confusion and uncertainty regarding the functions and roles of NPs. Qualitative studies focussing on the perceived impact on the care settings into which NPs are introduced are scarce, but are valuable in providing a complete contextual account of NPs in care delivery settings. This study aimed to investigate the perceived impact of the NP on the delivery of care in the ED by senior doctors, nurses, and NPs. Results will facilitate adoption and best use of this human resource innovation. METHODS: A cross-sectional qualitative study was undertaken in the Emergency Departments (EDs) of two large Australian metropolitan public teaching hospitals. Semi structured, in-depth interviews were conducted with five nurse practitioners, four senior doctors (staff specialists and ED directors) and five senior nurses. Transcribed interviews were analysed using a grounded theory approach to develop themes in relation to the conceptualisation of the impact of the NP role on the ED. Member checking of results was conducted by revisiting the sites to clarify findings with participants and further explore emergent themes. RESULTS: The impact of the NP role was perceived differently by different groups of participants. Whilst NPs were observed to deliver few quantitative improvements to ED functioning from the perspective of ED directors, NPs believed that they assisted doctors in managing the increasing subacute presentations to the contemporary ED. NPs also believed they embraced a preventative paradigm of care which addressed the long term priorities of chronic disease prevention and cost containment in the broader healthcare environment. The ambiguous position of the NP role, which crosses the gap between nursing and medicine, emerged and resulted in a duality of NP governance. CONCLUSIONS: Interpretation of the NPs' role occurred through different frames of reference. This has implications for the development of the NP role in the ED. Collaboration and dialogue between various stakeholders, such as ED doctors and senior nursing management is required. PMID- 24053509 TI - Validation of an osteoporosis self-assessment tool to identify primary osteoporosis and new osteoporotic vertebral fractures in postmenopausal Chinese women in Beijing. AB - BACKGROUND: This study aimed to validate the effectiveness of the Osteoporosis Self-assessment Tool for Asians (OSTA) in identifying postmenopausal women at increased risk of primary osteoporosis and painful new osteoporotic vertebral fractures in a large selected Han Chinese population in Beijing. METHODS: We assessed the performance of the OSTA in 1201 women. Subjects with an OSTA index > -1 were classified as the low risk group, and those with an index <= -1 were classified as the increased risk group. Osteoporosis is defined by a T-score <= 2.5 standard deviations according to the WHO criteria. All painful, new vertebral fractures were identified by X-ray and MRI scans with correlating clinical signs and symptoms. We determined the sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve for correctly selecting women with osteoporosis and painful new vertebral fractures. RESULTS: Of the study subjects, 29.3% had osteoporosis, and the prevalence of osteoporosis increased progressively with age. The areas under the ROC curves of the OSTA index (cutoff = -1) to identify osteoporosis in the femoral neck, total hip, and lumbar spine were 0.824, 0.824, and 0.776, respectively. The sensitivity and specificity of the OSTA index (cutoff = -1) to identify osteoporosis in healthy women were 66% and 76%, respectively. With regard to painful new vertebral fractures, the area under the ROC curve relating the OSTA index (cutoff = -1) to new vertebral fractures was 0.812. CONCLUSIONS: The OSTA may be a simple and effective tool for identifying the risk of osteoporosis and new painful osteoporotic vertebral fractures in Han Chinese women. PMID- 24053510 TI - Comparison of contemporary methods for estimating prostate tumour volume in pathological specimens. AB - OBJECTIVE: To evaluate the accuracy of various prostate tumour volume (TV) estimation methods. To determine the most appropriate estimation method for current clinical practice. PATIENTS AND METHODS: Radical prostatectomy (RP) specimens from multiple institutions were analysed by a single uro-pathologist between September 2009 and May 2011. Tumour properties including thickness, width and length were collected and TV was established using computer-assisted image analysis (CAIA). TV estimation methods including; square, cuboidal and ellipsoidal estimations were calculated using previously reported formulae. The estimation methods were compared against the 'gold-standard' and the accuracy of identifying clinically significant tumours of TV >=0.5 cc was determined. RESULTS: In all, 299 consecutive specimens were analysed by a single uropathologist. The median index TV on CAIA was 1.42 cc. Of the four estimation methods, the ellipsoid methods produced the closest correlation with the gold standard (r(2) 0.91, P = 0.71). This correlation lost accuracy when larger tumours (TV >4 cc) were excluded from the analysis (r(2) = 0.73, P = 0.003). Sensitivity and specificity for identifying clinically significant tumours was 94% and 92% respectively, when using the ellipsoid estimation. CONCLUSIONS: In current uro-pathology, the ellipsoidal estimation method appears to be the most suitable for estimating TV in prostate cancers. This method is cheap, reproducible and sensitive and can be safely used as a surrogate for CAIA volumes when such technology is not available. PMID- 24053511 TI - The first national clinical audit of prostate cancer care. PMID- 24053513 TI - Evaluation of ABO blood group as a prognostic marker in renal cell carcinoma (RCC). AB - OBJECTIVE: To evaluate ABO blood group as a prognostic marker in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: This retrospective study included 556 consecutive patients who underwent surgery for RCC at a single institution. The associations of ABO blood group with clinical and pathological variables were assessed using Kruskal-Wallis and chi-squared tests. The impact on overall survival (OS) and RCC-specific survival (RCC-SS) was analysed using univariable and multivariable Cox proportional hazards regression models. RESULTS: Blood group O was associated with the absence of lymph node metastases (P = 0.034) and the presence of bilateral RCC (P = 0.017). No associations with age, gender, body mass index, Charlson comorbidity index, T stage, M stage, grade and histological subtype were observed. In univariable and multivariable survival analysis, ABO blood group was not associated with OS and RCC-SS. CONCLUSIONS: In the present study, ABO blood group was not linked with RCC prognosis. Blood group O may be associated with the absence of lymph node metastases and the presence of bilateral RCC. External validation in larger cohorts is necessary. PMID- 24053512 TI - Identification of genes expressed in the sex pheromone gland of the black cutworm Agrotis ipsilon with putative roles in sex pheromone biosynthesis and transport. AB - BACKGROUND: One of the challenges in insect chemical ecology is to understand how insect pheromones are synthesised, detected and degraded. Genome wide survey by comparative sequencing and gene specific expression profiling provide rich resources for this challenge. A. ipsilon is a destructive pest of many crops and further characterization of the genes involved in pheromone biosynthesis and transport could offer potential targets for disruption of their chemical communication and for crop protection. RESULTS: Here we report 454 next generation sequencing of the A. ipsilon pheromone gland transcriptome, identification and expression profiling of genes putatively involved in pheromone production, transport and degradation. A total of 23473 unigenes were obtained from the transcriptome analysis, 86% of which were A. ipsilon specific. 42 transcripts encoded enzymes putatively involved in pheromone biosynthesis, of which 15 were specifically, or mainly, expressed in the pheromone glands at 5 to 120-fold higher levels than in the body. Two transcripts encoding for a fatty acid synthase and a desaturase were highly abundant in the transcriptome and expressed more than 40-fold higher in the glands than in the body. The transcripts encoding for 2 acetyl-CoA carboxylases, 1 fatty acid synthase, 2 desaturases, 3 acyl-CoA reductases, 2 alcohol oxidases, 2 aldehyde reductases and 3 acetyltransferases were expressed at a significantly higher level in the pheromone glands than in the body. 17 esterase transcripts were not gland specific and 7 of these were expressed highly in the antennae. Seven transcripts encoding odorant binding proteins (OBPs) and 8 encoding chemosensory proteins (CSPs) were identified. Two CSP transcripts (AipsCSP2, AipsCSP8) were highly abundant in the pheromone gland transcriptome and this was confirmed by qRT-PCR. One OBP (AipsOBP6) were pheromone gland-enriched and three OBPs (AipsOBP1, AipsOBP2 and AipsOBP4) were antennal-enriched. Based on these studies we proposed possible A. ipsilon biosynthesis pathways for major and minor sex pheromone components. CONCLUSIONS: Our study identified genes potentially involved in sex pheromone biosynthesis and transport in A. ipsilon. The identified genes are likely to play essential roles in sex pheromone production, transport and degradation and could serve as targets to interfere with pheromone release. The identification of highly expressed CSPs and OBPs in the pheromone gland suggests that they may play a role in the binding, transport and release of sex pheromones during sex pheromone production in A. ipsilon and other Lepidoptera insects. PMID- 24053515 TI - Effect of nutritional support on mitochondrial complex I activity in malnourished patients with anorexia nervosa. AB - Previous studies have shown a reduction in lymphocyte mitochondrial complex I activity (CIA) in malnourished patients, which is restored after refeeding. Our aim was to evaluate the usefulness of CIA as an indicator of nutritional status in anorexia nervosa patients. Twelve malnourished anorexia nervosa females (mean age, 24.5 years) were admitted to the Eating Disorders Unit. Basal and weekly anthropometrics, bioelectric impedance (BIA), body composition, and CIA were performed until discharge. Patients were matched to 25 healthy females and refeeding was adjusted according to the Unit's protocol. Statistics were used as appropriated and significance was reached at p < 0.05. Patients showed a significant reduction in body mass index, fat mass and fat free mass (FFM), triceps skinfold, and waist circumference on admission as compared with the control group. Parameters improved during hospitalization, but they failed to reach normal values at discharge. Compared with controls, CIA was significantly lower in patients on admission (2.16 vs. 5.68 nmol.min(-1).mg protein(-1)). Refeeding and weight gain did not restore CIA. A positive association (r(2) = 0.69) was found between FFM and CIA in patients at discharge. Malnourished females with anorexia nervosa have lower CIA than controls that is not recovered after refeeding. This could be because of a low FFM exacerbated by physical inactivity while in hospital. PMID- 24053514 TI - X-linked intellectual disability type Nascimento is a clinically distinct, probably underdiagnosed entity. AB - X-linked intellectual disability type Nascimento (MIM #300860), caused by mutations in UBE2A (MIM *312180), is characterized by craniofacial dysmorphism (synophrys, prominent supraorbital ridges, deep-set, almond-shaped eyes, depressed nasal bridge, prominent columella, hypoplastic alae nasi, and macrostomia), skin anomalies (hirsutism, myxedematous appearance, onychodystrophy), micropenis, moderate to severe intellectual disability (ID), motor delay, impaired/absent speech, and seizures. Hitherto only five familial point mutations and four different deletions including UBE2A have been reported in the literature.We present eight additional individuals from five families with UBE2A associated ID - three males from a consanguineous family, in whom we identified a small deletion of only 7.1 kb encompassing the first three exons of UBE2A, two related males with a UBE2A missense mutation in exon 4, a patient with a de novo nonsense mutation in exon 6, and two sporadic males with larger deletions including UBE2A. All affected male individuals share the typical clinical phenotype, all carrier females are unaffected and presented with a completely skewed X inactivation in blood. We conclude that 1.) X-linked intellectual disability type Nascimento is a clinically very distinct entity that might be underdiagnosed to date. 2.) So far, all females carrying a familial UBE2A aberration have a completely skewed X inactivation and are clinically unaffected. This should be taken in to account when counselling those families. 3.) The coverage of an array should be checked carefully prior to analysis since not all arrays have a sufficient resolution at specific loci, or alternative quantitative methods should be applied not to miss small deletions. PMID- 24053516 TI - Oral supplementation with the rutin improves cardiovagal baroreflex sensitivity and vascular reactivity in hypertensive rats. AB - The hypothesis that oral supplementation with the flavonoid rutin improves baroreflex sensitivity and vascular reactivity in hypertensive (2-kidney-1-clip (2K1C)) rats was tested. Sixty-four rats were divided in 4 groups: sham + saline; sham + rutin; 2K1C + saline, and 2K1C + rutin. Six weeks after 2K1C surgery, the animals were treated with saline or rutin (40 mg.kg(-1).day(-1)) by gavage for 7 days. Baroreflex sensitivity test using phenylephrine (8 MUg.kg(-1), iv) and sodium nitroprusside (25 MUg.kg(-1), iv), vascular reactivity, and thiobarbituric acid reactive substances assay were performed. Baroreflex sensitivity in hypertensive rats was impaired and compared with sham (-2.77 +/- 0.15 vs. -1.53 +/- 0.27 beats.min(-1).mm Hg(-1); n = 8; p < 0.05). Oral supplementation with rutin restored baroreflex sensitivity in 2K1C rats (-2.40 +/- 0.24 vs. -2.77 +/- 0.15 beats.min(-1).mm Hg(-1); n = 8; p > 0.05). Besides, hypertensive rats have greater contraction to phenylephrine (129.49% +/- 4.46% vs. 99.50% +/- 11.36%; n = 8; p < 0.05), which was restored by rutin (99.10% +/- 1.77% vs. 99.50% +/- 11.36%; n = 8; p > 0.05). Furthermore, vasorelaxation to acetylcholine was diminished in hypertensive rats (96.42% +/- 2.80% vs. 119.35% +/- 5.60%; n = 8; p < 0.05), which was also restored by rutin (117.55% +/- 6.94% vs. 119.35% +/- 5.60%; n = 8; p > 0.05). Finally, oxidative stress was greater in hypertensive rats (1.54 +/- 0.12 vs. 0.53 +/- 0.12 nmol MDA.mL(-1); n = 8; p < 0.05) and rutin supplementation significantly decreased oxidative stress in those animals (0.70 +/- 0.13 vs. 1.54 +/- 0.12 nmol MDA.mL(-1); n = 8; p < 0.05). We concluded that oral supplementation with rutin restores impaired baroreflex sensitivity and vascular reactivity in hypertensive rats by decreasing oxidative stress. PMID- 24053517 TI - Effects of different protein and glycemic index diets on metabolic profiles and substrate partitioning in lean healthy males. AB - Dietary glycemic index (GI) and protein affects postprandial insulin responses and consequently 24 h glucose metabolism and therefore substrate partitioning. This study investigated the mechanistic effects of different protein and GI diets on 24 h profiles of metabolic markers and substrate partitioning. After 3 days of diet and physical activity standardization, 10 healthy male subjects (BMI: 22.5 +/- 0.6 kg/m(2)) stayed in a respiration chamber 4 times for 36 h each time to measure substrate partitioning. All subjects randomly received four isoenergetic diets: a normal (15En%) dairy protein and low GI (<40 units) (NDP-LGI) diet; a high (25En%) dairy protein and low GI (HDP-LGI) diet; a normal vegetable protein and low GI (NVP-LGI) diet; or a normal dairy protein and high GI (>60 units) (NDP HGI) diet. During the day, blood was sampled at fixed time points for the measurement of metabolic markers and satiety hormones. The HDP-LGI diet increased 24 h protein oxidation and sleeping metabolic rate (SMR) compared with the NDP LGI diet (p < 0.002). No significant differences in 24 h carbohydrate and fat oxidation (day and night) were found between all intervention diets. Net incremental area under the curve (net iAUC) of 24 h plasma glucose decreased in the HDP-LGI diet compared with the NDP-LGI diet (p < 0.01), but no effect was observed on insulin levels. No difference in appetite profiles were observed between all intervention diets. The lower 24 h glycemic profile as a result of a high dairy protein diet did not lead to changes in 24 h substrate partitioning in lean healthy subjects with a normal insulin sensitivity. PMID- 24053518 TI - Metabolic equivalent concept in apparently healthy men: a re-examination of the standard oxygen uptake value of 3.5 mL.kg(-1).min(-1.). AB - This study compared resting oxygen uptake (VO2) with the standard metabolic equivalent (MET) value of 3.5 mL.kg(-1).min(-1), tested the accuracy of a previously published prediction model for resting VO2, and proposed a new prediction model for a more homogeneous population. One hundred and twenty-five apparently healthy men, aged 17-38 years, visited the laboratory for the assessment of resting VO2. The mean resting VO2 of 3.21 mL.kg(-1).min(-1) (95% confidence interval (CI), 3.13 to 3.30) was significantly lower than the standard MET value of 3.5 mL.kg(-1).min(-1) (mean difference, 0.29; 95% CI, 0.20 to 0.37; t = 6.7; p < 0.001). The prediction model proposed by a previous study, derived from a heterogeneous sample, exhibited no predictive ability in our more homogeneous sample. However, our population-specific regression model, which included body surface area and percent body fat as predictors, demonstrated relatively poor predictive ability, with a low R(2) (0.22) and high standard error of the estimate (0.42 mL.kg(-1).min(-1)). Pearson's correlation coefficients for body surface area and resting VO2, and for percent body fat and resting VO2, were 0.20 (p = 0.022) and -0.36 (p < 0.001), respectively. In conclusion, the standard MET value of 3.5 mL.kg(-1).min(-1) considerably overestimates mean resting VO2 in a relatively large group of apparently healthy men. Our population-specific prediction model for resting VO2 demonstrated relatively poor accuracy, although it was considerably more accurate than the previously published model. Further research needs to be conducted to establish accurate population-specific prediction models. PMID- 24053519 TI - Neuromechanical assessment of lidocaine test block in spastic lower limbs. AB - The objective of this study was to quantify in spastic lower limbs the changes in reflex EMGs and in ankle stiffness after a lidocaine block of the soleus nerve to better understand physiological effects of lidocaine. Twenty patients were prospectively included and assessed before and after lidocaine block of the soleus nerve. We studied clinical and neuromechanical parameters of the triceps surae, including quantification of the maximum Hoffmann's reflex (Hmax) and tendinous reflex (T) normalized to the maximum direct motor response (Mmax), and passive ankle stiffness assessed by sinusoidal length perturbations. All patients whatever the aetiology of spasticity were improved in clinical parameters of spasticity after the block (62% reduction of the Ashworth score, 85% reduction of stretch reflex scores, increased score on the Physicians' Rating Scale). All patients presented a reduction of the Hmax-Mmax ratio (mean reduction of 67%) and the T-Mmax ratio (82%). Ankle stiffness was decreased by an average of 23%. Measured stiffness was correlated with the Ashworth score and the T-Mmax ratio. Relatively greater change in the T reflex than in the H reflex suggests that lidocaine block reduces hyperreflexia not only by interfering with generation of afferent volleys in the injected nerve, but also probably by altering generation of the volleys at the level of muscle spindles in the affected spastic muscles, presumably by blocking the transmission along gamma-efferent fibers. PMID- 24053520 TI - Comparison of heart and respiratory rate variability measures using an intermittent incremental submaximal exercise model. AB - To better understand the alterations in cardiorespiratory variability during exercise, the present study characterized the patterns of change in heart rate variability (HRV), respiratory rate variability (RRV), and combined cardiorespiratory variability (HRV-RRV) during an intermittent incremental submaximal exercise model. Six males and six females completed a submaximal exercise protocol consisting of an initial baseline resting period followed by three 10-min bouts of exercise at 20%, 40%, and 60% of maximal aerobic capacity (VO2max). The R-R interval and interbreath interval variability were measured at baseline rest and throughout the submaximal exercise. A group of 93 HRV, 83 RRV, and 28 HRV-RRV measures of variability were tracked over time through a windowed analysis using a 5-min window size and 30-s window step. A total of 91 HRV measures were able to detect the presence of exercise, whereas only 46 RRV and 3 HRV-RRV measures were able to detect the same stimulus. Moreover, there was a loss of overall HRV and RRV, loss of complexity of HRV and RRV, and loss of parasympathetic modulation of HRV (up to 40% VO2max) with exercise. Conflicting changes in scale-invariant structure of HRV and RRV with increases in exercise intensity were also observed. In summary, in this simultaneous evaluation of HRV and RRV, we found more consistent changes across HRV metrics compared with RRV and HRV-RRV. PMID- 24053521 TI - Glucose intolerance induced by glucocorticoid excess is further impaired by co administration with beta-hydroxy-beta-methylbutyrate in rats. AB - Glucocorticoid (GC) excess alters glucose homeostasis and promotes modifications in murinometric and anthropometric parameters in rodents and humans, respectively. beta-hydroxy-beta-methylbutyrate (HMB), a leucine metabolite, has been proposed as a nutritional strategy for preventing muscle wasting, but few data regarding its effects on glucose homeostasis are available. Here, we analyzed whether the effects of GC excess on glucose homeostasis may be attenuated or exacerbated by the concomitant ingestion of HMB. Adult Wistar rats (90-days-old) were assigned to four groups: (1) vehicle treated (Ctl), (2) dexamethasone (DEX) treated (Dex), (3) HMB treated (Hmb), and (4) DEX plus HMB treated (DexHmb). Dex groups received DEX (1 mg.kg body weight (BW)(-1), intraperitoneal) for 5 consecutive days. HMB groups ingested HMB (320 mg.kg BW( 1), oral gavage) for the same 5 days. HMB ingestion did not attenuate the effects of DEX on food intake and body weight loss, changes in masses of several organs, insulin resistance, and glucose intolerance (p > 0.05). In fact, in DexHmb rats, there was increased fasting glycemia and exacerbated glucose intolerance with the main effect attributed to DEX treatment (p < 0.05). HMB exerted no attenuating effect on plasma triacylglycerol levels from DexHmb rats, but it seems to attenuate the lipolysis induced by beta-adrenergic stimulation (20 MUmol.L(-1) isoproterenol) in fragments of retroperitoneal adipose tissue from DexHmb rats. Therefore, HMB does not attenuate the diabetogenic characteristics of GC excess. In fact, the data suggest that HMB may exacerbate GC-induced glucose intolerance. PMID- 24053522 TI - Moderate to high levels of exercise are associated with higher resting energy expenditure in community-dwelling postmenopausal women. AB - Postmenopausal women experience an age-related decline in resting energy expenditure (REE), which is a risk factor for energy imbalance and metabolic disease. Exercise, because of its association with greater lean tissue mass and other factors, has the potential to mediate REE decline, but the relation between exercise and REE in postmenopausal women is not well characterized. This study tests the hypothesis that exercise energy expenditure (EEE) is positively associated with REE and can counter the effects of age and menopause. It involves a cross-sectional sample of 31 healthy postmenopausal women (aged 49-72 years) with habitual exercise volumes at or above levels consistent with current clinical recommendations. Subjects kept exercise diaries for 4 weeks that quantified exercise activity and were measured for body composition, maximal oxygen uptake, and REE. Multiple regression analysis was used to test for associations between EEE, age, body composition, and REE. There was a significant positive relation between EEE and lean tissue mass (fat-free mass and fat-free mass index). The relation between REE and EEE remained significant even after controlling for lean tissue mass. These results support the hypothesis that exercise is positively associated with REE and can counter the negative effects of age and menopause. They also indicate a continuous relation between exercise and REE across ranges of exercise, from moderate to high. Exercise at levels that are at or above current clinical guidelines might, in part, ameliorate the risk for energy imbalance and metabolic disease because of its positive relation with REE. PMID- 24053523 TI - Increased corticospinal excitability prior to arm cycling is due to enhanced supraspinal but not spinal motoneurone excitability. AB - Human studies have not assessed supraspinal or spinal motoneurone excitability in the quiescent state prior to a rhythmic and alternating cyclical motor output. The purpose of the current study was to determine whether supraspinal and (or) spinal motoneurone excitability was modulated in humans prior to arm cycling when compared with rest with no intention to move. We hypothesized that corticospinal excitability would be enhanced prior to arm cycling due, in part, to increased spinal motoneurone excitability. Supraspinal and spinal motoneurone excitability were assessed via transcranial magnetic stimulation (TMS) of the motor cortex and transmastoid stimulation of the corticospinal tract, respectively. Surface electromyography recordings of TMS motor evoked potentials (MEPs) and cervicomedullary MEPs (CMEPs) were made from the relaxed biceps brachii muscle prior to rhythmic arm cycling and at rest with no intention to move. The amplitude of the MEPs was greater (mean increase: +9.8% of maximal M wave; p = 0.006) and their onset latencies were shorter (mean decrease: -1.5 ms; p < 0.05) prior to cycling when compared with rest. The amplitudes of the CMEPs at any of 3 stimulation intensities were not different between conditions. We conclude that premovement enhancement of corticospinal excitability is greater prior to arm cycling than at rest because of increases in supraspinal but not spinal motoneurone excitability. PMID- 24053524 TI - Moderate-intensity exercise affects perceived hunger and fullness but not appetite-related hormones in late pregnancy. AB - The effect of exercise on appetite and appetite-related hormones during pregnancy is not known. This study found that 30 min of moderate-intensity stationary cycling transiently attenuated hunger and increased fullness in late gestational women (n = 12). Exercise did not affect perceived appetite or appetite-related hormones in response to subsequent caloric consumption. These observations suggest that appetite responses do not intrinsically compensate for the additional energy expenditure induced by exercise, at least in the short term. PMID- 24053525 TI - Effects of resistance training associated with whey protein supplementation on liver and kidney biomarkers in rats. AB - The aim of this study was to investigate the impact of whey protein (WP) supplementation and resistance training (RT) on liver and kidney biomarkers. The sedentary + WP group showed higher levels of plasma liver and kidney dysfunction markers compared with the other groups. In addition, WP supplementation associated with RT resulted in physiologic cardiac hypertrophy. WP supplementation without RT affected liver and kidney function. PMID- 24053526 TI - Discussion of "Influence of netball-based exercise on energy intake, subjective appetite and plasma acylated ghrelin in adolescent girls". PMID- 24053528 TI - Physical activity among preschoolers during indoor and outdoor childcare play periods. AB - Preschoolers' (n = 31) physical activity (PA) levels during indoor and outdoor childcare hours were explored using accelerometers. Participants engaged in 0.54 min/h (SD = 0.59) of moderate-to-vigorous PA (MVPA) and 14.42 min/h (SD = 6.78) of total PA (TPA) indoors compared with 5.03 min/h (SD = 4.92) of MVPA and 31.68 min/h (SD = 0.83) of TPA outdoors. Boys and girls engaged in significantly more TPA outdoors; however, only boys demonstrated a significant increase in MVPA outdoors. PMID- 24053532 TI - Retraction: VO2p, HR and HHb kinetics in young and older adults during cycling in acute hypoxia. PMID- 24053533 TI - Ethical principles of health research involving Indigenous peoples. PMID- 24053534 TI - One-electron oxidation of an organic molecule by B(C6F5)3; isolation and structures of stable non-para-substituted triarylamine cation radical and bis(triarylamine) dication diradicaloid. AB - The methylene-bridged triphenylamine 2 has been oxidized to planar radical cation 2(*+) by B(C6F5)3 or Ag(+). Further reaction of 2(*+)[Al(ORF)4](-) and 2 with trace amounts of silver salt resulted in dication 3(2+), providing a rare example of structurally characterized bis(triarylamine) "bipolarons". 3(2+) can be directly prepared by the reaction of 3 with 2 equiv of Ag(+). X-ray structural analysis together with theoretical calculation shows that 3(2+) has singlet diradical character and is analogous to Chichibabin's hydrocarbons. PMID- 24053535 TI - Palladium-catalyzed methylation of alkynyl C(sp)-H bonds with dimethyl sulfonium ylides. AB - A novel palladium-catalyzed methylation protocol for the synthesis of methyl functionalized internal alkynes has been established. This methylation method is achieved through a C(sp)-C(sp(3)) bond formation process and represents a new synthetic application of sulfonium ylides. PMID- 24053536 TI - Preparation and characterization of bionic bone structure chitosan/hydroxyapatite scaffold for bone tissue engineering. AB - Three-dimensional oriented chitosan (CS)/hydroxyapatite (HA) scaffolds were prepared via in situ precipitation method in this research. Scanning electron microscopy (SEM) images indicated that the scaffolds with acicular nano-HA had the spoke-like, multilayer and porous structure. The SEM of osteoblasts which were polygonal or spindle-shaped on the composite scaffolds after seven-day cell culture showed that the cells grew, adhered, and spread well. The results of X ray powder diffractometer and Fourier transform infrared spectrometer showed that the mineral particles deposited in the scaffold had phase structure similar to natural bone and confirmed that particles were exactly HA. In vitro biocompatibility evaluation indicated the composite scaffolds showed a higher degree of proliferation of MC3T3-E1 cell compared with the pure CS scaffolds and the CS/HA10 scaffold was the highest one. The CS/HA scaffold also had a higher ratio of adhesion and alkaline phosphate activity value of osteoblasts compared with the pure CS scaffold, and the ratio increased with the increase of HA content. The ALP activity value of composite scaffolds was at least six times of the pure CS scaffolds. The results suggested that the composite scaffolds possessed good biocompatibility. The compressive strength of CS/HA15 increased by 33.07% compared with the pure CS scaffold. This novel porous scaffold with three dimensional oriented structure might have a potential application in bone tissue engineering. PMID- 24053537 TI - Allergology in Europe, the blueprint. AB - The number of patients with allergic diseases in Europe, and thus relevant demand for health care, is continuously increasing. In this EAACI-UEMS position paper, a rationale is given for the medical specialty of allergology. General practitioners and general paediatricians usually cannot elucidate and address all causative factors. Throughout Europe, therefore, the expertise of allergologists (allergists) is required. In collaboration with other medical professionals, they take care of allergic patients, in private practices or in specialized public centres. A well-structured collaboration between allergists and allergy centres offers the possibility of rapid signalling of new trends developing in the population of allergic patients (e.g., in food and drug allergy). Allergy centres also can perform clinical (and basic) research, teach medical students, future allergists and provide postgraduate training. To prevent that the quality of care in one or several countries within Europe lags behind developments in other countries, the UEMS Section and Board on Allergology together with the European Academy of Allergy and Clinical Immunology advocates the status of a full specialty of allergology in each European country, with a further intention to align their activities (blueprint, curriculum and centre visitation) with the UEMS Section of Paediatrics. PMID- 24053538 TI - Validation study of the Chinese Early Development Instrument (CEDI). AB - BACKGROUND: The Early Development Instrument (EDI) is a comprehensive instrument used to assess school readiness in preschool children. This study was carried out to evaluate the psychometric properties of the Chinese version of the EDI (CEDI) in Hong Kong. METHODS: One hundred and sixty-seven children were purposefully sampled from kindergartens in two districts with very different socioeconomic statuses. The CEDI was assessed for concurrent validity, internal consistency and test-retest reliability. The developmental vulnerability identified using the CEDI scores was further examined in relation to the socioeconomic status of the district and family. RESULTS: The CEDI displayed adequate internal consistency, with Cronbach's alphas ranging from 0.70 to 0.95 on its five domains. Concurrent validity was supported by moderate and significant correlations (0.25 to 0.49) on the relevant domains between the CEDI and a comparable measure. The level of test retest reliability was good, with a kappa statistic of 0.89. In general, girls outperformed boys, particularly in the social, emotional and communication/general knowledge domains. After controlling for the uneven distribution of sex, children from socioeconomically disadvantaged districts and families were found to be at greater risk of developmental vulnerability than their more advantaged counterparts. CONCLUSION: The evidence gathered in this study supports the CEDI's use as a valid and reliable instrument in assessing school readiness and identifying developmentally vulnerable children in Chinese populations. Its preliminary findings on the socioeconomic gradients of child development suggest that the CEDI is a promising tool for leveraging evidence based, context-sensitive policies and practices to foster the development of all children. PMID- 24053540 TI - Efficient visible-light photocatalytic hydrogen evolution and enhanced photostability of core/shell CdS/g-C3N4 nanowires. AB - CdS/g-C3N4 core/shell nanowires with different g-C3N4 contents were fabricated by a combined solvothermal and chemisorption method and characterized by X-ray powder diffraction, scanning electronic microscopy, transmission electron microscopy, and UV-vis diffuse reflection spectroscopy. The photocatalytic hydrogen-production activities of these samples were evaluated using Na2S and Na2SO3 as sacrificial reagents in water under visible-light illumination (lambda>=420 nm). The results show that after a spontaneous adsorption process g C3N4 is successfully coated on CdS nanowires with intimate contact and can significantly improve the photocatalytic hydrogen-production rate of CdS nanowires, which reaches an optimal value of up to 4152 MUmol h(-1) g(-1) at the g-C3N4 content of 2 wt %. More importantly, g-C3N4 coating can substantially reinforce the photostability of CdS nanowires even in a nonsacrificial system. The synergic effect between g-C3N4 and CdS, which can effectively accelerate the charge separation and transfer corrosive holes from CdS to robust C3N4, was proposed to be responsible for the enhancement of the photocatalytic activity and photostability. The possible conditions necessary for the synergic effect to work in a CdS/g-C3N4 core/shell configuration is also discussed. PMID- 24053539 TI - One-year results of treatment with bevacizumab alone or ranibizumab alone for low visual acuity due to neovascular age-related macular degeneration. AB - PURPOSE: To investigate treatment with bevacizumab alone or ranibizumab alone in neovascular age-related macular degeneration (nAMD) patients with low visual acuity. METHODS: Data were analyzed retrospectively. Inclusion criteria were (1) pretreatment visual acuity of LogMAR 1.3 or worse and (2) treatment duration of at least 12 months. Injections were given monthly for the first 3 months and thereafter as needed. Data collected for each patient included best corrected visual acuity and central retinal thickness measured before treatment, at months 3, 6, 9, and 12 during treatment, and at the last follow-up visit. RESULTS: In the bevacizumab patients, mean visual acuity was initially 1.70 LogMAR; at months 3, 6, 9, and 12 during treatment it was 1.20, 1.11, 1.14, and 1.10 LogMAR, respectively, and at the last follow-up it was 1.12 LogMAR (P<0.01 for all differences with respect to the initial value). Mean injection number in the first 12 months was 5.3. In the ranibizumab patients, mean visual acuity was initially 1.53 LogMAR; at months 3, 6, 9, and 12 during treatment it was 1.18, 1.17, 1.17, and 1.28 LogMAR, respectively, and at the last follow-up it was 1.21 LogMAR (P<0.01 for all differences with respect to the initial value). Mean injection number in the first 12 months was 4.2. CONCLUSION: Patients with nAMD and low pretreatment visual acuities can benefit from treatment with bevacizumab or ranibizumab. PMID- 24053541 TI - Urinary tract stone raises subsequent risk for urinary tract cancer: a population based cohort study. AB - OBJECTIVE: To evaluate the association between urinary tract stone (UTS) and urinary tract cancer (UTC) in Taiwanese patients, as the results of epidemiological studies about the relationship between UTS and the development of UTC remain inconclusive. PATIENTS/SUBJECTS AND METHODS: We conducted a population based cohort study using data from the Taiwanese National Health Insurance system. The UTS cohort included 21 862 patients, and each patient was randomly frequency-matched for age, sex, and index year with two insured members of the general population who did not have UTS. Cox proportional hazard regression analysis was performed to estimate the effect of UTS on the risk of UTC. RESULTS: Patients with UTS were at a significantly higher risk of developing UTC compared with the comparison group (adjusted hazard ratio 4.66; 95% confidence interval 2.97-7.30). Women were at higher risk than men. Further analyses showed that the level of UTC was associated with that of UTS, and that the risk for UTC became more divergent for the two groups over time. CONCLUSIONS: Taiwanese patients with UTS, particularly women, had a higher risk for developing UTC than patients without UTS. The risk became more marked over time for this group. PMID- 24053542 TI - Neonatal intraventricular hemorrhage. PMID- 24053543 TI - Different impacts of short-chain fatty acids on saturated and polyunsaturated fatty acid biosynthesis in Aurantiochytrium sp. SD116. AB - Aurantiochytrium is an important docosahexaenoic acid (DHA) producer containing two kinds of fatty acid synthesis pathways, that is, the fatty acid synthase pathway (FAS) for saturated fatty acid synthesis and the polyketide synthase pathway (PKS) for polyunsaturated fatty acid synthesis. To understand the regulation mechanism between the two pathways, the impacts of six short-chain fatty acids on the fatty acid synthesis of Aurantiochytrium sp. SD116 were studied. All short-chain fatty acids showed little effect on the cell growth, but some of them significantly affected lipid accumulation and fatty acid composition. Pentanoic acid and isovaleric acid greatly inhibited the synthesis of saturated fatty acids, whereas the polyunsaturated fatty acid synthesis was not affected. Analysis of malic enzyme activity, which supplied NADPH for saturated fatty acids biosynthesis, indicated that the two fatty acid synthesis pathways can utilize different substrates and possess independent sources of NADPH. PMID- 24053544 TI - Toward a mechanistic understanding of ionic self-complementary peptide self assembly: role of water molecules and ions. AB - Ionic self-complementary peptides are considered an important class of self assembling peptides. In particular, RADARADARADARADA (RADA4) is well-known to form a relatively regular nanofiber structure that has been primarily studied in terms of its physicochemical properties, as related to its biomedical applications. However, the molecular level interactions that are involved in promoting the self-assembly of this peptide into nanofibers have not been fully elucidated. Herein, a thermodynamic analysis of the influences of peptide chemistry upon self-assembly is discussed for RADA4, RADA4-K5, and RADA4-S5. The regular nanofiber structure of the assembled peptides makes it a good candidate for isothermal titration calorimetry (ITC) studies for determining the propensity for self-assembly, the critical assembly concentration (CAC), and the role hydration and ion content play in the assembly of these peptides. First, solutions containing only RADA4-K5 did not self-assemble; illustrating even slight alterations in the asymmetric terminal amino acid chemistry affects assembly. The CAC of the remaining self-assembling peptides was between ~0.1 and ~0.15 mM. Interestingly, we found that self-assembly was entropically driven with hydrophobic forces being the main driving force for RADA4 and hydrogen bonding for RADA4-S5. The role of water molecules and counterions in self-assembly was also highlighted: assembly of RADA4 led to desolvation of interfacial surfaces, whereas the net number of water molecules in the assembled complex increased upon RADA4-S5 self-assembly. Moreover, it was found that counterions did not seem to contribute significantly to self-assembly: a result in contrast to current concepts regarding the role of electrostatic interactions in self-assembly of RADA4-like peptides. A molecular level understanding of peptide self-assembly will allow for further engineering of peptides for a vast array of biomedical applications. PMID- 24053545 TI - The dilemma of distance: patients with kidney cancer from regional Australia present at a more advanced stage. AB - OBJECTIVE: To determine whether patients from regional areas undergoing surgery for kidney cancer present with more advanced disease as a result of geographic isolation. PATIENTS AND METHODS: Retrospective analysis of 221 patients undergoing surgery for renal cell carcinoma (RCC) from January 2004 to June 2012, from both a metropolitan centre and a large inner regional hospital. Data was collected on age, gender, presentation (incidental or symptomatic), clinical stage and pathological features. The Australian Standard Geographical Classification-Remoteness Area (ASGC-RA) is a system developed to allow quantitative comparisons between metropolitan and rural Australia. A score was assigned to each patient based on their location of residence at the time of surgery: metropolitan, RA1; inner regional, RA2; outer regional, RA3. Statistical significance was specified as P < 0.05 on Pearson's chi-square tests. RESULTS: Patients in each ASGC-RA group did not differ significantly in age, sex or mode of presentation. Pathological T stage on presentation increased with increasing ASGC-RA and thus distance from tertiary centres (P = 0.004). The proportion of patients with >=T3 disease rose from 30% of RA1 to 73% of RA3 patients (P = 0.016) treated at our tertiary centre. Similarly, our regional centre had a larger proportion of patients presenting with >=T3 disease from RA3 (31% vs 5%, P = 0.003). When the 221 patients with RCC were analysed as a group, clinical T stage was significantly associated with ASGC-RA (P < 0.001), symptomatic presentation (P < 0.001), N stage (P < 0.001), M stage (P < 0.001) and Fuhrman grade (P < 0.001). CONCLUSIONS: Our data quantifies the detrimental effect of physical distance on the health outcomes of regional Australians with kidney cancer. Australia's unique geography and rural culture may preclude any attempts to centralise cancer care to specialised metropolitan units, as has occurred in other countries. PMID- 24053546 TI - Modelling changes in the components of eggs from broiler breeders over time. AB - 1. Because the components of the egg differ in nutrient content, and the proportions of these components change over time, the daily intake of nutrients required to produce an egg will also change with time. Information on these relationships is essential when attempting to determine the nutrient requirements of a broiler breeder hen at different stages of lay, and in predicting performance when the hen is supplied with a given amount of food with a given nutrient composition. 2. Yolk weight is related to hen age and may be predicted using a linear-by-linear function, the coefficients of which are the same for Cobb and Ross breeders. Allometric functions may be used to predict albumen weight from yolk weight, and shell weight from the weight of the egg contents. Egg weight is given by the sum of the three components. 3. The proportion of yolk increased with advancing age whilst the proportions of albumen and shell decreased. However, at a given age, larger eggs contain proportionally more albumen. Eggs from Cobb hens had proportionately more albumen than Ross eggs towards the end of lay. 4. A stochastic population model verified that these functions accurately reflect the proportional changes in the egg components with advancing hen age and at a given age, over a range of egg weights. PMID- 24053547 TI - Influence of the cavity size of water-soluble cryptophanes on their binding properties for cesium and thallium cations. AB - The binding properties of water-soluble cryptophane 1 toward cesium and thallium cations, in basic solution, have recently been reported. In this Article, we show that water-soluble cryptophane-222 (2), cryptophane-223 (3), and cryptophane-233 (4), bearing zero, one, and two propylenedioxy linkers, respectively, also efficiently bind these two cations under similar experimental conditions. Their binding properties are thoroughly studied by (133)Cs and (205)Tl NMR spectroscopy, while the binding constants are determined by isothermal titration calorimetry (ITC) experiments under various experimental conditions. Complexation of cesium and thallium is also evidenced by electronic circular dichroism (ECD) using the enantiopure MM-2 compound. This study reveals that the cavity size of the cryptophane is not the main parameter to observe efficient binding. In contrast, the number of phenolate moieties surrounding the cryptophane backbone seems to be pivotal for the complexation of these two cations. These results are important in the field of detoxification. PMID- 24053548 TI - A thermophilic gram-negative nitrate-reducing bacterium, Calditerrivibrio nitroreducens, exhibiting electricity generation capability. AB - To exploit the potential diversity of thermophilic exoelectrogens, two-chamber microbial fuel cells (MFCs) were inoculated with thermophilic anaerobic digester sludge and operated at 55 degrees C without supplementing with exogenous redox mediator. The MFC generated a maximum power density of 823 mW m(-2) after 200 h of operation. Molecular phylogenetic analyses suggested that the microbial population on the anode was dominated by a species closely related to a thermophilic nitrate-reducing bacterium Calditerrivibrio nitroreducens, for which a strain (Yu37-1) has been isolated in pure culture. Thus, a pure culture of the C. nitroreducens strain Yu37-1 was inoculated into MFC to examine the electricity generation capability. Without an exogenous mediator, MFCs stably produced electricity with a maximum power density of 272 mW m(-2) for >400 h of operation. The MFC current recovered to the original level within few hours after medium replacement, suggesting that the electricity generation was caused by the anodic microorganisms. Cyclic voltammetry indicated that redox systems (E3 and Ec) with similar potentials (-0.14 and -0.17 V) made the main contributions to the exoelectrogenic activities of the sludge-derived consortium and C. nitroreducens Yu37-1, respectively. This study undertook the bioelectrochemical characterization of C. nitroreducens as the first example of a thermophilic Gram negative exoelectrogen. PMID- 24053549 TI - Lifestyle Matters for maintenance of health and wellbeing in people aged 65 years and over: study protocol for a randomised controlled trial. AB - BACKGROUND: Healthy, active ageing is strongly associated with good mental wellbeing which in turn helps to prevent mental illness. However, more investment has been made into research into interventions to prevent mental illness than into those designed to improve mental wellbeing. This applied research programme will provide high quality evidence for an intervention designed to improve and sustain mental wellbeing in older adults. METHODS/DESIGN: This study was a multi centre, pragmatic, two-arm, parallel group, individually randomised controlled trial to determine the population benefit of an occupational therapy based intervention for community living people aged 65 years or older. Participants (n = 268) will be identified in one city in the North of England and in North Wales through GP mail-outs, signposting by local authority, primary care staff and voluntary sector organisations and through community engagement. Participants will be randomised to one of two treatment arms: an intervention (Lifestyle Matters programme); or control (routine access to health and social care). All participants will be assessed at baseline, 6 and 24 months post-randomisation. The primary outcome, which is a person reported outcome, is the SF-36 Mental Health dimension at six months post randomisation. Secondary outcome measures have been selected to measure psychosocial, physical and mental health outcomes. They include other dimensions of the SF36, EQ-5D-3L, Brief Resilience Scale, General Perceived Self Efficacy Scale, PHQ-9, de Jong Gierveld Loneliness Scale, Health and Social Care Resource Use and the wellbeing question of the Integrated Household Survey 2011. A cost effectiveness analysis will investigate the incremental cost per Quality Adjusted Life Years (QALYs) of the Lifestyle Matters intervention compared with treatment as usual. DISCUSSION: The questions being posed through this research are important given the increasing numbers of older people, pressure on the public purse and the associated need to support good health in the extended lifespan. The proposed trial will determine the clinical and cost effectiveness of the intervention delivered in a UK context. The results will support commissioners and providers with decisions about implementation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN67209155. PMID- 24053550 TI - Endogenous fungal endophthalmitis: risk factors, clinical features, and treatment outcomes in mold and yeast infections. AB - BACKGROUND: The purpose of the current study was to analyze risk factors, clinical features, and treatment outcomes in patients with endogenous fungal endophthalmitis with yeast and mold infections. For this retrospective consecutive case series, microbiologic and clinical records were reviewed to identify all patients with intraocular culture-proven endogenous fungal endophthalmitis treated at a single institution between January 1, 1990 and December 31, 2011. RESULTS: Sixty-seven eyes of 53 patients were identified; 51 eyes of 39 patients had positive cultures for yeast and 16 eyes of 14 patients had positive cultures for molds. Patients with molds as a causative organism had significantly shorter duration of symptoms prior to diagnosis (molds 3.8 days, yeast 21.0 days, p = 0.002), were more likely to be receiving iatrogenic immunosuppression (molds 57.1%, yeast 7.7%, p = 0.001), have a history of whole organ transplantation (molds 35.7%, yeast 2.6%, p = 0.001), and were more likely to have hypopyon at the time of diagnosis (molds 37.5%, yeast 6.0%, p = 0.001). Patients with endogenous endophthalmitis caused by molds had significantly worse visual acuity at the time of diagnosis (logMAR visual acuity molds 1.80, yeast 1.15, p = 0.008) and at final visit (logMAR visual acuity molds 1.97, yeast 1.05, p = 0.005) compared to those patients with yeast as a causative organism. There was no significant difference in the rate of retinal detachment between the two groups (mold 12.5%, yeast 30.6%, p = 0.201). Patients with cultures positive for mold were significantly more likely to undergo enucleation (molds 25.0%, yeast 0%, p < 0.001). CONCLUSIONS: Systemic risk factors for patients with endogenous fungal endophthalmitis caused by molds were iatrogenic immunosuppression and a history of whole-organ transplantation. Shorter duration of symptoms before diagnosis and higher rates of hypopyon occurred in mold cases. While endogenous fungal endophthalmitis is generally associated with poor visual acuity outcomes, infection with mold species was associated with worse visual acuity on presentation and on final follow-up than infection with yeast species. Enucleation rates were much higher in mold cases. PMID- 24053551 TI - Players and processes behind the national health insurance scheme: a case study of Uganda. AB - BACKGROUND: Uganda is the last East African country to adopt a National Health Insurance Scheme (NHIS). To lessen the inequitable burden of healthcare spending, health financing reform has focused on the establishment of national health insurance. The objective of this research is to depict how stakeholders and their power and interests have shaped the process of agenda setting and policy formulation for Uganda's proposed NHIS. The study provides a contextual analysis of the development of NHIS policy within the context of national policies and processes. METHODS: The methodology is a single case study of agenda setting and policy formulation related to the proposed NHIS in Uganda. It involves an analysis of the real-life context, the content of proposals, the process, and a retrospective stakeholder analysis in terms of policy development. Data collection comprised a literature review of published documents, technical reports, policy briefs, and memos obtained from Uganda's Ministry of Health and other unpublished sources. Formal discussions were held with ministry staff involved in the design of the scheme and some members of the task force to obtain clarification, verify events, and gain additional information. RESULTS: The process of developing the NHIS has been an incremental one, characterised by small-scale, gradual changes and repeated adjustments through various stakeholder engagements during the three phases of development: from 1995 to 1999; 2000 to 2005; and 2006 to 2011. Despite political will in the government, progress with the NHIS has been slow, and it has yet to be implemented. Stakeholders, notably the private sector, played an important role in influencing the pace of the development process and the currently proposed design of the scheme. CONCLUSIONS: This study underscores the importance of stakeholder analysis in major health reforms. Early use of stakeholder analysis combined with an ongoing review and revision of NHIS policy proposals during stakeholder discussions would be an effective strategy for avoiding potential pitfalls and obstacles in policy implementation. Given the private sector's influence on negotiations over health insurance design in Uganda, this paper also reviews the experience of two countries with similar stakeholder dynamics. PMID- 24053552 TI - Prognosis of patients with pelvic lymph node (LN) metastasis after radical prostatectomy: value of extranodal extension and size of the largest LN metastasis. AB - OBJECTIVE: To assess the prognostic role of extranodal extension (ENE) and the size of the largest lymph node (LN) metastasis in predicting early biochemical relapse (eBCR) in patients with LN metastasis after radical prostatectomy (RP). PATIENTS AND METHODS: We evaluated BCR-free survival in men with LN metastases after RP and pelvic LN dissection performed in six high-volume centres. Multivariable Cox regression tested the role of ENE and diameter of largest LN metastasis in predicting eBCR after adjusting for clinicopathological variables. We compared the discrimination of multivariable models including ENE, the size of largest LN metastasis and the number of positive LNs. RESULTS: Overall, 484 patients were included. The median (interquartile range, IQR) follow-up was 16.1 (6-27.5) months. The median (IQR) number of removed LNs was 10 (4-14), and the median (IQR) number of positive LNs was 1 (1-2). ENE was present in 280 (58%) patients, and 211 (44%) had their largest metastasis >10 mm. Patients with ENE and/or largest metastasis of >10 mm had significantly worse eBCR-free survival (all P < 0.01). On multivariable analysis, number of positive LNs (<=2 vs >2) and the diameter of LN metastasis (<=10 vs >10 mm), but not ENE, were significant predictors of eBCR (all P < 0.003). ENE and diameter of LN metastasis increased the area under the curve of a baseline multivariable model (0.663) by 0.016 points. CONCLUSIONS: The diameter of the largest LN metastasis and the number of positive LNs are independent predictors of eBCR. Considered together, ENE and the diameter of the largest LN metastasis have less discrimination than the number of positive LNs. PMID- 24053554 TI - Examining patient safety attitudes among urology trainees. AB - OBJECTIVES: To identify current attitudes to patient safety among urology trainees. To examine whether these have changed with the recent increase in emphasis on patient safety and the introduction of new working procedures in operating theatres. SUBJECTS AND METHODS: Subjects included 28 urology trainees, based in the West of Scotland, UK. Trainee attitudes were examined using the Operating Room Management Attitudes Questionnaire, a validated tool for examining attitudes towards patient safety. RESULTS: Attitudes to teamwork were highly positive, with 89-100% of trainees acknowledging the need to share information and conduct pre- and postoperative briefs, and 82-96% being accepting of multidisciplinary feedback on performance. Attitudes to preoperative briefing and multidisciplinary feedback were improved compared with a similar historical cohort. Trainees were reluctant to acknowledge the effect of stress and fatigue on personal performance; 50% felt they worked effectively in critical phases of operations even when tired, only 50% would tell team members their workload was becoming excessive and only 36% of trainees recognized that personal problems could affect their performance. There was no significant change in these attitudes from 2006 data. Regarding leadership and confidence assertion, 68% of trainees felt that leadership in the operating theatre should rest with the medical staff, 18% stated senior decisions or actions should not be questioned unless they threaten safety and 7% that they should not be questioned at all. This was similar to previous data. CONCLUSIONS: Attitudes to briefing and multidisciplinary feedback appear to have improved since the introduction of the World Health Organization surgical checklist and wider use of feedback tools; other safety attitudes remain largely unchanged. Urology trainees may benefit from further training to better understand the mechanisms of error development, to raise awareness of human performance limitation, particularly the effects of stress and fatigue, and to develop techniques to challenge decisions/respond to challenges. PMID- 24053553 TI - Long-term outcomes in healthy adults after radiofrequency ablation of T1a renal tumours. AB - OBJECTIVE: To report the long-term oncological and renal function outcomes in healthy adults treated with radiofrequency ablation (RFA) for small renal masses. MATERIALS AND METHODS: We retrospectively analysed the medical records of otherwise healthy patients (those with American Society of Anesthesiologists symptom score 1 or 2) with clinical T1a renal tumours who underwent RFA at our institution between March 2001 and July 2012. Radiographic follow-up with contrast imaging was performed at 6 weeks, 6 months, 1 year and annually thereafter. Local recurrence was defined as any new enhancing lesion (>10 HU) after the initial negative post-treatment computed tomography results. The estimated glomerular filtration rates (eGFRs) before and after RFA were calculated using the Cockgroft-Gault equation. RESULTS: We performed RFA on 58 renal tumours in 52 patients. The mean tumour size was 2.2 cm with a median (interquartile range) follow-up of 60 (48-90) months. Three (5.1%) of the treated masses had tumour recurrence after initial RFA. The 5- and 10-year recurrence free survival rate was 94.2%. There were no recurrences after 3 years. Three (5.1%) patients died during the follow-up, which gave 5- and 10-year overall survival rates of 95.7% and 91.1%. No patient developed metastatic renal cell carcinoma (RCC) and none died from RCC. Paired analysis showed that the eGFR values at a median follow-up of 40 months did not differ significantly from those before RFA. CONCLUSION: With long-term follow-up, RFA provides durable oncological and functional outcomes for selected T1a renal tumours in otherwise healthy patients. PMID- 24053555 TI - Detection of human leptospirosis as a cause of acute fever by capture ELISA using a Leptospira interrogans serovar Copenhageni (M20) derived antigen. AB - BACKGROUND: Leptospirosis is a potentially lethal zoonosis mainly affecting low resource tropical countries, including Peru and its neighbouring countries. Timely diagnosis of leptospirosis is critical but may be challenging in the regions where it is most prevalent. The serodiagnostic gold standard microagglutination test (MAT) may be technically prohibitive. Our objective in this study was to assess the sensitivity, specificity, and predictive value of an IgM antibody capture enzyme-linked immunoassay (MAC-ELISA) derived from the M20 strain of Leptospira interrogans serovar Copenhageni (M20) by comparison to MAT, which was used as the gold standard method of diagnosis. METHODS: Acute and convalescent sera from participants participating in a passive febrile surveillance study in multiple regions of Peru were tested by both IgM MAC-ELISA and MAT. The sensitivity, specificity, positive and negative predictive value (PPV, NPV) of the MAC-ELISA assay for acute, convalescent and paired sera by comparison to MAT were calculated. RESULTS: The sensitivity, specificity, PPV and NPV of the MAC-ELISA assay for acute sera were 92.3%, 56.0%, 35.3% and 96.6% respectively. For convalescent sera, the sensitivity, specificity, PPV and NPV of the MAC-ELISA assay were 93.3%, 51.5%, 63.6% and 89.5% respectively. For paired sera, the sensitivity, specificity, PPV and NPV of the MAC-ELISA assay were 93.6%, 37.5%, 59.2%, 85.7% respectively. CONCLUSIONS: The M20 MAC-ELISA assay performed with a high sensitivity and low specificity in the acute phase of illness. Sensitivity was similar as compared with MAT in the convalescent phase and specificity remained low. Paired sera were the most sensitive but least specific by comparison to MAT serodiagnosis. NPV for acute, convalescent and paired sera was high. The limited specificity and high sensitivity of the MAC ELISA IgM suggests that it would be most valuable to exclude leptospirosis in low resource regions that lack immediate access to definitive reference laboratory techniques such as MAT. PMID- 24053556 TI - Ultrasound features of shoulder involvement in patients with ankylosing spondylitis: a case-control study. AB - BACKGROUND: During Ankylosing spondylitis (AS) courses, shoulder involvement is common. However, etiologies of shoulder pain in patients with AS remain to be defined. The aim of this study was to investigate the prevalence of ultrasound (US) abnormalities in shoulders of patients with ankylosing spondylitis (AS), and to determine predictive factors of ultrasound shoulder enthesitis. METHODS: 38 patients with AS were included with 38 age and sex-matched healthy controls. All patients fulfilled the modified New York criteria for ankylosing spondylitis. Clinical and demographical data were recorded. US examination of bilateral shoulders was performed by a musculoskeletal sonographer according to a defined protocol that included imaging of the insertions of supraspinatus, subscapularis and infraspinatus tendons, rotator cuff tendons, subacromial-subdeltoid bursa, acromioclavicular joint, and glenohumeral joint. RESULTS: The mean age of patients and controls was 36 years, each group of patients and controls comprised 22 men (57.9%) and 16 women (42.1%). Disease duration was 9.6 +/- 7.2 years. Among 38 patients with AS, 21 had coxitis (55%) and 19 had previous or current shoulder pain (50%). AS shoulders presented significantly more ultrasound enthesitis than controls shoulders (43 shoulders (56.6%) versus 8 shoulders (10.5%) respectively). Involvement of rotator cuff tendons was significantly higher in patients with AS compared with control subjects (16/38 (42.1%) versus 6 (15.2%) respectively). However, involvement of gleno-humeral and acromio clavicular joints was infrequent in both groups. In patients with AS, we found that the presence of coxitis was the only significant predictive factors of shoulder enthesitis (Odds Ratio (OR) = 9.4; Confidence interval (CI) 95% (1.10; 81.9), p = 0.04). CONCLUSIONS: Ultrasound abnormalities of shoulders are common in patients with AS, and the most frequent abnormalitie was enthesitis, which was associated with the presence of coxitis. PMID- 24053557 TI - High-frequency mechanical stirring initiates anisotropic growth of seeds requisite for synthesis of asymmetric metallic nanoparticles like silver nanorods. AB - High-speed stirring at elevated temperatures is shown to be effective in the symmetry-breaking process needed for the growth of the hard-to-synthesize silver nanorods from the polyol reduction of silver ions. This process competes with the facile formation of more symmetrical, spherical and cubic, nanoparticles. Once the seed is formed, further growth proceeds predominantly along the long axis, with a consequent increase of the particles' aspect ratio (that of the nanorod). When stirring is stopped shortly after seed formation, nanorods with a broad distribution of aspect ratios are obtained, while when the high-frequency stirring continues the distribution narrows significantly. The width of the nanorods can only be increased if the initial concentration of Ag(+) ions increases. Reducing the stirring speeds during seed formation lowers the yield of nanorods. Molecular dynamics simulations reveal that the formation of a nanometer scale thin boundary region between a solid facet of the nanoparticle and the liquid around it, and the accommodation processes of metal (Ag) atoms transported through this boundary region from the liquid to the solid growth interface, are frustrated by sufficiently fast shear flow caused by high-frequency stirring. This arrests growth on seed facets parallel to the flow, leading, together with the preferential binding of the capping polymer to the (100) facet, to the observed growth in the (110) direction, resulting in silver nanorods capped at the ends by (111) facets and exposing (100) facets on the side walls. PMID- 24053559 TI - MCP-1-2518A>G polymorphism and myocardial infarction risk: a meta-analysis and meta-regression. AB - OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1), a key chemokine in atherosclerotic inflammation, plays an important role in the etiology of myocardial infarction (MI). Emerging evidence has shown that the common polymorphism (-2518A>G; rs1024611) in the MCP-1 gene may contribute to the risk of MI, but individually published studies showed inconclusive results. This meta analysis aimed to derive a more precise estimation of the associations between MCP-1-2518A>G polymorphism and susceptibility to MI. METHODS: A literature search of PubMed, Embase, Web of Science, and China BioMedicine (CBM) databases was conducted on articles published before May 15th, 2013. The crude odds ratios with 95% confidence intervals were calculated. RESULTS: Eleven case-control studies were included with a total 2325 MI patients and 6310 healthy controls. The meta analysis results indicated that MCP-1-2518A>G polymorphism was associated with an increased risk of MI. In further subgroup analysis based on ethnicity, there were significant associations between MCP-1-2518A>G polymorphism and an increased risk of MI among Asian populations. However, no statistically significant association was found among Caucasian populations. Univariate and multivariate meta regression analyses showed that ethnicity may be the major source of heterogeneity. No publication bias was detected in this meta-analysis. CONCLUSION: In conclusion, the current meta-analysis indicates that MCP-1-2518A>G polymorphism may be a risk factor for MI, especially among Asian populations. PMID- 24053560 TI - Transforming growth factor-beta3 gene polymorphisms and nonsyndromic cleft lip and palate risk: a meta-analysis. AB - AIMS: To investigate the association between transforming growth factor-beta3 (TGF-beta3) genetic polymorphisms and nonsyndromic cleft lip and palate (NSCLP) risk. METHODS: An extensive literature search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through June 1st, 2013. Case-control studies addressing the correlation between TGF-beta3 gene polymorphisms and NSCLP risk. The genotype distribution of the controls should conform to Hardy-Weinberg equilibrium. The quality of the included studies was assessed independently by two authors based on the Newcastle Ottawa scale. All analyses were calculated using the STATA 12.0 software. RESULTS: The association between TGF-beta3 gene polymorphisms and NSCLP risk was assessed. Eleven case-control studies were included with a total of 1601 NSCLP cases and 1463 healthy controls. Our meta-analysis results indicated that mutant variants of the TGF-beta3 gene may be associated with an increased risk of NSCLP, especially among Asian populations. Further subgroup analyses also revealed significant associations between mutant variants of the TGF-beta3 gene and an increased risk of NSCLP in the population-based and polymerase chain reaction restriction fragment length polymorphism studies. Meta-regression analyses showed that ethnicity may be a major source of heterogeneity. CONCLUSION: Our meta analysis suggests that TGF-beta3 gene polymorphisms may contribute to NSCLP susceptibility, especially among Asian populations. PMID- 24053558 TI - Transcriptome profiling of Gossypium barbadense inoculated with Verticillium dahliae provides a resource for cotton improvement. AB - BACKGROUND: Verticillium wilt, caused by the fungal pathogen Verticillium dahliae, is the most severe disease in cotton (Gossypium spp.), causing great lint losses worldwide. Disease management could be achieved in the field if genetically improved, resistant plants were used. However, the interaction between V. dahliae and cotton is a complicated process, and its molecular mechanism remains obscure. To understand better the defense response to this pathogen as a means for obtaining more tolerant cultivars, we monitored the transcriptome profiles of roots from resistant plants of G. barbadense cv. Pima90 53 that were challenged with V. dahliae. RESULTS: In all, 46,192 high-quality expressed sequence tags (ESTs) were generated from a full-length cDNA library of G. barbadense. They were clustered and assembled into 23126 unigenes that comprised 2661 contigs and 20465 singletons. Those unigenes were assigned Gene Ontology terms and mapped to 289 KEGG pathways. A total of 3027 unigenes were found to be homologous to known defense-related genes in other plants. They were assigned to the functional classification of plant-pathogen interactions, including disease defenses and signal transduction. The branch of "SA->NPR1->TGA >PR-1->Disease resistance" was first discovered in the interaction of cotton-V. dahliae, indicating that this wilt process includes both biotrophic and necrotrophic stages. In all, 4936 genes coding for putative transcription factors (TF) were identified in our library. The most abundant TF family was the NAC group (527), followed by G2-like (440), MYB (372), BHLH (331), bZIP (271) ERF, C3H, and WRKY. We also analyzed the expression of genes involved in pathogen associated molecular pattern (PAMP) recognition, the activation of effector triggered immunity, TFs, and hormone biosynthesis, as well as genes that are pathogenesis-related, or have roles in signaling/regulatory functions and cell wall modification. Their differential expression patterns were compared among mock-/inoculated- and resistant/susceptible cotton. Our results suggest that the cotton defense response has significant transcriptional complexity and that large accumulations of defense-related transcripts may contribute to V. dahliae resistance in cotton. Therefore, these data provide a resource for cotton improvement through molecular breeding approaches. CONCLUSIONS: This study generated a substantial amount of cotton transcript sequences that are related to defense responses against V. dahliae. These genomics resources and knowledge of important related genes contribute to our understanding of host-pathogen interactions and the defense mechanisms utilized by G. barbadense, a non-model plant system. These tools can be applied in establishing a modern breeding program that uses marker-assisted selections and oligonucleotide arrays to identify candidate genes that can be linked to valuable agronomic traits in cotton, including disease resistance. PMID- 24053561 TI - Association between interleukin-6 gene polymorphisms and bone mineral density: a meta-analysis. AB - BACKGROUND: Many studies have examined the association between interleukin-6 (IL 6) gene polymorphisms and bone mineral density (BMD). However, the results remain conflicting. To assess the relationship more precisely, a meta-analysis was performed. METHODS: The PubMed, Embase, Chinese BioMedical Literature (CBM), Wanfang, and China National Knowledge Infrastructure (CNKI) database were searched for relevant articles published up to March 2013. Weighted mean difference (WMD) and 95% confidence interval (95% CI) were calculated using a fixed-effects or random-effects model. RESULTS: A total of 16 articles with 11,957 subjects were investigated in this meta-analysis. Overall, -634C/G polymorphism was significantly associated with BMD at the femoral neck (WMD, 0.016 g/cm(2); 95% CI, -0.028 to -0.003 g/cm(2)), lumbar spine (WMD, -0.049 g/cm(2); 95% CI, -0.069 to -0.030 g/cm(2)), and whole body (WMD, -0.023 g/cm(2); 95% CI, -0.037 to -0.009 g/cm(2)) for GG versus CC+CG. In subgroup analyses stratified by ethnicity, individuals carrying -634GG genotype had a significantly lower mean BMD at any skeletal site examined, compared with individuals with 634CC or -634CG genotype in Asian populations. For -174G/C polymorphism, the BMD differences between CC+CG and GG genotype were 0.004 g/cm(2) at the distal radius (95% CI, 0.004 to 0.005 g/cm(2)), 0.011 g/cm(2) at the trochanter (95% CI, 0.002 to 0.020 g/cm(2)), and 0.017 g/cm(2) at the Ward's triangle (95% CI, 0.003 to 0.032 g/cm(2)). No significant publication bias was observed in either the 634C/G or -174G/C polymorphism. CONCLUSIONS: This suggests that there are modest effects of the -634C/G and -174G/C polymorphisms on BMD. Large-scale and well designed studies are required to further investigate gene-gene and gene environment interactions on IL-6 polymorphisms and BMD in various populations. PMID- 24053562 TI - The impact of clinical conditions and social factors on the psychological distress of cancer patients: an explorative study at a consultation and liaison service in a rural general hospital. AB - BACKGROUND: In recent decades, increasing attention has been paid to the subjective dimension of cancer, especially to psychosocial screening procedures, major psychiatric disorders but also psychological and psychosocial distress, and finally to met needs of oncologic patients. This study aims first to describe cancer patients in a rural hospital attended by a psycho-oncological consultation liaison team, second to assess predictors for psychological distress in cancer patients, and finally to identify predictors for recommendation of further psychosocial support. METHODS: The sample (n = 290) comprises a full survey of patients at breast and bowel cancer services (n=209) and patients referred by other medical and surgical services because of psychosocial impairment (n = 81). All patients were assessed by means of the PO-Bado (Psycho-Oncological Basic Documentation) expert rating scale. Assessment of predictors for psychological distress was conducted by multivariate regression models and assessment for predictors for need for outpatient psychosocial support by a logistic regression analysis. All analyses were conducted using STATA 12. RESULTS: Most members of the assessed sample (average age 65, 82% women) were not severely impaired from a functional and psychological point of view. A total of 14% had received psychiatric treatment before. Mood swings, anxiety, grief, and fatigue were the most important distress symptoms. Selectively referred patients vs. full survey patients of cancer centres, as well as bowel vs. breast cancer patients show a higher level of psychological and physical distress. Fatigue, assessed metastases, and functional limitations were the best predictors for psychological burden. Referral mode, gender, age, family problems, fatigue, and previous psychiatric treatment were associated with further need of psychosocial support. CONCLUSIONS: Psycho-oncological consultation and liaison services may offer support to patients in an early stage of cancer, especially in cancer centres. Because of selectively referred patients show a higher burden, the use of basic screening instruments could be meaningful. Fatigue, metastases status, and functional limitations may better predict psychological distress than pain, duration of illness, psychosocial conditions or previous psychiatric treatment. More attention has to be paid to outpatient follow-up with older cancer patients, those with family problems, and those suffering from significant fatigue. PMID- 24053563 TI - Insights into AT1 receptor activation through AngII binding studies. AB - This study investigates the binding of angiotensin II (AngII) to the angiotensin II type 1 receptor (AT1R), taking into consideration several known activation elements that have been observed for G-protein-coupled receptors (GPCRs). In order to determine the crucial interactions of AngII upon binding, several MD simulations were implemented using AngII conformations derived from experimental data (NMR ROEs) and in silico flexible docking methodologies. An additional goal was to simulate the induced activation mechanism and examine the already known structural rearrangements of GPCRs upon activation. Performing MD simulations to the AT1R - AngII - lipids complex, a series of dynamic changes in the topology of AngII and the intracellular part of the receptor were observed. Overall, the present study proposes a complete binding profile of AngII to the AT1R, as well as the key transitional elements of the receptor and the agonist peptide upon activation through NMR and in silico studies. PMID- 24053564 TI - Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05). AB - OBJECTIVE: To evaluate the efficacy and safety of gemcitabine and cisplatin in combination with sorafenib, a tyrosine-kinase inhibitor, compared with chemotherapy alone as first-line treatment in advanced urothelial cancer. PATIENTS AND METHODS: The study was a randomized phase II trial. Its primary aim was to show an improvement in progression-free survival (PFS) of 4.5 months by adding sorafenib to conventional chemotherapy. Secondary objectives were objective response rate (ORR), overall survival (OS) and toxicity. The patients included in the trial had histologically confirmed locally advanced and/or metastatic urothelial cancer of the bladder or upper urinary tract. Chemotherapy with gemcitabine (1250 mg/qm on days 1 and 8) and cisplatin (70 mg/qm on day 1) repeated every 21 days, was administered to all patients in a double-blind randomization of additional sorafenib (400 mg twice daily) vs placebo (two tablets twice daily) on days 3-21. Treatment continued until progression or unacceptable toxicity, the maximum number of cycles was limited to eight. The response assessment was repeated after every two cycles. RESULTS: Between October 2006 and October 2010, 98 of 132 planned patients were recruited. Nine patients were ineligible. The final analysis included 40 patients in the sorafenib and 49 patients in the placebo arm. There were no significant differences between the two arms concerning ORR (sorafenib: complete response [CR] 12.5%, partial response [PR] 40%; placebo: CR 12%, PR 35%), median PFS (sorafenib: 6.3 months, placebo: 6.1 months) or OS (sorafenib: 11.3 months, placebo: 10.6 months). Toxicity was moderately higher in the sorafenib arm. Diarrrhoea occurred significantly more often in the sorafenib arm and hand-foot syndrome occurred only in the sorafenib arm. The study was closed prematurely because of slow recruitment. CONCLUSION: Although the addition of sorafenib to standard chemotherapy showed acceptable toxicity, the trial failed to show a 4.5 months improvement in PFS. PMID- 24053565 TI - Kinetics, cross-reactivity, and specificity of Bet v 1-specific IgG4 antibodies induced by immunotherapy with birch pollen. AB - BACKGROUND: IgE antibodies specific for the major birch pollen allergen frequently cross-react with Bet v 1 homologous food proteins, for example Cor a 1 in hazelnut and Mal d 1 in apple. Specific immunotherapy with birch pollen (BP SIT) induces IgG4 antibodies that inhibit IgE binding to Bet v 1. However, information on cross-reactivity of BP-SIT-induced Bet v 1-specific IgG4 antibodies with food allergens is limited. In this study, we investigated the kinetics of production, cross-reactivity, and IgE-blocking activity of Bet v 1 specific IgG4 antibodies emerging during conventional BP-SIT and whether IgG4 epitopes overlapped with IgE epitopes. METHODS: IgE and IgG4 levels specific for Bet v 1, Mal d 1, and Cor a 1 were determined in 42 birch pollen-allergic patients before and during BP-SIT. Inhibition of IgE binding was studied by IgE facilitated antigen-binding assays and basophil activation tests. Furthermore, inhibition of IgE-mediated activation of food allergen-reactive Bet v 1-specific T-cell lines was assessed. Competitive immunoscreening of phage-displayed peptides was applied to select mimotopes recognized by IgE and IgG4 antibodies, respectively. The resulting mimotopes were mapped on the surface of the 3D structure of the allergens using a computer-based algorithm. RESULTS: BP-SIT significantly increased Bet v 1- and food allergen-reactive IgG4 antibodies. In parallel, allergen-specific IgE levels decreased significantly. Sera containing food allergen-reactive IgG4 antibodies inhibited IgE binding, basophil activation, and IgE-mediated food allergen-induced T-cell proliferation. Predicted IgE and IgG4 epitopes on all allergens showed high overlap. CONCLUSION: Our results indicate that BP-SIT may induce Bet v 1-specific IgG4 antibodies that cross-react with related food allergens and inhibit IgE binding by epitope competition. PMID- 24053566 TI - Nudging socially isolated people towards well-being with the 'Happiness Route': design of a randomized controlled trial for the evaluation of a happiness-based intervention. AB - BACKGROUND: The Happiness Route is an innovative intervention that uses a happiness-based approach for people with an accumulation of risk factors for low well-being: socially isolated people with health impairments and a low socioeconomic status. The goal of this intervention is to improve well-being by engaging participants in intrinsically motivated activities with methods from positive psychology. We hypothesize that the primary outcome measure, emotional, social and psychological well-being of participants of the Happiness Route, will increase in comparison to the traditional and commonly-used problem-based approach. Secondary outcome measures are health-related quality of life, psychosocial functioning and health care consumption. METHODS AND DESIGN: Participants will be socially isolated people with health problems and a low socioeconomic status. Participants will be recruited in ten Dutch communities and candidates will be signed up by intermediaries, professionals from the health and social sector. Randomly assigned, half of the participants will follow the Happiness Route and half of the participants will follow the active, problem focused control group 'Customized Care'. In total, 256 participants will be included. In both conditions, participants will receive counseling sessions from trained counselors. In the control group, participants will talk about their problems and the care they get and counselors help to optimize their care. In the Happiness Route, the counselor ask questions such as "How do you want to live your life?". The intervention helps people to find their 'passion', i.e., a positive goal-engaged and intrinsically motivated activity. It enables them to follow their passion through by a once-only personal happiness budget (maximal ?500). We use well-validated and reliable questionnaires to measure primary and secondary outcome measures at baseline, directly after the intervention and at a nine-month follow-up. DISCUSSION: Shortcomings of earlier intervention studies in positive psychology will be tackled with this study, such as having a target group who is especially vulnerable for low well-being. The practice-based setting is especially interesting, as it can give valuable insights in how positive psychology interventions work in practice, but can also give rise to several challenges. TRIAL REGISTRATION: Dutch Trial Register, trial registration number TC=3377NTR.http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3377. PMID- 24053567 TI - Occipitocervical fusion. PMID- 24053568 TI - A pilot newborn screening program for Mucopolysaccharidosis type I in Taiwan. AB - BACKGROUND: Mucopolysaccharidosis type I (MPS I) is a genetic disease caused by the deficiency of alpha-L-iduronidase (IDUA) activity. MPS I is classified into three clinical phenotypes called Hurler, Scheie, and Hurler-Scheie syndromes according to their clinical severity. Treatments for MPS I are available. Better outcomes are associated with early treatment, which suggests a need for newborn screening for MPS I. The goal of this study was to determine whether measuring IDUA activity in dried blood on filter paper was effective in newborn screening for MPS I. METHODS: We conducted a newborn screening pilot program for MPS I from October 01, 2008 to April 30, 2013. Screening involved measuring IDUA activity in dried blood spots from 35,285 newborns using a fluorometric assay. RESULTS: Of the 35,285 newborns screened, 19 did not pass the tests and had been noticed for a recall examination. After completing further recheck process, 3 were recalled again for leukocyte IDUA enzyme activity testing. Two of the three had deficient leukocyte IDUA activity. Molecular DNA analyses confirmed the diagnosis of MPS I in these two newborns. CONCLUSIONS: It is feasible to use the IDUA enzyme assay for newborn screening. The incidence of MPS I in Taiwan estimated from this study is about 1/17,643. PMID- 24053569 TI - Progression to detrusor muscle invasion during urothelial carcinoma surveillance is associated with poor prognosis. AB - OBJECTIVE: To evaluate survival in patients after radical cystectomy (RC) who presented with non-muscle-invasive urothelial carcinoma and progressed to muscle invasion during surveillance. Our secondary objective was to evaluate the association between clinical factors before RC and survival. PATIENTS AND METHODS: In all, 981 consecutive Mayo Clinic RC patients without a history of radiation or systemic chemotherapy were reviewed. Of these, 190 had RC after they progressed from non-muscle invasive disease to muscle invasion (progressed to >=pT2). These patients were compared to 310 patients who had RC before muscle invasion (<=pT1), and 481 patients who had muscle invasion at initial presentation (presented with >=pT2). Survival estimates were generated using the Kaplan-Meier method and compared using the log-rank test, while adjusted analyses were performed using Cox proportional hazard regression models. RESULTS: Patients who progressed to muscle invasion on surveillance had a higher risk of death than patients who initially presented with muscle invasion (overall survival hazard ratio [HR] 1.3; 95% confidence interval [CI] 1.0, 1.5). The estimated 5-year cancer-specific survival was 85.4% for patients presenting with <=pT1, 52.9% for patients who progressed to >=pT2, and 62.4% for patients who presented with >=pT2 (P < 0.001). The corresponding 5-year overall survival rates were 70.0%, 42.1%, and 49.5% (P < 0.001). Of the patients who initially presented with non-muscle invasive disease, progression to muscle invasion was associated with increased risk of cancer-specific death (adjusted HR 2.38; 95% CI 1.6, 3.5). Lack of information about patients who presented without muscle invasion and never received RC is the major limitation of this study. CONCLUSIONS: Despite close surveillance, many patients who progress to muscle invasion will die from bladder cancer. Patients who progress to muscle invasion on surveillance seem to have particularly aggressive disease and may benefit from multimodal treatments. PMID- 24053570 TI - Evaluation of lung flute in sputum samples for molecular analysis of lung cancer. AB - BACKGROUND: Molecular analysis of sputum provides a promising approach for lung cancer diagnosis, yet is limited by the difficulty in collecting the specimens from individuals who can't spontaneously expectorate sputum. Lung Flute is a small self-powered audio device that can induce sputum by generating sound waves and vibrating in the airways of the lungs. Here we propose to evaluate the usefulness of Lung Flute for sputum sampling to assist diagnosis of lung cancer. METHODS: Forty-three stage I lung cancer patients and 47 cancer-free individuals who couldn't spontaneously cough sputum were instructed to use Lung Flute for sputum sampling. Expressions of two microRNAs, miRs-31 and 210, were determined in the specimens by qRT-PCR. The results were compared with sputum cytology. RESULTS: Sputum was easily collected from 39 of 43 (90.7%) lung cancer patients and 42 of 47 (89.4%) controls with volume ranges from 1 to 5 ml (median, 2.6 ml). The specimens had less than 4% oral squamous cells, indicating that sputum was obtained from low respiratory tract. Expressions of miRs-31 and 210 in sputum were considerably higher in cancer patients than cancer-free individuals (8.990 vs. 4.514; 0.6847 vs. 0.3317; all P <0.001). Combined use of the two miRNAs produced a significantly higher sensitivity (61.5% vs. 35.9%, P = 0.002) and a slightly lower specificity (90.5% vs. 95.2%, p = 0.03) compared with cytology for lung cancer diagnosis. CONCLUSION: Lung Flute could potentially be useful in convenient and efficient collection of sputum for molecular diagnosis of lung cancer. PMID- 24053571 TI - "Non-canonical protein-DNA interactions identified by ChIP are not artifacts": response. AB - BACKGROUND: Studies of protein association with DNA on a genome wide scale are possible through methods like ChIP-Chip or ChIP-Seq. Massive problems with false positive signals in our own experiments motivated us to revise the standard ChIP Chip protocol. Analysis of chromosome wide binding of the alternative sigma factor sigma32 in Escherichia coli with this new protocol resulted in detection of only a subset of binding sites found in a previous study by Wade and colleagues. We suggested that the remainder of binding sites detected in the previous study are likely to be false positives. In a recent article the Wade group claimed that our conclusion is wrong and that the disputed sites are genuine sigma32 binding sites. They further claimed that the non-detection of these sites in our study was due to low data quality. RESULTS/DISCUSSION: We respond to the criticism of Wade and colleagues and discuss some general questions of ChIP-based studies. We outline why the quality of our data is sufficient to derive meaningful results. Specific points are: (i) the modifications we introduced into the standard ChIP-Chip protocol do not necessarily result in a low dynamic range, (ii) correlation between ChIP-Chip replicates should not be calculated based on the whole data set as done in transcript analysis, (iii) control experiments are essential for identifying false positives. Suggestions are made how ChIP-based methods could be further optimized and which alternative approaches can be used to strengthen conclusions. CONCLUSION: We appreciate the ongoing discussion about the ChIP-Chip method and hope that it helps other scientist to analyze and interpret their results. The modifications we introduced into the ChIP-Chip protocol are a first step towards reducing false positive signals but there is certainly potential for further optimization. The discussion about the sigma32 binding sites in question highlights the need for alternative approaches and further investigation of appropriate methods for verification. PMID- 24053572 TI - Molecular dynamics simulation of diffusion and structure of some n-alkanes in near critical and supercritical carbon dioxide at infinite dilution. AB - The diffusion coefficients of n-alkanes (from CH4 to C14H30) in near critical and supercritical carbon dioxide at infinite dilution have been studied by molecular dynamics simulation. The simulation results agree well with experiment, which suggests that the simulation method is a powerful tool to obtain diffusion coefficients of solutes in fluids at high pressures. The local structures of such fluids are further investigated by calculating radial distribution functions and coordination numbers. Meanwhile, the dihedral, end-to-end distance and radius of gyration, which are calculated to characterize the flexibility of n-alkanes, are used to reasonably explain the abnormal trends on radial distribution functions and coordination numbers. Moreover, it is found that the flexibility effects on diffusion in pure n-alkanes and infinitely dilute n-alkane/CO2 system are different. The differences in MD simulation results of molecular diffusion in such systems could be qualitatively explained by the flexibility. PMID- 24053573 TI - beta-Technetium dichloride: solid-state modulated structure, electronic structure, and physical properties. AB - A second polymorph of technetium dichloride, beta-TcCl2, has been synthesized from the reaction of Tc metal and chlorine in a sealed tube at 450 degrees C. The crystallographic structure and physical properties of beta-TcCl2 have been investigated. The structure of beta-TcCl2 consists of infinite chains of face sharing [Tc2Cl8] units; within a chain, the Tc=Tc vectors of two adjacent [Tc2Cl8] units are ordered in the long-range where perpendicular and/or parallel arrangement of Tc=Tc vectors yields a modulated structure. Resistivity and Seebeck measurements performed on a beta-TcCl2 single crystal indicate the compound to be a p-type semiconductor while a magnetic susceptibility measurement shows technetium dichloride to be diamagnetic. A band gap of 0.12(2) eV was determined by reflectance spectroscopy measurements. Theoretical calculations at the density functional level were utilized for the investigation of other possible stable forms of TcCl2. PMID- 24053574 TI - Integrating life-cycle environmental and economic assessment with transportation and land use planning. AB - The environmental outcomes of urban form changes should couple life-cycle and behavioral assessment methods to better understand urban sustainability policy outcomes. Using Phoenix, Arizona light rail as a case study, an integrated transportation and land use life-cycle assessment (ITLU-LCA) framework is developed to assess the changes to energy consumption and air emissions from transit-oriented neighborhood designs. Residential travel, commercial travel, and building energy use are included and the framework integrates household behavior change assessment to explore the environmental and economic outcomes of policies that affect infrastructure. The results show that upfront environmental and economic investments are needed (through more energy-intense building materials for high-density structures) to produce long run benefits in reduced building energy use and automobile travel. The annualized life-cycle benefits of transit oriented developments in Phoenix can range from 1.7 to 230 Gg CO2e depending on the aggressiveness of residential density. Midpoint impact stressors for respiratory effects and photochemical smog formation are also assessed and can be reduced by 1.2-170 Mg PM10e and 41-5200 Mg O3e annually. These benefits will come at an additional construction cost of up to $410 million resulting in a cost of avoided CO2e at $16-29 and household cost savings. PMID- 24053575 TI - Comparison of changes in production and egg composition in relation to in vivo estimates of body weight and composition of brown and white egg layers during the first egg-laying period. AB - 1. The aim of this study was to compare the changes in the production and in the body and egg composition of 45 TETRA SL brown egg layers and 45 TETRA BLANCA white egg layers during the first egg-laying period. 2. Changes in the body composition of the hens were followed in vivo by means of computed tomography (CT) four-weekly, between 20 and 72 weeks of age. The measurements covered the whole body of the hens using overlapping 10 mm slice thicknesses on a Siemens Somatom Emotion 6 multislice CT scanner. 3. The yolk, albumen and shell ratio of the eggs, produced on the days of the CT measurements by the hens, were determined and their composition was analysed chemically. 4. The body fat content of the hens increased continuously until 44 weeks of age and plateaued thereafter in both genotypes. However, the body fat content of the white egg layers was always higher than that of the brown egg layers. 5. The yolk ratio and the dry matter and crude fat content of the eggs of white egg layers were higher than the brown egg layers throughout the experiment. 6. Moderate correlations were observed in both genotypes between the body fat content of the hens and egg yolk ratio of their eggs. PMID- 24053576 TI - Renal tumour nephrometry score does not correlate with the risk of radiofrequency ablation complications. AB - OBJECTIVES: To assess whether the R.E.N.A.L. nephrometry score (consists of [R]adius [tumour size as maximal diameter], [E]xophytic/endophytic properties of the tumour, [N]earness of tumour deepest portion to the collecting system or sinus, [A]nterior [a]/posterior [p] descriptor and the [L]ocation relative to the polar line) is associated with complication risk in patients that have radiofrequency ablation (RFA) for small renal masses (SRMs). To evaluate a standardised system for predicting complication risks which has not been studied. PATIENTS AND METHODS: We reviewed the records of all patients who underwent RFA at our institution between May 2001 and May 2011. RFA was performed using a temperature-based system and a 25-G nine-tine array needle probe. Patients with preoperative imaging available for R.E.N.A.L. nephrometry scoring were included. R.E.N.A.L. composite scores, tertile stratification and preoperative patient characteristics were analysed for significance in relation to complications. Complications were defined using the Clavien-Dindo classification system. RESULTS: In all, 199 patients had preoperative R.E.N.A.L. nephrometry scores available; 170 underwent percutaneous RFA and 29 laparoscopic RFA. The mean (range) American Society of Anesthesiologists (ASA) score was 2.6 (1-4). The mean (range) tumour size was 2.4 (0.7-5.4) cm. Overall, 14 complications were identified; 10 minor (Clavien I-II) and four major (Clavien III-IV). There was no significant association between complications and R.E.N.A.L. nephrometry score, R.E.N.A.L. nephrometry tertiles, tumour diameter, tumour location or ASA score (P > 0.05). CONCLUSION: R.E.N.A.L. nephrometry scoring fails to predict complications of RFA for SRMs when using a temperature-based nine-tine array probe. PMID- 24053578 TI - Make no bones about it: cells could soon be reprogrammed to grow replacement bones? AB - Recent developments in nuclear reprogramming allow the generation of patient matched stem cells with broad potential for applications in cell therapies, disease modeling and drug discovery. An increasing body of work is reporting the derivation of lineage-specific progenitors from human-induced pluripotent stem cells (hiPSCs), which could in the near future be used to engineer personalized tissue substitutes, including those for reconstructive therapies of bone. Although the potential clinical impact of such technology is not arguable, significant challenges remain to be addressed before hiPSC-derived progenitors can be employed to engineer bone substitutes of clinical relevance. The most important challenge is indeed the construction of personalized multicellular bone substitutes for the treatment of complex skeletal defects that integrate fast, are immune tolerated and display biofunctionality and long-term safety. As recent studies suggest, the merging of iPSC technology with advanced biomaterials and bioreactor technologies offers a way to generate bone substitutes in a controllable, automated manner with potential to meet the needs for scale-up and requirements for translation into clinical practice. It is only via the use of state-of-the-art cell culture technologies, process automation under GMP compliant conditions, application of appropriate engineering strategies and compliance with regulatory policies that personalized lab-made bone grafts can start being used to treat human patients. PMID- 24053577 TI - Auricular acupuncture for prehypertension and stage 1 hypertension: study protocol for a pilot multicentre randomised controlled trial. AB - BACKGROUND: Hypertension, a worldwide public health problem, is a major risk factor for cardiovascular and kidney disease, and the medical and economic burden of hypertension is increasing. Auricular acupuncture has been used to treat various diseases, including hypertension. Several studies have shown that auricular acupuncture treatment decreases blood pressure in patients with hypertension; however, the scientific evidence is still insufficient. Therefore, we aimed to perform a randomised controlled clinical trial in patients with prehypertension and stage 1 hypertension to evaluate the effect and safety of auricular acupuncture. METHODS/DESIGNS: This on-going study is a two parallel arm, assessor-blinded, randomised controlled trial. Sixty participants with prehypertension and stage 1 hypertension will be recruited and randomly allocated into two groups in a 1:1 ratio. Participants in the auricular acupuncture group will receive auricular acupuncture treatment two times per week for 4 weeks. Participants in the usual care group will not receive any acupuncture treatment during the study period. All participants in both groups will be provided with verbal and written educational materials regarding the dietary and physical activity habits for controlling high blood pressure, and they will self-manage their lifestyle, including diet and exercise, during the study. The primary outcome is the 24-h average systolic and diastolic blood pressure, as measured with an ambulatory monitor. The secondary outcomes are the mean change in the average systolic and diastolic blood pressure during day- and night-time, the circadian rhythm of blood pressure, the mean arterial pressure, the change in blood pressure before and after auricular acupuncture treatment, the EuroQOL-5D (EQ-5D), heart rate variability (HRV), body mass index (BMI) and laboratory examination, including lipid profile and high sensitivity C-reactive protein (hs CRP). Safety will be assessed at every visit. DISCUSSION: This pilot multicentre randomised controlled trial will explore the feasibility of further auricular acupuncture research and provide important clinical evidence for the effect and safety of auricular acupuncture on blood pressure in patients with prehypertension and stage 1 hypertension compared with usual care. TRIAL REGISTRATION: Clinical Research Information Service: KCT0000169. PMID- 24053579 TI - Local pH-responsive diazoketo-functionalized photoresist for multicomponent protein patterning. AB - Selective surface immobilization of multiple biomolecule components, under mild conditions where they do not denature, is attractive for applications in biosensors and biotechnology. Here, we report on a biocompatible and pH responsive photoresist containing diazoketo-functionalized methacrylate, methacrylic acid, and poly(ethylene glycol) methacrylate monomers, where the photolithographic process may be carried out in a local pH range to minimize biomolecular denaturation. The polymer is insoluble or sparsely soluble in pH 6.4 or more acidic solution or deionized water, but soluble in a basic solution, pH 7.9 or more. After UV exposure, however, carboxylic acid groups are generated by Wolff rearrangement and photodissociation of the diazoketo groups in the polymer chain, leading to dissolution of UV-exposed polymer at pH 6.4. Using the property of the pH-solubility switching, we demonstrate dual streptavidin patterning using only biological buffers, pH 6.4 and 7.9 solutions, and double exposure patterning to confirm the sustainability of the diazoketo groups in unexposed regions despite carrying out several wet processes. PMID- 24053580 TI - Tunable protein release from acetalated dextran microparticles: a platform for delivery of protein therapeutics to the heart post-MI. AB - The leading cause of death in the United States is cardiovascular disease. The majority of these cases result from heart failure post-myocardial infarction (MI). We present data providing evidence for use of acetalated dextran (AcDex) microparticles as a delivery vehicle for therapeutics to the heart post-MI. We harnessed the tunable degradation and acid-sensitivity of AcDex in the design of microparticles for intramyocardial injection. The particles released a model protein, myoglobin, and a sensitive growth factor, basic fibroblast growth factor (bFGF), over a wide range of time frames (from days to weeks) based on the percentage of cyclic acetals in the AcDex, which was easily controlled with acetalation reaction time. The release was shown in low pH environments, similar to what is found in an infarcted heart. bFGF maintained activity after release from the microparticles. Finally, biocompatibility of the microparticles was assessed. PMID- 24053581 TI - HIV-1 drug resistance in recently HIV-infected pregnant mother's naive to antiretroviral therapy in Dodoma urban, Tanzania. AB - BACKGROUND: HIV resistance affects virological response to therapy and efficacy of prophylaxis in mother-to-child-transmission. The study aims to assess the prevalence of HIV primary resistance in pregnant women naive to antiretrovirals. METHODS: Cross sectional baseline analysis of a cohort of HIV + pregnant women (HPW) enrolled in the study entitled Antiretroviral Management of Antenatal and Natal HIV Infection (AMANI, peace in Kiswahili language). The AMANI study began in May 2010 in Dodoma, Tanzania. In this observational cohort, antiretroviral treatment was provided to all women from the 28th week of gestation until the end of the breastfeeding period. Baseline CD4 cell count, viral load and HIV drug resistance genotype were collected. RESULTS: Drug-resistance analysis was performed on 97 naive infected-mothers. The prevalence of all primary drug resistance and primary non-nucleoside reverse-transcriptase inhibitors resistance was 11.9% and 7.5%, respectively. K103S was found in two women with no M184V detection. HIV-1 subtype A was the most commonly identified, with a high prevalence of subtype A1, followed by C, D, C/D recombinant, A/C recombinant and A/D recombinant. HIV drug- resistance mutations were detected in A1 and C subtypes. CONCLUSION: Our study reports an 11.9% prevalence rate of primary drug resistance in naive HIV-infected pregnant women from a remote area of Tanzania. Considering that the non-nucleoside reverse-transcriptase inhibitors are part of the first-line antiretroviral regimen in Tanzania and all of Africa, resistance surveys should be prioritized in settings where antiretroviral therapy programs are scaled up. PMID- 24053582 TI - Infected forearm nonunion treated by bone transport after debridement. AB - BACKGROUND: This is a therapeutic study to evaluate the results of the management of forearm infected nonunion using bone transport with external fixators after debridement. METHODS: We have retrospectively reviewed a consecutive series of 21 patients from October 1994 to June 2010 in our institution who were treated for the forearm infected nonunion by bone transport with external fixator after debridement. There were 12 males and 9 females. The mean age of the patients was 27.1 years. Of the initial fractures, nonunion of the radius alone invovled in 7 patients, nonunion of the ulna alone invovled in 12, and nonunion of the radius and ulna invovled in 2. Nineteen limbs (85.7%) were in active infected state with sinus and drainage. The mean amount of bone defect was 3.1 cm (range 1.8-4.6 cm) as measured on plain radiographs. RESULTS: The mean follow-up was 77.5 months. All patients achieved bony union and were satisfied with the functional and cosmetic outcome. All the infection had been controlled. The mean external fixation index was 42.5 day/cm. The average time for wound healing was 42 days. The mean length gained was 3.5 cm (2.1-5.3 cm). CONCLUSIONS: The technique of bone transport after debridement is a safe, effective, and minimally invasive treatment for forearm infected nonunion. PMID- 24053583 TI - Contribution of the Japan International Cooperation Agency health-related projects to health system strengthening. AB - BACKGROUND: The Japan International Cooperation Agency (JICA) has focused its attention on appraising health development assistance projects and redirecting efforts towards health system strengthening. This study aimed to describe the type of project and targets of interest, and assess the contribution of JICA health-related projects to strengthening health systems worldwide. METHODS: We collected a web-based Project Design Matrix (PDM) of 105 JICA projects implemented between January 2005 and December 2009. We developed an analytical matrix based on the World Health Organization (WHO) health system framework to examine the PDM data and thereby assess the projects' contributions to health system strengthening. RESULTS: The majority of JICA projects had prioritized workforce development, and improvements in governance and service delivery. Conversely, there was little assistance for finance or medical product development. The vast majority (87.6%) of JICA projects addressed public health issues, for example programs to improve maternal and child health, and the prevention and treatment of infectious diseases such as AIDS, tuberculosis and malaria. Nearly 90% of JICA technical healthcare assistance directly focused on improving governance as the most critical means of accomplishing its goals. CONCLUSIONS: Our study confirmed that JICA projects met the goals of bilateral cooperation by developing workforce capacity and governance. Nevertheless, our findings suggest that JICA assistance could be used to support financial aspects of healthcare systems, which is an area of increasing concern. We also showed that the analytical matrix methodology is an effective means of examining the component of health system strengthening to which the activity and output of a project contributes. This may help policy makers and practitioners focus future projects on priority areas. PMID- 24053584 TI - Prospective evaluation of a preoperative biomarker panel for prediction of upstaging at radical cystectomy. AB - OBJECTIVES: To prospectively test whether a panel of biomarkers could identify patients with organ-confined disease likely to be upstaged at radical cystectomy (RC), as retrospective studies have found that cell-cycle- and proliferation related biomarkers can help improve prognostic accuracy after RC. PATIENTS AND METHODS: We prospectively performed p53, p21, p27, Ki67, and cyclin E1 immunohistochemical staining on transurethral resection of the bladder (TURB) specimens from 87 patients treated with RC for organ-confined urothelial carcinoma of the bladder (UCB). The number of altered biomarkers was categorised as 'favourable' (<=2 altered markers) or 'unfavourable' (>2). RESULTS: Expression of p53, p21, p27, cyclin E1, and Ki67 were altered in 61 (70%), 19 (22%), 26 (30%), four (5%), and 70 (80%) patients, respectively. The median number of positive markers was two. In all, 47 (54%) patients were upstaged when T-stage was considered alone and 49 (56%) when T- and/or N-stage were considered both as upstaging. In multivariable analyses that adjusted for the effects of age, clinical stage, concomitant carcinoma in situ, and time from TURB to RC, an 'unfavourable' biomarker score was independently associated with T-stage upstaging (hazard ratio [HR] 3.3, P = 0.024) but not T- and/or N-stage upstaging (HR 2.76, P = 0.06). Addition of p27, number of positive markers, and biomarker score each increased the discrimination of a base model for prediction of T-stage upstaging (5%, 6%, and 5%, respectively) and T- and/or N-stage upstaging (4%, 6%, and 3%, respectively). CONCLUSIONS: Cell-cycle- and proliferation-related markers in the TURB specimen improve the prediction of upstaging at RC. Such a marker panel may help identify patients with non-muscle-invasive UCB who are clinically under-staged needing RC and patients with muscle-invasive UCB who are likely to be non-organ-confined thereby potentially benefiting from neoadjuvant chemotherapy. PMID- 24053585 TI - A size-dependent sodium storage mechanism in Li4Ti5O12 investigated by a novel characterization technique combining in situ X-ray diffraction and chemical sodiation. AB - A novel characterization technique using the combination of chemical sodiation and synchrotron based in situ X-ray diffraction (XRD) has been detailed illustrated. The power of this novel technique was demonstrated in elucidating the structure evolution of Li4Ti5O12 upon sodium insertion. The sodium insertion behavior into Li4Ti5O12 is strongly size dependent. A solid solution reaction behavior in a wide range has been revealed during sodium insertion into the nanosized Li4Ti5O12 (~44 nm), which is quite different from the well-known two phase reaction of Li4Ti5O12/Li7Ti5O12 system during lithium insertion, and also has not been fully addressed in the literature so far. On the basis of this in situ experiment, the apparent Na(+) ion diffusion coefficient (DNa+) of Li4Ti5O12 was estimated in the magnitude of 10(-16) cm(2) s(-1), close to the values estimated by electrochemical method, but 5 order of magnitudes smaller than the Li(+) ion diffusion coefficient (D(Li+) ~10(-11) cm(2) s(-1)), indicating a sluggish Na(+) ion diffusion kinetics in Li4Ti5O12 comparing with that of Li(+) ion. Nanosizing the Li4Ti5O12 will be critical to make it a suitable anode material for sodium-ion batteries. The application of this novel in situ chemical sodiation method reported in this work provides a facile way and a new opportunity for in situ structure investigations of various sodium-ion battery materials and other systems. PMID- 24053586 TI - Oncological outcomes after robot-assisted radical prostatectomy: long-term follow up in 4803 patients. AB - OBJECTIVE: To evaluate oncological outcomes in patients undergoing robot-assisted radical prostatectomy (RARP) at a high-volume tertiary centre with focus on biochemical recurrence (BCR); previous studies on oncological outcomes for patients undergoing RARP for prostate cancer are limited to small series. PATIENTS AND METHODS: In all, 5152 consecutive patients underwent RARP from 2001 to 2010; 4803 patients comprised the study cohort after exclusions. BCR was defined as a serum prostate-specific antigen (PSA) level of >=0.2 ng/mL with a confirmatory value. BCR-free survival (BCRFS), metastasis-free survival (MFS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method and Cox hazards regression models were generated. RESULTS: The mean preoperative PSA level was 6.1 ng/mL, pathological Gleason grade and stage were >=7 in 68% and >=pT3 in 34% of patients. There was BCR in 470 patients (9.8%), 31 patients developed metastatic disease (0.7%) and 13 patients died from prostate cancer (0.3%) during a mean (range) follow-up of 34.6 (1-116.7) months. Actuarial 8-year BCRFS, MFS and CSS were 81%, 98.5% and 99.1%, respectively. In patients with node positive disease, actuarial 5-year BCRFS, MFS, and CSS were 26%, 82%, and 97%. For organ-confined disease, predictors of BCR included pathology Gleason grade (primary Gleason 5 vs 3, hazard ratio [HR] 5.52, P = 0.018; Gleason 4 vs 3, HR 1.97, P = 0.001), preoperative PSA level (10-20 vs <=10 ng/mL, HR 2.38, P = 0.001), and surgical margin status (positive vs negative, HR 3.84, P < 0.001) CONCLUSIONS: RARP appears to confer effective long-term biochemical control. To our knowledge, this is the largest report of oncological outcomes in a RARP series to date. PMID- 24053587 TI - Oral health status and treatment needs among psychiatric inpatients in Rennes, France: a cross-sectional study. AB - BACKGROUND: Severe mental disorders have a chronic course associated with a high risk for co-morbid somatic illnesses and premature mortality and oral health is critical for overall systemic health. But general health care needs in this population are often neglected. Some studies have aimed at determining the oral health status of psychiatric in-patients but to date, no emphasis has been placed on oral health of psychiatric patients in France. The goal of this study was to assess the oral health and treatment needs of institutionalized patients in a large psychiatric hospital, where a dental service was available and free, to compare it with the average population, with psychiatric in-patients in other countries and to provide recommendations for psychiatrists and care-giving staff. METHODS: The dental status (DMFT), the oral hygiene (OHIS: Simplified Oral Hygiene Index), the saliva flow rate were recorded on a randomized patient sample. Demographic and medical data were retrieved from the institutional clinical files. RESULTS: Among the 161 examined patients, 95 (59.0%) were men and 66 (41.0%) were women. The mean age was 46.9 +/- 17.5 years. The majority was diagnosed schizophrenia (36.6%) or mood disorders (21.1%). The mean OHIS was 1.7 +/- 1.1. Among the 147 patients who agreed to carry out the salivary examination, the average saliva flow rate was 0.3 g +/- 0.3 g/min. Saliva flow under the average rest saliva flow (0.52 mg/min) was found for 80.3% of the patient. The mean DMFT was 15.8 +/- 8.8 (D = 3.7 +/- 4.4, M = 7.3 +/- 9.4, F = 4.7 +/- 4.9) and significantly increased with age (p < 0.001) and degree of disability (p = 0.003) (stepwise linear regression). Eighteen patients (11.2%) were edentulous. CONCLUSIONS: The DMFT was similar to low income French population but psychiatric patients had almost 4 times more decayed teeth, slightly less missing teeth and 1.5 times less filled teeth. Oral health appeared to be better than in most other countries. But compared to general population, the still unmet dental and prosthetic needs indicated the major need of enhanced access to dental care and specific preventive programs. PMID- 24053588 TI - The presence of heat-labile factors interfering with binding analysis of fibrinogen with ferritin in horse plasma. AB - BACKGROUND: Horse fibrinogen has been identified as a plasma specific ferritin binding protein. There are two ways in the binding of ferritin-binding protein with ferritin: one is direct binding and the other is indirect binding which is heme-mediated. The aim of this study was to analyze the binding between horse fibrinogen and ferritin. FINDINGS: Although fibrinogen in horse plasma did not show the binding to ferritin coated on the plate wells, after following heat treatment (60 degrees C, 30 min) of horse plasma, plasma fibrinogen as well as purified horse fibrinogen bound to plates coated with horse spleen ferritin, but not with its apoferritin which lost heme as well as iron after the treatment of reducing reagent. Binding of purified or plasma fibrinogen to ferritin was inhibited by hemin and Sn-protoporphyrin IX (Sn-PPIX), but not by PPIX or Zn PPIX. CONCLUSIONS: Heat-treatment of horse plasma enabled plasma fibrinogen to bind to plate well coated with holo-ferritin. From the binding analysis of fibrinogen and ferritin, it is suggested that horse fibrinogen recognized iron or tin in complexed with the heme- or the hemin-ring, and also suggest that some fibrinogens circulate in the form of a complex with ferritin and/or heat-labile factors which inhibit the binding of fibrinogen with ferritin. PMID- 24053589 TI - Particle deflection in a poly(dimethylsiloxane) microchannel using a propagating surface acoustic wave: size and frequency dependence. AB - We study the effect of a propagating surface acoustic wave (PSAW) with different frequencies on particles with different sizes in microfluidic channels. We find that the deflection critically depends on the applied frequency as well as on the particle size. For fixed frequencies, large particles are deflected and migrate perpendicular to the flow direction while smaller particles only follow the streamlines of the flow field. However, with increasing frequency of the PSAW above a size dependent limit, small particles are also actuated. This relation can be characterized by the wavenumber k and the particle radius r using the parameter kappa = k . r. For the onset of deflection, we find a critical value kappac ? 1.28 +/- 0.20. Finally, we demonstrate how this device can be used for particle separation. PMID- 24053591 TI - Whole-genome sequencing and infectious disease: a novel application of sequencing technology. PMID- 24053590 TI - Successful resection of hepatocellular cancer not amenable to Milan criteria and durable complete remission induced by systemic polichemotherapy after development of metastases - should we think about revising the current treatment guidelines in selected patients? AB - OBJECTIVES: To refresh clinical diagnostic and therapeutic dilemmas in patients presenting with hepatocellular cancer (HCC) and to report a rare success of systemic polichemotherapy in metastatic HCC. METHODS: Case report of a patient with successfully resected HCC although initially deemed inoperable according to current guidelines, and who was successfully treated by systemic polichemotherapy after development of metastatic disease, resulting in a sustained complete remission. RESULTS: We describe a 71-year-old female with HCC initially treated by atypical liver resection, although not amenable to initial surgery according to current treatment guidelines, which resulted in 6 months disease-free interval. After development of pulmonary metastases, the patient was treated by systemic polichemotherapy, due to local unavailability of novel biologic agents. After 3 months of chemotherapy biochemical remission was confirmed, and after 10 months of active treatment complete radiological remission was verified according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, now exceeding 9 months in duration. CONCLUSION: There is an increasing body of evidence that criteria for surgical interventions in HCC should be revised and expanded, and our case is an example of such an approach. Although novel biologic therapies are not widely available in all regions of the world due to their cost, currently there are no hard recommendations for use of chemotherapy in such areas. Since this is a large problem in clinical practice, we conclude that chemotherapy should be offered to selected patients of good performance status if novel agents are unavailable. PMID- 24053592 TI - Characterizing episodic breathlessness in patients with advanced disease. AB - BACKGROUND: Episodic breathlessness is a common and distressing symptom in advanced cancer and nonmalignant diseases but there is a lack of evidence on the characteristics of the symptom. OBJECTIVE: The aim of this study was to determine the duration, severity, frequency and timing of breathlessness episodes in patients with advanced diseases. METHODS: Explorative analysis of pooled cross sectional data on episodic breathlessness collected in personal interviews with patients suffering from chronic obstructive pulmonary disease, lung cancer, chronic heart failure, or motor neuron disease. Interviews were conducted as part of two studies in the UK and in Germany that included the same questions on duration, frequency, timing, and peak severity of breathlessness episodes. Severity was measured on the modified Borg scale (0-10). RESULTS: One hundred and twenty-nine patients, 61% male, mean age of 67 years (SD 9.8), were included. The episodes described were mainly short (75%<=10 min), severe (mean 6.5 (SD 2.4), and occurred mostly daily. Frequency of episodes triggered by exertion could hardly be determined as these varied depending on patients' activity. CONCLUSION: Our study reveals clinically important information on the characteristics of episodic breathlessness in patients with advanced diseases. Findings have implications for the treatment of episodic breathlessness since most short-acting drugs in use have a longer onset of action compared to the duration of episodes. We need to determine patient-relevant therapeutic targets for future evaluation of adequate pharmacological and nonpharmacological management options that are urgently warranted. PMID- 24053593 TI - Predictors of intensive end-of-life and hospice care in Latino and white advanced cancer patients. AB - BACKGROUND: The role of end-of-life (EOL) care preferences and conversations in receipt of care near death for Latinos is unclear. OBJECTIVE: This study examines rates and predictors of intensive EOL and hospice care among Latino and white advanced cancer patients. DESIGN: Two-hundred-and-ninety-two self-reported Latino (n=58) and white (n=234) Stage IV cancer patients participated in a U.S. multisite, prospective, cohort study from September 2002 to August 2008. The Latino and white, non-Hispanic participants were interviewed and followed until death, a median of 118.5 days from baseline. MEASUREMENTS: Patient-reported, baseline predictors of EOL care included EOL care preference; terminal illness acknowledgement; EOL discussion; completion of a DNR order; and religious coping. Caregiver postmortem interviews provided information regarding EOL care received. Intensive EOL care was defined as resuscitation and/or ventilation followed by death in an intensive care unit. Hospice was either in- or outpatient. RESULTS: Latino and white patients received intensive EOL and hospice care at similar rates (5.2% and 3.4% for intensive care, p=0.88; 70.7% versus 73.4% for hospice, p=0.33). No white or Latino patient who reported a DNR order or EOL discussion at baseline received intensive EOL care. Religious coping and a preference for life extending care predicted intensive EOL care for white patients (adjusted odds ratio [aOR] 6.69 [p=0.02] and aOR 6.63 [p=0.01], respectively), but not for Latinos. No predictors were associated with Latino hospice care. CONCLUSIONS: EOL discussions and DNR orders may prevent intensive EOL care among Latino cancer patients. Efforts should continue to engage Latino patients and caregivers in these activities. PMID- 24053594 TI - Bladder outlet obstruction (BOO) in men with castration-resistant prostate cancer. AB - OBJECTIVE: To evaluate the frequency of bladder outlet obstruction (BOO) and detrusor overactivity (DO) in patients with castration-resistant prostate cancer (CRPC) and lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: Our prospective urodynamics database was queried. Inclusion criteria were CRPC and an International Prostate Symptom Score (IPSS) >= 20. Exclusion criteria were previous local therapy to the prostate gland, known urethral stricture disease, and a neurological component of LUTS. Twenty-one patients were identified. Urodynamic findings were analysed and compared with those of a matched cohort of 42 patients with benign prostatic enlargement (BPE). RESULTS: The median age of patients in the CRPC group was 74 years, and the median prostate-specific antigen (PSA) level at the time of the urodynamic study was 90 ng/mL. According to the BOO index, three patients (14%) were obstructed, three were equivocally obstructed (14%) and 15 were unobstructed. DO was seen in 12 patients (57%). Compared with the BPE group, patients with CRPC had lower cystometric bladder capacities (P = 0.003), were less likely to have BOO (14 vs 43%, P = 0.009) and more likely to have DO (57 vs 29%, P = 0.028). CONCLUSIONS: This study generates the hypothesis that only a minority of CRPC patients with LUTS have BOO, and that more than half of patients have DO. LUTS in CRPC may therefore be seldom attributable to BOO, but are, at least in part, related to DO and reduced cystometric capacity. A urodynamic investigation may be necessary before palliative transurethral resection of the prostate to select appropriate candidates. Larger prospective studies are needed to confirm our findings. PMID- 24053595 TI - Multifocal lymphangioendotheliomatosis with devastating intracranial hemorrhage. AB - An in utero female was found to have a small hemorrhage at the foramen of Monro, hydrocephalus, and what was originally interpreted as a Dandy-Walker variant. At birth she had macrocephaly and numerous cutaneous, multifocal, red-pink blanchable macules. Postnatal MRI demonstrated a hemorrhagic soft-tissue mass involving the upper brainstem, thalamus, and basal ganglia most consistent with in utero complex multifocal intracranial hemorrhage. The skin lesions were thought to be consistent with multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT). The size and location of the hemorrhage precluded operative intervention, although the hydrocephalus was treated with a ventricular shunt. The child continues to have severe developmental delays. Multifocal lymphangioendotheliomatosis with thrombocytopenia is a multifocal vascular disorder most commonly involving the skin and gastrointestinal tract. Intracranial hemorrhages are rare in this context. This case is the third reported instance of MLT with associated intracranial hemorrhage and the only case described in the neurosurgical literature. The authors review the presenting features and pathophysiology of this condition. PMID- 24053596 TI - Telomere maintenance as a target for drug discovery. AB - The observation that the enzyme telomerase is up-regulated in 80-90% of cancer cells isolated from primary human tumors but is absent in neighboring cells of healthy tissue has resulted in significant efforts to validate telomerase as an anticancer drug target and to develop effective approaches toward its inhibition. In addition to inhibitors that target the enzymatic function of telomerase, efforts toward immunotherapy using peptides derived from its catalytic subunit hTERT and hTERT-promoter driven gene therapy have made significant advances. The increased level of telomerase in cancer cells also provides a potential platform for cancer diagnostics. Telomerase inhibition leads to disruption of a cell's ability to maintain the very ends of the chromosomes, which are called telomeres. Thus, the telomere itself has also attracted attention as an anticancer drug target. In this Perspective, interdisciplinary efforts to realize the therapeutic potential of targeting telomere maintenance with a focus on telomerase are discussed. PMID- 24053597 TI - The obesity-asthma link in different ages and the role of body mass index in its investigation: findings from the Genesis and Healthy Growth Studies. AB - BACKGROUND: To date, an obesity/asthma link is well defined in adults; however, the nature of such a link is obscure in children, partly due to Body Mass Index (BMI) limitations as a surrogate fat mass marker in childhood. We thus opted to investigate the association of adiposity with asthma in children of different ages, using several indices to assess fat mass. METHODS: Wheeze ever/in the last 12 months (current) and physician-diagnosed asthma were retrospectively reported via questionnaire by the parents of 3641 children, participating in two cross sectional studies: 1626 children aged 2-5 (the Genesis Study) and 2015 children aged 9-13 (the Healthy Growth Study). Perinatal data were recorded from the children's medical records or reported by parents. Anthropometric measurements (i.e., BMI, waist/hip circumference, biceps/triceps/subscapular/suprailiac skinfold thickness) were conducted in both cohorts; bioelectric impedance analysis (BIA) was conducted only in preadolescent children. RESULTS: In children aged 2-5, asthma was positively correlated with conicity index, waist/hip circumference, waist-to-height ratio, skinfold thickness, and skinfold-derived percentage fat mass (P < 0.05) but not BMI or BMI-defined overweight/obesity, after adjusting for several confounders. In children aged 9-13, asthma was positively associated with conicity index, waist circumference, waist-to-height ratio, skinfold thickness, skinfold-derived percentage fat mass, BIA-derived percentage fat mass, BMI, and BMI-defined overweight/obesity, following adjustment (P < 0.05). Current/ever wheeze was not consistently associated with fat mass in either population. CONCLUSIONS: Fat mass is positively linked to asthma in both 2-5 and 9-13 age spans. However, the failure of BMI to correlate with preschool asthma suggests its potential inefficiency in asthma studies at this age range. PMID- 24053598 TI - Simultaneous evaluation of multiple rotationally excited states of H3(+), H3O(+), and CH5(+) using diffusion Monte Carlo. AB - An extension to diffusion Monte Carlo (DMC) is proposed for simultaneous evaluation of multiple rotationally excited states of fluxional molecules. The method employs an expansion of the rotational dependence of the wave function in terms of the eigenstates of the symmetric top Hamiltonian. Within this DMC approach, each walker has a separate rotational state vector for each rotational state of interest. The values of the coefficients in the expansion of the rotational state vector associated with each walker, as well as the locations of the walkers, evolve in imaginary time under the action of a propagator based on the imaginary-time time-dependent Schrodinger equation. The approach is first applied to H3(+), H2D(+), and H3O(+) for which the calculated energies can be compared to benchmark values. For low to moderate values of J the DMC results are found to be accurate to within the evaluated statistical uncertainty. The rotational dependence of the vibrational part of the wave function is also investigated, and significant rotation-vibration interaction is observed. Based on the successful application of this approach to H3(+), H2D(+), and H3O(+), the method was applied to calculations of the rotational energies and wave functions for CH5(+) with v = 0 and J <= 10. Based on these calculations, the rotational energy progression is shown to be consistent with that for a nearly spherical top molecule, and little evidence of rotation-vibration interaction is found in the vibrational wave function. PMID- 24053599 TI - CP110 and its network of partners coordinately regulate cilia assembly. AB - Cilia are hair-like protrusions found at the surface of most eukaryotic cells. They can be divided into two types, motile and non-motile. Motile cilia are found in a restricted number of cell types, are generally present in large numbers, and beat in a coordinated fashion to generate fluid flow or locomotion. Non-motile or primary cilia, on the other hand, are detected in many different cell types, appear once per cell, and primarily function to transmit signals from the extracellular milieu to the cell nucleus. Defects in cilia formation, function, or maintenance are known to cause a bewildering set of human diseases, or ciliopathies, typified by retinal degeneration, renal failure and cystic kidneys, obesity, liver dysfunction, and neurological disorders. A common denominator between motile and primary cilia is their structural similarity, as both types of cilia are composed of an axoneme, the ciliary backbone that is made up of microtubules emanating from a mother centriole/basal body anchored to the cell membrane, surrounded by a ciliary membrane continuous with the plasma membrane. This structural similarity is indicative of a universal mechanism of cilia assembly involving a common set of molecular players and a sophisticated, highly regulated series of molecular events. In this review, we will mainly focus on recent advances in our understanding of the regulatory mechanisms underlying cilia assembly, with special attention paid to the centriolar protein, CP110, its interacting partner Cep290, and the various downstream molecular players and events leading to intraflagellar transport (IFT), a process that mediates the bidirectional movement of protein cargos along the axoneme and that is essential for cilia formation and maintenance. PMID- 24053600 TI - The efficacy of a standardised product from dried leaves of Solanum glaucophyllum as source of 1,25-dihydroxycholecalciferol for poultry. AB - 1. Chemical characterisation of an extract of Solanum glaucophyllum (SG) leaves affirmed the predominant presence of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) glycosides. The compound 1-(beta-D-glucopyranosyl)-1alpha,25 dihydroxycholecalciferol was isolated for the first time from a natural source. 2. Vitamin D activity of the extract was confirmed by the calcaemic properties shown in a quail eggshell bioassay. The results suggested a 1,25(OH)2D3 bioavailability of approximately 15%. 3. A broiler feeding experiment replicated in time was carried out with 6 treatments. A basic control diet containing 25 MUg cholecalciferol/kg was supplemented with 2.5 and 5 MUg free 1,25(OH)2D3/kg, with a product based on dried SG leaves (Panbonis) providing 10 MUg of 1,25(OH)2D3 glycosides/kg, with two concentrations of an SG extract providing 8.8 and 37.8 MUg of 1,25(OH)2D3-glycosides/kg. 4. Tibia breaking strength and stiffness were numerically greater in all treatment groups with free 1,25(OH)2D3 and with SG products compared to controls, though the overall treatment effects only had probabilities in the range of P = 0.07 to P = 0.1. Values for both characteristics increased progressively, with additions of synthetic 1,25(OH)2D3; values with the dried SG product were similar to those with 5 MUg synthetic 1,25(OH)2D3/kg. 5. Plasma calcium was mildly elevated (P < 0.05) in treatment groups. The SG extract treatment containing 37.8 MUg 1,25(OH)2D3/kg gave the highest plasma calcium concentration and lowest bodyweight, signs of marginal hypervitaminosis D. Plasma 1,25(OH)2D3 concentrations were in the normal range for all treatments. 6. Tibial dyschondroplasia occurred in only one replicate. The incidences were 31% in controls but considerably lower or zero with all other treatments. 7. Bioavailability of 1,25(OH)2D3 in the SG product seemed to be higher in broiler chickens than in Japanese quails. 8. It is concluded that the inclusion of the dried SG product as a source of vitamin D3 in broiler diets at a dietary concentration of 1 g/kg, providing 10 MUg 1,25(OH)2D3/kg, is safe and efficacious. PMID- 24053601 TI - Prostate-specific antigen doubling time as a progression criterion in an active surveillance programme for patients with localized prostate cancer. AB - OBJECTIVES: To elucidate the role of prostate-specific antigen (PSA) doubling time (PSAdt) as a progression criterion in patients with low-risk prostate cancer managed by active surveillance (AS). To assess the correlation between PSAdt during AS and final histopathology after radical prostatectomy (RP) in patients meeting predefined progression criteria. PATIENTS AND METHODS: A total of 258 consecutive patients on an AS programme were included in the study. The PSAdt was calculated in patients with two or more PSA values, and 95% confidence intervals (CIs) were calculated in patients with four or more PSA values. Progression risk groups were defined as follows: high-risk: PSAdt <3 years, rebiopsy Gleason score (GS) >=4 + 3, more than three positive biopsy cores, and/or bilateral tumour or cT >=2c disease; intermediate-risk: PSAdt 3-5 years, GS = 3 + 4 or cT2b disease; and low-risk: PSAdt >5 years, without histopathological or clinical progression. Definitive treatment was recommended for patients in the high-risk group and treatment options were discussed with those in the intermediate-risk group. RESULTS: A total of 2291 PSA values obtained during AS were available, of which 2071 were considered valid in the 258 patients. PSAdt values with 95% CIs were calculated in 221 patients based on a median of 8 PSA values. The 95% CIs for PSAdt overlapped considerably and in up to 91% of the patients, the 95% CIs overlapped among the risk group definitions. A total of 26% (68/258 patients) underwent RP after meeting the progression criteria. There was no association between preoperative PSAdt and final histopathology (P = 0.87). CONCLUSION: The uncertainty of calculated PSAdt during AS leads to a significant risk of patients being misclassified in terms of risk of progression, which limits the use of PSAdt in the management of patients on AS. PMID- 24053602 TI - Systematic review and meta-analysis of the clinical effectiveness of bipolar compared with monopolar transurethral resection of the prostate (TURP). AB - To compare monopolar and bipolar transurethral resection of the prostate (TURP) for clinical effectiveness and adverse events. We conducted an electronic search of MEDLINE, Embase, CENTRAL, Science Citation Index, and also searched reference lists of articles and abstracts from conference proceedings for randomised controlled trials (RCTs) comparing monopolar and bipolar TURP. Two reviewers independently undertook data extraction and assessed the risk of bias in the included trials using the tool recommended by the Cochrane Collaboration. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. From the 949 abstracts that were identified, 94 full texts were assessed for eligibility and a total of 24 trials were included in the review. No statistically significant differences were found in terms of International Prostate Symptom Score (IPSS) or health-related quality of life (HRQL) score. Results for maximum urinary flow rate were significant at 3, 6 and 12 months (all P < 0.001), but no clinically significant differences were found and the meta-analysis showed evidence of heterogeneity Bipolar TURP was associated with fewer adverse events including transurethral resection syndrome (risk ratio [RR] 0.12, 95% confidence interval [CI] 0.05-0.31, P < 0.001), clot retention (RR 0.48, 95% CI 0.30-0.77, P = 0.002) and blood transfusion (RR 0.53, 95% CI 0.35-0.82, P = 0.004) Several major methodological limitations were identified in the included trials; 22/24 trials had a short follow-up of <=1 year, there was no evidence of a sample size calculation in 20/24 trials and the application of GRADE showed the evidence for most of the assessed outcomes to be of moderate quality, including all those in which statistical differences were found. Whilst there is no overall difference between monopolar and bipolar TURP for clinical effectiveness, bipolar TURP is associated with fewer adverse events and therefore has a superior safety profile. Various methodological limitations were highlighted in the included trials and as such the results of this review should be interpreted with caution. There is a need for further well-conducted, multicentre RCTs with long-term follow-up data. PMID- 24053603 TI - From bis(silylene) and bis(germylene) pincer-type nickel(II) complexes to isolable intermediates of the nickel-catalyzed Sonogashira cross-coupling reaction. AB - The first [ECE]Ni(II) pincer complexes with E = Si(II) and E = Ge(II) metallylene donor arms were synthesized via C-X (X = H, Br) oxidative addition, starting from the corresponding [EC(X)E] ligands. These novel complexes were fully characterized (NMR, MS, and XRD) and used as catalyst for Ni-catalyzed Sonogashira reactions. These catalysts allowed detailed information on the elementary steps of this catalytic reaction (transmetalation -> oxidative addition -> reductive elimination), resulting in the isolation and characterization of an unexpected intermediate in the transmetalation step. This complex, {[ECE]Ni acetylide -> CuBr} contains both nickel and copper, with the copper bound to the alkyne pi-system. Consistent with these unusual structural features, DFT calculations of the {[ECE]Ni acetylide -> CuBr} intermediates revealed an unusual E-Cu-Ni three-center-two-electron bonding scheme. The results reveal a general reaction mechanism for the Ni-based Sonogashira coupling and broaden the application of metallylenes as strong sigma-donor ligands for catalytic transformations. PMID- 24053604 TI - IgG4-related intracranial hypertrophic pachymeningitis with skull hyperostosis: a case report. AB - BACKGROUND: Immunoglobulin G4 (IgG4)-related disease is a systemic syndrome, characterized by sclerosing lesions and usually associated with a raised serum IgG4 level; the pancreas, salivary glands, and lacrimal glands are typically affected. Recently, it has been suggested that IgG4-related sclerosing disease represents a subset of cases previously diagnosed as idiopathic hypertrophic pachymeningitis. This rare inflammatory disorder causes localized or diffused thickening of intracranial dura mater. Headache, cranial nerve palsy, and ataxia are the most common clinical manifestations.Herein, we report the clinical and histopathological features of a rare case of IgG4-related intracranial hypertrophic pachymeningitis involving cranial hyperostosis. CASE PRESENTATION: A 52-year-old man presented with refractory generalized tonic-clonic seizure. Magnetic resonance imaging revealed thickening of the meninges with enhancement near the superior sagittal sinus; skull bone defect was also noted. Extensive excision of affected skull bone and dura was performed, providing the diagnosis of IgG4-related pachymeningitis. After the surgery, the patient's seizure stopped and he was smoothly tapered off antiepileptic medication. CONCLUSION: To our knowledge, this is the first reported case of IgG4-related pachymeningitis with concomitant skull hyperostosis. PMID- 24053605 TI - Two-stage alkaline-enzymatic pretreatments to enhance biohydrogen production from sunflower stalks. AB - Because of their rich composition in carbohydrates, lignocellulosic residues represent an interesting source of biomass to produce biohydrogen by dark fermentation. Nevertheless, pretreatments should be applied to enhance the solubilization of holocelluloses and increase their further conversion into biohydrogen. The aim of this study was to investigate the effect of thermo alkaline pretreatment alone and combined with enzymatic hydrolysis to enhance biohydrogen production from sunflower stalks. A low increase of hydrogen potentials from 2.3 +/- 0.9 to 4.4 +/- 2.6 and 20.6 +/- 5.6 mL of H2 g(-1) of volatile solids (VS) was observed with raw sunflower stalks and after thermo alkaline pretreatment at 55 degrees C, 24 h, and 4% NaOH and 170 degrees C, 1 h, and 4% NaOH, respectively. Enzymatic pretreatment alone showed an enhancement of the biohydrogen yields to 30.4 mL of H2 g(-1) of initial VS, whereas it led to 49 and 59.5 mL of H2 g(-1) of initial VS when combined with alkaline pretreatment at 55 and 170 degrees C, respectively. Interestingly, a diauxic effect was observed with sequential consumption of sugars by the mixed cultures during dark fermentation. Glucose was first consumed, and once glucose was completely exhausted, xylose was used by the microorganisms, mainly related to Clostridium species. PMID- 24053607 TI - Extensively duplicated and transcriptionally active recent lateral gene transfer from a bacterial Wolbachia endosymbiont to its host filarial nematode Brugia malayi. AB - BACKGROUND: Lymphatic filariasis is a neglected tropical disease afflicting more than 120 million people, while another 1.3 billion people are at risk of infection. The nematode worm Brugia malayi is one of the causative agents of the disease and exists in a mutualistic symbiosis with Wolbachia bacteria. Since extensive lateral gene transfer occurs frequently between Wolbachia and its hosts, we sought to measure the extent of such LGT in B. malayi by whole genome sequencing of Wolbachia-depleted worms. RESULTS: A considerable fraction (at least 115.4-kbp, or 10.6%) of the 1.08-Mbp Wolbachia wBm genome has been transferred to its nematode host and retains high levels of similarity, including 227 wBm genes and gene fragments. Complete open reading frames were transferred for 32 of these genes, meaning they have the potential to produce functional proteins. Moreover, four transfers have evidence of life stage-specific regulation of transcription at levels similar to other nematode transcripts, strengthening the possibility that they are functional. CONCLUSIONS: There is extensive and ongoing transfer of Wolbachia DNA to the worm genome and some transfers are transcribed in a stage-specific manner at biologically relevant levels. PMID- 24053608 TI - Clinical significance of ureteric 'skip lesions' at the time of radical cystectomy: the M.D. Anderson experience and literature review. AB - OBJECTIVE: To assess the incidence and clinical significance of 'skip lesions' that are present in proximal but not in distal ureteric sections, which are occasionally found during the pathological examination of ureteric margins during radical cystectomy (RC). PATIENTS AND METHODS: We identified 660 patients who underwent a RC and had at least two permanent margins for a given ureter. In all, 1173 ureters were analysed and classified as follows: 'normal' (no tumour, reactive atypia, mild or moderate dysplasia) or 'abnormal' (severe dysplasia, carcinoma in situ (CIS), or tumour). Transitions from 'normal' distal pathology to 'abnormal' on proximal section(s) determined frequency of skip lesions. Fisher's exact test and the log-rank test were used to study correlations. RESULTS: Ureteric skip lesions were found in 4.8% patients (2.9% ureters). Pathology of skip lesions was CIS in 55.9%, transitional cell carcinoma in 23.5% and severe dysplasia in 20.6%. Skip lesions were associated with lymphovascular invasion (34.4% vs 13.7%, P = 0.004) and advanced pT stage (P = 0.007). On multivariate analysis, skip lesions correlated with lower median overall survival (OS) (inestimable vs 8.2 years, P = 0.014) in patients with pT0 or pTa disease and a trend towards lower OS (2.7 vs 8.8 years, P = 0.066) in pTis disease. Concordance between frozen distal margin and permanent proximal margin varied; sensitivity was 80% in those without and 20% in those with skip lesions. CONCLUSIONS: The presence of a ureteric skip lesion may be associated with lower survival in patients with pT0, pTa or pTis urothelial carcinoma. Thus, while uncommon, ureteric skip lesions should be reported in pathological findings. PMID- 24053606 TI - Cardiac implications of hypoglycaemia in patients with diabetes - a systematic review. AB - BACKGROUND: Hypoglycaemia has been associated with increased cardiovascular (CV) risk and mortality in a number of recent multicentre trials, but the mechanistic links driving this association remain ill defined. This review aims to summarize the available data on how hypoglycaemia may affect CV risk in patients with diabetes. METHODS: This was a systematic review of available mechanistic and clinical studies on the relationship between hypoglycaemia and cardiovascular risk. Study outcomes were compiled from relevant articles, and factors contributing to hypoglycaemia-mediated CVD and its complications are discussed. RESULTS: Six recent comprehensive clinical trials have reinforced the critical importance of understanding the link between hypoglycaemia and the CV system. In addition, 88 studies have indicated that hypoglycaemia mechanistically contributes to CV risk by increasing thrombotic tendency, causing abnormal cardiac repolarization, inducing inflammation, and contributing to the development of atherosclerosis. These hypoglycaemia-associated risk factors are conducive to events such as unstable angina, non-fatal and fatal myocardial infarction, sudden death, and stroke in patients with diabetes. CONCLUSIONS: Emerging data suggest that there is an impact of hypoglycaemia on CV function and mechanistic link is multifactorial. Further research will be needed to ascertain the full impact of hypoglycaemia on the CV system and its complications. PMID- 24053610 TI - A mild, selective copper-catalyzed oxidative phosphonation of alpha-amino ketones. AB - A novel and selective method of simple copper-salt catalyzed phosphonation of alpha-amino carbonyl compounds to afford imidoylphosphonates is reported. This reaction system has a broad reaction scope. The convenient and environmentally benign process makes this protocol very attractive. PMID- 24053609 TI - Cardiovascular rehabilitation soon after stroke using feedback-controlled robotics-assisted treadmill exercise: study protocol of a randomised controlled pilot trial. AB - BACKGROUND: After experiencing a stroke, most individuals also suffer from cardiac disease, are immobile and thus have low endurance for exercise. Aerobic capacity is seriously reduced in these individuals and does not reach reasonable levels after conventional rehabilitation programmes. Cardiovascular exercise is beneficial for improvement of aerobic capacity in mild to moderate stroke. However, less is known about its impact on aerobic capacity, motor recovery, and quality-of-life in severely impaired individuals. The aim of this pilot study is to explore the clinical efficacy and feasibility of cardiovascular exercise with regard to aerobic capacity, motor recovery, and quality-of-life using feedback controlled robotics-assisted treadmill exercise in non-ambulatory individuals soon after experiencing a stroke. METHODS/DESIGN: This will be a single-centred single blind, randomised control trial with a pre-post intervention design. Subjects will be recruited early after their first stroke (<=20 weeks) at a neurological rehabilitation clinic and will be randomly allocated to an inpatient cardiovascular exercise programme that uses feedback-controlled robotics-assisted treadmill exercise (experimental) or to conventional robotics-assisted treadmill exercise (control). Intervention duration depends on the duration of each subject's inpatient rehabilitation period. Aerobic capacity, as the primary outcome measure, will be assessed using feedback-controlled robotics-assisted treadmill-based cardiopulmonary exercise testing. Secondary outcome measures will include gait speed, walking endurance, standing function, and quality-of-life. Outcome assessment will be conducted at baseline, after each 4-week intervention period, and before clinical discharge. Ethical approval has been obtained. DISCUSSION: Whether cardiovascular exercise in non-ambulatory individuals early after stroke has an impact on aerobic capacity, motor recovery, and quality-of life is not yet known. Feedback-controlled robotics-assisted treadmill exercise is a relatively recent intervention method and might be used to train and evaluate aerobic capacity in this population. The present pilot trial is expected to provide new insights into the implementation of early cardiovascular exercise for individuals with severe motor impairment. The findings of this study may guide future research to explore the effects of early cardiovascular activation after severe neurological events. TRIAL REGISTRATION: This trial is registered with the Clinical Trials.gov Registry (NCT01679600). PMID- 24053611 TI - Clinical trials of amyloid-based immunotherapy for Alzheimer's disease: end of beginning or beginning of end? AB - INTRODUCTION: Amyloid deposit and hyperphosphorylated Tau protein contribute to pathological changes seen in Alzheimer's disease (AD) and imply that removal may reverse the cognitive decline. Immunotherapy is a potential way of reducing the load of amyloid or Tau in the brain. AREAS COVERED: This review summarizes recent clinical trials that have investigated immunotherapy to treat AD and its potential mechanisms. In addition, the potential opportunities as well as challenges of immunotherapy for AD in clinical trials are also discussed. EXPERT OPINION: Amyloid-based immunotherapy for AD is a novel method with potential; however, some clinical trials were terminated because of the adverse effects. Further studies need to determine the following questions: (i) which is better, passive, or active immunotherapy; (ii) which could be used for the vaccine, amyloid or Tau; (iii) which is better, short- or long-antigen vaccine; and (iv) the route of delivery for antigen or antibody. PMID- 24053612 TI - Prevalence and correlates of depressive symptoms in HIV-positive patients: a cross-sectional study among newly diagnosed patients in Yaounde, Cameroon. AB - BACKGROUND: Depression is one of the most common neuropsychiatric complications of HIV disease, and in turn it is associated with worse HIV-related outcomes. Data on depression among HIV-infected patients in Cameroon are scarce. In this study, we report the prevalence and correlates of depressive symptoms among newly diagnosed HIV-infected patients in Yaounde, Cameroon. METHODS: Interviews were conducted with 100 newly diagnosed HIV-infected patients at three referral hospitals of Yaounde. Depression was assessed using the nine-item Patient Health Questionnaire (PHQ-9). A positive depression screen was defined as PHQ-9 score greater than 9. RESULTS: The overall prevalence of depressive symptoms was 63% (95% CI: 53.2 to 71.8), the majority having symptoms corresponding to moderate depression. Multiple logistic regression analysis showed that probable depressed patients were more likely than those who were not depressed to have had experience of alcohol abuse (OR: 19.03, 95% CI 3.11-375.85; p = 0.0083), and a 100 CD4 cells/mm3 fewer was associated with a 2.9 times increase of the odds of probable depression (95% CI 1.88-4.84; p < 0.0001). CONCLUSIONS: Our findings indicate a high prevalence of depressive symptoms in newly diagnosed HIV-infected patients in our setting, and their association with alcohol abuse and severe immunosuppression. This study also highlights the necessity to integrate mental health interventions into routine HIV clinical care in Cameroon. PMID- 24053614 TI - Insight into the packing pattern of beta2 fibrils: a model study of glutamic acid rich oligomers with 13C isotopic edited vibrational spectroscopy. AB - Polyglutamic acid at low pH forms aggregates and self-assembles into a spiral, fibril-like superstructure formed as a beta2-type sheet conformation that has a more compact intersheet packing than commonly found. This is stabilized by three centered bifurcated hydrogen bonding of the amide carbonyl involving the protonated glutamic acid side chain. We report vibrational spectroscopic results and analyses for oligopeptides rich in glutamic acid enhanced with (13)C isotope labeling in a study modeling low pH poly-Glu self-assembly. Our results indicate bifurcated H-bonding and beta2 aggregation can be attained in these model decamers, confirming they have the same conformations as poly-Glu. We also prepared conventional beta1-sheet aggregates by rapid precipitation from the residual peptides in the higher pH supernatant. By comparing the isotope-enhanced IR and VCD spectra with theoretical predictions, we deduced that the oligo-Glu beta2 structure is based on stacked, twisted, antiparallel beta-sheets. The best fit to theoretical predictions was obtained for the strands being out of register, sequentially stepped by one residue, in a ladder-like fashion. The alternate beta1 conformer for this oligopeptide was similarly shown to be antiparallel but was less ordered and apparently had a different registry in its aggregate structure. PMID- 24053615 TI - Looking for prognosticators in ovine anaplasmosis: discriminant analysis of clinical and haematological parameters in lambs belonging to differently susceptible breeds experimentally infected with Anaplasma ovis. AB - BACKGROUND: A study was carried out to evaluate the response of different native sheep breeds to experimental infection with Anaplasma ovis, the most prevalent sheep tick-borne pathogen in Apulia (Southern Italy). Thirty-four lambs belonging to a Northern European breed (Suffolk) and two Southern Italian breeds (Comisana and Altamurana) were infected. Eleven clinical as well as haematological parameters were monitored at different temporal resolutions on the same subjects before and after the infection, resulting in a data set of 435 observations. The present work, aiming to further the research, presents the results of a multivariate analysis carried out to identify which parameters out of the eleven considered are the most reliable parameters to be considered as markers of the disease phenotype as well as prognosticators of practical clinical importance. RESULTS: Data were analysed by discriminant analysis. Out of the eleven considered variables (red blood cells, packed cell volume, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin content, haemoglobin concentration, white blood cells, neutrophils, leukocytes, platelets, rectal temperature), only seven were included in the step-wise model since significantly increasing the Mahlanobis distance between the two closest groups. Both discriminant functions resulted to be highly significant (P < 0.0001) and the percentage of variation accounted for by the first discriminant function was 63.6% of the variance in the grouping variable. CONCLUSIONS: Taken together, the observed results stress the marked differentiation among the three breeds in terms of physio-pathological phenotypes indicating packed cell volume and red blood cell count as the most informative parameters in the routine clinical practice for A. ovis infection in sheep. PMID- 24053613 TI - Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension. AB - AIMS: Angiotensin II (AngII)-induced superoxide (O2(*-)) production by the NADPH oxidases and mitochondria has been implicated in the pathogenesis of endothelial dysfunction and hypertension. In this work, we investigated the specific molecular mechanisms responsible for the stimulation of mitochondrial O2(*-) and its downstream targets using cultured human aortic endothelial cells and a mouse model of AngII-induced hypertension. RESULTS: Western blot analysis showed that Nox2 and Nox4 were present in the cytoplasm but not in the mitochondria. Depletion of Nox2, but not Nox1, Nox4, or Nox5, using siRNA inhibits AngII induced O2(*-) production in both mitochondria and cytoplasm. Nox2 depletion in gp91phox knockout mice inhibited AngII-induced cellular and mitochondrial O2(*-) and attenuated hypertension. Inhibition of mitochondrial reverse electron transfer with malonate, malate, or rotenone attenuated AngII-induced cytoplasmic and mitochondrial O2(*-) production. Inhibition of the mitochondrial ATP sensitive potassium channel (mitoK(+)ATP) with 5-hydroxydecanoic acid or specific PKCE peptide antagonist (EAVSLKPT) reduced AngII-induced H2O2 in isolated mitochondria and diminished cytoplasmic O2(*-). The mitoK(+)ATP agonist diazoxide increased mitochondrial O2(*-), cytoplasmic c-Src phosphorylation and cytoplasmic O2(*-) suggesting feed-forward regulation of cellular O2(*-) by mitochondrial reactive oxygen species (ROS). Treatment of AngII-infused mice with malate reduced blood pressure and enhanced the antihypertensive effect of mitoTEMPO. Mitochondria-targeted H2O2 scavenger mitoEbselen attenuated redox-dependent c-Src and inhibited AngII-induced cellular O2(*-), diminished aortic H2O2, and reduced blood pressure in hypertensive mice. INNOVATION AND CONCLUSIONS: These studies show that Nox2 stimulates mitochondrial ROS by activating reverse electron transfer and both mitochondrial O2(*-) and reverse electron transfer may represent new pharmacological targets for the treatment of hypertension. PMID- 24053616 TI - Preoperative serum albumin is associated with mortality and complications after radical cystectomy. AB - OBJECTIVE: To determine the association between preoperative serum albumin and mortality and postoperative complications after radical cystectomy (RC) and urinary diversion. PATIENTS AND METHODS: We conducted a retrospective review of 1097 RCs performed for the treatment of bladder cancer between 1992 and 2005. All data were entered prospectively into a hospital-based complications database. We used multivariable logistic regression to assess the association between preoperative serum albumin and complications and mortality <=90 days of RC, while controlling for preoperative patient and disease characteristics. RESULTS: Low preoperative serum albumin was identified in 14% of the cohort. Preoperative serum albumin was a predictor of postoperative complications (adjusted odds ratio [OR] per unit increase in albumin: 0.61, 95% confidence interval [CI] 0.42-0.90) and 90-day mortality (OR 0.33, 95% CI 0.14-0.75) when controlling for sex, race, age-adjusted Charlson score, body mass index, prior history of abdominal surgery, clinical stage, and neoadjuvant chemotherapy. As serum albumin decreased, the risk of complications and mortality increased. CONCLUSIONS: In addition to age adjusted Charlson score, low preoperative serum albumin is a significant predictor of complications and mortality after RC. Serum albumin testing can be used to identify individuals at high-risk of morbidity and mortality. PMID- 24053617 TI - Structure-activity relationship study of indole-2-carboxamides identifies a potent allosteric modulator for the cannabinoid receptor 1 (CB1). AB - The cannabinoid CB1 receptor is involved in complex physiological functions. The discovery of CB1 allosteric modulators generates new opportunities for drug discovery targeting the pharmacologically important CB1 receptor. 5-Chloro-3 ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ORG27569; 1) represents a new class of indole-2-carboxamides that exhibit allostery of CB1. To better understand the SAR, a group of indole-2-carboxamide analogues were synthesized and assessed for allostery of the CB1 receptor. We found that within the structure of indole-2-carboxamides, the presence of the indole ring is preferred for maintaining the modulator's high binding affinity for the allosteric site but not for generating allostery on the orthosteric site. However, the C3 substituents of the indole-2-carboxamides significantly impact the allostery of the ligand. A robust CB1 allosteric modulator 5-chloro-N-(4 (dimethylamino)phenethyl)-3-pentyl-1H-indole-2-carboxamide (11j) was identified. It showed an equilibrium dissociation constant (KB) of 167.3 nM with a markedly high binding cooperativity factor (alpha = 16.55) and potent antagonism of agonist-induced GTPgammaS binding. PMID- 24053618 TI - Impact of peri-operative blood transfusion on the outcomes of patients undergoing radical cystectomy for urothelial carcinoma of the bladder. AB - OBJECTIVE: To determine the association between peri-operative blood transfusion (PBT) and oncological outcomes in a large multi-institutional cohort of patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). PATIENTS AND METHODS: We conducted a retrospective analysis of 2895 patients treated with RC for UCB. Univariable and multivariable Cox regression models were used to analyse the effect of PBT administration on disease recurrence, cancer specific mortality, and any-cause mortality. RESULTS: Patients' median (interquartile range [IQR]) age was 67 (60, 73) years and the median (IQR) follow up was 36.1 (15, 84) months. Patients who received PBT were more likely to have advanced disease (P < 0.001), high grade tumours (P = 0.047) and nodal metastasis (P = 0.004). PBT was associated with a higher risk of disease recurrence (P = 0.003), cancer-specific mortality (P = 0.017), and any-cause mortality (P = 0.010) in univariable, but not multivariable, analyses (P > 0.05). In multivariable analyses, pathological tumour stage, pathological nodal stage, soft tissue surgical margin, lymphovascular invasion and administration of adjuvant chemotherapy were independent predictors of disease recurrence, cancer-specific mortality and any-cause mortality (all P values <0.002). CONCLUSIONS: Patients with UCB who underwent RC and received PBT had a greater risk of disease recurrence, cancer-specific mortality and any-cause mortality in univariable, but not multivariable, analysis. Although the greater need for PBT with more advanced disease is probably caused by a number of factors, including surgical and cancer related factors, the present analysis showed that the disease characteristics rather than need for PBT led to worse outcomes. PMID- 24053619 TI - Expression of SCUBE2 gene declines in high grade endometrial cancer and associates with expression of steroid hormone receptors and tumor suppressor PTEN. AB - SCUBE2 (Signal peptide-CUB-epidermal growth factor-like domain-containing 2) gene codes for a cell-surface glycoprotein. In breast cancer, SCUBE2 transcript levels are part of important prognostic and predictive gene signatures and are linked to expression of estrogen receptor alpha (ERalpha). To elucidate the role of this gene in endometrial cancer, we compared SCUBE2 expression in malignant and normal endometrial tissue specimens. We then examined its correlation with steroid hormone receptors and PTEN and compared it to SCUBE2 expression in breast cancer samples. Expression of SCUBE2 was found to be decreased in G3 endometrial cancer when compared to postmenopausal endometrium or to G1 tumors (p < 0.05). In postmenopausal endometrium, SCUBE2 transcript levels were more than twice as high as in premenopausal women. In breast cancer, SCUBE2 expression was found to be notably reduced particularly in ERalpha-negative G3 tumors. Both in endometrial and breast cancer we observed a significant positive correlation of SCUBE2 transcript levels with expression of ERalpha, PR and PTEN. Our data suggest that SCUBE2, like in breast cancer, associates with ERalpha and might have a potential as prognostic or predictive marker in endometrial cancer. PMID- 24053620 TI - Kinetics study of the reaction of OH radicals with C5-C8 cycloalkanes at 240-340 K using the relative rate/discharge flow/mass spectrometry technique. AB - Rate constants of reactions of hydroxyl radical with cyclopentane (k1), cyclohexane (k2), cycloheptane (k3), and cyclooctane (k4) have been acquired at 240-340 K and a total pressure of about 1 Torr using the technique of relative rate combined with discharge flow and mass spectrometry (RR/DF/MS). At 298 K, the rate constants are determined using two reference compounds, which are averaged to be k1 = (4.81 +/- 0.88) * 10(-12), k2 = (6.41 +/- 0.85) * 10(-12), k3 = (10.30 +/- 1.44) * 10(-12), and k4 = (1.42 +/- 0.27) * 10(-11) cm(3) molecule(-1) s(-1). The Arrhenius expressions at 240-340 K for these reactions are determined to be k1(T) = (2.43 +/- 0.50) * 10(-11)exp[-(481 +/- 58)/T], k2(T) = (3.96 +/- 0.60) * 10(-11)exp[-554 +/- 42)/T], k3(T) = (5.74 +/- 0.66) * 10(-11)exp[-527 +/- 33)/T], and k4(T) = (1.12 +/- 0.21) * 10(-10)exp[-626 +/- 53)/T]. Using the kcycloalkane+OH(277 K) values measured in the present work, the atmospheric lifetime for cyclopentane, cyclohexane, cycloheptane, and cyclooctane is estimated to be about 78, 64, 38, and 29 h, respectively. PMID- 24053621 TI - Mortality and complications after prostate biopsy in the Prostate, Lung, Colorectal and Ovarian Cancer Screening (PLCO) trial. AB - OBJECTIVE: To examine mortality and morbidity after prostate biopsy in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening (PLCO) trial. SUBJECTS AND METHODS: Abstractors from the PLCO trial recorded the types and dates of diagnostic follow-up procedures after positive screens and documented the types and dates of resultant complications. Cancers and deaths among the participants were tracked. The mortality rate in the 120-day period after prostate biopsy was compared with a control rate of deaths in the 120-day period after a negative screen in men without biopsy. Multivariate analysis was performed to control for potential confounders, including age, comorbidities and smoking. Rates of any complication, infectious and non-infectious complications were computed among men with a negative biopsy. Multivariate analysis was used to examine the risk factors for complications. RESULTS: Of the 37,345 men enrolled in the PLCO trial (intervention arm), 4861 had at least one biopsy after a positive screen and 28,661 had a negative screen and no biopsy. The 120-day mortality rate after biopsy was 0.95 (per 1000), compared with the control group rate of 1.8; the multivariate relative risk was 0.49 (95% CI: 0.2-1.1). Among 3706 negative biopsies, the rates (per 1000) of any complication, infectious and non-infections complications were 20.2, 7.8 and 13.0, respectively. A history of prostate enlargement or inflammation was significantly associated with higher rates of both infectious (odds ratio [OR] = 3.7) and non-infectious (OR = 2.2) complications. Black race was associated with a higher infectious complications rate (OR = 7.1) and repeat biopsy was associated with lower rates of non infectious complications (OR = 0.3). CONCLUSION: Mortality rates were not found to be higher after prostate biopsy in the PLCO trial and complications were relatively infrequent, with several risk factors identified. PMID- 24053622 TI - Use of a perceptually-regulated test to measure maximal oxygen uptake is valid and feels better. AB - A maximal, perceptually-regulated exercise test (PRETmax) whereby participants control the intensity according to preset ratings of perceived exertion (RPE) may induce more positive affective responses than a conventional 'experimenter controlled' incremental ramp test (Iramp). The authors aimed to assess (1) if a PRETmax could be used to measure VO(2max) and (2) if affective responses differed between the PRETmax and Iramp. Sixteen participants (age 20.5, s=1.2 y) completed a PRETmax which required them to adjust the resistance on a recumbent cycle ergometer to correspond to prescribed RPEs of 9, 11, 13, 15, 17 and 20 and an Iramp. Both tests ended with volitional exhaustion. Affect was recorded every minute throughout exercise using the Feeling Scale (FS). There was no difference (P>0.05) between VO(2max) measured by PRETmax (43.5, s=4.1 ml kg(-1) min(-1)) and Iramp (44.3, s=4.9 ml kg(-1) min(-1)). Participants reported feeling significantly less negative (P<0.001) throughout the PRETmax compared to Iramp (average mean difference FS = 1.4, s=0.1). The PRETmax has application in situations where the direct measurement of VO(2max) is required and the affective responses of the individual are considered to be important. PMID- 24053623 TI - Comparative genomics reveals distinct host-interacting traits of three major human-associated propionibacteria. AB - BACKGROUND: Propionibacteria are part of the human microbiota. Many studies have addressed the predominant colonizer of sebaceous follicles of the skin, Propionibacterium acnes, and investigated its association with the skin disorder acne vulgaris, and lately with prostate cancer. Much less is known about two other propionibacterial species frequently found on human tissue sites, Propionibacterium granulosum and Propionibacterium avidum. Here we analyzed two and three genomes of P. granulosum and P. avidum, respectively, and compared them to two genomes of P. acnes; we further highlight differences among the three cutaneous species with proteomic and microscopy approaches. RESULTS: Electron and atomic force microscopy revealed an exopolysaccharide (EPS)-like structure surrounding P. avidum cells, that is absent in P. acnes and P. granulosum. In contrast, P. granulosum possesses pili-like appendices, which was confirmed by surface proteome analysis. The corresponding genes were identified; they are clustered with genes encoding sortases. Both, P. granulosum and P. avidum lack surface or secreted proteins for predicted host-interacting factors of P. acnes, including several CAMP factors, sialidases, dermatan-sulphate adhesins, hyaluronidase and a SH3 domain-containing lipoprotein; accordingly, only P. acnes exhibits neuraminidase and hyaluronidase activities. These functions are encoded on previously unrecognized island-like regions in the genome of P. acnes. CONCLUSIONS: Despite their omnipresence on human skin little is known about the role of cutaneous propionibacteria. All three species are associated with a variety of diseases, including postoperative and device-related abscesses and infections. We showed that the three organisms have evolved distinct features to interact with their human host. Whereas P. avidum and P. granulosum produce an EPS-like surface structure and pili-like appendices, respectively, P. acnes possesses a number of unique surface-exposed proteins with host-interacting properties. The different surface properties of the three cutaneous propionibacteria are likely to determine their colonizing ability and pathogenic potential on the skin and at non-skin sites. PMID- 24053625 TI - Soy biodiesel and petrodiesel emissions differ in size, chemical composition and stimulation of inflammatory responses in cells and animals. AB - Debate about the biological effects of biodiesel exhaust emissions exists due to variation in methods of exhaust generation and biological models used to assess responses. Because studies in cells do not necessarily reflect the integrated response of a whole animal, experiments were conducted in two human cell lines representing bronchial epithelial cells and macrophages and female mice using identical particle suspensions of raw exhaust generated by a Volkswagen light duty diesel engine using petrodiesel (B0) and a biodiesel blend (B20: 20% soy biodiesel/80% B0 by volume). Tailpipe particle emissions measurement showed B0 generated two times more particle mass, larger ultrafine particle number distribution modes, and particles of more nonpolar organic composition than the B20 fuel. Biological assays (inflammatory mediators, oxidative stress biomarkers) demonstrated that particulate matter (PM) generated by combustion of the two fuels induced different responses in in vitro and in vivo models. Concentrations of inflammatory mediators (Interleukin-6, IL-6; Interferon-gamma-induced Protein 10, IP-10; Granulocyte-stimulating factor, G-CSF) in the medium of B20-treated cells and in bronchoalveolar lavage fluid of mice exposed to B20 were ~20-30% higher than control or B0 PM, suggesting that addition of biodiesel to diesel fuels will reduce PM emissions but not necessarily adverse health outcomes. PMID- 24053624 TI - Breast and gynecologic cancer-related extremity lymphedema: a review of diagnostic modalities and management options. AB - Lymphedema remains a poorly understood entity that can occur after lymphadenectomy. Herein, we will review the pathogenesis of lymphedema, diagnostic modalities and the natural history of extremity involvement. We will review the incidence of upper extremity lymphedema in patients treated for breast malignancies and lower extremity lymphedema in those treated for gynecologic malignancy. Finally, we will review traditional treatment modalities for lymphedema, as well as introduce new surgical treatment modalities that are under active investigation. PMID- 24053626 TI - Exploring binding and effector functions of natural human antibodies using synthetic immunomodulators. AB - The ability to profile the prevalence and functional activity of endogenous antibodies is of vast clinical and diagnostic importance. Serum antibodies are an important class of biomarkers and are also crucial elements of immune responses elicited by natural disease-causing agents as well as vaccines. In particular, materials for manipulating and/or enhancing immune responses toward disease causing cells or viruses have exhibited significant promise for therapeutic applications. Antibody-recruiting molecules (ARMs), bifunctional organic molecules that redirect endogenous antibodies to pathological targets, thereby increasing their recognition and clearance by the immune system, have proven particularly interesting. Notably, although ARMs capable of hijacking antibodies against oligosaccharides and electron-poor aromatics have proven efficacious, systematic comparisons of the prevalence and effectiveness of natural anti-hapten antibody populations have not appeared in the literature. Herein we report head to-head comparisons of three chemically simple antigens, which are known ligands for endogenous antibodies. Thus, we have chemically synthesized bifunctional molecules containing 2,4-dinitrophenyl (DNP), phosphorylcholine (PC), and rhamnose. We have then used a combination of ELISA, flow cytometry, and cell viability assays to compare these antigens in terms of their abilities both to recruit natural antibody from human serum and also to direct serum-dependent cytotoxicity against target cells. These studies have revealed rhamnose to be the most efficacious of the synthetic antigens examined. Furthermore, analysis of 122 individual serum samples has afforded comprehensive insights into population-wide prevalence and isotype distributions of distinct anti-hapten antibody populations. In addition to providing a general platform for comparing and studying anti-hapten antibodies, these studies serve as a useful starting point for the optimization of antibody-recruiting molecules and other synthetic strategies for modulating human immunity. PMID- 24053627 TI - The effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice after endoscopic treatment: a prospective, randomized, and controlled study. AB - BACKGROUND: In patients with obstructive jaundice, multi-organ dysfunction may develop. METHODS/DESIGN: This trial is a prospective, open-label, randomized, and controlled study with the objective to evaluate the effect of ursodeoxycholic acid in liver functional restoration in patients with obstructive jaundice after endoscopic treatment. The aim of this study is to evaluate the effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice after endoscopic treatment. The hypothesis of this trial is that patients with obstructive jaundice, in which will be administered UDCA, in the early phase after endoscopic intervention will have better and faster functional restoration of the liver than patients in the control group.Patients with obstructive jaundice, randomly, will be divided into two groups: (A) test group in which will be administered ursodeoxycholic acid twenty-four hours after endoscopic procedure and will last fourteen days, and (B) control group.Serum testing will include determination of bilirubin, alanine transaminase, aspartate transaminase, gama-glutamil transpeptidase, alkaline phosphatase, albumin, and cholesterol levels. These parameters will be determined one day prior endoscopic procedure, and on the third, fifth, seventh, tenth, twelfth and fourteenth days after endoscopic intervention. DISCUSSION: This trial is a prospective, open label, randomized, and controlled study to asses the effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice in the early phase after endoscopic treatment. PMID- 24053629 TI - Indications, results and safety profile of transperineal sector biopsies (TPSB) of the prostate: a single centre experience of 634 cases. AB - OBJECTIVE: To describe a protocol for transperineal sector biopsies (TPSB) of the prostate and present the clinical experience of this technique in a UK population. PATIENTS AND METHODS: A retrospective review of a single-centre experience of TPSB approach was undertaken that preferentially, but not exclusively, targeted the peripheral zone of the prostate with 24-38 cores using a 'sector plan'. Procedures were carried out under general anaesthetic in most patients. Between January 2007 and August 2011, 634 consecutive patients underwent TPSB for the following indications: prior negative transrectal biopsy (TRB; 174 men); primary biopsy in men at risk of sepsis (153); further evaluation after low-risk disease diagnosed based on a 12-core TRB (307). RESULTS: Prostate cancer was found in 36% of men after a negative TRB; 17% of these had disease solely in anterior sectors. As a primary diagnostic strategy, prostate cancer was diagnosed in 54% of men (median PSA level was 7.4 ng/mL). Of men with Gleason 3+3 disease on TRB, 29% were upgraded and went on to have radical treatment. Postoperative urinary retention occurred in 11 (1.7%) men, two secondary to clots. Per-urethral bleeding requiring hospital stay occurred in two men. There were no cases of urosepsis. CONCLUSIONS: TPSB of the prostate has a role in defining disease previously missed or under-diagnosed by TRB. The procedure has low morbidity. PMID- 24053628 TI - Successful control of a Methicillin-resistant Staphylococcus aureus outbreak in a neonatal intensive care unit: a retrospective, before-after study. AB - BACKGROUND: Aim of this study was to provide a detailed description of a Methicillin-resistant Staphylococcus aureus (MRSA) outbreak management strategy in the neonatal intensive care unit of a university hospital. METHODS: This was a retrospective, "before-after" study, over two consecutive 18-month periods. The outbreak management strategy was performed by a multidisciplinary team and included: extensive healthcare workers (HCW) involvement, education, continuous hand-hygiene training and active MRSA colonization surveillance. The actions implemented were identified based on an anonymous, voluntary, reporting system, carried out among all the HCW, and regular audit and feedback were provided to the nursing staff. The main measured outcome was the rate of MRSA infections before and after the implementation of the outbreak management strategy. Piecewise linear Poisson regression was performed and the model adjusted for confounding variables. The secondary outcome was the rate of laboratory-confirmed bloodstream infections before and after the outbreak management strategy. The rates of MRSA colonization, implementation of proposed actions, observed compliance for hand-hygiene and insertion/care of central lines were also recorded during the second period. RESULTS: 1015 newborns were included. The rate of MRSA infections throughout the two periods fell from 3.5 to 0.7 cases per 1000 patient-days (p=0.0005). The piecewise Poisson regression analysis adjusted for confounding variables showed a significant decrease in the MRSA infection rate after the outbreak management strategy (p=0.046). A significant decrease in positive laboratory confirmed blood cultures was observed over the two periods (160 vs 83; p<0.0001). A significant decline in the MRSA colonization rate occurred over the second period (p=0.001); 93% of the proposed actions were implemented. The compliance rate for hand-hygiene and insertion/care of central lines was respectively 95.9% and 62%. CONCLUSIONS: The implementation of multiple, simultaneous, evidence-based management strategies is effective for controlling nosocomial infections. Outbreak management strategies may benefit from tools improving the communication between the institutional and scientific leadership and the ground-level staff. These measures can help to identify individualized solutions addressing specific unit needs. PMID- 24053630 TI - Maturation-dependent response of neurogenesis after traumatic brain injury in children. AB - OBJECT: Traumatic brain injury (TBI) is the leading cause of acquired disability in children, yet innate repair mechanisms are incompletely understood. Given data from animal studies documenting neurogenesis in response to trauma and other insults, the authors investigated whether similar responses could be found in children of different ages after TBI. METHODS: Immunohistochemistry was used to label doublecortin (DCX), a protein expressed by immature migrating neuroblasts (newborn neurons), in specimens from patients ranging in age from 3 weeks to 10 years who had died either after TBI or from other causes. Doublecortin-positive (DCX+) cells were examined in the subventricular zone (SVZ) and periventricular white matter (PWM) and were quantified within the granule cell layer (GCL) and subgranular zone (SGZ) of the dentate gyrus to determine if age and/or injury affect the number of DCX+ cells in these regions. RESULTS: The DCX+ cells decreased in the SVZ as patient age increased and were found in abundance around a focal subacute infarct in a 1-month-old non-TBI patient, but were scarce in all other patients regardless of age or history of trauma. The DCX+ cells in the PWM and dentate gyrus demonstrated a migratory morphology and did not co-localize with markers for astrocytes, microglia, or macrophages. In addition, there were significantly more DCX+ cells in the GCL and SGZ of the dentate gyrus in children younger than 1 year old than in older children. The density of immature migrating neuroblasts in infants (under 1 year of age) was significantly greater than in young children (2-6 years of age, p = 0.006) and older children (7-10 years of age, p = 0.007). CONCLUSIONS: The main variable influencing the number of migrating neuroblasts observed in the SVZ, PWM, and hippocampus was patient age. Trauma had no discernible effect on the number of migrating neuroblasts in this cohort of patients in whom death typically occurred within hours to days after TBI. PMID- 24053631 TI - The cost-effectiveness of a family meetings intervention to prevent depression and anxiety in family caregivers of patients with dementia: a randomized trial. AB - BACKGROUND: Dementia imposes a heavy burden on health and social care systems as well as on family caregivers who provide a substantial portion of the care. Interventions that effectively support caregivers may prevent or delay patient institutionalization and hence be cost-effective. However, evidence about the cost-effectiveness of such interventions is scarce. The aim of this study was to evaluate the cost-effectiveness of a family meetings intervention for family caregivers of dementia patients in comparison with usual care over a period of 12 months. METHODS: The economic evaluation was conducted from a societal perspective alongside a randomized trial of 192 primary caregivers with community dwelling dementia patients. Outcome measures included the Quality Adjusted Life Years (QALY) of caregivers and patients and the incidence of depression and anxiety disorders in caregivers. Missing cost and effect data were imputed using multiple imputations. Bootstrapping was used to estimate uncertainty around the cost-differences and the incremental cost-effectiveness ratio (ICER). The bootstrapped cost-effect pairs were plotted on a cost-effectiveness plane and used to estimate cost-effectiveness curves. RESULTS: No significant differences in costs and effects between the groups were found. At 12 months, total costs per patient and primary caregiver dyad were substantial: ?77,832 for the intervention group and ?75,201 for the usual care group (adjusted mean difference per dyad ?4,149, 95% CI -13,371 to 21,956, ICER 157,534). The main cost driver was informal care (66% of total costs), followed by patients' day treatment and costs of hospital and long-term care facility admissions (23%). Based on the cost effectiveness acceptability curves, the maximum probability that the intervention was considered cost-effective in comparison with usual care reached 0.4 for the outcome QALY per patient-caregiver dyad and 0.6 for the caregivers' incidence of depression and/or anxiety disorders regardless of the willingness to pay. CONCLUSIONS: The annual costs of caring for a person with dementia were substantial with informal care being by far the largest contributor to the total societal costs. Based on this study, family meetings cannot be considered a cost effective intervention strategy in comparison with usual care. TRIAL REGISTRATION: ISRCTN register, ISRCTN90163486. PMID- 24053632 TI - Surface display of recombinant proteins on Escherichia coli by BclA exosporium of Bacillus anthracis. AB - BACKGROUND: The anchoring motif is one of the most important aspects of cell surface display as well as efficient and stable display of target proteins. Thus, there is currently a need for the identification and isolation of novel anchoring motifs. RESULTS: A system for the display of recombinant proteins on the surface of Escherichia coli was developed using the Bacillus anthracis exosporal protein (BclA) as a new anchoring motif. For the surface display of recombinant proteins, the BAN display platform was constructed in which a target protein is linked to the C-terminus of N-terminal domain (21 amino acids) of BclA. The potential application of BAN platform for cell surface display was demonstrated with two model proteins of different size, the Bacillus sp. endoxylanase (XynA) and monooxygenase (P450 BM3m2). Through experimental analysis including outer membrane fractionation, confocal microscopy and activity assay, it was clearly confirmed that both model proteins were successfully displayed with high activities on the E. coli cell surface. CONCLUSIONS: These results of this study suggest that the strategy employing the B. anthracis BclA as an anchoring motif is suitable for the display of heterologous proteins on the surface of E. coli and consequently for various biocatalytic applications as well as protein engineering. PMID- 24053633 TI - I will dance in my aqua gown! A personal reflection. PMID- 24053634 TI - Opportunities for deprescribing statins in patients with poor cancer prognosis. PMID- 24053635 TI - Stability and dynamic processes in 16VE iridium(III) ethyl hydride and rhodium(I) sigma-ethane complexes: experimental and computational studies. AB - Iridium(I) and rhodium(I) ethyl complexes, (PONOP)M(C2H5) (M = Ir (1-Et), Rh (2 Et)) and the iridium(I) propyl complex (PONOP)Ir(C3H7) (1-Pr), where PONOP is 2,6 (tBu2PO)2C5H3N, have been prepared. Low-temperature protonation of the Ir complexes yields the alkyl hydrides, (PONOP)Ir(H)(R) (1-(H)(Et)(+) and 1 (H)(Pr)(+)), respectively. Dynamic (1)H NMR characterization of 1-(H)(Et)(+) establishes site exchange between the Ir-H and Ir-CH2 protons (DeltaG(exH)(?)( 110 degrees C) = 7.2(1) kcal/mol), pointing to a sigma-ethane intermediate. By dynamic (13)C NMR spectroscopy, the exchange barrier between the alpha and beta carbons ("chain-walking") was measured (DeltaG(exC)(?)(-110 degrees C) = 8.1(1) kcal/mol). The barrier for ethane loss is 17.4(1) kcal/mol (-40 degrees C), to be compared with the reported barrier to methane loss in 1-(H)(Me)(+) of 22.4 kcal/mol (22 degrees C). A rhodium sigma-ethane complex, (PONOP)Rh(EtH) (2 (EtH)(+)), was prepared by protonation of 2-Et at -150 degrees C. The barrier for ethane loss (DeltaG(dec)(?)(-132 degrees C) = 10.9(2) kcal/mol) is lower than for the methane complex, 2-(MeH)(+), (DeltaG(dec)(?)(-87 degrees C) = 14.5(4) kcal/mol). Full spectroscopic characterization of 2-(EtH)(+) is reported, a key feature of which is the upfield signal at -31.2 ppm for the coordinated CH3 group in the (13)C NMR spectrum. The exchange barrier of the hydrogens of the coordinated methyl group is too low to be measured, but the chain-walking barrier of 7.2(1) kcal/mol (-132 degrees C) is observable by (13)C NMR. The coordination mode of the alkane ligand and the exchange pathways for the Rh and Ir complexes are evaluated by DFT studies. On the basis of the computational studies, it is proposed that chain-walking occurs by different mechanisms: for Rh, the lowest energy path involves a eta(2)-ethane transition state, while for Ir, the lowest energy exchange pathway proceeds through the symmetrical ethylene dihydride complex. PMID- 24053636 TI - Estimation of endogenous protein and amino acid ileal losses in weaned piglets by regression analysis using diets with graded levels of casein. AB - BACKGROUND: Many studies have investigated endogenous loss of proteins and amino acids (AAs) at the ileal level in growing pigs. However, only a few studies have researched this subject in piglets. Knowledge regarding AA ileal digestibility in piglets would be helpful during the formulation of diets for weaning piglets, rather than just using coefficients obtained in growing pigs. Therefore, in this study, we sought to estimate endogenous protein and AA ileal losses in piglets. Furthermore, apparent and true ileal digestibility (AID and TID) of protein and AAs from casein were measured. RESULTS: The average flow of protein was 20.8 g/kg of dry matter intake (DMI). Basal protein loss, as estimated by regression, was 16.9 g/kg DMI. Glutamic acid, arginine, and aspartic acid (2.2, 1.4, and 1.2 g/kg DMI, respectively) were the AAs for which greater losses were seen. The AID of protein and AAs increased as the protein level in the diet increased. A higher increment in AID was observed between diets with 80 and160 g CP/kg of feed; this finding was mainly attributable to increases in glycine and arginine (46.1% and 18%, respectively). The TID of protein was 97.8, and the TID of AAs varied from 93.9 for histidine to 100.2 for phenylalanine. CONCLUSIONS: The basal endogenous protein loss in piglets was 16.9 g/kg DMI. Endogenous protein was rich in glutamic acid, aspartic acid, and arginine, which represented 32.7% of endogenous protein loss in weaning piglets. The TID of casein was high and varied from 93.0 for histidine to 100.2 for phenylalanine. PMID- 24053637 TI - The 1-year decline in estimated glomerular filtration rate (eGFR) after radical nephrectomy in patients with renal masses and matched living kidney donors is the same. AB - OBJECTIVES: To determine short-term differences in renal function evolution between patients with renal cell carcinoma (RCC) submitted to radical nephrectomy (RN) and living kidney donors matched for age and gender. To assess the role of co-morbidity as a risk factor for developing an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m(2) . PATIENTS AND METHODS: In this retrospective study patients undergoing Radical Nefrectomy (RN) between January 2000 and February 2011 for suspicion of localised RCC were matched by age and gender to living kidney donors. Renal function was compared between the groups using the Modification in Diet and Renal Disease (MDRD) equation at 1 year after RN. Charlson co-morbidity score, incidence of hypertension, diabetes and cardiovascular disease were compared and assessed as predictors for developing an eGFR of <60 mL/min/1.73 m(2) . RESULTS: In all, 196 patients were included, 98 in each group. The mean age was respectively 60.6 (RCC group) and 59.1 years (donors). The 1-year postoperative mean eGFR (available in 89 patients with RCC and 87 donors) was similar, at a mean (sd) of 56.7 (16.4) mL/min/1.73 m(2) in patients with RCC and 56.2 (9.8) mL/min/1.73 m(2) in donors (P = 0.83). In patients with RCC the incidence and severity of co-morbidities was significantly higher. A preoperative eGFR of 60-89 mL/min/1.73 m(2) was the only independent risk factor for developing a postoperative eGFR of <60 mL/min/1.73 m(2) (odds ratio 4.4, confidence interval 2.1-9.5, P < 0.001, 95% confidence interval). CONCLUSIONS: In our cohorts with advanced age the 1-year follow-up eGFR was similar in both groups. Despite increased co-morbidity in the RCC group there was no increased decline in renal function. Only reduced preoperative eGFR could be identified as risk factor for developing a postoperative eGFR of <60 mL/min/1.73 m(2) . PMID- 24053639 TI - The architecture of colloidal quantum dot solar cells: materials to devices. PMID- 24053638 TI - "It's a different condom, let's see how it works": young men's reactions to and experiences of female condom use during an intervention trial in South Africa. AB - Although male partner cooperation is often essential for successful use of the female condom, only a few studies have directly assessed men's experiences of using the device. We examined barriers to and facilitators of female condom use via qualitative in-depth interviews with 38 young men (18 to 28 years) in South Africa whose partners, all university students, were enrolled in a female condom intervention trial. In all, 21 men used the female condom; the remaining 17 did not attempt use. The main facilitators to female condom use were convenience of use for men, curiosity to see how female condoms compared to male condoms, enhanced sexual sensation, and perceptions of better safety and comfort of the device compared to male condoms. The main barriers were men's limited familiarity with the device, insertion difficulties, and men's concerns about loss of control over sexual encounters. We recommend that human immunodeficiency virus (HIV) prevention and condom promotion programs around the world target men directly for education on female condoms and that they also work with couples jointly around issues of safer-sex communication and negotiation. PMID- 24053640 TI - Psychometric properties of the abbreviated version of the Scale to Assess Unawareness in Mental Disorder in schizophrenia. AB - BACKGROUND: The Scale to Assess Unawareness in Mental Disorder (SUMD) is widely used in clinical trials and epidemiological studies but more rarely in clinical practice because of its length (74 items). In clinical practice, it is necessary to provide shorter instruments. The aim of this study was to investigate the validity and reliability of the abbreviated version of the SUMD. METHODS: DESIGN: We used data from four cross-sectional studies conducted in several psychiatric hospitals in France. INCLUSION CRITERIA: a diagnosis of schizophrenia based on DSM-IV criteria. DATA COLLECTION: socio-demographic and clinical data (including duration of illness, Positive and Negative Syndrome Scale, and the Calgary Depression Scale); quality of life; SUMD. STATISTICAL ANALYSIS: confirmatory factor analyses, item-dimension correlations, Cronbach's alpha coefficients, Rasch statistics, relationships between the SUMD and other parameters. We tested two different scoring models and considered the response 'not applicable' as '0' or as missing data. RESULTS: Five hundred and thirty-one patients participated in this study. The 3-factor structure of the SUMD (awareness of the disease, consequences and need for treatment; awareness of positive symptoms; and awareness of negative symptoms) was confirmed using LISREL confirmatory factor analysis for the two models. Internal item consistency and reliability were satisfactory for all dimensions. External validity testing revealed that dimension scores correlated significantly with all PANSS scores, especially with the G12 item (lack of judgement and awareness). Significant associations with age, disease duration, education level, and living arrangements showed good discriminant validity. CONCLUSION: The abbreviated version of the SUMD appears to be a valid and reliable instrument for measuring insight in patients with schizophrenia and may be used by clinicians to accurately assess insight in clinical settings. PMID- 24053641 TI - Preparation of lactose-free pasteurized milk with a recombinant thermostable beta glucosidase from Pyrococcus furiosus. AB - BACKGROUND: Lactose intolerance is a common health concern causing gastrointestinal symptoms and avoidance of dairy products by afflicted individuals. Since milk is a primary source of calcium and vitamin D, lactose intolerant individuals often obtain insufficient amounts of these nutrients which may lead to adverse health outcomes. Production of lactose-free milk can provide a solution to this problem, although it requires use of lactase from microbial sources and increases potential for contamination. Use of thermostable lactase enzymes can overcome this issue by functioning under pasteurization conditions. RESULTS: A thermostable beta-glucosidase gene from Pyrococcus furiosus was cloned in frame with the Saccharomyces cerecisiae a-factor secretory signal and expressed in Pichia pastoris strain X-33. The recombinant enzyme was purified by a one-step method of weak anion exchange chromatography. The optimum temperature and pH for this beta-glucosidase activity was 100 degrees C and pH 6.0, respectively. The enzyme activity was not significantly inhibited by Ca2+. We tested the additive amount, hydrolysis time, and the influence of glucose on the enzyme during pasteurization and found that the enzyme possessed a high level of lactose hydrolysis in milk that was not obviously influenced by glucose. CONCLUSIONS: The thermostablity of this recombinant beta-glucosidase, combined with its neutral pH activity and favorable temperature activity optima, suggest that this enzyme is an ideal candidate for the hydrolysis of lactose in milk, and it would be suitable for application in low-lactose milk production during pasteurization. PMID- 24053642 TI - Nonallergic comorbidities of atopic eczema: an overview of systematic reviews. AB - The aims of this overview are to synthesize the current evidence of published systematic reviews (SRs) on nonallergic comorbidities of atopic eczema (AE). EMBASE and MEDLINE were searched for SRs published from inception to November 2012. SRs were selected independently based on predefined inclusion criteria. Methodological quality of SRs included was assessed by two independent reviewers using the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR) checklist. Nine SRs met all inclusion criteria. Six reviews addressing the association between AE and cancer suggest a decreased risk of glioma, meningioma, and acute lymphoblastic leukemia in patients with current or previous AE. One SR reported a consistent positive association of AE with attention-deficit hyperactivity disorder (ADHD). Diabetes mellitus type 1 and multiple sclerosis (MS) were not significantly related to AE in reviews based on cross-sectional and case-control studies. Patients with AE appear to be at decreased risk of brain tumors. The relationship of AE with Th1- and Th17-mediated (auto-)inflammatory conditions such as diabetes mellitus type 1 and MS should be clarified in prospective observational studies. Children with AE are at increased risk of ADHD. SRs on the risk of depression and Th17-mediated disorders such as inflammatory bowel disease of patients with AE are missing. PMID- 24053643 TI - Identification of parameter correlations for parameter estimation in dynamic biological models. AB - BACKGROUND: One of the challenging tasks in systems biology is parameter estimation in nonlinear dynamic models. A biological model usually contains a large number of correlated parameters leading to non-identifiability problems. Although many approaches have been developed to address both structural and practical non-identifiability problems, very few studies have been made to systematically investigate parameter correlations. RESULTS: In this study we present an approach that is able to identify both pairwise parameter correlations and higher order interrelationships among parameters in nonlinear dynamic models. Correlations are interpreted as surfaces in the subspaces of correlated parameters. Based on the correlation information obtained in this way both structural and practical non-identifiability can be clarified. Moreover, it can be concluded from the correlation analysis that a minimum number of data sets with different inputs for experimental design are needed to relieve the parameter correlations, which corresponds to the maximum number of correlated parameters among the correlation groups. CONCLUSIONS: The information of pairwise and higher order interrelationships among parameters in biological models gives a deeper insight into the cause of non-identifiability problems. The result of our correlation analysis provides a necessary condition for experimental design in order to acquire suitable measurement data for unique parameter estimation. PMID- 24053645 TI - Male circumcision wound healing in human immunodeficiency virus (HIV)-negative and HIV-positive men in Rakai, Uganda. AB - OBJECTIVE: To assess completed wound healing after medical male circumcision (MMC) among human immunodeficiency virus (HIV)-negative and HIV-positive men with cluster of differentiation 4 (CD4) counts of <350 and >=350 cells/mm(3) , as minimal data are available on the safety of MMC among HIV-positive men with low CD4 counts. PATIENTS AND METHODS: In all, 262 HIV-negative and 177 HIV-positive consenting males aged >=12 years accepted MMC using the dorsal slit procedure and were enrolled in the study. Socio-demographic and behavioural data and blood for HIV testing and CD4 counts were collected at baseline. Participants were followed weekly to collect information on resumption of sex, condom use and both self reported and clinically assessed wound healing. The proportions healed among HIV positive men were compared with HIV-negative men. Time to complete wound healing was assessed by Kaplan-Meier survival analysis. RESULTS: There were no statistically significant differences in the proportion of men healed by HIV status. At 4 weeks, the proportions healed were 85.9% in HIV-negative men, 77.4% in HIV-positive men with a CD4 count of >=350 cells/mm(3) and 87.1% in HIV positive men with a CD4 count of <350 cells/mm(3) . The median time to healing was 4 weeks and did not vary by HIV or CD4 status. All men had certified complete wound healing at 6 weeks after MMC. In all, 1.4% of HIV-positive men with a CD4 count of <350 cells/mm(3) resumed sex before healing, compared with 8.5% among HIV-positive men with a CD4 count of >=350 cells/mm(3) (P = 0.052) and 7.8% (P = 0.081) among HIV-negative men. CONCLUSION: Inclusion of HIV-positive men with low CD4 counts in MMC services is not deleterious to postoperative wound healing. PMID- 24053644 TI - Nrf2 regulates angiogenesis: effect on endothelial cells, bone marrow-derived proangiogenic cells and hind limb ischemia. AB - AIMS: Nuclear factor E2-related factor 2 (Nrf2), a key cytoprotective transcription factor, regulates also proangiogenic mediators, interleukin-8 and heme oxygenase-1 (HO-1). However, hitherto its role in blood vessel formation was modestly examined. Particularly, although Nrf2 was shown to affect hematopoietic stem cells, it was not tested in bone marrow-derived proangiogenic cells (PACs). Here we investigated angiogenic properties of Nrf2 in PACs, endothelial cells, and inflammation-related revascularization. RESULTS: Treatment of endothelial cells with angiogenic cytokines increased nuclear localization of Nrf2 and induced expression of HO-1. Nrf2 activation stimulated a tube network formation, while its inhibition decreased angiogenic response of human endothelial cells, the latter effect reversed by overexpression of HO-1. Moreover, lack of Nrf2 attenuated survival, proliferation, migration, and angiogenic potential of murine PACs and affected angiogenic transcriptome in vitro. Additionally, angiogenic capacity of PAC Nrf2(-/-) in in vivo Matrigel assay and PAC mobilization in response to hind limb ischemia of Nrf2(-/-) mice were impaired. Despite that, restoration of blood flow in Nrf2-deficient ischemic muscles was better and accompanied by increased oxidative stress and inflammatory response. Accordingly, the anti-inflammatory agent etodolac tended to diminish blood flow in the Nrf2(-/ ) mice. INNOVATION: Identification of a novel role of Nrf2 in angiogenic signaling of endothelial cells and PACs. CONCLUSION: Nrf2 contributes to angiogenic potential of both endothelial cells and PACs; however, its deficiency increases muscle blood flow under tissue ischemia. This might suggest a proangiogenic role of inflammation in the absence of Nrf2 in vivo, concomitantly undermining the role of PACs in such conditions. PMID- 24053646 TI - 3-aroylmethylene-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-ones as potent Nrf2/ARE inducers in human cancer cells and AOM-DSS treated mice. AB - Nrf2-mediated activation of ARE regulates expression of cytoprotective enzymes against oxidative stress, inflammation, and carcinogenesis. We have discovered a novel structure (1) as an ARE inducer via luciferase reporter assay to screen the in-house database of our laboratory. The potency of 1 was evaluated by the expression of NQO-1, HO-1, and nuclear translocation of Nrf2 in HCT116 cells. In vivo potency of 1 was studied using AOM-DSS models, showing that the development of colorectal adenomas was significantly inhibited. Administration with 1 lowered the expression of IL-6, IL-1beta, and promoted Nrf2 nuclear translocation. These results indicated that 1 is a potent Nrf2/ARE activator, both in vitro and in vivo. Forty-one derivatives were synthesized for SAR study, and a more potent compound 17 was identified. To our knowledge, this is a potent ARE activator. Besides, its novel structure makes it promising for further optimization. PMID- 24053647 TI - Randomized trial of HTK versus warm blood cardioplegia for right ventricular protection in mitral surgery. AB - OBJECTIVES: To clarify the reliability of the one-shot histidine-tryptophane ketoglutarate (HTK) cardioplegia for right ventricular (RV) myocardial protection during mitral surgery, in patients with or without pre-operative RV dysfunction. DESIGN: Sixty patients undergoing isolated mitral surgery were randomized to myocardial protection with either one-shot HTK or intermittent warm blood cardioplegia (WBC). The RV function was assessed by echocardiography and hemodynamic assessment. Pre-operative tricuspid annular plane systolic excursion (TAPSE), an index of RV systolic function was used to dichotomize groups into patients having impaired (TAPSE < 15) or preserved (TAPSE >= 15) RV function. RESULTS: There were no significant intergroup differences in the post-operative indexes of RV function in cases with TAPSE >= 15. In patients having TAPSE < 15 we observed statistically worse RV ejection fraction (RVEF, 15% +/- 2% vs. 24% +/ 3%), end-diastolic volume (RVEDV, 188 mL +/- 20 vs. 179 mL +/- 14) and fractional area change (RVFAC, 21% +/- 6% vs. 30% +/- 3%) after use of the HTK solution versus patients who received the WBC. These differences were associated with longer mechanical ventilation and ICU times in patients with impaired RV function and receiving HTK cardioplegia. In a substudy ten patients with TAPSE < 15 received intra-operative topical myocardial cooling in addition to HTK. The addition of topical cooling to HTK cardioplegia yielded statistically significant amelioration in post-operative RV function compared with patients who received the HTK solution without topical cooling (RVEF: 23% +/- 3% vs. 15% +/- 2%; RVEDV: 180 mL +/- 9 vs. 188 mL +/- 18; RVFAC: 8.5% +/- 1% vs. 6% +/- 2%). CONCLUSIONS: The one shot HTK solution offers inferior RV protection compared with WBC, mainly in patients with depressed pre-operative RV function. When adopting HTK cardioplegia the addition of topical cooling is strongly advised. PMID- 24053648 TI - Developing a microbiological growth inhibition screening assay for the detection of 27 veterinary drugs from 13 different classes in animal feedingstuffs. AB - Many regulations prohibit using veterinary drugs in feedingstuffs to protect consumers and animals alike. Within this investigation we developed a simple, cost-efficient primary screening method for detecting antibiotics and coccidiostats in animal feeds. Thirty-two veterinary drugs were originally considered. Following matrix-free testing to optimise detection, an assay based on matrix extraction with methanol/acetonitrile/phosphate buffer followed by inoculation and diffusion in agar plates was developed. Final validation was performed with 14 representative drugs (one per drug class) and four bacteria (Escherichia coli ATCC11303 and ATCC27166, Staphylococcus aureus ATCC6538P, Micrococcus luteus ATCC9341) in bovine, lamb and swine fodder, measuring growth inhibition zones. Of the original drugs tested, 27 remained detectable in feed matrices at or below 20 mg kg(-1). Of the 14 validated representatives, two had estimated minimum detectable concentrations of 10-11 mg kg(-1), others of 5 mg kg(-1) or lower, an earlier minimum European Union inclusion rate for many veterinary drugs. No significant matrix effect on inhibition zones was detected. Per cent wrong negative deviations ranged from 0% (nine of 14 compounds) to 20 27% (two of 14), while inter-day precision based on inhibition zones had relative standard deviations (RSDs) of 6-109% (mean of 40%). When setting a 1 mm inhibition zone, the maximum observed for negative controls, as a cut-off level, no false-positives were found. While not all targeted antibiotics were detectable in complex matrices, the majority of veterinary drugs were detected with reasonable sensitivity, indicating that this method could be suitable for screening feedingstuffs prior to further confirmatory investigation of positive findings such as by LC-MS/MS. PMID- 24053649 TI - Alignment-free supervised classification of metagenomes by recursive SVM. AB - BACKGROUND: Comparison and classification of metagenome samples is one of the major tasks in the study of microbial communities of natural environments or niches on human bodies. Bioinformatics methods play important roles on this task, including 16S rRNA gene analysis and some alignment-based or alignment-free methods on metagenomic data. Alignment-free methods have the advantage of not depending on known genome annotations and therefore have high potential in studying complicated microbiomes. However, the existing alignment-free methods are all based on unsupervised learning strategy (e.g., PCA or hierarchical clustering). These types of methods are powerful in revealing major similarities and grouping relations between microbiome samples, but cannot be applied for discriminating predefined classes of interest which might not be the dominating assortment in the data. Supervised classification is needed in the latter scenario, with the goal of classifying samples into predefined classes and finding the features that can discriminate the classes. The effectiveness of supervised classification with alignment-based features on metagenomic data have been shown in some recent studies. The application of alignment-free supervised classification methods on metagenome data has not been well explored yet. RESULTS: We developed a method for this task using k-tuple frequencies as features counted directly from metagenome short reads and the R-SVM (Recursive SVM) for feature selection and classification. We tested our method on a simulation dataset, a real dataset composed of several known genomes, and a real metagenome NGS short reads dataset. Experiments on simulated data showed that the method can classify the classes almost perfectly and can recover major sequence signatures that distinguish the two classes. On the real human gut metagenome data, the method can discriminate samples of inflammatory bowel disease (IBD) patients from control samples with high accuracy, which cannot be separated when comparing the samples with unsupervised clustering approaches. CONCLUSIONS: The proposed alignment-free supervised classification method can perform well in discriminating of metagenomic samples of predefined classes and in selecting characteristic sequence features for the discrimination. This study shows as an example on the feasibility of using metagenome sequence features of microbiomes on human bodies to study specific human health conditions using supervised machine learning methods. PMID- 24053650 TI - Pediatric spinal pilomyxoid astrocytoma. AB - Pediatric spinal pilomyxoid astrocytoma (PMA) is an extremely rare tumor that merits recognition as a specific, unique entity. The authors present the case of an intramedullary PMA in the thoracic spinal cord of an 11-year-old boy who presented with back pain, scoliosis, and multiple lung nodules. The patient underwent T5-11 laminoplasty and near-total resection of the spinal tumor. The final pathological diagnosis was WHO Grade II PMA. The patient did well for 14 months until the tumor progressed both clinically and radiographically. A literature review focusing on the clinical characteristics, histology, and treatment of PMAs provides a better understanding of these rare lesions. Because of the small number of cases optimal treatment guidelines have not been established, but gross-total resection and adjuvant chemotherapy with alkylating agents appear to confer a better long-term prognosis. Pediatric patients with PMAs can remain recurrence free at least 5 years after surgery, although these tumors may disseminate or dedifferentiate into more malignant gliomas. Recognition of intramedullary PMA as a unique entity in children is vital to the development of specific surgical and adjuvant treatment regimens. PMID- 24053652 TI - Pd-catalyzed direct arylation of nitro(pentafluorosulfanyl)benzenes with aryl bromides. AB - Limited methods for the synthesis of SF5-substituted compounds significantly restrict their widespread application. A Pd-catalyzed direct arylation of nitro(pentafluorosulfanyl)benzenes with aryl bromides is reported. This protocol provides a facile and straightforward access to diversified SF5-containing aryl derivatives. The notable features of this reaction are its synthetic simplicity, high reaction efficiency, and good regioselectivity. PMID- 24053651 TI - Predictors of survival in patients with disease recurrence after radical nephroureterectomy. AB - OBJECTIVES: To evaluate the prognostic value of the Bajorin criteria in a multi institutional cohort of patients with disease recurrence after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). To investigate whether clinical, pathological and/or biological factors at time of disease recurrence are also associated with cancer-specific outcomes in these patients. PATIENTS AND METHODS: We identified 242 patients with disease recurrence after RNU for UTUC from 11 centres. With regard to the Bajorin criteria, patients were categorized into three groups based on two risk factors: Karnofsky performance status <80% and the presence of visceral metastasis. Assessed variables included pathological characteristics, time to disease recurrence, age-adjusted Charlson comorbidity index (ACCI), American Society of Anesthesiologists (ASA) score, and laboratory tests at time of disease recurrence. RESULTS: Overall, 185 patients died from their disease; the median survival was 9 months. The survival rates at 1 year were 53, 33, and 39% for patients with no (n = 18), one (n = 109) and two (n = 115) risk factors, respectively, with no significant difference between the groups. In univariable analyses, higher pT-stage, tumour necrosis, non-administered salvage chemotherapy, higher ACCI score, higher ASA score, lower albumin level and higher white blood cell count were significantly associated with a shorter time to cancer-specific mortality. CONCLUSIONS: We confirmed the poor yet variable outcomes of patients with disease recurrence after RNU. While the Bajorin criteria seem to have limited prognostic value in this specific cohort, we found several other clinical variables to be associated with worse cancer-specific mortality. If validated, these factors should be taken into consideration for clinical trial design. PMID- 24053653 TI - The preclinical discovery and development of ezogabine for the treatment of epilepsy. AB - INTRODUCTION: The weak anticonvulsant activity of the analgesic flupirtine led to the creation of ezogabine; an analogue which demonstrated both stronger antiepileptic activity and weaker analgesic effects. It's use as an anticonvulsant has been particularly effective in treating patients who have therapy-resistant epilepsy. Ezogabine binds to the KCNQ potassium channel, thereby decreasing the membrane potential threshold for its activation and increasing the probability of its maximum opening. AREAS COVERED: This drug discovery case history provides an overview of the history of the anticonvulsant, ezogabine, and presents relevant information pertaining to its discovery and preclinical development. The article helps explain the methods of discovery through the explanation of ezogabine's mechanism of action. Further, the authors also highlight the drugs clinical development and its postlaunch developments. EXPERT OPINION: More intense investment in research on the molecular mechanism of action early in the preclinical development of a drug could allow for the more suitable planning of preclinical studies and for the early discovery of specific, but important drug toxicities. This investment would make transitioning from the preclinical to the clinical phase easier and could result in better planning for what will be more productive clinical studies. PMID- 24053654 TI - Glycolic acid production in the engineered yeasts Saccharomyces cerevisiae and Kluyveromyces lactis. AB - BACKGROUND: Glycolic acid is a C2 hydroxy acid that is a widely used chemical compound. It can be polymerised to produce biodegradable polymers with excellent gas barrier properties. Currently, glycolic acid is produced in a chemical process using fossil resources and toxic chemicals. Biotechnological production of glycolic acid using renewable resources is a desirable alternative. RESULTS: The yeasts Saccharomyces cerevisiae and Kluyveromyces lactis are suitable organisms for glycolic acid production since they are acid tolerant and can grow in the presence of up to 50 g l(-1) glycolic acid. We engineered S. cerevisiae and K. lactis for glycolic acid production using the reactions of the glyoxylate cycle to produce glyoxylic acid and then reducing it to glycolic acid. The expression of a high affinity glyoxylate reductase alone already led to glycolic acid production. The production was further improved by deleting genes encoding malate synthase and the cytosolic form of isocitrate dehydrogenase. The engineered S. cerevisiae strain produced up to about 1 g l(-1) of glycolic acid in a medium containing d-xylose and ethanol. Similar modifications in K. lactis resulted in a much higher glycolic acid titer. In a bioreactor cultivation with D xylose and ethanol up to 15 g l(-1) of glycolic acid was obtained. CONCLUSIONS: This is the first demonstration of engineering yeast to produce glycolic acid. Prior to this work glycolic acid production through the glyoxylate cycle has only been reported in bacteria. The benefit of a yeast host is the possibility for glycolic acid production also at low pH, which was demonstrated in flask cultivations. Production of glycolic acid was first shown in S. cerevisiae. To test whether a Crabtree negative yeast would be better suited for glycolic acid production we engineered K. lactis in the same way and demonstrated it to be a better host for glycolic acid production. PMID- 24053656 TI - Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. AB - BACKGROUND: Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects. METHODS: A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15 mg twice-daily for 21 days, followed by 20 mg once-daily) with standard-therapy (enoxaparin 1.0 mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12 months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75. RESULTS: A total of 8282 patients were enrolled; 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 (2.1%) rivaroxaban-treated patients compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66-1.19; pnoninferiority < 0.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37-0.79; p = 0.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots, and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban were similar compared with standard-therapy. CONCLUSION: The single-drug approach with rivaroxaban resulted in similar efficacy to standard therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups. TRIAL REGISTRATION EINSTEIN-PE: ClinicalTrials.gov, NCT00439777; EINSTEIN-DVT: ClinicalTrials.gov, NCT00440193. PMID- 24053657 TI - Serum calcium concentration and prostate cancer risk: a multicenter study. AB - This study sought to further evaluate the possible effects of serum calcium level on prostate cancer (PC) risk, with considering the age, body mass index (BMI), and sex steroid hormones. Using data from a prospective multicenter study, serum calcium concentration, as well as thorough demographic and medical characteristics, were determined in 194 cases with newly diagnosed, clinicopathologically confirmed PC and 317 controls, without any malignant disease, admitted to the same network of hospitals. Serum total and ionized calcium levels were categorized into tertiles. Multivariate logistic regression model was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) after adjustment for major potential confounders, including age, BMI, smoking, alcohol, education, occupation, marital status, family history of PC, and sex hormones level. The mean serum calcium level (+/-SD) in case and control groups was 9.22 (+/-0.46) mg/dl and 9.48 (+/-0.51) mg/dl, respectively (P < 0.001). After adjustment for mentioned confounders, a significant trend of decreasing risk was found for serum total calcium concentration (OR = 0.27, 95% CI = 0.12-0.59, comparing the highest with the lowest tertile) and ionized calcium (OR = 0.25, 95% CI = 0.10-0.58). An increase of 1 mg/dl in serum calcium level was associated with a significant decrease in PC risk (OR = 0.52; 95% CI = 0.34-0.76). Our findings reveal the inverse association between serum total and ionized concentrations and PC risk, which supports the hypothesis that calcium may protect against PC. Furthermore, no evidence was found regarding age, BMI, and sex steroid hormones to modify the association between serum calcium and PC risk. PMID- 24053659 TI - Gold-mediated expulsion of dinitrogen from organic azides. AB - Organoazides and their nitrogen expulsion chemistry have attracted the attention of many scientists because they serve as a useful source of nitrene fragments and interesting nitrene rearrangement products. Gold-mediated reactions are also of significant current interest. This manuscript describes several important discoveries based at the intersection of these fields. In particular, we report the first isolable gold organoazides ([(SIPr)AuN(1-Ad)NN][SbF6], [(SIPr)AuN(2 Ad)NN][SbF6] and [(SIPr)AuN(Cy)NN][SbF6]; SIPr = a N-heterocyclic carbene; 1 AdNNN = 1-azidoadamantane; 2-AdNNN = 2-azidoadamantane; CyNNN = azidocyclohexane), and their gold-mediated nitrogen expulsion chemistry, and the isolation of formal nitrene rearrangement products of "1-AdN", "2-AdN" and "CyN" (including the elusive 4-azahomoadamant-3-ene) as their gold complexes. We have also performed a computational study to understand and explain the observed structure of gold-coordinated 1-AdNNN and 2-AdNNN and their nitrogen elimination pathways, which implies that the conversion of the organoazide complex to the imine is a concerted process without a nitrene/nitrenoid intermediate. Kinetic studies of [(SIPr)AuN(2-Ad)NN][SbF6] from 30 to 50 degrees C indicate that nitrogen elimination is a first-order process. The experimentally determined activation parameters are in good agreement with the calculated values. PMID- 24053658 TI - Prospective comparison of quality-of-life outcomes between ileal conduit urinary diversion and orthotopic neobladder reconstruction after radical cystectomy: a statistical model. AB - OBJECTIVE: To conduct a prospective comparison of quality-of-life (QoL) outcomes in patients who underwent ileal conduit (IC) urinary diversion with those who underwent orthotopic neobladder (ONB) reconstruction after radical cystectomy for invasive bladder cancers. PATIENTS AND METHODS: Between January 2007 and December 2012, 227 patients underwent radical cystectomy and either IC urinary diversion or ONB (sigmoid or ileal) reconstruction. Contraindications for ON were impaired renal function (serum creatinine >2 mg/dL), chronic inflammatory bowel disease, previous bowel resection and tumour involvement at the bladder neck/prostatic urethra. Patients who did not have these contraindications chose to undergo either IC or ONB reconstruction, after impartial counselling. Baseline characteristics, including demographic profile, body mass index, comorbidities, histopathology of the cystoprostatectomy (with lymph nodes) specimen, pathological tumour stage, postoperative complications, adjuvant therapy and relapse, were recorded and compared. The European Organization for Research and Treatment of Cancer QoL questionnaire C30 version 3 was used to analyse QoL before surgery and 6, 12 and 18 months after surgery. RESULTS: Of the 227 patients, 28 patients in the IC group and 35 in the ONB group were excluded. The final analysis included 80 patients in the IC and 84 in the ONB group. None of the baseline characteristics were significantly different between the groups, except for age, but none of the baseline QoL variables were found to be correlated with age. In the preoperative phase, there were no significant differences in any of the QoL domains between the IC or the ONB groups. At 6, 12 and 18 months in the postoperative period, physical functioning (P < 0.001, P < 0.001 and P = 0.001, respectively), role functioning (P = 0.01, P = 0.01 and P = 0.003, respectively), social functioning (P = 0.01, P = 0.01 and P = 0.01, respectively) and global health status/QoL (P < 0.001, P < 0.001 and P = 0.002, respectively) were better in patients in the ONB group than in those in the IC group and the differences were significant. The financial burden related to bladder cancer treatment was significantly lower in the ONB group than in the IC group at 6, 12 and 18 months of follow-up (P = 0.05, P = 0.05 and P = 0.005, respectively) CONCLUSIONS: ONB is better than IC in terms of physical functioning, role functioning, social functioning, global health status/QoL and financial expenditure. ONB reconstruction provides better QoL outcomes than does IC urinary diversion. PMID- 24053660 TI - Live surgical education: a perspective from the surgeons who perform it. AB - OBJECTIVE: To evaluate the experience and views regarding live surgical broadcasts (LSB) among European urologists attending the European Association of Urology Robotic Urology Society (ERUS) congress in September 2012. MATERIALS AND METHODS: An anonymous survey was distributed via email inviting the participants of the ERUS congress with experience of LSB to share their opinions about LSB. The outcomes measured included; personal experience of LSB, levels of anxiety faced and the perceived surgical quality. The impact of factors, such as communication/team-working, travel fatigue and lack of specific equipment were also evaluated. RESULTS: In all, 106 surgeons responded with 98 (92.5%) reporting personal experience of LSB; 6.5% respondents noted 'significant anxiety' increasing to 19.4% when performing surgery away from home (P < 0.001). Surgical quality was perceived as 'slightly worse' and 'significantly worse' by 16.1% and 2.2%, which deteriorated further to 23.9% and 3.3% respectively in a 'foreign' environment (P = 0.005). In all, 10.9% of surgeons 'always' brought their own surgical team compared with 37% relying on their host institution; 2.4% raised significant concerns with their team and 18.8% encountered significantly more technical difficulties. Lack of specific equipment (10.3%), language difficulties (6.2%) and jet lag (7.3%) were other significant factors reported. In all, 75% of surgeons perceived the audience wanted a slick demonstration; however, 52.2% and 42.4% respectively also reported the audience wished the surgeon to struggle or manage a complication during a LSB. CONCLUSIONS: A small proportion of surgeons had significantly heightened anxiety levels and lower perceived performance during LSB, which in a 'foreign' environment seemed to affect a greater proportion of surgeons. Various factors appear to impact surgical performance raising concerns about the appropriateness of unregulated LSB as a teaching method. To mitigate these concerns, surgeons' performing live surgery feel that the operation needs to be well planned using appropriate equipment; with many considering bringing their own team or operating from home on a video link. PMID- 24053662 TI - Sub-Doppler resolution in the THz frequency domain: 1 kHz accuracy at 1 THz by exploiting the Lamb-dip technique. AB - We report the first thorough investigation of the Lamb-dip effect in the THz region, which in turn allows sub-Doppler resolution to be exploited in this frequency region. It is demonstrated that an accuracy of 1 kHz, or even better (i.e., an accuracy better than 1 part in 10(9)), and a frequency resolution of 50 kHz (i.e., a resolution better than 5 parts in 10(8)) can be routinely obtained in our laboratory. It has also shown that Lamb-dip spectra can be recorded using either a Fabry-Perot interferometric cell or a free-space cell. Hydrogen sulfide (H2S), sulfur dioxide (SO2), deuterated water (D2O), and methyl fluoride (CH3F) have been selected as examples for demonstrating the accuracy and resolution reachable, thus providing the most accurate frequency values in the 1.0-1.2 THz frequency range for these molecules. Measurements for SO2 have also been employed in a global fit, thus improving its spectroscopic parameters for the vibrational ground state. PMID- 24053661 TI - Effectiveness of influenza vaccine against laboratory-confirmed influenza, in the late 2011-2012 season in Spain, among population targeted for vaccination. AB - BACKGROUND: In Spain, the influenza vaccine effectiveness (VE) was estimated in the last three seasons using the observational study cycEVA conducted in the frame of the existing Spanish Influenza Sentinel Surveillance System. The objective of the study was to estimate influenza vaccine effectiveness (VE) against medically attended, laboratory-confirmed influenza-like illness (ILI) among the target groups for vaccination in Spain in the 2011-2012 season. We also studied influenza VE in the early (weeks 52/2011-7/2012) and late (weeks 8 14/2012) phases of the epidemic and according to time since vaccination. METHODS: Medically attended patients with ILI were systematically swabbed to collect information on exposure, laboratory outcome and confounding factors. Patients belonging to target groups for vaccination and who were swabbed <8 days after symptom onset were included. Cases tested positive for influenza and controls tested negative for any influenza virus. To examine the effect of a late season, analyses were performed according to the phase of the season and according to the time between vaccination and symptoms onset. RESULTS: The overall adjusted influenza VE against A(H3N2) was 45% (95% CI, 0-69). The estimated influenza VE was 52% (95% CI, -3 to 78), 40% (95% CI, -40 to 74) and 22% (95% CI, -135 to 74) at 3.5 months, 3.5-4 months, and >4 months, respectively, since vaccination. A decrease in VE with time since vaccination was only observed in individuals aged >= 65 years. Regarding the phase of the season, decreasing point estimates were only observed in the early phase, whereas very low or null estimates were obtained in the late phase for the shortest time interval. CONCLUSIONS: The 2011 2012 influenza vaccine showed a low-to-moderate protective effect against medically attended, laboratory-confirmed influenza in the target groups for vaccination, in a late season and with a limited match between the vaccine and circulating strains. The suggested decrease in influenza VE with time since vaccination was mostly observed in the elderly population. The decreasing protective effect of the vaccine in the late part of the season could be related to waning vaccine protection because no viral changes were identified throughout the season. PMID- 24053663 TI - Can soil gas VOCs be related to groundwater plumes based on their isotope signature? AB - The isotope evolution of tetrachloroethene (PCE) during its transport from groundwater toward the soil surface was investigated using laboratory studies and numerical modeling. During air-water partitioning, carbon and chlorine isotope ratios evolved in opposite directions, with a normal isotope effect for chlorine (epsilon = -0.200/00) and an inverse effect for carbon (epsilon = +0.460/00). During the migration of PCE from groundwater to the unsaturated zone in a 2D laboratory system, small shifts of carbon and chlorine isotope ratios (+0.80/00) were observed across the capillary fringe. Numerical modeling showed that these shifts are due to isotope fractionation associated with air-water partitioning and gas-phase diffusion. Carbon and chlorine isotope profiles were constant throughout the unsaturated zone once a steady state was reached. However, depending on the thickness of the unsaturated zone and its lithology, depletion in heavy isotopes may occur with distance during the transient migration of contaminants. Additionally, variations of up to +1.50/00 were observed in the unsaturated zone for chlorine isotopes during water table fluctuations. However, at steady state, it is possible to link a groundwater plume to gas-phase contamination and/or to differentiate sources of contamination based on isotope ratios. PMID- 24053664 TI - Distinctive emotional responses of clinicians to suicide-attempting patients--a comparative study. AB - BACKGROUND: Clinician responses to patients have been recognized as an important factor in treatment outcome. Clinician responses to suicidal patients have received little attention in the literature however, and no quantitative studies have been published. Further, although patients with high versus low lethality suicidal behaviors have been speculated to represent two distinct populations, clinicians' emotional responses to them have not been examined. METHODS: Clinicians' responses to their patients when last seeing them prior to patients' suicide attempt or death were assessed retrospectively with the Therapist Response/Countertransference Questionnaire, administered anonymously via an Internet survey service. Scores on individual items and subscale scores were compared between groups, and linear discriminant analysis was applied to determine the combination of items that best discriminated between groups. RESULTS: Clinicians reported on patients who completed suicide, made high lethality attempts, low-lethality attempts, or died unexpected non-suicidal deaths in a total of 82 cases. We found that clinicians treating imminently suicidal patients had less positive feelings towards these patients than for non suicidal patients, but had higher hopes for their treatment, while finding themselves notably more overwhelmed, distressed by, and to some degree avoidant of them. Further, we found that the specific paradoxical combination of hopefulness and distress/avoidance was a significant discriminator between suicidal patients and those who died unexpected non-suicidal deaths with 90% sensitivity and 56% specificity. In addition, we identified one questionnaire item that discriminated significantly between high- and low-lethality suicide patients. CONCLUSIONS: Clinicians' emotional responses to patients at risk versus not at risk for imminent suicide attempt may be distinct in ways consistent with responses theorized by Maltsberger and Buie in 1974. Prospective replication is needed to confirm these results, however. Our findings demonstrate the feasibility of using quantitative self-report methodologies for investigation of the relationship between clinicians' emotional responses to suicidal patients and suicide risk. PMID- 24053665 TI - Deformity stabilization and improvement in men with untreated Peyronie's disease. AB - OBJECTIVE: To define predictors of the deformity stabilisation and improvement in men with untreated Peyronie's disease (PD). PATIENTS AND METHODS: The study population consisted of patients with PD-associated uniplanar curvature, who opted for no treatment and were followed for at least 12 months. All patients had deformity assessment (DA) performed on initial presentation and at follow-up. Stabilisation of PD was defined as no change between DAs (+/-10 degrees ), while improvement and progression were defined as >=10 degrees change. Patients were subdivided into different groups based on time to presentation: <=6 months (A), 7 12 months (B), and 13-18 months (C). Multivariable analysis was used to define predictors of stabilisation and improvement. RESULTS: In all, 176 men met the inclusion criteria. The mean age was 54 years, with a mean (sd) PD duration of 9 (12) months and mean curvature of 42 (27) degrees . In all, 67% of the entire population had no change in deformity over time, 12% improved with a mean (sd) change of 27 (14) degrees , and 21% worsened with a mean (sd) change of 22 (11) degrees . On multivariate analysis, predictors of stabilisation included: time to presentation of >6 months (odds ratio [OR] 2.4, P < 0.01), per decade increase in age (OR 1.5, P < 0.05), and age (r = 0.32, P < 0.05). Predictors of improvement included: time to presentation of <=6 months (OR 4.1, P < 0.001), and per decade decrease in age (OR 2.1, P < 0.01). CONCLUSIONS: In men with uniplanar curvature, PD stabilisation and improvement rates change with time-to-presentation and patient age. These data may aid in counselling patients with PD. PMID- 24053666 TI - Estrogen-related receptor beta deficiency alters body composition and response to restraint stress. AB - BACKGROUND: Estrogen-related receptors (ERRs) are orphan nuclear hormone receptors expressed in metabolically active tissues and modulate numerous homeostatic processes. ERRs do not bind the ligand estrogen, but they are able to bind the estrogen response element (ERE) embedded within the ERR response elements (ERREs) to regulate transcription of genes. Previous work has demonstrated that adult mice lacking Errbeta have altered metabolism and meal patterns. To further understand the biological role of Errbeta, we characterized the stress response of mice deficient for one or both alleles of Errbeta. RESULTS: Sox2-Cre:Errbeta mice lack Errbeta expression in all tissues of the developing embryo. Sox2-Cre:Errbeta+/lox heterozygotes were obese, had increased Npy and Agrp gene expression in the arcuate nucleus of the hypothalamus, and secreted more corticosterone in response to stress. In contrast, Sox2 Cre:Errbetalox/lox homozygotes were lean and, despite increased Npy and Agrp gene expression, did not secrete more corticosterone in response to stress. Sox2 Cre:Errbeta+/lox and Sox2-Cre:Errbetalox/lox mice treated with the Errbeta and Errgamma agonist DY131 demonstrated increased corticotropin-releasing hormone (Crh) expression in the paraventricular nucleus of the hypothalamus, although corticosterone levels were not affected. Nes-Cre:Errbetalox/lox mice, which selectively lack Errbeta expression in the nervous system, also demonstrated elevated stress response during an acoustic startle response test and decreased expression of both Crh and corticotropin-releasing hormone receptor 2 (Crhr2). CONCLUSIONS: Loss of Errbeta affects body composition, neuropeptide levels, stress hormones, and centrally-modulated startle responses of mice. These results indicate that Errbeta alters the function of the hypothalamic-pituitary adrenocortical axis and indicates a role for Errbeta in regulating stress response. PMID- 24053667 TI - Comparative genomics reveals that a fish pathogenic bacterium Edwardsiella tarda has acquired the locus of enterocyte effacement (LEE) through horizontal gene transfer. AB - BACKGROUND: Edwardsiella tarda is an enterobacterium which causes edwardsiellosis, a fatal disease of cultured fishes such as red sea bream, eel, and flounder. Preventing the occurrence of E. tarda infection has thus been an important issue in aquaculture. E. tarda has been isolated from other animals and from many environments; however, the relationship between the genotype and evolutionary process of this pathogen is not fully understood. To clarify this relationship, we sequenced and compared the genomes of pathogenic and non pathogenic E. tarda strains isolated from fish, human, and eel pond using next generation sequencing technology. RESULTS: Eight strains of E. tarda were sequenced with high accuracy (>99.9%) with coverages from 50- to 400-fold. The obtained reads were mapped to a public reference genome. By comparing single nucleotide and insertion/deletion polymorphisms, we found that an attenuated strain of E. tarda had a loss-of-function mutation in a gene related to the type III secretion system (T3SS), suggesting that this gene is involved in the virulence of E. tarda. A comprehensive gene comparison indicated that fish pathogenic strains possessed a type VI secretion system (T6SS) and pilus assembly genes in addition to the T3SS. Moreover, we found that an E. tarda strain isolated from red sea bream harbored two pathogenicity islands of T3SS and T6SS, which were absent in other strains. In particular, this T3SS was homologous to the locus of enterocyte effacement (LEE) in enteropathogenic and enterohemorrhagic Escherichia coli. Evolutionary analysis suggested that this locus, here named Et-LEE (E. tarda LEE), was introgressed into the E. tarda genome through horizontal transfer. CONCLUSIONS: We found significant differences in the presence/absence of virulence-related genes among E. tarda strains, reflecting their evolutionary relationship. In particular, a single genotype previously proposed for fish-pathogenic strains may be further divided into two subgroups. Furthermore, the current study demonstrated, for the first time, that a fish pathogenic bacterium carried a LEE-like pathogenicity island which was previously reported only in zoonotic pathogenic enterobacteria. These findings will contribute to the exploration of strain-specific drug targets against E. tarda in aquafarms, while also shedding light on the evolution of pathogenesis in enterobacteria. PMID- 24053668 TI - Proteomic and comparative genomic analysis of two Brassica napus lines differing in oil content. AB - Ultrastructural observations, combined with proteomic and comparative genomic analyses, were applied to interpret the differences in protein composition and oil-body characteristics of mature seed of two Brassica napus lines with high and low oil contents of 55.19% and 36.49%, respectively. The results showed that oil bodies were arranged much closer in the high than in the low oil content line, and differences in cell size and thickness of cell walls were also observed. There were 119 and 32 differentially expressed proteins (DEPs) of total and oil body proteins identified. The 119 DEPs of total protein were mainly involved in the oil-related, dehydration-related, storage and defense/disease, and some of these may be related to oil formation. The DEPs involved with dehydration-related were both detected in total and oil-body proteins for high and low oil lines and may be correlated with the number and size of oil bodies in the different lines. Some genes that corresponded to DEPs were confirmed by quantitative trait loci (QTL) mapping analysis for oil content. The results revealed that some candidate genes deduced from DEPs were located in the confidence intervals of QTL for oil content. Finally, the function of one gene that coded storage protein was verified by using a collection of Arabidopsis lines that can conditionally express the full length cDNA from developing seeds of B. napus. PMID- 24053672 TI - Genistein induces G2/M arrest in gastric cancer cells by increasing the tumor suppressor PTEN expression. AB - Genistein, a major isoflavone found in soybeans, exhibits anticarcinogenic properties. The inhibitory effect of genistein on cell proliferation is associated with G2/M cell cycle arrest and inhibition of cdc2 activities. Here we assessed the role of PTEN in regulation of genistein-mediated G2/M cell cycle arrest in the gastric cancer cell lines (SGC-7901 and BGC-823). After 24 h following treatment, genistein induced a concentration-dependent accumulation of cells in the G2/M phase of the cell cycle. The sustained G2/M arrest by genistein in SGC-7901 and BGC-823 cells is associated with increased phospho-cdc2 (Tyr15) and decreased cdc2 protein. Genistein treatment increased Wee1 levels and decreased phospho-Wee1 (Ser 642). Moreover, genistein substantially decreased the Ser473 and Thr308 phosphorylation of Akt and upregulated PTEN expression. Downregulation of PTEN by siRNA in genistein-treated cells increased phospho-Wee1 (Ser642), whereas decreased phospho-Cdc2 (Tyr15), resulting in decreased the G2/M cell cycle arrest. Therefore, induction of G2/M cell cycle arrest by genistein involved upregulation of PTEN. PMID- 24053669 TI - Role of unfolded protein response dysregulation in oxidative injury of retinal pigment epithelial cells. AB - AIMS: Age-related macular degeneration (AMD), a major cause of legal blindness in the elderly, is associated with genetic and environmental risk factors, such as cigarette smoking. Recent evidence shows that cigarette smoke (CS) that contains high levels of potent oxidants preferably targets retinal pigment epithelium (RPE) leading to oxidative damage and apoptosis; however, the mechanisms are poorly understood. The present study aimed to investigate the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in CS-related RPE apoptosis. RESULTS: ER stress and proapoptotic gene C/EBP homologous protein (CHOP) were induced in the RPE/choroid complex from mice exposed to CS for 2 weeks and in human RPE cells treated with hydroquinone, a potent oxidant found at high concentrations in CS. Suppressing ER stress or inhibiting CHOP activation by pharmacological chaperones or genetic approaches attenuated hydroquinone-induced RPE cell apoptosis. In contrast to enhanced CHOP activation, protein level of active X-box binding protein 1 (XBP1), a major regulator of the adaptive UPR, was reduced in hydroquinone-treated cells. Conditional knockout of XBP1 gene in the RPE resulted in caspase-12 activation, increased CHOP expression, and decreased antiapoptotic gene Bcl-2. Furthermore, XBP1-deficient RPE cells are more sensitive to oxidative damage induced by hydroquinone or NaIO3, a CS-unrelated chemical oxidant. Conversely, overexpressing XBP1 protected RPE cells and attenuated oxidative stress-induced RPE apoptosis. INNOVATION AND CONCLUSION: These findings provide strong evidence suggesting an important role of ER stress and the UPR in CS-related oxidative injury of RPE cells. Thus, the modulation of the UPR signaling may provide a promising target for the treatment of AMD. PMID- 24053673 TI - Multivariate optimisation of an ultrasound assisted-matrix solid-phase dispersion method combined with LC-fluorescence detection for simultaneous extraction and determination of aflatoxins in pistachio nut samples. AB - This paper describes the application of ultrasound-assisted matrix solid-phase dispersion as an extraction and clean-up procedure for aflatoxins (B1, B2, G1 and G2) and subsequent determination by LC-fluorescence detection. A Box-Behnken design was used to determine the parameters influencing the extraction procedure through response surface methodology and experimental design. The influence of different variables including type of dispersing phase, sample-to-dispersing phase ratio, type and quantity of clean-up phase, ultrasonication time, ultrasonication temperature, nature and volume of the elution solvent were investigated in the optimisation study. C18, graphitic carbon black and acetonitrile were selected as dispersing phase, clean-up phase and elution solvent, respectively. The optimised values were sample-to-dispersing phase ratio of 1:1, 50 mg of graphitic carbon black, 11 min ultrasonication time, 30 degrees C ultrasonication temperature and 3 ml acetonitrile. Under the optimal conditions the limits of detection (LODs) were ranged from 0.04-0.11 ug kg(-1) and the relative standard deviations (RSDs) of the extraction method were less than 8.6%. The recoveries of the matrix solid-phase dispersion process ranged from 74% to 78% with relative standard deviation lower than 9% in all cases. Finally, the matrix solid-phase dispersion was successfully applied to extraction of trace amounts of aflatoxins in pistachio samples. PMID- 24053674 TI - Discovery of pteridin-7(8H)-one-based irreversible inhibitors targeting the epidermal growth factor receptor (EGFR) kinase T790M/L858R mutant. AB - The EGFR T790M variant is an important mutation, resulting in approximately 50% of the clinically acquired resistance to approved EGFR inhibitors. Starting with a previously reported pyrimidine-based EGFR inhibitor, a novel pteridin-7(8H)-one scaffold with a high 3D similarity was found and transformed into irreversible inhibitors of the EGFR T790M mutant. The most potent compounds, 3q and 3x, exhibited excellent enzyme inhibitory activities, with subnanomolar IC50 values for both the wild-type and T790M/L858R double mutant EGFRs, as well as potent cellular antiproliferative activities against both gefitinib-sensitive and resistant cancer cell lines. The in vivo antitumor efficacy study demonstrated that compound 3x significantly inhibited tumor growth and induced tumor stasis in an EGFR-T790M/L858R-driven human nonsmall-cell lung cancer xenograft mouse model. This work demonstrated the utility of this sophisticated computational design strategy for fast 3D scaffold hopping with competitive bioactivities to meet an important clinical need. PMID- 24053675 TI - Analysis of limited-sequence head computed tomography for children with shunted hydrocephalus: potential to reduce diagnostic radiation exposure. AB - OBJECT: Despite its diagnostic utility, head CT scanning imparts risks of radiation exposure. Children with shunt-treated hydrocephalus exhibit increased risks of radiation toxicity due to the higher vulnerability of developing, immature tissues and frequent scanning. Several methods have been used to achieve dose reduction, including modifications of CT scanner tube current and potential. This retrospective study explores the use of a newly defined limited sequence of axial head CT slices to evaluate children with shunted hydrocephalus and decrease radiation exposure from diagnostic CT scans. METHODS: Consistent sequences of 7 axial slices were extracted from previously performed standard head CT scans in children with shunted hydrocephalus. Chronologically distinct limited sequences of each patient were blindly, retrospectively reviewed by 2 pediatric neuroradiologists and 1 pediatric neurosurgeon. Limited-sequence CT evaluation focused on the adequacy of portraying the ventricular system, changes in ventricular size, and visualization of the proximal catheter. Reviewers assessed all original full series head CT scans at least 4 months later for comparison. Adequacy and accuracy of the limited-sequence CT compared with the gold standard head CT was investigated using descriptive statistics. Effective dose (ED) estimates of the limited-sequence and standard head CT scans were compared using descriptive statistics and the Mann-Whitney test. RESULTS: Two serial head CT scans from each of 50 patients (age range 0-17 years; mean age 5.5 years) were reviewed both in standard and limited-sequence forms. The limited-sequence CT adequately portrayed the ventricular system in all cases. The inaccuracy rate for assessing changes in ventricular size by majority assessment (2 of 3 reviewers evaluating inaccurately) was 3 (6%) of 50. In 1 case, the inaccurate assessment would not have altered clinical management, corresponding to a 2 (4%) of 50 clinically relevant inaccuracy rate. As compared with the gold standard complete head CT series, the limited-sequence CT exhibited high sensitivity (100%) and specificity (91%) for portraying changes in ventricular caliber. Additionally, the limited-sequence CT displayed the ventricular catheter in 91.7% of scans averaged across 3 observers. Among all scans reviewed, 97 pairs of standard head CT and complementary limited-sequence CT scans contained adequate dosing information to calculate the effective dose (ED). The ED50 of the limited sequence CT (0.284 mSv) differed significantly from the ED50 of the standard head CT (4.27 mSv) (p < 0.0001). The limited-sequence CT reflected a median absolute reduction of 4.10 mSv and a mean percent reduction of 91.8% in ED compared with standard head CT. CONCLUSIONS: Limited-sequence head CT scanning provided adequate and accurate diagnostic information in children with shunted hydrocephalus. Techniques including minimization of axial slice quantity and modification of CT scanner parameters can achieve significant dose reduction, maintaining a balance between diagnostic utility and patient safety. PMID- 24053676 TI - Analysis of L-glutamic acid fermentation by using a dynamic metabolic simulation model of Escherichia coli. AB - BACKGROUND: Understanding the process of amino acid fermentation as a comprehensive system is a challenging task. Previously, we developed a literature based dynamic simulation model, which included transcriptional regulation, transcription, translation, and enzymatic reactions related to glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and the anaplerotic pathway of Escherichia coli. During simulation, cell growth was defined such as to reproduce the experimental cell growth profile of fed-batch cultivation in jar fermenters. However, to confirm the biological appropriateness of our model, sensitivity analysis and experimental validation were required. RESULTS: We constructed an L-glutamic acid fermentation simulation model by removing sucAB, a gene encoding alpha-ketoglutarate dehydrogenase. We then performed systematic sensitivity analysis for L-glutamic acid production; the results of this process corresponded with previous experimental data regarding L glutamic acid fermentation. Furthermore, it allowed us to predicted the possibility that accumulation of 3-phosphoglycerate in the cell would regulate the carbon flux into the TCA cycle and lead to an increase in the yield of L glutamic acid via fermentation. We validated this hypothesis through a fermentation experiment involving a model L-glutamic acid-production strain, E. coli MG1655 DeltasucA in which the phosphoglycerate kinase gene had been amplified to cause accumulation of 3-phosphoglycerate. The observed increase in L glutamic acid production verified the biologically meaningful predictive power of our dynamic metabolic simulation model. CONCLUSIONS: In this study, dynamic simulation using a literature-based model was shown to be useful for elucidating the precise mechanisms involved in fermentation processes inside the cell. Further exhaustive sensitivity analysis will facilitate identification of novel factors involved in the metabolic regulation of amino acid fermentation. PMID- 24053677 TI - Functional and oncological outcomes of patients aged <50 years treated with radical prostatectomy for localised prostate cancer in a European population. AB - OBJECTIVE: To address the biochemical and functional outcomes after radical prostatectomy (RP) of men aged <50 years in a large European population. PATIENTS AND METHODS: Among 13,268 patients who underwent RP for clinically localised prostate cancer at our centre (1992-2011), 443 (3.3%) men aged <50 were identified. Biochemical recurrence (BCR) and functional outcomes (International Index of Erectile Function [IIEF-5], use of pads), were prospectively evaluated and compared between men aged <50 years and older patients. RESULTS: Men aged <50 years were more likely to harbour D'Amico low-risk (49.4 vs 34.9%, P < 0.001), organ-confined (82.6 vs 69.4%, P < 0.001) and low-grade tumours (Gleason score <7: 33.1 vs 28.7%, P < 0.001). Multivariate Cox regression analysis showed that age <50 years (hazard ratio 0.99; confidence interval 0.72-1.31; P = 0.9) was not a predictor of BCR. Urinary continence was more favourable in younger patients, resulting in continence rates of 97.4% vs 91.6% in most recent years (2009-2011) for patients aged <50 vs >=50 years. After RP, a median IIEF-5 drop of 4 points in younger men vs 8 points in older patients was recorded (P < 0.001). Favourable recovery of urinary continence and erectile function in patients aged <50 years compared with their older counterparts was confirmed after multivariable adjustment. CONCLUSION: Men aged <50 years diagnosed with localised prostate cancer should not be discouraged from RP, as the postoperative rates of urinary incontinence and erectile dysfunction are low and probability of BCR-free survival at 2 and 5 years is high. PMID- 24053678 TI - Raltegravir does not revert efflux activity of MDR1-P-glycoprotein in human MDR cells. AB - BACKGROUND: Raltegravir (Isentress(r))(RALT) has demonstrated excellent efficacy in both treatment-experienced and naive patients with HIV-1 infection, and is the first strand transfer integrase inhibitor to be approved for use in HIV infected adults worldwide. Since the in vivo efficacy of this class of antiviral drugs depends on their access to intracellular sites where HIV-1 replicates, we analyzed the biological effects induced by RALT on human MDR cell systems expressing multidrug transporter MDR1-P-glycoprotein (MDR1-Pgp). METHODS: Our study about RALT was performed by using a set of consolidated methodologies suitable for evaluating the MDR1-Pgp substrate nature of chemical and biological agents, namely: i) assay of drug efflux function; ii) analysis of MDR reversing capability by using cell proliferation assays; iii) monoclonal antibody UIC2 (mAb) shift test, as a sensitive assay to analyze conformational transition associated with MDR1-Pgp function; and iv) induction of MDR1-Pgp expression in MDR cell variant subjected to RALT exposure. RESULTS: Functional assays demonstrated that the presence of RALT does not remarkably interfere with the efflux mechanism of CEM-VBL100 and HL60 MDR cells. Accordingly, cell proliferation assays clearly indicated that RALT does not revert MDR phenotype in human MDR1-Pgp expressing cells. Furthermore, exposure of CEM-VBL10 cells to RALT does not induce MDR1-Pgp functional conformation intercepted by monoclonal antibody (mAb) UIC2 binding; nor does exposure to RALT increase the expression of this drug transporter in MDR1-Pgp expressing cells. CONCLUSIONS: No evidence of RALT interaction with human MDR1-Pgp was observed in the in vitro MDR cell systems used in the present investigation, this incorporating all sets of studies recommended by the FDA guidelines. Taken in aggregate, these data suggest that RALT may express its curative potential in all sites were HIV-1 penetrates, including the MDR1-Pgp protected blood/tissue barrier. Moreover RALT, evading MDR1-Pgp drug efflux function, would not interfere with pharmacokinetic profiles of co-administered MDR1-Pgp substrate antiretroviral drugs. PMID- 24053679 TI - Health worker factors associated with prescribing of artemisinin combination therapy for uncomplicated malaria in rural Tanzania. AB - BACKGROUND: Improving malaria case management is partially dependent on health worker compliance with clinical guidelines. This study assessed health worker factors associated with correct anti-malarial prescribing practices at two sites in rural Tanzania. METHODS: Repeated cross-sectional health facility surveys were conducted during high and low malaria transmission seasons in 2010 and collected information on patient consultations and health worker characteristics. Using logistic regression, the study assessed health worker factors associated with correct prescription for uncomplicated malaria defined as prescription of artemisinin-based combination therapy (ACT) for patients with fever and Plasmodium falciparum asexual infection based on blood slide or malaria rapid diagnostic test (RDT) according to national treatment guidelines. RESULTS: The analysis included 685 patients with uncomplicated malaria who were seen in a health facility with ACT in stock, and 71 health workers practicing in 30 health facilities. Overall, 58% of malaria patients were correctly treated with ACT. Health workers with three or more years' work experience were significantly more likely than others to prescribe correctly (adjusted odds ratio (aOR) 2.9; 95% confidence interval (CI) 1.2-7.1; p = 0.019). Clinical officers (aOR 2.2; 95% CI 1.1-4.5; p = 0.037), and nurse aide or lower cadre (aOR 3.1; 95% CI 1.3-7.1; p = 0.009) were more likely to correctly prescribe ACT than medical officers. Training on ACT use, supervision visits, and availability of job aids were not significantly associated with correct prescription. CONCLUSIONS: Years of working experience and health worker cadre were associated with correct ACT prescription for uncomplicated malaria. Targeted interventions to improve health worker performance are needed to improve overall malaria case management. PMID- 24053680 TI - A chemical biological strategy to facilitate diabetic wound healing. AB - A complication of diabetes is the inability of wounds to heal in diabetic patients. Diabetic wounds are refractory to healing due to the involvement of activated matrix metalloproteinases (MMPs), which remodel the tissue resulting in apoptosis. There are no readily available methods that identify active unregulated MMPs. With the use of a novel inhibitor-tethered resin that binds exclusively to the active forms of MMPs, coupled with proteomics, we quantified MMP-8 and MMP-9 in a mouse model of diabetic wounds. Topical treatment with a selective MMP-9 inhibitor led to acceleration of wound healing, re epithelialization, and significantly attenuated apoptosis. In contrast, selective pharmacological inhibition of MMP-8 delayed wound healing, decreased re epithelialization, and exhibited high apoptosis. The MMP-9 activity makes the wounds refractory to healing, whereas that of MMP-8 is beneficial. The treatment of diabetic wounds with a selective MMP-9 inhibitor holds great promise in providing heretofore-unavailable opportunities for intervention of this disease. PMID- 24053681 TI - Disproportionation in Li-O2 batteries based on a large surface area carbon cathode. AB - In this paper we report on a kinetics study of the discharge process and its relationship to the charge overpotential in a Li-O2 cell for large surface area cathode material. The kinetics study reveals evidence for a first-order disproportionation reaction during discharge from an oxygen-rich Li2O2 component with superoxide-like character to a Li2O2 component. The oxygen-rich superoxide like component has a much smaller potential during charge (3.2-3.5 V) than the Li2O2 component (~4.2 V). The formation of the superoxide-like component is likely due to the porosity of the activated carbon used in the Li-O2 cell cathode that provides a good environment for growth during discharge. The discharge product containing these two components is characterized by toroids, which are assemblies of nanoparticles. The morphologic growth and decomposition process of the toroids during the reversible discharge/charge process was observed by scanning electron microscopy and is consistent with the presence of the two components in the discharge product. The results of this study provide new insight into how growth conditions control the nature of discharge product, which can be used to achieve improved performance in Li-O2 cell. PMID- 24053683 TI - Photochemical formation of hydroxyl radical from effluent organic matter: role of composition. AB - The photochemical formation of hydroxyl radical (HO(*)) from effluent organic matter (EfOM) depends upon the chemical properties of this heterogeneous mixture. In this study, two EfOM samples collected from wastewater treatment plants (WWTP A and B) were fractionated by both hydrophobicity (bulk and non-humic) and apparent molecular weight (AMW). The apparent quantum yield for HO(*) formation (PhiHO(*)) and the maximum fluorescence quantum yield (PhiF) were subsequently measured for each subfraction. The formation rates of HO(*) (considering only the hydrogen-peroxide-independent pathways) for the bulk waters were 4.8 * 10(-10) and 9.6 * 10(-11) M s(-1) for WWTP A and B, respectively. For the AMW fractions, the values of PhiHO(*) increased as the AMW of the material decreased. For the WWTP A sample, the PhiHO(*) increased from 2.54 * 10(-4) (bulk water) to 6.29 * 10(-4) for the <1 kDa fraction, and for the WWTP B sample, the value of PhiHO(*) increased from 6.50 * 10(-5) for bulk water to 3.45 * 10(-4) for the <1 kDa fraction. In the case of fluorescence, the values of PhiF ranged from 2.37 * 10( 4) (bulk water) to 3.48 * 10(-4) (<1 kDa fraction) for WWTP A and 3.19 * 10(-4) (bulk water) to 5.75 * 10(-4) (<1 kDa fraction) for WWTP B. There was a linear correlation between PhiHO(*) and PhiF, suggesting that different photophysical processes occur in the chemical components of the fractions. Understanding the formation of HO(*) from EfOM is essential for understanding wastewater-impacted aquatic systems because these results influence the photochemical degradation and mineralization of trace organic contaminants. PMID- 24053684 TI - Detection of persistent organic pollutants binding modes with androgen receptor ligand binding domain by docking and molecular dynamics. AB - BACKGROUND: Persistent organic pollutants (POPs) are persistent in the environment after release from industrial compounds, combustion productions or pesticides. The exposure of POPs has been related to various reproductive disturbances, such as reduced semen quality, testicular cancer, and imbalanced sex ratio. Among POPs, dichlorodiphenyldichloroethylene (4,4'-DDE) and polychlorinated biphenyls (PCBs) are the most widespread and well-studied compounds. Recent studies have revealed that 4,4'-DDE is an antagonist of androgen receptor (AR). However, the mechanism of the inhibition remains elusive. CB-153 is the most common congener of PCBs, while the action of CB-153 on AR is still under debate. RESULTS: Molecular docking and molecular dynamics (MD) approaches have been employed to study binding modes and inhibition mechanism of 4,4'-DDE and CB-153 against AR ligand binding domain (LBD). Several potential binding sites have been detected and analyzed. One possible binding site is the same binding site of AR natural ligand androgen 5alpha-dihydrotestosterone (DHT). Another one is on the ligand-dependent transcriptional activation function (AF2) region, which is crucial for the co-activators recruitment. Besides, a novel possible binding site was observed for POPs with low binding free energy with the receptor. Detailed interactions between ligands and the receptor have been represented. The disrupting mechanism of POPs against AR has also been discussed. CONCLUSIONS: POPs disrupt the function of AR through binding to three possible biding sites on AR/LBD. One of them shares the same binding site of natural ligand of AR. Another one is on AF2 region. The third one is in a cleft near N terminal of the receptor. Significantly, values of binding free energy of POPs with AR/LBD are comparable to that of natural ligand androgen DHT. PMID- 24053685 TI - Focal cryoablation: a treatment option for unilateral low-risk prostate cancer. AB - OBJECTIVES: To assess oncological (biochemical and histological recurrence) and functional (urinary and potency) outcomes in patients with unilateral low-risk organ-confined prostate cancer (PCa) treated with focal cryoablation (FC). PATIENTS AND METHODS: From January 2009 to March 2012, patients with localized PCa who refused active surveillance were assigned to a FC protocol. This was a prospective, single-arm cohort study. Inclusion criteria were: unilateral disease, clinical stage T1c to T2a, prostate-specific antigen (PSA) concentration <10 ng/mL, low volume index lesion and Gleason score <=6 (3+3). Hemi-ablation was carried out using the Precise(TM) cryoablation system (Galil Medical, Inc., Arden Hills, MN, USA). Oncological (PSA values) and functional (International Prostate Symptom Score and International Index of Erectile Function (IIEF)-5 score) outcomes were analysed at 3-, 6- and 12-month follow-up. The primary endpoint for oncological efficacy, no cancer in ipsilateral side, was based on the 12-month mandatory biopsy. RESULTS: A total of 48 consecutive patients with a mean age of 67 years were included. The median (interquartile range) follow-up was 13.2 (7.4 26.5) months. Follow-up prostate biopsies were negative for the treated lobe in 86% of patients. The mean PSA concentration dropped significantly at 3 months (by 55%) but did not correlate well with positive biopsy results. Urinary symptoms were unchanged. A slight decrease in the IIEF-5 score was present at 3 months, but did not differ significantly from baseline at 6-month follow-up. There were 15% grade 1 and 4% grade 2 complications (Clavien classification). CONCLUSIONS: Focal cryoablation is a low-morbidity option in selected patients with low-risk PCa. We showed PSA concentration to be an unreliable marker for monitoring FC and recommend a protocol of mandatory biopsies for follow-up. A multicentre randomized controlled trial is necessary to confirm the low-morbidity and the biopsy-proven PCa cure rates. PMID- 24053686 TI - Single-molecule studies of RNA polymerases. PMID- 24053687 TI - One pot synthesis of Mg2Al(OH)6Cl.1.5H2O layered double hydroxides: the epoxide route. AB - Pure Mg2Al(OH)6Cl.1.5H2O layered double hydroxide (LDH) has been synthesized at room temperature by a one-pot method, homogeneously driven by chloride-assisted glycidol rupture (epoxide route). Well-defined nanoplatelet texture was achieved and the LDH crystallization mechanism discussed. Nanoplatelets self-assemble in the form of highly oriented films with excellent optical properties. LDH films exhibited stability toward detaching in aqueous solutions and allowed a fast anionic exchange preserving a high transparency. PMID- 24053682 TI - Role of heme oxygenase-1 in postnatal differentiation of stem cells: a possible cross-talk with microRNAs. AB - SIGNIFICANCE: Heme oxygenase-1 (HO-1) converts heme to biliverdin, carbon monoxide, and ferrous ions, but its cellular functions are far beyond heme metabolism. HO-1 via heme removal and degradation products acts as a cytoprotective, anti-inflammatory, immunomodulatory, and proangiogenic protein, regulating also a cell cycle. Additionally, HO-1 can translocate to nucleus and regulate transcription factors, so it can also act independently of enzymatic function. RECENT ADVANCES: Recently, a body of evidence has emerged indicating a role for HO-1 in postnatal differentiation of stem and progenitor cells. Maturation of satellite cells, skeletal myoblasts, adipocytes, and osteoclasts is inhibited by HO-1, whereas neurogenic differentiation and formation of cardiomyocytes perhaps can be enhanced. Moreover, HO-1 influences a lineage commitment in pluripotent stem cells and maturation of hematopoietic cells. It may play a role in development of osteoblasts, but descriptions of its exact effects are inconsistent. CRITICAL ISSUES: In this review we discuss a role of HO 1 in cell differentiation, and possible HO-1-dependent signal transduction pathways. Among the potential mediators, we focused on microRNA (miRNA). These small, noncoding RNAs are critical for cell differentiation. Recently we have found that HO-1 not only influences expression of specific miRNAs but also regulates miRNA processing enzymes. FUTURE DIRECTIONS: It seems that interplay between HO-1 and miRNAs may be important in regulating fates of stem and progenitor cells and needs further intensive studies. PMID- 24053688 TI - Glomerular C1q deposition and serum anti-C1q antibodies in anti-glomerular basement membrane disease. AB - BACKGROUND: Anti-glomerular basement membrane (GBM) disease is a well-known antibody-induced autoimmune disease. A few patients have glomerular C1q deposition, but it is usually absent on renal histopathology. The role of C1q deposition in kidney injury is unclear. Recently, anti-C1q antibodies are demonstrated to be pathogenic in the target organ damage of many autoimmune diseases, by facilitating C1q deposition and enhancing complement activation via classical pathway. In the current study, we investigated the associations between anti-C1q antibodies in sera and C1q deposition in kidney of patients with anti GBM disease. RESULTS: It was shown that the severity of kidney injury was comparable between patients with and without C1q deposition, including the prevalence of oliguria/auria, the median percentage of crescents in glomeruli and the mean concentration of serum creatinine. Serum anti-C1q antibodies were detected in 15/25 (60%) patients with a low titer. The prevalence of C1q deposition in kidney was comparable between patients with and without serum anti C1q antibodies (26.7% vs. 30.0%, p > 0.05). No association was found between anti C1q antibodies and the severity of kidney injury. CONCLUSIONS: The classical pathway of complement may not play a pathogenic role in the kidney injury of human anti-GBM disease. Anti-C1q antibodies could be detected in more than half of patients, which need further investigations. PMID- 24053689 TI - An evaluation of the global network of field epidemiology and laboratory training programmes: a resource for improving public health capacity and increasing the number of public health professionals worldwide. AB - BACKGROUND: Given that many infectious diseases spread rapidly, across borders and species, there is a growing worldwide need to increase the number of public health professionals skilled in controlling infectious epidemics. Needed also are more public health professionals skilled in non-communicable disease surveillance and interventions. As a result, we surveyed all 57 field epidemiology training programmes (FETPs) that are members of the Training Program in Epidemiology and Public Health Interventions Network (TEPHINET), to evaluate the progress of the FETPs, the only global applied epidemiology network, toward increasing public health capacity globally. METHODS: Data on the FETP programmes and the training they provide were abstracted from TEPHINET membership surveys and verified with FETP directors for all FETPs that were members of TEPHINET in 2012. Data on abstracts submitted to the recent TEPHINET Global Scientific Conference, on recent accomplishments by each FETP, and on quality improvement were also compiled to provide a worldwide view of the public health human resource capacity produced by these programmes. RESULTS: A total of 6980 public health professionals worldwide have graduated from an FETP or from the Center for Disease Control and Prevention's Epidemiology Intelligence Service (EIS). FETP residents and graduates participate in key public health prevention, control, and response activities. Each FETP has adapted its curriculum and objectives over time to align with its country's public health priorities. FETPs are well integrated into their national public health infrastructures, and they have many partners at the national, regional and global levels. CONCLUSION: FETPs are a competent and diverse source of highly skilled public health professionals who contribute significantly to public health's global human resource needs. This finding is evidenced by 1) the training curricula that were adapted over time to meet public health's human resource needs, 2) the FETPs' continued support from internal and external partners, 3) the increasing number of FETP residents and graduates and their increasing contribution to effective public health work, and 4) the increased quality improvement initiatives facilitated through the FETPs membership in one global network, TEPHINET. PMID- 24053690 TI - High clustering rates of multidrug-resistant Mycobacterium tuberculosis genotypes in Panama. AB - BACKGROUND: Tuberculosis continues to be one of the leading causes of death worldwide and in the American region. Although multidrug-resistant tuberculosis (MDR-TB) remains a threat to TB control in Panama, few studies have focused in typing MDR-TB strains. The aim of our study was to characterize MDR Mycobacterium tuberculosis clinical isolates using PCR-based genetic markers. METHODS: From 2002 to 2004, a total of 231 Mycobacterium tuberculosis isolates from TB cases country-wide were screened for antibiotic resistance, and MDR-TB isolates were further genotyped by double repetitive element PCR (DRE-PCR), (GTG)5-PCR and spoligotyping. RESULTS: A total of 37 isolates (0.85%) were resistant to both isoniazid (INH) and rifampicin (RIF). Among these 37 isolates, only two (5.4%) were resistant to all five drugs tested. Dual genotyping using DRE-PCR and (GTG)5 PCR of MDR Mycobacterium tuberculosis isolates revealed eight clusters comprising 82.9% of the MDR-TB strain collection, and six isolates (17.1%) showed unique fingerprints. The spoligotyping of MDR-TB clinical isolates identified 68% as members of the 42 (LAM9) family genotype. CONCLUSION: Our findings suggest that MDR Mycobacterium tuberculosis is highly clustered in Panama's metropolitan area corresponding to Panama City and Colon City, and our study reveals the genotype distribution across the country. PMID- 24053691 TI - Does robot-assisted laparoscopic ileocystoplasty (RALI) reduce peritoneal adhesions compared with open surgery? AB - OBJECTIVES: To compare perioperative outcomes between open ileocystoplasty and robot-assisted laparoscopic ileocystoplasty (RALI) in a porcine model, as objective data comparing outcomes between these two approaches in children with neurogenic bladder are lacking. We specifically examined differences in postoperative peritoneal adhesion formation between the groups. MATERIALS AND METHODS: In all, 20 pigs were assigned to an open ileocystoplasty or RALI study arm. All the pigs underwent an initial urodynamic study (UDS). In the RALI arm, reconstructive steps were performed intracorporeally using a standard da Vinci((r)) system. Postoperatively, variables including first stool, weight gain, and complications were recorded. After 42 days, the pigs underwent a final UDS followed by adhesion assessment. Intraperitoneal adhesions were quantified by a third-party 'blinded' surgeon according to previously described objective scoring systems. RESULTS: Preoperative variables including UDS were similar in both groups. Overall operating time was significantly shorter for open ileocystoplasty than for RALI (149 vs 287 min, P < 0.001, respectively). Postoperatively, all variables including time to first stool, weight gain, and urodynamic parameters were similar amongst the groups. Pigs in the open arm developed significantly more adhesions (P = 0.02) and adhesions with a higher complexity (P = 0.04). CONCLUSIONS: In this porcine model, RALI achieved similar functional outcomes as the open approach, but required longer procedural times. The number and complexity of surgical adhesions among the groups favoured the RALI cohort. This may be of clinical significance in the paediatric spina bifida population, who generally undergo multiple surgical procedures in their lifetime, with increased risk for development of adhesions and subsequent intestinal obstruction. PMID- 24053692 TI - Simultaneous analysis of acrylamide and its key precursors, intermediates, and products in model systems by liquid chromatography-triple quadrupole mass spectrometry. AB - A new analytical setup allowing the simultaneous analysis of precursors, intermediates and products in Maillard reaction model systems was developed to investigate the formation and mitigation kinetics of acrylamide. It was based on high-performance liquid chromatography combined with electrospray ionization triple quadrupole tandem mass spectrometry (HPLC-MS/MS). Chromatography and mass spectrometry conditions were optimized to permit simultaneous monitoring of compounds relevant to acrylamide, such as asparagine, glucose, glycine, N-(1 deoxy-D-fructos-1-yl)-glycine (DFG), N-(1-deoxy-D-fructos-1-yl)-asparagine (DFA), and four reaction products between acrylamide and glycine. A fairly good separation was achieved on a Venusil MP-C18 column using an isocratic eluent of 0.5% formic acid in water at a flow rate of 0.4 mL/min. Triple quadrupole mass spectrometry in multiple reaction monitoring mode (MRM) was applied to obtain good sensitivity. All of the ten key reaction compounds were separated and determined in a single run within 15 min. High correlation coefficients (r > 0.99) of the ten analytes were obtained in their respective linear ranges. The method was capable to accurately quantify the ten key compounds in model systems during heating. The results showed that acrylamide formed in Maillard reaction could be reduced by reacting directly with glycine, and acrylamide concentration constantly decreased by about 60% within the 180 min heating at 150 degrees C when glycine was equal to asparagine and glucose in molecular concentration in model systems. This method helps achieve reduction in both time and labor of analysis of a large number of samples. PMID- 24053693 TI - Validation of pretreatment neutrophil-lymphocyte ratio as a prognostic factor in a European cohort of patients with upper tract urothelial carcinoma. AB - OBJECTIVE: To investigate the potential prognostic significance of the neutrophil lymphocyte ratio (NLR) in a large European cohort of patients with upper urinary tract urothelial cell carcinoma (UUT-UCC). PATIENTS AND METHODS: We retrospectively evaluated data from 202 consecutive patients with non-metastatic upper urinary tract urothelial cell carcinoma (UUT-UCC), who underwent surgery between 1990 and 2012 at a single tertiary academic centre. Patients' cancer specific survival (CSS) and overall survival (OS) were assessed using the Kaplan Meier method. To evaluate the independent prognostic significance of the NLR, multivariate proportional Cox regression models were applied for both endpoints. RESULTS: A higher NLR was significantly associated with shorter CSS (P = 0.002, log-rank test), as well as with shorter OS (P < 0.001, log-rank test). Multivariate analysis identified a high NLR as an independent prognostic factor for patients' CSS (hazard ratio 2.72, 95% CI 1.25-5.93, P = 0.012), and OS (hazard ratio 2.48, 95% CI 1.31-4.70, P = 0.005). CONCLUSIONS: In the present cohort, patients with a high preoperative NLR had higher cancer-specific and overall mortality after radical surgery for UUT-UCC, compared with those with a low preoperative NLR. This easily identifiable laboratory measure should be considered as an additional prognostic factor in UUT-UCC in future. PMID- 24053694 TI - Obstructive lung diseases and inhaler treatment: results from a national public pragmatic survey. AB - BACKGROUND: The opinions held by the general population on obstructive lung disease and inhaler devices could influence asthma and chronic obstructive pulmonary disorder (COPD) management and treatment adherence.The aim of the present public pragmatic survey was to evaluate the opinions, beliefs and perceptions of Italian people with respect to respiratory diseases as well as their perspectives on the use of inhaler devices. METHODS: This survey was conducted on a group of 2,008 individuals forming a representative sample of the Italian population aged 15 years and over. It was based on personal interviews that were administered in the homes of the respondents using a structured questionnaire that took approximately 30 minutes. RESULTS: Awareness of obstructive lung diseases is poor. Asthma, but not COPD, was perceived as a common and increasingly prevalent disease by the majority of the interviewees. Allergy, pollution and smoking were considered to be responsible for both of these diseases. The rates at which the respondents claimed to be suffering from asthma and COPD were lower than expected (4% and 2%, respectively). Inhaled drugs were recognised as the main treatment by 65% of the respondents. The great majority of respondents attributed positive characteristics to the inhaler device (e.g., safety, reliability, effectiveness, ease of use and practicality). Compared to people who have never used inhaler devices, individuals who suffer from asthma or COPD were more confident in their use and showed a greater belief in their safety, reliability and trustworthiness. People older than 64 years showed less attention to the properties of these devices. CONCLUSIONS: The present results highlight the need for public interventions aimed at improving awareness of obstructive lung disease and reveal various potentialities and critical issues for inhaler device usage. Switching of devices was considered feasible by most of the interviewees, as long as the choice is carefully explained by their physician. PMID- 24053695 TI - Managing executive dysfunction following acquired brain injury and stroke using an ecologically valid rehabilitation approach: a study protocol for a randomized, controlled trial. AB - BACKGROUND: We have been investigating an ecologically valid strategy-training approach to enable adults with executive dysfunction to attain everyday life goals. Here, we report the protocol of a randomized controlled trial of the effects of this training compared to conventional therapy in a sample of community-dwelling adults with acquired brain injury and/or stroke. METHODS/DESIGN: We will recruit 100 community-dwelling survivors at least six months post-acquired brain injury or stroke who report executive dysfunction during a telephone interview, confirmed in pre-training testing. Following pre training testing, participants will be randomized to the ecologically valid strategy training or conventional therapy and receive two one-hour sessions for eight weeks (maximum of 15 hours of therapy). Post-testing will occur immediately following the training and three months later. The primary outcome is self reported change in performance on everyday life activities measured using the Canadian Occupational Performance Measure, a standardized, semi-structured interview. Secondary outcomes are objective measurement of performance change from videotapes of treatment session, Performance Quality Rating Scale; executive dysfunction symptoms, Behavioural Rating Inventory of Executive Function - Adult; participation in everyday life, Mayo-Portland Adaptability Inventory Participation Index; and ability to solve novel problems, Instrumental Activities of Daily Living Profile. DISCUSSION: This study is of a novel approach to promoting improvements in attainment of everyday life goals through managing executive dysfunction using an ecologically valid strategy training approach, the Cognitive Orientation to daily Occupational Performance. This study compares the efficacy of this approach with that of conventional therapy. The approach has the potential to be a valuable treatment for people with chronic acquired brain injury and/or stroke. TRIAL REGISTRATION: clinicaltrials.gov, Trial Identification Number: NCT01414348. PMID- 24053696 TI - New synthesis and tritium labeling of a selective ligand for studying high affinity gamma-hydroxybutyrate (GHB) binding sites. AB - 3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA, 1) is a potent ligand for the high-affinity GHB binding sites in the CNS. An improved synthesis of 1 together with a very efficient synthesis of [(3)H]-1 is described. The radiosynthesis employs in situ generated lithium trimethoxyborotritide. Screening of 1 against different CNS targets establishes a high selectivity, and we demonstrate in vivo brain penetration. In vitro characterization of [(3)H]-1 binding shows high specificity to the high-affinity GHB binding sites. PMID- 24053697 TI - Food intake and the risk of endometrial endometrioid adenocarcinoma in Japanese women. AB - The present study examined the association between food intake and endometrial cancer restricted to endometrial endometrioid adenocarcinoma (EEA) using a case control study in Japanese women. One hundred sixty-one cases and 380 controls who completed a questionnaire regarding demographic, lifestyle, and food frequency questionnaire were analyzed. Odds ratio (OR) between selected food intakes and EEA were calculated by logistic regression analysis. After adjustment putative confounding factors, the higher intakes of vegetables [odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.26-0.83], peanuts (OR = 0.48, CI = 0.27-0.86), fish (OR = 0.52, CI = 0.29-0.93), boiled egg (OR = 0.24, CI = 0.33-0.92), instant noodles (OR = 1.94, CI = 1.12-3.34), instant food items (OR = 2.21, CI = 1.31 3.74), and deep-fried foods (OR = 2.87, CI = 1.58-5.21) were associated with a risk for EEA. The inverse association with a risk of EEA was also seen in higher intakes (g/1000 kcal) for vegetables (0.45, CI = 0.25-0.81) and fish (0.53, CI = 0.30-0.94) as compare to lower intake. Higher intake of vegetables, peanuts, fish, and boiled egg was associated with a reduced risk for EEA, whereas instant noodles, instant food items, and deep-fried foods was associated with an increased risk for EAA as compared to lower levels of intake. PMID- 24053698 TI - Pediatric allergy and immunology in Asia-coming of age. PMID- 24053699 TI - Nutrition in early life, immune-programming and allergies: the role of epigenetics. AB - Early life nutritional exposures are significant determinants of the development and future health of all organ systems. The dramatic rise in infant immune diseases, most notably allergy, indicates the specific vulnerability of the immune system to early environmental changes. The associated parallel rise in metabolic diseases including obesity, childhood type 2-diabetes and non-alcoholic fatty liver disease highlights the interplay between modern dietary patterns and increasing abnormalities of both immune and metabolic health. The low-grade inflammation that characterize these non-communicable diseases (NCDs) suggests a central role of the immune system in the pathogenesis of these conditions. Understanding how environmental influences disrupt the finely balanced development of immune and metabolic programing is of critical importance. Diet sensitive pathways are likely to be crucial in these processes. While epigenetic mechanism provides a strong explanation of how nutritional exposures can affect the fetal gene expression and subsequent disease risk, other diet-induced tissue compositional changes may also contribute directly to altered immune and metabolic function. Although modern dietary changes are complex and involve changing patterns of many nutrients, there is also interest in the developmental effects of specific nutrients such as folic acid levels, which have clear epigenetic effects on programming. Here we examine the current knowledge of the nutritional-programming of immune health and how research into nutritional epigenetics in the context of allergic disease as one of the earliest onset NCDs can expand our knowledge to discover the biological processes sensitive to nutritional exposures in early life to prevent later disease risk. PMID- 24053700 TI - Epigenetics of human asthma and allergy: promises to keep. AB - OBJECTIVE: The interest in asthma epigenetics is high because epigenetic mechanisms likely contribute to the environmental origins of the disease and its phenotypic variability. This review presents the main findings of asthma epigenetics and the challenges that still delay progress. DATA SOURCES: We examined the current literature on asthma epigenetics (31 reviews and 25 original data publications). STUDY SELECTIONS: We focused on DNA methylation studies in populations. RESULTS: Both genome-wide and candidate gene studies have explored DNA methylation in allergic disease. Genome-wide studies ask whether and which regions of the genome are differentially methylated in relation to the phenotype of interest. Identification of such regions provides clues about the identity of the genes, pathways and networks underpinning a phenotype and connects these networks to the phenotype through epigenetic mechanisms. Candidate gene studies examine DNA methylation in genes chosen because of their known or hypothesized role in immunity, responses to environmental stimuli or disease pathogenesis. Most existing studies in asthma and allergy focused on candidate genes involved in the response to environmental pollutants. CONCLUSION: Asthma epigenetics is still in its infancy. The paucity of primary literature originates from methodological and analytical challenges of genome-wide studies, the difficulties in interpreting small differences in DNA methylation, and the need to develop robust bioinformatic tools for pathway, network and system analyses of epigenetic data. Once these challenges have been overcome, epigenetic studies will likely provide important insights about the inception and pathogenesis of allergic disease and will help define disease endotypes. PMID- 24053701 TI - Sublingual immunotherapy for house dust mite allergy in Southeast Asian children. AB - OBJECTIVE: To determine the use and efficacy of sublingual immunotherapy (SLIT) for house dust mite (HDM) allergies in Southeast Asian children. DATA SOURCES: Aliterature search was performed in Pubmed and the Asian Pacific Journal of Allergy and Immunology. We also evaluated the literature for similar studies performed in Asia. STUDY SELECTIONS: Clinical trials involving children that assess SLIT for HDM allergies in Southeast Asia and Asia. RESULTS: There are no published studies on the use of SLIT for HD Mallergies in Southeast Asian children. However, there are seven studies from Asia which show that there are discrepancies over the benefits of SLIT for HDM allergies in Asian children. Limitations in these studies include small sample sizes and short study periods. CONCLUSIONS: We cannot say with certainty what the impact of SLIT is on HDM allergies in Southeast Asian children due to the lack of data. The available studies performed in Asia have their limitations but are suggestive of the potential of SLIT for HDM allergies in Southeast Asian children. This review highlights that good quality clinical research in this area in the Southeast Asian setting is warranted. PMID- 24053702 TI - Oral and sublingual immunotherapy for food allergy. AB - OBJECTIVE: Food allergies continue to be an increasingly common disorder, however, no treatment strategies are currently approved for the routine management of individuals with food allergies. Encouraging results from early open-label studies have sparked great interest in oral and sublingual immunotherapy, and thus several randomized controlled trials have recently been conducted to establish the safety and efficacy of these treatment strategies. The aim of this review is to examine the recent studies for peanut, milk and egg allergies. DATA SOURCES: Open-label and randomized control trials are discussed. STUDY SELECTIONS: Studies focusing on peanut, milk and egg allergies are included. RESULTS: Current evidence indicates that desensitization is possible for the majority of subjects who undergo oral immunotherapy. Clinical improvement has been associated with favorable immunologic changes, including smaller skin prick test wheal sizes and increased allergen-specific IgG4 levels. Adverse reactions are common, however, and thus safety concerns remain. Sublingual immunotherapy thus far has not proven to be as effective as oral immune-therapy. CONCLUSION: Oral and sublingual immunotherapy are promising treatments for food allergy. Optimization and standardization of protocols, along with additional assessments of safety are still needed. PMID- 24053703 TI - Development of the siriraj clinical asthma score. AB - INTRODUCTION: Acute asthmatic attack in children commonly occurs despite the introduction of effective controllers such as inhaled corticosteroids and leukotriene modifiers. Treatment of acute asthmatic attack requires proper evaluation of attack severity and appropriate selection of medical therapy. In children, measurement of lung function is difficult during acute attack and thus clinical asthma scoring may aid physician in making further decision regarding treatment and admission. METHODS: We enrolled 70 children with acute asthmatic attack with age range from 1 to 12 years (mean +/- SD = 51.5 +/- 31.8 months) into the study. Twelve selected asthma severity items were assessed by 2 independent observers prior to administration of salbutamol nebulization (up to 3 doses at 20 minutes interval). Decision for further therapy and admission was made by emergency department physician. Three different scoring systems were constructed from items with best validity. Sensitivity, specificity and accuracy of these scores were assessed. Inter-rater reliability was assessed for each score. Review of previous scoring systems was also conducted and reported. RESULTS: Three severity items had poor validity, i.e., cyanosis, depressed cerebral function, and I:E ratio (p > 0.05). Three items had poor inter-rater reliability, i.e., breath sound quality, air entry, and I:E ratio. These items were omitted and three new clinical scores were constructed from the remaining items. Clinical scoring system comprised retractions, dyspnea, O2 saturation, respiratory rate and wheezing (rangeof score 0-10) gave the best accuracy and inter-rater variability and were chosen for clinical use-Siriraj Clinical Asthma Score (SCAS). CONCLUSION: A Clinical Asthma Score that is simple, relatively easy to administer and with good validity and variability is essential for treatment of acute asthma in children. Several good candidate scores have been introduced in the past. We described the development of the Siriraj Clinical Asthma Score (SCAS) in this report and reviewed the literature on the development of clinical asthma score for use in children. PMID- 24053704 TI - Endemic infections in Southeast Asia provide new insights to the phenotypic spectrum of primary immunodeficiency disorders. AB - Primary immunodeficiency disorders (PIDs) are rare genetic diseases of the immune system. With improving awareness of PIDs among clinicians, the number of patients diagnosed with PIDs is rising rapidly in Southeast Asia. However, delayed diagnosis remains common and adversely affects the prognosis of these patients. In this review, we provide simple phenotypic approach to the diagnosis of PIDs based on pattern recognition. Through multi-centered collaborative studies in the Asian Primary Immunodeficiency Network (APID), we present unique patterns of infectious diseases associated with PIDs in Southeast Asia, including BCG disease, tuberculosis, melioidosis, Penicillium marneffei and Chromobacterium violaceum infections. These initial observations suggest the possibility of utilizing these infections that rarely affect normal healthy children as 'indicators' for PIDs, which is of particular relevance for clinicians working in Southeast Asia. PMID- 24053705 TI - Comparison of conjunctival and nasal provocation tests in allergic rhinitis children with Dermatophagoides pteronyssinus sensitization. AB - BACKGROUND: Nasal provocation tests (NPTs) are indicated in confirming the diagnosis of allergic rhinitis if the clinical history, skin tests or sIgE are inconclusive. NPTs are time- consuming, technically difficult and expensive to perform. Consequently, conjunctival provocation tests (CPTs), which are easier, cheaper and safer should be considered as an alternative method. No recent study has compared CPTs with NPTs in allergic rhinitis children. OBJECTIVE: To compare CPTs with NPTs in allergic rhinitis children with house dust mite sensitization METHODS: Fifty-five children with allergic rhinitis were included. Thirty-six children had positive skin prick tests (SPTs) to Dermatophagoides pteronyssinus (Dp). NPTs were performed by spraying 0.1 ml of Dp extract with concentrations of 50, 200 and 500 AU/ml to each nostril at 15 minute interval. The clinical symptom scores, anterior rhinomanometry results and nasal peak flow testing were performed to assess the responses. For CPTs, 0.1 ml of the same concentration of allergen extract was droppedinto one eye and the control solution was dropped into the other. The responses were assessed by clinical symptom scores. The tests were stopped when the subject reported a positive response, or continued to the maximum concentration. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of CPT compared with NPT are 97.1% (84.7-99.9), 90.5% (69.6-98.8), 94.3% (80.8-99.3), 95% (75.1-99.9) and 94.5 (84.9 98.9), respectively in all patients. Among individual allergic rhinitis subjects the sensitivity, specificity, PPV and NPV are 100%. CONCLUSIONS: CPT can be an alternative test for NPT in allergic rhinitis children with house dust mite sensitization, even if they do not have conjunctival symptoms. PMID- 24053706 TI - Two year follow-up of clinical and inflammation parameters in children monosensitized to mites undergoing subcutaneous and sublingual immunotherapy. AB - BACKGROUND: Both SCIT (subcutaneous immunotherapy) and SLIT (sublingual immunotherapy) have clinical and immunologic efficacy in children with rhinitis and asthma but comparative studies are scarce. OBJECTIVE: To investigate the clinical and immunological efficacy of mite-specific SLIT and SCIT in children with rhinitis and asthma. METHOD: Thirty children monosensitized to house dust mite were randomized to receive either active SCIT or SLIT or placebo for 1 yr in a double-blind double-dummy placebo controlled design (Yukselen A et al., Int Arch Allergy Immunol 2012; 157:288-298). Thereafter, the placebo group was randomized to receive SCIT or SLIT, and for 1 yr all patients received active treatment with SCIT or SLIT. Symptom scores, drug usage, titrated skin prick tests, nasal and bronchial allergen provocation doses, serum house dust mite specific immunglobulin E, sIgG4, IL-10 and IFN- g levels were evaluated. RESULTS: The reduction of clinical scores with SLIT was more evident after 2 years of treatment in comparison to both the baseline and DBPC phase of the study. The change in titrated skin prick tests and nasal provocative doses was more prominent with both SCIT and SLIT at the end of the open phase. Although the increase inbronchial provocative doses was not significant at the end of the first year of treatment with SLIT, it reached a statistically significant difference after two years of treatment. CONCLUSION: The clinical efficacy of SLIT is more prominent at the end of the second year, although this improvement is observed from the first year of treatment with SCIT in mite-sensitive children. PMID- 24053707 TI - Recent 5-year trends of asthma severity and allergen sensitization among children in southern Thailand. AB - BACKGROUND: Asthma is a major public health issue that affects morbidity. The greater severity of asthma requires more health care resource utilization. OBJECTIVE: To investigate the possible changes in disease severity and allergen sensitization of children with asthma in an interim period of 5 years. METHODS: We retrospectively reviewed the charts of 200 patients with established asthma in the pediatric allergy clinic. The data were collected in different time periods with 100 consecutive cases in each group starting in January of 2004 and in January of 2009. All patients underwent a skin prick test (SPT) to common allergens, with positive and negative controls. SPTs with a mean wheal diameter 3 mm greater than a negative control were considered test-positive. RESULTS: The mean ages of patients in the 2004 and 2009 groups were 7.54 and 7.73 years. Compared with patients in the 2004 group, the 2009 group had more severe asthma (p = 0.006). The distribution of asthma severity was mild (intermittent and mild persistent) 98.0% in 2004 and 87.9% in 2009, and moderate to severe persistent 2.0% in 2004 and 12.1% in 2009. The prevalence of patients sensitized to both house dust (HD) and house dust mites (HDM) increased from 21.2% in 2004 to 34.3% in 2009 (p =0.007). Sensitization to allergens of HD, HDM and cockroach increased to 14.1% in 2009 from 9.1% in 2004 (p =0.021). CONCLUSIONS: During the years between 2004 and 2009, asthma severity increased with increasing sensitization to HD, HDM and cockroach. Awareness of these changes and further studies are required. PMID- 24053708 TI - Interleukin-13 and RANTES polymorphisms in relation to asthma in children of Chinese Han nationality. AB - BACKGROUND: IL-13 (interleukin-13) and RANTES (Regulated upon Activation, Normal T cells Expressed and Secreted) are the important asthma inflammatory mediators. OBJECTIVE: The present study aimed to investigate the single and combined associations between the polymorphism (SNP) loci in IL-13 and RANTES genes with the development of asthma in children of Chinese Han nationality. METHODS: The risk associated with genotypes of three IL-13 SNPs and two RANTES SNPs was determined by the Chi2 test in 384 children with asthma and an equal number of healthy controls matched by sex. RESULTS: Between the experimental and control groups, no statistically significant differences (P >0.05) were found in genotype distribution and allele frequency among three loci (IL-13 C-1112T, IL-13 C1923T, and RANTES A-403G). However, significant diversity was observed among IL-13 A2044G (P =0.0001) and RANTES G-28C (P =0.0001). Moreover, the frequency of IL-13 A2044G A/A and RANTES G-28C G/G in the asthma group was significantly higher than in the control group (odds ratio [OR] =2.59, P =0.0001; OR =3.00, P =0.0001, respectively). Carriers of both IL-13 A2044G A/A and RANTES G-28C G/G have a more significant risk for developing asthma than those with only a single polymorphism. CONCLUSIONS: The three loci (IL-13 C-1112T, IL-13 C1923T, and RANTES A-403G) make little contribution to the development of asthma in children of Chinese Han nationality. IL-13 A2044G and RANTES G-28C are significantly associated with childhood asthma. IL-13 A2044G A/A and RANTES G-28C G/G have a significant and combined effect on the development of asthma. PMID- 24053709 TI - Risk factors associated with poor controlled pediatric asthma in a university hospital. AB - BACKGROUND: Many studies in adults had identified factors associated with partly or uncontrolled asthma. In children, factors related to asthma control were not well defined. OBJECTIVE: To find the factors related to partly or uncontrolled asthma in children. METHODS: Asthmatic children who had severity at least in the mild persistent level, were recruited. The asthma control levels were classified as controlled, partly controlled and uncontrolled according to the GINA guideline. Risk factors were compared between the patients with controlled and partly controlled/ uncontrolled asthma groups. RESULTS: One hundred and ten patients (42.7% females) were included. The mean age was 10.3 +/- 2.7 years old. There were 55 patients (50%) in the controlled, 54 patients(49.1%) in partly controlled and 1 patient (0.9%) in uncontrolled asthma group. For asthma severity, 97 patients (88.2%) were in mild persistent, 11 patients (10%) in moderate persistent and 2 patients (1.8%) in severe persistent groups. The risk factors for partly controlled/ uncontrolled asthma compared to controlled asthma were moderate/ severe persistent asthma (adjusted OR 18.87 (95% CI 1.92 - 200.00)) and sinusitis (p = 0.04). Using the air conditioner decreased risk of partly controlled/uncontrolled asthma (adjusted OR 0.30 (95% CI 0.10 - 0.91)). The proportion of patients who used medium dose inhaled corticosteroid (ICS) plus long-acting inhaled beta2-agonist (LABA) were significantly higher in partly controlled/ uncontrolled asthma than controlled asthma (p = 0.004). CONCLUSION: Risk factors associated with partly controlled/ uncontrolled asthma were moderate/ severe persistent asthma and sinusitis. Using air conditioner seemed to reduce risk of partly controlled/ uncontrolled asthma. PMID- 24053710 TI - Robot-assisted radical cystectomy (RARC) with intracorporeal neobladder - what is the effect of the learning curve on outcomes? AB - OBJECTIVE: To evaluate the effect of the learning curve on operative, postoperative, and pathological outcomes of the first 67 totally intracorporeal robot-assisted radical cystectomies (RARCs) with neobladders performed by two lead surgeons at Karolinska University Hospital. PATIENTS AND METHODS: Between December 2003 and October 2012, 67 patients (61 men and six women) underwent RARC with orthotopic urinary diversion by two main surgeons. Data were collected prospectively on patient demographics, peri- and postoperative outcomes including operation times, conversion rates, blood loss, complication rates, pathological data and length of stay (LOS) for these 67 consecutive patients. The two surgeons operated on 47 and 20 patients, respectively. The patients were divided into sequential groups of 10 in each individual surgeon's series and assessed for effect of the learning curve. RESULTS: Patient demographics and clinical characteristics were similar in both surgeons' groups. The overall total operation times trended down in both surgeons' series from a median time of 565 min in the first group of 10 cases, to a median of 345 min in the last group for surgeon A (P < 0.001) and 413 to 385 min for surgeon B (not statistically significant). Risk of conversion to open surgery also decreased with a 30% conversion rate in the first group to zero in latter groups (P < 0.01). Overall complications decreased as the learning curve progressed from 70% in the first group to 30% in the later groups (P < 0.05), although major complications were not statistically different when compared between the groups. Patient demographics did not change over time. The mean estimated blood loss was unchanged across groups with increasing experience. The pathological staging, mean total lymph node yield and number of positive margins were also unchanged across groups. There was a decrease in LOS from a mean of 19 days in the first group to a mean (range) of 9 (4-78) days in the later groups, although the median LOS was unchanged and therefore not statistically significant. CONCLUSIONS: Totally intracorporeal RARC with intracorporeal neobladder is a complex procedure, but it can be performed safely, with a structured approach, at a high volume established robotic surgery centre without compromising perioperative and pathological outcomes during the learning curve for surgeons. An experienced robotic team and mentor can impact the learning curve of a new surgeon in the same centre resulting in decreased operation times early in their personal series, reducing conversion rates and complication rates. PMID- 24053711 TI - Training of European urology residents in laparoscopy: results of a pan-European survey. AB - OBJECTIVE: To assess the participation of European urology residents in urological laparoscopy, their training patterns and facilities available in European Urology Departments. MATERIALS AND METHODS: A survey, consisting of 23 questions concerning laparoscopic training, was published online as well as distributed on paper, during the Annual European Association of Urology Congress in 2012. Exposure to laparoscopic procedures, acquired laparoscopic experience, training patterns, training facilities and motivation were evaluated. Data was analysed with descriptive statistics. RESULTS: In all, 219 European urology residents answered the survey. Conventional laparoscopy was available in 74% of the respondents' departments, while robotic surgery was available in 17% of the departments. Of the respondents, 27% were first surgeons and 43% were assistants in conventional laparoscopic procedures. Only 23% of the residents rated their laparoscopic experience as at least 'satisfactory'; 32% of the residents did not attend any course or fellowship on laparoscopy. Dry laboratory was the most frequent setting for training (33%), although 42% of the respondents did not have access to any type of laparoscopic laboratory. The motivation to perform laparoscopy was rated as 'high' or 'very high' by 77% of the respondents, and 81% considered a post-residency fellowship in laparoscopy. CONCLUSIONS: Urological laparoscopy is available in most European training institutions, with residents playing an active role in the procedure. However, most of them consider their laparoscopic experience to be poor. Moreover, the availability of training facilities and participation in laparoscopy courses and fellowships are low and should be encouraged. PMID- 24053712 TI - JunD/AP1 regulatory network analysis during macrophage activation in a rat model of crescentic glomerulonephritis. AB - BACKGROUND: Function and efficiency of a transcription factor (TF) are often modulated by interactions with other proteins or TFs to achieve finely tuned regulation of target genes. However, complex TF interactions are often not taken into account to identify functionally active TF-targets and characterize their regulatory network. Here, we have developed a computational framework for integrated analysis of genome-wide ChIP-seq and gene expression data to identify the functional interacting partners of a TF and characterize the TF-driven regulatory network. We have applied this methodology in a rat model of macrophage dependent crescentic glomerulonephritis (Crgn) where we have previously identified JunD as a TF gene responsible for enhanced macrophage activation associated with susceptibility to Crgn in the Wistar-Kyoto (WKY) strain. RESULTS: To evaluate the regulatory effects of JunD on its target genes, we analysed data from two rat strains (WKY and WKY.LCrgn2) that show 20-fold difference in their JunD expression in macrophages. We identified 36 TFs interacting with JunD/Jun and JunD/ATF complexes (i.e., AP1 complex), which resulted in strain-dependent gene expression regulation of 1,274 target genes in macrophages. After lipopolysaccharide (LPS) stimulation we found that 2.4 fold more JunD/ATF-target genes were up-regulated as compared with JunD/Jun-target genes. The enriched 314 genes up-regulated by AP1 complex during LPS stimulation were most significantly enriched for immune response (P = 6.9 * 10-4) and antigen processing and presentation functions (P = 2.4 * 10-5), suggesting a role for these genes in macrophage LPS-stimulated activation driven by JunD interaction with Jun/ATF. CONCLUSIONS: In summary, our integrated analyses revealed a large network of TFs interacting with JunD and their regulated targets. Our data also suggest a previously unappreciated contribution of the ATF complex to JunD-mediated mechanisms of macrophage activation in a rat model of crescentic glomerulonephritis. PMID- 24053713 TI - Prevalence of and factors related to the use of antidepressants and benzodiazepines: results from the Singapore Mental Health Study. AB - BACKGROUND: Prescription and use of antidepressants and benzodiazepines are common in the general population. Prescription of psychotropic drugs is a complex process: patient, physician and healthcare characteristics mediate, interact and influence it. The current study aimed to establish the prevalence and factors associated with the use of antidepressants (ADs) and benzodiazepines (BZDs) in Singapore. METHODS: The Singapore Mental Health Study (SMHS) was a nationally representative survey of Singapore Residents aged 18 years and above. Face-to face interviews were conducted from December 2009 to December 2010. The diagnoses of mental disorders were established using the Composite International Diagnostic Interview version 3.0 (CIDI-3.0). The pharmacoepidemiology section was used to collect information on medication use. RESULTS: The overall prevalence estimates for ADs and BZDs use during the 12 months prior to the interview were 1.1% and 1.2% respectively. In all, 2.0% had used ADs and/or BZDs. 'Help seeking for emotional or mental health problems' was the most important predictor for the use of ADs and BZDs-help seekers were much more likely to use ADs (adjusted OR: 31.62, 95% CI: 13.36-74.83) and more likely to use BZDs than non--help seekers in the previous 12 months (adjusted OR: 34.38, 95% CI: 12.97-91.16). Only 27.6% of those with 12-month major depressive disorder (MDD) had sought formal medical help for their problems and ADs were being used by just over a quarter of this 'help-seeking group' (26.3%). CONCLUSIONS: We found that the use of ADs and BZDs in our population was relatively low, and 'help-seeking' was the most important predictor of the use of ADs and BZDs. In concordance with research from other Western countries, use of ADs was low among those with 12-month MDD. PMID- 24053714 TI - Utilizing food effects to overcome challenges in delivery of lipophilic bioactives: structural design of medical and functional foods. AB - INTRODUCTION: The oral bioavailability of many lipophilic bioactives, such as pharmaceuticals and nutraceuticals, is relatively low due to their poor solubility, permeability and/or chemical stability within the human gastrointestinal tract (GIT). The oral bioavailability of lipophilic bioactives can be improved by designing food matrices that control their release, solubilization, transport and absorption within the GIT. AREAS COVERED: This article discusses the challenges associated with delivering lipophilic bioactive components, the impact of food composition and structure on oral bioavailability and the design of functional and medical foods for improving the oral bioavailability of lipophilic bioactives. EXPERT OPINION: Food-based delivery systems can be used to improve the oral bioavailability of lipophilic bioactives. There are a number of potential advantages to delivering lipophilic bioactives using functional or medical foods: greater compliance than conventional delivery forms; increased bioavailability and efficacy; and reduced variability in biological effects. However, food matrices are structurally complex multicomponent materials and research is still needed to identify optimum structures and compositions for particular bioactives. PMID- 24053715 TI - Extended vs non-extended pelvic lymph node dissection and their influence on recurrence-free survival in patients undergoing radical cystectomy for bladder cancer: a systematic review and meta-analysis of comparative studies. AB - OBJECTIVE: To compare extended pelvic lymph node dissection (ePLND) with non extended pelvic lymph node dissection (non-ePLND) and assess their influence on recurrence-free survival (RFS) in patients undergoing radical cystectomy for bladder cancer. METHODS: Through a comprehensive search of the PubMed, Embase and Cochrane Library databases in September 2012, we performed a systematic review and cumulative meta-analysis of all comparative studies assessing the extent of pelvic lymph node dissection (PLND) and its influence on RFS. RESULTS: Six studies with a total of 2824 patients were identified. Overall analysis showed a significantly better RFS rate in patients who had undergone ePLND than in those who had undergone non-ePLND (hazard ratio [HR]: 0.65; P < 0.001). A subgroup analysis found that, compared with non-ePLND, ePLND was associated with a better RFS rate for both patients with negative lymph nodes (HR: 0.68; P = 0.007) and those with positive lymph nodes (HR: 0.58; P < 0.001). When stratified by pathological T stage, ePLND provided additional RFS benefits for patients with pT3-4 disease (HR: 0.61; P < 0.001), but not for patients with <=pT2 disease (HR: 0.95; P = 0.81). CONCLUSIONS: The results of this meta-analysis indicate that ePLND provides a RFS benefit compared with non-ePLND. On subgroup analysis, ePLND provides better RFS not only for patients who had positive lymph nodes and pT3-4 disease, but also for patients with negative lymph nodes. Two randomized controlled trials on ePLND vs non-ePLND are awaited which should provide more clinically meaningful results. PMID- 24053716 TI - Effect of Nd:YAG laser pulse energy on mercury vapor release from the dental amalgam. AB - OBJECTIVE: The aim of this study was to evaluate the effect of different pulse energies of Nd:YAG laser on the amalgam ablation, and its effect on the amount of mercury vapor release from amalgam. BACKGROUND DATA: Toxic vapor release from amalgam restorations at the laser focus site is possible. MATERIALS AND METHODS: Forty-five amalgam samples (4 mm in diameter and 5 mm in height) were placed in sealed containers and underwent Nd:YAG laser irradiation with pulse energies of 50, 150, and 250 mJ at a distance of 1 mm from the amalgam surface for 4 sec. Subsequently, 150 mL of air was collected from the inside of the container using an Apex Pump to analyze the amount of mercury vapor in the air samples using a mercury vapor analyzer. Data were analyzed using Kruskal-Wallis and Mann-Whitney U tests (p<0.05). RESULTS: The amount of mercury vapor release significantly increased with an increase in the pulse energy of Nd:YAG laser (p<0.001). In addition, the amount of mercury vapor release with 250 mJ pulse energy was significantly higher compared with the standard mercury vapor concentration (50 MUg/m(3)) (p<0.001). Nd:YAG laser produced cavities on the amalgam surface, which increased in size with an increase in the energy of the laser beam. CONCLUSIONS: The amount of mercury vapor significantly increased with an increase in the pulse energy of the laser beam, and was significantly higher than the standard mercury vapor concentration with 250 mJ pulse energy. PMID- 24053717 TI - Conversion of azides into diazo compounds in water. AB - Diazo compounds are in widespread use in synthetic organic chemistry but have untapped potential in chemical biology. We report on the design and optimization of a phosphinoester that mediates the efficient conversion of azides into diazo compounds in phosphate buffer at neutral pH and room temperature. High yields are maintained in the presence of common nucleophilic or electrophilic functional groups, and reaction progress can be monitored by colorimetry. As azido groups are easy to install and maintain in biopolymers or their ligands, this new mode of azide reactivity could have substantial utility in chemical biology. PMID- 24053718 TI - NADPH oxidase, NOX1, mediates vascular injury in ischemic retinopathy. AB - AIMS: Ischemic retinal diseases such as retinopathy of prematurity are major causes of blindness due to damage to the retinal microvasculature. Despite this clinical situation, retinopathy of prematurity is mechanistically poorly understood. Therefore, effective preventative therapies are not available. However, hypoxic-induced increases in reactive oxygen species (ROS) have been suggested to be involved with NADPH oxidases (NOX), the only known dedicated enzymatic source of ROS. Our major aim was to determine the contribution of NOX isoforms (1, 2, and 4) to a rodent model of retinopathy of prematurity. RESULTS: Using a genetic approach, we determined that only mice with a deletion of NOX1, but not NOX2 or NOX4, were protected from retinal neovascularization and vaso obliteration, adhesion of leukocytes, microglial accumulation, and the increased generation of proangiogenic and proinflammatory factors and ROS. We complemented these studies by showing that the specific NOX inhibitor, GKT137831, reduced vasculopathy and ROS levels in retina. The source of NOX isoforms was evaluated in retinal vascular cells and neuro-glial elements. Microglia, the immune cells of the retina, expressed NOX1, 2, and 4 and responded to hypoxia with increased ROS formation, which was reduced by GKT137831. INNOVATION: Our studies are the first to identify the NOX1 isoform as having an important role in the pathogenesis of retinopathy of prematurity. CONCLUSIONS: Our findings suggest that strategies targeting NOX1 have the potential to be effective treatments for a range of ischemic retinopathies. PMID- 24053719 TI - Inter-observer agreement according to malaria parasite density. AB - BACKGROUND: Recent developments in diagnostic techniques for malaria, particularly DNA probes and sero-immunology, have raised questions as to how these techniques might be used to facilitate malaria diagnosis at the most peripheral levels of the primary health care system. At present, malaria diagnosis is based on the standard microscopic examination of blood films in most field epidemiologic studies and is likely to remain so in the immediate future in Africa. The objective of this study was to assess inter-observer agreement for the examination of Giemsa-stained slides for Plasmodium falciparum parasites. METHODS: Children aged 0 to 10 years were enrolled yearly in Bancoumana village (West Africa), mainly during the transmission season (June to October). The blood smears obtained from the persistently negative children in June 1996, August 1996, October 1996 and March 1997 were systematically re-examined. A stratified random sample (10%) proportional to the following parasite density classes 1-100, 101-5000, and 5001 and over was taken from the slides collected. The kappa statistics and the intra-class correlation were used as measures of agreement the first and the second slide examinations. RESULTS: The weighted kappa statistic, widely used as a chance-corrected measure for nominal agreement, showed excellent inter-observer agreement (kappa(w)=0.7926; 95% CI [0.7588, 0.8263]; p=0.01). The intra-class correlation co-efficient had the same value of 0.7926 confirming the appropriateness of the weighted kappa statistic. Inter-observer agreement for slides read as negative by one observer, or as containing more than 100 parasites per MUl, was excellent: 97% (493/506) and 92% (145/158), respectively. In contrast, the inter-observer agreement for slides read by one observer as containing 1-100 parasites/MUl was poor, 36% (96/268). CONCLUSIONS: In field conditions in Mali, there was a high reproducibility for slides reported as negative or as having more than 100 parasites per MUl. However, smears with readings of 1-100 parasites per MUl were less reproducible and should be re examined carefully. PMID- 24053721 TI - 'Why must I wait?' The performance of legitimacy in a hospital emergency department. AB - This article examines the processes of negotiation that occur between patients and medical staff over accessing emergency medical resources. The field extracts are drawn from an ethnographic study of a UK emergency department (ED) in a large, inner city teaching hospital. The article focuses on the triage system for patient prioritisation as the first point of access to the ED. The processes of categorising patients for priority of treatment and care provide staff with the opportunities to maintain control over what defines the ED as a service, as types of work and as particular kinds of patients. Patients and relatives are implicated in this categorical work in the course of interactions with staff as they provide reasons and justifications for their attendance. Their success in legitimising their claim to treatment depends upon self-presentation and identity work that (re)produces individual responsibility as a dominant moral order. The extent to which people attending the ED can successfully perform as legitimate is shown to contribute to their placement into positive or negative staff constituted patient categories, thus shaping their access to the resources of emergency medicine and their experience of care. PMID- 24053722 TI - Parameterizing soil emission and atmospheric oxidation-reduction in a model of the global biogeochemical cycle of mercury. AB - Using the GEOS-Chem atmosphere-land-ocean coupled mercury model, we studied the significances of two processes, soil emission and atmospheric oxidation reduction, in the global biogeochemical cycling of mercury and their parametrization to improve model performance. Implementing an empirical equation for soil emission flux (Esoil) including soil mercury concentration, solar radiation, and surface air temperature as parameters enabled the model to reproduce the observed seasonal variations of Esoil, whereas the default setting, which uses only the former two parameters, failed. The modified setting of Esoil also increased the model-simulated atmospheric concentration in the summertime surface layer of the lower- and midlatitudes and improved the model reproducibility for the observations in Japan and U.S. in the same period. Implementing oxidation of atmospheric gaseous elemental mercury (Hg(0)) by ozone with an updated rate constant, as well as the oxidation by bromine atoms (Br) in the default setting, improved the model reproducibility for the dry deposition fluxes observed in Japan. This setting, however, failed to reproduce the observed seasonal variations of atmospheric concentrations in the Arctic sites due to the imbalance between oxidation and reduction, whereas the model with Br as the sole Hg(0) oxidant in the polar atmosphere could capture the variations. PMID- 24053723 TI - Microscopic mechanisms of confinement-induced slow solvation. AB - Several studies show that the dynamics of solvent molecules around a solute slows down in a nanoscale confined geometry compared to the bulk condition. Here we perform numerical simulations to investigate the microscopic mechanisms of such slowing down. We show a substantial slowing down of solvation dynamics around a solute in strong solvophilic confinements due to suppression of fluid diffusion in the presence of solvophilic walls, along with restricted solvent dynamics due to geometrical constraints. The solvation in strong solvophobic confinements becomes slower than the same in the bulk as well, but not as significantly as in the solvophilic case. This is due to the competition between restriction in solvent dynamics and faster in-plane solvent diffusion. We place our findings in perspective of various solvation dominated chemical processes in nanoconfined geometry. PMID- 24053720 TI - Prothymosin alpha and a prothymosin alpha-derived peptide enhance T(H)1-type immune responses against defined HER-2/neu epitopes. AB - BACKGROUND: Active cancer immunotherapies are beginning to yield clinical benefit, especially those using peptide-pulsed dendritic cells (DCs). Different adjuvants, including Toll-like receptor (TLR) agonists, commonly co-administered to cancer patients as part of a DC-based vaccine, are being widely tested in the clinical setting. However, endogenous DCs in tumor-bearing individuals are often dysfunctional, suggesting that ex vivo educated DCs might be superior inducers of anti-tumor immune responses. We have previously shown that prothymosin alpha (proTalpha) and its immunoreactive decapeptide proTalpha(100-109) induce the maturation of human DCs in vitro. The aim of this study was to investigate whether proTalpha- or proTalpha(100-109)-matured DCs are functionally competent and to provide preliminary evidence for the mode of action of these agents. RESULTS: Monocyte-derived DCs matured in vitro with proTalpha or proTalpha(100 109) express co-stimulatory molecules and secrete pro-inflammatory cytokines. ProTalpha- and proTalpha(100-109)-matured DCs pulsed with HER-2/neu peptides induce TH1-type immune responses, prime autologous naive CD8-positive (+) T cells to lyse targets expressing the HER-2/neu epitopes and to express a polyfunctional profile, and stimulate CD4+ T cell proliferation in an HER-2/neu peptide dependent manner. DC maturation induced by proTalpha and proTalpha(100-109) is likely mediated via TLR-4, as shown by assessing TLR-4 surface expression and the levels of the intracellular adaptor molecules TIRAP, MyD88 and TRIF. CONCLUSIONS: Our results suggest that proTalpha and proTalpha(100-109) induce both the maturation and the T cell stimulatory capacity of DCs. Although further studies are needed, evidence for a possible proTalpha and proTalpha(100-109) interaction with TLR-4 is provided. The initial hypothesis that proTalpha and the proTalpha derived immunoactive decapeptide act as "alarmins", provides a rationale for their eventual use as adjuvants in DC-based anti-cancer immunotherapy. PMID- 24053724 TI - Weight-reducing gastroplasty with Roux-en-Y gastric bypass: impact on vitamin D status and bone remodeling markers. AB - BACKGROUND: Despite the weight loss benefits of bariatric surgery, studies have shown considerably compromised nutritional conditions, particularly in relation to bone metabolism, in patients who have undergone this procedure. The goal of this study was evaluate bone metabolism alterations after gastroplasty through the concentrations of carboxy-terminal cross-linking telopeptides of type-I collagen (CTX) and bone-specific alkaline phosphatase (BSAP) and vitamin D status. METHODS: This study, conducted at the Botucatu School of Medicine University Hospital, UNESP, analyzed 22 women with body mass index (BMI) values higher than 35 kg/m(2) who had undergone Roux-en-Y gastric bypass (RYGB) surgery, prior to and 3 and 6 months after the procedure. RESULTS: The patients were evaluated in relation to their anthropometric profile. Obese patients showed a vitamin D status that was compatible with moderate depletion, thus correlating negatively with parathyroid hormone (PTH) and positively with CTX. After surgery, 25-hydroxyvitamin D [25(OH)D] and CTX concentrations increased significantly. Other tests (calcium, phosphorus, magnesium, total AP and BSAP, and PTH) did not differ between the times of analysis and remained stable within the range of normality. Body fat correlated only with 25(OH)D concentrations and was inversely proportional to their increase. There was a positive correlation between PTH and CTX prior to surgery. CONCLUSIONS: Hypovitaminosis D is prevalent in obese individuals, and RYGB is related to CTX increase without BSAP alteration in the first follow-up semester. PMID- 24053725 TI - Use of donor bladder tissues for in vitro research. AB - OBJECTIVES: To evaluate deceased non-heart beating (DNHB) donors and deceased heart beating (DHB) brain-stem dead donors, as sources of viable urological tissue for use in biomedical research. To identify sources of viable human bladder tissue as an essential resource for cell biological research aimed at understanding human diseases of the bladder and for developing new tissue engineering and regenerative medicine strategies for bladder reconstruction. Typically, normal human urinary tract tissue is obtained from adult or paediatric surgical patients with benign urological conditions, but few surgical procedures yield useful quantities of healthy bladder tissue for research. PATIENTS AND METHODS: Research ethics committee approval was obtained for collection of donor bladder tissue. Consent for DHB donors was undertaken by the Donor Transplant Coordinators. Tissue Donor Coordinators were responsible for consent for DNHB donors and the retrieval of bladders was coordinated through the National Blood Service Tissue Banking Service. All retrievals were performed by practicing urologists and care was taken to maintain sterility and to minimise bacterial contamination. Two bladders were retrieved from DNHB donors and four were retrieved from DHB donors. RESULTS: By histology, DNHB donor bladder tissue exhibited marked urothelial tissue damage and necrosis, with major loss or absence of urothelium. No cell cultures could be established from these specimens, as the urothelial cells were not viable in primary culture. Bladder urothelium from DHB donors was intact, but showed some damage, including loss of superficial cells and variable separation from the basement membrane. All four DHB bladder specimens yielded viable urothelial cells that attached in primary culture, but cell growth was slow to establish and cultures showed a limited capacity to form a functional barrier epithelium and a propensity to senesce early. CONCLUSIONS: We have shown that normal human bladder urothelial cell cultures can be established and serially propagated from DHB donor bladders. However, our study suggests that rapid post-mortem changes to the bladder affect the quality and viability of the urothelium, rendering tissue from DNHB donors an inadequate source for urothelial cell culture. Our experience is that whereas patients are willing to donate surgical tissue for research, there is a barrier to obtaining consent from next of kin for retrieved tissues to be used for research purposes. PMID- 24053726 TI - A novel paramagnetic relaxation enhancement tag for nucleic acids: a tool to study structure and dynamics of RNA. AB - In this work, we present a novel 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) radical phosphoramidite building block, which can be attached to the 5'-terminus of nucleic acids. To investigate the paramagnetic relaxation enhancement (PRE) emanating from this radical center, we incorporated the TEMPO label into various types of RNAs. We measured proton PREs for selectively (13)C-isotope labeled nucleotides to derive long-range distance restraints in a short 15 nucleotide stem-loop model system, underscoring the potential of the 5'-TEMPO tag to determine long-range distance restraints for solution structure determination. We subsequently applied the distance-dependent relaxation enhancement induced by the nitroxide radical to discern two folding states in a bistable RNA. Finally, we investigated the fast conformational sampling of the HIV-1 TAR RNA, a paradigm for structural flexibility in nucleic acids. With PRE NMR in combination with molecular dynamics simulations, the structural plasticity of this RNA was analyzed in the absence and presence of the ligand L-argininamide. PMID- 24053727 TI - Cytoreductive nephrectomy in patients with metastatic non-clear-cell renal cell carcinoma (RCC). AB - OBJECTIVE: To determine whether patients with metastatic non-clear-cell renal cell carcinoma (RCC) benefit from cytoreductive nephrectomy (CN). PATIENTS AND METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) programme to identify a population-based sample of 4914 patients diagnosed with metastatic RCC between 2000 and 2009. Of the 4914 patients, 591 had non-clear-cell histology. The median follow-up was 20 months. The primary outcome measure was RCC-specific mortality. RESULTS: Approximately 64% of patients underwent CN. Patients with non-clear-cell histology who underwent CN had lower RCC-specific and all-cause mortality than those who did not (P < 0.001 in both cases). After adjustment for age, gender, race, marital status, year of diagnosis, geographical location and histology, the associations between CN and lower RCC-specific mortality (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.48-0.80, P < 0.001) and between CN and all-cause mortality (HR 0.45, 95% CI 0.37-0.55, P < 0.001) remained highly significant. Among patients diagnosed between 2006 and 2009 (targeted therapy era), the results remained unchanged (HR 0.50, 95% CI 0.34 0.72, P < 0.001 and HR 0.43, 95% CI 0.31-0.59, P < 0.001, respectively). An interaction model found lower all-cause mortality for all histologies after CN. CONCLUSIONS: Patients from the SEER programme with metastatic non-clear-cell RCC, including those treated in the targeted therapy era, appear to derive a survival benefit from CN, an association which remained significant regardless of histological subtype. This observation suggests that CN should remain standard in patients with advanced RCC who are deemed to be surgical candidates. PMID- 24053728 TI - Evaluation of DNA damage in COPD patients and its correlation with polymorphisms in repair genes. AB - BACKGROUND: We investigated a potential link between genetic polymorphisms in genes XRCC1 (Arg399Gln), OGG1 (Ser326Cys), XRCC3 (Thr241Met), and XRCC4 (Ile401Thr) with the level of DNA damage and repair, accessed by comet and micronucleus test, in 51 COPD patients and 51 controls. METHODS: Peripheral blood was used to perform the alkaline and neutral comet assay; and genetic polymorphisms by PCR/RFLP. To assess the susceptibility to exogenous DNA damage, the cells were treated with methyl methanesulphonate for 1-h or 3-h. After 3-h treatment the % residual damage was calculated assuming the value of 1-h treatment as 100%. The cytogenetic damage was evaluated by buccal micronucleus cytome assay (BMCyt). RESULTS: COPD patients with the risk allele XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) showed higher DNA damage by comet assay. The residual damage was higher for COPD with risk allele in the four genes. In COPD patients was showed negative correlation between BMCyt (binucleated, nuclear bud, condensed chromatin and karyorrhexic cells) with pulmonary function and some variant genotypes. CONCLUSION: Our results suggest a possible association between variant genotypes in XRCC1 (Arg399Gln), OGG1 (Ser326Cys), XRCC3 (Thr241Met), and XRCC4 (Ile401Thr), DNA damage and progression of COPD. PMID- 24053730 TI - Self-perceived sleepiness in emergency training physicians: prevalence and relationship with quality of life. AB - INTRODUCTION: Sleep deprivation among training physicians is of growing concern; training physicians are susceptible due to their prolonged work hours and rotating work schedules. The aim of this study was to determine the prevalence of self-perceived sleepiness in emergency training physicians, and to establish a relationship between self-perceived sleepiness, and quality of life. METHODS: Prospective survey in Ibn Sina University hospital Center in Morocco from January to April 2011 was conducted. Questionnaires pertaining to socio-demographic, general, and sleep characteristics were completed by training physician who ensured emergency service during the month preceding the survey. They completed the Epworth sleepiness scale (ESS) which assessed the self-perceived sleepiness, and the EuroQol-5 dimensions (EQ-5D) scale which assessed the general quality of life. RESULTS: Total 81 subjects (49 men and 32 women) were enrolled with mean age of 26.1 +/- 3.4 years. No sleepiness was found in 24.7% (n = 20), excessive sleepiness 39.5% (n = 32), and severe sleepiness in 35.8% (n = 29) of training physicians. After adjusting for multiple confounding variables, four independent variables were associated with poorer quality of life index in training physician; unmarried (beta -0.2, 95% CI -0.36 to -0.02; P = 0.02), no physic exercise (beta -0.2, 95% CI -0.39 to 0.006; P = 0.04), shift-off sleep hour less than 6 hours (beta -0.13, 95% CI -0.24 to -0.02; P = 0.01), and severe sleep deprivation(beta -0.2, 95% CI -0.38 to -0.2; P = 0.02). CONCLUSION: Nearly two third of training physicians had suffered from sleepiness. There is an association between poor quality of life and severe sleepiness in unmarried physicians, sleeping less than 6 hours in shift-off day, and doing no physical activity. PMID- 24053729 TI - Beneficial association of serum ghrelin and peptide YY with bone mineral density in the Newfoundland population. AB - BACKGROUND: Ghrelin and peptide YY (PYY) are appetite regulating hormones secreted from the gastrointestinal tract (gut). Aside from their known effect on energy homeostasis, accumulating data indicates that these gut hormones also affect bone metabolism. However, data regarding the influence of ghrelin and PYY on bone density in humans is very limited, and the results are inconclusive. Therefore, this study was designed to investigate the potential association between circulating ghrelin and PYY with bone density indices in the general population. METHODS: A total of 2257 adult subjects from the CODING (Complex Diseases in the Newfoundland Population: Environment and Genetics) study participated in this investigation. Acylated ghrelin and total PYY were measured in serum after a 12-hour fasting, with the Enzyme- Linked Immunosorbent Assay (ELISA) method. Bone mineral density was measured by dual-energy X-ray absorptiometry at the spine, femoral neck, and total hip. Multiple regression analyses adjusting for age, BMI, physical activity, smoking, and alcohol consumption were employed to analyze the association between serum ghrelin and PYY with bone mineral density parameters. RESULTS: Significant positive associations of ghrelin concentration with L2-L4 BMD, L2-L4 Z-score, femoral neck BMD, femoral neck Z-score, total hip BMD, and total hip Z-score were found in women. No significant correlations between ghrelin and bone density indices were present in men. After dividing the female group into pre-menopausal and post menopausal, ghrelin was positively correlated with femoral neck Z-score, and total hip Z-score in pre-menopausal women and L2-L4 BMD, and Z-score in post menopausal group. Moreover, no significant association was discovered between serum PYY and bone density at any site. CONCLUSION: Our results suggest a beneficial association of circulating ghrelin concentration with bone density in women at the population level. This association is independent of major confounding factors including BMI, physical activity, age, alcohol consumption, and smoking. Effect of menopause on this association seemed to be site specific. However, PYY does not seem to be associated with bone density parameters. PMID- 24053731 TI - Removing financial barriers to access reproductive, maternal and newborn health services: the challenges and policy implications for human resources for health. AB - BACKGROUND: The last decade has seen widespread retreat from user fees with the intention to reduce financial constraints to users in accessing health care and in particular improving access to reproductive, maternal and newborn health services. This has had important benefits in reducing financial barriers to access in a number of settings. If the policies work as intended, service utilization rates increase. However this increases workloads for health staff and at the same time, the loss of user fee revenues can imply that health workers lose bonuses or allowances, or that it becomes more difficult to ensure uninterrupted supplies of health care inputs.This research aimed to assess how policies reducing demand-side barriers to access to health care have affected service delivery with a particular focus on human resources for health. METHODS: We undertook case studies in five countries (Ghana, Nepal, Sierra Leone, Zambia and Zimbabwe). In each we reviewed financing and HRH policies, considered the impact financing policy change had made on health service utilization rates, analysed the distribution of health staff and their actual and potential workloads, and compared remuneration terms in the public sectors. RESULTS: We question a number of common assumptions about the financing and human resource inter-relationships. The impact of fee removal on utilization levels is mostly not sustained or supported by all the evidence. Shortages of human resources for health at the national level are not universal; maldistribution within countries is the greater problem. Low salaries are not universal; most of the countries pay health workers well by national benchmarks. CONCLUSIONS: The interconnectedness between user fee policy and HRH situations proves difficult to assess. Many policies have been changing over the relevant period, some clearly and others possibly in response to problems identified associated with financing policy change. Other relevant variables have also changed.However, as is now well recognised in the user fee literature, co-ordination of health financing and human resource policies is essential. This appears less well recognised in the human resources literature. This coordination involves considering user charges, resource availability at health facility level, health worker pay, terms and conditions, and recruitment in tandem. All these policies need to be effectively monitored in their processes as well as outcomes, but sufficient data are not collected for this purpose. PMID- 24053732 TI - Electrocautery-induced cavernous nerve injury in rats that mimics radical prostatectomy in humans. AB - OBJECTIVE: To investigate the early and delayed effects of cavernous nerve electrocautery injury (CNEI) in a rat model, with the expectation that this model could be used to test rehabilitation therapies for erectile dysfunction (ED) after radical prostatectomy (RP). MATERIALS AND METHODS: In all, 30 male Sprague Dawley rats were randomly divided equally into two groups (15 per group). The control group received CNs exposure surgery only and the experimental group received bilateral CNEI. At 1, 4 and 16 weeks after surgery (five rats at each time point), the ratio of maximal intracavernosal pressure (ICP) to mean arterial pressure (MAP) was measured in the two groups. Neurofilament expression in the dorsal penile nerves was assessed by immunofluorescent staining and Masson's trichrome staining was used to assess the smooth muscle to collagen ratio in both groups. RESULTS: At the 1-week follow-up, the mean ICP/MAP was significantly lower in the CNEI group compared with the control group, at 9.94% vs 70.06% (P < 0.05). The mean ICP/MAP in the CNEI group was substantially increased at the 4- (35.97%) and 16-week (37.11%) follow-ups compared with the 1-week follow-up (P < 0.05). At all three follow-up time points, the CNEI group had significantly decreased neurofilament staining compared with the control group (P < 0.05). Also, neurofilament expressions in the CNEI group at both 4 and 16 weeks were significantly higher than that at 1 week (P < 0.05), but there was no difference between 4 and 16 weeks (P > 0.05). The smooth muscle to collagen ratio in the CNEI group was significantly lower than in the control group at the 4- and 16 week follow-ups (P < 0.05), and the ratio at 16 weeks was further reduced compared with that at 4 weeks (P < 0.05). CONCLUSIONS: In the CNEI rat model, we found the damaging effects of CNEI were accompanied by a decline in ICP, reduced numbers of nerve fibres in the dorsal penile nerve, and exacerbated fibrosis in the corpus cavernosum. This may provide a basis for studying potential preventative measures or treatment strategies to ameliorate ED caused by CNEI during RP. PMID- 24053733 TI - Prevalence of Epstein-Barr Virus in a population of patients with inflammatory bowel disease: a prospective cohort study. AB - BACKGROUND: The Epstein-Barr Virus (EBV) is truly prolific, with a prevalence of more than 90% in the adult human population. There are, however, little data available on the prevalence of EBV among patients with Inflammatory Bowel Disease (IBD), a population that is frequently immunosuppressed and thus at risk for severe, often fatal, primary infection. AIM: To identify the prevalence of EBV in a population of patients with IBD and to compare it with that of the general population. METHODS: A database of 2500 IBD patients previously followed at the University of Alberta IBD Centre was queried; 60 of these patients were randomly chosen to participate. A total of 220 patients attending the IBD Centre for clinical appointment were also prospectively asked to participate. Participants completed serological testing for VCA-IgM, VCA-IgG and EBNA-IgG, to determine prior EBV exposure. RESULTS: A total of 263 patients underwent testing. Results for EBV seroprevalence of specific age groups were as follows: 18-20 years (n = 17), 29% seronegative; 21-25 years (n = 31), 29% seronegative; 26-30 years (n = 35), 31-35 years (n = 18) and 36-40 years (n = 25), 100% seropositive. Finally, 3% of those older than 40 (n = 117) were seronegative. EBV seroprevalence was similar for Crohn's disease and ulcerative colitis. Azathioprine was associated with seropositivity (P = 0.048). CONCLUSION: The prevalence of EBV seronegativity in the IBD population aged 18-25 years was similar to that described in the general population, and above age 25 years, seropositivity approached 100%. PMID- 24053734 TI - Trends and inequalities in the surgical management of ureteric calculi in the USA. AB - OBJECTIVE: To assess trends in the surgical management of ureteric calculi over a 10-year period. MATERIALS AND METHODS: An analysis of the 5% Medicare Public Use Files, from 2001, 2004, 2007 and 2010, was performed to assess the use of ureteroscopy (URS), extracorporal shockwave lithotripsy (ESWL) and ureterolithotomy (UL) in treating ureteric calculi. Patients were identified using International Classification of Diseases 9th edition (Clinical Modification) and Current Procedure Terminology codes. Statistical analyses using the Fisher and chi-squared tests, and multivariate logistic regression analysis (dependent variables: URS, ESWL, UL, treatment, no treatment; independent variables: age, gender, ethnicity, geography and year of treatment) were performed. RESULTS: A total of 299 920 patients with ureteric calculi were identified. Of these, 115 200 underwent surgery. Men (odds ratio [OR] = 1.15, P < 0.001) were more likely, while patients from ethnic minorities (OR = 0.84, P = 0.004) were less likely to be treated. Patients in the West of the USA were also less likely to be treated (OR = 0.76, P < 0.001) as were patients aged <65 or >84 years old (P = 0.29). The predominant surgical approach was URS (65.2%), followed by ESWL (33.6%) and UL (1.2%). The use of URS increased over time, while the use of ESWL and UL declined. Women (OR = 1.25, P < 0.001) were more likely to undergo URS. Patients in the South of the USA (OR = 1.51, P < 0.001) and patients from ethnic minorities were more likely to undergo ESWL (OR = 1.23, P = 0.03). CONCLUSIONS: The surgical treatment of ureteric calculi changed significantly between 2001 and 2010. The use of URS expanded at the expense of ESWL and UL. Multiple inequalities existed in overall surgical treatment rates and in the choice of treatment; age, gender, ethnicity and geography influenced both whether patients underwent surgical intervention and the type of surgical approach used. PMID- 24053735 TI - Intimate partner violence and help-seeking--a cross-sectional study of women in Sweden. AB - BACKGROUND: Intimate partner violence (IPV) is a global public health concern with possible detrimental consequences for its victims. Studies have found prevalence rates of 15 to 71% for IPV. There is evidence that IPV exposed women perceive barriers to help-seeking and many remain undetected by care givers and authorities. This cross-sectional study aimed to examine IPV exposed women in relation to help-seeking versus non help-seeking from the social services or women's shelters with regard to social and psychological characteristics as well as relationship with the perpetrator and type of violence exposure. METHODS: Two groups of Swedish IPV exposed women were included: non help-seekers (n = 128) were recruited through ads in newspapers, while help-seekers (n = 347) were recruited from four social service sites and twenty women's shelters around Sweden. Participants were assessed with questionnaires regarding age, education, occupation and relation to the perpetrator as well as validated instruments measuring psychological distress, psychosocial functioning alcohol use and violence. Analyses were made using Chi2 and multivariate logistic regression. RESULTS: Help-seekers had significantly more often children together with the perpetrator than non help-seekers (64% and 29% respectively) and a high association was found in the fully adjusted model (Adj. OR = 5.46 95% CI 2.99 9.97). Many women in both groups reported a poor social situation and high levels of psychological distress, although more psychological distress was associated with elevated odds for help-seeking (Adj. OR = 2.83 95% CI 1.84-4.34). No differences were found between the groups regarding violence exposure and most women in both groups had experienced severe violence from an intimate partner (95% to 98%). CONCLUSIONS: Results indicate a high problem load among women who had not contacted the social services or women's shelters due to IPV, and that non help-seekers had similar experiences of severe IPV as help-seekers. This stresses a need to identify IPV exposed women outside specialized settings within the social services and women's shelters. Asking about partner violence in various health and social care settings could be a feasible strategy to identify battered women and provide them with alternatives for help that ultimately could lead to a life without violence. PMID- 24053736 TI - Elimination of butylcycloheptylprodigiosin as a known natural product inspired by an evolutionary hypothesis for cyclic prodigiosin biosynthesis. AB - The cyclic prodigiosins are an important family of bioactive natural products that continue to be the subject of numerous structural, synthetic, and biosynthetic studies. In particular, the structural assignments of the isomeric cyclic prodigiosins butylcycloheptylprodigiosin (BCHP) and streptorubin B have been the cause of significant confusion. Herein, we report detailed studies regarding the electron impact (EI) mass spectra of synthetic BCHP and streptorubin B that have allowed us to distinguish the two compounds in the absence of quality historical isolation NMR data. On the basis of these fragmentation differences, the status of BCHP as a natural product is challenged. The proposed mechanism of fragmentation is supported by the EI mass spectra of synthetic pentyl-chain analogues of BCHP and streptorubin B, X-ray crystallography, and DFT calculations. Elimination of BCHP from the prodigiosin family supports a proposed evolutionary hypothesis for the surprising biosynthesis of cyclic prodigiosins. PMID- 24053737 TI - SynTView - an interactive multi-view genome browser for next-generation comparative microorganism genomics. AB - BACKGROUND: Dynamic visualisation interfaces are required to explore the multiple microbial genome data now available, especially those obtained by high-throughput sequencing - a.k.a. "Next-Generation Sequencing" (NGS) - technologies; they would also be useful for "standard" annotated genomes whose chromosome organizations may be compared. Although various software systems are available, few offer an optimal combination of feature-rich capabilities, non-static user interfaces and multi-genome data handling. RESULTS: We developed SynTView, a comparative and interactive viewer for microbial genomes, designed to run as either a web-based tool (Flash technology) or a desktop application (AIR environment). The basis of the program is a generic genome browser with sub-maps holding information about genomic objects (annotations). The software is characterised by the presentation of syntenic organisations of microbial genomes and the visualisation of polymorphism data (typically Single Nucleotide Polymorphisms - SNPs) along these genomes; these features are accessible to the user in an integrated way. A variety of specialised views are available and are all dynamically inter connected (including linear and circular multi-genome representations, dot plots, phylogenetic profiles, SNP density maps, and more). SynTView is not linked to any particular database, allowing the user to plug his own data into the system seamlessly, and use external web services for added functionalities. SynTView has now been used in several genome sequencing projects to help biologists make sense out of huge data sets. CONCLUSIONS: The most important assets of SynTView are: (i) the interactivity due to the Flash technology; (ii) the capabilities for dynamic interaction between many specialised views; and (iii) the flexibility allowing various user data sets to be integrated. It can thus be used to investigate massive amounts of information efficiently at the chromosome level. This innovative approach to data exploration could not be achieved with most existing genome browsers, which are more static and/or do not offer multiple views of multiple genomes. Documentation, tutorials and demonstration sites are available at the URL: http://genopole.pasteur.fr/SynTView. PMID- 24053738 TI - Effects of counterion and solvent on proton location and proton transfer dynamics of N-H...N hydrogen bond of monoprotonated 1,8-bis(dimethylamino)naphthalene. AB - The proton location and proton transfer (PT) dynamics of a hydrogen bond are under the influence of the static and dynamical properties of the solvent and counterions. In the present study, the N-H distances were determined for salts of 1,8-bis(dimethylamino)naphthalene, DMANH(+)X(-) (X(-) = BPh4(-), ClO4(-), and Cl( )), in acetonitrile (AN) solution, and DMANH(+)Br(-) in water by observing the (15)N spin-lattice relaxation caused by the (15)N-(1)H magnetic dipolar coupling under assumption that the PT time was shorter than the NH reorientation time (~10(-11) s). The obtained N-H distances decreased in the following order: DMANH(+)BPh4(-) > DMANH(+)ClO4(-) > DMANH(+)Br(-)/H2O > DMANH(+)Cl(-), indicating that interactions with the environment affect the PT potentials. To understand the results at the molecular level, Car-Parrinello molecular dynamics simulations were performed for DMANH(+), DMANH(+) in water, and DMANH(+)-Cl(-) ion-pair in AN. The results of simulation suggest that (1) the N-H distance decreases in the presence of a solvent and counterion; (2) the PT time is probably ~10(-12) s, which confirms the above assumption used for the NMR relaxation data analyses; and (3) fluctuation of the interactions with the solvent or counterion has a significant role in PT. Quantum nuclear effects on the hydrogen bond were also examined. PMID- 24053739 TI - Cannabinoid receptor 1 also plays a role in healthy bladder. PMID- 24053740 TI - The definitions and staging systems of acute kidney injury and their limitations in practice. AB - INTRODUCTION: It is now evident that even minimal reductions in glomerular filtration rate (GFR) are associated with a dramatic increase in mortality. The term acute kidney injury (AKI) describes an acute fall of estimated GFR (eGFR) and allows patient stratification based on AKI severity. REVIEW: The Risk, Injury, Failure, Loss and End-stage kidney disease (RIFLE) system defines AKI by a change in serum creatinine (SCr) level or eGFR from a baseline value, and urine output per kilogram of body weight over a specified time period. The Acute Kidney Injury Network (AKIN) definition was based on the RIFLE system but added an absolute change in SCr of >= 0.3 mg/dL, omitted eGFR criteria and included a time constraint of 48 hours. The AKIN system also omitted the stages "Loss" and "End stage" and allocated patients who needed acute dialysis to stage-3. The most recent Kidney Disease Improving Global Outcomes (KDIGO) guidelines retained the AKIN staging criteria but allowed a time frame of seven days for a 50% increase in SCr. The KDIGO criteria do not rely on changes in GFR for staging except in children under the age of 18 years. AKI misclassification may result from the lack of a uniform approach to estimate baseline SCr and the changes in SCr concentrations resulting from acute severe illness and altered fluid balance. In addition, exact data on urine output are not always available resulting in underutilization of the urine output criteria. CONCLUSION: The existing definitions of AKI rely on imperfect markers of renal function rather than direct measures of kidney damage, but remain an important diagnostic and prognostic tool. PMID- 24053741 TI - Dense deposit disease: a 29-years electron microscopy experience. AB - INTRODUCTION: Dense Deposit Disease (DDD) is a devastating renal disease that leads to renal failure within 10 years of diagnosis in about half of affected patients. In this study, we evaluated the relative prevalence and pathological features of DDD diagnosed at our center over a 29 years period. METHODS: We reviewed the clinical and pathological features of all cases of DDD diagnosed at the Electron Microscopy Unit of Ain Shams University (ASUSH) between January 1983 and December 2011. RESULTS: From a total of 3283 renal biopsies, 33 (1%) were diagnosed with DDD (10 children and 23 adults). Nephrotic syndrome was the predominant clinical presentation of DDD (51.5%), and was commoner in children than adults (80% vs. 43%, p=0.03). Capillary wall thickening was seen in all cases (100%). Crescents were more commonly seen in children than adults (70% vs. 21.7%, p=0.008) while interstitial fibrosis was more commonly seen in adults (78.3% vs. 40%, p=0.03). The commonest histological pattern seen under light microscopy was membranoproliferative (27.3%), followed by crescentic (21.2%), membranous (21.2%), diffuse proliferative (18.2%), lobular (6.1%) and mesangial proliferative (6.1%) patterns. Immunohistochemistry was available for 25 cases and showed intense linear staining for C3 along capillary walls. Electron microscopic examination revealed glomerular basement membrane (GBM) thickening and intra-membranous and tubular basement membrane deposits in all cases (100%). CONCLUSION: DDD is a rare disease in Egypt, found in only 1% of renal biopsies. Pathological features of the disease differ between adults and children; children have predominantly glomerular damage whereas tubuleinterstitial lesions are more often encountered in adults. PMID- 24053742 TI - The spectrum of glomerular diseases as studied by immunofluorescence microscopy a single center study in Iraq. AB - INTRODUCTION: Immunofluorescence (IF) microscopy is an important tool for the diagnosis of glomerular diseases. In this study, we focused on using IF technique together with light microscopy (LM) and clinical features in the diagnosis of different types of glomerulonephritis (GN). We aimed to evaluate the spectrum of glomerular diseases in our center and compare it with other centers in Iraq as well as in other countries. METHODS: We studied a total of 58 kidney biopsies taken between June 2010 and June 2012. All biopsies were examined by LM and 56 of them were examined by IF technique. Clinical information was recorded in a predesigned form before taking the biopsy. RESULTS: Nephrotic syndrome was the predominant clinical presentation in this study (75.9%). Focal segmental glomerulosclerosis (FSGS) was the commonest GN in this study (29.3%) followed by minimal change disease (20.7%) and membranous glomerulonephritis (13.8%). Immune deposition was observed in 37.5% of cases and the predominant deposit was immunoglobulin G (IgG). In all cases but one, deposition was granular and was found in the glomerular basement membrane (GBM) and/ or in the mesangium. In one case, IF showed dominant positive staining (3+) for complement factor 1q (C1q) in the glomerular mesangium and slightly positive staining for complement factor 3 (C3) in the same mesangeal areas. Two cases (3.4%) fulfilled the clinical, serological and histopathological criteria of lupus nephritis (LN). CONCLUSION: Nephrotic syndrome was the predominant clinical presentation and FSGS was the most commonly diagnosed GN in this study. Using IF technique and correlating it with LM, clinical, biochemical and serological markers was very useful for the correct diagnosis of glomerular diseases. PMID- 24053743 TI - Depression in Iraqi hemodialysis patients. AB - INTRODUCTION: Affective disorders, particularly depression, are the commonest and probably the most important psychopathological complication of end stage renal disease (ESRD). Depression has the potential to alter adversely the medical outcome of ESRD patients and the psychological stress can affect patient's adherence to medication regimen. In Iraq as well as many other Arab countries, the true prevalence of depression among ESRD patients is unknown. The objective of this study was to determine the prevalence of depression among a cohort of Iraqi hemodialysis (HD) patients and relate it to their socio-demographic characteristics. METHODS: We recruited patients from two HD centers in Baghdad, excluding patients with history of depression or other psychiatric disorders prior to the initiation of HD. The Arabic version of diagnostic and statistical manual of mental disorders fourth edition (DSM-IV) was used to diagnose depression. Beck's Depression Inventory was used to grade its severity. Clinical and laboratory data of the study group were documented and related to the diagnosis of depression. RESULTS: Seventy-five Iraqi patients on maintenance HD were included in the study. Patients' duration on HD ranged from six months to five years. The prevalence of depression among this cohort of HD patients was 80%. The prevalence of severe, moderate and mild depression was 25%, 50% and 25% respectively. The mean depression score was 17.1. Female gender, unemployment, and marital status had statistically significant associations with depression. CONCLUSION: Depression is common in this group of Iraqi HD patients and its prevalence is comparable to the results of similar studies in other societies. PMID- 24053744 TI - Acupuncture efficacy in the treatment of persistent primary nocturnal enuresis. AB - INTRODUCTION: This study aimed to assess the therapeutic efficacy of traditional Chinese acupuncture in the treatment of persistent primary nocturnal enuresis (PNE). METHODS: Fifty children and adolescents suffering from persistent PNE were recruited from the Pediatrics and Urology Outpatient Clinic of Zagazig University Hospital during the year 2010. They included 31 boys and 19 girls, with a mean age of 116 +/- years (range 9-17 years). The children and their parents underwent thorough counseling followed by two courses of treatment, each course administered over 10 consecutive days. Patients were instructed to continue regular follow-up, every three months, after starting the therapy. The response rate (cure, improvement, or failure) was monitored by recording dry nights and the number of spontaneous arousals to void per week on a calendar. Children who showed partial or no response after six months of observation received another two courses of acupuncture therapy, and were followed up for a further six months period. RESULTS: After the initial two courses of treatment, the cure rate at six months was 76% with an additional 18% achieving partial improvement. Twelve children needed another two courses of treatment. After one year of follow-up, 92% of patients showed complete cure and 8% showed failure of acupuncture therapy. CONCLUSION: Acupuncture treatment in patients with PNE appears effective in increasing the percentage of dry nights, with stable results even after the end of treatment courses. Further controlled studies are needed to confirm these results and to elucidate the therapeutic mechanism of acupuncture. KEYWORDS: Acupuncture Therapy; Nocturnal Enuresis; Traditional Medicine. PMID- 24053745 TI - Acute tubulo-interstitial nephritis with positive anti-neutrophil cytoplasmic antibodies. AB - INTRODUCTION: Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis involving the kidney usually comprises pauci-immune, necrotizing glomerulonephritis with crescents. Mononuclear tubulo-interstitial infiltrates are common in ANCA associated vasculitis, but these have usually been described in conjunction with glomerulitis. Acute tubulo-interstitial nephritis (ATIN) is a common cause of acute kidney injury that is most frequently induced by drugs or infections. Idiopathic ATIN has rarely been reported in association with the presence of a positive ANCA. These two entities seem to share a common immunological basis. CASE REPORT: We report a 75 years-old male patient who presented with acute kidney injury and his serum tested positive for p-ANCA by indirect immunofluoresence with a titer of 1/320. Testing by ELISA demonstrated anti-myeloperoxidase (MPO) specificity with a level of 28.8 IU/mL. His kidney biopsy showed features of ATIN with no glomerular involvement. Treatment with corticosteroids led to improvement of his kidney function and serology for ANCA became negative. In this case report ATIN seems to be associated with ANCA positivity, in the absence of other obvious causes for the acute tubulo interstitial insult. CONCLUSION: ATIN can be associated with positive ANCA without features of renal-limited vasculitis or systemic vasculitis. This can occur in the absence of drug exposure. The outcome in our case was favorable with corticosteroid therapy. PMID- 24053746 TI - Idiopathic membranous nephropathy preceding the onset of rheumatoid arthritis: a case report. AB - INTRODUCTION: Membranous nephropathy (MN) in the context of rheumatoid arthritis (RA), is often an iatrogenic complication due to the nephrotoxic effects of antirheumatic drugs. Rare cases of non-iatrogenic association between these two diseases were reported in the literature. CASE REPORT: A 30-year-old female patient presented in September 2005 with nephrotic syndrome. Renal biopsy showed features consistent with MN. Search for etiology was negative, particularly lupus serology which remained negative throughout the course of her illness. Accordingly, she was diagnosed as a case of idiopathic MN. Initially, she was treated with angiotensin converting enzyme inhibitors and angiotensin receptor blockers which maintained her protein excretion below nephrotic range for two years. Her nephrotic syndrome then relapsed and was treated with steroids and chlorambucil, according to the Ponticelli protocol. A few months later, she presented with early morning joint stiffness, polyarthritis involving the small joints of the hands, and strongly positive rheumatoid factor, fulfilling the diagnostic criteria of rheumatoid arthritis (RA). Her serum creatinine remained normal and a second renal biopsy revealed the same features of MN. Her RA was treated with pulsed methylprednisolone followed by oral steroids and methotrexate resulting in remission of the joints disease and the nephrotic syndrome. Remission was maintained for the last two years up to the time of this report. CONCLUSION: We hereby report a case of secondary membranous nephropathy that preceded the onset of rheumatoid arthritis by three years. PMID- 24053747 TI - Nephrogenic diabetes insipidus with intracranial calcification in a child with thalassemia minor. AB - INTRODUCTION: There are numerous causes for intracranial calcification in children. We describe an unusual cause of intracranial calcification in a child, namely, nephrogenic diabetes insipidus (NDI). CASE REPORT: A 12-year-old boy presented with seizures and developmental delay. MRI of the brain revealed intracranial calcification. Evaluation showed findings suggestive of NDI. The lack of evidence of any other metabolic defect suggests that these calcifications were secondary to NDI. He also had anemia for which he was investigated and diagnosed as thalassemia minor. Detailed literature review failed to reveal any reported association between NDI and thalassemia minor. CONCLUSION: We report this case to emphasize the importance of early diagnosis and treatment of NDI to prevent organic brain damage. PMID- 24053748 TI - Prevalence of non-communicable diseases and its awareness among inhabitants of Sokoto metropolis: outcome of a screening program for hypertension, obesity, diabetes mellitus and overt proteinuria. AB - INTRODUCTION: Developing countries confront double jeopardy of prevalent infectious disease and increasing Non-Communicable Diseases (NCD) with imminent projected epidemic proportions. Nigeria has witnessed tremendous socio-economic changes and rural to urban migration culminating in emergence of NCD. The impact of these diseases on the lives of people is enormous when measured in terms of outcomes. We initiated a screening program among inhabitants of Sokoto metropolis in an attempt to unravel the prevalence and pattern of NCD. METHODS: This is a descriptive cross sectional study involving 535 participants who were randomlyselected during World Kidney Day Screening in Sokoto. Health promotion talk was organized for the participants before commencing the screening. We took anthropometric measurements and calculated body mass index (BMI) and waist/hip ratio for all individuals. We also checked blood pressure and blood glucose levels and performed urinalysis for all participants. RESULTS: There were 535 participants including 332 males and 203 females with a mean age of 37 +/- 17 years. Overweight, obesity and morbid obesity were found in 12.3%, 6.7% and 0.9% of participants respectively. About 11% had waist/hip ratio greater than 1. The prevalence of pre-hypertension and hypertension was 8.5% and 30.2% respectively. Elevated random blood glucose levels were found in 6% of participants while 17.9% had at least 1+ of proteinuria in urinalysis. CONCLUSION: Non-communicable diseases are common in our environment and the level of awareness is low. Regular health education and screening programs are necessary in order to reduce the menace. PMID- 24053749 TI - A preliminary survey of un-diagnosed hypertension among Nubians and Coptics in Atbara and Eldamer Cities, Sudan: does ethnicity affect prevalence? AB - INTRODUCTION: Hypertension is a non-communicable disease of increasing importance in developing countries. Due to its silent nature and serious complications, active screening is essential in case detection. The aim of this study was to determine the prevalence of undiagnosed hypertension and to find out whether there are ethnic variations in prevalence between two Sudanese ethnicities. METHODS: This is a cross-sectional community-based study in which 100 subjects from Nuba tribe and 70 Coptics not previously known to have hypertension volunteered to participate. Blood pressure was measured and a questionnaire delineating demographic, clinical and social data was obtained from each participant. RESULTS: Female to male ratio was 2:1. The mean age was 39.5 +/- 8 years for Nubians and 40.5 +/- 5.5 years for Coptics. High blood pressure was detected in 48% of Nubians and 24.3% of Coptics (p>0.001). The prevalence of stage II hypertension was higher in Nubians compared to Coptics (25% vs. 3.8%; p<0.001). Besides the ethnic variation, other significant differences between the two groups were illiteracy and alcohol consumption, both of which were significantly commoner among Nubians. CONCLUSION: Undiagnosed high blood pressure is common in our local community, with some variations in prevalence and severity among different ethnic groups. Key words: Coptics; Nubians; River Nile State; Sudan; Undiagnosed hypertension. PMID- 24053750 TI - Omani propolis: chemical profiling, antibacterial activity and new propolis plant sources. AB - BACKGROUND: Propolis (bee glue) is a resinous honeybee product having a long history of application in many countries as a traditional remedy for treating wounds, burns, soar throat, stomach disorders, etc. It has been proved to possess beneficial biological effects, including antimicrobial, antioxidant, anti inflammatory, cytotoxic, antiulcer, and many others. Bees gather propolis from diverse resinous plant parts and in different phytogeographic regions its chemical composition might vary significantly. In this article we report the results of the first study on the chemical profiles of propolis from Oman, its plant origin and antibacterial activity. RESULTS: The chemical profiles of Omani propolis extracts were obtained by GC-MS analysis after silylation. Over 50 individual compounds were identified in the samples, belonging to different compound types: sugars, polyols, hydroxy acids, fatty acids, cardanols and cardols, anacardic acids, flavan derivatives, triterpenes, prenylated flavanones and chalcones. The profiles were dissimilar from other known propolis types. They demonstrate that although Oman is not a large country, the plant sources of propolis vary significantly, even in the same apiary and the same season. Based on chemical profiles, and isolation and identification of major marker compounds (new propolis constituents), new plant sources of propolis were found: Azadiracta indica (neem tree) and Acacia spp. (most probably A. nilotica). The ethanol extracts of the studied propolis samples demonstrated activity against S. aureus (MIC < 100 MUg. mL-1) and E. coli (MIC < 380 MUg. mL-1). CONCLUSION: Omani propolis is different form the known propolis types and demonstrates significant chemical diversity. Its most important plant source is the resin of Azadirachta indica, and as a result its typical components are S5-prenyl flavanones. Other plant sources have been identified, too, playing some role in resin collection by bees in Oman: Acacia spp. (most probably A. nilotica) and Mangifera indica. The results demonstrate also the potential of Omani propolis as antimicrobial. PMID- 24053754 TI - The Stanford Institute for Chemical Biology. PMID- 24053755 TI - Structure and electrochemical performance of nitrogen-doped carbon film formed by electron cyclotron resonance sputtering. AB - A nitrogen-doped nanocarbon film electrode with mixed sp(2) and sp(3) bonds formed using the electron cyclotron resonance (ECR) sputtering method was studied with respect to the relationship between nitrogen concentration and electrochemical performance. The film (N-ECR) has a nanocrystalline structure, and the sp(3) content increases with increasing nitrogen concentration unlike the recently reported nitrogen-containing tetrahedral amorphous carbon film.1 The film has a very smooth surface with an average roughness of 0.1 to 0.2 nm, which is almost independent of nitrogen concentration. In contrast, the ratio of nitrogen-containing graphite-like bonding is high at low nitrogen concentrations, and then pyridine-like bonding increases as the nitrogen concentration increases. These variations in the chemical structures and the sp(2) and sp(3) content greatly change the electrochemical performance. The N-ECR electrode shows a wider potential window (~3.8 V) than a pure nanocarbon electrode (~3.1 V) due to its higher sp(3) content. The N-ECR electrode (N = 9.0 at. %) shows improved electrochemical activity because the lowest peak separation of Fe(CN)6(3-/4-) was observed at this nitrogen concentration. The oxygen and hydrogen peroxide (H2O2) reduction potentials at the N-ECR electrode shifted about 0.3 and 0.15 V, respectively, and the peak height of H2O2 is greatly increased. As a result, a linear relationship was obtained from 0.2 to 17 mM for the reductive current detection of H2O2. The N-ECR electrode also shows better activity for oxidizing certain biomolecules. The oxidation potentials of guanosine and adenosine decreased about 0.1 V, suggesting that the N-ECR electrode is suitable for use as a biosensing platform. PMID- 24053756 TI - Determining who responds better to a computer- vs. human-delivered physical activity intervention: results from the community health advice by telephone (CHAT) trial. AB - BACKGROUND: Little research has explored who responds better to an automated vs. human advisor for health behaviors in general, and for physical activity (PA) promotion in particular. The purpose of this study was to explore baseline factors (i.e., demographics, motivation, interpersonal style, and external resources) that moderate intervention efficacy delivered by either a human or automated advisor. METHODS: Data were from the CHAT Trial, a 12-month randomized controlled trial to increase PA among underactive older adults (full trial N = 218) via a human advisor or automated interactive voice response advisor. Trial results indicated significant increases in PA in both interventions by 12 months that were maintained at 18-months. Regression was used to explore moderation of the two interventions. RESULTS: Results indicated amotivation (i.e., lack of intent in PA) moderated 12-month PA (d = 0.55, p < 0.01) and private self consciousness (i.e., tendency to attune to one's own inner thoughts and emotions) moderated 18-month PA (d = 0.34, p < 0.05) but a variety of other factors (e.g., demographics) did not (p > 0.12). CONCLUSIONS: Results provide preliminary evidence for generating hypotheses about pathways for supporting later clinical decision-making with regard to the use of either human- vs. computer-delivered interventions for PA promotion. PMID- 24053757 TI - Health care savings with the patient-centered medical home: Community Care of North Carolina's experience. AB - This study evaluated the financial impact of integrating a systemic care management intervention program (Community Care of North Carolina) with person centered medical homes throughout North Carolina for non-elderly Medicaid recipients with disabilities during almost 5 years of program history. It examined Medicaid claims for 169,676 non-elderly Medicaid recipients with disabilities from January 2007 through third quarter 2011. Two models were used to estimate the program's impact on cost, within each year. The first employed a mixed model comparing member experiences in enrolled versus unenrolled months, accounting for regional differences as fixed effects and within physician group experience as random effects. The second was a pre-post, intervention/comparison group, difference-in-differences mixed model, which directly matched cohort samples of enrolled and unenrolled members on strata of preenrollment pharmacy use, race, age, year, months in pre-post periods, health status, and behavioral health history. The study team found significant cost avoidance associated with program enrollment for the non-elderly disabled population after the first years, savings that increased with length of time in the program. The impact of the program was greater in persons with multiple chronic disease conditions. By providing targeted care management interventions, aligned with person-centered medical homes, the Community Care of North Carolina program achieved significant savings for a high-risk population in the North Carolina Medicaid program. PMID- 24053758 TI - Wellbeing-enhancing occupation and organizational and environmental contributors in long-term dementia care facilities: an explorative study. AB - BACKGROUND: Occupation remains an unmet need in long-term dementia care. To increase residents' occupation, knowledge of types of occupation related to wellbeing, and organizational and environmental characteristics encouraging involvement in these types of occupation, is indispensable. METHODS: In this explorative study, Dementia Care Mapping was used to study involvement in different types of occupation and wellbeing among 57 residents of 10 dementia care facilities. For each type of occupation, mean experienced wellbeing was studied. Occupation types with high mean wellbeing scores were classified as "wellbeing-enhancing occupation." Care facilities were ranked according to the mean time residents spent in types of wellbeing-enhancing occupation. Using information on staff-to-resident ratio, individual space, and items of the Physical Environment Evaluation Component of Dementia Care Mapping, organizational and environmental characteristics of the facilities were compared to study their relationship with wellbeing-enhancing occupation. RESULTS: Reminiscence, leisure, expression, and vocational occupation had greatest potential to enhance wellbeing, but these types were seldom offered. Much variation existed in the extent to which wellbeing-enhancing occupation was provided. Long-term care facilities that did so more frequently generally had a more homelike atmosphere, supported social interaction through the environment, and had no central activity program. CONCLUSIONS: This study suggests that it is possible to engage residents in wellbeing-enhancing occupation, within current means of budget and staff. The physical environment and care organization might play a role, but the key factor seems to equip staff with skills to integrate wellbeing-enhancing occupation into care practice. PMID- 24053759 TI - Disseminated intravascular coagulation following malaria due to Plasmodium vivax: a thromboelastography-based study. AB - BACKGROUND: Disseminated intravascular coagulation (DIC) due to Plasmodium vivax is scarcely reported in comparison to Plasmodium falciparum. In complicated malaria, thrombocytopaenia and haemostatic alterations lead to increased activation of coagulation cascade and fibrinolytic system. Thromboelastography (TEG) is a haemostasis system which measures the viscoelastic strength of blood clot in the coagulation pathway. It detects the initial derangement in clotting cascade involving in platelet interaction and fibrinolysis. Hence, it can document the early changes in coagulation in vitro, and thereby guide the management. The current study was aimed at detection of DIC in patients with P. vivax malaria based on TEG. METHODS: Ethylene diamine tetraacetic acid (EDTA) blood samples from acute febrile patients were tested by microscopy and immunochromatographic test for malaria. A total of 31 confirmed cases of vivax malaria were enrolled for this study. All the samples were tested by thromboelastography and conventional tests parameters for detection of any coagulation derangement. RESULTS: Of 31, 17 (55%) were classified as complicated and 14/31 (45%) were uncomplicated. Among 23 cases with thrombocytopaenia, non overt (early stage) DIC was detected in 18 cases by TEG and 17 cases by the conventional methods. CONCLUSION: It seems that the burden of DIC in vivax malaria is much higher than the world literature reported. TEG can be utilized as an important tool for early detection of DIC and guiding the management in malaria patients. PMID- 24053761 TI - Equilibrium thickness of large liquid lenses spreading over another liquid surface. AB - This article discusses the equilibrium states and more particularly the equilibrium thickness of large lenses of a liquid spread over the surface of a denser liquid. Both liquids are supposed to be nonvolatile and immiscible. Taking into account the effect of intermolecular forces in addition to the sign of the spreading parameters leads to four possible states. The three first are similar to the states of equilibrium of a liquid spread on a solid surface: total wetting where the floating liquid spreads until it reaches an equilibrium thickness on the order of the molecular size, partial wetting where the floating liquid forms a lens of macroscopic thickness in equilibrium with a "dry" bath, and pseudopartial wetting where the floating liquid spreads as a lens of macroscopic thickness in equilibrium with a thin film covering the bath. The last regime, called pseudototal wetting, consists of a macroscopic lens of the floating liquid covered with a thin film of the bath. These four regimes are described through a free-energy minimization, and their equilibrium thicknesses are predicted. A comparison of this model with experimental results available in the literature and dedicated experiments for the pseudototal wetting state are reported. PMID- 24053760 TI - Protocol for diagnostic test accuracy study: the efficacy of screening for common dental diseases by dental care professionals. AB - BACKGROUND: The bulk of service delivery in dentistry is delivered by general dental practitioners, when a large proportion of patients who attend regularly are asymptomatic and do not require treatment. This represents a substantial and unnecessary cost, given that it is possible to delegate a range of tasks to dental care professionals, who are a less expensive resource. Screening for the common dental diseases by dental care professionals has the potential to release general dental practitioner's time and increase the capacity to care for those who don't currently access services. The aim of this study is to compare the diagnostic test accuracy of dental care professionals when screening for dental caries and periodontal disease in asymptomatic adults aged eighteen years of age. METHODS/DESIGN: Ten dental practices across the North-West of England will take part in a diagnostic test accuracy study with 200 consecutive patients in each practice. The dental care professionals will act as the index test and the general dental practitioner will act as the reference test. Consenting asymptomatic patients will enter the study and see either the dental care professionals or general dental practitioner first to remove order effects. Both sets of clinicians will make an assessment of dental caries and periodontal disease and enter their decisions on a record sheet for each participant. The primary outcome measure is the diagnostic test accuracy of the dental care professionals and sensitivity, specificity, positive predictive value and negative predictive values will be reported. A number of clinical factors will be assessed for confounding. DISCUSSION: The results of this study will determine whether dental care professionals can screen for the two most prevalent oral diseases. This will inform the literature and is apposite given the recent policy change in the United Kingdom towards direct access. PMID- 24053762 TI - Carbon emissions of infrastructure development. AB - Identifying strategies for reconciling human development and climate change mitigation requires an adequate understanding of how infrastructures contribute to well-being and greenhouse gas emissions. While direct emissions from infrastructure use are well-known, information about indirect emissions from their construction is highly fragmented. Here, we estimated the carbon footprint of the existing global infrastructure stock in 2008, assuming current technologies, to be 122 (-20/+15) Gt CO2. The average per-capita carbon footprint of infrastructures in industrialized countries (53 (+/- 6) t CO2) was approximately 5 times larger that that of developing countries (10 (+/- 1) t CO2). A globalization of Western infrastructure stocks using current technologies would cause approximately 350 Gt CO2 from materials production, which corresponds to about 35-60% of the remaining carbon budget available until 2050 if the average temperature increase is to be limited to 2 degrees C, and could thus compromise the 2 degrees C target. A promising but poorly explored mitigation option is to build new settlements using less emissions-intensive materials, for example by urban design; however, this strategy is constrained by a lack of bottom-up data on material stocks in infrastructures. Infrastructure development must be considered in post-Kyoto climate change agreements if developing countries are to participate on a fair basis. PMID- 24053763 TI - Prognostic implication of neuropilin-1 upregulation in human nasopharyngeal carcinoma. AB - OBJECTIVE: As a receptor for both vascular endothelial growth factors and semaphorin, neuropilin-1 (NRP-1) is reported to be up-regulated in cells of several cancers. However, its roles in human nasopharyngeal carcinoma (NPC) are still unclear. Therefore, the goal of this study was to investigate the expression pattern of NRP-1 in NPC tissues, to clarify the clinical significance of NRP-1 expression in NPC as well as the potential prognostic implication of NRP 1 expression. METHODS: Immunohistochemistry was performed to detect the expression of NRP-1 in tumor tissue samples from 266 NPC patients. The association of NRP-1 protein expression with the clinicopathological characteristics and the prognosis of NPC were subsequently assessed. RESULTS: Immunohistochemical analysis showed that 176 of 266 (66.17%) paraffin-embedded archival NPC biopsies showed high expression of NRP-1, but no non-cancerous nasopharyngeal specimens showed positive expression of NRP-1. In addition, high NRP-1 expression was significantly associated with advanced clinical stage (P = 0.02), positive recurrence (P = 0.001) and metastasis status (P = 0.001) of NPC. Moreover, the NPC patients with higher NRP-1 expression had shorter overall survival, whereas patients with lower NRP-1 expression had better survival (P < 0.001). Furthermore, the multivariate analysis indicated that the overexpression of NRP-1 protein was an independent prognostic factor for overall survival (P = 0.001) in NPC patients. CONCLUSION: These findings suggest for the first time that NRP-1 upregulation may be a novel biomarker for the prediction of advanced tumor progression and unfavorable prognosis in NPC patients who may benefit from alternative treatment strategy and targeted treatment. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1507827881105018. PMID- 24053764 TI - Efficient chromium(II)-catalyzed cross-coupling reactions between Csp2 centers. AB - Low-toxicity chromium(II) chloride catalyzes at 25 degrees C within minutes the coupling reactions of various (hetero)arylmagnesium reagents with N-heterocyclic halides, aromatic halogenated ketones or imines, and alkenyl iodides. Remarkably, much lower amounts of homo-coupling side products are obtained compared to related iron, cobalt, or manganese cross-couplings. PMID- 24053765 TI - Prospective memory across the lifespan: investigating the contribution of retrospective and prospective processes. AB - Prospective memory performance follows an inverted U-shaped function across the lifespan. Findings on the relative contribution of purely prospective memory and retrospective memory processes within prospective memory to this trajectory are scarce and inconclusive. We analyzed age-related differences in prospective memory performance across the lifespan in a cross-sectional design including six age groups (N = 99, 7-83 years) and investigated possible mechanisms by experimentally disentangling the relative contributions of retrospective memory and purely prospective memory processes. Results confirmed the inverted U-shaped function of prospective memory performance across the lifespan. A significant interaction between process type and age group was observed indicating differential relative contributions of retrospective memory and purely prospective memory processes on the development of prospective memory performance. Our results showed that mainly the pure prospective memory processes within prospective memory lead to lower prospective memory performance in young children and old adults. Moreover, the relative contributions of the retrospective memory and purely prospective memory processes are not uniform at both ends of the lifespan, i.e., in later adulthood the purely prospective memory processes seem to determine performance to an even greater extent than in childhood. Nevertheless, age effects were also observed in the retrospective component which thus contributed to the prospective memory performance differences between the age groups. PMID- 24053766 TI - Prospective analysis of penile length changes after radical prostatectomy. AB - OBJECTIVES: To assess the impact of radical prostatectomy (RP) on penile dimensions. To assess the impact of phosphodiesterase-5 inhibitor (PDE5i) use on penile length changes. PATIENTS AND METHODS: Men undergoing RP were enrolled in this prospective study before surgery. Demographic, clinical and PDE5i frequency of-use data were collected. Erectile function was measured using the erectile function domain (EFD) of the International Index of Erectile Function. A single evaluator measured stretched flaccid penile length (SFPL) before RP, and at 2 and 6 months after RP. Repeated measures analysis was used to test differences in SFPL between timepoints. Pearson correlation was used for univariate analyses and multiple regression was used for multivariable analysis. RESULTS: A total of 118 patients were evaluated at baseline, with 76 and 63 patients evaluated at 2 and 6 months, respectively. At 2 months, there was a 2.4-mm mean decrease in SFPL, while at 6 months there was no significant difference. At 6 months, those subjects who took a daily PDE5i had no SFPL loss (n = 36, 1+/-6.7 mm gain, P = 0.37 compared with baseline), while those subjects who did not consistently take a PDE5i had SFPL loss (n = 27, 4.4+/-6.6 mm loss, P < 0.002 compared with baseline). In multivariable analysis, PDE5i use at 6 months and 6-month EFD score without on-demand PDE5i were significant predictors of 6-month SFPL loss, suggesting that an increase in these variables leads to SFPL preservation. CONCLUSIONS: In this rigorously conducted prospective study of SFPL changes after RP, there was evidence of SFPL loss at 2 months, but not at 6 months after RP. PDE5i use moderated SFPL loss, with patients who regularly used PDE5i having no loss in SFPL. PMID- 24053767 TI - Paucity of evidence for urinary tract outcomes in closed spinal dysraphism: a systematic review. AB - OBJECTIVES: To describe the long-term upper (UUT) and lower urinary tract (LUT) outcomes in patients with closed spinal dysraphism (CSD). CSD differs from open spinal dysraphism (OSD) by its long asymptomatic course and consequent later diagnosis. The outcome of UUT and LUT function in adults with CSD is relatively unknown. PATIENTS AND METHODS: A systematic review was performed following the standards of the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. An extensive search was made of PubMed and EMBASE. Included were papers on adults with any form of primary CSD that described bladder and/or kidney function. Only English and Dutch language papers were included. Excluded were papers on patients aged <18 years and patients with secondary tethered cord following childhood OSD repair. International Continence Society terminology was used to describe LUT outcomes. RESULTS: Eventually, only seven studies (90 patients) were included and none of these described renal outcomes. Five of the seven papers were on outcomes after untethering surgery during adulthood. Urological complaints were present in 54/79 (68.4%) patients. Urodynamic studies (48 patients available) revealed detrusor underactivity in 46.5% of the evaluated cases, detrusor overactivity in 32.6% and normal findings in 16.3% of the studied patients. Symptomatic improvement after surgery for tethered cord occurred in 33.3-90.0%, depending on the subgroup studied. Urodynamic improvement rates ranged from 11.1% to 54.5% (but based on three studies with only 24 patients). Success of surgery depended on the time between onset of symptoms and operation, and (sometimes) type of lesion. CONCLUSIONS: Few data are available on long-term urological outcomes in adult patients with CSD. More extensive research on follow-up, including the functional status of the UUT, is recommended. Based upon the little evidence available, we think life-long follow-up (from birth into adulthood) of those with CSD and neurogenic bladder is advisable. PMID- 24053768 TI - 3' terminal diversity of MRP RNA and other human noncoding RNAs revealed by deep sequencing. AB - BACKGROUND: Post-transcriptional 3' end processing is a key component of RNA regulation. The abundant and essential RNA subunit of RNase MRP has been proposed to function in three distinct cellular compartments and therefore may utilize this mode of regulation. Here we employ 3' RACE coupled with high-throughput sequencing to characterize the 3' terminal sequences of human MRP RNA and other noncoding RNAs that form RNP complexes. RESULTS: The 3' terminal sequence of MRP RNA from HEK293T cells has a distinctive distribution of genomically encoded termini (including an assortment of U residues) with a portion of these selectively tagged by oligo(A) tails. This profile contrasts with the relatively homogenous 3' terminus of an in vitro transcribed MRP RNA control and the differing 3' terminal profiles of U3 snoRNA, RNase P RNA, and telomerase RNA (hTR). CONCLUSIONS: 3' RACE coupled with deep sequencing provides a valuable framework for the functional characterization of 3' terminal sequences of noncoding RNAs. PMID- 24053769 TI - Radiofrequency ablation (RFA) of renal cell carcinoma (RCC): experience in 200 tumours. AB - OBJECTIVES: To evaluate our clinical experience with percutaneous image-guided radiofrequency ablation (RFA) of 200 renal tumours in a large tertiary referral university institution. PATIENTS AND METHODS: Image-guided RFA (ultrasonography or computed tomography [CT]) of 200 renal tumours in 165 patients from June 2004 to 2012 was prospectively evaluated. Institutional Review Board approval was granted. The treatment response and technical success were defined by absence of contrast enhancement within the tumour on contrast enhanced CT or magnetic resonance imaging. Both major and minor complications, glomerular filtration rate (GFR) before and after RFA, the management and outcomes of the complications, as well as oncological outcome were prospectively documented. Multivariate analysis was used to determine variables associated with major complications and also the percentage GFR change after RFA. The overall (OS), 5-year cancer-specific (CSS), local recurrence-free (LRFS) and metastasis-free survival (MFS) rates are presented using the Kaplan-Meier curves. RESULTS: In all, 200 tumours were RF ablated with a mean (range) tumour size of 2.9 (1-5.6) cm and the mean (range) patient age was 67.7 (21-88.6) years with a mean follow-up period of 46.1 months. The primary technical and overall technical success rate was 95.5% and 98.5%, respectively. Two independent predictors of successful RFA in a single sitting were tumour size (<3 cm) and exophytic location in multivariate logistic regression analysis. Major complications included ureteric injury (six patients), calyceal-cutaneous fistula (one), acute tubular necrosis (one) and abscess (two). Two independent predictors of ureteric injury were central location and lower pole position. Within this cohort of patients, only four patients developed significant renal function deterioration i.e. >25% decreased in GFR. In all, 161 (98%) patients of the 165 patients have preservation of renal function. Any change in renal function after RFA was not influenced by tumour factors or solitary kidney status. In our clinical series, this yielded a 5-year OS, CSS, LRFS and MFS rates of 75.8%, 97.9%, 93.5% and 87.7% respectively. CONCLUSIONS: Image-guided RFA is a safe, nephron sparing and effective treatment for small renal cell carcinoma (RCC) tumours with a low rate of recurrence and has good 5 year CSS and MFS rates. PMID- 24053770 TI - Predictors of loss to follow-up before HIV treatment initiation in Northwest Ethiopia: a case control study. AB - BACKGROUND: In Ethiopia, there is a growing concern about the increasing rates of loss to follow-up (LTFU) in HIV programs among people waiting to start HIV treatment. Unlike other African countries, there is little information about the factors associated with LTFU among pre-antiretroviral treatment (pre-ART) patients in Ethiopia. We conducted a case-control study to investigate factors associated with pre-ART LTFU in Ethiopia. METHODS: Charts of HIV patients newly enrolled in HIV care at Gondar University Hospital (GUH) between September 11, 2008 and May 8, 2011 were reviewed. Patients who were "loss to follow-up" during the pre-ART period were considered to be cases and patients who were "in care" during the pre-ART period were controls. Logistic regression analysis was used to explore factors associated with pre-ART LTFU. RESULTS: In multivariable analyses, the following factors were found to be independently associated with pre-ART LTFU: male gender [Adjusted Odds Ratio (AOR) = 2.00 (95% CI: 1.15, 3.46)], higher baseline CD4 cell count (251-300 cells/MUl [AOR = 2.64 (95% CI: 1.05, 6.65)], 301 350 cells/MUl [AOR = 5.21 (95% CI: 1.94, 13.99)], and >350 cells/MUl [AOR = 12.10 (95% CI: 6.33, 23.12)] compared to CD4 cell count of <= 200 cells/MUl) and less advanced disease stage (WHO stage I [AOR = 2.81 (95% CI: 1.15, 6.91)] compared to WHO stage IV). Married patients [AOR = 0.39 (95% CI: 0.19, 0.79)] had reduced odds of being LTFU. In addition, patients whose next visit date was not documented on their medical chart [AOR = 241.39 (95% CI: 119.90, 485.97)] were more likely to be LTFU. CONCLUSION: Our study identified various factors associated with pre-ART LTFU. The findings highlight the importance of giving considerable attention to pre-ART patients' care from the time that they learn of their positive HIV serostatus. The completeness of the medical records, the standard of record keeping and obstacles to retrieving charts also indicate a serious problem that needs due attention from clinicians and data personnel. PMID- 24053771 TI - EXPRESS study shows significant regional differences in 1-year outcome of extremely preterm infants in Sweden. AB - AIM: The aim of this study was to investigate differences in mortality up to 1 year of age in extremely preterm infants (before 27 weeks) born in seven Swedish healthcare regions. METHODS: National prospective observational study of consecutively born, extremely preterm infants in Sweden 2004-2007. Mortality was compared between regions. Crude and adjusted odds ratios and 95% CI were calculated. RESULTS: Among 844 foetuses alive at mother's admission for delivery, regional differences were identified in perinatal mortality for the total group (22-26 weeks) and in the stillbirth and perinatal and 365-day mortality rates for the subgroup born at 22-24 weeks. Among 707 infants born alive, regional differences were found both in mortality before 12 h and in the 365-day mortality rate for the subgroup (22-24 weeks) and for the total group (22-26 weeks). The mortality rates were consistently lower in two healthcare regions. There were no differences in the 365-day mortality rate for infants alive at 12 h or for infants born at 25 weeks. Neonatal morbidity rates among survivors were not higher in regions with better survival rates. Perinatal practices varied between regions. CONCLUSION: Mortality rates in extremely preterm infants varied considerably between Swedish healthcare regions in the first year after birth, particularly between the most immature infants. PMID- 24053772 TI - Percutaneous nephrolithotomy in England: practice and outcomes described in the Hospital Episode Statistics database. AB - OBJECTIVE: To investigate the postoperative outcomes of percutaneous nephrolithotomy (PCNL) in English National Health Service (NHS) hospitals. PATIENTS AND METHODS: We extracted records from the Hospital Episode Statistics (HES) database for all patients undergoing PCNL between March 2006 and January 2011 in English NHS hospitals. Outcome measures were haemorrhage, infection within the index admission, and rates of emergency readmission and in-hospital mortality within 30 days of surgery. RESULTS: A total of 5750 index PCNL procedures were performed in 165 hospitals. During the index admission, haemorrhage was recorded in 81 patients (1.4%), 192 patients (3.8%) had a urinary tract infection (UTI), 95 patients (1.7%) had fever, and 41 patients (0.7%) had sepsis. There were 595 emergency readmissions in 518 patients (9.0%). Reasons for readmission were varied: 70 (1.2%) with UTI, 15 (0.3%) sepsis, 73 (1.3%) haematuria, 25 (0.4%) haemorrhage, and 25 (0.4%) acute urinary retention. There were 13 (0.2%) in-hospital deaths within 30 days of surgery. CONCLUSIONS: Haemorrhage and infection represent relatively common and potentially severe complications of PCNL. Mortality is extremely rare after PCNL (about one in 400 procedures overall) but almost one in 10 patients have an unplanned hospital readmission within 30 days of surgery. Complications of PCNL may be under reported in the HES database and need to be corroborated using other data sources. PMID- 24053773 TI - Anaphylaxis associated with gadolinium-based contrast agents: data from the Food and Drug Administration's Adverse Event Reporting System and review of case reports in the literature. AB - OBJECTIVES: To summarize reports of anaphylaxis associated with gadolinium-based contrast agents (GBCAs) reported to the Food and Drug Administrations Adverse Event Reporting System (FAERS), examine the safety signals of anaphylaxis from GBCAs, and perform a literature review of relevant case reports. METHODS: FAERS (1/1988-8/2012) was searched using groups of preferred event terms for anaphylaxis combined with all drug names for GBCAs Signal detection involved determination of proportional reporting ratios (PRRs) and empirical Bayes geometric means (EBGM). Published case reports were identified through a Medline search (1/1988-7/2013). RESULTS: There were 614 GBCA FAERS reports of anaphylaxis, resulting in a safety signal (PRR = 6.2, 95% confidence interval (CI) = 5.7 - 6.7; EBGM = 5.1 CI = 5.6 - 6.6). Among GBCAs, 43% were associated with gadopentetate dimeglumine (PRR = 4.9, CI = 4.3 - 5.5; EBGM = 4.8, CI = 4.3 - 5.4), 29% with gadobenate dimeglumine (PRR = 17.5, CI = 15.2 - 20.2; EBGM = 17.1, CI = 14.6 - 19.8) , and 17% with gadoteridol (PRR = 5.7, CI = 4.7 - 6.8; EBGM = 5.6, CI = 4.6 - 56.7). There were 14 anaphylaxis case reports in the literature. CONCLUSIONS: GBCAs used as medical imaging agents, can cause life-threatening or fatal anaphylaxis. There were differences in disproportionality of reporting between between agents. Although differences in numbers of reports of anaphylaxis reflect relative utilization rates of the various agents, disproportionality analyses (PRR, EBGM) disclose significant safety signals of anaphylaxis associated with most GBCAs. PMID- 24053774 TI - Intermediate repeat expansion length in C9orf72 may be pathological in amyotrophic lateral sclerosis. AB - An expanded hexanucleotide repeat in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia. All studies to date state that patients have a pathological expansion if they carry 30 or more repeats. We analysed the frequency of C9orf72 repeat expansions in a population based cohort of patients with ALS, and demonstrate that patients with between 20 and 30 repeats are phenotypically similar to patients with an expanded repeat length above 30 repeats. We propose that an intermediate repeat length may be associated with features of the C9orf72 phenotype in ALS patients. PMID- 24053775 TI - Diagnostic laboratory testing for Charcot Marie Tooth disease (CMT): the spectrum of gene defects in Norwegian patients with CMT and its implications for future genetic test strategies. AB - BACKGROUND: Current genetic test algorithms for Charcot Marie Tooth (CMT) disease are based on family details and comprehensive clinical and neurophysiological data gathered under ideal conditions for clinical assessment. However, in a diagnostic laboratory setting relying on external test requisitions and patient samples, such conditions are not always met. Our objective was therefore to perform a retrospective evaluation of the data given in laboratory request forms and to assess their quality and applicability with regard to the recommended algorithms for CMT diagnostics. As we are the main test centre for CMT in Norway our results also provide an overview of the spectrum of gene defects in the Norwegian CMT population. METHODS: Genetic testing was performed according to polyneuropathy type; demyelinating/mixed: PMP22 duplication, MPZ, EGR2, LITAF, NEFL, PMP22, GJB1, axonal: MFN2, MPZ, NEFL, and GJB1. RESULTS: Diagnostic testing of index patients was requested in 435 of the 549 cases. Seventy-two (16.6%) positive molecular genetic findings were made. The majority (94.6%) of mutation positive cases showed disease onset before 50 years of age. PMP22 (duplication), MPZ, GJB1 and MFN2 mutations constituted 95.8% of the positive findings. Within the nerve conduction study groups, mutation detection rates were; demyelinating 33.8%; mixed 29.0%; axonal 8.8%; unspecified 16.5%. CONCLUSION: We suggest a simplified algorithm intended for referral centres, dealing with DNA/blood samples, which involves the assessment of age at onset and neurophysiological data followed by testing of four genes; PMP22 (duplication), MPZ, GJB1 and MFN2. Patients negative for mutations in those four genes should be subjected to evaluation at an interdisciplinary inherited neuropathy clinic with the capacity for extended molecular genetic analysis by next generation sequencing. PMID- 24053776 TI - Predicting gene regulatory networks of soybean nodulation from RNA-Seq transcriptome data. AB - BACKGROUND: High-throughput RNA sequencing (RNA-Seq) is a revolutionary technique to study the transcriptome of a cell under various conditions at a systems level. Despite the wide application of RNA-Seq techniques to generate experimental data in the last few years, few computational methods are available to analyze this huge amount of transcription data. The computational methods for constructing gene regulatory networks from RNA-Seq expression data of hundreds or even thousands of genes are particularly lacking and urgently needed. RESULTS: We developed an automated bioinformatics method to predict gene regulatory networks from the quantitative expression values of differentially expressed genes based on RNA-Seq transcriptome data of a cell in different stages and conditions, integrating transcriptional, genomic and gene function data. We applied the method to the RNA-Seq transcriptome data generated for soybean root hair cells in three different development stages of nodulation after rhizobium infection. The method predicted a soybean nodulation-related gene regulatory network consisting of 10 regulatory modules common for all three stages, and 24, 49 and 70 modules separately for the first, second and third stage, each containing both a group of co-expressed genes and several transcription factors collaboratively controlling their expression under different conditions. 8 of 10 common regulatory modules were validated by at least two kinds of validations, such as independent DNA binding motif analysis, gene function enrichment test, and previous experimental data in the literature. CONCLUSIONS: We developed a computational method to reliably reconstruct gene regulatory networks from RNA-Seq transcriptome data. The method can generate valuable hypotheses for interpreting biological data and designing biological experiments such as ChIP-Seq, RNA interference, and yeast two hybrid experiments. PMID- 24053777 TI - The transcriptional programme of the androgen receptor (AR) in prostate cancer. AB - The androgen receptor (AR) is essential for normal prostate and prostate cancer cell growth. AR transcriptional activity is almost always maintained even in hormone relapsed prostate cancer (HRPC) in the absence of normal levels of circulating testosterone. Current molecular techniques, such as chromatin immunoprecipitation sequencing (ChIP-seq), have permitted identification of direct AR-binding sites in cell lines and human tissue with a distinct coordinate network evident in HRPC. The effectiveness of novel agents, such as abiraterone acetate (suppresses adrenal androgens) or enzalutamide (MDV3100, potent AR antagonist), in treating advanced prostate cancer underlines the on-going critical role of the AR throughout all stages of the disease. Persistent AR activity in advanced disease regulates cell cycle activity, steroid biosynthesis and anabolic metabolism in conjunction with regulatory co-factors, such as the E2F family, c-Myc and signal transducer and activator of transcription (STAT) transcription factors. Further treatment approaches must target these other factors. PMID- 24053778 TI - Strong cellulase inhibitors from the hydrothermal pretreatment of wheat straw. AB - BACKGROUND: The use of the enzymatic hydrolysis of lignocellulose with subsequent fermentation to ethanol provides a green alternative for the production of transportation fuels. Because of its recalcitrant nature, the lignocellulosic biomass must be pretreated before enzymatic hydrolysis. However, the pretreatment often results in the formation of compounds that are inhibitory for the enzymes or fermenting organism. Although well recognized, little quantitative information on the inhibition of individual cellulase components by identified inhibitors is available. RESULTS: Strong cellulase inhibitors were separated from the liquid fraction of the hydrothermal pretreatment of wheat straw. HPLC and mass spectroscopy analyses confirmed that the inhibitors were oligosaccharides (inhibitory oligosaccharides, IOS) with a degree of polymerization from 7 to 16. The IOS are composed of a mixture of xylo- (XOS) and gluco-oligosaccharides (GOS). We propose that XOS and GOS are the fragments of the xylan backbone and mixed-linkage beta-glucans, respectively. The IOS were approximately 100 times stronger inhibitors for Trichoderma reesei cellobiohydrolases (CBHs) than cellobiose, which is one of the strongest inhibitors of these enzymes reported to date. Inhibition of endoglucanases (EGs) by IOS was weaker than that of CBHs. Most of the tested cellulases and hemicellulases were able to slowly degrade IOS and reduce the inhibitory power of the liquid fraction to some extent. The most efficient single enzyme component here was T. reesei EG TrCel7B. Although reduced by the enzyme treatment, the residual inhibitory power of IOS and the liquid fraction was strong enough to silence the major component of the T. reesei cellulase system, CBH TrCel7A. CONCLUSIONS: The cellulase inhibitors described here may be responsible for the poor yields from the enzymatic conversion of the whole slurries from lignocellulose pretreatment under conditions that do not favor complete degradation of hemicellulose. Identification of the inhibitory compounds helps to design better enzyme mixtures for their degradation and to optimize the pretreatment regimes to minimize their formation. PMID- 24053779 TI - Psychometric assessment of scales for a Model of Goal Directed Vegetable Parenting Practices (MGDVPP). AB - BACKGROUND: Vegetable intake has been related to lower risk of chronic illnesses in the adult years. The habit of vegetable intake should be established early in life, but many parents of preschoolers report not being able to get their child to eat vegetables. The Model of Goal Directed Behavior (MGDB) has been employed to understand vegetable parenting practices (VPP) to encourage a preschool child's vegetable intake. The Model of Goal Directed Vegetable Parenting Practices (MGDVPP) provides possible determinants and may help explain why parents use effective or ineffective VPP. Scales to measure effective and ineffective vegetable parenting practices have previously been validated. This manuscript presents the psychometric characteristics and factor structures of new scales to measure the constructs in MGDVPP. METHODS: Participants were 307 parents of preschool (i.e. 3 to 5 year old) children, used for both exploratory (EFA) and confirmatory factor analyses (CFA). Data were collected via an internet survey. First, EFA were conducted using the scree plot criterion for factor extraction. Next, CFA assessed the fit of the exploratory derived factors. Then, classical test theory procedures were employed with all scales. Finally, Pearson correlations were calculated between each scale and composite effective and ineffective VPP as a test of scale predictive validity. RESULTS: Twenty-nine subscales (164 items) within 11 scales were extracted. The number of items per subscale ranged from 2 to 13, with three subscales having 10 or more items and 12 subscales having 4 items or less. Cronbach's alphas varied from 0.13 to 0.92, with 17 being 0.70 or higher. Most alphas <0.70 had only three or four items. Twenty-five of the 29 subscales significantly bivariately correlated with the composite effective or ineffective VPP scales. DISCUSSION: This was the initial examination of the factor structure and psychometric assessment of MGDVPP scales. Most of the scales displayed acceptable to desirable psychometric characteristics. Research is warranted to add items to those subscales with small numbers of items, test their validity and reliability, and characterize the model's influence on child vegetable consumption. PMID- 24053780 TI - Sampler for collection and analysis of low vapor pressure chemical (LVPC) particulates/aerosols. AB - Detection of low vapor pressure chemicals (LVPCs) such as pesticides and other toxic/hazardous materials on various environmental surfaces as well as LVPC aerosols is a significant challenge for current vapor phase detectors. We describe a novel sampling device which utilizes stainless steel screens coated with a sticky polydimethylsiloxane coating for collecting LVPCs aerosolized off of a surface. Results are presented for the collection and detection of a pesticide simulant, dimethyl methylphosphonate sorbed onto silica gel (DMMP/SG), using direct analysis in real time-cylindrical ion trap mass spectrometry (DART CITMS). PMID- 24053781 TI - "If you want to go fast, go alone. If you want to go far, go together": a call for a Nordic engagement in the development of family medicine in Africa. PMID- 24053782 TI - Metabolic changes in cardiomyocytes during sepsis. AB - Different types of shock induce distinct metabolic changes. The myocardium at rest utilizes free fatty acids as its primary energy source, a mechanism that changes to aerobic glycolysis during sepsis and is in contrast to hemorrhagic shock. The immune system also uses this mechanism, changing its substrate utilization to activate innate and adaptive cells. Cardiomyocytes share a number of features similar to antigen-presenting cells and may use this mechanism to augment the immune response at the reversible expense of cardiac function. PMID- 24053783 TI - Planning for tomorrow whilst living for today: the views of people with dementia and their families on advance care planning. AB - BACKGROUND: Advance care planning (ACP) is increasingly prominent in many countries; however, the evidence base for its acceptability and effectiveness is limited especially in conditions where cognition is impaired, as in dementia. METHOD: This qualitative study used semi-structured interviews with people with mild to moderate dementia (n = 17) and family carers (n = 29) to investigate their views about planning for their future generally and ACP specifically. RESULTS: People with dementia and their families make a number of plans for the future. Most people undertook practical, personal, financial, and legal planning. However participants did not make formal advance care plans with the exception of appointing someone to manage their financial affairs. Five barriers to undertaking ACP were identified: lack of knowledge and awareness, difficulty in finding the right time, a preference for informal plans over written documentation, constraints on choice around future care, and lack of support to make choices about future healthcare. CONCLUSIONS: Health and social care professionals can build on people's preferences for informal planning by exploring the assumptions underlying them, providing information about the possible illness trajectory and discussing the options of care available. Health and social care professionals also have a role to play in highlighting the aspects of ACP which seem to be most relevant to the wishes and aspirations of people with dementia. PMID- 24053785 TI - Development of toroidal nanostructures by self-assembly: rational designs and applications. AB - Toroidal nanostructures are symmetrical ring-shaped structures with a central internal pore. Interestingly, in nature, many transmembrane proteins such as beta barrels and alpha-helical bundles have toroidal shapes. Because of this similarity, toroidal nanostructures can provide a template for the development of transmembrane channels. However, because of the lack of guiding principles for the construction of toroids, researchers have not widely studied the self assembly of toroidal nanostructures as compared with the work on other supramolecular architectures. In this Account, we describe our recent efforts to construct toroidal nanostructures through the self-assembly of rationally designed building blocks. In one strategy for building these structures, we induce interfacial curvatures within the building blocks. When we laterally graft a bulky hydrophilic segment onto a p-oligophenyl rod or beta-sheet peptides, the backbones of the self-assembled structures can bend in response to the steric effect of these large side groups, driving the p-oligophenyl rod or beta-sheet peptides to form nanosized toriods. In another strategy, we can build toroids from bent-shaped building blocks by stacking the macrocycles. Aromatic segments with an internal angle of 120 degrees can associate with each other in aqueous solution to form a hexameric macrocycle. Then these macrocycles can stack on top of each other via hydrophobic and pi-pi interactions and form highly uniform toroidal nanostructures. We provide many examples that illustrate these guiding principles for constructing toroidal nanostructures in aqueous solution. Efforts to create toroidal nanostructures through the self-assembly of elaborately designed molecular modules provide a fundamental approach toward the development of artificial transmembrane channels. Among the various toroids that we developed, a few nanostructures can insert into lipid membranes and allow limited transport in vesicles. PMID- 24053784 TI - Preference for wine is associated with lower hip fracture incidence in post menopausal women. AB - BACKGROUND: Past studies of relationships between alcohol and hip fracture have generally focused on total alcohol consumed and not type of alcohol. Different types of alcohol consist of varying components which may affect risk of hip fracture differentially. This study seeks to examine the relationship between alcohol consumption, with a focus on type of alcohol consumed (e.g. beer, wine, or hard liquor) and hip fracture risk in post-menopausal women. METHODS: The longitudinal cohort consisted of U.S. post-menopausal women aged 50-79 years enrolled between 1993-1998 in the Women's Health Initiative Clinical Trials and Observational Study (N=115,655). RESULTS: Women were categorized as non-drinkers, past drinkers, infrequent drinkers and drinkers by preference of alcohol type (i.e. those who preferred wine, beer, hard liquor, or who had no strong preference). Mean alcohol consumption among current drinkers was 3.3 servings per week; this was similar among those who preferred wine, beer and liquor. After adjustment for potential confounders, alcohol preference was strongly correlated with hip fracture risk (p = 0.0167); in particular, women who preferred wine were at lower risk than non-drinkers (OR=0.78; 95% CI 0.64-0.95), past drinkers (OR=0.85; 95% CI 0.72-1.00), infrequent drinkers (OR=0.73; 95% CI 0.61-0.88), hard liquor drinkers (OR=0.87; 95% CI 0.71-1.06), beer drinkers (OR=0.72; 95% CI 0.55-0.95) and those with no strong preference (OR=0.89; 95% CI 0.89; 95% CI 0.73 1.10). CONCLUSIONS: Preference of alcohol type was associated with hip fracture; women who preferentially consumed wine had a lower risk of hip fracture compared to non-drinkers, past drinkers, and those with other alcohol preferences. PMID- 24053786 TI - Record high hole mobility in polymer semiconductors via side-chain engineering. AB - Charge carrier mobility is still the most challenging issue that should be overcome to realize everyday organic electronics in the near future. In this Communication, we show that introducing smart side-chain engineering to polymer semiconductors can facilitate intermolecular electronic communication. Two new polymers, P-29-DPPDBTE and P-29-DPPDTSE, which consist of a highly conductive diketopyrrolopyrrole backbone and an extended branching-position-adjusted side chain, showed unprecedented record high hole mobility of 12 cm(2)/(V.s). From photophysical and structural studies, we found that moving the branching position of the side chain away from the backbone of these polymers resulted in increased intermolecular interactions with extremely short pi-pi stacking distances, without compromising solubility of the polymers. As a result, high hole mobility could be achieved even in devices fabricated using the polymers at room temperature. PMID- 24053787 TI - Reformulation and solution of the master equation for multiple-well chemical reactions. AB - We consider an alternative formulation of the master equation for complex-forming chemical reactions with multiple wells and bimolecular products. Within this formulation the dynamical phase space consists of only the microscopic populations of the various isomers making up the reactive complex, while the bimolecular reactants and products are treated equally as sources and sinks. This reformulation yields compact expressions for the phenomenological rate coefficients describing all chemical processes, i.e., internal isomerization reactions, bimolecular-to-bimolecular reactions, isomer-to-bimolecular reactions, and bimolecular-to-isomer reactions. The applicability of the detailed balance condition is discussed and confirmed. We also consider the situation where some of the chemical eigenvalues approach the energy relaxation time scale and show how to modify the phenomenological rate coefficients so that they retain their validity. PMID- 24053788 TI - A novel approach for quantitative assessment of mucosal damage in inflammatory bowel disease. AB - AIMS: One of the main reliable histological features to suggest the diagnosis of inflammatory bowel disease is the presence of significant distortion of the crypt architecture indicating the chronic nature of the disease resulting in mucosal damage. This feature has a considerable intra-observer and inter-observer variability leading to significant subjectivity in colonic biopsy assessment. In this paper, we present a novel automated system to assess mucosal damage and architectural distortion in inflammatory bowel disease (IBD). METHODS: The proposed system relies on advanced image understating and processing techniques to segment digitally acquired images of microscopic biopsies, then, to extract key features to quantify the crypts irregularities in shape and distribution. These features were used as inputs to an artificial intelligent classifier that, after a training phase, can carry out the assessment automatically. RESULTS: The developed system was evaluated using 118 IBD biopsies. 116 out of 118 biopsies were correctly classified as compared to the consensus of three expert pathologists, achieving an overall precision of 98.31%. CONCLUSIONS: An automated intelligent system to quantitatively assess inflammatory bowel disease was developed. The proposed system utilized advanced image understanding techniques together with an intelligent classifier to conduct the assessment. The developed system proved to be reliable, robust, and minimizes subjectivity and inter- and intra-observer variability. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1797721309305023. PMID- 24053789 TI - User-determined end of net life in Senegal: a qualitative assessment of decision making related to the retirement of expired nets. AB - BACKGROUND: Procurement and distribution of long-lasting insecticidal nets (LLINs) in the African region has decreased from 145 million in 2010 to 66 million nets in 2012. As resources for LLIN distribution appear to stagnate, it is important to understand the users' perception of the life span of a net and at what point and why they stop using it. In order to get the most value out of distributed nets and to ensure that they are used for as long as possible, programmes must communicate to users about how to assess useful net life and how to extend it. METHODS: Data were collected from 114 respondents who participated in 56 in-depth interviews (IDIs) and eight focus group discussions (FGDs) in August 2012 in eight regions in Senegal. Households were eligible for the study if they owned at least one net and had an available household member over the age of 18. Data were coded by a team of four coders in ATLAS.ti using a primarily deductive approach. RESULTS: Respondents reported assessing useful net life using the following criteria: the age of net, the number and size of holes and the presence of mosquitoes in the net at night. If they had the means to do so, many respondents preferred the acquisition of a new net rather than the continued use of a very torn net. However, respondents would preferentially use newer nets, saving older, but useable nets for the future or sharing them with family or friends. Participants reported observing alternative uses of nets, primarily for nets that were considered expired. CONCLUSIONS: The results indicate that decisions regarding the end of net life vary among community members in Senegal, but are primarily related to net integrity. Additional research is needed into user-determined end of net life as well as care and repair behaviours, which could extend useful net life. The results from this study and from future research on this topic should be used to understand current behaviours and develop communication programmes to prolong the useful life of nets. PMID- 24053790 TI - Assessing the anatomical characteristics of renal masses has a limited effect on the prediction of pathological outcomes in solid, enhancing, small renal masses: results using the PADUA classification system. AB - OBJECTIVE: To evaluate whether assessing the anatomical characteristics of renal masses increases the accuracy of prediction of tumour pathology in small renal masses (SRMs). PATIENTS AND METHODS: We retrospectively reviewed 1129 consecutive patients who underwent extirpative surgeries for a clinical T1 renal mass, for which the preoperative aspects and dimensions used for an anatomical (PADUA) classification were available. Multivariate logistic regression analyses of demographic and anatomical characteristics were performed. Nomograms to predict malignancy and high grade pathology were constructed using a basic model (age, sex and tumour size), and an extended model (anatomical characteristics incorporated into the basic model), and the area under the curve (AUC) between models was compared. RESULTS: Age, sex and tumour size were significantly associated with malignancy and high grade pathology in the T1 and T1a category (except sex for high grade pathology in T1a tumours). Exophytic rate (T1 and T1a) and renal sinus or urinary collecting system involvement (only T1a) were also significant predictors of high grade pathology. Nomograms using the extended model for malignancy showed an insignificant AUC increase compared with those using the basic model (T1, from 0.771 to 0.780, P = 0.149, and T1a, from 0.803 to 0.819, P = 0.055). For high grade pathology, the extended model achieved a significant AUC increase (from 0.595 to 0.643, P = 0.014) in the T1a category, but the AUC for both T1 and T1a tumours showed merely modest competence (0.654 and 0.643, respectively). CONCLUSION: Age, sex and tumour size are the primary predictors of tumour pathology of SRMs, and incorporating other anatomical characteristics has only a limited positive effect on the accuracy of prediction of pathological outcomes. PMID- 24053791 TI - A simple and general method to determine reliable pseudocontact shifts in lanthanide complexes. AB - Pseudocontact shifts (PCS) contain a wealth of geometric information, which makes paramagnetic NMR one of the best methods for accurate geometric determinations in solution. It is well-known that PCS are intrinsically linked to Fermi contact (FC) shifts, and the separation of the two terms is achieved through linearization methods, which heavily rely on (a) isostructurality (even concerning a labile axial site) and (b) the validity of Bleaney's constants. Recently we proposed a method that circumvents both assumptions in the case of axially symmetric complexes, and presently we generalize it to lower symmetry. Our method is model-free and thus does not rely on any structural hypothesis. Our results compare very well with recently published data obtained through an accurate ab initio approach. PMID- 24053792 TI - Bladder function in a cannabinoid receptor type 1 knockout mouse. AB - OBJECTIVE: To evaluate bladder function in an established cannabinoid type 1 (CB1) receptor knockout (KO) mouse model via organ-bath (in vitro) and urodynamic (cystometric; in vivo) experiments. MATERIALS AND METHODS: In all, 20 8-week-old female wildtype (WT) mice (C57BL/6) and 20 age-matched CB1 KO mice were used. Six mice from each group were used for the organ-bath experiments, where the contractile responses of bladder tissue strips after carbachol exposure (carbachol concentration response curve [CCRC]; myogenic contraction) and during electrical field stimulation (EFS; neurogenic contraction) were assessed. In all, 14 mice per group were used for cystometric experiments without any anaesthesia, in which standard urodynamic variables were assessed 3 days after bladder catheterisation. RESULTS: The CCRCs of bladder strips from CB1 KO mice were similar to those of WT mice. However, during EFS the bladder strips from the CB1 KO mice had significantly lower contractile responses than WT preparations, indicating that in CB1 KO mice the neuronal component of bladder contraction was different. In cystometric experiments the CB1 KO mice had a higher micturition frequency (shorter mean [sem] inter-micturition interval of 3.24 [0.29] vs 7.32 [0.5] min), a lower bladder capacity (0.09 [0.01] vs 0.18 [0.01] mL) and micturition volume (0.07 [0.01] vs 0.14 [0.01] mL), a lower bladder compliance (0.007 [0.001] vs 0.02 [0.002] mL/cmH2 O), and higher spontaneous bladder activity (5.1 [0.5] vs 2.6 [0.6] cmH2 O) than WT mice (all P < 0.05, Student's t test). In WT mice, systemic administration of rimonabant (SR141716), a CB1 receptor antagonist, resulted in urodynamic changes similar to those seen in the CB1 KO mice. CONCLUSIONS: In vitro, bladder strips from CB1 KO mice responded to muscarinic receptor stimulation similarly as the WT controls, but were less responsive to electrical stimulation of nerves. In vivo, CB1 KO mice had a higher micturition frequency and more spontaneous activity than WT mice. The present findings suggest that CB1 receptors are involved in peripheral and central nervous control of micturition. PMID- 24053793 TI - Comparison of early postoperative morbidity after robot-assisted and open radical cystectomy: results of a prospective observational study. AB - OBJECTIVE: To evaluate early postoperative morbidity in patients undergoing either robot-assisted (RARC) or open radical cystectomy (ORC) for bladder cancer. PATIENTS AND METHODS: A total of 100 patients underwent RARC (between August 2009 and August 2012) and 42 underwent ORC (between October 2007 and July 2009) as treatment for bladder cancer. Data on the patients' peri-operative course were collected prospectively up to the 90th postoperative day for the RARC group and up to the 60th postoperative day for the ORC group. Postoperative complications were recorded based on the Clavien-Dindo classification system. Both groups were compared with regard to patient and tumour characteristics, surgical and peri operative outcomes. RESULTS: The RARC and ORC groups were well matched with regard to age, body mass index, gender distribution, type of urinary diversion and pathological tumour characteristics (all P > 0.1), but patients in the RARC group had more serious comorbidities according to the Charlson comorbidity index (P = 0.034). Although surgical duration was longer in the RARC group (P < 0.001) the estimated blood loss was lower (P < 0.001) and transfusion requirement was less (P < 0.001). Overall 59 patients (59%) in the RARC group and 39 patients (93%) in the ORC group experienced postoperative complications of any Clavien Dindo grade <90 days and <60 days after surgery, respectively (P < 0.001; relative risk reduction 0.36). Major complications (grades 3a-5) were also less frequent after RARC (24 [24%] vs 18 patients [43%]; P = 0.029) with a relative risk reduction of 0.44. In the subgroup of patients with an ileum conduit as a urinary diversion (RARC, n = 76 vs ORC, n = 31) the overall rate of complications (43 [57%] vs 28 [90%] patients; P < 0.001) and the rate of major complications (17 [22%] vs 15 [48%] patients; P = 0.011) were lower in the RARC group with relative risk reductions of 0.37 and 0.54, respectively. CONCLUSIONS: A significant reduction in early postoperative morbidity was associated with the robotic approach. Despite more serious comorbidities and a 30-day longer follow up in the RARC group, patients in the RARC group experienced fewer postoperative complications than those in the ORC group. Major complications, in particular, were less frequent after RARC. PMID- 24053795 TI - The 2013 International Psychogeriatric Association Junior Research Awards in Psychogeriatrics. PMID- 24053794 TI - Continuous vs conventional bipolar plasma vaporisation of the prostate and standard monopolar resection: a prospective, randomised comparison of a new technological advance. AB - OBJECTIVES: To evaluate in a prospective, randomised trial the surgical efficiency and safety of a new energy source enabling a continuous bipolar plasma vaporisation of the prostate (C-BPVP) by comparing with standard vaporisation (S BPVP) and monopolar transurethral resection of the prostate (TURP) in men with benign prostatic hyperplasia (BPH). To comparatively assess the short-term functional outcome of the three methods. PATIENTS AND METHODS: In all, 180 men with BPH with prostate volumes of 30-80 mL, maximum urinary flow rates (Q(max)) of <10 mL/s and International Prostate Symptom Score (IPSS) of >19 were equally randomised for C-BPVP, S-BPVP and monopolar TURP. All men were evaluated preoperatively and at 1, 3 and 6 months after surgery by IPSS, Q(max), health related quality of life (HRQL) score and post-void residual urine volume (PVR). The prostate volume and PSA level were postoperatively assessed at 6 months. RESULTS: The mean operation time was significantly reduced in C-BPVP vs S-BPVP and TURP, with a substantial 22.4% and 39.1% decrease in duration for C-BPVP when compared with S-BPVP and TURP, respectively. The mean haemoglobin level decrease (0.4 and 0.6 vs 1.4 g/dL), capsular perforation rate (1.7% and 3.3% vs 10%), postoperative haematuria rate (1.7% and 1.7% vs 13.3%), catheterisation period (24.1 and 23.9 vs 73.6 h) and hospital stay (2.1 and 2.2 vs 4.5 days) were significantly lower for C-BPVP and S-BPVP vs TURP. At 1, 3 and 6 months follow up, there were statistically ameliorated IPSS and Q(max) measurements in the C BPVP and S-BPVP series, while similar HRQL scores, PVRs, PSA levels and postoperative prostate volumes were found in all three study arms. CONCLUSIONS: The operation time for C-BPVP was on average 20% and 40% quicker than S-BPVP and TURP, respectively. Both C-BPVP and S-BPVP had better perioperative safety and improved follow-up voiding and symptom scores than TURP. PMID- 24053796 TI - Noninvasive surrogates of intracranial pressure: another piece added with magnetic resonance imaging of the cerebrospinal fluid thickness surrounding the optic nerve. AB - Optic nerve sheath diameter enlargement measured by ultrasound is known to be associated with raised intracranial pressure (ICP). Magnetic resonance imaging (MRI) of the cerebrospinal fluid (CSF) surrounding the optic nerve has been found, in an elegant study published in Critical Care, to correlate well with lumbar CSF opening pressure, confirming previously published studies. A simple and rapid T2-weighted fat-suppressed sequence was used to noninvasively measure the CSF width surrounding the optic nerve, allowing one to predict lumbar CSF pressure with relatively good performances, taking into consideration the body mass index and the mean arterial blood pressure. Based on these results and when brain MRI is indicated in situations at risk for increased ICP, the optic CSF thickness measurement could be systematically performed and used as a surrogate marker of raised ICP. PMID- 24053797 TI - Sensing single mixed-monolayer protected gold nanoparticles by the alpha hemolysin nanopore. AB - Gold nanoparticles are widely used in various applications in fields including chemistry, engineering, biology, medicine, and electronics. These materials can be synthesized and modified with ligands containing different functional groups. Among nanoparticles' characteristics, chemical surface composition is likely to be a crucial feature, demanding robust analytical methodologies for its assessment. Single molecule analysis using the biological nanopores alpha hemolysin and its E111A mutant is presented here as a promising methodology to stochastically sense organic monolayer protected gold-nanoparticles with different ligand shell compositions. By monitoring the ionic current across a single protein nanopore, differences in the physical and chemical characteristics (e.g., size, ligand shell composition, and arrangement) of individual nanoparticles can be distinguished based on the differences in the current blockade events that they cause. Such differences are observed in the spread of both the amplitude and duration of current blockades. These values cannot be correlated with a single physical characteristic. Instead the spread represents a measure of heterogeneity within the nanoparticle population. While our results compare favorably with the more traditional analytical methodologies, further work will be required to improve the accuracy of identification of the NPs and understand the spread of values within a nanoparticle preparation as well as the overlap between similar preparations. PMID- 24053798 TI - Suppression of protein kinase C theta contributes to enhanced myogenesis in vitro via IRS1 and ERK1/2 phosphorylation. AB - BACKGROUND: Differentiation and fusion of skeletal muscle myoblasts into multi nucleated myotubes is required for neonatal development and regeneration in adult skeletal muscle. Herein, we report novel findings that protein kinase C theta (PKCtheta) regulates myoblast differentiation via phosphorylation of insulin receptor substrate-1 and ERK1/2. RESULTS: In this study, PKCtheta knockdown (PKCthetashRNA) myotubes had reduced inhibitory insulin receptor substrate-1 ser1095 phosphorylation, enhanced myoblast differentiation and cell fusion, and increased rates of protein synthesis as determined by [3H] phenylalanine incorporation. Phosphorylation of insulin receptor substrate-1 ser632/635 and extracellular signal-regulated kinase1/2 (ERK1/2) was increased in PKCthetashRNA cells, with no change in ERK5 phosphorylation, highlighting a PKCtheta-regulated myogenic pathway. Inhibition of PI3-kinase prevented cell differentiation and fusion in control cells, which was attenuated in PKCthetashRNA cells. Thus, with reduced PKCtheta, differentiation and fusion occur in the absence of PI3-kinase activity. Inhibition of the ERK kinase, MEK1/2, impaired differentiation and cell fusion in control cells. Differentiation was preserved in PKCthetashRNA cells treated with a MEK1/2 inhibitor, although cell fusion was blunted, indicating PKCtheta regulates differentiation via IRS1 and ERK1/2, and this occurs independently of MEK1/2 activation. CONCLUSION: Cellular signaling regulating the myogenic program and protein synthesis are complex and intertwined. These studies suggest that PKCtheta regulates myogenic and protein synthetic signaling via the modulation of IRS1and ERK1/2 phosphorylation. Myotubes lacking PKCtheta had increased rates of protein synthesis and enhanced myotube development despite reduced activation of the canonical anabolic-signaling pathway. Further investigation of PKCtheta regulated signaling may reveal important interactions regulating skeletal muscle health in an insulin resistant state. PMID- 24053799 TI - OTOF mutation screening in Japanese severe to profound recessive hearing loss patients. AB - BACKGROUND: Auditory neuropathy spectrum disorder (ANSD) is a unique form of hearing loss that involves absence or severe abnormality of auditory brainstem response (ABR), but also the presence of otoacoustic emissions (OAEs). However, with age, the OAEs disappear, making it difficult to distinguish this condition from other nonsyndromic hearing loss. Therefore, the frequency of ANSD may be underestimated. The aim of this study was to determine what portion of nonsyndromic hearing loss is caused by mutations of OTOF, the major responsible gene for nonsyndromic ANSD. METHODS: We screened 160 unrelated Japanese with severe to profound recessive nonsyndromic hearing loss (ARNSHL) without GJB2 or SLC26A4 mutations, and 192 controls with normal hearing. RESULTS: We identified five pathogenic OTOF mutations (p.D398E, p.Y474X, p.N727S, p.R1856Q and p.R1939Q) and six novel, possibly pathogenic variants (p.D450E, p.W717X, p.S1368X, p.R1583H, p.V1778I, and p.E1803A). CONCLUSIONS: The present study showed that OTOF mutations accounted for 3.2-7.3% of severe to profound ARNSHL patients in Japan. OTOF mutations are thus a frequent cause in the Japanese deafness population and mutation screening should be considered regardless of the presence/absence of OAEs. PMID- 24053800 TI - Heat-moisture treatment under mildly acidic conditions alters potato starch physicochemical properties and digestibility. AB - Potato starch was subjected to heat-moisture treatment (HMT; 120 degrees C, 3 h) under mildly acidic conditions (pH 5, 6, or 6.5 [control]) at moisture levels of 15, 20 or 25%. HMT starches exhibited significantly delayed pasting times and reduced overall paste viscosities, amylose leaching, and granular swelling characteristics relative to native starch, as well as enhanced levels of thermo stable resistant starch (~24%). HMT appeared to alter/enhance short-range chain associations (FT-IR) within amorphous and/or crystalline regions of starch granules. However, the extent of physicochemical change and RS enhancement during HMT was most facilitated by a mildly acidic condition (pH 6) at higher treatment moisture levels (20 or 25%). These conditions promoted limited hydrolysis of amylopectin molecules, primarily at alpha-(1->6) branch points, likely enhancing mobility and interaction of starch chains during HMT. Thus, a slightly acidic pH might reduce conditions and/or timeframe needed to impart physicochemical changes and reduced digestibility to potato starch. PMID- 24053801 TI - Microencapsulation of purple Brazilian cherry juice in xanthan, tara gums and xanthan-tara hydrogel matrixes. AB - The purple Brazilian cherry (Eugenia uniflora L.) juice was encapsulated in xanthan, tara and xanthan-tara hydrogel matrixes. Encapsulation efficiency, Differential Scanning Calorimetry (DSC), X-ray diffractometry, release profile, stability of carotenoids, phenolic compounds and antioxidant activity of microparticles were evaluated. Encapsulation was confirmed. The highest encapsulation efficiency was obtained with xanthan gum and hydrogel was mostly indicated for the release of carotenoids in GFS and IFS medium. Phenolic compounds had the highest release rate but not in a gradually way, regardless of wall material and fluids under analysis. Stored microparticles at 4 and 25 degrees C, showed carotenoid degradation. Xanthan and hydrogel wall material provided the greatest stability to these compounds. The microparticles' anti oxidant activity decreased during storage due to the degradation of carotenoids. PMID- 24053802 TI - In vitro and in vivo digestion of octenyl succinic starch. AB - This study aimed to understand effects of octenyl succinic anhydride (OSA) modification of normal corn (NCS) and high-amylose corn (HA7) starch on their enzymatic hydrolysis rates. After modification with 3% and 10% OSA, resistant starch (RS) contents of the cooked OS-NCS increased from 0.8% of the control starch to 6.8% and 13.2% (Englyst Method), respectively, whereas that of the cooked OS-HA7 decreased from 24.1% to 23.7% and 20.9%, respectively. When the cooked NCS, HA7 and OS (10%)-HA7 were used to prepare diets for rats at 55% (w/w) starch, RS contents of the diets were 1.1%, 13.2% and 14.6%, respectively. After feeding to the rats, 20.2-31.1% of the starch in the OS (10%)-HA7-diet was not utilized in vivo and was found in rat feces, which was substantially larger than that of the HA7-diet (<=4.9%) and NCS-diet (<=0.2%). The body weights of the rats, however, remained similar between different groups. PMID- 24053803 TI - Xyloglucan-based diblock co-oligomer: synthesis, self-assembly and steric stabilization of proteins. AB - We propose a novel plant-based amphiphilic diblock co-oligomers (BCO) surfactant containing only carbohydrate segments and examine its potential as a biosourced stabilizer. The synthesis of an amphiphilic xyloglucan-based BCO, composed of a hydrophilic xyloglucan oligosaccharide (XGO) block "clicked" to a hydrophobic peracetylated XGO is described. Dynamic light scattering experiments correlated with transmission electron microscopy observations showed that this new class of amphiphilic BCO self-assembles in water to form spherical micelles with a hydrodynamic diameter of 22 nm. Preliminary studies indicate that the XGO-based BCO sterically stabilizes gliadin and zein nanoparticle suspensions. The stabilization results were compared to those using pluronic F-68, a commercial surfactant. For gliadin nanoparticles, both surfactants result in essentially the same morphology and polydispersity. However, for the zein nanoparticles, the XGO based BCO stabilizer gave lower polydispersity. PMID- 24053804 TI - Characterization of alpha-tocopherol as interacting agent in polyvinyl alcohol starch blends. AB - In this study, the interactions of alpha-tocopherol (alpha-TOH) in PVOH-starch blends were investigated. alpha-TOH is an interacting agent possesses a unique molecule of polar chroman "head" and non-polar phytyl "tail" which can improve surface interaction of PVOH and starch. It showed favorable results when blending PVOH-starch with alpha-TOH, where the highest tensile strengths were achieved at 60 wt.% PVOH-starch blend for 1 phr alpha-TOH and 50 wt.% for 3 phr alpha-TOH, respectively. This due to the formation of miscible PVOH-starch as resulted by the compatibilizing effect of alpha-TOH. Moreover, the enthalpy of melting (DeltaHm) of 60 wt.% PVOH-starch and 50 wt.% PVOH-starch added with 1 and 3 phr alpha-TOH respectively were higher than DeltaHm of the neat PVOH-starch blends. The thermogravimetry analysis also showed that alpha-TOH can be used as thermal stabilizer to reduce weight losses at elevated temperature. The surface morphologies of the compatible blends formed large portion of continuous phase where the starch granules interacted well with alpha-TOH by acting as compatilizer to reduce surface energy of starch for embedment into PVOH matrix. PMID- 24053806 TI - Radii of gyration of sodium carboxymethylcellulose in aqueous and mixed solvent media from viscosity measurement. AB - The viscosities of three sodium carboxymethylcellulose samples with molecular weights of 90,000 [degree of substitution (DS): 0.7], 250,000 (DS: 0.9), and 700,000 (DS: 0.9) have been reported in water and methanol-water mixtures in salt free and salt-containing solutions at 35 degrees C. The results were analyzed in terms of a phenomenological approach for the viscosity of polymer solutions to determine the intrinsic viscosities [eta] of the polyelectrolyte samples. This contribution presents a new and convenient method for the determination of the root-mean-square radii of gyration of the polyion chains using the [eta] values obtained as a function of the added salt concentration. The polyion coils are found to expand at low ionic strength and these collapse drastically with increasing ionic strength. Addition of methanol to the medium in which these samples are dissolved causes a contraction of the polyion chains, although this influence is less pronounced than that of the added salt. PMID- 24053805 TI - Alginate esters via chemoselective carboxyl group modification. AB - Alginates are (1->4) linked linear copolysaccharides composed of beta-D mannuronic acid (M) and its C-5 epimer, alpha-L-guluronic acid (G). Several strategies for synthesis of carboxyl modified alginate derivatives exist in the literature. Most of these however employ aqueous chemistries, such as carbodiimide coupling reactions. Based on our recently discovered method for homogeneous dissolution of tetrabutylammonium (TBA)-alginate, we now describe use of tetrabutylammonium fluoride (TBAF)-based two component solvent systems as media for synthesis of carboxyl-modified alginate esters. Partially and fully esterified benzyl, butyl, ethyl, and methyl alginates were synthesized via reaction with the corresponding alkyl halides. The newly synthesized derivatives were soluble in polar aprotic solvents without the addition of TBAF. Saponification was performed to demonstrate that alkylation was completely regioselective for carboxylate groups in preference to hydroxyl groups to form esters. We demonstrate the utility of these alginate esters to enhance aqueous solubility of the flavonoid naringenin by formation of solid dispersions. PMID- 24053807 TI - Extraction and chemical characterization of starch from S. lycocarpum fruits. AB - In this study the pulp from Solanum lycocarpum fruits was used as raw material for extraction of starch, resulting in a yield of 51%. The starch granules were heterogeneous in size, presenting a conical appearance, very similar to a high amylose cassava starch. The elemental analysis (CHNS) revealed 64.33% carbon, 7.16% hydrogen and 0.80% nitrogen. FT-IR spectroscopy showed characteristic peaks of polysaccharides and NMR analysis confirmed the presence of the alpha-anomer of d-glucose. The S. lycocarpum starch was characterized by high value of intrinsic viscosity (3515 mPa s) and estimated molecular weight around 645.69 kDa. Furthermore, this starch was classified as a B-type and high amylose content starch, presenting 34.66% of amylose and 38% crystallinity. Endothermic transition temperatures (To=61.25 degrees C, Tp=64.5 degrees C, Tc=67.5 degrees C), gelatinization temperature (DeltaT=6.3 degrees C) ranges and enthalpy changes (DeltaH=13.21 J g(-1)) were accessed by DCS analysis. These results make the S. lycocarpum fruit a very promising source of starch for biotechnological applications. PMID- 24053808 TI - Continuous production of beta-cyclodextrin from starch by highly stable cyclodextrin glycosyltransferase immobilized on chitosan. AB - Cyclodextrin glycosyltransferase (CGTase) from Thermoanaerobacter sp. was covalently immobilized on glutaraldehyde-activated chitosan spheres and used in a packed bed reactor to investigate the continuous production of beta-cyclodextrin (beta-CD). The optimum temperatures were 75 degrees C and 85 degrees C at pH 6.0, respectively for free and immobilized CGTase, and the optimum pH (5.0) was the same for both at 60 degrees C. In the reactor, the effects of flow rate and substrate concentration in the beta-CD production were evaluated. The optimum substrate concentration was 4% (w/v), maximizing the beta-CD production (1.32 g/L) in a flow rate of 3 mL/min. In addition, the biocatalyst had good operational stability at 60 degrees C, maintaining 61% of its initial activity after 100 cycles of batch and 100% after 100 h of continuous use. These results suggest the possibility of using this immobilized biocatalyst in continuous production of CDs. PMID- 24053809 TI - Physicochemical and molecular modeling studies of cefixime-L-arginine cyclodextrin ternary inclusion compounds. AB - In an attempt to improve the physicochemical properties of cefixime (CEF), its supramolecular inclusion compounds were prepared with beta-cyclodextrin (betaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) in presence and/or absence of ternary component L-arginine (ARG) using spray drying technique. Initially, the phase solubility studies revealed a stoichiometry of 1:1 molar ratio with an AL type of phase solubility curve. The stability constants of binary systems were remarkably improved in presence of ARG, indicating positive effect of its addition. The inclusion complexes were characterized by FTIR, XRPD, DSC, SEM, particle size analysis, and dissolution studies. Further, molecular mechanic (MM) calculations were performed to investigate the possible orientations of CEF inside betaCD cavity in presence and/or absence of ternary component. In case of physicochemical studies, the ternary systems performed well as a result of comprehensive effect of ternary complexation and particle size reduction achieved by a spray drying technology. PMID- 24053810 TI - Carboxymethyl chitosan-poly(amidoamine) dendrimer core-shell nanoparticles for intracellular lysozyme delivery. AB - Intracellular delivery of native, active proteins is challenging due to the fragility of most proteins. Herein, a novel polymer/protein polyion complex (PIC) nanoparticle with core-shell structure was prepared. Carboxymethyl chitosan grafted-terminal carboxyl group-poly(amidoamine) (CM-chitosan-PAMAM) dendrimers were synthesized by amidation and saponification reactions. (1)H NMR was used to characterize CM-chitosan-PAMAM dendrimers. The TEM images and results of lysozyme loading efficiency indicated that CM-chitosan-PAMAM dendrimers could self assemble into core-shell nanoparticles, and lysozyme was efficiently encapsulated inside the core of CM-chitosan-PAMAM dendrimer nanoparticles. Activity of lysozyme was completely inhibited by CM-chitosan-PAMAM Dendrimers at physiological pH, whereas it was released into the medium and exhibited a significant enzymatic activity in an acidic intracellular environment. Moreover, the CM-chitosan-PAMAM dendrimer nanoparticles did not exhibit significant cytotoxicity in the range of concentrations below 3.16 mg/ml. The results indicated that these CM-chitosan-PAMAM dendrimers have excellent properties as highly potent and non-toxic intracellular protein carriers, which would create opportunities for novel applications in protein delivery. PMID- 24053811 TI - Enhanced anti-topoisomerase II activity by mucoadhesive 4-CBS-chitosan/poly (lactic acid) nanoparticles. AB - In this study, the biodegradable mucoadhesive 4-carboxybenzensulfonamide chitosan (4-CBS-chitosan)/poly (lactic acid) (PLA) nanoparticles were fabricated by the electrospray ionization technique for enhancing anti-topoisomerase II (Topo II) activity. The obtained (4-CBS-chitosan/PLA)-DOX nanoparticles were characterized using SEM, particle size analyzer. We emphasis on encapsulation efficiency, in vitro drug release behavior and also performed in vitro studies of Topo II inhibitory activity using gel electrophoresis. In addition, the cytotoxicity of the 4-CBS-chitosan/PLA nanoparticles using MTT assay was also studied. The mean particle size of spherical shaped (4-CBS-chitosan/PLA)-DOX is less than 300 nm. The DOX loaded 4-CBS-chitosan/PLA composite nanoparticles produced high entrapment efficiency of 85.8% and provided the prolonged release of DOX extended to 26 days and also still had strong Topo II inhibitory activity up to 77.4%. Overall, it was shown that 4-CBS-chitosan/PLA nanoparticles could be promising carriers for controlled delivery of anticancer drugs. PMID- 24053812 TI - Poly-(cyclo)dextrins as ethoxzolamide carriers in ophthalmic solutions and in contact lenses. AB - Efficient ophthalmic therapy requires the development of strategies that can provide sufficiently high drug levels in the ocular structures for a prolonged time. This work focuses on the suitability of poly-(cyclo)dextrins as carriers able to solubilize the carbonic anhydrase inhibitor (CAI) ethoxzolamide (ETOX), which is so far used for oral treatment of glaucoma. Topical ocular treatment should notably enhance the efficiency/safety profile of the drug. Natural alpha-, beta- and gamma-cyclodextrins and a maltodextrin were separately polymerized using citric acid as cross-linker agent under mild conditions. The resultant hydrophilic polymers exhibited larger capability to solubilize ETOX than the pristine (cyclo)dextrins. Moreover, they provided sustained drug diffusion in artificial lachrymal fluid. Interestingly the poly-(cyclo)dextrins solutions facilitate the loading of remarkably high doses of ETOX in poly(2-hydroxyethyl methacrylate)-based contact lenses. Exploiting ionic interactions between functional groups in the contact lenses and remnant free carboxylic acids in the citric acid linkers of poly-(cyclo)dextrins led to the retention of the drug loaded poly-(cyclo)dextrins and, in turn, to sustained release for several weeks. PMID- 24053813 TI - Glucogalactan: a polysaccharide isolated from the cell-wall of Verticillium lecanii. AB - A water-soluble polysaccharide was extracted with alkali from the cell wall of Verticillium lecanii (also called Lecanicillium lecanii). After freezing and thawing, the water-soluble fraction was purified by gel filtration chromatography on Sepharose CL-6B and eluted as one peak by HPSEC/RID. Monosaccharide analysis showed galactose and glucose (1.1:1), with traces of mannose (<1%). The structural characteristics were determined by spectroscopic analysis, FT-IR and 1D and 2D (1)H and (13)C NMR, and methylation results. On the basis of the data obtained, the following structure of the polysaccharide (E3SIV fraction) was established: [Formula: see text] where n~22 and m~22. PMID- 24053814 TI - Immobilization of the proteins in the natural rubber with dialdehyde sodium alginate. AB - The biodegradable dialdehyde sodium alginate (DASA) was exploited to immobilize the proteins in the natural rubber latex (NRL) and the variations of the properties for the NRL films were estimated in detail. As demonstrated, the proteins were distributed more uniformly in the NRL films with DASA and the extractable protein (EP) content was effectively decreased. Particularly, the EP content was lowered to a value about 46 MUg/g with 0.40% DASA, which could meet with the demands of the allergy protein threshold limit of 50 MUg/g as described in ASTM D 5712 standard. Furthermore, there was some improve on the burial degradability of the NRL films modified with DASA. The mechanical properties, however, had no evident variation in the presence of DASA. In conclusion, the immobilization of the proteins with DASA should be a potential alternative to tackle the protein allergy problem for the NRL and its products. PMID- 24053815 TI - Fabrication of distilled water-soluble chitosan/alginate functional multilayer composite microspheres. AB - Polysaccharides-based functional microspheres were fabricated under mild conditions. Firstly, magnetic alginate microspheres were prepared by emulsification/internal gelation and acted as substrates. Then the multilayer composite microspheres (MCM) were obtained through the layer-by-layer assembly of the distilled water-soluble chitosan and alginate. The components, morphology, and size distribution of the microspheres were characterized by element analysis (EA), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM) and laser particle size analyzer (LPSA). Both EA and XPS analysis results indicated that alternate immersion was an effective method for preparing MCM. Vibrating sample magnetometer, SEM and LPSA results showed that the microspheres had good dispersion, uniform particle size and were superparamagnetic. In addition, in vitro drug release behaviors of the microspheres were investigated by using hemoglobin (HB) and Coomassie brilliant blue G250 (CBB) as model drugs. It was found that the release rates of both HB and CBB from the composite microspheres were slower than those from the substrates. PMID- 24053816 TI - Improving reactive ink jet printing via cationization of cellulosic linen fabric. AB - Cellulose linen fabric samples subjected to cationization using different cationizing agents: dodecyl trimethyl ammonium bromide (DTAB), tetra methyl ammonium hydroxide (TMAH), and Quat-188, via pad batch technique, followed by ink jet printing with reactive dyes. The %N as well as the K/S of the cationized samples was found to be depends on: (a) the nature of the cationizing agent and (b) on the time of batching. As the latter increases both of the nitrogen content and K/S increases to a maximum depending on the nature of the reagent used. Further increase in the batching time up to 30 h is accompanied by a decrease in both the %N and K/S irrespective of the nature of the cationizing agent used. Cationization improves the printability of reactive dye ink jet printed linen fabrics with no remarkable effect on the overall color fastness properties. PMID- 24053817 TI - Optimization of antioxidant exopolysaccharidess production by Bacillus licheniformis in solid state fermentation. AB - Response surface methodology was applied to optimize physical and nutritional variables for the production of antioxidant exopolysaccharidess (EPSs) by Bacillus licheniformis UD061 in solid state fermentation with squid processing byproduct and maize cob meal used as a carbon and nitrogen source and solid matrix. The factors noted with Plackett-Burman design for optimization of EPSs production were NaCl, MgSO4.7H2O, and moisture level. These factors were further optimized using Box-Behnken design and response surface methodology. Using this methodology, the quadratic regression model of EPSs production was built. Maximum EPSs production was obtained under the optimal conditions of 4.08 g L(-1) NaCl, 0.71 g L(-1) MgSO4.7H2O, and 60.49% moisture level. A production of 14.68 mg gds( 1), which was well in agreement with the predicted value, was achieved by this optimized procedure. PMID- 24053818 TI - Therapeutic effect of Ginkgo biloba polysaccharide in rats with focal cerebral ischemia/reperfusion (I/R) injury. AB - An araban type polysaccharide (GBPw) was purified from the leaves of Ginkgo biloba. The present study aimed to investigate the protective effects of GBPw on focal ischemia/reperfusion (I/R) injury in rat brain. The results of this study demonstrated that GBPw had a positive effect on the rat brain when administered 7 days before focal cerebral I/R injury. This effect was evident with the improvements in neurological deficits, reduction in infarct volume, MDA content and the levels of pro-inflammatory cytokines (TNF-alpha and IL-1beta), and elevation in the SOD and MPO activities and the levels of anti-inflammatory cytokine (IL-10). Thus, the beneficial effects of GBPw on cerebral I/R injury may result from the reduction of oxidative stress and the inhibition of NO production and inflammation induced by I/R. The neuroprotective effects of GBPw supplement may have potential implication in the future for prevention/protection against cerebral ischemic stroke. PMID- 24053819 TI - Concentration dependent effects of dextran on the physical properties of acid milk gels. AB - The effect of dextran from Leuconostoc mesenteroides (DEX500), added to milk prior to acidification with glucono-delta-lactone (GDL) or Streptococcus thermophilus DSM20259, was studied with respect to polysaccharide concentration. The incorporation of 5-30 g/kg DEX500 significantly affected gelation behavior. Increasing DEX500 concentrations resulted in a linear increase of gel stiffness (GDL gels: R(2)=0.96; microbial acidification: R(2)=0.94; P<0.05) and 30 g/kg DEX500 resulted in a 2-fold higher stiffness compared to gels without polysaccharide. The respective stirred gels depicted a significant reduction in syneresis, which decreased from 30.4% (0 g/kg DEX500) to 22.0% (30 g/kg DEX500) for chemically acidified gels after 1 d of storage. Physical characteristics of DEX500 in aqueous solution were helpful to explain its behavior in the complex system milk. PMID- 24053820 TI - Ultrasonication of insulin-loaded microgel particles produced by internal gelation: impact on particle's size and insulin bioactivity. AB - Alginate-dextran sulfate (ADS) microgel has been used to protect insulin from gastrointestinal attack and as a carrier to promote insulin permeation through intestinal epithelium. The throughput of ADS submicron particles generation by emulsification/internal gelation is limited by its wide size distribution. The aim of this work was to study the recovery protocol influence on ADS particles through the determination of its impact on particles' size distribution and bioactivity. ADS particles showed a wide and multimodal distribution, characterized by a high aggregation phenomenon. In an attempt to reverse particles' tendency to aggregate and to homogenize particle size ADS populations were submitted to ultrasonication, while particle size distribution, physical and chemical stability, and the bioactivity of entrapped insulin were investigated. After ultrasonication a narrower particle population shifted to the nanoscale, with higher physical stability and significant insulin bioactivity was obtained. Emulsification internal/gelation followed by ultrasonication constituted a valid strategy to obtain ADS particles at the submicron range, with high stability and without significantly compromising insulin bioactivity, so offering promises, under previously well established conditions, to evaluate impact of ADS particle's size on biopharmaceutical and pharmacokinetics phases. PMID- 24053821 TI - Optimization of cationic amino starch synthesis using biogenic amines. AB - Harvesting microalgae presents a challenge in selecting the most economical method for low cost algal bioproducts. Previous studies have shown coagulation flocculation to be the most efficient method for large scale microalgae harvesting. This study focused on modifying native potato starch with biogenic amines and optimizing the reaction parameters. Such modification rendered the starch cationic, with an ability to destabilize microalgae suspensions or colloids. The effect of time, temperature, and reactant concentrations on the zeta potential of the cationic amino starch was studied. Biogenic amines including putrescine, histamine, cadaverine, and tyramine were selected for study based on the number of nitrogen groups in their structure. Zeta potential for histamine cationic amino starch was significantly higher (+9.0+/-2.0 mV) at lower reaction temperatures, regardless of the amine to starch ratio and reaction time intervals. Putrescine, cadaverine, and tyramine cationic amino starches exhibited significantly higher zeta potential values (13.76+/-3.60, 6.81+/-1.64, and 5.68+/ 1.60 mV, respectively) with amine to starch ratio higher than reaction stoichiometry, irrespective of reaction temperature or time intervals. This optimization study has presented a basis for designing reaction conditions for the synthesis of cationic amino starch from an inhomogeneous mix of biogenic amines derived from waste sources. PMID- 24053822 TI - Xylans are a valuable alternative resource: production of D-xylose, D-lyxose and furfural under microwave irradiation. AB - The influence of microwave irradiation on hydrolysis of xylan and simultaneous epimerization of the D-xylose to D-lyxose has been studied. An acidic solution of xylan was treated with catalytic amount of sodium molybdate and the composition of the reaction mixture was analyzed. Short reaction times of hydrolysis and subsequent epimerization reaction provided an equilibrium reaction mixture of D xylose and D-lyxose (1.6:1) without significant formation of undesirable side products. Obtained pentoses can be reduced to the corresponding alditols (D xylitol and D-lyxitol) in very good yields (88% and 85%) or can be further dehydrated to furfural (53%). Combined use of Mo(VI) catalyst and microwave irradiation allows better conversions and substantial reduction of reaction times (400-fold) compared to that obtained by conventional heating. Studied stereospecific transformation of xylan proceeds with high selectivity, short reaction times and very good yields that makes this approach attractive also for preparative purposes. PMID- 24053823 TI - Enhancement of rhubarb extract solubility and bioactivity by 2-hydroxypropyl-beta cyclodextrin. AB - Rhubarb is a traditional Chinese medicinal herb, and the ethanolic extract of rhubarb consists of active anthraquinones, which are hydrophobic and have antiproliferative effects on hepatoma cell lines. To increase the aqueous solubility of rhubarb and study the consequent bioavailability, the ethanolic extract of rhubarb was complexed with 2-hydroxypropyl-beta-cyclodextrin (HP-beta CD), a cyclic oligosaccharide that has a hydrophilic outer surface and a hydrophobic central cavity, to form a rhubarb-HP-beta-CD complex. This complex was characterized by performing nuclear magnetic resonance spectroscopy, two dimensional rotating frame spectroscopy and thin layer chromatography to confirm the inclusion of anthraquinones from rhubarb extract in HP-beta-CD (weight ratio of rhubarb extract:HP-beta-CD=1:9). We investigated the effects of complexing rhubarb extract with HP-beta-CD on the growth of Huh7 and HepG2 cells by performing cytotoxicity analysis, cellular uptake test, and colony formation assay. Our results showed that complexation of rhubarb extract with HP-beta-CD increased the aqueous solubility and bioavailability of rhubarb and thus enhanced its effect on hepatoma cells. PMID- 24053824 TI - Characterization of cellulose acetates according to DS and molar mass using two dimensional chromatography. AB - A two-dimensional liquid chromatographic method (2D LC) was developed to analyze the heterogeneities of cellulose acetates (CA) in the DS-range DS=1.5-2.9 with respect to both, molar mass and degree of substitution (DS). The method uses gradient liquid chromatography (HPLC) as the first dimension in order to separate by DS followed by separation of the different fractions by size (SEC) in the second dimension. The 2D experiments revealed different correlations between gradient and SEC elution volume. These correlations might arise from differences in the synthetic conditions. The newly developed 2D LC separation therefore provides new insights into the heterogeneity of CAs. PMID- 24053825 TI - Effects of the amylose-amylopectin ratio on starch-hydrocolloid interactions. AB - Combinations of 4 rice starches with amylose (AM) contents of 0%, 15%, 22%, and 28% and 8 hydrocolloids (xanthan, guar gum, CMC, sodium alginate, HPMC, kappa-, iota-, lambda-carrageenan) were used (4.75% starch and 0.25% hydrocolloid). With a few exceptions, addition of a hydrocolloid increased peak and final eta, breakdown, setback, G", and eta(*), K, and etaa,100 values. It is concluded that the AM content of the starch was a greater determinant of pasting, paste, and gel properties than was the added hydrocolloid at the 19:1 (w/w) starch-hydrocolloid ratio used. Reinforced is the previous conclusion that the properties of a starch hydrocolloid combination are determined by the specific combination. PMID- 24053826 TI - Evaluation of the mechanical damage on wheat starch granules by SEM, ESEM, AFM and texture image analysis. AB - The effect of mechanical damage on wheat starch granules surface, at a microstructural level, was investigated by scanning electron microscopy (SEM), environmental scanning electron microscopy (ESEM), atomic force microscopy (AFM), and image textural analysis. The SEM and ESEM images of the native sample showed that the starch granules had smooth, flat surfaces and smooth edges. The samples with higher damaged starch content exhibited granular distortion, irregularity and less uniformity. The fractal dimension of contour parameter increased with mechanical damage, indicating that the surface irregularities quantitatively increased due to the damage. The surfaces of damaged granules showed depressions of different shapes and sizes. The roughness parameters and fractal dimension of the surface increased as a result of the mechanical damage. The surface of damaged granules showed higher entropy and lower homogeneity values when damaged starch increased. The results indicated that the mechanical process caused structural modifications at nano level. PMID- 24053827 TI - Immunomodulatory activities of polysaccharides isolated from Taxillus chinensis and Uncaria rhyncophylla. AB - Taxillus chinensis and Uncaria rhyncophylla are the herbs used in traditional Chinese anticancer formulations. During the past decade, research on plant polysaccharides has gained importance due to their therapeutic value and minimum side effects. In this study, hot water extraction method was employed to isolate polysaccharides from the stems of T. chinensis and stems with hooks of U. rhyncophylla. Size-exclusion chromatography was then used for further fractionation. Separated fractions from T. chinensis were designated as TCP-1, TCP-2 and TCP-3 and those from U. rhyncophylla were termed UC-1 and UC-2. Their sugar compositions were estimated using gas chromatography that revealed the presence fructose, glucose, xylose, arbinose, and rhamnose. Amino acid analysis of these fractions has indicated that they are protein-bound polysaccharides. The antioxidant activities were investigated using DPPH and yeast assays. The ability of these polysaccharide fractions to stimulate mouse macrophages was measured using Griess reagent and ELISA test. The results revealed that some of the isolated fractions (TCP-2, TCP-3, UC-1 and UC-2) displayed significant antioxidant activities and were also found to be effective immunomodulators in a concentration-dependent manner. Outcomes of this research strongly indicate that U. rhyncophylla and T. chinensis have therapeutic potential to be used for the treatment of cancer. PMID- 24053828 TI - A galactomannan polysaccharide from Punica granatum imparts in vitro and in vivo anticancer activity. AB - Galactomannan polysaccharide (PSP001) was isolated from the fruit rind of Punica granatum and was previously reported to have excellent antioxidant and immunomodulatory properties. The cytotoxicity of PSP001 was evaluated in the human cancer cell lines A375, HCT116, and HepG2 as well as the murine cancer cell lines DLA and EAC over a wide range of concentrations. PSP001 exhibited significant cytotoxicity against cancer cells through the induction of apoptosis with no in vivo toxicity up to a concentration of 2000 mg/kg body weight when assessed in BALB/c mice. The antitumor efficacy of PSP001 was tested in DLA and EAC murine ascites and EAC solid tumor mouse models. PSP001 alone and in combination with doxorubicin produced a significant reduction in the tumor burden and increased life span in both models compared to the controls. The results suggest that PSP001 has the potential to be developed as an anticancer agent either alone or as an adjuvant to chemotherapy. PMID- 24053830 TI - The effect of low-frequency ultrasound on the activity and efficiency of a commercial cellulase enzyme. AB - A commercial acidic cellulase enzyme complex was chosen in order to gain detailed information about the effect of low-frequency ultrasound (horn at 40 kHz) on the enzyme activity. The performance of the enzyme under sonication was also evaluated in a cellulose-cellulase model reaction. The filter paper activity of the enzyme and the yield of the enzyme catalysed hydrolysis were determined as a function of the parameters of the sonicated environment (treatment time, amplitude, with and without a reflector) and compared with the data measured in a non-sonicated bath. Depending on the parameters of the sonication, the enzyme is susceptible to ultrasound and its activity can significantly decrease. Despite the serious reduction of the enzyme activity, the outcome of the enzyme catalysed hydrolysis was always positive, implying that the advantageous effects of sonication impressed on the heterogeneous enzyme reaction always overcome the undesirable enzyme modifying effect of ultrasound. PMID- 24053829 TI - Purification and characterisation of a bifunctional alginate lyase from novel Isoptericola halotolerans CGMCC 5336. AB - A novel halophilic alginate-degrading microorganism was isolated from rotten seaweed and identified as Isoptericola halotolerans CGMCC5336. The lyase from the strain was purified to homogeneity by combining of ammonium sulfate fractionation and anion-exchange chromatography with a specific activity of 8409.19 U/ml and a recovery of 25.07%. This enzyme was a monomer with a molecular mass of approximately 28 kDa. The optimal temperature and pH were 50 degrees C and pH 7.0, respectively. The lyase maintained stability at neutral pH (7.0-8.0) and temperatures below 50 degrees C. Metal ions including Na(+), Mg(2+), Mn(2+), and Ca(2+) notably increased the activity of the enzyme. With sodium alginate as the substrate, the Km and Vmax were 0.26 mg/ml and 1.31 mg/ml min, respectively. The alginate lyase had substrate specificity for polyguluronate and polymannuronate units in alginate molecules, indicating its bifunctionality. These excellent characteristics demonstrated the potential applications in alginate oligosaccharides production with low polymerisation degrees. PMID- 24053831 TI - Structural and physical properties of granule stabilized starch obtained by branching enzyme treatment. AB - Chemical cross-linking of starch is an important modification used in the industry for granule stabilization. It has been demonstrated that treatment with branching enzyme (BE) can stabilize the granular structure of starch and such treatment thereby provides a potential clean alternative for chemical modification. This study demonstrates that such BE-assisted stabilization of starch granules led to partial protection from BE catalysis of both amylose (AM) and amylopectin (AP) in their native state as assessed by triiodide complexation, X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). The granule stabilizing effects were inversely linked to hydration of the starch granules, which was increased by the presence of starch-phosphate esters and suppressed by extreme substrate concentration. The data support that the granule stabilization is due to the intermolecular transglycosylation occurring in the initial stages of the reaction prior to AM-AP phase separation. The enzyme activity needed to obtain granule stabilization was therefore dependent on the hydration capability of the starch used. PMID- 24053832 TI - Fabrication and characterisation of alpha-chitin nanofibers and highly transparent chitin films by pulsed ultrasonication. AB - alpha-Chitin nanofibers were fabricated with dried shrimp shells via a simple high-intensity ultrasonic treatment under neutral conditions (60 KHz, 300 W, pH=7). The diameter of the obtained chitin nanofibers could be controlled within 20-200 nm by simply adjusting the ultrasonication time. The pulsed ultrasound disassembled natural chitin into high-aspect-ratio nanofibers with a uniform width (19.4 nm after 30 min sonication). The EDS, FTIR, and XRD characterisation results verified that alpha-chitin crystalline structure and molecular structure were maintained after the chemical purification and ultrasonic treatments. Interestingly, ultrasonication can slightly increase the degree of crystallinity of chitin (from 60.1 to 65.8). Furthermore, highly transparent chitin films (the transmittance was 90.2% at a 600 nm) and flexible ultralight chitin foams were prepared from chitin nanofiber hydrogels. PMID- 24053833 TI - The effect of pH on hydrolysis, cross-linking and barrier properties of starch barriers containing citric acid. AB - Citric acid cross-linking of starch for e.g. food packaging applications has been intensely studied during the last decade as a method of producing water insensitive renewable barrier coatings. We managed to improve a starch formulation containing citric acid as cross-linking agent for industrial paper coating applications by adjusting the pH of the starch solution. The described starch formulations exhibited both cross-linking of starch by citric acid as well as satisfactory barrier properties, e.g. fairly low OTR values at 50% RH that are comparable with EVOH. Furthermore, it has been shown that barrier properties of coated papers with different solution pH were correlated to molecular changes in starch showing both hydrolysis and cross-linking of starch molecules in the presence of citric acid. Hydrolysis was shown to be almost completely hindered at solution pH>=4 at curing temperatures<=105 degrees C and at pH>=5 at curing temperatures<=150 degrees C, whereas cross-linking still occurred to some extent at pH<=6.5 and drying temperatures as low as 70 degrees C. Coated papers showed a minimum in water vapor transmission rate at pH 4 of the starch coating solution, corresponding to the point where hydrolysis was effectively hindered but where a significant degree of cross-linking still occurred. PMID- 24053834 TI - Structure and anticoagulant activity of fucosylated glycosaminoglycan degraded by deaminative cleavage. AB - Fucosylated glycosaminoglycans (FGs) are complex glycosaminoglycans that exhibit potent anticoagulant activity. To study the relationship between molecular size and biological activity, oligosaccharides with (2,5)-anhydro-D-talose units at new reducing ends were prepared by hydrazine deacetylation and nitrous acid depolymerization. The product chemical structures were analyzed by one- and two dimensional NMR methods. Additionally, anticoagulant activities were evaluated by clotting assay and chromogenic substrate cleavage. The results demonstrated that under mild deacetylation and deaminative cleavage conditions, both products were relatively homogeneous and sulfated fucose branch types and sulfate substituents remained stable. These depolymerized FGs with different molecular sizes had potent intrinsic anticoagulant activities, which were similar to those that were obtained by free-radical depolymerization with similar molecular weights. Decreasing molecular weight may weaken activity but not significantly affect factor Xase and heparin cofactor II (HCII)-mediated thrombin inhibition. PMID- 24053835 TI - Effects of extraction methods on the antioxidant activities of polysaccharides obtained from Flammulina velutipes. AB - Four polysaccharides (CFP, UFP, MFP and EFP) were extracted from Flammulina velutipes using hot water, ultrasonic, microwave or enzymatic methods optimized by orthogonal test. Preliminary structural characterizations were conducted using physicochemical properties. Polysaccharides extracted by all four methods showed similar physicochemical characteristics and FT-IR spectra. However, SEM images of tissues of F. velutipes were significantly different. EFP demonstrated better antioxidant activities against hydroxyl radical as well as improved metal chelating activity. UFP showed higher DPPH scavenging activity, but CFP exhibited higher antioxidant activity in reducing power. Hence, these polysaccharides can be used as natural antioxidants in functional foods or medicine. Further experiments on the biological activities of these four polysaccharides are currently in progress. PMID- 24053836 TI - All-cellulose and all-wood composites by partial dissolution of cotton fabric and wood in ionic liquid. AB - After cotton fabric (CF) and hinoki lumber (HL) were dipped in 1-butyl-3 methylimidazolium chloride (BMIMCl) at 100 degrees C, the BMIMCl-impregnated CF and HL were hot-pressed to give CF-BMIMCl and HL-BMIMCl composites, respectively. The BMIMCl contained in the composites was removed by Soxhlet extraction, and subsequently annealed to produce all-cellulose and all-wood composites (CF-A and HL-A). The SEM analyses revealed that cellulose fibers combined together for CF-A and the surface of HL-A became smooth, respectively. The XRD measurements indicated that the crystallinity index of cellulose component decreased by the hot press, increased by the extraction, and further increased by the annealing for both the composites. The tensile modulus of CF-A increased with increasing pressure of hot-press. Although tensile strength of HL-A was a little lower than that of original HL, tensile modulus of the former was much higher than that of the latter. PMID- 24053837 TI - Utilization of biopolymer in resist printing of linen fabrics using reactive dyes. AB - A novel utilization of chitosan as a cationic biopolymer in the chemical resist printing of linen fabrics and its polyester blend using reactive dyes. The effects of ratio and concentration of various resist-printing agents and processing conditions are observed and discussed. The concentration of chitosan, type of resist agent, and the ratio of chitosan to resist agent were varied to determine their effects on the efficiency of resist-printing. Regardless of the type of fabric, the resist effect on printed fabrics expressed as % decrease in K/S was obtained at optimal chitosan concentration of 1% with a mixture of chitosan/maleic acid as a resist salt at a ratio of 25:75. Thus, chitosan can be used pure or in admixture with different resist salts successfully in chemical resist printing. PMID- 24053838 TI - Antibacterial hydrogel coating by electrophoretic co-deposition of chitosan/alkynyl chitosan. AB - Despite much effort has been paid to develop aseptic implant devices, the infection associated with medical implant still remains a significant problem. Here, we report a potential coating material derived from a natural biopolymer chitosan. Firstly, chitosan functionalized with alkynyl moiety (ACS) was prepared by reaction between chitosan and 3-bromopropyne. The structure of the alkynyl chitosan was characterized by FT-IR, (1)H NMR, XRD, TGA and element analysis. The minimum inhibitory concentration (MIC) of ACS with a degree of substitution (DS) of 0.40 was 0.03% against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Subsequently, the alkynyl chitosan was co-deposited with chitosan on stainless steel wire to fabricate a composite hydrogel. The composite hydrogel exhibited better antibacterial activities than pure chitosan hydrogel. PMID- 24053839 TI - Effect of granular characteristics on pasting properties of starch blends. AB - Pasting and morphology properties of starch blends composed of waxy (waxy rice and waxy corn) and non-waxy (normal corn, tapioca and potato) starches at various ratios were investigated for elucidating effect of granular characteristics on pasting of blends. Pasting profiles of blends were between those of the component starches alone, while the changes varied with starch source. Results reveal obvious water competition during pasting for blends composed of waxy starch and highly swelling non-waxy (tapioca or potato) starch. On the contrary, starch blends composed of waxy starch and non-waxy (normal corn) starch with restricted swelling showed less water competition during pasting, and the pasting attributes could be estimated from those of the component starches following the mixing ratio. Results indicate that the pasting properties of starch blends composed of waxy and non-waxy starches depend on not only the mixing ratio, but also the granular characteristics of component starch. PMID- 24053840 TI - Response to "A note on an alternative DSC approach to study hydration of hyaluronan". PMID- 24053841 TI - Nano-cellulosic materials: the impact of water on their dissolution in DMAc/LiCl. AB - The dissolution behaviour of disassociated cellulosic materials in N,N dimethylacetamide/lithium chloride (DMAc/LiCl) was investigated. The parameters monitored were chromatographic elution profiles and recovered mass by means of gel permeation chromatography (GPC) with RI detection. In order to elucidate the impact of the disassembly on cellulosic fibres, comparative studies were performed with the non-disassociated cellulose counterparts. The importance of the presence of water was addressed by Karl Fischer titration and solvent exchange experiments. Morphological changes during the dissolution process were studied by scanning electron microscopy (SEM). Dissolution of fibrillated cellulosic materials is impeded compared to the non-fibrillated material. This is a consequence of the high-surface-area fibrils prone to retain high amounts of water. Dissolution behaviour of nano-crystalline cellulosic materials appeared to be source-dependent. Due to the absence of entangled networks, these materials retain only water bound at the surface of the nano-crystallites, indicative of both the exposed surface area and solubility. The small cellulose nano-particles extracted from dissolving pulp show lower solubility compared to the large NCC particles from cotton. PMID- 24053842 TI - Properties of novel polyvinyl alcohol/cellulose nanocrystals/silver nanoparticles blend membranes. AB - Novel polyvinyl alcohol (PVA) blend membranes containing cellulose nanocrystals (CNs) and silver nanoparticles (AgNPs) were prepared via a simple method. CNs were prepared by sulfuric acid treatment of microcrystalline cellulose. AgNO3 aqueous solution mixed with the CNs aqueous suspension and was reduced by NaBH4 at room temperature. Purified CNs/AgNPs nanocomposites as functional fillers mixed with polyvinyl alcohol to prepare blend membrane. The morphology, mechanical properties, and antibacterial activities of PVA/CNs/AgNPs composite films were investigated. The PVA/CNs/AgNPs composite films were stable and homogeneous. The tensile strength of PVA was increased from 57.02 MPa to 81.21 MPa when filled with CNs/AgNPs. Antibacterial ratio of PVA/CNs/AgNPs composite against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus was 96.9% and 88.2%, respectively. The CNs/AgNPs nanocomposites could be applied as bi-functional nanofillers within PVA to improve the mechanical properties and antibacterial activities. PMID- 24053843 TI - Effect of single and dual heat-moisture treatments on properties of rice, cassava, and pinhao starches. AB - The effects of single and dual heat-moisture treatment (HMT) of rice, cassava and pinhao starches at 100 degrees C and 120 degrees C were investigated. The starches were adjusted to 22% w.b. moisture content and subjected to single HMT (autoclaved for 2 h) or dual HMT (after being autoclaved for 1 h, the material was allowed to stand for 24 h and was autoclaved again for more 1 h). Starch crystallinity, solubility, swelling power, thermal properties, pasting properties, and gel hardness were evaluated. The temperature variation affected more the starch properties than the single or dual HMT. The starch subjected to single HMT at 120 degrees C was the most applicable to food applications, where low swelling power, low viscosity and high thermal stability are necessary. PMID- 24053845 TI - Reaction of octenylsuccinic anhydride with a mixture of granular starch and soluble maltodextrin. AB - The reaction of octenylsuccinic anhydride (OSA) with a mixture of granular waxy maize starch and soluble maltodextrin was investigated. OSA was reacted with a 1:1 (w/w) mixture of the granular starch and maltodextrin at OSA levels of 1.5, 3, 9, and 15% (wt% based on starch weight). After the first 0.5h of the reaction, degree of substitution (DS) on maltodextrin reached 0.021, 0.030, 0.080, and 0.10 for 1.5, 3, 9, and 15% OSA, respectively, whereas DS for granular starch was only 0.0020, 0.0087, 0.014, and 0.016. At 2h of the reaction, the bound OS ratio of maltodextrin to granular starch was 10.8 when OSA concentration was 1.5% and the ratio decreased to ca. 5 at higher OSA concentrations. OSA preferred to react with maltodextrin than semi-crystalline granular starch when both existed in the system. OSA reacted with maltodextrin at a much faster rate and to a greater extent than with granular starch, but a significant amount of OSA reacted with granular starch at 3-15% OSA concentrations. PMID- 24053844 TI - Overview of bacterial cellulose composites: a multipurpose advanced material. AB - Bacterial cellulose (BC) has received substantial interest owing to its unique structural features and impressive physico-mechanical properties. BC has a variety of applications in biomedical fields, including use as biomaterial for artificial skin, artificial blood vessels, vascular grafts, scaffolds for tissue engineering, and wound dressing. However, pristine BC lacks certain properties, which limits its applications in various fields; therefore, synthesis of BC composites has been conducted to address these limitations. A variety of BC composite synthetic strategies have been developed based on the nature and relevant applications of the combined materials. BC composites are primarily synthesized through in situ addition of reinforcement materials to BC synthetic media or the ex situ penetration of such materials into BC microfibrils. Polymer blending and solution mixing are less frequently used synthetic approaches. BC composites have been synthesized using numerous materials ranging from organic polymers to inorganic nanoparticles. In medical fields, these composites are used for tissue regeneration, healing of deep wounds, enzyme immobilization, and synthesis of medical devices that could replace cardiovascular and other connective tissues. Various electrical products, including biosensors, biocatalysts, E-papers, display devices, electrical instruments, and optoelectronic devices, are prepared from BC composites with conductive materials. In this review, we compiled various synthetic approaches for BC composite synthesis, classes of BC composites, and applications of BC composites. This study will increase interest in BC composites and the development of new ideas in this field. PMID- 24053846 TI - Functional finishes of stretch cotton fabrics. AB - Functionalized cotton cellulose/spandex woven fabrics with different structures namely plain (1/1), twill (2/2) and satin were produced. Factors affecting the imparted functional properties such as weave structure and constituents of the finishing formulations including ether or ester cross-linker and catalyst type, silicone-micro-emulsion, water/oil repellent, Ag-NP(,)s and TiO2-NP(,)s were studied. The treated fabrics were found to have easy care property together with one or more of the imparted functional properties such as soft-handle, water/oil repellence, antibacterial, UV-protection and self cleaning. The effectiveness of the imparted properties is not seriously affected even after 10 washing cycles. Surface modifications as well as the composition of certain samples were confirmed by SEM images and EDX spectra. Mode of interactions was also suggested. PMID- 24053847 TI - Radiation dose dependent change in physiochemical, mechanical and barrier properties of guar gum based films. AB - Mechanical and water vapor barrier properties of biodegradable films prepared from radiation processed guar gum were investigated. Films prepared from GG irradiated up to 500 Gy demonstrated significantly higher tensile strength as compared to non-irradiated control films. This improvement in tensile strength observed was demonstrated to be due to the ordering of polymer structures as confirmed by small angle X-ray scattering analysis. Exposure to doses higher than 500 Gy, however, resulted in a dose dependent decrease in tensile strength. A dose dependent decrease in puncture strength with no significant differences in the percent elongation was also observed at all the doses studied. Water vapor barrier properties of films improved up to 15% due to radiation processing. Radiation processing at lower doses for improving mechanical and barrier properties of guar based packaging films is demonstrated here for the first time. PMID- 24053848 TI - Chemical modification of chitin by grafting with polystyrene using ammonium persulfate initiator. AB - Chitin was successfully grafted with polystyrene by free radical mechanism using ammonium persulfate (APS) initiator. The reaction was carried out in aqueous medium. The effect of pH, chitin:monomer weight ratio, APS, reaction time and reaction temperature were investigated. The results showed that the optimum conditions for grafting of polystyrene were found as follows: pH 7, chitin:monomer weight ratio of 1:3, 0.4 g of APS, reaction temperature of 60 degrees C and reaction time 2 h. The graft copolymer was characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis (TGA) and differential scanning electron microscopy (DSC). Gel permeation chromatography (GPC) analysis carried out on the hydrolyzed graft copolymer showed that the Mn and Mw were 6.3395*10(4) g/mol and 1.69283*10(5) g/mol, respectively, with polydispersity index of 2.7. PMID- 24053849 TI - Synthesis and characterization of novel stimuli-responsive hydrogels based on starch and L-aspartic acid. AB - Starch is a hydrophilic biopolymer that is desirable in synthesizing new hydrogels. L-Aspartic acid is a multifunctional amino acid that can be used to modify starch in order to introduce new functional groups on its chains. In this research, a series of novel natural hydrogels based on starch and L-aspartic acid have been synthesized. These hydrogels exhibited temperature-responsive swelling behavior, pH sensitivity and superabsorbency properties. They were characterized by Nuclear Magnetic Resonance (NMR), Infra-Red Spectroscopy (IR), and X-ray Diffraction (XRD). The thermal properties of the hydrogels were evaluated using Thermo-Gravimetric Analysis (TGA) and Differential Scanning Calorimetery (DSC). Swelling studies were carried out at various temperatures and pHs. All of the hydrogels exhibited a high swelling ratio; in aqueous media, this value was greater at higher pH than at lower pH. These properties introduce a novel carrier having applications in delivery systems. PMID- 24053850 TI - Beneficial effects of a polysaccharide from Salvia miltiorrhiza on myocardial ischemia-reperfusion injury in rats. AB - In the present study, one water-soluble polysaccharide (SMP1) was isolated from the roots of Salvia miltiorrhiza. The cardio-protective potential of SMP1 was studied in the ischemia-reperfusion (I/R) model of rats in vivo. Results showed that 30 min of left anterior descending coronary artery occlusion (LAD) followed by 4 h of reperfusion markedly decreased myocardial superoxide dismutase (SOD), Na(+)-K(+)-ATPase and Ca(2+)-Mg(2+)-ATPase activities and increased myocardial malondialdehyde (MDA) level and serum activities of creatine kinase (CK) and lactate dehydrogenase (LDH) in I/R rats. An increase in infarct size and high apoptosis index of cardiac cell were also observed in IR rats. Administration of SMP1 400 and 800 mg/kg significantly reversed these biochemical parameters in the I/R rats to the normal levels in sham control rats. The infarct sizes and the percent of TUNEL-positive cells were found significantly decreased in SMP1 treated groups compared to I/R rats. Taken together, the present study clearly suggests SMP1 has a protective effect against myocardial I/R injury in rats by ameliorating oxidative stress and inhibiting myocardial apoptosis. PMID- 24053851 TI - Separation of TiO2 particles from water and water/methanol mixtures by cationic dextran derivatives. AB - Cationic polysaccharides with N-alkyl-N,N-dimethyl-N-(2-hydroxypropyl)ammonium chloride pendent groups attached to a dextran backbone were used to flocculate titanium dioxide (TiO2) particles suspended in water as well in water/methanol mixtures (90:10 and 50:50 v/v %). The investigations were performed with respect to the polycation dose, the suspension medium composition and the length of alkyl substituent at the quaternary nitrogen (alkyl=ethyl, octyl, dodecyl). The supernatant residual turbidity values were much lower for TiO2 particles dispersed in solvent mixtures than in water. This finding was explained by the solvent mixtures effect on the charges of both the particle surface and polyelectrolyte chains. The alkyl substituent length did not affect in a dramatic way the separation of TiO2 particles. The supernatant zeta potential dependence on the polycation dose when water/methanol mixtures were used as dispersion medium indicated a charge patch mechanism for the flocculation of TiO2 particles, which was supported by particle aggregates size measurements. PMID- 24053852 TI - Click grafting of seaweed polysaccharides onto PVC surfaces using an ionic liquid as solvent and catalyst. AB - Seaweed antibacterial polysaccharides were grafted onto poly(vinylchloride) (PVC) surfaces using an original click chemistry pathway. PVC isothiocyanate surfaces (PVC-NCS) were first prepared by nucleophilic substitution of the chloride groups by isothiocyanate groups in DMSO/water medium. Then, unmodified Ulvan, Fucan, Laminarin or Zosterin was directly grafted onto the PVC-NCS surface using 1-ethyl 3-methyl imidazolium phosphate, an ionic liquid, as solvent and catalyst. To attest the grafting effectiveness, the new PVC surfaces were well characterized by AFM, XPS and contact angle measurements. PMID- 24053853 TI - Characterisation of cell wall polysaccharides from rapeseed (Brassica napus) meal. AB - To enable structural characteristics of individual cell wall polysaccharides from rapeseed (Brassica napus) meal (RSM) to be studied, polysaccharide fractions were sequentially extracted. Fractions were analysed for their carbohydrate (linkage) composition and polysaccharide structures were also studied by enzymatic fingerprinting. The RSM fractions analysed contained pectic polysaccharides: homogalacturonan in which 60% of the galacturonic acid residues are methyl esterified, arabinan branched at the O-2 position and arabinogalactan mainly type II. This differs from characteristics previously reported for Brassica campestris meal, another rapeseed cultivar. Also, in the alkali extracts hemicelluloses were analysed as xyloglucan both of the XXGG- and XXXG-type decorated with galactosyl, fucosyl and arabinosyl residues, and as xylan with O-methyl-uronic acid attached. The final residue after extraction still contained xyloglucan and remaining (pectic) polysaccharides next to cellulose, showing that the cell wall matrix of RSM is very strongly interconnected. PMID- 24053855 TI - Multivariate-parameter optimization of aroma compound release from carbohydrate oil-protein model emulsions. AB - Optimization for retention and partition coefficient of ethyl acetate in emulsion model systems was investigated using response surface methodology in this paper. The effects of emulsion model ingredients, tragacanth gum (TG) (0.5-1 wt%), whey protein isolate (WPI) (2-4 wt%) and oleic acid (5-10%, v/v) on retention and partition coefficient of ethyl acetate were studied using a five-level three factor central composite rotatable design (CCRD). Results showed that the regression models generated adequately explained the data variation and significantly represented the actual relationships between the independent and response parameters. The results showed that the highest retention (97.20+/ 0.51%) and lowest partition coefficient (4.51+/-0.13%) of ethyl acetate were reached at the TG concentration 1 wt%, WPI concentration 4 wt% and oleic acid volume fraction 10% (v/v). PMID- 24053854 TI - Influence of Psyllium, sugar beet fibre and water on gluten-free dough properties and bread quality. AB - Celiac patients generally have a low intake of protein and fibre attributed to their gluten-free (GF) diet. To satisfy the increasing demand for healthier products, this research focused on the effects of the supplementation of Psyllium (P) and sugar beet fibre (SB) on the mixing and leavening behaviour of gluten free doughs. Four doughs, having different consistencies that made them suitable to be poured into moulds or to be shaped, and their corresponding breads were evaluated. The results obtained suggested that a lower consistency is preferred to assure good dough performances during leavening, in particular when ingredients having a high water affinity are included into the recipe. Both P and SB improved the workability of the doughs, but P played a central role on GF bread development, thanks to its film forming ability, and evidenced a more effective antistaling effect, thanks to its high water binding capacity. PMID- 24053856 TI - Study of the mechanism of formation of hyaluronan putty at pH 2.5: part I. Experimental measurements. AB - This paper reports on the elucidation of the possible mechanism for forming the putty structure of hyaluronan (HA) at low pH (2.5) using rheological methods. Oscillation and stress relaxation tests on a series HA putty samples containing various concentrations of salt indicated that ionic forces were not the driving force for their formation, but hydrogen bonds were responsible for driving two or more HA molecular chains together to form a three dimensional network. Our results indicated/confirmed that the carboxyl group of the glucuronic acid and acetamido group of N-acetylglucosamine moieties on two neighboring HA chains are involved in the formation of the intermolecular hydrogen bonding, which lead to the formation of the putty at pH 2.5. PMID- 24053858 TI - Analytical characterization of some synthetic cannabinoids, derivatives of indole 3-carboxylic acid. AB - By means of gas chromatography with high resolution mass spectrometry (GC-HRMS), ultra-high performance liquid chromatography in combination with high resolution tandem mass spectrometry (UHPLC-HRMS), nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FT-IR), structure of a series from a novel synthetic cannabinoids, derivatives of indole-3-carboxylic acid, was established. Methods for determination of the compounds in mixtures, involving chromatographic separation with mass-spectroscopic determination, were elaborated. Analytical data obtained in the paper will make reliable identification of synthetic cannabinoids of the new type during forensic examination possible. PMID- 24053857 TI - Study of the mechanism of formation of hyaluronan putty at pH 2.5: part II- theoretical analysis. AB - A new method was developed for quantitative determination of the viscoelastical characteristics of hyaluronic acid (HA) putty (formed at pH 2.5) using a stress relaxation approach. A concept of entanglement network numbers (ENN) was applied to provide a quantitative measure for the strength of HA putty. Based on the new approach, the relationship between ENN and HA concentration was established. The new approach was successfully applied to evaluate the effect of temperature, urea concentration and pH on putty strength as well as estimate the effects of glucose, beta1-3-linked D-glucuronic acid and beta1-4 linked D-N acetylglucosamine, on the ENN of HA solutions quantitatively. The ENN established in the current study can be extended to other non-cross linked hydrogels, i.e. they are formed by hydrogen bonds, ionic interactions or other non-covalent bonds. PMID- 24053859 TI - Parenteral buprenorphine-naloxone abuse is a major cause of fatal buprenorphine related poisoning. AB - Buprenorphine (BPN) medication for opioid maintenance treatment in Finland consists predominantly of buprenorphine-naloxone (BNX). Both BPN and BNX are associated with diversion, abuse and non-medically supervised use worldwide. Our purpose was to estimate the proportion of BNX to all BPN-related fatalities. The material consisted of 225 deceased drug abusers in Finland from January 2010 to June 2011 with a positive BPN and/or norbuprenorphine (NOR) and/or naloxone (NX) finding in urine. The data were divided into three groups based on the urine NX and BPN concentrations. The "Parenteral BNX" group (>100 MUg/l NX) was presumed to consist of injecting or snorting BNX abusers and the "Parenteral BPN" group (>50 MUg/l BPN, 0 MUg/l NX) of injecting or snorting BPN abusers, while the "Other BNX or BPN" group (<=100 MUg/l NX, or <=50 MUg/l BPN combined with 0 MUg/l NX) was presumed to consist of mainly sublingual BNX or BPN users. In 12.4% of cases the NX urine concentration was higher than the threshold 100 MUg/l. In fatal BPN poisonings, the proportion of parenteral BNX was 28.4%. In the "Parenteral BNX", "Parenteral BPN" and "Other BNX or BPN" groups, the proportion of fatal BPN poisonings was 67.9, 31.0 and 22.6%, respectively. BNX abuse can be fatal. Among the 225 BPN-related fatalities, parenteral abuse of BNX was shown to be common (12.4%) and BNX poisoning was the underlying cause of death in 8.4%. Parenteral BNX caused fatal BPN poisoning proportionally more often than parenteral BPN. PMID- 24053860 TI - Heat stress and sudden infant death syndrome--stress gene expression after exposure to moderate heat stress. AB - The aim of the present study was to investigate stress gene expression in cultured primary fibroblasts established from Achilles tendons collected during autopsies from sudden infant death syndrome (SIDS) cases, and age-matched controls (infants dying in a traumatic event). Expression of 4 stress responsive genes, HSPA1B, HSPD1, HMOX1, and SOD2, was studied by quantitative reverse transcriptase PCR analysis of RNA purified from cells cultured under standard or various thermal stress conditions. The expression of all 4 genes was highly influenced by thermal stress in both SIDS and control cells. High interpersonal variance found in the SIDS group indicated that they represented a more heterogeneous group than controls. The SIDS group responded to thermal stress with a higher expression of the HSPA1B and HSPD1 genes compared to the control group, whereas no significant difference was observed in the expression of SOD2 and HMOX1 between the two groups. The differences were related to the heat shock treatment as none of the genes were expressed significantly different in SIDS at base levels at 37 degrees C. SOD2 and HMOX1 were up regulated in both groups, for SOD2 though the expression was lower in SIDS at all time points measured, and may be less related to heat stress. Being found dead in the prone position (a known risk factor for SIDS) was related to a lower HSPA1B up-regulation in SIDS compared to SIDS found on their side or back. The study demonstrates the potential usefulness of gene expression studies using cultured fibroblasts established from deceased individuals as a tool for molecular and pathological investigations in forensic and biomedical sciences. PMID- 24053861 TI - Artificial neural network analysis of hydrocarbon profiles for the ageing of Lucilia sericata for post mortem interval estimation. AB - In analytical chemistry large datasets are collected using a variety of instruments for multiple tasks, where manual analysis can be time-consuming. Ideally, it is desirable to automate this process while obtaining an acceptable level of accuracy, two aims that artificial neural networks (ANNs) can fulfil. ANNs possess the ability to classify novel data based on their knowledge of the domain to which they have been exposed. ANNs can also analyse non-linear data, tolerate noise within data and are capable of reducing time taken to classify large amounts of novel data once trained, making them well-suited to the field of analytical chemistry where large datasets are present (such as that collected from gas chromatography-mass spectrometry (GC-MS)). In this study, the use of ANNs for the autonomous analysis of GC-MS profiles of Lucilia sericata larvae is investigated, where ANNs are required to estimate the age of the larvae to aid in the estimation of the post mortem interval (PMI). Two ANN analysis approaches are presented, where the ANN correctly classified the data with accuracy scores of 80.8% and 87.7% and Cohen's Kappa coefficients of 0.78 and 0.86. Inspection of these results shows the ANN to confuse two consecutive days which are of the same life stage and as a result are very similar in their chemical profile, which can be expected. The grouping of these two days into one class further improved results where accuracy scores 89% and 97.5% were obtained for the two analysis approaches. PMID- 24053862 TI - Rapid screening for detection and differentiation of detergent powder adulteration in infant milk formula by LC-MS. AB - Reports of infant milk formula adulteration by detergent powders as economic frauds and poisoning incidents are common as detergents are readily available and are inexpensive household items. Liquid chromatography (LC)-Qtrap and LC-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) in combination with chemometrics were effectively employed to detect the presence of detergent powder adulterated in infant milk formula. Partial least square analysis (PLS) regression was also utilized to quantify the amount of detergent powder in adulterated infant milk formula without the need to purchase any standards. Dodecylbenzenesulfonate (C12-LAS) was identified and verified as the marker which existed in detergent powder using LC-QTOF-MS. The amount of C12-LAS present in the admixture was successfully quantified through standard addition method. PMID- 24053863 TI - Development of a simple one-pot extraction method for various drugs and metabolites of forensic interest in blood by modifying the QuEChERS method. AB - A rapid and convenient extraction method has been developed for the determination of various drugs and metabolites of forensic interest in blood by modifying the dispersive solid-phase extraction method "QuEChERS". The following 13 analytes with various chemical properties were used for the method development and its validation: amphetamine, methamphetamine, zolpidem, the carboxylate-form major metabolite of zolpidem M-1, flunitrazepam, 7-aminoflunitrazepam, phenobarbital, triazolam, alpha-hydroxytriazolam, brotizolam, alpha-hydroxybrotizolam, chlorpromazine, and promethazine. The modification of the QuEChERS method includes the use of relatively large amounts of inorganic salts in order to coagulate blood, which allows easy isolation of the organic extract phase. A combination of 100 mg anhydrous magnesium sulfate as a dehydrating agent, 50mg sodium chloride as a salting-out agent, and 500 MUL acetonitrile containing 0.2% acetic acid as the organic solvent provided the optimum conditions for processing a 100 MUL whole blood sample. The recoveries of the analytes spiked into whole blood at 0.5 MUg/mL ranged between 59% and 93%. Although the addition of the graphitized carbon Envi-carb for cleanup decreased the recoveries of zolpidem and its carboxylate-form metabolite M-1, it was very effective in avoiding interferences by cholesterol. The present method can provide a rapid, effective, user-friendly, and relatively hygienic method for the simultaneous extraction of a wide range of drugs and metabolites in whole blood specimens. PMID- 24053864 TI - Life history data on the fly parasitoids Aleochara nigra Kraatz and A. asiatica Kraatz (Coleoptera: Staphylinidae), and their potential application in forensic entomology. AB - Knowledge of the developmental time of the immature stages of necrophagous flies has been the main tool for estimating minimum post-mortem intervals (min PMIs) in forensic entomology. Many parasitic insects can alter the development of immature stages of flies and thus affect min PMI estimates. The larvae of most species of Aleochara rove beetles are ectoparasitoids of the pupae of cyclorrhapha flies. Among them, some species that parasitise necrophagous flies may have forensic importance. Two Taiwanese Aleochara species, A. nigra and A. asiatica, which visit carrion sites were studied herein. All five necrophagous (Hemipyrellia ligurriens, Lucilia cuprina, Chrysomya megacephala, C. rufifacies and sarcophagid sp.) and one non-necrophagous fly species (Bactrocera dorsalis) we examined have the potential to be parasitised by these two Aleochara species, but differences among the acceptability and suitability of these hosts to rove beetle species suggested that rove beetles may prefer specific hosts. Each stage of the beetle life history was recorded to estimate developmental durations at six different temperatures. The larval stage together with the pupal stage of both beetle species was longer than the pupal stages of their hosts, implying the possibility of elongating the min PMI estimation. In addition, the host weight and larval duration of these two Aleochara beetles were positively correlated; thus, potential applications can be expected when using parasitised fly pupae in min PMI estimations. PMID- 24053865 TI - Feasibility study into use of elemental impurities of sulfamide for use in characterizing different vendors by inductively coupled plasma/mass spectrometry. AB - Inductively coupled plasma-mass spectrometery (ICP-MS) was used to quantitate elemental impurities in sulfamide from seven common vendors, Acros, Aldrich, Alfa Aesar, Fluka (Lot #1 and Lot #2), Maybridge, Pfaltz and Bauer, and Spectrum (Lot #1 and Lot #2) with the goal of using these impurities to differentiate the sulfamide samples and link the sulfamide back to its vendor. This attribution of the sulfamide back to its vendor is forensically relevant since sulfamide is a precursor to the deadly neurotoxin, tetramethylenedisulfotetramine (TETS). Solution ICP mass spectra identified statistically different concentrations of Cu, Fe, Ni, and Zn among some of the vendors and even in the same lots of the same vendor. These elemental concentrations were entered into discriminant functions which resulted in successful discrimination among the vendors. The two lots of Spectrum were also differentiated while one lot of Fluka was misclassified as the other Fluka lot. These preliminary results indicate the feasibility of using inorganic impurities to cluster vendors with the potential for association or disassociation of an unknown back to a vendor. PMID- 24053866 TI - A comparison of the performance of quality controls prepared from spiked, fortified and authentic hair for ethyl glucuronide analysis. AB - Ethyl glucuronide (EtG) quantification in hair was assessed using quality controls prepared by three methods: (a) spiking hair samples with known concentrations of EtG, (b) fortifying hair by incubation of blank hair with EtG for several days or (c) use of authentic hair samples positive for EtG. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed on a Shimadzu model 8030 instrument and validated for the quantification of EtG. For two concentration levels, approximately 50 and 500 pg/mg QCs, EtG concentrations were measured in duplicate (N=2) on 8 days (N=16) and intra-assay precision (repeatability) and inter-assay precision determined using one-way analysis of variance. EtG concentrations measured in authentic hair exhibited poor intra assay precision, with coefficients of variation of 25.1 and 20.9%, compared with 17.7 and 18.5% for fortified hair and 17.4 and 11.3% for spiked hair, for the lower and higher concentrations respectively. The inter-assay precision for authentic hair was also poorer, 35.7 and 22.5%, compared with fortified (28.2 and 19.8%) and spiked (18.4 and 13.2%) hair for the lower and higher concentrations. Although spiked QCs resulted in a better repeatability and inter-assay precision, the values obtained for QCs prepared from fortified and authentic hair are likely to be more representative of case specimens. These results have implications on the interpretation of EtG concentrations when spiked QCs are used to validate methods. PMID- 24053867 TI - Analysis of lipsticks using Raman spectroscopy. AB - In this study, 80 lipsticks were obtained and evaluated using Raman spectroscopy at excitation wavelengths of 532 and 780 nm. Fluorescence severely limited analysis with the 532 nm line while the 780 nm line proved useful for all samples analyzed. It was possible to differentiate 95% of the lipsticks evaluated based on one or more Raman peaks. However, there were no peak trends observed that could be used to identify a manufacturer or categorize a sample. In situ analysis of lipstick smears was found to be possible even from several Raman active substrates, but was occasionally limited by background fluorescence and in extreme cases, photodegradation. PMID- 24053868 TI - Coleoptera of forensic interest: a study of seasonal community composition and succession in Lisbon, Portugal. AB - Some Coleoptera are recognised as being forensically important as post-mortem interval (PMI) indicators, especially in the later stages of cadaver decomposition. Because insect species and their timings of appearance in cadavers vary according to geographic location, it is important to know their succession patterns, as well as seasonality at a regional level. In this study, we aimed to contribute to broaden this knowledge by surveying beetle communities from the Lisbon area during the four seasons of the year, using piglet carcasses as animal models. Five stages were recognised during the decomposition process and they could be separated taking into account the occurrence and abundance of the specific groups of Coleoptera collected. Decay stages in general recorded higher abundance and richness of beetle species. A total of 82 species were identified, belonging to 28 families, in a total of 1968 adult Coleoptera collected. Autumn yielded the highest values of species abundance and richness, while the lowest values were recorded during winter. Staphylinidae was the most abundant family in all seasons, although in spring and summer Dermestidae was also quite dominant. In general, most species were related to the decay stages, particularly Margarinotus brunneus (Histeridae) and Creophilus maxillosus (Staphylinidae), and also Saprinus detersus (Histeridae) and Thanatophilus sinuatus (Silphidae), while only few were related to the dry stage, namely Oligota pusillima (Staphylinidae) and Dermestidae spp. larvae. On the other hand, Anotylus complanatus and Atheta pertyi (Staphylinidae) were apparently more associated with the fresh and bloated stages, respectively. The presence of some species was markedly seasonal, allowing a season characterisation based on the occurrence of certain taxa, which can be useful for forensic purposes. PMID- 24053869 TI - Shape measurement tools in footwear analysis: a statistical investigation of accidental characteristics over time. AB - Presence of accidental characteristics on footwear strengthens the linkage of a given piece of footwear to a footwear impression left at a crime-scene. Thus an understanding of rate of appearance and disappearance of these characteristics is of importance. Artificial cut-marks, 1-3mm in depth, were cut into outsoles of 11 pairs of athletic shoes. Loss of these cut-marks and acquisition of new accidental characteristics/wear patterns were monitored over a seven-week time span. Feature-vector methods were used to acquire multivariate data on wear/acquisition rates. A repeatability study indicated the feature vector method could detect small differences among shoes relative to measurement uncertainty. The shoes displayed a strong retention of artificial cut-marks over the study interval. Net rate of wear was 0.1% of the textured area of the shoe per week, predominantly in the heel and ball area. Results indicate accidental characteristics can reasonably be expected to persist over time. PMID- 24053870 TI - Biological organisms as volatile compound detectors: a review. AB - The detection and identification of volatile compounds is essential to the successful undertaking of numerous forensic analyses. Biological olfactory systems possess the extraordinary ability to not only detect many thousands of distinct volatile compounds (odors) but also to discriminate between them. Whole organism biological sensors, such as detection canines, have been employed in forensic science as volatile compound detectors for many years. A variety of insects including bees, wasps, and moths, which have also been shown to detect volatile compounds of forensic significance, have been investigated for their potential application in field-based detection systems. While the fundamental aim for many developers of portable instruments is to replicate the remarkable ability of biological olfactory systems, such analytical equipment is yet to possess the detection and discriminatory powers achieved by biological sensors. Recent literature reveals an increasing interest in olfactory receptors - the biological components that impart olfactory ability - for detecting volatile compounds associated with forensically significant substances such as explosives and illicit drugs. This paper reviews the literature regarding the current, and potential future, use of biological organisms as sensors for forensic science applications. PMID- 24053871 TI - The performance of BALISTIKA 2010 system for 9 mm * 19 mm and 7.65 mm * 17 mm cartridge case correlation. AB - The firearm identification has two examination phases; the first phase is "one by one" cartridge case or bullet identification. The second phase is "Open Case File (OCF)" examination. Due to the size of the OCF archive, the OCF examination with only comparison microscopes takes a long time and is an unfeasible process. The Computerized Ballistic Identification Systems (CBIS) has become an essential tool for archive examination by correlation and preliminary eliminations. In this study, two objectives were pursued; the first is measuring the performance of the BALISTIKA 2010 system on cartridge case acquisition of handguns, correlation and examination. The second objective is the examination of the performance on the correlation according to brand and models of firearms. Detailed experimental results are demonstrated for about 2000 cartridge cases. PMID- 24053872 TI - Towards the integration of matrix assisted laser desorption ionisation mass spectrometry imaging into the current fingermark examination workflow. AB - A wide range of fingermark enhancement techniques (FET) is currently employed to visualise latent fingermarks at crime scenes. However, if smudged, partial, distorted or absent in the National Fingerprint Database, crime scene marks may be not useful for identification purposes. In these circumstances, a technology enabling chemical imaging of both endogenous and exogenous species contained within the fingermark could provide additional and associative investigative information, to profile the suspect's activities prior to the crime. Matrix Assisted Laser Desorption Ionisation Mass Spectrometry Imaging (MALDI MSI) has proven to be such a technique, enabling investigative information to be gathered, for example, on what substances the donor has come in contact with and what they have ingested. Nonetheless, to be employed, MALDI MSI has to be validated and its compatibility with FET tested for integration into the standard fingermark examination workflow. For the first time, a direct comparison has been made between the efficiency of a range of FET and MALDI MSI under different conditions. This information will build towards validation of the technology. Also, for the first time, MALDI MSI has been successfully employed as a sequential step following fingermark enhancement using many of the currently employed FET. Additionally, known enhancers have been "re-visited" by combining them with a MALDI matrix, providing both improved fingermark development and chemical species detection via MALDI MSI. The result reported here are good indication in favour of the integration of MALDI MSI into the current fingermark examination workflow for gathering additional investigative information. PMID- 24053873 TI - A comparison of breath- and blood-alcohol test results from real-life policing situations: a one-year study of data from the Central Hessian police district in Germany. AB - So far, studies investigating the comparability of breath alcohol concentration (BrAC) with blood alcohol concentration (BAC) have focused on the accuracy of BrAC testing instruments. The presented study, conducted with cases from the district of the Middle Hessian Police Headquarters, is to the best of our knowledge the first to compare both methods under real-life conditions in normal policing situations. For a 1-year period, alcohol-impaired drunk-driving suspects, who were by criminal procedure required to give a blood sample, were offered a voluntary, additional BrAC test with a "Drager Alcotest 7110 Evidential". The BrAC test was to be administered as soon as possible after the suspect had been apprehended, without, however, delaying the collection of the blood sample. Ninety-two cases could be included in our study. In 30 cases, a blood sample was not taken; in 11 cases, a BrAC test could not be performed. In the remaining 51 cases, we found the following pairings of BrAC and BAC results: BrAC>=0.55 mg/l and BAC>=1.10/00 (n=39); 0.25 mg/l<=BrAC<0.55 mg/l and 0.50/00<=BAC<1.10/00 (n=5); BrAC>=0.55 mg/l and BAC<1.10/00 (n=4); BrAC<0.55 mg/l and BAC>=1.10/00 (n=3). The mean value for the conversion factor, Q, was 2.120/00l/mg. In accord with numerous other studies, our study results would suggest a value of 2.10/00 l/mg to German legislature as a new statutory value for Q. In borderline cases, of which there were already 7 in our study with 51 cases, suspects could benefit both from a BrAC test or a BAC test, with the benefit lastly depending more on early testing time than on the test method used. Our results support the call for the earliest possible measurement of alcohol concentration values after a drunk driving offense was committed. In some situations, this can probably only be accomplished with BrAC testing. A supplementary blood sample and BAC testing could compensate for the known weaknesses of BrAC testing. Thus, the complementary use of both methods might be a viable option. PMID- 24053874 TI - Modern statistical models for forensic fingerprint examinations: a critical review. AB - Over the last decade, the development of statistical models in support of forensic fingerprint identification has been the subject of increasing research attention, spurned on recently by commentators who claim that the scientific basis for fingerprint identification has not been adequately demonstrated. Such models are increasingly seen as useful tools in support of the fingerprint identification process within or in addition to the ACE-V framework. This paper provides a critical review of recent statistical models from both a practical and theoretical perspective. This includes analysis of models of two different methodologies: Probability of Random Correspondence (PRC) models that focus on calculating probabilities of the occurrence of fingerprint configurations for a given population, and Likelihood Ratio (LR) models which use analysis of corresponding features of fingerprints to derive a likelihood value representing the evidential weighting for a potential source. PMID- 24053875 TI - A simple DNA coprecipitation method for the detection of diatoms in heart blood. AB - We developed a method for detecting and enumerating diatoms in the heart blood of drowning victims and evaluate its utility for diagnosing death by drowning. For purification of diatoms from blood, the DNA binding ability of the diatom frustule in the presence of a chaotropic agent was utilized. The procedure is basically the same as the commonly used method for DNA purification from blood using Proteinase K treatment and denaturation by a chaotropic agent. DNA adsorbed to the diatom (DNA/diatom complex) is recovered by ethanol precipitation, and the DNA is subsequently digested using DNase. Purified diatoms could be clearly observed under a microscope. Diatoms spiked in the blood of non-drowned cadavers (n=15) were well recovered, and were detected in heart blood from all drowning victims (n=22). The mean number of diatoms found in 5 ml of blood from drowning victims was 7.8+/-5.8 (mean+/-SD), and the number of diatoms detected in the blood of the left ventricle (6.1+/-5.8) was approximately two times higher than that of the right ventricle (3.0+/-2.7, p<0.05). These results suggest that this simple and safe method can become an effective tool for diagnosing the cause of death as drowning. PMID- 24053876 TI - Screening for trace explosives by AccuTOFTM-DART(r): an in-depth validation study. AB - Ambient ionization mass spectrometry is finding increasing utility as a rapid analysis technique in a number of fields. In forensic science specifically, analysis of many types of samples, including drugs, explosives, inks, bank dye, and lotions, has been shown to be possible using these techniques [1]. This paper focuses on one type of ambient ionization mass spectrometry, Direct Analysis in Real Time Mass Spectrometry (DART-MS or DART), and its viability as a screening tool for trace explosives analysis. In order to assess viability, a validation study was completed which focused on the analysis of trace amounts of nitro and peroxide based explosives. Topics which were studied, and are discussed, include method optimization, reproducibility, sensitivity, development of a search library, discrimination of mixtures, and blind sampling. Advantages and disadvantages of this technique over other similar screening techniques are also discussed. PMID- 24053877 TI - Elemental analysis of white electrical tapes by wavelength dispersive X-ray fluorescence spectrometry. AB - The aim of this study was to analyze and discriminate electrical tapes using the wavelength dispersive X-ray fluorescence (XRF) spectrometry and statistical techniques. The backings of 46 white electrical tapes were analyzed. A discrimination of 90.4% was performed only by quantitative analysis of major elements (relative ratio of Cl to Ca). Ten distinct groups with a discrimination of 78.9% were yielded only by qualitative analysis of trace elements. Ninety-nine electrical tape pairs which could not be discriminated by major elements were further compared with the characteristics of trace elements. The overall discriminating power of 96.1% was obtained by the combination of quantitative and qualitative analysis. The ability of XRF technique to discriminate different electrical tapes was similar to several well-known methods combined. PMID- 24053878 TI - Simultaneous labeling of multiple components in a single fingermark. AB - A fingermark contains important forensic information of the donor, not only in its ridge pattern, but also in the chemical composition of its secretion. Detection and identification of these secretions can be done by immunolabeling. In this study, we describe for the first time a reproducible immunolabeling method that allows the simultaneous detection of multiple components of interest. This method not only reduces the manipulation of fingermarks, but also different types of information can be obtained about the donor in one labeling session. To prove the concept of this technique, we selected two general components as antigens of interest, dermcidin and the human serum albumin. Conjugation of both antibodies to two different synthetic fluorophores, followed by simultaneous incubation of both conjugated antibodies, resulted in successful multiple immunolabeling of fingermarks left on a porous nitrocellulose membrane and on a non-porous glass slide surface. In order to minimize false positives to prevent non-specific binding of antibodies to fingermarks and surface carriers, careful blocking and washing steps were found crucial. With this reproducible protocol, high quality images could be obtained from the multiple labeled fingermarks. In conclusion, simultaneous multiple immunolabeling of antibodies in fingermarks can identify specific components in the secretion of the fingermark, including components related to hygiene, diet, time of day, contacts gender and drug use. Multiple immunolabeling therefore has the potential to make a major impact in the forensic field. PMID- 24053879 TI - The systematic profiling of false identity documents: method validation and performance evaluation using seizures known to originate from common and different sources. AB - False identity documents constitute a potential powerful source of forensic intelligence because they are essential elements of transnational crime and provide cover for organized crime. In previous work, a systematic profiling method using false documents' visual features has been built within a forensic intelligence model. In the current study, the comparison process and metrics lying at the heart of this profiling method are described and evaluated. This evaluation takes advantage of 347 false identity documents of four different types seized in two countries whose sources were known to be common or different (following police investigations and dismantling of counterfeit factories). Intra source and inter-sources variations were evaluated through the computation of more than 7500 similarity scores. The profiling method could thus be validated and its performance assessed using two complementary approaches to measuring type I and type II error rates: a binary classification and the computation of likelihood ratios. Very low error rates were measured across the four document types, demonstrating the validity and robustness of the method to link documents to a common source or to differentiate them. These results pave the way for an operational implementation of a systematic profiling process integrated in a developed forensic intelligence model. PMID- 24053880 TI - Modeling microbial ethanol production by E. coli under aerobic/anaerobic conditions: applicability to real postmortem cases and to postmortem blood derived microbial cultures. AB - The mathematical modeling of the microbial ethanol production under strict anaerobic experimental conditions for some bacterial species has been proposed by our research group as the first approximation to the quantification of the microbial ethanol production in cases where other alcohols were produced simultaneously with ethanol. The present study aims to: (i) study the microbial ethanol production by Escherichia coli under controlled aerobic/anaerobic conditions; (ii) model the correlation between the microbial produced ethanol and the other higher alcohols; and (iii) test their applicability in: (a) real postmortem cases that had positive BACs (>0.10 g/L) and co-detection of higher alcohols and 1-butanol during the original ethanol analysis and (b) postmortem blood derived microbial cultures under aerobic/anaerobic controlled experimental conditions. The statistical evaluation of the results revealed that the formulated models were presumably correlated to 1-propanol and 1-butanol which were recognized as the most significant descriptors of the modeling process. The significance of 1-propanol and 1-butanol as descriptors was so powerful that they could be used as the only independent variables to create a simple and satisfactory model. The current models showed a potential for application to estimate microbial ethanol - within an acceptable standard error - in various tested cases where ethanol and other alcohols have been produced from different microbes. PMID- 24053881 TI - Forensic pathological evaluation of postmortem pulmonary CT high-density areas in serial autopsy cases of sudden cardiac death. AB - Previous studies suggested substantial postmortem interference with pulmonary CT findings. The present study evaluated postmortem CT (PM-CT) morphology of the lung, compared with histology, in autopsy cases of sudden cardiac death without recovery from cardiac arrest (SCD, n=22) with regard to the posture at the time of death and postmortem interference from a forensic pathological viewpoint. In witnessed cases (n=5), a case of SCD in a prone position had anterior consolidation with weak hypostatic opacification in the posterior about 18 h later. Among unwitnessed deaths (n=17), 8 cases of death lying prone, sitting facedown and lying laterally had possible gravity-dependent opacity about 15-38 h postmortem. Hypostatic opacification with 'niveau' formation was not evident in more than half of the cases (n=15). Histological findings for ground glass opacification and consolidation on PM-CT varied by case, involving intraalveolar edema and hemorrhages, accompanied by marked congestion; however, possible postmortem hypostatic opacification mostly represented intraalveolar edema. CT morphology of acute pulmonary congestion in SCD may often remain without serious postmortem interference in cases without clinical intervention involving massive fluid infusion, suggesting plain PM-CT findings of the lung to be useful for investigating the death process when combined with histology; however, the possible influence of the hydration status of the lungs at the time of death should be assessed by evaluation of CT and autopsy findings. PMID- 24053882 TI - Raman spectroscopy for forensic analysis of inks in questioned documents. AB - The methods for perpetrating forgery and alteration of documents are becoming increasingly more sophisticated. Forensic examinations of questioned documents routinely involve physical and chemical analysis of inks. Raman spectroscopy is a very attractive technique for ink analysis because it combines chemical selectivity with ease and fast analysis and it does not require sample preparation nor leads to destruction of the evidence. However, some limitations of this technique include low sensitivity and the overwhelming phenomenon of fluorescence, which can be solved by resonance Raman spectroscopy and surface enhanced Raman spectroscopy. This article aims to demonstrate the great potential of the Raman-based techniques by providing an overview of their application to forensic examinations of ink evidence from pens and printers. Moreover, it is also addressed the chemistry of ink-paper interactions and the problematic of intersecting lines. PMID- 24053883 TI - Ethyl glucuronide findings in hair samples from the mummies of the Capuchin Catacombs of Palermo. AB - The Capuchin Catacombs of Palermo contain over 1800 preserved bodies: friars, priests and laypeople including men, women, and children. The bodies were accessible to family members who could visit the deceased and commemorate them through prayers. The "Sicily Mummy Project" analyzed hair samples from 38 mummies to determine the presence of ethyl glucuronide (EtG) using a routine procedure in our accredited laboratory of liquid chromatography coupled with mass spectrometry. The limit of quantification was 2.3 pg/mg. The hair samples were from 1.5 to 12 cm in length. All samples were analyzed in 2 segments (seg. A 0-3 cm and seg. B the remainder). Samples <4 cm in length were cut in half. In 31 out of 76 segments positive results were obtained for EtG, with concentrations between 2.5 and 531.3 pg/mg (mean 73.8, median 13.3 pg/mg). In 14 cases positive results were obtained for both segments. In one sample a positive result was obtained for segment A but not for segment B and in a further two samples only for segment B. The results indicate that EtG analyses can be performed on mummy hair samples even several hundred years after death to identify evidence for significant alcohol consumption during life. PMID- 24053884 TI - Studies on RNA integrity and gene expression in human myocardial tissue, pericardial fluid and blood, and its postmortem stability. AB - Analyses of gene expression of ischemic myocardial injury and repair related proteins has been carried out for the first time in samples from five specific sites of the myocardium, pericardial fluid and blood from thirty cadavers in relation to post-mortem interval (PMI). RNA integrity was evaluated by RNA integrity number (RIN), with values ranging from 6.57 to 8.11; sufficiently high levels of integrity to permit further gene amplification. No significant correlations between RIN and PMI in any samples were detected. Prior to target gene expression analysis, a normalization strategy was carried out to assess candidate reference gene stability, involving the analysis and comparison of four common housekeeping genes (Glyceraldehide-3-phosphate dehydrogenase, beta-actin, TATA box binding protein and Cyclophilin A). Gene expression of cardiac troponin I (TNNI3), myosin light chain 3 (MYL3), matrix metalloprotease 9 (MMP9), transforming growth factor beta 1 (TGFB1), and vascular endothelial growth factor A (VEGFA) in myocardial zones and body fluids were subsequently studied by real time quantitative PCR. Expression levels of all the proteins studied in cardiac zone samples were similar. No statistical differences for expression were detected among proteins taken from any myocardial area. No significant differences were detected for TNNI3 and TGFB1 gene expressions when compared with samples at or under 12h-PMI or over 12h-PMI. However, differences in MYL3, MMP9, and VEGFA gene expression in body fluids were found at PMI periods of over 12h. These interesting results may contribute to the refinement of current knowledge regarding cardiac metabolism and improve understanding of the underlying mechanisms involved in myocardium ischemia and its repair. PMID- 24053885 TI - Determination of ethyl glucuronide levels in hair for the assessment of alcohol abstinence. AB - This study examined the potential of a highly sensitive LC-MS/MS method for the determination of EtG in head hair (i) to ascertain alcohol abstinence, (ii) to estimate the basal level of EtG (sub-ppb concentrations) in head hair in a population of alcohol abstainers and (iii) to suggest a revision of cut-off values for assessing alcohol abstinence. An UHPLC-MS/MS protocol previously developed was modified and validated again to detect low EtG levels in head hair samples from a population of 44 certain abstainers and teetotalers. Basal level of EtG in hair was determined by a standard addition quantification method. The validated UHPLC-MS/MS method allowed detecting and quantifying 0.5 and 1.0 pg/mg of EtG in hair, respectively. EtG concentrations lower than 1.0 pg/mg were determined for 95% of abstainers; 30% of them had non-detectable (<0.5 pg/mg) EtG values. Two samples evidenced EtG concentrations higher than 1.0 pg/mg that were subsequently explained by unintentional ethanol exposure. The method's feature of high analytical sensitivity makes it particularly suitable for alcohol abstinence ascertainment and, in the same time, allows to tentatively estimate basal EtG concentrations in hair around 0.8+/-0.4 pg/mg. This finding opens a discussion on the possible origin of basal EtG concentration and potential sources of bias in the evaluation of alcohol abstinence. Cut-off value in the range of 1.0-2.0 pg/mg can be reliably proposed to support alcohol abstinence. PMID- 24053886 TI - Overweight and obesity in young Turkish, Moroccan and Surinamese migrants of the second generation in the Netherlands. AB - OBJECTIVE: To examine differences in overweight and obesity of second-generation Turkish, Moroccan and Surinamese migrants v. first-generation migrants and the ethnic Dutch. We also studied the influence of sociodemographic factors on this association. DESIGN: Data were collected in 2008 in a cross-sectional postal and online health survey. SETTING: Four major Dutch cities. SUBJECTS: In the survey 42 686 residents aged 16 years and over participated. Data from Dutch (n 3615) and second/first-generation Surinamese (n 230/139), Turkish (n 203/241) and Moroccan (n 172/187) participants aged 16-34 years were analysed using logistic regression with overweight (BMI >= 25.0 kg/m2) and obesity (BMI >= 30.0 kg/m2) as dependent variables. BMI was calculated from self-reported body height and weight. Sociodemographic variables included sex, age, marital status, educational level, employment status and financial situation. RESULTS: After controlling for age, overweight (including obesity) was more prevalent in most second-generation migrant subgroups compared with the Dutch population, except for Moroccan men. Obesity rates among second-generation migrant men were similar to those among the Dutch. Second-generation migrant women were more often obese than Dutch women. Ethnic differences were partly explained by the lower educational level of second generation migrants. Differences in overweight between second- and first generation migrants were only found among Moroccan and Surinamese men. CONCLUSIONS: We did not find a converging trend for the overweight and obesity prevalence from second-generation migrants towards the Dutch host population. Therefore, preventive interventions should also focus on second-generation migrants to stop the obesity epidemic. PMID- 24053887 TI - Adipose tissue alterations in critical illness: a paradox as to patient outcomes. AB - Adipocyte morphological changes in critically ill patients have been reported, potentially providing beneficial effects. Marques and colleagues reported that these morphological adipocyte changes, as well as accumulation of M2 phenotype macrophages, occur irrespective of nutritional status in the critically ill. The present study provides insight into the alterations that occur, although further studies are needed to fully understand the role that adipose tissue plays in the critically injured. PMID- 24053888 TI - Heart dysfunction in patients with acute ischemic stroke or TIA does not predict all-cause mortality at long-term follow-up. AB - BACKGROUND: Despite heart failure being a substantial risk factor for stroke, few studies have evaluated the predictive value of heart dysfunction for all-cause mortality in patients with acute ischemic stroke, in particular in the elderly. The aim of this study was to investigate whether impaired heart function in elderly patients can predict all-cause mortality after acute ischemic stroke or transient ischemic attack (TIA). METHODS: A prospective long-term follow-up analysis was performed on a hospital cohort consisting of n = 132 patients with mean age 73 +/- 9 years, presenting with acute ischemic stroke or transient ischemic attack, without atrial fibrillation. All patients were examined by echocardiography during the hospital stay. Data about all-cause mortality were collected at the end of the follow-up period. The mean follow-up period was 56 +/ 22 months. RESULTS: In this cohort, 58% of patients with acute ischemic stroke or TIA had heart dysfunction. Survival analysis showed that heart dysfunction did not predict all-cause mortality in this cohort. Furthermore, in multivariate regression analysis age (HR 5.401, Cl 1.97-14.78, p < 0.01), smoking (HR 3.181, Cl 1.36-7.47, p < 0.01), myocardial infarction (HR 2.826, Cl 1.17-6.83, p < 0.05) were independent predictors of all-cause mortality. CONCLUSION: In this population with acute ischemic stroke or TIA and without non-valvular atrial fibrillation, impaired heart function does not seem to be a significant predictor of all-cause mortality at long-term follow-up. PMID- 24053889 TI - Occult lymph node metastases in patients with carcinoma invading bladder muscle: incidence after neoadjuvant chemotherapy and cystectomy vs after cystectomy alone. AB - OBJECTIVE: To investigate the effect of neoadjuvant chemotherapy (NAC) on the incidence of lymph node (LN) metastases in clinically node-negative (cN0) patients with carcinoma invading the bladder muscle (MIBC). PATIENTS AND METHODS: Between 1990 and 2012, 828 consecutive patients underwent radical cystectomy (RC) with extended pelvic LN dissection (ePLND), of whom 441 had cT2-4N0M0 stage disease. A total of 83 patients received NAC then underwent RC and 358 patients underwent RC only. The ePLND template and the indication for NAC remained the same during the study period. The incidence of occult LN metastases was compared between the groups. Unadjusted and adjusted odds ratios (ORs) were calculated to investigate the influence of NAC, cT stage, gender and the preoperative staging technique used (computed tomography [CT] or positron emission tomography/CT) on the occurrence of LN metastases. Overall survival (OS) and disease-specific survival were analysed using the Kaplan-Meier method. RESULTS: Patients in the NAC group more often had locally advanced MIBC than patients in the non-NAC group (cT3-4: 88.0 vs 30.2%). In the NAC group, 19.3% of patients had LN metastases vs 28.5% of the patients in the non-NAC group (P = 0.099). In the patients with cT3 4 disease, the occurrence of LN metastases was significantly lower in the NAC group than in the non-NAC group (21.9 vs 40.7%, respectively, P = 0.002). In multivariable analysis, adjusting for cT stage, gender and staging method, NAC was independently associated with a lower likelihood of LN metastases (OR: 0.41, 95% CI 0.21-0.79; P = 0.008). Among the patients with cT3-4 disease, the median OS was significantly longer in the NAC group than in the non-NAC group (68.0 vs 23.0 months, P = 0.047) CONCLUSION: These data suggest that, along with a downstaging effect on the primary bladder tumour, NAC is associated with a lower incidence of occult LN metastases at the time of RC. PMID- 24053890 TI - Timing of surgery of the anterior cruciate ligament. AB - PURPOSE: We aimed to perform a systematic review of the literature concerned with timing of surgery after anterior cruciate ligament injury. METHODS: A systematic electronic search in Medline through PubMed, Embase, and the Cochrane Library was carried out in October 2011. All English-language randomized controlled clinical trials, prospective comparative cohort studies, and prognostic and diagnostic studies published from January 1995 to August 2011 were eligible for inclusion. All articles addressing timing of surgery were eligible for inclusion regardless of injury-to-surgery interval, graft type, surgical technique, or rehabilitation. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist guided the reporting and data abstraction. Methodologic quality of all included articles was carefully assessed. RESULTS: We included 22 articles (3,583 patients) in the systematic review. Study design, research methodology, surgical technique, and outcome measurements differed greatly among included articles. The injury-to-surgery interval, classified as early and delayed, ranged from within 2 days to 7 months and 3 weeks to 24 years, respectively. Eight articles promoted early reconstruction, whereas the majority of articles found no difference in outcome between early and delayed surgery. Two articles were inconclusive. CONCLUSIONS: There were few or no differences in subjective and objective outcomes related to timing of anterior cruciate ligament reconstruction. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies. PMID- 24053891 TI - Respiratory uncoupling by increased H(+) or K(+) flux is beneficial for heart mitochondrial turnover of reactive oxygen species but not for permeability transition. AB - BACKGROUND: Ischemic preconditioning has been proposed to involve changes in mitochondrial H(+) and K(+) fluxes, in particular through activation of uncoupling proteins and ATP-sensitive K(+) channels (MitoKATP). The objectives of the present study were to explore how increased H(+) and K(+) fluxes influence heart mitochondrial physiology with regard to production and scavenging of reactive oxygen species (ROS), volume changes and resistance to calcium-induced mitochondrial permeability transition (mPT). RESULTS: Isolated rat heart mitochondria were exposed to a wide concentration range of the protonophore CCCP or the potassium ionophore valinomycin to induce increased H(+) and K(+) conductance, respectively. Simultaneous monitoring of mitochondrial respiration and calcium retention capacity (CRC) demonstrated that the relative increase in respiration caused by valinomycin or CCCP correlated with a decrease in CRC, and that no level of respiratory uncoupling was associated with enhanced resistance to mPT. Mitochondria suspended in hyperosmolar buffer demonstrated a dose dependent reduction in CRC with increasing osmolarity. However, mitochondria in hypoosmolar buffer to increase matrix volume did not display increased CRC. ROS generation was reduced by both K(+)- and H(+)-mediated respiratory uncoupling. The ability of heart mitochondria to detoxify H2O2 was substantially greater than the production rate. The H2O2 detoxification was dependent on respiratory substrates and was dramatically decreased following calcium-induced mPT, but was unaffected by uncoupling via increased K(+) and H(+) conductance. CONCLUSION: It is concluded that respiratory uncoupling is not directly beneficial to rat heart mitochondrial resistance to calcium overload irrespective of whether H(+) or K(+) conductance is increased. The negative effects of respiratory uncoupling thus probably outweigh the reduction in ROS generation and a potential positive effect by increased matrix volume, resulting in a net sensitization of heart mitochondria to mPT activation. PMID- 24053892 TI - Long-term outcomes in ranibizumab-treated patients with retinal vein occlusion; the role of progression of retinal nonperfusion. AB - PURPOSE: To determine the percentage of ranibizumab-treated patients with retinal vein occlusion (RVO) who had resolution of edema for at least 6 months after the last injection, along with factors and outcomes that correlate with resolution. DESIGN: Post hoc analysis of open-label clinical trial. METHODS: Twenty patients with branch RVO (BRVO) and 20 with central RVO (CRVO) received ranibizumab monthly for 3 months and as needed for recurrent/persistent macular edema, no more frequently than every 2 months. Patients still requiring injections after month 40 received scatter and grid laser photocoagulation to try to reduce the need for injections. Main outcome measures included the percentage of patients who had resolution of edema, change in best-corrected visual acuity (BCVA) from baseline, and change in area of retinal nonperfusion in central subfields. RESULTS: Nine patients with BRVO (45%) had edema resolution from injections alone after a mean of 20.2 months, 4 resolved after addition of laser, 4 were unresolved through 72 months, and 3 exited prior to resolution. Five patients with CRVO (25%) resolved from injections alone after a mean of 14.0 months, 8 remained unresolved through 72 months despite addition of laser, and 7 exited prior to resolution. For BRVO or CRVO, there was a negative correlation between posterior retinal nonperfusion area and BCVA at months 18, 24, and 36 (P < .05). CONCLUSIONS: In patients with RVO, infrequent ranibizumab injections to control edema may not be sufficient to prevent progression of retinal nonperfusion, which may contribute to loss of visual gains. PMID- 24053893 TI - Uncorrected binocular performance after biaspheric ablation profile (PresbyMAX) for presbyopic corneal treatment. PMID- 24053894 TI - Reply: To PMID 23415597. PMID- 24053895 TI - The diagnostic utility of anterior chamber paracentesis for polymerase chain reaction in anterior uveitis. PMID- 24053896 TI - Reply: To PMID 23317648. PMID- 24053897 TI - Reply: To PMID 23721944. PMID- 24053898 TI - Posterior iris-claw aphakic intraocular lens implantation in children. PMID- 24053899 TI - Activin receptor-like kinase 1 as a target for anti-angiogenesis therapy. AB - INTRODUCTION: Formation of blood vessels from pre-existing ones, also termed angiogenesis, is of crucial importance for the outgrowth of tumours beyond 1 - 2 mm3. Therefore, anti-angiogenic therapies, mainly focussing on inhibition of vascular endothelial growth factor (VEGF) are used in clinical therapy. However, although initially reducing tumour size, therapy resistance occurs frequently and new targets are needed. A possible target is activin receptor-like kinase (ALK) 1, a transforming growth factor (TGF)-beta type-I receptor, which binds bone morphogenetic protein (BMP)-9 and -10 with high affinity and has an important role in regulating angiogenesis. AREAS COVERED: Several approaches to interfere with ALK1 signalling have been developed, that is, ALK1 neutralising antibodies and a soluble ALK1 extracellular domain/Fc fusion protein (ALK1-Fc), acting as a ligand trap. In this review, we discuss the involvement of ALK1 in angiogenesis, in a variety of diseases and the current status of the development of ALK1 inhibitors for cancer therapy. EXPERT OPINION: Based on current, mainly preclinical studies on inhibition of ALK1 signalling by ligand traps and neutralising antibodies, targeting ALK1 seems very promising. Both ALK1-Fc and neutralising antibodies strongly inhibit angiogenesis in vitro and in vivo. The results from the first Phase I clinical trials are to be reported soon and multiple Phase II studies are ongoing. PMID- 24053900 TI - Short-term effects of a course of manual therapy and exercise in people with moderate chronic obstructive pulmonary disease: a preliminary clinical trial. AB - OBJECTIVE: The purpose of this preliminary study was to demonstrate the feasibility of a study that measures the short-term effects of a course of manual therapy (MT) and exercise (Ex) in people with moderate chronic obstructive pulmonary disease (COPD). METHODS: Fifteen participants (9 males; mean age, 56.1 years), with moderate COPD (mean % predicted forced expiratory volume in the first second [FEV1% predicted], 61.8%), were randomly allocated to 1 of 3 groups: soft tissue therapy only (ST); ST and spinal manipulation (SM); or ST, SM, and Ex. The intervention continued for 4 weeks. Outcome measures included FEV1, forced vital capacity (FVC), chronic respiratory questionnaire (CRQ-SAS) scores, distance walked in a 6-minute walking test, and monitoring for adverse events. RESULTS: There was an increase in FVC for the SM + ST + Ex group compared with ST only and ST + SM (1.01 and 1.00 L, respectively). Distance walked increased in the ST + SM and ST + SM + Ex groups compared with ST only (120.0 and 168.0 m, respectively). Dyspnea levels decreased in the ST + SM and ST + SM + Ex groups compared with ST only (0.64 and 0.44, respectively). There were no major or moderate adverse events reported following ST or SM interventions. CONCLUSIONS: For this small group of patients, combining MT with Ex produced short improvements in FVC, distance walked, and dyspnea levels, with no major or moderate adverse events. This preliminary study showed that a larger study evaluating the clinical outcomes of MT for people with moderate COPD appears feasible. PMID- 24053901 TI - Characteristics of mercury emission from linear type of spent fluorescent lamp. AB - In order to recycle the linear type of SFL (spent fluorescent lamp), mercury from SFL should be controlled to prevent leaking into the environment. For mercury emission from SFL, mercury concentration is estimated in the parts of SFL such as glass tube, phosphor powder, and base cap using the end-cutting unit. It is also evaluated mercury emission in the effluent gas in the end-cutting unit with changing flow rate. From the results of mercury emission from SFLs, phosphor powder has greater than 80% of mercury amount in SFL and about 15% of mercury amount contained in glass tube. The initial mercury concentration in vapor phase is almost decreased linearly with increasing airflow rate from 0.7 L/min to 1.3 L/min. It is desirable that airflow rate should be high until the concentration of mercury vapor will be stable because the stabilized concentration becomes to be low and the stabilized time goes to be short as increased airflow rate. From KET and TCLP results, finally, phosphor powder should be managed as a hazardous waste but base-cap and glass are not classified as hazardous wastes. PMID- 24053902 TI - Morbimortality associated to acute kidney injury in patients admitted to pediatric intensive care units. AB - AIM: To describe the morbimortality associated to the development of acute kidney injury (AKI) defined by the pediatric adaptation of the RIFLE criteria in a Pediatric Intensive Care Unit (PICU). DESIGN: A retrospective cohort study was carried out. SETTING: Children admitted to a PICU in a tertiary care hospital. Patients or participants A total of 320 children admitted to a tertiary care hospital PICU during the year 2011. Neonates and renal transplant patients were excluded. Primary endpoints AKI was defined and classified according to the pediatric adaptation to the RIFLE criteria. PICU and hospital stays, use of mechanical ventilation and mortality were used to evaluate morbimortality. RESULTS: A total of 315 children met the inclusion criteria, with a median age of 19 months (range 6-72). Of these patients, 128 presented AKI (73 reached the Risk category and 55 reached the Injury and Failure categories). Children with AKI presented a longer PICU stay (6.0 [4.0-12.5] vs. 3.5 [2.0-7.0] days) and hospital stay (17 [10-32] vs. 10 [7-15] days), and a greater need for mechanical ventilation (61.7 vs. 36.9%). The development of AKI was an independent factor of morbidity, associated with a longer PICU and hospital stay, and with a need for longer mechanical ventilation, with a proportional relationship between increasing morbidity and the severity of AKI. CONCLUSION: The development of AKI in critically ill children is associated with increased morbimortality, which is proportional to the severity of renal injury. PMID- 24053903 TI - External validation of the Simplified Acute Physiology Score (SAPS) 3 in Spain. AB - OBJECTIVE: To evaluate SAPS 3 performance in Spain, assessing discrimination and calibration in a multicenter study. DESIGN: A prospective, multicenter study was carried out. PATIENTS AND SETTING: A prospective cohort study was performed in Spanish hospitals between 2006 and 2011. MEASUREMENTS AND RESULTS: A total of 2171 patients were included in the study. The mean age was 61.4+/-16.09 years, the ICU mortality was 11.6%, and hospital mortality 16.03%. The SAPS 3 score was 46.29+/-14.34 points, with a probability of death for our geographical area of 18.57%, and 17.97% for the general equation. The differences between observed-to predicted mortality were analyzed with the Hosmer-Lemeshow test, which yielded H=31.71 (p<0.05) for our geographical area and H=20.05 (p<0.05) for the general equation. SAPS 3 discrimination with regard to hospital mortality, tested using the area under the ROC curve, was 0.845 (0.821-0.869). CONCLUSION: Our study shows good discrimination of the SAPS 3 system in Spain, but also inadequate calibration, with differences between predicted and observed mortality. There are more similarities with regard to the general equation than with respect to our geographical area equation, and in both cases the SAPS 3 system overestimates mortality. According to our results, Spanish ICU mortality is lower than in other hospitals included in the multicenter study that developed the SAPS 3 system, in patients with similar characteristics and severity of illness. PMID- 24053904 TI - Two-year clinical outcomes of stent fractures following primary femoropopliteal stenting. PMID- 24053905 TI - Is prolonged mechanical ventilation of cancer patients futile? AB - The issue of limiting life-sustaining treatments for intensive care unit (ICU) patients is complex. The ethical principles applied by ICU staff when making treatment-limitation decisions must comply with the law of their country. Until 2011, the law in Taiwan prohibited the withdrawal of mechanical ventilation. Consequently, patients with severe underlying diseases could receive prolonged mechanical ventilation. In a study conducted by Shih and colleagues in patients with cancer in Taiwan, continuous mechanical ventilation for more than 21 days was associated with poor outcomes, particularly in the subgroups of patients with metastases, lung cancer, or liver cancer. These results highlight the need for appropriate legislation regarding the withdrawal of life-sustaining treatments in patients, especially those for whom no effective cancer treatments are available. PMID- 24053907 TI - Comparison of breastfeeding in rural areas of Sweden and Australia - a cohort study. AB - BACKGROUND: Breastfeeding rates in Sweden and Australia appears to be decreasing in both countries. National statistics shows that 87% of infants in Sweden and 73% in Australia receive any breastfeeding two months of age. AIM: To compare women's experiences of breastfeeding in Sweden and Australia and to identify factors associated with breastfeeding two months after birth. METHODS: A cohort study in two rural hospitals in mid Sweden (n=300) and north-eastern Victoria in Australia (n=91) during 2007-2009. Participants responded to questionnaires in mid pregnancy and two months after birth. Crude and adjusted odds ratios with a 95% confidence interval were used to detect differences between women in both cohorts. FINDINGS: Women in Sweden (88.3%) were more likely to report any breastfeeding of the baby two months after birth (OR 2.41; 95% CI: 1.33-4.38) compared to women in Australia (75.8%) but were less satisfied with breastfeeding support and information. The most important factor associated with breastfeeding at two months postpartum for the Swedish women was to have received sufficient information about breastfeeding on the postnatal ward (OR 2.3; 95% CI 1.41-4.76) while for the Australian women receiving the best possible help when breastfeeding for the first time was most important (OR 4.3; 95% CI 1.50-12.46). CONCLUSION: The results indicate that Swedish women were more likely than their Australian counterparts to breastfeed the baby two months after birth. The findings demonstrated the importance of sufficient information and help when breastfeeding is initiated. PMID- 24053906 TI - Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer. AB - OBJECTIVE: To assess the association between diabetes mellitus (DM) and metformin use with prognosis and outcomes of non-muscle-invasive bladder cancer (NMIBC) PATIENTS AND METHODS: We retrospectively evaluated 1117 patients with NMIBC treated at four institutions between 1996 and 2007. Cox regression models were used to analyse the association of DM and metformin use with disease recurrence, disease progression, cancer-specific mortality and any-cause mortality. RESULTS: Of the 1117 patients, 125 (11.1%) had DM and 43 (3.8%) used metformin. Within a median (interquartile range) follow-up of 64 (22-106) months, 469 (42.0%) patients experienced disease recurrence, 103 (9.2%) experienced disease progression, 50 (4.5%) died from bladder cancer and 249 (22.3%) died from other causes. In multivariable Cox regression analyses, patients with DM who did not take metformin had a greater risk of disease recurrence (hazard ratio [HR]: 1.45, 95% confidence interval [CI] 1.09-1.94, P = 0.01) and progression (HR: 2.38, 95% CI 1.40-4.06, P = 0.001) but not any-cause mortality than patients without DM. DM with metformin use was independently associated with a lower risk of disease recurrence (HR: 0.50, 95% CI 0.27-0.94, P = 0.03). CONCLUSION: Patients with DM and NMIBC who do not take metformin seem to be at an increased risk of disease recurrence and progression; metformin use seems to exert a protective effect with regard to disease recurrence. The mechanisms behind the impact of DM on patients with NMIBC and the potential protective effect of metformin need further elucidation. PMID- 24053908 TI - Family structure and childhood obesity: results of the IDEFICS Project. AB - OBJECTIVE: To analyse the association between family structure and adiposity in children. DESIGN: Cross-sectional and longitudinal analysis of the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study cohort. SETTING: Primary schools and kindergartens. SUBJECTS: Children (n 12 350; aged 7.9 (SD 1.8) years) for the cross-sectional analysis and children (n 5236; at baseline: normal weight, aged 5.9 (SD 1.8) years) for the longitudinal study underwent anthropometry. Family structure was analysed as (i) number and type of cohabiting adults and (ii) number of siblings. RESULTS: In the cross-sectional analysis, after controlling for covariates, children living with grandparents had significantly higher BMI Z score than those living with both parents (0.63; 95% CI 0.33, 0.92 v. 0.19; 95% CI 0.17, 0.22; P < 0.01); in addition, the higher the number of siblings, the lower the BMI Z-score (only child = 0.31; 95% CI 0.24, 0.38; 1 sibling = 0.19; 95% CI 0.16, 0.23; 2 siblings = 0.15; 95% CI 0.09, 0.20; >2 siblings = 0.07, 95% CI 0.04, 0.19; P < 0.001). Over the 2-year follow-up, differences in weight gain were observed across family-structure categories. Further, the risk of incidence of overweight/obesity was significantly lower the higher the number of siblings living in the household (v. only child: 1 sibling = 0.74, 95% CI 0.57, 0.96; 2 siblings = 0.63, 95% CI 0.45, 0.88; >2 siblings = 0.40, 95% CI 0.21, 0.77), independently of confounders. CONCLUSIONS: The study suggests that an independent association between family structure and childhood obesity exists. PMID- 24053909 TI - [The role of interleukin-1beta on the pulmonary fibrosis in mice exposed to crystalline silica]. AB - OBJECTIVE: This study was designed to evaluate the role of interleukin (IL)-1beta in the development of fibrosis in mice exposed to silica. METHODS: The total of 96 Male C57BL/6 mice were divided into four groups. (1) blank control group, (2) PBS group in which mice were instilled with PBS only, (3) silica + IL-1beta mAb group in which mice were instilled with 2.5 mg silica dust and 40 ug anti-IL 1beta mAb, (4) silica group in which mice were instilled with 2.5 mg silica dust and 40 ug IgG. The final volume of suspension or PBS instilled into the mouse was 50 ul. At 7, 28 and 84 days after treatment, 8 mice were sacrificed in each group. Then BALF was collected for the count of inflammatory cells and cytokines determination. The lung tissues were collected for the detecting of mRNA levels of fibrogenic molecules. RESULTS: The collagen deposition induced by silica in the lung tissues was partly inhibited by anti-IL-1beta. A intensely pulmonary cytokines such as IL-1beta, TNF-alpha, MCP-1 were induced by crystalline silica exposure, and partly inhibited by anti-IL-1beta. The levels of TGF-beta and fibronectin in silica exposed mice were significantly elevated than those in control mice at days 28 and 84 after treatment (P < 0.01). And the mRNA levels of TGF-beta, collagen I and fibronectin were significantly decreased in silica+IL 1beta mAb group when compared with those in silica group at days 7, 28 and 84 (P < 0.01). There was a significant decrease of the ratios of IFN-gamma/IL-4 in both silica+anti-IL-1beta mAb and silica groups when compared with those in control mice at the above three time points (P < 0.01). However, the IFN-gamma/IL-4 ratios in silica+anti-IL-1beta group were significantly higher than those in silica group at 7, 28 and 84 days (P < 0.05 or P < 0.01). CONCLUSION: IL-1beta may promote the pulmonary fibrosis in mice exposed to silica. PMID- 24053910 TI - [The pulmonary toxicity study of nano-silica particles on rats through dynamic inhalation]. AB - OBJECTIVE: To investigate the pulmonary toxicity of different concentrations of nano-silica (nano-SiO2) under continuous dynamic inhalation conditions in the rat. METHODS: 48 male Sprague-Dawley rats were randomly divided into four groups, including the dispersant control group (saline) and nano-SiO2 low-dose group (0.3%, w/v), the middle-dose group (1%) and the high-dose group (3%). Animals were sacrificed at 28 d after exposure under continuous dynamic inhalation conditions, and bronchoalveolar lavage fluid (BALF) and lung tissue were collected. And following items were observed: body coefficient, BALF related items (leukocytes and classification, total protein content, LDH activity), lung tissue pathological changes (HE staining), and pulmonary fibrosis forming (collagen fiber VG staining). RESULTS: Compared to the dispersant control group, there was no significant change on lung organ coefficient in Nano-SiO2 group (P < 0.05). The BALF total WBC count in 1% and 3% in nano-SiO2 groups showed higher value than the dispersant control group (P < 0.05). No obvious changes were found on total protein content and LDH activity in nano-SiO2 groups compared to the dispersant control group (P > 0.05). For differential WBC counts, lymphocyte count in BALF in nano-SiO2 groups was significantly decreased (P < 0.05), monocyte and macrophage counts were significantly increased (P < 0.05), but there was no difference on the proportion of neutrophils (P > 0.05). HE staining results showed that the obvious thickening of alveolar wall in nano-SiO2 groups, inflammatory cell infiltration also increased around the bronchial and vascular wall. Lung fibrosis VG staining showed no significant change of collagen fiber distribution. CONCLUSION: Under our experimental conditions, the continuous dynamic inhalation of nano-SiO2 only caused the significant inflammation in rat lungs, pulmonary fibrosis phenomenon could not be observed significantly. PMID- 24053911 TI - [Paraquat involves differentiation of human neural stem cells via Notch signaling]. AB - OBJECTIVE: To investigate effects of paraquat on the mRNA expression of key elements of Notch signaling (Notch1, Jagged1 and DTX1) during differentiation process of human neural stem cells (hNSCs). METHODS: hNSCs exposed to PQ at the concentrations 0.10, 1.00, 10.00 M. Cell proliferation ability was assessed using MTT assay and mRNA expressions of Notch1, Jagged1 and DTX1 were detected by Real time RT-PCR at 2, 4, 8, 12 d of differentiation. RESULTS: Compared with control group, NOTCH1, JAG1 mRNA expression levels exposed to PQ at the concentration of 0.10 M significantly reduced at 2, 4, 8 d and significantly went up at 12d (P < 0.01). Compared with control group, NOTCH1, JAG1 and DTX1 mRNA expression levels exposed to PQ at the concentration of 10.00 M significantly reduced at 2, 8, 12 d (P < 0.01). PQ could down-regulate Notch1, Jagged1 and DTX1 mRNA expressions at the early stage of differentiation, then up-regulate Notch1 mRNA expression, and down-regulate Notch1, Jagged1 and DTX1 mRNA expressions at the end of differentiation. CONCLUSION: Notch signaling pathway may be involved in differentiation of neural stem cell exposed to PQ. PMID- 24053912 TI - [Influence of genetic polymorphisms of epoxide hydrolase 1 on metabolism of styrene in body]. AB - OBJECTIVE: To investigate the role of genetic polymorphisms of epoxide hydrolase 1 (EPHX1) in the metabolism of styrene in vivo. METHODS: Fifty-six styrene exposed workers, who worked in the painting workshop of an enterprise for manufacturing glass fiber-reinforced plastic yachts in Shandong Province, China for over one year and were protected in approximately the same way, were selected as study subjects. The 8-hour time-weighted average concentration (8 h-TWA) of styrene and the concentrations of mandelic acid (MA) and phenyl glyoxylic acid (PGA) as urinary metabolites were measured. The genetic polymorphisms of EPHX1 were detected by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The urinary concentrations of MA and PGA were 177.25+/-82.36 mg/g Cr and 145.91+/-69.73 mg/g Cr, respectively, and the 8 h-TWA of styrene was 133.28+/-95.81 mg/m3. Urinary concentrations of MA and PGA were positively correlated with 8 h-TWA of styrene (R=0.861, P < 0.05; R=0.868, P < 0.05). The subjects were divided into high-exposure group (8 h-TWA >50 mg/m(3)) and low-exposure group (8 h-TWA <= 50 mg/m(3), and in the two groups, the urinary concentrations of MA and PGA were significantly higher in the individuals carrying high-activity genotypes of EPHX1 than in those carrying low-activity genotypes of EPHX1 (P < 0.05). CONCLUSION: Genetic polymorphisms of EPHX1 play an important role in the metabolic process of styrene in vivo. PMID- 24053913 TI - [Effects of benzo(a)pyrene exposure on oxidative stress and ATPase in the hippocampus of rats]. AB - OBJECTIVE: To investigate the effects of benzo[a]pyrene (B[a]P) exposure on the behaviors and hippocampal oxidative stress and ATPase in rats and the molecular mechanism of neurobehavioral toxicity of B[a]P. METHODS: A total of 120 male SD rats (21 days old) were randomly and equally assigned to five groups: blank control group, vegetable oil (solvent control) group, and 2.5, 5, and 10 mg/kg B[a]P exposure groups. The rats in B[a]P exposure groups were injected intraperitoneally with B[a]P once a day for 4 consecutive weeks. Then, Morris water maze and shuttle box were used to evaluate the learning and memory abilities of rats; colorimetric assay was used to measure the activities of superoxide dismutase (SOD), Na(+)/K(+)-ATPase, and Ca(2+)/Mg(2+)-ATPase and the content of malonaldehyde (MDA) in the hippocampus; the concentration of Ca(2+) in the hippocampus was measured by fluorescent labeling. RESULTS: Compared with the blank control group and solvent control group, the B[a]P exposure groups exhibited significant increases in escape latency, active avoidance response latency, and passive avoidance response latency and significant decreases in number of platform crossings and active avoidance response frequency in the last test (P < 0.05 for all comparisons), with a dose-effect relationship. In addition, the B[a]P exposure groups had significantly lower activities of SOD, Na(+)/K(+)-AT-Pase, and Ca(2+)/Mg(2+)-ATPase and significantly higher MDA level and Ca(2+) concentration than the blank control group and solvent control group (P < 0.05 for all comparisons), with a dose-effect relationship. CONCLUSION: The neurobehavioral toxicity of B[a]P may be related to increased oxidative stress and decreased activities of Na(+)/K(+)-ATPase and Ca(2+)/Mg(2+)-ATPase in the hippocampus of rats. PMID- 24053914 TI - [Investigation on occupational stress of workers in clean workshops of electric company]. AB - OBJECTIVE: The aim is to learn the situation of work stress, burnout and depression in clean workshops of electronic company by investigation, and provide the clues for the further interventions as well as the basic data for the future evaluation. METHODS: The survey was carried out in a electronic company in Xishan,Wuxi city. The subjects including all the 395 employees in clean workshops and 205 in ordinary workshops were asked to fill in an anonymous cross-sectional questionnaire, in which the distributions of age, gender, job duration, working time and working strength were similar between two kinds of workshops. The response rate was 98.9%. RESULTS: There were no significant differences between clean and ordinary workshops in age, gender, smoking, drinking and working hours, except for employed years. It was not found that any differences between two kinds of workshop for the rates of burnout, depression and stress. However, the rates of burnout, depression and stress were 19.7%(77/391), 24.8%(97/391) and 88.5%(346/391) in clean workshops and 19.3%(39/202), 23.8%(48/202) and 84.6%(171/202) in ordinary workshops. There were no significant differences between two workshops for the scores of burnout and depression, but the stress score in clean workshops was higher than that of ordinary workshop (P = 0.015). Further stratified analysis found that stress score of male in clean workshop was higher than that of female (P = 0.002), while it was inverse in ordinary workshops (P = 0.034). In addition, the stress score of male in clean workshops was significantly higher than that of male in ordinary one (P = 0.003). The stress score of workers with age >=22 year old was higher than that of age <22 in clean workshops, while the stress rate of workers with job duration >=1.6 years was more than that of those with the shorter job duration. The risk of stress in clean workshops was as 3.78 times as ordinary one and the 95% confidence interval was 1.54~9.31 after adjusted age and gender. There were negative correlations between stress and society support in both clean and ordinary workshops. CONCLUSION: The levels of work stress, burnout and depression were high in this electronic company. The stress in clean workshops was more serious than that of ordinary ones, especially for the males. PMID- 24053915 TI - [Expression of serum cytokines in patients with pneumoconiosis by antibody chip]. AB - OBJECTIVE: To investigate the changes in expression of serum cytokines in patients with pneumoconiosis using cytokine antibody chips (CACs). METHODS: The CAC technology was applied to measure the serum levels of 60 cytokines in 12 patients with pneumoconiosis and 3 normal controls. RESULTS: In the patients with pneumoconiosis, the highly expressed serum cytokines included interleukin (IL) 1alpha, IL-1beta, IL-2, ILs 4-16, macrophage colony-stimulating factor, interferon-gamma, tumor necrosis factor (TNF)-alpha, TNF-beta, human bone morphogenetic protein-6, fibroblast growth factor-7, neurotrophin-3, and stem cell factor, and the lowly expressed serum cytokines included recombinant human I 309, monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3, MCP-4, macrophage inflammatory protein (MIP)-1-delta, and MIP-3-alpha. CONCLUSION: Patients with pneumoconiosis have changes in the expression of most serum cytokines. PMID- 24053916 TI - [The characteristics and trends of acute pesticide poisoning of Shaoxing in 2006 to 2011]. AB - OBJECTIVE: To describe the epidemiological characteristics of acute pesticide poisoning in Shaoxing, China during 2006-2011 and to provide a reference for the prevention and control of pesticide poisoning. METHODS: The data on pesticide poisoning in Shaoxing during 2006-2011 were obtained from the China Information System for Disease Control and Prevention and were then analyzed. RESULTS: A total of 2024 cases of acute pesticide poisoning were reported in Shaoxing during 2006-2011, and 44 cases were missed, accounting for 2.1% (44/2068) of all cases. Among the 2024 cases, 119 (5.9%) died; the fatality rates of productive poisoning and unproductive poisoning were 1.0% (3/289) and 6.7% (116/1735), respectively. The reported cases included 1038 (51.3%) females and 986 (48.7%) males, and there were no significant differences in the ratio between male and female cases of acute pesticide poisoning from 2006 to 2011 (chi2 = 9.16, P = 0.10). The 2024 cases had a mean age of 47.0+/-18.7 years; the male cases had a significantly higher mean age than the female cases (50.7+/-19.0 vs 43.4+/-17.8 years, t = 9.01, P < 0.001). Among the 2024 cases, 289 (14.3%) suffered productive poisoning, and 1735 (85.7%) suffered unproductive poisoning. In the 986 male cases, 219 (22.2%) suffered productive poisoning; in the 1038 female cases, 968 (93.3%) suffered unproductive poisoning. The pesticides that caused poisoning included insecticide (86.7%, 1754/2024), herbicide (5.1%, 104/2024), rodenticide (3.6%, 72/2024), and bactericide, mixed preparation, biochemical pesticides, and other four categories of pesticides (4.6%, 94/2024); of the 1754 cases caused by insecticide, 1455 (83.0%) were attributed to organophosphorus insecticide. CONCLUSION: The incidence of unproductive acute pesticide poisoning is high in Shaoxing, and it mainly affects females. Most cases of acute pesticide poisoning are aged 30~60 years. Insecticide is the main cause of poisoning. It is necessary to enhance health knowledge popularization and safety management of pesticides. PMID- 24053917 TI - [Focus on occupational disease monitoring results analysis of Bao'an district, Shenzhen in 2011 to 2012]. PMID- 24053918 TI - [Effects of polybrominated diphenyl ether-153 lactation exposure on the concentrations of intracellular calcium ion and calcium-activated related enzymes levels of adult rats' cerebral cortex]. AB - OBJECTIVE: To investigate the effects of polybrominated diphenyl ether-153 (BDE 153) exposure during lactation period on the calcium ion (Ca(2+)) concentration and calcium-activated enzyme levels in cerebral cortical cells among adult rats and to provide a scientific basis for the study on the developmental neurotoxicity of BDE-153. METHODS: Forty newborn male rats were randomly and equally divided into four groups according to their body weights and litters: 1, 5, and 10 mg/kg BDE-153 groups and olive oil solvent control group. On postnatal day 10 (PND 10), the BDE-153 groups were administrated BDE-153 (0.1 ml/10 g body weight) by intraperitoneal injection, while the olive oil solvent control group was given an equal volume of olive oil. Two months later, these rats were decapitated, and the cerebral cortex was separated quickly on an ice-cold dish. The Ca(2+) concentration in cerebral cortical cells was measured by flow cytometry. The activities of calcineurin (CaN) and Ca(2+)-Mg(2+)-ATP enzyme were determined by colorimetric method. The mRNA and protein expression of calpain-1 and calpain-2 was measured by real-time quantitative PCR and Western blot. RESULTS: The mean fluorescence intensities of intracellular Ca(2+) in control group and 1, 5, and 10 mg/kg BDE-153 groups were 10.83, 1.48, 1.93, and 0.62, respectively; the 1, 5, and 10 mg/kg BDE-153 groups had significantly lower intercellular Ca(2+) concentrations than the control group (P < 0.05). The activities of CaN and Ca(2+)-Mg(2+)-ATP enzyme and mRNA and protein expression of calpain-1 showed no significant differences between the 1, 5, and 10 mg/kg BDE 153 groups and control group (P > 0.05). The protein expression of calpain-2 increased as the dose of BDE-153 rose. Compared with the control group (mRNA: 0.81+/-0.26; protein: 0.15+/-0.07), the 5 and 10 mg/kg BDE-153 groups had significantly higher mRNA expression of calpain-2 (5 mg/kg BDE-153 group: 1.16+/ 0.52; 10 mg/kg BDE-153 group: 1.32+/-0.23) and significantly higher protein expression of calpain-2 (5 mg/kg BDE-153 group: 0.31+/-0.07; 10 mg/kg BDE-153 group: 0.37+/-0.06) (P < 0.05). The 10 mg/kg BDE-153 group had significantly higher protein expression of calpain-2 than the 1 mg/kg BDE-153 group (0.37+/ 0.06 vs 0.22+/-0.07, P < 0.05). CONCLUSION: Ca(2+-) mediated calpain-2 activation may be one of the main mechanisms of BDE-153 neurotoxicity. PMID- 24053919 TI - [The inhibitory effect of latent transforming growth factor beta1 activation and silicosis by CD36 targeted RNA interference in silicosis model of rat]. AB - OBJECTIVE: To investigate the inhibitory effects of CD36-targeting RNA interference on the latent transforming growth factor beta1 (L-TGF-beta1) activation and silicotic fibrosis in rat silicosis model. METHODS: Wistar rats were divided into four groups: saline control group (n=24), SiO2 model group (10 mg SiO2 per rat) (n=24), SiO2+Lv-shCD36 group (lentiviral vector expressing specific shRNA against CD36) (n=24), and SiO2+Lv-shCD36-NC group (non-silence control lentivirus) (n=24). At 7, 21, and 28 d after instillation, the rats were sacrificed. The activity of TGF-beta1 in bronchoalveolar lavage fluid (BALF) was measured by evaluating its inhibitory effect on the proliferation of mink lung epithelial cells. The pathological changes of lung tissue were observed by HE staining and van Gieson staining. The hydroxyproline content in the lungs was determined by alkaline lysis method. RESULTS: At 7 d after instillation, the expression of CD36 mRNA in alveolar macrophages was significantly lower in the SiO2+Lv-shCD36 group than in the saline control group, SiO2 model group, and SiO2+Lv-shCD36-NC group (P < 0.05); the quantity and percentage of active TGF beta1 in BALF were significantly lower in the SiO2+Lv-shCD36 group than in the SiO2 model group and SiO2+Lv-shCD36-NC group (P < 0.05). At 28 d after instillation, there were cellular silicotic nodules in the lungs of rats in SiO2+Lv-shCD36 group and fibrotic cellular silicotic nodules in the lungs of rats in SiO2 model group and SiO2+Lv-shCD36-NC group. At 21 and 28 d after instillation, the hydroxyproline content was significantly lower in the SiO2+Lv shCD36 group than in the SiO2 model group and SiO2+Lv-sh CD36-NC group (P < 0.05). CONCLUSION: CD36-targeting RNA interference has inhibitory effects on the L-TGF-beta1 activation and silicotic fibrosis in rat silicosis model. PMID- 24053920 TI - [The effect of suppressive oligodeoxynucleotides on interferon-gamma and phosphorylation of signal transducers and activators of transcription 4 expression of silica-induced pulmonary inflammation in mice]. AB - OBJECTIVE: To investigate the protective effect of suppressive oligodeoxynucleotides (Sup ODN) on interferon-gamma (IFN-gamma) and signal transducers and activators of transcription (pSTAT4) expression of Silica-induced pulmonary inflammation in Mice. METHODS: Sixty Balb/c mice were randomly divided into 4 groups, normal control group, silicious group, suppressive oligodeoxynucleotides (Sup ODN) group, control oligodeoxynucleotides (Con ODN) group. Except the normal control group injected normal saline, the rest groups were induced by the intratracheal instillation of 0.1 ml (5 g/L) of sterilized silica suspension. Sup ODN group and Con ODN group were treated by i.p. injection of 0.3 ml (1mg/mL) of suppressive or control ODN 3 h before silica administration. After 7 days, the animals were killed and levels of IFN-gamma were detected by ELISA. The pathologic changes in lung tissues of mice were observed with HE staining. Expressions of IFN-gamma and pSTAT4 in lung tissue were detected with immunohistochemistry and quantified by Image-Pro Plus 7.0. RESULTS: HE staining showed that the lung tissue of silicious group were damaged seriously than Sup ODN group. Compared with the normal control group (serum: (280.1+/-41.3) pg/ml, lung tissue: (0.249+/-0.373), IFN-gamma increased in silicious group (serum: (886.3+/-81.7) pg/ml, lung tissue: (0.270+/-0.300) (P < 0.05). Compared with the normal control group and Con ODN group [(894.5+/-91.6) pg/ml], IFN-gamma in the serum of Sup ODN group decreased significantly (P < 0.01). Compared with the silicious group , IFN-gamma in lung tissue decreased in Sup ODN group (0.241+/-0.250) (P < 0.05). Compared with the normal control group (0.279+/-0.353), pSTAT4 in lung tissue increased significantly in silicious group (0.313+/-0.231) (P < 0.01). Compared with the silicious group, pSTAT4 in lung tissue decreased significantly in Sup ODN group (0.269+/-0.523) (P < 0.01). CONCLUSION: Sup ODN attained protective effect on Silica treated mice by suppressing expression of IFN-gamma and pSTAT4. PMID- 24053921 TI - [Pathological changes of major organs after rats inhaled methyl ethyl ketone peroxide aerosol]. AB - OBJECTIVE: To investigate the pathological changes of major organs in rats that have inhaled methyl ethyl ketone peroxide (MEKP) aerosol and to provide clues to the oxidative damage mechanism of MEKP. METHODS: A total of 100 Sprague-Dawley rats (male-to-female ratio = 1:1) were randomly and equally divided into blank control group, solvent control group, and 50, 500, and 1000 mg/m(3) MEKP exposure groups to inhale clean air, solvent aerosol, or MEKP for 6 h per day, 5 d per week, for 13 weeks. A rat model of subchronic MEKP exposure was established. The clinical manifestations during exposure were recorded. The organ coefficients of the kidney, thymus, and testis were calculated. The histopathological changes of the lung, liver, and testis were observed by HE staining. RESULTS: The male rats in 1000 mg/m(3) MEKP exposure group had significantly lower organ coefficients of the kidney and testis than those in blank control group, solvent control group, and 50 and 500 mg/m(3) MEKP exposure groups (P < 0.05). The rats in 1000 mg/m(3) MEKP exposure group had a significantly lower organ coefficient of the thymus than those in blank control group and solvent control group (P < 0.05). Some rats in 500 and 1000 mg/m3 MEKP exposure groups had significant damage to the lung, liver, and testis, which demonstrated a worsening trend as the dose increased. Pulmonary hyperinflation, hyperemia, bleeding, interstitial pneumonia, and even lung abscess were seen in the damaged lung. Nuclear enrichment, hepatocyte steatosis, and mild cellular edema in the portal area were seen in the damaged liver. Variable degeneration, necrosis, and dysplasia of spermatogenic cells and significant decrease in sperms in spermatogenic cells were seen in the damaged testis. The female rats in blank control group, solvent control group, and 50, 500, and 1000 mg/m(3) MEKP exposure groups showed no pathological changes in the ovary. CONCLUSION: Inhalation of MEKP aerosol can cause oxidative damage to the liver, lung, kidney, thymus, and testis in rats, particularly to the testis in male rats. PMID- 24053922 TI - [Expression of peroxiredoxin I in the rats exposed to silica]. AB - OBJECTIVE: To evaluate the change in protein expression of peroxiredoxin I (Prx I) during pulmonary fibrosis among rats exposed to silica dust and to investigate the role of Prx I in pulmonary fibrosis. METHODS: Ninety male Wistar rats were randomly divided into control group (n = 60) and experimental group (n = 30). The control group received intratracheal perfusion of saline (1 ml), while the experimental group received intratracheal perfusion of suspension of silica dust (50 mg/ml) to establish a rat model of silicosis. At 1, 2, 3, 4, 6, or 8 weeks after treatment, 10 rats in control group and 5 rats in experimental group were sacrificed. The lung tissues were collected for conventional pathological observation. The protein expression of Prx I at each time point was measured by immunohistochemistry and Western blot. RESULTS: Among the rats exposed to silica dust, Prx I was seen in the form of brown particles that were mainly distributed in the alveolar septa and the cytoplasm of alveolar epithelial cells, macrophages, vascular endothelial cells, and smooth muscle cells around the blood vessels and tracheae. The control group showed weak protein expression of Prx I, and the experimental group had significantly higher protein expression of Prx I than the control group at all time points (P < 0.05). In the experimental group, the protein expression of Prx I was upregulated significantly at 1 and 2 weeks and decreased at 3~8 weeks. CONCLUSION: The change in protein expression of Prx I may be one of the important causes of the onset and development of pulmonary fibrosis in rats exposed to free silica. PMID- 24053923 TI - [Changes of serum neuron-specific enolase and serum ferritin levels in patients with pneumoconiosis]. AB - OBJECTIVE: To investigate the changes in serum neuron-specific enolase (NSE) and serum ferritin (SF) in patients with pneumoconiosis and their relationship with the onset of pneumoconiosis. METHODS: The serum NSE and SF levels in the peripheral blood of patients with pneumoconiosis were measured by electrochemical fluorescence immunoassay. RESULTS: The patients with first-stage pneumoconiosis and second-stage pneumoconiosis had significantly higher serum NSE and SF levels than the control group (23.0264+/-14.0410 and 44.9776+/-26.5208 ng/ml vs 8.1480+/ 3.7512 ng/ml, P < 0.05; 267.2515+/-186.5809 and 579.1371+/-433.9326 ng/ml vs 120.8613+/-74.2809 ng/ml, P < 0.05), and the patients with second-stage pneumoconiosis had significantly higher serum NSE and SF levels than those with first-stage pneumoconiosis (P < 0.05). After treatment, the serum NSE level decreased significantly in the patients with pneumoconiosis (21.1675+/-17.5942 ng/ml vs 33.4490+/-21.6948 ng/ml, P < 0.05), but it was still significantly higher than that in the control group (P < 0.05). The treatment did not produce significant changes in SF level among these patients (P > 0.05). CONCLUSION: Patients with pneumoconiosis have elevated serum NSE and SF levels, which may be related to the onset and progression of this disease. PMID- 24053924 TI - [Therapeutic effect of lung lavage with large capacity of pneumoconiosis complicated with chronic obstructive pulmonary disease]. PMID- 24053925 TI - [Analysis of the damage of acute arsine poisoning on respiratory system]. PMID- 24053926 TI - [Clinical effect of hyperbaric oxygen therapy on groupment acute carbon monoxide poisoning]. AB - OBJECTIVE: To summarize the clinical experience of hyperbaric oxygen therapy in the patients with groupment acute carbon monoxide poisoning. METHOD: 172 patients with acute carbon monoxide poisoning were received hyperbaric oxygen therapy besides some other regular therapies from january 2007 to december 2011. The clinical effect were analyzed retrospectively. RESULTS: 160 patients were cured (93%), 12 cases improved (7%), the total effective rate was 100%. The cure rate of the patients with hyperbaric oxygen therapy within 6 hours after the poisoning for 100% (115/115), It was significantly higher than that of patients treated for more than 6 hours [The cure rate was 78.9% (45/57)], The difference was statistically significant (P < 0.05). CONCLUSION: Treated by hyperbaric oxygen therapy early enough in the patients with acute carbon monoxide poisoning, can prevent or reduce the occurrence of delayed encephalopathy, decreasing disability and mortality. PMID- 24053927 TI - [A case report of occupational asthma caused by inhalation of plush fiber treated with whole-lung lavage]. PMID- 24053928 TI - [A case report: occupational aspergilloma]. PMID- 24053929 TI - [Determination of zopiclone in serum by ultraviolet spectrophotometry]. PMID- 24053930 TI - [Determination of isoniazid in acid duydraxide serum by ultraviolet spectrophotometry]. PMID- 24053931 TI - [A commentary on cases of occupational chronic benzene poisoning]. PMID- 24053932 TI - [The role of calcium homeostasis disorders in hepatic injury]. PMID- 24053933 TI - [Research progress on occupational exposure biomarker of N, N-dimethylformamide]. PMID- 24053934 TI - [Changes in diagnostic criteria for pneumoconiosis in China]. PMID- 24053935 TI - Adaptive backstepping sliding mode control of flexible ball screw drives with time-varying parametric uncertainties and disturbances. AB - This paper presents a method to model and design servo controllers for flexible ball screw drives with dynamic variations. A mathematical model describing the structural flexibility of the ball screw drive containing time-varying uncertainties and disturbances with unknown bounds is proposed. A mode compensating adaptive backstepping sliding mode controller is designed to suppress the vibration. The time-varying uncertainties and disturbances represented in finite-term Fourier series can be estimated by updating the Fourier coefficients through function approximation technique. Adaptive laws are obtained from Lyapunov approach to guarantee the convergence and stability of the closed loop system. The simulation results indicate that the tracking accuracy is improved considerably with the proposed scheme when the time-varying parametric uncertainties and disturbances exist. PMID- 24053936 TI - Pharmacogenetic considerations for non-Hodgkin's lymphoma therapy. AB - INTRODUCTION: Chemotherapy is the current standard treatment for hematological malignancies for both curative and palliative purposes. Unfortunately, in the current treatment scenario chemotherapy resistance is an issue that is know to lead to a relapse in cancer. The multidrug resistance 1 (MDR1) gene is often involved in drug resistance and, so far, the best studied mechanism of resistance relates to the level of P-glycoprotein (P-gp) expression on cancer cells; however, correlation with single nucleotide polymorphism (SNP) in the MDR1 gene has also been observed via a number of different mechanisms that interfere with function and expression of P-gp. AREAS COVERED: This article describes the influence of P-gp expression and SNP on the MDR1 gene in non-Hodgkin's lymphoma (NHL) and their effect on both its risk and outcome. The authors also provide a brief summary of the more important therapeutic options, which aim to overcome this drug resistance mechanism, and discuss their known mechanisms of action. EXPERT OPINION: There is evidence pertaining to an association between the outcome of NHL and P-gp expression. However, the authors emphasize the need for more studies to reinforce this evidence. Furthermore, there is a definite need for the therapeutic targets, which provide tumor cellular lines of interest, to be tested in humans, in order to better evaluate their toxicity and overall effect on the outcome. The ultimate aim of this research is to develop specifically designed therapies that are tailored to the intrinsic characteristics of specific patients. PMID- 24053937 TI - Photochemical transformation of terbutaline (pharmaceutical) in simulated natural waters: degradation kinetics and mechanisms. AB - In this study, varied nature organic matter isolates were employed to investigate the indirect photo transformation of terbutaline, which is a major feed additive medicine to increase the proportion of lean meat in the livestock. In the indirect photolysis of terbutaline under solar simulated irradiation, (1)O2 plays an important role among the *OH and (3)DOM*. The reaction rate constant of (1)O2 was determined as (7.1 +/- 0.3) * 10(6) M(-1) s(-1) at pH 7.0, while the reaction rate constant of *OH was (6.87 +/- 0.43) * 10(9) M(-1) s(-1). The contribution of singlet oxygen to the indirect photolysis of terbutaline (19-44%) was higher than that of the hydroxyl radical (1-7%). The pseudo first order rate constants for the photodegradation of terbutaline increase with increasing pH, which indicates that pH mainly affects the reaction rate of the singlet oxygen with the phenolic part of the terbutaline. The Quinone was identified as the main photosensitized product through LC-MS/MS analysis. It is also proposed that the degradation pathway of terbutaline involves reaction between the phenolic part of terbutaline and singlet oxygen. This finding strongly suggests that singlet oxygen was important factor for the photodegradation of terbutaline in natural waters. PMID- 24053938 TI - Preparation and antibacterial activity of lysozyme and layered double hydroxide nanocomposites. AB - It is necessary to develop "green" disinfection technology which does not produce disinfection by-products. Lysozyme-layered double hydroxide nanocomposites (LYZ LDHs) were prepared by intercalating LYZ in LDH for the first time. Their antibacterial activity was evaluated using staphylococcus aureus as a target. The bacteria removal mechanism was also studied. Characterization of LYZ-LDHs by X ray diffraction and Fourier transform infrared spectroscopy indicated that LYZ was successfully intercalated in LDH, compressed and deformed without secondary structural change. LYZ-LDHs showed excellent bactericidal effectiveness against staphylococcus aureus. The antibacterial performance of LYZ-LDHs was found to be affected by the LYZ/LDH ratio and the pH of the bacteria-containing water. The bacteria removal efficiency of LYZ-LDHs with LYZ/LDH mass ratio of 0.8 was consistently above 94% over the pH range of 3-9. LYZ-LDHs adsorbed bacteria to their surface by LDH and then killed them by the immobilized LYZ. This new material integrated the bactericidal ability of LYZ and adsorption ability of LDH. Moreover, the antibacterial ability of LYZ-LDHs was persistent and not limited by the adsorption capacity. PMID- 24053939 TI - Fate of carbamazepine and anthracene in soils watered with UV-LED treated wastewaters. AB - Water disinfection technologies based on ultraviolet (UV) radiations emitted by Light-Emitting Diodes (LED), as a wastewater tertiary treatment, have been shown to be promising for water reuse. Here, we assessed the fate of two ubiquitous pollutants, carbamazepine and anthracene, in soil watered with either UV-LED treated wastewaters or irrigation water. After 3 months, anthracene and carbamazepine were transformed two and three times faster respectively, in soils watered with UV-LED wastewater than in soils watered with tap water (probably because of the addition of organic matter by the effluent). Laccase activity was induced in the presence of the pollutants and anthraquinone was found as anthracene product of oxidation by laccases. Moreover, the addition of these pollutants into soil did not affect the functional diversity of autochthonous microbial communities assessed by Ecolog plates. Cellulase, protease and urease activities increased in soils watered with UV-LED treated wastewaters (UV-LED WW), showing transformation of organic matter from the effluent and lipase activity increased by anthracene addition, confirming the potential role of these enzymes as indicators of hydrocarbon contamination. PMID- 24053940 TI - Is biological treatment a viable alternative for micropollutant removal in drinking water treatment processes? AB - In western societies, clean and safe drinking water is often taken for granted, but there are threats to drinking water resources that should not be underestimated. Contamination of drinking water sources by anthropogenic chemicals is one threat that is particularly widespread in industrialized nations. Recently, a significant amount of attention has been given to the occurrence of micropollutants in the urban water cycle. Micropollutants are bioactive and/or persistent chemicals originating from diverse sources that are frequently detected in water resources in the pg/L to MUg/L range. The aim of this review is to critically evaluate the viability of biological treatment processes as a means to remove micropollutants from drinking water resources. We first place the micropollutant problem in context by providing a comprehensive summary of the reported occurrence of micropollutants in raw water used directly for drinking water production and in finished drinking water. We then present a critical discussion on conventional and advanced drinking water treatment processes and their contribution to micropollutant removal. Finally, we propose biological treatment and bioaugmentation as a potential targeted, cost-effective, and sustainable alternative to existing processes while critically examining the technical limitations and scientific challenges that need to be addressed prior to implementation. This review will serve as a valuable source of data and literature for water utilities, water researchers, policy makers, and environmental consultants. Meanwhile this review will open the door to meaningful discussion on the feasibility and application of biological treatment and bioaugmentation in drinking water treatment processes to protect the public from exposure to micropollutants. PMID- 24053941 TI - The effects of fuel composition and ammonium sulfate addition on PCDD, PCDF, PCN and PCB concentrations during the combustion of biomass and paper production residuals. AB - The use of waste wood as an energy carrier has increased during the last decade. However, the higher levels of alkali metals and chlorine in waste wood compared to virgin biomass can promote the formation of deposits and organic pollutants. Here, the effect of fuel composition and the inhibitory effects of ammonium sulfate, (NH4)2SO4, on the concentrations of persistent organic pollutants (POPs) in the flue gas of a lab-scale combustor was investigated. Ammonium sulfate is often used as a corrosion-preventing additive and may also inhibit formation of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). In addition to PCDDs and PCDFs, polychlorinated naphthalenes (PCN) and biphenyls (PCB) were also analyzed. It was found that the flue gas composition changed dramatically when (NH4)2SO4 was added: CO, SO2, and NH3 levels increased, while those of HCl decreased to almost zero. However, the additive's effects on POP formation were less pronounced. When (NH4)2SO4 was added to give an S:Cl ratio of 3, only the PCDF concentration was reduced, indicating that this ratio was not sufficient to achieve a general reduction in POP emissions. Conversely, at an S:Cl ratio of 6, significant reductions in the WHO-TEQ value and the PCDD and PCDF contents of the flue gas were observed. The effect on the PCDF concentration was especially pronounced. PCN formation seemed to be promoted by the elevated CO concentrations caused by adding (NH4)2SO4. PMID- 24053942 TI - Cow excrements enhance the occurrence of tetracycline resistance genes in soil regardless of their oxytetracycline content. AB - Fertilizing soils with animal excrements from farms with common antibiotic use represents a risk of disseminating antibiotic resistance genes into the environment. In the case of tetracycline antibiotics, it is not clear, however, whether the presence of antibiotic residues further enhances the gene occurrence in manured soils. We established a microcosm experiment in which 3 farm soils that had no recent history of fertilization with animal excrements were amended on a weekly basis (9 times) with excrements from either an oxytetracycline treated or an untreated cow. Throughout the study, the concentration of oxytetracycline in excrements from the treated cow was above 500 MUg g(-1)dw, whereas no oxytetracycline was detected in excrements from the healthy cow. Both excrements contained tetracycline resistance (TC-r) genes tet(L), tet(M), tet(V), tet(Z), tet(Q) and tet(W). The excrements from the treated cow also contained the tet(B) gene, and a higher abundance of tet(Z), tet(Q) and tet(W). Three weeks after the last excrement addition, the individual TC-r genes differed in their persistence in soil: tet(Q) and tet(B) were not detectable while tet(L), tet(M), tet(Z) and tet(W) were found in all 3 soils. There were, however, no significant differences in the total number, nor in the abundance, of TC-r genes between soil samples amended with each excrement type. The oxytetracycline-rich and the oxytetracycline-free excrement therefore contributed equally to the increase of tetracycline resistome in soil. Our results indicate that other mechanisms than OTC-selection pressure may be involved in the maintenance of TC-r genes in manured soils. PMID- 24053943 TI - Geochemical distribution of polycyclic aromatic hydrocarbons in soils and sediments of El-Tabbin, Egypt. AB - Polycyclic aromatic hydrocarbons (PAHs) were extracted from 30 samples (24 soils and 6 stream sediments) collected in El-Tabbin area in the southern part of Greater Cairo, Egypt. Isopleth maps of PAHs clarified the regional variability and identified the most affected regions in the area suffering from high pollution. The total PAH concentrations were 53.4-5558.0 ng g(-1) in the sample extracts. The highest values were found in a soil sample near a coke factory, with the highest concentration of single PAHs, which were 1064.8 ng g(-1) of fluoranthene and 1286.4 ng g(-1) of phenanthrene. The calculated ratios and indexes allowed to elucidate origin of the organic compounds and to identify emission sources. The overall molecular patterns are signatures of pyrolysis of fossil fuels and biomass. Petrogenic contamination was recognised in the sediment samples due to petroleum products deliveries from ships. Also perylene was prominent especially in samples of the River Nile sediments as a diagenetic product of fungi. Other detailed information on petrogenic sources was provided by analysis of alkanes and calculation of alkane ratios. PMID- 24053944 TI - Reduction of Cr(VI) into Cr(III) by Spirulina dead biomass in aqueous solution: kinetic studies. AB - Microalga species are potential scavengers of heavy metals. The active functional groups of a number of biomaterials are capable to detoxify Cr(VI) to Cr(III). A 2nd order kinetic model was developed in terms of concentration of protonated acidic groups of Spirulina sp. biomass for the reduction of Cr(VI) into Cr(III). Cr(VI) reduction reaction grounded on the concentration of functional groups was validated over a broad range of pH, temperature and anionic strength. Lower pH favoured Cr(VI) reduction reaction and the experimental results well fitted to the kinetic model. The overall rate constant, kt, decreased logarithmically from 22.7 to 2.8 mM-1 s-1 with rise of pH from 0.5 to 6.0. Whereas, k(t) increased nearly by 23% with elevation temperature from 25 to 45 degrees C. Higher concentration (>0.235 mM) of background anions (Cl-, SO42- and NO3-) was resulted in decreases in k(t) values. The rate constant expression developed can be employed to quantify Cr(VI) reduction into Cr(III) using Spirulina biomass. PMID- 24053945 TI - Mitochondrial complex III and related bc-complexes. PMID- 24053946 TI - Roles of microRNAs in the Caenorhabditis elegans nervous system. AB - The first microRNA was discovered in Caenorhabditis elegans in 1993, and since then, thousands of microRNAs have been identified from almost all eukaryotic organisms examined. MicroRNAs function in many biological events such as cell fate determination, metabolism, apoptosis, and carcinogenesis. So far, more than 250 microRNAs have been identified in C. elegans; however, functions for most of these microRNAs are still unknown. A small number of C. elegans microRNAs are associated with known physiological roles such as developmental timing, cell differentiation, stress response, and longevity. In this review, we summarize known roles of microRNAs in neuronal differentiation and function of C. elegans, and discuss interesting perspectives for future studies. PMID- 24053947 TI - Derivation of putative porcine embryonic germ cells and analysis of their multi lineage differentiation potential. AB - Embryonic germ (EG) cells are cultured pluripotent stem cells derived from the primordial germ cells (PGCs) that migrate from the dorsal mesentery of the hindgut to the developing genital ridge. In this study, the morphology of the porcine genital ridge was assessed in embryos harvested on days 22-30 of pregnancy. PGCs from embryos at these stages were cultured to obtain porcine EG cell lines, and EG-like cells were derived from PGCs from embryos harvested on days 24-28 of pregnancy. The EG-like cells expressed Oct4, Sox2, Nanog, SSEA-3, SSEA-4 and alkaline phosphatase (AP). These cells were able to form embryoid bodies (EBs) in suspension culture and differentiate into cells representative of the three germ layers as verified by a-fetoprotein (AFP), alpha-smooth muscle actin (alpha-SMA), and Nestin expression. Spontaneous differentiation from the porcine EG-like cells of delayed passage in vitro showed that they could differentiate into epithelial-like cells, mesenchymal-like cells and neuron-like cells. In vitro directed differentiation generated osteocytes, adipocytes and a variety of neural lineage cells, as demonstrated by alizarin red staining, oil red O staining, and immunofluorescence for neuronal class III beta-tubulin (Tuj1), glial fibrillary protein (GFAP) and galactosylceramidase (GALC), respectively. These results indicate that porcine EG-like cells have the potential for multi-lineage differentiation and are useful for basic porcine stem cell research. PMID- 24053948 TI - Abscisic acid suppresses the highly occurred somatic homologous recombination in Arabidopsis rfc1 mutant. AB - The phytohormone abscisic acid (ABA) regulates many aspects of plant growth, including seed germination, root growth and cell division. Previous study indicates that ABA treatment increases DNA damage and somatic homologous recombination (HR) in Arabidopsis abo4/pol E (aba overly-sensitive 4 /DNA polymerase E) mutants. DNA replication factor C (RFC) complex is required for loading PCNA (Proliferating Cell Nuclear Antigen) during DNA replication. The defect in RFC1, the largest subunit of RFC, causes the high HR and DNA damage sensitivity in Arabidopsis. Here we found that like pol epsilon/abo4, rfc1 is sensitive to ABA in both ABA-inhibiting seed germination and root growth. However, ABA treatment greatly reduces HR and also reduces the expression of the DNA-damaged marker genes in rfc1. These results suggest that RFC1 plays critical roles in ABA-mediated HR in Arabidopsis. PMID- 24053949 TI - Genetic and proteomic analyses of a Xanthomonas campestris pv. campestris purC mutant deficient in purine biosynthesis and virulence. AB - Bacterial proliferation in hosts requires activation of a number of housekeeping pathways, including purine de novo biosynthesis. Although inactivation of purine biosynthesis genes can attenuate virulence, it is unclear which biochemical or virulence factors are associated with the purine biosynthesis pathway in vivo. We report that inactivation of purC, a gene encoding phosphoribosylaminoimidazole succinocarboxamide synthase, caused complete loss of virulence in Xanthomonas campestris pv. campestris, the causal agent of black rot disease of cruciferous plants. The purC mutant was a purine auxotroph; it could not grow on minimal medium, whereas addition of purine derivatives, such as hypoxanthine or adenine plus guanine, restored growth of the mutant. The purC mutation also significantly enhanced the production of an unknown purine synthesis associated pigment and extracellular polysaccharides by the bacterium. In addition, comparative proteomic analyses of bacteria grown on rich and minimal media revealed that the purC mutation affected the expression levels of diverse proteins involved in purine and pyrimidine synthesis, carbon and energy metabolisms, iron uptake, proteolysis, protein secretion, and signal transduction. These results provided clues to understanding the contributions of purine synthesis to bacterial virulence and interactions with host immune systems. PMID- 24053950 TI - Association analysis of four single nucleotide polymorphisms with leukocyte telomere length in two Chinese populations. PMID- 24053951 TI - Fine mapping and analysis of DWARF TILLER1 in controlling rice architecture. PMID- 24053953 TI - [Misdiagnosis of pneumoconiosis or silicotuberculosis in China: a pooled analysis of 1178 cases]. AB - OBJECTIVE: To investigate the situation and causes of misdiagnosis of pneumoconiosis or silicotuberculosis in China by pooled analysis, and to provide a reference for the clinical diagnosis of pneumoconiosis in China and reduce the misdiagnosis rate. METHODS: A computer search was performed to collect the studies on the misdiagnosis of pneumoconiosis or silicotuberculosis published in China from 1985 to 2013. The obtained data were subjected to pooled analysis to investigate the causes of misdiagnosis and seek the measures for reducing misdiagnosis. RESULTS: Fifty-nine studies involving 1178 cases of misdiagnosed pneumoconiosis or silicotuberculosis were collected. There were 13 causes of misdiagnosis, and the most common one was the poor ability of identification due to inadequate experience in reading chest X-ray films (45.93%), followed by neglect of patient's occupational history (44.99%). Other causes of misdiagnosis included complex X-ray findings that are difficult to judge (29.03%), poor quality of chest radiographs (23.09%), and lack of regular health supervision (19.95%). CONCLUSION: Inadequate experience of physicians is the main cause of misdiagnosis of pneumoconiosis or silicotuberculosis. To reduce misdiagnosis of the disease, measures should be taken to enhance the training and evaluation of knowledge and skills of diagnosis and differential diagnosis of pneumoconiosis among physicians. PMID- 24053952 TI - Lymphocytic meningitis and spinal neurocysticercosis: a case report and literature review. PMID- 24053954 TI - [Dynamic monitoring and analysis of occupational hazards in working environment of foundry plant from 1987 to 2010]. AB - OBJECTIVE: To investigate the characteristics and changing trend of occupational hazards in the working environment of a foundry plant from 1987 to 2010. METHODS: The foundry plant of a large-scale automobile company in Hubei Province, China was chosen as the study site. The data on occupational hazards in the working environment of the foundry plant in the past years were collected, and additional measurements were performed. The means and geometric means of the concentrations of occupational hazards were calculated. The characteristics and changing trend of occupational hazards from 1987 to 2010 were presented. RESULTS: There were dust, chemical, and physical occupational hazards in the working environment of the foundry plant, with silica dust, noise, and heat stress as the main ones. Dust, mainly silica dust, is found in all aspects of foundry. The mean concentration of silica dust was high (3.2~8.2 mg/m(3)), exceeding the national occupational exposure limit (1 mg/m(3)). The mean concentrations of silica dust varied across different types of work, with higher levels in cast shakeout and finishing, overhead crane operation, and sand preparation. The mean concentration of respirable dust in the foundry plant was low (0.38 mg/m(3)), not exceeding the national occupational exposure limit (0.7 mg/m(3)). There were high concentrations of grinding wheel dust (10.6 mg/m(3)) and welding fume (5.7 mg/m(3)) in cast shakeout and finishing, exceeding the national occupational exposure limit (8 and 4 mg/m(3)). Coal dust was mainly found in melting as well as cast shakeout and finishing, with higher concentration in the former (4.7 mg/m(3). The main chemical occupational hazard in the environment of the foundry plant was formaldehyde (1.23 mg/m(3)), exceeding the national occupational exposure limit (0.5 mg/m(3)). The concentrations of ammonia, phenol, metal fume, sulfur dioxide, hydrogen sulfide, and phosphine in the foundry plant were low. The mean concentration of polycyclic aromatic hydrocarbons was 0.1405 ug/m(3), with a higher level in pouring. The main physical occupational hazards in the working environment of the foundry plant were noise and heat stress. Noise, mainly steady noise, was distributed in all workshops of the foundry plant, with a mean intensity of 85.1 db (A). Noise levels varied across different types of work, higher in cast shakeout and finishing (89.3 db (A)) and moulding (85.4 db (A)). Heat stress mainly existed in overhead crane operation (35.1 degrees C), pouring (33.3 degrees C), and melting (32.8 degrees C). CONCLUSION: Dust, chemical, and physical occupational hazards co-existed in the working environment of the foundry plant. High concentration of dust was widely distributed in many workshops and across many types of work, but the dust concentration showed a downward trend. Chemical occupational hazards included ammonia, phenol, hydrogen sulfide, and metal fume, most at low concentrations. High-intensity noise was widely distributed in all working positions of foundry process and mainly from equipment operation, collision between parts, and gas injection. High-intensity heat stress mainly existed in overhead crane operation, pouring, and melting. PMID- 24053955 TI - [DNA damage of splenic lymphocytes in pregnant mice exposed to carbon disulfide in implantation phase]. AB - OBJECTIVE: To investigate the DNA damage of splenic lymphocytes in pregnant mice exposed to carbon disulfide (CS2) in the implantation phase and to explore the mechanism of abnormal implantation induced by CS2 from the perspective of immune injury. METHODS: Mice were exposed to CS2 at different doses or at different time points in the implantation phase to establish model 1 and model 2. For model 1, mice were assigned to four groups to receive a single intraperitoneal injection of low-dose CS2 (0.1 LD50, 157.8 mg/kg), middle-dose CS2 (0.2 LD50, 315.7 mg/kg), and high-dose CS2 (0.4 LD50, 631.4 mg/kg) as well as an equal volume of olive oil (control) on gestational day (GD) 4. For model 2, mice were assigned to four groups to receive a single intraperitoneal injection of CS2 (0.4 LD50, 631.4 mg/kg) or an equal volume of olive oil (control) on GD3, GD4, GD5, and GD6. At the end, single cell suspension of splenic lymphocytes was prepared. Cell viability was measured by trypan blue staining, and the DNA damage of splenic lymphocytes was evaluated by alkaline single cell gel electrophoresis assay. RESULTS: The middle-dose and high-dose exposure groups showed significantly more DNA damage of splenic lymphocytes than the control group (P < 0.01); there was significant regression relationship between indicators of DNA damage and exposure doses (P < 0.01). The GD3, GD4, GD5, and GD 6 exposure groups showed significantly more DNA damage of splenic lymphocytes than the control group (P < 0.01), and the GD 4 exposure group had the most DNA damage. CONCLUSION: Exposure to CS2 in the implantation phase can induce DNA damage of splenic lymphocytes in pregnant mice, and the DNA damage was aggravated with the increase in CS2 concentration. GD4 may be the sensitive time point for DNA damage of splenic lymphocytes induced by CS2 in pregnant mice. PMID- 24053956 TI - [Effect of maternal BDE-209 exposure on sexual development in male offspring rats]. AB - OBJECTIVE: To investigate the effect of maternal decabromodiphenyl ether (BDE 209) exposure on the sexual development in male offspring rats. METHODS: Twenty four pregnant Sprague-Dawley rats were randomly divided into three BDE-209 exposure groups and one control group. The three BDE-209 exposure groups were given BDE-209 (100, 300, and 900 mg/kg) by gavage on gestational days 12~18, and the control group was given corn oil. The body weight and body length of each newborn male rat was measured at postnatal days 4, 10, 16, and 21. Twelve newborn male rats were randomly selected from each group; anogenital distance was measured at postnatal day 21, serum testosterone was measured, and the organ coefficient of testis was calculated. RESULTS: The newborn male rats in all exposure groups showed declining trends in body weight and body length compared with those in the control group, and the 900 mg/kg BDE-209 exposure group had significantly lower body weight and body length than the control group at postnatal days 4, 10,16, and 21 (P < 0.01). At postnatal day 21, the 100, 300, and 900 mg/kg BDE-209 exposure groups had anogenital distances of 17.82+/-2.35 mm, 16.32+/-1.66 mm, and 15.80+/-1.34 mm, respectively, demonstrating a significant decrease with increased exposure dose (P < 0.05), but no significant difference was found when comparing these values with that of the control group (16.64+/-2.38 mm) (P > 0.05). There were no significant differences in serum testosterone and organ coefficients of testis and epididymis between the control group and BDE-209 exposure groups (P > 0.05). CONCLUSION: Maternal exposure to BDE-209 has adverse effect on the growth of male offspring rats, but it leads to no significant changes in sexual development. PMID- 24053957 TI - [Effect of subchronic inhalation of ethylbenzene on expression of heme oxygenase 1 in rat renal tissues]. AB - OBJECTIVE: To investigate the effect of ethylbenzene on the expression of heme oxygenase-1 (HO-1) intrarenal tissues. METHODS: Forty male Sprague-Dawley rats were randomly and equally allocated to control group, low-dose exposure group, moderate-dose exposure group, and high-dose exposure group to inhale different doses of ethylbenzene (0, 433.5 mg/m(3) (100 ppm), 4335.0 mg/m(3) (1000 ppm), and 6500.0 mg/m(3) (1500 ppm)) for 6 h per day, 5 days per week, for 13 weeks. After the rat model of subchronic ethylbenzene exposure was established, the activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) in renal tissues were measured, and the mRNA and protein expression levels of HO-1 in renal tissues were measured by real-time PCR and Western blot. RESULTS: Compared with the control group, all exposure groups showed significantly decreased activities of GSH-Px and CAT in renal tissues and the moderate- and high-dose exposure groups showed significantly decreased activity of SOD in renal tissues (P < 0.05). All exposure groups showed significantly higher expression of HO-1 than the control group (P < 0.05). The high-dose exposure group showed significantly higher expression of HO-1 than the low- and moderate-dose exposure group (P < 0.05), and the moderate- and high-dose exposure group had significantly higher expression of HO-1 than the control group and low dose exposure group (P < 0.05). CONCLUSION: A certain dose of ethylbenzene can induce elevated expression of HO-1 and decreased antioxidant levels in rat renal tissues, thus leading to oxidative stress damage. PMID- 24053958 TI - [Expression of caspase-3, Bcl-2, and Bax in pentavalent vanadium-induced neuronal apoptosis]. AB - OBJECTIVE: To investigate the expression of caspase-3, Bcl-2, and Bax in pentavalent vanadium-induced neuronal apoptosis and the neurotoxicity of pentavalent vanadium to in vitro cultured rat neurons. METHODS: Neurons from rats were cultured in vitro and treated with different concentrations of V2O5. Neuronal apoptosis was evaluated by TdT-mediated dUTP-biotin nick end labeling (TUNEL). The expression of caspase-3, Bcl-2, and Bax in neurons was measured by Western blot. The images collected by gel imaging system and scanner were analyzed. RESULTS: The TUNEL showed that compared with the control group, the middle- and high-dose exposure groups had significantly increased apoptosis index (AI) of neurons (P < 0.05 or P < 0.01). The Western blot showed that compared with the control group, the middle- and high-dose exposure groups had significantly increased expression of caspase-3 and Bax and significantly decreased expression of Bcl-2 (P <0.05 or P < 0.01). The AI of neurons was positively correlated with the expression of caspase-3 and Bax (r = 0.943, P < 0.01; r = 0.937, P < 0.01) and negatively correlated with the expression of Bcl-2 (r = -0.908, P < 0.01). CONCLUSION: Pentavalent vanadium may induce neuronal apoptosis, and the expression of caspase-3, Bcl-2, and Bax, which regulate apoptosis, plays an important role in the neuronal apoptosis induced by pentavalent vanadium. PMID- 24053959 TI - [Investigation of social support for inpatients with occupational diseases]. AB - OBJECTIVE: To investigate and analyze the social support for inpatients with occupational diseases and to provide reference and basis for relevant medical and nursing interventions. METHODS: The social support rating scale (SSRS) was used to investigate the social support for 95 inpatients with occupational diseases. RESULTS: The total SSRS score of these patients was significantly lower than the national norm (32.5+/-9.31 vs 34.56+/-3.73, P < 0.05). The social support was mainly from the family, but medical staff and spiritual support were the main source and type of social support that are expected. CONCLUSION: Patients with occupational diseases have gained little social support, in both economic and spiritual aspects. In clinical practice, the patient's demand for knowledge of diseases and spiritual needs should be satisfied, and appropriate social support should be provided. PMID- 24053960 TI - [Changes in peripheral hemogram among workers with short-term lead exposure]. AB - OBJECTIVE: To examine the effect of short-term occupational lead exposure on the inflammatory response system in blood among workers. METHODS: A total of 255 lead exposed workers (length of service <=1 year) at an electronics factory in Dongguan, China (exposure group), as well as 205 managers without any occupational exposure at another factory (control group), were included in the study. Occupational physical examination was done to get peripheral blood counts. The blood lead levels of workers were determined by atomic absorption spectrometry. The relationship between blood lead and peripheral hemogram was analyzed using SPSS software. RESULTS: The exposure group had blood lead levels of 0.07~1.70 umol/L, falling within the normal range. The leukocyte count, percentage of granulocytes, and absolute value of granulocytes were significantly higher in the exposure group than in the control group, and the results remained unchanged after adjustment for age and sex (P < 0.05). There were no significant differences in red blood cell count and hemoglobin value between the two groups (P > 0.05). CONCLUSION: Short-term occupational lead exposure may increase the counts of inflammatory cells in blood, but it has little effect on red blood cells and hemoglobin. PMID- 24053961 TI - [Analysis of risk factors for dry eye syndrome in visual display terminal workers]. AB - OBJECTIVE: To analyze the risk factors for dry eye syndrome in visual display terminal (VDT) workers and to provide a scientific basis for protecting the eye health of VDT workers. METHODS: Questionnaire survey, Schirmer I test, tear break up time test, and workshop microenvironment evaluation were performed in 185 VDT workers. Multivariate logistic regression analysis was performed to determine the risk factors for dry eye syndrome in VDT workers after adjustment for confounding factors. RESULTS: In the logistic regression model, the regression coefficients of daily mean time of exposure to screen, daily mean time of watching TV, parallel screen-eye angle, upward screen-eye angle, eye-screen distance of less than 20 cm, irregular breaks during screen-exposed work, age, and female gender on the results of Schirmer I test were 0.153, 0.548, 0.400, 0.796, 0.234, 0.516, 0.559, and -0.685, respectively; the regression coefficients of daily mean time of exposure to screen, parallel screen-eye angle, upward screen-eye angle, age, working years, and female gender on tear break-up time were 0.021, 0.625, 2.652, 0.749, 0.403, and 1.481, respectively. CONCLUSION: Daily mean time of exposure to screen, daily mean time of watching TV, parallel screen-eye angle, upward screen eye angle, eye-screen distance of less than 20 cm, irregular breaks during screen exposed work, age, and working years are risk factors for dry eye syndrome in VDT workers. PMID- 24053962 TI - [Effect of exposure to extremely low-frequency electromagnetic fields on liver function of workers]. AB - OBJECTIVE: To examine the effect of exposure to extremely low-frequency electromagnetic fields (ELF EMFs) on the liver function of workers. METHODS: The workers in a factory were selected as subjects, and the recent physical examination data of these workers were collected. The workers aged 20~40 years and with more than 2 years' working experience were included for analysis; considering the intensity of electromagnetic field, the workers exposed to less electromagnetic radiation were assigned to exposure I group (n = 123), those exposed to more electromagnetic radiation to exposure II group (n = 229), and those not exposed to electromagnetic radiation to control group (n = 212). There were no significant differences in sex, age, height, and body weight between the three groups (P > 0.05). Physical examination, including measurements of direct bilirubin (DBil), alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), and albumin, was performed in a health examination center. The intensity of electromagnetic field was measured by EFA-300 power frequency electromagnetic field analyzer, and the intensity of noise by AWA5610D integrating sound level meter. RESULTS: The intensities of electric field and the magnetic field in exposure II group were significantly higher than those in the exposure I group. The levels of ALT, ALP, AST, GGT and albumin in exposure II group were significantly higher than those in exposure I group and control group. However, the level of direct bilirubin in exposure II group was significantly lower than that in exposure I group and control group. CONCLUSION: Occupational exposure to ELF EMFs may affect human liver function. PMID- 24053963 TI - [Effects of electromagnetic radiation on health and immune function of operators]. AB - OBJECTIVE: To investigate the effects of electromagnetic radiation on the physiological indices and immune function of operators. METHODS: The general conditions and electromagnetic radiation awareness rate of 205 operators under electromagnetic radiation were evaluated using a self-designed questionnaire. Physical examination, electrocardiography, and routine urine test were performed in these operators. Peripheral blood was collected from the operators under electromagnetic radiation for blood cell counting and biochemical testing, and their peripheral blood lymphocytes were cultured for determination of chromosomal aberrant frequency and micronucleus frequency. The data from these operators (exposure group) were compared with those of 95 ordinary individuals (control group). RESULTS: The chief complaint of giddiness, tiredness, dizziness, and amnesia showed significant differences between the exposure group and control group (P < 0.01), and the difference in headache became larger with an increase in working years. The awareness rate of electromagnetic radiation damage was significantly higher in the exposure group than in the control group. The difference in bradycardia was significant between the two groups (P <0.01), and the incidence was higher with longer working years. Significant differences between the two groups were also found in the numbers of individuals with elevated alanine aminotransferase, total bilirubin, and direct bilirubin (P < 0.01), populations with increased lymphocyte ratio and decreased neutrophil ratio (P < 0.01), populations with positive occult blood, urobilinogen, and bilirubin tests, and the number of individuals with increased micronucleus frequency of cultured peripheral blood lymphocytes (P < 0.01). In addition, the exposure group had significantly increased complement C3 and C4 (P < 0.01), significantly increased IgG (P < 0.05), and significantly decreased IgM (P < 0.01), as compared with the control group. CONCLUSION: Electromagnetic radiation may lead to the changes in physiological indices, genetic effects, and immune function and affect the health and immune function in operators. The adverse effects are increased as the working years increase. So it is important to strengthen occupational protection of operators under electromagnetic radiation. PMID- 24053964 TI - [Autophagy in lung tissue of rats exposed to silica dust]. AB - OBJECTIVE: To investigate the autophagy of effector cells in lung tissue at different time points when rats were exposed to free SiO2 dust. METHODS: Sixty Wistar rats (220~230 g) were selected and allocated to experimental group (n = 30) and control group (n = 30). In the experimental group, a rat silicosis model was established by infusing SiO2 suspension into the trachea of rats. Six rats in each group were sacrificed on days 1, 7, 14, 21, or 28 of dust exposure. Lung tissue samples were collected to prepare lung tissue sections. The pulmonary inflammation and fibrosis were observed by HE staining. The proautophagosome, autophagosome, and autophagolysosome in lung tissue sections were observed under a transmission electron microscope. RESULTS: On day 1 of dust exposure, many proautophagosomes and autophagosomes were seen in both experimental group and control group. On day 7 of dust exposure, the experimental group had more autophagosomes in lung tissue than the control group. On day 14 of dust exposure, the experimental group had fewer autophagosomes than the control group. On days 21 and 28, autophagolysosomes were seen in macrophage plasma in both experimental group and control group; the autophagolysosomes in experimental group showed cloudy swelling and expansion, and some were vacuolated, and these changes were more significant on day 28. CONCLUSION: Free SiO2 dust can induce autophagy in the lung tissue of rats, with varying degrees at different time points of dust exposure. PMID- 24053965 TI - [Formation of pyrrole adducts in 2,5-hexanedione-containing human serum cultured in vitro]. AB - OBJECTIVE: To investigate the relationship between formation of pyrrole adducts and concentration of 2, 5-hexanedione (2, 5-HD) and to provide an experimental basis for the study on toxicity of n-hexane. METHODS: Serum samples were collected from normal persons and were then filtered and sterilized. They were mixed with 2,5-HD to obtain sera with final 2, 5-HD concentrations of 10, 25, 50, 100, and 200 mg/L, and blank serum was also prepared. The sera were cultured at 37 degrees C and taken at different time points. Colorimetry was used to quantify the pyrrole adducts formed in sera, and gas chromatography was used to measure the remaining 2, 5-HD levels in sera. RESULTS: The content of pyrrole adducts increased as the culture proceeded and was dependent on the dose of 2, 5-HD; at the end of the experiment, the content of pyrrole adducts differed significantly across all concentration groups (P < 0.5). The concentrations of 2,5-HD decreased as the culture proceeded; at the end of the experiment, the concentrations of 2, 5-HD, from the highest to the lowest, decreased by 29%, 55%, 22%, 44%, and 40%, respectively. The decrease in 2, 5-HD had a positive correlation with the increase in pyrrole adducts, and the correlation coefficients for 200~10 mg/L 2, 5-HD were 0.865, 0.697, 0.835, 0.823, and 0.814, respectively. CONCLUSION: The content of formed pyrrole adducts increases as the concentration of 2,5-HD rises; there is a positive correlation between the decrease in 2, 5-HD and the increase in pyrrole adducts in human serum. PMID- 24053966 TI - [A case of radiodermatitis following percutaneous coronary intervention]. PMID- 24053967 TI - [Clinical analysis on 62 cases of subacute n-hexane poisoning]. PMID- 24053968 TI - [Successful treatment of paraquat poisoning with hemolytic anemia: a report of 1 case]. PMID- 24053969 TI - [Method for determining brodifacoum in workplace air by high-performance liquid chromatography]. AB - OBJECTIVE: To establish a method for determining brodifacoum in workplace air by high-performance liquid chromatography (HPLC). METHODS: Brodifacoum in workplace air was collected with a polytetrafluoroethylene filter and desorbed by mixed solution of methanol and dichloromethane (20:80, V:V), and was then separated using an ODS column and determined by an ultraviolet detector; retention time was used for identification, and peak area was used for quantification. RESULTS: The concentration of brodifacoum showed a linear relationship with peak area within 0.2~10.0 ug/ml; the elution efficiency was 91.6%~95.1%; the detection limit was 0.08 ug/ml (injection volume: 20 ul eluate); the minimum detectable concentration was 0.000 67 mg/m(3) (calculated by 240 L air sample). CONCLUSION: This HPLC method is convenient and simple for air collection and sample preparation and meets the methodological requirements. Therefore, this method can be used for the determination of brodifacoum in workplace air. PMID- 24053970 TI - [Method for determining o-tolidine in workplace air by gas chromatography]. AB - OBJECTIVE: To establish a method for determining o-tolidine in workplace air by gas chromatography. METHODS: o-tolidine in workplace air was collected with a glass fiber filter, desorbed with methanol, and determined by gas chromatography flame ionization detector. RESULTS: The concentration of o-tolidine showed a linear relationship with peak area within 0.04~9.00 ug/ml; the detection limit was 0.04 ug/ml; the minimum detectable concentration was 0.0002 mg/m(3) (calculated by 375 L air sample); the sampling efficiency was 93%~100%; the elution efficiency was 94%~96%; the relative standard deviation was 0.8-2.5%. Sample could be stored at 4 degrees C for at least 8 days and at room temperature for as long as 6 days. CONCLUSION: This determination method meets the requirements of Guide for establishing occupational heath standards-Part 4 Determination methods of air chemicals in workplace (GBZ/T 210.4-2008) and is suitable for determination of o-tolidine in workplace air. PMID- 24053971 TI - [Method for determining nitrogen dioxide in workplace air by ion-exchange chromatography]. AB - OBJECTIVE: To evaluate the method for collecting NO2 in workplace air using a solid adsorbent and determining the concentration of NO2 by ion-exchange chromatography. METHODS: NO2 in workplace air was collected using sampling tubes filled with 13X molecular sieve soaked with triethanolamine, and the samples were desorbed with a certain concentration of triethanolamine solution to obtain NO2( ). NO2(-) was separated with an anion exchange chromatography column and quantified by a conductivity detector. The concentration of NO2 was determined based on the conversion coefficient of NO2 and NO2(-). RESULTS: Different concentrations of NO2 (standard gas) was collected using the sampling tubes at different time points, and the sampling efficiency and desorption efficiency could reach more than 90%. The penetrating capacity of sampling tubes was more than 1.1 mg. The comparative test shows that there was no significant difference between the new method and national standard method (solution absorption) (P > 0.05). The samples could be stored at room temperature for more than 16 days. The calibration curve plotted in the new method was linear in the range of 0.1~20.0 ug/ml, with a correlation coefficient of 0.9998; the detection limit was 0.01 ug/ml; the minimum detectable concentration was 0.05 mg/m(3) (V0 = 3.0 L). CONCLUSION: This determination method meets the requirements of Guide for establishing occupational heath standards-Part 4 Determination methods of air chemicals in workplace (GBZ/T 210.4-2008) and shows obvious advantages for determination of NO2 in workplace air. PMID- 24053972 TI - Development and standardization of a furosemide stress test to predict the severity of acute kidney injury. AB - INTRODUCTION: In the setting of early acute kidney injury (AKI), no test has been shown to definitively predict the progression to more severe stages. METHODS: We investigated the ability of a furosemide stress test (FST) (one-time dose of 1.0 or 1.5 mg/kg depending on prior furosemide-exposure) to predict the development of AKIN Stage-III in 2 cohorts of critically ill subjects with early AKI. Cohort 1 was a retrospective cohort who received a FST in the setting of AKI in critically ill patients as part of Southern AKI Network. Cohort 2 was a prospective multicenter group of critically ill patients who received their FST in the setting of early AKI. RESULTS: We studied 77 subjects; 23 from cohort 1 and 54 from cohort 2; 25 (32.4%) met the primary endpoint of progression to AKIN III. Subjects with progressive AKI had significantly lower urine output following FST in each of the first 6 hours (p<0.001). The area under the receiver operator characteristic curves for the total urine output over the first 2 hours following FST to predict progression to AKIN-III was 0.87 (p = 0.001). The ideal-cutoff for predicting AKI progression during the first 2 hours following FST was a urine volume of less than 200mls(100ml/hr) with a sensitivity of 87.1% and specificity 84.1%. CONCLUSIONS: The FST in subjects with early AKI serves as a novel assessment of tubular function with robust predictive capacity to identify those patients with severe and progressive AKI. Future studies to validate these findings are warranted. PMID- 24053973 TI - Does substance use disorder affect clinical expression in first-hospitalization patients with schizophrenia? Analysis of a prospective cohort. AB - Although several papers reported a wide range of negative outcomes among patients with both schizophrenia and Substance Use Disorder (SUD), only a few studies evaluated the impact of SUD on psychopathology and thus on the length of first hospitalization. The aim of the present study was to compare clinical expression of first-episode of schizophrenia between inpatients with and without SUD, giving close attention to the length of stay. One hundred and thirty inpatients at first episode of schizophrenia were assigned to either SUD or not SUD group depending on SUD diagnosis and were assessed through BPRS at admission, during hospitalization and at discharge. Cross-sectional and longitudinal statistical analysis were performed to investigate differences between groups and also a linear regression was used to evaluate relationship between length of stay and BPRS scores. SUD group showed more disorganization at admission, less marked improvement of symptoms (disorganization, thought disturbance, anergia), and longer hospital stay than not SUD group. Moreover BPRS total score during hospitalization was a significant positive predictor for length of stay. Taken together, these findings suggest that SUD patients have a more severe and drug resistant expression of schizophrenia, hence, they need longer treatment to achieve the overall symptoms improvement required for discharge. PMID- 24053974 TI - Association between thyroid profile and perfluoroalkyl acids: data from NHNAES 2007-2008. AB - The effect of six perfluoroalkyl acids (PFAAs), namely, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDE), perfluorohexane sulfonic acid (PFHxS), 2-(N-methyl-perfluorooctane sulfonamide) acetic acid (MPAH), and perfluorononanoic acid (PFNA) on the levels of six thyroid function variables, namely, thyroid stimulating hormone (TSH), free and total thyroxine (FT4, TT4), free and total triiodothyronine (FT3, TT3), and thyroglobulin (TGN) was evaluated. Data from National Health and Nutrition Examination Survey for the years 2007-2008 were used for this evaluation. TSH levels increased with increase in levels of PFOA (p<0.01). There were no statistically significant associations between the levels of FT3, and FT4 with the levels of any of the six PFAAs. Levels of TT3 were found to increase with the levels of PFOA (p=0.01) and TT4 levels were found to increase with increase in PFHxS levels (p<0.01). Males had statistically significantly higher levels of FT3 than females and females had statistically significantly higher levels of TT4 than males. As compared to non-Hispanics whites and Hispanics, non-Hispanic blacks had lower levels of TSH, FT3, TT3, and TT4 but Hispanics had the lowest levels of TGN. Age was negatively associated with FT3 and TT3 but positively associated with FT4 and TT4. Non-smokers had higher levels of TSH and TT4 than smokers and smokers had higher levels of FT3 and TGN than non-smokers. Iodine deficiency was associated with increased levels of TSH, TT3, TT4, and TGN. PMID- 24053975 TI - Interferon-gamma responses to Mycobacterium tuberculosis Rpf proteins in contact investigation. AB - Mycobacterium tuberculosis Resuscitation-promoting factor proteins (Rpf) induce stronger T-cell responses in latently infected individuals (LTBI) than in pulmonary tuberculosis patients (PTB), but there are scarce data concerning the responses to Rpf among LTBI with different contact levels. We therefore enrolled LTBI individuals infected through household contacts with PTB as well as people with community exposure who were determined to be LTBI through Interferon-gamma (IFN-gamma) release assays (IGRAs) and TB antibodies test, and we studied interferon-gamma responses to Rv0867c and Rv2389c which demonstrated the highest recognition of all Rpfs. The results demonstrated that LTBI infected through household contacts possessed higher interferon-gamma production and higher frequencies of CD4(+)IFN-gamma(+) T-cells to Rv0867c and Rv2389c than did the community exposed individuals. These findings suggest that the interferon-gamma response to Rv0867c and Rv2389c may help to distinguish LTBI caused by different levels of exposure to M. tuberculosis. PMID- 24053976 TI - microR-142-3p down-regulates IRAK-1 in response to Mycobacterium bovis BCG infection in macrophages. AB - MicroRNAs (miRNAs) have been demonstrated to play a pivotal role in the regulation of target gene expression at the post-transcriptional level. In order to better understand the role of miRNA in the immunological regulation of macrophages against Mycobacterium bovis BCG infection, we explored the alteration of immune-related miRNA profile in macrophage RAW264.7 cells in response to BCG infection in this study. Our results demonstrated that miR-142-3p was a potential to negatively regulate the production of pro-inflammatory mediators NF-kappaB (NF kappaB1), TNF-alpha and IL-6 in the macrophages in part through a mechanism of targeting IRAK-1 gene and post-transcriptionally down-regulating IRAK-1 protein expression. PMID- 24053977 TI - Conjunctivochalasis is the precursor to pterygium. AB - Pterygium is a fibrovascular proliferative condition of the ocular surface with no known pathological mechanism. This condition affects vision due to dry eyes, astigmatism or physical occlusion of the visual axis for severe cases. The only definitive treatment for this condition is surgical excision. Interestingly, it is a lesion that may be related to UV radiation and elaboration of proteases. Conjunctivochalasis is a dry eye related condition that is exemplified by excessive conjunctiva or the mucous membrane of the front of the eye around the cornea. Both pterygium and conjunctivochalasis are associated with elaboration of matrix metalloproteinases as well as inflammatory cytokines. We propose that under specific conditions, conjunctivochalasis in the nasal part of the conjunctiva can progress to pterygium. The progression of conjunctivochalasis to pterygium may be related to special kinds of oxidative or inflammatory damage that affects only the part of the loose conjunctival tissue adjacent to the cornea. Protease expressed may then breakdown the conjunctival and corneal epithelium causing the head of pterygium to be very adherent to the cornea. This explains the fact that surgically excised pterygium tissue has stromal tissue enclosed by epithelia on both surfaces. In addition, it explains the existence of a surgical plane when an instrument is passed under the neck of the pterygium tissue but not at the apex. The implications of this hypothesis are first, treatment should be directed to the protection of conjunctivochalasis before it transforms to pterygium. This may be achieved by anti-inflammatory measures, anti protease treatment, or preventing the triggering of the changes at the head of pterygium, such as avoidance of sunlight. Second, during resection of pterygium, it may not be necessary to resect the pterygium too extensively away from the cornea, since this effectively removes relatively normal conjunctiva. PMID- 24053978 TI - Attachment and self-consciousness: a dynamic connection between schizophrenia and panic. AB - INTRODUCTION: Attachment theory offers an evolutionary explanation for the occurrence of panic states. The distance between a mother and child causes the sensation of fear. The experience of feared annihilation, an intense fear reaction (panic), is presented as a threat to the individual's cohesiveness, disrupting the mental representation of self-consciousness, specifically self unity. Alterations in self-consciousness in schizophrenia are so important that they are mostly included among Kurt Schneider's first-ranked symptoms. HYPOTHESES: Based on clinical trials, case reports, and brain imaging and pharmacological studies, a paradigm is proposed to explain the relationship between panic anxiety and psychosis. CONCLUSION: The psychosis-anxiety pathophysiology explanation needs further investigation into the brain areas that integrate self-monitoring with fear areas, but it seems possible to note the importance of the anterior cingulate cortex. PMID- 24053979 TI - Anticipatory guidance, recognition, response, and sequelae of child sexual abuse. PMID- 24053980 TI - What price progress: delayed cerebrovascular lesions in cancer survivors. PMID- 24053981 TI - Are diagnostic criteria for tuberous sclerosis still relevant? PMID- 24053982 TI - Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. AB - BACKGROUND: Tuberous sclerosis complex is highly variable in clinical presentation and findings. Disease manifestations continue to develop over the lifetime of an affected individual. Accurate diagnosis is fundamental to implementation of appropriate medical surveillance and treatment. Although significant advances have been made in the past 15 years in the understanding and treatment of tuberous sclerosis complex, current clinical diagnostic criteria have not been critically evaluated or updated since the last clinical consensus conference in 1998. METHODS: The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important diagnostic implications and was charged with reviewing prevalence and specificity of disease-associated clinical findings and their impact on suspecting and confirming the diagnosis of tuberous sclerosis complex. RESULTS: Clinical features of tuberous sclerosis complex continue to be a principal means of diagnosis. Key changes compared with 1998 criteria are the new inclusion of genetic testing results and reducing diagnostic classes from three (possible, probable, and definite) to two (possible, definite). Additional minor changes to specific criterion were made for additional clarification and simplification. CONCLUSIONS: The 2012 International Tuberous Sclerosis Complex Diagnostic Criteria provide current, updated means using best available evidence to establish diagnosis of tuberous sclerosis complex in affected individuals. PMID- 24053984 TI - Relationship of serum ferritin levels to sleep fragmentation and periodic limb movements of sleep on polysomnography in autism spectrum disorders. AB - OBJECTIVE: Although children with autism spectrum disorders experience a range of sleep disturbances, exact mechanisms are not well-characterized. We investigated the association of serum-ferritin to sleep fragmentation and periodic limb movements of sleep using polysomnography in children with autism spectrum disorders. METHODS: We conducted a retrospective chart review of children with autism spectrum disorders followed from 1990 to 2010. Inclusion criteria were availability of polysomnography data and ferritin levels within 12 months of each other. The following variables on polysomnography characterized sleep fragmentation: increased arousal index, alpha intrusions, and reduced sleep efficiency. The data were compared with age- and gender-matched controls. RESULTS: Of 9791 children with autism spectrum disorders identified, 511 had a ferritin level, 377 had polysomnography data, and 53 had both ferritin and polysomnography data. As compared with the controls (86 ng/mL), the median ferritin level was 27 ng/mL in the study autism spectrum disorders population (53 patients) (P < 0.01), 27 ng/mL in autism spectrum disorder subjects with periodic limb movements of sleep (25 patients) (P = 0.01), and 24 ng/mL in autism spectrum disorders subjects with sleep fragmentation (21 patients) (P = 0.02). Within the autism spectrum disorders population, median ferritin levels were significantly lower in patients with poor sleep efficiency (7 ng/mL) versus those with normal sleep efficiency (29 ng/mL) (P = 0.01). The prevalence of periodic limb movements of sleep was 47% in autism spectrum disorders compared with 8% in controls (P < 0.01). CONCLUSION: Children with autism spectrum disorders had significantly lower ferritin levels compared with controls. In addition, they experience a higher prevalence of sleep fragmentation, obstructive sleep apnea, and periodic limb movements of sleep than children with ASD and no sleep complaints. Our preliminary observations, which have not been described before, need to be validated in multicenter prospective studies. PMID- 24053985 TI - Isolated cerebellar tuberculoma. PMID- 24053983 TI - Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. AB - BACKGROUND: Tuberous sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and varied presentations and progression can be life threatening with significant impact on cost and quality of life. Current surveillance and management practices are highly variable among region and country, reflective of the fact that last consensus recommendations occurred in 1998 and an updated, comprehensive standard is lacking that incorporates the latest scientific evidence and current best clinical practices. METHODS: The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 separate subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important clinical management implications and was charged with formulating key clinical questions to address within its focus area, reviewing relevant literature, evaluating the strength of data, and providing a recommendation accordingly. RESULTS: The updated consensus recommendations for clinical surveillance and management in tuberous sclerosis complex are summarized here. The recommendations are relevant to the entire lifespan of the patient, from infancy to adulthood, including both individuals where the diagnosis is newly made as well as individuals where the diagnosis already is established. CONCLUSIONS: The 2012 International Tuberous Sclerosis Complex Consensus Recommendations provide an evidence-based, standardized approach for optimal clinical care provided for individuals with tuberous sclerosis complex. PMID- 24053987 TI - [Fitness or frailty? Does age matter? New horizons in geriatrics]. PMID- 24053986 TI - A pediatric case of painful legs and moving toes syndrome. PMID- 24053988 TI - [Benefits of music therapy as therapy no pharmacology and rehabilitation moderate dementia]. AB - An in-depth review is presented the possible benefits of music therapy in relation to the cognitive and/or behavioural level of elderly patients with dementia. We have carried out a systematic review of randomized controlled trials, case-control and pilot studies published from January 2000 to January 2012 using the Cochrane Database of Systematic Reviews, MEDLINE, Dialnet and CSIC. We focused on comparison of music therapy as non-pharmacological therapy, in patients over 65 years of age with moderate dementia, with regular therapeutic and occupational treatment. Ten articles were selected based on the inclusion criteria. The analysis of the results suggest that music Therapy influences the elderly people with dementia in a positive way by improving levels of behavioural and cognitive functioning and social participation. PMID- 24053989 TI - Laparoscopic nephrectomy in dogs: an initial experience of 16 experimental procedures. AB - Left laparoscopic nephrectomy was performed in 16 dogs to describe the surgical techniques and initial experiences associated with operation time and surgery complications. The renal vein and artery were occluded by three ligating clips, respectively, and the ureter was sectioned after ligation with ligating clips at the level of the iliac vessels. A morcellation technique was used to remove the kidney from the abdominal cavity after placing it into a specimen retrieval bag. Total operation time and time spent for each different surgical stage in the first five operations were compared with those in the last five of the 16 operations. The factors that affected the differences of total operation time were examined, including sex, bodyweight, number of operations, incision length, and surgical stages. Six intra-operative complications occurred including splenic hemorrhage (3 cases), torn specimen retrieval bag during kidney morcellation (1 case), and subcutaneous emphysema (2 cases). Surgical time for laparoscopic nephrectomy was affected primarily by the time spent for renal vascular pedicle section and could be decreased as the number of cases increased. Thus, laparoscopic nephrectomy using ligating clips and morcellation for kidney removal could be considered where nephrectomy is indicated in dogs. PMID- 24053990 TI - Bovine viral diarrhoea: pathogenesis and diagnosis. AB - Bovine viral diarrhoea virus (BVDV) is the most prevalent infectious disease of cattle. It causes financial losses from a variety of clinical manifestations and is the subject of a number of mitigation and eradication schemes around the world. The pathogenesis of BVDV infection is complex, with infection pre- and post-gestation leading to different outcomes. Infection of the dam during gestation results in fetal infection, which may lead to embryonic death, teratogenic effects or the birth of persistently infected (PI) calves. PI animals shed BVDV in their excretions and secretions throughout life and are the primary route of transmission of the virus. These animals can usually be readily detected by virus or viral antigen detection assays (RT-PCR, ELISA), except in the immediate post-natal period where colostral antibodies may mask virus presence. PI calves in utero (the 'Trojan cow' scenario) currently defy detection with available diagnostic tests, although dams carrying PI calves have been shown to have higher antibody levels than seropositive cows carrying non-PI calves. Acute infection with BVDV results in transient viraemia prior to seroconversion and can lead to reproductive dysfunction and immunosuppression leading to an increased incidence of secondary disease. Antibody assays readily detect virus exposure at the individual level and can also be used in pooled samples (serum and milk) to determine herd exposure or immunity. Diagnostic tests can be used to diagnose clinical cases, establish disease prevalence in groups and detect apparently normal but persistently infected animals. This review outlines the pathogenesis and pathology of BVD viral infection and uses this knowledge to select the best diagnostic tests for clinical diagnosis, monitoring, control and eradication efforts. Test methods, types of samples and problems areas of BVDV diagnosis are discussed. PMID- 24053991 TI - Rivaroxaban demonstrates in vitro anticoagulant effects in canine plasma. AB - Rivaroxaban is an oral direct factor X inhibitor used in human thrombotic disorders and its oral administration makes it an attractive potential anticoagulant for dogs. The objective of this study was to evaluate the in vitro anticoagulant effect of rivaroxaban on canine pooled platelet-poor plasma (PPP). Pooled PPP was collected from 20 healthy adult Beagle dogs. Aliquots of pooled citrated PPP were treated in vitro with DMSO solutions of rivaroxaban (98% purity) to obtain 19 final concentrations ranging from 0 to 1000 mg/L of drug. Samples were immediately submitted for the following coagulation assays: prothrombin time (PT), activated partial thromboplastin time (aPTT), tissue factor-induced thrombin generation and anti-factor Xa activity. Concentration effect data were analyzed with various nonlinear regression models for stimulatory or inhibitory effects. Rivaroxaban caused a concentration-dependent prolongation of all coagulation parameters. Rivaroxaban concentration for 50% baseline inhibition of the propagation phase of thrombin (rate index) was 0.024 mg/L, and for 50% baseline inhibition of the optical density in the anti-factor Xa activity assay was 0.053 mg/L. At these concentrations, PT and aPTT remained within the reference range. Two-fold prolongation from baseline of PT and aPTT was achieved with higher concentrations, i.e. 1.24 and 1.69 mg/L, respectively. Thrombin generation was completely suppressed by concentrations >=0.8 mg/L. In conclusion, rivaroxaban showed an in vitro concentration-dependent anticoagulant effect on canine plasma. Thrombin generation and anti-factor Xa activity were more sensitive and accurate than PT and aPTT in detecting the anticoagulant effect of rivaroxaban. PMID- 24053992 TI - Chiari-like malformations: is compliance the issue? PMID- 24053993 TI - The use of infrared thermography as a non-invasive method for fever detection in sheep infected with bluetongue virus. AB - Fever, which is closely linked to viraemia, is considered to be both the main and the earliest clinical sign in sheep infected with bluetongue virus (BTV). The aim of this study was to evaluate the potential use of infrared thermography (IRT) for early detection of fever in sheep experimentally infected with bluetongue virus serotype 1 (BTV-1) and serotype 8 (BTV-8). This would reduce animal stress during experimental assays and assist in the development of a screening method for the identification of fever in animals suspected of being infected with BTV. Rectal and infrared eye temperatures were collected before and after BTV inoculation. The two temperature measures were positively correlated (r=0.504, P<0.05). The highest correlation between rectal and infrared temperatures was observed when temperatures were above physiological levels. IRT discriminated between febrile and non-febrile sheep with a sensitivity of 85% and specificity of 97%. The results showed that eye temperature measured using IRT was a useful non-invasive method for the assessment of fever in sheep infected with BTV under experimental conditions. Further research is required to evaluate the use of IRT under field conditions to identify potentially infected animals in bluetongue surveillance programmes. PMID- 24053994 TI - Retinal nerve fiber layer progression in glaucoma: a comparison between retinal nerve fiber layer thickness and retardance. AB - OBJECTIVE: To investigate the performance of spectral-domain optical coherence tomography (OCT) and scanning laser polarimetry to detect progressive retinal nerve fiber layer (RNFL) changes and to determine whether reduction of the RNFL retardance occurred before thinning of the RNFL in glaucoma. DESIGN: Prospective, longitudinal study. PARTICIPANTS: One hundred eighty-four eyes of 116 glaucoma patients and 43 normal eyes of 23 healthy individuals. METHODS: Patients were followed up every 4 months for at least 36 months with RNFL retardance (GDx Enhanced Corneal Compensation; Carl Zeiss Meditec) and RNFL thickness (Cirrus HD OCT; Carl Zeiss Meditec) measured in the same visit. Progressive RNFL retardance and thickness changes were evaluated with event-based analysis (Guided Progression Analysis; Carl Zeiss Meditec) with reference to the RNFL retardance change map and the RNFL thickness change map, respectively. The area and frequency distribution of RNFL changes were examined by overlaying the RNFL retardance change maps and the RNFL thickness change maps in the latest follow up. The agreement of RNFL retardance and RNFL thickness progression was evaluated with kappa statistics. MAIN OUTCOME MEASURES: Number of eyes with progressive RNFL changes over time. RESULTS: A total of 2472 OCT thickness maps and 2472 RNFL retardance maps were collected and reviewed with a mean follow-up of 55.1 months. Twenty-seven eyes (14.6%; 26 glaucoma patients) showed progressive RNFL thinning, whereas 8 eyes (4.3%; 8 glaucoma patients) showed progressive reduction of RNFL retardance. Seven eyes (3.8%; 7 glaucoma patients) had progression that was detected by both instruments, all with progressive RNFL thinning detected before progressive reduction of RNFL retardance became evident, and the mean lag time was 13.4 months (range, 4.0-37.6 months). The agreement between RNFL thickness and RNFL retardance progression was fair (kappa, 0.357). Progressive loss of RNFL thickness was observed most frequently at the inferotemporal 223 degrees to 260 degrees , whereas the inferotemporal 227 degrees to 263 degrees and superior 56 degrees to 117 degrees were observed most commonly for progressive loss of RNFL retardance. In the normal group, no eyes showed reduction in RNFL thickness or retardance. CONCLUSIONS: At a comparable level of specificity, progressive RNFL thinning was detected more often than progressive reduction of RNFL retardance. For eyes with progressive loss of RNFL thickness and RNFL retardance, the former preceded the latter. PMID- 24053995 TI - The International Vitreomacular Traction Study Group classification of vitreomacular adhesion, traction, and macular hole. AB - OBJECTIVE: The International Vitreomacular Traction Study (IVTS) Group was convened to develop an optical coherence tomography (OCT)-based anatomic classification system for diseases of the vitreomacular interface (VMI). DESIGN: The IVTS applied their clinical experience, after reviewing the relevant literature, to support the development of a strictly anatomic OCT-based classification system. PARTICIPANTS: A panel of vitreoretinal disease experts was the foundation of the International Classification System. METHODS: Before the meeting, panel participants were asked to review 11 articles and to complete 3 questionnaires. The articles were preselected based on searches for comprehensive reviews covering diseases of the VMI. Responses to questionnaires and the group's opinions on definitions specified in the literature were used to guide the discussion. MAIN OUTCOME MEASURES: Optical coherence tomography-based anatomic definitions and classification of vitreomacular adhesion, vitreomacular traction (VMT), and macular hole. RESULTS: Vitreomacular adhesion is defined as perifoveal vitreous separation with remaining vitreomacular attachment and unperturbed foveal morphologic features. It is an OCT finding that is almost always the result of normal vitreous aging, which may lead to pathologic conditions. Vitreomacular traction is characterized by anomalous posterior vitreous detachment accompanied by anatomic distortion of the fovea, which may include pseudocysts, macular schisis, cystoid macular edema, and subretinal fluid. Vitreomacular traction can be subclassified by the diameter of vitreous attachment to the macular surface as measured by OCT, with attachment of 1500 MUm or less defined as focal and attachment of more than 1500 MUm as broad. When associated with other macular disease, VMT is classified as concurrent. Full thickness macular hole (FTMH) is defined as a foveal lesion with interruption of all retinal layers from the internal limiting membrane to the retinal pigment epithelium. Full-thickness macular hole is primary if caused by vitreous traction or secondary if directly the result of pathologic characteristics other than VMT. Full-thickness macular hole is subclassified by size of the hole as determined by OCT and the presence or absence of VMT. CONCLUSIONS: This classification system will support systematic diagnosis and management by creating a clinically applicable system that is predictive of therapeutic outcomes and is useful for the execution and analysis of clinical studies. PMID- 24053996 TI - The ocular consequences and applicability of minimally invasive 25-gauge transvitreal retinochoroidal biopsy. AB - OBJECTIVE: To determine the applicability and ocular morbidity of the 25-gauge transvitreal retinochoroidal biopsy technique in the management of intraocular tumors. DESIGN: Retrospective, consecutive, observational, single-surgeon case series. PARTICIPANTS: A total of 124 biopsies were performed in 123 patients with intraocular tumors in the posterior segment from January 1, 2009, through December 31, 2011. METHODS: The biopsies were performed under general anesthesia with standard 25-gauge vitrectomy equipment. The vitreous body and the retinotomies were left untreated with the exception of 1 patient in whom a complete vitrectomy and oil tamponade were performed. Histopathologic examination of all samples was performed and cytogenetic testing with fluorescence in situ hybridization and multiplex ligation-dependent probe amplification were performed in the uveal melanomas. Median follow-up time was 26.3 months (range, 2.0-47.2 months). MAIN OUTCOME MEASURES: Histopathologic diagnosis and chromosome 3 analysis of the biopsy-obtained tissue sample. Clinical observations included visual acuity, retinal detachment, vitreous hemorrhage, and secondary enucleation. RESULTS: Histopathologic diagnosis was obtained in 97.6% (n = 121) of the intraocular tumors, and chromosome 3 status could be determined in 97.3% (n = 110) of uveal melanoma patients. Preoperative retinal detachment was present in 65% (n = 55). Apart from in 1 case, all retinal detachments remained stable during surgery. Additionally, 7.1% (n = 6) of cases demonstrated retinal detachment during the follow-up period, and vitreous hemorrhage was observed in 96.5% of cases (n = 82) 1 day after surgery. Both conditions regressed spontaneously in nearly all cases. Retinal detachment surgery and vitrectomy resulting from persistent vitreous hemorrhage was performed in 3.5% (n = 3) and 5.9% (n = 5) of patients, respectively. The frequency of secondary enucleated eyes was 6.7% (n = 5). Free tumor cells after biopsy were described in 15.9% (n = 7), but no tumor recurrence at the sclerotomy sites was observed. A decrease in visual acuity from better than 0.1 (20/200) at diagnosis to 0.1 or worse at 1 and 3 years of follow-up was observed in 21.7% (n = 13) and 41.7% (n = 5) of patients, respectively. CONCLUSIONS: The 25-gauge transvitreal retinochoroidal biopsy provides a large sample, adequate for histopathologic examination and cytogenetic analysis. The procedure is associated with a low risk of ocular complications. PMID- 24053997 TI - Diagnosis of occult melanoma using transient receptor potential melastatin 1 (TRPM1) autoantibody testing: a novel approach. AB - PURPOSE: To report the first case of melanoma-associated retinopathy (MAR) and underlying occult melanoma diagnosed based on the presence of serum transient receptor potential melastatin 1 (TRPM1) autoantibodies. DESIGN: Interventional case report with basic science correlation. PARTICIPANTS: One patient with MAR. INTERVENTION: Testing for the presence of serum TRPM1 autoantibodies. MAIN OUTCOME MEASURES: Diagnosis of an occult melanoma involving the axillary lymph nodes (unknown primary site) and MAR based on the presence of TRPM1 autoantibodies in the patient's serum. RESULTS: The patient's clinical exam was remarkable for mild intraocular inflammation in both eyes and retinal hemorrhages with an apparent choroidal neovascularization in the left eye, which was confirmed by fluorescein angiography and indocyanine green angiography testing. Humphrey visual field 30-2 SITA-fast (Humphrey Visual Field Analyzer, Carl Zeiss Meditec, Inc, Dublin, CA) demonstrated diffuse depression in both eyes out of proportion to the clinical exams, prompting electroretinography testing that revealed an electronegative response. Dark-adapted thresholds were markedly elevated and mediated by cones. Due to concern for MAR, a systemic work-up for melanoma was performed by the primary care physician that was unrevealing. Given our continued clinical suspicion for MAR, the patient's serum was sent for evaluation for TRPM1 autoantibodies. The patient's serum applied to normal human retina exhibited positivity in the inner nuclear layer. Application of the patient's serum to wild-type and TRPM1 knockout mouse retina revealed strongly labeled bipolar cells in the wild-type retina, but not in the TRPM1 knockout retina, indicating TRPM1-dependent immunoreactivity. The antigen was confirmed as TRPM1 by labeling of TRPM1-transfected human embryonic kidney 293 cells. Additional systemic work-up prompted by this finding resulted in identification of an occult metastatic melanoma involving the axillary lymph nodes with an unknown primary site. The patient underwent surgical excision of the occult melanoma without evidence of other sites of metastases. He also received intravenous immunoglobulin therapy and his vision has stabilized. CONCLUSIONS: This is the first reported case of a melanoma-associated retinopathy diagnosed utilizing the innovative approach of testing for serum TRPM1 autoantibodies. PMID- 24053998 TI - Visual impairment and blindness in spanish adults: geographic inequalities are not explained by age or education. AB - OBJECTIVES: The objectives of this study were to examine for the first time the prevalence of visual impairment and blindness among adults in Spain, to explore regional differences, and to assess whether they may vary as a function of sex or be explained by age and individual or regional socioeconomic position. DESIGN: Data were obtained from the 2008 Spanish Survey on Disability, Personal Autonomy, and Dependency Situations, a cross-sectional survey based on a representative sample of the noninstitutionalized population of Spain. PARTICIPANTS: The sample was composed of 213 626 participants aged >=15 years (103 093 men and 110 533 women); 360 were blind (160 men and 200 women), 4048 had near visual impairment (1397 men and 2651 women), and 4034 had distance visual impairment (1445 men and 2589 women). METHODS: The prevalence of near and distance visual impairment was calculated for each region. Multiple logistic regression models were fitted to calculate odds ratios and 95% confidence intervals. All analyses were stratified by sex. MAIN OUTCOME MEASURES: Visual impairment was based on 3 questions aimed at identifying blindness and near and distance visual impairment. RESULTS: The prevalence (percentage) of blindness was 0.17 (men, 0.16; women, 0.18): 1.89 for near visual impairment (men, 1.36; women, 2.40), 1.89 for distance visual impairment (men, 1.40; women, 2.34), and 2.43 for any visual impairment (men, 1.81; women, 3.02). Regional inequalities in the prevalence of visual impairment were observed, correlated with regional income, and the prevalence was consistently higher among women than men. The magnitude of the inequalities remained after adjusting for age and educational level, and a north-to-south pattern of increasing prevalence was observed. CONCLUSIONS: Regional and sex inequalities in the prevalence of visual impairment and blindness were observed in Spain, with a north-to-south gradient of increasing prevalence that was not explained by age or individual educational level but was correlated with regional level of economic development. Factors that could be prioritized for future policies and research include differential regional economic development, rural environment, quality of eye care services, diabetes, ultraviolet light exposure, or gender inequalities in diagnostic and therapeutic health care. PMID- 24053999 TI - Mortality in patients with central retinal vein occlusion. AB - PURPOSE: To assess mortality in patients with central retinal vein occlusion (CRVO). DESIGN: Registry-based cohort study. PARTICIPANTS AND CONTROLS: Four hundred thirty-nine photographically verified CRVO patients and a control cohort of 2195 unexposed subjects matched by age and gender and alive on the date CRVO was diagnosed in the corresponding case. METHODS: Data from nationwide registries were used to compare mortality rates in CRVO patients with a control cohort over a mean follow-up of 5.1 years for cases and of 5.7 years for controls. MAIN OUTCOME MEASURES: Hazard ratios (HRs) obtained by Cox regression and standardized mortality ratios (SMRs) stratified by age and gender served as measures of relative mortality risk. RESULTS: Mortality was higher in patients with CRVO (HR, 1.45; 95% confidence interval [CI], 1.19-1.76) than in the control cohort, adjusted for age, gender, and time of diagnosis. Mortality was comparable between the 2 groups (HR, 1.19; 95% CI, 0.96-1.46) when adjusting for overall occurrence of cardiovascular disease and diabetes. Subgroup analysis found that the age stratified mortality rate was increased significantly in the total group of men (SMR, 1.27; 95% CI, 1.03-1.56) and in women 60 to 69 years of age (SMR, 1.94; 95% CI, 1.22-3.08). CONCLUSIONS: Central retinal vein occlusion was associated with an overall increase in mortality compared with controls that was attributed statistically to cardiovascular disorders and diabetes. We recommend treatment of hypertension and diabetes, if present, and referral of patients found to have CRVO who are not already being treated by a primary care physician. PMID- 24054000 TI - Differential brain and spinal cord cytokine and BDNF levels in experimental autoimmune encephalomyelitis are modulated by prior and regular exercise. AB - The interactions between a prior program of regular exercise and the development of experimental autoimmune encephalomyelitis (EAE)-mediated responses were evaluated. In the exercised EAE mice, although there was no effect on infiltrated cells, the cytokine and derived neurotrophic factor (BDNF) levels were altered, and the clinical score was attenuated. Although, the cytokine levels were decreased in the brain and increased in the spinal cord, BDNF was elevated in both compartments with a tendency of lesser demyelization volume in the spinal cord of the exercised EAE group compared with the unexercised. PMID- 24054001 TI - Pudendal nerve palsy in trauma and elective orthopaedic surgery. AB - The incidence of pudendal nerve palsy following routine trauma and elective orthopaedic surgery procedures ranges from 1.9% to 27.6%. Excessive and/or prolonged traction against the perineal post of a traction table, leading to direct compression and localised ischaemia to the nerve are suggested mechanisms of injury. Misuse of traction and the inappropriate placement of the perineal post, leading to crushing and stretching of the pudendal nerve, are two main contributing factors leading to its postoperative palsy. The sequelae may be sensory, motor or mixed. In most cases, these injuries are transient and tend to resolve within several weeks or months. However, complete neurological recovery may be unpredictable and the effects of ongoing dysfunction potentially disastrous for the individual. In terms of preventative measures, magnitude and duration of traction time should be minimised; traction should be limited to the critical operative steps only. Additionally, the perineal post should be placed between the genitalia and the contralateral leg. A well-padded, large-diameter perineal post should be used (>10cm). Adequate muscle relaxation during anaesthesia is particularly important in young men who have strong muscles and thus require larger traction forces when compared to elderly patients. Orthopaedic surgeons should be aware of the pathophysiology behind the development of this palsy and the measures that can be employed to reduce its occurrence. In procedures where a traction table is employed, consenting for pudendal nerve palsy should be considered by the surgical team. PMID- 24054002 TI - Surgical management and outcome of blunt major liver injuries: experience of damage control laparotomy with perihepatic packing in one trauma centre. AB - INTRODUCTION: This retrospective study aimed to assess the clinical experience and outcome of damage control laparotomy with perihepatic packing in the management of blunt major liver injuries. MATERIALS AND METHODS: From January 1998 to December 2006, 58 patients of blunt major liver injury, American Association for the Surgery of Trauma-Organ Injury Scale (AAST-OIS) equal or greater than III, were operated with perihepatic packing at our institute. Demographic data, intra-operative findings, operative procedures, adjunctive managements and outcome were reviewed. To determine whether there was statistical difference between the survivor and non-survivor groups, data were compared by using Mann-Whitney U test for continuous variables, either Pearson's chi-square test or with Yates continuity correction for contingency tables, and results were considered statistically significant if p<0.05. RESULTS: Of the 58 patients, 20 (35%) were classified as AAST-OIS grade III, 24 (41%) as grade IV, and 14 (24%) as grade V. At laparotomy, depending on the severity of injuries, all 58 patients underwent various liver-related procedures and perihepatic packing. The more frequent liver-related procedures included debridement hepatectomy (n=21), hepatorrhaphy (n=19), selective hepatic artery ligation (n=11) and 7 patients required post-laparotomy hepatic transarterial embolization. Of the 58 patients, 28 survived and 30 died with a 52% mortality rate. Of the 30 deaths, uncontrolled liver bleeding in 24-h caused 25 deaths and delayed sepsis caused residual 5 deaths. The mortality rate versus OIS was grade III: 30% (6/20), grade IV: 54% (13/24), and grade V: 79% (11/14), respectively. On univariate analysis, the significant predictors of mortality were OIS grade (p=0.019), prolonged initial prothrombin time (PT) (p=0.004), active partial thromboplastin time (APTT) (p<0.0001) and decreased platelet count (p=0.005). CONCLUSIONS: The mortality rate of surgical blunt major liver injuries remains high even with perihepatic packing. Since prolonged initial PT, APTT and decreased platelet count were associated with high risk of mortality, we advocate combination of damage control resuscitation with damage control laparotomy in these major liver injuries. PMID- 24054003 TI - [Cesarean section and sismotherapy in a severe psychotic parturient: A case report]. AB - Psychiatric disorders may complicate the pregnancy and is one of the causes of maternal and fetal morbidity. We report the case of a patient with severe decompensated schizophrenia during her pregnancy that required prolonged hospitalization in psychiatric ward. The psychiatric status of the patient required the realization of a caesarean section at 36 weeks of amenorrhea. In our case, we decided to perform this cesarean section under general anaesthesia, since regional anaesthesia was not feasible in this patient in a state of uncontrolled agitation. Moreover, general anaesthesia permitted to combine cesarean section with a first session of electroconvulsive therapy, which had been declined during pregnancy. Given the huge amount of antipsychotic agents administered to the patient, we also studied their transplacental transfer and found a very high loxapine concentration in the fetus. Finally, this case raised several important ethical issues related to the management of the mother and her fetus in case of severe psychiatric disorders. PMID- 24054004 TI - Measurements of serial plasma levels of albumin mRNA for management of patients post transplant: does it add value? PMID- 24054005 TI - [Status quo of research on HGFc-Met signaling pathway in cancers]. PMID- 24054006 TI - [Relationship between the expression level of miR-29c and biological behavior of gastric cancer]. AB - OBJECTIVE: To study the function and clinicopathological significance of RNA-29c (miR-29c) in the carcinogenesis and development of gastric cancer. METHODS: MicroRNA microarray was applied to assess the miRNAs expression profile of gastric cancer. Quantitative real-time PCR was used to detect the expression of miR-29c in 64 cases of gastric cancer tissues and corresponding normal gastric epithelium, as well as cell lines GES-1, BGC-823 and SGC-7901 cells. MTT assay and flow cytometry were applied to detect the effects of forced expression of miR 29c in gastric cancer BGC-823 cells including cell proliferation, apoptosis, cell cycle and drug sensitivity. Quantitative real-time PCR, Western blot and luciferase reporter assay were used to explore the targeted relationship between miR-29c and myeloid cell leukemia-1 (Mcl-1). RESULTS: Compared with normal gastric epithelium, seven microRNAs (miR-374b*, miRPlus-E1212, miR-338-5p, miR 297, miR-21, miR-135b, miR-18a) were significantly up-regulated more than 2 folds, and nine microRNAs (miR-29b-2*, miR-1260, miRPlus-E1241, miR-S1-5p, miR 148a, miR-29c, miR-647, miR-196b*, ebv-miR-BART5) were significantly down reguated in gastric cancer tissues. The average expression level of miR-29c in gastric cancer tissues was 0.70 +/- 0.34 and in corresponding normal epithelium was 1.00 +/- 0.06 (P < 0.05). miR-29c expression was related to tumor size, lymph node metastasis, clinical stage, Lauren classification, Borrmann classification and Ming classification (P < 0.05). The poorer differentiation degree of gastric cell lines, the lower was miR-29c expression level (P < 0.05). Overexpression of miR-29c in gastric cancer BGC-823 cells suppressed cell proliferation, stimulated cell apoptosis, induced cell cycle arrest in S phase and increased the chemotherapy sensitivity to drug docetaxel (all were P < 0.05). The average expression level of Mcl-1 mRNA in gastric cancer tissues was 3.47 +/- 1.34 and corresponding epithelialium was 1.00 +/- 0.20 (P < 0.05). The expression level of miR-29c was negatively related with that of Mcl-1 mRNA in gastric cancer tissues. miR-29c directly targeted to regulation of Mcl-1 expression. CONCLUSIONS: There are special miRNA expression profile in gastric cancer. The expression of miR-29c is closely related to biological behavior of human gastric cancer. miR-29c is involved in targeted regulation of Mcl-1, and may be one of mechanisms of the carcinogenesis of gastric cancer. PMID- 24054007 TI - [Sphingosine kinase 1 enhances the proliferation and invasion of human colon cancer LoVo cells through up-regulating FAK pathway and the expression of ICAM-1 and VCAM-1]. AB - OBJECTIVE: To investigate the effects of sphingosine kinase 1 (SphK1) on the proliferation, migration and invasion of human colon cancer LoVo cells, and to explore the related mechanisms. METHODS: Human colon cancer LoVo cells were divided into three groups: phorbol 12-myristate 13-acetate (PMA) was used to induce the activation of SphK1 in the PMA group, N,N-dimethylsphingosine (DMS) used to suppress the activity of SphK1 in DMS group, and the cells treated with equal amount of 0.9 % NaCl instead of drugs served as the control group. The activity of SphK1 was assayed by autoradiography, the cell proliferation was assessed by MTT assay, cell migration and invasion were examined by Boyden chamber assay, concentrations of sICAM-1 and sVCAM-1 were assayed by ELISA, and RT-PCR and Western blot were used to evaluate the mRNA and protein expression in the cells. RESULTS: The activity of SphK1 was efficiently induced by PMA and significantly suppressed by DMS. PMA induced cell proliferation in a time- and dose-dependent manner. On the contrast, DMS suppressed cell proliferation in a time- and dose-dependent manner. After treating with PMA, the number of migrating and invasing cells were increased to 143.36 +/- 8.73 and 118.46 +/- 6.25, significantly higher than those of the control group (75.48 +/- 6.12 and 64.19 +/ 5.36). After treating with DMS, the number of migrating and invasing cells were decreased to 38.57 +/- 3.24 and 32.48 +/- 4.27, significantly lower than those of the control group (P < 0.01). The relative expression levels of FAK, ICAM-1 and VCAM-1 mRNA in the PMA group were 0.82 +/- 0.06, 0.74 +/- 0.05 and 0.89 +/- 0.09, and those in the DMS group were 0.23 +/- 0.02, 0.26 +/- 0.03 and 0.37 +/- 0.04, with significant differences between the PMA, DMS and control groups (P < 0.01). Compared with the control group, the relative expression levels of FAK and p-FAK proteins in the PMA group (0.52 +/- 0.06 and 0.51 +/- 0.06) were significantly elevated, and those of the DMS group (0.20 +/- 0.03 and 0.09 +/- 0.02) were significantly decreased. In addition, the concentrations of sICAM-1 and sVCAM-1 were significantly elevated with the activation of SphK1. On the contrary, those of the DMS group were significantly reduced with the suppression of SphK1 (Both P < 0.01). CONCLUSIONS: SphK1 may enhance the proliferation, migration and invasion of colon cancer LoVo cells through activating FAK pathway and up-regulating the expression of ICAM-1 and VCAM-1. PMID- 24054008 TI - [Effect of Ech1 overexpression on biological behavior of mouse hepatocarcinoma Hca-P cells in vitro]. AB - OBJECTIVE: To investigate the effect of enoyl coenzyme A hydratase-1 (Ech1) on the proliferation and invasion ability of mouse hepatocarcinoma Hca-P cells in vitro. METHODS: Recombinant pcDNA3.1(+)-Ech1 gene and pcDNA3.1(+) were transfected into Hca-P cells by cationic liposomes introduction. Clone of PEch1 cells that stably expressing Ech1 and clone of control Pvector cells were screened by G418. The Ech1 expression was identified subsequently by reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The malignant behaviors of the cell lines were compared by proliferation, invasion and migration test. RESULTS: The cell line Hca-P cells stably expressing Ech1 gene was constructed. The relative expression of Ech1 mRNA in the PEch1 group was 3.21 +/- 0.43 and in the Pvector group was 1.44 +/- 0.03, with a significant difference between the two groups (P = 0.029). The results of ELISA revealed that the expression of Ech1 protein was 0.140 +/- 0.005 in the PEch1 group, 0.088 +/- 0.003 in the Pvector group, and 0.078 +/- 0.006 in the Hca-P group, showing a significant difference between the PEch1 group and the Pvector and Hca-P groups (P < 0.05). Transwell migration test showed that the number of penetrated cells in the PEch1 group was 143.00 +/- 7.25 cells, significantly higher than that of the Pvector group (95.73 +/- 3.88 cells) and un-treated Hca-1 group (106.67 +/- 3.54 cells, both P < 0.05). The Transwell invasion assay showed that the number of penetrated cells was 77.20 +/- 5.46 cells in the PEch1 group, significantly higher than 46.34 +/- 4.35 cells in the Pvector group and 49.80 +/- 5.21 cells in the un-treated Hca-1 group (both P < 0.05). CONCLUSIONS: The results showed that overexpressed Ech1 in Hca-P cells may significantly increase the cell proliferation in a time-dependent manner. The up regulation of Ech1 may increase to some extent the migration and invasion capacity of Hca-P cells. The efforts aiming at up-regulation of Ech1 expression may become a therapeutic target in the treatment of hepatocarcinoma. PMID- 24054009 TI - [Feasibility of volume perfusion CT (VPCT) imaging in antiangiogenic treatment of rabbit VX2 soft-tissue tumor]. AB - OBJECTIVE: To explore the feasibility of volume perfusion CT imaging to dynamically monitor and evaluate the response of rabbit VX2 soft-tissue tumor to antiangiogenic treatment. METHODS: To establish an experimental animal model of VX2 soft tissue tumor on 20 New Zealand white rabbits. Twenty rabbits were randomly divided into 2 groups. The therapy group was treated with recombinant human endostatin (3 mg.kg-1.d-1) for 7 days, and the control group received saline in the same dose only. Four times of CT volume perfusion scan were performed before treatment and on the second, forth, seventh days of treatment, respectively. The value of blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability (PMB) in the VX2 tumors were measured after scanning. The microvessel density (MVD) and expression of vascular endothelial growth factor (VEGF) in the tumors were determined using immunohistochemical staining. RESULTS: The tumor volume of the therapy group was (1.36 +/- 0.73) cm3 on the forth day of treatment and (1.69 +/- 0.68) cm3 on the seventh day of the treatment. The tumor volume of the control group was (2.35 +/- 0.62) cm3 on the fourth day of treatment and (3.87 +/- 0.93) cm3 on the seventh day of the treatment (P < 0.05). On the seventh day of treatment, tumor necrosis ratio of the therapy group and the control group was (25.58 +/- 5.51)% and (42.93 +/- 4.34)%, respectively (P < 0.05). Comparing the perfusion parameters between the two groups on the same day, and the second, forth, seventh days of treatment, the value of PMB of the therapy group was (70.36 +/- 23.46) ml.100 ml-1.min-1, (79.64 +/- 13.68) ml.100 ml-1.min 1 and (84.76 +/- 3.55) ml.100 ml-1.min-1, respectively, and that in the control group was (26.61 +/- 6.47) ml.100 ml-1.min-1, (33.74 +/- 16.47) ml.100 ml-1.min-1 and (30.47 +/- 10.64) ml.100 ml-1.min-1, respectively (P < 0.05). The value of BF in the therapy group and control group was (71.19 +/- 12.21) ml.100 ml-1.min-1 and (43.56 +/- 12.21) ml.100 ml-1.min-1, respectively, on the seventh day of treatment (P < 0.05). The parameters on different days in the same group were compared. In the control group, the value of BF on the seventh day of treatment was significantly lower than that before and on the second and forth days of treatment (P < 0.05). However, in the therapy group, the value of PMB on the second, forth, and seventh days of treatment was significantly higher than that before treatment (P < 0.05). MVD of tumor in the control group was increased gradually, whereas increased on the first day and then decreased more in the therapy group. The VEGF expressions did not differ significantly between the experimental and control groups. CONCLUSIONS: Volume perfusion CT is helpful to quantify the tumor perfusion and evaluate the functional changes of tumor vasculature, and then evaluate the early therapeutic effect of antiangiogenic treatment. PMID- 24054010 TI - [Comparison of two quantitation methods of circulating tumor cells in patients with small cell lung cancer]. AB - OBJECTIVE: To establish a quantitative method to detect circulating tumor cells (CTC) in patients with small cell lung cancer, and analyze its sensitivity and stability. METHODS: A specific primer and probe for prepro-gastrin-releasing peptide (preproGRP) was designed and a quantitative RT-PCR method was established to detect preproGRP mRNA. Cell incorporation method was used to evaluate the sensitivity. Magnetic cell sorting (MACS) was used to isolate and purify CTC from peripheral blood, and the MACS in combination with morphological diagnosis were used for cell counting. RESULTS: The isolation rate of CTC by MACS was 30% and the lower detection limit was 5 cells per ml blood. The sensitivity of quantitative RT-PCR in detection of preproGRP mRNA in CTC was 0.64 cells per reaction, and the lower detection limit was 50 cells per ml blood, which was lower than that of MACS. However, the cell numbers calculated by Ct value was in greater accordance (about 80%) with actual cell numbers than that obtained by MACS. CONCLUSIONS: PreproGRP quantitative RT-PCR and MACS have both advantages and disadvantages in detecting CTC of SCLC patients. MACS has a higher sensitivity, and is more favorable when CTC count is below 50 per ml blood. Meanwhile, preproGRP mRNA quantitative RT-PCR is more reliable in calculating actual cell numbers. PMID- 24054011 TI - [Correlation of methylation of CpG island in cystathionine beta synthase promoter and clinicopathological features in colorectal cancer]. AB - OBJECTIVE: To explore the association between methylation of cystathionine-beta synthase (CBS) promoter and clinicopathological features in colorectal cancer. METHODS: Bisulfate sequencing PCR, real-time RT-PCR, and immunohistochemistry were used to investigate the methylation of CpG island in CBS promoter of 95 sporadic colorectal cancers. Software SPSS PASW Statistics was used to analyze the data of the hypermethylation levels in the malignant tissues and the correlation with pathological parameters and clinical outcome. RESULTS: Methylation levels in tumor tissue of patients [(64.9 +/- 14.3)%]with colorectal cancer were significantly higher than that in normal tissues[(27.5 +/- 13.1)%, P < 0.001]. The CBS mRNA levels in the hypomethylation group (7.22 +/- 1.91) were significantly higher than that in the hypermethylation group (2.78 +/- 1.12, P < 0.01). Univariate analysis showed that age, pT stage, pN stage, liver metastases, pTNM stage, and CBS hypermethylation level significantly correlated with the survival and recurrence rates of colorectal cancer patients (All P < 0.05). Multivariate analysis showed that CBS hypermethylation level and liver metastasis were independent factors significantly correlated with the recurrence rate and overall survival of the patients (All P < 0.05). CONCLUSIONS: Our study indicates that methylation of CpG island in CBS promoter is correlated with the occurrence and progression of colorectal cancer and plays a role in its tumorigenesis. It might serve as a useful marker for early diagnosis, targeted therapy and prediction of prognosis in colorectal cancer. PMID- 24054012 TI - [Correlation of 18F-FDG uptake with tumor-proliferating antigen Ki-67 expression in aggressive lymphoma]. AB - OBJECTIVE: To investigate the correlation between 18F-FDG uptake in positron emission tomography/computed tomography imaging and tumor-proliferating antigen Ki-67 expression in aggressive lymphoma. METHODS: Data of 18F-FDG PET-CT imaging and immunohistochemical detection of Ki-67 expression of seventy-seven cases with initially diagnosed aggressive lymphoma were retrospectively analyzed. The intensity of 18F-FDG accumulation was determined by calculating the maximum standardized uptake value (SUVmax) and average standardized uptake value (SUVave). The average SUV at biopsy site (BxSUVave), SUVmax at biopsy site (BxSUVmax) and SUVmax at the highest tumor activity site of the body (BmSUVmax) were collected. RESULTS: The BmSUVmax, BxSUVmax, and BxSUVave were 13.4 +/- 6.8, 11.9 +/- 6.8 and 7.3 +/- 4.4, respectively,and Ki-67 was (61.2 +/- 20.4)% in the 77 aggressive lymphomas. The BmSUVmax was significantly higher than the BxSUVmax or BxSUVave (P < 0.05). The BmSUVmax, BxSUVmax and BxSUVave were positively correlated with the Ki-67 expression in aggressive lymphoma (P < 0.05). A positive correlation was revealed between the BxSUVmax and BmSUVmax (P < 0.05), and between the BxSUVmax and BxSUVave (P < 0.05). No significant correlation was found between the BmSUVmax or BxSUVmax and the Ki-67 in DLBCL (P > 0.05). A positive correlation was observed between the BmSUVmax or BxSUVmax and the Ki-67 expression in NK/T cell lymphoma (P < 0.05). CONCLUSION: The increasing trend of 18F-FDG uptake is correlated with the Ki-67 expression in aggressive lymphoma. The results of this study suggest that the metabolic information obtained by using BmSUVmax may help to compensate the limited sampling of histological examination at the biopsy site. Significant correlation in NK/T cell lymphoma suggests that the metabolic information from positron emission tomography computed tomography may offer a useful parameter in the prognosis and management of this disease. PMID- 24054014 TI - [Expression of pGSK-3alpha/beta Tyr279/216 and XIAP proteins in cholangiocarcinoma and their clinical significance]. AB - OBJECTIVE: To investigate the expressions of the active form of glycogen synthase kinase-3(GSK-3)-pGSK-3alpha/beta (Tyr279/216) and its downstream moleculor X linked inhibitor of apoptosis protein (XIAP) in cholangiocarcinoma and to analyze their correlation with clinicopathological and survival significance. METHODS: Immunohistoehemistry was used to detect the expressions of the active form of GSK 3- pGSK-3alpha/beta (Tyr279/216) and its downstream moleculor XIAP proteins in 50 cholangiocarcinoma tissues and 20 normal bile duct tissues. RESULTS: The positive rates of pGSK-3alpha/beta (Tyr279/216) and XIAP were 62.0% and 68.0% in cholangiocarcinoma, and 10.0% and 25.0% in normal bile duct tissues, respectively. The intensity of pGSK-3alpha/beta (Tyr279/216) and XIAP expressions in cholangiocarcinoma were significantly higher than that in the normal bile duct tissues (P < 0.001), and there was a significant correlation between pGSK 3alpha/beta (Tyr279/216) and XIAP expressions (r = 0.544, P < 0.001). The expression of pGSK-3alpha/beta(Tyr279/216) protein in cholangiocarcinoma was associated with TNM stage (P = 0.042), histological grade (P = 0.031), whereas the expression of XIAP protein in cholangiocarcinoma was correlated with CEA level (P = 0.006). Patients with positive expression of pGSK-3alpha/beta (Tyr279/216) and XIAP demonstrate a significantly worse prognosis than that of patients with negative expression of pGSK-3alpha/beta (Tyr279/216) and XIAP for overall survival (P = 0.002, P = 0.018). Multivariate survival analysis revealed that positive pGSK-3alpha/beta (Tyr279/216) expression provided significant independent prognostic value for overall survival (P = 0.002). CONCLUSIONS: The expressions of pGSK-3alpha/beta(Tyr279/216) and XIAP proteins were significantly associated with the development and progression of cholangiocarcinoma. pGSK 3alpha/beta(Tyr279/216) may be an important prognostic factor for survival of patients with cholangiocarcinoma. PMID- 24054013 TI - [Clinicopathological and prognostic significance of the expression of ADAM17 mRNA and protein in esophageal squamous cell carcinoma]. AB - OBJECTIVE: To investigate the expression of A disintegrin and metalloproteinase 17 (ADAM17) mRNA and ADAM17 protein in esophageal squamous cell carcinoma (ESCC), and to evaluate their correlation with clinicopathological features and prognosis. METHODS: The expression of ADAM17 mRNA in 50 ESCC and 50 normal esophageal tissues was detected by RT-PCR. The expression of ADAM17 protein in 80 ESCC and 80 normal esophageal tissues was detected with immunohistochemioal staining (SP). Log rank test and Cox proportional hazards analysis were used to analyze the prognosis of ESCC. RESULTS: The expression of ADAM17 mRNA in 50 ESCC and 50 normal esophageal tissues was 0.937 +/- 0.241 and 0.225 +/- 0.077, respectively. The positive expression rates of ADAM17 protein in 80 ESCC and 80 normal esophageal tissues was 66.2% and 6.2%, respectively. The expressions of ADAM17 mRNA and ADAM17 protein in the ESCC were significantly higher than those in normal esophageal tissues (P < 0.01). The expressions of ADAM17 mRNA and protein were positively correlated with lymph node metastasis and TNM staging (P < 0.05). There were no correlations between the expressions of ADAM17 mRNA and protein and sex, age and histological grade (P > 0.05) . The expression of ADAM17 protein was positively correlated with EGFR protein (P < 0.01). The lymph node metastasis, TNM staging and the expression of ADAM17 and EGFR protein were independent prognostic factors. CONCLUSIONS: ADAM17 mRNA and protein are highly expressed in ESCC than in normal esophageal tissues and may play an important role in the development, invasion and metastasis of ESCC. They may be used as prognostic factors of ESCC. PMID- 24054015 TI - [Differences and clinical significance of receptor expression between primary and locally recurrent breast tumor tissues]. AB - OBJECTIVE: To compare the difference of receptor expression between primary and locally recurrent breast tumor tissues, and analyze their impact on survival of the patients. METHODS: The expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) of primary and locally recurrent breast tumor tissues of 70 breast cancer patients were analyzed by immunohistochemistry or fluorescence in situ hybridization. The impact of the differences on overall survival (OS) and post-recurrence survival (PRS) of the patients was analyzed. RESULTS: The effective discrepancy rates between primary and locally recurrent breast cancer tissues were 26.1% (18/69) for ER, 50.0% (34/68) for PR, and 10.3%(4/39) for HER-2 expressions. In the 60 cases who had complete follow-up data, 23 patients (38.3%) died and the median overall survival was 107 months (11-288 months). The 3-, 5- and 10-year overall survival rates were 84.3%, 71.6% and 45.7%, respectively. Kaplan-Meier survival analysis showed that the changes of ER expression had significant impact on the OS (P = 0.001) and PRS (P < 0.001), but PR had no significant effect on OS (P = 0.416) and PRS (P = 0.056). However, the OS and PRS for patients with PR+ locally recurrent tumors were better than that of PR- patients regardless of the primary tumor PR status. The expression of HER-2 had no significant effect on the OS (P = 0.840) and PRS (P = 0.544) of the patients. CONCLUSIONS: An expression discrepancy of ER, PR and HER-2 exists between primary and locally recurrent breast cancer tissues, it significantly affects the survival of the patients. Re-evaluation of the expressions of ER, PR and HER-2 receptor in locally recurrent breast tumor tissue is beneficial for their therapy and prognosis. PMID- 24054016 TI - [Clinical analysis of relevant factors causing postoperative recurrence of laryngeal cancer after partial laryngectomy]. AB - OBJECTIVE: To discuss the clinical relevant factors causing recurrence and failure of laryngeal cancer after partial laryngectomy. METHODS: The clinical data of 183 patients with laryngeal cancer who underwent partial laryngectomy from January 2005 to July 2009 in our hospital were analyzed retrospectively. 12 selected factors which might cause recurrence including sex, age, smoking condition, drinking condition, laryngeal cancer type, T stage, N stage, clinical stage, pathological grade, mode of operation, radiotherapy and margin status were analyzed. RESULTS: In the 183 patients, 37 cases were recurrence, the recurrence rate was 20.2%, 3-year survival rate was 83.1%, and 5-year-expected survival rate was 71.8%. Seven factors, i.e. T stage, N stage, pathological grades, surgical margins, radiotherapy, drinking and smoking condition were associated with recurrence after partial laryngectomy. Multivariate analysis showed that drinking condition, surgical margins, adjuvant radiotherapy and pN stage were the main factors affecting the prognosis of patients with partial laryngectomy, and they all were risk factors. CONCLUSIONS: Simple surgical treatment of early laryngeal cancer alone can achieve satisfactory therapeutic effect. However, multidisciplinary treatment mode of the operation combined with radiotherapy should be considered for patients with advanced laryngeal carcinoma and positive surgical margins. PMID- 24054017 TI - [Value of contrast-enhanced ultrasound (CEUS) in the differential diagnosis between benign and malignant renal neoplasms]. AB - OBJECTIVE: To investigate the value of contrast enhanced ultrasound (CEUS) imaging in the differential diagnosis between benign and malignant renal neoplasms. METHODS: Two hundred and forty-five cases of renal space-occupying lesions confirmed by biopsy or surgical pathology were included in this study. The CEUS features of the renal space-occupying lesions, i.e., the enhancement degree, homogeneity of enhancement, washing-in and washing-out time and enhancement pattern, were retrospectively analyzed. RESULTS: There were 210 cases of malignant renal tumors and 35 cases of benign lesions. The CEUS modes of the malignant renal tumors included "quick in and quick out" 82 cases, "quick in and slow out" 64 cases, "slow in and quick out" 18 cases and "slow in and slow out" 46 cases; good enhancement 150 cases (71.4%) and inhomogeneous enhancement 180 cases (85.7%).Both the contrast agent filling defect area and solid component enhancement of solid-cystic tumors were important features of malignant renal tumors. In the 35 cases of benign lesions,the CEUS modes included "quick in and quick out" 4 cases, "quick in and slow out" 8 cases, "slow in and quick out" 10 cases and "slow in and slow out" 13 cases. Most of the benign tumors showed low enhancement 51.4% (18/35) and inhomogeneous enhancement 54.3% (19/35). There were significant differences between the malignant and benign renal neoplasms in CEUS mode, degree of enhancement and homogeneity of enhancement (P < 0.05), and in time of increasing, peak time, peak intensity and peak intensity ratio (P < 0.05). The accuracy rates of contrast-enhanced ultrasound for diagnosis of benign and malignant tumors were 77.1% and 83.8%, respectively, while the two dimensional ultrasound diagnosis of benign and malignant tumors were 68.6% and 76.7%, respectively, with a significant difference (P < 0.05). CONCLUSIONS: CEUS may provide more information to improve the diagnostic accuracy for renal neoplasms, and may play important role in differential diagnosis between benign and malignant renal lesions. PMID- 24054018 TI - [Outcomes of chemotherapy in patients with EGFR mutation-negative non-small cell lung cancer]. AB - OBJECTIVE: To evaluate the efficacy of chemotherapy for patients with EGFR (exon 19 and 21) mutation-negative non-small cell lung cancer (NSCLC). METHODS: One hundred and forty NSCLC patients with negative EGFR mutation (90 cases) or EGFR mutation (50 cases) underwent gemcitabine or vinorelbine plus cisplatin or carboplatin chemotherapy. RESULTS: In the EGFR mutation-negative patients, there were PR in 26 cases, SD in 48 cases, PD in 16 cases, the disease control rate was 82.2%. In the patients with EGFR mutation, there were PR in 14 cases, SD in 23 cases, PD in 13 cases, the disease control rate was 74.0%. The difference of disease control rates in the two groups was not significant (P = 0.250). The progression free survival (PFS) of EGFR mutation-negative patients was 4.2 months (95%CI 3.8-4.6) vs. 4.0 months (95%CI 3.6-4.4) in patients with EGFR mutation, with a significant difference (P = 0.021). The overall survival (OS) of EGFR mutation-negative patients was 9.2 months (95%CI 8.4-10.0) vs. 7.8 months (95%CI, 6.9-8.7) of patients with EGFR mutation (P = 0.028). CONCLUSIONS: Chemotherapy can prolong the PFS and OS of EGFR mutation-negative patients. However, only the extension of OS has practical significance. PMID- 24054019 TI - [Analysis of clinicopathological factors associated with false-negative rate of sentinel lymph node biopsy in breast cancer patients: experience of a single center]. AB - OBJECTIVE: The purpose of this study was to investigate the clinicopathologic factors associated with false-negative rate of sentinel lymph node biopsy (SLNB) in breast cancer, and to explore how to reduce the false-negative rate of SLNB. METHODS: The clinicopathological data of 2265 patients with invasive breast carcinoma who underwent sentinel lymph nodes biopsy (SLNB) in Shandong Cancer Hospital between November 1999 and December 2011 were retrospectively analyzed. We screened 1228 patients who received axillary lymph node dissection after SLNB, and studied the clinicopathological factors that could be associated with false negative rate of SLNB. RESULTS: The false negative rate of this group was 10.7% (73/683), accuracy rate was 94.1% (1155/1228), and negative predictive value was 88.2% (545/618). Clinical tumor size (all P < 0.05), calendar year of surgery (all P < 0.05) and numbers of detected SLNs (all P < 0.05) were significantly related with false negative rate and accuracy rate of SLNB, determined by single factor analysis. Logistic regression model analysis showed that calendar year of surgery (P = 0.034) and numbers of detected SLNs (P = 0.012) were independent predictive factors for the false negative rate of SLNB. CONCLUSIONS: False negative rate and accuracy rate of SLNB are significantly related to the calendar year of surgery and number of detected SLNs. Strict case selection, standard operation procedure, increaseing numbers of detected SLNs, and improvement of the skill of operators are effective measures to reduce the false negative rate of SLNB. PMID- 24054020 TI - [Comparison of two gastric cancer screening schemes in a high-risk population]. AB - OBJECTIVE: To evaluate the effects of two gastric cancer screening schemes for early detection of gastric cancer in a high-risk population. METHODS: A cluster random sampling method was used to select local residents aged 40-69 years from Linqu County, Shandong Province. "Serum pepsinogen initial screening combined with further endoscopic examination (PG scheme)" and "direct endoscopic examination (endoscopy scheme)" were conducted. The associations between screening schemes and detection rates of gastric cancer, and early gastric cancer/high-grade intraepithelial neoplasia were evaluated by unconditional logistic regression analysis. RESULTS: Overall, 3654 and 2290 participants completed PG and endoscopy schemes, respectively. A total of 11 (0.30%) cases of gastric cancer and 10 (0.27%) cases of high-grade intraepithelial neoplasia were detected by PG scheme, of which 7 (0.19%) cases were early gastric cancer. While, 19 (0.83%) cases of gastric cancer and 10 (0.44%) cases of high-grade intraepithelial neoplasia were detected by endoscopy scheme, with 12 (0.52%) cases of early gastric cancer. Compared with the PG scheme, the endoscopy scheme had a significantly higher detection rates of gastric cancer (OR = 2.83, 95%CI 1.34-5.98), and early gastric cancer/high-grade intraepithelial neoplasia (OR = 2.12, 95%CI 1.12-4.02). CONCLUSIONS: The endoscopy scheme is more effective in the detection of gastric cancer in a high-risk population, particularly for early gastric cancer/high-grade intraepithelial neoplasia than the PG scheme. PMID- 24054021 TI - [Expert consensus on multidisciplinary treatment for pancreatic cancer]. PMID- 24054022 TI - The Upper Palaeolithic site of Kalavan 1 (Armenia): an Epigravettian settlement in the Lesser Caucasus. AB - The open-air site of Kalavan 1 is located in the Aregunyats mountain chain (at 1640 m above sea level) on the northern bank of Lake Sevan. It is the first Upper Palaeolithic site excavated in Armenia. Led by an Armenian-French team, several excavations (2005-2009) have revealed a well preserved palaeosoil, dated to around 14,000 BP (years before present), containing fauna, lithic artefacts, as well as several hearths and activity areas that structure the settlement. The initial studies enable placement of the site in its environment and justify palaeoethnological analysis of the Epigravettian human groups of the Lesser Caucasus. PMID- 24054023 TI - Chromosomal gains and losses in human papillomavirus-associated neoplasia of the lower genital tract - a systematic review and meta-analysis. AB - BACKGROUND: Overexpression of the human papillomavirus (HPV) oncogenes E6 and E7 is necessary for the development of distinct lower genital tract cancers. However, secondary cellular genomic alterations are mandatory to promote progression of HPV-induced premalignant stages. We aimed at identifying the chromosomal regions most frequently gained and lost and the disease stage at which the latter occurs. These regions might be relevant for carcinogenesis and could serve as diagnostic markers to identify premalignant lesions with high progression risk towards invasive cancer. METHODS: We performed a systematic literature review and meta-analysis of studies listed in PubMed that analysed chromosomal copy number alterations by comparative genomic hybridisation (CGH) in HPV-positive and -negative cancers or premalignant lesions of the anogenital tract (cervix, anus, vagina, penis and vulva). FINDINGS: Data were extracted and analysed from 32 studies. The most common alterations in cervical squamous cell carcinoma (SCC) (12 studies, 293 samples) were gains at 3q with a rate of 0.55 (95% confidence interval (CI) 0.43-0.70), losses at 3p (0.36, 95%CI 0.27-0.48) and losses at 11q (0.33, 95%CI 0.26-0.43). Gains at 3q were particularly frequent in HPV16-positive cervical SCC (0.84, 95%CI 0.78-0.90). Also more than one quarter of high grade cervical intraepithelial neoplasia (CIN) harboured gains of 3q (0.27, 95%CI 0.20-0.36), but the rate in low grade CIN was low (0.02, 95%CI 0.00-0.09). For HPV-associated vulvar SCC (four studies, 30 samples) the same common alterations as in cervical SCC were reported. Studies on non-cervical and non-vulvar SCC and premalignant lesions of the lower genital tract are scarce. INTERPRETATION: 3q gains were most frequently found in HPV16-positive cervical SCC. The results suggest the selection of HPV-transformed cell clones harbouring 3q gains in high grade premalignant lesions, while alterations in low grade lesions are rare. PMID- 24054028 TI - Menthol: a simple monoterpene with remarkable biological properties. AB - Menthol is a cyclic monoterpene alcohol which possesses well-known cooling characteristics and a residual minty smell of the oil remnants from which it was obtained. Because of these attributes it is one of the most important flavouring additives besides vanilla and citrus. Due to this reason it is used in a variety of consumer products ranging from confections such as chocolate and chewing gum to oral-care products such as toothpaste as well as in over-the-counter medicinal products for its cooling and biological effects. Its cooling effects are not exclusive to medicinal use. Approximately one quarter of the cigarettes on the market contain menthol and small amounts of menthol are even included in non mentholated cigarettes. Natural menthol is isolated exclusively from Mentha canadensis, but can also be synthesised on industrial scale through various processes. Although menthol exists in eight stereoisomeric forms, (-)-menthol from the natural source and synthesised menthol with the same structure is the most preferred isomer. The demand for menthol is high and it was previously estimated that the worldwide use of menthol was 30-32,000 metric tonnes per annum. Menthol is not a predominant compound of the essential oils as it can only be found as a constituent of a limited number of aromatic plants. These plants are known to exhibit biological activity in vitro and in vivo such as antibacterial, antifungal, antipruritic, anticancer and analgesic effects, and are also an effective fumigant. In addition, menthol is one of the most effective terpenes used to enhance the dermal penetration of pharmaceuticals. This review summarises the chemical and biological properties of menthol and highlights its cooling effects and toxicity. PMID- 24054030 TI - Foreword. Genetic disciplines surrounding haploid DNA markers. PMID- 24054029 TI - Mass spectrometric base composition profiling: Implications for forensic mtDNA databasing. AB - In forensic genetics mitochondrial DNA (mtDNA) is usually analyzed by direct Sanger-type sequencing (STS). This method is known to be laborious and sometimes prone to human error. Alternative methods have been proposed that lead to faster results. Among these are methods that involve mass-spectrometry resulting in base composition profiles that are, by definition, less informative than the full nucleotide sequence. Here, we applied a highly automated electrospray ionization mass spectrometry (ESI-MS) system (PLEX-ID) to an mtDNA population study to compare its performance with respect to throughput and concordance to STS. We found that the loss of information power was relatively low compared to the gain in speed and analytical standardization. The detection of point and length heteroplasmy turned out to be roughly comparable between the technologies with some individual differences related to the processes. We confirm that ESI-MS provides a valuable platform for analyzing mtDNA variation that can also be applied in the forensic context. PMID- 24054031 TI - Genetic variation in cytokine-related genes and migraine susceptibility. AB - Migraine is classified by the World Health Organization (WHO) as being one of the top 20 most debilitating diseases. According to the neurovascular hypothesis, neuroinflammation may promote the activation and sensitisation of meningeal nociceptors, inducing the persistent throbbing headache characterized in migraine. The tumor necrosis factor (TNF) gene cluster, made up of TNFalpha, lymphotoxin alpha (LTA), and lymphotoxin beta (LTB), has been implicated to influence the intensity and duration of local inflammation. It is thought that sterile inflammation mediated by LTA, LTB, and TNFalpha contributes to threshold brain excitability, propagation of neuronal hyperexcitability and thus initiation and maintenance of a migraine attack. Previous studies have investigated variants within the TNF gene cluster region in relation to migraine susceptibility, with largely conflicting results. The aim of this study was to expand on previous research and utilize a large case-control cohort and range of variants within the TNF gene cluster to investigate the role of the TNF gene cluster in migraine. Nine single nucleotide polymorphisms (SNPs) were selected for investigation as follows: rs1800683, rs2229094, rs2009658, rs2071590, rs2239704, rs909253, rs1800630, rs1800629, and rs3093664. No significant association with migraine susceptibility was found for any of the SNPs tested, with further testing according to migraine subtype and gender also showing no association for disease risk. Haplotype analysis showed that none of the tested haplotypes were significantly associated with migraine. PMID- 24054032 TI - Lack of association of hepatic estrogen receptor-alpha expression with histopathological and biochemical findings in chronic hepatitis C. AB - Estrogens exert a protective effect against hepatic steatosis and fibrosis. Loss of estrogen receptor-alpha (ER-alpha) in the liver is associated with hepatic steatosis and inflammation in animal models. We conducted a study in order to investigate the presence and extent of ER-alpha expression in HCV infection, and its relationship with histological and biochemical findings. Ninety biopsy-proven chronic hepatitis C (CHC) patients were enrolled in the study. Liver biopsy specimens were immunohistochemically stained for ER-alpha expression. Nuclear ER alpha expression percentage was calculated. ER-alpha was positive in 69 of the patients (76%). ER-alpha positive and negative groups were not significantly different in terms of age, gender, necroinflammatory activity, fibrosis, steatosis, serum levels of AST, ALT, ALP, GGT, and bilirubin. ER-alpha expression percentage was not correlated with fibrosis, steatosis, necroinflammatory activity and biochemical findings. Although estrogens are known to be protective against fibrosis and steatosis in animal models, we did not find any significant correlation between ER-alpha expression and histopathological and biochemical findings in CHC patients. These findings should be verified in further large scale studies. PMID- 24054033 TI - Downregulation of GLTSCR2 expression is correlated with breast cancer progression. AB - Glioma tumor-suppressor candidate region gene2 (GLTSCR2) is a recently identified nucleolus-localized protein participating in the regulation of cell cycle progression and apoptosis. Down-regulation of GLTSCR2 in several types of cancers and increased transforming activity in GLTSCR2-downregulated cancer cells indicated its tumor suppressive potential. The aim of this study was to evaluate GLTSCR2 expression in breast cancer and to investigate the question of whether reduced expression of GLTSCR2 may have any pathological significance in breast cancer development or progression. In this study, we performed quantitative RT PCR and immunohistochemistry to evaluate the expression of GLTSCR2 and relevance with clinicopathological factors in the invasive ductal carcinoma (IDC). GLTSCR2 expression was reduced in 48% of IDC (n=426) by a semi-quantitative scoring system using tissue microarray. GLTSCR2 mRNA was significantly reduced by 0.16 fold in 15 out of 17 (88%) cases of IDC. Reduction of GLTSCR2 was significantly correlated with increased histological grade (p<0.005), increased tumor size (p<0.001), axillary lymph node involvement (p<0.001) and decreased disease free survival (p<0.025). In addition, we show that upregulation of GLTSCR2 decreases the invasive potential of breast cancer cells. Taken together, our data suggest that GLTCR2 may play a role in the tumorigenesis, progression and biological behavior in breast cancer. PMID- 24054034 TI - Schwannomatosis presenting as pancreatic and submandibular gland schwannoma. AB - Schwannomatosis is a well-established third form of neurofibromatosis, characterized by the presence of multiple non-vestibular, non-intradermal schwannomas, often associated with chronic pain. Herein, we report a 41-year-old man with a history of paternal neurofibromatosis 1, who presented with partially cystic tumors in the pancreas and in the right submandibular gland. Besides, he complained of neuropathic pain in the right inguinal and suprapubic area. Magnetic resonance imaging revealed multiple intradural-extramedullary tumors at the cervical, thoracic and lumbar spinal canal, suggestive of schwannomas. The vestibular nerves were not involved. Pathological examination of the glandular tumors disclosed benign schwannomas. These tumors had substantial myxoid stroma and prominent cystic change, and showed a mosaic pattern of loss of INI1/SMARCB1 expression by immunohistochemistry. Later, the patient developed three nodules in the right lung which were interpreted as schwannomas. To our knowledge, this is the first report of schwannomatosis presenting as pancreatic and salivary gland schwannomas. PMID- 24054035 TI - Amniotic band syndrome associated with an atypical iris and optic nerve defect. AB - We report the case of an 8-year-old boy who presented with right cleft lip and palate, left Tessier number 3 and 11 clefts, and limb abnormalities because of amniotic band syndrome. He was found to have an atypical iris and optic disk nasal defect and a right-sided ptosis, which have not been previously reported with amniotic band syndrome. PMID- 24054036 TI - DRESS syndrome in a child treated for toxoplasma retinochoroiditis. AB - Children treated for toxoplasma retinochoroiditis may experience a range of severe adverse drug responses. Drug reaction with eosinophilia and systemic symptoms syndrome is a life-threatening idiosyncratic drug reaction with a 10% mortality. We present a case of drug reaction with eosinophilia and systemic symptoms syndrome in a child on standard combination treatment with oral sulfadiazine, pyrimethamine, folinic acid, and steroids for toxoplasma retinochoroiditis. Early clinical recognition and appropriate treatment led to a complete recovery and no longterm sequelae. The parents of children during sulfadiazine treatment should be counseled on the potential significance of nonspecific illness. PMID- 24054037 TI - Positional vertical opsoclonus: a transient phenomenon in normal healthy twins. AB - Opsoclonus is characterized by rapid bursts of involuntary, multidirectional, saccades without an intersaccadic interval. Three types of opsoclonus that occur in infancy have been identified, 2 of which are associated with a systemic or neurologic condition. The third is a benign condition that occurs transiently in healthy neonates and preterm babies. We report a case of 2 healthy twins who presented with transient opsoclonus, which was confined only to the vertical plane and manifested only in a supine position. Opsoclonus disappeared when the cheek was tapped. These eye movements began at 3 months and completely resolved by 6 months of age. PMID- 24054038 TI - The unique association of iris heterochromia with Hermansky-Pudlak syndrome. AB - Melanin biosynthesis is reduced in oculocutaneous albinism, an autosomal recessive disorder. Hermansky-Pudlak syndrome is associated with oculocutaneous albinism but also has systemic complications. The ocular and systemic phenotypes vary, depending, in part, on the genetic mutations. This report presents a case of a patient with Hermansky-Pudlak syndrome and the unique association of iris heterochromia. PMID- 24054039 TI - Rectus muscle resection in Graves' ophthalmopathy. PMID- 24054040 TI - The challenges to ophthalmologic follow-up care for at-risk pediatric populations. PMID- 24054041 TI - Markedly asymmetric buphthalmos but without anisometropia in a girl with primary congenital glaucoma. AB - Amblyogenic anisometropia is common in children with primary congenital glaucoma who have asymmetric buphthalmos. We report the case of a 6-year-old girl with markedly asymmetric buphthalmos but without anisometropia. Biometry confirmed that the more buphthalmic eye was longer than the contralateral eye and also had flatter keratometry. PMID- 24054042 TI - [Implementation of a post-discharge surgical site infection system in herniorrhaphy and mastectomy procedures]. AB - INTRODUCTION: Monitoring surgical site infection (SSI) performed during hospitalization can underestimate its rates due to the shortening in hospital stay. The aim of this study was to determine the actual rates of SSI using a post discharge monitoring system. METHODS: All patients who underwent herniorraphy or mastectomy in the Hospital Universitario Ramon y Cajal from 1 January 2011 to 31 December 2011 were included. SSI data were collected prospectively according to the continuous quality improvement indicators (Indicadores Clinicos de Mejora Continua de la Calidad [INCLIMECC]) monitoring system. Post-discharge follow-up was conducted by telephone survey. RESULTS: A total of 409patients were included in the study, of whom 299 underwent a herniorraphy procedure, and 110 underwent a mastectomy procedure. For herniorrhaphy, the SSI rate increased from 6.02% to 7.6% (the post-discharge survey detected 21.7% of SSI). For mastectomy, the SSI rate increased from 1.8% to 3.6% (the post-discharge survey detected 50% of SSI). CONCLUSIONS: Post-discharge monitoring showed an increased detection of SSI incidence. Post-discharge monitoring is useful to analyze the real trend of SSI, and evaluate improvement actions. Post-discharge follow-up methods need to standardised. PMID- 24054043 TI - [Co-infection with influenza type A (H1N1)pdm09 and influenza type B in a patient with human immunodeficiency virus infection]. PMID- 24054044 TI - [Bacteraemia due to Streptococcus equi spp. zooepidemicus in a liver transplant recipient]. PMID- 24054045 TI - Combination therapy with carboplatin and thalidomide suppresses tumor growth and metastasis in 4T1 murine breast cancer model. AB - Carboplatin, efficient cytostatics for cancer therapy, could induce apoptosis and inhibit the growth of vascular endothelium in several tumor cell lines and xenograft models. It has been suggested that the antitumor effect of chemotherapy could be increased by combining it with an antiangiogenesis agent in anticancer strategy. The present study explored the potential to increase the antitumor effect of carboplatin by combining it with thalidomide in mouse 4T1 breast cancer models, and the underlining mechanism was investigated. The systemic administration of carboplatin and thalidomide significantly decreased tumor growth through increased tumor cell apoptosis compared with either control group. Collectively, these findings suggest that combined treatment has shown synergistic suppression in tumor progression according to the analysis. Furthermore, also was observed reduction in number of lung metastases as compared to isolated treatments and increased survival of the animals. The present study may be important in future exploration of the potential application of the combined approach in the treatment of breast cancer. PMID- 24054046 TI - A rising star: pharmacological development in China. PMID- 24054047 TI - Left ventricular systolic function in ischemic mitral regurgitation: time to look beyond ejection fraction. PMID- 24054048 TI - Measurement of pulmonary pressures and pulmonary resistance: is Doppler ready for prime time? PMID- 24054049 TI - New resources for evolving uses of cardiac ultrasound-the importance of a collaborative spirit. PMID- 24054050 TI - Sonographer travel grants: expanding horizons and fueling passions. PMID- 24054052 TI - Collaboration across the health care and education interface: what is it like for teachers of children with traumatic brain injury? AB - For those involved in supporting and educating children with traumatic brain injury, the interface between health care and education is complex. This paper reports the findings of a study exploring how teachers of children with traumatic brain injury experience collaboration with health-care professionals. A phenomenological approach was used to understand teachers' experience of collaboration. Semi-structured interviews were undertaken with five teachers who taught children with traumatic brain injury in a regional area of Australia. The findings revealed that the experience of collaboration for teachers is characterised by moving through three national spaces (starting out in the interactive space, moving into a collaborative space and embracing the collaborative space). As they move through these spaces, teachers widen their self-sufficient practice horizon to develop reciprocity with health-care professionals. The findings from this study highlight a need for health-care professionals to be sensitive to, and aware of, teachers' familiarity with interdisciplinary collaboration, issues related to knowledge differentials and time constraints. PMID- 24054054 TI - New WHO recommendations on prevention and treatment of postpartum hemorrhage. AB - Improving health care for women during childbirth in order to prevent and treat postpartum hemorrhage (PPH) is an essential step toward achieving Millennium Development Goal 5. In March 2012, WHO held a Technical Consultation on the Prevention and Treatment of Postpartum Haemorrhage to review current evidence and to update previously published PPH guidelines. The present paper provides an overview of the most recent WHO guidelines for both prevention and treatment of PPH, with an emphasis on the key messages and changes. PMID- 24054053 TI - A comparative analysis of role attainment and impairment in binge-eating disorder and bulimia nervosa: results from the WHO World Mental Health Surveys. AB - Background. Cross-national population data from the WHO World Mental Health surveys are used to compare role attainments and role impairments associated with binge-eating disorder (BED) and bulimia nervosa (BN). Methods. Community surveys assessed 23 000 adults across 12 countries for BED, BN and ten other DSM-IV mental disorders using the WHO Composite International Diagnostic Interview. Age of-onset was assessed retrospectively. Ten physical disorders were assessed using standard conditions checklists. Analyses examined reciprocal time-lagged associations of eating disorders (EDs) with education, associations of early onset (i.e., prior to completing education) EDs with subsequent adult role attainments and cross-sectional associations of current EDs with days of role impairment. Results. BED and BN predicted significantly increased education (females). Student status predicted increased risk of subsequent BED and BN (females). Early-onset BED predicted reduced odds of current (at time of interview) marriage (females) and reduced odds of current employment (males). Early-onset BN predicted increased odds of current work disability (females and males). Current BED and BN were both associated with significantly increased days of role impairment (females and males). Significant BED and BN effects on adult role attainments and impairments were explained by controls for comorbid disorders. Conclusions. Effects of BED on role attainments and impairments are comparable with those of BN. The most plausible interpretation of the fact that these associations are explained by comorbid disorders is that causal effects of EDs are mediated through secondary disorders. Controlled treatment effectiveness studies are needed to trace out long-term effects of BED-BN on secondary disorders. PMID- 24054056 TI - Receptors involved in cell activation by antiphospholipid antibodies. AB - The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein beta2 glycoprotein 1 (beta2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbalpha, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2+ -binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS. PMID- 24054055 TI - Risk factors for intraoperative hemorrhage at evacuation of a cesarean scar pregnancy following uterine artery embolization. AB - OBJECTIVE: To determine risk factors associated with massive uterine bleeding during dilation and suction curettage (D&C) after uterine artery embolization (UAE) for the treatment of cesarean scar pregnancy (CSP). METHODS: Data from 128 CSP patients treated with D&C after UAE were analyzed to assess risk factors associated with massive uterine bleeding (blood loss 500mL or more) during D&C after UAE. RESULTS: In total, 15 CSP patients had massive bleeding during D&C after UAE. Univariate analysis showed that a greater gestational age (GA), a larger CSP mass size, a thinner myometrium at the implantation site, a GA of 8weeks or more, a CSP mass diameter of 6cm or more, and evidence of fetal heartbeat were risk factors for massive bleeding (P<0.05). In a binary logistic regression analysis, GA of 8weeks or more and CSP mass diameter of 6cm or more remained as the only significant risk factors for massive bleeding (OR 11.49 [95% CI 1.08-122.13] and OR 96.59 [95% CI 6.20-150.57], respectively; P<0.05). CONCLUSION: For CSP masses with a GA of 8weeks or more and a diameter of 6cm or more, the outcome of surgical evacuation after UAE tends to be unsatisfactory. PMID- 24054057 TI - Black esophagus (acute esophageal necrosis) after spinal anesthesia. AB - Acute esophagic necrosis or black esophagus is an uncommon clinical entity that owes its name to the endoscopic view of the necrotic esophageal mucosa. It is always related with a critical medical condition and usually has an ischemic etiology. We report the first case of acute esophageal necrosis after a spinal anesthetic for partial hip joint arthroplasty. We discuss the underlying pathophysiological mechanisms. PMID- 24054058 TI - [As regards "Post-menopausal osteoporosis: primary prevention or excessive medication"]. PMID- 24054059 TI - [Fracture risk according to the FRAX tool in a primary care centre]. PMID- 24054060 TI - [Management of referrals between primary and specialised care]. PMID- 24054061 TI - Development of brief versions of the Wechsler Intelligence Scale for schizophrenia: considerations of the structure and predictability of intelligence. AB - Short forms (SF) of the Wechsler Intelligence Scale have been developed to enhance its practicality. However, only a few studies have addressed the Wechsler Intelligence Scale Revised (WAIS-R) SFs based on data from patients with schizophrenia. The current study was conducted to develop the WAIS-R SFs for these patients based on the intelligence structure and predictability of the Full IQ (FIQ). Relations to demographic and clinical variables were also examined on selecting plausible subtests. The WAIS-R was administered to 90 Japanese patients with schizophrenia. Exploratory factor analysis (EFA) and multiple regression analysis were conducted to find potential subtests. EFA extracted two dominant factors corresponding to Verbal IQ and Performance IQ measures. Subtests with higher factor loadings on those factors were initially nominated. Regression analysis was carried out to reach the model containing all the nominated subtests. The optimality of the potential subtests included in that model was evaluated from the perspectives of the representativeness of intelligence structure, FIQ predictability, and the relation with demographic and clinical variables. Taken together, the dyad of Vocabulary and Block Design was considered to be the most optimal WAIS-R SF for patients with schizophrenia, reflecting both intelligence structure and FIQ predictability. PMID- 24054062 TI - Risk factors for post-deployment posttraumatic stress disorder in national guard/reserve service members. AB - Identification of factors that increase risk for PTSD in military personnel following deployments is critical to early intervention and prevention. The study tested hypothesized main and moderating risk factors for PTSD in National Guard/Reserve members deployed to Iraq or Afghanistan. Members of the National Guard/Reserves (n=238) completed diagnostic interviews and measures of risk factors at a post-deployment assessment conducted an average of four and a half months following return from deployment. Hierarchical multivariate logistic regression analyses were used to test hypotheses. Higher levels of combat exposure, life and family concerns during deployment, and post-deployment social support independently predicted PTSD. Life/family concerns during deployment and perceived adequacy of training and preparation were significant moderators of the association between combat exposure and PTSD. Among those with higher levels of both combat exposure and life and family stress, 27% had PTSD in contrast to 3% of those with high exposure but lower levels of such stress during deployment. In addition to combat exposure, life and family stress during deployment is a particularly important predictor of PTSD. The findings highlight the importance of identifying and addressing such stress. PMID- 24054063 TI - The time is right to launch large-scale controlled treatment effectiveness studies of early-onset binge eating disorders and bulimia nervosa in student populations. PMID- 24054064 TI - Expression and significance of leptin receptor, p-STAT3 and p-AKT in diffuse large B-cell lymphoma. AB - We investigated the expression and clinical significance of leptin receptor (OBR), p-STAT3 and p-AKT in patients with diffuse large B-cell lymphoma (DLBCL) by immunohistochemical analysis. Immunohistochemistry revealed high expression of OBR, p-STAT3 and p-AKT in 45.0% (36/80), 28.8% (23/80) and 18.8% (15/80) cases of DLBCL, respectively, and minimal staining in 100% (20/20) cases of RLH (P<0.05). Compared with GCB group, the non-GCB group had higher p-STAT3 expression rate (21/57 vs. 2/23, P<0.01). The expression of OBR was positively related with that of p-STAT3 and p-AKT in DLBCL patients (P<0.05). Our data suggest that OBR stimulates the JAK/STAT and PI3K/AKT signaling pathway and induces the phosphorylation of STAT3 and AKT. This may be involved in carcinogenesis and prognosis of DLBCL. The specific inhibitions could interfere in the combination of leptin with OBR and obstruct the JAK/STAT and PI3K/AKT signaling pathways, which could lead to new research and treatment strategies for DLBCL treatment. PMID- 24054065 TI - Nutritional status, food intake and cardiovascular disease risk in individuals with schizophrenia in southern Brazil: a case-control study. AB - OBJECTIVES: To verify food consumption patterns and presence of risk anthropometric parameters in schizophrenic patients, trying to assess some modifiable cardiovascular risk. METHOD: Twenty-five schizophrenic outpatients, attended at the Hospital de Clinicas de Porto Alegre, Brazil, and 25 healthy controls matched by sex, age and body mass index (BMI) were included. Demographic (age, sex and socioeconomic status), anthropometric (weight, height and waist circumference), clinical (antipsychotics) and dietary consumption data (food frequency questionnaire) were obtained. RESULTS: There was a 40% frequency of overweight and 40% of obesity as verified by BMI, and 80% of increased risk of metabolic complications as measured by waist circumference. Most of the patients (68%) used atypical antipsychotics and no association was found between the distribution of the nutritional status according to BMI and type of antipsychotic used. There was a higher intake of total calories, calories and protein per kilogram of body weight, percentage of carbohydrates, and lower intake of omega 6, phytosterols, vitamin A and alpha-tocopherol by cases. Cholesterol and sodium intake did not differ between groups (365 +/- 152 mg of cholesterol in cases and 313 +/- 146 mg in controls; (3499 +/- 1695 mg sodium by cases and 2874 +/- 800 by controls). CONCLUSION: In this sample of schizophrenic patients there was a higher intake of calories and lower consumption of alpha-tocoferol and phitosterols, compared to controls. There was also elevated sodium, and cholesterol intake, and high frequency of overweight and central obesity. PMID- 24054066 TI - Solvated liquid-lignin fractions from a Kraft black liquor. AB - A softwood Kraft black liquor was acidified with carbon dioxide at 115 degrees C and 6.2 bar over a pH range of 13.6-9.5, resulting in the precipitation of liquefied-lignin fractions as a separate phase. Seven such "liquid-lignin" fractions were produced, with each fraction being phase-separated within a narrow pH band of 0.5 units. The fractions were found to be highly hydrated phases, containing 32.3-48.2 wt.% water; as a result, their measured melting points were quite low, 90.7-110.5 degrees C. In contrast, no melting point was detected up to 375 degrees C for any of the lignin fractions after drying. Significant reductions in metals content were observed for the lignin fractions compared to the original black-liquor feed. PMID- 24054067 TI - The Brain Prize 2013: the optogenetics revolution. AB - The 2013 Grete Lundbeck European Brain Research Prize was awarded to Ernst Bamberg, Edward Boyden, Karl Deisseroth, Peter Hegemann, Gero Miesenbock, and Georg Nagel 'for their invention and refinement of optogenetics'. Why optogenetics? And why this sextet? To appreciate why, we turn first to some of the core questions of neuroscience and the technical difficulties that long obstructed their resolution. PMID- 24054068 TI - Cultural perceptions and health behaviors related to safe motherhood among village women in Eastern Sudan: Ethnographic study. AB - BACKGROUND: Meeting the health needs of Sudanese women, especially those living in village areas, is imperative and cannot be accomplished without understanding the cultural perceptions and health behaviors related to safe motherhood. Nevertheless, there is little literature exploring these perspectives through qualitative study, as most of the studies performed in Sudan applied quantitative methods and focused on urban areas. OBJECTIVE: This study aims to explore cultural perceptions and behaviors relevant to safe motherhood among Sudanese village women. DESIGN/METHOD: A qualitative method using an ethnographic approach was applied for the study. Semi-structured in-depth interviews were conducted with six village women of reproductive age living in a village in Gadarif State, Eastern Sudan. FINDINGS: The thematic content analysis revealed socio-economic factors, religious values and local beliefs shaping the village women's perceptions of their behaviors related to motherhood safety. Particular concerns included responses to health problems, preference for birth with traditional birth attendants, female genital mutilation/female genital cutting and a lack of utilizing family planning. CONCLUSIONS: An implication arising from this study is that maternal services should develop a collaboration between village midwives and traditional birth attendants. This study further suggests that educational messages must be delivered to family relatives with consideration of the cultural influences highlighted by the village women. PMID- 24054069 TI - Academisation of nursing: An ethnography of social transformations in Chile. AB - BACKGROUND: Nursing in Chile is considered to be the leading example of professional development in Latin America - nurses must undertake five years of university education on a full-time programme. Academisation of nursing education is a key aspect in the evolution into professional status. The consequences of education, however, are commonly related to the replication of social institutions and structures that perpetuate social inequalities. OBJECTIVE: The study's aim was to comprehend the consequences of nursing academisation and its relationships with the social transformations which that country has witnessed. METHODS: We draw upon ethnographic data, gathered between 2010 and 2011 in a 500 bed, high-quality university hospital in Chile. Participants were nurses ranging from beginners to experienced professionals and recruited from wards representing technically expert nursing and caring-oriented nursing. The data were organised to allow the development of concepts and patterns, using the Grounded Theory approach. RESULTS: Despite the fact that Chilean nursing originated from the educated elite class, today's nurses share a middle-class consciousness, and a sense of class distinction is encouraged throughout academic training - the 'eliteness' of professional groups. This discourse antagonises middle-class people who 'should' adopt a professional-class identity. A tension among nurses surfaced, based on a competition for a scarce resource: social mobility. Furthermore, an antagonist stratification between university-trained nurses and auxiliary nurses has developed, and in the process the title 'nurse' and the practice of 'nursing' have been monopolised by university-trained nurses, resulting in a relationship of domination-subordination. CONCLUSIONS: The academisation process followed by Chilean nursing is rooted in the social-class transformations of that country. Such process has been ineffective in preventing social inequalities, resulting in the reproduction of earlier historical class differences in nursing, inhibiting nurses' individual development. Class differences are manifest in the socially constructed distinction between the nurse and the auxiliary nurse, resulting in a schism of the nursing family. By reconstituting a broken-up occupation, the political power of nursing could be strengthened. PMID- 24054070 TI - Lack of care in nursing: is character the missing ingredient? PMID- 24054071 TI - Squamous cell carcinoma of the hand: a 20-year review. AB - PURPOSE: Squamous cell carcinoma (SCC) is a common malignancy of the hand; yet, recurrence rates, metastatic rates, and long-term survival rates have not been well defined. This study evaluated the risk factors for local and regional recurrence for this diagnosis. METHODS: Records of patients treated for SCC of the hand over a 20-year period in a single institution were reviewed. Data collected included patient demographics, tumor characteristics, and preoperative and postoperative care received. Overall survival, recurrence-free survival, and survival free of SCC in the same upper extremity were analyzed. RESULTS: A total of 86 patients were identified. Mean age at the time of initial presentation was 69 years (range, 39-89 y). Mean follow-up was 6.4 years (range, 1-15 y). Overall survival was 88% and 57% at 5 and 10 years, respectively. Recurrence-free survival was 67% and 50% at 5 and 10 years, respectively. Rate of metastasis was 4%. Lymph node biopsy was performed in 4 patients who had clinical lymphadenopathy; 2 patients had positive nodes. Average time to first recurrence was 4.1 years (range, 0.5-11 y). Web space location, bilateral tumors, multiple tumors, and prior history of SCC were associated with an increased risk of recurrence. Survival free of SCC in the same upper extremity was 72% and 54% at 5 and 10 years, respectively. Younger age, history of transplantation, multiple tumors, and use of flap or skin graft for closure were associated with an increased risk of another SCC developing in the same extremity. No benefit was noted with wide, Mohs, or shave resection in terms of overall survival, recurrence-free survival, or SCC occurrence in the ipsilateral upper extremity. CONCLUSIONS: Squamous cell carcinoma tumors of the hand have a high tendency for local recurrence but a low rate of metastasis. Specific characteristics of the tumor may increase chances of recurrence. The technique of tumor excision did not have a major role in outcome. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 24054072 TI - Cervical radiculopathy and myelopathy: presentations in the hand. PMID- 24054073 TI - Complications of trapeziectomy with or without suspension arthroplasty. PMID- 24054074 TI - [Online platforms for neuropsychological rehabilitation: current status and lines of work]. AB - INTRODUCTION: The incidence of neurological and psychiatric diseases and disorders has increased in recent years, and similarly, the number of technological tools facilitating neuropsychological rehabilitation for family members and therapists has also grown. The purpose of this article is to describe some of these tools and indicate the needs they cover. DEVELOPMENT: This article reviews some currently well-known neuropsychological rehabilitation platforms, compares them, and proposes future lines of work to be considered when developing tools that meet real needs. In this review, we list the main advantages and shortcomings of each of the tools and establish benchmarks for evaluating them. In comparing these platforms, we may observe their advantages on the one hand, and areas needing improvement on the other. CONCLUSIONS: This review demonstrates that more of these tools are entering the market, but many aspects of neurorehabilitation remain uncovered. Additional studies evaluating these tools' effectiveness are also needed. PMID- 24054075 TI - [Fulminant myopathy caused by aortic thrombus in an anticoagulated patient]. PMID- 24054076 TI - Biotechnology for the bio- and green economy. PMID- 24054077 TI - Does "healthy" fast food exist? The gap between perceptions and behavior. PMID- 24054078 TI - Cyberbullying among adolescents: implications for empirical research. PMID- 24054079 TI - The role of the pediatrician in family-based treatment for adolescent eating disorders: opportunities and challenges. AB - Empiric research supports that family-based treatment (FBT) is an effective treatment for adolescents with eating disorders. This review outlines the role of the pediatrician in FBT for adolescent eating disorders, specifically focusing on how pediatric care changes during treatment, and discusses current challenges and misconceptions regarding FBT. Although FBT introduces unique challenges to pediatricians trained in earlier eating disorder treatment approaches, effective support of the approach by pediatricians is critical to its success. PMID- 24054080 TI - A population-level assessment of factors associated with uptake of adolescent targeted vaccines in Michigan. AB - PURPOSE: Increases in adolescent vaccine coverage are needed. The aim of this study was to identify population-level clinical and demographic factors associated with adolescent vaccination. METHODS: A retrospective analysis of data from the Michigan Care Improvement Registry (MCIR), a statewide immunization registry, was performed for 2006-2010. The sample included 1,252,655 adolescents aged 11-18 years. Vaccine coverage levels were calculated for tetanus-diphtheria acellular pertussis (Tdap), meningococcal conjugate (MCV4), flu (seasonal influenza), and human papillomavirus, females only (HPV) vaccines. For the subset of adolescents enrolled in Medicaid, claims data were used to obtain information about the type of visits in which vaccines were administered. RESULTS: As of 2010, statewide coverage levels for Tdap and MCV4 vaccines were 46.0% and 46.5%, respectively whereas only 15% of females had completed the HPV vaccine series. Only one in four female adolescents were up to date for all three of these vaccines. Statewide coverage among adolescents for flu vaccine during the 2009 2010 season was 8%. Age was the most significant predictor of HPV vaccination, whereas health care-associated factors (provider type and childhood immunization history) were the strongest predictors for the other three vaccines. Older adolescents were less likely to have received the flu vaccine but more likely to have receive HPV vaccine doses than younger adolescents. Among Medicaid-enrolled adolescents, most Tdap, MCV, and first-dose HPV vaccines, but only 29% of flu doses, were administered during preventive visits. CONCLUSIONS: Noted variability in adolescent vaccine coverage by age, vaccine type, and health care-associated factors provides a framework for developing future outreach activities to increase adolescent vaccine use. PMID- 24054081 TI - The authors reply. PMID- 24054082 TI - Adolescent consent for vaccination: a position paper of the Society for Adolescent Health and Medicine. AB - Vaccines currently recommended for adolescents by the Advisory Committee on Immunization Practices have the potential to improve the health of youth by preventing conditions such as: tetanus, pertussis, meningococcal disease, influenza, and genital warts, as well as later adult outcomes such as cervical and other human papillomavirus-related cancers. Adolescent vaccine coverage lags behind that for younger age groups. A requirement to obtain parental consent for vaccination can present a significant barrier to improving adolescent vaccine uptake across all health care settings in which adolescents access care. The ability of minors to consent to vaccination can influence whether adolescents receive indicated vaccines during adolescent health care visits when parents are absent and when adolescents are seen for confidential services. State laws govern consent for the delivery of health care to minors. All states have some laws that allow minors to consent to health care based either on their status or on the services they are seeking. Some of these laws would allow them to consent to vaccination. It is the Position of the Society for Adolescent Health and Medicine that, within ethical and legal guidelines, it will be important to develop strategies that maximize opportunities for minors to receive vaccinations when parents are not physically present, including opportunities for them to give their own consent. PMID- 24054083 TI - A hypothesis to explain childhood cancers near nuclear power plants. AB - Over 60 epidemiological studies world-wide have examined cancer incidences in children near nuclear power plants (NPPs): most of them indicate leukemia increases. These include the 2008 KiKK study commissioned by the German Government which found relative risks (RR) of 1.6 in total cancers and 2.2 in leukemias among infants living within 5 km of all German NPPs. The KiKK study has retriggered the debate as to the cause(s) of these increased cancers. A suggested hypothesis is that the increased cancers arise from radiation exposures to pregnant women near NPPs. However any theory has to account for the >10,000 fold discrepancy between official dose estimates from NPP emissions and observed increased risks. An explanation may be that doses from spikes in NPP radionuclide emissions are significantly larger than those estimated by official models which are diluted through the use of annual averages. In addition, risks to embryos/fetuses are greater than those to adults and haematopoietic tissues appear more radiosensitive in embryos/fetuses than in newborn babies. The product of possible increased doses and possible increased risks per dose may provide an explanation. PMID- 24054084 TI - Impact of environmental conditions on the suitability of microconstituents as markers for determining nutrient loading from reclaimed water. AB - Nitrogen and phosphorous loading into waterways from designated beneficial uses of reclaimed water is a growing concern in many parts of the United States. Numerous studies have documented that organic microconstituents present in the reclaimed water can be utilized as indicators of its influence on surface water bodies. However, little to no information is available on the environmental attenuation of these microconstituents relative to the nutrients, which is a critical component in determining the effectiveness or limitations of those markers as a tool for elucidating their origins. In this study, the stability of selected markers (sucralose, carbamazepine, gadolinium anomaly, iohexol, and atenolol) was evaluated through bench-scale studies designed to simulate environmental conditions associated with biodegradation, adsorption, and photolysis. The primary pathway for nitrogen reduction was biodegradation (greater than 99%) while the highest phosphorous removal was due to adsorption (30-80%). Soils with low organic content were selected for this study. Sucralose was the most recalcitrant microconstituent in the environment with less than 15% removal by adsorption, biodegradation, or photolysis. Iohexol was too susceptible to photolysis (90% removal), and atenolol was susceptible to biodegradation (60 80% removal). Gd anomaly was fairly stable (less than 30% removal) in the environment. Carbamazepine was another efficacious marker for wastewater, but was susceptible (50% removal) to photolysis. Of the selected microconstituents, only atenolol showed any similarity with the attenuation observed for nitrate and none of the microconstituents showed any similarity with the attenuation observed for phosphorus. PMID- 24054085 TI - Coverage of intermittent preventive treatment and insecticide-treated nets for the control of malaria during pregnancy in sub-Saharan Africa: a synthesis and meta-analysis of national survey data, 2009-11. AB - BACKGROUND: Pregnant women in malaria-endemic countries in sub-Saharan Africa are especially vulnerable to malaria. Recommended prevention strategies include intermittent preventive treatment with two doses of sulfadoxine-pyrimethamine and the use of insecticide-treated nets. However, progress with implementation has been slow and the Roll Back Malaria Partnership target of 80% coverage of both interventions by 2010 has not been met. We aimed to review the coverage of intermittent preventive treatment, insecticide-treated nets, and antenatal care for pregnant women in sub-Saharan Africa and to explore associations between coverage and individual and country-level factors, including the role of funding for malaria prevention. METHODS: We used data from nationally representative household surveys from 2009-11 to estimate coverage of intermittent preventive treatment, use of insecticide-treated nets, and attendance at antenatal clinics by pregnant women in sub-Saharan Africa. Using demographic data for births and published data for malaria exposure, we also estimated the number of malaria exposed births (livebirths and stillbirths combined) for 2010 by country. We used meta-regression analysis to investigate the factors associated with coverage of intermittent preventive treatment and use of insecticide-treated nets. RESULTS: Of the 21.4 million estimated malaria-exposed births across 27 countries in 2010, an estimated 4.6 million (21.5%, 95% CI 19.3-23.7) were born to mothers who received intermittent preventive treatment. Insecticide-treated nets were used during pregnancy for 10.5 million of 26.9 million births across 37 countries (38.8%, 34.6-43.0). Antenatal care was attended at least once by 16.3 of 20.8 million women in 2010 (78.3%, 75.2-81.4; n=26 countries) and at least twice by 14.7 of 19.6 million women (75.1%, 72.9-77.3; n=22 countries). For the countries with previous estimates for 2007, coverage of intermittent preventive treatment increased from 13.1% (11.9-14.3) to 21.2% (18.9-23.5; n=14 countries) and use of insecticide-treated nets increased from 17.9% (15.1-20.7) to 41.6% (37.2-46.0; n=24 countries) in 2010. A fall in coverage by more than 10% was seen in two of 24 countries for intermittent preventive treatment and in three of 30 countries for insecticide-treated nets. High disbursement of funds for malaria control and a long time interval since adoption of the relevant policy were associated with the highest coverage of intermittent preventive treatment. High disbursement of funds for malaria control and high total fertility rate were associated with the greatest use of insecticide-treated nets, whereas a high per-head gross domestic product (GDP) was associated with less use of nets than was a lower GDP. Coverage of intermittent preventive treatment showed greater inequity overall than use of insecticide-treated nets, with richer, educated, and urban women more likely to receive preventive treatment than their poorer, uneducated, rural counterparts. INTERPRETATION: Although coverage of intermittent preventive treatment and use of insecticide-treated nets by pregnant women has increased in most countries, coverage remains far below international targets, despite fairly high rates of attendance at antenatal clinics. The effect of the implementation of WHO's 2012 policy update for intermittent preventive treatment, which aims to simplify the message and align preventive treatment with the focused antenatal care schedule, should be assessed to find out whether it leads to improvements in coverage. FUNDING: Bill & Melinda Gates Foundation. PMID- 24054086 TI - Malaria in pregnancy: increasing access and improving delivery of interventions. PMID- 24054087 TI - Cultural imperatives and the ethics of verbal autopsies in rural Ghana. AB - BACKGROUND: Due to a paucity of statistics from vital registration systems in developing countries, the verbal autopsy (VA) approach has been used to obtain cause-specific mortality data by interviewing lay respondents on the signs and symptoms experienced by the deceased prior to death. In societies where the culture of mourning is adhered to, the use of VA could clash with traditional norms, thus warranting ethical consideration by researchers. OBJECTIVE: The study was designed to explore the ethics and cultural context of collecting VA information through a demographic and health surveillance system in the Kassena Nankana District (KND) of Ghana. STUDY DESIGN: Data were collected through qualitative in-depth interviews (IDIs) with four field staff involved in the routine conduct of VAs, four physicians who code VAs, 20 selected respondents to the VA tool, and eight opinion leaders in the KND. The interviews were supplemented with observation by the researchers and with the field notes of field workers. Interviews were audio-recorded, and local language versions transcribed into English. Thematic analysis was performed using QSR NVivo 8 software. RESULTS: The data indicate that cultural sensitivities in VA procedures at both the individual and family levels need greater consideration not only for ethical reasons but also to ensure the quality of the data. Discussions of some deaths are culturally prohibited and therefore lead to refusal of interviews. Families were also concerned about the confidentiality of information because of the potential of blame for the death. VA teams do not necessarily engage in culturally appropriate bereavement practices such as the presentation of tokens. The desire by families for feedback on the cause of death, which is currently not provided by researchers, was frequently expressed. Finally, no standard exists on the culturally acceptable time interval between death and VA interviews. CONCLUSION: Ethical issues need to be given greater consideration in the collection of cause of death data, and this can be achieved through the establishment of processes that allow active engagement with communities, authorities of civil registrations, and Institutional Review Boards to take greater account of local contexts. PMID- 24054088 TI - Self-reported prevalence of chronic non-communicable diseases and associated factors among older adults in South Africa. AB - INTRODUCTION: Little is known about the prevalence and predictors of chronic non communicable diseases (NCDs) of older adults in South Africa. This study aims to investigate the self-reported prevalences of major chronic NCDs and their predictors among older South Africans. METHODS: We conducted a national population-based cross-sectional survey with a sample of 3,840 individuals aged 50 years or above in South Africa in 2008. The outcome variable was the self reported presence of chronic NCDs suffered, namely, arthritis, stroke, angina, diabetes, chronic lung disease, asthma, depression, and hypertension. The exposure variables were sociodemographic characteristics: age, gender, education, wealth status, race, marital status, and residence. Multivariate logistic regression was used to determine sociodemographic factors predictive of the presence of chronic NCDs. RESULTS: The prevalence of chronic NCDs was 51.8%. The prevalence of multimorbidity (>=2 chronic conditions) was 22.5%. Multivariate logistic regression analysis showed that being female, being in age groups 60-79 and 70-79, being Coloured or Asian, having no schooling, having greater wealth, and residing in an urban area were associated with the presence of NCDs. CONCLUSION: The rising burden of chronic NCDs affecting older people places a heavy burden on the healthcare system as a result of increased demand and access to healthcare services. Concerted effort is needed to develop strategies for the prevention and management of NCDs, especially among economically disadvantaged individuals who need these services the most. PMID- 24054089 TI - Evaluation of antibacterial, antifungal and cytotoxic effects of Holothuria scabra from the North Coast of the Persian Gulf. AB - Bioactive compounds of the gonad, respiration tree, and body wall of the sea cucumber Holothuria scabra collected from the North Coast of the Persian Gulf were extracted using ethyl acetate, methanol and water-methanol mixtures. Extracts were evaluated for their antibacterial and antifungal activities against Aspergillus niger, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli. The activity was determined using the disc diffusion test. Cytotoxic activities of the extracts were determined by brine shrimp lethality assay. Results showed the existence of an antifungal activity of all extracts against A. niger with MIC ranging from 3 to 9MUg/mL. The highest antifungal activity was found in respiration tree (methanol) with an inhibition zone of about 50mm against A. niger at 18MUg/mL extract concentration. Cytotoxic activity was obtained for methanolic extracts only. Methanol extract of the gonads showed the highest cytotoxic effect (LC50=50.5MUg/mL) continuing with RT methanol extract (LC50=70MUg/mL). PMID- 24054090 TI - In vivo and in vitro expression pattern of Toll-like receptors in Mycobacterium avium subspecies paratuberculosis infection. AB - Johne's disease (JD) caused by Mycobacterium avium subspecies paratuberculosis (MAP) is a chronic infectious disease of ruminants. Activation of the Toll-like receptors (TLR) in response to microbial stimuli, including MAP, initiates responses in immune cells of the blood and within peripheral tissues. TLR2, 4 and 9 are believed to play a critical role in the initiation of immune responses against mycobacteria. In this study we report on the in vivo expression pattern of these receptors in sheep and cattle experimentally exposed to MAP. Experiments using the mouse macrophage cell line, RAW 264.7, and on isolated bovine monocytes were also carried out to assess the expression pattern of TLR2 and 4 in response to MAP and the non-pathogenic mycobacterial strain, M. smegmatis. Results from the in vivo study showed that there was a significant upregulation of TLR2 (P<0.05) at early time-points post-inoculation in the peripheral blood cells of sheep exposed to MAP S strain that went on to develop severe (multibacillary) disease. However, in the cattle during the initial months post-exposure to MAP C strain, TLR2 was significantly downregulated (P<0.05). TLR4 was significantly upregulated (P<0.05) at later stages (12 months post-inoculation) in MAP-exposed sheep with multibacillary disease; however significant differences in TLR4 expression were not observed in cattle. Expression of TLR9 was unchanged in MAP exposed sheep and cattle. In vitro studies on mouse macrophages supported the findings of in vivo TLR2 gene expression increases seen in the sheep, in that the TLR2 receptor expression in response to MAP-infection was significantly increased in comparison to cells infected with a non-virulent mycobacterium, M. smegmatis. A likely role for TLR2 in the pathogenesis of Johne's disease is proposed. PMID- 24054091 TI - A new tetravalent canine leptospirosis vaccine provides at least 12 months immunity against infection. AB - A key success factor in the vaccination of dogs against leptospirosis is long term protection against establishment of the renal carrier state, in order to protect other dogs, as well as humans, against this re-emerging zoonotic disease. In this paper, we describe the ability of a new European tetravalent vaccine containing antigen from Leptospira interrogans (sensu lato) serogroups Icterohaemorrhagiae, Canicola, Grippotyphosa and Australis to control infection and renal excretion in dogs at 12 months after vaccination. In order to demonstrate the efficacy of all four vaccine components, four separate challenge studies were performed. For each study two groups of dogs were used (a group receiving the leptospirosis vaccine and a control group). Twelve months after the second vaccination all dogs in the vaccine and control groups were challenged, both intraperitoneally and conjunctivally, using a pathogenic challenge strain from one of four serogroups. Parameters recorded post-challenge were: clinical signs of disease, change in body temperature, total leucocyte count, thrombocyte count, presence of challenge organisms in blood, urine and kidney tissue, and evidence of interstitial nephritis at necropsy four weeks after challenge. The vaccine was able to either prevent or significantly reduce infection following challenge with the strains of all four serogroups. The vaccine was also able to prevent or significantly reduce renal infection following Canicola and Icterohaemorrhagiae challenge, and there was a trend of reduction of renal infection with Australis (serovar Bratislava). In the case of the Grippotyphosa study, challenge led to no detectable renal infection in any dog of the control group. In conclusion, in this study significant protective immunity was achieved in dogs 12 months after a basic vaccination schedule of two doses against strains of serogroups Canicola, Icterohaemorrhagiae, Grippotyphosa and Australis. PMID- 24054092 TI - Apoptosis of lymph node and peripheral blood cells in ovine Johne's disease. AB - Ovine Johne's disease (OJD) is a degenerative wasting condition of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). Similar to other pathogenic mycobacterial infections it is a slow-progressing chronic disease and subclinically infected individuals can spread the disease while appearing healthy. MAP infects macrophages and the host responds by mounting a cell mediated immune response. Disease progression is associated with immune dysfunction but the reasons are unknown. Increasing our current knowledge of the immunological mechanisms involved in disease progression, including apoptotic responses, may allow advancements in the area of early diagnosis, identification of resistant animals and disease control. We describe lymphocyte apoptosis in peripheral blood mononuclear cells (PBMC) and lymph node cells from sheep exposed to MAP as well as from healthy non-exposed sheep. Apoptosis in intestinal lymph node cells from MAP-exposed infected sheep, but not in MAP-exposed uninfected sheep, increased in response to MAP antigen. In this first longitudinal study of lymphocyte apoptosis using an experimental infection model of MAP infection, we found that there was a transient increase of ex vivo PBMC apoptosis in MAP exposed sheep soon after exposure to MAP (4 months post inoculation). MAP antigen specific apoptosis occurred later, at 12 months post inoculation. The cells involved were mainly gammadelta and CD4(+) T cells. Antigen-mediated lymphocyte apoptosis during mycobacterial disease progression could contribute to the immune dysfunction in Johne's disease. PMID- 24054093 TI - Developmental disruption by binge-eating disorder and bulimia nervosa: critical windows for detection and intervention. PMID- 24054094 TI - Images in emergency medicine. Child with diarrhea and rash. Acrodermatitis enteropathica. PMID- 24054095 TI - Commentary: driving into the sunset. PMID- 24054096 TI - Change of shift. How may we serve? PMID- 24054097 TI - Annals of Emergency Medicine Journal Club. Observational health services studies using nationwide administrative data sets: understanding strengths and limitations of the National Hospital Ambulatory Medical Care Survey: answers to the May 2013 Journal Club questions. PMID- 24054098 TI - Images in emergency medicine. Man with rushing fluid from his umbilicus. Flood syndrome. PMID- 24054099 TI - The lytic lottery. PMID- 24054100 TI - In reply. PMID- 24054101 TI - A call to actions wisely chosen. PMID- 24054102 TI - In reply. PMID- 24054103 TI - Pragmatic interpretation of the study of nontraumatic subarachnoid hemorrhage in the setting of negative cranial computed tomography results: external validation of a clinical and imaging prediction rule. PMID- 24054104 TI - In reply. PMID- 24054105 TI - Sensitivity of computed tomography for subarachnoid hemorrhage. PMID- 24054106 TI - In reply. PMID- 24054107 TI - Disaster medical response. Policy statement. PMID- 24054108 TI - EMTALA and on-call responsibility for emergency department patients. Policy statement. PMID- 24054109 TI - Guidelines about the role of physician assistants and advanced practice registered nurses in the emergency department. PMID- 24054110 TI - Providers of unsupervised emergency department care. Policy statement. PMID- 24054111 TI - Public training in cardiopulmonary resuscitation and public access defibrillation. Policy statement. PMID- 24054112 TI - Handling of hazardous materials. Policy statement. PMID- 24054113 TI - Support for National Disaster Medical System and other response teams. Policy statement. PMID- 24054114 TI - School bus safety. Policy statement. PMID- 24054115 TI - Emergency ambulance destination. Policy statement. PMID- 24054116 TI - Medical services coding. Policy statement. PMID- 24054117 TI - EMS regionalization of care. Policy statement. PMID- 24054118 TI - Out-of-hospital 12-lead ECG. Policy statement. PMID- 24054119 TI - Early defibrillation programs. Policy statement. PMID- 24054120 TI - The thermodynamic basis for the use of lipophilic efficiency (LipE) in enthalpic optimizations. AB - Approaches to improve the efficiency of molecular optimizations have received great attention and numerous efficiency metrics have been introduced to assist in this effort. Optimization of properties is equally important to optimization of potency and therefore these metrics contain potency versus property calculations. Widespread use of a metric does not guarantee its accuracy and a further understanding of which, if any, metric increases the probability of success was sought. An analysis of LE, LELP and LipE based on theoretical and experimental data was performed demonstrating that LipE most strongly correlates with compound quality as defined by enthalpy-driven binding. The basis for the prioritization of LipE over other metrics in enthalpic optimizations is described. PMID- 24054121 TI - The binding of okadaic acid analogs to recombinant OABP2.1 originally isolated from the marine sponge Halichondria okadai. AB - The binding between [24-(3)H]okadaic acid (OA) and a recombinant OA binding protein OABP2.1 was examined using various OA analog, including methyl okadaate, norokadanone, 7-deoxy OA, and 14,15-dihydro OA, 7-O-palmitoyl DTX1, to investigate the structure activity relationship. Among them, 7-O-palmitoyl DTX1, which is one of the diarrhetic shellfish poisoning (DSP) toxins identified in shellfish, displayed an IC50 for [24-(3)H]OA binding at 51+/-6.3nM (Mean+/-SD). In addition, a synthetic compound, N-pyrenylmethyl okadamide, exhibited its IC50 at 10+/-2.9nM (Mean+/-SD). These results suggested that the recombinant OABP2.1 and the N-pyrenylmethyl okadamide might be core substances in a novel assay for the DSP toxins. PMID- 24054122 TI - Synthesis and biological evaluation of a new series of N-ylides as protein farnesyltransferase inhibitors. AB - A new family of 30 benzoylated N-ylides 4 and 5 was synthesized and evaluated for the inhibitory activity on human protein farnesyltransferase. Most of these novel compounds possessed in vitro inhibition potencies in the micromolar range. The nature of the substituents on the pyridine and phenyl units proved to be important in determining inhibitory activity and generally, the replacement of the cyanoacrylonitrile function by a cyanoethylacrylate group decreased the biological potential on farnesyltransferase. These results completed our SAR study on this original class of N-ylides. PMID- 24054123 TI - Potent inhibition of norovirus by dipeptidyl alpha-hydroxyphosphonate transition state mimics. AB - The design, synthesis, and evaluation of a series of dipeptidyl alpha hydroxyphosphonates is reported. The synthesized compounds displayed high anti norovirus activity in a cell-based replicon system, as well as high enzyme selectivity. PMID- 24054124 TI - Pressurized liquid extraction of polycyclic aromatic hydrocarbons from silicone rubber passive samplers. AB - Silicone rubber passive samplers effectively concentrate organic contaminants from water and are simple-to-use and robust. However, during the extraction of analytes from the samplers with organic solvents, oligomers associated with the rubber are inevitably extracted and this creates analytic challenges. Additionally, extraction methods that use Soxhlet or shaking are time-consuming and use large volumes of solvent. We evaluated a new method for the extraction of polycyclic aromatic hydrocarbons from silicone rubber passive samplers that uses pressurized liquid extraction with gel permeation chromatography. Extraction with dichloromethane at 100 degrees C provided better recoveries compared to that of 50 degrees C. The recoveries of 14 individual PAHs ranged from 81% to 102% and the mean recovery was 93% (standard deviation=7). Relative to comparable methods in which Soxhlet or shaking were used for the extraction, this method uses considerably less solvent and time. PMID- 24054125 TI - Determination of total and unbound warfarin and warfarin alcohols in human plasma by high performance liquid chromatography with fluorescence detection. AB - Two analytical procedures are presented for the determination of the total content and unbound fraction of both warfarin and warfarin alcohols in human plasma. Chromatographic separation was carried out in isocratic conditions at 25 degrees C on a C-18 reversed-phase column with a mobile phase consisting of a 70% buffer phosphate 25mM at pH=7, 25% methanol and 5% acetonitrile at a flow rate of 1.2mL/min. Fluorescence detection was performed at 390nm (excitation wavelength 310nm). Neither method showed any detectable interference or matrix effect. Inter day recovery of the total warfarin and warfarin alcohols at a concentration level of 1000ng/mL was 89+/-3% and 73+/-3%, respectively, whereas for their unbound fraction (at a concentration level of 10ng/mL) was 66+/-8% and 90+/-7%, respectively. The intra- and inter-day precision (assessed as relative standard deviation) was <10% for both methods. The limits of detection were 0.4 and 0.2ng/mL for warfarin and warfarin alcohols, respectively. The methods were successfully applied to a pooled plasma sample obtained from 69 patients undergoing warfarin therapy. PMID- 24054126 TI - On-target titanium dioxide-based enrichment for characterization of phosphorylations in the Adenovirus pIIIa protein. AB - A recently developed titanium dioxide (TiO2) based on-target method for phosphopeptide enrichment and matrix assisted laser desorption-ionization mass spectrometry (MALDI MS) analysis was used to investigate phosphorylations in the Adenovirus type 2 structural protein pIIIa. Lysates of purified virus particles were separated on 1-D SDS-PAGE and the band for the pIIIa protein was excised for tryptic digestion into peptides that were enriched with the on-target method. The enrichment provided by the method clearly improved the detectability of phosphorylated peptides and the results show for the first time evidence for multi-phosphorylated peptides in pIIIa. Moreover, three novel phosphorylations were identified in the protein sequence, even though the precise positions could not be determined. These results illustrate the potential of the method for the characterization of novel phosphoproteomes in biological samples of medical relevance. PMID- 24054127 TI - Bladder capacity as a predictor of voided continence after failed exstrophy closure. AB - OBJECTIVE: To evaluate potential predictors of voided continence among bladder exstrophy patients with a history of a failed closure. PATIENTS AND METHODS: The authors reviewed all patients who underwent a bladder neck reconstruction (BNR) with a history of one or more failed exstrophy closures between 1979 and 2007. The following data were collected for each patient: number of failures, site of surgery, mode of failure, presence of osteotomy, bladder capacity, need for additional procedures, and continence status. RESULTS: Among patients who underwent successful reclosure following one or more failed closures, 52 patients underwent BNR, and 24 (46%) were continent at last follow-up. Bladder capacity was the only variable predictive of voided continence. The median bladder capacity at the time of BNR differed between those who achieved continence (100 mL) and those who did not (65 mL) (p = 0.005). ROC analysis showed an optimal pre BNR bladder capacity cutoff for predicting future BNR success of between 80 and 100 mL. CONCLUSION: As previously shown in patients with successful primary closure of exstrophy, these data suggest that bladder capacity also has predictive value in the success of BNR after failed exstrophy closure. PMID- 24054128 TI - Dickkopf-1 is a key regulator of myeloma bone disease: opportunities and challenges for therapeutic intervention. AB - Myeloma bone disease (MBD) is the most visible aspect of plasma cell myeloma (PCM), which is characterized by the displacement of hematopoiesis and the formation of osteolytic bone lesions. The secreted glycoprotein Dickkopf-1 (DKK1), an inhibitor of the Wnt signaling pathway, is broadly expressed in myeloma cells but highly restricted in normal tissues. DKK1 plays a critical role in several aspects of bone biology and actively participates in regulating MBD by inhibiting osteoblasts and by activating osteoclasts. Based on these findings, ongoing research has been targeting DKK1 to find novel therapeutic strategies for MBD, such as DKK1-neutralizing antibodies, proteasome inhibitors, and vaccines. All these strategies have produced encouraging clinical results and consequently, revealed the significance of DKK1 in MBD. This review discusses the recent advances in our understanding of the DKK1 pathway signaling and how DKK1 can be exploited in the therapeutic intervention of MBD. PMID- 24054129 TI - Imaging findings of spontaneous bilateral renal artery dissection. AB - Bilateral spontaneous renal artery dissection is extremely rare with computed tomography angiography being an efficient noninvasive alternative to catheter angiography for its diagnosis. We report the case of a 65-year-old woman with bilateral spontaneous renal artery dissection resulting in bilateral renal infarctions and hydroureteronephrosis. PMID- 24054130 TI - Deep lateral transurethral incisions for recurrent bladder neck contracture: promising 5-year experience using a standardized approach. AB - OBJECTIVE: To evaluate our 5-year experience with deep lateral transurethral incisions of bladder neck contracture (TUIBNC), identify risk factors associated with failure of procedure, and assess outcomes of men subsequently treated for concomitant or de novo stress urinary incontinence (SUI). MATERIALS AND METHODS: We reviewed 50 consecutive patients who underwent TUIBNC between June 2007 and January 2012. TUIBNC was standardized to include initial dilation followed by deep transurethral incisions. All patients were evaluated cystoscopically after a 2-month interval; those with recurrent bladder neck contracture (RBNC) underwent a second TUIBNC. For patients with concomitant SUI, we assessed the timing between TUIBNC and subsequent artificial urinary sphincter (AUS) placement and its outcome. Perioperative characteristics were reviewed to identify factors associated with failure. RESULTS: Of the 50 patients analyzed, most were refractory, 78% having failed previous TUIBNC. After TUIBNC, 72% required no further surgery for obstruction at a mean follow-up of 12.9 months. Of the 14 who failed initial TUIBNC, 7 underwent repeat TUIBNC with success, representing an overall success rate of 86% after 2 procedures. Significant factors associated with treatment failure were >10 pack/year smoking history (P = .039) and >= 2 previous endoscopic BNC procedures (P = .03). Of 39 men (78%) with concomitant SUI, two-thirds underwent AUS placement after an average of 2.9 months after TUIBNC. Only 2 of 26 (8%) patients required repeat transurethral procedures after AUS placement for RBNC. CONCLUSION: Deep lateral TUIBNC alone is a highly effective treatment modality for RBNC. Smokers and those having 2 or more previous transurethral procedures appear to have greater risk for failure. Subsequent AUS placement can be safely performed with >90% long-term urethral patency. PMID- 24054131 TI - Characterization of polychlorinated biphenyls and brominated flame retardants in sludge, sediment and fish from municipal dumpsite at Surabaya, Indonesia. AB - We investigated the PCBs, PBDEs and HBCDs contamination in sludge, sediments and fish from various locations including raw leachate pond, leachate treatment plans (LTPs), control wells and reference site at open landfill of municipal dumpsite, Surabaya City, Indonesia. 62 PCBs and 14 PBDEs congeners, and 3 HBCDs isomers were identified and quantified using GC-MS and LC-MS/MS, respectively. Concentration ranges and median (value in parentheses) of PCBs, PBDEs and HBCDs were from not detected (ND) to 60 (3.9) ng g(-1) dw, 0.0075 to 45 (4.5) ng g(-1) dw and ND to 2.8 (0.052) ng g(-1) dw in sludge and sediments, respectively. While in two polled of fish samples were 30-55 ng g(-1) lw, 6.6-11 ng g(-1) lw and 1.6 3.3 ng g(-1) lw, respectively. Among the sampling sites, the highest level of PCBs and PBDEs were detected in sludge from raw leachate pond. However, PCBs and PBDEs levels were showing decreased in LTP-1 that could be due to the bacterial degradation but not in LTP-2, HBCDs were more stable in both LTPs. Levels of PCBs and BFRs in sludge at the present study were lower than those reported in sewage sludge reported from some other countries. PCBs profiles were mainly composed in that order by CB-138, -153, -180, -101, -118 and -28, while by BDE-47, -99, -100, -153, -154 and -28 for PBDEs in sludge, sediments and fish. Profiles of HBCDs were predominantly composed by gamma- and alpha-isomers in sludge and fish, respectively. Debromination, dechlorination, commercial formulations used and congener-specific accumulation of those contaminants are the factors influenced the profiles. PMID- 24054132 TI - Soil attenuation of As(III, V) and Se(IV, VI) seepage potential at ash disposal facilities. AB - Leachate from ash landfills is frequently enriched with As and Se but their off site movement is not well understood. The attenuation potential of As and Se by soils surrounding selected landfills during leachate seepage was investigated in laboratory column studies using simulated ash leachate. As(III, V) and Se(IV, VI) concentrations as well as pH, flow rate, and a tracer were monitored in influent and effluent for up to 800 pore volumes followed by sequential desorption, extraction, and digestion of column segments. Column breakthrough curves (BTCs) were compared to predictions based on previously measured sorption isotherms. Early As(V) breakthrough and retarded As(III) breakthrough relative to predicted BTCs are indicative of oxidative transformation during seepage. For Se(VI), which exhibits linear sorption and the lowest sorption propensity, measured BTCs were predicted fairly well by equilibrium sorption isotherms, except for the early arrival of Se(IV) in one site soil, which in part, may be due to higher column pH values compared to batch isotherms. Most of the As and Se retained by soils during leaching was found to be strongly sorbed (60-90%) or irreversibly bound (10-40%) with <5% readily desorbable. Redox potential favoring transformation to the more sorptive valence states of As(V) and Se(IV) will invoke additional attenuation beyond equilibrium sorption-based predictions. With the exception of Se(IV) on one site soil, results indicate that attenuation by down-gradient soils of As and Se in ash landfill seepage will often be no less than what is predicted by equilibrium sorption capacity with further attenuation expected due to favorable redox transformation processes, thus mitigating contaminant plumes and associated risks. PMID- 24054133 TI - Remarkable efficiency of ultrafine superparamagnetic iron(III) oxide nanoparticles toward arsenate removal from aqueous environment. AB - Arsenates, when present in water resources, constitute a risk to human health. In order to remove them, various technologies have been developed; out of them, sorption approach is widely adopted employing a wide spectrum of suitable sorbent materials. Nanoparticles of iron oxide are frequently used due to a high surface area and ability to control them by external magnetic field. In this work, we report on a simple and cheap synthesis of ultrafine iron(III) oxide nanoparticles with a narrow size distribution and their exploitation in the field of arsenate removal from aqueous environment. It is shown that the adsorption capacity is enhanced by a mesoporous nature of nanoparticle arrangement in their system due to strong magnetic interactions they evolve between nanoparticles. A complete arsenate removal is achieved at Fe/As ratio equal to ~20/1 and at pH in the range from 5 to 7.6. Under these conditions, the arsenates are completely removed within several minutes of treatment. Among iron-oxide-based nanosystems synthesized and employed in arsenate remediation issues so far, our assembly of iron(III) oxide nanoparticles shows the highest Freundlich adsorption coefficient and equilibrium sorption capacity under conditions maintained. Taking into account simple and low-cost preparation procedure, product high yields, almost monodispersed character, room-temperature superparamagnetic behavior, and strong magnetic response under small applied magnetic fields, the synthesized iron(III) oxide nanoparticles can be regarded as a promising candidate for exploitation in the field of removing undesired toxic pollutants from various real water systems. PMID- 24054134 TI - Potential for in situ chemical oxidation of acid extractable organics in oil sands process affected groundwater. AB - The process of bitumen extraction from oil sands in Alberta, Canada leads to an accumulation of toxic acid-extractable organics (AEOs) in oil sands process water (OSPW). Infiltration of OSPW from tailings ponds and from their retaining sand dykes and subsequent transport towards surface water has occurred. Given the apparent lack of significant natural attenuation of AEOs in groundwater, remediation may be required. This laboratory study evaluates the potential use of unactivated persulfate and permanganate as in situ oxidation agents for remediation of AEOs in groundwater. Naphthenic acids (NAs; CnH2n+zO2), which are a component of the acutely toxic AEOs, were degraded by both oxidants in OSPW samples. Permanganate oxidation yielded some residual dissolved organic carbon (DOC) whereas persulfate mineralized the AEO compounds with less residual DOC. Acid-extractable organics from oxidized OSPW had essentially no Microtox toxicity. PMID- 24054135 TI - Impact of DNAPL contact on the structure of smectitic clay materials. AB - Smectitic clays have a flexible structure that may be impacted by contact with dense nonaqueous phase liquids (DNAPLs) present at hazardous waste sites. Measurements of the basal spacing of air-dry clays contacted with pure chlorinated solvents and chlorinated DNAPL wastes showed that the intraparticle spacing is similar to that in air. Basal spacings of water-saturated clays contacted with pure chlorinated solvents are similar to those in contact with water, even after extended equilibration times (300 d). In contrast, contact with chlorinated DNAPL wastes reduced the basal spacing of water-saturated sodium smectites in a relatively short time frame, resulting in cracks that were as large as 1mm in aperture. The penetration of these wastes into the intraparticle spacing of clay and the resultant cracking may contribute to the accumulation of chlorinated compounds in clay layers observed in the field and the extended remediation times associated with this mass storage. PMID- 24054136 TI - [Motivational interviewing use for promoting health behavior: an approach of doctor/patient relationship]. AB - Many situations in common medical practice, especially in chronic diseases, require patients to be mobilized for health behavior decisions: for daily intake of an antihypertensive drug, performing a mammography for cancer screening, as well as adopting new diet habits in diabetes. Ability to initiate a health behavior depends on several parameters. Some of them are related to the patient, his personality, his illness and treatment's perception; others directly rely on the physician, his attitude and his communication style during the visit, independently of patient's level of resistance to change. Motivational interviewing (MI) is a communication technique, first developed for patients presenting a substance abuse disorder, to explore their ambivalence, overcome their resistances and give them the willingness of a better self-care. Its general principles and basic techniques can be applied by every practitioner and deserve to be better known, given that scientific literature provides evidence for generalizing it in a variety of medical conditions, in structured patient education programs as well as in usual follow-up, for which time is generally restricted. This article provides an overview of MI recent applications and argues for its diffusion in everyday medical practice. PMID- 24054137 TI - Intracellular stability of tyrosine hydroxylase: phosphorylation and proteasomal digestion of the enzyme. AB - Tyrosine hydroxylase (TH), the rate-limiting enzyme in the biosynthesis of catecholamines, is a key protein involved in the pathogenesis of neurodegenerative diseases such as Parkinson's disease. Elucidation of the mechanisms regulating the synthesis, degradation, and activity of TH should be a first target in order to understand the role of this enzyme in pathogenesis. Recently, several reports suggest that the ubiquitin-proteasome pathway is a prerequisite for the degradation of TH and that the N-terminal part of TH plays a critical role in the degradation. In this report, we propose the mechanism by which the N-terminal part of TH regulates the degradation of this enzyme. Moreover, we integrate our findings with recent progress in other areas of TH regulation. PMID- 24054138 TI - Tyrosine hydroxylase: regulation by feedback inhibition and phosphorylation. AB - Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of the catecholamines dopamine, noradrenaline, and adrenaline. In response to short-term stimuli, TH activity is regulated by feedback inhibition by the catecholamines and relief of that inhibition by phosphorylation. This chapter examines the current understanding of these regulatory mechanisms and the roles that they play in different catecholaminergic cells. This chapter also examines hierarchical phosphorylation in TH and how it provides a mechanism for the differential regulation of the major human TH isoforms. PMID- 24054139 TI - GTP cyclohydrolase regulation: implications for brain development and function. AB - Tetrahydrobiopterin (BH4) is essential for the biosynthesis of dopamine, noradrenaline, and serotonin, which serve as cofactors for tyrosine hydroxylase (TH) and tryptophan hydroxylase. GTP cyclohydrolase (GCH) is the first and rate limiting enzyme for BH4 biosynthesis. Genetic defects in an allele of the GCH gene can result in dopa-responsive dystonia due to partial BH4 deficiency. To explore the transcriptional control of the GCH gene, we analyzed the signaling pathway. Bacterial lipopolysaccharide (LPS) greatly enhanced the expression of GCH in RAW264 cells, and the induction of GCH by LPS was suppressed by treatment with either a MEK1/2 inhibitor or an inhibitor for the NF-kappaB pathway. Next, we analyzed two types of biopterin-deficient transgenic mice. We found that both mice exhibited motor disorders with slight differences. Dopamine and TH protein levels were markedly and concurrently increased from birth (P0) to P21 in wild type mice, and these increases were abolished in both types of biopterin deficient mice. Our results suggest that the developmental manifestation of psychomotor symptoms in BH4 deficiency might be attributable at least partially to the high dependence of dopaminergic development on the availability of BH4. PMID- 24054140 TI - Brain neurons partly expressing dopaminergic phenotype: location, development, functional significance, and regulation. AB - In addition to catecholaminergic neurons possessing all the enzymes of catecholamine synthesis and the specific membrane transporters, neurons partly expressing the catecholaminergic phenotype have been found a quarter of a century ago. Most of them express individual enzymes of dopamine (DA) synthesis, tyrosine hydroxylase (TH), or aromatic l-amino acid decarboxylase (AADC), lacking the DA membrane transporter and the vesicular monoamine transporter, type 2. These so called monoenzymatic neurons are widely distributed throughout the brain in ontogenesis and adulthood being in some brain regions even more numerous than dopaminergic (DA-ergic) neurons. Individual enzymes of DA synthesis are expressed in these neurons continuously or transiently in norm and pathology. It has been proven that monoenzymatic TH neurons and AADC neurons are capable of producing DA in cooperation. It means that l-3,4-dihydroxyphenylalanine (l-DOPA) synthesized from l-tyrosine in monoenzymatic TH neurons is transported to monoenzymatic AADC neurons for DA synthesis. Such cooperative synthesis of DA is considered as a compensatory reaction under a failure of DA-ergic neurons, for example, in neurodegenerative diseases like hyperprolactinemia and Parkinson's disease. Moreover, l-DOPA, produced in monoenzymatic TH neurons, is assumed to play a role of a neurotransmitter or neuromodulator affecting the target neurons via catecholamine receptors. Thus, numerous widespread neurons expressing individual complementary enzymes of DA synthesis serve to produce DA in cooperation that is a compensatory reaction at failure of DA-ergic neurons. PMID- 24054141 TI - Granins and catecholamines: functional interaction in chromaffin cells and adipose tissue. AB - Catecholamines (CAs) and granin peptides are costored in dense-core vesicles within the chromaffin cells of the adrenal medulla and in other endocrine organs and neurons. Granins play a major functional and structural role in chromaffin cells but are ubiquitous proteins, which are present also in secretory cells of the nervous, endocrine, and immune systems, where they regulate a number of cellular functions. Furthermore, recent studies also demonstrate that granin derived peptides can functionally interact with CA to modulate key physiological functions such as lipolysis and blood pressure. In this chapter, we will provide a brief update on the interaction between CA and granins at the cellular and organ levels. We will first discuss recent data on the regulation of exocytosis of CA and peptides from the chromaffin cells by the sympathetic nervous system with a specific reference to the prominent role played by splanchnic nerve derived pituitary adenylate cyclase-activating peptide (PACAP). Secondly, we will discuss the role of granins in the storage and regulation of exocytosis in large dense-core vesicles. Finally, we will provide an up-to-date review of the roles played by two granin-derived peptides, the chromogranin A-derived peptide catestatin and the VGF-derived peptide TLQP-21, on lipolysis and obesity. In conclusion, the knowledge gathered from recent findings on the role played by proteins/peptides in the sympathetic/target cell synapses, discussed in this chapter, would contribute to and provide novel mechanistic support for an increased appreciation of the physiological role of CA in human pathophysiology. PMID- 24054142 TI - Interactions of neuropeptide y, catecholamines, and angiotensin at the vascular neuroeffector junction. AB - Work from our laboratory has established that angiotensin II (Ang II) produces a greater enhancement of the nerve stimulation (NS)-induced release (overflow) of both norepinephrine (NE) and neuropeptide Y (NPY) and a greater increase in perfusion pressure of the mesenteric arterial bed obtained from the spontaneously hypertensive rat (SHR) compared to age-matched Wistar-Kyoto (WKY) or Sprague Dawley rats. The enhancement of NS-induced NPY release was blocked by the AT1 receptor antagonist EMD 66684 and the AT2 receptor antagonist PD 123319. Both captopril and EMD 66684 decreased NPY and NE overflow from SHR mesenteric beds, suggesting an endogenous renin-angiotensin system (RAS) is active in the mesenteric artery. We also observed that the recently discovered new arm of the RAS, namely, angiotensin (1-7) (Ang-(1-7)), attenuated the NS-induced increase in NE and NPY release and the accompanied increased perfusion pressure. These inhibitory effects were greater in blood vessels obtained from SHR compared to WKY. We suggest that inhibition of sympathetic neurotransmission contributes to the mechanism(s) by which Ang-(1-7) acts to inhibit the vasoconstrictor effect of Ang II. Administration of the MAS receptor antagonist D-Ala(7)Ang-(1-7) attenuated the decrease in both NE and NPY release due to Ang-(1-7) administration. The AT2 receptor antagonist PD 123391 attenuated the effect of Ang-(1-7) on NE release without affecting the decrease in NPY release. We observed a shift in the balance between Ang II and Ang-(1-7) levels in the SHR with an increase in Ang II and a decrease in Ang-(1-7) in the blood and mesenteric artery. This appears to be due to an increase in angiotensin converting enzyme (ACE) in the mesenteric artery of the SHR. PMID- 24054143 TI - Neural circuit mechanism for learning dependent on dopamine transmission: roles of striatal direct and indirect pathways in sensory discrimination. AB - The dorsal striatum in basal ganglia circuit mediates learning processes contributing to instrumental motor actions. The striatum receives excitatory inputs from many cortical areas and the thalamic nuclei and dopaminergic inputs from the ventral midbrain and projects to the output nuclei through direct and indirect pathways. The neural mechanism remains unclear as to how these striatofugal pathways control the learning processes of instrumental actions. Here, we addressed the behavioral roles of the two striatofugal pathways in the performance of sensory discrimination by using immunotoxin (IT)-mediated cell targeting. IT targeting of the striatal direct pathway in mutant mice lengthened the response time but did not affect the accuracy of the response selection in visual discrimination. Subregion-specific pathway targeting revealed a delay in motor responses generated by elimination of the direct pathway arising from the dorsomedial striatum (DMS) but not from the dorsolateral striatum (DLS). These findings indicate that the direct pathway, in particular that from the DMS, contributes to the regulation of the response time in visual discrimination. In addition, IT targeting of the striatal indirect pathway originating from the DLS in transgenic rats impaired the accuracy of response selection in auditory discrimination, whereas the response time remained normal. These data demonstrate that the DLS-derived indirect pathway plays an essential role in the control of the selection accuracy of learned motor responses. Our results suggest that striatal direct and indirect pathways act cooperatively to regulate the selection accuracy and response time of learned motor actions in the performance of discriminative learning. PMID- 24054144 TI - Selective ablation of dopamine beta-hydroxylase neurons in the brain by immunotoxin-mediated neuronal targeting: new insights into brain catecholaminergic circuitry and catecholamine-related diseases. AB - The locus coeruleus (LC) has been implicated in a variety of physiological functions including sleep/wakefulness, cognition/memory, stress/emotion, and pain. Marked loss of LC-noradrenergic (NAergic) neurons is observed in autopsy specimens of patients with Alzheimer's disease and Parkinson's disease (PD), and part of the clinical symptoms of these diseases may be related to dysfunction of the LC. Neurotoxins have been utilized to ablate LC-NAergic neurons in experimental animals for elucidating the pathophysiological implication of the loss of LC, but there are methodological drawbacks in previously utilized methods. We employed immunotoxin-mediated neuronal targeting to overcome these problems. Following complete disruption of the LC-NAergic neurons by immunotoxin, mice showed behavioral changes, which resembled the nonmotor symptoms of PD. The LC-NAergic neurons did not regenerate following ablation, so the immunotoxin mediated neuronal targeting may be useful especially for studying the long-term effects of the loss of LC-NAergic neurons on brain functions. PMID- 24054146 TI - The enduring centrality of dopamine in the pathophysiology of schizophrenia: in vivo evidence from the prodrome to the first psychotic episode. AB - Dopamine has been thought to be central to the pathophysiology of schizophrenia for the last four decades. However, the last decade or so has seen a considerable advance in understanding of dopamine's role in the neurobiology of schizophrenia. This has been informed by advances in neuroimaging, preclinical models, and the study of the prodrome to schizophrenia. Studies using these approaches have identified that the major locus of dopaminergic dysfunction is presynaptic, characterized by elevated dopamine synthesis and release capacity. Moreover, this is seen in the prodrome to the illness, is linked to the symptoms, and increases with the onset of frank symptoms. It has also become clear that there is no marked alteration in dopamine transporter or D2/3 receptor availability in schizophrenia in general, and, similarly, there do not seem to be D2/3 receptor alterations in people at high clinical risk of psychosis. These findings highlight the enduring role of dopamine in the onset of schizophrenia. They suggest that presynaptic dopamine dysregulation underlies the onset of psychosis and are in line with an integrative model accounting for many of the genetic and environmental risk factors for schizophrenia. PMID- 24054145 TI - Catecholamine/Serotonin interactions: systems thinking for brain function and disease. AB - This chapter brings together the work of several leading laboratories, each an outstanding example of integrative approaches to complex diseases of the central nervous system. Cognitive dysfunction and negative symptoms associated with schizophrenia are believed to result from hypofunction of the mesocortical dopaminergic projections to prefrontal cortex (PFC). Noradrenergic targets for the augmentation of dopaminergic function in PFC show promise to improve cognitive deficits as well as negative symptoms. Serotonergic targets for the modulation of mesocortical dopaminergic neurotransmission include 5-HT2A and 5 HT1A receptors. The hallmark of Parkinson's disease is the destruction of nigrostriatal dopaminergic neurons. l-DOPA, a metabolic precursor of dopamine, is the standard of treatment. However, the ectopic release of dopamine (DA) from serotonin neurons and the clearance of extracellular DA by the norepinephrine transporter in areas enriched with noradrenergic terminals contribute to extracellular DA produced by l-DOPA and offer opportunities to improve l-DOPA therapy. The high-affinity transporters for monoamines are the primary targets for antidepressant drugs. However, many patients experience suboptimal therapeutic benefit or fail to respond to treatment. Organic cation transporters and plasma membrane monoamine transporter serve an important function in regulating monoamine neurotransmission and hold potential utility as targets for the development of therapeutic drugs. Improved therapeutic approaches will arise from not only understanding how monoamines influence one another within the central nervous system as an integrated whole but also addressing the pathophysiology of specific core symptoms or distinct syndromal dimensions (cognitive impairment, motor slowing, and negative affect) regardless of disease classification, for example, psychotic, affective, and neurodegenerative. PMID- 24054147 TI - Catecholamine metabolites affected by the copper-dependent enzyme dopamine-beta hydroxylase provide sensitive biomarkers for early diagnosis of menkes disease and viral-mediated ATP7A gene therapy. AB - Menkes disease is a lethal X-linked recessive disorder of copper metabolism caused by mutations in ATP7A, a copper-transporting ATPase with diverse and important biological functions. Partial deficiency of dopamine-beta-hydroxylase is a biochemical hallmark of this illness due to the normal role of ATP7A in delivery of copper as an enzymatic cofactor. We exploited this fact to develop a diagnostic test for Menkes disease, which proved highly sensitive and specific. The assay has enabled early identification of affected patients, leading to enhanced survival and improved neurodevelopment after early copper treatment, including some completely normal outcomes. In preclinical efforts to develop improved therapies for patients with non-copper-responsive ATP7A mutations, we used brain-directed adeno-associated viral gene therapy to rescue a murine model of the disease. Statistically significant improvement in brain catechol ratios correlated with enhanced survival, and cerebrospinal fluid catechols represent candidate surrogate markers of treatment effect in a future gene therapy clinical trial. PMID- 24054148 TI - Biomarkers, mechanisms, and potential prevention of catecholamine neuron loss in Parkinson disease. AB - This chapter is on biomarkers, mechanisms, and potential treatment of catecholamine neuron loss in Parkinson disease (PD). PD is characterized by a movement disorder from loss of nigrostriatal dopamine neurons. An intense search is going on for biomarkers of the disease process. Theoretically, cerebrospinal fluid (CSF) levels of the deaminated DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), should be superior to other neurochemical indices of loss of central dopamine. CSF DOPAC is low in PD-even in patients with recent onset of Parkinsonism. Cardiac norepinephrine depletion is as severe as the loss of putamen dopamine. PD importantly involves nonmotor manifestations, including anosmia, dementia, REM behavior disorder, and orthostatic hypotension, and all of these nonmotor features are associated with neuroimaging evidence for cardiac sympathetic denervation, which seems to occur independently of the movement disorder and striatal dopaminergic lesion. Analogy to a bank robber's getaway car conveys the catecholaldehyde hypothesis, according to which buildup of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), the immediate product of the action of monoamine oxidase on cytosolic dopamine, causes or contributes to the death of dopamine neurons. Decreased vesicular uptake of dopamine and decreased DOPAL detoxification by aldehyde dehydrogenase (ALDH) determine this buildup. Vesicular uptake is also markedly decreased in the heart in PD. Multiple factors influence vesicular uptake and ALDH activity. Evidence is accruing for aging-related induction of positive feedback loops and an autotoxic final common pathway in the death of catecholamine neurons, mediated by metabolites produced continuously in neuronal life. The catecholaldehyde hypothesis also leads to testable experimental therapeutic ideas. PMID- 24054149 TI - AADC deficiency: occurring in humans, modeled in rodents. AB - Aromatic l-amino acid decarboxylase (AADC) is a homodimeric pyridoxal phosphate dependent enzyme responsible for the syntheses of dopamine and serotonin. Defects in the AADC gene result in neurotransmitter deficiencies. Patients with AADC deficiency have severe motor and autonomic dysfunctions. A mouse model of AADC deficiency was recently established. These mice grow poorly and move awkwardly during infancy. They also show high anxiety when they grow up. Because drug therapy provides little or no benefit for many patients with AADC deficiency, a gene therapy has been attempted. The gene therapy employed an adeno-associated virus viral vector that can express the human AADC protein. The vector was injected to the brain of several children with AADC deficiency. The therapy was well tolerated, and all treated patients showed improvement. In the future, the mouse model will also help the development of treatments for AADC deficiency. PMID- 24054152 TI - Catecholamine receptors: prototypes for GPCR-based drug discovery. AB - Drugs acting at G protein-coupled receptors (GPCRs) constitute ~40% of those in current clinical use. GPCR-based drug discovery remains at the forefront of drug development, especially for new treatments for psychiatric illness and neurological disease. Here, the basic framework of GPCR signaling learned through the elucidation of catecholamine receptor signaling through G proteins and beta arrestins, and X-ray crystallographic structure determination is reviewed. In silico docking studies developed in tandem with confirmatory empirical data gathering from binding and signaling experiments have allowed this basic framework to be expanded to drug hunting through predictive in silico searching as well as high-throughput and high-content screening approaches. For efforts moving forward for the deployment of new GPCR-acting drugs, collaborative efforts between industry and government/academic research in target validation at the molecular and cellular levels have become progressively more common. Polypharmacological approaches have become increasingly available for learning more about the mechanisms of GPCR-targeted drugs, based on interaction not with a single, but with a wide range of GPCR targets. These approaches are likely to aid in drug repurposing efforts, yield valuable insight on the side effects of currently employed drugs, and allow for a clearer picture of the actual targets of "atypical" drugs used in a variety of therapeutic contexts. PMID- 24054151 TI - Localization and expression of VMAT2 aross mammalian species: a translational guide for its visualization and targeting in health and disease. AB - VMAT2 is the vesicular monoamine transporter that allows DA, NE, Epi, His, and 5 HT uptake into neurons and endocrine cells. A second isoform, VMAT1, has similar structure and function, but does not recognize histamine as a substrate. VMAT1 is absent from neurons, and its major function appears to be in endocrine cells, that is, enterochromaffin cells, which scavenge 5-HT, but not histamine, from dietary sources. This chapter provides an update on the neuroanatomical distribution of VMAT2 across various mammalian species, including human, primate, pig, rat, and mouse. When necessary, VMAT1 expression is provided as a contrast. The main purpose of this chapter is to allow clinicians, in particular endocrinologists and diagnosing neuroradiologists and neuropathologists, an acquaintanceship with the possibilities for VMAT2 as a target for in vivo imaging, and drug development, based on this updated information. PMID- 24054150 TI - Role of hypoxia and HIF2alpha in development of the sympathoadrenal cell lineage and chromaffin cell tumors with distinct catecholamine phenotypic features. AB - Hypoxia has wide-ranging impact in normal physiology and disease processes. This stimulus evokes changes in gene expression mediated by transcription factors termed hypoxia-inducible factors (HIFs) that affect numerous processes: angiogenesis, cell survival, cellular metabolism, stem cell self-renewal and multipotency, migration, invasiveness, and metastatic progression in tumor cells. Over the past decade, increasing numbers of reports have emerged documenting differential roles of HIF1alpha and HIF2alpha in these processes. In cells of the sympathoadrenal lineage, both HIFs differentially mediate influences of hypoxia on catecholamine synthesis and secretion, but HIF2alpha signaling has particularly prominent functions in regulating developmental processes of growth and differentiation. This chapter discusses the role of HIF2alpha and HIF1alpha in the context of the development, phenotypic features, and functions of chromaffin cells. Moreover, current knowledge about tumor formation in cells of the sympathoadrenal lineage, leading to catecholamine-producing pheochromocytomas and paragangliomas, is analyzed in the light of the HIF2alpha signaling network. PMID- 24054153 TI - Stress-triggered changes in peripheral catecholaminergic systems. AB - The sympathetic nervous system not only regulates cardiovascular and metabolic responses to stress but also is altered by stress. The sympathoneural and sympathoadrenomedullary systems are modified by different metabolic pathways and have different responses to short- and to long-term stressors. Stress also induces nonneuronal catecholamine enzymes, primarily through corticosteroids. Catecholamine synthetic enzymes are induced by different pathways in response to short- and long-term acting stressors, like cold exposure or immobilization, and differently in the sympathetic ganglia and the adrenal medulla. However, a long term exposure to one stressor can increase the response to a second, different stressor. Tyrosine hydroxylase gene transcription increases after only 5min of immobilization through phosphorylation of CREB, but this response is short lived. However, repeated stress gives a longer-lived response utilizing transcription factors such as Egr-1 and Fra-2. Glucocorticoids and ACTH also induce sympathoneural enzymes leading to distinct patterns of short-term and long-lived activation of the sympathetic nervous system. Nonneuronal phenylethanolamine N methyltransferase (PNMT) develops early in the heart and then diminishes. However, intrinsic cardiac adrenergic cells remain and nonneuronal PNMT is present in many cells of the adult organism and increases in response to glucocorticoids. Both stress-induced and administered glucocorticoids induce fetal PNMT and hypertension. Human stressors such as caring for an ill spouse or sleep apnea cause a persistent increase in blood norepinephrine, increased blood pressure, and downregulated catecholamine receptors. Hypertension is associated with a loss of slow-wave sleep, when sympathetic nerve activity is lowest. These findings indicate that stress-induced alteration of the sympathetic nervous system occurs in man as in experimental animals. PMID- 24054154 TI - Neuropeptide-catecholamine interactions in stress. AB - Neuropeptides and catecholamines act as neurotransmitters within circuits of the central and peripheral nervous systems that mediate both systemic and psychological stress responses, as well as long-term adaptation and maladaptation to stress recognizable clinically as survival with resilience, or survival with cost, as manifested in anxiety, depression, PTSD, and other human behavioral disorders. The interactions between catecholamines and neuropeptides within some of these circuits are summarized in this chapter and described in detail in the three chapters following. PMID- 24054155 TI - Neuropeptide regulation of the locus coeruleus and opiate-induced plasticity of stress responses. AB - Stress has been implicated as a risk factor in vulnerability to the initiation and maintenance of opiate abuse and is thought to play an important role in relapse in subjects with a history of abuse. Conversely, chronic opiate use and withdrawal are stressors and can potentially predispose individuals to stress related psychiatric disorders. Because the interaction of opiates with stress response systems has potentially widespread clinical consequences, it is important to delineate how specific substrates of the stress response and endogenous opioid systems interact and the specific points at which stress circuits and endogenous opioid systems intersect. The purpose of this review is to present and discuss the results of studies that have unveiled the complex circuitry by which stress-related neuropeptides and endogenous opioids coregulate activity of the locus coeruleus (LC)-norepinephrine (NE) system and how chronic morphine, or stress, disturbs this regulation. PMID- 24054157 TI - Pituitary adenylate cyclase-activating polypeptide (PACAP): a master regulator in central and peripheral stress responses. AB - The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is a master regulator of central and peripheral stress responses required to restore and maintain homeostasis. PACAP modulates the hypothalamic-pituitary-adrenal (HPA) axis in response to acute psychogenic but not systemic stressors, through activation of corticotropin-releasing hormone (CRH) release to drive adrenal corticosterone (CORT) output. During direct high-frequency stimulation of the splanchnic nerve that is designed to mimic stress, PACAP regulates adrenomedullary catecholamine secretion. In addition to transmission, PACAP simultaneously facilitates the biosynthesis of adrenomedullary catecholamines through stimulus-secretion-synthesis coupling. During periods of chronic psychogenic stress, PACAP-mediated CORT elevation fails to desensitize and contributes to the development of maladaptive behaviors such as anxiety and depression. Based on these findings, PACAP regulates not only adaptive responses to stress but also maladaptive responses to sustained psychological stress. PACAP receptor antagonists could have therapeutic relevance in preventing hyperactivity of the HPA axis and offering protection against chronic stress-associated anxiety and depression. PMID- 24054156 TI - Identifying links in the chain: the dynamic coupling of catecholamines, peptide synthesis, and peptide release in hypothalamic neuroendocrine neurons. AB - Compared to neurons that communicate using synapses, some neuroendocrine neurons release relatively large quantities of peptide into the vasculature to control neuroendocrine function. Maintaining adequate amounts of peptide for release through controlled biosynthesis is therefore critical for their function. But how neuroendocrine-or in fact, any neuropeptide-neurons link appropriate levels of peptide biosynthesis with the action potentials that drive peptide release is unknown. Here, we review possible mechanisms in paraventricular hypothalamic CRH neuroendocrine neurons to coordinate these processes in response to catecholaminergic inputs. We show that CRH synthesis and release mechanisms are not invariably linked as CRH neurons are activated. Instead, coupling mechanisms exist in the premotor network that provides their synaptic inputs and in their intracellular signal transduction mechanisms, where transmitter-regulated phosphorylation of p44/42 mitogen-activated protein kinases (ERK1/2) may play a prominent role. These versatile and dynamic coupling mechanisms provide a way to link peptide biosynthesis and release. PMID- 24054158 TI - Preface. The Tenth International Catecholamine Symposium (XICS). PMID- 24054159 TI - Poor outcome of patients with myelodysplastic syndrome after azacitidine treatment failure. AB - BACKGROUND: Limited data have been reported describing the outcome and prognosis of patients with MDS in whom treatment with azanucleosides has failed. We report our single-institutional experience of patients with higher-risk MDS in whom therapy with azacitidine has failed. PATIENTS AND METHODS: This was a retrospective study of MDS patients treated at the Moffitt Cancer Center in whom azacitidine treatment regimens had failed. Patients were identified through the Moffitt database, and clinical data were extracted. Azacitidine failure was defined as failure to achieve hematologic improvement or better after at least 4 cycles of therapy, loss of response, or disease progression during therapy. The objectives were to characterize response to salvage therapies after azacitidine failure and to estimate the overall survival. All responses were defined according to the International Working Group 2006 criteria, and survival was estimated using the Kaplan-Meier method. RESULTS: A total of 59 patients in whom azacitidine treatment had failed were identified. The median age at treatment failure was 68 years, and most were Caucasian male patients. Thirteen patients received intensive chemotherapy with an overall response rate of 31%. Six patients were treated with decitabine, and none responded. Median overall survival of the entire cohort after azacitidine failure was 5.8 months (95% confidence interval, 1.3-10.3 months), with an estimated 12-month survival of 17%. CONCLUSION: Patients with higher-risk MDS in whom azacitidine treatment has failed have a poor prognosis and low probability of response to salvage treatments. The standard of care after azanucleoside failure should be enrollment in clinical trials. PMID- 24054160 TI - Global Health Action: surviving infancy and taking first steps. PMID- 24054161 TI - A step in the right direction, towards a feminist policy analysis. PMID- 24054162 TI - Effect of organic vapors on Au, Ag, and Au-Ag alloy nanoparticle films with adsorbed 2,6-dimethylphenyl isocyanide. AB - The physicochemical properties of metallic substrates are affected by the environment in different ways. It is generally difficult to determine these effects because the molecules in the environment interact weakly with metallic substrates. In this work, we demonstrate that even the effect of volatile organic compounds (VOCs) can be identified by utilizing the surface-enhanced Raman scattering of isocyanide molecules. The NC stretching band of 2,6-dimethylphenyl isocyanide (2,6-DMPI) adsorbed on Au, for instance, is blueshifted by 6 cm(-1) under an acetone flow and is redshifted by 20 cm(-1) under an ammonia flow. The same band of 2,6-DMPI adsorbed on Ag and Au0.5Ag0.5 alloy films is, however, redshifted equally by 8 and 13 cm(-1) under acetone and ammonia flows, respectively. This indicates that although the surface plasmons of Au0.5Ag0.5 alloy nanoparticles are clearly distinct from those of Ag (as well as Au) nanoparticles, both Au0.5Ag0.5 and Ag nanoparticles show a similar response to VOCs. These observations led us to conclude that the outermost parts of Au-Ag alloy nanoparticles are enriched with Ag atoms and that only the surfaces of metal nanoparticles, and not the bulk material, are affected by VOCs. PMID- 24054163 TI - Assembling photoluminescent tri(8-quinolinolato)aluminum into periodic mesoporous organosilicas. AB - Mesostructured and mesoporous materials are emerging as a new class of optical materials. However, their synthesis is nontrivial. In this work, periodic mesostructured metal complex-containing silicas of MCM- and SBA-type bearing homogeneously distributed photoluminescent tri(8-quinolinolato)aluminum inside the channel walls (denoted as Alq3@PMO-MCM and Alq3@PMO-SBA, respectively) have been achieved via one-pot co-assembling of inorganic/surfactant/optically active species. A comprehensive multianalytical characterization of the structural and optical properties demonstrates that both Alq3@PMO-MCM and Alq3@PMO-SBA series gainfully combine the photoluminescent properties of Alq3 with the porous features of PMOs. Regularly arranged pores provide high surface area to disperse optically active components well and render Alq3-containing PMOs promising materials for optoelectronic applications. PMID- 24054164 TI - Response to letter by Balta et al. PMID- 24054165 TI - Acute kidney injury following MitraClip implantation in high risk patients: incidence, predictive factors and prognostic value. PMID- 24054166 TI - [Complex fracture-dislocation of the proximal interphalangeal joint. A case report and focus on palmar proximal interphalangeal fractures-dislocations]. AB - The palmar fracture-dislocation of the proximal interphalangeal (PIP) joint of fingers is an uncommon injury. We report a complex form in a 16-year old teenager, associating a palmar fracture-dislocation and a fracture of the base of the middle phalanx with the dorsal fragment dislocated between the neck of the proximal phalange and the palmar plate. The management was surgical with open reduction and fixation of the fragments by K-wires and temporary PIP arthrorisis. The result at 6months of follow- up after removal of the wires and physiotherapy was satisfactory. The patient was painless with a range of motion of 115 degrees . Clinically, the sagittal and frontal stability of the joint both in flexion and extension was maintained. Osseous healing was obtained on X-ray control. The patient went back to his usual activities. A focus on palmar fracture dislocations of PIP joint is presented through incidence, mechanism and treatment. PMID- 24054167 TI - Salpingoscopy after a single dose of methotrexate for treatment of tubal pregnancy. PMID- 24054168 TI - Effect of ultrasonic treatment on the morphology of casein particles. AB - In this study, the effect of ultrasonic treatment duration on the morphology of self-assembled casein particles was investigated by atomic force microscopy (AFM), low vacuum scanning electron microscopy (SEM) and transmission electron microscopy (TEM). In the case of AFM images, the particle analysis which was carried out by the SPIP program showed that the self-assembled casein particles after being ultrasonically treated for 2 min got smaller in size compared to the casein particles that have not been exposed to any ultrasonic treatment. Surprisingly, however, increasing the ultrasonic time exposure of the particles resulted in an opposite effect where larger particles or aggregates seemed to be present. We show that by comparing the results obtained by AFM, SEM and TEM, the information extracted from the AFM images and analyzed by SPIP program give more detailed insights into particle sizes and morphology at the molecular level compared to SEM and TEM images, respectively. PMID- 24054169 TI - Treatment - mother-infant inpatient units. AB - Infants of parents with psychiatric disorders may be particularly vulnerable and have a higher risk of developing psychiatric disorders in adulthood. Until the second half of the 20th century, women and infants were cared for separately. Today, hospitalisation of women with their babies in psychiatric mother-baby units enables psychiatric care of women and promotion of parent-infant interactions and child development. The distribution of psychiatric mother-baby units around the world, as well as within countries, varies strongly. Reasons for this may be related to the absence of national perinatal mental health policies related to psychiatric mother-baby unit location, differences in sources of referral for admission, and criteria for psychiatric mother-baby unit admission. Two principal national epidemiologic studies, in England and in France and Belgium, have described issues related to discharge from such care, as have smaller local studies, but no epidemiologic studies have yet demonstrated that joint inpatient psychiatric mother-baby unit care is cost-effective compared with separate care. PMID- 24054171 TI - Unclear study methods still confusing readers despite CONSORT guidelines (e.g., lidocaine patch does relieve pain of covered rib fractures). PMID- 24054170 TI - The content and delivery of psychological interventions for perinatal depression by non-specialist health workers in low and middle income countries: a systematic review. AB - Psychological interventions delivered by non-specialist health workers are effective for the treatment of perinatal depression in low- and middle-income countries. In this systematic review, we describe the content and delivery of such interventions. Nine studies were identified. The interventions shared a number of key features, such as delivery provided within the context of routine maternal and child health care beginning in the antenatal period and extending postnatally; focus of the intervention beyond the mother to include the child and involving other family members; and attention to social problems and a focus on empowerment of women. All the interventions were adapted for contextual and cultural relevance; for example, in domains of language, metaphors and content. Although the competence and quality of non-specialist health workers delivered interventions was expected to be achieved through structured training and ongoing supervision, empirical evaluations of these were scarce. Scalability of these interventions also remains a challenge and needs further attention. PMID- 24054172 TI - Low papillary structures in lepidic lung adenocarcinoma: any relationship with micropapillary lung adenocarcinoma? PMID- 24054173 TI - The effect of nail polish on pulse oximetry readings. AB - INTRODUCTION: Pulse oximeters utilise the pulsatile nature of arterial blood flow to distinguish it from venous flow and estimate oxygen saturation in arterial blood. Pulse oximetry is primarily used in hospital wards, emergency rooms, intensive care units, operating rooms and home care. AIM: The objective of this study is to determine whether the use of nail polish of various colours have an effect on oximeter readings of oxygen saturation value. METHOD: The sample group of this study is comprised of 40 healthy women. In the first phase of the study, readings were taken on left and right hand fingers, with no nail polish, to determine any differences in oxygen saturation value. In the second phase of the study, 10 different colours of nail polish, namely dark red, yellow, dark blue, green, purple, brown, white, metallic, black and pink, of the same brand were applied. Readings were recorded once oxygen saturation values on the screen became stable. Number and percentage distributions along with Wilcoxon signed ranks and Friedman test were used in the analysis of data. CONCLUSION: Only red nail polish did not yield statistically significant reading results. We conclude that different nail polish colours cause a clinically significant change in pulse oximeter readings in healthy volunteers. PMID- 24054174 TI - Change in readmissions and follow-up visits as part of a heart failure readmission quality improvement initiative. AB - OBJECTIVES: The study objectives were to quantify the change in 7-day follow-up visits and 30-day readmissions as part of a hospital quality improvement initiative and to characterize events at 7-day follow-up visits. Some data suggest that outpatient assessments of patients with heart failure within 7 days of hospital discharge may prevent readmissions, although little is known about patient needs at 7-day follow-up visits. METHODS: We performed a single-center, retrospective chart review of all heart failure discharges at the University of Connecticut Health Center (398 patients) the year before (2008) and the year after (2011) a quality improvement initiative that included mandatory 7-day follow-up visits. We quantified the change in 30-day readmission rate after the initiative, frequency of 7-day follow-up visits, and events at follow-up visits. RESULTS: The average age of patients with heart failure was 79.9 years in 2011, with 45.9% having systolic heart failure. Thirty-day all-cause readmissions decreased from 27.5% to 19.1% after our quality improvement initiative (P = .024). Frequency of 7-day follow-up visits increased from 19.6% to 46.9% (P < .01). Eighty-one percent of 7-day visits occurred in the University of Connecticut Heart Failure Center with a cardiologist or heart failure nurse practitioner. Fifty-one percent of patients had blood work drawn, and 26% had a medication dose changed. Only 13% of patients had no discrepancy between the discharge and follow-up medication lists. CONCLUSIONS: Our hospital's 30-day readmission rate for patients with heart failure decreased in parallel with an increase in 7-day follow-up visits. Patients with heart failure were complex and often had diagnostic testing and medication changes at follow-up visits. PMID- 24054175 TI - Handgrip strength predicts persistent walking recovery after hip fracture surgery. AB - BACKGROUND: In older people, hip fractures often lead to disability and death. We evaluated handgrip strength, an objective measure of physical function for bedridden patients, as a predictor of walking recovery in the year after fracture surgery. METHODS: This multicenter prospective cohort study included 504 patients, aged 70 years or more, who were admitted to the hospital for hip fracture surgery and were formerly able to walk independently. A multidimensional geriatric evaluation that included a physical examination, Short Portable Mental Status Questionnaire, Geriatric Depression Scale, Charlson Index, Basic Activities of Daily Living, and grip strength was administered at the time of admission. Follow-ups were performed every 3 months for 1 year after surgery to assess functional status and survival. The walking recovery probability was evaluated using multivariable logistic regression models. RESULTS: The mean age of the participants was 85.3 +/- 5.5 years, and 76.1% of the participants were women. The mean grip strength was greater in men (beta: 6.6 +/- 0.62, P < .001) and was directly related to the Short Portable Mental Status Questionnaire results (P < .001), Basic Activities of Daily Living results (P < .001), serum vitamin D levels (P = .03), and time before surgery (P < .001), whereas it was inversely related to age (P < .001), Geriatric Depression Scale score (P < .001), and Charlson Index (P < .001). After adjusting for confounders, the grip strength was directly associated with the probability of both incident and persistent walking recovery (odds ratio highest tertile vs lowest tertile, 2.84, confidence interval, 1.76-4.59 and 2.79, confidence interval, 1.35-5.79, respectively). CONCLUSIONS: In older patients with hip fractures, early grip strength evaluation might provide important prognostic information regarding the patient's future functional trajectory. PMID- 24054176 TI - Risk factors for aspiration in community-acquired pneumonia: analysis of a hospitalized UK cohort. AB - BACKGROUND: There is a move toward finding clinically useful "phenotypes" in community-acquired pneumonia: groups of patients displaying distinct clinical characteristics, microbiology, and prognosis. Aspiration pneumonia is an intuitive clinical phenotype; however, to date there are no recognized diagnostic criteria, and data regarding outcomes in suspected aspiration are limited. METHODS: An observational study of 1348 patients hospitalized with community acquired pneumonia in the United Kingdom examined both short- and long-term outcomes for patients at risk of aspiration pneumonia. Patients were defined as "at risk" in the presence of chronic neurologic disorders, esophageal disorders and dysphagia, impaired conscious level, vomiting, or witnessed aspiration. The primary outcome was 30-day mortality. Secondary outcomes included 1-year mortality, readmissions, and recurrent pneumonia within 1 year. RESULTS: Some 13.8% of the cohort were classified as "at risk of aspiration." These patients were older (median age, 74 years [interquartile range, 60-84] vs 66 years [interquartile range, 49-77]; P < .0001) and more likely to have comorbidities (chronic liver disease 11.3% vs 3.7%, P < .0001; congestive heart failure 28% vs 17.1%, P = .0004; and stroke 26.9% vs 9.5%, P < .0001). Patients at risk of aspiration pneumonia had a poorer short-term outcome (30-day mortality 17.2% vs 7.7%, P < .0001), but after adjusting for their greater severity of illness and comorbidities this difference was not significant (odds ratio 1.05; 95% confidence interval [CI], 0.63-1.76; P = .8). However, patients with aspiration risk factors were at greater risk of poor long-term outcomes with increased 1 year mortality (hazard ratio [HR], 1.73; 95% CI, 1.15-2.58), increased risk of rehospitalization (HR, 1.52; 95% CI, 1.21-1.91), and a strong association with recurrent admissions with pneumonia (HR, 3.13; 95% CI, 2.05-4.78) after multivariable adjustment. CONCLUSIONS: Using risk factors to identify patients at risk of aspiration pneumonia identifies a distinct clinically useful phenotype of patients with greater severity of disease and poorer long-term outcomes. PMID- 24054177 TI - Dietary sodium restriction: take it with a grain of salt. AB - The American Heart Association recently strongly recommended a dietary sodium intake of <1500 mg/d for all Americans to achieve "Ideal Cardiovascular Health" by 2020. However, low sodium diets have not been shown to reduce cardiovascular events in normotensive individuals or in individuals with pre-hypertension or hypertension. Moreover, there is evidence that a low sodium diet may lead to a worse cardiovascular prognosis in patients with cardiometabolic risk and established cardiovascular disease. Low sodium diets may adversely affect insulin resistance, serum lipids, and neurohormonal pathways, leading to increases in the incidence of new cardiometabolic disease, the severity of existing cardiometabolic disease, and greater cardiovascular and all-cause mortality. Although a high sodium intake also may be deleterious, there is good reason to believe that sodium intake is regulated within such a tight physiologic range that there is little risk to leaving sodium intake to inherent biology as opposed to likely futile attempts at conscious control. PMID- 24054178 TI - Hereditary hemochromatosis: missed diagnosis or misdiagnosis? AB - BACKGROUND: Hereditary hemochromatosis is a disorder that can cause iron overload and organ damage. Hereditary hemochromatosis is characterized by mutations in the HFE gene. HFE C282Y homozygotes and compound heterozygotes (C282Y/H63D) are at risk of developing manifestations of hemochromatosis. Abnormal iron study results also occur in many liver and hematologic diseases. The aim of this study was to evaluate the accuracy of diagnosis of hereditary hemochromatosis. METHODS: Pertinent clinical and laboratory data, including HFE genotype, were tabulated from the electronic medical records of patients with the International Classification of Diseases 9th Revision code 275, "disorders of iron metabolism," who were seen at a tertiary referral center between January 2002 and May 2012. RESULTS: HFE genotyping was obtained in only 373 of 601 patients (62%); 200 were C282Y homozygotes or compound heterozygotes. Of the 173 patients with nonhereditary hemochromatosis genotypes, 53% were misdiagnosed with hereditary hemochromatosis and 38% underwent phlebotomy. In two thirds of these cases, the misdiagnosis was made by a nonspecialist. In the remaining 228 patients who were not genotyped, 80 were diagnosed with hereditary hemochromatosis and 64 were phlebotomized. Of patients misdiagnosed with hemochromatosis, 68% had known liver disease and 5% had a hematologic cause of abnormal iron study results. CONCLUSIONS: Abnormal iron study results in patients with nonhereditary hemochromatosis genotypes commonly lead to a misdiagnosis of hereditary hemochromatosis and inappropriate treatment with phlebotomy. This error often is seen in the setting of elevated iron study results secondary to chronic liver diseases. Furthermore, hereditary hemochromatosis is commonly diagnosed and treated without HFE genotyping. We suggest that phlebotomy centers require a documented HFE genotype before initiating phlebotomy. PMID- 24054180 TI - Memento mori: investigating mummies for ancient diseases. PMID- 24054179 TI - Increased risk of recurrent gout attacks with hospitalization. AB - BACKGROUND: Although anecdotal evidence suggests that the risk of recurrent gout attack increases with hospitalization, no study has formally tested this hypothesis. METHODS: We conducted an online case-crossover study of individuals with gout. We obtained information on gout attacks over a 1-year period, including onset date, symptoms and signs, medications, and exposure to potential risk factors, including hospitalization, during the 2-day hazard period before each gout attack. The same exposure information also was obtained over 2-day intercritical gout control periods. We performed conditional logistic regression to examine the relationship of hospitalization with recurrent gout attacks and whether such a relationship was modified by concomitant use of anti-gout medications. RESULTS: Of 724 participants (mean age, 54.5 years; 78.5% male), 35 hospitalizations occurred during a hazard or control period. The adjusted odds of gout attacks was increased 4-fold with hospitalization (odds ratio, 4.05; 95% confidence interval, 1.78-9.19) compared with no hospitalization. The effect of hospitalization tended to attenuate with the use of allopurinol, colchicine, or nonsteroidal anti-inflammatory drugs, but not statistically significantly. CONCLUSIONS: Our study confirmed that the risk of gout attacks increases among patients with gout during hospitalization. Appropriate measures should be considered for prevention of gout attacks during hospitalization for patients with preexisting gout. PMID- 24054181 TI - Probing interactions in fungal PKS. AB - Biosynthesis of polyketides can depend on interactions between the acyl carrier proteins (ACPs) which hold the growing chains and their enzymatic partners. In this issue of Chemistry & Biology, Bruegger and colleagues demonstrate that mechanism-based probes tethered to the ACPs of fungal nonreducing polyketide synthases can provide insights into these contacts. PMID- 24054182 TI - Screening for a diamond in the rough. AB - Contrary to the standard of eliminating antimicrobial hits that collapse bacterial proton motive force (PMF), in this issue of Chemistry and Biology, Farha and colleagues describe the value of screens to identify molecules that dissipate PMF, yet are nonbacteriolytic and selectively toxic. PMID- 24054183 TI - Structural disorder in expanding the functionome of aminoacyl-tRNA synthetases. AB - Over the past decade, aminoacyl-tRNA synthetases (AARSs) have emerged as a new class of regulatory proteins with widespread functions beyond their classic role in protein synthesis. The functional expansion concurs with the incorporation of new domains and motifs to AARSs and coincides with the emergence of the multi synthetase complex (MSC) during the course of eukaryotic evolution. Notably, the new domains in AARSs are often found to be structurally disordered or to be linked to the enzyme cores via unstructured linkers. We performed bioinformatic analysis and classified the 20 human cytoplasmic AARSs into three groups based on their propensities for structural disorder. The analysis also suggests that, while the assembly of the MSC mainly involves ordered structural domains, structurally disordered regions play an important role in activating and expanding the regulatory functions of AARSs. PMID- 24054185 TI - Why we should continue to publish case reports. PMID- 24054184 TI - Prevalence and predictors of irritable bowel syndrome among medical students and interns in King Abdulaziz University, Jeddah. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a frequent, costly, and potentially disabling gastrointestinal disorder. Medical education is among the most challenging and the most stressful education, and this may predispose to high rates of IBS. OBJECTIVE: To determine the prevalence and predictors of IBS among medical students and interns in King Abdulaziz University, Jeddah, Saudi Arabia. METHODS: A cross-sectional study was conducted among 597 medical students and interns selected by multistage stratified random sample method in 2012. A confidential, anonymous, and self-administered questionnaire was used to collect personal and sociodemographic data, level of emotional stress, and food hypersensitivity during the past 6 months. Rome III Criteria and the Standardized Hospital Anxiety and Depression Scale were also used. RESULTS: The prevalence of IBS was 31.8%. Multiple logistic regression analysis revealed that the first predictor of IBS was female gender (aOR=2.89; 95.0% CI: 1.65-5.05). The second predictor was presence of morbid anxiety (aOR=2.44; 95.0% CI: 1.30-4.55). Living in a school dormitory, emotional stress during 6 months preceding the study, and the academic year were the next predictors. CONCLUSIONS: High prevalence of IBS prevailed among medical students and interns. Female gender, morbid anxiety, living in school dormitory, emotional stress, and higher educational level (grade) were the predictors of IBS. Screening of medical students for IBS, psychological problems, and reducing stress by stress management are recommended. PMID- 24054186 TI - Asymptomatic and symptomatic postoperative visual dysfunction after cardiovascular surgery with cardiopulmonary bypass: a small-sized prospective observational study. AB - OBJECTIVE: Postoperative visual dysfunction (POVD) after cardiovascular surgery rarely is reported, since it is more likely underdetected and underreported. This study was designed to verify the presence of POVD, including a variety of asymptomatic as well as symptomatic visual dysfunctions after cardiovascular surgery with cardiopulmonary bypass (CPB). DESIGN: A prospective observational study. SETTING: Cardiothoracic surgery in a medical university hospital. PARTICIPANTS: Seventy-one patients undergoing elective cardiovascular surgery with CPB. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were assessed by a battery of 7 neuro-ophthalmic examinations preoperatively and postoperatively, including fundus, visual field, eye movement, color vision, visual acuity, intraocular pressure, and critical flicker frequency. Patients were considered to have POVD if they had postoperative new abnormal findings of neuro-ophthalmic examinations. One patient was excluded due to a failure of postoperative neuro-ophthalmic examinations. In 16 of 70 patients analyzed in this study, selective cerebral perfusion was required for aortic arch surgery. Of 70 patients, a total of 8 patients (11.4%) had postoperative new abnormal findings in neuro-ophthalmic examinations, including new visual field deficits in 4, reduced visual acuity in 4, and/or increased intraocular pressure in 1 patient. Of these 8 patients, symptomatic POVD was recognized in 1 patient (1.4%) with postoperative visual field deficit and reduced visual acuity. There were no new abnormal findings compared with preoperative results in postoperative funduscopy, eye movement, color vision, and critical flicker frequency. CONCLUSIONS: These results indicated that the asymptomatic as well as symptomatic POVD can develop after cardiovascular surgery with CPB, and their incidence may be relatively high. PMID- 24054187 TI - A randomized open-label phase I pilot study of the safety and efficacy of total intravenous anesthesia with fospropofol for coronary artery bypass graft surgery. AB - OBJECTIVE: To determine safety and efficacy of the water-soluble prodrug fospropofol for anesthesia in cardiac surgery and to compare the pharmacodynamic profiles of fospropofol and propofol. DESIGN: Pilot study and a prospective, phase I, open-label, single-center, randomized clinical trial. SETTING: University hospital; single institution. PARTICIPANTS: Sixteen patients undergoing elective first-time coronary artery bypass surgery. INTERVENTIONS: Patients were randomized to receive total intravenous anesthesia with fospropofol (n = 8) or propofol (n = 8) combined with alfentanil as total intravenous anesthesia. Bispectral index, arterial blood pressure, and heart rate were recorded continuously, and pulmonary artery catheter measurements were obtained. Plasma concentrations of formate, phosphate, and Ca(2+) were monitored closely. Safety and tolerability were assessed by adverse events, neurologic examinations, clinical laboratory tests, and vital signs. MEASUREMENTS AND MAIN RESULTS: The total doses of fospropofol and propofol during anesthesia were 11.3+/-2.5 and 4.4+/-1.0 mg/kg/h, respectively. According to the achieved bispectral index (BIS) values, fospropofol was as effective as propofol in providing general anesthesia and sedation. There were no clinical signs of formate toxicity in the fospropofol group. The only treatment-related adverse event after administration of fospropofol was a transient burning sensation in the perineal and perianal region during induction of sedation or anesthesia. CONCLUSIONS: Fospropofol could be used to provide general anesthesia in patients undergoing coronary artery bypass graft surgery. Further larger studies are needed to prove the safety of fospropofol when given to provide general anesthesia for major cardiac surgical procedures. PMID- 24054188 TI - Treatment of ventricular assist-device-associated gastrointestinal bleeding with hormonal therapy. PMID- 24054189 TI - Case 5--2013: Pregnant patient with uncorrected, undiagnosed total anomalous pulmonary venous return and severe pulmonary hypertension. PMID- 24054190 TI - Pro: LVAD: patient's desire for termination of VAD therapy should be challenged. PMID- 24054191 TI - Con: Patient's desire for termination of destination LVAD therapy should be respected. PMID- 24054192 TI - Steroids for adult cardiac surgery with cardiopulmonary bypass: update on dose and key randomized trials. PMID- 24054193 TI - Now you see it, now you don't: 3D echocardiographic evaluation of a prosthetic aortic valve. PMID- 24054194 TI - Three-dimensional echocardiography: another dimension of imaging or complexity? PMID- 24054195 TI - Review: the Boston Echo Course Physics and Hemodynamics Workshop. PMID- 24054196 TI - Incremental value of real time 3D transesophageal echocardiography to detect coronary ostium in patients undergoing transapical aortic valve implantation. PMID- 24054197 TI - Prasugrel-related late cardiac tamponade after coronary artery bypass surgery in a patient with a recently implanted bare metal stent. PMID- 24054198 TI - Plasma exchange transfusion for management of altered heparin responsiveness before cardiopulmonary bypass. PMID- 24054199 TI - "Blind" placement of a bronchial blocker in a patient with a difficult airway. PMID- 24054200 TI - Acute compartment syndrome after axillary cannulation. PMID- 24054201 TI - Noninvasive ventilation practice in cardiac surgery patients: insights from a European survey. PMID- 24054202 TI - Challenges in the design of drug therapy study on rats. PMID- 24054203 TI - Reply to Yesil et al. PMID- 24054204 TI - Acid and rennet gels exhibit strong differences in the kinetics of milk protein digestion and amino acid bioavailability. AB - This study aimed at determining the kinetics of milk protein digestion and amino acid absorption after ingestion by six multi-canulated mini-pigs of two gelled dairy matrices having the same composition, similar rheological and structural properties, but differing by their mode of coagulation (acidification/renneting). Duodenal, mid-jejunal effluents and plasma samples were collected at different times during 7h after meal ingestion. Ingestion of the acid gel induced a peak of caseins and beta-lactoglobulin in duodenal effluents after 20min of digestion and a peak of amino acids in the plasma after 60min. The rennet gel induced lower levels of both proteins in the duodenum (with no defined peak) as well as much lower levels of amino acids in the plasma than the acid gel. Plasma ghrelin concentrations suggested a potentially more satiating effect of the rennet gel compared to the acid gel. This study clearly evidences that the gelation process can significantly impact on the nutritive value of dairy products. PMID- 24054206 TI - Study of kefir grains application in sourdough bread regarding rope spoilage caused by Bacillus spp. AB - Sourdough breads prepared with kefir grains resulted in appearance of rope spoilage at the 15th day of bread storage, while the control samples (sourdough breads prepared with wild microflora) were spoiled approximately at the 7th day. Denaturing Gradient Gel Electrophoresis (DGGE) analysis confirmed the above macroscopic observation since Bacillus spp. were detected on sourdough breads prepared with kefir grains at the 15th day of bread storage. The content of organic acids that play synergistic role regarding the enhancement of bread self life was also determined. Lactic acid concentration of sourdough breads prepared with kefir grains were approximately 41-82% higher than the control samples, while acetic acid concentration was about 0.5-1-fold higher respectively. The concentration of some other organic acids studied was also found in higher levels (up to 0.06MUg/g) than the control samples. These findings could probably explain the stability of breads prepared with kefir grains against rope spoilage. PMID- 24054205 TI - Delineating the protein changes in Asian noodles induced by vacuum mixing. AB - In this study, the effect of vacuum mixing on Asian noodle qualities was investigated based on protein components changes and gluten formation. The results showed that the proportion of salt-soluble proteins decreased in vacuum mixed noodles while alcohol and alkali soluble proteins increased. The free sulfyhydryl content decreased significantly (P<0.05) in low protein (LP) noodles while slight and not significant (P>0.05) decrease was detected in high protein (HP) samples. Remarkable protein aggregates were observed in non-reduced SDS-PAGE patterns for LP noodles. The changes in secondary structure were reflected by the increase in alpha-helix and beta-sheet as well as the decrease in beta-turns. Furthermore, vacuum mixing conferred a more continuous and compact microstructure to both HP and LP noodle sheets as well as an increased breaking force and extensibility. In addition, less deterioration in noodle structure and water migration was observed by magnetic resonance imaging (MRI) for vacuum mixed samples during storage. PMID- 24054207 TI - Developed of a method for the genetic identification of ling species (Genypterus spp.) in seafood products by FINS methodology. AB - In the present work a method of authentication of Genypterus and their substitute species was developed, by means of Polymerase Chain Reaction (PCR) technique followed by phylogenetic analysis (FINS, Forensically Informative Nucleotide Sequencing). The methodology developed allows the identification of all the studied species using the mitochondrial cytochrome oxidase subunit I gene (COXI) as molecular marker. Substitutions of the species belonging to Genypterus genera by other species with minor value can take place, since in a lot of seafood products , is not possible the assignation to a particular species based on morphological traits, because it are removed in the transformation process. In this work several methodological strategies were developed and all of them allow the authentication of the studied species in any kind of products, from fresh or frozen fish, to ready-cooked meal. Therefore, the proposed methodology can be used as a routine method to avoid the mislabelling in the marketing of Genypterus species. Also this methodological approximation is suitable to assess the correct seafood traceability of the products elaborated from the mentioned species. PMID- 24054208 TI - Interactions between tea catechins and casein micelles and their impact on renneting functionality. AB - Many studies have shown that tea catechins bind to milk proteins. This research focused on the association of tea polyphenols with casein micelles, and the consequences of the interactions on the renneting behaviour of skim milk. It was hypothesized that epigallocatechin-gallate (EGCG), the main catechin present in green tea, forms complexes with the casein micelles and that the association modifies the processing functionality of casein micelles. The binding of EGCG to casein micelles was quantified using HPLC. The formation of catechin-casein micelles complexes affected the rennet induced gelation of milk, and the effect was concentration dependent. Both the primary as well as the secondary stage of gelation were affected. These experiments clearly identify the need for a better understanding of the effect of tea polyphenols on the processing functionality of casein micelles, before milk products can be used as an appropriate platform for delivery of bioactive compounds. PMID- 24054209 TI - Effect of extrusion cooking on the physicochemical properties, resistant starch, phenolic content and antioxidant capacities of green banana flour. AB - Green banana flour was extruded through a co-rotating twin-screw extruder with constant barrel temperature. The objectives of this study were to determine the effect of extrusion cooking variables (feed moisture, FM, 20% and 50%; screw speed, SS, 200 and 400rpm) and storing of the extruded flours at 4 degrees C for 24h on the physicochemical properties, resistant starch (RS), pasting properties and antioxidant capacities. Extrusion cooking at higher FM and lower SS increased the amylose content, which was expressed in highest RS content. Water adsorption index (WAI) and pasting properties were increased, while water solubility index (WSI), total phenolic content (TPC) and antioxidant activities (FRAP, ABTS(+), DPPH) in free and bound phenolics were decreased compared to the other extruded samples. Storing the extruded flours at 4 degrees C for 24h prior to oven drying was the main factor leading to a further increase in the content of amylose, RS, TPC and WSI values, as well as pasting properties - in particular peak viscosity. Compared to native banana flour, extrusion cooking caused significant changes in all studied properties of the extruded flours, except for soluble DF and antioxidant capacity (ABTS(+) and DPPH) of bound phenolics. PMID- 24054210 TI - Discrimination of commercial cheeses from fatty acid profiles and phytosterol contents obtained by GC and PCA. AB - In this study, a method for discriminating natural mozzarella cheese from cheese substitutes, using fatty acid profiles, phytosterol contents, and statistical comparison, was developed. A total of 27 cheeses were evaluated: eight natural mozzarella cheeses (NMCs), four imitation mozzarella cheeses (IMCs), 12 processed cheeses (PCs) and three mixed cheeses (MCs) composed of NMCs and IMCs. The fatty acid composition of the NMC class was distinct from those of the IMC and MC classes, but statistically similar (p<0.05) to that of the PC class. The phytosterol content of the NMC class, determined via gas chromatography-mass spectrometry, was distinct from the IMCs, but similar (p<0.05) to a portion of the PCs. Principal component analysis (eigenvalue?1) indicated that the NMCs can be differentiated from the IMCs, but discrimination between the NMCs and the PCs could not be achieved. PMID- 24054211 TI - Quantitative determination of plant phenolics in Urtica dioica extracts by high performance liquid chromatography coupled with tandem mass spectrometric detection. AB - A method for quantification of 45 plant phenolics (including benzoic acids, cinnamic acids, flavonoid aglycones, C- and O-glycosides, coumarins, and lignans) in plant extracts was developed, based on reversed phase HPLC separation of extract components, followed by tandem mass spectrometric detection. The phenolic profile of 80% MeOH extracts of the stinging nettle (Urtica dioica L.) herb, root, stem, leaf and inflorescence was obtained by using this method. Twenty-one of the investigated compounds were present at levels above the reliable quantification limit, with 5-O-caffeoylquinic acid, rutin and isoquercitrin as the most abundant. The inflorescence extracts were by far the richest in phenolics, with the investigated compounds amounting 2.5-5.1% by weight. As opposed to this, the root extracts were poor in phenolics, with only several acids and derivatives being present in significant amounts. The results obtained by the developed method represent the most detailed U. dioica chemical profile so far. PMID- 24054212 TI - Effect of heat moisture treatment on physicochemical and morphological properties of wheat starch and xylitol mixture. AB - The effect of heat moisture treatment (HMT, 100 degrees C, 10h) on the physicochemical and morphological properties of wheat starch and xylitol mixture (SX) were studied by using Rapid Visco-Analyser (RVA), differential scanning calorimetry (DSC), scanning electron microscope (SEM) and X-ray diffraction pattern (X-ray). The research found that the peak viscosity (PV), trough viscosity (TV), final viscosity (FV) and breakdown (BD) of SX decreased markedly after HMT, whereas pasting temperature increased. Compared with SX, To, Tp and Tc of SX treated with HMT (H-SX) increased and DeltaH decreased. The results of SEM showed that numerous xylitol granules appeared on the surface of starch granule in SX, and a layer of similar membrane adhered on the surface of starch granules in H-SX. After gelatinization and freeze-dried, the gel network structure of H-SX was tighter than that of SX. The amorphous region of H-SX was higher than that of SX. PMID- 24054213 TI - Developing an effective means to reduce 5-hydroxymethyl-2-furfural from caramel colour. AB - Supercritical carbon dioxide fluid extraction was used to extract 5-hydroxymethyl 2-furfural from caramel colour (solid content was about 75%). The procedure was carried out by response surface methodology using a quadratic polynomial model. Extraction pressure, time, temperature and ethanol content were selected as the independent variables. Conditions to obtain the highest extraction ratio of 5 hydroxymethyl-2-furfural were determined to be an extraction pressure of 21.65MPa, time of 46.7min, temperature of 35 degrees C and 70% ethanol content of caramel colour. The predicted 5-hydroxymethyl-2-furfural extraction ratio was 87.42%. Under the conditions stated above, the experimental value of 5 hydroxymethyl-2-furfural extraction ratio was 86.98%, which was similar to the predicted value by the model. This study indicated that supercritical carbon dioxide fluid extraction can effectively reduce 5-hydroxymethyl-2-furfural from caramel colour, which can help food industry to improve the safety of the food material, as well as provide more healthy caramel colour for human beings. PMID- 24054214 TI - Polyphenolic compounds as chemical markers of wine ageing in contact with cherry, chestnut, false acacia, ash and oak wood. AB - The nonanthocyanic phenolic composition of four red wines, one white, and one rose aged using barrels and chips of cherry, chestnut, false acacia, ash and oak wood was studied by LC-DAD-ESI/MS, to identify the phenolic compounds that woods other than oak contribute to wines, and if some of them can be used as chemical markers of ageing with them. A total of 68 nonanthocyanic phenolic compounds were identified, 15 found only in wines aged with acacia wood, 6 with cherry wood, and 1 with chestnut wood. Thus, the nonanthocyanic phenolic profile could be a useful tool to identify wines aged in contact with these woods. In addition, some differences in the nonanthocyanic phenolic composition of wines were detected related to both the levels of compounds provided by each wood species and the different evolution of flavonols and flavanols in wines during ageing in barrels or in contact with chips. PMID- 24054215 TI - Artificially-aged cachaca samples characterised by direct infusion electrospray ionisation mass spectrometry. AB - Direct infusion electrospray ionisation mass spectrometry in the negative ion mode [ESI(-)-MS] was employed to evaluate the authenticity of aged cachacas, a traditional and valuable Brazilian alcoholic beverage prepared from the distillation of brewed sugarcane juice and aged in barrels made of common woods. Counterfeit samples were prepared by adding dyes, sawdust or essences to a freshly-distiled, much less valuable sample (white cachaca) to simulate the 1 2years long natural ageing in wooden barrels. A simple visual inspection revealed remarkable differences between the ESI(-)-MS of the authentic samples (aged in oak or amburana casks) and the artificially-aged counterfeit samples. A set of diagnostic ions were detectable in the ESI(-)-MS of the authentic samples aged in oak (m/z 197, 241, 301 and 307) and amburana (m/z 271 and 377/379). This fast and direct methodology seems useful as a routine procedure to monitor this highly profitable and common counterfeit practice. PMID- 24054216 TI - Simultaneous determination of amino acids in tea leaves by micellar electrokinetic chromatography with laser-induced fluorescence detection. AB - A rapid and effective method of micellar electrokinetic chromatography with laser induced fluorescence detection was developed for the simultaneous determination of amino acids in tea leaves. Pre-column derivatization of the analytes used 4 chloro-7-nitrobenzofurazan (NDB-Cl). Optimal separation was achieved at +20kV using an uncoated fused silica capillary (40.0cm effective length, 50.2cm total length, 75MUm internal diameter), as well as 20mM sodium borate (pH 8.5), 20mM Brij 35, and acetonitrile 10% (v/v) as running buffers. Within 11min, 15 amino acids were separated completely. The optimized method demonstrated good linearity (r(2)?0.9990), precision (?6.65%), accuracy (85.50-112.74%), and sensitivity (0.1ng/mL-100ng/mL). The method successfully determined the quantity of amino acids in five different tea leaves; furthermore, theanine was identified as the most abundant amino acid in teas. The proposed method showed great potential in further investigations on the biofunctions of different tea samples. PMID- 24054217 TI - Phenolic acids, anthocyanins, and antioxidant capacity in rice (Oryza sativa L.) grains at four stages of development after flowering. AB - This study investigated differences in total phenolic content (TPC), antioxidant capacity, and phenolic acids in free, conjugated and bound fractions of white (unpolished), red and black rice at 1-, 2-, and 3-weeks of grain development after flowering and at maturity. Unlike the TPC (mg/100g) of white rice (14.6 33.4) and red rice (66.8-422.2) which was significantly higher at 1-week than at later stages, the TPC of black rice (56.5-82.0) was highest at maturity. The antioxidant capacity measured by DPPH radical scavenging and ORAC methods generally followed a similar trend as TPC. Only black rice had detectable anthocyanins (26.5-174.7mg/100g). Cyanidin-3-glucoside (C3G) and peonidin-3 glucoside (P3G) were the main anthocyanins in black rice showing significantly higher levels at 2- and 3-weeks than at 1-week development and at maturity. At all stages, the phenolic acids existed mainly in the bound form as detected by HPLC and confirmed by LC-MS/MS. Black rice (20.1-31.7mg/100g) had higher total bound phenolic acids than white rice and red rice (7.0-11.8mg/100g). Protocatechuic acid was detected in red rice and black rice with relatively high levels at 1-week development (1.41mg/100g) and at maturity (4.48mg/100g), respectively. Vanillic acid (2.4-5.4mg/100g) was detected only in black rice where it peaked at maturity. p-Coumaric acid (<3.5mg/100g) did not differ significantly at most stages with somewhat high levels at 1-week for red and black rice. Ferulic acid (4.0-17.9mg/100g), the most abundant bound phenolic acid, had an inconsistent trend with higher levels being observed in black rice where it peaked at maturity. Isoferulic acid levels (0.8-1.6mg/100g) were generally low with slightly elevated values being observed at maturity. Overall black rice had higher total bound phenolic acids than white and red rice while white rice at all stages of development after flowering. PMID- 24054218 TI - Rapid and sensitive ultrasonic-assisted derivatisation microextraction (UDME) technique for bitter taste-free amino acids (FAA) study by HPLC-FLD. AB - Amino acids, as the main contributors to taste, are usually found in relatively high levels in bitter foods. In this work, we focused on seeking a rapid, sensitive and simple method to determine FAA for large batches of micro-samples and to explore the relationship between FAA and bitterness. Overall condition optimisation indicated that the new UDME technique offered higher derivatisation yields and extraction efficiencies than traditional methods. Only 35min was needed in the whole operation process. Very low LLOQ (Lower limit of quantification: 0.21-5.43nmol/L) for FAA in twelve bitter foods was obtained, with which BTT (bitter taste thresholds) and CABT (content of FAA at BTT level) were newly determined. The ratio of CABT to BTT increased with decreasing of BTT. This work provided powerful potential for the high-throughput trace analysis of micro-sample and also a methodology to study the relationship between the chemical constituents and the taste. PMID- 24054219 TI - Pectic polysaccharides of the fresh plum Prunus domestica L. isolated with a simulated gastric fluid and their anti-inflammatory and antioxidant activities. AB - A pectic polysaccharide, designated as PD, was extracted from fresh plums (Prunus domestica L.) with a simulated gastric fluid. Galacturonan, which was partially substituted with methyl and O-acetyl ester groups, and rhamnogalacturonan were the main constituents of the linear regions of the sugar chains of PD. The ramified region contained mainly 1,4-linked beta-d-galactopyranose residues and, to a lesser extent, 1,5-linked alpha-l-arabinofuranose residues. The separation of PD, by DEAE-cellulose column chromatography, yielded two pectic fractions: PD 1 and PD-2, eluted with 0.1 and 0.2 M NaCl, respectively. Enzymatic digestion of PD with 1,4-alpha-d-polygalacturonase yielded the fraction PD-E. The parent pectin PD and the PD-1 fraction were found to diminish the adhesion of peritoneal leukocytes at the concentrations of 0.05-1.0mg/ml. However, the PD-E fraction failed to have an effect on cell adhesion at the concentrations of 0.05-0.1mg/ml. PD, PD-1 and PD-E were found to inhibit the production of superoxide anion radicals by reducing xanthine oxidase activity by 38%, 97% and 47%, respectively. Therefore, the PD-1 fraction appeared to be an active fragment of pectic macromolecule isolated from fresh plum with a simulated gastric fluid. PMID- 24054220 TI - Renoprotective effects of Maillard reaction products generated during heat treatment of ginsenoside Re with leucine. AB - The structural change of ginsenoside and the generation of Maillard reaction products (MRPs) are important to the increase in the biological activities of Panax ginseng. This study was carried out to identify the renoprotective active component of P. ginseng using the Maillard reaction model experiment with ginsenoside Re and leucine. Ginsenoside Re was gradually converted into less polar ginsenosides Rg2, Rg6 and F4 by heat-processing, followed by separation of the glucosyl moiety at carbon-20. The free radical-scavenging activity of the ginsenoside Re-leucine mixture was increased by heat-processing. The improved free radical-scavenging activity by heat-processing was mediated by the generation of MRPs from the reaction of glucose and leucine. The cisplatin induced LLC-PK1 renal cell damage was also significantly reduced by treatment with MRPs. Moreover, the heat-processed glucose-leucine mixture (major MRPs from the ginsenoside Re-leucine mixture) showed protective effects against cisplatin induced oxidative renal damage in rats through the inhibition of caspase-3 activation. PMID- 24054221 TI - Influence of germination and extrusion with CO(2) injection on physicochemical properties of wheat extrudates. AB - Whole wheat and germinated wheat flour were extruded in a laboratory co-rotating twin screw extruder with die temperatures (90 and 130 degrees C), screw speeds (150 and 200rpm) and CO2 injection. The effects of germination and extrusion process on specific mechanical energy (SME) input, expansion ratio, specific length, piece density, elastic modulus, breaking strength, colour, water solubility index (WSI), water absorption index (WAI) and microstructure were determined. The study showed that the use of germinated wheat flour increased the specific length, lightness and the WSI. When CO2 was injected, the expansion ratios (only 90 degrees C die temperature for extruded germinated wheat) and lightness were significantly increased (p<0.05). The chemical properties (crude protein, fat, ash, reducing sugar, gamma-aminobutyric acid, soluble arabinoxylans, beta-glucan and phytic acid) were also investigated. The germination step and extrusion process mainly affected the chemical properties. However, the difference of die temperatures, screw speed and CO2 injection had slight effect on the chemical properties. PMID- 24054222 TI - A new ultra-rapid UHPLC/MS/MS method for assessing glucoraphanin and sulforaphane bioavailability in human urine. AB - Sulforaphane (SFN) is the product of the enzymatic hydrolysis of glucoraphanin (GR), the main glucosinolate present in broccoli sprouts. The beneficial actions attributed to SFN are mainly supported by in dietary study not clear. Surely the panellists ate more than just the broccoli portion - please clarify vitro experiments; further in vivo assays are necessary to analyse the described biological actions in humans. A new ultra-fast, accurate, robust, and selective UHPLC/MS/MS procedure (2-min chromatogram; >87% recovery; LOQ and LOD of 20-156 and 4-20nmol L(-1), respectively; and intra- and inter-day variations lower than 10%) was used for the simultaneous determination of GR and SFN in human urine. The analytical capacity of this novel method was further tested by determining the bioavailability of GR and its metabolic derivatives in urine from volunteers after the consumption of 1/2 and 1 servings of broccoli sprouts (30 and 60g, respectively). Bioavailability values for SFN of up to 40% after a single intake of both 1/2 and 1 servings showed the suitability of the new method for the determination of exogenous metabolites following dietary interventions. PMID- 24054223 TI - Effect of a Thermoascus aurantiacus thermostable enzyme cocktail on wheat bread qualitiy. AB - Thermophilic fungus Thermoascus aurantiacus (CBMAI 756) on solid-state fermentation using corncob as a nutrient source produces an enzyme pool with the potential to be used in bread making. In this paper, the use of this enzyme cocktail as a wheat bread improver was reported. Both products released by flour arabinoxylan degradation and bread quality were investigated. The main product released through enzyme activity after prolonged incubation was xylose indicating the presence of xylanase; however, a small amount of xylobiose and arabinose also confirmed the presence of xylosidase and alpha-l-arabinofuranosidase, respectively. Enzyme mixture "in vitro" mainly attacked water-unextractable arabinoxylan contributing to beneficial effect in bread making. The use of an optimal enzyme concentration (35U xylanase/100g of flour) increased specific volume (22%), reduced crumb firmness (25%), and reduced amylopectin retrogradation (17%) during bread storage. In conclusion, the enzyme cocktail produced by T. aurantiacus CBMAI 756 can improve wheat bread quality. PMID- 24054224 TI - Relationship analysis between flavonoids structure and subcritical water extraction (SWE). AB - Subcritical water (about 10MPa) is an excellent solvent for extracting non-polar flavonoids by varying the temperature-dependent dielectric constant. This study determined the optimum conditions for subcritical water extraction (SWE), such as the time and temperature, for extracting flavonoids from eight plants, and their dependence on the chemical structure of flavonoids (polarity of side chains and the presence of sugar, and double bonds). Flavonoids having an OH side chain (quercetin at 170 degrees C/10min) were optimally extracted at lower temperatures than O-CH3 (isorhamnetin at 190 degrees C/15min) and H (kaempferol at 190 degrees C/15min) side chains. The optimal temperatures of the glycoside forms including sugar, such as quercitrin (110 degrees C/5min), spiraeoside (150 degrees C/15min), and isoquercitrin (150 degrees C/15min), were lower than of the less polar aglycones (170 degrees C/10min and 190 degrees C/15min). Apigenin, having double bonds, was extracted well at a higher temperature (190 degrees C/15min) than naringenin (170 degrees C/15min) in SWE. PMID- 24054225 TI - Structure and digestibility of endosperm water-soluble alpha-glucans from different sugary maize mutants. AB - The structure and digestibility of endosperm water-soluble alpha-glucans from different sugary-1 maize mutants (Zhongtian 8#, Zhongtian 2# and Pintian 8#) were investigated. The yield of pure glucan was in the range of 25.91-34.38%. The alpha-glucan belonged to a typical native nano-scale particle and the average particle size was in the following order: Zhongtian 8# >Pintian 8# >Zhongtian 2#. The weight-average molar mass of glucans ranged from 1.69 to 2.08*10(7)g/mol. The branch densities and alpha-1,6 linkages of Zhongtian 8#, Zhongtian 2# and Pintian 8#, were 8.60%, 8.77% and 9.51%, 7.71%, 6.58% and 6.81%, respectively. The resistant starch (10.06%) of Pintian 8# was lower than other two cultivars. The study showed that water-soluble glucan exhibited alpha-1,4-linked backbone with alpha-1,6 branch sites and digestibility was influenced by granule size, ratio of alpha-1,4 to alpha-1,6 linkages, molecular fine structure in this set of sugary maize mutants. PMID- 24054226 TI - Konjac glucomannan-induced changes in thiol/disulphide exchange and gluten conformation upon dough mixing. AB - Effects of konjac glucomannan (KGM) on the changes in gluten upon dough mixing were investigated in this study. Wheat flour was blended with KGM and processed into dough. Farinographic analysis showed that KGM caused a significant increase in water absorption and dough development time to reach maximum consistency. Comparison of electrophoretic protein profile from control dough and KGM-dough revealed that protein fractions were similar in molecular size distribution, but the lability of glutenin aggregates slightly differed. Addition of KGM to gluten induced negative effects on exchange between sulfhydryl groups and disulphide bonds. Fourier transform-Raman spectroscopy indicated that secondary structure of gluten proteins was differentially modified related with water absorption of flours before dough formation. This study reveals that when KGM is added to the dough, conformational behaviours of gluten proteins are changed and the hydroxyl groups of KGM might be involved in the interaction by forming strong intermolecular hydrogen bonding system. PMID- 24054227 TI - Dissipation and residues of clethodim and its oxidation metabolites in a rape field ecosystem using QuEChERS and liquid chromatography/tandem mass spectrometry. AB - A rapid, sensitive and selective method using Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) procedure for simultaneous determination of clethodim and its oxidation metabolites (clethodim sulfoxide and clethodim sulphone) in soil, rape plant and rape seed was developed using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). The limits of detection (LODs) of the proposed method ranged from 0.002mg/kg to 0.01mg/kg, and average recoveries were 78.7-104.2%. The trial results showed that clethodim dissipated so rapidly that few clethodim residues were detectable. Clethodim sulfoxide dissipated quickly in rape plant and soil with half-lives of 4.3 and 4.0days, respectively. Clethodim sulphone showed a tendency of rapid increase initially followed by a decrease in rape plant but could not be detected in soil. The terminal residues of clethodim in rape seedsat harvest time were below the maximum residue limit (MRL, 0.5mg/kg). PMID- 24054228 TI - Starch chain interactions within the amorphous and crystalline domains of pulse starches during heat-moisture treatment at different temperatures and their impact on physicochemical properties. AB - Pulse (faba bean [FB], black bean [BB] and pinto bean [PB]) starches were heat moisture treated (HMT) at 80, 100 and 120 degrees C for 12h at a moisture content of ~23%. Structural changes on HMT were monitored by microscopy, HPAEC-PAD, ATR FTIR, WAXS, DSC and susceptibility towards acid and enzyme hydrolysis. Amylopectin chain length distribution remained unchanged in all starches on HMT. In all starches, HMT increased crystallinity and gelatinisation temperatures. The gelatinization enthalpy remained unchanged in some starches, whereas it decreased slightly in other starches on HMT. Slowly digestible starch content decreased at all temperatures of HMT, whereas resistant starch content increased at HMT80 and HMT100 (HMT80>HMT100), but decreased at HMT120. Birefringence, B-type crystallites and acid hydrolysis decreased on HMT. The extent of the above changes varied amongst starch sources and genotypes. HMT altered the X-ray pattern from A+B->A. The results of this study showed that structural reorganisation of starch chains during HMT temperature was influenced by starch chain flexibility, starch chain interactions and crystalline stability of the native granules. PMID- 24054229 TI - Aroma enhancement in wines using co-immobilized Aspergillus niger glycosidases. AB - A major fraction of monoterpenes and norisoprenoids in young wines is conjugated to sugars representing a significant reservoir of aromatic precursors. To promote their release, beta-glucosidase, alpha-arabinosidase, and alpha-rhamnosidase from a commercial Aspergillus niger preparation, were immobilized onto acrylic beads. The aim of this work was the development and application of an immobilized biocatalyst, due to the well-known advantages over soluble enzyme preparations: control of the reaction progress and preparation of enzyme-free products. In addition, the obtained derivative showed increased stability in simile wine conditions. After the treatment of Muscat wine with the biocatalyst for 20days, free monoterpenes increased significantly (from 1119 to 2132MUg/L, p<0.01) with respect to the control wine. Geraniol was increased 3,4-fold over its flavor thresholds, and accordingly its impact on sensorial properties was very relevant: nine of ten judges considered treated wine more intense in fruit and floral notes. PMID- 24054230 TI - A fast, simple and green method for the extraction of carbamate pesticides from rice by microwave assisted steam extraction coupled with solid phase extraction. AB - This paper presented a fast, simple and green sample pretreatment method for the extraction of 8 carbamate pesticides in rice. The carbamate pesticides were extracted by microwave assisted water steam extraction method, and the extract obtained was immediately applied on a C18 solid phase extraction cartridge for clean-up and concentration. The eluate containing target compounds was finally analysed by high performance liquid chromatography with mass spectrometry. The parameters affecting extraction efficiency were investigated and optimised. The limits of detection ranging from 1.1 to 4.2ngg(-1) were obtained. The recoveries of 8 carbamate pesticides ranged from 66% to 117% at three spiked levels, and the inter- and intra-day relative standard deviation values were less than 9.1%. Compared with traditional methods, the proposed method cost less extraction time and organic solvent. PMID- 24054231 TI - Chemical profiling of triacylglycerols and diacylglycerols in cow milk fat by ultra-performance convergence chromatography combined with a quadrupole time-of flight mass spectrometry. AB - An ultra-performance convergence chromatography (UPC(2)) system coupled with quadrupole time-of-flight mass spectrometry (Q-TOF-MS) was successfully utilised to analyse triacylglycerols and diacylglycerols in cow milk fat. This novel approach obtained an improved resolution of triacylglycerols in comparison to previously reported chromatographic methods combined with MS detector in a shorter analytical time. A total of 49 triacylglycerols and 7 diacylglycerols were identified according to their secondary MS profiles and elementary composition. Furthermore, UPC(2) is an environmental friendly analytical method with a drastic reduction of organic solvent usage. The established UPC(2)-MS approach has potential application in lipidomics as an alternative method besides LC-MS and GC-MS. PMID- 24054232 TI - Development and application of recombinant antibody-based immunoassays to tetraconazole residue analysis in fruit juices. AB - Tetraconazole is currently used as a fungicide in fruit and vegetables. The aim of this work was the development of immunochemical techniques based on recombinant antibodies for the screening of tetraconazole residues in fruit juices. Recombinant antibodies were produced from a hybridoma cell line secreting a monoclonal antibody specific for tetraconazole and from lymphocytes of mice hyperimmunised with tetraconazole haptens conjugated to bovine serum albumin. From these antibodies, enzyme-linked immunosorbent assays in the conjugate-coated format were developed, which were able to detect tetraconazole standards down to 1ng/mL. From recovery studies with spiked samples, these immunoassays determined tetraconazole in orange and apple juices with acceptable reproducibility (coefficients of variation below 25%) and recoveries (ranging from 78% to 145%) for a screening technique. The analytical performance of RAb-based immunoassays was fairly similar to that of the MAb-based immunoassays. Due to their simplicity and high sample throughput, the developed recombinant-based immunoassays can be valuable analytical tools for the screening of tetraconazole residues in fruit juices at regulatory levels. PMID- 24054233 TI - An assay for pro-oxidant reactivity based on phenoxyl radicals generated by laccase. AB - A transient species may be detected with UV-vis and EPR spectroscopy during turnover of a laccase with quercetin; this species is assigned as a quercetin derived radical, based on EPR spectra as well the observed UV-vis similarities (a 540nm centred band) with previously reported data. The rates of formation and decay of this species correlate well (r=0.9946) with the pro-oxidant reactivity manifested by flavonoids in the presence of laccase. An assay for the pro-oxidant reactivity of natural products is hence proposed based on the results reported here; its application is demonstrated for a series of pure compounds as well as for several propolis extracts. This assay has the advantages of using a biologically relevant process (haemoglobin oxidation), and not requiring the addition of oxidising agents such as peroxide or superoxide. Correlations, or the lack thereof, between the pro-oxidant parameters and the redox potentials, antioxidant capacities and lipophilicities, were analysed. The laccase employed in our study does display reactivity-related similarities to a range of other proteins, including human plasma ceruloplasmin. PMID- 24054234 TI - Comparison of NIRS approach for prediction of internal quality traits in three fruit species. AB - NIR Spectroscopy ability was investigated to assess the fruit structure effect (passion fruit, tomato and apricot) on prediction performance of soluble solids content (SSC) and titratable acidity (TA). Relationships between spectral wavelengths and SSC and TA were evaluated through the application of chemometric techniques based on partial least squares (PLS). Good prediction performance was obtained for apricot with correlation coefficients of 0.93 and 0.95 for SSC and TA and root mean square errors of prediction (RMSEP%) of 3.3% and 14.2%, respectively. For the passion fruit and tomato, the prediction models were not satisfactorily accurate due to the high RMSEP. Results showed that NIR technology can be used to evaluate apricot internal quality, however, it was not appropriate to evaluate internal quality in fruits with thick skin, (passion fruit), and/or heterogeneous internal structure (tomato). PMID- 24054235 TI - Nutritional and sensory quality during refrigerated storage of fresh-cut mints (Mentha*piperita and M. spicata). AB - The effect of storage time on quality attributes of refrigerated fresh-cut mints (Mentha*piperita and M. spicata) was studied. Atmosphere composition, respiratory activity, weight loss, surface colour, total chlorophyll, carotenoids, browning potential, total phenols, flavonoids, radical-scavenging activity, ascorbic acid and essential oil yield and composition were analysed. Respiratory activity of peppermint and spearmint samples diminished moderately (42% and 28%, respectively) after 21days at 0 degrees C. A slight modification of the internal atmosphere was achieved. Surface colour, chlorophyll, carotenoid and antioxidant compounds remained almost constant. The yield of essential oil did not change or it showed an apparent increase after 21days at 0 degrees C, depending on plant growth stage. The characteristic flavour components of peppermint (menthone and menthol) increased, while the contents of the main constituents of spearmint essential oil showed minor variations after storage. The conditions assayed for packaging and storing fresh-cut mints were adequate to achieve a relatively long shelf life and they retained their antioxidant properties. PMID- 24054236 TI - New benzoate derivatives and hirsutane type sesquiterpenoids with antimicrobial activity and cytotoxicity from the solid-state fermented rice by the medicinal mushroom Stereum hirsutum. AB - In addition to the fruiting bodies, mushroom mycelia can be used as functional foods and nutraceutical materials. In this study, two new benzoate derivatives (1 and 2) and three new sesquiterpenoids (3-5) were isolated from the mycelia of Stereum hirsutum. Their chemical structures were elucidated by NMR experiments. The absolute configuration in 3 was assigned by X-ray crystallographic analysis. In bioactivities evaluation, compounds 1 and 2 showed antimicrobial effects against methicillin-resistant Staphylococcusaureus, and S. aureus with the MIC values of 25.0MUg/mL; compounds 1 and 3 inhibited the NO overproduction in the LPS-induced macrophages with the IC50 values of 19.17 and 15.44MUM, and also displayed cytotoxicity against A549 and HepG2 with IC50 in the range of 10-50MUM. These results support the usage of the mycelia of S. hirsutum as a good functional food. PMID- 24054237 TI - Active peptides from skate (Okamejei kenojei) skin gelatin diminish angiotensin-I converting enzyme activity and intracellular free radical-mediated oxidation. AB - Skin gelatin of skate (Okamejei kenojei) was hydrolyzed using Alcalase, flavourzyme, Neutrase and protamex. It was found that the Alcalase hydrolysate exhibited the highest angiotensin-I converting enzyme (ACE) inhibitory activity. Then, Alcalase hydrolysate was further hydrolyzed with protease and separated by an ultrafiltration membrane system. Finally, two peptides responsible for ACE inhibitory activity were identified to be MVGSAPGVL (829Da) and LGPLGHQ (720Da), with IC50 values of 3.09 and 4.22MUM, respectively. Moreover, the free radical scavenging activity of the purified peptides was determined in human endothelial cells. In addition, the antioxidative mechanism of the purified peptides was evaluated by protein and gene expression levels of antioxidant enzymes. The current study demonstrated that the peptides derived from skate skin gelatin could be used in the food industry as functional ingredients with potent antihypertensive and antioxidant benefits. PMID- 24054238 TI - Regional sensory and chemical characteristics of Malbec wines from Mendoza and California. AB - Malbec grapes are widely grown and studied in Argentina, whereas the smaller production in California is less well known. This study sought to define and compare Malbec wine compositions from various regions in Mendoza, Argentina and California, USA. The Malbec wines were clearly separated, based on their chemical and sensory profiles, by wine region and country. Descriptors of Malbec wines were aromas of cooked vegetal, earthy, soy and volatile acidity, as well as acidic taste and astringent mouthfeel, regardless of the region of origin. Malbec wines from Mendoza generally had more ripe fruit, sweetness, and higher alcohol levels, while the Californian Malbec wines had more artificial fruit and citrus aromas, and bitter taste. Compositional differences between the two countries were related more to altitude than precipitation and growing degree days. To our knowledge, this is the first time that an extensive regionality study has been attempted for Malbec wines. PMID- 24054239 TI - Kinetic changes of nutrients and antioxidant capacities of germinated soybean (Glycine max L.) and mung bean (Vigna radiata L.) with germination time. AB - The objectives of this research were to systematically assess the functional values of germinated soybean and mung bean, and to determine the optimal germination time for yielding functional substances. Changes in phenolics, ascorbic acid, isoflavone, as well as antioxidant capacities of soybean and mung bean during germination were investigated. Results showed that germination had positive enhancement effects on bioactive compounds in beans. Both compositions and contents of isoflavones in soybean were influenced by germination, three-day germination was optimal time for production of germinated soybean with the highest total isoflavone content (4.68mg/g dry product), the contents of genistein, daidzein, total aglycone in germinated soybean were increased 3, 2.4, and 2.5 folds, respectively, as compared to non-germinated soybean. Current results indicate that germinated beans are better raw materials than non germinated beans for gaining health beneficial substances. PMID- 24054240 TI - Homoarginine, beta-ODAP, and asparagine contents of grass pea landraces cultivated in Turkey. AB - The seeds of grass pea (Lathyrus sativus L.), a drought tolerant crop, were analysed for quantitative determination of the free amino acids beta-N-oxalyl-l alpha,beta-diaminopropionic acid (beta-ODAP), homoarginine and asparagine by a simple and fast capillary electrophoretic method. In boric acid (80mM, pH 8.0) running buffer system, not only were alpha and beta-ODAP successfully separated, but also an efficient sample stacking was achieved during hydrodynamic sample introduction. The validated method was used for quantification of beta-ODAP, homoarginine and asparagine in seed extracts of 52 Lathyrus local landraces from various regions of Turkey and one released cultivar. The concentration ranges of amino acids were found as 0.21-1.27% (w/w) for homoarginine, 0.10-0.87% (w/w) for beta-ODAP and 0.006-0.47% (w/w) for asparagine. A positive correlation between homoarginine and beta-ODAP quantities in seeds of 53 Lathyrus local landraces was shown to exist (r(2)=0.649). PMID- 24054241 TI - Garnacha Tintorera-based sweet wines: detailed phenolic composition by HPLC/DAD ESI/MS analysis. AB - Sweet wines are traditionally elaborated in Galicia (the N.W. corner of Spain). The denomination of origin (DO) Valdeorras, one of the five DOs in Galicia, wants to promote the production and marketing of new sweets wines. The first one is made with dried red grapes Vitis vinifera L. Garnacha Tintorera (GNSW); this cultivar is a teinturier cultivar which has excellent potential to produce wines from raisined grapes. The second one, a fortified sweet wine aged in oak barrels (GFSW). Additionally a dry young wine (GBW) was produced from the same variety. Their aroma profiles and chromatic characteristics (determined by simple spectrophotometric methods) have been previously established. Now, proanthocyanidins, flava-3-ol monomers, anthocyanins, phenolic acids, flavonols and resveratrol were determined by HPLC, for the same three wines. The highest concentration of total proanthocyanidins (PAs) was evaluated in the GBW (525mgL( 1)), which was about 2-fold the concentration in the GNSW (236mgL(-1)) and about more 10-fold the concentration in the GFSW (44mgL(-1)). No apparent difference in the aDP (mean degree of polymerisation) was observed for the GBW (1.9) and the GNSW (2.1), whereas a slightly lower value was obtained for the GFSW (1.5). Total anthocyanin concentration was described as follow as GBW: 390mgL(-1)?GNSW: 57mgL( 1)>GFSW: 25mgL(-1), which indicates that sweet wines were polymerised in great extent. Only vitisin A and B were found the main concentration in GFSW when compared to GBW by the ageing process. In sweet wines, phenolic acids (hydroxybenzoic and hydroxycinnamic acids) and flavonols were lowest when compared to GBW and resveratrol not was found in sweet wines. PMID- 24054242 TI - Development of a sensitive monoclonal antibody-based indirect competitive enzyme linked immunosorbent assay for analysing chlorantraniliprole residues. AB - Chlorantraniliprole (CAP) is a new anthranilic diamide insecticide acting with high efficacy on ryanodine receptors of most of the species within the Lepidoptera order and has been used worldwide. To monitor its residue in food and environmental samples, we developed an indirect competitive enzyme-linked immunosorbent assay (icELISA), based on monoclonal antibodies. The established icELISA possesses a concentration of producing 50% inhibition (IC50) of 1.60ng/mL. In addition, the assay had the average recoveries of 79-119% when CAP was fortified in tap water, soil, spinach (Spinacia oleracea), and rape (Brassica campestris). Moreover, the icELISA results of spinach samples were confirmed by high performance liquid chromatography-mass spectrometry. Overall, we demonstrate that the developed immunoassay could be used as the quick and convenient determination method of CAP residues in environmental and agricultural samples. PMID- 24054243 TI - Phenolic profile and antioxidant activity in selected seeds and sprouts. AB - The aim of this study was to investigate the effect of germination on the phenolic acids and flavonoids profile, as well as antioxidant activity (AA), in selected edible seeds of mung beans, radish, broccoli and sunflower. Germination increased the total phenolic (TP) and flavonoid (TF) levels, as well as the AA of the seeds, and influenced the profile of free and bound phenolic compounds. Among the samples, mung bean was characterised by lowest levels of TP and TF, as well as AA, evaluated using ABTS, DPPH and FRAP assays. Sunflower and radish sprouts were the most rich in phenolic compounds. Insignificant amounts of free phenolic acids were found in the free phenolic acid fraction; alkaline hydrolysis of the seeds and sprouts extracts provided the majority of the phenolic acids. The amounts of free and bound flavonoids were inconsiderable both for seeds and sprouts. PMID- 24054244 TI - Quality evaluation of the edible blue-green alga Nostoc flagelliforme using a chlorophyll fluorescence parameter and several biochemical markers. AB - Nostoc flagelliforme is an edible blue-green alga with herbal and dietary values. Due to the diminishing supply of natural N. flagelliforme and the large investment on the development of its cultivation technology, it is anticipated that artificially cultured N. flagelliforme will soon sustain the market supply. Once this change occurs, the storage-associated quality problem will become the focus of attention for future trade. In this paper, we used a chlorophyll fluorescence parameter, maximum quantum efficiency of Photosystem II (Fv/Fm), and several biomarkers to evaluate the quality of several N. flagelliforme samples. It was found that longer storage times resulted in darker coloured solutions (released pigments) and decreased amounts of chlorophyll a (Chl a) and water soluble sugars (WSS). Additionally, a higher Fv/Fm value suggests better physiological recovery and quality. In actual application, determination of Fv/Fm would be the first step for evaluating the quality of N. flagelliforme, and the biochemical indexes would serve as good secondary markers. PMID- 24054245 TI - Effects of heat stress during grain filling on the structure and thermal properties of waxy maize starch. AB - Clarifying the waxy maize starch physicochemical characteristics response to heat stress could modify starch quality. The effects of heat stress during grain filling (1-40day after pollination) on starch structure and thermal properties of four waxy maize varieties were investigated. The mean day/night temperature during grain filling for heat stress and control treatments was 35.2/16.1 degrees C and 27.4/15.6 degrees C, respectively. Heat stress during grain filling increased the starch average granule size and the proportion of long chains in amylopectin. Starch granules under heat stress presented more pitting or uneven surfaces. X-ray peak intensities in response to heat stress were variety dependent. Heat stress during grain filling decreased the swelling power and increased the gelatinization temperature and retrogradation percentage, while the gelatinization enthalpy was not affected. In conclusion, heat stress during grain filling significantly affected structural characteristics of waxy maize starch and consequently, changed its swelling and thermal properties. PMID- 24054246 TI - Highly efficient solvent-free synthesis of 1,3-diacylglycerols by lipase immobilised on nano-sized magnetite particles. AB - Recently, 1,3-DAGs (1,3-diacylglycerols) have attracted considerable attention as healthy components of food, oil and pharmaceutical intermediates. Generally, 1,3 DAG is prepared by lipase-mediated catalysis in a solvent free system. However, the system's high reaction temperature (required to reach the reactants' melting point), high substrate concentration and high viscosity severely reduce the lipase's activity, selectivity and recycling efficiency. In this report, MjL (Mucor javanicus lipase) was found to have the best performance in the solvent free synthesis of 1,3-DAGs of several common commercial lipases. By covalent binding to amino-group-activated NSM (nano-sized magnetite) particles and cross linking to form an enzyme aggregate coat, MjL's specific activity increased 10 fold, and was able to be reused for 10 cycles with 90% residual activity at 55 degrees C. 1,3-DAGs of lauric, myristic, palmitic, stearic, oleic and linoleic acid were prepared using the resulting immobilised enzyme, all with yields greater than 90%, and the reaction time was also greatly reduced. PMID- 24054247 TI - Differentiation of lemon essential oil based on volatile and non-volatile fractions with various analytical techniques: a metabolomic approach. AB - Due to the importance of citrus lemon oil for the industry, fast and reliable analytical methods that allow the authentication and/or classification of such oil, using the origin of production or extraction process, are necessary. To evaluate the potential of volatile and non-volatile fractions for classification purposes, volatile compounds of cold-pressed lemon oils were analyzed, using GC FID/MS and FT-MIR, while the non-volatile residues were studied, using FT-MIR, (1)H-NMR and UHPLC-TOF-MS. 64 Lemon oil samples from Argentina, Spain and Italy were considered. Unsupervised and supervised multivariate analyses were sequentially performed on various data blocks obtained by the above techniques. Successful data treatments led to statistically significant models that discriminated and classified cold-pressed lemon oils according to their geographic origin, as well as their production processes. Studying the loadings allowed highlighting of important classes of discriminant variables that corresponded to putative or identified chemical functions and compounds. PMID- 24054248 TI - Chemical modification of an acidic polysaccharide (TAPA1) from Tremella aurantialba and potential biological activities. AB - TAPA1 was previously isolated from Tremella aurantialba fruiting bodies. In this paper, an acetylated derivative (TAPA1-ac) and a deactylated derivative (TAPA1 deac) of TAPA1 were prepared, and their characterization and immunostimulating activities were reported. Acetylation and deacetylation were found to occur actually by FT-IR and NMR spectra, together with calculational results. The degree of substitution (DS) of acetyl groups in TAPA1-ac was 0.23 and the content was 5.82%, which was higher than those of TAPA1 (0.03% and 0.70%, respectively) and TAPA1-deac (all were zero). Compared with TAPA1, TAPA1-ac showed significant immunostimulation effects on mouse spleen lymphocytes (MSLs) proliferation and nitric oxide (NO) production by macrophages RAW264.7, whereas TAPA1-deac showed markedly lower effects. These findings seemed to suggest that immunostimulating activities, including MSLs stimulation activity and NO production potency, might relate to the DS and content of acetyl groups, indicating that acetylation of TAPA1 was an effective way of enhancing immuno-stimulating activities. PMID- 24054249 TI - Determination of polycyclic aromatic hydrocarbons (PAH4) in food by vesicular supramolecular solvent-based microextraction and LC-fluorescence detection. AB - An organic solvent-free microextraction was proposed as a simple and fast sample treatment for the determination of PAH4 (viz. benz[a]anthracene, chrysene, benzo[b]fluorantene and benzo[a]pyrene). The method involved the stirring of 200mg of foodstuff with 200MUL of a supramolecular solvent made up of octanoic acid/tetrabutylammonium octanoate vesicles for 10min. Then, the extract was analysed by liquid chromatography/fluorescence detection. Neither dilution nor further clean-up steps of the extracts were needed. The limit of quantitation of the method (0.3-0.7MUgkg(-1)) was below the threshold limit established for benzo[a]pyrene in food by EU directives (1-10MUgkg(-1)). The method was successfully applied to the analysis of smoked meat and fish, bivalve mollusks and processed cereal-based food for infants. Benzo[a]pyrene was quantified and/or detected in most of the analysed samples. The recoveries obtained for PAH4 were from 92% to 103% with relative standard deviations less than 5%. PMID- 24054250 TI - Determination of sulfonylureas in cereal samples with electrophoretic method using ionic liquid with dispersed carbon nanotubes as electrophoretic buffer. AB - A capillary electrophoresis method to determine four sulfonylureas in grain samples was developed using 10mM of 1-butyl-3-methyl imidazolium tetrafluoroborate (bminBF4) as electrophoretic buffer solution. 2mgL(-1) of Surfactant Coated-Single Wall-Carbon Nanotubes (SC-SWCNTs) was added to the buffer solution to improve the resolution. In this way, the separation of nicosulfuron, ethoxysulfuron, sulfometuron methyl and chlorsulfuron was carried out in 16min without using organic solvents. A clean up-preconcentration procedure was done prior to inject the sample into the CE instrument, in order to achieve the established maximum residue limits (MRLs). So, the detection limits (LODs) for each analytes were between 16.8 and 26.6MUgkg(-1). The relative standard deviations (RSDs) were in the range 1.9-6.7%. A recovery study using the so-called matrix matched calibration demonstrates that no matrix interferences were found throughout the determination. The recovery percentages were ranged between 80% and 113%. PMID- 24054251 TI - Comparison of phenolic compounds of orange juice processed by pulsed electric fields (PEF) and conventional thermal pasteurisation. AB - Processing of orange juice by pulsed electric fields (PEF) and thermal pasteurisation was carried out to compare changes in total phenolic concentration, hydroxybenzoic acid, hydroxycinnamic acids, flavonols, flavones and flavonones before and after being stored at 4 degrees C for 180days. Changes in the initial total phenolic concentration of the samples varied depending on the applied electric field intensity and thermal pasteurisation. Hesperidin and chlorogenic acids were detected as the most abounded flavonoid and phenolic acids in the orange juice, respectively. Except for syringic acid and neoeriocitrin, the concentration of the phenolic compounds indentified in the orange juice samples enhanced after the PEF or thermal pasteurisation. The samples treated with PEF had more stable flavonoids and phenolic acids than those treated with the thermal pasteurisation. The PEF-treated samples had higher sensory scores than the heat-treated samples. PMID- 24054252 TI - Antitumour and antioxidant potential of some selected Pakistani honeys. AB - Antitumour potential of honey is attributed to its excellent antioxidant activity which in turn depends on the geographical origin. The present study focuses on exploration of antioxidant and antitumour potential as well as total phenolic contents (TPC) of 58 Pakistani honeys involving spectrochemical techniques and potato disk assay. Agrobacterium tumefaciens was used to induce tumours in potato disks. All analysed honey samples exhibited 1.33+/-0.00-155.16+/-0.98mg/100g of TPC, 50% 2,2-diphenyl picryl hydrazyl (DPPH) inhibition, ?7.36+/-0.43-39.86+/ 2.34mg/100g qurecitin equivalent antioxidant contents, ?13.69+/-0.91-65.50+/ 1.37mg/100g ascorbic acid equivalent antioxidant contents, 64.65+/-0.43-1780.74+/ 11.79mM ferric reducing antioxidant power and 60% peroxide inhibition. Antitumour activity observed for 43 natural and 10 commercial samples was ?20%. Two samples from Faisalabad region showed 87.50+/-5.50% and 79.00+/-5.56% antitumour activity which were reference standard. It was concluded that Pakistani honeys possessed excellent antioxidant and antitumour potential overall. PMID- 24054253 TI - New approaches to determination of HMF. AB - Several techniques have been used for hydroxymethylfurfural (HMF) detection in foods. Most of these involve the protein hydrolysation step process to determine the presence of organic acid with heat treatment. The affinity and separability of HMF to/from some proteins were exhibited in this study. Also, the dependency of HMF level was determined in the presence of some substances such as reductive and non-reductive sugars, gums and polysaccharides due to high temperature and acidity during the hydrolysation stage. Consequently, the HMF levels of the samples were evaluated separately either by no treatment or by the acid-heat treated method. The HMF amount which was measured by the conventional method was found to be dependent on the sample amount. The binding capacity of HMF to casein was about 10% but did not bind to the gluten in the model system. However it was not released from the caseine by acid hydrolysation in the solvent. PMID- 24054254 TI - Protective effects of Ziyang tea polysaccharides on CCl4-induced oxidative liver damage in mice. AB - This study was designed to investigate the hepatoprotective effects of the tea polysaccharides (ZTPs) extracted from a selenium-enriched Ziyang green tea (Camellia sinensis). ZTPs were identified as the heteropolysaccharides with glucose (31.4%), arabinose (23.5%) and galactose (21.8%) being the main constitutive monosaccharides. ZTPs displayed noteworthy scavenging effects against DPPH, OH and O2(-), and high antioxidant effects in vitro, and the effects were further verified by suppressing CCl4-induced oxidative liver damage in mice at 100, 200 and 400mg/kg BW. Administration of ZTPs in mice prior to CCl4 significantly prevented the CCl4-induced increases in serum alanine aminotransferase, aspartate aminotransferase and lactic dehydrogenase, as well as hepatic malondialdehyde level. Mice treated with ZTPs showed normal glutathione peroxidase and superoxide dismutase activities, relative to CCl4-treated group. ZTPs also prevented the CCl4-caused liver histological alteration, as indicated by histopathological evaluation. These findings demonstrate that ZTPs have protective effects against acute CCl4-induced oxidative liver damage. PMID- 24054255 TI - Stability of vitamin D(3) encapsulated in nanoparticles of whey protein isolate. AB - Vitamin D(3) was entrapped in whey protein isolate (WPI) nanoparticles prepared by different calcium concentration and aggregation pH. Its stability was investigated in presence of air for 7days. Residual of vitamin D(3) in nanoparticles was higher compared to control samples (water, native WPI and denaturized WPI). Presence of calcium in composition of particles resulted in formation of compact structure and inhibition of oxygen diffusion in particle. Lower concentration of vitamin D(3) (280MUg/ml versus 560MUg/ml) had negative effect on residual amount of vitamin. The loss of vitamin D(3) during storage time was described by a second order reaction. The results illustrate that these nanoparticles can be used in clear or non clear beverages as enriching agent. PMID- 24054256 TI - Application of a high-throughput process analytical technology metabolomics pipeline to Port wine forced ageing process. AB - Metabolomics aims at gathering the maximum amount of metabolic information for a total interpretation of biological systems. A process analytical technology pipeline, combining gas chromatography-mass spectrometry data preprocessing with multivariate analysis, was applied to a Port wine "forced ageing" process under different oxygen saturation regimes at 60 degrees C. It was found that extreme "forced ageing" conditions promote the occurrence of undesirable chemical reactions by production of dioxane and dioxolane isomers, furfural and 5 hydroxymethylfurfural, which affect the quality of the final product through the degradation of the wine aromatic profile, colour and taste. Also, were found high kinetical correlations between these key metabolites with benzaldehyde, sotolon, and many other metabolites that contribute for the final aromatic profile of the Port wine. The use of the kinetical correlations in time-dependent processes as wine ageing can further contribute to biological or chemical systems monitoring, new biomarkers discovery and metabolic network investigations. PMID- 24054257 TI - Factors affecting the binding of trout HbI and HbIV to washed cod mince model system and their influence on lipid oxidation. AB - Electrostatic interactions between haemoglobin (Hb) and muscle components of fish may be an initial step of Hb-mediated lipid oxidation. This mechanism was investigated by examining the interaction of anionic HbIV and cationic HbI with insoluble components of washed cod mince under different pH and salt conditions. Lipid oxidation was monitored in parallel using the thiobarbituric acid reactive substances (TBARS) test. Higher binding of HbI to washed cod mince occurred compared to HbIV, yet HbIV better promoted lipid oxidation. An increase in pH from 5.7 to 6.3 and further to 7.0 lowered both Hb-binding and TBARS development. Addition of NaCl decreased Hb-binding but still did not influence Hb-mediated lipid oxidation. Thus, Hb binding had no consistent effect on lipid oxidation of washed cod mince. Rapid haemin release from the anionic Hb appeared to be a primary facilitator of lipid oxidation, overshadowing the greater binding ability of the cationic Hb. PMID- 24054258 TI - Quantification of bioactive compounds in pulps and by-products of tropical fruits from Brazil. AB - This study aimed to quantify the levels of resveratrol, coumarin, and other bioactives in pulps and by-products of twelve tropical fruits from Brazil obtained during pulp production process. Pineapple, acerola, monbin, cashew apple, guava, soursop, papaya, mango, passion fruit, surinam cherry, sapodilla, and tamarind pulps were evaluated as well as their by-products (peel, pulp's leftovers, and seed). Total phenolic, anthocyanins, yellow flavonoids, beta carotene and lycopene levels were also determined. Resveratrol was identified in guava and surinam cherry by-products and coumarin in passion fruit, guava and surinam cherry by-products and mango pulp. These fruit pulp and by-products could be considered a new natural source of both compounds. Overall, fruit by-products presented higher (P<0.05) bioactive content than their respective fruit pulps. This study provides novel information about tropical fruits and their by-products bioactive composition, which is essential for the understanding of their nutraceutical potential and future application in the food industry. PMID- 24054259 TI - Study on the simultaneous determination of seven benzoylurea pesticides in Oolong tea and their leaching characteristics during infusing process by HPLC-MS/MS. AB - A method for the simultaneous determination of 7 benzoylurea pesticides (chlorfluazuron, diflubenzuron, fluazuron, flufenoxuron, hexaflumuron, teflubenzuron and triflumuron) in the manufactured Oolong tea leaves and its infusion was described. The method has a LOD of 0.03-1.00ng/mL, a recovery of 90.4-103% for made tea and 90.3-102% for tea-infused liquid, respectively. By using the proposed method, the leaching characteristics of above 7 pesticides during infusing process were investigated. The experimental results revealed that: (1) diflubenzuron can be most easily extracted out during infusing process, followed by triflumuron, teflubenzuron, hexaflumuron, chlorfluazuron, flufenoxuron and fluazuron. (2) The leaching of flufenoxuron and chlorfluazuron during infusing process seems to be controlled by only their solubility, whereas, the leaching of other 5 benzoylurea insecticides was primarily controlled by their partitioning coefficient between made tea and hot water. The results of this study are helpful for the accurate evaluation of the safety of Oolong tea. PMID- 24054260 TI - Separation of long chain fatty acids with different number of unsaturated bonds by fractional extraction: experimental and COSMO-RS study. AB - Long chain unsaturated fatty acids (LCUFAs) are important food components and dietary supplements due to their beneficial health effects. The key process to produce high-purity LCUFAs is to separate long chain fatty acids (LCFAs) with different degrees of unsaturation and chain lengths. This process faces great challenge because of similar physico-chemical properties of fatty acids concerned. In this work, fractional extraction is proposed to separate LCFAs, using eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), conjugated linoleic acids (CLAs), oleic acid (OA) and stearic acid (SA) as model LCFAs. COSMO-RS calculations were performed for fast extractant screening and exploring the potential separation mechanism. Satisfactory distribution coefficients and high selectivities were obtained in extraction equilibrium experiments. Simulation and experimental validation of fractional extraction were performed, and high purity and high yield of CLAs were obtained. EPA and DHA could be separated thoroughly from OA, though they could not be separated each other. PMID- 24054261 TI - Characterisation of different digestion susceptibility of lupin seed globulins. AB - This study describes in vitro digestion of lupin seed globulins by pancreatin, trypsin and chymotrypsin. Lupin seed globulins turned out to be almost totally susceptible to chymotrypsin digestion. When panceratin or trypsin were used for digestion of lupin seed globulins, gamma-conglutin appeared to be resistant to proteolysis. Different fluorescence spectroscopic methods such as fluorescence anisotropy, fluorescence lifetimes and fluorescence quenching measurements were used for detailed characterisation of this phenomenon. A potential reason for gamma-conglutin insensitivity to digestion may be related to the fact that lysine, as well as arginine, are positively charged at cell physiological pH. Simultaneously, flavonoids at this pH are partially ionised, which may lead to the occurrence of ionic interactions between these molecules at pH 7.5. The confirmation of this explanation may be the fact that gamma-conglutin and vitexin form a static complex, which was observed using fluorescence quenching measurements. PMID- 24054262 TI - Non-volatile taste components of several cultivated mushrooms. AB - Five species of dried mushrooms are commercially available in China, namely Agrocybe cylindracea, Pleurotus cystidiosus, Agaricus blazei, Pleurotus eryngii, and Coprinus comatus, and their nonvolatile taste components were studied. Trehalose (12.23-301.63mg/g) and mannitol (12.37-152.11mg/g) were considered as the major mushroom sugar/polyol in the five test species. The total free amino acid levels ranged from 4.09 to 22.73mg/g. MSG-like components contents ranged from 0.97 to 4.99mg/g. 5'-Nucleotide levels ranged from 1.68mg/g in P. eryngii to 3.79mg/g in C. comatus. Fumaric acid (96.11mg/g) in P. cystidiosus were significantly higher compared with the other mushrooms, and citric acid (113.13mg/g), as the highest of any organic acid among the five mushrooms, were found in A. blazei. Equivalent umami concentrations values in these five test mushrooms ranged from 11.19 to 88.37g/100g dry weight. A. blazei, C.comatus and A. cylindracea possessed highly strong umami taste. PMID- 24054263 TI - Isolation, analysis and structures of phototoxic fagopyrins from buckwheat. AB - Buckwheat products are commonly used in health foods and food supplements. However, public awareness regarding the presence of photodynamic naphthodianthrones fagopyrins that can cause photosensitization is low. At least two additional compounds with structures similar to that of fagopyrin are known to exist; however, the structures of these compounds have never been determined. In this work, we improved the extraction procedure and the chromatographic analysis of fagopyrins by developing a simple, sensitive and high-resolution high performance liquid chromatography (HPLC) analytical method using fluorescence detection. We observed at least six fagopyrin derivatives, which were isolated and characterized via UV-Vis absorption, NMR spectroscopy and mass spectrometry. We determined the structures of two new derivatives (fagopyrin A and fagopyrin E) and proved the existence of protofagopyrins that can transform into fagopyrins upon light exposure. Our methods complement the existing knowledge regarding fagopyrins and will allow for their further analysis, isolation and investigation of their biological activity. PMID- 24054264 TI - Chemical, morphological and functional properties of Brazilian jackfruit (Artocarpus heterophyllus L.) seeds starch. AB - Starches used in food industry are extracted from roots, tubers and cereals. Seeds of jackfruit are abundant and contain high amounts of starch. They are discarded during the fruit processing or consumption and can be an alternative source of starch. The starch was extract from the jackfruit seeds and characterised to chemical, morphological and functional properties. Soft and hard jackfruit seeds showed starch content of 92.8% and 94.5%, respectively. Starch granules showed round and bell shape and some irregular cuts on their surface with type-A crystallinity pattern, similar to cereals starches. The swelling power and solubility of jackfruit starch increased with increasing temperature, showing opaque pastes. The soft seeds starch showed initial and final gelatinisation temperature of 36 degrees C and 56 degrees C, respectively; while hard seeds starch presented initial gelatinisation at 40 degrees C and final at 61 degrees C. These results suggest that the Brazilian jackfruit seeds starches could be used in food products. PMID- 24054265 TI - Characterisation of secondary metabolites in saffron from central Italy (Cascia, Umbria). AB - Saffron's quality depends on the concentration of secondary metabolites, such as crocins, picrocrocin and safranal. The aim of this research was to evaluate the influence of drying conditions on the secondary metabolite contents of saffron produced in the area of Cascia, in central Italy. Different aliquots of the same saffron sample were subjected to various dehydration conditions and analysed by UV-Vis spectrophotometry to determine crocins, picrocrocin and safranal.. Safranal was also analysed by high resolution gas chromatography, while the crocins and picrocrocin were determined by high-performance liquid chromatography with diode array and mass spectrometric detectors. The results of chromatographic analyses showed that the samples dried in the milder conditions had the lowest content of secondary metabolites. Moreover the sample dried at 60 degrees C for 55min presented the highest contents of trans-crocin-4 and picrocrocin, while safranal was most represented in saffron dried at 55 degrees C for 95min. PMID- 24054266 TI - Examination of molecular mechanism for the enhanced thermal stability of anthocyanins by metal cations and polysaccharides. AB - Anthocyanins exhibit colour variation over wide pH range but the colour stability is relatively low at the physiological pH. To improve the stability of anthocyanins in neutral to weakly acidic pH region, effects of metal cations and polysaccharides on the colour stability of cyanidin-3-glucoside (C3G) were examined by ultraviolet-visible and resonance Raman spectroscopies. C3G was thermally stabilized by the addition of Fe(3+) but formed aggregation. However, further addition of anionic polysaccharides enhanced the thermal stability of C3G without aggregation. Similar stabilisation was confirmed for delphinidin-3 glucoside (D3G) but not for pelargonidin-3-glucoside. The stability of anthocyanins considerably varied depending on pHs and kinds of metal cations, polysaccharides and buffer molecules. The characteristic resonance Raman bands of C3G-Fe(3+) and D3G-Fe(3+) complexes were significantly affected by the addition of alginate, (18)O/(16)O-isotope substitution, and Fe(2+)/Fe(3+)-replacement. These results suggest that alginate associates with C3G through Fe(3+) to form a stable complex, which enhances the thermal stability of C3G. PMID- 24054267 TI - Alternative sample treatments for the determination of sulfonamides in milk by HPLC with fluorescence detection. AB - This paper presents two sample treatments, dispersive liquid-liquid microextraction (DLLME) and QuEChERS for the determination of 9 sulfonamides, regulated by the EU Council in milk samples. Both methods represent useful alternatives to conventional procedures based mainly in solid-phase extraction, in terms of simplicity, reduction of organic solvents, sample throughput and effectiveness for cleaning-up complex samples. They have been evaluated and compared in terms of efficiency, trueness, sensitivity and precision, using HPLC with fluorescence detection employing a previous derivatisation step with fluorescamine. Clean extracts were obtained with recoveries between 90.8-104.7% and 83.6-104.8% for DLLME and QuEChERS, respectively. Matrix-matched calibration curves were established for both methods using milk samples spiked at four concentration levels. LODs (3xS/N) lower than 1.21MUgL(-)(1) and 2.73MUgL(-)(1) for DLLME and QuEChERS, respectively, were obtained in all cases. The precision, in terms of repeatability and intermediate precision, was lower than 10% in all cases. PMID- 24054268 TI - Automatic spot preparation and image processing of paper microzone-based assays for analysis of bioactive compounds in plant extracts. AB - The colorimetric determination of the concentration of phytochemicals in plant extract samples using a spotting automatic system, mobile phone camera and a computer with developed software for quantification is described. Method automation was achieved by using a robotic system for spotting. The instrument was set to disperse the appropriate aliquots of the reagents and sample on a Whatman paper sheet. Spots were photographed and analysed by ImageJ software or by applying the developed MatLab based algorithm. The developed assay was found to be effective, with a linear response at the concentration range of 0.03 0.25g/L for polyphenols. The detection limit of the proposed method is sub 0.03g/L. The paper microzone-based assays for flavonoids and amino acids/peptides were also developed and evaluated as applicable. Comparing the results with conventional PMUZP methods demonstrates that both methods yield similar results. At the same time, the proposed method has an attractive advantage in analysis time and repeatability/reproducibility. PMID- 24054269 TI - Application of random forests to select premium quality vegetable oils by their fatty acid composition. AB - In order to discriminate premium quality from inexpensive edible oils, the fatty acid profiles of tea, rapeseed, corn, sunflower and sesame oil were compared with the ones from extra virgin olive oil (EVOO). Fatty acid methyl esters were quantified by GC/MS. Principal component analysis (PCA) and random forests (RF) were applied to cluster the samples. RF showed a better ability of discrimination and also revealed the contribution of each variable to the clustering model. The multidimensional scaling (MDS) plot of the RF proximity matrix demonstrated that tea oil was similar to EVOO. Meanwhile, it was observed that the total content of cis-monounsaturated fatty acids (79.48%) in tea oil was close to EVOO (80.71%), especially the oleic acid (77.38% and 77.45%, respectively). The results suggest that tea oil might be a good edible oil choice, considering the high oleic acid content and similar fatty acid profiles compared to those of EVOO. PMID- 24054270 TI - Electron spin resonance spectral analysis of irradiated royal jelly. AB - The analysis of unpaired electron components in royal jelly was carried out using electron spin resonance (ESR) with the aim to develop a detection method for irradiated royal jelly. The ESR spectrum of royal jelly had natural signals derived from transition metals, including Fe(3+) and Cu(2+), and a signal line near g=2.00. After irradiation, a new splitting asymmetric spectrum with overall spectrum width ca. 10mT at g=2.004 was observed. The intensities of the signals at g=2.004 increased in proportion to the absorbed dose in samples under different storage conditions: fresh frozen royal jelly and dried royal jelly powder at room temperature. The signal intensity of the fresh frozen sample was stable after irradiation. One year after 10kGy irradiation of dried powder, the signal intensity was sevenfold greater than before irradiation, although the intensity continued to steadily decrease with time. This stable radiation-induced radical component was derived from the poorly soluble constituent of royal jelly. PMID- 24054271 TI - Relating the variation of secondary structure of gelatin at fish oil-water interface to adsorption kinetics, dynamic interfacial tension and emulsion stability. AB - The objectives of this study were to quantify the relationship between secondary structure of gelatin and its adsorption at the fish-oil/water interface and to quantify the implication of the adsorption on the dynamic interfacial tension (DST) and emulsion stability. The surface hydrophobicity of the gelatin solutions decreased when the pH increased from 4.0 to 6.0, while opposite tend was observed in the viscosity of the solution. The DST values decreased as the pH increased from 4.0 to 6.0, indicating that higher positive charges (measured trough zeta potential) in the gelatin solution tended to result in higher DST values. The adsorption kinetics of the gelatin solution was examined through the calculated diffusion coefficients (Deff). The addition of acid promoted the random coil and beta-turn structures at the expense of alpha-helical structure. The addition of NaOH decreased the beta-turn and increased the alpha-helix and random coil. The decrease in the random coil and triple helix structures in the gelatin solution resulted into increased Deff values. The highest diffusion coefficients, the highest emulsion stability and the lowest amount of random coil and triple helix structures were observed at pH=4.8. The lowest amount of random coil and triple helix structures in the interfacial protein layer correlated with the highest stability of the emulsion (highest ESI value). The lower amount of random coil and triple helix structures allowed higher coverage of the oil-water interface by relatively highly ordered secondary structure of gelatin. PMID- 24054272 TI - Isoflavones and soyasaponins in soy infant formulas in Brazil: profile and estimated consumption. AB - In the present study we determine the contents of isoflavones and soyasaponins in seven soy-based infant formulas available in the Brazilian market to estimate the intake of these bioactive compounds by infants. The mean contents of isoflavones and soyasaponins were 65.9mg/kg and 55.0mg/100g, respectively. beta-Glycosylated isoflavones and soyasaponin B-I were the most abundant components in the analysed samples. The mean estimated intake of isoflavones by infants fed soy-based formulas was 0.8mg/day/kg of body weight, which is twice that of Japanese adults. For soyasaponins, the mean estimated intake was 9.2mg/day/kg of body weight, which is up to 6 times higher than the daily intake of saponins from beans by vegetarians. Considering the estimated intake of these bioactive compounds from soy-based formulas and the paucity of data regarding their bioavailability, the potential biological effects of isoflavones and soyasaponins in infants should not be overlooked and merits further investigation. PMID- 24054273 TI - Determination of volatile components of saffron by optimised ultrasound-assisted extraction in tandem with dispersive liquid-liquid microextraction followed by gas chromatography-mass spectrometry. AB - In the present research, a combined extraction method of ultrasound-assisted extraction (UAE) in conjunction with dispersive liquid-liquid microextraction (DLLME) was applied to isolation and enrichment of saffron volatiles. The extracted components of the saffron were separated and determined by gas chromatography-mass spectrometry (GC-MS) technique. The mixture of methanol/acetonitrile was chosen for the extraction of the compounds and chloroform was used at the preconcentration stage. The important parameters, such as composition of extraction solvent, volume of preconcentration solvent, ultrasonic applying time, and salt concentration were optimised by using a half fraction factorial central composite design (CCD). Under the optimal conditions, the linear dynamic ranges (LDRs) were 10-10,000mgL(-)(1). The determination coefficients (R(2)) were from 0.9990 to 0.9997. The limits of detection (LODs) and limits of quantification (LOQs) for the extracted compounds were 6-123mgL( )(1) and 20-406mgL(-)(1), respectively. The relative standard deviations (RSDs) were 2.48-9.82% (n=3). The enhancement factors (EFs) were 3.6-41.3. PMID- 24054274 TI - Biochemical features of native red wines and genetic diversity of the corresponding grape varieties from Campania region. AB - Campania region has always been considered one of the most appreciated Italian districts for wine production. Wine distinctiveness arises from their native grapevines. To better define the chemical profile of Campania autochthonous red grape varieties, we analysed the phenolic composition of Aglianico di Taurasi, Aglianico del Vulture, Aglianico del Taburno, Piedirosso wines, and a minor native variety, Lingua di Femmina in comparison with Merlot and Cabernet Sauvignon, as reference cultivars. A genetic profiling was also carried out using microsatellite molecular markers with high polymorphic and unambiguous profiles. Principal component analysis applied to 72 wines based on the 18 biochemical parameters, explained 77.6% of the total variance and highlighted important biological entities providing insightful patterns. Moreover, comparison of SSR based data with phenylpropanoid molecules exhibited a statistically significant correlation. Our approach might be reasonably adopted for future characterisations and traceability of grapevines and corresponding wines. PMID- 24054275 TI - In vitro digestibility of bovine beta-casein with simulated and human oral and gastrointestinal fluids. Identification and IgE-reactivity of the resultant peptides. AB - Stability during digestion is considered an important feature in determining the allergenicity of food proteins. This study aimed to provide an immunological characterisation of the digestion products of the major cow's milk allergen beta casein (beta-CN) produced by in vitro orogastrointestinal hydrolysis with simulated and human digestive fluids. beta-CN was unaffected by oral digestion, but quickly broke down during the early stages of gastric digestion. The degradation with human fluids was faster than that with commercial enzymes. There were similarities in the peptide patterns of the hydrolysates produced in both models, showing 20 peptides in common after gastric digestion. After gastroduodenal digestion, the human fluids gave less numerous and shorter peptides. The IgE binding of most of the individual sera used to the hydrolysates produced with simulated and human fluids increased at the end of the gastric phase and decreased when the duodenal digestion was completed. Two IgE-binding synthetic peptides: beta-CN (57-68) and beta-CN (82-93), which matched fragments released by beta-CN following in vitro digestion with simulated and human fluids, consisted of the most immunoreactive areas of the protein. The similarities found between the in vitro simulated digestion system and that using human digestive fluids suggest that the former would provide a reasonably good estimation of the potential allergenicity of protein digests. PMID- 24054276 TI - A comparison of the nutritional value and food safety of organically and conventionally produced wheat flours. AB - Growing interest in organic agriculture has prompted this study aiming to evaluate nutritional content of wheat flours originating from organic and conventional production systems. Obtained results showed that organic samples had significantly lower protein content and lower levels of Ca, Mn and Fe compared to conventional samples. Protein digestibility and levels of K, Zn and Mo were significantly higher in organic than in conventional wheat flours. Regarding undesirable metals, significantly higher levels of As and Cd were found in conventional compared to organic wheat flours. Although the mean concentrations of zearalenone and ochratoxin A were higher in conventional than in organic flours, this difference was not significant. This study revealed that organic agriculture has the potential to yield products with some relevant improvements in terms of high quality proteins and microelements contents, while the reduction in contamination with toxic elements and mycotoxins may be accomplished. PMID- 24054277 TI - Structural characteristics and antioxidant activities of different families of 4 acetamido-TEMPO-oxidised curdlan. AB - Regioselective oxidation was applied to commercial curdlan for the preparation of its water-soluble derivatives with improved antioxidant activities, using a 4 acetamido-2,2, 6,6-tetramethylpiperidine-1-oxyl radical/NaClO/NaClO2 system at pH 4.8 and 40 degrees C. The structural features, molecular properties, and chain conformations of the oxidised curdlans were determined using Fourier transform (FT) infrared and FT Raman spectroscopy, carbon nuclear magnetic resonance, X-ray diffraction, and size-exclusion chromatography with multi-angle laser-light scattering analyses. The C6 primary hydroxyls of curdlan were successfully oxidised into carboxylate groups with less depolymerization, and no aldehyde groups were formed during oxidation. The crystalline region of curdlan was destroyed after oxidation. The oxidised curdlans formed random coils in aqueous solution, and the chain became more flexible and expanded with increasing carboxylate contents from 2.07mmol/g to 4.87mmol/g. The high polyglucuronic acid derivative (Cur-24) showed the best antioxidant activity in TEAC and FRAP assays, thus it could be explored as novel potential antioxidants for dietary and therapeutic applications. PMID- 24054278 TI - Disease-related nutritional risk and mortality in systemic sclerosis. AB - BACKGROUND & AIMS: To evaluate the relationship between mortality and nutritional risk associated with disease activity in Systemic Sclerosis (SSc). METHODS: A single-centre prospective cohort study involving 160 SSc outpatients (median age, 62 years [25th-75th, 54-68]). Nutritional risk was assessed by the Malnutrition Universal Screening Tool (MUST), a screening tool that combines anthropometric parameters of nutritional status (body mass index [BMI] and percentage of unintentional weight loss [WL]) with the presence of an "acute disease" (as defined by a disease activity score >=3 according to Valentini's criteria). RESULTS: Prevalence of high nutritional risk (MUST score >=2) was 24.4% [95%CI, 17.4-31.3]. A low nutritional risk (MUST = 1) was detected in 30% of our study sample. In hazard analysis (median follow-up duration = 46 months [25th-75th percentile, 31-54]), high nutritional risk was significantly associated with mortality (HR = 8.3 [95%CI, 2.1-32.1]). The performance of the model based on nutritional risk including disease activity (Harrell's c = 0.74 [95%CI, 0.59 0.89]) was superior to that based on active disease alone (HR = 6.3 [95%CI, 1.8 21.7]; Harrell's c = 0.68 [95%CI, 0.53-0.84]). Risk scored only by anthropometric parameters (prevalence, 9.4% [95%CI, 4.6-14.2]) was not associated with mortality: HR = 2.8 [95%CI, 0.6-13.2]. CONCLUSIONS: In SSc outpatients MUST significantly predicts mortality. The combined assessment of nutritional parameters and disease activity significantly improves the evaluation of mortality risk. Disease-related nutritional risk screening should be systematically included in the clinical workup of every SSc patient. PMID- 24054279 TI - Environmental efficiency of alternative dairy systems: a productive efficiency approach. AB - Agriculture across the globe needs to produce "more with less." Productivity should be increased in a sustainable manner so that the environment is not further degraded, management practices are both socially acceptable and economically favorable, and future generations are not disadvantaged. The objective of this paper was to compare the environmental efficiency of 2 divergent strains of Holstein-Friesian cows across 2 contrasting dairy management systems (grazing and nongrazing) over multiple years and so expose any genetic * environment (G * E) interaction. The models were an extension of the traditional efficiency analysis to account for undesirable outputs (pollutants), and estimate efficiency measures that allow for the asymmetric treatment of desirable outputs (i.e., milk production) and undesirable outputs. Two types of models were estimated, one considering production inputs (land, nitrogen fertilizers, feed, and cows) and the other not, thus allowing the assessment of the effect of inputs by comparing efficiency values and rankings between models. Each model type had 2 versions, one including 2 types of pollutants (greenhouse gas emissions, nitrogen surplus) and the other 3 (greenhouse gas emissions, nitrogen surplus, and phosphorus surplus). Significant differences were found between efficiency scores among the systems. Results indicated no G * E interaction; however, even though the select genetic merit herd consuming a diet with a higher proportion of concentrated feeds was most efficient in the majority of models, cows of the same genetic merit on higher forage diets could be just as efficient. Efficiency scores for the low forage groups were less variable from year to year, which reflected the uniformity of purchased concentrate feeds. The results also indicate that inputs play an important role in the measurement of environmental efficiency of dairy systems and that animal health variables (incidence of udder health disorders and body condition score) have a significant effect on the environmental efficiency of each dairy system. We conclude that traditional narrow measures of performance may not always distinguish dairy farming systems best fitted to future requirements. PMID- 24054280 TI - Effect of various high-pressure treatments on the properties of reduced-fat Cheddar cheese. AB - A major problem with reduced-fat cheese is the difficulty in attaining the characteristic flavor and texture of typical full-fat versions. Some previous studies have suggested that high hydrostatic pressure (HHP) can accelerate the ripening of full-fat cheeses. Our objective was to investigate the effect of HHP on reduced-fat (~7.3% fat) Cheddar cheese, with the goal of improving its flavor and texture. We used a central composite rotatable design with response surface methodology to study the effect of pressure and holding time on the rheological, physical, chemical, and microbial characteristics of reduced-fat Cheddar cheese. A 2-level factorial experimental design was chosen to study the effects of the independent variables (pressure and holding time). Pressures were varied from around 50 to 400 MPa and holding times ranged from 2.5 to 19.5 min. High pressure was applied 1 wk after cheese manufacture, and analyses were performed at 2 wk, and 1, 3, and 6 mo. The insoluble calcium content as a percentage of total Ca in cheeses were not affected by pressure treatment. Pressure applications >= 225 MPa resulted in softer cheese texture during ripening. Pressures >= 225 MPa increased melt, and resulted in higher maximum loss tangent values at 2 wk. Pressure treatment had a greater effect on cheese microbial and textural properties than holding time. High-pressure-treated cheeses also had higher pH values than the control. We did not observe any significant difference in rates of proteolysis between treatments. In conclusion, holding times of around 5 min and pressures of >= 225 MPa could potentially be used to improve the excessively firm texture of reduced-fat cheese. PMID- 24054281 TI - Mastitis control in Swedish dairy herds. AB - The aim of this study was to investigate which preventive measures targeting mastitis are implemented in Swedish dairy herds with different housing and milking systems. Data were collected through a self-administered postal questionnaire sent to 898 dairy farmers, stratified by housing and milking system, in May 2011. The questionnaire contained general questions about the herd and the person responsible for the udder health of the cows, and specific questions about perceived udder health and the implementation of preventive measures. The response rate was 48%. The median herd size of participating herds was 80 cows, and the median herd average milk yield per cow was 9,586 kg of milk. External validity was assessed by comparing participating herds with nonresponders in respect to key performance indicators in the Swedish official milk recording system; no significant differences were found. When herds with combined systems had been removed, 400 herds with tiestalls and pipeline milking, freestalls and parlor milking, and freestalls with an automatic milking system remained. Differences between herd types were analyzed using the Kruskal-Wallis test and Fisher's exact test. The results showed that herd types differed in their rates of implementation of different preventive measures. Freestall herds with milking parlors implemented more preventive measures related to milking hygiene and milking routines than did tiestall herds. A milking order based on the udder health status of the cows was frequently implemented in tiestall herds, but not in most herds with an automatic milking system or most freestall herds with milking parlors. Irrespective of herd type, the proportion of herds in which cows were kept standing for at least 30 min after milking was low. A substantial proportion of herds ignored the udder health status of lactating cows when grouping them, and few herds grouped dry cows according to udder health status, although this occurred more frequently in tiestall herds. A large proportion of herds, especially those with tiestalls, did not allow cows and heifers to calve in single pens that were cleaned between animal occupations. These findings can be used to tailor advice on mastitis specifically to different herd types and thus improve the efficiency of mastitis control. PMID- 24054282 TI - Effects of alfalfa hay particle size in high-concentrate diets supplemented with unsaturated fat: chewing behavior, total-tract digestibility, and milk production of dairy cows. AB - This study evaluated the effects of increasing the physically effective neutral detergent fiber (peNDF) intake of lactating dairy cows fed high-concentrate diets supplemented with unsaturated fat on intake, eating behavior, diet sorting, chewing activity, total-tract digestibility, and milk production and composition. Diets contained 24% alfalfa hay (AH), 16% corn silage, 58% concentrate, and 2% yellow grease [dry matter (DM) basis], and dietary peNDF content was increased by varying the particle size (PS) of the AH. Nine multiparous cows averaging 87.8 +/ 14.8d in milk and weighing 653 +/- 53 kg were randomly assigned to a triplicate 3 * 3 Latin square. During each 21-d period, cows were offered 1 of 3 total mixed rations that varied in PS of AH: fine, medium, and long, with a geometric mean particle length of 3.00, 3.57 and 3.87 mm, respectively. Increasing PS quadratically affected DM intake (DMI; 24.7, 25.4, and 23.7 kg/d, for fine, medium, and long, respectively), but cumulative DMI at 2, 4, and 6h after feeding was similar across treatments, averaging 23.4, 35.6 and 46.4% of total DMI for the 3 time points, respectively. Increased peNDF intake did not affect feed sorting, but increased daily eating time, and eating and total chewing time per kilogram of DMI. Daily rumination time exhibited a quadratic response, with highest rumination time for the medium diet. Dietary PS had no effects on digestibility in the total tract, but we observed, for fine, medium, and long diets, quadratic responses in milk production (41.5, 43.3, and 40.4 kg/d), 4% fat corrected milk production, and milk protein yield. Milk fat content decreased linearly with increasing PS, but milk fat content and fat:protein ratio were low for all treatments, likely due to adding unsaturated fat to a diet containing a high level of nonfiber carbohydrates (42.2% of DM). The composition, degree of saturation, and total conjugated linoleic acid content of fatty acids in milk fat were not affected by the change in peNDF content of the diet. The study indicates that a moderate increase in the PS of AH in diets containing unsaturated fat elevates peNDF intake and increases chewing activity, DMI, milk yield and milk fat production. However, the effects of dietary PS were quadratic, with maximum DMI and milk production observed with diets supplying 24% dietary peNDF (measured as the proportion of the ration retained on sieves >1.18 mm multiplied by dietary neutral detergent fiber content; DM basis). PMID- 24054283 TI - Estimates of genetic parameters and eigenvector indices for milk production of Holstein cows. AB - The objectives of the present study were to estimate genetic parameters of monthly test-day milk yield (TDMY) of the first lactation of Brazilian Holstein cows using random regression (RR), and to compare the genetic gains for milk production and persistency, derived from RR models, using eigenvector indices and selection indices that did not consider eigenvectors. The data set contained monthly TDMY of 3,543 first lactations of Brazilian Holstein cows calving between 1994 and 2011. The RR model included the fixed effect of the contemporary group (herd-month-year of test days), the covariate calving age (linear and quadratic effects), and a fourth-order regression on Legendre orthogonal polynomials of days in milk (DIM) to model the population-based mean curve. Additive genetic and nongenetic animal effects were fit as RR with 4 classes of residual variance random effect. Eigenvector indices based on the additive genetic RR covariance matrix were used to evaluate the genetic gains of milk yield and persistency compared with the traditional selection index (selection index based on breeding values of milk yield until 305 DIM). The heritability estimates for monthly TDMY ranged from 0.12 +/- 0.04 to 0.31 +/- 0.04. The estimates of additive genetic and nongenetic animal effects correlation were close to 1 at adjacent monthly TDMY, with a tendency to diminish as the time between DIM classes increased. The first eigenvector was related to the increase of the genetic response of the milk yield and the second eigenvector was related to the increase of the genetic gains of the persistency but it contributed to decrease the genetic gains for total milk yield. Therefore, using this eigenvector to improve persistency will not contribute to change the shape of genetic curve pattern. If the breeding goal is to improve milk production and persistency, complete sequential eigenvector indices (selection indices composite with all eigenvectors) could be used with higher economic values for persistency. However, if the breeding goal is to improve only milk yield, the traditional selection index is indicated. PMID- 24054284 TI - Dairy producer attitudes to pain in cattle in relation to disbudding calves. AB - Pain is an important indicator of poor welfare of livestock. Despite this, pain has largely gone unrecognized in farm animals due to attitudes of producers and veterinarians, although they play a key role in monitoring and managing the perception of animal pain. Producer attitudes toward animal welfare influence livestock management and production. The aim was to quantify dairy producer attitudes to the painfulness of various cattle diseases and disbudding, a painful routine procedure performed on farm to ensure safer handling of cattle. A questionnaire on disbudding-related opinions and practices was sent to 1,000 Finnish dairy producers (response rate: 45%). Attitudes toward disbudding were gauged using a 5-point Likert scale and attitudes to cattle pain scored on an 11 point numerical rating scale. Principal components analysis was used to assess the loadings, which were further tested for differences between producer gender and housing systems with Mann-Whitney U-tests, and between herd milk yield, herd size, and age and work experience of producers with a Kruskal-Wallis test. Four main factors were identified: factor I ("taking disbudding pain seriously"), factor II ("sensitivity to pain caused by cattle diseases"), factor III ("ready to medicate calves myself"), and factor IV ("pro horns"). Female producers took disbudding pain more seriously, were more sensitive to pain caused to cattle by diseases, and were more ready to medicate disbudded calves than male producers. Producers with tie-stalls favored horns over producers with freestalls. Male producers with tie-stalls were sensitive to cattle pain and preferred horns over male producers with freestalls. Female producers with freestalls were more ready to medicate calves, but did not prefer horns more than female producers with tie stalls. Taking disbudding seriously correlated with sensitivity to pain caused by cattle diseases. Producers with low-milk-yielding herds were less willing to medicate calves and more willing to keep cattle with horns than producers with higher-yielding herds. Older producers were more sensitive to cattle pain than middle-aged and younger producers. No effect was established for taking disbudding pain seriously: the pro-horn factor was associated with work experience, age, and herd size. Women rated pain higher and were more positive toward pain medication for animals than men. Maintaining horns are more important for producers with tie-stalls than for those with freestalls. PMID- 24054285 TI - Short communication: Lymphoproliferative response to lipopolysaccharide and incidence of infections in periparturient dairy cows. AB - This preliminary study aimed at assessing whether the in vitro proliferation of peripheral blood mononuclear cells in response to lipopolysaccharide permits individual characterization of periparturient dairy cows, and whether this parameter may be associated with incidence of infections and with some of the single nucleotide polymorphisms located on the toll-like receptor 4 (TLR4) gene. Based on the average response of peripheral blood mononuclear cells to lipopolysaccharide over 7 time points during the transition period, 31 cows were categorized as low (LO), medium (MED), and high (HI) responders. This categorization identified 7 HI, 19 MED, and 5 LO cows, respectively. Genomic DNA was genotyped for P-226 C>G and E3+2021 C>T TLR4 single nucleotide polymorphisms. Monitoring of the health status revealed that 8 of the 31 cows suffered from clinical mastitis, metritis, or interdigital dermatitis during the first 60d in milk. The association study pointed out that none of the HI cows and all of the LO cows developed an infection; cows with the CCGT haplotype remained healthy and none of them belonged to the LO responder category. PMID- 24054286 TI - Timed artificial insemination programs during the summer in lactating dairy cows: comparison of the 5-d Cosynch protocol with an estrogen/progesterone-based protocol. AB - The objective of this study was to compare a GnRH-based to an estrogen/progesterone (E2/P4)-based protocol for estrous cycle synchronization and fixed timed artificial insemination (TAI), both designed for synchronization of ovulation and to reduce the period from follicular emergence until ovulation in cows with a synchronized follicular wave. A total of 1,190 lactating Holstein cows (primiparous: n=685 and multiparous: n=505) yielding 26.5 +/- 0.30 kg of milk/d at 177 +/- 5.02 d in milk were randomly assigned to receive one of the following programs: 5-d Cosynch protocol [d -8: controlled internal drug release (CIDR) + GnRH; d -3: CIDR removal + PGF2alpha; d -2: PGF2alpha; d 0: TAI + GnRH] or E2/P4 protocol (d -10: CIDR + estradiol benzoate; d -3: PGF2alpha; d -2: CIDR removal + estradiol cypionate; d 0: TAI). Rectal temperature and circulating progesterone (P4) were measured on d -3, -2, 0 (TAI), and 7. The estrous cycle was considered to be synchronized when P4 was >= 1.0 ng/mL on d 7 in cows that had luteolysis (P4 <= 0.4 ng/mL on d 0). To evaluate the effects of heat stress, cows were classified by number of heat stress events: 0, 1, and 2-or-more measurements of elevated body temperature (>= 39.1 degrees C). Pregnancy success (pregnancy per artificial insemination, P/AI) was determined at d 32 and 60 after TAI. The cows in the 5-d Cosynch protocol had increased circulating P4 at the time of PGF2alpha injection (2.66 +/- 0.13 vs. 1.66 +/- 0.13 ng/mL). The cows in the E2/P4 protocol were more likely to be detected in estrus (62.8 vs. 43.4%) compared with the cows in the 5-d Cosynch protocol, and expression of estrus improved P/AI in both treatments. The cows in the 5-d Cosynch protocol had greater percentage of synchronized estrous cycle (78.2%), compared with cows in the E2/P4 protocol (70.7%). On d 60, the E2/P4 protocol tended to improve P/AI (20.7 vs. 16.7%) and reduced pregnancy loss from 32 to 60 d (11.0 vs. 19.6%), compared with the 5-d Cosynch protocol. In cows withtheir estrous cycle synchronized, the E2/P4 protocol had greater P/AI (25.6 vs. 17.7%) on d 60 and lower pregnancy loss from 32 to 60 d (6.7 vs. 21.7%) compared with cows in the 5 d Cosynch protocol. Follicle diameter affected pregnancy loss from 32 to 60d only in the cows in the 5-d Cosynch protocol, with smaller follicles resulting in greater pregnancy loss. Pregnancy per AI at d 60 was different between protocols in the cows with 2 or more measurements of heat stress (5-d Cosynch=12.2% vs. E2/P4=22.8%), but not in the cows without or with 1 heat stress measurement. In conclusion, the 5-d Cosynch protocol apparently produced better estrous cycle synchronization than the E2/P4 protocol but did not improve P/AI. The potential explanation for these results is that increased E2 concentrations during the periovulatory period can improve pregnancy success and pregnancy maintenance, and this effect appears to be greatest in heat-stressed cows when circulating E2 may be reduced. PMID- 24054287 TI - Detection and enumeration of Staphylococcus aureus from bovine milk samples by real-time polymerase chain reaction. AB - The aim of this study was to develop and evaluate a real-time quantitative PCR (qPCR)-based method to detect and quantify Staphylococcus aureus in bronopol preserved milk samples from subclinical intramammary infections (IMI). Serial dilutions of milk artificially inoculated with Staph. aureus ATCC 29213 were used to establish a standard curve (cfu/mL) of the qPCR assay targeting the Staph. aureus thermonuclease-encoding gene nuc according to the strain plate count. The analytical sensitivity, specificity, and repeatability of the qPCR assay were determined. A total of 60 milk samples, collected from mammary quarters without abnormal appearance and with positive isolation of Staph. aureus, were submitted to both the qPCR protocol and Staph. aureus plate counting and results from both methods were compared. Staphylococcus aureus from bronopol-preserved, subclinical IMI milk samples were not accurately enumerated by qPCR compared with plate counting of the nonpreserved, raw milk sample. The detection limit of the qPCR protocol of inoculated Staph. aureus ATCC 29213 in bronopol-preserved milk samples was 1.04 * 10(1) cfu/mL. The qPCR protocol can be a high-throughput and rapid diagnostic assay to accurately detect Staph. aureus IMI from bronopol preserved milk samples compared with a traditional culturing method. However, the proposed qPCR protocol is not accurate for counting of Staph. aureus in bronopol preserved milk samples from naturally infected mammary glands. PMID- 24054288 TI - Dietary starch source and protein degradability in diets containing sucrose: effects on ruminal measures and proposed mechanism for degradable protein effects. AB - A feeding study was conducted to evaluate ruminal effects of starch source (STA) and rumen-degradable dietary protein (RDP) in diets with added sucrose. The experimental design was an incomplete Latin square with three 21-d periods, 8 ruminally cannulated lactating cows, and a 2 * 2 factorial arrangement of treatments. Treatments were STA (dry ground corn or high-moisture corn) as more slowly and more rapidly fermenting starch sources, respectively, and relative amount of RDP (+RDP: added protein from soybean meal; -RDP: heat-treated expeller soybean product partially substituted for soybean meal). Diets were formulated to be isonitrogenous and similar in starch and neutral detergent fiber concentrations. Dry matter (DM) intake was 1 kg greater with +RDP compared with RDP diets. For ruminal digesta measures made 2 h postfeeding, weight of digesta DM was unaffected by treatment; total kilograms of wet digesta and kilograms of liquid tended to be greater with +RDP than with -RDP, and no effect was observed of STA * RDP. Digesta DM percentage was greater with -RDP than with +RDP. At 2 h postfeeding, ruminal pool sizes (mol) of lactate and total AA were larger and those of total organic acids (OA) and ammonia tended to be larger with +RDP than with -RDP; no effects of STA or STA * RDP were detected. Rumen-degradable protein effects on lactate and OA pool sizes may be due to a protein-mediated increase in fermentation rate of carbohydrate. Organic acid concentrations at 2 h postfeeding did not show the same response pattern or significance as the pool size data; high-moisture corn tended to be greater than dry ground corn and no effect was observed for RDP or STA * RDP. Concentration and pool size for OA were more weakly correlated [coefficient of determination (R(2)) = 0.66] than was the case for other ruminal analytes (R(2) >0.80). Organic acid pool size and kilograms of digesta liquid were strongly correlated (R(2) = 0.79), whereas concentration and kilograms of liquid were much less so (R(2) = 0.21). The correlation of OA moles with kilograms of liquid likely relates to the homeostatic mechanism of water flux across the rumen wall to reduce the osmotic gradient with blood as intraruminal moles of solute change. This action compresses the range of ruminal OA concentrations. With kilograms of ruminal liquid differing across individual measurements, the ruminal OA concentration data are not on the equivalent basis required to be reliably useful for assessing the effect of treatments. Further evaluation of protein effects on carbohydrate fermentation and of methods that allow accurate comparison of treatments for their effect on ruminal OA production are warranted. PMID- 24054289 TI - Short communication: Herd-level reproductive performance and its relationship with lameness and leg injuries in freestall dairy herds in the northeastern United States. AB - The objectives of this study were to describe herd-level reproductive outcomes and their associations with the prevalence of lameness, hock injuries and knee injuries in freestall dairy herds in the northeastern United States. Five reproductive outcomes (calving to conception interval, CCI; calving interval, CI; conception risk at the first artificial insemination, CR1; insemination rate, IR; and pregnancy rate, PR) were measured from Dairy Comp 305 (Valley Agricultural Software, Tulare, CA) for a 12-mo period for all multiparous cows in each of the 53 herds assessed. The prevalence of lameness, hock injuries, and knee injuries was assessed in 1 high-producing group. The means (+/- standard deviation) for the 5 reproductive outcomes were as follows: CCI = 128 +/- 10 d, CI = 404 +/- 10 d, CR1 = 36 +/- 5%, IR = 60 +/- 7%, and PR = 20 +/- 3%. The average prevalence of clinical lameness, hock injuries, and knee injuries were 45 +/- 20%, 58 +/- 31%, and 16 +/- 15%, respectively. Univariable associations between the reproductive outcomes and the prevalence of lameness and leg injuries were tested and significant predictors were submitted to a model that controlled for the confounding effects of herd size, 305-d mature equivalent milk production of the high-producing group, and use of deep bedding. A higher prevalence of lameness was associated with poorer reproductive performance, although the relationships were weak: herds with a higher prevalence of lameness had longer average CCI (slope estimate = 0.16 +/- 0.07; R(2)= 0.09) and CI (slope estimate = 0.14 +/- 0.07; R(2) = 0.07). These results indicate that management to reduce lameness may improve reproductive performance. PMID- 24054290 TI - The role of veterinarians and feed-store vendors in the prescription and use of antibiotics on small dairy farms in rural Peru. AB - This study aimed to describe and compare the role of veterinarians and feed-store vendors in the use of antibiotics on small dairy farms in Cajamarca, Peru, a major dairy-producing center characterized by small, rural farms with poor, mostly uneducated farmers. We used a purposive sampling strategy to recruit 12 veterinarians into 2 focus group discussions and supplemented these data with 8 semi-structured interviews with feed-store vendors. Participants reported that inappropriate antibiotic usage was widespread among their clients, which may prevent the efficient use of drugs on farms where animal disease can be devastating to the livelihood of the farmer. Participants also identified many barriers to appropriate prescribing and use, including availability of drugs, competition from other prescribers, economic constraints and habits of farmers, and limited farmer knowledge of drugs and disease. Veterinarians expressed mistrust toward nonprofessional prescribers, whereas feed-store vendors felt that veterinarians were important partners in promoting the health of their clients' animals. PMID- 24054291 TI - Identifying efficient dairy heifer producers using production costs and data envelopment analysis. AB - During November and December 2011, data were collected from 44 dairy operations in 13 Pennsylvania counties. Researchers visited each farm to collect information regarding management practices and feeding, and costs for labor, health, bedding, and reproduction for replacement heifers from birth until first calving. Costs per heifer were broken up into 4 time periods: birth until weaning, weaning until 6 mo of age, 6 mo of age until breeding age, and heifers from breeding to calving. Milk production records for each herd were obtained from Dairy Herd Improvement. The average number of milking cows on farms in this study was 197.8 +/- 280.1, with a range from 38 to 1,708. Total cost averaged $1,808.23 +/- $338.62 from birth until freshening. Raising calves from birth to weaning cost $217.49 +/- 86.21; raising heifers from weaning age through 6 mo of age cost $247.38 +/- 78.89; raising heifers from 6 mo of age until breeding cost $607.02 +/- 192.28; and total cost for bred heifers was $736.33 +/- 162.86. Feed costs were the largest component of the cost to raise heifers from birth to calving, accounting for nearly 73% of the total. Data envelopment analysis determined that 9 of the 44 farms had no inefficiencies in inputs or outputs. These farms best combined feed and labor investments, spending, on average, $1,137.40 and $140.62/heifer for feed and labor. These heifers calved at 23.7 mo of age and produced 88.42% of the milk produced by older cows. In contrast, the 35 inefficient farms spent $227 more on feed and $78 more on labor per heifer for animals that calved 1.6 mo later and produced only 82% of the milk made by their mature herdmates. Efficiency was attained by herds with the lowest input costs, but herds with higher input costs were also able to be efficient if age at calving was low and milk production was high for heifers compared with the rest of the herd. PMID- 24054292 TI - Preliminary selection for potential probiotic Bifidobacterium isolated from subjects of different Chinese ethnic groups and evaluation of their fermentation and storage characteristics in bovine milk. AB - A total of 29 strains of Bifidobacterium were isolated from 18 samples of human feces in different ethnic minority regions of China. All isolates were identified as Bifidobacterium longum (9 strains) and Bifidobacterium pseudocatenulatum (20 strains) based on 16S rRNA gene sequencing and phylogenetic analysis. These strains were preliminarily tested for their suitability to become probiotics by assessing their ability to survive adequately at low pH conditions and their tolerance of different concentrations of bile salts and simulated gastrointestinal juices. In vitro tests were sequentially used to predict the survival of these strains in the simulated conditions in the human gastrointestinal tract. These strains were first exposed to pH 2.5 for 3h, and 7 out of the 29 strains were discriminated from the others by their high survival rates. Out of these 7 strains, 4 were found to grow and survive well at an even lower pH of 2.0 and in high bile salt concentration. Apart from the gastrointestinal survival capacity, both fermentation efficiency and storage characteristics are important criteria for selecting for suitable potential probiotic strains. Therefore, the fermentation efficiency in bovine milk and the bacterial viability during the storage in the resultant fermented milk were also evaluated for these 4 selected strains. In this study, we isolated and identified 29 novel Bifidobacterium strains. Based on our initial evaluation, at least 4 of them may serve as valuable resources for further dairy probiotic strain selection. PMID- 24054293 TI - Genome-wide association analysis to identify genotype * environment interaction for milk protein yield and level of somatic cell score as environmental descriptors in German Holsteins. AB - Genotype by environment interaction (G * E) has been widely reported in dairy cattle. If the environment can be measured on a continuous scale, reaction norms can be applied to study G * E. The average herd milk production level has frequently been used as an environmental descriptor because it is influenced by the level of feeding or the feeding regimen. Another important environmental factor is the level of udder health and hygiene, for which the average herd somatic cell count might be a descriptor. In the present study, we conducted a genome-wide association analysis to identify single nucleotide polymorphisms (SNP) that affect intercept and slope of milk protein yield reaction norms when using the average herd test-day solution for somatic cell score as an environmental descriptor. Sire estimates for intercept and slope of the reaction norms were calculated from around 12 million daughter records, using linear reaction norm models. Sires were genotyped for ~54,000 SNP. The sire estimates were used as observations in the association analysis, using 1,797 sires. Significant SNP were confirmed in an independent validation set consisting of 500 sires. A known major gene affecting protein yield was included as a covariable in the statistical model. Sixty (21) SNP were confirmed for intercept with P <= 0.01 (P <= 0.001) in the validation set, and 28 and 11 SNP, respectively, were confirmed for slope. Most but not all SNP affecting slope also affected intercept. Comparison with an earlier study revealed that SNP affecting slope were, in general, also significant for slope when the environment was modeled by the average herd milk production level, although the two environmental descriptors were poorly correlated. PMID- 24054294 TI - Short communication: Antimicrobial efficacy of intramammary treatment with a novel biphenomycin compound against Staphylococcus aureus, Streptococcus uberis, and Escherichia coli-induced mouse mastitis. AB - Bovine mastitis undermines udder health, jeopardizes milk production, and entails prohibitive costs, estimated at $2 billion per year in the dairy industry of the United States. Despite intensive research, the dairy industry has not managed to eradicate the 3 major bovine mastitis-inducing pathogens: Staphylococcus aureus, Streptococcus uberis, and Escherichia coli. In this study, the antimicrobial efficacy of a newly formulated biphenomycin compound (AIC102827) was assessed against intramammary Staph. aureus, Strep. uberis, and E. coli infections, using an experimental mouse mastitis model. Based on its effective and protective doses, AIC102827 applied into the mammary gland was most efficient to treat Staph. aureus, but also adequately reduced growth of Strep. uberis or E. coli, indicating its potential as a broad-spectrum candidate to treat staphylococcal, streptococcal, and coliform mastitis in dairy cattle. PMID- 24054295 TI - Microwave-assisted extraction and determination of dicyandiamide residue in infant formula samples by liquid chromatography-tandem mass spectrometry. AB - A simple, precise, accurate, and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of dicyandiamide residue in infant formula samples. Following microwave-assisted extraction with 5% formic acid and clean-up on a Sep-Pak AC-2 SPE cartridge, samples were separated on a ZIC-HILIC HPLC column (150 * 2.1mm i.d., 5-um film thickness; Merck KGaA, Darmstadt, Germany) with 20mM ammonium acetate solution acetonitrile as mobile phase at a flow rate of 0.25 mL/min. A linear calibration curve was obtained in the concentration range from 1.0 to 50 ng/mL. Infant formula samples were fortified with dicyandiamide at 3 levels, producing average recovery yields of 83.6 to 95.7%. The limits of detection and quantification of dicyandiamide were 3 and 10 MUg/kg, respectively. Due to its simplicity and accuracy, the straightforward method is particularly suitable for routine dicyandiamide detection. PMID- 24054296 TI - Effects of seasonal change and parity on raw milk composition and related indices in Chinese Holstein cows in northern China. AB - This study was to investigate the effects of seasonal change and parity on milk composition and related indices, and to analyze the relationships among milk indices in Chinese Holstein cows from an intensive dairy farm in northern China. The 6,520 sets of complete Dairy Herd Improvement data were obtained and grouped by natural month and parity. The data included daily milk yield (DMY), milk solids percentage (MSP), milk fat percentage (MFP), milk protein percentage (MPP), milk lactose percentage (MLP), somatic cell count (SCC), somatic cell score (SCS), milk production loss (MPL), and fat-to-protein ratio (FPR). Data analysis showed that the above 9 indices were affected by both seasonal change and parity. However, the interaction between parity and seasonal change showed effects on MLP, SCS, MPL, and DMY, but no effects on MFP, MPP, MSP, and FPR. Duncan's multiple comparison on seasonal change showed that DMY (23.58 kg/d), MSP (12.35%), MPP (3.02%), and MFP (3.81%) were the lowest in June, but SCC (288.7 * 10(3)/mL) and MPL (0.69 kg/d) were the lowest in January; FPR (1.32) was the highest in February. Meanwhile, Duncan's multiple comparison on parities showed that MSP, MPP, and MLP were reduced rapidly in the fourth lactation, but SCC and MPL increased with increasing parities. The canonical correlation analysis for indices showed that SCS had high positive correlation with MPL (0.8360). Therefore, a few models were developed to quantify the effects of seasonal change and parity on raw milk composition using the Wood model. The changing patterns of milk composition and related indices in different months and parities could provide scientific evidence for improving feeding management and nutritional supplementation of Chinese Holstein cows. PMID- 24054297 TI - Repeated mixing and isolation: measuring chronic, intermittent stress in Holstein calves. AB - Objectives of this study were to determine the physiological effects of psychological stress applied to dairy calves and to test if molasses consumption could be used to validate that a stressed condition was achieved. Twenty male calves (3 wk old) received jugular catheters and were randomly assigned to control (CTR; n = 4 pens of 1 calf per pen) or social stress treatments (STR; n = 4 pens of 4 calves per pen). The STR treatment included 5 cycles of 24-h isolation followed by regrouping with unfamiliar animals for 48 h (over 15 d). An ACTH challenge (0.1 IU/kg of body weight) was used to determine adrenal fatigue. Peak and total cortisol concentrations were greater for STR calves until the ACTH challenge. After the ACTH challenge, CTR calf cortisol increased and STR calf cortisol continued to decrease, suggesting adrenal fatigue. The number of calves that became positive for fecal shedding of Salmonella after the acute stress of being moved and the number of calves that were positive after the move decreased with each move. Fifty-six percent of STR calves changed from negative to positive for shedding after the first move compared with 18.75% of STR calves remaining negative after the third move. Difference in fecal shedding of Enterobacteriaceae from samples taken before and after moving calves on d 6 was less than that on d 2, 3, and 5. Leukocyte counts were not different, but trends for day effects were detected for neutrophil and monocyte percentages. Molasses consumption was greater for STR calves on d 2 and 11, as was total consumption. Latency to lie after eating also increased as the study progressed; STR calves required more time to lie after eating on d 12 than on d 3, and latency to lie was greater for STR than CTR on d 4, 8, 12, and 14. The STR calves also stood more than the CTR calves in the 4-h afternoon period on d 4, 5, 7, and 14. However, during the 4-h morning observations on d 14 (ACTH challenge), CTR calves stood more than STR calves. This model induced chronic stress, as characterized by adrenal fatigue, which was confirmed by molasses consumption and behavior changes. Therefore, molasses consumption could be used to confirm social stress in experimental models. PMID- 24054298 TI - The effect of internal teat sealant products (Teatseal and Orbeseal) on intramammary infection, clinical mastitis, and somatic cell counts in lactating dairy cows: a meta-analysis. AB - The objective of this study was to assess the efficacy of internal teat sealant products containing bismuth subnitrate (Teatseal and Orbeseal; Pfizer Animal Health, West Ryde, Australia) when used alone, or in the presence of antibiotic dry cow therapy (ADCT), before or at drying off on the incidence of new intramammary infections (IMI), clinical mastitis, and milk somatic cell count (SCC) during lactation. The literature search identified 18 English-language publications on the use of Teatseal in dairy cattle. A total of 12 studies with 17 subtrials or comparisons including 13 positive control subtrials (internal teat sealant and ADCT vs. ADCT) and 4 negative control subtrials (internal teat sealant vs. untreated) examining IMI were included in the analysis. Internal teat sealants, alone or in the presence of ADCT, reduced the risk of acquiring new IMI after calving by 25% [risk ratio (RR)=0.75; 95% confidence interval (CI): 0.67 to 0.83]. Internal teat sealants reduced the risk of IMI by 73% compared with untreated cows (RR=0.27; 95% CI: 0.13 to 0.55). The results of both meta-analyses of IMI, with positive and negative controls, were heterogeneous [I(2) (a statistic that describes the proportion of total variation in study effect estimates that is due to heterogeneity)=65.4 and 92.1%]. No farm or cow factors studied significantly contributed to the heterogeneity of the results. A total of 16 studies (21 subtrials), including 14 positive control subtrials and 7 negative control subtrials, examining clinical mastitis were included in the analysis. Internal teat sealants alone and in the presence of ADCT reduced the risk of clinical mastitis after calving in lactating cows by 29% (RR=0.71; 95% CI: 0.62 to 0.82), and 48% (RR=0.52; 95% CI: 0.37 to 0.75), respectively. The results of the meta-analysis on clinical mastitis with positive controls were homogeneous (I(2)=33.6%), whereas the results of studies with negative controls were heterogeneous (I(2)=60.4%). No farm or cow factors studied that had sufficient data to evaluate significantly contributed to the heterogeneity of the results. The estimated linear score (LS) of milk SCC after calving in published studies (n=3) and for studies that provided raw data (n=2), was significantly lower for cattle treated with internal teat sealants and ADCT in 3 studies than for cattle treated with internal teat sealants only. The estimated LS of pooled raw data of 3 studies from 32 herds showed that the LS of cows treated with internal teat sealant and ADCT was not significantly different than those treated with ADCT only. This study found that the application of internal teat sealants in the presence of ADCT or the use of internal teat sealants alone at dry off significantly reduced the incidence of IMI and clinical mastitis in lactating dairy cows compared with respective control groups. Further studies are needed to investigate the effect of internal teat sealants on postpartum milk SCC in lactating dairy cows. PMID- 24054299 TI - Assessing the research and education needs of the organic dairy industry in the northeastern United States. AB - Demographic and management data about organic dairies have been reported previously, but the current study is the first needs assessment of research and educational priorities of organic dairy farmers in the northeastern United States based directly upon their input. Our objectives were to (1) develop an initial understanding of the emerging research and educational needs of organic dairy farmers in the northeastern United States via focus group interviews, and (2) prioritize the needs identified by the focus groups with a broader population of organic dairy farmers via survey methods. Focus group interviews determined the questions used for the survey questionnaire distributed to 1,200 members of the Northeast Organic Dairy Producers Alliance. The members were asked about demographic information, but more importantly, challenges concerning business management and marketing, organic certification, and animal nutrition, health, and reproduction. The results (183 respondents, 15% response rate) were parsed by region (New England farms compared with New York and Pennsylvania farms), herd size (i.e., 12 to 37, 38 to 59, and >60 cows), and years of organic certification (<4 yr vs. >= 4 yr); however, no differences between regions were observed for demographic data. The average farm consisted of 309 acres and 57 milking cows, on which most of the forage was homegrown but grains were purchased (73% of farms). Among the greatest challenges identified by the farmers were obtaining a steady, fair price for milk (85% respondents); determining dry matter intake for animals on pasture (76%); and controlling nuisance flies (89%). Needs for additional research included organic treatments for mastitis (92% respondents), growing forages for organic production (84%), and developing value-added products (84%). Farms with <4 yr of organic certification were concerned with level of knowledge and experience of local certifiers, whereas organic producers with >= 4 yr of organic certification were more interested in field testing of new organic products. Opportunities for educational programs included learning about direct marketing possibilities (76% respondents) and providing training to regional veterinarians interested in organic remedies (91%). In conclusion, the information obtained from the current needs assessment provides a foundation for future research proposals and educational outreach programs, germane to stakeholder needs, which could benefit the organic dairy industry within the region and beyond. PMID- 24054300 TI - Short communication: Rumination and feeding behavior before and after calving in dairy cows. AB - The objectives of the current study were to describe changes in rumination and feeding behavior around calving. Rumination time, feeding time, and dry matter intake were monitored in 11 freestall-housed cows from 96 h before to 48 h after calving. Data were summarized in 2-h and 24-h periods, adjusting for calving time. Differences between baseline (96 to 24h before calving) and subsequent 24-h periods were evaluated. Compared with baseline, cows spent, on average, 63 +/- 30 min/24h less time ruminating and 66 +/- 16 min/24h less time feeding in the 24-h period before calving. These behaviors continued to decline during the 24-h period after calving when, compared with baseline, time spent ruminating decreased on average by 133 +/- 35 min/24h and time spent feeding decreased by 82 +/- 18 min/24h. Dry matter intake tended to decrease by 3.8 +/- 1.9 kg in the 24 h period before calving but returned to baseline values in the 24-h following calving. Rumination time and time spent feeding started to decline approximately 4 and 8h before calving, respectively, and increased in the 4 to 6h following calving. Rumination time and time spent feeding show promise as tools to identify cows close to calving. PMID- 24054301 TI - Subclinical hypocalcemia, plasma biochemical parameters, lipid metabolism, postpartum disease, and fertility in postparturient dairy cows. AB - A study was conducted to evaluate the potential association between Ca status at calving and postpartum energy balance, liver lipid infiltration, disease occurrence, milk yield and quality parameters, and fertility in Holstein cows. One hundred cows were assigned to 1 of 2 groups based on whole-blood ionized Ca concentration ([iCa]) on the day of calving [d 0; hypocalcemic [iCa] <1.0 mmol/L (n=51); normocalcemic [iCa] >= 1.0 mmol/L (n=49)]. Cows were blocked based on calving date and parity. Blood samples were collected approximately 14 d from expected calving date (d -14), the day of calving (d 0), and on d 3, 7, 14, 21, and 35 postpartum for measurement of plasma nonesterified fatty acid, iCa, total Ca, glucose, and total and direct bilirubin concentrations, and plasma aspartate aminotransferase and gamma glutamyl transferase activities. Liver biopsies were obtained from a subset of cows on d 0, 7, and 35 for quantification of lipid content. Milk samples were collected on d 3, 7, 14, 21, and 35 postpartum for measurement of somatic cell count and percentages of protein, fat, and solids-not fat. Data for peak test-day milk yield, services per conception, and days open were obtained from Dairy Herd Improvement Association herd records. Disease occurrence was determined based on herd treatment records. Hypocalcemic cows had significantly higher nonesterified fatty acids on d 0. Hypocalcemic cows also had significantly more lipid in hepatocytes on d 7 and 35 postpartum. However, no statistically significant differences were observed between groups for plasma aspartate aminotransferase and gamma glutamyl transferase activities or total and direct bilirubin concentrations. Milk protein percentage was lower in hypocalcemic cows on d 21 and 35. However other milk quality variables (somatic cell count, milk fat percentage, and solids-not-fat) and milk yield variables (peak test-day milk yield and 305-d mature-equivalent 4% fat-corrected milk yield) did not differ between groups. No differences were observed between groups in the occurrence of clinical mastitis, ketosis, displaced abomasum, dystocia, retained placenta, metritis, or fertility measures (percentage cycling at 50-60 d postpartum, services per conception, or days open). These data suggest that early lactation fatty acid metabolism differs between cows with subclinical hypocalcemia and their normocalcemic counterparts. PMID- 24054302 TI - Hepatic and extrahepatic expression of serum amyloid A3 during lactation in dairy cows. AB - Serum amyloid A3 (SAA3) is the predominant SAA isoform secreted by mammary epithelial cells in dairy cows; it is also expressed in bovine adipose tissue (AT). The adipokine SAA3 is linked to obesity and insulin resistance of AT and the respective inflammatory response, at least in mice. Dietary treatment with conjugated linoleic acids (CLA) reportedly also affects insulin sensitivity and inflammatory status in monogastrics. Both SAA3 and CLA thus seem to alter similar functions. Based on changes in insulin sensitivity and the inflammatory status throughout lactation, we hypothesized that the mRNA abundance of SAA3 in various tissues might be regulated as well and that CLA could be a modulator of SAA3 mRNA expression. In 2 trials, 21 pluriparous and 25 primiparous Holstein cows were fed 100g/d of a CLA or a control fat supplement from d 1 to 182 or 105 postpartum, respectively. Biopsies from liver and subcutaneous (s.c.) AT from pluriparous cows and samples from 3 different visceral AT and 3 s.c. AT, muscle, mammary gland, and liver tissue from slaughtered primiparous cows were obtained. In an adipocyte cell culture system, cell samples were collected during differentiation of bovine preadipocytes at d 0, 2, 6, 8, 10, 12, and 13 relative to the onset of differentiation. The SAA3 mRNA abundance in tissues and in differentiating bovine preadipocytes was measured by real-time PCR. The presence of the SAA protein was confirmed by Western blotting. Treatment with CLA yielded only few and inconsistent effects on SAA3 mRNA abundance. In both trials, SAA3 mRNA peaked at d 1 postpartum in all tissues except in mesenteric AT, in which the change was not significant. The highest SAA3 mRNA expression was observed in the mammary gland, followed by omental AT. The SAA protein was present in the visceral and s.c. AT depots investigated. Adipocytes as one source of SAA3 were confirmed by the SAA3 mRNA profile in differentiating adipocytes. The longitudinal changes observed point to SAA3 being involved in the inflammatory situation around parturition. PMID- 24054303 TI - A first step toward genomic selection in the multi-breed French dairy goat population. AB - The objectives of this study were to describe, using the goat SNP50 BeadChip (Illumina Inc., San Diego, CA), molecular data for the French dairy goat population and compare the effect of using genomic information on breeding value accuracy in different reference populations. Several multi-breed (Alpine and Saanen) reference population sizes, including or excluding female genotypes (from 67 males to 677 males, and 1,985 females), were used. Genomic evaluations were performed using genomic best linear unbiased predictor for milk production traits, somatic cell score, and some udder type traits. At a marker distance of 50kb, the average r(2) (squared correlation coefficient) value of linkage disequilibrium was 0.14, and persistence of linkage disequilibrium as correlation of r-values among Saanen and Alpine breeds was 0.56. Genomic evaluation accuracies obtained from cross validation ranged from 36 to 53%. Biases of these estimations assessed by regression coefficients (from 0.73 to 0.98) of phenotypes on genomic breeding values were higher for traits such as protein yield than for udder type traits. Using the reference population that included all males and females, accuracies of genomic breeding values derived from prediction error variances (model accuracy) obtained for young buck candidates without phenotypes ranged from 52 to 56%. This was lower than the average pedigree-derived breeding value accuracies obtained at birth for these males from the official genetic evaluation (62%). Adding females to the reference population of 677 males improved accuracy by 5 to 9% depending on the trait considered. Gains in model accuracies of genomic breeding values ranged from 1 to 7%, lower than reported in other studies. The gains in breeding value accuracy obtained using genomic information were not as good as expected because of the limited size (at most 677 males and 1,985 females) and the structure of the reference population. PMID- 24054304 TI - Minimizing photooxidation in pasteurized milk by optimizing light transmission properties of green polyethylene films. AB - The effect of different amounts of transmitted green light on photooxidation in pasteurized milk was studied. Five different green films produced with combinations of pigments and additives to minimize exposure to harmful wavelengths with regard to photosensitizers (400-450 and 600-650 nm) were evaluated. In addition, a non-colored transparent film and an orange film were compared with 1 selected green film. Pasteurized milk (3.9% fat) was packed in an air atmosphere and exposed to light for 14, 20, 26, and 32 h at 4 degrees C under the different films. Samples stored in the dark were control samples. The results showed that the most-effective green film had low overall light transmission, and also almost completely blocked light wavelengths shorter than 450 nm and wavelengths longer than 600 nm, which prevented photooxidation of riboflavin and chlorophyllic compounds. Chlorophyll degradation was highly correlated with sensory properties (coefficient of determination = 0.80-0.94). To preserve milk quality, total blocking of all visible light would be preferable. If total blocking is not feasible, then light transmission for wavelength below 450 nm and above 650 nm should be minimized (e.g., less than 5%). The newly developed green film can be used as a prototype for protection of dairy products to reduce the degradation of photosensitizers. PMID- 24054305 TI - Molecular characterization and clonal diversity of methicillin-susceptible Staphylococcus aureus in milk of cows with mastitis in Brazil. AB - Mastitis is an important disease for the dairy industry worldwide, causing economic losses and reducing milk quality and production. Staphylococcus aureus is a worldwide agent of this intramammary infection, which also causes foodborne diseases. The objective of this study was to determine the frequency of methicillin-susceptible Staphylococcus aureus (MSSA) isolates in milk of mastitis cows in Brazil and to analyze the genetic lineages and the content of antimicrobial resistance genes and virulence factors among these isolates. Fifty six MSSA isolates were recovered from 1,484 milk samples (positive for the California mastitis test) of 518 cows from 11 different farms in Brazil (representing 51% of total Staph. aureus obtained), and they were further characterized. Methicillin-susceptible Staphylococcus aureus were isolated from 3.7% of California mastitis test-positive tested milk samples and from 6.2% of tested mastitic cows. Methicillin-susceptible Staphylococcus aureus isolates were characterized by spa typing, agr typing, and multilocus sequence typing, and resistance and virulence traits were investigated by PCR. Seven spa types were identified among MSSA (% of isolates): t127 (44.6), t605 (37.5), t002, t1784, t2066 (1.8), and 2 new ones: t10856 (10.7) and t10852 (1.8). Five distinct sequence types (ST) were detected (% of isolates): ST1 (46.4), ST126 (37.5), ST133 (10.7), ST5 (3.6), and a novel ST registered as ST2493 (1.8). Resistances were detected for streptomycin, chloramphenicol, and tetracycline. One strain contained the chloramphenicol resistance gene (fexA; included within transposon Tn558) and 3 strains contained the tetracycline resistance gene [tet(K)]. Methicillin-susceptible Staphylococcus aureus strains were susceptible to most of the antibiotics studied and lacked the virulence genes of Panton-Valentine leukocidin (lukF/S-PV), toxic shock syndrome toxin 1 (tst), exfoliative toxin A (eta), and exfoliative toxin B (etb), as well as the genes of the immune evasion cluster. Methicillin-susceptible Staphylococcus aureus isolates were detected in a relatively low proportion of cows with mastitis (6.2%) and recovered isolates presented high diversity of genetic lineages, with CC1 and CC126 the predominant clonal complexes, and CC133 also being detected. Larger epidemiological studies with molecular characterization of isolates are required to deepen the knowledge on the circulating genetic lineages among the cow population with mastitis. PMID- 24054306 TI - Influence of 4-week intraduodenal supplementation of quercetin on performance, glucose metabolism, and mRNA abundance of genes related to glucose metabolism and antioxidative status in dairy cows. AB - Quercetin has been shown to be a potent antioxidant, acts hepatoprotectively, and affects glucose and lipid metabolism in monogastrics. If this is also true in ruminants, quercetin could be beneficial in periparturient high-yielding dairy cows by ameliorating the negative effects of free radical formation and reducing the severity of liver lipidosis and ketosis. In a first attempt to evaluate effects of a long-term quercetin treatment, we intraduodenally administered twice daily 18 mg of quercetin (Q)/kg of body weight to 5 late-lactation (215d in milk) dairy cows over a period of 28 d. Frequent blood samples were taken before and during administration to determine plasma concentrations of flavonols and metabolites. Before and after 1 and 4 wk of Q administration, glycogen and fat content as well as mRNA expression of selected genes were measured in liver biopsies. Furthermore, euglycemic, hyperinsulinemic, and hyperglycemic clamp studies were conducted before and after 2 wk of Q administration. During the experiment, dry matter intake and most other zootechnical data remained unchanged. Milk protein content was increased in wk 2 and 4 of Q administration compared with basal values, whereas fat and lactose contents of milk remained unchanged. Plasma nonesterified fatty acids, gamma-glutamyl transferase, cholesterol, glutamate dehydrogenase, triglyceride, and albumin concentrations, as well as liver fat and glycogen concentrations, were not affected by Q supplementation. Plasma glucose and beta-hydroxybutyrate concentrations in plasma decreased and increased, respectively, under the influence of quercetin. During hyperglycemic clamp conditions, the relative increase of plasma insulin was higher after 2 wk of Q administration, and a tendency for an increased rQUICKI (revised quantitative insulin sensitivity check index) was observed. The relative mRNA expression levels of selected genes related to glucose metabolism, fat metabolism, and antioxidative status were not altered after 1 or 4 wk of Q supplementation. In conclusion, the effects on insulin release and sensitivity support the assumption that administration of Q could have positive effects on the metabolic adaption of high-yielding cows to early lactation. The increase of milk protein content in response to Q supplementation needs to be verified. PMID- 24054307 TI - Successful Visna/maedi control in a highly infected ovine dairy flock using serologic segregation and management strategies. AB - A control system for Visna/maedi virus (VMV) infection based on serologic segregation and management strategies was applied in an infected Spanish dairy Manchega breed sheep flock (n=670) that was affected by a severe respiratory process associated to VMV. The control started in 2004 and consisted on the serological study of animals, segregation in two different flocks (seropositive and seronegative), separate management of flocks, selection of young female lambs for replacement only from seronegative ewes offspring, immediate removal of seropositive animals detected in the seronegative flock and a management tending toward the reduction and final culling of the seropositive flock. The serological control was repeated yearly or twice a year, approximately. Initial VMV seroprevalence of the undivided flock was 66.4% (January 2004) that descended to 47.3%, 12.8%, 2.2% and 0.2% between July 2004 and May 2006. Residual seroprevalence fluctuated slightly thereafter with a peak of 2.2% in April 2008. After segregation, number of animals in the seronegative flock was 378 that descended to 323 in October 2005. Since then, this number has increased steadily reaching 650 sheep in December 2011. The seropositive flock was progressively reduced by culling until its total disappearance in June 2010. This work presents the detailed results obtained in the control strategy against VMV in a single dairy sheep flock by implementing a segregation system based on serologic testing. The system is highly successful, as it reduces to residual levels VMV infection in about two years without the need of culling a high number of animals, as required by other methods. Moreover, the original size flock was been recovered within 8 years and has led to a subjective improvement of animal health and welfare in the flock. The residual seroprevalence could be eliminated at this stage by applying more sensitive molecular or other serological techniques to reach eradication. PMID- 24054308 TI - Orthopedic Multidimensional Prognostic Index (Ortho-MPI) in the elderly with hip or neck femur fracture: a pilot study. AB - The Orthopedic Multidimensional Prognostic Index (Ortho-MPI) was performed and validated in order to ameliorate the decision-making process as regards the elderly with hip or neck femur fractures. A retrospective study was performed. 95 patients 65 years old and over with a diagnosis of hip or femur fracture were enrolled. A standardized comprehensive orthopedic geriatric assessment was performed. It included information on: depressive symptoms, functional and instrumental activities of daily living, cognitive and nutritional status, laboratory tests, risk of pressure sore, comorbidities and comorbidity. The Ortho MPI was calculated. After six months their initial assessment, patients were recalled in order to know if they live too or not. The survival condition was associated to the prognostic capacity calculated by the Ortho-MPI. Results showed that higher Ortho-MPI Index value was associated with higher six months-later mortality. In an unvaried analysis model the Ortho-MPI index was associated with death event of the elderly patients enrolled (OR=1.05; 95% CI, 1.01-1.10; z=2.27; p=0.023). This association was also validated by considering different ages between participants (OR=1.05; 95% CI, 1.004-1.11; z=2.13; p=0.033). Furthermore, each specific index considered in the total Ortho-MPI was associated with the death event of the elderly patients. In conclusion it was shown that the Ortho MPI Index could be used to predict outcome in the elderly with hip or femur fracture. PMID- 24054309 TI - Improving accuracy and efficiency of mutual information for multi-modal retinal image registration using adaptive probability density estimation. AB - Mutual information (MI) is a popular similarity measure for performing image registration between different modalities. MI makes a statistical comparison between two images by computing the entropy from the probability distribution of the data. Therefore, to obtain an accurate registration it is important to have an accurate estimation of the true underlying probability distribution. Within the statistics literature, many methods have been proposed for finding the 'optimal' probability density, with the aim of improving the estimation by means of optimal histogram bin size selection. This provokes the common question of how many bins should actually be used when constructing a histogram. There is no definitive answer to this. This question itself has received little attention in the MI literature, and yet this issue is critical to the effectiveness of the algorithm. The purpose of this paper is to highlight this fundamental element of the MI algorithm. We present a comprehensive study that introduces methods from statistics literature and incorporates these for image registration. We demonstrate this work for registration of multi-modal retinal images: colour fundus photographs and scanning laser ophthalmoscope images. The registration of these modalities offers significant enhancement to early glaucoma detection, however traditional registration techniques fail to perform sufficiently well. We find that adaptive probability density estimation heavily impacts on registration accuracy and runtime, improving over traditional binning techniques. PMID- 24054310 TI - Death of a child and parental wellbeing in old age: evidence from Taiwan. AB - The death of a child is one of the most traumatic events that a parent can experience. The psychological and physical consequences of bereavement are well established, and the consequences are more severe for mothers than fathers. However, little is known about how the death of an adult child affects parental wellbeing in old age or how the deceased child's sex may moderate the association. We use data from the Taiwanese Longitudinal Study of Aging (TLSA) to investigate how the death of a son or a daughter differentially affects the wellbeing of older parents, measured by depressive symptoms and self-rated health. We find that for mothers, a son's death is associated with an increase in depressive symptoms and a decline in self-rated health, but fathers' health is not adversely affected by a son's death. There is little evidence that a daughter's death has a negative effect on either maternal or paternal wellbeing. We situate these findings within their social and cultural contexts and discuss social policies that would reduce gender and health inequality. PMID- 24054311 TI - Venous air embolism: an under-recognized and potentially catastrophic complication in orthopaedic surgery. AB - INTRODUCTION: Venous air embolism (VAE) is the entry of air or other medical gases into the central venous system, producing an air embolism to the right heart or pulmonary artery. VAE is a largely iatrogenic complication with potentially devastating sequelae that can occur in a variety of surgical procedures. METHOD: Within orthopaedics, VAE has been associated with both open and arthroscopic surgeries with the patient in a variety of positions (ie, prone, supine, sitting). These articles, as well as reports of VAE in other surgical settings outside of orthopaedics, are examined. CONCLUSION: Diagnosis of VAE requires a high index of suspicion, as clinical presentation ranges from completely asymptomatic to fatal cardiopulmonary collapse. The vigilant surgeon should carefully watch for air entry at the operative site and the astute anesthesiologist must closely monitor end-tidal CO2 (ETCO2). Prevention of VAE is of paramount importance, as management is largely supportive and aimed at inhibiting further air ingress. PMID- 24054312 TI - Pseudoaneurysm after shoulder arthroscopy. PMID- 24054313 TI - Dermal allograft reconstruction of a chronic pectoralis major tear. PMID- 24054314 TI - RE: Response to "Acupuncture: it is time for scientifically well-designed study". PMID- 24054315 TI - Othello syndrome and chronic dopaminergic treatment in patients with Parkinson's disease. PMID- 24054316 TI - The role of inflammation in postresuscitation myocardial dysfunction. PMID- 24054317 TI - Increased cardiotrophin-1 in subjects with impaired glucose tolerance and newly diagnosed diabetes. PMID- 24054318 TI - Aborted sudden unexplained death in epilepsy in a neuromuscular disorder leading to Takotsubo syndrome. PMID- 24054319 TI - Double, double...What's the trouble? AB - Parasystole can be subtle, making the diagnosis difficult to recognize. PMID- 24054320 TI - Garner interference and temporal information processing. AB - The aim of the study was to explore whether temporal information processing can interfere with performance of a non-temporal task. A new methodology based on the Garner paradigm was employed. Participants were asked to classify two-dimensional stimuli according to either length or duration, with and without variation in the other (task-irrelevant) dimension. Garner interference was detected only with respect to classification by length when irrelevant variation in duration was present. Stroop interference was detected only in classification by length across compatible and non-compatible values of length and duration. Classification by length took more time when done with variation in duration than when duration was constant. Classification by length also took more time when length and duration were not compatible than when they were compatible. The findings indicate that the processing of duration is similar to the processing of other perceptual dimensions. The processing of duration consumes attentional resources and can interfere with the processing of other perceptual dimensions. The findings support attentional models of prospective duration judgment. PMID- 24054321 TI - New territory for T follicular helper cells. AB - T follicular helper (Tfh) cells have been thrust into the limelight since the recent discovery of their unique developmental program. Exciting new insights into the regulation of Tfh development, migration, and function were presented at the first Gordon Conference on Tfh cells held in Hong Kong and summarized here. PMID- 24054322 TI - Pseudokiller, qu'est-ce que c'est? AB - Necroptosis is mediated by engagement of RIP kinases and a downstream pseudokinase, MLKL. In this issue of Immunity, Murphy et al. (2013) show that it operates at or close to the final execution mechanism of the death process. PMID- 24054323 TI - Removing the TREX1 safety net: oxidized DNA overcomes immune silencing by exonuclease TREX1. AB - If DNA accumulates in the cytosol, it activates innate immunity via recently described DNA sensors. In this issue of Immunity, Gehrke et al. (2013) show that oxidized DNA is resistant to degradation by TREX1 and thus has heightened immunostimulatory capacity. PMID- 24054324 TI - Autophagy meets phagocytosis. AB - Autophagy can degrade intracellular bacteria, but how this pathway contributes to phagocytosis is unclear. In this issue of Immunity, Bonilla et al. (2013) demonstrate an additional role for autophagy in Mycobacterium tuberculosis internalization by macrophages. PMID- 24054325 TI - A breath of fresh aire. AB - The origin and function of extrathymic Aire-expressing cells (eTACs) is incompletely defined. In this issue of Immunity, Gardner et al. (2013) show that eTACs are a distinct tolerogenic cell population that functionally inactivates CD4+ T cells to induce peripheral tolerance. PMID- 24054326 TI - A bloody mess: dendritic cells use hemophagocytosis to regulate viral inflammation. AB - Previous studies have highlighted the immune-dampening effects of apoptotic cell uptake by phagocytes. Ohyagi et al. (2013) expose a unique mechanism of immune regulation during viral infection, which is mediated through phagocytosis of apoptotic red cells by dendritic cells. PMID- 24054328 TI - Antigen availability determines CD8+ T cell-dendritic cell interaction kinetics and memory fate decisions. AB - T cells are activated by antigen (Ag)-bearing dendritic cells (DCs) in lymph nodes in three phases. The duration of the initial phase of transient, serial DC T cell interactions is inversely correlated with Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessary for full fledged T cell activation. Here we have shown that this is not the case. CD8+ T cells interacting with DCs presenting low-dose, short-lived Ag did not transition to phase 2, whereas higher Ag dose yielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effector differentiation but yielded different transcriptome signatures at 12 hr and 24 hr. T cells that experienced phase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunological amnesia. Thus, T cells make fate decisions within hours after Ag exposure, resulting in long-term memory or abortive effector responses, correlating with T cell-DCs interaction kinetics. PMID- 24054329 TI - Sustained interactions between T cell receptors and antigens promote the differentiation of CD4+ memory T cells. AB - During CD4+ T cell activation, T cell receptor (TCR) signals impact T cell fate, including recruitment, expansion, differentiation, trafficking, and survival. To determine the impact of TCR signals on the fate decision of activated CD4+ T cells to become end-stage effector or long-lived memory T helper 1 (Th1) cells, we devised a deep-sequencing-based approach that allowed us to track the evolution of TCR repertoires after acute infection. The transition of effector Th1 cells into the memory pool was associated with a significant decrease in repertoire diversity, and the major histocompatibility complex (MHC) class II tetramer off rate, but not tetramer avidity, was a key predictive factor in the representation of individual clonal T cell populations at the memory stage. We conclude that stable and sustained interactions with antigens during the development of Th1 responses to acute infection are a determinative factor in promoting the differentiation of Th1 memory cells. PMID- 24054327 TI - Mechanisms of NOD-like receptor-associated inflammasome activation. AB - A major function of a subfamily of NLR (nucleotide-binding domain, leucine-rich repeat containing, or NOD-like receptor) proteins is in inflammasome activation, which has been implicated in a multitude of disease models and human diseases. This work will highlight key progress in understanding the mechanisms that activate the best-studied NLRs (NLRP3, NLRC4, NAIP, and NLRP1) and in uncovering inflammasome NLRs. PMID- 24054330 TI - The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. AB - NOD2 is an intracellular sensor that contributes to immune defense and inflammation. Here we investigated whether NOD2 mediates its effects through control of microRNAs (miRNAs). miR-29 expression was upregulated in human dendritic cells (DCs) in response to NOD2 signals, and miR-29 regulated the expression of multiple immune mediators. In particular, miR-29 downregulated interleukin-23 (IL-23) by targeting IL-12p40 directly and IL-23p19 indirectly, likely via reduction of ATF2. DSS-induced colitis was worse in miR-29-deficient mice and was associated with elevated IL-23 and T helper 17 signature cytokines in the intestinal mucosa. Crohn's disease (CD) patient DCs expressing NOD2 polymorphisms failed to induce miR-29 upon pattern recognition receptor stimulation and showed enhanced release of IL-12p40 on exposure to adherent invasive E. coli. Therefore, we suggest that loss of miR-29-mediated immunoregulation in CD DCs might contribute to elevated IL-23 in this disease. PMID- 24054331 TI - Biomechanical characteristics of barefoot footstrike modalities. AB - Barefoot running has increased in popularity over recent years, with suggested injury risk and performance benefits. However, despite many anecdotal descriptions of barefoot running styles, there is insufficient evidence regarding the specific characteristics of barefoot running. The present study provided reference data for four footstrike modalities adopted across a large cohort of habitually shod male runners while running barefoot: heel strikers (HS), midfoot strikers (MS), forefoot strikers (FS) and a newly defined group, toe runners (TR contact made only with the forefoot), compared with the three modalities previously reported. Plantar pressure analysis was used for the classification of footstrike modality, with clearly distinguishable pressure patterns for different modalities. In the present study, the distribution of footstrike types was similar to that previously observed in shod populations. The absence of differences in ground contact time and stride length suggest that potential performance benefits of a non-HS style are more likely to be a function of the act of running barefoot, rather than of footstrike type. Kinematic data for the knee and ankle indicate that FS and TR require a stiffer leg than HS or MS, while ankle moment and plantar pressure data suggest that a TR style may put greater strain on the plantar-flexors, Achilles tendon and metatarsal heads. TR style should therefore only be adopted with caution by recreational runners. These findings indicate the importance of considering footstrike modality in research investigating barefoot running, and support the use of four footstrike modalities to categorise running styles. PMID- 24054333 TI - Prognostic factors of early metastasis and mortality in dogs with appendicular osteosarcoma after receiving surgery: an individual patient data meta-analysis. AB - Recently an aggregated data meta-analysis showed that serum alkaline phosphatase (SALP) and proximal humerus location are predictors for shorter survival in canine osteosarcoma. To identify additional prognostic factors of mortality and metastasis an individual patient data meta-analysis (IPDMA) was conducted. Individual patient data from 20 studies, identified via the VSSO society, were pooled. Univariable and multivariable hazard ratios (HR) for metastasis and mortality were assessed, using stratified Cox models. The study included 1405 dogs who received surgical treatment, of which the metastasis status was measured in 1155 dogs and mortality status in 1336 dogs; median survival was 256 days. High versus normal SALP and weight (kg) were associated with an increase in hazard of metastasis [HR 1.34 (95%CI 1.07; 1.68) and HR 1.02 (per kg increase) (95%CI 1.01; 1.03)] and for mortality [HR 1.43 (95%CI 1.16; 1.77) and HR 1.02 (95%CI 1.01; 1.02)]. Distal radius tumor was associated with a lower hazard of metastasis compared to other locations: HR 0.75 (95%CI 0.58; 0.96). Proximal humerus and distal femur or proximal tibia location were related with an increased mortality: HR 1.53 (95%CI 1.26; 1.84) and HR 1.23 (95%CI 1.01; 1.49) compared to other locations. Older age (years) was associated with a higher hazard for mortality [HR 1.06 per year (95%CI 1.03; 1.09)] but not for metastasis: HR 1.03 (95%CI 0.99; 1.06). These results confirm findings from a recent aggregated data meta-analysis and (in addition) showed that tumor location, SALP, weight were prognostic factors for both mortality and metastasis. Age was a prognostic factor for mortality but not for metastasis. PMID- 24054332 TI - Dysplasia at the margin? Investigating the case for subsequent therapy in 'low risk' squamous cell carcinoma of the oral tongue. AB - PURPOSE: This is a retrospective analysis of the impact of moderate dysplasia at the resection margin for early stage cancer of the oral tongue. MATERIALS AND METHODS: Patients with T1-2N0 oral tongue cancer treated with surgery alone at Fox Chase Cancer Center (FCCC) from 1990 to 2010 were reviewed. Tumor and margin characteristics were abstracted from the pathology report. Overall survival (OS), disease-free survival (DFS) and local control (LC) were calculated using the Kaplan Meier method. Predictors of LC, OS and DFS were analyzed. RESULTS: 126 Patients met the inclusion criteria. Dysplasia was present at the final margin in 36% of the cases (severe: 9%, moderate: 15%, mild: 12%). Median follow-up was 52 months. 3 and 5-year actuarial LC for the entire cohort was 77% and 73%, respectively. Actuarial 5-year LC and DFS were significantly worse for patients with moderate or severe dysplasia at the margin vs. none or mild dysplasia at the margin (49% vs 82%, p=0.005 and 49% vs 80%, p=0.008, respectively); 3-year comparisons were not significant. When analyzed separately, the detrimental local effect of moderate dysplasia at the margin persisted (p=0.02) and the effect of severe dysplasia at the margin was approaching significance (p=0.1). Mild dysplasia at the margin did not significantly impair LC or DFS. Multivariate analysis demonstrated worse LC (HR: 2.99, p=0.006) and DFS (HR: 2.84, p=0.008) associated with severe or moderate dysplasia at the margin. CONCLUSIONS: Both severe and moderate dysplasia at the margin appear to be correlated with inferior LC and DFS. Additional therapy may be justified, despite added morbidity. PMID- 24054334 TI - Nanotube-modified dentin adhesive--physicochemical and dentin bonding characterizations. AB - OBJECTIVE: The aim of this study was to investigate the effect of aluminosilicate clay nanotubes (Halloysite, HNT) incorporated into the adhesive resin of a commercially available three-step etch and rinse bonding system (Adper Scotchbond Multi-Purpose/SBMP) on dentin bond strength, as well as the effect on several key physicochemical properties of the modified adhesive. METHODS: Experimental adhesives were prepared by adding five distinct HNT amounts (5-30 wt.%) into the adhesive resin (w/v) of the SBMP dentin bonding system. Bond strength to human dentin, microhardness, and degree of conversion (DC) of the modified adhesives were assessed. RESULTS: From the shear bond strength data, it was determined that HNT incorporation at a concentration of 30 wt.% resulted in the highest bond strength to dentin that was statistically significant (p=0.025) when compared to the control. Even though a significant increase in microhardness (p<0.001) was seen for the 30 wt.% HNT-incorporated group, a significantly lower DC (p<0.001) was recorded when compared to the control. SIGNIFICANCE: It was concluded that HNT can be incorporated up to 20 wt.% without jeopardizing important physicochemical properties of the adhesive. The modification of the SBMP dentin bonding agent with 20 wt.% HNT appears to hold great potential toward contributing to a durable dentin bond; not only from the possibility of strengthening the bond interface, but also due to HNT intrinsic capability of encapsulating therapeutic agents such as matrix metalloproteinase (MMP) inhibitors. PMID- 24054336 TI - Increasing serum soluble angiotensin-converting enzyme 2 activity after intensive medical therapy is associated with better prognosis in acute decompensated heart failure. AB - BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is an endogenous counterregulator of the renin-angiotensin system that has been recently identified in circulating form. We aimed to investigate the relationship among changes in soluble ACE2 (sACE2) activity, myocardial performance, and long-term clinical outcomes in patients with acute decompensated heart failure (ADHF). We hypothesized that increasing sACE2 activity levels during intensive medical treatment are associated with improved myocardial performance and long-term clinical outcomes. METHODS AND RESULTS: In 70 patients admitted to the intensive care unit with ADHF, serum sACE2 activity levels, echocardiographic data, and hemodynamic variables were collected within 12 hours of admission (n = 70) and 48 72 hours after intensive medical treatment (n = 57). The median [interquartile range] baseline and 48-72-hour serum sACE2 activity levels were 32 [23-43] ng/mL and 40 [28-60] ng/mL, respectively. Baseline serum sACE2 activity levels correlated with surrogate measures of right ventricular diastolic dysfunction, including right atrial volume index (RAVi; r = 0.31; P = .010), tricuspid E/A ratio (r = 0.39; P = .007), and B-type natriuretic peptide (r = 0.32; P = .008). However, there were no correlations between serum sACE2 and left ventricular systolic or diastolic dysfunction. After intensive medical therapy, a 50% increase in baseline serum sACE2 levels predicted a significant reduction in risk of death, cardiac transplantation, or ADHF rehospitalization, including after adjustment for baseline age, RAVi, and BNP levels (hazard ratio 0.35, 95% confidence interval 0.12-0.84; P = .018). CONCLUSIONS: In patients admitted with ADHF, increasing serum sACE2 activity levels during intensive medical therapy predict improved outcomes independently from underlying cardiac indices. PMID- 24054337 TI - Medical resource use, costs, and quality of life in patients with acute decompensated heart failure: findings from ASCEND-HF. AB - BACKGROUND: The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomly assigned 7,141 participants to nesiritide or placebo. Dyspnea improvement was more often reported in the nesiritide group, but there were no differences in 30-day all-cause mortality or heart failure readmission rates. We compared medical resource use, costs, and health utilities between the treatment groups. METHODS AND RESULTS: There were no significant differences in inpatient days, procedures, and emergency department visits reported for the first 30 days or for readmissions to day 180. EQ-5D health utilities and visual analog scale ratings were similar at 24 hours, discharge, and 30 days. Billing data and regression models were used to generate inpatient costs. Mean length of stay from randomization to discharge was 8.5 days in the nesiritide group and 8.6 days in the placebo group (P = .33). Cumulative mean costs at 30 days were $16,922 (SD $16,191) for nesiritide and $16,063 (SD $15,572) for placebo (P = .03). At 180 days, cumulative costs were $25,590 (SD $30,344) for nesiritide and $25,339 (SD $29,613) for placebo (P = .58). CONCLUSIONS: The addition of nesiritide contributed to higher short-term costs and did not significantly influence medical resource use or health utilities compared with standard care alone. PMID- 24054339 TI - Cardiovascular management of cancer patients with chemotherapy-associated left ventricular systolic dysfunction in real-world clinical practice. AB - BACKGROUND: Chemotherapy-induced left ventricular systolic dysfunction (LVSD) may limit survival in cancer patients and therefore should be treated timely with appropriate heart failure medication. This study aimed to evaluate quality of cardiac care in cancer patients with documented chemotherapy-induced LVSD in real world clinical practice. METHODS: Using an institutional echo database, we screened 1,520 cancer patients for first documentation of chemotherapy-associated LVSD, defined as left ventricular ejection fraction (LVEF) <=45%. Hospital charts of all 63 patients meeting inclusion criteria were reviewed regarding patient characteristics and frequency of heart failure medication prescription. RESULTS: Patients were 61 (interquartile range [IQR], 50-70) years old, mostly symptomatic, and had an average LVEF of 34 +/- 8%. Most patients received anthracyclines (73%) and/or alkylating agents (73%) as part of their chemotherapeutic regimen. Median time from cancer diagnosis to first documentation of LVSD was 2.2 (0.7-5.2) years. Fewer than two-thirds of patients received guideline-recommended heart failure medication, and only one-half of patients received cardiology consult. Cardiology consultation was associated with a significantly higher frequency of heart failure medication prescription (100% vs. 52% for angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (P < .0001); 94% vs. 41% for beta-blocker (P < .0001) and better survival (71% vs. 41%; P < .05). CONCLUSIONS: Chemotherapy-associated LVSD is insufficiently treated in cancer patients. Cardiology consultation improves rates of heart failure medication and therefore should be advocated in all patients with chemotherapy-induced LVSD. PMID- 24054338 TI - Novel urinary biomarkers in detecting acute kidney injury, persistent renal impairment, and all-cause mortality following decongestive therapy in acute decompensated heart failure. AB - BACKGROUND: New urinary biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18), are proposed to allow a more reliable early diagnosis and prognosis of acute kidney injury (AKI) in acute decompensated heart failure (ADHF). Our aim was to compare the predictive value of urinary NGAL, KIM-1, and IL-18 for the occurrence of AKI, persistent renal impairment, and mortality in ADHF. METHODS AND RESULTS: Eighty-three patients admitted for ADHF were analyzed. Urinary creatinine (Cr), NGAL, KIM-1, and IL-18 were measured at baseline. Serum Cr was measured daily during the next 4 days and again at outpatient follow-up after 6 months. Mortality data were prospectively collected. Urinary NGAL, KIM-1, and IL-18 were modestly correlated with each other (Spearman rho <=0.61) and poorly correlated with estimated glomerular filtration rate (eGFR; Spearman rho <=0.28). None predicted AKI, defined as a 25% decrease in eGFR, during the index hospitalization, but urinary IL-18/Cr was the strongest predictor of persistently elevated serum Cr >=0.3 mg/dL after 6 months compared with baseline (area under the receiver operating characteristic curve 0.674; P = .013). Urinary IL-18 was also significantly associated with all-cause mortality (hazard ratio 1.48, 95% confidence interval 1.16-1.87; P = .001). CONCLUSIONS: Like urinary NGAL, urinary KIM-1 and IL-18 are relatively modest predictors of AKI in ADHF. Among these novel renal biomarkers examined, further investigations regarding the prognostic value of urinary IL-18 are warranted. PMID- 24054340 TI - Association between physical activity measurements and key parameters of cardiopulmonary exercise testing in patients with heart failure. AB - BACKGROUND: A hallmark characteristic of heart failure (HF) is reduced physical activity (PA) patterns. The relationship between key cardiopulmonary exercise testing (CPX) variables and PA patterns has not been investigated. Therefore, we evaluated PA patterns in patients with ischemic HF and its relationship to peak oxygen consumption (VO2), the minute ventilation/carbon dioxide production (VE/VCO2) slope, and the oxygen uptake efficiency slope (OUES). METHODS AND RESULTS: Sixteen patients with HF wore an accelerometer for six days to measure total steps/day as well as percentage of time at light, moderate, and vigorous PA. Symptom-limited CPX was performed on a treadmill using a ramping protocol. Total steps correlated with VO2 (r = 0.64 P < .05), the VE/VCO2 slope (r = -0.72; P < .05), and the OUES (0.63; P < .05). The percentage of time at light-intensity PA correlated with the VE/VCO2 slope (r = 0.58; P < .05) and the OUES (r = -0.51; P < .05). The percentage of time at vigorous-intensity PA correlated with peak VO2 (r = 0.55; P < .05) and the VE/VCO2 slope (r = -0.52; P < .05). CONCLUSIONS: PA assessed by accelerometer is significantly associated with key CPX variables in patients with HF. PMID- 24054341 TI - Mild cognitive impairment, screening, and patient perceptions in heart failure patients. AB - OBJECTIVE: Cognitive impairments are prevalent in heart failure (HF) patients, worsening outcomes but often undetected.The aim of this study was to screen HF outpatients for mild cognitive impairment (MCI), determine the areas of cognition affected, patient awareness of cognitive change, and associated factors. METHOD AND RESULTS: HF patients (n = 128) newly registered for the Management of Cardiac Function program, free from neurocognitive disorder, and with sufficient visual acuity were assessed with the use of the Montreal Cognitive Assessment tool (MoCA). MCI was classified as MoCA score <=22. The sample was elderly (mean, 80.65 years; SD, 11.52). Mean MoCA score was 24.58 (SD 3.45), 22% were classified as impaired, 45% had noticed a change in cognition, and 15% reported that they were affected in their daily lives. Patients noticing this impact had lower MoCA scores (22.74, SD 3.0) than those who did not (25.17, SD 2.96; P <= .02). Most impairments occurred for delayed recall, visuospatial/executive function, and abstraction. The odds of impairment increased by the presence of ischemic heart disease (odds ratio, 4.18; 95% confidence interval, 1.15-15.69). CONCLUSIONS: In HF outpatients without a dementia diagnosis, MCI is prevalent. Screening for MCI and incorporation of compensatory strategies are essential. PMID- 24054342 TI - A comprehensive symptom diary intervention to improve outcomes in patients with HF: a pilot study. AB - BACKGROUND: Patients with heart failure must monitor for and recognize escalating symptoms to take action to relieve symptoms and decrease hospitalizations. However, symptom monitoring is not commonly performed. One way to promote patients' engagement in symptom monitoring is by providing a symptom diary. PURPOSE: The aim of this study was to test the effect of a comprehensive daily symptom diary intervention on event-free survival and health-related quality of life (HRQOL). METHODS: Patients were randomized into either intervention (n = 23) or usual-care groups (n = 21). The intervention group received a symptom diary with self-care education and counseling at baseline with 5 follow-up calls for 3 months. All patients were interviewed to obtain survival data at 1 month and 3 months. HRQOL was measured at baseline, 1 month, and 3 months. Kaplan-Meier curves with the log-rank test were used to compare group differences in time to first event. Linear mixed models were conducted to examine the relationship between groups and changes in HRQOL over 3 months. RESULTS: The intervention group had longer event-free survival than the usual-care group (P = .03). There were no differences in changes in HRQOL scores between the groups over 3 months. CONCLUSIONS: Positive effects of the intervention on survival were found. However, there was no significant difference in changes in HRQOL. PMID- 24054343 TI - Autonomic regulation therapy for the improvement of left ventricular function and heart failure symptoms: the ANTHEM-HF study. AB - BACKGROUND: Outcomes of heart failure (HF) have improved dramatically with the use of blockers of the sympathetic and renin-angiotensin-aldosterone systems, as well as with more prevalent use of implantable cardiac defibrillators and cardiac resynchronization therapy. Despite these interventions, however, the overall prognosis of HF patients remains poor. Recently, stimulation of the right cervical vagus nerve in patients with symptomatic heart failure has been evaluated. Results suggest that vagal nerve stimulation provides sustained improvement in left ventricular (LV) function and symptoms associated with HF. However, much remains to be learned about the risks and benefits of therapies that alter autonomic regulatory function for the treatment of heart failure. METHODS: The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF) study has been designed to address several key clinical questions about the role of autonomic regulation therapy (ART) in patients with LV dysfunction and chronic symptomatic heart failure. CONCLUSIONS: ANTHEM-HF should provide additional and valuable information regarding the safety and the relationship between the site and intensity of ART and its salutary effects on HF. PMID- 24054344 TI - Reply: To PMID 23207079. PMID- 24054345 TI - Cardiac performance by noninvasive bilevel positive airway pressure (BiPAP) in acute-on-chronic heart failure: pressure dependence or nervous activity. PMID- 24054346 TI - Reliability and validity of pressure and temporal parameters recorded using a pressure-sensitive insole during running. AB - Running biomechanics has received increasing interest in recent literature on running-related injuries, calling for new, portable methods for large-scale measurements. Our aims were to define running strike pattern based on output of a new pressure-sensitive measurement device, the Runalyser, and to test its validity regarding temporal parameters describing running gait. Furthermore, reliability of the Runalyser measurements was evaluated, as well as its ability to discriminate different running styles. Thirty-one healthy participants (30.3 +/- 7.4 years, 1.78 +/- 0.10 m and 74.1 +/- 12.1 kg) were involved in the different study parts. Eleven participants were instructed to use a rearfoot (RFS), midfoot (MFS) and forefoot (FFS) strike pattern while running on a treadmill. Strike pattern was subsequently defined using a linear regression (R(2)=0.89) between foot strike angle, as determined by motion analysis (1000 Hz), and strike index (SI, point of contact on the foot sole, as a percentage of foot sole length), as measured by the Runalyser. MFS was defined by the 95% confidence interval of the intercept (SI=43.9-49.1%). High agreement (overall mean difference 1.2%) was found between stance time, flight time, stride time and duty factor as determined by the Runalyser and a force-measuring treadmill (n=16 participants). Measurements of the two devices were highly correlated (R >= 0.80) and not significantly different. Test-retest intra-class correlation coefficients for all parameters were >= 0.94 (n=14 participants). Significant differences (p<0.05) between FFS, RFS and habitual running were detected regarding SI, stance time and stride time (n=24 participants). The Runalyser is suitable for, and easily applicable in large-scale studies on running biomechanics. PMID- 24054347 TI - Validation of a protocol for the estimation of three-dimensional body center of mass kinematics in sport. AB - Since strictly related to balance and stability control, body center of mass (CoM) kinematics is a relevant quantity in sport surveys. Many methods have been proposed to estimate CoM displacement. Among them, segmental method appears to be suitable to investigate CoM kinematics in sport: human body is assumed as a system of rigid bodies, hence the whole-body CoM is calculated as the weighted average of the CoM of each segment. The number of landmarks represents a crucial choice in the protocol design process: one have to find the proper compromise between accuracy and invasivity. In this study, using a motion analysis system, a protocol based upon the segmental method is validated, adopting an anatomical model comprising 14 landmarks. Two sets of experiments were conducted. Firstly, our protocol was compared to the ground reaction force method (GRF), accounted as a standard in CoM estimation. In the second experiment, we investigated the aerial phase typical of many disciplines, comparing our protocol with: (1) an absolute reference, the parabolic regression of the vertical CoM trajectory during the time of flight; (2) two common approaches to estimate CoM kinematics in gait, known as sacrum and reconstructed pelvis methods. Recognized accuracy indexes proved that the results obtained were comparable to the GRF; what is more, during the aerial phases our protocol showed to be significantly more accurate than the two other methods. The protocol assessed can therefore be adopted as a reliable tool for CoM kinematics estimation in further sport researches. PMID- 24054348 TI - The effects of clothes on independent walking in toddlers. AB - The spatiotemporal features of walking in toddlers are known to be related to the level of maturation of the central nervous system. However, previous studies did not assess whether there could be an effect of clothes on the acquisition of walking. In this study, it was hypothesized that clothes modify the toddlers' walking. To test this hypothesis, 22 healthy toddlers divided into 3 groups of walking experience were assessed in four clothing conditions (Diaper+Trousers; Diaper+Pants of tracksuit; Diaper; Underwear). Results revealed significant effects of clothing on velocity and step length of toddlers from 6 to 18 months of walking experience. These results suggested that biomechanical constraints induced by the textile features alter the walking of toddlers. Therefore, in studies of toddler's gait, the clothing worn should be carefully mentioned and controlled. PMID- 24054349 TI - Detection of co-regulation of local structure and magnitude of stride time variability using a new local detrended fluctuation analysis. AB - Detrended fluctuation analysis (DFA) is a popular method to numerically define the persistent structure of stride time variability. The conventional DFA assumes that the persistent structure in stride time variability is consistent in time and can be numerically defined by a single DFA scaling exponent. However, stride time regulation has to be adaptive to both environmental and internal perturbations and consequently, the persistent structure of stride time variability will have to be modulated in time. The present article introduces a new local detrended fluctuation analysis (DFAloc) that is able to detect modulation in the structure of stride time variability generated by phase couplings between temporal scales. DFAloc was used in a reanalysis of the data set of stride time variability of Hausdorff et al. and a data set available at www.physionet.org. The results showed that there were significant phase couplings between temporal scales that generate an inverse correlation (r=-0.54 to -0.83) between the local structure and local magnitude of the stride time variability. Furthermore, the modulation of the local structure was significantly influenced by gait speed, external pace making, and age (all p's<0.05). These results suggest several specific modifications of contemporary theories that have been suggested for the persistent structure of stride time variability found by the conventional DFA. PMID- 24054350 TI - Which functional impairments are the main contributors to pelvic anterior tilt during gait in individuals with cerebral palsy? AB - While past investigations focused on describing pelvic motion patterns in the frontal and transversal plane, the sagittal plane "double bump" pattern commonly found in children with cerebral palsy was only rarely investigated, especially concerning the underlying pathology. 375 ambulatory (GMFCS I-III) patients with bilateral spastic cerebral palsy were included in this study. Gait and clinical data (ROM, strength, spasticity) were classified in two different ways: (a) into two groups of normal and enhanced mean anterior pelvic tilt and (b) into two groups of moderate and excessive ROM in pelvic tilt. The results reveal that increased mean pelvic tilt is mainly associated with gait features of reduced hip extension and increased pelvic and trunk obliquity ROM but with increased knee ROM. In the clinical exam this corresponds to a smaller passive knee extension deficit and reduced knee flexor strength. It seems that flexors to extensors strength imbalance at the knee is a major feature why mean pelvic position is tilted anterior whereas maximum passive hip extension is of minor importance. Contrarily, excessive sagittal pelvic ROM is associated with increased knee flexion at initial contact and reduced knee ROM. Furthermore, Duncan-Ely- and Tardieu-tests show both increased values in this group with excessive pelvic range of motion indicating for spastic rectus femoris activation. The results of our study indicate that the two gait variables are influenced by different specific mechanisms which are now described for the first time. Since the pelvis plays a central role during gait, these findings should be considered when planning single event multilevel surgery in patients with cerebral palsy. PMID- 24054351 TI - Assessment of the post-exercise glycemic response to food: considering prior nutritional status. PMID- 24054353 TI - Adopting a commercial clinical decision support for imaging product: our experience. PMID- 24054352 TI - Standardization meets stories: contrasting perspectives on the needs of frail individuals at a rehabilitation unit. AB - BACKGROUND: Repeated encounters over time enable general practitioners (GPs) to accumulate biomedical and biographical knowledge about their patients. A growing body of evidence documenting the medical relevance of lifetime experiences indicates that health personnel ought to appraise this type of knowledge and consider how to incorporate it into their treatment of patients. In order to explore the interdisciplinary communication of such knowledge within Norwegian health care, we conducted a research project at the interface between general practice and a nursing home. METHODS: In the present study, nine Norwegian GPs were each interviewed about one of their patients who had recently been admitted to a nursing home for short-term rehabilitation. A successive interview conducted with each of these patients aimed at both validating the GP's information and exploring the patient's life story. The GP's treatment opinions and the patient's biographical information and treatment preferences were condensed into a biographical record presented to the nursing home staff. The transcripts of the interviews and the institutional treatment measures were compared and analysed, applying a phenomenological-hermeneutical framework. In the present article, we compare and discuss: (1) the GPs' specific recommendations for their patients; (2) the patients' own wishes and perceived needs; and (3) if and how this information was integrated into the institution's interventions and priorities. RESULTS: Each GP made rehabilitation recommendations, which included statements regarding both the patient's personality and life circumstances. The nursing home staff individualized their selection of therapeutic interventions based on defined standardized treatment approaches, without personalizing them. CONCLUSION: We found that the institutional voice of medicine consistently tends to override the voice of the patient's lifeworld. Thus, despite the institution's best intentions, their efforts to provide appropriate rehabilitation seem to have been jeopardized to some extent. PMID- 24054354 TI - Making an impression. PMID- 24054355 TI - Dynamic touch is affected in children with cerebral palsy. AB - Children with developmental disorders such as cerebral palsy have limited opportunities for effortful interactions with objects and tools. The goal of the study was to investigate whether children with cerebral palsy have deficits in their ability to perceive object length by dynamic touch when compared to typically developing children. Fourteen children with typical development and 12 children with cerebral palsy were asked to report the length of hand-held rods after wielding them out of sight. Multilevel regression models indicated that I1 (maximum principal moment of inertia) was a significant predictor of perceived length - LP (p<.0001). The effect of I1 on LP was significantly different among children (p=.001) and the presence of cerebral palsy (group factor) partially explained such variance (p=.002). In addition, accuracy and reliability of the length judgments made by children with cerebral palsy were significantly lower than the typically developing children (p<.05). Theoretical and clinical implications of these results were identified and discussed. PMID- 24054356 TI - Contemporary approaches to the diagnosis and management of physical urticaria. PMID- 24054357 TI - Imported fire ant allergy: case presentation and review of incidence, prevalence, diagnosis, and current treatment. PMID- 24054358 TI - Sino-nasal outcome test (SNOT-22): a predictor of postsurgical improvement in patients with chronic sinusitis. AB - BACKGROUND: A number of factors are critical when considering the expected benefit of surgical intervention in patients with chronic rhinosinusitis (CRS) who have failed medical therapy. OBJECTIVE: To evaluate the Sino-nasal Outcome Test (SNOT-22) and other patient demographic characteristics as predictors of postsurgical improvement in patients with CRS. METHODS: Consecutive adult subjects presenting to the Otolaryngology Clinics at the University of Virginia with refractory CRS that required surgery were included. Patients were excluded if they had not completed both preoperative and postoperative SNOT-22 evaluations. Demographic and baseline measures, including asthma and smoking status, total immunuglobulin E (IgE), absolute eosinophil counts, and Lund-Mackay computed tomography (CT) scoring were also obtained for each subject. Regression analyses were performed. RESULTS: One hundred four subjects met criteria and were included. These subjects showed a 51% overall improvement in postsurgical SNOT-22 evaluations (95% confidence interval [CI]: [45, 57%], P < .001). Multivariate regression analysis revealed that SNOT-22 items related to "runny nose," "cough," and "sadness" were independent predictors of postsurgical SNOT-22 improvement (P < .05, for all). Although "runny nose" had a direct correlation with improvement, more severe "sadness" and "cough" scores had a negative impact on degree of improvement. Similarly, analyses indicated that questions categorized as pertaining to nasal or ear symptoms were uniquely associated with postsurgical improvement in SNOT-22 scores (P < .001 and P = .015, respectively). Neither Lund Mackay CT scoring, total IgE, nor absolute eosinophil counts correlated with improvement in postsurgical SNOT-22 scores. CONCLUSION: Physicians can use components of the SNOT-22 to predict likelihood of symptom improvement after surgical intervention in subjects with CRS. PMID- 24054359 TI - Use of nasal inspiratory flow rates in the measurement of aspirin-induced respiratory reactions. AB - BACKGROUND: Nasal ketorolac challenge with modified oral aspirin challenge is a safe and effective alternative for desensitizing patients with aspirin exacerbated respiratory disease. In addition to clinical judgment, objective tests assessing nasal flow may help in diagnosing nasal reactions. OBJECTIVE: To evaluate the feasibility of peak nasal inspiratory flow (PNIF) as an objective measurement in the assessment of a reaction to nasal ketorolac and to determine changes in PNIF that have adequate sensitivity and specificity. METHODS: One hundred fifty-one patients referred to the Scripps Clinic for aspirin challenge and desensitization and 14 healthy controls participated in the study. Percentages of decrease in PNIF during reactions were compared with the nonreactors' measurements. A receiver operating characteristic curve was constructed to assess the diagnostic performance of PNIF measurement during a clinically positive nasal challenge. RESULTS: A total of 165 subjects participated in the study. One hundred fourteen patients (69.1%) clinically reacted to the nasal ketorolac challenge. There was no statistical difference between nasal reactors and nonreactors regarding sex, baseline forced expiratory volume in 1 second, and use of systemic steroid before challenge. The mean percentage of decrease in PNIF was significantly higher in the reactor group ( 0.30 +/- 0.29 vs -0.07 +/- 0.16, P < .001). A cutoff value of 25% decrease in PNIF had the maximum sensitivity and specificity (56.1% and 94.1%). CONCLUSION: The high specificity of a 25% decrease in PNIF found in receiver operating characteristic curve analysis indicated that PNIF measurements can be useful for assessing nasal reactions during nasal ketorolac challenges in the diagnosis of aspirin-exacerbated respiratory disease. PMID- 24054360 TI - Wheeze phenotypes in young children have different courses during the preschool period. AB - BACKGROUND: Rules for predicting the course of asthma in wheezy infants have low specificity. OBJECTIVE: To determine if the novel phenotypes-mild early viral wheeze (EVW), atopic multiple-trigger wheeze (MTW), and nonatopic uncontrolled wheeze (NAUW)-have different courses during the preschool period. METHODS: Part of the prospectively followed Trousseau Asthma Program cohort was phenotyped using cluster analysis with 12 parameters (sex, asthma severity and control with inhaled corticosteroid [ICS], parental asthma, allergic rhinitis, eczema, food allergy, EVW or MTW, and allergen exposure trigger). Wheezing trajectories were assessed by crossing the original phenotypes with the phenotypes obtained at 5 years. RESULTS: Four clusters were identified at 5 years of age: asymptomatic children (n = 47) with no wheezing (98%), children with mild EVW (n = 40, 87% with EVW, 50% with EVW controlled with low-dose ICS), those with atopic MTW (n = 30, 100% with MTW, only 17% with MTW controlled with low-dose ICS, more significant for pollen asthmatic trigger), and those with atopic severe UW (n = 33, 63% with UW uncontrolled despite high doses of ICS, more significant for allergic rhinitis and dust as asthmatic trigger). Those with mild EVW became asymptomatic or remained with mild EVW. Those with atopic MTW remained with atopic MTW and those with NAUW developed severe UW in most cases. CONCLUSION: These results show that remission is most frequently observed in mild EVW and that no remission is observed in atopic MTW. PMID- 24054361 TI - Exposure to environmental tobacco smoke, human E-cadherin C-160A polymorphism, and childhood asthma. AB - BACKGROUND: Environmental tobacco smoke (ETS) is a risk factor for asthma. Importantly, cigarette smoke can decrease the adherence of epithelial cells and increase detachment. The adhesion molecule E-cadherin (CDH1) has an essential role in the formation of epithelial junction. Turnover of the extracellular matrix, which is characterized by airway remodeling, depends on the imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs). OBJECTIVE: To evaluate the effects of ETS exposure and CDH1, MMP-3, and TIMP-1 genetic polymorphisms on childhood asthma. METHODS: The CDH1 C-160A, MMP-3 -1171, and TIMP-1 T372C genotypes were identified by polymerase chain reaction in 299 asthmatic children and 383 healthy controls. RESULTS: More ETS exposure (>5 vs 0 cigarettes/day; odds ratio [OR], 1.45; 95% confidence interval [CI], 1.05-2.01) and the presence of CDH1 AA/CA genotypes (OR, 1.53; 95% CI, 1.08-2.17) were associated with childhood asthma. Compared with children with less ETS exposure (0-5 cigarettes/day) and the CDH1 CC genotype, those with less ETS exposure and the CDH1 AA/CA genotypes and those with more ETS exposure and the CDH1 CC genotype had a moderate risk of asthma. The greatest risk for asthma was in children with more ETS exposure and the CDH1 AA/CA genotypes (OR, 3.03; 95% CI, 1.81-5.06), and this interaction between CDH1 polymorphism and ETS exposure was significant. In addition, asthma cases with more ETS exposure or the CDH1 AA/CA genotypes had obviously increased eosinophil counts. CONCLUSION: Susceptible CDH1 genotypes might modulate the development of asthma, especially for children exposed to ETS. PMID- 24054362 TI - Elevation of S100 calcium binding protein A9 in sputum of neutrophilic inflammation in severe uncontrolled asthma. AB - BACKGROUND: Neutrophilic airway inflammation is frequently observed in severe uncontrolled asthma (UA) and controlled asthma (CA). However, there is no sputum biomarker to differentiate the 2 conditions. OBJECTIVE: To identify biomarkers of severe uncontrolled asthma with neutrophilic airway inflammation. METHODS: Sputum with a neutrophil content larger than 70% was pooled from 5 patients with severe UA and from 10 patients with CA. Two-dimensional electrophoresis was adopted for differential display proteomics, and candidate proteins were identified using matrix-assisted laser adsorption/ionization-time of flight mass spectrometric analysis. S100 calcium binding protein A9 (S100A9) was identified by western blot and its level was measured in sputum from asthmatics with varying disease severity, patients with chronic obstructive lung disease, and normal controls using enzyme-linked immunosorbent assay. RESULTS: Fourteen protein spots exhibited differences in relative intensity between patients with severe UA and those with CA. Matrix-assisted laser adsorption/ionization-time of flight/time of flight of these spots showed an increase in human neutrophil peptide-2, S100A9, beta-amylase, neutrophil gelatinase-associated lipocalin, 4-aminobutyrate transaminase, and cystatin SA in patients with UA compared with patients with CA. There was a decrease in the plunc precursor, complement C3 component, immunoglobulin heavy-chain variable region, glial fibrillary acidic protein isoform-1, IgM kappaIIIb SON, MLL-AF4 der(11) fusion protein, cytokeratin-8, and recombinant IgG4 heavy chain. S100A9 was detected at a higher level in western blots of neutrophilic sputum from patients with severe UA vs CA. S100A9 levels were significantly increased, as measured by enzyme-linked immunosorbent assay, in neutrophilic UA compared with CA, eosinophilic UA and CA, and chronic obstructive lung disease. CONCLUSION: S100A9 in sputum may be a biomarker of neutrophilic inflammation in severe UA. PMID- 24054363 TI - Therapeutic effects of anti-B7-H3 antibody in an ovalbumin-induced mouse asthma model. AB - BACKGROUND: B7 molecules play a key role in regulating allergen-induced T cell activation in asthma, which may occur through T cell recruitment and T helper cell differentiation on allergen provocation. Initial studies have shown that B7 H3 (CD276), a recently identified B7 family member, plays a critical role in the development of Th2 cells. OBJECTIVE: To investigate the effects of anti-B7-H3 monoclonal antibody (mAb) in a mouse model of allergic asthma. METHODS: The asthma model was established by ovalbumin (OVA) sensitization and challenging in female BALB/c mice. Total cell numbers in bronchoalveolar lavage fluid (BALF) were determined, and the expression levels of interferon gamma (IFN-gamma), interleukin (IL)-4, and IL-17 in BALF were measured by enzyme-linked immunosorbent assay. Pulmonary eosinophil infiltration and mucus production were detected by hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS), respectively. B7-H3 expression was detected by immunohistochemistry in frozen tissue sections. RESULTS: Anti-B7-H3 mAb treatment alleviated the asthmatic syndrome, decreased the levels of B7-H3-positive cells in the lung tissues, abrogated hypercellularity, eosinophil infiltration, and mucus production, and inhibited IL-4 and IL-17 production in BALF at the induction phase as compared with the immunoglobulin G (IgG) control group (P < .01). In addition, the treatment of anti-B7-H3 mAb at the induction phase could increase the expression levels of IFN-gamma as compared with the IgG control group (P < .01). Anti-B7-H3 mAb treatment at the effector phase did not inhibit the asthma response. CONCLUSION: Blockade of B7-H3 signals may provide a novel therapeutic approach to the treatment of allergic asthma. PMID- 24054364 TI - Identification of peanuts and tree nuts: are allergists smarter than their patients? AB - BACKGROUND: It has been reported that peanut- or tree nut-allergic individuals and their guardians are poorly capable of differentiating various tree nuts and peanuts. No information exists on the ability of allergists to differentiate peanuts and tree nuts. OBJECTIVE: To measure the ability of allergists and other specialists within the allergy and immunology field to identify various types of tree nuts and peanuts. METHODS: A nut box with a clear cover was constructed and contained various tree nuts and peanuts in shelled and unshelled forms. Attendees at the 2012 national meeting of the American Academy of Allergy, Asthma, and Immunology were offered participation by viewing the nut box and filling in their responses to a questionnaire. A similar procedure was conducted in the Food Allergy Center at Children's Medical Center (Dallas, TX) for guardians of children with and without peanut or tree nut allergies. RESULTS: Allergists were better able to identify and differentiate tree nuts and peanuts than guardians of peanut- or tree nut-allergic children, guardians of children without food allergies, and allergy and immunology fellows in training. CONCLUSION: It is important for allergists to educate peanut- and tree nut-allergic individuals and their guardians on the proper avoidance of peanuts and tree nuts. This includes education in the ability to identify peanuts and tree nuts. In addition, allergy and immunology fellows in training may benefit from education in proper peanut and tree nut identification. PMID- 24054365 TI - Genetic factors account for most of the variation in serum tryptase--a twin study. AB - BACKGROUND: Mast cells are involved in a number of diseases, including inflammatory diseases such as asthma. Tryptase is a known marker of mast cell burden and activity. However, little is known about the genetic influence on serum tryptase variation. Also, only few and conflicting data exist on serum tryptase in asthma. OBJECTIVE: To estimate the overall contribution of genetic and environmental factors to the variation in serum tryptase and to examine the correlation between serum tryptase and asthma, rhinitis, markers of allergy, airway inflammation, and airway hyperresponsiveness (AHR) in a sample of Danish twins. METHODS: A total of 575 twins underwent a skin prick test and had lung function, AHR to methacholine, exhaled nitric oxide and serum tryptase measured. Multiple regression and variance components models (using the statistical package SOLAR) were computed. RESULTS: Serum tryptase values were available in 569 subjects. Intraclass correlations of serum tryptase in monozygotic and dizygotic twin pairs were 0.84 and 0.42 (P < .001). Variance decomposition showed that genetic factors accounted for 82% (95% confidence interval 74-90, P < .001) of the variation in serum tryptase. Body mass index and sex, but not asthma, rhinitis, or AHR, were correlated to serum tryptase. CONCLUSION: As much as 82% of the variation in serum tryptase is due to genetic factors. Body mass index and sex, but not asthma or AHR to methacholine, correlate to serum tryptase. A genetic overlap may exist between serum tryptase and body mass index. PMID- 24054366 TI - Hereditary angioedema with C1 inhibitor deficiency: clinical presentation and quality of life of 193 French patients. AB - BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life threatening disease. New specific treatments are available. OBJECTIVE: To identify patients' features and patients' best therapeutic option. METHODS: A 1 year, multicenter, retrospective study was performed. The primary objective was to examine the clinical presentation of HAE. Secondary objectives included patient characteristics, management of HAE over 12 months, and health-related quality of life using the SF-36v2 questionnaire. RESULTS: One hundred ninety three patients were included, and 69.4% were women. In the 12-month period, the mean number of HAE attacks was 7.6. Among the 568 reported attacks, localizations were the abdomen (57.1%), peripheral limbs (42.5%), upper airway (7.9%), and face (6.9%); 31.6% of attacks were severe and occurred statistically more often in women (P < .02). Compared with a population of allergic patients, all age- and sex-adjusted scores were significantly lower in patients with HAE (P < .05) except for the physical component summary. Health-related quality of life negatively correlated with the annual number of attacks and was markedly altered for patients having more than 5 attacks per year (P < .05 for all dimensions). CONCLUSION: HAE is a severe disease that places a heavy burden on quality of life. PMID- 24054367 TI - Measurement of IgE to pollen allergen components is helpful in selecting patients for immunotherapy. AB - BACKGROUND: Pollen allergy still represents an important cause of allergic morbidity worldwide. Accurate diagnostic methods are important to determine the disease-causing allergen. OBJECTIVE: To describe the sensitization patterns of patients with spring pollinosis and to make a real-life evaluation of the usefulness of a predetermined IgE molecular profile compared with other sensitization methods for choosing the composition of immunotherapy. METHODS: One hundred seventy-five patients with a diagnosis of spring pollinosis completed a skin prick test study with Olea europaea, Phleum pratense, palm profilin, and peach peel and an in vitro study of the application of a specific recombinant IgE protocol (nOle e1, rPhl p1-5b, rPhl p12, rPhl p7, and rPru p3). Immunotherapy using the 2 methods was compared. RESULTS: A high sensitization to nOle e1 and rPhl p1-5b was found. Profilin, polcalcin, and lipid transfer proteins seemed irrelevant for the differential diagnosis of olea and grass pollen sensitization in the most southern area of the Iberian Peninsula. Application of the component resolved the diagnosis, and the choice of immunotherapy was changed in more than 50% of patients. CONCLUSION: These results support the necessity of the habitual use of this kind of protocol in routine allergologic practice. PMID- 24054368 TI - Bathing frequency recommendations for pediatric atopic dermatitis: are we adding to parental frustration? PMID- 24054369 TI - Predictors of indoor exposure to mouse allergen in inner-city elementary schools. PMID- 24054370 TI - Update on influenza vaccination of egg allergic patients. PMID- 24054371 TI - A familial study of filaggrin mutation in atopic dermatitis. PMID- 24054372 TI - Food and aeroallergen sensitization in adult eosinophilic esophagitis. PMID- 24054373 TI - Author response. PMID- 24054374 TI - Systematic reviews and heterogeneity. PMID- 24054375 TI - Allergen of the month--Oriental plane tree. PMID- 24054376 TI - Is there a relationship between severity of coronary artery disease and severity of erectile dysfunction? AB - INTRODUCTION: The correlation between erectile dysfunction (ED) and coronary artery disease has been emphasized and ED has been recognized as a potential independent risk factor and/or predictor of coronary artery disease (CAD). We evaluated the association between the number of occluded coronary arteries in myocardial infarction (MI) patients with the severity of ED, and investigated the influence of related risk factors in our study group. MATERIALS AND METHODS: 183 male patients who underwent coronary angiography because of acute MI from November 2009 to May 2011 were included. Following the stabilization of patients after the treatment, each patient was evaluated for erectile functionality. Risk factors such as age, diabetes, smoking, waist circumference, hypertension, and hematologic parameters were recorded. RESULTS: Among 183 patients with a mean age of 55.2 years who underwent coronary angiography due to acute MI, 100 (54.64 %) had ED, while the ED rate was 45.36 % (44/97) in cases of single-vessel disease, 64.5 % (31/48) in cases of two-vessel disease, and 65.7 % (25/38) in cases of three-vessel disease. The mean IIEF score was 24.2 +/- 4.3, 20.4 +/- 4.9 and 20.5 +/- 4.2 for single or two or three-vessel disease, respectively. The presence of hypertension aggravated ED only in patients with three-vessel disease and increased total and LDL cholesterol levels in patients with single-vessel or two vessel disease were accompanied by significantly decreasing IIEF scores. CONCLUSION: The severity of ED correlated with the number of occluded vessels documented by coronary angiography, in male patients with acute myocardial infarction. In addition, the presence of hypertension had a significant influence over erectile function only in patients with three-vessel occlusion. PMID- 24054377 TI - Sexual function after non-nerve-sparing radical cystoprostatectomy: a comparison between ileal conduit urinary diversion and orthotopic ileal neobladder substitution. AB - OBJECTIVE: To compare the erectile function (EF) and sexual desire (SD) in men after radical cystoprostatectomy (RCP) who had either an ileal conduit urinary diversion or orthotropic ileal neobladder substitution. MATERIALS AND METHODS: Eighty one sexually active men with bladder cancer were enrolled in this prospective study. After RCP according to patients' preferences they underwent either ileal conduit urinary diversion (n = 41) or orthotropic ileal neobladder substitution (n = 40). EF and SD were assessed using International Index of Erectile Function (IIEF) questionnaire. Patients were assessed at 4-week before surgery and were followed up at 1, 6, and 12-month postoperatively using the same questionnaire. RESULTS: Postoperatively the EF and SD domains deteriorated significantly in both groups, but in a small proportion of the patients submitted to ileal neobladder they gradually improved with time (P = 0.006). At 12-month postoperative period, 4 (9.8 %) and 14 (35.0 %) patients in ileal conduit and ileal neobladder groups were able to achieve erections hard enough for vaginal penetration and maintained their erection to completion of intercourse, respectively (P = 0.006). Among patients in the ileal conduit and ileal neobladder groups, additional 4 (9.8 %) and 7 (17.1 %) patients were able to get some erection, but were unable to maintain their erection to completion of intercourse (P = 0.02). At 12-month follow up period 24.4 % of the ileal conduit and 45.0 % of the ileal neobladder patients rated their sexual desire very high or high (P = 0.01). CONCLUSION: When performed properly, orthotopic ileal neobladder substitution after RCP offers better long-term results in terms of EF and SD. PMID- 24054378 TI - Long-term follow-up of polypropylene bone anchored slings. AB - INTRODUCTION: The transvaginal bone anchored polypropylene sling (BAS) has proven to be a successful treatment for patients with SUI. However, there is limited data on long-term outcomes following BAS with polypropylene mesh. We report our series of patients who had at least 3 years of follow-up after placement of BAS. MATERIALS AND METHODS: A retrospective review of prospectively collected data of patients undergoing BAS for stress urinary incontinence (SUI) with minimum 3 year follow-up was performed. Outcomes and complications were determined from annual mailed post-operative questionnaires. RESULTS: 142 patients who had undergone BAS and had answered post-operative questionnaires at a minimum of 3 years were identified. Average follow-up was 58 months (range 36-97 months). The overall success rate was 71 % with a dry rate of 27 %. Complications occurred in 9 % of patients, more commonly in patients without a history of anti-incontinence procedure. CONCLUSIONS: Although less commonly used, BAS with polypropylene mesh is associated with an acceptable success rate at long term follow-up but a low completely dry rate. PMID- 24054379 TI - The outcome of transobturator anterior vaginal wall prolapse repair using porcine dermis graft: intermediate term follow-up. AB - INTRODUCTION AND HYPOTHESIS: We evaluated the anatomical success and complications of Perigee(r) with porcine dermis Graft in the repair of anterior vaginal wall prolapse (AVWP) MATERIALS AND METHODS: After Institutional Review Board (IRB) approval, the charts of all patients who underwent AVWP repair using the Perigee/InteXen(r) kit from July 2005 to July 2009 were reviewed. Patients who had less than 6-month follow-up were excluded. Preoperative data including patient age, previous AVWP repairs, hysterectomy status, preoperative dyspareunia and pertinent physical findings were collected and recorded. Postoperative success was defined as anatomical stage 0 or I using the Pelvic Organ Prolapse Quantification (POP-Q) scoring system. Graft related complications were also recorded. RESULTS: Out of 89 patients, 69 completed at least 6-month follow-up. Median follow-up was 13 (6-48) months. Seventeen patients (25%) had previous AVWP repair and 32 (46%) had previous hysterectomy. Preoperatively, AVWP stage II was found in 9 (13%), stage III in 27 (39%) and stage IV in 33 (48%) patients. Anatomic success was found in 48 (69%) patients, with 23 (33%) having stage 0 and 25 (36%) stage I AVWP. Intraoperative complications included incidental cystotomy in one patient and bladder perforation in one. Postoperative complications included vaginal exposure and dyspareunia in one case, wound dehiscence in one and tenderness over the graft arm with dyspareunia in one. CONCLUSIONS: The use of porcine dermis in AVWP repair is safe with minimal graft related complications; however, anatomical success is lower than that reported with the use of synthetic grafts. PMID- 24054380 TI - Treatment of anterior vaginal wall prolapse with and without polypropylene mesh: a prospective, randomized and controlled trial - Part I. AB - OBJECTIVE: To compare the use of polypropylene mesh (PM) and the traditional anterior vaginal wall colporraphy in women with anterior vaginal wall prolapse (AVWP) using objective and subjective tests and evaluation of quality of life (QoL). MATERIALS AND METHODS: One hundred women were randomly distributed in two preoperatory groups. The first group (mesh) (n = 45) received a PM implant and the control group (n = 55) was submitted to traditional colporraphy. Postoperatory follow-up was done after 12 months. The primary objective was the correction of the Ba point <= -2 POP-Q (Pelvic Organ Prolapse Quantification System) and the secondary objective was the improvement of vaginal symptoms and QoL through ICIQ-VS (International Consultation on Incontinence Questionnaire - Vaginal Symptoms). Complications related to the use of PM or not were also described. RESULTS: There was a significant difference between all POP-Q measures of pre- and postoperatory periods of each group in particular. There was a significant difference of the Ba point of the postoperatory period between the Mesh and Control group. The mean of Ba point in the Mesh group was statistically lower than of the Control group, depicting the better anatomical result of the first group. Both techniques improved vaginal symptoms and QoL. The most frequent complication of the Mesh group was prepubic hematoma in the perioperative period. In 9.3% of the cases treated with mesh it was observed PM exposition at the anterior vaginal wall after 12 months, being most of them treated clinically. CONCLUSION: The treatment of AVWP significantly improved the Ba point in the Mesh group in comparison to the Control group. There were no differences of the vaginal symptoms and QoL between the two groups after 12 months. There were few and low grade complications on both groups. PMID- 24054381 TI - Treatment of anterior vaginal wall prolapse with and without polypropylene mesh: a prospective, randomized and controlled trial - Part II. AB - OBJECTIVE: To compare the effects of two surgical procedures for the correction of anterior vaginal wall prolapse (AVWP) on the lower urinary tract symptoms (LUTS) using symptom questionnaires and quality of life (QoL). MATERIALS AND METHODS: One hundred women with Pelvic Organ Prolapse Quantification stage (POP Q) >= 2 were randomly distributed in two preoperatory groups. The first group (mesh) (n = 45) received a polypropylene mesh (PM) implant and the control group (n = 55) was submitted to anterior colporraphy with or without synthetic sling. Postoperatory follow-up was done after 12 months. The primary objective was to compare the effect of the surgeries on LUTS using the final scores of the International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form (ICIQ-UI SF) and Overactive Bladder Questionnaire (OAB-V8), as well as the analysis of the incapacitating urinary symptoms and "de novo" urinary symptoms after 12 months of surgery in both groups. RESULTS: Although there was a different number of women in each group, randomization was adequate, resulted in homogeneous groups that could be compared regarding socio demographic, clinical and gynecological (POP-Q) variables. Patients of both groups showed improvements regarding LUTS and QoL, whether using polypropylene mesh or not, based on the final scores of the ICIQ-UI SF and OAB-V8 questionnaires after 12-month follow up. There were few incapacitating and "de novo " urinary symptoms, without any significant statistical difference between both groups after 12 months of surgery. CONCLUSION: There was a general improvement of LUTS and QoL in both groups after 12-month follow-up. However, there was no significant difference of LUTS, as well as the more incapacitating and "de novo " urinary symptoms between both groups after 12 months of surgery. PMID- 24054382 TI - Human Papilloma Virus: Prevalence, distribution and predictive value to lymphatic metastasis in penile carcinoma. AB - OBJECTIVES: To evaluate the prevalence, distribution and association of HPV with histological pattern of worse prognosis of penile cancer, in order to evaluate its predictive value of inguinal metastasis, as well as evaluation of other previous reported prognostic factors. MATERIAL AND METHODS: Tumor samples of 82 patients with penile carcinoma were tested in order to establish the prevalence and distribution of genotypic HPV using PCR. HPV status was correlated to histopathological factors and the presence of inguinal mestastasis. The influence of several histological characteristics was also correlated to inguinal disease free survival. RESULTS: Follow-up varied from 1 to 71 months (median 22 months). HPV DNA was identified in 60.9% of sample, with higher prevalence of types 11 and 6 (64% and 32%, respectively). There was no significant correlation of the histological characteristics of worse prognosis of penile cancer with HPV status. Inguinal disease-free survival in 5 years did also not show HPV status influence (p = 0.45). The only independent pathologic factors of inguinal metastasis were: stage T >= T1b-T4 (p = 0.02), lymphovascular invasion (p = 0.04) and infiltrative invasion (p = 0.03). CONCLUSIONS: HPV status and distribution had shown no correlation with worse prognosis of histological aspects, or predictive value for lymphatic metastasis in penile carcinoma. PMID- 24054383 TI - Comparison of postoperative analgesic efficacy of penile block, caudal block and intravenous paracetamol for circumcision: a prospective randomized study. AB - PURPOSE: To evaluate the postoperative analgesic efficacy of penile block, caudal block and intravenous paracetamol administration following circumcision. MATERIALS AND METHODS: In this prospective randomized study a total of 159 patients underwent circumcision under general anesthesia at urology clinic of Ufuk University Faculty of Medicine and Sorgun State Hospital between May 2012 and September 2012. The patients were randomized to three groups to receive penile block (Group 1), caudal block (Group 2) and intravenous paracetamol administration (group 3). Pain measurement of the patients was done via CHEOPS scoring system at 30,60,120 and 180 minutes postoperatively and compared. Statistical tests were performed with a conventional statistics program and statistical significance was set at a p value of < 0.05. RESULTS: The mean age of the patients was 5.7 years. Patients in group 1 had significantly lower pain score at 30 minutes compared to other two groups. At 60 minutes groups 1 and 2 had significantly lower score compared to group 3. At 120 and 180 minutes no difference between the groups was observed. No significant major complications were observed in all 3 groups. CONCLUSION: Penile block and caudal block provide similar pain scores and painless postoperative periods after circumcision under general anesthesia. Intravenous paracetamol is insufficient at the early postoperative period. The three procedures were shown to be safe for analgesia following circumcision. PMID- 24054384 TI - A prospective evaluation of plastibell(r) circumcision in older children. AB - INTRODUCTION AND OBJECTIVE: Circumcision is one of the oldest surgical procedures and one of the most frequently performed worldwide. It can be done by many different techniques. This prospective series presents the results of Plastibell(r) circumcision in children older than 2 years of age, evaluating surgical duration, immediate and late complications, time for plastic device separation and factors associated with it. MATERIALS AND METHODS: We prospectively analyzed 119 children submitted to Plastic Device Circumcision with Plastibell(r) by only one surgeon from December 2009 to June 2011. In all cases the surgery was done under general anesthesia associated with dorsal penile nerve block. Before surgery length of the penis and latero-lateral diameter of the glans were measured. Surgical duration, time of Plastibell(r) separation and use of analgesic medication in the post-operative period were evaluated. Patients were followed on days 15, 45, 90 and 120 after surgery. RESULTS: Age at surgery varied from 2 to 12.5 (5.9 +/- 2.9) years old. Mean surgical time was 3.7 +/- 2.0 minutes (1.9 to 9 minutes). Time for plastic device separation ranged from 6 to 26 days (mean: 16 +/- 4.2 days), being 14.8 days for children younger than 5 years of age and 17.4 days for those older than 5 years of age (p < 0.0001). The diameter of the Plastibell(r) does not interfered in separations time (p = 0,484). Late complications occurred in 32 (26.8%) subjects, being the great majority of low clinical significance, especially prepucial adherences, edema of the mucosa and discrete hypertrophy of the scar, all resolving with clinical treatment. One patient still using diaper had meatus stenosis and in one case the Plastibell(r) device stayed between the glans and the prepuce and needed to be removed manually. CONCLUSIONS: Circumcision using a plastic device is a safe, quick and an easy technique with low complications, that when occur are of low clinical importance and of easy resolution. The mean time for the device to fall is shorter in children under 6 years of age and it is not influenced by the diameter of the device. PMID- 24054385 TI - Anti-urolithiatic effect of cow urine ark on ethylene glycol-induced renal calculi. AB - PURPOSE: To investigate the anti-urolithiatic effect of cow urine ark (medicinal distilled cow urine) on ethylene glycol (EG) induced renal calculi. MATERIALS AND METHODS: 36 male Wistar rats were randomly divided into 6 equal groups. Group I animals served as vehicle control and received distilled water for 28 days. Group II to VI animals received 1% v/v EG in distilled water for 28 days. Group II served as EG control. Group III and IV (preventive groups) received cow urine ark orally for 28 days in doses of 1 mL/kg and 2 mL/kg, respectively. Group V and VI (treatment groups) received 1 mL/kg and 2 mL/kg cow urine ark orally, respectively from 15th to 28th days. 24-hour urine samples were collected on day 0 and 28. Urine volume and oxalate levels were measured. On day 28, blood was collected for biochemical parameters. Animals were sacrificed and kidneys were harvested, weighed and histopathologically evaluated for calcium oxalate (CaOx) crystals. To calculate the percentage of inhibition of mineralization, simultaneous flow static in-vitro model was used. RESULTS: EG significantly increased urine oxalate, serum creatinine, blood urea level; kidney weight and CaOx deposits. Provision of cow urine ark resulted in significantly lower levels of urine oxalate, serum creatinine, blood urea and CaOx depositions as compared to Group II. (p value < 0.05) It also significantly restored kidney weight. (p value < 0.05) Cow urine ark inhibited 40% and 35% crystallization of CaOx and calcium phosphate, respectively. CONCLUSION: Cow urine ark is effective in prevention and treatment of EG induced urolithiasis in Wistar rats. PMID- 24054386 TI - Infrared Thermometer: an accurate tool for temperature measurement during renal surgery. AB - PURPOSE: To evaluate infrared thermometer (IRT) accuracy compared to standard digital thermometer in measuring kidney temperature during arterial clamping with and without renal cooling. MATERIALS AND METHODS: 20 pigs weighting 20Kg underwent selective right renal arterial clamping, 10 with (Group 1 - Cold Ischemia with ice slush) and 10 without renal cooling (Group 2 - Warm Ischemia). Arterial clamping was performed without venous clamping. Renal temperature was serially measured following clamping of the main renal artery with the IRT and a digital contact thermometer (DT): immediate after clamping (T0), after 2 (T2), 5 (T5) and 10 minutes (T10). Temperature values were expressed in mean, standard deviation and range for each thermometer. We used the T student test to compare means and considered p < 0.05 to be statistically significant. RESULTS: In Group 1, mean DT surface temperature decrease was 12.6 +/- 4.1 degrees C (5-19 degrees C) while deep DT temperature decrease was 15.8 +/- 1.5 degrees C (15-18 degrees C). For the IRT, mean temperature decrease was 9.1 +/- 3.8 degrees C (3-14 degrees C). There was no statistically significant difference between thermometers. In Group 2, surface temperature decrease for DT was 2.7 +/- 1.8 degrees C (0-4 degrees C) and mean deep temperature decrease was 0.5 +/- 1.0 degrees C (0-3 degrees C). For IRT, mean temperature decrease was 3.1 +/- 1.9 degrees C (0-6 degrees C). No statistically significant difference between thermometers was found at any time point. CONCLUSIONS: IRT proved to be an accurate non-invasive precise device for renal temperature monitoring during kidney surgery. External ice slush cooling confirmed to be fast and effective at cooling the pig model. PMID- 24054387 TI - Does stone entrapment with "Uro-Net" improve Ho:YAG laser lithotripsy efficiency in percutaneous nephrolithotomy and cystolithopaxy?: an in vitro study. AB - PURPOSE: to test the effect of stone entrapment on laser lithotripsy efficiency. MATERIALS AND METHODS: Spherical stone phantoms were created using the BegoStone(r) plaster. Lithotripsy of one stone (1.0 g) per test jar was performed with Ho:YAG laser (365 um fiber; 1 minute/trial). Four laser settings were tested: I-0.8 J,8 Hz; II-0.2J,50 Hz; III-0.5 J,50 Hz; IV-1.5 J,40 Hz. Uro-Net (US Endoscopy) deployment was used in 3/9 trials. Post-treatment, stone fragments were strained though a 1mm sieve; after a 7-day drying period fragments and unfragmented stone were weighed. Uro-Net nylon mesh and wire frame resistance were tested (laser fired for 30s). All nets used were evaluated for functionality and strength (compared to 10 new nets). Student's T test was used to compare the studied parameters; significance was set at p < 0.05. RESULTS: Laser settings I and II caused less damage to the net overall; the mesh and wire frame had worst injuries with setting IV; setting III had an intermediate outcome; 42% of nets were rendered unusable and excluded from strength analysis. There was no difference in mean strength between used functional nets and non-used devices (8.05 vs. 7.45 lbs, respectively; p = 0.14). Setting IV was the most efficient for lithotripsy (1.9 +/- 0.6 mg/s; p < 0.001) with or without net stabilization; setting III was superior to I and II only if a net was not used. CONCLUSIONS: Laser lithotripsy is not optimized by stone entrapment with a net retrieval device which may be damaged by high energy laser settings. PMID- 24054388 TI - Extending boundaries in minimally invasive procedures with simultaneous bilateral video endoscopic inguinal lymphadenectomy (veil) for penile cancer: initial Denver health medical center and ABC school of medicine experience and surgical considerations. AB - PURPOSE: To report the surgical technique, procedural outcomes, and feasibility of simultaneous bilateral Video Endoscopic Inguinal Lymphadenectomy (VEIL) in the management of patients with indication for inguinal lymphadenectomy. SURGICAL TECHNIQUE: VEIL was applied in all patients using the oncological landmarks (the adductor longus muscle medially, the sartorius muscle laterally and the inguinal ligament superiorly). A 1.5 cm incision was made 2 cm distally to the lower vertex of the femoral triangle. A second incision was made 2 cm proximally and 6 cm medially. Two 10 mm Hasson trocars were inserted in these incisions and the working space was insufflated with CO2 at 5-15 mmHg. The final trocar was placed 2 cm proximally and 6 cm laterally from the first port. RESULTS: A total of 5 VEIL procedures in 3 patients were performed. Two patients underwent simultaneous bilateral VEIL while another underwent simultaneous bilateral surgery with VEIL on the right and open lymphadenectomy on the left side due to an enlarged node. All laparoscopic procedures were successfully performed without conversion and maintained the oncological templates. One lymphocele occurred in the patient who underwent the open procedure. None of the patients presented with skin necrosis after the procedure. Mean number of nodes retrieved was 6 from each side and 2 patients presented with positive inguinal nodes. After one year of follow-up no recurrences were observed. CONCLUSION: Simultaneous lymphadenectomy procedures are feasible. Improvement in operative and anesthesia time could decrease the morbidity associated with inguinal lymphadenectomy while maintaining the oncological principles. PMID- 24054389 TI - Endoscopic management of ureteral calculus in a patient with ureterosigmoidostomy diversion. AB - Lithiasis after urinary diversion is an uncommon condition that poses therapeutic challenges. The authors report the case of a patient submitted to cystectomy and ureterosigmoidostomy 35 years ago due to bladder endometriosis. The patient presented with a ureteral stone and was treated by retrograde endoscopic extraction. PMID- 24054390 TI - Female urethral diverticulum. PMID- 24054391 TI - Symptomatic extraperitoneal bladder perforation following transurethral bladder surgery: imaging with ct urography. PMID- 24054392 TI - Endoscopic use of cyanoacrylate glue in the treatment of urethral fistula. AB - PURPOSE: The aim of this video is to demonstrate an endoscopic and minimally invasive repair of an urethrocutaneous fistula with cyanoacrylate glue. MATERIALS AND METHODS: A 56 year-old-man with post-infectious urethral stricture and recurrent perineal abscess formation due to urethral fistulas. RESULTS: The operative time was 60 minutes, no major complications were observed perioperatively and postoperatively. At a follow-up time of 6 months the patient had no evidence of recurrent fistula and abscess formation. CONCLUSIONS: The endoscopic use of cyanoacrylate glue represents a safe and minimally invasive approach that might be offered as a first line option for the treatment of urinary fistulas in selected patients, especially those with narrow and long tracts. PMID- 24054393 TI - Pure laparoscopic radical heminephrectomy for a large renal-cell carcinoma in a horseshoe kidney. AB - INTRODUCTION: Horseshoe Kidneys are the most common renal fusion anomaly. When surgery is contemplated for renal-cell carcinoma in such kidneys, aberrant vasculature and isthmusectomy are the major issues to consider. We describe a case of a pure laparoscopic radical heminephrectomy with hand-sewn management of the isthmus for a 11 cm tumour in a horseshoe kidney. PRESENTATION: A 47-year-old man complaining of palpable left flank mass for two months. Magnetic resonance of the abdomen revealed a 11 cm renal mass arising from the left moiety of an incidentally discovered horseshoe kidney. Preoperative CT angiography revealed a dominant anterior renal artery feeding the upper and midpole, with two other arteries feeding the lower pole and isthmus. The patient was placed in a modified flank position. A four-port transperitoneal technique was used, the colon was reflected. Renal pedicle was dissected and the renal arteries and renal vein were secured with polymer clips. The kidney was fully mobilized and a Satinsky clamp was placed on the isthmus for its division. A running 2-0 vicryl hand-sewn was used for parenchyma hemostasis. The specimen was extracted intact in a plastic bag through an inguinal incision. RESULTS: The operative time was 220 minutes, and the estimated blood loss was 200 mL. There were no immediate or delayed complications. The patient resumed oral intake on postoperative day 1 and was discharged on postoperative day 2. Pathologic examination of the specimen confirmed a 11 cm organ-confined chromophobe renal-cell carcinoma, with negative margins. DISCUSSION: Laparoscopic oncologic surgery in patients with horseshoe kidneys can be technically challenging. The presence of a large cancer in a horseshoe kidney should not preclude a purely laparoscopic approach. With the aid of a Satinsky clamp, the isthmus can be sharply divided and sutured in a fashion similar to the open technique. To our knowledge, this report represents the largest cancer (11 cm) removed laparoscopically in the context of a horseshoe kidney. PMID- 24054394 TI - Prostate cancer screening with PSA: "Aequanimitas". PMID- 24054395 TI - Electrical stimulation for urinary incontinence in women: a systematic review. AB - BACKGROUND: Electrical stimulation is commonly recommended to treat urinary incontinence in women. It includes several techniques that can be used to improve stress, urge, and mixed symptoms. However, the magnitude of the alleged benefits is not completely established. OBJECTIVES: To determine the effects of electrical stimulation in women with symptoms or urodynamic diagnoses of stress, urge, and mixed incontinence. SEARCH STRATEGY: Our review included articles published between January 1980 and January 2012. We used the search terms "urinary incontinence", "electrical stimulation ", " intravaginal ", " tibial nerve " and " neuromodulation " for studies including female patients. SELECTION CRITERIA: We evaluated randomized trials that included electrical stimulation in at least one arm of the trial, to treat women with urinary incontinence. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the data from the trials, for inclusion or exclusion, and methodological analysis. MAIN RESULTS: A total of 30 randomized clinical trials were included. Most of the trials involved intravaginal electrical stimulation. Intravaginal electrical stimulation showed effectiveness in treating urge urinary incontinence, but reported contradictory data regarding stress and mixed incontinence. Tibial-nerve stimulation showed promising results in randomized trials with a short follow-up period. Sacral nerve stimulation yielded interesting results in refractory patients. CONCLUSIONS: Tibial-nerve and intravaginal stimulation have shown effectiveness in treating urge urinary incontinence. Sacral-nerve stimulation provided benefits in refractory cases. Presently available data provide no support for the use of intravaginal electrical stimulation to treat stress urinary incontinence in women. Further randomized trials are necessary to determine the magnitude of benefits, with long-term follow-up, and the effectiveness of other electrical stimulation therapies. PMID- 24054396 TI - Carbonic Anhydrase IX is not a predictor of outcomes in non-metastatic clear cell renal cell carcinoma - a digital analysis of tissue microarray. AB - INTRODUCTION: The knowledge about the molecular biology of clear cell renal cell carcinoma (ccRCC) is evolving, and Carbonic Anhydrase type IX (CA-IX) has emerged as a potential prognostic marker in this challenging disease. However, most of the literature about CA-IX on ccRCC comes from series on metastatic cancer, with a lack of series on non-metastatic cancer. The objective is to evaluate the expression of CA-IX in a cohort of non-metastatic ccRCC, correlating with 1) overall survival, and 2) with established prognostic parameters (T stage, tumor size, Fuhrman nuclear grade, microvascular invasion and peri-renal fat invasion). MATERIALS AND METHODS: This is a retrospective cohort study. We evaluated 95 patients with non-metastatic clear cell renal cell carcinoma, as to the expression of CA-IX. The analyzed parameters where: overall survival (OS), TNM stage, tumor size (TS), Fuhrman nuclear grade (FNG), microvascular invasion (MVI), peri-renal fat invasion (PFI). We utilized a custom built tissue microarray, and the immunoexpression was digitally quantified using the Photoshop (r) software. RESULTS: The mean follow-up time was 7.9 years (range 1.9 to 19.5 years). The analysis of CA-IX expression against the selected prognostic parameters showed no correlation. The results are as follows: Overall survival (p = 0.790); T stage (p = 0.179); tumor size (p = 0.143); grouped Fuhrman nuclear grade (p = 0.598); microvascular invasion (p = 0.685), and peri-renal fat invasion (p = 0.104). CONCLUSION: Carbonic anhydrase type IX expression does not correlate with overall survival and conventional prognostic parameters in non metastatic clear cell renal cell carcinoma. PMID- 24054397 TI - Voiding chain cystourethography: assessing a historical test's role in selection for urethrolysis. AB - OBJECTIVE: To analyze the benefit of voiding chain cystourethrography (VCC) [placing a radiographic opaque chain into the urethra and bladder and asking the patient to void under fluoroscopy] in the urodynamic evaluation of female bladder outlet obstruction (BOO). MATERIALS AND METHODS: Females with post anti incontinence operation voiding dysfunction who underwent urodynamic evaluation augmented with VCC and later had urethrolysis were identified. Six diagnostic criteria for obstruction were applied to each patient: (1) VCC ( obstructed: chain was angulated and could not be voiding out) (2) Video urodynamic study (VUDS) (detrusor contraction combined with radiographic obstruction) (3) maximum flow (Qmax) <= 15 cc/sec, detrusor pressure (pDet)@ Qmax >= 20 cm H20 (4) Qmax <= 11 cc/sec, pDet@ Qmax >= 25 cm H20 (5) Qmax <= 12 cc/sec, pDet@ Qmax >= 25 cm H20 (6) Blaivas-Groutz (B-G) nomogram. Urethrolysis results were reviewed. Agreement in assessment of BOO criteria was assessed by estimating the proportion of pair wise agreements along with an exact binomial 95% confidence interval (CI) and by estimating kappa along with a 95 % CI. RESULTS: Twenty-one patients were identified. Twenty of the 22 urethrolyses (91%) were clinically successful. Diagnosis of BOO was most common for VCC (86 %) and then B-G Nomogram (67 %). Agreement with the VCC was relatively poor for each of the five other methods (14% -62%) with the video urodynamic study (VUDS) being the best. Three patients with successful urethrolysis were diagnosed only by the VCC. All of kappa values regarding agreement with the VCC were low; the highest value of 0.15 was observed for VUDS. CONCLUSION: VCC may augment selection criteria for urethrolysis. PMID- 24054398 TI - Efficacy and safety of propiverine and terazosine combination for one year in male patients with luts and detrusor overactivity. AB - PURPOSE: To evaluate the long term efficacy and safety of the use of propiverine and terazosine combination in patients with LUTS and DO by a placebo controlled study. MATERIALS AND METHODS: One hundred patients were enrolled in the study. They were randomized into two groups (each group consisted of 50 patients). Terazosine and placebo were administered to the patients in Group 1 and terazosine plus propiverine HCL was administered to Group 2. The patients were evaluated by international prostate symptom score (IPSS), the first four questions of IPSS (IPSS4), the 8th question of IPSS (quality of life-QoL), overactive bladder symptom score questionnaire (OAB-q V8), PSA test, urodynamic studies, post voiding residue (PVR). All patients were followed for one year and were reassessed for comparison. RESULTS: IPSS, IPSS4, OAB symptoms, QoL score, PVR, and Qmax scores of the groups did not differ. After one year treatment, there was significant improvement in IPSS, IPSS4, OAB symptoms, QoL and Qmax values in Group 2. No significant improvement was noted for the same parameters in Group 1. CONCLUSION: This is the first study to show long term safety and efficacy of anticholinergic therapy for patients with LUTS. In patients with OAB or DO, long term anticholinergic treatment may be regarded as a treatment option. PMID- 24054399 TI - Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma. AB - Chimeric antigen receptors (CAR)-transduced T cells hold great promise in the treatment of malignant disease. Here, we demonstrate that intracerebral injection with a human, epidermal growth factor receptor variant III (EGFRvIII)-specific, third generation CAR successfully treats glioma in mice. Importantly, these results endorse clinical translation of this CAR in patients with EGFRvIII expressing brain tumors. PMID- 24054400 TI - Sporadic hyperekplexia presenting with an ataxic gait. AB - We describe a 62-year-old man with a sporadic form of hyperekplexia who presented with an unsteady gait, present since the age of 47. His clinical examination revealed an insecure broad-based gait and difficulty with tandem walking but no other abnormalities. For nearly a decade the patient was misdiagnosed with an idiopathic ataxia. A video electroencephalogram combined with an electromyogram during sudden auditory stimulus demonstrated an excessive startle response. An extensive work-up ruled out all the known causes of symptomatic hyperekplexia including anti-glycine receptor antibodies. Treatment with clonazepam markedly reduced the threshold and intensity of the startle response, enabling him to recover independence. Hyperekplexia is frequently associated with an awkward and hesitating gait, but these gait abnormalities might be confused with other causes of gait disorders if one is not aware of this disease. We report this patient to highlight that a correct diagnosis of hyperekplexia is crucial, because its treatment may change quality of life. PMID- 24054401 TI - Essential hypertension as a result of neurochemical changes at the rostral ventrolateral medulla. AB - Acute ischemia of the brainstem has been known to produce hypertension. After an initial review of central nervous system mechanisms contributing to systemic hypertension and the impact of the rostral ventrolateral medulla (RVLM) on arterial pressure, the authors propose that essential hypertension involves neurochemical changes at the level of the RVLM which are triggered by cerebral ischemia. Experimental and clinical data are presented to show that there is a link between ischemia of the brainstem and chronic hypertension. Atherosclerosis of the cerebral circulation leads to ischemia of the RVLM and other regions with autonomic function. This ischemic process results in increased availability of angiotensin II in the RVLM, which maintains the chronic hypertensive state via either direct stimulation of the RVLM or exacerbation of brainstem ischemia due to increased vasoconstriction. PMID- 24054402 TI - Successful long-term control of lymphomatous meningitis with intraventricular rituximab. AB - Most primary central nervous system lymphomas (PCNSL) are highly malignant B-cell non-Hodgkin lymphomas. First-line therapy consists of high-dose methotrexate based chemotherapy with or without whole brain radiotherapy. However, no standard of care is defined for refractory or recurrent PCNSL. We report a patient with lymphomatous meningitis, which was refractory to standard treatment but was successfully controlled for more than 6 years with intraventricular rituximab. Apart from two infections of the Ommaya reservoir, no severe side effects of intraventricular long-term treatment could be detected. This report indicates that intraventricular administration of rituximab might be beneficial in select patients with refractory or recurrent lymphomatous meningitis. PMID- 24054403 TI - Meta-analysis of the influence of DRD3 Ser9Gly variant on susceptibility for essential tremor. AB - The dopamine D3 receptor (DRD3) Ser9Gly variant has attracted more attention since the variant was observed to be associated with risk of essential tremor (ET). A number of association studies concerning the DRD3 Ser9Gly variant and ET susceptibility have been conducted in various populations. However, some results were contradictory. To derive a more precise estimation of the relationship between the DRD3 Ser9Gly variant and the genetic risk of ET, we performed a comprehensive meta-analysis which included seven case-control studies. The meta analysis was conducted in four genetic models: dominant, recessive, heterozygous, and homozygous. The odds ratio and 95% confidence intervals were used as the measure of association. The combined results of overall analysis showed a lack of association of the DRD3 Ser9Gly variant and ET, regardless of the genetic model of Ser9Gly. Publication bias and heterogeneity were absent in most analyses. In conclusion, the present meta-analysis does not support the notion that the DRD3 Ser9Gly variant is a genetic risk factor for ET. PMID- 24054404 TI - [Nutritional education of the coronary patient in practice]. AB - BACKGROUND: The Mediterranean diet is one of the food models which showed its ability at the patient at high cardiovascular risk in numerous cohort studies and two major interventional studies: Lyon Heart Study in 1999 and PREDIMED in 2013. AIM OF THE STUDY: Propose a practical assistance in the analysis of the dietary habits of the coronary patient with a simplified food frequency questionnaire. PATIENTS AND METHODS: Hundred coronary patients followed a program of cardiac rehabilitation and benefited from a nutritional education. The analysis of their dietary habits was made with the questionnaire of frequency of consumption of Rennes upon their arrival and 6months later. We have coded again these data by means of a simplified questionnaire with 15 items and compared the results and their evolution in 6months. RESULTS: On studied 200 questionnaires, the score of Rennes was 10.6+/-4.5 and the simplified score 8.2+/-3.4 with a coefficient of correlation of Pearson r=0.94 (0.91-0.95) at risk P<0.0001. Initial scores were respectively 8.0+/-4.4 and 6.3+/-3.4 (r=0.93) and the scores at 6months 13.1+/ 2.9 and 10.1+/-2.2 (r=0.86). The evolution of the scores of 100 patients were respectively 14.2+/-11.7% and 12.6+/-11% (P<0.26). CONCLUSION: The use of a simplified questionnaire allows to analyze the dietary habits of the coronary patient and to estimate their evolution during a therapeutic educational program. PMID- 24054405 TI - [Use and limitations of invasive coronary strategy in nonagerians]. AB - BACKGROUND: Nonagenarians are systematically excluded from studies of interventional cardiology. Few data exist on the usefulness, safety, and results of coronary angiography (CA) and percutaneous coronary intervention (PCI) in this population. PURPOSE: To evaluate the benefits and hazards of CA and PCI in nonagenarians. METHODS: Retrospective study conducted from the database (Cardioreport((r))) of the CH de Versailles, from January 2001 to December 2011. RESULTS: From the 15,806 procedures performed in the center during the period, 107 (0.9%) were done in 97 patients aged >=90years. Half of them underwent PCI. Median age was 92+/-2years (range: 90 to 100), 56% were women. Main indication was an acute coronary syndrome (77%, acute STEMI in 39%). The first group (n=58) had a single CA leading to strengthen medical treatment, and CABG in one case. The second group (n=49) had a CA followed by immediate (41) or delayed (8) PCI. The primary success rate of PCI was 90%. Radial route was used in 94% in the period 2009-2011 (51% overall). Failure of arterial access (4%) and difficulties of catheterization (13%) were rare. Severe complications occurred in 19%. They were local (11 hematomas, 6 severe, 4 transfusions, and 1 fatal acute ischemia of a lower limb), and general (1 stroke, 1 death by left main rupture during PCI). Twenty percent of the complications (11% of severe ones) were directly related to the procedure. Overall hospital mortality was 10%. CONCLUSIONS: Angiography is feasible in nonagenarians by radial approach without failures and with a reduced rate of complications. PCI was indicated in about half of the cases. PCI may be proposed in nonagerians with a high success rate, and an acceptable risk of local and general complications. PMID- 24054406 TI - [Incidence, associated factors, and follow-up of hospital heart failure complicating acute anterior myocardial infarction successfully treated by primary angioplasty]. AB - Heart failure (HF) complicating acute myocardial infarction (AMI) is of poor prognosis and is often associated with patient's characteristics and success of reperfusion strategies. However, few data is available regarding the high-risk subgroup of patients with anterior AMI treated successfully by primary angioplasty. The aim of the study was to assess the incidence, associated factors, and the future of HF occurring during hospitalisation, in the setting of anterior AMI treated successfully by primary angioplasty. METHODS: Eighty-five consecutive patients with anterior AMI treated successfully by primary angioplasty (final angiographic TIMI flow grade=3, without residual stenosis) were included. Clinical, biochemical, angiographic, and echocardiographic data were prospectively collected and compared between patients with (Killip 2 and 3) and without HF during hospitalisation. RESULTS: Fifteen patients had HF (18%) during hospitalisation and 70 did not. By comparison to patients without HF, patients with HF were more frequently diabetics, had troponin peak and CPK, leucocytes count, and fasting glucose higher, LVEF and wall motion score index in the left anterior descending territory (WMSi-lad) poorer, and a lower non invasive coronary flow reserve (CFR) in the LAD 24hours after angioplasty (all, P<0.05). In multivariate analysis, fasting glucose, leucocytes count after angioplasty, CFR and WMSi-lad were independently associated with HF, even after adjusting with angiographic variables (all, P<0.05). At 6months, patients with HF had less recovery of LV function and higher frequency of adverse LV remodelling (58% versus 20%, P<0.01) by comparison to patients without HF. CONCLUSION: In conclusion, HF is not uncommon even after successful primary angioplasty for anterior AMI (nearly one patient out of 5), is associated with hyperglycaemia and inflammation, a poor microvascular reperfusion, and left ventricular systolic function, and is more frequently complicated by adverse LV remodelling and lack of LV recovery. PMID- 24054407 TI - Fasciola hepatica: variations in redial development and cercarial production in relation to the geographic origin of the parasite. AB - Two hundred Galba truncatula, originating from a French population, were subjected to single-miracidium infections with an allopatric isolate (origin, Argentina) of Fasciola hepatica. The control group was constituted by 100 snails coming from the same population and exposed to sympatric miracidia of F. hepatica according to the same protocol. Snail samples were collected bimonthly from both groups between day 14 and day 112 p.e. (at 20 degrees C) and snail dissections were performed to count free rediae, intraredial morulae and free cercariae. Third and fourth generation rediae were significantly more numerous in the allopatric group, while the number of first generation rediae was significantly lower. In the sympatric group, the decrease in the number of intraredial morulae in the first, second and third redial generations was significantly faster. Free cercariae within the snail body were significantly more numerous in the sympatric than in the allopatric groups, whatever the date of snail dissection. The changes in redial development and cercarial production noted in the Argentinean group might be due to the evolution of South American flukes in a divergent way after the introduction of foreign infected ruminants in this continent from the 15th century. PMID- 24054408 TI - Triage of elderly trauma patients: a population-based perspective. AB - BACKGROUND: Elderly patients are frequently undertriaged. However, the associations between triage patterns and outcomes from a population perspective are unknown. We hypothesized that triage patterns would be associated with differences in outcomes. STUDY DESIGN: This is a population-based, retrospective, cohort study of all injured adults aged 55 years or older, from 3 counties in California and 4 in Utah (2006 to 2007). Prehospital data were linked to trauma registry data, state-level discharge data, emergency department records, and death files. The primary outcome was 60-day mortality. Patients treated at trauma centers were compared with those treated at nontrauma centers. Undertriage was defined as an Injury Severity Score (ISS) >15, with transport to a nontrauma center. RESULTS: There were 6,015 patients in the analysis. Patients who were taken to nontrauma centers were, on average, older (79.4 vs 70.7 years, p < 0.001), more often female (68.6% vs 50.2%, p < 0.01), and less often had an ISS >15 (2.2% vs 6.7%, p < 0.01). There were 244 patients with an ISS >15 and the undertriage rate was 32.8% (n = 80). Overall 60-day mortality for patients with an ISS >15 was 17%, with no difference between trauma and nontrauma centers in unadjusted or adjusted analyses. However, the median per-patient costs were $21,000 higher for severely injured patients taken to trauma centers. CONCLUSIONS: This is the first population-based analysis of triage patterns and outcomes in the elderly. We have shown high rates of undertriage that are not associated with higher mortality, but are associated with higher costs. Future work should focus on determining how to improve outcomes for this population. PMID- 24054409 TI - Too frail for surgery? Initial results of a large multidisciplinary prospective study examining preoperative variables predictive of poor surgical outcomes. AB - BACKGROUND: The decision as to whether a patient can tolerate surgery is often subjective and can misjudge a patient's true physiologic state. The concept of frailty is an important assessment tool in the geriatric medical population, but has only recently gained attention in surgical patients. Frailty potentially represents a measureable phenotype, which, if quantified with a standardized protocol, could reliably estimate the risk of adverse surgical outcomes. STUDY DESIGN: Frailty was prospectively evaluated in the clinic setting in patients consenting for major general, oncologic, and urologic procedures. Evaluation included an established assessment tool (Hopkins Frailty Score), self administered questionnaires, clinical assessment of performance status, and biochemical measures. Primary outcome was 30-day postoperative complications. RESULTS: There were 189 patients evaluated: 117 from urology, 52 from surgical oncology, and 20 from general surgery clinics. Mean age was 62 years, 59.8% were male, and 71.4% were Caucasian. Patients who scored intermediately frail or frail on the Hopkins Frailty Score were more likely to experience postoperative complications (odds ratio [OR] 2.07, 95% CI 1.05 to 4.08, p = 0.036). Of all other preoperative assessment tools, only higher hemoglobin (p = 0.033) had a significant association and was protective for 30-day complications. CONCLUSIONS: The aggregate score of patients as "intermediately frail or frail" on the Hopkins Frailty Score was predictive of a patient experiencing a postoperative complication. This preoperative assessment tool may prove beneficial when weighing the risks and benefits of surgery, allowing objective data to guide surgical decision-making and patient counseling. PMID- 24054410 TI - Invited commentary. PMID- 24054411 TI - Surgical care and career opportunities in a changing practice paradigm. PMID- 24054412 TI - Do thyroid-stimulating hormone, body weight, or body mass index serve as adequate markers to guide levothyroxine dose titration? PMID- 24054413 TI - Reply: To PMID 23318118. PMID- 24054414 TI - Attrition rates for surgical faculty: are we proposing the right solutions? PMID- 24054415 TI - SILC: significantly inferior laparoscopic cholecystectomy? PMID- 24054416 TI - Comparing single-incision to 4-port laparoscopic cholecystectomy. PMID- 24054418 TI - Resection of pancreatic tumors involving the anterior surface of the superior mesenteric/portal veins axis: an alternative procedure to pancreaticoduodenectomy with vein resection. PMID- 24054419 TI - Teres hepatis ligament flap plasty to prevent pancreatic fistula after tumor enucleation. PMID- 24054420 TI - Determination of the adsorption isotherm of the naproxen enantiomers on (S,S) Whelk-O1 in supercritical fluid chromatography. AB - The adsorption isotherms of the naproxen enantiomers were measured on a Kromasil Whelk-O1 column, eluted with mixtures of supercritical carbon dioxide and methanol or ethanol. Five chromatographic methods were used: frontal analysis, frontal analysis by characteristic points, elution by characteristic points, retention time method and the inverse method. In all methods, the effects of the two modifiers were compared. The use of these methods suffers from limitations due to supercritical fluid chromatographic instruments. These problems and drawbacks are discussed. The accurate and precise determination of the isotherm parameters was not possible with the instrument currently used. In contrast, the different methods allow to show qualitatively that the adsorption of the naproxen enantiomers show heterogeneous mechanism on the adsorbent surface common in chiral chromatography. Finally, the experimental high concentration elution band profiles of naproxen are compared with those calculated from the isotherm parameters provided by the five different methods. PMID- 24054421 TI - Extraction of three nitrophenols using polypyrrole-coated magnetic nanoparticles based on anion exchange process. AB - In this research, the applicability of polypyrrole-coated Fe3O4 nanoparticles (Fe3O4@PPy NPs) as an anion exchange magnetic nanosorbent is demonstrated. For this purpose, three nitrophenols were selected as models which are acidic compounds with low logP values and their extraction in neutral form (only based on hydrophobic interactions) is difficult. The extracted nitrophenols were separated and determined by high-performance liquid chromatography-UV detection. The size, morphology and surface coating of synthesized Fe3O4@PPy NPs have been characterized via different techniques such as Fourier transform infrared spectroscopy, transmission electron microscopy, scanning electron microscopy and thermo-gravimetric analysis. The important parameters influencing the extraction efficiency were studied and optimized. Under the optimum extraction conditions (300mL sample solution with pH 10, extraction and desorption times of 10 and 2min, respectively, 500MUL of 0.1M HNO3 in acetonitrile as eluent, and 40mg of adsorbent), a linear range between 0.75 and 100MUgL(-1) (R(2)>0.997), and limits of detection ranging from 0.3 to 0.4MUgL(-1) were obtained. Preconcentration factors in the range of 125-180 were achieved and relative standard deviations (RSDs%) were less than 4.9 (n=4) for the three nitrophenols. The analytical method was successfully applied for environmental water samples such as tap water, rain water and river water. The recoveries varied within the range of 84 109% confirming good performance of the method in various waters samples. The results showed that the proposed method is a rapid, convenient and feasible technique for determination of nitrophenols in aqueous samples. PMID- 24054422 TI - Evaluation of gas chromatography-atmospheric pressure chemical ionization-mass spectrometry as an alternative to gas chromatography-electron ionization-mass spectrometry: avocado fruit as example. AB - Although GC-APCI-MS was developed more than 40 years ago this coupling is still far from being a routine technique. One of the reasons explaining the limited use of GC-APCI so far is the lack of spectral database which facilitates the identification of the compounds under study. The first application of a very recently developed GC-APCI database to identify as many compounds as possible in a complex matrix such as avocado fruit is presented here. The results achieved by using this database has been checked against those obtained using traditional GC EI-MS and a comparison of the MS signals observed in both ionization sources has been carried out. 100 compounds belonging to different chemical families were identified in the matrix under study. Considering the results of this study, the wide range of application (in terms of polarity and size of analytes) and the robustness of APCI as interface, the high quality of TOF spectra, and our library as a publicly available resource, GC-APCI-TOF MS is definitively a valuable addition to the "metabolomics toolbox". PMID- 24054423 TI - Simultaneous determination of volatile organic compounds and carbonyls in mainstream cigarette smoke using a sorbent cartridge followed by two-step elution. AB - We developed a simple method for the simultaneous determination of volatile organic compounds (VOCs) and carbonyls in the mainstream cigarette smoke using a sorbent cartridge at ambient temperature without the traditional cryogenic impinger. A sorbent cartridge is installed between intake filter and the pump of the smoking machine. Collection of cigarette mainstream smoke is performed according to the Canadian Intense regime or the ISO regime. As adsorbent, Carboxen 572 (CX-572) is the most suitable for collection of VOCs and carbonyls in the mainstream cigarette smoke. Elution of VOCs and carbonyls from CX-572 is performed by the two-step elution with carbon disulfide and methanol. VOCs are eluted by first elution with carbon disulfide and carbonyls are eluted by second elution with methanol. For VOCs, a portion of eluate is analyzed by gas chromatography-mass spectrometry. For carbonyls, a portion of eluate is derivatized with enriched 2,4-dinitrophenylhydrazine solution and analyzed by high-performance liquid chromatography. Measurement values by CX-572 cartridge method are very close to those obtained by traditional impinger method except for 2-butanone. Impinger methods use 2,4-dinitrophenylhydrazine solution containing 50% water and 2-butanone-DNPhydrazone may be hydrolyzed with water. In the CX-572 method, the hydrolysis of 2-butanone is prevented because the eluate solution contains no water. CX-572 method can measure cigarette smoke resulting from not only one whole cigarette but also from one puff volume because of its high sensitivity and simple operation. PMID- 24054424 TI - Cutaneous melanoma. AB - In the past decade, major advances have been made in the understanding of melanoma. New predisposition genes have been reported and key somatic events, such as BRAF mutation, directly translated into therapeutic management. Surgery for localised melanoma and regional lymph node metastases is the standard of care. Sentinel-node biopsy provides precise staging, but has not been reported to affect survival. The effect of lymph-node dissection on survival is a topic of investigation. Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF mutated melanoma. The combination of BRAF inhibitors and MEK inhibitors might improve progression-free survival further and, possibly, increase overall survival. Response patterns differ substantially-anti-CTLA4 immunotherapy can induce long-term responses, but only in a few patients, whereas targeted drugs induce responses in most patients, but nearly all of them relapse because of pre existing or acquired resistance. Thus, the long-term prognosis of metastatic melanoma remains poor. Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability. Biomarkers that have predictive value remain elusive in melanoma, although emerging data for adjuvant therapy indicate that interferon sensitivity is associated with ulceration of the primary melanoma. Intense investigation continues for clinical and biological markers that predict clinical benefit of immunotherapeutic drugs, such as interferon alfa or anti-CTLA4 antibodies, and the mechanisms that lead to resistance of targeted drugs. PMID- 24054425 TI - To speak, or not to speak? The feasibility of imaging overt speech in children with epilepsy. AB - We systematically compared fMRI results for covert (silent) and overt (spoken) versions of a language task in a representative sample of children with lesional focal epilepsy being considered for neurosurgical treatment (N=38, aged 6-17 years). The overt task was advantageous for presurgical fMRI assessments of language; it produced higher quality scans, was more sensitive for identifying activation in core language regions on an individual basis, and provided an online measure of performance crucial for improving the yield of presurgical fMRI. PMID- 24054426 TI - Oxidative stress markers in the neocortex of drug-resistant epilepsy patients submitted to epilepsy surgery. AB - PURPOSE: While there is solid experimental evidence of brain oxidative stress in animal models of epilepsy, it has not been thoroughly verified in epileptic human brain. Our purpose was to determine and to compare oxidative stress markers in the neocortex of epileptic and non-epileptic humans, with the final objective of confirming oxidative stress phenomena in human epileptic brain. METHODS: Neocortical samples from drug-resistant epilepsy patients submitted to epilepsy surgery (n=20) and from control, non-epileptic cortex samples (n=11) obtained from brain bank donors without neurological disease, were studied for oxidative stress markers: levels of reactive oxygen species (ROS), such as superoxide anion (O2(-)); activity of antioxidant enzymes: superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione reductase (GR); and markers of damage to biomolecules (lipid peroxidation and DNA oxidation). RESULTS: Compared with non-epileptic controls, the neocortex of epileptic patients displayed increased levels of superoxide anion (P<=0.001), catalase (P<=0.01), and DNA oxidation (P<=0.001); a decrease in GPx (P<=0.05), and no differences in SOD, GR and lipid peroxidation. CONCLUSIONS: Our findings in humans are in agreement with those found in animal models, supporting oxidative stress as a relevant mechanism also in human epilepsy. The concurrent increase in catalase and decrease in GPx, together with unchanged SOD levels, suggests catalase as the main antioxidant enzyme in human epileptic neocortex. The substantial increase in the levels of O2(-) and 8-oxo-dG in epileptic patients supports a connection between chronic seizures and ROS-mediated neural damage. PMID- 24054427 TI - The effect of epilepsy surgery on caregiver quality of life. AB - PURPOSE: Epilepsy surgery has been shown to improve patient quality of life (QOL). Little is known about its effect on caregiver QOL. METHODS: The study population comprised of 26 persons with epilepsy (PWE) who underwent long term video EEG monitoring at Massachusetts General Hospital for presurgical evaluation along with 16 caregivers. The PWE completed epilepsy directed QOL (QOLIE-31) and psychological (Beck depression-BDI and anxiety inventory-BAI) questionnaires before and after surgery. Their participating caregivers completed generic health related QOL (SF36v2) and disease burden (Zarit caregiver burden inventory-ZCBI) questionnaires before and after surgery. Demographic data for all participants and disease/surgery related data for the PWE were collected. Statistical analysis was performed to compare PWE and caregiver QOL before and after surgery. RESULTS: Mean patient age was 37 years. Most (77%) suffered from symptomatic partial epilepsy for approximately 18 years prior to surgery, averaging 4 seizures per month and 2.2 antiepileptic drugs (AEDs). 78% of them underwent an anterior temporal lobectomy and the rest extra-temporal resections. On follow up at approximately 9 months, 69% had a surgical outcome of Engel class I, 23% of class II and 8% class IV. Postoperatively, the PWE remained on average on 1.9 AEDs. There was a statistically significant improvement for both the aggregate QOLIE-31 score and all its subscales (except for medication effects) as well as the BAI scores. 96% of the PWE felt that the decision to go through surgery was worthwhile. Mean caregivers age was 47 years. Half of them were spouses to the PWE and the majority of the rest their parents. 50% of them stated that their overall time devoted to patient's care decreased after surgery and 50% that it remained unchanged. The mental component scale (SF36v2, MCS) of caregiver QOL showed statistically significant improvement. ZCBI score and the physical component scale of their QOL (SF36v2, PCS) did not significantly vary before and after surgery. 75% of caregivers deemed their QOL better post surgery vs 19% similar. 94% of the caregivers felt that the decision to go through surgery was worthwhile. CONCLUSIONS: Successful epilepsy surgery has a positive impact not only to patient QOL but also to their caregiver. To the best of our knowledge, this is the first pilot study to systematically address the impact of epilepsy surgery on caregivers providing additional support to epilepsy surgery as the optimal treatment modality in carefully selected patients. These findings call for further investigation on the caregiver quality of life in epilepsy and for its inclusion in the treatment plan and quality indicators for epilepsy surgery. PMID- 24054428 TI - Childhood epilepsy and maternal antibodies to microbial and tissue antigens during pregnancy. AB - INTRODUCTION: Several epidemiologic studies show associations between mother's infections during pregnancy and an increased risk of mental and neurological disorders in the offspring. Such associations could be due to the direct or indirect effects of infectious agents, including immune responses to infectious agents that display molecular mimicry with host antigens. We measured a range of antigen-specific maternal IgG antibodies to examine if any were associated with risk for childhood epilepsy in offspring. METHODS: We used a case-cohort design within the Danish National Birth Cohort (DNBC) to examine maternal IgG antibodies to 25 microbial and tissue antigens during pregnancy and their association with the risk of epilepsy in offspring. The source population of this study was 68,250 live born singletons with up to 10 years of follow up. We randomly identified a sample of 282 children as a subcohort and included 275 children with a verified diagnosis of epilepsy as cases. Maternal antibodies were categorized into 6 groups (<50, 50-59, 60-69, 70-79, 80-89, >=90 percentile) according to the level in the subcohort. We used a Prentice-weighted Cox regression model to estimate the hazard ratio (HR) and 95% confidence interval (CI) for epilepsy according to measured antibodies. RESULTS: Higher levels of maternal antibodies against herpes simples virus type 1 (anti-HSV1) were associated with a slightly higher risk of childhood epilepsy (HR for trend=1.09, 95% CI: 0.99-1.21), while higher levels of maternal antibodies against pneumococcal polysaccharide 18 (anti-PnPS18) were associated with a lower risk of childhood epilepsy (HR for trend=0.90, 95% CI: 0.81-1.01). Among the subtypes, a significantly higher risk associated with anti HSV1 antibodies was seen for childhood absence epilepsy (HR for trend=2.08, 95% CI: 1.12-3.85) and for epileptic encephalopathies (HR for trend=1.49, 95% CI: 1.01-2.22). The significantly lower risk associated with anti-PnPS18 antibodies was observed for infantile spasms (HR for trend=0.47, 95% CI: 0.27-0.83). CONCLUSIONS: Maternal anti-HSV1and anti-PnPS18 antibodies during pregnancy may be associated with the risk of epilepsy in offspring, but any potential etiologic and preventative implications of these associations warrant further exploration. PMID- 24054429 TI - [A case of nasal tip necrosis after hyaluronic acid injection]. AB - Hyaluronic acid (HA) is the most used dermal filler. Some complications associated with its use have been described, but most of them are rare and benign. We report an exceptional case of skin necrosis of the tip of the nose, in a 22-year-old patient, after HA injection. The initial appearance may occurred subsequent aesthetic sequels. After necrotic tissue excision, patient was followed in rapid succession. Daily local care has led to wound healing, without any important sequel. This rare complication reminds us that HA injections are not without risk, despite their apparent simplicity of use. Moreover, the case presented confirms the potential healing of the nasal tip, allowing treatment with wound healing, rather than other early invasive procedure. PMID- 24054430 TI - Spontaneous pneumocephalus in vertically acquired, late-onset neonatal Citrobacter meningitis. PMID- 24054431 TI - Oral propranolol for retinopathy of prematurity: risks, safety concerns, and perspectives. AB - OBJECTIVE: To evaluate safety and efficacy of oral propranolol administration in preterm newborns affected by an early phase of retinopathy of prematurity (ROP). STUDY DESIGN: Fifty-two preterm newborns with Stage 2 ROP were randomized to receive oral propranolol (0.25 or 0.5 mg/kg/6 hours) added to standard treatment or standard treatment alone. To evaluate safety of the treatment, hemodynamic and respiratory variables were continuously monitored, and blood samples were collected weekly to check for renal, liver, and metabolic balance. To evaluate efficacy of the treatment, the progression of the disease (number of laser treatments, number of bevacizumab treatments, and incidence of retinal detachment) was evaluated by serial ophthalmologic examinations, and plasma soluble E-selectin levels were measured weekly. RESULTS: Newborns treated with propranolol showed less progression to Stage 3 (risk ratio 0.52; 95% CI 0.47 0.58, relative reduction of risk 48%) or Stage 3 plus (relative risk 0.42 95% CI 0.31-0.58, relative reduction of risk 58%). The infants required fewer laser treatments and less need for rescue treatment with intravitreal bevacizumab (relative risk 0.48; 95% CI 0.29-0.79, relative reduction of risk 52 %), a 100% relative reduction of risk for progression to Stage 4. They also had significantly lower plasma soluble E-selectin levels. However, 5 of the 26 newborns treated with propranolol had serious adverse effects (hypotension, bradycardia), in conjunction with episodes of sepsis, anesthesia induction, or tracheal stimulation. CONCLUSION: This pilot study suggests that the administration of oral propranolol is effective in counteracting the progression of ROP but that safety is a concern. PMID- 24054432 TI - Injuries in adolescents with childhood-onset epilepsy compared with sibling controls. AB - OBJECTIVE: To compare the occurrence of injuries in adolescents with childhood onset epilepsy and matched sibling controls. STUDY DESIGN: Retrospective case control lifetime injury assessments were obtained from a community-based cohort of adolescents with childhood-onset epilepsy diagnosed 9 years earlier and their siblings. The children with epilepsy (n = 501; mean age, 15.3 years) included those with complicated (abnormal neurologic examination or IQ <80; n = 133) and uncomplicated (normal neurologic examination and IQ >=80; n = 368) epilepsy. Children with uncomplicated epilepsy were matched to sibling controls (n = 210 pairs). The children reported whether or not they had ever (before and after epilepsy diagnosis) experienced injuries "serious enough to require medical attention" and if so, the type of treatment required. RESULTS: Almost one-half (49.1%) of the children with epilepsy experienced injury, of whom 8.9% required surgery/hospitalization and 17.1% had injury related to a seizure. Fewer children with uncomplicated epilepsy had seizure-related injuries versus those with complicated epilepsy (13.6% vs 27.4%; P <= .01). The proportion of children with epilepsy with any injury by type (not mutually exclusive) were: 25.2% with fractures (n = 126); 24.4% with head injuries (n = 122); 10.2% with other injuries (n = 51); 8.4% with dental injuries (n = 42); and 8% with burns/scalds (n = 40). A similar proportion of children with uncomplicated epilepsy experienced any injury (overall and by type) compared to matched sibling controls, with the exception that more children with uncomplicated epilepsy had head injuries (30.0% vs 19.5%; P < .02). CONCLUSION: With the exception of head injuries, we found no evidence of an increased risk of injury in a representative cohort of children with epilepsy compared with matched sibling controls. This finding may reflect the fact that the sample was not biased to more severe cases, or that safety precautions to prevent injury were widely used. PMID- 24054433 TI - Progressive heterotopic ossification: the arduousness of an accurate diagnosis. PMID- 24054434 TI - In Cyprus, 'midwifery is dying...'. A qualitative exploration of midwives' perceptions of their role as advocates for normal childbirth. AB - BACKGROUND: advocacy has been identified as vital for improving maternal and newborn health. In many countries, midwives struggle to advocate for women; in Cyprus, there has been no research into perceptions of advocacy amongst midwives. AIM: this study provides an exploration of the perceptions of midwives as client advocates for normal childbirth in Cyprus. DESIGN: a qualitative approach was adopted, using participant observation and semi-structured interviews with a purposive sample of twenty experienced midwives. A thematic approach was taken for the analysis. FINDINGS: five main interconnected themes emerged, two of which, 'Lack of professional recognition' and 'Deficiencies in basic or continuing education' presented barriers to midwives' adoption of an advocacy role. Three themes reflected structural factors that also discouraged midwives from acting as advocates: these were 'physician dominance', 'medicalisation of childbirth' and 'lack of institutional support'. CONCLUSION: advocacy is a demanding and challenging role and midwives should be empowered to feel confident in undertaking this role through continuing professional education programmes and professional recognition. In order to be effective advocates, midwives needed to be recognised and valued by the public and by other health professionals as equal partners within the multidisciplinary team. However, midwives in Cyprus find themselves in difficult situations when advocating normal childbirth due to medical domination of the health services, medicalisation of childbirth and inadequate institutional support. IMPLICATIONS FOR PRACTICE: in this setting, midwives need to gain professional recognition, to have more effective basic and continuing education programmes and receive better support from managers and policy makers in order to become advocates for normal childbirth. PMID- 24054435 TI - Age at menopause and determinants of hysterectomy and menopause in a multi-ethnic community: the Hilo Women's Health Study. AB - OBJECTIVES: A lifespan approach was used to evaluate age at menopause, and determinants of surgical and natural menopause, in the multi-ethnic community of Hilo, Hawaii. STUDY DESIGN: Participants aged 40-60 years (n=898) were drawn from a larger, randomly generated sample recruited by postal questionnaires. Median age at natural menopause was computed by probit analysis. Logistic regression analysis was applied to examine determinants of hysterectomy, and Cox regression analysis was used to examine risk factors for an earlier age at menopause. MAIN OUTCOME MEASURES: History of hysterectomy, age at menopause. RESULTS: Frequency of hysterectomy was 19.2% at a mean age of 40.5 years. The likelihood of hysterectomy increased with older ages, lower education, mixed ancestry, having been overweight at age 30, and married 20 years prior to survey. Median age at natural menopause was 53.0 years. Smoking and not being married 10 years before survey were associated with an earlier age at menopause. CONCLUSIONS: Median age at menopause was later than the national average. Ethnicity and education were determinants of hysterectomy, but not associated with age at natural menopause. Events later in the lifespan (e.g., smoking and not being married 10 years prior to the survey) were more important than earlier events (e.g., childhood residence) in relation to age at menopause. The timing of weight gain and marital status appear to be important in relation to surgical menopause, and the timing of marital status appears to be important in relation to the timing of natural menopause. PMID- 24054436 TI - Kinematic property of target motion conditions gaze behavior and eye-hand synergy during manual tracking. AB - This study investigated how frequency demand and motion feedback influenced composite ocular movements and eye-hand synergy during manual tracking. Fourteen volunteers conducted slow and fast force-tracking in which targets were displayed in either line-mode or wave-mode to guide manual tracking with target movement of direct position or velocity nature. The results showed that eye-hand synergy was a selective response of spatiotemporal coupling conditional on target rate and feedback mode. Slow and line-mode tracking exhibited stronger eye-hand coupling than fast and wave-mode tracking. Both eye movement and manual action led the target signal during fast-tracking, while the latency of ocular navigation during slow-tracking depended on the feedback mode. Slow-tracking resulted in more saccadic responses and larger pursuit gains than fast-tracking. Line-mode tracking led to larger pursuit gains but fewer and shorter gaze fixations than wave-mode tracking. During slow-tracking, incidences of saccade and gaze fixation fluctuated across a target cycle, peaking at velocity maximum and the maximal curvature of target displacement, respectively. For line-mode tracking, the incidence of smooth pursuit was phase-dependent, peaking at velocity maximum as well. Manual behavior of slow or line-mode tracking was better predicted by composite eye movements than that of fast or wave-mode tracking. In conclusion, manual tracking relied on versatile visual strategies to perceive target movements of different kinematic properties, which suggested a flexible coordinative control for the ocular and manual sensorimotor systems. PMID- 24054437 TI - Persistent coordination patterns in a complex task after 10 years delay: subtitle: how validate the old saying "once you have learned how to ride a bicycle, you never forget!". AB - Motor learning studies have for a long time focused on performance variables (in terms of speed or accuracy) in assessing learning, transfer and retention of motor skills. We argue, however, that learning essentially resides in changes in coordination variables (in terms of qualitative organization of behavior) and that relevant tests for assessing the effectiveness of learning and retention should consider these variables. The aim of this experiment was to test the retention of a complex motor skill, after a long-term delay. Ten years ago, five participants were involved in an experiment during which they practiced for 39 sessions of ten 1-min trials on a ski-simulator. All participants volunteered for a retention test, ten years after, for one session of ten 1-min trials. Analyses focused on the oscillations of the platform of the simulator. Performance was assessed in terms of amplitude and frequency. Coordination was accounted for by an analysis of dynamical properties of the motion of the platform, and especially the nature of the damping function that was exploited for sustaining the limit cycle dynamics. Results showed a significant decrement in performance variables. In contrast, all participants adopted from the first trial onwards the coordination mode they learned 10years ago. These results confirm the strong persistence of coordination modes, once acquired and stabilized in the behavioral repertoire. They also support the importance of coordination variables for a valid assessment of learning and retention. PMID- 24054438 TI - Risk factors for the failure of antimuscarinic treatment with solifenacin in women with overactive bladder. AB - OBJECTIVE: To evaluate the outcomes of women treated with Solifenacin 5 mg once a day for overactive bladder (OAB) to identify the factors associated with the risk of treatment failure. METHODS: Women with OAB symptoms for at least 3 months were considered for this study. At visit 0, patients received a 3-day voiding diary. Eligibility was determined at visit 1, 2 weeks later, on the basis of the results recorded in the 3-day voiding diary. To be included, patients had to have experienced at least 3 episodes of urgency during the 3-day voiding diary period. Eligible women received a 12-week antimuscarinic therapy with oral Solifenacin 5 mg once a day. At the follow-up examination, objective outcomes included changes from baseline in the 3-day voiding diary data. Subjective efficacy was evaluated using the Overactive Bladder Questionnaire Short Form (OABq-SF), the Indevus urgency severity scale (USS) questionnaire, and the Patient Global Impression of Improvement. RESULTS: A total of 675 (69.3%) women met the inclusion criteria and were directed to Solifenacin therapy. After a 12-week treatment, 632 (93.6%) women were assessed for office evaluation, and 101 (16%) patients were considered as nonresponders. The antimuscarinics were effective both in terms of improvement of questionnaires scores and in terms of reduction of episodes of urgency/24 hour (P <.0001). In multivariable analysis, the number of episodes of urgency/24 hour, baseline OABq-SF symptom severity score, and baseline USS were independent predictors of Solifenacin failure. CONCLUSION: Some markers of OAB severity, such as the higher number of episodes of urgency/24 hour and the higher OABq-SF symptom severity score and USS at baseline, were associated with a lower therapeutic efficacy of Solifenacin. PMID- 24054439 TI - Bilateral polyorchidism with diffuse microlithiasis: a case report of an adolescent with 4 testes. AB - Polyorchidism is a rare congenital anomaly, with only 140 pathologically proven cases reported. Bilateral polyorchidism is far less common than triorchidism. Most cases present as a painless scrotal mass or are found incidentally during evaluation of other inguinoscrotal pathologies. We report a case of bilateral polyorchidism with 4 testes, 2 in each hemiscrotum that presented as left-sided testicular pain and hydrocele. PMID- 24054441 TI - Early prenatal detection of an intra-abdominal cryptorchid testicular teratoma. AB - Intra-abdominal prenatally detected testicular neoplasms are rare; however, increased use of prenatal ultrasonography has led to the discovery of these uncommon neoplasms. We report the fifth case of a prenatally detected intra abdominal testicular teratoma, which, in this instance, was detected early in pregnancy as a cystic mass within the fetal abdomen that subsequently underwent torsion later in pregnancy before delivery. PMID- 24054440 TI - Dietary management of idiopathic hyperoxaluria and the influence of patient characteristics and compliance. AB - OBJECTIVE: To assess the efficacy of dietary management for the treatment of idiopathic hyperoxaluria in a large tertiary care center and examine the influence of patient factors, compliance, and follow-up on oxalate reduction, which has not been previously investigated. METHODS: Retrospectively, 149 patients with kidney stones with idiopathic hyperoxaluria who received dietary management at our stone clinic were evaluated. Changes in urinary parameters on 24-hour urine collections were calculated for all patients and those with abnormal values in the overall short-term (30-240 days) and long-term (>240 days) time periods. Changes in urinary oxalate were evaluated with respect to patient characteristics and compliance measures. RESULTS: Urine oxalate and supersaturation of calcium oxalate were significantly (P < .001) reduced by 8.9 +/- 19.2 mg/d and 1.7 +/- 4.3, respectively. A total of 48.3% of the patients reduced their urinary oxalate to normal. Urine oxalate reductions were similar in the short-term and long-term periods. Women lowered urine oxalate nearly twice as much as men (12.7 +/- 2.0 mg/d vs 6.7 +/- 2.2 mg/d, P = .022) and body mass index (BMI) negatively correlated with oxalate reduction (Pearson's r = -0.213). Reported noncompliance and keeping follow-up appointments did not affect oxalate, however, there was a significant correlation between increasing urine volume and reducing oxalate (Pearson's r = -0.21). CONCLUSION: This study confirms that meaningful reductions of urine oxalate and supersaturation of calcium oxalate can be achieved with dietary management of hyperoxaluria on a larger clinical scale. Furthermore, we identified that women and patients with low BMIs had greater urine oxalate reductions and urine volume may also be used by clinicians as a measure of dietary compliance. PMID- 24054442 TI - [Double tachycardia: association of an atrial flutter and a fascicular ventricular tachycardia]. AB - Double tachycardia is an uncommon type of tachycardia. We report the case of a 42 year-old patient, admitted in our department for palpitations. Two types of tachycardia, narrow and wide QRS one, have been documented in the moment of palpitations. The electrophysiology study highlights an atrial flutter and a fascicular ventricular tachycardia. The patient had no recurrence of palpitations after atrial flutter ablation and medical treatment by verapamil for his ventricular tachycardia. This is the first published case combining an atrial flutter and a ventricular tachycardia. PMID- 24054443 TI - [Diagnostic and prognostic value of the head-up tilt test for patients with unexplained syncope: results of a French survey]. AB - OBJECTIVE: Evaluate the diagnostic and prognostic input of head-up tilt test in the exploration of unexplained syncope. METHOD: Between January 2009 and December 2012, all patients undergoing a head-up tilt test for recurrent syncope were studied. Follow-up data were obtained using telephone interviews and medical record reviews. RESULTS: A head-up tilt test was realized in 77 patients (47.8+/ 20years, 53% female) for an exploration of syncope. The tilt test elicited syncope or pre-syncope in 57 patients (74%). The positive response included vaso vagal syncope in 53 patients and psychogenic syncope in 4 patients. After a mean follow-up of 32+/-11months (range 6-54months), 90% of patients had not a recurrence of syncope. Of note, the incidence of recurrence was the same regardless of whether the patients had a positive (n=5/48; 10%) or a negative head-up tilt test response (n=2/19; 10%). CONCLUSION: The tilt test has a certain diagnostic value in the exploration of unexplained syncope. Recurrence rate of syncope after a tilt test is low. However, our study suggests no correlation between head-up tilt test results and the likelihood of recurring syncope. PMID- 24054444 TI - [Ischemic stroke after cardioversion and atrial flutter ablation in a patient taking dabigatran]. AB - This article reports an acute ischemic stroke after cardioversion and atrial flutter catheter ablation in a patient on treatment by dabigatran 110mg twice daily. Trans-esophageal echocardiography did not show any thrombi. Even if this event cannot be attributed to the treatment, this article indicates that prospective studies are necessary. PMID- 24054445 TI - [Totally asymptomatic coronary left main artery critical stenosis: when non invasive tests are falsely reassuring]. AB - Left main coronary artery severe stenosis is frequently very symptomatic and is considered as a classical contraindication for non-invasive ischemia testing. When performed, those tests usually yield a large area of ischemia associated with a rich symptomatology. We report the case of a 69-year-old completely asymptomatic man in whom both treadmill effort testing and dobutamine stress echocardiography were falsely reassuring as they eliminated significant ischemia despite the presence of a critical stenosis of distal left main artery ultimately confirmed by angiography. Dobutamine 2D strain performed afterwards was pathological and could have corrected the initially reassuring diagnosis. PMID- 24054446 TI - [Permanent junctional reciprocating tachycardia (Coumel type): a rare but curable form of tachycardia]. AB - We report the case of a 52 year-old man experiencing recurrent and incessant tachycardias despite antiarrhythmic drugs. Electrophysiological exploration confirmed the diagnosis of permanent junctional reentrant tachycardias (Coumel tachycardia). This tachycardia has been treated successfully by catheter ablation. The mechanisms of this tachycardias are explained. PMID- 24054447 TI - Anion release and uptake kinetics: structural changes of layered 2-dimensional ZnNiHN upon uptake of acetate and chlorinated acetate anions. AB - X-ray diffraction and UV-vis spectroscopy were used for the investigation of ion exchange reaction kinetics of nitrates with acetate (Ac), chloro acetate (ClAc), dichloro acetate (dClAc) and trichloro acetate (tClAc) anions, using zinc nickel hydroxy nitrate (ZnNiHN) as the exchange precursor. The exchange reactions conducted at 24, 30, 40 and 50 degrees C revealed that rate constants were inversely related to the calculated anion electronic spatial extent (ESE), while a direct relationship between rate constants and the average oxygen charges was observed. Temporal solid phase structural transformations were shown to be affected by the nature of the guest anions. The amount of nitrates released into solution has been shown to decrease as the guest anions became more chlorinated. Use of isoconversional approach revealed that activation energies changed significantly with alpha during dClAc intercalation than for the other anions. The topotactic intercalation of the guest anions, except dClAc, followed the Avrami-Erofe'ev kinetic model for the entire reaction progress. PMID- 24054448 TI - The caring presence of nursing: a qualitative focus. PMID- 24054449 TI - Utility of dexmedetomidine in sedation for radiofrequency ablation of atrial fibrillation. PMID- 24054450 TI - Reply: Utility of dexmedetomidine in sedation for radiofrequency ablation of atrial fibrillation. PMID- 24054451 TI - Patient-nurse anesthetist interaction during regional anesthesia and surgery based on video recordings. AB - PURPOSE: The purpose of this study was to interpret and describe the patient nurse anesthetist (NA) interaction during regional anesthesia. DESIGN: Video recordings conducted during orthopedic surgery at a surgical clinic in Sweden formed the basis for the study, in which three patients and three NAs participated. METHODS: A hermeneutic analysis was conducted on the data. FINDING: The findings of the analysis demonstrated that the NA was in either "present" presence or "absent" presence in the awake patient's visual field during surgery. The NA's professional actions at times dominated the patient's existential being in the intraoperative situation. The findings conveyed insights about the patient NA interaction that open up possibilities for nurses to understand and reflect upon their own practice in an expanded way. CONCLUSIONS: Using video recordings for reflections enables development of professional skills that positively influence the care quality for patients during regional anesthesia. PMID- 24054452 TI - The courage to surrender--placing one's life in the hands of the other. AB - PURPOSE: The aim of this study was to investigate how adult patients experience and cope with the anesthesia induction period, that is, before and during total intravenous induction. DESIGN: Grounded theory, based on the Charmaz framework, was used to explore what it is that characterizes patients' thoughts and feelings in this situation and how they handle the time period up to loss of consciousness. METHODS: Patients were interviewed using an open-ended method. FINDINGS: The core category: Constructing a foundation for surrendering one's life into the hands of the other illustrates the main concern of the 17 informants. This concern is illuminated by three main categories: Preparing oneself to surrender, trying to retain control, and accepting and surrendering/Refusing to accept and not surrendering. The informants struggled to place their life in the nurse anesthetist's/anesthesiologist's hands in a cycle of circumspection, preemption, and control. CONCLUSIONS: In order to enable a dignified surrender, it is essential that the nurse anesthetist/anesthesiologist understands the patient's experience of loss of control. PMID- 24054453 TI - The interaction between the patient and nurse anesthetist immediately before elective coronary artery bypass surgery. AB - PURPOSE: Establishing a purposive interaction with a patient who is in a vulnerable situation before coronary artery bypass graft (CABG) surgery poses a challenge for the nurse anesthetist. The aim of this study was to identify and describe the interaction between the patient and the nurse anesthetist immediately before elective CABG surgery. DESIGN: An observational study using a grounded theory design was used. METHODS: A theoretical selection of patients and nurse anesthetists was made. A total of 11 situations of patient/nurse anesthetist interaction were observed. The data were analyzed using the constant comparative method. FINDINGS: A core category of reassurance emerged from other categories of continuity, confirmation, and control. Continuity was characterized by expedient anesthesia nursing of high quality, confirmation was related to communication in a trusting atmosphere, and control was associated with skilled nursing interventions in the thoracic operating theatre. CONCLUSIONS: Reassurance can be achieved through a well-structured anesthesia nursing performance in the thoracic operating theatre, and by focusing on the patient and continuously giving him/her information during the preoperative preparation phase. PMID- 24054454 TI - Listening to music during regional anesthesia: patients' experiences and the effect on mood. AB - PURPOSE: Many patients experience a sense of anxiety and insecurity during the perianesthesia period. It is important to the care relationship that the nurse be able to help the patient to establish a degree of control over their situation and thus regain their own sense of security. Music therapy can be a useful tool to accomplish this. The purpose of this study was to determine the effect of a music intervention on patient's mood and self-reported satisfaction. DESIGN: A multimodal research design using an open-ended interview and quantitative anxiety scale was used. METHODS: A total of 15 patients were interviewed with an open question in addition to completing the Hospital Anxiety and Depression (HAD) scale. The interviews were analyzed using qualitative content analysis and the HAD scale according to standard practice. FINDINGS: An analysis of the interviews revealed a main theme: a feeling of satisfaction, and three subthemes: positive experience, inner peace, and detachment from reality. It emerged from the interviews that it was important for the patients to select music themselves. Patients had a positive experience, inner peace, and detachment from reality with changes in the patients' state of mind before and after the musical intervention. The anxiety level significantly decreased (P = .019) after the patients listened to music during surgery compared with the prevalence of anxiety before listening to music. CONCLUSIONS: This study shows that music has a positive impact on patients undergoing anesthesia. PMID- 24054455 TI - The relevance of modified early warning and pediatric early warning scores in the postanesthesia care unit. PMID- 24054456 TI - Promoting evidence-based nursing procedures by partnering with a vendor. PMID- 24054457 TI - The digital demise of medical doctor dictatorship. PMID- 24054458 TI - Preoperative assessment and teaching of postoperative discharge instructions: the importance of understanding health literacy. PMID- 24054459 TI - Patients with Parkinson's disease in the perioperative setting. PMID- 24054460 TI - Time to go global! The development of the International Collaboration of Perianesthesia Nurses: guest editorial. PMID- 24054461 TI - Risk of adverse pregnancy outcome in women exposed to livestock: a study within the Danish National Birth Cohort. AB - Maternal infection in pregnancy is a known risk factor for adverse pregnancy outcome, and a number of zoonotic pathogens may constitute a risk to pregnant women and their fetuses. With animal contact as a proxy for the risk of zoonotic infection, this study aimed to evaluate pregnancy outcome in women with self reported occupational or domestic contact with livestock compared to pregnant women without such contact. The Danish National Birth Cohort collected information on pregnancy outcome from 100 418 pregnant women (1996-2002) from which three study populations with occupational and/or domestic exposure to livestock and a reference group of women with no animal contact was sampled. Outcome measures were miscarriage, very preterm birth (before gestational week 32), preterm birth (before 37 gestational weeks), small for gestational age (SGA), and perinatal death. Adverse reproductive outcomes were assessed in four different exposure groups of women with occupational or domestic exposure to livestock with no association found between exposure to livestock and miscarriage, preterm birth, SGA or perinatal death. These findings should diminish general occupational health concerns for pregnant women with exposures to a range of different farm animals. PMID- 24054462 TI - Auditory processing and hallucinations in schizophrenia. AB - The aim of this study was to investigate whether deficits in auditory processing are associated with auditory hallucinations in patients with schizophrenia. It was hypothesised that individuals with a diagnosis of schizophrenia would demonstrate deficits in processing the spectral and temporal aspects of sound and that such deficits would be more pronounced in patients with a history of auditory hallucinations (hallucinators) than those without such a history (non hallucinators). A community sample meeting clinical criteria for schizophrenia or schizoaffective disorder (19 hallucinators, 15 non-hallucinators) and a matched healthy control group (n=17) completed a broad range of auditory processing tasks involving pitch discrimination of modulated (temporal) and unmodulated (spectral) pure tones, auditory streaming and affective prosodic identification, as well as measures assessing current psychiatric symptoms. In all experimental tasks patients were impaired compared to controls. Specifically hallucinators performed worse than non-hallucinators and controls for pitch discrimination of unmodulated tones and auditory streaming, and both hallucinators and non-hallucinators performed significantly worse than controls for discrimination of modulated tones and affective prosody. These findings suggest that impaired temporal processing may contribute to general difficulties identifying affective speech prosody in patients with schizophrenia, while spectral processing deficits may specifically compromise melodic streaming in hallucinators, which combined with deficits in temporal processing, contribute to the experience of auditory hallucinations. PMID- 24054463 TI - Membrane bending: the power of protein imbalance. AB - Many cellular processes require membrane deformation, which is driven by specialized protein machinery and can often be recapitulated using pure lipid bilayers. However, biological membranes contain a large amount of embedded proteins. Recent research suggests that membrane-bound proteins with asymmetric distribution of mass across the bilayer can influence membrane bending in a nonspecific manner due to molecular crowding. This mechanism is physical in nature and arises from collisions between such 'mushroom-shaped' proteins. It can either facilitate or impede the action of protein coats, for example COPII, during vesicle budding. We describe the physics of how molecular crowding can influence membrane bending and discuss the implications for other cellular processes, such as sorting of glycosylphosphatidylinositol-anchored proteins (GPI APs) and production of intraluminal vesicles. PMID- 24054464 TI - Switching to antipsychotic monotherapy can improve attention and processing speed, and social activity in chronic schizophrenia patients. AB - OBJECTIVE: This study sought to examine whether switching polypharmacy therapy to monotherapy would improve the cognitive function and social function of patients with schizophrenia. METHODS: Thirty-nine patients with schizophrenia who were receiving therapy with two antipsychotics were randomly divided into a switch to monotherapy group (switching group) and a polypharmacy continued group (continuing group). For the patients allocated to the switching group, the dose level of one of the two antipsychotic drugs was gradually reduced to zero. Psychotic symptoms, cognitive function and social function scale scores were assessed immediately before and 24 weeks after switching, and the time courses of these scores were compared between the two groups. RESULTS: Compared with the continuing group, the switching group demonstrated significantly greater improvement in attention after switching (p = 0.02). Furthermore, the improvement in daily living (p = 0.038) and work skills (p = 0.04) was significantly greater in the switching group. In an analysis of the correlation among sub-items with respect to the degrees of improvement, a significant correlation was noted between improvement in executive function and improvement in daily living (r = 0.64, p = 0.005) and between improvement in work skills and improvement in attention (r = -0.51, p = 0.038). CONCLUSION: In patients with schizophrenia receiving polypharmacy, switching to monotherapy resulted in improvements in attention. Furthermore, improvements in executive function led to improvements in daily living, and improvements in attention led to improvements in work skills. Thus, switching to monotherapy is a useful option. PMID- 24054465 TI - Variations of morphology and photosynthetic performances of Ulva prolifera during the whole green tide blooming process in the Yellow Sea. AB - Since 2007, the world's largest macroalgal blooms have occurred along the coastal area of the Yellow Sea for 6 consecutive years. In 2012, shipboard surveying and satellite remote sensing were used to monitor the whole blooming process. The blooms originated in Rudong sea area of the South Yellow Sea where bloom patches were of dark green and filamentous thalli were the dominant morphology. The scale of the blooms reached its peak size in Rizhao sea area of the North Yellow Sea, and decreased promptly and became insignificant in Qingdao coast where the blooms turned yellow, mostly with air sac blades. Meanwhile, vegetative cells of the green tide algae changed into cytocysts gradually from which germ cells were released as the blooms drifted northward. Additionally, chlorophyll contents and fluorescence activity of free-floating thalli in the North Yellow Sea were both significantly lower than that in the South Yellow Sea. Those studies presented here contributed to increasing our understanding about how the green tide declined gradually in the North Yellow Sea. PMID- 24054466 TI - Canadian Society of Nephrology commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD. AB - The KDIGO (Kidney Disease: Improving Global Outcomes) 2012 clinical practice guideline for anemia management in patients with chronic kidney disease provides the structural and evidence base for the Canadian Society of Nephrology commentary on this guideline's relevancy and application to the Canadian health care system. While in general agreement, we provide commentary on 11 of the 61 KDIGO guideline statements. Specifically, we agreed that a therapeutic trial of iron is appropriate in cases in which a reduction in erythropoiesis-stimulating agent (ESA) dosage or avoidance of ESA and transfusion is desired, transferrin saturations are >30%, and ferritin concentrations are >500 MUg/L. However, we concluded that there is insufficient evidence to support an upper target or threshold for ferritin and transferrin saturation levels. We agree with the initiation of ESA treatment when hemoglobin (Hb) level is 90-100 g/L; however, we specifically state that an acceptable range for Hb level is 95-115 g/L, with a target of 100-110 g/L, and add caution to individualization above this range due to concerns regarding the safety of ESAs. We agree that ESAs should be used with considerable caution in patients with active malignancy, history of stroke, or history of malignancy, and we suggest initiating ESA therapy at Hb level of 90 g/L and to aim for a Hb level in the range of 90-105 g/L. The reader is encouraged to note the level of evidence and review the entire KDIGO anemia guideline to interpret the guideline statements and commentary appropriately. PMID- 24054467 TI - Left posterior parietal theta burst stimulation affects gestural imitation regardless of semantic content. AB - OBJECTIVE: Neuro-imaging studies have suggested that the ability to imitate meaningless and meaningful gestures may differentially depend on superior (SPL) and inferior (IPL) parietal lobule. Therefore, we hypothesized that imaging guided neuro-navigated continuous theta burst stimulation (cTBS) over left SPL mainly affects meaningless and over left IPL predominantly meaningful gestures. METHODS: Twelve healthy subjects participated in this study. High resolution structural MRI was used for imaging guided neuro-navigation cTBS. Participants were targeted with one train of cTBS in three experimental sessions: sham stimulation over vertex and real cTBS over left SPL and IPL, respectively. An imitation task, including 24 meaningless and 24 meaningful gestures, was performed 'offline'. RESULTS: cTBS over both left IPL and SPL significantly interfered with gestural imitation. There was no differential effect of SPL and IPL cTBS on gesture type (meaningless versus meaningful). CONCLUSIONS: Our findings confirm that left posterior parietal cortex plays a predominant role in gestural imitation. However, the hypothesis based on the dual route model suggesting a differential role of SPL and IPL in the processing of meaningless and meaningful gestures could not be confirmed. SIGNIFICANCE: Left SPL and IPL play a common role within the posterior-parietal network in gestural imitation regardless of semantic content. PMID- 24054468 TI - Sutureless implantation of the perceval s aortic valve prosthesis through right anterior minithoracotomy. AB - BACKGROUND: Many new, less invasive strategies are proposed for aortic valve operation in elderly patients. Rapid deployment sutureless aortic valve prosthesis has been recently introduced. We analyzed our experience with a sutureless valve implanted through a minimally invasive approach. METHODS: A retrospective observational study with prospectively registered data was conducted on 137 patients undergoing aortic valve replacement through a right anterior minithoracotomy. Between April 2011 and January 2013, 137 consecutive patients underwent aortic valve replacement with a recently introduced, rapid deployment, sutureless pericardial valve in minithoracotomy access (47 men; mean age, 76.6 +/- 7.1 years). There were 35 obese patients with a body mass index of more than 30 kg/m(2). Mean logistic EuroSCORE I was 10.0; 74 (54%) patients were in New York Heart Association functional class III and IV. In all, 19 (13.9%), 45 (32.8%), and 73 (53.3%) patients received 21-, 23-, and 25-mm valve prostheses, respectively. RESULTS: The mean aortic cross-clamp and cardiopulmonary bypass times were 59.3 +/- 19 min and 92.3 +/- 27 min, respectively. No operative mortality occurred. Median stay in the intensive care unit was 1 day, with assisted ventilation necessary for a median of 6 hours. Three cases of postoperative ischemic stroke were observed (1 patient with a previous history of an ischemic cerebral event). Median hospital length of stay was 6 days. CONCLUSIONS: A sutureless valve for minimally invasive aortic valve replacement is a feasible, effective, and safe tool. Ultimately amplifying indications for less invasive aortic valve replacement in a high surgical risk subset of patients, it can become a valid alternative for transcatheter aortic valve implantation. PMID- 24054469 TI - Comment on: Algorithm for weight loss after gastric bypass surgery considering body mass index, gender, and age from the bariatric outcome longitudinal database. PMID- 24054471 TI - Common threads in atrial fibrillation and heart failure. AB - The prevalence of both chronic heart failure and atrial fibrillation is increasing as a result of systemic multimorbid risk and improved therapy of acute heart disease. Current treatment options are unsatisfactory especially regarding antiarrhythmic drugs. We propose that a systems biology approach to increase understanding of cardiac arrhythmias offers the best immediate way forward. Such an approach would be based on an accumulation of large clinical datasets, and application of next-generation sequencing in conjunction with selected experimental and computer-based models. Such an approach would in turn facilitate the development and targeted application of currently available and novel therapeutic approaches. PMID- 24054470 TI - Bariatric-related medical malpractice experience: survey results among ASMBS members. AB - BACKGROUND: The medicolegal aspects of bariatric surgery are very difficult to analyze scientifically because there is no central, searchable database of closed case claims and little incentive for malpractice insurers to divulge data. Examining medicolegal data may provide insight into the financial and psychological burden on physicians. Detailed data also may be used to improve patient safety and determine common causes of negligence. METHODS: All U.S.-based members of the American Society of Metabolic and Bariatric Surgeons were asked to complete a survey regarding their bariatric-related medical malpractice experience. RESULTS: Of the 1672 eligible members that received the survey, 330 responded (19.7%). Mean years in practice was 15.3 +/- 9. Mean annual cost of malpractice insurance was $59,200 +/- $52,000 (N = 197). The respondent surgeons experienced 1.5 +/- 3.2 lawsuits on average over the course of their practice. Of the 330 respondents, 144 (48%) did not report a bariatric-related lawsuit filed against them. Of the 464 lawsuits reported by 156 surgeons, 126 were settled out of court (27%), 249 were dropped (54%), and 54 (18%) went to trial. Seventy-two percent of cases that went to trial were found to be in favor of the defense. The mean lifetime amount paid for suits was $250,000+/-$660,000. The probability of a bariatric surgeon experiencing a lawsuit was independently associated with the years in practice (P = .03) and number of total cases the surgeon has performed (P = .01). The annual cost of malpractice insurance was independently predicted by the amount paid in previous claims (P = .01). CONCLUSIONS: The probability of a medical malpractice lawsuit correlates positively to the number of procedures performed and the number of years the surgeon has been in practice. PMID- 24054472 TI - Continuous monitoring of atrial fibrillation in heart failure. AB - In patients with atrial fibrillation (AF) undergoing cardiac resynchronization therapy (CRT) for heart failure, continuous monitoring of the percentage of biventricular BiV% pacing has shown that the greatest improvement and reduction in mortality occur with a BiV pacing greater than 98%. Continuous monitoring of BiV pacing has improved the CRT management of patients with AF. Continuous monitoring has generated important new questions about anticoagulant therapy, which require randomized trials. Anticoagulant therapy should probably be considered in patients who have a high risk of thromboembolism according to standard scoring systems. PMID- 24054473 TI - Ventricular rate control of atrial fibrillation in heart failure. AB - In the last few years, there has been a major shift in the treatment of atrial fibrillation (AF) in the setting of hear failure (HF), from rhythm to ventricular rate control in most patients with both conditions. In this article, the authors focus on ventricular rate control and discuss the indications; the optimal ventricular rate-control target, including detailed results of the Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison Between Lenient versus Strict Rate Control II (RACE II) study; and the pharmacologic and nonpharmacologic options to control the ventricular rate during AF in the setting of HF. PMID- 24054474 TI - Rhythm control of atrial fibrillation in heart failure. AB - Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular pathologies with severe prognostic implications that show bidirectional interactions. Rate and rhythm control are the main therapeutic strategies for patients with AF and HF. There is a paucity of safe and effective antiarrhythmic drugs for rhythm control of AF in HF, with amiodarone and (in the United States) dofetilide as the only imperfect options. The basic mechanisms of AF are discussed and the evidence and limitations of AF rhythm control options for patients with HF are reviewed. In addition, novel potential antiarrhythmic strategies for rhythm control of AF are highlighted. PMID- 24054475 TI - Upstream therapy for atrial fibrillation in heart failure. AB - Atrial fibrillation (AF) is a common arrhythmia that occurs as the result of various pathophysiologic processes. Heart failure increases the likelihood of AF. Several aspects of the morphologic and electrophysiologic alterations promoting AF in heart failure (congestive heart failure [CHF]) have been studied in animal models and patients with CHF. Under these conditions, ectopic activity originating from the pulmonary veins or other sites is more likely to occur and trigger longer episodes of AF. This article summarizes the impact of angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and statins, so called upstream therapy, in patients who have CHF with AF. PMID- 24054476 TI - Stroke prevention in atrial fibrillation in heart failure. AB - Heart failure and atrial fibrillation are major problems of modern cardiology with important clinical, prognostic, and socioeconomic implications. The risks are high morbidity, impaired quality of life, poor outcome, and increased risk of stroke. Oral anticoagulation with vitamin K antagonists or novel licensed medicines should be considered unless contraindicated. Possible benefits of sinus rhythm maintenance are not entirely clear and need to be explored further. Relatively scarce data are available on stroke prevention in atrial fibrillation in heart failure with preserved ejection fraction; this requires further research. PMID- 24054477 TI - Impact of atrial fibrillation on outcomes in heart failure. AB - The prevalence of atrial fibrillation (AF) and heart failure increases with advancing age. It is estimated that the annual incidence of AF in the general heart failure population is approximately 5%, whereas as many as 40% of patients with advanced heart failure have AF. The goals of therapy in patients with heart failure and AF are symptom control and prevention of arterial thromboembolism. The adverse hemodynamic events of AF may lead to symptom deterioration and reduced exercise capacity. This review addresses the impact of AF on heart failure outcomes as they pertain to prognosis and management. PMID- 24054478 TI - Atrial fibrillation in heart failure in the older population. AB - Atrial fibrillation (AF) is an important and often-underrecognized cause of cardiovascular morbidity and mortality. It is an arrhythmia that is commonly seen in the older patient; the median age of patients with AF in early studies was 75 years. Heart failure (HF) is also more frequently seen in the older patient with an approximate doubling of HF prevalence with each decade of life. There is clear interaction between AF and HF, with evidence that HF can lead to AF and AF exacerbates HF. This review focuses on the specific aspect of AF management in elderly patients with HF. PMID- 24054479 TI - Case selection for cardiac resynchronization in atrial fibrillation. AB - Remarkably little evidence exists that cardiac resynchronization therapy (CRT) is effective in patients who have atrial fibrillation (AF) but who otherwise seem suitable for this treatment. The landmark trials of CRT generally excluded patients with AF because atrioventricular (AV) resynchronization was considered a possibly important mechanism by which CRT might deliver its benefits. The only landmark trial that included many patients with AF confirmed marked benefit among patients in sinus rhythm but no benefit among those with AF. Evidence is lacking that biventricular rather than AV resynchronization is an important mechanism for delivering the benefits of CRT. PMID- 24054480 TI - Cardiac resynchronization therapy mechanisms in atrial fibrillation. AB - This article examines how to assess the reliability of potential techniques for performing optimization of biventricular pacemakers in patients with atrial fibrillation. It explores the magnitude of improvement that is likely to be obtained with the optimization of biventricular pacing in this clinical setting and discusses the lessons that can be learned with regard to the mechanisms of action of biventricular pacing in the general heart failure population. PMID- 24054481 TI - The role of ablation of the atrioventricular junction in patients with heart failure and atrial fibrillation. AB - Ablation of the atrioventricular junction (AVJ) is a technically easy procedure that is safe and has a high success rate as an intervention for effective ventricular rate control in patients in symptomatic atrial fibrillation. AVJ ablation has been reported to improve quality of life, left ventricular ejection fraction, and exercise duration in these patients and minimize the incidence of inappropriate shocks. Because right ventricular pacing after AVJ ablation may result in decrease in left ventricular function and worsening of heart failure symptoms, there is increasing evidence to support the effectiveness of cardiac resynchronization therapy in atrial fibrillation populations. PMID- 24054482 TI - Ablation of atrial tachycardia and atrial flutter in heart failure. AB - Atrial tachycardia and atrial flutter are common tachyarrhythmias in the heart failure population. They commonly lead to, exacerbate, and increase the morbidity and mortality associated with heart failure and, thereby, warrant urgent and early definitive therapy in the form of catheter ablation. Catheter ablation requires careful patient stabilization and extensive preprocedural planning, particularly with regards to anesthesia, strategy, catheter choice, mapping system, and fluid balance, to increase efficacy and limit adverse effects. Heart failure may limit the success of catheter ablation with higher reported recurrence rates, and in selected patients, a hybrid epicardial-endocardial ablation can be considered. PMID- 24054483 TI - Catheter ablation of atrial fibrillation in heart failure. AB - Atrial fibrillation in the presence of heart failure is an independent predictor of mortality and is associated with increased hospitalizations and worsening New York Heart Association functional class. Despite these associations, large-scale trials have not shown a benefit in rhythm restoration. However, further analysis of these trials showed that patients who remained in sinus rhythm did have improved survival rates. Studies to examine the efficacy of catheter ablation of atrial fibrillation were therefore conducted and reported efficacy rates ranging from 50% to 92% at maintaining sinus rhythm with associated improvements in left ventricular ejection fraction, quality of life, and New York Heart Association functional class. PMID- 24054484 TI - Surgical treatment of atrial fibrillation in the heart failure population. AB - Surgery to correct a structural heart valve problem can restore sinus rhythm in approximately one-fifth of patients with atrial fibrillation (AF), and the addition of a maze procedure will increase this proportion. Evidence shows that the maze procedure may restore atrial function in some patients and may have beneficial effects on functional symptoms and prognosis. The role of the maze procedure as an isolated treatment for lone AF in the context of heart failure with no structurally correctable cause is unknown. Future progress will determine the appropriate indications for treatment and the risks and benefits of any intervention. PMID- 24054485 TI - Atrial fibrillation and heart failure: it takes two to tango. Foreword. PMID- 24054486 TI - Atrial fibrillation and heart failure. Preface. PMID- 24054487 TI - Bacterial neuraminidase inhibitory effects of prenylated isoflavones from roots of Flemingia philippinensis. AB - Bacterial neuraminidase (NA) is one of the key enzymes involved in pathogenesis of inflammation during infection. The organic extract of the roots of Flemingia philippinensis showed high bacterial NA inhibitory activity with an IC50 of around 5MUg/mL. Activity-guided separation of the methanol extract yielded nine prenylated isoflavones together with the novel species isoflavone (2) which was given the name flemingsin. Isolated prenylated isoflavones (1-9) were evaluated for NA inhibition and their IC50 values were determined to range between 0.30 and 56.8MUM. The most potent inhibitor 4 (IC50=300nM, Ki=130nM) features a catechol motif in the B-ring and a furan in the A-ring. Structure-activity analysis also showed a 4-hydroxyl group within the B-ring was essential for NA inhibitory activity, because isoflavone (9) having protected 4-hydroxyl group was much less potent than its hydroxylated counterpart. All neuraminidase compounds screened were found to be reversible noncompetitive inhibitors. Furthermore, the most active NA inhibitors (1-9) were proven to be present in the native roots in high quantities by HPLC and LC-DAD-ESI/MS. PMID- 24054488 TI - (99m)Tc-MORF oligomers specific for bacterial ribosomal RNA as potential specific infection imaging agents. AB - PURPOSE: Radiolabeled oligomers complementary to the 16S rRNA in bacteria were investigated as bacterial infection imaging agents. METHODS AND RESULTS: Identical sequences with backbones phosphorodiamidate morpholino (MORF), peptide nucleic acid (PNA), and phosphorothioate DNA (PS-DNA) were (99m)Tc-labeled and evaluated for binding to bacterial RNA. MORF binding to RNA from Escherichia coli strains SM101 and K12 was 4- and 150-fold higher compared to PNA and PS-DNA, respectively. Subsequently MORF oligomer in fluorescence in situ hybridization showed a stronger signal with study MORF compared to control in fixed preparations of two E. coli strains and Klebsiella pneumoniae. Flow cytometry analysis showed study MORF accumulation to be 8- and 80-fold higher compared to the control in live K. pneumoniae and Staphylococcus aureus, respectively. Further, fluorescence microscopy showed increased accumulation of study MORF over control in live E. coli and K. pneumonia. Binding of (99m)Tc-study MORF to RNA from E. coli SM101 and K12 was 30.4 and 117.8pmol, respectively, per 10(10) cells. Mice with K. pneumoniae live or heat-killed (sterile inflammation) in one thigh at 90min for both (99m)Tc-study MORF and control showed higher accumulation in target thighs than in blood and all other organs expect for kidneys and small intestine. Accumulation of (99m)Tc-study MORF was significantly higher (p=0.009) than that of the control in the thigh with sterile inflammation. CONCLUSION: A (99m)Tc-MORF oligomer complimentary to the bacterial 16S rRNA demonstrated binding to bacterial RNA in vitro with specific accumulation into live bacteria. Radiolabeled MORF oligomers antisense to the bacterial rRNA may be useful to image bacterial infection. PMID- 24054489 TI - Synthesis and study of antiproliferative, antitopoisomerase II, DNA-intercalating and DNA-damaging activities of arylnaphthalimides. AB - A series of arylnaphthalimides were designed and synthesized to overcome the dose limiting cytotoxicity of N-acetylated metabolites arising from amonafide, the prototypical antitumour naphthalimide whose biomedical properties have been related to its ability to intercalate the DNA and poison the enzyme Topoisomerase II. Thus, these arylnaphthalimides were first evaluated for their antiproliferative activity against two tumour cell lines and for their antitopoisomerase II in vitro activities, together with their ability to intercalate the DNA in vitro and also through docking modelization. Then, the well-known DNA damage response in Saccharomyces cerevisiae was employed to critically evaluate whether these novel compounds can damage the DNA in vivo. By performing all these assays we conclude that the 5-arylsubstituted naphthalimides not only keep but also improve amonafide's biological activities. PMID- 24054490 TI - Synthesis, structural characterization and cell death-inducing effect of novel palladium(II) and platinum(II) saccharinate complexes with 2 (hydroxymethyl)pyridine and 2-(2-hydroxyethyl)pyridine on cancer cells in vitro. AB - Four palladium(II) and platinum(II) saccharinate (sac) complexes with 2 (hydroxymethyl)pyridine (2-hmpy) and 2-(2-hydroxyethyl)pyridine (2-hepy), namely trans-[Pd(2-hmpy)2(sac)2].H2O (1), trans-[Pt(2-hmpy)2(sac)2].3H2O (2), trans [Pd(2-hepy)2(sac)2] (3) and trans-[Pt(2-hepy)2(sac)2] (4), have been synthesized and characterized by elemental analysis, UV-vis, IR and NMR. Single crystal X-ray analysis reveals that the metal(II) ions in each complex are coordinated by two sac and two 2-hmpy or 2-hepy ligands with a trans arrangement. Anticancer effects of 1-4 were tested against four different cancer cell lines (A549 and PC3 for lung cancer, C6 for glioblastoma, and Hep3B for liver cancer). Cytotoxicity was first screened by the MTT assay and the results were further confirmed by the ATP assay. The mode of cell death was determined by both histological and biochemical methods. Among the metal complexes, complex 2 resulted in relatively stronger anti-growth effect in a dose-dependent manner (3.13-200MUM), compared to the others, by inducing apoptosis. PMID- 24054492 TI - A rare association of pulmonary hypertension and dextrocardia with Poland syndrome. AB - Poland syndrome is a rare congenital abnormality with an estimated incidence of 1 in 20,000 to 1 in 30,000 live births. We report and discuss this rare combination of pulmonary hypertension and dextrocardia with Poland syndrome. This case report also highlights the underlying pathogenetic mechanisms during foetal development and the potential to misdiagnose cardiac ischaemia in a patient with an anatomic anomaly. PMID- 24054491 TI - A synthetic compound, 4-acetyl-3-methyl-6-(3,4,5-trimethoxyphenyl)pyrano[3,4 c]pyran-1,8-dione, ameliorates ovalbumin-induced asthma. AB - Eosinophilia is one of the characteristic signs of allergic inflammation. Massive migration of eosinophils to the airways can cause epithelial tissue injury, contraction of airway smooth muscle and increased bronchial responsiveness. Previously, we discovered a new compound, 1H,8H-pyrano[3,4-c]pyran-1,8-dione (PPY), derived from the fruit of Vitex rotundifolia L. and evaluated its anti inflammatory and anti-asthmatic properties. In this study, we synthesized a new modified compound, 4-acetyl-3-methyl-6-(3,4,5-trimethoxyphenyl) pyrano[3,4 c]pyran-1,8-dione (PPY-345), which was based on the PPY skeleton, and we evaluated its anti-asthmatic effects. To evaluate the anti-asthmatic effect of PPY-345 in vitro, A549 lung epithelial cells were stimulated with TNF-alpha, IL-4 and IL-1-beta to induce the expression of CCL11 (Eotaxin), a chemokine involved in eosinophil chemotaxis. To characterize the anti-asthmatic properties of PPY 345 in vivo, we examined the influence of PPY-345 in an ovalbumin (OVA)-induced asthma model. PPY-345 treatments significantly reduced CCL11 secretion. PPY-345 treatment did not inhibit the translocation of NF-kappaB into the nucleus but suppressed the phosphorylation of signal transducers and activators of transcription 6 (STAT6). PPY-345 treatment significantly reduced airway hyperreactivity as measured by whole-body plethysmography. PPY-345 further reduced total cells, including eosinophil, macrophage and lymphocytes, in the BAL fluid, goblet cell hyperplasia and myosin light chain 2 positive smooth muscle cell area in the lung tissue. Additionally, PPY-345 significantly suppressed the levels of OVA-IgE present in the serum. These results suggested that PPY-345 could improve asthma symptoms in OVA-sensitized mice. PMID- 24054493 TI - Postoperative pulmonary hypertensive crisis caused by inverted left atrial appendage after cardiopulmonary bypass surgery for congenital heart disease in a neonate. AB - Postoperative pulmonary hypertensive crisis (PHC) caused by an inverted left atrial appendage (ILAA) is a rare complication following cardiac surgery. We present a case of 23 day-old male infant who developed postoperative PHC attacks after undergoing cardiopulmonary bypass (CPB) surgery for repair of the coactation of aorta. A hyperechogenic left atrial mass was detected via bedside transthoracic echocardiography (TTE), which was identified as an ILAA and corrected following repeat surgery. In this case, both the negative pressure in vent catheter and the long left atrial appendage (LAA) with a narrow base led to an irreversible ILAA. As in this neonate, ILAA had significant influence on the left atrial volume and caused PHC since the ILAA was located on the mitral valve orifice and interfered with the blood flow through the valve. Therefore, we recommend that the vent catheter should be turned off before removing to avoid this potential complication. Additionally, LAA should be carefully inspected after CPB surgery, and intra-operative and post-operative transoesophageal echocardiography (TEE) should be performed to detect ILAA intraoperatively so as to avoid the reoperation. When an ILAA is diagnosed postoperatively, whether conservative treatment or surgery will depend on the balance of benefit and risk for a particular patient. PMID- 24054494 TI - Dexamethasone pretreatment alleviates intestinal ischemia-reperfusion injury. AB - BACKGROUND: Activated mast cells are involved in the pathogenesis of intestinal ischemia-reperfusion (I/R)-related injury. Dexamethasone has been widely used to protect organs from I/R injury. This study was conducted to investigate the impact of treatment with dexamethasone at different stages of the II/R process on mast cell infiltration and activity and intestinal injury. METHODS: Kunming mice were randomized and subjected to a sham surgery or the II/R induction by clamping the superior mesenteric artery for 30 min and then reperfusion. During the II/R induction, the mice were treated intravenously with dexamethasone (10 mg/kg) for 30 min before ischemia (pretreatment group), at 5 min after clamping the superior mesenteric artery (isc-treatment group), or at the beginning of perfusion (rep treatment group), respectively. The levels of intestinal injury, mast cell infiltration and activity, tumor necrosis factor alpha (TNFalpha) and myeloperoxidase (MPO) activity in the intestines, and mouse survival rates were measured. RESULTS: The death rates, levels of intestinal injury, mast cell infiltration and activity, and tumor necrosis factor alpha and myeloperoxidase activity in the intestinal tissues from the II/R group were similar to those from the isc-treatment and rep-treatment groups of mice and were significantly higher than those from the sham group. In contrast, pretreatment with dexamethasone significantly mitigated the II/R-induced mast cell infiltration and activity, inflammation, and intestinal injury and reduced the death rates in mice. CONCLUSIONS: Pretreatment with dexamethasone inhibits II/R injury by reducing mast cell-related inflammation in mice. PMID- 24054495 TI - Polymicrobial sepsis is associated with decreased hepatic oxidative phosphorylation and an altered metabolic profile. AB - BACKGROUND: Organ failure in sepsis accounts for significant mortality worldwide. Mitochondrial and metabolic responses are central to the overall response of the cell, and thus of the organ and organism. Adaptive responses in metabolism are critical to the recovery at the cellular level. The purpose of these investigations was to test the hypothesis that sepsis is associated with decreased aerobic respiration and significant metabolic changes in the liver. METHODS: C57BL/6 mice underwent cecal ligation and puncture (CLP) with a 21 gauge needle or an operation without CLP. Mice were euthanized from 0-24 h after the procedure and liver tissue was harvested. Tissue oxygen consumption and mitochondrial complex activity were measured. Global biochemical profiles of 311 metabolites were performed at the 8-h time point (n = 8/group) and analyzed by gas chromatography-mass spectrometry and liquid chromatography tandem mass spectrometry platforms by Metabolon (Durham, North Carolina). The influence of lipopolysaccharide (LPS) on aerobic and anaerobic respiration in primary mouse hepatocytes was also investigated. RESULTS: CLP in vivo or LPS in vitro resulted in a significant decrease in hepatic oxygen consumption. There was a significant decrease in oxidative phosphorylation measured at 12 h. LPS also resulted in a significant increase in anaerobic respiration in hepatocytes. Interestingly, the metabolomic analysis resulted in a metabolic shift in the liver from carbohydrate based energy to utilization of fatty acids and amino acids. This included an increase in every tricarboxylic acid cycle intermediate and derivative, suggesting an increased flux into the cycle from fatty acid beta-oxidation and anaplerotic contributions from amino acids. CONCLUSIONS: Sepsis results in a metabolic response and profile consistent with increased anaerobic respiration, which occurs prior to significant changes in hemodynamics. The metabolic responses of cells and organs may be important adaptive responses to prevent organ failure and death. PMID- 24054496 TI - Nasal inhalation of butorphanol in combination with ketamine quickly elevates the mechanical pain threshold in the model of chronic constriction injury to the sciatic nerve of rat. AB - BACKGROUND: The aim of the present study is to explore the impact of butorphanol in combination with ketamine via nasal inhalation (NI) on neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve in a rat model. METHODS: CCI rats (n = 12) were equally randomized to four groups based on the treatments received as follows: 100 MUL of 0.9% normal saline via NI (NS/NI group); 100 MUg of butorphanol plus 1 mg of ketamine via NI (B + K/NI group); 100 MUg of butorphanol alone via NI (B/NI group); and 100 MUg of butorphanol plus 1 mg of ketamine via subcutaneous injection (B + K/SC group). Mechanical pain threshold was measured at 10 min, 30 min, 2 h, 4 h, and 6 h after drug administration. RESULTS: The mechanical pain threshold in the B + K/NI group was improved significantly 4 h after drug administration as compared with that in the B/NI or B + K/SC group (P < 0.05). The onset and intensity of drug action in the B + K/NI group were better than those of the other two groups, but the duration of drug action was not prolonged. CONCLUSIONS: NI of butorphanol in combination with ketamine quickly elevates the mechanical pain threshold in a rat neuropathic pain model induced by CCI to the sciatic nerve. PMID- 24054497 TI - A case report and epidemiological investigation of axillary lymph node abscess caused by Corynebacterium ulcerans in an HIV-1-positive patient. AB - A human immunodeficiency virus-1 (HIV-1)-positive male undergoing antiretroviral therapy was diagnosed with an axillary lymph node abscess caused by Corynebacterium ulcerans, and an environmental survey revealed that the patient's cat as the source of infection. PMID- 24054498 TI - Repeated exposure of mouse dermal fibroblasts at a sub-cytotoxic dose of UVB leads to premature senescence: a robust model of cellular photoaging. AB - BACKGROUND: Photoaging skin is due to accumulative effect of UV irradiation that mainly imposes its damage on dermal fibroblasts. To mimic the specific cellular responses invoked by long term effect of UVB, it is preferable to develop a photo damaged model in vitro based on repeated UVB exposure instead of a single exposure. OBJECTIVE: To develop a photo-damaged model of fibroblasts by repeated UVB exposure allowing for investigation of molecular mechanism underlying premature senescence and testing of potential anti-photoaging compounds. METHODS: Mouse dermal fibroblasts (MDFs) at early passages (passages 1-3) were exposed to a series of 4 sub-cytotoxic dose of UVB. The senescent phenotypes were detected at 24 or 48h after the last irradiation including cell viability, ROS generation, mitochondrial membrane potential, cell cycle, production and degradation of extracellular matrix. RESULTS: Repeated exposure of UVB resulted in remarkable features of senescence. It effectively avoided the disadvantages of single dose such as induction of cell death rather than senescence, inadequate stress resulting in cellular self-rehabilitation. CONCLUSION: Our work confirms the possibility of detecting cellular machinery that mediates UVB damage to fibroblasts in vitro by repeated exposure, while the potential molecular mechanisms including cell surface receptors, protein kinase signal transduction pathways, and transcription factors remain to be further evaluated. PMID- 24054500 TI - Interspecies differences with in vitro and in vivo models of vascular tissue engineering. AB - In arterial replacement there is a clear clinical need for a functional substitute possessing appropriate haemocompatible properties to be implanted as small diameter artery. Endothelial cell seeding constitutes an appreciated method to improve blood compatibility on the condition that cells firmly adhere to the support. Along this way, an innovative technique based on multilayered polyelectrolyte films (PEM) as cell adhesive substrate was previously validated in vitro and in vivo in a small-animal model. In this study, we extended the work on a larger animal (sheep) to validate furthermore the paradigm of PEM functionalization for vascular substitutes. We tested in vitro: the efficiency of PEM to induce endothelial progenitor differentiation in sheep endothelial cells; the ability of PEM to sustain cell proliferation and allow resistance to shear stress; the fate of PEM-coated de-endothelialized human saphenous veins under flow conditions, a prerequisite step before in vivo experiments. Despite in vitro differences we were encouraged by testing in vivo PEM-coated prosthesis as carotid replacement in sheep, but without success. In order to explain the implantation failure, an in vitro haemocompatibility evaluation was performed that highlighted interspecies differences able to explain, at least in part, the graft failure obtained. PMID- 24054499 TI - Umbilical cord and bone marrow mesenchymal stem cell seeding on macroporous calcium phosphate for bone regeneration in rat cranial defects. AB - Human umbilical cord mesenchymal stem cells (hUCMSCs) are inexhaustible and can be harvested at a low cost without an invasive procedure. However, there has been no report on comparing hUCMSCs with human bone marrow MSCs (hBMSCs) for bone regeneration in vivo. The aim of this study was to investigate hUCMSC and hBMSC seeding on macroporous calcium phosphate cement (CPC), and to compare their bone regeneration in critical-sized cranial defects in rats. Cell attachment, osteogenic differentiation and mineral synthesis on RGD-modified macroporous CPC were investigated in vitro. Scaffolds with cells were implanted in 8-mm defects of athymic rats. Bone regeneration was investigated via micro-CT and histological analysis at 4, 12, and 24 weeks. Three groups were tested: CPC with hUCMSCs, CPC with hBMSCs, and CPC control without cells. Percentage of live cells and cell density on CPC in vitro were similarly good for hUCMSCs and hBMSCs. Both cells had high osteogenic expressions of alkaline phosphatase, osteocalcin, collagen I, and Runx2. Bone mineral density and trabecular thickness in hUCMSC and hBMSC groups in vivo were greater than those of CPC control group. New bone amount for hUCMSC-CPC and hBMSC-CPC constructs was increased by 57% and 88%, respectively, while blood vessel density was increased by 15% and 20%, than CPC control group at 24 weeks. hUCMSC-CPC and hBMSC-CPC groups generally had statistically similar bone mineral density, new bone amount and vessel density. In conclusion, hUCMSCs seeded on CPC were shown to match the bone regeneration efficacy of hBMSCs in vivo for the first time. Both hUCMSC-CPC and hBMSC-CPC constructs generated much more new bone and blood vessels than CPC without cells. Macroporous RGD-grafted CPC with stem cell seeding is promising for craniofacial and orthopedic repairs. PMID- 24054501 TI - Combined RNA interference of adenine nucleotide translocase-2 and ganciclovir therapy in hepatocellular carcinoma. AB - PURPOSE: The purpose of this study was to investigate the anticancer effects of combined RNA interference (RNAi) of the adenine nucleotide translocase-2 (ANT2) gene and ganciclovir (GCV) therapy for treatment of hepatocellular carcinoma cells (Huh 7) in an animal model. METHODS: The Huh 7/NTG stable cell line was established by transfection of a vector with the human sodium iodide symporter (hNIS), HSV1-sr39 thymidine kinase (tk), and enhanced green florescent protein (EGFP) fusion gene into Huh 7 cells. mRNA expressions of these genes were evaluated by RT-PCR analysis. The functions of hNIS and HSV1-sr39tk were verified with (125)I uptake and (3)H-penciclovir (PCV) uptake tests. EGFP and hNIS expression was confirmed with confocal microscopy after immunocytochemical staining. We treated the tumor cells with ANT2 shRNA or GCV or both ANT2 shRNA and GCV and treated the in vivo mouse model with a Huh 7/NTG tumor xenograft. The therapeutic effects of the in vivo study were assessed with caliper measurements and gamma camera imaging using (99m)Tc-pertechnetate. RESULTS: Huh 7/NTG cells showed a cell number-dependent increase in (125)I uptake and a 24-fold higher (3)H-PCV uptake compared to parent Huh 7 cells. Huh 7/NTG cells transfected with ANT2 shRNA had lower ANT2 mRNA expression and more impaired proliferation activity than cells transfected with scramble shRNA. Proliferation of Huh 7/NTG cells was also inhibited by GCV treatment. Combined GCV and ANT2 shRNA therapy further inhibited cell proliferation in the in vitro study. The combined therapy with GCV and ANT2 shRNA showed a further decrease in tumor growth in the mouse model. CONCLUSIONS: Our results suggest that the combined RNA interference with ANT2 and GCV therapy inhibited hepatocellular carcinoma cell proliferation more than single GCV therapy or ANT2 shRNA therapy in vitro and in vivo. Therefore it could be applied treating incurable hepatocellular carcinoma. PMID- 24054502 TI - Guide-catheter extension system facilitated multiple bioresorbable vascular scaffolds (ABSORB(r)) delivery in a very long and resistant coronary artery lesion. AB - We report the case of a 77-year-old male patient who was admitted to our institution for non-ST segment elevation myocardial infarction. Coronary angiography showed a sub-occlusive lesion of the distal left anterior descending artery (LAD) in the context of a diffuse atherosclerotic disease involving a very long segment of the vessel (about 80mm in length by visual estimation). Pre dilatation was performed in the mid calcified segment of the LAD with a non compliant balloon inducing vessel dissection. An everolimus-eluting bioresorbable vascular scaffold (EEBVS) was then advanced in the LAD but the first delivery attempt at the distal site failed because of friction between the EEBVS struts and the calcified vessel wall. In order to facilitate EEBVS delivery, a 5Fr catheter system (Heart Rail II, Terumo, Tokyo, Japan) was advanced in the mid LAD within a standard 6Fr guiding catheter facilitating a non-traumatic deep intubation up to the mid LAD. This strategy increased back-up support facilitating the delivery, beyond the site of resistance, of four EEBVS implanted in overlap. This case demonstrated the successful use of a guide catheter extension system to deliver multiple EEBVS in a patient with a long, calcified LAD lesion. PMID- 24054503 TI - Facilitating the comparison of multiple visual items on screen: the example of electronic architectural plan correction. AB - This paper describes two experiments designed to (1) ascertain whether the way in which architectural plans are displayed on a computer screen influences the quality of their correction by humans, and (2) identify the visual exploration strategies adopted in this type of task. Results of the first "spot the difference" experiment showed that superimposing the plans yielded better error correction performances than displaying them side by side. Furthermore, a sequential display mode, where the second plan only gradually appeared on the screen, improved error search effectiveness. In the second experiment, eye movement recordings revealed that superimposition increased plan comparison efficiency by making it easier to establish coreference between the two sources of information. The improvement in effectiveness in the sequential condition was shown to be linked to the attentional guidance afforded by this display mode, which helped users to make a more thorough exploration of the plans. PMID- 24054504 TI - Effects of forearm and palm supports on the upper extremity during computer mouse use. AB - The use of forearm and palm supports has been associated with lower neck and shoulder muscle activity as well as reduced musculoskeletal discomfort during keyboard use, however, few studies have investigated their effect during computer mouse use. Eight men and eight women completed several computer mousing tasks in six arm support conditions: Forearm Support, Flat Palm Support, Raised Palm Support, Forearm + Flat Palm Support, Forearm + Raised Palm Support, and No Support. Concurrently, an infrared three-dimensional motion analysis system measured postures, six-degree-of-freedom force-torque sensors measured applied forces & torques, and surface electromyography measured muscle activity. The use of forearm support compared to the no support condition was significantly associated with less shoulder muscle activity & torque, and the raised palm support was associated with less wrist extension. Forearm supports reduced shoulder flexion torque by 90% compared to no support. The use of either support also resulted in lower applied forces to the mouse pad. Participants reported less musculoskeletal discomfort when using a support. These results provide recommendations for office workstation setup and inform ergonomists of effective ways to reduce musculoskeletal exposures. PMID- 24054506 TI - Nationwide survey of Arima syndrome: a note of doubt. PMID- 24054505 TI - Effects of continuous positive airway pressure therapy on systemic inflammation in obstructive sleep apnea: a meta-analysis. AB - OBJECTIVES: Our meta-analysis was performed to estimate the effect of continuous positive airway pressure (CPAP) therapy on systemic inflammation in patients with obstructive sleep apnea (OSA). METHODS: A comprehensive literature search of PubMed and EMBASE was performed for literature published up to January 2013. Standardized mean difference (SMD) was calculated to estimate the treatment effects of pre- and post-CPAP therapy. RESULTS: A total of 35 studies involving 1985 OSA patients were included in the meta-analysis. Each study investigated one or more inflammatory markers: 24 studies on C-reactive protein (CRP), 16 studies on IL-6, 3 studies on IL-8, and 12 studies on tumor necrosis factor alpha (TNF alpha). The results showed that the SMD (95% confidence interval [CI]) for CRP, IL-6, IL-8, and TNF-alpha were 0.452 (95% CI, 0.252-0.651), 0.299 (95% CI, 0.001 0.596), 0.645 (95% CI, 0.362-0.929), and 0.478 (95% CI, 0.219-0.736) in pre- and post-CPAP therapy, respectively. The subgroup analyses seemed to support better benefits with therapy duration of >=3 months and more adequate compliance (>=4 h/night). CONCLUSIONS: CPAP therapy could partially suppress systemic inflammation in OSA patients, and substantial differences were present among the various inflammatory markers. PMID- 24054507 TI - Saving 100,000 lives each year in Europe. PMID- 24054508 TI - Epidemiology and management of cardiac arrest: what registries are revealing. AB - Major European institutions report cardiovascular disease (CVD) as the first cause of death in adults, with cardiac arrest and sudden death due to coronary ischaemia as the primary single cause. Global incidence of CVD is decreasing in most European countries, due to prevention, lifestyle and treatment. Mortality of acute coronary events inside the hospital decreases more rapidly than outside the hospital. To improve the mortality of cardiac arrest outside the hospital, reliable epidemiological and process figures are essential: "we can only manage what we can measure". Europe is a patchwork of 47 countries (total population of 830 million), with a 10-fold difference in incidence of coronary heart disease between North and South, East and West, and a 5-fold difference in number of EMS treated cardiac arrest (range 17-53/1000,000/year). Epidemiology of cardiac arrest should not be calculated as a European average, but it is appropriate to describe the incidence of cardiac arrest, the resuscitation process, and the outcome in each of the European regions, for benchmarking and quality management. Epidemiological reports of cardiac arrest should specify definitions, nominator (number of cases) and denominator (study population). Recently some regional registries in North America, Japan and Europe fulfilled these conditions. The European Registry of Cardiac Arrest (EuReCa) has the potential to achieve these objectives on a pan-European scale. For operational applications, the Utstein definition of "Cardiac arrest" is used which includes the potential of survival. For application in community health, the WHO definition of "sudden death" is frequently used, describing the mode of death. There is considerable overlap between both definitions. But this explains that no single method can provide all information. Integrating data from multiple sources (local, national, multinational registries and surveys, death certificates, post-mortem reports, community statistics, medical records) may create a holistic picture of cardiac arrest in the community. PMID- 24054509 TI - ERC initiatives to reduce the burden of cardiac arrest: the European Cardiac Arrest Awareness Day. AB - The rate of survival from out-of-hospital cardiac arrest in Europe remains unacceptably low and could be increased by better bystander cardiopulmonary resuscitation (CPR) rates. The European Resuscitation Council has announced that there will be a European Cardiac Arrest Awareness Day every year on the 16th of October. This is to coincide with the goals of the Written Declaration passed by the European Parliament in June 2012 that emphasised the importance of equal access to CPR and automated external defibrillator (AED) training. The topic of this year's Awareness Day is 'Children Saving Lives' and it is hoped that all national resuscitation councils will promote awareness of the benefits of training all children in CPR and AED use and lobby for legislative change to ensure that all children receive this training. Children are not just the adults of tomorrow - they are the lifesavers of today and tomorrow. PMID- 24054510 TI - International CPR guidelines - perspectives in CPR. AB - The International Liaison Committee on Resuscitation (ILCOR) co-ordinates regular reviews of cardiopulmonary resuscitation (CPR) science and publishes consensus on science statements and treatment recommendations. These outputs are used by international resuscitation organisations to generate clinical guidelines. This review will outline the history behind the development of international CPR guidelines and will provide a detailed description of the current guideline generating process. A perspective is provided on the future of this process and the prospects for completely unified international CPR guidelines. PMID- 24054511 TI - Modern BLS, dispatch and AED concepts. AB - Basic Life Support has changed significantly over the last 15 years. Evidence based changes in recommendations involved compression rate, compression depth and the ratio between compressions and ventilations. There is much evidence that early basic life support increases the probability of survival two- to three fold. Recognition of a cardiac arrest remains challenging for witness and dispatcher. Educating the public in basic life support and recognition of cardiac arrest are key factors in improving survival of cardiac arrest. The large differences in survival between countries and regions clearly indicate that education and implementation must be high on the agenda in each community. Dispatchers play an increasingly important role in the process, both in rapid recognition of the cardiac arrest as well as giving telephone guidance to those bystanders that had not followed a training in basic life support. Those instructions should only instruct to deliver chest compressions. For those who have been trained in BLS and who are willing to give full CPR, should administer ventilations and chest compressions according to the guidelines. The AED plays a key role in early management of cardiac arrest and can substantially contribute to better survival. Logistics of placement of AEDs and the optimal way to bring AEDs to a victim require much more efforts, especially for victims in residential area's, where the great majority of cases of cardiac arrest occur. PMID- 24054512 TI - Therapeutic hypothermia following cardiac arrest. AB - More than 10 years ago, the randomised studies of therapeutic hypothermia after cardiac arrest showed significant improvement of neurological outcome and survival. Since then, it has become clear that most of the possible adverse events of therapeutic hypothermia are mild and can easily be controlled by proper administration of intensive care. Although implementation of this effective therapy is quite successful, many questions of the exact treatment protocol still remain unanswered. Therapeutic hypothermia treatment therefore must be tailored to the specific patient's needs. Hence, the exact level of target temperature, duration of cooling, rewarming, timing of the therapy and concomitant medication to facilitate therapeutic hypothermia will be important in the future. Additionally, the use of a post-resuscitation treatment bundle (specialised cardiac-arrest centres including intensive post-resuscitation care, appropriate haemodynamic and respiratory management, therapeutic hypothermia and percutaneous coronary intervention) could further improve treatment of cardiac arrest. PMID- 24054513 TI - Cardiac aetiology of cardiac arrest: percutaneous coronary interventions during and after cardiopulmonary resuscitation. AB - Management and prevention of cardiac arrest in the setting of heart disease is a challenge for modern cardiology. After reviewing the aetiology of sudden cardiac death and discussing the way to identify candidates at risk, we emphasise the role of percutaneous coronary interventions during and after cardiopulmonary resuscitation in the treatment of patients with return of spontaneous circulation after cardiac arrest. PMID- 24054514 TI - Prognostication after cardiac arrest. AB - The best predictor of good outcome after cardiac arrest is awakening from coma. The longer it takes to regain consciousness, the greater the risk of permanent brain injury. A reliable neurological assessment could previously be performed on day 3 after arrest; absence of or a stereotypic motor reaction to pain and absence of cranial nerve reflexes were reliable predictors of poor outcome, but this has changed. The introduction of therapeutic hypothermia and concurrent sedation and muscle relaxation has affected the reliability of the clinical investigation. This is probably due to increased use of sedative drugs and delayed metabolism during hypothermia but could, in addition, be explained by delayed maturation and recovery processes of brain ischaemia. A clinical neurological assessment should no longer be the sole decisive method for prognostication after cardiac arrest. Instead, a clinical investigation should be used in combination with independent and objective methods, above all neurophysiology (electroencephalography and somatosensory evoked potentials), while biomarkers and brain imaging may be valuable adjuncts. PMID- 24054515 TI - SOPs and the right hospitals to improve outcome after cardiac arrest. AB - Approximately 400,000 Europeans are yearly resuscitated from out-of-hospital cardiac arrest (OHCA).(1,2) Despite evolving evidence based guidelines for cardiopulmonary resuscitation (CPR), survival rates after OHCA has not improved much in several places around the world. However, a potential for improved survival is absolutely present, based on the huge spread in worldwide survival; some cities with survival over 20-30% and some cities with just a few percent.(1,2) These survival differences can partly be explained by different definitions of OHCA,(2) but mainly due to the overall quality of the local Chain of Survival (COS)(3); early arrest recognition and call for help, early CPR, early defibrillation and early post resuscitation care. By identifying and thereafter improving weak links in the local COS, survival can indeed increase. This review will focus on the quality of the last link in the COS, the hospital treatment after return of spontaneuous circulation (ROSC), and how good quality post resuscitation care can improve not only survival, but survival with neurologically intact outcome. PMID- 24054516 TI - European Resuscitation Council (ERC) - the Network to fight against cardiac arrest in Europe. AB - The ideas of collaboration and formation of scientific societies and registries for cardiac arrest were developed in the 18th century. The European Resuscitation Council (ERC) was formed in 1990. Nowadays, the ERC network consists of 30 National Resuscitation Councils (NRCs), which have an obligation to ensure that effective resuscitation services are provided and to promote education, training, and research in all aspects of resuscitation science. The central role of NRCs in decreasing the incidence of cardiac arrest may be highlighted and enhanced by the incorporation and implementation of the following suggestions. NRCs should emphasize and actively participate in acute care training of healthcare professionals and of lay rescuers. Implementation of current resuscitation guidelines should be a priority of each NRC and identification of the weakest link in the chain of survival should be a priority. PMID- 24054517 TI - Schoolchildren as lifesavers in Europe - training in cardiopulmonary resuscitation for children. AB - Sudden cardiac arrest is a major contributor to avoidable deaths in Europe. Immediate initiation of basic life support (BLS) by lay bystanders is among the most successful strategies in its treatment. Despite the fact that more than half of all cardiac arrests are witnessed in a number of European countries, layperson resuscitation is initiated in only one-fifth of all cases. One strategy to promote bystander BLS is to establish cardiac resuscitation training in schools. BLS instructions for schoolchildren - including the use of automatic external defibrillators (AEDs) - have been shown to be feasible independently of the children's age or physical ability. Nonetheless, it appears reasonable to implement age-adjusted curricula. The earlier in the course of life-long learning BLS instruction begins, the more sustainable training may be. PMID- 24054518 TI - A comparative study of the neuropsychiatric and neurocognitive phenotype in two microdeletion syndromes: velocardiofacial (22q11.2 deletion) and Williams (7q11.23 deletion) syndromes. AB - PURPOSE: 22q11.2 deletion syndrome (22q11.2DS) and Williams syndrome (WS) are common neurogenetic microdeletion syndromes. The aim of the present study was to compare the neuropsychiatric and neurocognitive phenotypes of 22q11.2DS and WS. METHODS: Forty-five individuals with 22q11.2DS, 24 with WS, 22 with idiopathic developmental disability (DD) and 22 typically developing (TD) controls were compared for the rates of psychiatric disorders as well as cognitive executive and visuospatial functions. RESULTS: We found that while anxiety, mood and disruptive disorders had an equally high prevalence among individuals with 22q11.2DS, WS and DDs, the 22q11.2DS group had the highest rates of psychotic disorders and the WS group had the highest rates of specific phobia. We also found that the WS group demonstrated more severe impairments in both executive and visuospatial functions than the other groups. WS and 22q11.2DS subjects had worse Performance-IQ than Verbal-IQ, a feature typical of non-verbal learning disorders. CONCLUSION: These findings offer a wide perspective on unique versus common phenotypes in 22q11.2DS and WS. PMID- 24054519 TI - Hepatitis E virus in England and Wales: indigenous infection is associated with the consumption of processed pork products. AB - Indigenously acquired hepatitis E infections have increased substantially in England and Wales since 2010. Epidemiological investigations were undertaken to determine risk factors for the acquisition of infection. A case-control study (25 cases, 75 controls) was used to test the hypothesis that hepatitis E infection was related to consumption of pork products. In a multivariable model, consumption of pork pie [odds ratio (OR) 6.33, 95% confidence interval (CI) 1.41 28.48, P = 0.009] and consumption of ham and sausages purchased from a major UK supermarket chain (OR 10.12, 95% CI 1.68-60.81, P = 0.023) were significantly associated with indigenous infection. The consumption of sausages and ham purchased from the supermarket was highly correlated; however. separate models showed that each variable was significantly associated with infection (OR 7.59, 95% CI 1.81-31.84, P = 0.004 and OR 10.98, 95% CI 1.84-65.35, P = 0.003, respectively). Although contamination of sausages with HEV has previously been shown this study also raises concerns about other processed pork products and whether current practice in preparing these products is sufficient to prevent transmission of HEV. PMID- 24054521 TI - A new German Government: leadership for health? PMID- 24054520 TI - Pre-attentive information processing and impulsivity in bipolar disorder. AB - Early responses to stimuli can be measured by sensory evoked potentials (EP) using repeated identical stimuli, S1 and S2. Response to S1 may represent efficient stimulus detection, while suppression of response to S2 may represent inhibition. Early responses to stimuli may be related to impulsivity. We compared EP reflecting stimulus detection and inhibition in bipolar disorder and healthy controls, and investigated relationships to impulsivity. Subjects were 48 healthy controls without family histories of mood disorder and 48 with bipolar disorder. EP were measured as latencies and amplitudes for auditory P50 (pre-attentional), N100 (initial direction of attention) and P200 (initial conscious awareness), using a paired-click paradigm, with identical stimuli 0.5 s apart. Impulsivity was measured by questionnaire and by laboratory tests for inability to suppress responses to stimuli or to delay response for a reward. Analyses used general linear models. S1 amplitudes for P50, N100, and P200, and gating of N100 and P200, were lower in bipolar disorder than in controls. P50 S1 amplitude correlated with accurate laboratory-task responding, and S2 amplitude correlated with impulsive task performance and fast reaction times, in bipolar disorder. N100 and P200 EP did not correlate with impulsivity. These findings were independent of symptoms, treatment, or substance-use history. EPs were not related to questionnaire-measured or reward-based impulsivity. Bipolar I disorder is characterized by reduced pre-attentional and early attentional stimulus registration relative to controls. Within bipolar disorder, rapid-response impulsivity correlates with impaired pre-attentional response suppression. These results imply specific relationships between ERP-measured response inhibition and rapid-response impulsivity. PMID- 24054522 TI - Action on ambient air pollution. PMID- 24054523 TI - What can the UN General Assembly do for global health? PMID- 24054524 TI - High stakes at the UN on the Sustainable Development Goals. PMID- 24054525 TI - The world we want: an end to child marriage. PMID- 24054526 TI - What works in saving children: the essentials. PMID- 24054528 TI - Global health governance after 2015. PMID- 24054529 TI - Global health governance after 2015. PMID- 24054530 TI - Global health governance after 2015 - Authors' reply. PMID- 24054531 TI - Global health governance after 2015. PMID- 24054532 TI - Immunisation against meningococcus B. PMID- 24054533 TI - Immunisation against meningococcus B. PMID- 24054534 TI - Patterns in coverage of maternal, newborn, and child health interventions: projections of neonatal and under-5 mortality to 2035. AB - BACKGROUND: Urgent calls have been made for improved understanding of changes in coverage of maternal, newborn, and child health interventions, and their country level determinants. We examined historical trends in coverage of interventions with proven effectiveness, and used them to project rates of child and neonatal mortality in 2035 in 74 Countdown to 2015 priority countries. METHODS: We investigated coverage of all interventions for which evidence was available to suggest effective reductions in maternal and child mortality, for which indicators have been defined, and data have been obtained through household surveys. We reanalysed coverage data from 312 nationally-representative household surveys done between 1990 and 2011 in 69 countries, including 58 Countdown countries. We developed logistic Loess regression models for patterns of coverage change for each intervention, and used k-means cluster analysis to divide interventions into three groups with different historical patterns of coverage change. Within each intervention group, we examined performance of each country in achieving coverage gains. We constructed models that included baseline coverage, region, gross domestic product, conflict, and governance to examine country-specific annual percentage coverage change for each group of indicators. We used the Lives Saved Tool (LiST) to predict mortality rates of children younger than 5 years (henceforth, under 5) and in the neonatal period in 2035 for Countdown countries if trends in coverage continue unchanged (historical trends scenario) and if each country accelerates intervention coverage to the highest level achieved by a Countdown country with similar baseline coverage level (best performer scenario). RESULTS: Odds of coverage of three interventions (antimalarial treatment, skilled attendant at birth, and use of improved sanitation facilities) have decreased since 1990, with a mean annual decrease of 5.5% (SD 2.7%). Odds of coverage of four interventions--all related to the prevention of malaria--have increased rapidly, with a mean annual increase of 27.9% (7.3%). Odds of coverage of other interventions have slowly increased, with a mean annual increase of 5.3% (3.5%). Rates of coverage change varied widely across countries; we could not explain the differences by measures of gross domestic product, conflict, or governance. On the basis of LiST projections, we predicted that the number of Countdown countries with an under-5 mortality rate of fewer than 20 deaths per 1000 livebirths per year would increase from four (5%) of the 74 in 2010, to nine (12%) by 2035 under the historical trends scenario, and to 15 (20%) under the best performer scenario. The number of countries with neonatal mortality rates of fewer than 11 per 1000 livebirths per year would increase from three (4%) in 2010, to ten (14%) by 2035 under the historical trends scenario, and 67 (91%) under the best performer scenario. The number of under-5 deaths per year would decrease from an estimated 7.6 million in 2010, to 5.4 million (28% decrease) if historical trends continue, and to 2.3 million (71% decrease) under the best performer scenario. INTERPRETATION: Substantial reductions in child deaths are possible, but only if intensified efforts to achieve intervention coverage are implemented successfully within each of the Countdown countries. FUNDING: The Bill & Melinda Gates Foundation. PMID- 24054535 TI - The unfinished agenda in child survival. AB - 10 years ago, The Lancet published a Series about child survival. In this Review, we examine progress in the past decade in child survival, with a focus on epidemiology, interventions and intervention coverage, strategies of health programmes, equity, evidence, accountability, and global leadership. Knowledge of child health epidemiology has greatly increased, and although more and better interventions are available, they still do not reach large numbers of mothers and children. Child survival should remain at the heart of global goals in the post 2015 era. Many countries are now making good progress and need the time and support required to finish the task. The global health community should show its steadfast commitment to child survival by amassing knowledge and experience as a basis for ever more effective programmes. Leadership and accountability for child survival should be strengthened and shared among the UN system; governments in high-income, middle-income, and low-income countries; and non-governmental organisations. PMID- 24054536 TI - Peripheral air embolism. PMID- 24054537 TI - Ischemic stroke in patients with atrial fibrillation receiving oral anticoagulation. AB - BACKGROUND: Atrial fibrillation is the most common cause of embolic stroke associated to heart disease. Oral anticoagulation with vitamin K antagonists substantially reduces this risk. AIMS: We assessed a group of patients with prior diagnosis of atrial fibrillation who sustained an ischemic stroke while receiving an adequate regime of oral anticoagulation. METHODS: We evaluated consecutive patients with ischemic stroke and prior diagnosis of atrial fibrillation. We determined demographics, clinical characteristics, TOAST stroke subtypes, CHADS2 scores, and prior or concomitant use of oral anticoagulants. RESULTS: We studied 112 patients. Thirty nine of them (35%) had received an adequate dose of a vitamin K antagonist during the 24-hour period preceding the stroke. There were no differences in demographics, vascular risk factors, CHADS2 scores, nor medications use between patients who were or were not receiving anticoagulation. Other potential etiologies for stroke occurrence were found in 8 (21%) anticoagulated patients, and in 3 (4%) non-anticoagulated subjects (p<0.01). Anticoagulated patients had a mean international normalized ratio (INR) of 2.3 +/ 1.3 (median 2.05), and INR was within therapeutic ranges (i.e., >= 2) in 54% of these subjects. CONCLUSIONS: A substantial proportion of patients with atrial fibrillation who have an ischemic stroke are already receiving oral anticoagulation. Sub-optimal levels of anticoagulation and additional etiologies explain, only in part, this failure. Further research is needed to help find adequate therapeutic strategies in atrial fibrillation patients who sustain an ischemic stroke while receiving oral anticoagulation. PMID- 24054538 TI - Genetic features of Huntington disease in Cuban population: implications for phenotype, epidemiology and predictive testing. AB - Huntington disease is the most frequent polyglutamine disorder with variable worldwide prevalence. Although some Latin American populations have been studied, HD prevalence in Cuban population remains unknown. In order to characterize the disease in Cuba, the relative frequency of HD was determined by studying 130 patients with chorea and 63 unrelated healthy controls, emphasizing in the molecular epidemiology of the disease. Sixty-two patients with chorea belonging to 16 unrelated families carried a pathological CAG expansion in the HTT gene, ranging from 39 to 67 repeats. Eighty-three percent of them come from the eastern region of the country. A significant inverse correlation between age at onset and expanded CAG repeats was seen. Intermediate alleles in affected individuals and controls represented 4.8% and 3.97% respectively, which have been a putative source of de novo mutation. This study represents the largest molecular characterization of Huntington disease in the Cuban population. These results may have significant implications for an understanding of the disease, its diagnosis and prognosis in Cuban patients, giving health professionals the tools to implement confirmatory genetic testing, pre-symptomatic testing and clinical trials in this population. PMID- 24054539 TI - A parallel increase in placental oxidative stress and antioxidant defenses occurs in pre-gestational type 1 but not gestational diabetes. AB - We aimed to determine the oxidative stress status in placentas obtained from gestational (GDM) and type 1 (T1D) diabetic pregnancies. Malonaldehyde and protein carbonyls, two biomarkers of oxidative damage, were higher in T1D but not in GDM placentas. Also, higher reduced glutathione and lower oxidized glutathione levels and higher glutathione peroxidase activity were found in T1D but not in GDM placentas. These results suggest that T1D placentas may develop a protective antioxidant mechanism to overcome higher oxidative stress levels. PMID- 24054540 TI - Postdate pregnancy: changes of placental/membranes 11beta-hydroxysteroid dehydrogenase mRNA and activity. AB - 11beta-Hydroxysteroid dehydrogenase 1 and 2 (11beta-HSD1 and 11beta-HSD2) are involved in the complex mechanism of human parturition. The present study examined mRNA expression and activity of membrane 11beta-HSD1 and placental 11beta-HSD2 in postdate pregnancies according to response of labor induction. In comparison to postdate women who had spontaneous delivery or after induction the non-responders showed significantly low c and high 11beta-HSD2 expression and activity These data suggest that disrupted expression and activity of 11beta-HSDs may occur in some postdate pregnancies. PMID- 24054541 TI - Atrial fibrillation: stroke prevention in focus. AB - INTRODUCTION: Atrial fibrillation (AF) is a common arrhythmia and a risk factor for stroke and other, adverse events. Internationally there have been recent advancements in the therapies available for, stroke prevention in AF. Nurses will care for individuals with AF across a variety of primary and acute, care settings and should be familiar with evidence based therapies. AIM: This paper provides a review of the epidemiology of AF and stroke, stroke and bleeding risk, assessment tools and evidence based treatments for the prevention of stroke in AF including the use of, novel anti-thrombin agents. METHOD: A review of key databases was conducted from 2002 to 2012 using the key search terms 'atrial, fibrillation' 'anticoagulation' 'risk assessment' and 'clinical management'. The following electronic, databases were searched: CINAHL, Medline, Scopus, the Cochrane Library and Google Scholar., Reference lists were manually hand searched. Key clinical guidelines from National Institute for, Clinical Excellence (NICE, UK), American Heart Association (AHA, USA), American College of Cardiology, (ACC, USA) and the European Society of Cardiology (ESC) and key government policy documents were, also included. Articles were included in the review if they addressed nursing management with a focus, on Australia. RESULTS: Many treatment options exist for AF. Best practice guidelines make a variety of, recommendations which include cardioversion, ablation, pulmonary vein isolation, pharmacological, agents for rate or rhythm control approaches, and antithrombotic therapy (including anticoagulation, and antiplatelet therapy). Treatment should be patient centred and individualised based upon, persistency of the rhythm, causal nature, risk and co-morbid conditions. CONCLUSION: AF is a common and burdensome condition where treatment is complex and not without, risk. Nurses will encounter individuals with AF across a variety of primary and acute care areas, understanding the risk of AF and appropriate therapies is important across all care settings. Treatment, must be individually tailored to the needs of the patient and balanced with the best available evidence. PMID- 24054542 TI - Kubios HRV--heart rate variability analysis software. AB - Kubios HRV is an advanced and easy to use software for heart rate variability (HRV) analysis. The software supports several input data formats for electrocardiogram (ECG) data and beat-to-beat RR interval data. It includes an adaptive QRS detection algorithm and tools for artifact correction, trend removal and analysis sample selection. The software computes all the commonly used time domain and frequency-domain HRV parameters and several nonlinear parameters. There are several adjustable analysis settings through which the analysis methods can be optimized for different data. The ECG derived respiratory frequency is also computed, which is important for reliable interpretation of the analysis results. The analysis results can be saved as an ASCII text file (easy to import into MS Excel or SPSS), Matlab MAT-file, or as a PDF report. The software is easy to use through its compact graphical user interface. The software is available free of charge for Windows and Linux operating systems at http://kubios.uef.fi. PMID- 24054543 TI - Comparability versus statistical correctness. PMID- 24054544 TI - QALY as evaluation tool in a health surveillance program. AB - BACKGROUND: Quality adjusted life years (QALYs), based on health related quality of life (HRQL), are a commonly used concept in health economics. The aim of this study was to apply the concept of QALY to the evaluation of a surveillance program for health related effects of PCB exposure and measure the impact of occupational PCB-exposure on the remaining QALYs of participants. METHODS: The internal PCB exposure was determined by gas chromatography with mass spectrometry in plasma. The HRQOL was assessed via the EQ-5D-3L instrument and combined with the remaining lifetime (RLE) at the time point of cessation of exposure. For comparative reasons we used both the linear calculation and the complex-number model from Prieto and Sacristan. The impact of several PCB congeners was regressed on the percentage of discounted QALYs on RLE via hierarchical multiple regression, controlling for gender, relational and educational status. RESULTS: Findings were able to detect a small but significant effect of elevated plasma levels of PCB on QALY for the linear calculation and partially for the complex number calculation. This means that an internal exposure to PCB reduced HRQOL in the RLE of participants in the surveillance program. CONCLUSION: QALYs can be applied successfully to monitor HRQL effects in surveillance programs. The exposure to a hazardous substance has an influence on QALYs. Findings have to be interpreted as a first hint. In the following assessment it has to be monitored whether there is an improvement or worsening of HRQL. PMID- 24054545 TI - Country clustering applied to the water and sanitation sector: a new tool with potential applications in research and policy. AB - The fields of global health and international development commonly cluster countries by geography and income to target resources and describe progress. For any given sector of interest, a range of relevant indicators can serve as a more appropriate basis for classification. We create a new typology of country clusters specific to the water and sanitation (WatSan) sector based on similarities across multiple WatSan-related indicators. After a literature review and consultation with experts in the WatSan sector, nine indicators were selected. Indicator selection was based on relevance to and suggested influence on national water and sanitation service delivery, and to maximize data availability across as many countries as possible. A hierarchical clustering method and a gap statistic analysis were used to group countries into a natural number of relevant clusters. Two stages of clustering resulted in five clusters, representing 156 countries or 6.75 billion people. The five clusters were not well explained by income or geography, and were distinct from existing country clusters used in international development. Analysis of these five clusters revealed that they were more compact and well separated than United Nations and World Bank country clusters. This analysis and resulting country typology suggest that previous geography- or income-based country groupings can be improved upon for applications in the WatSan sector by utilizing globally available WatSan related indicators. Potential applications include guiding and discussing research, informing policy, improving resource targeting, describing sector progress, and identifying critical knowledge gaps in the WatSan sector. PMID- 24054546 TI - Functional bombesin receptors in urinary tract of rats and human but not of pigs and mice, an in vitro study. AB - AIMS: Bombesin receptors (BB receptors) and/or bombesin related peptides are expressed in the lower urinary tract, though their function and distribution in different species is largely unknown. This study examines whether BB receptor agonists can contract bladder smooth muscle in rats, mice, pigs and humans. METHODS: Bladder strips were placed in tissue baths for in vitro contractility. Neuronally evoked contractions were elicited using electric field stimulation (EFS). Effects of the BB receptor agonists, neuromedin B (NMB; BB1 receptor agonist) and gastrin-releasing peptide (GRP; BB2 receptor agonist) on baseline tone and EFS-induced contractions were monitored. RESULTS: In rat and human bladder strips, NMB and GRP (10(-11)-10(-6)M) increased EFS-induced contractions in a concentration dependent manner. In these species, NMB and GRP also increased baseline tension. In mouse and pig bladder strips, NMB and GRP (10(-8)-3*10(-6)M) had no effects on either parameter. CONCLUSIONS: These data suggest that bombesin receptors BB receptor 1 and/or BB receptor 2 increase bladder contractions in rat and human. The site of action of these receptors may be pre- and/or post synaptic, increasing release of transmitters or enhancing smooth muscle excitability, respectively. Thus, BB1 receptor and/or BB2 receptor may offer therapeutic targets for voiding dysfunction associated with impaired bladder contractility; however, species differences must be considered when studying these receptors. Part of this work was published in an abstract form at the SFN meeting New Orleans, 2012. PMID- 24054547 TI - Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: the potential risk of extensive radiation pneumonitis. AB - PURPOSE: To evaluate the toxicity and efficacy of thoracic stereotactic body radiotherapy (SBRT) in patients with subclinical interstitial lung disease (ILD). METHODS AND MATERIALS: One hundred patients with 124 lung tumors were treated with SBRT at our institution according to our own protocols; patients with subclinical (untreated and oxygen-free) ILD were treated with SBRT, while those with clinical ILD (post- or under treatment) were not. The administration of 48 Gy in four fractions was used in 103 (83%) of the 124 tumors. The presence of subclinical ILD in the pre-SBRT CT findings was reviewed by two chest radiologists. The relationships between radiation pneumonitis (RP) and clinical factors were investigated. RESULTS: Subclinical ILD was recognized in 16 (16%) of 100 patients. Grade 2-5 RP was recognized in 13 (13%) of 100 patients. Grade 2-5 RP was observed in three (19%) of 16 patients with subclinical ILD. Subclinical ILD was not found to be a significant factor influencing Grade 2-5 RP; however, extensive RP beyond the irradiated field, including the contralateral lung, was recognized in only three patients with subclinical ILD, and the rate of extensive RP was significantly high in the patients with subclinical ILD. Grade 4 or 5 extensive RP was recognized in only two patients with subclinical ILD. Dosimetric factors of the lungs (V5, V10, V15, V20, V25, MLD) were significantly associated with Grade 2-5 RP. The three-year overall survival and local control rates of all patients were 53% and 86%, respectively. No significant differences were seen in either overall survival or local control rates between the patients with ILD and those without ILD. CONCLUSIONS: Subclinical ILD was not found to be a significant factor for Grade 2-5 RP or clinical outcomes in the current study; however, uncommon extensive RP can occur in patients with subclinical ILD. PMID- 24054548 TI - LKB1 mutant in a KRAS activated adenocarcinoma of the lung associated with Peutz Jeghers syndrome: a case report. AB - We present a case of a 54-year-old woman who was diagnosed with a KRAS positive adenocarcinoma of the lung on the basis of a Peutz-Jeghers syndrome (PJS), which was unknown before. PJS is a rare hereditary disease, which may be associated with the development of poor outcome adenocarcinomas and LKB1-gene mutations. A very rare type of a LKB1 mutation was found, not previously described in lung cancer. Although seldom screened for LKB-1 mutations are found in up to 30% of lung adenocarcinomas and may be druggable therapeutic targets, in particular in KRAS mutant tumours in the near future as recent preclinical results with nucleotides demonstrate. PMID- 24054549 TI - Racial disparities in the use of outpatient mastectomy. AB - BACKGROUND: Racial disparities exist within many domains of cancer care. This study was designed to identify differences in the use of outpatient mastectomy (OM) based on patient race. METHODS: We identified patients in the American College of Surgeons National Surgical Quality Improvement Program Participant Use File (during the years 2007-2010) who underwent a mastectomy. The association between mastectomy setting, patient race, patient age, American Society of Anesthesiology physical status classification, functional status, mastectomy type, and hospital teaching status was determined using the chi-square test. A multivariable logistic regression analysis was developed to assess the relative odds of undergoing OM by race, with adjustment for potential confounders. RESULTS: We identified 47,318 patients enrolled in the American College of Surgeons National Surgical Quality Improvement Program Participant Use File who underwent a mastectomy during the study time frame. More than half (62.6%) of mastectomies were performed in the outpatient setting. All racial minorities had lower rates of OM, with 63.8% of white patients; 59.1% of black patients; 57.4% of Asian, Native Hawaiian, or Pacific Islander patients; and 43.9% of American Indian or Alaska Native patients undergoing OM (P < 0.001). After adjustment for multiple confounders, black patients, American Indian or Alaska Native patients, and those of unknown race were all less likely to undergo OM (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.80-0.93; OR, 0.55; 95% CI, 0.41-0.72; and OR, 0.70; 95% CI, 0.64-0.76, respectively) compared with white patients. CONCLUSIONS: Disparities exist in the use of OM among racial minorities. Further studies are needed to identify the role of cultural preferences, physician attitudes, and insurer encouragements that may influence these patterns of use. PMID- 24054550 TI - Delivery of epithelial autografts and cutaneous wound healing in burn patients. PMID- 24054551 TI - Clinical parameters, intestinal function, and IGF1 concentrations in colostrum deprived and colostrum-fed newborn pony foals. AB - Colostrum (COL) contains cytokines and growth factors that may enhance intestinal development in neonates. The hypothesis of this study was that besides providing immunoglobulins, COL is important for intestinal function and meconium release in foals. Newborn foals were either fed COL (n = 5) or an equal amount of milk replacer (MR, n = 7) during the first 24 hours of life. To ensure passive immunity, all foals received 1 L plasma. Postnatal development, meconium release, intestinal motility, white blood cell count, insulin-like growth factor 1, and intestinal absorptive function (xylose absorption test) were evaluated. Clinical findings and meconium release were not affected by feeding of COL or MR. Ultrasonography revealed a slightly larger jejunum and stomach in group COL versus MR (P < 0.05). The percentage of polymorphonuclear leucocytes was higher in foals of group MR versus group COL (P < 0.05) and the percentage of lymphocytes was lower in MR compared with COL foals (P < 0.05). Plasma insulin like growth factor 1 concentration increased during the first 14 days after birth in both groups. A xylose absorption test on Day 5 revealed similar increases in plasma xylose concentrations after oral intake. In conclusion, feeding of COL versus MR was without effect on meconium release and intestinal absorptive function. Differences between foals fed COL and MR with regard to intestinal function are apparently without clinical relevance. In foals that have not received maternal COL, there is no major risk of intestinal problems if they are fed MR and provided with immunoglobulins by transfusion of plasma. PMID- 24054552 TI - Effect of non-sperm cells removal with single-layer colloidal centrifugation on myeloperoxidase concentration in post-thaw equine semen. AB - Myeloperoxidase (MPO) is a pro-oxidant enzyme contained in and released by neutrophils during degranulation or after lysis. Post-thaw semen contains MPO and its concentration is associated with decreased sperm motility. Recently, MPO concentration in post-thaw semen was shown to be associated with the presence of non-sperm cells (NSC). The objective of this study was to evaluate the effect of a single-layer colloidal centrifugation before cryopreservation on NSC and MPO concentrations in equine semen. The experimental design consisted of freezing semen with or without previous centrifugation through two concentrations of single-layer colloid media. Non-sperm cells and MPO concentrations were assessed in pellet and upper layer at each step of the procedure and MPO was detected in cells by immunocytochemistry. Single-layer colloid centrifugation decreased NSC and MPO concentrations in post-thaw semen. The MPO concentration was correlated with concentration of NSC in the upper layer of the supernatant. In post-thaw semen, with or without previous single-layer colloid centrifugation, MPO concentration was correlated with concentration of NSC. Overall, neutrophils were rarely observed and NSC were mainly epithelial cells or cellular debris, as demonstrated by MPO immunocytochemistry. At all steps of the semen processing and cryopreservation, MPO immunostaining was clearly identified only on NSC. In conclusion, our study shows that NSC present in fresh semen release MPO during freezing. PMID- 24054553 TI - Sensitivity of a real-time polymerase chain reaction for Tritrichomonas fetus in direct individual and pooled preputial samples. AB - The objective of this study was to evaluate the sensitivity of a commercially available real-time polymerase chain reaction (PCR) test for the detection of Tritrichomonas fetus in individual and pooled direct preputial samples. Two samples were collected and processed once a week from nine T. fetus-infected bulls (n = 121) and placed into either an InPouch TF or 2 mL of PBS. Preputial samples were also collected into both media and PBS from 1016 other bulls. All pouches were cultured and evaluated as per manufacturer's instructions. The prepuce samples collected directly into PBS were individually evaluated using real-time PCR by a commercial diagnostic laboratory. Direct preputial samples were then randomly divided for pooling into groups of 5 and 10 samples, ensuring that every pool had one sample from a known infected bull before testing using real-time PCR. Sensitivity was estimated for culture and real-time PCR of the 121 direct and culture-enriched individual samples from nine infected bulls. There were no differences (P = 0.12) among the sensitivity estimates for culture, 95.0% (95% confidence interval [CI]: 89.6%-97.7%); real-time PCR of culture-enriched samples, 95.9% (95% CI: 90.7-98.2); and direct preputial samples, 90.1% (95% CI: 83.5-94.2). There was also no significant difference (P = 0.08) between the sensitivity of real-time PCR for direct preputial samples in 110 pools of 5 (83.6%, 95% CI: 75.6-89.4) or 10 samples (77.3%, 95% CI: 68.6-84.1). The use of three sequential direct samples, collected in PBS at weekly intervals and tested by real-time PCR, increased the sensitivity to 100% for pools of 5 and 96% for pools of 10. In conclusion, direct preputial samples collected in PBS and tested by real-time PCR individually have comparable sensitivity to culture and real time PCR in enriched samples. The use of pooled direct preputial samples appears to be relatively sensitive. However, this strategy requires repeated sampling to optimize sensitivity. Real-time PCR testing of preputial samples collected directly into PBS with the option of pooling would decrease the cost associated with screening bulls, and increase the feasibility of large epidemiological studies and active surveillance. PMID- 24054554 TI - Surface plasmon resonance additivity of gold nanoparticles for colorimetric identification of cysteine and homocysteine in biological fluids. AB - In this work, with the assistance of the additivity of surface plasmon resonance band of nonionic fluorosurfactant-stabilized gold nanoparticles, we developed a new colorimetric assay approach of cysteine (Cys) and homocysteine (Hcy) in biological fluids, requiring no use of separation techniques. The detection limits of Cys and Hcy can be as low as 0.4 MUM. The applicability of the method was validated by spiking known amount of Cys and Hcy in human urine and plasma samples. Recoveries were in the range of 97.2-106.7%. The present approach is simple, high selective and reproducible. In addition, the universality of the additivity of surface plasmon resonance band was demonstrated by virtue of silver nanoparticles. Therefore, the proposed method has a great potentiality in disease diagnosis associated with Cys and Hcy. PMID- 24054555 TI - Reproducibility of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) measurements in mussel shells and comparison with micro-drill sampling and solution ICP-MS. AB - The accumulation of trace elements (Mg, Mn, Sr, Ba) in Unio pictorum L. mussel shells from Lake Balaton has been assessed using a Laser Ablation (LA) system coupled to either a quadrupole-based or a sector-field inductively coupled plasma mass spectrometer (ICP - MS), as well as by a combination of micro-drill sampling and solution ICP-MS. The LA-ICP-MS measurements were carried out in the holes made by the micro-drilling system. The longitudinal concentration profiles obtained with the different methods show similar patterns. However, the absolute concentrations determined at individual spots (holes) can be quite different. Especially Ba shows erratic peaks at a very small spatial scale. A paired, two sample t-test between LA-ICP-MS longitudinal profiles and between LA-ICP-MS and micro-drill/solution ICP-MS profiles indicates that, in most cases, there is no significant difference between the concentration profiles of Ba, Mg, Mn and Sr. Average shell concentrations of Mg, Mn, Sr and Ba, as obtained by LA-ICP-MS and micro-drill/solution ICP-MS, compare well with bulk shell concentrations as obtained by acid digestion/ICP-MS of larger shell pieces. Next to the four elements mentioned above, also the concentrations of Cd, Co, Cr, Cu, Ni, Pb and Zn could be determined by bulk shell analysis. The element concentrations in 11 shells, all sampled at the same site, show a relative standard deviation (RSD) between 2% (Ni) and 46% (Zn). LA-ICP-MS and micro-drill solution ICP-MS are not sensitive enough for the determination of ultra-trace elements in Lake Balaton's mussel shells. We estimated the amount of shell material necessary to determine Ni, Pb, Cr and Cu by micro-drilling ICP-MS (for a concentration that equals 3 times their limit of detection) at, respectively, 0.04, 0.82, 2.7 and 0.4 mg, while the amount sampled by micro-drilling is about 0.06 mg. PMID- 24054556 TI - Removal of malathion from aqueous solution using De-Acidite FF-IP resin and determination by UPLC-MS/MS: equilibrium, kinetics and thermodynamics studies. AB - In the present study, De-Acidite FF-IP resin was used to remove a highly toxic and persistent organophosphorus pesticide (malathion) from the aqueous solution. Batch experiments were performed as a function of various experimental parameters such as effect of pH (2-10), contact time (10-120 min), resin dose (0.05-0.5 g), initial malathion concentration (0.5-2.5 ug mL(-1)) and temperature (25-65 degrees C). The concentration of malathion was determined using a sensitive, selective and rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The uptake rate of malathion on De-Acidite FF IP resin was rapid and equilibrium established within 40 min. Kinetics studies showed better applicability for pseudo-second-order model. The equilibrium data was fitted to Langmuir and Freundlich isotherm models and the isotherm constants were calculated for malathion. The values of thermodynamic parameters (DeltaG(0), DeltaH(0) and DeltaS(0)) were computed from the Van't Hoff plot of lnKC vs. 1/T which showed that the adsorption of malathion was feasible, endothermic and spontaneous. The regeneration studies were carried out which demonstrated a decrease in the recovery of malathion from 95% to 68% after five consecutive cycles. Breakthrough and exhaustive capacities of malathion were found to be 1.25 mg g(-1) and 3.5 mg g(-1), respectively. PMID- 24054557 TI - Biopolymer capped silver nanoparticles as fluorophore for ultrasensitive and selective determination of malathion. AB - This paper describes a novel luminescent sensor for malathion using chitosan capped silver nanoparticles (Chi-AgNPs) as fluorophore. The Chi-AgNPs were synthesized by the wet-chemical method and were characterized by absorption, fluorescence, HR-TEM, XRD and DLS techniques. The Chi-AgNPs show the absorption maximum at 394 nm and emission maximum at 536 nm. While adding 10 uM malathion, yellow color Chi-AgNPs was changed to brown and the absorbance was decreased along with a redshift. The observed spectral and color changes were mainly due to the aggregation of Chi-AgNPs. This was confirmed by zeta potential, DLS and HR TEM studies. No significant absorption spectral change was observed for Chi-AgNPs in the presence of less than micromolar concentrations of malathion. However, the emission intensity of Chi-AgNPs was decreased and the emission maximum was shifted toward higher wavelength in the presence of picomolar concentration of malathion. Based on the decrease in emission intensity, the concentration of malathion was determined. The Stern-Volmer constant, Gibbs free energy change, association constant, quantum yield and binding constant were calculated and the quenching mechanism was proposed. The Chi-AgNPs show good selectivity toward the determination of 10nM malathion in the presence of 1000-fold higher concentrations of common interferents. A good linearity was observed for the emission intensity against 1 * 10(-9)-10 * 10(-12)M malathion and the detection limit was found to be 94 fM L(-1) (S/N=3). The proposed method was successfully applied to determine malathion in fruits and water samples and the obtained results were validated with HPLC. PMID- 24054558 TI - Metal-organic framework-199/graphite oxide hybrid composites coated solid-phase microextraction fibers coupled with gas chromatography for determination of organochlorine pesticides from complicated samples. AB - The hybrid material of a copper-based metal-organic framework (MOF-199) and graphite oxide (GO) was explored as the solid-phase microextraction (SPME) coating for the first time. This fiber was fabricated by using 3-amino propyltriethoxysilane (APTES) as the cross-linking agent, which enhanced its durability and allowed more than 140 replicate extractions. With the incorporation of GO, the MOF-199/GO fibers with GO contents ranging from 5 to 15 wt% exhibited enhanced adsorption affinity to organochlorine pesticides (OCPs) compared to MOF or GO individually. This improvement was linked to the enhanced dispersive forces (increased volume of small pores) that provided by the dense carbon layers of GO. Combining the superior properties of high porosity of MOFs and the unique layered character of GO, the MOF-199/GO (10 wt%) fiber exhibited higher adsorption affinity to some OCPs than commercial polydimethylsiloxane (PDMS) and polydimethylsiloxane/divinylbenzene (PDMS/DVB) fibers. This new fiber was developed for headspace (HS) SPME of eight OCPs followed by GC/ECD analysis. The limits of detection were 2.3-6.9 ng/L. The relative standard deviation (RSD) for five replicate extractions using one fiber ranged from 5.3% to 8.8%. The fiber-to-fiber reproducibility was 5.2-12.8%. This method was successfully used for simultaneous determination of eight OCPs from river water, soil, water convolvulus and longan with satisfactory recoveries of 90.6-104.4%, 82.7-96.8%, 72.2-107.7% and 82.8-94.3%, respectively. These results indicated the MOF-199/GO composite provided a promising alternative in sample pretreatment. PMID- 24054559 TI - Solubility of hot fuel particles from Chernobyl--influencing parameters for individual radiation dose calculations. AB - Nuclear fuel particles of Chernobyl origin are carriers of increased radioactivity (hot particles) and are still present in the atmosphere of the Chernobyl exclusion zone. Workers in the zone may inhale these particles, which makes assessment necessary. The residence time in the lungs and the transfer in the blood of the inhaled radionuclides are crucial for inhalation dose assessment. Therefore, the dissolution of several kinds of nuclear fuel particles from air filters sampled in the Chernobyl exclusion zone was studied. For this purpose filter fragments with hot particles were submersed in simulated lung fluids (SLFs). The activities of the radionuclides (137)Cs, (90)Sr, (239+240)Pu and (241)Am were measured in the SLF and in the residuum of the fragments by radiometric methods after chemical treatment. Soluble fractions as well as dissolution rates of the nuclides were determined. The influence of the genesis of the hot particles, represented by the (137)Cs/(239+240)Pu ratio, on the availability of (137)Cs was demonstrated, whereas the dissolution of (90)Sr, (239+240)Pu and (241)Am proved to be independent of genesis. No difference in the dissolution of (137)Cs and (239+240)Pu was observed for the two applied types of SLF. Increased solubility was found for smaller hot particles. A two-component exponential model was used to describe the dissolution of the nuclides as a function of time. The results were applied for determining individual inhalation dose coefficients for the workers at the Chernobyl construction site. Greater dose coefficients for the respiratory tract and smaller coefficients for the other organs were calculated (compared to ICRP default values). The effective doses were in general lower for the considered radionuclides, for (241)Am even by one order of magnitude. PMID- 24054560 TI - Fast LC-MS/MS analysis of tacrolimus, sirolimus, everolimus and cyclosporin A in dried blood spots and the influence of the hematocrit and immunosuppressant concentration on recovery. AB - We developed a method for the analysis of four immunosuppressants in dried blood spot (DBS) samples to facilitate therapeutic drug monitoring for transplant patients outside the hospital. An 8mm disc from the central part of the DBS was punched, extracted and followed by LC-MS/MS analysis. The method was validated with ranges from 1.00-50.0 ug/L for tacrolimus, sirolimus and everolimus, and from 20.0-2000 ug/L for cyclosporin A. The validation showed a maximum overall bias of 13.0% for the sirolimus LLOQ, while the maximum overall CV was 15.7% for the everolimus LLOQ. All four immunosuppressants showed to be stable in DBS for at least 7 days at 22 degrees C. The volume of the blood spot showed to have minor effect on measured concentrations. A cross-validation test between the 31 ET CHR paper and the Whatman FTA DMPK-C cards showed no significant difference between the two types of paper. During validation the hematocrit (HT) showed to have significant influence on the analytical results. When the measured concentrations were corrected for the effect of the HT, biases improved significantly. Additional recovery tests proved that the combination of especially low HT and high concentration does not only affect the spot size but can also affect the extraction recoveries of sirolimus and especially everolimus. Although the tested parameters like HT and concentrations are extreme and unlikely for routine analysis of outpatients, the fundamental effect of the combination of these parameters on extraction recoveries are proven with this research. The protein binding in the blood and hydrogen binding to the cellulose of the paper is suggested to influence extractions and gives new insights in the extraction methodology of DBS samples. The observed HT effect during the validation appeared to be negligible during the correlation study as no concentration corrections for the HT values were needed. Nevertheless, results from DBS samples with extremely high concentrations combined with extremely low HT values should be interpreted with caution. The patient correlation study showed good correlations with R(2) values higher than 0.87 between venous whole blood and venous DBS samples were observed for all four immunosuppressants. The Passing & Bablok plots showed positive biases of the slopes of 18% for tacrolimus and less than 12% for sirolimus, everolimus and cyclosporin A. The validated method, proved stability of the immunosuppressants in DBS, and the correlation study showed the capability of the DBS method to be used as an alternative for whole blood analysis in therapeutic drug monitoring. PMID- 24054561 TI - Sequential determination of Cd and Cr in biomass samples and their ashes using high-resolution continuum source graphite furnace atomic absorption spectrometry and direct solid sample analysis. AB - High-resolution continuum source graphite furnace atomic absorption spectrometry, because of the use of only one radiation source for all elements, offers the possibility of sequential determination of two or more elements from the same sample aliquot if their volatilities are significantly different. Cd and Cr were determined sequentially in samples of biomass and biomass ashes employing direct solid sample analysis. The use of a chemical modifier was found to be not necessary, and calibration could be carried out using aqueous standard solutions. A pyrolysis temperature of 400 degrees C and an atomization temperature of 1500 degrees C were used for the determination of Cd; no losses of Cr were observed at this temperature. After the atomization of Cd the wavelength was changed and Cr atomized at 2600 degrees C. The limits of detection (LOD) and quantification (LOQ) were 1.1 MUg kg(-1) and 3.7 MUg kg(-1), respectively, for Cd and 21 MUg kg( 1) and 70 MUg kg(-1), respectively, for Cr using the most sensitive line at 357.869 nm, or 90 MUg kg(-1) and 300 MUg kg(-1), respectively, using the less sensitive line at 428.972 nm. The precision, expressed as relative standard deviation was around 10%, which is typical for direct solid sample analysis. The values found for Cd in biomass samples were between <1.1 ug kg(-1) and 789 ug kg( 1), whereas those for Cr were between 7.9 mg kg(-1) and 89 mg kg(-1); the values found in the ashes were significantly lower for Cd, between <1.1 ug kg(-1) and 6.3 ug kg(-1), whereas the trend was not so clear for Cr, where the values were between 3.4 mg kg(-1) and 28 mg kg(-1). PMID- 24054562 TI - A new approach in sample treatment combined with UHPLC-MS/MS for the determination of multiclass mycotoxins in edible nuts and seeds. AB - A sensitive, simple and rapid method for the determination of fourteen mycotoxins in nuts and seeds (including almonds, peanuts, sunflower seeds, pumpkin seeds, walnuts, macadamia nuts, pistachios, hazelnuts and pine nuts) has been developed using ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The sample treatment comprises a first step based on QuEChERS procedure for the determination of fumonisin B1, fumonisin B2, deoxynivalenol, fusarenon-X, T-2 and HT-2 toxin, citrinin, sterigmatocystin, zearalenone and ochratoxin A. A subsequent clean-up step based on the dispersive liquid-liquid microextraction (DLLME) was necessary for the determination of aflatoxins (B1, B2, G1 and G2), since their determination was not possible applying only the QuEChERS-based extraction. The method was validated for peanuts as representative matrix and was subsequently evaluated for the other eight matrices. Quantification limits obtained for aflatoxins, the unique mycotoxins legislated on these matrices, were lower than the maximum levels allowed by the current legislation, while quantification limits obtained for the other mycotoxins were lower than the limits usually permitted by the legislation in other food matrices. Precision of the method was always lower than 11%, and recoveries ranged between 60.7% and 104.3%. PMID- 24054563 TI - Determination of the refractive index of microparticles by utilizing light dispersion properties of the particle and an immersion liquid. AB - The knowledge of the refractive index of a particle is important in sensing and imaging applications, e.g., in biology, medicine and process industry. The refractive index of tiny solid particles such as microsize particles can be determined by the so-called liquid immersion technique. This study deals with three different types of interrogation methods to get the refractive index of a particle in a liquid matrix. These methods utilize thermo-optical properties and wavelength-dependent refractive index of the particle and the immersion liquids, as well as, the classical method using a set of in advance prepared set of immersion liquids with different refractive indices. The emphasis is on a method to get especially the wavelength-dependent refractive index of microparticles and exploiting different wavelength-dependences of immersion liquid and a solid particle because identification of a particle is more reliable if the refractive index of the particle is known at several wavelengths. In this study glycerol water mixtures served as immersion liquids to obtain the refractive index of CaF2 at several discrete wavelengths in the spectral range 200-500 nm. The idea is to find the maximum value of light transmission of suspension by scanning the wavelength of a commercial spectrophotometer. The light dispersion-based method is suggested as a relatively easy, economic and fast method to determine the refractive index of a particle by a spectrophotometer at several wavelengths of light. The accuracy of the detection of the refractive index is suggested to be better than +/- 0.005 refractive index units. PMID- 24054564 TI - A review on the electrochemical biosensors for determination of microRNAs. AB - MicroRNAs (miRNAs) are a family of non-protein-coding, endogenous, small RNAs. They are a group of gene regulators that function mainly by binding the 3' untranslated regions of specific target messenger RNA (mRNA) leading to gene inactivation by repression of mRNA transcription or induction of mRNA. Mature miRNAs are short molecules approximately 22 nucleotides in length. They regulate a wide range of biological functions from cell proliferation and death to cancer progression. Cellular miRNA expression levels can be used as biomarkers for the onset of disease states and in gene therapy for genetic disorders. Methods for detection of miRNA mainly include northern blotting, microarray, polymerase chain reaction (PCR). This review focuses on the use of electrochemical biosensors for the detection of microRNA. PMID- 24054565 TI - Development and validation of a general approach to predict and quantify the synergism of anti-cancer drugs using experimental design and artificial neural networks. AB - The combination of two or more drugs using multidrug mixtures is a trend in the treatment of cancer. The goal is to search for a synergistic effect and thereby reduce the required dose and inhibit the development of resistance. An advanced model-free approach for data exploration and analysis, based on artificial neural networks (ANN) and experimental design is proposed to predict and quantify the synergism of drugs. The proposed method non-linearly correlates the concentrations of drugs with the cytotoxicity of the mixture, providing the possibility of choosing the optimal drug combination that gives the maximum synergism. The use of ANN allows for the prediction of the cytotoxicity of each combination of drugs in the chosen concentration interval. The method was validated by preparing and experimentally testing the combinations with the predicted highest synergistic effect. In all cases, the data predicted by the network were experimentally confirmed. The method was applied to several binary mixtures of cisplatin and [Cu(1,10-orthophenanthroline)2(H2O)](ClO4)2, Cu(1,10 orthophenanthroline)(H2O)2(ClO4)2 or [Cu(1,10-orthophenanthroline)2(imidazolidine 2-thione)](ClO4)2. The cytotoxicity of the two drugs, alone and in combination, was determined against human acute T-lymphoblastic leukemia cells (CCRF-CEM). For all systems, a synergistic effect was found for selected combinations. PMID- 24054566 TI - Development and application of methods for the determination of silver in polymeric dressings used for the care of burns. AB - Open vessel and microwave digestion methods have been developed for the determination of total silver in six commercial dressing used for the treatment of skin burns. An extraction method using TMAH has also been developed to determine the amount of silver present in the exudates found on the surface after dressing removal so an estimation of the patient dose can be made. All microwave methods had a quantitative recovery, whereas the open vessel had recoveries that ranged from 80 to 100%. The silver concentrations were determined by inductively coupled plasma mass spectrometry using an external calibration. In the absence of suitable reference materials, isotope dilution analysis was applied to validate the accuracy of results obtained by external calibration. All the products had a total Ag content that agreed with the values declared by the producer, which ranged from 10 to 0.2% Ag by weight. One of the methods was applied to the indirect determination of Ag released in vivo by ActicoatTM Flex 3, a dressing composed of silver nanoparticles on a polymer net. Silver levels were determined in used dressings after application to patients with partial thickness skin burns. A maximum of 62% of the silver was found to have been released onto the patient where hemopurulent exudate occurred, indicating that the dressing was virtually exhausted after 3 days of use. We conclude that the Ag released into the patient's tissues is closely correlated with the local severity of the wound. PMID- 24054567 TI - Ion suppression; a critical review on causes, evaluation, prevention and applications. AB - The consequences of matrix effects in mass spectrometry analysis are a major issue of concern to analytical chemists. The identification of any ion suppressing (or enhancing) agents caused by sample matrix, solvent or LC-MS system components should be quantified and measures should be taken to eliminate or reduce the problem. Taking account of ion suppression should form part of the optimisation and validation of any quantitative LC-MS method. For example the US Food and Drug Administration has included the evaluation of matrix effects in its "Guidance for Industry on Bioanalytical Method Validation" (F.D.A. Department of Health and Human Services, Guidance for industry on bioanalytical method validation, Fed. Regist. 66 (100) 2001). If ion suppression is not assessed and corrected in an analytical method, the sensitivity of the LC-MS method can be seriously undermined, and it is possible that the target analyte may be undetected even when using very sensitive instrumentation. Sample analysis may be further complicated in cases where there are large sample-to-sample matrix variations (e.g. blood samples from different people can sometimes vary in certain matrix components, shellfish tissue samples sourced from different regions where different phytoplankton food sources are present, etc) and therefore exhibit varying ion-suppression effects. Although it is widely agreed that there is no generic method to overcome ion suppression, the purpose of this review is to: provide an overview of how ion suppression occurs, outline the methodologies used to assess and quantify the impact of ion suppression, discuss the various corrective actions that have been used to eliminate ion suppression in sample analysis, that is to say the deployment of techniques that eliminate or reduce the components in the sample matrix that cause ion suppression. This review article aims to collect together the latest information on the causes of ion suppression in LC-MS analysis and to consider the efficacy of common approaches to eliminate or reduce the problem using relevant examples published in the literature. PMID- 24054568 TI - Detection of digoxin in urine samples by surface-assisted laser desorption/ionization mass spectrometry with dispersive liquid-liquid microextraction. AB - A novel method for the detection of digoxin using dispersive liquid-liquid microextraction (DLLME) coupled to the surface-assisted laser desorption/ionization mass spectrometric detection (SALDI/MS) was developed. Acetone and chloroform were used as the disperser solvent and extraction solvents, respectively. After the extraction, digoxin was detected using SALDI/MS with colloidal palladium as the matrix. Under optimal extraction and detection conditions, the calibration curve, which ranged from 0.01 to 0.50 MUM, was observed to be linear. The limit of detection (LOD) at a signal-to-noise ratio of 3 was 2 nM for digoxin. With a sample-to-extract volume ratio of 400, the enrichment factor for digoxin was calculated to be 252. This novel method was successfully applied for the determination of digoxin in human urine samples. PMID- 24054569 TI - A novel amide stationary phase for hydrophilic interaction liquid chromatography and ion chromatography. AB - A novel amide stationary phase (ASP) for hydrophilic interaction liquid chromatography (HILIC) has been prepared via the Click chemistry method. It was based on the strategy that the amino group of Asparagine was easily transferred to the corresponding azido group and then clicked onto terminal alkyne-silica gel in the presence of Cu(I)-based catalyst. For the tested polar compounds including nucleosides and nucleic acid bases, ASP-based column has demonstrated good performance in terms of separation efficiency and column stability, and the retention mechanism was found to match well the typical HILIC retention. In addition, the ASP described here showed much better selectivity in separation of inorganic anions under ion chromatography mode relative to other kinds of commercial ASP. PMID- 24054570 TI - Colorimetric and electrochemical genosensors for the detection of Escherichia coli DNA without amplification in seawater. AB - Monitoring seawater, particularly recreational water, for indicator bacteria presence is required to protect the public from exposure to fecal pollution and to guarantee the safety of the swimming areas. Two methods for the detection and quantification of Escherichia coli DNA were developed: a colorimetric assay in a microplate and an electrochemical biosensor. These assays were based on the double hybridization recognition of a single-strand DNA capture probe immobilized onto the microplate or the screen-printed carbon electrode to its complementary ssDNA, which is hybridized with an ssDNA signal probe labeled with horseradish peroxidase enzyme. The hybridization recognition step used the colorimetric monitoring of the oxidation state of the 3,3',5,5'-tetramethylbenzidine. The electrochemical monitoring of the oxidation state of 5 methyl-phenazinium methyl sulfate was allowed when the horseradish-peroxidase was in the presence of the mediator (5 methyl-phenazinium methyl sulfate and hydrogen peroxide). These approaches allow for the detection and quantification of 10(2) to 10(3) cells of E. coli in 5l of seawater samples in less than 5h. Detection was achieved without a nucleic acid amplification step. The specificity of the two methods against E. coli was demonstrated by testing a panel of bacteria. The two methods can be used for on-site monitoring of seawater quality. PMID- 24054571 TI - Using the iPhone as a device for a rapid quantitative analysis of trinitrotoluene in soil. AB - Mobile 'smart' phones have become almost ubiquitous in society and are typically equipped with a high-resolution digital camera which can be used to produce an image very conveniently. In this study, the built-in digital camera of a smart phone (iPhone) was used to capture the results from a rapid quantitative colorimetric test for trinitrotoluene (TNT) in soil. The results were compared to those from a digital single-lens reflex (DSLR) camera. The colored product from the selective test for TNT was quantified using an innovative application of photography where the relationships between the Red Green Blue (RGB) values and the concentrations of colorimetric product were exploited. The iPhone showed itself to be capable of being used more conveniently than the DSLR while providing similar analytical results with increased sensitivity. The wide linear range and low detection limits achieved were comparable with those from spectrophotometric quantification methods. Low relative errors in the range of 0.4 to 6.3% were achieved in the analysis of control samples and 0.4-6.2% for spiked soil extracts with good precision (2.09-7.43% RSD) for the analysis over 4 days. The results demonstrate that the iPhone provides the potential to be used as an ideal novel platform for the development of a rapid on site semi quantitative field test for the analysis of explosives. PMID- 24054572 TI - Validation of one-step cleanup and separation method of polychlorinated biphenyls, organochlorine pesticides, and polycyclic aromatic hydrocarbons from atmospheric gas- and particle-phase samples. AB - A one-step cleanup method is described for the determination of PAHs, PCBs and OCPs in air (gas and particulate phase) samples. Analytes were extracted from ambient air samples using soxhlet extraction with a solvent mixture of dichloromethane and petroleum ether (1:4) for 24h. They were concentrated, separated and fractionated on a florisil and alumina column. The amounts of florisil (1g or 2g) with/without alumina were tested in the cleanup column. The study systematically investigated the effects of solvent types, and the amounts of florisil and alumina, on the performance of the cleanup process. The first fraction was eluted with 25 mL hexane, and analyzed for PCBs. The second fraction was collected via 40 mL hexane-ethyl acetate (1:1) solvent mixture, and analyzed for OCPs and PAHs. The optimized method yielded average recoveries between 88% and 99% for PCBs; 56% and 118% for PAHs; and 51% and 128% for OCPs. Other validation parameters were also investigated, such as MDL, LOQ, linear range, sensitivity (r(2)). An oven-program optimization and adjustment of GC-MS were performed. For internal quality control, surrogate recoveries and field blanks values were calculated. External calibration curves were prepared for PAHs, and internal calibration curves were preferred for OCP and PCBs. PMID- 24054573 TI - An aptamer-based bio-barcode assay with isothermal recombinase polymerase amplification for cytochrome-c detection and anti-cancer drug screening. AB - Based on a recently reported ultra-sensitive bio-barcode (BBC) assay, we have developed an aptamer-based bio-barcode (ABC) alternative to detect a cell death marker cytochrome-c (Cyto-c) and its subsequent application to screen anti-cancer drugs. Aptamer is a short single-stranded DNA selected from a synthetic DNA library by virtue of its high binding affinity and specificity to its target based on its unique 3D structure from the nucleotide sequence after folding. In the BBC assay, an antigen (Ag) in analytes is captured by a micro-magnetic particle (MMP) coated with capturing antibodies (Abs). Gold nanoparticles (NPs) with another recognition Ab against the same target and hundreds of identical DNA molecules of known sequence are subsequently added to allow the formation of sandwich structures ([MMP-Ab1]-Ag-[Ab2-NP-DNA]). After isolating the sandwiches by a magnetic field, the DNAs hybridized to their complementary DNAs covalently bound on the NPs are released from the sandwiches after heating. Acting as an Ag identification tag, these bio-barcode DNAs with known DNA sequence are then amplified by polymerase chain reaction (PCR) and detected by fluorescence. In our ABC assay, we employed a Cyto-c-specific aptamer to substitute both the recognition Ab and barcode DNAs on the NPs in the BBC assay; and a novel isothermal recombinase polymerase amplification for the time-consuming PCR. The detection limit of our ABC assay for the Cyto-c was found to be 10 ng/mL and this new assay can be completed within 3h. Several potential anti-cancer drugs have been tested in vitro for their efficacy to kill liver cancer with or without multi-drug resistance. PMID- 24054574 TI - Ultrasound-assisted dispersive liquid-liquid microextraction for the speciation of traces of chromium using electrothermal atomic absorption spectrometry. AB - A microextraction procedure for the speciation of very low concentrations (0.005 0.2 ug L(-1)) of chromium is discussed. To the aqueous sample (10 mL), diluted hydrochloric acid, sodium chloride and a small amount of tributylphosphate (80 uL) are incorporated, and the mixture is submitted to ultrasounds for 10 min. The organic phase recovered after centrifuging is injected into the electrothermal atomizer, and the signal due to hexavalent chromium obtained. The repetition of the procedure using another aliquot in which all the chromium present is oxidized to Cr (VI) allows the Cr(III) content to be obtained by difference. The enrichment factor is 240 and the detection limit 0.002 ug L(-1) chromium. The relative standard deviation for ten consecutive microextractions of a 0.1 ug L( 1) chromium solution is close to 8%. The procedure is applied to waters and to the leachates obtained from low cost toys made of plastic materials. PMID- 24054575 TI - Sensitive determination of paraquat by square wave anodic stripping voltammetry with chitin modified carbon paste electrode. AB - A novel analytical approach has been developed and evaluated for the quantitative analysis of paraquat herbicides which can be found at trace levels in olive oil and olives. The aim of this work is to optimize all factors that can influence this determination by a carbon paste electrode modified with chitin (Chit-CPE). The best responses were obtained with square wave potential in diluted Na2SO4 as supporting electrolyte. The influence of various parameters on the Chit-CPE was investigated. Under the optimized working conditions, calibration graphs were linear in the concentration ranges of 5.0 * 10(-9)-1.0 * 0(-5) mol L(-1). For 180 s preconcentration, detection limits of 2.67 * 10(-10) mol L(-1) (peak 2) was obtained at the signal noise ratio (SNR) of 3. To evaluate the reproducibility of the newly developed electrode, the measurements of 1.0 * 10(-5) mol L(-1) PQ were carried out for seven times at Chit-CPE and the relative standard deviation was 5.2%. The analytical methodology was successfully applied to monitor the paraquat content in olives and olive oil. PMID- 24054576 TI - In situ metathesis ionic liquid formation dispersive liquid-liquid microextraction for copper determination in water samples by electrothermal atomic absorption spectrometry. AB - In situ synthesis of ionic liquid extractant for dispersive liquid-liquid microextraction (in situ IL DLLME) combined with electrothermal atomic absorption spectrometry (ET AAS) for determination of copper in water samples was developed. Analytical signals were obtained without the back-extraction of copper from the IL phase prior to its determination by AAS. Some essential parameters of the microextraction and detection techniques such as the pH of sample solution, volume of components for in situ synthesis, matrix interferences and main parameters of graphite furnace atomizer have been studied. Under optimal conditions, high extraction efficiency for copper was achieved for the extraction of 0.7 ug L(-1) in 10.0 mL of sample solution employing 8 MUL of 1-hexyl-3 methylimidazolium bis[(trifluoromethyl)sulfonyl]imide (HmimNTf2) as the extraction solvent. The detection limit was found as 0.004 ug L(-1) with an enrichment factor of 200. The relative standard deviation (RSD) for seven replicate measurements of 0.7 ug L(-1) in sample solution was 4%. The accuracy of the proposed method was evaluated by analysis of the Certified Reference Materials: NIST SRM 2709 (San Joaquin Soil), NBS SRM 2704 (Buffalo River Sediment), NRCC DOLT-2 (Dogfish Liver) and NIST SRM 1643e (Trace Element in Water). The measured copper contents in the reference materials were in satisfactory agreement with the certified values. The method was successfully applied to analysis of the tap, lake and mineral water samples. PMID- 24054577 TI - Method of low tantalum amounts determination in niobium and its compounds by ICP OES technique. AB - A method of determination of low amounts of tantalum in niobium and niobium compounds without its prior separation by means of inductively coupled plasma optical emission spectrometry (ICP-OES) has been worked out. The method involves dissolution of the analyzed samples of niobium as well as its various compounds (oxides, fluorides, chlorides, niobates(V)) in fluoride environments, precipitation of sparingly soluble niobic(tantalic) acid (Nb2O5(Ta2O5) . xH2O), converting them into soluble complex compounds by means of oxalic acid with addition of hydrogen peroxide and finally analyzing directly obtained solutions by ICP-OES. This method permits determination of Ta in niobium at the level of 10(-3)% with relatively good precision (<= 8% RSD) and accuracy (recovery factor: 0.9-1.1). Relative differences in the results obtained by two independent methods (ICP-OES and ICP-MS) do not exceed 14%, and other elements present in niobium compounds (Ti, W, Zr, Hf, V, Mo, Fe, Cr) at the level of 10(-2)% do not affect determination. PMID- 24054578 TI - A new fluorescence "off-on" chemodosimeter for L-cysteine based on water-soluble polythiophene. AB - A novel water-soluble cationic conjugated polymer, denoted as poly 2,5-[3-(1,1 dimethyl-4-piperidine methylene)thiophene] chloride(PDPMT-Cl was a novel fluorescent material. Fluorescence can be quenched by [AuCl4](-) effectively. On addition of l-cysteine (l-Cys) in [AuCl4](-)-PDPMT-Cl, fluorescence recovered. A new method to detect l-Cys was established successfully by designing a fluorescent "off-on" probe. The method showed good sensitivity and selectivity. Under optimized condition, the fluorescence intensity was linear to l-Cys concentration varying from 1.0 * 10(-8)M to 6.0 * 10(-5)M (gamma=0.9982). The detection limit (3sigma) was 1.39 * 10(-10)M. The method was successfully used for the determination of l-Cys in human serum and compound amino acid injection. PMID- 24054579 TI - A calibration strategy in bioimaging trace elements in rat brain tissue by LA ICP TOF-MS method. AB - A calibration step in an analytical procedure is often not adequately treated, although it is a very important step in the analysis. Also, the approach to the nomenclature seems to be disrespectful. In order to resolve this problem we chose a new classification based on both how the calibration dependence is reconstructed, and how the measurement data is then transformed. In this paper we discussed the steps of a developed calibration procedure in the determination of trace elements in rat brain tissues by the Laser Ablation Inductively Coupled Plasma Time of Flight Mass Spectrometry (LA ICP-TOF-MS) method. The developed calibration procedure uses the long established calibration method - the method of standard addition - although the standard samples are in this case the rat brain tissue samples. The results show the usefulness of the procedure developed in the presented analytical problem related to the analysis of solid samples, which is where the work is original. PMID- 24054580 TI - Development of conductometric biosensor array for simultaneous determination of maltose, lactose, sucrose and glucose. AB - The aim of this work was to develop an array of biosensors for simultaneous determination of four carbohydrates in solution. Several enzyme systems selective to lactose, maltose, sucrose and glucose were immobilised on the surface of four conductometric transducers and served as bio-recognition elements of the biosensor array. Direct enzyme analysis carried out by the developed biosensors was highly sensitive to the corresponding substrates. The analysis lasted 2 min. The dynamic range of substrate determination extended from 0.001 mM to 1.0-3.0mM, and strongly depended on the enzyme system used. An effect of the solution pH, ionic strength and buffer capacity on the biosensors responses was investigated; the conditions of simultaneous operation of all biosensors were optimised. The data on cross-impact of the substrates of all biosensors were obtained; the biosensor selectivity towards possible interfering carbohydrates was tested. The developed biosensor array showed good signal reproducibility and storage stability. The biosensor array is suited for simultaneous, quick, simple, and selective determination of maltose, lactose, sucrose and glucose. PMID- 24054581 TI - Electrospun cellulose acetate nanofibers as thin layer chromatographic media for eco-friendly screening of steroids adulterated in traditional medicine and nutraceutical products. AB - Nanofibers fabricated from cheap, naturally derived biopolymer, namely cellulose acetate via facile electrospinning technique were successfully applied for the first time to use as separation media for thin layer chromatography (TLC). From the optimization studies, uniform, bead-free nanofibers with good adherence to the backing plates were obtained by electrospinning 17% (w/v) cellulose acetate solution prepared in acetone/N,N-dimethylacetamide (2:1, v-v), using a feed rate of 0.6 mL/h and an electrostatic field strength of 17.5 kV/15 cm for 4h. The nanofibers exhibited reversed phase characteristics, thereby offering the possibility to use simple, polar and more environmental friendly mixtures of water and alcohols as mobile phase. In this work, the application of the fabricated fibers was illustrated by using them combined with the optimal mobile phase e.g. ethanol/water (40:60, v-v) for the screening of steroids adulterated in traditional medicine and nutraceutical products. Due to the satisfactory separation performance, electrospun cellulose acetate nanofibers were shown to be an efficient alternative for TLC media and could be potentially used for the development of green and facile analytical methods. PMID- 24054582 TI - Gold nanoparticle-modified graphite pencil electrode for the high-sensitivity detection of hydrazine. AB - A novel gold nanoparticle-modified graphite pencil electrode (AuNP-GPE) is prepared just by immersing a bare GPE in AuNP solution, followed by heating for 15 min. The bare and modified GPEs are characterized by FE-SEM imaging and cyclic voltammetry. The AuNP-GPEs showed excellent electrocatalytic activities with respect to hydrazine oxidation, with good reproducibility. To reduce the quantification and detection limits, and increase the hydrazine sensitivity, the pH and square wave voltammetry parameters are optimized. A square wave voltammetry study as a function of the hydrazine concentration showed that the AuNP-GPE detector's quantification limit was 100 nmol L(-1) hydrazine, much lower than the value obtained using amperometry (10 umol L(-1)). The limits of detection (at 3sigma) for hydrazine sensing at AuNP-GPEs using square wave voltammetry and amperometry were 42 nmol L(-1) and 3.07 umol L(-1). Finally, the modified electrode was used to determine the hydrazine concentration in drinking water, and satisfactory results are obtained. This simple, rapid, low-cost method for fabricating a modified electrode is an attractive approach to the development of new sensors. PMID- 24054583 TI - Molecularly imprinted electrochemical sensor based on amine group modified graphene covalently linked electrode for 4-nonylphenol detection. AB - In this work, an imprinted electrochemical sensor based on electrochemical reduced graphene covalently modified carbon electrode was developed for the determination of 4-nonylphenol (NP). An amine-terminated functional graphene oxide was covalently modified onto the electrode surface with diazonium salt reactions to improve the stability and reproducibility of the imprinted sensor. The electrochemical properties of each modified electrodes were investigated with differential pulse voltammetry (DPV). The electrochemical characteristic of the imprinted sensor was also investigated using electrochemical impedance spectroscopy (EIS) in detail. The response currents of the imprinted electrode exhibited a linear relationship toward 4-nonylphenol concentration ranging from 1.0 * 10(-11) to 1.0 * 10(-8) gm L(-1) with the detection limit of 3.5 * 10(-12) gm L(-1) (S/N=3). The fabricated electrochemical imprinted sensor was successfully applied to the detection of 4-nonylphenol in rain and lake water samples. PMID- 24054584 TI - Direct electrochemistry of hemoglobin immobilized on the water-soluble phosphonate functionalized multi-walled carbon nanotubes and its application to nitric oxide biosensing. AB - The direct electron transfer and electrocatalysis of hemoglobin (Hb) immobilized on the phosphonate functionalized multi-walled carbon nanotubes (MWCNTs) are investigated. Fourier transform infrared (FT-IR) spectra, UV-vis spectra and cyclic voltammetry (CV) analyses reveal that the phosphonate functionalized MWCNTs have good biocompatibility for Hb immobilization, and promote the electron communication between Hb and electrode. The immobilized Hb shows a pair of redox peak with a formal potential of -406 +/- 10 mV (vs. SCE) and the electrochemical behavior of Hb was a surface-controlled process in a pH 7.0 phosphate buffer solution. And the immobilized Hb can act in an electrocatalytic manner in the electrochemical reduction of nitric oxide (NO). Accordingly, an unmediated NO electrochemical biosensor is constructed. Under optimized experimental conditions, the NO electrochemical biosensor shows the fast response (less than 3s), the wide linear range (1.5 * 10(-7) to 2.7 * 10(-4)M) and the low detection limit (1.5 * 10(-8)M), which is attributed to the good mass transport, the large Hb loading per unit area and the fast electron transfer rate of Hb. PMID- 24054585 TI - Using nanostructured conductive carbon tape modified with bismuth as the disposable working electrode for stripping analysis in paper-based analytical devices. AB - Low cost disposable working electrodes are specifically desired for practical applications of electrochemical detection considering maturity of electrochemical stations and data collection protocols. In this paper double-sided conductive adhesive carbon tape with nanostructure was applied to fabricate disposable working electrodes. Being supported by indium tin oxide glass, the prepared carbon tape electrodes were coated with bismuth film for stripping analysis of heavy metal ions. By integrating the bismuth modified electrodes with paper-based analytical devices, we were able to differentiate Zn, Cd and Pb ions with the sample volume of around 15 MUL. After the optimization of parameters, including modification of bismuth film and the area of the electrodes, etc., Pb ions could be measured in the linear range from 10 to 500 MUg/L with the detection limit of 2 MUg/L. Our experimental results revealed that the disposable modified electrodes could be used to quantify migrated lead from toys with the results agreed well with that using atomic absorption spectrometry. Although bismuth modification and stripping analysis could be influenced by the low conductivity of the carbon tape, the low cost disposable carbon tape electrodes take the advantages of large-scaled produced double-sided carbon tape, including its reproducible nanostructure and scaled-up fabrication process. In addition, the preparation of disposable electrodes avoids time-consuming pretreatment and experienced operation. This study implied that the carbon tape might be an alternative candidate for practical applications of electrochemical detection. PMID- 24054586 TI - Fast, facile and ethidium bromide-free assay based on the use of adsorption indicator for the estimation of polyethylenimine to nucleic acid ratio of complete polyplex assembly for gene delivery. AB - A new method was developed for the estimation of polyethylenimine (PEI) to nucleic acid ratio at which the polyplex was completely formed. The assay relied on the attraction of dichlorofluoresceinate dye to adsorb on self-assembling particles as counterions, as induced by the surface charge of the polyplex which became positive once PEI associated equivalently with nucleic acid. This phenomenon resulted in the appearance of pink colored pellets of the polyplex after centrifugation. By the other means, sodium hydroxide solution might be added to free the adsorbed dye into the solution, producing conspicuous green fluorescence under UV light (366 nm). The assay was well applied to the polyplex formulations of PEI and plasmid DNA or siRNA with satisfactory detectability and gave the results in agreement with those from gel retardation method and zeta potential analysis. Importantly, the proposed method required no sophisticated instruments, time-consuming gel electrophoresis, carcinogenic ethidium bromide as well as costly dyes and the analysis could be accomplished within less than 10 min. Hence, it was a fast, facile, cost-effective and safe-for-operator alternative method, suited for the investigation of the optimal PEI to nucleic acid ratio for gene delivery. PMID- 24054587 TI - Optimization of pressurized liquid extraction (PLE) for rapid determination of mineral oil saturated (MOSH) and aromatic hydrocarbons (MOAH) in cardboard and paper intended for food contact. AB - Packaging can represent a primary source of food contamination with mineral oil saturated hydrocarbons (MOSH) and aromatic hydrocarbons (MOAH), especially when recycled cardboard or mineral oil based printing inks are used. A pressurized liquid extraction (PLE) method, followed by on-line LC-GC analysis, has been optimized for rapid mineral oil determination in cardboard and paper samples. The proposed method involves extraction with hexane (2 cycles) at 60 degrees C for 5 min, and allows for the processing of up to 6 samples in parallel with minimal sample manipulation and solvent consumption. It gave good repeatability (coefficient of variation lower than 5%) and practically quantitative extraction yield (less than 2% of the total contamination found in a third separate cycle). The method was applied to different cardboards and paper materials intended for food contact. Results obtained were similar to those obtained by applying classical solvent extraction with hexane/ethanol 1:1 (v/v) as described by Lorenzini et al. [20]. PMID- 24054588 TI - A reversible competition colorimetric assay for the detection of biothiols based on ruthenium-containing complex. AB - A novel reversible colorimetric sensor, which based on a competitive ligation of Hg(2+) by thiols, cysteine (Cys) or glutathione (GSH), and thiocyanate (SCN) on the N3 dye (bis(4,4'-dicarboxy-2,2'-bipyridine) dithiocyanato ruthenium (II)), was developed for the detection of biothiols. First, Hg(2+) ions coordinate to the sulfur atom of the dyes' SCN groups, and this interaction induces a change in color from red to yellow, owing to the formation of a complex of Hg(2+)-N3. Then, in the presence of biothiols, the red color of N3 is recovered concomitantly with the dissociation of the Hg(2+)-N3 complex, due to the extraction of Hg(2+) by biothiols. Thus the corresponding color variation in the process of the dissociation of the Hg(2+)-N3 complex can be employed for the quantitative detection of thiols using UV-vis spectroscopy. In particular, the transformation can be readily viewed with the naked eye. A good linear relationship between the change in absorbance (DeltaAbs) of Hg(2+)-N3 at 461 nm and the thiol concentration was obtained in the range of 0.5-25 MUM, and the detection limits are then calculated to be 57 and 52 nM for Cys and GSH, respectively. The proposed colorimetric assay displays a high selectivity for Cys over various other amino acids and GSSG (oxidized glutathione). PMID- 24054589 TI - Micro coulometric titration in a liquid drop. AB - Miniaturized coulometric titration in a liquid drop has been investigated. Assays of ascorbic acid and thiosulfate with iodine titration were chosen as models. Constant volumes of falling liquid drops containing sample or reagent are manipulated via gravimetrical force to move along a slope hydrophobic path and directed to stop or to move out from an electrode. Such manipulation is useful for delivery of sample and reagents, in a way of flow without tubing. Electrochemical generation of titrant, in this case, iodine, is started at the electrode and micro coulometric titration can be performed in a drop by applying constant current. Timing in the titration can be made via naked eye with a stopwatch or via recording with a webcam camera connecting to a computer to detect the change due to the blue color complex of the excess iodine and starch. PMID- 24054590 TI - Evaluation of direct analysis in real time ionization-mass spectrometry (DART-MS) in fish metabolomics aimed to assess the response to dietary supplementation. AB - Ambient mass spectrometry employing a direct analysis in real time (DART) ion source coupled to a medium high-resolution/accurate mass time-of-flight mass spectrometer (TOFMS) was used as a rapid tool for metabolomic fingerprinting to study the effects of supplemental feeding with cereals (triticale) on the composition of muscle metabolites of common carp (Cyprinus carpio L.). First, the sample extraction and DART-TOFMS instrumental conditions were optimized to obtain the broadest possible representation of ionizable compounds occurring in the extracts obtained from common carp muscle. To this end, a simultaneous (all-in one) extraction procedure was developed employing water and cyclohexane mixture as the extraction solvents. Under these conditions both polar as well as non polar metabolites were isolated within a single extraction step. Next, the metabolomic fingerprints (mass spectra) of a large set of common carp muscle extracts were acquired. Finally, the experimental data were statistically evaluated using principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Using this approach, differentiation of common carp muscle in response to dietary supplementation (feeding with and without cereals) was feasible. Correct classification was obtained based on the assessment of polar and as well as non-polar extracts fingerprints. The current study showed that DART-TOFMS metabolomic fingerprinting represents a rapid and powerful analytical strategy enabling differentiation of common carp muscles according to feeding history by recording metabolomic fingerprints of ionizable components under the conditions of ambient MS. PMID- 24054591 TI - A novel europium-sensitive fluorescent nano-chemosensor based on new functionalized magnetic core-shell Fe3O4@SiO2 nanoparticles. AB - A novel Eu(3+)-sensitive fluorescent chemosensor is introduced. It is based on magnetic core-shell silica nanoparticle which is functionalized by Cinchonidine (CD-Fe3O4@SiO2). The nano-chemosensor was synthesized and characterized by Fourier transform infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA), transmission electron microscopy (TEM), scanning electron microscopy (SEM), UV-visible absorption and fluorescence emission. The fluorescent nano chemosensor shows a selective interaction with Eu(3+) ion. Fluorescence studies revealed that the emission intensity of the functionalized magnetic core-shell silica nanoparticles (CD-Fe3O4@SiO2 NPs) increases significantly by addition of various concentrations of Eu(3+) ion. While in case of mono, di, and other trivalent cations, weak changes or either no changes in intensity were observed. The enhancement in fluorescence intensity of nano-chemosensor is because of the strong covalent binding of Eu(3+) ion to CD-Fe3O4@SiO2 NPs with a large binding constant value of 1.7 * 10(5) mol L(-1). PMID- 24054592 TI - Mitochondria proteome profiling: a comparative analysis between gel- and gel-free approaches. AB - Mitochondrial proteomics emerged aiming to disclose the dynamics of mitochondria under various pathophysiological conditions. In the present study we investigated the relative merits of gel-based (2DE and SDS-LC) and gel-free (2D-LC) protein separation approaches and protein identification algorithms (Mascot and Paragon) in the proteome profiling of mitochondria isolated from cultured fibroblasts, a sample traditionally used for diagnosis purposes. Combining data retrieved from 2DE, 2D-LC and SDS-LC and search methods, a total of 696 non-redundant proteins were identified. An overlap of only 19% between the proteins identified by the three different methods was observed when Mascot and Paragon were used. Regarding protein ID, a consistency in the number of identified proteins per sample was noticed for 2DE approach. Independent of the methodological approach chosen, it was noticed that the predominance in mitochondria of hydrophilic proteins with 20 50 kDa and pI 5-6 and 8-9; however, 2D-LC and SDS-LC allowed the enrichment of proteins with a mass below 30 kDa and of basic proteins with pI values above 8. In conclusion, data from the present study highlight the power of integrating different separation technologies and protein identification algorithms. PMID- 24054593 TI - Effects of the operation parameters on HILIC separation of flavonoids on zwitterionic column. AB - The hydrophilic interaction chromatography (HILIC) coupled to mass spectrometry was employed to study retention behavior of several flavonoids from their different groups using the polymeric zwitterionic stationary phase (ZIC-pHILIC). It contains sulfobetaine-bonded ligand with an inner positively charged quaternary ammonium and an outer negatively charged sulfonate functional groups. Two organic solvents - acetonitrile (ACN) and methanol (MeOH) - were compared as a component of mobile phase. Separation parameters such as a content of organic modifier, pH of an eluent and a column temperature were studied. Retention of flavonoids is controlled primarily by a partition between the mobile phase eluent and a water-enriched layer on the hydrophilic stationary phase with some contribution from hydrogen bonding formation. Using MeOH, in contrast to ACN, strongly retained compounds (myricetin, morin, rutin and quercetrin) could be eluted under isocratic conditions. A better sensitivity was achieved with MeOH as mobile phase component, particularly for quercetin, naringenin and kaempferol. The method was applied to the determination of flavonoids in fruit juices. PMID- 24054594 TI - Sample preparation for arsenic speciation in terrestrial plants--a review. AB - Arsenic is an element widely present in nature. Additionally, it may be found as different species in several matrices and therefore it is one of the target elements in chemical speciation. Although the number of studies in terrestrial plants is low, compared to matrices such as fish or urine, this number is raising due to the fact that this type of matrix are closely related to the human food chain. In speciation analysis, sample preparation is a critical step and several extraction procedures present drawbacks. In this review, papers dealing with extraction procedures, analytical methods, and studies of species conservation in plants cultivated in terrestrial environment are critically discussed. Analytical procedures based on extractions using water or diluted acid solutions associated with HPLC-ICP-MS are good alternatives, owing to their versatility and sensitivity, even though less expensive strategies are shown as feasible choices. PMID- 24054595 TI - Pressurised liquid extraction of volatile compounds in coffee bean. AB - In this work, we reported a novel application of pressurised liquid extraction (PLE) on coffee bean. The condition of PLE was carefully optimised with the aid of response surface methodology (RSM) including adjustment of experimental parameters (solvent type and sample to hydromatrix ratio) and other operating parameters (i.e. temperature (50-100 degrees C), pressure (1000-2000 psi) and static extraction time (5-15 min)). The coffee extracts obtained under three different extraction conditions were evaluated through descriptive sensory analysis. Then, the results showed that those targeted compounds obtained from PLE were nearly three times higher (1473 ppm) than conventional solvent extraction (571 ppm). Thus, PLE demonstrated the feasibility of producing a series of coffee extracts under controllable extraction conditions in correlation with desirable sensory attributes. This approach has not previously reported to characterise the aroma of coffee bean. PMID- 24054596 TI - Application of electro-enhanced solid-phase microextraction for determination of phthalate esters and bisphenol A in blood and seawater samples. AB - The electro-enhanced solid-phase microextraction (EE-SPME) method was developed for the determination of endocrine disruptor compounds such as phthalate esters and bisphenol A in human blood and seawater samples. After EE-SPME, samples were analyzed by gas chromatography-mass spectrometry (GC-MS). In this approach, commercial SPME fiber was used in direct-immersion mode with an applied potential to extract di-ethyl phthalate, di-butyl phthalate, benzyl butyl phthalate and bisphenol A. The applied potential facilitates and enhances the extraction efficiency of the target analytes. Various experimental conditions influencing performance of the EE-SPME such as extraction time, applied potential and ionic strength were optimized. Under the optimum conditions, EE-SPME was more efficient than a conventional SPME approach. Very good linearity was observed for all analytes in a range between 1 and 100 ug L(-1) with correlation of determination (R(2)) between 0.963 and 0.996. The limits of a detection based signal-to-noise of 3 were from 0.004 to 0.15 ug L(-1). The reproducibility of EE-SPME was evaluated and the relative standard deviations were between 1.0% and 5.0% (n=9). The proposed method was applied to human blood samples stored in transfusion bags and seawater. Results showed that the proposed EE-SPME was simple and suitable for trace level analysis. PMID- 24054597 TI - Green method based on a flow-batch analyzer system for the simultaneous determination of ciprofloxacin and dexamethasone in pharmaceuticals using a chemometric approach. AB - A green FBA method with UV detection was developed for simultaneous determination of ciprofloxacin (CIP) and dexamethasone (DEX) in ophthalmic and otic preparations. A lab-made mixing detection chamber (MDC) was designed and coupled to the spectrophotometer in order to perform the mixing of solutions and the detection in the same receptacle. Only water was used as solvent and no previous separation of the components was required. Both analytes have a strong absorption between 190 and 370 nm in aqueous medium, at pH 7. However, the spectrum of DEX is embedded in the CIP spectrum. Thus, while CIP was analyzed using univariate calibration, DEX analysis was carried out comparing partial least squares (PLS-1) and multiple linear regression (MLR). The latest required a previous variable selection step, which was performed using the genetic algorithm (GA) and the successive projections algorithm (SPA). The FBA system made it possible to automatically prepare the calibration and validation sets. The statistical parameters, in terms of relative errors of calibration and prediction, were acceptable for the determination of both CIP and DEX. Also, a comparative study of chemometric models was carried out. Commercial samples were analyzed and the obtained results are in close agreement with HPLC pharmacopeia methods. The joint interval test for the slope and the intercept was used to test for the presence of bias. There were no statistical differences between the proposed method and the reference method (alpha=0.05). The sample throughput was 10h(-1). The combination of automation and chemometric tools allows us to develop an environmental friendly method for the quality control of CIP and DEX in pharmaceuticals. PMID- 24054598 TI - Impact of glutathione-HbA1c on HbA1c measurement in diabetes diagnosis via array isoelectric focusing, liquid chromatography, mass spectrometry and ELISA. AB - Hemoglobin A1c (HbA1c) has been proven to be a key biomarker for diabetes screening, and glutathiolation of HbA1c (viz., GSS-HbA1c) has been identified. However, the impact of GSS-HbA1c on the measurement of HbA1c for diabetes screening has not been quantitatively assessed yet. To address the issue, the micropreparative capillary isoelectric focusing (cIEF) developed in our previous work was used for the high resolution separation and purification of hemoglobin (Hb) species. The main fractions of HbA0, HbA3 and HbA1c extracted from the developed cIEF were identified by validated Mono S method. The proposed GSS-HbA1c fractions in the cIEF were pooled and identified by electrospray ionization mass spectrometry (ESI-MS). The HbA1c enzyme-linked immunosorbent assay (ELISA) kit was employed for further quantitative analysis of GSS-HbA1c. A total of 34 blood samples with HbA1c levels from 4.2% to 13.4% were assessed via the above comprehensive strategy of IEF-HPLC-MS-ELISA. It was demonstrated that the HbA1c levels detected by cation exchange LC were considerably influenced by the glutathiolation of Hb and the range of detected GSS-HbA1c values was between 0.23% and 0.74%. The results and developed cIEF methods have considerable significances for investigation of diabetes and clinical diagnosis. PMID- 24054599 TI - A highly stable, sensitive, regenerable and rapid immunoassay for detecting aflatoxin B1 in corn incorporating covalent AFB1 immobilization and a recombinant Fab antibody. AB - A highly robust immunoassay applicable for the detection of aflatoxin B1 (AFB1) using a Fab antibody fragment was developed. A key factor was the use of covalently immobilized AFB1 which allowed an almost three fold increase in sensitivity, reduced assay time and regeneration with retention of binding capacity. Various factors that might affect the sensitivity of the assay such as pH, organic solvents, storage stability and wash stringency were critically evaluated. It was also demonstrated that the assay was applicable for determination of AFB1 in corn samples at concentration within the European union regulatory limits. PMID- 24054600 TI - Extraction and quantification of phosphorus derived from DNA and lipids in environmental samples. AB - Understanding the flux and turnover of phosphorus (P) in the environment is important due to the key role P plays in eutrophication and in the ambition to find cost-effective measures to mitigate it. Orthophosphate diesters, including DNA and phospholipids (PLs), represent a potentially degradable P pool that could support future primary production and eutrophication. In this study, extraction techniques were optimized and combined with colorimetric determination of extracted P to provide a selective quantification method for DNA-P and PL-P in agricultural soil, sediment and composted manure. The proposed method is rapid and reproducible with an RSD of <10%. Recovery, evaluated by spiking the sample matrices with DNA and PL standards, was over 95% for both DNA and PLs. The method can be used for the determination of the pool size of the two organic P fractions. Results show that DNA-P comprises 3.0% by weight of the total P (TP) content in the studied soil, 10.4% in the sediment and 8.4% in the compost samples. The values for PL-P are 0.5%, 6.0% and 1.7% for soil, sediment and compost, respectively. PMID- 24054601 TI - Capillary microextraction combined with fluorinating assisted electrothermal vaporization inductively coupled plasma optical emission spectrometry for the determination of trace lanthanum, europium, dysprosium and yttrium in human hair. AB - In this work, a congo red modified single wall carbon nanotubes (CR-SWCNTs) coated fused-silica capillary was prepared and used for capillary microextraction (CME) of trace amounts of lanthanum (La), europium (Eu), dysprosium (Dy) and yttrium (Y) in human hair followed by fluorinating assisted electrothermal vaporization-inductively coupled plasma-optical emission spectrometry (FETV-ICP OES) determination. The adsorption properties and stability of the prepared CR SWCNTs coated capillary along with the various factors affecting the separation/preconcentration of La, Eu, Dy and Y by CME were investigated in detail. Under the optimized conditions, with a consumption of 2 mL sample solution, a theoretical enrichment factor of 50 and a detection limit (3sigma) of 0.12 ng mL(-1) for La, 0.03 ng mL(-1) for Eu, 0.11 ng mL(-1) for Dy and 0.03 ng mL(-1) for Y were obtained, respectively. The preparation reproducibility of the CR-SWCNTs coated capillary was investigated and the relative standard deviations (RSDs) were ranging from 4.1% (Eu) to 4.4% (La) (CLa, Dy=1.4 ng mL(-1); CY, Eu=0.25 ng mL(-1), n=7) in one batch, and from 5.7% (Eu) to 6.1% (Y) (CLa, Dy=1.4 ng mL(-1); CY, Eu=0.25 ng mL(-1), n=5) among different batches. The proposed method was applied to the analysis of real-world human hair sample and the recoveries for the spiked sample were in the range of 93-105%. The method was also applied to the determination of La, Eu, Dy and Y in Certified Reference Material of GBW07601 human hair, and the determined values were in good agreement with the certified values. PMID- 24054602 TI - On-line solid-phase extraction coupled to liquid chromatography tandem mass spectrometry optimized for the analysis of steroid hormones in urban wastewaters. AB - An analytical method based on on-line SPE-LC-APCI-MS/MS has been developed for the detection and quantification of eight selected estrogenic and progestagenic steroid hormones; estrone (E1), 17beta-estradiol (E2), estriol (E3), 17alpha ethinylestradiol (EE2), levonorgestrel (LEVO), medroxyprogesterone (MEDRO), norethindrone (NORE) and progesterone (PROG) in wastewater matrices. The injection volume could range from 1 to 10-mL according to the expected concentration of steroid hormones in matrix. The method characteristics are: analysis time per sample (<15 min), acceptable recovery values (71-95%), good precision (RSD <= 10%) and limits of detection at the low-nanogram per liter levels in affluent and effluent wastewaters (8-60 ng L(-1)). In particular, a detailed discussion of optimization parameters impacting overall performance of the method has been presented (sample collection, filtration and storage). All optimization and validation experiments for the on-line SPE method and chromatographic separation were performed in environmentally-relevant wastewater matrices. This method represents a compromise between analysis time, higher sample throughput capabilities, sample volume and simplicity for the analysis of both progestagenic and estrogenic steroid hormones in a single run, with LODs and LOQs sufficiently low to detect and quantify them in environmental wastewater matrices. Thus, the applicability of the method was tested on affluent and effluent wastewaters from two wastewater treatment facilities using different processes (biological and physico-chemical) to evaluate their removal efficiency for the detected steroid hormones. PMID- 24054603 TI - Sequential injection system for simultaneous determination of sucrose and phosphate in cola drinks using paired emitter-detector diode sensor. AB - This work presents the simultaneous determination of sucrose and phosphate by using sequential injection (SI) system with a low cost paired emitter-detector diode (PEDD) light sensor. The PEDD uses two 890 nm LEDs. Measurement of sucrose in Brix unit was carried out based on the detection of light refraction occurring at the liquid interface (the schlieren effect) between the sucrose solution and water. Phosphate was measured from the formation of calcium phosphate with turbidimetric detection. With careful design of the loading sequence and volume (sample--precipitating reagent--sample), simultaneous detection of sucrose and phosphate was accomplished with the single PEDD detector. At the optimized condition, linear calibrations from 1 to 7 Brix sucrose and from 50 to 200mg PO4(3-)L(-1) were obtained. Good precision at lower than 2% RSD (n=10) for both analytes with satisfactory throughput of 21 injections h(-1) was achieved. The method was successfully applied for the determination of sucrose and phosphate in cola drinks. The proposed method is readily applicable for automation and is found to be an alternative method to conventional procedures for on-line quality control process in cola drink industry. PMID- 24054604 TI - Determination of steroids in the dissolved and in the suspended phases of wastewater and Danube River samples by gas chromatography, tandem mass spectrometry. AB - In this paper, a new working approach is described for the analysis of steroids as environmental water pollutants. As novelty to the field, steroids were identified and quantified both in the dissolved and in the suspended phases, as their trimethylsilyl-(oxime)-ether derivatives, applying a recently developed tandem gas chromatographic mass spectrometric (GC-MS/MS) method, applying multiple reaction monitoring (MRM) acquisition, suitable for their quantitation in the low ng/L level, in wastewater and in Danube River samples. In addition to the analysis of filtrates obtained by the common solid phase extraction (SPE) enrichment, even the insoluble, isolated by filtration prior to the SPE, and usually discarded part of steroids were identified and quantified, simultaneously, for the first time. For this purpose a new, time, labor, cost efficient and quantitative, ultrasound assisted extraction process was developed. Reproducibility, reliability and practical utility of the ultrasound assisted extraction process were proved by the proportionality of the extracted suspended steroids obtained from different sample volumes: prepared from 0.5L and 1.0 L influent wastewater, as well as from 3 L, 5 L and 10 L Danube River water samples. Steroids' concentrations, identified and quantified in suspended conditions, showed proportionality, characterized with the relative standard deviation percentages (RSD%) of analyses: varying in case of Danube River water in the range of 0.92-6.0%, with an average of 4.10% RSD, while in the case of influent wastewater in the range of 1.59-5.8%, with an average of 4.03% RSD. Partition of steroids, between the dissolved and suspended phases of influent and effluent wastewaters and river water samples, meaning, the total amounts of steroids that the ecosystem is liable to, were defined in river water samples for the first time. Distribution of found steroids revealed that their considerable and/or overwhelming part (relating to their total amounts), are present in suspended phases: in average, 71% from wastewater and 64% from Danube River samples. PMID- 24054605 TI - Simultaneous determination of organotin compounds in textiles by gas chromatography-flame photometry following liquid/liquid partitioning with tert butyl ethyl ether after reflux-extraction. AB - A rapid and relatively clean method for determining six organotin compounds (OtC) in textile goods with a gas chromatograph equipped with a conventional flame photometric detector (GC-FPD) has been developed. After the reflux-extraction to use methanol containing 1% (v/v) of hydrochloric acid, five hydrophobic OtC (e.g. tributyltin: TBT) and slightly less hydrophobic dibutyltin (DBT) could be drawn out through partitioning between the methanolic buffer solution and tert-butyl ethyl ether instead of hazardous dichloromethane, of which usage is provided by the official-methods notified in Japan, and following the ethylation procedure to use sodium tetraethylborate, the OtC were determined with the GC-FPD. The recoveries of DBT, TBT, tetrabutyltin, triphenyltin, dioctyltin, and trioctyltin from textile products (cloth diaper, socks, and undershirt) were 60-77, 89-98, 86 94, 71-78, 85-109, and 70-79% respectively, and their coefficients of variation were 2.5-16.5%. Calibration curves for OtC were linear (0.01-0.20 MUg as Sn mL( 1)), and the correlation coefficients were 0.9922-1.0000. Their detection limits were estimated to be 2.7-9.7 n gas Sn g(-1). These data suggested that this method would be applicable to their simultaneous determination. Five retailed textile goods were analyzed by this proposed method, and 0.013-0.65 ug as Sn g( 1) of OtC (e.g. DBT) were determined in three. Moreover, a possibility that various OtC including non-targeted species in textile would be specifically detected by applying the studying speciation-technique of controlling signal intensity-flame fuel gas pressures of the GC-FPD was found. PMID- 24054606 TI - Detection of glutathione based on nickel hexacyanoferrate film modified Pt ultramicroelectrode by introducing cetyltrimethylammonium bromide and Au nanoparticles. AB - A novel method for glutathione (GSH) detection in real blood sample with a nickel hexacyanoferrate (NiHCF) film modified Pt ultramicroelectrode (UME) was proposed. The electrochemical properties of NiHCF film modified Pt UME were improved by introducing cetyltrimethylammonium bromide (CTAB) and Au nanoparticles (AuNPs) into NiHCF film. The novel hybrid films (NiHCF/CTAB/AuNPs) were prepared by electrodepositing NiHCF and AuNPs in the presence of CTAB on the surface of Pt UME. The results indicated that the prepared NiHCF/CTAB/AuNPs Pt UME had a sensitive respond toward the oxidation of GSH and could be used for its selective determination in the presence of other coexisting interferents in real blood samples. The calibration curve for GSH was found to be linear from 0.2-1 MUM, and the limit of detection (S/N=3) was 0.08 MUM. The strategy explored here might provide a new pathway to design NiHCF/CTAB/AuNPs film microsensor for in situ detecting GSH, which had unique characteristics and potential applications in the fields of sensor and medical diagnosis. PMID- 24054607 TI - Synthesis of haptens and selective enzyme-linked immunosorbent assay of octachlorostyrene. AB - A sensitive, competitive indirect enzyme-linked immunosorbent assay (ELISA) was developed for the detection of octachlorostyrene (OCS), a persistent and bioaccumulative toxicant. To achieve the most sensitive antibody, several haptens with different linkers that simulated the special structure of OCS were synthesized and conjugated to carrier proteins. Polyclonal rabbit antibodies against different immunizing antigens were obtained and screened against different coating antigens. Under the optimized conditions, this indirect ELISA shows a linear detection range from 1.4 to 86.3 ng/mL, with an IC50 value of 4.46 ng/mL and a limit of detections (LOD) of 0.1 ng/mL. Twelve kinds of compounds were tested for calculating cross-reactivities, and almost all of them showed little cross-reactivity (<5%). Water and sera samples spiked with OCS were analyzed by ELISA and the achieved recoveries were satisfied with a mean recovery of 92%. This immunoassay can be used as a rapid and convenient tool to monitoring OCS in environmental samples. PMID- 24054608 TI - Resolving antibody-peptide complexes with different ligand stoichiometries reveals a marked affinity enhancement through multivalency. AB - Natural antibodies adopt multivalent constructs to effect superior binding affinities with their antigens. Notwithstanding that the structure of antibodies have been well understood, how antibodies harness multivalency effect to achieve superior binding affinity toward the antigens still remains unclear. Such investigation is often hampered by the difficulty in resolving receptor-ligand complexes with different stoichiometries in the binding solution, especially when the ligand is a small molecule or a short peptide. Here we employed a unique anti FLAG(TM) mAb M2 and FLAG(TM) peptides system, together with fluorescence detection coupled capillary electrophoresis (CE-FL) to reveal how M2 achieves exceptional high affinity with FLAG peptides through multivalency. Complexation of fluorescently labeled FLAG(TM) peptides with M2 leads to a pronounced mobility shift of the fluorescent peak in CE. Remarkably, CE-FL rendered a base-line separation of 1:1 and 1:2 M2-FLAG(TM) complexes, allowing the quantification of different M2-FLAG(TM) species. The quantitative analysis leads to a detailed dissection of the first (functional affinity) and second binding affinities (intrinsic affinity) between M2 and FLAG1 peptide. The marked difference (10(3) 10(4) fold) between these two affinities indicated that multivalency effect plays a key role for M2 to achieve highly efficient binding to FLAG(TM) peptides. PMID- 24054609 TI - Laccase biosensors based on different enzyme immobilization strategies for phenolic compounds determination. AB - Different enzyme immobilization approaches of Trametes versicolor laccase (TvL) onto gold surfaces and their influence on the performance of the final bioanalytical platforms are described. The laccase immobilization methods include: (i) direct adsorption onto gold electrodes (TvL/Au), (ii) covalent attachment to a gold surface modified with a bifunctional reagent, 3,3' Dithiodipropionic acid di (N-succinimidyl ester) (DTSP), and (iii) integration of the enzyme into a sol-gel 3D polymeric network derived from (3-mercaptopropyl) trimethoxysilane (MPTS) previously formed onto a gold surface (TvL/MPTS/Au). The characterization and applicability of these biosensors are described. Characterization is performed in aqueous acetate buffer solutions using atomic force microscopy (AFM), providing valuable information concerning morphological data at the nanoscale level. The response of the three biosensing platforms developed, TvL/Au, TvL/DTSP/Au and TvL/MPTS/Au, is evaluated in the presence of hydroquinone (HQ), used as a phenolic enzymatic substrate. All systems exhibit a clear electrocatalytic activity and HQ can be amperometrically determined at 0.10 V versus Ag/AgCl. However, the performance of biosensors - evaluated in terms of sensitivity, detection limit, linear response range, reproducibility and stability - depends clearly on the enzyme immobilization strategy, which allows establishing its influence on the enzyme catalytic activity. PMID- 24054610 TI - Fast emulsion-based method for simultaneous determination of Co, Cu, Pb and Se in crude oil, gasoline and diesel by graphite furnace atomic absorption spectrometry. AB - A method for the simultaneous determination of Co, Cu, Pb and Se in crude oil, gasoline and diesel samples using emulsion-based sampling and GF AAS is proposed. 400mg of sample was weighted in volumetric flask following the sequential addition of 125 uL of hexane and 7.5 mL of Triton X-100((r)) (20% mv(-1)). Subsequently, the mixture was stirred in ultrasonic bath, during 30 min, before dilution to 25 mL with deionized water. Aliquots of 20 MUL of reference solution or sample emulsion were co-injected into the graphite tube with 10 MUL of 2 g L( 1) Pd(NO3)2. The pyrolysis and atomization temperatures were 1300 degrees C and 2250 degrees C, respectively. The limits of detection (n=10, 3sigma) and characteristic masses were 0.02 MUg g(-1) (0.32 MUg L(-1)) and 18 pg for Co, 0.03 MUg g(-1) (0.48 MUg L(-1)) and 15 pg for Cu, 0.04 MUg g(-1) (0.64 MUg L(-1)) and 48 pg for Pb, and 0.11 MUg g(-1) (1.76 MUg L(-1)) and 47 pg for Se. The reliabilities of the proposed method for Co and Se were checked by SRM((r)) 1634c Residual Oil analysis. The found values are in accordance to the SRM at 95% confidence level (Student's t-test). Each sample was spiked with 0.18 MUg g(-1) of Co, Cu, Pb and Se and the recoveries varied from 92% to 116% for Co, 83% to 117% for Cu, 72% to 117% for Pb, and 82% to 122% for Se. PMID- 24054611 TI - 3-(10'-Phenothiazinyl)propionic acid is a potent primary enhancer of peroxidase induced chemiluminescence and its application in sensitive ELISA of methylglyoxal modified low density lipoprotein. AB - Using a full factorial design the optimization of experimental conditions of enhanced chemiluminescence reaction (ECR) catalyzed by horseradish peroxidase (HRP) in the presence of 3-(10'-phenothiazinyl)propionic acid (PPA) as a primary enhancer was performed. The effect of concentrations of PPA, hydrogen peroxide, MORPH, luminol, and Tris on a ratio of peroxidase-catalyzed CL to background was studied. The detection limit value of HRP in ECR with PPA was 0.09 pM. Using PPA the ultra-sensitive chemiluminescent ELISA for determination of methylglyoxal modified low density lipoprotein was developed. The detection limit value for the developed method was 0.5 ng mL(-1). The obtained results open up very promising perspectives for using PPA to improve the sensitivity of enzyme immunoassay kits. PMID- 24054612 TI - Fast enantioseparation by HPLC on a modified carbon nanotube monolithic stationary phase with a pyrenyl aminoglycoside derivative. AB - This work deals with the development of a carbon nanotube (CNT) monolithic column coated with a pyrenyl derivative as chiral selector. For this, a solution of pyrenyl neomycine A was pumping through a monolithic CNT column previously developed by our group. This coating was stable against the desorption for months when aqueous mobile phases were used. This column was applied to the chiral separation of underivatized amino acids. As well, ultra fast separations in the range of seconds were achieved using high flow-rates. PMID- 24054613 TI - Qualitative evaluation of maternal milk and commercial infant formulas via LIBS. AB - This study focuses on the use of laser-induced breakdown spectroscopy (LIBS) for the evaluation of the nutrients in maternal milk and some commercially available infant formulas. The results of such evaluation are vital for adequate and healthy feeding for babies during lactation period. Laser-induced breakdown spectroscopy offers special advantages in comparison to the other conventional analytical techniques. Specifically, LIBS is a straightforward technique that can be used in situ to provide qualitative analytical information in few minutes for the samples under investigation without preparation processes. The samples studied in the current work were maternal milk samples collected during the first 3 months of lactation (not colostrum milk) and samples from six different types of commercially available infant formulas. The samples' elemental composition has been compared with respect to the relative abundance of the elements of nutrition importance, namely Mg, Ca, Na, and Fe using their spectral emission lines in the relevant LIBS spectra. In addition, CN and C2 molecular emission bands in the same spectra have been studied as indicators of proteins content in the samples. The obtained analytical results demonstrate the higher elemental contents of the maternal milk compared with the commercial formulas samples. Similar results have been obtained as for the proteins content. It has been also shown that calcium and proteins have similar relative concentration trends in the studied samples. This work demonstrates the feasibility of adopting LIBS as a fast, safe, less costly technique evaluating qualitatively the nutrients content of both maternal and commercial milk samples. PMID- 24054614 TI - Preparation of phenyl group-functionalized magnetic mesoporous silica microspheres for fast extraction and analysis of acetaldehyde in mainstream cigarette smoke by gas chromatography-mass spectrometry. AB - Acetaldehyde is regarded as a toxic mainstream cigarette smoke constituent, and measurement of acetaldehyde in complex real samples is difficult owing to its high volatility and reactivity. In this work, phenyl group-functionalized magnetic mesoporous microspheres were developed as the solid-phase extraction sorbents for enrichment and analysis of acetaldehyde in mainstream cigarette smoke. The functional magnetic microspheres were first synthesized through a facile one-pot co-condensation approach. The prepared nanomaterials possessed abundant silanol groups in the exterior surface and numerous phenyl groups in the interior pore-walls, as well as a large surface area (273.5m(2)/g), strong superparamagnetism and uniform mesopores (3.3 nm). Acetaldehyde in mainstream cigarette smoke was collected in water and derivatizated with O-2,3,4,5,6 (pentafluorobenzyl)hydroxylamine. The formed acetaldehyde oximes were extracted and enriched by the prepared adsorbents via pi-pi interactions and subsequently analyzed using GC-MS. Extraction conditions such as amounts of sorbents, eluting solvent, adsorption and desorption time were investigated and optimized to achieve the best efficiency. Method validations including linearity, recovery, repeatability, and limit of detection were also studied. It was found that the suggested methodology provided low detection limit of 0.04 mg/mL, good recovery of 88-92%, intra-day and inter-day RSD values of 4.5% and 10.1%, and linear range of 0.25-4 mg/mL (R(2)=0.999). The results indicated that the proposed method based on phenyl-functionalized magnetic mesoporous microspheres was rapid, efficient and convenient for the enrichment and analysis of acetaldehyde in tobacco. PMID- 24054615 TI - Rapid and simultaneous analysis of ten aromatic amines in mainstream cigarette smoke by liquid chromatography/electrospray ionization tandem mass spectrometry under ISO and "Health Canada intensive" machine smoking regimens. AB - Ten primary aromatic amines (AAs) in mainstream cigarette smoke under both ISO and "Health Canada intensive" machine smoking regimens were determined in this work, which were suspected to be carcinogenic compounds. The measured AAs included aniline, ortho-toluidine, meta-toluidine, para-toluidine, 1 naphthylamine, 2-naphthylamine, 3-aminobiphenyl, 4-aminobiphenyl, meta phenylenediamine and meta-anisidine. For rapidly and sensitively analyzing these AAs, a liquid chromatography-electrospray ionization tandem mass spectrometric (LC-MS/MS) method coupled with solid phase extraction (SPE) was developed. The particulate phase of mainstream cigarette smoke was collected on a Cambridge filter pads, while the gas phase was trapped by 25 mL 5% HCl solution. Then, the pad was extracted in an ultrasonic bath with the impinger HCl solution. After being neutralized with NaOH, the extract was purified with a HLB solid phase extraction column, and then was analyzed with LC-MS/MS using isotope-labeled internal standard. The overall sample pretreatment and analysis time was less than 1.5h. The limits of detection for all targets ranged from 0.05 ng cig(-1) to 0.96 ng cig(-1) with the recoveries in the range of 75.0-131.8%. And the intra day and inter-day precisions were less than 10% and 16%, respectively. Under HCI machine smoking regimen, the AAs yields in mainstream cigarette smoke were much higher and the average increases were greater than 100% compared with those under ISO smoking condition. PMID- 24054616 TI - Furoic and mefenamic acids as new matrices for matrix assisted laser desorption/ionization-(MALDI)-mass spectrometry. AB - The present study introduces two novel organic matrices for matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS) for the analysis of small molecules. The first matrix is "2-amino-4,5-diphenylfuran-3-carboxylic acid" (also called furoic acid, FA) which was synthesized and then characterized by ultraviolet (UV), infrared (FTIR), nuclear magnetic resonance NMR ((1)H and (13)C) and mass spectrometry. The compound has organic semiconductor properties and exhibits intense UV-absorption which is suitable for the UV-MALDI laser (N2 laser, 337 nm). The second matrix is mefenamic acid (MA). The two matrices can be successfully applied for various classes of compounds including adenosine-5' triphosphate (ATP, 0.5 uL(10.0 nmol)), spectinomycin (spect, 0.5 uL(14.0 nmol)), glutathione (GSH, 0.5 uL(9.0 nmol)), sulfamethazole (SMT, 0.5 uL(2.0 nmol)) and mixture of peptides gramicidin D (GD, 0.5uL (9.0 nmol)). The two matrices can effectively absorb the laser energy, resulting in excellent desorption/ionization of small molecules. The new matrices offer a significant enhancement of ionization, less fragmentation, few interferences, nice reproducibility, and excellent stability under vacuum. Theoretical calculations of the physical parameters demonstrated increase in polarizability, molar volume and refractivity than the conventional organic matrices which can effectively enhance the proton transfer reactions between the matrices with the analyte molecules. While the reduction in density, surface tension and index of refraction can enhance homogeneity between the two new matrices with the analytes. Due to the sublimation energy of mefenamic acid is (1.2 times) higher than that of the DHB, it is more stable to be used in the vacuum. PMID- 24054617 TI - Physicochemical properties of silica gel coated with a thin layer of polyaniline (PANI) and its application in non-suppressed ion chromatography. AB - Physicochemical properties of a new sorbent and its potential application in non suppressed ion chromatography (IC) have been investigated. The sorbent was obtained in a process of covering silica gel particles with a film of polyaniline (PANI). The properties of silica modified with polyaniline such as particle size, porosity, average quantity of polyaniline covering carrier and density of sorbent were determined. In our study the following methods were used: microscopic analysis, laser diffraction technique, combustion analysis, mercury porosimetry and helium pycnometry. Column with the newly obtained packing was used for the separation of inorganic anions. Optimized chromatographic system was successfully employed for analysis of iodide and bromide in selected pharmaceutical products (Bochnia salt and Iwonicz salt) applied in chronic respiratory disease. Analysis was carried out using 0.1M solution of HCl in mixture of methanol/water (50:50v/v) as a mobile phase; the flow rate was 0.3 mL min(-1), temperature was 24 degrees C and lambda=210 nm. Validation parameters such as correlation coefficient, RSD values, recovery, detection and quantification limits were found to be satisfactory. PMID- 24054618 TI - Determination of m-dinitrobenzene based on novel type of sensor using thiol porphyrin mixed monolayer-tethered polyaniline with intercalating fullerenols. AB - A novel sensor based on thiol-porphyrin mixed monolayer-tethered polyaniline (PANI) with intercalating fullerenols was applied to sensitively detect m dinitrobenzene (m-DNB) by differential pulse voltammetry (DPV). The thiolated polyaniline was examined by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The electrode modification of thiol-porphyrin mixed monolayer tethered polyaniline with intercalating fullerenols exhibited a higher analytical sensitivity versus that of thiol-porphyrin mixed monolayer-tethered polyaniline, because the fullerenols in mixed monolayer could improve the preconcentration efficiencies of m-DNB. Under optimum conditions, the linear calibration curves ranged from 0.029 to 10,000 nmol L(-1) for m-DNB, with a limit of detection (S/N=3) of 9.72 pmol L(-1). PMID- 24054619 TI - Separation of a binary mixture of pesticides in fruits using a flow-through optosensor. AB - A flow-through optosensor is here proposed for the determination of mixtures of two widely used pesticides, carbendazim and o-phenylphenol, in fruits. The pesticides are separated on-line using an additional amount of solid support, C18 silica gel, in the flow-through cell. The resolution is performed due to the different retention/desorption kinetics of the analytes when interacting with the C18 microbeads. Therefore, both separation and determination are integrated in the same cell, considerably simplifying the system. In addition, the use of Sequential Injection Analysis provides a high degree of automation and minimum wastes generation. After the analytes are separated, their native fluorescence is measured, obtaining linearity in the 2.0-30 and 1.1-20 mg kg(-1) ranges for carbendazim and o-phenylphenol. The detection limits are 0.60 and 0.33 mg kg(-1) for carbendazim and o-phenylphenol respectively. The proposed method fulfills the maximum residue limits (MRLs) established in Europe and USA for these pesticides in cherries, pineapple, and mango: 5-10 mg kg(-1). In order to demonstrate the suitability of the method, several samples have been analyzed and the obtained results compared with a chromatographic method. PMID- 24054620 TI - Preconcentration and spectrophotometric determination of oxymetholone in the presence of its main metabolite (mestanolone) using modified maghemite nanoparticles in urine sample. AB - A novel and sensitive extraction procedure using maghemite nanoparticles (gamma Fe2O3) modified with sodium dodecyl sulfate (SDS), as an efficient solid phase, was developed for removal, preconcentration and spectrophotometric determination of trace amounts of oxymetholone (OXM), in the presence of mestanolone (MSL). Combination of nanoparticle adsorption and easily magnetic separation was used for the extraction and desorption of OXM. The preparation of gamma-Fe2O3 nanoparticles were obtained by co-precipitation method and their surfaces were modified by SDS. The size and properties of the produced gamma-Fe2O3 nanoparticles were determined by X-ray diffraction analysis, FT-IR and scanning electron microscopy measurements. OXM and MSL became adsorbed at pH 3.0. The adsorbed drugs were then desorbed and determined spectrophotometrically using a selective complexation reaction for OXM. The calibration graph was linear in the range 15.0-3300.0 ng mL(-1) of OXM with a correlation coefficient of 0.9948. The detection limit of the method for determination of OXM was 4.0 ng mL(-1). The method was applied for the determination of OXM in human urine samples. PMID- 24054621 TI - Selenium determination in biscuits and pasta: development of chronopotentiometric stripping determination by using a sulphide as an internal standard. AB - Being common in chromatographic techniques internal standard method is rarely applied in electrochemical stripping determinations. One of the reasons for such rare use of this elegant quantification method is because optimal conditions of accumulation at the electrode for individual compounds producing a reproducible signal may vary significantly. These criteria are much stricter when selenium is in question due to very complex mechanism of its accumulation at mercury electrodes which implies simultaneous cathodic mercury dissolution and chemical reaction. Elements that are in the analytical step stripped cathodically from mercury electrodes are rare, further limiting the application of the internal standard method when electrochemical selenium determination is in question. In this work the possibility of using sulphide for selenium quantification by chronopotentiometric stripping analysis was investigated. Optimal experimental parameters were defined in two-component systems. Dimensionless factors defining the ratio of proportionality constants of the two elements were calculated for different selenium concentration ranges at different sulphide contents. Sulphide content that was chosen as adequate for selenium concentrations reasonably to be expected in food samples was 500 ug/dm(3). Determined detection limit of chronopotentiometric stripping determination of selenium by using a sulphide as an internal standard was 0.04 ug/dm(3) (RSD=7.6%; n=5). Defined quantification method was confirmed by analysing spiked standard solutions and standard reference material. The method was used for selenium determination in biscuit and pasta samples. Calculated contents were statistically compared with those obtained by using graphite furnace atomic absorption spectrometry. PMID- 24054622 TI - Magnetic molecularly imprinted polymer for the selective extraction of sildenafil, vardenafil and their analogs from herbal medicines. AB - The successfully developed magnetic molecularly imprinted polymers (MMIPs) toward six synthetic phosphodiesterase type-5 (PDE-5) inhibitors were described. Sildenafil was used as template for the preparation of MMIPs using superparamagnetic core-shell nanoparticle as supporter. The obtained MMIPs were characterized using transmission electron microscope, Fourier transform infrared, X-ray diffraction, and vibrating sample magnetometer. High performance liquid chromatography (HPLC) with diode array detector (DAD) was used for the analysis of target analytes. The application of MMIPs as selective sorbent in the cleanup of herbal medicine samples prior to HPLC offered simple sample preparation. The adsorption capacity and selectivity of prepared MMIPs and magnetic non molecularly imprinted polymers were investigated. The binding isotherms were obtained for sildenafil and fitted by Freundlich isotherm model. Structurally similar compound of sildenafil and a reference compound protocatechuic acid were used for investing the selective recognition of MMIPs. PMID- 24054623 TI - Development and validation of an UPLC method for determination of content uniformity in low-dose solid drugs products using the design space approach. AB - A simple and reproducible UPLC method was developed and validated for the quantitative analysis of finasteride in low-dose drug products. Method validation demonstrated the reliability and consistency of analytical results. Due to the regulatory requirements of pharmaceutical analysis in particular, evaluation of robustness is vital to predict how small variations in operating conditions affect the responses. Response surface methodology as an optimization technique was used to evaluate the robustness. For this, a central composite design was implemented around the nominal conditions. Statistical treatment of the responses (retention factor and drug concentrations expressed as percentage of label claim) showed that methanol content in mobile-phase and flow rate were the most influential factors. In the optimization process, the compromise decision support problem (cDSP) strategy was used. Construction of the robust domain from response surfaces provided tolerance windows for the factors affecting the effectiveness of the method. The specified limits for the USP uniformity of dosage units assay (98.5-101.5%) and the purely experimental variations based on the repeatability test for center points (nominal conditions repetitions) were used as criteria to establish the tolerance windows, which allowed definition design space (DS) of analytical method. Thus, the acceptance criteria values (AV) proposed by the USP uniformity of assay only depend on the sampling error. If the variation in the responses corresponded to approximately twice the repeatability standard deviation, individual values for percentage label claim (%LC) response may lie outside the specified limits; this implies the data are not centered between the specified limits, and that this term plus the sampling error affects the AV value. To avoid this fact, the limits specified by the Uniformity of Dosage Form assay (i.e., 98.5-101.5%) must be taken into consideration to fix the tolerance windows for each factor. All these results were verified by the Monte Carlo simulation. In conclusion, the level of variability for different factors must be calculated for each case, and not arbitrary way, provided a variation is found higher than the repeatability for center points and secondly, the %LC response must lie inside the specified limits i.e., 98.5-101.5%. If not the UPLC method must be re-developed. PMID- 24054624 TI - Electrodeposited apatite coating for solid-phase microextraction and sensitive indirect voltammetric determination of fluoride ions. AB - Electrodeposition was used to prepare a new solid phase microextraction (SPME) coatings. Two apatite SPME coatings, dicalcium phosphate dihydrate (DCPD or brushite) and hydroxyapatite (HAP) were validly and homogeneously one-step electrodeposited on glassy carbon electrode (GCE) under different conditions. The coatings were characterized by XRD, FTIR, SEM, CV and EIS. The apatite SPME coatings showed excellent and selective adsorbability to fluoride ions. A novel indirect voltammetric strategy for sensitive detection of fluoride was proposed using K3Fe(CN)6 as indicating probe. The detection principle of fluoride ions was based on the increment of steric hindrance after fluoride adsorption, which resulting in the decrease of the amperometric signal to Fe(CN)6(3-). The liner ranges were 0.5-20.0 MUmol/L for n-DCPD/GCE with the limit of detection of 0.14 MUmol/L and 0.1-50.0 MUmol/L for n-HAP/GCE with the limit of detection of 0.069 MUmol/L, respectively. The developed method was applied to the analysis of water samples (lake, spring and tap water) and the recovery values were found to be in the range of 90-106%. PMID- 24054625 TI - Double-functionalized gold nanoparticles with split aptamer for the detection of adenosine triphosphate. AB - A newly designed functionalization type for gold nanoparticles (AuNP) with split aptamer has been developed for the detection of adenosine triphosphate (ATP). The ATP aptamer was split into two parts with their 5' prime or 3' prime modified with thiol. Both the 5' SH and 3' SH modified strands for each split aptamer fragment were functionalized onto the same AuNP to construct double functionalized AuNP-DNA conjugates. Thus, the split aptamer can be reassembled into intact folded structure in the presence of ATP molecule with two potential assembly types, which induces the assembly of AuNP-DNA conjugates. In this double functionalized system, the traditional assembly type might facilitate another assembly type, which was found to give much higher LSPR change in the presence of ATP than the traditional assembly type, and improve the sensitivity for ATP detection. Time courses of the assemble processes with different assembly types, Mg(2+) concentrations, and aptamer fragments densities on AuNP were followed using the absorption ratio at 650 nm and 520 nm. ATP response with this newly designed system was investigated using absorption spectra and dynamic light scattering method. PMID- 24054626 TI - Nanocomposite-based rapid, visual, and selective luminescence turn-on assay for Hg2+ sensing in aqueous media. AB - Composite nanospheres containing dithizone, luminescent LaVO4:Eu(3+) nanoparticles (NPs), and amphiphilic polymer have been composed for the rapid, selective, and visual luminescence turn-on detection of mercury ions (Hg(2+)) in water. Due to the absorption of dithizone, the strong red luminescence of LaVO4:Eu(3+) NPs encapsulated in nanospheres was quenched noticeably. As a result, these as-prepared nanocomposites (NCs) demonstrate very weak red luminescence. However, in the presence of Hg(2+), the red luminescence of nanocomposites was turned on dramatically, which can be attributed to the strong binding of mercury (II) ions by dithizone and forming a complex without absorption in the red emission range. Meanwhile, other cations have no influence on the detection of Hg(2+), suggesting a good selectivity for Hg(2+) sensing. Due to the high photostability and chemical stability of the nanocomposites, operation simplicity, low cost, and good selectivity, this newly developed method is highly desirable for field assay of Hg(2+) in aqueous media ranging from 40.0 nM to 4.0 MUM with a limit of detection of 32.0 nM and a good linearity (r=0.9980). Therefore, a facile, rapid, selective, and visual luminescence turn on technology has been successfully developed for Hg(2+) detection. PMID- 24054627 TI - Ultrasound-assisted low-density solvent dispersive liquid-liquid extraction for the determination of alkanolamines and alkylamines in cosmetics with ion chromatography. AB - A new one-step sample preparation technique termed ultrasound-assisted low density solvent dispersive liquid-liquid extraction (UA-LDS-DLLE) coupled with ion chromatography (IC) was developed for the determination of three alkanolamines and two alkylamines in complex samples. Sample matrices were rapidly dissolved and dispersed to form cloudy solutions by using two solvents, where target analytes were transferred into acid solutions, while liposoluble substances were dissolved in cyclohexane. The obtained extracts could be used directly for injection analysis without any additional purification because the potential matrix interferences had been effectively eliminated in extraction process. The extraction efficiency could be markedly enhanced and the extraction could be quickly accomplished within 13 min under the synergistic effects of ultrasound radiation, vibration and heating. Various parameters influencing extraction efficiency were evaluated using orthogonal array experimental design. The extraction performance of the approach was demonstrated for the determination of target analytes in 15 commercial cosmetics covering very different matrices. Linearity ranges of 0.3-50 mg L(-1) and limits of detection varying from 0.072 to 0.12 mg L(-1) were achieved. The recoveries ranged from 86.9-108.5% with the relative standard deviations (RSDs) of 1.2-6.2%. The method was proved to be a simple and effective extraction technique that provided an attractive alternative to the analysis of trace amounts of target analytes in large numbers of cosmetics. PMID- 24054629 TI - Detection of the improvised explosives ammonium nitrate (AN) and urea nitrate (UN) using non-aqueous solvents with electrospray ionization and MS/MS detection. AB - In this study methods for the detection of trace levels of the improvised explosives urea nitrate and ammonium nitrate were developed using electrospray ionization with infusion. By using a non-aqueous solvent mixture containing 95% acetone with 5% 2-methoxyethanol we were able to preserve the urea and ammonium nitrate ion pairs and discriminate between these and other similar salts. Negative ion electrospray ionization was used for urea nitrate detection and positive ion electrospray ionization was used for ammonium nitrate. Two specific adduct ions were detected for each explosive with ammonium nitrate producing m/z 178 [2AN+NH4](+) and m/z 258 ions [3AN+NH4](+) while urea nitrate produced m/z 185 [UN+NO3](-) and m/z 248 [UN+HNO3+NO3](-) The specificity of the analysis was examined by mixing the different explosives with various salts and interferents. Adduct ions formed in the gas phase were found to be useful in distinguishing between ion pairs and mixed salts. Overall the method demonstrates the sensitive detection of both explosives, and more specifically the potential to determine intact urea nitrate. PMID- 24054628 TI - Measurement of total antioxidant capacity of human plasma: setting and validation of the CUPRAC-BCS method on routine apparatus ADVIA 2400. AB - BACKGROUND: Quantification of Total Antioxidant Capacity (TAC) of human plasma is an important clinical target, since many diseases are suspected to be related with oxidative stress. The CUPRAC-BCS (BCS=Bathocuproinedisulfonic acid) method was chosen since it works using the photometric principle, with stable and inexpensive reagents and at physiological pH. METHODS: The method is based on the complex equilibria between Cu(II)-BCS (reagent) and Cu(I)-BCS. Cu(I)-BCS complex is formed by reducing ability of the plasma redox active substances. The photometric signal is achieved at 478 nm and calibration is performed using urate as a reference substance. RESULTS: Linearity, linear working range, sensitivity, precision, LoD, LoQ, selectivity and robustness have been considered to validate the method. Absorbance at 478 nm was found linear from 0.0025 up to 2.0 mmol L( 1) of urate reference solution. Precision was evaluated as within-day repeatability, Sr=4 umol L(-1), and intermediate-precision, SI(T)=15 umol L(-1). LoD and LoQ, resulted equal to 7.0 umol L(-1) and 21 umol L(-1) respectively while robustness was tested having care for pH variation during PBS buffer preparation. Tests on plasma (80 samples) and on human cerebrospinal fluid (30 samples) were conducted and discussed. CONCLUSIONS: By the analytical point of view, the photometric method was found to be simple, rapid, widely linear and reliable for the routine analysis of a clinical laboratory. By the clinical point of view, the method response is suitable for the study of chemical plasma quantities related to redox reactivity. PMID- 24054630 TI - Advanced discriminating criteria for natural organic substances of cultural heritage interest: spectral decomposition and multivariate analyses of FT-Raman and FT-IR signatures. AB - Natural organic substances are involved in many aspects of the cultural heritage field. Their presence in different forms (raw, heated, mixed), with various conservation states, constitutes a real challenge regarding their recognition and discrimination. Their characterization usually involves the use of separative techniques which imply destructive sampling and specific analytical preparations. Here we propose a non destructive approach using FT-Raman and infrared spectroscopies for the identification and differentiation of natural organic substances. Because of their related functional groups, they usually present similar vibrational signatures. Nevertheless the use of appropriate signal treatment and statistical analysis was successfully carried out to overcome this limitation, then proposing new objective discriminating methodology to identify these substances. Spectral decomposition calculations were performed on the CH stretching region of a large set of reference materials such as resins, oils, animal glues, and gums. Multivariate analyses (Principal Component Analyses) were then performed on the fitting parameters, and new discriminating criteria were established. A set of previously characterized archeological resins, with different surface aspects or alteration states, was analyzed using the same methodology. These testing samples validate the efficiency of our discriminating criteria established on the reference corpus. Moreover, we proved that some alteration or ageing of organic materials is not an issue to their recognition. PMID- 24054631 TI - Preliminary study on classification of rice and detection of paraffin in the adulterated samples by Raman spectroscopy combined with multivariate analysis. AB - Rice has played an important role in staple food supply of over approximately one half of the world population. In this study, Raman spectroscopy and several multivariate data analysis methods were applied for discrimination of rice samples from different districts of China. A total of 42 samples were examined. It is shown that the representative Raman spectra in each group are different according to geographical origin after baseline correction to enhance spectral features. Moreover, adulteration of rice is a serious problem for consumers. In addition to the obvious effect on producer profits, adulteration can also cause severe health and safety problems. Paraffin was added to give the rice a desirable translucent appearance and increase its marketability. Detection of paraffin in the adulterated rice samples was preliminarily investigated as well. The results showed that Raman spectroscopy data with chemometric techniques can be applied to rapid detecting rice adulteration with paraffin. PMID- 24054632 TI - Ionic liquid-based totally organic solvent-free emulsification microextraction coupled with high performance liquid chromatography for the determination of three acaricides in fruit juice. AB - A novel, totally organic solvent-free emulsification microextraction (TEME) technique using ionic liquids (ILs) is proposed in this study. Seven bis(trifluoromethylsulfonyl)imide ionic liquids were synthesized. After comparing the physicochemical properties of the ionic liquids and their application to microextraction experiments, 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C6MIM][NTf2]), which has moderate surface tension and viscosity, was selected as the extraction solvent. The dispersion of ILs and mass transfer were accelerated by ultrasound irradiation and temperature control processes. Therefore, no dispersive organic solvent was needed. Several variables, such as ionic liquid volume, duration of the ultrasound extraction, dispersion temperature, ionic strength and centrifugation time were investigated and optimized. Under the optimum conditions, the calibration curve was linear in the range of 0.1-600 MUg L(-1) for chlorfenapyr and fenpyroximate and 0.5-600 MUg L(-1) for spirodiclofen, with correlation coefficients of 0.9994-0.9999. The enrichment factors were between 261 and 285. The limits of detection (LODs) were 0.02-0.06 MUg L(-1). Real fruit juice samples (at fortified levels of 10 MUg L( 1) and 30 MUg L(-1)) were successfully analyzed using the proposed method. The relative recoveries and enrichment factors were in the range of 92-104%. PMID- 24054633 TI - Quantitative evaluation of multiple adulterants in roasted coffee by Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS) and chemometrics. AB - The current study presents an application of Diffuse Reflectance Infrared Fourier Transform Spectroscopy for detection and quantification of fraudulent addition of commonly employed adulterants (spent coffee grounds, coffee husks, roasted corn and roasted barley) to roasted and ground coffee. Roasted coffee samples were intentionally blended with the adulterants (pure and mixed), with total adulteration levels ranging from 1% to 66% w/w. Partial Least Squares Regression (PLS) was used to relate the processed spectra to the mass fraction of adulterants and the model obtained provided reliable predictions of adulterations at levels as low as 1% w/w. A robust methodology was implemented that included the detection of outliers. High correlation coefficients (0.99 for calibration; 0.98 for validation) coupled with low degrees of error (1.23% for calibration; 2.67% for validation) confirmed that DRIFTS can be a valuable analytical tool for detection and quantification of adulteration in ground, roasted coffee. PMID- 24054634 TI - Fabrication of coated graphite electrode for the selective determination of europium (III) ions. AB - Preliminary complexation study showed that two ligands (ionophores) (2-((2-phenyl 2-(pyridin-2-yl)hydazono)methyl)pyridine) [L1], (2-((2-phenyl-2-(pyridin-2 yl)hydazono) methyl)phenol) [L2] can act as europium selective electrode. Europium selective coated graphite electrodes (CGE) were prepared by using ligands [L1] and [L2] and their potentiometric characteristics were determined. Membranes having different compositions of poly(vinylchloride) (PVC), the different plasticizers, anionic additives and ionophores were coated onto the graphite surface. The potential response measurements showed that the best performance was exhibited by the proposed CGE. This electrode had the widest working concentration range, Nernstian slope and fast response times of 10s. The selectivity studies showed that this electrode have higher selectivity towards Eu(3+) over a large number of cations. Furthermore, the electrode generated constant potentials in the pH range 2.7-9.0. This electrode can be used to quantify europium in soil, binary mixtures and also used as an indicator electrode in the potentiometric titration of Eu(3+) with EDTA. The proposed electrode was also successfully applied to the determination of fluoride ions in real samples. PMID- 24054635 TI - Amplified electrochemiluminescence of luminol based on hybridization chain reaction and in situ generate co-reactant for highly sensitive immunoassay. AB - In this work, we described a simple and highly sensitive electrochemiluminescence (ECL) strategy for IgG detection. Firstly, L-cysteine functionalized reduced graphene oxide composite (L-cys-rGO) was decorated on the glassy carbon electrode (GCE) surface. Then anti-IgG was immobilized on the modified electrode surface through the interaction between the carboxylic groups of the L-cys-rGO and the amine groups in anti-IgG. And then biotinylated anti-IgG (bio-anti-IgG) was assembled onto the electrode surface based on the sandwich-type immunoreactions. By the conjunction of biotin and streptavidin (SA), SA was immobilized, which in turn, combined with the biotin labeled initiator strand (S1). In the presence of two single DNA strands of glucose oxidase labeled S2 (GOD-S2) and complementary strand (S3), S1 could trigger the hybridization chain reaction (HCR) among S1, GOD-S2 and S3. Herein, due to HCR, numerous GOD was efficiently immobilizated on the sensing surface and exhibited excellent catalysis towards glucose to in situ generate amounts of hydrogen peroxide (H2O2), which acted as luminol's co reactant to significantly enhance the ECL signal. The proposed ECL immunosensor presented predominate stability and high sensibility for determination of IgG in the range from 0.1 pg mL(-1) to 100 ng mL(-1) with a detection limit of 33 fg mL( 1) (S/N=3). Additionally, the designed ECL immunosensor exhibited a promising application for other protein detection. PMID- 24054636 TI - Novel pro-oxidant activity assay for polyphenols, vitamins C and E using a modified CUPRAC method. AB - In this study, a direct assay, a modified CUPRAC (Cupric Ion Reducing Antioxidant Capacity) method, is developed to determine transition metal ion (Cu(II)) catalyzed pro-oxidant activity of polyphenolic compounds, vitamins C and E, and herbal samples in the presence of proteins containing thiol groups. Since transition metal ion-catalyzed pro-oxidant activity of phenolics is usually initiated with the reduction of the metal to lower oxidation states (as a prerequisite of Fenton-type reactions), this method involves the reduction of copper(II) ions to copper(I) by polyphenolic compounds (simultaneously giving rise to reactive species), binding of the formed Cu(I) to egg white protein -SH groups, and liberation of copper(I)-neocuproine (Cu(I)-Nc) chelate (showing maximum absorbance at 450 nm) by treating the incubation product with a neocuproine-ammonium acetate mixture. The proposed method is validated against atomic absorption spectrometric (AAS) determination of protein-bound copper and protein carbonyl assay of oxidative stress. The proposed assay is faster and more specific than the carbonyl assay, and uses low-cost reagents and equipment. Pro oxidant activity (i.e. proportional to absorbance) varies linearly over a relatively wide range with concentration, as opposed to the reciprocal correlations (i.e. linear regression of 1/(pro-oxidant activity) versus 1/concentration) of other similar assays. The pro-oxidant activity order of the tested antioxidant compounds in terms of 'Quercetin Equivalent Pro-oxidant Activity' (QREPA) coefficients is: gallic acid > epicatechin > quercetin ~ catechin > alpha-tocopherol > rosmarinic acid > trolox > caffeic acid > ascorbic acid. PMID- 24054637 TI - High-dimensional nested analysis of variance to assess the effect of production season, quality grade and steam pasteurization on the phenolic composition of fermented rooibos herbal tea. AB - A nested analysis of variance combined with simultaneous component analysis, ASCA, was proposed to model high-dimensional chromatographic data. The data were obtained from an experiment designed to investigate the effect of production season, quality grade and post-production processing (steam pasteurization) on the phenolic content of the infusion of the popular herbal tea, rooibos, at 'cup of-tea' strength. Specifically, a four-way analysis of variance where the experimental design involves nesting in two of the three crossed factors was considered. For the purpose of the study, batches of fermented rooibos plant material were sampled from each of four quality grades during three production seasons (2009, 2010 and 2011) and a sub-sample of each batch was steam pasteurized. The phenolic content of each rooibos infusion was characterized by high performance liquid chromatography (HPLC)-diode array detection (DAD). In contrast to previous studies, the complete HPLC-DAD signals were used in the chemometric analysis in order to take into account the entire phenolic profile. All factors had a significant effect on the phenolic content of a 'cup-of-tea' strength rooibos infusion. In particular, infusions prepared from the grade A (highest quality) samples contained a higher content of almost all phenolic compounds than the lower quality plant material. The variations of the content of isoorientin and orientin in the different quality grade infusions over production seasons are larger than the variations in the content of aspalathin and quercetin 3-O-robinobioside. Ferulic acid can be used as an indicator of the quality of rooibos tea as its content generally decreases with increasing tea quality. Steam pasteurization decreased the content of the majority of phenolic compounds in a 'cup-of-tea' strength rooibos infusion. PMID- 24054638 TI - Permanganate-bromide-silver nanoparticles as a new chemiluminescence system and its application to captopril determination. AB - A novel chemiluminescence (CL) system based on the oxidation of bromide by permanganate in sulfuric acid medium is introduced. The enhancing effect of silver nanoparticles (NPs), synthesized by chemical reduction method, on this reaction was studied. It was demonstrated that spherical silver nanoparticles with average size of 18 nm had a most remarkable catalytic effect on this reaction. CL emission wavelengths and UV-vis spectra were used to characterize the system and propose a possible mechanism. Furthermore, it was found that captopril inhibits the action of NPs and decreases the intensity of CL. Based on this phenomenon, a new CL method was developed for the determination of captopril in the 3.0 * 10(-10) to 1.0 * 10(-7) mol L(-1) concentration range with a detection limit (3s) of 0.12 nmol L(-1). The method was successfully applied to the determination of captopril in pharmaceutical formulations, human urine and serum samples. PMID- 24054639 TI - Determination of alcohol sulfates and alcohol ethoxysulfates in marine and river sediments using liquid chromatography-tandem mass spectrometry. AB - A novel and successful method has been developed for the identification and quantification of alcohol sulfates (AS) homologues and alcohol ethoxysulfates (AES) ethoxymers in marine and river sediment samples. The method involves the extraction of 5.00 g of dry sample with methanol using pressurized liquid extraction (PLE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). 2 Octylbenzene sulfonic acid sodium salt (2OC8-LAS) was used as internal standard. The analytical methods were applied to marine sediments collected from the coast of Almeria (South-east Spain) and river sediments collected from the Monachil river (Granada, South-east Spain). For AS homologues, the found limits of detection were 0.04-0.08 MUg g(-1) for marine and river sediments. For AES ethoxymers, the found limits of detection were 0.03-0.09 MUg g(-1) and 0.06-0.22 MUg g(-1) for marine and river sediments, respectively. The highest concentrations of AS and AES were found in river sediment samples. Significant differences were also observed between the behavior of short-chain compounds (C12) and long-chain compounds (C14 to C18). The influence of the physic-chemical properties of water on the occurrence of these compounds was also evaluated, and differences between long- and short-chain compounds were also observed. Additionally, principal components analyses were carried out in order to study the relationship between variables and to evaluate the sources of data variability and behavior patterns. Finally, important conclusions were drawn regarding the environmental behavior of AS and AES. PMID- 24054640 TI - A simple thermodynamic approach to predict responses from polymer-coated quartz crystal microbalance sensors exposed to organic vapors. AB - As of lately, the demand for developing artificial sensors with improved capabilities for the detection of explosives, toxics or drugs has increased. Ideally, sensor devices should provide high sensitivity and give a response that is specific to a given target molecule without being influenced by possible interfering molecules in the atmosphere. These properties strongly depend on the structure of the chemical compound used as a sensitive material. It is thus crucial to select the right compound and this step would be facilitated with the aid of predictive tools. The present investigations have been focused on a family of functionalized polysiloxane polymers deposited on a QCM device, producing only weak interactions compatible with reversible sensors. The quartz frequency variation at equilibrium has been linked to the partition coefficient that was evaluated using a thermodynamic description of the adsorption process. We have shown that the relative responses of two polymers can be directly determined from the Gibbs free enthalpy of mixing as determined from NMR measurements performed on neat liquid mixtures. An equivalence of this term-including both enthalpy and entropy contributions-to the energy interaction term calculated using Hansen solubility coefficients, has been demonstrated previously. These results constitute a basis for the development of a numerical program for calculating equilibrium sensor responses. For small molecules, the adsorption kinetics can be easily accounted for by a Fick diffusion coefficient estimated from the Van der Waals volume. PMID- 24054641 TI - Development of a highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) for the detection of phenylethanolamine A in tissue and feed samples and confirmed by liquid chromatography tandem mass spectrometry (LC-MS/MS). AB - Phenylethanolamine A (PA) is a new emerged beta-adrenergic agonist illegally used as feed additives for growth promotion. In this study, a highly sensitive and specific indirect competitive enzyme-linked immunosorbent assay (ELISA) for the detection of PA in tissue and feed samples was developed and confirmed by liquid chromatography tandem mass spectrometry (LC-MS/MS). By reduction of nitryl group to amino group, the PA derivative was synthesized and coupled to carrier proteins with diazobenzidine method. The antisera obtained from four immunized rabbits were characterized in terms of sensitivity and specificity. All antisera displayed high sensitivity with IC50 values lower than 0.48 ng mL(-1). The most sensitive ELISA was established with IC50 and limit of detection (LOD) values of 0.049 ng mL(-1) and 0.003 ng mL(-1), respectively. The cross-reactivity (CR) values of the antisera with three frequently used beta-adrenergic agonists (clenbuterol, salbutamol and ractopamine) were lesser than 0.39%; there was no CR of the antisera with other six compounds including two structurally related substances (isoproterenol, phenylephrine). To investigate the accuracy and precision of the assay, swine kidney, liver, meat and feed samples were fortified with PA at different content and analyzed by ELISA. Acceptable recovery rates of 92.2-113.7% and intra-assay coefficients of variation of 3.8-10.9% (n=3) were achieved. Seven spiked samples were simultaneously analyzed by ELISA and LC MS/MS. There was a high correlation coefficient of 0.9956 (n=7) between the two methods. The proposed ELISA proven to be a feasible quantitative/screening method for PA analysis in tissue and feed samples with the properties of high sensitivity and specificity, high sample throughput and low expensive. PMID- 24054642 TI - Study of extraction procedures for protein analysis in plankton samples by OFFGEL electrophoresis hyphenated with Lab-on-a-chip technology. AB - Extraction procedures for protein analysis from plankton samples were studied. OFFGEL electrophoresis combined with Lab-on-a-chip technology has been applied for protein analysis in plankton samples. BCR-414 (plankton) certified reference material from the European Commission was used to evaluate the protein extraction procedures. Three protein extraction procedures were studied: (1) by using Tris HCl buffer containing a protease inhibitor cocktail, (2) urea/triton X-100 buffer extraction, and (3) using the phenol/sodium dodecyl sulphate method after different washing steps with 10% trichloroacetic acid/acetone solution and methanol. The pellet of proteins obtained was dried and then dissolved in the OFFGEL buffer. Proteins were separated according to their isoelectric points by OFFGEL electrophoresis. This separation was performed using 24 cm, pH 3-10 IPG Dry Strips. The proteins present in each liquid fraction (24 fractions) were separated according to their molecular weight using a microfluidic Lab-on-a-chip electrophoresis with the Protein 80 LabChip kit. This kit allows for the separation of proteins with a molecular weight ranging from 5 to 80 kDa. Taking into account the intensity and the number of the protein bands obtained, the protein extraction procedure using the phenol/sodium dodecyl sulphate after different wash steps with 10% trichloroacetic acid/acetone solution was selected. The developed method was applied for protein determination in a fresh marine plankton sample. The proteins found in this sample have a molecular weight ranging from 6.4 to 57.3 kDa, and the proteins with highest molecular weight were in the OFFGEL fractions with an isoelectric point ranging from 4.40 to 8.60. The concentration of proteins were calculated using external calibration with Bovine Serum Albumin, and the protein concentrations varied from 50.0 to 925.9 ng uL( 1). PMID- 24054643 TI - Ethoximation-silylation approach for mono- and disaccharide analysis and characterization of their identification parameters by GC/MS. AB - The qualitative and quantitative analysis of complex carbohydrate mixtures is a challenging problem. When tackled by GC/MS, close retention times and largely similar mass spectra with no specific features complicate unambiguous identification, especially of monosaccharides. An optimized pre-capillary ethoximation-silylation GC/MS method for determination of monosaccharides and disaccharides was applied to a wide range of analytes (46 compounds). The two step derivatization resulted in a pair of syn and anti peaks with specific retention and intensity ratio. The resulting dataset of mass spectra was subjected to a PCA-based pattern recognition. An oxime peak identifier (OPI) of the carbohydrate analytes, based on the combination of an internal standard and the corresponding syn/anti peak ratios, increased the reliability of the identification of reducing carbohydrates. Finally, the introduced EtOx-TMS derivatization method was applied to four different carbohydrate matrices (agave sirup, maple sirup, palm sugar, and honey). PMID- 24054644 TI - ATR-FTIR spectroscopy for the determination of Na4EDTA in detergent aqueous solutions. AB - Fourier transform infrared spectroscopy in the attenuated total reflectance mode (ATR-FTIR) combined with partial last square (PLS) algorithms was used to design calibration and prediction models for a wide range of tetrasodium ethylenediaminetetraacetate (Na4EDTA) concentrations (0.1 to 28% w/w) in aqueous solutions. The spectra obtained using air and water as a background medium were tested for the best fit. The PLS models designed afforded a sufficient level of precision and accuracy to allow even very small amounts of Na4EDTA to be determined. A root mean square error of nearly 0.37 for the validation set was obtained. Over a concentration range below 5% w/w, the values estimated from a combination of ATR-FTIR spectroscopy and a PLS algorithm model were similar to those obtained from an HPLC analysis of NaFeEDTA complexes and subsequent detection by UV absorbance. However, the lowest detection limit for Na4EDTA concentrations afforded by this spectroscopic/chemometric method was 0.3% w/w. The PLS model was successfully used as a rapid and simple method to quantify Na4EDTA in aqueous solutions of industrial detergents as an alternative to HPLC UV analysis which involves time-consuming dilution and complexation processes. PMID- 24054645 TI - Isotope dilution mass spectrometry for quantitative elemental analysis of powdered samples by radiofrequency pulsed glow discharge time of flight mass spectrometry. AB - In recent years particular effort is being devoted to the development of pulsed glow discharges (PGDs) for mass spectrometry because this powering operation mode could offer important ionization analytical advantages. However, the capabilities of radiofrequency (RF) PGD coupled to a time of flight mass spectrometry (ToFMS) for accurate isotope ratio measurements have not been demonstrated yet. This work is focused on investigating different time positions along the pulse profile for the accurate measurement of isotope ratios. As a result, a method has been developed for the direct and simultaneous multielement determination of trace elements in powdered geological samples by RF-PGD-ToFMS in combination with isotope dilution mass spectrometry (IDMS) as an absolute measurement method directly traceable to the International System of Units. Optimized operating conditions were 70 W of applied radiofrequency power, 250 Pa of pressure, 2 ms of pulse width and 4 ms of pulse period, being argon the plasma gas used. To homogeneously distribute the added isotopically-enriched standards, lithium borate fusion of powdered solid samples was used as sample preparation approach. In this way, Cu, Zn, Ba and Pb were successfully determined by RF-PGD-ToF(IDMS) in two NIST Standard Reference Materials (SRM 2586 and SRM 2780) representing two different matrices of geological interest (soil and rock samples). Cu, Zn, Ba and Pb concentrations determined by RF-PGD-ToF(IDMS) were well in agreement with the certified values at 95% confidence interval and precisions below 12% relative standard deviation were observed for three independent analyses. Elemental concentrations investigated were in the range of 81-5770 mg/kg, demonstrating the potential of RF-PGD-ToF(IDMS) for a sensitive, accurate and robust analysis of powdered samples. PMID- 24054646 TI - Waterpipe smoking: analysis of the aroma profile of flavored waterpipe tobaccos. AB - In the last years the habit of smoking waterpipes has spread worldwide, especially among young people and emerged as global health issue. Although research is now under way for no less than 40 years in the field of waterpipe smoking, in comparison to cigarette smoking there is still insufficient knowledge on the real composition and the toxicity of the smoke inhaled and the resulting levels of exposure against particular hazardous ingredients. In most cases for waterpipe smoking a highly flavored tobacco called "moassel" is used. However, the number, quantity and toxicity of the added flavorings are widely unknown. In this study the static headspace gas chromatography-mass spectrometry (SHS-GC-MS) was used to identify 79 volatile flavor compounds present in waterpipe tobacco. Among these eleven compounds were analyzed quantitatively. The results show that waterpipe tobacco contains high amounts of the fragrance benzyl alcohol as well as considerable levels of limonene, linalool and eugenol, all of which are known as being allergenic in human skin. The proposed SHS-GC-MS method has been validated and found to be accurate, simple and characterized by low limits of detection (LOD) in the range of 0.016 to 4.3 ug/g tobacco for benzaldehyde and benzyl alcohol, respectively. The identification and characterization of waterpipe tobacco ingredients indeed reveals crucial for the assessment of potential health risks that may be posed by these additives in smokers. PMID- 24054647 TI - Improvements and application of a modified gas chromatography atomic fluorescence spectroscopy method for routine determination of methylmercury in biota samples. AB - Improvements to the application of a combined solid-phase microextraction followed by gas chromatography coupled to pyrolysis and atomic fluorescence spectrometry method (SPME-GC-AFS) for methylmercury (MeHg) determination in biota samples are presented. Our new method includes improvements in the methodology of determination and the quantification technique. A shaker instead of a stirrer was used, in order to reduce the possibility of sample contamination and to simplify cleaning procedures. Then, optimal rotation frequency and shaking time were settled at 800 rpm and 10 min, respectively. Moreover, the GC-AFS system was equipped with a valve and an argon heater to eliminate the effect of the decrease in analytical signal caused by the moisture released from SPME fiber. For its determination, MeHg was first extracted from biota samples with a 25% KOH solution (3h) and then it was quantified by two methods, a conventional double standard addition method (AC) and a modified matrix-matched calibration (MQ) which is two times faster than the AC method. Both procedures were successfully tested with certified reference materials, and applied for the first time to the determination of MeHg in muscle samples of goosander (Mergus merganser) and liver samples of white-tailed eagle (Haliaeetus albicilla) with values ranging from 1.19 to 3.84 mg/kg dry weight (dw), and from 0.69 to 6.23 mg kg(-1) dw, respectively. PMID- 24054648 TI - Simultaneous solid phase extraction and derivatization of aliphatic primary amines prior to separation and UV-absorbance detection. AB - To overcome the problem of poor sensitivity of capillary electrophoresis-UV absorbance for the detection of aliphatic amines, a solid phase extraction and derivatization scheme was developed. This work demonstrates successful coupling of amines to a chromophore immobilized on a solid phase and subsequent cleavage and analysis. Although the analysis of many types of amines is relevant for myriad applications, this paper focuses on the derivatization and separation of amines with environmental relevance. This work aims to provide the foundations for future developments of an integrated sample preparation microreactor capable of performing simultaneous derivatization, preconcentration, and sample cleanup for sensitive analysis of primary amines. PMID- 24054649 TI - Design and evaluation of an electrochemical immunosensor for measles serodiagnosis using measles-specific Immunoglobulin G antibodies. AB - The design of electrochemical immunosensors for the detection of measles-specific antibodies is reported. The measles-antigen modified surface was used as an antibody capture surface. The detection of measles-specific IgG antibodies was accomplished using the voltammetric method and horse-radish peroxidase (HRP) labeled secondary antibody (anti-IgG) as a detecting antibody. The potential applications of the designed immunosensor were evaluated in buffer and serum solutions. The immunosensor exhibited good linearity at concentrations less than 100 ng mL(-1) with R(2)=0.997 and the limit of detection of 6.60 ng mL(-1) at 3sigma. The potential application of the immunosensor was evaluated in the deliberately infected human and newborn calf serum samples with measles-IgG antibody mimicking real-life samples. The designed electrochemical immunosensor could differentiate between infected and un-infected serum samples as higher catalytic currents were obtained for infected serum samples. PMID- 24054650 TI - Glyphosate detection with ammonium nitrate and humic acids as potential interfering substances by pulsed voltammetry technique. AB - Pulsed voltammetry has been used to detect and quantify glyphosate on buffered water in presence of ammonium nitrate and humic substances. Glyphosate is the most widely used herbicide active ingredient in the world. It is a non-selective broad spectrum herbicide but some of its health and environmental effects are still being discussed. Nowadays, glyphosate pollution in water is being monitored but quantification techniques are slow and expensive. Glyphosate wastes are often detected in countryside water bodies where organic substances and fertilizers (commonly based on ammonium nitrate) may also be present. Glyphosate also forms complexes with humic acids so these compounds have also been taken into consideration. The objective of this research is to study the interference of these common pollutants in glyphosate measurements by pulsed voltammetry. The statistical treatment of the voltammetric data obtained lets us discriminate glyphosate from the other studied compounds and a mathematical model has been built to quantify glyphosate concentrations in a buffer despite the presence of humic substances and ammonium nitrate. In this model, the coefficient of determination (R(2)) is 0.977 and the RMSEP value is 2.96 * 10(-5) so the model is considered statistically valid. PMID- 24054651 TI - Characterization of soluble and bound EPS obtained from 2 submerged membrane bioreactors by 3D-EEM and HPSEC. AB - This research study deals with the quantification and characterization of the EPS obtained from two 25 L bench scale membrane bioreactors (MBRs) with micro-(MF MBR) and ultrafiltration (UF-MBR) submerged membranes. Both reactors were fed with synthetic water and operated for 168 days without sludge extraction, increasing their mixed liquor suspended solid (MLSS) concentration during the experimentation time. The characterization of soluble EPS (EPSs) was achieved by the centrifugation of mixed liquor and bound EPS (EPSb) by extraction using a cationic resin exchange (CER). EPS characterization was carried out by applying the 3-dimensional excitation-emission matrix fluorescence spectroscopy (3D-EEM) and high-performance size exclusion chromatography (HPSEC) with the aim of obtaining structural and functional information thereof. With regard to the 3D EEM analysis, fluorescence spectra of EPSb and EPSs showed 2 peaks in both MBRs at all the MLSS concentrations studied. The peaks obtained for EPSb were associated to soluble microbial by-product-like (predominantly protein-derived compounds) and to aromatic protein. For EPSs, the peaks were associated with humic and fulvic acids. In both MBRs, the fluorescence intensity (FI) of the peaks increased as MLSS and protein concentrations increased. The FI of the EPSs peaks was much lower than for EPSb. It was verified that the evolution of the FI clearly depends on the concentration of protein and humic acids for EPSb and EPSs, respectively. Chromatographic analysis showed that the intensity of the EPSb peak increased while the concentrations of MLSS did. Additionally, the mean MW calculated was always higher the higher the MLSS concentrations in the reactors. MW was higher for the MF-MBR than for the UF-MBR for the same MLSS concentrations demonstrating that the filtration carried out with a UF membrane lead to retentions of lower MW particles. PMID- 24054652 TI - Design of interpenetrated network MWCNT/poly(1,5-DAN) on interdigital electrode: toward NO2 gas sensing. AB - In this paper, poly(1,5-diaminonaphthalene) was interpenetrated into the network made of multiwalled carbon nanotubes (MWCNT) on platinum interdigital electrode (IDE) by electro-polymerization of 1,5-diaminonaphthalene (1,5-DAN). The electro polymerization process of 1,5-DAN on MWCNT was controlled by scanning the cyclic voltage at 50 mV s(-1) scan rate between -0.1 V and +0.95 V vs. saturated calomel electrode (SCE). The results of voltammetric responses and Raman spectroscopy represented that the films MWCNT/poly(1,5-DAN) were successfully created by this polymerization process. The films MWCNT/poly(1,5-DAN) were investigated for gas sensing to NO2 at low concentration level. The gas-sensing results showed that the response-recovery times were long and strongly affected by thickness of the film MWCNT/poly(1,5-DAN). Nevertheless, these films represented auspicious results for gas sensors operating at room temperature. PMID- 24054653 TI - Photoluminescent C-dots@RGO for sensitive detection of hydrogen peroxide and glucose. AB - We have demonstrated sensitive detections of hydrogen peroxide (H2O2) and glucose using reduced graphene oxide decorated with carbon dots (C-dots@RGO). The C dots@RGO prepared from catechin (reducing agent and carbon source) and graphene oxide via hydrothermal routes possesses excitation-wavelength-dependence photoluminescence (PL) characteristics, with maximum excitation and emission wavelengths of 365 and 440 nm, respectively. The C-dots@RGO is stable in solution containing NaCl up to 350 mM, but is quenched by reactive oxygen species (ROS). ROS reacts with H2O2 and thus its PL quenching toward the C-dots@RGO is minimized. When using C-dots@RGO and glucose oxidase (GOx), the PL assay allows detection of glucose in the presence of 10 uM of bovine serum albumin, with linearity over a concentration range from 1 to 60 uM (r=0.99) and a limit of detection (at a signal-to-noise ratio of 3) of 140 nM. The practicality of this assay has been validated by determining the concentrations of glucose in serum and saliva samples, with results of 5.1 +/- 0.6mM (n=3) and 117.9 +/- 8.1 MUM (n=3), respectively. Our simple and sensitive assay opens a new avenue of developing assays for various analytes using C-dots@RGO in conjunction with different enzymes. PMID- 24054654 TI - Ultralayered Co3O4 as a new adsorbent for preconcentration of Pb(II) from water, food, sediment and tobacco samples. AB - In this study, ultralayered Co3O4 adsorbent was synthesized and characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The surface area of the solid material was found to be 75.5m(2)g(-1) by BET method. The ultralayered Co3O4 was used for the first time as an effective adsorbent for the preconcentration of the Pb(II) ions in various samples prior to flame atomic absorption detection. Analytical parameters affecting the solid phase extraction of Pb(II) such as pH, adsorption and elution contact time, eluent volume and concentration, sample volume and common matrix ions were investigated. The recovery values for Pb(II) were found to be >= 92% even in the presence of 75,000 mg L(-1) Na(I), 75,000 mg L(-1) K(I), and 75,000 mg L(-1) Ca(II) ions. 10s vortexing time was enough for both adsorption and elution contact times. The elution was easily made with 2 mL of 2.0 mol L(-1) HNO3. The reusability (170 cycles) and adsorption capacity (35.5 mg g(-1)) of ultralayered Co3O4 were excellent. The preconcentration factor of the method and detection limit were found to be 175 and 0.72 ug L(-1), respectively. The described method was validated with certified reference material (RM 8704 Buffalo River Sediment, BCR 482 Licken and SPS-WW1 Batch 111-Wastewater) and spiked real samples. It was also applied for the preconcentration of Pb(II) ions in various water (well water, mineral water, waste water and sea water), food (cauliflower and barley), street sediment and tobacco samples. PMID- 24054655 TI - Dispersive liquid liquid microextraction combined with electrothermal vaporization inductively coupled plasma mass spectrometry for the speciation of inorganic selenium in environmental water samples. AB - A novel method based on dispersive liquid liquid microextraction (DLLME) followed by electrothermal vaporization inductively coupled plasma mass spectrometry (ETV ICP-MS) determination was proposed for the speciation of inorganic selenium by using 5-mercapto-3-phenyl-1,3,4-thiadiazole-2-thione potassium salt (Bismuthiol II) as both chelating reagent and chemical modifier. In this method, 500 MUL ethanol (as disperser solvent) containing 70 MUL chloroform (as extraction solvent) and 0.2 g L(-1) Bismuthiol II (as chelating reagent) was rapidly injected into a sample solution to form cloudy solution. The complex of Se(IV) with Bismuthiol II was rapidly extracted into the extraction solvent at pH 2.0, while Se(VI) was remained in the aqueous solutions. Thus, the separation of Se(IV) and Se(VI) could be realized. After centrifugation, the complex of Se(IV) and Bismuthiol II concentrated in the extraction solvent was introduced into the ETV-ICP-MS for determination of Se(IV). Se(VI) was reduced to Se(IV) prior to determination of total selenium, and its assay was based on subtracting Se(IV) from total selenium. The main factors influencing the DLLME and the vaporization behavior of selenium in ETV were investigated systematically. Under the optimal conditions, the limit of detection (LOD) for Se(IV) was 0.047 ng mL(-1). The relative standard deviation (RSD) was 7.2% (CSe(IV)=1.0 ng mL(-1), n=8) with an enhancement factor of 64.8-fold from only 5 mL of water sample. The proposed method was successfully applied to the speciation of inorganic selenium in different environmental water samples with recoveries ranging from 94.8 to 108% for the spiking samples. In order to validate the proposed method, a Certified Reference Material of Environment Water (GBW(E)080395) was analyzed, and the determined value obtained was in good agreement with the certified value. PMID- 24054656 TI - Individual volatile fatty acids determination by chromogenic derivatization coupled to multi-syringe chromatography. AB - In this paper, a new multisyringe chromatography (MSC) system is proposed for a simple and accurate measurement of individual volatile fatty acids (VFA) in anaerobic treatment processes. The determination method is based on the derivatization of VFA with N-(1-naphthyl) ethylenediamine (EDAN) followed by the separation of VFA derivatives on an Onyx C18 monolithic column (25 mm * 4.6mm i.d.). Chromatographic separation conditions have been investigated and were found to be optimal with a mixture of acetonitrile and formic acid 0.1% (ratio 35/65), providing good separation of C2-C5 VFA in 8 min. Optimization of the derivatization reaction was also carried out with special attention paid to the buffering capacity of the reaction medium, so as to be able to deal with samples of various characteristics in terms of alkalinity or of VFA concentration range. Individual VFA could be quantified between 0.05-2.5 g L(-1) with LOD of 0.01-0.02 g L(-1). Overall procedure time was about 18 min for one analytical cycle, which fulfils the requirement of real-time monitoring of an anaerobic digester. Validation of the system developed has been assessed by application of the procedure to sludge samples from various origins, and comparative results with gas chromatography analyses showed satisfactory correlation (R2>0.98). PMID- 24054657 TI - Magnetic multi-wall carbon nanotube nanocomposite as an adsorbent for preconcentration and determination of lead (II) and manganese (II) in various matrices. AB - Magnetic multi-wall carbon nanotube (MMWCNT) nanocomposite was synthesized and used as an adsorbent for preconcentration and determination of lead (II) and manganese (II). The properties of MMWCNT were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Energy dispersive X-ray spectrometry (EDS) and fourier transform infrared spectrophotometer (FT-IR). This adsorbent was found to be advantageous over conventional solid phase extraction (SPE) in terms of operational simplicity and low time-consuming. MMWCNT, carrying target metals, was easily separated from the aqueous solutions with the help of an external magnet; so, no filtration or centrifugation was necessary. After extraction and collection of MMWCNT, the adsorbed analytes were eluted and analyzed by flame atomic absorption spectrometry (FAAS). Experiments were carried out to investigate the influence of different sorption/desorption parameters. Under the optimized conditions, detection limits and enhancement factors of the proposed method for Pb and Mn were 1.0 and 0.6 ug L(-1), 390 and 697 respectively. The presented procedure was successfully applied for determination of Pb(II) and Mn (II) contents in lipstick, rice samples and accuracy was evaluated analyzing a certified reference material Seronorm(TM) Urine LOT NO2525. PMID- 24054658 TI - Optimization of the arsenazo-III method for the determination of uranium in water and plant samples. AB - This work reports a reliable, fast and optimized photometric technique based on the specific chemical complexation of uranyl ion with arsenazo-III. In the case of solid samples (plant samples), for which mineralization under acidic and oxidative conditions was used, addition of ascorbic acid led to stabilization of the arsenazo-uranyl complex over time. The results, in total agreement with data obtained from alpha and gamma spectrometries, demonstrate that the present technique is able to precisely quantify uranium in water as well as in plant samples, within the MUg/L and mg/g ranges respectively. PMID- 24054659 TI - An integrated approach to the simultaneous selection of variables, mathematical pre-processing and calibration samples in partial least-squares multivariate calibration. AB - A new optimization strategy for multivariate partial-least-squares (PLS) regression analysis is described. It was achieved by integrating three efficient strategies to improve PLS calibration models: (1) variable selection based on ant colony optimization, (2) mathematical pre-processing selection by a genetic algorithm, and (3) sample selection through a distance-based procedure. Outlier detection has also been included as part of the model optimization. All the above procedures have been combined into a single algorithm, whose aim is to find the best PLS calibration model within a Monte Carlo-type philosophy. Simulated and experimental examples are employed to illustrate the success of the proposed approach. PMID- 24054660 TI - Real-time and sensitive detection of Salmonella Typhimurium using an automated quartz crystal microbalance (QCM) instrument with nanoparticles amplification. AB - The accidental contamination of Salmonella in raw and processed foods is a major problem for the food industry worldwide. At present many of the currently used methods for Salmonella detection are time and labour intensive. Therefore, rapid detection is a key to the prevention and identification of problems related to health and safety. This paper describes the application of a new quartz crystal microbalance (QCM) instrument with a microfluidic system for the rapid and real time detection of Salmonella Typhimurim. The QCMA-1 bare gold sensor chip which contain two sensing array was modified by covalently immobilising the monoclonal capture antibody on the active spot and a mouse IgG antibody on the control spot using a conventional amine coupling chemistry (EDC-NHS). The binding of the Salmonella cells onto the immobilised anti-Salmonella antibody alters the sensor frequency which was correlated to cells concentration in the buffer samples. Salmonella cells were detected using direct, sandwich, and sandwich assay with antibody conjugated gold-nanoparticles. The performance of the QCM immunosensor developed with gold-nanoparticles gave the highest sensitivity with a limit of detection (LOD) ~10-20 colony forming unit (CFU) ml(-1) compared to direct and sandwich assay (1.83 * 10(2) CFU ml(-1) and 1.01 * 10(2) CFU ml(-1), respectively). The sensor showed good sensitivity and selectivity for Salmonella in the presence of other bacteria in real food samples and helped in reducing the pre-enrichment step, hence, demonstrating the potential of this technology for the rapid and sensitive microbial analysis. PMID- 24054661 TI - Determination of nitroaromatic and nitramine type energetic materials in synthetic and real mixtures by cyclic voltammetry. AB - Nitro-explosives contain reducible aromatic -NO2 groups or cyclic >N-NO2 bonds that may undergo reductive cleavage. This work reports the development of a cyclic voltammetric (CV) assay for nitro-aromatics (trinitrotoluene (TNT), dinitrotoluene (DNT)) and nitramines (1,3,5-trinitro-1,3,5-triazacyclohexane (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX)) using a glassy carbon electrode. This determination was first used for these energetic materials by resolving current responses of reduction potentials primarily due to one constituent but partly contributed by other constituents. Calibration curves of current intensity versus concentration were linear in the range of 30-120 mg L( 1) for RDX with a limit of detection (LOD) of 10.2 mg L(-1), 40-120 mg L(-1) for HMX (LOD=11.7 mg L(-1)), 40-120 mg L(-1) for TNT (LOD=11.2 mg L(-1)), and 40-140 mg L(-1) for DNT (LOD=10.8 mg L(-1)). Results showed that the CV method could provide a sensitive approach for the simultaneous determination of RDX and TNT in synthetic and real mixtures. Deconvolution of current contributions of mixtures at peak potentials of constituents was performed by multiple linear regression. The proposed method was successfully applied to the analysis of military explosives comp A5 and octol, and method validation was performed both against HPLC on a comp B (TNT+RDX) sample and against GC-MS on real post-blast residual samples containing both explosives. PMID- 24054662 TI - A new electrochemical sensor for OH radicals detection. AB - A new, cheap modified electrode for indirect detection of OH radical is described. A glassy carbon (GC) electrode was modified with a polyphenol film prepared by oxidative potentiostatic electropolymerization of 0.05 M phenol in 1M H2SO4. The film having a thickness of ~10nm perfectly covered the GC surface and inhibited the charge transfer of many redox species. The degradation of the polyphenol film, that was induced by OH radicals generated by Fenton reaction or by H2O2 photolysis, is the analytical signal and it was evaluated by cyclic voltammetry and chronoamperometry using the redox probe Ru(NH3)6(3+). Some simulations of the kinetics of the reactions occurring in the solution bulk and near the electrode surface were carried out to fully understand the processes that lead to the analytical signal. The modified electrode was used to evaluate the performances of different TiO2-based photocatalysts and the results were successfully compared with those obtained from a traditional HPLC method that is based on the determination of the hydroxylation products of salicylic acid. PMID- 24054663 TI - Simultaneous analysis of eight phenolic environmental estrogens in blood using dispersive micro-solid-phase extraction combined with ultra fast liquid chromatography-tandem mass spectrometry. AB - A novel, simple and sensitive method was developed for the simultaneous determination of eight phenolic environmental estrogens in blood by using the dispersive micro-solid-phase extraction (d-u-SPE) procedure combined with ultra fast liquid chromatography-tandem quadrupole mass spectrometry (UFLC-MS/MS). The excellent nanomaterials tetraethylenepentamine-functionalized magnetic polymer was used as an adsorbent, and the main factors affecting the extraction efficiency were investigated in detail. All target compounds showed good linearities in the tested range with correlation coefficients (r) higher than 0.999. The mean recoveries were in the range of 85.0-105.0%. The intra-day and inter-day relative standard deviations (RSDs) were lower than 4.9% and 5.2%, respectively. The limits of quantification for the eight phenolic environmental estrogens were between 0.075 and 0.42 ug L(-1). The developed method can be applied to the routine analyses for the determination of the eight phenolic environmental estrogens in blood samples. PMID- 24054664 TI - Rapid identification of volatile compounds in fresh seaweed. AB - Volatile component profiles of fresh seaweed Laminaria spp and Undaria pinnatifida were analyzed using dynamic headspace for volatile profile evaluation, which allows the direct analysis of small quantities of sample without previous treatment and have been identified by GC-MS. Alcohols were the most important class of volatile compounds identified in Wakame and Kombu (25 and 29% respectively); nine alcohols were identified. The hydrocarbons group constitute the second most important family of volatiles, in both samples entire similar % area total 13-14%, being the butane the most abundant hydrocarbon. Aldehydes and halogenated compounds are higher in Laminaria spp (10-9% total area), whereas Undaria pinnatifida presents 4-0.23% respectively. PMID- 24054665 TI - A novel organic-inorganic hybrid monolithic column prepared in-situ in a microchip and its application for the determination of 2-amino-4-chlorophenol in chlorzoxazone tablets. AB - gamma-Alumina nanoparticles (gamma-Al2O3) were introduced to the conventional poly(methacrylic acid-co-ethylene glycol dimethacrylate) (MAA-co-EGDMA) monolith to prepare a novel organic-inorganic hybrid monolith, poly(MAA-co-EGDMA)-Al2O3 monolith. The polymerization was induced in-situ with UV irradiation in an ultraviolet transparent polymethyl methacrylate (PMMA) microfluidic chip. The monolith-based solid phase microextraction system was used for the on-line determination of 2-amino-4-chlorophenol (ACP) in chlorzoxazone tablets coupled with an optical fiber spectrophotometer. Several parameters affecting the adsorption/desorption, including sample pH value, sample flow rate, sampling time, eluent flow rate, and eluting time, were investigated in detail. Under the optimized conditions, limit of detection (LOD) and limit of quantification (LOQ) of the method were calculated to be 2.8 and 9.1 ug L(-1), respectively, with the relative standard deviation (RSD) of 3.1%. PMID- 24054666 TI - Dispersive liquid-liquid microextraction for the determination of vitamins D and K in foods by liquid chromatography with diode-array and atmospheric pressure chemical ionization-mass spectrometry detection. AB - A simple and rapid method was developed using reversed-phase liquid chromatography (LC) with both diode array (DAD) and atmospheric pressure chemical ionization mass spectrometric (APCI-MS) detection, for the simultaneous analysis of the vitamins ergocalciferol (D2), cholecalciferol (D3), phylloquinone (K1), menaquinone-4 (K2) and a synthetic form of vitamin K, menadione (K3). The Taguchi experimental method, an orthogonal array design (OAD), was used to optimize an efficient and clean preconcentration step based on dispersive liquid-liquid microextraction (DLLME). A factorial design was applied with six factors and three levels for each factor, namely, carbon tetrachloride volume, methanol volume, aqueous sample volume, pH of sample, sodium chloride concentration and time of the centrifugation step. The DLLME optimized procedure consisted of rapidly injecting 3 mL of acetonitrile (disperser solvent) containing 150 uL carbon tetrachloride (extraction solvent) into the aqueous sample, thereby forming a cloudy solution. Phase separation was performed by centrifugation, and the sedimented phase was evaporated with nitrogen, reconstituted with 50 uL of acetonitrile, and injected. The LC analyses were carried out using a mobile phase composed of acetonitrile, 2-propanol and water, under gradient elution. Quantification was carried out by the standard additions method. The APCI-MS spectra, in combination with UV spectra, permitted the correct identification of compounds in the food samples. The method was validated according to international guidelines and using a certified reference material. The validated method was applied for the analysis of vitamins D and K in infant foods and several green vegetables. There was little variability in the forms of vitamin K present in vegetables, with the most abundant vitamer in all the samples being phylloquinone, while menadione could not be detected. Conversely, cholecalciferol, which is present in food of animal origin, was the main form in infant foods, while ergocalciferol was not detected. PMID- 24054667 TI - Speciation of antimony(III) and antimony(V) by electrothermal atomic absorption spectrometry after ultrasound-assisted emulsification of solidified floating organic drop microextraction. AB - A simple, sensitive and efficient method of ultrasound-assisted emulsification of solidified floating organic drop microextraction (USE-SFODME) coupled to electrothermal atomic absorption spectrometry for the speciation of antimony at different oxidation state Sb(III)/Sb(V) in environmental samples was established. In this method, the hydrophobic complex of Sb(III) with sodium diethyldithiocarbamate (DDTC) is extracted by 1-undecanol at pH 9.0, while Sb(V) remains in aqueous phase. Sb(V) content can be calculated by subtracting Sb(III) from the total antimony after reducing Sb(V) to Sb(III) by l-cysteine. Various factors affecting USE-SFODME including pH, extraction solvent and its volume, concentration of DDTC, sonication time, and extraction temperature were investigated. Under the optimized conditions, the calibration curve was linear in the range from 0.05 to 10.0 ng mL(-1), with the limit of detection (3sigma) 9.89 ng L(-1) for Sb(III). The relative standard deviation for Sb(III) was 4.5% (n=9, c=1.0 ng mL(-1)). This method was validated against the certified reference materials (GSB 07-1376-2001, GBW07441), and applied to the speciation of antimony in environmental samples (soil and water samples) with satisfactory results. PMID- 24054668 TI - A DNA machine for sensitive and homogeneous DNA detection via lambda exonuclease assisted amplification. AB - This work designs a DNA machine with three assistant DNAs and lambda exonuclease (Exo-lambda) for sensitive and homogeneous fluorescent detection of DNA. The selective digestion of Exo-lambda to blunt or recessed 5'-phosphorylated strand of probe 1-probe 2 duplex results in the release of target DNA and probe 2 to produce the fluorescence restoring of fluorophore labeled to probe 1. The released target DNA could hybridize with another probe 1-probe 2 duplex to trigger the target recycling for signal amplification, while the released probe 2 hybridized with molecular beacon to restore its fluorescence for signal enhancement. This DNA machine showed a fast response to target DNA with a linear concentration range from 0.4 pM to 4 nM. The limit of detection was 68 fM at a signal-to-noise ratio of 3. The high selectivity of the method may result from the Exo-lambda's specific recognition-site of double-stranded DNA and the specific hybridization of target DNA with probe 1-probe 2 duplex. This DNA machine with the homogenous detection, rapid response as well as simplicity provides a new approach for sensitive detection of DNA. PMID- 24054669 TI - Multifunctional phenylboronic acid-tagged fluorescent silica nanoparticles via thiol-ene click reaction for imaging sialic acid expressed on living cells. AB - Multifunctional fluorescent silica nanoparticles with phenylboronic acid tags were developed for labeling sialic acid on the surface of living cancer cells. In this paper, fluorescent silica nanoparticles (FSNPs) with strong and stable emission at 515 nm were firstly prepared through a reverse microemulsion process, and then modified with highly selective phenylboronic acid (PBA) tags on their surface via an aqueous 'thiol-ene' click reaction. These nanoparticles had a hydrodynamic diameter of 92.6 +/- 9.1 nm, and a bright fluorescence signal, which is 366 times higher than that of a single dye molecule. Meanwhile, these PBA tagged FSNPs were found very stable in aqueous solution as well as in cell culture medium, verified by transmission electron microscopy, X-ray photoelectron spectroscopy and zeta potential analysis. The over-expressed sialic acid (SA) on the membrane of living HeLa cells was visualized in situ by a confocal laser scanning microscopy, ascribed to the specific interaction between PBA and SA. Thus, the PBA-FSBPs showed a great potential in probing SA expressed on living cells with high selectivity and sensitivity. PMID- 24054670 TI - Highly sensitive resonance light scattering bioassay for heparin based on polyethyleneimine-capped Ag nanoclusters. AB - Ag nanoclusters (NCs) possessed distinct physical and chemical attributes that made them excellent scaffolds for the development of novel bio-analytical methodology. In the present work, a green approach for the preparation of Ag nanoclusters (NCs) was proposed on the basis of templated polyethyleneimine (PEI) assisted in-situ reductive crystallization of Ag (I), and then a sensitive resonance light scattering bioassay for the determination of heparin was established on the basis of the enhanced resonance light scattering of the PEI capped Ag NCs during the presence of heparin. Further investigation indicated that the molecular weight of PEI, the PEI/Ag (I) ratio and the pH value of reaction conditions had great influence on the formation of Ag NCs, which was directly correlated to resonance light scattering. The bioassay allows sensitive and selective detection of heparin with a detection limit of 27.5 nM, and successfully applied for the determination of heparin in human serum samples. PMID- 24054671 TI - Anionic polythiophene derivative as peroxidase mimetics and their application for detection of hydrogen peroxide and glucose. AB - In this paper, we discovered that the anionic polythiophenes derivative, poly[2 (3-thienyl)ethyloxy-4-butylsulfonate] (PTEBS), possesses intrinsic peroxidase like activity that can catalyze the reaction of peroxidase substrate 3,3',5,5' tetramethylbenzidine (TMB) in the presence of H2O2 to produce a blue color reaction, which provides colorimetric detection of H2O2. PTEBS exhibits several advantages such as high catalytic efficiency, good stability, and rapid response over horseradish peroxidase (HRP). By coupling the oxidation of glucose catalyzed by glucose oxidase, a simple, inexpensive, highly sensitive and selective colorimetric method for glucose detection has been developed. The absorbance was proportional to the concentration of glucose in the range from 0.01 to 0.5mM with a detection limit of 0.004 mM. This work is not only of importance for a better understanding of the unique properties of polythiophenes derivative but also of great potential for medical diagnostics and biotechnology. PMID- 24054672 TI - Brush polymer modified and lectin immobilized core-shell microparticle for highly efficient glycoprotein/glycopeptide enrichment. AB - Protein glycosylation regulates numerous important biological processes and plays key roles in many diseases including cancer, diabetes and inflammation. The ability to efficiently profile variation of protein glycosylation in biological samples is very useful for identifying new diagnostic biomarkers or developing new therapeutic approaches. Due to the low availability of glycoprotein/glycopeptide from natural sources, enrichment before mass spectrometry (MS) analysis is usually a prerequisite. Affinity enrichment using lectins is currently one of the most widely adopted approaches. Conventionally, lectins are immobilized on solid supporting materials for sample recovery. However, the limited specific surface area, high steric hindrance and rigid nature of such supporting materials restricts lectin loading amount and results in low flexibility as well as accessibility of the immobilized lectins. Therefore, we proposed using core-shell microparticles composed of silica core and brush-like polymer chains shell for improved lectin immobilization. The surface bound brush-like polymer are synthesized by in situ growth of polymer chains from microparticle surface using surface initiated atom transfer radical polymerization (SI-ATRP). The flexible non-crosslinked polymer chains not only provide numerous binding sites, but also work as three-dimensional support for lectin immobilization, which leads to high loading amount and good accessibility of the immobilized lectin. Successful enrichment which facilitated glycoprotein/glycopeptide identification is demonstrated. PMID- 24054673 TI - Selective turn-on fluorescence sensor for Ag+ using cysteamine capped CdS quantum dots: determination of free Ag+ in silver nanoparticles solution. AB - Cadmium sulfide quantum dots capped with cysteamine (Cys-CdS QDs) were demonstrated as a selective fluorescence probe for sensing of free trace silver ions. The fluorescence intensity of the Cys-CdS QDs can be enhanced only in the presence of free Ag(+) and the fluorescence spectrum was slightly red shift from the original spectra. In addition, the fluorescence intensities were linearly increased upon increasing Ag(+) concentration. At the optimized condition for Ag(+) detection, when adding other metal ions to the Cys-CdS QDs solution, fluorescence spectra of Cys-CdS QDs did not change significantly revealing good selectivity of the sensors towards Ag(+). The working linear concentration range was found to be 0.1-1.5 uM with LOD of 68 nM. The proposed sensor was then applied to detect free Ag(+) in the silver nanoparticles solution. The results showed that the proposed sensor can be efficiently used with good accuracy and precision providing the simple method for detection of free Ag(+) in silver nanoparticles of quality control products. PMID- 24054674 TI - Enhanced wavelength modulation SPR biosensor based on gold nanorods for immunoglobulin detection. AB - In this study, gold nanorods (GNRs) and graphene oxide (GO) were used to enhance the sensitivity of wavelength modulation surface plasmon resonance (SPR) biosensor to detect bovine IgG. GNRs were prepared by a method of seed-mediated growth and immobilized on the Au film through 1,6-hexanedithiol by covalent attachment. GO was prepared by a modified Hummers and Offeman's method and can be assembled on the sensor surface through electrostatic interaction with GNRs. Meanwhile, GO was used as a support to immobilize antibody directly. The biosensor based on GNRs/GO sensing membrane exhibits a satisfactory response for bovine IgG in the concentration range of 0.075-40.00 ug mL(-1). For comparison, the biosensor based on 3-mercaptopropinic acid (MPA) and the biosensor based on GNRs/MPA sensing membrane were also studied for the detection of bovine IgG. The biosensor based on MPA shows a response for bovine IgG in the concentration range of 2.50-40.00 ug mL(-1). The biosensor based on GNRs/MPA sensing membrane shows a response for bovine IgG in the concentration range of 0.30-40.00 ug mL(-1). As a result, the biosensor based on GNRs/GO sensing membrane was found to be the most sensitive of the three types of biosensors. PMID- 24054675 TI - Te oxide nanowires as advanced materials for amperometric nonenzymatic hydrogen peroxide sensing. AB - A new nonenzymatic platinum Te oxide nanowires modified electrode (Pt/TeO2-NWs) for amperometric detection of hydrogen peroxide (H2O2) is proposed. The modified electrode has been developed by direct drop casting, with TeO2 nanowires (TeO2 NWs), synthesized by thermal evaporation of Te(0) in an oxygen atmosphere. The morphological and spectroscopic characterization of the TeO2-NWs as synthesized on Pt foil was performed by scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) analysis. XPS and XRD analyses are especially involved to gain information on the chemical environment of TeO2 NWs in contact with Pt surface. Moreover electrochemical characterization of these new modified Pt/TeO2-NWs modified electrodes was performed by Cyclic Voltammetry (CV) and Cronoamperometry (CA) in phosphate buffer (pH=7; I=0.2) to investigate the sensing properties of this material against H2O2. The proposed sensor exhibits a wide linear and dynamic range from 2 uM to 16 mM (R(2)=0.9998) and the detection limit is estimated to be 0.6 uM (S/N=3). Moreover, this sensor shows a rapid amperometric response time of less than 5s and possessed good reproducibility. These results indicate that Pt/TeO2-NWs composite is suitable to be used as material for sensing applications. PMID- 24054676 TI - Differentiation of glucose-containing disaccharides isomers by fragmentation of the deprotonated non-covalent dimers using negative electrospray ionization tandem mass spectrometry. AB - In this work, the glucose-containing disaccharide isomers were studied using negative electrospray ionization tandem mass spectrometry (ESI-MS/MS). Interestingly, the full-scan mass spectra of the disaccharides revealed that the deprotonated dimers were the predominant gas phase ions during ionization process. Importantly, several diagnostic fragment ions relative to linkage positions and anomeric configurations, arising from the covalent bond dissociation of dimers without breakdown of the non-covalent complexes, can be detected in the tandem mass spectra. Based on the scarce fragmentation characteristic, an original and simple approach for structural discrimination of disaccharide isomers was put forward. In addition, density functional theory (DFT) was employed to find out the reason why several fragmentations of intramolecular sugar bonds had preceded breakdown of the non-covalent complexes. PMID- 24054677 TI - Determination of carbonyl compounds in particulate matter PM2.5 by in-tube solid phase microextraction coupled to capillary liquid chromatography/mass spectrometry. AB - In this paper, a new procedure based on in-tube solid phase microextraction (IT SPME)-capillary liquid chromatography hyphenated to mass spectrometry detection by using microelectrospray ionisation (CapLC-MS), has been reported. The device was proposed to quantify 12 carbonyl compounds (10 aliphatic aldehydes, an unsaturated aldehyde and a ketone) derivatized with 2,4-dinitrophenylhidrazine (DNPH) reagent in aqueous extracts of PM2.5. This methodology involves the on line preconcentration of DNPH-carbonyl compounds derivatives coupled to the CapLC MS system, efficiently providing appropriate sensitivity for the determination of the target analytes. Detection limits for the analytes ranged between 0.9 and 8.2 ng L(-1). These values represent a remarkable improvement over the existing methods since PM2.5 analysis can be carried out avoiding off-line preconcentration steps. The procedure is also proved useful for analysing water samples. Under the optimised conditions, IT-SPME-CapLC-MS shows satisfactory recovery values (80-90%) for spiked samples. PMID- 24054678 TI - Evaluation of adsorbents for volatile methyl siloxanes sampling based on the determination of their breakthrough volume. AB - Volatile methyl siloxanes (VMS) have been detected in many different atmospheres such as biogas, sewage sludge, landfill gas, gasoline and ambient air. In these different atmospheres, their presence can involve several contamination problems and negative effects in industrial processes, their identification and quantification become a real challenge. Up to now there is no standardized procedure for VMS quantification, the sampling step remaining the major obstacle. Sampling gas through sorbent tube followed by analysis on TD-GC-MS is one of the reliable possibilities. It gathers sampling and preconcentration in one step and allows discrimination between all VMS, despite the difficulty to choose the appropriate adsorbent in order to avoid loss of analytes during sampling. In this context, this work deals with the comparison of different types of adsorbents based on the determination of the VMS breakthrough volume (BV). Although Tenax TA is the most widely used adsorbent, experiments show low BV values for the lightest VMS. At 25 degrees C, the BV of TMS and L2 are, respectively, 0.2 and 0.44 L g(-1) which can contribute to an underestimation in concentration during their quantification. Carbosieve SIII usually used for C2-C5, did not adsorb light VMS as it was expected, and breakthrough volume obtained for VMS are more than ten times less than the values obtained for Tenax. On other hand, Chromosorb 106 and Carboxen 1000 in association with Carbotrap C and Carbotrap proved to be appropriated for VMS sampling, due to the high breakthrough volumes obtained for the lightest compounds comparing to the other adsorbents. The BVs of TMS for Carboxen 1000 and Chromosorb 106 are 1.2 * 10(4) and 39 L g(-1), respectively, and 49 * 10(4) and 1142 L g(-1) for L2, respectively. PMID- 24054679 TI - Tile-based Fisher-ratio software for improved feature selection analysis of comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry data. AB - Comprehensive two-dimensional (2D) gas chromatography coupled with time-of-flight mass spectrometry (GC * GC-TOFMS) is a highly capable instrumental platform that produces complex and information-rich multi-dimensional chemical data. The data can be initially overwhelming, especially when many samples (of various sample classes) are analyzed with multiple injections for each sample. Thus, the data must be analyzed in such a way as to extract the most meaningful information. The pixel-based and peak table-based Fisher ratio algorithmic approaches have been used successfully in the past to reduce the multi-dimensional data down to those chemical compounds that are changing between the sample classes relative to those that are not changing (i.e., chemical feature selection). We report on the initial development of a computationally fast novel tile-based Fisher-ratio software that addresses the challenges due to 2D retention time misalignment without explicitly aligning the data, which is often a shortcoming for both pixel based and peak table-based algorithmic approaches. Concurrently, the tile-based Fisher-ratio algorithm significantly improves the sensitivity contrast of true positives against a background of potential false positives and noise. In this study, eight compounds, plus one internal standard, were spiked into diesel at various concentrations. The tile-based F-ratio algorithmic approach was able to "discover" all spiked analytes, within the complex diesel sample matrix with thousands of potential false positives, in each possible concentration comparison, even at the lowest absolute spiked analyte concentration ratio of 1.06, the ratio between the concentrations in the spiked diesel sample to the native concentration in diesel. PMID- 24054680 TI - Determination of N-nitrosamines and nicotine in air particulate matter samples by pressurised liquid extraction and gas chromatography-ion trap tandem mass spectrometry. AB - N-nitrosamines are potentially hazardous pollutants, classified as probable carcinogenic and mutagenic by the U.S. Environmental Protection Agency (EPA). In this paper, the presence of these pollutants was studied in air samples taken at different locations of Tarragona (urban and harbour). As a result, a reliable method has been developed for determining N-nitrosamines and nicotine based on pressurised liquid extraction (PLE) and gas chromatography-(chemical ionisation) ion trap tandem mass spectrometry (GC-(CI)MS/MS). The chromatographic analysis enables the determination of these compounds in less than 13 min with total separation and good resolution between the compounds. Recovery values were higher than 80% for most of the compounds and the repeatability of the method was under 18% (5 ng m(-3), %RSD, n=4). MDLs were between 0.1 ng m(-3) (NMor and NPip) and 2 ng m(-3) (NMEA). NMor, NPyr, NPip and nicotine were the most frequent compounds in urban and harbour samples at concentration levels between 0.3 ng m(-3) (NPyr) and 12.5 ng m(-3) (nicotine) and between 0.13 ng m(-3) (NPyr) and 3.8 ng m(-3) (nicotine), respectively. PMID- 24054681 TI - Sb(V) and Sb(III) distribution in human erythrocytes: speciation methodology and the influence of temperature, time and anticoagulants. AB - In this research a new method was developed and optimized for the determination of Sb(V) and Sb(III) in human erythrocytes fractions (plasma and cytoplasm) by high performance liquid chromatography with hydride generation atomic fluorescence spectrometry. The method considers the first step of samples cleaning by protein precipitation by salting out followed by C18 solid phase extraction, EDTA elution, and finally a chromatographic separation by using anion exchange PRPX-100 (100 mm * 4.1mm) and EDTA 20 mmol L(-1) as mobile phase. The method was optimized by experimental design with a recovery of 90% for Sb(V) and 55-75% for Sb(III) approximately. The analytical method was applied to study the distribution of Sb(V) and Sb(III) in human erythrocytes considering temperature and time of incubations and with special attention about the influence of the anticoagulant. Results showed that both Sb(V) and Sb(III) are capable to enter the red blood cell in a proportion of approximately 40-60%. On the other hand, both species are then excreted from the interior of the cell, where the percentage considerably decreased from approximately 60 to less than 30% within the cell. An increase in the culture temperature increases the capacity of Sb(V) and Sb(III) to penetrate the membrane barrier and reach the cytoplasm. In order to preserve the original distribution of Sb in blood, heparin seems to be the best anticoagulant for sample preservation. PMID- 24054682 TI - Analytical application of polymethylene blue-multiwalled carbon nanotubes modified glassy carbon electrode on anticancer drug irinotecan and determination of its ionization constant value. AB - The voltammetric behavior of anticancer drug irinotecan (IRT) was investigated at poly (methylene blue)/multi-walled carbon nanotube (PMB/MWCNT) modified glassy carbon electrode (GCE). The modified electrode surface was characterized by a scanning electron microscope (SEM). The PMB/MWCNT modified GCE exhibits a distinct shift of the oxidation potential of IRT on the cathodic direction and a considerable enhancement of the peak current compared with bare electrode. The calibration curve was linear between the concentration range 8.0 * 10(-6) and 8.0 * 10(-5)M with the detection limit of 2.14 * 10(-7)M by differential pulse voltammetry in pH 10.0 Britton-Robinson buffer solution. Controlled potential coulometry was applied to find transferred electron numbers due to the oxidation of IRT. In this study, the pKa value of IRT was also determined by the dependence of the retention factor on the pH of the mobile phase. The effect of the mobile phase composition on the ionization constant was studied by measuring the pKa at different acetonitrile-water mixtures, ranging between 35 and 50% (v/v) using the reversed-phase liquid chromatography (RP-LC) method with UV detector. IRT was exposed to thermal, photolytic, hydrolytic and oxidative stress conditions, and the stressed samples were detected by the proposed method. Sensitive, rapid, and fully validated electrochemical and RP-LC methods for the determination of IRT in its dosage form were presented in details. PMID- 24054683 TI - Sol-gel molecularly imprinted polymer for selective solid phase microextraction of organophosphorous pesticides. AB - A sol-gel technique was applied for the preparation of water-compatible molecularly imprinted polymer (MIP) for solid phase microextraction (SPME) using diazinon as template and polyethylene glycol as functional monomer. The MIP coated fiber demonstrated much better selectivity to diazinon and its structural analogs in aqueous cucumber sample than in distilled water, indicating its potential in real samples. Thanks to its specific adsorption as well as rough and porous surface, the coating revealed rather larger extraction capability than the non-imprinted polymer and commercial fibers. In addition, the fiber exhibited excellent thermal (about 350 degrees C) and chemical stability (organic and inorganic). After optimization of several parameters affecting extraction efficiency, a method based on MIP-SPME combined with gas chromatography was developed for the determination of organophosphorus pesticides (OPPs) in vegetable samples. The limits of detection for the tested OPPs were in the range of 0.017-0.77 MUg kg(-1). The proposed method was applied to evaluate OPPs in spiked cucumber, green pepper, Chinese cabbage, eggplant and lettuce samples, and recoveries of 81.2-113.5% were obtained by the standard addition method with three spiking levels in each kind of vegetable. PMID- 24054684 TI - Chemometric tools to highlight non-intentionally added substances (NIAS) in polyethylene terephthalate (PET). AB - In an effort to identify non-intentionally added substances (NIAS), which is still a challenging task for analytical chemists, PET pellets, preforms and bottles were analyzed by an optimized headspace solid phase microextraction coupled to gas chromatography-mass spectrometry (HS-SPME/GC-MS). Fingerprints obtained by the proposed method were analyzed by three chemometric tools: Principal Components Analysis (PCA), Independent Components Analysis (ICA) and a multi-block method (Common Components and Specific Weights Analysis CCSWA) in order to extract pertinent variations in NIAS concentrations. Total ion current (TIC) chromatograms were used for PCA and ICA while extracted ion chromatograms (EIC) were used for CCSWA, each ion corresponding to a block. PCA managed to discriminate pellets and preforms from bottles due to several NIAS. Volatiles like 2-methyl-1,3-dioxolane, ethylene glycol, ethylbenzene and xylene were responsible for the discrimination of pellets and preforms. Less volatile compounds like linear aldehydes and phthalates were responsible for the discrimination of bottles. ICA showed more specific discriminations especially for bottles and pellets while CCSWA managed to discriminate preforms. The proposed methodology, combining HS-SPME/GC-MS with chemometric tools proved its efficiency in highlighting NIAS in PET samples in a relatively simple and fast approach compared to classical techniques. PMID- 24054685 TI - Multi-branched triphenylamine-rhodamine derivatives: synthesis and fluorescent sensing for Cu2+ and Hg2+ ions. AB - Three multi-branched rhodamine based fluorescent probes TPARH1-3 have been designed and synthesized by incorporating the rhodamine fluorophore with triphenylamine. The probe TPARH1 displayed high sensitivity to Cu(2+) in aqueous CH3CN. The probes TPARH2 and TPARH3 showed high sensitivity towards Hg(2+) in aqueous EtOH medium as reflected by their signalling responses. The cooperative effects of multi-branched structures towards metal ions were carried out by UV vis absorption titrations and time scanning fluorescence spectroscopic. In addition, the binding mode was proposed based on the job's plot. The absorption of probes 1-3 at 558 nm went through a maximum at a molar fraction of 0.5, indicating a 1:1 stoichiometry of the Hg(2+) to 1, 2 and 3 in the complex, respectively. PMID- 24054686 TI - Ion-paired extraction of cephalosporins in acetone prior to their analysis by capillary liquid chromatography in environmental water and meat samples. AB - Ion-pair extraction of cephalosporins from aqueous solution into acetone by the addition of ammonium sulfate to a 1:2 (v/v) acetone-water solvent was carried out followed by their determination using reversed-phase capillary liquid chromatography. The analytes included are cephoperazone, cefquinome, cephalexin, cephapirin, cephaloniun, cephamandole, cephazolin and cephadroxile. In order to form the ion-pair, hexadecyltrimethylammonium bromide (CTAB) was selected as cationic ion-pairing agent at a concentration of 0.9 mM using 10mM phosphate buffer at pH 8 as the optimum condition for the aqueous solution. The applied methodology, named salting-out assisted liquid/liquid extraction (SALLE) involves the use of 1.25 g of ammonium sulfate as salting-out agent. The separation of cephalosporins using a Luna C18 (150 mm * 0.3mm, 5 um, 100 A) column was achieved under the following conditions: a gradient program combining solvent A (0.1% formic acid in water, pH 4) and solvent B (acetonitrile-methanol (50:50, v/v)), at a flow rate of 20 ul min(-1), column temperature 35 degrees C and injection volume 7 ul with UV detection at 250 nm. The limits of quantification for the studied compounds were between 4.3 and 22.7 MUg/L for water samples and 4.1 and 73.3 MUg/kg in the case of beef samples, lower than the maximum residue limits permitted by the EU for this kind of food. The developed methodology has demonstrated its suitability for the analysis of these widely applied antibiotics in environmental water and meat samples, including beef and pork muscle, with high sensitivity, precision and satisfactory recoveries. PMID- 24054687 TI - Enhanced photoluminescence and characterization of multicolor carbon dots using plant soot as a carbon source. AB - Carbon dots (C-dots) are a class of novel fluorescent nanomaterials, which have drawn great attention for their potential applications in bio-nanotechnology. Multicolor C-dots have been synthesized by chemical nitric acid oxidation using the reproducible plant soot as raw material. TEM analysis reveals that the prepared C-dots have an average size of 3.1 nm. The C-dots are well dispersed in aqueous solution and are strongly fluorescent under the irradiation of ultra violet light. X-ray photoelectron spectroscopy characterization demonstrates that the O/C atomic ratio for C-dots change to from 0.207 to 0.436 due to the chemical oxidation process. The photo bleaching experiment reveals that the C-dots show excellent photostability as compared with the conventional organic dyes, fluorescein and rhodamine B. The fluorescence intensity of the C-dots did not change significantly in the pH range of 3-10. To further enhance the fluorescence quantum yield, the C-dots were surface modified with four types of passivation ligands, 4,7,10-trioxa-1,13-tridecanediamine (TTDDA), poly-L-lysine (PLL), cysteine and chitosan and the fluorescence quantum yields of the TTDDA, PLL, cysteine and chitosan passivated C-dots were improved 1.53-, 5.94-, 2.00- and 3.68-fold, respectively. Fourier-transform infrared (FTIR) spectra were employed to characterize the surface groups of the C-dots. The bio-application of the C dots as fluorescent bio-probes was evaluated in cell imaging and ex vivo fish imaging, which suggests that the C-dots may have potential applications in biolabeling and bioimaging. PMID- 24054688 TI - Magnetic solid-phase extraction based on magnetic multi-walled carbon nanotubes for the determination of polycyclic aromatic hydrocarbons in grilled meat samples. AB - A sensitive and reliable method for determination of polycyclic aromatic hydrocarbons (PAHs) in grilled meat samples was developed and validated. The method is based on magnetic solid phase extraction (MSPE) and GC-MS analysis. Magnetic carbon nanotubes (MCNTs) which have excellent adsorption capabilities, were used as adsorbent to extract PAHs, an important class of carcinogens, from meat samples. To obtain the best extraction yields, the influencing factors, including primary extraction conditions, the amount of adsorbent, adsorption and desorption time, salt addition and desorption solvent were investigated in detail. Under optimized conditions, the LODs and LOQs achieved were in the range of 0.035-0.100 and 0.075-0.200 ug Kg(-1) respectively. The calibration curves were linear (r(2) >= 0.988) over the concentration ranges from 0.100 ug Kg(-1) to 250 ug Kg(-1) The relative standard deviations (RSDs) obtained by carrying out intra- and inter-day precision studies were less than 13.7% and 13.9%, respectively which confirms reproducibility of the method. In addition, the recoveries of analyzed PAHs ranged from 81.3% to 96.7% with the RSDs less than 12.7 %. Finally, the established MSPE-GC-MS method was successfully applied to determine PAHs in charcoal grilled/barbecued meat samples. benzo[a]anthracene, benzo[b]fluoranthene, Benzo[a]pyrene and chrysene were detected in beef, lamb and chicken meat samples with the mean cumulative concentration of 4.000, 3.414 and 0.931 ug Kg(-1) respectively. Taken together, the MSPE-GC-MS method developed in current study provides a new option for the determination of PAHs in grilled/barbecued meat samples. PMID- 24054689 TI - Development of a method for the analysis of underivatized amino acids by liquid chromatography/tandem mass spectrometry: application on Standard Reference Material 1649a (urban dust). AB - A liquid chromatography-tandem mass spectrometry analytical procedure has been developed for the detection and quantitative determination of underivatized amino acids at low concentrations in a Standard Reference Material-urban dust. In order to minimize interferences of other compounds, an accelerated solvent extraction followed by a solid phase extraction on two different cartridges was applied prior to LC-MS-MS. Fourteen amino acids were separated by high resolution liquid chromatography, detected and quantified by multiple reaction monitoring on a triple quadrupole. The proposed methodology has been applied for the first time on Standard Reference Material 1649a (urban dust) from the National Institute of Standards and Technology, that does not report certification values for these compounds. This methodology avoids the derivatization step and allows the amino acid quantification in a complex matrix, such as that of atmospheric particulate matter, and represent a good method suitable to analyze this class of compounds in atmospheric aerosol. The selected strategy demonstrated to be fit-for-purpose, by applying it to a real atmospheric sample with the aim to verify the efficacy of the study and to provide information about the organic matter content. PMID- 24054690 TI - Microplates in liquid chromatography--new solution in clinical research? A review. AB - Microplates are routinely used in Radio- or Immuno-assays. Recently, microplates have found use not only in analytical but also in the pre-analytical phase in bioanalyses (sample storage, sample preparation). New connection of this technology to liquid chromatography could be economical, fast and simple solution for many routine laboratories handling large sequences of biological samples. This review summarises the application of microplates in bioanalytical laboratories. Different types of sorbents, materials and shapes of microplates are discussed, and the main advantages and disadvantages of microplates used in clinical research are presented. PMID- 24054691 TI - Low cost methodology for estrogens monitoring in water samples using dispersive liquid-liquid microextraction and HPLC with fluorescence detection. AB - A new low cost methodology for estrogens' analysis in water samples was developed in this work. Based on dispersive liquid-liquid microextraction followed by high performance liquid chromatography with fluorescence detection, the developed method is fast, cheap, easy-to-use, uses low volumes of organic solvents and has the possibility of a large number of samples to be extracted in parallel. Under optimum conditions (sample volume: 8 mL; extraction solvent: 200 MUL of chlorobenzene; dispersive solvent: 2000 MUL of acetone), the enrichment factor and extraction recoveries were 145 and 72% for 17beta-estradiol (E2) and 178 and 89% for 17alpha-ethinylestradiol (EE2), respectively. Limits of detection of 2.0 ng L(-1) for E2 and 6.5 ng L(-1) for EE2 were achieved, allowing the detection and quantification of these compounds in surface and waste water samples with concentrations from 12 to 32 ng L(-1) for E2 and from 11 to 18 ng L(-1) for EE2. Also, recovery tests were performed to evaluate possible matrix effects. Recoveries between 98% and 106% were obtained using humic acids (HA) to simulate the effect of organic matter, and between 86% and 120% in real water samples. PMID- 24054692 TI - Curium analysis in plutonium uranium mixed oxide by x-ray fluorescence and absorption fine structure spectroscopy. AB - Plutonium uranium mixed oxide (MOX) fuels are being used in commercial nuclear reactors. The actinides in these fuels need to be analyzed after irradiation for assessing their behaviour with regards to their environment and the coolant. In this work the study of the local occurrence, speciation and next-neighbour environment of curium (Cm) in the (Pu,U)O2 lattice within an irradiated (60 MW d kg(-1) average burn-up) MOX sample was performed employing micro-x-ray fluorescence (u-XRF) and micro-x-ray absorption fine structure (u-XAFS) spectroscopy. The chemical bonds, valences and stoichiometry of Cm (~ 0.7 wt% in the rim and ~ 0.03 wt% in the centre) are determined from the experimental data gained for the irradiated fuel material examined in its centre and peripheral (rim) zones of the fuel. Curium occurrence is also reduced from the centre (hot) to the periphery (colder) because of the condensation of these volatile oxides. In the irradiated sample Cm builds up as Cm(3+) species (>90%) within a [CmO8](13 ) or [CmO7](11-) coordination environment and no (<10%) Cm(IV) can be detected in the rim zone. Curium dioxide is reduced because of the redox buffering activity of the uranium dioxide matrix and of its thermodynamic instability. PMID- 24054693 TI - The fabrication of nanochain structure of gold nanoparticles and its application in ractopamine sensing. AB - The illegal food additives including ractopamine and melamine throw a serious threat to human health. In this paper, the ractopamine and melamine were first used to form the nanochain structure of citrate-stabilized gold nanoparticles (AuNPs) with a convenient and inexpensive method. The fabricated nanochain structure consisting of several AuNPs was characterized by Scanning Electron Microscopy. A new longitudinal surface plasma resonance, which could be adjusted from visible to near infrared range, was observed in absorption spectra due to the aggregation of AuNPs. This could be well explained by Finite Different Time Domain algorithm theoretically. As confirmed by Fourier Transform Infrared Spectroscopy, the complex formed by hydrogen-bonding interaction between melamine and ractopamine could effectively promote the aggregation of AuNPs that was useful to develop the sensitivity and selectivity for the detection of ractopamine. Hence, the plasmonic coupling phenomenon of gold nanochain could be applied in bio-assay for ractopamine through the change of solution's color and optical absorption band with naked eye or absorption spectra. The linear range was broadened to (1.23 * 10(-7)M, 1.11 * 10(-6)M) and the limit of detection was extended to 4.10 * 10(-8)M (S/N=3). More importantly, this time-saving method will be promising in rapid and selective detection of beta-agonist for clinical applications. PMID- 24054694 TI - An ICP-MS procedure to determine Cd, Co, Cu, Ni, Pb and Zn in oceanic waters using in-line flow-injection with solid-phase extraction for preconcentration. AB - An automated procedure including both in-line preconcentration and multi-element determination by an inductively coupled plasma mass spectrometer (ICP-MS) has been developed for the determination of Cd, Co, Cu, Ni, Pb and Zn in open-ocean samples. The method relies on flow injection of the sample through a minicolumn of chelating (iminodiacetate) sorbent to preconcentrate the trace metals, while simultaneously eliminating the major cations and anions of seawater. The effectiveness of this step is tested and reliability in results are secured with a rigorous process of quality assurance comprising 36 calibration and reference samples in a run for analysis of 24 oceanic seawaters in a 6-h program. The in line configuration and procedures presented minimise analyst operations and exposure to contamination. Seawater samples are used for calibration providing a true matrix match. The continuous automated pH measurement registers that chelation occurs within a selected narrow pH range and monitors the consistency of the entire analytical sequence. The eluent (0.8M HNO3) is sufficiently strong to elute the six metals in 39 s at a flow rate of 2.0 mL/min, while being compatible for prolonged use with the mass spectrometer. Throughput is one sample of 7 mL every 6 min. Detection limits were Co 3.2 pM, Ni 23 pM, Cu 46 pM, Zn 71 pM, Cd 2.7 pM and Pb 1.5 pM with coefficients of variation ranging from 3.4% to 8.6% (n=14) and linearity of calibration established beyond the observed concentration range of each trace metal in ocean waters. Recoveries were Co 96.7%, Ni 102%, Cu 102%, Zn 98.1%, Cd 92.2% and Pb 97.6%. The method has been used to analyse ~800 samples from three voyages in the Southern Ocean and Tasman Sea. It has the potential to be extended to other trace elements in ocean waters. PMID- 24054695 TI - Near-full length sequencing of 16S rDNA and RFLP indicates that Rhizobium etli is the dominant species nodulating Egyptian winter Berseem clover (Trifolium alexandrinum L.). AB - Egyptian winter Berseem clover (EWBC) is one of the main important forage legume crops in Egypt that is used for animal feeding in winter and it occupies about 2.5 million feddans (Feddan=4200m(2)) in winter agricultural rotation systems. Forty-eight rhizobial isolates that nodulated this legume host from different geographical regions within Egypt were isolated. RFLP analyses of 16S rDNA (1.5kb) and whole ribosomal DNA (5kb), the sequencing of 16S rDNA, and the sequencing of nodC, nifH and house keeping genes were used to identify these isolates. The RFLP analysis of 16S rDNA (1.5kb) among 15 representative strains with three enzymes generated two genotypes. The largest genotype was similar to Rhizobium etli CFN42T (93.33%) except for strain 902 that failed to re-nodulate EWBC. RFLP analysis of complete ribosomal DNA (5kb) produced five genotypes. The majority of tested strains shared the genotype with R. etli CFN42T (53.33%). Only one strain (1002) shared the genotype with Rhizobium leguminosarum sv. trifolii 3023. The other four strains were comprised of two unique genotypes. Phylogenetic analysis of 16S rDNA sequences revealed that seven representative strains could be divided into two genetic clusters sharing the ancestral clad with R. etli CFN42T. A phylogenetic tree based on nodC gene sequence confirmed that all the examined strains shared the genetic lineage with R. leguminosarum sv. trifolii WSM1325. The phylogenetic trees of house keeping genes are supported strongly the identification of majority of strains as a novel symbiovar of R. etli with new lineages. PMID- 24054696 TI - Chironomus plumosus larvae increase fluxes of denitrification products and diversity of nitrate-reducing bacteria in freshwater sediment. AB - Benthic invertebrates affect microbial processes and communities in freshwater sediment by enhancing sediment-water solute fluxes and by grazing on bacteria. Using microcosms, the effects of larvae of the widespread midge Chironomus plumosus on the efflux of denitrification products (N2O and N2+N2O) and the diversity and abundance of nitrate- and nitrous-oxide-reducing bacteria were investigated. Additionally, the diversity of actively nitrate- and nitrous-oxide reducing bacteria was analyzed in the larval gut. The presence of larvae increased the total effluxes of N2O and N2+N2O up to 8.6- and 4.2-fold, respectively, which was mostly due to stimulation of sedimentary denitrification; incomplete denitrification in the guts accounted for up to 20% of the N2O efflux. Phylotype richness of the nitrate reductase gene narG was significantly higher in sediment with than without larvae. In the gut, 47 narG phylotypes were found expressed, which may contribute to higher phylotype richness in colonized sediment. In contrast, phylotype richness of the nitrous oxide reductase gene nosZ was unaffected by the presence of larvae and very few nosZ phylotypes were expressed in the gut. Gene abundance of neither narG, nor nosZ was different in sediments with and without larvae. Hence, C. plumosus increases activity and diversity, but not overall abundance of nitrate-reducing bacteria, probably by providing additional ecological niches in its burrow and gut. PMID- 24054697 TI - Improvement of MALDI-TOF MS profiling for the differentiation of species within the Acinetobacter calcoaceticus-Acinetobacter baumannii complex. AB - MALDI-TOF MS is currently becoming the method of choice for rapid identification of bacterial species in routine diagnostics. Yet, this method suffers from the inability to differentiate reliably between some closely related bacterial species including those of the Acinetobacter calcoaceticus-Acinetobacter baumannii (ACB) complex, namely A. baumannii and Acinetobacter nosocomialis. In the present study, we evaluated a protocol which was different from that used in the Bruker Daltonics identification system (MALDI BioTyper) to improve species identification using a taxonomically precisely defined set of 105 strains representing the four validly named species of the ACB complex. The novel protocol is based on the change in matrix composition from alpha-cyano-4 hydroxycinnamic acid (saturated solution in water:acetonitrile:trifluoroacetic acid, 47.5:50:2.5, v/v) to ferulic acid (12.5mgml(-1) solution in water:acetonitrile:formic acid 50:33:17, v/v), while the other steps of sample processing remain unchanged. Compared to the standard protocol, the novel one extended the range of detected compounds towards higher molecular weight, produced signals with better mass resolution, and allowed the detection of species-specific signals. As a result, differentiation of A. nosocomialis and A. baumannii strains by cluster analysis was improved and 13 A. nosocomialis strains, assigned erroneously or ambiguously by using the standard protocol, were correctly identified. PMID- 24054698 TI - Surviving the waning days of fee-for-service payments. PMID- 24054699 TI - Evidence for multiple forms and modifications of human POT1. AB - Human POT1, a widely studied telomere protector protein is perceived to be expressed as a single 70kDa form. A survey of the literature as well as different commercially available antibodies against POT1 suggests occurrence of multiple forms of POT1. Knowledge about possible various forms of an important protein like POT1 is necessary for our understanding about its function. We have discovered that POT1 exists in at least three consistently occurring forms; 90, 70 and 45kDa. The unexpected molecular weights of POT1 seem to be associated with SUMO1 and ubiquitin conjugation; the latter occurring at a double lysine residue at 289-KK-290. We also present evidence that the relative abundance of the different POT1 forms can be altered by experimental modulation of POT1 nuclear localization. We thus present strong evidence that there are post-translational modifications of POT1 that can affect its molecular weight as well as intracellular localization and function. PMID- 24054700 TI - Measurement of DNA base and nucleotide excision repair activities in mammalian cells and tissues using the comet assay--a methodological overview. AB - There is an increasing demand for phenotyping assays in the field of human functional genetics. DNA repair activity is representative of this functional approach, being seen as a valuable biomarker related to cancer risk. Repair activity is evaluated by incubating a cell extract with a DNA substrate containing lesions specific for the DNA repair pathway of interest. Enzymic incision at the lesion sites can be measured by means of the comet assay (single cell gel electrophoresis). The assay is particularly applicable for evaluation of base and nucleotide excision repair pathways (BER and NER). Substrate DNA containing oxidised purines gives a measure of BER, while UV-induced photolesions are the substrate for NER. While applications of comet-based DNA repair assays continue to increase, there are no commonly accepted standard protocols, which complicates inter-laboratory comparisons of results. Here we provide a comprehensive summary of protocols for the comet-based BER- and NER-specific in vitro DNA repair assays that can be applied to a wide spectrum of biological material--cultured cell lines, blood cells, animal tissue samples and human biopsies. Our intention is to provide a detailed and user-friendly account of the assays, including practical tips and recommendations to help in setting them up. By proposing standard protocols, we hope to facilitate comparison of results obtained in different laboratories. PMID- 24054701 TI - Cancer chemotherapy: a rapidly moving train. PMID- 24054702 TI - Targeted therapies in oncology come of age. PMID- 24054704 TI - Discovery of novel drugs for promising targets. AB - BACKGROUND: Once a promising drug target is identified, the steps to actually discover and optimize a drug are diverse and challenging. OBJECTIVE: The goal of this study was to provide a road map to navigate drug discovery. METHODS: Review general steps for drug discovery and provide illustrating references. RESULTS: A number of approaches are available to enhance and accelerate target identification and validation. Consideration of a variety of potential mechanisms of action of potential drugs can guide discovery efforts. The hit to lead stage may involve techniques such as high-throughput screening, fragment-based screening, and structure-based design, with informatics playing an ever increasing role. Biologically relevant screening models are discussed, including cell lines, 3-dimensional culture, and in vivo screening. The process of enabling human studies for an investigational drug is also discussed. CONCLUSIONS: Drug discovery is a complex process that has significantly evolved in recent years. PMID- 24054703 TI - Targeted therapy in chronic lymphocytic leukemia: past, present, and future. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the western world. Recent advances in understanding the biology of B-cell malignancies have resulted in the development of novel agents targeting key prosurvival pathways in the neoplastic B cell. OBJECTIVE: The goal of this article was to summarize current literature on the emerging therapeutic approaches in CLL and B-cell malignancies. METHODS: A literature review was performed, identifying pathways and key clinical trials involving novel therapies in CLL, with special emphasis on B-cell receptor (BCR)-targeting agents. RESULTS: Understanding the biology of the BCR-signaling pathway has led to identification of novel molecular targets. Most notably, inhibitors of Bruton tyrosine kinase and phosphatidylinositide 3-kinase-delta have entered clinical trials and demonstrated high response rates in CLL, including high-risk disease. Cyclin dependent kinase inhibitors may evolve into an alternative therapeutic approach in CLL. New drugs that target molecules within and outside of the BCR-signaling pathway have shown promise in preclinical studies. CONCLUSIONS: Both preclinical and early clinical trial results involving novel targeted therapies suggest that the standard treatment paradigm in CLL and B-cell malignancies will soon change. Particular attention should be paid to the BCR-targeting agents, whose favorable adverse effect profile may improve the lives of elderly patients with CLL. PMID- 24054705 TI - Epidermal growth factor receptor: pathway, therapies, and pipeline. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) pathway is important in tumor growth, survival, and metastasis and is now the target of several therapeutic agents. OBJECTIVES: This paper seeks to review the EGFR pathway, the study and use of EGFR-directed agents in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC), and related new drug development. METHODS: PubMed was searched for English-language articles by MeSH and title terms of EGFR published from 2006 to 2013, using the limits of clinical trials as well as reviews. Reference lists were assessed for relevant articles, and guidelines were searched. Clinicaltrials.gov and meeting abstracts were queried for investigational agents. Eligible papers included those concerning EGFR biology, NSCLC or CRC studies involving EGFR-directed agents, and/or investigational drugs targeting EGFR and/or associated pathways. RESULTS: The activity of oral tyrosine kinase inhibitors (TKIs) against EGFR has improved survival in NSCLC, and these agents particularly effective in cancers with an EGFR mutation. Resistance to TKIs is most commonly related to a second, T790M, mutation, or to MET amplification, with newer agents directed against these mechanisms. Conversely, in CRC, TKIs have been ineffective, whereas monoclonal antibodies have improved survival. Both primary and secondary KRAS mutations in CRC abrogate mAb effectiveness. Several targets, including MET, BRAF, and PI3K, may serve useful in combination with anti-EGFR drugs. CONCLUSIONS: Exploitation of EGFR-directed therapies has offered improvement in survival and quality of life in NSCLC and CRC. New therapies directed at EGFR may offer further improvements. However, resistance mechanisms suggest that combination therapies or multitargeted agents will be crucial in making significant future advances. PMID- 24054706 TI - Real-world application of the roadmap model in chronic hepatitis B patients with telbivudine therapy. AB - BACKGROUND: The roadmap concept provides a strategy to maximize hepatitis B virus suppression and minimize drug resistance by add-on or switching therapy in patients with a suboptimal response at Week 24. The efficacy of this strategy in routine clinical practice remains to be validated. OBJECTIVE: The aim of our study was to validate the roadmap concept in the treatment of chronic hepatitis B, and to investigate the virologic efficacy and kinetics of quantitative hepatitis B surface antigen (qHBsAg) during telbivudine therapy in a real-world setting. METHODS: A prospective, cohort study enrolled 96 consecutive, treatment naive patients with chronic hepatitis B receiving telbivudine therapy. At Week 24, only 17 of 42 (40%) partial or inadequate responders (hepatitis B virus DNA 60-2000 and >2000 IU/mL, respectively) followed the roadmap model and consented to adefovir add-on therapy. The remaining patients continued to receive telbivudine monotherapy. RESULTS: At Week 96, none of the patients receiving adefovir add-on therapy, and 28% of patients receiving telbivudine monotherapy, either partial or inadequate responders, developed genotypic resistance (P = 0.03). Poor early qHBsAg kinetics (an increase in qHBsAg >0.4 log IU/mL at Week 12) was the only significant predictor of genotypic resistance (adjusted hazard ratio = 13.83; 95% CI, 1.79-106.76; P = 0.01). Telbivudine monotherapy was efficacious in 94% of partial responders who did not have poor early qHBsAg kinetics, remaining free of drug resistance after 2 years. CONCLUSIONS: The application of the roadmap model with add-on adefovir therapy prevented genotypic resistance. However, telbivudine monotherapy achieved a good response in the majority of partial responders who did not have poor early qHBsAg kinetics. Poor early qHBsAg kinetics was an early predictor of genotypic resistance at Week 96. Modification of the roadmap model to incorporate early qHBsAg kinetics may further optimize the efficacy of the treatment strategy of hepatitis B virus. PMID- 24054707 TI - Familial hypercholesterolaemia in primary care: knowledge and practices among general practitioners in Western Australia. AB - AIM: To determine general practitioners' (GPs') knowledge and practice regarding familial hypercholesterolaemia (FH) in Western Australia. METHOD: A structured questionnaire was anonymously completed by GPs. Information was sought on awareness and knowledge of FH including, diagnosis, inheritance, prevalence, cardiovascular risk, management practices and opinions on FH screening. RESULTS: 191 GPs completed the survey, 62% were familiar with FH, 80% correctly defined FH and 68% identified the typical lipid profile, but only 33% were aware of national guidelines. There were knowledge deficits in prevalence, inheritance, and clinical features of FH, with correct responses in 27%, 45% and 38%, respectively. Most (84%) GPs considered themselves the most effective health professionals to detect FH, with 90% preferring laboratory interpretative commenting to highlight individuals at risk of FH. GPs identified appropriate cholesterol lowering drugs as mono (95%) or combination therapies (74%). CONCLUSION: The majority of GPs considered they were the most effective health practitioners for managing FH and preferred laboratory reports to alert them of possible FH. Although GPs knowledge of cholesterol lowering therapies was good, their awareness of national guidelines, hereditability, prevalence and diagnostic features of FH was suboptimal. Implementing a community model of care for FH requires more extensive GP education. PMID- 24054708 TI - Curb your premium: the impact of monitoring malpractice claims. AB - We study a policy aimed at increasing the level of information on medical malpractice costs and the risk exposure of local public healthcare providers. The policy is based on enhanced monitoring of medical malpractice claims by the level of government that rules providers in a multilevel institutional setting. In particular, we implement a difference-in-differences strategy using Italian data at the provider level from 2001 to 2008 to evaluate the impact of monitoring claims on medical liability expenditures, measured as insurance premiums and legal expenditures, which was adopted by only some Regions. Our results show that this information-enhancing policy reduces paid premiums by around 15%. This reduced-form effect might arise by higher bargaining power on the demand side or increased competition on the supply side of the insurance market. Validity tests show that our findings are not driven by differential pre-policy trends between treated and control providers. Moreover, this policy could be cheaply implemented also in other institutional contexts with positive effects. PMID- 24054709 TI - A systematic review of medical practice variation in OECD countries. AB - BACKGROUND: Major variations in medical practice have been documented internationally. Variations raise questions about the quality, equity, and efficiency of resource allocation and use, and have important implications for health care and health policy. OBJECTIVE: To perform a systematic review of the peer-reviewed literature on medical practice variations in OECD countries. METHODS: We searched MEDLINE to find publications on medical practice variations in OECD countries published between 2000 and 2011. We present an overview of the characteristics of published studies as well as the magnitude of variations for select high impact conditions. RESULTS: A total of 836 studies were included. Consistent with the gray literature, there were large variations across regions, hospitals and physician practices for almost every condition and procedure studied. Many studies focused on high-impact conditions, but very few looked at the causes or outcomes of medical practice variations. CONCLUSION: While there were an overwhelming number of publications on medical practice variations the coverage was broad and not often based on a theoretical construct. Future studies should focus on conditions and procedures that are clinically important, policy relevant, resource intensive, and have high levels of public awareness. Further study of the causes and consequences of variations is important. PMID- 24054710 TI - Commentary--Digging deeper into tumor invasion as a prognostic factor for oral squamous cell carcinoma. PMID- 24054711 TI - "M" is for "mentorship". PMID- 24054712 TI - 7 SuperTracker features you've never heard of. PMID- 24054713 TI - The results of an international germ study: should registered dietitians be surprised by the surprise? PMID- 24054714 TI - Position of the Academy of Nutrition and Dietetics: interventions for the prevention and treatment of pediatric overweight and obesity. AB - It is the position of the Academy of Nutrition and Dietetics that prevention and treatment of pediatric overweight and obesity require systems-level approaches that include the skills of registered dietitians, as well as consistent and integrated messages and environmental support across all sectors of society to achieve sustained dietary and physical-activity behavior change. This position paper provides guidance and recommendations for levels of intervention targeting overweight and obesity prevention and treatment from preschool age through adolescence. Methods included a review of the literature from 2009 to April 2012, including the Academy's 2009 evidence analysis school-based reviews. Multicomponent interventions show the greatest impact for primary prevention; thus, early childhood and school-based interventions should integrate behavioral and environmental approaches that focus on dietary intake and physical activity using a systems-level approach targeting the multilevel structure of the socioecological model as well as interactions and relationships between levels. Secondary prevention and tertiary prevention/treatment should emphasize sustained family-based, developmentally appropriate approaches that include nutrition education, dietary counseling, parenting skills, behavioral strategies, and physical-activity promotion. For obese youth with concomitant serious comorbidities, structured dietary approaches and pharmacologic agents should be considered, and weight-loss surgery can be considered for severely obese adolescents. Policy and environmental interventions are recommended as feasible and sustainable ways to support healthful lifestyles for children and families. The Academy supports commitment of resources for interventions, policies, and research that promote healthful eating and physical-activity behaviors to ensure that all youth have the opportunity to achieve and maintain a weight that is optimal for health. PMID- 24054715 TI - Probiotics: where do we stand? PMID- 24054716 TI - Predicting symptomatic intracerebral hemorrhage after intravenous thrombolysis: stroke territory as a potential pitfall. AB - BACKGROUND: Stroke vascular territories may influence response to thrombolysis, although supporting data are limited. The aim of the study was to test the hypothesis that the current available prediction scores might inaccurately estimate the risk of symptomatic intracerebral hemorrhage (SICH) after intravenous thrombolysis in patients with posterior circulation stroke. METHODS: We applied the Safe Implementation of Thrombolysis in Stroke (SITS) SICH risk score to data from four hospital-based stroke registries. Patients were grouped according to anterior or posterior circulation stroke. The main outcome measure was SICH per various definitions. Performance of the risk score was assessed with the c statistic. RESULTS: Data of 518 thrombolyzed patients (434 anterior, 84 posterior) were studied. The overall rate of SICH varied from 3.5% to 6.9% depending on the SICH definition. Patients with posterior circulation stroke were less likely to have post-thrombolysis SICH per NINDS (P=0.042), per ECASS II (P=0.013), or any ICH (P=0.001), and their rate of SICH was markedly lower than predicted (1.2% versus 7.1% by the NINDS definition; 0% versus 4.8%, ECASS II; 0% versus 1.6%, SITS-MOST). The SITS SICH risk score shows moderate model discrimination across the SICH definitions, with c statistic ranging from 0.64 to 0.70. CONCLUSIONS: The risk of SICH after intravenous thrombolysis in patients with posterior circulation stroke was low enough to render the SITS SICH risk score or other similar prediction models unnecessary. Awareness of stroke territory might help clinicians judiciously use the risk assessment models. PMID- 24054717 TI - Prevalence of extramedullary relapses is higher after allogeneic stem cell transplantation than after chemotherapy in adult patients with acute myeloid leukemia. AB - Although studies have demonstrated a high prevalence of extramedullary (EM) relapse after allogeneic stem cell transplantation (allo-SCT) in patients with acute myeloid leukemia (AML), the prevalence of EM relapse has not been compared with that after chemotherapy. This study investigated the prevalence of EM relapse among 498 adult AML patients (median age, 57 years; range, 15-82 years) who underwent intensive chemotherapy. A total of 281 relapses occurred in 210 patients (36 after allo-SCT; 245 after chemotherapy), and 33 relapses (11.7%) were accompanied by EM disease. Among these relapses, EM disease was more frequently observed at relapse after allo-SCT than after chemotherapy (25% vs. 9%, respectively; p=0.008). Eight of 33 relapses after the first allo-SCT had EM disease, and only presence of extensive chronic graft-versus-host disease (GVHD) was identified as a predisposing factor for EM relapse. Additionally, the 1-year overall survival rate after relapse was not significantly different when comparing those with EM relapse and those with BM relapse (38% vs. 16%, respectively; p=0.279). These data suggest that AML patients undergoing allo-SCT should be closely followed for signs of EM relapse, especially those with extensive chronic GVHD. PMID- 24054718 TI - The pros and cons of new prognostic eutos score for chronic myeloid leukemia patients. PMID- 24054719 TI - CEBPA single mutation can be a possible favorable prognostic indicator in NPM1 and FLT3-ITD wild-type acute myeloid leukemia patients with intermediate cytogenetic risk. AB - The aim of this study was to evaluate the prognostic impact of CEBPA single mutation in acute myeloid leukemia (AML) patients with intermediate cytogenetic risk. CEBPA single and double mutations were detected in 11 (9.7%) and 17 (15.1%) of 113 NPM1 wild-type patients, but no CEBPA mutations were detected in a group of 44 NPM1 mutated patients. Among patients with NPM1/FLT3-ITD wild-type, those with CEBPA double mutations (P=0.013 and 0.007 for overall survival and relapse free survival, respectively) or a single mutation (P=0.039 and 0.020 for overall survival and relapse-free survival, respectively) demonstrated a favorable prognosis compared with CEBPA wild-type patients. Subsequent multivariate analysis confirmed the favorable prognostic impact of CEBPA single and double mutations. Despite the low statistical power of this study due to the small number of patients, our preliminary data suggest that CEBPA single mutation may be associated with favorable clinical outcomes in NPM1/FLT3-ITD wild-type AML patients with intermediate cytogenetic risk. PMID- 24054720 TI - Reduced-intensity conditioning therapy with fludarabine, idarubicin, busulfan and cytarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndrome. AB - We retrospectively analyzed allogenic stem cell transplantation (allo-SCT) outcomes in 82 patients with AML or MDS were conditioned with fludarabine, idarubicin, intravenous-busulfan and cytarabine (FIBA) or busulfan and cyclophosphamide (BuCy). Compared to BuCy regimen, reduced intensity conditioning (RIC) with FIBA was associated with a lower incidence of severe acute GVHD, lower NRM and a similar relapse rate. There was no significant difference in the 3 year overall survival (OS), but this is possibly due to the limited number of patients. The FIBA regimen is promising to replace BuCy regimen because of better security and similar relapse rate. PMID- 24054721 TI - Oxidative burst and neutrophil elastase contribute to clearance of Aspergillus fumigatus pneumonia in mice. AB - Polymorphonuclear neutrophils (PMN) are important for the control of invasive aspergillosis (IA), a major threat to immunocompromised individuals. For clearance of Aspergillus fumigatus infections, PMN employ their potent oxidative and non-oxidative mechanisms. To clarify the relative contribution of these mechanisms, we analyzed p47(phox-/-), gp91(phox-/-) and elastase (ELA) deficient mice (ELANE) after intratracheal infection with A. fumigatus. Infected p47(phox-/ ) and gp91(phox-/-) mice died within 4 days and had a significant higher fungal burden in the lungs compared to wild-type controls. Interestingly, the survival of ELANE mice after infection was unimpaired suggesting that ELA is not essential here. Nevertheless, A. fumigatus clearance was delayed in ELANE mice indicating a partial contribution of ELA to fungal immunity. Comparing p47(phox-/-), gp91(phox /-) or ELANE mice for PMN activation and recruitment to the lungs, we were unable to detect significant differences in vitro or in vivo among mutant or wild-type strains suggesting intact PMN functionality of basic effector mechanisms. Fungal killing in vitro by ELA deficient PMN was comparably reduced as in p47(phox-/-) and gp91(phox-/-) deficient PMN corroborating the importance of oxidative and non oxidative PMN mechanisms for the control of fungal outgrowth. Taken together, this suggests that intact oxidative as well as non-oxidative PMN effector functions are highly relevant for the control of A. fumigatus infections in vitro and in vivo. While ELA contributes to clearance of A. fumigatus, the oxidative functions are essential for survival. PMID- 24054722 TI - Pathogenesis of human hemangiosarcomas and hemangiomas. AB - Hemangiosarcomas are uncommon aggressive vascular tumors that have recently become the focus of attention because several chemicals and pharmaceuticals increase their incidence in mice. The relevance of these mouse vascular tumors to humans is unclear. In the present study, we semiquantitatively evaluated the expression profiles of hematopoietic stem cell markers (CD117 [c-kit], CD133, CD34, and CD45), endothelial cell markers (vascular endothelial growth factor receptor 2, CD31, and factor VIII-related antigen), and a myeloid lineage cell marker (CD14) in human hemangiosarcoma (n = 12) and hemangioma (n = 10) specimens using immunohistochemistry. CD133 was completely negative in almost all cases of hemangiosarcomas and hemangiomas. Most hemangiosarcomas, but not hemangiomas, stained for CD117 and CD45. Both groups diffusely expressed CD34, vascular endothelial growth factor receptor 2, and factor VIII-related antigen; however, hemangiomas had more intense and diffuse CD34 and factor VIII-related antigen expression compared with hemangiosarcomas, whereas CD31 was positive in all hemangiosarcomas but only half of the hemangiomas. CD14 staining was negative in most hemangiosarcoma and hemangioma cases. Our results indicate that multipotential bone marrow-derived hematopoietic stem cells or early endothelial progenitor cells (EPCs) expressing CD117, CD34, and CD45 are involved in hemangiosarcoma formation, whereas hemangiomas originate from late EPCs or differentiated endothelial cells, which have lost the expression of most hematopoietic stem cell markers. This contrasts with our previous results that demonstrated that both hemangiosarcomas and hemangiomas in mice may be derived from early EPCs that are not completely differentiated. PMID- 24054723 TI - Visibility of Histoplasma within histiocytes on hematoxylin and eosin distinguishes disseminated histoplasmosis from other forms of pulmonary histoplasmosis. AB - The visibility of Histoplasma within histiocytes on hematoxylin and eosin is a well-known feature of disseminated histoplasmosis. However, it is unclear whether this finding can be used to differentiate disseminated histoplasmosis involving the lung from other forms of pulmonary histoplasmosis. The aim of this study was to determine whether the visibility of Histoplasma within histiocytes on hematoxylin and eosin in lung biopsies suggests disseminated disease. Lung biopsies in which Histoplasma was identified were re-examined to determine whether organisms were visible within histiocytes on hematoxylin and eosin. Clinical findings were reviewed retrospectively to determine the type of histoplasmosis. Histoplasma was visible within histiocytes on hematoxylin and eosin in lung biopsies from 4 patients (2 men, 2 women, 50-74 years) who presented with pulmonary manifestations without definite evidence of disseminated disease at the time of biopsy. Subsequently, all 4 manifested clinical and/or microbiologic features of disseminated disease (positive extrapulmonary cultures and fatal outcome in 2, positive extrapulmonary cultures in 1, and multiorgan failure and fatal outcome in 1). In contrast, organisms were identified on silver stains but could not be visualized on hematoxylin and eosin in 42 patients, none of whom showed clinical or microbiologic evidence of disseminated disease (pulmonary histoplasmoma, 38; acute pulmonary histoplasmosis, 4). In lung biopsies, the visibility of Histoplasma within histiocytes on hematoxylin and eosin suggests disseminated disease. Recognition of the significance of this finding is helpful in diagnosing disseminated disease in patients who present primarily with pulmonary manifestations without definite clinical evidence of dissemination at the time of biopsy. PMID- 24054724 TI - A case of oligodendroglioma with prominent neuronal differentiation. AB - We report a case of oligodendroglioma showing marked neuronal differentiation, which arose in the right frontal lobe of a 46-year-old woman. The resected tumor was composed of a mixture of oligodendroglioma, gangliocytoma, and neurocytoma areas with predominance of gangliocytoma-like areas. The oligodendroglioma areas showed immunoreactivity for Olig2 and mutant isocitrate dehydrogenase 1 protein, whereas the gangliocytoma and neurocytoma areas were positive for synaptophysin and NeuN. Ki-67 labeling index was approximately 5% to 10% in the oligodendroglioma areas. Molecular cytogenetic analyses demonstrated chromosomal losses of 1p and 19q and a mutation of isocitrate dehydrogenase 1 (G395A, R132H) in both the oligodendroglioma and gangliocytoma areas. These data suggest that this tumor is an oligodendroglioma associated with prominent neuronal differentiation. There seems to be a close relationship between oligodendroglial progenitor cells and neuronal cells. PMID- 24054725 TI - Saturated spreading, an alternative to Fick's law: comment on "Morphogenetic action through flux-limited spreading", by M. Verbeni, O. Sanchez, E. Mollica, I. Siegl-Cachedenier, A. Carleton, I. Guerrero, A. Ruiz i Altaba, J. Soler. PMID- 24054726 TI - Cannabis use and brain structural alterations of the cingulate cortex in early psychosis. AB - As cannabis use is more frequent in patients with psychosis than in the general population and is known to be a risk factor for psychosis, the question arises whether cannabis contributes to recently detected brain volume reductions in schizophrenic psychoses. This study is the first to investigate how cannabis use is related to the cingulum volume, a brain region involved in the pathogenesis of schizophrenia, in a sample of both at-risk mental state (ARMS) and first episode psychosis (FEP) subjects. A cross-sectional magnetic resonance imaging (MRI) study of manually traced cingulum in 23 FEP and 37 ARMS subjects was performed. Cannabis use was assessed with the Basel Interview for Psychosis. By using repeated measures analyses of covariance, we investigated whether current cannabis use is associated with the cingulum volume, correcting for age, gender, alcohol consumption, whole brain volume and antipsychotic medication. There was a significant three-way interaction between region (anterior/posterior cingulum), hemisphere (left/right cingulum) and cannabis use (yes/no). Post-hoc analyses revealed that this was due to a significant negative effect of cannabis use on the volume of the posterior cingulum which was independent of the hemisphere and diagnostic group and all other covariates we controlled for. In the anterior cingulum, we found a significant negative effect only for the left hemisphere, which was again independent of the diagnostic group. Overall, we found negative associations of current cannabis use with grey matter volume of the cingulate cortex, a region rich in cannabinoid CB1 receptors. As this finding has not been consistently found in healthy controls, it might suggest that both ARMS and FEP subjects are particularly sensitive to exogenous activation of these receptors. PMID- 24054727 TI - The 2012 guidelines for severe sepsis and septic shock: an update for emergency nursing. PMID- 24054728 TI - Incidence and cost of nurse workplace violence perpetrated by hospital patients or patient visitors. AB - INTRODUCTION: Workplace violence against nurses is a serious problem. Nurses from a US urban/community hospital system employing more than 5,000 nurses researched the incidence of workplace violence against nurses perpetrated by patients or visitors in their hospital system. METHODS: Survey research and retrospective database review methods were used. Nurse participants (all system-employed nurse types) completed a 34-item validated survey in electronic format. Retrospective database review provided annual nurse workplace violence injury treatment and indemnity charges. Institutional review board approval was received. RESULTS: Survey research participants (N = 762) were primarily white female registered nurses, aged 26 to 64 years, with more than 10 years of experience. Over the past year, 76.0% experienced violence (verbal abuse by patients, 54.2%; physical abuse by patients, 29.9%; verbal abuse by visitors, 32.9%; and physical by visitors, 3.5%), such as shouting or yelling (60.0% by patients and 35.8% by visitors), swearing or cursing (53.5% by patients and 24.9% by visitors), grabbing (37.8% by patients and 1.1% by visitors), and scratching or kicking (27.4% by patients and 0.8% by visitors). Emergency nurses (12.1%) experienced a significantly greater number of incidents (P < .001). Nurses noted more than 50 verbal (24.3%) and physical (7.3%) patient/visitor violence incidents over their careers. Most serious career violence incidents (n = 595, 78.1%) were physical (63.7%) (60.8% by patients and 2.9% by visitors), verbal (25.4%) (18.3% by patients and 7.1% by visitors), and threatened physical assault (10.9%) (6.9% by patients and 4.0% by visitors). Perpetrators were primarily white male patients, aged 26 to 35 years, who were confused or influenced by alcohol or drugs. Per database review, annual workplace violence charges for the 2.1% of nurses reporting injuries were $94,156 ($78,924 for treatment and $15,232 for indemnity). DISCUSSION: Nurses are too commonly exposed to workplace violence. Hospitals should enhance programs for training and incident reporting, particularly for nurses at higher risk of exposure, caring for patients with dementia or Alzheimer disease, patients with drug-seeking behavior, or drug- or alcohol-influenced patients. PMID- 24054729 TI - Outcomes of emergency nurse-administered digital blocks in a community hospital emergency department. AB - INTRODUCTION: Digital blocks are traditionally performed by physicians, physician assistants, and nurse practitioners. Procedures manuals emphasize that digital blocks are usually performed by a physician or an advanced practice nurse. In our community hospital, emergency nurses have performed digital blocks according to protocol for the past 30 years without known complications or diminished patient satisfaction. The goal of this study was to validate the effectiveness, safety, and patient satisfaction of emergency nurse-administered digital block. METHODS: Retrospective and prospective study designs were used. The retrospective arm included telephone interviews of patients who received a digital block between January 2011 and April 2012. The response rate for the retrospective survey was 23% (n = 30). The prospective arm included telephone interviews of patients who received a digital block between May 2012 and October 2012. The response rate for the prospective survey was 71.7% (n = 53). Descriptive statistics and qualitative content analysis were used in the data analysis. RESULTS: Patients who received emergency nurse-administered digital blocks rated effectiveness using the pain scale (a 0 to10 scale, with 10 being the most painful), with the following results: 74.3% reported no pain; 10.5% reported a pain level of 1 out of 10; 7.9% reported a pain level of 2 out of 10; 2.6% reported a pain level of 3 out of 10; and 2.6% reported a pain level of 4 out of 10. Safety was measured by reported complications; 5.2% of patients reported the complication of persistent numbness over 24 hours that eventually resolved. The patient satisfaction rate was 92.1%; patients who reported a score of 7 out of 10 or better (on a scale of 0 to10, with 10 being highly satisfied) were classified as satisfied. DISCUSSION: Emergency nurse-administered digital blocks were found to be effective and safe and contributed to a high level of patient satisfaction. PMID- 24054730 TI - Management of febrile neutropenia in a patient with acute leukemia. PMID- 24054731 TI - A 34-year-old triathlete with hyperthermia. PMID- 24054732 TI - Study on the sorption behaviour of estrone on marine sediments. AB - The sorption behaviour of estrone (E1) on marine sediments treated by different methods was systematically investigated. About 22 h was required for sorption equilibrium of E1. Sorption isotherms of E1 were well fitted with Freundlich model. The sorption behaviour of E1 on HCl-treatment and H2O-treatment sediments related significantly with the sediment organic carbon contents. Additionally, clay minerals and surface areas of sediments played dominant roles in the sorption of E1 on H2O2-treatment sediments. Some external factors which could affect sorption behaviour of E1 were also investigated. Our results showed that the sorption capacity of E1 on the sediments increased with the increasing concentrations of cationic surfactant cetyltrimethylammonium bromide (CTAB), nonionic surfactant polyoxyethylene (80) sorbitan esters (Tween 80) and salinity of seawater. In contrast, the sorption capacity of E1 decreased with the increasing concentration of anionic surfactant sodium dodecylbenzene sulfonate (SDBS), pH value and temperature of seawater. PMID- 24054733 TI - Extreme irgarol tolerance in an Ulva lactuca L. population on the Swedish west coast. AB - The herbicide irgarol 1051 is commonly used on ship hulls to prevent growth of algae, but as a component of self-eroding paints it can also spread in the surrounding waters and affect non-target organisms. The effect of irgarol on settlement and growth of zoospores from the marine macro algae Ulva lactuca from the Gullmar fjord on the Swedish west coast was investigated in the present study. The zoospores were allowed to settle and grow in the presence of irgarol, but neither settlement - nor growth inhibition was observed at concentrations of up to 2000 nmol l(-1). This is between 10 and 100 times higher than effect concentrations reported earlier for algae. Irgarol also induced the greening effect (4-fold increase in chlorophyll a content) in the settled zoospore/germling population, typical for photosystem II inhibitors like irgarol. This study support previous findings that irgarol constitutes a selection pressure in the marine environment. PMID- 24054734 TI - Lived experiences of women with recurring ovarian cancer. AB - BACKGROUND: Women with recurring ovarian cancer are living longer, due to advances in treatment options. They are now often outpatients, experiencing rapid encounters on treatment days. Whether this shift in care meets women's needs has been scarcely explored scientifically. PURPOSE OF THE STUDY: This study aimed to illuminate the phenomenon of living with recurring ovarian cancer as experienced by women in that condition. METHODS AND SAMPLE: A descriptive phenomenological method was used. Eight open-ended interviews with four women were performed approximately three and five years after the first recurrence of ovarian cancer. During these years the women had repeated clinically and radiologically verified recurrence requiring chemotherapy. KEY RESULTS: The phenomenon of living with recurring ovarian cancer meant that the women felt forced to pay attention to the failing body in order to avoid a potential breakdown. The growing limitation of their intermittent strength meant that strength had to be captured and protected. Sharing their lives with others was difficult, due to the different living conditions. The women found no space to mediate their experiences, either in close relationships or with health care professionals. But, the circumstances they lived under also generated a gratitude for the unexpected extra time. CONCLUSIONS: The findings revealed that the four women were grateful to live a while longer, but needed to share their state of being. The findings are indeed directed to health care professionals, who need to provide a more patient-centred care to meet the women's needs. PMID- 24054735 TI - A comparison of 2 laboratory methods to test dental unit waterline water quality. AB - The performance of 2 American Public Health Association standard laboratory methods, the R2A spread plate and the SimPlate(TM) for heterotrophic plate count, for quantifying heterotrophic microorganisms in dental waterline samples was evaluated. Microbial counts were underestimated on SimPlate(TM) compared with R2A, and the results indicated a poor correlation between the 2 methods. PMID- 24054736 TI - Molecular characterization, serotyping, and antibiotic susceptibility profile of Leptospira interrogans serovar Copenhageni isolates from Brazil. AB - Leptospira interrogans serogroup Icterohaemorrhagiae is the major serogroup infecting humans worldwide, and rodents and dogs are the most significant transmission sources in urban environments. Knowledge of the prevalent serovars and their maintenance hosts is essential to understand the epidemiology of leptospirosis. In this study, 20 Leptospira isolates were evaluated by pulsed field gel electrophoresis (PFGE), variable number tandem-repeat analysis (VNTR), serotyping, and determination of antimicrobial resistance profile. Isolates, originated from bovine, canine, human, and rodent sources, were characterized by microscopic agglutination test with polyclonal and monoclonal antibodies and were identified as L. interrogans serogroup Icterohaemorrhagiae serovar Copenhageni. MICs of antimicrobials often used in veterinary medicine were determined by broth microdilution test. Most of tested antibiotics were effective against isolates, including penicillin, ampicillin, and ceftiofur. Higher MIC variability was observed for fluoroquinolones and neomycin; all isolates were resistant to trimethoprim/sulfamethoxazole and sulphadimethoxine. Isolates were genotyped by PFGE and VNTR; both techniques were unable to discriminate between serovars Copenhageni and Icterohaemorrhagiae, as expected. PFGE clustered all isolates in 1 pulsotype, indicating that these serovars can be transmitted between species and that bovine, rodent, and dogs can maintain them in the environment endangering the human population. PMID- 24054737 TI - mmm: an R package for analyzing multivariate longitudinal data with multivariate marginal models. AB - Modeling multivariate longitudinal data has many challenges in terms of both statistical and computational aspects. Statistical challenges occur due to complex dependence structures. Computational challenges are due to the complex algorithms, the use of numerical methods, and potential convergence problems. Therefore, there is a lack of software for such data. This paper introduces an R package mmm prepared for marginal modeling of multivariate longitudinal data. Parameter estimations are achieved by generalized estimating equations approach. A real life data set is applied to illustrate the core features of the package, and sample R code snippets are provided. It is shown that the multivariate marginal models considered in this paper and mmm are valid for binary, continuous and count multivariate longitudinal responses. PMID- 24054738 TI - Magnets in the GI tract. PMID- 24054739 TI - Enhanced imaging in the GI tract: spectroscopy and optical coherence tomography. PMID- 24054740 TI - "Drivers ed" with a road test for the capsule endoscopist. PMID- 24054741 TI - Narrow-band imaging in the prediction of submucosal invasive colon cancer: how "NICE" is it? PMID- 24054742 TI - Training the next generation of advanced endoscopists in EUS-guided biliary and pancreatic drainage: learning from master endoscopists. PMID- 24054743 TI - Endoscopic treatment of Zenker's diverticula. PMID- 24054744 TI - Assessment of comfort during colonoscopy: a nurse- or patient-rated scale? PMID- 24054745 TI - Response. PMID- 24054746 TI - Initial experience of a through-the-scope balloon device for ileal intubation in Crohn's disease. PMID- 24054747 TI - Endoscopes for endoscopists with small hands: a call to meet an unmet demand. PMID- 24054748 TI - Risk stratification by using an esophageal capsule. PMID- 24054749 TI - Response. PMID- 24054751 TI - Heavy metal and trace element bioaccumulation in target tissues of four edible fish species from the Danube River (Serbia). AB - Pikeperch (Sander lucioperca), European catfish (Silurus glanis), burbot (Lota lota), and common carp (Cyprinus carpio) were collected from the Danube River (Belgrade section, Serbia), and samples of liver, muscle, and gills were analyzed for Al, As, B, Ba, Cd, Co, Cr, Cu, Fe, Hg, Li, Mn, Mo, Ni, Pb, Se, Sr, and Zn using inductively coupled plasma optical emission spectrometry (ICP-OES) to highlight the importance of species and tissue selection in monitoring research, contaminant studies, and human health research. The Kruskal-Wallis test revealed significant differences between fish species in regard to metal levels in liver, muscle, and gills. The principal component analysis (PCA) indicated that the studied fish species could be grouped on the basis of the level of analyzed elements in liver and gills. The Mann-Whitney test showed two subsets (one comprising two piscivorous species, pikeperch and catfish, and the other, two polyphagous species, burbot and carp) in regard to Cr and Hg levels in liver (higher levels in piscivorous species), as well as B, Fe, and Hg in gills (B and Fe with higher levels in polyphagous and Hg in piscivorous species), and As in muscle (higher levels in polyphagous species). Carp had distinctly higher levels of Cd, Cu, and Zn in liver in comparison to other three species. None of the elements exceeded the maximum acceptable concentrations (MAC). However, since Hg levels are close to the prescribed MAC levels, the consumption of these fishes can be potentially hazardous for humans. PMID- 24054750 TI - Modeling heart disease in a dish: from somatic cells to disease-relevant cardiomyocytes. AB - A scientific milestone that has tremendously impacted the cardiac research field has been the discovery and establishment of human-induced pluripotent stem cells (hiPSC). Key to this discovery has been uncovering a viable path in generating human patient and disease-specific cardiac cells to dynamically model and study human cardiac diseases in an in vitro setting. Recent studies have demonstrated that hiPSC-derived cardiomyocytes can be used to model and recapitulate various known disease features in hearts of patient donors harboring genetic-based cardiac diseases. Experimental drugs have also been tested in this setting and shown to alleviate disease phenotypes in hiPSC-derived cardiomyocytes, further paving the way for therapeutic interventions for cardiac disease. Here, we review state-of-the-art methods to generate high-quality hiPSC and differentiate them towards cardiomyocytes as well as the full range of genetic-based cardiac diseases, which have been modeled using hiPSC. We also provide future perspectives on exploiting the potential of hiPSC to compliment existing studies and gain new insights into the mechanisms underlying cardiac disease. PMID- 24054752 TI - Significant relationships among frost tolerance and net photosynthetic rate, water use efficiency and dehydrin accumulation in cold-treated winter oilseed rapes. AB - Five winter oilseed rape cultivars (Benefit, Californium, Cortes, Ladoga, Navajo) were subjected to 30 days of cold treatment (4 degrees C) to examine the effect of cold on acquired frost tolerance (FT), dehydrin (DHN) content, and photosynthesis-related parameters. The main aim of this study was to determine whether there are relationships between FT (expressed as LT50 values) and the other parameters measured in the cultivars. While the cultivar Benefit accumulated two types of DHNs (D45 and D35), the other cultivars accumulated three additional DHNs (D97, D47, and D37). The similar-sized DHNs (D45 and D47) were the most abundant; the others exhibited significantly lower accumulations. The highest correlations were detected between LT50 and DHN accumulation (r= 0.815), intrinsic water use efficiency (WUEi; r=-0.643), net photosynthetic rate (r=-0.628), stomatal conductance (r=0.511), and intracellular/intercellular CO2 concentration (r=0.505). Those cultivars that exhibited higher Pn rate in cold (and further a significant increase in WUEi) had higher levels of DHNs and also higher FT. No significant correlation was observed between LT50 and E, PRI, or NDVI. Overall, we have shown the selected physiological parameters to be able to distinguish different FT cultivars of winter oilseed rape. PMID- 24054753 TI - Variation of antioxidants and secondary metabolites in nitrogen-deficient barley plants. AB - Barley (Hordeum vulgare cv. Bojos) plants cultured in low nitrogen (N) containing Hoagland solution (20 mg/l) were exposed to N deficiency (-N) over 15 days. Plants revealed relatively high tolerance to total N deficit because shoot length was not altered and dry biomass was depleted by ca. 30% while root length increased by ca. 50% and dry biomass remained unaffected. Soluble proteins and free amino acids decreased more pronouncedly in the roots. Antioxidants (glutathione and ascorbic acid) decreased in the shoots but increased or were not affected in the roots. Ascorbate peroxidase and glutathione reductase activities were depleted in shoots and/or roots while guaiacol peroxidase activity was stimulated in the shoots. In accordance, fluorescence signal of reactive oxygen species (ROS) and nitric oxide was elevated in shoots but no extensive changes were observed in roots if +N and -N treatments are compared. At the level of phenolic metabolites, slight increase in soluble phenols and some phenolic acids and strong elevation of flavonoid homoorientin was found in the shoots but not in the roots. Fluorescence microscopy in terms of detection of phenols is also discussed. We also briefly discussed accuracy of quantification of some parameters owing to discrepancies in the literature. It is concluded that N deficiency induces increase in shoot phenolics but also elevates symptoms of oxidative stress while increase in root antioxidants probably contributes to ROS homeostasis aimed to maintain root development. PMID- 24054754 TI - Identification and expression of different dehydrin subclasses involved in the drought response of Trifolium repens. AB - Reverse transcribed RNAs coding for YnKn, YnSKn, SKn, and KS dehydrin types in drought-stressed white clover (Trifolium repens) were identified and characterized. The nucleotide analyses revealed the complex nature of dehydrin coding sequences, often featured with alternative start and stop codons within the open reading frames, which could be a prerequisite for high variability among the transcripts originating from a single gene. For some dehydrin sequences, the existence of natural antisense transcripts was predicted. The differential distribution of dehydrin homologues in roots and leaves from a single white clover stolon under normal and drought conditions was evaluated by semi quantitative RT-PCR and immunoblots with antibodies against the conserved K-, Y- and S-segments. The data suggest that different dehydrin classes have distinct roles in the drought stress response and vegetative development, demonstrating some specific characteristic features. Substantial levels of YSK-type proteins with different molecular weights were immunodetected in the non-stressed developing leaves. The acidic SK2 and KS dehydrin transcripts exhibited some developmental gradient in leaves. A strong increase of YK transcripts was documented in the fully expanded leaves and roots of drought-stressed individuals. The immunodetected drought-induced signals imply that Y- and K segment containing dehydrins could be the major inducible Late Embryogenesis Abundant class 2 proteins (LEA 2) that accumulate predominantly under drought. PMID- 24054755 TI - Primary repair of tetralogy of Fallot in infants: transatrial/transpulmonary or transventricular approach. AB - OBJECTIVE: Right ventricular (RV) dysfunction is a significant cause of morbidity and mortality after surgical correction of tetralogy of Fallot (TOF). Transatrial/transpulmonary repair avoids a ventriculotomy (in contrast to the transventricular approach) in order to preserve the structure and function of the right ventricle. We performed a pilot prospective randomized controlled trial in infants with TOF undergoing primary repair. METHODS: A pilot prospective controlled clinical trial was conducted in infants with TOF undergoing primary repair between January 2008 and December 2009. One hundred and six patients were recruited in the trial and divided into a transatrial-transpulmonary approach group (Group A; n = 53) and a transventricular approach group (Group B; n = 53), depending on the different surgical techniques used. RESULTS: Preoperative patient characteristics and procedure-related variables were similar. There were no deaths in Group A, while two patients died in Group B. There were significant differences in cardiopulmonary bypass time (95.02 +/- 23.8 vs. 85.23 +/- 22.63 minutes, p = 0.032), cross-clamp time (69.4 +/- 10.36 vs. 61.17 +/- 9.38 minutes, p = 0.035), inotropic support (1.63 +/- 0.97 vs. 2.1 +/- 1.09 days, p = 0.02), intubation time (26.62 +/- 12.48 vs. 33.02 +/- 17.55 hours, p = 0.033), duration of stay in the intensive care unit (ICU) (2.25 +/- 1.28 vs. 2.85 +/- 1.46 days, p = 0.026), and the incidence of arrhythmia [3 patients (5.7%) vs. 10 patients (18.9%), p = 0.038]. No significant differences in right/left ventricular pressure ratio and hospital stay were observed. CONCLUSION: Transatrial/transpulmonary repair of TOF is associated with excellent surgical results and immediately follow-up. PMID- 24054756 TI - Comparison of topical isosorbide mononitrate, topical diltiazem, and their combination in the treatment of chronic anal fissure. AB - BACKGROUND/OBJECTIVE: Chronic anal fissure is a painful condition that is associated with an increase in internal anal sphincter pressure. The main aim of this study is to evaluate the efficacy and adverse effects of topical isosorbide 5 mononitrate and topical diltiazem, when administered either as single agents or in combination, in the treatment of anal fissure. METHODS: Patients with chronic anal fissure were enrolled in the study. They were randomized into three groups: Group A (0.2% isosorbide 5 mononitrate users), Group B (2% diltiazem users), and Group C (2%diltiazem + 0.2% isosorbide 5 mononitrate users). Pain was evaluated using a visual analog scale (VAS). Level of strain during defecation was graded on a 4-point scale. RESULTS: A total of 55 patients were enrolled in the study. The average ages of patients in Groups A, B, and C were 37.94 +/- 16.19, 42.83 +/ 13.21, 40 +/- 13.58 years, respectively. After treatment, pain completely abated in 55.6% of patients in Group A, 27.8% (n = 5) in Group B, and 42.1% (n = 8) in Group C. The decreases in average VAS values prior to and after treatment in Groups A, B, and C were statistically significant (p values 0.0001, 0.001, and 0.0001, respectively). Average strain scores prior to and after treatment were 2.11/0.72 for Group A, 2.17/0.94 for Group B, and 1.95/0.47 for Group C. Strain during defecation prior to and after treatment in Groups A, B, and C was statistically significant (p values 0.001, 0.001, and 0.003, respectively). CONCLUSION: Topical diltiazem and a combination of nitrate and diltiazem can be used in the treatment of anal fissure. However, the agents are not significantly superior each other. PMID- 24054757 TI - A novel duct-lobular segmentectomy for breast tumors with nipple discharge using near-infrared indocyanine green fluorescence imaging. AB - A 44-year-old woman was referred to our hospital with pathological nipple discharge from her left breast. Ultrasonography revealed a solid tumor beneath her left areola that measured 17 mm in diameter with a dilated mammary duct. Contrast-enhanced magnetic resonance imaging showed an early-enhanced cystic tumor and a dilated mammary duct. We performed a duct-lobular segmentectomy using near-infrared indocyanine green (ICG)-fluorescence imaging. Under general anesthesia, a silicone tube was inserted into an orifice of a fluid-discharging mammary duct, and 1 mL dye-fluorescence liquid containing ICG and indigo carmine was injected into the mammary duct. A periareolar incision was made, and the fluorescence image of the demarcated mammary duct segment was obtained. The mammary duct segment was dissected, along with the demarcation line. The cystic lesion and dilated mammary duct were fully resected, and the pathological diagnosis was intraductal papilloma of the breast. We report that near-infrared ICG fluorescence could be applied for imaging of the mammary duct segment, and the fluorescence image allowed for easier duct-lobular segmentectomy for nipple discharge. PMID- 24054758 TI - Undifferentiated embryonal sarcoma of the liver with focal osteoid picture-a case report. AB - Undifferentiated embryonal sarcoma of the liver (UESL) is a rare primary liver tumor. Less than 100 adult cases were reported. It has female and right lobe preponderance. In pathological features, focal osteoid picture in UESL is never reported. We present a 63-year-old male patient with left lobe UESL with focal osteoid picture. He was admitted for a palpable solid mass, with left upper quadrant abdominal pain for 4 months. Abdominal computed tomography showed a huge well-circumscribed mass at left upper quadrant, 21.3 * 13 * 27.9 cm(3) in size, with multiple septa in delayed phase. En bloc resection including lateral segmentectomy, splenectomy, and cholecystectomy were performed, but tumor rupture was noted. The pathologic diagnosis was ruptured UESL. The postoperative course was uneventful, and adjuvant radiotherapy without chemotherapy was performed. Peritoneal seeding with massive ascites was noted in the 9(th) month after operation. Even after receiving salvage chemotherapy, he died 1 year after operation. Early complete surgical resection with adjuvant chemotherapy may improve prognosis of UESL. But the overall survival of UESL did not improve until recently. We present this case along with a literature review of the clinical pictures, diagnosis, pathology presentation, pathologicogenesis of focal osteoid picture, treatment, and prognosis for UESL of another 23 new reported cases since 2007. PMID- 24054759 TI - Evaluation of microfocused ultrasound with visualization for lifting, tightening, and wrinkle reduction of the decolletage. AB - BACKGROUND: Laxity and rhytides are manifestations of photodamage on the chest. OBJECTIVE: We sought to evaluate efficacy and safety of microfocused ultrasound with visualization treatment of decolletage laxity and rhytides. METHODS: In all, 24 subjects with moderate to severe rhytides, as measured by a validated 5-point photonumeric scale (Fabi/Bolton Chest Wrinkle Scale), received microfocused ultrasound with visualization treatment. Efficacy was measured at 90 and 180 days by the Fabi/Bolton Chest Wrinkle Scale, mid-clavicular to nipple distance, masked assessment, Physician and Subject Global Aesthetic Improvement Scales, and patient satisfaction. Adverse events were recorded. RESULTS: Rhytides improved over time (P < .0001), with 46% and 62% of subjects showing a 1- to 2-point improvement at days 90 and 180, respectively. Mean (SD) mid-clavicular to nipple distance decreased (P < .0001), from 20.9 (1.57) cm to 19.8 (1.50) cm and 19.5 (1.59) cm, at days 90 and 180, respectively. At day 90, 100% were improved by Subject Global Aesthetic Improvement Scale score (P < .0001) and 96% were improved by Physician Global Aesthetic Improvement Scale score (P < .0001), with similar findings at day 180. All subjects were satisfied or very satisfied at day 90, with similar results at day 180. Improvement by masked assessment at day 90 was 71%. LIMITATIONS: Single-center study, small sample size, and only Fitzpatrick skin types I and II enrolled were limitations. CONCLUSION: There was appreciable efficacy and patient satisfaction after a single microfocused ultrasound with visualization treatment in wrinkle reduction and lifting of the decolletage. PMID- 24054760 TI - Product of the Physician Global Assessment and body surface area: a simple static measure of psoriasis severity in a longitudinal cohort. AB - BACKGROUND: The Psoriasis Area and Severity Index (PASI) is considered the gold standard assessment tool for psoriasis severity, but PASI is limited by its complexity and insensitivity in people with mild psoriasis. OBJECTIVE: We sought to evaluate the product of a Physician Global Assessment (PGA) and Body Surface Area (BSA) (PGAxBSA) as an alternative to PASI. METHODS: Psoriasis severity was evaluated at 6-month intervals in participants of the Utah Psoriasis Initiative registry. Correlation coefficients were used to compare PGAxBSA with PASI and the Simplified PASI (SPASI). RESULTS: Between August 2008 and November 2010, 435 assessments were completed in 226 participants. The median PASI score was 3.2 (interquartile range 1.8-5.4) and the median BSA was 3.0% (interquartile range 1.0%-5.0%). PGAxBSA had higher correlations with PASI than SPASI (0.87 vs 0.76, P < .001). PGAxBSA also had higher correlations with a Global Patient Assessment of psoriasis severity (0.65) than both PASI (0.59, P < .001) and SPASI (0.51, P < .001). LIMITATIONS: The use of PGAxBSA for measuring severe psoriasis and response to therapy is unclear, because most participants had mild to moderate psoriasis and data were not collected at predefined intervals in relation to therapy initiation. Interrater reliability was not assessed. CONCLUSIONS: PGAxBSA is a simple and sensitive instrument for measuring psoriasis severity. PMID- 24054761 TI - Dose-dependent induction of preneoplastic lesions by the tobacco-specific nitrosamine carcinogen NNK in the in ovo carcinogenicity assessment (IOCA) assay. AB - The potential of the carcinogenic tobacco specific nitrosamine 4-(N-methyl-N nitrosamino)-1-(3-pyridyl)-1-1-butanone (NNK) to induce preneoplastic hepatocellular altered foci (HAF) was tested in the in ovo carcinogenicity assessment (IOCA) assay. Single doses of NNK over a dose range from 0.1 mg to 6 mg were injected into fertilized turkey eggs prior to incubation for 24 days. The livers were investigated by histological, histochemical and morphometric methods. Mortality was increased for eggs exposed to 6 mg. In this group, the whole livers were severely altered, showing pronounced changes of nucleus size and signs of cell death. At the dose of 2 mg various types of foci of altered hepatocytes (HAF) were observed. Basophilic cell foci of the solid or tubular type were most frequent. The NNK-induced HAF were very similar to the preneoplastic lesions that occur in the livers of mammals during hepatocarcinogenesis which are regarded as early indicators of carcinogenesis. The similarity to the HAF in rodents included histochemically detectable alterations like decreased activities of glucose-6 phosphatase, adenosine triphosphatase and glycogen phosphorylase. At doses of 1 mg or below, no HAF were detected. At all dose levels an increased occurrence of enlarged hepatocytes with enlarged nuclei and prominent nucleoli (karyomegalic hepatocytes) were observed. The increase in karyomegalic hepatocytes was also statistically significant at the low dose of 0.1 mg/kg NNK but the dose-effect curve for their induction was clearly non-linear. Induction of HAF and karyomegalic hepatocytes in ovo is a simple (one dose), rapid (24 days) and inexpensive (no animal purchase or housing) experimental approach for studies on chemically induced hepatocarcinogenesis. PMID- 24054762 TI - Medroxyprogesterone acetate is associated with increased sleep spindles during non-rapid eye movement sleep in women referred for polysomnography. AB - Sleep spindles are characteristic electroencephalographic waveforms that may play functionally significant roles in sleep-dependent memory consolidation, cortical development, and neuropsychiatric disorders. Circumstantial evidence has connected endogenous progesterone and its metabolites to the production of sleep spindles; however, the effects of exogenous progestins on sleep spindles have not been described in women. We examined differences in sleep spindle frequency and morphology in a clinical sample of women (n=21) referred for polysomnography taking depot medroxyprogesterone acetate (MPA), relative to a matched comparison group. Consistent with our hypotheses, women taking MPA demonstrated significantly higher sleep spindle density and maximal amplitude relative to comparison patients. Our results suggest that progestins potentiate the generation of sleep spindles, which may have significant implications for research that examines the role of these waveforms in learning, development, and mental illness. PMID- 24054763 TI - Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome. AB - BACKGROUND: Androgen deprivation therapy (ADT) often worsens fatigue in patients with prostate cancer, producing symptoms similar to chronic fatigue syndrome (CFS). Comparing expression (mRNA) of many fatigue-related genes in patients with ADT-treated prostate cancer versus with CFS versus healthy controls, and correlating mRNA with fatigue severity may clarify the differing pathways underlying fatigue in these conditions. METHODS: Quantitative real-time PCR was performed on leukocytes from 30 fatigued, ADT-treated prostate cancer patients (PCF), 39 patients with CFS and 22 controls aged 40-79, together with ratings of fatigue and pain severity. 46 genes from these pathways were included: (1) adrenergic/monoamine/neuropeptides, (2) immune, (3) metabolite-detecting, (4) mitochondrial/energy, (5) transcription factors. RESULTS: PCF patients showed higher expression than controls or CFS of 2 immune transcription genes (NR3C1 and TLR4), chemokine CXCR4, and mitochondrial gene SOD2. They showed lower expression of 2 vasodilation-related genes (ADRB2 and VIPR2), 2 cytokines (TNF and LTA), and 2 metabolite-detecting receptors (ASIC3 and P2RX7). CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=-0.50, p<0.005 and r=-0.34, p<0.05). Purinergic P2RY1 was correlated only with PCF fatigue and pain severity (r=+0.43 and +0.59, p=0.025 and p=0.001). CONCLUSIONS: PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue. PMID- 24054764 TI - [Vitamin D: skeletal and muscular effects]. AB - Insufficient serum levels of 25-hydroxyvitamin D [25(OH)D] is a risk factor for osteoporosis. A new paradigm is emerging with the locally synthesized 1,25(OH)2D within osteoblasts and osteoclasts as the essential pathway for the effects of 25(OH)D in regulating bone remodeling via direct or indirect activation of the specific receptor VDR. Vitamin D has positive effects on fracture risk, muscular function and risk of falls; these effects are observed when serum levels of 25(OH)D are above 30 ng/ml (75 nmol/l). Vitamin D dosing interval may be relevant for reducing the risk of fracture, with evidence suggesting positive effects with short intervals of 3 months or less. It is recommended to maintain an optimal serum level of 25(OH)D when managing patients with osteoporosis or at risk of this bone disease. PMID- 24054765 TI - [Vitamin D and pregnancy]. AB - Vitamin D insufficiency is characterized, since 2005, by 25(OH)D concentration less than 75 nmol/L (or 30 ng/mL). Vitamin D could interfere with many mechanisms involved in preeclampsia's pathogenesis including trophoblastic invasion and immunomodulation as well as blood pressure control and proteinuria. Occurrence of preeclampsia and gestational diabetes seems to be linked to vitamin D deficiency but recent data in the literature are contradictory. Vitamin D supplementation during pregnancy is controversial. Some societies consider it unnecessary and others recommend up to 2000 UI/d. There is no reported case of teratogenicity linked with vitamin D intake. PMID- 24054766 TI - [Vitamin D and neurology]. AB - Vitamin D deficiency is associated with a higher risk of multiple sclerosis and also with a higher relapse rate as well as a higher number of MRI lesions. Elders with vitamin D deficiency have worse cognitive performance. Vitamin D deficiency is a risk factor for developing Alzheimer's disease. Ischemic stroke are more frequent and more severe in patients with low vitamin D levels. Carotid atherosclerosis is more frequent and more severe in patients with vitamin D deficiency. Vitamin D deficiency is associated with a higher risk and worse prognosis of Parkinson's disease. In the different neurological disorders discussed herein, gene polymorphisms that could alter vitamin D metabolism are also associated with a higher incidence or a worse disease prognosis. Despite the links between vitamin D deficiency and the risks of developing neurological disorders, there is, to date, no proof that supplementation could alter the course of these diseases. PMID- 24054767 TI - Complications of endoscopic ultrasound fine needle aspiration on pancreatic cystic lesions: final results from a large prospective multicenter study. AB - BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration of pancreatic cystic lesions has been reported to have a higher complication rate than that of solid lesions, but the real complication rate is unknown. Aim of the study was to identify the complication rate of endoscopic ultrasound-guided fine needle aspiration and related risk factors. METHODS: Prospective multicenter study at four referral centres. Data were collected from January 2010 to July 2012, searching for all adverse events related to guided fine needle aspiration. All complications occurring up to day 90 were recorded. RESULTS: 298 patients (43.9% male, mean age 63.2 +/- 15.4 years) underwent endoscopic ultrasound-guided needle aspiration of pancreatic cystic lesions. Mean size was 34.1 +/- 9 mm. Adverse events occurred in 18 patients (6%): mild complications in 12/18 (66.6%), and moderate complications in 6/18 (33.3%). Seven were immediate, 6 early, and 5 late. All resolved with medical therapy. CONCLUSIONS: Endoscopic ultrasound guided fine needle aspiration of pancreatic cystic lesions has been found to be associated with a higher complication rate than for solid lesions; however, the risk rate is acceptable considering the complication grade and the important diagnostic role of the technique in the management of pancreatic cystic lesions. PMID- 24054768 TI - Antiviral triple therapy with boceprevir in a chronic hepatitis C haemodialysis patient awaiting kidney re-transplantation. PMID- 24054769 TI - The mean number of adenomas per procedure should become the gold standard to measure the neoplasia yield of colonoscopy: a population-based cohort study. AB - BACKGROUND: Measuring adenoma detection is a priority in the quality improvement process for colonoscopy. Our aim was (1) to determine the most appropriate quality indicators to assess the neoplasia yield of colonoscopy and (2) to establish benchmark rates for the French colorectal cancer screening programme. METHODS: Retrospective study of all colonoscopies performed in average-risk asymptomatic people aged 50-74 years after a positive guaiac faecal occult blood test in eight administrative areas of the French population-based programme. RESULTS: We analysed 42,817 colonoscopies performed by 316 gastroenterologists. Endoscopists who had an adenoma detection rate around the benchmark of 35% had a mean number of adenomas per colonoscopy varying between 0.36 and 0.98. 13.9% of endoscopists had a mean number of adenomas above the benchmark of 0.6 and an adenoma detection rate below the benchmark of 35%, or inversely. Correlation was excellent between mean numbers of adenomas and polyps per colonoscopy (Pearson coefficient r=0.90, p<0.0001), better than correlation between mean number of adenomas and adenoma detection rate (r=0.84, p=0.01). CONCLUSION: The mean number of adenomas per procedure should become the gold standard to measure the neoplasia yield of colonoscopy. Benchmark could be established at 0.6 in the French programme. PMID- 24054771 TI - [Community outbreak of Pseudomonas aeruginosa folliculitis associated with a spa]. PMID- 24054770 TI - [Prolonged hospitalization in patients admitted for acute heart failure in the short stay unit (EPICA-UCE study): study of associated factors]. AB - BACKGROUND AND OBJECTIVE: To study the factors associated with prolonged hospitalization in patients admitted for acute heart failure (AHF) in Spanish short-stay units (SSUs). PATIENTS AND METHODS: This was a multicentre, multipurpose cohort study with prospective follow-up including all patients admitted for AHF in the 11 SSUs of the EAHFE registry. Demographic data, previous illness, baseline cardiorespiratory and functional status, acute episode and admission and follow up variables at 60 days were recorded. The primary outcome was prolonged hospitalization in the SSU (>72h). A logistic regression model was used to control the effects of confounding factors. RESULTS: Eight-hundred and nineteen patients were included with a mean age of 80.9 (SD 8.4) years, 483 (59.0%) being women. The median length stay was 3.0 (IQR 2.0-5.0) days with an in hospital mortality of 2.7%. The independent factors associated with prolonged hospitalization were the coexistence of chronic obstructive pulmonary disease (odds ratio [OR] 1.56; 95% IC 1.02-2.38; P=.040) and anaemia (OR 1.72; 95% CI 1.21-2.44; P=.002), basal oxygen saturation<90% on arrival to the Emergency Department (OR 2.21, 95% CI 1.51-3.23; P<.001), hypertensive episode as the precipitating factor of the AHF (protective factor OR 0.49; 95% CI 0.26-0.93; P=.028) and admission on Thursday (OR 1.90; 95% CI 1.19-3.05; P=.008). There were no significant differences between both groups regarding to in-hospital mortality (2.4 vs. 3.0%), mortality (4.1 vs. 4.2%) or revisit at 60 days (18.4 vs. 21.6%). CONCLUSIONS: Several factors including hypertensive episode, insufficiency respiratory, anaemia, chronic obstructive pulmonary disease, and admission on Thursday should be taken into account in patients with AHF admitted in SSU stay to avoid prolonged hospitalization. PMID- 24054772 TI - [Basal ganglia calcification and seizures]. PMID- 24054773 TI - [Detection of drug-drug interactions in prescription between levels of health care in human immunodeficiency virus-infected patients]. PMID- 24054774 TI - [Shoe dermatitis]. PMID- 24054775 TI - [Ipilimumab-induced poliosis]. PMID- 24054776 TI - [Nutritional abnormalities in chronic obstructive pulmonary disease]. AB - Nutritional abnormalities are associated with chronic obstructive pulmonary disease with a frequency ranging from 2 to 50%, depending on the geographical area and the study design. Diagnostic tools include anthropometry, bioelectrical impedance, dual energy radioabsortiometry and deuterium dilution, being the body mass and the lean mass indices the most frequently used parameters. While the most important consequences of nutritional abnormalities are muscle dysfunction and exercise limitation, factors implicated include an imbalance between caloric intake and consumption, and between anabolic and catabolic hormones, inflammation, tobacco smoking, poor physical activity, hypoxemia, some drugs and aging/comorbidities. The most important molecular mechanism for malnutrition associated with chronic obstructive pulmonary disease appears to be the mismatching between protein synthesis and breakdown. Among the therapeutic measures proposed for these nutritional abnormalities are improvements in lifestyle and nutritional support, although the use of anabolic drugs (such as secretagogues of the growth hormone) offers a new therapeutic strategy. PMID- 24054777 TI - A pilot study on low-density lipoprotein receptor-related protein-1 in Chinese patients with abdominal aortic aneurysm. AB - OBJECTIVE: There are no published data on the expression of low-density lipoprotein receptor-related protein 1 (LRP1) in human aortic tissues with abdominal aortic aneurysm (AAA), although some researchers have suggested that LRP1 may be a crucial regulator in the pathogenesis of AAA. The aim of this pilot study is to investigate LRP1 expression in aortic tissues from Chinese patients with AAA compared with normal control tissues. MATERIALS AND METHODS: This study used human abdominal aortic tissues with or without AAA as a research model. Aneurysmal abdominal aortas were collected from Chinese patients with AAA (n = 12) during open surgical aneurysmal repair at our institution, and normal control non-aneurysmal abdominal aortas were collected from Chinese healthy organ donors (n = 12) during organ transplantation. Protein expression of LRP1 was analyzed by western blotting and immunohistochemistry. RESULTS: LRP1 protein expression was significantly lower in AAA (mean LRP1AAA/LRP1(Normal Control) = 0.51 +/- 0.28) than in normal control aortic tissues (mean LRP1(Normal Control)/LRP1(Normal Control) = 1 +/- 0.18) in our small sample cohort (p < .001). No significant correlation was shown between LRP1 protein expression and the size of AAA (p > .05). CONCLUSIONS: Our pilot result suggests that a reduction in LRP1 protein expression may be associated with aneurysm progression. PMID- 24054778 TI - The circuitous route to pivotal mechanisms in aortic aneurysm formation. Commentary regarding EJVES8677R. PMID- 24054779 TI - Sternoclavicular osteoradionecrosis following treatment for head and neck cancer. AB - Osteoradionecrosis (ORN) is a well described complication of radiation therapy (RT) for head and neck cancer (HNC), with a past reported incidence as high as 10 18% [1,4] mostly involving the mandible. ORN rarely involves the sternoclavicular complex in HNC patients treated with RT. Here, we present a case of HNC treated with combined (cytotoxic) chemotherapy and radiation therapy (CCRT) complicated by ORN and osteomyelitis of the sternoclavicular complex involving large segments of both clavicles, the sternum, and the trachea. PMID- 24054780 TI - Siting landfills and incinerators in areas of historic unpopularity: surveying the views of the next generation. AB - The Campania Region in Southern Italy has suffered many problems with municipal solid waste management since the mid-1990s, leading to significant public disturbances and subsequent media coverage. This paper reports on the current views and knowledge of young people (university students) in this region about waste management operations and facilities, specifically the siting of landfills and incinerators. By means of a structured questionnaire, opinion and knowledge were systematically examined by degree type and course year. The study took place in 2011 at the University of Salerno campus. A sample of 900 students, comprising 100 students for each of the nine considered faculties, and 20 students for every academic course year, was randomly selected. Only about a quarter of respondents were not opposed to the siting of a landfill or an incinerator in their city. This clearly highlights that historic opposition to the construction of waste facilities is difficult to overcome and that distrust for previous poor management or indiscretions is long-lived and transcends generations. Students from technical faculties expressed the most reasonable opinion; opinion and knowledge were statistically related (Chi-square test, p<0.05) to the attended faculty, and the knowledge grew linearly with progression through the university. This suggests that awareness of waste management practices develops with experience and understanding of environmental issues. There is general acceptance that many stakeholders - technicians, politicians and citizens - all have to be part of the decision process when siting a new waste management facility. The opinions of the young respondents were significantly influenced by their level of environmental knowledge. PMID- 24054781 TI - Prenatal pelvic MRI: additional clues for assessment of urogenital obstructive anomalies. AB - OBJECTIVE: Ultrasound prenatal evaluation of pelvic cystic mass can be challenging. After having ruled out a cloaca anterior to a large hydrocolpos, it is important to differentiate between combined urogenital anomalies such as urogenital sinus and isolated genital anomalies. PATIENTS AND METHODS: We reviewed the charts of 13 women referred for a third trimester pelvic MRI for cystic pelvic mass discovered in second trimester ultrasound. We evaluated MRI compared with postnatal surgical findings in order to determine clues for improving prenatal diagnoses. RESULTS: MRI excluded the diagnosis of cloacal malformation in nine cases with no false negative. Once a cloaca is ruled out, a different signal between the bladder and the hydrocolpos on T2 sequences is in favor of an isolated genital obstruction. In contrast, in case of urogenital sinus, the vagina is filled with a mixture of genital secretions and urine, which gives it an MRI signal similar to the bladder on T2 sequences. CONCLUSION: Third trimester fetal MRI is an essential exam for characterization of pelvic cystic mass diagnosed by ultrasound. This exam appears valuable for invalidating the diagnosis of cloacal malformation and for differentiating between isolated genital obstruction and urogenital sinus. PMID- 24054782 TI - Relationships among the abundances of plastic debris in different size classes on beaches in South Korea. AB - Plastic debris on six beaches near the Nakdong River Estuary, South Korea, was sampled in May and September 2012 and classified into three size classes, large microplastics (1-5 mm), mesoplastics (5-25 mm), and macroplastics (>25 mm). The relationships among the abundances of the size classes were then examined. The abundances of each size category in May (before rainy season) and in September (after rainy season) were 8205 and 27,606 particles/m(2) for large microplastics, 238 and 237 particles/m(2) for mesoplastics, and 0.97 and 1.03 particles/m(2) for macroplastics, respectively. Styrofoam was the most abundant item both in microplastic and mesoplastic debris, while intact plastics were most common in macroplastic debris. The abundances of meso- and micro-plastics were the most strongly correlated. There was a higher correlation between the abundances of macro- and meso-plastics than between macro- and micro-plastics. PMID- 24054783 TI - Multivariate analysis of heavy metal contaminations in seawater and sediments from a heavily industrialized harbor in Southern Taiwan. AB - Heavy metal pollution, including chromium, zinc, arsenic, cadmium, mercury, copper, lead, and aluminum, in the largest industrial harbor in southern Taiwan was investigated. Increasing metal contamination was observed by monitoring heavy metal concentrations in seawater and sediments and estimating the enrichment factors, particularly those inside the harbor. Compared to other metal-polluted harbors worldwide, the presence of chromium in the sediments was relatively high. Excluding the background contribution, the harbor area was polluted by outflows from river mouths, wastewater discharging pipes, and point sources near industrial activities within the harbor. It is shown by principal component and cluster analyses that metal contamination was affected by a wide range of different and complex contamination mechanisms inside and outside the harbor, suggesting managing the pollution using straightforward strategies, i.e., solutions that only consider a single source or single pathway of metal emissions, is problematic. PMID- 24054784 TI - Good Environmental Status of marine ecosystems: what is it and how do we know when we have attained it? AB - The European Marine Strategy Framework Directive (MSFD) requires EU Member States (MS) to achieve Good Environmental Status (GEnS) of their seas by 2020. We address the question of what GEnS entails especially with regard to the level at which targets are set (descriptors, criteria, indicators), to scales for assessments (regional, sub-divisions, site-specific), and to difficulties in putting into practice the GEnS concept. We propose a refined and operational definition of GEnS, indicating the data and information needed to all parts of that definition. We indicate the options for determining when GEnS has been met, acknowledge the data and information needs for each option, and recommend a combination of existing quantitative targets and expert judgement. We think that the MSFD implementation needs to be less complex than shown for other similar directives, can be based largely on existing data and can be centred on the activities of the Regional Seas Conventions. PMID- 24054785 TI - Potential of bioremediation for buried oil removal in beaches after an oil spill. AB - Bioremediation potential for buried oil removal, an application still lacking thorough research, was assessed in a specifically designed system in which an artificially contaminated oil layer of sand was buried in a sand column subjected to tidal simulation. The efficiency of biostimulation (BS, fertilizer addition) and bioaugmentation (BA, inoculation of pre-stimulated indigenous hydrocarbon degrading microorganisms plus fertilizer) compared to natural attenuation was tested during a 180-day experimental period. The effect of BA was evident after 60 days (degradation of hydrocarbons reached 80%). BS efficacy was revealed only after 120 days. Microorganisms and nutrients added at the top of the sand column were able to reach the buried oil layer and contributed to faster oil elimination, an important feature for effective bioremediation treatments. Therefore, autochthonous BA with suitable nutritive conditions results in faster oil-biodegradation, appears to be a cost-effective methodology for buried oil remediation and contributes to the recovery of oil-impacted areas. PMID- 24054786 TI - Bioavailability of heavy metals in water and sediments from a typical Mediterranean Bay (Malaga Bay, Region of Andalucia, Southern Spain). AB - Concentrations of heavy metals were measured in sediment and water from Malaga Bay (South Spain). In the later twentieth century, cities such as Malaga, have suffered the impact of mass summer tourism. The ancient industrial activities, and the actual urbanization and coastal development, recreation and tourism, wastewaters treatment facilities, have been sources of marine pollution. In sediments, Ni was the most disturbing metal because Ni concentrations exceeded the effects range low (ERL), concentration at which toxicity could start to be observed in 85% of the samples analyzed. The metal bioavailability decreased in the order: Cd>Ni>Pb>Cu>Cr. In the sea water samples, Cd and Pb were the most disturbing metals because they exceeded the continuous criteria concentration (CCC) of US EPA in a 22.5% and 10.0% of the samples, respectively. Statistical analyses (ANOVA, PCA, CA) were performed. PMID- 24054787 TI - Matters of concern: a qualitative study of emergency care from the perspective of patients. AB - STUDY OBJECTIVE: A key to improving the quality of emergency care is improvement of the contact between patient and emergency department (ED) staff. We investigate what patients actually experience during their ED visit to better understand the patterns of relationships among patients and health care professionals. METHODS: This was an ethnographic study. We conducted observations at the ED of a large general teaching hospital. Patients were enrolled in the study on the basis of convenience sampling. We thoroughly analyzed 16 cases in a grounded theory approach, using the constant comparative methods (ie, starting the analysis with the collection of data). This approach enabled us to conceptualize the experiences of patients step by step, using the ethnographic data to refine and test the theoretical categories that emerged. RESULTS: Our data show that patients at the ED continuously and actively labor to deal with their disorder, its consequences, and the situation they are in. Characteristics of these "patient concerns" indicate a certain trouble, have a personal character, impose themselves with a certain urgency, and require patient effort. We have established a qualitative taxonomy of 5 categories of patient concerns: anxiety, expectations, care provision, endurance, and recognition. CONCLUSION: Diligence for patient concerns enables ED staff to have a fruitful insight into patients' actual experience. It offers significant clues to improving relationship building in emergency care practice between patients and health care professionals. PMID- 24054788 TI - Is outpatient emergency department care profitable? Hourly contribution margins by insurance for patients discharged from an emergency department. AB - STUDY OBJECTIVE: We determine the contribution margin per hour (ie, profit) by facility evaluation and management (E&M) billing level and insurance type for patients treated and discharged from an urban, academic emergency department (ED). METHODS: Billing and demographic data for patients treated and discharged from an ED with greater than 100,000 annual visits between 2003 and 2009 were collected from hospital databases. The primary outcome was contribution margin per patient per hour. Contribution margin by insurance type (excluding self-pay) was determined at the patient level by subtracting direct clinical costs from contractual revenue. Hospital overhead and physician expenses and revenue were not included. RESULTS: In 523,882 outpatient ED encounters, contribution margin per hour increased with increasingly higher facility billing level for patients with commercial insurance ($70 for E&M level 1 to $177 at E&M level 5) but decreased for patients with Medicare ($44 for E&M level 1 to $29 at E&M level 5) and Medicaid ($73 for E&M level 1 to -$16 at E&M level 5). During the study years, cost, charge, revenue, and length of stay increased for each billing level. CONCLUSION: In our hospital, contribution margin per hour in ED outpatient encounters varied significantly by insurance type and billing level; commercially insured patients were most profitable and Medicaid patients were least profitable. Contribution margin per hour for patients commercially insured increased with higher billing levels. In contrast, for Medicare and Medicaid patients, contribution margin per hour decreased with higher billing levels, indicating that publicly insured ED outpatients with higher acuity (billing level) are less profitable than similar, commercially insured patients. PMID- 24054789 TI - "Thunderstruck": penetrating thoracic injury from lightning strike. AB - Lightning strike victims are rarely presented at an emergency department. Burns are often the primary focus. This case report describes the improvised explosive device like-injury to the thorax due to lightning strike and its treatment, which has not been described prior in (kerauno)medicine. Penetrating injury due to blast from lightning strike is extremely rare. These "shrapnel" injuries should however be ruled out in all patients struck by lightning. PMID- 24054790 TI - [Solid pseudopapillary tumor of the pancreas: Case report and review of the literature]. PMID- 24054791 TI - [Axillary lymphadenopathy as the debut of a carcinoma arising in a fibroadenoma]. PMID- 24054793 TI - Haem-based sensors: a still growing old superfamily. AB - The haem-based sensors are chimeric multi-domain proteins responsible for the cellular adaptive responses to environmental changes. The signal transduction is mediated by the sensing capability of the haem-binding domain, which transmits a usable signal to the cognate transmitter domain, responsible for providing the adequate answer. Four major families of haem-based sensors can be recognized, depending on the nature of the haem-binding domain: (i) the haem-binding PAS domain, (ii) the CO-sensitive carbon monoxide oxidation activator, (iii) the haem NO-binding domain, and (iv) the globin-coupled sensors. The functional classification of the haem-binding sensors is based on the activity of the transmitter domain and, traditionally, comprises: (i) sensors with aerotactic function; (ii) sensors with gene-regulating function; and (iii) sensors with unknown function. We have implemented this classification with newly identified proteins, that is, the Streptomyces avermitilis and Frankia sp. that present a C terminal-truncated globin fused to an N-terminal cofactor-free monooxygenase, the structural-related class of non-haem globins in Bacillus subtilis, Moorella thermoacetica, and Bacillus anthracis, and a haemerythrin-coupled diguanylate cyclase in Vibrio cholerae. This review summarizes the structures, the functions, and the structure-function relationships known to date on this broad protein family. We also propose unresolved questions and new possible research approaches. PMID- 24054792 TI - Cost-benefit analysis comparing laparoscopic and open ventral hernia repair. AB - OBJECTIVE: Laparoscopic surgery is a successful treatment option offering significant advantages to patients compared with open ventral hernia repair. A cost-benefit analysis was performed to compare the clinical results and economic costs of the open and laparoscopic techniques for anterior abdominal wall hernia repair, in order to determine the more efficient procedure. MATERIAL AND METHODS: We performed a prospective study of 140 patients with primary and incisional hernia, and analyzed clinical data, morbidity, costs of surgery and hospital stay costs. RESULTS: The cost of disposable surgical supplies was higher with laparoscopic repair but reduced the average length of stay (P<.001) and patient morbidity (P<.001). The total cost of the laparoscopic procedure was, therefore, less than initially estimated, yielding a savings of 1,260? per patient (2,865? vs. 4,125?). CONCLUSIONS: Laparoscopic ventral hernia repair is associated with a reduced complication rate, a lower average length of stay and with lower total costs. Laparoscopic repair can save 1.260? for each patient, and so this procedure should be considered a cost-effective approach. PMID- 24054794 TI - The diversity of 2/2 (truncated) globins. AB - Small size globins that have been defined as 'truncated haemoglobins' or as '2/2 haemoglobins' have increasingly been discovered in microorganisms since the early 1990s. Analysis of amino acid sequences allowed to distinguish three groups that collect proteins with specific and common structural properties. All three groups display 3D structures that are based on four main alpha-helices, which are a subset of the conventional eight-helices globin fold. Specific features, such as the presence of protein matrix tunnels that are held to promote diffusion of functional ligands to/from the haem, distinguish members of the three groups. Haem distal sites vary for their accessibility, local structures, polarity, and ligand stabilization mechanisms, suggesting functional roles that are related to O2/NO chemistry. In a few cases, such activities have been proven in vitro and in vivo through deletion mutants. The issue of 2/2 haemoglobin varied biological functions throughout the three groups remains however fully open. PMID- 24054795 TI - Protoglobin: structure and ligand-binding properties. AB - Protoglobin is the first globin identified in Archaea; its biological role is still unknown, although it can bind O2, CO and NO reversibly in vitro. The X-ray structure of Methanosarcina acetivorans protoglobin revealed several peculiar structural features. Its tertiary structure can be considered as an expanded version of the canonical globin fold, characterised by the presence of a pre-A helix (named Z) and a 20-residue N-terminal extension. Other unusual trends are a large distortion of the haem moiety, and its complete burial in the protein matrix due to the extended CE and FG loops and the 20-residue N-terminal loop. Access of diatomic ligands to the haem has been proposed to be granted by two tunnels, which are mainly defined by helices B/G (tunnel 1) and B/E (tunnel 2), and whose spatial orientation and topology give rise to an almost orthogonal two tunnel system unprecedented in other globins. At a quaternary level, protoglobin forms a tight dimer, mostly based on the inter-molecular four-helix bundle built by the G- and H-helices, similar to that found in globin-coupled sensor proteins, which share with protoglobin a common phylogenetic origin. Such unique structural properties, together with an unusually low O2 dissociation rate and a selectivity ratio for O2/CO binding that favours O2 ligation, make protoglobin a peculiar case for gaining insight into structure to function relationships within the globin superfamily. While recent structural and biochemical data have given answers to important questions, the functional issue is still unclear and it is expected to represent the major focus of future investigations. PMID- 24054796 TI - The globins of Campylobacter jejuni. AB - Campylobacter jejuni is a zoonotic Gram-negative bacterial pathogen that is exposed to reactive nitrogen species, such as nitric oxide, from a variety of sources. To combat the toxic effects of this nitrosative stress, C. jejuni upregulates a small regulon under the control of the transcriptional activator NssR, which positively regulates the expression of a single-domain globin protein (Cgb) and a truncated globin protein (Ctb). Cgb has previously been shown to detoxify nitric oxide, but the role of Ctb remains contentious. As C. jejuni is amenable to genetic manipulation, and its globin proteins are easily expressed and purified, a combination of mutagenesis, complementation, transcriptomics, spectroscopic characterisation and structural analyses has been used to probe the regulation, function and structure of Cgb and Ctb. This ability to study Cgb and Ctb with such a multi-pronged approach is a valuable asset, especially since only a small fraction of known globin proteins have been functionally characterised. PMID- 24054797 TI - Haemoglobins of Mycobacteria: structural features and biological functions. AB - The genus Mycobacterium is comprised of Gram-positive bacteria occupying a wide range of natural habitats and includes species that range from severe intracellular pathogens to economically useful and harmless microbes. The recent upsurge in the availability of microbial genome data has shown that genes encoding haemoglobin-like proteins are ubiquitous among Mycobacteria and that multiple haemoglobins (Hbs) of different classes may be present in pathogenic and non-pathogenic species. The occurrence of truncated haemoglobins (trHbs) and flavohaemoglobins (flavoHbs) showing distinct haem active site structures and ligand-binding properties suggests that these Hbs may be playing diverse functions in the cellular metabolism of Mycobacteria. TrHbs and flavoHbs from some of the severe human pathogens such as Mycobacterium tuberculosis and Mycobacterium leprae have been studied recently and their roles in effective detoxification of reactive nitrogen and oxygen species, electron cycling, modulation of redox state of the cell and facilitation of aerobic respiration have been proposed. This multiplicity in the function of Hbs may aid these pathogens to cope with various environmental stresses and survive during their intracellular regime. This chapter provides recent updates on genomic, structural and functional aspects of Mycobacterial Hbs to address their role in Mycobacteria. PMID- 24054798 TI - The globins of cyanobacteria and algae. AB - Approximately, 20 years ago, a haemoglobin gene was identified within the genome of the cyanobacterium Nostoc commune. Haemoglobins have now been confirmed in multiple species of photosynthetic microbes beyond N. commune, and the diversity of these proteins has recently come under increased scrutiny. This chapter summarizes the state of knowledge concerning the phylogeny, physiology and chemistry of globins in cyanobacteria and green algae. Sequence information is by far the best developed and the most rapidly expanding aspect of the field. Structural and ligand-binding properties have been described for just a few proteins. Physiological data are available for even fewer. Although activities such as nitric oxide dioxygenation and oxygen scavenging are strong candidates for cellular function, dedicated studies will be required to complete the story on this intriguing and ancient group of proteins. PMID- 24054799 TI - The Dos family of globin-related sensors using PAS domains to accommodate haem acting as the active site for sensing external signals. AB - Sensor proteins play crucial roles in maintaining homeostasis of cells by sensing changes in extra- and intracellular chemical and physical conditions to trigger biological responses. It has recently become clear that gas molecules function as signalling molecules in these biological regulatory systems responsible for transcription, chemotaxis, synthesis/hydrolysis of nucleotide second messengers, and other complex physiological processes. Haem-containing sensor proteins are widely used to sense gas molecules because haem can bind gas molecules reversibly. Ligand binding to the haem in the sensor proteins triggers conformational changes around the haem, which results in their functional regulation. Spectroscopic and crystallographic studies are essential to understand how these sensor proteins function in these biological regulatory systems. In this chapter, I discuss structural and functional relationships of haem-containing PAS and PAS-related families of the sensor proteins. PMID- 24054800 TI - The globins of cold-adapted Pseudoalteromonas haloplanktis TAC125: from the structure to the physiological functions. AB - Evolution allowed Antarctic microorganisms to grow successfully under extreme conditions (low temperature and high O2 content), through a variety of structural and physiological adjustments in their genomes and development of programmed responses to strong oxidative and nitrosative stress. The availability of genomic sequences from an increasing number of cold-adapted species is providing insights to understand the molecular mechanisms underlying crucial physiological processes in polar organisms. The genome of Pseudoalteromonas haloplanktis TAC125 contains multiple genes encoding three distinct truncated globins exhibiting the 2/2 alpha helical fold. One of these globins has been extensively characterised by spectroscopic analysis, kinetic measurements and computer simulation. The results indicate unique adaptive structural properties that enhance the overall flexibility of the protein, so that the structure appears to be resistant to pressure-induced stress. Recent results on a genomic mutant strain highlight the involvement of the cold-adapted globin in the protection against the stress induced by high O2 concentration. Moreover, the protein was shown to catalyse peroxynitrite isomerisation in vitro. In this review, we first summarise how cold temperatures affect the physiology of microorganisms and focus on the molecular mechanisms of cold adaptation revealed by recent biochemical and genetic studies. Next, since only in a very few cases the physiological role of truncated globins has been demonstrated, we also discuss the structural and functional features of the cold-adapted globin in an attempt to put into perspective what has been learnt about these proteins and their potential role in the biology of cold adapted microorganisms. PMID- 24054801 TI - Microbial eukaryote globins. AB - A bioinformatics survey of about 120 protist and 240 fungal genomes and transcriptomes revealed a broad array of globins, representing five of the eight subfamilies identified in bacteria. Most conspicuous is the absence of protoglobins and globin-coupled sensors, except for a two-domain globin in Leishmanias, that comprises a nucleotidyl cyclase domain, and the virtual absence of truncated group 3 globins. In contrast to bacteria, co-occurrence of more than two globin subfamilies appears to be rare in protists. Although globins were lacking in the Apicomplexa and the Microsporidia intracellular pathogens, they occurred in the pathogenic Trypanosomatidae, Stramenopiles and certain fungi. Flavohaemoglobins (FHbs) and related single-domain globins occur across the protist groups. Fungi are unique in having FHbs co-occurring with sensor single domain globins (SSDgbs). Obligately biotrophic fungi covered in our analysis lack globins. Furthermore, SSDgbs occur only in a heterolobosean amoeba, Naegleria and the stramenopile Hyphochytrium. Of the three subfamilies of truncated Mb-fold globins, TrHb1s appear to be the most widespread, occurring as multiple copies in chlorophyte and ciliophora genomes, many as multidomain proteins. Although the ciliates appear to have only TrHb1s, the chlorophytes have Mb-like globins and TrHb2s, both closely related to the corresponding plant globins. The presently available number of protist genomes is inadequate to provide a definitive census of their globins. Bayesian molecular analyses of single-domain 3/3 Mb-fold globins suggest a close relationship of chlorophyte and haptophyte globins, including choanoflagellate and Capsaspora globins to land plant symbiotic and non symbiotic haemoglobins and to vertebrate neuroglobins. PMID- 24054802 TI - Preface. Microbial globins--status and opportunities. PMID- 24054803 TI - ISHLT International Registry for Heart and Lung Transplantation--into the fourth decade, from strength to strength. PMID- 24054804 TI - The Registry of the International Society for Heart and Lung Transplantation: Thirtieth Official Adult Heart Transplant Report--2013; focus theme: age. PMID- 24054805 TI - The Registry of the International Society for Heart and Lung Transplantation: Thirtieth Adult Lung and Heart-Lung Transplant Report--2013; focus theme: age. PMID- 24054806 TI - The Registry of the International Society for Heart and Lung Transplantation: Sixteenth Official Pediatric Heart Transplantation Report--2013; focus theme: age. PMID- 24054807 TI - The Registry of the International Society for Heart and Lung Transplantation: Sixteenth Official Pediatric Lung and Heart-Lung Transplantation Report--2013; focus theme: age. PMID- 24054808 TI - Single-lung transplantation can be performed with acceptable outcomes using selected donors with heavy smoking history. AB - BACKGROUND: We attempt to determine if adult, single-lung transplantation could be performed with acceptable results in heavy-smoking donors (HSDs; > 20 pack years). METHODS: The United Network of Organ Sharing database was examined for adult single-lung transplantation from 2005 to 2011. RESULTS: Of the 3,704 single lung transplantations, 498 (13.4%) were from HSDs. The 2 groups were similar in recipient age (60.6 vs. 60.7 years, p = 0.20), male gender (61.3% vs. 59.8%, p = 0.54), ischemic time (4.1 vs. 4.2 hours, p = 0.11), and pre-transplant forced expiratory volume in 1 second (FEV1; 41.1% vs. 40.0% predicted). Recipients of HSDs had lower lung allocation score (39.7 vs. 38.0, p = 0.02), less human leukocyte antigen mismatches (4.6 vs. 4.5, p = 0.01), and higher class I panel reactive antibody (2.9% vs. 3.8%, p < 0.001). HSDs were older (33.0 vs. 41.3 years, p < 0.001) and less likely male (62.5 vs. 56.0%, p = 0.01). Recipients with HSDs had longer length of stay (20.5 vs. 23.0 days, p < 0.001) and lower peak FEV1 after single-lung transplantation (80.1% vs. 73.4%, p < 0.001). Freedom from bronchiolitis obliterans syndrome (p = 0.64), post-single-lung transplantation decrement in FEV1 (p = 0.07), and median survival (1,516 vs. 1,488 days, p = 0.10) were similar. Multivariable analysis found receiving lungs from actively smoking HSDs was associated with mortality (hazard ratio [HR], 1.23, 95% confidence interval [CI], 1.05-1.45; p = 0.01). Use of HSDs who were not actively smoking was not associated with mortality (HR, 0.84; 95% CI, 0.59 1.19; p = 0.33). Mortality was associated with recipient age, longer ischemic time, race mismatch, class I panel reactive antibody > 10%, mechanical ventilation, and extracorporeal membrane oxygenation as a bridge to transplantation. CONCLUSIONS: Although single-lung transplantation with actively smoking HSDs results in worse results, outcomes are acceptable and should continue to be considered. PMID- 24054809 TI - Medical therapy in dilated cardiomyopathy and pulmonary arterial banding in children. PMID- 24054810 TI - Radiologic-pathologic correlation in liver angiomyolipoma in a 68-year-old woman. PMID- 24054811 TI - Fluid and electrolyte secretion in the inflamed gut: novel targets for treatment of inflammation-induced diarrhea. AB - Diarrheal disease can occur in the context of both inflammatory and infectious challenges. Inflammation can result in changes in ion transporter expression or simply mislocalization of the protein. In addition to development of diarrhea, an altered secretory state can lead to changes in mucus secretion and luminal pH. Bacterial infection can lead to subversion of host cell signaling, leading to transporter mislocalization and hyposecretion, promoting bacterial colonization. Novel therapeutic strategies are currently being developed to ameliorate transporter defects in the setting of inflammation or bacterial infection including, for example, administration of probiotics and fecal microbiota transplantation. This review will highlight recent findings in the literature detailing these aspects of ion transport in the inflamed gut. PMID- 24054812 TI - Higher calorie diets increase rate of weight gain and shorten hospital stay in hospitalized adolescents with anorexia nervosa. AB - PURPOSE: Current recommendations for refeeding in anorexia nervosa (AN) are conservative, beginning around 1,200 calories to avoid refeeding syndrome. We previously showed poor weight gain and long hospital stay using this approach and hypothesized that a higher calorie approach would improve outcomes. METHODS: Adolescents hospitalized for malnutrition due to AN were included in this quasi experimental study comparing lower and higher calories during refeeding. Participants enrolled between 2002 and 2012; higher calories were prescribed starting around 2008. Daily prospective measures included weight, heart rate, temperature, hydration markers and serum phosphorus. Participants received formula only to replace refused food. Percent Median Body Mass Index (%MBMI) was calculated using 50th percentile body mass index for age and sex. Unpaired t tests compared two groups split at 1,200 calories. RESULTS: Fifty-six adolescents with mean (+/-SEM) age 16.2 (+/-.3) years and admit %MBMI 79.2% (+/-1.5%) were hospitalized for 14.9 (+/-.9) days. The only significant difference between groups (N = 28 each) at baseline was starting calories (1,764 [+/-60] vs. 1,093 [+/-28], p < .001). Participants on higher calories had faster weight gain (.46 [+/-.04] vs. .26 [+/-.03] %MBMI/day, p < .001), greater daily calorie advances (122 [+/-8] vs. 98 [+/-6], p = .024), shorter hospital stay (11.9 [+/-1.0] vs. 17.6 [+/-1.2] days, p < .001), and a greater tendency to receive phosphate supplementation (12 vs. 8 participants, p = .273). CONCLUSIONS: Higher calorie diets produced faster weight gain in hospitalized adolescents with AN as compared with the currently recommended lower calorie diets. No cases of the refeeding syndrome were seen using phosphate supplementation. These findings lend further support to the move toward more aggressive refeeding in AN. PMID- 24054813 TI - Peer influence on marijuana use in different types of friendships. AB - PURPOSE: Although several social network studies have demonstrated peer influence effects on adolescent substance use, findings for marijuana use have been equivocal. This study examines whether structural features of friendships moderate friends' influence on adolescent marijuana use over time. METHODS: Using 1-year longitudinal data from the National Longitudinal Study of Adolescent Health, this article examines whether three structural features of friendships moderate friends' influence on adolescent marijuana use: whether the friendship is reciprocated, the popularity of the nominated friend, and the popularity/status difference between the nominated friend and the adolescent. The sample consists of students in grade 10/11 at wave I, who were in grade 11/12 at wave II, from two large schools with complete grade-based friendship network data (N = 1,612). RESULTS: In one school, friends' influence on marijuana use was more likely to occur within mutual, reciprocated friendships compared with nonreciprocated relationships. In the other school, friends' influence was stronger when the friends were relatively popular within the school setting or much more popular than the adolescents themselves. CONCLUSIONS: Friends' influence on youth marijuana use may play out in different ways, depending on the school context. In one school, influence occurred predominantly within reciprocated relationships that are likely characterized by closeness and trust, whereas in the other school adopting friends' drug use behaviors appeared to be a strategy to attain social status. Further research is needed to better understand the conditions under which structural features of friendships moderate friends' influence on adolescent marijuana use. PMID- 24054814 TI - Training caregivers of disabled patients after stroke. PMID- 24054815 TI - The right to participate in high-risk research. PMID- 24054817 TI - Role of curcumin in idiopathic pulmonary arterial hypertension treatment: a new therapeutic possibility. AB - The idiopathic pulmonary arterial hypertension is a complex disease that mainly affects pulmonary arterial circulation. This undergoes a remodeling with subsequent reduction of flow in the small pulmonary arteries. Because of this damage an increased vascular resistance gradually develops, and over time it carries out in heart failure. The inflammatory process is a key element in this condition, mediated by various cytokines. The inflammatory signal induces activation of NF-kappaB, and prompts TGF-beta-related signaling pathway. Clinical evolution leads to progressive debilitation, greatly affecting the patient quality of life. The actual therapeutic approaches, are few and expensive, and include systemic drugs such as prostanoids, phosphodiesterase inhibitors and antagonists of endothelin-1 (ERBs). Some researchers have long investigated the anti-inflammatory effects of curcumin. It shows a role for inactivation of NF kappaB-mediated inflammation. On the basis of these findings we propose a potential role of curcumin and its pharmacologically fit derivatives for treatment of idiopathic pulmonary arterial hypertension. PMID- 24054818 TI - Inhibition of HSP90 could be possible mechanism for anti-cancer property of amniotic membrane. AB - Amniotic membrane (AM), the innermost layer of the fetal membrane, is considered as a suitable candidate for cancer therapy. In order to develop the AM as a new cancer therapeutic approach, it is essential to understand the molecular mechanism of the AM anti-cancer properties. Previous studies demonstrated that anti-proliferative effects of the AM on tumor cells were associated with induction of cell cycle arrest. Moreover, it has been shown that unknown substances in the AM induce apoptosis in cancer cells and inhibit angiogenesis in tumors. In contrast to the effects of the AM, heat shock proteins (HSPs), in particular HSP90, play a crucial role in development of tumorgenesis. HSP90 inhibits apoptosis in cancer cells and enhances angiogenesis and cell cycle progression. Based on the opposite effects of the amniotic membrane ingredients and HSP90, we hypothesized here that possible mechanism of the AM anti-cancer effects is through inhibition of HSP90. PMID- 24054819 TI - The E1 beta-subunit of pyruvate dehydrogenase is surface-expressed in Lactobacillus plantarum and binds fibronectin. AB - Lactobacillus plantarum is among the species with a probiotic activity. Adhesion of probiotic bacteria to host tissues is an important principle for strain selection, because it represents a crucial step in the colonization process of either pathogens or commensals. Most bacterial adhesins are proteins, and a major target for them is fibronectin, an extracellular matrix glycoprotein. In this study we demonstrate that PDHB, a component of the pyruvate dehydrogenase complex, is a factor contributing to fibronectin-binding in L. plantarum LM3. By means of fibronectin overlay immunoblotting assay, we identified a L. plantarum LM3 surface protein with apparent molecular mass of 35 kDa. Mass spectrometric analysis shows that this protein is the pyruvate dehydrogenase E1 beta-subunit (PDHB). The corresponding pdhB gene is located in a 4-gene cluster encoding pyruvate dehydrogenase. In LM3-B1, carrying a null mutation in pdhB, the 35 kDa adhesin was not anymore detectable by immunoblotting assay. Nevertheless, the pdhB null mutation did not abolish pdhA, pdhC, and pdhD transcription in LM3-B1. By adhesion assays, we show that LM3-B1 cells bind to immobilized fibronectin less efficiently than wild type cells. Moreover, we show that pdhB expression is negatively regulated by the CcpA protein and is induced by bile. PMID- 24054820 TI - Quality assurance mechanisms for the unregulated research environment. AB - Discussions on research quality and reproducibility are appearing in the pages of scientific journals with heightened significance and gaining media attention. Many institutions have developed guidelines to address the topic of quality in basic research, but questions remain about how best to implement and monitor compliance. Herein we present quality assurance (QA) mechanisms developed specifically for the unregulated discovery research environment to preempt growing concerns arising in both academia and industry for data-driven applications of biotechnology. PMID- 24054816 TI - A structured training programme for caregivers of inpatients after stroke (TRACS): a cluster randomised controlled trial and cost-effectiveness analysis. AB - BACKGROUND: Most patients who have had a stroke are dependent on informal caregivers for activities of daily living. The TRACS trial investigated a training programme for caregivers (the London Stroke Carers Training Course, LSCTC) on physical and psychological outcomes, including cost-effectiveness, for patients and caregivers after a disabling stroke. METHODS: We undertook a pragmatic, multicentre, cluster randomised controlled trial with a parallel cost effectiveness analysis. Stroke units were eligible if four of five criteria used to define a stroke unit were met, a substantial number of patients on the unit had a diagnosis of stroke, staff were able to deliver the LSCTC, and most patients were discharged to a permanent place of residence. Stroke units were randomly assigned to either LSCTC or usual care (control group), stratified by geographical region and quality of care, and using blocks of size 2. Patients with a diagnosis of stroke, likely to return home with residual disability and with a caregiver providing support were eligible. The primary outcome for patients was self-reported extended activities of daily living at 6 months, measured with the Nottingham Extended Activities of Daily Living (NEADL) scale. The primary outcome for caregivers was self-reported burden at 6 months, measured with the caregivers burden scale (CBS). We combined patient and caregiver costs with primary outcomes and quality-adjusted life-years (QALYs) to assess cost effectiveness. This trial is registered with controlled-trials.com, number ISRCTN 49208824. FINDINGS: We assessed 49 stroke units for eligibility, of which 36 were randomly assigned to either the intervention group or the control group. Between Feb 27, 2008, and Feb 9, 2010, 928 patient and caregiver dyads were registered, of which 450 were in the intervention group, and 478 in the control group. Patients' self-reported extended activities of daily living did not differ between groups at 6 months (adjusted mean NEADL score 27.4 in the intervention group versus 27.6 in the control group, difference -0.2 points [95% CI -3.0 to 2.5], p value=0.866, ICC=0.027). The caregiver burden scale did not differ between groups either (adjusted mean CBS 45.5 in the intervention group versus 45.0 in the control group, difference 0.5 points [95% CI -1.7 to 2.7], p value=0.660, ICC=0.013). Patient and caregiver costs were similar in both groups (length of the initial stroke admission and associated costs were L13,127 for the intervention group and L12,471 for the control group; adjusted mean difference L1243 [95% CI -1533 to 4019]; p value=0.380). Probabilities of cost-effectiveness based on QALYs were low. INTERPRETATION: In a large scale, robust evaluation, results from this study have shown no differences between the LSCTC and usual care on any of the assessed outcomes. The immediate period after stroke might not be the ideal time to deliver structured caregiver training. FUNDING: Medical Research Council. PMID- 24054821 TI - Moving from political declaration to action on reducing the global burden of cardiovascular diseases: a statement from the Global Cardiovascular Disease Taskforce. PMID- 24054823 TI - Novel concepts in lipoprotein particle metabolism and regulation. PMID- 24054822 TI - Physical activity is associated with bone geometry of premenarcheal girls in a dose-dependent manner. AB - OBJECTIVE: To determine the relationship between habitual physical activity (PA) level and peripheral qualitative computed tomography-determined quantitative tibia characteristics of premenarcheal girls. METHODS: Premenarcheal girls matched for age (10-13 years), bone age and maturity level were assigned into: a) low PA group (LPA, n=25), b) moderate PA group (MPA, n=17), and c) high PA group (HPA, n=18). Participants' daily dietary intake, tibia's geometry and serum levels of calcium and vitamin D were assessed. RESULTS: Premenarcheal girls demonstrating HPA exhibited greater pericortical thickness, cross-sectional area (CSA) and bone mineral content (BMC) (p<.001) in cortical bone, greater BMC, volumetric bone density (vBMD) and polar stress strength index (SSIp) in trabecular bone (p<0.001-0.05) and greater total BMC (p<.05) and vBMD (p<.01) when compared to their physically inactive or moderately active counterparts. MPA exhibited greater values of cortical BMC (p<.01) and SSIp (p<.05) than LPA. Partial correlation analysis (adjusted for BMI) revealed modest associations between PA score and bone geometry parameters (r=0.36-0.49, p<.05) at 38% of tibia length. CONCLUSIONS: Habitual PA affects geometry of both cortical and trabecular areas of a long bone of premenarcheal girls in a dose-dependent manner. Specifically, PA increases both the density and size of cortical bone but only the density of trabecular bone during preadolescence. Given the importance of peak bone mass for future fracture risk, high levels of PA during childhood could be a major target for public health interventions aimed at optimising bone health in prepubertal children when the greatest bone gains occur. PMID- 24054824 TI - [Quality of life and overall survival in high risk patients after radical cystectomy with a simple urinary derivation]. AB - OBJECTIVE: To evaluate quality of life (QoL) and overall survival after radical cystectomy with cutaneous ureterostomies for locally advanced bladder cancer in elderly patients with high surgical risk. METHODS: Fifty eight patients older than 74 years (mean age 80,6+/-4,3) with locally advanced bladder cancer (group A), underwent radical cystectomy and ureterocutaneous diversion. Patients completed the EORTC QLQC30 before and six months after surgery to assess functional, clinical and QoL outcomes. The same evaluation was carried out in a control group (group B) of 29 patients (mean age 82,3+/-3,8 years), who had refused cystectomy. Questionnaires were also administered to patients of both groups who survived at least 20 months and 5 years. RESULTS: All patients presented with an ASA score >=3. Mean hospital stay was 15.1 days (+/-4.8) in group A and 23.5 days (+/-4.1) in Group B. No intraoperative complications occurred in group A. Postoperative overall survival evaluated within 6 months in group A was 97% versus 79% in group B (p<0.001). CONCLUSION: Radical cystectomy with cutaneous ureterostomy represents a valid alternative in elderly patients with invasive bladder cancer and high operative risk. Comparison between two groups showed a statistically significant difference for almost all the Qol related parameters and for short and medium term overall survival. PMID- 24054825 TI - [Return to work after elective inguinal hernia repair]. PMID- 24054826 TI - [Intestinal obstruction due to the use of a surgical hemostatic agent]. PMID- 24054827 TI - Cord blood B-type natriuretic peptide levels in placental insufficiency: correlation with fetal Doppler and pH at birth. AB - OBJECTIVE: To examine the correlation of cardiac B-type natriuretic peptide (BNP) concentrations in umbilical cord blood at birth with fetal Doppler parameters and pH at birth. STUDY DESIGN: Prospective cross-sectional study with the following inclusion criteria: women with a singleton pregnancy, placental insufficiency characterized by increased pulsatility index (PI) of the umbilical artery (UA), intact membranes, and absence of fetal abnormalities. The exclusion criteria kept out cases of newborns with postnatal diagnosis of abnormality and cases in which the blood analysis was not performed. The Doppler parameters used were the UA PI, middle cerebral artery (MCA) PI, cerebroplacental ratio (CPR), and ductus venosus (DV) PI for veins (PIV), all converted into zeta scores. Blood samples were obtained from the umbilical cord immediately after delivery to measure the pH of the UA and the BNP. RESULTS: Thirty-two pregnancies with placental insufficiency were included, 21 (65%) with positive diastolic flow and 11 (35%) with absent or reversed end diastolic flow in the UA. The concentration of BNP correlated significantly with the UA PI z-score (rho=0.43, P=0.016), the CPR z-score (rho= 0.35, P=0.048), the DV PIV z-score (rho=0.61, P<0.001), pH at birth (rho=-0.39, P=0.031), and gestational age (rho=-0.51, P=0.003). In the multiple regression analysis, antenatal parameters were included; the DV PIV z-score (P=0.008) was found to be an independent parameter correlating with BNP at birth. Correlation between BNP and the DV PIV z-score was borne out by the regression equation Log[BNP]=2.34+0.13*DV (F=18.8, P<0.001). Correlation between BNP and pH at birth was confirmed by the regression equation Log[BNP]=21.36-2.62*pH (F=7.69, P=0.01). CONCLUSION: The results suggest that fetal cardiac dysfunction identified by BNP concentrations at birth correlated independently with changes in DV PIV and correlated negatively with pH values at birth. PMID- 24054828 TI - Proteomic analysis related to stress urinary incontinence following vaginal trauma in female mice. AB - OBJECTIVE: The molecular mechanisms underlying stress urinary incontinence (SUI) are not clear. In light of the limited availability of human tissue for study, we explored the changes in the urethra of C57BL/6 mice with experimentally induced SUI. STUDY DESIGN: Twelve virgin female mice were randomized into two groups: one group undergoing vaginal distension (VD) for 1h with an 8-mm dilator, and a non instrumented control group. Four days after VD, leak point pressures (LPP) and maximum urethral closure pressure (MUCP) were assessed in these mice under urethane (1g/kg, i.p.) anesthesia. After measuring LPP and MUCP, the animals were sacrificed, and the urethras were removed for proteomic analysis using 2 dimensional differential gel electrophoresis (2D DIGE) and liquid chromatography tandem mass spectrometry (LC-MS/MS) technology. Lastly, interaction between these proteins was further analyzed using MetaCore. RESULTS: LPP and MUCP values were significantly decreased in the 8-mm VD groups compared with the non-instrumented control group. Sixty-eight differentially expressed proteins of urethra from female mice with and without VD were identified. Of these, 19 proteins were up regulated and 49 were down-regulated. The majority of the VD-induced proteins were involved in generation of precursor metabolites and energy, oxidation of reduction, regulation of apoptosis, and glycolysis. Myosin expression in the urethra was significantly decreased in the 8-mm VD group as compared with the control group. CONCLUSIONS: As a model of simulated birth trauma, VD can induce SUI in female mice. Under-expression of myosin plays a plausible role in the pathogenesis of SUI following vaginal trauma. PMID- 24054829 TI - Does ethnicity moderate dementia's biomarkers? AB - We have used structural equation models to explicitly distinguish functional status, and therefore "dementia-relevant" variance in cognitive task performance (i.e., "delta") from that which is unrelated to a dementing process. Our approach results in a relatively "error-free" continuous variable that can serve as a dementia-specific phenotype. In this study, we associate delta with cytokines and other serum biomarkers in a well characterized Alzheimer's disease cohort, the Texas Alzheimer's Research and Care Consortium. Independent of covariates, delta is associated significantly with 12 serum biomarkers. These associations appear to be specific to non-Hispanic white participants. PMID- 24054830 TI - Tolerability and pharmacokinetic properties of ciprofloxacin dry powder for inhalation in patients with cystic fibrosis: a phase I, randomized, dose escalation study. AB - BACKGROUND: Inhaled antibacterial agents are used to manage chronic pulmonary infections in cystic fibrosis (CF) and non-CF bronchiectasis. However, established nebulized preparations impose a substantial time burden on patients. A dry powder formulation of ciprofloxacin for inhalation (ciprofloxacin DPI) has been developed using PulmoSphereTM (Novartis, Pharma AG, Basel, Switzerland) technology (administered using a T-326 inhaler) to maximize antibacterial activity and convenience. OBJECTIVE: This study investigated the tolerability and pharmacokinetic properties of multiple-dose once-daily and twice-daily ciprofloxacin DPI in adults with CF. METHODS: A Phase I, randomized, single blind, placebo-controlled, dose-escalation study in patients with CF (median age 29.0 years [19-40]), stable pulmonary status, and chronic Pseudomonas aeruginosa colonization. Sequential cohorts received ciprofloxacin DPI 32.5 mg qd (1 capsule for inhalation; n = 6), 65 mg qd (2 capsules for inhalation; n = 6), or 32.5 mg (n = 6) bid for 7 days. Each group was placebo controlled. RESULTS: Twenty-five patients were enrolled (12 men; median age, 29.0 years [range, 19-40 years]; 6, 6, 6, and 7 patients in the ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid and placebo groups, respectively). No serious treatment-emergent adverse events or clinically relevant changes in tolerability parameters, including lung function measurements, were reported. Twenty-one patients (ciprofloxacin, n = 17; placebo, n = 4) experienced 29 mild drug-related treatment-emergent adverse events, including bitter taste (ciprofloxacin, 17 patients; placebo, 2) and bronchospasm (ciprofloxacin, 3; placebo, 2). Ciprofloxacin DPI was absorbed rapidly after inhalation. Systemic exposure to ciprofloxacin was low and comparable between single and multiple dosing in all 3 dose groups, suggesting an absence of substantial drug accumulation. The geometric mean AUCs after the last dose were 0.383, 1.472, and 0.781 mg . h/L with ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. The range of geometric mean t(1/2) in plasma was 3.4 to 9.5 hours. Sputum concentrations of ciprofloxacin were high, with substantial variability. Geometric mean ciprofloxacin concentrations (%CV) in induced sputum were 57.7 (118.2), 177.5 (53.4), and 149.7 (249.7) mg/L 0.75 hours after the last dose of ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. CONCLUSIONS: Ciprofloxacin DPI was well tolerated, especially with respect to lung function, with minimal systemic exposure compared with data from previous studies of oral and intravenous administration, and with no apparent accumulation at steady state. Sputum ciprofloxacin concentrations above 100-times the minimum inhibitory concentration for P aeruginosa were detected. Ciprofloxacin DPI may be effectively delivered to the lungs at microbiologically active concentrations while minimizing the risk for systemic intolerabilities. Eudra clinical trial identifier: 2006-003690-26. PMID- 24054831 TI - Is magnetic resonance imaging comparable with computed tomography in the diagnosis of retroperitoneal metastasis in patients with testicular cancer? PMID- 24054832 TI - Perceived benefits of a radiology resident mentoring program: comparison of residents with self-selected vs assigned mentors. AB - PURPOSE: It has been suggested that assigned mentoring relationships are less successful than those that develop by free choice. This study evaluates radiology residents' overall experience with a mentoring program and compares the responses of those who self-selected mentors with those who were assigned mentors. METHODS: A voluntary Web-based survey was sent to 27 radiology residents in postgraduate years 3-5. Data collected included the following: year in residency, method of mentor assignment, duration of relationship, frequency and types of communication, perceived value of mentoring, overall satisfaction with the program, and the perceived impact of mentoring. RESULTS: Twenty-five of 27 residents (93%) responded, with 14 having self-selected mentors (56%) and 11 having assigned mentors (44%). Both groups unanimously agreed that mentoring is beneficial or critical to their training; however, those residents with self selected mentors were significantly more satisfied with the mentoring program (4 vs 3.3; P = .04) and more likely to consider their mentor as their primary mentor compared with those with assigned mentors (11 [79%] vs 4 [36%]; P = .049). Although all residents perceived a benefit, residents with self-selected mentors rated almost all mentoring parameters more positively than those with assigned mentors, although most of these parameters did not reach statistical significance. CONCLUSION: Residents highly value the importance of mentoring. However, residents who self-select their mentors are more likely to be satisfied with a mentoring program. PMID- 24054833 TI - Roles for corticotropin-releasing factor receptor type 1 in energy homeostasis in mice. AB - OBJECTIVE: Expression of corticotropin-releasing factor type 1 receptor (CRFR1) has been shown on pancreatic beta cells, and its activation potentiates glucose stimulated insulin secretion (GSIS). However, the roles of CRFR1 in energy metabolism beyond insulin release remain elusive. MATERIALS/METHODS: We characterized the metabolic phenotypes of mice lacking CRFR1 (CRFR1KO mice) under conditions of energy excess. RESULTS: When fed a normal diet, the glucose profile of CRFR1KO mice in response to a glucose tolerance test was similar to that of wild-type (WT) mice, while serum insulin levels were significantly lower in CRFR1KO mice, reflecting high insulin sensitivity in part due to very low glucocorticoid levels. Histology of the pancreas revealed islet hypoplasia in CRFR1KO mice, suggesting a role of CRFR1 in maintaining the beta cell mass in a manner similar to incretins. In response to a high-fat diet, CRFR1KO mice showed insulin resistance, but serum insulin levels during glucose challenge remained at a low level, indicating defective GSIS. In addition, CRFR1KO mice showed resistance to diet-induced obesity and hepatic steatosis. Although total food intake was not different between CRFR1KO and WT mice, oxygen consumption was significantly increased in CRFR1KO mice. The increased energy expenditure may explain the lean phenotype of CRFR1KO mice under conditions of energy excess. CONCLUSIONS: Our results suggest that CRFR1 plays important roles in whole body energy homeostasis, providing compelling evidence of the close relationship between energy homeostasis and the function of the hypothalamic-pituitary-adrenal axis. PMID- 24054834 TI - Jaccoud's arthropathy associated with Reynold's syndrome. PMID- 24054835 TI - Reactivation of hepatitis virus B infection in a patient with rheumatoid arthritis after treatment with rituximab. PMID- 24054836 TI - Expression and mechanism of regulation of PP2A/Pr65 in ameloblastoma. AB - OBJECTIVE: This study aimed to investigate the expression of PP2A/PR65 protein in ameloblastoma and the molecular mechanisms underlying the regulation of PP2A/PR65. The association between PP2A/PR65 and the clinicopathological characteristics of tumor specimens in ameloblastoma were to provide a theoretical basis for the diagnosis, therapy and prognosis of ameloblastoma. STUDY DESIGN: Streptavidin-peroxidase (S-P) immunohistochemical staining was used to detect PP2A/Pr65 expression changes in a total of 68 cases of ameloblastoma, six ameloblastic carcinomas, 21 squamous cell carcinomas and seven normal oral mucosas. Western blot was used to analyze PP2A/PR65 protein expression in 15 cases of ameloblastoma and three cases of normal oral mucosa. RESULTS: Of the 68 cases analyzed, four cases were negative, 25 cases were weakly positive, 20 cases were moderately positive and 19 cases were strongly positive. In six cases of ameloblastic carcinoma, three cases were weak positive, one case was positive, two cases were strongly positive and none were negative. In 21 cases of squamous cell carcinomas, three cases were negative, 17 cases were weakly positive, one case was moderately positive and none were strongly positive. Western blot analysis showed that, PP2A/Pr65 protein expression was lower in ameloblastoma tissue compared with normal oral mucosa. CONCLUSIONS: Reduced expression of PP2A/PR65 in ameloblastoma compared with normal oral mucosa indicates that PP2A/PR65 is involved in the occurrence and development of ameloblastoma. PMID- 24054837 TI - Immune mechanisms in type 1 diabetes. AB - There are three prerequisites for development of the autoimmune disease type 1 diabetes (T1D). First, beta cell-reactive T cells need to be activated; second, the response needs to be proinflammatory; and finally, immune regulation of autoreactive responses must fail. Here, we describe our current understanding of the cell types and immune mechanisms involved in each of these steps leading to T1D. Novel findings regarding beta cell involvement in its own destruction, the importance of the microbiota for instruction of the immune system, and recent data from studies in T1D patients are discussed. In addition, we summarise therapeutic approaches to T1D, and how these relate to the immune mechanisms involved in disease development. PMID- 24054838 TI - Infection prevention in anesthesia practice: a tool to assess risk and compliance. AB - Transmission of bacterial and viral infections to patients from improper anesthesia infection prevention and control practices continues to be reported. "Recommendations for Infection Control for the Practice of Anesthesiology" were recently revised. The process used to develop an anesthesia infection prevention assessment tool is described. The tool is intended to encourage collaboration between infection preventionists and anesthesia providers in an effort to assess infection prevention and control practices in various health care anesthesia settings. PMID- 24054839 TI - Reflections on the days of phospholipase C. PMID- 24054840 TI - MRC Centre for Neuromuscular Diseases 1st (1st December 2010), and 2nd (2nd May 2012) myotonic dystrophy workshops, London, UK and the myotonic dystrophy standards of care and national registry meeting, Newcastle, UK July 2011. PMID- 24054841 TI - [Genetic identification of a case of Noonan syndrome and treatment with growth hormone]. PMID- 24054842 TI - Embracing mechanical forces in cell biology. PMID- 24054843 TI - Analogs of Changsha near-infrared dyes with large Stokes Shifts for bioimaging. AB - The construction of fluorescent imaging probes has contributed significantly to the recent advances in biology and medicine. Near infrared (NIR) fluorescent probes are favorable to be employed in fluorescence imaging in living animals. Rhodamine dyes have been widely used as a robust platform for development of fluorescent probes for a wide variety of targets. However, the absorption and emission wavelengths of classical rhodamine derivatives are below 600 nm. Thus, it is desirable to construct rhodamine analogs with longer absorption and emission wavelengths, preferably in the NIR region. Toward this end, our group has previously constructed Changsha (CS) NIR dyes while retaining the rhodamine like fluorescence ON-OFF switching mechanism. However, like classic rhodamines, these rhodamine NIR derivatives still have small Stokes shifts (typically less than 35 nm), which can lead to serious self-quenching and fluorescence detection error due to excitation backscattering effects. This shortcoming may constrain the full potential of their applications. Thus, there is a need to develop rhodamine NIR derivatives with large Stokes shifts. In this work, we have designed and synthesized a class of analogs of CS NIR dyes with large Stokes shifts. Among the new dyes presented herein, the dye 1c displays a high fluorescence quantum yield in biological media and thus promising for in vivo imaging applications. Furthermore, using 1c as a platform, we further constructed the NIR fluorescent turn-on probe 3, which is suitable for imaging endogenously produced HClO in the RAW264.7 macrophage cells, demonstrating the value of our new NIR functional fluorescent dye 1c. PMID- 24054844 TI - Hypoxia-induced therapeutic neovascularization in a mouse model of an ischemic limb using cell aggregates composed of HUVECs and cbMSCs. AB - Cell transplantation for therapeutic neovascularization holds great promise for treating ischemic diseases. This work prepared three-dimensional aggregates of human umbilical vein endothelial cells (HUVECs) and cord-blood mesenchymal stem cells (cbMSCs) with different levels of internal hypoxia by a methylcellulose hydrogel system. We found that few apoptosis occurred in these cell aggregates, despite developing a hypoxic microenvironment in their inner cores. Via effectively switching on the hypoxia-inducible factor-1alpha-dependent angiogenic mechanisms, culturing the internally hypoxic HUVEC/cbMSC aggregates on Matrigel resulted in formation of extensive and persistent tubular networks and significant upregulation of pro-angiogenic genes. As the level of internal hypoxia created in cell aggregates increased, the robustness of the tubular structures developed on Matrigel increased, and expression levels of the pro angiogenic genes also elevated. Transplantation of hypoxic HUVEC/cbMSC aggregates into a mouse model of an ischemic limb significantly promoted formation of functional vessels, improved regional blood perfusion, and attenuated muscle atrophy and bone losses, thereby rescuing tissue degeneration. Notably, their therapeutic efficacy was clearly dependent upon the level of internal hypoxia established in cell aggregates. These analytical results demonstrate that by establishing a hypoxic environment in HUVEC/cbMSC aggregates, their potential for therapeutic neovascularization can be markedly enhanced. PMID- 24054845 TI - Photostable water-dispersible NIR-emitting CdTe/CdS/ZnS core-shell-shell quantum dots for high-resolution tumor targeting. AB - Near-infrared (NIR, 700-900 nm) fluorescent quantum dots are highly promising as NIR bioprobes for high-resolution and high-sensitivity bioimaging applications. In this article, we present a class of NIR-emitting CdTe/CdS/ZnS core-shell-shell quantum dots (QDs), which are directly prepared in aqueous phase via a facile microwave synthesis. Significantly, the prepared NIR-emitting QDs possess excellent aqueous dispersibility, strong photoluminescence, favorable biocompatibility, robust storage-, chemical-, and photo-stability, and finely tunable emission in the NIR range (700-800 nm). The QDs are readily functionalized with antibodies for use in immunofluorescent bioimaging, yielding highly spectrally and spatially resolved emission for in vitro and in vivo imaging. In comparison to the large size of 15-30 nm of the conventional NIR QDs, the extremely small size (~ 4.2 nm or 7.5 nm measured by TEM or DLS, respectively) of our QDs offers great opportunities for high-efficiency and high sensitivity targeted imaging in cells and animals. PMID- 24054846 TI - The reduction in immunogenicity of neurotrophin overexpressing stem cells after intra-striatal transplantation by encapsulation in an in situ gelling collagen hydrogel. AB - Delivery of neurotrophic factors to the brain via genetically modified bone marrow-derived mesenchymal stem cells (MSCs) offers a promising neuroprotective strategy for neurodegenerative diseases. However, MSCs delivered to the CNS typically show poor survival post-transplantation, which is accompanied by microglial activation and astrocyte recruitment at the graft site. Recent studies have shown the potential of biomaterials to provide a supportive matrix for transplanted cells which may assist in the grafting process. In this study, an in situ gelling type I collagen hydrogel was evaluated as an intracerebral transplantation matrix for delivery of glial cell line-derived neurotrophic factor (GDNF)-overexpressing MSCs to the rat brain (GDNF-MSCs). In vitro analyses demonstrated that this collagen hydrogel did not affect the viability of the GDNF MSCs nor did it prevent GDNF secretion into the surrounding medium. In vivo analyses also confirmed that the collagen hydrogel did not negatively impact on the survival of the cells and permitted GDNF secretion into the striatal parenchyma. Importantly, this study also revealed that transplanting GDNF-MSCs in a collagen hydrogel significantly diminished the host brain's response to the cells by reducing the recruitment of both microglia and astrocytes at the site of delivery. In conclusion, this hydrogel, which is composed of the natural extracellular matrix, collagen, was shown to be a well-tolerated cell delivery platform technology which could be functionalised to further aid cell support and graft integration. PMID- 24054847 TI - Enhanced wound healing by topical administration of mesenchymal stem cells transfected with stromal cell-derived factor-1. AB - The objective of this study was to investigate the ability of mesenchymal stem cells (MSC) genetically engineered with stromal cell-derived factor-1 (SDF-1) to heal skin wounds. When transfected with SDF-1 plasmid DNA, MSC which were isolated from the bone marrow of rats, secreted SDF-1 for 7 days. In vitro cell migration assay revealed that the SDF-1-engineered MSC (SDF-MSC) enhanced the migration of MSC and dermal fibroblasts to a significantly greater extent than MSC. The SDF-MSC secreted vascular endothelial growth factor, hepatocyte growth factor, and interleukin 6 at a significantly high level. A skin defect model of rats was prepared and MSC and SDF-MSC were applied to the wound to evaluate wound healing in terms of wound size and histological examinations. The wound size decreased significantly faster with SDF-MSC treatment than with MSC and PBS treatments. The length of the neoepithelium and the number of blood vessels newly formed were significantly larger. A cell-tracing experiment with fluorescently labeled cells demonstrated that the percent survival of SDF-MSC in the tissue treated was significantly high compared with that of MSC. It was concluded that SDF-1 genetic engineering is a promising way to promote the wound healing activity of MSC for a skin defect. PMID- 24054848 TI - CGKRK-modified nanoparticles for dual-targeting drug delivery to tumor cells and angiogenic blood vessels. AB - Antiangiogenic therapy shows great advantages in clinical cancer treatment while no overall survival has been achieved. The compromised results were mainly contributed by intrinsic/acquired antiangiogenic drug resistance and increased local invasion or distant metastasis after antiangiogenic therapy. Here we constructed a CGKRK peptide-modified PEG-co-PCL nanoparticulate drug delivery system (DDS), aiming at targeting both tumor angiogenic blood vessels and tumor cells to achieve enhanced anti-tumor activity as well as holding a great potential to overcome the drawbacks of antiangiogenic therapy alone. The obtained CGKRK-functionalized PEG-co-PCL nanoparticles (CGKRK-NP) with a particle size of 117.28 +/- 10.42 nm and zeta potential of -15.7 +/- 3.32 mV, exhibited an enhanced accumulation via an energy-dependent, lipid raft/caveolae-mediated endocytosis with the involvement of microtubules in human umbilical vein endothelial cells (HUVEC) and an energy-dependent, lipid raft/caveolae-mediated endocytosis with the participation of Golgi apparatus in human U87MG cells. Using coumarin-6 as the fluorescence probe, in vitro U87MG tumor spheroids assays showed that CGKRK-NP effectively penetrated into the tumor spheroids. Selective accumulation and extensive bio-distribution of CGKRK-NP at tumor site was confirmed by in vivo imaging and tumor section analysis. After drug loading, CGKRK-NP enhanced cytotoxicity and apoptosis induction activity of the loaded PTX on both HUVEC cells and U87MG cells and improved its inhibition effect on the growth of U87MG tumor spheroids. The smallest tumor volume was achieved by those mice bearing subcutaneous U87MG tumor following the treatment of PTX-loaded CGKRK NP. The findings here indicated that CGKRK peptide-functionalized nanoparticulate DDS could be used as an effective tumor angiogenic blood vessels and tumor cells dual-targeting DDS and might provide a great promising approach for reducing the disadvantages of antiangiogenic therapy alone. PMID- 24054849 TI - Bone regeneration around N-acetyl cysteine-loaded nanotube titanium dental implant in rat mandible. AB - New strategies involving drugs loading onto implant surfaces are required to enhance osseointegration and shorten healing time after implantation. In this study, we examined the feasibility of N-acetyl cysteine (NAC)-loaded nanotube titanium (NLN-Ti) implants as a potential drug delivery system. To determine the effect of NLN-Ti in in vitro and in vivo, viability and ROS formation was assessed and enzyme-linked immunosorbant assay (ELISA), Western blot, micro computed tomography (MU-CT), hematoxylin and eoxin (H&E) staining and immunohistochemical (IHC) analysis were done. In vitro, cell viability was increased and inflammatory responses and reduced oxidative stress-related defense were decreased with MC 3T3-E1 cells exposed to a sustained release of NAC from NLN-Ti implants. Following NLN-Ti implant installation, MU-CT revealed an increase of newly formed bone volume and bone mineral density in the mandibles of Sprague Dawley rats. Relatively well formed new bone was demonstrated in close contact to the NLN-Ti implant surface by H&E staining. IHC revealed significantly higher expression of bone morphogenetic protein-2, -7 and heme oxygenase-1, and reduced expression of receptor activator of nuclear factor-kappa B ligand. The data indicate that NLN-Ti implants enhance osseointegration and highlight the value of the small animal model in assessing diverse biological responses to dental implants. PMID- 24054850 TI - B-type natriuretic peptide and infarct size in ST-elevation myocardial infarction. PMID- 24054851 TI - The acupunctured lung. AB - We discuss a 72-year-old woman admitted with acute shortness of breath and severe sharp chest pain several hours after receiving acupuncture therapy. She was subsequently diagnosed as having an iatrogenic pneumothorax secondary to acupuncture. We discuss the complications of acupuncture and why patients should be informed of the risks of such procedures. PMID- 24054852 TI - Correlation of optic nerve sheath diameter measurements by computed tomography and magnetic resonance imaging. AB - BACKGROUND: Traditionally, intracranial pressure is measured by direct ventriculostomy, which is invasive. Noninvasive measures such as bedside ultrasound and magnetic resonance imaging have been advocated and utilized recently to assess the intracranial pressure. The role of this study is to determine the degree of agreement between measurements of the optic nerve sheath diameter by computed tomography (CT) and magnetic resonance imaging (MRI). MATERIALS AND METHODS: Retrospective chart review of 100 consecutive patients who had both MRI and CT scan of the head from January 1, 2011, until March 31, 2013, at our center was performed. A discrepancy of 0.2 mm between the 2 measurements was set as acceptable difference. The measurements of optic nerve sheath diameter (ONSD) were compared for agreement between the 2 modalities using the method by Bland and Altman. RESULTS: A total of 100 patients with both MRI and CT scan of the head were selected. Of these 100 patients, 24 were male and 76 were female. The average age was 63 years. No ONSD abnormality was detected in any of the patients. The discrepancy in measurements of the ONSD between CT and MRI in transverse plane was less than the predetermined cut-off value of 0.2 mm. Within subject variance was estimated at 0.0058 for both CT and MRI. CONCLUSION: Comparable results without significant discrepancy as predetermined by the study groups were obtained from CT scan. Measurement of ONSD by CT scan can be used to indirectly asses the intracranial pressure in addition to clinical assessment and other signs of increased intracranial pressure on CT scan. PMID- 24054853 TI - Segmental zoster abdominal paresis (zoster pseudohernia): a review of the literature. AB - Herpes zoster is a distinct clinical syndrome that may present with a segmental zoster paresis. Although thoracic dermatomes are the most commonly affected, paresis of the abdominal muscles has been less frequently reported. To review the existing published evidence regarding this unusual clinical entity, a literature search of PubMed and Google was performed. In total, 35 articles that described 36 individual cases were identified. The information from all the cases was tabulated for the analysis. The mean age was 67.5 years. The ratio of men to women was approximately 4:1. The left and right side were approximately equally affected. The most affected associated dermatome was T11. In 88.9% of the patients, the typical herpetic rash preceded the abdominal weakness. The mean latent period from rash to onset of abdominal muscle weakness was 3.5 weeks. Electrodiagnostic studies confirmed the diagnosis in 95% of the tested patients. Complete recovery with conservative measures occurred in 79.3% of the patients who were followed-up for recovery, with a mean time for recovery of 4.9 months. Visceral neuropathy co-occurred in 19.4% of the patients. Because of its self limited nature and good prognosis, recognition of this complication is important to prevent unnecessary diagnostic studies and procedures. Electrodiagnostic studies can be effectively used to confirm the diagnosis. Because visceral neuropathy commonly co-occurs with segmental zoster abdominal paresis, it should be actively investigated and treated. PMID- 24054854 TI - Multivariate regression: the pitfalls of automated variable selection. PMID- 24054855 TI - Image-guided diagnostic injections with anesthetic versus magnetic resonance arthrograms for the diagnosis of suspected hip pain. PMID- 24054856 TI - Medial foot pain in a runner: a case presentation. AB - A 27-year-old runner presented to our sports medicine clinic with 4 months of medial foot pain after an eversion ankle sprain. Initial radiographs were negative for fracture. Her symptoms improved but plateaued after 1 month. She was unable to continue running and noticed a new prominence at her right medial foot. Results of a physical examination showed pes planus, a prominent navicular in her right foot and mild weakness of inversion at the right ankle. Magnetic resonance imaging showed bone edema adjacent to a navicular synchondrosis, which confirmed a diagnosis of type 2 accessory navicular with synchondrosis injury. The patient was treated conservatively with a progressive rehabilitation course. PMID- 24054857 TI - Fibrolipomatous hamartoma of the median nerve: comparison of magnetic resonance imaging and ultrasound. PMID- 24054858 TI - Natural anti-insulin autoantibodies in cats: enzyme-linked immunosorbent assay for the determination of plasma anti-insulin IgG and its concentrations in domestic cats. AB - Anti-insulin immunoglobulin G (IgG) has been found in the sera of healthy cats. To determine the concentrations of these antibodies, an enzyme-linked immunosorbent assay (ELISA) for anti-insulin IgG was developed. ELISA maintained the linearity of a standard concentration line between 67.5 and 2160 ng/ml. The coefficients of variances (CVs) of intra-assays in two different plasma samples were 4.0% and 3.7%, respectively. The inter-assay CVs in two different plasma samples were 5.1% and 6.9%, respectively. The dilution curves of two samples were rectilinear. Anti-insulin IgG was detected in all 84 of the healthy cats that were tested. Plasma anti-insulin IgG concentrations ranged from 80 to 1578 MUg/ml, with a median concentration of 221 MUg/ml, and this value correlated positively with total plasma IgG concentrations (r=0.383, p<0.01). In an intravenous glucose tolerance test, plasma anti-insulin IgG concentrations did not alter, even with changes in plasma glucose and insulin concentrations. The ELISA that was developed was able to determine plasma anti-insulin IgG in domestic cats, and confirmed that all healthy cats had plasma anti-insulin IgG. Determining the plasma concentrations of anti-insulin IgG in cats with various pathological conditions might clarify the role of anti-insulin IgG. PMID- 24054859 TI - Predictors of length of hospital stay among older adults admitted to acute care wards: a multicentre observational study. AB - BACKGROUND: Reduction in length of hospital stay (LOS) is considered as a potential strategy to optimize resource consumption and reduce health care costs. We analysed predictors of increased LOS among older patients admitted to acute care wards according to type of admission (through the Emergency Room [ER] or elective). METHODS: We analysed data of 1123 older patients, aged 65years or older, consecutively admitted to seven acute care wards. LOS was defined as the number of days from admission to discharge (or death) and categorized according to its median value (10days). RESULTS: Mean age of participants was 81+/-7years and 56% were women. Patients admitted through ER had a shorter LOS compared with those elective (10.4+/-6.7 vs. 12.0+/-6.7days; p<0.0001). Factors associated with LOS >10days, for patients admitted through ER, were female gender (OR 0.58; 95% C.I. 0.37-0.90), erythrocyte sedimentation rate (OR 1.02; 95% C.I. 1.01-1.03), and excessive polypharmacy (use of >=10 drugs during stay) (OR 3.60; 95% C.I. 1.40-9.25). Predictors for elective patients were chronic alcohol consumption (OR 0.54; 95% C.I. 0.32-0.93), walking speed >=0.8m/s (OR 0.31; 95% C.I. 0.14-0.72), excessive polypharmacy (OR 4.78; 95% C.I. 1.92-11.90), pressure ulcers (OR 2.60; 95% C.I. 1.01-6.79), cerebrovascular disease (OR 0.49; 95% C.I. 0.24-0.99) and dementia (OR 0.18; 95% C.I. 0.08-0.39). CONCLUSIONS: LOS differed between patients admitted through emergency and through elective admission. Demographic and clinical parameters can affect LOS and polypharmacy was the strongest and the only common risk factor in both groups. PMID- 24054861 TI - Increased expression of phosphorylated NBS1, a key molecule of the DNA damage response machinery, is an adverse prognostic factor in patients with de novo myelodysplastic syndromes. AB - The expression of activated forms of key proteins of the DNA damage response machinery (pNBS1, pATM and gammaH2AX) was assessed by means of immunohistochemistry in bone marrow biopsies of 74 patients with de novo myelodysplastic syndromes (MDS) and compared with 15 cases of de novo acute myeloid leukemia (AML) and 20 with reactive bone marrow histology. Expression levels were significantly increased in both MDS and AML, compared to controls, being higher in high-risk than in low-risk MDS. Increased pNBS1 and gammaH2AX expression possessed a significant negative prognostic impact for overall survival in MDS patients, whereas pNBS1 was an independent marker of poor prognosis. PMID- 24054860 TI - Role of microRNA deregulation in the pathogenesis of diffuse large B-cell lymphoma (DLBCL). AB - MicroRNAs (miRNAs) are small endogenous RNA molecules that regulate gene expression at the post-transcriptional level through its sequence complementation with target mRNAs. An individual miRNA species can simultaneously influence the expression of multiple genes and conversely, several miRNAs can synchronously control expression of specific gene product mRNA levels. Thus, miRNAs expression in cells has to be precisely regulated and alterations in miRNA levels may cause an aberrant expression of genes involved in oncogenic pathways and consequently result in cancer development. Indeed, miRNA expression is often deregulated in many cancers, including B-cell lymphomas. Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas with different genetic backgrounds, morphologic features, and responses to therapy. Over the past decade, miRNAs emerged as a new tool for understanding DLBCL biology, and promising candidate molecular markers in DLBCL classification and treatment. In this review, we will focus on miRNAs aberrantly expressed in DLBCL and discuss the putative mechanisms of this deregulation. Additionally, we will summarize miRNAs' involvement in the identification of DLBCL subgroups, and their potential role as diagnostic/prognostic biomarkers as well as specific therapeutic targets for DLBCL. PMID- 24054862 TI - [Mandibular actinomycosis]. AB - INTRODUCTION: Actinomycosis is a rare disease. The cervicofacial region is the most frequent localization. A chronic pus discharge, sometimes tumor-like, suggests the diagnosis, which is often confirmed by anatomopathology. The treatment is surgical debridement and antibiotic therapy, frequently long-term. We report three cases of mandibular actinomycosis. CASE REPORTS: A 21-year-old male patient presented with a fistulized swelling of the right jaw. A 48-year-old male patient was referred for alveolar healing delay after avulsion of teeth 32, 33, and 34. A 38-year-old female patient presented with a left mandibular swelling and restricted mouth opening. In the three cases, the diagnosis of actinomycosis was made by histology. The clinical outcome was good following alveolar curettage (and sequestrectomy for 1 patient) and antibiotic therapy. DISCUSSION: Mandibular actinomycosis is caused by Actinomyces israelii. Lesions if untreated may evolve to osteitis and sequestration. Early diagnosis is crucial. PMID- 24054863 TI - [A tumour of tail of the eyebrow]. PMID- 24054864 TI - A population-based competing-risks analysis of survival after nephrectomy for renal cell carcinoma. AB - OBJECTIVES: Variability in survival after surgical treatment is observed in patients with renal cell carcinoma (RCC), thereby affirming the heterogeneity of the disease. The aim of our study was to provide a clinically relevant and detailed assessment of survival following surgical excision in patients with RCC of all stages according to age, stage, and grade. MATERIALS AND METHODS: A retrospective population-based analysis of 42,090 patients in the United States who were treated with partial nephrectomy (PN) or radical nephrectomy (RN) for RCC of all stages between the years 1988 and 2008 was performed. Competing-risks Poisson regression analyses focusing on cancer-specific mortality (CSM) or other cause mortality (OCM) were executed. Stratification was performed according to age groups (<= 59, 60-69, 70-79, and >= 80 y), the American Joint Committee on Cancer stage (I, II, III, and IV), and the Fuhrman grade (I-II and III-IV). RESULTS: Increasing stage was associated with higher CSM rates (from 2%-9% to 54% 79% for stage I and IV), regardless of age. Similarly, high tumor grade was associated with higher CSM rates (from 2%-64% to 6%-79% for low and high grade). However, OCM was nonnegligible amongst persons aged 70 to 79 years (11%-24%) and >= 80 years (17%-44%), regardless of stage and grade. In subanalyses focusing on stage I RCC, CSM (3%-10%) rates were slightly higher for RN-treated patients, regardless of age and grade. However, in individuals aged 70 to 79 years with high-grade RCC, OCM rates were slightly higher for PN relative to RN (25.5% vs. 23.5%). In those aged >= 80 years, OCM rates were higher for PN compared with RN, both for low-grade (39.4% vs. 32.7%) and high-grade disease (52.0% vs. 42.8%). CONCLUSIONS: Tumor grade and American Joint Committee on Cancer stage represent important prognostic factors for the prediction of CSM, despite adjustment for patient age. However, OCM rates were nonnegligible in elderly individuals (>= 70 y) with low-grade and stage I to III RCC. PMID- 24054865 TI - Urine markers for detection and surveillance of bladder cancer. AB - OBJECTIVES: Bladder cancer detection and surveillance includes cystoscopy and cytology. Urinary cytology is limited by its low sensitivity for low-grade tumors. Urine markers have been extensively studied to help improve the diagnosis of bladder cancer with the goal of complementing or even replacing cystoscopy. However, to date, no marker has reached widespread use owing to insufficient evidence for clinical benefit. MATERIAL AND METHODS: Pubmed/Medline search was conducted to identify original articles, review articles, and editorials regarding urine-based biomarkers for screening, early detection, and surveillance of urothelial carcinoma of the bladder. Searches were limited to the English language, with a time frame of 2000 to 2013. Keywords included urothelial carcinoma, bladder cancer, transitional cell carcinoma, biomarker, marker, urine, diagnosis, recurrence, and progression. RESULTS: Although several urinary markers have shown higher sensitivity compared with cytology, it remains insufficient to replace cystoscopy. Moreover, most markers suffer from lower specificity than cytology. In this review, we aimed to summarize the current knowledge on commercially available and promising investigational urine markers for the detection and surveillance of bladder cancer. CONCLUSIONS: Well-designed protocols and prospective, controlled trials are needed to provide the basis to determine whether integration of biomarkers into clinical decision making will be of value for bladder cancer detection and screening in the future. PMID- 24054866 TI - Quantification of peripheral blood CD133 mRNA in identifying metastasis and in predicting recurrence of patients with clear cell renal cell carcinoma. AB - OBJECTIVES: To investigate whether CD133 messenger ribonucleic acid (mRNA) could provide useful information to identify metastasis or predict recurrence in patients with clear cell renal cell carcinoma (cRCC). METHODS AND MATERIALS: This study included 86 patients with cRCC and 30 healthy controls. Real-time reverse transcriptase-polymerase chain reaction was used to quantify CD133 mRNA in peripheral blood mononuclear cells before nephrectomy. RESULTS: The average CD133 mRNA in patients with metastatic cRCC (1.546 +/- 0.291) was significantly higher than that in those with localized cRCC (1.034 +/- 0.316, P = 0.022) or in controls (0.042 +/- 0.028, P = 0.001). Metastasis could be identified with a sensitivity of 82.6% at specificity of 69.8% by CD133 mRNA. Among patients with localized cRCC, there was a significant difference in CD133 mRNA between the patients with recurrence (1.136 +/- 0.127) and without recurrence (1.010 +/- 0.091, P = 0.047). Recurrence could be identified with a sensitivity of 75.0% at specificity of 61.8%. Patients with a higher CD133 mRNA had a significantly higher recurrence rate than those with a low CD133 mRNA (P = 0.019). CONCLUSIONS: CD133 mRNA can be useful for identifying metastasis, predicting recurrence, and stratifying the patients into different risk groups for possible adjuvant treatment. PMID- 24054867 TI - iNOS expression and NO production contribute to the direct effects of BCG on urothelial carcinoma cell biology. AB - OBJECTIVES: Evidence suggests that oxidative stress occurring as a consequence of inducible nitric oxide synthase/nitric oxide (iNOS/NO) contributes to the biologic effects of bacille Calmette-Guerin (BCG). Objective of this study is to examine iNOS expression, NO production, and the biologic effect of NO on established intermediate end points for the human urothelial carcinoma cell response to BCG. MATERIALS AND METHODS: Quantitative reverse transcriptase polymerase chain reaction and real-time measurement of NO was used to assess iNOS and NO production, respectively, in 2 human urothelial carcinoma (UC) cell lines, in response to BCG. The effect of blocking NO production using the specific iNOS inhibitor 1400W was determined for multiple intermediate end points characterizing BCG's direct effects on tumor cell biology. Activation of nuclear factor kappa B and nuclear factor (erythroid-derived 2)-like 2 signaling pathways, transactivation of genes, including p21, CD54, IL6, IL8, CXCL1, CXCL3, CCL20, and cytotoxicity, as measured by vital dye exclusion, lactate dehydrogenase release, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay were measured in response to BCG with and without iNOS inhibition. RESULTS: Exposure of UC cells to BCG significantly increased both iNOS expression and NO production. Inhibition of iNOS activity with 1400W significantly inhibited BCG's direct biologic effect on UC cells for all of the end points evaluated. CONCLUSIONS: iNOS expression, NO production, and the associated oxidative stress play a central role in the response of UC cells to BCG exposure. Manipulation of oxidative stress may afford an opportunity to enhance the antitumor effects of BCG. PMID- 24054868 TI - Cav1.3 channel alpha1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers. AB - Widespread use of L-type calcium channel blockers for treating hypertension has led to multiple epidemiologic studies to assess the risk of prostate cancer incidence. These studies revealed a reverse correlation between the likelihood of prostate cancer risk and the use of L-type calcium channel blockers among men without family history but the mechanism was not clear. In this study, we examined the expression profiles of multiple L-type calcium channel genes in prostate cancers and determined their functional roles in androgen receptor (AR) transactivation and cell growth. By reanalyzing the ONCOMINE database, we found that L-type calcium channel CACNA1D gene expression levels in cancer tissues were significantly higher than noncancer tissues in 14 of 15 published complementary deoxyribonucleic acid microarray data sets, of which 9 data sets showed an increase of 2- to 17-folds. Quantitative polymerase chain reaction and immunostaining experiments revealed that CACNA1D gene and its coding protein alpha1D were highly expressed in prostate cancers, especially in castration resistant diseases, compared with benign prostate tissues. Consistent with the notion of CACNA1D as an ERG-regulated gene, CACNA1D gene expression levels were significantly higher in prostate cancers with TMPRSS2-ERG gene fusion compared with the cases without this gene fusion. Blocking L-type channel's function or knocking down CACNA1D gene expression significantly suppressed androgen stimulated Ca(2+) influx, AR transactivation, and cell growth in prostate cancer cells. Taken together, these data suggest that CACNA1D gene overexpression is associated with prostate cancer progression and might play an important role in Ca(2+) influx, AR activation, and cell growth in prostate cancer cells. PMID- 24054869 TI - Validation of copy number variants associated with prostate cancer risk and prognosis. AB - OBJECTIVE: Two recent studies have reported novel heritable copy number variants on chromosomes 2p, 15q, and 12q to be associated with prostate cancer (PCa) risk in non-Hispanic Caucasians. The goal of this study was to determine whether these findings could be independently confirmed in the Caucasian population from the South Texas area. METHODS AND MATERIALS: The study subjects consisted of participants of the San Antonio Biomarkers of Risk for PCa cohort and additional cases ascertained in the same metropolitan area. We genotyped all 7 of the reported copy number variants using real-time quantitative polymerase chain reaction in 1,536 (317 cases and 1,219 controls) non-Hispanic Caucasian men, and additionally, we genotyped 632 (191 cases and 441 controls) Hispanic Caucasian men for one of these variants, a deletion on 2p24.3. RESULTS: Association of the deletion on 2p24.3 with overall PCa risk did not meet our significance criteria but was consistent with previous reports (odds ratio, 1.40; 95% confidence interval 0.99-2.00; P = 0.06). Among Hispanic Caucasians, this deletion is much less prevalent (minor allele frequencies of 0.059 and 0.024 in non-Hispanic and Hispanic Caucasians, respectively) and did not show evidence of association with risk for PCa. Interestingly, among non-Hispanic Caucasians, carrying a homozygous deletion of 2p24.3 was significantly associated with high-grade PCa as defined by Gleason score sum >=8 (odds ratio, 27.99; 95% confidence interval 1.99-392.6; P = 0.007 [the Fisher exact test]). The remaining 6 copy number variable regions either were not polymorphic in our cohort of non-Hispanic Caucasians or showed no evidence of association. CONCLUSIONS: Our findings are consistent with the reported observation that a heritable deletion on 2p24.3 is associated with PCa risk in non-Hispanic Caucasians. Additionally, our observations indicate that the 2p24.3 variant is associated with risk for high-grade PCa in a recessive manner. We were unable to replicate any association with PCa for the variants on chromosomes 15q and 12q, which may be explained by regional population differences in low frequency variants and disease heterogeneity. PMID- 24054870 TI - Blood loss associated with radical cystectomy: a prospective, randomized study comparing Impact LigaSure vs. stapling device. AB - OBJECTIVES: Radical cystectomy (RC) is associated with significant blood loss and transfusion requirement. We performed a prospective, randomized trial to compare blood loss, operative time, and cost using 2 different and commonly employed approaches to tissue ligation and division during RC: mechanical (stapler device) and electrosurgical (heat-sealing device). METHODS AND MATERIALS: Eighty patients undergoing RC for urothelial bladder carcinoma were randomized to use of either an Endo GIA Stapler or Impact LigaSure device for tissue ligation and division. Primary outcomes were blood loss, operative time, and device costs. Data were analyzed with Wilcoxon rank sum test and Welch 2-sample t test. RESULTS: There were no significant demographic or preoperative differences between the cohorts. Mean estimated blood loss was similar between the electrosurgical (687 ml) and stapler (708 ml) arms (P = 0.850). There were no significant differences between cohorts when comparing operative times or transfusion requirement. There was a significant increase in the mean number of adjunctive suture ligatures used in the stapling device arm (3.0 vs. 1.5, P = 0.047). Total device costs were significantly lower with the LigaSure compared with the GIA Stapler ($625.00 vs. $1490.10, P<0.001). There were no complications attributable to either device. CONCLUSIONS: This prospective, randomized study demonstrates no significant difference in blood loss, transfusion requirement, or safety between mechanical vs. electrosurgical control of the vascular pedicles. The LigaSure device, however, is significantly less costly than the GIA Stapler and required fewer additional measures for hemostasis. PMID- 24054871 TI - The combination of an mTORc1/TORc2 inhibitor with lapatinib is synergistic in bladder cancer in vitro. AB - OBJECTIVE: To examine the ability of dual mTORc1/c2 inhibitors in conjunction with lapatinib to function in a synergistic manner to inhibit cell proliferation and anchorage-independent growth in bladder cancer cell lines. MATERIALS AND METHODS: We examined patient tumor samples for overexpression of pS6, p4EBP1, pAkt, and phosphorylated epidermal growth factor receptor (pEGFR) using a tissue microarray containing 84 cases. Three bladder cancer cell lines, T24, HT1376, and UM-UC-3, were analyzed for cell proliferation after treatment with mTORc1/c2 inhibitors OSI-027 or PP242. Western blots were used to verify that the drugs were inhibiting phosphorylation of target proteins within the mTOR pathway, and they were compared with rapamycin inhibition. We also analyzed cell proliferation and anchorage-independent growth after treatment with OSI-027 and lapatinib in combination. PARP cleavage and autophagic flux were measured by examining levels of LC3B and p62 by western blotting. RESULTS: Tumor samples show increased expression of pEGFR (38% vs. 8%) and HER2 (38% vs. 4%) and decreased expression of pAkt S473 (7.5% vs. 29%) and pAkt T308 (50% vs. 84%) relative to normal tissue. Significant differences between normal and tumor samples for staining with pEGFR (P = 0.0188), HER 2 (P = 0.0017), pATK S473 (P = 0.0128), and pAkt T308 (P = 0.0015) is observed. Expression of proteins within the EGFR/HER2 pathway or within the mTOR pathway is correlated. No correlation was found between staining and tumor stage. OSI-027 and PP242 diminish cell proliferation in all 3 cell lines with IC50 values ranging from 0.63 to 17.95uM. Both drugs inhibit phosphorylation of both mTORc1 and mTORc2 pathway components. OSI-027 and lapatinib inhibit cell proliferation and anchorage-independent growth in a synergistic manner. One cell line exhibited apoptosis in response to combination drug treatment, whereas the other 2 cell lines have increased levels of autophagy indicative of resistance to apoptosis. CONCLUSIONS: The combination of OSI-027 and lapatinib results in antitumor synergy and further exploration of this combination should be undertaken. PMID- 24054873 TI - New treatments for men with castration-resistant prostate cancer: can we move from small steps to giant leaps? PMID- 24054874 TI - Probiotics for rectal volume variation during radiation therapy for prostate cancer. AB - PURPOSE: To investigate the effect of the probiotic Lactobacillus acidophilus on the percentage volume change of the rectum (PVCR), a crucial factor of prostate movement. METHODS AND MATERIALS: Prostate cancer patients managed with tomotherapy as a radical treatment were enrolled in the study to take a probiotic capsule containing 1.0*10(8) colony-forming units of L acidophilus or a placebo capsule twice daily. Radiation therapy was performed at a dose of 78 Gy in 39 fractions. The PVCR, defined as the difference in rectal volume between the planning computed tomographic (CT) and daily megavoltage CT images, was analyzed. RESULTS: Forty patients were randomized into 2 groups. The L acidophilus group showed significantly lower median rectal volume and median PVCR values than the placebo group. L acidophilus showed a significant reduction effect on the PVCR (P<.001). However, the radiation therapy fraction number did not significantly influence the PVCR. CONCLUSIONS: L acidophilus was useful in reducing the PVCR, which is the most important determining factor of prostate position, during radiation therapy for prostate cancer. PMID- 24054872 TI - Next-generation sequencing of advanced prostate cancer treated with androgen deprivation therapy. AB - BACKGROUND: Androgen-deprivation therapy (ADT) is standard treatment for locally advanced or metastatic prostate cancer (PCa). Many patients develop castration resistance (castration-resistant PCa [CRPC]) after approximately 2-3 yr, with a poor prognosis. The molecular mechanisms underlying CRPC progression are unclear. OBJECTIVE: To undertake quantitative tumour transcriptome profiling prior to and following ADT to identify functionally important androgen-regulated pathways or genes that may be reactivated in CRPC. DESIGN, SETTING, AND PARTICIPANTS: RNA sequencing (RNA-seq) was performed on tumour-rich, targeted prostatic biopsies from seven patients with locally advanced or metastatic PCa before and approximately 22 wk after ADT initiation. Differentially regulated genes were identified in treatment pairs and further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on cell lines and immunohistochemistry on a separate CRPC patient cohort. Functional assays were used to determine the effect of pathway modulation on cell phenotypes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We searched for gene expression changes affecting key cell signalling pathways that may be targeted as proof of principle in a CRPC in vitro cell line model. RESULTS AND LIMITATIONS: We identified ADT regulated signalling pathways, including the Wnt/beta-catenin signalling pathway, and observed overexpression of beta-catenin in a subset of CRPC by immunohistochemistry. We validated 6 of 12 (50%) pathway members by qRT-PCR on LNCaP/LNCaP-AI cell RNAs, of which 4 (67%) demonstrated expression changes consistent with RNA-seq data. We show that the tankyrase inhibitor XAV939 (which promotes beta-catenin degradation) reduced androgen-independent LNCaP-AI cell line growth compared with androgen-responsive LNCaP cells via an accumulation of cell proportions in the G0/G1 phase and reduction in the S and G2/M phases. Our biopsy protocol did not account for tumour heterogeneity, and pathway inhibition was limited to pharmacologic approaches. CONCLUSIONS: RNA-seq of paired PCa samples revealed ADT-regulated signalling pathways. Proof-of-principle inhibition of the Wnt/beta-catenin signalling pathway specifically delays androgen independent PCa cell cycle progression and proliferation and warrants further investigation as a potential target for therapy for CRPC. PMID- 24054875 TI - Risk of leptomeningeal disease in patients treated with stereotactic radiosurgery targeting the postoperative resection cavity for brain metastases. AB - PURPOSE: We sought to determine the risk of leptomeningeal disease (LMD) in patients treated with stereotactic radiosurgery (SRS) targeting the postsurgical resection cavity of a brain metastasis, deferring whole-brain radiation therapy (WBRT) in all patients. METHODS AND MATERIALS: We retrospectively reviewed 175 brain metastasis resection cavities in 165 patients treated from 1998 to 2011 with postoperative SRS. The cumulative incidence rates, with death as a competing risk, of LMD, local failure (LF), and distant brain parenchymal failure (DF) were estimated. Variables associated with LMD were evaluated, including LF, DF, posterior fossa location, resection type (en-bloc vs piecemeal or unknown), and histology (lung, colon, breast, melanoma, gynecologic, other). RESULTS: With a median follow-up of 12 months (range, 1-157 months), median overall survival was 17 months. Twenty-one of 165 patients (13%) developed LMD at a median of 5 months (range, 2-33 months) following SRS. The 1-year cumulative incidence rates, with death as a competing risk, were 10% (95% confidence interval [CI], 6%-15%) for developing LF, 54% (95% CI, 46%-61%) for DF, and 11% (95% CI, 7%-17%) for LMD. On univariate analysis, only breast cancer histology (hazard ratio, 2.96) was associated with an increased risk of LMD. The 1-year cumulative incidence of LMD was 24% (95% CI, 9%-41%) for breast cancer compared to 9% (95% CI, 5%-14%) for non-breast histology (P=.004). CONCLUSIONS: In patients treated with SRS targeting the postoperative cavity following resection, those with breast cancer histology were at higher risk of LMD. It is unknown whether the inclusion of whole-brain irradiation or novel strategies such as preresection SRS would improve this risk or if the rate of LMD is inherently higher with breast histology. PMID- 24054877 TI - From the editor. PMID- 24054876 TI - Common non-epigenetic drugs as epigenetic modulators. AB - Epigenetic effects are exerted by a variety of factors and evidence increases that common drugs such as opioids, cannabinoids, valproic acid, or cytostatics may induce alterations in DNA methylation patterns or histone conformations. These effects occur via chemical structural interactions with epigenetic enzymes, through interactions with DNA repair mechanisms. Computational predictions indicate that one-twentieth of all drugs might potentially interact with human histone deacetylase, which was prospectively experimentally verified for the compound with the highest predicted interaction probability. These epigenetic effects add to wanted and unwanted drug effects, contributing to mechanisms of drug resistance or disease-related and unrelated phenotypes. Because epigenetic changes might be transmitted to offspring, the need for reliable and cost effective epigenetic screening tools becomes acute. PMID- 24054879 TI - Rapidly growing skin lesion. PMID- 24054880 TI - Heart failure beliefs and self-care adherence while being treated in an emergency department. AB - BACKGROUND: Heart failure (HF) emergency department (ED) visits are commonly due to HF self-care nonadherence. OBJECTIVE: Our objective was to assess the accuracy of HF beliefs and adherence to self care in patients using an ED for acute HF. METHODS: A cross-sectional, correlational study using validated surveys of HF beliefs and self-care adherence was conducted. A multivariable regression model was used to control for significant baseline factors. RESULTS: In 195 adults, mean HF beliefs score was 2.8 +/- 0.3, significantly below the accurate cutoff score of 3.0 (p < 0.001). Mean HF self-care adherence score was 5.1 (10 reflects best adherence). Of HF-related self-care behaviors, adherence was highest for taking medications without skipping or missing doses (7.8 +/- 3.3) and lowest for daily weight monitoring (3.5 +/- 3.5). Higher accuracy in HF beliefs was associated with higher education level (p = 0.01), younger age (p < 0.001), and choosing low-sodium restaurant foods (p = 0.04), but not with adherence to other self-care behaviors. Self-care adherence was associated with the belief that the HF care plan must be followed forever (p = 0.04), but not with other HF beliefs; and there was a trend toward lower HF self-care adherence when HF belief scores were more accurate. After controlling for significant baseline factors, HF beliefs were not associated with self-care adherence (p = 0.15). CONCLUSIONS: Patients seeking ED care for decompensated HF had inaccurate HF beliefs and poor self-care adherence. Lack of association between HF beliefs and self care (and trend of an inverse relationship) reflects a need for predischarge HF education, including an explanation of what HF means and how it can be better controlled through self-care behaviors. PMID- 24054878 TI - IAP/APA evidence-based guidelines for the management of acute pancreatitis. AB - BACKGROUND: There have been substantial improvements in the management of acute pancreatitis since the publication of the International Association of Pancreatology (IAP) treatment guidelines in 2002. A collaboration of the IAP and the American Pancreatic Association (APA) was undertaken to revise these guidelines using an evidence-based approach. METHODS: Twelve multidisciplinary review groups performed systematic literature reviews to answer 38 predefined clinical questions. Recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The review groups presented their recommendations during the 2012 joint IAP/APA meeting. At this one-day, interactive conference, relevant remarks were voiced and overall agreement on each recommendation was quantified using plenary voting. RESULTS: The 38 recommendations covered 12 topics related to the clinical management of acute pancreatitis: A) diagnosis of acute pancreatitis and etiology, B) prognostication/predicting severity, C) imaging, D) fluid therapy, E) intensive care management, F) preventing infectious complications, G) nutritional support, H) biliary tract management, I) indications for intervention in necrotizing pancreatitis, J) timing of intervention in necrotizing pancreatitis, K) intervention strategies in necrotizing pancreatitis, and L) timing of cholecystectomy. Using the GRADE system, 21 of the 38 (55%) recommendations, were rated as 'strong' and plenary voting revealed 'strong agreement' for 34 (89%) recommendations. CONCLUSIONS: The 2012 IAP/APA guidelines provide recommendations concerning key aspects of medical and surgical management of acute pancreatitis based on the currently available evidence. These recommendations should serve as a reference standard for current management and guide future clinical research on acute pancreatitis. PMID- 24054881 TI - Cardiac complications of adult methamphetamine exposures. AB - BACKGROUND: Methamphetamine use is an increasing problem in the United States. Despite the similarities to cocaine in clinical presentation, methamphetamine effects on the cardiovascular system are not as clearly understood. OBJECTIVES: The purpose of this retrospective review is to evaluate the cardiovascular outcomes of methamphetamine exposures reported to both the California Poison Control System (CPCS) and two Level 1 trauma centers. METHODS: CPCS records from 2000-2009, as well as inpatient and emergency department charts from two Level 1 trauma centers during the time frame of 2000-2004 were reviewed. Charts of adults with coded methamphetamine exposures were included. RESULTS: Records of 2356 adults with methamphetamine exposure were assigned levels of severity according to National Poison Data System Medical Outcomes Criteria. Out of the combined charts reviewed from the CPCS data and hospital registries, 584 cases were coded as minor effects, 450 as moderate effects, 208 as major effects, and 28 as deaths. Of the included 1270 cases, 627 electrocardiograms (ECGs) were analyzed. Together, troponins and ECGs showed evidence of myocardial ischemia in 82 total cases, which is 6.5% of the cases reviewed. Cocaine was a co-ingestant in 10 of the 82 cases. CONCLUSIONS: This study presents a large cohort of methamphetamine users. The study found that chest pain and myocardial ischemia were reported in a number of cases. Although no true incidence can be taken from this dataset, it provides a large-scale review of methamphetamine use and its possible association with acute coronary syndromes. PMID- 24054882 TI - Intraosseous administration of thrombolytics for pulmonary embolism. AB - BACKGROUND: Massive pulmonary embolism is associated with cardiac dysfunction and ischemia, hemodynamic collapse, and significant potential for death. The American College of Chest Physicians and American College of Emergency Physicians each supports thrombolytic administration to hemodynamically unstable patients with acute pulmonary embolism. OBJECTIVES: In the resuscitation of patients with massive pulmonary embolism and obstructive shock, difficulty with vascular access can hinder care. Alternative options may facilitate delivery of thrombolytics and enhance patient management. CASE REPORT: The case presented is a 36-year-old woman with massive pulmonary embolism associated with hemodynamic instability. She was treated with thrombolytics through a tibial intraosseous line. CONCLUSIONS: To the best of our knowledge, this is the first identified case of a patient not in cardiac arrest in whom thrombolytics were administered via an intraosseous line. Similarly, we believe this is also the first reported case of thrombolytics delivered via an intraosseous line for massive pulmonary embolism in the United States. PMID- 24054883 TI - Perspectives on visitors in the emergency department: their role and importance. AB - BACKGROUND: Visitors may play a significant role in patient care by interceding on patients' behalf and advocating proper care. STUDY OBJECTIVES: The objectives of this study were to determine the percentage of emergency department (ED) patients with visitors, whether this varied by gender or race, and to compare patient and visitor perspectives on the role and importance of visitors. METHODS: This cross-sectional study was done in a 46,035 adult-visit, urban ED during a consecutive 96-h period. A "visitor" was defined as any non-health-care provider present in a patient's room. Perspectives of visitors' role were assessed in five domains: transportation, emotional support, physical care, communication, and advocacy. RESULTS: Forty-two percent of patients had at least one visitor during their ED stay. Visitor presence was unaffected by patients' age, gender, or triage score; however, 57% of white patients had at least one visitor during their stay, compared to 39% for non-Whites (p = 0.02). When patients had one or more visitors, gender and triage score did not influence the number of visitors; however, older patients and nonwhite patients had greater numbers of visitors (age >= 40 years, 1.5 +/- 0.8 vs. age < 40, 1.2 +/- 0.6 visitors/patient; p = 0.03 and nonwhite patients, 1.4 +/- 0.7 vs. white patients, 1.1 +/- 0.3 visitors/patient; p = 0.03). Seventy-eight percent of patients felt that visitors were important to their care. CONCLUSIONS: Visitors represent a valuable resource for patients, and methods of partnering with visitors to improve outcomes merit further work. PMID- 24054884 TI - Spontaneous tracheal rupture: a case report. AB - BACKGROUND: Upper-airway disruption is a rare but potentially life-threatening phenomenon. It can occur spontaneously, be due to trauma, or be iatrogenically induced. Even more rare are such events reported in the pediatric population. OBJECTIVE: This article discusses the presentation, diagnostic difficulties, and management of spontaneous tracheal rupture in a child. CASE REPORT: A 3-year-old boy was brought by emergency medical services to our emergency department with a presumptive diagnosis of anaphylaxis. With progressive swelling and respiratory distress, the patient quickly deteriorated. He received i.v. epinephrine, chest compressions, and bag-valve mask ventilation. He was intubated without difficulty and with no noted airway edema. Concomitant bilateral needle thoracostomies were performed and subsequent bilateral tube thoracostomies were placed. Immediately after intubation and chest tube placements, the patient's oxygen saturations and heart rate improved. Bronchoscopy failed to demonstrate any evident pathology. However, computed tomography scan revealed a defect in the posterior wall of the trachea proximal to the termination of the endotracheal tube. Cardiothoracic surgery was consulted and performed a primary repair of the tracheal defect. The patient was extubated soon after surgery, and he was discharged home neurologically intact. CONCLUSIONS: The initial presentation of spontaneous tracheal rupture can be misleading and difficult to diagnose. After resuscitation, stabilization, and diagnosis, both surgical repair and nonoperative management have been reported as successful treatment measures for tracheal disruption. PMID- 24054885 TI - The diagnostic accuracy of Bohler's angle in fractures of the calcaneus. AB - BACKGROUND: Bohler's historical tuber-joint angle of the calcaneus has been used since 1931. Surprisingly, there is a paucity of literature on its use. OBJECTIVES: To confirm the normal range for Bohler's angle and determine the angle with the highest accuracy in the diagnosis of calcaneal fractures. METHODS: A retrospective cohort study was performed. The study cohort comprised 424 patients spanning a 5-year period from April 2005 to March 2010. Bohler's angle was measured by two independent observers on lateral x-ray study using the digital angle tool from the Picture Archival and Communication System. Data were analyzed using Stata 8 statistical software package. RESULTS: The mean Bohler's angle in patients without calcaneal fracture was 29.4 degrees . In this group there was no difference in Bohler's angle between male and female patients, left and right feet, or across age. In those patients with calcaneal fractures, a Bohler's angle below 25 degrees was moderately predictive of calcaneal fracture (sensitivity = 100%, specificity = 82%), an angle below 23 degrees was highly predictive of calcaneal fracture (sensitivity = 100%, specificity = 89%), and an angle below 21 degrees was strongly suggestive of calcaneal fracture (sensitivity = 99%, specificity = 99%). A Bohler's angle of <= 20 degrees had the highest diagnostic accuracy. CONCLUSION: A Bohler's angle of 20 degrees or less is highly accurate in determining the presence or absence of calcaneal fracture. Bohler's angle serves as a useful screening tool in fracture diagnosis. PMID- 24054886 TI - Seat belt injury to the inguinal region presenting with hemorrhagic shock. AB - BACKGROUND: Seat belts uncommonly result in various injuries to the abdominal area, such as mesenteric tears, bowel perforations, and abdominal aortic ruptures. We describe a case of a massive subcutaneous hematoma causing hemorrhagic shock from significant lacerations to the inguinal region, related to the use of a seat belt. OBJECTIVES: To describe a seat belt injury to the inguinal region that presented with a massive subcutaneous hematoma, and to speculate about the mechanism that caused the injury. CASE REPORT: A 60-year-old woman, who was wearing a seat belt, was brought to our tertiary hospital Emergency Department after a head-on motor vehicle accident. The patient had vascular injury around the right inguinal region resulting in hemorrhagic shock. Transcatheter arterial embolization (TAE) was successfully performed to stop the bleeding. CONCLUSION: Seat belts can cause serious injury to the inguinal region, mainly due to shearing forces. In addition to gauze packing, TAE was used effectively to control the hemorrhage in this patient. PMID- 24054887 TI - Pyruvate Ringer's solution corrects lactic acidosis and prolongs survival during hemorrhagic shock in rats. AB - BACKGROUND: Lactic acidosis is a life-threatening complication of hemorrhagic shock. There is no ideal therapy for it in the clinical setting. OBJECTIVE: This study was designed to investigate whether pyruvate Ringer's solution could treat hypoxic lactic acidosis associated with lethal hemorrhagic shock in rats. METHODS: A total of 54 rats were subjected to hemorrhagic shock with mean arterial pressure (MAP) of 40 mm Hg for 1 h. They were then randomly divided into three groups (n = 18 each): Group N had no fluid resuscitation; Group L received lactated Ringer's solution infusion; and Group P received pyruvate Ringer's solution infusion. The survival rate was investigated after 24 h. In addition, a second set of 54 rats was selected for blood sampling, with identical methods for shock and resuscitation being followed, to determine arterial pH, blood gas analysis, lactate, pyruvate, and organs' enzyme activities at various time points. The MAP was monitored for 6 h in both populations. RESULTS: Pyruvate Ringer's solution significantly increased the survival rate of rats subjected to fatal shock and receiving pyruvate Ringer's solution (Group P) by 1.5 times the survival rate in Group L at 24 h after fluid resuscitation (55.6% vs. 22.2%, respectively; p < 0.05). Pyruvate infusion maintained a higher MAP and fully corrected severe acidosis 1 h after resuscitation in comparison to the lactated infusion, and markedly decreased blood lactate levels and the lactate-to-pyruvate ratio 4 h after resuscitation. It also significantly improved serum markers of organ dysfunction. CONCLUSION: Pyruvate Ringer's solution efficiently treated hypoxic lactic acidosis and significantly increased the survival rate in rats with lethal hemorrhagic shock. Pyruvate Ringer's solution is potentially applicable to clinical resuscitation in humans. PMID- 24054888 TI - A review of associations between family or shared meal frequency and dietary and weight status outcomes across the lifespan. AB - OBJECTIVE: To summarize the research literature on associations between family meal frequency and dietary outcomes as well as weight status across the lifespan. METHODS: Reviewed literature of family or shared meals with dietary and weight outcomes in youth, adults, and older adults. RESULTS: Across the lifespan, eating with others, particularly family, is associated with healthier dietary outcomes. Among children and adolescents, these findings appear to be consistent for both boys and girls, whereas mixed findings are seen by gender for adult men and women. The findings of associations between family or shared meals and weight outcomes across the lifespan are less consistent and more complicated than those of dietary outcomes. CONCLUSIONS AND IMPLICATIONS: Now is the time for the field to improve understanding of the mechanisms involved in the positive associations seen with family meal frequency, and to move forward with implementing interventions aimed at increasing the frequency of, and improving the quality of, food served at family meals, and evaluating their impact. Given the more limited findings of associations between family or shared meals and weight outcomes, capitalizing on the positive benefits of family and shared meals while addressing the types of foods served, portion sizes, and other potential mechanisms may have a significant impact on obesity prevention and reduction. Future research recommendations are provided. PMID- 24054889 TI - HLA-G regulates the invasive properties of JEG-3 choriocarcinoma cells by controlling STAT3 activation. AB - The expression of human leucocyte antigen-G (HLA-G) in trophoblasts plays a crucial role in successful embryonic implantation, and reduced HLA-G expression might contribute to adverse obstetric outcomes. In this study, we silenced HLA-G expression using RNA interference in JEG-3 cells, resulting in a notably attenuated invasion capacity of the cells in a Transwell assay; however, no alterations in cell proliferation or apoptosis were observed. The down-regulation of HLA-G dampened the activation of signal transducer and activator of transcription 3 (STAT3), whereas the up-regulation of HLA-G promoted STAT3 activation and invasion in JEG-3 cells treated with human galectin-1. Most importantly, interleukin-6 (IL-6), but not galectin-1, was shown to rescue invasion deficiency in a dose-dependent manner. Thus, we demonstrate that HLA-G is able to regulate JEG-3 cell invasion by influencing STAT3 activation, which may underlie the implantation defects accompanying HLA-G hypo-expression in pre eclampsia. PMID- 24054890 TI - Fractional volume of placental vessels in women with diabetes using a novel stereological 3D power Doppler technique. AB - OBJECTIVES: In maternal diabetes the placenta is large with abnormal vascular development and increased villous volume. We used a novel stereological 3D power Doppler ultrasound technique to investigate differences in-vivo in the placental fractional volume of power Doppler signal (FrVol-PD) between women with and without diabetes. METHODS: We recruited 17 pregnant women with pre-gestational diabetes and 20 controls, all with anterior placentae. Each subject had ultrasound scans (Voluson 730 Expert) every 4 weeks between 12 and 32 weeks gestation. 3D power Doppler data were acquired and the placenta manually outlined using VOCAL (4D View). Power Doppler signal within the resultant volume was counted in a 3D manner adapting the random but systematic techniques used in stereology. RESULTS: Subjects were of similar age, BMI and parity. From 16 weeks the mean (SD) placental FrVol-PD was higher in the non-diabetic than in the diabetic group: 16 weeks - 0.125 (0.03) versus 0.108 (0.03), 20 weeks - 0.144 (0.05) versus 0.104 (0.03), 24 weeks - 0.145 (0.05) versus 0.128 (0.03), 28 weeks - 0.159 (0.05) versus 0.133 (0.02) and 32 weeks - 0.154 (0.03) versus 0.123 (0.04). These differences were significant between control and diabetic subjects [F(1,35) = 4.737, p = 0.036] and across gestation [F(3,140) = 8.294, p < 0.001]. CONCLUSION: Using a novel stereological-based ultrasound technique we have demonstrated the reliability of this application in the placenta. This technique shows promise for non-invasive assessment of placental function: further studies are required to identify if structural changes in a diabetic placenta are accompanied by altered function, manifest as reduced perfusion demonstrable in vivo. PMID- 24054891 TI - The eggshell features and clutch viability of the broad-snouted caiman (Caiman latirostris) are associated with the egg burden of organochlorine compounds. AB - Organochlorine compounds (OCCs) are toxic and have been identified as endocrine disrupting chemicals (EDCs). The broad-snouted Caiman (Caiman latirostris) is an oviparous species widely distributed in South America with potential to accumulate OCCs. The eggshell is formed during passage of the eggs through the oviduct. Since the oviduct is a target of hormone actions, exposure to OCCs could modify eggshell quality, thus affecting clutch viability. Eight clutches were collected from wetlands of Parana River tributaries, in north-eastern Argentina. Two to four eggs per clutch were used to establish the burden of OCCs, eggshell thickness and eggshell porosity. The remaining eggs were incubated in controlled conditions. Ten days after hatching, hatchling survival was assessed. Organochlorine pesticide residues (OCPs) were found in all clutches, while polychlorinated biphenyls (PCBs) were present in all but one clutch. The principal contributors to the OCP burden were members of the DDT family and oxychlordane. Eggshell thickness was 400.9+/-6.0 MUm and, unexpectedly, no association between eggshell thickness and the OCC burden was found. The number of pores in the outer surface was 25.3+/-4.3 pores/cm2. A significant inverse correlation between porosity and OCC burden was found (Pearson r= -0.81, p= 0.01). Furthermore, a decrease in caiman survival with decreased pore density was observed (Pearson r= 0.73, p= 0.04). Our findings highlight another potential negative impact of current and past use of OCCs on wildlife species. PMID- 24054892 TI - External attentional focus enhances movement automatization: a comprehensive test of the constrained action hypothesis. AB - An external focus of attention has been shown to result in superior motor performance compared to an internal focus of attention. This study investigated whether this is due to enhanced levels of movement automatization, as predicted by the constrained action hypothesis (McNevin, Shea, & Wulf, 2003). Thirty healthy participants performed a cyclic one-leg extension-flexion task with both the dominant and non-dominant leg. Focus of attention was manipulated via instructions. The degree of automatization of movement was assessed by measuring dual task costs as well as movement execution parameters (i.e., EMG activity, movement fluency, and movement regularity). Results revealed that an external focus of attention led to significantly better motor performance (i.e., shorter movement duration) than an internal focus. Although dual task costs of the motor task did not differ as a function of attentional focus, cognitive dual task costs were significantly higher when attention was directed internally. An external focus of attention resulted in more fluent and more regular movement execution than an internal focus, whereas no differences were found concerning muscular activity. These results indicate that an external focus of attention results in more automatized movements than an internal focus and, therefore, provide support for the constrained action hypothesis. PMID- 24054893 TI - The smoothness of unconstrained head movements is velocity-dependent. AB - Non-smooth, irregular movements reported in persons with neck pain have been suggested to signify motor impairment. However, irregular movements are additionally observed during slow movements in healthy participants. We therefore examined whether the smoothness of head movements is related to the movement speed in 26 healthy participants. Six unconstrained small and large amplitude head movements were completed in the sagittal plane at three different self chosen speeds. Kinematic variables were calculated from position data and overall smoothness of the movement was assessed by the normalized jerk cost (NJC). Relationship between NJC and average movement angular velocity was analyzed using a mixed factor model. Movement duration, angular velocity, NJC and number of submovements differed significantly between speed conditions for all movement directions and amplitudes (all p<.05). We found a strong relationship between the average angular velocity and NJC across all movement directions and amplitudes (all p<.0001). Large amplitude movements showed higher NJC for a given movement velocity than small amplitude movements (p<.001). We have shown that the smoothness of head movements is strongly related to the movement velocity, thus fast movements are smooth while slow movements are jerky. In addition, movements of larger amplitude are less smooth than movements of smaller amplitude. PMID- 24054894 TI - Competing together: Assessing the dynamics of team-team and player-team synchrony in professional association football. AB - This study investigated movement synchronization of players within and between teams during competitive association football performance. Cluster phase analysis was introduced as a method to assess synchronies between whole teams and between individual players with their team as a function of time, ball possession and field direction. Measures of dispersion (SD) and regularity (sample entropy - SampEn - and cross sample entropy - Cross-SampEn) were used to quantify the magnitude and structure of synchrony. Large synergistic relations within each professional team sport collective were observed, particularly in the longitudinal direction of the field (0.89+/-0.12) compared to the lateral direction (0.73+/-0.16, p<.01). The coupling between the group measures of the two teams also revealed that changes in the synchrony of each team were intimately related (Cross-SampEn values of 0.02+/-0.01). Interestingly, ball possession did not influence team synchronization levels. In player-team synchronization, individuals tended to be coordinated under near in-phase modes with team behavior (mean ranges between -7 and 5 degrees of relative phase). The magnitudes of variations were low, but more irregular in time, for the longitudinal (SD: 18+/-3 degrees ; SampEn: 0.07+/-0.01), compared to the lateral direction (SD: 28+/-5 degrees ; SampEn: 0.06+/-0.01, p<.05) on-field. Increases in regularity were also observed between the first (SampEn: 0.07+/-0.01) and second half (SampEn: 0.06+/-0.01, p<.05) of the observed competitive game. Findings suggest that the method of analysis introduced in the current study may offer a suitable tool for examining team's synchronization behaviors and the mutual influence of each team's cohesiveness in competing social collectives. PMID- 24054895 TI - Self-controlled KR schedules: does repetition order matter? AB - The impact of an experimenter-defined repetition schedule on the utility of a self-controlled KR context during motor skill acquisition was examined. Participants were required to learn three novel spatial-temporal tasks in either a random or blocked repetition schedule with or without the opportunity to control their KR. Results from the retention period showed that participants provided control over their KR schedule in a random repetition schedule demonstrated superior learning. However, performance measures from the transfer test showed that, independent of repetition schedule, learners provided the opportunity to control their KR schedule demonstrated superior transfer performance compared to their yoked counterparts. The dissociated impact of repetition schedule and self-controlled KR schedules on retention and transfer is discussed. PMID- 24054896 TI - Utilization of visual feedback of the hand according to target view availability in the online control of prehension movements. AB - The aim of this study was to investigate the role of online vision of a target object and the participant's moving hand in the early phase of reach-to-grasp movements. We designed an experiment that separately manipulated the visibility of a moving hand and the target object by using two liquid crystal shutter plates placed in the same horizontal plane (25 cm above the experimental table). When target view was available immediately after movement onset, the effect of hand view in the early phase of movement was very limited. The effect of hand view appeared when target view in the early phase of movement was not available. This was even the case for the condition where the temporal range of non-availability of target view after movement initiation was 150 ms. Therefore, online vision (of target and hand) for controlling grasping was utilized in a flexible fashion that depended on the visual environment. PMID- 24054897 TI - The biomechanical effects of a new design of lateral wedge insole on the knee and ankle during walking. AB - Lateral wedged insoles are a common treatment in individuals with medial tibiofemoral osteoarthritis of the knee joint. One concern has been the potential for increased foot and ankle pain due to increased eversion. The purpose of this study was to assess the biomechanical effectiveness of a typical lateral wedged insole and a combined insole with a lateral wedge and off-the-shelf anti pronatory device in shoes while walking. A cross-over randomized design was used where each insole was worn by fifteen healthy subjects while three-dimensional motion data were collected in three different conditions: (1) control condition (with standard shoes), (2) with an insole with a lateral wedge and additional off the-shelf anti-pronatory support (supporting), and (3) with an insole with a lateral wedge with no additional support (unsupported) in the standard shoes. The unsupported insole significantly increased the amount of ankle/subtalar joint complex eversion than the other experimental conditions, with the supporting insole reducing the ankle/subtalar joint complex eversion, and was found to be more comfortable. Both the supporting and unsupported lateral wedged insoles significantly reduced knee loading (external knee adduction moment reduction 8.5% and 9.1%, respectively), the knee adduction angular impulse. This new design of lateral wedge may offer increased adherence in future osteoarthritis population studies while offering reductions in joint loading. PMID- 24054898 TI - Gradual training reduces practice difficulty while preserving motor learning of a novel locomotor task. AB - Motor learning strategies that increase practice difficulty and the size of movement errors are thought to facilitate motor learning. In contrast to this, gradual training minimizes movement errors and reduces practice difficulty by incrementally introducing task requirements, yet remains as effective as sudden training and its large movement errors for learning novel reaching tasks. While attractive as a locomotor rehabilitation strategy, it remains unknown whether the efficacy of gradual training extends to learning locomotor tasks and their unique requirements. The influence of gradual vs. sudden training on learning a locomotor task, asymmetric split belt treadmill walking, was examined by assessing whole body sagittal plane kinematics during 24 hour retention and transfer performance following either gradual or sudden training. Despite less difficult and less specific practice for the gradual cohort on day 1, gradual training resulted in equivalent motor learning of the novel locomotor task as sudden training when assessed by retention and transfer a day later. This suggests that large movement errors and increased practice difficulty may not be necessary for learning novel locomotor tasks. Further, gradual training may present a viable locomotor rehabilitation strategy avoiding large movement errors that could limit or impair improvements in locomotor performance. PMID- 24054899 TI - Posture-movement responses to stance perturbations and upper limb fatigue during a repetitive pointing task. AB - Localized muscle fatigue and postural perturbation have separately been shown to alter whole-body movement but little is known about how humans respond when subjected to both factors combined. Here we sought to quantify the kinematics of postural control and repetitive upper limb movement during standing surface perturbations and in the presence of fatigue. Subjects stood on a motion-based platform and repetitively reached between two shoulder-height targets until noticeably fatigued (rating of perceived exertion=8/10). Every minute, subjects experienced a posterior and an anterior platform translation while reaching to the distal target. Outcomes were compared prior to and with fatigue (first vs. final minute data). When fatigued, regardless of the perturbation condition, subjects decreased their shoulder abduction and increased contralateral trunk flexion, a strategy that may relieve the load on the fatiguing upper limb musculature. During perturbations, kinematic adaptations emerged across the trunk and arm to preserve task performance. In contrast to our expectation, the kinematic response to the perturbations did not alter in the presence of fatigue. Kinematic adaptations in response to the perturbation predominantly occurred in the direction of the reach whereas fatigue adaptations occurred orthogonal to the reach. These findings suggest that during repetitive reaching, fatigue and postural perturbation compensations organize so as to minimize interaction with each other and preserve the global task characteristics of endpoint motion. PMID- 24054900 TI - Multifractal formalisms of human behavior. AB - With the mounting realization that variability is an inevitable part of human behavior comes the need to integrate this phenomenon in concomitant models and theories of motor control. Among other things, this has resulted in a debate throughout the last decades about the origin of variability in behavior, the outcome of which has important implications for motor control theories. To date, a monofractal formalism of variability has been used as the basis for arguing for component- versus interaction-oriented theories of motor control. However, monofractal formalism alone cannot decide between the opposing sides of the debate. The present theoretical overview introduces multifractal formalisms as a necessary extension of the conventional monofractal formalism. In multifractal formalisms, the scale invariance of behavior is numerically defined as a spectrum of scaling exponents, rather than a single average exponent as in the monofractal formalism. Several methods to estimate the multifractal spectrum of scaling exponents - all within two multifractal formalisms called large deviation and Legendre formalism - are introduced and briefly discussed. Furthermore, the multifractal analyses within these two formalisms are applied to several performance tasks to illustrate how explanations of motor control vary with the methods used. The main section of the theoretical overview discusses the implications of multifractal extensions of the component- and interaction oriented models for existing theories of motor control. PMID- 24054901 TI - Asymmetrical loading affects intersegmental dynamics during the swing phase of walking. AB - Much of the work related to lower extremity inertia manipulations has focused on temporal, kinematic and traditional inverse dynamics assessments during locomotion. Intersegmental dynamics is an analytical technique that provides further insights into mechanisms underlying linked-segment motion. The purpose of this study was to determine how intersegmental dynamics during the swing phase of walking are altered during asymmetrical lower extremity loading. Participants walked overground at a speed of 1.57 ms(-1) with 0, 0.5, 1.0, and 2.0 kg attached to one foot. Net, interaction, gravitational, and muscle moments were computed. Moment magnitudes at joints of the loaded leg increased systematically with increasing load, whereas unloaded leg moments were unaffected by loading. With increasing load, relative contributions of interaction moments about the knee and hip and gravitational moment about the ankle increased (i.e., 21%, 8%, and 44% increases, respectively), whereas the relative contributions of muscle moments about all three joints declined (i.e., -4%, -13%, and -8% decreases for the ankle, knee, and hip, respectively for unloaded vs. 2.0 kg). These results suggest that altered inertia properties of the limb not only affected the amount of muscular effort required to swing the leg, but also changed the nature of the interaction between segments. PMID- 24054902 TI - Vertical and leg stiffness and stretch-shortening cycle changes across maturation during maximal sprint running. AB - The purpose of this study was to investigate whether vertical and leg stiffness, and stretch-shortening cycle (SSC) ability differed in developing athletes of various maturity status during maximal sprint running. Seventy-four male participants between 8 and 16 years of age were categorized into pre-, mid- or post-peak height velocity (PHV) and sprinted for 30 meters on a non-motorized treadmill. Dimensionless vertical stiffness increased significantly (p<.05) from pre-, to mid- and post-PHV state, while dimensionless leg stiffness was significantly higher in post- compared to mid- (18.4%) and pre-PHV participants (44.5%). Eccentric power was significantly lower in pre- compared to the mid- and post-PHV participants. Concentric power increased from pre- to mid- and post-PHV state. An analysis of covariance revealed no significant differences between all groups in dimensionless vertical and leg stiffness, eccentric and concentric time and power when controlling for years from PHV (maturation). Eccentric or concentric power, were found to be the best predictors of maximum velocity across all maturation groups (r2=.37-.68). It seems that maturation affects the ability to absorb and produce power and furthermore these variables are important predictors of maximal running velocity. PMID- 24054903 TI - The role of oncoplastic breast surgery in the management of breast cancer treated with primary chemotherapy. AB - OBJECTIVE: The purpose of this study was to evaluate the benefit of Oncoplastic Breast Conserving Surgery (BCS) compared to standard BCS after primary CT, in terms of oncologic safety and cosmetic outcomes. BACKGROUND: The development of new drugs has led to greater use of primary chemotherapy (CT) for bulky breast cancer (BC) and has allowed wider indications for conservative surgery. PATIENTS AND METHODS: We identified 259 patients consecutively treated with BCS for primary BC from January 2002 to November 2010. All patients had undergone Oncoplastic Breast Surgery (OBS) or standard BCS after primary CT. Mastectomy rates, and oncological and cosmetic outcomes were compared. RESULTS: A total of 45 OBS and 214 standard BCS were analyzed. The median tumor size was 40 mm in the two groups (p = 0.66). The median operative specimen volumes were larger in the OBS group than in the standard group (respectively, 180 cm3 and 98 cm3, p < 0.0001). Re-excision (9% vs. 2%) and mastectomy (24% vs. 18%) rates were similar (p = 0.22 and p = 0.30) in the standard BCS group and in the OBS group respectively. At a median follow-up of 46 months, local relapse (p = 0.23) and distant relapse (p = 0.35) rates were similar. CONCLUSION: OBS allows excision of larger volumes of residual tumor after primary CT. OBS outcomes results were similar to those of standard BCS. Oncoplastic Breast Conserving Surgery (BCS) after primary chemotherapy allows wider breast resection than standard BCS. Survival and relapse probabilities are similar in both groups. PMID- 24054904 TI - Assessing the level of breast cancer awareness among recently diagnosed patients in Ain Shams University Hospital. AB - Breast cancer is the leading female malignancy among Egyptian women. The majority of Egyptian breast cancer patients present at late stages of the disease with a large tumor size compared to Western countries. Low breast cancer awareness, social and cultural factors were suggested to play crucial role in late presentation of breast cancer among Egyptians. The aim of our present study is to establish a questionnaire-based survey that can assess levels of breast cancer awareness among Egyptians. Patients enrolled were interviewed and answered 60 questions related to knowledge, symptoms, risk factors, prevention and management options of breast cancer. We evaluated our interactions with breast cancer patients and defined the level of awareness gained from education and culture of Egyptian women. Our results described that Egyptian breast cancer patients lack knowledge about their illness and condition. The lowest levels of awareness were related to age, education and culture. We concluded that breast cancer public awareness and women education programs covering factors identified in our study is warranted among Egyptian population. Overview OBJECTIVE: To assess breast cancer awareness among recently diagnosed breast cancer Egyptian patients. SUBJECTS AND METHODS: Among 289 interviewed breast cancer patients we enrolled 45 patients who fulfilled the study inclusion criteria. Participants were asked to answer a validated 60-item questionnaire that inquires about socio-demographic characteristics, knowledge of breast cancer symptoms, risk factors, symptoms, prevention, general management and willingness to participate in awareness campaigns. The average of interview time was about 45 min, depending on patient's age and education level. RESULTS: The mean age of included patients was 48.2 +/- 10.19 years. Geographical distribution revealed that 66.7% patients were from Cairo and the rest were from other governorates, including Aswan, Sharqia, Mansora, Qena, Kalyobia, Elminya and Sohag. Among interviewed patients 85% were non-working housewives, 42.2% of them were illiterate. Questions about knowledge of breast cancer revealed that 53.33% of patients knew an acquaintance with breast cancer; however, they spent a median time of 3 months to seek medical advice after recognizing the first symptom with a delay range between a month and 72 months. We found that 73% of the participants presented to a physician with the same first recognized symptom and 75.6% didn't think of cancer then as a possible diagnosis. Total breast cancer knowledge scores had an average of 13.3 (out of 35 knowledge points), with 93% of the patients recognizing "painless breast mass" as a breast cancer symptom and 44% only recognized the concept of breast self examination. Interestingly, 61.4% identified breastfeeding as a risk factor for breast cancer, 60% did not recognize mammography as an early detection method, and 57.7% agreed that clinical breast examination (CBE) is important for early detection. Regarding management, 75% said breast cancer was potentially curable and 60% said medical care could be helpful regardless the age of presentation. CONCLUSION: Egyptian breast cancer patients knew little about their condition. Less awareness was related to age and education level. Low knowledge of risk factors, early detection and management of breast cancer should be addressed by designing patient education programs, where less educated patients are supported by health care professionals to participate in the management of breast cancer. Moreover, we found that 67% and 97% of enrolled breast cancer patients were willing as well to participate in spreading awareness among their community and among their own families, respectively. PMID- 24054905 TI - The pressing need for Interventional Radiology Centers. PMID- 24054906 TI - Dermoid cyst in the floor of the mouth. Answer to the e-quid "Dysphagia and snoring without odynophagia". PMID- 24054907 TI - Joint registries as continuous surveillance systems: the experience of the Catalan Arthroplasty Register (RACat). AB - The aim was to present results on prosthesis performance in Catalonia for the period 2005-2010. All publicly funded hospitals submit in an electronic format data on hip and knee arthroplasties: patients' insurance identification number, hospital, joint (hip/knee), type of arthroplasty (primary/revision), side (right/left), date of surgery and prosthesis (manufacturer name and catalogue number). A standard survival analysis based on Kaplan-Meier estimation was carried out. Fifty-two hospitals have sent information to the RACat which has data on 36,951 knee and 26,477 hip arthroplasties. Cumulative prostheses revision risks at 3 years were 3.3% (95% CI: 3.1-3.6) for knee, 2.9% (95% CI: 2.5-3.3) for total hip and 2.5% (95% CI: 2.0-3.1) for partial hip. When compared to other registries a higher risk of revision was observed. PMID- 24054908 TI - Effects of dietary energy and calcium levels on performance, egg shell quality and bone metabolism in hens. AB - This study investigated the effects of dietary energy and calcium levels on laying performance, eggshell quality and bone metabolism of layers. One hundred and sixty-two 19-week-old Hy-Line brown laying hens in 54 battery cages were allocated to one of nine dietary treatments with control, middle and high levels of energy (11.50, 12.68 and 13.37 MJ/kg, respectively) and low, control and high levels of calcium (2.62%, 3.7% and 4.4%, respectively) for 60 days, using a 3 * 3 factorial arrangement. Compared with the control energy diet, high- and middle energy diets increased fat deposition and egg weight, decreased feed intake and bone quality and had no effects on eggshell quality. The high-energy diet reduced the serum phosphate concentration and elevated osteocalcin mRNA expression in the keel bone without increasing osteocalcin protein. Dietary calcium intake did not affect fat deposition, feed intake or egg weight. Low dietary calcium resulted in weaker eggshells and poorer bone quality than that from hens fed the control diet. High dietary calcium increased serum calcium concentration, osteoprotegerin mRNA and osteocalcin protein and inhibited serum alkaline phosphatase activity and decreased its mRNA compared with low or control dietary calcium. The high energy and high-calcium diet significantly reduced egg production. Compared with the control energy diet, high- and middle-energy diets increased fat deposition but had negative effects on bone metabolic homeostasis. Dietary calcium did not influence fat deposition but a high-calcium diet benefited bone homeostasis, while a low-calcium diet was associated with poorer eggshell quality and bone homeostasis. PMID- 24054909 TI - Elevated non-esterified fatty acids and beta-hydroxybutyrate and their association with transition dairy cow performance. AB - Dairy cows pass through a period of negative energy balance as they transition from late gestation to early lactation. Poor adaptation through this period, expressed as excessively elevated concentrations of non-esterified fatty acids (NEFAs) pre- or post-partum and elevated concentrations of beta-hydroxybutyrate post-partum, increases an individual animal's risk of post-partum disease, removal from the herd, reproductive difficulty, and reduced milk production. Field studies have shown that subclinical ketosis often affects 40% of cows in a herd although the incidence can be as high as 80%. Peak incidence occurs at 5 days in milk, and cows that develop subclinical ketosis in the first week of lactation have a higher risk of negative effects and reduced milk production than cows that develop subclinical ketosis in the second week of lactation. Herds with more than a 15-20% prevalence of excessively elevated concentrations of NEFAs and beta-hydroxybutyrate in early lactation have higher rates of negative subsequent events, poorer reproduction, and lower milk yield than herds with a lower prevalence of negative energy balance. This paper reviews (1) strategies for testing of energy-related metabolites, (2) consequences of poor adaptation to negative energy balance (for individual animals and for herds), (3) treatment approaches for affected cows, and (4) economic considerations for testing and treating cows with poor adaptation to negative energy balance. PMID- 24054910 TI - How does ecological disturbance influence genetic diversity? AB - Environmental disturbance underpins the dynamics and diversity of many of the ecosystems of the world, yet its influence on the patterns and distribution of genetic diversity is poorly appreciated. We argue here that disturbance history may be the major driver that shapes patterns of genetic diversity in many natural populations. We outline how disturbance influences genetic diversity through changes in both selective processes and demographically driven, selectively neutral processes. Our review highlights the opportunities and challenges presented by genetic approaches, such as landscape genomics, for better understanding and predicting the demographic and evolutionary responses of natural populations to disturbance. Developing this understanding is now critical because disturbance regimes are changing rapidly in a human-modified world. PMID- 24054911 TI - Contributions of natural and sexual selection to the evolution of premating reproductive isolation: a research agenda. AB - Speciation by divergent natural selection is well supported. However, the role of sexual selection in speciation is less well understood due to disagreement about whether sexual selection is a mechanism of evolution separate from natural selection, as well as confusion about various models and tests of sexual selection. Here, we outline how sexual selection and natural selection are different mechanisms of evolutionary change, and suggest that this distinction is critical when analyzing the role of sexual selection in speciation. Furthermore, we clarify models of sexual selection with respect to their interaction with ecology and natural selection. In doing so, we outline a research agenda for testing hypotheses about the relative significance of divergent sexual and natural selection in the evolution of reproductive isolation. PMID- 24054912 TI - 3D surface roughness measurement for scaliness scoring of psoriasis lesions. AB - Psoriasis is an incurable skin disorder affecting 2-3% of the world population. The scaliness of psoriasis is a key assessment parameter of the Psoriasis Area and Severity Index (PASI). Dermatologists typically use visual and tactile senses in PASI scaliness assessment. However, the assessment can be subjective resulting in inter- and intra-rater variability in the scores. This paper proposes an assessment method that incorporates 3D surface roughness with standard clustering techniques to objectively determine the PASI scaliness score for psoriasis lesions. A surface roughness algorithm using structured light projection has been applied to 1999 3D psoriasis lesion surfaces. The algorithm has been validated with an accuracy of 94.12%. Clustering algorithms were used to classify the surface roughness measured using the proposed assessment method for PASI scaliness scoring. The reliability of the developed PASI scaliness algorithm was high with kappa coefficients>0.84 (almost perfect agreement). PMID- 24054913 TI - Rapid point-of-care HIV testing in youth: a systematic review. AB - PURPOSE: This review examines the literature surrounding acceptability of, and preference for, rapid point-of-care (POC) human immunodeficiency virus (HIV) testing in youth, documents notification rates when youth were offered rapid POC testing, and identifies the sociodemographic factors associated with testing. METHODS: The reviewers searched the scholarly literature indexed in MEDLINE, Embase, CINAHL, and PsycInfo using a set of keywords related to youth and rapid POC HIV testing. A total of 14 articles were included in the review. RESULTS: Four themes were identified: (1) Youth will accept rapid POC testing, particularly if offered; (2) youth prefer rapid POC testing to traditional testing; (3) youth receive their rapid POC HIV test results; and (4) older youth and those with HIV risk factors or a concurrent genitourinary diagnosis are more likely to accept rapid POC HIV testing when it is offered. CONCLUSIONS: Evidence shows that youth accept and prefer rapid POC HIV tests when offered. The routine use of rapid POC HIV tests in emergency departments and adolescent primary care clinics should be considered because of higher uptake in these environments. Youth receive their rapid POC test results more frequently and sooner than traditional test results. However, further work is needed to develop HIV testing programs that target younger adolescents. PMID- 24054914 TI - A population-based examination of maltreatment history among adolescent mothers in California. AB - PURPOSE: To document the abuse and neglect histories of adolescent mothers using official child protection records. METHODS: Vital birth records were used to identify adolescents 12-19 years of age who were born in California and gave birth in 2009. These records were linked to statewide child protective service data to determine maternal history of alleged and substantiated maltreatment victimization, as well as placement in foster care. RESULTS: A total of 35,098 adolescents gave birth in 2009. Before conception, 44.9% had been reported for maltreatment, 20.8% had been substantiated as victims, and 9.7% had spent time in foster care. CONCLUSIONS: These population-based data indicate that many adolescent mothers have had contact with child protective services as alleged or substantiated victims of abuse or neglect. Understanding the impact of childhood and adolescent maternal maltreatment on both early childbearing risk and subsequent parenting capacity is critical to the development of responsive service interventions. PMID- 24054915 TI - [Prevalence of metabolic syndrome in elderly patients]. AB - OBJECTIVES: To determine the prevalence of metabolic syndrome (MS) according to the definitions of the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) and the International Diabetes Federation (IDF) and its relation to cardiovascular disease (CVD) in hospitalized elderly patients. MATERIAL AND METHODS: This descriptive and prospective study (February-March 2011) included 200 consecutive patients hospitalized in a Geriatric Department. Sociodemographic, clinical and biochemical data was collected. RESULTS: The prevalence of MS was 65% (NCEP-ATP III) and 67.5% (IDF) and was greater in women (NCEP-ATP III=72.8%, IDF=73.6%) than in men (NCEP-ATP III=50.7%; IDF=56.3%). The mean age of patients diagnosed with MS by both diagnostic criteria were similar: 84.7 years. MS was not associated with an increased prevalence of CVD. CONCLUSIONS: MS is highly prevalent in elderly hospitalized patients, being higher in women, with both diagnostic criteria (NCEP- ATP III and IDF). In our population the MS was not associated with an increased prevalence of CVD. PMID- 24054916 TI - Multidetector computed tomography in life-threatening hemoptysis. AB - Life-threatening hemoptysis is a severe condition that requires rapid diagnosis and treatment. One of the treatments of choice is embolization. The initial assessment aims to locate the origin and cause of bleeding. The technological advance of the development of multidetector computed tomography (MDCT) has changed the management of patients with life-threatening hemoptysis. MDCT angiography makes it possible to evaluate the cause of bleeding and locate the vessels involved both rapidly and noninvasively; it is particularly useful for detecting ectopic bronchial arteries, nonbronchial systemic arteries, and pulmonary pseudoaneurysms. Performing MDCT angiography systematically before embolization enables better treatment planning. In this article, we review the pathophysiology and causes of life-threatening hemoptysis (including cryptogenic hemoptysis) and the MDCT angiography technique, and we review how to systematically evaluate the images (lung parenchyma, airways, and vascular structures). PMID- 24054917 TI - The chemo and the mona: inhalants, devotion and street youth in Mexico City. AB - This paper understands inhalant use--the deliberate inhalation of volatile solvents or glues with intentions of intoxication--as a socially and culturally constituted practice. It describes the inhalant use of young street people in Mexico City from their perspective ("the vicioso or inhalant fiend's point of view"). BACKGROUND: Even if inhalant use is globally associated with economic inequality and deprivation, there is a marked lack of ethnography. Incomprehension and indignation have blocked our understanding of inhalant use as a form of marginalised drug use. The current explanation models reduce inhalant consumption to universal factors and individual motives; separating the practice from its context, these models tend to overlook gustatory meanings and experiences. METHODS: The paper is informed by long-term, on-going fieldwork with young street people in Mexico City. Fieldwork was done from 1990 through 2010, in regular periods of fieldwork and shorter visits, often with Mexican colleagues. We created extensive sets of fieldnotes, which were read and re-read. RESULTS: "Normalcy" is a striking feature of inhalant use in Mexico City. Street-wise inhabitants of popular neighbourhoods have knowledge about inhalants and inhalant users, and act accordingly. Subsequently, Mexico City's elaborate street culture of sniffing is discussed, that is, the range of inhalants used, how users classify the substances, and their techniques for sniffing. The paper also distinguishes three patterns of inhalant use, which more or less correlate with age. These patterns indicate embodiments of street culture: the formation within users of gusto, that is, an acquired appetite for inhalants, and of vicio, the inhalant fiends' devotion to inhalants. CONCLUSION: What emerges from the ethnographic findings is an elaborate street culture of sniffing, a complex configuration of shared perspectives and embodied practices, which are shaped by and shaping social exclusion. These findings are relevant to appreciate and address the inhalant fiends' acquired appetite and habit. PMID- 24054918 TI - Attachment, affective temperament, and personality disorders: a study of their relationships in psychiatric outpatients. AB - BACKGROUND: As the result of extensive translational and cross-disciplinary research, attachment theory is now a construct with significant neuropsychiatric traction. The correlation of attachment with other influential conceptual models (i.e. temperament and personality) is therefore of interest. Consequently, we explored how two attachment dimensions (attachment anxiety and attachment avoidance) correlated with measures of temperament and personality in 357 psychiatric outpatients. METHODS: We performed a retrospective review of four questionnaires (the Experiences in Close Relationship scale (ECR-R), Temperament and Character inventory (TCI), Temperament Evaluation of the Memphis, Pisa, Paris and San Diego questionnaire (TEMPS-A), and Personality Self-Portrait Questionnaire (PSQ)). Frequency measures and correlations were examined, as was the predictive value of attachment security for a personality disorder (PD). RESULTS: Significant, robust correlations were found between attachment anxiety and (1) several negative affective temperaments (dysthymic and cyclothymic); (2) several indices of personality pathology (low self-directedness (TCI), DSM-IV paranoid, borderline, histrionic, avoidant and dependent personality traits). Attachment avoidance had fewer large correlations. In an exploratory model, the negative predictive value of attachment security for a PD was 86%. LIMITATIONS: Subjects were a relatively homogeneous subset of ambulatory psychiatric outpatients. PD diagnoses were via self-report. CONCLUSIONS: Clinically, these findings highlight the significant overlap between attachment, affective temperament, and personality and support the value of attachment as a screen for PDs. More broadly, given our growing understanding of the neurobiology of attachment (i.e. links with the oxytocin system), these results raise interesting questions about underlying biological systems and psychiatric treatment. PMID- 24054919 TI - Confirmatory factor analysis and measurement invariance by gender, age and levels of psychological distress of the short TEMPS-A. AB - BACKGROUND: The Temperament Evaluation of Memphis, Pisa, Paris and San Diego - Autoquestionnaire (TEMPS-A) is a widely used self-reported tool aimed at measuring the affective temperaments that define the bipolar spectrum, with cyclothymic, depressive, irritable, hyperthymic, and anxious subscales. Confirmatory factor analysis (CFA) was rarely used to confirm the expected five factor model. Measurement invariance was never tested. METHODS: Cross-sectional, survey design involving 649 Italian college students (males: 47%). The short 39 item TEMPS-A and the 12-item General Health Questionnaire (GHQ-12) were used as measures of the affective temperaments and of psychological distress, respectively. CFA was applied to the TEMPS-A. Measurement invariance by gender, age and levels of psychological distress on the GHQ-12 was calculated with the establishment of subsequent equivalence constraints in the model parameters across groups. RESULTS: The expected five-factor model had the best fit for all CFA indexes. Configural, metric and scalar invariance of the five-factor model of the TEMPS-A was proved across gender, age and levels of psychological distress of the participants. The hyperthymic temperament subscale has low or no links with the other affective temperament subscales, which were interrelated with medium to large effect sizes. LIMITATIONS: College students might be not representative of the general population. No information on the clinical status of the students was available beyond self-report data. CONCLUSION: The study proved the measurement invariance of the (short) TEMPS-A, which is a pre-requisite to compare groups or individuals in cross-sectional and longitudinal surveys. Generalizability cannot be assumed without replication of the findings in clinical samples. PMID- 24054920 TI - Left Atrial Appendage Occlusion Study II (LAAOS II). AB - BACKGROUND: Occlusion of the left atrial appendage (LAA) is a potential alternative to anticoagulation for patients with atrial fibrillation (AF); however, evidence of its safety and efficacy is lacking. The Left Atrial Appendage Occlusion Study II (LAAOS II) explored the feasibility of a definitive trial of LAA occlusion for stroke prevention in AF. METHODS: A cross-sectional study of 1889 consecutive patients undergoing cardiac surgery was performed to determine the prevalence of AF and risk factors for stroke. We also randomized 51 patients with AF and increased stroke risk to LAA occlusion (n = 26) or no occlusion and oral anticoagulation (n = 25) to assess the rate of recruitment and the safety of LAA amputation. RESULTS: In the cross-sectional study, 204 patients (10.8%) had AF and 98 (5.2%) met trial eligibility. Fifty-one patients were recruited into the trial at a rate of 1.6 patients per centre per month. No patient with occlusion had significant bleeding at the LAA site. At 1 year, 4 patients (15.4%) in the occlusion arm and 5 patients (20.0%) in the no-occlusion arm experienced death, myocardial infarction (MI), stroke, noncerebral systemic emboli, or major bleeding (relative risk [RR], 0.71; 95% confidence interval [CI], 0.19-2.66; P = 0.61). The predominant component of the composite was stroke, with 1 in the occlusion arm and 3 in the no-occlusion arm. CONCLUSIONS: LAA occlusion can be safely performed at the time of cardiac surgery. A large trial to evaluate the clinical efficacy of LAA occlusion in patients undergoing cardiac surgery is possible in motivated centres with some modifications to the design of LAAOS II. PMID- 24054921 TI - Early opening of dormant septal collaterals during alcohol septal ablation: a possible hazard of remote necrosis. AB - Alcohol septal ablation has become a common method to relieve left ventricular outflow track gradient in selected patients with hypertrophic obstructive cardiomyopathy. There is only limited knowledge regarding inadvertent remote (nontarget) myocardial necrosis caused by septal collateral recruitment. Herein we describe a case of unexpected contrast medium leakage through newly opened septal collateral circulation immediately after low-dose ethanol injection suggesting that angiographic inspection of collateral recruitment is necessary in all cases of repeat ethanol injection. PMID- 24054922 TI - Changes in circulating progenitor cells are associated with outcome in heart failure patients: a longitudinal study. AB - BACKGROUND: Circulating progenitor cells (CPCs) are involved in the process of endothelial repair and are a prognostic factor in cardiovascular diseases. We evaluated the association between serial measurements of CPCs and functional capacity and outcomes in heart failure (HF). METHODS: We included 156 consecutive consenting ambulatory HF patients (left ventricular ejection fraction < 40%). We evaluated CPCs and functional capacity (peak VO2) every 6 months for up to 2 years. CPCs were measured as early-outgrowth colony-forming units (EO-CFUs) and circulating CD34+, VEGFR2+ and/or CD133+ cells. We recorded mortality, HF hospital admissions, transplant, and ventricular assist device. RESULTS: The mean age was 55 +/- 15 years. A decrease in CD34+VEGFR2+ cells was independently associated with increased functional capacity; a 10-cell decrease in CD34+VEGFR2+ cells was associated with an increase of 0.2 mL/kg/min in peak VO2 (P < 0.05). We found an interaction effect (P = 0.02) between EO-CFUs and diabetes: in patients without diabetes, a 10-EO-CFU increase was independently associated with increased peak VO2 of 0.28 mL/kg/min (P = 0.01), and in patients with diabetes, a decrease in EO-CFUs was associated with an increased peak VO2 (P < 0.05). Higher EO-CFUs were associated with reduced mortality (hazard ratio, 0.25; 95% confidence interval, 0.09-0.69). CONCLUSIONS: We noted differential relations between CPCs and outcomes in patients with vs without diabetes. Higher EO-CFUs and lower CD34+VEGFR2+ cells were associated with improved functional capacity and reduced mortality in nondiabetic patients. In patients with diabetes, lower EO-CFUs were associated with improved functional capacity. The basis for these differences requires further examination. PMID- 24054923 TI - Percutaneous retrograde closure of mitral paravalvular leak in patients with mechanical aortic valve prostheses. AB - Mechanical aortic valve prostheses are considered a limiting factor when contemplating percutaneous closure of mitral paravalvular leaks using a retrograde approach. However, transfemoral artery access and a retrograde approach have advantages over a trans-septal anterograde approach when the paravalvular defect is large with a significant gradient or when the defect is medial to the mitral valve. We describe a novel technique of mitral paravalvular leak closure in the presence of a mechanical aortic valve prosthesis, which we performed successfully in 3 patients. The technique uses a retrograde approach and arteriovenous wire loop. PMID- 24054924 TI - Life expectancy of humans is increasing. PMID- 24054925 TI - Gender and longevity: why do men die earlier than women? Comparative and experimental evidence. AB - Sex differences in lifespan exist world-wide, with women outliving men by more than a decade in some countries. The gender gap is not a uniquely human phenomenon; most sexually reproducing species examined show sex differences in patterns of ageing, yet a comprehensive explanation does not exist. Here, we discuss how ageing responds to natural selection on traits that arise as a consequence of sexuality. Sexual dimorphisms in vertebrates are mediated by sex steroids, such as androgens and oestrogens, and we examine their regulation of biological processes that can affect ageing and lifespan. The sexes can respond differently to dietary restriction and altered activity of nutrient-sensing pathways, with females showing a greater plasticity for life extension. We suggest that the cross-regulation of steroid hormone and nutrient-sensing signalling pathways is a promising process for further study in understanding the biological basis for the gender gap. PMID- 24054927 TI - Gender aspects in type 2 diabetes mellitus and cardiometabolic risk. AB - Men are well known to have a higher risk than women for cardiovascular disease. In recent years, however, studies show adult men also have higher risk for type 2 diabetes, an observation which has important clinical implications, particularly in the public health arena. This chapter explores the relevant data underlying this observation, examines potential mechanisms including life course changes in insulin resistance and role of adiposity, and discusses relevant clinical implications and solutions. PMID- 24054926 TI - Gender differences and disparities in all-cause and coronary heart disease mortality: epidemiological aspects. AB - This overview is primarily concerned with large recent prospective cohort studies of adult populations, not patients, because the latter studies are confounded by differences in medical and surgical management for men vs. women. When early papers are uniquely informative they are also included. Because the focus is on epidemiology, details of age, sex, sample size, and source as well as study methods are provided. Usually the primary outcomes were all-cause or coronary heart disease (CHD) mortality using baseline data from midlife or older adults. Fifty years ago few prospective cohort studies of all-cause or CHD mortality included women. Most epidemiologic studies that included community-dwelling adults did not include both sexes and still do not report men and women separately. Few studies consider both sex (biology) and gender (behavior and environment) differences. Lifespan studies describing survival after live birth are not considered here. The important effects of prenatal and early childhood biologic and behavioral factors on adult mortality are beyond the scope of this review. Clinical trials are not discussed. Overall, presumptive evidence for causality was equivalent for psychosocial and biological exposures, and these attributes were often associated with each other. Inconsistencies or gaps were particularly obvious for studies of sex or gender differences in age and optimal measures of body size for CHD outcomes, and in the striking interface of diabetes and people with the metabolic syndrome, most of whom have unrecognized diabetes. PMID- 24054928 TI - Obesity and weight management in the elderly: a focus on men. AB - The rising rate of overweight/obesity among the ever-growing ageing population is imposing massive and rapidly changing burdens of ill health. The observation that the BMI value associated with the lowest relative mortality is slightly higher in older than in younger adults, mainly through its reduced impact on coronary heart disease, has often been misinterpreted that obesity is not as harmful in the elderly, who suffer a large range of disabling consequences of obesity. All medical consequences of obesity are multi-factorial and most alleviated by modest, achievable weight loss (5-10 kg) with an evidence-based maintenance strategy. But severe obesity, e.g. BMI >40 may demand greater weight loss e.g. >15 kg to reverse type 2 diabetes. Since relatively reduced physical activity and reduced muscle mass (sarcopenic obesity) are common in the elderly, combining exercise and modest calorie restriction optimally reduces fat mass and preserves muscle mass - age presents no obstacle and reducing polypharmacy is a valuable outcome. The currently licensed drug orlistat has no age-related hazards and is effective in a low fat diet, but the risks from bariatric surgery begin to outweigh benefits above age 60. For the growing numbers of obese elderly with diabetes, the glucagon-like peptide-1 (GLP-1) receptor analogue liraglutide appears a safe way to promote and maintain substantial weight loss. Obesity and sarcopenia should be prevented from younger age and during life-transitions including retiral to improve future health outcomes and quality of life, with a focus on those in "obese families". PMID- 24054929 TI - Osteoporosis in older men: recent advances in pathophysiology and treatment. AB - Osteoporosis remains underrecognized and undertreated but more so in men, adding considerably to fracture burden and costs. Fracture-related morbidity and mortality is higher in men, partly due to greater frailty. Improved peak bone mass, geometry and turn-over contribute to lower fracture incidence in men. Bioavailable androgens and oestrogens regulate these aspects of musculoskeletal sexual dimorphism, yet the direct cellular and molecular targets of sex steroids in bone remain incompletely understood. Screening with clinical risk factors and dual energy X-ray absorptiometry are advised in men from age 70 (or 50 with additional risk factors). We now have compelling evidence that osteoporosis drugs are equally effective in men and women, not only to increase bone density but also to prevent osteoporotic fractures. The use of testosterone or selective androgen receptor modulators for osteoporosis, sarcopenia, frailty and falls in men with late-onset hypogonadism requires further investigation. PMID- 24054931 TI - Diagnosis and treatment of late-onset hypogonadism: systematic review and meta analysis of TRT outcomes. AB - Late-onset hypogonadism (LOH) is a relatively common conditions affecting the aging male. The aim of this review is to summarize the available evidence regarding LOH and its interaction with general health. LOH is often comorbid to obesity and several chronic diseases. For this reason lifestyle modifications should be strongly encouraged in LOH subjects with obesity, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) and good treatment balance of chronic diseases. Medical therapy of LOH should be individualized depending on the etiology of the disease and the patient's expectations. Available evidence seems to suggest that testosterone replacement therapy is able to improve central obesity (subjects with MetS) and glycometabolic control (patients with MetS and T2DM), as well as to increase lean body mass (HIV, chronic obstructive pulmonary disease), along with insulin resistance (MetS) and peripheral oxygenation (chronic kidney diseases). However, it should be recognized that the number of studies on benefits of T supplementation is too limited to draw final conclusions. Longer and larger studies are needed to better clarify the role of TRT in such chronic conditions. PMID- 24054930 TI - Growth hormone in the aging male. AB - Secretion of growth hormone (GH) and IGF-1 levels decline during advancing years of-life. These changes (somatopause) are associated with loss of vitality, muscle mass, physical function, together with the occurrence of frailty, central adiposity, cardiovascular complications, and deterioration of mental function. For GH treatment to be considered for anti-aging, improved longevity, organ specific function, or quality of life should be demonstrable. A limited number of controlled studies suggest that GH supplementation in older men increases lean mass by ~2 kg with similar reductions in fat mass. There is little evidence that GH treatment improves muscle strength and performance (e.g. walking speed or ability to climb stairs) or quality of life. The GHRH agonist (tesamorelin) restores normal GH pulsatility and amplitude, selectively reduces visceral fat, intima media thickness and triglycerides, and improves cognitive function in older persons. This report critically reviews the potential for GH augmentation during aging with emphasis on men since women appear more resistant to treatment. PMID- 24054932 TI - Sexual function of the ageing male. AB - With the progressive increase in the proportion of older people, there is an increasing interest in characterizing the modifications of sexual health and the effect of its perturbations as a function of the aging process. The aim of this review is to summarize the available evidence regarding the age-dependent modifications of male sexual function and their interaction with general health and age-dependent modification of endocrine function. Elderly patients are often affected by multiple organic diseases which can interfere with sexual function. Despite this evidence, several studies have indicated that, with advancing age, normal erections are not an absolute prerequisite to remain sexually active. Good physical health, the availability of a partner, and a regular and stable pattern of sexual activity earlier in life predict the maintenance of sexual activity in old age. Conversely, there are no convincing data that hormonal changes, associated with aging, have a primary role in underlying changes in sexual function in healthy aging men. Nonetheless, sexual dysfunctions especially in elderly people are poor investigated. Asking about sexual health remains difficult or embarrassing for many primary care physicians. In addition, many patients find it difficult to raise sexual issues with their doctor. This situation often results in sexual issues not being adequately addressed thus resulting in depression, social withdrawal and delayed diagnosis of underlying medical conditions often resulting in forthcoming cardiovascular events. Education and permission from a health care professional may help to alter such misconceptions. Information from physicians regarding normal age-related changes in sexuality and encouragement, together with advice on how to continue meaningful sexual relations, may play a key role in altering such negative attitudes. PMID- 24054933 TI - Androgens and prostate cancer; pathogenesis and deprivation therapy. AB - Although androgen receptor signaling is critical for prostate cancer growth and survival, evidence supporting a favorable risk-benefit ratio of androgen deprivation therapy (ADT) is currently limited to men with high-risk or metastatic disease. This is in part because ADT has been associated with a number of constitutional and somatic side effects, consistent with the widespread tissue expression of sex steroid receptors. ADT is the most common contemporary cause of severe hypogonadism, and men receiving this therapy represent a unique model of severe sex steroid deficiency with a defined time of onset. This review will present an update on the role of ADT in the treatment of prostate cancer, will summarize recent evidence regarding ADT-associated adverse effects with particular emphasis on cardiometabolic and musculoskeletal health, and will provide recommendations for further research. PMID- 24054934 TI - Effects of age on male fertility. AB - Later parenting is considered by many to have advantages, parents-to-be may feel themselves more stable to rear children. In addition, many men start a second family later in life. Thus, paternal age becomes an emerging issue. Aging affects male fertility by a scope of factors, which are not fully understood to date. Generally, the amount of produced sperm cells as well as their motility decreases with age, as testicular histological architecture deteriorates. Decreased fecundity and an increased risk for disturbed pregnancies occur with advancing paternal age. Some rare autosomal dominant pathologies are clearly related to paternal age. Altered patterns of epigenetics/gene expression in aging sperm seem to affect a range of neurocognitive disorders and also metabolic dyshomeostasis across generations. Such effects refer to men older than 40 years and may have impact on socio-economic issues. Nevertheless, councelling of older men seeking paternity should be patient-oriented and weigh statistical probabilities against the right for individual life-planning. PMID- 24054935 TI - Quality of life after radical prostatectomy: can we give a "lifetime guarantee" to our patients? PMID- 24054937 TI - [Spontaneous rupture of a uterine myoma]. PMID- 24054938 TI - Association of serum bicarbonate with clinical outcomes in CKD: could an increase in serum bicarbonate be a double-edged sword? PMID- 24054939 TI - Dialysate bicarbonate: the case for foot-dragging. PMID- 24054940 TI - Hip fractures in hemodialysis patients. PMID- 24054941 TI - Quiz page October 2013: When things are not as they seem: a woman with anion gap metabolic acidosis after ingesting antifreeze. PMID- 24054942 TI - Deletion modification enhances anthrax specific immunity and protective efficacy of a hepatitis B core particle-based anthrax epitope vaccine. AB - Protective antigen (PA) is one of the major virulence factors of anthrax and is also the major constituent of the current anthrax vaccine. Previously, we found that the 2beta2-2beta3 loop of PA contains a dominant neutralizing epitope, the SFFD. We successfully inserted the 2beta2-2beta3 loop of PA into the major immunodominant region (MIR) of hepatitis B virus core (HBc) protein. The resulting fusion protein, termed HBc-N144-PA-loop2 (HBcL2), can effectively produce anthrax specific protective antibodies in an animal model. However, the protective immunity caused by HBcL2 could still be improved. In this research, we removed amino acids 79-81 from the HBc MIR of the HBcL2. This region was previously reported to be the major B cell epitope of HBc, and in keeping with this finding, we observed that the short deletion in the MIR not only diminished the intrinsic immunogenicity of HBc but also stimulated a higher titer of anthrax specific immunity. Most importantly, this deletion led to the full protection of the immunized mice against a lethal dose anthrax toxin challenge. We supposed that the conformational changes which occurred after the short deletion and foreign insertion in the MIR of HBc were the most likely reasons for the improvement in the immunogenicity of the HBc-based anthrax epitope vaccine. PMID- 24054943 TI - Donor non-specific MICA antibodies in renal transplant recipients. AB - Despite recent advances in solid organ transplantations, an antibody mediated rejection caused by donor specific antibodies is still a major problem in kidney graft survival. Besides HLA-induced humoral response, antibodies against MICA antigens have recently attracted attention because of their possible role in graft rejection. The aim of our study was to establish whether renal recipients produce antibodies against MICA molecules due to the transplantation and if they are specific for MICA antigens of the donors. MICA antibody screening was performed in 124 kidney recipient sera. 22 sera, that were found to be MICA antibody positive, were further examined for MICA antibody profiles and compared with donor MICA alleles. The analysis of MICA antibody positive sera showed mostly more complex reactivity patterns. A significant fraction of patient sera (59%) reacted not only with the donor MICA antigens, but also with other MICA patterns. A match between antibody specificities and MICA antigens was observed in 41% of renal recipients only. On the other hand, as much as in 36% of recipient sera were detected antibodies against their own MICA molecules. We did not prove a complete correlation between the recipient MICA antibody specificities and MICA antigens of the donor. We assume that MICA antibody induction occurs not only due to the allogeneic stimulation itself but also due to other factors that need to be elucidated. PMID- 24054944 TI - Reshaping of T-lymphocyte compartment in adult prepubertaly ovariectomised rats: a putative role for progesterone deficiency. AB - This study explores the role of ovarian hormones in the phenotypic shaping of peripheral T-cell pool over the reproductive lifespan of rats. For this purpose, 2-month-old prepubertally ovariectomised (Ox) rats, showing oestrogen and progesterone deficiency, and 11-month-old Ox rats, exhibiting only progesterone deficiency, were examined for thymus output, and cellularity and composition of major TCRalphabeta+ peripheral blood lymphocyte (PBL) and splenocyte subsets. Although ovariectomy increased thymic output in both 2- and 11-month-old rats, the count of both CD4+ and CD8+ PBLs and splenocytes increased only in the former. In the blood and spleen of 11-month-old Ox rats only the count of CD8+ cells increased. Although ovariectomy affected the total CD4+ count in none of the examined compartments from the 11-month-old rats, it increased CD4+FoxP3+ PBL and splenocyte relative proportions over those in the age-matched controls. The age-related differences in the cellularity and the major subset composition in Ox rats were linked to the differences in the ovarian steroid hormone levels registered in 2- and 11-month-old rats. The administration of progesterone to Ox rats during the seven days before the sacrificing confirmed contribution of this hormone deficiency to the ovariectomy-induced changes in the TCRalphabeta+ PBL and splenocyte pool from 11-month-old rats. The expansion of the CD8+ splenocyte subset in the 11-month-old Ox rats reflected increases in cellularity of memory and, particularly, naive cells. This was due to greater thymic output of CD8+ cells and homeostatic proliferation than apoptosis in 11-month-old Ox rats when compared with age-matched sham-Ox control rats. The homeostatic changes within CD8+ splenocyte pool from 11-month-old Ox rats, most likely, reflected the enhanced splenic IL-7 and TGF-beta mRNA expression. Overall, in adult female rats, circulating oestrogen and progesterone provide maintenance of T-cell counts, a diversity of T-cell repertoire, and the main T-cell subset composition in the periphery. Progesterone deficiency affects mainly the CD8+ lymphocyte compartment through increasing thymic CD8+ cell export and upsetting homeostatic regulation within the CD8+ splenocyte pool. These alterations were reversible through progesterone supplementation. PMID- 24054945 TI - IGKC and FcgammaR genotypes and humoral immunity to HER2 in breast cancer. AB - Immunoglobulin kappa constant (IGKC) gene has recently been identified as a strong prognostic marker in several human solid tumors, including breast cancer. Although the mechanisms underlying the IGKC signature are not yet known, identification of tumor-infiltrating plasma cells as the source of IGKC expression strongly suggests a role for humoral immunity in breast cancer progression. The primary aim of the present investigation was to determine whether the genetic variants of IGKC, KM (kappa marker) allotypes, are risk factors for breast cancer, and whether they influence the magnitude of humoral immunity to epidermal growth factor receptor 2 (HER2), which is overexpressed in 25-30% of breast cancer patients and is associated with poor prognosis. Using a matched case-control design, we genotyped a large (1719 subjects) study population from Japan and Brazil for KM alleles. Both cases and controls in this study population had been previously characterized for GM (gamma marker) and Fcgamma receptor (FcgammaR) alleles, and the cases had also been characterized for anti-HER2 antibodies. Conditional logistic regression analysis of the data showed that KM1 allele additively contributed to the risk of breast cancer in the Japanese subjects from Nagano: Compared to KM3 homozygotes, KM1 homozygotes were almost twice as likely to develop breast cancer (OR=1.77, CI 1.06-2.95). Additionally, KM genotypes-individually and in particular epistatic combinations with FcgammaRIIa genotypes-contributed to the magnitude of anti-HER2 antibody responsiveness in the Japanese patients. This is the first report implicating KM alleles in the immunobiology of breast cancer. PMID- 24054946 TI - Exploring the roles of integrin binding and cytoskeletal reorganization during mesenchymal stem cell mechanotransduction in soft and stiff hydrogels subjected to dynamic compression. AB - The objective of this study was to explore how the response of mesenchymal stem cells (MSCs) to dynamic compression (DC) depends on their pericellular environment and the development of their cytoskeleton. MSCs were first seeded into 3% agarose hydrogels, stimulated with the chondrogenic growth factor TGF beta3 and exposed to DC (~10% strain at 1Hz) for 1h on either day 7, 14, or 21 of culture. At each time point, the actin, vimentin and tubulin networks of the MSCs were assessed using confocal microscopy. Similar to previous results, MSCs displayed a temporal response to DC; however, no dramatic changes in gross cytoskeletal organization were observed with time in culture. Vinculin (a membrane-cytoskeletal protein in focal adhesions) staining appeared more intense with time in culture. We next aimed to explore how changes to the pericellular environment, independent of the duration of exposure to TGF-beta3, would influence the response of MSCs to DC. To this end, MSCs were encapsulated into either 'soft' or 'stiff' agarose hydrogels that are known to differentially support pericellular matrix (PCM) development. The application of DC led to greater relative increases in the expression of chondrogenic marker genes in the stiffer hydrogels, where the MSCs were found to have a more well developed PCM. These increases in gene expression were not observed following the addition of RGDS, an integrin blocker, suggesting that integrin binding plays a role in determining the response of MSCs to DC. Microtubule organization in MSCs was found to adapt in response to DC, but this effect was not integrin mediated, as this cytoskeletal reorganization was also observed in the presence of RGDS. In conclusion, although the PCM, integrin binding, and cytoskeletal reorganization are all involved in mechanotransduction of DC, none of these factors in isolation was able to completely explain the temporal mechanosensitivity of MSCs to dynamic compression. PMID- 24054948 TI - Anticoccidial effects of a novel triazine nitromezuril in broiler chickens. AB - The anticoccidial efficacy of 2-(3-methyl-4-(4-nitrophenoxy)phenyl)-1,2,4 triazine-3,5(2H,4H)-dione (nitromezuril, NZL), a novel triazine compound, was evaluated in three different studies under experimental conditions. The anticoccidial efficacy was chiefly evaluated using the anticoccidial index (ACI). The resistance level was determined by calculating ACI, percentage optimum anticoccidial activity (POAA), reduction in lesion scores (RLS) and relative oocyst production (ROP). In the dose determination study (study A), NZL was added to the diet at doses of 1, 2, 3, 4, 5 and 6 mg/kg to test its efficacy against coccidiosis caused by Eimeria tenella. Groups treated with NZL 1mg/kg feed could observe the faecal dropping scores and caecal lesions. ACIs of NZL-treated groups reached 179-199. In the study on the anticoccidial efficacy of 3mg/kg NZL in the diet (study B), only a few faecal oocysts and slight lesions were observed. NZL significantly promoted weight gain (WG) and reduced lesion scores (LS) compared to controls receiving diclazuril (DZL) (P<0.05). ACIs of NZL-treated groups were 193, 192, 191 and 163 for E. tenella, Eimeria necatrix, Eimeria acervulina and Eimeria maxima, respectively, whereas those of DZL-treated groups were 185, 176, 176 and 148. In the cross-drug resistance study (study C), ACIs of NZL and toltrazuril (TZL)-treated groups ranged from 188 to 204, which were significantly higher than those of DZL-treated groups (P<0.05). NZL- and TZL-treated groups were sensitive to experimentally induced DZL-resistant E. tenella, whereas DZL treated groups showed complete resistance. No cross-resistance was observed between DZL and NZL or TZL. Based on the abovementioned studies, it was concluded that diets containing 3 mg/kg NZL had an excellent efficacy in preventing coccidiosis in broiler chickens. The activity of 3mg/kg NZL in the diet was equal or superior to that of 1 mg/kg DZL. These results are of great significance for the future applications of NZL; however, its actual mechanism of action remains unknown. NZL is a potential novel anticoccidial agent suitable for further development. PMID- 24054947 TI - Subgroup analysis of symptoms and their effect on functioning, exercise capacity, and physical activity in patients with severe chronic obstructive pulmonary disease. AB - BACKGROUND: Little is known about symptom clusters and their effect on outcomes in people with chronic obstructive pulmonary disease (COPD). PURPOSES: To determine whether subgroups of patients with COPD could be identified by symptom ratings, whether they differed on selected demographic and clinical characteristics, and whether they differed on functioning, exercise capacity, and physical activity. METHOD: Subjects with severe COPD (n = 596) were drawn from the National Emphysema Treatment Trial dataset. Data were drawn from questionnaires and clinical measures. RESULTS: Two subgroup clusters emerged from four symptoms. Mean age and the proportion of participants with higher education, higher income levels, and using oxygen at rest were significantly different between subgroups. Participants with high levels of symptoms had lower functioning and decreased exercise capacity. Symptom cluster subgroups were significantly associated with social functioning. CONCLUSION: These findings suggest that screening for high levels of symptoms may be important in patients with severe COPD. PMID- 24054949 TI - Cryptosporidium from a free-ranging marsupial host: bandicoots in urban Australia. AB - Expansion of human settlement has increased the interface between people and bandicoots with implications for the emergence and spread of zoonotic parasites. The host status of bandicoots inhabiting suburban areas and their potential role in Cryptosporidium transmission remains unresolved. Our study aimed to determine the prevalence and identity of Cryptosporidium in two sympatric bandicoot species. Cryptosporidium signatures were detected in twelve bandicoot faecal samples (n=98) through amplification of the 18S rRNA. Phylogenetic inference placed the isolates in a clade with Cryptosporidium parvum, a species with a broad host range and zoonotic potential, or loosely related to Cryptosporidium hominis. However, the identity of the bandicoot isolates was not fully resolved and whether they were infected or simply passively transmitting oocysts is unknown. This study revealed that free-ranging bandicoots of northern Sydney were shedding Cryptosporidium oocysts at a prevalence of 12.2% (95% CI [6.76, 20.8]), similar to marsupial species that act as reservoirs for Cryptosporidium. Our findings expand the range of hosts known to shed Cryptosporidium in urban areas. PMID- 24054950 TI - With whom did you have sex? Evaluation of a partner notification training for STI professionals using motivational interviewing. AB - OBJECTIVE: To enhance partner notification (PN) practices in Dutch STI clinics, a PN training using motivational interviewing as core strategy was offered to STI professionals and evaluated. METHODS: The effectiveness of PN training on professionals' attitude, self-efficacy, skills and behavior toward PN, was examined using within-subject and between-subject comparison. Before the training and at three months follow-up, a questionnaire was completed by the intervention group (n=54) and a non-random control group (n=37). RESULTS: In the within subject comparison, positive changes were observed in self-efficacy, skills, and PN behaviors (all p<.05), but not in attitudes toward PN. When we examined differences in change-scores between the intervention and control group, self efficacy was no longer significant. CONCLUSION: The PN training significantly improved PN skills and -behavior, but had no effect on professionals' attitudes or self-efficacy toward PN. The selection of a convenience control sample seems to offer a more rigorous test of hypotheses than pre-post evaluation only. PRACTICE IMPLICATIONS: The beneficial effect of PN training of STI professionals seems to support a wider roll-out of the training to all STI clinics in the Netherlands, although effects on the number of partners notified and transmissions prevented need to be examined in future research. PMID- 24054951 TI - Osler's nodes and Janeway lesions are not the result of small-vessel vasculitis. PMID- 24054952 TI - Dysnatremia: a clear and present risk for surgery. PMID- 24054953 TI - Are vena cava filters effective in the treatment of pulmonary embolism? PMID- 24054954 TI - From papyrus to the electronic tablet: a brief history of the clinical medical record with lessons for the digital age. AB - A major transition is underway in documentation of patient-related data in clinical settings with rapidly accelerating adoption of the electronic health record and electronic medical record. This article examines the history of the development of medical records in the West in order to suggest lessons applicable to the current transition. The first documented major transition in the evolution of the clinical medical record occurred in antiquity, with the development of written case history reports for didactic purposes. Benefiting from Classical and Hellenistic models earlier than physicians in the West, medieval Islamic physicians continued the development of case histories for didactic use. A forerunner of modern medical records first appeared in Paris and Berlin by the early 19th century. Development of the clinical record in America was pioneered in the 19th century in major teaching hospitals. However, a clinical medical record useful for direct patient care in hospital and ambulatory settings was not developed until the 20th century. Several lessons are drawn from the 4000-year history of the medical record that may help physicians improve patient care in the digital age. PMID- 24054955 TI - Gun ownership and firearm-related deaths. AB - BACKGROUND: A variety of claims about possible associations between gun ownership rates, mental illness burden, and the risk of firearm-related deaths have been put forward. However, systematic data on this issue among various countries remain scant. Our objective was to assess whether the popular notion "guns make a nation safer" has any merits. METHODS: Data on gun ownership were obtained from the Small Arms Survey, and for firearm-related deaths from a European detailed mortality database (World Health Organization), the National Center for Health Statistics, and others. Crime rate was used as an indicator of safety of the nation and was obtained from the United Nations Surveys of Crime Trends. Age standardized disability-adjusted life-year rates due to major depressive disorder per 100,000 inhabitants with data obtained from the World Health Organization database were used as a putative indicator for mental illness burden in a given country. RESULTS: Among the 27 developed countries, there was a significant positive correlation between guns per capita per country and the rate of firearm related deaths (r = 0.80; P <.0001). In addition, there was a positive correlation (r = 0.52; P = .005) between mental illness burden in a country and firearm-related deaths. However, there was no significant correlation (P = .10) between guns per capita per country and crime rate (r = .33), or between mental illness and crime rate (r = 0.32; P = .11). In a linear regression model with firearm-related deaths as the dependent variable with gun ownership and mental illness as independent covariates, gun ownership was a significant predictor (P <.0001) of firearm-related deaths, whereas mental illness was of borderline significance (P = .05) only. CONCLUSION: The number of guns per capita per country was a strong and independent predictor of firearm-related death in a given country, whereas the predictive power of the mental illness burden was of borderline significance in a multivariable model. Regardless of exact cause and effect, however, the current study debunks the widely quoted hypothesis that guns make a nation safer. PMID- 24054957 TI - Effective reduction of blood product use in a community teaching hospital: when less is more. AB - BACKGROUND: The increased morbidity and mortality associated with liberal blood product usage have been convincingly demonstrated. The clinical problems they pose have prompted development of more restrictive evidence-based transfusion criteria. Education alone has a limited impact on the adoption of these criteria into practice. New York Methodist Hospital undertook a proactive approach to reduce unnecessary transfusions. METHOD: In November 2008, an interventional monitoring program to ensure adherence to transfusion criteria for packed red blood cells (PRBC), platelets, fresh frozen plasma (FFP), and cryoprecipitate transfusions was started. Blood bank technologists routinely monitored transfusion requests against a list of established criteria and experienced clinicians reviewed and adjudicated transfusion requests when the blood bank technologist's action was appealed. RESULTS: Transfusion usage decreased sharply in Year 1 (November 2008-October 2009) and continued to decrease in Year 2 (November 2009-October 2010). PRBC use decreased by 30.1% and 37.7%, with a 47.6% decrease in multi-unit transfusions; platelet use decreased by 24.3% and 41.2%; fresh frozen plasma use decreased by 41.8% and 31.1%; and cryoprecipitate use decreased by 38.7% and 56.1% during monitoring Years 1 and 2, respectively. Decreases occurred despite a 4.0% increase in hospital admissions during the monitoring years. The decreased blood product usage was accompanied by 28.6% reduction in complications. A 26.1% decrease in blood product requests from Year 1 to Year 2 suggested a practice change by the ordering physicians themselves. The total cost of blood products decreased by $2,235,676. CONCLUSION: We established a successful method to reduce transfusions of all blood products using strict adherence to evidence-based criteria and continuous monitoring. Our model translates into improved patient safety by decreasing the number of unnecessary transfusions. This also led to a significant reduction in hospital expenses. PMID- 24054956 TI - Rate-control versus rhythm-control strategies and outcomes in septuagenarians with atrial fibrillation. AB - BACKGROUND: The prevalence of atrial fibrillation substantially increases after 70 years of age. However, the effect of rate-control versus rhythm-control strategies on outcomes in these patients remains unclear. METHODS: In the randomized Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 4060 patients (mean age 70 years, range 49-80 years) with paroxysmal and persistent atrial fibrillation were randomized to rate-control versus rhythm-control strategies. Of these, 2248 were 70-80 years, of whom 1118 were in the rate-control group. Propensity scores for rate-control strategy were estimated for each of the 2248 patients and were used to assemble a cohort of 937 pairs of patients receiving rate-control versus rhythm-control strategies, balanced on 45 baseline characteristics. RESULTS: Matched patients had a mean age of 75 years; 45% were women, 7% were nonwhite, and 47% had prior hospitalizations due to arrhythmias. During 3.4 years of mean follow-up, all-cause mortality occurred in 18% and 23% of matched patients in the rate-control and rhythm control groups, respectively (hazard ratio [HR] associated with rate control, 0.77; 95% confidence interval [CI], 0.63-0.94; P = .010). HRs (95% CIs) for cardiovascular and noncardiovascular mortality associated with rate control were 0.88 (0.65-1.18) and 0.62 (0.46-0.84), respectively. All-cause hospitalization occurred in 61% and 68% of rate-control and rhythm-control patients, respectively (HR 0.76; 95% CI, 0.68-0.86). HRs (95% CIs) for cardiovascular and noncardiovascular hospitalization were 0.66 (0.56-0.77) and 1.07 (0.91-1.27), respectively. CONCLUSION: In septuagenarian patients with atrial fibrillation, compared with rhythm-control, a rate-control strategy was associated with significantly lower mortality and hospitalization. PMID- 24054958 TI - Educational Innovations Project--program participation and education publications. PMID- 24054959 TI - Elevated phosphorus levels and risk of kidney disease. PMID- 24054960 TI - Venous and arterial viscosity-associated thrombosis in hemoglobin SC disease. PMID- 24054961 TI - The reply. PMID- 24054962 TI - Antinuclear antibody test: when to order? PMID- 24054963 TI - The reply. PMID- 24054964 TI - Differential cyanosis. PMID- 24054965 TI - Dilutional hyponatremia in a community hospital setting: case report. AB - Transurethral resection of the prostate (TURP) syndrome describes the symptomatic absorption of hypotonic irrigation fluid used during a TURP procedure, the culmination of which could possibly lead to death. During the procedure, electrocautery is used to excise the urethral-occluding prostate tissue while an irrigation solution removes incisional debris and facilitates a clear surgical view. Through direct communication with the prostatic circulatory system, rapid absorption of irrigation solution can occur. Compared with bipolar and laser resectoscopes which allow the use of isotonic irrigation solution, monopolar resectoscopes require the use of an electrolyte-free irrigation solution to prevent electricity scatter. This presents a unique patient safety challenge for the smaller institutions around the world which continue to implement this technology. This article discusses a case report of a patient with TURP syndrome admitted to our surgical intensive care unit. PMID- 24054966 TI - Comprehensive anterior segment normal values generated by rotating Scheimpflug tomography. AB - PURPOSE: To identify normal values for tomographic parameters that are considered useful in screening patients for refractive surgery. SETTING: Private center, Albany, New York, USA. DESIGN: Database study. METHODS: A Pentacam HR Scheimpflug system was used to examine 1 randomly selected eye of patients to determine normal values of 21 parameters considered the most clinically applicable for surgical screening. Normality of data was evaluated using the Kolmogorov-Smirnov test. Statistical analyses were performed using the Student t test to compare means and the 2-paired sample Wilcoxon signed-rank test. Results are displayed in 95.0% and 97.5% confidence intervals (CIs). RESULTS: The study evaluated 341 adults. High-end outliers at the 97.5% CI were 46.1 diopters (D) for flat keratometry (K), 47.4 D for steep K, 3.4 D for astigmatism, 3.8 MUm for anterior chamber depth, 4 MUm for front apical elevation, 5 MUm for front elevation at the thinnest point, and 12 MUm for front elevation in the central 4.0 mm. Respective posterior elevation values were 7 MUm, 13 MUm, and 25 MUm, with a progression index maximum of 1.53 and mean of 1.19, difference between apical and thinnest pachymetric reading of 7 MUm, a maximum K of 48.2 D, and an inferior-superior ratio of 1.44 D. Low-end outliers were a maximum Ambrosio relational thickness of 335 and a mean of 425, minimum pachymetry of 479 MUm, thickness at the apex of 481 MUm, and central 4.0 mm corneal volume of 6.31 mm(3). CONCLUSION: Scheimpflug derived corneal tomography identified key refractive surgery parameters that may be useful in screening refractive surgical patients. PMID- 24054967 TI - Efficacy and safety of prophylactic intracameral moxifloxacin injection in Japan. AB - PURPOSE: To report endophthalmitis rates after cataract surgery and the incidence of complications after intracameral moxifloxacin injection. SETTING: Nineteen clinics in Japanese institutions. DESIGN: Retrospective survey cohort study. METHODS: The number of surgeries and endophthalmitis cases in the past 4 years before and after the introduction of intracameral moxifloxacin was evaluated. The survey was performed by mail or interview in February 2013. RESULTS: All institutions used total-replacement administration rather than small-volume injection. At 3 institutions, 50 to 100 MUg/mL moxifloxacin; at 9 institutions, 100 to 300 MUg/mL moxifloxacin; and at 7 institutions, 500 MUg/mL moxifloxacin was administered. The highest concentration (500 MUg/mL) was administered in 14,124 cases. Endophthalmitis cases occurred 1 month or sooner postoperatively in 8 of 15,958 cases (ie, 1 in 1955) without intracameral moxifloxacin administration and in 3 of 18,794 cases (ie, 1 in 6265) with intracameral moxifloxacin administration. CONCLUSIONS: Intracameral moxifloxacin (50 to 500 MUg/mL) administration decreased the risk for endophthalmitis by 3-fold. In more than 18,000 cases, moxifloxacin administration of 500 MUg/mL or less did not result in severe complications, such as toxic anterior segment syndrome or corneal endothelial cell loss. PMID- 24054968 TI - Giant spiral shaped spermatozoa of Diasemopsis comoroensis (Diptera, Diopsidae) with a unique ultrastructural component. AB - In this study we describe a new kind of sperm gigantism in the stalk-eyed fly, Diasemopsis comoroensis (Diptera, Diopsidae). The sperm cells have a length of up to 1.7 mm and can be coiled into a compact 'slinky' spiral. Their ultrastructure involves a prominent electron dense central band, which runs the entire length of the sperm tail and in some regions constitutes its largest element in cross section. We propose that this organelle is either a giant centriole adjunct or a kind of accessory body derived from it, and that it takes part in coiling the sperm tail. To our knowledge, no comparable structure has been described before. PMID- 24054969 TI - UPA > LNG, but Not Good Enough. PMID- 24054970 TI - [Small-colony variants of Staphylococcus aureus: Usefulness of various test for diagnosis and susceptibility study]. AB - INTRODUCTION: Small colony variants of Staphylococcus aureus (SCVSA) are a sub population with special features. METHODS: The phenotypic features and antibiotic susceptibility of four clinical isolates SCVSA were studied. RESULTS: Colonies grew in the usual culture media, except in Mueller Hinton. All isolates were resistant to ciprofloxacin and co-trimoxazole. DISCUSSION: As SCVSA are isolated with low frequency, it is necessary to determine the optimal methods for their identification and antibiotic susceptibility study. PMID- 24054971 TI - Correlation of inflammatory and cardiovascular biomarkers with pneumonia severity scores. AB - PURPOSE: To assess the correlation of procalcitonin (PCT), C-reactive protein (CRP), neopterin, mid-regional pro-atrial natriuretic peptide (MR-proANP), and mid-regional pro-adrenomedullin (MR-proADM) with severity risk scores: severe CAP (SCAP) and SMART-COP in patients with community-acquired pneumonia (CAP), as well as short term prognosis and to determine the correlation with mortality risk scores. METHODS: Eighty-five patients with a final diagnosis of pneumonia were consecutively included during a two month period. Epidemiological, clinical, microbiological, and radiological data were recorded. Patients were stratified according to the PSI, CURB-65, SCAP and SMART-COP. Complications were defined as respiratory failure/shock, need of ICU, and death. Plasma samples were collected at admission. RESULTS: MR-proANP and MR-proADM showed significantly higher levels in high risk SCAP group in comparison to low risk. When considering SMART-COP none of the biomarkers showed statistical differences. MR-proADM levels were high in patients with high risk of needing intensive respiratory or vasopressor support according to SMRT-CO. Neopterin and MR-proADM were significantly higher in patients that developed complications. PCT and MR-proADM showed significantly higher levels in cases of a definite bacterial diagnosis in comparison to probable bacterial, and unknown origin. MR-proANP and MR-proADM levels increased statistically according to PSI and CURB-65. CONCLUSIONS: Biomarker levels are higher in pneumonia patients with a poorer prognosis according to SCAP and SMART COP indexes, and to the development of complications. PMID- 24054972 TI - [Clinical and epidemiological differences between Bordetella pertussis and respiratory syncytial virus infections in infants: a matched case control study]. AB - INTRODUCTION: An increase in cases of pertussis, mainly in young infants, has been reported in the last few years. The clinical presentation of this disease is very similar to that produced by respiratory syncytial virus (RSV), which makes the diagnosis difficult. OBJECTIVE: To compare the clinical and epidemiological characteristics between Bordetella pertussis and RSV infections in infants admitted to hospital. MATERIAL AND METHODS: An analytical matched case-control study was conducted during the period 2008-2011. Cases were defined as infants admitted with pertussis confirmed by PCR in nasopharyngeal aspirate. Each case was matched by age, sex and date of admission to two controls defined as patients with RSV infection detected by immunochromatography in nasal aspirate. Demographic, clinical, laboratory data were compared. RESULTS: Seventy eight patients (26 cases of pertussis and 52 controls RSV+) were included. Sociodemographic characteristics were similar in both groups. Cases had more days of symptoms prior to admission, longer hospital stays, and increased frequency of epidemic family environment. Apnoea and cyanosis were more frequent. Cases of pertussis were more likely to have apnoea, cyanosis, and lymphocytosis while RSV infections had more frequent fever, vomiting and respiratory distress. CONCLUSIONS: The clinical presentations of pertussis and RSV infection are similar, but there are some characteristics that can help to distinguish between them. PMID- 24054973 TI - Effects of bilayer gelatin/beta-tricalcium phosphate sponges loaded with mesenchymal stem cells, chondrocytes, bone morphogenetic protein-2, and platelet rich plasma on osteochondral defects of the talus in horses. AB - Osteochondrosis (OC) is a common and clinically important joint disorder in horses. However, repair of the OC region is difficult because of the avascular nature of cartilage. This study aimed to evaluate the efficacy of bilayer gelatin/beta-tricalcium phosphate (GT) sponges loaded with mesenchymal stem cells (MSCs), chondrocytes, bone morphogenetic protein-2 (BMP-2), and platelet rich plasma (PRP) for the repair of osteochondral defects of the talus in horses. Full thickness osteochondral defects were created on both the lateral trochlear ridges of the talus (n = 6). In the test group, a basic GT sponge loaded with MSCs and BMP-2 (MSC/BMP2/GT) was inserted into the lower part of the defect, and an acidic GT sponge loaded with chondrocyte, MSCs, and PRP (Ch/MSC/PRP/GT) was inserted into the upper part of the defect. In the control group, the defect was treated only with bilayer GT sponges. Repair of osteochondral defects was assessed by radiography, quantitative computed tomography (QCT), and macroscopic and histological evaluation. The test group showed significantly higher radiographic, QCT, macroscopic, and histological scores than the control group. This study demonstrated that the bilayer scaffolds consisting of Ch/MSC/PRP/GT for the chondrogenic layer and MSC/BMP2/GT for the osteogenic layer promoted osteochondral regeneration in an equine model. The bilayer scaffolds described here may be useful for treating horses with OC. PMID- 24054974 TI - Unreconstructable acute distal humeral fractures and their sequelae treated with distal humeral hemiarthroplasty: a two-year to eleven-year follow-up. AB - BACKGROUND: The aim of this study was to describe for the first time the medium to long-term outcome after distal humeral hemiarthroplasty (DHH). METHODS: Twenty six patients (mean age, 62; range, 29-92 years) treated with DHH for intra articular distal humeral fractures and its sequelae were studied retrospectively. RESULTS: Four patients had died and 4 had been revised to total elbow arthroplasty: 2 for periprosthetic fractures and 2 for primary component loosening (all in prostheses without an anterior flange). Six other complications had occurred: ulnar neuritis, 4; stiffness, 1; and wound necrosis, 1. Seventeen patients underwent assessment at a mean of 80 months after surgery. The mean values of the American Shoulder and Elbow Surgeons (ASES) elbow score (pain, 9.93; function, 25; satisfaction, 9.06); Mayo Elbow Performance Score (90); Quick Disabilities of Arm, Shoulder and Hand (19), and EuroQol EQ5D (Index, 0.84; Visual Analog Scale, 80) outcome measures demonstrated good function and satisfaction with little pain. The mean flexion extension arc was 116 degrees . There was no evidence of instability. Radiologic evidence of ulnar wear was seen in 13 patients and may be related to prosthetic design to some extent. Worse wear was associated with a higher ASES pain score, lower satisfaction score, and lower EuroQoL Visual Analog Scale of quality of life. Degree of wear correlates with time after surgery but not with age at the time of surgery. CONCLUSION: DHH offers a treatment option for unreconstructable distal humeral fractures and is associated with a good long-term outcome. LEVEL OF EVIDENCE: Level IV, case series, treatment study. PMID- 24054975 TI - Association of suprascapular neuropathy with rotator cuff tendon tears and fatty degeneration. AB - BACKGROUND: The mutual influence of suprascapular neuropathy (SSN) and rotator cuff tendon tears on muscle pathology is unclear. Debate continues as to how retracted cuff tears can lead to SSN and whether SSN or tendon retraction causes muscle fatty degeneration. METHODS: A cohort of 87 patients suspected of having SSN was identified from a prospectively collected registry. All underwent electromyography/nerve conduction velocity study (EMG/NCV) and magnetic resonance imaging (MRI) of their shoulders. EMG/NCVs were performed and interpreted by electrodiagnosticians, and MRI cuff tendon quality and muscle fatty degeneration were interpreted by two surgeons. RESULTS: Out of 87 patients, 32 patients had SSN on EMG/NCV, and 55 patients had normal suprascapular nerve. MRI showed that 59 of 87 supraspinatus had no fatty degeneration or mild fatty streaks (Goutallier grades 0 and 1), and 28 patients had significant fatty degeneration (grades 2-4); infraspinatus fatty degeneration was similar. Review of supraspinatus tendon showed 41 patients with intact tendons or partial tears, and 46 with full tears. Infraspinatus tendons pathology was similar. Tendon pathology and fatty degeneration were related (P-value<.001), with more severe tendon pathology leading to higher degree of fatty degeneration. Infraspinatus tendon tears were associated with SSN (P = .01), but SSN was not related to fatty degeneration of either supraspinatus or infraspinatus (P-values .65, .54). CONCLUSION: The exact association and etiology of SSN in patients with rotator cuff pathology remain unclear. SSN is correlated to tendon tear size, but it does not have significant influence on fatty degeneration of either supraspinatus or infraspinatus. PMID- 24054976 TI - Surface light scattering and visual function of diffractive multifocal hydrophobic acrylic intraocular lenses 6 years after implantation. AB - PURPOSE: To evaluate the surface light scattering associated with diffractive multifocal intraocular lenses (IOLs) and visual function 6 years after implantation. SETTING: Private practice. DESIGN: Retrospective comparative case series. METHODS: Patients received a hydrophobic acrylic IOL and were followed for more than 6 years. Six years postoperatively, the intensity of the surface light scattering was measured using a Scheimpflug camera-based anterior segment analyzer. The corrected distance (CDVA) and near (CNVA) visual acuities and contrast sensitivity were assessed. RESULTS: Twenty eyes of 10 patients received a diffractive multifocal IOL (Acrysof Restor SA60D3, study group), and 16 eyes of 8 patients received a monofocal IOL (Acrysof SA60AT, control group). Six years postoperatively, the anterior surface light scattering was more than 100 computer compatible tape units in both groups, with no significant difference between groups (P=.417). The mean CDVA and CNVA in the study group were -0.06 logMAR +/- 0.04 (SD) and -0.04 +/- 0.05 logMAR, respectively; however, the CNVA in both groups decreased compared with that at 1 year, as did the CDVA in the control group. Contrast sensitivity was within normal range at all spatial frequencies in both groups. There were no significant correlations between surface light scattering and the changes in corrected visual acuities (distance or near) between 1 year and 6 years postoperatively in either group. CONCLUSION: Although there was significantly increased surface light scattering 6 years postoperatively, the visual function with a diffractive multifocal IOL was comparable to that with a monofocal IOL. PMID- 24054977 TI - Visual outcomes comparison of 2 femtosecond laser platforms for laser in situ keratomileusis. AB - PURPOSE: To compare the efficacy, predictability, and safety outcomes of 2 femtosecond laser platforms for flap creation during laser in situ keratomileusis (LASIK) for myopia and myopic astigmatism. SETTING: Singapore National Eye Centre, Singapore. DESIGN: Retrospective case review. METHODS: In this single center multisurgeon study, patients had LASIK with flaps created using a Visumax 500 kHz or Intralase 60 kHz femtosecond laser system. Ablation was performed with the Wavelight Allegretto Eye-Q 400 Hz excimer laser in all patients. Preoperative and 3-month postoperative manifest refraction, attempted treatment spherical equivalent (SE), visual acuity, and complications were compared. RESULTS: The 500 kHz femtosecond laser group comprised 381 patients (381 eyes) and the 60 kHz femtosecond laser group, 362 patients (362 eyes). Three months postoperatively, the uncorrected distance visual acuity was 20/40 or better in 99.1% of eyes in the 60 kHz laser group and 99.4% of eyes in the 500 kHz laser group (P=.678). Regarding predictability, 98.6% of eyes and 97.4% of eyes, respectively, were within +/- 1.0 diopter of the attempted SE correction postoperatively (P=.228). The safety index was similar in the 60 kHz laser group and the 500 kHz laser group (mean 1.06 +/- 0.16 [SD] versus 1.05 +/- 0.14) (P=.321). CONCLUSION: The safety, predictability, and efficacy profiles of the 500 kHz femtosecond platform for LASIK were excellent and comparable to those of the 60 kHz platform. PMID- 24054978 TI - The multiple layers of non-genetic regulation of PTEN tumour suppressor activity. AB - Mutations and deletions of the tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) are frequently involved in the development of cancer. However, PTEN is also tightly controlled by various non-genomic mechanisms. This review focuses on those mechanisms, namely on the epigenetic silencing of PTEN, post-transcriptional regulation by non-coding RNAs and post translational modification. We summarise their involvement in cancer in general, and place some emphasis on leukaemia, where PTEN genetic lesions are relatively uncommon and, strikingly, high levels of PTEN expression frequently associate with PTEN functional inactivation. Overall, it is apparent that rather than looking strictly for PTEN genetic lesions and PTEN expression status, the key to evaluating the real impact of PTEN as a 'quasi-insufficient' tumour suppressor must rely on the complete understanding of PTEN's 'functional dose', incorporating the multiple layers of PTEN regulation in the cell that are ultimately compromised in a given cancer. PMID- 24054979 TI - Non-linear dose-response relationship between cigarette smoking and pancreatic cancer risk: evidence from a meta-analysis of 42 observational studies. AB - BACKGROUND: Question remains about the shape of the dose-response relationship between cigarette smoking and pancreatic cancer risk. METHODS: Relevant studies were identified by searching PubMed, ISI Web of Science and China National Knowledge Infrastructure (CNKI) databases and by reviewing the reference lists of retrieved articles. Random-effects models were applied to estimate summary relative risks (RRs). RESULTS: Forty-two publications were finally included. The overall meta-analysis showed evidence of non-linear association between smoking intensity and pancreatic cancer risk (P for non-linearity=0.000). Compared with non-smokers, the summary RRs were 1.5 (95% confidence interval (CI): 1.4, 1.6) for 10 cigarettes/day, 1.9 (95% CI: 1.8, 2.0) for 20 cigarettes/day, 2.0 (95% CI: 1.9, 2.1) for 30 cigarettes/day and 2.1 (95% CI: 1.9, 2.3) for 40 cigarettes/day with marginal between-study heterogeneity (I(2)=29%). Similar results were also found for smoking duration and cumulative amount of cigarettes smoked. Besides, the summary RR for former smokers reduced with increasing time since quitting smoking compared with current smokers without heterogeneity (P for non linearity=0.008, I(2)=0%). The results of stratified analysis by study design were comparable to those of overall meta-analysis. When stratified by sex, non linear dose-response associations were detected for all metrics of cigarette smoking in women, while linear relationships were observed for smoking duration and cumulative amount of cigarettes smoked in men except for smoking intensity. CONCLUSION: This meta-analysis reveals a non-linear dose-response association between cigarette smoking and pancreatic cancer risk, but it might differ between sexes. PMID- 24054980 TI - Nintendo(r) Wii Fit based sleepiness tester detects impairment of postural steadiness due to 24 h of wakefulness. AB - A field-usable sleepiness tester could reduce sleepiness related accidents. 15 subjects' postural steadiness was measured with a Nintendo((r)) Wii Fit balance board every hour for 24 h. Body sway was quantified with complexity index, CI, and the correlation between CI and alertness predicted by a three-process model of sleepiness was calculated. The CI group average was 8.9 +/- 1.3 for alert and 7.9 +/- 1.4 for sleep deprived subjects (p < 0.001, rho = 0.94). The Wii Fit board detects the impairment of postural steadiness. This may allow large scale sleepiness testing outside the laboratory setting. PMID- 24054981 TI - Minimizing inter-subject variability in fNIRS-based brain-computer interfaces via multiple-kernel support vector learning. AB - Brain signal variation across different subjects and sessions significantly impairs the accuracy of most brain-computer interface (BCI) systems. Herein, we present a classification algorithm that minimizes such variation, using linear programming support-vector machines (LP-SVM) and their extension to multiple kernel learning methods. The minimization is based on the decision boundaries formed in classifiers' feature spaces and their relation to BCI variation. Specifically, we estimate subject/session-invariant features in the reproducing kernel Hilbert spaces (RKHS) induced with Gaussian kernels. The idea is to construct multiple subject/session-dependent RKHS and to perform classification with LP-SVMs. To evaluate the performance of the algorithm, we applied it to oxy hemoglobin data sets acquired from eight sessions and seven subjects as they performed two different mental tasks. Results show that our classifiers maintain good performance when applied to random patterns across varying sessions/subjects. PMID- 24054982 TI - Effect of age on myocardial function assessed by two-dimensional speckle-tracking echocardiography in healthy beagle dogs. AB - OBJECTIVES: The objective of this study was to evaluate the effect of age on myocardial function assessed by two-dimensional speckle-tracking echocardiography (2D-STE) in healthy dogs. ANIMALS: Thirty-two healthy Beagles were used. METHODS: Myocardial function was assessed in each dog by using 2D-STE, and the results were compared between young and old dogs. RESULTS: The myocardial deformations in systole, besides the apical rotation rate, were not significantly different between young and old dogs. In contrast, the early diastolic circumferential strain rate, basal rotation rate, and torsion rate were significantly lower in old dogs than in young dogs (P = 0.03, P = 0.033, and P = 0.015, respectively). Late diastolic longitudinal and radial strain rates were significantly higher in old dogs than in young dogs (P = 0.002 and P = 0.018, respectively). CONCLUSIONS: Young and old dogs showed similar systolic myocardial deformations, but significant differences in the values of some diastolic deformation variables were found between young and old dogs, highlighting the need for using age matched control subjects in studies of diastolic function. PMID- 24054983 TI - Hematocrit elevation associated with testosterone administration. PMID- 24054984 TI - The characterization of low pathogenic avian influenza viruses isolated from wild birds in northern Vietnam from 2006 to 2009. AB - Due to concerns that wild birds could possibly spread H5N1 viruses, surveillance was conducted to monitor the types of avian influenza viruses circulating among the wild birds migrating to or inhabiting in northern Vietnam from 2006 to 2009. An H5N2 virus isolated from a Eurasian woodcock had a close phylogenetic relationship to H5 viruses recently isolated in South Korea and Japan, suggesting that H5N2 has been shared between Vietnam, South Korea, and Japan. An H9N2 virus isolated from a Chinese Hwamei was closely related to two H9N2 viruses that were isolated from humans in Hong Kong in 2009, suggesting that an H9N2 strain relevant to the human isolates had been transmitted to and maintained among the wild bird population in Vietnam and South China. The results support the idea that wild bird species play a significant role in the spread and maintenance of avian influenza and that this also occurs in Vietnam. PMID- 24054985 TI - Prevalence of borreliosis, anaplasmosis, ehrlichiosis and Dirofilaria immitis in dogs and vectors in Voronezh Reserve (Russia). AB - Most of the dogs studied for the prevalence of CVBD have previously received acaricidal and insecticidal treatments. In the present work, a very specific population of dogs (Group 1) that had never been treated against ticks and mosquitoes was studied. Moreover, the territory occupied by this population has also never been treated, because it is a protected area--Voronezh Natural Reserve. Canine patients from veterinary clinics (Group 2) that had been treated against VBD vectors were studied for comparison. Eighty-two dogs (Group 1) were enrolled in June, 2008. Blood samples were tested using the IDEXX SNAP((r)) 4Dx((r)) test. A specific heartworm antigen was detected in 12.2% samples. The seroprevalence for Anaplasma phagocytophilum was found to be 34.1%. The antibodies to Borrelia C6 peptide and to Ehrlichia canis were detected in 2.4% of the samples. Almost all dogs with infections had no clinical signs. Only 3 mixed infected dogs showed non-specific clinical signs. During the tick season, 358 Ixodes ricinus were collected; the prevalence of Borrelia burgdorferi s.l. and Anaplasma phagocytophilum was 21.9% and 0.6%, respectively. Four hundred and forty dogs (Group 2) were studied for comparison. Antibodies to B. burgdorferi s.l. were detected only in one dog, seroprevalence for A. phagocytophilum represented 1.1%, no E. canis seropositive dogs were identified, and 8.2% dogs were found infected with Dirofilaria immitis. Fifty-six percent of dogs with dirofilariosis had clinical signs. All dogs with anaplasmosis showed specific clinical signs--fever, anemia, splenitis. Three dogs died within a few days. PMID- 24054986 TI - Epigenetic roles of MLL oncoproteins are dependent on NF-kappaB. AB - MLL fusion proteins in leukemia induce aberrant transcriptional elongation and associated chromatin perturbations; however, the upstream signaling pathways and activators that recruit or retain MLL oncoproteins at initiated promoters are unknown. Through functional and comparative genomic studies, we identified an essential role for NF-kappaB signaling in MLL leukemia. Suppression of NF-kappaB led to robust antileukemia effects that phenocopied loss of functional MLL oncoprotein or associated epigenetic cofactors. The NF-kappaB subunit RELA occupies promoter regions of crucial MLL target genes and sustains the MLL dependent leukemia stem cell program. IKK/NF-kappaB signaling is required for wild-type and fusion MLL protein retention and maintenance of associated histone modifications, providing a molecular rationale for enhanced efficacy in therapeutic targeting of this pathway in MLL leukemias. PMID- 24054987 TI - Prognostic factors in electrical burns: a review of 101 patients. AB - PURPOSE: Electrical burn wounds are among the most devastating of burns, with wide-ranging injuries. We aimed to document the factors affecting the mortality rate of patients presenting with electrical burn wounds to our regional burn centre. METHODS: This retrospective study was conducted on 101 patients from January 2009 to June 2012. Factors were classified under 11 topics and evaluated according to their relationship with the mortality rate. RESULTS: The major causes of death in burn victims were multiple organ failure and infection. Twenty six percent of the 101 patients died, all of whom were male. One (1.4%) of the patients who survived was female; 73 (98.6%) survivors were male. The mean age in the deceased group was statistically higher than that of the other patients (32.7 vs. 35.6 years; P < 0.05). All-cause mortality was 2.79 times higher for larger burns (> 25% total body surface area). The values for creatine kinase, creatine kinase-MB, total body surface area of burn, hospitalised period in the intensive care unit and intubation rate were significantly higher in the exitus group. Renal injury requiring haemofiltration was associated with an almost 12-fold increased risk for mortality. There was no statistically significant difference between patients regarding surgical interventions. CONCLUSION: Electrical injury remains a major cause of mortality and long-term disability among young people. Our data demonstrated several risk factors associated with increased mortality rate in patients with electrical burn wounds. PMID- 24054988 TI - The determination of total burn surface area. PMID- 24054990 TI - The ClockDelta19 mutation in mice fails to alter the primary and secondary reinforcing properties of nicotine. AB - BACKGROUND: Clock genes have been demonstrated to play a role in behavioral responses to a variety of drugs of abuse, including cocaine, amphetamine, morphine, and ethanol. However, no studies to date have examined the role of Clock genes on nicotine-mediated behaviors. We examined the involvement of Clock, one of several Clock genes, on the effects of nicotine by examining mice with the ClockDelta19 mutation in behaviors commonly used to assess drug effects in rodents. METHODS: We first measured the locomotor effects of nicotine in mutants and wild type mice in response to repeated nicotine injections (0.175 mg/kg, IP). To assess the secondary properties of nicotine, we measured the ability of nicotine (0.175 mg/kg, IP) to induce a conditioned place preference. Finally, we measured the primary reinforcing properties of nicotine at two doses (0.01 and 0.03 mg/kg/infusion, IV) using the self-administration paradigm. RESULTS: Mutant mice demonstrated no difference in magnitude of the sensitized response to nicotine as compared to wild-type controls. In the conditioned place preference paradigm, mutant and wild-type mice demonstrated a similar preference for a nicotine-paired environment. And finally, mutant and wild-type mice demonstrated a similar acquisition of nicotine self-administration, as indicated by the number of responses on a nicotine-paired lever and the number of nicotine reinforcers achieved during sessions. CONCLUSIONS: The ClockDelta19 mutation appears to have no effect on the reinforcing properties of nicotine, in contrast to its demonstrated role in cocaine reinforcement. Further studies are needed to determine the effect of other Clock genes on nicotine reinforcement. PMID- 24054989 TI - Alcohol use and trauma exposure among male and female veterans before, during, and after military service. AB - BACKGROUND: The present study examined lifespan and combat-related trauma exposure as predictors of alcohol use among male and female veterans. Posttraumatic stress and depressive symptoms were examined as mediators of the effects of trauma exposure on alcohol use. METHODS: Data were examined from 1825 (1450 male, 375 female) veterans and active duty service members who took part in a multi-site research study conducted through the Department of Veterans Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center (VISN 6 MIRECC). RESULTS: For both men and women, depressive symptoms significantly mediated the effects of non-combat trauma exposure experienced before, during and after the military, as well as combat-exposure, on alcohol use. With posttraumatic stress symptoms, the models for men and women differed. For men, the effects of non-combat trauma exposure during and after military service, and combat exposure, on alcohol use were mediated by PTSD symptoms; however, for women, PTSD symptoms did not mediate these relationships. CONCLUSION: Findings are discussed in the context of potential gender differences in response to trauma such as use of alcohol to cope with traumatic events. PMID- 24054991 TI - Insulin-like growth factor-1 and risk of late-onset Alzheimer's disease: findings from a family study. AB - Insulin-like growth factor-1 (IGF-1), part of an evolutionary conserved signaling pathway in both mammalian and non-mammalian species, is inferred in neurodegenerative disorders including Alzheimer's disease (AD). A murine model for AD shows that reduced IGF-1 signaling prevents AD-like characteristics. However, variation in serum levels of IGF-1 and risk of AD in humans has yet to be determined. We used a proven family design, comparing middle-aged offspring with and without a parental history of AD. The offspring under study carry an increased risk of AD but do not yet experience cognitive impairment. A total of 206 offspring from 92 families with a parental history of AD were compared with 200 offspring from 97 families without a parental history of AD. Apolipoprotein-E (APOE) genotypes and serum IGF-1 levels were compared in subjects with and without a parental history of AD using linear regression, adjusted for APOE genotype and other possible demographic and clinical confounders. Offspring with a parental history of AD were more likely to be an APOE epsilon4 allele carrier (46.5% vs. 21%, p = 0.001) than were offspring without such a parental history. Offspring with a parental history of AD had higher IGF-1 levels than subjects without such a history, in both unadjusted and adjusted analyses (18.3 mmol/L vs. 16.7 mmol/L, p = 0.001). In conclusion, higher serum IGF-1 levels in middle age are associated with risk of AD disease in older age, independent of APOE genotype. PMID- 24054993 TI - Markers of endothelial dysfunction and cerebral blood flow in older adults. AB - We investigated the association of 2 markers of endothelial dysfunction, tissue plasminogen activator (t-PA) and Von Willebrand factor (VWF), with cerebral blood flow (CBF) in 541 older participants at high risk for cardiovascular disease. Serum levels of t-PA and VWF were measured at baseline. Participants underwent 2 successive brain magnetic resonance imaging scans, first at baseline and the then after a mean follow-up of 33 months. Total CBF was determined in each scan and also standardized for brain parenchymal volume. At baseline, higher t-PA was associated with lower CBF (p = 0.034). In the longitudinal analysis, higher levels of VWF were associated with a steeper decline in CBF (p = 0.043). There was no association between t-PA and decrease in CBF. These associations were independent of sociodemographic and cardiovascular factors. In conclusion, elevated markers of endothelial dysfunction are associated with lower CBF in older adults at risk for cardiovascular disease. PMID- 24054992 TI - IPAF inflammasome is involved in interleukin-1beta production from astrocytes, induced by palmitate; implications for Alzheimer's Disease. AB - Inflammatory response has been strongly implicated in the pathogenesis of numerous diseases, including Alzheimer's disease (AD). However, little is known about the molecular mechanisms initiating the generation of inflammatory molecules in the central nervous system, such as interleukin-1beta (IL-1beta). Previously we identified that palmitate can induce primary astrocytes to produce cytokines, causing AD-like changes in primary neurons. Here we investigated and identified that palmitate induced the activation of ice protease-activating factor (IPAF)-apoptosis-associated speck-like protein containing a caspase activation and recruitment domains (CARD) (ASC) inflammasome in astrocytes leading to the maturation of IL-1beta, thereby implicating that not only pathogen related factors can activate the IPAF-ASC inflammasome. Moreover, downregulating IPAF (which was found to be regulated by cAMP response element-binding protein) in astrocytes through silencing to decrease IL-1beta secretion from the astrocytes reduced the generation of amyloid-beta42 by primary neurons. Furthermore, the expression levels of IPAF and ASC were found significantly elevated in a subgroup of sporadic AD patients, suggesting an involvement of the IPAF-ASC inflammasome in the inflammatory response associated with AD, and thus could be a potential therapeutic target for AD. PMID- 24054994 TI - Considerations in prophylaxis for tumor-associated epilepsy: prevention of status epilepticus and tolerability of newer generation AEDs. AB - OBJECTIVE: To identify risk factors for the development of tumor-associated epilepsy (TAE) and potential benefit of newer generation AEDs in seizure prevention. METHODS: We performed an IRB approved retrospective study of newly diagnosed GBM patients at the University of Rochester between 1/1/05 and 5/13/11. Records were reviewed to describe demographics, seizure incidence, occurrence of status epilepticus, and AED use and toxicity. RESULTS: 172 patients with newly diagnosed GBM were included in the study. 53.4% developed TAE. 31.4% had seizure prior to diagnosis. 118 patients were seizure-free at diagnosis: 32.2% developed post-diagnosis TIE (PostTAE) and 60.2% remained seizure-free. 70 seizure-free patients received an AED peri-operatively. 36 were weaned off AEDs and 31 were continued. Incidence of PostTAE and time to first seizure were comparable in AED treated and untreated patients. 4 PostTAE patients presented with status epilepticus (SE), all were not AED treated. AEDs were withdrawn in 10 patients due to toxicity: 9 from phenytoin and 1 from levetiracetam. CONCLUSION: There is a high incidence of PostTAE in GBM. Prophylactic AED therapy did not reduce PostTAE but may have prevented SE. Minimal toxicity was observed on 2nd generation AEDs. The high burden of epilepsy in this population and tolerability of newer AEDS suggest that AAN guidelines should be revisited. PMID- 24054995 TI - Molecular analysis of mycobacteria isolated in Mexican patients with different immunodeficiencies in a tertiary care hospital. AB - BACKGROUND AND AIMS: The prevalence of infections with Mycobacterium tuberculosis (MTB) and non-tuberculous mycobacteria (NTM) species in patients with immunodeficiencies in Mexico is unknown. The aim of this study was to identify, at the molecular level, the mycobacterial species most frequently affecting patients with immunodeficiencies and evaluate the genotypic diversity of MTB complex strains. METHODS: We conducted a retrospective study of 97 strains in patients with the diagnosis of pulmonary (all isolates were of pathological significance) or extrapulmonary tuberculosis. PCR analysis was performed to determine whether they belonged to the MTB complex (MTC) or the Mycobacterium avium complex (MAC). Noncharacterized NTM were sequenced and, finally, MTC were genotyped by MIRUs-VNTR and spoligotyping. RESULTS: Of the 97 mycobacterial strains isolated, 53% were M. tuberculosis, 10% M. bovis, 24% M. avium, 9% M. simiae, 2% M. kansasii and 2% M. gordonae. A great genetic diversity was found by MIRU-VNTR with the greatest polymorphism in MIRU 10, 16, 23 and 27. By spoligotyping, the predominant family was T1. Combining both methods, the association of 13 strains in four different groups was found. CONCLUSIONS: This is the first molecular analysis of mycobacteria isolated from patients with immunodeficiencies in Mexico, describing the prevalence of different mycobacterial species in this population. A great genetic diversity of MTB strains was identified. This is also the first report in Mexico describing clinically important isolates of M. simiae. PMID- 24054996 TI - Enhancement of antinociception but not constipation by combinations containing tramadol and metamizole in arthritic rats. AB - BACKGROUND AND AIMS: The use of a combination of analgesics could provide an optimal pain treatment with minimal side effects. Combinations of tramadol and some nonsteroidal anti-inflammatory drugs have demonstrated synergistic antinociceptive effects as well as a significantly reduced occurrence of adverse effects. The purpose of this study was to investigate the antinociceptive and constipation effects of tramadol and metamizole alone or in combination in rats and to discern among the types of drug interactions that exist using dose response curves and an isobolographic analysis. METHODS: The antinociceptive effects of tramadol and metamizole, alone or in various combination ratios, were quantitatively evaluated using the "pain-induced functional impairment model in the rat." Additionally, the constipation effect was evaluated using the charcoal meal test. RESULTS: Tramadol (3.2-56.2 mg/kg) and metamizole (56.2-562.3 mg/kg) demonstrated a dose-dependent response with tramadol being more efficacious and potent than metamizole. Twenty-five different combinations of tramadol with metamizole were analyzed, and the evaluated combinations exhibited antinociceptive effects that were either additive or potentiative. An optimal combination was established with 3.2 mg/kg of tramadol and 316.2 mg/kg of metamizole. However, the constipation observed with this combination was more severe than that observed with the administration of tramadol alone. Our results reveal a possible interaction between the two drugs, which may be pharmacokinetic and/or pharmacodynamic in nature. CONCLUSIONS: The preclinical antinociceptive interaction and adverse effects produced by the combination of tramadol and metamizole suggests that caution should be exercised when using this combination in the clinical therapy of pain. PMID- 24054997 TI - Association between rs2981582 polymorphism in the FGFR2 gene and the risk of breast cancer in Mexican women. AB - BACKGROUND AND AIMS: The rs2981582 single nucleotide polymorphism in the fibroblast growth factor receptor 2 gene has been consistently associated with an increased risk of breast cancer. We evaluated the effect of rs2981582 polymorphism in the FGFR2 gene on the risk of breast cancer and its interaction with non-genetic risk factors. METHODS: A population-based case-control study was conducted in Mexico. Data from 687 cases and 907 controls were analyzed. RESULTS: The T allele of the rs2981582 polymorphism was associated with an increased risk of breast cancer (ORper allele = 1.24, 95% CI 1.06-1.46). There was also an interaction between this polymorphism and alcohol consumption (p = 0.043). The effect of alcohol consumption on the risk of breast cancer varied according to the allelic variants of the rs2981582 polymorphism in the FGFR2 gene: OR = 3.97 (95% CI 2.10-7.49), OR = 2.01 (95% CI 1.23-3.29) and OR = 1.21 (95% CI 0.48-3.05) for genotypes CC, CT and TT, respectively. CONCLUSIONS: This is the first study exploring the association between rs2981582 polymorphism in the FGFR2 gene and breast cancer risk in Mexican women. The interaction found may be of great public health interest because alcohol consumption is a modifiable breast cancer risk factor. Therefore, replication of this finding is of foremost importance. PMID- 24054998 TI - Lymphomyeloid contribution of an immune-restricted progenitor emerging prior to definitive hematopoietic stem cells. AB - In jawed vertebrates, development of an adaptive immune-system is essential for protection of the born organism against otherwise life-threatening pathogens. Myeloid cells of the innate immune system are formed early in development, whereas lymphopoiesis has been suggested to initiate much later, following emergence of definitive hematopoietic stem cells (HSCs). Herein, we demonstrate that the embryonic lymphoid commitment process initiates earlier than previously appreciated, prior to emergence of definitive HSCs, through establishment of a previously unrecognized entirely immune-restricted and lymphoid-primed progenitor. Notably, this immune-restricted progenitor appears to first emerge in the yolk sac and contributes physiologically to the establishment of lymphoid and some myeloid components of the immune-system, establishing the lymphomyeloid lineage restriction process as an early and physiologically important lineage commitment step in mammalian hematopoiesis. PMID- 24054999 TI - Mobile assistive technologies for the visually impaired. AB - There are around 285 million visually impaired people worldwide, and around 370,000 people are registered as blind or partially sighted in the UK. Ongoing advances in information technology (IT) are increasing the scope for IT-based mobile assistive technologies to facilitate the independence, safety, and improved quality of life of the visually impaired. Research is being directed at making mobile phones and other handheld devices accessible via our haptic (touch) and audio sensory channels. We review research and innovation within the field of mobile assistive technology for the visually impaired and, in so doing, highlight the need for successful collaboration between clinical expertise, computer science, and domain users to realize fully the potential benefits of such technologies. We initially reflect on research that has been conducted to make mobile phones more accessible to people with vision loss. We then discuss innovative assistive applications designed for the visually impaired that are either delivered via mainstream devices and can be used while in motion (e.g., mobile phones) or are embedded within an environment that may be in motion (e.g., public transport) or within which the user may be in motion (e.g., smart homes). PMID- 24055002 TI - Decreased dynamical complexity during quiet stance in children with autism spectrum disorders. AB - BACKGROUND: Postural control deficits in individuals with Autism Spectrum Disorders (ASD) are widely acknowledged; however, the underlying biomechanical features of these deficits remain unknown. Nonlinear analyses provide insight into the nature of how movement is controlled and have the potential to provide new insight into the postural control abnormalities associated with ASD. The purpose of this study was to further investigate postural control deficits in children with ASD through linear and nonlinear analyses of center of pressure (COP) data. METHODS: We evaluated COP data during quiet standing for 16 children with ASD and 17 age-matched typically developing (TD) children. The magnitude of COP fluctuations (COP ranges, velocity, and sway area) and complexity of postural control dynamics, quantified by multiscale entropy (MSE), were compared across groups. RESULTS: Children with ASD displayed larger fluctuations in their COP data, observed in COP ranges (95.5% mediolaterally and 46.9% anteroposteriorly, p<0.05 respectively) and COP sway area (885%, p<0.05). Children with ASD also displayed less complexity in their COP data, observed in the MSE complexity index (CI) (32.4% mediolaterally and 35.7% anteroposteriorly, p<0.05 respectively). CONCLUSIONS: The present study successfully revealed that children with ASD have more repetitive patterns in their COP data, indicating a less complex control of posture, on multiple time scales, during quiet stance. These findings suggest a more regular or restricted control of posture and may be an initial step in linking postural instability to stereotypic behavior and the neurobiology of ASD. PMID- 24055001 TI - Gly161 mutations associated with Primary Hyperoxaluria Type I induce the cytosolic aggregation and the intracellular degradation of the apo-form of alanine:glyoxylate aminotransferase. AB - Primary Hyperoxaluria Type I (PH1) is a severe rare disorder of metabolism due to inherited mutations on liver peroxisomal alanine:glyoxylate aminotransferase (AGT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme whose deficiency causes the deposition of calcium oxalate crystals in the kidneys and urinary tract. PH1 is an extremely heterogeneous disease and there are more than 150 disease-causing mutations currently known, most of which are missense mutations. Moreover, the molecular mechanisms by which missense mutations lead to AGT deficiency span from structural, functional to subcellular localization defects. Gly161 is a highly conserved residue whose mutation to Arg, Cys or Ser is associated with PH1. Here we investigated the molecular bases of the AGT deficit caused by Gly161 mutations with expression studies in a mammalian cellular system paired with biochemical analyses on the purified recombinant proteins. Our results show that the mutations of Gly161 (i) strongly reduce the expression levels and the intracellular half-life of AGT, and (ii) make the protein in the apo-form prone to an electrostatically-driven aggregation in the cell cytosol. The coenzyme PLP, by shifting the equilibrium from the apo- to the holo-form, is able to reduce the aggregation propensity of the variants, thus partly decreasing the effect of the mutations. Altogether, these results shed light on the mechanistic details underlying the pathogenicity of Gly161 variants, thus expanding our knowledge of the enzymatic phenotypes leading to AGT deficiency. PMID- 24055003 TI - Self-paced versus fixed speed treadmill walking. AB - Instrumented treadmills are increasingly used in gait research, although the imposed walking speed is suggested to affect gait performance. A feedback controlled treadmill that allows subjects to walk at their preferred speed, i.e. functioning in a self-paced (SP) mode, might be an attractive alternative, but could disturb gait through accelerations of the belt. We compared SP with fixed speed (FS) treadmill walking, and also considered various feedback modes. Nineteen healthy subjects walked on a dual-belt instrumented treadmill. Spatio temporal, kinematic and kinetic gait parameters were derived from both the average stride patterns and stride-to-stride variability. For 15 out of 70 parameters significant differences were found between SP and FS. These differences were smaller than 1cm, 1 degrees , 0.2 Nm and 0.2 W/kg for respectively stride length and width, joint kinematics, moments and powers. Since this is well within the normal stride variability, these differences were not considered to be clinically relevant, indicating that SP walking is not notably affected by belt accelerations. The long-term components of walking speed variability increased during SP walking (43%, p<0.01), suggesting that SP allows for more natural stride variability. Differences between SP feedback modes were predominantly found in the timescales of walking speed variability, while the gait pattern was similar between modes. Overall, the lack of clinically significant differences in gait pattern suggests that SP walking is a suitable alternative to fixed speed treadmill walking in gait analysis. PMID- 24055000 TI - Cardiac matrix: a clue for future therapy. AB - Cardiac muscle is unique because it contracts ceaselessly throughout the life and is highly resistant to fatigue. The marvelous nature of the cardiac muscle is attributed to its matrix that maintains structural and functional integrity and provides ambient micro-environment required for mechanical, cellular and molecular activities in the heart. Cardiac matrix dictates the endothelium myocyte (EM) coupling and contractility of cardiomyocytes. The matrix metalloproteinases (MMPs) and their tissue inhibitor of metalloproteinases (TIMPs) regulate matrix degradation that determines cardiac fibrosis and myocardial performance. We have shown that MMP-9 regulates differential expression of micro RNAs (miRNAs), calcium cycling and contractility of cardiomyocytes. The differential expression of miRNAs is associated with angiogenesis, hypertrophy and fibrosis in the heart. MMP-9, which is involved in the degradation of cardiac matrix and induction of fibrosis, is also implicated in inhibition of survival and differentiation of cardiac stem cells (CSC). Cardiac matrix is distinct because it renders mechanical properties and provides a framework essential for differentiation of cardiac progenitor cells (CPC) into specific lineage. Cardiac matrix regulates myocyte contractility by EM coupling and calcium transients and also directs miRNAs required for precise regulation of continuous and synchronized beating of cardiomyocytes that is indispensible for survival. Alteration in the matrix homeostasis due to induction of MMPs, altered expression of specific miRNAs or impaired signaling for contractility of cardiomyocytes leads to catastrophic effects. This review describes the mechanisms by which cardiac matrix regulates myocardial performance and suggests future directions for the development of treatment strategies in cardiovascular diseases. PMID- 24055004 TI - Relative influence of process variables during non-catalytic wet oxidation of municipal sludge. AB - Individual and interactive effects of process variables on the degradation of fermented municipal sludge were examined during wet oxidation. The process was carried out at 220-240 degrees C using 1:1-2:1 oxygen to biomass ratio and 300 500 rpm stirring speed. Response surface methodology coupled with a faced-centred central composite design was used to evaluate the effect of these variables on total suspended solids, volatile suspended solids and total chemical oxygen demand. Multivariate analysis was conducted for the initial and near completion stages of reaction: 5 and 60 min treatments, respectively. Temperature had the most significant effect on degradation rate throughout. During the initial stage the effect of mixing intensity was less significant than that of oxygen ratio. Mixing intensity did not influence degradation rate at the later stage in the process. During the near completion stage, the interaction of temperature and oxygen ratio had significant effect on sludge degradation. PMID- 24055005 TI - Analysis of substrate specificity in CobT homologs reveals widespread preference for DMB, the lower axial ligand of vitamin B(12). AB - Cobamides such as vitamin B12 (cobalamin) are produced exclusively by prokaryotes and used by many other organisms as cofactors for diverse metabolic processes. Cobamides are cobalt-containing tetrapyrroles with upper and lower axial ligands. The structure of the lower ligand varies in cobamides produced by different bacteria. We investigated the biochemical basis of this structural variability by exploring the reactivity of homologs of CobT, the enzyme responsible for activating lower ligand bases for incorporation into cobamides. Our results show that CobT enzymes can activate a range of lower ligand substrates, and the majority of the enzymes tested preferentially attach 5,6-dimethylbenzimidazole (DMB), the lower ligand of cobalamin. This suggests that many bacteria that synthesize cobamides other than cobalamin in pure culture may produce cobalamin in mixed communities by attaching DMB when it is available in the environment. PMID- 24055007 TI - Cobamide structure depends on both lower ligand availability and CobT substrate specificity. AB - Cobamides are members of the vitamin B12 family of cofactors that function in a variety of metabolic processes and are synthesized only by prokaryotes. Cobamides produced by different organisms vary in the structure of the lower axial ligand. Here we explore the molecular factors that control specificity in the incorporation of lower ligand bases into cobamides. We find that the cobT gene product, which activates lower ligand bases for attachment, limits the range of lower ligand bases that can be incorporated by bacteria. Furthermore, we demonstrate that the substrate specificity of CobT can be predictably altered by changing two active site residues. These results demonstrate that sequence variations in cobT homologs contribute to cobamide structural diversity. This analysis could open new routes to engineering specific cobamide production and understanding cobamide-dependent processes. PMID- 24055006 TI - A small molecule screen identifies selective inhibitors of urea transporter UT-A. AB - Urea transporter (UT) proteins, including UT-A in kidney tubule epithelia and UT B in vasa recta microvessels, facilitate urinary concentrating function. A screen for UT-A inhibitors was developed in MDCK cells expressing UT-A1, water channel aquaporin-1, and YFP-H148Q/V163S. An inwardly directed urea gradient produces cell shrinking followed by UT-A1-dependent swelling, which was monitored by YFP H148Q/V163S fluorescence. Screening of ~90,000 synthetic small molecules yielded four classes of UT-A1 inhibitors with low micromolar half-maximal inhibitory concentration that fully and reversibly inhibited urea transport by a noncompetitive mechanism. Structure-activity analysis of >400 analogs revealed UT A1-selective and UT-A1/UT-B nonselective inhibitors. Docking computations based on homology models of UT-A1 suggested inhibitor binding sites. UT-A inhibitors may be useful as diuretics ("urearetics") with a mechanism of action that may be effective in fluid-retaining conditions in which conventional salt transport blocking diuretics have limited efficacy. PMID- 24055008 TI - Protective role of low-dose TGF-beta1 in early diabetic nephropathy induced by streptozotocin. AB - OBJECTIVE: To determine whether low-dose TGF-beta1 and/or IL-6-receptoralpha monoclonal antibody (anti-IL-6Ralpha) can be used to delay renal damage and preserve renal function by rebalancing regulatory T (Treg)/Th17 cells during the course of early diabetic nephropathy (DN) induced by streptozotocin (STZ). METHODS: Diabetes was induced in C57BL/6 mice by multiple STZ injection. Low-dose TGF-beta1 (0.1 MUg/mouse/week) and/or anti-IL-6Ralpha (10 MUg/mouse/week) were administered 6 dozes after STZ injection. After 40 days of diabetes onset, metabolic indices, renal structure, activated Akt and Stat3, Treg/Th17 balance, markers and inflammatory cytokines, and oxidative stress in glomeruli were assessed. RESULTS: Low-dose TGF-beta1, instead of causing renal damage, decreased blood glucose, ameliorated kidney hypertrophy, attenuated oxidative stress, maintained activated Stat3, and induced Treg/Th17 balance in early DN. Interestingly, low-dose TGF-beta1+anti-IL-6Ralpha or anti-IL-6Ralpha alone did not attenuate DN. CONCLUSIONS: This study provides convincing experimental evidence of the protective effects of low-dose TGF-beta1 in improving metabolic disorder and slowing renal damage in early DN. PMID- 24055009 TI - Examining the evidence in pursuit of the highest possible brachytherapy standards. PMID- 24055010 TI - Principles of medicating children with neurodevelopmental and sleep disorders--a review. AB - Conflict between the demands of the environment in which a child lives and the child's intrinsic sleep signature, produces stress-behaviour difficulties in the child. Distorted development, especially distorted brain development, often leads to distorted intrinsic sleep signatures. The sleep-behaviour outcome, arising from the conflict between each child's sleep signature and the environmental niche in which they live, can be modified by medications, on the one hand, and taking the role of kin, peer and social networks seriously. Medications alter the intrinsic sleep signature of the child and the stress response. Non-medical interventions address the demands and constraints of the child's environmental niche. When the main medication strategy to address distorted sleep involves brain stimulation, those children that do not respond will often need a reversal of medication priorities; an inhibitory strategy as a short to medium term support, sleep regulation being primary for longer term management, and stimulatory strategies used sparingly, if at all. We are often dealing with vulnerable populations, not all of which are reliable or accurate sources of information. Features of a presentation alerting the clinician to non-medication factors contributing to the failure of treatment are discussed. PMID- 24055011 TI - Pediatric dermatology in Spain. PMID- 24055012 TI - Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC. AB - The PI3K/AKT/mTOR pathway regulates cell growth and proliferation and is often dysregulated in cancer due to mutation, amplification, deletion, methylation and post-translational modifications. We and others have shown that activation of this pathway in non-small cell lung cancer (NSCLC) leads to a more aggressive disease which correlates to poor prognosis for patients. A multitude of selective inhibitors are in development which target key regulators in this pathway, however the success of PI3K targeted inhibition has been hampered by a high rate of innate and acquired resistance. Response to PI3K inhibition may be improved by co-targeting potential mediators of resistance, such as related cell surface receptors or other intracellular signaling pathways which cross-talk with the PI3K pathway. Inhibition of the PI3K pathway may also overcome radioresistance, chemoresistance and immune evasion in NSCLC. The identification of appropriate patient cohorts who will benefit from PI3K co-targeted inhibition strategies will be key to the success of these inhibitors. PMID- 24055013 TI - Musician's dystonia in pianists: long-term evaluation of retraining and other therapies. AB - OBJECTIVE: Musician's dystonia is characterized by loss of voluntary motor control in extensively trained movements on an instrument. The condition is difficult to treat. This retrospective study reports on the interventions received by a homogeneous cohort of pianists with musician's dystonia and the subjective and objective changes reported in task performance. METHODS: This is a retrospective descriptive study. Fifty four pianists with musician's dystonia who had received care in a Movement Disorders Clinic completed a self report questionnaire regarding type and effectiveness of treatment received over the last 4 years. Pianists' fine motor control was assessed objectively by measuring the temporal regularity of their scale playing. RESULTS: Nearly all patients (98.0%) reported deficits in motor tasks other than musical playing. Half of the patients were taking medications (Botulinum toxin (53%), Trihexyphenidyl (51%)). Subjects reported participating in multiple therapies: retraining (87%), hand therapy (42%), relaxation techniques (38%), physiotherapy (30%), psychotherapy (23%), acupuncture (21%) and body techniques (21%). Self-reported improvements in motor performance were reported by 81.5% of the subjects with 5.6% reporting a complete recovery. Objective gains in task-specific motor performance were documented in 42.9% of the subjects (with deterioration in 4.8%). Retraining therapy, relaxation techniques and change in teacher explained 52% of the variance in subjective outcomes. CONCLUSIONS: Musician's dystonia not only interferes with musical performance but other fine motor tasks. Objectively, approximately 50% of patients improved task performance following participation in a variety of intervention strategies, but subjectively, 80% of subjects reported improvement. PMID- 24055014 TI - Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson's disease. AB - OBJECTIVE: IPX066 is an extended release carbidopa/levodopa formulation designed to rapidly attain and maintain therapeutic plasma concentrations for a prolonged duration, allowing dosing intervals of approximately 6 h. The objective was to assess the efficacy, safety, and impact on quality of life of IPX066 in the treatment of levodopa-naive Parkinson's disease (PD) patients. METHODS: This was a randomized, double-blind, placebo-controlled, 30-week study of 381 levodopa naive patients assigned to placebo or IPX066 containing 145, 245 or 390 mg of levodopa administered three times daily (TID). The primary efficacy measure was change from Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (Part II) + motor scores (Part III), at 30 weeks. Secondary outcome measures included UPDRS total and subscores, patient and clinician global impressions (PGI-I, CGI-I), and the Parkinson's Disease Questionnaire (PDQ-39). RESULTS: All IPX066 dosages were superior to placebo throughout the study and at 30 weeks (P < 0.0001). The mean improvement in UPDRS Parts II + III at 30 weeks compared to baseline was 11.7, 12.9, and 14.9 points for the three dosages and 0.6 points for placebo (P < 0.0001, all dosages). PDQ 39 total scores improved with IPX066 (P <= 0.034, all dosages). The most commonly reported adverse events with IPX066 included nausea, dizziness, and headache. No unexpected drug-related serious adverse events were reported. CONCLUSION: IPX066 provided significant clinical benefits at the three dosages tested compared to placebo and was well tolerated in levodopa-naive PD patients. Of the dosages tested, IPX066 145 mg TID appeared to provide the best overall balance between efficacy and safety. PMID- 24055015 TI - Cellular resolution functional imaging in behaving rats using voluntary head restraint. AB - High-throughput operant conditioning systems for rodents provide efficient training on sophisticated behavioral tasks. Combining these systems with technologies for cellular resolution functional imaging would provide a powerful approach to study neural dynamics during behavior. Here we describe an integrated two-photon microscope and behavioral apparatus that allows cellular resolution functional imaging of cortical regions during epochs of voluntary head restraint. Rats were trained to initiate periods of restraint up to 8 s in duration, which provided the mechanical stability necessary for in vivo imaging while allowing free movement between behavioral trials. A mechanical registration system repositioned the head to within a few microns, allowing the same neuronal populations to be imaged on each trial. In proof-of-principle experiments, calcium-dependent fluorescence transients were recorded from GCaMP-labeled cortical neurons. In contrast to previous methods for head restraint, this system can be incorporated into high-throughput operant conditioning systems. PMID- 24055017 TI - An unusual urethral foreign body. AB - INTRODUCTION: Lower urinary tract foreign body insertions have a low incidence. The motives for insertion of a variety of objects are difficult to comprehend. This case warrants discussion given the great management challenge faced by the oddity and infrequency with which a fork is encountered in the penile urethra. PRESENTATION OF CASE: A 70-year-old man presents to the Emergency Department with a bleeding urethral meatus following self-insertion of a fork into the urethra to achieve sexual gratification. Multiple retrieval methods were contemplated with success achieved via forceps traction and copious lubrication. DISCUSSION: The presentation of urethral foreign bodies can vary widely, as can the type of object inserted. The most prevalent motivation for self-insertion of urethral foreign bodies is autoerotism. Motivations ought to be explored in light of possible underlying psychological or psychiatric conditions. The most appropriate surgical extraction technique can be guided by physical examination and imaging. Endoscopic removal is often successful, depending on the object's physical attributes and morphology. It is important to arrange appropriate follow-up, as late complications can occur such as urethral strictures. CONCLUSION: Psychological and surgical arms encompass the management plan. Foreign body retrieval is determined by its physical attributes and morphology with the aim to minimise urothelial trauma and preserve erectile function. Essentially, endourological extraction serves the primary means of retrieval. Cystourethoscopy is important to diagnose urothelial injuries and to ensure complete removal of foreign bodies following extraction. PMID- 24055018 TI - Plasma level of neopterin as a marker of disease activity in treated rheumatoid arthritis patients: association with gender, disease activity and anti-CCP antibody. AB - Immune system activation is known to be involved in the progression of rheumatoid arthritis (RA). The pro-inflammatory cytokine interferon-gamma in various cells, including monocytes, induces neopterin production. Plasma level of neopterin has been measured in many autoimmune diseases and can be used as a marker of cellular immunity activation. In this study we measured the plasma level of neopterin in 418 treated RA patients and 398 age and sex matched healthy people by high pressure liquid chromatography (HPLC) method. Disease activity score was calculated in all patients by DAS-CRP method. Plasma level of neopterin was compared between RA and control groups. We also determined the association between neopterin level with gender and disease activity score in RA patients. Significantly higher level of neopterin was observed in RA patients compared to healthy controls. Moreover, there was higher neopterin level in male RA patients versus female patients. Plasma neopterin level was increased in patients with active disease and also was correlated with disease activity parameters. There was a significant correlation of plasma level of neopterin with age in both RA and control group and also age of onset and disease duration in RA patients. Anti CCP positive patients had higher level of neopterin in comparison to anti-CCP negative patients and there was a significant correlation between neopterin level and anti-CCP titer. Our results indicated that neopterin is a sensitive marker for assaying background inflammation and disease activity score in RA patients and may be used as a marker for evaluation of therapy efficacy. PMID- 24055016 TI - ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function. AB - The generation of Abeta, the main component of senile plaques in Alzheimer's disease (AD), is precluded by alpha-secretase cleavage within the Abeta domain of the amyloid precursor protein (APP). We identified two rare mutations (Q170H and R181G) in the prodomain of the metalloprotease, ADAM10, that cosegregate with late-onset AD (LOAD). Here, we addressed the pathogenicity of these mutations in transgenic mice expressing human ADAM10 in brain. In Tg2576 AD mice, both mutations attenuated alpha-secretase activity of ADAM10 and shifted APP processing toward beta-secretase-mediated cleavage, while enhancing Abeta plaque load and reactive gliosis. We also demonstrated ADAM10 expression potentiates adult hippocampal neurogenesis, which is reduced by the LOAD mutations. Mechanistically, both LOAD mutations impaired the molecular chaperone activity of ADAM10 prodomain. Collectively, these findings suggest that diminished alpha secretase activity, owing to LOAD ADAM10 prodomain mutations, leads to AD-related pathology, strongly supporting ADAM10 as a promising therapeutic target for this devastating disease. PMID- 24055019 TI - Inhibitory effect of 9-hydroxy-6,7-dimethoxydalbergiquinol from Dalbergia odorifera on the NF-kappaB-related neuroinflammatory response in lipopolysaccharide-stimulated mouse BV2 microglial cells is mediated by heme oxygenase-1. AB - The heartwood of Dalbergia odorifera T. Chen (Leguminosae) is an important source of traditional Korean and Chinese medicines. 9-Hydroxy-6,7 dimethoxydalbergiquinol (HDDQ), a compound isolated from D. odorifera, has various biological activities. The aim of this study was to determine the efficacy of HDDQ in modulating the regulation of anti-inflammatory activity through the upregulation of heme oxygenase (HO)-1 in BV2 microglia. HDDQ inhibited the protein expression of inducible nitric oxide synthase (iNOS), iNOS derived nitric oxide (NO), and the production of cyclooxygenase (COX)-2 and COX-2 derived prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated mouse BV2 microglia. HDDQ also reduced tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) production, and suppressed the phosphorylation and degradation of IkappaB-alpha and the nuclear translocation of p65 in mouse BV2 microglia in response to LPS. Furthermore, HDDQ upregulated HO-1 expression via nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in mouse BV2 microglia. Using tin protoporphyrin (SnPP), an HO activity inhibitor, we verified that the inhibitory effects of HDDQ on the proinflammatory mediators NO, PGE2, TNF-alpha, and IL-1beta, and nuclear factor kappa B (NF-kappaB) DNA-binding activity are associated with the induction of HO-1 expression. Our data suggest that HDDQ has therapeutic potential against neurodegenerative diseases caused by neuroinflammation. PMID- 24055020 TI - Selective modulation of lymphoproliferation and cytokine production via intracellular signaling targets by alpha1- and alpha2-adrenoceptors and estrogen in splenocytes. AB - The mechanistic implications of the presence of sympathetic noradrenergic innervation in lymphoid organs in synaptic association with lymphocytes open to the influence of hormonal fluctuations throughout reproductive age in females has not been investigated yet. OBJECTIVES: The aim of the present study is to investigate the role of alpha-adrenoceptors (alpha-ARs) and estrogen in modulating immune responses in the spleen through intracellular signaling targets such as ERK 1/2, CREB, Akt, NF-kappaB. METHODS: Splenocytes from young Sprague Dawley rats were incubated with alpha1- and alpha2- AR specific agonists, phenylephrine and clonidine, without and with 17b-estradiol or specific antagonists prazosin and idazoxan to examine their effects on proliferation, cytokine production, nitric oxide production, and intracellular signaling molecules. RESULTS: alpha1-AR stimulation inhibited lymphocyte proliferation and IFN-g production and enhanced IL-2, p-ERK and p-CREB expression. Co-stimulation using estrogen enhanced cytokine production and suppressed p-Akt expression. alpha1-AR blockade reversed agonist-induced IL-2 production alone. alpha2-AR stimulation inhibited lymphocyte proliferation, p-ERK and p-CREB expression, and increased p-NF-kB and p-Akt expression. Co-stimulation with estrogen increased IL 2 and suppressed p-CREB expression. alpha2-AR Idazoxan prevented IL-2 production in the absence and presence of estrogen, and reversed clonidine-induced increase in NO production and p-ERK and p-Akt expression in the presence of estrogen. CONCLUSIONS: These results suggest that the cell-mediated immune responses are selectively modulated depending upon the subtypes of alpha-AR and further, these effects are differentially regulated in the presence of estrogen mediated through selective alteration in the intracellular signaling pathways involving ERK, CREB, Akt, and NF-kappaB. PMID- 24055021 TI - Effects of Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) pretreatment on septic rats. AB - To evaluate the effects of Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) injection on the survival rate of rats post cecal ligation and puncture (CLP), Sprague-Dawley (SD) rats were subcutaneously injected with 0.125 ml, 0.25 ml or 0.5 ml PA-MSHA for 8 days or 16 days before CLP. The survival rate and physiological appearance of rats in each group were monitored daily post CLP. The expression of Toll-like receptor 4 (TLR4) and cytokines related to inflammation was evaluated. We found that the 0.5 ml-8d (0.5 ml PA-MSHA injected for 8 days) group had the highest 7-day survival rate (91.7%), which was significantly improved compared with the CLP-only group (33.3%). Furthermore, our results showed that PA-MSHA effectively increased serum pro-inflammatory mediators (TNF alpha, IL-1beta and IL-6) at the early stage (8 days) but increased anti inflammatory mediators (IL-4 and IL-10) at the late stage (16 days). PA-MSHA significantly up-regulated the mRNA expression of TLR4 at 8 and 16 days. After PA MSHA pretreatment, CLP had no marked effect on the levels of most inflammatory factors. To explore potential protective mechanisms of PA-MSHA against CLP, we examined the effect of PA-MSHA on murine macrophage-like RAW264.7 cells and found that PA-MSHA induced endotoxin tolerance. In conclusion, this study suggested that precisely controlling the dosage and time of PA-MSHA administration can effectively increase the rat survival rate post CLP, which may be mediated through regulating inflammatory mediators and inducing endotoxin tolerance. PMID- 24055022 TI - Differential expression of alpha II spectrin in monocytes of tuberculosis patients. AB - Monocytes play a crucial role in immune response to tuberculosis. The present study focuses on identifying differences in the monocyte proteome profile of tuberculosis patients, household contacts and healthy controls. Differential protein expression was studied by two-dimensional (2D) gel electrophoresis. One of the spots consistently showed either lower intensity or was absent in patients and was identified as alpha II-spectrin. The decreased expression of alphaII spectrin was further validated by quantitative PCR (qPCR) and western blot analysis. This study suggests the possible role of decreased levels of alphaII spectrin in the pathology of tuberculosis. PMID- 24055023 TI - Ethical considerations in deep brain stimulation for psychiatric illness. AB - Deep brain stimulation (DBS) is an efficacious surgical treatment for many conditions, including obsessive-compulsive disorder and treatment-resistant depression. DBS provides a unique opportunity to not only ameliorate disease but also to study mood, cognition, and behavioral effects in the brain. However, there are many ethical questions that must be fully addressed in designing clinical research trials. It is crucial to maintain sound ethical boundaries in this new era so as to permit the proper testing of the potential therapeutic role DBS may play in ameliorating these devastating and frequently treatment refractory psychiatric disorders. In this review, we focus on the selection of patients for study, informed consent, clinical trial design, DBS in the pediatric population, concerns about intentionally or inadvertently altering an individual's personal identity, potential use of DBS for brain enhancement, direct modification of behavior through neuromodulation, and resource allocation. PMID- 24055024 TI - Ultraviolet reduction of erythromycin and tetracycline resistant heterotrophic bacteria and their resistance genes in municipal wastewater. AB - Antibiotic resistance in wastewater is becoming a major public health concern, but poorly understood about impact of disinfection on antibiotic resistant bacteria and antibiotic resistance genes. The UV disinfection of antibiotic resistant heterotrophic bacteria and their relevant genes in the wastewater of a municipal wastewater treatment plant has been evaluated. Two commonly used antibiotics, erythromycin and tetracycline were selected because of their wide occurrences in regard to the antibiotic resistance problem. After UV treatment at a fluence of 5mJcm(-2), the log reductions of heterotrophic bacteria resistant to erythromycin and tetracycline in the wastewater were found to be 1.4+/-0.1 and 1.1+/-0.1, respectively. The proportion of tetracycline-resistant bacteria (5%) was nearly double of that before UV disinfection (3%). Tetracycline-resistant bacteria exhibited more tolerance to UV irradiation compared to the erythromycin resistant bacteria (p<0.05). Gene copy numbers were quantified via qPCR and normalized to the volume of original sample. The total concentrations of erythromycin- and tetracycline-resistance genes were (3.6+/-0.2)*10(5) and (2.5+/ 0.1)*10(5) copies L(-1), respectively. UV treatment at a fluence of 5mJcm(-2) removed the total erythromycin- and tetracycline-resistance genes by 3.0+/-0.1 log and 1.9+/-0.1 log, respectively. UV treatment was effective in reducing antibiotic resistance in the wastewater. PMID- 24055025 TI - Theoretical investigation on photodechlorination mechanism of polychlorinated biphenyls. AB - Photodechlorination is a key process affecting the fate and effect of polychlorinated biphenyls (PCBs) in the environment. However, there are still numerous gaps in our knowledge, which become apparent in photodechlorination mechanism of PCBs. We investigated the conformations of 35 PCB congeners in the ground state and the first triplet excited state (T1), and predicted the photodechlorination pathway of the PCBs by calculating bond dissociation energies of the C-Cl bonds and activation energies of the C-Cl bond dissociation in the excited T1 state. Results show that the torsional degree of the two benzene rings of the PCBs depends on the number of ortho chlorines because of steric effect in the ground state. The two benzene rings of the PCBs with low photoreactivity tend to be coplanar and their torsional degree becomes lower in the excited T1 state compared with those in the ground state. The serious deformation and non-coplane of the benzene rings of some PCBs (e.g. PCB138) in the excited T1 state reduces the conjugation between the two benzene rings, implying that these PCBs have high photoreactivity. The dissociation of the C-Cl bond is the rate-determining step in the photodechlorination reactions of PCBs when the hydrogen donor is methanol. The main photodechlorination pathways predicted in this study are in good agreement with previous experimental results. Our results have provided new insights into mechanism of PCBs photodechlorination, which could be useful in the future in utilizing quantum chemistry calculation in investigating the environmental behavior and fate of organic pollutants. PMID- 24055026 TI - Polychlorinated dioxins, furans (PCDD/Fs), dioxin-like polychlorinated biphenyls (dl-PCBs) and indicator PCBs (ind-PCBs) in egg and egg products in Turkey. AB - The aim of the study is to determine concentrations of polychlorinated dibenzo-p dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), dioxin-like polychlorinated biphenyls (dl-PCBs) and indicator PCBs (ind-PCBs) in eggs from cage hens without soil contact, pasteurized egg samples and imported egg yolk powder samples in Turkey. Concentrations of PCDD/Fs, PCDD/Fs and dl-PCBs, and ind PCBs in eggs and pasteurized egg samples are in the range of 0.247-1.527 pg WHO TEQ(2005)g(-1) fat, 0.282-1.762 pg WHO-TEQ(2005)g(-1) fat and 202-1,235 pg g(-1) fat, respectively. For egg yolk powder samples, concentrations of PCDD/Fs, PCDD/Fs and dl-PCBs, and ind-PCBs are in the range of 0.122-0.494 pg WHO TEQ(2005)g(-1) fat, 0.214-0.640 pg WHO-TEQ(2005)g(-1) fat and 217-1,498 pg g(-1) fat, respectively. All results for PCDD/Fs, PCDD/Fs and dl-PCBs, and ind-PCBs are below the values of 2.5 pg WHO-TEQ(2005)g(-1) fat, 5.0 pg WHO-TEQ(2005)g(-1) fat and 40 ng g(-1) fat imposed in Turkish Regulation for eggs and egg products, respectively. In all samples 2,3,4,7,8-PeCDF, 2,3,7,8-TCDD, 1,2,3,7,8-PeCDD and PCB126 are the most prominent congeners. Mean estimated daily exposure to PCDD/Fs and dl-PCBs for Turkish population from egg is 0.011 pg WHO-TEQ(2005)d(-1)kg body weight (bw)(-1). Although the exposure levels are below the TDI of 2 pg WHO TEQ(1998)kg bw(-1), the results were based only on consumption of egg. In order to estimate total dietary intake for Turkish population, various food items should be investigated. PMID- 24055027 TI - The Vibrio campbellii quorum sensing signals have a different impact on virulence of the bacterium towards different crustacean hosts. AB - Pathogenic bacteria communicate with small signal molecules in a process called quorum sensing, and they often use different signal molecules to regulate virulence gene expression. Vibrio campbellii, one of the major pathogens of aquatic organisms, regulates virulence gene expression by a three channel quorum sensing system. Here we show that although they use a common signal transduction cascade, the signal molecules have a different impact on the virulence of the bacterium towards different hosts, i.e. the brine shrimp Artemia franciscana and the commercially important giant freshwater prawn Macrobrachium rosenbergii. These results suggest that the use of multiple types of signal molecules to regulate virulence gene expression is one of the features that allow bacteria to infect different hosts. Our findings emphasize that it is highly important to study the efficacy of quorum sensing inhibitors as novel biocontrol agents under conditions that are as close as possible to the clinical situation. PMID- 24055028 TI - Bjorn Lindman: fifty years in science and technology. AB - Bjorn Lindman has for fifty years had an active role in science and technology. His main contributions are briefly described. In the science part particular emphasis is put on his studies of ion binding, of amphiliphilc self-association, of molecular diffusion in solution and of polymer-surfactant systems. Furthermore we describe his role in introducing scientific areas, his role in scientific collaborations and his contributions to scientific organizations. The text is concluded by some personal reflections by the author. PMID- 24055029 TI - Principles of electrostatic interactions and self-assembly in lipid/peptide/DNA systems: applications to gene delivery. AB - Recently, great progress has been achieved in development of a wide variety of formulations for gene delivery in vitro and in vivo, which include lipids, peptides and DNA (LPD). Additionally, application of natural histone-DNA complexes (chromatin) in combination with transfection lipids has been suggested as a potential route for gene delivery (chromofection). However, the thermodynamic mechanisms responsible for formation of the ternary lipid-peptide DNA supramolecular structures have rarely been analyzed. Using recent experimental studies on LPD complexes (including mixtures of chromatin with cationic lipids) and general polyelectrolyte theory, we review and analyze the major determinants defining the internal structure, particle composition and size, surface charge and ultimately, transfection properties of the LPD formulations. PMID- 24055030 TI - MUC1 activates JNK1 and inhibits apoptosis under genotoxic stress. AB - The MUC1 transmembrane glycoprotein is aberrantly overexpressed in diverse human carcinomas and has been shown to inhibit apoptosis induced by genotoxic agents. In the present work, we report that MUC1 binds to and activates JNK1, an important member of the mitogen-activated protein kinases (MAPK) superfamily. The physical interaction between MUC1 cytoplasmic domain (MUC1-CD) and JNK1 was established by GST-pull-down assay in vitro and co-immunoprecipitation assay in vivo. We show that MUC1 activates JNK1 and inhibits cisplatin-induced apoptosis in human colon cancer HCT116 cells. Pharmacological inhibition of JNK or knockdown of JNK significantly reduces the ability of MUC1 to inhibit cisplatin induced apoptosis. Together, our data indicate that MUC1 can inhibit apoptosis via activating JNK1 pathway in response to genotoxic anticancer agents. PMID- 24055031 TI - A class II phosphoinositide 3-kinase plays an indispensable role in hepatitis C virus replication. AB - Phosphoinositides function as fundamental signaling molecules and play roles in diverse cellular processes. Certain types of viruses may employ host cell phosphoinositide signaling systems to facilitate their replication cycles. Here we demonstrate that the beta isoform of class II PI3K (PI3K-C2beta) plays an indispensable role in hepatitis C virus (HCV) propagation in human hepatocellular carcinoma cells. Knockdown of PI3K-C2beta abrogated HCV propagation in the cell. Using an HCV replicon system, we found that knockdown of PI3K-C2beta substantially repressed the full-genome replication, while showing relatively small reductions in sub-genome replication, in which structural proteins including core protein were deleted. We also found that HCV core protein showed the binding activity towards D4-phosphorylated phosphoinositides and overlapped localization with phosphatidylinositol 3,4-bisphosphate in the cell. These results suggest that the phosphoinositide generated by PI3K-C2beta plays an indispensable role in the HCV replication cycle through the binding to HCV core protein. PMID- 24055032 TI - Clinical significance of proliferation, apoptosis and senescence of nasopharyngeal cells by the simultaneously blocking EGF, IGF-1 receptors and Bcl xl genes. AB - BACKGROUND: In previous work, we constructed short hairpin RNA (shRNA) expression plasmids that targeted human EGF and IGF-1 receptors messenger RNA, respectively, and demonstrated that these vectors could induce apoptosis of human nasopharyngeal cell lines (CNE2) and inhibit ligand-induced pAkt and pErk activation. METHOD: We have constructed multiple shRNA expression vectors of targeting EGFR, IGF1R and Bcl-xl, which were transfected to the CNE2 cells. The mRNA expression was assessed by RT-PCR. The growth of the cells, cell cycle progression, apoptosis of the cells, senescent tumor cells and the proteins of EGFR, IGF1R and Bcl-xl were analyzed by MTT, flow cytometry, cytochemical therapy or Western blot. RESULTS: In group of simultaneously blocking EGFR, IGF1R and Bcl xl genes, the mRNA of EGFR, IGF1R and Bcl-xl expression was decreased by (66.66+/ 3.42)%, (73.97+/-2.83)% and (64.79+/-2.83)%, and the protein expressions was diminished to (67.69+/-4.02)%, (74.32+/-2.30)%, and (60.00+/-3.34)%, respectively. Meanwhile, the cell apoptosis increased by 65.32+/-0.18%, 65.16+/ 0.25% and 55.47+/-0.45%, and senescent cells increased by 1.42+/-0.15%, 2.26+/ 0.15% and 3.22+/-0.15% in the second, third and fourth day cultures, respectively. CONCLUSIONS: Simultaneously blocking EGFR, IGF1R and Bcl-xl genes is capable of altering the balance between proliferating versus apoptotic and senescent cells in the favor of both of apoptosis and senescence and, therefore, the tumor cells regression. PMID- 24055034 TI - Expression of aquaporin8 in human astrocytomas: correlation with pathologic grade. AB - Aquaporin8 (AQP8), a member of the aquaporin (AQP) protein family, is weakly distributed in mammalian brains. Previous studies on AQP8 have focused mainly on the digestive and the reproductive systems. AQP8 has a pivotal role in keeping the fluid and electrolyte balance. In this study, we investigated the expression changes of AQP8 in 75 cases of human brain astrocytic tumors using immunohistochemistry, Western blotting, and reverse transcription polymerase chain reaction. The results demonstrated that AQP8 was mainly distributed in the cytoplasm of astrocytoma cells. The expression levels and immunoreactive score of AQP8 protein and mRNA increased in low-grade astrocytomas, and further increased in high-grade astrocytomas, especially in glioblastoma. Therefore, AQP8 may contribute to the proliferation of astrocytomas, and may be a biomarker and candidate therapy target for patients with astrocytomas. PMID- 24055035 TI - WITHDRAWN: Down-regulation of long non-coding RNA TUG1 suppresses melanoma cell proliferation and induces apoptosis via up-regulating microRNA-9. AB - This article has been withdrawn at the request of the author. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 24055033 TI - Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropin beta gene promoter. AB - The MED1 subunit of the Mediator transcriptional coregulator complex is a nuclear receptor-specific coactivator. A negative feedback mechanism of thyroid stimulating hormone (TSH, or thyrotropin) expression in the thyrotroph in the presence of triiodothyronine (T3) is employed by liganded thyroid hormone receptor beta (TRbeta) on the TSHbeta gene promoter, where conventional histone modifying coactivators act as corepressors. We now provide evidence that MED1 is a ligand-dependent positive cofactor on this promoter. TSHbeta gene transcription was attenuated in MED1 mutant mice in which the nuclear receptor-binding ability of MED1 was specifically disrupted. MED1 stimulated GATA2- and Pit1-mediated TSHbeta gene promoter activity in a ligand-independent manner in cultured cells. MED1 also stimulated transcription from the TSHbeta gene promoter in a T3 dependent manner. The transcription was further enhanced when the T3-dependent corepressors SRC1, SRC2, and HDAC2 were downregulated. Hence, MED1 is a T3 dependent and -independent coactivator on the TSHbeta gene promoter. PMID- 24055036 TI - RSK2-induced stress tolerance enhances cell survival signals mediated by inhibition of GSK3beta activity. AB - Our previous studies demonstrated that RSK2 plays a key role in cell proliferation and transformation induced by tumor promoters such as epidermal growth factor (EGF) in mouse and human skin cells. However, no direct evidence has been found regarding the relationship of RSK2 and cell survival. In this study, we found that RSK2 interacted and phosphorylated GSK3beta at Ser9. Notably, GSK3beta phosphorylation at Ser9 was suppressed in RSK2(-/-) MEFs compared with RSK2(+/+) MEFs by stimulation of EGF and calcium ionophore A23187, a cellular calcium stressor. In proliferation, we found that RSK2 deficiency suppressed cell proliferation compared with RSK2(+/+) MEFs. In contrast, GSK3beta(-/-) MEFs induced the cell proliferation compared with GSK3beta(+/+) MEFs. Importantly, RSK2(-/-) MEFs were induced severe cellular morphology change by A23187 and enhanced G1/G0 and sub-G1 accumulation of the cell cycle phase compared with RSK2(+/+) MEFs. The sub-G1 induction in RSK2(-/-) MEFs by A23187 was correlated with increase of cytochrome c release, caspase-3 cleavage and apoptotic DNA fragmentation compared with RSK2(+/+) MEFs. Notably, return back of RSK2 into RSK2(-/-) MEFs restored A23187-induced morphological change, and decreased apoptosis, apoptotic DNA fragmentation and caspase-3 induction compared with RSK2(-/-)/mock MEFs. Taken together, our results demonstrated that RSK2 plays an important role in stress-tolerance and cell survival, resulting in cell proliferation and cancer development. PMID- 24055037 TI - Syntaxin-4 is essential for IgE secretion by plasma cells. AB - The humoral immune system provides a crucial first defense against the invasion of microbial pathogens via the secretion of antigen specific immunoglobulins (Ig). The secretion of Ig is carried out by terminally differentiated B lymphocytes called plasma cells. Despite the key role of plasma cells in the immune response, the mechanisms by which they constitutively traffic large volumes of Ig out of the cell is poorly understood. The involvement of Soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in the regulation of protein trafficking from cells has been well documented. Syntaxin-4, a member of the Qa SNARE syntaxin family has been implicated in fusion events at the plasma membrane in a number of cells in the immune system. In this work we show that knock-down of syntaxin-4 in the multiple myeloma U266 human plasma cell line results in a loss of IgE secretion and accumulation of IgE within the cells. Furthermore, we show that IgE co-localises with syntaxin-4 in U266 plasma cells suggesting direct involvement in secretion at the plasma membrane. This study demonstrates that syntaxin-4 plays a critical role in the secretion of IgE from plasma cells and sheds some light on the mechanisms by which these cells constitutively traffic vesicles to the surface for secretion. An understanding of this machinery may be beneficial in identifying potential therapeutic targets in multiple myeloma and autoimmune disease where over production of Ig leads to severe pathology in patients. PMID- 24055038 TI - Identification of the redox partners of ERdj5/JPDI, a PDI family member, from an animal tissue. AB - ERdj5 (also known as JPDI) is a member of PDI family conserved in higher eukaryotes. This protein possesses an N-terminal J domain and C-terminal four thioredoxin domains each having a redox active site motif. Despite the insights obtained at the cellular level on ERdj5, the role of this protein in vivo is still unclear. Here, we present a simple method to purify and identify the disulfide-linked complexes of this protein efficiently from a mouse tissue. By combining acid quenching and thiol-alkylation, we identified a number of potential redox partners of ERdj5 from the mouse epididymis. Further, we show that ERdj5 indeed interacted with two of the identified proteins via formation of intermolecular disulfide bond. Thus, this approach enabled us to detect and identify redox partners of a PDI family member from an animal tissue. PMID- 24055039 TI - Pathomechanism of intravertebral clefts in osteoporotic compression fractures of the spine. AB - BACKGROUND CONTEXT: Intravertebral cleft (IVC) associated with vertebral collapse is not uncommon in osteoporotic compression fracture. However, the pathomechanism of IVC is poorly understood. Bone ischemia is indicated in the current hypothesis. PURPOSE: To clarify the pathomechanism of IVC in delayed posttraumatic vertebral collapse, referred to as Kummell's disease. STUDY DESIGN: Magnetic resonance (MR) angiography and histology of segmental arteries and vertebral bodies in delayed posttraumatic vertebral collapse were investigated. PATIENT SAMPLE: All elderly patients admitted to the authors' spine clinic of tertiary referral center for a 105-month period. OUTCOME MEASURES: All imaging tests including plain radiographs, computed tomography, and MR angiography were reviewed by authors using a double-blind method. All operations were performed by one experienced surgeon. The statistical data were analyzed using SPSS program. METHODS: Evaluations using MR angiography and computed tomography were performed in 22 patients. Twelve of the 22 patients underwent corpectomy and anterior interbody fusion. At operation, segmental artery and bone surrounding IVC were harvested and microscopically evaluated. RESULTS: Magnetic resonance angiography showed occlusions of bilateral segmental arteries in nine of 22 patients. Seven patients had unilateral occlusion. In six patients, no occlusion was seen. Microscopically, the left segmental arteries of three patients were completely obstructed by thrombosis. Histologic examination of necrotic bone showed fragile trabecular bone and sparse osteocytes. CONCLUSIONS: The findings of thrombosis of the segmental arteries of the vertebral body with IVC could suggest a mechanism by which IVC is formed, and the progressive collapse may develop following osteoporotic spinal fracture. PMID- 24055040 TI - Cytoskeletal proteins participate in conserved viral strategies across kingdoms of life. AB - The discovery of tubulin-like cytoskeletal proteins carried on the genomes of bacteriophages that are actively used for phage propagation during both the lytic and lysogenic cycle have revealed that there at least two ways that viruses can utilize a cytoskeleton; co-opt the host cytoskeleton or bring their own homologues. Either strategy underscores the deep evolutionary relationship between viruses and cytoskeletal proteins and points to a conservation of viral strategies that crosses the kingdoms of life. Here we review some of the most recent discoveries about tubulin cytoskeletal elements encoded by phages and compare them to some of the strategies utilized by the gammaherpesvirues of mammalian cells. PMID- 24055041 TI - [Prevention of venous thromboembolic disease in the critical patient: an assessment of clinical practice in the Community of Madrid]. AB - OBJECTIVE: To analyze measures referred to venous thromboembolic prophylaxis in critically ill patients. DESIGN: An epidemiological, cross-sectional (prevalence cut), multicenter study was performed using an electronic survey. Comparison of results with quality indexes of the Spanish Society of Intensive Care Medicine, the American College of Chest Physician guidelines and international studies. SETTING: Intensive Care Units (ICUs) in the Community of Madrid (Spain). PATIENTS: All patients admitted to the ICU on the day of the survey. VARIABLES OF INTEREST: General aspects of venous thromboembolic prophylaxis and protocols used (risk stratification and ultrasound screening). A descriptive analysis was performed, continuous data being expressed as the mean or median, and categorical data as percentages. RESULTS: A total of 234 patients in 18 ICUs were included. Eighteen percent (42/234) received no prophylaxis, and 55% had no contraindication to pharmacological prophylaxis. Of the 192 patients receiving prophylaxis, 84% received pharmacological prophylaxis, 14% mechanical prophylaxis and 2% combined prophylaxis. Low molecular weight heparin was the only pharmacological prophylaxis used, with a majority use of enoxaparin (17 of 18 ICUs). In patients with mechanical prophylaxis (31/192), antiembolic stockings were the most commonly used option (58%). Pharmacological prophylaxis contraindications were reported in 20% of the patients (46/234), the most frequent cause being thrombocytopenia (28% of the cases). Fifty percent of the ICUs used no specific venous thromboembolic prophylaxis protocol. CONCLUSIONS: Pharmacological prophylaxis with low molecular weight heparin was the most frequently used venous thromboembolic prophylactic measure. In patients with contraindications to pharmacological prophylaxis, mechanical measures were little used. The use of combined prophylaxis was anecdotal. Many of our ICUs lack specific prophylaxis protocols. PMID- 24055042 TI - Association between subjective and cortisol stress response depends on the menstrual cycle phase. AB - The relation between the physiologic and subjective stress responses is inconsistently reported across studies. Menstrual cycle phases variations have been found to influence the psychophysiological stress response; however little is known about possible cycle phase differences in the relationship between physiological and subjective stress responses. This study examined the effect of menstrual cycle phase in the association between subjective stress and physiological response. Forty-five women in either the follicular (n=21) or the luteal phase of the menstrual cycle were exposed to a psychosocial stress task. Salivary cortisol, cardiovascular, and subjective stress were assessed throughout the experiment. Results revealed a significant group difference in the association between peak levels of cortisol and post task subjective stress. In women in the follicular phase a negative association was observed (r(2)=0.199, p=0.04), while this relation was positive in the group of women in the luteal phase (r(2)=0.227, p=0.02). These findings suggest a possible role of sex hormones in modulating the cortisol stress response function in emotion regulation. PMID- 24055043 TI - ALK1-Smad1/5 signaling pathway in fibrosis development: friend or foe? AB - Fibrosis is a common phenomenon associated with several pathologies, characterized by an excessive extracellular matrix deposition that leads to a progressive organ dysfunction. Thus fibrosis has a relevant role in chronic diseases affecting the kidney, the liver, lung, skin (scleroderma) and joints (arthritis), among others. The pathogenesis of fibrosis in different organs share numerous similarities, being one of them the presence of activated fibroblasts, denominated myofibroblast, which act as the main source of extracellular matrix proteins. Transforming growth factor beta-1 (TGF-beta1) is a profibrotic cytokine that plays a pivotal role in fibrosis. The TGF-beta1/ALK5/Smad3 signaling pathway has been studied in fibrosis extensively. However, an increasing number of studies involving the ALK1/Smad1 pathway in the fibrotic process exist. In this review we offer a perspective of the function of ALK1/Smad1 pathway in renal fibrosis, liver fibrosis, scleroderma and osteoarthritis, suggesting this pathway as a powerful therapeutical target. We also propose several strategies to modulate the activity of this pathway and its consequences in the fibrotic process. PMID- 24055044 TI - Triphenylphosphonium salts of 1,2,4-benzothiadiazine 1,1-dioxides related to diazoxide targeting mitochondrial ATP-sensitive potassium channels. AB - The present work aims at identifying new ion channel modulators able to target mitochondrial ATP-sensitive potassium channels (mitoKATP channels). An innovative approach should consist in fixing a cationic and hydrophobic triphenylphosphonium fragment on the structure of known KATP channel openers. Such phosphonium salts are expected to cross the biological membranes and to accumulate into mitochondria. Previous works revealed that the presence of an (R)-1-hydroxy-2 propylamino chain at the 3-position of 4H-1,2,4-benzothiadiazine 1,1-dioxides KATP channel openers increased, in most cases, the selectivity towards the pancreatic-type (SUR1/Kir6.2) KATP channel. In order to target cardiac mitoKATP channels, we decided to introduce a triphenylphosphonium group through an ester link on the SUR1-selective (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4 benzothiadiazine 1,1-dioxide. The new compounds were found to preserve an inhibitory activity on insulin secretion (SUR1-type KATP channel openers) while no clear demonstration of an impact on mitochondria from cardiomyocytes (measurement of oxygen consumption, respiratory parameters and ATP production on H9C2 cells) was observed. However, the most active (inhibition of insulin release) compound 17 was found to penetrate the cardiac cells and to reach mitochondria. PMID- 24055045 TI - Rate-adjusted cross-linking reaction by photoresponsive alpha-bromoaldehyde (PBA) conjugated ODN. AB - We developed a photoresponsive alpha-bromoaldehyde-conjugated oligonucleotide (PBA-ODN). The PBA-ODN selectively reacted and formed covalent bonds with target oligonucleotides having adenine or cytosine at the frontal position of the aldehyde derivative. Kinetic studies revealed that PBA-ODN has increased kinetic rates for the formation of cross-linked duplexes compared with the corresponding alpha-chloroaldehyde-conjugated oligonucleotide (PCA-ODN). PMID- 24055046 TI - Synthesis and biological evaluation of 1,2,4-trisubstituted imidazoles as inhibitors of transforming growth factor-beta type I receptor (ALK5). AB - A series of 2-(6-methylpyridin-2-yl)-1H-imidazoles were synthesized and evaluated for ALK5 inhibitory activity in cell-based luciferase reporter assays. The compound 4-(((1-(benzo[d][1,3]dioxol-5-yl)-2-(6-methylpyridin-2-yl)-1H-imidazol-4 yl)methyl)amino)benzenesulfonamide (27a) exhibited slightly higher inhibition (IC50=0.24MUM) than SB431542 (IC50=0.35MUM), a well known potent ALK5 inhibitor. The binding mode of 27a generated by flexible docking study shows that it fits well into the site cavity of ALK5 by forming several tight interactions. PMID- 24055047 TI - Synthesis of 15-methylene-eburnamonine from (+)-vincamine, evaluation of anticancer activity, and investigation of mechanism of action by quantitative NMR. AB - The biological role of installing a critical exocyclic enone into the structure of the alkaloid, (-)-eburnamonine, and characterization of the new chemical reactivity by quantitative NMR without using deuterated solvents are described. This selective modification to a natural product imparts potent anticancer activity as well as bestows chemical reactivity toward nucleophilic thiols, which was measured by quantitative NMR. The synthetic strategy provides an overall conversion of 40%. In the key synthetic step, a modified Peterson olefination was accomplished through the facile release of trifluoroacetate to create the requisite enone in the presence of substantial steric hindrance. PMID- 24055048 TI - The effectiveness of gonadotropin-releasing hormone antagonist in poor ovarian responders undergoing in vitro fertilization: a systematic review and meta analysis. AB - OBJECTIVE: To evaluate the effectiveness of gonadotropin-releasing hormone (GnRH) antagonist in poor ovarian responders undergoing in vitro fertilization (IVF). DESIGN: Systematic review and meta-analysis. SETTING: Affiliated hospital with a medical university. PATIENT(S): None. INTERVENTION(S): Electronic search. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate, number of oocytes retrieved, cycle cancellation rate. RESULT(S): A total of 12 published studies (1,332 cases) were included. Both the stimulation period (mean difference [MD], -0.43; 95% confidence interval [CI], -0.68 to -0.17) and the gonadotropin dosage (MD, -5.41; 95% CI, -7.51 to -3.31) were statistically significantly lower in the GnRH antagonist protocol than in the long GnRH agonist protocol. Both the endometrial thickness (MD -0.45; 95% CI, -0.76 to -0.13) and estrogen (E2) level on the day of hCG administration (MD, -1,299.15; 95% CI, -1,716.34 to -881.95) were statistically significantly lower in the GnRH antagonist protocol than the GnRH agonist protocol. Fewer oocytes were retrieved for the GnRH antagonist protocol than the long GnRH agonist protocol (MD, -0.34; 95% CI, -0.54 to -0.13) or the short GnRH agonist protocol (MD, -0.54; 95% CI, -0.9, 8 to -0.10). The cycle cancellation and clinical pregnancy rates were not statistically significantly different between the two groups. CONCLUSION(S): Compared with GnRH agonist protocols, the GnRH antagonist protocol is associated with fewer oocytes retrieved, lower E2 levels, and thinner endometrium whereas the clinical pregnancy and cycle cancellation rates are similar. PMID- 24055049 TI - Association of blood type and patient characteristics with ovarian reserve. AB - OBJECTIVE: To assess whether blood type was associated with diminished ovarian reserve (DOR) (day-3 follicle-stimulating hormone level >10 IU/L), controlling for history of tobacco smoking, body mass index (BMI), history of endometriosis, ovarian surgery, previous pregnancy, and maternal age. DESIGN: Cross-sectional study. SETTING: Academic medical center, Division of Reproductive Endocrinology and Infertility. PATIENT(S): Women undergoing in vitro fertilization (IVF) from 2006-2011 (n = 305). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Presence of DOR in relation to a patient's blood type. RESULT(S): Other investigators have reported an increased risk for DOR in patients with blood type O and a protective effect on ovarian reserve for blood type A. We observed no association between a woman's blood type and DOR. We found an increased risk for DOR in patients aged 35 and older. Obesity (BMI >= 30 vs. BMI <25) was associated with lower odds of DOR. CONCLUSION(S): In comparison with blood type A, blood type O is not associated with an increase in DOR. We found no clinical implications for using blood type as a risk factor for DOR. PMID- 24055050 TI - Safety and feasibility of performing two consecutive ovarian stimulation cycles with the use of letrozole-gonadotropin protocol for fertility preservation in breast cancer patients. AB - OBJECTIVE: To investigate the safety and feasibility of performing two consecutive ovarian stimulation cycles with the use of letrozole protocol for fertility preservation in breast cancer patients. DESIGN: Retrospective cohort study. SETTING: Academic fertility preservation center. PATIENT(S): Seventy-eight women <= 45 years, diagnosed with stage <= 3 breast cancer, who desired fertility preservation. INTERVENTION(S): Two consecutive cycles versus a single ovarian stimulation cycle with a letrozole-follicle-stimulating hormone (FSH) protocol. MAIN OUTCOME MEASURE(S): Embryo or oocyte cryopreservation outcomes, time interval from surgery to chemotherapy, and breast cancer recurrence rates. RESULT(S): Sixty-one patients underwent single-cycle stimulation and 17 received two stimulation cycles. The mean total number of oocytes harvested (16.1 +/- 13.2 vs. 9.1 +/- 5.2) and embryos generated (6.4 +/- 2.9 vs. 3.7 +/- 3.1) were statistically significantly higher in patients who underwent two cycles versus one cycle. The time interval from surgery to chemotherapy was similar between the two-cycle and single-cycle groups (63.7 +/- 7.7 vs. 58.0 +/- 12.1 days). After a mean follow-up interval of 58.5 +/- 13.6 months, the recurrence rates were similar between the two-cycle (0 of 17) and single-cycle (2 of 49) patients. CONCLUSION(S): It appears to be safe and feasible to perform two consecutive ovarian stimulation cycles to increase the oocyte/embryo yield for fertility preservation. PMID- 24055051 TI - Live birth after uterine transplantation remains challenging. PMID- 24055053 TI - Stearoyl CoA desaturase is required to produce active, lipid-modified Wnt proteins. AB - Wnt proteins contain palmitoleic acid, an unusual lipid modification. Production of an active Wnt signal requires the acyltransferase Porcupine and depends on the attachment of palmitoleic acid to Wnt. The source of this monounsaturated fatty acid has not been identified, and it is not known how Porcupine recognizes its substrate and whether desaturation occurs before or after fatty acid transfer to Wnt. Here, we show that stearoyl desaturase (SCD) generates a monounsaturated fatty acid substrate that is then transferred by Porcupine to Wnt. Treatment of cells with SCD inhibitors blocked incorporation of palmitate analogs into Wnt3a and Wnt5a and reduced Wnt secretion as well as autocrine and paracrine Wnt signaling. The SCD inhibitor effects were rescued by exogenous addition of monounsaturated fatty acids. We propose that SCD is a key molecular player responsible for Wnt biogenesis and processing and that SCD inhibition provides an alternative mechanism for blocking Wnt pathway activation. PMID- 24055054 TI - Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. AB - Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it. PMID- 24055056 TI - Addiction of t(8;21) and inv(16) acute myeloid leukemia to native RUNX1. AB - The t(8;21) and inv(16) chromosomal aberrations generate the oncoproteins AML1 ETO (A-E) and CBFbeta-SMMHC (C-S). The role of these oncoproteins in acute myeloid leukemia (AML) etiology has been well studied. Conversely, the function of native RUNX1 in promoting A-E- and C-S-mediated leukemias has remained elusive. We show that wild-type RUNX1 is required for the survival of t(8;21) Kasumi-1 and inv(16)-ME-1 leukemic cells. RUNX1 knockdown in Kasumi-1 cells (Kasumi-1(RX1-KD)) attenuates the cell-cycle mitotic checkpoint, leading to apoptosis, whereas knockdown of A-E in Kasumi-1(RX1-KD) rescues these cells. Mechanistically, a delicate RUNX1/A-E balance involving competition for common genomic sites that regulate RUNX1/A-E targets sustains the malignant cell phenotype. The broad medical significance of this leukemic cell addiction to native RUNX1 is underscored by clinical data showing that an active RUNX1 allele is usually preserved in both t(8;21) or inv(16) AML patients, whereas RUNX1 is frequently inactivated in other forms of leukemia. Thus, RUNX1 and its mitotic control targets are potential candidates for new therapeutic approaches. PMID- 24055057 TI - Heterochromatin reorganization during early mouse development requires a single stranded noncoding transcript. AB - The equalization of pericentric heterochromatin from distinct parental origins following fertilization is essential for genome function and development. The recent implication of noncoding transcripts in this process raises questions regarding the connection between RNA and the nuclear organization of distinct chromatin environments. Our study addresses the interrelationship between replication and transcription of the two parental pericentric heterochromatin (PHC) domains and their reorganization during early embryonic development. We demonstrate that the replication of PHC is dispensable for its clustering at the late two-cell stage. In contrast, using parthenogenetic embryos, we show that pericentric transcripts are essential for this reorganization independent of the chromatin marks associated with the PHC domains. Finally, our discovery that only reverse pericentric transcripts are required for both the nuclear reorganization of PHC and development beyond the two-cell stage challenges current views on heterochromatin organization. PMID- 24055055 TI - Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. AB - To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation. PMID- 24055058 TI - Double-stranded RNA-binding protein 4 is required for resistance signaling against viral and bacterial pathogens. AB - Plant viruses often encode suppressors of host RNA silencing machinery, which occasionally function as avirulence factors that are recognized by host resistance (R) proteins. For example, the Arabidopsis R protein, hypersensitive response to TCV (HRT), recognizes the turnip crinkle virus (TCV) coat protein (CP). HRT-mediated resistance requires the RNA-silencing component double stranded RNA-binding protein 4 (DRB4) even though it neither is associated with the accumulation of TCV-specific small RNA nor requires the RNA silencing suppressor function of CP. HRT interacts with the cytosolic fraction of DRB4. Interestingly, TCV infection both increases the cytosolic DRB4 pool and inhibits the HRT-DRB4 interaction. The virulent R8A CP derivative, which induces a subset of HRT-derived responses, also disrupts this interaction. The differential localization of DRB4 in the presence of wild-type and R8A CP implies the importance of subcellular compartmentalization of DRB4. The requirement of DRB4 in resistance to bacterial infection suggests a universal role in R-mediated defense signaling. PMID- 24055060 TI - Membrane-sculpting BAR domains generate stable lipid microdomains. AB - Bin-Amphiphysin-Rvs (BAR) domain proteins are central regulators of many cellular processes involving membrane dynamics. BAR domains sculpt phosphoinositide-rich membranes to generate membrane protrusions or invaginations. Here, we report that, in addition to regulating membrane geometry, BAR domains can generate extremely stable lipid microdomains by "freezing" phosphoinositide dynamics. This is a general feature of BAR domains, because the yeast endocytic BAR and Fes/CIP4 homology BAR (F-BAR) domains, the inverse BAR domain of Pinkbar, and the eisosomal BAR protein Lsp1 induced phosphoinositide clustering and halted lipid diffusion, despite differences in mechanisms of membrane interactions. Lsp1 displays comparable low diffusion rates in vitro and in vivo, suggesting that BAR domain proteins also generate stable phosphoinositide microdomains in cells. These results uncover a conserved role for BAR superfamily proteins in regulating lipid dynamics within membranes. Stable microdomains induced by BAR domain scaffolds and specific lipids can generate phase boundaries and diffusion barriers, which may have profound impacts on diverse cellular processes. PMID- 24055059 TI - In vivo T-box transcription factor profiling reveals joint regulation of embryonic neuromesodermal bipotency. AB - The design of effective cell replacement therapies requires detailed knowledge of how embryonic stem cells form primary tissues, such as mesoderm or neurectoderm that later become skeletal muscle or nervous system. Members of the T-box transcription factor family are key in the formation of these primary tissues, but their underlying molecular activities are poorly understood. Here, we define in vivo genome-wide regulatory inputs of the T-box proteins Brachyury, Eomesodermin, and VegT, which together maintain neuromesodermal stem cells and determine their bipotential fates in frog embryos. These T-box proteins are all recruited to the same genomic recognition sites, from where they activate genes involved in stem cell maintenance and mesoderm formation while repressing neurogenic genes. Consequently, their loss causes embryos to form an oversized neural tube with no mesodermal derivatives. This collaboration between T-box family members thus ensures the continuous formation of correctly proportioned neural and mesodermal tissues in vertebrate embryos during axial elongation. PMID- 24055061 TI - IL-15 cis presentation is required for optimal NK cell activation in lipopolysaccharide-mediated inflammatory conditions. AB - Natural killer (NK) cells have antitumor, antiviral, and antibacterial functions, and efforts are being made to manipulate them in immunotherapeutic approaches. However, their activation mechanisms remain poorly defined, particularly during bacterial infections. Here, we show that upon lipopolysaccharide or E. coli exposure, dendritic cells (DCs) produce three cytokines-interleukin 2 (IL-2), IL 18, and interferon beta (IFN-beta)-necessary and sufficient for NK cell activation. IFN-beta enhances NK cell activation by inducing IL-15 and IL-15 receptor alpha not only in DCs but, surprisingly, also in NK cells. This process allows the transfer of IL-15 on NK cell surface and its cis presentation. cis presented NK cell-derived and trans-presented DC-derived IL-15 contribute equally to optimal NK cell activation. PMID- 24055062 TI - Characterization and analysis of the composition and dynamics of the mammalian riboproteome. AB - Increasing evidence points to an important role for the ribosome in the regulation of biological processes and as a target for deregulation in disease. Here, we describe a SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry approach to probing mammalian riboproteomes. Using a panel of cell lines, as well as genetic and pharmacological perturbations, we obtained a comparative characterization of the cellular riboproteome. This analysis identified a set of riboproteome components, consisting of a diverse array of proteins with a strong enrichment for RNA binding proteins. Importantly, this global analysis uncovers a high incidence of genetic alterations to riboproteome components in cancer, with a distinct bias toward genetic amplification. We further validated association with polyribosomes for several riboproteome components and demonstrate that enrichment at the riboproteome can depend on cell type, genetics, or cellular stimulus. Our results have important implications for the understanding of how ribosomes function and provide a platform for uncovering regulators of translation. PMID- 24055063 TI - Autoimmune polyendocrine syndromes. AB - Autoimmune polyendocrine syndromes (APS), also called polyglandular autoimmune syndromes (PGAS), are a heterogeneous group of rare diseases characterized by autoimmune activity against more than one endocrine organs, although non endocrine organs can be affected. The two major autoimmune polyendocrine syndromes, (type1-type2/APS-1 and APS-2), both have Addison's disease as a prominent component. Further autoimmune polyendocrine syndromes include APS3 and APS4. The major autoimmune polyendocrine syndromes have a strong genetic component with the type 2 syndrome occurring in multiple generations and the type I syndrome in siblings. It is well recognized that more than 20years may elapse between the onset on one endocrinopathy and the diagnosis of the next, for example, almost 40-50% of subjects with Addison's disease will develop an associated endocrinopathy. The discovery of the polyendocrine autoimmune syndromes offered the possibility to understand autoimmune disorders with particular interest for type 1A diabetes and the neuroendocrine immunology (NEI) is further contributing to understand the links. PMID- 24055064 TI - Pharmacokinetics. AB - Pharmacokinetics (PK) is the study of the time course of the absorption, distribution, metabolism and excretion (ADME) of a drug, compound or new chemical entity (NCE) after its administration to the body. Following a brief introduction as to why knowledge of the PK properties of an NCE is critical to its selection as a lead candidate in a drug discovery program and/or its use as a functional research tool, the present article presents an overview of PK principles, including practical guidelines for conducting PK studies as well as the equations required for characterizing and understanding the PK of an NCE and its metabolite(s). A review of the determination of in vivo PK parameters by non compartmental and compartmental methods is followed by a brief overview of allometric scaling. Compound absorption and permeability are discussed in the context of intestinal absorption and brain penetration. The volume of distribution and plasma protein and tissue binding are covered as is the clearance (systemic, hepatic, renal, biliary) of both small and large molecules. A section on metabolite kinetics describes how to estimate the PK parameters of a metabolite following administration of an NCE. Lastly, mathematical models used to describe pharmacodynamics (PD), the relationship between the NCE/compound concentration at the site of action and the resulting effect, are reviewed and linked to PK models in a section on PK/PD. PMID- 24055065 TI - Risk factors for pericardial effusion in native valve infective endocarditis and its influence on outcome. AB - Data on the incidence, associated factors, and prognosis of pericardial effusion (PE) in patients with infective endocarditis (IE) are scarce. Patients with native valve IE were prospectively followed in our center from 1990 to 2007. A logistic regression analysis was performed to identify independent variables associated with PE and mortality. We included 479 episodes of IE from 459 patients (70% men, mean age 51 years). Small-to-moderate PE was observed in 109 episodes (23%) and large-to-very large PE was observed in 9 episodes (2%). Patients with small-to-moderate PE had a greater prevalence of intravenous drug use (38% vs 23%) and more frequent right-sided IE than patients without PE (33% vs 17%). Patients with large-to-very large PE had a higher rate of systemic emboli (22% vs 18%) and periannular abscess (22% vs 6%) than patients without PE. Renal failure was associated with a higher risk of PE (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.3 to 3.3); age was associated with a lower risk of PE (OR 0.98, 95% CI 0.97 to 0.99). One-year mortality of patients with IE with large to-very large PE was higher than that of patients with small-to-moderate and absence of PE (56%, 18%, and 24%, respectively, p = 0.033). Large-to-very large PE increases the 1-year mortality of IE (OR 3.0, 95% CI 1.2 to 7.9). In conclusion, renal failure and younger age are associated with a higher risk of PE. Large-to-very large PE was associated with an increase in 1-year mortality. PMID- 24055067 TI - CD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs. AB - CD4(+) helper T cells orchestrate protective immunity against pathogens, yet can also induce undesired pathologies including allergies, transplant rejection and autoimmunity. Non-depleting CD4-specific antibodies such as clone YTS177.9 were found to promote long-lasting T cell tolerance in animal models. Thus, CD4 blockade could represent a promising therapeutic approach for human autoimmune diseases. However, the mechanisms underlying anti-CD4-induced tolerance are incompletely resolved. Particularly, multiple immune cells express CD4 including Foxp3(+) regulatory T cells (Tregs) and dendritic cells (DCs), both controlling the activation of CD4(+)Foxp3(-) helper T cells. Utilizing mixed leukocyte reactions (MLRs) reflecting physiological interactions between T cells and DCs, we report that anti-CD4 treatment inhibits CD4(+)Foxp3(-) T cell proliferation in an IL-2-independent fashion. Notably, YTS177.9 binding induces a rapid internalization of CD4 on both CD4(+)Foxp3(-) T cells and Foxp3(+) Tregs. However, no expansion or activation of immunosuppressive CD4(+)Foxp3(+) Tregs was observed following anti-CD4 treatment. Additionally, cytokine production, maturation and T cell priming capacity of DCs are not affected by anti-CD4 exposure. In line with these data, the selective ablation of Foxp3(+) Tregs from MLRs by the use of diphtheria toxin (DT)-treated bacterial artificial chromosome (BAC)-transgenic DEREG mice completely fails to abrogate the suppressive activity of multiple anti-CD4 antibodies. Instead, tolerization is associated with the defective expression of various co-stimulatory receptors including OX40 and CD30, suggesting altered signaling through the TCR complex. Consistent with our findings in mice, anti-CD4 treatment renders human CD4(+) T cells tolerant in the absence of Tregs. Thus, our results establish that anti-CD4 antibodies can directly tolerize pathogenic CD4(+)Foxp3(-) helper T cells. This has important implications for the treatment of human inflammatory diseases. PMID- 24055066 TI - Major and minor electrocardiographic abnormalities and their association with underlying cardiovascular disease and risk factors in Hispanics/Latinos (from the Hispanic Community Health Study/Study of Latinos). AB - The association of electrocardiographic (ECG) abnormalities with cardiovascular disease and risk factors has been extensively studied in whites and African Americans. Comparable data have not been reported in Hispanics/Latinos. The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multicenter, community-based, prospective cohort study of men and women of diverse backgrounds aged 18 to 74 years who self-identified as Hispanic/Latinos. Participants (n = 16,415) enrolled from March 2008 to June 2011. We describe the prevalence of minor and major ECG abnormalities and examined their cross-sectional associations with cardiovascular disease and risk factors. The Minnesota code criteria were used to define minor and major ECG abnormalities. Previous cardiovascular disease and risk factors were based on data obtained at baseline examination. Significant differences in prevalent ECG findings were found between men and women. Major ECG abnormalities were present in 9.2% (95% confidence interval 8.3 to 10.1) of men and 6.6% (95% confidence interval 5.8 to 7.3) of women (p <0.0001). The odds of having major ECG abnormalities significantly increased with age, presence of >=3 cardiovascular risk factors, and prevalent cardiovascular disease, in both men and women. Significant differences in major ECG abnormalities were found among the varying groups; Puerto Ricans and Dominicans had more major abnormalities compared with Mexican men and women. In conclusion, in a large cohort of Hispanic/Latino men and women, prevalence of major abnormalities was low, yet strong associations of major ECG abnormalities with cardiovascular disease and risk factors were observed in both men and women. PMID- 24055068 TI - The effect of low larkspur (Delphinium spp.) co-administration on the acute toxicity of death camas (Zigadenus spp.) in sheep. AB - In most cases where livestock are poisoned by plants in a range setting, there is more than one potential poisonous plant in the same area. Two poisonous plants that are often found growing simultaneously in the same location are death camas (Zigadenus spp.) and low larkspur (Delphinium spp.). Sheep are known to be susceptible to death camas poisoning while they are thought to be resistant to larkspur. The objective of this study was to determine if co-administration of low larkspur would exacerbate the toxicity of death camas in sheep. A dose finding study was performed to find a dose of death camas that caused minimal clinical signs of poisoning. Sheep were observed for clinical signs of poisoning as well as changes in heart rate and muscle fatigue. Sheep dosed with 1.14 g of death camas per kg BW showed slight frothing and lethargy, whereas sheep dosed with death camas and low larkspur showed slightly more noticeable clinical signs of poisoning. Sheep dosed with only low larkspur, at 7.8 g/kg BW, showed no signs of poisoning. Although we observed a qualitative difference in clinical signs of intoxication in sheep co-treated with death camas and low larkspur we did not detect any quantitative differences in heart rate, exercise-induced muscle fatigue, or differences in serum zygacine kinetics. Consequently, the results from this study suggest that low larkspur does not affect the toxicity of death camas in sheep. The results from this study increase knowledge and understanding regarding the acute toxicity of death camas and low larkspur in sheep. As combined intoxications are most likely common, this information will be useful in further developing management recommendations for ranchers and in designing additional experiments to study the toxicity of death camas to other livestock species. PMID- 24055069 TI - The production of monovalent and anti-idiotype antivenom against Mesobuthus eupeus (Scorpionida: Buthidae) venom in rabbits. AB - The antivenom production against poisonous creatures encounters a number of difficulties. Interestingly, according to the network theory the conventional antigens are not necessarily needed for producing antibodies against the venoms. In this investigation, the antivenom against Mesobuthus eupeus venom was produced based on the aforementioned theory. Polyclonal antibodies against M. eupeus venom were obtained from the immunized rabbits and the specific antibodies were isolated. After separation of Fab2, immunization process and production of the monovalent and anti-idiotype, these antivenoms were analyzed for the determination of their neutralizing power. The level of the produced antibodies in different stages of this study was also measured by ELISA assay. Four hundred and fifty micrograms of the venom can be neutralized by 4.2, 18 and 291 mg of monovalent, polyvalent and anti-idiotype antivenom, respectively. The ELISA results revealed that idiotypic antigens were six times more immunogenic than anti-idiotypes. The anti-idiotype antivenom can be produced on a large scale with minimum venom consumption. In addition, they are non-toxicant in immunized animals and can be used as a vaccine in people at the risk of scorpion stings. PMID- 24055070 TI - Pediatric brucellosis: a case study. PMID- 24055071 TI - Coverage of palliative and hospice care for pediatric patients with a life limiting illness: a policy brief. PMID- 24055073 TI - Special issue in Hearing Research: human auditory neuroimaging. PMID- 24055072 TI - Implementation of family-based treatment for adolescents with anorexia nervosa. AB - Although the implementation of new treatment models can be a challenging process for health care services, the outcomes can be greatly beneficial to patients and service providers. This article describes the process of change experienced within our multidisciplinary specialist eating disorder service when we implemented a new evidence-based model of care focusing on outpatient family based treatment (FBT). Clinical outcomes were positive, including a 56% decrease in admissions, a 75% decrease in readmissions, and a 51% decrease in total bed days. Of families referred to FBT, 83% completed treatment and 97% of completers achieved >90% of their expected body weight. Despite these gains, many challenges were experienced, including misgivings about the suitability of FBT and difficulties in adhering to changes in professional roles. We describe these challenges, describe how they were overcome, and review factors perceived to be critical to the program's success, including integration of medical and mental health services, communication, and training. PMID- 24055074 TI - Identification of protein binding partners of ALK-5 kinase inhibitors. AB - We have investigated the binding characteristics of a potent member of the bis ortho-substituted five-membered nitrogen heterocycle class of ALK-5 kinase inhibitors with lysates of cultured HEK-293 cells to identify protein binding partners of potential biological significance. An affinity chromatographic resin containing an immobilized ALK-5 kinase inhibitor, 2-phenyl-4-[3-(pyridin-2-yl)-1H pyrazol-4-yl]pyridine, was used to capture specific proteins from the cell lysate. The soluble inhibitor was then used to specifically elute the proteins which selectively bound to the pharmacophore ligand structure. Application of 2-D SDS-PAGE analysis with positive and negative controls demonstrated the inhibitor bound several different proteins via selective molecular recognition processes. The structural features of the specifically eluted proteins were identified by peptide mass fingerprinting (PMF) methods and included proteins with structural, metabolic and chaperone functions. Furthermore, these PMF results identified the therapeutic target in various cancer treatment studies, HSP-70, as a potential high-affinity binding partner. These observations warrant examination of bis ortho-substituted five-membered nitrogen heterocycles as dual ALK-5/HSP-70 inhibitors for anti-cancer drug development. PMID- 24055075 TI - Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro-1'H spiro[chromene-2,4'-piperidine]-1'-carboxamides as TRPM8 antagonists. AB - A novel series of N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1' carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in vitro potency were studied. The effects of selected functional groups on the 4 position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that (R)-(-)-isomers were in general more potent than the corresponding (S)-(+)-isomers. The isomer (R)-(-) 10e (IC50: 8.9nM) showed a good pharmacokinetic profile upon oral dosing at 10mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain. PMID- 24055077 TI - Towards new C6-rigid S-DABO HIV-1 reverse transcriptase inhibitors: synthesis, biological investigation and molecular modeling studies. AB - A series of C6-rigid S-DABO analogs characterized by a substituted benzoyl group at C6 position of the pyrimidine ring has been synthesized and biological evaluation as NNRTIs against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 as well as HIV-2 strain ROD in MT-4 cell cultures. Most of the compounds exhibited moderate antiviral activities. Among them, compound 7q displayed the highest anti-HIV-1 activity with an EC50 value of 0.26MUM and a selectivity index (SI) of 541. The preliminary structure-activity relationship (SAR) of these new S-DABOs was investigated, the target RT was confirmed and docking study was performed. PMID- 24055076 TI - Binding mode characterization of 6alpha- and 6beta-N-heterocyclic substituted naltrexamine derivatives via docking in opioid receptor crystal structures and site-directed mutagenesis studies: application of the 'message-address' concept in development of mu opioid receptor selective antagonists. AB - Highly selective opioid receptor antagonists are essential pharmacological probes in opioid receptor structural characterization and opioid agonist functional studies. Currently, there is no highly selective, nonpeptidyl and reversible mu opioid receptor antagonist available. Among a series of naltrexamine derivatives that have been designed and synthesized, two compounds, NAP and NAQ, were previously identified as novel leads for this purpose based on their in vitro and in vivo pharmacological profiles. Both compounds displayed high binding affinity and selectivity to the mu opioid receptor. To further study the interaction of these two ligands with the three opioid receptors, the recently released opioid receptor crystal structures were employed in docking studies to further test our original hypothesis that the ligands recognize a unique 'address' domain in the mu opioid receptor involving Trp318 that facilitates their selectivity. These modeling results were supported by site-directed mutagenesis studies on the mu opioid receptor, where the mutants Y210A and W318A confirmed the role of the latter in binding. Such work not only enriched the 'message-address' concept, also facilitated our next generation ligand design and development. PMID- 24055078 TI - Synthesis of amino-hydroxy-benzocycloheptenones as potent, selective, non peptidic dinuclear zinc metalloaminopeptidase inhibitors. AB - Racemic trisubstituted benzocycloheptanes were synthesized and evaluated for their ability to inhibit metalloaminopeptidase activities. A highly selective nanomolar inhibitor of a prototypical 'two zinc' aminopeptidase from the M28 family was observed with these tridentate species, while bidentate analogs proved to be highly selective for the 'one zinc' M1 family of enzymes. The selectivity profile of these new, low molecular weight structures may guide the design of specific, non-peptidic inhibitors of binuclear aminopeptidases. PMID- 24055079 TI - Novel complex crystal structure of prolyl hydroxylase domain-containing protein 2 (PHD2): 2,8-Diazaspiro[4.5]decan-1-ones as potent, orally bioavailable PHD2 inhibitors. AB - We have discovered a novel complex crystal structure of the PHD2 enzyme with its inhibitor, the 2,8-diazaspiro[4.5]decan-1-one analogue 4b. The widely reported salt bridge between Arg383 of the enzyme and its inhibitors in all complex structures published thus far was not observed in our case. In our complex structure compound 4b forms several novel interactions with the enzyme, which include a hydrogen bond with Arg322, a pi-cation interaction with Arg322, a pi-pi stacking with Trp389, and a pi-pi stacking with His313. Guided by the structural information, SAR studies were performed on the 2,8-diazaspiro[4.5]decan-1-one series leading to the discovery of compound 9p with high potency and good oral pharmacokinetic profile in mice. PMID- 24055080 TI - Phenyl substituted 3-hydroxypyridin-2(1H)-ones: inhibitors of influenza A endonuclease. AB - Inhibition of the endonuclease activity of influenza RNA-dependent RNA polymerase is recognized as an attractive target for the development of new agents for the treatment of influenza infection. Our earlier study employing small molecule fragment screening using a high-resolution crystal form of pandemic 2009 H1N1 influenza A endonuclease domain (PAN) resulted in the identification of 5-chloro 3-hydroxypyridin-2(1H)-one as a bimetal chelating ligand at the active site of the enzyme. In the present study, several phenyl substituted 3-hydroxypyridin 2(1H)-one compounds were synthesized and evaluated for their ability to inhibit the endonuclease activity as measured by a high-throughput fluorescence assay. Two of the more potent compounds in this series, 16 and 18, had IC50 values of 11 and 23nM in the enzymatic assay, respectively. Crystal structures revealed that these compounds had distinct binding modes that chelate the two active site metal ions (M1 and M2) using only two chelating groups. The SAR and the binding mode of these 3-hydroxypyridin-2-ones provide a basis for developing a new class of anti influenza drugs. PMID- 24055081 TI - Editorial comment. PMID- 24055082 TI - Re: Editorial comment on monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial (Eur Urol 2012; 61: 917-925): S. A. Kaplan J Urol 2013; 189: 1448-1449. PMID- 24055083 TI - Reply by authors. PMID- 24055084 TI - Reply by author. PMID- 24055085 TI - Editorial comment. PMID- 24055086 TI - Statement that clinical studies had demonstrated bioCSL's seasonal influenza vaccines had acceptable safety profile in all age groups is not supported by the data. PMID- 24055087 TI - In vitro attenuated Histomonas meleagridis does not revert to virulence, following serial in vivo passages in turkeys or chickens. AB - The efficacy of vaccinating poultry against histomonosis was demonstrated recently. In the present study, the reversion to virulence and the residual pathogenicity of an in vitro attenuated, clonal strain of Histomonas meleagridis were tested in two consecutive experiments. The European Pharmcopoeia (Ph. Eur.) monograph for testing such features for coccidiosis live vaccines in chickens has served as a guideline. In the first experiment, attenuated histomonads were used in successive infection cycles in five groups of either five chickens or turkeys, respectively. All birds were killed at 14 days post infection (d.p.i.) to record lesion scores (LS) from livers and caeca. In the second experiment, the 5 times in vivo passaged histomonads were used to infect groups of 30 chickens and turkeys each, together with birds infected with virulent H. meleagridis. At three different time points 10 birds/group were killed and tissues of caeca, livers and lungs were used for PCR and immunohistochemistry (IHC) to confirm the presence of parasites. In the first experiment, various lesion scores were recordable in the livers and caeca of turkeys, with the highest LS 4 noticed once in the liver. In comparison, no lesions were seen in organs from chickens. In the second experiment, only mild lesions in the caeca of both turkeys and chickens were found. Liver lesions recorded as score 1 were noticed in just one individual of each species. PCR and IHC revealed that the attenuated and backpassaged histomonads were not present in liver samples but confined to the caeca, different to virulent H. meleagridis. Overall, no clinical signs or death occurred in turkeys or chickens inoculated orally and cloacally with 10(4) backpassaged histomonads in comparison with virulent parasites. Consequently, for the first time, the stable attenuation and safety of histomonads has been demonstrated, thus providing major implications for vaccine development. PMID- 24055088 TI - Fiscal consequences of changes in morbidity and mortality attributed to rotavirus immunisation. AB - Changes in population health status are known to influence government fiscal transfers both in terms of lost tax revenue and increased expenditure for health and social services. To estimate the fiscal impact of changes in morbidity and mortality attributed to rotavirus immunisation, we developed a government perspective model to estimate discounted net tax revenue for Ghana and Vietnam. The model derived the impact of rotavirus morbidity and mortality on lifetime productive capacity and related tax transfers, and demand for government transfers in relation to education and healthcare in immunised and non-immunised cohorts. The discounted age-specific net tax revenue was derived by deducting transfers from gross taxes and discounting for time preference. In Ghana, taking into account immunisation costs, tax and transfers, the estimated net discounted tax for the immunised cohort was estimated to generate $2.6 billion in net taxes up to age 65. In Vietnam, the net revenue attributed to the immunised cohort reached $55.17 billion suggesting an incremental benefit of approximately $29 million. We posit that the government perspective fiscal framework described here is a valid approach for estimating how governments benefit from investments in immunisation that can be considered supplementary to conventional cost effectiveness approaches for defining value. PMID- 24055089 TI - Identification of biomarkers to detect residual pertussis toxin using microarray analysis of dendritic cells. AB - In this study we aimed to identify genes that are responsive to pertussis toxin (PTx) and might eventually be used as biological markers in a testing strategy to detect residual PTx in vaccines. By microarray analysis we screened six human cell types (bronchial epithelial cell line BEAS-2B, fetal lung fibroblast cell line MRC-5, primary cardiac microvascular endothelial cells, primary pulmonary artery smooth muscle cells, hybrid cell line EA.Hy926 of umbilical vein endothelial cells and epithelial cell line A549 and immature monocyte-derived dendritic cells) for differential gene expression induced by PTx. Immature monocyte-derived dendritic cells (iMoDCs) were the only cells in which PTx induced significant differential expression of genes. Results were confirmed using different donors and further extended by showing specificity for PTx in comparison to Escherichia coli lipopolysaccharide (LPS) and Bordetella pertussis lipo-oligosaccharide (LOS). Statistical analysis indicated 6 genes, namely IFNG, IL2, XCL1, CD69, CSF2 and CXCL10, as significantly upregulated by PTx which was also demonstrated at the protein level for genes encoding secreted proteins. IL-2 and IFN-gamma gave the strongest response. The minimal PTx concentrations that induced production of IL-2 and IFN-gamma in iMoDCs were 12.5 and 25IU/ml, respectively. High concentrations of LPS slightly induced IFN-gamma but not IL-2, while LOS and detoxified pertussis toxin did not induce production of either cytokine. In conclusion, using microarray analysis we evaluated six human cell lines/types for their responsiveness to PTx and found 6 PTx-responsive genes in iMoDCs of which IL2 is the most promising candidate to be used as a biomarker for the detection of residual PTx. PMID- 24055090 TI - Epithelial-mesenchymal transition increases during the progression of in situ to invasive basal-like breast cancer. AB - Epithelial-mesenchymal transition (EMT) is known to play an important role in breast cancer invasion and metastatic progression. However, the pattern of expression of EMT markers in the progression from in situ to invasive breast carcinoma is not clear. To investigate this, we performed immunohistochemical analyses of EMT markers (expression of vimentin, smooth muscle actin, osteonectin, and N-cadherin; loss of E-cadherin; alteration of beta-catenin), breast cancer stem cell (CSC) markers (CD44(+)/CD24(-), ALDH1), and CD146, an EMT inducer, in invasive carcinomas and ductal carcinoma in situ (DCIS) of the breast. Expression of EMT markers was closely associated with the basal-like subtype and CSC phenotype in invasive carcinoma but not in pure DCIS, except for vimentin. The expression of smooth muscle actin and N-cadherin, loss of E cadherin, and alteration of beta-catenin were significantly higher in invasive carcinomas than in pure DCIS (P = .015, P = .029, P = .001, and P = .007, respectively). Subgroup analyses revealed greater loss of E-cadherin and alteration of beta-catenin in invasive carcinoma than in pure DCIS in basal-like subtype (P = .001) but not in non-basal-like subtypes. Moreover, expression of EMT markers and CD146 was higher in the invasive than in the DCIS component of basal-like cancers. Our study confirmed that EMT is an intrinsic characteristic of basal-like subtype and is associated with CSC phenotype. Furthermore, we showed higher expression of EMT markers in invasive carcinomas than in pure DCIS, especially in basal-like subtype, and in the invasive component of basal-like breast cancers, suggesting that EMT may be involved in the progression from in situ to invasive basal-like breast cancers. PMID- 24055091 TI - High LC3 expression correlates with poor survival in patients with oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is a destructive disease with very poor prognosis and no effective treatment. Autophagy is a dynamic cellular process involved in various physiological processes and diseases including cancer that degrades cytoplasmic proteins and organelles. The role of autophagy in the pathogenesis of OSCC is not yet understood. Microtubule-associated protein light chains 3 (LC3) is a reliable autophagosome markers for monitoring autophagy. In the present study, LC3 expression was determined in a cohort of 90 OSCC samples by immunohistochemistry. The results were correlated with clinical and pathological characteristics of patients. High LC3 expression (N = 57; 63.3%) correlated with stage (P < .0001), tumor size (P < .0001), and lymph node involvement (P = .0003) and with an increased risk of death (P < .0001; hazard ratio, 3.59) in a univariate analysis. In the multivariate analysis adjusted for grade, stage, and alcohol, betel, and tobacco consumption, high LC3 expression retained statistical significance with regard to survival (P = .0043; hazard ratio, 2.99). The Kaplan-Meier survival curve also showed that high LC3 expression was significantly associated with poor overall survival (P = .0001). Elevated LC3 expression, which corresponds to increased level of autophagy activity, is a frequent event and an indicator of poor prognosis in human OSCC. PMID- 24055092 TI - Can chronic disease management programs improve outcomes in patients with cirrhosis? PMID- 24055093 TI - [Pancreatic panniculitis in an 81 year-old patient]. PMID- 24055094 TI - [Acute coronary syndrome in nonagenarians: clinical evolution and validation of the main risk scores]. AB - INTRODUCTION: Several risk scores regarding the probability of death/complications in the acute setting and during the follow-up of patients admitted with acute coronary syndromes (ACS) have been published, such as the GRACE, TIMI and ZWOLLE risk score. Our objective was to assess the prognosis of nonagenarians admitted to a coronary care unit with an ACS, as well as the usefulness of each of these scores. MATERIAL AND METHODS: A retrospective analysis was performed on nonagenarians with an ACS admitted between 2003 and 2011. Vital status was determined at 14, 30 days, and 6 months after the ACS, and later during the follow-up. The risk scores were evaluated by area under the curve ROC (AUC). RESULTS: A total of 45 patients with an ACS, 26 (57.8%) with ST segment elevation and 19 (42.2%) with non-ST elevation. The GRACE- AUC for in hospital mortality was excellent, 0.91, (95% CI: 0.82-1; P<.001), and for the combined event (in-hospital mortality and re-infarction) was 0.83 (95% CI: 0.66 1.0; P<.01). However, the GRACE-AUC at 6 months for mortality was 0.34 (95% CI: 0.09-0.58; P=.45), and for the combined event it was 0.51 (95% CI: 0.26-0.77; P=.95). The TIMI-AUC and ZWOLLE-AUC did not reach statistical significance. CONCLUSIONS: It is useful calculate the GRACE risk score in order to estimate risk and survival in the acute phase of ACS in nonagenarians. This can help appropriate in making invasive or conservative treatment decisions. PMID- 24055095 TI - [Chronic disease, mortality and disability in an elderly Spanish population: the FRADEA study]. AB - INTRODUCTION: The objective of this study was to analyse the relationships between the major chronic diseases and multiple morbidity, with mortality, incident disability in basic activities of daily living, and loss of mobility in the elderly. MATERIAL AND METHODS: A total of 943 participants were selected from the FRADEA Study, using available baseline data of chronic diseases, and at the follow-up visit of mortality, incident disability, and loss of mobility. The analysis was made of the unadjusted and adjusted association between the number of chronic diseases, the number of 14 pre-selected diseases, and the presence of two or more chronic diseases (multiple morbidity) with adverse health events recorded. RESULTS: Participants with a higher number of diseases (OR 1.11; 95% CI: 1.02-1.22), and 14 pre-selected diseases (OR 1.19; 95% CI: 1.03-1.38) had a higher adjusted mortality risk, but not a higher incident disease or mobility loss risk. Subjects with multiple morbidity had a higher non-significant mortality risk (HR 1.45; 95% CI: 0.87-2.43), than those without multiple morbidity. Disability-free mean time in participants with and without multiple morbidity was 846+/-34 and 731+/-17 days, respectively (Log-rank chi(2) 7.45. P=.006), and with our without mobility loss was 818+/-32 and 696+/-13 days, respectively (Log rank chi(2) 10.99. P=.001). CONCLUSIONS: Multiple morbidity was not associated with mortality, incident disability in ADL, or mobility loss in adults older than 70 years, although if mortality is taken into account, the number of chronic diseases is linear. PMID- 24055096 TI - On the Autistic Spectrum Disorder concordance rates of twins and non-twin siblings. AB - Using the Interactive Autism Network Research Database, the Autistic Spectrum Disorder concordance rates for twins and non-twin siblings were calculated. For males, females and both genders together, the concordance rate for dizygotic twins is approximately twice that of non-twin siblings. We also determined that the concordance rate for non-twin siblings decreases as the interval between pregnancies increases. Our results appear to indicate that the uterine environment may contribute to autism concordance rates. PMID- 24055097 TI - Defining the burden of respiratory syncytial virus infection. PMID- 24055098 TI - Evaluation of functional capacity for exercise in children and adolescents with sickle-cell disease through the six-minute walk test. AB - OBJECTIVE: To evaluate lung functional capacity (FC) for physical exercise in children and adolescents with sickle cell disease (SCD) through the six-minute walk test (6MWT). METHOD: A cross-sectional prospective study was performed to evaluate the FC of 46 patients with SCD through the 6MWT. The following parameters were assessed: heart rate (HR), respiratory rate (RR), peripheral pulse oxygen saturation (SpO2), peak expiratory flow (PEF), blood pressure (systolic and diastolic), dyspnea, and leg fatigue (modified Borg scale) at rest, in the end of the test, and ten minutes after the 6MWT. The total distance walked was also recorded. For statistical analysis, the parametric variables were analyzed using the paired Student's t-test, analysis of variance (ANOVA), and Bonferroni multiple comparisons, with a significance level set at p <= 0.05. RESULTS: The 46 patients were aged age 9.15+/-3.06 years, presented baseline Hb of 9.49+/-1.67g/dL, and walked 480.89+/-68.70 m. SCD diagnosis was as follows: group 1- HbSS (n=20)/HbSbeta(0)-thalassemia (n=3) and group 2 - HbSC (n=20)/HbSbeta(+)-thalassemia (n=3). Regarding total distance walked, patients in group 1 walked a shorter distance than patients in group 2 (459.39+/-57.19 vs. 502.39+/-73.60 m; p=0.032). There was no statistical difference regarding PEF in the three moments of evaluation. The SpO2 in ambient air and SpO2 with O2 differed between groups 1 and 2 (p<0.001 vs. p=0.002), as well as the RR (p=0.001). CONCLUSION: These patients showed a lower FC for exercise than that predicted for the age range in the literature. Patients diagnosed with HbSS/Sbeta0-thalassemia had a lower performance in the test than those with HbSC/Sbeta(+)-thalassemia regarding total distance walked, RR, and SpO2 after the 6MWT. PMID- 24055099 TI - Finite-time control for nonlinear spacecraft attitude based on terminal sliding mode technique. AB - In this paper, a fast terminal sliding mode control (FTSMC) scheme with double closed loops is proposed for the spacecraft attitude control. The FTSMC laws are included both in an inner control loop and an outer control loop. Firstly, a fast terminal sliding surface (FTSS) is constructed, which can drive the inner loop tracking-error and the outer loop tracking-error on the FTSS to converge to zero in finite time. Secondly, FTSMC strategy is designed by using Lyaponov's method for ensuring the occurrence of the sliding motion in finite time, which can hold the character of fast transient response and improve the tracking accuracy. It is proved that FTSMC can guarantee the convergence of tracking-error in both approaching and sliding mode surface. Finally, simulation results demonstrate the effectiveness of the proposed control scheme. PMID- 24055100 TI - Recurrent fuzzy neural network backstepping control for the prescribed output tracking performance of nonlinear dynamic systems. AB - This paper proposes a backstepping control system that uses a tracking error constraint and recurrent fuzzy neural networks (RFNNs) to achieve a prescribed tracking performance for a strict-feedback nonlinear dynamic system. A new constraint variable was defined to generate the virtual control that forces the tracking error to fall within prescribed boundaries. An adaptive RFNN was also used to obtain the required improvement on the approximation performances in order to avoid calculating the explosive number of terms generated by the recursive steps of traditional backstepping control. The boundedness and convergence of the closed-loop system was confirmed based on the Lyapunov stability theory. The prescribed performance of the proposed control scheme was validated by using it to control the prescribed error of a nonlinear system and a robot manipulator. PMID- 24055101 TI - The energetic state of mitochondria modulates complex III biogenesis through the ATP-dependent activity of Bcs1. AB - Our understanding of the mechanisms involved in mitochondrial biogenesis has continuously expanded during the last decades, yet little is known about how they are modulated to optimize the functioning of mitochondria. Here, we show that mutations in the ATP binding domain of Bcs1, a chaperone involved in the assembly of complex III, can be rescued by mutations that decrease the ATP hydrolytic activity of the ATP synthase. Our results reveal a Bcs1-mediated control loop in which the biogenesis of complex III is modulated by the energy-transducing activity of mitochondria. Although ATP is well known as a regulator of a number of cellular activities, we show here that ATP can be also used to modulate the biogenesis of an enzyme by controlling a specific chaperone involved in its assembly. Our study further highlights the intramitochondrial adenine nucleotide pool as a potential target for the treatment of Bcs1-based disorders. PMID- 24055103 TI - A unique tool to selectively detect the chondrogenic IIB form of human type II procollagen protein. AB - Type II collagen, the major fibrillar collagen of cartilage, is synthesized as precursor forms (procollagens) containing N- and C-terminal propeptides. Three splice variants are thought to be translated to produce procollagen II isoforms (IIA/D and IIB) which differ in their amino propeptide parts. The IIA and IID are transient embryonic isoforms that include an additional cysteine-rich domain encoded by exon 2. The IIA and IID transcripts are co-expressed during chondrogenesis then decline and the IIB isoform is the only one expressed and synthesized in fully differentiated chondrocytes. Additionally, procollagens IIA/D can be re-expressed by dedifferentiating chondrocytes and in osteoarthritic cartilage. Therefore, it is an important point to determine which isoform(s) is (are) synthesized in vivo in normal and pathological situations and in vitro, to fully assess the phenotype of cells producing type II collagen protein. Antibodies directed against the cysteine-rich extra domain found in procollagens IIA and IID are already available but antibodies detecting only the chondrogenic IIB form of type II procollagen were missing so far. A synthetic peptide encompassing the junction between exon 1 and exon 3 of the human sequence was used as immunogen to produce rabbit polyclonal antibodies to procollagen IIB. After affinity purification on immobilized peptide their absence of crossreaction with procollagens IIA/D and with the fibrillar procollagens I, III and V was demonstrated by Western blotting. These antibodies were used to reveal at the protein level that the treatment of dedifferentiated human chondrocytes by bone morphogenic protein (BMP)-2 induces the synthesis of the IIB (chondrocytic) isoform of procollagen II. In addition, immunohistochemical staining of bovine cartilage demonstrates the potential of these antibodies in the analysis of the differential spatiotemporal distribution of N-propeptides of procollagens IIA/D and IIB during normal development and in pathological situations. PMID- 24055102 TI - Sestrins orchestrate cellular metabolism to attenuate aging. AB - The Sestrins constitute a family of evolutionarily conserved stress-inducible proteins that suppress oxidative stress and regulate AMP-dependent protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling. By virtue of these activities, the Sestrins serve as important regulators of metabolic homeostasis. Accordingly, inactivation of Sestrin genes in invertebrates resulted in diverse metabolic pathologies, including oxidative damage, fat accumulation, mitochondrial dysfunction, and muscle degeneration, that resemble accelerated tissue aging. Likewise, Sestrin deficiencies in mice led to accelerated diabetic progression upon obesity. Further investigation of Sestrin function and regulation should provide new insights into age-associated metabolic diseases, such as diabetes, myopathies, and cancer. PMID- 24055104 TI - Assessment of attention in male and female Brattleboro rats using a self-paced five-choice serial reaction time task. AB - The Brattleboro rat is a mutant variation of the Long-Evans strain that exhibits negligible central nervous system levels of vasopressin, a neuropeptide that may influence behavioral and cognitive processes. Compared to Long-Evans rats, Brattleboro rats exhibit diminished fear conditioning and have impairments in spatial memory and sensory gating. The present study sought to further evaluate the cognitive profile of vasopressin-deficient rats by studying attention in male and female Brattleboro and heterozygous rats using a self-paced version of the five-choice serial reaction time task. Male Brattleboro rats required significantly more sessions to meet the training criteria than those by heterozygotic and Long-Evans (wild type) rats. Female Brattleboro rats displayed significantly poorer attention accuracy compared to heterozygotic and Long-Evans rats. Taken together, the present findings add further evidence that vasopressin deficiency diminishes cognitive functioning. PMID- 24055105 TI - Neural mechanisms of phonemic restoration for speech comprehension revealed by magnetoencephalography. AB - In daily communication, we can usually still hear the spoken words as if they had not been masked and can comprehend the speech when spoken words are masked by background noise. This phenomenon is known as phonemic restoration. Since little is known about the neural mechanisms underlying phonemic restoration for speech comprehension, we aimed to identify the neural mechanisms using magnetoencephalography (MEG). Twelve healthy male volunteers with normal hearing participated in the study. Participants were requested to carefully listen to and understand recorded spoken Japanese stories, which were either played forward (forward condition) or in reverse (reverse condition), with their eyes closed. Several syllables of spoken words were replaced by 300-ms white-noise stimuli with an inter-stimulus interval of 1.6-20.3s. We compared MEG responses to white noise stimuli during the forward condition with those during the reverse condition using time-frequency analyses. Increased 3-5 Hz band power in the forward condition compared with the reverse condition was continuously observed in the left inferior frontal gyrus [Brodmann's areas (BAs) 45, 46, and 47] and decreased 18-22 Hz band powers caused by white-noise stimuli were seen in the left transverse temporal gyrus (BA 42) and superior temporal gyrus (BA 22). These results suggest that the left inferior frontal gyrus and left transverse and superior temporal gyri are involved in phonemic restoration for speech comprehension. Our findings may help clarify the neural mechanisms of phonemic restoration as well as develop innovative treatment methods for individuals suffering from impaired speech comprehension, particularly in noisy environments. PMID- 24055106 TI - Prevalence of Babesia and Anaplasma in ticks infesting dogs in Great Britain. AB - Ticks are important vectors of disease in companion animals and transmit an extensive range of viral, bacterial and protozoan pathogens to dogs and cats. They may also be vectors of zoonotic pathogens which affect the health of in contact owners. In recent years, babesiosis, and anaplasmosis have all shown signs of increased prevalence and distribution in various parts of Europe. Here, the prevalence of Anaplasma spp. and Babesia spp. pathogens in Ixodes ticks, collected from dogs in the UK in 2009, were evaluated using PCR and sequence analysis of the 16S rDNA or 18S rDNA regions respectively. Species identification was performed by alignment with existing sequences in GenBank. After sequencing, 5 out of 677 tick samples (0.74%) contained rDNA which shared 97-100%% sequence homology with Anaplasma phagocytophilum. Of these, three samples came from Ixodes ricinus and two from Ixodes hexagonus. Sixteen out of 742 ticks (2.4%) were positive for Babesia and of these 11 showed 97-100% homology with B. gibsoni. All of these 11 samples were derived from I. ricinus. One sample, again from I. ricinus, showed 99% homology for B. divergens. Four of the Babesia spp sequences were of the "venatorum" or EU1 type, three of which came from I. ricinus and one from an Ixodes canisuga. This strain has been associated with severe human cases of babeisiosis. A further 246 positive results, which appeared to show the presence of Anaplasma following PCR, were shown by sequence analysis to be derived from the bacterium Candidatus "Midichloria mitochondrii", which to date has been assumed to be non-pathogenic. The results are of interest because the presence of B. gibsoni in the UK further confirms the worldwide distribution of this piroplasm and supports the inference that I. ricinus may act as a vector for Babesia of the gibsoni-complex. PMID- 24055107 TI - Discovery of the Rdl mutation in association with a cyclodiene resistant population of horn flies, Haematobia irritans (Diptera: Muscidae). AB - The horn fly, Haematobia irritans irritans, is an obligate blood-feeding parasite of cattle that causes significant economic impact in many countries. We investigated the resistance of a horn fly population from Louisiana/USA to endosulfan, a cyclodiene insecticide. Bioassays were performed in 2010 and 2011 in order to determine the resistance ratio of the population to endosulfan and a PCR assay was developed to detect the Rdl mutation which is the replacement of an alanine with a serine at the GABA receptor locus that has been associated with resistance to cyclodienes in other insect species. Endosulfan tags had provided 8 weeks of effective control in 2010 but only 1 week in 2011. After only one summer (June-September/2010) of exposure to the endosulfan tagged cattle, there was a significant increase in the resistance ratio for endosulfan in the fly population. Most flies surveyed by the PCR diagnostic assay were homozygous susceptible at the Rdl locus, the resistant (R) allele was mainly present in the heterozygous state and there was no difference in the frequency of the R allele between female and male flies. After the first year's exposure of the horn flies to the endosulfan tags, the frequency of the R allele increased significantly. However, after one year without endosulfan treatment (2011-2012), the frequency of the R allele significantly dropped. These results indicate that target site resistance was responsible, at least in part, for the resistance and that a fitness cost is possibly associated with the Rdl mutation. PMID- 24055108 TI - How to conciliate Popper with Cartesius: comment on: "Consciousness in the universe. A review of the 'Orch OR' theory" by S. Hameroff and R. Penrose. PMID- 24055109 TI - Progressive dysarthria and dysphagia in an otherwise healthy girl. PMID- 24055110 TI - Topical enzyme-replacement therapy restores transglutaminase 1 activity and corrects architecture of transglutaminase-1-deficient skin grafts. AB - Transglutaminase-1 (TG1)-deficient autosomal-recessive congenital ichthyosis (ARCI) is a rare and severe genetic skin disease caused by mutations in TGM1. It is characterized by collodion babies at birth, dramatically increased transepidermal water loss (TEWL), and lifelong pronounced scaling. The disease has a tremendous burden, including the problem of stigmatization. Currently, no therapy targeting the molecular cause is available, and the therapeutic situation is deplorable. In this study, we developed the basis for a causative therapy aiming at the delivery of the enzyme to the inner site of the keratinocytes' plasma membrane. We prepared sterically stabilized liposomes with encapsulated recombinant human TG1 (rhTG1) and equipped with a highly cationic lipopeptide vector to mediate cellular uptake. The liposomes overcame the problems of insufficient cutaneous delivery and membrane penetration and provided excellent availability and activity of rhTG1 in primary keratinocytes. To demonstrate the general feasibility of this therapeutic approach in a humanized context, we used a skin-humanized mouse model. Treatment with rhTG1 liposomes resulted in considerable improvement of the ichthyosis phenotype and in normalization of the regenerated ARCI skin: in situ monitoring showed a restoration of TG1 activity, and cholesterol clefts vanished ultrastructurally. Measurement of TEWL revealed a restoration of epidermal barrier function. We regard this aspect as a major advance over available nonspecific approaches making use of, for example, retinoid creams. We conclude that this topical approach is a promising strategy for restoring epidermal integrity and barrier function and provides a causal cure for individuals with TG1 deficiency. PMID- 24055111 TI - Genetic mapping with multiple levels of phenotypic information reveals determinants of lymphocyte glucocorticoid sensitivity. AB - Clinical response to glucocorticoids, steroid hormones widely used as pharmaceuticals, varies extensively in that many individuals (~30%) show a weak response to treatment. Although little is known about the molecular basis of this variation, regulatory polymorphisms are likely to play a key role given that glucocorticoids act largely through activation of a transcription factor, the glucocorticoid receptor. In an effort to characterize the molecular basis of variation in glucocorticoid sensitivity, we measured in vitro lymphocyte glucocorticoid sensitivity and transcriptome-wide response to glucocorticoids in peripheral-blood mononuclear cells from African American healthy donors. We found that variation in lymphocyte glucocorticoid sensitivity was correlated with transcriptional response at 27 genes (false-discovery rate < 0.1). Furthermore, a genome-wide association scan revealed a quantitative trait locus (QTL) for lymphocyte glucocorticoid sensitivity (rs11129354, p = 4 * 10(-8)); it was also associated with transcriptional response at multiple genes, including many (14/27) where transcriptional response was correlated with lymphocyte glucocorticoid sensitivity. Using allelic-imbalance assays, we show that this QTL is a glucocorticoid-dependent cis-regulatory polymorphism for RBMS3, which encodes an RNA-binding protein known as a tumor suppressor. We found that siRNA mediated knockdown of RBMS3 expression increased cellular proliferation in PBMCs, consistent with the role of the gene as a negative regulator of proliferation. We propose that differences in lymphocyte glucocorticoid sensitivity reflect variation in transcriptional response, which is influenced by a glucocorticoid dependent regulatory polymorphism that acts in cis relative to RBMS3 and in trans to affect the transcriptional response of multiple distant genes. PMID- 24055113 TI - Actionable, pathogenic incidental findings in 1,000 participants' exomes. AB - The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large scale study has yet estimated the number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants' pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (~3.4% for European descent and ~1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine. PMID- 24055112 TI - Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. AB - Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ~65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects. Mutations in SPAG1 were identified in one family with three affected siblings. Further screening of SPAG1 in 98 unrelated affected individuals (62 with ODA+IDA defects, 35 with ODA defects, 1 without available ciliary ultrastructure) revealed biallelic loss-of-function mutations in 11 additional individuals (including one sib-pair). All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities. Additionally, all individuals with mutations who had defined ciliary ultrastructure had ODA+IDA defects. SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms. Zebrafish morpholino studies of spag1 produced cilia related phenotypes previously reported for PCD-causing mutations in genes encoding cytoplasmic proteins. Together, these results demonstrate that mutations in SPAG1 cause PCD with ciliary ODA+IDA defects and that exome sequencing is useful to identify genetic causes of heterogeneous recessive disorders. PMID- 24055114 TI - Effects of back massage on chemotherapy-related fatigue and anxiety: supportive care and therapeutic touch in cancer nursing. AB - This quasi-experimental and cross-sectional study was carried out to determine the efficacy of back massage, a nursing intervention, on the process of acute fatigue developing due to chemotherapy and on the anxiety level emerging in cancer patients receiving chemotherapy during this process. The study was conducted on 40 patients. To collect the data, the Personal Information Form, the State Anxiety part of Spielberger State-Trait Anxiety Inventory and the Brief Fatigue Inventory were used. In our study, it was determined that mean anxiety scores decreased in the intervention group patients after chemotherapy. The level of fatigue in the intervention group decreased statistically significantly on the next day after chemotherapy (p=.020; effect size=0.84). At the same time, the mean anxiety scores of the patients in the intervention group decreased right after the massage provided during chemotherapy (p=.109; effect size=0.37) and after chemotherapy. In line with our study findings, it can be said that back massage given during chemotherapy affects anxiety and fatigue suffered during the chemotherapy process and that it significantly reduces state anxiety and acute fatigue. Therefore, the effective use of back massage in the process of chemotherapy by oncology nurses who have a key role in cancer treatment and care can make it more modulated. PMID- 24055115 TI - A Rangwapithecus gordoni mandible from the early Miocene site of Songhor, Kenya. AB - A mandible of Rangwapithecus gordoni from the early Miocene site of Songhor, Kenya, provides additional information about this relatively poorly known taxon. The R. gordoni sample is small, being composed of dental and a few gnathic parts. The fossil described here provides examples of previously unknown dental and mandibular anatomy, and confirms former reassignments of isolated anterior teeth based on less certain evidence. The phylogenetic status of Rangwapithecus, its distribution, and paleobiology are briefly reviewed. Rangwapithecus shows a suite of dental and gnathic features that warrants its generic distinction from Proconsul. Derived features shared with Nyanzapithecus and Turkanapithecus indicate that it is an early member of the subfamily Nyanzapithecinae. Its molar morphology suggests a considerable component of folivory in its diet. A review of the hypodigm shows Rangwapithecus to be restricted to Songhor. This distribution parallels that of Limnopithecus evansi, and is mirrored by Limnopithecus legetet and Micropithecus clarki suggesting that Songhor may have differed ecologically from other more or less contemporary sites in the region. PMID- 24055116 TI - Foramen magnum position in bipedal mammals. AB - The anterior position of the human foramen magnum is often explained as an adaptation for maintaining balance of the head atop the cervical vertebral column during bipedalism and the assumption of orthograde trunk postures. Accordingly, the relative placement of the foramen magnum on the basicranium has been used to infer bipedal locomotion and hominin status for a number of Mio-Pliocene fossil taxa. Nonetheless, previous studies have struggled to validate the functional link between foramen magnum position and bipedal locomotion. Here, we test the hypothesis that an anteriorly positioned foramen magnum is related to bipedalism through a comparison of basicranial anatomy between bipeds and quadrupeds from three mammalian clades: marsupials, rodents and primates. Additionally, we examine whether strepsirrhine primates that habitually assume orthograde trunk postures exhibit more anteriorly positioned foramina magna compared with non orthograde strepsirrhines. Our comparative data reveal that bipedal marsupials and rodents have foramina magna that are more anteriorly located than those of quadrupedal close relatives. The foramen magnum is also situated more anteriorly in orthograde strepsirrhines than in pronograde or antipronograde strepsirrhines. Among the primates sampled, humans exhibit the most anteriorly positioned foramina magna. The results of this analysis support the utility of foramen magnum position as an indicator of bipedal locomotion in fossil hominins. PMID- 24055117 TI - Zinc, magnesium and NMDA receptor alterations in the hippocampus of suicide victims. AB - BACKGROUND: There is evidence for an association between suicidal behavior and depression. Accumulating data suggests that depression is related to a dysfunction of the brain's glutamatergic system, and that the N-methyl-d aspartate (NMDA) receptor plays an important role in antidepressant activity. Zinc and magnesium, the potent antagonists of the NMDA receptor complex, are involved in the pathophysiology of depression and exhibit antidepressant activity. METHODS: The present study investigated the potency of Zn(2+) and Mg(2+) to [(3)H] MK-801, which binds to the NMDA receptor channel in the hippocampus of suicide victims (n=17) and sudden death controls (n=6). Moreover, the concentrations of zinc and magnesium (by flame atomic absorption spectrometry) and levels of NMDA subunits (NR2A and NR2B) and PSD-95 protein (by Western blotting) were determined. RESULTS: Our results revealed that there was a statistically significant decrease (by 29% and 40%) in the potency of zinc and magnesium (respectively) to inhibit [(3)H] MK-801 binding to NMDA receptors in the hippocampus in suicide tissue relative to the controls. These alterations were associated with increased NR2A (+68%) and decreases in both the NR2B (-46%) and PSD-95 (-35%) levels. Furthermore, lower concentrations (-9%) of magnesium (although not of zinc) were demonstrated in suicide tissue. CONCLUSIONS: Our findings indicate that alterations in the zinc, magnesium and NMDA receptor complex in the hippocampus are potentially involved in the pathophysiology of suicide-related disorders (depression), which may lead to functional NMDA receptor hyperactivity. PMID- 24055119 TI - Duplex-guided percutaneous transluminal angioplasty in iliac arterial occlusive disease. AB - BACKGROUND: Chronic renal insufficiency (CRI) is a growing global problem. PTA can be performed without nephrotoxic contrast, utilizing Doppler-ultrasound (Duplex) guidance. Duplex-guided infra-inguinal interventions and access-related interventions have been reported. Duplex-guided iliac interventions have not been performed to any extent because of the anatomic location. In our study we evaluated the safety and efficacy of Duplex-guided percutaneous transluminal angioplasty (DuPTA) in iliac arteries. METHODS: From June 2012 until February 2013, 31 patients (35 iliac lesions), underwent DuPTA. Indications ranged from Rutherford 3 to 5. Preoperative evaluation included Ankle Brachial Index (ABI), Duplex and MRA. Procedural success was defined as crossing the lesion with a guidewire and dilating or stenting the lesion. Clinical success was defined as 50% reduction in peak systolic velocity (PSV) or clinical improvement. PSV was evaluated after PTA, then at 2 weeks. Clinical results were assessed 2 weeks after the procedure. RESULTS: Procedural success was achieved in 94% of patients (33/35), all of whom also had clinical success. Post-procedural PSV reduction showed an average improvement of 63% (431 cm/s to 153 cm/s). Mean preoperative ABI was 0.72 and improved to 0.88 postoperatively. CONCLUSIONS: PTA using Duplex guidance in significant iliac stenosis is a safe method with major advantages in patients at high risk for developing contrast-induced nephropathy. PMID- 24055118 TI - Cigarette smoking and completed suicide: results from 3 prospective cohorts of American adults. AB - BACKGROUND: Prior reports have indicated a potential dose-response relationship between smoking and suicide. However, this relationship is controversial. METHODS: This study evaluated the association between smoking and risk of death from suicide in three large-scale cohorts of U.S. men and women (n=253,033). Suicides were identified from death certificates among 43,816 men enrolled in the Health Professionals Follow-up Study (HPFS) between 1986 and 2008, 116,566 women in the Nurses' Health Study (NHS) between 1976 and 2008, and 92,651 women in the NHS II between 1989 and 2007. Information on smoking was obtained at baseline and updated every 2 years. Relative risks (RRs) of suicide were estimated using Cox proportional hazards regression models. Cohort specific RRs were pooled using random-effects models. Suicide deaths were determined by physician review of death certificates. RESULTS: A total of 457 deaths from suicide were documented. Compared to never smokers, the pooled multivariate RR (95% confidence interval [CI]) of suicide was 1.15 (0.91-1.45) for former smokers and 2.69 (2.11-3.42) for current smokers. A nonmonotonic dose-response relationship was noted between the number of cigarettes smoked per day (CPD) and suicide risk (P trend<0.001). Compared to never smokers, the pooled multivariate RR (95% CI) was 2.59 (1.77 3.79) for those with 1-14 CPD, 2.03 (1.39-2.94) for those with 15-24 CPD, and 4.13 (2.96-5.78) for those with >= 25 CPD. LIMITATIONS: Smoking was self-reported and had some degree of measurement error. Participants were not a representative sample of the U.S. population. CONCLUSIONS: Results from three large cohorts suggest a nonmonotonic dose-response association between smoking and suicide risk. PMID- 24055120 TI - Multiple lung parenchymal abnormalities: Don't panic, let's be pragmatic! The 6 question rule - a checklist strategy. AB - Analysis of multiple lung parenchymal abnormalities on HRCT is a real diagnostic challenge. These abnormalities may be due to a disease of the pulmonary interstitial tissue, the bronchial tree, the cardiovascular system or to abnormal alveolar filling with fluid, blood, cells or tumor, several of these etiologies possibly being concomitant. Systematic pathophysiological reasoning, in the form of a logical checklist, guides reflection and covers many of the most frequent diagnoses and potentially treatable emergencies that can be identified by the non specialist radiologist. This approach also provides a basis for deepening knowledge of each area. The use of the mnemonic FIBROVAKIM (fibrosis-bronchi vascular-cancer-infection-medication) is easy to apply and summarizes this strategy. PMID- 24055121 TI - Plasma cells release membrane microparticles in a mouse model of multiple myeloma. AB - Microparticles (MPs) released from the plasma membrane play a role in tumor progression. Involvement of MPs in myeloma (MM) has been poorly investigated. Because of the strong interaction of MM cells with bone microenvironment, we hypothesized an implication of MPs in MM using a murine model. Forty-four mice were injected with 5THL-MM cells and compared with 14 non-injected mice. Blood was collected at the early and end stages of MM development (EMM and LMM) to characterize the circulating MPs. At LMM, MPs were isolated from bone marrow (BM) of long bones of 22 mice, after centrifugation. Electron microscopy immunohistochemistry and Western blotting using CD138 were performed on BM derived MPs. At EMM, MPs circulating level was significantly lower versus controls. In LMM, a significant increase of the total MP number from plasma was observed versus controls. Characterization of circulating MPs showed an increase of leukocyte- and erythrocyte-derived MPs. In LMM, serum M-protein was correlated with circulating MP number. BM-derived MPs increased in LMM and expressed CD138. Anti-CD138 coupled with nanobeads localized at the MP surface. There is evidence of an association between increase of MPs and MM development; the results underscore the participation of plasma cell-derived MPs originating from BM. PMID- 24055122 TI - Determination of the surface morphology of gold-decahedra nanoparticles using an off-axis electron holography dual-lens imaging system. AB - The purpose of this paper is to show surface irregularities in gold decahedra nanoparticles extracted by using off-axis electron holography in a JEOL ARM 200F microscope. Electron holography has been used in a dual-lens system within the objective lenses: main objective lens and objective minilens. Parameters such as biprism voltage, fringe spacing (sigma), fringe width (W) and optimum fringe contrast have been calibrated. The reliability of the transmission electron microscope performance with these parameters was carried out through a plug-in in the Digital-Micrograph software, which considers the mean inner potential within the particle leading a precise determination of the morphological surface of decahedral nanoparticles obtained from the reconstructed unwrapped phase and image processing. We have also shown that electron holography has the capability to extract information from nanoparticle shape that is currently impossible to obtain with any other electron microscopy technique. PMID- 24055123 TI - Left atrial and left ventricular diastolic function in chronic Chagas disease. AB - BACKGROUND: Left atrial (LA) and left ventricular (LV) diastolic function analysis can yield new strategies to recognize early cardiac involvement and prognostic indicators in Chagas disease. METHODS: Patients with Chagas disease with the indeterminate (n = 69) or with the cardiac form (32 with changes limited to electrocardiography [stage A], 25 with changes in LV systolic function but no heart failure [HF; stage B], and 26 with HF) underwent evaluation of LV diastolic function (mitral inflow, pulmonary vein flow, color M-mode echocardiography, and tissue Doppler analysis), and LA function by three-dimensional echocardiography and strain analysis and were prospectively followed for the occurrence of clinical events. Echocardiograms were also obtained from 32 controls. RESULTS: LV diastolic dysfunction was gradually more prevalent and severe across groups from patients with the indeterminate form of Chagas disease to patients with HF. Tissue Doppler was the best tool to demonstrate the worsening of LV diastolic function across the groups (E' velocity: controls, 12.6 +/- 2.3 cm/sec; patients with the indeterminate form, 12.1 +/- 3.1 cm/sec; stage A, 10.3 +/- 2.9 cm/sec; stage B, 8.3 +/- 2.8 cm/sec; patients with HF, 5.6 +/- 1.9; P < .0001). Although maximum LA volume was increased only in patients with HF, minimum LA volume (controls, 8 +/- 2 mL/m(2); patients with the indeterminate form, 8 +/- 2 mL/m(2); stage A, 9 +/- 3 mL/m(2); stage B, 11 +/- 4 mL/m(2); patients with HF, 27 +/- 17 mL/m(2); P < .0001) and precontraction LA volume (controls, 11 +/- 3 mL/m(2); patients with the indeterminate form, 12 +/- 3 mL/m(2); stage A, 13 +/- 4 mL/m(2); stage B, 16 +/- 5 mL/m(2); patients with HF, 32 +/- 19 mL/m(2); P < .0001) were increased in all cardiac form groups. LA conductive function was depressed in all cardiac form groups, while LA contractile function was depressed only in patients with HF. Cox proportional-hazards regression analysis revealed that end-systolic LV diameter (hazard ratio, 1.6; 95% confidence interval, 0.9 2.8; P = .09), E' velocity (hazard ratio, 0.5; 95% confidence interval, 0.3-0.8; P = .001), and peak negative global LA strain (hazard ratio, 1.21; 95% confidence interval, 1.02-1.4; P = .03), were independent predictors of clinical events. CONCLUSIONS: LV diastolic dysfunction was found in all forms of chronic Chagas disease, including those without LV systolic dysfunction. LV diastolic dysfunction may contribute to changes in LA volume and conductive function found in early stages of the cardiac form. Both LV diastolic function and LA contractile function were independent predictors of clinical events. PMID- 24055124 TI - Head-to-head comparison of peak upright bicycle and post-treadmill echocardiography in detecting coronary artery disease: a randomized, single-blind crossover study. AB - BACKGROUND: Post-treadmill digital echocardiography (post-TME) is the most widely used form of exercise echocardiography, but ischemia can rapidly resolve in the postexercise period; peak upright bicycle digital echocardiography (UBE) has the advantage of providing images at peak exercise that reflect normal physiology. However, the comparative accuracy of the two methods in detecting ischemia in the same patients is unknown. To compare the relative diagnostic value of peak UBE and post-TME in detecting coronary artery disease, both tests were performed in 86 consecutive patients undergoing coronary angiography. METHODS: Eighty-six patients referred for evaluation of coronary disease underwent peak UBE (starting at 25 W, with 25-W increments every 3 min) and post-TME (Bruce protocol) in a random sequence. Digitized images of peak UBE and post-TME were interpreted in a random and blinded fashion. RESULTS: More transient wall motion abnormalities were detected with peak UBE than post-TME (55 vs 42, P < .001), and such exercise induced wall motion abnormalities were more extensive (5.5 +/- 3.0 vs 3.4 +/- 2.1 dyskinetic segments, P < .001) and more severe (regional wall motion score index, 2.7 +/- 0.5 vs 2.5 +/- 0.5; P = .003). By angiography, 59 patients had coronary artery disease (a coronary stenosis of >=50% diameter narrowing); the sensitivity of peak UBE for detecting coronary artery disease was greater than that of post TME in the population as a whole (88% vs 66%, P < .01) and in the single-vessel subgroup (72% vs 44%, P < .05), with no worsening in specificity (89% vs 89%, P = NS). CONCLUSIONS: Peak UBE is more capable of detecting ischemia than post-TME, and this is achieved with no worsening of specificity. Thus, peak UBE should be preferred in patients able to perform bicycle exercise. PMID- 24055125 TI - Interinstitutional measurements of left ventricular volumes, speckle-tracking strain, and dyssynchrony using three-dimensional echocardiography. AB - BACKGROUND: Three-dimensional echocardiographic (3DE) analysis provides better measurements of left ventricular (LV) volumes, ejection fraction, myocardial deformation, and dyssynchrony. Many studies have shown that this technique has high intrainstitutional reproducibility. However, interinstitutional reproducibility is low, limiting its adoption. The aim of this study was to determine if standardization of training could reduce the interinstitutional variability in 3DE data analysis. METHODS: In total, 50 full-volume, transthoracic 3DE data sets of the left ventricle were analyzed by two readers. Measurements obtained included LV volumes, ejection fraction, global longitudinal strain, and two dyssynchrony indices. The cases represented a wide spectrum of ejection fraction. After initial analysis of 21 studies, readers formally met to standardize their analytic approach on six additional cases. Five months after the intervention, 23 new cases were analyzed. Paired t tests were performed to identify systematic institutional differences in measurements. Interinstitutional variability was quantified using intraclass correlation coefficients and variability. RESULTS: Before the intervention, there was a systematic bias in LV volumes, which was eliminated after intervention. Intraclass correlation coefficients showed that the intervention improved agreement in measurements of LV volumes, strain, and dyssynchrony between the two centers and decreased variability. CONCLUSIONS: A simple intervention to standardize analysis can reduce interinstitutional variability of measurements obtained from 3DE analysis. This intervention is needed before the use of 3DE measurement in multicenter trials and to increase the reproducibility of such measurements in routine clinical practice. PMID- 24055126 TI - Effects of transesophageal echocardiography simulator training on learning and performance in cardiovascular medicine fellows. AB - BACKGROUND: The role of transesophageal echocardiography (TEE) simulation in cardiology fellows' learning is unknown. Standard TEE training at the authors' institution occurs during the second of 3 clinical years. Fellows spend 2 months in the TEE laboratory learning through hands-on experience. The addition of TEE simulation to this experience may improve proficiency, speed learning, and increase fellows' comfort with TEE. This study was designed to compare methods of TEE simulator training with standard training. METHODS: Group A (n = 8) consisted of fellows who had completed standard TEE training. Fellows starting their second clinical year were randomly assigned to group B (n = 10), simulator training during month 1, or group C (n = 9), simulator training during month 2. All groups completed 2 months of standard TEE training. All groups underwent assessment of TEE performance and a self-assessment of ability and comfort level with TEE. RESULTS: Groups B and C had higher total assessment scores than group A. Groups B and C had higher numbers of views achieved without assistance (P = .01). After month 1, group B had higher total scores and number of views achieved without assistance compared with group C (P = .02 and P = .02, respectively). The length of time of the examination tended to be lower for group B, and fellows in group B had greater comfort with TEE than those in group C (P = .01). CONCLUSIONS: These data suggest that TEE simulator training improves proficiency and helps speed learning and comfort with TEE. PMID- 24055127 TI - Endocan immunoreactivity in the mouse brain: method for identifying nonfunctional blood vessels. AB - Endocan is a secreted proteoglycan that has been shown to indicate angiogenic activity: remodeling in several tumor types in humans and mice. Serum endocan levels also indicate prognosis and has been proposed as a biomarker for certain cancers. Recently, monoclonal antibodies directed against mouse endocan have been developed allowing for further characterization of endocan function and potentially as a marker for angiogenesis through immunoreactivity in endothelial tip cells. The results of the current study show that endocan immunoreactivity in the mouse brain is present in blood vascular networks including but not limited to the cortex, hippocampus and paraventricular nucleus of the hypothalamus in C57BL/6J and FVB/N mice. Endocan immunoreactivity did not vary during postnatal development or by sex. Interestingly, after vascular perfusion with fluorescein isothiocyanate (FITC), endothelial cells positive for FITC were immunonegative for endocan suggesting FITC interference with the immunohistochemistry. A small number of FITC-negative blood vessels were endocan immunoreactive suggesting the identification of new blood vessels that are not yet functional. The current study shows that endocan is normally present in the mouse brain and prior vascular perfusion with FITC may provide a useful tool for identify newly forming blood vessels. PMID- 24055128 TI - Development of a diphtheria toxin-based recombinant porcine IL-2 fusion toxin for depleting porcine CD25+ cells. AB - Regulatory T cells (Tregs) have been widely recognized as crucial players in controlling immune responses. Because their major role is to ensure that the immune system is not over reactive, Tregs have been the focus of multiple research studies including those investigating transplantation tolerance, autoimmunity and cancer treatment. On their surface Tregs constitutively express CD25, a high affinity receptor for the cytokine interleukin-2 (IL-2). The reagents constructed in this study were generated by genetically linking porcine IL-2 to the truncated diphtheria toxin (DT390). This reagent functions by first binding to the cell surface via the porcine IL-2/porcine CD25 interaction then the DT390 domain facilitates internalization followed by inhibition of protein synthesis resulting in cell death. Four versions of the porcine IL-2 fusion toxin were designed in an interest to find the most effective isoform: 1) monovalent glycosylated porcine IL-2 fusion toxin (Gly); 2) monovalent non-N-glycosylated porcine IL-2 fusion toxin (NonGly); 3) bivalent glycosylated porcine IL-2 fusion toxin (Bi-Gly); 4) bivalent non-N-glycosylated porcine IL-2 fusion toxin (Bi NonGly). Using a porcine CD25(+) B cell lymphoma cell line (LCL13271) in vitro analysis of the fusion toxins' ability to inhibit protein synthesis demonstrated that the Bi-NonGly fusion toxin is the most efficient reagent. These in vitro results are consistent with binding affinity as the Bi-NonGly fusion toxin binds strongest to CD25 on the same LCL13271 cells. The Bi-Gly fusion toxin significantly prolonged the survival (p=0.028) of tumor-bearing NOD/SCID IL-2 receptor gamma(-/-) (NSG) mice injected with LCL13271 cells compared with untreated controls. This recombinant protein has great potential to function as a useful tool for in vivo depletion of porcine CD25(+) cells for studying immune regulation. PMID- 24055129 TI - Statistical approaches for analyzing immunologic data of repeated observations: a practical guide. AB - Translational research not only encompasses transitioning from animal to human models but also must address the greater heterogeneity of humans when designing and analyzing experiments. Appropriate study designs can address heterogeneity through a priori data collection, and taking repeated measures can improve the power and efficiency of a study to detect clinically meaningful differences. Although common in other areas of biomedical research, modern statistical methods using repeated measurements on the same subject and accounting for their potential correlations are not widely utilized in immunologic studies. To highlight these analytic issues, we present a practical guide to understanding and applying analytic methods from commonly used T-tests without adjusting for multiple comparisons to mixed models with subject-specific adjustments for correlations using our data on Toll-like receptor-induced cytokine production in monocytes from young and older adults. PMID- 24055130 TI - [Medicalization I. 'Disease labeling: All business.']. AB - Western societies have displaced problems from the subjective and social fields over to medicine, and the search for the perfect health has become an obsession and a pathogenic predominant factor. Paradoxically, the number of ilnesses and sick people arises proportionally with health levels. We now tend to add "disease labels" in daily clinical practice to behaviors and events that are nothing but elements of character or even healthy reactions to laboral and familial conflicts or mourning. In this article, we analyze the factors that determine this "medicalization" process and its consequences, with a particular emphasis in the iatrogenesis of unnecessary medical interventions. PMID- 24055131 TI - [Medicalization of life at the GP level: Where are we headed to?]. AB - The power of medicine has lately enhanced the idea of medicalizing any aspects of life that can be perceived as medical problems. Medicine sometimes creates false needs and there is nowadays an increasing number of situations are medicalized with the pretext of treating fake diseases such as spring fatigue, shyness o natural biological processes like menopause. Despite the better life conditions, we now attend more people that complain about discomfort that may have more to do with "feeling sick" than with authentic disease. There is an endless list: sadness, hyperactive children, anorexia, bulimia, vigorexia or problematic teenagers, amongst others. In this article we revise some interventions that, contribute to promote these situations also from the own doctor's office. Everyday adversity acquires today the status of disease, hence the remarkable increase in these consultations in the diverse sanitary services. PMID- 24055132 TI - The fragmented proximal pole scaphoid nonunion treated with rib autograft: case series and review of the literature. AB - Nonunions of the proximal pole of the scaphoid are a challenge to treat given the limited vascular supply. This challenge is potentiated when the proximal pole is unsalvageable. When the proximal pole of the scaphoid is fragmented or otherwise unsalvageable, traditional reconstructive procedures such as vascularized or nonvascularized bone grafting are not possible. Salvage procedures such as proximal row carpectomy or scaphoid excision and partial wrist fusion would not be ideal in the case of an unsalvageable proximal pole scaphoid nonunion in the absence of radiocarpal arthrosis. In this relatively uncommon circumstance, we favor the use of rib osteochondral autograft reconstruction of the proximal pole of the scaphoid. We report 3 cases with greater than 2-years of follow-up evaluation and also review the literature. PMID- 24055133 TI - Decellularized human tendon-bone grafts for composite flexor tendon reconstruction: a cadaveric model of initial mechanical properties. AB - PURPOSE: After complex hand trauma, restoration of tendon strength is challenging. Tendon insertion tears typically heal as fibrous scars after surgical reconstruction and create a weak point at the tendon-bone interface. In addition, major tendon loss may overwhelm the amount of available autograft for reconstruction. An off-the-shelf product may help address these challenges. We hypothesized that decellularized human flexor digitorum profundus and distal phalanx tendon-bone composite grafts were a feasible option for flexor tendon reconstruction after complex hand trauma. By replacing the entire injured composite segment, the need for tendon repair within the tendon sheath, reconstruction of the tendon-bone interface, and use of limited autograft could be eliminated. METHODS: Paired human cadaver forearms were dissected to obtain the flexor digitorum profundus tendon with an attached block of distal phalanx. Tendon-bone grafts were pair-matched and divided into 2 groups: decellularized grafts (n = 12) and untreated (control) grafts (n = 11). Grafts in the decellularized group were subjected to physiochemical decellularization. Pair matched tendon-bone grafts (decellularized and untreated) were placed back into the flexor tendon sheath and secured distally using a tie-over button and proximally by weaving the graft into the flexor digitorum superficialis tendon in the distal forearm. The ultimate load, location of failure, and excursion were determined. RESULTS: Decellularized tendon-bone composite grafts demonstrated no significant difference in ultimate failure load or stiffness compared with untreated grafts. Both groups eventually failed in varied locations along the repair. The most common site of failure in both groups was the tie-over button. The decellularized group failed at the tendon-bone insertion in 3 specimens (25%) compared with none in the untreated group. Both groups demonstrated an average tendon excursion of approximately 82 mm before failure. CONCLUSIONS: Decellularization of human flexor tendon-distal phalanx tendon-bone constructs did not compromise initial strength despite chemical and mechanical decellularization in a cadaveric model. At the time of repair, decellularized flexor tendon-bone grafts can exceed the strength and excursion needed for hand therapy immediately after reconstruction. CLINICAL RELEVANCE: These tendon-bone grafts may become an option for complex hand reconstruction at or near tendon bone insertions and throughout the tendon sheath. Further work is required to assess the role of reseeding in an in vivo model. PMID- 24055134 TI - The utility of prenatal ultrasound as a screening tool for upper extremity congenital anomalies. AB - PURPOSE: To quantify the detection rate and accuracy of prenatal ultrasound in patients with congenital upper extremity anomalies. METHODS: A total of 100 patients with congenital upper extremity reduction or duplication anomalies were enrolled prospectively in this investigation at the initial visit to our congenital hand clinic. Demographic and pregnancy-related data were collected along with prenatal diagnoses. We recorded all ultrasound-identified upper extremity anomalies as reported by the parents. Finally, we compared the prenatal diagnosis with the final congenital hand clinic diagnosis. RESULTS: The first ultrasound was performed at a mean 11 weeks' gestation, and patients underwent an average of 8 prenatal ultrasounds (range, 1-40 prenatal ultrasounds). Sixty patients underwent standard ultrasound and 40 had a 3-dimensional ultrasound as well. Of the 100 patients, 31 had an upper extremity anomaly by ultrasound. Of the 31 prenatal ultrasound diagnoses, 18 were confirmed as accurate during evaluation in the congenital hand clinic. Three-dimensional ultrasound was more sensitive for the detection of upper extremity anomalies. CONCLUSIONS: The overall detection rate and accuracy of ultrasonography for upper extremity anomalies were low despite advancements in imaging technology. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 24055135 TI - A multi faceted quality improvement programme results in improved outcomes for the selective non-operative management of penetrating abdominal trauma in a developing world trauma centre. AB - INTRODUCTION: The selective non-operative management (SNOM) of penetrating abdominal trauma (PAT) is well established in our environment. As a quality improvement initiative, we aimed to re-evaluate patient outcomes with PAT. This follows the application of new imaging and diagnostic modalities using protocolised management algorithms. METHODOLOGY: A prospectively maintained digital registry was retrospectively interrogated and all patients with PAT treated by our service from January 2012 to March 2013 were included in this study. RESULTS: A total of 325 patients sustained PAT during the fourteen-month study period. This included 238 SWs, 80 GSWs and 7 impalement injuries. 11 patients had eviscerated bowel, and 12 had eviscerated omentum. A total of 123 patients (38%) were selected for a trial of SNOM. This included 103 SWs, 15 GSWs and 5 impalement injuries. Emergency laparotomy was performed on 182 patients (115 SWs, 65 GSWs and 2 impalement injuries) and 21 patients with left sided thoraco-abdominal SWs underwent definitive diagnostic laparoscopy (DL). SNOM was successful in 122 cases (99%) and unsuccessful in one case (1%). In the laparotomy group 161 (88%) patients underwent a therapeutic procedure, in 12 cases (7%) the laparotomy was non-therapeutic and in 9 cases (5%) the laparotomy was negative. In the laparoscopy group (24), two patients required conversion for colonic injuries and one for equipment failure. Seven (33.3%) laparoscopies were therapeutic with the identification and intra-corporeal repair of seven left hemi diaphragm injuries. CONCLUSION: We have improved our results with the SNOM of PAT and have also managed to safely and successfully extend the role of SNOM to abdominal GSWs. We have selectively adopted newer modalities such as laparoscopy to assess stable patients with left thoraco-abdominal SWs and abdominal CT scan for the SNOM of abdominal GSWs. PMID- 24055136 TI - Compounded progesterone and the Behavioral Model of Health Services Use. AB - Compounded progesterone (P4) is a product that, from a clinical experience-based perspective, effectively relieves a range of symptoms. In contrast, from a conventional evidence-based medicine perspective, P4 is ineffective. As P4 is not a product prescribed by conventional medicine, it is unlikely to be prescribed by family doctors, which increases the barriers to utilization. Utilization of medicines is influenced by many contextual and individual characteristics. The Behavioral Model of Health Services Use provides a multidimensional framework to conceptualize utilization of health services including medicine use. The 4 main components of this model are: contextual characteristics, individual characteristics, health behaviors and outcomes. This paper reports on the application of The Behavioral Model of Health Services Use to medicines and shows how it can be applied to the use of P4. The model enables some of the positive reinforcement that contributes to women continuing to use P4 to be explained. The Behavioral Model of Health Services Use was found to offer the potential to identify and then address issues with access to prescription medicines. PMID- 24055137 TI - Consumer, physician, and payer perspectives on primary care medication management services with a shared resource pharmacists network. AB - BACKGROUND: Health care reform initiatives are examining new care delivery models and payment reform alternatives such as medical homes, health homes, community based care transitions teams, medical neighborhoods and accountable care organizations (ACOs). Of particular interest is the extent to which pharmacists are integrated in team-based health care reform initiatives and the related perspectives of consumers, physicians, and payers. OBJECTIVES: To assess the current knowledge of consumers and physicians about pharmacist training/expertise and capacity to provide primary care medication management services in a shared resource network; determine factors that will facilitate/limit consumer interest in having pharmacists as a member of a community-based "health care team;" determine factors that will facilitate/limit physician utilization of pharmacists for medication management services; and determine factors that will facilitate/limit payer reimbursement models for medication management services using a shared resource pharmacist network model. METHODS: This project used qualitative research methods to assess the perceptions of consumers, primary care physicians, and payers on pharmacist-provided medication management services using a shared resource network of pharmacists. Focus groups were conducted with primary care physicians and consumers, while semi-structured discussions were conducted with a public and private payer. RESULTS: Most consumers viewed pharmacists in traditional dispensing roles and were unaware of the direct patient care responsibilities of pharmacists as part of community-based health teams. Physicians noted several chronic disease states where clinically-trained pharmacists could collaborate as health care team members yet had uncertainties about integrating pharmacists into their practice workflow and payment sources for pharmacist services. Payers were interested in having credentialed pharmacists provide medication management services if the services improved quality of patient care and/or prevented adverse drug events, and the services were cost neutral (at a minimum). CONCLUSIONS: It was difficult for most consumers and physicians to envision pharmacists practicing in non-dispensing roles. The pharmacy profession must disseminate the existing body of evidence on pharmacists as care providers of medication management services and the related impact on clinical outcomes, patient safety, and cost savings to external audiences. Without such, new pharmacist practice models may have limited acceptance by consumers, primary care physicians, and payers. PMID- 24055138 TI - Sustainable agriculture: possible trajectories from mutualistic symbiosis and plant neodomestication. AB - Food demand will increase concomitantly with human population. Food production therefore needs to be high enough and, at the same time, minimize damage to the environment. This equation cannot be solved with current strategies. Based on recent findings, new trajectories for agriculture and plant breeding which take into account the belowground compartment and evolution of mutualistic strategy, are proposed in this opinion article. In this context, we argue that plant breeders have the opportunity to make use of native arbuscular mycorrhizal (AM) symbiosis in an innovative ecologically intensive agriculture. PMID- 24055139 TI - A unified nomenclature of NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER family members in plants. AB - Members of the plant NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER (NRT1/PTR) family display protein sequence homology with the SLC15/PepT/PTR/POT family of peptide transporters in animals. In comparison to their animal and bacterial counterparts, these plant proteins transport a wide variety of substrates: nitrate, peptides, amino acids, dicarboxylates, glucosinolates, IAA, and ABA. The phylogenetic relationship of the members of the NRT1/PTR family in 31 fully sequenced plant genomes allowed the identification of unambiguous clades, defining eight subfamilies. The phylogenetic tree was used to determine a unified nomenclature of this family named NPF, for NRT1/PTR FAMILY. We propose that the members should be named accordingly: NPFX.Y, where X denotes the subfamily and Y the individual member within the species. PMID- 24055140 TI - CRKL promotes cell proliferation in gastric cancer and is negatively regulated by miR-126. AB - V-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) is a member of CRK family and act as an adaptor protein participating in intra-cellular signal transduction. The role of CRKL in gastric cancer (GC) remains unclear. In this study, we show that CRKL was aberrantly highly expressed in both GC tumor specimens and cell lines (SGC-7901, MKN-45, MKN-28 and SUN-16). The expression of CRKL was significantly correlated with GC clinicopathologic features including tumor size, local invasion, lymph node metastasis and TNM stages. Knock-down of CRKL in SGC-7901 cells induced a suppression of cell proliferation along with a significant arrest of cell cycle in G0/G1 phase, however, no significant influence was observed on cell apoptosis. We validate that miR-126, a suppressor in GC, was a negative regulator of CRKL by directly combining with the 3' untranslated region of CRKL mRNA, and over-expression of miR-126 inhibited the protein expression of CRKL significantly. These results suggest that CRKL may function as an oncogene in GC by promoting the GC cell proliferation, which provides us a likely biomarker and a potential target for GC prevention, diagnosis and therapeutic treatment. Moreover, the targeting relationship between CRKL and miR-126 partly reveals the mechanism of miR-126 on GC suppression. PMID- 24055141 TI - Antibody mediated CDCP1 degradation as mode of action for cancer targeted therapy. AB - CUB-domain-containing-protein-1 (CDCP1) is an integral membrane protein whose expression is up-regulated in various cancer types. Although high CDCP1 expression has been correlated with poor prognosis in lung, breast, pancreas, and renal cancer, its functional role in tumor formation or progression is incompletely understood. So far it has remained unclear, whether CDCP1 is a useful target for antibody therapy of cancer and what could be a desired mode of action for a therapeutically useful antibody. To shed light on these questions, we have investigated the cellular effects of a therapeutic antibody candidate (RG7287). In focus formation assays, prolonged RG7287 treatment prevented the loss of contact inhibition caused by co-transformation of NIH3T3 cells with CDCP1 and Src. In a xenograft study, MCF7 cells stably overexpressing CDCP1 reached the predefined tumor volume faster than the parental MCF7 cells lacking endogenous CDCP1. This tumor growth advantage was abolished by RG7287 treatment. In vitro, RG7287 induced rapid tyrosine phosphorylation of CDCP1 by Src, which was accompanied by translocation of CDCP1 to a Triton X-100 insoluble fraction of the plasma membrane. Triggering these effects required bivalency of the antibody suggesting that it involves CDCP1 dimerization or clustering. However, this initial activation of CDCP1 was only transient and prolonged RG7287 treatment induced internalization and down-regulation of CDCP1 in different cancer cell lines. Antibody stimulated CDCP1 degradation required Src activity and was proteasome dependent. Also in three different xenograft models with endogenous CDCP1 expression RG7287 treatment resulted in significant tumor growth inhibition concomitant with substantially reduced CDCP1 levels as judged by immunohistochemistry and Western blotting. Thus, despite transiently activating CDCP1 signaling, the RG7287 antibody has a therapeutically useful mode of action. PMID- 24055143 TI - Diagnosing acute appendicitis: is there any role of ultrasonography? PMID- 24055142 TI - V-ATPase inhibition overcomes trastuzumab resistance in breast cancer. AB - The HER2 oncogene targeting drug trastuzumab shows remarkable efficacy in patients overexpressing HER2. However acquired or primary resistance develops in most of the treated patients why alternative treatment strategies are strongly needed. As endosomal sorting and recycling are crucial steps for HER2 activity and the vacuolar H+-ATPase (V-ATPase) is an important regulator of endocytotic trafficking, we proposed that targeting V-ATPase opens a new therapeutic strategy against trastuzumab-resistant tumor cells in vitro and in vivo. V-ATPase inhibition with archazolid, a novel inhibitor of myxobacterial origin, results in growth inhibition, apoptosis and impaired HER2 pro-survival signaling of the trastuzumab-resistant cell line JIMT-1. This is accompanied by a decreased expression on the plasma membrane and accumulation of HER2 in the cytosol, where it colocalizes with endosomes, lysosomes and autophagosomes. Importantly, microscopic analysis of JIMT-1 xenograft tumor tissue of archazolid treated mice confirms the defect in HER2-recycling which leads to reduced tumor growth. These results suggest that V-ATPase inhibition by archazolid induces apoptosis and inhibits growth of trastuzumab-resistant tumor cells by retaining HER2 in dysfunctional vesicles of the recycling pathway and consequently abrogates HER2 signaling in vitro as well as in vivo. V-ATPase inhibition is thus suggested as a promising strategy for treatment of trastuzumab-resistant tumors. PMID- 24055144 TI - Staged marginal contoured and central excision technique in the surgical management of perianal Paget's disease. AB - BACKGROUND: Extramammary Paget's disease (EMPD) is an adenocarcinoma of the apocrine glands with unknown exact prevalence and obscure etiology. It has been divided into primary EMPD and secondary EMPD, in which an internal malignancy is usually associated. Treatment for primary EMPD usually consists of wide lesion excision with negative margins. Multiple methods have been proposed to obtain free-margin status of the disease. These include visible border lesion excision, punch biopsies, and micrographic and frozen-section surgery, with different results but still high recurrence rates. METHODS: The investigators propose a method consisting of a staged contoured marginal excision using "en face" permanent pathologic analysis preceding the steps of central excision of the lesion and the final reconstruction of the surgical defect. RESULTS: Advantages of this method include adequate margin control allowing final reconstruction and tissue preservation, while minimizing patient discomfort. CONCLUSIONS: The staged contoured marginal and central excision technique offers a new alternative to the armamentarium for surgical oncologists for the management of EMPD in which margin control is imperative for control of recurrence rates. PMID- 24055145 TI - Tuberculous-destroyed lung: cardiovascular CT findings and prognostic imaging factors. AB - The purpose of this study was to evaluate cardiovascular computed tomography (CT) findings in tuberculous-destroyed lung (TDL) and to correlate these imaging features with survival. CT was assessed for the diameter of the pulmonary artery (dPA) and ascending aorta, the diameters of ventricles, ventricular septal bowing (VSB), extent of TDL, or hypertrophied bronchial artery and others. Seventy-three percent of the TDL patients had a dPA greater than 29 mm. The right ventricle (RV)/left ventricle (LV) ratio in 70% of the patients was greater than 1.0, and VSB was observed in 18%. The RV/LV ratio was the only independent risk factor for poor survival in statistical analysis. PMID- 24055146 TI - Preoperative staging of colorectal cancer: accuracy of single portal venous phase multidetector computed tomography. AB - In this study, we aimed to investigate the accuracy of single portal venous phase multidetector computed tomography (MDCT) in preoperative staging of colorectal cancer. MDCT, surgery, and pathological results of 159 patients with pathologically proven colorectal adenocarcinoma were evaluated retrospectively. In T staging, the accuracy was 96% for <= T2 tumors, 92% for T3 tumors, and 96% for T4 tumors. In N staging, the accuracy was 68% for N0 tumors, 74% for N1 tumors, and 71% for N2 tumors. In conclusion, the accuracy of single portal venous phase MDCT is reasonably high in T staging, but it is not sufficiently high enough in N staging. PMID- 24055147 TI - Dairy recommendations for ill pediatric patients. PMID- 24055148 TI - Ameloblastic fibroma: a stage in the development of a hamartomatous odontoma or a true neoplasm? Critical analysis of 162 previously reported cases plus 10 new cases. AB - OBJECTIVE: To analyze neoplastic and hamartomatous variants of ameloblastic fibromas (AFs). STUDY DESIGN: Analysis of 172 cases (162 previously reported, 10 new). RESULTS: AF emerged as a lesion primarily of children and adolescents (mean age, 14.9 years), with about 80% diagnosed when odontogenesis is completed (age, < 22 years). Around 28% of all AFs were small and asymptomatic, and 72% exhibited moderate-to-severe bone expansion. CONCLUSIONS: There are 2 variants of AF: neoplastic and hamartomatous. Lesions in patients aged >22 years are considered true neoplasms, while those in younger patients may be either true neoplasms or odontomas in early stages of development. Although the histopathology of hamartomatous and neoplastic variants of AF are indistinguishable, clinical and radiologic features can be of some help to distinguish between them. Asymptomatic small unilocular lesions with no or minimal bone expansion in young individuals are likely to be developing odontomas, and large, expansile lesions with extensive bone destruction are neoplasms. PMID- 24055149 TI - The effect of drilling speed on early bone healing to oral implants. AB - OBJECTIVE: This study evaluated the effect of drilling speed on early bone healing in dog tibiae. STUDY DESIGN: Thirty-six implants (4.0-mm diameter * 10-mm length) were placed in the proximal tibiae of 6 beagles with drilling speeds of 100, 500, and 1000 rpm, and insertion torque was recorded. Bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO) were evaluated. RESULTS: Significant increase from 1 to 3 weeks was observed for all groups for BIC, whereas no significant differences between 1 and 3 weeks were detected for the 100- and 500-rpm groups for BAFO (P > .34 and P > .46, respectively). A significant difference from 1 to 3 weeks was observed for the 1000-rpm group (P < .03). The 100- and 500-rpm groups presented significantly higher BAFO than the 1000-rpm group at 1 week (P = .002). CONCLUSIONS: Drilling speed is one of the decisive factors for early osseointegration, and overall, drilling at 1000 rpm seemed to yield the strongest biologic responses. PMID- 24055150 TI - Susceptibility profile of a Brazilian yeast stock collection of Candida species isolated from subjects with Candida-associated denture stomatitis with or without diabetes. AB - OBJECTIVE: This study investigated the susceptibility of 198 clinical isolates of Candida species against caspofungin, amphotericin B, itraconazole, and fluconazole. STUDY DESIGN: Suspensions of the microorganisms were spread on Roswell Park Memorial Institute (RPMI) agar plates. Etest strips were placed on the plates, and the minimal inhibitory concentration (MIC) was read after incubation (48 h at 37 degrees C). Data were analyzed by a factorial analysis of variance and a 2 * 2 post hoc test (alpha = .05). RESULTS: C glabrata showed the highest MIC values (P < .001) against caspofungin, itraconazole, and fluconazole. For amphotericin B, the MIC values of C tropicalis and C glabrata (P = .0521) were higher than those of C albicans (P < .001). Itraconazole was the least effective antifungal; 93.3% of the C glabrata isolates, 3.3% of the C albicans, and 1.3% of the C tropicalis were resistant. All microorganisms were susceptible to caspofungin and amphotericin B. CONCLUSIONS: Caspofungin and amphotericin B should be recommended as an effective alternative for the management of oral Candida infections when treatment with topical or other systemic drugs has definitely failed. PMID- 24055151 TI - Legislated changes to federal pension income in Canada will adversely affect low income seniors' health. AB - OBJECTIVE: This study uses a population health intervention modeling approach to project the impact of recent legislated increases in age eligibility for Canadian federally-funded pension benefits on low income seniors' health, using food insecurity as a health indicator. METHOD: Food insecurity prevalence and income source were assessed for unattached low income (<$20,000 CAD) persons aged 60-64 years (population weighted n=151,350) versus seniors aged 65-69 years (population weighted n=151,485) using public use data from the Canadian Community Health Survey Cycle 4.1 (2007-2008). RESULTS: Seniors' benefits through federal public pension plans constituted the main source of income for the majority (79.4%) of low income seniors aged 65-69 years, in contrast to low income seniors aged 60-64 years who reported their main income from employment, employment insurance, Workers' Compensation, or welfare. The increase in income provided by federal pension benefits for low income Canadians 65 and over coincided with a pronounced (50%) decrease in food insecurity prevalence (11.6% for seniors >=65 years versus 22.8% for seniors <65 years). CONCLUSION: Raising the age of eligibility for public pension seniors' benefits in Canada from 65 to 67 years will negatively impact low income seniors' health, relegating those who are food insecure to continued hardship. PMID- 24055152 TI - The clinical course of hepatitis E virus infection in patients of a tertiary Dutch hospital over a 5-year period. AB - BACKGROUND: Hepatitis E virus (HEV) has long been known as a major cause of acute hepatitis in developing countries with occasional travel-related cases in developed countries, most of them belonging to genotype 1. Currently, genotype 3 HEV is recognized as an emerging public health issue in developed countries and can cause a chronic hepatitis in immunocompromised patients. OBJECTIVES: The aim of this study was to get an overview of the clinical course of HEV infection, from July 2007 to December 2012, and further characterize HEV in patients of the University Medical Center Groningen (UMCG) over a 5-year time period. METHODS: Since the second half of 2007, patients in the UMCG with unexplained hepatitis were screened for HEV and clinical data were collected. HEV was characterized by sequencing of the ORF1 and ORF2 regions. RESULTS: In total, 34 patients of the 1129 tested patients showed HEV viremia. The majority of the infected patients were immunocompromised; 18 were solid organ transplant (SOT) patients and 9 were patients immunocompromised for other reasons. Seven patients diagnosed with HEV were immunocompetent. Viral genotyping revealed genotype 3 isolates, mostly genotype 3c. CONCLUSION: Non-travel related HEV hepatitis is an important diagnosis. In immunocompromised patients HEV infection often has major clinical impact, necessitating medical intervention including antiviral treatment. In immunocompetent patients, the detection could expand our understanding about the route of transmission and the relation with the zoonotic origin. Therefore, besides an increasing awareness for HEV among clinicians and medical microbiologists, diagnostics should be routinely incorporated into standard patients care. PMID- 24055153 TI - WAPL-mediated removal of cohesin protects against segregation errors and aneuploidy. AB - The classical X shape of mitotic human chromosomes is the consequence of two distinct waves of cohesin removal. First, during prophase and prometaphase, the bulk of cohesin is driven from chromosome arms by the cohesin antagonist WAPL. This arm-specific cohesin removal is referred to as the prophase pathway [1-4]. The subsequent cleavage of the remaining centromeric cohesin by Separase is known to be the trigger for anaphase onset [5-7]. Remarkably the biological purpose of the prophase pathway is unknown. We find that this pathway is essential for two key mitotic processes. First, it is important to focus Aurora B at centromeres to allow efficient correction of erroneous microtubule-kinetochore attachments. In addition, it is required to facilitate the timely decatenation of sister chromatids. As a consequence, WAPL-depleted cells undergo anaphase with segregation errors, including both lagging chromosomes and catenanes, resulting in micronuclei and DNA damage. Stable WAPL depletion arrests cells in a p53 dependent manner but causes p53-deficient cells to become highly aneuploid. Our data show that the WAPL-dependent prophase pathway is essential for proper chromosome segregation and is crucial to maintain genomic integrity. PMID- 24055154 TI - Extremes of lineage plasticity in the Drosophila brain. AB - An often-overlooked aspect of neural plasticity is the plasticity of neuronal composition, in which the numbers of neurons of particular classes are altered in response to environment and experience. The Drosophila brain features several well-characterized lineages in which a single neuroblast gives rise to multiple neuronal classes in a stereotyped sequence during development. We find that in the intrinsic mushroom body neuron lineage, the numbers for each class are highly plastic, depending on the timing of temporal fate transitions and the rate of neuroblast proliferation. For example, mushroom body neuroblast cycling can continue under starvation conditions, uncoupled from temporal fate transitions that depend on extrinsic cues reflecting organismal growth and development. In contrast, the proliferation rates of antennal lobe lineages are closely associated with organismal development, and their temporal fate changes appear to be cell cycle-dependent, such that the same numbers and types of uniglomerular projection neurons innervate the antennal lobe following various perturbations. We propose that this surprising difference in plasticity for these brain lineages is adaptive, given their respective roles as parallel processors versus discrete carriers of olfactory information. PMID- 24055155 TI - Evolution of camouflage drives rapid ecological change in an insect community. AB - BACKGROUND: Evolutionary change in individual species has been hypothesized to have far-reaching consequences for entire ecological communities, and such coupling of ecological and evolutionary dynamics ("eco-evolutionary dynamics") has been demonstrated for a variety systems. However, the general importance of evolutionary dynamics for ecological dynamics remains unclear. Here, we investigate how spatial patterns of local adaptation in the stick insect Timema cristinae, driven by the interaction between multiple evolutionary processes, structure metapopulations, communities, and multitrophic interactions. RESULTS: Observations of a wild T. cristinae metapopulation show that locally imperfect camouflage reduces population size and that the effect of such maladaptation is comparable to the effects of more traditional ecological factors, including habitat patch size and host-plant species identity. Field manipulations of local adaptation and bird predation support the hypothesis that maladaptation reduces population size through an increase in bird predation. Furthermore, these field experiments show that maladaptation in T. cristinae and consequent increase in bird predation reduce the pooled abundance and species richness of the co occurring arthropod community, and ultimately cascade to decrease herbivory on host plants. An eco-evolutionary model of the observational data demonstrates that the demographic cost of maladaptation decreases habitat patch occupancy by T. cristinae but enhances metapopulation-level adaptation. CONCLUSIONS: The results demonstrate a pervasive effect of ongoing evolution in a spatial context on population and community dynamics. The eco-evolutionary model makes testable predictions about the influence of the spatial configuration of the patch network on metapopulation size and the spatial scale of adaptation. PMID- 24055156 TI - Phospho-H2A and cohesin specify distinct tension-regulated Sgo1 pools at kinetochores and inner centromeres. AB - Accurate chromosome segregation requires coordination between the dissolution of sister-chromatid cohesion and the establishment of proper kinetochore-microtubule attachment. During mitosis, sister-chromatid cohesion at centromeres enables the biorientation of and tension across sister kinetochores. The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl. Cleavage of centromeric cohesin by separase allows sister chromatids connected to microtubules from opposing poles to be evenly partitioned into daughter cells. The centromeric localization of Sgo1 requires histone H2A phosphorylation at T120 (H2A-pT120) by the kinase Bub1. The exact role of H2A-pT120 in Sgo1 regulation is, however, unclear. Here, we show that cohesin and H2A-pT120 specify two distinct pools of Sgo1-P2A at inner centromeres and kinetochores, respectively, in human cells. Bub1 inactivation delocalizes cohesin-Sgo1 to chromosome arms. Kinetochore tension triggers Sgo1 dephosphorylation and redistributes Sgo1 from inner centromeres to kinetochores. Incomplete Sgo1 redistribution causes chromosome nondisjunction. Our study suggests that Bub1-mediated H2A phosphorylation penetrates kinetochores and that this histone mark contributes to a tension-sensitive Sgo1-based molecular switch for chromosome segregation. PMID- 24055157 TI - CK1 is required for a mitotic checkpoint that delays cytokinesis. AB - Failure to accurately partition genetic material during cell division causes aneuploidy and drives tumorigenesis. Cell-cycle checkpoints safeguard cells from such catastrophes by impeding cell-cycle progression when mistakes arise. FHA RING E3 ligases, including human RNF8 and CHFR and fission yeast Dma1, relay checkpoint signals by binding phosphorylated proteins via their FHA domains and promoting ubiquitination of downstream targets. Upon mitotic checkpoint activation, S. pombe Dma1 concentrates at spindle pole bodies (SPBs) in an FHA dependent manner and ubiquitinates Sid4, a scaffold of Polo kinase, to suspend cytokinesis. However, the kinase or kinases that phosphoprime Sid4 for Dma1 mediated ubiquitination are unknown. Here, we report that the highly conserved protein kinase CK1 transmits the signal necessary to stall cytokinesis by phosphopriming Sid4 for Dma1-mediated ubiquitination. Like Dma1, CK1 accumulates at SPBs during a mitotic arrest and associates stably with SPB components, including Sid4. Our results establish CK1 as an integral component of a mitotic, ubiquitin-mediated checkpoint pathway. PMID- 24055159 TI - Thermally stable harpin, HrpZPss is sensitive to chemical denaturants: probing tryptophan environment, chemical and thermal unfolding by fluorescence spectroscopy. AB - Harpins - a group of proteins that elicit hypersensitive response (HR) in non host plants - are secreted by certain Gram-negative plant pathogenic bacteria upon interaction with the plant. In the present study, the microenvironment and solvent accessibility of the sole tryptophan residue (Trp-167) in harpin HrpZPss, secreted by Pseudomonas syringae pv. syringae, have been characterized by fluorescence spectroscopic studies. Emission lambdamax of the native protein at 328 nm indicates that Trp-167 is buried in a hydrophobic region in the interior of the protein matrix. Significant quenching (53%) was seen with the neutral quencher, acrylamide at 0.5 M concentration, whereas quenching by ionic quenchers, I(-) (~10%) and Cs(+) (negligible) was considerably lower. In the presence of 6.0 M guanidine hydrochloride (GdnHCl) the emission lambdamax shifted to 350.5 nm, and quenching by both neutral and ionic quenchers increased significantly, suggesting complete exposure of the indole side chain to the aqueous medium. Fluorescence studies on the thermal unfolding of HrpZPss are fully consistent with a complex thermal unfolding process and high thermal stability of this protein, inferred from previous differential scanning calorimetric and dynamic light scattering studies. However, the protein exhibits low resistance to chemical denaturants, with 50% unfolding seen in the presence of 1.77 M GdnHCl or 3.59 M urea. The ratio of m value, determined from linear extrapolation model, for GdnHCl and urea-induced unfolding was 1.8 and suggests the presence of hydrophobic interactions, which could possibly involve leucine zipper-like helical regions on the surface of the protein. PMID- 24055158 TI - SPIRAL2 determines plant microtubule organization by modulating microtubule severing. AB - One of the defining characteristics of plant growth and morphology is the pivotal role of cell expansion. While the mechanical properties of the cell wall determine both the extent and direction of cell expansion, the cortical microtubule array plays a critical role in cell wall organization and, consequently, determining directional (anisotropic) cell expansion. The microtubule-severing enzyme katanin is essential for plants to form aligned microtubule arrays; however, increasing severing activity alone is not sufficient to drive microtubule alignment. Here, we demonstrate that katanin activity depends upon the behavior of the microtubule-associated protein (MAP) SPIRAL2 (SPR2). Petiole cells in the cotyledon epidermis exhibit well-aligned microtubule arrays, whereas adjacent pavement cells exhibit unaligned arrays, even though SPR2 is found at similar levels in both cell types. In pavement cells, however, SPR2 accumulates at microtubule crossover sites, where it stabilizes these crossovers and prevents severing. In contrast, in the adjacent petiole cells, SPR2 is constantly moving along the microtubules, exposing crossover sites that become substrates for severing. Consequently, our study reveals a novel mechanism whereby microtubule organization is determined by dynamics and localization of a MAP that regulates where and when microtubule severing occurs. PMID- 24055160 TI - Identification of multiple antimicrobial peptides from the skin of fine-spined frog, Hylarana spinulosa (Ranidae). AB - In this study, peptidomics and genomics analyses were used to study antimicrobial peptides from the skin of Hylarana spinulosa. Twenty-nine different antimicrobial peptide precursors were characterized from the skin of H. spinulosa, which produce 23 mature antimicrobial peptides belonging to 12 different families. To confirm the actual presence and characteristics of these antimicrobial peptides in the skin tissue extractions from H. spinulosa, we used two distinct methods, one was peptide purification method that combined gel filtration chromatography and reversed-phase high performance liquid chromatography (RP-HPLC), and the other was peptidomics approach based on liquid chromatography in conjunction with tandem mass spectrometry (LC-MS/MS). In the peptidomics approach, incomplete tryptic digestion and gas-phase fractionation (GPF) analysis were used to increase peptidome coverage and reproducibility of peptide ion selection. Multiple species of microorganisms were chosen to test and analyze the antimicrobial activities and spectrum of these antimicrobial peptides. PMID- 24055161 TI - The Depression Impairment Scale for Parents (DISP): a new scale for the measurement of impairment in depressed parents. AB - Children of depressed parents are at increased risk of developing mood disorders but mechanisms of intrafamilial transmission are currently unclear. One rarely investigated area is the impact of depression on a parent's everyday functioning. Currently there are no validated assessments of depression-specific parental impairment. The creation of such a measure would complement depression symptom counts, providing a more comprehensive account of the parent's depression. We therefore aimed to develop a valid and reliable measure of impairment specifically associated with parental depression. In a longitudinal study of parents with recurrent unipolar depression and their offspring, we collected data from 337 parents. These participants completed the Depression Impairment Scale for Parents (DISP), a questionnaire assessing depression-associated impairment in multiple domains of functioning. Factor analysis revealed that this measure consisted of two factors - impairment in routine tasks/activities and impairment in family functioning - that together accounted for 51.04% of variance. The scale evidenced good internal consistency (Cronbach's alpha=0.82). The DISP also displayed good construct and criterion validity as evidenced by significant associations with established measures of depression severity and global impairment. These results demonstrate that the DISP is a valid and reliable measure of depression-associated impairment in parents. PMID- 24055162 TI - Factors associated with suicide method among psychiatric patients in a general hospital in Korea. AB - This study aims to highlight the factors associated with suicide method among psychiatric patients in a general hospital in Korea. In a sample of 467 suicides by patients who had received mental health care in a general hospital in Korea, the relationship between suicide method and time of death as well as clinical characteristics, including psychiatric adiagnosis, was examined using multinomial logistic regression analysis. Compared with the general population, psychiatric patients, regardless of disorder, committed suicide by jumping from heights more often than by hanging (OR=2.35-8.64). In particular, patients with psychotic disorders and female patients were more likely to use jumping from a height than hanging to kill themselves (OR=2.98 and 1.83, respectively). Patients were more likely to use suicide methods other than hanging (e.g., OR=6.7 for jumping, 5.3 for drowning, and 2.7 for self-poisoning) between midnight and dawn. Possible suicide-prevention strategies suggested by this study include limiting access to or fencing off tall structures in close proximity to psychiatric institutions and residential care homes. At night, limiting access to or instituting heightened supervision of tall structures is specifically indicated. PMID- 24055163 TI - TFR2-related hereditary hemochromatosis as a frequent cause of primary iron overload in patients from Central-Southern Italy. AB - OBJECTIVE: Hereditary hemochromatosis (HH) is a common Mendelian disorder of iron metabolism. Eighty percent of northern Europeans descendant HH patients carry the same mutation (p.C282Y) in the HFE gene. Simultaneously, due to a founder effect, its frequency varies considerably between different populations. In Central Southern Italy the prevalence of p.C282Y mutation is low and in several patients the disease has different causes. Four additional rarer forms have been described. Type 3 HH has been reported in about 50 families and no more than 30 TFR2 pathogenic mutations have been globally identified. The aim of this study is to assess the TFR2 role in non-HFE HH pathogenesis. STUDY DESIGN AND SETTING: TFR2 sequence analysis was performed on 45 Italian patients without HFE mutations. RESULTS: This study revealed TFR2 biallelic pathogenic mutations in 7/45 (15.6%) individuals. Moreover monoallelic TFR2 deleterious defects (18%) or polymorphisms with unclear meaning (36%) were identified. Besides, we recognized 10 novel variants and 9 described changes. CONCLUSION: We believe this to be the largest series of type 3 HH patients described so far. Present findings support the hypothesis of a main role of the TFR2 gene in HH pathogenesis in those regions, such as Central-Southern Italy, where the p.C282Y frequency is low. PMID- 24055164 TI - Treatment-related harms: what was planned and what was reported? National Cancer Institute's Co-operative group phase III randomized controlled trials: a systematic review. PMID- 24055165 TI - New concepts of breast cell communication to bone. AB - Lactation is the most extreme case of normal physiological bone loss during a lifetime, and breast cancers have a strong tendency to metastasize to bone. In both the physiological and pathological circumstances, parathyroid hormone related peptide (PTHrP) plays a central role. Until recently there were no regulatory mechanisms to explain the induction of endocrine PTHrP secretion from breast cells during lactation. The mammary epithelium possesses a local serotonin signaling system which drives PTHrP expression during lactation and in breast cancer cells. The mammary gland serotonin system is highly induced in response to alveolar dilation due to milk secretion. Discovery of serotonergic control of PTHrP suggests that it may be possible to manipulate the breast-to-bone axis by targeting serotonin signaling. PMID- 24055166 TI - Treatment of Lesch-Nyhan disease with S-adenosylmethionine: experience with five young Malaysians, including a girl. AB - BACKGROUND: Lesch-Nyhan disease (LND) is a rare X-linked recessive neurogenetic disorder caused by deficiency of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8) which is responsible for recycling purine bases into purine nucleotides. Affected individuals have hyperuricemia leading to gout and urolithiasis, accompanied by a characteristic severe neurobehavioural phenotype with compulsive self-mutilation, extrapyramidal motor disturbances and cognitive impairment. AIM: For its theoretical therapeutic potential to replenish the brain purine nucleotide pool, oral supplementation with S-adenosylmethionine (SAMe) was trialed in 5 Malaysian children with LND, comprising 4 related Malay children from 2 families, including an LND girl, and a Chinese Malaysian boy. RESULTS: Dramatic reductions of self-injury and aggressive behaviour, as well as a milder reduction of dystonia, were observed in all 5 patients. Other LND neurological symptoms did not improve during SAMe therapy. DISCUSSION: Molecular mechanisms proposed for LND neuropathology include GTP depletion in the brain leading to impaired dopamine synthesis, dysfunction of G protein-mediated signal transduction, and defective developmental programming of dopamine neurons. The improvement of our LND patients on SAMe, particularly the hallmark self-injurious behaviour, echoed clinical progress reported with another purine nucleotide depletion disorder, Arts Syndrome, but contrasted lack of benefit with the purine disorder adenylosuccinate lyase deficiency. This first report of a trial of SAMe therapy in LND children showed remarkably encouraging results that warrant larger studies. PMID- 24055167 TI - Characterization of the cardiovascular control during modified head-up tilt test in healthy adult humans. AB - It is unknown whether modified head-up tilt (MTILT) with inclination of the back rest, thigh rest and shank rest of 60, 0 and 15 degrees respectively challenges autonomic control as assessed from beat-to-beat variability of heart period (HP) and systolic arterial pressure (SAP). In 15 healthy adult humans we found that during MTILT the SAP power in the low frequency band increased and baroreflex sensitivity assessed in the high frequency band decreased. Conversely, the HP power in the high frequency band was unmodified. MTILT can be fruitfully exploited to stress sympathetic control directed to vessels in bedridden, uncooperative patients. PMID- 24055168 TI - Optimal treatment of hypothyroidism associated with live birth in cases of previous recurrent placental abruption and stillbirth. AB - OBJECTIVE: To examine the clinical management of and placentas from pregnant women with hypothyroidism and obstetric history of recurrent stillbirth in order to identify possible etiologic mechanisms. METHODS: Two cases involving 26-year old women with hypothyroidism and history of recurrent stillbirth are reported. Placentas from all of the women's pregnancies were compared in order to identify histologic similarities. RESULTS: In both cases, multifocal hemorrhagic infarctions and abruptions were seen, indicating progressive uteroplacental ischemic damage leading to stillbirth. Thrombophilia, infection, and diabetes tests were all negative. With meticulous monitoring and normalization of thyroid function by end of first/early second trimester in subsequent pregnancies, there were live births and no evidence of infarction on placental histology. CONCLUSION: The 2 reported cases raise the possibility of uteroplacental ischemia and placental abruption being mechanisms by which hypothyroidism can lead to stillbirth; they also highlight the potential of minimizing this risk via adequate levothyroxine treatment from early pregnancy. PMID- 24055169 TI - Concomitant bilateral adnexal entanglement in a 7-year-old girl with precocious puberty. PMID- 24055170 TI - Abnormality, rationality, and sanity. AB - A growing body of studies suggests that neurological and mental abnormalities foster conformity to norms of rationality that are widely endorsed in economics and psychology, whereas normality stands in the way of rationality thus defined. Here, we outline the main findings of these studies, discuss their implications for experimental design, and consider how 'sane' some benchmarks of rationality really are. PMID- 24055171 TI - Shadow enhancers flanking the HoxB cluster direct dynamic Hox expression in early heart and endoderm development. AB - The products of Hox genes function in assigning positional identity along the anterior-posterior body axis during animal development. In mouse embryos, Hox genes located at the 3' end of HoxA and HoxB complexes are expressed in nested patterns in the progenitors of the secondary heart field during early cardiogenesis and the combined activities of both of these clusters are required for proper looping of the heart. Using Hox bacterial artificial chromosomes (BACs), transposon reporters, and transgenic analyses in mice, we present the identification of several novel enhancers flanking the HoxB complex which can work over a long range to mediate dynamic reporter expression in the endoderm and embryonic heart during development. These enhancers respond to exogenously added retinoic acid and we have identified two retinoic acid response elements (RAREs) within these control modules that play a role in potentiating their regulatory activity. Deletion analysis in HoxB BAC reporters reveals that these control modules, spread throughout the flanking intergenic region, have regulatory activities that overlap with other local enhancers. This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development. Regulatory analysis of the HoxA complex reveals that it also has enhancers in the 3' flanking region which contain RAREs and have the potential to modulate expression in endoderm and heart tissues. Together, the similarities in their location, enhancer output, and dependence on retinoid signaling suggest that a conserved cis-regulatory cassette located in the 3' proximal regions adjacent to the HoxA and HoxB complexes evolved to modulate Hox gene expression during mammalian cardiac and endoderm development. This suggests a common regulatory mechanism, whereby the conserved control modules act over a long range on multiple Hox genes to generate nested patterns of HoxA and HoxB expression during cardiogenesis. PMID- 24055172 TI - Spry1 and Spry2 are necessary for eyelid closure. AB - Sproutys (Sprys) are downstream targets and negative feedback regulators of the FGF-Ras-ERK signaling pathway. Our previous studies have shown that Spry1 and Spry2, through negative modulation of FGF-ERK signaling, allow lens vesicle separation from the overlying ectoderm and regulate corneal epithelial proliferation. Here we show that Spry1 and Spry2 are necessary for eyelid closure. Murine palpebral conjunctival epithelial cells that differentiate as inner eyelids and adjacent mesenchymal cells express Spry1 and Spry2 prior to eyelid closure. Conditional deletion of both Spry1 and Spry2, but not either one alone, in the ocular surface epithelial cells result in the "EOB" (eyes open at birth) phenotype suggesting redundant roles for these proteins during eyelid closure. Spry mutant eyelids show increased proliferation of conjunctival epithelial cells with concomitant induction of FGF targets, Erm, Pea3 and Dusp6 and elevated ERK phosphorylation. Peridermal cells at the leading edge of Spry mutant eyelids showed reduced c-Jun, but not ERK, phosphorylation, reduced F actin polymerization and reduced motility in vitro. Spry mutant eyelids also showed disruptions in epithelial mesenchymal interactions reflected in the enhanced mesenchymal Spry1 and Spry4 expression, disaggregation of BMP4-positive mesenchymal cells and loss of Shh in the eyelid epithelium. Spry mutant eyelids also showed increased Wnt signaling and reduced expression of Foxc1 and Foxc2, two transcription factors previously shown to be necessary for eyelid closure. Collectively, our results show that conjunctival epithelial Spry1 and Spry2 redundantly promote eyelid closure by (a) stimulating ERK-independent, c-Jun mediated peridermal migration, (b) suppressing conjunctival epithelial proliferation through FGF-ERK signaling, (c) mediating conjunctival epithelial mesenchymal interactions and (d) maintaining expression of Foxc1 and Foxc2. PMID- 24055174 TI - Analysis of central Hox protein types across bilaterian clades: on the diversification of central Hox proteins from an Antennapedia/Hox7-like protein. AB - Hox proteins are among the most intensively studied transcription factors and represent key factors in establishing morphological differences along the anterior-posterior axis of animals. They are generally regarded as highly conserved in function, a view predominantly based on experiments comparing a few (anterior) Hox proteins. However, the extent to which central or abdominal Hox proteins share conserved functions and sequence signatures remains largely unexplored. To shed light on the functional divergence of the central Hox proteins, we present an easy to use resource aimed at predicting the functional similarities of central Hox proteins using sequence elements known to be relevant to Hox protein functions. We provide this resource both as a stand-alone download, including all information, as well as via a simplified web-interface that facilitates an accurate and fine-tuned annotation of novel Hox sequences. The method used in the manuscript is, so far, the only published sequence-based method capable of differentiating between the functionally distinct central Hox proteins with near-identical homeodomains (such as the Drosophila Antp, Ubx and Abd-A Hox proteins). In this manuscript, a pairwise-sequence-similarity based approach (using the bioinformatics tool CLANS) is used to analyze all available central Hox protein sequences. The results are combined with a large-scale species phylogeny to depict the presence/absence of central Hox sequence-types across the bilaterian lineage. The obtained pattern of distribution of the Hox sequence-types throughout the species tree enables us to infer at which branching point a specific type of central Hox protein was present. Based on the Hox sequences currently available in public databases, seven sequence-similarity groups could be identified for the central Hox proteins, two of which have never been described before (Echi/Hemi7 and Echi/Hemi8). Our work also shows, for the first time, that Antp/Hox7-like sequences are present throughout all bilaterian clades and that all other central Hox protein groups are specific to sub-lineages in the protostome or deuterostome branches only. PMID- 24055173 TI - MyoD-expressing progenitors are essential for skeletal myogenesis and satellite cell development. AB - Skeletal myogenesis in the embryo is regulated by the coordinated expression of the MyoD family of muscle regulatory factors (MRFs). MyoD and Myf-5, which are the primary muscle lineage-determining factors, function in a partially redundant manner to establish muscle progenitor cell identity. Previous diphtheria toxin (DTA)-mediated ablation studies showed that MyoD+ progenitors rescue myogenesis in embryos in which Myf-5-expressing cells were targeted for ablation, raising the possibility that the regulative behavior of distinct, MRF-expressing populations explains the functional compensatory activities of these MRFs. Using MyoD(iCre) mice, we show that DTA-mediated ablation of MyoD-expressing cells results in the cessation of myogenesis by embryonic day 12.5 (E12.5), as assayed by myosin heavy chain (MyHC) and Myogenin staining. Importantly, MyoD(iCre/+);R26(DTA/+) embryos exhibited a concomitant loss of Myf-5+ progenitors, indicating that the vast majority of Myf-5+ progenitors express MyoD, a conclusion consistent with immunofluorescence analysis of Myf-5 protein expression in MyoD(iCre) lineage-labeled embryos. Surprisingly, staining for the paired box transcription factor, Pax7, which functions genetically upstream of MyoD in the trunk and is a marker for fetal myoblasts and satellite cell progenitors, was also lost by E12.5. Specific ablation of differentiating skeletal muscle in ACTA1Cre;R26(DTA/+) embryos resulted in comparatively minor effects on MyoD+, Myf-5+ and Pax7+ progenitors, indicating that cell non autonomous effects are unlikely to explain the rapid loss of myogenic progenitors in MyoD(iCre/+);R26(DTA/+) embryos. We conclude that the vast majority of myogenic cells transit through a MyoD+ state, and that MyoD+ progenitors are essential for myogenesis and stem cell development. PMID- 24055175 TI - Incidence of thrombosis in children with tunneled central venous access devices versus peripherally inserted central catheters (PICCs). AB - INTRODUCTION: The recent proliferation of deep vein thrombosis in children has been attributed to the increased use of central venous catheters, specifically tunneled lines and peripherally inserted central catheters. A formal comparison of the incidence rate for deep vein thrombosis between tunneled lines and peripherally inserted central catheters has not been undertaken. METHODS: Children < 18 years of age who were admitted to Children's Hospital Los Angeles from July, 2005 to July, 2012 were eligible for inclusion. Data were extracted from the hospital discharge database which includes data on all procedures and up to 20 diagnoses per admission. Diagnoses and procedures were identified by International Classification of Disease, Ninth Revision coding. Patients were excluded if they received more than one central line. Data collected included type of central line, deep vein thrombosis event, and underlying medical illnesses classified according to chronic complex conditions. RESULTS: Over the seven year study period there was an overall rate of 73 deep vein thromboses per 10,000 hospital discharges. Of the 6915 eligible subjects, 181 had a deep vein thrombosis for an overall incidence rate of 2.6%. There were 152 thrombi (2.6%) in subjects with peripherally inserted central catheters and 29 thrombi (3.1%) in subjects with tunneled lines [OR=.83 (0.55, 1.29), p=0.38]. CONCLUSION: Despite the relative ease and simplicity of use of peripherally inserted central catheters leading to a substantial rise in their use, this study demonstrates that such lines pose a substantial risk for venous thrombosis and no difference in incidence was detected between such lines and tunneled lines. PMID- 24055176 TI - Quality of life and satisfaction with treatment in subjects with type 2 diabetes: results in Spain of the PANORAMA study. AB - OBJECTIVES: Few studies are available on quality of life and treatment satisfaction of patients with type 2 diabetes mellitus (T2DM). Both of them were the primary objectives of the PANORAMA (NCT00916513) study. Metabolic control, treatment patterns, and management by healthcare professionals were also evaluated. MATERIAL AND METHODS: This multicenter, cross-sectional, observational study randomly recruited>40 year-old patients with T2DM from Spanish healthcare centers. HbA1c was measured using the same technique in all patients, who also completed quality of life (EQ-5D and ADDQoL) and treatment satisfaction (DTSQ) questionnaires and the Hypoglycemia Fear Survey (HFS-II). RESULTS: Fifty-four investigators recruited 751 patients, 60.3% of whom had HbA1c levels <7%. Approximately 25% of patients on monotherapy had HbA1c values >= 7%, Patients with longer disease duration and more complex treatments, especially with insulin, showed the poorer control. Despite good overall treatment satisfaction (mean 29.3+/-6.1, 0 to 36-point scale), patients with a poorer metabolic control, previous hypoglycemia episodes, and more complex therapies had a worse QoL and a greater fear of suffering hypoglycemia. CONCLUSIONS: Despite advances in metabolic control, there are still areas to improve. Early addition of safe drugs to monotherapy would help achieve control objectives without increasing the risk of hypoglycemia, and delaying the start of insulin therapy. This would also improve QoL and treatment satisfaction. PMID- 24055177 TI - Is there consistency in cephalometric landmark identification amongst oral and maxillofacial surgeons? AB - There may be significant variation amongst oral and maxillofacial surgeons (OMFS) in the identification and placement of cephalometric landmarks for orthognathic surgery, and this could impact upon the surgical plan and final treatment outcome. In an effort to assess this variability, 10 lateral cephalometric radiographs were selected for evaluation by 16 OMFS with different levels of surgical knowledge and experience, and the position of 21 commonly used cephalometric landmarks were identified on radiographs displayed on a computer screen using a computer mouse on a pen tablet. The database consisted of real position measurements (x, y) to determine the consistency of landmark identification between surgeons and within individual surgeons. Inter-examiner analysis demonstrated that most landmark points had excellent reliability (intra class correlation coefficient >0.90). Regardless of the level of surgeon experience, certain landmarks presented consistently poor reliability, and intra examiner reliability analysis demonstrated that some locations had a higher average difference for both x and y axes. In particular, porion, condylion, and gonion showed poor agreement and reliability between examiners. The identification of most landmarks showed some inconsistencies within different parameters of evaluation. Such variability among surgeons may be addressed by the consistent use of high-quality images, and also by periodic surgeon education of the definition of the specific landmarks. PMID- 24055178 TI - Needed: a knowledge translation skill set. PMID- 24055179 TI - A reference method for the evaluation of femoral head joint center location technique based on external markers. AB - Accurate localization of joint centers is essential in movement analysis. However, joint centers cannot be directly palpated and alternative methods must be used. To assess the relative merits of these methods, a medical image based reference should be used. The EOS((r)) system, a new low dose bi-planar X-rays imaging technique may be considered. The aim of this study was to evaluate the accuracy of hip joint center (HJC) localization using the EOS((r)) system. Seventeen healthy young adults participated in the study. Femoral heads and pelvic external markers were localized using the EOS((r)) system and the HJCs were expressed in the movement analysis coordinate system. Results showed that external marker localization was reliable within 0.15 mm for trained assessors. Mean accuracy for HJC localization was 2.9 mm (SD: 1.3, max: 6.2). The EOS based method therefore appeared reliable and may be used for femoral head localization or as a reference to assess the accuracy of other methods for HJC localization. PMID- 24055180 TI - Questionnaire OSA-18 has poor validity compared to polysomnography in pediatric obstructive sleep apnea. AB - OBJECTIVE: To evaluate the diagnostic value of the quality-of-life instrument OSA 18 by comparing it with objective data from polysomnography in children with sleep-disordered breathing. STUDY DESIGN: Cross-sectional. PATIENTS AND METHODS: Full-night polysomnographic data were obtained from 225 subjects, 139 boys and 86 girls, median age 4.5 years (1-12) in our sleep laboratory. Their caregivers answered the OSA-18 quality-of-life instrument (range 18-126). The polysomnographic parameter, the apnea-hypopnea index (AHI) was compared with the total symptom score (TSS) and with the subscale of sleep disturbance (SD) from the OSA-18 questionnaire. Receiver operating characteristic (ROC) curves were created to test the predictive value of OSA-18. RESULTS: With the TSS of the OSA 18 at >=60, compared with AHI levels of >1 and >=5, the sensitivity was 55.2% and 59.3% respectively, and the specificity 40.9% and 48.4%, respectively. With the TSS>80 and AHI levels of >=5 and >=10, the sensitivity was 24.6% and 32.1%, respectively. For the subscale of SD, the majority of the subjects showed poor correlation with the AHI values. The ROC area under the curve for different levels of the AHI (>1, >=5, and >=10) was 0.49, 0.57, and 0.56, respectively. CONCLUSIONS: The OSA-18 questionnaire showed poor validity in detecting and predicting pediatric OSA. The majority of the children with severe OSA would not be correctly diagnosed if the OSA-18 were used as a dominant diagnostic tool. PMID- 24055181 TI - Preface to the special issue: immunity to infectious diseases of fish. PMID- 24055182 TI - The presence of resuscitation equipment and influencing factors at General Practitioners' offices in Denmark: a cross-sectional study. AB - BACKGROUND: Automated external defibrillators (AEDs) have proven effective when used by GPs. Despite this and the latest guidelines from the European Resuscitation Council, there are no recommendations for Danish GPs regarding proper equipment to treat cardiac arrest. Currently, there are no published data on the distribution of AEDs among GPs in Denmark. AIM: To assess the prevalence of resuscitation equipment and educated staff among Danish GPs and the parameters influencing the absence of AEDs at GP offices. METHODS: A cross-sectional questionnaire-based survey among the 2030 GPs registered in Denmark. Questions concerned demographics, occurrence of resuscitation equipment and attitude towards acquisition of an AED. RESULTS: With a response rate >70%, we found that the prevalence of AEDs in GP offices is low (31.7%). Limited financial possibilities and relevant treatment by ambulance personnel were stated as the primary causes for not having an AED. In general, Danish primary care physicians believe that AEDs should be governmentally sponsored. Positive influential factors on the acquisition of an AED were education, number of physicians in the GP office and previous experience of cardiac arrest. CONCLUSIONS: Danish primary care physicians are generally not equipped with AEDs despite the proven effect of AEDs in GP offices. The main reasons for not acquiring an AED are financial considerations and believing that response time by ambulance services and nearby health facilities are the optimal treatment. We recommend better education and information in order to facilitate future acquisition of AEDs among GPs. PMID- 24055183 TI - Inventory of MRI applications and workers exposed to MRI-related electromagnetic fields in the Netherlands. AB - OBJECTIVE: This study aims to characterise and quantify the population that is occupationally exposed to electromagnetic fields (EMF) from magnetic resonance imaging (MRI) devices and to identify factors that determine the probability and type of exposure. MATERIALS AND METHODS: A questionnaire survey was used to collect information about scanners, procedures, historical developments and employees working with or near MRI scanners in clinical and research MRI departments in the Netherlands. RESULTS: Data were obtained from 145 MRI departments. A rapid increase in the use of MRI and field strength of the scanners was observed and quantified. The strongest magnets were employed by academic hospitals and research departments. Approximately 7000 individuals were reported to be working inside an MRI scanner room and were thus considered to have high probability of occupational exposure to static magnetic fields (SMF). Fifty-four per cent was exposed to SMF at least one day per month. The largest occupationally exposed group were radiographers (n ~ 1700). Nine per cent of the 7000 involved workers were regularly present inside a scanner room during image acquisition, when exposure to additional types of EMF is considered a possibility. This practice was most prevalent among workers involved in scanning animals. CONCLUSION: The data illustrate recent trends and historical developments in magnetic resonance imaging and provide an extensive characterisation of the occupationally exposed population. A considerable number of workers are potentially exposed to MRI-related EMF. Type and frequency of potential exposure depend on the job performed, as well as the type of workplace. PMID- 24055184 TI - Accuracy of non assisted glenohumeral joint injection in the office setting. AB - PURPOSE: The diagnostic and therapeutic success of shoulder joint injection depends on its accuracy. Two recent studies reported high success (93-96%) for non-imaging-assisted anterior injection in anesthetized patients. This study examined the accuracy of anterior shoulder injection in awake patients under conditions similar to the office setting. METHODS: The study group consisted of 166 consecutive patients with shoulder pain who underwent diagnostic magnetic resonance arthrography at a tertiary medical center in 2011-2012. As part of the examination, contrast material was injected into the glenohumeral joint via an anterior approach by a certified musculoskeletal radiologist without any image assistance. Success was defined as contrast material limited to the intra articular joint on the scan, without scatter to the periauricular tissue. RESULTS: A successful injection was verified by magnetic resonance arthography in 163 patients (98.2%). CONCLUSIONS: Non-assisted anterior shoulder injection is highly accurate (98.2%) in the hands of an experienced radiologist, even in awake patients. PMID- 24055185 TI - Arterial spin-labeling MR imaging in Moyamoya disease compared with clinical assessments and other MR imaging findings. AB - PURPOSE: Our purpose was to identify the causal factors for the perfusion distribution obtained with ASL-MRI by comparing ASL-MRI with clinical information and other MRI findings in moyamoya disease. METHODS: Seventy-one patients with moyamoya disease underwent ASL-MRI and other MRI, including fluid-attenuated inversion recovery imaging (FLAIR) and three-dimensional time-of-flight magnetic resonance angiography (MRA) on 3.0-Tesla MRI system. Cerebral blood flow (CBF) values (ASL values) for the cerebral hemispheres (142 sides) were measured on CBF maps generated by ASL-MRI. Relationships between the ASL values and the following 9 factors were assessed: sex, family history, revascularization surgery, age at MR exam, age at onset, the steno-occlusive severity on MRA (MRA score), degree of basal collaterals, degree of leptomeningeal high signal intensity seen on FLAIR, and size of ischemic or hemorrhagic cerebrovascular accident lesion (CVA score). RESULTS: Patients with a family history had significantly higher ASL values than those without such a history. There were significant negative correlations between ASL values and age at MR exam, MRA score, and CVA score. CONCLUSIONS: ASL MRI may have cause-and-effect or mutual associations with family history, current patient age, size of CVA lesion, and intracranial arterial steno-occlusive severity in Moyamoya disease. PMID- 24055186 TI - How to measure breast cancer tumoral size at MR imaging? AB - OBJECTIVE: To compare the accuracy of different MR sequences to measure tumor size. METHODS: Eighty-six women (mean age: 53 years (30-78)) who underwent preoperative MRI for breast cancer were included. Maximal diameters of the index tumor (IT) and of the whole extent of the tumor (WET) were measured on T2 weighted (T2W) sequences, on dynamic contrast-enhanced (DCE) T1-weighted (T1W) sequences and on Maximal Intensity Projection (MIP) reconstructions. Agreements with pathological size were evaluated using concordance correlation coefficient (k). RESULTS: Median pathological size of IT was 20mm (13-25 mm, interquartile range). Median pathological size of the WET was 29 mm (16-50mm, interquartile range). Measurement of IT showed a good concordance with pathological size, with best results using T2W (k = 0.690) compared to MIP (k = 0.667), early-subtracted DCE frame (k = 0.630) and early-native DCE frame (k = 0.588). IT was visible on T2W in 83.7% and accurately measured within 5mm in 69.9%. Measurement of WET was superior using early-subtracted DCE frame (k = 0.642) compared to late-native frame (k = 0.635), early-native frame (k = 0.631), late-subtracted frame (k = 0.620) and MIP (k = 0.565). However, even using early-subtracted frame, WET was accurately measured within 5mm only 39.3%. CONCLUSION: If visible, IT size is best measured on T2W with a good accuracy (69%) whereas WET is best estimated on early-subtracted DCE frame. However, when adjacent additional sites exist around IT, suspected surrounding disease components need to be proved by pathological analysis. PMID- 24055187 TI - Interventions to prevent the initiation of injection drug use: a systematic review. AB - BACKGROUND: Injection drug use has been identified as a key source of morbidity and mortality, primarily from overdose and the transmission of blood-borne diseases such as HIV. Experts have therefore called for the prioritization of resources toward the prevention of injection drug use. However, these strategies have not been systematically assessed. METHODS: PRISMA guidelines were used to systematically review and extract findings from the peer-reviewed literature evaluating the effectiveness of interventions to prevent injecting initiation. We searched 10 English language electronic databases (PubMed, PsycINFO, EMBASE, Cochrane CENTRAL, CINAHL, Web of Science, TOXNET, AIDSLINE, AMED and ERIC), the Internet (Google, Google Scholar), and article reference lists, from database inception to June 1st, 2012. RESULTS: Overall, out of 384 studies identified in the initial search, eight met the inclusion criteria. Studies evaluated four different types of interventions: social marketing, peer-based behavior modification, treatment, and drug law enforcement. Four studies observed a significant effect of the intervention on reducing rates of injecting initiation. Peer-based behavior modification and addiction treatment interventions were found to be most effective. Two of three studies assessing the impact of drug law enforcement on patterns of injecting initiation found no impact on injecting initiation, while one study reported inconclusive results. CONCLUSION: There exists a limited scientific literature on strategies to prevent injecting initiation. Resources should be allocated toward increased research and development of effective interventions to prevent this phenomenon. PMID- 24055189 TI - Targeting sphingosine kinase 1 (SphK1) and apoptosis by colon-specific delivery formula of resveratrol in treatment of experimental ulcerative colitis in rats. AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disorder (IBD) that has an elevated risk of developing into colon cancer. In trials to develop new therapeutic alternatives for UC, it is important to fulfill modifying effects on pathogenic targets and to reach the colon in a high concentration. Thus, the current work has investigated a colon-specific delivery formula of resveratrol in targeting sphingosine kinase 1 (SphK1) and apoptotic pathways to control pathogenesis and its progression to any expected neoplasm. This work was conducted on 40 Wister albino rats equally divided into 4 groups where group I served as the normal control group. The untreated oxazolone-induced colitis in group II exhibited significant increase in SphK1 activity as well as activity of both myeloperoxidase (MPO) and caspase-3 with concomitant mild DNA fragmentation in colonic tissue. Colonic SphK1 activity showed significant positive correlation with the disease activity index (DAI) and histopathological score in this group. Comparable with treatment by the native resveratrol formula, nRes (group III), treatment by the colon-specific delivery resveratrol formula, cRes (group IV) caused significant decrease in the activity of SphK1 and MPO with massive DNA fragmentation in colonic tissue and non significant change in caspase-3 activity. The lowest DAI and histopathological score have been recorded in the group treated by the colon-specific delivery resveratrol formula. In conclusion, the anti-inflammatory and apoptotic effects of resveratrol could be attributed to its inhibitory effect on sphingosine kinase 1 (SphK1) providing a useful therapeutic tool to break the link between inflammation and carcinogenesis risk in ulcerative colitis. PMID- 24055188 TI - Synergistic anti-proliferative effect of resveratrol and etoposide on human hepatocellular and colon cancer cell lines. AB - Resveratrol is an active component of grape, which has been shown to inhibit proliferation of a wide variety of tumor cells. The ability of resveratrol to enhance anti-proliferative effects of etoposide in wild type p53 liver carcinoma (HepG2) and colon cancer (HCT-116) cells was investigated with focusing on p53 activation. HepG2 cells and HCT-116 cells were treated with resveratrol and/or etoposide in a time- and dose-dependent manner and their proliferative response was evaluated by XTT assay. The expression of p53 protein was assessed using Western blot. Resveratrol exerted anti-proliferative activity on both cell types in a dose (25-100 MUM)- and time (24-72 h)-dependent manner. Interestingly in HepG2 cells, resveratrol exhibited the same levels of cytotoxicity as etoposide (10 MUM) when the cells treated with >= 25 MUM for 48-72 h. In contrast to HepG2, resveratrol significantly enhanced anti-proliferative effects of etoposide in HCT 116 cells. P53 expression was up-regulated by resveratrol and etoposide and pre incubation of both cells with resveratrol increased levels of etoposide-induced p53 expression. In line with cytotoxicity effect, combination therapy showed stronger activation of p53 in HCT-116 compared to HepG2. It seems that resveratrol exerts differential synergistic effect with etoposide on proliferation of cancer cells from different origin which is mainly accompanied by p53 activation. Our data represent a future strategy to provide much safer and more effective treatment for colon cancer. PMID- 24055190 TI - Rho kinase activation mediates adrenergic and cholinergic smooth muscle contractile responses in the mouse prostate gland. AB - With age an increase in prostatic smooth muscle tone mediated by alpha1L adrenoceptors contributes to the lower urinary tract symptoms associated with benign prostatic hyperplasia. Current treatments for benign prostatic hyperplasia include alpha1-adrenoceptor antagonists which inhibit smooth muscle contraction. However, muscarinic receptors also mediate prostatic smooth muscle contraction and targeting a convergent signalling pathway may be a more effective treatment strategy. This study determined signalling pathways involved in contraction by measuring isometric force developed by prostates from wild type, alpha1A adrenoceptor and M3-muscarinic receptor knockout mice mounted in organ baths in response to, electrical field stimulation or exogenously applied agonists, in the presence or absence of signalling pathway inhibitors. Fluorescence immunohistochemistry was also used to confirm functional observations. Contractile responses mediated by carbachol were reduced by inhibitors of phospholipase C (U73122; 3-10 uM), L-type Ca(2+) channels (nifedipine; 1 uM), Rho kinase (Y-27632; 10-30 uM), but not protein kinase C (GF109203 X;10 uM). Nifedipine (1 uM), Y-27632 (10 uM), and GF109203 X (10 uM) inhibited nerve mediated contractile responses. Y-27632 (10-30 uM) inhibited noradrenaline mediated contractions. RhoA and ROCK2 were found to be immunolocalised with prostatic smooth-muscle. Contractions mediated by M3-muscarinic receptors in the mouse prostate involve the prototypical phospholipase C signalling pathway, as well as L-type Ca(2+) channels. Adrenergic and cholinergic components of smooth muscle contraction in the mouse prostate both involve the activation of the Rho kinase pathway, which may be a suitable common pathway for more effective treatments of symptoms associated with benign prostatic hyperplasia. PMID- 24055192 TI - Fracture resistance of endodontically treated teeth restored with intra-radicular post: the effects of post system and dentine thickness. AB - To investigate the influence of post system and amount of remaining root tissue on the fracture resistance of endodontically treated teeth. Seventy upper canine teeth were divided into seven groups (n=10), one control (sound teeth) and six experimental groups resulting from the interaction between the two study factors: post system (FB, fiber post; FPC, fiber post relined with resin composite; CPC, cast Ni-Cr alloy post and core) and amount of remaining root tooth tissue (2 or 1mm of thick root). All teeth were restored with metal crowns and exposed to 250,000 cycles in a controlled chewing simulator. The samples were submitted to the fracture resistance test in a universal testing machine, at an angle of 135 degrees and speed of 0.5mm/min, until fracture occurred. Failure modes were observed, and the data of fracture resistance, in Newtons, were submitted to the analysis of variance (ANOVA), followed by Tukey's test (alpha=0.05). Roots restored with FPC had the highest fracture strength of the experimental groups, being statistically similar to the intact teeth group (P>0.05). FP and CPC did not differ statistically (P>0.05) and were statistically lower than those of FPC (P<0.05). No statistically significant difference was observed between amounts of remaining root tooth tissue to the same post systems (P>0.05). A prevalence of irreparable failures was observed in specimens restored with CPC, whereas FP and FPC posts showed more repairable failures. The post system had an influence significant on fracture resistance. However, the remaining dentine with 2- or 1 mm thickness was not an important factor for the fracture resistance. PMID- 24055191 TI - Gender difference in epileptogenic effects of 2-BFI and BU224 in mice. AB - Imidazoline I2 receptors are involved in pain modulation and psychiatric disorders and its ligands may represent a new therapeutic strategy against pain and depression. In particular, 2-BFI and BU224 are the two most widely studied I2 receptor ligands and have antinociceptive and antidepressant-like activities in rodents. However, little is known of the toxicological effects and potential gender differences of these I2 receptor ligands. This study examined the epileptogenic activities of 2-BFI and BU224 in male and female mice and also examined their underlying receptor mechanisms. 2-BFI (10-40 mg/kg, i.p.) and BU224 (10-40 mg/kg) produced epileptic seizures in a dose-related manner, as did the epileptogenic agent, pentylenetetrazole (PTZ, 15-60 mg/kg). However, female mice were significantly more sensitive than male mice in all the measures. The commonly used I2 receptor antagonist, idazoxan (10mg/kg), did not block the onset and magnitude of the epileptic seizures or lethality induced by 2-BFI and BU224. When studied in combination, PTZ potentiated the epileptogenic effect of 2-BFI and BU224. The lack of antagonism by idazoxan of the epileptogenic activities of 2-BFI and BU224 suggests that the epileptogenic effects of 2-BFI and BU224 are mediated by non-imidazoline I2 receptors and that I2 receptors remain a viable therapeutic target for neurological disorders such as pain. PMID- 24055193 TI - Comparison of carboplatin-paclitaxel to docetaxel-cisplatin-5-flurouracil induction chemotherapy followed by concurrent chemoradiation for locally advanced head and neck cancer. AB - OBJECTIVES: In head and neck squamous cell carcinoma (HNSCC), docetaxel, cisplatin and 5-fluorouracil (TPF) has become an accepted induction chemotherapy regimen. However, carboplatin-paclitaxel (CT) regimens have shown comparable outcomes. Here, we compared the outcomes of patients treated with either TPF or CT as induction chemotherapy followed by definitive chemoradiation. PATIENTS AND METHODS: We performed a single-institution retrospective analysis of patients with Stage III-IV HNSCC. From a database of 803 patients, we identified 143 patients treated with TPF or CT induction chemotherapy between 1999 and 2012. RESULTS: 53 patients and 90 patients received TPF or CT induction chemotherapy, respectively. The median follow-up was 18.9 months. The 1 year locoregional control was 80.5% for CT compared to 55.5% for TPF (HR 0.32, P=.0002). The 1 year progression free survival was 73.2% for CT compared to 60.7% for TPF (HR 0.57; P=.02). On multivariable analysis, CT remained significant for LRC (HR 0.28; P=0.04). TPF induction chemotherapy was associated with worse renal toxicity as measured by peak creatinine increases during induction chemotherapy (P=0.001). TPF was also associated with a trend toward more chemotherapy dose reductions or changes in systemic agents during concurrent chemoradiation (43.4% for TPF vs. 27.8% for CT; P=0.06). CONCLUSIONS: Compared to TPF induction chemotherapy, CT induction chemotherapy had at least similar if not better LRC and PFS in patients while having less renal toxicity. Thus, CT induction chemotherapy may benefit patients with locally advanced HNSCC by facilitating adequate chemoradiation regimens that enhanced disease control. PMID- 24055194 TI - Midkine-deficient mice delayed degeneration and regeneration after skeletal muscle injury. AB - Midkine (MK), a heparin-binding growth factor, was previously found to be expressed in the rat myotube-forming stage. We investigated MK gene-deficient (Mdk(-/-)) mice in terms of skeletal muscle degeneration and regeneration after injury by bupivacaine injection into the tibialis anterior muscle. Injured muscles showed intense inflammatory cell infiltration. Myotubes, myofibers with centrally located nuclei in their cytoplasm, were significantly smaller in Mdk(-/ ) mice than in wild type (Mdk(+/+)) mice 7 days after injury (p=0.02). The distribution of myotube sizes showed quantitative differences between the two groups at 5 and 7 days, but not at 14 days. Many small myotubes were found in the regenerative area of Mdk(-/-) mice compared with that of Mdk(+/+)mice 5 and 7 days after injury. The expression of Iba1, a macrophage marker, was significantly lower in Mdk(-/-) mice 3 days after injury (p=0.01). The number of desmin positive cells like myoblasts in Mdk(-/-) mice was significantly fewer than that in Mdk(+/+) mice 3 days after injury. Our results suggested that deletion of MK results in a delay in regeneration, preceded by decelerated migration of macrophages to the damaged area, and that MK has a role in cell differentiation and maturation after skeletal muscle injury. PMID- 24055195 TI - A morphological study of the vomeronasal organ and the accessory olfactory bulb in the Korean roe deer, Capreolus pygargus. AB - The vomeronasal organ (VNO) and accessory olfactory bulb (AOB) of the Korean roe deer (Capreolus pygargus) were studied histologically to evaluate their morphological characteristics. Grossly, the VNO, encased by cartilage, has a paired tubular structure with a caudal blind end and a rostral connection through incisive ducts on the hard palate. In the VNO, the vomeronasal sensory epithelium (VSE) consists of galectin-3-positive supporting cells, protein gene product (PGP) 9.5-positive receptor cells, and basal cells. The vomeronasal respiratory epithelium (VRE) consists of a pseudostratified epithelium. The AOB strata included a vomeronasal nerve layer (VNL), a glomerular layer (GL), a mitral/tufted cell layer, and a granular cell layer. All lectins used in this study, including Bandeiraea simplicifolia agglutinin isolectin B4 (BSI-B4), soybean agglutinin (SBA), Ulex europaeus agglutinin I (UEA-I), and Triticum vulgaris wheat germ agglutinin (WGA), labeled the VSE with varying intensity. In the AOB, both the VNL and the GL reacted with BSI-B4, SBA, and WGA with varying intensity, but not with UEA-I. This is the first morphological study of the VNO and AOB of the Korean roe deer, which are similar to those of goats. PMID- 24055196 TI - Apoptotic pathways in ovarian surface epithelium of human embryos during embryogenesis and carcinogenesis: close relationship of developmental plasticity and neoplasm. AB - Cell differentiation and different pathways of cell death were immunohistochemically analyzed in ovaries of six human embryos, 20 serous borderline tumors (SBT) and ovarian serous carcinomas (OSC) using markers for apoptosis (caspase-3, AIF, TUNEL) and stemness (Oct-4). In the 5-8-week ovaries, caspase-3 was absent in the ovarian surface epithelium (ose) and mildly positive in the ovarian stroma (os), AIF was expressed moderately, while Oct-4 expression gradually decreased during that period. Some ovarian cells expressed only caspase 3 or AIF together with TUNEL, while both caspase-3 and AIF were co-expressed in other ovarian cells. Mild expression of Oct-4 and caspase-3 characterized some cells of SBT, while their expression varied from mild to strong in OSC. AIF displayed mild to strong expression in ose of SBT and moderate to strong expression in OSC, while no expression of AIF was observed in os of both tumors. In the ose of both SBT and OSC, caspase-3 and AIF were co-expressed only occasionally, while AIF and Oct-4 were co-expressed strongly. Our study showed the presence of stemness cells and different pathways of cell death (caspase-3 and AIF-mediated) in the ovarian tissue during development and carcinogenesis, indicating the correlation between developmental plasticity in human embryonic ovaries and OSC. PMID- 24055197 TI - Galactosylation of IgG1 modulates FcgammaRIIB-mediated inhibition of murine autoimmune hemolytic anemia. AB - Murine immune effector cells express three different stimulatory FcgammaRs (FcgammaRI, FcgammaRIII and FcgammaRIV) and one inhibitory receptor, FcgammaRIIB. Competitive engagement of stimulatory and inhibitory FcgammaRs has been shown to be critical for the development of immune complex-mediated inflammatory disorders. Because of the previous demonstration that FcgammaRIIB was unable to inhibit FcgammaRIII-mediated autoimmune hemolytic anemia induced by 105-2H IgG1 anti-RBC mAb, we reevaluated the regulatory role of FcgammaRIIB on the development of anemia using two additional IgG1 anti-RBC mAbs (34-3C and 3H5G1) and different 34-3C IgG subclass-switch variants. We were able to induce a more severe anemia in FcgammaRIIB-deficient mice than in FcgammaRIIB-sufficient mice after injection of 34-3C and 3H5G1 IgG1, but not 105-2H IgG1. Structural analysis of N-linked oligosaccharides attached to the CH2 domain revealed that 105-2H was poorly galactosylated as compared with the other mAbs, while the extent of sialylation was comparable between all mAbs. In addition, we observed that a more galactosylated 105-2H variant provoked more severe anemia in FcgammaRIIB deficient mice than FcgammaRIIB-sufficient mice. In contrast, the development of anemia induced by three non-IgG1 subclass variants of the 34-3C mAb was not down regulated by FcgammaRIIB, although they were more galactosylated than its IgG1 variant. These data indicate that FcgammaRIIB-mediated inhibition of autoimmune hemolytic anemia is restricted to the IgG1 subclass and that galactosylation, but not sialylation, of IgG1 (but not other IgG subclasses) is critical for the interaction with FcgammaR, thereby determining the pathogenic potential of IgG1 autoantibodies. PMID- 24055198 TI - [Atrioventricular crosstalk with unipolar leads: a cause of ventricular asystole and syncope]. AB - In this article, we describe a case of ventricular asystole in a patient implanted with a cardiac pacemaker. The patient had a device replacement. The new pacemaker has been connected to old unipolar leads. The detection has been, inadvertently, programmed in a bipolar mode. This programmation induced an inhibition of the atrial and ventricular pacing due to oversensing of myopotentials. An inhibition of ventricular stimulation has been recorded also because of ventricular detection of the unipolar atrial stimulation (atrioventricular crosstalk). Lack of ventricular stimulation induced in this dependant patient ventricular asystole and syncope. PMID- 24055199 TI - Prefrontal cortical dysfunction during visual perspective-taking in schizophrenia. AB - Schizophrenia is characterized by marked impairments in a broad and diverse array of social-cognitive domains. Fundamental deficits in the ability to visualize and shift to the perspectives of others and the neural networks that support this ability may contribute to many of these impairments. This study sought to investigate deficits in prefrontal brain function and connectivity in patients with schizophrenia during visual perspective-taking, and the degree to which such deficits contribute to higher-order impairments in social cognition. A total of 20 outpatients with schizophrenia and 20 age- and gender-matched healthy volunteers completed a basic, visual perspective-taking task during functional magnetic resonance imaging, along with a behavioral assessment of theory of mind after neuroimaging. Results revealed hypoactivity in the medial prefrontal (anterior cingulate) and orbitofrontal cortices during perspective-taking trials compared to control trials in schizophrenia patients relative to healthy controls. In addition, patients demonstrated significant deficits in negative connectivity between medial prefrontal and medial-temporal regions during perspective-taking, which fully mediated behavioral impairments observed in theory of mind. These findings suggest that disruptions are present in the most fundamental aspects of perspective-taking in schizophrenia, and that these disruptions impact higher-order social information processing. PMID- 24055200 TI - Stigmatization of schizophrenia in Flemish newspapers. PMID- 24055201 TI - The crisis of minimal self-awareness in schizophrenia: a meta-analytic review. AB - Disturbances of the minimal self, characterized by abnormal sense of the body, body ownership and agency have been proposed as the phenomenological phenotype of schizophrenia. However, self-disturbances have not been extensively investigated, in part, due to the subjective nature of such processes, and the associated difficulty of studying these phenomena using empirical methodology. Of 115 potential studies on self-awareness in schizophrenia, a total of 25 studies met the inclusion criteria for the meta-analysis comprising 690 patients with schizophrenia and 979 healthy controls. We calculated Hedge's g to obtain a better estimate for the standardized mean difference in small samples. We identified significant basic self-disturbance in schizophrenia, as compared with healthy controls (25 studies, effect size=0.51). Additional comparison of three sub-categories of the sense of body ownership (4 studies, effect size=0.91), the sense of agency (15 studies, effect size=0.49), and self-reported subjective experiences (6 studies, effect size=0.57) also confirmed group differences. The complete set of 25 studies, and the studies in the sub-categories showed the statistical homogeneity of the characteristics. After a correction for potential publication bias using the trim-and-fill method, the main findings for all studies combined remained significant. Overall, patients with schizophrenia showed deficits in the sense of the minimal self, driven by abnormal sense of body ownership and sense of agency. Interestingly, the disturbed sense of agency in schizophrenia suggests an exaggerated self-consciousness rather than a diminished sense of self. Further research that utilizes sophisticated study designs is needed to examine the nature of self-disturbances in schizophrenia. PMID- 24055202 TI - Theory of mind and social judgments in people at clinical high risk of psychosis. AB - BACKGROUND: Social cognitive deficits are consistently reported in psychotic populations. Few studies have longitudinally investigated social cognition in clinical high-risk (CHR) populations. AIMS: Longitudinally examine theory of mind (ToM) and social judgments in a CHR sample to investigate the stability of performance over time and potential ability to predict conversion to psychosis. METHOD: 147 CHR individuals and 85 help seeking controls (HSC) were assessed for up to 2years; 28 participants developed psychosis across both groups. Generalized linear mixed models for repeated measures were used to examine change over time for ratings on the three social cognitive indices of ToM, trustworthiness, and approachability. Hierarchical regression was used to test whether social cognitive variables explain more variance in conversion than IQ. RESULTS: CHR individuals showed a positive bias in approachability judgments over time compared to HSC. Baseline ToM performance significantly (p<.05) predicted later conversion beyond IQ scores. These results were attenuated when controlling for baseline symptom level. CONCLUSIONS: Although ToM deficits might predate conversion to psychosis, one must consider initial symptoms as well. Social judgments were not associated with conversion to schizophrenia. PMID- 24055203 TI - Engineering large functional plasmids for biosafety. AB - Large bacterial plasmid constructs (generally 25-100 kb, but can be greater), such as those engineered with DNA encoding specific functions such as protein secretion or specialized metabolism, can carry antibiotic resistance genes and/or conjugation systems that typically must be removed before use in medical or environmental settings due to biosafety concerns. However, a convenient in vivo recombineering approach for intact large plasmids to sequentially remove multiple different genes using non-antibiotic selection methods is not described in the literature to our knowledge. We developed strategies and reagents for convenient removal of antibiotic resistance markers and conjugation genes while retaining non-antibiotic-based plasmid selection to increase practical utility of large engineered plasmids. This approach utilizes targeted lambda Red recombination of PCR products encoding the trpE and asd genes and as well as FLP/FRT-mediated marker removal. This is particularly important given that use of restriction enzymes with plasmids of this size is extremely problematic and often not feasible. This report provides the first example of the trpE gene/tryptophan prototrophy being used for recombineering selection. We applied this strategy to the plasmids R995+SPI-1 and R995+SPI-2 which encode cloned type III secretion systems to allow protein secretion and substrate delivery to eukaryotic cells. The resulting constructs are functional, stably maintained under conditions where the original constructs are unstable, completely defective for conjugative transfer, and transferred via electroporation. PMID- 24055204 TI - Combined evaluation of nutrition and hydration in dialysis patients with bioelectrical impedance vector analysis (BIVA). AB - BACKGROUND & AIMS: Body hydration changes continuously in hemodialysis patients. The Subjective Global Assessment (SGA) is used for the nutritional evaluation but it does not allow a direct evaluation of hydration. Bioelectrical impedance vector analysis (BIVA) is very sensitive to hydration. The potential of the combined evaluation of hydration and nutrition with SGA and BIVA is still lacking. METHODS: Observational cross-sectional study on 130 (94 Male) uremic patients undergoing chronic hemodialysis three times a week. Nutritional status was evaluated with the SGA. Each subject was classified as SGA-A (normal nutritional status), SGA-B (moderate malnutrition), or SGA-C (severe malnutrition). Body hydration was evaluated with BIVA. The two vector components resistance (R) and reactance (Xc) were normalized by the subject's height and standardized as bivariate Z-score, i.e. Z(R) and Z(Xc). RESULTS: Undernutrition influenced impedance vector distribution both before and after a dialysis session. In pre-dialysis, the mean vector of SGA A was inside the 50% tolerance ellipse. In SGA B and C, Z(R) was increased and Z(Xc) decreased, indicating a progressive loss of soft tissue mass. Fluid removal with dialysis increased both Z(R) and Z(Xc) in SGA A and B but not in C. With ROC curve analysis on the slope of increase, we found the cutoff value of 27.8 degrees below which undernutrition was present, either moderate or severe. The area under the ROC curve was 77.7 degrees (95% CI 69.5-84.5, P < .0001) with sensitivity 75.9%, specificity 78.6%, positive predicted value 74.6%, and negative predicted value 79%. CONCLUSIONS: The distribution of impedance vectors is associated with the SGA classification of patients. The change in body hydration in each SGA category can be detected with BIVA. PMID- 24055205 TI - Treatment of unruptured intracranial aneurysms with the pipeline embolization device. AB - The pipeline embolization device (PED; ev3 Endovascular, Plymouth, MN, USA) is a flow-diverter used in the endovascular treatment of intracranial aneurysms, particularly those with unfavorable configurations. It causes progressive flow redirection leading to aneurysm thrombosis. This study aimed to present a systematic review of the published literature on the clinical outcomes of PED. A Medline search of the English language literature was performed using the keywords "intracranial aneurysms" and "pipeline embolization device" or "flow diverters". The inclusion criteria were: n>10 patients; unruptured aneurysms; documentation of complications; and at least 3 months of follow-up. A total of 13 studies, with 905 patients and 1043 aneurysms, were included. The mean age was 53.8 years, with women comprising 76.3% of patients. The mean aneurysm diameter was 11.1mm with 37% classed as large aneurysms and 10% classed as giant. The cumulative mortality rate was 2.3%. Seventeen patients had a stroke (1.9%), while 19 (2.0%) had a transient ischemic attack and 21 patients (2.3%) had an intracranial hemorrhage. The two outcome measures were the cumulative event rate (16.7%) and the 6 month aneurysm occlusion rate (79.7%). A funnel plot with study size plotted against the two outcome measures revealed publication bias. Data from recent studies suggest that complication and mortality rates associated with PED may be similar to other contemporary endovascular techniques, with a better 6 month aneurysm occlusion rate. More prospective clinical trials are warranted to further validate these results. PMID- 24055206 TI - The change of attentional blink and repetition blindness after cerebellar lesions. AB - Attentional blink is the failure to identify a second target following a first target when both have appeared in a rapid serial visual presentation (RSVP) task. Repetition blindness is an additional difficulty to recognize the second same target in a RSVP task. Attentional blink and repetition blindness have many phenomenal similarities and can be experimentally dissociated. Repetition blindness may reflect the visual information processing stage prior to the central limitation stages. Many studies suggest that the cerebellum is involved in cognitive abilities, including attentional blink. fMRI studies have shown cerebellum activation in RSVP tasks, but the details of how the cerebellum is involved in the mechanism of attentional blink is unclear. In this study, we investigated attentional blink and repetition blindness performance in 10 patients with focal lesions of the cerebellum and 10 healthy controls using the RSVP task. Patients with cerebellar lesions demonstrated a longer attentional blink duration and a larger magnitude compared with controls. The performance of repetition blindness was lower than that of attentional blink in the control group, but the differences between the attentional blink and repetition blindness conditions in the patient group had no significance. The performance of repetition blindness between the two groups showed no significance. These data indicate that the cerebellum may be related to the central processing stage of visual temporal attention. Also, we provide new evidence to support the idea that the cerebellum is involved in non-motor functions. PMID- 24055207 TI - Growth and weight of children with craniopharyngiomas based on the tumour location and growth pattern. AB - This study aimed to characterise the weight and growth of children with craniopharyngiomas and to analyse the role of the tumour location and growth pattern in the development of obesity and growth retardation in these children. We retrospectively analysed the records of 109 consecutive children with primary craniopharyngiomas. The patients were divided into two subgroups according to the location of the tumour: intrasellar (Group A); and the floor of the third ventricle (Group B). Height and body mass index were measured at standardised ages and at time points before, after, and at the time of diagnosis. Endocrinological and hypothalamic measurements before and after surgery were compared. Reduced growth rates occurred in early infancy and persisted until diagnosis in Group A, but were only present from age 5-6 in Group B. Therefore, reduced growth rates occur early in the history of intrasellar tumours, whereas rapid postoperative weight gain invariably occurs in patients with third ventricle tumours, which is a significant predictive factor for severe long term obesity in patients with childhood craniopharyngiomas. PMID- 24055208 TI - Operative management of brainstem hemangioblastomas. AB - Brainstem hemangioblastomas are technically challenging lesions. The authors retrospectively analyzed their experience in 24 patients with brainstem hemangioblastomas to evaluate the management strategies used over time and the results of microsurgical treatment. All patients were operated on between 2007 and 2012. The patients received postoperative follow-up by neuroradiological and neurological examinations. The maximum diameter of the tumors ranged from 2.0 to 4.5 cm (mean 3.6 cm). Gross total resection was achieved in 24 patients (100%). Two patients (8%) had new neurological deficits or worsening of pre-existing deficits. One patient (4%) died because of brain stem dysfunction after the operation. Radical en bloc surgical resection of brainstem hemangioblastomas in symptomatic patients is a safe and effective primary treatment. Preoperative embolization is not necessary. It is very important and necessary to differentiate and dissect precisely at the interface of the tumor surface and the brainstem with a meticulous microsurgical technique until the tumor is removed en bloc. The preoperative neurological status of the patient predicts the postoperative functional outcome. Asymptomatic patients with hemangioblastoma may be followed clinically with MRI surveillance at regular intervals. PMID- 24055209 TI - Rasagiline induced hypersexuality in Parkinson's disease. AB - Impulse control disorders (ICD) are increasingly recognized in patients with Parkinson's disease (PD), particularly when treated with commonly used dopamine agonists such as pramipexole and ropinirole. Less evident is the possible association between monoamine oxidase inhibitors type B (MAO-B) and the development of ICD. Rasagiline is a second generation MAO-B I inducing moderate symptomatic and possibly disease modifying benefits with apparently good tolerability and safety profile in PD patients. Rasagiline is effective and well tolerated in PD as a monotherapy or in combination with levodopa. Here, we report a patient with PD who developed ICD when treated de novo with MAO-B inhibitors. PMID- 24055210 TI - Primary Sjogren's syndrome presenting as acute cerebellitis. AB - A 64-year-old previously healthy man presented with acute ataxia. He was diagnosed with acute cerebellitis on the basis of clinical features, negative MRI of the head and lymphocytic pleocytosis in cerebrospinal fluid. A detailed work up for etiology revealed auto-antibodies for Sjogren's syndrome. He responded well to cyclophosphamide and steroids. PMID- 24055211 TI - Sporadic inclusion body myositis presenting with severe camptocormia. AB - Sporadic inclusion body myositis (sIBM) is a slowly progressive idiopathic inflammatory myopathy. The characteristic early quadriceps and finger flexor muscle weakness often leads to the diagnosis of sIBM, especially when all canonical pathological features of sIBM are not present on muscle biopsy. Weakness of the paraspinal muscles, resulting in head drop and/or camptocormia, is a rare clinical finding along the course of sIBM, and even more rare as the presenting feature. We describe two patients with sIBM manifesting with camptocormia as the sole clinical manifestation for several years prior to the diagnosis by muscle biopsy. This observation emphasizes the role of sIBM in the etiology of camptocormia and the need to consider this common myopathy as a cause of weakness, despite the lack of classic quadriceps and finger flexor muscle weakness years after the onset of the paraspinal muscle weakness. PMID- 24055212 TI - Efficacy and safety of rotigotine in Japanese patients with restless legs syndrome: a phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group study. AB - OBJECTIVE: We aimed to ascertain the efficacy and safety of transdermal rotigotine (2 and 3mg/24h) in Japanese patients with restless legs syndrome (RLS). METHODS: In our double-blind placebo-controlled study, 284 Japanese patients with idiopathic RLS were randomly assigned to receive rotigotine 2mg/24h or 3mg/24h, or placebo, for 13 weeks. The primary endpoint was the change in International Restless Legs Syndrome Study Group rating scale (IRLS) total score. RESULTS: The placebo-subtracted decreases in IRLS total score for rotigotine 2 mg/24 h and 3 mg/24 h were -2.8+/-1.3 and -3.1+/-1.3, respectively, which were significant (P<0.05). The interaction between baseline Pittsburgh Sleep Quality Index (PSQI) and treatment group for the change in IRLS total score was significant, indicating greater improvements in IRLS total score in patients with severe insomnia. Overall, 80.0%, 86.2%, and 51.6% of patients in the rotigotine 2 mg/24 h, 3 mg/24 h, and placebo groups, respectively, experienced adverse events (AEs) including application site reactions in 42.1%, 50.0%, and 7.4% of patients, respectively. None of the AEs were severe. CONCLUSIONS: Our results showed that rotigotine was effective without major safety concerns at doses of up to 3 mg/24 h in Japanese patients with RLS. PMID- 24055213 TI - Effects of prolyl-hydroxylase inhibition and chronic intermittent hypoxia on synaptic transmission and plasticity in the rat CA1 and dentate gyrus. AB - Chronic intermittent hypoxia (CIH) is an underlying component of obstructive sleep apnoea and has been shown to have deleterious and damaging effects on central neurons and to impair synaptic plasticity in the CA1 region of the rat hippocampus. CIH has previously been shown to impair synaptic plasticity and working memory. CIH is a potent inducer of hypoxia inducible factor (HIF), a key regulator in a cell's adaptation to hypoxia that plays an important role in the fate of neurons during ischemia. Levels of HIF-1alpha are regulated by the activity of a group of enzymes called HIF-prolyl 4-hydroxylases (PHDs) and these have become potential pharmacological targets for preconditioning against ischemia. However little is known about the effects of prolyl hydroxylase inhibition and CIH on synaptic transmission and plasticity in sub-regions of the hippocampus. Male Wistar rats were treated for 7-days with either saline, CIH or PHD inhibition (dimethyloxaloylglycine, DMOG; 50mg/kg, i.p.). At the end of treatment all three groups showed no change in synaptic excitability using paired pulse paradigms. However long-term potentiation (LTP) was impaired in the CA1 region of the hippocampus in both CIH and DMOG treated animals. LTP induced in the dentate gyrus was not significantly affected by either CIH or DMOG treatment. We also investigated the effect of 7-day CIH and DMOG treatment on the recovery of synaptic transmission following an acute 30min hypoxic insult. CIH treated animals showed an improved rate of recovery of synaptic transmission following re oxygenation in both the CA1 and the dentate gyrus. These results suggest that LTP induction in the CA1 region is more sensitive to both CIH and DMOG treatments than the dentate gyrus. PMID- 24055214 TI - Translational PET imaging research. AB - The goal of any early central nervous system (CNS) drug development program is always to test the mechanism and not the molecule in order to support additional research investments in late phase clinical trials. Confirmation that drugs reach their targets using translational positron emission tomography (PET) imaging markers of engagement is central to successful clinical proof-of-concept testing and has become an important feature of most neuropsychiatric drug development programs. CNS PET imaging can also play an important role in the clinical investigation of the neuropharmacological basis of psychiatric disease and the optimization of drug therapy. PMID- 24055215 TI - Screening of novel malaria DNA vaccine candidates using full-length cDNA library. AB - No licensed malaria vaccine exists, in spite of intensive development efforts. We have been investigating development of a DNA vaccine to prevent malaria infection. To date, we have established a full-length cDNA expression library from the erythrocytic-stage murine malaria parasite, Plasmodium berghei. We found that immunization of mice with combined 2000 clones significantly prolonged survival after challenge infection and that splenocytes from the immunized mice showed parasite-specific cytokine production. We determined the 5'-end one-pass sequence of these clones and mapped a draft genomic sequence for P. berghei for use in screening vaccine candidates for efficacy. In this study, we annotated these cDNA clones by comparing them with the genomic sequence of Plasmodium falciparum. We then divided them into several subsets based on their characteristics and examined their protective effects against malaria infection. Consequently, we selected 104 clones that strongly induced specific IgG production and decreased the mortality rate in the early phase. Most of these 104 clones coded for unknown proteins. The results suggest that these clones represent potential novel malaria vaccine candidates. PMID- 24055217 TI - Survival of first-stage larvae of the cat lungworm Troglostrongylus brevior (Strongylida: Crenosomatidae) under different conditions. AB - Troglostrongylus brevior has recently been recognised as a neglected causative agent of broncho-pulmonary infestation in domestic cats. Nonetheless, information on the biology and ecology of this nematode is still scarce. In this study, the survival of T. brevior first-stage larvae (L1) was evaluated in water and in faecal samples at different controlled temperatures in the laboratory (i.e., 4 and 26 degrees C) or in the outdoor environment (mean temperature 14+/-3.1 degrees C). Vitality of larvae was microscopically assessed every 7days, until their death. Larval survival ranged from 7days in both water and faeces at 26 degrees C up to 142days at 4 degrees C, respectively. Larvae maintained in the environment (14 degrees C) survived from 35 up to 63days in faeces and water, respectively. Data herein presented clearly indicate that the survival of T. brevior L1s is negatively correlated with temperature (P<0.001). According to the results of this study, the infection in mollusc intermediate hosts in the Mediterranean area may easily occur during winter/spring, while during hot and dry seasons a reduction of transmission should be expected. PMID- 24055216 TI - Plasmodium falciparum: generation of pure gametocyte culture by heparin treatment. AB - In vitro culture of Plasmodium falciparum gametocytes is essential for studying sexual development of the parasite. Here we describe a simple method for producing synchronous gametocyte culture without contamination of asexual stages. This method employs heparin's activity in blocking merozoite invasion of erythrocytes to eliminate asexual stage parasites from gametocyte culture. We show that following induction of gametocyte formation, addition of heparin in culture medium for four days effectively eliminates asexual stages and produces pure, synchronous cultures of gametocytes. Compared with the commonly used N acetylglucosamine treatment method, heparin treatment requires shorter time to eliminate asexual stages and causes significantly less hemolysis in late stage gametocyte cultures. PMID- 24055218 TI - Update of contemporary antimicrobial resistance rates across China: reference testing results for 12 medical centers (2011). AB - Antimicrobial resistance (R) surveillance across Asia and especially in China has documented unique patterns and mechanisms. This 2011 study reports results for 2278 isolates from 12 hospitals in China (94-216 strains/site); most from bacteremia (20.4%), pneumonias (29.1%), or skin and skin structure infections (20.9%). Samples were tested by reference broth microdilution methods, interpreted by published susceptibility (S) breakpoints. The most common species were Staphylococcus aureus (343, 45.8% MRSA), Escherichia coli (EC; 288), Pseudomonas aeruginosa (PSA; 221), Klebsiella spp. (KSP; 208), acinetobacters (ACB; 178), enterobacters (155), Streptococcus pneumoniae (SPN; 154, 46.8% penicillin-S), and enterococci (ENT; 137). Among 849 Gram-positive (GP) cocci, linezolid, tigecycline (TIG), daptomycin, and vancomycin provided best antimicrobial coverage (>=99.7% S). Resistance patterns of concern were 0.3% VISA, 15.4% teicoplanin non-S coagulase-negative staphylococci, 1.5% vancomycin-R ENT (all Enterococcus faecium), 1.9% levofloxacin-R beta-haemolytic streptococci, and 35.1 and 12.7% ceftriaxone-non-S rates for SPN and viridans group streptococci, respectively. For Gram-negative bacilli, R among Enterobacteriaceae was highest against beta-lactams (extended spectrum beta-lactamase-phenotype strains at 73.6 and 42.8% in EC and KSP, respectively; carbapenem-R was only 2.1 4.3% with KPC and IMP type enzymes detected in KSP). The widest spectrum agents were cefoperazone/sulbactam (79.5-86.1%), piperacillin/tazobactam (88.9-92.0%), TIG (98.6-100%), amikacin (AMK; 91.8-93.7%), and meropenem (95.7-97.1% S). PSA was most inhibited by AMK (90.5% S) and colistin (COL; 99.5%), with cefepime (67.9%) best among the tested beta-lactams. Only COL (100% S) and TIG (MIC90, 2 MUg/mL) showed significant potencies against ACB. In conclusion, R among pathogens from 12 Chinese hospitals illustrates several agents active against GP pathogens, but more serious R problems were noted among Enterobacteriaceae, PSA, and ACB. Combination treatment for the latter multidrug-R strains appears necessary, guided by local antibiograms and national surveillance results applying reference methods. PMID- 24055219 TI - Male bisexual arousal: a matter of curiosity? AB - Conflicting evidence exists regarding whether bisexual-identified men are sexually aroused to both men and women. We hypothesized that a distinct characteristic, level of curiosity about sexually diverse acts, distinguishes bisexual-identified men with and without bisexual arousal. Study 1 assessed men's (n=277) sexual arousal via pupil dilation to male and female sexual stimuli. Bisexual men were, on average, higher in their sexual curiosity than other men. Despite this general difference, only bisexual-identified men with elevated sexual curiosity showed bisexual arousal. Those lower in curiosity had responses resembling those of homosexual men. Study 2 assessed men's (n=72) sexual arousal via genital responses and replicated findings of Study 1. Study 3 provided information on the validity on our measure of sexual curiosity by relating it to general curiosity and sexual sensation seeking (n=83). Based on their sexual arousal and personality, at least two groups of men identify as bisexual. PMID- 24055220 TI - Reprint of "Neurofeedback and standard pharmacological intervention in ADHD: a randomized controlled trial with six-month follow-up". AB - The present study is a randomized controlled trial that aims to evaluate the efficacy of Neurofeedback compared to standard pharmacological intervention in the treatment of attention deficit/hyperactivity disorder (ADHD). The final sample consisted of 23 children with ADHD (11 boys and 12 girls, 7-14 years old). Participants carried out 40 theta/beta training sessions or received methylphenidate. Behavioral rating scales were completed by fathers, mothers, and teachers at pre-, post-treatment, two-, and six-month naturalistic follow-up. In both groups, similar significant reductions were reported in ADHD functional impairment by parents; and in primary ADHD symptoms by parents and teachers. However, significant academic performance improvements were only detected in the Neurofeedback group. Our findings provide new evidence for the efficacy of Neurofeedback, and contribute to enlarge the range of non-pharmacological ADHD intervention choices. To our knowledge, this is the first randomized controlled trial with a six-month follow-up that compares Neurofeedback and stimulant medication in ADHD. PMID- 24055221 TI - Mechanical nociception thresholds in lame sows: evidence of hyperalgesia as measured by two different methods. AB - Lameness is a frequently occurring, painful condition of breeding sows that may result in hyperalgesia, i.e., an increased sensitivity to pain. In this study a mechanical nociception threshold (MT) test was used (1) to determine if hyperalgesia occurs in sows with naturally-occurring lameness; (2) to compare measurements obtained with a hand-held probe and a limb-mounted actuator connected to a digital algometer; and (3) to investigate the systematic left-to right and cranial-to-caudal differences in MT. Twenty-eight pregnant sows were investigated, of which 14 were moderately lame and 14 were not lame. Over three testing sessions, repeated measurements were taken at 5 min intervals on the dorsal aspects of the metatarsi and metacarpi of all limbs. The MT was defined as the force in Newtons (N) that elicited an avoidance response, and this parameter was found to be lower in limbs affected by lameness than in normal limbs (P<0.05). Forelimbs had higher MTs than hindlimbs (P<0.001). The hand-held probe systematically yielded lower values than the actuator (P<0.001), and the MT differed between morning and afternoon testing sessions (P<0.001), as well as between days (P<0.001). The findings provide evidence that lame sows experience hyperalgesia. Systematic differences between forelimb and hindlimb MT must be taken into account when such assessments are performed. PMID- 24055222 TI - First seizure in the older patient: clinical features and prognosis. AB - PURPOSE: The prognosis of first seizure in the elderly has rarely been studied. Despite this, anti-epileptic drug treatment following first seizure is often recommended in older adults due to the perception that recurrence is inevitable and associated with significant morbidity. This study aims to establish whether older patients presenting with first-ever seizure are more likely to have a second seizure or not, and to examine their clinical features including seizure related morbidity. METHODS: Prospective observational study of adults seen by a hospital-based first seizure service between 2000 and 2011. The prognosis and clinical features of older (aged >=65 years) and younger (aged 16-64 years) patients were compared. KEY FINDINGS: 139 of 1008 patients with first-ever unprovoked seizure were aged >=65 years (mean age 74 years). The majority of these older patients were healthy (95% ambulant, 81% Rankin score <=2). The likelihood of a second seizure at one year was 53% (95% CI 45-62) in older patients and 48% (95% CI 44-51) in younger patients. Independent predictors of seizure recurrence were remote symptomatic etiology, first seizure arising from sleep, epileptiform abnormality on EEG and partial seizures but not age. Older patients were less likely to suffer a seizure-related injury with both the presenting seizure and the first recurrence. CONCLUSIONS: With first-ever seizure age is not an independent predictor of seizure recurrence and older patients are less likely to sustain a seizure-related injury. Treatment decisions in older patients presenting with first-ever seizure should be based on established risk factors for seizure recurrence rather than age. PMID- 24055223 TI - Imidazolium-based functional monomers for the imprinting of the anti-inflammatory drug naproxen: comparison of acrylic and sol-gel approaches. AB - Imidazolium-based monomers were, for the first time, employed in a comprehensive investigation of the molecular imprinting process of naproxen in both acrylic and sol-gel tridimensional networks. To this end, molecularly imprinted polymer (MIP) and xerogel (MIX) were both optimized for performance, by testing different porogen, template speciation and component ratios. The developed imprints were characterized for their pore properties (nitrogen adsorption analysis), site heterogeneity, binding properties and other performance parameters such as the imprinting factor, selectivity (HPLC column tests), column efficiency and mass transfer kinetics (frontal analysis study). MIP exhibited mesoporosity (Dp 29nm), whereas MIX did not, which was reflected in both the lower number of accessible imprinted sites (4.9MUmol/g versus 3.7MUmol/g) and the slower binding/dissociation in MIX. The naproxen/ibuprofen selectivity ratio was estimated as 6.2 for the MIX and 2.5 for the MIP. Given the high importance of capacity and fast mass transfer in typical applications of imprinted materials, and the satisfactory selectivity of MIP, it can be concluded that the acrylic approach was globally the most advantageous. Still, the remarkably high selectivity of MIX and its reasonable capacity demonstrate that future work devoted to further optimization of both formats is worthwhile. PMID- 24055224 TI - Rapid trace level determination of sulfonamide residues in honey with online extraction using short C-18 column by high-performance liquid chromatography with fluorescence detection. AB - A sensitive and inexpensive quantification method with online extraction using a short C-18 column for sulfonamide residues in honey by high performance liquid chromatography with fluorescence detector was developed and validated. In sample preparation, acid hydrolysis was used to break the N-glycoside bond between the honey sugar and sulfonamide drugs and derivatization of sulfonamide residues with fluorescamine was conducted at pH 3.5 using a citrate buffer (0.5M) in the honey matrix. The chromatography was carried out on Zorbax Extended C-18 (250mm*4.6mm; 5MUm) column, using a mixture of acetonitrile and an acetate buffer (pH 4.50, 20mM) as a mobile phase. A Zorbax Extended C-18 (12mm*4.6mm; 5MUm) column was used for online extraction of fifteen sulfonamide residues from honey sample with the help of a two position valve. The limit of quantification of sulfonamide residues in honey was less than 3ngg(-1), and the percentage recovery of study compounds in spiked honey sample was from 80% for sulfacetamide to 100% of sulfachloropyridazine. The developed method has excellent linearity for all studied sulfonamides with a correlation coefficient 0.993. PMID- 24055225 TI - Effect of methanol concentration on the speed-resolution properties in adiabatic supercritical fluid chromatography. AB - The influence of the modifier concentration in supercritical mixtures of carbon dioxide and methanol on the speed-resolution properties of columns packed with 1.7MUm core-shell particles was investigated from a theoretical viewpoint. Molar fractions of methanol up to 30% were considered. The column was assumed to be operated under strict adiabatic conditions in order to maximize its efficiency. Four inlet temperatures were tested, between 297 and 337K. Four different pressure drops along the column were considered, between 25 and 200bar. The physico-chemical properties (density, viscosity, and heat capacity) of the mixtures of carbon dioxide and methanol were derived from the NIST REFPROP program for temperatures between 287 and 337K and pressures between 150 and 390bar. The axial heterogeneity of the column was taken into account by segmenting it into 500 hundreds slices in each of which all physical and chromatographic properties were assumed to be uniform. The apparent kinetic Poppe plots were built from the apparent column efficiency calculated from the sum of the increments of the retention times and time variances from the column inlet to its outlet. The numerical results showed that the axial heterogeneity of the column due to axial variations of the temperature and the equilibrium constant decreases with increasing molar fraction of methanol in the eluent when the pressure drop is increased from 25 to 200bar. The methanol content decreases the speed-resolution of the column more particularly when the analysis is done at low pressure drops. The results demonstrate also that under adiabatic conditions, for pressure drops larger than 100bar, an increase of methanol concentration does not cause a dramatic loss of speed-resolution. For example, at 310K and with a pressure drop of 25bar, the longest column is expected to deliver 17,000 plates; increasing the molar fractions of methanol from 0 to 30% decreases this efficiency by about 15% and increases the analysis time by +140%. In contrast, under the same experimental conditions except for a pressure drop of 200bar, the maximum efficiency (130,000 plates) would remain unchanged and the analysis time increase by only 40%. PMID- 24055226 TI - A new liquid chromatography-mass spectrometry-based strategy to integrate chemistry, morphology, and evolution of eggplant (Solanum) species. AB - This study presents a strategy based on repeatable reversed-phase LC-TOF-MS methods and statistical tools, including untargeted PCA and targeted PLS/OPLS-DA models, to analyze 31 accessions representing 24 species in the eggplant genus Solanum (Solanaceae), including eight species whose metabolic profiles were studied for the first time. Sixty-two Solanum metabolites were identified after detailed analysis of UV absorbance spectra, mass spectral fragmentation patterns, NMR spectra, and/or co-injection experiments with authentic standards. Among these were two new 5-O-caffeoylquinic acid derivatives that were identified by analyzing their MS/MS fragmentation. Based on these results, a Solanum metabolic database (SMD) and a detailed biosynthetic pathway of Solanum metabolites were created. Results of analyses identified seven marker metabolites that distinguish four Solanum sections, and revealed species-specific chemical patterns. Combining LC-MS data with multivariate statistical analysis was proven effective in studying the metabolic network within the large genus Solanum, allowing for integration of complicated chemistry, morphology, and evolutionary relationships. PMID- 24055227 TI - Structural characterization of the N-glycosylation of individual soybean beta conglycinin subunits. AB - Soybean (Glycine max) 7S beta-conglycinin is a seed storage protein consisting of homo- and hetero-trimers of three subunits, namely alpha (~67 kDa), alpha' (~71 kDa), and beta (~50 kDa), non-covalently associated. The N-glycans released from the whole beta-conglycinin have been already characterized by (1)H NMR some decades ago. Nevertheless, the actual glycosylation of the potential sites and the glycoforms of the individual subunits have not been specifically investigated so far. In this study, up-to-date chromatographic, electrophoretic and mass spectrometric strategies have been combined to achieve the structural characterization of the glycoforms of the three individual beta-conglycinin subunits. Glycosylation sites were assigned by analyzing the tryptic glycopeptides of the isolated subunits. Underivatized N-glycans were purified with a two-step clean-up, consisting in sequential reversed-phase and activated porous graphitized carbon micro-chromatography, and profiled by matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS). PMID- 24055228 TI - Half-width plots, a simple tool to predict peak shape, reveal column kinetics and characterise chromatographic columns in liquid chromatography: state of the art and new results. AB - Peak profiles in chromatography are characterised by their height, position, width and asymmetry; the two latter depend on the values of the left and right peak half-widths. Simple correlations have been found between the peak half widths and the retention times. The representation of such correlations has been called half-width plots. For isocratic elution, the plots are parabolic, although often, the parabolas can be approximated to straight-lines. The plots can be obtained with the half-widths/retention time data for a set of solutes experiencing the same kinetics, eluted with a mobile phase at fixed or varying composition. When the analysed solutes experience different resistance to mass transfer, the plots will be solute dependent, and should be obtained with the data for each solute eluted with mobile phases at varying composition. The half width plots approach is a simple tool that facilitates the prediction of peak shape (width and asymmetry) with optimisation purposes, reveal the interaction kinetics of solutes in different columns, and characterise chromatographic columns. This work shows half-width plots for different situations in isocratic elution, including the use of different flows, the effect of temperature, the modification of the stationary phase surface by an additive, the existence of specific interactions within the column, and the comparison of columns. The adaptation to gradient elution is also described. Previous knowledge on half width plots is structured and analysed, to which new results are added. PMID- 24055229 TI - A finite parallel zone model to interpret and extend Giddings' coupling theory for the eddy-dispersion in porous chromatographic media. AB - The finite length parallel zone (FPZ)-model is proposed as an alternative model for the axial- or eddy-dispersion caused by the occurrence of local velocity biases or flow heterogeneities in porous media such as those used in liquid chromatography columns. The mathematical plate height expression evolving from the model shows that the A- and C-term band broadening effects that can originate from a given velocity bias should be coupled in an exponentially decaying way instead of harmonically as proposed in Giddings' coupling theory. In the low and high velocity limit both models converge, while a 12% difference can be observed in the (practically most relevant) intermediate range of reduced velocities. Explicit expressions for the A- and C-constants appearing in the exponential decay-based plate height expression have been derived for each of the different possible velocity bias levels (single through-pore and particle level, multi particle level and trans-column level). These expressions allow to directly relate the band broadening originating from these different levels to the local fundamental transport parameters, hence offering the possibility to include a velocity-dependent and, if, needed retention factor-dependent transversal dispersion coefficient. Having developed the mathematics for the general case wherein a difference in retention equilibrium establishes between the two parallel zones, the effect of any possible local variations in packing density and/or retention capacity on the eddy-dispersion can be explicitly accounted for as well. It is furthermore also shown that, whereas the lumped transport parameter model used in the basic variant of the FPZ-model only provides a first approximation of the true decay constant, the model can be extended by introducing a constant correction factor to correctly account for the continuous transversal dispersion transport in the velocity bias zones. PMID- 24055230 TI - Chromatographic resolution of closely related species: separation of warfarin and hydroxylated isomers. AB - Recent developments in the field of organic synthesis are leading to increasingly complex mixtures of closely related species (positional isomers, regioisomers, diastereomers, etc.) that often prove challenging for chromatographic analysis and separation. In this study we investigate the separation of a representative mixture of warfarin and 5 different monohydroxylation isomers to assess whether conventional techniques are suitable for addressing this separation challenge, or whether 'next generation' separation tools such as multidimensional chromatography may be required. In this example, modifications of results obtained from conventional achiral and chiral chromatography method development screening platforms afford rapid separation of all components for both achiral and chiral analysis, with supercritical fluid chromatography showing the best performance in both cases (1.8min for separation of six components by achiral SFC and 8.0min for separation of twelve components by chiral SFC). While other more complex mixtures may require additional tools, these results suggest that new applications of existing separation platforms may be useful for creating the chromatographic methods required to support this new area of synthetic chemistry. PMID- 24055231 TI - The association of polymorphisms of the vitamin D receptor gene with psoriasis in the Han population of northeastern China. AB - BACKGROUND: The vitamin D receptor (VDR) is a master regulator of epidermal barrier function, inflammation, stem-cell proliferation, and microbial defense. OBJECTIVE: To evaluate the association between the VDR and psoriasis in the northeastern Chinese Han population. METHODS: In this case-control study, 342 patients with psoriasis and 341 controls were genotyped for five common VDR gene polymorphisms (ApaI, TaqI, BsmI, FokI, and Cdx2) by the Multiplex SNapSHOT method. RESULTS: The frequency of ApaI (rs7975232) allele A was significantly increased in psoriasis relative to the control group (27.8% vs. 22.1%, p=0.018); the allele A of the ApaI polymorphism showed a 1.35-fold increased risk of developing psoriasis. Haplotype analyses showed the BsmI/ApaI/TaqI/Cdx2/FokI GATGC to be significantly over-represented in psoriasis patients compared with controls (p=0.012). The BsmI/ApaI/TaqI haplotype GCT was presented to a lesser extent in psoriasis patients in comparison with control patients (72.2% vs. 77.9%, p=0.012). CONCLUSIONS: These data suggest that VDR polymorphisms are associated with psoriasis in Northeastern Han Chinese population. PMID- 24055232 TI - The matricellular protein periostin contributes to proper collagen function and is downregulated during skin aging. AB - BACKGROUND: Periostin is a secreted 90kDa matricellular protein, which is predominantly expressed in collagen-rich tissues. Collagen is the most abundant protein in mammals and has great tensile strength. Recent investigations have shown that periostin influences collagen fibrillogenesis and biomechanical properties of murine connective tissues. OBJECTIVE: We investigated the function of periostin concerning collagen homeostasis during intrinsic and extrinsic skin aging. For this purpose, human skin samples of young and old donors as well as samples of photoaged and sun-protected skin areas were analyzed for periostin expression. Using in vitro models, we determined the cell types responsible for periostin expression and performed functional analyses with periostin knockdown cells. METHODS: TaqMan Real-Time PCR, UV irradiation, knockdown experiments, immunostaining, electron microscopy, collagen degradation assay, collagen crosslink analysis. RESULTS: Periostin expression is highest in the papillary dermis and downregulated during skin aging. Fibroblasts and non-follicular skin derived precursors were identified as main source for periostin expression in human skin. Periostin knockdown in fibroblasts has no effect on collagen expression, but results in an increased fibril diameter and aberrant collagen structure. This leads to an increased susceptibility of collagen toward proteases, whereas recombinant periostin protects collagen fibrils from degradation. CONCLUSION: Our data show that periostin plays an important role for proper collagen assembly and homeostasis. During skin aging periostin expression decreases and contributes to the phenotype of aged skin. PMID- 24055233 TI - Abdominal cocoon or idiopathic encapsulating peritoneal sclerosis: magnetic resonance imaging. PMID- 24055234 TI - Three-field or two-field resection for thoracic esophageal cancer: a meta analysis. AB - BACKGROUND: There have been many controversies about the optimal extent of lymphadenectomy for thoracic esophageal cancer, whether three-field lymphadenectomy is superior to two-field lymphadenectomy with respect to the 5 year survival rate and perioperative morbidities and mortality. METHODS: A comprehensive search of PubMed and Embase for relevant studies comparing three field and two-field lymphadenectomies for thoracic esophageal cancer was conducted using the Preferred Reporting Items for Systemic Reviews and Meta Analyses standards. Hazard ratios (HRs) were extracted from these studies to give pooled estimates of the effect of the two surgical procedures on the 5-year survival rate and perioperative morbidities and mortality. RESULTS: Thirteen studies were included for analysis. Compared with two-field lymphadenectomy, three-field lymphadenectomy provided a higher 5-year survival rate (HR 0.64, 95% confidence interval [CI]: 0.56 to 0.73, p = 0.000) and incidence of anastomotic leakage (HR 1.46, 95% CI: 1.19 to 1.79, p = 0.000), with a comparative perioperative mortality (HR 0.64, 95% CI: 0.38 to 1.10, p = 0.110) and incidence of vocal cord palsy (HR 1.12, 95% CI: 0.82 to 1.54, p = 0.470) and pulmonary complications (HR 1.00, 95% CI: 0.89 to 1.12, p = 0.760). CONCLUSIONS: Published evidence indicated that three- field lymphadenectomy could be a priority for thoracic esophageal cancer, especially for tumors with positive lymph nodes. Given the lack of large-sample randomized controlled studies, further evaluations are necessary. PMID- 24055235 TI - Cut-and-transfer technique for ischemic mitral regurgitation and severe tethering of mitral leaflets. AB - BACKGROUND: Chronic ischemic mitral regurgitation (MR) denotes abnormal function of normal leaflets resulting from left ventricular enlargement. We present the midterm results of a tailored mitral repair technique using a combination of the following subvalvular procedures: (1) detachment and reimplantation of secondary chordae on the free edge of the anterior leaflet ("cut-and-transfer" technique), (2) relocation of the posterior papillary muscle (PPM) closer to the mitral annulus, and (3) infarct plication on the lateral wall of the left ventricle. METHODS: From 2008 to 2011, 49 patients with moderate to severe ischemic MR underwent coronary surgery plus mitral valve repair using the cut-and-transfer and PPM relocation techniques. All the patients received a "true-sized" semirigid complete annuloplasty ring. In 20 patients, a plication of the lateral wall of the left ventricle was performed to reduce the tethering of the mitral leaflets. The mean number of coronary grafts per patient was 3.4 +/- 0.4. RESULTS: Hospital mortality was 2%. No patient died during 1-year follow-up and New York Heart Association (NYHA) class improved from 3.4 +/- 0.5 to 1.4 +/- 0.6 (p < 0.0001). The 1-year echocardiogram showed the following changes from baseline: mitral regurgitation grade (0-4) 2.9 +/- 0.4 versus 0.2 +/- 0.4 (p < 0.0001), left ventricular end-systolic volume index (mL/m(2)) 52.7 +/- 13.1 versus 48.2 +/- 10.1 (p = 0.07), left ventricular end-systolic index (mL/m(2)) 92.9 +/- 16.5 versus 83.4 +/- 15.9 (p <0.005), and ejection fraction (%) 37.8 +/- 6.3 versus 44.2 +/- 8.1 (p < 0.0001). CONCLUSIONS: Both clinical and echocardiographic results show that reducing the tethering of the mitral leaflets with tailored interventions on subvalvular apparatus without undersizing the mitral annulus can safely and effectively correct chronic ischemic MR. PMID- 24055236 TI - Preoperative hematocrit is a powerful predictor of adverse outcomes in coronary artery bypass graft surgery: a report from the Society of Thoracic Surgeons Adult Cardiac Surgery Database. AB - BACKGROUND: Small series have identified a relationship between preoperative hematocrit (HCT) and outcomes in coronary artery bypass graft (CABG) surgery. The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD) began collecting preoperative HCT data in 2008. In this study, analyses were performed to determine the impact of preoperative HCT on perioperative morbidity and mortality among patients undergoing isolated CABG. METHODS: Data were collected on 182,599 patients who underwent primary isolated on-pump CABG between 2008 and 2009 and were included in the STS ACSD. Data were included only from centers that performed more than 100 on-pump cases per year during the period of study. Dialysis patients as well as those with previous cardiovascular operations or missing data for HCT were excluded. We then performed multivariable analysis using the 2008 STS CABG risk model as a guide, including HCT as a predictor. Logistic regression was performed for operative mortality and other adverse outcomes. RESULTS: Overall operative mortality was 1.6% (3,005 of 182,599). Compared with patients with anemia (HCT <33%), patients with HCT of at least 42% had lower mortality (1.1% versus 3.4%; p < 0.0001) and lower rates of renal failure (2.0% versus 7.8%; p < 0.0001), stroke (0.9% versus 1.8%; p < 0.0001), prolonged ventilation (8.4% versus 17.5%; p < 0.0001), and deep sternal wound infection (0.3% versus 0.6%; p < 0.0001). In adjusted analyses, each 5-point decrease in preoperative HCT was associated with an 8% higher odds of death (odds ratio, 1.08; p = 0.0003), a 22% increase in the odds of postoperative renal failure (odds ratio, 1.22; p < 0.0001), and a 10% increase in the risk of deep sternal wound infection (odds ratio, 1.10; p < 0.01). Similar results were observed among patients (n = 74,292) undergoing elective CABG. The percentage of patients receiving perioperative blood transfusion decreased from 88.5% in the anemic group (HCT <33%) to 32.5% in patients with HCT of at least 42% (p < 0.0001). CONCLUSIONS: Preoperative HCT is a powerful independent predictor of perioperative mortality as well as renal failure and deep sternal wound infection in patients undergoing isolated primary CABG operations. These findings should prompt investigation of strategies to increase preoperative HCT. PMID- 24055237 TI - Grant et al. 1926 did not provide the first description of left ventricular hypertrabeculation/noncompaction. PMID- 24055238 TI - Occurrence of hepatitis B virus genotype B and B+C mixed infections in Chennai, South India. PMID- 24055239 TI - Prior exposure to enriched environment reduces nitric oxide synthase after transient MCAO in rats. AB - Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury is neuroprotective in animal models. However, little is known about of the neuroprotective effects of EE exposure prior to injury. The current study examined the effects of prior EE exposure on inducible and neuronal nitric oxide syntheses (iNOS and nNOS) after transient middle cerebral artery occlusion (tMCAO) in rats. A total of 72 rats were exposed to EE or standard housing condition (SC) for 1 month, followed by 90-min MCAO and reperfusion or sham surgery, leading to the following three groups: (1) EE+MCAO (n=24), (2) SC+MCAO (n=24), (3) SC+sham (n=24). Rats were sacrificed at 1, 6, or 24h after MCAO (n=6/group) for iNOS and nNOS mRNA quantification by real-time PCR and at 24h after MCAO (n=6/group) for iNOS and nNOS protein quantification by Western blot or were evaluated for neurological function outcomes, then sacrificed to assess infarct volume (n=6/group). Results showed that prior exposure to EE reduced iNOS and nNOS mRNA and protein and improved neurological status after MCAO without affecting infarct volume, suggesting that EE may provide neuroprotection via ischemic preconditioning. PMID- 24055240 TI - Impact of graft position on failure of single-stage bulbar urethroplasties with buccal mucosa graft. AB - OBJECTIVE: To determine whether patency rates after bulbar urethroplasty with buccal mucosa graft onlay differ on the basis of whether the graft is placed ventrally or dorsally. METHODS: This was a retrospective single-center study of all single-stage bulbar urethroplasties performed from 2001 to 2011 by 2 surgeons in which buccal mucosa was used as an onlay graft. Failure was defined as the need for endoscopic or open revision of the reconstruction or the placement of a suprapubic catheter for urinary retention. RESULTS: A total of 103 patients were reviewed; 41 underwent dorsal onlay, and 62 underwent ventral onlay. Mean age was 40.8 years. Most patients (84%) underwent a previous procedure, which consisted of direct vision internal urethrotomy in 69%, dilation in 53%, and urethroplasty in 14%. Mean stricture length was 3.9 cm. At a mean follow-up of 36 months, failure occurred in 19 patients (12 ventral and 7 dorsal). The vast majority of these patients (79%) were successfully treated with a single dilation or direct vision internal urethrotomy. There was no difference in failure rate or time to failure according to whether graft position was ventral or dorsal. In multivariate analysis, diabetes was predictive of failure (odds ratio 8.7; 95% confidence interval 1.6-46.5; P = .01). CONCLUSION: Single-stage bulbar urethroplasty with buccal mucosa graft is an effective procedure for patients with a bulbar urethral stricture that is not amenable to primary anastomosis. From our experience, we cannot conclude that dorsal or ventral graft position is inherently superior. Patients with diabetes may be more likely to require additional procedures after bulbar urethroplasty with buccal grafting. PMID- 24055241 TI - Predicting risk of prostate cancer in men receiving finasteride: effect of prostate volume, number of biopsy cores, and American Urological Association symptom score. AB - OBJECTIVE: To examine the effect of prostate volume, number of biopsy cores, and American Urological Association symptom score (AUASS) for prostate cancer risk assessment among men receiving finasteride in the Prostate Cancer Prevention Trial. METHODS: Data from 4509 men on the finasteride arm of the Prostate Cancer Prevention Trial who were on treatment at the time of their AUASS and prostate specific antigen (PSA) measurement before biopsy were included in multivariable logistic regression analyses. RESULTS: Six hundred eighty-two (15.1%) participants had prostate cancer; 257 (37.7%) of these had high-grade disease. For prostate cancer risk, the model included PSA (odds ratio corresponding to a 2 fold increase in PSA: 2.70; P <.0001), digital rectal examination (2.53; P <.0001), age (1.03; P = .001), and prostate volume (odds ratio 0.54 for a 2-fold increase in volume; P <.0001). For high-grade disease, PSA (3.39; P <.0001), digital rectal examination (2.75; P <.0001), age (1.05; P = .001), and volume (0.55; P <.0001) were statistically significant. AUASS was not statistically significant in any of the models that included prostate volume, but was in models in which volume was not included. The number of biopsy cores did not significantly improve risk assessment in any of the models considered. CONCLUSION: Although in the general population, obtaining a cancer diagnosis is improved by assessing prostate volume and increasing the number of biopsy cores, neither steps are required in men receiving finasteride. Obtaining fewer biopsy cores in men receiving finasteride preserves biopsy sensitivity and will likely reduce cost and morbidity. PMID- 24055242 TI - Editorial comment. PMID- 24055243 TI - Editorial comment. PMID- 24055244 TI - Recent trends in the urology workforce in the United States. AB - The present study examines the current status of urology physician manpower in the United States, in the context of trends in the demographics, geographic distribution, and practice make-up of urologists. Physicians were identified as surgeons and classified into surgical groups using a combination of American Medical Association primary and secondary self-reported specialties and American Board of Medical Specialties certifications. From these groups, urologic surgeons were isolated for analysis. The supply of urologists per capita has declined since 1981 - most dramatically since 1991. With an average age of 52.5 years, urology is one of the oldest surgical specialties. Over 7% of urologists are older than 70 years and 44% are older than 55 years, suggesting an aging urology workforce. The number of female urologists has grown almost a 1000-fold and represents a growing and younger cohort of the workforce. The number of rural urologists and the number of international medical graduates have continued to decline since 1981. Over the past 10 years, an increasing number of urologists are now in group practices (over 60%), and these tended to be younger and in urban settings. In contrast to most other surgical specialties, there has been a decrease in the supply of urologists relative to population growth, which is expected to be exacerbated by an aging and relatively older urology physician workforce, particularly in rural areas, a slight increase in female urologists, and the gravitation of younger urologists toward group practice in urban areas. PMID- 24055246 TI - Validation of a European Spanish-version of the University of California performance Skills Assessment (Sp-UPSA) in patients with schizophrenia and bipolar disorder. AB - AIMS: To validate the Spanish version of the University of California Performance Skills Assessment (UPSA) in patients with severe mental disorders. METHODS: Naturalistic, 6month follow-up, multicentre, validation study. 139 patients with schizophrenia, 57 bipolar patients and 31 controls were evaluated using the following scales: Spanish UPSA (Sp-UPSA), Clinical Global Impression, Severity (CGI-S), Global Assessment of Functioning (GAF), and Personal and Social Performance (PSP). RESULTS: Reliability: Internal consistency (Cronbach's alpha) was 0.81 in schizophrenia and 0.58 in bipolar patients. Test-retest was 0.74 and 0.65 (p<0.0001) respectively. Construct validity: Pearson correlation coefficients between Sp-UPSA and PSP total scores were 0.42 (p<0.0001) for schizophrenia and 0.44 (p=0.001) for bipolar patients. For Sp-UPSA and GAF scores correlation coefficients were 0.43 and 0.52 (p<0.0001) respectively. Discriminant validity: The Sp-UPSA discriminated between patients and controls. In schizophrenia patients it also discriminated among different levels of illness severity according to CGI-S scores. In control versus patients with schizophrenia contrasts, the area under the curve was 0.89 and a cut-off point of 85 provided a sensitivity of 82.7% and a specificity of 77.4%. In bipolar patients, the area under the curve was 0.85 and a cut-off point of 90 provided a sensitivity of 82.5% and a specificity of 64.5%. CONCLUSION: The Spanish UPSA is a reliable and valid instrument for assessing functional capacity in severe mentally ill patients. It seems to be appropriate for use in clinical trials and in everyday clinical practice as a means of monitoring functional outcomes. PMID- 24055245 TI - Structure, dynamics and biophysics of the cytoplasmic protein-protein complexes of the bacterial phosphoenolpyruvate: sugar phosphotransferase system. AB - The bacterial phosphotransferase system (PTS) couples phosphoryl transfer, via a series of bimolecular protein-protein interactions, to sugar transport across the membrane. The multitude of complexes in the PTS provides a paradigm for studying protein interactions, and for understanding how the same binding surface can specifically recognize a diverse array of targets. Fifteen years of work aimed at solving the solution structures of all soluble protein-protein complexes of the PTS has served as a test bed for developing NMR and integrated hybrid approaches to study larger complexes in solution and to probe transient, spectroscopically invisible states, including encounter complexes. We review these approaches, highlighting the problems that can be tackled with these methods, and summarize the current findings on protein interactions. PMID- 24055247 TI - A short C-terminal tail prevents mis-targeting of hydrophobic mitochondrial membrane proteins to the ER. AB - Sdh3/Shh3, a subunit of mitochondrial succinate dehydrogenase, contains transmembrane domains with a hydrophobicity comparable to that of endoplasmic reticulum (ER) proteins. Here, we show that a C-terminal reporter fusion to Sdh3/Shh3 results in partial mis-targeting of the protein to the ER. This mis targeting is mediated by the signal recognition particle (SRP) and depends on the length of the C-terminal tail. These results imply that if nuclear-encoded mitochondrial proteins contain strongly hydrophobic transmembrane domains and a long C-terminal tail, they have the potential to be recognized by SRP and mis targeted to the ER. PMID- 24055248 TI - Experience with extracorporeal membrane oxygenation in massive and submassive pulmonary embolism in a tertiary care center. PMID- 24055250 TI - Spatiotemporal patterns provoked by environmental variability in a predator-prey model. AB - The emergence of spatiotemporal patterns in the distribution of species is one of the most striking phenomena in ecology and nonlinear science. Since it is known that spatial inhomogeneities can significantly affect the dynamics of ecological populations, in the present paper we investigate the impact of environmental variability on the formation of patterns in a spatially extended predator-prey model. In particular, we utilize a predator-prey system with a Holling III functional response and introduce random spatial variations of the kinetic parameter signifying the intrinsic growth rate of the prey, reflecting the impact of a heterogeneous environment. Our results reveal that in the proximity of the Hopf bifurcation environmental variability is able to provoke pattern formation, whereby the coherence of the patterns exhibits a resonance-like dependence on the variability strength. Furthermore, we show that the phenomenon can only be observed if the spatial heterogeneities exhibit large enough regions with high growth rates of the prey. Our findings thus indicate that variability could be an essential pattern formation mechanism of the populations. PMID- 24055249 TI - Determination of a predictive cutoff value of NT-proBNP testing for long-term survival in ED patients with acute heart failure. AB - OBJECTIVE: The main objective of this study was to determine a predictive cutoff value for plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) that could successfully predict the long-term (4-year) survival of patients with acute heart failure (HF) at the time of admission to the emergency department (ED). To our best knowledge, our study is the first research done to identify a predictive cutoff value for admission NT-proBNP to the prescriptive 4-year survival of patients admitted to ED with acute HF diagnosis. METHODS: NT-proBNP levels were measured in plasma obtained from 99 patients with dyspnea and left ventricular dysfunction upon admission to the ED. The end point was survival from the time of inclusion through 4 years. RESULTS: The mean age of the patients in this study was 71.1 +/- 10.3 years; 50 of these patients were female. During the 4-year follow-up period, 76 patients died; survivors were significantly younger than non survivors (64.26 +/- 11.42 years vs 72.83 +/- 11.07 years, P = .002). The optimal NT-proBNP cutoff point for predicting 4-year survival at the time of admission was 2300 pg/mL, which had 85.9% sensitivity and 39.1% specificity (95% confidence interval, area under the curve: 0.639, P = .044). CONCLUSION: Elevated NT-proBNP levels at the time of admission are a strong and independent predictor of all cause mortality in patients with acute HF 4 years after admission. Furthermore, the optimal cutoff level of NT-proBNP used to predict 4-year survival had high sensitivity. However, especially in the case of long-term survival, additional prospective, large, and multicenter studies are required to confirm our results. PMID- 24055251 TI - Mechanisms of nC60 removal by the alum coagulation-flocculation-sedimentation process. AB - This study explored the mechanisms for nC60 removal in pure water and filtered saline wastewater by the alum coagulation-flocculation-sedimentation process through analyzing the hydrolyzed aluminum species and exploring the complexation of nC60 with aluminum hydroxide precipitates. Sweep flocculation (enmeshment and adsorption) with Alc is the most dominant mechanism contributing to the nC60 removal in pure water. In filtered saline wastewater, hetero-precipitation of Alb with nC60, colloids, and dissolved solids also contributes to the nC60 removal. Alkalinity affected the nC60 removal by changing the hydrolyzed aluminum species distributions. XPS, FTIR, and SEM evidences suggest that the enmeshment and adsorption of nC60 onto the aluminum hydroxide precipitates can be described as the inner-sphere complexation. Based on the above observations, conceptual models for nC60 removal by the alum coagulation-flocculation-sedimentation process in the different water matrices are proposed. PMID- 24055252 TI - Synthesis of organic-inorganic hybrid microspheres and the corresponding mesoporous silica nanoparticles. AB - Poly(methacrylic acid-co-3-(methacryloxy)propyltrimethoxysilane) (P(MAA-co-MPS)) organic-inorganic hybrid microspheres were prepared by distillation-precipitation copolymerization of MAA and MPS in acetonitrile in absence of any surfactant and additive. The resultant hybrids had a spherical shape when the MPS inorganic precursor was varied from 0% to 60% in the comonomers during the polymerization. The hybrid microspheres can be facilely cross-linked via the hydrolysis of methoxy groups of polyMPS network and further self-condensation of the hydroxyl groups of silanols. As a result, the hybrid microspheres were facilely converted to mesoporous silica particles via the removal of the organic component through calcination. The narrow dispersed mesoporous silica had a high surface area of 554.2 m(2)/g as well as the average pore size of 8 nm and pore volume of 0.24 cm(3)/g. The corresponding microspheres were characterized by TEM, FT-IR, TGA, and nitrogen sorption-desorption. PMID- 24055253 TI - Microwave-assisted synthesis of small Ru nanoparticles and their role in degradation of congo red. AB - Polyethyleneglycol (PEG) stabilized Ru nanoparticles (NPs) were synthesized by single pot rapid microwave (MUW) method in presence of glucose as reducing agent. The MUW reaction for different amounts of added glucose and PEG was monitored by UV-vis spectroscopy. Small sized NPs (2-5 nm) were obtained with appropriate amounts of glucose and PEG. The size of particles decreased with increasing MUW power and decreasing irradiation time (keeping input energy constant), as observed by dynamic light scattering and transmission electron microscopy, which means one has size control via preparation process. X-ray diffraction pattern confirmed hcp lattice of synthesized Ru(0) NPs. To demonstrate their usefulness, a model reaction was selected in which degradation of azo bonds of congo red dye was catalyzed by Ru NPs. This is first report where Ru NPs were employed in catalytic decolorization of an azo dye, which is an important application in waste water treatment. It was found that the NPs acted as an electron mediator in transfer of electron from reducing agent to azo bond. Rate of the reaction increased drastically by introducing Ru NPs in the system and decolorization of dye was accelerated by factor of 200, which is substantial improvement in facilitating this important reaction. PMID- 24055254 TI - AQU-1, a chromosomal class C beta-lactamase, among clinical Aeromonas dhakensis isolates: distribution and clinical significance. AB - Aeromonas dhakensis, a recently described Aeromonas sp. formerly called Aeromonas aquariorum, is associated with human infections. In this study, a chromosomal gene, blaAQU-1, was identified in A. dhakensis AAK1 that constitutes a 1143-bp open reading frame and is 87% identical to the gene encoding CepH in Aeromonas hydrophila. An Escherichia coli TOP10 cell transformant harbouring blaAQU-1 was resistant to cefotaxime but not to cefepime. mRNA expression of blaAQU-1 in the cefotaxime-resistant mutant strain AAK1m was 70-fold higher than in the wild strain AAK1. In all 16 A. dhakensis isolates (the major species of 51 consecutive Aeromonas blood isolates collected from June 1999 to June 2001) as well as in A. aquariorum MDC47(T) and A. hydrophila subsp. dhakensis LMG 19562(T), but not in the reference strains or clinical isolates of other A. hydrophila subspecies, Aeromonas caviae, Aeromonas veronii or Aeromonas enteropelogenes, blaAQU-1 related genes were detected by PCR. Overall, 13 (81%) of the 16 A. dhakensis blood isolates exhibited either cefotaxime resistance or the in vitro emergence of derepressed cefotaxime-resistant mutants. In vivo selection of an A. dhakensis resistant mutant was noted in a burn patient undergoing cefotaxime monotherapy. These observations suggest that AQU-1 is a chromosomal cephalosporinase in A. dhakensis. Cefotaxime monotherapy for severe A. dhakensis infections should be used cautiously. PMID- 24055255 TI - Patients enrolled in randomised clinical trials are not representative of critically ill patients in clinical practice: observational study focus on tigecycline. AB - It is being increasingly recognised by clinicians and scientists that participants in randomised clinical trials (RCTs) of antibiotics of last resort do not represent the patients who will later be treated with these drugs. Data on this subject are limited and have not been investigated systematically. This observational study aimed to examine this hypothesis quantitatively, using the example of tigecycline. To evaluate the influence of recruitment, patients eligible for clinical trials were retrospectively compared with ineligible patients regarding baseline and clinical characteristics as well as outcome parameters, e.g. length of hospital stay, intensive care unit (ICU) stay, ventilation and mortality. The clinical characteristics of 187 patients illustrated differences in the nature and severity of disease, co-morbidities and outcome. Eligible and ineligible patients differed in a number of parameters, e.g. median APACHE II score (15.5 vs. 28.0), number of liver transplantations (5% vs. 18%; P=0.048), septic shock (21% vs. 49%; P=0.001), need for mechanical ventilation (30% vs. 79%; P<0.001), mean length of ICU stay (19.3 days vs. 40.7 days) and death (19% vs. 46%; P=0.001). Critically ill patients were under represented in clinical trials. Moreover, only a minority of patients in clinical practice (13%) were potentially eligible for a pivotal RCT. The disparities likely result from strict exclusion criteria in RCTs and recruitment bias. These data emphasise the importance of including critically ill patients in RCTs of antibiotics against multiresistant bacteria in order to account for those who will later be treated. PMID- 24055256 TI - Bone mineral density status and frequency of osteoporosis and clinical fractures in 155 patients with psoriatic arthritis followed in a university hospital. AB - OBJECTIVE: To assess the bone mineral density (BMD) and the frequency of osteoporosis and clinical fractures in a large group of Spanish patients with psoriatic arthritis (PsA). PATIENTS AND METHODS: BMD was determined by DXA in all the patients who were willing to participate and had peripheral PsA regularly evaluated in a tertiary university hospital. All patients underwent a physical examination and general laboratory analysis. We gathered demographic and clinical variables related with BMD and risk of fractures. We also recorded the history of clinical low impact fractures. The population of reference to calculate T-score and Z-score came from a Spanish database. RESULTS: One hundred and fifty-five patients were included (64 postmenopausal women, 26 premenopausal women and 65 men). The clinical forms of PsA were: 46% oligoarticular and 54% polyarticular. Mean disease duration was 13.7+/-9.4 years and mean ESR was 21.8+/-13.9mm/h; 66% of patients had received glucocorticoid treatment. We found no differences in BMD status between the patients and the Spanish general population, neither in the whole series nor in each defined subgroup. Frequency of osteoporosis was 16%; it was higher in postmenopausal women (28%) than in men (9%) or premenopausal women (4%). Frequency of clinical fractures was 13%; it accounted specially in postmenopausal women. CONCLUSIONS: The magnitude of the problem of osteoporosis in PsA seems to be mild. PMID- 24055257 TI - Hyperlax Ehlers-Danlos syndrome: benign hypermobility? PMID- 24055258 TI - Cannabinoid receptor 2 activation: a means to prevent monocyte-endothelium engagement. AB - This Commentary highlights the article by Rom et al which shows that selective cannabinoid receptor 2 activation in leukocytes decreases key steps in monocyte blood brain barrier engagement suppressing inflammatory leukocyte responses and preventing neuroinflammation. PMID- 24055260 TI - Indications of DXA in women younger than 65 yr and men younger than 70 yr: the 2013 Official Positions. AB - Dual-energy X-ray absorptiometry (DXA) is the method of choice to assess fracture risk for women 65 yr and older and men 70 yr and older. The 2007 International Society for Clinical Densitometry Official Positions had developed guidelines for assessing bone density in younger women during and after the menopausal transition and in men 50-69 yr and the 2008 National Osteoporosis Foundation (NOF) guidelines recommended testing in postmenopausal women younger than 65 yr and men 50-69 yr only in the presence of clinical risk factors. The purpose of the 2013 DXA Task Force was to reassess the NOF guidelines for ordering DXA in postmenopausal women younger than 65 yr and men 50-69 yr. The Task Force reviewed the literature published since the 2007 Position Development Conference and 2008 NOF, reviewing clinical decision rules such as the Osteoporosis Screening Tool and FRAX and sought to keep recommendations simple to remember and implement. Based on this assessment, the NOF guidelines were endorsed; DXA was recommended in those postmenopausal women younger than 65 yr and men 50-69 yr only in the presence of clinical risk factors for low bone mass, such as low body weight, prior fracture, high-risk medication use, or a disease or condition associated with bone loss. PMID- 24055261 TI - Protein degradation during the diatom cell cycle: annotation and transcriptional analysis of SCF and APC/C ubiquitin ligase genes in Phaeodactylum tricornutum. AB - In every eukaryotic organism, unidirectional cell cycle progression is driven by controlled proteolysis. Here, we present the identification of two ubiquitin ligase complexes in the diatom Phaeodactylum tricornutum, the SCF and APC/C, being important for temporal controlled degradation of key cell division proteins. We annotated and analyzed the conservation of all subunits of both complexes in P. tricornutum. Expression analysis during a synchronized cell cycle showed that the SCF complex subunits are transcribed at the G1-to-S phase transition. In contrast, expression of the APC/C subunits is relatively constant, except for its activators that are differentially expressed: CDC20 is highly expressed at mitosis, while CDH1 is transcribed at late M and during G1, suggesting temporal activation of the different complexes. Furthermore, we performed in silico prediction of APC/C targets through destruction box (D-box) and KEN box analysis, two known degrons for substrate recognition of the APC/C complexes. For this, we focused on the expanded set of diatom cyclins, including the diatom-specific cyclins. Interestingly, we could find D-boxes for most mitotically expressed cyclins, but also some of the G1/S cyclins. Thus, it appears that in analogy with what is known in other organisms, tight post translational control of the diatom cyclins might contribute to the well coordinated cell cycle progression. PMID- 24055259 TI - Selective activation of cannabinoid receptor 2 in leukocytes suppresses their engagement of the brain endothelium and protects the blood-brain barrier. AB - Cannabinoid receptor 2 (CB2) is highly expressed in immune cells and stimulation decreases inflammatory responses. We tested the idea that selective CB2 activation in human monocytes suppresses their ability to engage the brain endothelium and migrate across the blood-brain barrier (BBB), preventing consequent injury. Intravital videomicroscopy was used to quantify adhesion of leukocytes to cortical vessels in lipopolysaccharide-induced neuroinflammation, after injection of ex vivo CB2-activated leukocytes into mice; CB2 agonists markedly decreased adhesion of ex vivo labeled cells in vivo. In an in vitro BBB model, CB2 activation in monocytes largely attenuated adhesion to and migration across monolayers of primary human brain microvascular endothelial cells and diminished BBB damage. CB2 stimulation in monocytes down-regulated active forms of integrins, lymphocyte function-associated antigen 1 (LFA-1), and very late antigen 4 (VLA-4). Cells treated with CB2 agonists exhibited increased phosphorylation levels of inhibitory sites of the actin-binding proteins cofilin and VASP, which are upstream regulators of conformational integrin changes. Up regulated by relevant stimuli, Rac1 and RhoA were suppressed by CB2 agonists in monocytes. CB2 stimulation decreased formation of lamellipodia, which play a key role in monocyte migration. These results indicate that selective CB2 activation in leukocytes decreases key steps in monocyte-BBB engagement, thus suppressing inflammatory leukocyte responses and preventing neuroinflammation. PMID- 24055262 TI - Introduction to the minisymposium on mucosal healing in inflammatory bowel disease. PMID- 24055263 TI - Symptoms and side effects: delicate balance in the management of patients with neurogenic bladder. PMID- 24055264 TI - Prophylaxis in urology is no longer easy--should we use more or fewer antibiotics? PMID- 24055265 TI - Benign prostatic hyperplasia and lower urinary tract symptoms--when to pull the trigger on surgery? PMID- 24055266 TI - Effect of beta3-adrenergic receptor on atrial L-type Ca(2+) current in rats with chronic heart failure. AB - OBJECTIVES: To investigate the effect of selective beta3-adrenoreceptor agonist BRL-37344 on L-type Ca(2+) current (Ica,L) and mRNA expression of L-type Ca(2+) channel alpha2delta-2 (Cacna2d2) in rats with chronic heart failure (CHF). METHODS: Twenty-four male Wistar rats were divided into normal control (n=6) and CHF group (n=18), which were further divided into CHF control and BRL group (0.4nmol/kg, IV, twice weekly for four weeks). Echocardiography was performed to assess the structure and function of the left atrium (LA). RESULTS: The LA in the BRL group (4.4 +/- 0.2mm) was larger than in the normal control (3.5 +/- 0.3mm, P<0.01) or CHF control (4.0 +/- 0.2mm, P<0.05) group. The LA ejection fraction in the BRL group (36.2 +/- 4.2%) was lower than in the normal control (58.0 +/- 3.1%, P<0.01) or CHF control group (42.3 +/- 4.8%, P<0.05). There was no difference in Ica,L density between the BRL group and CHF control group (8.3 +/- 1.7 vs. 8.2 +/- 2.6 pA/pF, P>0.05), which was higher than in the normal control group (6.0 +/- 1.8 pA/pF, P<0.01). There was no difference in the mRNA expression of alpha2delta-2 (Cacna2d2) between the BRL group and CHF control group (0.264 +/ 0.005 vs. 0.243 +/- 0.017, P>0.05), which was also higher than in the normal control group (0.137 +/- 0.013, P<0.01). CONCLUSION: beta3-Adrenoreceptor stimulation with BRL-37344 was associated with an increase in LA diameter and a decrease in LA function in chronic heart failure. These structural and function changes were not related to Ica,L or L-type Ca(2+) channel alpha2delta-2 (Cacna2d2) subunit in the LA myocytes. PMID- 24055267 TI - Gastrointestinal-related uremic toxins in peritoneal dialysis: a pilot study with a 5-year follow-up. AB - BACKGROUND AND AIMS: P-cresyl sulfate (PCS) and indoxyl sulfate (IS) were not only novel but essential factors associated with cardiovascular disease and mortality in patients with chronic kidney disease and hemodialysis. However, little evidence exams the effect in peritoneal dialysis (PD) patients. METHODS: This pilot study recruited 46 stable PD patients in a single medical center. Serum levels of IS, PCS and biochemistry were measured concurrently. Clinical outcomes including cardiovascular, all-cause mortality and PD failure event were recorded during a 5-year follow-up. RESULTS: Serum levels of free and total PCS were lower in patients with residual renal function (11.67 +/- 6.92, p = 0.014, 0.77 +/- 0.48, p = 0.046, respectively). Multivariate Cox regression analysis showed age (HR: 1.07, p = 0.01), serum CO2 (HR: 0.67, p = 0.02) and total PCS (HR: 1.05, p <0.01) were independently associated with cardiovascular events; only free PCS (HR: 1.42, p <0.01) reached significant correlation with all-cause mortality. Total IS (HR: 1.27, p = 0.03) significantly correlated with PD failure event after adjusting other confounding factors. Kaplan-Meier analysis revealed that patients with higher total and free PCS levels had higher cardiovascular events (log rank p <0.01, log rank p = 0.05, respectively) and mortality event (log rank p = 0.02, log rank p = 0.03, respectively) than those with lower levels. In addition, total IS (log rank p = 0.04), total PCS (log rank p = 0.01) and free PCS (log rank p <0.01) could independently predict PD failure event during the study period. CONCLUSIONS: Our findings suggest PCS and IS may be a valuable surrogate in predicting poor clinical outcomes in PD patients. PMID- 24055268 TI - Increase in West Nile virus infections imported to Germany in 2012. AB - Following the first confirmed imported West Nile virus (WNV) infection in 2011, the number of imported WNV infections to Germany increased in 2012. Two cases of West Nile neuroinvasive disease (WNND) and two cases of West Nile fever (WNF) were reported. The WNND cases were imported from Montenegro and Greece, including the first fatal case for Germany. The WNF cases were imported from Tunisia and Egypt. The cases were unambiguously confirmed according to laboratory criteria of European Centre for Disease Prevention and Control (ECDC). In this report we summarize the clinical and laboratory findings in order to sensitize physicians in Germany for this imported viral disease. PMID- 24055269 TI - JC and BK polyomavirus-specific immunoglobulin G responses in patients thymectomized in early childhood. AB - BACKGROUND: JC (JCPyV) and BK polyomaviruses (BKPyV) infect 50-90% of the general population and thereafter persist with asymptomatic shedding. Previous studies have revealed a delayed antibody response to neo-antigens in children and adolescents who were thymectomized due to congenital heart defects. OBJECTIVES: The present longitudinal study aimed at analyzing the seroprevalence and the antibody persistence against BKPyV and JCPyV in a 3-years time period in thymectomized patients (TP) compared to healthy controls (HC). STUDY DESIGN: Given the widespread primary and secondary exposure to BKPyV and JCPyV, we examined the impact of childhood thymectomy on specific IgG levels by ELISA using the respective virus-like particles. RESULTS: IgG-anti-BKPyV levels which were lower at beginning of the study increased in TP after a 3-years time interval and correlated with age. In contrast, IgG-anti-BKPyV levels decreased in HC within the same time period. Individuals losing humoral immunity against BKPyV and JCPyV were seen in both TP and HC. CONCLUSIONS: Although seroprevalence and maintenance of antibodies against BKPyV and JCPyV were similar between TP and HC, a more dynamic process was suggested for TP, with a probably delayed humoral immune response in some patients but similar waning of antibodies compared to HC. Our study supports the hypothesis that in thymectomy, similar to vaccination, antibody responses to neo-antigens are delayed. The assessment of long-term antibody stability together with cellular reactivity and detection of viremic episodes will elucidate further aspects of controlling of persistent viral infections in thymectomized individuals and the role of a complete thymus. PMID- 24055270 TI - Inter-rater and intra-rater reliability of cerebral blood flow measures obtained using the Brain Acoustic Monitor. AB - BACKGROUND: Current assessment of sport-related concussion involves a multifaceted approach including neurocognitive testing, symptom report, and balance assessment. Lacking from this paradigm is a truly objective measure of the physiological changes associated with concussion. NEW METHOD: A device called the Brain Acoustic Monitor (BAM) has been developed to detect cerebral blood flow changes resulting from traumatic brain injury by amplification and comparison of sound waves created by cerebral arteries and a reference artery. The reliability of its measures is unknown, limiting its use in day-to-day assessment of concussion. Therefore, the purpose of this study was to determine the inter- and intra-rater reliability associated with BAM measures. Twenty healthy participants were assessed on two occasions, separated by at least 24h. Ten subjects were measured during the initial session by two assessors for inter-rater comparisons. Measures of positive-to-negative signal deflection (ratio) and frequency divergence from a reference arterial signal (divergence) were calculated and analyzed using Intra-class correlations (2,1). RESULTS: Inter-rater reliability ranged from poor to excellent, showing greater reliability in right brain vs. left brain measures. Intra-rater reliability was similar with a range of poor to good. COMPARISON WITH EXISTING METHODS: These findings are comparable to the reliability of current methods of concussion assessment, specifically neurocognitive testing. CONCLUSION: All BAM values obtained in our healthy subjects were well below scores that would reflect potential head injury. These findings emphasize the potential usefulness of this device in future research concerning serial measurement of cerebral perfusion pressure changes associated with sport concussion. PMID- 24055271 TI - 3D in vivo femoro-tibial kinematics of tri-condylar total knee arthroplasty during kneeling activities. AB - BACKGROUND: Kneeling position can serve as an important posture, providing stability and balance from a standing position to sitting on the floor or vice versa. The purpose of the current study was to determine the kinematics during kneeling activities after subjects were implanted with a tri-condylar total knee arthroplasty. MATERIALS AND METHODS: Kinematics was evaluated in 54 knees using fluoroscopy and a three-dimensional model fitting approach. RESULTS: The average knee flexion at before contact status, at complete contact and at maximum flexion was 98.1+/-9.0 degrees , 107.2+/-6.7 degrees , and 139.6+/-12.3 degrees , respectively. On average, there was no gross anterior displacement from before contact status to complete contact. Only slight posterior rollback motion of both condyles from complete contact to maximum flexion was observed. Three of 39 (7.7%) knees experienced anterior movement of both condyles more than 2mm from before contact status to complete contact. Reverse rotation pattern from before contact status to complete contact and then normal rotation pattern from complete contact to maximum flexion were observed. Condylar lift-off greater than 1.0 mm was observed in 45 knees (83.3%). CONCLUSION: The presence of the ball-and-socket joint articulation provides sufficient antero-posterior stability in these designs to enable the patients to kneel safely without the incidence of any dislocation. CLINICAL RELEVANCE: This study suggests a safe implant design for kneeling. PMID- 24055272 TI - Meniscectomy of horizontal tears of the lateral meniscus anterior horn using the joystick technique. AB - Unstable inferior leaves of the anterior horn in horizontal tears of the lateral meniscus are challenging lesions for most orthopedic surgeons due to the poor viewing angle and the instability of these lesions. Resection of an exact volume is required for the successful treatment of horizontal tears in the lateral meniscus anterior horn. We report a method based on the joystick technique. PMID- 24055273 TI - Activation of inflammasomes in adipose tissue of women with gestational diabetes. AB - Gestational diabetes mellitus (GDM) is characterised by maternal peripheral insulin resistance, increased inflammation, and increasing levels of circulating free fatty acids (FFAs) and advanced glycation endproducts (AGEs). Caspase-1 is a key component of the inflammasome, which is activated upon cellular infection or stress to trigger the maturation IL-1beta, a pro-inflammatory cytokine that mediated insulin resistance. The aim of this study was to determine whether the inflammasome is activated in adipose tissue from women with gestational diabetes mellitus (GDM) and if it interferes with the insulin signalling pathway leading to the insulin resistance that is evident in GDM. Protein expression of active caspase-1 and mature IL-1beta secretion was increased in adipose tissue of women with GDM. Treatment of adipose tissue with IL-1beta decreased insulin-stimulated phosphorylation of IRS-1, GLUT-4 expression and glucose uptake. Low-grade inflammation (induced by LPS), the FFA palmitate and AGE conjugated to BSA (AGE BSA), induced IL-1beta secretion via inflammasome activation. In conclusion, the present findings describe an important role for adipose tissue inflammasome activation in the development of insulin resistance associated in pregnancies complicated by GDM. PMID- 24055274 TI - AMPK activator-mediated inhibition of endoplasmic reticulum stress ameliorates carrageenan-induced insulin resistance through the suppression of selenoprotein P in HepG2 hepatocytes. AB - Carrageenan (CGN) has been shown to cause inflammation through toll-like receptor 4, which may play an important role in insulin resistance and type 2 diabetes mellitus. Selenoprotein P (SeP) has recently been identified as a novel hepatokine that causes insulin resistance. Here, we report that treatment of HepG2 cells with CGN increased both CCAAT enhancer binding protein homologous protein (CHOP) and SeP expression. Pretreatment with 4-phenylbutyrate (4-PBA), an endoplasmic reticulum stress inhibitor, and PD98059, a c-Jun N-terminal kinase (JNK) inhibitor, reversed CGN-induced SeP expression. Moreover, both 4-PBA and knock-down of SeP improved CGN-induced insulin resistance. In addition, we found that adenosine monophosphate-activated protein kinase (AMPK) activators ameliorated CGN-induced insulin resistance in addition to suppressing CHOP and SeP expression. In conclusion, CGN-induced ER stress increased the expression of SeP through the JNK pathway, while AMPK activators ameliorated CGN-induced insulin resistance via SeP inhibition through the AMPK-mediated alleviation of ER stress in hepatocytes. PMID- 24055275 TI - Looking at nuclear receptors from a new angle. AB - While the structures of the DNA- and ligand-binding domains of many nuclear receptors have been determined in great detail; the mechanisms by which these domains interact and possibly 'communicate' is still under debate. The first crystal structures of receptor dimers bound to ligand, DNA and coactivator peptides provided new insights in this matter. The observed binding modes revealed exciting new interaction surfaces between the different nuclear receptor domains. Such interfaces are proposed to be the route through which allosteric signals from the DNA are passed on to the ligand-binding domain and the activating functions of the receptor. The structural determinations of DNA-bound receptor dimers in solution, however, revealed an extended structure of the receptors. Here, we discuss these apparent contradictory structural data and their possible implications for the functioning of nuclear receptors. PMID- 24055276 TI - Hormonal regulation of beta-catenin during development of the avian oviduct and its expression in epithelial cell-derived ovarian carcinogenesis. AB - Beta-catenin (CTNNB1) is a dual function molecule that acts as a key component of the cadherin complex and WNT signaling pathway. It has a crucial role in embryogenesis, tumorigenesis, angiogenesis and progression of metastasis. Recently, it has been suggested that the CTNNB1 complex is a major regulator of development of the mouse oviduct and uterus. However, little is known about the CTNNB1 gene in chickens. Therefore, in this study, we focused on the CTNNB1 gene in the chicken reproductive tract and hormonal control of its expression in the chicken oviduct. CTNNB1 was localized specifically to the luminal and glandular epithelium of the four segments of chicken oviduct and DES (diethylstilbestrol, a synthetic non-steroidal estrogen) increased its expression primarily in LE of the magnum. In addition, CTNNB1 mRNA and protein were expressed abundantly in glandular epithelium of endometrioid-type ovarian carcinoma, but not in normal ovaries. Moreover, CTNNB1 expression was post-transcriptionally regulated via its 3'-UTR by binding with target miRNAs including miR-217, miR-1467, miR-1623 and miR-1697. Collectively, these results indicate that CTNNB1 is a novel gene regulated by estrogen in epithelial cells of the chicken oviduct and that it is also abundantly expressed in epithelial cells of endometrioid-type ovarian carcinoma suggesting that it could be used as a marker for diagnosis of ovarian cancer in laying hens and women. PMID- 24055277 TI - Modeling conditions of pigmented integument by dissipative structures. PMID- 24055278 TI - Development and validation of a comorbidity scoring system for patients with cirrhosis. AB - BACKGROUND & AIMS: At least 40% of patients with cirrhosis have comorbidities that increase mortality. We developed a cirrhosis-specific comorbidity scoring system (CirCom) to help determine how these comorbidities affect mortality and compared it with the generic Charlson Comorbidity Index. METHODS: We used data from nationwide health care registries to identify Danish citizens diagnosed with cirrhosis in 1999-2008 (n = 12,976). They were followed through 2010 and characterized by 34 comorbidities. We used Cox regression to assign severity weights to comorbidities with an adjusted mortality hazard ratio (HR) >= 1.20. Each patient's CirCom score was based on, at most, 2 of these comorbidities. Performance was measured with Harrell's C statistic and the Net Reclassification Index (NRI) and results were compared with those obtained using the Charlson Index (based on 17 comorbidities). Findings were validated in 2 separate cohorts of patients with alcohol-related cirrhosis or chronic hepatitis C. RESULTS: The CirCom score included chronic obstructive pulmonary disease, acute myocardial infarction, peripheral arterial disease, epilepsy, substance abuse, heart failure, nonmetastatic cancer, metastatic cancer, and chronic kidney disease; 24.2% of patients had 1 or more of these, and mortality correlated with the CirCom score. Patients' CirCom score correlated with their Charlson Comorbidity Index (Kendall's tau = 0.57; P < .0001). Compared with the Charlson Index, the CirCom score increased Harrell's C statistic by 0.6% (95% confidence interval: 0.3%-0.8%). The NRI for the CirCom score was 5.2% (95% confidence interval: 3.7% 6.9%), and the NRI for the Charlson Index was 3.6% (95% confidence interval: 2.3% 5.0%). Similar results were obtained from the validation cohorts. CONCLUSIONS: We developed a scoring system to predict mortality among patients with cirrhosis based on 9 comorbidities. This system had higher C statistic and NRI values than the Charlson Comorbidity Index, and is easier to use. It could therefore be a preferred method to predict death or survival of patients and for use in epidemiologic studies. PMID- 24055279 TI - Endogenous regulation of visceral pain via production of opioids by colitogenic CD4(+) T cells in mice. AB - BACKGROUND & AIMS: A dysregulated response of CD4(+) T cells against the microbiota contributes to the development of inflammatory bowel disease. Effector CD4(+) T cells, generated in response to microbe-derived antigens, can reduce somatic inflammatory pain through the local release of opioids. We investigated whether colitogenic CD4(+) T cells that accumulate in the inflamed colon also produce opioids and are able to counteract inflammation-induced visceral pain in mice. METHODS: Colitis was induced via transfer of naive CD4(+)CD45RB(high) T cells to immune-deficient mice or by administration of dextran sulfate sodium. Mice without colitis were used as controls. Samples of colon tissue were collected, and production of opioids by immune cells from inflamed intestine was assessed by quantitative polymerase chain reaction and cytofluorometry analyses. The role of intestinal opioid tone in inflammation-induced visceral hypersensitivity was assessed by colorectal distention. RESULTS: In mice with T cell- or dextran sulfate sodium-induced colitis, colitogenic CD4(+) T cells (T helper 1 and Th17 cells) accumulated in the inflamed intestine and expressed a high level of endogenous opioids. In contrast, macrophages and epithelial cells did not express opioids; opioid synthesis in the myenteric plexus was not altered on induction of inflammation. In mice with colitis, the local release of opioids by colitogenic CD4(+) T cells led to significant reduction of inflammation associated visceral hypersensitivity. CONCLUSIONS: In mice, colitogenic Th1 and Th17 cells promote intestinal inflammation and colonic tissue damage but have simultaneous opioid-mediated analgesic activity, thereby reducing abdominal pain. PMID- 24055280 TI - Tricuspid regurgitation jet velocity suggestive of severe pulmonary hypertension. PMID- 24055281 TI - Feasibility of speckle-tracking echocardiography for assessment of left ventricular dysfunction after cardiopulmonary bypass. AB - OBJECTIVES: Effects of temporary biventricular pacing after cardiopulmonary bypass are unpredictable, and the utility of speckle-tracking echocardiography in this setting is unclear. Accordingly, speckle-tracking analysis of transgastric echocardiograms taken during cardiac surgery was assessed as a potential tool to measure strain, synchrony, and twist as indices to predict response. DESIGN: Prospective observational study, in part, with a randomized controlled study of temporary permanent biventricular pacing after cardiopulmonary bypass. SETTING: Single-center study at university-affiliated tertiary care hospital. PARTICIPANTS: Twenty-one cardiac surgery candidates with ejection fraction <=40% and QRS duration >=100 ms or who were undergoing double-valve surgery. INTERVENTIONS: Transgastric views of the basal, midpapillary, and apical levels of the left ventricle were acquired before and after bypass. MEASUREMENTS AND MAIN RESULTS: Midpapillary sections were analyzable in 38% of patients. The remainder had epicardial borders extending beyond the field of view (24%) or inadequate image quality (38%). Only 9% of basal or apical sections were analyzable. Midpapillary radial strain and synchrony changed insignificantly after bypass. Variation in fractional area change correlated with changes in radial strain (p = 0.041) but not with synchrony. CONCLUSIONS: Intraoperative transgastric echocardiography is inadequate for speckle-tracking analysis with current techniques. Intraoperative predictors of temporary biventricular pacing response are lacking. PMID- 24055282 TI - The emergence of concierge emergency medicine. PMID- 24055283 TI - New-onset variable width tachycardia. PMID- 24055284 TI - Lost foreign body in the ear. PMID- 24055285 TI - The role of protein-bound water molecules in microbial rhodopsins. AB - Protein-bound internal water molecules are essential features of the structure and function of microbial rhodopsins. Besides structural stabilization, they act as proton conductors and even proton storage sites. Currently, the most understood model system exhibiting such features is bacteriorhodopsin (bR). During the last 20 years, the importance of water molecules for proton transport has been revealed through this protein. It has been shown that water molecules are as essential as amino acids for proton transport and biological function. In this review, we present an overview of the historical development of this research on bR. We furthermore summarize the recently discovered protein-bound water features associated with proton transport. Specifically, we discuss a pentameric water/amino acid arrangement close to the protonated Schiff base as central proton-binding site, a protonated water cluster as proton storage site at the proton-release site, and a transient linear water chain at the proton uptake site. We highlight how protein conformational changes reposition or reorient internal water molecules, thereby guiding proton transport. Last, we compare the water positions in bR with those in other microbial rhodopsins to elucidate how protein-bound water molecules guide the function of microbial rhodopsins. This article is part of a Special Issue entitled: Retinal Proteins - You can teach an old dog new tricks. PMID- 24055286 TI - The female pelvic floor through midlife and aging. AB - Female pelvic floor is a complex functional unit involved in multiple functions that extend beyond the sole support of pelvic organs. Pelvic floor dysfunction globally affects micturition, defecation and sexual activity. Evolutionary modifications such ad adaptation to upright standing, walking and the need to deliver fetuses with larger head diameters made the fascial and muscle support of the pelvic floor vulnerable, therefore predisposing women to pelvic organ prolapse and incontinence. Different than in males, the female pelvic floor undergoes a number of adaptive changes related to life and endocrine events. Most of the clinical manifestations of these changes become apparent after menopause and throughout aging in women. This review article summarizes the key aspects of the pathophysiology and the clinics of the modifications of the pelvic floor in women through midlife and beyond. A particular focus is given to the relationship between urinary and bowel dysfunction. PMID- 24055287 TI - Structure-activity relationship of carbamate-linked cationic lipids bearing hydroxyethyl headgroup for gene delivery. AB - A novel series of carbamate-linked cationic lipids containing hydroxyl headgroup were synthesized and included in formulations for transfection assays. The DNA lipid complexes were characterized for their ability to bind DNA, their size, zeta-potential and cytotoxicity. Compared with our previously reported cationic transfection lipid DDCDMA lacking the hydroxyl group and the commercially available, these cationic liposomes exhibited relatively higher transfection efficiency. PMID- 24055288 TI - Why do primigravidae request caesarean section in a normal pregnancy? A qualitative study in Iran. AB - OBJECTIVE: to gain a deeper understanding of why Iranian primigravidae request caesarean section without any medical indication. DESIGN: qualitative study. Data were gathered through semi-structured interviews, and thematic analysis was undertaken. SETTING: four health care centres at Hamadan University of Medical Sciences, Hamadan, Iran. PARTICIPANTS: 14 primigravidae who requested caesarean section without any medical indication. FINDINGS: reasons for requesting caesarean section were related to fear of childbirth (labour pain, injury to mother or infant), complications after vaginal delivery (vaginal prolapse, urinary incontinence, sexual dysfunction), trust in obstetricians, and lack of trust in maternity ward staff. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: the main reasons given for requesting caesarean section show that there is urgent need for effective antenatal assessment to enable pregnant women to ask questions and express their concerns. In order to promote vaginal birth, there is a need to develop antenatal education and strategies to enhance women's knowledge, confidence and competence about vaginal birth. Health care providers should be re educated about the observance of medical ethics and professional rules in their practices, and change their attitudes and behaviours to vaginal birth. Evaluation, improvement and change in maternity care policies are recommended to promote natural childbirth. PMID- 24055289 TI - Five year outcomes of hypofractionated simultaneous integrated boost irradiation in breast conserving therapy; patterns of recurrence. AB - In 2005, we introduced hypofractionated 3-dimensional conformal radiotherapy with a simultaneous integrated boost (3D-CRT-SIB) technique after breast conserving surgery. In a consecutive series of 752 consecutive female invasive breast cancer patients (stages I-III) the 5-year actuarial rate for local control was 98.9%. This new technique gives excellent 5-year local control. PMID- 24055290 TI - A retrospective comparison of proton therapy and carbon ion therapy for stage I non-small cell lung cancer. AB - BACKGROUND AND PURPOSE: This retrospective study aimed to compare the clinical outcomes and late toxicities of proton therapy (PT) with those of carbon ion therapy (CIT) for stage I non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: A total of 111 patients who underwent particle therapy for stage I NSCLC between April 2003 and December 2009 were enrolled in this study. PT (n=70) and CIT (n=41) were delivered to total doses of 52.8-80 GyE in 4-26 fractions and 52.8-70.2 GyE in 4-26 fractions, respectively. The median follow-up time was 41 months. RESULTS: Differences in outcome between the PT and CIT groups regarding 3 year overall survival (72% and 76%, respectively), progression-free survival (44% and 53%, respectively), and local control (81% and 78%, respectively) were not statistically significant. In multivariate analysis, the type of treatment beam did not correlate with overall survival. The severity of late toxicities was comparable between the two groups. CONCLUSIONS: Clinical results in the PT group were comparable to those in the CIT group. However, this study was a retrospective analysis of a highly heterogeneous population. Consequently, more homogeneous prospective data, large multicentric databases and, ideally, randomized trials are warranted. PMID- 24055291 TI - Quinazolino linked 4beta-amidopodophyllotoxin conjugates regulate angiogenic pathway and control breast cancer cell proliferation. AB - A series of new conjugates of quinazolino linked 4beta-amidopodophyllotoxins 10aa af and 10ba-bf were synthesized and evaluated for their anticancer activity against human pancreatic carcinoma (Panc-1) as well as breast cancer cell lines such as MCF-7 and MDA-MB-231 by employing MTT assay. Among these conjugates, some of them like 10bc, 10bd, 10be and 10bf exhibited high potency of cytotoxicity. Flow cytometric analysis showed that these conjugates arrested the cell cycle in the G2/M phase and caused the increase in expression of p53 and cyclin B1 protein with concomitant decrease in Cdk1 thereby suggesting the inhibitory action of these conjugates on mitosis. Interestingly, we observed a decrease in expression of proteins that control the tumor micro environment such as VEGF-A, STAT-3, ERK1/2, ERK-p, AKT-1 ser 473 phosphorylation in compounds treated breast cancer cells. Further, these effective conjugates have exhibited inhibitory action on integrin (alphaVbetaIII). Furthermore, the MCF-7 cells that were arrested and lost the proliferative capacity undergo mitochondrial mediated apoptosis by activation of caspases-9. Thus these conjugates have the potential to control breast cancer cell growth by effecting tumor angiogenesis and invasion. PMID- 24055292 TI - Growing evidence for 'time to sign'. PMID- 24055293 TI - The experience of providing support about menopausal symptoms to women with breast cancer. AB - PURPOSE: The purpose of this study was to describe the experiences and expectations of both women with breast cancer and the health professionals who care for them, in relation to the management of menopausal symptoms. METHOD: A qualitative, exploratory study using a combination of focus groups and in depth individual interviews was carried out to collect data from women with breast cancer (14) and Health Professionals (15). KEY RESULTS: A number of categories arose including breast cancer experience, menopausal symptoms, seeking support, taking control; with a number of contributory factors. CONCLUSION: The findings illustrated the complexity of supporting women experiencing menopausal symptoms following their breast cancer diagnosis. They also captured the difficulty women have in isolating these symptoms from their experiences of breast cancer and associated management from diagnosis and beyond. The results indicate that health professionals are working and reacting to individual requests for support in isolation of the team. There is a need to assess and manage women both individually and within a multidisciplinary context. This would allow complex issues that span across the pre, peri, or post-menopausal stages, to be identified and resolved effectively. PMID- 24055294 TI - Development of specific scFv antibodies to detect neurocysticercosis antigens and potential applications in immunodiagnosis. AB - We have shown previously that detection of circulating antibodies against mimotopes selected by phage display were useful in neurocysticercosis diagnosis. However, circulating antigens may also be useful in patients' clinical follow-up. Therefore, we aimed to select novel combinatorial antibodies, single-chain variable fragment (scFv), which can be used for specific antigens with pre defined affinity and specificity without prior immunization. A phage scFv antibody library was selected against Taenia solium mimotopes displayed on phages coupled in beads and total saline extract of T. solium metacestodes (S) immobilized on microtiter plate wells. After two rounds of selection, 96 phage clones were evolved and validated against each target by enzyme linked immunosorbent assay (ELISA), and dot-blot, and three specific antibodies (B6, G10 and A4) were further characterized by sequencing and indirect immunofluorescence (IFI) assays. IFI revealed tegument staining for the B6, while the others showed a non-uniform staining in the whole parasite. The selected scFvs were used to capture their antigen targets that were elucidated through mass spectrometry, and used for antibody detection in NC patients' sera by ELISA, which achieved sensitivities greater than 97% and specificities above 95%. We have successfully developed scFv antibodies against important mimotopes used in NC diagnosis, and can be further explored to detect circulating antigens for clinical follow-up of patients with NC. Our strategy also highlighted the possibility of using this combinatorial approach to select, capture and characterize specific antigens to better understand this intriguing parasite infection and disease evolution. PMID- 24055296 TI - Tactile underrepresentation of the forehead along the vertical axis. PMID- 24055295 TI - Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression. AB - BACKGROUND: Nonsense mutations in filaggrin (FLG) represent a significant genetic factor in the cause of atopic dermatitis (AD). OBJECTIVE: It is of great importance to find drug candidates that upregulate FLG expression and to determine whether increased FLG expression controls the development of AD. METHODS: We screened a library of bioactives by using an FLG reporter assay to find candidates that promoted FLG mRNA expression using a human immortalized keratinocyte cell line (HaCaT). We studied the effect of the compound on keratinocytes using the human skin equivalent model. We examined the effect of the compound on AD-like skin inflammation in NC/Nga mice. RESULTS: JTC801 promoted FLG mRNA and protein expression in both HaCaT and normal human epidermal keratinocytes. Intriguingly, JTC801 promoted the mRNA and protein expression levels of FLG but not the mRNA levels of other makers for keratinocyte differentiation, including loricrin, keratin 10, and transglutaminase 1, in a human skin equivalent model. In addition, oral administration of JTC801 promoted the protein level of Flg and suppressed the development of AD-like skin inflammation in NC/Nga mice. CONCLUSION: This is the first observation that the compound, which increased FLG expression in human and murine keratinocytes, attenuated the development of AD-like skin inflammation in mice. Our findings provide evidence that modulation of FLG expression can be a novel therapeutic target for AD. PMID- 24055297 TI - Intraoperative motor evoked potential monitoring - a position statement by the American Society of Neurophysiological Monitoring. AB - The following intraoperative MEP recommendations can be made on the basis of current evidence and expert opinion: (1) Acquisition and interpretation should be done by qualified personnel. (2) The methods are sufficiently safe using appropriate precautions. (3) MEPs are an established practice option for cortical and subcortical mapping and for monitoring during surgeries risking motor injury in the brain, brainstem, spinal cord or facial nerve. (4) Intravenous anesthesia usually consisting of propofol and opioid is optimal for muscle MEPs. (5) Interpretation should consider limitations and confounding factors. (6) D-wave warning criteria consider amplitude reduction having no confounding factor explanation: >50% for intramedullary spinal cord tumor surgery, and >30-40% for peri-Rolandic surgery. (7) Muscle MEP warning criteria are tailored to the type of surgery and based on deterioration clearly exceeding variability with no confounding factor explanation. Disappearance is always a major criterion. Marked amplitude reduction, acute threshold elevation or morphology simplification could be additional minor or moderate spinal cord monitoring criteria depending on the type of surgery and the program's technique and experience. Major criteria for supratentorial, brainstem or facial nerve monitoring include >50% amplitude reduction when warranted by sufficient preceding response stability. Future advances could modify these recommendations. PMID- 24055298 TI - The lateral habenula is a common target of cocaine and dexamethasone. AB - The lateral habenular nucleus (LHb) receives projections from areas rich in dopaminergic neurons and sends efferent fibers to these areas, suggesting that the LHb has a role in dopaminergic reward-related activity. The LHb is also implicated in multiple stress reactions, including responses to painful stimuli. However, it is unclear whether the LHb facilitates glucocorticoid/cocaine interactions by serving as a common target of both. In this study we investigated the effect of cocaine and dexamethasone (a synthesized glucocorticoid) on pain related neurons (pain-excitatory and pain-inhibitory). Cocaine treatment effectively increased the firing rate of 89.7% of pain-excitatory neurons (cocaine-up response) and decreased the firing rate of 81.8% of pain-inhibitory neurons (cocaine-down response) in the LHb, suggesting that LHb neurons respond to cocaine via different mechanisms. Dexamethasone enhanced the firing rate of the cocaine-up neurons, while cocaine-down neurons were not influenced, indicating that both drugs may elicit an electrophysiological response at the same LHb neuron. Effects of either cocaine or dexamethasone alone, or both combined, on FOS expression in the LHb were observed via immunohistochemistry. Single administration of either cocaine or dexamethasone increased the number of FOS-positive neurons in the LHb. Pretreatment with dexamethasone and then cocaine markedly enhanced the number of FOS-positive neurons in the LHb relative to cocaine treatment alone, suggesting that stress and addictive drugs exert a synergistic effect on the LHb. We conclude that the LHb responds to cocaine via more than one mechanism and is a common target of both cocaine and the dexamethasone. PMID- 24055300 TI - Promoting physiologic transition at birth: re-examining resuscitation and the timing of cord clamping. AB - Delayed clamping of the umbilical cord is recommended for term and preterm infants who do not require resuscitation. However, the approach to the newly born infant with signs of fetal compromise, prematurity and extremely low birthweight, or prolonged apnea is less clear. Human and experimental animal data show that delaying the clamping of the umbilical cord until after the onset of respirations promotes cardiovascular stability in the minutes immediately after birth. Rather than regarding delayed cord clamping as a fixed time period before resuscitation begins, a more physiologic concept of transition at birth should encompass the relative timing of onset of respirations and cord occlusion. Further research to explore the potential benefits of resuscitation with the cord intact is needed. PMID- 24055299 TI - Cerebral 5-HT2A receptor binding, but not mGluR2, is increased in tryptophan hydroxylase 2 decrease-of-function mice. AB - Transgenic mice with a knock-in (KI) of a tryptophan hydroxylase 2 (Tph2) R439H mutation, analogous to the Tph2 R441H single-nucleotide polymorphism originally identified in a late life depression cohort, have markedly reduced levels of 5 hydroxytryptamine (5-HT). These Tph2KI mice are therefore interesting as a putative translational model of low endogenous 5-HT function that allows for assessment of adaptive changes in different anatomical regions. Here, we determined 5-HT2A receptor binding in several brain regions using in vitro receptor autoradiography and two different radioligands. When using the 5-HT2A receptor selective antagonist radioligand (3)H-MDL100907, we found higher binding in the prefrontal cortex (10%, P=0.009), the striatum (26%, P=0.005), and the substantia nigra (21%, P=0.027). The increase was confirmed in the same regions with the 5-HT2A/C receptor agonist, (3)H-CIMBI-36 (2-(4-Bromo-2,5 dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine). 5-HT2A receptors establish heteromeric receptor complexes with metabotropic glutamate 2 receptors (mGluR2), but binding levels of the mGluR2/3 ligand (3)H-LY341495 were unaltered in brain areas with increased 5-HT2A receptor levels. These data show that in distinct anatomical regions, 5-HT2A receptor binding sites are up-regulated in 5-HT deficient mice, and this increase is not associated with changes in mGluR2 binding. PMID- 24055301 TI - Importance of maintaining the newly born temperature in the normal range from delivery to admission. AB - Over the last 50 years an increasing amount of evidence on neonatal resuscitation and stabilisation practices has led to written recommendations on all aspects of newborn care in the first few minutes of life. Much evidence for thermoregulatory management of both term and preterm infants has existed for decades and more recently research has identified new techniques to maintain normothermia in newly born infants. The use of increased environmental temperatures, skin-to-skin care, radiant warmers, plastic coverings and hats, exothermic mattresses and heated humidified gases have or are undergoing evaluation. However, despite the apparent acceptance of these techniques, a substantial number of infants continue to become hypothermic soon after delivery, leading to an increased risk of comorbidities and of death. Gaps in our knowledge remain and further research opportunities are available. However, we must also ensure that established thermoregulatory methods for which the evidence already exists are given as much emphasis as other aspects of newborn care and are implemented meticulously in all healthcare settings. PMID- 24055302 TI - Crustacean oxi-reductases protein sequences derived from a functional genomic project potentially involved in ecdysteroid hormones metabolism - a starting point for function examination. AB - A transcriptomic assembly originated from hypodermis and Y organ of the crustacean Pontastacus leptodactylus is used here for in silico characterization of oxi-reductase enzymes potentially involved in the metabolism of ecdysteroid molting hormones. RNA samples were extracted from male Y organ and its neighboring hypodermis in all stages of the molt cycle. An equimolar RNA mix from all stages was sequenced using next generation sequencing technologies and de novo assembled, resulting with 74,877 unique contigs. These transcript sequences were annotated by examining their resemblance to all GenBank translated transcripts, determining their Gene Ontology terms and their characterizing domains. Based on the present knowledge of arthropod ecdysteroid metabolism and more generally on steroid metabolism in other taxa, transcripts potentially related to ecdysteroid metabolism were identified and their longest possible conceptual protein sequences were constructed in two stages, correct reading frame was deduced from BLASTX resemblances, followed by elongation of the protein sequence by identifying the correct translation frame of the original transcript. The analyzed genes belonged to several oxi-reductase superfamilies including the Rieske non heme iron oxygenases, cytochrome P450s, short-chained hydroxysteroid oxi-reductases, aldo/keto oxireductases, lamin B receptor/sterol reductases and glucose-methanol-cholin oxi-reductatses. A total of 68 proteins were characterized and the most probable participants in the ecdysteroid metabolism where indicated. The study provides transcript and protein structural information, a starting point for further functional studies, using a variety of gene-specific methods to demonstrate or disprove the roles of these proteins in relation to ecdysteroid metabolism in P. leptodactylus. PMID- 24055303 TI - Molecular and functional characterization of the first tick CAP2b (periviscerokinin) receptor from Rhipicephalus (Boophilus) microplus (Acari: Ixodidae). AB - The cDNA of the receptor for CAP(2b)/periviscerokinin (PVK) neuropeptides, designated Rhimi-CAP(2b)-R, was cloned from synganglia of tick Rhipicephalus (Boophilus) microplus. This receptor is the ortholog of the insect CAP(2b)/PVK receptor, as concluded from analyses of the predicted protein sequence, phylogenetics and functional expression. Expression analyses of synganglion, salivary gland, Malpighian tubule, and ovary revealed Rhimi-CAP(2b)-R transcripts. The expression in mammalian cells of the open reading frame of Rhimi CAP(2b)-R cDNA fused with a hemagglutinin tag at the receptor N-terminus was confirmed by immunocytochemistry. In a calcium bioluminescence assay the recombinant receptor was activated by the tick Ixodes scapularis CAP(2b)/PVK and a PVK analog with EC50s of 64 nM and 249 nM, respectively. Tick pyrokinins were not active. This is the first report on the functional characterization of the CAP(2b)/PVK receptor from any tick species which will now permit the discovery of the physiological roles of these neuropeptides in ticks, as neurohormones, neuromodulators and/or neurotransmitters. PMID- 24055304 TI - Progress in the establishment and strengthening of national immunization technical advisory groups: analysis from the 2013 WHO/UNICEF joint reporting form, data for 2012. AB - The majority of industrialized and some developing countries have established National Immunization Technical Advisory Groups (NITAGs). To enable systematic global monitoring of the existence and functionality of NITAGs, in 2011, WHO and UNICEF included related questions in the WHO/UNICEF Joint Reporting Form (JRF) that provides an official means to globally collect indicators of immunization program performance. These questions relate to six basic process indicators. According to the analysis of the 2013 JRF, data for 2012, notable progress was achieved between 2010 and 2012 and by the end of 2012, 99 countries (52%) reported the existence of a NITAG with a formal legislative or administrative basis (with a high of 86% in the Eastern Mediterranean Region - EMR), among the countries that reported data in the NITAG section of the JRF. There were 63 (33%) countries with a NITAG that met six process indicators (47% increase over the 43 reported in 2010) including a total of 38 developing countries. 11% of low income countries reported a NITAG that meets all six process criteria, versus 29% of middle income countries and 57% of the high income ones. Countries with smaller populations reported the existence of a NITAG that meets all six process criteria less frequently than more populated countries (23% for less populated countries versus 43% for more populated ones). However, progress needs to be accelerated to reach the Global Vaccine Action Plan (GVAP) target of ensuring all countries have support from a NITAG. The GVAP represents a major opportunity to boost the institutionalization of NITAGs. A special approach needs to be explored to allow small countries to benefit from sub-regional or other countries advisory groups. PMID- 24055305 TI - An adult zebrafish model for preclinical tuberculosis vaccine development. AB - Tuberculosis remains a major global health challenge despite extensive vaccination schemes with the current live vaccine, Bacillus Calmette-Guerin. Tuberculosis vaccine research has been hampered by a scarcity of animal models which replicate human disease and are suitable for large-scale studies. We have shown recently that Mycobacterium marinum, a close relative of Mycobacterium tuberculosis, causes an infection resembling human tuberculosis in adult zebrafish (Danio rerio). In the present study we use this model to show that BCG vaccination as well as DNA vaccination with selected mycobacterial antigens (Ag85B, CFP-10 and ESAT-6) protects adult zebrafish from mycobacterial infection. Using a low-dose (~20-30 bacteria) intraperitoneal M. marinum infection, both the number of granulomas and the amount of infected organs were reduced in the DNA vaccinated fish. Likewise, when infecting with a lethal infection dose (~20,000 27,000 bacteria), vaccination significantly reduced both mortality and bacterial counts in a manner dependent on the adaptive immune response. Protective effects of vaccination were associated with enhanced expression of interferon gamma. Our results indicate that the zebrafish is a promising new model for preclinical tuberculosis vaccine research. PMID- 24055306 TI - Safety and immunogenicity of revaccination with reduced dose intradermal and standard dose intramuscular influenza vaccines in adults 18-64 years of age. AB - BACKGROUND: This clinical trial examined the safety and immunogenicity of annual revaccination with Fluzone((r)) Intradermal (Sanofi Pasteur, Swiftwater, PA) vaccine compared to a standard intramuscular (IM) split-virion trivalent influenza vaccine (Fluzone((r)), Sanofi Pasteur). METHODS: This phase II, active controlled, multi-centre, open-label trial was conducted in 2009 and 2010, and enrolled 1250 adults 18-64 years of age who were randomly selected from participants in a phase III influenza vaccine trial the previous year (NCT00772109). Subjects who had previously received the ID vaccine were randomized 2:1 to be revaccinated with the ID or IM vaccine and those who previously received the IM vaccine were randomized 1:1. Solicited reactions were recorded on the day of vaccination and continuing for the next 7 days, non serious adverse events for 28 days, and serious adverse events for 6 months after vaccination. Hemagglutination inhibition antibody titres were assessed pre vaccination and at day 28. RESULTS: Reactions were well-tolerated and resolved in the first 7 days, but erythema, induration, swelling, pruritus and ecchymosis were reported by more subjects receiving the ID vaccine than the IM vaccine. Compared to receipt of IM vaccine in the previous year, ID vaccine in the previous year led to statistically higher rates of erythema, swelling and induration after IM vaccine in the second year. Injection-site pain and systemic reactions did not differ between ID and IM vaccines. No treatment-related serious adverse events were reported. Geometric mean antibody titres, seroprotection rates, and seroconversion rates were non-inferior for the ID and IM vaccines for all three viral strains. CONCLUSIONS: The ID vaccine was as immunogenic as the IM vaccine, and raised no safety concerns. It can be used interchangeably with the IM vaccine for annual revaccination in adults 18-64 years of age in consecutive years without safety concerns. PMID- 24055307 TI - Is nosocomial Escherichia coli bacteremia a predictive risk factor for mortality? AB - The objective of this study was to determine risk factors associated with mortality in patients with nosocomial Escherichia coli bacteremia from January 2009 to January 2011. In a retrospective study the medical records of 88 patients over 18 years with nosocomial bacteremia caused by E. coli were analyzed. In univariate analysis several risk factors, including chronic renal failure, altered mental status, leukocytosis, and higher Charlson index of comorbidities were associated with mortality. In multivariate analysis only altered mental status remained independently associated with mortality. Mental confusion can be a risk factor for mortality in patients with E. coli bacteremia. PMID- 24055308 TI - Tuberculin skin testing in inflammatory bowel disease patients from an endemic area of Brazil. AB - OBJECTIVE: Inflammatory bowel disease (IBD) is a chronic disorder involving the gastrointestinal tract. Immunosuppressive drugs are usually prescribed to treat IBD patients, and this treatment can lead to tuberculosis reactivation. This paper aimed to analyze tuberculin skin test (TST) results in IBD patients at a reference center in Brazil. METHODS: We evaluated TST results in IBD patients using a cross-sectional study. We also analyzed the medical records of patients treated at a reference IBD outpatient unit where TST is routinely performed. RESULTS: We reviewed 119 medical records of 57 (47.9%) Crohn's disease (CD), 57 (47.9%) ulcerative colitis (UC) and 5 (4.2%) indeterminate colitis (IC) patients. The mean (SD) age was 43.5 (13.7) years old. TST was positive in 24 (20.2%) of the patients. TST was positive in 16/57 (28.1%) UC and 6/57 (10.5%) CD patients (prevalence ratio [PR] 2.7). Forty-one patients (34.5%) were taking immunosuppressive drugs (azathioprine or prednisone) at the time of the TST, and six of these patients (14.6%) had positive test results. Two patients using infliximab had negative TST results. Thirty-five of the 41 patients (85.4%) on immunosuppressive treatment were anergic compared with 73.1% (57/78) of the untreated patients (PR 1.2). CONCLUSIONS: Patients with IBD have TST results similar to the general Brazilian population. Within the IBD population, CD patients have a lower frequency of TST positivity than UC patients. PMID- 24055309 TI - Molecular epidemiology of CTX-M producing Enterobacteriaceae isolated from bloodstream infections in Rio de Janeiro, Brazil: emergence of CTX-M-15. AB - OBJECTIVE: The present study was designed to evaluate the molecular epidemiology of CTX-M producing Klebsiella pneumoniae, Enterobacter cloacae and Escherichia coli isolated from bloodstream infections at tertiary care hospitals in the State of Rio de Janeiro, Brazil. MATERIAL AND METHODS: A total of 231 nonduplicate Enterobacteriaceae were isolated from five Brazilian hospitals between September 2007 and September 2008. The antimicrobial susceptibility testing was performed by disk diffusion method according to the Clinical Laboratory Standard Institute. Isolates showing resistance to third-generation cephalosporins were screened for ESBL activity by the double-disk synergy test. The presence of blaCTX-M, blaCTX-M 15 and blaKPC genes was determined by Polymerase Chain Reaction (PCR) amplification and DNA sequencing. The molecular typing of CTX-M producing isolates was performed by pulsed-field gel electrophoresis (PFGE). RESULTS AND DISCUSSION: Ninety-three isolates were screened as ESBL positive and 85 (91%) were found to carry CTX-M-type, as follows: K. pneumoniae 59 (49%), E. cloacae 15 (42%), and E. coli 11 (15%). Ten isolates resistant for carbapenems in K. pneumoniae were blaKPC-2 gene positive. Among CTX-M type isolates, CTX-M-15 was predominant in more than 50% of isolates for K. pneumoniae, E. coli, and E. cloacae. PFGE analysis of CTX-M producing isolates showed the predominance of CTX M-15 in 10 of 24 pulsotypes in K. pneumoniae, 6 of 13 in E. cloacae and 3 of 6 in E. coli. CTX-M-15 was also predominant among KPC producing isolates. In conclusion, this study showed that CTX-M-15 was circulating in Rio de Janeiro state in 2007-2008. This data reinforce the need for continuing surveillance because this scenario may have changed over the years. PMID- 24055311 TI - HPV infection, risk factors and viral load among Mexican male college students. AB - OBJECTIVES: To determine the prevalence of HPV and the risky sexual behaviors associated to it in a sample of male college students, taking into account genotype and viral load. METHODS: From 2002 to 2003, male students from the Autonomous University of Morelos State completed a questionnaire and provided self-collected genital samples to detect and quantify HPV. We performed a bivariate and a multivariate logistic regression analysis to identify correlates associated with the infection and to assess the viral load as a function of the viral infecting type. The fragments of beta-globin gene and L1 of HPV, were amplified, purified and cloned, to evaluate viral load. RESULTS: Among 253 subjects, HPV prevalence was 19.4%, and HPV16 was the most common subtype. History of STIs (OR=4.8; 95% CI 1.2-18.9), contraceptive pill use by female partner (OR=2.6; 95% CI 1.1-6.3) and exchanging sex for money (OR=4.9; 95% CI 1.2 20) were associated to the HPV infection. HPV16 viral load was 7.8 copies (HPV/beta-globin) compared to 0.9 copies for other HPV types. DISCUSSION: HPV16 displayed the highest viral load, and it was the most prevalent. It was found that using contraceptive pills by female partners was associated with HPV infection. PMID- 24055310 TI - Peginterferon plus ribavirin and sustained virological response rate in HCV related advanced fibrosis: a real life study. AB - BACKGROUND: Tolerance and response to antiviral HCV treatment is poor in advanced fibrosis. The aim of this study was to assess SVR rate and its predictive factors in HCV advanced fibrosis patients treated in real life with full dose PEG-IFN plus RBV and to evaluate the adverse events related to treatment. METHODS: A multicentric, retrospective study was conducted at six university hospitals. METAVIR F3 and F4 HCV monoinfected patients who were treated with PEG-IFN and RBV had their data analyzed. A stepwise logistic regression analysis was performed to identify the variables independently related to SVR. Adverse events were recorded during treatment. RESULTS: 308 patients were included, 75% genotype 1 and 23% genotype 3. METAVIR F3 was present in 39% and F4 in 61% of patients. The median Child Pugh score for F4 patients was 5 (5-9). The global SVR rate was 34%, 11% were relapsers and 55% were nonresponders. SVR rates were similar between patients treated with PEG-IFN alfa 2a or alfa 2b (p=0.24). SVR rates according to Child-Pugh score were 26% (Child A) and 18% (Child B). The independent factors related to SVR in F4 patients were genotype 3, RVR and fewer Child Pugh score points. Treatment interruption occurred in 31% patients and death occurred in 1.9%, all with liver cirrhosis. CONCLUSION: Treatment of HCV in patients with advanced fibrosis should not be postponed. However, a very careful evaluation of cirrhotic patients must be performed before treatment is indicated and careful monitoring is required during treatment. PMID- 24055312 TI - Is overweight an issue in phenylketonuria? AB - Dietary treatment may be associated with an increased risk of obesity in phenylketonuria (PKU). The earliest studies describe a tendency for overweight in PKU, but not all recent publications confirm this, although there are an increasing number of studies describing increased obesity in female patients with PKU. There is little data describing the metabolic consequences of obesity in PKU. It is difficult to interpret and compare published results due to variable patient age, differing dietary treatment approaches, poor treatment adherence, inconsistencies in metabolic control achieved, variable criteria used to classify overweight. There is also a lack of comparison with normal population data which is widely variable between countries. Generally in PKU it is unknown if obesity etiology is a result of the underlying condition, a treatment consequence, or an outcome of inadequate metabolic control. Differences in treatment strategies, target ranges for blood phenylalanine concentrations and severity of PKU can alter nutritional intakes and dietary experiences which ultimately modulate the course of overweight development. It is clear further investigation is required. Treating overweight and obesity in the general population is difficult and no studies have described the impact of obesity treatment strategies in PKU. However, the PKU management team has an important role in monitoring nutritional status and preventing overweight and obesity. It is important that PKU treatment attends to the general aspects of nutrition, feeding behavior and exercise in order to prevent the development of overweight in these individuals. PMID- 24055313 TI - Cloning, expression and phylogenetic analysis of a divergent laccase multigene family in Auricularia auricula-judae. AB - Laccases (p-diphenol: oxygen oxidoreductase; EC 1.10.3.2) are multi-copper oxidases encoded by gene family in white rot fungi. Auricularia auricula-judae is one kind of white rot fungi with a soft, jelly-like texture and an ear-like shape. In the present study, seven laccase genes containing the signature sequences L1-L4 were isolated from A. auricula-judae strain Au916 on the basis of the mycelium-derived transcriptome. In the basidiomycetes, the predicted substrate binding loops of the A. auricula-judae laccases were found to be uncommon. Phylogenetic analysis showed that the laccases of the Auricularia were nested into the ascomycete laccases, indicating that the laccase genes from Auricularia are distinctly different in function from other basidiomycetes. Among the seven laccases, the intron positions and cluster distributions in the NJ tree varied from each other and the expression patterns of seven genes estimated by qRT-PCR were also discrepant. The lcc3 gene was highly expressed not only in the free-living mycelium but also in substrate mycelium, furthermore, the lcc5 gene was mostly expressed during the fruiting body formation and maturation indicating that lcc5 might play a major role during the sexual reproduction stage. PMID- 24055314 TI - A motif in the vertebrate telomerase N-terminal linker of TERT contributes to RNA binding and telomerase activity and processivity. AB - Telomerase is a ribonucleoprotein reverse transcriptase that replicates the ends of chromosomes, thus maintaining genome stability. Telomerase ribonucleoprotein assembly is primarily mediated by the RNA binding domain (TRBD) of the enzyme. Here we present the high-resolution TRBD structure of the vertebrate, Takifugu rubripes (trTRBD). The structure shows that with the exception of the N-terminal linker, the trTRBD is conserved with the Tribolium castaneum and Tetrahymena thermophila TRBDs, suggesting evolutionary conservation across species. The structure provides a view of the structural organization of the vertebrate specific VSR motif that binds the activation domain (CR4/5) of the RNA component of telomerase. It also reveals a motif (TFLY) that forms part of the T-CP pocket implicated in template boundary element (TBE) binding. Mutant proteins of conserved residues that consist of part of the T and TFLY motifs disrupt trTRBD TBE binding and telomerase activity and processivity, supporting an essential role of these motifs in telomerase RNP assembly and function. PMID- 24055315 TI - Structure of the Mtb CarD/RNAP beta-lobes complex reveals the molecular basis of interaction and presents a distinct DNA-binding domain for Mtb CarD. AB - CarD from Mycobacterium tuberculosis (Mtb) is an essential protein shown to be involved in stringent response through downregulation of rRNA and ribosomal protein genes. CarD interacts with the beta-subunit of RNAP and this interaction is vital for Mtb's survival during the persistent infection state. We have determined the crystal structure of CarD in complex with the RNAP beta-subunit beta1 and beta2 domains at 2.1 A resolution. The structure reveals the molecular basis of CarD/RNAP interaction, providing a basis to further our understanding of RNAP regulation by CarD. The structural fold of the CarD N-terminal domain is conserved in RNAP interacting proteins such as TRCF-RID and CdnL, and displays similar interactions to the predicted homology model based on the TRCF/RNAP beta1 structure. Interestingly, the structure of the C-terminal domain, which is required for complete CarD function in vivo, represents a distinct DNA-binding fold. PMID- 24055316 TI - High-speed atomic force microscopic observation of ATP-dependent rotation of the AAA+ chaperone p97. AB - p97 (also called VCP and CDC-48) is an AAA+ chaperone, which consists of a substrate/cofactor-binding N domain and two ATPase domains (D1 and D2), and forms a homo-hexameric ring. p97 plays crucial roles in a variety of cellular processes such as the ubiquitin-proteasome pathway, the endoplasmic reticulum-associated protein degradation, autophagy, and modulation of protein aggregates. Mutations in human p97 homolog VCP are linked to neurodegenerative diseases. The key mechanism of p97 in these various functions has been proposed to be the disassembly of protein complexes. To understand the molecular mechanism of p97, we studied the conformational changes of hexameric CDC-48.1, a Caenorhabditis elegans p97 homolog, using high-speed atomic force microscopy. In the presence of ATP, the N-D1 ring repeatedly rotates ~23 +/- 8 degrees clockwise and resets relative to the D2 ring. Mutational analysis reveals that this rotation is induced by ATP binding to the D2 domain. PMID- 24055318 TI - [Proteinuria and renal stones: a causal or casual relationship?]. PMID- 24055317 TI - Allosteric regulation of DNA cleavage and sequence-specificity through run-on oligomerization. AB - SgrAI is a sequence specific DNA endonuclease that functions through an unusual enzymatic mechanism that is allosterically activated 200- to 500-fold by effector DNA, with a concomitant expansion of its DNA sequence specificity. Using single particle transmission electron microscopy to reconstruct distinct populations of SgrAI oligomers, we show that in the presence of allosteric, activating DNA, the enzyme forms regular, repeating helical structures characterized by the addition of DNA-binding dimeric SgrAI subunits in a run-on manner. We also present the structure of oligomeric SgrAI at 8.6 A resolution, demonstrating the conformational state of SgrAI in its activated form. Activated and oligomeric SgrAI displays key protein-protein interactions near the helix axis between its N termini, as well as allosteric protein-DNA interactions that are required for enzymatic activation. The hybrid approach reveals an unusual mechanism of enzyme activation that explains SgrAI's oligomerization and allosteric behavior. PMID- 24055319 TI - [Advances in the knowledge and management of autoimmune lymphoproliferative syndrome]. AB - Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis. ALPS often manifest in childhood with cytopenias, chronic non-malignant lymphoproliferation and autoimmune complications. A number of new insights have improved the understanding of the genetics and biology of ALPS. The treatment of the disease has changed and mycophenolate mofetil and sirolimus have been demonstrated to have marked activity against the disease, improving quality of life for many patients. These will be discussed in this review. PMID- 24055320 TI - [Autoimmune cytopenias: diagnosis before treatment. Reply by the authors]. PMID- 24055321 TI - [Consensus document: recommendations for the use of equations to estimate glomerular filtration rate in children]. AB - The appearance of the K/DOQI guidelines in 2002 on the definition, evaluation and staging of chronic kidney disease (CKD) have led to a major change in how to assess renal function in adults and children. These guidelines, recently updated, recommended that the study of renal function is based, not only on measuring the serum creatinine concentration, but this must be accompanied by the estimation of glomerular filtration rate (GFR) obtained by an equation. However, the implementation of this recommendation in the clinical laboratory reports in the paediatric population has been negligible. Numerous studies have appeared in recent years on the importance of screening and monitoring of patients with CKD, the emergence of new equations for estimating GFR, and advances in clinical laboratories regarding the methods for measuring plasma creatinine and cystatin C, determined by the collaboration between the departments of paediatrics and clinical laboratories to establish recommendations based on the best scientific evidence on the use of equations to estimate GFR in this population. The purpose of this document is to provide recommendations on the evaluation of renal function and the use of equations to estimate GFR in children from birth to 18 years of age. The recipients of these recommendations are paediatricians, nephrologists, clinical biochemistry, clinical analysts, and all health professionals involved in the study and evaluation of renal function in this group of patients. PMID- 24055322 TI - [Neonatal hyperthyroidism and pulmonary hypertension]. PMID- 24055323 TI - [High-flow therapy during paediatric admissions: a new horizon in the treatment of bronchiolitis. Reply by the authors]. PMID- 24055324 TI - [Oral-facial-digital syndrome type II: clinical case and differential diagnosis]. PMID- 24055325 TI - [Successful implantation of a pacemaker in a 1,500 g newborn with a congenital heart defect]. PMID- 24055326 TI - Observational research--opportunities and limitations. AB - Medical research continues to progress in its ability to identify treatments and characteristics associated with benefits and adverse outcomes. The principal engine for the evaluation of treatment efficacy is the randomized controlled trial (RCT). Due to the cost and other considerations, RCTs cannot address all clinically important decisions. Observational research often is used to address issues not addressed or not addressable by RCTs. This article provides an overview of the benefits and limitations of observational research to serve as a guide to the interpretation of this category of research designs in diabetes investigations. The potential for bias is higher in observational research but there are design and analysis features that can address these concerns although not completely eliminate them. Pharmacoepidemiologic research may provide important information regarding relative safety and effectiveness of diabetes pharmaceuticals. Such research must effectively address the important issue of confounding by indication in order to produce clinically meaningful results. Other methods such as instrumental variable analysis are being employed to enable stronger causal inference but these methods also require fulfillment of several key assumptions that may or may not be realistic. Nearly all clinical decisions involve probabilistic reasoning and confronting uncertainly, so a realistic goal for observational research may not be the high standard set by RCTs but instead the level of certainty needed to influence a diagnostic or treatment decision. PMID- 24055327 TI - Depletion of circulating progenitor cells precedes overt diabetes: a substudy from the VA enhanced fitness trial. AB - BACKGROUND: One theory of aging and disease development is that chronic injury (pathology) results in activation of regenerative processes and initial repair, with overt disease arising only after exhaustion of reparative capability leads to inadequate repair. While depletion of circulating progenitor cells (CPCs) has been noted in diabetes, the degree to which CPC depletion predates and is associated with propensity to develop overt disease is unclear. METHODS: The Enhanced Fitness trial enrolled overweight/obese (body mass index >25) sedentary patients with glucose intolerance but without overt diabetes. Baseline CPCs were measured in 129 patients based on the cell surface markers CD34, CD133, and aldehyde dehydrogenase (ALDH) activity. HgbA1C, fasting insulin and glucose levels, and HOMA calculations were ascertained. RESULTS: Lower counts of early angiogenic CPCs identified as CD34(+), CD34(+)CD133(+), and ALDH-bright (ALDH(br)) cells were associated with impairments in glucose homeostasis as reflected by HgbA1C, but not fasting insulin, glucose, or HOMA-IR. These associations remained when corrected for age and cardiovascular risk factors. CONCLUSIONS/INTERPRETATION: The numbers of CD34(+) and ALDH(br) CPCs were significantly lower in patients with impaired glucose tolerance. Depletion of reparative capacity as reflected by loss of CPCs may presage overt disease as exemplified in this pre-diabetes model. PMID- 24055328 TI - Pulmonary outcome in former preterm, very low birth weight children with bronchopulmonary dysplasia: a case-control follow-up at school age. AB - OBJECTIVE: To assess and compare long-term pulmonary outcomes in former preterm born, very low birth weight (VLBW) children with and without bronchopulmonary dysplasia (BPD) born in the surfactant era. STUDY DESIGN: Pulmonary function tests (ie, spirometry, body plethysmography, and gas transfer testing) were performed in children with a history of VLBW and BPD (n = 28) and compared with a matched preterm-born VLBW control group (n = 28). Medical history was evaluated by questionnaire. RESULTS: At time of follow-up (mean age, 9.5 years), respiratory symptoms (36% vs 8%) and receipt of asthma medication (21% vs 0%) were significantly more frequent in the preterm-born children with previous BPD than in those with no history of BPD. The children with a history of BPD had significantly lower values for forced expiratory volume in 1 second (z-score 1.27 vs -0.4; P = .008), forced vital capacity (z-score -1.39 vs -0.71 z-score; P = .022), and forced expiratory flow rate at 50% of forced vital capacity (z-score -2.21 vs -1.04; P = .048) compared with the preterm control group. CONCLUSION: Preterm-born children with a history of BPD are significantly more likely to have lung function abnormalities, such as airway obstruction and respiratory symptoms, at school age compared with preterm-born children without BPD. PMID- 24055330 TI - Multimodal exercises simultaneously stimulating cortical and brainstem pathways after unilateral corticospinal lesion. AB - In the context of injury to the corticospinal tract (CST), brainstem-origin circuits may provide an alternative system of descending motor influence. However, subcortical circuits are largely under subconscious control. To improve volitional control over spared fibers after CST injury, we hypothesized that a combination of physical exercises simultaneously stimulating cortical and brainstem pathways above the injury would strengthen corticobulbar connections through Hebbian-like mechanisms. We sought to test this hypothesis in mice with unilateral CST lesions. Ten days after pyramidotomy, mice were randomized to four training groups: (1) postural exercises designed to stimulate brainstem pathways (BS); (2) distal limb-grip exercises preferentially stimulating CST pathways (CST); (3) simultaneous multimodal exercises (BS+CST); or (4) no training (NT). Behavioral and anatomical outcomes were assessed after 20 training sessions over 4 weeks. Mice in the BS+CST training group showed a trend toward greater improvements in skilled limb performance than mice in the other groups. There were no consistent differences between training groups in gait kinematics. Anatomically, multimodal BS+CST training neither increased corticobulbar fiber density of the lesioned CST rostral to the lesion nor collateral sprouting of the unlesioned CST caudal to the lesion. Further studies should incorporate electrophysiological assessment to gauge changes in synaptic strength of direct and indirect pathways between the cortex and spinal cord in response to multimodal exercises. PMID- 24055329 TI - Location and cellular stages of natural killer cell development. AB - The identification of distinct tissue-specific natural killer (NK) cell populations that apparently mature from local precursor populations has brought new insight into the diversity and developmental regulation of this important lymphoid subset. NK cells provide a necessary link between the early (innate) and late (adaptive) immune responses to infection. Gaining a better understanding of the processes that govern NK cell development should allow us to harness better NK cell functions in multiple clinical settings, as well as to gain further insight into how these cells undergo malignant transformation. In this review, we summarize recent advances in understanding sites and cellular stages of NK cell development in humans and mice. PMID- 24055332 TI - Experimental assessment of the neo-vascularisation of acellular dermal matrix in the wound bed pretreated with mesenchymal stem cell under subatmospheric pressure. AB - Neo-vascularisation of the acellular dermal matrix (ADM) is an essential procedure if a full-thickness wound is closed with ADM and skin is grafted over the ADM. In this study, we aimed to improve the neo-vascularisation of ADM by combining the effects of negative pressure wound therapy (NPWT) and mesenchymal stem cells (MSCs) on angiogenesis. In this study, 28 female Sprague-Dawley rats were used and divided into four groups. Full-thickness dorsal skin defects were created in 2 * 2 cm dimensions. The wounds were treated with only the ADM in group 1, the ADM and NPWT in group 2, the ADM and MSCs in group 3 and the ADM, NPWT and MSCs in group 4. By the ninth day of surgery, the excisional biopsy samples were histologically examined to identify the rates of ADM adherence to the recipient bed; the newly formed blood vessels which penetrate the ADM vertically and vascularisation were evaluated by immunohistochemical staining. The graft adherence rates were higher in group 4 than in the other groups statistically, p = 0.003. The numbers of cluster of differentiation 31 (CD31) stained newly formed microvessels were higher in group 4 than in the other groups statistically, p < 0.05. All subjects in group 4 had the vertical vessels in normal calibration with open lumen vessels which penetrate the ADM. These findings suggest that MSC transplantation induces angiogenesis more efficiently than NPWT. The combination of the NPWT with MSC in this study has shown a synergistic effect on angiogenesis and has affected the neo-vascularisation of the ADM significantly. PMID- 24055331 TI - Systems approaches to human autoimmune diseases. AB - Systemic autoimmune diseases result from interactions between genes and environmental triggers that lead to dysregulation of both innate and adaptive immunity. Systems biology approaches enable the global characterization of complex systems at the DNA, RNA and protein levels. Recent technological breakthroughs such as deep sequencing or high-throughput proteomics are revealing novel inflammatory pathways involved in autoimmunity. Herein, we review recent developments, challenges and promising avenues in the use of systems approaches to understand human systemic autoimmune and autoinflammatory diseases. PMID- 24055333 TI - Biological effects of cellular stretch on human dermal fibroblasts. AB - Pathological scars are fibroproliferative skin disorders that are characterised by the accumulation of fibroblasts and collagens. It is increasingly understood that their development and progression may be related to local skin mechanics, such as stretching. The present study evaluated the morphological and functional effects of cellular stretch on normal human dermal fibroblasts and explored the mechanotransduction mechanisms that may be involved. When fibroblasts were subjected to 24 h of cyclic axial stretching (10 cycles min(-1)), they migrated faster and for a longer distance than unstretched cells. The increased migration resulted in the cells reorienting themselves perpendicular to the direction of stretching. This was associated with reduced cellular apoptosis and unchanged proliferation. Stretching did not increase collagen synthesis but did elevate collagen degradation. These biological effects appeared to be mediated by the integrin and Wnt mechanotransduction pathways, which transmitted the mechanical stimulus via cell-substrate interactions, cell-cell junctions and indirect cell cell communications. A better understanding of such fibroblast mechanoresponses in vitro will help the development of novel interventions that can prevent, reduce or even reverse pathological scar formation and/or progression in vivo. PMID- 24055334 TI - From cue to meaning: brain mechanisms supporting the construction of expectations of pain. AB - The brain mechanisms by which sensory cues become transformed into expectations of impending events are a critical component of cognitive tuning of sensory processing. However, distinctions among the afferent processing of cue-related activity itself versus those mechanisms supporting the contextual meaning imparted to the cue remain limited. Do sensory cues with equal meaning engage similar patterns of brain activations even if they are delivered in separate modalities? To address this question, we used functional magnetic resonance imaging of an expectation paradigm in which cues were delivered with visual or innocuous thermal stimuli. Cues were designed to be highly meaningful because they predicted the delivery of high and low painful stimuli. As expected, the cues themselves activated unimodal sensory cortices. This cue modality-specific activation was transformed into a pattern of activity reflecting cue meaning. Cues signaling high pain produced greater activity in the left dorsolateral prefrontal cortex and anterior cingulate cortex. Such activity is consistent with the graded encoding of the magnitude of expected pain. In contrast, cues signaling low pain produced greater activity in the right intraparietal sulcus. This activation may reflect processes directing spatial attention to the stimulated body region in order to more accurately evaluate the relatively weak, low pain stimulus. Taken together, these findings indicate that cues arising from different sensory modalities ultimately engage common brain mechanisms that reflect the meaning of the cue. This meaning-related activity is presumably critical for preparing sensory systems to optimally process afferent information. PMID- 24055335 TI - Ethanol impairs microtubule formation via interactions at a microtubule associated protein-sensitive site. AB - Prolonged ethanol abuse has been associated with brain injury caused by impaired synaptogenesis, cellular migration, neurogenesis, and cell signaling, all of which require proper microtubule functioning. However, the means by which ethanol may impair microtubule formation or function and the role that microtubule associated proteins (MAPs) have in mediating such effects are not clear. In the present studies, purified MAP-deficient (2 mg/mL) and MAP-rich (pre-conjugated; 1 mg/mL) bovine alpha/beta tubulin dimer was allowed to polymerize at 37 degrees C, forming microtubules in the presence or absence of ethanol (25-500 mM). Microtubule formation was assessed in a 96-well format using a turbidity assay, with absorption measured at 340 nm for 45 min. Additional studies co-exposed alpha/beta tubulin dimers to 50 mM ethanol and purified MAPs (0.1 mg/mL) for 45 min. Polymerization of MAP-deficient tubulin was significantly decreased (at 15 45 min of polymerization) during exposure to ethanol (>25 mM). In contrast, ethanol exposure did not alter polymerization of alpha/beta tubulin dimers pre conjugated to MAPs, at any concentration. Concurrent exposure of MAP-deficient tubulin with purified MAPs and ethanol resulted in significant and time-dependent decreases in tubulin polymerization, with recovery from inhibition at later time points. The present results suggest that ethanol disrupts MAP-independent microtubule formation and MAP-dependent microtubule formation via direct actions at an MAP-sensitive microtubule residue, indicating that disruption of neuronal microtubule formation and function may contribute to the neurodegenerative effects of binge-like ethanol intake. PMID- 24055336 TI - Sex differences in oxytocin receptor binding in forebrain regions: correlations with social interest in brain region- and sex- specific ways. AB - Social interest reflects the motivation to approach a conspecific for the assessment of social cues and is measured in rats by the amount of time spent investigating conspecifics. Virgin female rats show lower social interest towards unfamiliar juvenile conspecifics than virgin male rats. We hypothesized that the neuropeptide oxytocin (OT) may modulate sex differences in social interest because of the involvement of OT in pro-social behaviors. We determined whether there are sex differences in OT system parameters in the brain and whether these parameters would correlate with social interest. We also determined whether estrus phase or maternal experience would alter low social interest and whether this would correlate with changes in OT system parameters. Our results show that regardless of estrus phase, females have significantly lower OT receptor (OTR) binding densities than males in the majority of forebrain regions analyzed, including the nucleus accumbens, caudate putamen, lateral septum, bed nucleus of the stria terminalis, medial amygdala, and ventromedial hypothalamus. Interestingly, male social interest correlated positively with OTR binding densities in the medial amygdala, while female social interest correlated negatively with OTR binding densities in the central amygdala. Proestrus/estrus females showed similar social interest to non-estrus females despite increased OTR binding densities in several forebrain areas. Maternal experience had no immediate or long-lasting effects on social interest or OT brain parameters except for higher OTR binding in the medial amygdala in primiparous females. Together, these findings demonstrate that there are robust sex differences in OTR binding densities in multiple forebrain regions of rats and that OTR binding densities correlate with social interest in brain region- and sex-specific ways. PMID- 24055337 TI - Langerhans cells in odontogenic epithelium. PMID- 24055338 TI - Novel Middle East respiratory syndrome coronavirus. PMID- 24055339 TI - First description of lung abscess caused by ST23 clone capsule genotype K1 Klebsiella pneumoniae. PMID- 24055340 TI - Spontaneous movements in the supine position of preterm infants with intellectual disability. AB - OBJECTIVE: Spontaneous movements at 2 months of corrected age in preterm infants with intellectual disability (ID) were investigated by assessing individual motor elements separated from movements involving the entire body. METHODS: Video recordings of 20 preterm infants with ID (16 males, 4 females; median gestational age 26 weeks; median birth weight 810 g) were analyzed and were compared with those of 21 normal preterm infants (8 males, 13 females; median gestational age 30 weeks; median birth weight 1216 g). RESULTS: In the preterm infants with ID at 2 months corrected age, startle response, lateral decumbent position, predominant shoulder rotation, and maintaining hip adduction were more frequently observed and hand sucking, maintaining shoulder abduction, to-and-fro shoulder abduction, to-and-fro elbow flexion, isolated hip adduction, to-and-fro hip abduction, and leg lift were less frequently seen than in the normal preterm infants (Fisher's exact test, p<0.05). CONCLUSION: Abnormal spontaneous movements at 2 months of age in preterm infants with ID result from persistent immature movements and non emergence of mature movements. PMID- 24055341 TI - Early onset and focal spike discharges as indicators of poor prognosis for myoclonic-astatic epilepsy. AB - BACKGROUND: Myoclonic-astatic epilepsy (MAE) is an epileptic syndrome characterized by unique myoclonus, myoclonic-astatic, or astatic seizures in childhood. MAE prognosis vary from spontaneous remission to intractable seizures with profound mental retardation. AIM: Identifying early risk factors may optimize the treatment of children with MAE. Our hypothesis is early onset age and focal spike discharges on EEG indicate a poor MAE prognosis. METHODS: Using the medical records of 9 children with MAE, we analyzed their clinical histories, EEG findings, and seizure symptoms. All patients were given follow-up observations/treatments by our department for at least 2 years after MAE onset. RESULTS: Five of the patients were given favorable prognoses because their seizures disappeared within 2 years of onset; the other 4 received poor prognoses because their seizures continued more than 2 years. MAE onset in patient with refractory seizures was earlier than that in those with a favorable prognosis (7 24 months vs. 23-38 months). All the patients with refractory seizures showed moderate or severe mental retardation. Among the 5 patients with good prognosis, EEGs showed two with focal spike discharges and three with only generalized spike discharges. In contrast, all cases with a poor prognosis had focal spike discharges. CONCLUSIONS: MAE onset in patients with refractory seizures occurs earlier than in those with favorable prognosis. Prognosis was excellent when EEG findings show no focal spike discharges. Both early seizure onset and the focal spike discharges associated with MAE are indicators of poor prognosis. PMID- 24055342 TI - The imprinted H19 lncRNA antagonizes let-7 microRNAs. AB - Abundantly expressed in fetal tissues and adult muscle, the developmentally regulated H19 long noncoding RNA (lncRNA) has been implicated in human genetic disorders and cancer. However, how H19 acts to regulate gene function has remained enigmatic, despite the recent implication of its encoded miR-675 in limiting placental growth. We noted that vertebrate H19 harbors both canonical and noncanonical binding sites for the let-7 family of microRNAs, which plays important roles in development, cancer, and metabolism. Using H19 knockdown and overexpression, combined with in vivo crosslinking and genome-wide transcriptome analysis, we demonstrate that H19 modulates let-7 availability by acting as a molecular sponge. The physiological significance of this interaction is highlighted in cultures in which H19 depletion causes precocious muscle differentiation, a phenotype recapitulated by let-7 overexpression. Our results reveal an unexpected mode of action of H19 and identify this lncRNA as an important regulator of the major let-7 family of microRNAs. PMID- 24055343 TI - Functionally diverse microRNA effector complexes are regulated by extracellular signaling. AB - Because microRNAs (miRNAs) influence the expression of many genes in cells, discovering how the miRNA pathway is regulated is an important area of investigation. We found that the Drosophila miRNA-induced silencing complex (miRISC) exists in multiple forms. A constitutive form, called G-miRISC, is comprised of Ago1, miRNA, and GW182. Two distinct miRISC complexes that lack GW182 are regulated by mitogenic signaling. Exposure of cells to serum, lipids, or the tumor promoter PMA suppressed formation of these complexes. P-miRISC is comprised of Ago1, miRNA, and Loqs-PB, and it associates with mRNAs assembled into polysomes. The other regulated Ago1 complex associates with membranous organelles and is likely an intermediate in miRISC recycling. The formation of these complexes is correlated with a 5- to 10-fold stronger repression of target gene expression inside cells. Taken together, these results indicate that mitogenic signaling regulates the miRNA effector machinery to attenuate its repressive activities. PMID- 24055344 TI - Chromatin remodelers fine-tune H3K36me-directed deacetylation of neighbor nucleosomes by Rpd3S. AB - Chromatin remodelers have been implicated in the regulation of histone-modifying complexes. However, the underlying mechanism remains poorly understood. The Rpd3S histone deacetylase complex is recruited by elongating RNA polymerase II to remove histone acetylation at coding regions in a manner that is dependent on methylation of lysine 36 on histone 3 (H3K36me), and Rpd3S prefers dinucleosomes. Here, we show that the binding of Rpd3S to dinucleosomes and its catalytic activity are sensitive to the length of nucleosomal linker in a nonlinear fashion. Intriguingly, we found that H3K36me on one nucleosome stimulates Rpd3S to deacetylate the neighboring nucleosomes when those two nucleosomes are within an optimal distance. Finally, we demonstrate that chromatin remodelers enhance Rpd3S activity by altering nucleosomal spacing, suggesting that chromatin remodelers prime chromatin configuration to fine-tune subsequent histone modification reactions. This mechanism is important for accurate temporal control of chromatin dynamics during the transcription elongation cycle. PMID- 24055345 TI - PAF and EZH2 induce Wnt/beta-catenin signaling hyperactivation. AB - Fine control of Wnt signaling is essential for various cellular and developmental decision-making processes. However, deregulation of Wnt signaling leads to pathological consequences, one of which is cancer. Here, we identify a function of PAF, a component of translesion DNA synthesis, in modulating Wnt signaling. PAF is specifically overexpressed in colon cancer cells and intestinal stem cells and is required for colon cancer cell proliferation. In Xenopus laevis, ventrovegetal expression of PAF hyperactivates Wnt signaling, developing a secondary axis with beta-catenin target gene upregulation. Upon Wnt signaling activation, PAF dissociates from PCNA and binds directly to beta-catenin. Then, PAF recruits EZH2 to the beta-catenin transcriptional complex and specifically enhances Wnt target gene transactivation, independently of EZH2's methyltransferase activity. In mice, conditional expression of PAF induces intestinal neoplasia via Wnt signaling hyperactivation. Our studies reveal an unexpected role of PAF in regulating Wnt signaling and propose a regulatory mechanism of Wnt signaling during tumorigenesis. PMID- 24055346 TI - The chromatin scaffold protein SAFB1 renders chromatin permissive for DNA damage signaling. AB - Although the general relevance of chromatin modifications for genotoxic stress signaling, cell-cycle checkpoint activation, and DNA repair is well established, how these modifications reach initial thresholds in order to trigger robust responses remains largely unexplored. Here, we identify the chromatin-associated scaffold attachment factor SAFB1 as a component of the DNA damage response and show that SAFB1 cooperates with histone acetylation to allow for efficient gammaH2AX spreading and genotoxic stress signaling. SAFB1 undergoes a highly dynamic exchange at damaged chromatin in a poly(ADP-ribose)-polymerase 1- and poly(ADP-ribose)-dependent manner and is required for unperturbed cell-cycle checkpoint activation and guarding cells against replicative stress. Altogether, our data reveal that transient recruitment of an architectural chromatin component is required in order to overcome physiological barriers by making chromatin permissive for DNA damage signaling, whereas the ensuing exclusion of SAFB1 may help prevent excessive signaling. PMID- 24055347 TI - Proteome-wide identification of poly(ADP-Ribosyl)ation targets in different genotoxic stress responses. AB - Poly(ADP-ribos)ylation (PARylation) is a reversible posttranslational modification found in higher eukaryotes. However, little is known about PARylation acceptor proteins. Here, we describe a sensitive proteomics approach based on high-accuracy quantitative mass spectrometry for the identification of PARylated proteins induced under different cellular stress conditions. While confirming the majority of known PARylated substrates, our screen identifies numerous additional PARylation targets. In vivo and in vitro validation of acceptor proteins confirms that our methodology targets covalent PARylation. Nuclear proteins encompassing nucleic acid binding properties are prominently PARylated upon genotoxic stress, consistent with the nuclear localization of ARTD1/PARP1 and ARTD2/PARP2. Distinct differences in proteins becoming PARylated upon various genotoxic insults are observed, exemplified by the PARylation of RNA processing factors THRAP3 and TAF15 under oxidative stress. High-content imaging reveals that PARylation affects the nuclear relocalization of THRAP3 and TAF15, demonstrating the potential of our approach to uncover hitherto unappreciated processes being controlled by specific genotoxic-stress-induced PARylation. PMID- 24055349 TI - Safety and immunogenicity of 13-valent pneumococcal conjugate vaccine in infants: a meta-analysis. AB - Pneumococcal infections are a major cause of morbidity and mortality worldwide. Pneumococcal conjugate vaccines represent major progress in the prevention of invasive pneumococcal disease in the paediatric population. We performed a meta analysis, in accordance with the PRISMA statement, in order to assess the immunogenicity and safety of 13-valent pneumococcal conjugate vaccines in infants. A literary search was conducted using electronic databases and specialized journals were searched manually. Inclusion criteria were: clinical trials with infants vaccinated with 13-valent pneumococcal conjugate, compared to 7-valent vaccine. We recorded the results in terms of the immunogenicity and safety of the vaccines. The quality of the studies included was assessed using the CASP and Jadad checklists. We included nine randomized clinical trials of 258 potentially relevant references in the meta-analysis. The studies included had high-moderate quality. Both vaccines were well tolerated in all groups of infants, and most local reactions and systemic events were of mild or medium intensity and typical of any injected vaccine. All studies included in the meta analysis showed high immunogenicity for both pneumococcal vaccines in all tested serotypes. An anti-polysaccharide antibody concentration of >=0.35 MUg/mL was achieved in at least 89% of the infants. Our results suggest that the 13-valent pneumococcal conjugate vaccine has a similar safety profile, and is as effective as, the 7-valent vaccine in the prevention of invasive pneumococcal disease caused by the seven common serotypes, and could provide expanded protection against the six additional serotypes. PMID- 24055348 TI - Bovine papillomavirus-like particles presenting conserved epitopes from membrane proximal external region of HIV-1 gp41 induced mucosal and systemic antibodies. AB - Two conserved epitopes, located in the membrane-proximal external region (MPER) of the human immunodeficiency virus type 1 (HIV-1) gp41, are recognized by two HIV-1 broadly neutralizing antibodies 2F5 and 4E10, and are promising targets for vaccine design in efforts to elicit anti-HIV-1 broadly neutralizing antibodies. Since most HIV-1 infections initiate at mucosal surfaces, induction of mucosal neutralizing antibodies is necessary and of utmost importance to counteract HIV-1 infection. Here, we utilized a mucosal vaccine vector, bovine papillomavirus (BPV) virus-like particles (VLPs), as a platform to present HIV-1 neutralizing epitopes by inserting the extended 2F5 or 4E10 epitope or the MPER domain into D E loop of BPV L1 respectively. The chimeric VLPs presenting MPER domain resembled the HIV-1 natural epitopes better than the chimeric VLPs presenting single epitopes. Oral immunization of mice with the chimeric VLPs displaying the 2F5 epitope or MPER domain elicited epitope-specific serum IgGs and mucosal secretory IgAs. The induced antibodies specifically recognized the native conformation of MPER in the context of HIV-1 envelope protein. The antibodies induced by chimeric VLPs presenting MPER domain are able to partially neutralize HIV-1 viruses from clade B and clade C. PMID- 24055351 TI - Influenza cost and cost-effectiveness studies globally--a review. AB - Every year, approximately 10-20% of the world's population is infected with influenza viruses, resulting in a significant number of outpatient and hospital visits and substantial economic burden both on health care systems and society. With recently updated WHO recommendations on influenza vaccination and broadening vaccine production, policy makers in middle- and low-income countries will need data on the cost of influenza disease and the cost effectiveness of vaccination. We reviewed the published literature to summarize estimates of cost and cost effectiveness of influenza vaccination. We searched PUBMED (MEDLINE), EMBASE, WEB of KNOWLEDGE, and IGOOGLE using the key words 'influenza', 'economic cost', 'cost effectiveness', and 'economic burden'. We identified 140 studies which estimated either cost associated with seasonal influenza or cost effectiveness/cost-benefit of influenza vaccination. 118 of these studies were conducted in World Bank defined high income, 22 in upper-middle income, and no studies in low and lower middle income countries. The per capita cost of a case of influenza illness ranged from $30 to $64. 22 studies reported that influenza vaccination was cost saving; reported cost-effectiveness ratios were $10,000/outcome in 13 studies, $10,000 to $50,000 in 13 studies, and >=$50,000 in 3 studies. There were no studies from low income countries and few studies among pregnant women. Substantial differences in methodology limited the generalization of results. Decision makers in lower income countries lack economic data to support influenza vaccine policy decisions, especially of pregnant women. Standardized cost effectiveness studies of influenza vaccination of WHO-recommended risk groups' methods are urgently needed. PMID- 24055350 TI - Assessment of HPV 16 and HPV 18 antibody responses by pseudovirus neutralization, Merck cLIA and Merck total IgG LIA immunoassays in a reduced dosage quadrivalent HPV vaccine trial. AB - We assessed HPV 16 and 18 antibody responses of female subjects enrolled in a 2- vs. 3-dose quadrivalent HPV (Q-HPV) vaccine trial (ClinicalTrials.gov NCT00501137) using the Merck competitive Luminex (cLIA) and total IgG Luminex (TIgG) immunoassays, and a pseudovirus neutralizing antibody (PsV NAb) assay. Subjects were enrolled in one of three groups: (1) 9-13yr, 2 doses of Q-HPV at 0, 6 months (n=259); (2) 9-13yr, 3 doses at 0, 2, 6 months (n=260); and (3) 16-26yr, 3 doses at 0, 2, 6 months (n=305). Sera were collected from all subjects at baseline, months 7 and 24, and from half the subjects at months 18 and 36. High correlation was observed between all three assays. At month 36, HPV 16 antibodies remained detectable in all subjects by all assays, whereas 86.4%, 99.6% and 100% of subjects respectively were HPV 18 cLIA, TIgG and PsV NAb (partial neutralization endpoint) seropositive. The proportion seropositive for HPV 18 by cLIA at 36 months was not significantly different for 2-dose girls vs. 3-dose adults (85.9% vs. 79.4%; p=0.51), whereas the proportion for 3-dose girls was significantly higher than for 3-dose adults (95.3% vs. 79.4%; p<0.01). The HPV 18 seropositive proportions by the TIgG and PsV NAb (partial neutralization endpoint) assays were the same for all subjects. High baseline HPV 16 and HPV 18 seropositivity was observed for the TIgG assay and it is unclear if all the detected TIgG antibodies are type-specific and/or neutralizing. For the PsV NAb assay, 90% and partial neutralization geometric mean titres were consistently 2-8 fold higher than for 100% neutralization, which enabled detection of HPV 18 NAb in subjects who lost detectable cLIA antibodies over time. We conclude that the PsV NAb assay is more sensitive than the cLIA, and likely more specific than the TIgG assay. PMID- 24055352 TI - Neonatal colonization of germ-free mice with Bifidobacterium longum prevents allergic sensitization to major birch pollen allergen Bet v 1. AB - The main goal in reversing the allergy epidemic is the development of effective prophylactic strategies. We investigated the prophylactic effect of neonatal mother-to-offspring mono-colonization with Bifidobacterium longum ssp. longum CCM 7952 on subsequent allergic sensitization. Adult male and female germ-free (GF) mice were mono-colonized with B. longum, mated and their offspring, as well as age-matched GF controls, were sensitized with the major birch pollen allergen Bet v 1. Furthermore, signaling pathways involved in the recognition of B. longum were investigated in vitro. Neonatal mono-colonization of GF mice with B. longum suppressed Bet v 1-specific IgE-dependent beta-hexosaminidase release as well as levels of total IgE and allergen-specific IgG2a in serum compared to sensitized GF controls. Accordingly, Bet v 1-induced production of both Th1- and Th2 associated cytokines in spleen cell cultures was significantly reduced in these mice. The general suppression of Bet v 1-specific immune responses in B. longum colonized mice was associated with increased levels of regulatory cytokines IL-10 and TGF-beta in serum. In vitro, B. longum induced low maturation status of bone marrow-derived dendritic cells and production of IL-10 in TLR2-, MyD88-, and MAPK dependent manner. Our data demonstrate that neonatal mono-colonization with B. longum reduces allergic sensitization, likely by activation of regulatory responses via TLR2, MyD88, and MAPK signaling pathways. Thus, B. longum might be a promising candidate for perinatal intervention strategies against the onset of allergic diseases in humans. PMID- 24055353 TI - The risk of fever following one dose of trivalent inactivated influenza vaccine in children aged >=6 months to <36 months: a comparison of published and unpublished studies. AB - There are limited summary data published on the risk of fever and febrile seizures in children following influenza vaccination. We performed a review of the risk of fever and febrile seizures following receipt of trivalent inactivated influenza vaccine (TIV) in children aged >=6 months to <36 months, searching PubMED and Google Scholar for English language articles from 2000 onwards, and initiated or ongoing unpublished studies since September 2007 using Clinicaltrials.gov. Exclusions included other vaccine co-administration, missing ages or participant numbers, or unmeasured fever. We reviewed articles and collated results using a standard data extraction template. We identified a total of 909 published papers and unpublished trials from a search conducted on 23 January 2013, 669 from Google Scholar, 114 from PubMed and 126 from the Clinicaltrials.gov online database. After excluding 890 published papers or unpublished trials, 5 published papers and 14 unpublished trials were included in this review. Extracted data on number of events, children at risk and time of follow-up were converted to the risk of fever, which was averaged per week of follow-up (referred to as 'averaged weekly risk'). Following one dose of TIV, the median averaged weekly risk of any fever (>=37.5 degrees C) was 26.0% (range 10.3 70.0%) in unpublished trials compared to 8.2% (range 5.3-28.3%) in published papers (p=0.04). The median averaged weekly risk of severe fever (>=39.0 degrees C) was 3.2% (range 0-10.0%) and 2.0% (range 0.6-17.0%), respectively (p=0.91). Variation in the reporting of fever by participant age groups, time since vaccination and the definition or measurement of fever resulted in a wide range of risk estimates. Reporting of febrile reactions should be standardised to allow comparison between manufacturers and influenza seasons. PMID- 24055354 TI - Post-authorization safety surveillance of a liquid pentavalent vaccine in Guatemalan children. AB - OBJECTIVE: Combination vaccines have improved the efficiency of delivery of new vaccines in low and middle-income countries. Post-authorization monitoring of adverse events (AEs) after vaccination with a liquid pentavalent DTwP-HepB-Hib combination vaccine was conducted in Guatemalan infants. METHODS: A prospective observational safety study of the incidence of medical attended events (MAEs) and serious adverse events (SAEs) in children who received pentavalent and oral polio vaccines at 2, 4 and 6 months of age was conducted in two clinics at the Institute of Guatemala. Parents were contacted by telephone after each dose. All outpatient, emergency department visits, and hospitalizations were monitored. A self-controlled analysis was conducted to determine if there was evidence of increased risk of MAEs or SAEs following vaccines as compared to control time windows. RESULTS: Of 3000 recruited infants, 2812 (93.7%) completed the third dose and 2805 (93.5%) completed follow-up. Ten AEs in eight infants, of which four SAEs in four infants, were classified as related to the vaccine. Thirteen deaths were reported due to common illnesses of infancy, and none were judged to be related to the vaccine. The mortality rate (4.4 per 1000) was lower than expected for the population. The incidence-rate-ratio for healthcare visits was lower in post-vaccination time windows than for control windows; after the first vaccine dose, the rate ratios for the risk periods of 0-1, 2-6, and 7-30 days post-vaccination were 0.3, 0.5, and 0.7, respectively (all statistically significantly different from the reference value of 1.0 for the 31-60 day control period). CONCLUSION: The liquid pentavalent vaccine was associated with lower rates of health care visits and not associated with increases in SAEs or hospitalizations. Systems can be set up in low to middle income countries to capture all health care visits to monitor the safety of new vaccines. PMID- 24055355 TI - A subunit vaccine candidate derived from a classic H5N1 avian influenza virus in China protects fowls and BALB/c mice from lethal challenge. AB - In recent years, numerous human infections with avian influenza viruses in Asia have raised the concern that the next influenza pandemic is imminent. The most effective way to combat human avian influenza is through vaccination of the public. In this study, we developed an influenza A recombinant protein (rH5HA) directed against the hemagglutinin (HA) of a classic H5N1 high pathogenic avian influenza virus isolated in South China in 1996. Following purification of the recombinant protein expressed from a baculovirus expression system, we evaluated the efficiency of rH5HA on specific pathogen free (SPF) chicken, commercial chicken, and in BALB/c mice in an infection-protection model. The results demonstrated that rH5HA induced antibody responses and provided full protection in both SPF chickens and commercial chickens. Protective immunity was generated within 2 weeks in chickens as young as 7-day post-hatch using a minimum amount of rH5HA protein (2MUg/bird/vaccination). The serum antibody generated from rH5HA immunization was protective and lasted more than 6 months. Our data also demonstrated that rH5HA immunization protected BALB/c mice from a lethal challenge with pathogenic avian influenza virus. These results suggested that vaccination with rH5HA could be a vaccine candidate for the control of H5N1 avian influenza in poultry, in mice, and potentially in other mammals including human. PMID- 24055356 TI - Involvements of stress hormones in the restraint-induced conditioned place preference. AB - The conditioned place preference (CPP) paradigm is widely used when examining the reinforcing effects of drugs. Some previous studies have shown that an acute stressor, such as restraint could also induce CPP. Although the modulating effects of stress hormones on various forms of learning are well known, the finding that a stressor has a potentially direct role in the reinforcement mechanism is novel. This study focused on the function of stress hormones in restraint-induced CPP in Wistar rats administered agonist or antagonist of 2 critical stress hormones prior to conditioning. Results showed that peripheral applications of corticosterone (CORT, 1, 3, 5, and 10 mg/kg, subcutaneously) failed to induce CPP. Furthermore, a glucocorticoid (GC) antagonist (mifepristone, 10, 40, or 100 mg/kg, sc) failed to block the restraint-induced CPP. Intracerebroventricular injection of a selective corticotropin-releasing factor receptor 1 (CRFR1) antagonist antalarmin (1 MUg/5 MUl), on the contrary, completely blocked the restraint-induced CPP. We concluded that CRFR1 plays an essential role in the neural mechanism of restraint-induced CPP. Negative feedback of CORT from peripheral sources may not be involved in this phenomenon. PMID- 24055357 TI - Voluntary exercise counteracts Abeta25-35-induced memory impairment in mice. AB - Exercise has been shown to enhance hippocampus-related cognition and slow the progression of Alzheimer's disease (AD). However, whether voluntary exercise directly decreases the neurotoxicity of amyloid peptide (Abeta) needs to be determined. In the present study, two-month old male C57bl/6 mice were intracerebroventricularly injected with Abeta25-35, and then allowed for voluntary exercise for 12 days. Y-maze test revealed that voluntary exercise mitigated spatial memory impairment induced by Abeta25-35. Consistently, Abeta25 35 treated mice with exercise showed reduced neuronal degeneration and synaptic protein loss in the hippocampus compared with sedentary controls. Moreover, voluntary exercise significantly ameliorated oxidative stress markers and increased vessel branches in the hippocampus of Abeta25-35 treated mice. Our results suggest that voluntary exercise counteracts the neurotoxicity of Abeta by reducing oxidative stress and increasing angiogenesis, which may underlie the beneficial effect of exercise on AD. PMID- 24055358 TI - Sleepwalking: long-term home video monitoring. PMID- 24055359 TI - Dose distribution response in HDRB measured with EBT2 and compared with PLATO SYSTEM. AB - Dose distribution of a High Dose Rate Brachytherapy (BHDR) oncological treatment with (192)Ir was measured using a Gafchromic EBT2 film. The film calibration was performed with a (60)Co unit and a LINAC of 6 mV and 18 mV. Gafchromic behavior of a dosimeter varies in respect of energy. Experimental results of dose distribution match with those planned in the PLATO commercial system, they also show that there is a difference of 2.11% between the planning system and isodoses measured. PMID- 24055360 TI - Results of an EC laboratory comparison on 40K, 90Sr and 137Cs in dried bilberry powder. AB - The evaluation is presented of a laboratory comparison (LC) on (90)Sr, (40)K and (137)Cs in dried bilberries organised in 2011 by the IRMM. The activity concentrations reported by 88 participant laboratories are compared to the reference values of the new reference material IRMM-426 Wild Berries. Nine per cent and 17% of activity concentration results for (137)Cs and (40)K, respectively, deviate more than 20% from the reference values, a result worse than that obtained in previous LCs. For (90)Sr, about 88% of results lie within 30% of the reference value, better than observed in previous LCs. But only 58% of (90)Sr results are satisfactory in terms of the En criterion, indicating difficulties with a complete uncertainty estimation. PMID- 24055361 TI - Short-term effect of whole-body vibration training on balance, flexibility and lower limb explosive strength in elite rhythmic gymnasts. AB - The purpose of this study was to examine whether whole-body vibration (WBV) training results in short-term performance improvements in flexibility, strength and balance tests in comparison to an equivalent exercise program performed without vibration. Eleven elite rhythmic gymnasts completed a WBV trial, and a control, resistance training trial without vibration (NWBV). The vibration trial consisted of eccentric and concentric squatting exercises on a vibration platform that was turned on, whereas the NWBV involved the same training protocol with the platform turned off. Balance was assessed using the Rhythmic Weight Shift (RWS) based on the EquiTest Dynamic Posturography system; flexibility was measured using the sit & reach test, and lower limb explosive strength was evaluated using standard exercises (squat jump, counter movement jump, single leg squat). All measurements were performed before (pre) immediately after the training program (post 1), and 15 minutes after the end of the program (post 15). Data were analyzed using repeated measures ANOVA was used with condition (WBV-NWBV) as the primary factor and time (pre, post 1, post 15) as the nested within subjects factor, followed by post-hoc pairwise comparison with Bonferroni corrections. Results confirmed the hypothesis of the superiority of WBV training, especially in the post 15 measurement, in all flexibility and strength measures, as well as in a number of balance tests. PMID- 24055362 TI - Effect of altered surfaces on postural sway characteristics in elderly subjects. AB - Mobility is essentially based on successful balance control. The evaluation of functional strategies for postural stability is requisite for effective balance rehabilitation and fall prevention in elderly subjects. Our objective was to clarify control mechanisms of different standing positions reflecting challenges of typical everyday life situations. For this purpose, elderly subjects stood on different surfaces resulting in a change of the biomechanical constraints. Sway parameters out of time and frequency domain were calculated from center-of pressure (COP) excursions. Besides the classic quantification of the amount of sway variability, we investigated the temporal organization of postural sway by means of nonlinear time series analysis. Limb load symmetry was quantified via foot pressure insoles. We found task dependent motor outputs: (1) asymmetrical loading in all conditions; (2) altered amount and structure of COP movements with dissimilar changes in medio-lateral and anterior-posterior direction; (3) changes of the motor output affect several time scales especially when standing on a balance board or with one foot on a step. Our results indicate that elderly subjects preferred forcefully one limb which supports a step-initiation strategy. Modifications of the postural sway structure refer to the interaction of multiple control mechanisms to cope with the altered demands. The identification of postural strategies employed in daily activities augments the ecological validity of postural control studies. PMID- 24055363 TI - Skill transfer, affordances and dexterity in different climbing environments. AB - This study explored how skills in one region of a perceptual-motor landscape of performance, created in part by previous experience in rock climbing, can shape those that emerge in another region (ice climbing). Ten novices in rock climbing and five intermediate rock climbers were observed climbing an icefall. Locations of right and left ice tools and crampons were videotaped from a frontal camera. Inter-individual variability of upper and lower limb couplings and types of action regarding icefall properties were assessed by cluster hierarchical analysis, distinguishing three clusters. Pelvis vertical displacement, duration and number of pelvis pauses were also analyzed. Experienced rock climbers were grouped in the same cluster and showed the highest range and variability of limb angular locations and coordination patterns, the highest vertical displacement and the shortest pelvis plateaux durations. Non-fluent climbers (clusters 2 and 3) showed low range and variability of limb angular locations and coordination patterns. In particular, climbers of cluster 3 exhibited the lowest vertical displacement, the longest plateaux durations and the greatest ratio between tool swinging and definitive anchorage. Our results exemplified the positive influence of skills in rock climbing on ice climbing performance, facilitated by the detection of affordances from environmental properties. PMID- 24055364 TI - Nurse-led epilepsy follow-up clinic in India: is it feasible and acceptable to patients? A pilot study. AB - PURPOSE: India has an epilepsy treatment gap of up to 90%. Shortage of doctors, especially in rural communities makes getting epilepsy treatment almost impossible for the vast majority. Nurses are relatively more in number and available even in smaller cities and villages. This pilot study investigated if a nurse-led epilepsy follow-up clinic is feasible in India and is acceptable to patients. METHOD: A II year Nursing postgraduate student was given 8h of didactic teaching tailored for epilepsy patient follow-up, followed by supervised observation time in the epilepsy clinic with a neurologist before conducting epilepsy follow-up clinics independently. Epilepsy patients >= 10 years of age and in follow-up for >= 6 months were included. They were independently followed up both in the nurse-led clinic and in the neurologist's clinic. Outcome was measured in terms of interrater agreement (kappa) between the recommendations of the neurologist and the nurse in five domains. Patient satisfaction for nurse-led clinic was also evaluated. RESULTS: The interrater agreement between the trained nurse and neurologist in following-up 175 enrolled patients was 76-94%; most unanimity (kappa=94%) seen in identifying AED adverse effects while least agreement (kappa=76%) was present regarding decisions to modify AED. The mean patient satisfaction score was 37.63 +/- 3.26 (maximum possible score 40). CONCLUSION: It is feasible for trained nurses to run epilepsy follow-up clinics in India and patients are likely to be satisfied with this approach. PMID- 24055365 TI - An anti-inflammatory role of A20 zinc finger protein during trauma combined with endotoxin challenge. AB - OBJECTIVE: To investigate the anti-inflammatory role of A20 zinc finger protein during trauma combined with bacterial endotoxin challenge and explore the molecular mechanism underlying this process. METHODS: Traumatic bone impact injury was induced in the hind limbs of mice. One hour after injury, mice were challenged with purified gram-negative bacterial endotoxins, lipopolysaccharides (LPSs), by tail vein injection. Effects on A20 messenger RNA and protein expressions were assessed by reverse transcription-polymerase chain reaction and Western blotting, respectively. A20 recombinant adenoviruses, full-length (pAdA20 1-775) and N-terminal mutant (pAdA20 1-367), were constructed and used to infect RAW264.7 macrophage cells or mice. Responses in the tumor necrosis factor alpha (TNF-alpha)-nuclear factor kappaB (NF-kappaB) signaling pathway were evaluated by enzyme-linked immunosorbent assay (for TNF-alpha) and electrophoretic mobility shift assay (for NF-kappaB). RESULTS: Trauma combined with LPS challenge and LPS challenge alone dramatically promoted A20 expression in mouse liver tissues. LPS challenge increased A20 messenger RNA levels appreciably in RAW264.7 cells within 1 h. Full-length A20 recombinant adenoviruses (pAdA20 1-775) suppressed NF-kappaB activity and TNF-alpha expression and protected against liver damage and animal death otherwise induced by trauma combined with LPS challenge. CONCLUSIONS: A20 zinc finger protein plays an anti-inflammatory role and protects against liver injury associated with trauma combined with LPS challenge. PMID- 24055366 TI - Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. AB - Respiratory chain complexes assemble into functional quaternary structures called supercomplexes (RCS) within the folds of the inner mitochondrial membrane, or cristae. Here, we investigate the relationship between respiratory function and mitochondrial ultrastructure and provide evidence that cristae shape determines the assembly and stability of RCS and hence mitochondrial respiratory efficiency. Genetic and apoptotic manipulations of cristae structure affect assembly and activity of RCS in vitro and in vivo, independently of changes to mitochondrial protein synthesis or apoptotic outer mitochondrial membrane permeabilization. We demonstrate that, accordingly, the efficiency of mitochondria-dependent cell growth depends on cristae shape. Thus, RCS assembly emerges as a link between membrane morphology and function. PMID- 24055368 TI - 'Telling their stories' on a dual diagnosis training course: forensic mental health service users' perspective on their challenges, benefits and future strategies. AB - A five day training course on dual diagnosis was developed by the authors in 2008 and delivered annually within the Irish forensic mental health service. Service users were invited to tell their stories on the training course. Literature suggests several therapeutic outcomes for service users such as raised self esteem, empowerment and new insight into their problems. However little is known from an Irish service users' perspective. This qualitative descriptive study was aimed at exploring the experiences of service users' telling their stories on a dual diagnosis training course. Data was collected using one-to-one interviews from seven service users. Qualitative data was analysed thematically. Three themes emerged from the analysis: the benefits, the challenges for the service users and strategies for their future involvement. Service users reported psychological, personal and social benefits and there were perceived benefits for the learners. Public speaking, preparing for the talk and taking questions from the trainees were the main challenges. They suggested several strategies for overcoming challenges in the future courses. In this article, while the authors discuss the need for empowering service users and providing them with adequate support, there are also practical and useful suggestions for the course coordinators/nurse educators. Authors recognise that service user involvement requires extensive time and significant support in preparing and training for their participation which may impact upon resources. PMID- 24055367 TI - Poly(ADP-ribosyl)ation regulates insulator function and intrachromosomal interactions in Drosophila. AB - Insulators mediate inter- and intrachromosomal contacts to regulate enhancer promoter interactions and establish chromosome domains. The mechanisms by which insulator activity can be regulated to orchestrate changes in the function and three-dimensional arrangement of the genome remain elusive. Here, we demonstrate that Drosophila insulator proteins are poly(ADP-ribosyl)ated and that mutation of the poly(ADP-ribose) polymerase (Parp) gene impairs their function. This modification is not essential for DNA occupancy of insulator DNA-binding proteins dCTCF and Su(Hw). However, poly(ADP-ribosyl)ation of K566 in CP190 promotes protein-protein interactions with other insulator proteins, association with the nuclear lamina, and insulator activity in vivo. Consistent with these findings, the nuclear clustering of CP190 complexes is disrupted in Parp mutant cells. Importantly, poly(ADP-ribosyl)ation facilitates intrachromosomal interactions between insulator sites measured by 4C. These data suggest that the role of insulators in organizing the three-dimensional architecture of the genome may be modulated by poly(ADP-ribosyl)ation. PMID- 24055369 TI - Apelin and its receptor APJ in cardiovascular diseases. AB - Apelin is an adipokine that has been identified as an endogenous ligand for the orphan receptor APJ. Apelin and APJ are expressed in a diverse range of tissues with particular preponderance for the heart and vasculature. Apelin has powerful positive inotropic actions and causes endothelium- and nitric oxide-dependent vasodilatation. Growing evidence shows that apelin/APJ system functions as a critical mediator of cardiovascular homeostasis and is involved in the pathophysiology of cardiovascular diseases. Targeting apelin/APJ axis produces protection against cardiovascular diseases. In the current review we have summarized recent data concerning the role and therapeutic potential of apelin/APJ in several major cardiovascular diseases. An increased understanding of the cardiovascular actions of apelin/APJ system will help to develop novel therapeutic interventions for cardiovascular diseases. PMID- 24055370 TI - X-linked glycogen storage disease IXa manifested in a female carrier due to skewed X chromosome inactivation. AB - BACKGROUND: Glycogen storage disease (GSD) is a group of inherited metabolic disorders due to enzymatic deficiency involved in glycogen breakdown. In various subtypes of GSD, GSD IXa is an X-linked recessive disorder, which only manifested in males. Here, we report a case of X-linked GSD IXa manifested in a female Chinese patient accompanying a skewed X-chromosome inactivation (XCI). METHODS: A 29-y-old Chinese female was admitted to evaluate mild hepatomegaly, which was repeatedly observed in serial abdominal ultrasonographic examinations. GSDIXa was suspected. To identify the mutation and the disease mechanism, we performed sequencing analysis of the PHKA2 gene, XCI assay and cDNA expression analysis. RESULTS: Sequencing analysis revealed a heterozygous mutation in the PHKA2 gene (c.3614C>T; p.P1205L) of the patient. In XCI assay, the proband showed a skewed XCI pattern cDNA expression analysis showed a preferential expression of the mutant allele in leukocytes of the patient. CONCLUSIONS: This is a rare report of X-linked GSD IXa manifested in a female carrier with skewed XCI. Skewed XCI can play a key role in the manifestation of X-linked recessive disorders in female carriers. PMID- 24055371 TI - Reactivation of NCAM1 defines a subpopulation of human adult kidney epithelial cells with clonogenic and stem/progenitor properties. AB - The nephron is composed of a monolayer of epithelial cells that make up its various compartments. In development, these cells begin as mesenchyme. NCAM1, abundant in the mesenchyme and early nephron lineage, ceases to express in mature kidney epithelia. We show that, once placed in culture and released from quiescence, adult human kidney epithelial cells (hKEpCs), uniformly positive for CD24/CD133, re-express NCAM1 in a specific cell subset that attains a stem/progenitor state. Immunosorted NCAM1(+) cells overexpressed early nephron progenitor markers (PAX2, SALL1, SIX2, WT1) and acquired a mesenchymal fate, indicated by high vimentim and reduced E-cadherin levels. Gene expression and microarray analysis disclosed both a proximal tubular origin of these cells and molecules regulating epithelial-mesenchymal transition. NCAM1(+) cells generated clonal progeny when cultured in the presence of fetal kidney conditioned medium, differentiated along mesenchymal lineages but retained the unique propensity to generate epithelial kidney spheres and produce epithelial renal tissue on single cell grafting in chick CAM and mouse. Depletion of NCAM1(+) cells from hKEpCs abrogated stemness traits in vitro. Eliminating these cells during the regenerative response that follows glycerol-induced acute tubular necrosis worsened peak renal injury in vivo. Thus, higher clone-forming and developmental capacities characterize a distinct subset of adult kidney-derived cells. The ability to influence an endogenous regenerative response via NCAM1 targeting may lead to novel therapeutics for renal diseases. PMID- 24055372 TI - Management of fractures of the zygomaticomaxillary complex. AB - The zygomaticomaxillary complex (ZMC) has important aesthetic, structural, and functional roles that need to be preserved and/or restored during treatment of facial fractures. Surgical treatment of ZMC fractures is indicated when there is displacement of the bony fragments, and open reduction and internal fixation is the treatment of choice in cases of comminution or fracture instability. The surgical approaches used for fracture reduction as well as the type, number, and location of the fixation will be determined by the pattern of the fracture and the surgeon's preference. This article discusses the main points of the management of ZMC fractures. PMID- 24055373 TI - Knowing what to expect, forecasting monthly emergency department visits: A time series analysis. AB - OBJECTIVE: To evaluate an automatic forecasting algorithm in order to predict the number of monthly emergency department (ED) visits one year ahead. METHODS: We collected retrospective data of the number of monthly visiting patients for a 6 year period (2005-2011) from 4 Belgian Hospitals. We used an automated exponential smoothing approach to predict monthly visits during the year 2011 based on the first 5 years of the dataset. Several in- and post-sample forecasting accuracy measures were calculated. RESULTS: The automatic forecasting algorithm was able to predict monthly visits with a mean absolute percentage error ranging from 2.64% to 4.8%, indicating an accurate prediction. The mean absolute scaled error ranged from 0.53 to 0.68 indicating that, on average, the forecast was better compared with in-sample one-step forecast from the naive method. CONCLUSION: The applied automated exponential smoothing approach provided useful predictions of the number of monthly visits a year in advance. PMID- 24055374 TI - PDT-induced epigenetic changes in the mouse cerebral cortex: a protein microarray study. AB - BACKGROUND: Photodynamic therapy (PDT) is used for cancer treatment including brain tumors. But the role of epigenetic processes in photodynamic injury of normal brain tissue is unknown. METHODS: 5-Aminolevulinic acid (ALA), a precursor of protoporphyrin IX (PpIX), was used to photosensitize mouse cerebral cortex. PpIX accumulation in cortical tissue was measured spectrofluorometrically. Hematoxylin/eosin, gallocyanin-chromalum and immunohistochemical staining were used to study morphological changes in PDT-treated cerebral cortex. Proteomic antibody microarrays were used to evaluate expression of 112 proteins involved in epigenetic regulation. RESULTS: ALA administration induced 2.5-fold increase in the PpIX accumulation in the mouse brain cortex compared to untreated mice. Histological study demonstrated PDT-induced injury of some neurons and cortical vessels. ALA-PDT induced dimethylation of histone H3, upregulation of histone deacetylases HDAC-1 and HDAC-11, and DNA methylation-dependent protein Kaiso that suppressed transcriptional activity. Upregulation of HDAC-1 and H3K9me2 was confirmed immunohistochemically. Down-regulation of transcription factor FOXC2, PABP, and hBrm/hsnf2a negatively regulated transcription. Overexpression of phosphorylated histone H2AX indicated activation of DNA repair, but down regulation of MTA1/MTA1L1 and PML - impairment of DNA repair. Overexpression of arginine methyltransferase PRMT5 correlated with up-regulation of transcription factor E2F4 and importin alpha5/7. CONCLUSION: ALA-PDT injures and kills some but not all neurons and caused limited microvascular alterations in the mouse cerebral cortex. It alters expression of some proteins involved in epigenetic regulation of transcription, histone modification, DNA repair, nuclear protein import, and proliferation. GENERAL SIGNIFICANCE: These data indicate epigenetic markers of photo-oxidative injury of normal brain tissue. PMID- 24055375 TI - A phospholipase A2 gene is linked to Jack bean urease toxicity in the Chagas' disease vector Rhodnius prolixus. AB - BACKGROUND: Ureases are multifunctional enzymes that display biological activities independent of their enzymatic function, including exocytosis induction and insecticidal effects. The hemipteran Rhodnius prolixus is one of the known susceptible models for this toxicity. It has been shown that Jack bean urease (JBU) has deleterious effects on R. prolixus, and these effects are modulated by eicosanoids, which are synthesized in a cascade involving phospholipase A2 (PLA2) enzymes. METHODS: R. prolixus genome was screened for putative PLA2s and matching transcripts were cloned. Predicted amino acid sequences were analyzed and transcript distribution among tissues was determined by qPCR. RNAi techniques were used and subsequent JBU toxicity assays were performed. RESULTS: Two PLA2 genes were identified, Rhopr-PLA2III and Rhopr PLA2XII. The transcripts are widely distributed in the tissues but at different levels. The analyses fit the putative proteins into groups III and XII of secretory PLA2s. After 70% of Rhopr-PLA2XII expression was knocked down, JBU's toxicity was decreased by more than 50% on 5th instars R. prolixus. CONCLUSIONS: Rhopr-PLA2XII gene is linked to JBU's toxic effect in R. prolixus and our findings support previous studies demonstrating that eicosanoids modulate this toxicity. GENERAL SIGNIFICANCE: Besides identifying and characterizing two PLA2 genes in the major Chagas' disease vector R. prolixus, we have shown that the potent toxicity of JBU is linked to one of these genes. Our results contribute to the general comprehension of urease's mechanisms of action in insects, and, potentially, to studies on the control of the Chagas' disease parasite transmission. PMID- 24055376 TI - The N-terminal sequence of tyrosine hydroxylase is a conformationally versatile motif that binds 14-3-3 proteins and membranes. AB - Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the synthesis of catecholamine neurotransmitters, and a reduction in TH activity is associated with several neurological diseases. Human TH is regulated, among other mechanisms, by Ser19-phosphorylation-dependent interaction with 14-3-3 proteins. The N-terminal sequence (residues 1-43), which corresponds to an extension to the TH regulatory domain, also interacts with negatively charged membranes. By using X-ray crystallography together with molecular dynamics simulations and structural bioinformatics analysis, we have probed the conformations of the Ser19 phosphorylated N-terminal peptide [THp-(1-43)] bound to 14-3-3gamma, free in solution and bound to a phospholipid bilayer, and of the unphosphorylated peptide TH-(1-43) both free and bilayer bound. As seen in the crystal structure of THp-(1 43) complexed with 14-3-3gamma, the region surrounding pSer19 adopts an extended conformation in the bound state, whereas THp-(1-43) adopts a bent conformation when free in solution, with higher content of secondary structure and higher number of internal hydrogen bonds. TH-(1-43) in solution presents the highest mobility and least defined structure of all forms studied, and it shows an energetically more favorable interaction with membranes relative to THp-(1-43). Cationic residues, notably Arg15 and Arg16, which are the recognition sites of the kinases phosphorylating at Ser19, are also contributing to the interaction with the membrane. Our results reveal the structural flexibility of this region of TH, in accordance with the functional versatility and conformational adaptation to different partners. Furthermore, this structural information has potential relevance for the development of therapeutics for neurodegenerative disorders, through modulation of TH-partner interactions. PMID- 24055377 TI - Transmembrane segments form tertiary hairpins in the folding vestibule of the ribosome. AB - Folding of membrane proteins begins in the ribosome as the peptide is elongated. During this process, the nascent peptide navigates along 100A of tunnel from the peptidyltransferase center to the exit port. Proximal to the exit port is a "folding vestibule" that permits the nascent peptide to compact and explore conformational space for potential tertiary folding partners. The latter occurs for cytosolic subdomains but has not yet been shown for transmembrane segments. We now demonstrate, using an accessibility assay and an improved intramolecular crosslinking assay, that the helical transmembrane S3b-S4 hairpin ("paddle") of a voltage-gated potassium (Kv) channel, a critical region of the Kv voltage sensor, forms in the vestibule. S3-S4 hairpin interactions are detected at an early stage of Kv biogenesis. Moreover, this vestibule hairpin is consistent with a closed state conformation of the Kv channel in the plasma membrane. PMID- 24055378 TI - A novel 8-nm protein cage formed by Vibrio cholerae acylphosphatase. AB - Here we show the formation of an ~8-nm cage formed by the self-assembly of acylphosphatase from Vibrio cholerae O395 (Vc-AcP). The 12-subunit cage structure forms spontaneously and is stabilized through binding of sulfate ions at its exterior face and interfacial regions. Crystal structure and studies in solutions illuminate the basis for the formation of the cage, while a single (Cys20->Arg) mutation (Vc-AcP-C20R) transforms Vc-AcP to a potent enzyme but disrupts the assembly into a trimer. PMID- 24055379 TI - Mechanism of assembly of the non-covalent spectrin tetramerization domain from intrinsically disordered partners. AB - Interdomain interactions of spectrin are critical for maintenance of the erythrocyte cytoskeleton. In particular, "head-to-head" dimerization occurs when the intrinsically disordered C-terminal tail of beta-spectrin binds the N terminal tail of alpha-spectrin, folding to form the "spectrin tetramer domain". This non-covalent three-helix bundle domain is homologous in structure and sequence to previously studied spectrin domains. We find that this tetramer domain is surprisingly kinetically stable. Using a protein engineering Phi-value analysis to probe the mechanism of formation of this tetramer domain, we infer that the domain folds by the docking of the intrinsically disordered beta spectrin tail onto the more structured alpha-spectrin tail. PMID- 24055380 TI - Changing trends in the presentation of colorectal liver metastases in a single hepatobiliary tertiary referral centre over fourteen years. AB - AIM: National Institute for Clinical Excellence guidelines suggest that patients who have undergone potentially curative treatment for colorectal cancer (CRC) should be followed up for 3 years. The aim of this study was to investigate whether the time to presentation with colorectal liver metastases (CRLM) has changed over time. This information, which is currently unknown, may inform future decisions regarding follow-up. METHODS: Patients presenting with metachronous isolated liver metastases between 1997 and 2011 were included. Timings of presentation with CRLM, rates of liver resection, survival data and factors associated with delayed presentation were investigated. RESULTS: 269 patients were included in the study. Those having their primary CRC resection between 1997 and 2007 presented earlier with liver metastases over time (r = 0.33, 95% CI -0.45 to -0.20). However, 26% of patients who developed CRLM did so beyond 3 years. There was no significant difference in rates of liver resections for those presenting within, or beyond, 3 years (p = 0.21). There was no significant difference in survival for those presenting with resectable CRLM within, or beyond, 3 years (Exp(b) = 0.60, 95% CI 0.28-1.28). No factors associated with late presentation were identified. CONCLUSIONS: These results suggest that CRC follow-up should be extended to 5 years. Follow-up interventions should be more frequent in the early stages reflecting the trend towards earlier presentation with CRLM. The economic implications of extending follow-up compare favourably to other NHS funded initiatives. PMID- 24055381 TI - [The importance of the clinical report in the management of a surgical unit]. PMID- 24055382 TI - Quality of transitions in older medical patients with frequent readmissions: opportunities for improvement. AB - BACKGROUND: Medical patients with a recent previous hospitalisation are at very high risk of subsequent readmission. Evidence suggests that improving key transition processes may reduce hospital readmissions. This study describes quality of transition processes in frequently admitted medical patients, to inform system improvements for this high risk group. METHODS: Retrospective records review of consecutive medical inpatients aged 50 years or older in a major metropolitan teaching hospital in Australia with a recent (within 6 months) prior hospitalisation. Information was sought on 4 key processes: discharge summary completed and sent within 2 weeks; discharge medication reconciliation; patient/carer discharge education; and timely scheduling of outpatient review with the treating team. Readmission rates were obtained from a state-wide admissions database. RESULTS: Discharge processes for 209 live discharges in 164 patients were reviewed. Although timely discharge summary completion (81%) and discharge medication reconciliation by a pharmacist (81%) were high, there were major gaps in patient education (33%) and in timely outpatient review (12%). Outpatient systems appear poorly organised to support high quality transitions. Readmission rates were high (23% at 30 days and 58% at 180 days). Individual discharge quality processes did not predict readmissions. DISCUSSION: Gaps in transitional care of frequently attending medical patients provide potential targets for improvement. In particular, opportunities for better patient/carer education and timely, structured outpatient review may inform design of improved transitions for this high risk group, to be tested in prospective controlled trials. PMID- 24055383 TI - Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. AB - BACKGROUND: Accurately estimating surgical risks is critical for shared decision making and informed consent. The Centers for Medicare and Medicaid Services may soon put forth a measure requiring surgeons to provide patients with patient specific, empirically derived estimates of postoperative complications. Our objectives were to develop a universal surgical risk estimation tool, to compare performance of the universal vs previous procedure-specific surgical risk calculators, and to allow surgeons to empirically adjust the estimates of risk. STUDY DESIGN: Using standardized clinical data from 393 ACS NSQIP hospitals, a web-based tool was developed to allow surgeons to easily enter 21 preoperative factors (demographics, comorbidities, procedure). Regression models were developed to predict 8 outcomes based on the preoperative risk factors. The universal model was compared with procedure-specific models. To incorporate surgeon input, a subjective surgeon adjustment score, allowing risk estimates to vary within the estimate's confidence interval, was introduced and tested with 80 surgeons using 10 case scenarios. RESULTS: Based on 1,414,006 patients encompassing 1,557 unique CPT codes, a universal surgical risk calculator model was developed that had excellent performance for mortality (c-statistic = 0.944; Brier score = 0.011 [where scores approaching 0 are better]), morbidity (c statistic = 0.816, Brier score = 0.069), and 6 additional complications (c statistics > 0.8). Predictions were similarly robust for the universal calculator vs procedure-specific calculators (eg, colorectal). Surgeons demonstrated considerable agreement on the case scenario scoring (80% to 100% agreement), suggesting reliable score assignment between surgeons. CONCLUSIONS: The ACS NSQIP surgical risk calculator is a decision-support tool based on reliable multi institutional clinical data, which can be used to estimate the risks of most operations. The ACS NSQIP surgical risk calculator will allow clinicians and patients to make decisions using empirically derived, patient-specific postoperative risks. PMID- 24055384 TI - Improving survival rates after civilian gunshot wounds to the brain. AB - BACKGROUND: Gunshot wounds to the brain are the most lethal of all firearm injuries, with reported survival rates of 10% to 15%. The aim of this study was to determine outcomes in patients with gunshot wounds to the brain, presenting to our institution over time. We hypothesized that aggressive management can increase survival and the rate of organ donation in patients with gunshot wounds to the brain. STUDY DESIGN: We analyzed all patients with gunshot wounds to the brain presenting to our level 1 trauma center over a 5-year period. Aggressive management was defined as resuscitation with blood products, hyperosmolar therapy, and/or prothrombin complex concentrate (PCC). The primary outcome was survival and the secondary outcome was organ donation. RESULTS: There were 132 patients with gunshot wounds to the brain, and the survival rates increased incrementally every year, from 10% in 2008 to 46% in 2011, with the adoption of aggressive management. Among survivors, 40% (16 of 40) of the patients had bi hemispheric injuries. Aggressive management with blood products (p = 0.02) and hyperosmolar therapy (p = 0.01) was independently associated with survival. Of the survivors, 20% had a Glasgow Coma Scale score >= 13 at hospital discharge. In patients who died (n = 92), 56% patients were eligible for organ donation, and they donated 60 organs. CONCLUSIONS: Aggressive management is associated with significant improvement in survival and organ procurement in patients with gunshot wounds to the brain. The bias of resource use can no longer be used to preclude trauma surgeons from abandoning aggressive attempts to save patients with gunshot wound to the brain. PMID- 24055385 TI - Development of a multiplex PCR assay based on the 16S-23S rRNA internal transcribed spacer for the detection and identification of rodent Pasteurellaceae. AB - The rodents Pasteurellaceae have to be excluded from the specified pathogen free experimental animal facilities. Despite the biological and economic importance of Pasteurellaceae in relation to experimental animals just a few molecular based methods are available for their detection and identification. The aim of the present investigation was to develop a multiplex PCR assay allowing detection of all rodent Pasteurellaceae and identification of [Pasteurella] pneumotropica biotype Jawetz, [P.] pneumotropica biotype Heyl and [Actinobacillus] muris, as the most prevalent members of the group. For this, a Pasteurellaceae common forward primer located on the 16S rRNA gene was used in conjunction with four different reverse primers specific for [P.] pneumotropica biotype Jawetz, [P.] pneumotropica biotype Heyl, [A.] muris and a common reverse primer for all rodent Pasteurellaceae, all targeting the 16S-23S rRNA internal transcribed spacer sequences. The performance characteristics of the assay were tested against 125 Pasteurellaceae isolates belonging to eleven different species and including 34 strains of [P.] pneumotropica biotype Jawetz, 44 strains of [P.] pneumotropica biotype Heyl and 37 strains of [A.] muris. Additionally, eight other mouse associated bacterial species which could pose a diagnostic problem were included. The assay showed 100% sensitivity and specificity. Identification of the clinical isolates was validated by ITS profiling and when necessary by 16S rRNA gene sequencing. This multiplex PCR represents the first molecular tool able to detect and differentiate in a single assay among the Pasteurellaceae found in laboratory mouse and may become a reliable alternative to the present diagnostic methods. PMID- 24055386 TI - A new, rapid and sensitive bioluminescence assay for drug screening on Leishmania. AB - We validated a new method, based on luciferine/luciferase bioluminescence, for drug screening on promastigotes of different Leishmania species. Results obtained with this new, rapid, reproducible, and reliable method are in good accordance with results obtained by the conventional MTT assay. This bioluminescence assay has a lower detection limit. PMID- 24055387 TI - PNA-FISH assays for early targeted bacteraemia treatment. AB - PNA-FISH S. aureus/CNS and GNR Traffic Light assays were compared with standard culture methods for identifying bacteraemia in 156 blood cultures from 131 patients. Results correlated with final culture results in 153 cultures. Retrospective case note review revealed that earlier targeted treatment would have occurred in 10.7% of cases. PMID- 24055388 TI - A method for purifying high quality and high yield plasmid DNA for metagenomic and deep sequencing approaches. AB - Deep sequencing techniques used in metagenomic approaches have greatly advanced the study of microbial communities in various environments. However, one microbial segment that has remained largely unexplored is the natural plasmids residing within microbial environments. Plasmids are perceived as mobile genetic elements that exist extra-chromosomally and occasionally carry accessory genes that confer an advantage to their host in its ecological niche. They are thus thought to play an important evolutionary role in microbial communities by laterally introducing genes and traits into microbial genomes. Despite their importance, technical obstacles still limit the metagenomic study of natural plasmids using deep sequencing techniques. These include low copy number of the plasmids and heterogeneity of microbes in environmental samples, reflected in the low abundance of each individual plasmid. Furthermore, the extracted plasmids usually contain remnants of chromosomal DNA that can potentially interfere with the analysis of unique plasmid traits. We have recently studied the rumen metagenomic plasmid population using a newly developed procedure that successfully overcomes these obstacles. This procedure enables extraction of pure plasmid DNA suited for deep sequencing studies. Here we present a detailed description and characterization of this procedure which could potentially allow the study of plasmids in other environmental niches. PMID- 24055389 TI - Transarterial chemoembolisation (TACE) with gemcitabine: phase II study in patients with liver metastases of breast cancer. AB - OBJECTIVE: Evaluation of the efficacy and tolerability of transarterial chemoembolization with gemcitabine in patients with inoperable liver metastases of breast cancer. MATERIALS AND METHODS: Open-label, prospective non-randomized single-center study design; patients had previous chemotherapy including anthracyclines and/or taxanes in the metastatic setting, adequate bone marrow reserve, sufficient liver/renal function, no centralnervous system metastases, Karnovsky-performance-status >70%, and life expectancy >12 weeks. Forty-three patients were enrolled (median 58 years, range 48-71). A suspension of gemcitabine 1.200mg/m(2), 2-10 ml/m(2) of Lipiodol, and 5 ml of a degradable starch microsphere (Embocept) suspension, were administered intra-arterially up to 3 times with a 4-weaks-interval. Dose-limiting toxicit is defined as grade 4 thrombocytopenia, neutropenia, or nonhematologic toxicity>grade 3. Tumor response was evaluated by magnetic resonance (MRI) and computed tomography (CT) imaging. RESULTS: All patients tolerated the treatment well; with no dose limiting toxicities. Imaging follow-up according to the RECIST-criteria (Response Evaluation Criteria in Solid Tumors) revealed a partial response in 3 patients, stable disease in 16 patients and progression in 22 patients. The progression free survival was 3.3 months. A significant correlation exists only with the factor vascularization: strongly vascularized tumors show a significantly lowered response. Patients with complete or partial response and the main fraction of the stable disease group showed in the MRI and angiography only a moderate vascularization. The resulting estimate of the total survival rate amounts to a median of 10.2 months. CONCLUSION: Transarterial chemoembolization with gemcitabine is well tolerated and provides an alternative treatment method for patients with liver metastases of breast cancer. PMID- 24055390 TI - Low seroprevalence of hepatitis E virus infection in pregnant women in Yunnan, China. PMID- 24055391 TI - Methicillin-resistant and methicillin-susceptible community-acquired Staphylococcus aureus infection among children. AB - Methicillin-resistant Staphylococcus aureus has emerged as a pathogen associated with community-acquired infections worldwide. We report the spectrum of community acquired S. aureus infections and compare the patients infected with methicillin susceptible or methicillin-resistant strains among patients aged <20 years. Overall, 90 cases of community-acquired S. aureus were detected in an 11-year period. Clinical and microbiological data were registered. Fifty-nine (66%) patients were male and the median age was two years. The majority (87%) of the patients were hospitalized and chronic underlying illnesses were detected in 27 (30%) cases. Overall, 34 (37.8%) patients had skin/soft tissue infections and 56 (62.2%) patients had deep-seated infection. Four (5.1%) patients were transferred to the intensive care unit and two (2.6%) died. Complications were detected in 17 (18.9%) cases, such as pleural effusion (41.2%), osteomyelitis (23.5%), and sepsis (17.6%). Six (6.7%) methicillin-resistant strains were detected. Patients infected with methicillin-susceptible or methicillin-resistant strains had similar baseline characteristics and treatment outcomes. Approximately 93% of the cases received systemic antibiotics, out of which 59 (65.5%) used oxacillin or cefalotin. Both methicillin-susceptible and methicillin-resistant S. aureus strains resulted in morbidity and death among children in this setting where methicillin-resistant strains are infrequent. PMID- 24055392 TI - Lymphocytic myocarditis at autopsy in patients with dengue fever. PMID- 24055393 TI - Nosocomial infections caused by Elizabethkingia meningoseptica: an emergent pathogen. AB - We hereby describe the clinical and epidemiological features and, outcomes of nine patients with Elizabethkingia meningoseptica infections in two hospitals over a 2-year period. All infections caused by this pathogen were nosocomial, or healthcare associated infections, in hemodialysis settings whereas none was correlated with hospital outbreaks. PMID- 24055394 TI - Association between insulin resistance and sustained virologic response in hepatitis C treatment, genotypes 1 versus 2 and 3: systematic literature review and meta-analysis. AB - BACKGROUND/AIMS: Controversial results have been found in literature for the association between insulin resistance and sustained virologic response to standard chronic hepatitis C treatment. This study aims to provide a systematic literature review with meta-analysis, in order to evaluate if insulin resistance interferes with sustained virologic response in patients infected by the HCV genotype 1 versus HCV genotypes 2 and 3, undergoing treatment with interferon and ribavirin or pegylated interferon and ribavarin. METHODS: Systematic search was performed on main electronic databases until May 2012. Primary outcome was sustained virologic response, defined as undetectable levels of HCV-RNA six months after the end of treatment. Meta-analytic measure was estimated using Dersimonian and Laird's method, using Stata software. RESULTS: Thirteen studies involving 2238 infected patients were included. There was a statistically significant association between insulin resistance and lower sustained virologic response rate, and this difference occurred in HCV genotype G1 (OR: 2.23; 95% CI: 1.59-3.13) and G2/G3 (OR: 4.45; 95% CI: 1.59-12.49). In addition, a difference was seen in the cut-offs used for defining insulin resistance by Homeostasis Model Assessment of Insulin Resistance. To minimize this limitation, sub-analysis that excluded the studies that did not use 2 as a cut-off value was performed and the results still demonstrated association between insulin resistance and sustained virologic response, for both genotypic groups. CONCLUSION: This meta analysis provides evidence that elevated Homeostasis Model Assessment of Insulin Resistance is associated with a lower sustained virologic response rate in patients with hepatitis C treated with interferon and ribavirin or pegylated interferon and ribavarin, regardless of their genotype. PMID- 24055395 TI - Radiochromic film dosimetry: considerations on precision and accuracy for EBT2 and EBT3 type films. AB - Gafchromic(r) EBT2 film is a widely used dosimetric tool for quality assurance in radiation therapy. In 2012 EBT3 was presented as a replacement for EBT2 films. The symmetric structure of EBT3 films to reduce face-up/down dependency as well as the inclusion of a matte film surface to frustrate Newton Ring artifacts present the most prominent improvements of EBT3 films. The aim of this study was to investigate the characteristics of EBT3 films, to benchmark the films against the known EBT2-features and to evaluate the dosimetric behavior over a time period greater than 6 months. All films were irradiated to clinical photon beams (6 MV, 10 MV and 18 MV) on an Elekta Synergy Linac equipped with a Beam Modulator MLC in solid water phantom slabs. Film digitalization was done with a flatbed transparency scanner (Type Epson Expression 1680 Pro). MATLAB(r) was used for further statistical calculations and image processing. The investigations on post irradiation darkening, film orientation, film uniformity and energy dependency resulted in negligible differences between EBT2 and EBT3 film. A minimal improvement in face-up/down dependence was found for EBT3. The matte film surface of EBT3 films turned out to be a practical feature as Newton rings could be eliminated completely. Considering long-term behavior (> 6 months) a shift of the calibration curve for EBT2 and EBT3 films due to changes in the dynamic response of the active component was observed. In conclusion, the new EBT3 film yields comparable results to its predecessor EBT2. The general advantages of radiochromic film dosimeters are completed by high film homogeneity, low energy dependence for the observed energy range and a minimized face-up/down dependence. EBT2 dosimetry-protocols can also be used for EBT3 films, but the inclusion of periodical recalibration-interval (e.g. once a quarter) is recommended for protocols of both film generations. PMID- 24055396 TI - The science of implantation emerges blinking into the light. AB - Although embryo implantation is essential for human survival, it remains an enigmatic biological phenomenon. Following fertilization, the resulting blastocyst must signal its presence to the mother, attach to the luminal epithelium of the endometrium and embed into the decidualising stroma. Failure to do so results in infertility, which affects around 9% of women. Subsequent placental development requires remodelling of maternal blood vessels by trophoblast cells from the placenta, that invade deep into the decidua. Failure in these very early stages can compromise fetal development, resulting in diseases of pregnancy such as intrauterine growth restriction or pre-eclampsia which can also impact on health in adulthood. Abnormal implantation therefore constitutes a significant disease burden in humans. Although we have known for many years that successful implantation requires an embryo that is competent to implant and an endometrium that is receptive, the molecular basis of these processes remains poorly understood. Our inability to identify implantation competent embryos or to diagnose/treat the non-receptive endometrium therefore limits our ability to intervene through assisted reproduction techniques. This Implantation Symposium aims to review recent exciting developments in our understanding of the biology of early implantation and to highlight the rapid progress being made to translate these into improved diagnosis and treatment. PMID- 24055397 TI - Are assisted reproduction health professionals still letting down their patients? PMID- 24055398 TI - Enrichment and characterization of Thy1-positive male germline stem cells (mGSCs) from dairy goat (Capra hircus) testis using magnetic microbeads. AB - In mammalian testis, male germline stem cells (mGSCs) are originated from primordial germ cells and developed into spermatocyte and spermatid. In our previous studies, we had isolated a pluripotent mGSCs from goat testes and tested their pluripotency and differentiation potential in vitro and in vivo, which revealed that the isolated and cultured dairy goat mGSCs maintained the characteristics of mGSCs. However, Thy1, a marker of mGSCs, was not examined in detail. In this study, the dairy goat mGSCs were purified by differential plating followed by magnetic-activated cell sorting (MACS) using Thy1 antibody. The quantitative reverse transcription polymerase chain reaction and immunofluorescence analyses revealed that the transcription and expression of Thy1, CD49f, Plzf, Oct4, Gfra1, and Vasa were higher in Thy1-positive cells when compared with Thy1-negative cells. The detection results of culturing dairy goat mGSCs indicated that the Thy1-positive cells maintained the characteristics of mGSCs, grew relatively faster than Thy1-negative cells, and the percentage of alkaline phosphatase-positive cells and colonies were significantly higher in Thy1-positive mGSCs than Thy1-negative cells. Collectively, these results indicate that THY1 is a marker of undifferentiated spermatogonia in goat testes, the technique of magnetic-activated cell sorting using Thy1 antibody could be an efficient method to enrich mGSCs in goat. PMID- 24055399 TI - Genetic polymorphisms, growth performance, hematological parameters, serum enzymes, and reproductive characteristics in phenotypically normal Landrace boars produced by somatic cell nuclear transfer. AB - Understanding the performances of cloned pigs and their offspring is critical to evaluate the practical applications of somatic cell nuclear transfer. In this study, genetic polymorphism, growth performance, hematological parameters, and reproduction characteristics of cloned Landrace boars were compared with those of controls. In addition, the growth performance of clone offspring was also evaluated. A total of 479 reconstructed embryos were transferred to five recipient pigs and resulted in the delivery of 14 piglets (overall cloning of 2.9%) from two litters. Analyses of microsatellite markers and polymorphisms of the specific genes confirmed that the 14 clones were genetically identical to the nuclear donor and maintained the desirable genotypes. Growth performance of five healthy, phenotypically normal cloned boars from one litter and eight of their male offspring did not differ from age, breed, and management-matched controls. Although some significant differences were observed between cloned and control boars in hematological and serum enzymes, most of these parameters were within the normal range. Cloned boars had less (P < 0.05) normal sperm in the ejaculated boars than in control boars (71.4% vs. 77.9%, respectively), but sperm production (ejaculate volume, sperm concentration, and total sperm) did not differ between these groups. In addition, use of frozen-thawed semen from cloned boars for insemination produced results that seemed comparable to a control. In conclusion, the present study reported that somatic cell nuclear transfer is effective in reproducing preferred genetic traits and has potential applications to conserve elite bloodlines in a routine pig breeding program. PMID- 24055400 TI - miR-370 targeted FoxM1 functions as a tumor suppressor in laryngeal squamous cell carcinoma (LSCC). AB - microRNAs, a family of small non-coding RNAs, involve in the pathogenesis of several types of cancers, including laryngeal squamous cell carcinoma (LSCC). MiR 370 is frequently aberrant expressed in various types of human cancer including LSCC. However, the role for miR-370 in LSCC remains elusive. Here, we demonstrate that miR-370 was down-regulated in human LSCC tissues. Furthermore, there was an inverse relationship between Forkhead Box ml (FoxM1), which was up-regulated and miR-370 expression in LSCC tissues. FoxM1 was subsequently predicted by bioinformatics and verified to be a target of miR-370 by Luciferase reporter assay. Restored expression of miR-370 in Hep2 cells significantly inhibited cell proliferation. In conclusion, our results suggest that miR-370 may function as a tumor suppressor in LSCC through downregulation of FoxM1, suggesting that miR-370 could serve as a novel potential maker for LSCC therapy. PMID- 24055401 TI - Mitochondrial mutations and ageing: can mitochondrial deletion mutants accumulate via a size based replication advantage? AB - The mitochondrial theory of ageing is one of the main contenders to explain the biochemical basis of the ageing process. An important line of support comes from the observation that mtDNA deletions accumulate over the life course in post mitotic cells of many species. A single mutant expands clonally and finally replaces the wild-type population of a whole cell. One proposal to explain the driving force behind this accumulation states that the reduced size leads to a shorter replication time, which provides a selection advantage. However, this idea has been questioned on the grounds that the mitochondrial half-life is much longer than the replication time, so that the latter cannot be a rate limiting step. To clarify this question, we modelled this process mathematically and performed extensive deterministic and stochastic computer simulations to study the effects of replication time, mitochondrial half-life and deletion size. Our study shows that the shorter size does in principle provide a selection advantage, which can lead to an accumulation of the deletion mutant. However, this selection advantage diminishes the shorter is the replication time of wt mtDNA in relation to its half-life. Using generally accepted literature values, the resulting time frame for the accumulation of mutant mtDNAs is only compatible with the ageing process in very long lived species like humans, but could not reasonably explain ageing in short lived species like mice and rats. PMID- 24055402 TI - The parvalbumin-positive interneurons in the mouse dentate gyrus express GABAA receptor subunits alpha1, beta2, and delta along their extrasynaptic cell membrane. AB - Neuronal circuitries in the hippocampus are involved in navigation and memory and are controlled by major networks of GABAergic interneurons. Parvalbumin (PV) expressing interneurons in the dentate gyrus (DG) are identified as fast-spiking cells, playing a crucial role in network oscillation and synchrony. The inhibitory modulation of these interneurons is thought to be mediated mainly through GABAA receptors, the major inhibitory neurotransmitter receptors in the brain. Here we show that all PV-positive interneurons in the granular/subgranular layer (GL/SGL) of the mouse DG express high levels of the GABAA receptor delta subunit. PV-containing interneurons in the hilus and the molecular layer, however, express the delta subunit to a lower extent. Only 8% of the somatostatin containing interneurons express the delta subunit, whereas calbindin- or calretinin-containing interneurons in the DG seem not to express the GABAA receptor delta subunit at all. Hence, these cells receive a GABAergic control different from that of PV-containing interneurons in the GL/SGL. Experiments investigating a possible co-expression of GABAA receptor alpha1, alpha2, alpha3, alpha4, alpha5, beta1, beta2, beta3, or gamma2 subunits with PV and delta subunits indicated that alpha1 and beta2 subunits are co-expressed with delta subunits along the extrasynaptic membranes of PV-interneurons. These results suggest a robust tonic GABAergic control of PV-containing interneurons in the GL/SGL of the DG via delta subunit-containing receptors. Our data are important for better understanding of the neuronal circuitries in the DG and the role of specific cell types under pathological conditions. PMID- 24055403 TI - The role of androgen receptor in transcriptional modulation of cannabinoid receptor type 1 gene in rat trigeminal ganglia. AB - We have previously shown that anti-hyperalgesic effects of cannabinoid agonists under inflammatory condition are much greater in male than female, and that inflammatory cytokines upregulate cannabinoid receptor type 1 (CB1) expression in male, but not female, trigeminal ganglia (TG) in a testosterone-dependent manner. In this study, we investigated the mechanisms underlying the testosterone mediated regulation of peripheral CB1 expression. We hypothesized that testosterone upregulates CB1 through transcriptional modulation by androgen receptor (AR). Interleukin-1 beta (IL-1beta), a pro-inflammatory cytokine, upregulated CB1 mRNA expression in TG of male rats. The cytokine-induced upregulation was prevented by the pretreatment with flutamide, a specific antagonist for AR, but not by ICI 182,780, a specific antagonist for estrogen receptor, suggesting that the effects of testosterone are not mediated by estradiol, a testosterone metabolite. The expression levels of AR and IL-1beta receptors were comparable between male and female TG, suggesting that the male specific IL-1beta effects on CB1 upregulation occurs downstream to these receptors. The chromatin immunoprecipitation assay showed AR binding to the CB1 promoter in the rat TG. Furthermore, luciferase reporter assay revealed that AR activated the CB1 gene in response to testosterone or dihydrotestosterone treatment. These experiments provided compelling evidence that testosterone regulates CB1 gene transcription in TG through AR following cytokine stimulation. These results should provide mechanistic bases for understanding cytokine-hormone neuron interactions in peripheral cannabinoid systems, and have important clinical implications for pain patients in whom testosterone level is naturally low, gradually declining or pharmacologically compromised. PMID- 24055404 TI - Interneurons containing somatostatin are affected by learning-induced cortical plasticity. AB - The maintenance of neural circuit stability is a dynamic process that requires the plasticity of many cellular and synaptic components. By changing the excitatory/inhibitory balance, inhibitory GABAergic plasticity can regulate excitability, and contribute to neural circuit function and refinement in learning and memory. Increased inhibitory GABAergic neurotransmission has been shown in brain structures involved in the learning process. Previously, we showed that classical conditioning in which tactile stimulation of one row of vibrissae (conditioned stimulus, CS) was paired with a tail shock (unconditioned stimulus, UCS) in adult mice results in the increased density of GABAergic interneurons and increased expression of glutamic acid decarboxylase (GAD)-67 in barrels of the "trained" row cortical representation. In inhibitory neurons of the rat cortex GAD co-localizes with several proteins and peptides. We found previously that the density of the parvalbumin (GAD+/Prv+)-containing subpopulation is not changed after conditioning. In the present study, we examined GABAergic somatostatin (Som)-, calbindin (CB)- and calretinin (CR)-positive interneurons in the cortical representation of "trained" vibrissae after training. Cells showing double immunostaining for GAD/Som, GAD/CR and GAD/CB were counted in the barrels representing vibrissae activated during the training and in control, untouched rows. We found a substantial increase of GAD/Som-containing cells in the trained row representation. No changes in the density of GAD/CR or GAD/CB neurons were observed. These results suggest that Som-containing interneurons are involved in learning-induced changes in the inhibitory cortical network. PMID- 24055405 TI - Penile metastases of rectal adenocarcinoma. AB - INTRODUCTION: Penile metastases are very rare and arise most frequently from genitourinary cancers. Penile metastases from rectal adenocarcinoma are less common and only 50 or so cases have been reported. CASE PRESENTATION: We present a 43-year-old man with penile metastases from a rectal adenocarcinoma. Two years before admittance to our department, abdomino-perineal resection of the rectum (Miles operation) was performed for a Dukes B (T3N0M0) rectal adenocarcinoma; the surgical resection margins wee negative. Adjuvant chemotherapy and radiotherapy treatment were administered. One year after initial management, excision of a local recurrence was performed followed by further chemotherapy. The patient subsequently noticed lesions of the penis measuring up to 1.2 cm in diameter. Biopsy revealed metastatic adenocarcinoma. Computed tomography showed normal structure of penis with subcutaneous nodular thickening. Soon thereafter, the entire shaft of the penis becomes indurated and the patient developed urinary obstruction. A suprapubic cystostomy was performed. The patient died within 6 months. DISCUSSION: Penile metastases arise most frequently from genitourinary cancers, primarily from the bladder and the prostate gland. Metastasis to the penis from a rectal adenocarcinoma occurs much less commonly. Other reported primary origins of penile metastases include malignancies of the lung, nasopharynx and melanoma. The major symptoms are penile nodular mass, malignant priapism, penile pain and tenderness, difficulty in micturition, and urinary retention. Possible routes of metastasis are arterial, retrograde venous spread, retrograde lymphatic spread, but direct tumor infiltration/extension is also possible. Penile metastases from rectal adenocarcinoma usually occur within 2 years after diagnosis of the primary tumor. The prognosis is very poor regardless of treatment modality. Treatment is more often palliative than curative. Survival usually varies from 7 months to 2 years. Long-term survival (9 years) has been seen after aggressive surgical treatment (penile amputation) with best results for patients when penile metastasis was the only evident region of recurrence. CONCLUSION: The prognosis of metastasis to the penis is very poor; the best results have been achieved with surgery but only for lesions where metastasis is limited to the penis. PMID- 24055407 TI - Evaluating the fetus at risk for cardiopulmonary compromise. AB - The in-utero environment is relatively hypoxic, but fetal physiologic adaptation assures adequate tissue oxygen supply. Fetal reactions to acute or chronic hypoxia are different and are modified by the preceding fetal condition. Acute fetal hypoxia episodes are often not preventable. By contrast, good obstetric care during labor may prevent poor fetal outcome in many cases of acute fetal hypoxia. The pathophysiology of chronic fetal hypoxia caused by placental insufficiency differs from chronic fetal hypoxia seen during the last weeks of diabetic pregnancies. The efficacy of antenatal fetal surveillance methods in preventing perinatal complications is different in these two conditions. Electronic fetal heart rate testing and Doppler flow assessment methods have been successful in detecting chronic fetal hypoxia caused by placental insufficiency. However, these methods have been unable to prevent chronic fetal hypoxia complications in diabetic pregnancies. Therefore, research to find new strategies and early and reliable biomarkers is necessary to assess fetal well-being and to decide when to deliver the fetus. PMID- 24055408 TI - In regard to: Letter to the Editor "the impact of early life exposure to diagnostic and therapeutic radiation on childhood cancer risk". Phys Med 2013 29, 221-223. PMID- 24055406 TI - Driver mutations among never smoking female lung cancer tissues in China identify unique EGFR and KRAS mutation pattern associated with household coal burning. AB - Lung cancer in never smokers, which has been partially attributed to household solid fuel use (i.e., coal), is etiologically and clinically different from lung cancer attributed to tobacco smoking. To explore the spectrum of driver mutations among lung cancer tissues from never smokers, specifically in a population where high lung cancer rates have been attributed to indoor air pollution from domestic coal use, multiplexed assays were used to detect >40 point mutations, insertions, and deletions (EGFR, KRAS, BRAF, HER2, NRAS, PIK3CA, MEK1, AKT1, and PTEN) among the lung tumors of confirmed never smoking females from Xuanwei, China [32 adenocarcinomas (ADCs), 7 squamous cell carcinomas (SCCs), 1 adenosquamous carcinoma (ADSC)]. EGFR mutations were detected in 35% of tumors. 46% of these involved EGFR exon 18 G719X, while 14% were exon 21 L858R mutations. KRAS mutations, all of which were G12C_34G>T, were observed in 15% of tumors. EGFR and KRAS mutations were mutually exclusive, and no mutations were observed in the other tested genes. Most point mutations were transversions and were also found in tumors from patients who used coal in their homes. Our high mutation frequencies in EGFR exon 18 and KRAS and low mutation frequency in EGFR exon 21 are strikingly divergent from those in other smoking and never smoking populations from Asia. Given that our subjects live in a region where coal is typically burned indoors, our findings provide new insights into the pathogenesis of lung cancer among never smoking females exposed to indoor air pollution from coal. PMID- 24055409 TI - Trasferrin receptor 2 gene regulation by microRNA 221 in SH-SY5Y cells treated with MPP+ as Parkinson's disease cellular model. AB - Parkinson's disease (PD) is one of the most frequent human neurodegenerations. The neurodegeneration in PD is related to cellular iron increase but the mechanisms involved in iron accumulation remain unclear. Transferrin receptor type 2 (TFR2) is a protein expressed on cell membrane and involved in the cellular iron uptake. We hypothesized that microRNA 221 could regulate the expression of TfR2 in an in vitro model of Parkinson's disease, SH-SY5Y cells treated with MPP+. The miRNA 221 was selected by in silico analysis of several miRNAs predicted to target the TFR2 gene in SHSY5Y cells treated with MPP+. Taqman miRNA assay was used to evaluate the expression of the selected miRNAs. Using a luciferase assay we demonstrated the inhibition of TFR2 by miRNA 221. We show that in PD cellular model, TFR2 expression is regulated by miRNA 221. TFR2 and miR 221 are inversely correlated in SHSY5Y cells during the treatment with MPP+. Moreover, overexpression of miRNA 221 decreases the expression of TFR2, respectively, at the mRNA and protein levels. The inhibition of endogenous miRNA 221 also is able to regulate TFR2. These data suggest that miRNA 221 regulate TFR2 in PD model. PMID- 24055411 TI - Estimating the collapse of aggregated fine soil structure in a mountainous forested catchment. AB - This paper describes the relationship of forest soil dryness and antecedent rainfall with suspended sediment (SS) yield due to extreme rainfall events and how this relationship affects the survival of forest plants. Several phenomena contribute to this relationship: increasing evaporation (amount of water vapour discharged from soil) due to increasing air temperature, decreasing moisture content in the soil, the collapse of aggregates of fine soil particles, and the resulting effects on forest plants. To clarify the relationships among climate variation, the collapse of soil particle aggregates, and rainfall-runoff processes, a numerical model was developed to reproduce such aggregate collapse in detail. The validity of the numerical model was confirmed by its application to the granitic mountainous catchment of the Nagara River basin in Japan and by comparison with observational data. The simulation suggests that important problems, such as the collapse of forest plants in response to decreases in soil moisture content and antecedent rainfall, will arise if air temperature continues to increase. PMID- 24055410 TI - The effects of changing water content, relaxation times, and tissue contrast on tissue segmentation and measures of cortical anatomy in MR images. AB - Water content is the dominant chemical compound in the brain and it is the primary determinant of tissue contrast in magnetic resonance (MR) images. Water content varies greatly between individuals, and it changes dramatically over time from birth through senescence of the human life span. We hypothesize that the effects that individual- and age-related variations in water content have on contrast of the brain in MR images also have important, systematic effects on in vivo, MRI-based measures of regional brain volumes. We also hypothesize that changes in water content and tissue contrast across time may account for age related changes in regional volumes, and that differences in water content or tissue contrast across differing neuropsychiatric diagnoses may account for differences in regional volumes across diagnostic groups. We demonstrate in several complementary ways that subtle variations in water content across age and tissue compartments alter tissue contrast, and that changing tissue contrast in turn alters measures of the thickness and volume of the cortical mantle: (1) We derive analytic relations describing how age-related changes in tissue relaxation times produce age-related changes in tissue gray-scale intensity values and tissue contrast; (2) We vary tissue contrast in computer-generated images to assess its effects on tissue segmentation and volumes of gray matter and white matter; and (3) We use real-world imaging data from adults with either Schizophrenia or Bipolar Disorder and age- and sex-matched healthy adults to assess the ways in which variations in tissue contrast across diagnoses affects group differences in tissue segmentation and associated volumes. We conclude that in vivo MRI-based morphological measures of the brain, including regional volumes and measures of cortical thickness, are a product of, or at least are confounded by, differences in tissue contrast across individuals, ages, and diagnostic groups, and that differences in tissue contrast in turn likely derive from corresponding differences in water content of the brain across individuals, ages, and diagnostic groups. PMID- 24055412 TI - Effects of plateletpheresis on blood coagulation parameters in healthy donors at National Blood Centre, Kuala Lumpur, Malaysia. AB - Plateletpheresis is a method used to remove platelet from the body either from random volunteer donors, patient's family members or HLA matched donors. A cross sectional study was carried out on 59 plateletpheresis donors aged between 18 and 55 years at National Blood Center (NBC), Kuala Lumpur. We compared the blood parameters before and after plateletpheresis and we found that the platelet count, FVIII, fibrinogen and thrombophilia markers anti-thrombin (AT), protein C and protein S were significantly reduced (p<0.05) with prolonged PT and APTT. There were significant changes in blood coagulation parameters but it is within acceptable range. PMID- 24055413 TI - Histone deacetylase inhibitors in multiple myeloma. PMID- 24055414 TI - Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. AB - BACKGROUND: We aimed to assess efficacy and tolerability of vorinostat in combination with bortezomib for treatment of patients with relapsed or refractory multiple myeloma. METHODS: In our randomised, double-blind, placebo-controlled, phase 3 trial, we enrolled adults (>=18 years) at 174 university hospitals in 31 countries worldwide. Eligible patients had to have non-refractory multiple myeloma that previously responded to treatment (one to three regimens) but were currently progressing, ECOG performance statuses of 2 or less, and no continuing toxic effects from previous treatment. We excluded patients with known resistance to bortezomib. We randomly allocated patients (1:1) using an interactive voice response system to receive 21 day cycles of bortezomib (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11) in combination with oral vorinostat (400 mg) or matching placebo once-daily on days 1-14. We stratified patients by baseline tumour stage (International Staging System stage 1 or stage >=2), previous bone-marrow transplantation (yes or no), and number of previous regimens (1 or >=2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed adverse events in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number 00773747. FINDINGS: Between Dec 24, 2008, and Sept 8, 2011, we randomly allocated 317 eligible patients to the vorinostat group (315 of whom received at least one dose) and 320 to the placebo group (all of whom received at least one dose). Median PFS was 7.63 months (95% CI 6.87-8.40) in the vorinostat group and 6.83 months (5.67-7.73) in the placebo group (hazard ratio [HR] 0.77, 95% CI 0.64 0.94; p=0.0100). 312 (99%) of 315 patients in the vorinostat group and 315 (98%) of 320 patients in the placebo group had adverse events (300 [95%] adverse events in the vorinostat group and 282 [88%] in the control group were regarded as related to treatment). The most common grade 3-4 adverse events were thrombocytopenia (143 [45%] patients in the vorinostat group vs 77 [24%] patients in the placebo group), neutropenia (89 [28%] vs 80 [25%]), and anaemia (53 [17%] vs 40 [13%]). INTERPRETATION: Although the combination of vorinostat and bortezomib prolonged PFS relative to bortezomib and placebo, the clinical relevance of the difference in PFS between the two groups is not clear. Different treatment schedules of bortezomib and vorinostat might improve tolerability and enhance activity. FUNDING: Merck. PMID- 24055415 TI - The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. AB - BACKGROUND: 5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10 year follow-up of the START trials testing 13 fraction and 15 fraction regimens. METHODS: From 1999 to 2002, women with completely excised invasive breast cancer (pT1-3a, pN0-1, M0) were enrolled from 35 UK radiotherapy centres. Patients were randomly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment (where prescribed). Randomisation was computer-generated and stratified by centre, type of primary surgery (breast conservation surgery or mastectomy), and tumour bed boost radiotherapy. In START A, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41.6 Gy or 39 Gy in 13 fractions over 5 weeks. In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. Eligibility criteria included age older than 18 years and no immediate surgical reconstruction. Primary endpoints were local-regional tumour relapse and late normal tissue effects. Analysis was by intention to treat. Follow-up data are still being collected. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: START-A enrolled 2236 women. Median follow-up was 9.3 years (IQR 8.0-10.0), after which 139 local regional relapses had occurred. 10-year rates of local-regional relapse did not differ significantly between the 41.6 Gy and 50 Gy regimen groups (6.3%, 95% CI 4.7-8.5 vs 7.4%, 5.5-10.0; hazard ratio [HR] 0.91, 95% CI 0.59-1.38; p=0.65) or the 39 Gy (8.8%, 95% CI 6.7-11.4) and 50 Gy regimen groups (HR 1.18, 95% CI 0.79 1.76; p=0.41). In START-A, moderate or marked breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group. Normal tissue effects did not differ significantly between 41.6 Gy and 50 Gy groups. START-B enrolled 2215 women. Median follow-up was 9.9 years (IQR 7.5-10.1), after which 95 local-regional relapses had occurred. The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group (4.3%, 95% CI 3.2 5.9) and the 50 Gy group (5.5%, 95% CI 4.2-7.2; HR 0.77, 95% CI 0.51-1.16; p=0.21). In START-B, breast shrinkage, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group. INTERPRETATION: Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer. The results support the continued use of 40 Gy in 15 fractions, which has already been adopted by most UK centres as the standard of care for women requiring adjuvant radiotherapy for invasive early breast cancer. FUNDING: Cancer Research UK, UK Medical Research Council, UK Department of Health. PMID- 24055417 TI - Dyslipidemia and kidney stone risk. AB - PURPOSE: We studied the impact of dyslipidemia on 24-hour urinalysis and stone composition. MATERIALS AND METHODS: We retrospectively identified patients with nephrolithiasis who underwent 24-hour urinalysis and lipid profile evaluation within 3 months. Patients were divided into groups based on total cholesterol, high density lipoprotein, nonhigh density lipoprotein and triglycerides. The groups were compared based on demographic data, diabetes, hypertension and each component of 24-hour urinalysis and stone composition. Multivariate analysis and linear regression were performed to control for potential confounders, including age, gender, body mass index, diabetes and hypertension. RESULTS: A total of 2,442 patients with a mean age of 51.1 years were included in study. On multivariate analysis patients with high total cholesterol had significantly higher urinary potassium and calcium, those with low high density lipoprotein or high triglycerides had significantly higher urinary sodium, oxalate and uric acid with lower pH, and those with high nonhigh density lipoprotein had higher urinary sodium and uric acid. Regarding stone composition, high total cholesterol and triglycerides were significantly associated with a higher uric acid stone rate (p = 0.006 and <0.001, respectively). Linear regression showed a significant association of nonhigh density lipoprotein with higher urinary sodium (p = 0.011) and uric acid (p <0.001) as well as triglycerides and higher uric acid (p = 0.017), and lower urinary pH (p = 0.005). CONCLUSIONS: There is a link between dyslipidemia and kidney stone risk that is independent of other components of metabolic syndrome such as diabetes and obesity. Specific alterations in the patient lipid profiles may portend unique aberrations in urine physicochemistry and stone risk. PMID- 24055416 TI - Emotional reactivity and its impact on neural circuitry for attention-emotion interaction in childhood and adolescence. AB - Attention modulation when confronted with emotional stimuli is considered a critical aspect of executive function, yet rarely studied during childhood and adolescence, a developmental period marked with changes in these processes. We employed a novel, and child-friendly fMRI task that used emotional faces to investigate the neural underpinnings of the attention-emotion interaction in a child and adolescent sample (n=23, age M=13.46, SD=2.86, range=8.05-16.93 years). Results implied modulation of activation in the orbitofrontal cortex (OFC) due to emotional distractor valence, which marginally correlated with participant age. Additionally, parent-reported emotional reactivity predicted the trajectory of BOLD signal increase for fearful emotional face distractors such that participants low in emotional reactivity had a steeper latency to peak activation. Results imply that the use of the OFC to modulate attention in the face of social/emotional stimuli may mature with age and may be tightly coupled with adaptive emotional functioning. Findings are discussed in the context of risk for the development of psychiatric disorders, where increased emotional reactivity is particularly apparent. PMID- 24055418 TI - Crystallization of high-strength nano-scale leucite glass-ceramics. AB - OBJECTIVES: Fine-grained, high strength, translucent leucite dental glass ceramics are synthesized via controlled crystallization of finely milled glass powders. The objectives of this study were to utilize high speed planetary milling of an aluminosilicate glass for controlled surface crystallization of nano-scale leucite glass-ceramics and to test the biaxial flexural strength. METHODS: An aluminosilicate glass was synthesized, attritor or planetary milled and heat-treated. Glasses and glass-ceramics were characterized using particle size analysis, X-ray diffraction and scanning electron microscopy. Experimental (fine and nanoscale) and commercial (Ceramco-3, IPS Empress Esthetic) leucite glass-ceramics were tested using the biaxial flexural strength (BFS) test. Gaussian and Weibull statistics were applied. RESULTS: Experimental planetary milled glass-ceramics showed an increased leucite crystal number and nano-scale median crystal sizes (0.048-0.055 MUm(2)) as a result of glass particle size reduction and heat treatments. Experimental materials had significantly (p<0.05) higher mean BFS and characteristic strength values than the commercial materials. Attritor milled and planetary milled (2h) materials showed no significant (p>0.05) strength difference. All other groups' mean BFS and characteristic strengths were found to be significantly different (p<0.05) to each other. The mean (SD) MPa strengths measured were: Attritor milled: 252.4 (38.7), Planetary milled: 225.4 (41.8) [4h milling] 255.0 (35.0) [2h milling], Ceramco-3: 75.7 (6.8) and IPS Empress: 165.5 (30.6). SIGNIFICANCE: Planetary milling enabled synthesis of nano-scale leucite glass-ceramics with high flexural strength. These materials may help to reduce problems associated with brittle fracture of all ceramic restorations and give reduced enamel wear. PMID- 24055419 TI - Understanding alternative fluxes/effluxes through comparative metabolic pathway analysis of phylum actinobacteria using a simplified approach. AB - Actinobacteria are known for their diverse metabolism and physiology. Some are dreadful human pathogens whereas some constitute the natural flora for human gut. Therefore, the understanding of metabolic pathways is a key feature for targeting the pathogenic bacteria without disturbing the symbiotic ones. A big challenge faced today is multiple drug resistance by Mycobacterium and other pathogens that utilize alternative fluxes/effluxes. With the availability of genome sequence, it is now feasible to conduct the comparative in silico analysis. Here we present a simplified approach to compare metabolic pathways so that the species specific enzyme may be traced and engineered for future therapeutics. The analyses of four key carbohydrate metabolic pathways, i.e., glycolysis, pyruvate metabolism, tri carboxylic acid cycle and pentose phosphate pathway suggest the presence of alternative fluxes. It was found that the upper pathway of glycolysis was highly variable in the actinobacterial genomes whereas lower glycolytic pathway was highly conserved. Likewise, pentose phosphate pathway was well conserved in contradiction to TCA cycle, which was found to be incomplete in majority of actinobacteria. The clustering based on presence and absence of genes of these metabolic pathways clearly revealed that members of different genera shared identical pathways and, therefore, provided an easy method to identify the metabolic similarities/differences between pathogenic and symbiotic organisms. The analyses could identify isoenzymes and some key enzymes that were found to be missing in some pathogenic actinobacteria. The present work defines a simple approach to explore the effluxes in four metabolic pathways within the phylum actinobacteria. The analysis clearly reflects that actinobacteria exhibit diverse routes for metabolizing substrates. The pathway comparison can help in finding the enzymes that can be used as drug targets for pathogens without effecting symbiotic organisms within the same host. This may help to prevail over the multiple drug resistance, for designing broad spectrum drugs, in food industries and other clinical research areas. PMID- 24055420 TI - Ossification of the posterior longitudinal ligament related genes identification using microarray gene expression profiling and bioinformatics analysis. AB - Ossification of the posterior longitudinal ligament (OPLL) is a kind of disease with physical barriers and neurological disorders. The objective of this study was to explore the differentially expressed genes (DEGs) in OPLL patient ligament cells and identify the target sites for the prevention and treatment of OPLL in clinic. Gene expression data GSE5464 was downloaded from Gene Expression Omnibus; then DEGs were screened by limma package in R language, and changed functions and pathways of OPLL cells compared to normal cells were identified by DAVID (The Database for Annotation, Visualization and Integrated Discovery); finally, an interaction network of DEGs was constructed by string. A total of 1536 DEGs were screened, with 31 down-regulated and 1505 up-regulated genes. Response to wounding function and Toll-like receptor signaling pathway may involve in the development of OPLL. Genes, such as PDGFB, PRDX2 may involve in OPLL through response to wounding function. Toll-like receptor signaling pathway enriched genes such as TLR1, TLR5, and TLR7 may involve in spine cord injury in OPLL. PIK3R1 was the hub gene in the network of DEGs with the highest degree; INSR was one of the most closely related genes of it. OPLL related genes screened by microarray gene expression profiling and bioinformatics analysis may be helpful for elucidating the mechanism of OPLL. PMID- 24055421 TI - A splice donor site mutation in HOXD13 underlies synpolydactyly with cortical bone thinning. AB - Synpolydactyly 1(SPD1) is a dominantly inherited distal limb anomaly that is characterized by incomplete digit separation and increased number of digits. SPD1 is most commonly caused by polyalanine repeat expansions and mutations in the homeodomain of the HOXD13. We report a splice donor site mutation in HOXD13 associated in most cases with cortical bone thinning. In vitro study of transcripts and truncated protein analysis indicated that c.781+1G>A mutation results in truncated HOXD13 protein p.G190fsX4. Luciferase assay indicated that the truncated HOXD13 protein failed to bind to DNA. The mechanism for this phenotype was truncated protein loss of function. PMID- 24055422 TI - Effects of myogenin on muscle fiber types and key metabolic enzymes in gene transfer mice and C2C12 myoblasts. AB - Skeletal muscle fiber type composition is one of the important factors influencing muscle growth and meat quality. As a member of the myogenic transcription factors, myogenin (MyoG) is required for embryonic myoblast differentiation, but the expression of MyoG continues in mature muscle tissue of adult animals, especially in oxidative metabolic muscle, which suggests that MyoG may play a more extended role. Therefore, using MyoG gene transfer mice and C2C12 myoblasts as in vivo and in vitro models, respectively, we elected to study the role of MyoG in muscle fiber types and oxidative metabolism by using overexpression and siRNA suppression strategies. The overexpression of MyoG by DNA electroporation in mouse gastrocnemius muscle had no significant effect on fiber type composition but upregulated the mRNA expression (P<0.01) and enzyme activity (P<0.05) of oxidative succinic dehydrogenase (SDH). In addition, downregulation of the activity of the glycolytic enzymes lactate dehydrogenase (LDH, P<0.05) and pyruvate kinase (PK, P<0.05) was observed in MyoG gene transfer mice. In vitro experiments verified the results obtained in mice. Stable MyoG transfected differentiating C2C12 cells showed higher mRNA expression levels of myosin heavy chain (MyHC) isoform IIX (P<0.01) and SDH (P<0.05), while the LDH mRNA was attenuated. The enzyme activities of SDH (P<0.01) and LDH (P<0.05) were similarly altered at the mRNA level. When MyoG was knocked down in C2C12 cells, MyHC IIX expression (P<0.05) was decreased, but the mRNA level (P<0.05) and the enzyme activity (P<0.05) of SDH were increased. Downregulating MyoG also increased the activity of the glycolytic enzymes PK (P<0.05) and hexokinase (HK, P<0.05). Based on those results, we concluded that MyoG barely changes the MyHC isoforms, except MyHC IIX, in differentiating myoblasts but probably influences the shift from glycolytic metabolism towards oxidative metabolism both in vivo and in vitro. These results contribute to further understand the role of MyoG in skeletal muscle energy metabolism and also help to explore the key genes that regulate meat quality. PMID- 24055423 TI - Identification and characterization of FaSOC1, a homolog of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 from strawberry. AB - A MADS-box gene SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) integrates multiple flowering signals to regulate floral transition in Arabidopsis. Strawberry (Fragaria spp.) is an economically important fruit crop, but its molecular control of flowering is largely unknown. In this study, a SOC1-like gene, FaSOC1, was isolated and characterized from strawberry. The open reading frame of FaSOC1 was 648bp, encoding a protein of 215 amino acids. Sequence alignment and phylogenetic analysis showed that the FaSOC1 protein contained a highly conserved MADS domain and a SOC1 motif, and that it was a member of the SOC1-like genes of dicots. The FaSOC1 protein mainly localized in the cytoplasm of onion epidermal cells and Arabidopsis protoplasts, and showed no transcriptional activation activity in yeast cells. Under the floral induction conditions, the expression of FaSOC1 increased during the first 2weeks of short day treatment, but declined dramatically during three to 4weeks. FaSOC1 was highly expressed in reproductive organs, including shoot apices, floral buds, flowers, stamens and sepals. Overexpression of FaSOC1 in wild-type Arabidopsis caused early flowering and upregulated the expression of flowering time genes LFY and AP1. In addition, the yeast two-hybrid and BiFC assays confirmed that FaSOC1 could interact with AGL24. In conclusion, these results suggest that FaSOC1 is a flowering promoter in strawberry. PMID- 24055424 TI - Gudu, an Armadillo repeat-containing protein, is required for spermatogenesis in Drosophila. AB - The Drosophila annotated gene CG5155 encodes a protein that contains 10 Armadillo repeats and has an unknown function. To fill this gap, we performed loss-of function studies using RNAi. By analysis of four independent Drosophila RNAi lines targeting two non-overlapping regions of the CG5155 transcript, we demonstrate that this gene is required for male fertility. Therefore, we have named this gene Gudu. The transcript of Gudu is highly enriched in adult testes. Knockdown of Gudu by a ubiquitous driver leads to defects in the formation of the individualization complex that is required for spermatid maturation, thereby impairing spermatogenesis. Furthermore, testis-specific knockdown of Gudu by crossing the RNAi lines with the bam-Gal4 driver is sufficient to cause the infertility and defective spermatogenesis. Since Gudu is highly homologous to vertebrate ARMC4, also an Armadillo-repeat-containing protein enriched in testes, our results suggest that Gudu and ARMC4 are a subfamily of Armadillo-repeat containing proteins that may have an evolutionarily conserved function in spermatogenesis. PMID- 24055425 TI - Does increasing the nodal yield improve outcomes in contemporary patients without nodal metastasis undergoing radical prostatectomy? AB - OBJECTIVES: To determine if the number of lymph nodes (LNs) removed is an independent predictor of biochemical recurrence (BCR) in patients without LN metastases undergoing radical prostatectomy (RP). MATERIAL AND METHODS: Retrospective analysis of 7,310 patients treated at 7 centers with RP and pelvic LN dissection for clinically localized prostate cancer between 2000 and 2011. Patients with LN metastases (n = 398) and other reasons (stated later in the article) (n = 372) were excluded, which left 6,540 patients for the final analyses. RESULTS: Overall, median biopsy and RP Gleason score were both 7; median prostate specific antigen level was 6 ng/ml (interquartile range [IQR]: 5); and median number of LNs removed was 6 (IQR: 8). A total of 3,698 (57%), 2,064 (32%), and 508 (8%) patients had >= 6, >= 10, and >= 20 LNs removed, respectively. Patients with more LNs removed were older, had a higher prostate specific antigen level, had higher clinical and pathologic T stage, and had higher RP Gleason score (all P<0.002). Within a median follow-up of 21 (IQR: 16) months, more LNs removed was associated with an increased risk of BCR (continuous: P = 0.021; categorical: P = 0.014). In multivariable analyses that adjusted for the effects of standard clinicopathologic factors, none of the nodal stratifications predicted BCR. CONCLUSIONS: The number of LNs did not have any prognostic significance in our contemporary cohort of patients with LN-negative prostate cancer. This suggests that the risk of missed clinically significant micrometastasis may be minimal in patients currently treated with RP and having a lower LN yield. PMID- 24055426 TI - Predicting response to bacillus Calmette-Guerin (BCG) in patients with carcinoma in situ of the bladder. AB - PURPOSE: Currently, there is no reliable tool to predict response to intravesical bacillus Calmette-Guerin (BCG). Based on the fact that BCG is a Th1-polarizing immunotherapy, we attempt to correlate the pretreatment immunologic tumor microenvironment (Th1 or Th2) with response to therapy. MATERIALS AND METHODS: Bladder cancer patients with initial diagnosis of carcinoma in situ (Tis) were stratified based on their response to BCG treatment. A total of 38 patients met inclusion criteria (20 patients who responded and 18 patients who did not respond). Immunohistochemical (IHC) methods known to assess the type of immunologic microenvironment (Th1 vs. Th2) were performed on tumor tissue obtained at initial biopsy/resection: the level of tumor eosinophil infiltration and degranulation (Th2 response); the number of tumor-infiltrating GATA-3(+) (Th2 polarized) lymphocytes; and the number of tumor-infiltrating T-bet(+) (Th1 polarized) lymphocytes. Results obtained from these metrics were correlated with response to treatment with BCG immunotherapy. RESULTS: The IHC metrics of the tumor immune microenvironment prior to BCG treatment were each statistically significant predictors of responders (R) vs. nonresponders (NR). Eosinophil infiltration and degranulation was higher for R vs. NR: 1.02 +/- 0.17 vs. 0.5 +/- 0.12 (P = 0.01) and 1.1 +/- 0.15 vs. 0.56 +/- 0.15 (P = 0.04), respectively. Ratio of GATA-3(+) (Th2-polarized) lymphocytes to T-bet(+) (Th1-polarized) lymphocytes was higher for R vs. NR: 4.85 +/- 0.94 vs. 0.98 +/- 0.19 (P<0.001). The 3 markers were combined to create a Th2 signature biomarker, which was a statistically significant (P<0.0001) predictor of R vs. NR. All IHC markers demonstrated that a preexisting Th1 immunologic environment within the tumor was predictive of BCG failure. CONCLUSION: The Th1 vs. Th2 polarization of bladder tumor immune microenvironment prior to treatment with BCG represents a prognostic metric of response to therapy. If a patient has a preexisting Th1 immunologic response within the tumor, there is no value in using a therapy intended to create a Th1 immunologic response. An algorithm integrating 3 IHC methods provided a sensitive and specific technique that may become a useful tool for pathologists and urologists to predict response to BCG in patients with carcinoma in situ of the bladder. PMID- 24055427 TI - Differentiating progressive from nonprogressive T1 bladder cancer by gene expression profiling: applying RNA-sequencing analysis on archived specimens. AB - OBJECTIVES: To identify gene signatures in transitional cell carcinoma that can differentiate high-grade T1 nonprogressive (T1NP) bladder cancer (BCa) from those T1 progressive (T1P) tumors that progress to muscularis propria-invasive T2 tumors. MATERIALS AND METHODS: We performed a high-throughput RNA sequencing (RNA Seq) on formalin-fixed and paraffin-embedded BCa specimens with clinical pathologic characteristics best representing the general clinical development of the disease. For the T1NP group, only patients with long-term follow-up (6-17y) and periodic examinations (average of 4 resections and 9 cytology tests) were selected. For the T1P group, only patients in whom a complete resection was performed after a minimum of 8 months after the initial T1 diagnosis were selected, therefore eliminating the possibility of underdiagnosis. Only samples in which muscularis propria was present and uninvolved were included, further assuring a correct diagnosis. The RNA-Seq reads were mapped to the human genome build NCBI 36 (hg18) using TopHat with no mismatch. After alignment to the transcriptome and expression quantification, a linear statistical model was built using Limma between T1NP and T1P samples to identify differentially expressed genes. RESULTS: Overall, 5,561 genes were mapped to all samples and used for RNA Seq analysis to identify a gene signature that was significantly and differentially expressed between patients with T1NP BCa and patients with T1P BCa. Signature-based stratification indicated the gene signature correlated notably with the time of T1 development to T2 tumor, suggesting that the molecular signature might be used as an independent predictor for the pace of high-grade T1 BCa progression. CONCLUSIONS: This is the first demonstration that RNA-Seq can be applied as a powerful tool to study BCa using formalin-fixed and paraffin-embedded specimens. We identified a gene signature that can distinguish patients diagnosed with high-grade T1 BCas that remain as non-muscle invasive tumors from those patients with cancers progressing to muscle-invasive tumors. Our findings will make future large-scale clinical cohort studies and clinical trial-based studies possible and help the development of prognostic tools for accurate prediction of T1 BCa progression that may considerably influence the clinical decision-making process, treatment regimen, and patient survival. PMID- 24055428 TI - Posttreatment prognostic nomogram for patients with metastatic urothelial cancer completing first-line cisplatin-based chemotherapy. AB - BACKGROUND: Models to predict the outcome of patients with metastatic urothelial cancer (UC), based on pretreatment variables, have previously been developed. However, patients often request "updated" prognostic estimates based upon their response to treatment. PATIENTS AND METHODS: Data were pooled from 317 patients enrolled in 8 trials evaluating first-line cisplatin-based chemotherapy in metastatic UC. Variables were combined in the Cox proportional hazards model to produce a nomogram to predict survival from the end of treatment. The nomogram was validated externally using data from a phase III trial. RESULTS: The median survival from end of treatment was 10.65 months (95% confidence interval; 9.20 13.24); 69% of patients had died. Baseline and posttreatment variables were evaluated. Baseline performance status, baseline number of visceral metastatic sites, baseline white blood counts, and response to treatment were included in the final model. The nomogram achieved a bootstrap-corrected concordance index of 0.68. Upon external validation, the nomogram achieved a concordance index of 0.67. CONCLUSIONS: A model derived from pretreatment and posttreatment variables was constructed to predict survival from the completion of first-line chemotherapy in patients with metastatic UC. This model may be useful for patient counseling and for stratification of trials exploring "maintenance" therapy. PMID- 24055429 TI - The predictive value of positive urine cytology for outcomes following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma: a multi-institutional study. AB - BACKGROUND AND OBJECTIVE: Few studies have addressed the predictive value of positive urine cytology for prognosis in patients with upper tract urothelial carcinoma (UTUC). We investigated whether the status of preoperative urine cytology could provide additional prognostic information following radical nephroureterectomy (RNU). MATERIALS AND METHODS: The study included 474 patients with primary nonmetastatic UTUC (pTa-4N0M0) from a retrospective multi institutional cohort. The median follow-up period was 35 months. Associations between the status of urine cytologic evaluation and outcomes were analyzed using multivariate Cox regression models. Urine cytology was evaluated preoperatively using voided samples. Disease recurrence was defined as any relapse in nonbladder lesions and was coded separately from intravesical recurrence. RESULTS: Positive urine cytology was detected in 184 patients (38.8%) preoperatively. Disease recurrence occurred in 127 patients, while intravesical recurrence occurred in 219 patients; 83 patients died of UTUC during follow-up. Kaplan-Meier analysis revealed that only the incidence of intravesical recurrence was significantly associated with the status of urine cytologic evaluation (P = 0.024); the intravesical recurrence-free survival rates at 1 and 3 years following RNU were 61.4% and 46.2% in patients with positive urine cytology and 71.1% and 51.6% in their counterparts, respectively. Multivariate analysis showed that gender (hazard ratio [HR] = 1.74, 95% confidence interval [CI]; 1.28-2.43), tumor multifocality in RNU specimens (HR = 1.64, 95% CI; 1.09-2.47), and positive urine cytology (HR = 1.41, 95% CI; 1.08-1.85) were independent risk factors for subsequent intravesical recurrence. CONCLUSIONS: The results showed the prognostic value of positive urine cytology in patients with primary UTUC, and preoperative positive urine cytology may be associated with a significant increase in the prevalence of intravesical recurrence following RNU. PMID- 24055430 TI - The accuracy of multiparametric MRI in men with negative biopsy and elevated PSA level--can it rule out clinically significant prostate cancer? AB - PURPOSE: To assess the performance of multiparametric magnetic resonance imaging (mp-MRI) in patients with previous negative transrectal ultrasound (TRUS) guided prostate biopsy. MATERIALS AND METHODS: Fifty-four patients with at least 1 previous negative TRUS prostate biopsy underwent mp-MRI in the form of T2 weighted, diffusion-weighted, and dynamic contrast-enhanced imaging. This was followed by transperineal template systematic prostate biopsies. Analysis was done based on 2 sectors per prostate, right and left (108 sectors out of 54 prostates). mp-MRI was scored using an ordinal scale 1 to 5 based on the suspicion of the presence of clinically significant disease. We used 6 different definitions for clinically significant disease and tested the performance of mp MRI at each single definition. RESULTS: Median age was 64 (range, 39-75), median PSA level was 10 (range, 2-23), and median number of biopsies was 45 (range, 21 137). Cancer of any volume and any grade was detected in 34 of 54 (63%) patients. mp-MRI accuracy at detection of clinically significant cancer using University College London (UCL) definition 2 (any Gleason score of 4 or maximum cancer core length of >= 4 mm or both) showed sensitivity of 76%, specificity of 42%, positive predictive value of 38%, and negative predictive value of 79%. For a different definition of significant tumor (UCL definition 1; dominant Gleason score 4 or maximum cancer core length >= 6 mm or both), the sensitivity was 90%, specificity 42%, positive predictive value 26%, and negative predictive value 95%. CONCLUSIONS: mp-MRI showed good performance at both detection and ruling out clinically significant disease, according to the definition used. mp-MRI can then be used as a triage test in the population with persistently elevated or rising PSA levels to select patients that can avoid unnecessary prostate biopsy. PMID- 24055431 TI - Single-incision mini-slings versus standard midurethral slings in surgical management of female stress urinary incontinence: an updated systematic review and meta-analysis of effectiveness and complications. AB - CONTEXT: An updated systematic review and meta-analysis of randomised controlled trials (RCTs) comparing single-incision mini-slings (SIMS) versus standard midurethral slings (SMUS) in the surgical management of female stress urinary incontinence (SUI). OBJECTIVE: To evaluate the clinical efficacy, safety, and cost effectiveness of SIMS compared with SMUS in the treatment of female SUI. EVIDENCE ACQUISITION: A literature search was performed for all RCTs and quasi RCTs comparing SIMS with either transobturator tension-free vaginal tape (TO-TVT) or retropubic tension-free vaginal tape (RP-TVT). The literature search had no language restrictions and was last updated on May 2, 2013. The primary outcomes were patient-reported and objective cure rates at 12 to 36 mo follow-up. Secondary outcomes included operative data; peri- and postoperative complications, and repeat continence surgery. Data were analysed using RevMan software. Meta-analyses of TVT-Secur versus SMUS are presented separately as the former was recently withdrawn from clinical practice. EVIDENCE SYNTHESIS: A total of 26 RCTs (n=3308 women) were included. After excluding RCTs evaluating TVT Secur, there was no evidence of significant differences between SIMS and SMUS in patient-reported cure rates (risk ratio [RR]: 0.94; 95% confidence interval [CI], 0.88-1.00) and objective cure rates (RR: 0.98; 95% CI, 0.94-1.01) at a mean follow-up of 18.6 mo. These results pertained on comparing SIMS versus TO-TVT and RP-TVT separately. SIMS had significantly lower postoperative pain scores (weighted means difference [WMD]: -2.94; 95% CI, -4.16 to -1.73) and earlier return to normal activities and to work (WMD: -5.08; 95% CI, -9.59 to -0.56 and WMD: -7.20; 95% CI, -12.43 to -1.98, respectively). SIMS had a nonsignificant trend towards higher rates of repeat continence surgery (RR: 2.00; 95% CI, 0.93 4.31). CONCLUSIONS: This meta-analysis shows that, excluding TVT-Secur, there was no evidence of significant differences in patient-reported and objective cure between currently used SIMS and SMUS at midterm follow-up while associated with more favourable recovery time. Results should be interpreted with caution due to the heterogeneity of the trials included. PMID- 24055432 TI - Incontinence: do we speak the same language? PMID- 24055433 TI - Retrospective studies on active surveillance for low-risk prostate cancer: beware of a narrow view of the matter. PMID- 24055434 TI - Post-mitotic role of the cell cycle machinery. AB - The process of cell division is highly complex. The DNA of the genome must be accurately replicated and segregated into two precisely equal portions; the cytoskeleton must be actively rearranged; and the cellular motor forces that allow the separation of the replicated chromosomes and the splitting of the mother cell into two daughters must be kept under strict spatial and temporal regulation. Not surprisingly for a process of this complexity, there is a wide range of proteins whose location and activity must be accurately controlled to ensure both efficiency and precision. Although the demands placed on these cell cycle proteins are high, once cells such as neurons differentiate they enter a long non-mitotic phase where evolution has conspired to repurpose many of these proteins, leading them to assume new and often unrelated cellular tasks. In neurons there is a wide range of non-cycling functions for these 'cell cycle' proteins and this review covers some of the best-known examples. There is little apparent logic to the second use, but the sheer number of examples suggests that there must be a significant evolutionary advantage to this repurposing strategy. PMID- 24055435 TI - Characterization and multi-step transketolase-omega-transaminase bioconversions in an immobilized enzyme microreactor (IEMR) with packed tube. AB - The concept of de novo metabolic engineering through novel synthetic pathways offers new directions for multi-step enzymatic synthesis of complex molecules. This has been complemented by recent progress in performing enzymatic reactions using immobilized enzyme microreactors (IEMR). This work is concerned with the construction of de novo designed enzyme pathways in a microreactor synthesizing chiral molecules. An interesting compound, commonly used as the building block in several pharmaceutical syntheses, is a single diastereoisomer of 2-amino-1,3,4 butanetriol (ABT). This chiral amino alcohol can be synthesized from simple achiral substrates using two enzymes, transketolase (TK) and transaminase (TAm). Here we describe the development of an IEMR using His6-tagged TK and TAm immobilized onto Ni-NTA agarose beads and packed into tubes to enable multi-step enzyme reactions. The kinetic parameters of both enzymes were first determined using single IEMRs evaluated by a kinetic model developed for packed bed reactors. The Km(app) for both enzymes appeared to be flow rate dependent, while the turnover number kcat was reduced 3 fold compared to solution-phase TK and TAm reactions. For the multi-step enzyme reaction, single IEMRs were cascaded in series, whereby the first enzyme, TK, catalyzed a model reaction of lithium hydroxypyruvate (HPA) and glycolaldehyde (GA) to L-erythrulose (ERY), and the second unit of the IEMR with immobilized TAm converted ERY into ABT using (S) alpha-methylbenzylamine (MBA) as amine donor. With initial 60mM (HPA and GA each) and 6mM (MBA) substrate concentration mixture, the coupled reaction reached approximately 83% conversion in 20 min at the lowest flow rate. The ability to synthesize a chiral pharmaceutical intermediate, ABT in relatively short time proves this IEMR system as a powerful tool for construction and evaluation of de novo pathways as well as for determination of enzyme kinetics. PMID- 24055437 TI - Emergence of extensively drug-resistant OXA-72-producing Acinetobacter baumannii in Recife, Brazil: risk of clonal dissemination? AB - Two new examples of OXA-72-producing Acinetobacter baumannii isolate resistant to a broad spectrum of antimicrobials, but not polymyxin B, have been identified in Recife, Brazil. Molecular typing indicated a close genetic link with the OXA-72 producing A. baumannii previously isolated in Sao Paulo, suggesting the possibility of clonal dissemination within the country. PMID- 24055436 TI - Real-time imaging of exocytotic mucin release and swelling in Calu-3 cells using acridine orange. AB - Mucus secretion is the first-line of defence against the barrage of irritants inhaled into human lungs, but abnormally thick and viscous mucus results in many respiratory diseases. Understanding the processes underlying mucus pathology is hampered, in part, by lack of appropriate experimental tools for labeling and studying mucin granule secretion from live cells with high sensitivity and temporal resolution. In this report we present original spectroscopic properties of acridine orange (AO) which could be utilized to study granule release and mucin swelling with various advanced fluorescence imaging approaches. Low concentration (<200 MUM) AO solutions presented absorption maximum at 494 nm, emission maximum at 525 nm and only ~1.76 ns fluorescence lifetime. By contrast at high concentrations (4-30 mM) favoring formation of AO aggregates, a very different absorption with maximum at ~440 nm, dramatically red-shifted emission with maximum at 630 nm, and over 10-fold increased fluorescence lifetime (~20 ns) was observed. To verify potential utility of AO for real-time imaging we have performed confocal, total internal reflection fluorescence (TIRF) and fluorescence lifetime imaging (FLIM) of AO-stained Calu-3 cells. We found similar red-shifted fluorescence spectra and long fluorescence lifetime in intracellular granules as compared to that in the cytoplasm consistent with granular AO accumulation. Mechanical stimulation of Calu-3 cells resulted in multiple exocytotic secretory events of AO-stained granules followed by post-exocytotic swelling of their fluorescently-labeled content that was seen in single-line TIRF images as rapidly-expanding bright-fluorescence patches. The rate of their size expansion followed first-order kinetics with diffusivity of 3.98+/-0.07*10(-7)c m(2)/s, as expected for mucus gel swelling. This was followed by fluorescence decrease due to diffusional loss of AO that was ~10-fold slower in the secreted mucus compared to bulk aqueous solution. In summary, we showed that AO-staining could be utilized for real-time TIRF imaging of mucin granule exocytosis and mucin swelling with high sensitivity and temporal resolution. Considering unique AO fluorescence properties that permit selective excitation of AO monomers versus aggregates, our study lays the groundwork for future development of two-color excitation scheme and two-color fluorescence FLIM live-cell imaging assay with potentially many biological applications. PMID- 24055438 TI - Colonic bacterial metabolism of corticosteroids. AB - The aim of this study was to investigate the stability of four corticosteroids in the presence of human colonic bacteria to understand better their luminal behaviour when delivered orally in the treatment of inflammatory bowel disease. The stability of prednisolone, budesonide, beclometasone (17, 21) dipropionate (BDP) and its active metabolite, beclometasone-17-monopropionate (17-BMP), were investigated at three different concentrations following incubation in a mixed faecal inoculum (simulated human colonic fluid) under anaerobic conditions. Prednisolone, at all three concentrations, was completely degraded within 3 h. The degradation of budesonide progressed at a slower rate, with complete degradation occurring within 7h; the degradation of the S epimer of budesonide was faster than the R epimer. BDP degraded completely within 2 h while its active metabolite 17-BMP was comparatively stable. In contrast to the results in the faecal inoculum, all molecules were stable in the simulated colonic fluid in the absence of human faeces (control). This study demonstrates that prednisolone, BDP and budesonide are completely metabolized in simulated human colonic fluid and confirms the role of colonic bacteria in the metabolism of corticosteroids. PMID- 24055439 TI - Optimization of the inter-tablet coating uniformity for an active coating process at lab and pilot scale. AB - The objective of this study was to enhance the inter-tablet coating uniformity in an active coating process at lab and pilot scale by statistical design of experiments. The API candesartan cilexetil was applied onto gastrointestinal therapeutic systems containing the API nifedipine to obtain fixed dose combinations of these two drugs with different release profiles. At lab scale, the parameters pan load, pan speed, spray rate and number of spray nozzles were examined. At pilot scale, the parameters pan load, pan speed, spray rate, spray time, and spray pressure were investigated. A low spray rate and a high pan speed improved the coating uniformity at both scales. The number of spray nozzles was identified as the most influential variable at lab scale. With four spray nozzles, the highest CV value was equal to 6.4%, compared to 13.4% obtained with two spray nozzles. The lowest CV of 4.5% obtained with two spray nozzles was further reduced to 2.3% when using four spray nozzles. At pilot scale, CV values between 2.7% and 11.1% were achieved. Since the test of uniformity of dosage units accepts CV values of up to 6.25%, this active coating process is well suited to comply with the pharmacopoeial requirements. PMID- 24055440 TI - Role of the elasticity of pharmaceutical materials on the interfacial mechanical strength of bilayer tablets. AB - The effect of the elasticity of various pharmaceutical materials on the interfacial adhesion in bilayer tablets was investigated. The elastic properties of five pharmaceutical products were characterized by their total elastic recovery. To test the interfacial strength of the bilayer tablets a new flexural test was proposed. Thanks to the test configuration, the experimental breaking force is directly correlated with the interfacial layer strength. Depending on the materials, the fracture occurred over the interface or in one of the two layers. In most cases, the highest breaking forces were obtained when the materials had close elastic recovery. On the contrary, for materials with different elastic recovery, the breaking forces were reduced. The observed changes in the interfacial mechanical strength were statistically analyzed. Such an approach has an importance in the growing interest in the Quality by Design (QbD) concept in pharmaceutical industry. PMID- 24055441 TI - Investigation of dry powder aerosolization mechanisms in different channel designs. AB - Aerosolization efficiency is the key characteristic of dry powder inhaler (DPI). However, lack of knowledge about powder dispersion and deposition is still a major obstacle to further improve inhaler. In the current work, both the in vitro deposition experiments and numerical simulations were employed to investigate the performance of three different DPI channel designs. The powder model was commercially available Seretide Accuhaler, which contains carrier lactose and drug mixture of fluticasone propionate (FP) and salmeterol xinafoate (SX). The in vitro results, such as the mass mediate aerodynamic diameter (MMAD), fine particle fraction (FPF) and fine particle dose (FPD), were obtained by the Next Generation Impactor (NGI). The values of MMAD were significantly (p<0.05) affected by channel design. However, based on the FPF result, the three channel designs had similar capabilities of aerosolization. It was demonstrated that particle-wall collision was the dominant mechanism for the detachment and de agglomeration at these conditions. Furthermore, good linear correlations were found between the FPD values on the first 4 stages of NGI and the outlet velocities of their corresponding particles, which would be used for a potential on-line approach to the evaluation of DPI efficiency. PMID- 24055442 TI - Middle East Respiratory Syndrome (MERS) coronavirus. What travel health advice should be given to Hajj pilgrims? PMID- 24055443 TI - First-in-human evaluation of a bioabsorbable polymer-coated sirolimus-eluting stent: imaging and clinical results of the DESSOLVE I Trial (DES with sirolimus and a bioabsorbable polymer for the treatment of patients with de novo lesion in the native coronary arteries). AB - OBJECTIVES: This first-in-human multicenter study sought to examine prospectively the safety and efficacy of a new, cobalt chromium thin-strut, coronary absorbable polymer-coated, sirolimus-eluting stent. BACKGROUND: Bioabsorbable polymers on drug-eluting stents may lower the long-term risks of inflammation, delayed healing, and adverse events. METHODS: We enrolled patients with symptomatic coronary artery disease with stable or unstable angina pectoris and >50% diameter stenosis, amenable to coverage with a <=23-mm long stent in a vessel 2.5 to 3.5 mm in diameter. All patients received dual antiplatelet therapy after implantation. Patients, in groups of 10, underwent repeat angiography, intravascular ultrasound, and optical coherence tomography at 4, 6, or 8 months, and all patients were seen or contacted at 18 months of follow-up. RESULTS: The median (range) in-stent late lumen loss (LLL) was 0.03 mm (-0.22 to 0.21 mm), 0.10 mm (-0.03 to 1.2 mm), and 0.08 mm (-0.01 to 0.28 mm), at 4, 6, and 8 months, respectively. At 18 months, the median in-stent LLL was 0.08 mm (-0.30 to 0.46 mm). On optical coherence tomography, the proportion of uncovered stent struts decreased from a median of 7.3% (range 0.4% to 46.3%) at 4 months to 0% (range: 0% to 3.4%) at 18 months. The percentage of neointimal volume obstruction by intravascular ultrasound increased from a median of 5.3% to 9.1% between 4 and 6 months and remained nearly unchanged thereafter through 18 months of follow-up. The only recorded major adverse cardiac event was a myocardial infarction. CONCLUSIONS: At 18 months of follow-up, this absorbable polymer-coated, cobalt chromium sirolimus-eluting stent was associated with a low and stable in-stent LLL, complete strut coverage, and no stent thrombosis. (First-In-Human Trial of the MiStent Drug-Eluting Stent [DES] in Coronary Artery Disease [DESSOLVE-I]; NCT01247428). PMID- 24055445 TI - Achieving sustainable first door-to-balloon times of 90 minutes for regional transfer ST-segment elevation myocardial infarction. AB - OBJECTIVES: A network approach to transfer ST-segment elevation myocardial infarction (STEMI) patients can achieve durable first door-to-balloon times (1st D2B) for percutaneous coronary intervention (PCI) within 90 min. BACKGROUND: Nationally, a minority of STEMI patients from referral centers obtain 1st D2B in <2 h and even fewer in <90 min. METHODS: Included were transfer STEMI patients from 9 network hospitals treated in 2007 compared with 2008 to 2011 after installing the following initiatives: 1) established hospital referral system; 2) goal-oriented performance protocols; 3) expedited transport by ground or air; 4) first hospital activation of the PCI hospital catheterization laboratory; and 5) outreach coordinator and patient-level web-based feedback to the referring hospital. RESULTS: A total of 101 STEMI patients transported in 2007 were compared with 442 STEMI patients transferred after starting these initiatives for STEMI from 2008 to 2011, with the median door-in to door-out time decreased from 44 to 35 min (p < 0.0001), the median 1st D2B decreasing from 109.5 to 88.0 min (p < 0.0001), and the percentage under 90 min increased from 22.8% to 55.9% (p < 0.0001). Overall, throughout the study period (2007 to 2011), the transport times remained consistent (median 36.5 vs. 36.0 min, p = 0.98), whereas the PCI hospital D2B decreased from 20.0 to 16.0 min (p < 0.0001). Length of stay and in hospital mortality remained low at 3.0 days and under 4%, respectively. CONCLUSIONS: A system-wide network program can achieve sustained (over 4 years) 1st D2B times of <90 min. PMID- 24055444 TI - A clinical and angiographic study of the XIENCE V everolimus-eluting coronary stent system in the treatment of patients with multivessel coronary artery disease: the EXECUTIVE trial (EXecutive RCT: evaluating XIENCE V in a multi vessel disease). AB - OBJECTIVES: This study sought to investigate the efficacy and performance of the XIENCE V everolimus-eluting stent (EES) (Abbott Vascular, Santa Clara, California) in the treatment of de novo coronary lesions in patients with 2- to 3 vessel multivessel coronary artery disease (MV-CAD). BACKGROUND: Drug-eluting stents (DES) have emerged as an alternative to conventional coronary artery bypass surgery in patients with MV-CAD although first-generation DES yielded inferior efficacy and safety compared with surgery. METHODS: Prospective, randomized (1:1), multicenter feasibility trial was designed to assess angiographic efficacy of EES compared with the TAXUS paclitaxel-eluting stent (PES) in 200 patients, and a prospective, open-label, single-arm, controlled registry was designed to analyze the clinical outcome of EES at 1-year follow-up in 400 MV-CAD patients. For the randomized trial, the primary endpoint was in stent late loss at 9 months. For the registry, the primary endpoint was a composite of all-cause death, myocardial infarction, and ischemia-driven target vessel revascularization at 12 months. RESULTS: The primary endpoint per single lesion was significantly lower in the EES group compared with the PES group ( 0.03 +/- 0.49 mm vs. 0.23 +/- 0.51 mm, p = 0.001). Similar results were observed when analyzing all lesions (0.05 +/- 0.51 mm vs. 0.24 +/- 0.50 mm, p < 0.001). Clinical outcome at 1 year yielded a composite of major adverse cardiac events of 9.2% in the single-arm registry, and 11.1% and 16.5% in the EES and PES randomized groups, respectively (p = 0.30). CONCLUSIONS: The EXECUTIVE trial was a randomized pilot trial dedicated to the comparison of the efficacy of 2 different DES among patients with 2- to 3-vessel MV-CAD. The study shows lower in stent late loss at 9 months with the EES XIENCE V compared with the PES TAXUS Liberte, and a low major adverse cardiac event rate at 1 year in patients with 2 to 3-vessel MV-CAD. (EXECUTIVE [EXecutive RCT: Evaluating XIENCE V in a Multi Vessel Disease]; NCT00531011). PMID- 24055446 TI - Redefining the gut as the motor of critical illness. AB - The gut is hypothesized to play a central role in the progression of sepsis and multiple organ dysfunction syndrome. Critical illness alters gut integrity by increasing epithelial apoptosis and permeability and by decreasing epithelial proliferation and mucus integrity. Additionally, toxic gut-derived lymph induces distant organ injury. Although the endogenous microflora ordinarily exist in a symbiotic relationship with the gut epithelium, severe physiological insults alter this relationship, leading to induction of virulence factors in the microbiome, which, in turn, can perpetuate or worsen critical illness. This review highlights newly discovered ways in which the gut acts as the motor that perpetuates the systemic inflammatory response in critical illness. PMID- 24055447 TI - Pancreatic beta cell proliferation by intermittent hypoxia via up-regulation of Reg family genes and HGF gene. AB - AIMS: Although accumulating evidence suggests the associations between sleep apnea syndrome (SAS) and type 2 diabetes, the direct effect of intermittent hypoxia (IH) on pancreatic beta cell proliferation remains a missing piece of the puzzle. MAIN METHODS: Rat RINm5F beta cells, hamster HIT-T15 beta cells, and human 1.1B4 beta cells were exposed to normoxia (21% O2, 5% CO2, and balance N2), to sustained hypoxia (SH: 1% O2, 5% CO2, and balance N2), or to intermittent hypoxia (IH: 64 cycles of 5 min SH and 10 min normoxia) for 24 h. After the treatment, cellular proliferation and apoptosis were measured by WST-8 assay and TUNEL method, respectively. The expression of regenerating gene (Reg) family, interleukin (IL)-6, and hepatocyte growth factor (HGF) was determined by real time RT-PCR. KEY FINDINGS: The cellular proliferation of HIT-T15, RINm5F and 1.1B4 cells by IH was significantly increased, whereas apoptosis of these cells was unchanged. Real-time RT-PCR revealed that the mRNA levels of Reg family genes, IL-6, a typical Reg family gene inducer, and HGF, an inhibitor of high concentration of Reg protein-induced apoptosis, were increased in IH-treated cells. In addition, siRNAs against rat Reg family genes except for PAP I/Reg 2 attenuated IH-induced beta cell proliferation. SIGNIFICANCE: IH stress stimulates pancreatic beta cell to induce IL-6 gene expression. By the IL-6 stimulation, beta cells over-express Reg family genes as well as HGF gene. Reg family proteins stimulate beta cell proliferation and HGF inhibits apoptosis of beta cells. As a result, beta cell numbers are increased by IH. PMID- 24055448 TI - Neurological approaches for investigating West Nile virus disease and its treatment in rodents. AB - West Nile virus (WNV) has had a major public health impact since its emergence in the Western Hemisphere; in 2012, nearly 3000 cases of WN neuroinvasive disease were identified in the United States. The underlying mechanisms of WN neurologic disease can only be studied to a limited extent in patients, but can be investigated in much greater detail in animal models. In this paper, we describe how we and others have employed a variety of electrophysiological and neurological techniques to study experimental WNV infections in hamsters and mice. The methods have included electrophysiological motor unit number estimation; optogenetic photoactivation of the spinal cord and electromyography; plethysmography; measurement of heart rate variability as an indication of autonomic nervous system dysfunction; and an assessment of spatial memory loss using the Morris water maze. These techniques provide a more refined assessment of disease manifestations in rodents than traditional measurements of weight loss and mortality, and should make it possible to identify targets for therapeutic intervention and to directly assess the effects of novel treatments. PMID- 24055449 TI - Single-stranded DNA aptamer that specifically binds to the influenza virus NS1 protein suppresses interferon antagonism. AB - Non-structural protein 1 (NS1) of the influenza A virus (IAV) inhibits the host's innate immune response by suppressing the induction of interferons (IFNs). Therefore, blocking NS1 activity can be a potential strategy in the development of antiviral agents against IAV infection. In the present study, we selected a single-stranded DNA aptamer specific to the IAV NS1 protein after 15 cycles of systematic evolution of ligands by exponential enrichment (SELEX) procedure and examined the ability of the selected aptamer to inhibit the function of NS1. The selected aptamer binds to NS1 with a Kd of 18.91+/-3.95nM and RNA binding domain of NS1 is determined to be critical for the aptamer binding. The aptamer has a G rich sequence in the random sequence region and forms a G-quadruplex structure. The localization of the aptamer bound to NS1 in cells was determined by confocal images, and flow cytometry analysis further demonstrated that the selected aptamer binds specifically to NS1. In addition, luciferase reporter gene assay, quantitative RT-PCR, and enzyme-linked immunosorbent assay (ELISA) experiments demonstrated that the selected aptamer had the ability to induce IFN-beta by suppressing the function of NS1. Importantly, we also found that the selected aptamer was able to inhibit the viral replication without affecting cell viability. These results indicate that the selected ssDNA aptamer has strong potential to be further developed as a therapeutic agent against IAV. PMID- 24055450 TI - Selection and characterization of viruses resistant to the dual acting pyrimidinedione entry and non-nucleoside reverse transcriptase inhibitor IQP 0410. AB - The 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT)-like compounds with homocyclic moieties at the N-1 of the pyrimidinedione, including the highly potent lead compound IQP-0410, inhibit HIV-1 at sub-nanomolar concentrations primarily through a typical non-nucleoside mechanism involving allosteric inhibition at the hydrophobic binding pocket of the HIV-1 RT. Like all NNRTIs, the pyrimidinediones have no activity against HIV-2 RT. The pyrimidinediones, however, also possess a second mode of action involving inhibition of virus entry at nanomolar concentrations which extends their range of action to include HIV-2. Entry inhibition occurs through recognition of a complex conformational binding site formed upon interaction of the virus with target cells, but does not involve direct inhibition of gp120-CD4 binding. In order to further explore the means by which the pyrimidinediones act, resistant strains of HIV-1 and HIV-2 were selected in cell culture and molecularly and biologically characterized. With HIV 1, three phases of resistance selection occurred which involve an initial appearance of single amino changes in the NNRTI binding pocket, followed by changes in the envelope glycoproteins gp120 and gp41, and subsequent multiple additional changes in the RT, resulting in high level resistance to IQP-0410. With HIV-2, resistance to entry inhibition was achieved with no resistance engendering mutations detected in the HIV-2 RT. Detailed molecular and biological characterization of IQP-0410-resistant viruses was performed to define the resistance-engendering mutations present in the RT and envelope and to quantify cross-resistance to other HIV inhibitors. PMID- 24055452 TI - Time for universality to reduce inequity. PMID- 24055453 TI - Health post-2015: evidence and power. PMID- 24055451 TI - Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study. AB - BACKGROUND: Since June, 2012, Middle East respiratory syndrome coronavirus (MERS CoV) has, worldwide, caused 104 infections in people including 49 deaths, with 82 cases and 41 deaths reported from Saudi Arabia. In addition to confirming diagnosis, we generated the MERS-CoV genomic sequences obtained directly from patient samples to provide important information on MERS-CoV transmission, evolution, and origin. METHODS: Full genome deep sequencing was done on nucleic acid extracted directly from PCR-confirmed clinical samples. Viral genomes were obtained from 21 MERS cases of which 13 had 100%, four 85-95%, and four 30-50% genome coverage. Phylogenetic analysis of the 21 sequences, combined with nine published MERS-CoV genomes, was done. FINDINGS: Three distinct MERS-CoV genotypes were identified in Riyadh. Phylogeographic analyses suggest the MERS-CoV zoonotic reservoir is geographically disperse. Selection analysis of the MERS-CoV genomes reveals the expected accumulation of genetic diversity including changes in the S protein. The genetic diversity in the Al-Hasa cluster suggests that the hospital outbreak might have had more than one virus introduction. INTERPRETATION: We present the largest number of MERS-CoV genomes (21) described so far. MERS-CoV full genome sequences provide greater detail in tracking transmission. Multiple introductions of MERS-CoV are identified and suggest lower R0 values. Transmission within Saudi Arabia is consistent with either movement of an animal reservoir, animal products, or movement of infected people. Further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed. FUNDING: Saudi Arabian Ministry of Health, Wellcome Trust, European Community, and National Institute of Health Research University College London Hospitals Biomedical Research Centre. PMID- 24055454 TI - Tracking the transmission and evolution of MERS-CoV. PMID- 24055456 TI - Men with inflammatory bowel disease are rarely counseled regarding effects of immunosuppressive therapy on fertility and pregnancy. PMID- 24055455 TI - The effect of detergents on the basement membrane complex of a biologic scaffold material. AB - The basement membrane complex (BMC) is a critical component of the extracellular matrix (ECM) that supports and facilitates the growth of cells. This study investigates four detergents commonly used in the process of tissue decellularization and their effect upon the BMC. The BMC of porcine urinary bladder was subjected to 3% Triton-X 100, 8mM 3-[(3 cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), 4% sodium deoxycholate or 1% sodium dodecyl sulfate (SDS) for 24h. The BMC structure for each treatment group was assessed by immunolabeling, scanning electron microscopy (SEM) and second harmonic generation (SHG) imaging of the fiber network. The composition was assessed by quantification of dsDNA, glycosaminoglycans (GAG) and collagen content. The results showed that collagen fibers within samples treated with 1% SDS and 8mM CHAPS were denatured, and the ECM contained fewer GAG compared with samples treated with 3% Triton X-100 or 4% sodium deoxycholate. Human microvascular endothelial cells (HMEC) were seeded onto each BMC and cultured for 7 days. Cell-ECM interactions were investigated by immunolabeling for integrin beta-1, SEM imaging and semi-quantitative assessment of cellular infiltration, phenotype and confluence. HMEC cultured on a BMC treated with 3% Triton X-100 were more confluent and had a normal phenotype compared with HMEC cultured on a BMC treated with 4% sodium deoxycholate, 8mM CHAPS and 1% SDS. Both 8mM CHAPS and 1% SDS damaged the BMC to the extent that seeded HMEC were able to infiltrate the damaged sub-basement membrane tissue, showed decreased confluence and an atypical phenotype. The choice of detergents used for tissue decellularization can have a marked effect upon the integrity of the BMC of the resultant bioscaffold. PMID- 24055457 TI - Cancer surveillance for patients with colonic Crohn's disease: will your patients benefit? PMID- 24055458 TI - Atomic force microscopy studies of APOBEC3G oligomerization and dynamics. AB - The DNA cytosine deaminase APOBEC3G (A3G) is a two-domain protein that binds single-stranded DNA (ssDNA) largely through its N-terminal domain and catalyzes deamination using its C-terminal domain. A3G is considered an innate immune effector protein, with a natural capacity to block the replication of retroviruses such as HIV and retrotransposons. However, knowledge about its biophysical properties and mechanism of interaction with DNA are still limited. Oligomerization is one of these unclear issues. What is the stoichiometry of the free protein? What are the factors defining the oligomeric state of the protein? How does the protein oligomerization change upon DNA binding? How stable are protein oligomers? We address these questions here using atomic force microscopy (AFM) to directly image A3G protein in a free-state and in complexes with DNA, and using time-lapse AFM imaging to characterize the dynamics of A3G oligomers. We found that the formation of oligomers is an inherent property of A3G and that the yield of oligomers depends on the protein concentration. Oligomerization of A3G in complexes with ssDNA follows a similar pattern: the higher the protein concentrations the larger oligomers sizes. The specificity of A3G binding to ssDNA does not depend on stoichiometry. The binding of large A3G oligomers requires a longer ssDNA substrate; therefore, much smaller oligomers form complexes with short ssDNA. A3G oligomers dissociate spontaneously into monomers and this process primarily occurs through a monomer dissociation pathway. PMID- 24055459 TI - Levels, sources and potential risks of polycyclic aromatic hydrocarbons (PAHs) in multimedia environment along the Jinjiang River mainstream to Quanzhou Bay, China. AB - This study investigated the levels, sources and potential risks of polycyclic aromatic hydrocarbons (PAHs) in soil, water (dissolved phase, suspended particulate matter) and sediment along the Jinjiang River mainstream to Quanzhou Bay. The distribution coefficient of SigmaPAHs varied disorderly along the Jinjiang River, indicating the non-equilibrium status for the partition. The various distribution features of SigmaPAHs in the sediments of the north and south coast of Quanzhou Bay were probably due to the flow motions in the bay. High correlations of PAHs were found between different media, suggesting the approximately same source of PAHs. Furthermore, three source factors and their contributions were extracted using the positive matrix factorization model. Toxicity and biological risk were assessed using toxic equivalent quantity and sediment quality guideline quotient. The contamination of PAHs in the soil and sediments may turn to unconspicuous risks for the environment and humans except very few sites with moderate pollution. PMID- 24055460 TI - Developing human capital for successful implementation of international marine scientific research projects. AB - The oceans play a crucial role in the global environment and the sustainability of human populations, because of their involvement in climate regulation and provision of living and non-living resources to humans. Maintenance of healthy oceans in an era of increasing human pressure requires a high-level understanding of the processes occurring in the marine environment and the impacts of anthropogenic activities. Effective protection and sustainable resource management must be based, in part, on knowledge derived from successful research. Current marine research activities are being limited by a need for high-quality researchers capable of addressing critical issues in broad multidisciplinary research activities. This is particularly true for developing countries which will require the building of capacity for marine scientific research. This paper reviews the current activities aimed at increasing marine research capacity in developing and emerging countries and analyses the challenges faced, including: appropriate alignment of the research goals and societal and policy-relevant needs; training in multidisciplinary research; increasing capacity for overall synthesis of scientific data; building the capacity of technical staff; keeping highly qualified personnel in marine scientific research roles; cross-cultural issues in training; minimising duplication in training activities; improving linkages among human capital, project resources and infrastructure. Potential solutions to these challenges are provided, along with some priorities for action aimed at improving the overall research effort. PMID- 24055461 TI - Polycyclic aromatic hydrocarbons in the coastal water, surface sediment and mullet Liza klunzingeri from northern part of Hormuz strait (Persian Gulf). AB - The concentrations of 16 polycyclic aromatic hydrocarbons (PAHs) were determined in mullet (Liza klunzingeri), water and sediment from northern part of Hormuz strait (Persian Gulf). The concentration levels of total PAHs in L. klunzingeri, water and sediment were 133.99-268.57 ng g(-1)dry weight, 3.12-5.88 ng l(-1) and 42.29-228.9 ng g(-1) dry weight, respectively. Based on isomer ratios, analysis of the PAHs source in the sediment demonstrated that the PAHs come from pyrogenic and petrogenic origin. Risk assessment showed PAHs threshold concentrations to occasionally be exceeded in the study area. PMID- 24055462 TI - Evaluation of the long-term variability of seawater salinity and temperature in response to natural and anthropogenic stressors in the Arabian Gulf. AB - Evaluating the long-term variability of the seawater salinity and temperature due to climate change is a limiting economical and operational factor in planning the design of new and expansion of existing desalination plants. This need is amplified in the Arabian Gulf due to the natural arid climate and anthropological stresses related to energy exploration and ongoing major developments. The lack of data in this region further adds additional dimension to the problem. The present work represents a systematic innovative approach to evaluate the anticipated long-term changes in the seawater salinity and temperature under the stresses of projected climate change and massive industrial effluents using statistical correlation and hydrodynamic simulation. The proposed approach employs the direct relation between the net freshwater losses (evaporation) entrenched with the investigated stressors and the mean sea salinity and sea temperature variation of an inverse estuary to formulate the statistical correlation and the hydrodynamic simulation conditions. PMID- 24055463 TI - Influenza A virus induction of oxidative stress and MMP-9 is associated with severe lung pathology in a mouse model. AB - Infection by different strains of influenza virus presents different pictures. Whether the pathogenicity of influenza virus is defined by the ability of the virus to induce differential immunopathological responses in the lungs still remains unclear. We compared the immunopathological response induced by influenza virus A/WSN/33 (H1N1) and that by A/Panama-like (H3N2) virus in C57BL/6 mice. WSN virus, in contrast to Panama-like virus, induced high mortality and severe lung pathology accompanied by massive Gr-1(+) and CD11b(+) cell infiltration and high levels of CXCL6/GCP-2, CCL2/MCP-1 and TIMP-1 production. Infection by WSN virus but not by Panama-like virus induced up-regulation of the active and latent forms of MMP-9 in the lungs and MMP-2/9 inhibitor partially reduced WSN virus-induced lung pathology. Both Gr-1(+) and CD11b(+) cells in WSN virus-infected lungs produced reactive oxygen and nitrogen species (ROS/RNS). While wild type mice infected by WSN virus had severe lung pathology and the presence of oxidized phospholipids and numerous MMP-9(+) cells in the lungs, ncf1 deficiency ablated their expression and manifested less lung pathology. Employing a pulmonary mouse model we demonstrated in this study that infection by virulent influenza virus is characterized by a heavy cellular infiltration, severe lung pathology which is accompanied by oxidative stress and MMP-9 production. PMID- 24055464 TI - Two novel circo-like viruses detected in human feces: complete genome sequencing and electron microscopy analysis. AB - The application of viral metagenomic techniques and a series of PCRs in a human fecal sample enabled the detection of two novel circular unisense DNA viral genomes with 92% nucleotide similarity. The viruses were tentatively named circo like virus-Brazil (CLV-BR) strains hs1 and hs2 and have genome lengths of 2526 and 2533 nucleotides, respectively. Four major open reading frames (ORFs) were identified in each of the genomes, and differences between the two genomes were primarily observed in ORF 2. Only ORF 3 showed significant amino acid similarities to a putative rolling circle replication initiator protein (Rep), although with low identity (36%). Our phylogenetic analysis, based on the Rep protein, demonstrated that the CLV-BRs do not cluster with members of the Circoviridae, Nanoviridae or Geminiviridae families and are more closely related to circo-like genomes previously identified in reclaimed water and feces of a wild rodent and of a bat. The CLV-BRs are members of a putative new family of circular Rep-encoding ssDNA viruses. Electron microscopy revealed icosahedral (~23 nm) structures, likely reflecting the novel viruses, and rod-shaped viral particles (~65-460 * 21 * 10 nm in length, diameter, and axial canal, respectively). Circo-like viruses have been detected in stool samples from humans and other mammals (bats, rodents, chimpanzees and bovines), cerebrospinal fluid and sera from humans, as well as samples from many other sources, e.g., insects, meat and the environment. Further studies are needed to classify all novel circular DNA viruses and elucidate their hosts, pathogenicity and evolutionary history. PMID- 24055465 TI - Identification of two severe fever with thrombocytopenia syndrome virus strains originating from reassortment. AB - Recently, a novel bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV), was isolated in central China. The virus can cause multi-clinical symptoms: severe fever, thrombocytopenia, leukocytopenia, with a mortality rate of ~10%. Several studies show that SFTSV could undergo rapid evolution via gene mutation and homologous recombination. However, as an important evolutionary force for segmented-genome viruses, reassortment has not been reported in SFTSV. In this study, we identified two SFTSV strains of which the S segment has different origin from M and L, suggesting that reassortment might be potential force driving rapid change of SFTSV. This result might shed new light on the evolutionary behavior of the novel virus. PMID- 24055466 TI - Structural and inhibitor studies of norovirus 3C-like proteases. AB - Noroviruses have a single-stranded, positive sense 7-8kb RNA genome, which encodes a polyprotein precursor processed by a virus-encoded 3C-like cysteine protease (3CLpro) to generate mature non-structural proteins. Because processing of the polyprotein is essential for virus replication, norovirus 3CLpro has been targeted for the discovery of anti-norovirus small molecule therapeutics. Thus, we performed functional, structural and inhibition studies of norovirus 3CLpro with fluorescence resonance energy transfer (FRET) assay, X-ray crystallography, and NMR spectroscopy with a synthetic protease inhibitor. Three 3CLpro from Norwalk virus (NV, genogroup I), MD145 (genogroup II) and murine norovirus-1 (MNV 1, genogroup V) were optimized for a FRET assay, and compared for the inhibitory activities of a synthetic protease inhibitor (GC376). The apo 3D structures of NV 3CLpro determined with X-ray crystallography and NMR spectroscopy were further analyzed. In addition, the binding mode of NV 3CLpro-GC376 was compared with X ray crystallography and NMR spectroscopy. The results of this report provide insight into the interaction of NV 3CLpro with substrate/inhibitor for better understanding of the enzyme and antiviral drug development. PMID- 24055467 TI - Moderation of hematological and plasma biochemical indices of sub-chronic salt loaded rats by aqueous extract of the sclerotia of Pleurotus tuberregium (Fr) Sing's: implications for the reduction of cardiovascular risk. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The sclerotia of Pleurotus tuberregium are used in Southern Nigeria for the management of diabetes and hypertension, yet there is scarcity of information in the literature regarding the evaluation of the biochemical basis of its antihypertensive property, as well as the biochemical impact of its administration to the hypertensive. Thus, in this study, the ability of an aqueous extract of the sclerotia of Pleurotus tuberregium to moderate biochemical and hematological indices was investigated in normal and sub chronic salt-loaded rats. MATERIALS AND METHODS: The normal and treatment control groups received a diet consisting 100% of the commercial feed, while the test control, reference and test treatment groups received an 8% salt-loaded diet. The extract was orally administered daily at 100 and 200 mg/kg body weight; while the moduretics was administered at 1 mg/kg. The normal and test control groups received appropriate volumes of water by the same route. RESULTS: On gas chromatographic analysis of the crude aqueous extract, 29 known flavonoids (mainly 47.71% kaempferol and 37.36% quercetin), four saponins (mainly 72.93% avenacin B1 and 26.80% avenacin A1), six hydroxycinnamic acid derivatives (mainly 57.57% p-coumaric and 42.10% caffeic acid), ten carotenoids (mainly 58.44% carotene and 28.16% lycopene) and seven phytosterols (mainly 98.16% sitosterol) were detected. Also detected were nine benzoic acid derivatives (mainly 44.19% ferulic acid and 25.92% rosmarinic acid), six lignans (mainly 70.88% galgravin and 22.69% retusin), three allicins (mainly 71.92% diallyl thiosulphinate and 23.68% methyl allyl thiosulphinate), seven glycosides (mainly 84.86% arbutin and 12.01% ouabain), 31 alkaloids (mainly 48.82% lupanine, 32.26% augustamine) and 24 terpenes (mainly 60.66% limonene and 6.52% geranyl acetate). Compared to test control, the treatment significantly, dose-dependently lowered (P < 0.05) the mean cell volume, atherogenic indices (cardiac risk ratio, atherogenic coefficient and atherogenic index of plasma), plasma alanine and aspartate transaminase activities, mean cell hemoglobin, sodium, bicarbonate, urea, blood urea nitrogen, triglyceride, total-, non-high density lipoprotein-, low density lipoprotein- and very low density lipoprotein cholesterol concentrations, and neutrophils, monocytes and platelets counts of the treated animals. However, it significantly, dose-dependently increased (P < 0.05) the hemoglobin concentration, mean cell hemoglobin, red cells and lymphocytes counts, plasma high density lipoprotein cholesterol, calcium, potassium, chloride, creatinine, albumin and total protein concentrations of the treated animals. CONCLUSIONS: All these results support the use of the plant in traditional health care, for the management of hypertension, and highlight the cardio-protective potential of the sclerotia, whilst suggesting that its antihypertensive activity may be mediated through alteration of plasma levels of sodium and potassium, or increases in muscle tone brought about by changes in plasma calcium levels. PMID- 24055468 TI - Antidiabetic effects of Swertia macrosperma extracts in diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Swertia macrosperma is a traditional folk medicine used for its anti-hepatitis, antipyretic and antidotal effects as "Dida" or "Zangyinchen" in Tibet, Yunnan and Guizhou province for a long time, and it has been reported for its anti-diabetic effects in a Chinese patent. Swertia macrosperma was reported rich in xanthones, iridoids, seco-iridoids and their glycosides, several of which had been documented as potential antidiabetic agents. The objective of this study was to investigate the antidiabetic effect of Swertia macrosperma in diabetic rats. MATERIALS AND METHODS: This study was designed firstly to evaluate the effect of Swertia macrosperma on glucose consumption in HepG2 cells. Based on the result in HepG2 cells, the antidiabetic effect of ethanol extract (EE) and n-butanol extract (BE) were investigated in diabetic rats induced by high fat fed and streptozotocin. The effects of EE and BE on fasting blood glucose, oral glucose tolerance test, serum insulin, glycosylated hemoglobin, serum lipid level, serum antioxidant parameters, glucokinase, glucose-6-phosphatase activities and glycogen content in liver tissue were measured, histology examination of pancreatic tissue was also carried out. RESULTS: After 4 weeks treatment with EE and BE, apparently decreased fasting blood glucose concentrations were observed in these treated groups, compared with the diabetic control groups. Additionally, improvement in serum antioxidant parameters and lipid profile were evidenced clearly. Moreover, EE and BE had effects of protecting the pancreatic beta-cells and stimulating insulin secretion from the remaining pancreatic beta-cells, evidenced by pancreatic histology examination. Increased glucokinase activity and decreased glucose-6 phosphatase activity were observed in liver. CONCLUSION: The results of in vivo and in vitro experiment suggested that EE and BE of Swertia macrosperma had excellent effects on controlling the hyperglycemia and hyperlipidemia in diabetic rats. PMID- 24055469 TI - Comparison of active constituents, acute toxicity, anti-nociceptive and anti inflammatory activities of Porana sinensis Hemsl., Erycibe obtusifolia Benth. and Erycibe schmidtii Craib. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Erycibe obtusifolia and Erycibe schmidtii, which belong to the same genus as Erycibe, are widely used in traditional medicine for the treatment of joint pain and rheumatoid arthritis (RA). Porana sinensis has become a widely used substitute for Erycibe obtusifolia and Erycibe schmidtii as they have declined in the wild. In the present work, the content of the main active components, the acute toxicity, the anti-nociceptive and anti-inflammatory activities of Porana sinensis, Erycibe obtusifolia and Erycibe schmidtii were compared, and the mechanisms of anti-nociceptive and anti-inflammatory activities were discussed. MATERIALS AND METHODS: A quantitative HPLC (high performance liquid chromatography) method was first developed to compare the content of the main active components (scopoletin, scopolin and chlorogenic acid). The anti inflammatory and anti-nociceptive activities of 40% ethanolic extracts of the three plants were compared using the models of xylene-induced ear edema, formalin induced inflammation, carrageenan-induced air pouch inflammation, acetic acid induced writhing and formalin-induced nociception. The acute toxicity of the 40% ethanolic extracts of the three plants was studied. RESULTS: The assay suggested a large content of scopoletin, scopolin and chlorogenic acid in the three plants. The 40% ethanolic extracts of the three plants were almost non-toxic at the dose of 5g/kg and all of them showed significant anti-inflammatory effects in the tests of xylene-induced ear edema and formalin-induced inflammation. In the carrageenan-induced air pouch inflammation test, the synthesis of PGE2 was significantly inhibited by all the extracts. They significantly inhibited the number of contortions induced by acetic acid and the second phase of the formalin induced licking response. Naloxone was not able to reverse the analgesic effect of these extracts. CONCLUSION: The study identifies the similarity of the three plants in their main active components as well as acute toxicity, anti nociceptive and anti-inflammatory activities. It supports the use of Porana sinensis as a suitable substitute, but further studies are needed to confirm this. PMID- 24055470 TI - Polysulfide exerts a protective effect against cytotoxicity caused by t buthylhydroperoxide through Nrf2 signaling in neuroblastoma cells. AB - Polysulfide is a bound sulfur species derived from endogenous H2S. When mouse neuroblastoma, Neuro2A cells were exposed to tert-butyl hydroperoxide after treatment with polysulfide, a significant decline in cell toxicity was observed. Rapid uptake of polysulfides induced translocation of Nrf2 into the nucleus, resulting in acceleration of GSH synthesis and HO-1 expression. We demonstrated that polysulfide reversibly modified Keap1 to form oxidized dimers and induced the translocation of Nrf2. Moreover, polysulfide treatment accelerated Akt phosphorylation, which is a known pathway of Nrf2 phosphorylation. Thus, polysulfide may mediate the activation of Nrf2 signaling, thereby exerting protective effects against oxidative damage in Neuro2A cells. PMID- 24055471 TI - ADAM 10 is over expressed in oral squamous cell carcinoma and contributes to invasive behaviour through a functional association with alphavbeta6 integrin. AB - A disintegrin and metalloprotease (ADAM) proteins are upregulated in cancer and can interact with integrin receptors. We investigated whether such interactions may have functional significance in oral squamous cell carcinoma (OSCC). ADAM 10 expression was increased in OSCC tissue and cell lines compared to normal oral mucosa. Silencing of ADAM 10 reduced migration and invasion specifically in OSCC cells over-expressing alphavbeta6 integrin. This may result from ADAM 10-induced up-regulation of MMPs. We conclude ADAM 10 may influence OSCC invasion by functionally interacting with alphavbeta6 integrin which we have previously shown is over expressed in OSCC. PMID- 24055472 TI - Discovery of cellobionic acid phosphorylase in cellulolytic bacteria and fungi. AB - A novel phosphorylase was characterized as new member of glycoside hydrolase family 94 from the cellulolytic bacterium Xanthomonas campestris and the fungus Neurospora crassa. The enzyme catalyzed reversible phosphorolysis of cellobionic acid. We propose 4-O-beta-D-glucopyranosyl-D-gluconic acid: phosphate alpha-D glucosyltransferase as the systematic name and cellobionic acid phosphorylase as the short names for the novel enzyme. Several cellulolytic fungi of the phylum Ascomycota also possess homologous proteins. We, therefore, suggest that the enzyme plays a crucial role in cellulose degradation where cellobionic acid as oxidized cellulolytic product is converted into alpha-D-glucose 1-phosphate and D gluconic acid to enter glycolysis and the pentose phosphate pathway, respectively. PMID- 24055473 TI - NMR structure and MD simulations of the AAA protease intermembrane space domain indicates peripheral membrane localization within the hexaoligomer. AB - We have determined the solution NMR structure of the intermembrane space domain (IMSD) of the human mitochondrial ATPase associated with various activities (AAA) protease known as AFG3-like protein 2 (AFG3L2). Our structural analysis and molecular dynamics results indicate that the IMSD is peripherally bound to the membrane surface. This is a modification to the location of the six IMSDs in a model of the full length yeast hexaoligomeric homolog of AFG3L2 determined at low resolution by electron cryomicroscopy [1]. The predicted protein-protein interaction surface, located on the side furthest from the membrane, may mediate binding to substrates as well as prohibitins. PMID- 24055474 TI - Role of phospholemman and the 70 kDa inhibitor protein in regulating Na+/K+ ATPase activity in pulmonary artery smooth muscle cells under U46619 stimulation. AB - Treatment of bovine pulmonary smooth muscle cells with U46619 inhibited the Na(+)/K(+) ATPase activity in two parallel pathways: one of which is mediated via glutathionylation of the pump and the other by augmenting the inhibitory activity of the 70kDa inhibitor protein of Na(+)/K(+) ATPase. Although phospholemman deglutathionylates the pump leading to its activation, the inhibitor is responsible for irreversible inhibition of Na(+)/K(+) ATPase in an isoform specific manner during treatment of the cells with U46619. PMID- 24055475 TI - Chicken IL-6 is a heat-shock gene. AB - The febrile response is elicited by pyrogenic cytokines including IL-6 in response to microorganism infections and diseases in vertebrates. Mammalian HSF1, which senses elevations in temperature, negatively regulates the response by suppressing pyrogenic cytokine expression. We here showed that HSF3, an avian ortholog of mammalian HSF1, directly binds to and activates IL-6 during heat shock in chicken cells. Other components of the febrile response mechanism, such as IL-1beta and ATF3, were also differently regulated in mammalian and chicken cells. These results suggest that the febrile response is exacerbated by a feed forward circuit composed of the HSF3-IL-6 pathway in birds. PMID- 24055477 TI - Prolonged cardiac arrest: successful resuscitation with extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation support can extend the duration of cardiopulmonary resuscitation (CPR), but prolonged CPR may develop multiple organ failure, and neurologic death is a major complication. We present a case of a 35 year-old woman with fulminant myocarditis secondary to H1N1 influenza A infection, in which cardiac arrest was refractory to prolonged conventional CPR. Extracorporeal membrane oxygenation was initiated 250 minutes after prolonged CPR. Extracorporeal membrane oxygenation provided cardiopulmonary life support for prolonged CPR, achieving a sustained return of spontaneous circulation, which allowed further treatment and made a good recovery with intact cerebral performance. PMID- 24055476 TI - Preliminary development of a clinical decision rule for acute aortic syndromes. AB - OBJECTIVE: Patients with suspected acute aortic syndromes (AAS) often undergo computed tomography (CT) with negative results. We sought clinical and diagnostic criteria to identify low-risk patients, an initial step in developing a clinical decision rule. METHODS: We retrospectively identified all adults presenting to our emergency department (ED) from January 1, 2006, to August 1, 2010, who underwent CT angiography for suspected AAS without prior trauma or AAS. A total of 1465 patients met inclusion criteria; a retrospective case-controlled review (ratio 1:4) was conducted. Cases were diagnosed with aortic dissection, intramural hematoma, penetrating atherosclerotic ulcer, or ruptured aneurysm. RESULTS: Of the patients who underwent CT, 2.7% (40/1465) had an AAS; 2 additional cases were diagnosed after admission (ED miss rate, 5% [2/42]). Patients with AAS were significantly older than controls (66 vs 59 years; P = .008). Risk factors included abnormal chest radiograph (sensitivity, 79% [26/33]; specificity, 82% [113/137]) and acute chest pain (sensitivity, 83% [29/35]; specificity, 71% [111/157]). None of the 19 patients with resolved pain upon ED presentation had AAS. These data support a 2-step rule: first screen for ongoing pain; if present, screen for acute chest pain or an abnormal chest radiograph. This approach achieves a 54% (84/155) reduction in CT usage with a sensitivity for AAS of 96% (95% confidence interval, 89%-100%), negative predictive value of 99.8% (99.4%-100%), and a false-negative rate of 1.7% (1/84). CONCLUSIONS: Our results demonstrate a need to safely identify patients at low risk for AAS who can forgo CT. We developed a preliminary 2-step clinical decision rule, which requires validation. PMID- 24055478 TI - A unique presentation of renal cell carcinoma: both upper and lower gastrointestinal bleeding. AB - Renal cell carcinoma (RCC) constitutes 3% of all adult malignancies and may present with various symptoms due to local growth, metastasis, and paraneoplastic syndrome. Gastrointestinal hemorrhage because of RCC is a very rare event and more commonly seen as a recurrence of RCC many years after nephrectomy. Both upper and lower gastrointestinal bleeding due to direct invasion of RCC has not been reported yet in the literature. Herein, we report a case of 78-year-old man with both massive upper and lower gastrointestinal bleeding as a presenting symptom of RCC. PMID- 24055479 TI - Predictive value of the Cincinnati Prehospital Stroke Scale for identifying thrombolytic candidates in acute ischemic stroke. AB - BACKGROUND: Despite the usefulness of the Cincinnati Prehospital Stroke Scale (CPSS) for rapid recognition of acute stroke, its ability to assess stroke severity is unclear. We investigated the usefulness of CPSS for assessment of stroke severity by comparing CPSS and National Institutes of Health Stroke Scale (NIHSS) scores in patients who were candidates for thrombolytic therapy at hospital admission within 6 hours of symptom onset. METHODS: We conducted a retrospective analysis of a prospective registry database of consecutive patients included in the brain salvage through emergency stroke therapy program. In the emergency department, CPSS score was determined by emergency medical technicians. A CPSS cut-off score was estimated for candidates of thrombolytic therapy by comparing CPSS and NIHSS scores of patients who actually received thrombolytic therapy. Clinical outcomes were compared among patients with scores near the cut off. Independent predictors of outcome were evaluated by multivariate logistic regression analysis. RESULTS: Strong correlations were observed between CPSS and NIHSS scores within 3 hours (R = 0.778) and 6 hours (R = 0.769) of symptom onset. The optimal cut-off score was 2 for CPSS was associated with actual usage of intravenous tissue plasminogen activator (odds ratio [OR] 34.455; 95% confidence interval [CI] 7.924-149.817, P < .0001) and actual usage of thrombolytic therapy overall (intravenous tissue plasminogen activator or intra-arterial urokinase) (OR 36.310; 95% CI 10.826-121.782, P < .0001). CONCLUSION: The CPSS is an effective prehospital stroke scale for the determination of stroke severity and identification of candidates for thrombolytic therapy. PMID- 24055480 TI - Different urinalysis appearances in children with simple and perforated appendicitis. AB - PURPOSE: This study aimed to determine whether routine urinalysis may serve as a tool in discriminating between acute appendicitis and perforated appendicitis in children. BASIC PROCEDURES: We prospectively collected 357 patients with clinically suspected acute appendicitis. Urinalysis was performed in patients with clinically suspected acute appendicitis before surgical intervention. Routine urinalysis is composed of 2 examinations: chemical tests for abnormal chemical constituents and microscopic tests for abnormal insoluble constituents. Receiver operating characteristic curves for urine white blood cell (WBC) counts and urine red blood cell (RBC) counts in distinguishing between patients with simple appendicitis and patients with perforated appendicitis were also analyzed. MAIN FINDINGS: Urine ketone bodies, leukocyte esterase, specific gravity, pH, WBC, and RBC counts were all significant parameters among patients with normal appendices, simple appendicitis, and perforated appendicitis (all P < .05). Based on multivariate logistic regression analysis, positive urine ketone bodies and nitrate were significant parameters in predicting perforated appendicitis (P = .002 and P = .008, respectively). According to the results of receiver operating characteristic curves, the appropriate cutoff values were 2.0/high-power field for urine RBC counts and 4.0/high-power field for urine WBC counts in predicting perforated appendicitis in children. PRINCIPAL CONCLUSIONS: Routine urinalysis may serve to aid in discriminating between simple and perforated appendicitis. Clinically, we believe that these urine parameters may aid primary emergency physicians with decision making in patients with clinically suspected appendicitis. PMID- 24055481 TI - Efficacy of urine alkalinization by oral administration of sodium bicarbonate: a prospective open-label trial. AB - BACKGROUND: Urine alkalinization is indicated for various medical conditions. Alkalinization is usually achieved by intravenous administration of alkali substances titrated by repeated urinalyses. Some situations such as mass casualty events might require urine alkalinization by the oral route. We evaluated the efficacy of oral sodium bicarbonate administration for urine alkalinization. METHODS: In a prospective open-label trial, 4 g of sodium bicarbonate was administered orally 3 times daily to 9 healthy volunteers for 24 hours. Serial blood and urine samples were collected, and urine pH was evaluated. Plasma electrolytes and pH were also measured for safety purposes. RESULTS: All participants had a urine pH of at least 7 after 10 hours. At 20 hours, all participants had a urine pH of at least 8. No adverse effects or abnormal blood results were documented during the 24-hour follow-up. CONCLUSIONS: Oral administration of a standard dose of sodium bicarbonate tablets resulted in effective urine alkalinization. Further research is needed to investigate the natural course of urine pH after cessation of our protocol and the efficacy of longer periods of treatment. PMID- 24055482 TI - Short series of upper limb acute arterial occlusions in 4 different etiologies and review of literature. AB - Upper limb acute arterial occlusions are uncommon, and when compared with lower limb occlusions, only a few cases have been reported. Although atrial fibrillation is the most common cause, many conditions may lead to ischemia. In this article, 8 cases of upper limb arterial ischemia due to 4 different etiologies were reported (7 brachial, 1 axillary), and the literature was reviewed. PMID- 24055483 TI - Expression profiling of the triterpene saponin biosynthesis genes FPS, SS, SE, and DS in the medicinal plant Panax notoginseng. AB - Panax notoginseng (Burk) F. H. Chen, an economically significant medicinal plant with hemostatic and health tonic activities, has been used in Traditional Chinese Medicine (TCM) for more than 3,000 years. Triterpene saponins are responsible for most of the pharmacological activities of P. notoginseng. Here, we cloned five cDNA sequences encoding the key enzymes involved in triterpene saponin biosynthesis, namely, PnFPS, PnSS, PnSE1, PnSE2, and PnDS, and analyzed the conserved domains and phylogenetics of their corresponding proteins. Their organ specific expression patterns in four-year-old P. notoginseng were detected by real-time PCR, showing that they were all most highly expressed in flowers. In addition, four of the genes, excluding PnSE2, were upregulated in leaves following stimulation with methyl jasmonate. This study is the first comprehensive analysis of the expression patterns of pivotal genes for triterpene saponin biosynthesis in P. notoginseng and provides a basis to further elucidate the molecular mechanism for the biosynthesis of these medically important compounds. PMID- 24055484 TI - Mitochondrial DNA mutations in diabetes mellitus patients in Chinese Han population. AB - BACKGROUND AND OBJECTIVE: Mutations of mitochondrial DNA are associated with diabetes mellitus (DM). The present case-control study aimed to investigate the mutations of mitochondrial DNA in DM patients of Chinese Han ethnicity. METHODS AND RESULTS: A total of 770 DM patients and 309 healthy control individuals were enrolled. The mitochondrial DNA was extracted from blood cells and analyzed by the polymerase chain reaction-restriction fragment length polymorphism assay. In the diabetes group, there were 13 (1.69%) individuals carrying the mt3243 A -> G mutation while none of the healthy control had this mutation. Though the 14709, 3316, 3394, and 12026 mutation variants were identified in 9, 17, 18 and 28 in DM patients respectively, there were no significant differences compared with control group. And the 3256, 8296, 8344, 8363, 3426 and 12258 mutations were not detected in either group. In the diabetes group, two double mutations were identified: A3243G+T3394C and A3243G+A12026G. CONCLUSION: Our data suggested that mitochondrial gene tRNA(Leu(UUR)) 3243 A -> G mutation may be one risk of prevalence of DM and associated with worse clinical status in Chinese Han population. PMID- 24055485 TI - Genetic association of ADIPOQ gene variants with type 2 diabetes, obesity and serum adiponectin levels in south Indian population. AB - OBJECTIVE: To investigate the genetic association of eight variants of the adiponectin gene with type 2 diabetes mellitus (T2DM), obesity and serum adiponectin level in the south Indian population. METHODS: The study comprised of 1100 normal glucose tolerant (NGT) and 1100 type 2 diabetic, unrelated subjects randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Fasting serum adiponectin levels were measured by radioimmunoassay. The variants were screened by polymerase chain reaction restriction fragment length polymorphism. Linkage disequilibrium was estimated from the estimates of haplotype frequencies. RESULTS: Of the 8 variants, four SNPs namely, +276 G/T (rs1501299), -4522 C/T (rs822393), -11365 C/G (rs266729), and +712 G/A (rs3774261) were significantly associated with T2DM in our study population. The -3971 A/G (rs822396) and -11391 G/A (rs17300539) SNPs' association with T2DM diabetes was mediated through obesity (where the association with type 2 diabetes was lost after adjusting for BMI). There was an independent association of +276 G/T (rs1501299) and -3971 A/G (rs822396) SNPs with generalized obesity and +349 A/G (rs2241767) with central obesity. Four SNPs, -3971 A/G (rs822396), +276 G/T (rs1501299), -4522 C/T (rs822393) and Y111H T/C (rs17366743) were significantly associated with hypoadiponectinemia. The haplotypes GCCATGAAT and AGCGTGGGT conferred lower risk of T2DM in this south Indian population. CONCLUSION: The adiponectin gene variants and haplotype contribute to the genetic risk towards the development of type 2 diabetes, obesity and hypoadiponectinemia in the south Indian population. PMID- 24055486 TI - 3q26.31-q29 duplication and 9q34.3 microdeletion associated with omphalocele, ventricular septal defect, abnormal first-trimester maternal serum screening and increased nuchal translucency: prenatal diagnosis and aCGH characterization. AB - We present prenatal diagnosis and array comparative genomic hybridization characterization of 3q26.31-q29 duplication and 9q34.3 microdeletion in a fetus with omphalocele, ventricular septal defect, increased nuchal translucency, abnormal first-trimester maternal screening and facial dysmorphism with distinct features of the 3q duplication syndrome and Kleefstra syndrome. The 26.61-Mb duplication of 3q26.31-q29 encompasses EPHB3, CLDN1 and CLDN16, and the 972-kb deletion of 9q34.3 encompasses EHMT1. We review the literature of partial trisomy 3q associated with omphalocele and discuss the genotype-phenotype correlation in this case. PMID- 24055487 TI - Knockdown of a putative Halloween gene Shade reveals its role in ecdysteroidogenesis in the small brown planthopper Laodelphax striatellus. AB - Ecdysteroid hormone 20-hydroxyecdysone (20E) plays fundamental roles in insect development and reproduction, whereas the primary role of ecdysone (E) is the precursor for 20E. A cytochrome P450 monooxygenase (CYP), encoded by a Halloween gene Shade (Shd, cyp314a1), catalyzes the conversion of E into 20E in representative insect species in Diptera, Lepidoptera and Orthoptera. We describe here the cloning and characterization of LsShd in a hemipteran insect species, the small brown planthopper Laodelphax striatellus. LsSHD has five insect conserved P450 motifs, i.e., Helix-C, Helix-I, Helix-K, PERF and heme-binding motifs. Temporal expression pattern of LsShd was determined through the fourth instar and the early fifth-instar stages by qPCR. LsShd showed two expression peaks in day 2 and day 5 fourth-instar nymphs, and two troughs in day 1 fourth and fifth instars. Dietary introduction of double-stranded RNA (dsRNA) of LsShd into nymphs successfully knocked down the target gene, decreased expression level of ecdysone receptor (LsEcR) gene, and caused nymphal lethality and delayed development. Ingestion of 20E did not increase LsShd expression level, but almost completely rescued LsEcR mRNA level, and relieved the negative effects on the survival and development in LsShd-dsRNA-exposed nymphs. In contrast, dietary introduction of E had little rescue effects. Thus, our data suggest that the ecdysteroidogenic pathway is conserved in insects, and LsSHD functions to regulate metamorphotic processes by converting E to 20E even in a hemipteran insect, L. striatellus. PMID- 24055488 TI - Polymorphic core promoter GA-repeats alter gene expression of the early embryonic developmental genes. AB - Protein complexes that bind to 'GAGA' DNA elements are necessary to replace nucleosomes to create a local chromatin environment that facilitates a variety of site-specific regulatory responses. Three to four elements are required for the disruption of a preassembled nucleosome. We have previously identified human protein-coding gene core promoters that are composed of exceptionally long GA repeats. The functional implication of those GA-repeats is beginning to emerge in the core promoter of the human SOX5 gene, which is involved in multiple developmental processes. In the current study, we analyze the functional implication of GA-repeats in the core promoter of two additional genes, MECOM and GABRA3, whose expression is largely limited to embryogenesis. We report a significant difference in gene expression as a result of different alleles across those core promoters in the HEK-293 cell line. Across-species homology check for the GABRA3 GA-repeats revealed that those repeats are evolutionary conserved in mouse and primates (p<1 * 10(-8)). The MECOM core promoter GA-repeats are also conserved in numerous species, of which human has the longest repeat and complexity. We propose a novel role for GA-repeat core promoters to regulate gene expression in the genes involved in development and evolution. PMID- 24055489 TI - The impact of renin-angiotensin system, angiotensin I converting enzyme (insertion/deletion), and angiotensin II type 1 receptor (A1166C) polymorphisms on breast cancer survival in Iran. AB - INTRODUCTION: Several proteins of renin-angiotensin system (RAS) have been implicated in the process of growth promotion or inhibition of breast tissue and cancer cells. This study aimed to investigate the association between angiotensin I converting enzyme (ACE) insertion/deletion (I/D) and angiotensin receptor-1 (AGTR1) A1166C polymorphisms and survival of 110 women with breast cancer. MATERIALS AND METHODS: The I/D and A1166C polymorphisms were evaluated by using Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) in 110 breast cancer patients who had been treated between 2007 and 2009. Genomic DNA was extracted from a Formalin-Fixed Paraffin-Embedded (FFPE) tissue of breast cancer sample blocks. All the potential clinical and pathological prognostic variables were analyzed to establish the impact of I/D and A1166C polymorphisms on disease-free and overall survival rates. Disease-free and overall survival rates were the primary endpoints of the study. RESULTS: The ACE (I/D) polymorphism was associated with 3-year disease-free survival. Disease-free survival in DD carriers was significantly increased compared to ID plus II carriers (HR=4.75; 95% CI, 1.39-16.24; p=0.013). No significant association was found between AGTR1 (A1166C) and 3-year disease-free survival (p=0.233). Also, the ACE (I/D) and AGTR1 (A1166C) polymorphisms were not associated with breast cancer overall survival. CONCLUSION: The ACE (I/D) polymorphism was associated with 3-year disease-free survival of the women with breast cancer. Besides, disease-free survival in DD carriers was significantly increased compared to ID plus II carriers. PMID- 24055490 TI - Does time matter? An investigation of knowledge and attitudes following blood transfusion training. AB - The Scottish National Blood Transfusion service have developed an educational programme aimed at ensuring a high standard of care for blood transfusions to minimise risk to patients and healthcare practitioners. This paper investigates whether knowledge and understanding of, and attitudes towards, safe practice declined over time following completion of module 1 of the programme. An online survey was administered to a range of healthcare practitioners who had completed the module. The survey tool tested knowledge and ascertained views on blood transfusion practice and perceptions of the module's importance. Comparisons were made between participants 6-8 weeks, 12-14 months and 22-24 months since module completion. In-depth interviews were conducted with a sub-sample of survey respondents to explore attitudes in more detail. Findings indicate evidence of a slight though statistically significant reduction in the degree of emphasis respondents placed on the importance of understanding aspects of transfusions as time lapsed, but no difference was found in knowledge between those who took the course more recently and those who were up to two years post-module. The study's findings indicate that recognition of the importance of safe practice declines over time and thus also suggests that frequent refresher courses are important to maintain safe practice. PMID- 24055491 TI - [Considerations on the design of a new competency-based resident programme and the need to combine it with the classic teaching-learning model]. PMID- 24055492 TI - Combined epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor and chemotherapy in non-small-cell lung cancer: chemo-refractoriness of cells harboring sensitizing-EGFR mutations in the presence of gefitinib. AB - BACKGROUND: Combined epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with chemotherapy is believed to be more effective in treating non small-cell lung cancer (NSCLC) with sensitizing-EGFR mutation (SEM). This hypothesis failed to be realized clinically and needs to be examined in vitro. MATERIALS AND METHODS: Using the tetrazolium colorimetric assay and classical isobole method, we investigated the combination effects of 6 gefitinib chemotherapeutic doublets (gefitinib/cisplatin, gemcitabine, pemetrexed, paclitaxel, docetaxel, or vinorelbine) in a panel of 15 NSCLC cell lines. RESULTS: Upon treatment with the 6 gefitinib-chemotherapeutic doublets, the 12 cell lines that did not harbor SEM displayed a broad spectrum of group results, from obvious synergism to robust antagonism. The values of group mean combination index (mCIs) ranged from 0.769 to 1.201. In contrast, the 3 cell lines with SEM showed a tendency toward consistent antagonism to the tested doublets, impressively, with a narrow range of higher group mCIs (0.993-1.141). In the presence of gefitinib, the SEM or gefitinib-sensitive group was more chemo refractory than the non-SEM (index of chemo-refractoriness (RI): 69.33 versus 42.67; P = 0.036) or gefitinib-resistant group (68.25 versus 40.64, P = 0.0108), respectively. The results of using the gefitinib/drug combinations with the gefitinib-sensitive non-SEM cell line H322 and the gefitinib-resistant EGFR mutant H820 shared patterns similar to those with the SEM and non-SEM cell lines, respectively. CONCLUSION: Gefitinib-treated EGFR-TKI-sensitive NSCLC cells showed a wide spectrum of chemo-refractoriness, suggesting that concomitantly combined EGFR-TKI-chemotherapy might not be a good treatment strategy for NSCLC harboring SEM. PMID- 24055493 TI - Incentive loss and hippocampal gene expression in inbred Roman high- (RHA-I) and Roman low- (RLA-I) avoidance rats. AB - Two recent microarray and qRT-PCR studies showed that inbred Roman high- (RHA-I, low anxiety and frustration vulnerability) and low-avoidance (RLA-I, high anxiety and frustration vulnerability) rats, psychogenetically selected on the basis of their divergence in two-way avoidance performance, differed in basal whole-brain and hippocampal expression of genes related to neurotransmission, emotion, stress, aversive learning, and drug seeking behavior. We have extended these studies by analyzing strain differences in hippocampal gene expression following a frustrative experience involving reward downshift, i.e. instrumental successive negative contrast (iSNC), a phenomenon in which the sudden reduction of an expected reward induces frustration/anxiety. Food-deprived male Roman rats were exposed to a reduction in the amount of solid food presented in the goal of a straight alley (from 12 pellets in "training" trials - i.e. preshift trials- to 2 pellets in "frustration testing" trials - i.e. postshift trials-). The iSNC effect, as measured by response latencies in the "postshift" trials, appeared only in RLA-I rats (i.e. higher response latencies in the 12-2 RLA-I group as compared to the 2-2 RLA-I control group in postshift trials). Two and a half hours after the "postshift" behavioral test, hippocampi were removed and stored ( 80 degrees C) until analysis. Microarray analysis of these hippocampi showed that four differentially-expressed, and qRT-PCR-validated genes (TAAR2, THAP1, PKD2L1, NANOS), have relevance for brain function and behavior, including schizophrenia, depression, anxiety, and drug addiction, thus showing the usefulness of Roman strains as a genetic model for research on the neurogenetic basis of frustration. PMID- 24055494 TI - Zebrafish as a model system for mitochondrial biology and diseases. AB - Animal models for studying human disease are essential to the continuing evolution of medicine. Rodent models are attractive for the obvious similarities in development and genetic makeup compared with humans, but have cost and technical limitations. The zebrafish (Danio rerio) represents an ideal alternative vertebrate model of human disease because of its high conservation of genetic information and physiological processes, inexpensive maintenance, and optical clarity facilitating direct observation. This review highlights recent advances in understanding genetic disease states associated with the dynamic organelle, the mitochondrion, using the zebrafish. Mitochondrial diseases that have been replicated in the zebrafish include those affecting the nervous and cardiovascular systems, as well as red blood cell function. Gene silencing techniques, including morpholino knockdown and transcription activator-like (TAL) effector endonucleases, have been exploited to demonstrate how loss of function can induce human disease-like states in zebrafish. Moreover, modeling mitochondrial diseases has been facilitated greatly by the creation of transgenic fish with fluorescently labeled mitochondria for in vivo visualization of these structures. In addition, behavioral assays have been developed to examine changes in motor activity and sensory responses, particularly in larval stages. Zebrafish are poised to advance our understanding of the pathogenesis of human mitochondrial diseases beyond the current state of knowledge and provide a key tool in the development of novel therapeutic approaches to treat these conditions. PMID- 24055495 TI - Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin. AB - Basic and clinical research has demonstrated that dementia of sporadic Alzheimer's disease (sAD) type is associated with dysfunction of the insulin receptor (IR) system followed by decreased glucose transport via glucose transporter GLUT4 and decreased glucose metabolism in brain cells. An alternative source of energy is d-galactose (the C-4-epimer of d-glucose) which is transported into the brain by insulin-independent GLUT3 transporter where it might be metabolized to glucose via the Leloir pathway. Exclusively parenteral daily injections of galactose induce memory deterioration in rodents and are used to generate animal aging model, but the effects of oral galactose treatment on cognitive functions have never been tested. We have investigated the effects of continuous daily oral galactose (200 mg/kg/day) treatment on cognitive deficits in streptozotocin-induced (STZ-icv) rat model of sAD, tested by Morris Water Maze and Passive Avoidance test, respectively. One month of oral galactose treatment initiated immediately after the STZ-icv administration, successfully prevented development of the STZ-icv-induced cognitive deficits. Beneficial effect of oral galactose was independent of the rat age and of the galactose dose ranging from 100 to 300 mg/kg/day. Additionally, oral galactose administration led to the appearance of galactose in the blood. The increase of galactose concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same galactose dose. Oral galactose exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of cognitive deficits associated with glucose hypometabolism in AD. PMID- 24055496 TI - A glimpse into the future - Personalized medicine for smoking cessation. AB - The devastating consequences of tobacco smoking for individuals and societies motivate studies to identify and understand the biological pathways that drive smoking behaviors, so that more effective preventions and treatments can be developed. Cigarette smokers respond to nicotine in different ways, with a small number of smokers remaining lifelong low-level smokers who never exhibit any symptoms of dependence, and a larger group becoming nicotine dependent. Whether or not a smoker transitions to nicotine dependence has clear genetic contributions, and variants in the genes encoding the alpha5-alpha3-beta4 nicotinic receptor subunits most strongly contribute to differences in the risk for developing nicotine dependence among smokers. More recent work reveals a differential response to pharmacologic treatment for smoking cessation based on these same genetic variants in the alpha5-alpha3-beta4 nicotinic receptor gene cluster. We anticipate a continuing acceleration of the translation of genetic discoveries into more successful treatment for smoking cessation. Given that over 400,000 people in the United States and over 5 million people world-wide die each year from smoking related illnesses, an improved understanding of the mechanisms underlying smoking behavior and smoking cessation must be a high public health priority so we can best intervene at both the public health level and the individual level. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 24055498 TI - Inhibition of aberrant cyclin-dependent kinase 5 activity attenuates isoflurane neurotoxicity in the developing brain. AB - Aberrant CDK5 activity is implicated in a number of neurodegenerative disorders. Isoflurane exposure leads to neuronal apoptosis, and subsequent learning and memory defects in the developing brain. The present study was designed to examine whether and how CDK5 activity plays a role in developmental isoflurane neurotoxicity. Rat pups and hippocampal neuronal cultures were exposed to 1.5% isoflurane for 4 h. The protein and mRNA levels of CDK5, p35 and p25 were detected by western blot and QReal-Time PCR. CDK5 activity was evaluated in vitro using Histone H1 as a substrate. Roscovitine (an inhibitor of CDK5) was applied before isoflurane treatment, cleaved Caspase-3, Bcl-2, Bax, MEF2 and phospho MEF2A-Ser-408 expressions were determined. Dominant-Negative CDK5 was transfected before isoflurane treatment. Neuronal apoptosis was evaluated by Flow cytometry (FCM) and TUNEL-staining. Cognitive functions were assessed by Morris water maze. We found that isoflurane treatment led to an aberrant CDK5 activation due to its activator p25 that was cleaved from p35 by calpain. Inhibition of CDK5 activity with Roscovitine enhanced Bcl-2, and decreased cleaved Caspase-3 and Bax expressions. In addition, isoflurane exposure resulted in a decrease of MEF2 and increase of phospho-MEF2A-Ser-408, which were rescued by Roscovitine or Dominant Negative CDK5 transfection. Dominant-Negative CDK5 transfection also decreased the percentage of TUNEL-positive cells in isoflurane neurotoxicity. Moreover, Roscovitine remarkably alleviated the learning and memory deficits induced by postnatal isoflurane exposure. These results indicated that aberrant CDK5 activity-dependent MEF2 phosphorylation mediates developmental isoflurane neurotoxicity. Inhibition of CDK5 overactivation contributes to the relief of isoflurane neurotoxicity in the developing brain. PMID- 24055497 TI - Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability. AB - Nicotine stimulates brain reward circuitries, most prominently the mesocorticolimbic dopamine system, and this action plays a critical in establishing and maintaining the tobacco smoking habit. Compounds that attenuate nicotine reward are considered promising therapeutic candidates for tobacco dependence, but many of these agents have other actions that limit their potential utility. Nicotine is also highly noxious, particularly at higher doses, and aversive reactions to nicotine after initial exposure can decrease the likelihood of developing a tobacco habit in many first time smokers. Nevertheless, relatively little is known about the mechanisms of nicotine aversion. The purpose of this review is to present recent new insights into the neurobiological mechanisms that regulate avoidance of nicotine. First, the role of the mesocorticolimbic system, so often associated with nicotine reward, in regulating nicotine aversion is highlighted. Second, genetic variation that modifies noxious responses to nicotine and thereby influences vulnerability to tobacco dependence, in particular variation in the CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster, will be discussed. Third, the role of the habenular complex in nicotine aversion, primarily medial habenular projections to the interpeduncular nucleus (IPN) but also lateral habenular projections to rostromedial tegmental nucleus (RMTg) and ventral tegmental area (VTA) are reviewed. Forth, brain circuits that are enriched in nAChRs, but whose role in nicotine avoidance has not yet been assessed, will be identified. Finally, the feasibility of developing novel therapeutic agents for tobacco dependence that act not by blocking nicotine reward but by enhancing nicotine avoidance will be considered. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 24055499 TI - Chrna5 genotype determines the long-lasting effects of developmental in vivo nicotine exposure on prefrontal attention circuitry. AB - Maternal smoking during pregnancy repeatedly exposes the developing fetus to nicotine and is linked with attention deficits in offspring. Corticothalamic neurons within layer VI of the medial prefrontal cortex are potential targets in the disruption of attention circuitry by nicotine, a process termed teratogenesis. These prefrontal layer VI neurons would be likely targets because they are developmentally excited and morphologically sculpted by a population of nicotinic acetylcholine receptors (nAChRs) that are sensitive to activation and/or desensitization by nicotine. The maturational effects of these alpha4beta2* nAChRs and their susceptibility to desensitization are both profoundly altered by the incorporation of an alpha5 subunit, encoded by the chrna5 gene. Here, we investigate nicotine teratogenesis in layer VI neurons of wildtype and alpha5(-/-) mice. In vivo chronic nicotine exposure during development significantly modified apical dendrite morphology and nAChR currents, compared with vehicle control. The direction of the changes was dependent on chrna5 genotype. Surprisingly, neurons from wildtype mice treated with in vivo nicotine resembled those from alpha5(-/-) mice treated with vehicle, maintaining into adulthood a morphological phenotype characteristic of immature mice together with reduced nAChR currents. In alpha5(-/-) mice, however, developmental in vivo nicotine tended to normalize both adult morphology and nAChR currents. These findings suggest that chrna5 genotype can determine the effect of developmental in vivo nicotine on the prefrontal cortex. In wildtype mice, the lasting alterations to the morphology and nAChR activation of prefrontal layer VI neurons are teratogenic changes consistent with the attention deficits observed following developmental nicotine exposure. PMID- 24055500 TI - Characterization of altered intrinsic excitability in hippocampal CA1 pyramidal cells of the Abeta-overproducing PDAPP mouse. AB - Transgenic mice that accumulate Abeta peptides in the CNS are commonly used to interrogate functional consequences of Alzheimer's disease-associated amyloidopathy. In addition to changes to synaptic function, there is also growing evidence that changes to intrinsic excitability of neurones can arise in these models of amyloidopathy. Furthermore, some of these alterations to intrinsic properties may occur relatively early within the age-related progression of experimental amyloidopathy. Here we report a detailed comparison between the intrinsic excitability properties of hippocampal CA1 pyramidal neurones in wild type (WT) and PDAPP mice. The latter is a well-established model of Abeta accumulation which expresses human APP harbouring the Indiana (V717F) mutation. At the age employed in this study (9-10 months) CNS Abeta was elevated in PDAPP mice but significant plaque pathology was absent. PDAPP mice exhibited no differences in subthreshold intrinsic properties including resting potential, input resistance, membrane time constant and sag. When CA1 cells of PDAPP mice were given depolarizing stimuli of various amplitudes they initially fired at a higher frequency than WT cells. Commensurate with this, PDAPP cells exhibited a larger fast afterdepolarizing potential. PDAPP mice had narrower spikes but action potential threshold, rate of rise and peak were not different. Thus not all changes seen in our previous studies of amyloidopathy models were present in PDAPP mice; however, narrower spikes, larger ADPs and the propensity to fire at higher frequencies were consistent with our prior work and thus may represent robust, cross-model, indices of amyloidopathy. This article is part of a Special Issue entitled 'Neurodevelopment Disorder'. PMID- 24055501 TI - Presynaptic 5-HT1B receptor-mediated synaptic suppression to the subplate neurons in the somatosensory cortex of neonatal rats. AB - Serotonin (5-HT), the target of numerous psychiatric medicines, plays important roles in neural development. In this study we examined the direct effects of 5-HT on the physiological properties of neurons in the cortical subplate, a structure that develops early in life and is important for the maturation of cortical circuits. Acute brain slices were prepared from neonatal rats and the intrinsic and synaptic properties of subplate neurons (SPns) were evaluated before and after 5-HT bath-application. In all concentrations tested, 5-HT did not affect the intrinsic properties of SPns. However, thalamus-evoked excitatory postsynaptic currents (eEPSCs) in SPn were significantly suppressed by 5-HT in a dose-dependent manner. Because 5-HT did not affect AMPA- or NMDA-induced currents, it is unlikely that a 5-HT-mediated postsynaptic mechanism reduced EPSCs. Subsequent to 5-HT application, increased paired-pulse ratios and decreased MK-801 blocking rates were noted, indicating the presence of a presynaptic 5-HT receptor-mediated suppressive effect in the thalamocortical afferent (TCA)-SPn synapses. To elucidate the type(s) of 5-HT receptor involved in this process, various 5-HT receptor agonists and antagonists were tested. CP93129, a 5-HT(1B) receptor agonist, mimicked the effect of 5-HT and in the contrary, the 5-HT(1B) receptor antagonist SB224289 prevented 5-HT-mediated synaptic suppression. Our cumulative data demonstrated the presynaptic 5-HT(1B) receptor-mediated suppressive effect on the excitatory synapses between TCAs and SPns in the somatosensory cortex of neonatal rats. Early exposure to drugs that might interrupt 5-HT homeostasis should be considered. PMID- 24055503 TI - The ubiquitin-proteasome-system. PMID- 24055502 TI - The actions of Pasteurella multocida toxin on neuronal cells. AB - Pasteurella multocida toxin (PMT) activates the G-proteins Galphai(1-3), Galpha(q), Galpha11, Galpha12 and Galpha13 by deamidation of specific glutamine residues. A number of these alpha subunits have signalling roles in neurones. Hence we studied the action of this toxin on rat superior cervical ganglion (SCG) neurones and NG108-15 neuronal cells. Both Galpha(q) and Galpha11 could be identified in SCGs with immunocytochemistry. PMT had no direct action on Kv7 or Cav2 channels in SCGs. However PMT treatment enhanced muscarinic receptor mediated inhibition of M-current (Kv7.2 + 7. 3) as measured by a 19-fold leftward shift in the oxotremorine-M concentration-inhibition curve. Agonists of other receptors, such as bradykinin or angiotensin, that inhibit M-current did not produce this effect. However the amount of PIP2 hydrolysis could be enhanced by PMT for all three agonists. In a transduction system in SCGs that is unlikely to be affected by PMT, Go mediated inhibition of calcium current, PMT was ineffective whereas the response was blocked by pertussis toxin as expected. M1 muscarinic receptor evoked calcium mobilisation in transformed NG108-15 cells was enhanced by PMT. The calcium rises evoked by uridine triphosphate acting on endogenous P2Y2 receptors in NG108-15 cells were enhanced by PMT. The time and concentration dependence of the PMT effect was different for the resting calcium compared to the calcium rise produced by activation of P2Y2 receptors. PMT's action on these neuronal cells would suggest that if it got into the brain, symptoms of a hyperexcitable nature would be seen, such as seizures. PMID- 24055504 TI - A comparison of statistical methods for detecting context-modulated functional connectivity in fMRI. AB - Many cognitive and clinical neuroscience research studies seek to determine how contextual factors modulate cognitive processes. In fMRI, hypotheses about how context modulates distributed patterns of information processing are often tested by comparing functional connectivity between neural regions A and B as a function of task conditions X and Y, which is termed context-modulated functional connectivity (FC). There exist two exploratory statistical approaches to testing context-modulated FC: the beta-series method and psychophysiological interaction (PPI) analysis methods. While these approaches are commonly used, their relative power for detecting context-modulated FC is unknown, especially with respect to real-world experimental parameters (e.g., number of stimulus repetitions, inter trial-interval, stimulus duration). Here, we use simulations to compare power for detecting context-modulated FC between the standard PPI formulation (sPPI), generalized PPI formulation (gPPI), and beta series methods. Simulation results demonstrate that gPPI and beta series methods are generally more powerful than sPPI. Whether gPPI or beta series methods performed more powerfully depended on experiment parameters: block designs favor the gPPI, whereas the beta series method was more powerful for designs with more trial repetitions and it also retained more power under conditions of hemodynamic response function variability. On a real dataset of adolescent girls, the PPI methods appeared to have greater sensitivity in detecting task-modulated FC when using a block design and the beta series method appeared to have greater sensitivity when using an event-related design with many trial repetitions. Implications of these performance results are discussed. PMID- 24055505 TI - Hierarchical unbiased graph shrinkage (HUGS): a novel groupwise registration for large data set. AB - Normalizing all images in a large data set into a common space is a key step in many clinical and research studies, e.g., for brain development, maturation, and aging. Recently, groupwise registration has been developed for simultaneous alignment of all images without selecting a particular image as template, thus potentially avoiding bias in the registration. However, most conventional groupwise registration methods do not explore the data distribution during the image registration. Thus, their performance could be affected by large inter subject variations in the data set under registration. To solve this potential issue, we propose to use a graph to model the distribution of all image data sitting on the image manifold, with each node representing an image and each edge representing the geodesic pathway between two nodes (or images). Then, the procedure of warping all images to their population center turns to the dynamic shrinking of the graph nodes along their graph edges until all graph nodes become close to each other. Thus, the topology of image distribution on the image manifold is always preserved during the groupwise registration. More importantly, by modeling the distribution of all images via a graph, we can potentially reduce registration error since every time each image is warped only according to its nearby images with similar structures in the graph. We have evaluated our proposed groupwise registration method on both infant and adult data sets, by also comparing with the conventional group-mean based registration and the ABSORB methods. All experimental results show that our proposed method can achieve better performance in terms of registration accuracy and robustness. PMID- 24055506 TI - Test-retest reliability of fMRI-based graph theoretical properties during working memory, emotion processing, and resting state. AB - The investigation of the brain connectome with functional magnetic resonance imaging (fMRI) and graph theory analyses has recently gained much popularity, but little is known about the robustness of these properties, in particular those derived from active fMRI tasks. Here, we studied the test-retest reliability of brain graphs calculated from 26 healthy participants with three established fMRI experiments (n-back working memory, emotional face-matching, resting state) and two parcellation schemes for node definition (AAL atlas, functional atlas proposed by Power et al.). We compared the intra-class correlation coefficients (ICCs) of five different data processing strategies and demonstrated a superior reliability of task-regression methods with condition-specific regressors. The between-task comparison revealed significantly higher ICCs for resting state relative to the active tasks, and a superiority of the n-back task relative to the face-matching task for global and local network properties. While the mean ICCs were typically lower for the active tasks, overall fair to good reliabilities were detected for global and local connectivity properties, and for the n-back task with both atlases, smallworldness. For all three tasks and atlases, low mean ICCs were seen for the local network properties. However, node specific good reliabilities were detected for node degree in regions known to be critical for the challenged functions (resting-state: default-mode network nodes, n-back: fronto-parietal nodes, face-matching: limbic nodes). Between-atlas comparison demonstrated significantly higher reliabilities for the functional parcellations for global and local network properties. Our findings can inform the choice of processing strategies, brain atlases and outcome properties for fMRI studies using active tasks, graph theory methods, and within-subject designs, in particular future pharmaco-fMRI studies. PMID- 24055507 TI - Bioreducible hyaluronic acid conjugates as siRNA carrier for tumor targeting. AB - The successful clinical translation of siRNA-based therapeutics requires efficient carrier systems that can specifically deliver siRNA within the cytosol of the target cells. Although numerous polymeric nanocarriers forming ionic complexes with siRNA have been investigated for cancer therapy, their poor stability and lack of tumor targetability have impeded their in vivo applications. To surmount these limitations, we synthesized a novel type of biodegradable hyaluronic acid-graft-poly(dimethylaminoethyl methacrylate) (HPD) conjugate that can form complexes with siRNA and be chemically crosslinked via the formation of the disulfide bonds under facile conditions. The crosslinked siRNA-HPD (C-siRNA-HPD) complexes exhibited high stability in a 50% serum solution, as compared to the uncrosslinked siRNA-HPD (U-siRNA-HPD) complexes and free siRNA. Both the C-siRNA-HPD and U-siRNA-HPD complexes were efficiently taken up by the CD44-overexpressing melanoma cells (B16F10), but not by the normal fibroblast cells (NIH3T3). When the RFP-expressing B16F10 cells were treated with the complexes or free siRNA, the C-siRNA-HPD complexes showed the highest decrease in RFP expression. In vivo studies demonstrated the selective accumulation of C-siRNA-HPD complexes at the tumor site after their systemic administration into tumor-bearing mice, resulting in an efficient gene silencing effect. Overall, these results suggest that the HPD conjugate could be used as an efficient carrier for the tumor-targeted delivery of siRNA. PMID- 24055509 TI - Cloning, molecular characterization, and expression analysis of the signal transducer and activator of transcription 3 (STAT3) gene from grass carp (Ctenopharyngodon idellus). AB - Signal transducer and activator of transcription 3 (STAT3) binds to Janus kinase 2 (JAK2) to initiate the JAK2/STAT3 signal transduction pathway, which plays an important role in cancer cell proliferation, immune regulation, reproduction, lipid metabolism, and other physiological processes of the organism. In this study, the cDNA sequence of the STAT3 gene from grass carp was cloned using RACE (rapid-amplification of cDNA ends). Twelve characteristics of the STAT3 gene and its encoded protein sequence were predicted and analyzed using bioinformatics methods; these features included the general physical and chemical properties, the hydrophobicity, the secondary structure and the three-dimensional structure of the protein. Quantitative real-time PCR was employed to detect grass carp STAT3 expression pattern in different tissues. The results showed that the full length STAT3 gene from grass carp is 2739-bp long and contains a 216-bp 5'UTR, a 300-bp 3'UTR, and a 2223-bp open reading frame (ORF) that encodes a 740-amino acid peptide. The deduced protein exhibited 99%~94% homology to the STAT3 protein of zebrafish (Danio rerio), medaka (Oryzias latipes), turbot (Scophthalmus maximus), white-spotted char (Salvelinus leucomaenis), mandarin fish (Siniperca chuatsi), rainbow trout (Oncorhynchus mykiss), and green pufferfish (Tetraodon fluviatilis). The deduced grass carp STAT3 protein contains a protein interaction domain, an alpha domain, a DNA binding domain, and an SH2 domain. The STAT3 protein of grass carp is a hydrophilic and non-secretory protein, and its molecular mass and isoeletronic point were found to be 98,5412.1 Da and 6.39, respectively. The structural elements of STAT3 included alpha-helixes, beta sheets, and loops. The grass carp STAT3 is expressed in all of the six tissues tested, which were the liver, spleen, gill, muscle, heart, and brain. The highest expression level was found in the liver (P < 0.05), whereas a significantly lower expression level was found in the spleen, gills, brain, and muscle (P < 0.05), and the lowest expression level was found in the heart (P < 0.05). This study provides a basis for further structural and functional exploration of the STAT3 from grass carp, including its deduced protein and its signal transduction function. PMID- 24055508 TI - Leptin receptor somatic mutations are frequent in HCV-infected cirrhotic liver and associated with hepatocellular carcinoma. AB - BACKGROUND & AIMS: Hepatocellular carcinoma develops in patients with chronic hepatitis or cirrhosis via a stepwise accumulation of various genetic alterations. To explore the genetic basis of development of hepatocellular carcinoma in hepatitis C virus (HCV)-associated chronic liver disease, we evaluated genetic variants that accumulate in nontumor cirrhotic liver. METHODS: We determined the whole exome sequences of 7 tumors and background cirrhotic liver tissues from 4 patients with HCV infection. We then performed additional sequencing of selected exomes of mutated genes, identified by whole exome sequencing, and of representative tumor-related genes on samples from 22 cirrhotic livers with HCV infection. We performed in vitro and in vivo functional studies for one of the mutated genes. RESULTS: Whole exome sequencing showed that somatic mutations accumulated in various genes in HCV-infected cirrhotic liver tissues. Among the identified genes, the leptin receptor gene (LEPR) was one of the most frequently mutated in tumor and nontumor cirrhotic liver tissue. Selected exome sequencing analyses detected LEPR mutations in 12 of 22 (54.5%) nontumorous cirrhotic livers. In vitro, 4 of 7 (57.1%) LEPR mutations found in cirrhotic livers reduced phosphorylation of STAT3 to inactivate LEPR-mediated signaling. Moreover, 40% of Lepr-deficient (C57BL/KsJ-db/db) mice developed liver tumors after administration of thioacetamide compared with none of the control mice. CONCLUSIONS: Based on analysis of liver tissue samples from patients, somatic mutations accumulate in LEPR in cirrhotic liver with chronic HCV infection. These mutations could disrupt LEPR signaling and increase susceptibility to hepatocarcinogenesis. PMID- 24055510 TI - Genomic structure and immunological response of an STAT4 family member from rock bream (Oplegnathus fasciatus). AB - The Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway plays a critical role in host defense against viral and bacterial infections. STAT proteins are a group of transcription factors that translocate into the nucleus and are critical for the induction of many genes crucial for the allergic cascade and immune defense. In the present study, a member of the STAT4 family was identified from rock bream (RbSTAT4) at the genomic level, and its transcriptional regulation in response to different pathological stimuli under in vivo conditions was investigated. The genomic sequence of RbSTAT4 is approximately 15.6 kb in length, including a putative core promoter region and 24 exons interrupted by 23 introns. Bioinformatics analysis of RbSTAT4 identified the presence of typical and conserved features of the STAT4 family, including the STAT_int domain, STAT alpha domain, STAT bind domain, linker domain, SH2 domain, and transcriptional activation domain. According to the phylogenetic analysis, RbSTAT4 exhibited the closest evolutionary proximity with the STAT4 member from mandarin fish (Siniperca chuatsi). The RbSTAT4 transcript in healthy rock breams was detected to have ubiquitous expression in 11 different tissues examined, where liver and spleen tissues showed moderate expressions compared with the highest expression level detected in gill tissue. The time-course in vivo immune stimulation of rock bream with lipopolysaccharide, poly I:C, live Edwardsiella tarda, and rock bream iridovirus caused significant transcriptional regulation of the RbSTAT4 expression in gill, head kidney, and spleen tissues, suggesting that RbSTAT4 is involved in immune regulation mechanisms and/or signaling cascades, orchestrating against both bacterial and viral pathogens. PMID- 24055511 TI - Valeriana officinalis extract and its main component, valerenic acid, ameliorate D-galactose-induced reductions in memory, cell proliferation, and neuroblast differentiation by reducing corticosterone levels and lipid peroxidation. AB - Valeriana officinalis is used in herbal medicine of many cultures as mild sedatives and tranquilizers. In this study, we investigated the effects of extract from valerian root extracts and its major component, valerenic acid on memory function, cell proliferation, neuroblast differentiation, serum corticosterone, and lipid peroxidation in adult and aged mice. For the aging model, D-galactose (100 mg/kg) was administered subcutaneously to 6-week-old male mice for 10 weeks. At 13 weeks of age, valerian root extracts (100 mg/kg) or valerenic acid (340 MUg/kg) was administered orally to control and D-galactose treated mice for 3 weeks. The dosage of valerenic acid (340 MUg/kg), which is the active ingredient of valerian root extract, was determined by the content of valerenic acid in valerian root extract (3.401+/-0.066 mg/g) measured by HPLC. The administration of valerian root extract and valerenic acid significantly improved the preferential exploration of new objects in novel object recognition test and the escape latency, swimming speeds, platform crossings, and spatial preference for the target quadrant in Morris water maze test compared to the D galactose-treated mice. Cell proliferation and neuroblast differentiation were significantly decreased, while serum corticosterone level and lipid peroxidation in hippocampus were significantly increased in the D-galactose-treated group compared to that in the control group. The administration of valerian root extract significantly ameliorated these changes in the dentate gyrus of both control and D-galactose-treated groups. In addition, valerenic acid also mitigated the D-galactose-induced reduction of these changes. These results indicate that valerian root extract and valerenic acid enhance cognitive function, promote cell proliferation and neuroblast differentiation, and reduce serum corticosterone and lipid peroxidation in aged mice. PMID- 24055512 TI - Vacuum-assisted wound closure versus alginate for the treatment of deep perivascular wound infections in the groin after vascular surgery. AB - BACKGROUND: Vacuum-assisted wound closure (VAC) therapy may heal wounds faster than conventional dressings after surgical debridement of perivascular groin infections after vascular surgery. METHODS: Patients with deep infected wounds (Szilagyi grade III) were surgically revised and left open for secondary healing, then randomized to either VAC or alginate (Sorbalgon) therapy, between February 2007 and November 2011. To test the hypothesis, it was calculated that 42 patients needed to be included (90% power, 5% level of significance). It was decided to perform an interim analysis after inclusion of 20 patients. RESULTS: Among 66 patients undergoing groin revision, 20 patients were included in this study. Patients were randomized to VAC (n = 10) or alginate (n = 10). The two groups were comparable in patient and wound characteristics. Time to full skin epithelialization was significantly shorter in the VAC group (median, 57 days) compared with the alginate group (median, 104 days; P = .026). The number of positive wound cultures of bacteria and C-reactive protein values decreased equally in both groups between surgical revision and day 21. One femur amputation was performed in each group as a consequence of the groin infection, one patient died during the in-hospital stay in the alginate group, and none died in the VAC group. CONCLUSIONS: VAC achieves faster healing than alginate therapy after wound debridement for deep perivascular wound infections in the groin after vascular surgery. This finding does not allow further inclusion of patients from an ethical point of view, and this study was, therefore, stopped prematurely. PMID- 24055513 TI - ITalian Excluder Registry and results of Gore Excluder endograft for the treatment of elective infrarenal abdominal aortic aneurysms. AB - BACKGROUND: To report the midterm results of elective endovascular aortic repair (EVAR) of abdominal aortic aneurysms (AAAs) in a multicenter, clinical unsponsored registry using the Gore Excluder endograft. METHODS: This study is a retrospective analysis of a multicenter, prospective registry that involved nine centers in Italy. Periodic clinical and radiographic follow-up with computed tomography scans were performed at 1, 6, and 12 months after the procedure, and on a yearly basis thereafter. RESULTS: A total of 872 patients underwent elective EVAR. Primary technical success was 97.5%, and hospital mortality was 1.0% (9/872). At least 816 (93.6%) patients underwent a follow-up control. Freedom from all-cause death was estimated to be 97.9% at 1 year, 93.4% at 3 years, and 88.5% at 5 years. Aneurysm-related mortality was 1.6% (n = 13) with only two late AAA-related deaths observed at 21 and 36 months. Significant predictors of all cause mortality included age (P < .001) and AAA maximum diameter (P = .027). Overall conversion rate was 2.3% (n = 19). Mean elapsed time from initial intervention to surgical conversion was 23 +/- 18 months (range, 0-52 months). Late rupture was detected in four (0.5%) cases: two of these patients died after conversion. The rate of any reintervention was 9.4% (n = 77); most of them were required within the first 24 months. The leading cause of reintervention was endoleak (n = 41; 5.0%). Limb thrombosis occurred in nine (1.1%) cases. Freedom from reintervention at 1, 3, and 5 years of follow-up were 98.6%, 94.6%, and 86.5%. CONCLUSIONS: The ITalian Gore Excluder Registry is the largest clinical unsponsored registry using a single device, with the longest follow-up period so far. The present experience confirms the effectiveness of EVAR using the Gore Excluder with low rates of mortality, migration, reintervention, and limb thrombosis. PMID- 24055514 TI - Potential role of erythropoietin receptors and ligands in attenuating apoptosis and inflammation in critical limb ischemia. AB - OBJECTIVE: Managing critical limb ischemia (CLI) is challenging. Furthermore, ischemic myopathy prevents good functional outcome after revascularization. Hence, we have focused on limiting the tissue damage rather than angiogenesis, which has traditionally been the motivation to develop nonsurgical treatments for CLI. Erythropoietin (EPO) protects ischemic tissue, and this property may also benefit CLI. The objective of this study was to examine the expression of the tissue-protective EPO receptor complex (EPOR-CD131 [beta-chain of interleukin (IL)-3/IL-5/granulocyte macrophage colony-stimulating factor receptor]) in skeletal muscle obtained from humans with CLI. Because native EPO is thrombogenic, the antiapoptotic and anti-inflammatory effects of a nonhematopoietic helix-B peptide of EPO (ARA 290) were investigated on ischemic myotubes in vitro. METHODS: Tissue was obtained from gastrocnemius muscle of 12 patients undergoing amputation for CLI and from 12 patients without limb ischemia. The expression of EPOR and CD131 was demonstrated by immunohistochemistry and Western blot. A validated in vitro model of myotube ischemia was used in which mature C2C12 myotubes were cultured 6 to 12 hours in a depleted media and gas mixture (20% CO2 and 80% N2). The myotubes were pretreated with EPO or ARA 290 before exposure to simulated ischemia. Apoptosis and cell death were determined by cleaved caspase-3 assay and lactate dehydrogenase release assay. Enzyme-linked immunosorbent assay measured the inflammatory cytokines. RESULTS: EPOR and CD131 were expressed and significantly upregulated in CLI (average optical density [OD] in Western blot [control vs CLI] EPOR, 0.05 U vs 0.1 U; CD131, 0.10 U vs 0.22 U; P < .01). There was colocalization of EPOR and CD131 in the sarcolemma (cell membrane) of the skeletal myofiber. There was no difference in the distribution of colocalization between the CLI and the normal muscle. The ischemic myotubes treated by ARA 290 in vitro had a significantly decreased number of apoptotic cells (ischemia vs ischemia plus ARA 290: 71.1% vs 55.1%; P < .01), cleaved caspase-3 (OD of ischemia vs ischemia plus ARA 290: 0.15 U vs 0.02 U; P < .01), lactate dehydrogenase release (ischemia vs ischemia plus ARA 290: 32.5 U/L vs 21.3 U/L; P < .01), and IL-6 release (OD at 450 nm, ischemia vs ischemia plus ARA 290: 0.18 vs 0.13; P < .01). CONCLUSIONS: This study demonstrates the expression and the upregulation of EPOR and CD131 in CLI and also shows that EPOR and CDI are colocalized in the cell membrane of both ischemic and control muscle fiber. The in vitro experiments demonstrate that ARA 290 decreases inflammation and apoptosis of ischemic myotubes. ARA 290 may potentially be used as adjunctive treatment for CLI. PMID- 24055515 TI - Agreement between site-reported and ultrasound core laboratory results for duplex ultrasound velocity measurements in the Carotid Revascularization Endarterectomy versus Stenting Trial. AB - OBJECTIVE: Patients in the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) had duplex ultrasound (DU) scans prior to treatment and during follow-up to document the severity of carotid disease and the anatomic outcome of carotid endarterectomy (CEA) or carotid artery stenting (CAS). An ultrasound core laboratory (UCL) reviewed DU data from the clinical sites. This analysis was done to determine the agreement between site-reported and UCL-verified DU velocity measurements. METHODS: Clinical site DU worksheets, B-mode images, and Doppler velocity waveforms for the treated carotid arteries were reviewed at the UCL. The highest internal carotid artery peak systolic velocity (PSV) and associated Doppler angle were verified. If the angle was misaligned by >3 degrees, it was remeasured at the UCL and the PSV was recalculated. Agreement for PSV was defined as site-reported PSV within +/- 5% of UCL-verified PSV. Transcription errors were corrected by the UCL but were not considered as disagreements. Follow-up analysis was limited to patients who received the assigned treatment. RESULTS: The UCL reviewed 1702 prior-to-treatment and 1743 12-month follow-up DU scans (873 CEA, 870 CAS) from 111 clinical sites. Site-reported and UCL-verified PSV agreed in 1124 (66%) of the prior-to-treatment scans and 1200 (69%) of the follow-up scans. In those cases with a disagreement, Doppler angle accounted for disagreement in 339 (59%) of the prior-to-treatment scans and 277 (51%) of the follow-up scans. Based on a threshold PSV for >= 70% stenosis of >= 230 cm/s on the prior-to treatment scans and >= 300 cm/s on the follow-up scans, UCL review resulted in reclassification of stenosis severity in 75 (4.4%) of the prior-to-treatment scans and 13 (0.75%) of the follow-up scans. There is evidence that the proportion of reclassification at follow-up was greater for CAS (10 scans; 1.2%) than for CEA (three scans; 0.34%) (P = .057). CONCLUSIONS: There was a high rate of agreement between site-reported and UCL-verified DU results in CREST, and UCL review was associated with a low rate of stenosis reclassification. However, angle alignment errors were quite common and prompted recalculation of velocity in 20% of prior-to-treatment scans and 18% of follow-up scans. The use of a UCL provides a uniform process for DU interpretation and can identify sources of error and suggest technical improvements for future studies. PMID- 24055516 TI - The oral administration of trans-caryophyllene attenuates acute and chronic pain in mice. AB - Trans-caryophyllene is a sesquiterpene present in many medicinal plants' essential oils, such as Ocimum gratissimum and Cannabis sativa. In this study, we evaluated the antinociceptive activity of trans-caryophyllene in murine models of acute and chronic pain and the involvement of trans-caryophyllene in the opioid and endocannabinoid systems. Acute pain was determined using the hot plate test (thermal nociception) and the formalin test (inflammatory pain). The chronic constriction injury (CCI) of the sciatic nerve induced hypernociception was measured by the hot plate and von Frey tests. To elucidate the mechanism of action, mice were pre-treated with naloxone or AM630 30 min before the trans caryophyllene treatment. Afterwards, thermal nociception was evaluated. The levels of IL-1beta were measured in CCI-mice by ELISA. Trans-caryophyllene administration significantly minimized the pain in both the acute and chronic pain models. The antinociceptive effect observed during the hot plate test was reversed by naloxone and AM630, indicating the participation of both the opioid and endocannabinoid system. Trans-caryophyllene treatment also decreased the IL 1beta levels. These results demonstrate that trans-caryophyllene reduced both acute and chronic pain in mice, which may be mediated through the opioid and endocannabinoid systems. PMID- 24055517 TI - Isolation and antiproliferative activity of Lotus corniculatus lectin towards human tumour cell lines. AB - The objective of the study was to investigate the anti cancer activity of a lectin isolated from Lotus corniculatus seeds. A tetrameric 70kDa galactose specific lectin was purified using two step simple purification protocol which involved affinity chromatography on AF-BlueHC650M and gel filtration on Sephadex G-100. The lectin was adsorbed on AF-BlueHC650M and desorbed using 1M NaCl in the starting buffer. Gel filtration on Sephadex G-100 yielded a major peak absorbance that gave two bands of 15kDa and 20kDa in SDS PAGE. Hemagglutination activity was completely preserved, when the temperature was in the range of 20-60 degrees C. However, drastic reduction in activity occurred at temperatures above 60 degrees C. Full hemagglutination activity was retained at ambient pH 4-12. Thereafter no activity was observed above pH 13. Hemaglutination of the lectin was inhibited by d-galactose. The lectin showed a strong antiproliferative activity towards human leukemic (THP-1) cancer cells followed by lung cancer (HOP62) cells and HCT116 with an IC50 of 39MUg/ml and 50MUg/ml and 60MUg/ml respectively. Flow cytometry analysis showed an increase in the percentage of cells in sub G0G1 phase confirming that Lotus corniculatus lectin induced apoptosis. Morphological observations showed that Lotus corniculatus lectin (LCL) treated THP-1 cells displayed apparent apoptosis characteristics such as nuclear fragmentation, appearance of membrane enclosed apoptotic bodies and DNA fragmentation. Lotus corniculatus lectin (LCL) effectively inhibits the cell migration in a dose dependent manner as indicated by the wound healing assay. PMID- 24055518 TI - Grape polyphenols and propolis mixture inhibits inflammatory mediator release from human leukocytes and reduces clinical scores in experimental arthritis. AB - Polyphenols from red fruits and bee-derived propolis (PR) are bioactive natural products in various in vitro and in vivo models. The present study shows that hematotoxicity-free doses of grape polyphenols (GPE) and PR differentially decreased the secretion of pro-inflammatory cytokines from activated human peripheral blood leucocytes. While GPE inhibited the monocytes/macrophage response, propolis decreased both monokines and interferon gamma (IFNgamma) production. When used together, their distinct effects lead to the attenuation of all inflammatory mediators, as supported by a significant modulation of the transcriptomic profile of pro-inflammatory genes in human leukocytes. To enforce in vitro data, GPE+PR were tested for their ability to improve clinical scores and cachexia in chronic rat adjuvant-induced arthritis (AA). Extracts significantly reduced arthritis scores and cachexia, and this effect was more significant in animals receiving continuous low doses compared to those receiving five different high doses. Animals treated daily had significantly better clinical scores than corticoid-treated rats. Together, these findings indicate that the GPE+PR combination induces potent anti-inflammatory activity due to their complementary immune cell modulation. PMID- 24055519 TI - Sesquiterpene dimer (DSF-52) from Artemisia argyi inhibits microglia-mediated neuroinflammation via suppression of NF-kappaB, JNK/p38 MAPKs and Jak2/Stat3 signaling pathways. AB - Microglia-involved neuroinflammation is thought to promote brain damage in various neurodegenerative disorders. Therefore, novel therapeutics suppressing microglia over-activation could prove useful for neuroprotection in inflammation mediated neurodegenerative diseases. DSF-52 is a novel sesquiterpene dimer compound isolated from medical plant Artemisia argyi by our group. In this study, we investigated whether DSF-52 inhibited the neuroinflammatory responses in lipopolysaccharide (LPS)-activated microglia. Our findings showed that DSF-52 inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), as well as mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), interleukin-1beta (IL-1beta), granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage inflammatory protein-1alpha (MIP-1alpha) in LPS-activated BV-2 microglia. Moreover, DSF-52 markedly up-regulated mRNA levels of anti-inflammatory cytokine IL-10. Mechanism study indicated that DSF-52 suppressed Akt/IkappaB/NF-kappaB inflammation pathway against LPS treatment. Also, DSF-52 down-regulated the phosphorylation levels of JNK and p38 MAPKs, but not ERK. Furthermore, DSF-52 blocked Jak2/Stat3 dependent inflammation pathway through inhibiting Jak2 and Stat3 phosphorylation, as well as Stat3 nuclear translocation. We concluded that the inhibitory ability of DSF-52 on microglia-mediated neuroinflammation may offer a novel neuroprotective modality and could be potentially useful in inflammation-mediated neurodegenerative diseases. PMID- 24055520 TI - Induction of steroid sulfatase expression in PC-3 human prostate cancer cells by insulin-like growth factor II. AB - Human steroid sulfatase (STS) plays an important role in regulating the formation of biologically active estrogens and may be a promising target for treating estrogen-mediated carcinogenesis. The molecular mechanism of STS gene expression, however, is still not clear. Growth factors are known to increase STS activity but the changes in STS expression have not been completely understood. To determine whether insulin-like growth factor (IGF)-II can induce STS gene expression, the effects of IGF-II on STS expression were studied in PC-3 human prostate cancer cells. RT-PCR and Western blot analysis showed that IGF-II treatment significantly increased the expression of STS mRNA and protein in concentration- and time-dependent manners. To understand the signaling pathway by which IGF-II induces STS gene expression, the effects of specific PI3-kinase/Akt and NF-kappaB inhibitors were determined. When the cells were treated with IGF-II and PI3-kinase/Akt inhibitors, such as LY294002, wortmannin, or Akt inhibitor IV, STS expression induced by IGF-II was significantly blocked. Moreover, we found that NF-kappaB inhibitors, such as MG-132, bortezomib, Bay 11-7082 or Nemo binding domain (NBD) binding peptide, also strongly prevented IGF-II from inducing STS gene expression. We assessed whether IGF-II activates STS promoter activity using transient transfection with a luciferase reporter. IGF-II significantly stimulated STS reporter activity. Furthermore, IGF-II induced expression of 17beta-hydroxysteroid dehydrogenase (HSD) 1 and 3, whereas it reduced estrone sulfotransferase (EST) gene expression, causing enhanced estrone and beta-estradiol production. Taken together, these results strongly suggest that IGF-II induces STS expression via a PI3-kinase/Akt-NF-kappaB signaling pathway in PC-3 cells and may induce estrogen production and estrogen-mediated carcinogenesis. PMID- 24055521 TI - The effect of nonuniform magnetic targeting of intracoronary-delivering mesenchymal stem cells on coronary embolisation. AB - Magnetic targeting has been recently introduced to enhance cell retention in animals with acute myocardial infarction. However, it is unclear whether the magnetic accumulation of intravascular cells increases the risk of coronary embolism. Upon finite element analysis, we found that the permanent magnetic field was nonuniform, manifestated as attenuation along the vertical axis and polarisation along the horizontal axis. In the in vitro experiments, iron labelled mesenchymal stem cells (MSCs) were accumulated in layers predominantly at the edge of the magnet. In an ischaemic rat model subjected to intracavitary MSCs injection, magnetic targeting induced unfavourable vascular embolisation and an inhomogeneous distribution of the donor cells, which prevented the enhanced cell retention from translating into additional functional benefit. These potential complications of magnetic targeting should be thoroughly investigated and overcome before clinical application. PMID- 24055522 TI - An epidermal growth factor derivative with binding affinity for hydroxyapatite and titanium surfaces. AB - An epidermal growth factor (EGF) derivative with affinity for apatite and titanium surfaces was designed using a peptide moiety derived from salivary statherin, a protein that adheres to hydroxyapatite. Since the active sequence has two phosphoserine residues, the EGF derivative was prepared by organic synthesis, and a 54 residue peptide was successfully prepared using this method. Circular dichroism spectra indicated that the conformation of EGF was not significantly altered by the addition of the affinity peptide sequence and the mitogenic activity was only slightly reduced when compared with the wild-type protein. However, the binding affinity of the modified EGF to hydroxyapatite and titanium was significantly higher than the unmodified EGF. The phosphate groups in the affinity sequence contributed to the affinity of modified EGF to both apatite and titanium. The modified EGF significantly enhanced the growth of cells on hydroxyapatite and titanium. It was also demonstrated that the bound EGF enhanced the signal transduction for longer periods than unbound EGF. In conclusion, the modified EGF had significantly higher binding affinity for apatite and titanium than soluble EGF, and the bound EGF significantly enhanced cell growth by long-lasting activation of intracellular signal transduction. PMID- 24055523 TI - Acid-degradable core-shell nanoparticles for reversed tamoxifen-resistance in breast cancer by silencing manganese superoxide dismutase (MnSOD). AB - Drug resistance acquired by cancer cells is a significant challenge in the clinic and requires impairing the responsible pathological pathway. Administering chemotherapeutics along with silencing resistance-basis activity using RNA interference (RNAi) is expected to restore the activity of the chemotherapeutic and generate synergistic cancer eradication. This study attempted to reverse tamoxifen (TAM)-resistance in breast cancer by silencing a mitochondrial enzyme, manganese superoxide dismutase (MnSOD), which dismutates TAM-induced reactive oxygen species (ROS) (i.e., superoxide) to less harmful hydrogen peroxide and hampers therapeutic effects. Breast cancer cells were co-treated with TAM and MnSOD siRNA-delivering nanoparticles (NPs) made of a siRNA/poly(amidoamine) (PAMAM) dendriplex core and an acid-degradable polyketal (PK) shell. The (siRNA/PAMAM)-PK NPs were designed for the PK shell to shield siRNA from nucleases, minimize detrimental aggregation in serum, and facilitate cytosolic release of siRNA from endosomal compartments. This method of forming the PK shell around the siRNA/PAMAM core via surface-initiated photo-polymerization enables ease of tuning NPs' size for readily controlled siRNA release kinetics. The resulting NPs were notably homogenous in size, resistant to aggregation in serum, and invulnerable to heparan sulfate-mediated disassembly, compared to siRNA/PAMAM dendriplexes. Gel electrophoresis and confocal microscopy confirmed efficient siRNA release from the (siRNA/PAMAM)-PK NPs upon stimuli-responsive hydrolysis of the PK shell. Sensitization of TAM-resistant MCF7-BK-TR breast cancer cells with (MnSOD siRNA/PAMAM)-PK NPs restored TAM-induced cellular apoptosis in vitro and significantly suppressed tumor growth in vivo, as confirmed by biochemical assays and histological observations. This study implies that combined gene silencing and chemotherapy is a promising strategy to overcoming a significant challenge in cancer therapy. PMID- 24055524 TI - The performance of thiol-terminated PEG-paclitaxel-conjugated gold nanoparticles. AB - A series of thiol-terminated polyethylene glycol (PEG)-paclitaxel (PTX) derivatives are designed and synthesized to fabricate PTX-conjugated gold nanoparticles (PTX@GNPs) and improve their overall performance. By extending the molecular weight of PEG from 400 to 1000 Da, the optimized water solubility of the conjugate reaches 184 mg/mL, equal to 4.6 * 10(5) times that of PTX alone (0.4 MUg/mL). High drug loading is obtained by eliminating the steric hindrance between PTX molecules on the surface of GNPs. The gold conjugate shows double simultaneous stimulation-induced drug release behavior in the presence of both esterase and high concentrations of glutathione. The synergic release characteristics of this conjugate results in significant performance improvements, including prolonged circulation due to high stability in vivo, targeted release of PTX inside tumor cells, and increased tumor cell killing efficiency. Improving the in vitro properties of the conjugate not only significantly enhances its therapeutic efficacy in a murine liver cancer model, but also allows drug-conjugated gold nanoparticles to be used as a promising nanoprodrug system in the cancer therapeutics. PMID- 24055526 TI - Novel candidate genes for 46,XY gonadal dysgenesis identified by a customized 1 M array-CGH platform. AB - Half of all patients with a disorder of sex development (DSD) do not receive a specific molecular diagnosis. Comparative genomic hybridization (CGH) can detect copy number changes causing gene haploinsufficiency or over-expression that can lead to impaired gonadal development and gonadal DSD. The purpose of this study was to identify novel candidate genes for 46,XY gonadal dysgenesis (GD) using a customized 1 M array-CGH platform with whole-genome coverage and probe enrichment targeting 78 genes involved in sex development. Fourteen patients with 46,XY gonadal DSD were enrolled in the study. Nine individuals were analyzed by array CGH. All patients were included in a follow up sequencing study of candidate genes. Three novel candidate regions for 46,XY GD were identified in two patients. An interstitial duplication of the SUPT3H gene and a deletion of C2ORF80 were detected in a pair of affected siblings. Sequence analysis of these genes in all patients revealed no additional mutations. A large duplication highlighting PIP5K1B, PRKACG and FAM189A2 as candidates for 46,XY GD, were also detected. All five genes are expressed in testicular tissues, and one is shown to cause gonadal DSD in mice. However detailed functional information is lacking for these genes. PMID- 24055525 TI - Functionalization of scaffolds with chimeric anti-BMP-2 monoclonal antibodies for osseous regeneration. AB - Recent studies have demonstrated the ability of murine anti-BMP-2 monoclonal antibodies (mAb) immobilized on an absorbable collagen sponge (ACS) to mediate de novo bone formation, a process termed antibody-mediated osseous regeneration (AMOR). The objectives of this study were to assess the efficacy of a newly generated chimeric anti-BMP-2 mAb in mediating AMOR, as well as to evaluate the suitability of different biomaterials as scaffolds to participate in AMOR. Chimeric anti-BMP-2 mAb was immobilized on 4 biomaterials, namely, titanium microbeads (Ti), alginate hydrogel, macroporous biphasic calcium phosphate (MBCP) and ACS, followed by surgical implantation into rat critical-size calvarial defects. Animals were sacrificed after 8 weeks and the degree of bone fill was assessed using micro-CT and histomorphometry. Results demonstrated local persistence of chimeric anti-BMP-2 mAb up to 8 weeks, as well as significant de novo bone regeneration in sites implanted with chimeric anti-BMP-2 antibody immobilized on each of the 4 scaffolds. Ti and MBCP showed the highest volume of bone regeneration, presumably due to their resistance to compression. Alginate and ACS also mediated de novo bone formation, though significant volumetric shrinkage was noted. In vitro assays demonstrated cross-reactivity of chimeric anti-BMP-2 mAb with BMP-4 and BMP-7. Immune complex of anti-BMP-2 mAb with BMP-2 induced osteogenic differentiation of C2C12 cells in vitro, involving expression of RUNX2 and phosphorylation of Smad1. The present data demonstrated the ability of chimeric anti-BMP-2 mAb to functionalize different biomaterial with varying characteristics to mediate osteogenesis. PMID- 24055527 TI - The psychological impact of cryptic chromosomal abnormalities diagnosis announcement. AB - This qualitative study aims to describe the psychological impact of the diagnosis announcement of pathogenic Copy Number Variations (pCNVs). We performed semi structured interviews of 60 parents of 41 affected children and 5 geneticists who announced the diagnoses. The diagnosis of the best characterized microdeletion syndromes, often defined by patronymic names (e.g. Williams syndrome), is generally made on a clinical basis by geneticists and confirmed by fluorescence in situ hybridization analysis. Chromosomal microarray, on the contrary, can allow the disclosure of rare pCNVs named after cytogenetic formulas, with poorly known clinical consequences: this makes doctors feel less confident with these diagnosis announcements. The disclosure of pCNVs named after cytogenetic formulas does not facilitate the parental mental representation of the disease, leading some parents to call into question the genotype-phenotype correlation or the very notion of a diagnosis. The announcement of inherited pCNVs can increase the feeling of parental guilt; the disclosure of de novo pCNVs can induce a feeling of "breakage" in the mental representation of the parent-child vertical transmission. In conclusion, our study shows that the disclosure of pCNVs has a significant psychological impact: a multidisciplinary approach to the diagnosis announcement, including a psychological support, should be systematically warranted. PMID- 24055528 TI - Description of another case of 3q26.33-3q27.2 microdeletion supports a recognizable phenotype. PMID- 24055529 TI - Tissue and circulating microRNA influence reproductive function in endometrial disease. AB - microRNA (miRNA) have emerged as important epigenetic modulators of gene expression in diverse pathological and physiological processes. In the endometrium, miRNA appear to have a role in the dynamic changes associated with the menstrual cycle, in implantation and in the pathophysiology associated with reproductive disorders such as recurrent miscarriage and endometriosis. This review explores the role of miRNA in endometrial physiology and endometrial disorders of reproduction and also raises the prospect that circulating miRNA may modulate endometrial function or reflect disordered endometrial activity. The clinical potential to use miRNA in diagnostic tests of endometrial function or in the treatment of endometrial disorders will also be discussed. PMID- 24055530 TI - In-vitro model systems for the study of human embryo-endometrium interactions. AB - Implantation requires highly orchestrated interactions between the developing embryo and maternal endometrium. The association between abnormal implantation and reproductive failure is evident, both in normal pregnancy and in assisted reproduction patients. Failure of implantation is the pregnancy rate-limiting step in assisted reproduction, but, as yet, empirical interventions have largely failed to address this problem. Better understanding of the mechanisms underlying human embryo-endometrium signalling is a prerequisite for the further improvement of assisted reproduction outcomes and the development of effective interventions to prevent early pregnancy loss. Studying human embryo implantation is challenging since in-vivo experiments are impractical and unethical, and studies in animal models do not always translate well to humans. However, in recent years in-vitro models have been shown to provide a promising way forward. This review discusses the principal models used to study early human embryo development and initial stages of implantation in vitro. While each model has limitations, exploiting these models will improve understanding of the molecular mechanisms and embryo-endometrium cross-talk at the early implantation site. They provide valuable tools to study early embryo development and pathophysiology of reproductive disorders and have revealed novel disease mechanisms such as the role of epigenetic modifications in recurrent miscarriage. PMID- 24055531 TI - Walk-, run- and gallop-like gait patterns in human sideways locomotion. AB - The purpose of this study is to examine the characteristics of gait patterns in human preferred sideways locomotion at increasing speeds. Fifteen healthy young males were asked to step sideways on a treadmill at various speeds of 1.3-6.1 km/h. The times of foot contact and take-off were analyzed. Three gait patterns were observed. At slow speeds, all of the subjects performed a walk-like pattern. When the treadmill speed exceeded approximately 3.5 km/h, the subjects preferred gait patterns with a flight phase. Most of the subjects performed an asymmetric gait pattern that was similar to a forward gallop, whereas only two out of fifteen subjects performed a run-like gait pattern. Because the left and right legs are positioned along the movement direction, it might be more efficient to divide roles between the leading and trailing limbs at high speeds: the leading limb functions to produces breaking and vertical force, and the trailing limb mainly absorbs the impact of foot contact and generates propulsive forces. PMID- 24055532 TI - Effect of pain location on spatial reorganisation of muscle activity. AB - INTRODUCTION: We aimed to determine whether the changes in muscle activity (in terms of both gross electromyography (EMG) and motor unit (MU) discharge characteristics) observed during pain are spatially organized with respect to pain location within a muscle which is the main contributor of the task. METHODS: Surface and fine-wire EMG was recorded during matched low-force isometric plantarflexion from soleus (from four quadrants with fine-wire EMG and from the medial/lateral sides with surface EMG), both gastrocnemii heads, peroneus longus, and tibialis anterior. Four conditions were tested: two control conditions that each preceded contractions with pain induced in either the lateral (Pain(L)) or medial (Pain(M)) side of soleus. RESULTS: Neither the presence (p = 0.28) nor location (p = 0.19) of pain significantly altered gross muscle activity of any location (lateral/medial side of soleus, gastrocnemii, peroneus longus and tibialis anterior). Group data from 196 MUs show redistribution of MU activity throughout the four quadrants of soleus, irrespective of pain location. The significant decrease of MU discharge rate during pain (p < 0.0001; Pain(L): 7.3 +/- 0.9-6.9 +/- 1.1 Hz, Pain(M): 7.0 +/- 1.1 to 6.6 +/- 1.1 Hz) was similar for all quadrants of the soleus (p = 0.43), regardless of the pain location (p = 0.98). There was large inter-participant variation in respect to the characteristics of the altered MU discharge with pain. CONCLUSION: Results from both surface and fine-wire EMG recordings do not support the hypothesis that muscle activity is reorganized in a simple systematic manner with respect to pain location. PMID- 24055533 TI - Scapular orientation following repetitive prone rowing: implications for potential subacromial impingement mechanisms. AB - While fatigue of the rotator cuff demonstrably causes superior humeral head migration and concomitant risk of impingement, the relationship between specific muscular fatigue, scapular dyskinesis and impingement risk is less clear. The purpose of this study was to examine changes in scapular orientation following a simulated prone rowing fatiguing protocol that targeted the scapula stabilizing muscles while attempting to alleviate rotator cuff muscular demands. Scapular orientation and muscle activity were collected from participants before and immediately after the fatiguing task. This task fatigued both the stabilizing (upper and middle trapezius, and latissimus dorsi) and rotator cuff (supraspinatus, and infraspinatus) muscles. The upper extremity muscle fatigue pattern caused by the protocol did not elicit any significantly changes in three dimensional scapular position with all post-fatigue changes being <= 1 degrees (p = 0.17-0.58). These results indicated that scapular reorientation is likely not the dominant mechanism of fatigue-induced subacromial impingement development. However, the substantial variability present in the kinematics prevents complete exclusion of scapular dyskinesis as a secondary causal mechanism of impingement. PMID- 24055534 TI - Prevalence, quality of care, and complications in long term care residents with diabetes: a multicenter observational study. AB - BACKGROUND: Few studies have reported on the quality of diabetes care and glycemic control adjusted for medication use in long term care (LTC) facilities. METHODS: This observational study analyzed diabetes prevalence and management and the impact of glycemic control on clinical outcome in elderly subjects admitted to 3 community LTC facilities. RESULTS: Among 1409 LTC residents (age 79.7 +/- 12 years), the prevalence of diabetes was 34.2%. Subjects with diabetes were either on no pharmacological agents (10%) or were treated with sliding scale regular insulin (SSI, 25%), oral antidiabetic drugs (OAD, 5%), insulin (34%), or with combination of OAD and insulin (26%). Patients with diabetes had a mean daily BG of 156 +/- 39 mg/dL and a mean admission HbA1c of 6.7% +/- 1.1%. Compared with nondiabetes, residents with diabetes had higher number of complications (54% vs 45%, P < .001), infections (26% vs 21%, P = .036), emergency room (ER) and hospital transfers (37% vs 30%, P = .003), but similar mortality (15% vs 14%, P = .56). A total of 43% of residents with diabetes had a BG less than 70 mg/dL, and those with hypoglycemia had longer median length of stay (LOS, 52 vs 29 days, P < .001), more ER or hospital transfers (56% vs 69%, P = .005), and mortality (20% vs 10%, P = .002) compared with residents without hypoglycemia. CONCLUSION: Diabetes is common in LTC residents and is associated with higher resource utilization and complications. Hypoglycemia is common and is associated with increased need of emergency room visits and hospitalization and higher mortality. Our findings emphasize the need for randomized trials evaluating the impact of different approaches to glycemic management on clinical outcome in LTC residents with diabetes. PMID- 24055535 TI - Hydroxylation of long chain fatty acids by CYP147F1, a new cytochrome P450 subfamily protein from Streptomyces peucetius. AB - Cytochrome P450 (CYP) 147F1 from Streptomyces peucetius is a new CYP subfamily of that has been identified as omega-fatty acid hydroxylase. We describe the identification of CYP147F1 as a fatty acid hydroxylase by screening for the substrate using a substrate binding assay. Screening of substrates resulted in the identification of fatty acid groups of compounds as potential hits for CYP147F1 substrates. Fatty acids from C10:0 to C18:0 all showed type I shift spectra indicating their potential as substrates. Among several fatty acids tested, lauric acid, myrsitic acid, and palmitic acid were used to characterize CYP147F1. CYP147F1 activity was reconstituted using putidaredoxin reductase and putidaredoxin from Pseudomonas putida as surrogate electron transfer partners. Kinetic parameters, including the dissociation constant, Km, NADH consumption assay, production formation rate, and coupling efficiency for CYP147F1 were also determined. PMID- 24055536 TI - Redesign of MST enzymes to target lyase activity instead promotes mutase and dehydratase activities. AB - The isochorismate and salicylate synthases are members of the MST family of enzymes. The isochorismate synthases establish an equilibrium for the conversion chorismate to isochorismate and the reverse reaction. The salicylate synthases convert chorismate to salicylate with an isochorismate intermediate; therefore, the salicylate synthases perform isochorismate synthase and isochorismate pyruvate lyase activities sequentially. While the active site residues are highly conserved, there are two sites that show trends for lyase-activity and lyase deficiency. Using steady state kinetics and HPLC progress curves, we tested the "interchange" hypothesis that interconversion of the amino acids at these sites would promote lyase activity in the isochorismate synthases and remove lyase activity from the salicylate synthases. An alternative, "permute" hypothesis, that chorismate-utilizing enzymes are designed to permute the substrate into a variety of products and tampering with the active site may lead to identification of adventitious activities, is tested by more sensitive NMR time course experiments. The latter hypothesis held true. The variant enzymes predominantly catalyzed chorismate mutase-prephenate dehydratase activities, sequentially generating prephenate and phenylpyruvate, augmenting previously debated (mutase) or undocumented (dehydratase) adventitious activities. PMID- 24055537 TI - Vibrational and electronic spectroscopy of the retro-carotenoid rhodoxanthin in avian plumage, solid-state films, and solution. AB - Rhodoxanthin is one of few retro-carotenoids in nature. These chromophores are defined by a pattern of single and double bond alternation that is reversed relative to most carotenoids. Rhodoxanthin is found in the plumage of several families of birds, including fruit doves (Ptilinopus, Columbidae) and the red cotingas (Phoenicircus, Cotingidae). The coloration associated with the rhodoxanthin-containing plumage of these fruit dove and cotinga species ranges from brilliant red to magenta or purple. In the present study, rhodoxanthin is characterized in situ by UV-Vis reflectance and resonance Raman spectroscopy to gain insights into the mechanisms of color-tuning. The spectra are compared with those of the isolated pigment in solution and in thin solid films. Key vibrational signatures are identified for three isomers of rhodoxanthin, primarily in the fingerprint region. Electronic structure (DFT) calculations are employed to describe the normal modes of vibration, and determine characteristic modes of retro-carotenoids. These results are discussed in the context of various mechanisms that change the electronic absorption, including structural distortion of the chromophore or enhanced delocalization of pi-electrons in the ground state. From the spectroscopic evidence, we suggest that the shift in absorption is likely a consequence of perturbations that primarily affect the excited state of the chromophore. PMID- 24055538 TI - [Reflections on humour in the care relationship]. PMID- 24055539 TI - Electrophysiological correlates of block-wise strategic adaptations to consciously and unconsciously triggered conflict. AB - The role of consciousness in conflict adaptation has been a topic of much debate. The purpose of the current study was to investigate the neural correlates of block-wise conflict adaptations elicited by conscious and unconscious conflicting stimuli in a meta-contrast masked priming task. Event-related potentials (ERPs) were recorded while individuals responded to prime-target pairs in mostly congruent (80% congruent trials, 20% incongruent trials) and mostly incongruent blocks of trials (20% congruent trials, 80% incongruent trials). Mean response times and error rates revealed that the conflict effect (incongruent trials congruent trials) was reduced in mostly incongruent blocks relative to mostly congruent blocks. Furthermore, conflict related ERP signals (the amplitude difference between congruent and incongruent trials) for three ERP components (early occipito-parietal negativity, the fronto-central N2 and the centro parietal P3) were attenuated in mostly incongruent blocks compared to mostly congruent blocks, reflecting block-wise adaptation to the frequency of conflict. The conflict-related frontal N2 component differentiated most strongly between visibility conditions. These results further specify the electrophysiological correlates of block-wise strategic adaptations to consciously and unconsciously elicited conflict. PMID- 24055540 TI - Oscillatory support for rapid frequency change processing in infants. AB - Rapid auditory processing and auditory change detection abilities are crucial aspects of speech and language development, particularly in the first year of life. Animal models and adult studies suggest that oscillatory synchrony, and in particular low-frequency oscillations play key roles in this process. We hypothesize that infant perception of rapid pitch and timing changes is mediated, at least in part, by oscillatory mechanisms. Using event-related potentials (ERPs), source localization and time-frequency analysis of event-related oscillations (EROs), we examined the neural substrates of rapid auditory processing in 4-month-olds. During a standard oddball paradigm, infants listened to tone pairs with invariant standard (STD, 800-800 Hz) and variant deviant (DEV, 800-1200 Hz) pitch. STD and DEV tone pairs were first presented in a block with a short inter-stimulus interval (ISI) (Rapid Rate: 70 ms ISI), followed by a block of stimuli with a longer ISI (Control Rate: 300 ms ISI). Results showed greater ERP peak amplitude in response to the DEV tone in both conditions and later and larger peaks during Rapid Rate presentation, compared to the Control condition. Sources of neural activity, localized to right and left auditory regions, showed larger and faster activation in the right hemisphere for both rate conditions. Time-frequency analysis of the source activity revealed clusters of theta band enhancement to the DEV tone in right auditory cortex for both conditions. Left auditory activity was enhanced only during Rapid Rate presentation. These data suggest that local low-frequency oscillatory synchrony underlies rapid processing and can robustly index auditory perception in young infants. Furthermore, left hemisphere recruitment during rapid frequency change discrimination suggests a difference in the spectral and temporal resolution of right and left hemispheres at a very young age. PMID- 24055541 TI - Reprint of Comparison of two approaches for identification of haplotypes and point mutations in Candida albicans and Saccharomyces cerevisiae. AB - The human fungal pathogen Candida albicans displays a very high degree of plasticity, including the types of genomic changes frequently observed with cancer cells, such as gross chromosomal rearrangements, aneuploidy, and loss of heterozygosity. Despite its relevance to every aspect of genetics and evolution of this pathogen, our understanding of the mutation process and its bearing on organismal fitness remains quite limited. Here, we have evaluated and compared two approaches to estimate the mutation frequency at three ORFs/regions (HIS4, CEN4 and EST2) of the C. albicans genome. Sequencing of individual DNA molecules (clone-by-clone sequencing) identified de novo mutations at these DNA regions, whose frequency was similar to that observed for S. cerevisiae at homolog sites following the same approach. However, mutations were not detected when the same regions were directly sequenced from the pooled DNA. In addition, in the absence of the homologous recombination protein Rad52, mutation frequency within these sites remained unaltered. The use of an alternative polymerase also found mutations. These results suggest that at least some mutations are artifacts caused by the polymerase used, advising that post-PCR procedures might generate mutations which may become undistinguishable from the genuine mutations and thus may interfere with mutational analysis. Furthermore, we recommend that new mutations found in the sequences of cloned alleles used for the determination of haplotypes should be contrasted with the sequence yielded by the pooled DNA. PMID- 24055542 TI - Temporal trends in canine leishmaniosis in the Balearic Islands (Spain): a veterinary questionnaire. Prospective canine leishmaniosis survey and entomological studies conducted on the Island of Minorca, 20 years after first data were obtained. AB - Leishmaniosis is present in the Mediterranean region of Europe, where Leishmania infantum is responsible for the disease, dogs are the main reservoir, and sand flies of the Phlebotomus genus, subgenus Larroussius, are proven vectors. Some areas, including Minorca in the Balearic Islands, are considered free of the disease, despite the presence of vectors. However, in the context of the current expansion of canine leishmaniosis in parts of Europe, an epidemiological study using a veterinary questionnaire was carried out to establish the current situation of the disease in the Balearic Islands. While 50% of veterinarians thought that the incidence of canine leishmaniosis had not changed over time, 26.2% perceived an increasing trend, mainly those from Minorca, where most of the veterinarians polled (88.1%) considered the new diagnosed cases as autochthonous. A cross-sectional serological study performed in this island gave a seroprevalence rate of 24%. Seroprevalence among animals of local origin and with no history of movements to endemic areas was 31%. The presence of autochthonous canine leishmaniosis in Minorca was not correlated with an increase in vector density. The environmental and climatic factors that influenced the distribution and density of Phlebotomus perniciosus on the island and the possible causes of the apparent emergence of canine leishmaniosis in Minorca are discussed. PMID- 24055543 TI - Behavioral and electrophysiological responses of Culex quinquefasciatus to certain fatty acid esters. AB - Oviposition response of gravid Culex quinquefasciatus females to a series of synthetic fatty acid esters was evaluated at 10ppm under laboratory conditions. Octyl tridecanoate and propyl octadecanoate elicited 85% and 73% increased ovipositional responses respectively, compared to control, among the 16 esters tested. Other 14 esters showed highly significant repellency (67-96%) to gravid females. Standard 3-methyl indole received 69% increased egg deposition compared to control. In the Y-tube olfactometer, gravid C. quinquefasciatus females exhibited 78, 64% and 58% orientation respectively to octyl tridecanoate, propyl octadecanoate and 3-methyl indole. Gravid females exhibited 19-41% reduced orientation toward treatment odors of other esters significantly different from respective control. Electroantennogram studies revealed 4-18-fold increased antennal response, in which 3-methyl indole, octyl tridecanoate and propyl octadecanoate elicited 8-, 18- and 15-fold EAG response respectively, compared to control. Relative EAG response of octyl tridecanoate compared to standard 3 methyl indole was significantly different. Reduced EAG responses were elicited by FAE-06, -08, -13, -14 and -15, while the relative EAG responses of other esters were at par with the standard stimulus. These, esters could be utilized potentially as oviposition attractants and repellents against C. quinquefasciatus females to reduce the breeding in polluted water along with existing integrated vector control methods. PMID- 24055544 TI - The roles of kairomones, synomones and pheromones in the chemically-mediated behaviour of male mosquitoes. AB - Despite decades of intensive study of the chemical ecology of female mosquitoes, relatively little is known about the chemical ecology of males. This short review summarizes the current state of knowledge of the chemicals that mediate male mosquito behaviour. Various trophic interactions including insect-plant, insect host, and insect-insect responses are emphasized. The relevance of the chemical ecology of male mosquitoes in the context of vector control programmes is discussed. PMID- 24055546 TI - Inferring geographic range evolution of a pantropical tribe in the coffee family (Lasiantheae, Rubiaceae) in the face of topological uncertainty. AB - In this study we explore what historical biogeographic events are responsible for the wide and disjunct distribution of extant species in Lasiantheae, a pantropical group of trees and shrubs in the coffee family. Three of the genera in the group, Lasianthus, Saldinia, and Trichostachys, are found to be monophyletic, while there are indications that the fourth, Ronabea, is paraphyletic. We also address how the uncertainty in topology and divergence times affects the level of confidence in the biogeographic reconstruction. A data set consisting of chloroplast and nuclear ribosomal DNA data was analyzed using a Bayesian relaxed molecular clock approach to estimate phylogenetic relationships and divergence times, and the dispersal-extinction-cladogenesis (DEC) method to reconstruct geographic range evolution. Our results show that the Lasiantheae stem lineage originated in the neotropics, and the group expanded its range to the palaeotropics during the Eocene, either by continental migration through the boreotropics or by transatlantic long-distance dispersal. Two cases of Oligocene/Miocene over water-dispersal were also inferred, once from the paleotropics to the neotropics within Lasianthus, and once to Madagascar, concurrent with the origin of Saldinia. A lot of the diversification within Lasianthus took place during the Miocene and may have been influenced by climatic factors such as a period of markedly warm and moist climate in Asia and the aridification of the interior of the African continent. When biogeographic reconstructions were averaged over a random sample of 1000 dated phylogenies, the confidence in the biogeographic reconstruction decreased for most nodes, compared to when a single topology was used. A good understanding of phylogenetic relationships is necessary to understand the biogeographic history of a group, bit since the phylogeny is rarely completely known it is important to include phylogenetic uncertainty in biogeographic analysis. For nodes where the resolution is uncertain, the use of a single "best" topology as a basis for biogeographic analysis will result in inflated confidence in a biogeographic reconstruction which may be just one of several possible reconstructions. PMID- 24055545 TI - Taxonomic assessment of Anopheles crawfordi and An. dangi of the Hyrcanus Group of subgenus Anopheles in Vietnam. AB - Anopheles dangi, introduced as a new species of the Hyrcanus Group of subgenus Anopheles in an illustrated dichotomous key for the identification of the Anopheles mosquitoes of Vietnam published in 1987, was distinguished from Anopheles crawfordi based on the presence of a humeral pale spot on the base of the costal vein of the wing. However, this character has been known to occur occasionally in An. crawfordi. To determine whether An. dangi is distinct from An. crawfordi, we analyzed nucleotide sequences of the COI, COII and Cyt-b genes of mtDNA and the D3 gene of rDNA obtained from specimens collected in south central Vietnam that were identified as An. dangi and An. crawfordi based on the presence or absence, respectively, of a humeral pale spot. Maximum Likelihood and Bayesian analyses of the sequences showed a low mean genetic distance of 0.004 for specimens identified as An. crawfordi and 0.008 for those identified as An. dangi. The mean genetic distance between the two nominal species was 0.006, compared with 0.077 for any group versus the outgroup taxa Anopheles dirus and Anopheles minimus, and the specimens of the two forms clustered in a single strongly supported clade. Consequently, An. dangi is merely a morphological variant of An. crawfordi and is deemed to be a synonym of that nominal species. PMID- 24055547 TI - Cytotoxicity of ammonium hexafluorosilicate on human gingival fibroblasts. AB - Ammonium hexafluorosilicate (SiF), which is claimed to significantly improve occlusion of dentinal tubules, was proposed as a novel desensitizer for dentine hypersensitivity (DH). However, the cytotoxicity of SiF on oral cells is lacking. The purpose of this study was to investigate the cytotoxicity of SiF on human gingival fibroblasts (hGFs) under different dosages (0.001%, 0.01%, 0.1%, and 1%) and treatment durations (1, 5, 10, and 30min). Cell proliferation, mitochondrial membrane potential (MMP) and cell cycle were tested by MTT assay, JC-1 staining and flow cytometry, respectively. Glutathione (GSH) depletion was analyzed to further investigate the underlying mechanism of SiF-induced cytotoxicity. MTT assay showed that there was significantly lower number of viable cells when the hGFs were treated with 0.01% (10min), 0.1% (10 and 30min) and 1% (5, 10, and 30min) SiF than the control group (p<0.05). MMP decreased and GSH depletion increased dramatically along with higher concentrations (0.1% and 1% SiF) and prolonged times (10 and 30min). DNA synthesis [S (%)] of cells treated with 0.1% and 1% SiF (5, 10, and 30min) was significantly lower than the control group (p<0.05). Our results indicate exposure to up to 0.01% SiF for less than 5min causes low or no cytotoxicity in vitro. PMID- 24055549 TI - Transfusion strategy in gastrointestinal bleeding: less is best? PMID- 24055550 TI - Is scorpion antivenom cost-effective as marketed in the United States? AB - PURPOSE: The purpose of this study was to analyze the cost-effectiveness of scorpion antivenom compared to no antivenom, in the United States, using a decision analysis framework. METHODS: A decision analytic model was created to assess patient course with and without antivenom. Costs were determined from the perspective of a health care payer. Cost data used in the model were extracted from Arizona Medicaid. The probability of clinical events occurring with and without antivenom was obtained from the published literature, medical claims obtained from Arizona Medicaid, and results of recent clinical trials. Patients that became so ill that mechanical ventilator support was necessary were considered treatment failures. A Monte Carlo simulation was run 1000 times and sampled simultaneously across all variable distributions in the model. RESULTS: The mean success rate was 99.87% (95% CI 99.64%-99.98%) with scorpion antivenom and 94.31% (95% CI 91.10%-96.61%) without scorpion antivenom. The mean cost using scorpion antivenom was $10,708 (95% CI $10,556 - $11,010) and the mean cost without scorpion antivenom was $3178 (95% CI $1627 - $5184). Since the 95% CIs do not overlap for either the success or cost, use of the scorpion antivenom was significantly more effective and significantly more expensive than no antivenom. Cost-effectiveness analysis found that the scorpion antivenom was not cost effective at its current price as marketed in the United States. CONCLUSION: The scorpion antivenom marketed in the United States is extremely effective, but too costly to justify its use in most clinical situations. Formulary committees should restrict the use of this antivenom to only the most severe scorpion envenomations. PMID- 24055548 TI - Invasive aspergillosis in patients with severe alcoholic hepatitis. AB - BACKGROUND & AIMS: Severe alcoholic hepatitis (AH) has a poor short-term prognosis. Although infections are frequent complications of AH, the incidence of invasive aspergillosis (IA) and its impact on outcome remain unknown. METHODS: We prospectively followed 94 biopsy-proven severe AH episodes for 3 months. We retrospectively reviewed our diagnosis of IA based on EORTC/MSG and AspICU criteria, except for host factors. RESULTS: Fifteen IA (6 proven, 8 probable, and 1 possible) were diagnosed after a median delay of 26 days following diagnosis of AH. The sites of infection were the lungs (n=11) and central nervous system (n=2), while IA was disseminated in 2 cases. Baseline MELD score >=24 and ICU admission were independent risk factors for IA. Thirteen IA occurred in the context of corticosteroids, and 2 had received no specific treatment for AH. Non response to corticosteroids at day 7 was not a risk factor for IA, but IA was associated with absence of liver improvement at day 28. Despite antifungal treatment, 3-month transplant-free survival of patients with IA was 0% compared to 53% in those without IA. IA, Lille score >=0.45, and overt encephalopathy were independent predictors of transplant-free mortality. CONCLUSIONS: IA is a frequent complication of severe AH and carries a very high risk of mortality. Systematic screening for IA should be recommended in these patients. Further studies are needed to identify high-risk populations requiring antifungal prophylactic treatment. PMID- 24055551 TI - Pathogenic mechanisms underlying adverse reactions induced by intravenous administration of snake antivenoms. AB - Snake antivenoms are formulations of immunoglobulins, or immunoglobulin fragments, purified from the plasma of animals immunized with snake venoms. Their therapeutic success lies in their ability to mitigate the progress of toxic effects induced by snake venom components, when administered intravenously. However, due to diverse factors, such as deficient manufacturing practices, physicochemical characteristics of formulations, or inherent properties of heterologous immunoglobulins, antivenoms can induce undesirable adverse reactions. Based on the time lapse between antivenom administration and the onset of clinical manifestations, the World Health Organization has classified these adverse reactions as: 1 - Early reactions, if they occur within the first hours after antivenom infusion, or 2 - late reactions, when occurring between 5 and 20 days after treatment. While all late reactions are mediated by IgM or IgG antibodies raised in the patient against antivenom proteins, and the consequent formation of immune complexes, several mechanisms may be responsible for the early reactions, such as pyrogenic reactions, IgE-mediated reactions, or non IgE mediated reactions. This work reviews the hypotheses that have been proposed to explain the mechanisms involved in these adverse reactions to antivenoms. The understanding of these pathogenic mechanisms is necessary for the development of safer products and for the improvement of snakebite envenomation treatment. PMID- 24055552 TI - Biological assays on the effects of Acra3 peptide from Turkish scorpion Androctonus crassicauda venom on a mouse brain tumor cell line (BC3H1) and production of specific monoclonal antibodies. AB - Constitutes of the venom scorpion are a rich source of low molecular mass peptides which are toxic to various organisms, including man. Androctonus crassicauda is one of the scorpions from the Southeastern Anatolia of Turkey with public health importance. This work is focused on the investigation of biological effects of Acra3 peptide from Androctonus crassicauda. For this purpose, Acra3 isolated from crude venoms was tested for its cytotoxicity on BC3H1 mouse brain tumor cells using tetrazolium salt cleavage and lactate dehydrogenase activity assays. To determine whether the cytotoxic effects of Acra3 was related to the induction of apoptosis, the morphology of the cells and the nuclear fragmentation was examined by using Acridin Orange staining and DNA fragmentation assay, respectively. Caspase 3 and caspase 9 activities were measured spectrophotometrically and flow cytometric assay was performed using Annexin-V FITC and Propidium Iodide staining. Furthermore toxic peptide Acra3 was used as an antigen for immunological studies. Results showed that Acra3 exerted very strong cytotoxic effect on BC3H1 cells with an IC50 value of 5 MUg/ml. Exposure of the cells to 0.1 and 0.5 MUg/ml was resulted in very strong appearance of the apoptotic morphology in a dose dependent manner. On the other side, not any DNA fragmentation was observed after treatment of the cells. Caspase 3 and 9 activities were slightly decreased with Acra3. Results from flow cytometry and lactate dehydrogenase activity assays indicate that Acra3 exerts its effects by inducing a stronger necrosis than apoptosis in BC3H1 cells. To evaluate its immunogenicity, monoclonal antibody (MAb) specific for Acra3 antigen (5B9) was developed by hybridoma technology using spleen and lymph nodes of mice and immunoglobulin type of antibody was found to be IgM. We suggest that Acra3 may exert its effects by inducing both necrotic and apoptotic pathway in some way on mouse brain tumor cells. These findings will be useful for understanding the mechanism of cell death caused by venom in vitro. Anti-Acra3 monoclonal antibody can be further used as a bioactive tools for exploring the structure/function relationship and the pharmacological mechanism of scorpion peptide neurotoxins. PMID- 24055553 TI - Spatial and thematic distribution of research on cyanotoxins. AB - Cyanobacteria in surface water are well known for their ability to form toxic blooms responsible for animal mortality and human poisoning. Accompanying major progress in science and technology, the state of knowledge of cyanotoxins has dramatically increased over the last two decades. The bibliometric approach applied in this study shows the evolution of research and identifies major gaps to be filled by future work. Although the publication rate has gradually increased from one hundred to three hundred articles per year since the 1990s, half of the literature available focuses on microcystins and another quarter on saxitoxins. Other cyanotoxins such as beta-N-methylamino-l-alanine or cylindrospermopsin remain vastly disregarded. Moreover, most of the publications deal with toxicity and ecology while other research areas, such as environmental and public health, require additional investigation. The analysis of the literature highlights the main journals for the communication of knowledge on cyanotoxins but also reveals that 90% of the research is originated from only ten countries. These countries are also those with the highest H-index and average number of citation per article. Nonetheless, the ranking of these countries is significantly altered when the amount of publications is normalized based on the population, the number of universities, the national gross domestic product or the government revenue. However, the lower amount of publications from Eastern Europe, Africa and South America could also reflect the lack of monitoring campaigns in these regions. This lack could potentially lead to the underestimation of the prevalence of toxic cyanobacterial blooms and the diversity of toxins worldwide. PMID- 24055554 TI - A Subspace Pursuit-based Iterative Greedy Hierarchical solution to the neuromagnetic inverse problem. AB - Magnetoencephalography (MEG) is an important non-invasive method for studying activity within the human brain. Source localization methods can be used to estimate spatiotemporal activity from MEG measurements with high temporal resolution, but the spatial resolution of these estimates is poor due to the ill posed nature of the MEG inverse problem. Recent developments in source localization methodology have emphasized temporal as well as spatial constraints to improve source localization accuracy, but these methods can be computationally intense. Solutions emphasizing spatial sparsity hold tremendous promise, since the underlying neurophysiological processes generating MEG signals are often sparse in nature, whether in the form of focal sources, or distributed sources representing large-scale functional networks. Recent developments in the theory of compressed sensing (CS) provide a rigorous framework to estimate signals with sparse structure. In particular, a class of CS algorithms referred to as greedy pursuit algorithms can provide both high recovery accuracy and low computational complexity. Greedy pursuit algorithms are difficult to apply directly to the MEG inverse problem because of the high-dimensional structure of the MEG source space and the high spatial correlation in MEG measurements. In this paper, we develop a novel greedy pursuit algorithm for sparse MEG source localization that overcomes these fundamental problems. This algorithm, which we refer to as the Subspace Pursuit-based Iterative Greedy Hierarchical (SPIGH) inverse solution, exhibits very low computational complexity while achieving very high localization accuracy. We evaluate the performance of the proposed algorithm using comprehensive simulations, as well as the analysis of human MEG data during spontaneous brain activity and somatosensory stimuli. These studies reveal substantial performance gains provided by the SPIGH algorithm in terms of computational complexity, localization accuracy, and robustness. PMID- 24055556 TI - Testing the effects of suppression and reappraisal on emotional concordance using a multivariate multilevel model. AB - In theory, the essence of emotion is coordination across experiential, behavioral, and physiological systems in the service of functional responding to environmental demands. However, people often regulate emotions, which could either reduce or enhance cross-system concordance. The present study tested the effects of two forms of emotion regulation (expressive suppression, positive reappraisal) on concordance of subjective experience (positive-negative valence), expressive behavior (positive and negative), and physiology (inter-beat interval, skin conductance, blood pressure) during conversations between unacquainted young women. As predicted, participants asked to suppress showed reduced concordance for both positive and negative emotions. Reappraisal instructions also reduced concordance for negative emotions, but increased concordance for positive ones. Both regulation strategies had contagious interpersonal effects on average levels of responding. Suppression reduced overall expression for both regulating and uninstructed partners, while reappraisal reduced negative experience. Neither strategy influenced the uninstructed partners' concordance. These results suggest that emotion regulation impacts concordance by altering the temporal coupling of phasic subsystem responses, rather than by having divergent effects on subsystem tonic levels. PMID- 24055557 TI - [Vitamin D and kidney diseases]. AB - Calcitriol and analogs inhibit renin-angiotensin system, which has a pivotal role in glomerular and tubulo-interstitial damages and proteinuria, and inhibit NF kappaB activation which is known to play an important role in renal diseases by promoting inflammation and fibrogenesis. Vitamin D presents interesting pleiotropic effects for the CKD patient (reduction of mortality, antiproteinuric effect and anti-inflammatory properties). "Native" vitamin D (cholecalciferol or ergocalciferol) administration in these patients also decrease parathyroid hormone levels. Native vitamin D administration in CKD patients is safe and does not lead to increased risk of vascular calcification, despite the known hypercalcemic and hyperphosphoremic properties of the molecule in its active form. Native vitamin D administration is not associated with an increased risk of renal stones, at pharmacological doses and without important concomitant administration of calcium salts. In the field of renal transplantation, experimental studies show that vitamin D analogs have a protective role against acute rejection but clinical studies remain mainly observational. PMID- 24055558 TI - Kisspeptin induces expression of gonadotropin-releasing hormone receptor in GnRH producing GT1-7 cells overexpressing G protein-coupled receptor 54. AB - Kisspeptin signaling through its receptor is crucial for many reproductive functions. However, the molecular mechanisms and biomedical significance of the regulation of GnRH neurons by kisspeptin have not been adequately elucidated. In the present study, we found that kisspeptin increases GnRH receptor (GnRHR) expression in a GnRH-producing cell line (GT1-7). Because cellular activity of G protein-coupled receptor 54 (GPR54) and GnRHR was limited in GT1-7 cells, we overexpressed these receptors to clarify receptor function. Using luciferase reporter constructs, the activity of both the serum response element (Sre) promoter, a target for extracellular signal-regulated kinase (ERK), and the cyclic AMP (cAMP) response element (Cre) promoter were increased by kisspeptin. Although GnRH increased Sre promoter activity, the Cre promoter was not significantly activated by GnRH. Kisspeptin, but not GnRH, increased cAMP accumulation in these cells. Kisspeptin also increased the transcriptional activity of GnRHR; however, the effect of GnRH on the GnRHR promoter was limited and not significant. Transfection of GT1-7 cells with constitutively active MEK kinase (MEKK) and protein kinase A (PKA) increased GnRHR expression. In addition, GnRHR expression was further increased by co-overexpression of MEKK and PKA. The Cre promoter, but not the Sre promoter, was also further activated by co overexpression of MEKK and PKA. GnRH significantly increased the activity of the GnRHR promoter in the presence of cAMP. The present findings suggest that kisspeptin is a potent stimulator of GnRHR expression in GnRH-producing neurons in association with ERK and the cAMP/PKA pathways. PMID- 24055555 TI - Resting-state functional connectivity and reading abilities in first and second languages. AB - An intriguing discovery in recent years is that resting-state functional connectivity (RSFC) is associated with cognitive performance. The current study investigated whether RSFC within the reading network was correlated with Chinese adults' reading abilities in their native language (L1, Chinese) and second language (L2, English). Results showed that RSFC within the reading network was positively correlated to reading abilities in L1 and L2, and RSFC between reading areas and the default network was negatively correlated to reading abilities in L1 and L2. Further conjunction and contrast analyses revealed that L1 and L2 shared similar RSFC correlates including connectivities between the areas for visual analysis (e.g., bilateral posterior fusiform gyrus, lateral occipital cortices, and right superior parietal lobules) and those for phonological processing (e.g., bilateral precentral gyri and postcentral gyrus, Wernicke's area). These results indicate that RSFC is a potential neural marker for reading abilities in both L1 and L2, with important theoretical implications for reading in L1 and L2. PMID- 24055559 TI - Catecholamine levels in groundwater and stream amphipods and their response to temperature stress. AB - Temperature stress in invertebrates is known to be reflected by changes in catecholamine levels. However, the mechanisms of stress response are not fully understood. Groundwater and surface water amphipods are expected to be differently adapted to temperature elevations due to the different temperature regimes in their habitats and consequently, show a different stress response. No data have been published so far regarding the effects of stress on catecholamine patterns in groundwater invertebrates and accordingly, comparisons with surface water fauna are also missing. In this study, we compared the average catecholamine levels in two taxonomically related amphipod species: Niphargus inopinatus, living in groundwater with constant water temperatures throughout the year, and Gammarus pulex, a surface water stream amphipod frequently exposed to diurnal and seasonal temperature fluctuations. Furthermore, we tracked the immediate changes in whole-animal catecholamine levels in response to heat stress in both species. Pronounced differences in the catecholamine levels of the two species became apparent, with the average dopamine (DA) level of N. inopinatus being almost 1000 times higher than that in G. pulex. The noradrenaline (NA) concentrations in N. inopinatus were on average two orders of magnitude higher than in G. pulex, and for adrenaline (A), the difference constituted one order of magnitude. When exposed to short-term heat stress, both species showed a response in terms of catecholamine levels, but the observed patterns were different. In N. inopinatus, temperature stress was reflected by the appearance of adrenaline, while in G. pulex a significant increase in noradrenaline levels occurred in the treatment with the highest temperature elevation. PMID- 24055560 TI - Somatotropic axis genes are expressed before pituitary onset during zebrafish and sea bass development. AB - The somatotropic axis, or growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis, of fish is involved in numerous physiological process including regulation of ionic and osmotic balance, lipid, carbohydrate and protein metabolism, growth, reproduction, immune function and behavior. It is thought that GH plays a role in fish development but conflicting results have been obtained concerning the ontogeny of the somatotropic axis. Here we investigated the developmental expression of GH, GH-receptor (GHR) and IGF-1 genes and of a GH-like protein from fertilization until early stages of larval development in two Teleosts species, Danio rerio and Dicentrarchus labrax, by PCR, in situ hybridization and Western blotting. GH, GHR and IGF-1 mRNA were present in unfertilized eggs and at all stages of embryonic development, all three displaying a similar distribution in the two species. First located in the whole embryo (until 12 hpf in zebrafish and 76 hpf in sea bass), the mRNAs appeared then distributed in the head and tail, from where they disappeared progressively to concentrate in the forming pituitary gland. Proteins immunoreactive with a specific sea bass anti-GH antibody were also detected at all stages in this species. Differences in intensity and number of bands suggest that protein processing varies from early to later stages of development. The data show that all actors of the somatotropic axis are present from fertilization in these two species, suggesting they plays a role in early development, perhaps in an autocrine/paracrine mode as all three elements displayed a similar distribution at each stage investigated. PMID- 24055561 TI - Growth hormone overexpression generates an unfavorable phenotype in juvenile transgenic zebrafish under hypoxic conditions. AB - Growth hormone (GH) has numerous functions in different organisms. A recently described function for GH is its role in protecting against damage caused by a decrease in oxygen levels. To evaluate the effects of GH-transgenesis on hypoxia tolerance, we used a GH-transgenic zebrafish model. We found that the transgenic fish have higher mortality rates when exposed to low oxygen levels (1.5 mg O2L( 1)) for 24 h. The lower capacity of GH-transgenic fish to manage a hypoxic environment was investigated by analyzing different metabolic and molecular factors. The transgenic fish showed increased oxygen consumption, which confirms the larger oxygen demand imposed by transgenesis. At the gene expression level, transgenesis increased lactate dehydrogenase (LDH) and creatine kinase muscle (CKM) expression in fish under normoxic conditions. This result suggests that excessive GH expression stimulates the synthesis of enzymes involved in anaerobic metabolism. Conversely, the interaction between transgenesis and hypoxia caused an increased expression of hemoglobin (Hb), hypoxia-inducible factor (HIF1a) and prolyl-4-hydroxylase (PHD) genes. Additionally, GH-transgenesis increased LDH activity and increased lactate content. Taken together, these findings indicate that GH-transgenesis impaired the ability of juvenile zebrafish to sustain an aerobic metabolism and induced anaerobic metabolism when the fish were challenged with low oxygen levels. PMID- 24055562 TI - Perioperative acute myocardial infarction increases mortality following noncardiac surgery. AB - OBJECTIVE: To provide insight into diagnosis, treatment, and prevention of perioperative myocardial infarction (PMI). DESIGN: The authors retrospectively analyzed PMI characteristics in patients undergoing noncardiac surgery and identified risk factors for death. SETTING: An affiliated teaching hospital with about 1500 beds. PARTICIPANTS: The authors screened electronic medical records and retrospectively analyzed clinical data from 117,856 patients who underwent noncardiac surgery during the period from August 2003 through June 2011. INTERVENTIONS: Patients were divided into two groups based on survival at 30 days after PMI. MEASUREMENTS AND MAIN RESULTS: PMI was reported in 61 patients, for an overall incidence rate of 5.2 per 10,000. PMI incidence increased significantly with age, with a rate of 0.97 per 10,000 for the 45- to 60-year-old group, and increasing to a rate of 40.4 per 10,000 for the>75-year-old group (p<0.001). The mortality rate of non-PMI patients (n = 117,795) was 0.32%, whereas the mortality rate for the 61 PMI patients was 36.1% (p<0.001). PMI occurred acutely (within 48 to 72 hours of surgery) in the majority of patients (78.7%), and only 18% of these patients complained of chest pain. The majority of patients who suffered PMI had non-ST segment elevation acute myocardial infarction (78.7%). By multiple logistic regression analysis, lack of anticoagulation/antiplatelet therapy and cardiogenic shock were independent risk factors for death in PMI patients (p = 0.001 for both). CONCLUSIONS: PMI incidence increased significantly with advanced age. PMI increased mortality following non-cardiac surgery. The independent risk factors for death in PMI patients following noncardiac surgery were lack of anticoagulation/antiplatelet therapy and cardiogenic shock. PMID- 24055563 TI - FloTrac/Vigileo(TM) (third generation) and MostCare((r))/PRAM versus echocardiography for cardiac output estimation in vascular surgery. AB - OBJECTIVE: To compare the FloTrac/Vigileo(TM) cardiac output (COFT/V) and the MostCare((r))/PRAM cardiac output (COMC/P) versus transthoracic echocardiographic cardiac output estimation (reference method; CO(ECHO)). DESIGN: Prospective observational study. SETTING: Single center, Cardio-Thoracic and Vascular Surgery/Intensive Care Unit. PARTICIPANTS: Patients undergoing elective vascular surgery. INTERVENTIONS: Cardiac output measurement with two pulse contour methods: the FloTrac/Vigileo(TM) and the MostCare((r))/PRAM before (T1) and after (T2) fluid loading versus echocardiography (reference method). MEASUREMENTS AND MAIN RESULTS: One hundred fifty-six CO measurements were performed in 26 patients. The data showed poor agreement between CO(ECHO) and CO(FT/V): r(2) = 0.29 (T1) and 0.27 (T2); bias -0.37 (T1) and -0.40 (T2) L/min; limits of agreement from -3.10 to 2.42 (T1) and from -3.0 to 2.2 (T2) L/min. The percentage error was 51.7% (T1) and 49.3% (T2). Conversely, COMC/P resulted in agreement with echocardiography: r(2) = 0.76 (T1) and 0.80 (T2); bias -0.01 (T1) and -0.06 (T2) L/min; limits of agreement from -1.13 to 1.11 (T1) and from -0.90 to 0.80 (T2) L/min, with a PE of 22.4% (T1) and of 17.0% (T2). CONCLUSIONS: In patients undergoing vascular surgery, the FloTrac/Vigileo(TM) did not demonstrate that it was a reliable system for CO monitoring when compared with echocardiography derived CO. However, MostCare((r))/PRAM was shown to estimate CO with a good level of agreement with echocardiographic measures. PMID- 24055564 TI - Arsenic ecotoxicology: the interface between geosphere, hydrosphere and biosphere. PMID- 24055565 TI - Effects of a force production task and a working memory task on pain perception. AB - The goal in the current study was to examine the analgesic effects of a pinch grip-force production task and a working memory task when pain-eliciting thermal stimulation was delivered simultaneously to the left or right hand during task performance. Control conditions for visual distraction and thermal stimulation were included, and force performance measures and working memory performance measures were collected and analyzed. Our experiments revealed 3 novel findings. First, we showed that accurate isometric force contractions elicit an analgesic effect when pain-eliciting thermal stimulation was delivered during task performance. Second, the magnitude of the analgesic effect was not different when the pain-eliciting stimulus was delivered to the left or right hand during the force task or the working memory task. Third, we found no correlation between analgesia scores during the force task and the working memory task. Our findings have clinical implications for rehabilitation settings because they suggest that acute force production by one limb influences pain perception that is simultaneously experienced in another limb. From a theoretical perspective, we interpret our findings on force and memory driven analgesia in the context of a centralized pain inhibitory response. PERSPECTIVE: This article shows that force production and working memory have analgesic effects irrespective of which side of the body pain is experienced on. Analgesia scores were not correlated, however, suggesting that some individuals experience more pain relief from a force task as compared to a working memory task and vice versa. PMID- 24055566 TI - Occlusion of all aortic arch great vessels: acute revascularization to perform endovascular stroke therapy. AB - BACKGROUND: We present a case of a patient with a left-sided stroke and occlusion of all aortic arch great vessels who was treated successfully with endovascular intervention followed by delayed cardiothoracic revascularization. CASE REPORT: A 46-year-old man presented with acute onset of dense right hemiparesis, facial droop, and aphasia with an initial National Institute of Health Stroke Score of 15. The patient was taken for emergent angiography after failing intravenous tissue plasminogen activator thrombolysis. Dedicated angiography of the aortic arch revealed occlusion of all great vessels, including the right brachiocephalic, left common carotid, and left subclavian artery. Delayed arterial filling of the right brachiocephalic and left subclavian artery by aberrant collaterals was seen. More distally, flow into the bilateral subclavian arteries, right common carotid artery, and left vertebral artery was appreciated. Serial balloon angioplasty of the left common carotid artery origin reconstituted flow. Subsequent selective angiogram of the left internal carotid artery revealed a proximal middle cerebral artery occlusion. Intra-arterial injection of tissue plasminogen activator followed by mechanical thrombectomy and intracranial stenting restored flow in the middle cerebral artery. Two months later the patient underwent aortic arch reconstruction with bifurcated graft to the brachiocephalic artery and left common carotid artery. At 1-year follow-up, the patient's examination revealed almost complete resolution of right hemiparesis with minimal hand weakness and mild expressive aphasia. CONCLUSIONS: We report a rare case of occlusion of all aortic arch great vessels. Combined endovascular intervention and surgical revascularization resulted in an excellent durable outcome. PMID- 24055567 TI - Postconcussion syndrome and mild head injury: the role of early diagnosis using neuropsychological tests and functional magnetic resonance/spectroscopy. AB - OBJECTIVE: Postconcussion syndrome (PCS) is usually underestimated in cases of mild head injury (MHI). It is one of the most common causes of physical, cognitive, and psychomotor disturbances that affect the quality of life, work, and social reintegration of individuals. Until now, we did not have evidence of structural abnormalities shown by traditional imaging methods. We describe a series of instruments that confirm PCS with satisfactory evidence. METHODS: We conducted a clinical prospective study of 19 adult patients selected from a pool of 320 adults who had MHI. The cognitive, executive, and memory functions of subjects were examined within the first 72 hours using neuropsychological tests. These results were analyzed with neurological examination and functional MR/spectroscopy. RESULTS: Neurobehavioral alterations were found in 47% of cases, with posttraumatic amnesia. Around 55% of subjects experienced physical disturbances such as headache and postural vertigo due to PCS. The spectroscopy reports revealed neurometabolite disturbances in 54% of cases, particularly N acetylaspartate (Naa) and the Naa/lactate ratio in the frontal lobe. We observed a relationship between metabolite disturbances in spectroscopy and the digit span backward test (P = .045). CONCLUSIONS: This first diagnostic strategy supports with scientific evidence the presence of PCS in MHI. We identified physical and neuropsychological abnormalities from this group, affecting the areas of memory and learning. Evidence of neurometabolite disturbances were found specifically in the frontal lobe. It is necessary to complete comparative follow-up for an extended period of time. The neuropsychological and spectroscopy tests allow us to confirm the diagnosis of a syndrome that is usually neglected. PMID- 24055568 TI - A safe and effective technique for harvesting the occipital artery for posterior fossa bypass surgery: a cadaveric study. AB - OBJECTIVE: The occipital artery (OA) is an important donor artery for posterior fossa revascularization. Harvesting the OA is believed to be difficult and time consuming due to its 3-dimensional course through different suboccipital tissue layers. We propose a safe and effective means of dissecting the OA. METHODS: The course of the OA was explored in 5 cadaveric heads (10 sides). The OA was divided into 3 segments based on the vertical muscle layer it ran through; subcutaneous, transitional, and intramuscular. Three different approaches were attempted, and their respective advantages and disadvantages were assessed. RESULTS: The subcutaneous segment of the OA was found to run above the galea without traversing any vertical layers, and was thus easily dissected down to the superior nuchal line (SNL). The segment between the SNL and the digastric groove, traditionally the suboccipital segment, was divided into transitional and intramuscular segments. After detaching and retracting the suboccipital muscles, the OA was found to run in a single vertical layer of connective tissue. Dissection of the transitional segment was more involved as it ran between the SNL and the superior edge of the splenius capitis muscle, and vertically through the galea aponeurotica and the tendon of the sternocleidomastoid muscle. CONCLUSIONS: This segmentation provided a safe and effective procedure for harvesting the OA, in which dissection of the transitional segment is a critical step. Although the course of the OA is complex, precise anatomical knowledge of the suboccipital muscles and a stepwise dissection make harvesting the OA relatively simple. PMID- 24055569 TI - Clinical correlates of high cervical fractional anisotropy in acute cervical spinal cord injury. AB - OBJECTIVE: Fractional anisotropy (FA) of the high cervical cord (C1-C2), rostral to the injury site, correlates with upper limb function in patients with chronic cervical spinal cord injury (SCI). In acute cervical SCI, this relationship has not been investigated. The objective of this study was to identify functional correlates of FA of the high cervical cord in a series of patients with acute cervical SCI. METHODS: Traumatic cervical SCI patients who underwent presurgical cervical spine diffusion tensor imaging at our institution were reviewed for this study. FA of the whole cord as well as the lateral corticospinal tracts (CSTs) was calculated on axial images from C1-C2. Upper limb motor (C5-T1) and sensory (C2-T1) function scores were extracted from the admission American Spinal Injury Association (ASIA) examinations. Correlation analysis for FA with ASIA examinations was performed using a Pearson correlation. RESULTS: Twelve subjects (9 men, 3 women; mean age 54.7 +/- 4.0 years) underwent cervical spine diffusion tensor imaging at a mean duration of 3.6 +/- 0.9 days postinjury. No patient had cord compression or intramedullary T2-weighted hyperintensities within the C1-C2 segments. FA correlated with upper limb motor score (whole cord: r = 0.59, P = .04; CST: 0.67, P = .01) and the ASIA grade (whole cord: r = 0.61, P = .03; CST: r = 0.71, P = .009). No correlation was found between FA and sensory scores. CONCLUSIONS: FA of the whole cervical cord as well as the CST, rostral to the injury site, is associated with preserved upper limb motor function as well as superior ASIA grades after acute cervical SCI. FA of the high cervical cord is a potential biomarker of neural injury after acute cervical SCI. PMID- 24055570 TI - Microsurgical clipping of previously coiled aneurysms. AB - OBJECTIVE: This study sought to show and analyze the main authors' experience (P.R. and J.M.C.) in previously coiled aneurysm surgery as an emerging challenge in today's neurosurgical practice. METHODS: Twelve female and 8 male patients, whose ages ranged from 32 to 56 years (average 43.5), underwent surgery between April 2009 and September 2012 in 2 centers. Reasons for surgery were 13 partially occluded aneurysms and 7 recanalized aneurysms. RESULTS: There was no mortality in this series. Aneurysmal sites were 5 anterior communicating artery aneurysms, 5 posterior communicating artery aneurysms, 3 middle cerebral artery aneurysms, 6 paraclinoid carotid artery aneurysms, and 1 aneurysm in the pericallosal artery. A patient sustained a postsurgical frontal infarction with mild neurological deficit. One of the aneurysms presented with an arterial branch at the level of the aneurysmal neck; therefore, partial clipping and packing was required. Microsurgical clipping in the remaining patients was performed successfully. Eight cases required partial coil removal before clipping. CONCLUSIONS: Surgical management of previously coiled aneurysms is an emerging challenge in neurosurgery. Incomplete or ineffective embolizations pose an increased risk for the patient, thus requiring surgical treatment. Although not advisable, coil removal might be necessary when in the vicinity of the aneurismal neck in order to place the clip correctly. The authors believe that adequate patient selection and careful preoperative planning are essential to reduce the incidence of patients with unsuccessful coils who will later need surgical treatment. PMID- 24055571 TI - Impact of fellowship training on research productivity in academic neurological surgery. AB - BACKGROUND: An increasing number of neurological surgeons have sought fellowship training in recent years, and previous analyses have suggested these practitioners are more likely to pursue an academic career. Scholarly productivity is a key component in academic advancement. OBJECTIVE: We used the h index to evaluate whether fellowship training impacts research productivity and whether any differences exist in scholarly output among practitioners in the various neurosurgical subspecialties. METHODS: Online listings from academic neurological surgery departments were used to organize faculty by academic rank and fellowship training. Using the Scopus database, we calculated the h-index for 869 full-time clinical faculty. RESULTS: Mean h-index did not differ between fellowship- and nonfellowship-trained practitioners (h = 12.6 vs. 13.0, P = 0.96). When organized by academic rank, the difference between h-indices of those who completed fellowships was substantially greater at all ranks, with statistical significance at the associate professor rank (P = 0.003). Upon further examination by individual subspecialties, significant differences in relative research impact were noted (P < 0.0001). The stereotactic and functional fellowship was found to have the greatest mean h-index score, whereas the trauma/critical care fellowship had the lowest. CONCLUSION: No significant difference existed between the mean h-index scores of neurological surgeons who completed fellowships and those who did not. However, when stratified by academic rank, a trend was observed showing greater mean h-index scores for those who completed fellowships. This trend persists across nearly all subspecialties. Overall, being a senior faculty member corresponds with a greater h-index score, regardless of whether a fellowship was completed. PMID- 24055572 TI - The prevalence of the ponticulus posticus (arcuate foramen) and its importance in the Goel-Harms procedure: meta-analysis and review of the literature. AB - OBJECTIVE: We reviewed published radiographic and cadaver series describing the incidence of the anatomical anomaly ponticulus posticus and discuss its relevance to C1 lateral mass screw (C1LMS) insertion. METHODS: Online databases were searched for English-language articles describing the presence of ponticulus posticus in cadaver and radiographic studies. Forty-four reports describing 21,789 patients (n = 15,542) or bony/cadaver specimens (n = 6247) fulfilled inclusion criteria. Meta-analysis techniques were applied to estimate the prevalence of this anomaly. RESULTS: The overall prevalence of ponticulus posticus was 16.7%. The anomaly was identified in 18.8% of cadaver, 17.2% of computed tomographic, and 16.6% on radiographic studies. The anomaly composed a complete foramen in 9.3% of patients and was partial/incomplete in 8.7%. It was present bilaterally in 5.4% of cases and unilateral in 7.6%. There was no significant difference in prevalence between males (15.8%) and females (14.6%). Review of that literature demonstrated a dramatic increase in the number of patients treated with C1LMS through the posterior arch since first described in 2002, necessitating recognition of this anomaly when performing the Goel-Harms procedure. CONCLUSION: The atlantal anomaly ponticulus posticus is not rare, occurring in 16.7% of patients in radiographic and cadaver studies. This anomaly may give the false impression that the posterior arch of the atlas is of adequate size to accommodate a C1LMS and may lead to inadvertent vertebral artery injury. Careful assessment via preoperative multiplanar computed tomographic imaging should be performed before consideration of C1LMS implantation. PMID- 24055574 TI - Delphi-based assessment of fall-related risk factors in acute rehabilitation settings according to the International Classification of Functioning, Disability and Health. AB - OBJECTIVE: To apply the International Classification of Functioning, Disability and Health (ICF) model to fall prevention by developing an ICF core set for fall risks in acute rehabilitation settings. DESIGN: Fall risk factors were identified based on a systematic review of the literature and linked to ICF categories. A consensus process was conducted using a Delphi-based evaluation technique. SETTING: University-based hospital. PARTICIPANTS: Multidisciplinary participants (N=20) from different institutions. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A 5-point Likert-type scale was used to weigh the importance of each risk category. The level of agreement for each consensus was assessed based on Spearman rho and semi-interquartile range indices. Categories with a mean score >=4 in the third round of evaluation were included in this ICF core set. RESULTS: The core set comprised 34 fall risk categories that were distributed as follows: 18 categories on body functions, 2 on body structures, 8 on activities and participation, 4 on environmental factors, and 2 categories on personal factors. CONCLUSIONS: An ICF core set for falls in acute rehabilitation settings was developed in this study. Further validation is required. PMID- 24055573 TI - Anti-inflammatory properties of prostaglandin E2: deletion of microsomal prostaglandin E synthase-1 exacerbates non-immune inflammatory arthritis in mice. AB - Prostanoids and PGE2 in particular have been long viewed as one of the major mediators of inflammation in arthritis. However, experimental data indicate that PGE2 can serve both pro- and anti-inflammatory functions. We have previously shown (Kojima et al., J. Immunol. 180 (2008) 8361-8368) that microsomal prostaglandin E synthase-1 (mPGES-1) deletion, which regulates PGE2 production, resulted in the suppression of collagen-induced arthritis (CIA) in mice. This suppression was attributable, at least in part, to the impaired generation of type II collagen autoantibodies. In order to examine the function of mPGES-1 and PGE2 in a non-autoimmune form of arthritis, we used the collagen antibody-induced arthritis (CAIA) model in mice deficient in mPGES-1, thereby bypassing the engagement of the adaptive immune response in arthritis development. Here we report that mPGES-1 deletion significantly increased CAIA disease severity. The latter was associated with a significant (~3.6) upregulation of neutrophil, but not macrophage, recruitment to the inflamed joints. The lipidomic analysis of the arthritic mouse paws by quantitative liquid chromatography/tandem mass spectrometry (LC/MS/MS) revealed a dramatic (~59-fold) reduction of PGE2 at the peak of arthritis. Altogether, this study highlights mPGES-1 and its product PGE2 as important negative regulators of neutrophil-mediated inflammation and suggests that specific mPGES-1 inhibitors may have differential effects on different types of inflammation. Furthermore, neutrophil-mediated diseases could be exacerbated by inhibition of mPGES-1. PMID- 24055575 TI - Jaw-opening force test to screen for Dysphagia: preliminary results. AB - OBJECTIVE: To assess the jaw-opening force test (JOFT) for dysphagia screening. DESIGN: Criterion standard. SETTING: University dental hospital. PARTICIPANTS: Patients complaining of dysphagia (N=95) and with symptoms of dysphagia with chronic underlying causes (mean age +/- SD, 79.3+/-9.61y; range, 50-94y; men: n=49; mean age +/- SD, 77.03+/-9.81y; range, 50-94y; women: n=46; mean age +/- SD, 75.42+/-9.73y; range, 51-93y) admitted for treatment between May 2011 and December 2012 were included. INTERVENTIONS: None. MAIN OUTCOME MEASURES: All patients were administered the JOFT and underwent fiberoptic endoscopic evaluation of swallowing (FEES). The mean jaw-opening strength was compared with aspiration (ASP) and pharyngeal residue observations of the FEES, which was used as the criterion standard. RESULTS: A receiver operating characteristic (ROC) curve analysis was performed. Forces of <=3.2kg for men and <=4kg for women were appropriate cutoff values for predicting ASP with a sensitivity and specificity of .57 and .79 for men and .93 and .52 for women, respectively. Based on the ROC analyses for predicting pharyngeal residue, forces of <=5.3kg in men and <=3.9kg in women were appropriate cutoff values, with a sensitivity and specificity of .80 and .88 for men and .83 and .81 for women, respectively. CONCLUSIONS: The JOFT could be a useful screening tool for predicting pharyngeal residue and could provide useful information to aid in the referral of patients for further diagnostic imaging testing. However, given its low sensitivity to ASP the JOFT should be paired with other screening tests that predict ASP. PMID- 24055576 TI - Intragastric administration of glutamate increases REM sleep in rats. AB - Monosodium glutamate, a umami taste substance is commonly used flavor enhancer. The effect of intragastric administration of 1.5 ml of 0.12M monosodium glutamate on sleep-wake was studied in 10 adult male Wistar rats. Sleep-wake parameters were recorded through chronically implanted electroencephalogram, electrooculogram and electromyogram electrodes using a digital recording system (BIOPAC system Inc. BSL PRO 36, USA). The sleep-wake was recorded for 6h after the intragastric administration of either glutamate or saline. Sleep-wake stages were analyzed as wake, slow wave sleep and REM sleep. Compared to saline, intragastric administration of glutamate significantly increased REM sleep duration and episode frequency. REM sleep duration was increased in all the three 2h bins, 10:00-12:00 h (p=0.037), 12:00-14:00 h (p=0.037) and 14:00-16:00 h (p=0.007). The slow wave sleep and total sleep time were not affected. It is concluded that intragastric glutamate administration increases REM sleep. PMID- 24055577 TI - Myeloid cell alterations in the mouse placenta precede the onset of labor and delivery. AB - OBJECTIVE: Immature myeloid cells (IMCs) are bone marrow-derived cells that normally differentiate into granulocytes, macrophages, and dendritic cells (DCs) but expand in pathological conditions such as malignancy. DCs are antigen presenting cells that regulate the immune response. Both IMCs and DCs were shown to take part in angiogenesis; however, little is known of their function in the placenta. We sought to determine whether alterations in DC and IMC populations in the placenta precede the onset of delivery. STUDY DESIGN: Experiments were performed on 6-8 week old C57Bl/6 female mice. Placentas from pregnant mice that were killed on designated days, immunostained using fluorescently labeled anti CD11b, Gr-1, CD11c, major histocompatibility II (MHCII), and CD45, and analyzed by flow cytometry and immunofluorescent microscopy. RESULTS: Throughout the latter part of pregnancy toward labor and delivery, the CD45(+)CD11b(+)Gr1(+)-IMC population decreased 29 +/- 9.1% (day 12) and 30 +/- 9.9% (day 15), vs 21 +/- 8.1% (day18, n = 21, 15, and 27; P = .006 and P = .004, respectively), whereas the CD45(+)CD11c(+)MHCII(+)-DC population increased 0.87 +/- 0.3% (day 12) and 0.70 +/- 0.3% (day 15) vs 1.81 +/- 1.3% (day 18, n = 21, 15, and 27, P = .002 and P = .001, respectively). Both myeloid cell populations were localized adjacent to CD31(+) endothelial cells in sites of placental angiogenesis. CONCLUSION: Labor and delivery are preceded by proangiogenic-myeloid cell alterations, reflected by a decrease in IMCs and an increase in DCs populating the mouse placenta. The intriguing possibility that delivery is preceded by the maturation of IMCs in part into DCs warrants further studies. PMID- 24055579 TI - Inside out: On rare occasions, ring pessaries can cause genital incarceration. PMID- 24055578 TI - History of preterm birth and subsequent cardiovascular disease: a systematic review. AB - A history of preterm birth (PTB) may be an important lifetime risk factor for cardiovascular disease (CVD) in women. We identified all peer-reviewed journal articles that met study criteria (English language, human studies, female, and adults >=19 years old), that were found in the PubMed/MEDLINE databases, and that were published between Jan. 1, 1995, and Sept. 17, 2012. We summarized 10 studies that assessed the association between having a history of PTB and subsequent CVD morbidity or death. Compared with women who had term deliveries, women with any history of PTB had increased risk of CVD morbidity (variously defined; adjusted hazard ratio [aHR] ranged from 1.2-2.9; 2 studies), ischemic heart disease (aHR, 1.3-2.1; 3 studies), stroke (aHR, 1.7; 1 study), and atherosclerosis (aHR, 4.1; 1 study). Four of 5 studies that examined death showed that women with a history of PTB have twice the risk of CVD death compared with women who had term births. Two studies reported statistically significant higher risk of CVD-related morbidity and death outcomes (variously defined) among women with >=2 pregnancies that ended in PTBs compared with women who had at least 2 births but which ended in only 1 PTB. Future research is needed to understand the potential impact of enhanced monitoring of CVD risk factors in women with a history of PTB on risk of future CVD risk. PMID- 24055580 TI - Antenatal corticosteroid administration: understanding its use as an obstetric quality metric. AB - OBJECTIVE: In 1994, the National Institutes of Health recommended a full course of antenatal corticosteroids (ACS) to women who were at risk of delivery at 24-32 weeks of gestation. In 2010, the Joint Commission on Accreditation of Healthcare Organization incorporated ACS administration rates as a perinatal core quality measure. The objective of this study is (1) to assess ACS administration rates among eligible patients at a tertiary care center and (2) to identify modifiable factors to optimize administration rates. STUDY DESIGN: A retrospective chart review of preterm deliveries at <37 weeks of gestation from July 2009 to July 2011 was performed. Hospital level data, delivery information, obstetric history, and neonatal outcomes were abstracted. Categoric variables were compared with the use of the chi(2) test. Continuous variables were compared with the use of a 2 sample t-test, Wilcoxon rank-sum, or Kruskal Wallis tests. RESULTS: Nine hundred four women had preterm delivery; 38% of them delivered from 24-34 weeks of gestation. Of the eligible patients, 81.3% received at least 1 dose of ACS, and 69.6% received both doses before delivery. The median time from evaluation to ACS administration was 2.6 hours (interquartile range, 1.6-4.8 hours). Thirty-three percent of the patients who did not receive ACS had had a previous triage visit within 2 weeks of delivery (66.6% of them were evaluated for symptoms of preterm labor) vs 2.8% for those women who received ACS. CONCLUSION: Of the eligible patients, 81.3% received at least 1 dose of ACS. Tangible opportunities that were identified for systems-based improvement in ACS administration rates included decreasing the time interval from patient evaluation to ACS administration and standardizing outpatient follow-up evaluation for patients who were discharged with symptoms of preterm labor. PMID- 24055581 TI - Position statement on fetal myelomeningocele repair. AB - Following the promising multicenter randomized trial results of in utero fetal myelomeningocele repair; we anticipate that an increasing number of tertiary care centers may want to offer this therapy. It is essential to establish minimum criteria for centers providing open fetal myelomeningocele repair to ensure optimal maternal and fetal/pediatric outcomes, as well as patient safety both short- and long-term; and to advance our knowledge of the role and benefit of fetal surgery in the management of fetal myelomeningocele. The fetal myelomeningocele Maternal-Fetal Management Task Force was initially convened by the Eunice Kennedy Shriver National Institute of Child Health and Human Development to discuss the implementation of maternal fetal surgery for myelomeningocele. The decision was made to develop the optimal practice criteria presented in this document for the purpose of medical and surgical leadership. These criteria are not intended to be used for legal or regulatory purposes. PMID- 24055582 TI - Clinical performance of a multivariate index assay for detecting early-stage ovarian cancer. AB - OBJECTIVE: We sought to analyze the effectiveness of a multivariate index assay (MIA) in identifying early-stage ovarian malignancy compared to clinical assessment, CA 125-II, and modified American Congress of Obstetricians and Gynecologists (ACOG) guidelines among women undergoing surgery for an adnexal mass. STUDY DESIGN: Patients were recruited in 2 related prospective, multi institutional trials involving 44 sites. All women had preoperative imaging and biomarker analysis. Preoperative biomarker values, physician assessment of ovarian cancer risk, and modified ACOG guideline risk stratification were correlated with surgical pathology. RESULTS: A total of 1016 patients were evaluable for MIA, CA 125-II, and clinical assessment. Overall, 86 patients (8.5%) had primary-stage I/II primary ovarian malignancy, with 70.9% having stage I disease and 29.1% having stage II disease. For all early-stage ovarian malignancies, MIA combined with clinical assessment had significantly higher sensitivity (95.3%; 95% confidence interval [CI], 88.6-98.2) compared to clinical assessment alone (68.6%; 95% CI, 58.2-77.4), CA 125-II (62.8%; 95% CI, 52.2 72.3), and modified ACOG guidelines (76.7%; 95% CI, 66.8-84.4) (P < .0001). Among the 515 premenopausal patients, the sensitivity for early-stage ovarian cancer was 89.3% (95% CI, 72.8-96.3) for MIA combined with clinical assessment, 60.7% (95% CI, 42.4-76.4) for clinical assessment alone, 35.7% (95% CI, 20.7-54.2) for CA 125-II, and 78.6% (95% CI, 60.5-89.8) for modified ACOG guidelines. Early stage ovarian cancer in postmenopausal patients was correctly detected in 98.3% (95% CI, 90.9-99.7) of cases by MIA combined with clinical assessment, compared to 72.4% (95% CI, 59.8-82.2) for clinical assessment alone, 75.9% (95% CI, 63.5 85.0) for CA 125-II, and 75.9% (95% CI, 63.5-85.0) for modified ACOG guidelines. CONCLUSION: MIA combined with clinical assessment demonstrated higher sensitivity for early-stage ovarian malignancy compared to clinical assessment alone, CA 125 II, and modified ACOG guidelines with consistent performance across menopausal status. PMID- 24055583 TI - Reproductive coercion and co-occurring intimate partner violence in obstetrics and gynecology patients. AB - OBJECTIVE: Reproductive coercion is male behavior to control contraception and pregnancy outcomes of female partners. We examined the prevalence of reproductive coercion and co-occurring intimate partner violence among women presenting for routine care at a large, urban obstetrics and gynecology clinic. STUDY DESIGN: Women aged 18-44 years completed a self-administered, anonymous survey. Reproductive coercion was defined as a positive response to at least 1 of 14 questions derived from previously published studies. Women who experienced reproductive coercion were also assessed for intimate partner violence in the relationship where reproductive coercion occurred. RESULTS: Of 641 women who completed the survey, 16% reported reproductive coercion currently or in the past. Among women who experienced reproductive coercion, 32% reported that intimate partner violence occurred in the same relationship. Single women were more likely to experience reproductive coercion as well as co-occurring intimate partner violence. CONCLUSION: Reproductive coercion with co-occurring intimate partner violence is prevalent among women seeking general obstetrics and gynecology care. Health care providers should routinely assess reproductive-age women for reproductive coercion and intimate partner violence and tailor their family planning discussions and recommendations accordingly. PMID- 24055584 TI - Circulating angiogenic factors in monochorionic twin pregnancies complicated by twin-to-twin transfusion syndrome and selective intrauterine growth restriction. AB - OBJECTIVE: To determine maternal plasma levels of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), placental growth factor (PLGF), and soluble endoglin (sEng) in monochorionic diamniotic (MC/DA) twin pregnancies complicated by twin-to-twin transfusion syndrome (TTTS) or selective intrauterine growth restriction (sIUGR). STUDY DESIGN: A longitudinal cohort study of pregnant women with MC/DA twins who were classified into 3 groups: (1) uncomplicated MC/DA twins (n = 22), (2) TTTS (n = 23), and (3) sIUGR (n = 15). Maternal plasma samples were obtained between 13-20 and 21-28 weeks of gestation and cord blood samples were collected at delivery. Maternal plasma concentrations of sVEGFR-1, PLGF, and sEng, as well as cord blood levels of sVEGFR-1 were measured by enzyme-linked immunoassay. RESULTS: Maternal plasma levels of sVEGFR-1 and sEng were significantly higher in patients with TTTS at the early and late second trimester compared with normal monochorionic pregnancies (P < .01). In contrast, in the sIUGR group, sVEGFR-1 and sEng levels were significantly higher only at the late second trimester (P < .05). PLGF levels were significantly lower at the early and late second trimester in both TTTS and sIUGR compared with controls (P < .01). Plasma concentrations of sVEGFR-1 were significantly higher among TTTS pregnancies compared with sIUGR at the late second trimester (P = .027). Cord blood levels of sVEGFR-1 were significantly higher in the smaller intrauterine growth restricted twin compared with the normal cotwin. CONCLUSION: Monochorionic pregnancies complicated by TTTS and sIUGR are characterized by decreased angiogenic activity. The disparity in severity of the antiangiogenic state between TTTS and sIUGR suggests that these 2 conditions may represent a continuum. PMID- 24055585 TI - Validity of utility measures for women with urge, stress, and mixed urinary incontinence. AB - OBJECTIVE: We sought to evaluate the construct validity of 3 health status classification system instruments-Health Utilities Index Mark 3 (HUI-3), EuroQol (EQ-5D), and Short Form 6D (SF-6D)-and a visual analog scale (VAS) for measuring utility scores in women with urge, stress, and mixed urinary incontinence. STUDY DESIGN: Utility scores were measured in 202 women with urinary incontinence. Pelvic floor symptom severity and quality of life were measured using the Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire, respectively. Construct, discriminant, and concurrent validity were evaluated. RESULTS: Significant correlations were noted between utility scores and the Pelvic Floor Distress Inventory (r = -0.22 to -0.42, P < .05) and the Pelvic Floor Impact Questionnaire (r = -0.32 to -0.50, P < .05). Mean utility scores were significantly lower for women with urge or mixed incontinence compared to stress incontinence for the EQ-5D (0.71 +/- 0.23, 0.73 +/- 0.26, and 0.81 +/- 0.16, respectively, P = .02) and the SF-6D (0.76 +/- 0.12, 0.74 +/- 0.12, and 0.81 +/- 0.11, respectively, P = .02) but not the HUI-3 or the VAS. There was a clinically important difference in utility scores (>0.03) between women with urge or mixed incontinence as compared to stress incontinence for the HUI-3, EQ-5D, and SF-6D but not the VAS. Utility preference scores were significantly lower for women with combined urinary and fecal incontinence (0.69-0.73) than urinary incontinence alone (0.77-0.84, P < .01). CONCLUSION: The HUI-3, EQ-5D, and SF-6D, but not the VAS, provide valid measurements for utility scores in women with stress, urge, and mixed urinary incontinence. PMID- 24055586 TI - Initial experience with a dual-balloon catheter for the management of postpartum hemorrhage. AB - OBJECTIVE: When uterotonics fail to cause sustained uterine contractions and satisfactory control of hemorrhage after delivery, tamponade of the uterus can be effective in decreasing hemorrhage secondary to uterine atony. STUDY DESIGN: These data are from a postmarketing surveillance study of a novel dual-balloon catheter tamponade device, the Belfort-Dildy Obstetrical Tamponade System (ebb). RESULTS: A total of 57 women were enrolled: 55 women had the diagnosis of postpartum hemorrhage, and 51 women had uterine balloon placement within the uterine cavity. This study reports the outcomes in the 51 women who had uterine balloon placement within the uterine cavity for treatment of postpartum hemorrhage, as defined by the "Instructions for Use." We further assessed 4 subgroups: uterine atony only (n = 28 women), placentation abnormalities (n = 8 women), both uterine atony and placentation abnormalities (n = 9 women), and neither uterine atony nor placentation abnormalities (n = 6 women). The median (range) time interval between delivery and balloon placement was 2.2 hours (0.3 210 hours) for the entire cohort (n = 51 women) and 1.3 hours (0.5-7.0 hours) for the uterine atony only group (n = 28 women). Bleeding decreased in 22/51 of cases (43%), stopped in 28/51 of cases (55%), thus decreased or stopped in 50/51 of the cases (98%) after balloon placement. Nearly one-half (23/51) of all women required uterine balloon volumes of >500 mL to control bleeding. CONCLUSION: We conclude that uterine/vaginal balloon tamponade is very useful in the management of postpartum hemorrhage because of uterine atony and abnormal placentation. PMID- 24055587 TI - Influence of qualitative research on women's health screening guidelines. AB - OBJECTIVE: Considerable time and resources are allocated to carry out qualitative research. The purpose of our study was to evaluate the availability of qualitative research on women's health screening and assess its influence on screening practice guidelines in the United States, Canada, and the United Kingdom. STUDY DESIGN: Medline, CINHAL, and WEB of Science databases were used to identify the availability of qualitative research conducted in the past 15 years on 3 different women's health screening topics: cervical cancer screening, breast cancer screening, and prenatal first-trimester screening. Key national practice guidelines on women's health screening were selected using the National Guideline Clearinghouse web site. Bibliometric analysis was used to determine the frequency of qualitative references cited in the guidelines. RESULTS: A total of 272 qualitative research papers on women's health screening was identified: 109 on cervical cancer screening, 104 on breast cancer screening, and 59 on prenatal first-trimester screening. The qualitative studies focused on health care provider perspectives as well as ethical, ethnographic, psychological, and social issues surrounding screening. Fifteen national clinical practice guidelines on women's health screening were identified. A total of 943 references was cited, only 2 of which comprised of qualitative research cited by only 1 clinical practice guideline. CONCLUSION: Although there is considerable qualitative research that has been carried out on women's health screening, its incorporation into clinical practice guidelines is minimal. Further exploration of the disconnect between the two is important for enhancing knowledge translation of qualitative research within clinical practice. PMID- 24055588 TI - [Freiberg disease, a rare cause of metatarsalgia]. PMID- 24055589 TI - [Conflicts of interests in clinical research in primary health care]. AB - Conflicts of interests between professionals and patients in biomedical research, is an ethical problem. None of the laws in Spain mention whether the clinical researcher has to clarify to participants the reasons why it proposes them to participate in a clinical trial. In this article, conflicts of interests in research are discussed in the context of primary healthcare. In this area conflicts of interests might alter the confidence between patients and healthcare professionals. Finally, we suggest some practical strategies that can help participants make the decision to participate in a clinical trial more willingly and freely. PMID- 24055590 TI - [Thyroid myopathy]. PMID- 24055591 TI - Granzyme B ELISPOT assay to measure influenza-specific cellular immunity. AB - The immunogenicity and efficacy of influenza vaccination are markedly lower in the elderly. Granzyme B (GrzB), quantified in fresh cell lysates, has been suggested to be a marker of cytotoxic T lymphocyte (CTL) response and a predictor of influenza illness among vaccinated older individuals. We have developed an influenza-specific GrzB ELISPOT assay using cryopreserved PBMCs. This method was tested on 106 healthy older subjects (ages 50-74) at baseline (Day 0) and three additional time points post-vaccination (Day 3, Day 28, Day 75) with influenza A/H1N1-containing vaccine. No significant difference was seen in GrzB response between any of the time points, although influenza-specific GrzB response appears to be elevated at all post-vaccination time points. There was no correlation between GrzB response and hemagglutination inhibition (HAI) titers, indicating no relationship between the cytolytic activity and humoral antibody levels in this cohort. Additionally, a significant negative correlation between GrzB response and age was observed. These results reveal a reduction in influenza-specific GrzB response as one ages. In conclusion, we have developed and optimized an influenza specific ELISPOT assay for use with frozen cells to quantify the CTL-specific serine protease GrzB, as a measure of cellular immunity after influenza vaccination. PMID- 24055592 TI - Validated detection of anti-GD2 antibody ch14.18/CHO in serum of neuroblastoma patients using anti-idiotype antibody ganglidiomab. AB - Human/mouse chimeric monoclonal antibody (mAb) ch14.18 is directed against disialoganglioside GD2 and has demonstrated activity and efficacy in high-risk neuroblastoma (NB). For the purpose of industrial production, ch14.18 was manufactured in Chinese hamster ovarian cells (ch14.18/CHO) in order to facilitate clinical trials in Europe. To determine immunopharmacological effects of ch14.18 in preclinical models and clinical trials, a validated method of quantitative detection of ch14.18/CHO in serum is an important tool. We recently described the generation and characterization of ganglidiomab, a monoclonal anti idiotype Ab (AIT) of ch14.18 (Lode et al., 2013), which was used to establish quantitative and validated enzyme-linked immunosorbent assay (ELISA) methods using ganglidiomab as a capture mAb. With these ELISA methods, we first demonstrated binding of ch14.18/CHO to ganglidiomab to a similar extent as to the nominal antigen GD2 and in contrast to GD1b and GM2 precursor and metabolite gangliosides, used as negative controls. In order to determine both low (0.5-3.1 MUg/ml) and high levels of ch14.18/CHO (1.0-25 MUg/ml) in the serum of NB patients treated with ch14.18/CHO, we established two ELISA methods with high and low sensitivity using 1/1001, and 1/5126 sample dilutions, respectively. For validation, we used a set of tailored quality controls (QC) containing distinct concentrations of ch14.18/CHO (1.0, 2.0, 7.0, and 20.0 MUg/ml). We determined the limit of detection (LOD) for both ELISA methods to be 0.50 MUg/ml for the high sensitivity and 1.02 MUg/ml for low sensitivity ELISA. The within-assay precision was 12% for high and 4% for low sensitivity ELISA, and the coefficients of variation (CV) were under 20% for all assays (3% for QC-1.0, 5% for QC-2.0, 7% for QC-7, and 3% for QC-20). With this method, we showed that neither eight freeze-thaw cycles nor storage at room temperature for up to 168 h affected ch14.18/CHO stability in serum. Finally, we analyzed ch14.18 Ab serum levels in selected NB patients receiving ch14.18/CHO as a continuous or bolus infusion with a peak concentration at the last day of Ab application (17.14 +/- 7.20mg/ml with continuous and 19.78 +/- 2.26 mg/ml with bolus infusion). In summary, we describe validated ELISA methods using ganglidiomab as a capture mAb suitable for the pharmacological evaluation of ch14.18/CHO in NB patients. PMID- 24055594 TI - Encoding negative events under stress: high subjective arousal is related to accurate emotional memory despite misinformation exposure. AB - Stress at encoding affects memory processes, typically enhancing, or preserving, memory for emotional information. These effects have interesting implications for eyewitness accounts, which in real-world contexts typically involve encoding an aversive event under stressful conditions followed by potential exposure to misinformation. The present study investigated memory for a negative event encoded under stress and subsequent misinformation endorsement. Healthy young adults participated in a between-groups design with three experimental sessions conducted 48 h apart. Session one consisted of a psychosocial stress induction (or control task) followed by incidental encoding of a negative slideshow. During session two, participants were asked questions about the slideshow, during which a random subgroup was exposed to misinformation. Memory for the slideshow was tested during the third session. Assessment of memory accuracy across stress and no-stress groups revealed that stress induced just prior to encoding led to significantly better memory for the slideshow overall. The classic misinformation effect was also observed - participants exposed to misinformation were significantly more likely to endorse false information during memory testing. In the stress group, however, memory accuracy and misinformation effects were moderated by arousal experienced during encoding of the negative event. Misinformed-stress group participants who reported that the negative slideshow elicited high arousal during encoding were less likely to endorse misinformation for the most aversive phase of the story. Furthermore, these individuals showed better memory for components of the aversive slideshow phase that had been directly misinformed. Results from the current study provide evidence that stress and high subjective arousal elicited by a negative event act concomitantly during encoding to enhance emotional memory such that the most aversive aspects of the event are well remembered and subsequently more resistant to misinformation effects. PMID- 24055593 TI - Extinguishing trace fear engages the retrosplenial cortex rather than the amygdala. AB - Extinction learning underlies the treatment for a variety of anxiety disorders. Most of what is known about the neurobiology of extinction is based on standard "delay" fear conditioning, in which awareness is not required for learning. Little is known about how complex, explicit associations extinguish, however. "Trace" conditioning is considered to be a rodent model of explicit fear because it relies on both the cortex and hippocampus and requires explicit contingency awareness in humans. Here, we explore the neural circuit supporting trace fear extinction in order to better understand how complex memories extinguish. We first show that the amygdala is selectively involved in delay fear extinction; blocking intra-amygdala glutamate receptors disrupted delay, but not trace extinction. Further, ERK phosphorylation was increased in the amygdala after delay, but not trace extinction. We then identify the retrosplenial cortex (RSC) as a key structure supporting trace extinction. ERK phosphorylation was selectively increased in the RSC following trace extinction and blocking intra RSC NMDA receptors impaired trace, but not delay extinction. These findings indicate that delay and trace extinction require different neural circuits; delay extinction requires plasticity in the amygdala whereas trace extinction requires the RSC. Anxiety disorders linked to explicit memory may therefore depend on cortical processes that have not been traditionally targeted by extinction studies based on delay fear. PMID- 24055596 TI - Ultrasound examination of the serratus anterior during scapular protraction in asymptomatic individuals: reliability and changes with contraction. AB - OBJECTIVE: To determine the ability of 2 clinicians to reliably measure the thickness of the serratus anterior (SA) muscle using ultrasound during scapular protraction and to determine whether that thickness changes during activation of the SA. DESIGN: A cross-sectional observational study. SETTING: An outpatient biomechanical laboratory. PARTICIPANTS: Twenty healthy, asymptomatic adults between the ages of 23 and 28 years. METHODS: Ultrasound imaging measurements were recorded during 3 conditions: (1) with the subject in a side-lying position and resting in a supported position of 90 degrees of shoulder flexion; (2) with the subject in a side-lying position and the shoulder in 90 degrees of shoulder flexion and actively protracting; and (3) with the subject in a side-lying position and the shoulder in 90 degrees of shoulder flexion while holding the protracted position against 15 lb of force. MAIN OUTCOME MEASUREMENTS: Reproducibility was examined with use of intraclass correlation coefficients (ICCs) and standard error of measurements. The thickness of the SA muscle measured during each condition was compared. RESULTS: Intratester and intertester ICC values were high. Ranges for ICCs were 0.892-0.979 for intratester reliability within a session, 0.900-0.912 for intratester reliability between sessions, and 0.929-0.939 for intertester reliability. Statistically significant differences in the thickness of the SA were found between the rest condition and the hold with resistance condition but not between the rest condition and the active hold condition. CONCLUSION: Findings of this study document the high reliability of ultrasound imaging in determining SA muscle thickness and thickness changes at rest and during contraction of the SA. Clinicians should be aware that resistance may need to be added to active scapular protraction in a side-lying position to produce a significant change in SA thickness from the rest position. This information can be used by clinicians who assess the SA and treat scapular dysfunction when activation or facilitation of the SA is required. PMID- 24055597 TI - Experimental investigation of design parameters on dry powder inhaler performance. AB - The study aims to investigate the impact of various design parameters of a dry powder inhaler on the turbulence intensities generated and the performance of the dry powder inhaler. The flow fields and turbulence intensities in the dry powder inhaler are measured using particle image velocimetry (PIV) techniques. In vitro aerosolization and deposition a blend of budesonide and lactose are measured using an Andersen Cascade Impactor. Design parameters such as inhaler grid hole diameter, grid voidage and chamber length are considered. The experimental results reveal that the hole diameter on the grid has negligible impact on the turbulence intensity generated in the chamber. On the other hand, hole diameters smaller than a critical size can lead to performance degradation due to excessive particle-grid collisions. An increase in grid voidage can improve the inhaler performance but the effect diminishes at high grid voidage. An increase in the chamber length can enhance the turbulence intensity generated but also increases the powder adhesion on the inhaler wall. PMID- 24055595 TI - Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans. AB - Pre-extinction administration of Delta9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely occurs via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a functional magnetic resonance imaging (fMRI) study using a randomized, double-blind, placebo-controlled, between-subjects design (N=14/group) coupled with a standard Pavlovian fear extinction paradigm and an acute pharmacological challenge with oral dronabinol (synthetic THC) in healthy adult volunteers. We examined the effects of THC on vmPFC and HIPP activation when tested for recall of extinction learning 24 h after extinction learning. Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD. Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders. PMID- 24055598 TI - Silymarin released from sterile wafers restores glucose impaired endothelial cell migration. AB - Reduced oxygen tension combined with high glucose concentration leads to chronic wounds in diabetic patients. Delayed wound healing is due in part to impaired angiogenesis as a result of reduced endothelial cell migration. Topical applications, in the form of sterile lyophilised wafers hold promise for the treatment of chronic diabetic wounds. In this study wafers containing silymarin were prepared using xanthan gum and sterilised with 25 and 40 kGy gamma radiation. The rheological properties of xanthan gels, before and after lyophilisation, were measured and it was concluded that an increased dose of gamma rays (40 kGy) increased the viscosity coefficient and yield stress of silymarin wafers. HPLC analysis indicated that 89-90% of silymarin was retained in the wafers after irradiation. Dermal microvascular cell migration studies in the presence of high glucose and reduced oxygen tension levels, using novel radial migration and wound healing assays developed 'in house', were also undertaken. Silymarin, when formulated as a lyophilised wafer, successfully retained its ability to overcome the high glucose induced reduction in endothelial cell migration. PMID- 24055599 TI - Effects of stimulus spatial frequency, size, and luminance contrast on orientation tuning of neurons in the dorsal lateral geniculate nucleus of cat. AB - It is generally thought that orientation selectivity first appears in the primary visual cortex (V1), whereas neurons in the lateral geniculate nucleus (LGN), an input source for V1, are thought to be insensitive to stimulus orientation. Here we show that increasing both the spatial frequency and size of the grating stimuli beyond their respective optimal values strongly enhance the orientation tuning of LGN neurons. The resulting orientation tuning was clearly contrast invariant. Furthermore, blocking intrathalamic inhibition by iontophoretically administering gamma-aminobutyric acid (GABA)A receptor antagonists, such as bicuculline and GABAzine, slightly but significantly weakened the contrast invariance. Our results suggest that orientation tuning in the LGN is caused by an elliptical classical receptive field and orientation-tuned surround suppression, and that its contrast invariance is ensured by local GABAA inhibition. This contrast-invariant orientation tuning in LGN neurons may contribute to the contrast-invariant orientation tuning seen in V1 neurons. PMID- 24055600 TI - Reduced wheel running and blunted effects of voluntary exercise in LPA1-null mice: the importance of assessing the amount of running in transgenic mice studies. AB - This work was aimed to assess whether voluntary exercise rescued behavioral and hippocampal alterations in mice lacking the lysophosphatidic acid LPA1 receptor (LPA1-null mice), studying the potential relationship between the amount of exercise performed and its effects. Normal and LPA1-null mice underwent 23 days of free wheel running and were tested for open-field behavior and adult hippocampal neurogenesis (cell proliferation, immature neurons, cell survival). Running decreased anxiety-like behavior in both genotypes but increased exploration only in the normal mice. While running affected all neurogenesis related measures in normal mice (especially in the suprapyramidal blade of the dentate gyrus), only a moderate increase in cell survival was found in the mutants. Importantly, the LPA1-nulls showed notably reduced running. Analysis suggested that defective running in the LPA1-null mice could contribute to explain the scarce benefit of the voluntary exercise treatment. On the other hand, a literature review revealed that voluntary exercise is frequently used to modulate behavior and the hippocampus in transgenic mice, but half of the studies did not assess the quantity of running, overlooking any potential running impairments. This study adds evidence to the relevance of the quantity of exercise performed, emphasizing the importance of its assessment in transgenic mice research. PMID- 24055601 TI - Development and pharmacological verification of a new mouse model of central post stroke pain. AB - Central post-stroke pain (CPSP) including thalamic pain is one of the most troublesome sequelae that can occur after a cerebrovascular accident. Although the prevalence of CPSP among stroke patients is relatively low, the persistent, often treatment-refractory, painful sensations can be a major problem and decrease the affected patient's quality of life. To better understand of the pathophysiological basis of CPSP, we developed and characterized a new mouse model of thalamic CPSP. This model is based on a hemorrhagic stroke lesion with collagenase in the ventral posterolateral nucleus of the thalamus. Histopathological analysis indicated that the thalamic hemorrhage produced a relatively confined lesion that destroys the tissue within the initial bleed, and also showed the presence of activated microglia adjacent to the core of hemorrhagic lesions. Behavioral analysis demonstrated that the animals displayed diclofenac-, morphine- or pregabalin-resistant mechanical allodynia and thermal hyperalgesia of the hind paw contralateral to the lesion for over 112 days. However, we found that minocycline, a microglial inhibitor, significantly ameliorated mechanical allodynia and thermal hyperalgesia. These results suggest that this model might be proved as a useful animal model for studying the neuropathology of thalamic syndrome, and developing improved therapeutics for CPSP. PMID- 24055602 TI - Increased sampling of both genes and taxa improves resolution of phylogenetic relationships within Magnoliidae, a large and early-diverging clade of angiosperms. AB - Magnoliidae have been supported as a clade in the majority of large-scale molecular phylogenetic studies of angiosperms. This group consists of about 10,000 species assigned to 20 families and four orders, Canellales, Piperales, Laurales, and Magnoliales. Some relationships among the families are still largely debated. Here, we reconstruct the phylogenetic relationships of Magnoliidae as a whole, sampling 199 species (representing ca. 75% of genera) and 12 molecular markers from the three genomes (plastid atpB, matK, trnL intron, trnL-trnF spacer, ndhF, rbcL; mitochondrial atp1, matR, mtSSU, mtLSU; nuclear 18s rDNA, 26S rDNA). Maximum likelihood, Bayesian and maximum parsimony analyses yielded congruent trees, with good resolution and high support values for higher level relationships. This study further confirms, with greater levels of support, two major clades in Magnoliidae: Canellales+Piperales and Laurales+Magnoliales. Relationships among the 20 families are, in general, well resolved and supported. Several previously ambiguous relationships are now well supported. For instance, the Aristolochiaceae s.l. (incl. Asaroideae, Aristolochioideae, and Lactoris) are monophyletic with high support when Hydnoraceae are excluded. The latter family was not included in most previous studies because of the lack of suitable plastid sequences, a consequence of the parasitic habit of its species. Here, we confirm that it belongs in Aristolochiaceae. Our analyses also provide moderate support for a sister group relationship between Lauraceae and Monimiaceae. Conversely, the exact position of Magnoliaceae remains very difficult to determine. This study provides a robust phylogenetic background to address the evolutionary history of an important and highly diverse clade of early-diverging angiosperms. PMID- 24055603 TI - Gene tree rooting methods give distributions that mimic the coalescent process. AB - Multi-locus phylogenetic inference is commonly carried out via models that incorporate the coalescent process to model the possibility that incomplete lineage sorting leads to incongruence between gene trees and the species tree. An interesting question that arises in this context is whether data "fit" the coalescent model. Previous work (Rosenfeld et al., 2012) has suggested that rooting of gene trees may account for variation in empirical data that has been previously attributed to the coalescent process. We examine this possibility using simulated data. We show that, in the case of four taxa, the distribution of gene trees observed from rooting estimated gene trees with either the molecular clock or with outgroup rooting can be closely matched by the distribution predicted by the coalescent model with specific choices of species tree branch lengths. We apply commonly-used coalescent-based methods of species tree inference to assess their performance in these situations. PMID- 24055604 TI - Sequential reassortments underlie diverse influenza H7N9 genotypes in China. AB - Initial genetic characterizations have suggested that the influenza A (H7N9) viruses responsible for the current outbreak in China are novel reassortants. However, little is known about the pathways of their evolution and, in particular, the generation of diverse viral genotypes. Here we report an in-depth evolutionary analysis of whole-genome sequence data of 45 H7N9 and 42 H9N2 viruses isolated from humans, poultry, and wild birds during recent influenza surveillance efforts in China. Our analysis shows that the H7N9 viruses were generated by at least two steps of sequential reassortments involving distinct H9N2 donor viruses in different hosts. The first reassortment likely occurred in wild birds and the second in domestic birds in east China in early 2012. Our study identifies the pathways for the generation of diverse H7N9 genotypes in China and highlights the importance of monitoring multiple sources for effective surveillance of potential influenza outbreaks. PMID- 24055605 TI - The interferon-inducible MxB protein inhibits HIV-1 infection. AB - The interferon-inducible myxovirus resistance (Mx) proteins play important roles in combating a wide range of virus infections. MxA inhibits many RNA and DNA viruses, whereas the antiviral activity of MxB is less well established. We find that human MxB inhibits HIV-1 infection by reducing the level of integrated viral DNA. Passaging HIV-1 through MxB-expressing cells allowed the evolution of a mutant virus that escapes MxB restriction. HIV-1 escapes MxB restriction by mutating the alanine residue at position 88 in the viral capsid protein (CA), with a consequent loss of CA interaction with the host peptidylprolyl isomerase cyclophilin A (CypA), suggesting a role for CypA in MxB restriction. Consistent with this, MxB associates with CypA, and shRNA-mediated CypA depletion or cyclosporine A treatment resulted in the loss of MxB inhibition of HIV-1. Taken together, we conclude that human MxB protein inhibits HIV-1 DNA integration by a CypA-dependent mechanism. PMID- 24055606 TI - Compromised potassium recycling in the cochlea contributes to conservation of endocochlear potential in a mouse model of age-related hearing loss. AB - The C57BL/6 strain is considered an excellent model to study age-related hearing loss (AHL). Aging C57BL/6 mice are characterized by profound hearing loss but conservation of the endocochlear potential (EP). Here we show 12-month-old C57BL/6 mice display a notable hearing loss at 4, 8, 16 and 32kHz while the EP is maintained at normal level. Morphological examination shows significant outer hair cells loss in the cochlear basal turn and atrophy of the stria vascularis (SV). Fluorescence immunohistochemical studies reveal that potassium channel KCNJ10 and KCNQ1 expression dramatically decreased in the SV. Concomitant with this, mRNA levels of KCNJ10 and KCNQ1 are also reduced. In addition, three other potassium transporters, including alpha1-Na,K-ATPase, alpha2-Na,K-ATPase and NKCC1, reduce their expression at mRNA levels as well. These observations suggest that conservation of the EP in aging C57BL/6 mice is attributable to the SV generating a new balance for potassium influx and efflux at a relatively lower level. PMID- 24055607 TI - Temporal changes of calbindin expression in the nodulus following unilateral labyrinthectomy in rats. AB - Following unilateral vestibular deafferentation, many of the oculomotor and postural symptoms, such as spontaneous ocular nystagmus and head tilt, gradually abate over time in a process known as 'vestibular compensation'. Although many experimental studies have indicated a role for the cerebellum during vestibular compensation, the effects of unilateral labyrinthectomy (UL) on cerebellar function and the role of cerebellum in post-lesional plasticity remain unclear. Thus, we investigated the temporal changes of calbindin expression in the ipsilateral and contralateral nodulus to the lesion side during vestibular compensation following UL in rats. Change of calbindin expression in the nodulus was measured by immunohistochemistry at 2, 6, 24 and 48hr following UL. The staining intensity of calbindin-positive Purkinje cells in the ipsilateral and contralateral nodulus to the lesion side was found to decrease 6hr after UL compared with the control and asymmetric calbindin expression between ipsilateral and contralateral nodulus 24hr after UL. Forty-eight hours after UL, calbindin expression returned to the control level, and asymmetric expression in both noduli also subsided. It is suggested that the regulation of calbindin expression may facilitate synaptic plasticity by adjusting the efficacy of biochemical responses of Purkinje cells according to the changes in neuronal activity in the vestibular nuclear complex during the early phase of vestibular compensation. Thus, the results revealed that the nodulus has a role during vestibular compensation through Purkinje cells. PMID- 24055608 TI - The effect of leptin on prepulse inhibition in a developmental model of schizophrenia. AB - Post-weaning social isolation is a developmental animal model of schizophrenia. Impairment of prepulse inhibition (PPI), possibly due to increased activity of the mesolimbic dopaminergic system, has frequently been reported in this model. There are some reports of increased level of leptin in schizophrenic patients. It has been shown that intracerebroventricular (ICV) injection of leptin decreases dopamine in the nucleus accumbens of rats. Here we investigated the effect of leptin on PPI impairment following social isolation. Five groups of Sprague Dawley rats were reared post weaning in social or isolated conditions for 14 weeks. PPI was measured before treatment in week 12, and after ICV injection of vehicle or different doses of leptin (1, 5, and 10MUg/5MUl) in week 14. Results showed reduced PPI in untreated isolated compared to socially-reared rats in week 12 (p=0.009), but not in week 14 (p=0.45). Results also showed that leptin dose dependently increased the basal PPI in isolated rats compared to vehicle, that was significant at a dose of 10MUg (p=0.002). A considerable but non-significant effect of treatment with leptin on startle response (p=0.13) was seen. In conclusion, our results reveal that leptin significantly increases PPI in socially-isolated rats. The findings of this study suggest possible antipsychotic properties for leptin. We suggest further studies on the possible disruption of leptin signaling in schizophrenia, and also the possible interaction of leptin with therapeutic effects of second generation antipsychotics. PMID- 24055609 TI - Family of phenylacetyl-CoA monooxygenases differs in subunit organization from other monooxygenases. AB - The phenylacetate degradation pathway is present in a wide range of microbes. A key component of this pathway is the four-subunit phenylacetyl-coenzyme A monooxygenase complex (PA-CoA MO, PaaACBE) that catalyzes the insertion of an oxygen in the aromatic ring of PA. This multicomponent enzyme represents a new family of monooxygenases. We have previously determined the structure of the PaaAC subcomplex of catalytic (A) and structural (C) subunits and shown that PaaACB form a stable complex. The PaaB subunit is unrelated to the small subunits of homologous monooxygenases and its role and organization of the PaaACB complex is unknown. From low-resolution crystal structure, electron microscopy and small angle X-ray scattering we show that the PaaACB complex forms heterohexamers, with a homodimer of PaaB bridging two PaaAC heterodimers. Modeling the interactions of reductase subunit PaaE with PaaACB suggested that a unique and conserved 'lysine bridge' constellation near the Fe-binding site in the PaaA subunit (Lys68, Glu49, Glu72 and Asp126) may form part of the electron transfer path from PaaE to the iron center. The crystal structure of the PaaA(K68Q/E49Q)-PaaC is very similar to the wild-type enzyme structure, but when combined with the PaaE subunit the mutant showed 20-50 times reduced activity, supporting the functional importance of the 'lysine bridge'. PMID- 24055610 TI - Analysis of predisposing factors in elderly people with type II odontoid fracture. AB - BACKGROUND CONTEXT: Type II odontoid fracture is the most frequent individual fracture in elderly people. An older person usually sustains a Type II odontoid fracture in a fall from standing or a seated height. A relationship between osteoarthritis in the upper cervical spine and Type II odontoid fracture has been reported. However, to our knowledge, few reports have investigated statistically whether disproportionate degeneration between joints influences the susceptibility to fracture. PURPOSE: The purpose of this study was to assess predisposition to Type II odontoid fracture in the elderly. STUDY DESIGN: Retrospective review of elderly patients sustained Type II odontoid fracture and other axis fractures. PATIENT SAMPLE: Thirty-eight patients aged 65 years and older with axis fractures. OUTCOME MEASURES: Evaluation of computed tomography findings by focusing on osteoporosis and the disproportion in degeneration between each of the upper cervical joints (atlantooccipital, atlantoodontoid, and lateral atlantoaxial joints). METHODS: Seventeen patients had a Type II odontoid fracture, and 21 patients had other axis fractures. Using the computed tomography findings, we classified osteoporosis at the dens-body junction and the severity of degenerative changes in the atlantoodontoid, atlantooccipital, and lateral atlantoaxial joints as none, mild, moderate, or severe. The proportion of patients with moderate or severe osteoporosis and degenerative changes in each joint and that of patients with disproportionate degenerative changes between joints (difference in grade of >=2 levels between joints) were compared statistically. The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this article. RESULTS: Patients with osteoporosis and with disproportionate degenerative changes between the atlantoodontoid and lateral atlantoaxial joints were significantly more likely to have a Type II odontoid fracture than other axis fractures. These two factors were also assessed in multivariate logistic analysis. The disproportionate degenerative change between the atlantoodontoid and lateral atlantoaxial joint remained significant, even after adjusting for osteoporosis. CONCLUSIONS: Older patients with the dens fixed to the atlas because of degeneration of the atlantoodontoid joint and a smooth lateral atlantoaxial joint seem to sustain Type II odontoid fractures because, during a simple fall, the rotation of the head produces torque force on the osteoporotic dens-body junction, which acts as the rotatory center. The presence of the disproportionate osteoarthritic degeneration between the atlantoodontoid and lateral atlantoaxial joints predisposes older people to a Type II odontoid fracture. PMID- 24055611 TI - Clinical validity of the nerve root sedimentation sign in patients with suspected lumbar spinal stenosis. AB - BACKGROUND CONTEXT: The nerve root sedimentation sign in transverse magnetic resonance imaging has been shown to discriminate well between selected patients with and without lumbar spinal stenosis (LSS), but the performance of this new test, when used in a broader patient population, is not yet known. PURPOSE: To evaluate the clinical performance of the nerve root sedimentation sign in detecting central LSS above L5 and to determine its potential significance for treatment decisions. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: One hundred eighteen consecutive patients with suspected LSS (52% women, median age 62 years) with a median follow-up of 24 months. OUTCOME MEASURES: Oswestry disability index (ODI) and back and leg pain relief. METHODS: We performed a clinical test validation study to assess the clinical performance of the sign by measuring its association with health outcomes. Subjects were patients referred to our orthopedic spine unit from 2004 to 2007 before the sign had been described. Based on clinical and radiological diagnostics, patients had been treated with decompression surgery or nonsurgical treatment. Changes in the ODI and pain from baseline to 24-month follow-up were compared between sedimentation sign positives and negatives in both treatment groups. RESULTS: Sixty-nine patients underwent surgery. Average baseline ODI in the surgical group was 54.7%, and the sign was positive in 39 patients (mean ODI improvement 29.0 points) and negative in 30 (ODI improvement 28.4), with no statistically significant difference in ODI and pain improvement between groups. In the 49 patients of the nonsurgical group, mean baseline ODI was 42.4%; the sign was positive in 18 (ODI improvement 0.6) and negative in 31 (ODI improvement 17.7). A positive sign was associated with a smaller ODI and back pain improvement than negative signs (both p<.01 on t test). CONCLUSIONS: In patients commonly treated with decompression surgery, the sedimentation sign does not appear to predict surgical outcome. In nonsurgically treated patients, a positive sign is associated with more limited improvement. In these cases, surgery might be effective, but this needs investigation in prospective randomized trials (Australian New Zealand Clinical Trial Registry, number ACTRN12610000567022). PMID- 24055612 TI - Thoracal flat back is a risk factor for lumbar disc degeneration after scoliosis surgery. AB - BACKGROUND CONTEXT: Lumbar segments below fused scoliotic spines are thought to be exposed to extraordinary stress. Although positive sagittal imbalance has come into focus, reports about factors influencing the outcome of these segments remain inconclusive. PURPOSE: Our study aimed at identifying spinal risk factors for the development of lumbar degenerative disc disease (DDD) in surgically treated patients with adolescent idiopathic scoliosis (AIS). STUDY DESIGN/SETTING: Retrospective comparative prognostic study (Level III) was conducted. Thirty-three patients were seen at an average follow-up of 7.5 years after either isolated selective anterior (n=18) or long combined anterior posterior fusion (n=15) for AIS. OUTCOME MEASURES: Self-reported Scoliosis Research Society 22 questionnaire, physical examination including the detection of segmental pain and unspecific back pain, preoperative and postoperative whole spine standing radiographs, and magnetic resonance imaging were obtained. METHODS: Radiographic evaluation included the measurement of regional, coronal, and sagittal curve parameters and the assessment of spinal balance. Magnetic resonance imaging evaluation was done for preoperative and postoperative lumbar discs, according to the classification of Pfirrmann. RESULTS: Patients with low DDD (Pfirrmann grading <3) had a significantly higher thoracal kyphosis angle (mean 28 degrees ) than patients with advanced DDD (mean 15 degrees ). There was a trend toward a more flat-type lumbar lordosis in patients with severe DDD. Positive sagittal imbalance was associated with advanced DDD. Follow-up coronal parameters, trunk imbalance, instrumentation length, and lowest instrumented vertebra selection had no influence on DDD. Specific segmental pain could be attributed to a significantly higher coronal trunk imbalance (21 vs. 11 mm). CONCLUSIONS: This study establishes thoracal flat back as a risk factor for lumbar DDD after spinal fusion and supports the pathogenetic role of positive sagittal imbalance in this process. PMID- 24055613 TI - Echocardiographic predictor of acute heart failure after spine surgery: a novel tissue Doppler index associated with a potentially fatal complication of the operation. AB - BACKGROUND CONTEXT: Acute heart failure (HF) is a potentially fatal complication after spine surgery. PURPOSE: We sought to identify clinical and echocardiographic predictors of postoperative HF in spine surgery patients. STUDY DESIGN: Retrospective observational study. PATIENT SAMPLE: A total of 305 patients (128 men; age, 65 +/- 9 years) who underwent spine surgery were consecutively enrolled. A transthoracic echocardiography was performed to all patients before the index operation. Patients with a history of HF or with left ventricular (LV) systolic dysfunction (LV ejection fraction <50%) were excluded. OUTCOME MEASURES: Heart failure was defined according to the Framingham criteria. The presence of postoperative dyspneic symptom and the sign of bilateral ankle edema were recorded by the physicians. Chest X-ray was mandatory for all patients and interpreted by the two physicians, including at least one radiologist. METHODS: Clinical, operative, and echocardiographic parameters were compared between patents with and without acute HF during the postoperative period (duration, 11 +/- 9 days). This study was supported by Boryung Pharmaceutical Company (Seoul, Republic of Korea; 13,440 USD). RESULTS: Postoperative HF occurred in 31 patients (10%). Compared with those without postoperative HF, these patients were older (73 +/- 7 vs. 64 +/- 9 years), had longer anesthesia time (7.4 +/- 4.2 vs. 3.6 +/- 2.1 hours), and were treated with a greater volume of fluid replacement during the operation (3.8 +/- 0.7 vs. 1.3 +/- 0.1 L) (p<.05 for all). On echocardiographic evaluation, the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/E') was higher (11 vs. 8) and left atrial volume index was larger (20 +/- 6 vs. 17 +/- 6 mL/m(2)) in patients with HF than in the control group (p<.05 for all), whereas the differences in LV ejection fraction and LV size were not significant. In multivariate analysis, E/E' (odds ratio, 1.399; 95% confidence interval, 1.169 1.674; p<.0001), age, and quantity of replaced volume during surgery were independent predictors of postoperative HF. CONCLUSIONS: Acute HF after spine surgery was rather common even in previously healthy patients. E/E' reflecting LV filling pressure predicted postoperative HF in patients who underwent spine surgery. PMID- 24055614 TI - The importance of adjuvant chemotherapy and pelvic radiotherapy in high-risk early stage endometrial carcinoma. AB - OBJECTIVE: To determine the impact of a policy change in which women with high risk early stage endometrioid endometrial cancer (EEC) received adjuvant chemoradiotherapy. METHODS: This is a population-based retrospective cohort study of British Columbia Cancer Registry patients diagnosed from 2008 to 2012 with high-risk early stage EEC, who received adjuvant chemoradiotherapy after primary surgery. High-risk early stage was defined as the presence of two or more high risk uterine factors: grade 3 tumor, more than 50% myometrial invasion, and/or cervical stromal involvement. Adjuvant therapy consisted of 3 or 4 cycles of carboplatin and paclitaxel chemotherapy, followed by pelvic radiotherapy. Sites and rate of recurrence were compared to a historical cohort diagnosed from 2005 to 2008 in which none of the patients received adjuvant chemoradiotherapy. Five year progression-free and overall survival rates were calculated. RESULTS: The study includes 55 patients. All patients except for 2 received at least 3 cycles of chemotherapy. All patients received pelvic radiotherapy except for 2 who received brachytherapy only. Median follow-up was 27 months (7-56 months). Four patients (7.3%) recurred, including three with distant recurrence only and one with both a pelvic and paraaortic nodal recurrence. The historical cohort had a 29.4% recurrence rate, and therefore the hazard ratio for recurrence was 0.27 (95% CI 0.02-4.11). Five-year progression-free and overall survival rates were 88.6% and 97.3%, respectively. CONCLUSION: Patients with high-risk early stage endometrial carcinoma treated with adjuvant chemoradiotherapy have a low rate of recurrence compared to those not receiving such therapy. PMID- 24055615 TI - Patterns of relapse in stage I-II uterine papillary serous carcinoma treated with adjuvant intravaginal radiation (IVRT) with or without chemotherapy. AB - OBJECTIVE: To evaluate patterns of relapse in early stage uterine papillary carcinoma (UPSC) patients receiving adjuvant intravaginal radiotherapy (IVRT) with or without chemotherapy. METHODS: From 1/1996 to 12/2010, 77 women with stage I-II UPSC underwent surgery followed by IVRT (median 21Gy). Stage IA patients without residual disease at surgery were excluded. IVRT and chemotherapy (carboplatin/taxane) was given to 61 (79%) patients and IVRT alone to 16 (21%). The median follow-up was 62 months for surviving patients. RESULTS: Of the 77 patients, 11 (14%) relapsed as follows: vaginal 2 (3%), pelvic 5 (6%), para aortic 5 (6%), peritoneal 6 (8%), and other distant sites 8 (10%). Of the 5 pelvic relapses, 2 were isolated and were salvaged. In those treated without chemotherapy, only 1/16 developed recurrence (mediastinal). The 5-year vaginal, pelvic, para-aortic, peritoneal, and distant recurrence rates were 2.7% (C.I. 0 6.2%), 5.8% (C.I. 0.6-11.0%), 5.4% (C.I. 0.6-10.1%), 5.3% (C.I. 0.5-10.1%) and 6.6% (C.I. 1.4-11.8%), respectively. The 5-year disease-free survival (DFS), and overall survival (OS) were 88% (C.I. 81-95%), and 91% (C.I. 84-97%), respectively. The only predictor of worse 5-year pelvic control was stage (96.2% stage IA vs 87.7% for stage IB-II, p=0.043). CONCLUSIONS: In stage I-II UPSC patients who predominantly receive adjuvant chemotherapy, IVRT as the sole form of adjuvant RT provides excellent locoregional control. The risk of isolated pelvic recurrence is too low to warrant routine use of external pelvic RT. PMID- 24055616 TI - Successful incorporation of robotic surgery into gynecologic oncology fellowship training. AB - BACKGROUND: The increasing role of robotic surgery in gynecologic oncology may impact fellowship training. The purpose of this study was to review the proportion of robotic procedures performed by fellows at the console, and compare operative times and lymph node yields to faculty surgeons. METHODS: A prospective database of women undergoing robotic gynecologic surgery has been maintained since 2008. Intra-operative datasheets completed include surgical times and primary surgeon at the console. Operative times were compared between faculty and fellows for simple hysterectomy (SH), bilateral salpingo-oophorectomy (BSO), pelvic (PLND) and paraaortic lymph node dissection (PALND) and vaginal cuff closure (VCC). Lymph nodes counts were also compared. RESULTS: Times were recorded for 239 SH, 43 BSOs, 105 right PLNDs, 104 left PLNDs, 34 PALND and 269 VCC. Comparing 2008 to 2011, procedures performed by the fellow significantly increased; SH 16% to 83% (p<0.001), BSO 7% to 75% (p=0.005), right PLND 4% to 44% (p<0.001), left PLND 0% to 56% (p<0.001), and VCC 59% to 82% (p=0.024). Console times (min) were similar for SH (60 vs. 63, p=0.73), BSO (48 vs. 43, p=0.55), and VCC (20 vs. 22, p=0.26). Faculty times (min) were shorter for PLND (right 26 vs. 30, p=0.04, left 23 vs. 27, p=0.02). Nodal counts were not significantly different (right 7 vs. 8, p=0.17 or left 7 vs. 7, p=0.87). CONCLUSIONS: Robotic surgery can be successfully incorporated into gynecologic oncology fellowship training. With increased exposure to robotic surgery, fellows had similar operative times and lymph node yields as faculty surgeons. PMID- 24055617 TI - On learning dynamics underlying the evolution of learning rules. AB - In order to understand the development of non-genetically encoded actions during an animal's lifespan, it is necessary to analyze the dynamics and evolution of learning rules producing behavior. Owing to the intrinsic stochastic and frequency-dependent nature of learning dynamics, these rules are often studied in evolutionary biology via agent-based computer simulations. In this paper, we show that stochastic approximation theory can help to qualitatively understand learning dynamics and formulate analytical models for the evolution of learning rules. We consider a population of individuals repeatedly interacting during their lifespan, and where the stage game faced by the individuals fluctuates according to an environmental stochastic process. Individuals adjust their behavioral actions according to learning rules belonging to the class of experience-weighted attraction learning mechanisms, which includes standard reinforcement and Bayesian learning as special cases. We use stochastic approximation theory in order to derive differential equations governing action play probabilities, which turn out to have qualitative features of mutator selection equations. We then perform agent-based simulations to find the conditions where the deterministic approximation is closest to the original stochastic learning process for standard 2-action 2-player fluctuating games, where interaction between learning rules and preference reversal may occur. Finally, we analyze a simplified model for the evolution of learning in a producer-scrounger game, which shows that the exploration rate can interact in a non-intuitive way with other features of co-evolving learning rules. Overall, our analyses illustrate the usefulness of applying stochastic approximation theory in the study of animal learning. PMID- 24055618 TI - Preface to the Theoretical Population Biology special issue on learning. PMID- 24055619 TI - Development of a capillary isoelectric focusing immunoassay to measure DJ-1 isoforms in biological samples. AB - We report on the development of a novel assay protocol for the separation and detection of charge isoforms of DJ-1 in biological samples by automated capillary isoelectric focusing followed by immunological detection. DJ-1 (PARK7) is considered as a biomarker candidate for Parkinson's disease and may potentially support the differentiation of clinical subtypes of the disease. The new method allows for separation and subsequent relative quantitative comparison of different isoforms of DJ-1 in biological samples. The assay was successfully applied to the analysis of DJ-1 isoform patterns in brains from mice subjected to normal or high-fat diet and revealed statistically significant group differences. Furthermore, in a pooled and concentrated sample of human cerebrospinal fluid that was depleted of albumin and immunoglobulin G, four different charge variants of DJ-1 could be detected. Taken together, the capillary isoelectric focusing immunoassay for DJ-1 represents a promising tool that may ultimately serve in clinical biomarker studies. PMID- 24055620 TI - Three complementary techniques for the clarification of temperature effect on low density lipoprotein-chondroitin-6-sulfate interaction. AB - A rigorous processing of adsorption data from quartz crystal microbalance technology was successfully combined with the data obtained by partial filling affinity capillary electrophoresis and molecular dynamics for the clarification of the temperature effect on the interaction of a major glycosaminoglycan chain chondroitin-6-sulfate (C6S) of proteoglycans with low-density lipoprotein (LDL) and with a peptide fragment of apolipoprotein B-100 (residues 3359-3377 of LDL, PPBS). Two experimental techniques and computational atomistic methods demonstrated a nonlinear pattern of the affinity of C6S at temperatures above 38.0 degrees C to both LDL and PPBS. The temperature affects the interaction of C6S with LDL and PPBS by influencing the structural behavior of glycosaminoglycan C6S and/or that of LDL. PMID- 24055621 TI - Cochlear implantation for chronic electrical stimulation in the mouse. AB - The mouse is becoming an increasingly attractive model for auditory research due to the number of genetic deafness models available. These genetic models offer the researcher an array of congenital causes of hearing impairment, and are therefore of high clinical relevance. To date, the use of mice in cochlear implant research has not been possible due to the lack of an intracochlear electrode array and stimulator small enough for murine use, coupled with the difficulty of the surgery in this species. Here, we present a fully-implantable intracochlear electrode stimulator assembly designed for chronic implantation in the mouse. We describe the surgical approach for implantation, as well as presenting the first functional data obtained from intracochlear electrical stimulation in the mouse. PMID- 24055622 TI - Age-related hearing loss patterns in Fischer 344/NHsd rats with cisplatin-induced hearing loss. AB - The current study was undertaken to explore the impact of cisplatin ototoxicity at a young adult age on the development of age-related hearing loss, both in terms of age of onset and severity of the hearing loss. For the study, 21 Fischer 344/NHsd rats were tested. All rats were tested for auditory brainstem responses (ABRs) at age 7 months and then 15 of the rats were exposed to 7 mg/kg cisplatin by intra-peritoneal infusion. The other 6 rats received saline infusions to serve as controls. Seven of the cisplatin rats were euthanized after an ABR test 7 days after cisplatin exposure to assess acute damage. The other 14 rats were tested monthly until age 18 months. Cisplatin caused acute ABR threshold shift at 30 and 40 kHz, but that acute hearing loss led to less age-related hearing loss at those frequencies. Cisplatin exposure led to a primarily additive interaction with age related hearing loss at 20 kHz, with some exacerbation of hearing loss at age 16 18 months, along with a larger lesion of missing outer hair cells in the corresponding region of the cochlea. ABR P1 amplitude input-output functions were not significantly affected by the cisplatin exposure when controlling for threshold shift. Results indicate that cisplatin ototoxicity and age-related hearing loss interact antagonistically in the cochlear region damaged by cisplatin, and primarily show an additive interaction in the frequencies lower than the focus of the cisplatin damage. PMID- 24055623 TI - Spatial release from masking improves sound pattern discrimination along a biologically relevant pulse-rate continuum in gray treefrogs. AB - Many frogs form large choruses during their mating season in which males produce loud advertisement calls to attract females and repel rival males. High background noise levels in these social aggregations can impair vocal perception. In humans, spatial release from masking contributes to our ability to understand speech in noisy social groups. Here, we tested the hypothesis that spatial separation between target signals and 'chorus-shaped noise' improves the ability of female gray treefrogs (Hyla chrysoscelis) to perform a behavioral discrimination task based on perceiving differences in the pulsatile structure of advertisement calls. We used two-stimulus choice tests to measure phonotaxis (approach toward sound) in response to calls differing in pulse rate along a biologically relevant continuum between conspecific (50 pulses s(-1)) and heterospecific (20 pulses s(-1)) calls. Signals were presented in quiet, in colocated noise, and in spatially separated noise. In quiet conditions, females exhibited robust preferences for calls with relatively faster pulse rates more typical of conspecific calls. Behavioral discrimination between calls differing in pulse rate was impaired in the presence of colocated noise but similar between quiet and spatially separated noise conditions. Our results indicate that spatial release from energetic masking facilitates a biologically important temporal discrimination task in frogs. We discuss these results in light of previous work on spatial release from masking in frogs and other animals. PMID- 24055624 TI - Multidimensional scaling between acoustic and electric stimuli in cochlear implant users with contralateral hearing. AB - This study investigated the perceptual relationship between acoustic and electric stimuli presented to CI users with functional contralateral hearing. Fourteen subjects with unilateral profound deafness implanted with a MED-EL CI scaled the perceptual differences between pure tones presented to the acoustic hearing ear and electric biphasic pulse trains presented to the implanted ear. The differences were analyzed with a multidimensional scaling (MDS) analysis. Additionally, speech performance in noise was tested using sentence material presented in different spatial configurations while patients listened with both their acoustic hearing and implanted ears. Results of alternating least squares scaling (ALSCAL) analysis consistently demonstrate that a change in place of stimulation is in the same perceptual dimension as a change in acoustic frequency. However, the relative perceptual differences between the acoustic and the electric stimuli varied greatly across subjects. A degree of perceptual separation between acoustic and electric stimulation (quantified by relative dimensional weightings from an INDSCAL analysis) was hypothesized that would indicate a change in perceptual quality, but also be predictive of performance with combined acoustic and electric hearing. Perceptual separation between acoustic and electric stimuli was observed for some subjects. However, no relationship between the degree of perceptual separation and performance was found. PMID- 24055625 TI - Plant viral elongated nanoparticles modified for log-increases of foreign peptide immunogenicity and specific antibody detection. AB - Elongated and flexuous recombinant nanoparticles were derived from Turnip mosaic virus to be used as bioscaffolds for increased peptide immunogenicity and peptide specific antibody sensing. For this purpose, a 20-amino acid peptide derived from human vascular endothelial growth factor receptor 3 (VEGFR-3) was fused to the N terminal region of Turnip mosaic virus coat protein (CP) by genetic insertion. The insertion was between codons corresponding to the first and second amino acids of the CP in two versions of a previously reported virus-derived vector. Systemic infections of two genetic constructs were achieved in two different plant hosts. The construct proved stable upon successive passages and generated virus nanoparticles identifiable under the electron microscope. The chimeric structures held the VEGFR-3 peptide. Purified VER3 nanoparticles were used to immunize mice, whose sera showed log increases of antibodies against the VEGFR-3 peptide when compared with mice immunized with peptide alone, thus providing the first quantitative data on the potential of elongated flexuous viruses for peptide immunogenicity increases. Purified VER3 nanoparticles also showed log increases in their ability to detect VER3 antibodies in sera, when used as reagents in ELISA assays, an application also used here for the first time. PMID- 24055627 TI - Evaluation of Rhodiola rosea supplementation on skeletal muscle damage and inflammation in runners following a competitive marathon. AB - Adaptogens modulate intracellular signaling and increase expression of heat shock protein 72 (HSP72). Rhodiola rosea (RR) is a medicinal plant with demonstrated adaptogenic properties. The purpose of this study was to measure the influence of RR supplementation on exercise-induced muscle damage, delayed onset of muscle soreness (DOMS), plasma cytokines, and extracellular HSP72 (eHSP72) in experienced runners completing a marathon. Experienced marathon runners were randomized to RR (n=24, 6 female, 18 male) or placebo (n=24, 7 female, 17 male) groups and under double-blinded conditions ingested 600mg/day RR extract or placebo for 30days prior to, the day of, and seven days post-marathon. Blood samples were collected, and vertical jump and DOMS assessed the day before, 15min post- and 1.5h post-marathon. DOMS was also assessed for seven days post marathon. Marathon race performance did not differ between RR and placebo groups (3.87+/-0.12h and 3.93+/-0.12h, respectively, p=0.722). Vertical jump decreased post-marathon (time effect, p<0.001) with no difference between groups (interaction effect, p=0.673). Post-marathon DOMS increased significantly (p<0.001) but the pattern of change did not differ between groups (p=0.700). Myoglobin (Mb), creatine phosphokinase (CPK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin (IL)-6, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), granulocyte-colony-stimulating factor (G-CSF), C reactive protein (CRP), and eHSP72 all increased post-marathon (all p<0.001), with no group differences over time (all p>0.300). In conclusion, RR supplementation (600mg/day) for 30days before running a marathon did not attenuate the post-marathon decrease in muscle function, or increases in muscle damage, DOMS, eHSP72, or plasma cytokines in experienced runners. PMID- 24055626 TI - Platelet glycoprotein Ibalpha ectodomain shedding and non-surgical bleeding in heart failure patients supported by continuous-flow left ventricular assist devices. AB - BACKGROUND: Non-surgical bleeding (NSB) is a major complication among heart failure (HF) patients supported by continuous-flow left ventricular assist devices (CF-LVADs). Understanding the hemostatic defects contributing to NSB after CF-LVAD implantation is crucial for prevention of this adverse event. The aim of this study was to examine the link between platelet glycoprotein Ibalpha (GPIbalpha) ectodomain shedding and NSB in CF-LVAD recipients and to identify a potential biomarker of NSB. METHODS: Serial blood samples were collected from 35 HF patients supported with CF-LVADs. Platelet function was evaluated by a platelet function analysis device and thromboelastography (TEG). Platelet GPIbalpha shedding, von Willebrand factor (vWF) antigen and vWF collagen binding capacity were determined using enzyme-linked immunosorbent assays (ELISAs). The structural analysis of vWF was performed by gel electrophoresis. These platelet function measures with vWF parameters of the patients who had NSB between 4 and 32 days after CF-LVAD implantation (bleeder) were analyzed against those without NSB (non-bleeder). Blood samples from 7 healthy individuals were collected to obtain healthy reference values for the laboratory assays. RESULTS: Elevated GPIbalpha shedding was found to be a pre-existing condition in all HF patients prior to CF-LVAD implantation. Post-operative level of GPIbalpha shedding increased and remained elevated in the bleeder group, whereas a consistent decrease was found in the non-bleeder group. A receiver operating characteristic (ROC) analysis indicated that the level of GPIbalpha shedding had a predictive power of NSB in patients on CF-LVAD support. CONCLUSIONS: Platelet GPIbalpha ectodomain shedding which attenuates platelet reactivity is associated with NSB. Plasma GPIbalpha level may potentially be used to refine bleeding risk stratification in CF-LVAD patients. PMID- 24055629 TI - The effect of temperature on the mechanical aspects of rigor mortis in a liquid paraffin model. AB - Rigor mortis is an important phenomenon to estimate the postmortem interval in forensic medicine. Rigor mortis is affected by temperature. We measured stiffness of rat muscles using a liquid paraffin model to monitor the mechanical aspects of rigor mortis at five temperatures (37, 25, 10, 5 and 0 degrees C). At 37, 25 and 10 degrees C, the progression of stiffness was slower in cooler conditions. At 5 and 0 degrees C, the muscle stiffness increased immediately after the muscles were soaked in cooled liquid paraffin and then muscles gradually became rigid without going through a relaxed state. This phenomenon suggests that it is important to be careful when estimating the postmortem interval in cold seasons. PMID- 24055628 TI - Reversal of multidrug resistance by the inhibition of ATP-binding cassette pumps employing "Generally Recognized As Safe" (GRAS) nanopharmaceuticals: A review. AB - Pumps of the ATP-binding cassette superfamily (ABCs) regulate the access of drugs to the intracellular space. In this context, the overexpression of ABCs is a well known mechanism of multidrug resistance (MDR) in cancer and infectious diseases (e.g., viral hepatitis and the human immunodeficiency virus) and is associated with therapeutic failure. Since their discovery, ABCs have emerged as attractive therapeutic targets and the search of compounds that inhibit their genetic expression and/or their functional activity has gained growing interest. Different generations of pharmacological ABC inhibitors have been explored over the last four decades to address resistance in cancer, though clinical results have been somehow disappointing. "Generally Recognized As Safe" (GRAS) is a U.S. Food and Drug Administration designation for substances that are accepted as safe for addition in food. Far from being "inert", some amphiphilic excipients used in the production of pharmaceutical products have been shown to inhibit the activity of ABCs in MDR tumors, emerging as a clinically translatable approach to overcome resistance. The present article initially overviews the classification, structure and function of the different ABCs, with emphasis on those pumps related to drug resistance. Then, the different attempts to capitalize on the activity of GRAS nanopharmaceuticals as ABC inhibitors are discussed. PMID- 24055630 TI - Probiotic properties of lactobacilli species isolated from children's feces. AB - In the present research, the 20 lactobacilli isolated from children feces aged 4 15 years old were investigated for their capabilities to survive at pH 2.0, 2.5, 3.0 and in the presence of 0.25, 0.50 and 0.75% bile salts, their effect on the growth of pathogens, in addition to their sensitivity against 13 selected antibiotics. All the lactobacilli strains were able to survive in low pH and bile salt conditions at pH 2.0 and 0.25% bile salt for 2 h. Moreover, all lactobacilli strains exhibited inhibitory activity against Escherichia coli ATCC 11229, Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 29213. In addition, all lactobacilli strains indicated resistance to teicoplanin, vancomycin, and bacitracin. The amount of exopolysaccharide (EPS) produced by the strains was 70 and 290 mg/L. The capabilities to autoaggregation and coaggregate with E. coli ATCC 11229 of the strains were also evaluated. High EPS-producing strains indicated significant autoaggregation and coaggregation capability with test bacteria (p < 0.01). The maximum cholesterol removal (76.5%) was observed by strain Lactobacillus pentosus T3, producing a high amount of exopolysaccharide, in 0.3%oxgall concentration (p < 0.05). Our results demonstrate that the capability to EPS production, acid-bile tolerance, antimicrobial activity, antibiotic resistance, aggregation and cholesterol removal of lactobacilli could be utilized for preliminary screening in order to identify potentially probiotic bacteria suitable for human. PMID- 24055631 TI - Salivary detection of periodontopathic bacteria in Fanconi's anemia patients. AB - Fanconi's anemia (FA) is characterized by bone marrow failure and can lead to infections such as periodontal disease. The aim of this study was to compare the prevalence of four periodontopathic bacteria including Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Fusobacterium nucleatum and Treponema denticola in saliva samples from children with and without FA. Paraffin stimulated saliva samples were collected from 71 children and adolescents, aged 6 18 years old. The samples were divided in three groups: FA without HSCT (n = 25), FA with HSCT (n = 23) and Non-FA (n = 24). The test bacteria were identified using a 16S rRNA-based PCR analysis. P. gingivalis was the most frequent species in all groups and T. denticola the less frequent. P. gingivalis was also common species in combinations in all groups. No statistically difference was observed between the groups for single bacteria, pair or triple combination. The combination of the four species was detected in one saliva sample of the FA without HSCT group and in five samples of the Non-FA group, with statistical difference between them (p < 0.05, Fisher exact test). Systemic alterations found in FA subjects did not affect the salivary distribution of the four bacteria analyzed. PMID- 24055632 TI - Some physiological and histological aspects of the gastrointestinal tract in a mouse model of chronic renal failure. AB - INTRODUCTION: It has been reported that mice with 5/6 nephrectomy- induced chronic renal failure (CRF) have reduced gastrointestinal transit (GIT) and increased fecal moisture content (FMC). We have recently shown that feeding adenine (0.2%, w/w) to mice can be used as a model of CRF. Here, we investigated the possible effects of adenine-induced CRF on several in vivo and in vitro aspects of GIT physiology and histology of the stomach, duodenum, ileum and colon in mice. METHODS: The effects of CRF induced by feeding adenine (0.2%, w/w for 2 or 4 weeks) on the gastric emptying index (GEI), GIT, FMC and bead expulsion test (BET) were investigated. GIT was measured by the charcoal meal test and GEI by the difference between full and empty stomach weights. Fresh and dried feces were weighed to calculate the FMC. Renal function was assessed histologically, and biochemically in plasma and urine. The light microscopic histology of the different parts of the gut, as well as the in vitro contractility of the isolated ileum was also assessed. RESULTS: Feeding adenine for 2 or 4 weeks resulted in CRF. The BET was significantly increased in mice given adenine for 2 but not 4 weeks, while the GEI was significantly increased in mice treated with adenine for 4 but not 2 weeks. No significant differences between control and adenine-treated mice were found in GIT, FMC or the histology of the different parts of the gut. Acetylcholine-induced contractions of the ileum of adenine-treated rats were not significantly different from those of the controls. DISCUSSION: Feeding adenine for either 2 or 4 weeks resulted in CRF, but it would appear that this model produces effects on the gastrointestinal tract that are milder than those reported before in animal models with 5/6 nephrectomy-induced-CRF. PMID- 24055633 TI - Determination of the PS I content of PS II core preparations using selective emission: a new emission of PS II at 780nm. AB - Routinely prepared PS II core samples are often contaminated by a significant (~1 5%) fraction of PS I, as well as related proteins. This contamination is of little importance in many experiments, but masks the optical behaviour of the deep red state in PS II, which absorbs in the same spectral range (700-730nm) as PS I (Hughes et al. 2006). When contamination levels are less than ~1%, it becomes difficult to quantify the PS I related components by gel-based, chromatographic, circular dichroism or EPR techniques. We have developed a fluorescence-based technique, taking advantage of the distinctively different low temperature emission characteristics of PS II and PS I when excited near 700nm. The approach has the advantage of providing the relative concentration of the two photosystems in a single spectral measurement. A sensitivity limit of 0.01% PS I (or better) can be achieved. The procedure is applied to PS II core preparations from spinach and Thermosynechococcus vulcanus. Measurements made of T. vulcanus PS II preparations prepared by re-dissolving crystallised material indicate a low but measurable PS I related content. The analysis provides strong evidence for a previously unreported fluorescence of PS II cores peaking near 780nm. The excitation dependence of this emission as well as its appearance in both low PS I cyanobacterial and plant based PS II core preparations suggests its association with the deep red state of PS II. PMID- 24055634 TI - Asthma and physical activity--a population based study results from the Swedish GA(2)LEN survey. AB - BACKGROUND: Having asthma has in previous reports been related to a lower physical activity level. At the same time the prevalence of asthma among elite athletes is high. The aim of this study was to investigate the association between physical activity level and asthma. METHODS: A postal questionnaire was completed by 25,610 individuals in Sweden. Current asthma was defined as having had an asthma attack during the last 12 months or current use of asthma medication. The participants were asked how often and for how many hours a week they were physically active. RESULTS: In the population 1830 subjects (7.1%) had current asthma. There was no significant difference in the proportion of subjects that reported being inactive or slightly physically active between asthmatic and non-asthmatics (57 vs. 58%) while the proportion of subjects that were vigorously physically active (>=2 times a week and >=7 h per week) was higher among the subjects with asthma (6.7 vs. 4.8%, p < 0.0001). Being vigorously physically active was independently related to current asthma (OR (95% CI)) 1.40 (1.11 1.77)), wheeze (1.39 (1.17-1.65)), wheeze and breathlessness (1.68 (1.38-2.04)), and wheezing without having a cold (1.39 (1.13-1.71)). The association between being vigorously physically active and wheeze was significantly stronger in women compared to men. CONCLUSIONS: There was no difference in the proportion of subjects with a reported low level of physical activity between asthmatics and non-asthmatics. Health care professionals should, however, be aware of the increased prevalence of asthma and asthma-related symptoms in vigorously physically active subjects. PMID- 24055635 TI - Acetylsalicylic acid (aspirin) and salicylic acid interaction with the human erythrocyte membrane bilayer induce in vitro changes in the morphology of erythrocytes. AB - Despite the well-documented information, there are insufficient reports concerning the effects of salicylate compounds on the structure and functions of cell membranes, particularly those of human erythrocytes. With the aim to better understand the molecular mechanisms of the interaction of acetylsalicylic acid (ASA) and salicylic acid (SA) with cell membranes, human erythrocyte membranes and molecular models were utilized. These consisted of bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), representative of phospholipid classes located in the outer and inner monolayers of the human erythrocyte membrane, respectively. The capacity of ASA and SA to perturb the multibilayer structures of DMPC and DMPE was evaluated by X ray diffraction while DMPC unilamellar vesicles (LUV) were studied by fluorescence spectroscopy. Moreover, we took advantage of the capability of differential scanning calorimetry (DSC) to detect the changes in the thermotropic phase behavior of lipid bilayers resulting from ASA and SA interaction with PC and PE molecules. In an attempt to further elucidate their effects on cell membranes, the present work also examined their influence on the morphology of intact human erythrocytes by means of defocusing and scanning electron microscopy, while isolated unsealed human erythrocyte membranes (IUM) were studied by fluorescence spectroscopy. Results indicated that both salicylates interact with human erythrocytes and their molecular models in a concentration dependent manner perturbing their bilayer structures. PMID- 24055636 TI - Phagocytes migration in response to an emergency call from the microbiota. PMID- 24055637 TI - Nucleos(t)ide analogs-based chemoprevention of liver cancer in hepatitis B patients: effective, yet in search of optimization. PMID- 24055638 TI - Fecal transplantation: beyond the aesthetic. PMID- 24055639 TI - Reply: To PMID 23323867. PMID- 24055640 TI - Reply: To PMID 23375997. PMID- 24055641 TI - Red ginseng extract inhibits the expression of MCP-1 and iNOS in Helicobacter pylori-infected gastric epithelial cells by suppressing the activation of NADPH oxidase and Jak2/Stat3. AB - ETHNOPHARMCOLOGICAL RELEVANCE: Helicobacter pylori induced oxidative stress represents an important mechanism leading to expression of inflammatory mediators. Korean red ginseng is used in traditional medicine to inhibit inflammation. However, the anti-inflammatory mechanism of red ginseng is still under investigation. Thus, we investigated whether Korean red ginseng extract (RGE) inhibits NADPH oxidase, a source of reactive oxygen species (ROS), and the Jak2/Stat3 pathway, which mediates the expression of inflammatory mediators, in Helicobacter pylori-infected gastric epithelial cells. MATERIALS AND METHODS: A standardized RGE was supplied by the Korea Ginseng Corporation. Human gastric epithelial cells (AGS) were treated with RGE and stimulated with Helicobacter pylori. NADPH oxidase activity, ROS levels, activation of Jak2/Stat3, and induction of MCP-1 and iNOS were determined. RESULTS: Helicobacter pylori infection resulted in an increase in ROS and activation of NADPH oxidase and Jak2/Stat3, which induced the expression of MCP-1 and iNOS in AGS cells. The induction of MCP-1 and iNOS was inhibited by both the Jak2/Stat3 inhibitor AG490 and RGE in Helicobacter pylori-infected cells. RGE suppressed NADPH oxidase activity by inhibiting translocation of cytosolic subunits p67phox and p47phox to the membrane and reduced ROS levels in Helicobacter pylori-infected cells. CONCLUSION: RGE inhibits the expression of MCP-1 and iNOS by suppressing the activation of NADPH oxidase and Jak2/Stat3 in Helicobacter pylori-infected gastric epithelial cells. PMID- 24055642 TI - Stress-whitening occurs in demineralized bone. AB - INTRODUCTION: The incidence of age-related bone fracture is increasing with average population age. Bone scatters more light (stress-whitens) during loading, immediately prior to failure, in a manner visually similar to polymer crazing. We wish to understand the stress-whitening process because of its possible effect on bone toughness. The goals of this investigation were a) to establish that stress whitening is a property of the demineralized organic matrix of bone rather than only a property of mineralized tissue and that stress whitening within the demineralized bone is dependent upon both b) hydrogen bonding and, c) the orientation of loading. METHODS: Demineralized cortical bone specimens were loaded in tension to failure (0.08 strain/s). The effect of hydrogen bonding on mechanical properties and the stress-whitening process was probed by altering the Hansen's hydrogen bonding parameter (deltah) of the immersing solution. RESULTS: Stress-whitening occurred in the demineralized bone. Stress-whitening was negatively correlated with deltah (R(2)=0.81, p<0.0001). Stress-whitening was significantly lower (p<0.0001) in specimens loaded orthogonally compared to those loaded parallel to the long (strong) axis. CONCLUSION: The stress-whitening observed was consistent with increased Mie scattering. We suggest that the change in Mie scattering was due to collagen fibril dehydration driven by the externally applied stress. The presence of stress-whitening in demineralized bone suggests that this process may be a property of the collagenous matrix and hence may be present in other collagenous tissues rather than an emergent property of the bone composite. PMID- 24055643 TI - Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice. AB - AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK alpha subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of C24 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome. PMID- 24055644 TI - Mixture effects at very low doses with combinations of anti-androgenic pesticides, antioxidants, industrial pollutant and chemicals used in personal care products. AB - Many xenobiotics have been identified as in vitro androgen receptor (AR) antagonists, but information about their ability to produce combined effects at low concentrations is missing. Such data can reveal whether joint effects at the receptor are induced at low levels and may support the prioritisation of in vivo evaluations and provide orientations for the grouping of anti-androgens in cumulative risk assessment. Combinations of 30 AR antagonists from a wide range of sources and exposure routes (pesticides, antioxidants, parabens, UV-filters, synthetic musks, bisphenol-A, benzo(a)pyrene, perfluorooctane sulfonate and pentabromodiphenyl ether) were tested using a reporter gene assay (MDA-kb2). Chemicals were combined at three mixture ratios, equivalent to single components' effect concentrations that inhibit the action of dihydrotesterone by 1%, 10% or 20%. Concentration addition (CA) and independent action were used to calculate additivity expectations. We observed complete suppression of dihydrotestosterone effects when chemicals were combined at individual concentrations eliciting 1%, 10% or 20% AR antagonistic effect. Due to the large number of mixture components, the combined AR antagonistic effects occurred at very low concentrations of individual mixture components. CA slightly underestimated the combined effects at all mixture ratios. In conclusion, large numbers of AR antagonists from a wide variety of sources and exposure routes have the ability of acting together at the receptor to produce joint effects at very low concentrations. Significant mixture effects are observed when chemicals are combined at concentrations that individually do not induce observable AR antagonistic effects. Cumulative risk assessment for AR antagonists should apply grouping criteria based on effects where data are available, rather than on criteria of chemical similarity. PMID- 24055645 TI - Letter to the editor. Response. PMID- 24055646 TI - Photocatalytic, sonocatalytic and sonophotocatalytic degradation of Rhodamine B using ZnO/CNTs composites photocatalysts. AB - A series of ZnO nanoparticles decorated on multi-walled carbon nanotubes (ZnO/CNTs composites) was synthesized using a facile sol method. The intrinsic characteristics of as-prepared nanocomposites were studied using a variety of techniques including powder X-ray diffraction (XRD), high resolution transmission electron microscope (HR-TEM), transmission electron microscope (TEM), scanning electron microscope (SEM) with energy dispersive X-ray analysis (EDX), Brunauer Emmett Teller (BET) surface area analyzer and X-ray photoelectron spectroscopy (XPS). Optical properties studied using UV-Vis diffuse reflectance spectroscopy confirmed that the absorbance of ZnO increased in the visible-light region with the incorporation of CNTs. In this study, degradation of Rhodamine B (RhB) as a dye pollutant was investigated in the presence of pristine ZnO nanoparticles and ZnO/CNTs composites using photocatalysis and sonocatalysis systems separately and simultaneously. The adsorption was found to be an essential factor in the degradation of the dye. The linear transform of the Langmuir isotherm curve was further used to determine the characteristic parameters for ZnO and ZCC-5 samples which were: maximum absorbable dye quantity and adsorption equilibrium constant. The natural sunlight and low power ultrasound were used as an irradiation source. The experimental kinetic data followed the pseudo-first order model in photocatalytic, sonocatalytic and sonophotocatalytic processes but the rate constant of sonophotocatalysis is higher than the sum of it at photocatalysis and sonocatalysis process. The sonophotocatalysis was always faster than the respective individual processes due to the more formation of reactive radicals as well as the increase of the active surface area of ZnO/CNTs photocatalyst. Chemical oxygen demand (COD) of textile wastewater was measured at regular intervals to evaluate the mineralization of wastewater. PMID- 24055647 TI - Trascriptome analysis of the Pacific white shrimp Litopenaeus vannamei exposed to nitrite by RNA-seq. AB - In the present study, transcriptome of nitrite-exposed Litopenaeus vannamei was performed using a newly developed high-throughput sequencing technology (Illumina RNA-seq). As many as 42,336 unigenes were generated with 561 bp of average length and 736 bp of unigene N50 after filtering and assembly. These unigenes from the de novo assembly were further annotated using BLAST and BLAST2GO softwares. A total of 23,532 unigenes were unambiguous alignments to the reference when BLAST against non-redundant protein sequence (Nr), non-redundant nucleotide (Nt), Swiss Prot, Gene Ontology database (GO), Clusters of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases available at NCBI. Numerous candidate genes associated with immune response, detoxification, apoptosis pathway were identified. Ten candidate genes related to immune responses and apoptosis were selected for validating the results of assembly and annotation by real-time quantitative PCR. Results revealed that the expressions of all these ten genes were up-regulated after nitrite exposure. Combining to our previous study, we speculate that all these selected genes may be involved in the response to nitrite stress. The study shows a systematic overview of the transcriptome analysis in L. vannamei, and provides valuable gene information for studying molecular mechanisms under nitrite exposure. PMID- 24055648 TI - Endocrine disruptors: a relevant issue for neuroendocrinology also! PMID- 24055649 TI - Record of a Zoophthora sp. (Entomophthoromycota: Entomophthorales) pathogen of the irruptive noctuid moth Eurois occulta (Lepidoptera) in West Greenland. AB - Eurois occulta undergoes extreme population fluctuations in Greenland, with long periods of low density punctuated by brief population explosions. During the summers of high E. occulta density in 2010 and 2011, large numbers of deceased late-instar larvae were observed in the summit disease position characteristic of entomophthoralean infection. Using genetic and morphological data, infected larvae from 2011 were determined to contain resting spores of a fungus of the genus Zoophthora, its first reported observation in the Arctic. In the absence of observation of primary spores or other identifying characters, a specific designation or description is not possible. PMID- 24055650 TI - RNA interference of cadherin gene expression in Spodoptera exigua reveals its significance as a specific Bt target. AB - Cadherin is a calcium-dependent cell surface molecule and has been proposed to be a target molecule of Bacillus thuringiensis Cry proteins. Based on a partial cadherin gene obtained from 454 pyrosequencing transcripts of the fifth instar Spodoptera exigua midgut, a full open reading frame of cadherin gene (SeCad1) was cloned. Its predicted amino acid sequence encodes extracellular 9 cadherin repeats, a transmembrane, and intracellular domain. SeCad1 gene was expressed in all developmental stages specifically in gut tissue by RT-PCR analysis. Expression of SeCad1 gene was suppressed by both injection and feeding of its specific double-stranded RNA (dsRNA(SeCad1)) in the fifth instar. The suppression of SeCad1 expression did not significantly influence on pupal and adult developments of S. exigua. However, the larvae treated with dsRNA(SeCad1) (100 ng/larva) significantly reduced susceptibility to B. thuringiensis ssp. aizawai. In contrast, the dsRNA(SeCad1)-treated larvae did not show any change in susceptibility to B. thuringiensis ssp. kurstaki. These results suggest that SeCad1 is a specific target molecule to Cry1C toxin from B. thuringiensis in S. exigua, but not to Cry1A toxin. PMID- 24055651 TI - The embryonic linker histone H1 variant of Drosophila, dBigH1, regulates zygotic genome activation. AB - Histone H1 is an essential chromatin component. Metazoans usually contain multiple stage-specific H1s. In particular, specific variants replace somatic H1s during early embryogenesis. In this regard, Drosophila was an exception because a single dH1 was identified that, starting at cellularization, is detected throughout development in somatic cells. Here, we identify the embryonic H1 of Drosophila, dBigH1. dBigH1 is abundant before cellularization occurs, when somatic dH1 is absent and the zygotic genome is inactive. Upon cellularization, when the zygotic genome is progressively activated, dH1 replaces dBigH1 in the soma, but not in the primordial germ cells (PGCs) that have delayed zygotic genome activation (ZGA). In addition, a loss-of-function mutant shows premature ZGA in both the soma and PGCs. Mutant embryos die at cellularization, showing increased levels of active RNApol II and zygotic transcripts, along with DNA damage and mitotic defects. These results show an essential function of dBigH1 in ZGA regulation. PMID- 24055653 TI - Where are we going with autologous transplantation for multiple myeloma? PMID- 24055652 TI - Lamina-associated polypeptide-1 interacts with the muscular dystrophy protein emerin and is essential for skeletal muscle maintenance. AB - X-linked Emery-Dreifuss muscular dystrophy is caused by loss of function of emerin, an integral protein of the inner nuclear membrane. Yet emerin null mice are essentially normal, suggesting the existence of a critical compensating factor. We show that the lamina-associated polypeptide1 (LAP1) interacts with emerin. Conditional deletion of LAP1 from striated muscle causes muscular dystrophy; this pathology is worsened in the absence of emerin. LAP1 levels are significantly higher in mouse than human skeletal muscle, and reducing LAP1 by approximately half in mice also induces muscle abnormalities in emerin null mice. Conditional deletion of LAP1 from hepatocytes yields mice that exhibit normal liver function and are indistinguishable from littermate controls. These results establish that LAP1 interacts physically and functionally with emerin and plays an essential and selective role in skeletal muscle maintenance. They also highlight how dissecting differences between mouse and human phenotypes can provide fundamental insights into disease mechanisms. PMID- 24055654 TI - Collection of hematopoietic stem cells after previous radioimmunotherapy is feasible and does not impair engraftment after autologous stem cell transplantation in follicular lymphoma. AB - Major concerns about radioimmunotherapy (RIT) administration early in the course of follicular lymphoma (FL) are long-term toxicity and the theoretical impairment of hematopoietic stem cell (HSC) harvest, but few data are available about mobilization rates after RIT. This study evaluates the impact of prior therapy with RIT (yttrium-90 ibritumomab tiuxetan) and different chemotherapy regimens in all FL patients (N = 103) attempting HSC mobilization at our institution over the last 7 years. Sixty-nine patients received R-CHOP (rituximab-cyclophosphamide doxorubicin-vincristine-prednisone) or CHOP-like regimens, 21 patients received R FM (rituximab-fludarabine-mitoxantrone), and 13 patients received RIT before HSC mobilization. Median CD34+ cell yield at first mobilization was 7.2 * 10(6)/kg in the R-CHOP group versus 4.3 in the R-FM group versus 1.7 in the RIT group (P = .02 R-CHOP versus R-FM; P < .0001 R-CHOP versus RIT; P < .02 R-FM versus RIT). Although 8 of 13 patients initially failed to collect enough HSC after RIT, a second and/or salvage harvest was successfully performed in 7 patients, with 10 of 13 patients (77%) finally undergoing autologous stem cell transplantation (ASCT). No differences in engraftment kinetics were observed between the three groups (R-CHOP versus R-FM versus RIT). Although mobilization was significantly impaired in patients previously treated with RIT, a salvage HSC harvest and ASCT after RIT were safe and feasible in most patients. PMID- 24055655 TI - Serum neutrophil extracellular trap levels predict thrombotic microangiopathy after allogeneic stem cell transplantation. AB - Transplantation-associated thrombotic microangiopathy (TA-TMA) is a devastating complication of hematopoietic stem cell transplantation. TA-TMA likely represents the final stage of vascular endothelial injury; however, its pathophysiology is largely unknown, making clinical management difficult. Recently, the association of neutrophil extracellular traps (NETs) with the development of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome has been reported. Thus, we explored whether NETs are also relevant to the occurrence of TA-TMA. We retrospectively analyzed post-transplant trends of serum NET levels in 90 patients, 11 of whom developed TA-TMA. Relative to baseline (before the conditioning regimen), elevated serum NET levels either at 4 weeks after transplantation or as early as the day of transplantation were associated with significantly increased risk of TA-TMA. In contrast, thrombomodulin, a potential marker for TA-TMA, was not helpful to predict the occurrence of TA-TMA in our study. In addition, we directly detected glomerular deposition of NETs in 2 TA TMA patients. Increased NET levels are a significant risk factor for TA-TMA, suggesting that NET level is a useful biomarker for TA-TMA. PMID- 24055656 TI - Isolation of a phylogenetically distinct rabies virus from a tufted capuchin monkey (Cebus apella) in Brazil. AB - A rabies virus isolate (BRmk1358 strain) was discovered from a rabid tufted capuchin monkey in Brazil. The present study determined the nucleotide sequence of the BRmk1358 strain and compared with the rabies viruses isolated from marmosets and other animals in the Americas. Phylogenetic analyses showed that the BRmk1358 strain formed a lineage distant from that of marmoset rabies virus within the Chiroptera-related rabies virus cluster. This result suggests that the source of rabies infection in the tufted capuchin monkey may have been bat, and that they have a risk to act as rabies reservoir in Brazil. PMID- 24055657 TI - Decreased level of intracellular cholesterol in peripheral blood mononuclear cells is associated with chronic hepatitis C virus infection. AB - Peripheral blood mononuclear cells (PBMCs) constitute the main extrahepatic place of, hepatitis C virus (HCV) replication. We aimed to determine the impact of CHC infection and microRNA-, 122 expression on cholesterol expression in PBMCs. HCV RNA strand, intracellular cholesterol, HMGCoA, reductase and miR-122 expression in PBMC were determined in 54 CHC patients. The study shows that significant decrease of intracellular cholesterol level in PBMC (p=0.000000), accompanied by serum hypocholesterolemia is the characteristic feature of chronic hepatitis C infection. Although, microRNA-122 expression was detectable in PBMCs of CHC patients (52.5%), the alteration of intracellular cholesterol level was independent of miR-122 expression. PMID- 24055658 TI - Improving adenovirus vector-mediated RNAi efficiency by lacking the expression of virus-associated RNAs. AB - Several studies have reported that short hairpin RNA (shRNA)-mediated RNA interference (RNAi) was competitively inhibited by the expression of adenovirus (Ad)-encoded small RNAs (VA-RNAs), which are expressed from a replication incompetent Ad vector, as well as a wild-type Ad; however, it remained to be clarified whether an shRNA-expressing Ad vector-mediated knockdown was inhibited by VA-RNAs transcribed from the same Ad vector genome. In this study, we demonstrated that a lack of VA-RNA expression from the Ad vector leads to an increase in knockdown efficiencies of Ad vector-mediated RNAi. In the cells transduced with a first-generation Ad vector (FG-Ad) expressing shRNA (FG-Ad shRNA), the copy numbers of shRNA and VA-RNAs incorporated into the RNA-induced silencing complex (RISC) was comparable. In contrast, higher amounts of shRNA were found in the RISC when the cells were transduced with an shRNA-expressing helper-dependent Ad (HD-Ad) vector, in which all viral genes, including VA-RNAs, were deleted (HD-Ad-shRNA), compared with FG-Ad-shRNA. HD-Ad vectors expressing shRNA against luciferase and p53 showed 7.4% and 37.3% increases in the knockdown efficiencies compared to the corresponding FG-Ad-shRNA, respectively, following in vitro transduction. Furthermore, higher levels of knockdown efficiencies were also found by the transduction with shRNA-expressing Ad vectors lacking VA-RNA expression (AdDeltaVR-shRNA) than by transduction with FG-Ad-shRNA. These results indicate that VA-RNAs expressed from an Ad vector inhibit knockdown by the shRNA expressing Ad vector and that HD-Ad-shRNA and AdDeltaVR-shRNA are a powerful framework for shRNA-mediated knockdown. PMID- 24055660 TI - Pharmaceuticals, perfluorosurfactants, and other organic wastewater compounds in public drinking water wells in a shallow sand and gravel aquifer. AB - Approximately 40% of U.S. residents rely on groundwater as a source of drinking water. Groundwater, especially unconfined sand and gravel aquifers, is vulnerable to contamination from septic systems and infiltration of wastewater treatment plant effluent. In this study, we characterized concentrations of pharmaceuticals, perfluorosurfactants, and other organic wastewater compounds (OWCs) in the unconfined sand and gravel aquifer of Cape Cod, Massachusetts, USA, where septic systems are prevalent. Raw water samples from 20 public drinking water supply wells on Cape Cod were tested for 92 OWCs, as well as surrogates of wastewater impact. Fifteen of 20 wells contained at least one OWC; the two most frequently-detected chemicals were sulfamethoxazole (antibiotic) and perfluorooctane sulfonate (perfluorosurfactant). Maximum concentrations of sulfamethoxazole (113 ng/L) and the anticonvulsant phenytoin (66 ng/L) matched or exceeded maximum reported concentrations in other U.S. public drinking water sources. The sum of pharmaceutical concentrations and the number of detected chemicals were both significantly correlated with nitrate, boron, and extent of unsewered residential and commercial development within 500 m, indicating that wastewater surrogates can be useful for identifying wells most likely to contain OWCs. Septic systems appear to be the primary source of OWCs in Cape Cod groundwater, although wastewater treatment plants and other sources were potential contributors to several wells. These results show that drinking water supplies in unconfined aquifers where septic systems are prevalent may be among the most vulnerable to OWCs. The presence of mixtures of OWCs in drinking water raises human health concerns; a full evaluation of potential risks is limited by a lack of health-based guidelines and toxicity assessments. PMID- 24055661 TI - Determination of 81 pharmaceutical drugs by high performance liquid chromatography coupled to mass spectrometry with hybrid triple quadrupole-linear ion trap in different types of water in Serbia. AB - The aim of the work was to study the occurrence of pharmaceuticals in waste, surface, underground, and drinking water samples collected in Serbia. A multi residue method for the analysis of 81 pharmaceutical drugs from different therapeutic classes in the various types of water was applied. Twenty-five composite water samples were prepared using solid-phase extraction and the presence of 81 pharmaceutical compounds in the extracts was analyzed by ultra high performance liquid chromatography coupled to mass spectrometry with hybrid triple quadrupole-linear ion trap (UPLC-QqLIT-MS/MS). Forty seven compounds of 81 drugs were found in four different types of analyzed water. The highest concentrations of ibuprofen of 20.1 MUg L(-1), 10,11-epoxycarbamazepine of 16.2 MUg L(-1), 2-hydroxycarbamazepine of 15.9 MUg L(-1) and acetaminophen of 15.7 MUg L(-1) were found in municipal waste water sample. Results revealed the presence of salicylic acid in 41.67% of water samples, carbamazepine in 36.11%, propranolol and irbesartan in 30.56%. The obtained results were discussed in relation to the relevant data available in literature. This is the first attempt to assess the occurrence of these 81 pharmaceutical residues in water samples in Serbia. PMID- 24055662 TI - Occurrence and transfer of a cyanobacterial neurotoxin beta-methylamino-L-alanine within the aquatic food webs of Gonghu Bay (Lake Taihu, China) to evaluate the potential human health risk. AB - To evaluate the health risk of cyanobacterial blooms, the levels of the neurotoxic non-protein amino acid, beta-methylamino-l-alanine (BMAA), was investigated in the freshwater ecosystem of Gonghu Bay in Lake Taihu. Lake Taihu is a large shallow lake contaminated by the excessive growth of Microcystis. Since BMAA has been measured in diverse cyanobacteria in different ecosystems all over the world, BMAA might also occur in Gonghu Bay. A long term monitoring of BMAA was done by HPLC-MS/MS method in cyanobacteria, mollusks, crustaceans and various fish species at different trophic levels of ecosystems in Gonghu Bay, some of which were popularly consumed by humans. Over the entire sampling period, the total average BMAA content in cyanobacteria, mollusks, crustaceans and various fish species were 4.12, 3.21, 3.76, and 6.05MUgBMAA/g dry weight, respectively. Thus, BMAA could be biosynthesized by the blooming cyanobacteria in which Microcystis dominates. This toxin can be transferred through ascending trophic levels of the aquatic ecosystem in Gonghu Bay. The bioaccumulation of BMAA was observed in aquatic animals, especially in some fish species during the bloom-outbreak and bloom-decline phases. The discovery of the chronic neurotoxin BMAA in a large limnic ecosystem together with possible pathways of accumulation within major food webs deserves serious consideration due to its potential long term risk to human health. PMID- 24055663 TI - Polyacrylamide application versus forest residue mulching for reducing post-fire runoff and soil erosion. AB - For several years now, forest fires have been known to increase overland flow and soil erosion. However, mitigation of these effects has been little studied, especially outside the USA. This study aimed to quantify the effectiveness of two so-called emergency treatments to reduce post-fire runoff and soil losses at the microplot scale in a eucalyptus plantation in north-central Portugal. The treatments involved the application of chopped eucalyptus bark mulch at a rate of 10-12 Mg ha(-1), and surface application of a dry, granular, anionic polyacrylamide (PAM) at a rate of 50 kg ha(-1). During the first year after a wildfire in 2010, 1419 mm of rainfall produced, on average, 785 mm of overland flow in the untreated plots and 8.4 Mg ha(-1) of soil losses. Mulching reduced these two figures significantly, by an average 52 and 93%, respectively. In contrast, the PAM-treated plots did not differ from the control plots, despite slightly lower runoff but higher soil erosion figures. When compared to the control plots, mean key factors for runoff and soil erosion were different in the case of the mulched but not the PAM plots. Notably, the plots on the lower half of the slope registered bigger runoff and erosion figures than those on the upper half of the slope. This could be explained by differences in fire intensity and, ultimately, in pre-fire standing biomass. PMID- 24055664 TI - Total mercury in snow and ice samples from Canadian High Arctic ice caps and glaciers: a practical procedure and method for total Hg quantification at low pg g(-1) level. AB - A newly developed procedure and method for studying total Hg (THg) in the High Arctic glaciers and ice caps, including container type selection, on-site sampling, sample protection and storage, and sample decontamination is reported in this study. Two analytical systems for THg quantification were also compared to confirm the accuracy and reproducibility. This study found that container types, storage time, sample protection from exposure to light and environment are all important for precise quantification of THg in snow and ice samples from the Canadian High Arctic glaciers and ice caps. With this newly developed procedure and method, we retrieved 28-year and 73-year archives for atmospheric THg deposition from Mt. Oxford and Agassiz Ice Cap respectively. Our results show that snow and ice samples contain THg concentrations varying from sub pg g(-1) to low pg g(-1). Comparison of THg concentration trends and fluxes from the two sites demonstrates that quantification of THg from the two locations with similar altitudes and latitudes can be reproducible, which suggests that historical THg information from atmospheric deposition can be preserved in snow and ice in the glaciers and ice caps. The high reproducibility of results achieved by this procedure and method, in return, confirmed its suitability for studies of THg in snow and ice samples from ice caps and glaciers. PMID- 24055659 TI - Lunch at school, at home or elsewhere. Where do adolescents usually get it and what do they eat? Results of the HELENA Study. AB - Considering the lack of uniformity regarding school meals in Europe, information on adolescents' school lunch patterns is of public health importance. Thus, the aim of this analysis was to describe and evaluate lunchtime energy and food intake of European adolescents at different lunch locations. Data on nutritional and health-related parameters were derived from the HEalthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study (HELENA-CSS). A sub-sample of 891 adolescents (47% male) with plausible data on total and lunchtime energy intake (2 * 24 h recall) as well as usual lunch location was considered. Food intake was compared to lunch of the Optimized Mixed Diet (OMD) for children and adolescents. Although energy intake was nearly in line with the recommendations, food intake was suboptimal compared to the OMD regardless of usual lunch location. Adolescents had more potatoes and less sweets at school, and more drinks (water, coffee and tea) and vegetables at home when each compared with the other locations. Food intake of adolescents getting their lunch elsewhere was characterized by the smallest amounts of potatoes and the highest amounts of sweets. Although lunch patterns may differ among countries, schools in Europe do not seem to reveal all their potential to offer access to a healthy lunch for adolescents yet. PMID- 24055665 TI - Basin-scale contributions of Cr, Ni and Co from Ortegal Complex to the surrounding coastal environment (SW Europe). AB - The enrichment of Cr and Ni in the coastal zones is usually associated with anthropogenic sources such as the tanning, galvanization, ceramic, and cement industries. However, geological complexes of specific lithologic composition located near shorelines may act as natural sources of metals to the continental shelf. Cape Ortegal (SW Europe) is an ultramafic complex that has Cr, Ni and Co enriched in rocks due to the minerals chromite, chromospinel, gersdorfite and pentlandite. Thus, the hypothesis that this geological complex contributes to metal enrichment in Ortigueira and Barqueiro Rias and the adjacent continental shelf was tested. Chromium, Ni, and Co were determined in water and in suspended particulate matter of ria tributaries, rainfall, surface sediments, mussels, and algae. High contents of Cr (max. 1670mg.kg(-1)) and Ni (max. 1360 mg . kg(-1)) were found in the sediments surrounding Cape Ortegal and the Ortigueira Ria as a result of erosion of exposed cliffs. Dissolved Cr and Ni concentrations in fluvial waters were significantly higher in the rivers that crosses the Ortegal Complex, i.e. Lourido (0.47 MUg Cr . L(-1); 9.4 MUg Ni . L(-1)) and Landoi (0.37 MUg Cr . L(-1); 4.3 MUg Ni . L(-1)), in comparison with the nearby basin out of the complex influence (Sor River: <0.01 MUg Cr . L(-1); 0.57 MUg Ni . L(-1)). The annual fluvial contributions of Cr and Ni to the Ortigueira Ria were higher than fluxes into the Barqueiro Ria. Moreover, the increase in Cr and Ni in the rainfall in summer demonstrated the importance of the atmosphere pathway for introducing these elements into the aquatic environment. As a consequence, the contents of these metals in soft tissues and shell of mussels and algae from the Ortigueira Ria were higher than the organisms from Barqueiro Ria. Thus, geological complexes, such as the Cape Ortegal, located in an uncontaminated area, can increase the land-sea exchange of trace metals. PMID- 24055666 TI - Endosulfan wet deposition in Southern Florida (USA). AB - The atmosphere is an important transport route for semi-volatile pesticides like endosulfan. Deposition, which depends on physical-chemical properties, use patterns, and climatic conditions, can occur at local, regional, and global scales. Adverse human and ecological impact may result. We measured endosulfan wet deposition in precipitation over a 4-year period within an area of high agricultural use in Southern Florida (USA) and in nearby Biscayne and Everglades National Parks. Endosulfan's two isomers and degradate, endosulfan sulfate, were detected at high frequency with the order of detection and concentration being beta-endosulfan>alpha-endosulfan>endosulfan sulfate. Within the agricultural area, detection frequency (55 to 98%) mean concentrations (5 to 87 ng L(-1)) and total daily deposition (200 ng m(-2) day(-1)) exceeded values at other sites by 5 to 30-fold. Strong seasonal trends were also observed with values at all monitored sites significantly higher during peak endosulfan use periods when vegetable crops were produced. Relatively high deposition in the crop production area and observations that concentrations exceeded aquatic life toxicity thresholds at all sites indicated that endosulfan volatilization and wet deposition are of ecotoxicological concern to the region. This study emphasizes the need to include localized volatilization and deposition of endosulfan and other semi-volatile pesticides in risk assessments in Southern Florida and other areas with similar climatic and crop production profiles. PMID- 24055667 TI - Practice-based evidence informs environmental health policy and regulation: a case study of residential lead-soil contamination in Rhode Island. AB - Prior to 1978, the exteriors of Rhode Island's municipal water towers were painted with lead-containing paint. Over time, this lead-containing paint either flaked-off or was mechanically removed and deposited on adjacent residential properties. Residents challenged inconsistencies across state agencies and federal requirements for collecting and analyzing soil samples. The purpose of this case study was to evaluate the efficacy of Rhode Island Department of Health (RIDOH) soil sampling regulations in determining the extent of lead contamination on residential properties using real world data. Researchers interviewed key government personnel, reviewed written accounts of events and regulations, and extracted and compiled lead data from environmental soil sampling on 31 residential properties adjacent to six municipal water towers. Data were available for 498 core samples. Approximately 26% of the residential properties had lead soil concentrations >1000 mg/kg. Overall, lead concentration was inversely related to distance from the water tower. Analysis indicated that surface samples alone were insufficient to classify a property as "lead safe". Potential for misclassification using RIDOH regulations was 13%. For properties deemed initially "lead free", the total number of samples was too few to analyze. Post-remediation lead-soil concentrations suggest the extent of lead contamination may have been deeper than initially determined. Additional data would improve the ability to draw more meaningful and generalized conclusions. Inconsistencies among regulatory agencies responsible for environmental health obfuscate transparency and erode the public's trust in the regulatory process. Recommendations for improvement include congruency across departmental regulations and specific modifications to lead-soil sampling regulations reflective of lowered CDC reference blood lead value for children 1 to 5 years old (5 MUg/dL). While scientific research informed the initial development of these environmental health policies and regulations, practice-based evidence did not support their efficacy in context of real world practice. PMID- 24055668 TI - Radiocesium sorption in relation to clay mineralogy of paddy soils in Fukushima, Japan. AB - Relationships between Radiocesium Interception Potential (RIP) and mineralogical characteristics of the clay fraction isolated from 97 paddy soils (Hama-dori, n = 25; Naka-dori, n = 36; Aizu, n = 36) in Fukushima Prefecture, Japan were investigated to clarify the mineralogical factors controlling the (137)Cs retention ability of soils (half-life 30.1 y). Of all the fission products released by the Fukushima accident, (137)Cs is the most important long-term contributor to the environmental contamination. The RIP, a quantitative index of the (137)Cs retention ability, was determined for the soil clays. The composition of clay minerals in the soil clays was estimated from peak areas obtained using X ray diffraction (XRD) analyses. The predominant clay mineral was smectite in soils from Hama-dori and Aizu, while this was variable for those from Naka-dori. Native K content of the soil clays was found to be an indicator of the amount of micaceous minerals. The average RIP for the 97 soil clays was 7.8 mol kg(-1), and ranged from 2.4 mol kg(-1) to 19.4 mol kg(-1). The RIP was significantly and positively correlated with native K content for each of the geographical regions, Hama-dori (r = 0.76, p < 0.001), Naka-dori (r = 0.43, p < 0.05), and Aizu (r = 0.76, P < 0.001), while it was not related to the relative abundance of smectite. The linear relationship between RIP and native K content not only indicate a large contribution of micaceous minerals to the (137)Cs retention ability of the soil clays, but also could be used to predict the (137)Cs retention ability of soil clays for other paddy fields in Fukushima and other areas. PMID- 24055669 TI - Persistent organic contaminants in Saharan dust air masses in West Africa, Cape Verde and the eastern Caribbean. AB - Anthropogenic semivolatile organic compounds (SOCs) that persist in the environment, bioaccumulate, are toxic at low concentrations, and undergo long range atmospheric transport (LRT) were identified and quantified in the atmosphere of a Saharan dust source region (Mali) and during Saharan dust incursions at downwind sites in the eastern Caribbean (U.S. Virgin Islands, Trinidad and Tobago) and Cape Verde. More organochlorine and organophosphate pesticides (OCPPs), polycyclic aromatic hydrocarbons (PAHs), and polychlorinated biphenyl (PCB) congeners were detected in the Saharan dust region than at downwind sites. Seven of the 13 OCPPs detected occurred at all sites: chlordanes, chlorpyrifos, dacthal, dieldrin, endosulfans, hexachlorobenzene (HCB), and trifluralin. Total SOCs ranged from 1.9-126 ng/m(3) (mean = 25 +/- 34) at source and 0.05-0.71 ng/m(3) (mean = 0.24 +/- 0.18) at downwind sites during dust conditions. Most SOC concentrations were 1-3 orders of magnitude higher in source than downwind sites. A Saharan source was confirmed for sampled air masses at downwind sites based on dust particle elemental composition and rare earth ratios, atmospheric back trajectory models, and field observations. SOC concentrations were considerably below existing occupational and/or regulatory limits; however, few regulatory limits exist for these persistent organic compounds. Long-term effects of chronic exposure to low concentrations of SOCs are unknown, as are possible additive or synergistic effects of mixtures of SOCs, biologically active trace metals, and mineral dust particles transported together in Saharan dust air masses. PMID- 24055670 TI - A comparative analysis of current microbial water quality risk assessment and management practices in British Columbia and Ontario, Canada. AB - Bacteria, protozoa and viruses are ubiquitous in aquatic environments and may pose threats to water quality for both human and ecosystem health. Microbial risk assessment and management in the water sector is a focus of governmental regulation and scientific inquiry; however, stark gaps remain in their application and interpretation. This paper evaluates how water managers practice microbial risk assessment and management in two Canadian provinces (BC and Ontario). We assess three types of entities engaged in water management along the source-to-tap spectrum (watershed agencies, water utilities, and public health authorities). We analyze and compare the approaches used by these agencies to assess and manage microbial risk (including scope, frequency, and tools). We evaluate key similarities and differences, and situate them with respect to international best practices derived from literatures related to microbial risk assessment and management. We find considerable variability in microbial risk assessment frameworks and management tools in that approaches 1) vary between provinces; 2) vary within provinces and between similar types of agencies; 3) have limited focus on microbial risk assessment for ecosystem health and 4) diverge considerably from the literature on best practices. We find that risk assessments that are formalized, routine and applied system-wide (i.e. from source-to-tap) are limited. We identify key limitations of current testing methodologies and looking forward consider the outcomes of this research within the context of new developments in microbial water quality monitoring such as tests derived from genomics and metagenomics based research. PMID- 24055671 TI - Fingerprinting groundwater pollution in catchments with contrasting contaminant sources using microorganic compounds. AB - Evaluating the occurrence of microorganics helps to understand sources and processes which may be controlling the transport and fate of emerging contaminants (ECs). A study was carried out at the contrasting instrumented environmental observatory sites at Oxford, on the peri-urban floodplain gravel aquifer of the River Thames and Boxford, in the rural valley of the River Lambourn on the chalk aquifer, in Southern England to explore the use of ECs to fingerprint contaminant sources and flow pathways in groundwater. At Oxford compounds were typical of a local waste tip plume (not only plasticisers and solvents but also barbiturates and N,N-diethyl-m-toluamide (DEET)) and of the urban area (plasticisers and mood-enhancing drugs such as carbamazepine). At Boxford the results were different with widespread occurrence of agricultural pesticides, their metabolites and the solvent trichloroethene, as well as plasticisers, caffeine, butylated food additives, DEET, parabens and trace polyaromatic hydrocarbons (PAHs). Groups of compounds used in pharmaceuticals and personal care products of different provenance in the environment could be distinguished, i) historical household and medical waste, ii) long-term household usage persistent in groundwater and iii) current usage and contamination from surface water. Co-contaminant and degradation products can also indicate the likely source of contaminants. A cocktail of contaminants can be used as tracers to provide information on catchment pathways and groundwater/surface water interactions. A prominent feature in this study is the attenuation of many EC compounds in the hyporheic zone. PMID- 24055672 TI - Goose fat, a promising nutrient for fish feeding, activates antioxidant enzymes in rainbow trout, Oncorhynchus mykiss. AB - The objective of this experiment was to test effects of different dietary lipids in rainbow trout feeding on the activity and expression of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S transferase (GST). Four iso-nitrogenous and iso-lipidic casein-gelatin based experimental diets were formulated. The sources of dietary lipids were cod liver oil (CO, rich in polyunsaturated fatty acids), goose fat (GF, rich in saturated fatty acids and monounsaturated fatty acids), soybean oil (SO, rich in linoleic acid), and a blend of CO, GF and SO. Dietary treatments had no significant effect on growth performance and survival was not affected. SOD, GPx and GST enzymes had the maximum activity in GF diet. However qPCR data showed that SOD and GPx mRNA levels were minimum in GF group. Overall data showed that rainbow trout liver enzymes were activated upon GF diet probably activating the enzyme structure itself without stimulating gene expression. PMID- 24055673 TI - Involvement of oxidative stress in municipal landfill leachate-induced toxicity in boar sperm. AB - Exposure to leachates generated from an improperly managed hazardous waste dump sites is detrimental to human health and the ecosystem. The present study investigated the effect of Olushosun municipal landfill leachate (OMLL) on sperm characteristics and antioxidant systems in boar sperm cells. The sperm cells were incubated with the leachate at final concentrations of 0, 1, 2, 4 and 8% for 3h at 37 degrees C. Sperm characteristics were monitored hourly during the incubation period whereas aminotransferases activities and oxidative stress indices were determined after the incubation period. Results revealed a time- and dose-dependent decline in sperm progressive motility from 1h post-treatment with 2, 4 and 8% OMLL whereas decreased sperm viability with elevated abnormalities were observed from 2 h post-treatment with 4 and 8% OMLL when compared with control. Exposure to OMLL caused a significant increase in aminotransferases, catalase and glutathione-S-transferase activities whereas it markedly decreased superoxide dismutase and glutathione peroxidase activities without affecting glutathione level in the treated sperm cells. Co-incubation of sperm with OMLL increased the levels of hydrogen peroxide and malondialdehyde levels. In conclusion, OMLL elicited spermatotoxicity via induction of oxidative stress possibly generated through an enhanced intracellular reactive oxygen species. PMID- 24055674 TI - Charge transfer through a cytochrome multiheme chain: theory and simulation. AB - We study sequential charge transfer within a chain of four heme cofactors located in the c-type cytochrome subunit of the photoreaction center of Rhodopseudomonas viridis from a theoretical perspective. Molecular dynamics simulations of the thermodynamic integration type are used to compute two key energies of Marcus' theory of charge transfer, the driving force ?G and the reorganization energy lambda. Due to the small exposure of the cofactors to the solvent and to charged amino acids, the outer sphere contribution to the reorganization energy almost vanishes. Interheme effective electronic couplings are estimated using ab initio wave functions and a well-parameterized semiempirical scheme for long-range interactions. From the resulting charge transfer rates, we conclude that at most the two heme molecules closest to the membrane participate in a fast recharging of the photoreaction center, whereas the remaining hemes are likely to have a different function, such as intermediate electron storage. Finally, we suggest means to verify or falsify this hypothesis. PMID- 24055675 TI - Novel complexes of Co(III) and Ni(II) containing peptide ligands: synthesis, DNA binding and photonuclease activity. AB - The new cobalt(III) and nickel(II) complexes of the type [M(L)2(H2O)2](n)(+) (where M = Co(III) or Ni(II) ion, n = 3 for Co and 2 for Ni, L = peptides Fmoc. Ala-val-OH (F-AVOH), Fmoc-Phe-Leu-Ome (F-PLOMe) and Z-Ala-Phe-CONH2 (Z-APCONH2)) were synthesized and structurally characterized by FTIR, (1)H NMR, elemental analysis and electronic spectral data. An octahedral geometry has been proposed for all the synthesized Co(III) and Ni(II) metal complexes. The binding property of the complexes with CT-DNA was studied by absorption spectral analysis, followed by viscosity measurement and thermal denaturation studies. Detailed analysis revealed that the metal complexes intercalates into the DNA base stack as intercalator. The photo induced cleavage studies shows that the complexes possess photonuclease property against pUC19 DNA under UV-Visible irradiation. PMID- 24055676 TI - An experimental and DFT study of a disulfide-linked Schiff base: synthesis, characterization and crystal structure of bis (3-methoxy-salicylidene-2 aminophenyl) disulfide in its anhydrous and monohydrate forms. AB - A detailed structural and spectroscopic study of the disulfide Schiff base obtained from condensation of 2-aminothiophenol and o-vanillin is reported. It includes the analyses of the anhydrous and monohydrate forms of the title compound. Structures of both solids were resolved by X-ray diffraction methods. A comparison between experimental and theoretical results is presented. The conformational space was searched and geometries were optimized both in gas phase and including solvent effects. Vibrational (IR and Raman) and electronic spectra were measured and assigned with the help of computational methods based on the Density Functional Theory. Calculated MEP-derived atomic charges were calculated to predict coordination sites for metal complexes formation. PMID- 24055677 TI - Temperature-dependent FTIR spectra of collagen and protective effect of partially hydrolysed fucoidan. AB - FTIR spectra of collagen (PC) and partially hydrolysed fucoidan (PHF) incorporated into collagen films were investigated at different temperatures between 20 degrees C and 100 degrees C. Changes within the bands of amide I, amide II and amide III may indicate stabilization of collagen by hydrogen bonds during its interaction with partially hydrolysed fucoidan. Spectroscopic studies revealed that partially hydrolysed fucoidan was bound to the collagen without affecting its triple helicity. Interactions of fucoidan with H2SO4 (mild acid hydrolysis), leading to changes of the sulphated band positions in the 800-590 cm(-1) region of IR spectra were observed. The effect of partially hydrolysed fucoidan on glucose-mediated collagen glycation and cross-linking of proteins in vitro was evaluated. It was observed that partially hydrolysed fucoidan incorporated into collagen films can be used as therapeutically active biomaterials that speed up the process of wound healing and may increase the anticancer activity of fucoidan. PMID- 24055678 TI - Characterisation of a portable Raman spectrometer for in situ analysis of art objects. AB - During the last decades, Raman spectroscopy has grown to an established analytical technique in archaeometry, art analysis and conservation science. Mobile Raman instruments were designed to be used for in situ characterisation and identification of inorganic and organic materials in art and archaeometry. This research paper aims to point out several aspects that need to be considered when selecting a mobile Raman spectrometer for in situ archaeometrical studies. We describe an approach to evaluate these parameters and apply this to a dual laser portable Raman spectrometer. Twofold characterisation of mobile Raman instrumentation for art analysis: (i) investigation of spectroscopic characteristics such as (amongst others) spectral resolution, spectral window, signal to noise ratio and limit of detection; (ii) evaluation of specific properties that are useful for mobile studies in archaeometry. These include options for easy positioning and focussing, the ability to reduce laser power on the surface of the art object and the working distance between the probehead and the artefact. Finally, the research was completed with field tests by studying the pigments of a mediaeval wall painting. PMID- 24055679 TI - From thorite to coffinite: a spectroscopic study of Th(1-x)U(x)SiO4 solid solutions. AB - Coffinite (USiO4), along with Th(1-x)U(x)SiO4 uranothorite solid solutions, are frequently present in reduced economically exploitable uranium ores. They could also control the concentration of uranium in the environment in the case of accidental release from underground radwaste repository. This paper reports for the first time a thorough FTIR and Raman study relative to the Th(1-x)U(x)SiO4 system, including synthetic analogues of thorite and coffinite end-members. Both sets of spectra confirmed the formulation of the samples and allowed to rule out the presence of structural water molecules and/or hydroxyl groups in the coffinite. Also, no characteristic signal of UO2(2+) uranyl ion was recorded, ensuring that uranium was fully incorporated under its tetravalent oxidation state. The variation of the positions corresponding to SiO4 internal vibration modes was then followed versus the chemical composition of the samples. If the FTIR spectra did not revealed any significant shift in the bands position, several Raman modes followed a linear trend as a function of the uranium incorporation rate. On this basis, Raman spectroscopy could be considered as a promising tool for the semi-quantitative determination of chemical composition of uranothorite samples, particularly for those coming from mineral ores. Finally, the data collected for the coffinite end-member, as the first to be obtained on pure synthetic samples, allowed a review of the results previously reported in the literature for this compound. PMID- 24055680 TI - Fluorescent detection of hydrogen peroxide and glucose with polyethyleneimine templated Cu nanoclusters. AB - An interesting, simple, and label-free strategy for the detection of hydrogen peroxide and glucose has been developed with polyethyleneimine (PEI)-capped copper nanoclusters as a fluorescence probe in aqueous solution. The PEI templated Cu nanoclusters which we have synthesized have an average diameter of 1.8 nm and show a blue emission at 480 nm. In the presence of hydrogen peroxide, the fluorescence of the Cu nanoclusters is quenched. Similarly, glucose oxidase catalyzes the oxidation of glucose to gluconic acid and H2O2, so we can also use this probe to detect glucose. Because of the high zymolyte specificity of glucose oxidase, the detection of glucose has good selectivity. Under the optimized experimental conditions, the linear ranges for H2O2 and glucose are 0.5-10 MUM and 10-100 MUM, respectively. And the detection limits for H2O2 and glucose are 0.4 and 8 MUM, respectively. Furthermore, we discussed the mechanism of fluorescence quenching which is caused by the interaction between H2O2 and Cu nanoclusters. This sensing system has been applied successfully to the detection of glucose in human serum samples. PMID- 24055682 TI - Cutinase: characteristics, preparation, and application. AB - Cutinases (E.C. 3.1.1.74) belong to the alpha/beta-hydrolase superfamily. They were initially discovered because they are secreted by fungi to hydrolyze the ester bonds of the plant polymer cutin. Since then, they have been shown to catalyze the hydrolysis of a variety of polymers, insoluble triacylglycerols, and low-molecular-weight soluble esters. Cutinases are also capable of catalyzing esterification and transesterification reactions. These relatively small, versatile, secreted catalysts have shown promise in a number of industrial applications. This review begins by describing the characteristics of cutinases, pointing out key differences among cutinases, esterases and lipases, and reviewing recent progress in engineering improved cutinases. It continues with a review of the methods used to produce cutinases, with the goal of obtaining sufficient quantities of material for use in industrial processes. Finally, the uses of cutinases in the textile industry are described. The studies presented here demonstrate that the cutinases are poised to become important industrial catalysts, replacing older technologies with more environmentally friendly processes. PMID- 24055681 TI - The effects of venlafaxine and cognitive behavioral therapy alone and combined in the treatment of co-morbid alcohol use-anxiety disorders. AB - The effects of the antidepressant venlafaxine (VEN-225 mg daily) and transdiagnostic cognitive behavioral treatment (CBT) alone and in combination on alcohol intake in subjects with co-morbid alcohol use disorders (AUDs) and anxiety disorders were compared. Drinking outcomes and anxiety were assessed for 81 subjects treated for 11 weeks with one of 4 conditions: 1) VEN-CBT, 2) VEN Progressive Muscle Relaxation therapy (PMR), 3) Placebo (PLC)-CBT and 4) a comparison group of PLC-PMR. For subjects who reported taking at least one dose of study medication, the Time*Group interaction was significant for percent days of heavy drinking and drinks consumed per day. For the measure of percent days heavy drinking, the paired comparison of PLC-CBT versus PLC-PMR group indicated that the PLC-CBT group had greater drinking reductions, whereas other groups were not superior to the comparison group. In Week 11, the proportion of subjects in the PLC-CBT group that had a 50% reduction from baseline in percent days heavy drinking was significantly greater than those in the comparison group. Of the 3 "active treatment" groups only the PLC-CBT group had significantly decreased heavy drinking when contrasted to the comparison group. This finding suggests that the transdiagnostic CBT approach of Barlow and colleagues may have value in the management of heavy drinking in individuals with co-morbid alcoholism and anxiety. PMID- 24055683 TI - Opiate exposure and withdrawal dynamically regulate mRNA expression in the serotonergic dorsal raphe nucleus. AB - Previous results from our lab suggest that hypofunctioning of the serotonergic (5 HT) dorsal raphe nucleus (DRN) is involved in stress-induced opiate reinstatement. To further investigate the effects of morphine dependence and withdrawal on the 5-HT DRN system, we measured gene expression at the level of mRNA in the DRN during a model of morphine dependence, withdrawal and post withdrawal stress exposure in rats. Morphine pellets were implanted for 72h and then either removed or animals were injected with naloxone to produce spontaneous or precipitated withdrawal, respectively. Animals exposed to these conditions exhibited withdrawal symptoms including weight loss, wet dog shakes and jumping behavior. Gene expression for brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB), corticotrophin releasing-factor (CRF)-R1, CRF-R2, alpha 1 subunit of the GABAA receptor (GABAA-alpha1), MU-opioid receptor (MOR), 5-HT1A receptor, tryptophan hydroxylase2 (TPH2) and the 5-HT transporter was then measured using quantitative real-time polymerase chain reaction at multiple time points across the model of morphine exposure, withdrawal and post withdrawal stress. Expression levels of BDNF, TrkB and CRF-R1 mRNA were decreased during both morphine exposure and following 7days of withdrawal. CRF-R2 mRNA expression was elevated after 7days of withdrawal. 5-HT1A receptor mRNA expression was decreased following 3h of morphine exposure, while TPH2 mRNA expression was decreased after 7days of withdrawal with swim stress. There were no changes in the expression of GABAA-alpha1, MOR or 5-HT transporter mRNA. Collectively these results suggest that alterations in neurotrophin support, CRF-dependent stress signaling, 5-HT synthesis and release may underlie 5-HT DRN hypofunction that can potentially lead to stress-induced opiate relapse. PMID- 24055684 TI - Synaptic deficits in layer 5 neurons precede overt structural decay in 5xFAD mice. AB - Synaptic decay and neurodegeneration are hallmarks of Alzheimer's disease that are thought to precede dementia. Recently, we have reported that the first signs of neuritic dystrophy in a new transgenic mouse model of familial Alzheimer's disease (FAD) called the "5xFAD" are axonal dystrophy followed by loss of spines on basal dendrites. The 5xFAD mouse has profound loss of layer 5 neurons by 12months, and these initial structural insults appear between 4 and 6months of age. Here, we test, for the first time, if synaptic failure of layer 5 neurons in the 5xFAD mouse precedes these structural changes. We used longitudinal, in vivo two-photon fluorescence imaging of bigenic 5xFAD/YFP mice to assess the overall structural stability of layer 5 neurons in young mice (age less than 14weeks). We found these neurons to be structurally and morphologically sound. In parallel, we used in vitro, whole-cell patch clamp electrophysiology of layer 5 pyramidal neurons, from mice aged 8-12weeks, to reveal significant pre- and postsynaptic defects in these cells. Thus our data suggest that layer 5 neurons in the 5xFAD mouse model have synaptic deficits at an early time point, before any overt structural dystrophy, and that such synaptic failure, with co-temporal biochemical changes, may be an early step in neuronal loss. PMID- 24055685 TI - Synergy effects of HbA1c and variants of APOE and BDNFVal66Met explains individual differences in memory performance. AB - We aimed at exploring if synergy effects of Brain-Derived Neurotrophic Factor (BDNF) Val(66)Met, Apolipoprotein E (APOE) and HbA1c (glycated haemoglobin) could explain individual differences in memory performance over 10 years in a population based sample of nondemented adults (N=888, 35-85 years at baseline). Episodic memory was affected by such agents, wheras semantic memory was spared. Both age and HbA1c were associated with episodic memory decline. BDNF(66)Met carriers with higher HbA1c levels evidenced slope decline in episodic recall. We found support for joint effects of BDNFVal(66)Met*APOE*HbA1c and BDNFVal(66)Met*APOE*age on rates of episodic memory change over ten years, after controlling for age, sex, education and cardiovascular diseases. We conclude that variants of genetic polymorphisms act in synergy with long-term blood glucose control in shaping patterns of cognitive aging. PMID- 24055686 TI - Co-activation of NR2A and NR2B subunits induces resistance to fear extinction. AB - Unpredictable stress is known to profoundly enhance susceptibility to fear and anxiety while reducing the ability to extinguish fear when threat is no longer present. Accordingly, partial aversive reinforcement, via random exposure to footshocks, induces fear that is resistant to extinction. Here we sought to determine the hippocampal mechanisms underlying susceptibility versus resistance to context fear extinction as a result of continuous (CR) and partial (PR) reinforcement, respectively. We focused on N-methyl-D-aspartate receptor (NMDAR) subunits 2A and B (NR2A and NR2B) as well as their downstream signaling effector, extracellular signal-regulated kinase (ERK), based on their critical role in the acquisition and extinction of fear. Pharmacological inactivation of NR2A, but not NR2B, blocked extinction after CR, whereas inactivation of NR2A, NR2B, or both subunits facilitated extinction after PR. The latter finding suggests that co activation of NR2A and NR2B contributes to persistent fear following PR. In contrast to CR, PR increased membrane levels of ERK and NR2 subunits after the conditioning and extinction sessions, respectively. In parallel, nuclear activation of ERK was significantly reduced after the extinction session. Thus, co-activation and increased surface expression of NR2A and NR2B, possibly mediated by ERK, may cause persistent fear. These findings suggest that patients with post-traumatic stress disorder (PTSD) may benefit from antagonism of specific NR2 subunits. PMID- 24055687 TI - True but not false memories are associated with the HTR2A gene. AB - Previous research reported that serotonin receptor 2A gene (HTR2A) polymorphisms were associated with memory. However, it is unknown whether these genetic variants were associated with both true and false memories. The current study of 336 Han Chinese subjects tested 30 single nucleotide polymorphisms (SNPs) within the HTR2A gene for potential associations with true and false memories. False memories were assessed using the Deese-Roediger-McDermott (DRM) paradigm, in which people falsely remember semantically related (but unpresented) words. We found that 11 SNPs within the HTR2A gene were associated with true memory (p=0.000076-0.043). The associations between true memory and seven adjacent SNPs (i.e., rs1923888, rs1745837, rs9567739, rs3742279, rs655888, rs655854, and rs2296972) were still significant after multiple testing corrections. Haplotype based association analysis revealed that, true memory was positively associated with haplotype A-C-C-G-C-T-A for these seven adjacent SNPs (p=0.000075), which was still significant after multiple testing correction. Only one SNP rs655854 was associated with false memory (p=0.023), and it was not significant after multiple testing correction. This study replicates, in an Asian population, that genetic variation in HTR2A is associated with episodic memory, and also suggests that this association is restricted to true memory. PMID- 24055688 TI - In vitro/in vivo characterization of nanocrystalline formulation of tranilast with improved dissolution and hepatoprotective properties. AB - The present study was undertaken to develop a nanocrystalline formulation of tranilast (NC/TL), an acidic anti-inflammatory agent, with the aim of improving its biopharmaceutical and hepatoprotective properties. NC/TL was prepared by wet mill technology, and its physicochemical properties were characterized in terms of morphology, crystallinity, particle size distribution, stability and dissolution. Even after the storage of NC/TL for 8 weeks under accelerated conditions, there were no significant transitions in the crystalline form, crystallinity and particle size distribution of wet-milled TL. The nanosized TL particles could be immediately dispersed when the NC/TL was introduced into aqueous medium, and the NC/TL exhibited significant improvement in the dissolution behavior even under acidic conditions, compared with crystalline TL and a physical mixture of TL and polymer (PM/TL). The hepatoprotective effects of orally dosed TL formulations were evaluated in a carbon tetrachloride (CCl4) treated rat model of acute liver injury. In a rat model of acute liver injury, repeated treatment with NC/TL (2 mg TL/kg) every 12h led to marked attenuation of hepatic damage as evidenced by decreases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and total reactive oxygen species levels. However, PM/TL was found to be less effective, and the difference in efficacy between NC/TL and PM/TL should be attributable to the highly enhanced dissolution behavior of NC/TL. Strategic application of NC formulation technology might be an efficacious approach for enhancing the therapeutic potential of TL to treat liver dysfunction. PMID- 24055689 TI - Real-time in vivo imaging of surface-modified liposomes to evaluate their behavior after pulmonary administration. AB - Our previous study demonstrated that surface modification of liposomes using polyvinyl alcohol with a hydrophobic anchor (PVA-R) achieved sustained absorption from the lung after pulmonary administration and prolonged the pharmacological effects of the model peptide drug. In the present study, the behavior of PVA-R modified liposomes in the lung and whole body was monitored using a real-time in vivo imaging system. Subsequently, the influence of surface modification with PVA R on liposomal behavior in lung tissue was examined. Indocyanine green (ICG) was used as a near-infrared label of PVA-R-modified liposomes and was used to observe their dynamic behavior using non-invasive in vivo imaging (IVIS(r) imaging system) after pulmonary administration to rats. PVA-R-modified submicron-sized liposomes (ssLips) induced long-term retention in the lung compared with unmodified liposomes. Moreover, liposome association with alveolar macrophages (NR8383) was decreased by PVA-R modification in vitro. Therefore, PVA-R modification may prevent rapid elimination of ssLips by macrophages, thereby increasing retention in the lung. PMID- 24055690 TI - Superparamagnetic iron oxide nanoparticles (SPIONs)-loaded Trojan microparticles for targeted aerosol delivery to the lung. AB - Targeted aerosol delivery to specific regions of the lung may improve therapeutic efficiency and minimise unwanted side effects. Targeted delivery could potentially be achieved with porous microparticles loaded with superparamagnetic iron oxide nanoparticles (SPIONs)-in combination with a target-directed magnetic gradient field. The aim of this study was to formulate and evaluate the aerodynamic properties of SPIONs-loaded Trojan microparticles after delivery from a dry powder inhaler. Microparticles made of SPIONs, PEG and hydroxypropyl-beta cyclodextrin (HPbetaCD) were formulated by spray drying and characterised by various physicochemical methods. Aerodynamic properties were evaluated using a next generation cascade impactor (NGI), with or without a magnet positioned at stage 2. Mixing appropriate proportions of SPIONs, PEG and HPbetaCD allowed Trojan microparticle to be formulated. These particles had a median geometric diameter of 2.8+/-0.3MUm and were shown to be sensitive to the magnetic field induced by a magnet having a maximum energy product of 413.8kJ/m(3). However, these particles, characterised by a mass median aerodynamic diameter (MMAD) of 10.2+/-2.0MUm, were considered to be not inhalable. The poor aerodynamic properties resulted from aggregation of the particles. The addition of (NH4)2CO3 and magnesium stearate (MgST) to the formulation improved the aerodynamic properties of the Trojan particles and resulted in a MMAD of 2.2+/-0.8MUm. In the presence of a magnetic field on stage 2 of the NGI, the amount of particles deposited at this stage increased 4-fold from 4.8+/-0.7% to 19.5+/-3.3%. These Trojan particles appeared highly sensitive to the magnetic field and their deposition on most of the stages of the NGI was changed in the presence compared to the absence of the magnet. If loaded with a pharmaceutical active ingredient, these particles may be useful for treating localised lung disease such as cancer nodules or bacterial infectious foci. PMID- 24055691 TI - Subretinal transfection of chitosan-loaded TLR3-siRNA for the treatment of experimental autoimmune uveitis. AB - The local interaction between retinal pigment epithelium (RPE) and immigrated effector T cells is crucial for the pathogenesis of autoimmune uveitis. After being activated by the pattern recognition receptors (PRRs) signaling pathway, RPE can present the antigen reactivated invading autoreactive T cells, resulting in uveitis. In the present study, we showed that the transfection of chitosan loaded TLR3-siRNA toward RPE could effectively remit experimental autoimmune uveitis (EAU) in B10RIII mice. Initially, we verified the constitutive expression of Tlr3 in RPE at high levels, which was not altered in response to TNFalpha, IFNgamma and IL-17A treatments. Compared with other TLRs, the activation of TLR3 signaling following polyIC treatment resulted in increased IL-6 and IFNgamma secretion from and MHCII expression on RPE. It is polyIC-, but not other TLR ligands, treated RPE showed significant synergetic effect with IL-17 on stimulating RPE secreting CXCL8 and CCl2, which might be resulted from elevated Il17ra expression in RPE following polyIC treatment. Furthermore, polyIC-treated RPE caused a robust stimulation of differentiation of CD4 cell toward Th1 or Th17 cells, in addition to the secretion of the cytokines IFNgamma and IL-17. The in vitro knockdown of TLR3 expression in RPE by chitosan/TLR3-siRNA transfection could effectively block polyIC-induced MHCII expression, pro-inflammatory cytokine secretion and autoreactive CD4 cell activation. Studies conducted in firefly luciferase gene transgenic mice demonstrated that the subretinal CS/Luci siRNA transfection specifically reduced the luciferase activity in RPE but not in the liver and spleen. Finally, the CS/TLR3-siRNA was locally administered in the EAU induced B10RIII mice. The results revealed that chitosan-mediated TLR3-siRNA transfection had a significant therapeutic effect on either delaying the outbreak or remitting the severity of uveitis. PMID- 24055692 TI - PTPN22 profile indicates a novel risk group in Alopecia areata. AB - Alopecia areata (AA) is a genetically determined autoimmune hair loss disorder. A polymorphism in protein tyrosine phosphatase N22 (PTPN22), which normally suppresses T-cell proliferation, has been associated with human autoimmune disease, including AA in European populations. PTPN22 genotype frequency in known to vary geographically. Accordingly, we conducted a case-control study of the PTPN22 1858C/1858T (C1858T) genotype frequency in North American Caucasians and non-Caucasians. Allele status was determined in 365 AA patients, 196 healthy related control subjects (RC) and 77 unrelated healthy control subjects (UrC). We found that AA patients are more likely to carry the PTPN22 C1858T genotype than UrCs (p = 0.075), and this association reached significance in patients with the most severe disease presentation (Alopecia universalis vs. UrC, p = 0.024). PTPN22 C1858T genotype frequency in RC did not differ from AA patients (p = 0.657), but was significantly increased in comparison with UrC (p = 0.050). PTPN22 1858C/T genotype frequency increased in related control subjects most closely associated with patients (one family members of AA patients vs. UrC subjects, p = 0.040). Our data suggests that AA patients (particularly those that are severely affected) and closely related control subjects may belong to a shared inheritance group with increased disease risk, distinct from secondary and tertiary relatives and unrelated individuals. These findings have implications for the study of candidate genes and susceptibility to AA that may influence future clinical monitoring of unaffected, but closely related family members of patients. PMID- 24055693 TI - Chitin enhances obese inflammation ex vivo. AB - Infection has been implicated as a co-risk factor for obesity, but the mechanism remains uncertain. Elevated levels of plasma chitinase 3-like 1 (CHI3L1) are found in obese individuals. Since CHI3L1 is produced by activated immune cells including macrophages and recognizes microbial N-acetylglucosamine polymer (chitin), we asked whether the plasma CHI3L1 protein change in obese individuals might alter their innate immune response to chitin. Thirty-six subjects (15 obese and 21 non-obese), ages 18-30 years, were recruited. Peripheral blood mononuclear cells (PBMCs) were cultured with chitin microparticles (CMP; 1-10 MUm) for 24h; tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and CHI3L1 in the culture supernatants were measured. We chose CMP, since neither large chitin beads (40-100 MUm), chitosan microparticles (1-10 MUm), nor soluble chitin induced the cytokine/CHI3L1 production by PBMCs isolated from non-obese PBMCs ex vivo. We found that the quantity of IL-6, but not TNF-alpha or CHI3L1, induced by CMP was significantly correlated with plasma IL-6, BMI, waist/hip circumferences, fasting plasma insulin, and insulin resistance. These findings suggest that chitin, a substrate of CHI3L1, further promotes obese inflammation in a size- and chemical composition- dependent manner. PMID- 24055694 TI - Early post-transplant immune monitoring can predict long-term kidney graft survival: soluble CD30 levels, anti-HLA antibodies and IgA-anti-Fab autoantibodies. AB - This study aimed to investigate the predictive power of anti-HLA antibodies, sCD30 levels and IgA-anti-Fab autoantibody before and early after transplantation in relation to long-term kidney allograft survival. Pre- and post-transplant sera samples of 59 living-unrelated donor kidney recipients were tested for above risk factors by enzyme-linked immunoabsorbent assay. 15 out of 59 cases experienced rejection episodes (failure group). Pre- and post-transplant high sCD30 levels were significantly associated with graft failure (P=0.02 and P=0.004) and decreased 4 year graft survival (P = 0.009 and P = 0.001). Higher frequency of post-transplant HLA class-II antibody in the absence of class-I antibody was observed in failure group (P=0.007). Patients with post-transplant HLA class-I and class-II antibodies either alone or in combination showed significant lower 4 year graft survival. Recipients with high sCD30 levels in the presence of HLA class-I or class-II antibodies within 2 weeks post-transplant had poor graft survival (P = 0.004 and P = 0.002, respectively). High levels of post-transplant IgA-anti-Fab antibody was more frequent in functioning-graft patients (P = 0.00001), correlated with decreased serum creatinine levels (P = 0.01) and associated with improved graft survival (P = 0.008). Our findings indicate the deleterious effect of early post-transplant HLA antibodies and increased sCD30 levels dependently and protective effect of IgA-anti-Fab antibodies on long-term renal graft outcomes. PMID- 24055695 TI - Genetic profile of KIR and HLA in southern Chinese Han population. AB - KIR and their HLA ligands are encoded by two of the most diverse gene families in the human genome. The function of KIR on the NK cell is highly dependent on the normal expression of class I HLA on the target cell. Previous population studies in southern Chinese have been focused on the KIR framework genes and genotypes but little is known about the compound profiles of KIR/HLA. The present study examined 503 unrelated individuals from southern Chinese Han population for the polymorphism of KIR and class I HLA genes. All 16 KIR genes were detected in the study population and the four framework genes KIR3DL2, 3DL3, 3DP1, and 2DL4 were present in all individuals. Thirty unique KIR gene profiles were found reflecting a rather limited number of KIR haplotypes in this population. KIRAA1 was the most common profile observed in 54.7% of the samples. Among the AA1 individuals, 15.6% were homozygous for the deleted KIR2DS4. Haplotype A (74.8%) was more common than haplotype B (25.2%). HLA-C1 was a much more common ligand for 2D KIRs than C2. Bw4-80I, Bw4-80T, and the Bw4-bearing HLA-A alleles were detected at similar frequencies. The matched KIR+HLA pairs 2DL2/3+C1 (98.1%), 3DL1+Bw4 (73.3%), 3DL2+A3/11 (60.0%) were the most common ones whereas 3DS1+Bw4-80I was the least common (9.4%). A total of 193 unique compound profiles of KIR-HLA were identified in 480 informative individuals, 130 of the profiles being detected only once. The study provided a comprehensive analysis of the KIR/HLA profiles in southern Chinese in regards of the presence/absence of KIR genes, HLA ligands, matched KIR+HLA pairs, and KIR/HLA compound profiles. The results could help to better understand the role played by KIR/HLA interaction in associated diseases and clinical transplantation in southern Chinese. PMID- 24055696 TI - T Allele of nonsense polymorphism (rs2039381, Gln71Stop) of interferon-epsilon is a risk factor for the development of intracerebral hemorrhage. AB - Interferons (IFNs) play key roles in various biologic responses including antiviral and immune reactions. We evaluated one possible risk factor in nonsense polymorphism (rs2039381, Gln71Stop) of interferon-epsilon (IFNE). We recruited stroke [119 ischemic stroke (IS) and 145 intracerebral hemorrhage (ICH)] and control (401), respectively. The nonsense SNP (rs2039381, Gln71Stop) of IFNE was selected. We identified individual genotype using sequencing. SNPStats and SPSS 18.0 programs were used to analyze genetic data. Genotype frequencies (C/C:C/T:T/T) in the ICH group and control group were 59.3:37.9:2.8 and 73.6:23.4:3.0, respectively. We found that rs2039381 was associated with ICH (OR = 2.01, 95% CI = 1.33-3.03, p = 0.001 in codominant1 model; OR = 1.91, 95% CI = 1.28-2.84, p = 0.0016 in dominant model; OR = 1.60, 95% CI = 1.14-2.26, p = 0.0074 in log-additive model). T allele frequency of rs2039381 was significantly higher in ICH than in controls. The nonsense SNP (rs2039381, Gln71Stop) of IFNE was associated with ICH (OR = 1.61, 95% CI = 1.14-2.26, p = 0.006). A nonsense SNP (rs2039381, Gln71Stop) of IFNE was associated with ICH in Korean population. Our findings raise the possibility that the T allele of rs2039381 is a risk factor which is susceptible to ICH. PMID- 24055697 TI - Associations between interleukin 1 polymorphisms and susceptibility to systemic lupus erythematosus: a meta-analysis. AB - OBJECTIVE: This study determined whether interleukin 1 (IL1) polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE). METHODS: A meta-analysis was conducted on the associations between the IL1A, IL1B, and IL1 receptor antagonist (IL1RN) polymorphisms and SLE. RESULTS: A total of 15 studies involving 1956 SLE cases and 2347 controls were included in the meta-analysis. The meta-analysis showed an association between SLE and the IL1A -889 T allele in the overall population and Europeans (OR = 0.858, 95% CI = 0.737-0.986, p = 0.032; OR = 0.827, 95% CI = 0.687-0.994, p = 0.043). Meta-analysis of the IL1RN polymorphism revealed an association with SLE in all study subjects (OR for IL1RN*2 = 1.539, 95% CI = 1.266-1.871, p = 1.5 * 10(-2)) and in Europeans and Asians (OR = 1.483, 95% CI = 1.187-1.852, p = 0.001; OR = 1.787, 95% CI = 1.167 2.736, p=0.008). No associations were found between SLE and the IL1B -511 C/T, 3953 C/T, and IL1A +4845 G/T polymorphisms. CONCLUSIONS: This meta-analysis suggests IL1A -889 C/T polymorphism is associated with susceptibility to SLE in Europeans, and that the IL1RN*2 allele is associated with susceptibility to SLE in Europeans and Asians. PMID- 24055698 TI - Radiation synthesis of multifunctional polymeric hydrogels for oral delivery of insulin. AB - Polyelectrolyte crosslinked hydrogel was synthesized using gamma radiation induced copolymerization of methacrylic acid (MAA), N,N-dimethyl aminoethyl methacrylate (DMAEMA) in aqueous solution to utilize for oral delivery of insulin. The influence of copolymer composition and pH value of the surrounding medium on the type of water diffusion in the glassy polymer was discussed. In addition, the swelling kinetics tests on MAA/DMAEMA (90/10) reveal that the swelling kinetics of the proposed hydrogel follows a Fickian diffusion process in media of pH 5, and an anomalous diffusion process in media of pH 1.5 and 7.2. The cross-linked three-dimensional polymers were characterized by scanning electron microscopy and FT-IR. In the matrices with increase in the content of MAA had shown increased bioadhesivity. Insulin was entrapped in these gels and the in vitro release profiles were established separately in both (SGF, pH 1.5) and (SIF, pH 7.2). The release profile of insulin showed negligible release in acidic media (SGF, pH 1.5) and sustained release in simulated intestinal fluid (SIF, pH 7.2). Drug release studies showed that the increasing content of MAA in the copolymer enhances release in SIF to design and improve insulin release behavior from these carriers. PMID- 24055699 TI - Subunit dynamics and nucleotide-dependent asymmetry of an AAA(+) transcription complex. AB - Bacterial enhancer binding proteins (bEBPs) are transcription activators that belong to the AAA(+) protein family. They form higher-order self-assemblies to regulate transcription initiation at stress response and pathogenic promoters. The precise mechanism by which these ATPases utilize ATP binding and hydrolysis energy to remodel their substrates remains unclear. Here we employed mass spectrometry of intact complexes to investigate subunit dynamics and nucleotide occupancy of the AAA(+) domain of one well-studied bEBP in complex with its substrate, the sigma(54) subunit of RNA polymerase. Our results demonstrate that the free AAA(+) domain undergoes significant changes in oligomeric states and nucleotide occupancy upon sigma(54) binding. Such changes likely correlate with one transition state of ATP and are associated with an open spiral ring formation that is vital for asymmetric subunit function and interface communication. We confirmed that the asymmetric subunit functionality persists for open promoter complex formation using single-chain forms of bEBP lacking the full complement of intact ATP hydrolysis sites. Outcomes reconcile low- and high-resolution structures and yield a partial sequential ATP hydrolysis model for bEBPs. PMID- 24055700 TI - Bioanalytical method for evaluating the pharmacokinetics of the GCP-II inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA). AB - 2-Phosphonomethyl pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II, an enzyme which catabolizes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to N-acetylaspartate (NAA) and glutamate. 2-PMPA demonstrates robust efficacy in numerous animal models of neurological disease, however its pharmacokinetics has not yet been fully described. 2-PMPA is a highly polar compound with multiple negative charges causing significant challenges for analysis in biological matrices. Here we report a derivatization method for the acidic groups that involved protein precipitation with acetonitrile followed by reaction with N-tert butyldimethysilyl-N-methyltrifluoroacetamide (MTBSTFA). The silylated analyte with transitions (683->551.4) and the internal standard (669->537.2) were monitored by tandem mass spectrometry with electrospray positive ionization mode. The method was subsequently used to evaluate 2-PMPA pharmacokinetics in rats. Intraperitoneal administration of 100mg/kg 2-PMPA resulted in maximum concentration in plasma of 275MUg/mL at 0.25h. The half-life, area under the curve, apparent clearance, and volume of distribution were 0.64h, 210MUg*h/mL, 7.93mL/min/kg, and 0.44L/kg, respectively. The tissue/plasma ratios in brain, sciatic nerve and dorsal root ganglion were 0.018, 0.120 and 0.142, respectively. In summary, a sensitive analytical method for 2-PMPA is reported that can be employed for similarly charged molecules. PMID- 24055701 TI - Characterization of the isomeric configuration and impurities of (Z)-endoxifen by 2D NMR, high resolution LC?MS, and quantitative HPLC analysis. AB - (Z)-Endoxifen (4-hydroxy-N-desmethyltamoxifen), an active metabolite generated via actions of CYP3A4/5 and CYP2D6, is a more potent selective estrogen receptor modulator (SERM) than tamoxifen. In the MCF-7 human mammary tumor xenograft model with female athymic mice, (Z)-endoxifen, at an oral dose of 4?8 mg/kg, significantly inhibits tumor growth. (Z)-Endoxifen's potential as an alternative therapeutic agent independent of CYP2D6 activities, which can vary widely in ER+ breast cancer patients, is being actively evaluated. This paper describes confirmation of the configuration of the active (Z)-isomer through 2D NMR experiments, including NOE (ROESY) to establish spatial proton?proton correlations, and identification of the major impurity as the (E)-isomer in endoxifen drug substance by HPLC/HRMS (HPLC/MS-TOF). Stability of NMR solutions was confirmed by HPLC/UV analysis. For pre-clinical studies, a reverse-phase HPLC?UV method, with methanol/water mobile phases containing 10 mM ammonium formate at pH 4.3, was developed and validated for the accurate quantitation and impurity profiling of drug substance and drug product. Validation included demonstration of linearity, method precision, accuracy, and specificity in the presence of impurities, excipients (for the drug product), and degradation products. Ruggedness and reproducibility of the method were confirmed by collaborative studies between two independent laboratories. The method is being applied for quality control of the API and oral drug product. Kinetic parameters of Z- to E-isomerization were also delineated in drug substance and in aqueous formulation, showing conversion at temperatures above 25 degrees C. PMID- 24055702 TI - Non-Gaussian probabilistic MEG source localisation based on kernel density estimation. AB - There is strong evidence to suggest that data recorded from magnetoencephalography (MEG) follows a non-Gaussian distribution. However, existing standard methods for source localisation model the data using only second order statistics, and therefore use the inherent assumption of a Gaussian distribution. In this paper, we present a new general method for non-Gaussian source estimation of stationary signals for localising brain activity from MEG data. By providing a Bayesian formulation for MEG source localisation, we show that the source probability density function (pdf), which is not necessarily Gaussian, can be estimated using multivariate kernel density estimators. In the case of Gaussian data, the solution of the method is equivalent to that of widely used linearly constrained minimum variance (LCMV) beamformer. The method is also extended to handle data with highly correlated sources using the marginal distribution of the estimated joint distribution, which, in the case of Gaussian measurements, corresponds to the null-beamformer. The proposed non-Gaussian source localisation approach is shown to give better spatial estimates than the LCMV beamformer, both in simulations incorporating non-Gaussian signals, and in real MEG measurements of auditory and visual evoked responses, where the highly correlated sources are known to be difficult to estimate. PMID- 24055703 TI - Impact of partial volume effect correction on cerebral beta-amyloid imaging in APP-Swe mice using [(18)F]-florbetaben PET. AB - We previously investigated the progression of beta-amyloid deposition in brain of mice over-expressing amyloid-precursor protein (APP-Swe), a model of Alzheimer's disease (AD), in a longitudinal PET study with the novel beta-amyloid tracer [(18)F]-florbetaben. There were certain discrepancies between PET and autoradiographic findings, which seemed to arise from partial volume effects (PVE). Since this phenomenon can lead to bias, most especially in the quantitation of brain microPET studies of mice, we aimed in the present study to investigate the magnitude of PVE on [(18)F]-florbetaben quantitation in murine brain, and to establish and validate a useful correction method (PVEC). Phantom studies with solutions of known radioactivity concentration were performed to measure the full-width-at-half-maximum (FWHM) resolution of the Siemens Inveon DPET and to validate a volume-of-interest (VOI)-based PVEC algorithm. Several VOI brain-masks were applied to perform in vivo PVEC on [(18)F]-florbetaben data from C57BL/6(N=6) mice, while uncorrected and PVE-corrected data were cross-validated with gamma counting and autoradiography. Next, PVEC was performed on longitudinal PET data set consisting of 43 PET scans in APP-Swe (13-20months) and age-matched wild-type (WT) mice using the previously defined masks. VOI-based cortex-to cerebellum ratios (SUVR) were compared for uncorrected and PVE-corrected results. Brains from a subset of transgenic mice were ultimately examined by autoradiography ex vivo and histochemistry in vitro as gold standard assessments, and compared to VOI-based PET results. The phantom study indicated a FWHM of 1.72mm. Applying a VOI-brain-mask including extracerebral regions gave robust PVEC, with increased precision of the SUVR results. Cortical SUVR increased with age in APP-Swe mice compared to baseline measurements (16months: +5.5%, p<0.005; 20months: +15.5%, p<0.05) with uncorrected data, and to a substantially greater extent with PVEC (16months: +12.2% p<0.005; 20months: +36.4% p<0.05). WT animals showed no binding changes, irrespective of PVEC. Relative to autoradiographic results, the error [%] for uncorrected cortical SUVR was 18.9% for native PET data, and declined to 4.8% upon PVEC, in high correlation with histochemistry results. We calculate that PVEC increases by 10% statistical power for detecting altered [(18)F]-florbetaben uptake in aging APP-Swe mice in planned studies of disease modifying treatments on amyloidogenesis. PMID- 24055704 TI - MEG source imaging method using fast L1 minimum-norm and its applications to signals with brain noise and human resting-state source amplitude images. AB - The present study developed a fast MEG source imaging technique based on Fast Vector-based Spatio-Temporal Analysis using a L1-minimum-norm (Fast-VESTAL) and then used the method to obtain the source amplitude images of resting-state magnetoencephalography (MEG) signals for different frequency bands. The Fast VESTAL technique consists of two steps. First, L1-minimum-norm MEG source images were obtained for the dominant spatial modes of sensor-waveform covariance matrix. Next, accurate source time-courses with millisecond temporal resolution were obtained using an inverse operator constructed from the spatial source images of Step 1. Using simulations, Fast-VESTAL's performance was assessed for its 1) ability to localize multiple correlated sources; 2) ability to faithfully recover source time-courses; 3) robustness to different SNR conditions including SNR with negative dB levels; 4) capability to handle correlated brain noise; and 5) statistical maps of MEG source images. An objective pre-whitening method was also developed and integrated with Fast-VESTAL to remove correlated brain noise. Fast-VESTAL's performance was then examined in the analysis of human median-nerve MEG responses. The results demonstrated that this method easily distinguished sources in the entire somatosensory network. Next, Fast-VESTAL was applied to obtain the first whole-head MEG source-amplitude images from resting-state signals in 41 healthy control subjects, for all standard frequency bands. Comparisons between resting-state MEG sources images and known neurophysiology were provided. Additionally, in simulations and cases with MEG human responses, the results obtained from using conventional beamformer technique were compared with those from Fast-VESTAL, which highlighted the beamformer's problems of signal leaking and distorted source time-courses. PMID- 24055705 TI - Detecting resting-state brain activity by spontaneous cerebral blood volume fluctuations using whole brain vascular space occupancy imaging. AB - Resting-state brain activity has been investigated extensively using BOLD contrast. However, BOLD signal represents the combined effects of multiple physiological processes and its spatial localization is less accurate than that of cerebral blood flow and volume (CBF and CBF, respectively). In this study, we demonstrate that resting-state brain activity can be reliably detected by spontaneous fluctuations of CBV-weighted signal using whole-brain gradient and spin echo (GRASE) based vascular space occupancy (VASO) imaging. Specifically, using independent component analysis, intrinsic brain networks, including default mode, salience, executive control, visual, auditory, and sensorimotor networks were revealed robustly by the VASO technique. We further demonstrate that task evoked VASO signal aligned well with expected gray matter areas, while blood oxygenation level dependent (BOLD) signal extended outside of these areas probably due to their different spatial specificity. The improved spatial localization of VASO is consistent with previous studies using animal models. Moreover, we showed that the 3D-GRASE VASO images had reduced susceptibility induced signal voiding, compared to the BOLD technique. This is attributed to the fact that VASO does not require T2* weighting, thus the acquisition can use a shorter TE and can employ spin-echo scheme. Consequently VASO-based functional connectivity signals were well preserved in brain regions that tend to suffer from signal loss and geometric distortion in BOLD, such as orbital prefrontal cortex. Our study suggests that 3D-GRASE VASO imaging, with its improved spatial specificity and less sensitivity to susceptibility artifacts, may have advantages in resting-state fMRI studies. PMID- 24055706 TI - Asymmetric packaging of polymerases within vesicular stomatitis virus. AB - Vesicular stomatitis virus (VSV) is a prototypic negative sense single-stranded RNA virus. The bullet-shape appearance of the virion results from tightly wound helical turns of the nucleoprotein encapsidated RNA template (N-RNA) around a central cavity. Transcription and replication require polymerase complexes, which include a catalytic subunit L and a template-binding subunit P. L and P are inferred to be in the cavity, however lacking direct observation, their exact position has remained unclear. Using super-resolution fluorescence imaging and atomic force microscopy (AFM) on single VSV virions, we show that L and P are packaged asymmetrically towards the blunt end of the virus. The number of L and P proteins varies between individual virions and they occupy 57 +/- 12 nm of the 150 nm central cavity of the virus. Our finding positions the polymerases at the opposite end of the genome with respect to the only transcriptional promoter. PMID- 24055707 TI - MiR-181b targets Six2 and inhibits the proliferation of metanephric mesenchymal cells in vitro. AB - MicroRNAs (miRNAs) are small non-coding RNAs that down-regulate gene expression by binding to target mRNA for cleavage or translational repression, and play important regulatory roles in renal development. Despite increasing genes have been predicted to be miRNA targets by bioinformatic analysis during kidney development, few of them have been verified by experiment. The objective of our study is to identify the miRNAs targeting Six2, a critical transcription factor that maintains the mesenchymal progenitor pool via self-renewal (proliferation) during renal development. We initially analyzed the 3'UTR of Six2 and found 37 binding sites targeted by 50 putative miRNAs in the 3'UTR of Six2. Among the 50 miRNAs, miR-181b is the miRNAs predicted by the three used websites. In our study, the results of luciferase reporter assay, realtime-PCR and Western blot demonstrated that miR-181b directly targeted on the 3'UTR of Six2 and down regulate the expression of Six2 at mRNA and protein levels. Furthermore, EdU proliferation assay along with the Six2 rescue strategy showed that miR-181b suppresses the proliferation of metanephric mesenchymal by targeting Six2 in part. In our research, we concluded that by targeting the transcription factor gene Six2, miR-181b inhibits the proliferation of metanephric mesenchymal cells in vitro and might play an important role in the formation of nephrons. PMID- 24055708 TI - 11beta-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes. AB - The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1). We recently reported that 11beta-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11beta-HSD1 in skin inflammation. Expression of 11beta-HSD1 was induced by UV-B irradiation and in response to the pro inflammatory cytokines, IL-1beta and TNFalpha. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11beta-HSD1 in response to pro-inflammatory cytokines, we knocked down 11beta-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1beta or TNFalpha stimulation was attenuated in NHEKs transfected with si11beta-HSD1 compared with control cells. In addition, IL-1beta-induced IL 6 production was enhanced in cultures containing 1 * 10(-13) M cortisol, whereas 1 * 10(-5) M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11beta-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations by 11beta HSD1 appears to modulate expression of inflammatory cytokines in NHEKs. PMID- 24055710 TI - Selective modulation of MHC class II chaperons by a novel IFN-gamma-inducible class II transactivator variant in lung adenocarcinoma A549 cells. AB - Class II transactivator (CIITA) plays a critical role in controlling major histocompatibility complex (MHC) class II gene expression. In this study, two novel alternatively spliced variants of human interferon (IFN)-gamma-inducible CIITA, one missing exon 7 (CIITADeltaE7), the other with TAG inserted at exon 4/5 junction (CIITA-TAG), were identified and characterized. Both variants are naturally occurring since they are present in primary cells. Unlike CIITA-TAG, CIITADeltaE7 is expressed more abundantly in lung adenocarcinoma A549 cells than in the non-transformed counterpart BEAS-2B cells following IFN-gamma stimulation. Transfection experiments showed that CIITADeltaE7 induced a markedly lower level of surface HLA-DR, -DP, -DQ expression than CIITA-TAG in A549 cells but not in BEAS-2B cells, although both variants elicited similar amounts of total DR, DP, and DQ proteins. This differential effect was correlated with, in A549 cells, decreased expression of Ii and HLA-DM genes, along with increased expression of HLA-DO genes. Ii and HLA-DM are chaperons assisting in HLA class II assembly, while HLA-DO functions to inhibit endosomal peptide loading and HLA class II membrane transport. These findings raise the possibility that CIITADeltaE7 interacts with unknown cancer-associated factors to selectively modulate genes involved in the assembly and transport of HLA class II molecules. PMID- 24055709 TI - TFEB activation promotes the recruitment of lysosomal glycohydrolases beta hexosaminidase and beta-galactosidase to the plasma membrane. AB - Lysosomes are membrane-enclosed organelles containing acid hydrolases. They mediate a variety of physiological processes, such as cellular clearance, lipid homeostasis, energy metabolism and pathogen defence. Lysosomes can secrete their content through a process called lysosome exocytosis in which lysosomes fuse with the plasma membrane realising their content into the extracellular milieu. Lysosomal exocytosis is not only responsible for the secretion of lysosomal enzymes, but it also has a crucial role in the plasma membrane repair. Recently, it has been demonstrated that lysosome response to the physiologic signals is regulated by the transcription factor EB (TFEB). In particular, lysosomal secretion is transcriptionally regulated by TFEB which induces both the docking and fusion of lysosomes with the plasma membrane. In this work we demonstrated that TFEB nuclear translocation is accompanied by an increase of mature glycohydrolases beta-hexosaminidase and beta-galactosidase on cell surface. This evidence contributes to elucidate an unknown TFEB biological function leading the lysosomal glycohydrolases on plasma membrane. PMID- 24055711 TI - The effect of visual therapy on the ocular motor control of seven- to eight-year old children with developmental coordination disorder (DCD). AB - The aims of this study were to determine the extent of ocular, motor control problems and the effect of visual therapy on such problems, among seven- to eight year-old children diagnosed with DCD. Thirty-two, children with a mean age of 95.66 months (SD +/- 3.54) participated in the study. The MABC was used to classify children into DCD categories (<15th, percentile) while the Sensory Input Systems Screening Test and QNST-II, were used to evaluate ocular motor control. A two-group pre-test-post-test, cross-over design was followed with a retention test two years, thereafter to determine the lasting effect of the visual therapy, intervention. The 18-week visual therapy programme was executed once a week, for 40 min during school hours, after which the two groups were, crossed over. Percentages of ocular motor control problems ranging, between 6.25% and 93.75% were found in both the groups before participating, in the visual therapy programme, with the highest percentage problems found, in visual pursuit with the left eye. Visual therapy contributed to a, significant improvement of 75-100% in visual pursuit, fixation, ocular, alignment and convergence, with significant lasting effects (p<0.001). Visual therapy is recommended for children with DCD experiencing poor, ocular motor control. PMID- 24055712 TI - Subjective well-being among family caregivers of individuals with developmental disabilities: the role of affiliate stigma and psychosocial moderating variables. AB - Studies have shown that stigmatization is linked to lower quality of life; however, only scant research has examined the association between family caregivers' internalization of stigma (affiliate stigma) and their subjective quality of life (subjective well-being, SWB). Furthermore, studies have rarely examined this association via comparison between caregivers of individuals with different developmental disabilities in addition to examining the influence of psychosocial protective factors. These were the aims of the current study. Family caregivers (N=176) of individuals with autism spectrum disorders (ASD), intellectual disabilities (ID), and physical disabilities (PD) completed a self report structured questionnaire including scales measuring SWB, affiliate stigma, burden, positive meaning in caregiving, social support and self-esteem. Results showed that SWB of family caregivers was below the average normative level and especially low for caregivers of individuals with ASD. The strongest predictors of SWB were caregivers' self-esteem, social support, positive meaning in caregiving, and affiliate stigma. Furthermore, an interaction was found between affiliate stigma and diagnosis, showing that among caregivers of individuals with ASD, greater levels of stigma were associated with lower ratings of SWB, whereas such an association was not found among caregivers of individuals with ID or PD. Findings from this study point to the importance of supporting caregivers across the life-span in order to decrease stigma, improve social support and self-esteem and improve SWB. Further, findings point to the need to respond differentially to the various developmental disabilities. PMID- 24055713 TI - Handwriting features of children with developmental coordination disorder- results of triangular evaluation. AB - Developmental coordination disorders (DCD) is one of the most common disorders affecting school-aged children. The study aimed to characterize the handwriting performance of children with DCD who write in Arabic, based on triangular evaluation. Participants included 58 children aged 11-12 years, 29 diagnosed with DCD based on the DSM-IV criteria and the M-ABC, and 29 matched typically developed controls. Children were asked to copy a paragraph on a sheet of paper affixed to a digitizer supplying objective measures of the handwriting process. The handwriting proficiency screening questionnaire (HPSQ) was completed by their teachers while observing their performance and followed by evaluation of their final written product. Results indicated that compared to controls, children with DCD required significantly more on-paper and in-air time per stroke while copying. In addition, global legibility, unrecognizable letters and spatial arrangement measures of their written product were significantly inferior. Significant group differences were also found between the HPSQ subscales scores. Furthermore, 82.8% of all participants were correctly classified into groups based on one discriminate function which included two handwriting performance measures. These study results strongly propose application of triangular standardized evaluation to receive better insight of handwriting deficit features of individual children with DCD who write in Arabic. PMID- 24055714 TI - Clinical burden and correlates of HIV and malaria co-infection, in northwest Nigeria. AB - The clinical burden of malaria and HIV/AIDS in sub-Saharan Africa is well described, but the dynamics of the interaction between the two diseases remain poorly understood. Using a cross-sectional study design, we assessed the prevalence and predictors of malaria infection among HIV-positive patients attending a referral center in urban Kano, northwest Nigeria. Structured questionnaires covering socio-demographic characteristics, HIV diagnosis and treatment, malaria preventive practices, clinical events and treatment were administered to HIV-infected adults (n=363). Information from questionnaires was supplemented with data from case notes. In the preceding year, nearly a third of respondents (32.2%; 95% CI=27.4-37.3) had at least one episode of fever, diagnosed as malaria on blood film examination. Half of all respondents (53.5%) admitted to using insecticide treated nets (ITN). One-third (35.8%) of participants were on malaria chemoprophylaxis at the time of the study. Female sex (adjusted Odds Ratio [aOR]=1.54, 95% confidence interval (CI): 1.32-2.73), immunosuppression (CD4+ cell count <350/MUL vs. 600/MUL, aOR=2.41, 95% CI 1.23 3.74) and non-use of ITN (aOR=1.97, 95% CI 1.17-2.85) predicted the occurrence of clinical malaria in patients. We report a high burden of malaria in HIV-infected patients attending a tertiary facility in urban Kano, Nigeria. Health communication, standardized protocols and ITN distribution should be integrated into comprehensive HIV programs in this setting. PMID- 24055715 TI - Protective actions of melatonin against heart damage during chronic Chagas disease. AB - Chronic cardiomyopathy is the most important clinical form of Chagas disease, and it is characterised by myocarditis that is associated with fibrosis and organ dysfunction. Alternative treatment options are important tools to modulate host immune responses. The main goal of this work was to evaluate the anti inflammatory actions of melatonin during the chronic phase of Chagas disease. TNF alpha, IL-10 and nitrite concentrations were evaluated as predictive factors of immune modulation. Creatine phosphokinase-MB (CK-MB), cardiac inflammatory foci and heart weight were assessed to evaluate the efficacy of the melatonin treatment. Male Wistar rats were infected with 1*10(5) blood trypomastigotes of the Y strain of Trypanosoma cruzi and kept untreated for 60 days to mimic chronic infection. After this period, the rats were orally treated with melatonin 50mg/kg/day, and the experiments were performed 90, 120, and 180 days post infection. Melatonin treatment significantly increased the concentration of IL-10 and reduced the concentrations of NO and TNF-alpha produced by cardiomyocytes. Furthermore, it led to decreased heart weight, serum CK-MB levels and inflammatory foci when compared to the untreated and infected control groups. We conclude that melatonin therapy is effective at protecting animals against the harmful cardiac inflammatory response that is characteristic of chronic T. cruzi infection. PMID- 24055716 TI - Improved performance and quantitative detection of copro-antigens by a monoclonal antibody based ELISA to diagnose human opisthorchiasis. AB - Copro-antigen detection has been advocated as a promising method for diagnosis of opisthorchiasis, particularly in people that harbored light infection or have had recent drug treatment. This study aimed to improve performance of a monoclonal antibody-based enzyme-linked immunosorbent assay (Mab-ELISA) for detection of Opisthorchis viverrini copro-antigen and assess the correlation between copro antigen and intensity of infection. Four different treatment methods of 71 samples from the Lawa endemic area, Khon Kaen province were assessed for copro antigen detection, namely (1) phosphate buffer saline (PBS), (2) heating (70 degrees C 30min), (3) alkaline (pH 9.6 in carbonate buffer), and (4) trichloroacetic acid (TCA) treatment. Comparison of these protocols showed that the TCA method gave the best performance in discriminating O. viverrini positive and negative samples with high sensitivity (97.9%) and moderate specificity (54.2%) compared with other methods. Application of TCA-based Mab-ELISA method for antigen detection in fecal samples obtained from an endemic area of opisthorchiasis revealed that 86 of 141 samples (61.0%) were positive compared with 68 (48.2%) by PBS-based protocol, while the formalin ethyl-acetate concentration technique (FECT) yielded a positive proportion of 71.6%. Among 40 egg-negative samples confirmed by a gold standard parasitological method (FECT) from the same endemic area, 19 (47.5%) were positive by the TCA-based while only 6 (15%) were positive by PBS-based Mab-ELISA protocol. In addition, levels of antigen detection significantly correlated with intensity of infection (egg per gram feces). The results show that the improved Mab-ELISA method has high sensitivity and also quantifiable diagnosis of opisthorchiasis. PMID- 24055717 TI - Prevalence of sulfadoxine-pyrimethamine resistance-associated mutations in dhfr and dhps genes of Plasmodium falciparum three years after SP withdrawal in Bahir Dar, Northwest Ethiopia. AB - Ethiopia changed the first-line anti-malarial drug for uncomplicated Plasmodium falciparum malaria from sulfadoxine-pyrimethamine (SP) to Coartem((r)) in 2004 following nation-wide assessment of the efficacy of both drugs in 2003. This study was conducted to assess the prevalence of sulfadoxine-pyrimethamine resistance-associated mutations in dhfr and dhps genes of P. falciparum three years after SP withdrawal in Bahir Dar, Northwest Ethiopia. A total of 165 blood spot samples were collected from patients infected with P. falciparum in Bahir Dar Health Center in 2005 (n=78) and 2008 (n=87) using Whatman (3M) filter papers. The three dhfr codons (dhfr108, dhfr 51 and dhfr 59) and the two dhps codons (dhfr 437 and 540) which are believed to determine SP resistance were detected by using nested PCR-based dot blot-hybridization technique. In dhfr, only the dhfr59Arg mutant-type showed statistically significant reduction from 80.3% in 2005 to 56.4% in 2008 (p<0.01) with a significant increase of the wild type dhfr59Cys haplotypes from 4.9% in 2005 to 29.5% in 2008 (p<0.01). The double mutants dhfr108Asn/51Ile were detected at rate of 98.4% in 2005 and 98.7% in 2008. A significant decrease in the triple dhfr (108Asn/51Ile/59Arg) mutation was observed from 2005 (78.6%) to 2008(56.4%) (p<0.01). The quadruple mutations of dhfr (108Asn/51Ile/59Arg)/dhps437Gly were significantly declined from 78.6% in 2005 to 53.8% in 2008 (p<0.01) while quintuple mutations (dhfr (108Asn/51Ile/59Arg)/dhps437Gly/dhps540Glu) showed a reduction from 60.6% to 37.2% after three years (p<0.01). In conclusion, the decline in the prevalence of dhfr/dhps combination mutations might indicate the re-emergence of sensitive parasites in the population following SP withdrawal. Therefore, further monitoring and assessment is important to determine the feasibility of re introduction of SP alone or in combination as a more affordable and safer drug in the future in Ethiopia. PMID- 24055718 TI - Mosquito larvicidal and antimicrobial activity of synthesized nano-crystalline silver particles using leaves and green berry extract of Solanum nigrum L. (Solanaceae: Solanales). AB - Silver nanoparticles (AgNPs) that are synthesized by using aqueous extracts of Solanum nigrum L., is a simple, non-toxic and ecofriendly green material. The present study is based on assessments of the larvicidal and antimicrobial activities of the synthesized AgNPs from fresh leaves, dry leaves and green berries of S. nigrum against larvae of Culex quinquefasciatus and Anopheles stephensi and four human pathogenic and five fish pathogenic bacteria respectively. The synthesized nanoparticles are characterized with UV-vis spectroscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and transmission electron microscope (TEM) analysis. The nanoparticles are spherical to polyhedral in shape with size of 50-100nm (average size of 56.6nm). In larvicidal bioassay with synthesized AgNPs, highest mortality are observed at 10ppm against An. stephensi with LC50 values of 1.33, 1.59, 1.56ppm and LC90 values of 3.97, 7.31, 4.76ppm for dry leaves, fresh leaves and berries respectively. Antibacterial activity test reveals better results against fish pathogenic bacteria than human pathogenic bacteria. Non target organism like Toxorhynchites larvae (mosquito predator), Diplonychus annulatum (predatory water bug) and Chironomus circumdatus larvae (chironomid) are also exposed to respective lethal concentrations (to mosquito larvae) of dry nanoparticles and no abnormality in the non target organisms are recorded. These results suggest that the synthesized AgNPs of S. nigrum have the potential to be used as an ideal eco friendly compound for the control of the mosquito larvae and harmful bacteria. PMID- 24055720 TI - Remote monitoring for implantable defibrillators: a nationwide survey in Italy. AB - BACKGROUND: Remote monitoring (RM) permits home interrogation of implantable cardioverter defibrillator (ICD) and provides an alternative option to frequent in-person visits. OBJECTIVE: The Italia-RM survey aimed to investigate the current practice of ICD follow-up in Italy and to evaluate the adoption and routine use of RM. METHODS: An ad hoc questionnaire on RM adoption and resource use during in-clinic and remote follow-up sessions was completed in 206 Italian implanting centers. RESULTS: The frequency of routine in-clinic ICD visits was 2 per year in 158/206 (76.7%) centers, 3 per year in 37/206 (18.0%) centers, and 4 per year in 10/206 (4.9%) centers. Follow-up examinations were performed by a cardiologist in 203/206 (98.5%) centers, and by more than one health care worker in 184/206 (89.3%) centers. There were 137/206 (66.5%) responding centers that had already adopted an RM system, the proportion of ICD patients remotely monitored being 15% for single- and dual-chamber ICD and 20% for cardiac resynchronization therapy ICD. Remote ICD interrogations were scheduled every 3 months, and were performed by a cardiologist in 124/137 (90.5%) centers. After the adoption of RM, the mean time between in-clinic visits increased from 5 (SD 1) to 8 (SD 3) months (P<.001). CONCLUSIONS: In current clinical practice, in clinic ICD follow-up visits consume a large amount of health care resources. The results of this survey show that RM has only partially been adopted in Italy and, although many centers have begun to implement RM in their clinical practice, the majority of their patients continue to be routinely followed-up by means of in clinic visits. PMID- 24055721 TI - Functional characterization of Rho family small GTPases in Fusarium graminearum. AB - Rho GTPases have multiple cellular and metabolic functions, including vesicular trafficking and pathogenesis, as signaling molecules in fungi. Wheat scab, caused by Fusarium graminearum, is one of the most important wheat diseases worldwide, yet the mechanisms associated with making this fungus such a devastating pathogen remain largely ambiguous. In an effort to better understand F. graminearum virulence, we functionally characterized all six Rho GTPases in F. graminearum. FgRHO1 was determined to be essential for fungal survival, while FgRho3 demonstrated functions only in vegetative growth and conidiation. Other four Rho GTPases, FgRho2, FgRho4, FgCdc42 and FgRac1, were multifunctional and were involved in sexual development and pathogenesis. While FgRho2 and FgRho4 were both involved in cell wall integrity, only FgRho4 showed a role in nuclear division and septum formation. FgRho4, FgCdc42 and FgRac1 were also important for hyphal growth and conidiation. All single deletion mutants showed impaired growth, particularly in conidial morphology, when compared to the wild-type progenitor. FgRac1 deletion mutants displayed a precocious, multi-site germ tube formation as well as hyperbranching of hyphae. Significantly we learned that FgRac1 negatively controls DON production whereas FgRho4 plays a positive role. FgCla4 was identified as a downstream target of FgRac1, but was dispensable for sexual development. We determined that FgRho GTPases contribute diversely to growth, conidiogenesis, sexual reproduction, DON production and pathogenesis in F. graminearum. PMID- 24055722 TI - Identification of novel mutations in the ABCA12 gene, c.1857delA and c.5653 5655delTAT, causing harlequin ichthyosis. AB - Harlequin ichthyosis (HI) is a severe autosomal recessive developmental disorder of the skin that is frequently but not always fatal in the first few days of life. In HI, mutations in both ABCA12 gene alleles must have a severe impact on protein function and most mutations are truncating. The presence of at least one nontruncating mutation (predicting a residual protein function) usually causes a less severe congenital ichthyosis (lamellar ichthyosis or congenital ichthyosiform erythroderma). Here we report on a girl with severe HI diagnosed by prenatal ultrasound at 33 5/7 week gestation. Ultrasound findings included ectropion, eclabium, deformed nose, hands and feet, joint contractures, hyperechogenic amniotic fluid and polyhydramnion. After birth, palliative treatment was provided and she died on her first day of life. Sequence analysis of the ABCA12 gene identified two novel mutations, c.1857delA (predicting p.Lys619) in exon 15 and c.5653-5655delTAT (predicting p.1885delTyr) in exon 37, each in heterozygous state. The c.5653-5655delTAT mutation is not truncating, but the deleted tyrosine at position 1885 is perfectly conserved among vertebrates and molecular studies evaluated the mutation as probably disease causing and damaging. PMID- 24055723 TI - New insights into helitron transposable elements in the mesopolyploid species Brassica rapa. AB - Helitrons are DNA transposable elements that are widely present in the genomes of diverse eukaryotic taxa. Helitrons are distinct from other transposons in their ability to capture gene fragments and their rolling-replication mechanism. Brassica rapa is a mesopolyploid species and one of the most important vegetable and oil crops globally. A total of 787 helitrons were identified in the B. rapa genome and were assigned to 662 families and 700 subfamilies. More than 21,806 repetitive sequences were found within the helitrons, whose G+C content correlated negatively to that of the host helitron. Each helitron contained an average of 2.9 gene fragments and 1.9 intact genes, of which the majority were annotated with binding functions in metabolic processes. In addition, a set of 114 nonredundant microRNAs were detected within 174 helitrons and predicted to regulate a set of 787 nonredundant target genes. These results suggest that helitrons contribute to genomic structural and transcriptional variation by capturing gene fragments and generating microRNAs. PMID- 24055719 TI - Biophysics of cell membrane lipids in cancer drug resistance: Implications for drug transport and drug delivery with nanoparticles. AB - In this review, we focus on the biophysics of cell membrane lipids, particularly when cancers develop acquired drug resistance, and how biophysical changes in resistant cell membrane influence drug transport and nanoparticle-mediated drug delivery. Recent advances in membrane lipid research show the varied roles of lipids in regulating membrane P-glycoprotein function, membrane trafficking, apoptotic pathways, drug transport, and endocytic functions, particularly endocytosis, the primary mechanism of cellular uptake of nanoparticle-based drug delivery systems. Since acquired drug resistance alters lipid biosynthesis, understanding the role of lipids in cell membrane biophysics and its effect on drug transport is critical for developing effective therapeutic and drug delivery approaches to overcome drug resistance. Here we discuss novel strategies for (a) modulating the biophysical properties of membrane lipids of resistant cells to facilitate drug transport and regain endocytic function and (b) developing effective nanoparticles based on their biophysical interactions with membrane lipids to enhance drug delivery and overcome drug resistance. PMID- 24055724 TI - Promoter variants at AP2 box region of Hsp70.1 affect thermal stress response and milk production traits in Frieswal cross bred cattle. AB - Heat shock proteins (Hsp) are known to play major role in protection of cells from thermal stress. Nucleotide polymorphisms within the promoter of Hsp affect degree of expression and inducibility of Hsp mRNA. The present study aimed to investigate the effect of polymorphism within promoter region on the cellular expression of Hsp70.1 mRNA and association of identified polymorphisms with the physiological parameters during summer stress and milk production traits in dairy cattle. Two hundred Frieswal cows were genotyped using double PCR-RFLP to identify deletion of cytosine within the Hsp70.1 promoter AP2 box at base position 895. Homozygous wild type genotypes (CC) were found in lower frequency (39.29, n=78) than heterozygous cytosine deletion mutant genotypes (C-) (60.71, n=122). In the observed physiological parameters (rectal temperature, respiration rate and heat tolerance coefficient), cows that were homozygous wild types had better significant (P<0.05) summer tolerance than the heterozygous deletion genotypes. Cytosine deletion mutation in the promoter region negatively affected (P<0.01) the expression of Hsp70.1 mRNA in peripheral bovine mononuclear cells (PBMC) subjected to in vitro heat stress. Further association of observed polymorphism with the milk production traits was significant as the heterozygous cytosine deletion cows had lower total milk yield, peak yield, yield at 300 days, protein% (P<0.01) and fat% (P<0.05) than the native wild type promoter cows. The results from the present study suggest that the promoter region of bovine hsp70.1 gene is polymorphic and may be useful in selection of dairy cows for relatively better thermotolerance and higher milk production. PMID- 24055725 TI - PCB-77 disturbs iron homeostasis through regulating hepcidin gene expression. AB - PCBs are a family of persistent environmental toxicants with a wide spectrum of toxic features, such as immunotoxicity, hepatoxicity, endocrine disruption effects, and oncogenic effects. To date, little has been done to investigate the potential influence of PCB exposure on iron metabolism. Deregulated iron would lead to either iron deficiency or iron excess, coupled with various diseases such as anemia or hemochromatosis. Iron metabolism is strictly governed by the hepcidin-ferroportin axis, and hepcidin is the key regulator that is secreted by hepatocytes. Here, we found that PCB-77 could go through plasma membrane and accumulate in hepatocytes. PCB-77 was demonstrated to suppress hepcidin expression in HepG2 and L-02 hepatocytes. Moreover, hepatic hepcidin was observed to be inhibited in mice upon administration of PCB-77. Due to reduced hepcidin concentration, serum iron content was increased, with a significant reduction of splenic iron content. Together, we deciphered the molecular mechanism responsible for PCB-conducted disturbance on iron homeostasis, i.e. through misregulating hepatic hepcidin expression. PMID- 24055727 TI - Growth inhibitory effects of three miR-129 family members on gastric cancer. AB - Reduced expression of microRNA-129 (miR-129) has been reported in several types of tumor cell lines as well as in primary tumor tissues. However, little is known about how miR-129 affects cell proliferation in gastric cancer. Here, we show that all miR-129 family members, miR-129-1-3p, miR-129-2-3p, and miR-129-5p, are down-regulated in gastric cancer cell lines compared with normal gastric epithelial cells. Furthermore, using the real-time cell analyzer assay to observe the growth effects of miR-129 on gastric cancer cells, we found that all three mature products of miR-129 showed tumor suppressor activities. To elucidate the molecular mechanisms underlying down-regulation of miR-129 in gastric cancer, we analyzed the effects of miR-129 mimics on the cell cycle. We found that increased miR-129 levels in gastric cancer cells resulted in significant G0/G1 phase arrest. Interestingly, we showed that cyclin dependent kinase 6 (CDK6), a cell cycle-associated protein involved in G1-S transition, was a target of miR-129. We also found that expression of the sex determining region Y-box 4 (SOX4) was inversely associated with that of miR-129-2-3p and miR-129-5p but not of miR-129 1-3p. Together, our data indicate that all miR-129 family members, not only miR 129-5p, as previously thought, play an important role in regulating cell proliferation in gastric cancer. PMID- 24055726 TI - MicroRNA expression analysis of rosette and folding leaves in Chinese cabbage using high-throughput Solexa sequencing. AB - In this study, a global analysis of miRNA expression from rosette leaves (RLs) and folding leaves (FLs) of Chinese cabbage (Brassica rapa L. ssp. pekinensis) was conducted using high-throughput Solexa sequencing. In total, over 12 million clean reads were obtained from each library. Sequence analysis identified 64 conserved miRNA families in each leaf type and 104 and 95 novel miRNAs from RLs and FLs, respectively. Among these, 61 conserved miRNAs and 61 novel miRNAs were detected in both types of leaves. Furthermore, six conserved and 21 novel miRNAs were differentially expressed between the two libraries. Target gene annotation suggested that these differentially expressed miRNAs targeted transcription factors, F-box proteins, auxin and Ca(2+) signaling pathway proteins, protein kinases and other proteins that may function in governing leafy head formation. This study advanced our understanding of the important roles of miRNAs in regulating leafy head development in Chinese cabbage. PMID- 24055728 TI - Prevalence and genetic analysis of alpha-thalassemia and beta-thalassemia in Chongqing area of China. AB - BACKGROUND AND AIMS: Thalassemia is one of the most common hereditary disorders. This study aimed to investigate the prevalence of thalassemia and the mutation spectrum in Chongqing, the southern area of China. METHODS: A total of 1057 children were recruited from Chongqing. Hematological parameters were examined and globin genes were genetically analyzed. RESULTS: The total frequency of thalassemia carriers was 7.76% in this group of children. Among these, alpha thalassemia was 5.20%, beta-thalassemia was 1.99% and abnormal hemoglobin variant was 0.57%. Furthermore, 24 cases of alpha-triplication were detected, frequency of which was 2.55%. The true prevalence of silent alpha-thalassemia was first reported in this study. In addition, six novel mutations that give rise to alpha thalassemia and two rare abnormal hemoglobin variants were first identified in Chinese population. CONCLUSIONS: Our data suggested that the population in Chongqing are at high risk of alpha- and beta-thalassemia. The findings will be useful for genetic counseling and the prevention of severe thalassemias in this area. PMID- 24055729 TI - Human C-reactive protein gene polymorphism and metabolic syndrome are associated with premature coronary artery disease. AB - The aim of this study was to investigate the association between C-reactive protein (CRP) gene polymorphism and metabolic syndrome (MetS) with premature coronary artery disease (PCAD). 116 patients with PCAD (58 with MetS and 58 without MetS) and 119 controls were included in the study. CRP gene +1059 G>C polymorphism was analyzed by polymerase chain reaction. Serum hs-CRP was measured using high-sensitivity enzyme-linked immunosorbent assay. Carriers of C allele of the CRP +1059 G>C polymorphism had 3.37 fold increased risk to develop MetS in patients with PCAD. In addition CRP gene and hs-CRP levels were independent risk factors for PCAD and MetS. The present study provides new evidence that the presence of CRP +1059 G>C polymorphism and hs-CRP levels are independent determinants of PCAD and MetS in Egyptians. The results of our study suggest a synergistic effect of CRP C allele with classical risk factors such as hypertension, obesity, dyslipidemia and MetS. PMID- 24055730 TI - Chromosome 17p13.3 deletion syndrome: aCGH characterization, prenatal findings and diagnosis, and literature review. AB - We report a molecular cytogenetic characterization of 17p13.3 deletion syndrome by array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH) and quantitative polymerase chain reaction (qPCR) in a fetus with lissencephaly, corpus callosum dysgenesis, ventriculomegaly, microcephaly, intrauterine growth restriction (IUGR), polyhydramnios and single umbilical artery. aCGH analysis revealed a 3.17-Mb deletion at 17p13.3, or arr [hg19] 17p13.3 (0-3,165,530)*1. The qPCR assays revealed a maternal origin of the deletion. Metaphase FISH analysis detected the absence of the LIS1 probe signal on the aberrant chromosome 17. The karyotype was 46,XX,del(17)(p13.3). We review the literature of chromosome 17p13.3 deletion syndrome with prenatal findings and diagnosis, and suggest that prenatal ultrasound detection of central nervous system anomalies such as lissencephaly, corpus callosum dysgenesis/agenesis, ventriculomegaly and microcephaly associated with IUGR, polyhydramnios, congenital heart defects, abdominal wall defects and renal abnormalities should include a differential diagnosis of chromosome 17p13.3 deletion syndrome. PMID- 24055732 TI - The regulation of gene expression in eukaryotes: bistability and oscillations in repressilator models. AB - To model the regulation of gene expression in eukaryotes by transcriptional activators and repressors, we introduce delays in conjugation with the mass action law. Delays are associated with the time gap between the mRNA transcription in the nucleoplasm and the protein synthesis in the cytoplasm. After re-parameterisation of the m-repressilator model with the Hill cooperative parameter n, for n=1, the m-repressilator is deducible from the mass action law and, in the limit n->infinity, it is a Boolean type model. With this embedding and with delays, if m is odd and n>1, we show that there is always a choice of parameters for which the m-repressilator model has sustained oscillations (limit cycles), implying that the 1-repressilator is the simplest genetic mechanism leading to sustained oscillations in eukaryotes. If m is even and n>1, there is always a choice of parameters for which the m-repressilator model has bistability. PMID- 24055731 TI - Assessing the feasibility and fidelity of an intervention for women with violent offenses. AB - Women convicted of assaultive or violent offenses represent a small but important subpopulation of adults involved in the criminal justice system. The limited treatment and rehabilitation programs that are available for these women are usually developed for male offenders and do not consider factors that are especially relevant to women, such as higher rates of mental health and substance use disorders as well as their likely histories of interpersonal violence. Moreover, women's trajectories into violent behavior - as well as their trajectories out - may differ from their male counterparts. Due to the absence of programs available for this unique population, a new gender-specific and trauma informed intervention, Beyond Violence, was developed. This paper describes a pilot study with a mixed-methods approach that assesses the feasibility and fidelity of the intervention within a state prison for women. Overall, various components of feasibility (i.e. engaging the target population, gaining institutional support, and finding skilled treatment staff), were realized, as were fidelity elements such as adherence to the intervention material, and high attendance and satisfaction by participants. The positive results of this pilot study increase the likelihood of dissemination of the intervention and a randomized control trial is currently underway. PMID- 24055733 TI - Exercise training in patients with chronic heart failure promotes restoration of high-density lipoprotein functional properties. AB - RATIONALE: High-density lipoprotein (HDL) exerts endothelial-protective effects via stimulation of endothelial cell (EC) nitric oxide (NO) production. This function is impaired in patients with cardiovascular disease. Protective effects of exercise training (ET) on endothelial function have been demonstrated. OBJECTIVE: This study was performed to evaluate the impact of ET on HDL-mediated protective effects and the respective molecular pathways in patients with chronic heart failure (CHF). METHODS AND RESULTS: HDL was isolated from 16 healthy controls (HDL(healthy)) and 16 patients with CHF-NYHA-III (HDL(NYHA-IIIb)) before and after ET, as well as from 8 patients with CHF-NYHA-II (HDL(NYHA-II)). ECs were incubated with HDL, and phosphorylation of eNOS-Ser(1177), eNOS-Thr(495), PKC-betaII-Ser(660), and p70S6K-Ser(411) was evaluated. HDL-bound malondialdehyde and HDL-induced NO production by EC were quantified. Endothelial function was assessed by flow-mediated dilatation. The proteome of HDL particles was profiled by shotgun LC-MS/MS. Incubation of EC with HDL(NYHA-IIIb) triggered a lower stimulation of phosphorylation at eNOS-Ser(1177) and a higher phosphorylation at eNOS-Thr(495) when compared with HDL(healthy). This was associated with lower NO production of EC. In addition, an elevated activation of p70S6K, PKC-betaII by HDL(NYHA-IIIb), and a higher amount of malondialdehyde bound to HDL(NYHA-IIIb) compared with HDL(healthy) was measured. In healthy individuals, ET had no effect on HDL function, whereas ET of CHF-NYHA-IIIb significantly improved HDL function. A correlation between changes in HDL-induced NO production and flow-mediated dilatation improvement by ET was evident. CONCLUSIONS: These results demonstrate that HDL function is impaired in CHF and that ET improved the HDL-mediated vascular effects. This may be one mechanism how ET exerts beneficial effects in CHF. PMID- 24055734 TI - Cyclic AMP suppresses TGF-beta-mediated adaptive Tregs differentiation through inhibiting the activation of ERK and JNK. AB - The second messenger cAMP is involved in the regulation of many cellular activities partially through modulating the MAPK pathways. The role of cAMP in TGF-beta-mediated adaptive Tregs differentiation remains elusive. In this work, we show that cAMP inhibits antigen-nonspecific proliferation of murine CD4+ T cells without significant promotion of apoptosis. Moreover, cAMP suppresses TGF beta-induced expression of forkhead transcription factor Foxp3. 6-MB-cAMP, a site selective activator of PKA, mimics the role of cAMP in TGF-beta-induced Foxp3 expression. Further exploration reveals that TGF-beta activates ERK and JNK, but not p38. cAMP and 6-MB-cAMP block TGF-beta-induced activation of ERK and JNK through transcription-independent manner and transcription-dependent manner, respectively. Since direct inhibition of ERK or JNK activity mimics the effects of cAMP during this process, our work suggests that cAMP suppresses TGF-beta mediated adaptive Tregs differentiation through, at least partially, inhibiting the activation of ERK and JNK. PMID- 24055735 TI - Nitric oxide donors: spermine/NO and diethylenetriamine/NO induce ovarian cancer cell death and affect STAT3 and AKT signaling proteins. AB - The important features of cancer cells are uncontrolled growth and proliferation, as well as the ability to metastasis. These features depend mainly on the constant overexpression and activity of various cell signaling proteins, such as signal transducer and activator of transcription 3 (STAT3) and serine-threonine protein kinase AKT proteins. Nitric oxide (NO) has the potential of being anti tumoral agent, however the exact character of anti-tumoral action of NO is still a matter of debate. In our research we used two NO donors, belonging to NONOates family, with different half-life times: spermine nitric oxide complex hydrate (SPER/NO t1/2=39min) and diethylenetriamine nitric oxide adduct (DETA/NO, t1/2=20h). We evaluated the cytotoxic effect of aforementioned NO donors on SK-OV 3 and OVCAR-3 ovarian cancer cell lines, as well as their effect on posttranslational modification of STAT3 and AKT proteins in these cells. We found that both NO donors present cytotoxic activity on the cancer cell lines, mainly through the induction of apoptosis. What is more, at the high concentration and longer exposure time they were also capable of inducing late apoptosis/necrosis. Both NO donors inhibited STAT3 and AKT3 proteins phosphorylation and down regulated their cytosolic levels, with DETA/NO being stronger inhibitor. We suggests, that NO donors have the potential to act as anti-tumoral agent through inhibiting cancer cell signaling and reducing their viability. PMID- 24055736 TI - Polymorphisms in the endothelial nitric oxide synthase gene in thalidomide embryopathy. AB - Thalidomide is one of the most potent teratogens known to humans. It is currently used for many clinical situations such as treatment of leprosy reactions and multiple myeloma. However, the teratogenic mechanisms by which it produces morphological defects still remain unclear. One of the hypotheses is the blockage of angiogenesis by reduction of nitric oxide (NO). In this study, we evaluated two functional polymorphisms of the endothelial nitric oxide synthase (eNOS) gene which is a constitutively expressed enzyme responsible for production of NO. The promoter -786T>C exon 7 (896G>T) polymorphisms were genotyped using real-time PCR for 28 individuals with thalidomide embryopathy (TE), 27 first-degree relatives of these individuals, and 68 individuals from the general population. Their allele, genotypic, and haplotypic frequencies were compared. A significant difference was observed in the -786T>C polymorphism genotypes (p=0.03) between the groups affected by TE and those unaffected (non-relatives). The TT genotype of the 896G>T polymorphism was observed in 10.7% of those affected and 2.9% of those unaffected, but the difference was not statistically significant (p=0.09). The haplotypic analysis indicated that the wild haplotype -786T/896G was distributed differently in the affected and unaffected groups (p=0.004). These results indicate that the individuals with TE have a higher frequency of alleles associated with lower expression of eNOS, indicating that this may be a genotype susceptible to TE. PMID- 24055737 TI - Oxytocin differentially modulates compromise and competitive approach but not withdrawal to antagonists from own vs. rivaling other groups. AB - In humans, oxytocin promotes cognitive and motivational tendencies that benefit the groups on which humans depend for their survival and prosperity. Here we examined decision making in an incentivized two-player poker game with either an in-group or out-group antagonist. Sixty nine healthy males received 24 IU oxytocin or matching placebo, and played four rounds of a simplified poker game. On each round they received either low or high value cards to create differences in competitive strength, and then responded to a bet placed by their (simulated) (in-group or out-group) antagonist. Under placebo, participants withdrew and competed depending on their own (low vs. high) competitive strength, regardless of their antagonist's group membership. Under oxytocin, however, participants settled more and competed less with an in-group as compared to an out-group antagonist; withdrawal was unaffected by group membership. We conclude that oxytocin sensitizes humans to the group membership of their interaction partner, rendering them relatively more benevolent and less competitive towards those seen as belonging to their own group. This article is part of a Special Issue entitled Oxytocin and Social Behav. PMID- 24055739 TI - Chicken SLAMF4 (CD244, 2B4), a receptor expressed on thrombocytes, monocytes, NK cells, and subsets of alphabeta-, gammadelta- T cells and B cells binds to SLAMF2. AB - The SLAM family of membrane receptors is involved in the regulation of immune responses by controlling cytokines production, cytotoxicity as well as cell development, differentiation and proliferation, but has only been described in chickens, recently. The aim of this study was to characterize the avian homologue to mammalian SLAMF4 (CD244, 2B4), a cell surface molecule which belongs to the SLAM family of membrane receptors. We generated a SLAMF4 specific monoclonal antibody (mab) designated 8C7 and analyzed the SLAMF4 expression on cells isolated from various lymphoid organs. Subsets of alphabeta and gammadelta T cells found in peripheral blood lymphocytes (PBL) and spleen coexpressed SLAMF4. The expression was restricted to CD8alpha(+) T cells, whereas CD4(+) T cells and all thymocytes showed little or no reactivity upon staining with the 8C7 mab. Blood and splenic gammadelta T cells could be further differentiated according to their expression levels of SLAMF4 into two and three subsets, respectively. SLAMF4 was absent from bursal and splenic B cells, however, it was expressed by a distinct fraction of circulating B cells that were characterized by high level expression of Bu1, Ig, and CD40. SLAMF4 was also present on NK cells isolated from intestine of adult chickens or embryonic splenocytes identified by their coexpression of the 28-4 NK cell marker. Moreover, SLAMF4 expression was found on thrombocytes and monocytes. The interaction of SLAMF4 with SLAMF2 was proven by a reporter assay and could be blocked with the 8C7 mab. In conclusion, the avian SLAMF4 expression markedly differs from mammals; it binds to SLAMF2 and will be an important tool to discriminate several gammadelta T cell subsets. PMID- 24055738 TI - Outgroup effects on root position and tree topology in the AFLP phylogeny of a rapidly radiating lineage of cichlid fish. AB - Phylogenetic analyses of rapid radiations are particularly challenging as short basal branches and incomplete lineage sorting complicate phylogenetic inference. Multilocus data of presence-absence polymorphisms such as obtained by AFLP genotyping overcome some of the difficulties, but also present their own intricacies. Here we analyze >1000 AFLP markers to address the evolutionary history of the Limnochromini, a cichlid fish lineage endemic to Lake Tanganyika, and to test for potential effects of outgroup composition on tree topology. The data support previous mitochondrial evidence on the tribe's taxonomy by confirming the polyphyly of the genus Limnochromis and - in contradiction to a recent taxonomic revision - nesting the genus Greenwoodochromis within the Limnochromini. Species relationships suggest that ecological segregation occurred during the rapid basal radiation of the Limnochromini. The large phylogenetic distance between candidate outgroup taxa and the Limnochromini radiation caused random outgroup effects. Bootstrap support for ingroup nodes was lower in outgroup-rooted than in midpoint-rooted trees, and root positions and ingroup tree topologies varied in response to the composition of the outgroup. These observations suggest that the predisposition for homoplastic evolution makes AFLP based phylogenetic analyses particularly susceptible to random biases introduced by too-distant outgroup taxa. PMID- 24055741 TI - Reply: Can FFR be reliably calculated from cardiac computed tomography without consideration of collateral flow? PMID- 24055740 TI - Lipoprotein subclass profiling reveals pleiotropy in the genetic variants of lipid risk factors for coronary heart disease: a note on Mendelian randomization studies. PMID- 24055742 TI - Can FFR be reliably calculated from cardiac computed tomography without consideration of collateral flow? PMID- 24055743 TI - Patient and hospital characteristics associated with inappropriate percutaneous coronary interventions. AB - OBJECTIVES: This study sought to examine whether rates of inappropriate percutaneous coronary intervention (PCI) differ by demographic characteristics and insurance status. BACKGROUND: Prior studies have found that blacks, women, and those who have public or no health insurance are less likely to undergo PCI. Whether this reflects potential overuse in whites, men, and privately insured patients, in addition to underuse in disadvantaged populations, is unknown. METHODS: Within the National Cardiovascular Data Registry CathPCI Registry, we identified 221,254 nonacute PCIs performed between July 2009 and March 2011. The appropriateness of PCI was determined using the Appropriate Use Criteria for coronary revascularization. Multivariable hierarchical regression was used to evaluate the association between patient demographics and insurance status and inappropriate PCI, as defined by the Appropriate Use Criteria. RESULTS: Of 211,254 nonacute PCIs, 25,749 (12.2%) were classified as inappropriate. After multivariable adjustment, men (adjusted odd ratio [OR]: 1.08 [95% CI: 1.05 to 1.11]; p < 0.001) and whites (adjusted OR: 1.09 [95% CI: 1.05 to 1.14]; p < 0.001) were more likely to undergo an inappropriate PCI in comparison with women and nonwhites. Compared with privately insured patients, those who had Medicare (adjusted OR: 0.85 [95% CI: 0.83 to 0.88]), other public insurance (adjusted OR: 0.78 [95% CI: 0.73 to 0.83]), and no insurance (adjusted OR: 0.56 [95% CI: 0.50 to 0.61]) were less likely to undergo an inappropriate PCI (p < 0.001). In addition, compared with urban hospitals, those admitted at rural hospitals were less likely to undergo inappropriate PCI, whereas those at suburban hospitals were more likely. CONCLUSIONS: For nonacute indications, PCIs categorized as inappropriate were more commonly performed in men, whites, and those who had private insurance. Higher rates of PCI in these patient populations may, in part, be due to procedural overuse. PMID- 24055745 TI - Trade-offs in appropriateness of percutaneous coronary intervention. PMID- 24055744 TI - The HAS-BLED score has better prediction accuracy for major bleeding than CHADS2 or CHA2DS2-VASc scores in anticoagulated patients with atrial fibrillation. AB - OBJECTIVES: The aim of this study was to test the hypothesis that a specific bleeding risk score, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), was better at predicting major bleeding compared with CHADS2 (congestive heart failure, hypertension, 75 years of age or older, diabetes mellitus, and previous stroke or transient ischemic attack) and CHA2DS2-VASc (congestive heart failure, hypertension, 75 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) in anticoagulated atrial fibrillation (AF) patients. BACKGROUND: The CHADS2 and CHA2DS2-VASc scores are well-validated stroke risk prediction scores for AF, but are also associated with increased bleeding and mortality. METHODS: We recruited 1,370 consecutive AF patients (49% male; median age, 76 years) receiving oral anticoagulation therapy from our outpatient anticoagulation clinic, all of whom were receiving acenocoumarol and had an international normalized ratio between 2.0 and 3.0 during the preceding 6 months. During follow-up, major bleeding events were identified by the 2005 International Society on Thrombosis and Haemostasis criteria. Model performance was evaluated by calculating the C-statistic, and the improvement in predictive accuracy was evaluated by calculating the net reclassification improvement and integrated discrimination improvement. RESULTS: After a median follow-up of 996 (range, 802 to 1,254) days, 114 patients (3.0%/year) presented with a major bleeding event; 31 of these events were intracranial hemorrhages (0.8%/year). Based on the C-statistic, HAS-BLED had a model performance superior to that of both CHADS2 and CHA2DS2-VASc (both p < 0.001). Both net reclassification improvement and integrated discrimination improvement analyses also show that HAS-BLED was more accurately associated with major bleeding compared with CHADS2 and CHA2DS2-VASc scores. CONCLUSIONS: In anticoagulated AF patients, a validated specific bleeding risk score, HAS-BLED, should be used for assessing major bleeding. The practice of using CHADS2 and CHA2DS2-VASc as a measure of high bleeding risk should be discouraged, given its inferior predictive performance compared with the HAS-BLED score. PMID- 24055746 TI - Noonan syndrome with complete atrioventricular canal defect with pulmonary stenosis. PMID- 24055747 TI - Pre- and post-operative diastolic dysfunction in patients with valvular heart disease: diagnosis and therapeutic implications. AB - Patients with valvular heart disease often have left ventricular diastolic dysfunction. This review summarizes the underlying mechanisms for diastolic dysfunction in patients with mitral and aortic valve disease. In addition to load, intrinsic myocardial abnormalities occur related to changes in sarcomeric proteins, abnormal calcium handling, and fibrosis. Echocardiography is the initial modality for the diagnosis of left ventricular diastolic function. Although there are challenges to conventional Doppler parameters of diastolic function, it is often possible to arrive at a clinically useful assessment of left ventricular filling pressures using a comprehensive approach. When needed, cardiac magnetic resonance and cardiac catheterization can be obtained. Medical therapy can be of value for the treatment of diastolic dysfunction, but there is a paucity of data evaluating its clinical utility. More importantly, diastolic dysfunction usually improves with timely surgical intervention, although surgery does not always lead to normalization of function. PMID- 24055748 TI - Response: Lipoprotein subclass profiling reveals pleiotropy in the genetic variants of lipid risk factors for coronary heart disease: a note on Mendelian randomization studies. PMID- 24055749 TI - High-throughput assay for temporal kinetic analysis of lytic coliphage activity. AB - Plaque analysis allows the determination of phage titer and multiplicity of infection. Yet, this overnight assay provides only endpoint results, ignoring kinetic aspects. We introduce an alternative high-throughput and rapid method for kinetic analysis of lytic coliphage activity. Escherichia coli was infected with serial dilutions of MS2 coliphage, and bacterial growth was monitored using a multi-well plate reader providing within hours the equivalent data as obtained overnight. Additional information is yielded, including phage replication rate, progeny size per cycle, and viral propagation during bacterial growth. This method offers further insights into physicochemical mechanisms of lytic coliphage infection and temporal control. It also provides a virus-host interaction acumen. PMID- 24055750 TI - Novel LC-MS/MS method for analyzing imperialine in rat plasma: development, validation, and application to pharmacokinetics. AB - A sensitive, selective, rapid liquid chromatography-electrospray ionization tandem mass spectrometric method was developed and validated in rat plasma to quantify imperialine, a major active constituent extracted from Bulbus Fritillariae Cirrhosae. Before analysis, plasma samples were pre-treated using cost-effective protein precipitation in order to extract imperialine and the internal standard, carbamzepine. The two analytes were then separated on a Diamonsil ODS chromatography column using gradient elution with a mobile phase of 0.1% aqueous formic acid and acetonitrile. Mass spectrometry was carried out in multiple reaction monitoring mode using a positive electrospray ionization interface. The calibration curve was linear (r(2)=0.9998) over the concentration range 2-1000ng/mL, while the validated limit of determination (LOD) was 0.5ng/mL. Precision varied from 0.1% to 7.1%, and the accuracy varied within +/-2%. The method proved robust to sample freezing and thawing, as well as short- and long term sample storage. The developed method was successfully applied to the pharmacokinetic study of imperialine in rats. Different amounts of imperialine were administered in single doses orally or through the caudal vena cava, and pharmacokinetic parameters were evaluated. Oral bioavailability with a dose of 1mg/kg was 31.2%; 5mg/kg, 53.6%; and 10mg/kg, 47.4%. PMID- 24055751 TI - Light scattering coupled with reversed phase chromatography to study protein self association under separating conditions. AB - An on-line method, coupling reversed phase chromatography with static light scattering, was developed to determine the association state of freshly eluted proteins. Under downstream process conditions, human insulin desB30 and human insulin AspB28 were tested at concentrations up to 8.5mg/mL. The refractive index increment (dn/dc) for insulin was found to depend strongly on the solvent used. A refractive index increment of 0.184+/-0.003mL/g was found in an aqueous buffer, pH 7.4, whereas the value was 0.155+/-0.003mL/g in 30%, w/w ethanol. The methodology combines on-line SLS and UV measurements with the pre-determined refractive index increment values. The developed on-line method was verified by standard off-line measurements establishing the association state at concentrations between 0.2 and 6.0mg/mL. The equipment was calibrated utilizing insulin under conditions reported to ensure either monomer or hexamer forms. The self-association of human insulin desB30 was found to be strongly suppressed in 30%, w/w ethanol at pH 7.4 in which the monomer predominates. When stabilized by zinc ions in 30%, w/w ethanol at pH 7.4, an average association number of 3.7 was found. These data demonstrate the effect of ethanol to lower strongly the energy advantage by protein self-association. Potassium chloride and/or calcium chloride in the eluents were found to be of no consequence to the association state. PMID- 24055752 TI - Ultra-high performance liquid chromatography coupled to mass spectrometry applied to the identification of valuable phenolic compounds from Eucalyptus wood. AB - Ultra-high performance liquid chromatography (UHPLC) was applied for the first time in the analysis of wood extracts. The potential of this technique coupled to ion trap mass spectrometry in the rapid and effective detection and identification of bioactive components in complex vegetal samples was demonstrated. Several dozens of compounds were detected in less than 30min of analysis time, corresponding to more than 3-fold reduction in time, when compared to conventional HPLC analysis of similar extracts. The phenolic chemical composition of Eucalyptus grandis, Eucalyptus urograndis (E. grandis*E. urophylla) and Eucalyptus maidenii wood extracts was assessed for the first time, with the identification of 51 phenolic compounds in the three wood extracts. Twenty of these compounds are reported for the first time as Eucalyptus genus components. Ellagic acid and ellagic acid-pentoside are the major components in all extracts, followed by gallic and quinic acids in E. grandis and E. urograndis and ellagic acid-pentoside isomer, isorhamnetin-hexoside and gallic acid in E. maidenii. The antioxidant scavenging activity of the extracts was evaluated, with E. grandis wood extract showing the lowest IC50 value. Moreover, the antioxidant activity of these extracts was higher than that of the commercial antioxidant BHT and of those of the corresponding bark extracts. These results, together with the phenolic content values, open good perspectives for the exploitation of these renewable resources as a source of valuable phenolic compounds. PMID- 24055753 TI - Preparative separation and purification of four cis-trans isomers of coumaroylspermidine analogs from safflower by high-speed counter-current chromatography. AB - High-speed counter-current chromatography (HSCCC) was successfully applied for the first time to isolate and purify four cis-trans isomers of coumaroylspermidine analogs from Safflower. HSCCC separation was achieved with a two-phase solvent system composed of chloroform-methanol-water (1:1:1, v/v/v) with the upper phase as the mobile phase. In a single run, a total of 1.3mg of N(1), N(5), N(10)-(E)-tri-p-coumaroylspermidine (EEE), 4.4mg of N(1)(E)-N(5)-(Z) N(10)-(E)-tri-p-coumaroylspermidine (EZE), 7.2mg of N(1)(Z)-N(5)-(Z)-N(10)-(E) tri-p-coumaroylspermidine (ZZE), and 11.5mg of N(1),N(5),N(10)-(Z)-tri-p coumaroylspermidine (ZZZ) were obtained from 100mg of crude sample. High Performance Liquid Chromatography (HPLC) analysis showed that the purities of these four components are 95.5%, 98.1%, 97.5% and 96.2%, respectively. The chemical structures were identified by ESI-MS, (1)H NMR and (13)C NMR. PMID- 24055754 TI - Using chat and text technologies to answer sexual and reproductive health questions: Planned Parenthood pilot study. AB - BACKGROUND: Teens and young adults in the United States are in need of sexual and reproductive health information, as evidenced by elevated rates of sexually transmitted infections (STIs), pregnancy, and births among this population. In person sexuality education programs are helpful, but they are unlikely to rapidly accommodate teens and young adults in a moment of crisis. Evidence suggests that technologies such as instant messaging (IM) and text messaging may be effective ways to provide teens and young adults with sexual and reproductive health information. In September 2010, Planned Parenthood Federation of America launched a text and IM program designed to provide immediate answers to urgent sexual and reproductive health questions from a reliable and confidential source and to link young people to sexual and reproductive health services if needed. OBJECTIVE: To assess whether this program is successful in reaching the target population, whether user characteristics vary by mode (IM vs text), and whether mode is associated with reaching individuals with high levels of worry or reducing worry postchat. METHODS: Data were collected from prechat and postchat surveys for all IM and text message conversations between September 2010 and August 2011. A bivariate analysis was conducted using chi-square tests for differences in the main covariates by mode of conversation. In the multivariable analysis, logistic regression was used to identify factors that were independently associated with prechat levels of worry and changes in worry postchat. RESULTS: A total of 32,589 conversations occurred during the program's first year. The odds of feeling very worried prechat were highest for IM users (adjusted odds ratio [AOR] 1.43, 95% CI 1.20-1.72), users 17 years and younger (AOR 1.62, 95% CI 1.50-1.74), Latino/Hispanic users (AOR 1.36, 95% CI 1.27-1.46), and black users (AOR 1.40, 95% CI 1.30-1.50). After controlling for the study covariates, there was no significant difference in the odds of feeling better (less worried) postchat between IM and text message users. Feeling better postchat was associated with being younger (<=17 years: AOR 1.42, 95% CI 1.17-1.72; 18-24 years: AOR 1.20, 95% CI 1.02-1.42), being Latino/Hispanic (AOR 1.31, 95% CI 1.10-1.55), reporting that the service was very helpful (AOR 3.47, 95% CI 3.24-4.32), and asking about emergency contraception (AOR 1.35, 95% CI 1.13-1.61). The odds of feeling better were lowest for users with questions about STIs (AOR 0.61, 95% CI 0.47-0.78). CONCLUSIONS: The results from the process evaluation suggest that the program was able to provide informational support to vulnerable groups, such as teens and racial minorities, in moments of particular worry. Differences between the IM and text message users reveal that each mode appeals to a different population and that both are necessary to reach a diverse audience. PMID- 24055755 TI - Exposure to tributyltin induces endoplasmic reticulum stress and the unfolded protein response in zebrafish. AB - Tributyltin (TBT) is a major marine contaminant and causes endocrine disruption, hepatotoxicity, immunotoxicity, and neurotoxicity. However, the molecular mechanisms underlying the toxicity of TBT have not been fully elucidated. We examined whether exposure to TBT induces the endoplasmic reticulum (ER) stress response in zebrafish, a model organism. Zebrafish-derived BRF41 fibroblast cells were exposed to 0.5 or 1 MUM TBT for 0.5-16 h and subsequently lysed and immunoblotted to detect ER stress-related proteins. Zebrafish embryos, grown until 32 h post fertilization (hpf), were exposed to 1 MUM TBT for 16 h and used in whole mount in situ hybridization and immunohistochemistry to visualize the expression of ER chaperones and an ER stress-related apoptosis factor. Exposure of the BRF41 cells to TBT caused phosphorylation of the zebrafish homolog of protein kinase RNA-activated-like ER kinase (PERK), eukaryotic translation initiation factor 2 alpha (eIF2alpha), and inositol-requiring enzyme 1 (IRE1), characteristic splicing of X-box binding protein 1 (XBP1) mRNA, and enhanced expression of activating transcription factor 4 (ATF4) protein. In TBT-exposed zebrafish embryos, ectopic expression of the gene encoding zebrafish homolog of the 78 kDa glucose-regulating protein (GRP78) and gene encoding CCAAT/enhancer binding protein homologous protein (CHOP) was detected in the precursors of the neuromast, which is a sensory organ for detecting water flow and vibration. Our in vitro and in vivo studies revealed that exposure of zebrafish to TBT induces the ER stress response via activation of both the PERK-eIF2alpha and IRE1-XBP1 pathways of the unfolded protein response (UPR) in an organ-specific manner. PMID- 24055756 TI - Effect of algal growth phase on Aureococcus anophagefferens susceptibility to hydrogen peroxide. AB - A cell's growth phase could affect its susceptibility to a biocide in microbial control. This study examines the growth phase dependent susceptibility of a brown tide bloom alga Aureococcus anophagefferens to microbial biocide hydrogen peroxide (H2O2). Test cultures of A. anophagefferens cells in exponential and stationary growth phase and similar initial cell density (1.6*10(6) cells mL(-1)) were exposed to 0.4-1.6 mg L(-1) H2O2. Changes in algal growth (in vivo fluorescence, total chlorophyll a, and cell density), cell physiology (maximum quantum yield of photosystem II, and total intracellular non-protein thiols), and H2O2 decomposition were quantified. Results show that the stationary phase cells are more susceptible to H2O2 than the exponential phase cells, and this is attributed to the weaker ROS (reactive oxygen species) scavenging system and consequently greater cell damage in stationary phase cells. The stationary phase cells potentially require 30-40% less H2O2 to reach 90% removal within 12 h of treatment as compared to the exponential phase cells. The results have practical implications in brown tide bloom control with respect to the timing and the dosage of H2O2 application. PMID- 24055757 TI - The interplay of health claims and taste importance on food consumption and self reported satiety. AB - Research has shown that subtle health claims used by food marketers influence pre intake expectations, but no study has examined how they influence individuals' post-consumption experience of satiety after a complete meal and how this varies according to the value placed on food taste. In two experiments, we assess how labeling a pasta salad as "healthy" or "hearty" influences self-reported satiety, consumption volume, and subsequent consumption of another food. Using MANOVA, Study 1 shows that individuals who report low taste importance consume less-yet feel just as satiated-when a salad is labeled "hearty" rather than "healthy." In contrast, for individuals with higher taste importance, consumption and self reported satiety are correlated and are both higher when a salad is labeled as "hearty" versus "healthy." Study 2 primes taste importance, rather than measuring it, and replicates these findings for consumption, but not for self-reported satiety. There was no effect on the consumption of other foods in either study. Overall, our findings add to earlier work on the impact of health labels by showing that subtle food descriptions also influence post-intake experiences of satiety, but that the direction of the effects depends on taste importance and on the selection of direct or indirect measures of satiety. PMID- 24055758 TI - Using virtual reality to study food cravings. AB - Food cravings (FCs) are associated with overeating and obesity and are triggered by environmental cues. The study of FCs is challenged by difficulty replicating the natural environment in a laboratory. Virtual reality (VR) could be used to deliver naturalistic cues in a laboratory. The purpose of this study was to investigate whether food related cues delivered by VR could induce greater FCs than neutral VR cues, photographic food cues, or real food. Sixty normal weight non-dieting women were recruited; and, to prevent a floor effect, half were primed with a monotonous diet (MD). Experimental procedures involved delivering neutral cues via VR and food related cues via VR, photographs, and real food in counterbalanced order while measuring subjective (self-report) and objective (salivation) FCs. FCs produced by VR were marginally greater than a neutral cue, not significantly different from picture cues, and significantly less than real food. The modest effects may have been due to quality of the VR system and/or measures of FC (i.e., self-report and salivation). FC threshold among non-dieting normal weight women was lowered with the use of a MD condition. Weight loss programs with monotonous diets may inadvertently increase FCs making diet compliance more difficult. PMID- 24055759 TI - Ammonia excretion and expression of transport proteins in the gills and skin of the intertidal fish Lipophrys pholis. AB - Intertidal pools are intensely challenging environments, due to rapid and extreme fluctuations in water conditions during the tidal cycle. Emersion is another challenge intertidal fishes may face. Mechanisms of ammonia excretion and ion regulation were studied in the resident amphibious blennid Lipophrys pholis. The ammonia transporters Rhcg1 and Rhcg2 were cloned and characterized. Fish were challenged for 24h to 1) emersion, 2) fresh water (FW), and 3) high environmental ammonia (HEA; 1mM NH4Cl), or 4) ammonia loading (1.5MUmol/g NH4HCO3). When air exposed, L. pholis maintained aquatic ammonia excretion rates (JAmm) while branchial Na(+)/K(+)-ATPase (NKA) activity increased, but no changes at the protein or mRNA levels of transporters were noted. In FW, JAmm decreased and osmotic problems were encountered. Skin NKA activity decreased, branchial Rhcg2, and skin Rhcg1 and Rhcg2 increased. Exposure to HEA only increased branchial Rhcg2 levels. Although internal ammonia loading only led to a modest non significant increase in JAmm, skin NKA (activity and alpha-subunit), carbonic anhydrase protein levels, and branchial Rhcg1 levels increased. In summary, variable responses were observed involving both gill and skin but given the instability of its habitat, the constitutive expression of transporters is likely also of importance. PMID- 24055760 TI - Breathing pattern and ventilatory chemosensitivity of the 1-day old Muscovy duck (Cairina moschata) in relation to its metabolic demands. AB - Adult birds have a ventilatory equivalent (pulmonary ventilation-oxygen consumption ratio, V E/ [Formula: see text] ) lower than mammals because of the superior gas exchange efficiency of their respiratory apparatus. In particular, adult Muscovy ducks (Cairina moschata) have been reported to have an extraordinary low ventilatory equivalent (~14mL STPD.mL BTPS(-1)). We asked if similar high efficiency was already apparent in duck hatchlings. Breathing pattern and VE were measured by the barometric technique and [Formula: see text] by an open-flow methodology in 1-day old Muscovy duck hatchlings (N=21); same measurements were performed on chicken hatchlings (N=21) for purpose of comparison. During air breathing VE/ [Formula: see text] was slightly, yet significantly, lower in ducklings (20.8) than in chicks (25.3), mostly because of a lower breathing frequency (f). The hatchlings of both species (N=14 per group) responded to inspired hypoxia (15 or 10% O2) or hypercapnia (2 or 4% CO2) with a clear hyperventilation; however, in ducklings the hypercapnic hyperventilation was smaller than in chicks because of a smaller increase in tidal volume and lower f. We conclude that duck and chicken hatchlings just a few hours old have the high ventilatory efficiency typical of birds, although possibly not as high as their adults. The low f and blunted VE response to hypercapnia of the newborn duck could be related to the aquatic habitat of the species. In such a case, it would mean that these characteristics are genetic traits, the phenotypic expression of which does not require diving experience. PMID- 24055761 TI - Can nonlinguistic musical training change the way the brain processes speech? The expanded OPERA hypothesis. AB - A growing body of research suggests that musical training has a beneficial impact on speech processing (e.g., hearing of speech in noise and prosody perception). As this research moves forward two key questions need to be addressed: 1) Can purely instrumental musical training have such effects? 2) If so, how and why would such effects occur? The current paper offers a conceptual framework for understanding such effects based on mechanisms of neural plasticity. The expanded OPERA hypothesis proposes that when music and speech share sensory or cognitive processing mechanisms in the brain, and music places higher demands on these mechanisms than speech does, this sets the stage for musical training to enhance speech processing. When these higher demands are combined with the emotional rewards of music, the frequent repetition that musical training engenders, and the focused attention that it requires, neural plasticity is activated and makes lasting changes in brain structure and function which impact speech processing. Initial data from a new study motivated by the OPERA hypothesis is presented, focusing on the impact of musical training on speech perception in cochlear implant users. Suggestions for the development of animal models to test OPERA are also presented, to help motivate neurophysiological studies of how auditory training using non-biological sounds can impact the brain's perceptual processing of species-specific vocalizations. This article is part of a Special Issue entitled . PMID- 24055762 TI - Cation-pi interactions in high resolution protein-RNA complex crystal structures. AB - In this work, we have analyzed the influence of cation-pi interactions to the stability of 59 high resolution protein-RNA complex crystal structures. The total number of Lys and Arg are similar in the dataset as well as the number of their interactions. On the other hand, the aromatic chains of purines are exhibiting more cation-pi interactions than pyrimidines. 35% of the total interactions in the dataset are involved in the formation of multiple cation-pi interactions. The multiple cation-pi interactions have been conserved more than the single interactions. The analysis of the geometry of the cation-pi interactions has revealed that the average distance (d) value falls into distinct ranges corresponding to the multiple (4.28 A) and single (5.50 A) cation-pi interactions. The G-Arg pair has the strongest interaction energy of -3.68 kcal mol(-1) among all the possible pairs of amino acids and bases. Further, we found that the cation-pi interactions due to five-membered rings of A and G are stronger than that with the atoms in six-membered rings. 8.7% stabilizing residues are involved in building cation-pi interactions with the nucleic bases. There are three types of structural motifs significantly over-represented in protein-RNA interfaces: beta-turn-ir, niche-4r and st-staple. Tetraloops and kink turns are the most abundant RNA motifs in protein-RNA interfaces. Amino acids deployed in the protein-RNA interfaces are deposited in helices, sheets and coils. Arg and Lys, involved in cation-pi interactions, prefer to be in the solvent exposed surface. The results from this study might be used for structure based prediction and as scaffolds for future protein-RNA complex design. PMID- 24055763 TI - In vitro cytotoxicity assessment based on KC(50) with real-time cell analyzer (RTCA) assay. AB - Technological advances in cytotoxicity analysis have now made it possible to obtain real time data on changes in cell growth, morphology and cell death. This type of testing has a great potential for reducing and refining traditional in vivo toxicology tests. By monitoring the dynamic response profile of living cells via the xCELLigence real-time cell analyzer for high-throughput (RTCA HT) system, cellular changes including cell number (cell index, CI) are recorded and analyzed. A special scaled index defined as normalized cell index (NCI) is used in the analysis which reduces the influence of inter-experimental variations. To assess the extent of exposure of the tested chemicals, a two-exponent model is presented to describe rate of cell growth and death. This model is embodied in the time and concentration-dependent cellular response curves, and the parameters k1 and k2 in this model are used to describe the rate of cell growth and death. Based on calculated k2 values and the corresponding concentrations, a concentration-response curve is fitted. As a result, a cytotoxicity assessment named KC50 is calculated. The validation of the proposed method is demonstrated by exposing six cell lines to 14 chemical compounds. Our findings suggest that the proposed KC50-based toxicity assay can be an alternative to the traditional single time-point assay such as LC50 (the concentration at which 50% of the cells are killed). The proposed index has a potential for routine evaluation of cytotoxicities. Another advantage of the proposed index is that it extracts cytotoxicity information when CI fails to detect the low toxicity. PMID- 24055764 TI - A large scale virtual screen of DprE1. AB - Tuberculosis continues to plague the world with the World Health Organization estimating that about one third of the world's population is infected. Due to the emergence of MDR and XDR strains of TB, the need for novel therapeutics has become increasing urgent. Herein we report the results of a virtual screen of 4.1 million compounds against a promising drug target, DrpE1. The virtual compounds were obtained from the Zinc docking site and screened using the molecular docking program, AutoDock Vina. The computational hits have led to the identification of several promising lead compounds. PMID- 24055765 TI - Systematic review of allelic exchange experiments aimed at identifying mutations that confer drug resistance in Mycobacterium tuberculosis. AB - BACKGROUND: Improving our understanding of the relationship between the genotype and the drug resistance phenotype of Mycobacterium tuberculosis will aid the development of more accurate molecular diagnostics for drug-resistant tuberculosis. Studies that use direct genetic manipulation to identify the mutations that cause M. tuberculosis drug resistance are superior to associational studies in elucidating an individual mutation's contribution to the drug resistance phenotype. METHODS: We systematically reviewed the literature for publications reporting allelic exchange experiments in any of the resistance associated M. tuberculosis genes. We included studies that introduced single point mutations using specialized linkage transduction or site-directed/in vitro mutagenesis and documented a change in the resistance phenotype. RESULTS: We summarize evidence supporting the causal relationship of 54 different mutations in eight genes (katG, inhA, kasA, embB, embC, rpoB, gyrA and gyrB) and one intergenic region (furA-katG) with resistance to isoniazid, the rifamycins, ethambutol and fluoroquinolones. We observed a significant role for the strain genomic background in modulating the resistance phenotype of 21 of these mutations and found examples of where the same drug resistance mutations caused varying levels of resistance to different members of the same drug class. CONCLUSIONS: This systematic review highlights those mutations that have been shown to causally change phenotypic resistance in M. tuberculosis and brings attention to a notable lack of allelic exchange data for several of the genes known to be associated with drug resistance. PMID- 24055766 TI - Temocillin and piperacillin/tazobactam resistance by disc diffusion as antimicrobial surrogate markers for the detection of carbapenemase-producing Enterobacteriaceae in geographical areas with a high prevalence of OXA-48 producers. AB - OBJECTIVES: To assess the performance of the agar disc diffusion method for the detection of carbapenemase-producing Enterobacteriaceae (CPE) referred to the national reference laboratories (NRLs) in Belgium and France. METHODS: All Enterobacteriaceae isolates referred to the NRLs for the confirmation of CPE in 2012 were included. The inhibition zone diameters of meropenem, piperacillin/tazobactam and temocillin using CLSI disc diffusion methodology were recorded. Phenotypic and molecular detection of carbapenemases was performed on all isolates. RESULTS: A total of 1354 Enterobacteriaceae isolates, including 435 (32.1%) confirmed CPE isolates [OXA-48 (n = 323), KPC (n = 60), VIM (n = 32) and NDM (n = 20)] and 919 carbapenemase-negative isolates, were tested. Using recommended interpretative criteria, non-susceptibility to meropenem had poor sensitivity (52.0% by CLSI susceptibility breakpoint and 80.0% by EUCAST screening breakpoints), while non-susceptibility to piperacillin/tazobactam (according to CLSI breakpoint) or to temocillin (according to Fuchs, Barry, Thornsberry et al. Eur J Clin Microbiol 1985; 4: 30-3) was highly sensitive (99.8% and 98.2%, respectively) but poorly specific (29.4% and 42.9%, respectively) for the detection of CPE. Temocillin diameters <12 mm alone had high specificity (90.0%) and the combination of temocillin diameters >=12 mm with piperacillin/tazobactam diameters >=16 mm observed in 40% of all referred isolates displayed excellent negative predictive value (99.2%). CONCLUSIONS: In geographical areas with a high prevalence of OXA-48 producers, recommended meropenem susceptibility or screening breakpoints failed to detect CPE in a large proportion of isolates. The combination of modified zone diameter cut-offs for piperacillin/tazobactam (>=16 mm) and temocillin (>=12 mm) can be used to rule out the presence of carbapenemase and avoid unnecessary additional testing for confirmation of CPE. PMID- 24055767 TI - Salidroside stimulates osteoblast differentiation through BMP signaling pathway. AB - Salidroside (SAL) is one of main active components of Rhodiola rosea L. and possesses diverse pharmacological effects. However, the direct role of SAL in bone metabolism remains elusive. In this study, effects of SAL on osteoblast differentiation of murine pluripotent mesenchymal cell line C3H10T1/2 and osteoblastic cell line MC3T3-E1 were examined. We first identified SAL as a potential BMP2 activator in a cell-based screening assay. SAL (0.5-10 MUM) could slightly promote the proliferation and greatly increase the alkaline phosphatase (ALP) activity in both cells. Furthermore, SAL increased the mRNA expressions of osteoblast marker genes in either C3H10T1/2 or MC3T3-E1 cells after treatment for different time. Moreover, the mineralization of C3H10T1/2 cells assayed by Alizarin red S staining was dose-dependently increased by SAL. Mechanistically, SAL increased the mRNA level of genes involved in the regulation of BMP signaling pathway, including BMP2, BMP6 and BMP7 and enhanced the phosphorylation of Smad1/5/8 and ERK1/2. The osteogenic effect of SAL was abolished by BMP antagonist noggin or by BMP receptor kinase inhibitor dorsomorphin. Further in vivo study demonstrated that SAL reversed bone loss in ovariectomized rats. Collectively, our findings indicate that SAL regulates bone metabolism through BMP signaling pathway. PMID- 24055768 TI - Toxic essential oils. Part III: identification and biological activity of new allylmethoxyphenyl esters from a Chamomile species (Anthemis segetalis Ten.). AB - To determine the exact structure of previously tentatively identified minor essential-oil constituents of a Chamomile species (Antemis segetalis Ten. (Asteraceae)), we have synthesized a small combinatorial library of 54 regioisomeric allylmethoxyphenyl pentanoates and 2-pentenoates (49 completely new compounds). GC-MS in combination with 1D- and 2D-NMR analyses of the library compounds provided unambiguous data that led to a straightforward identification of the mentioned A. segetalis constituents as eugenyl angelate, 2-methylbutanoate and 3-methylbutanoate (0.21, 0.22, and 0.13 mg/100 g of fresh plant material, respectively). To assess the safety and potential beneficial pharmacological uses of these naturally occurring esters and several other library compounds (these were tested to provide relevant data for a SAR (structure-activity relationship) analysis), we have studied the effect of these compounds in several models of toxicity (acute toxicity against Artemia salina, cytotoxicity against two cell lines (fibroblast and melanoma)), as well as their acetylcholinesterase inhibitory and antibacterial activities. Anthemis segetalis constituents showed low to moderate activity in all tests. The obtained results suggest that the intake of these compounds in naturally available amounts, on their own, would probably not represent a risk to human health but the possible adverse interactions with the plant matrix should not be neglected. PMID- 24055769 TI - Anti-inflammatory effect of austroinulin and 6-O-acetyl-austroinulin from Stevia rebaudiana in lipopolysaccharide-stimulated RAW264.7 macrophages. AB - Austroinulin (AI) and 6-O-acetyl-austroinulin (6-OAAI) are natural diterpenoids isolated from Stevia rebaudiana with anti-inflammatory activity. However, the mechanisms underlying their anti-inflammatory effects are not well understood. The purpose of this study was to investigate the effect of AI and 6-OAAI on nitric oxide (NO) production and their molecular mechanism in LPS-stimulated RAW264.7 macrophages. We found that AI and 6-OAAI inhibit the production of NO, iNOS, and pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1beta, and MCP-1) in LPS-stimulated RAW264.7 macrophages. In these same cells, AI and 6-OAAI also suppressed the phosphorylation of STAT1 and the production of interferon-beta (IFN-beta). Moreover, treatment with AI and 6-OAAI inhibited the activation of interferon regulatory factor-3 (IRF3) and NF-kappaB. Taken together, our results suggest that AI and 6-OAAI inhibit NO production and iNOS expression by blocking the activation of STAT1, IRF3, and NF-kappaB in LPS-stimulated RAW264.7 macrophages. PMID- 24055770 TI - Purification, physicochemical and immunological characterization of arginine kinase, an allergen of crayfish (Procambarus clarkii). AB - Arginine kinase (AK) has attracted considerable attention because it has been identified as a shellfish allergen. However, little information is available about AK in crayfish (Procambarus clarkii). In this study, crayfish AK was purified and cloned. Its physicochemical properties, processing stability, and immunological characteristics were analyzed. Crayfish AK was purified by column chromatography, which revealed a single band with molecular mass of 40 kDa; this result was further confirmed by mass spectrometry. The full-length gene sequence of crayfish AK was 1462 bp and encoded a protein of 357 amino acid residues. The results of this study revealed that crayfish AK is a glycoprotein with an isoelectric point of approximately 6.5. Thermal stability assays revealed that crayfish AK easily forms aggregates at temperatures >44 degrees C and was stable at pH 4.0-8.0. SDS-PAGE and dot blotting were used to assess processing stability of purified AK. The results revealed that the IgE-binding activity of crayfish AK is reduced after boiling. PMID- 24055771 TI - Dose-dependent folic acid and memantine treatments promote synergistic or additive protection against Abeta(25-35) peptide-induced apoptosis in SH-SY5Y cells mediated by mitochondria stress-associated death signals. AB - Increased dietary folic acid (FA) is associated with reduced risks of Alzheimer's disease (AD). The AD drug memantine (Mn) has had limited therapeutic effects for the treatment of patients with moderate to severe AD. This study investigated whether and the underlying mechanisms by which the combination of Mn and FA may have synergistic or additive effects in protecting against amyloid-beta(25-35) peptide (Abeta)-induced neurocytotoxicity. Abeta treatment of human neuroblastoma SH-SY5Y cells significantly induced a 6-fold increase of apoptotic cells compared with the Abeta-untreated group. Preincubation of Abeta-exposed cells with FA (500 MUM) or Mn (20 MUM) caused a 22% and 10% reduction of apoptotic cells, respectively, whereas the combo-treatments at such doses synergistically alleviated Abeta-induced apoptosis by 60% (P<0.05). The apoptotic protection by the combo-treatments coincided with attenuating Abeta-elicited mitochondrial (mt) membrane depolarization and abolishing Abeta-induced mt cytochrome c release to the cytosol. Increased levels of FA at 1000 MUM in combination with 20 MUM Mn exerted an additive protection against Abeta(25-35)-induced-apoptosis as compared to the isolate Mn group (P<0.05). The combo-treatments reversed Abeta-elicited mt membrane depolarization, attenuated Abeta-elicited mt cytochrome c release to the cytosol, and diminished Abeta-promoted superoxide generation. The apoptotic protection by such combo-treatments was partially abolished by carbonyl cyanide 3 chlorophenylhydrazone (mt membrane potential uncoupler) and sodium azide (mt cytochrome c oxidase inhibitor). Taken together, the data demonstrated that dose dependent FA and Mn synergistically or additively protected SH-SY5Y cells against Abeta-induced apoptosis, which was partially, if not completely, mediated by mt stress-associated death signals. PMID- 24055772 TI - Efficient derivation of cortical glutamatergic neurons from human pluripotent stem cells: a model system to study neurotoxicity in Alzheimer's disease. AB - Alzheimer's disease (AD) is among the most prevalent forms of dementia affecting the aging population, and pharmacological therapies to date have not been successful in preventing disease progression. Future therapeutic efforts may benefit from the development of models that enable basic investigation of early disease pathology. In particular, disease-relevant models based on human pluripotent stem cells (hPSCs) may be promising approaches to assess the impact of neurotoxic agents in AD on specific neuronal populations and thereby facilitate the development of novel interventions to avert early disease mechanisms. We implemented an efficient paradigm to convert hPSCs into enriched populations of cortical glutamatergic neurons emerging from dorsal forebrain neural progenitors, aided by modulating Sonic hedgehog (Shh) signaling. Since AD is generally known to be toxic to glutamatergic circuits, we exposed glutamatergic neurons derived from hESCs to an oligomeric pre-fibrillar forms of Abeta known as "globulomers", which have shown strong correlation with the level of cognitive deficits in AD. Administration of such Abeta oligomers yielded signs of the disease, including cell culture age-dependent binding of Abeta and cell death in the glutamatergic populations. Furthermore, consistent with previous findings in postmortem human AD brain, Abeta-induced toxicity was selective for glutamatergic rather than GABAeric neurons present in our cultures. This in vitro model of cortical glutamatergic neurons thus offers a system for future mechanistic investigation and therapeutic development for AD pathology using human cell types specifically affected by this disease. PMID- 24055773 TI - The sweetest pill to swallow: how patient neurobiology can be harnessed to maximise placebo effects. AB - The burgeoning interest in placebo effects over the last 10-15 years has fallen into two main research areas: elucidation of the neurobiological mechanisms recruited following placebo administration, and investigations into the situations and contexts in which placebo effects are evoked. There has been little attention focused on bridging these two i.e. how to actively translate and apply these neurobiological mechanisms into daily clinical practice in a responsible way. This article addresses this gap, first through a narrative review of the last 15 years of neuroscience findings with special attention focussed on the elucidation of the neurotransmitters, pathways and mechanisms involved in placebo effects, and secondly, at how these psycho(neuro)biological effects could be harnessed in medical care. PMID- 24055774 TI - Development of a homogeneous assay for measurement of high-density lipoprotein subclass cholesterol. AB - BACKGROUND: Several studies have suggested that measurement of high-density lipoprotein (HDL) 2 and HDL3 subfractions might be more useful for evaluating coronary risk than total HDL-cholesterol (C). However, methods of measuring HDL2 and HDL3 are quite laborious for general clinical use. Development of a quick and easy method of measuring HDL subfractions has been long-awaited. METHODS: Triglyceride (TG) rich lipoproteins (TRLs), low-density lipoprotein (LDL), HDL2, and HDL3 were used for screening of surfactants and enzymes to react selectively with HDL3-C and to decompose other lipoproteins. RESULTS: In order to develop HDL3-C homogeneous assay, polyoxyethylene styrenated phenyl ether derivative, for which the hydrophilic lipophilic balance (HLB) value is 13.6, was adopted as the most effective and specific surfactant for selection of HDL3 from HDL. Sphingomyelinase (SMase) reacted with TRLs and LDL preferentially, and decomposed them. HDL2-C was estimated by subtracting measured HDL3-C from total HDL-C, directly measured by homogeneous method. The homogeneous assay exhibited excellent correlations with the results of HDL3-C and HDL2-C measured by standard ultracentrifugation (R(2)=0.848 and 0.982, respectively). CONCLUSIONS: We established a rapid and effective, fully-automated assay for the measurement of HDL3-C. Furthermore, the subtraction of HDL3-C from total HDL-C allows concurrent determination of HDL2-C. PMID- 24055775 TI - Clinical significance of serum BAP, TRACP 5b and ICTP as bone metabolic markers for bone metastasis screening in lung cancer patients. AB - BACKGROUND: We investigated the clinical significance of serum bone-specific alkaline phosphatase (BAP), tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) and type I collagen carboxyterminal telopeptide (ICTP) as bone metabolic markers for bone metastasis (BM) screening in lung cancer patients. METHODS: Newly diagnosed advanced lung cancer patients with (N = 130) and without (N = 135) BM were enrolled in the study. Serum BAP, TRACP 5b and ICTP were measured before the treatment. RESULTS: BAP, TRACP 5b and ICTP values were higher in patients with BM compared with patients without BM (all P < 0.0001). Area under ROC curve (AUC) of BAP, TRACP 5b and ICTP was 0.760, 0.753 and 0.835 (all P < 0.0001), respectively. The cut-off values for BAP, TRACP 5b and ICTP were 21.8 MUg/l, 7.8 U/l and 8.8 MUg/l, respectively. When TRACP 5b and ICTP were combined, AUC was elevated to 0.895 (P < 0.0001), and the cut-off values were TRACP 5b 7.6 U/l and ICTP 8.4 MUg/l. CONCLUSIONS: We conclude that serum BAP, TRACP 5b and ICTP may serve as useful tools for BM screening in lung cancer patients. PMID- 24055776 TI - Plasma globotriaosylsphingosine (lysoGb3) could be a biomarker for Fabry disease with a Chinese hotspot late-onset mutation (IVS4+919G>A). AB - BACKGROUND: Previous studies revealed a high incidence of late-onset Fabry disease mutation, IVS4+919G>A, in Taiwan. However, the natural course is largely unclear and suitable biomarkers for monitoring disease progress are unavailable. METHODS AND RESULTS: Patients carrying IVS4+919G>A or classical Fabry mutations were enrolled in this study. The subjects ranged from newborn to eighty year old adults. Plasma globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) were measured by LC-MS/MS in subjects to evaluate the sensitivity of these two biomarkers. All adult males and symptomatic females could be distinguished from healthy controls by an elevated plasma lysoGb3 level. The lysoGb3 level was also related to the left ventricular mass considering gender and age (p<0.01). Moreover, approximately 70% of male and 45% of female newborns already had an elevated plasma lysoGb3 level which increased gradually as the subjects got older (p<0.01). CONCLUSIONS: Plasma lysoGb3 is a more sensitive and reliable biomarker than plasma Gb3. LysoGb3 also correlated with age and left ventricular mass index in Fabry patients with IVS4+919G>A mutation. Because lots of infants with the IVS4+919G>A mutation already had elevated lysoGb3 levels at birth, that indicates that the development of hypertrophic cardiomyopathy may require a long and insidious course after lysoGb3 accumulation. PMID- 24055777 TI - Production of 4-hydroxybutyric acid by metabolically engineered Mannheimia succiniciproducens and its conversion to gamma-butyrolactone by acid treatment. AB - gamma-Butyrolactone (GBL) is an important four carbon (C4) chemical, which has a wide range of industrial applications. GBL can be produced by acid treatment of 4 hydroxybutyric acid (4-HB), which is a derivative of succinic acid. Heterologous metabolic pathways were designed and established in succinic acid overproducing Mannheimia succiniciproducens LPK7 (ldhA pflD pta ackA mutant) by the introduction of heterologous genes that encode succinyl-CoA synthetase, CoA dependent succinate semialdehyde dehydrogenase, and either 4-hydroxybutyrate dehydrogenase in LPK7 (p3S4CD) or succinate semialdehyde reductase in LPK7 (p3SYCD). Fed-batch cultures of LPK7 (p3S4CD) and LPK7 (p3SYCD) resulted in the production of 6.37 and 6.34 g/L of 4-HB (molar yields of 0.143 and 0.139), respectively. Finally, GBL was produced by acid treatment of the 4-HB obtained from the fermentation broth with molar yield of 0.673. This study demonstrates that 4-HB, and potentially other four carbon platform chemicals, can be produced by the engineered rumen bacterium M. succiniciproducens. PMID- 24055778 TI - Activation of efferents from the basolateral amygdala during the retrieval of conditioned taste aversion. AB - The basolateral amygdala (BLA) is critical in the retrieval of conditioned taste aversion (CTA). Although BLA neurons have axonal connections with several brain regions, it is unclear which efferent pathways are functional in CTA. The present study investigated the involvement of efferents from BLA in CTA retrieval with manganese (Mn(2+))-enhanced magnetic resonance imaging (MEMRI). Rats receiving intraoral saccharin infusion paired with intraperitoneal administration of lithium chloride (LiCl) were presented with saccharin (C-S and BC-S groups) or water (C-W group) on the test day. The BC-S group was administered with LiCl 15 min before saccharin presentation on the conditioning day (backward conditioning, BC). Another two groups were injected with saline (S-S and S-W groups) instead of LiCl. On the test day, 50 nL of 40-mM manganese chloride (MnCl2) was injected into BLA before the intraoral fluid infusion. Using MRI, we analyzed Mn(2+) movements, which indicated the activation of efferent neurons. The C-S group showed the highest activities in several efferents from BLA. Of them, the activities of the efferents to the nucleus accumbens core (NAcC), the anterior part of the bed nucleus of the stria terminalis (aBNST), and the central amygdala (CeA) were larger in the C-S group than in the Q group, which was presented with a normally aversive quinine solution. Although rats equivalently rejected conditioned aversive saccharin and quinine, the aversive responses in the C-S group, and not the Q group, were due to CTA retrieval. Therefore, our results indicated that BLA efferents to NAcC, aBNST, and CeA were specifically activated during CTA retrieval, suggesting that these efferents are key components in the neural mechanisms of CTA. PMID- 24055779 TI - The role of International Sport Federations in the protection of the athlete's health and promotion of sport for health of the general population. AB - OBJECTIVE: To determine the priorities and activities of International Sport Federations (IFs) with respect to the promotion of health in their sport and for the general population. METHODS: All 35 IFs participating in Olympic Games in 2014 or in 2016 were asked to rate the importance of 10 indicated topics, and to report their programmes, guidelines or research activities on 16 health-related topics using an online questionnaire (response rate 97%). RESULTS: On average, the 'fight against doping' had the highest priority followed by 'health of their elite athlete' and 'image as a safe sport'. The topics with the lowest importance ratings were 'health of their recreational athlete', 'increasing the number of recreational athletes' and 'health of the general population'. All except one IF reported to have health-related programmes/guidelines/research activities; most IFs had 7 or 8 of the listed activities. Eight IFs (23.5%) stated to have activities for 'prevention of chronic diseases in the general population' but only FIFA and FINA reported related projects. CONCLUSIONS: IFs aimed to protect the health of their elite athletes through a variety of activities, however the health and number of their recreational athletes was of low importance for them. Thus, IFs are missing an important opportunity to increase the popularity of their sport, and to contribute to the health of the general population by encouraging physical activity through their sport. FIFA's 'Football for Health' and FINA's 'Swim for All' projects could serve as role models. PMID- 24055780 TI - Body composition in sport: a comparison of a novel ultrasound imaging technique to measure subcutaneous fat tissue compared with skinfold measurement. AB - BACKGROUND: Extremely low weight and rapid changes in weight and body composition have become major concerns in many sports, but sufficiently accurate field methods for body composition assessment in athletes are missing. This study aimed to explore the use of ultrasound methods for assessment of body fat content in athletes. METHODS: 19 female athletes (stature: 1.67(+/- 0.06) m, weight: 59.6(+/ 7.6) kg; age: 19.5(+/- 3.3) years) were investigated by three observers using a novel ultrasound method for thickness measurement of uncompressed subcutaneous adipose tissue and of embedded structures. Two observers also measured skinfold thickness at eight International Society for the Advancement of Kinanthrometry (ISAK) sites; mean skinfold values were compared to mean subcutaneous adipose tissue thicknesses measured by ultrasound. Interobserver reliability of imaging and evaluation obtained by this ultrasound technique: intraclass correlation coefficient ICC=0.968 (95% CI 0.957 to 0.977); evaluation of given images: ICC=0.997 (0.993 to 0.999). RESULTS: Skinfold compared to ultrasound thickness showed that compressibility of subcutaneous adipose tissue depends largely on the site and the person: regression slopes ranged from 0.61 (biceps) to 1.59 (thigh) and CIs were large. Limits of agreement ranged from 2.6 to 8.6 mm. Regression lines did not intercept the skinfold axis at zero because of the skin thickness being included in the skinfold. The four ISAK trunk sites caused ultrasound imaging problems in 13 of 152 sites (8 ISAK sites, 19 athletes). CONCLUSIONS: The ultrasound method allows measurement of uncompressed subcutaneous adipose tissue thickness with an accuracy of 0.1-0.5 mm, depending on the probe frequency. Compressibility of the skinfold depends on the anatomical site, and skin thickness varies by a factor of two. This inevitably limits the skinfold methods for body fat estimation. Ultrasound accuracy for subcutaneous adipose tissue measurement is limited by the plasticity of fat and furrowed tissue borders. Comparative US measurements show that skinfold measurements do not allow accurate assessment of subcutaneous adipose tissue thickness. PMID- 24055781 TI - Position statement on youth resistance training: the 2014 International Consensus. AB - The current manuscript has been adapted from the official position statement of the UK Strength and Conditioning Association on youth resistance training. It has subsequently been reviewed and endorsed by leading professional organisations within the fields of sports medicine, exercise science and paediatrics. The authorship team for this article was selected from the fields of paediatric exercise science, paediatric medicine, physical education, strength and conditioning and sports medicine. PMID- 24055782 TI - Current hydration guidelines are erroneous: dehydration does not impair exercise performance in the heat. AB - BACKGROUND: Laboratory studies that support the hydration guidelines of leading governing bodies have shown that dehydration to only -2% of body mass can lead to increase in body temperature and heart rate during exercise, and decrease in performance. These studies, however, have been conducted in relatively windless environments (ie, wind speed <12.9 km/h), without participants being blinded to their hydration status. AIM: To investigate the effect of blinded hydration status on cycling time-trial performance in the heat with ecologically valid facing wind speed conditions. METHODS: During three experimental trials, 10 cyclists were dehydrated to -3% body mass by performing 2 h of submaximal exercise (walking and cycling) in the heat, before being reinfused with saline to replace 100%, 33% or 0% of fluid losses, leaving them 0%, -2% or -3% hypohydrated, respectively. Participants then completed a 25 km time trial in the heat (33 degrees C, 40% relative humidity; wind speed 32 km/h) during which their starting hydration status was maintained by infusing saline at a rate equal to their sweat rate. The treatment was participant-blinded and the order was randomised. Completion time, power output, heart rate, rectal temperature and perceptual variables were measured. RESULTS: While rectal temperature was higher beyond 17 km of the time trial in the -3% vs 0% conditions (38.9+/-0.3 degrees C vs 38.6+/-0.3 degrees C; p<0.05), no other differences between trials were shown. CONCLUSION: When well-trained cyclists performed a 25 km cycling time trial under ecologically valid conditions and were blinded to their hydration status, performance, physiological and perceptual variables were not different between trials. These data do not support the residing basis behind many of the current hydration guidelines. PMID- 24055783 TI - Exploring the clinical course of neck pain in physical therapy: a longitudinal study. AB - OBJECTIVE: To investigate the short-term trajectory of recovery from mechanical neck pain, and predictors of trajectory. DESIGN: Prospective, longitudinal cohort study with 5 repeated measurements over 4 weeks. SETTING: Community-based physical therapy clinics. PARTICIPANTS: Convenience sample of community-dwelling adults (N=50) with uncomplicated mechanical neck disorders of any duration. INTERVENTIONS: Usual physical therapy care. MAIN OUTCOME MEASURES: Neck Disability Index (NDI), numeric rating scale (NRS) of pain intensity. RESULTS: A total of 50 consecutive subjects provided 5 data points over 4 weeks. Exploratory modeling using latent class growth analysis revealed a linear trend in improvement, at a mean of 1.5 NDI points and 0.5 NRS points per week. Within the NDI trajectory, 3 latent classes were identified, each with a unique trend: worsening (14.5%), rapid improvement (19.6%), and slow improvement (65.8%). Within the NRS trajectory, 2 unique trends were identified: stable (48.0%) and improving (52.0%). Predictors of trajectory class suggest that it may be possible to predict the trajectory. Results are described in view of the sample size. CONCLUSIONS: The mean trajectory of improvement in neck pain adequately fits a linear model and suggests slow but stable improvement over the short term. However, up to 3 different trajectories have been identified that suggest neck pain, and recovery thereof, is not homogenous. This may hold value for the design of clinical trials. PMID- 24055784 TI - Frequency, characteristics, and consequences of falls in multiple sclerosis: findings from a cohort study. AB - OBJECTIVE: To evaluate falls rate and the characteristics of falls (including fall-related injuries) in a multiple sclerosis (MS) cohort. DESIGN: As part of a study evaluating falls risk, a cohort of 150 participants prospectively recorded actual and near fall events using a daily diary over 3 months, as well as the circumstances of each fall including related injuries. SETTING: Community setting. PARTICIPANTS: A population-based sample of people (N=150) with a confirmed diagnosis of MS (Expanded Disability Status Scale, 3.5-6.5) was recruited via a patient-centered longitudinal study database of disease course in people with MS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Rate of actual and near falls, circumstances and consequences of falls (including rates and type of injury plus follow-up care). RESULTS: The response rate for the falls diary was 92.7%. A total of 672 actual falls and 3785 near falls were recorded, with a moderate correlation between the numbers of actual and near falls per person (rho=.474; 95% confidence interval, .34-.59). Men recorded significantly more falls than women. Falls were associated with a range of activities, although 27.6% occurred during general mobility activities such as walking, turning, and moving between positions. Injuries occurred in 11.1% of falls, with 6 individuals requiring medical attention. CONCLUSIONS: People with MS experience high numbers of falls, with associated injuries. Falls occur during a wide range of activities, reflecting their potential impact on daily life. Evaluating the characteristics of individuals who experience frequent near falls but few actual falls may be valuable for research and clinical practice. PMID- 24055785 TI - Diffusion tensor imaging study of the response to constraint-induced movement therapy of children with hemiparetic cerebral palsy and adults with chronic stroke. AB - OBJECTIVE: To investigate the relationship of white matter integrity and path of the corticospinal tract (CST) on arm function before and after constraint-induced (CI) movement therapy in children with hemiparetic cerebral palsy (CP) and adults with chronic stroke. DESIGN: Study 1 used a multiple-baseline pre-post design. Study 2 was a randomized controlled trial. SETTING: Outpatient rehabilitation laboratory. PARTICIPANTS: Study 1 included children with hemiparetic CP (n=10; mean age +/- SD, 3.2+/-1.7y). Study 2 included adults with chronic stroke (n=26; mean age +/- SD, 65.4+/-13.6y) who received either CI therapy or a comparison therapy. INTERVENTIONS: Children in study 1 received CI therapy for 3.5h/d for 15 consecutive weekdays. Adults in study 2 received either CI therapy or a comparison therapy for 3.5h/d for 10 consecutive weekdays. MAIN OUTCOME MEASURES: Diffusion tensor imaging was performed to quantify white matter integrity. Motor ability was assessed in children using the Pediatric Motor Activity Log-Revised and Pediatric Arm Function Test, and in adults with the Motor Activity Log and Wolf Motor Function Test. RESULTS: Participants in both studies improved in real world arm function and motor capacity. Children and adults with disrupted/displaced CSTs and children with reduced fractional anisotropy values were worse on pretreatment tests of motor function than participants with unaltered CSTs. However, neither integrity (fractional anisotropy) nor distorted or disrupted path of the CST affected motor improvement after treatment. CONCLUSIONS: Participants who had reduced integrity, displacement, or interruption of their CST performed worse on pretreatment motor testing. However, this had no effect on their ability to benefit from CI therapy. The results for children and adults are consistent with one another. PMID- 24055786 TI - Acute prenatal exposure to a moderate dose of valproic acid increases social behavior and alters gene expression in rats. AB - Prenatal exposure to moderate doses of valproic acid (VPA) produces brainstem abnormalities, while higher doses of this teratogen elicit social deficits in the rat. In this pilot study, we examined effects of prenatal exposure to a moderate dose of VPA on behavior and on transcriptomic expression in three brain regions that mediate social behavior. Pregnant Long Evans rats were injected with 350 mg/kg VPA or saline on gestational day 13. A modified social interaction test was used to assess social behavior and social preference/avoidance during early and late adolescence and in adulthood. VPA-exposed animals demonstrated more social investigation and play fighting than control animals. Social investigation, play fighting, and contact behavior also differed as a function of age; the frequency of these behaviors increased in late adolescence. Social preference and locomotor activity under social circumstances were unaffected by treatment or age. Thus, a moderate prenatal dose of VPA produces behavioral alterations that are substantially different from the outcomes that occur following exposure to a higher dose. At adulthood, VPA-exposed subjects exhibited transcriptomic abnormalities in three brain regions: anterior amygdala, cerebellar vermis, and orbitofrontal cortex. A common feature among the proteins encoded by the dysregulated genes was their ability to be modulated by acetylation. Analysis of the expression of individual exons also revealed that genes involved in post translational modification and epigenetic regulation had particular isoforms that were ubiquitously dysregulated across brain regions. The vulnerability of these genes to the epigenetic effects of VPA may highlight potential mechanisms by which prenatal VPA exposure alters the development of social behavior. PMID- 24055788 TI - Dynamic gene expression for metabolic engineering of mammalian cells in culture. AB - Recombinant mammalian cells are the major hosts for the production of protein therapeutics. In addition to high expression of the product gene, a hyper producer must also harbor superior phenotypic traits related to metabolism, protein secretion, and growth control. Introduction of genes endowing the relevant hyper-productivity traits is a strategy frequently used to enhance the productivity. Most of such cell engineering efforts have been performed using constitutive expression systems. However, cells respond to various environmental cues and cellular events dynamically according to cellular needs. The use of inducible systems allows for time dependent expression, but requires external manipulation. Ideally, a transgene's expression should be synchronous to the host cell's own rhythm, and at levels appropriate for the objective. To that end, we identified genes with different expression dynamics and intensity ranges using pooled transcriptome data. Their promoters may be used to drive the expression of the transgenes following the desired dynamics. We isolated the promoter of the Thioredoxin-interacting protein (Txnip) gene and demonstrated its capability to drive transgene expression in concert with cell growth. We further employed this Chinese hamster promoter to engineer dynamic expression of the mouse GLUT5 fructose transporter in Chinese hamster ovary (CHO) cells, enabling them to utilize sugar according to cellular needs rather than in excess as typically seen in culture. Thus, less lactate was produced, resulting in a better growth rate, prolonged culture duration, and higher product titer. This approach illustrates a novel concept in metabolic engineering which can potentially be used to achieve dynamic control of cellular behaviors for enhanced process characteristics. PMID- 24055787 TI - Development of an electronic alcohol screening and brief intervention program for hospital outpatients with unhealthy alcohol use. AB - BACKGROUND: Alcohol screening and brief intervention is recommended for widespread implementation in health care systems, but it is not used routinely in most countries for a variety of reasons. Electronic screening and brief intervention (e-SBI), in which patients complete a Web-based questionnaire and are provided with personalized feedback on their drinking, is a promising alternative to practitioner delivered intervention, but its efficacy in the hospital outpatient setting has not been established. OBJECTIVE: The objective of our study was to establish the feasibility of conducting a full-scale randomized controlled trial to determine whether e-SBI reduces alcohol consumption in hospital outpatients with hazardous or harmful drinking. METHODS: The study was conducted in the outpatient department of a large public hospital in Newcastle (population 540,000), Australia. Adults with appointments at a broad range of medical and surgical outpatient clinics were invited to complete an e-SBI program on a laptop, and to report their impressions via a short questionnaire. Follow-up assessments were conducted 2-8 weeks later by email and post. RESULTS: We approached 172 outpatients and 108/172 (62.8%) agreed to participate. Of the 106 patients capable of self-administering the e-SBI, 7/106 (6.6%) did not complete it (3 due to technical problems and 4 because they were called for their appointment), 15/106 (14.2%) indicated that they had not consumed any alcohol in the past 12 months, 43/106 (40.6%) screened negative for unhealthy alcohol use (scored less than 5 on the Alcohol Use Disorders Identification Test Consumption [AUDIT-C] questions), 33/106 (31.1%) screened positive for hazardous or harmful drinking (AUDIT-C score 5-9), and 8/106 (7.5%) screened positive for possible alcohol dependence (AUDIT-C score 10-12). Among the subgroup with hazardous or harmful drinking, 27/33 (82%) found the feedback on their drinking very, quite, or somewhat useful, 33/33 (100%) thought the intervention would appeal to most or some of the people who attend the service, and 22/30 (73%) completed the follow up. We also found that some well established procedures used in trials of e-SBI in the primary care setting did not translate to the hospital outpatient setting (1) we experienced delays because the e-SBI program had to be developed and maintained by the health service's information technology staff for security reasons, (2) recruiting patients as they left the reception desk was impractical because patients tended to arrive at the beginning of the clinics with few arrivals thereafter, and (3) use of a laptop in a fixed location resulted in some patients rushing through the e-SBI so they could return to their seat in the area they had been advised to wait in. CONCLUSIONS: e-SBI is acceptable to outpatients and with some adaptation to organizational and physical conditions, it is feasible to recruit and screen patients and to deliver the intervention without disrupting normal service provision. This suggests that e-SBI could be provided routinely in this important setting if shown to be efficacious. PMID- 24055789 TI - In vitro production of n-butanol from glucose. AB - The heat treatment of recombinant mesophiles having heterologous thermotolerant enzymes results in the one-step preparation of highly selective biocatalytic modules. The assembly of these modules enables us to readily construct an artificial metabolic pathway in vitro. In this work, we constructed a non natural, cofactor-balanced, and oxygen-insensitive pathway for n-butanol production using 16 thermotolerant enzymes. The whole pathway was divided into 7 parts, in each of which NAD(H)-dependent enzymes were assigned to be the last step, and the fluxes through each part were spectrophotometrically determined. This real-time monitoring technique enabled the experimental optimization of enzyme level to achieve a desired production rate. Through the optimized pathway, n-butanol could be produced from glucose with a molar yield of 82% at a rate of 8.2 umol l(-1) min(-1). Our approach would be widely applicable to the rational optimization of artificial metabolic pathways as well as to the in vitro production of value-added biomolecules. PMID- 24055790 TI - Model-driven rebalancing of the intracellular redox state for optimization of a heterologous n-butanol pathway in Escherichia coli. AB - The intracellular redox state plays an important role in the cellular physiology that determines the efficiency of chemical and biofuel production by microbial cell factories. However, it is difficult to achieve optimal redox rebalancing of synthetic pathways owing to the sensitive responses of cellular physiology according as the intracellular redox state changes. Here, we demonstrate optimal rebalancing of the intracellular redox state by model-driven control of expression using n-butanol production in Escherichia coli as a model system. The synthetic n-butanol production pathway was constructed by implementing synthetic constitutive promoters and designing synthetic 5'-untranslated regions (5'-UTR) for each gene. Redox rebalancing was achieved by anaerobically activating the pyruvate dehydrogenase (PDH) complex and additionally tuning the expression level of NAD(+)-dependent formate dehydrogenase (fdh1 from Saccharomyces cerevisiae) through rational UTR engineering. Interestingly, efficient production of n butanol required different amounts of reducing equivalents depending on whether the substrate was glucose or galactose. One intriguing implication of this work is that additional strain improvement can be achieved, even within given genetic components, through rebalancing intracellular redox state according to target products and substrates. PMID- 24055791 TI - Visible propagation from invisible exogenous cueing. AB - Perception and performance is affected not just by what we see but also by what we do not see-inputs that escape our awareness. While conscious processing and unconscious processing have been assumed to be separate and independent, here we report the propagation of unconscious exogenous cueing as determined by conscious motion perception. In a paradigm combining masked exogenous cueing and apparent motion, we show that, when an onset cue was rendered invisible, the unconscious exogenous cueing effect traveled, manifesting at uncued locations (4 degrees apart) in accordance with conscious perception of visual motion; the effect diminished when the cue-to-target distance was 8 degrees apart. In contrast, conscious exogenous cueing manifested in both distances. Further evidence reveals that the unconscious and conscious nonretinotopic effects could not be explained by an attentional gradient, nor by bottom-up, energy-based motion mechanisms, but rather they were subserved by top-down, tracking-based motion mechanisms. We thus term these effects mobile cueing. Taken together, unconscious mobile cueing effects (a) demonstrate a previously unknown degree of flexibility of unconscious exogenous attention; (b) embody a simultaneous dissociation and association of attention and consciousness, in which exogenous attention can occur without cue awareness ("dissociation"), yet at the same time its effect is contingent on conscious motion tracking ("association"); and (c) underscore the interaction of conscious and unconscious processing, providing evidence for an unconscious effect that is not automatic but controlled. PMID- 24055792 TI - A comparison of resin-modified glass-ionomer and resin composite polymerisation shrinkage stress in a wet environment. AB - OBJECTIVE: The aim of this study was to investigate the polymerisation shrinkage stress under water of four resin-modified glass-ionomers and three resin composite materials. METHODS: Transparent acrylic rods (5mm diameter*30mm) were prepared and secured into drill chucks connected to a universal testing machine. A plastics cup was placed around the lower rod and a distance of 1.00mm was established between the prepared surfaces which provided a C-factor of 2.5. For composite only, an adhesive layer (Scotchbond Universal Adhesive) was placed on the rod ends and cured to achieve a bond with the rod end. Materials were placed between the rods and a strain gauge extensometer was installed. Materials were light cured for 40s and the plastics cup was filled with ambient temperature water. To determine polymerisation shrinkage stress (sigmapol) three specimens of each material were tested for a 6-h period to determine mean maximum sigmapol (MPa), sigmapol rate (MPa/s) and final sigmapol (MPa). ANOVA and post hoc Tukey tests were used to determine significant differences between means. RESULTS: The highest mean maximum sigmapol of (5.4+/-0.5) MPa was recorded for RMGIC and (4.8+/-1.0) MPa for composite. The lowest mean final sigmapol of (0.8+/-0.4) MPa was recorded for RMGIC. For mean maximum sigmapol,sigmapol rate and final sigmapol there were significant differences between materials within groups, although no significant difference (p>0.05) was observed when comparing the RMGIC group to the composite group. CONCLUSION: When comparing mean sigmapol, maximum sigmapol, and sigmapol rates between individual RMGIC and composite materials significant differences (p<0.05) were observed. However when comparing the group RMGIC to composite no significant differences (p>0.05) were observed. The null hypothesis that there is no difference in the short term sigmapol of RMGIC materials when compared to composite materials is only partly rejected. RELEVANCE: Limited information is available on the comparison of RMGIC and resin composite sigmapol levels. This study provides information on the short term levels in a wet environment and will assist in understanding the initial sigmapol rates RMGIC place in cavities. PMID- 24055793 TI - Viscoelastic properties of a synthetic meniscus implant. AB - There are significant potential advantages for restoration of meniscal function using a bio-stable synthetic implant that combines long-term durability with a dependable biomechanical performance resembling that of the natural meniscus. A novel meniscus implant made of a compliant polycarbonate-urethane matrix reinforced with high modulus ultrahigh molecular weight polyethylene fibers was designed as a composite structure that mimics the structural elements of the natural medial meniscus. The overall success of such an implant is linked on its capability to replicate the stress distribution in the knee over the long-term. As this function of the device is directly dependent on its mechanical properties, changes to the material due to exposure to the joint environment and repeated loading could have non-trivial influences on the viscoelastic properties of the implant. Thus, the goal of this study was to measure and characterize the strain-rate response, as well as the viscoelastic properties of the implant as measured by creep, stress relaxation, and hysteresis after simulated use, by subjecting the implant to realistic joint loads up to 2 million cycles in a joint like setting. The meniscus implant behaved as a non-linear viscoelastic material. The implant underwent minimal plastic deformation after 2 million fatigue loading cycles. Under low compressive loads, the implant was fairly flexible, and able to deform relatively easily (E=120-200 kPa). However as the compressive load applied on the implant was increased, the implant became stiffer (E=3.8-5.2 MPa), to resist deformation. The meniscus implant appears well-matched to the viscoelastic properties of the natural meniscus, and importantly, these properties were found to remain stable and minimally affected by potentially degradative and loading conditions associated with long-term use. PMID- 24055794 TI - Chondroprotective supplementation promotes the mechanical properties of injectable scaffold for human nucleus pulposus tissue engineering. AB - A result of intervertebral disc (IVD) degeneration, the nucleus pulposus (NP) is no longer able to withstand applied load leading to pain and disability. The objective of this study is to fabricate a tissue-engineered injectable scaffold with chondroprotective supplementation in vitro to improve the mechanical properties of a degenerative NP. Tissue-engineered scaffolds were fabricated using different concentrations of alginate and calcium chloride and mechanically evaluated. Fabrication conditions were based on structural and mechanical resemblance to the native NP. Chondroprotective supplementation, glucosamine (GCSN) and chondroitin sulfate (CS), were added to scaffolds at concentrations of 0:0ug/mL (0:0-S), 125:100ug/mL (125:100-S), 250:200ug/mL (250:200-S), and 500:400ug/mL (500:400-S), GCSN and CS, respectively. Scaffolds were used to fabricate tissue-engineered constructs through encapsulation of human nucleus pulposus cells (HNPCs). The tissue-engineered constructs were collected at days 1, 14, and 28 for biochemical and biomechanical evaluations. Confocal microscopy showed HNPC viability and rounded morphology over the 28 day period. MTT analysis resulted in significant increases in cell proliferation for each group. Collagen type II ELISA quantification and compressive aggregate moduli (HA) showed increasing trends for both 250:200-S and the 500:400-S groups on Day 28 with significantly greater HA compared to 0:0-S group. Glycosaminoglycan and water content decreased for all groups. Results indicate the increased mechanical properties of the 250:200-S and the 500:400-S was due to production of a functional matrix. This study demonstrated potential for a chondroprotective supplemented injectable scaffold to restore biomechanical function of a degenerative disc through the production of a mechanically functional matrix. PMID- 24055795 TI - Stress relaxation behavior of tessellated cartilage from the jaws of blue sharks. AB - Much of the skeleton of sharks, skate and rays (Elasmobranchii) is characterized by a tessellated structure, composed of a shell of small, mineralized plates (tesserae) joined by intertesseral ligaments overlaying a soft cartilage core. Although tessellated cartilage is a defining feature of this group of fishes, the significance of this skeletal tissue type - particularly from a mechanical perspective - is unknown. The aim of the present work was to perform stress relaxation experiments with tessellated cartilage samples from the jaws of blue sharks to better understand the time dependent behavior of this skeletal type. In order to facilitate this aim, the resulting relaxation behavior for different loading directions were simulated using the transversely isotropic biphasic model and this model combined with generalized Maxwell elements to represent the tessellated layer. Analysis of the ability of the models to simulate the observed experimental behavior indicates that the transversely isotropic biphasic model can provide good predictions of the relaxation behavior of the hyaline cartilage. However, the incorporation of Maxwell elements into this model can achieve a more accurate simulation of the dynamic behavior of calcified cartilage when the loading is parallel to the tessellated layer. Correlation of experimental data with present combined composite models showed that the equilibrium modulus of the tessellated layer for this loading direction is about 45 times greater than that for uncalcified cartilage. Moreover, tessellation has relatively little effect on the viscoelasticity of shark cartilage under loading that is normal to the tessellated layer. PMID- 24055796 TI - Western-type diet induces senescence, modifies vascular function in non senescence mice and triggers adaptive mechanisms in senescent ones. AB - The effects of high-fat diet ingestion on senescence-induced modulation of contractile responses to phenylephrine (Phe) were determined in aortas of senescence-accelerated (SAMP8) and non-senescent (SAMR1) mice fed (8weeks) a Western-type high-fat diet (WD). Increased levels of senescence-associated beta galactosidase staining were found in aortas of SAMP8 and SAMR1 with WD. In SAMR1, WD did not modify Phe contraction in spite of inducing major changes in the mechanisms of regulation of contractile responses. Although WD increased NAD(P)H oxidase-derived O2(-) and augmented peroxynitrite formation, we found an increase of inducible NOS (iNOS)-derived NO production which may contribute to maintain Phe contraction in SAMR1 WD. On SAMP8, WD significantly decreased Phe-induced contractions when compared with SAMP8 under normal chow. This response was not dependent on changes of NOS expression, but rather as consequence of increased antioxidant capacity by superoxide dismutase (SOD1). A similar constrictor influence from cyclooxygenase (COX) pathway on Phe responses was found in SAMR1 and SAMP8 ND. However, WD removed that influence on SAMR1, and produced a switch in the balance from a vasoconstrictor to a vasodilator component in SAMP8. These results were associated to the increased COX-2 expression, suggesting that a COX 2-derived vasodilator prostaglandin may contribute to the vascular adaptations after WD intake. Taken together, our data suggest that WD plays a detrimental role in the vasculature of non-senescent mice by increasing pro-inflammatory (iNOS) and pro-oxidative signaling pathways and may contribute to increase vascular senescence. In senescent vessels, however, WD triggers different intrinsic compensatory alterations which include increase of antioxidant activity by SOD1 and vasodilator prostaglandin production via COX-2. PMID- 24055797 TI - The Th17/Treg balance is disturbed during aging. AB - Aging is associated with multiple changes in the proliferative and functional abilities of the immune system which are not related to any pathology but consequences in immunosenescence and inflammaging. T helper (TH) 17 cells have been implicated in the development of autoimmune and chronic inflammatory diseases in humans. Additionally, a reciprocal relationship between these pro inflammatory TH17 and the anti-inflammatory regulatory T cells (Tregs) has been described. Recent studies reported an increase of TH17 cells in aged humans and aged mice, but the role of TH17 cells and their relation to Tregs is poorly understood in human aging. This study investigated the proportion of TH17 (CD4+ IL23 receptor(R)+) cells and Tregs (CD4+ Foxp3+) as well as Interleukin (IL)-17 and IL-10 production in four different age groups from human healthy donors. The data revealed a continual increase of basal CD4+ IL23R+ cell amounts in the different age groups. By analyzing the balance of both T-cell subsets it was observed that, on a basal resting level, TH17 cells were significantly increased in older individuals whereas Tregs were reduced. However, the TH17/Treg ratio decreased age-dependently after stimulation and was accompanied by elevated Foxp3 mRNA and IL-10 protein expressions. In conclusion, changes of the TH17/Treg ratios in combination with altered cytokine expression during aging may contribute to an imbalance between the pro-inflammatory and the anti-inflammatory immune response. This indicates a higher susceptibility to develop inflammatory diseases with increasing age. PMID- 24055798 TI - Who reads Pharmacological Research? PMID- 24055799 TI - Up-regulation of KCa3.1 promotes human airway smooth muscle cell phenotypic modulation. AB - Airway smooth muscle (ASM) cell phenotype modulation, characterized by reversible switching between contractile and proliferative phenotypes, is considered to contribute to proliferative diseases such as allergic asthma and chronic obstructive pulmonary disease (COPD). KCa3.1 has been suggested to be involved in regulating ASM cell activation, proliferation, and migration. However, little is known regarding the exact role of KCa3.1 in ASM cell phenotypic modulation. To elucidate the role of KCa3.1 in regulating ASM cell phenotypic modulation, we investigated the effects of KCa3.1 channels on ASM contractile marker protein expression, proliferation and migration of primary human bronchial smooth muscle (BSM) cells. We found that PDGF increased KCa3.1 channel expression in BSM cells with a concomitant marked decrease in the expression of contractile phenotypic marker proteins including smooth muscle myosin heavy chain (SMMHC), smooth muscle alpha-actin (alpha-SMA), myocardin and KCa1.1. These changes were significantly attenuated by the KCa3.1 blocker, TRAM-34, or gene silencing of KCa3.1. Pharmacological blockade or gene silencing of KCa3.1 also suppressed PDGF-induced human BSM cell migration and proliferation accompanied by a decrease in intracellular free Ca(2+) levels as a consequence of membrane depolarization, resulting in a reduction in cyclin D1 level and cell cycle arrest at G0-G1 phase. Additionally, PDGF-induced up-regulation of KCa3.1 and down-regulation of BSM contractile marker proteins were regulated by the ERK inhibitor U0126 and the AKT inhibitor LY294002. These findings highlight a novel role for the KCa3.1 channel in human BSM cell phenotypic modulation and provide a potential target for therapeutic intervention for proliferative airway diseases. PMID- 24055800 TI - Tributyltin chloride induced testicular toxicity by JNK and p38 activation, redox imbalance and cell death in sertoli-germ cell co-culture. AB - The widespread use of tributyltin (TBT) as biocides in antifouling paints and agricultural chemicals has led to environmental and marine pollution. Human exposure occurs mainly through TBT contaminated seafood and drinking water. It is a well known endocrine disruptor in mammals, but its molecular mechanism in testicular damage is largely unexplored. This study was therefore, designed to ascertain effects of tributyltin chloride (TBTC) on sertoli-germ cell co-culture in ex-vivo and in the testicular tissue in-vivo conditions. An initial Ca(2+) rise followed by ROS generation and glutathione depletion resulted in oxidative damage and cell death. We observed p38 and JNK phosphorylation, stress proteins (Nrf2, MT and GST) induction and mitochondrial depolarization leading to caspase 3 activation. Prevention of TBTC reduced cell survival and cell death by Ca(2+) inhibitors and free radical scavengers specify definitive role of Ca(2+) and ROS. Sertoli cells were found to be more severely affected which in turn can hamper germ cells functionality. TBTC exposure in-vivo resulted in increased tin content in the testis with enhanced Evans blue leakage into the testicular tissue indicating blood-testis barrier disruption. Tesmin levels were significantly diminished and histopathological studies revealed marked tissue damage. Our data collectively indicates the toxic manifestations of TBTC on the male reproductive system and the mechanisms involved. PMID- 24055801 TI - Stability and pattern formation for competing populations with asymmetric nonlocal coupling. AB - We consider a model of two competing species with asymmetric nonlocal coupling in a competition for resources. The nonlocal coupling is via convolution integrals and the asymmetry is via convolution kernel functions which are not even functions of their arguments. The nonlocality is due to species mobility, so that at any fixed point in space the competition for resources depends not just on the populations at that point but on a suitably weighted average of the populations. We introduce two parameters, delta, describing the extent of the coupling, with delta=0 corresponding to local coupling, and alpha, describing the extent of the asymmetry, with alpha=0 corresponding to symmetric nonlocal interactions. We consider the case where the model admits a stable coexistence equilibrium solution. We perform a linear stability analysis and show that this solution can be destabilized by sufficient nonlocality, i.e., when delta increases beyond a critical value. We consider two specific kernel functions, (i) an asymmetric Gaussian and (ii) an asymmetric stepfunction. We compute the stability boundary as a function of alpha, and for delta beyond the stability boundary we determine unstable wavenumber bands. We compute nonlinear patterns for delta significantly beyond the stability boundary. Patterns consist of arrays of islands, regions of nonzero population, separated by either near-deadzones where the populations are small, but nonzero, or by deadzones where populations are exponentially small and essentially extinct. We find solutions consisting of propagating traveling waves of islands, solutions exhibiting colony formation, where a colony is formed just ahead of an island and eventually grows as the parent island decays, and modulated traveling waves, where competition between the two species allows propagation and inhibits colony formation. We explain colony formation and the modulated traveling waves as due to a positive feedback mechanism associated with small variations in the amplitude of the parent island. PMID- 24055803 TI - Shigella flexneri enteritis in risk-taking HIV-infected MSM. PMID- 24055802 TI - The emergence of drug resistant HIV variants at virological failure of HAART combinations containing efavirenz, tenofovir and lamivudine or emtricitabine within the UK Collaborative HIV Cohort. AB - BACKGROUND: Lamivudine (3TC) and emtricitabine (FTC) are guideline choices for combination highly active antiretroviral therapy (HAART). 3TC has a shorter intracellular half life than FTC and may be more likely to lead to the development of drug resistant HIV variants. METHODS: In this study we analysed linked data from the observational UK Collaborative HIV Cohort (CHIC) Study and UK HIV Drug Resistance Database (HDRD) to investigate the rate of development of K65R or M184V resistance mutations in patients failing on combinations containing tenofovir (TDF) and efavirenz (EFV) with either 3TC or FTC. Virological failure was defined as 1 viral load >400 copies/ml. Rates were stratified by demographic variables, baseline viral load, current CD4 count, current viral load and year of starting regimen. Significant associations were identified using Poisson regression models and multivariable analyses were performed adjusting for the variables above. Logistic regression was used to determine whether there were any significant associations between type of regimen and detection of resistance mutation. RESULTS: 5455 patients received either (or both) 3TC, TDF and EFV or FTC, TDF and EFV contributing 6465 treatment episodes over 9962 person-years follow up. 47 of these episodes were preceded by resistance tests showing development of K65R or M184V mutation and were hence excluded. The majority of treatment episodes consisted of FTC- (n = 5190) rather than 3TC- (n = 1228) based regimens. 21 cases of K65R were detected over the course of follow up, giving an overall event rate of 0.21 (95% CI: 0.12-0.31)/100 person years follow up (PYFU). The overall event rate for detection of M184V was 0.38 (95% CI: 0.26-0.5)/100 PYFU. 201 patients receiving either regimen for the first time experienced virological failure. Of those receiving 3TC (n = 53), 7 (13.2%), 12 (22.6%) and 15 (28.3%) developed K65R, M184V and either K65R or M184V respectively. Of those receiving FTC (n = 148), 13 (8.8%), 20 (13.5%) and 26 (17.6%) developed K65R, M184V and either K65R or M184V respectively. Although patients on 3TC were more likely to develop resistance, this was not statistically significant in univariable (OR 1.85 (95% CI: 0.89-3.85, p = 0.09)) or multivariable analyses (OR 1.89 (95% CI: 0.89-4.01, p = 0.1)). CONCLUSIONS: We have not found evidence of an increased risk of development of M184V and K65R in patients exposed to 3TC. PMID- 24055804 TI - Infectious etiology of acute exacerbations in severe COPD patients. AB - OBJECTIVES: Since the new GOLD guidelines were implemented no data have been published about the etiology of acute exacerbations (AECOPD) in severe COPD patients with a different frequency of annual episodes. METHODS: One hundred and eleven COPD patients (FEV1 < 50%) were prospectively followed up for a year. Good quality sputum samples recovered during AECOPD were processed, including quantitative culture and PCR detection of atypical bacteria. RESULTS: A total of 188 sputum samples were obtained from AECOPD episodes. Forty patients had a single episode, and 71 patients had >=2. In 128 episodes a single pathogen was isolated, while 42 episodes were polymicrobial (>=2 pathogens). Overall, the most frequent pathogen isolated was Pseudomonas aeruginosa (n = 54), followed by Haemophilus influenzae (n = 37), Streptococcus pneumoniae (n = 31), Moraxella catarrhalis (n = 29) and Staphylococcus aureus (n = 12). P. aeruginosa was the most frequent in both groups of patients (35% and 27% in those with 1 and >=2 AECOPD, respectively). H. influenzae was associated with patients with a single annual AECOPD (33% vs. 16%; P = 0.006), while Enterobacteriaceae were associated with frequent exacerbators (0% vs. 12%; P < 0.044). CONCLUSION: Overall, P. aeruginosa was the most frequent pathogen isolated from exacerbations. However, different bacterial etiology was observed depending on the number of annual episodes. PMID- 24055805 TI - Vasonatrin peptide, a novel protector of dopaminergic neurons against the injuries induced by n-methyl-4-phenylpyridiniums. AB - Vasonatrin peptide (VNP), a novel manmade natriuretic peptide, is known as a cardiovascular active substance. However, its neuroeffects are largely unknown. Here, cultured dopaminergic neurons from ventral mesencephalon of mouse were exposed to N-methyl-4-phenylpyridinium (MPP(+)), and the effects of VNP on the neurotoxicity of MPP(+) were investigated. As a result, MPP(+) caused injuries in the dopaminergic neurons. VNP significantly reduced the cytotoxicity of MPP(+) by increasing axon number and length of dopaminergic neurons, and by enhancing the cell viability. Also, the MPP(+)-induced depolymerization of beta-Tubulin III was attenuated by the treatment of VNP. In addition, VNP significantly increased the intracellular levels of cGMP. These effects of VNP were mimicked by 8-br-cGMP (a cell-permeable analog of cGMP), whereas inhibited by HS-142-1 (the antagonist of the particulate guanylyl cyclase-coupled natriuretic peptide receptors), or KT 5823 (a cGMP-dependent protein kinase inhibitor). Taken together, VNP attenuates the neurotoxicity of MPP(+) via guanylyl cyclase-coupled NPR/cGMP/PKG pathway, indicating that VNP might be a new effective reagent in the treatment of neuron degeneration of dopaminergic neurons in Parkinson's disease (PD). PMID- 24055807 TI - Interactive effect of galanin-like peptide (GALP) and spontaneous exercise on energy metabolism. AB - Galanin-like peptide (GALP) is a neuropeptide involved in energy metabolism. The interactive effect of GALP and exercise on energy metabolism has not been investigated. The aim of this study was to determine if energy metabolism in spontaneously exercising mice could be promoted by intracerebroventricular (ICV) GALP administration. Changes in respiratory exchange ratio in response to GALP ICV administration indicated that lipids were primarily consumed followed by a continuous consumption of glucose throughout the dark period in non-exercising mice. In mice permitted to spontaneously exercise on a running-wheel, GALP ICV administration increased the consumed oxygen volume and heat production level from 5 to 11h after administration. These effects occurred independently from the total running distance. The interaction between GALP ICV administration and spontaneous exercise decreased body weight within 24h (F(1,16)=5.772, p<0.05), with no significant interaction observed regarding food and water intake or total distance. Energy metabolism-related enzymes were assessed in liver and skeletal muscle samples, with a significant interaction on mRNA expression between GALP ICV administration and spontaneous exercise observed in phosphoenolpyruvate carboxykinase (F(1,16)=18.602, p<0.001) that regulates gluconeogenesis and glucose transporter-4 (F(1,16)=21.092, p<0.001). GALP significantly decreased the mRNA expression of sterol regulatory element-binding protein-1c (p<0.05) that regulates fatty acid synthesis regardless of spontaneous exercise with no changes to acetyl-CoA carboxylase a and fatty acid synthetase. These results indicate the GALP ICV administration can further promote energy metabolism when administered to spontaneously exercising mice. PMID- 24055808 TI - Particle-enhanced turbidimetric immunoassay for determination of serum neutrophil gelatinase-associated lipocalin on the Roche Cobas c501 analyzer. AB - OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL) has been reported to be a good marker for tubular damage and acute kidney injury. The aim of this study was to develop a high throughput assay for the quantification of serum NGAL (sNGAL). METHODS: Imprecision, interference, linearity, recovery, and reference values were evaluated on Cobas c501. RESULTS: The assay was linear over the dynamic range of the study (R(2)=0.9988). The total assay imprecision was below 5%. The assay recovery was estimated at 98.89%-102.61%. The assay displayed a good linearity over the range from 35 MUg/L to 4250 MUg/L. A typical high-dose hook effect was observed for the assay at NGAL concentration>28,800 MUg/L. No interference was observed with hemoglobin <= 5 g/L, bilirubin <= 0.3g/L, vitamin C <= 0.5 g/L, sodium heparin<= 5 g/L and intralipid <= 1%. The 95th centile for serum NGAL was <122.57 MUg/L from 454 healthy donors. There were no gender related differences for serum NGAL. There were significant age-related differences between the 21-44 and 45-75 year categories for serum NGAL. The reference value for sNGAL was <116.52 MUg/L in the 21-44 year group and <126.9 MUg/L in the 45-75 year group. CONCLUSIONS: The NGAL assay verified to be a reliable assay with convenient performance characteristics. The assay improves and simplifies the laboratory workload. PMID- 24055809 TI - Pregabalin determination in hair by ultra-high-performance liquid chromatography tandem mass spectrometry. AB - Pregabalin is an antiepileptic and analgesic drug, commercialized under the name of Lyrica, and generally used to treat neuropathic pain. The determination of pregabalin was performed by using spiked hair samples extracted in methanol and analyzed by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. The validation of a quantification method of pregabalin in hair has been successfully achieved (precision, accuracy, matrix effects and extraction yield). The limit of detection was 0.76 pg/mg and the lower limit of quantification was 2.5 pg/mg. A real case of pregabalin in hair has been analyzed using this method. The result showed a concentration of 540 pg/mg. PMID- 24055806 TI - A 'conovenomic' analysis of the milked venom from the mollusk-hunting cone snail Conus textile--the pharmacological importance of post-translational modifications. AB - Cone snail venoms provide a largely untapped source of novel peptide drug leads. To enhance the discovery phase, a detailed comparative proteomic analysis was undertaken on milked venom from the mollusk-hunting cone snail, Conus textile, from three different geographic locations (Hawai'i, American Samoa and Australia's Great Barrier Reef). A novel milked venom conopeptide rich in post translational modifications was discovered, characterized and named alpha conotoxin TxIC. We assign this conopeptide to the 4/7 alpha-conotoxin family based on the peptide's sequence homology and cDNA pre-propeptide alignment. Pharmacologically, alpha-conotoxin TxIC demonstrates minimal activity on human acetylcholine receptor models (100 MUM, <5% inhibition), compared to its high paralytic potency in invertebrates, PD50 = 34.2 nMol kg(-1). The non-post translationally modified form, [Pro](2,8)[Glu](16)alpha-conotoxin TxIC, demonstrates differential selectivity for the alpha3beta2 isoform of the nicotinic acetylcholine receptor with maximal inhibition of 96% and an observed IC50 of 5.4 +/- 0.5 MUM. Interestingly its comparative PD50 (3.6 MUMol kg(-1)) in invertebrates was ~100 fold more than that of the native peptide. Differentiating alpha-conotoxin TxIC from other alpha-conotoxins is the high degree of post translational modification (44% of residues). This includes the incorporation of gamma-carboxyglutamic acid, two moieties of 4-trans hydroxyproline, two disulfide bond linkages, and C-terminal amidation. These findings expand upon the known chemical diversity of alpha-conotoxins and illustrate a potential driver of toxin phyla-selectivity within Conus. PMID- 24055810 TI - Leptin and its influence on growth and progression in lung carcinomas. PMID- 24055811 TI - Flightless I homolog negatively regulates ChREBP activity in cancer cells. AB - The glucose-responsive transcription factor carbohydrate responsive element binding protein (ChREBP) plays an important role in regulating glucose metabolism in support of anabolic synthesis in both hepatocytes and cancer cells. In order to further investigate the molecular mechanism by which ChREBP regulates transcription, we used a proteomic approach to identify proteins interacting with ChREBP. We found several potential ChREBP-interacting partners, one of which, flightless I homolog (FLII) was verified to interact and co-localize with ChREBP in HCT116 colorectal cancer and HepG2 hepatocellular carcinoma cells. FLII is a member of the gelsolin superfamily of actin-remodeling proteins and can function as a transcriptional co-regulator. The C-terminal 227 amino acid region of ChREBP containing the DNA-binding domain interacted with FLII. Both the N-terminal leucine-rich repeat (LRR) domain and C-terminal gelsolin homolog domain (GLD) of FLII interacted and co-localized with ChREBP. ChREBP and FLII localized in both the cytoplasm and nucleus of cancer cells. Glucose increased expression and nuclear localization of ChREBP, and had minimal effect on the level and distribution of FLII. FLII knockdown using siRNAs increased mRNA and protein levels of ChREBP-activated genes and decreased transcription of ChREBP-repressed genes in cancer cells. Conversely, FLII overexpression negatively regulated ChREBP-mediated transcription in cancer cells. Our findings suggest that FLII is a component of the ChREBP transcriptional complex and negatively regulates ChREBP function in cancer cells. PMID- 24055812 TI - p85-RhoGDI2, a novel complex, is required for PSGL-1-induced beta1 integrin mediated lymphocyte adhesion to VCAM-1. AB - P-selectin glycoprotein ligand-1 and beta1 integrin play essential roles in T cell trafficking during inflammation. E-selectin and vascular cell adhesion molecule-1 are their ligands expressed on inflammation-activated endothelium. During the tethering and rolling of lymphocytes on endothelium, P-selectin glycoprotein ligand-1 binds E-selectin and induces signals. Subsequently, beta1 integrin is activated and mediates stable adhesion. However, the intracellular signal pathways from PSGL-1 to beta1 integrin have not yet been fully understood. Here, we find that p85, a regulatory subunit of phosphoinositide 3-kinase, forms a novel complex with Rho-GDP dissociation inhibitor-2, a lymphocyte-specific RhoGTPases dissociation inhibitor. Phosporylations of the p85-bound Rho-GDP dissociation inhibitor-2 on 130 and 153 tyrosine residues by c-Abl and Src were required for the complex to be recruited to P-selectin glycoprotein ligand-1 and thereby regulate beta1 integrin-mediated T cell adhesion to vascular cell adhesion molecule-1. Both shRNAs to Rho-GDP dissociation inhibitor-2 and p85 and over-expression of Rho-GDP dissociation inhibitor-2 Y130F and Y153F significantly reduced the above-mentioned adhesion. Although Rho-GDP dissociation inhibitor-2 in the p85-Rho-GDP dissociation inhibitor-2 complex was also phosphorylated on 24 tyrosine residue by Syk, the phosphorylation is not required for the adhesion. Taken together, we find that specific phosphorylations on 130 and 153 tyrosine residues of p85-bound Rho-GDP dissociation inhibitor-2 are pivotal for P-selectin glycoprotein ligand-1-induced beta1 integrin-mediated lymphocyte adhesion to vascular cell adhesion molecule-1. This will shed new light on the mechanisms that connect leukocyte initial rolling with subsequent adhesion. PMID- 24055814 TI - Homocysteine modifies extracellular ATP availability in macrophages. AB - Increased levels of plasma homocysteine (hyperhomocysteinemia-HHcy) are associated to the development of coronary artery disease (CAD), peripheral vascular disease and thrombosis. In addition, recent studies have shown that inflammation, probably mediated by macrophages, mediates the pathogenesis associated to high levels of homocysteine (Hcy). In the present study, we evaluated the Hcy effects in the ATP hydrolysis and its breakdown products in murine macrophages. The results showed that micromolar concentrations of Hcy increased the ATP, ADP and AMP hydrolysis. Additionally, our results show decreased inosine levels in the extracellular milieu of Hcy-exposed macrophages. The increasing in ATP, ADP and AMP hydrolysis are not explained by increased transcription or protein expression of NTPDases and ecto-5'-nucleotidase (ecto-5' NT/CD73) enzymes. Moreover, the formation of reactive oxygen species did not interfere in the Hcy effects, which suggest that Hcy or Hcy metabolites act directly on the modulation of NTPDases and ecto-5'-NT/CD73 activities. In conclusion, Hcy induces the rapid breakdown of ATP, ADP and AMP to adenosine (ADO), which is classically known as an anti-inflammatory response in immune cells. However, by the action of these enzymes, the extracellular adenosine generated during Hcy treatment probably is uptaken into the cells, as evidenced by the decreased in inosine formation, and thus collaborating to the inflammatory complications associates to HHcy. PMID- 24055813 TI - MARVELD1 regulates integrin beta1-mediated cell adhesion and actin organization via inhibiting its pre-mRNA processing. AB - Cell adhesion on an extracellular matrix (ECM) participates in cell motility, invasion, cell signal transduction and gene expression. Many nuclear proteins regulate cell-ECM adhesion through managing the transcription of cell adhesion related genes. Here, we identified MARVEL [MAL (The myelin and lymphocyte protein) and related proteins for vesicle trafficking and membrane link] domain containing 1 (MARVELD1) that could suppress cell spreading and complicate actin organization. Over-expression of MARVELD1 in NIH3T3 cells decreased the expression level of integrin beta1 and vinculin, and further led to dephosphorylation of focal adhesion kinase (FAK) at Tyr 397. We also found that MARVELD1 partially colocalized with serine/arginine-rich splicing factor 2 (SC35) and interacted with nuclear cap binding protein subunit 2 (CBP20). Finally, we demonstrated that pre-mRNA processing of integrin beta1 was affected by MARVELD1. Taken together, our studies demonstrate that MARVELD1 plays a role in pre-mRNA processing of integrin beta1, and thereby regulates cell adhesion and cell motility. These studies provide a novel regulatory mechanism of cell-ECM adhesion by nuclear protein in cells. PMID- 24055815 TI - Inhibition of phagocytosis reduced the classical activation of BV2 microglia induced by amyloidogenic fragments of beta-amyloid and prion proteins. AB - The inflammatory responses in Alzheimer's disease and prion diseases are dominated by microglia activation. Three different phenotypes of microglial activation, namely classical activation, alternative activation, and acquired deactivation, have been described. In this study, we investigated the effect of amyloidogenic fragments of amyloid beta and prion proteins (Abeta1-42 and PrP106 126) on various forms of microglial activation. We first examined the effect of Abeta1-42 and PrP106-126 stimulation on the mRNA expression levels of several markers of microglial activation, as well as the effect of cytochalasin D, a phagocytosis inhibitor, on microglial activation in Abeta1-42- and PrP106-126 stimulated BV2 microglia. results showed that Abeta1-42 and PrP106-126 induced the classical activation of BV2 microglia, decreased the expression level of alternative expression markers, and had no effect on the expression of acquired deactivation markers. Cytochalasin D treatment significantly reduced Abeta1-42- and PrP106-126-induced up-regulation of proinflammatory factors, but did not change the expression profile of the markers of alternative activation or acquired deactivation in BV2 cells which were exposed to Abeta1-42 and PrP106 126. Our results suggested that microglia interact with amyloidogenic peptides in the extracellular milieu-stimulated microglial classical activation and reduce its alternative activation, and that the uptake of amyloidogenic peptides from the extracellular milieu amplifies the classical microglial activation. PMID- 24055816 TI - Health-related quality of life in children with abdominal pain due to functional or organic gastrointestinal disorders. AB - OBJECTIVE: Comparing health-related quality of life (HRQOL) in children suffering from functional and organic gastrointestinal disorders and to identify predictors for HRQOL. METHODS: Children with functional (n = 70) and organic (n = 100) gastrointestinal disorders, aged 8-18 years and referred to a pediatric gastroenterologist, completed questionnaires assessing pain severity, coping, and HRQOL. RESULTS: The sample reported low HRQOL scores, even significantly lower compared with reference values of chronically ill children, derived from normative data of KINDL-R, a generic QOL questionnaire. HRQOL was not significantly associated with age, gender, duration of pain, and diagnosis (functional gastrointestinal disorder vs. organic gastrointestinal disorder). Pain severity and catastrophizing were significantly associated with HRQOL, with catastrophizing fully mediating the relationship between pain and HRQOL. CONCLUSION: The emotional burden associated with chronic abdominal pain regardless of its cause-is enormous. Interventions should target the children's coping strategies, as catastrophizing seems to be the causal link between pain and HRQOL. PMID- 24055817 TI - Progress and prospects for interspecific hybridization in buckwheat and the genus Fagopyrum. AB - Cultivated buckwheat, such as common (Fagopyrum esculentum Moench.) and tartary (Fagopyrum tataricum (L.) Gaertn.) buckwheat, is one of the most versatile crops for forage and food and has several benefits for human health. Interspecific hybridization between Fagopyrum species is of great importance to improvement of buckwheat. Hybridization would allow the transfer of agronomical beneficial characteristics from wild Fagopyrum species, including self-pollination and increased fertility, frost tolerance, and higher content of beneficial compounds. However, conventional breeding methods are only partially applicable because of the self-incompatibility and incompatibility barriers between different species. Present review summarizes the morphology of self-incompatibility, the genetic and cellular basis of incompatibility between different Fagopyrum species. In many interspecific crosses hybrid embryos are aborted after successful pollination due to post-zygotic incompatibility. The use of in vitro embryo rescue after interspecific hybridization has been successful in circumventing breeding barriers between Fagopyrum species. Methods applied successfully for the construction of interspecific hybrids are discussed in detail. PMID- 24055818 TI - The road to regenerative liver therapies: the triumphs, trials and tribulations. AB - The liver is one of the few organs that possess a high capacity to regenerate after liver failure or liver damage. The parenchymal cells of the liver, hepatocytes, contribute to the majority of the regeneration process. Thus, hepatocyte transplantation presents an alternative method to treating liver damage. However, shortage of hepatocytes and difficulties in maintaining primary hepatocytes still remain key obstacles that researchers must overcome before hepatocyte transplantation can be used in clinical practice. The unique properties of pluripotent stem cells (PSCs) and induced pluripotent stem cells (iPSCs) have provided an alternative approach to generating enough functional hepatocytes for cellular therapy. In this review, we will present a brief overview on the current state of hepatocyte differentiation from PSCs and iPSCs. Studies of liver regenerative processes using different cell sources (adult liver stem cells, hepatoblasts, hepatic progenitor cells, etc.) will be described in detail as well as how this knowledge can be applied towards optimizing culture conditions for the maintenance and differentiation of these cells towards hepatocytes. As the outlook of stem cell-derived therapy begins to look more plausible, researchers will need to address the challenges we must overcome in order to translate stem cell research to clinical applications. PMID- 24055820 TI - Structure and orientation study of Ebola fusion peptide inserted in lipid membrane models. AB - The fusion peptide of Ebola virus comprises a highly hydrophobic sequence located downstream from the N-terminus of the glycoprotein GP2 responsible for virus-host membrane fusion. The internal fusion peptide of GP2 inserts into membranes of infected cell to mediate the viral and the host cell membrane fusion. Since the sequence length of Ebola fusion peptide is still not clear, we study in the present work the behavior of two fusion peptides of different lengths which were named EBO17 and EBO24 referring to their amino acid length. The secondary structure and orientation of both peptides in lipid model systems made of DMPC:DMPG:cholesterol:DMPE (6:2:5:3) were investigated using PMIRRAS and polarized ATR spectroscopy coupled with Brewster angle microscopy. The infrared results showed a structural flexibility of both fusion peptides which are able to transit reversibly from an alpha-helix to antiparallel beta-sheets. Ellipsometry results corroborate together with isotherm measurements that EBO peptides interacting with lipid monolayer highly affected the lipid organization. When interacting with a single lipid bilayer, at low peptide content, EBO peptides insert as mostly alpha-helices mainly perpendicular into the lipid membrane thus tend to organize the lipid acyl chains. Inserted in multilamellar vesicles at higher peptide content, EBO peptides are mostly in beta-sheet structures and induce a disorganization of the lipid chain order. In this paper, we show that the secondary structure of the Ebola fusion peptide is reversibly flexible between alpha-helical and beta-sheet conformations, this feature being dependent on its concentration in lipids, eventually inducing membrane fusion. PMID- 24055821 TI - The projection structure of Kch, a putative potassium channel in Escherichia coli, by electron crystallography. AB - The kch gene, the only potassium channel gene in Escherichia coli, has the property to express both full-length Kch and its cytosolic domain (RCK) due to a methionine at position 240. The RCK domains are believed to form an octameric ring structure and regulate the gating of the potassium channels after having bound certain ligands. Several different gating ring structures have been reported for the soluble RCK domains, however, these were studied isolated from their transmembrane parts. We previously reported an octameric structure of Kch in solution by electron microscopy and single particle reconstruction, composed of two tetrameric full-length proteins through RCK interaction. To exclude the effect of the detergent, we have now performed an electron crystallographic study of the full-length Kch in membrane bound form. Well-ordered two-dimensional crystals were grown in a natural phospholipid environment. A projection map merged from the fifteen best images extended to 6A resolution. The c12 two-sided plane group of the two-dimensional crystals showed that Kch crystallized as two symmetrically related overlapping layers. The arrangement suggests that the two layers of RCK domains are shifted with respect to each other and the RCK octameric gating ring of Kch does not form under the crystallization condition. PMID- 24055819 TI - The minimalist architectures of viroporins and their therapeutic implications. AB - Many viral genomes encode small, integral membrane proteins that form homo oligomeric channels in membrane, and they transport protons, cations, and other molecules across the membrane barrier to aid various steps of viral entry and maturation. These viral proteins, collectively named viroporins, are crucial for viral pathogenicity. In the past five years, structures obtained by nuclear magnetic resonance (NMR), X-ray crystallography, and electron microscopy (EM) showed that viroporins often adopt minimalist architectures to achieve their functions. A number of small molecules have been identified to interfere with their channel activities and thereby inhibit viral infection, making viroporins potential drug targets for therapeutic intervention. The known architectures and inhibition mechanisms of viroporins differ significantly from each other, but some common principles are shared between them. This review article summarizes the recent developments in the structural investigation of viroporins and their inhibition by antiviral compounds. This article is part of a Special Issue entitled: Viral Membrane Proteins-Channels for Cellular Networking. PMID- 24055824 TI - Cardiac troponin T and NT-proBNP as biomarkers of early myocardial damage in amitriptyline-induced cardiovascular toxicity in rats. AB - The main objective of this study was to investigate whether cardiac troponin (cTn) and N-terminal, protein B-type natriuretic peptide (NT-proBNP) can be useful as indicators for amitriptyline cardiotoxicity which is a known drug having sublethal toxic cardiac effects. At the same time, this study looked at detecting potential histopathological changes specific to irreversible cardiac injuries in a rat model of amitriptyline cardiotoxicity. Male Wistar rats were randomly divided into 2 groups, control (saline) group and amitriptyline group (100 mg/kg body weight intraperitoneally, equivalent for lethal dose at 50%). Blood was collected 30 minutes after the administration. The cTn was measured using 3 different methods (2 methods designed for human use and a sandwich enzyme immunoassay specific for rat cTnT). The brain natriuretic peptide was measured by 2 different methods (1 for human and 1 specific for rats). Electrocardiography showed that the QRS complex (P < .0001) and the QT interval (P = .002) were significantly prolonged for amitriptyline-treated animals. Troponin T and NT proBNP had significantly increased levels in all the rats but showed positive results only when using rat-specific quantitative measurement. In certain rats, the histopathological examination identified a few small foci of acute myocardial necrosis. In conclusion, elevation of cTnT and NT-proBNP are early indicators of cardiotoxicity, yet the significance of irreversible myocardial damage in amitriptyline cardiotoxicity needs to be further understood. PMID- 24055823 TI - Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. AB - New treatments are needed for B-cell malignancies persisting after allogeneic hematopoietic stem cell transplantation (alloHSCT). We conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. T cells for genetic modification were obtained from each patient's alloHSCT donor. All patients had malignancy that persisted after alloHSCT and standard donor lymphocyte infusions (DLIs). Patients did not receive chemotherapy prior to the CAR T-cell infusions and were not lymphocyte depleted at the time of the infusions. The 10 treated patients received a single infusion of allogeneic anti-CD19-CAR T cells. Three patients had regressions of their malignancies. One patient with chronic lymphocytic leukemia (CLL) obtained an ongoing complete remission after treatment with allogeneic anti-CD19-CAR T cells, another CLL patient had tumor lysis syndrome as his leukemia dramatically regressed, and a patient with mantle cell lymphoma obtained an ongoing partial remission. None of the 10 patients developed graft versus-host disease (GVHD). Toxicities included transient hypotension and fever. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. These results show for the first time that donor-derived allogeneic anti-CD19-CAR T cells can cause regression of B-cell malignancies resistant to standard DLIs without causing GVHD. PMID- 24055825 TI - Identification of potential serum biomarkers in mercury-treated mice using a glycoproteomic approach. AB - Mercury is a well-recognized health hazard and a deleterious environmental contaminant. Exposure to mercury can cause neurotoxic manifestations, nephrotoxicity, and immune function alterations; however, the mechanisms and related proteins responsible for these effects are still unclear. Our goal is to understand the relationship between the toxicity of mercury and the proteins affected by this toxic heavy metal and to define biomarkers for mercury intoxication. Two different forms of mercury, organic methylmercury or inorganic mercury sulfide, were orally administered to the mice for 4 weeks. To reduce complexity of the serum proteome, we enriched glycoproteins from mice serum with lectin concanavalin A resin, and the tryptic peptides of the purified glycoproteins were subjected to nanoultra performance liquid chromatography Quadrupole time-of-flight for identification and label-free quantification. In this study, we characterized approximately 209 proteins from mice serum, and, among them, 21 proteins were differentially expressed in organic methylmercury treated mice serum compared with the control group. Two proteins, serum amyloid P component (SAP) and inter alpha-trypsin inhibitor heavy chain 4 (ITI-H4), were upregulated in organic methylmercury-treated mice and confirmed with different doses of both types of mercury by Western blot analysis. Results of immunohistochemistry also confirmed the validity of SAP and ITI-H4 as biomarker candidates for organic methylmercury exposure. Findings of this study may assist in understanding the relationship between toxicity of mercury and upregulated proteins in mouse serum. Furthermore, the proteins identified here might be used as biomarker candidates in mercury intoxication. PMID- 24055826 TI - BaeR protein from Salmonella enterica serovar Paratyphi A induces inflammatory response in murine and human cell lines. AB - BaeR is the response regulator of the two-component system, BaeSR, found in Escherichia coli (E. coli) and Salmonella. Several biological functions of BaeR, related to multidrug efflux and bacterial virulence, have been described. Herein, we report a putative function of BaeR during inflammatory response of the host by using BaeR protein of Salmonella enterica Paratyphi A (S. Paratyphi A) origin overexpressed in E. coli, and RAW 264.7 and THP-1 cells as in vitro models. BaeR (3 MUg/ml) upregulated iNOS mRNA expression in both cell lines, and induced significant production of NO. Greater than ten-fold (TNF-alpha), 24-fold (IL 1beta) and 156-fold (IL-6) increases in mRNA expression levels were observed in THP-1 cells treated with BaeR, compared to untreated controls. Furthermore, an eight-fold (IL-1beta), 12-fold (IL-6) and 41-fold (TNF-alpha) higher protein concentrations were observed in RAW 264.7 cells stimulated with BaeR, compared to control cells. Immunoblot analysis showed BaeR-induced phosphorylation of the MAPKs (ERK 1/2, JNK and p38 MAPK) in RAW 264.7 cells. Pharmacological inhibition of the three MAPKs using specific inhibitors resulted in significant reduction of BaeR-induced NO production and iNOS mRNA expression by inhibitors of JNK and p38 MAPK. Also, all inhibitors of the MAPKs significantly attenuated BaeR-induced IL 1beta, IL-6 and TNF-alpha at both transcript and protein levels with different degrees of inhibition. Taken together, our data suggest that BaeR is a putative inducer of inflammatory response and the MAPKs are involved in the process. PMID- 24055827 TI - Is axenicity crucial to cryopreserve microalgae? AB - Large culture collections of microalgae and cyanobacteria such as the Coimbra Collection of Algae (ACOI) hold unialgal cultures consisting of a population of cells/colonies of a certain species. These cultures are usually non-axenic, as other organisms such as bacteria and microfungi are also present in culture due to co-isolation. Attention has been recently given to partner organisms since studies indicate that some bacteria are important for nutrient uptake of the algal cells, acting as simbionts. Despite this benign effect in the actively growing cultures, when cryopreservation is applied for inactive-stage storage, these organisms may recover faster than the algae, thus affecting their recovery and the viability assessments. In this study, a set of mucilaginous ACOI microalgae were selected, cell features known for their relevance in cryopreservation success were recorded and simple two-step cryopreservation tests were applied. Thawed samples were transferred to fresh culture medium for recovery. Viability was assessed and partner organism proliferation (pop) was recorded. Results were analyzed by t-tests. Statistical models allowed us to support the known tendency for small, unicellular algae with no outer structures to be successfully cryopreserved and the negative effect of vacuoles in the cell prior to cryopreservation. On average cryopreservation with MeOH or Me2SO led to the recovery of nearly half the cells. It was found that the cryoprotection step with MeOH is when pop is triggered and that the use of Me2SO can prevent this effect. Progress on understanding the cultured consortia will assist the improvement of cryopreservation and research using microalgal cultures. PMID- 24055828 TI - Six physical education lessons a week can reduce cardiovascular risk in school children aged 6-13 years: a longitudinal study. AB - AIMS: Cardiovascular disease (CVD) originates during childhood and adolescence. Schools are potentially effective settings for early public health prevention strategies. The aim of this study was to evaluate the effect of six physical education (PE) lessons on children's CVD risk. METHODS: This longitudinal study in 10 public schools (1218 children, aged 6-13 years), 6 intervention and 4 control schools evaluates a natural experiment, where intervention schools tripled PE to six lessons per week compared to the mandatory two PE lessons in the control schools. Baseline (2008) and 2-year follow-up measures were anthropometrics, cardiorespiratory fitness, blood pressure and blood samples providing lipids and measures for insulin resistance. Based on these variables, a composite risk score was calculated and used for further analysis. Multivariate multilevel mixed effect regression models were used to estimate effect of intervention taking the hierarchical structure of data into account. Individual, class and school were considered random effects. Intra class correlation (ICC) was calculated. RESULTS: Intervention significantly lowered mean of composite risk score with 0.17 SD (95% CI: -0.34 to -0.01). Six PE lessons per week had a beneficial effect on triglycerides (TG) levels (-0.18 SD, 95% CI: -0.36 to 0.00), systolic blood pressure (SBP) (-0.22 SD, 95% CI: -0.42 to -0.02) and insulin resistance (HOMA-IR) (-0.17 SD, 95% CI: -0.34 to 0.01). CONCLUSIONS: Six PE lessons at school can reduce children's CVD risk measured as a composite risk score. The changes in risk score are considered substantial in the perspective of public health strategy for preventing CVD in later life. PMID- 24055829 TI - Tissue selectivity of ospemifene: pharmacologic profile and clinical implications. AB - The multifactorial consequences of menopausal estrogen deficiency affect numerous tissues throughout the body. Supplemental hormonal therapies carry the burden of a risk/benefit ratio that must be highly individualized. Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) agonist/antagonists designed to induce benefits comparable with estrogen while minimizing adverse effects. Here, we review the estrogen agonist/antagonist profile of ospemifene, a novel triphenylethylene derivative recently approved to treat dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause, both preclinically and clinically. Ospemifene binds ERalpha and ERbeta with approximately equal affinities. In preclinical models, ospemifene increased vaginal and uterine epithelial thickness and mucification to the same extent as estrogen. Ospemifene did not induce endometrial hyperplasia in animal models; there also was no stimulatory effect on endometrial cells. In rat and human mammary cells in vitro, ospemifene evokes a dose-dependent inhibition on estrogen-induced cell responses and cell proliferation, supporting an antiestrogenic effect in breast. In contrast, ospemifene has an estrogenic effect on bone, as seen by improved bone mineral density, strength, mass, and histomorphometry in preclinical models, consistent with improvements in markers of bone resorption and formation in postmenopausal women. Based on the preclinical evidence, ospemifene has beneficial estrogen-like effects on the vaginal epithelium, preliminary evidence to support a neutral endometrial profile, antiproliferative effects in breast, and estrogenic effects in bone. Taken together, especially regarding estrogen like effects on the vaginal epithelium, ospemifene presents a profile of tissue specific effects that appear novel among available SERMs and well-suited for the treatment of VVA. PMID- 24055830 TI - A new sulphate metabolite as a long-term marker of metandienone misuse. AB - Metandienone is one of the most frequently detected anabolic androgenic steroids in sports drug testing. Metandienone misuse is commonly detected by monitoring different metabolites excreted free or conjugated with glucuronic acid using gas chromatography mass spectrometry (GC-MS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) after hydrolysis with beta-glucuronidase and liquid liquid extraction. It is known that several metabolites are the result of the formation of sulphate conjugates in C17, which are converted to their 17-epimers in urine. Therefore, sulphation is an important phase II metabolic pathway of metandienone that has not been comprehensively studied. The aim of this work was to evaluate the sulphate fraction of metandienone metabolism by LC-MS/MS. Seven sulphate metabolites were detected after the analysis of excretion study samples by applying different neutral loss scan, precursor ion scan and SRM methods. One of the metabolites (M1) was identified and characterised by GC-MS/MS and LC-MS/MS as 18-nor-17beta-hydroxymethyl-17alpha-methylandrost-1,4,13-triene-3-one sulphate. M1 could be detected up to 26 days after the administration of a single dose of metandienone (5 mg), thus improving the period in which the misuse can be reported with respect to the last long-term metandienone metabolite described (18 nor-17beta-hydroxymethyl-17alpha-methylandrost-1,4,13-triene-3-one excreted in the glucuronide fraction). PMID- 24055831 TI - L712V mutation in the androgen receptor gene causes complete androgen insensitivity syndrome due to severe loss of androgen function. AB - Inability to respond to the circulating androgens is named as androgen insensitivity syndrome (AIS). Mutations in the androgen receptor (AR) gene are the most common cause of AIS. A cause and effect relationship between some of these mutations and the AIS phenotype has been proven by in vitro studies. Several other mutations have been identified, but need to be functionally validated for pathogenicity. Screening of the AR mutations upon presumptive diagnosis of AIS is recommended. We analyzed a case of complete androgen insensitivity syndrome (CAIS) for mutations in the AR gene. Sequencing of the entire coding region revealed C>G mutation (CTT-GTT) at codon 712 (position according to the NCBI database) in exon 4 of the gene, resulting in replacement of leucine with valine in the ligand-binding domain of the AR protein. No incidence of this mutation was observed in 230 normal male individuals analyzed for comparison. In vitro androgen binding and transactivation assays using mutant clone showed approximately 71% loss of ligand binding and about 76% loss of transactivation function. We conclude that CAIS in this individual was due to L712V substitution in the androgen receptor protein. PMID- 24055822 TI - Fluorescent approaches for understanding interactions of ligands with G protein coupled receptors. AB - G protein coupled receptors are responsible for a wide variety of signaling responses in diverse cell types. Despite major advances in the determination of structures of this class of receptors, the underlying mechanisms by which binding of different types of ligands specifically elicits particular signaling responses remain unclear. The use of fluorescence spectroscopy can provide important information about the process of ligand binding and ligand dependent conformational changes in receptors, especially kinetic aspects of these processes that can be difficult to extract from X-ray structures. We present an overview of the extensive array of fluorescent ligands that have been used in studies of G protein coupled receptors and describe spectroscopic approaches for assaying binding and probing the environment of receptor-bound ligands with particular attention to examples involving yeast pheromone receptors. In addition, we discuss the use of fluorescence spectroscopy for detecting and characterizing conformational changes in receptors induced by the binding of ligands. Such studies have provided strong evidence for diversity of receptor conformations elicited by different ligands, consistent with the idea that GPCRs are not simple on and off switches. This diversity of states constitutes an underlying mechanistic basis for biased agonism, the observation that different stimuli can produce different responses from a single receptor. It is likely that continued technical advances will allow fluorescence spectroscopy to play an important role in continued probing of structural transitions in G protein coupled receptors. This article is part of a Special Issue entitled: Structural and biophysical characterisation of membrane protein-ligand binding. PMID- 24055832 TI - The influence of depression symptoms on exploratory decision-making. AB - People with symptoms of depression show impairments in decision-making. One explanation is that they have difficulty maintaining rich representations of the task environment. We test this hypothesis in the context of exploratory choice. We analyze depressive and non-depressive participants' exploration strategies by comparing their choices to two computational models: (1) an "Ideal Actor" model that reflectively updates beliefs and plans ahead, employing a rich representation of the environment and (2) a "Naive Reinforcement Learning" (RL) model that updates beliefs reflexively utilizing a minimal task representation. Relative to non-depressive participants, we find that depressive participants' choices are better described by the simple RL model. Further, depressive participants were more exploratory than non-depressives in their decision-making. Depressive symptoms appear to influence basic mechanisms supporting choice behavior by reducing use of rich task representations and hindering performance during exploratory decision-making. PMID- 24055833 TI - Two-year-olds can begin to acquire verb meanings in socially impoverished contexts. AB - By two years of age, toddlers are adept at recruiting social, observational, and linguistic cues to discover the meanings of words. Here, we ask how they fare in impoverished contexts in which linguistic cues are provided, but no social or visual information is available. Novel verbs are presented in a stream of syntactically informative sentences, but the sentences are not embedded in a social context, and no visual access to the verb's referent is provided until the test phase. The results provide insight into how toddlers may benefit from overhearing contexts in which they are not directly attending to the ambient speech, and in which no conversational context, visual referent, or child directed conversation is available. PMID- 24055834 TI - Antiviral activity of methyl helicterate isolated from Helicteres angustifolia (Sterculiaceae) against hepatitis B virus. AB - The anti-HBV effect of methyl helicterate (MH), a triterpenoid isolated from the Chinese herb Helicteres angustifolia, was explored both in vitro and in vivo. In the HBV-transfected cell line HepG2.2.15, the secretion of HBsAg/HBeAg, the levels of HBV DNA and cccDNA, and the amount of viral RNA were significantly decreased after treatment with MH for 144h. In addition, MH had no inhibitory effect on the mitochondrial DNA content. In DHBV-infected ducklings, MH significantly reduced the serum DHBV DNA, liver total viral DNA, and cccDNA levels. Furthermore, analysis of the liver pathological changes confirmed the hepatoprotective effect of MH. These results indicate that MH efficiently inhibits HBV replication both in vitro and in vivo and that MH may be a major bioactive ingredient in H. angustifolia. PMID- 24055835 TI - Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations. AB - Neuraminidase inhibitors (NAIs) play vital roles in controlling human influenza epidemics and pandemics. However, the emergence of new human influenza virus mutant strains resistant to existing antiviral drugs has been becoming a major challenge. Therefore, it is critical to uncover the mechanisms of drug resistance and seek alternative treatments to combat drug resistance. In this study, molecular dynamics (MD) simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) were applied to investigate the different sensitivities of oseltamivir (OTV), zanamivir (ZNV), and peramivir (PRV) against the E119G mutant of 2009 A/H1N1 neuraminidase. The predicted binding free energies indicate that the E119G mutation in NA confers resistance to all of the three studied inhibitors. The ordering of the level of drug resistance predicted by the binding free energies for the three inhibitors is ZNV>PRV>OTV, which agrees well with the experimental data. Drug resistance arises primarily from the unfavorable shifts of the polar interactions between NA and the inhibitors. It comes as a surprise that the mutation of Glu119 that can form strong H-bonds with the inhibitors in the wild-type protein does not have direct impact on the binding affinities of both OTV and PRV due to the regulation of the strong unfavorable polar desolvation energies. The indirectly conformational variations of the inhibitors, which caused by the E119G mutation, are responsible for the loss of the binding free energies. However, for ZNV, the E119G mutation has both direct and indirect influences on the drug binding. The structural and quantitative viewpoint obtained from this study provides valuable information for the rational design of novel and effective drugs to combat drug resistance. PMID- 24055836 TI - Construction and characterisation of replicating foamy viral vectors expressing HIV-1 epitopes recognised by broadly neutralising antibodies. AB - With the aim to develop a replicating vector system for the delivery of HIV-1 antigens on the basis of an apathogenic foamy virus we recently showed that immunisation with purified recombinant hybrid antigens composed of the feline foamy virus Bet protein and parts of the transmembrane envelope protein of HIV-1 induced antibodies with an epitope specificity identical to that of the broadly neutralising antibody 2F5 (Muhle et al., Immunol Res., 2013, 56:61-72). Here we set out to further improve the HIV-1 inserts consisting of the membrane proximal external region (MPER) and the fusion peptide proximal region (FPPR) by stepwise shortening distinct linker residues between both domains. In a subset of these antigens, enhanced recognition by 2F5 and 4E10 was observed, indicating that a specific positioning of FPPR and MPER domains is critical for improved antibody binding. Introduction of these optimised inserts as well as of the MPER domain alone into the feline foamy virus backbone was compatible with virus replication, giving viral titres similar to wild-type virus after extended passaging. Most importantly, expression of the HIV-1 transgenes in infected feline CRFK cells remained stable in three out of four constructs and was detectable after serial passages for several weeks. These data encourage further testing of these vectors in vivo, which may allow insights into the necessity of affinity maturation for the induction of broadly reactive HIV-1 antibodies. PMID- 24055837 TI - Phenotypic and genotypic characterization of induced acyclovir-resistant clinical isolates of herpes simplex virus type 1. AB - Eleven strains of acyclovir (ACV)-resistant herpes simplex virus type 1 (HSV-1) were generated from HSV-1 clinical isolates by exposure to ACV. Genotype of the thymidine kinase (TK) and DNA polymerase (pol) genes from these mutants were further analyzed. Genotypic analysis revealed four non-synonymous mutations in TK gene associated with gene polymorphism and two to three non-synonymous mutations in DNA pol gene. Seven and six strains contained at least one resistance associated mutation at TK and DNA pol gene, respectively. Resistance-associated mutations within the TK gene consisted of 64% of non-synonymous frameshift mutations within the homopolymer region of G's and C's, and 36% of non-synonymous nucleotide substitutions of the conserved gene region (C336Y, R51W and R222H), nucleotide that produced stop codon (L288Stop) and two amino acid substitutions outside the conserved region (E39G & L208F). There were 10 non-synonymous amino acid substitutions located outside the conserved region with the unclear significance to confer resistance observed. Resistance-associated mutations in DNA pol gene include insertion of G at the homopolymer region of G's (794-797) and amino acid substitutions inside (V621S) or outside (H1228D) the conserved region. In silico analysis of the mutated TK (C336Y, R51W and L208F), and DNA pol (V621S and H1228D) suggested structural changes that might alter the stability of these proteins. However, there were several mutations with unclear significance to confer ACV-resistance identified, especially mutations outside the conserved region. PMID- 24055839 TI - Correlation between Raman sum and optical conductivity sum in La(2-x)Sr(x)CuO4. AB - In a strongly correlated electron system, the single-particle spectral function changes into a coherent peak and incoherent humps which extend over 1 eV. The incoherent parts lose the symmetry and k dependence, so that the Raman spectra with different symmetries become identical and they are expressed by the optical conductivity. We found that the B1g and B2g spectra in La(2-x)Sr(x)CuO4 become identical above 2000 cm(-1) in the underdoped phase, if Fleury-Loudon type B1g two-magnon scattering is removed. The first Raman susceptibility moment correlates with the generalized optical conductivity moment. The good correlation arises from the incoherent states of a hump from 1000 to 4000 cm(-1). The hump is the only structure of the incoherent electronic states in the mid-infrared absorption spectra below 1.4 eV at low carrier densities. The energy is twice the separated dispersion segments of the spin wave in the k(perpendicular) stripe direction. The incoherent state is formed by the magnetic excitations created by the hole hopping in the antiferromagnetic spin stripes in the real space picture. PMID- 24055840 TI - Lipidomics in drug discovery. AB - Lipidomics is a rapidly growing technology that can be used in biomedical research to study disease mechanisms, identify novel disease biomarkers and drug efficacy biomarkers, and reveal off-target effects. Lipidomics can also be used to elucidate the mechanism of action of different drug compounds or as readouts in Mendelian randomization approaches. Furthermore, lipidomics can be utilized to identify deviations in metabolic and/or signaling pathways in different stages of disease. Therefore, as we discuss here, this emerging technology also has a substantial potential in various drug discovery programs. PMID- 24055838 TI - Quantum dots and prion proteins: is this a new challenge for neurodegenerative diseases imaging? AB - A diagnostics of infectious diseases can be done by the immunologic methods or by the amplification of nucleic acid specific to contagious agent using polymerase chain reaction. However, in transmissible spongiform encephalopathies, the infectious agent, prion protein (PrP(Sc)), has the same sequence of nucleic acids as a naturally occurring protein. The other issue with the diagnosing based on the PrP(Sc) detection is that the pathological form of prion protein is abundant only at late stages of the disease in a brain. Therefore, the diagnostics of prion protein caused diseases represent a sort of challenges as that hosts can incubate infectious prion proteins for many months or even years. Therefore, new in vivo assays for detection of prion proteins and for diagnosis of their relation to neurodegenerative diseases are summarized. Their applicability and future prospects in this field are discussed with particular aim at using quantum dots as fluorescent labels. PMID- 24055841 TI - Polymer-drug conjugates: present state of play and future perspectives. AB - Polymer conjugation is an efficient approach to improve therapeutic properties of drugs and biological agents. Since the first synthetic polymer-drug conjugate entered clinical trials in 1994, this technology has undergone notable development for the introduction and study of novel polymers and for the progress in the biological rationale for designing conjugates. Not surprisingly, new polymers, in addition to the best known polyethylene glycol, poly[N-(2 hydroxypropyl)methacrylamide], are continuously conjugated with drugs to achieve biodegradable, stimuli-sensitive and targeted systems in an attempt to prolong blood circulation times and enhance drug concentrations at the intended site of action. This overview focuses on bioconjugates of water-soluble polymers with low molecular weight drugs. Additionally, the most recent achievements in the polymer drug conjugate field and several promising approaches for the future are discussed. PMID- 24055842 TI - Multifunctional and multitargeted nanoparticles for drug delivery to overcome barriers of drug resistance in human cancers. AB - The recurrence and metastatic spread of cancer are major drawbacks in cancer treatment. Although chemotherapy is one of the most effective methods for the treatment of metastatic cancers, it is nonspecific and causes significant toxic damage. The development of drug resistance to chemotherapeutic agents through various mechanisms also limits their therapeutic potential. However, as we discuss here, the use of nanodelivery systems that are a combination of diagnostics and therapeutics (theranostics) is as relatively novel concept in the treatment of cancer. Such systems are likely to improve the therapeutic benefits of encapsulated drugs and can transit to the desired site, maintaining their pharmaceutical properties. The specific targeting of malignant cells using multifunctional nanoparticles exploits theranostics as an improved agent for delivering anticancer drugs and as a new solution for overriding drug resistance. PMID- 24055843 TI - [Preliminary comparative study between identification methods: API 32C(r) and MALDI-TOF(r)]. PMID- 24055844 TI - The clinical outcomes of percutaneous coronary intervention performed without pre procedural aspirin. AB - OBJECTIVES: The purpose of this study was to examine the incidence and outcomes of percutaneous coronary intervention (PCI) performed in patients who had not received pre-procedural aspirin. BACKGROUND: Aspirin is an essential component of peri-PCI pharmacotherapy. Previous studies suggest that pre-procedural aspirin is not administered to a clinically significant number of patients undergoing PCI. METHODS: We evaluated the incidence of PCIs performed without pre-procedural aspirin use among patients undergoing PCI from January 2010 through December 2011 at 44 hospitals in Michigan. Propensity-matched multivariate analysis was used to adjust for the nonrandom use of aspirin. RESULTS: Our study population comprised 65,175 patients, of whom 4,640 (7.1%) did not receive aspirin within 24 h before undergoing PCI. Aspirin nonreceivers were more likely to have had previous gastrointestinal bleeding or to present with cardiogenic shock or after cardiac arrest. In the propensity-matched analysis, absence of aspirin before PCI was associated with a higher rate of death (3.9% vs. 2.8%; odds ratio: 1.89 [95% confidence interval: 1.32 to 2.71], p < 0.001) and stroke (0.5% vs. 0.1%; odds ratio: 4.24 [95% confidence interval: 1.49 to 12.11], p = 0.007) with no difference in need for transfusions. This association was consistent across multiple pre-specified subgroups. CONCLUSIONS: A significant number of patients do not receive aspirin before undergoing PCI. Lack of aspirin before PCI was associated with significantly increased in-hospital mortality and stroke. Our study results support the need for quality efforts focused on optimizing aspirin use before PCI. PMID- 24055846 TI - Reply: first-in-humans randomized clinical trial of renal denervation for atrial arrhythmia raises concern. PMID- 24055845 TI - High-sensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin. AB - OBJECTIVES: The aim of this study was to evaluate the prognostic value of high sensitivity troponin T (hs-TnT) in addition to clinical risk factors and the CHA2DS2VASc (congestive heart failure, hypertension, 75 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) risk score in patients with atrial fibrillation (AF). BACKGROUND: The level of troponin is a powerful predictor of cardiovascular events and mortality. METHODS: A total of 14,897 patients with AF were randomized to treatment with apixaban or warfarin in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial. The associations between baseline hs-TnT levels and outcomes were evaluated using adjusted Cox regression models. RESULTS: Levels of hs-TnT were measurable in 93.5% of patients; 75% had levels >7.5 ng/l, 50% had levels >11.0 ng/l, and 25% had levels >16.7 ng/l. During a median 1.9-year period, the annual rates of stroke or systemic embolism ranged from 0.87% in the lowest hs-TnT quartile to 2.13% in the highest hs-TnT quartile (adjusted hazard ratio [HR]: 1.94; 95% confidence interval [CI]: 1.35 to 2.78; p = 0.0010). The annual rates in the corresponding groups ranged from 0.46% to 4.24% (adjusted HR: 4.31; 95% CI: 2.91 to 6.37; p < 0.0001) for cardiac death and from 1.26% to 4.21% (adjusted HR: 1.91; 95% CI: 1.43 to 2.56; p = 0.0001) for major bleeding. Adding hs-TnT levels to the CHA2DS2VASc score improved the C statistic from 0.620 to 0.635 for stroke or systemic embolism (p = 0.0226), from 0.592 to 0.711 for cardiac death (p < 0.0001), and from 0.591 to 0.629 for major bleeding (p < 0.0001). Apixaban reduced rates of stroke, mortality, and bleeding regardless of the hs-TnT level. CONCLUSIONS: Levels of hs-TnT are often elevated in patients with AF. The hs-TnT level is independently associated with an increased risk of stroke, cardiac death, and major bleeding and improves risk stratification beyond the CHA2DS2VASc risk score. The benefits of apixaban as compared with warfarin are consistent regardless of the hs-TnT level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984). PMID- 24055847 TI - Reply: no support for renal denervation in a meta-analysis. PMID- 24055848 TI - A novel sample preparation and on-line HPLC-DAD-MS/MS-BCD analysis for rapid screening and characterization of specific enzyme inhibitors in herbal extracts: case study of alpha-glucosidase. AB - Drug discovery from complex mixture like Chinese herbs is a challenge and extensive false positives make the obtainment of specific bioactive compounds difficult. In the present study, a novel sample preparation method was proposed to rapidly reveal the specific bioactive compounds from complex mixtures using alpha-glucosidase as a case. Firstly, aqueous and methanol extracts of 500 traditional Chinese medicines were carried out with the aim of finding new sources of alpha-glucosidase inhibitors. As a result, the extracts of fruit of Terminalia chebula (FTC), flowers of Rosa rugosa (FRR) and Eugenia caryophyllata (FEC) as well as husk of Punica granatum (HPG) showed high inhibition on alpha glucosidase. On-line liquid chromatography-diode array detection-tandem mass spectrometry and biochemical detection (HPLC-DAD-MS/MS-BCD) was performed to rapidly screen and characterize alpha-glucosidase inhibitors in these four extracts. After tentative identification, most of compounds with inhibitory activity in the investigated crude extracts were found to be tannins commonly recognized as non-specific enzyme inhibitors in vitro. Subsequently, the four extracts were treated with gelatin to improve specificity of the on-line system. Finally, two compounds with specific alpha-glucosidase inhibition were identified as corilagin and ellagic acid. The developed method could discover specific alpha glucosidase inhibitors in complex mixtures such as plant extracts, which could also be used for discovery of specific inhibitors of other enzymes. PMID- 24055849 TI - Screening for multiple weight loss and related drugs in dietary supplement materials by flow injection tandem mass spectrometry and their confirmation by liquid chromatography tandem mass spectrometry. AB - A new method has been developed using flow injection tandem mass spectrometry to semi-quantitatively screen for weight loss drugs, including sibutramine, N desmethylsibutramine, N-didesmethylsibutramine, and phenolphthalein in dietary supplements. Positive identification of these drugs in samples was further confirmed and quantified by liquid chromatography tandem mass spectrometry. The degradation products of sibutramine were observed and identified by LC-MS/MS which include N-desmethylsibutramine, N-didesmethylsibutramine, N formyldesmethylsibutramine, and N-formyldidesmethylsibutramine. PMID- 24055850 TI - Quantitation of tenofovir and emtricitabine in dried blood spots (DBS) with LC MS/MS. AB - A reversed-phase high performance liquid chromatographic (LC), tandem mass spectrometry (MS/MS) assay for the determination of tenofovir (TFV) and emtricitabine (FTC) in dried blood spots (DBS) from human whole blood was developed and validated. Whole blood samples were spotted, dried, and a 3mm punch was extracted with methanol for analysis by LC-MS/MS utilizing stable isotope labeled internal standards. The assay was validated over the range of 2.5 1000ng/mL for TFV and 2.5-5000ng/mL for FTC. The method was accurate (within +/ 15% of control) and precise (coefficient of variation <=15%) for hematocrit concentrations ranging from 25% to 76%; using edge punches vs. center punches; and spot volumes of 10-50MUL. Analytes were stable for five freeze/thaw cycles and up to 6 days at room temperature, whereas long-term storage required -20 degrees C or -80 degrees C. Comparison of TFV and FTC in DBS vs. plasma yielded r(2)>=0.96, indicating that DBS can be used as a plasma alternative for pharmacokinetic analyses in vivo. PMID- 24055851 TI - Phase quantification of antihypertensive drugs - Chlorthalidone, Hydrochlorothiazide, Losartan and combinations, Losartan/Chlorthalidone and Losartan/Hydrochlorothiazide - by the Rietveld method. AB - The identification and quantification of crystalline phases of antihypertensive drugs - Losartan potassium (LOS-K), Hydrochlorothiazide (HCTZ) and Chlorthalidone (CTD) were carried out by means of X-ray powder diffraction data and the Rietveld method. Quantitative phase analyses of Losartan potassium/Chlorthalidone (LOS K/CTD) and Losartan potassium/Hydrochlorothiazide (LOS-K/HCTZ) combinations were also evaluated. The results indicated that for diuretics (HCTZ and CTD) only one crystalline phase was found in samples, and for LOS-K the crystal structure showed similarity between the Bragg peaks to the phase described as monoclinic and space group P21/c. After one year storage, the orthorhombic one was also observed in this sample. PMID- 24055852 TI - Assessing Jasminum grandiflorum L. authenticity by HPLC-DAD-ESI/MS(n) and effects on physiological enzymes and oxidative species. AB - The dried flower buds of Jasminum grandiflorum L. are widely consumed as infusion and used in traditional medicine for psychiatric disorders. It is important to have a well-established method for the chemical characterization of J. grandiflorum since there are resemblances with a toxic species, Gelsemium sempervirens (L.) Jaume Saint-Hilaire. HPLC-DAD-ESI/MS(n) analysis allowed identifying six phenolic compounds for the first time. Moreover, the evaluation of in vitro activity against central nervous system (CNS) related enzymes was undertaken for the first time, as well as against reactive species in order to support the efficacy towards CNS disorders. PMID- 24055853 TI - Determination of the ratio between mercaptalbumin and nonmercaptalbumin by HPLC with fluorescence probe specifically binding to albumin. AB - A simple and selective HPLC-fluorescence (FL) method with FL probe, 4-[4-(4 dimethylaminophenyl)-5-phenyl-1H-imidazol-2-yl]benzoic acid methyl ester (DAPIM), for simultaneous determination of mercaptalbumin (HMA) and nonmercaptalbumin (HNA1) was developed. After HMA and HNA1 were separated on an ion-exchange column, they were on-line and post-column mixed with DAPIM. The DAPIM-albumin complex produces FL (lambdaex 370nm and lambdaem 510nm); however, DAPIM solution never gives the FL. Based on this mechanism, selective determination of HMA and HNA1 were achieved without any pretreatment and interfering peak. The proposed method was applied to the measurement of HMA and HNA1 in human serum of healthy volunteers and diabetes mellitus patients. PMID- 24055855 TI - Quantitative analysis of tenuifolin concentrations in rat plasma and tissue using LC?MS/MS: application to pharmacokinetic and tissue distribution study. AB - A sensitive, reliable and accurate reversed-phased liquid chromatography with tandem mass spectrometry (LC?MS/MS) in negative ion mode was developed and validated for the quantification of tenuifolin in rat plasma and tissue. A single step protein precipitation by methanol was used to prepare plasma and tissue homogenate samples. Tenuifolin and polydatin (internal standard, IS) were separated by HPLC using a C18 column and an isocratic mobile phase consisted of acetonitrile and water containing 0.05% formic acid (42:58, v/v) running at a flow rate of 0.2 ml/min for 6 min. Detection and quantification were performed using a mass spectrometer by the multiple reaction monitoring (MRM) in negative electrospray ionization mode. The transition monitored were m/z [M?H](?) 679.4 ? 455.4 for tenuifolin and m/z [M?H](?) 389.0 ? 227.2 for IS, respectively. Calibration curves were recovered over a concentration range of 0.5?1000 ng/ml for plasma, heart, liver, lung and kidney, 0.5?200 ng/ml for spleen, and 0.5?50 ng/ml for brain, respectively. The lower limit of quantification was 0.5 ng/ml for plasma and tissue homogenates. The inter-day precision (R.S.D.) was less than 12.9% and intra-day precision R.S.D. was less than 13.4%, while the inter-day accuracy (R.E.) was ranged from ?7.20 to 6.87% and intra-day accuracy (R.E.) was ranged from ?6.20 to 8.04% in plasma and tissue homogenates. This method was successfully applied to the pharmacokinetic and tissue distribution study of pure tenuifolin in rat. The pharmacokinetic study indicated that poor absorption into systemic circulation was observed after rat was administered orally tenuifolin, and the absolute bioavailability was low (0.83 +/- 0.28%). The results of tissue distribution showed the higher tenuifolin concentrations were found in liver, kidney and heart, and the small amount of drug was distributed quickly into the brain tissue at 5 min after the intravenous injection of tenuifolin. The fact that tenuifolin could cross the blood?brain barrier provided the material basis for pharmacological action of the tenuifolin in the treatment of memory loss. PMID- 24055854 TI - Absolute quantification of UGT1A1 in various tissues and cell lines using isotope label-free UPLC-MS/MS method determines its turnover number and correlates with its glucuronidation activities. AB - Uridine 5'-diphosphate-glucuronosyltransferase (UGT)1A1 is a major phase II metabolism enzyme responsible for glucuronidation of drugs and endogenous compounds. The purpose of this study was to determine the expression level of UGT1A1 in human liver microsomes and human cell lines by using an isotope label free LC-MS/MS method. A Waters Ultra performance liquid chromatography (UPLC) system coupled with an API 5500Qtrap mass spectrometer was used for the analysis. Two signature peptides (Pep-1, and Pep-2) were employed to quantify UGT1A1 by multiple reaction monitoring (MRM) approach. Standard addition method was used to validate the assay to account for the matrix effect. 17beta-Estradiol was used as the marker substrate to determine UGT1A1 activities. The validated method has a linear range of 200-0.0195nM for both signature peptides. The precision, accuracy, and matrix effect were in acceptable ranges. UGT1A1 expression levels were then determined using 8 individual human liver microsomes, a pooled human liver microsomes, three UGT1A1 genotyped human liver microsomes, and four cell lines (Caco-2, MCF-7, Hela, and HepG2). The correlations study showed that the UGT1A1 protein levels were strongly correlated with its glucuronidation activities in human liver microsomes (R(2)=0.85) and in microsomes prepared from cell lines (R(2)=0.95). Isotope-labeled peptides were not necessary for LC-MS/MS quantitation of proteins. The isotope label-free absolute quantification method used here had good accuracy, sensitivity, linear range, and reproducibility, and were used successfully for the accurate determination of UGT1A1 from tissues and cell lines. PMID- 24055856 TI - The Janus face of caffeine. AB - Caffeine is certainly the psychostimulant substance most consumed worldwide. Over the past years, chronic consumption of caffeine has been associated with prevention of cognitive decline associated to aging and mnemonic deficits of brain disorders. While its preventive effects have been reported extensively, the cognitive enhancer properties of caffeine are relatively under debate. Surprisingly, there are scarce detailed ontogenetic studies focusing on neurochemical parameters related to the effects of caffeine during prenatal and earlier postnatal periods. Furthermore, despite the large number of epidemiological studies, it remains unclear how safe is caffeine consumption during pregnancy and brain development. Thus, the purpose of this article is to review what is currently known about the actions of caffeine intake on neurobehavioral and adenosinergic system during brain development. We also reviewed other neurochemical systems affected by caffeine, but not only during brain development. Besides, some recent epidemiological studies were also outlined with the control of "pregnancy signal" as confounding variable. The idea is to tease out how studies on the impact of caffeine consumption during brain development deserve more attention and further investigation. PMID- 24055857 TI - Treatment strategies for complex behavioral insomnia in children with neurodevelopmental disorders. AB - PURPOSE OF REVIEW: This review describes recent research in pediatric behavioral insomnias in neurodevelopmental disorders and their treatment. RECENT FINDINGS: Insomnia in children with autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) is typically complex, chronic, and difficult to adequately control. Abnormalities in genetic and/or epigenetic regulation of sleep/wakefulness and its timing predispose patients with NDD to insomnia, although poor sleep hygiene, maladaptive associations, and limit-setting are likely to contribute. Parents are agents for change in problematic sleep behaviors in patients with NDD. We review the benefits of behavioral therapies and melatonin to treat sleep problems in children with NDD. Problematic sleep is so prevalent in some neurodevelopmental syndromes (Rett, Angelman, Williams, and Smith-Magenis) that it is part of their diagnostic criteria. SUMMARY: Children and adolescents with neurological disorders frequently have complex sleep disorders that require treatment. Understanding the basic pathology and treatment strategies provides an opportunity to improve well being and quality of life in those affected by NDD and their families. PMID- 24055859 TI - Poloxamer 188 reduces normal and phosphatidylserine-exposing erythrocyte adhesion to endothelial cells in dextran solutions. AB - Abnormal red blood cell (RBC) adhesion to endothelial cells (ECs) has been correlated with vascular complications in diseases such as sickle cell anemia and diabetes. Poloxamer 188 (P188) has been clinically tested to treat vaso occlusion. However, the underlying mechanism(s) have not been clarified, making a methodical application difficult. In this study, we investigate how and to what extent P188 reduces RBC adhesion to ECs in plasma-like solutions. RBC adhesion to ECs is studied in solutions containing dextran, which is known to induce adhesion via macromolecular depletion interaction. It is demonstrated that P188 itself does not induce adhesion of normal RBCs to ECs but significantly reduces the adhesion in solutions containing high molecular mass-dextran. In addition, it is shown that P188 can reduce the adhesion of RBCs with enhanced exposure of phosphatidylserine (PS). Measurements of the electrophoretic mobility indicate that P188 increases the local viscosity inside the electric double layer of RBCs. Based on these results this study suggests that P188 reduces macromolecular depletion interaction, via penetrating into the depletion layer. Taking into consideration that dextran mimics the effects of pro-adhesive non-adsorbing plasma proteins and macromolecules, our study therefore suggests a mechanism for the adhesion reducing effect of P188 and should thus be of potential value for a detailed understanding of how cell-cell interactions in pathological conditions can be reduced. PMID- 24055860 TI - Optimized immobilization of transketolase from E. coli in MgAl-layered double hydroxides. AB - Immobilization of TK from Escherichia coli (TKec) on MgAl-NO3 layered double hydroxides (LDH) was carried out by two processes: adsorption and coprecipitation. As a comparison, the adsorption method was realized either at pH 7.5 in buffered solutions (MOPS and Gly-Gly) or in pure water. For the coprecipitation method, the formation of the inorganic LDH support was realized directly in the presence of TKec solubilized in Gly-Gly. The prepared biohybrids, called respectively TKec@LDHads and TKec@LDHcop, were characterized by powder X ray diffraction, FTIR spectroscopy in comparison with TKec free reference products, i.e. MgAl-NO3, MgAl-Gly-Gly. The enzymatic activities of the various TKec@LDH biohybrids as well as their stabilities over time were investigated by UV-vis assay. A maximum of activity (12 U/mg of solid) was reached for TKec@MgAl Gly-Gly biohybrid prepared by coprecipitation. Finally, thin films were prepared through a one-step deposition on a polished support. The enzymatic activity of the resulting TKec@MgAl-Gly-Glycop film was tested over four recycling processes with a reproducible activity of 2.7 U/mg cm(2). PMID- 24055861 TI - Immune and inflammation responses to a 3-day period of intensified running versus cycling. AB - Functional overreaching has been linked to alterations in immunity and host pathogen defense, but little is known as to whether or not running and cycling evoke different responses. This study compared inflammation, muscle damage and soreness, and innate immune function responses to a 3-day period of intensified exercise in trained long distance runners (N=13, age 34.4+/-2.4year) and cyclists (N=22, age 36.6+/-1.7year, P=0.452). Upper respiratory tract infection (URTI) symptomatology was monitored for 12weeks using the Wisconsin Upper Respiratory Symptom Survey (WURSS), and subjects from both athletic groups came to the lab during week five and exercised 2.5h/day for 3days in a row at 70% VO2max. Blood samples were collected before and after the 3-day period of exercise, with recovery samples collected 1-, 14-, and 38h-post-exercise. Samples were analyzed for muscle damage [creatine kinase (CK), myoglobin (MYO)], inflammation (CRP, IL 6, IL-8, IL-10, MCP), and innate immunity [granulocyte and monocyte phagocytosis (GR-PHAG and MO-PHAG) and oxidative burst activity (GR-OBA and MO-OBA)]. Runners compared to cyclists experienced significantly more muscle damage (CK 133% and MYO 404% higher post-3days exercise), inflammation (CRP 87%, IL-6 256%, IL 8 61%, IL-10 32%, MCP 29%), and delayed onset of muscle soreness (DOMS, 87%). The 3-day period of exercise caused significant downturns in GR-PHAG, MO-PHAG, GR-OBA, MO OBA by 14- and 38h-recovery, but the pattern of change did not differ between groups. No group differences were measured for 12-week URTI severity (18.3+/-5.6 and 16.6+/-4.0, P=0.803) and symptom scores (33.4+/-12.6 and 24.7+/-5.8, P=0.477). These data indicate that a 3-day period of functional overreaching results in substantially more muscle damage and soreness, and systemic inflammation in runners compared to cyclists, but without group differences for 12-week URTI symptomatology and post-exercise decrements in innate immune function. PMID- 24055863 TI - The vast complexity of primary open angle glaucoma: disease genes, risks, molecular mechanisms and pathobiology. AB - Primary open angle glaucoma (POAG) is a complex progressive optic nerve neuropathy triggered by both environmental and genetic risk factors. Several ocular tissues, including the ciliary body, trabecular meshwork and optic nerve head, and perhaps even brain tissues, are involved in a chain of pathological events leading to POAG. Genetic risk evidence for POAG came from family linkage studies implicating a small number of disease genes (MYOC, OPTN, WDR36). Recent Genome Wide Association Studies (GWAS) identified a large number of new POAG loci and disease genes, such as CAV1, CDKN2B and GAS7. In the current study, we reviewed over 120 family and GWA studies. We selected in total 65 (candidate) POAG disease genes and proceeded to assess their function, mRNA expression in POAG relevant eye tissues and possible changes in disease state. We found that the proteins corresponding to these 65 (candidate) POAG disease genes take part in as few as four common functional molecular networks. Functions attributed to these 4 networks were developmental (dys)function, lipid metabolism, and inflammatory processes. For the 65 POAG disease genes, we reviewed the available (transgenic) mouse models of POAG, which may be useful for future functional studies. Finally, we showed that the 65 (candidate) POAG genes substantially increased the specificity and sensitivity of a discriminative POAG risk test. This suggests that personal risk assessment and personalized medicine for POAG are on the horizon. Taken together, the data presented are essential to comprehend the role of genetic variation in POAG, and may provide leads to understand the pathophysiology of POAG as well as other neurodegenerative disorders, such as Alzheimer's disease. PMID- 24055862 TI - Sleep and behavior during vesicular stomatitis virus induced encephalitis in BALB/cJ and C57BL/6J mice. AB - Intranasal application of vesicular stomatitis virus (VSV) produces a well characterized model of viral encephalitis in mice. Within one day post-infection (PI), VSV travels to the olfactory bulb and, over the course of 7 days, it infects regions and tracts extending into the brainstem followed by clearance and recovery in most mice by PI day 14 (PI 14). Infectious diseases are commonly accompanied by excessive sleepiness; thus, sleep is considered a component of the acute phase response to infection. In this project, we studied the relationship between sleep and VSV infection using C57BL/6 (B6) and BALB/c mice. Mice were implanted with transmitters for recording EEG, activity and temperature by telemetry. After uninterrupted baseline recordings were collected for 2 days, each animal was infected intranasally with a single low dose of VSV (5*10(4) PFU). Sleep was recorded for 15 consecutive days and analyzed on PI 0, 1, 3, 5, 7, 10, and 14. Compared to baseline, amounts of non-rapid eye movement sleep (NREM) were increased in B6 mice during the dark period of PI 1-5, whereas rapid eye movement sleep (REM) was significantly reduced during the light periods of PI 0-14. In contrast, BALB/c mice showed significantly fewer changes in NREM and REM. These data demonstrate sleep architecture is differentially altered in these mouse strains and suggests that, in B6 mice, VSV can alter sleep before virus progresses into brain regions that control sleep. PMID- 24055864 TI - Relational congruence facilitates neural mapping of spatial and temporal magnitudes in preverbal infants. AB - Mental representations of space, time, and number are fundamental to our understanding of the world around us. It should come as no surprise that representations of each are functional early in human development, appear to share a common format, and may be maintained by overlapping cortical structures. The consequences of these similarities for early learning and behavior are poorly understood. We investigated this issue by assessing neurophysiological processing of audio-visual temporal and spatial magnitude pairs using event-related potentials (ERPs) with young infants. We observed differential early processing and later enhanced attentional processing for pairings of spatial and temporal magnitudes that were relationally congruent (short visual character paired with a short auditory tone or long visual character paired with a long auditory tone) compared to the same stimuli paired in a relationally incongruent manner (short visual character with the long auditory tone or long visual character with a short tone). Unlike previous studies, these results were not dependent on a redundancy of information between the senses or an alignment of congruent magnitude properties within a single sense modality. Rather, these results demonstrate that mental representations of space and time interact to bias learning before formal instruction or the acquisition of spatial language. PMID- 24055865 TI - Different developmental trajectories for anticipation and receipt of reward during adolescence. AB - Typical adolescent behaviour such as increased risk-taking and novelty-seeking is probably related to developmental changes in the brain reward system. This functional MRI study investigated how brain activation related to two components of reward processing (Reward Anticipation and Reward Outcome) changes with age in a sample of 39 children, adolescents and young adults aged 10-25. Our data revealed age-related changes in brain activity during both components of reward processing. Activation related to Reward Anticipation increased with age, while activation related to Reward Outcome decreased in various regions of the reward network. This shift from outcome to anticipation was confirmed by subsequent analyses showing positive correlations between age and the difference in activation between Reward Anticipation and Reward Outcome. The shift was predominantly present in striatal regions and was accompanied by a significant effect of age on behaviour, with older participants showing more response speeding on potentially rewarding trials than younger participants. This study provides evidence for functional changes in the reward system which may underlie typical adolescent behaviour. PMID- 24055866 TI - miR-128 regulates non-myocyte hyperplasia, deposition of extracellular matrix and Islet1 expression during newt cardiac regeneration. AB - Cardiovascular disease is a global scourge to society, with novel therapeutic approaches required in order to alleviate the suffering caused by sustained cardiac damage. MicroRNAs (miRNAs) are being touted as one such approach in the fight against heart disease, acting as possible post-transcriptional molecular triggers responsible for invoking cardiac regeneration. To further ones understanding of miRNAs and cardiac regeneration, it is prudent to learn from organisms that can intrinsically regenerate their hearts following injury. Using the red-spotted newt, an adult chordate capable of cardiac regeneration, we decided to delve deeper into the role miRNAs play during this process. RNA isolated from regenerating newt heart samples, was used in a microarray screen, to identify significantly expressed candidate miRNAs during newt cardiac regeneration. We performed quantitative qPCR analysis on several conserved miRNAs and found one in particular, miR-128, to be significantly elevated when cardiac hyperplasia is at its peak following injury. In-situ hybridisation techniques revealed a localised expression pattern for miR-128 in the cardiomyocytes and non cardiomyocytes in close proximity to the regeneration zone and in vivo knockdown studies revealed a regulatory role for miR-128 in proliferating non-cardiomyocyte populations and extracellular matrix deposition. Finally, 3'UTR reporter assays revealed Islet1 as a biological target for miR-128, which was confirmed further through in vivo Islet1 transcriptional and translational expression analysis in regenerating newt hearts. From these studies we conclude that miR-128 regulates both cardiac hyperplasia and Islet1 expression during newt heart regeneration and that this information could be translated into future mammalian cardiac studies. PMID- 24055867 TI - Are 8-oxoguanine (8-oxoGua) and 5-hydroxymethyluracil (5-hmUra) oxidatively damaged DNA bases or transcription (epigenetic) marks? AB - The oxidatively modified DNA base 8-oxo-7,8-dihydroguanine (8-oxoGua) is nontoxic and weakly mutagenic. Here we report on new data suggesting a potential for 8 oxoGua to affect the expression of several genes via epigenetic changes resulting in chromatin relaxation. Using pig thymus extract, we analyzed the distribution of 8-oxoGua among different nuclei fractions representative of transcriptionally active and silenced regions. The levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8 oxodG) found in transcriptionally active euchromatin (4.37/10(6) nucleotides) and in the matrix fraction (4.16/10(6) nucleotides) were about 5 times higher than in transcriptionally silenced heterochromatin (0.91/10(6) nucleotides). Other experimental data are presented which suggest that 8-oxoGua present in specific DNA sequences may be widely used for transcription regulation. Like 8-oxoGua, 5 hydroxymethyluracil (5-hmUra) is another oxidatively modified DNA base (the derivative is formed by thymine oxidation). Recent experimental evidence supports the notion that 5-hmUra plays an important role in active DNA demethylation. This involves overexpression of activation-induced cytidine deaminase (AID) and ten eleven translocation 1 (TET1) protein (the key proteins involved in active demethylation), which leads to global accumulation of 5-hmUra. Our preliminary data demonstrate a significant increase of the 5-hmUra levels in pig brain extract when compared with liver extract. The lack of 5-hmUra in Escherichia coli DNA also speaks for a role of this modification in the active demethylation process. It is concluded that 8-oxodG and 5-hmUra in DNA may be considered as epigenetic marks. PMID- 24055868 TI - Light affects fumonisin production in strains of Fusarium fujikuroi, Fusarium proliferatum, and Fusarium verticillioides isolated from rice. AB - Three Fusarium species associated with bakanae disease of rice (Fusarium fujikuroi, Fusarium proliferatum, and Fusarium verticillioides) were investigated for their ability to produce fumonisins (FB1 and FB2) under different light conditions, and for pathogenicity. Compared to darkness, the conditions that highly stimulated fumonisin production were yellow and green light in F. verticillioides strains; white and blue light, and light/dark alternation in F. fujikuroi and F. proliferatum strains. In general, all light conditions positively influenced fumonisin production with respect to the dark. Expression of the FUM1 gene, which is necessary for the initiation of fumonisin production, was in accordance with the fumonisin biosynthetic profile. High and low fumonisin producing F. fujikuroi strains showed typical symptoms of bakanae disease, abundant fumonisin-producing F. verticillioides strains exhibited chlorosis and stunting of rice plants, while fumonisin-producing F. proliferatum strains were asymptomatic on rice. We report that F. fujikuroi might be an abundant fumonisin producer with levels comparable to that of F. verticillioides and F. proliferatum, highlighting the need of deeper mycotoxicological analyses on rice isolates of F. fujikuroi. Our results showed for the first time the influence of light on fumonisin production in isolates of F. fujikuroi, F. proliferatum, and F. verticillioides from rice. PMID- 24055870 TI - Anomalous magnetization behaviour in a single crystal of vanadium spinel FeV2O4. AB - Spinel oxide FeV2O4, having the orbital degrees of freedom at Fe(2+) and V(3+) ions, exhibits multi-step magnetic phase transitions and successive structural phase transitions at low temperatures. In order to clarify the magnetic properties of FeV2O4, we have measured the temperature dependence of magnetization, isothermal magnetization curves and specific heat using a single crystal of FeV2O4. Temperature-induced magnetization jumps below the 110 K were observed in the zero-field-cooled magnetization curves. Furthermore, we found that the behaviours of the isothermal magnetization curves were quite different between the zero-field-cooled and field-cooled conditions. We suggest that the change of the magnetic domain structure under the magnetic field associated with the orbital states of Fe(2+) ions is the possible origin of these intriguing and anomalous magnetic properties in a single crystal of FeV2O4. PMID- 24055869 TI - Emerging roles of PPR proteins in trypanosomes: switches, blocks, and triggers. AB - Mitochondrial genomes of trypanosomes are composed of catenated maxicircles and mini-circles that are densely packed into a nucleoprotein structure called the kinetoplast. Maxicircle DNA (~25 kb long, 20-50 copies) resembles a typical mitochondrial genome bearing rRNA and respiratory complex subunits genes, and also contains 12 cryptogenes whose transcripts require U-insertion/deletion editing to assemble protein-coding sequences. Production of guide RNAs for the editing process remains the only established function of mini-circle DNA (~1 kb, ~10000 copies). Although editing remains the most studied step in mRNA biogenesis, recent investigations illuminated complex nucleolytic processing and pre- and post-editing 3' modification events that ultimately create translation competent mRNAs. Key mRNA 3' processing enzymes, such as KPAP1 poly(A) polymerase and RET1 TUTase, have been identified but the mechanisms regulating their activities remain poorly understood. Discoveries of multiple pentatricopeptide repeat-containing (PPR) proteins populating polyadenylation complex and ribosomal subunits opened exciting experimental prospects that may ultimately lead to an integrated picture of mitochondrial gene expression. PMID- 24055871 TI - An interview of Dr. Ernesto Carafoli with Charles Weissmann. PMID- 24055872 TI - The power of methods. AB - Major advances in science are usually launched by new methods or techniques. Because this essay is not intended as a history of science, I shall not invoke the invention of the microscope or telescope as the gateways to inner and outer space, but will restrict myself to developments I have witnessed, or almost witnessed, during my scientific lifetime. PMID- 24055873 TI - Dual expression of hTERT and VEGF prolongs life span and enhances angiogenic ability of aged BMSCs. AB - Previous studies have confirmed the therapeutic effects of bone marrow stromal cells (BMSCs) transplantation on cerebral ischemia. However, the proliferative, differentiative, and homing capacity of BMSC from the elderly are significantly reduced, especially after several passages expansion in vitro. In this study, by introducing lentivirus-mediated hTERT and VEGF genes to modify human BMSCs from aged donors, we observed extended lifespan, promoted angiogenic capacity while less enhanced tumorigenicity of the genetically engineering BMSCs. These results therefore suggest that the modification of aged BMSCs by dual expression of hTERT and VEGF may be used for autologous cell replacement for ischemic cerebrovascular disease in elderly patients. PMID- 24055874 TI - Surface-induced conformational and functional changes of bone morphogenetic protein-2 adsorbed onto single-walled carbon nanotubes. AB - Efficient immobilization of bone morphogenetic protein-2 (BMP-2) onto matrix is of crucial importance in the development of BMP-2-based bone tissue scaffold/implant. This often ties with precise control of desirable protein conformation and retention of protein activity. Recently, great attentions were paid to the regulation of protein conformation by tailoring the nanoscale surface properties. In this contribution, with hydrophilic COOH- and hydrophobic CH3 terminated single-walled carbon nanotubes (SWNTs-COOH and SWNTs-CH3) as models, we investigated the nanoscale interface-induced changes of adsorption dynamics, conformation, and bioactivity of recombinant human BMP-2 (rhBMP-2). Our data showed that SWNTs-COOH and SWNTs-CH3 bound rapidly to and induced unfolding of rhBMP-2 molecules, which promoted their interactions with corresponding receptors on cell surface and thus enhanced their bioactivities. In contrast, rhBMP-2 showed stronger affinity to the COOH-terminated surface than that terminated with CH3 groups, while better enhanced bioactivity on the SWNTs-CH3 surfaces. After released from SWNTs, the unfolded rhBMP-2 refolded and their activities from SWNTs-COOH and SWNTs-CH3 were reduced to 90% and 70% of the native rhBMP-2, respectively. Based on these results obtained, a model of the binding characteristics of rhBMP-2 onto SWNTs with different chemistry is presented. This study demonstrates the possibility of simple tailor-made nanoscale chemical surfaces to modulate the binding, conformation and bioactivity of BMP-2, allowing fabrication of BMP-2-based bone tissue scaffolds with high osteoinductivity and low BMP-2 dosage. PMID- 24055876 TI - Localization and proliferation of lymphatic vessels in the tympanic membrane in normal state and regeneration. AB - We clarified the localization of lymphatic vessels in the tympanic membrane and proliferation of lymphatic vessels during regeneration after perforation of the tympanic membrane by using whole-mount imaging of the tympanic membrane of Prox1 GFP mice. In the pars tensa, lymphatic vessel loops surrounded the malleus handle and annulus tympanicus. Apart from these locations, lymphatic vessel loops were not observed in the pars tensa in the normal tympanic membrane. Lymphatic vessel loops surrounding the malleus handle were connected to the lymphatic vessel loops in the pars flaccida and around the tensor tympani muscle. Many lymphatic vessel loops were detected in the pars flaccida. After perforation of the tympanic membrane, abundant lymphatic regeneration was observed in the pars tensa, and these regenerated lymphatic vessels extended from the lymphatic vessels surrounding the malleus at day 7. These results suggest that site-specific lymphatic vessels play an important role in the tympanic membrane. PMID- 24055875 TI - Structure and expression of a novel compact myelin protein - small VCP interacting protein (SVIP). AB - SVIP (small p97/VCP-interacting protein) was initially identified as one of many cofactors regulating the valosin containing protein (VCP), an AAA+ ATPase involved in endoplasmic-reticulum-associated protein degradation (ERAD). Our previous study showed that SVIP is expressed exclusively in the nervous system. In the present study, SVIP and VCP were seen to be co-localized in neuronal cell bodies. Interestingly, we also observed that SVIP co-localizes with myelin basic protein (MBP) in compact myelin, where VCP was absent. Furthermore, using nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopic measurements, we determined that SVIP is an intrinsically disordered protein (IDP). However, upon binding to the surface of membranes containing a net negative charge, the helical content of SVIP increases dramatically. These findings provide structural insight into interactions between SVIP and myelin membranes. PMID- 24055877 TI - Genotoxicity of intraperitoneal injection of lipoamphiphile CdSe/ZnS quantum dots in rats. AB - The main objective of the present in vivo rat study was to determine the genotoxicity of lipoamphiphile-coated CdSe/ZnS Quantum Dots (QDs), in several organs (brain, liver, kidneys, lungs and testicles). The second objective was to establish the correlations between the QDs genotoxic activity and the oxidative stress, the production of a proinflammatory cytokine (TNF-alpha), a stress induced chaperone protein, the phosphorylated heat shock protein 70 (pHsp70), and an increase in the caspase-3 apoptosis factor. Four QDs doses were injected into the peritoneal cavity (5, 5*10(-1), 5*10(-2) and 5*10(-3)MUg/kg). DNA lesions in the different organs were measured by the comet assay, and chromosome abnormalities were evaluated by the micronucleus assay on blood reticulocytes (MNRET). Twenty-four hours after the QDs injection, genotoxic effects were observed in the brain and liver and, only for the highest QDs concentration, in testicles. No genotoxic effect was seen in the kidney and lung. The MNRET test revealed a dose-response induction of micronuclei. In parallel, we did neither reveal oxidative stress nor significant variations of TNF-alpha, pHsp70, and caspase-3. In conclusion, the QDs exerted significant genotoxic effects in the brain and liver, even in the absence of any associated oxidative stress and inflammatory processes. PMID- 24055878 TI - Immunological role of prostaglandin E2 production in mouse auditory cells in response to LPS. AB - The effect of LPS on the production of prostaglandin E2 (PGE2) in mouse HEI-OC1 auditory cells was examined. HEI-OC1 auditory cells constitutively produce a small amount of PGE2. LPS augmented the PGE2 production via enhanced cyclooxygenase 2 (COX2) expression. LPS-induced augmentation of COX2 expression was dependent on up-regulation of COX2 mRNA expression. LPS induced the production of TNF-alpha, but not IL-1beta. An anti-TNF-alpha neutralizing Ab significantly inhibited PGE2 production and COX2 mRNA expression in response to LPS. LPS-induced PGE2 production was prevented by a series of pharmacological signaling inhibitors to NF-kappaB and MAPKs. Pam3CSK4 as a TLR2 ligand, as well as LPS as a TLR4 ligand, augmented the PGE2 production. However, poly I:C as a TLR3 ligand, imiquimod as a TLR7 ligand and CpG DNA as a TLR9 ligand did not augment it. HEI-OC1 cells expressed TLR2, TLR4 and TLR9, but not TLR3 or TLR7. The putative role of LPS-induced PGE2 production in auditory cells is discussed. PMID- 24055879 TI - Down-regulation of NF-kappaB signaling by Gordonia bronchialis prevents the activation of gut epithelial cells. AB - The immunomodulatory power of heat-killed Gordonia bronchialis was studied on gut epithelial cells activated with pro-inflammatory stimuli (flagellin, TNF-alpha or IL-1beta). Light emission of luciferase-transfected epithelial cells and mRNA expression of IL-1beta, TNF-alpha, IL-6, CCL20, IL-8 and MCP-1 were measured. NF kappaB activation was assessed by immunofluorescence and immunoblotting, and induction of reactive oxygen species (ROS) was evaluated. In vivo inhibitory properties of G. bronchialis were studied with ligated intestinal loop assay and in a mouse model of food allergy. G. bronchialis promoted the down-regulation of the expression of CCL20 and IL-1beta on activated epithelial cells in a dose dependent manner. A concomitant blocking of nuclear p65 translocation with increased production of ROS was found. In vivo experiments confirmed the inhibition of CCL20 expression and the suppression of IgE sensitization and hypersensitivity symptoms in the food allergy mouse model. In conclusion, heat killed G. bronchialis inhibited the activation of NF-kappaB pathway in human epithelial cells, and suppressed the expression of CCL20. These results indicate that G. bronchialis may be used to modulate the initial steps of innate immune activation, which further suppress the allergic sensitization. This approach may be exploited as a therapy for intestinal inflammation. PMID- 24055881 TI - Neural systems underlying thought suppression in young women with, and at-risk, for depression. AB - OBJECTIVE: Ruminative brooding is associated with increased vulnerability to major depression. Individuals who regularly ruminate will often try to reduce the frequency of their negative thoughts by actively suppressing them. We aimed to identify the neural correlates underlying thought suppression in at-risk and depressed individuals. METHODS: Three groups of women were studied; a major depressive disorder group, an at-risk group (having a first degree relative with depression) and controls. Participants performed a mixed block-event fMRI paradigm involving thought suppression, free thought and motor control periods. Participants identified the re-emergence of "to-be-suppressed" thoughts with a button press. RESULTS: During thought suppression the control group showed the greatest activation of the dorsolateral prefrontal cortex, followed by the at risk, then depressed group. During the re-emergence of intrusive thoughts compared to successful re-suppression of those thoughts, the control group showed the greatest activation of the anterior cingulate cortices, followed by the at risk, then depressed group. CONCLUSIONS: At-risk participants displayed anomalies in the neural regulation of thought suppression resembling the dysregulation found in depressed individuals. The predictive value of these changes in the onset of depression remains to be determined. PMID- 24055882 TI - Hydrogel microspheres for stabilization of an antioxidant enzyme: effect of emulsion cross-linking of a dual polysaccharide system on the protection of enzyme activity. AB - Catalase is an antioxidant enzyme abundant in natural resources. However, the enzyme is usually inactivated by gastric acid and digestive enzymes after oral ingestion. In this study, carboxymethyl chitosan (CM-chitosan) and hyaluronic acid (HA) conjugate hydrogel microspheres have been prepared by an emulsion cross linking technique to retain the activity of catalase in simulated gastrointestinal (GI) fluids. Cross-linking reduced the swelling capability and increased the resistance toward hyaluronidase digestion of prepared HA-CM chitosan hydrogel microspheres. Catalase entrapped in the hydrogel microspheres exhibited superior stability over a wide pH range (pH 2.0 and 6.0-8.0) as compared to the native enzyme. The entrapped catalase was also protected against degradation by digestive enzymes. Following the treatments, the catalase-loaded microspheres, in contrast to native catalase, could effectively decrease the intracellular H2O2 level and protect HT-29 colonic epithelial cells against H2O2 induced oxidative damage to preserve cell viability. These results suggested that the HA-CM-chitosan hydrogel microspheres can be used for entrapment, protection and intestinal delivery of catalase for H2O2 scavenging. PMID- 24055880 TI - Proposed mechanistic description of dose-dependent BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model. AB - Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes. PMID- 24055883 TI - Cultural differences in neuropsychological abilities required to perform intelligence tasks. AB - Different studies have demonstrated that culture has a basic role in intelligence tests performance. Nevertheless, the specific neuropsychological abilities used by different cultures to perform an intelligence test have never been explored. In this study, we examine the differences between Spaniards and Moroccans in the neuropsychological abilities utilized to perform the Beta III as a non-verbal intelligence test. The results showed that the Spaniard group obtained a higher IQ than the Moroccan group in the Beta III. Moreover, the neuropsychological abilities that predicted scores for the Beta III were dependent on the country of origin and were different for each subtest. Besides showing the cultural effect on non-verbal intelligence test performance, our results suggest that a single test may measure different functions, depending on the subject's cultural background. PMID- 24055884 TI - Comparability of the computerized Halstead Category Test with the original version. AB - The Halstead Category Test-Computer Version (HCT-CV) was developed with the goal of adapting the HCT to the computer while maintaining all essential features of the original test. We compared the HCT-CV results from clinical neuropsychological evaluations of 25 patients who were matched on a pairwise basis with 25 patients previously tested with the original version. Matching was done on age, education, and diagnosis. Results of group comparisons showed that the HCT-CV performed comparably with the original version, with mean score differences of <2 points. Correlations with the other subtests from the Halstead Reitan Neuropsychological Test Battery were also found to be comparable. Results suggest that the HCT-CV can be considered a satisfactory and comparable version of the HCT, while providing advantages in terms of ease of use and portability. PMID- 24055885 TI - The impact of mild traumatic brain injury on cognitive functioning following co occurring spinal cord injury. AB - Meta-analytic studies have shown that mild traumatic brain injury (MTBI) has relatively negligible effects on cognitive functioning at 90 or more days post injury. Few studies have prospectively examined the effects of MTBI in acute physical trauma populations. This prospective, cohort study compared the cognitive performance of persons who sustained a spinal cord injury (SCI) and a co-occurring MTBI (N = 53) to persons who sustained an SCI alone (N = 64) between 26 and 76 days (mean = 46) post-injury. The presence of MTBI was determined based on acute medical record review using a standardized algorithm. Primary outcome measures were seven neuropsychological tests that evaluated visual, verbal, and working memory, perceptual reasoning, and processing speed that controlled for potential upper extremity impairment. Persons who sustained SCI with or without MTBI had lower than expected performance across all neuropsychological tests, on average about 1 SD below the mean. Analysis of covariance indicated that persons with MTBI did not evidence greater impairment on any neuropsychological test. The aggregated effect size (Cohen's d) was -0.16. The strongest predictors of neuropsychological test scores were education, race, history of learning problems, and days from injury to rehabilitation admission. MTBI did not predict performance on any neuropsychological test. These findings are consistent with other controlled studies that indicate a single MTBI has negligible long-term impacts on cognition. PMID- 24055886 TI - Anisotropic composite human skull model and skull fracture validation against temporo-parietal skull fracture. AB - A composite material model for skull, taking into account damage is implemented in the Strasbourg University finite element head model (SUFEHM) in order to enhance the existing skull mechanical constitutive law. The skull behavior is validated in terms of fracture patterns and contact forces by reconstructing 15 experimental cases. The new SUFEHM skull model is capable of reproducing skull fracture precisely. The composite skull model is validated not only for maximum forces, but also for lateral impact against actual force time curves from PMHS for the first time. Skull strain energy is found to be a pertinent parameter to predict the skull fracture and based on statistical (binary logistical regression) analysis it is observed that 50% risk of skull fracture occurred at skull strain energy of 544.0mJ. PMID- 24055887 TI - Ceramide signaling in mammalian epidermis. AB - Ceramide, the backbone structure of all sphingolipids, as well as a minor component of cellular membranes, has a unique role in the skin, by forming the epidermal permeability barrier at the extracellular domains of the outermost layer of the skin, the stratum corneum, which is required for terrestrial mammalian survival. In contrast to the role of ceramide in forming the permeability barrier, the signaling roles of ceramide and its metabolites have not yet been recognized. Ceramide and/or its metabolites regulate proliferation, differentiation, and apoptosis in epidermal keratinocytes. Recent studies have further demonstrated that a ceramide metabolite, sphingosine-1-phosphate, modulates innate immune function. Ceramide has already been applied to therapeutic approaches for treatment of eczema associated with attenuated epidermal permeability barrier function. Pharmacological modulation of ceramide and its metabolites' signaling can also be applied to cutaneous disease prevention and therapy. The author here describes the signaling roles of ceramide and its metabolites in mammalian cells and tissues, including the epidermis. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias. PMID- 24055888 TI - tert-Butylhydroquinone (tBHQ) protects hepatocytes against lipotoxicity via inducing autophagy independently of Nrf2 activation. AB - Saturated fatty acids (SFAs) induce hepatocyte cell death, wherein oxidative stress is mechanistically involved. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master transcriptional regulator of cellular antioxidant defense enzymes. Therefore, Nrf2 activation is regarded as an effective strategy against oxidative stress-triggered cellular damage. In this study, tert-butylhydroquinone (tBHQ), a widely used Nrf2 activator, was initially employed to investigate the potential protective role of Nrf2 activation in SFA-induced hepatoxicity. As expected, SFA-induced hepatocyte cell death was prevented by tBHQ in both AML-12 mouse hepatocytes and HepG2 human hepatoma cells. However, the protective effect of tBHQ is Nrf2-independent, because the siRNA-mediated Nrf2 silencing did not abrogate tBHQ-conferred protection. Alternatively, our results revealed that autophagy activation was critically involved in the protective effect of tBHQ on lipotoxicity. tBHQ induced autophagy activation and autophagy inhibitors abolished tBHQ's protection. The induction of autophagy by tBHQ exposure was demonstrated by the increased accumulation of LC3 puncta, LC3-II conversion, and autophagic flux (LC3-II conversion in the presence of proteolysis inhibitors). Subsequent mechanistic investigation discovered that tBHQ exposure activated AMP activated protein kinase (AMPK) and siRNA-mediated AMPK gene silencing abolished tBHQ-induced autophagy activation, indicating that AMPK is critically involved in tBHQ-triggered autophagy induction. Furthermore, our study provided evidence that tBHQ-induced autophagy activation is required for its Nrf2-activating property. Collectively, our data uncover a novel mechanism for tBHQ in protecting hepatocytes against SFA-induced lipotoxicity. tBHQ-triggered autophagy induction contributes not only to its hepatoprotective effect, but also to its Nrf2 activating property. PMID- 24055890 TI - Transferrin as a drug carrier: Cytotoxicity, cellular uptake and transport kinetics of doxorubicin transferrin conjugate in the human leukemia cells. AB - Leukemias are one of most common malignancies worldwide. There is a substantial need for new chemotherapeutic drugs effective against this cancer. Doxorubicin (DOX), used for treatment of leukemias and solid tumors, is poorly efficacious when it is administered systemically at conventional doses. Therefore, several strategies have been developed to reduce the side effects of this anthracycline treatment. In this study we compared the effect of DOX and doxorubicin transferrin conjugate (DOX-TRF) on human leukemia cell lines: chronic erythromyeloblastoid leukemia (K562), sensitive and resistant (K562/DOX) to doxorubicin, and acute lymphoblastic leukemia (CCRF-CEM). Experiments were also carried out on normal cells, peripheral blood mononuclear cells (PBMC). We analyzed the chemical structure of DOX-TRF conjugate by using mass spectroscopy. The in vitro growth-inhibition assay XTT, indicated that DOX-TRF is more cytotoxic for leukemia cells sensitive and resistant to doxorubicin and significantly less sensitive to normal cells compared to DOX alone. During the assessment of intracellular DOX-TRF accumulation it was confirmed that the tested malignant cells were able to retain the examined conjugate for longer periods of time than normal lymphocytes. Comparison of kinetic parameters showed that the rate of DOX-TRF efflux was also slower in the tested cells than free DOX. The results presented here should contribute to the understanding of the differences in antitumor activities of the DOX-TRF conjugate and free drug. PMID- 24055891 TI - Different susceptibility of colon cancer DLD-1 and LOVO cell lines to apoptosis induced by DMU-212, a synthetic resveratrol analogue. AB - The cytotoxic activity of DMU-212 has been shown to vary in cell lines derived from the same type of cancer, i.e. ovarian, breast and colorectal ones. However, the molecular mechanism of DMU-212 cytotoxicity has not been clarified in colon cancer cells. This study aims to elucidate the mechanism of antitumor effects of DMU-212 in two human colon cancer cell lines, DLD-1 and LOVO. We showed the stronger cytotoxic activity in DLD-1 cells in which DMU-212 evoked a greater pro apoptotic effect as compared to that of LOVO cells. The analysis of the expression pattern of 84 apoptosis-related genes indicated transcripts specific to the mitochondria-mediated apoptosis pathway in both colon cancer cell lines used. We found that DMU-212 caused up-regulation of pro-apoptotic Bak1, Bok, Bik, Noxa, Bad, Bax, p53 and Apaf1 transcripts level in DLD-1 cell line, whereas anti apoptotic Bcl-2, Bcl-xL and Bag1 mRNA expression was decreased. Changes in apoptosis-related genes expression were less pronounced in LOVO cells which did not express CYP1B1 protein and showed lower expression of CYP1A1 protein level than that in DLD-1 cells. Our results suggest that anticancer activity of DMU-212 is closely related to its biotransformation catalysed by these cytochrome P450 isoenzymes. PMID- 24055889 TI - Autophagy paradox and ceramide. AB - Sphingolipid molecules act as bioactive lipid messengers and exert their actions on the regulation of various cellular signaling pathways. Sphingolipids play essential roles in numerous cellular functions, including controlling cell inflammation, proliferation, death, migration, senescence, tumor metastasis and/or autophagy. Dysregulated sphingolipid metabolism has been also implicated in many human cancers. Macroautophagy (referred to here as autophagy) "self eating" is characterized by nonselective sequestering of cytosolic materials by an isolation membrane, which can be either protective or lethal for cells. Ceramide (Cer), a central molecule of sphingolipid metabolism, has been extensively implicated in the control of autophagy. The increasing evidence suggests that Cer is highly involved in mediating two opposing autophagic pathways, which regulate either cell survival or death, which is referred here as autophagy paradox. However, the underlying mechanism that regulates the autophagy paradox remains unclear. Therefore, this review focuses on recent studies with regard to the regulation of autophagy by Cer and elucidates the roles and mechanisms of action of Cer in controlling autophagy paradox. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology. PMID- 24055892 TI - The roles of cyclic AMP-ERK-Bad signaling pathways on 6-hydroxydopamine-induced cell survival and death in PC12 cells. AB - The roles of cyclic AMP (cAMP)-ERK1/2-Bad signaling pathways in 6-hydroxydopamine (6-OHDA)-induced cell survival and death were investigated. In PC12 cells, 6-OHDA (10-100MUM) concentration-dependently increased the intracellular levels of cAMP mediated by the Ca(2+)-CaMKII-adenylyl cyclase system. 6-OHDA at the non-toxic level (10MUM) induced transient ERK1/2 phosphorylation and BadSer112 phosphorylation, which maintained cell survival. In contrast, the high levels of cAMP induced by toxic levels (50 and 100MUM) of 6-OHDA induced sustained ERK1/2 phosphorylaton and BadSer155 phosphorylation. The cells then moved to cell death process through Bcl2 phosphorylation and caspase-3 activation. BadSer155 phosphorylation by 6-OHDA was inhibited by PKA (H89) and MEK (U0126) inhibitors, indicating that it was mediated via the cAMP-PKA-sustained ERK1/2 system. In SK-N BE(2)C cells, the non-toxic level of 6-OHDA also showed transient ERK1/2 phosphorylation and BadSer112 phosphorylation, and toxic levels of 6-OHDA exhibited sustained ERK1/2 phosphorylation and BadSer155 phosphorylation. These results suggest that ERK1/2 phosphorylation by 6-OHDA shows biphasic functions on cell survival and death in PC12 cells. It is, therefore, proposed that the cAMP ERK1/2-Bad signaling pathways incurred by toxic levels of 6-OHDA play a role in dopamine neuron death of animal models of Parkinson's disease. PMID- 24055893 TI - Impact of iron oxide nanoparticles on brain, heart, lung, liver and kidneys mitochondrial respiratory chain complexes activities and coupling. AB - The present study evaluates the effects of iron oxide nanoparticles (ION) on mitochondrial respiratory chain complexes activities in five organs characterized by different oxidative capacities and strongly involved in body detoxification. Isolated mitochondria were extracted from brain, heart, lung, liver and kidneys in twelve Wistar rats (8 weeks) using differential centrifugations. Maximal oxidative capacities (Vmax), mitochondrial respiratory chain complexes activity using succinate (Vsucc, complexes II, III, and IV activities) or N, N, N', N' tetramethyl-p-phenylenediaminedihydrochloride (tmpd)/ascorbate (Vtmpd, complex IV activity) and, mitochondrial coupling (Vmax/Vo) were determined in controls and after exposure to 100, 200, 300 and 500MUg/ml Fe3O4. Data showed that baseline maximal oxidative capacities were 26.3+/-4.7, 48.9+/-4.6, 11.3+/-1.3, 27.0+/-2.5 and 13.4+/-1.7MUmol O2/min/g protein in brain, heart, lung, liver, and kidneys mitochondria, respectively. Complexes II, III, and IV activities also significantly differed between the five organs. Interestingly, as compared to baseline values and in all tissues examined, exposure to ION did not alter mitochondrial respiratory chain complexes activities whatever the nanoparticles (NPs) concentration used. Thus, ION did not show any toxicity on mitochondrial coupling and respiratory chain complexes I, II, III, and IV activities in these five major organs. PMID- 24055894 TI - Effect of some organic solvents on oxidative phosphorylation in rat liver mitochondria: Choice of organic solvents. AB - The effect of acetone, acetonitrile, dimethyl sulfoxide (DMSO), ethanol and methanol on oxidative phosphorylation (ATP synthesis) in rat liver mitochondria has been studied. All the organic solvents inhibited the oxidative phosphorylation in a concentration dependent manner, but with differences in potencies. Among the tested organic solvents, acetonitrile and acetone were more potent than ethanol, methanol, and DMSO. There was no significant difference in oxidative phosphorylation, compared to controls, when the concentrations of acetone was below 1% (v/v), of acetonitrile below 2% (v/v), of DMSO below 10% (v/v), of ethanol below 5% or of methanol below 2%, respectively. There was complete inhibition of oxidative phosphorylation at 50% (v/v) of acetone, acetonitrile and ethanol. But in the case of DMSO and methanol there were some residual activities observed at the 50% concentration level. DMSO showed least effect on oxidative phosphorylation with an IC50 value of 13.3+/-1.1% (v/v), followed by methanol (IC50 value 8.3+/-1.0), ethanol (IC50 value 4.6+/-1.1), acetone (IC50 value 4.3+/-1.0) and finally acetonitrile (IC50 value 2.1+/-1.0). All the organic solvents showed modulatory effects on 2,4-dinitrophenol (DNP) mediated inhibition of oxidative phosphorylation with potentiation of the action of DNP. Acetonitrile showed the highest potentiation effect followed by acetone, ethanol, methanol, and DMSO in presence of DNP. The use of organic solvents for investigation of the effects of compounds on oxidative phosphorylation in mitochondria should therefore include the use of relevant concentrations of the organic solvent in order to validate the contribution. PMID- 24055895 TI - Allethrin toxicity on human corneal epithelial cells involves mitochondrial pathway mediated apoptosis. AB - Pyrethroids including allethrin are the most common commercial household insecticides. The detrimental effects caused by pyrethroids on humans are gaining considerable attention. The present study was aimed to elucidate the effects of allethrin on the human corneal epithelial (HCE) cells. Allethrin inhibited the proliferation of HCE cells in a dose-dependent manner. In the presence of allethrin, cells showed membrane blebbing and nuclear fragmentation along with significant decrease in mitochondrial membrane potential resulting in increased cytochrome c (Cyt c) release into the cytosol. Further, flow cytometry analysis demonstrated a marked increase in sub G0-G1 cells, characteristic of apoptosis. Increased expression of pro-apoptotic protein, Bax, a simultaneous decrease of anti-apoptotic protein, Bcl-2, and activation of Caspase 3 was evident in the treated cells. In addition, extracellular matrix digesting metalloproteinase 9 (MMP-9) was also stimulated. Furthermore, significant increase in the gene expression of inflammatory cytokines, TNF-alpha and IL-1beta was observed. Taken together, these findings suggest that allethrin (IC50~85MUM) is toxic to HCE cells causing death through mitochondrial pathway. PMID- 24055896 TI - Gene expression changes induced by skin sensitizers in the KeratinoSensTM cell line: Discriminating Nrf2-dependent and Nrf2-independent events. AB - The KeratinoSensTM assay is an in vitro screen for the skin sensitization potential of chemicals. It is based on a luciferase reporter gene under the control of the antioxidant response element of the aldoketoreductase gene AKR1C2. The transferability, reproducibility, and predictivity of the KeratinoSensTM assay have been investigated in detail and it is currently under assessment at the European Center for Validation of Alternatives to animal testing (ECVAM). Here we investigate the sensitizer-induced gene expression in the KeratinoSensTM cell line at the mRNA level and discriminate Nrf2-dependent and Nrf2-independent events by using siRNA to better characterize this test system at the molecular level. The results show that (i) the sensitizer-induced luciferase signal in KeratinoSensTM cells is completely dependent on Nrf2. The same holds true for the luciferase induction observed for the false positive chemical Tween80, indicating that the false positive result is not due to recruitment of an alternative transcription factor. (ii) Luciferase induction parallels the induction of endogenous Nrf2-dependent genes, indicating that the luciferase signal is representative for the sensitizer-induced Nrf2-response. (iii) The induction by sensitizers of additional genetic markers related to heat shock proteins and cellular stress could be reproduced in the KeratinoSensTM cell line and they were shown to be Nrf2-independent. These results confirm that the KeratinoSensTM cell line is a rapid and adequate screening tool to assess the sensitizer-induced Nrf2 response in keratinocytes. PMID- 24055897 TI - Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons. AB - In this study we evaluated the neurotoxicity of eslicarbazepine acetate (ESL), and of its in vivo metabolites eslicarbazepine (S-Lic) and R-licarbazepine (R Lic), as compared to the structurally-related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), in an in vitro model of cultured rat hippocampal neurons. The non-related antiepileptic drugs (AEDs) lamotrigine (LTG) and sodium valproate (VPA) were also studied. We assessed whether AEDs modulate pro-survival/pro apoptotic pathways, such as extracellular-regulated kinase (ERK1/2), Akt and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). We found that neither ESL nor its metabolites, CBZ or LTG, up to 0.3mM, for 24h of exposure, decreased cell viability. OXC was the most toxic drug decreasing cell viability in a concentration-dependent manner, leading to activation of caspase-3 and PARP cleavage. VPA caused the appearance of the apoptotic markers, but did not alter cell viability. ESL, S-Lic and OXC decreased the levels of phospho-ERK1/2 and of phospho-Akt, when compared to basal levels, whereas CBZ decreased phospho SAPK/JNK and phospho-Akt levels. LTG and VPA increased the phosphorylation levels of SAPK/JNK. These results suggest that ESL and its main metabolite S-Lic, as well as CBZ, LTG and VPA, are less toxic to hippocampal neurons than OXC, which was the most toxic agent. PMID- 24055899 TI - Barriers to colorectal cancer screening in Palestine: a national study in a medically underserved population. AB - BACKGROUND & AIMS: Cultural, religious, and financial barriers can hinder uptake of colorectal cancer (CRC) screening in Arab communities. We aim to understand attitudes and barriers that contribute to the low rate of CRC screening among Palestinians in the West Bank. METHODS: We performed a national, cross-sectional study of Palestinian adults older than 50 years. A self-administered questionnaire was developed and validated. Data were randomly collected in all major districts of the West Bank. The primary outcome was the willingness to undergo CRC screening. Multivariable logistic regression models were used to assess the strength of association between the primary outcome and its predictors while controlling for possible confounders. RESULTS: Of 1601 people approached for an interview, 1352 agreed to participate (response rate, 84%). Only 193 had undergone CRC screening (14%); 1069 (79%) agreed to take a fecal occult blood test, 906 (67%) agreed to a colonoscopy examination, and 1098 (81%) were willing to undergo CRC screening if recommended by a physician. Only 194 (14%) said they had been informed about CRC screening by a physician. Urban residents were more likely to be screened for CRC than nonurban residents (odds ratio, 0.73; 95% confidence interval, 0.56-0.93; P = .011). Multivariable analysis showed that lack of education beyond elementary school or familiarity with CRC screening, distrust of Western medicine, religious objection, and finding the test to be embarrassing were all associated with decreased odds of accepting CRC screening. CONCLUSIONS: Based on a national, cross-sectional study of Palestinian adults, there are many cultural and religious barriers to CRC screening. Improving our understanding of these could increase screening among Arab populations in the Middle East and in Western countries. PMID- 24055898 TI - The HLA-B*39 allele increases type 1 diabetes risk conferred by HLA-DRB1*04:04 DQB1*03:02 and HLA-DRB1*08-DQB1*04 class II haplotypes. AB - To further characterise the effect of the HLA-B*39 allele on type 1 diabetes risk we assessed its role in different HLA-DR/DQ haplotypes and genotypes using 1764 nuclear families with a diabetic child collected in the framework of the Finnish Paediatric Diabetes Register. HLA assays were based on sequence specific hybridization using lanthanide labelled oligonucleotide probes. Transmissions of major HLA-DR/DQ haplotypes with and without the HLA-B*39 allele to diabetic index cases were analysed by direct haplotype and allele counting. The HLA-B*39 allele significantly increased the disease risk conferred by DRB1*04:04-DQA1*03 DQB1*03:02 and (DR8)-DQB1*04 haplotypes. The same effect was observed on genotype level as disease association for the HLA-B*39 allele was observed in multiple genotypes containing DRB1*04:04-DQA1*03-DQB1*03:02 or (DR8)-DQB1*04 haplotypes. Finally we considered the two common subtypes of the HLA-B*39 allele, B*39:01 and B*39:06 and observed their unequal distribution when stratified for specific DR DQ haplotypes. The risk for type 1 diabetes conferred by certain DR/DQ haplotypes is modified by the presence of the HLA-B*39 and this confirms the independent disease predisposing effect of the HLA-B*39 allele. The results can be applied in enhancing the sensitivity and specificity of DR/DQ based screening programs for subjects at disease risk. PMID- 24055900 TI - Recurrence of corneal neovascularization associated with lipid deposition after subconjunctival injection of bevacizumab. AB - PURPOSE: To report 7 cases of recurrent corneal neovascularization (NV) and lipid deposition after subconjunctival injection of bevacizumab for the treatment of corneal NV-induced lipid keratopathy. METHODS: We conducted a prospective interventional case series that included 20 eyes of chronic lipid keratopathy that received bevacizumab injection for the treatment of corneal NV and lipid deposition, including 7 eyes with recurrent corneal NV and lipid deposition after ceasing treatment. Repeated subconjunctival injections of bevacizumab were performed in 5 patients with recurrence. Penetrating keratoplasty was performed in 1 patient who had severely recurrent lipid deposition. Clinical presentation of corneal NV and lipid deposition, best-corrected visual acuity, and complications after treatments were recorded. RESULTS: Bevacizumab inhibited corneal NV and lipid depositions in 19 patients. Seven of the 20 patients (35%) had different patterns of recurrence of corneal NV/lipid deposition 6 to 15 months after discontinuing treatment. Five of the 7 patients in whom corneal NV/lipid deposition was recurrent received another course of repeated bevacizumab treatments. Three eyes had partial response to the second course of treatment. Two eyes had too short re-treatment course to have conclusions. One patient who received penetrating keratoplasty had successful result after surgery. CONCLUSIONS: Corneal NV and lipid deposition may recur after ceasing the subconjunctival bevacizumab injections for lipid keratopathy. Some patients respond at least partially to repeated injections. PMID- 24055901 TI - Assessment of signs of anterior blepharitis using standardized color photographs. AB - PURPOSE: To describe a standardized technique for acquiring and viewing photographic images of eyelids, assess the reproducibility and validity of a grading protocol for signs of anterior blepharitis, and to explore whether the signs depend on the eyelid or the area of the eyelid assessed. METHODS: Subjects with anterior blepharitis ranging from none to severe were examined by ophthalmologists at clinical sites. Digital images of the eyelids of subjects were acquired using a protocol that allowed for the calibration of color and luminance. Three ophthalmologists at a centralized reading center applied a novel protocol for grading features of anterior blepharitis from the digital images viewed on color-calibrated monitors. The agreement among graders was assessed using percent agreement and weighted kappa statistics (Kw), and the correlation of photographic and clinical gradings was assessed using Spearman correlation coefficients. RESULTS: Agreement among graders was excellent (Kw > 0.80) on the number of eyelid margin vessels and was substantial (Kw between 0.61 and 0.80) for erythema, collarettes, number of engorged vessels, and number of lashes. Grading of the photographic images and the clinical assessments of erythema and lid debris were moderately correlated (r = 0.27-0.45). The grades for different features depended on whether the upper or lower eyelid, eyelid skin or lid margin, and central or lateral lid were assessed. CONCLUSIONS: The application of a protocol to obtain and display calibrated digital images of eyelids supports the standardized assessment of anterior blepharitis in clinical care and research studies. PMID- 24055902 TI - Persistent corneal opacity after descemet stripping automated endothelial keratoplasty suggesting inert material deposits into the interface. AB - PURPOSE: To report a case of interface deposits after Descemet stripping automated endothelial keratoplasty (DSAEK) imaged by means of an electron microscope. METHODS: An 88-year-old man was referred with a history of corneal edema resulting from pseudophakic bullous keratopathy. A DSAEK was performed on his left eye without complications; however, the follow-up examination revealed a well-attached graft with persistent interface opacities at the donor-recipient interface. The DSAEK was repeated in this eye 1 year after the first surgery because of these corneal opacities that interfered with his vision. RESULTS: In the immediate postoperative period, the patient had adequate visual acuity with intact graft placement and a clear interface. Pathology and electron microscope analysis were performed on the removed endothelial graft, which revealed diffuse particles on the stromal surface of the endothelial graft. CONCLUSIONS: A repeated DSAEK procedure sufficiently removed this patient's corneal opacities and improved the visual acuity. The opacity is believed to have occurred because of residual viscoelastic material, which was used to maintain anterior chamber volume during surgery. This solution must be thoroughly removed to avoid similar complications. PMID- 24055903 TI - Comparison of the effects of topical cyclosporine a 0.05%, cyclosporine a 2%, epinastine hydrochloride 0.05%, and prednisolone acetate 1% on allergic inflammation in an experimental allergic conjunctivitis model. AB - PURPOSE: To investigate the effects of topical cyclosporine A 0.05%, cyclosporine A 2%, epinastine hydrochloride 0.05%, and prednisolone acetate 1% in an experimental allergic conjunctivitis model. METHODS: Forty Wistar albino male rats were randomly divided into 5 groups. All the rats were immunized by an intraperitoneal injection of 100 MUg of ovalbumin. After 2 weeks, topical treatment was administered: cyclosporine A 0.05% 4 times a day to group 1, cyclosporine A 2% 4 times a day to group 2, epinastine HCl 0.05% 2 times a day to group 3, and prednisolone acetate 1% 4 times a day to group 4 for the following 7 days. Group 5 was designated as the control group. Both eyes of the rats were enucleated on the 22nd day of the study. The excised sections were stained by toluidine blue for mast cell count and by hematoxylin-eosin for histopathological evaluation. RESULTS: The 2 solutions of cyclosporine A and epinastine were more effective than prednisolone acetate (P < 0.05) when compared with the control in histopathological scoring. There were statistically significant differences between the treatment groups and the control group (P < 0.05); however, no differences were observed between the treatment groups in the mast cell number. CONCLUSIONS: Topical 0.05% cyclosporine A is as effective as 2% cyclosporine A and epinastine in suppressing mast cell-mediated type I allergic conjunctivitis in an experimental allergic conjunctivitis model. PMID- 24055904 TI - Comparison of Horizontal corneal diameter measurements using the Orbscan IIz and Pentacam HR systems. AB - PURPOSE: To compare 2 automated devices for measuring the horizontal corneal diameter [white-to-white (WTW) distance]. METHODS: In this prospective comparative case series, the WTW distance was measured by independent examiners using the Pentacam HR and the Orbscan IIz in 101 eyes of 101 healthy refractive surgery candidates. Statistical evaluation was performed using the paired t test, Pearson correlation, and the Bland-Altman method for comparison of measurement techniques. RESULTS: The mean WTW distance measurements were 11.76 +/- 0.38 mm as obtained with the Pentacam HR and 11.66 +/- 0.37 mm as obtained with the Orbscan IIz (P < 0.001). The measurements were highly correlated (Pearson correlation coefficient = 0.948; P < 0.001). The 95% limits of agreement for the Pentacam HR versus the Orbscan IIz were -0.14 to 0.33 mm. CONCLUSIONS: The observed differences in WTW distance readings between the Pentacam HR and the Orbscan IIz are not clinically relevant, and the 2 devices could be used interchangeably in clinical practice. PMID- 24055905 TI - Subconjunctival injection of low-molecular-weight heparin-taurocholate 7 inhibits corneal neovascularization. AB - PURPOSE: To evaluate the effects of a subconjunctival injection of low-molecular weight heparin-taurocholate 7 (LHT7) on corneal neovascularization (CoNV) in rats. METHODS: Twenty-four Sprague-Dawley rats were divided into 4 groups of 6 animals each. Corneal centers were cauterized by the application of a silver/potassium nitrate solution for 8 seconds. Either 0.02 or 0.04 mL of 25 mg/mL of LHT7 (low- and high-LHT7 groups, respectively) was subconjunctivally injected on days 2 and 4 after the cauterization was done; 0.02 mL of 25 mg/mL of bevacizumab was injected into rats in the positive control group, with normal saline (NS) being administered to a negative control group. Digital photographs of the cornea were taken 1 and 2 weeks later to calculate the percentage of CoNV using the area of the neovascularized cornea. To compare the differences in CoNV between weeks 1 and 2, the change in CoNV was calculated by subtracting the percentage of CoNV at 1 week from that at 2 weeks. RESULTS: The percentage of CoNV did not differ among the 4 groups either 1 or 2 weeks after the cauterization (P > 0.05). In all groups except the NS group, the percentage of CoNV significantly decreased at 2 weeks compared with that at 1 week (all P < 0.05). Moreover, the changes of CoNV in the high-LHT7 and bevacizumab groups significantly decreased compared with that in the NS group (all P < 0.05). Two corneal stromal hemorrhages occurred, 1 in each LHT7 group. CONCLUSIONS: Despite complications, including corneal stromal hemorrhage, subconjunctival injection of LHT7 attenuated CoNV after chemical cauterization. PMID- 24055906 TI - Comparison of descemet-on versus descemet-off deep anterior lamellar keratoplasty. AB - PURPOSE: To determine the effect of retained donor Descemet membrane (DMs) on visual outcomes, contrast sensitivity (CS), higher-order aberrations (HOAs), and central graft thickness after deep anterior lamellar keratoplasty (DALK) using the big-bubble technique. METHODS: In this retrospective comparative study, keratoconic eyes undergoing a DALK using the big-bubble technique were enrolled. A bared DM was achieved in all cases. A donor cornea without (group 1; 48 eyes) or with (group 2; 22 eyes) DM was sutured to the recipient bed. The 2 groups were compared in terms of best spectacle-corrected visual acuity, keratometric astigmatism, refractive error, CS, HOAs, and central graft thickness at least 3 months after complete suture removal. Additionally, the rate of postoperative pseudoanterior chamber formation was compared between the study groups. RESULTS: The mean follow-up duration was 23.2 +/- 6.9 months in group 1 and 26.5 +/- 6.5 months in group 2 (P = 0.61). The postoperative best spectacle-corrected visual acuity was 0.18 +/- 0.08 logMAR and 0.24 +/- 0.30 logMAR, respectively (P = 0.36). The 2 groups had comparable postoperative keratometric astigmatism, spherical equivalent refraction, and HOAs. In terms of CS, however, group 1 demonstrated better results at a low spatial frequency. The mean postoperative central graft thickness was greater in group 2 (589.8 +/- 34.5 MUm) than in group 1 (523.6 +/- 63.0 MUm; P < 0.001). A pseudoanterior chamber developed in 3 eyes of group 1 and in 2 eyes of group 2 (P = 0.23). All cases were successfully managed by giving an intracameral air injection. CONCLUSIONS: DALK performed using the big-bubble technique for keratoconus may give better results in terms of CS if a donor cornea without DM is transplanted. PMID- 24055907 TI - Peripheral pigmented placoid corneal endotheliopathy. AB - PURPOSE: To present a case series of peripheral pigmented placoid corneal endotheliopathy (PPPCE). METHODS: A retrospective chart review of patient demographics, medical histories, and clinical characteristics was performed. Examinations included the following specialized imaging modalities: slit-lamp photography, gonioscopy, high-frequency ultrasound biomicroscopy, and anterior segment ocular coherence tomography. A PubMed and multiple corneal textbook literature search using the key words cornea, pigment, plaque, and endothelium revealed that no similar cases were reported. RESULTS: Five eyes in 4 asymptomatic female patients were affected. Their mean age was 53 years (range, 43-61 years), and 3 were of African American descent and 1 was of Hispanic descent. The PPPCE lesions had a vertical dimension of 0.2 to 1.7 mm and a horizontal dimension of 0.5 to 6.1 mm. All the PPPCE lesions were well demarcated, brown, and peripherally located on the inferior corneal endothelium. Clock-hour meridians extended from 4 to 7 o'clock, with the largest PPPCE lesion spanning 4.3 clock hours. Gonioscopy revealed distinct well-circumscribed brown pigmented plaques adherent to the corneal endothelium with no extension beyond the trabecular meshwork. Ultrasound biomicroscopy and anterior segment ocular coherence tomography revealed the presence of hyperreflective lesions with no corneal stromal invasion, edema, or epitheliopathy. There were no synchronous anterior or posterior segment abnormalities. The PPPCE lesions have remained unchanged for a mean of 17 months (range, 8-34). CONCLUSIONS: Four healthy patients were noted to have PPPCE lesions. Although their etiology remains unknown, PPPCE behavior, morphology, and inferior corneal location suggest an origin from iris stromal melanocytes or iris pigment epithelium. PMID- 24055908 TI - Managements for corneal neovascularization. PMID- 24055909 TI - Mechanism of dopamine D2 receptor-induced Ca(2+) release in PC-12 cells. AB - Intracellular Ca(2+) levels are tightly regulated in the neuronal system. The loss of Ca(2+) homeostasis is associated with many neurological diseases and neuropsychiatric disorders such as Parkinson's, Alzheimer's, and schizophrenia. We investigated the mechanisms involved in intracellular Ca(2+) signaling in PC 12 cells. The stimulation of NGF-differentiated PC-12 cells with 3MUM ATP caused an early Ca(2+) release followed by a delayed Ca(2+) release. The delayed Ca(2+) release was dependent on prior ATP priming and on dopamine secretion by PC-12 cells. Delayed Ca(2+) release was abolished in the presence of spiperone, suggesting that it is due to the activation of D2 dopamine receptors (D2R) by dopamine secreted by PC-12 cells. This was shown to be independent of PKA activation but dependent on PLC activity. An endocytosis step was required for inducing the delayed Ca(2+) release. Given the importance of calcyon in clathrin mediated endocytosis, we verified the role of this protein in the delayed Ca(2+) release phenomenon. siRNA targeting of calcyon blocked the delayed Ca(2+) release, decreased ATP-evoked IP3R-mediated Ca(2+) release, and impaired subsequent Ca(2+) oscillations. Our results suggested that calcyon is involved in an unknown mechanism that causes a delayed IP3R-mediated Ca(2+) release in PC-12 cells. In schizophrenia, Ca(2+) dysregulation may depend on the upregulation of calcyon, which maintains elevated Ca(2+) levels as well as dopamine signaling. PMID- 24055911 TI - Mutations that affect mitochondrial functions and their association with neurodegenerative diseases. AB - Mitochondria are essential for mammalian and human cell function as they generate ATP via aerobic respiration. The proteins required in the electron transport chain are mainly encoded by the circular mitochondrial genome but other essential mitochondrial proteins such as DNA repair genes, are coded in the nuclear genome and require transport into the mitochondria. In this review we summarize current knowledge on the association of point mutations and deletions in the mitochondrial genome that are detrimental to mitochondrial function and are associated with accelerated ageing and neurological disorders including Alzheimer's, Parkinson's, Huntington's and Amyotrophic lateral sclerosis (ALS). Mutations in the nuclear encoded genes that disrupt mitochondrial functions are also discussed. It is evident that a greater understanding of the causes of mutations that adversely affect mitochondrial metabolism is required to develop preventive measures against accelerated ageing and neurological disorders caused by mitochondrial dysfunction. PMID- 24055910 TI - The gep proto-oncogene Galpha12 mediates LPA-stimulated activation of CREB in ovarian cancer cells. AB - Lysophosphatidic acid (LPA) plays a critical role in the pathophysiology of ovarian cancers. Previous studies have shown that LPA stimulates the proliferation of ovarian cancer cells via Galpha12. The present study utilizing Protein/DNA array analyses of LPA-stimulated HeyA8 cells in which the expression of Galpha12 was silenced, demonstrates for the first time that Galpha12-dependent mitogenic signaling by LPA involves the atypical activation cAMP-response element binding protein (CREB). Results indicate that the robust activation of CREB by LPA is an early event that can be monitored by the phosphorylation of SER133 of CREB as early as 3min. The findings that the expression of the constitutively activated mutant of Galpha12 stimulates CREB even in the absence of LPA in multiple ovarian cancer cell lines confirm the direct role of Galpha12 in the activation of CREB. This is further substantiated by the observation that the silencing of Galpha12 drastically attenuates LPA-stimulated phosphorylation of CREB. Our results also establish that LPA-Galpha12-dependent activation of CREB is through a cAMP-independent, but Ras-ERK-dependent mechanism. More significantly, our findings indicate that the expression of the dominant negative S133A mutant of CREB leads to a reduction in LPA-stimulated proliferation of HeyA8 ovarian cancer cells. Thus, results presented here demonstrate for the first time that CREB is a critical signaling node in LPA-LPAR and Galpha12/gep proto-oncogene stimulated oncogenic signaling in ovarian cancer cells. PMID- 24055912 TI - An anomalous bifid distal ulna: A case report. AB - INTRODUCTION: We report a case of an osteochondroma in the form of an anomalous bifid distal ulna following mal-union of an epiphyseal injury. There has been no previous case of this reported in the medical literature. PRESENTATION OF CASE: A 19-year-old man presented with wrist stiffness and complete loss of pronation and supination twelve months after having undergone open reduction and internal fixation for a volarly displaced distal radius fracture. Further investigation with a CT scan showed a bifid distal ulna. As this was not present on plain radiographs one year prior, it was proposed that this was an osteochrondromatous growth caused by injury to the distal ulnar epiphysis. An operation was performed to excise one of the distal ulna heads, and reconstruct the TFCC to allow improved rotational movements. At one year follow-up, the patient has made an almost full recovery without complication. DISCUSSION: We postulate that the patient sustained an occult physeal injury resulting in an osteochondromatous lesion that grew towards the joint effectively forming a second ulna head. CONCLUSION: This is a unique case of the development of a bifid distal ulna due to physeal injury one year prior. Such a lesion has not previously been described in the distal ulna. PMID- 24055913 TI - Pulmonary mucinous cystadenocarcinoma presenting as a pleural mesothelioma. AB - INTRODUCTION: Primary Pulmonary Mucinous Cystadenocarcinoma PPMC is an extremely rare subtype of pulmonary adenocarcinoma, with only a few dozen cases reported in the literature to date. PRESENTATION OF CASE: We report a extremely rare case of pulmonary mucinous cystadenocarcinoma presenting as a pleural mesothelioma. 53 year-old man exposed to asbestos, he is admitted in hospital with a 5cm mass in right pleura. He was treated by wedge resection. Sparse groups of malignant cells were microscopically observed in pools of mucin. The postoperative histopathological findings were in accordance with the diagnosis of pulmonary mucinous cystadenocarcinoma on cystic adenoid malformation of lung. 5 years later, the patient has no recurrence. DISCUSSION: PPMC is usually asymptomatic; hemoptysis is seen occasionally. Preoperative diagnosis is very difficult to establish. Both FNA cytology and transbronchial lung biopsy seem inadequate. Our patient went on to undergo open lung biopsy and histopathological testing that confirmed the diagnosis of PMC. CONCLUSION: It is important to differentiate this rare pathological feature of the lung from other lung tumors as the treatment is surgical rather than medical. Thoracic surgeons should bear in mind this rare tumor for the differential diagnosis of a pleural mesothelioma because this tumor has a favorable prognosis. PMID- 24055914 TI - En bloc kidney transplant from an 18-month-old donor to an adult recipient: Case report and literature review. AB - INTRODUCTION: There is an ever-increasing need for organ donations globally. Paediatric kidney transplantation into adult recipients is a well-recognised technique to expand the donor pool. The transplantation can be done either via en bloc kidney transplant (EBKT) or as single kidney transplantation (SKT). PRESENTATION OF CASE: An EKBT from a 18-month-old (15kg) male patient was transplanted in a 35-year old, 85kg male with end stage renal failure (ESRF), secondary to Focal Segmental Glomerulosclerosis (FSGS) on haemodialysis. Post operative recovery was uneventful. Immuno-suppressant drugs used were tacrolimus, basiliximab and prednisolone. Doppler ultrasound scans performed post-operatively showed normal renal resistive indices in both kidneys. Serum creatinine decreased from 1200 to 170MUmol/L 57 with eGFR improving from 4 to 38mL/min/1.73m(2) at four weeks post-transplant. DISCUSSION: Given the low incidence of paediatric donors, EBKTs are relatively uncommon and subsequently published series tend to be centre specific with small numbers. The graft survival rates tell us that paediatric kidney donors should not be considered as marginal transplants. The difficulty is in determining when it is more appropriate to perform a paediatric EBKT as opposed to splitting and performing two SKT. Unfortunately there are no widely accepted guidelines to direct clinicians. CONCLUSION: This case report highlights the first EKBT performed at our institution. The current literature demonstrates that paediatric donors are excellent resources that should be procured whenever available. PMID- 24055915 TI - Late-onset congenital diaphragmatic hernia: A case report. AB - INTRODUCTION: A Bochdalek hernia is a posterior congenital defect of the diaphragm, usually on the left hemidiafragm, caused by a lack of closure of the pleuroperitoneal canal between the eighth and tenth week of fetal life during the embryonic development. It typically presents in the neonatal period with severe respiratory failure. PRESENTATION OF CASE: In this paper we present a 35 year old man with a 5-year history of episodes of severe dyspnea who arrived to the emergency room, during his medical work-up we incidentally found an intrathoracic gastric bubble, a laparoscopy was performed, founding a necrotic stomach and for defect correction. DISCUSSION: This pathology is infrequent in adults, among this age group, there are two different clinical presentations: asymptomatic patients who are diagnosed incidentally when abdominal organs are found in the thorax in a chest X-ray, and symptomatic patients due to side effects of incarceration, strangulation, hemorrhage and visceral perforation in the chest cavity. CONCLUSION: Diaphragmatic hernias are rare among adult population, and they are usually asymptomatic, in this case we presented a symptomatic patient, diagnosed with a chest X-ray and treated surgically. The surgical approach for the resolution of this pathology is variable and it depends on the presence and severity of visceral complications. PMID- 24055916 TI - Abdominal cocoon-A rare cause of intestinal obstruction. AB - INTRODUCTION: Abdominal cocoon syndrome is characterized by small bowel encapsulation by a fibro-collagenous membrane or "cocoon". It is a rare cause of intestinal obstruction. PRESENTATION OF CASE: A 42-year old man presented with sub-acute intestinal obstruction. Intra-operatively, the entire small bowel was found to be encapsulated in a dense fibrous sac. The peritoneal sac was excised, followed by lysis of the inter-loop adhesions. Postoperative recovery was unremarkable. DISCUSSION: Most patients with abdominal cocoon syndrome present with features of recurrent acute or chronic small bowel obstruction secondary to kinking and/or compression of the intestines within the constricting cocoon. An abdominal mass may also be present due to an encapsulated cluster of dilated small bowel loops. CONCLUSION: Abdominal cocoon is a rare condition causing intestinal obstruction and diagnosis requires a high index of suspicion because of the nonspecific clinical picture. CECT of the abdomen is a useful radiological tool to aid in preoperative diagnosis. Peritoneal sac excision and adhesiolysis is the treatment and the outcome is usually satisfactory. PMID- 24055917 TI - Blunt transection of rectus abdominis following seatbelt related trauma with associated small and large bowel injury. AB - INTRODUCTION: Closed rupture of rectus abdominis following seatbelt related trauma is rare. PRESENTATION OF CASE: We present the case of a 45 year old female who presented with closed rupture of the rectus abdominis in conjunction with damage to small bowel mesentery and infarction of small and large bowel following a high velocity road traffic accident. Multiple intestinal resections were required resulting in short bowel syndrome and abdominal wall reconstruction with a porcine collagen mesh. Post-operative complications included intra-abdominal sepsis and an enterocutaneous fistula. DISCUSSION: The presence of rupture of rectus abdominis muscle secondary to seatbelt injury should raise the suspicion of intra-abdominal injury. CONCLUSION: Our case highlights the need for suspicion, investigation and subsequent surgical management of intra-abdominal injury following identification of this rare consequence of seatbelt trauma. PMID- 24055918 TI - An unusual presentation of EATL type 1: Emergency surgery due to life-threatening gastrointestinal bleeding. AB - INTRODUCTION: Enteropathy-associated T-cell lymphoma (EATL) is a very rare malignancy. Reasons for hospital admission are variable. PRESENTATION OF CASE: 76 years old man admitted to emergency service with sudden and massive obscure gastrointestinal bleeding. There was no complaints in his history. After initial evaluation, emergency laparatomy had to be done. Bleeding lesion in proximal jejunum was resected. Histopathologically, the muscularis propria had abundant atypical lymphoid infiltrate in diffuse pattern. Atypical lymphoid cells expressed CD3 and CD30. The jejunal mucosa adjacent to the tumor showed effacement of normal villous architecture. DISCUSSION: EATL is known to cause anemia as a result of chronic bleeding. However in this case, the bleeding was abundant, irreplaceable and requiring emergency surgery. To our knowledge it is not reported previously. CONCLUSION: A sudden and massive gastrointestinal bleeding can be the first and unique sign of EATL. PMID- 24055919 TI - Solitary metastatic gallbladder malignant melanoma originated from the nasal cavity: A case report. AB - INTRODUCTION: Solitary gallbladder metastasis of malignant melanoma is rare and generally originates from skin melanoma. We report a case of gallbladder metastasis from a malignant melanoma of the nasal mucosa that was surgically treated. PRESENTATION OF CASE: A 77-year-old Japanese woman diagnosed with malignant melanoma of the left sinonasal cavity three years ago underwent follow up PET-CT and FDG uptake was detected only at the gallbladder. The nasal melanoma had been stable for the last 1.5 years after chemoradiation and her general condition was good. Cholecystectomy was performed with partial liver resection. Lymphadenectomy of the hepatoduodenal ligament was also performed. The tumor was soft and whitish, and was microscopically diagnosed as a poorly differentiated malignant melanoma that was not similar to the nasal cavity melanoma. No further metastasis is observed for more than 13 months after surgery. DISCUSSION: In the literature, cutaneous melanoma is described as the origin of most metastatic gallbladder melanomas; however, no skin lesion was evident in this case. We believe that the poorly differentiated compartment of the nasal melanoma had metastasized to the gallbladder. CONCLUSION: For patients with melanomas and gallbladder tumors, the possibility that metastasis could occur should be considered when selecting optimal treatment. Even when original melanoma is present, surgical treatment for gallbladder metastasis may be useful depending on the patient's conditions. PMID- 24055920 TI - Codfish may cause acute abdomen. AB - INTRODUCTION: Foreign bodies ingestion is frequent and can cause several complications. Perforation is rare but can occur in any segment of the gastrointestinal tract. Fish bones are one of the most frequent objects responsible. PRESENTATION OF CASE: A 77-year-old patient resorted to emergency room for severe abdominal pain with 5 days of evolution. A CT scan showed an undefined liquid collection involving a linear image with 25mm, suggestive of a foreign body. On laparotomy an abscess was resected with a fish bone inside. DISCUSSION: Bowel perforation by foreign bodies can mimic other abdominal emergency conditions. Since fish bone ingestion is usually not remembered, diagnosis can be late. Surgery is the treatment of choice and is most commonly performed by laparotomy. CONCLUSION: A low threshold of suspicion along with a good clinical history and radiological studies is extremely important in order to make a correct diagnosis. PMID- 24055921 TI - Ciliated hepatic cyst leading to squamous cell carcinoma of the liver - A case report and review of the literature. AB - INTRODUCTION: Ciliated hepatic foregut cysts (CHFC) are rare, typically benign liver lesions. Primary squamous cell carcinoma (SCC) of the liver is also a rare entity with only approximately 25 reported cases in the literature. Recently, there have been four reports of malignant transformation of CHFC into primary squamous cell carcinoma of the liver. Here we report a fifth with unique presentation and review the literature. PRESENTATION OF CASE: A 34 year-old man, with a history of ulcerative colitis, was incidentally found to have a 10cm lesion in the right anterior sector plus left medial section of the liver on computerized tomography (CT) scan. The patient was asymptomatic at presentation and neoplastic markers were not elevated. Sequential transarterial chemoembolization (TACE) and portal vein embolization (PVE) allowed for left lateral section plus segment 1 hypertrophy and subsequent resection. Histology later revealed the cyst to be a CHFC and showed its malignant transformation. At 6 month follow-up, the patient has lung and abdominal recurrence. DISCUSSION: With now the fifth case of malignant transformation of CHFC being reported, approximately 5% of all reported CHFC have undergone malignant transformation. This frequency, taken together with the aggressive disease course and poor prognosis, suggests that CHFC must not be presumed benign and should be regarded with clinical suspicion. CONCLUSION: Accurate diagnosis of CHFC is mandatory given its potential malignant transformation. Even in asymptomatic CHFC, surgical excision is recommended. In addition, in cases of otherwise unresectable lesions, sequential TACE and PVE may provide optimal hypertrophy of future liver remnant. PMID- 24055923 TI - Drug Marketing. The line between scientific uncertainty and promotion of snake oil. PMID- 24055924 TI - Shorter radiotherapy course just as effective for treating breast cancer, research finds. PMID- 24055922 TI - Exercise for lower limb osteoarthritis: systematic review incorporating trial sequential analysis and network meta-analysis. AB - OBJECTIVE: To determine whether there is sufficient evidence to conclude that exercise interventions are more effective than no exercise control and to compare the effectiveness of different exercise interventions in relieving pain and improving function in patients with lower limb osteoarthritis. DATA SOURCES: Nine electronic databases searched from inception to March 2012. STUDY SELECTION: Randomised controlled trials comparing exercise interventions with each other or with no exercise control for adults with knee or hip osteoarthritis. DATA EXTRACTION: Two reviewers evaluated eligibility and methodological quality. Main outcomes extracted were pain intensity and limitation of function. Trial sequential analysis was used to investigate reliability and conclusiveness of available evidence for exercise interventions. Bayesian network meta-analysis was used to combine both direct (within trial) and indirect (between trial) evidence on treatment effectiveness. RESULTS: 60 trials (44 knee, two hip, 14 mixed) covering 12 exercise interventions and with 8218 patients met inclusion criteria. Sequential analysis showed that as of 2002 sufficient evidence had been accrued to show significant benefit of exercise interventions over no exercise control. For pain relief, strengthening, flexibility plus strengthening, flexibility plus strengthening plus aerobic, aquatic strengthening, and aquatic strengthening plus flexibility, exercises were significantly more effective than no exercise control. A combined intervention of strengthening, flexibility, and aerobic exercise was also significantly more effective than no exercise control for improving limitation in function (standardised mean difference -0.63, 95% credible interval -1.16 to -0.10). CONCLUSIONS: As of 2002 sufficient evidence had accumulated to show significant benefit of exercise over no exercise in patients with osteoarthritis, and further trials are unlikely to overturn this result. An approach combining exercises to increase strength, flexibility, and aerobic capacity is likely to be most effective in the management of lower limb osteoarthritis. The evidence is largely from trials in patients with knee osteoarthritis. PROTOCOL REGISTRATION: PROSPERO (www.crd.york.ac.uk/prospero/) No CRD42012002267. PMID- 24055925 TI - "Super managers" to be sent into failing hospitals. PMID- 24055926 TI - Common mechanism in endothelin-3 and PAF receptor function for anti-inflammatory responses. AB - Platelet-activating factor (PAF) is a potent lipid mediator that is implicated in numerous inflammatory diseases. Under inflammatory conditions, PAF is biosynthesized through the remodelling pathway and elicits many inflammatory responses through binding to its specific PAF receptor. Endogenous bioactive endothelins (ETs: ET-1, -2, and -3) are also considered potent inflammatory mediators that play a critical role in many inflammatory diseases. In this perspective, we provide a brief overview of possible common mechanisms in ETs and PAF receptor function for inflammatory responses. Accumulating evidence strongly suggests that ET-3, but not ET-1 and ET-2, can attenuate PAF-induced inflammation through direct binding of the Tyr-Lys-Asp (YKD) region in the peptide to PAF and its metabolite/precursor lyso-PAF, followed by inhibition of binding between PAF and its receptor. Additionally, YKD sequence-containing peptides may be useful as a novel type of anti-inflammatory drugs targeting this mechanism. These findings should lead to new treatment strategies for numerous inflammatory diseases by targeting the common mechanism in ET and PAF receptor function. PMID- 24055927 TI - Nature of the magnetic ground state in the mixed valence compound CeRuSn: a single-crystal study. AB - We report on detailed low-temperature measurements of the magnetization, the specific heat and the electrical resistivity on high-quality CeRuSn single crystals. The compound orders antiferromagnetically at T(N) = 2.8 K with the Ce(3+) ions locked within the a-c plane of the monoclinic structure. Magnetization shows that below T(N) CeRuSn undergoes a metamagnetic transition when applying a magnetic field of 1.5 and 0.8 T along the a- and c-axis, respectively. This transition manifests in a tremendous negative jump of ~25% in the magnetoresistance. The value of the saturated magnetization along the easy magnetization direction (c-axis) and the magnetic entropy above T(N) derived from specific heat data correspond to the scenario of only one third of the Ce ions in the compound being trivalent and carrying a stable Ce(3+) magnetic moment, whereas the other two thirds of the Ce ions are in a nonmagnetic tetravalent and/or mixed valence state. This is consistent with the low-temperature CeRuSn crystal structure i.e., a superstructure consisting of three unit cells of the CeCoAl type piled up along the c-axis, and in which the Ce(3+) ions are characterized by large distances from the Ru ligands while the Ce-Ru distances of the other Ce ions are much shorter causing a strong 4f-ligand hybridization and hence leading to tetravalent and/or mixed valence Ce ions. PMID- 24055929 TI - Developing number-space associations: SNARC effects using a color discrimination task in 5-year-olds. AB - Human adults' numerical representation is spatially oriented; consequently, participants are faster to respond to small/large numerals with their left/right hand, respectively, when doing a binary classification judgment on numbers, known as the SNARC (spatial-numerical association of response codes) effect. Studies on the emergence and development of the SNARC effect remain scarce. The current study introduces an innovative new paradigm based on a simple color judgment of Arabic digits. Using this task, we found a SNARC effect in children as young as 5.5 years. In contrast, when preschool children needed to perform a magnitude judgment task necessitating exact number knowledge, the SNARC effect started to emerge only at 5.8 years. Moreover, the emergence of a magnitude SNARC but not a color SNARC was linked to proficiency with Arabic digits. Our results suggest that access to a spatially oriented approximate magnitude representation from symbolic digits emerges early in ontogenetic development. Exact magnitude judgments, on the other hand, rely on experience with Arabic digits and, thus, necessitate formal or informal schooling to give access to a spatially oriented numerical representation. PMID- 24055930 TI - Alcohol vapour detection at the three phase interface using enzyme-conducting polymer composites. AB - Immobilisation of enzymes on a breathable electrode can be useful for various applications where the three-phase interface between gas or chemical vapour, electrolyte and electrode is crucial for the reaction. In this paper, we report the further development of the breathable electrode concept by immobilisation of alcohol dehydrogenase into vapour-phase polymerised poly(3,4-ethylene dioxythiophene) that has been coated onto a breathable membrane. Typical alcohol sensing, whereby the coenzyme beta-Nicotinamide adenine dinucleotide (NADH) is employed as a redox-mediator, was successfully used as a model reaction for the oxidation of ethanol. This indicates that the ethanol vapour from the backside of the membrane has access to the active enzyme embedded in the electrode. The detecting range of the sensor is suitable for the detection of ethanol in fruit juices and for the baseline breath ethanol concentration of drunken driving. After continuous operation for 4.5h the system only showed a 20% decrease in the current output. The electrodes maintained 62% in current output after being refrigerated for 76 days. This work is continuing the progress of the immobilisation of specific enzymes for certain electrochemical reactions whereby the three-phase interface has to be maintained and/or the simultaneous separation of gas from liquid is required. PMID- 24055928 TI - Laboratory activities involving transmissible spongiform encephalopathy causing agents: risk assessment and biosafety recommendations in Belgium. AB - Since the appearance in 1986 of epidemic of bovine spongiform encephalopathy (BSE), a new form of neurological disease in cattle which also affected human beings, many diagnostic and research activities have been performed to develop detection and therapeutic tools. A lot of progress was made in better identifying, understanding and controlling the spread of the disease by appropriate monitoring and control programs in European countries. This paper reviews the recent knowledge on pathogenesis, transmission and persistence outside the host of prion, the causative agent of transmissible spongiform encephalopathies (TSE) in mammals with a particular focus on risk (re)assessment and management of biosafety measures to be implemented in diagnostic and research laboratories in Belgium. Also, in response to the need of an increasing number of European diagnostic laboratories stopping TSE diagnosis due to a decreasing number of TSE cases reported in the last years, decontamination procedures and a protocol for decommissioning TSE diagnostic laboratories is proposed. PMID- 24055931 TI - A paper-based microfluidic electrochemical immunodevice integrated with amplification-by-polymerization for the ultrasensitive multiplexed detection of cancer biomarkers. AB - A novel signal amplification strategy for ultrasensitive multiplexed detection of cancer biomarkers using a paper-based microfluidic electrochemical immunodevice is described. Specifically, a controlled radical polymerization reaction is triggered after the capture of target molecules on the immunodevice surface. Growth of long chain polymeric materials provides numerous sites for subsequent horseradish peroxidase (HRP) coupling, which in turn significantly enhances electrochemical signal output. The signal was further amplified through the use of graphene to modify the immunodevice surface to accelerate the electron transfer. Activators generated electron transfer for atom transfer radical polymerization (AGET ATRP) was used in this study for its high efficiency in polymer grafting and better tolerance toward oxygen in air. Glycidyl methacrylate (GMA) was examined to provide excess epoxy groups for HRP coupling. In the electrochemical immunodevice, eight carbon working electrodes, as well as their conductive pads, were screen-printed on a piece of square paper, and the same Ag/AgCl reference and carbon counter electrodes were shared with another piece of square paper via stacking. Using the HRP-O-phenylenediamine-H2O2 electrochemical detection system, four cancer biomarkers: carcinoembryonic antigen (CEA), alpha fetoprotein (AFP), cancer antigen 125 (CA125), and carbohydrate antigen 153 (CA153) were detected. A limit of detection of 0.01, 0.01, 0.05 and 0.05 ng mL( 1) was demonstrated, respectively. The results show that the proposed strategy offers great promises in providing a sensitive and cost-effective solution for biosensing applications. PMID- 24055932 TI - Phenylboronic acid modified silver nanoparticles for colorimetric dynamic analysis of glucose. AB - The development of advanced nanostructures that allow dynamic quantification of glucose level can contribute to tight glucose control in diabetes management and other medical/biological fields. In this paper, we demonstrated that the assemblies of the 5-amino-2-fluorophenylboronic acid modified silver nanoparticles (FPBA-AgNPs) can be employed for highly modulating, sensitive, and selective colorimetric sensing of glucose over a physiologically important concentration range of 0-20mM at a physiological pH of 7.4. The glucose-modulated assembly of the FPBA-AgNPs occurred by the regulable formation of interparticle linkages via the bridged binding of 1,2-cis-diols and 5,6-cis-diols (for furanose form; or 4,6-cis-diols for pyranose form), respectively, of a glucose molecule to two FPBA-AgNPs. The detection limit was 89.0 MUM. The mean error of glucose detection in a macro-bio-system, blood serum of adult, was smaller than 10%. Furthermore, we show that the glucose level variations associated with a model biological reaction process can be monitored by using the FPBA-AgNPs, whilst with the reaction mechanism remaining nearly unchanged. PMID- 24055933 TI - Glad assisted synthesis of NiO nanorods for realization of enzymatic reagentless urea biosensor. AB - NiO nanorods (Nr-NiO) synthesized under glancing angle deposition (GLAD) configuration in RF sputtering have been explored for potential application in urea biosensor. Vertically aligned cone shaped NiO nanorods synthesized over ITO coated glass (Nr-NiO/ITO/Glass) exhibit enhanced electrochemical current in a reagent less buffer due to its electro-catalytic species that are based on the shuttling of electrons between Ni(2+) and Ni(3+) in the octahedral site. The fabricated bioelectrode (Ur/Nr-NiO/ITO/glass) after immobilization of urease (Ur) shows excellent biosensing response characteristics with a relatively high sensitivity of about 48.0 MUA/(mM) and a good linearity over a wide range (0.83 16.65 Mm) of urea concentration with the long shelf life of about 20 weeks. The low value of the Michaelis-Menten constant (Km=0.47 mM) indicates the high affinity of immobilized urease (Ur) towards the analyte (urea). The high electro catalytic activity, along with the redox behavior of Nr-NiO, makes it an efficient matrix for the realization of a reagent less urea biosensor. PMID- 24055934 TI - Gold/phospholipid nanoconstructs as label-free optical probes for evaluating phospholipase A2 activity. AB - A facile, monophasic strategy, involving a cooperative solvent, dimethylformamide (DMF), to synthesize core/shell architectured gold-phospholipid hybrid nanoconstructs (PLGNPs) was presented herein. We employed the as-synthesized PLGNPs as enzymatic substrates and detecting probes, leading to the development of a novel, lag time-free quantitative assay to evaluate the activity of Ca(2+) dependent phospholipase A2 (PLA2), an inflammatory protein that (i) plays a role in the pathogenesis of many inflammatory diseases, (ii) is a mediator in atherosclerosis and ischemic damage to cardiomyocytes, and (iii) has been implicated in the cause of neurodegenerative diseases. Our new bioassay exhibited high specificity, improved speed (assay time:<= 20 min), acceptable sensitivity, and a limit of detection (1.82 nM, equivalent to 0.04 unit/mL and 260 ng/dL) below the cut-off value of circulating PLA2 (2.07 nM, equivalent to 290 ng/dL) present in serum samples collected from healthy testers. We characterized the as obtained PLGNPs using UV-vis spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering (DLS). These PLGNPs were considerably robust and biocompatible-displaying extraordinary stability against salt-induced aggregation, oxidant etching, and repetitive freeze/thaw treatment-because of the presence of their modifying interfacial thiol (1-dodecanethiol) and phospholipid [1,2-dihexadecanoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3 phospho-(1'-rac-glycerol)] units. PMID- 24055935 TI - Copper, zinc superoxide dismutase and nitrate reductase coimmobilized bienzymatic biosensor for the simultaneous determination of nitrite and nitrate. AB - This work presents a novel bienzymatic biosensor for the simultaneous determination of nitrite (NO2(-)) and nitrate (NO3(-)) ions using copper, zinc superoxide dismutase (SOD1) and nitrate reductase (NaR) coimmobilized on carbon nanotubes (CNT)-polypyrrole (PPy) nanocomposite modified platinum electrode. Morphological changes of the PPy and CNT modified electrodes were investigated using scanning electron microscopy. The electrochemical behavior of the bienzymatic electrode (NaR-SOD1-CNT-PPy-Pt) was characterized by cyclic voltammetry exhibiting quasi-reversible redox peak at +0.06 V and reversible redox peaks at -0.76 and -0.62V vs. Ag/AgCl, for the immobilized SOD1 and NaR respectively. The electrocatalytic activity of SOD1 towards NO2(-) oxidation observed at +0.8 V was linear from 100 nM to 1mM with a detection limit of 50 nM and sensitivity of 98.5 +/- 1.7 nA uM(-1)cm(-2). Similarly, the coimmobilized NaR showed its electrocatalytic activity towards NO3(-) reduction at -0.76 V exhibiting linear response from 500 nM to 10mM NO3(-) with a detection limit of 200 nM and sensitivity of 84.5 +/- 1.56 nA uM(-1)cm(-2). Further, the present bienzymatic biosensor coated with cellulose acetate membrane for the removal of non-specific proteins was used for the sensitive and selective determinations of NO2(-) and NO3(-) present in human plasma, whole blood and saliva samples. PMID- 24055936 TI - Metal ions-based immunosensor for simultaneous determination of estradiol and diethylstilbestrol. AB - Environmental estrogens (EEs) can cause various endocrine diseases. Herein, we designed an ultrasensitive electrochemical immunosensor for simultaneous detection of two typical EEs, estradiol and diethylstilbestrol. These two analytes were immobilized on graphene sheet (GS) modified glassy carbon electrode (GCE). Amino-group functionalized mesoporous Fe3O4 (Fe3O4-NH2) was loaded with Pb(2+) or Cd(2+), and then incubated with estradiol and diethylstilbestrol antibodies, respectively. Using an electrochemical analysis technique, two well separated peaks were generated by the redox reaction of Pb(2+) or Cd(2+), making the simultaneous detection of two analytes on the electrode possible. Subsequently, square wave anodic stripping voltammetry (SWASV) and electrochemical impedance spectroscopy (EIS) were used to investigate the electrochemical behaviors of the immunosensor. Under optimized conditions, the SWASV peak currents were proportional to the concentrations of estradiol and diethylstilbestrol in the range from 0.050 pg mL(-1) to 100 ng mL(-1) and 1.0 pg mL(-1) to 100 ng mL(-1), respectively. The immunosensor exhibited highly sensitive response to estradiol with a detection limit of 0.015 pg mL(-1) and diethylstilbestrol with a detection limit of 0.38 pg mL(-1). Furthermore, the immunosensor was satisfactorily employed to detect estradiol and diethylstilbestrol simultaneously in water samples. PMID- 24055937 TI - Monitoring intracellular calcium in response to GPCR activation using thin-film silicon photodiodes with integrated fluorescence filters. AB - G-protein coupled receptor (GPCRs) drug discovery is a thriving strategy in the pharmaceutical industry. The standard approach uses living cells to test millions of compounds in a high-throughput format. Typically, changes in the intracellular levels of key elements in the signaling cascade are monitored using fluorescence or luminescence read-out systems, which require external equipment for signal acquisition. In this work, thin-film amorphous silicon photodiodes with an integrated fluorescence filter were developed to capture the intracellular calcium dynamics in response to the activation of the endogenous muscarinic M1 GPCR of HEK 293T cells. Using the new device it was possible to characterize the potency of carbachol (EC50=10.5 uM) and pirenzepine (IC50=4.2 MUM), with the same accuracy as standard microscopy optical systems. The smaller foot-print provided by the detection system makes it an ideal candidate for the future integration in microfluidic devices for drug discovery. PMID- 24055938 TI - A bacteriophage detection tool for viability assessment of Salmonella cells. AB - Salmonellosis, one of the most common food and water-borne diseases, has a major global health and economic impact. Salmonella cells present high infection rates, persistence over inauspicious conditions and the potential to preserve virulence in dormant states when cells are viable but non-culturable (VBNC). These facts are challenging for current detection methods. Culture methods lack the capacity to detect VBNC cells, while biomolecular methods (e.g. DNA- or protein-based) hardly distinguish between dead innocuous cells and their viable lethal counterparts. This work presents and validates a novel bacteriophage (phage) based microbial detection tool to detect and assess Salmonella viability. Salmonella Enteritidis cells in a VBNC physiological state were evaluated by cell culture, flow-cytometry and epifluorescence microscopy, and further assayed with a biosensor platform. Free PVP-SE1 phages in solution showed the ability to recognize VBNC cells, with no lysis induction, in contrast to the minor recognition of heat-killed cells. This ability was confirmed for immobilized phages on gold surfaces, where the phage detection signal follows the same trend of the concentration of viable plus VBNC cells in the sample. The phage probe was then tested in a magnetoresistive biosensor platform allowing the quantitative detection and discrimination of viable and VBNC cells from dead cells, with high sensitivity. Signals arising from 3 to 4 cells per sensor were recorded. In comparison to a polyclonal antibody that does not distinguish viable from dead cells, the phage selectivity in cell recognition minimizes false-negative and false-positive results often associated with most detection methods. PMID- 24055939 TI - Device implantation complications during fellowship training: it is always the fellow's fault, or is it? PMID- 24055940 TI - High-density substrate-guided ventricular tachycardia ablation: role of activation mapping in an attempt to improve procedural effectiveness. AB - BACKGROUND: Advanced techniques of electroanatomical mapping efficiently guide ventricular tachycardia (VT) ablation strategies; in this context, the adjunctive value of combining activation mapping (AMap) to improve accuracy has not been elucidated. OBJECTIVE: To investigate whether conventional AMap further contributes to the identification of critical sites of VT reentry and whether this translates into a more effective ablation outcome in a cohort of patients undergoing VT ablation. METHODS: We prospectively enrolled 126 patients (mean age 65.3 +/- 10.5 years; left ventricular ejection fraction 33.3% +/- 7.2%) with ischemic (n = 89) or idiopathic (n = 37) dilated cardiomyopathy undergoing endocardial (n = 105) or endo-epicardial (n = 21) electroanatomical mapping and ablation. A substrate-guided strategy targeting surrogate markers of reentry was accomplished in all patients, but the feasibility and efficacy of AMap was preliminarily assessed for all induced VTs focusing on early VT suppression obtained during radiofrequency delivery. VT-free survival was assessed by ICD interrogation. RESULTS: AMap successfully guided ablation in 62 of 104 (59.6%) patients with inducible VT(s). At 1 year, 6 of 126 (4.8%) patients died; VT recurred in 28 of 126 (22.2%) patients. No significant difference in VT recurrence rate was observed between patients in whom AMap proved effective versus those in whom substrate-guided ablation was not corroborated by AMap (16 of 62 [25.8%] vs 12 of 64 [18.8%]; log-rank test, P = .3). CONCLUSIONS: Our findings support the efficacy of a substrate-guided strategy targeting specific markers of arrhythmogenicity identified during sinus rhythm. AMap proves highly efficient acutely but does not improve overall VT-free survival, suggesting that in patients with advanced cardiac disease, life-threatening arrhythmias can be successfully treated by ablation in sinus rhythm, thus limiting procedural risks. PMID- 24055941 TI - Noncontact mapping to guide ablation of right ventricular outflow tract arrhythmias. AB - BACKGROUND: There is limited data on outcomes after noncontact mapping (NCM) guided right ventricular outflow tract (RVOT) ventricular arrhythmia (VA) ablation. OBJECTIVES: To assess outcomes of NCM-guided RVOT VA ablation in a large cohort with extended follow-up, to determine optimal ablation site, and to analyze limitations of conventional mapping techniques. METHODS: In consecutive patients undergoing RVOT VA ablation, 2 sites of early activation--earliest activation (EA) and breakout (BO) sites--were identified on NCM maps. Pace mapping and activation mapping were performed at both sites. The area of depolarized myocardium during the first 10 ms of spontaneous VA and pacing was measured. The initial site of ablation was randomized to either EA or BO sites, with crossover to the alternate site if ablation was not successful. RESULTS: In 136 patients, prematurity of local activation and pace maps were similar at EA and BO sites. More myocardium was depolarized 10 ms after pacing than during spontaneous VA (12.9 +/- 7.8 cm(2) vs 5.3 +/- 3.9 cm(2); P < .01). Clinical success was more likely achieved when initial ablation was directed toward the EA site (P < .05). A wider EA-BO separation was associated with acute procedural failure (P < .01). With a follow-up of 36.2 +/- 17.5 months, the success rate after a single procedure without antiarrhythmic agents was 86.8%. CONCLUSIONS: NCM-guided RVOT VA ablation is highly effective, and clinical success is best achieved by ablating the EA site. Broad regions of early activation are associated with worsened clinical outcomes. Spatial resolution of activation and pace mapping is limited by rapid electrical propagation in the RVOT. PMID- 24055942 TI - Life-threatening ventricular arrhythmias during ajmaline challenge in patients with Brugada syndrome: incidence, clinical features, and prognosis. AB - BACKGROUND: Sustained ventricular arrhythmias (sVAs), such as polymorphic ventricular tachycardia or ventricular fibrillation, can complicate ajmaline challenge in patients with Brugada syndrome (BS). OBJECTIVE: To assess the incidence of life-threatening sVAs during ajmaline administration in a large series of patients with BS. In addition, clinical characteristics as well as prognosis of these patients were evaluated. METHODS: All consecutive patients with ajmaline-induced diagnosis of BS were eligible for this study. RESULTS: A total of 503 patients were included. Nine (1.8%) patients (44% men; mean age 26 +/- 18 years) developed a life-threatening sVA during ajmaline challenge. Three patients (33%)were children, and 2 (22%) patients experienced sVAs refractory to the first external defibrillation. One patient underwent venoarterial extracorporeal membrane oxygenation to restore sinus rhythm. Age at the time of ajmaline challenge was significantly lower in patients with sVAs compared with patients without sVAs (26 +/- 18 years vs 41 +/- 18 years; P = .01). Moreover, patients with sVAs presented more frequently with sinus node dysfunction compared with patients with normal response to ajmaline (22.2% vs 1.4%; P = .01). After a mean follow-up time of 29 +/- 8 months, none of the patients who had developed a sVA during ajmaline challenge died suddenly or developed further life-threatening ventricular arrhythmias. CONCLUSIONS: sVA during ajmaline challenge is not a rare event in BS occurring in 9 (1.8%) patients. Despite its challenging acute treatment, the occurrence of ajmaline-induced sVAs in patients with BS might not identify a category at higher risk for further arrhythmic events. PMID- 24055943 TI - Transcoronary ethanol for incessant epicardial ventricular tachycardia. PMID- 24055944 TI - An unusual defibrillator lead-associated echodensity. PMID- 24055946 TI - Arrhythmogenic right ventricular cardiomyopathy: arrhythmias upstream and downstream. PMID- 24055945 TI - To the editor- amiloride concentrations in clinical practice. PMID- 24055947 TI - Changes in QRS morphology during atrial fibrillation: what is the mechanism? PMID- 24055948 TI - To the editor- blind men and the J wave-confusing aspects of the 2013 HRS Statement on Inherited Arrhythmic Diseases. PMID- 24055950 TI - Afrotheria genome; overestimation of genome size and distinct chromosome GC content revealed by flow karyotyping. AB - Afrotheria genome size is reported to be over 50% larger than that of human, but we show that this is a gross overestimate. Although genome sequencing in Afrotheria is not complete, extensive homology with human has been revealed by chromosome painting. We provide new data on chromosome size and GC content in four Afrotherian species using flow karyotyping. Genome sizes are 4.13 Gb in aardvark, 4.01 Gb in African elephant, 3.69 Gb in golden mole and 3.31 Gb in manatee, whereas published results show a mean of 5.18 Gb for Afrotheria. Genome GC content shows a negative correlation with size, indicating that this is due to differences in the amount of AT-rich sequences. Low genome GC content and small variance in chromosome GC content are characteristic of aardvark and elephant and may be associated with the high degree of conserved synteny, suggesting that these are features of the Afrotherian ancestral genome. PMID- 24055951 TI - Genomic analysis of HAdV-B14 isolate from the outbreak of febrile respiratory infection in China. AB - Human adenovirus type 14 (HAdV-B14) was first reported in 1955 from the Netherlands and since then had been associated with outbreaks of febrile respiratory illness (FRI). In China, sporadic HAdV-B14 infections were first identified in 2010, in Guangzhou and Beijing. In 2012, an outbreak of FRI occurred in Beijing and the etiological agent was determined to be HAdV-B14. We present a complete HAdV-B14 genome sequence isolated from this recent FRI outbreak. Virus in 30 throat swab samples was detected using polymerase chain reaction assays, and confirmed by sequencing of the fiber, hexon and penton genes. Comparative genomics and phylogenetic analysis showed that the newly isolated HAdV-B14 (HAdV-B14 CHN) shared highest sequence homology with a 2006 isolate from the United States and clustered closely with other HAdV-B14 strains. It is expected that data from the present study will help in devising better protocols for virus surveillance, and in developing preventative measures. PMID- 24055949 TI - Electronic "expression" of the inward rectifier in cardiocytes derived from human induced pluripotent stem cells. AB - BACKGROUND: Human-induced pluripotent stem cell (h-iPSC)-derived cardiac myocytes are a unique model in which human myocyte function and dysfunction are studied, especially those from patients with genetic disorders. They are also considered a major advance for drug safety testing. However, these cells have considerable unexplored potential limitations when applied to quantitative action potential (AP) analysis. One major factor is spontaneous activity and resulting variability and potentially anomalous behavior of AP parameters. OBJECTIVE: To demonstrate the effect of using an in silico interface on electronically expressed I(K1), a major component lacking in h-iPSC-derived cardiac myocytes. METHODS: An in silico interface was developed to express synthetic I(K1) in cells under whole-cell voltage clamp. RESULTS: Electronic I(K1) expression established a physiological resting potential, eliminated spontaneous activity, reduced spontaneous early and delayed afterdepolarizations, and decreased AP variability. The initiated APs had the classic rapid upstroke and spike and dome morphology consistent with data obtained with freshly isolated human myocytes as well as the readily recognizable repolarization attributes of ventricular and atrial cells. The application of 1 uM of BayK-8644 resulted in anomalous AP shortening in h-iPSC-derived cardiac myocytes. When I(K1) was electronically expressed, BayK-8644 prolonged the AP, which is consistent with the existing results on native cardiac myocytes. CONCLUSIONS: The electronic expression of I(K1) is a simple and robust method to significantly improve the physiological behavior of the AP and electrical profile of h-iPSC-derived cardiac myocytes. Increased stability enables the use of this preparation for a controlled quantitative analysis of AP parameters, for example, drug responsiveness, genetic disorders, and dynamic behavior restitution profiles. PMID- 24055952 TI - Stable isotope fractionations during reactive transport of phosphate in packed bed sediment columns. AB - Characterizing reactivity and fate of contaminants in subsurface environments that are isolated from direct visualization is a major challenge. Stable isotopes coupled with concentration could be used as a potential tool to quantitatively analyze the chemical variability of the contaminant during reactive transport processes in the subsurface environment. This study was aimed at determining whether abiotic reactions of phosphate during its transport involve fractionation of oxygen isotopes in phosphate (delta(18)Op). It included the effects of solution chemistry and hydrodynamics on delta(18)Op values during phosphate transport through a packed-bed column prepared by using natural sediment collected from the Cape Cod aquifer in Massachusetts. Results show that the isotopic fractionation between effluent and influent phosphate at early stage of transport could be ~1.30/00 at higher flow rates with isotopically-light phosphate (P(16)O4) preferentially retained in the sediment column. This fractionation, however, decreased and became insignificant as more phosphate passed through the column. Mobilization of phosphate initially sorbed onto sediments caused a large kinetic isotopic fractionation with isotopically-light phosphate preferentially remobilized from the sediment column, but over longer time periods, this fractionation decreased and became insignificant as well. These results collectively suggest that abiotic reactive transport processes exert minimal influence on the delta(18)Op composition of subsurface systems. Alternatively, fluctuation in flow rate and subsequent remobilization of phosphate could be detectable through transient changes in delta(18)Op values. These findings extend the burgeoning application of delta(18)Op to identify the different sources and geochemical processes of phosphate in the subsurface environments. PMID- 24055953 TI - Sorption and mineralization of S-metolachlor and its ionic metabolites in soils and vadose zone solids: consequences on groundwater quality in an alluvial aquifer (Ain Plain, France). AB - This study characterizes the transfer of S-metolachlor (SMOC) and its metabolites, metolachlor ethane sulfonic acid (MESA) and metolachlor oxanilic acid (MOXA) to the alluvial aquifer. Sorption and mineralization of SMOC and its two ionic metabolites were characterized for cultivated soils and solids from the vadose (unsaturated) zone in the Ain Plain (France). Under sterile soil conditions, the absence of mineralization confirms the importance of biotic processes in SMOC degradation. There is some adsorption and mineralization of the parent molecule and its metabolites in the unsaturated zone, though less than in soils. For soils, the MESA adsorption constant is statistically higher than that of MOXA and the sorption constants of the two metabolites are significantly lower than that of SMOC. After 246 days, for soils, maximums of 26% of the SMOC, 30% of the MESA and 38% of the MOXA were mineralized. This partly explains the presence of these metabolites in the groundwater at concentrations generally higher than those of the parent molecule for MESA, although there is no statistical difference in the mineralization of the 3 molecules. The laboratory results make it possible to explain the field observations made during 27 months of groundwater quality monitoring (monthly sampling frequency). The evolution of both metabolite concentrations in the groundwater is directly related to recharge dynamics; there is a positive correlation between concentrations and the groundwater level. The observed lag of several months between the signals of the parent molecule and those of the metabolites is probably due to greater sorption of the parent molecule than of its metabolites and/or to degradation kinetics. PMID- 24055954 TI - Maturational differences in thalamocortical white matter microstructure and auditory evoked response latencies in autism spectrum disorders. AB - White matter diffusion anisotropy in the acoustic radiations was characterized as a function of development in autistic and typically developing children. Auditory evoked neuromagnetic fields were also recorded from the same individuals and the latency of the left and right middle latency superior temporal gyrus auditory ~50ms response (M50)(1) was measured. Group differences in structural and functional auditory measures were examined, as were group differences in associations between white matter pathways, M50 latency, and age. Acoustic radiation white matter fractional anisotropy did not differ between groups. Individuals with autism displayed a significant M50 latency delay. Only in typically developing controls, white matter fractional anisotropy increased with age and increased white matter anisotropy was associated with earlier M50 responses. M50 latency, however, decreased with age in both groups. Present findings thus indicate that although there is loss of a relationship between white matter structure and auditory cortex function in autism spectrum disorders, and although there are delayed auditory responses in individuals with autism than compared with age-matched controls, M50 latency nevertheless decreases as a function of age in autism, parallel to the observation in typically developing controls (although with an overall latency delay). To understand auditory latency delays in autism and changes in auditory responses as a function of age in controls and autism, studies examining white matter as well as other factors that influence auditory latency, such as synaptic transmission, are of interest. PMID- 24055955 TI - Lesbian and bisexual women's adjustment after a breast cancer diagnosis. AB - BACKGROUND: Little research has been devoted to lesbian and bisexual survivors' adjustment after breast cancer. OBJECTIVES: To determine differences between lesbian and bisexual survivors and to examine whether sexual minority-specific issues contribute to these survivors' adjustment. DESIGN: We recruited 180 lesbian and bisexual survivors with primary diagnoses of DCIS (ductal carcinoma in situ) or I-III nonrecurrent breast cancer from a cancer registry and the community. RESULTS: The characteristics of lesbian and bisexual survivors of breast cancer were similar, with few exceptions, such as partner status and gender of partner. Sexual minority-specific factors contributed toward explaining lesbian and bisexual survivors' anxiety and depression but did not contribute toward explaining survivors' physical and mental health. CONCLUSIONS: Awareness about vulnerabilities due to partner status and about the sexual minority specific issues that contribute to adjustment is important for medical and mental health professionals who have lesbian and bisexual breast cancer survivors as patients. PMID- 24055957 TI - Exponential stabilization of delayed recurrent neural networks: A state estimation based approach. AB - This paper is concerned with the stabilization problem of delayed recurrent neural networks. As the states of neurons are usually difficult to be fully measured, a state estimation based approach is presented. First, a sufficient condition is derived such that the augmented system under consideration is globally exponentially stable. Then, by employing a decoupling technique, the gain matrices of the controller and state estimator are achieved by solving some linear matrix inequalities. Finally, a delayed neural network with chaotic behaviors is exploited to demonstrate the applicability of the developed result. PMID- 24055958 TI - Global exponential dissipativity and stabilization of memristor-based recurrent neural networks with time-varying delays. AB - This paper addresses the global exponential dissipativity of memristor-based recurrent neural networks with time-varying delays. By constructing proper Lyapunov functionals and using M-matrix theory and LaSalle invariant principle, the sets of global exponentially dissipativity are characterized parametrically. It is proven herein that there are 2(2n(2)-n) equilibria for an n-neuron memristor-based neural network and they are located in the derived globally attractive sets. It is also shown that memristor-based recurrent neural networks with time-varying delays are stabilizable at the origin of the state space by using a linear state feedback control law with appropriate gains. Finally, two numerical examples are discussed in detail to illustrate the characteristics of the results. PMID- 24055956 TI - Mental health and substance use disparities among urban adolescent lesbian and bisexual girls. AB - BACKGROUND: Sexual minority girls (SMGs) report large substance use disparities and victimization experiences, yet there is a dearth of research that focuses exclusively on SMGs. OBJECTIVE: To examine substance use and mental health disparities among SMGs and to determine whether disparities were larger for African American compared with European American girls. METHOD: Data were used from Wave 11 of the Pittsburgh Girls Study, a multiple-cohort, prospective study of urban girls. Girls for the current analysis were aged 16 to 19 years. Fifty five percent were African American. One hundred and seventy-three (8.3%) identified as SMGs, and 1,891 identified as heterosexual. Multiple regression analyses controlling for age, race, and parent education were conducted. RESULTS: SMGs reported a robust pattern of large disparities in externalizing, internalizing, and borderline personality disorder symptoms. There was little evidence to suggest disparities were moderated by race. CONCLUSION: SMGs and their families would benefit from intervention and prevention programs to reduce disparities among this highly vulnerable population. PMID- 24055959 TI - On the construction of the relevance vector machine based on Bayesian Ying-Yang harmony learning. AB - Tipping's relevance vector machine (RVM) applies kernel methods to construct basis function networks using a least number of relevant basis functions. Compared to the well-known support vector machine (SVM), the RVM provides a better sparsity, and an automatic estimation of hyperparameters. However, the performance of the original RVM purely depends on the smoothness of the presumed prior of the connection weights and parameters. Consequently, the sparsity is actually still controlled by the choice of kernel functions and/or kernel parameters. This may lead to severe underfitting or overfitting in some cases. In this research, we explicitly involve the number of basis functions into the objective of the optimization procedure, and construct the RVM by maximizing the harmony function between "hypothetical" probability distribution in the forward training pathway and "true" probability distribution in the backward testing pathway, using Xu's Bayesian Ying-Yang (BYY) harmony learning technique. The experimental results have shown that our proposed methodology can achieve both the least complexity of structure and goodness of fit to data. PMID- 24055960 TI - Dynamical behaviors for discontinuous and delayed neural networks in the framework of Filippov differential inclusions. AB - This paper is concerned with the periodic dynamics of a class of delayed neural networks with discontinuous neural activation functions. Under the Filippov framework, the cone expansion and compression fixed point theorems of set-valued maps are successfully employed to derive the existence of the omega-periodic positive solution. However, before the discussion of the periodicity, there still remains a fundamental issue about viability to be solved due to the presence of general mixed time-delays involving both time-varying delays and distributed delays. This difficulty can be overcome by a transformation and the continuation theorem. Then, for the discontinuous and delayed neural network system with time periodic coefficients, the uniqueness and global exponential stability of the periodic state solution are proved by using non-smooth analysis theory with generalized Lyapunov approach. Furthermore, the global convergence in measure of the periodic output is also investigated. The obtained results are a very good extension and improvement of previous works on discontinuous dynamical neuron systems with a broad range of neuron activations dropping the assumption of boundedness or monotonicity. Finally, numerical simulations are provided to illustrate the effectiveness of the theoretical results. PMID- 24055962 TI - Qualitatively different immune response of the bumblebee host, Bombus terrestris, to infection by different genotypes of the trypanosome gut parasite, Crithidia bombi. AB - Insects have a complex and highly successful immune system that responds specifically to different types of parasites. Different genotypes of a parasite species can differ in infectivity and virulence; which is important for host parasite co-evolutionary processes, such as antagonistic, fluctuating selection. Such coevolution obviously requires a genetic basis, but little is known about how hosts immunologically respond to different genotypes. The common European bumblebee Bombus terrestris is infected by the highly prevalent trypanosome gut parasite, Crithidia bombi. Here we examined expression of 26 immunological and metabolic genes in response to infection by two clones of C. bombi and compared that with exposure to injection with a bacterial challenge. Exposure to the two clones of C. bombi elicits qualitatively different immune expression responses. Interestingly, infection with one clone results in up regulation of AMP's similar to bees given the bacterial challenge, while genes related to metabolism, signalling, and other effectors were similar between the two Crithidia exposures. Bees given different challenges were distinct enough to discern using linear discriminant analyses. We also found strong correlations, both positive and negative, among genes, which may shed light on how suites of genes are regulated and trade-offs in expression within this gene set. PMID- 24055961 TI - Phylogenomics of Brazilian epidemic isolates of Mycobacterium abscessus subsp. bolletii reveals relationships of global outbreak strains. AB - Rapidly growing, non-tuberculous mycobacteria (NTM) in the Mycobacterium abscessus (MAB) species are emerging pathogens that cause various diseases including skin and respiratory infections. The species has undergone recent taxonomic nomenclature refinement, and is currently recognized as two subspecies, M. abscessus subsp. abscessus (MAB-A) and M. abscessus subsp. bolletii (MAB-B). The recently reported outbreaks of MAB-B in surgical patients in Brazil from 2004 to 2009 and in cystic fibrosis patients in the United Kingdom (UK) in 2006 to 2012 underscore the need to investigate the genetic diversity of clinical MAB strains. To this end, we sequenced the genomes of two Brazilian MAB-B epidemic isolates (CRM-0019 and CRM-0020) derived from an outbreak of skin infections in Rio de Janeiro, two unrelated MAB strains from patients with pulmonary infections in the United States (US) (NJH8 and NJH11) and one type MAB-B strain (CCUG 48898) and compared them to 25 publically available genomes of globally diverse MAB strains. Genome-wide analyses of 27,598 core genome single nucleotide polymorphisms (SNPs) revealed that the two Brazilian derived CRM strains are nearly indistinguishable from one another and are more closely related to UK outbreak isolates infecting CF patients than to strains from the US, Malaysia or France. Comparative genomic analyses of six closely related outbreak strains revealed geographic-specific large-scale insertion/deletion variation that corresponds to bacteriophage insertions and recombination hotspots. Our study integrates new genome sequence data with existing genomic information to explore the global diversity of infectious M. abscessus isolates and to compare clinically relevant outbreak strains from different continents. PMID- 24055963 TI - Microbial community structures in a closed raw water distribution system biofilm as revealed by 454-pyrosequencing analysis and the effect of microbial biofilm communities on raw water quality. AB - This is the first report on the characterization of the microbial biofilm community structure and water quality change along a closed and stable raw water distribution system. 454-pyrosequencing was employed to investigate the microbial communities in four biofilm samples. 25,426 optimized sequences were obtained. Results showed Proteobacteria was the dominant phylum in each biofilm sample. The abundance of Nitrospiraes in M6 biofilm, Firmicutes in M8 biofilm, Actinobacteria in M9 biofilm were higher by comparing with other three biofilm samples. The M6 microbial biofilm community structure was similar to that of M7, dissimilar to that of M9. Dissolved oxygen and nitrogen was probably major factors to influence the microbial biofilm communities. Nitrospiraes in M6 biofilm and Firmicutes in M8 biofilm were crucial to remove ammonia nitrogen and nitrate in raw water. How to enrich functional microbes in biofilm to pretreat raw water is an important area of future research. PMID- 24055964 TI - Biodiesel production from Jatropha oil catalyzed by immobilized Burkholderia cepacia lipase on modified attapulgite. AB - Lipase from Burkholderia cepacia was immobilized on modified attapulgite by cross linking reaction for biodiesel production with jatropha oil as feedstock. Effects of various factors on biodiesel production were studied by single-factor experiment. Results indicated that the best conditions for biodiesel preparation were: 10 g jatropha oil, 2.4 g methanol (molar ratio of oil to methanol is 1:6.6) being added at 3h intervals, 7 wt% water, 10 wt% immobilized lipase, temperature 35 degrees C, and time 24h. Under these conditions, the maximum biodiesel yield reached 94%. The immobilized lipase retained 95% of its relative activity during the ten repeated batch reactions. The half-life time of the immobilized lipase is 731 h. Kinetics was studied and the Vmax of the immobilized lipases were 6.823 mmol L(-1). This immobilized lipase catalyzed process has potential industrial use for biodiesel production to replace chemical-catalyzed method. PMID- 24055965 TI - Preparation of novel alginate based anion exchanger from Ulva japonica and its application for the removal of trace concentrations of fluoride from water. AB - A green seaweed, Ulva japonica, was modified by loading multivalent metal ions such as Zr(IV) and La(III) after CaCl2 cross-linking to produce metal loaded cross-linked seaweed (M-CSW) adsorbents, which were characterized by elemental analysis, functional groups identification, and metal content determination. Maximum sorption potential for fluoride was drastically increased after La(III) and Zr(IV) loading, which were evaluated as 0.58 and 0.95 mmol/g, respectively. Loaded fluoride was quantitatively desorbed by using dilute alkaline solution for its regeneration. Mechanism of fluoride adsorption was inferred in terms of ligand exchange reaction between hydroxyl ion on co-ordination sphere of the loaded metal ions of M-CSW and fluoride ion in aqueous solution. Application of M CSW for the treatment of actual waste plating solution exhibited successful removal of fluoride to clear the effluent and environmental standards in Japan, suggesting high possibility of its application for the treatment of fluoride rich waste water. PMID- 24055966 TI - Isolation of a novel microalgae strain Desmodesmus sp. and optimization of environmental factors for its biomass production. AB - A novel strain of unicellular green algae was isolated from fresh water samples collected from Yesanpo National Geopark, Laishui County of Hebei Province, China. The morphological and genomic identification of this strain was carried out using 18s rRNA analysis. This novel strain was identified as Desmodesmus sp. named as EJ15-2. Environmental factors for biomass production of Desmodesmus sp. EJ15-2 grown under autotrophic condition (BG11 medium) was optimized using response surface methodology (RSM). A high correlation coefficient (R(2)=0.923, p <= 0.01) indicated the adaptability of the second-order equation matched well with the growth condition of this strain. The optimal conditions for a relatively high biomass production (up to 0.758 g/L) were at 30 degrees C, 98 MUmol/m(2)/s and 14:10 (L:D), respectively. PMID- 24055967 TI - Thermal decomposition of lignocellulosic biomass in the presence of acid catalysts. AB - Transformation of lignocellulosic biomass to biofuels involves multiple processes, in which thermal decomposition, hydrotreatment are the most central steps. Current work focuses on the impact of several solid acids and Keggin-type heteropolyacids on the decomposition temperature (Td) of pine wood and the characterization of the resulted products. It has been observed that a mechanical mixture of solid acids with pine wood has no influence on Td, while the use of heteropolyacids lower the Td by 100 degrees C. Moreover, the treatment of biomass with a catalytic amount of H3PW12O40 leads to formation of three fractions: solid, liquid and gas, which have been investigated by elemental analysis, TGA, FTIR, GC-MS and NMR. The use of heteropolyacid leads, at 300 degrees C, to a selective transformation of more than 50 wt.% of the holocellulose part of the lignocellulosic biomass. Moreover, 60 wt.% of the catalyst H3PW12O40 are recovered. PMID- 24055968 TI - Effects of organic loading rates on reactor performance and microbial community changes during thermophilic aerobic digestion process of high-strength food wastewater. AB - To evaluate the applicability of single-stage thermophilic aerobic digestion (TAD) process treating high-strength food wastewater (FWW), TAD process was operated at four organic loading rates (OLRs) from 9.2 to 37.2 kg COD/m(3)d. The effects of OLRs on microbial community changes were also examined. The highest volumetric removal rate (13.3 kg COD/m(3)d) and the highest thermo-stable protease activity (0.95 unit/mL) were detected at OLR=18.6 kg COD/m(3)d. Denaturing gradient gel electrophoresis (DGGE) profiles and quantitative PCR (qPCR) results showed significant microbial community shifts in response to changes in OLR. In particular, DGGE and phylogenetic analysis demonstrate that the presence of Bacillus sp. (phylum of Firmicutes) was strongly correlated with efficient removal of organic particulates from high-strength food wastewater. PMID- 24055969 TI - Influence of operating conditions for volatile fatty acids enrichment as a first step for polyhydroxyalkanoate production on a municipal waste water treatment plant. AB - This work describes the generation of volatile fatty acids (VFAs) as the first step of the polyhydroxyalkanoate (PHA) production cycle. Therefore four different substrates from a municipal waste water treatment plant (WWTP) were investigated regarding high VFA production and stable VFA composition. Due to its highest VFA yield primary sludge was used as substrate to test a series of operating conditions (temperature, pH, retention time (RT) and withdrawal (WD)) in order to find suitable conditions for a stable VFA production. The results demonstrated that although the substrate primary sludge differs in its consistence a stable composition of VFA could be achieved. Experiments with a semi-continuous reactor operation showed that a short RT of 4d and a small WD of 25% at pH=6 and around 30 degrees C is preferable for high VFA mass flow (MF=1913 mg VFA/(Ld)) and a stable VFA composition. PMID- 24055970 TI - Continuous cultivation of photosynthetic bacteria for fatty acids production. AB - In the present work, we introduced a novel approach for microbial fatty acids (FA) production. Photosynthetic bacteria, Rhodobacter sphaeroides KD131, were cultivated in a continuous-flow, stirred-tank reactor (CFSTR) at various substrate (lactate) concentrations. At hydraulic retention time (HRT) 4d, cell concentration continuously increased from 0.97 g dcw/L to 2.05 g dcw/L as lactate concentration increased from 30 mM to 60mM. At 70 mM, however, cell concentration fluctuated with incomplete substrate degradation. By installing a membrane unit to CFSTR, a stable performance was observed under much higher substrate loading (lactate 100mM and HRT 1.5d). A maximum cell concentration of 16.2g dcw/L, cell productivity of 1.9 g dcw/L/d, and FA productivity of 665 mg FA/L/d were attained, and these values were comparable with those achieved using microalgae. The FA content of R. sphaeroides was around 35% of dry cell weight, mainly composed of vaccenic acid (C18:1, omega-7). PMID- 24055971 TI - Production of biomass and lipid by the microalgae Chlorella protothecoides with heterotrophic-Cu(II) stressed (HCuS) coupling cultivation. AB - This work for the first time investigated lipid accumulation by a two-stage regime namely heterotrophic-Cu(II) stressed (HCuS) and underlying molecular basis of lipid biosynthesis in Chlorella protothecoides cells. The results showed that the optimized biomass and lipid yield were achieved by 6.47 g/L and 5.78 g/L with this strategy. The fatty acids compositions (almost 100% of them are C15 to C20) are ideal for preparing high quality biodiesel. Further, 30 differentially expressed proteins response to HCuS were involved in carbohydrate metabolism, carbon fixation, TCA cycle, lipid metabolism, protein biosynthesis, transportation and regulation, ATP and RNA biosynthesis, nucleotide metabolism, ROS scavenging. Especially, glycolysis pathway might be the important contributor for lipid accumulation. In future, further functional analysis of these altered proteins would help to reveal more concerning lipid biosynthesis pathway. PMID- 24055972 TI - Co-composting of eggshell waste in self-heating reactors: monitoring and end product quality. AB - Industrial eggshell waste (ES) is classified as an animal by-product not intended to human consumption. For reducing pathogen spreading risk due to soil incorporation of ES, sanitation by composting is a pre-treatment option. This work aims to evaluate eggshell waste recycling in self-heating composting reactors and investigate ES effect on process evolution and end product quality. Potato peel, grass clippings and rice husks were the starting organic materials considered. The incorporation of 30% (w/w) ES in a composting mixture did not affect mixture biodegradability, nor its capacity to reach sanitizing temperatures. After 25 days of composting, ES addition caused a nitrogen loss of about 10 g N kg(-1) of initial volatile solids, thus reducing nitrogen nutritional potential of the finished compost. This study showed that a composting mixture with a significant proportion of ES (30% w/w) may be converted into calcium-rich marketable compost to neutralize soil acidity and/or calcium deficiencies. PMID- 24055973 TI - Techno-economic analysis for brewer's spent grains use on a biorefinery concept: the Brazilian case. AB - A techno-economic analysis for use of brewer's spent grains (BSG) on a biorefinery concept for the Brazilian case is presented. Four scenarios based on different levels of heat and mass integration for the production of xylitol, lactic acid, activated carbon and phenolic acids are shown. A simulation procedure using the software Aspen Plus and experimental yields was used. Such procedure served as basis for the techno-economic and environmental assessment according to the Brazilian conditions. Full mass integration on water and full energy integration was the configuration with the best economic and environmental performance. For this case, the obtained economic margin was 62.25%, the potential environmental impact was 0.012 PEI/kg products, and the carbon footprint of the processing stage represented 0.96 kg CO2-e/kg of BSG. This result served as basis to draw recommendations on the technological, economic and environmental feasibility for implementation of such type of biorefinery in Brazil. PMID- 24055974 TI - In silico and experimental methods revealed highly diverse bacteria with quorum sensing and aromatics biodegradation systems--a potential broad application on bioremediation. AB - Phylogenetic overlaps between aromatics-degrading bacteria and acyl-homoserine lactone (AHL) or autoinducer (AI) based quorum-sensing (QS) bacteria were evident in literatures; however, the diversity of bacteria with both activities had never been finely described. In-silico searching in NCBI genome database revealed that more than 11% of investigated population harbored both aromatic ring hydroxylating-dioxygenase (RHD) gene and AHL/AI-synthetase gene. These bacteria were distributed in 10 orders, 15 families, 42 genus and 78 species. Horizontal transfers of both genes were common among them. Using enrichment and culture dependent method, 6 Sphingomonadales and 4 Rhizobiales with phenanthrene- or pyrene-degrading ability and AHL-production were isolated from marine, wetland and soil samples. Thin-layer-chromatography and gas-chromatography-mass-spectrum revealed that these Sphingomonads produced various AHL molecules. This is the first report of highly diverse bacteria that harbored both aromatics-degrading and QS systems. QS regulation may have broad impacts on aromatics biodegradation, and would be a new angle for developing bioremediation technology. PMID- 24055975 TI - Exploring microbial succession and diversity during solid-state fermentation of Tianjin duliu mature vinegar. AB - Tianjin duliu mature vinegar was one of famous Chinese traditional vinegars. The unique flavor and taste of vinegar are mainly generated by the multitudinous microorganisms during fermentation. In this research, the composition and succession of microbial communities in the entire solid-state fermentation were investigated, including starter daqu and acetic acid fermentation (AAF). Molds and yeasts in daqu, including Aspergillus, Saccharomycopsis and Pichia, decreased in AAF. The bacterial compositions increased from four genera in daqu to more than 13 genera in AAF. Principal component analysis showed that Acetobacter, Gluconacetobacter, Lactobacillus and Nostoc were dominant bacteria that were correlated well with AAF process. In the early fermentation period, lactic acid bacteria (LAB) decreased while acetic acid bacteria and Nostoc increased rapidly with the accumulation of total acids. Then, the abundance and diversity of LAB increased (more than 80%), indicating that LAB had important influences on the flavor and taste of vinegar. PMID- 24055976 TI - Inhibition of free ammonia to the granule-based enhanced biological phosphorus removal system and the recoverability. AB - The inhibition of free ammonia (FA) to the granule-based enhanced biological phosphorus removal (EBPR) system and the recoverability from macro- to micro scale were investigated in this study. FA was found to seriously deteriorate the EBPR performance and sludge characteristic (settleability and morphology). The FA inhibitory threshold of 17.76 mg NL(-1) was established. Acclimation phenomenon took place when poly-phosphate accumulating organisms (PAOs) were exposed for long time to constant FA concentration (8.88 mg NL(-1)). The repressed polysaccharides excretion could lead to breaking the stability and integrity of the granules. Therefore, the reduced particle size and granule disintegration were observed. The molecular analysis revealed that FA had a significant influence on the microbial communities and FA inhibition may provide a competitive advantage to glycogen accumulating organisms (GAOs) over PAOs. Interestingly, the community composition was found irreversible by recovery (Dice coefficients, 36.3%), although good EBPR performance was re-achieved. PMID- 24055977 TI - Cerebral blood flow and apoptosis-associated factor with electroacupuncture in a traumatic brain injury rat model. AB - OBJECTIVE: Electroacupuncture (EA) has been widely used for treatment of stroke, but there is little information on the effect of EA on the neuroprotective function in traumatic brain injury (TBI). The aim of the present study was to investigate the protective effects and mechanisms of EA treatment in a TBI rat model. METHODS: Male Sprague-Dawley rats were randomly divided into four groups: sham operation, TBI control, TBI+EA treated for 30 min or TBI+EA treated for 60 min. The animals were treated with EA immediately after TBI. The EA was applied at acupuncture points GV20, GV26, LI4 and KI1 with a dense-dispersed wave, frequencies of 0.2 and 1 Hz, and amplitude of 1 mA for 30 or 60 min. Regional blood flow, cell infarction volume, extent of neuronal apoptosis, expression of cell apoptosis-associated factor transforming growth-interacting factor (TGIF) were studied, and functional outcome was assessed by running speed test. All tests except regional blood flow were performed 72 h after TBI onset. RESULTS: Immediately after TBI, compared with the TBI control groups, the regional blood flow was significantly increased by EA treatment for 60 min. Compared with the TBI controls 72 h after TBI, the TBI-induced run speed impairment, infarction volume, neuronal apoptosis and apoptosis-associated TGIF expression were significantly improved by EA treatment. CONCLUSIONS: The treatment of TBI in the acute stage with EA for 60 min could increase the regional blood flow and attenuate the levels of TGIF in the injured cortex, might lead to a decrease in neuronal apoptosis and cell infarction volume, and might represent one mechanism by which functional recovery may occur. PMID- 24055978 TI - The spatial diamond-graphite transition in detonation nanodiamond as revealed by small-angle neutron scattering. AB - A spatial transition of the carbon state in detonation nanodiamond (DND) from crystalline diamond inside the particle to a graphite-like state at the DND surface is proposed on the basis of small-angle neutron scattering (SANS) analysis. The SANS contrast variation from concentrated (5 wt%) dispersions of DND in liquids (water, dimethylsulfoxide) reveals a shift in the mean scattering length density of DND as compared to pure diamond, which is related to the presence of a non-diamond component in the DND structure. At the same time, the diffusive character of the particle surface is deduced based on the deviation from the Porod law. The two observations are combined to conclude that the continuous radial density profile over the whole particle volume conforms to a simple power law. The profile naturally suggests that non-diamond states are concentrated mainly close to the particle surface; still there is no sharp boundary between the radial distributions of the two states of carbon in DND. PMID- 24055979 TI - Mitochondrial permeability transition pore is a potential drug target for neurodegeneration. AB - Mitochondrial permeability transition pore (mPTP) plays a central role in alterations of mitochondrial structure and function leading to neuronal injury relevant to aging and neurodegenerative diseases including Alzheimer's disease (AD). mPTP putatively consists of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocator (ANT) and cyclophilin D (CypD). Reactive oxygen species (ROS) increase intra-cellular calcium and enhance the formation of mPTP that leads to neuronal cell death in AD. CypD-dependent mPTP can play a crucial role in ischemia/reperfusion injury. The interaction of amyloid beta peptide (Abeta) with CypD potentiates mitochondrial and neuronal perturbation. This interaction triggers the formation of mPTP, resulting in decreased mitochondrial membrane potential, impaired mitochondrial respiration function, increased oxidative stress, release of cytochrome c, and impaired axonal mitochondrial transport. Thus, the CypD-dependent mPTP is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of AD. Designing small molecules to block this interaction would lessen the effects of Abeta neurotoxicity. This review summarizes the recent progress on mPTP and its potential therapeutic target for neurodegenerative diseases including AD. PMID- 24055980 TI - MitoQ, a mitochondria-targeted antioxidant, delays disease progression and alleviates pathogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. AB - Oxidative stress and mitochondrial dysfunction are involved in the progression and pathogenesis of multiple sclerosis (MS). MitoQ is a mitochondria-targeted antioxidant that has a neuroprotective role in several mitochondrial and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Here we sought to determine the possible effects of a systematic administration of MitoQ as a therapy, using an experimental autoimmune encephalomyelitis (EAE) mouse model. We studied the beneficial effects of MitoQ in EAE mice that mimic MS like symptoms by treating EAE mice with MitoQ and pretreated C57BL6 mice with MitoQ plus EAE induction. We found that pretreatment and treatment of EAE mice with MitoQ reduced neurological disabilities associated with EAE. We also found that both pretreatment and treatment of the EAE mice with MitoQ significantly suppressed inflammatory markers of EAE, including the inhibition of inflammatory cytokines and chemokines. MitoQ treatments reduced neuronal cell loss in the spinal cord, a factor underlying motor disability in EAE mice. The neuroprotective role of MitoQ was confirmed by a neuron-glia co culture system designed to mimic the mechanism of MS and EAE in vitro. We found that axonal inflammation and oxidative stress are associated with impaired behavioral functions in the EAE mouse model and that treatment with MitoQ can exert protective effects on neurons and reduce axonal inflammation and oxidative stress. These protective effects are likely via multiple mechanisms, including the attenuation of the robust immune response. These results suggest that MitoQ may be a new candidate for the treatment of MS. PMID- 24055982 TI - Dietary dilemmas, delusions, and decisions. AB - One of the most frequent questions gastroenterologists are asked about is diet, health, and disease; and some of the questions gastroenterologists are least comfortable answering are about diet, health, and disease. This disconnect occurs for several reasons. Although the subject of nutrition is taught in medical school, it usually covers malabsorption of nutrients, vitamins, and minerals that have limited relevance to the concerns of most patients. The modern physician does not see many cases of scurvy or beri beri. Physicians make decisions and recommendations from evidence-based medicine. Unfortunately, there is a dearth of sound data on diet and gastrointestinal diseases, forcing physicians to operate outside their comfort zone. PMID- 24055981 TI - Articular cartilage-derived cells hold a strong osteogenic differentiation potential in comparison to mesenchymal stem cells in vitro. AB - Cartilaginous matrix-degenerative diseases like osteoarthritis (OA) are characterized by gradual cartilage erosion, and also by increased presence of cells with mesenchymal stem cell (MSC) character within the affected tissues. Moreover, primary chondrocytes long since are known to de-differentiate in vitro and to be chondrogenically re-differentiable. Since both findings appear to conflict with each other, we quantitatively assessed the mesenchymal differentiation potential of OA patient cartilage-derived cells (CDC) towards the osteogenic and adipogenic lineage in vitro and compared it to that of MSC isolated from adipose tissue (adMSC) of healthy donors. We analyzed expression of MSC markers CD29, CD44, CD105, and CD166, and, following osteogenic and adipogenic induction in vitro, quantified their expression of osteogenic and adipogenic differentiation markers. Furthermore, CDC phenotype and proliferation were monitored. We found that CDC exhibit an MSC CD marker expression pattern similar to adMSC and a similar increase in proliferation rate during osteogenic differentiation. In contrast, the marked reduction of proliferation observed during adipogenic differentiation of adMSC was absent in CDC. Quantification of differentiation markers revealed a strong osteogenic differentiation potential for CDC, however almost no capacity for adipogenic differentiation. Since in the pathogenesis of OA, cartilage degeneration coincides with high bone turnover rates, the high osteogenic differentiation potential of OA patient-derived CDC may affect clinical therapeutic regimens aiming at autologous cartilage regeneration in these patients. PMID- 24055983 TI - Zenker's Diverticulum. AB - Zenker's diverticulum (ZD) is an outpouching of tissue through the Killian triangle that is believed to be caused by dysfunction of the cricopharyngeal muscle. ZD is a relatively uncommon disorder occurring in the elderly. The predominant symptom of ZD is dysphagia, and the most serious consequence is pulmonary aspiration. Videofluoroscopy confirms the diagnosis. Therapy of symptomatic ZD has evolved from an open surgical approach to less invasive transoral endoscopic techniques. Transoral endoscopic therapy using rigid instruments is performed primarily by otorhinolaryngologists, whereas transoral therapy using flexible endoscopes is performed by surgical endoscopists and gastroenterologists. The common goal of all modalities is severing of the septum between the esophageal lumen and the diverticulum containing the cricopharyngeal muscle. Although flexible endoscopic therapy was described nearly 20 years ago, it has experienced a recent resurgence paralleling the advancements of therapeutic endoscopy in other areas, such as endoscopic submucosal dissection. Direct head-to-head comparisons of rigid and flexible endoscopic therapy are lacking, and each approach has variations in techniques as well as advantages and disadvantages. In this article, we review the pathophysiology and management of patients with ZD with an emphasis on flexible endoscopic therapy. PMID- 24055984 TI - A rare cause of protein-losing enteropathy. PMID- 24055985 TI - Accuracy of spleen stiffness measurement in detection of esophageal varices in patients with chronic liver disease: systematic review and meta-analysis. AB - BACKGROUND & AIMS: Spleen stiffness measurement (SSM) is a promising noninvasive alternative to esophagogastroduodenoscopy (EGD) that could be used in the diagnosis of esophageal varices (EV) in patients with cirrhosis. However, its overall diagnostic accuracy in various clinical settings is unknown. We conducted a systematic review and meta-analysis of studies that compared the accuracy of SSM with that of EGD in detecting EV in patients with chronic liver disease. METHODS: Through a systematic search of bibliographic databases and conference proceedings, and contact with authors, we identified 12 studies that reported the accuracy of SSM, compared with EGD, in the diagnosis of any and/or clinically significant EV in adults with chronic liver disease. In a meta-analysis, we combined measures of test performance of individual studies. RESULTS: Based on pooled estimates, SSM detected the presence of any EV with 78% sensitivity (95% confidence interval [CI], 75%-81%), 76% specificity (95% CI, 72%-79%), a positive likelihood ratio (LR) of 3.4 (95% CI, 2.3-4.9), a negative LR of 0.2 (95% CI, 0.1 0.4), and a diagnostic odds ratio of 19.3 (95% CI, 7.5-49.8). In a meta-analysis of 9 studies, SSM detected the presence of clinically significant EV with 81% sensitivity (95% CI, 76%-86%), 66% specificity (95% CI, 61%-69%), a positive LR of 2.5 (95% CI, 1.7-3.9), a negative LR of 0.2 (95% CI, 0.1-0.5), and a diagnostic odds ratio of 12.6 (95% CI, 5.5-28.7). There was significant heterogeneity among studies owing to differences in elastography techniques and study locations. The included studies that were at risk for spectrum bias, review bias, and disease progression bias. CONCLUSIONS: Based on a meta-analysis, current techniques for measuring spleen stiffness are limited in their accuracy of EV diagnosis; these limitations preclude widespread use in clinical practice at this time. PMID- 24055986 TI - Fecal calprotectin: controlling the cost of care. PMID- 24055988 TI - Minimally invasive transcriptome profiling in salmon: detection of biological response in rainbow trout caudal fin following exposure to environmental chemical contaminants. AB - An increasing number of anthropogenic chemicals have demonstrated potential for disruption of biological processes critical to normal growth and development of wildlife species. Both anadromous and freshwater salmon species are at risk of exposure to environmental chemical contaminants that may affect migratory behavior, environmental fitness, and reproductive success. A sensitive metric in determination of the presence and impact of such environmental chemical contaminants is through detection of changes in the status of gene transcript levels using a targeted quantitative real-time polymerase chain reaction assay. Ideally, the wildlife assessment strategy would incorporate conservation-centered non-lethal practices. Herein, we describe the development of such an assay for rainbow trout, Oncorhynchus mykiss, following an acute 96 h exposure to increasing concentrations of either 17alpha-ethinyl estradiol or cadmium. The estrogenic screen included measurement of mRNA encoding estrogen receptor alpha and beta isoforms, vitellogenin, vitelline envelope protein gamma, cytochrome p450 family 19 subfamily A, aryl hydrocarbon receptor, and the stress indicator, catalase. The metal exposure screen included evaluation of the latter two mRNA transcripts along with those encoding the metallothionein A and B isoforms. Exposure-dependent transcript abundance profiles were detected in both liver and caudal fin supporting the use of the caudal fin as a non-lethally obtained tissue source. The potential for both transcriptome profiling and genotypic sex determination from fin biopsy was extended, in principle, to field-captured Chinook salmon (Oncorhynchus tshawytscha). PMID- 24055989 TI - Multibiomarker responses upon exposure to tetrabromobisphenol A in the freshwater fish Carassius auratus. AB - Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant. It has been released into aquatic environments, where it is toxic to aquatic organisms. In the present study, five enzymes, glutathione-S-transferase (GST), aspartate aminotransferase (AST), alanine aminotransferase (ALT), UDP glucuronosyltransferase (UDPGT), and the antioxidant enzyme glutathione reductase (GR) in serum and liver of crucian carp (Carassius auratus) were selected for screening. These enzymes may be suitable for use as early warning indicators of chronic TBBPA exposure. UDPGT, AST, ALT, and GR activities in serum were found to be as more sensitive to TBBPA as those of the liver. When the concentration of TBBPA exceeded 0.50-0.71 mg/L for an exposure period of 32 days, GST, AST, ALT, and UDPGT activities cannot be restored to normal levels, suggesting that fish exposed to TBBPA above this threshold may incur irreversible damage. The activities of AST, ALT, and GR increased more significantly than GST and UDPGT at the lowest concentration of 0.35 mg/L. AST showed the strongest activity with respect to toxic kinetics, followed by ALT and GR. This remained true from day 4 of exposure to TBBPA to day 32. However, GR showed the clearest and most significant dose-effect relationship. This shows that each of these three enzymes can be used as a biomarker for early warning applications focusing on TBBPA pollution. AST and ALT are suitable for use in conventional monitoring of water quality in areas at risk for TBBPA pollution, and GR is more suitable for use in burst TBBPA pollution accidents where GR activity in fish would change with the TBBPA concentration of the flowing water. PMID- 24055987 TI - Liver masses: a clinical, radiologic, and pathologic perspective. AB - Liver masses present a relatively common clinical dilemma, particularly with the increasing use of various imaging modalities in the diagnosis of abdominal and other symptoms. The accurate and reliable determination of the nature of the liver mass is critical, not only to reassure individuals with benign lesions but also, and perhaps more importantly, to ensure that malignant lesions are diagnosed correctly. This avoids the devastating consequences of missed diagnosis and the delayed treatment of malignancy or the unnecessary treatment of benign lesions. With appropriate interpretation of the clinical history and physical examination, and the judicious use of laboratory and imaging studies, the majority of liver masses can be characterized noninvasively. Accurate characterization of liver masses by cross-sectional imaging is particularly dependent on an understanding of the unique phasic vascular perfusion of the liver and the characteristic behaviors of different lesions during multiphasic contrast imaging. When noninvasive characterization is indeterminate, a liver biopsy may be necessary for definitive diagnosis. Standard histologic examination usually is complemented by immunohistochemical analysis of protein biomarkers. Accurate diagnosis allows the appropriate selection of optimal management, which is frequently reassurance or intermittent follow-up evaluations for benign masses. For malignant lesions or those at risk of malignant transformation, management depends on the tumor staging, the functional status of the uninvolved liver, and technical surgical considerations. Unresectable metastatic masses require oncologic consultation and therapy. The efficient characterization and management of liver masses therefore requires a multidisciplinary collaboration between the gastroenterologist/hepatologist, radiologist, pathologist, hepatobiliary or transplant surgeon, and medical oncologist. PMID- 24055990 TI - Are we in the dark ages of environmental toxicology? AB - Environmental toxicity is judged to be in a "dark ages" period due to longstanding limitations in the implementation of the simple conceptual model that is the basis of current aquatic toxicity testing protocols. Fortunately, the environmental regulatory revolution of the last half-century is not substantially compromised as development of past regulatory guidance was designed to deal with limited amounts of relatively poor quality toxicity data. However, as regulatory objectives have substantially increased in breadth and depth, aquatic toxicity data derived with old testing methods are no longer adequate. In the near-term explicit model description and routine assumption validation should be mandatory. Updated testing methods could provide some improvements in toxicological data quality. A thorough reevaluation of toxicity testing objectives and methods resulting in substantially revised standard testing methods, plus a comprehensive scheme for classification of modes/mechanisms of toxic action, should be the long term objective. PMID- 24055991 TI - A new questionnaire to assess endorsement of normative ethics in primary health care: development, reliability and validity study. AB - BACKGROUND: Assessing ethical endorsement is crucial to the study of professional performance and moral conduct. There are no specific instruments that verify patients and professional experiences of ethical practice in the specific area of primary health care (PHC). OBJECTIVE: To study the psychometric properties of two questionnaires to identify professional and patient endorsement of normative ethics. METHODS: A methodological study conducted in PHC centres from an urban area (Barcelona). A group of items from an ethical code were generated using a qualitative study with focus groups. Items underwent expert validation, item refinement and test-retest reliability. Two groups of items for PHC professionals and patients were validated. The structure of the constructs and the internal consistency were studied after participants completed the questionnaires. Principal component analysis with supplementary variables showed the utility of the validated questionnaires. RESULTS: The patients' questionnaire consisted of 17 general items plus 11 additional items on specific conditions, and the health professional's contained 24 general and 9 specific items. The construct of the questionnaires comprised a three-factor solution for patients and a five-factor solution for professionals. Principal component analysis with supplementary variables showed that patients with higher scores on ethical perception were associated with better opinions on health care quality and more confidence in professionals. In PHC professionals, higher scores were associated with effective knowledge of the code. CONCLUSIONS: Both questionnaires showed good psychometric properties and are valid to screen ethical attitudes. The instrument warrants further testing and use with culturally diverse patients and PHC professionals. PMID- 24055992 TI - Knowledge of Dutch GPs in caring for cancer patients using oral anticancer therapy at home. AB - BACKGROUND: The GP's role in cancer care is changing and will become increasingly important. One of the challenges for GPs in caring for cancer patients is their lack of specialized knowledge and the impossibility to keep up to date with developments in the field of oncology. We investigated GPs use of knowledge in the case of the increasing use of oral anticancer therapy at home. OBJECTIVE: The objective of the study was to find out the needs for knowledge improvement for GPs in caring for cancer patients at home, by analysing what kinds of knowledge Dutch GPs use and the ways they obtain knowledge in their daily practice of caring for patients using oral anticancer therapy at home. METHODS: Semi structured in-depth interviews were conducted between July and November 2011 with 15 Dutch GPs. A thematic analysis of interview transcripts was conducted. RESULTS: GPs recognize their lack of specialized knowledge and their inability to keep up to date with developments in the field of oncology. The analysis shows that GPs use different kinds of knowledge and skills they already have to care for their patients and obtain valuable knowledge about oral anticancer therapy via and from their patients. CONCLUSION: Apart from formal training, GPs may be supported to strengthen the strategies they already use, i.e. to actively mobilize different types and sources of knowledge and use the patient as a source of knowledge in caring for oncology patients at home. PMID- 24055993 TI - The costs of identifying undiagnosed prostate cancer in asymptomatic men in New Zealand general practice. AB - BACKGROUND: Screening for prostate cancer (PCa) using the prostate-specific antigen (PSA) test is widespread in New Zealand. Aim. This study estimates the costs of identifying a new case of PCa by screening asymptomatic men. METHODS: Men aged 40+, who had PSA tests in 31 general practices in the Midland Cancer Network region during 2010, were identified. Asymptomatic men without a history of PCa were eligible for this study. A decision tree was constructed to estimate the screening costs. We assumed GPs spent 3 minutes of the initial consultation on informed consent of PCa screening. RESULTS: About 70.7% of the estimated costs were incurred in general practice. The screening costs per cancer detected were NZ$10 777 (?5820; L4817). The estimated costs for men aged 60-69 were NZ$6268 compared to NZ$24 290 for men aged 40-49, NZ$30 022 for 50-59 and NZ$10 957 for those aged 70+. The costs for Maori were NZ$7685 compared to NZ$11 272 for non Maori. The costs for men without PSA testing history in 2007-09 were NZ$8887 compared to NZ$13 870 if the men had PSA tests in 2007-09. If we assumed a PSA test involved a full 15-minute general practice consultation, the estimated costs increased to NZ$26 877 per PCa identified. CONCLUSIONS: Screening of asymptomatic men for PCa is widely practiced. Most of the costs of screening were incurred in general practice. Calls for men to receive increased information on the harms and benefits of screening will substantially increase the costs. The current costs could be reduced by better targeting of screening. PMID- 24055994 TI - The human septin7 and the yeast CDC10 septin prevent Bax and copper mediated cell death in yeast. AB - The mechanisms of programmed cell death activate genetically encoded intracellular programs in a controlled manner, the most common form being apoptosis. Apoptosis is carried out through a cascade of caspase mediated proteolytic cleavages initiated by the oligomerization of Bax, a cardinal regulator of mitochondrial-mediated apoptosis. Heterologous expression of Bax in yeast causes cell death that shares a number of similarities to processes that occur in mammalian apoptosis. A screen of a cardiac cDNA library for suppressors of Bax-mediated apoptosis identified human septin7, a protein that belongs to the septin superfamily of conserved GTP-binding proteins that share a conserved cdc/septin domain. Analysis of the amino acid sequence deduced from the septin7 clone as well as the corresponding human septin7 gene revealed that a novel alternatively spliced transcript called septin7 variant4 (v4) was uncovered. Yeast cells overexpressing the human septin7 v4 cDNA were also capable of resisting copper-mediated cell death suggesting that it is not only a Bax suppressor but also an anti-apoptotic sequence. Analysis of septin7 function in a MCA1Delta yeast strain suggests that septin7 inhibits apoptosis in a caspase independent pathway. Overexpression of the yeast septin7 ortholog CDC10 also conferred resistance to the negative effects of copper as well as protecting cells from the overexpression of Bax. In contrast, septin7 was unable to prevent the increase in cell size associated with mutants lacking the endogenous yeast CDC10 gene. Taken together, our analysis suggests that anti-apoptosis is a novel yet evolutionarily conserved property of the septin7 sub-family of septins. PMID- 24055995 TI - Lipid rafts control human melanoma cell migration by regulating focal adhesion disassembly. AB - Tumor cell migration is a crucial step in the metastatic cascade, and interruption of this step is considered to be logically effective in preventing tumor metastasis. Lipid rafts, distinct liquid ordered plasma membrane microdomains, have been shown to influence cancer cell migration, but the underlying mechanisms are still not well understood. Here, we report that lipid rafts regulate the dynamics of actin cytoskeleton and focal adhesion in human melanoma cell migration. Disrupting the integrity of lipid rafts with methyl-beta cyclodextrin enhances actin stress fiber formation and inhibits focal adhesion disassembly, accompanied with alterations in cell morphology. Furthermore, actin cytoskeleton, rather than microtubules, mediates the lipid raft-dependent focal adhesion disassembly by regulating the dephosphorylation of focal adhesion proteins and the internalization of beta3 integrin. We also show that Src-RhoA Rho kinase signaling pathway is responsible for lipid raft disruption-induced stress fiber formation. Taken together, these observations provide a new mechanism to further explain how lipid rafts regulate the migration of melanoma cell and suggest that lipid rafts may be novel and attractive targets for cancer therapy. PMID- 24055996 TI - Electrochemical impedance spectroscopy as a method for electrical characterization of the bilayers formed from lipid-amino acid systems. AB - Bilayer lipid membranes composed of phosphatidylcholine and isoleucine or phosphatidylcholine and tyrosine were investigated using electrochemical impedance spectroscopy. Interaction between membrane components causes significant deviations from the additivity rule which can be explained by formation of the domain structures. The surface area of domains was calculated based on derived equations. We suggest that the stoichiometry of phosphatidylcholine-isoleucine domain is equal 3:1. In the case of tyrosine modified phosphatidylcholine membranes, domain with stoichiometry 7:1 should be taken into consideration. PMID- 24055997 TI - Adverse effects of diisooctyl phthalate on the male rat reproductive development following prenatal exposure. AB - In a first study, rats were given diisooctyl phthalate (DIOP, CAS 27554-26-3) at 0, 0.1, 0.5, and 1g/kg/day, by gavage, on gestation days 6-20 (GD). There was a significant increase in resorptions at 1g/kg/day and a reduction in fetal weights at 0.5 and 1g/kg/day. Malpositioned testes were observed in fetuses at 1g/kg/day, and supernumerary lumbar ribs and ossification delay at 0.5 and 1g/kg/day. In a follow-up study, DIOP administered on GD 12-19 reduced fetal testicular testosterone at 0.1g/kg/day and above. Finally, postnatal reproductive assessment was conducted in adult male offspring prenatally exposed to DIOP on GD 12-21. Abnormalities of reproductive system (e.g. hypospadias, non scrotal testes, and hypospermatogenesis) were observed in a few adult males at 0.5g/kg/day, and with a high incidence at 1g/kg/day. Thus, DIOP displayed an antiandrogenic activity and disrupted the male reproductive development. PMID- 24055999 TI - Trace elemental analysis of Indian natural moonstone gems by PIXE and XRD techniques. AB - A selected number of Indian Eastern Ghats natural moonstone gems were studied with a powerful nuclear analytical and non-destructive Proton Induced X-ray Emission (PIXE) technique. Thirteen elements, including V, Co, Ni, Zn, Ga, Ba and Pb, were identified in these moonstones and may be useful in interpreting the various geochemical conditions and the probable cause of their inceptions in the moonstone gemstone matrix. Furthermore, preliminary XRD studies of different moonstone patterns were performed. The PIXE technique is a powerful method for quickly determining the elemental concentration of a substance. A 3MeV proton beam was employed to excite the samples. The chemical constituents of moonstones from parts of the Eastern Ghats geological formations of Andhra Pradesh, India were determined, and gemological studies were performed on those gems. The crystal structure and the lattice parameters of the moonstones were estimated using X-Ray Diffraction studies, trace and minor elements were determined using the PIXE technique, and major compositional elements were confirmed by XRD. In the present work, the usefulness and versatility of the PIXE technique for research in geo-scientific methodology is established. PMID- 24055998 TI - Rationale and design of a randomized trial of home electronic symptom and lung function monitoring to detect cystic fibrosis pulmonary exacerbations: the early intervention in cystic fibrosis exacerbation (eICE) trial. AB - BACKGROUND: Acute pulmonary exacerbations are central events in the lives of individuals with cystic fibrosis (CF). Pulmonary exacerbations lead to impaired lung function, worse quality of life, and shorter survival. We hypothesized that aggressive early treatment of acute pulmonary exacerbation may improve clinical outcomes. PURPOSE: Describe the rationale of an ongoing trial designed to determine the efficacy of home monitoring of both lung function measurements and symptoms for early detection and subsequent early treatment of acute CF pulmonary exacerbations. STUDY DESIGN: A randomized, non-blinded, multi-center trial in 320 individuals with CF aged 14 years and older. The study compares usual care to a twice a week assessment of home spirometry and CF respiratory symptoms using an electronic device with data transmission to the research personnel to identify and trigger early treatment of CF pulmonary exacerbation. Participants will be enrolled in the study for 12 months. The primary endpoint is change in FEV1 (L) from baseline to 12 months determined by a linear mixed effects model incorporating all quarterly FEV1 measurements. Secondary endpoints include time to first acute protocol-defined pulmonary exacerbation, number of acute pulmonary exacerbations, number of hospitalization days for acute pulmonary exacerbation, time from the end of acute pulmonary exacerbation to onset of subsequent pulmonary exacerbation, change in health related quality of life, change in treatment burden, change in CF respiratory symptoms, and adherence to the study protocol. CONCLUSIONS: This study is a first step in establishing alternative approaches to the care of CF pulmonary exacerbations. We hypothesize that early treatment of pulmonary exacerbations has the potential to slow lung function decline, reduce respiratory symptoms and improve the quality of life for individuals with CF. PMID- 24056000 TI - Model simulation of inflow water to the Baltic Sea based on 129I. AB - The semi-enclosed Baltic Sea represents a vital economic and recreational resource for more than 90 million people inhabiting its coasts. Extensive contamination of this sea by a variety of anthropogenic pollutants has raised the concern of the people in the region. Quantifying seawater inflow is crucial for estimating potential environmental risks as well as to find the best remedial strategy. We present here a model to estimate water inflow from the North Sea to the Baltic Sea by utilizing 129I as a tracer. The results predicted inflow range of 230-450 km3/y with best fit value around 330 km3/y from the North Sea to the Baltic Sea during 1980-1999. Despite limited time series data on 129I, the model presented here demonstrates a new management tool for the Baltic Sea to calculate inflow water compared to conventional methods (such as salinity, temperature and hydrographic models). PMID- 24056001 TI - Influence of metal ions on the 68Ga-labeling of DOTATATE. AB - The influence of metal cations (Fe3+, Fe2+, In3+, Cu2+, Ca2+, Al3+, Co2+, Lu3+, Ni2+, Pb2+, Ti4+, Y3+, Yb3+, Zn2+, and Zr4+) on the radiolabeling yield of [68Ga(DOTATATE)] was evaluated. Our most important observation was that, within our experimental limit, the metal ion/ligand ratio plays a critical role on the influence of most metal ions. More in-depth studies, with Cu2+ and Fe3+, revealed that reaction temperature and concentration changes have little effect, but speciation changes with pH are crucial. Furthermore, we found that [68Ga(DOTATATE)] is stable in the presence of high concentrations of Fe3+, Zn2+ and Pb2+, but transmetalates with Cu2+ at 95 degrees C. PMID- 24056002 TI - Gold intercalation of boron-doped graphene on Ni(111): XPS and DFT study. AB - The intercalation of a graphene layer adsorbed on a metal surface by gold or other metals is a standard procedure. While it was previously shown that pristine, i.e., undoped, and nitrogen-doped graphene sheets can be decoupled from a nickel substrate by intercalation with gold atoms in order to produce quasi free-standing graphene, we find the gold intercalation behavior for boron-doped graphene on a Ni(111) surface to be more complex: for low boron contents (2-5%) in the graphene lattice only partial gold intercalation occurs and for higher boron contents (up to 20%) no intercalation is observed. In order to understand this different behavior, a density functional theory investigation is carried out, comparing undoped as well as substitutional nitrogen- and boron-doped graphene on Ni(111). We identify the stronger binding of the boron atoms to the nickel substrate as the factor responsible for the different intercalation behavior in the case of boron doping. However, the calculations predict that this energetic effect prevents the intercalation process only for large boron concentrations and that it can be overcome for smaller boron coverages, in line with our x-ray photoelectron spectroscopy experiments. PMID- 24056003 TI - Using weighted entropy to rank chemicals in quantitative high-throughput screening experiments. AB - Quantitative high-throughput screening (qHTS) experiments can simultaneously produce concentration-response profiles for thousands of chemicals. In a typical qHTS study, a large chemical library is subjected to a primary screen to identify candidate hits for secondary screening, validation studies, or prediction modeling. Different algorithms, usually based on the Hill equation logistic model, have been used to classify compounds as active or inactive (or inconclusive). However, observed concentration-response activity relationships may not adequately fit a sigmoidal curve. Furthermore, it is unclear how to prioritize chemicals for follow-up studies given the large uncertainties that often accompany parameter estimates from nonlinear models. Weighted Shannon entropy can address these concerns by ranking compounds according to profile specific statistics derived from estimates of the probability mass distribution of response at the tested concentration levels. This strategy can be used to rank all tested chemicals in the absence of a prespecified model structure, or the approach can complement existing activity call algorithms by ranking the returned candidate hits. The weighted entropy approach was evaluated here using data simulated from the Hill equation model. The procedure was then applied to a chemical genomics profiling data set interrogating compounds for androgen receptor agonist activity. PMID- 24056004 TI - The omentum and omentectomy in epithelial ovarian cancer: a reappraisal. Part I- Omental function and history of omentectomy. AB - OBJECTIVE: This article reviews the literature concerning the function of the omentum and how omentectomy came to be part of the staging and treatment of epithelial ovarian cancer. METHODS: A review of the English language literature based on a MEDLINE (PubMed) database search using the key words: ovary, cancer, carcinoma, omentum, and omentectomy. An additional collection of reports was found by systematically reviewing all references from retrieved papers. RESULTS: Descriptions of the omentum can be found as far back as the time of the ancient Egyptians. An immunologic role of the omentum was confirmed in 1980s when "milky spots" were described. Omentectomy arrived as part of the ovarian cancer guidelines in the 1960s after observing that the omentum was a frequent site of metastasis and that patients with removal of all diseased tissue did better. The exact role of the omentum in immunology and cancer remains incompletely understood. CONCLUSIONS: Historically, occult omental metastases in otherwise early disease have led to the inclusion of omentectomy for the purpose of accurate staging and for a possible therapeutic benefit. Laboratory studies on the role in cancer of the omental fat and milky spots are controversial. PMID- 24056005 TI - The omentum and omentectomy in epithelial ovarian cancer: a reappraisal: part II- The role of omentectomy in the staging and treatment of apparent early stage epithelial ovarian cancer. AB - OBJECTIVE: This article reviews the literature concerning the role of omentectomy in the staging and treatment of clinically apparent early stage epithelial ovarian cancer. METHODS: A review of the English language literature based on a MEDLINE (PubMed) database search using the keywords: ovary, cancer, carcinoma, omentum, and omentectomy. An additional collection of reports was found by systematically reviewing all references from retrieved papers. RESULTS: Historically, the realization that ovarian cancer cells have a predisposition to metastasize to the omentum has led to the inclusion of omentectomy, both for the purpose of accurate staging of ovarian cancer and for its possible therapeutic benefit. In apparently early stage epithelial ovarian cancer, microscopic disease in the omentum is found in 0-22% of the cases; however extra-ovarian disease isolated to the omentum is found in 2-7% of cases at most. There are no specific guidelines as to how much of the omentum should be removed, but pathology studies show that for the purpose of staging and detecting microscopic disease, omental biopsies are probably sufficient in a grossly normal appearing omentum. In cases where adjuvant chemotherapy is planned, the role of omentectomy appears to be primarily for staging, while its therapeutic role remains unclear in microscopic omental disease. CONCLUSIONS: In apparent early stage ovarian cancer, the presence of isolated omental metastases is relatively rare. For staging purposes in such cases, random omental biopsies rather than total omentectomy may suffice. Furthermore, chemotherapy appears to effectively treat microscopic disease and therefore if this is already planned the benefit of omentectomy is unclear. PMID- 24056007 TI - Molecular identification and cellular localization of a potential transport system involved in cystine/cysteine uptake in human lenses. AB - In this study we have sought to identify whether cystine uptake mechanisms previously identified in the rat lens are also found in the human lens. Using a combination of reverse transcriptase PCR, Western blotting and immunohistochemistry, we show that the light chain subunit of the cystine/glutamate exchanger (XC-), xCT, and members of the glutamate transporter family (XAG) which include the Excitatory Amino Acid Transporter 4 (EAAT4) and the Alanine Serine Cysteine Transporter 2 (ASCT2) are all present at the transcript and protein level in human lenses. We demonstrate that in young lenses xCT, EAAT4 and ASCT2 are expressed in all regions indicating that a potential cystine uptake pathway similar to that found in the rat might also exist in human lenses. However, with increasing age, the immunolabeling for all transporters decreases, with no xCT labelling detected in the centre of old donor lenses. Our results show that XC- and EAAT4/ASCT2 may work together to mediate cystine uptake in the lens core of young human lenses. This suggests that the lens contains uptake mechanisms that are capable of accumulating cystine/cysteine in the lens centre where cysteine can be used as an antioxidant or cystine utilised as a source for protein-S-S-cysteine (PSSC) formation to buffer against oxidative stress. With increasing age, transporters in the lens core undergo age dependent post translational modifications. However, despite processing of these transporters with age, our results indicate that this cystine uptake pathway could account for the increased PSSC levels previously observed in the nucleus of older human lenses. PMID- 24056006 TI - Human vaccines & immunotherapeutics: news. AB - Infant rotavirus vaccination provides for herd immunity Nonreplicating sporozoite vaccine protects humans against malaria Personalized brain cancer vaccine enters phase 2 trial Novel implantable therapeutic cancer vaccine to be tested in humans Clostridium difficile vaccine candidate successful in phase 1 CDC reports strong uptake of HPV vaccine in boys Whooping cough outbreak in Texas. PMID- 24056008 TI - Revised structures for the predominant O-polysaccharides expressed by Burkholderia pseudomallei and Burkholderia mallei. AB - O-Polysaccharides (OPS) were isolated from purified Burkholderia pseudomallei and Burkholderia mallei lipopolysaccharides by mild-acid hydrolysis and gel permeation chromatography. 1-D and 2-D (1)H and (13)C NMR spectroscopy experiments revealed that the OPS antigens were unbranched heteropolymers with the following structures: Collectively, our results demonstrate that the predominant OPS antigens expressed by B. pseudomallei and B. mallei isolates are structurally more complex than previously described and provide evidence that different capping residues are used by these closely related pathogens to terminate chain elongation. Additionally, they confirm that Burkholderia thailandensis and B. pseudomallei express OPS antigens that are essentially identical to one another. PMID- 24056009 TI - Glycosylation mediated-BAIL in aqueous solution. AB - The use of Bronsted acid ionic liquid (BAIL) as a catalyst for the activation of unreactive and unprotected glycosyl donors has been demonstrated for the first time in aqueous solution. PMID- 24056010 TI - Characterization of the Ashbya gossypii secreted N-glycome and genomic insights into its N-glycosylation pathway. AB - The riboflavin producer Ashbya gossypii is a filamentous hemiascomycete, closely related to the yeast Saccharomyces cerevisiae, that has been used as a model organism to study fungal developmental biology. It has also been explored as a host for the expression of recombinant proteins. However, although N glycosylation plays important roles in protein secretion, morphogenesis, and the development of multicellular organisms, the N-glycan structures synthesised by A. gossypii had not been elucidated. In this study, we report the first characterization of A. gossypii N-glycans and provide valuable insights into their biosynthetic pathway. By combined matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry profiling and nuclear magnetic resonance (NMR) spectroscopy we determined that the A. gossypii secreted N-glycome is characterized by high-mannose type structures in the range Man4 18GlcNAc2, mostly containing neutral core-type N-glycans with 8-10 mannoses. Cultivation in defined minimal media induced the production of acidic mannosylphosphorylated N-glycans, generally more elongated than the neutral N glycans. Truncated neutral N-glycan structures similar to those found in other filamentous fungi (Man4-7GlcNAc2) were detected, suggesting the possible existence of trimming activity in A. gossypii. Homologs for all of the S. cerevisiae genes known to be involved in the endoplasmatic reticulum and Golgi N glycan processing were found in the A. gossypii genome. However, processing of N glycans by A. gossypii differs considerably from that by S. cerevisiae, allowing much shorter N-glycans. Genes for two putative N-glycan processing enzymes were identified, that did not have homologs in S. cerevisiae. PMID- 24056011 TI - Influence of glucosamine on oligochitosan solubility and antibacterial activity. AB - Light scattering studies indicate that oligochitosan (short-chain chitosan) solutions contain aggregates at pH values below the critical pH of phase separation, while at or above this point the gel phase coexists with the aggregate solution. This work demonstrates for the first time that the presence of D-glucosamine in an oligochitosan solution shifts the critical pH to a higher value and improves the oligochitosan antibacterial activity against Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermis in neutral and slightly alkaline aqueous media. By comparing the results of light scattering studies and antimicrobial assays one can conclude that the antimicrobial activity of oligochitosan is dependent on its unimolecular form, not its supramolecular structures. The widening of the homogeneity region of an oligochitosan solution could lead to promising biomedical applications. PMID- 24056012 TI - Enzyme resistant feruloylated xylooligomer analogues from thermochemically treated corn fiber contain large side chains, ethyl glycosides and novel sites of acetylation. AB - In order to use corn fiber as a source for bioethanol production the enzymatic hydrolysis of the complex glucuronoarabinoxylans present has to be improved. Several oligosaccharides present in the supernatant of mild acid pretreated and enzymatically saccharified corn fiber that resist the current available enzymes were (semi)purified for structural analysis by NMR or ESI-MS(n). The structural features of 21 recalcitrant oligosaccharides are presented. A common feature of almost all these oligosaccharides is that they contain (part of) an alpha-l galactopyranosyl-(1->2)-beta-d-xylopyranosyl-(1->2)-5-O-trans-feruloyl-l arabinofuranose side chain attached to the O-3 position of the beta-1-4 linked xylose backbone. Several of the identified oligosaccharides contained an ethyl group at the reducing end hypothesized to be formed during SSF. The ethyl glycosides found are far more complex than previously described structures. A new feature present in more than half of the oligosaccharides is an acetyl group attached to the O-2 position of the same xylose to which the oligomeric side chain was attached to the O-3 position. Finding enzymes attacking these large side chains and the dense substituted xylan backbone will boost the hydrolysis of corn fiber glucuronoxylan. PMID- 24056013 TI - Biochemical characterization of a new beta-1,3-galactosyltransferase WbuP from Escherichia coli O114 that catalyzes the second step in O-antigen repeating-unit. AB - In this study, synthetic acceptor substrate GlcNAc alpha-PO3-PO3-(CH2)11-O-phenyl (GlcNAc-PP-PhU) was employed in glycosyl transferase assays to characterize the WbuP galactosyltransferase activity. This activity was time- and enzyme concentration-dependent. The optimal enzyme activity was observed at pH 6.5 and 25 degrees C. The enzyme requires Mn(2+) ions for maximal activity and detergents in the assay did not increase glycosyltransfer activity. The enzyme was shown to be specific for the UDP-Gal donor substrate. Kinetic parameters were determined for UDP-Gal, and GlcNAc-PP-PhU. The enzyme product was determined to have a beta 1,3-linkage using strategies based on exoglycosidase digestion combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) as well as collision-induced dissociation electrospray ionization ion trap multiple tandem MS (CID-ESI-IT-MS(n)). Our results conclusively demonstrate that the wbuP gene of Escherichia coli O114 encodes a UDP-Gal: GlcNAc alpha-pyrophosphate-lipid beta-1,3-Gal-transferase that transfers the second sugar moiety in the assembly of the O114 repeating unit. PMID- 24056015 TI - Consensus sequence determination and elucidation of the evolutionary history of a rotavirus Wa variant reveal a close relationship to various Wa variants derived from the original Wa strain. AB - The consensus nucleotide sequence of a human rotavirus Wa strain, with only a partially known passage history, was determined with sequence-independent amplification and next generation 454(r) pyrosequencing. This rotavirus Wa strain had the expected genome constellation of G1-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1 and was designated RVA/Human-tc/USA/WaCS/1974/G1P[8]. Phylogenetic analyses revealed a close relationship to four human rotavirus Wa variants (Wag5re, Wag7/8re, ParWa and VirWa) derived from the original 1974 human isolate. There were rearrangements in the Wag5re- and Wag7/8re variants in genome segments 5 (Wag5re) and 7 and 8 (Wag7/8re), which were not present in WaCS. Pairwise comparisons and a combined molecular clock for the Wa rotavirus genome indicated a close relationship between WaCS and ParWa and VirWa. These results suggest that WaCS is most probably an early cell culture adapted variant from the initial gnotobiotic pig passaged Wa isolate. Evolutionary pressure analysis identified a possible negative selected amino acid site in VP1 (genome segment 1) and a likely positive selected site in VP4 (genome segment 4). The WaCS may be more appropriate as a rotavirus Wa reference sequence than the current composite Wa reference genome. PMID- 24056016 TI - Global gene expression changes in BV2 microglial cell line during rabies virus infection. AB - Microglia plays a crucial role during virus pathogenesis in the central nervous system (CNS). Infection by rabies virus (RABV) causes a fatal infection in the CNS of all warm-blooded animals. However, the microglial responses to RABV infection have been scarcely reported. To better understand microglia-RABV interactions at the transcriptional level, a genome wide gene expression profile in mouse microglial cells line BV2 was performed using microarray analysis. The global messenger RNA changes in murine microglial cell line BV2 after 12, 24 and 48 h of infection with rabies virus CVS-11 strain were investigated using DNA Microarray and quantitative real-time PCR. Infection of CVS-11 at different time points induced different gene expression signatures in BV2 cells. The expression patterns of differentially expressed genes are shown by K-means clustering in four clusters in RABV- or mock-infected microglia at 12, 24 and 48h post infection (hpi). Gene ontology and network analysis of the differentially expressed genes in responses to RABV were performed by the Ingenuity Pathway Analysis system (IPA, Ingenuity(r) Systems, http://www.ingenuity.com). The results revealed that 28 genes were significantly up-regulated (P<0.01) and 1 gene was significantly down-regulated (P<0.01) in microglial cells at 12hpi, 72 genes were significantly up-regulated (P<0.01) and 24 genes were significantly down-regulated (P<0.01) at 24hpi, and 671 genes were significantly up-regulated (P<0.01) and 190 genes were significantly down-regulated (P<0.01) at 48hpi. Genes in BV2 were significantly regulated (P<0.01) in response to RABV infection and they were found to be interferon stimulated genes (Isg15, Isg20, Oasl1, Oasl2, Ifit2, Irf7 and Ifi203), chemokine genes (Ccl5, Cxcl10 and Ccrl2) and the proinflammatory factor gene (Interleukin 6). The results indicated that the differentially expressed genes from microglial cells after RABV infection were mainly involved in innate immune responses, inflammatory responses and host antiviral responses. PMID- 24056014 TI - Quantifying variation in the potential for antibody-mediated apparent competition among nine genotypes of the rodent malaria parasite Plasmodium chabaudi. AB - Within-host competition among parasite genotypes affects epidemiology as well as the evolution of virulence. In the rodent malaria Plasmodium chabaudi, competition among genotypes, as well as clone-specific and clone-transcending immunity are well documented. However, variation among genotypes in the induction of antibodies is not well understood, despite the important role of antibodies in the clearance of malaria infection. Here, we quantify the potential for antibodies induced by one clone to bind another (i.e., to cause antibody-mediated apparent competition) for nine genetically distinct P. chabaudi clones. We hypothesised that clones would vary in the strength of antibody induction, and that the propensity for clone-transcending immunity between a pair of clones would increase with increasing genetic relatedness at key antigenic loci. Using serum collected from mice 35 days post-infection, we measured titres of antibody to an unrelated antigen, Keyhole Limpet Haemocyanin (KLH), and two malaria antigens: recombinant Apical Membrane Antigen-1 (AMA-1) and Merozoite Surface Protein-119 (MSP-119). Amino acid sequence homology within each antigenic locus was used as a measure of relatedness. We found significant parasite genetic variation for the strength of antibody induction. We also found that relatedness at MSP-119 but not AMA-1 predicted clone-transcending binding. Our results help explain the outcome of chronic-phase mixed infections and generate testable predictions about the pairwise competitive ability of P. chabaudi clones. PMID- 24056017 TI - Tendons: energy managers during movement. PMID- 24056020 TI - Design, synthesis, and in vitro cancer cell growth inhibition evaluation and antimalarial testing of trioxanes installed in cyclic 2-enoate substructures. AB - A novel series of 1,2,4-trioxanes were synthesized from 2H-pyrans via photooxidation, and their antiproliferative and growth factor inhibitory activity has been investigated across a variety of human cancer cell lines. Compounds 5k, 5l, 5s, 7a and 7c exhibited the highest activity and selectivity against a human leukemia (MV4-11) cell line (IC50 = 0.5 MUM). Compound 5o showed the highest growth factor inhibitory activity against a melanoma (LOX-IMVI) cancer cell line (GI50 = 1.0 MUM). A SAR study has confirmed the importance of the 1,2,4-trioxane unit as a pharmacophore for anticancer activity. The computer-assisted database analysis, COMPARE, has suggested that the compounds have unique mechanisms of actions that were different from those of known anticancer drugs. Some of the selected trioxanes were tested against the NF54 strain, albeit showing weak antiplasmodial activity. The molecular docking of trioxanes and hemin reveals that a short distance (1.30 A) leads to their physical contact. The UV-vis spectroscopic analysis ensured the definite complexation between 1,2,4-trioxanes and hemin. The role of hemin-trioxane interaction in the hemin-induced oxidative damage has been studied using methylene blue as a substrate by UV-vis spectroscopy. PMID- 24056021 TI - Hyperactivity within an extensive cortical distribution associated with excessive sensitivity in error processing in unmedicated depression: a combined event related potential and sLORETA study. AB - Individuals with depression are excessively sensitive to negative feedback and therefore overly cautious. To explore the neural mechanisms of response monitoring which contributed to their impaired behavioral adjustment, we recruited 22 individuals with depressive disorder and 24 healthy controls. Component analysis of the error-related negativity (ERN) and correct-related negativity (CRN), and sLORETA analysis of the ERN and CRN were combined. The comparable error rate and longer reaction time (RT) in individuals with depression as compared to healthy controls suggested a trade-off between accuracy and speed. The amplitude of the ERN and CRN was significantly enhanced in depression. Further sLORETA localizations of the ERN and CRN showed a significantly stronger current density with an extensive distribution in the anterior cingulate cortex (ACC), medial frontal cortex (MFC), inferior parietal lobule (IPL) and superior temporal gyrus (STG) in individuals with depression than in healthy controls. Increased activities in the ACC and MFC indexed increased response monitoring during automatic error detection, while hyperactivity over IPL and STG might indicate high uncertainness after error responses in depression. The hyperactivity within an extensive cortical distribution might be the neural basis of the excessive sensitivity to errors and the conservative accuracy/speed strategy in depression. PMID- 24056022 TI - Reduced serum corin levels in patients with osteoporosis. AB - BACKGROUND: Corin is a cardiac protease that activates the natriuretic peptides. Corin is also expressed in chondrocytes and bone marrow-derived mesenchymal stem cells that undergo osteogenic differentiation, suggesting a potential role of corin in bone formation and homeostasis. METHODS: To test if corin levels are altered in patients with bone disease, we used ELISA to measure corin and osteocalcin levels in serum samples from healthy controls (n = 134) and patients with osteopenia (n = 53) and osteoporosis (n = 101). RESULTS: In patients with osteopenia and osteoporosis, serum corin levels were 510 +/- 228 and 478 +/- 183 pg/ml, respectively, which were significantly lower than that in healthy controls (682 +/- 240 pg/ml) (both p values<0.001). The reduced serum corin levels were found in both male and female patients. In multiple linear regression analysis, bone mineral density was identified as an independent predictor for serum corin levels. In patients with osteopenia and osteoporosis, but not normal controls, a negative correlation was found between serum corin and osteocalcin levels. CONCLUSION: Serum corin levels were reduced in patients with osteoporosis and the reduction was associated with high rates of bone turnover. Low serum corin levels may reflect impaired bone homeostasis in patients with osteoporosis. PMID- 24056023 TI - Performance evaluation and comparison of the newly developed Elecsys anti-HCV II assay with other widely used assays. AB - BACKGROUND: Anti-HCV assays remain the first choice for screening HCV infection in most clinical laboratories. The Elecsys anti-HCV II assay has been recently launched and we aimed to evaluate its performance compared with other widely used methods. METHODS: Four seroconversion panels, 861 consecutive sera under routine clinical conditions, 100 preselected sera with low positive anti-HCV results and 178 samples from patients infected with HIV were tested using Elecsys anti-HCV II, Architect anti-HCV and Vitros anti-HCV assays. Confirmatory testing was performed using RIBA and HCV RNA tests. Moreover, 203 samples with different HCV genotypes were assessed using Elecsys anti-HCV II. RESULTS: Elecsys anti-HCV II detected seroconversion 7-14 days earlier than the Architect and Vitros assays. Furthermore, it had 100% sensitivity and superior specificity in screening routine clinical samples, including those with low positive anti-HCV, and detected 97.6% (122/125) anti-HCV-positive samples from HIV-infected patients with HCV viremia. However, the anti-HCV levels in the genotype 3b samples were slightly underestimated. CONCLUSIONS: Elecsys anti-HCV II shortens the seroconversion window. It is suitable for screening HCV infection in clinical samples, including those from immunocompromised patients, due to the excellent sensitivity and specificity. Further investigation of the subtype inclusivity in a larger sample number might be warranted. PMID- 24056024 TI - Clinical challenges to ventilatory control. PMID- 24056025 TI - Individual differences underlying susceptibility to addiction: Role for the endogenous oxytocin system. AB - Recent research shows that the effects of oxytocin are more diverse than initially thought and that in some cases oxytocin can directly influence the response to drugs and alcohol. Large individual differences in basal oxytocin levels and reactivity of the oxytocin system exist. This paper will review the literature to explore how individual differences in the oxytocin system arise and examine the hypothesis that this may mediate some of the individual differences in susceptibility to addiction and relapse. Differences in the oxytocin system can be based on individual factors, e.g. genetic variation especially in the oxytocin receptor, age or gender, or be the result of early environmental influences such as social experiences, stress or trauma. The paper addresses the factors that cause individual differences in the oxytocin system and the environmental factors that have been identified to induce long-term changes in the developing oxytocin system during different life phases. Individual differences in the oxytocin system can influence effects of drugs and alcohol directly or indirectly. The oxytocin system has bidirectional interactions with the stress-axis, autonomic nervous system, neurotransmitter systems (e.g. dopamine, serotonin and GABA/glutamate) and the immune system. These systems are all important, even vital, in different phases of addiction. It is suggested that early life adversity can change the development of the oxytocin system and the way it modulates other systems. This in turn could minimise the negative feedback loops that would normally exist. Individuals may show only minor differences in behaviour and function unless subsequent stressors or drug use challenges the system. It is postulated that at that time individual differences in oxytocin levels, reactivity of the system or interactions with other systems can influence general resilience, drug effects and the susceptibility to develop problematic drug and alcohol use. PMID- 24056026 TI - Treatment with glucokinase activator, YH-GKA, increases cell proliferation and decreases glucotoxic apoptosis in INS-1 cells. AB - Glucokinase (GK), an enzyme that phosphorylates glucose to form glucose-6 phosphate, has a role in regulating insulin secretion and proliferation in beta cells. GK activators (GKAs) have been developed as new therapies for type 2 diabetes. In this study, we evaluated the proliferation and anti-apoptotic actions of YH-GKA, a novel and potent GKA, in INS-1 pancreatic beta-cells. YH-GKA treatment increased cell numbers at 3 mM glucose via upregulation of insulin receptor substrate-2 and subsequent activation of AKT/protein kinase B phosphorylation. YH-GKA also increased beta-catenin and cyclin D2 mRNA expression and inactivated GSK3beta by increasing phosphorylation. These proliferative effects of YH-GKA were attenuated by IRS-2 downregulation. Moreover, YH-GKA reduced annexin-V-stained cells and expression levels of cleaved poly (ADP ribose) polymerase and caspase-3 induced by glucotoxicity. YH-GKA inhibited apoptotic signaling via induction of ATP content, mitochondrial membrane potential, and citrate synthase activity and was correlated with changes of the mitochondrial function-related genes. YH-GKA also increased interaction between GK and voltage-dependent anion-selective channel protein. Our results suggest that the novel GKA, YH-GKA, promotes beta cell growth and prevents glucotoxic beta cell apoptosis. Therefore, YH-GKA may provide a therapy that compensates for beta cell loss in patients with type 2 diabetes. PMID- 24056027 TI - Fed and fasted state gastro-intestinal in vitro lipolysis: In vitro in vivo relations of a conventional tablet, a SNEDDS and a solidified SNEDDS. AB - The present study aims at evaluating the ability of a gastro-intestinal in vitro lipolysis model to predict the performance of two lipid formulations and a conventional tablet containing a poorly soluble drug, cinnarizine, in dogs, both in the fasted and fed state. A self-nano-emulsifying drug delivery system (SNEDDS) was either dosed in a hard gelatin capsule (SNEDDS-C) or loaded onto a porous tablet core (SNEDDS-T) and compared to a marketed conventional tablet (Conv) in an in vitro lipolysis model. The model simulates the digestion in the stomach and intestine during either the fasted or the fed state. Whole fat milk (3.5%) was used in the fed state model to mimic the dynamic lipolysis events after ingestion of food. The results were compared to a dog study published in this issue. In the fasted state in vitro lipolysis model, the amount of solubilized cinnarizine decreased in the order SNEDDS-C>SNEDDS-T>Conv, which correlated well with the in vivo bioavailability. In the fed state in vitro lipolysis model, cinnarizine was solubilized to the same degree for all formulations. Compared to the fasted state model, only the performance of the conventional tablet was improved, indicating food effect. This correlated with the in vivo study, where the tablet was the only formulation with a significant food effect. The fasted state model correlated well with the in vivo results and although the fed state model did not accurately predict the fed state in vivo results, it could predict which formulation that would exhibit a food effect. PMID- 24056028 TI - Yellow fever vaccine: an effective vaccine for travelers. AB - Yellow fever (YF) is an acute viral communicable disease transmitted by an arbovirus of the Flavivirus genus. It is primarily a zoonotic disease, especially the monkeys. Worldwide, an estimated 200,000 cases of yellow fever occurred each year, and the case-fatality rate is ~15%. Forty-five endemic countries in Africa and Latin America, with a population of close to 1 billion, are at risk. Up to 50% of severely affected persons from YF die without treatment. During 2009, 55 cases and 18 deaths were reported from Brazil, Colombia, and Peru. Brazil reported the maximum number of cases and death, i.e., 42 cases with 11 deaths. From January 2010 to March 2011, outbreaks of YF were reported to the WHO by Cameroon, Democratic Republic of Congo, Cote d'Ivoire, Guinea, Sierra Leone, Senegal, and Uganda. Cases were also reported in three northern districts of Abim, Agago, and Kitugun near the border with South Sudan. YF usually causes fever, muscle pain with prominent backache, headache, shivers, loss of appetite, and nausea or vomiting. Most patients improve, and their symptoms disappear after 3 to 4 d. Half of the patients who enter the toxic phase die within 10-14 d, while the rest recover without significant organ damage. Vaccination has been the single most important measure for preventing YF. The 17D-204 YF vaccine is a freeze-dried, live attenuated, highly effective vaccine. It is available in single-dose or multi-dose vials and should be stored at 2-8 degrees C. It is reconstituted with normal saline and should be used within 1 h of reconstitution. The 0.5 mL dose is delivered subcutaneously. Revaccination is recommended every 10 y for people at continued risk of exposure to yellow fever virus (YFV). This vaccine is available worldwide. Travelers, especially to Africa or Latin America from Asia, must have a certificate documenting YF vaccination, which is required by certain countries for entry under the International Health Regulations (IHR) of the WHO. PMID- 24056029 TI - Occurrence and exposure assessment of Fusarium mycotoxins in maize germ, refined corn oil and margarine. AB - Analytical methods were validated for the analysis of fumonisins (FB1 and FB2), deoxynivalenol (DON) and zearalenone (ZEA) in maize germ, corn oil and margarine. A survey of 74 samples consisting of 12 wet-milled maize germ, 12 dry-milled maize germ, 25 refined corn oil, and 25 corn oil margarine was conducted. Results revealed that 100% and 87.5% of maize germ samples presented FB1 and FB2, respectively, attaining concentrations for the sum of both toxins of 1302+/-541 MUg kg(-1) in wet-milled and 820+/-831 MUg kg(-1) in dry-milled maize germ. The lower incidence of FB1, FB2 and DON in edible oil and margarine (4-8%) may be related with the industrial processes for their obtaining besides the high water solubility of these mycotoxins. In contrast, 25% of maize germ samples were positive for ZEA as well as 32% of corn oil and 24% of margarine, which may be related with its lipophilic nature. A number of samples exceeded the maximum limits indicating that strict control is needed, though estimated dietary exposure was less than 0.2% tolerable daily intakes in all cases. PMID- 24056032 TI - Carrier-mediated magnetism in transition metal doped Bi2Se3 topological insulator. AB - The Dirac surface states of topological insulators are protected by time-reversal symmetry, suppressing backscattering. Magnetic impurities adsorbed on the surface of topological insulators are expected to degrade the coherence of these protected surface states, breaking time-reversal symmetry. Some results are in agreement with this prediction. There are others where no bandgap opening was observed. Here, based upon first principles calculations, we show that one mechanism that plays a key role in these controversial results is the intrinsic carrier concentration. The magnetic phase of Fe-, Co- and Ni-doped Bi2Se3 has been computed and compared to the same systems in the presence of n- or p-type doping. Our results show that the magnetic phase is dependent on both the carrier concentration and the magnetic impurity coverage, resulting in a phase diagram for the existence or not of the protected Dirac states. PMID- 24056030 TI - Inhibition of autophagy and glycolysis by nitric oxide during hypoxia reoxygenation impairs cellular bioenergetics and promotes cell death in primary neurons. AB - Excessive nitric oxide (NO) production is known to damage mitochondrial proteins and the autophagy repair pathway and so can potentially contribute to neurotoxicity. Accordingly, we hypothesized that protection against protein damage from reactive oxygen and nitrogen species under conditions of low oxygen by the autophagy pathway in neurons would be impaired by NO and enhance bioenergetic dysfunction. Rat primary cortical neurons had the same basal cellular respiration in hypoxia as in normoxia, whereas NO-exposed cells exhibited a gradual decrease in mitochondrial respiration in hypoxia. Upon reoxygenation, the respiration in NO-treated cells did not recover to prehypoxic levels. Hypoxia-reoxygenation in the presence of NO was associated with inhibition of autophagy, and the inability to recover during reoxygenation was exacerbated by an inhibitor of autophagy, 3-methyladenine. The effects of hypoxia could be recapitulated by inhibiting glycolytic flux under normoxic conditions. Under both normoxic and hypoxic conditions NO exposure induced immediate stimulation of glycolysis, but prolonged NO exposure, associated with irreversible inhibition of mitochondrial respiration in hypoxia, inhibited glycolysis. Importantly, we found that NO inhibited basal respiration under normoxic conditions only when glucose was absent from the medium or glycolysis was inhibited by 2-deoxy-d-glucose, revealing a novel NO-dependent mechanism for the inhibition of mitochondrial respiration that is modulated by glycolysis. Taken together these data suggest an oxygen-dependent interaction between mitochondrial respiration, glycolysis, and autophagy in protecting neuronal cells exposed to NO. Importantly, they indicate that mitochondrial dysfunction is intimately linked to a failure of glycolytic flux induced by exposure to NO. In addition, these studies provide new insights into the understanding of how autophagy and NO may play interactive roles in neuroinflammation-induced cellular damage, which is pertinent to our understanding of the pathology of neurodegenerative diseases in which excessive NO is generated. PMID- 24056031 TI - Mitochondrial glutathione depletion reveals a novel role for the pyruvate dehydrogenase complex as a key H2O2-emitting source under conditions of nutrient overload. AB - Once regarded as a "by-product" of aerobic metabolism, the production of superoxide/H2O2 is now understood to be a highly specialized and extensively regulated process responsible for exerting control over a vast number of thiol containing proteins, collectively referred to as the redox-sensitive proteome. Although disruptions within this process, secondary to elevated peroxide exposure, have been linked to disease, the sources and mechanisms regulating increased peroxide burden remain poorly defined and as such are difficult to target using pharmacotherapy. Here we identify the pyruvate dehydrogenase complex (PDC) as a key source of H2O2 within skeletal muscle mitochondria under conditions of depressed glutathione redox buffering integrity. Treatment of permeabilized myofibers with varying concentrations of the glutathione-depleting agent 1-chloro-2,4-dinitrobenzene led to a dose-dependent increase in pyruvate supported JH2O2 emission (the flux of H2O2 diffusing out of the mitochondrial matrix into the surrounding assay medium), with emission rates eventually rising to exceed those of all substrate combinations tested. This striking sensitivity to glutathione depletion was observed in permeabilized fibers prepared from multiple species and was specific to PDC. Physiological oxidation of the cellular glutathione pool after high-fat feeding in rodents was found to elevate PDC JH2O2 emission, as well as increasing the sensitivity of the complex to GSH depletion. These findings reveal PDC as a potential major site of H2O2 production that is extremely sensitive to mitochondrial glutathione redox status. PMID- 24056033 TI - Is a picture worth a thousand biopsies? Challenges in the diagnosis of endometriosis. PMID- 24056035 TI - Quality of care for poor Americans varies widely from state to state. PMID- 24056034 TI - Two bHLH-type transcription factors, JA-ASSOCIATED MYC2-LIKE2 and JAM3, are transcriptional repressors and affect male fertility. AB - The jasmonate (JA) plant hormones regulate responses to biotic and abiotic stress and aspects of plant development, including male fertility in Arabidopsis thaliana. The bHLH-type transcription factor JA-ASSOCIATED MYC2-LIKE1 (JAM1) negatively regulates JA signaling and gain-of-function JAM1 transgenic plants have impaired JA-mediated male fertility. Here we report that JAM2 and JAM3, 2 bHLHs closely related to JAM1, also act as transcriptional repressors. Moreover, overexpression of JAM2 and JAM3 also results in reduced male fertility. These results suggest that JAM1, JAM2, and JAM3 act redundantly as negative regulators of JA-mediated male fertility. PMID- 24056036 TI - German court rules that liquid nicotine is not a medicine. PMID- 24056037 TI - Lewisham appeal will decide which local commissioners can veto reconfigurations. PMID- 24056038 TI - The survival of mouse oocytes shows little or no correlation with the vitrification or freezing of the external medium, but the ability of the medium to vitrify is affected by its solute concentration and by the cooling rate. AB - As survival of mouse oocytes subjected to vitrification depends far more on the warming rate than on the cooling rate, we wished to determine whether the lack of correlation between survival and cooling rate was mirrored by a lack of correlation between cooling rate and vitrification of the medium (EAFS), and between survival and the vitrification of the medium. The morphological and functional survival of the oocytes showed little or no relation to whether or not the EAFS medium vitrified or froze. We studied if the droplet size and the elapsed time (between placing the droplet on the Cryotop and the start of cooling) affects the result through modification of the cooling rate and solute concentration. Dehydration was rapid; consequently, the time between the placing the droplets into a Cryotop and cooling must be held to a minimum. The size of the EAFS droplet that is being cooled does not seem to affect vitrification. Finally, the degree to which samples of EAFS vitrify is firmly dependent on both its solute concentration and the cooling rate. PMID- 24056040 TI - The E104D mutation increases the susceptibility of human triosephosphate isomerase to proteolysis. Asymmetric cleavage of the two monomers of the homodimeric enzyme. AB - The deficiency of human triosephosphate isomerase (HsTIM) generates neurological alterations, cardiomyopathy and premature death. The mutation E104D is the most frequent cause of the disease. Although the wild type and mutant exhibit similar kinetic parameters, it has been shown that the E104D substitution induces perturbation of an interfacial water network that, in turn, reduces the association constant between subunits promoting enzyme inactivation. To gain further insight into the effects of the mutation on the structure, stability and function of the enzyme, we measured the sensitivity of recombinant E104D mutant and wild type HsTIM to limited proteolysis. The mutation increases the susceptibility to proteolysis as consequence of the loss of rigidity of its overall 3-D structure. Unexpectedly, it was observed that proteolysis of wild type HsTIM generated two different stable nicked dimers. One was formed in relatively short times of incubation with proteinase K; as shown by spectrometric and crystallographic data, it corresponded to a dimer containing a nicked monomer and an intact monomer. The formation of the other nicked species requires relatively long incubation times with proteinase K and corresponds to a dimer with two clipped subunits. The first species retains 50% of the original activity, whereas the second species is inactive. Collectively, we found that the E104D mutant is highly susceptible to proteolysis, which in all likelihood contributes to the pathogenesis of enzymopathy. In addition, the proteolysis data on wild type HsTIM illustrate an asymmetric conduct of the two monomers. PMID- 24056041 TI - Structural and functional analysis of FIP2 binding to the endosome-localised Rab25 GTPase. AB - Rab small GTPases are the master regulators of intracellular trafficking in eukaryotes. They mediate spatial and temporal recruitment of effector proteins to distinct cellular compartments through GTP-induced changes in their conformation. Despite numerous structural studies, the molecular basis for Rab/effector specificity and subsequent biological activity remains poorly understood. Rab25, also known as Rab11c, which is epithelial-specific, has been heavily implicated in ovarian cancer development and independently appears to act as a tumour suppressor in the context of a distinct subset of carcinomas. Here, we show that Rab25 associates with FIP2 and can recruit this effector protein to endosomal membranes. We report the crystal structure of Rab25 in complex with the C terminal region of FIP2, which consists of a central dimeric FIP2 coiled-coil that mediates a heterotetrameric Rab25-(FIP2)2-Rab25 complex. Thermodynamic analyses show that, despite a relatively conserved interface, FIP2 binds to Rab25 with an approximate 3-fold weaker affinity than to Rab11a. Reduced affinity is mainly associated with lower enthalpic gains for Rab25:FIP2 complex formation, and can be attributed to subtle differences in the conformations of switch 1 and switch 2. These cellular, structural and thermodynamic studies provide insight into the Rab11/Rab25 subfamily of small GTPases that regulate endosomal trafficking pathways in eukaryotes. PMID- 24056042 TI - Extensive vascular remodeling in the spinal cord of pre-symptomatic experimental autoimmune encephalomyelitis mice; increased vessel expression of fibronectin and the alpha5beta1 integrin. AB - Alterations in vascular structure and function are a central component of demyelinating disease. In addition to blood-brain barrier (BBB) breakdown, which occurs early in the course of disease, recent studies have described angiogenic remodeling, both in multiple sclerosis tissue and in the mouse demyelinating model, experimental autoimmune encephalomyelitis (EAE). As the precise timing of vascular remodeling in demyelinating disease has yet to be fully defined, the purpose of the current study was to define the time-course of these events in the MOG35-55 EAE model. Quantification of endothelial cell proliferation and vessel density revealed that a large part of angiogenic remodeling in cervical spinal cord white matter occurs during the pre-symptomatic phase of EAE. At the height of vascular remodeling, blood vessels in the cervical spinal cord showed strong transient upregulation of fibronectin and the alpha5beta1 integrin. In vitro experiments revealed that alpha5 integrin inhibition reduced brain endothelial cell proliferation under inflammatory conditions. Interestingly, loss of vascular integrity was evident in all vessels during the first 4-7days post-immunization, but after 14days, was localized predominantly to venules. Taken together, our data demonstrate that extensive vascular remodeling occurs during the pre symptomatic phase of EAE and point to a potential role for the fibronectin alpha5beta1 integrin interaction in promoting vascular remodeling during demyelinating disease. PMID- 24056043 TI - Enhanced levels of plant cell cycle inhibitors hamper root-knot nematode-induced feeding site development. AB - Root-knot nematodes (RKN) are highly specialized, obligatory plant parasites. These animals reprogram root cells to form large, multinucleate, and metabolically active feeding cells (giant cells) that provide a continuous nutrient supply during 3-6 weeks of the nematode's life. The establishment and maintenance of physiologically fully functional giant cells are necessary for the survival of these nematodes. As such, giant cells may be useful targets for applying strategies to reduce damage caused by these nematodes, aiming the reduction of their reproduction. We have recently reported the involvement of cell cycle inhibitors of Arabidopsis, named Kip-Related Proteins (KRPs), on nematode feeding site ontogeny. Our results have demonstrated that this family of cell cycle inhibitors can be envisaged to efficiently disrupt giant cell development, based on previous reports which showed that alterations in KRP concentration levels can induce cell cycle transitions. Herein, we demonstrated that by overexpressing KRP genes, giant cells development is severely compromised as well as nematode reproduction. Thus, control of root-knot nematodes by modulating cell cycle-directed pathways through the enhancement of KRP protein levels may serve as an attractive strategy to limit damage caused by these plant parasites. PMID- 24056044 TI - RACK1 promotes neurite outgrowth by scaffolding AGAP2 to FAK. AB - RACK1 binds proteins in a constitutive or transient manner and supports signal transmission by engaging in diverse and distinct signalling pathways. The emerging theme is that RACK1 functions as a signalling switch, recruiting proteins to form distinct molecular complexes. In focal adhesions, RACK1 is required for the regulation of FAK activity and for integrating a wide array of cellular signalling events including the integration of growth factor and adhesion signalling pathways. FAK is required for cell adhesion and migration and has a well-established role in neurite outgrowth and in the developing nervous system. However, the mechanism by which FAK activity is regulated in neurons remains unknown. Using neuronal cell lines, we determined that differentiation of these cells promotes an interaction between the scaffolding protein RACK1 and FAK. Disruption of the RACK1/FAK interaction leads to decreased neurite outgrowth suggesting a role for the interaction in neurite extension. We hypothesised that RACK1 recruits proteins to FAK, to regulate FAK activity in neuronal cells. To address this, we immunoprecipitated RACK1 from rat hippocampus and searched for interacting proteins by mass spectrometry. We identified AGAP2 as a novel RACK1 interacting protein. Having confirmed the RACK1-AGAP2 interaction biochemically, we show RACK1-AGAP2 to localise together in the growth cone of differentiated cells, and confirm that these proteins are in complex with FAK. This complex is disrupted when RACK1 expression is suppressed using siRNA or when mutants of RACK1 that do not interact with FAK are expressed in cells. Similarly, suppression of AGAP2 using siRNA leads to increased phosphorylation of FAK and increased cell adhesion resulting in decreased neurite outgrowth. Our results suggest that RACK1 scaffolds AGAP2 to FAK to regulate FAK activity and cell adhesion during the differentiation process. PMID- 24056045 TI - Inhibition of late endosomal maturation restores Wnt secretion in Caenorhabditis elegans vps-29 retromer mutants. AB - Secretion of Wnt proteins is mediated by the Wnt sorting receptor Wls, which transports Wnt from the Golgi to the cell surface for release. To maintain efficient Wnt secretion, Wls is recycled back to the trans-Golgi network (TGN) through a retromer dependent endosome to TGN retrieval pathway. It has recently been shown that this is mediated by an alternative retromer pathway in which the sorting nexin SNX3 interacts with the cargo-selective subcomplex of the retromer to sort Wls into a retrieval pathway that is morphologically distinct from the classical SNX-BAR dependent retromer pathway. Here, we investigated how sorting of Wls between the two different retromer pathways is specified. We found that when the function of the cargo-selective subcomplex of the retromer is partially disrupted, Wnt secretion can be restored by interfering with the maturation of late endosomes to lysosomes. This leads to an accumulation of Wls in late endosomes and facilitates the retrieval of Wls through a SNX-BAR dependent retromer pathway. Our results are consistent with a model in which spatial separation of the SNX3 and SNX-BAR retromer complexes along the endosomal maturation pathway as well as cargo-specific mechanisms contribute to the selective retrieval of Wls through the SNX3 retromer pathway. PMID- 24056046 TI - Effective tooth-bleaching protocols capable of reducing H(2)O(2) diffusion through enamel and dentine. AB - OBJECTIVES: To evaluate the effects of experimental protocols on bleaching effectiveness and hydrogen peroxide (HP) diffusion through enamel and dentine. METHODS: Enamel/dentine discs were subjected to six bleaching sessions, consisting of 1 or 3 applications of 17.5% or 35%-HP gel for 5/15min, or 37% carbamide peroxide (CP) gel for 10/20min. Discs undergoing the regular protocol (35%-HP; 3*15min) constituted the positive control group. Colour change (DeltaE) was assessed (CIE L*a*b* system) after each session. HP diffusion was quantified (sessions 1, 3, and 6) in enamel/dentine discs adapted to artificial pulp chambers. Data were analysed by Pillai's Trace and Bonferroni test, or by one-way ANOVA and SNK/Tamhane's test (alpha=5%). RESULTS: All tooth-bleaching protocols significantly increased the DeltaE values. A reduction in HP diffusion and no significant difference in DeltaE compared with the positive control were observed for the following bleaching protocols: 17.5%-HP 3*15min, at the 4th session; and 35%-HP 1*15 and 3*5min, at the 5th session. HP diffusion in the 37%-CP 3*20min bleaching protocol was statistically similar to that in the positive control. The other experimental bleaching protocols significantly decreased HP diffusion through enamel/dentine discs, but the DeltaE values were statistically lower than those observed in the positive control, in all sessions. CONCLUSION: Shortening the contact time of a 35%-HP gel or reducing its concentration produces gradual tooth colour change and reduced HP diffusion through enamel and dentine. CLINICAL SIGNIFICANCE: A reduction in HP concentration, from 35% to 17.5%, in a bleaching gel or shortening its application time on enamel provides a significant tooth bleaching improvement associated with decreased HP diffusion across hard dental tissues. Therefore, these protocols may be an interesting alternative to be tested in the clinical situation. PMID- 24056047 TI - Auxin gradient is crucial for the maintenance of root distal stem cell identity in Arabidopsis. AB - The plant hormone auxin plays a critical role in the maintenance of root stem cell niches in Arabidopsis. We have recently reported that WUSCHEL-RELATED HOMEOBOX 5 (WOX5) transcription factor modulates free auxin production in the quiescent center (QC) of the root and its expression is inhibited in a feedback dependent manner by canonical auxin signaling that involves indole-3-acetic acid 17 (IAA17) auxin response repressor. WOX5-IAA17 feedback circuit assures the maintenance of auxin response maximum in the root tip and thereby contributes to the maintenance of distal stem cell (DSC) populations. Here, we provide evidence to show that an optimal auxin maximum in QC guided auxin signaling gradient in root tips is crucial for maintaining root DSC identity. PMID- 24056048 TI - Selected anthropogenic and natural radioisotopes in the Barents Sea and off the western coast of Svalbard. AB - The Murmansk Marine Biological Institute (MMBI) performed high-latitude expeditions to the Barents Sea during 2007-2009 where a scientist from the Radiation and Nuclear Safety Authority (STUK) participated. The aim of the expeditions was to study and map the current radiological situation throughout the Barents Sea. In the expeditions, samples of seawater, sediment and biota were collected for radioactivity studies. The (90)Sr and (137)Cs isotopes were analysed from the seawater samples and no spatial distribution in the concentrations of (90)Sr and (137)Cs was found. The sediment samples were analysed for gamma-emitting isotopes. In the statistical analysis performed only the (90)Sr was found to have no spatial distribution. In the (137)Cs concentrations two areas containing higher concentrations were observed: one in the western part of Svalbard and another in Franz Victoria Trough near the Franz Josef Land archipelago. The increase in the western coast of Svalbard suggests an Atlantic influence while in the Franz Victoria Trough source regions are possibly more complex. Since (137)Cs in marine sediments mainly originates from terrestrial sources, finding higher concentrations in the northern part of the Barents Sea may also suggest a contribution of (137)Cs carried by the ocean currents and by sea ice from the outside Barents Sea. In addition to gamma spectrometric measurements, the sediment samples were radiochemically analysed for (210)Pb. It was found that the unsupported fraction of (210)Pb showed significant spatial variation. The fraction of unsupported (210)Pb was reduced to 40-70% near Bear Island, Edge Island and in the Franz Josef Land archipelago. In these regions the sea is typically covered with sea ice during winter. The relatively low fraction of unsupported (210)Pb is possibly caused by blocking of wet and dry deposition of (210)Pb onto the sea by winter sea ice. In biota samples, only small traces, at the level of 0.2 Bq/kg w.w. of (137)Cs, were found. When the (137)Cs concentrations found in cod and in haddock were compared with studies done in the early 1990's an effective half-life of (137)Cs in cod and in haddock was deduced. For cod the estimated effective half-life of (137)Cs was between 5.8 and 7.5 years and for haddock between 5.3 and 9.5 years. Similarly, the concentrations of naturally occurring (210)Po and (210)Pb were from 0.1 to 0.3 Bq/kg w.w. The (210)Po/(210)Pb ratio varied from 1.8 to 30 indicating a more efficient bioaccumulation of (210)Po than its precursor (210)Pb. The dose to humans eating Barents Sea fish was estimated. Even for people consuming large quantities of Barents Sea fish the annual dose was found to be below 20 MUSv. The effective dose from anthropogenic (137)Cs was found to be less than 1% compared to the dose caused naturally occurring (210)Po and (210)Pb. PMID- 24056049 TI - Sorption and reduction of selenite on chlorite surfaces in the presence of Fe(II) ions. AB - The sorption and reduction of selenite on chlorite surfaces in the presence of Fe(II) ions were investigated as a function of pH, Se(IV) concentration, and Fe(II) concentration under an anoxic condition. The sorption of Se(IV) onto chlorite surfaces followed the Langmuir isotherm regardless of the presence of Fe(II) ions in the solution. The Se(IV) sorption was observed to be very low at all pH values when the solution was Fe(II)-free or the concentration of Fe(II) ions was as low as 0.5 mg/L. However, the Se(IV) sorption was enhanced at a pH > 6.5 when the Fe(II) concentration was higher than 5 mg/L because of the increased sorption of Fe(II) onto the chlorite surfaces. XANES (X-ray absorption near edge structure) spectra of the Se K-edge showed that most of the sorbed Se(IV) was reduced to Se(0) by Fe(II) sorbed onto the chlorite surfaces, especially at pH > 9. The combined results of field-emission scanning electron microscopy (FE-SEM) and X-ray diffraction (XRD) also showed that elemental selenium and goethite were formed and precipitated on the chlorite surfaces during the sorption of selenite. Consequently it can be concluded that Se(IV) can be reduced to Se(0) in the presence of Fe(II) ions by the surface catalytic oxidation of Fe(II) into Fe(III) and the formation of goethite at neutral and particularly alkaline conditions. Thus the mobility of selenite in groundwater is expected to be reduced by the presence of a relatively higher concentration of Fe(II) in subsurface environments. PMID- 24056050 TI - A statistical evaluation of the influence of housing characteristics and geogenic radon potential on indoor radon concentrations in France. AB - Radon-222 is a radioactive natural gas produced by the decay of radium-226, known to be the main contributor to natural background radiation exposure. Effective risk management needs to determine the areas in which the density of buildings with high radon levels is likely to be highest. Predicting radon exposure from the location and characteristics of a dwelling could also contribute to epidemiological studies. Beginning in the nineteen-eighties, a national radon survey consisting in more than 10,000 measurements of indoor radon concentrations was conducted in French dwellings by the Institute for Radiological Protection and Nuclear Safety (IRSN). Housing characteristics, which may influence radon accumulation in dwellings, were also collected. More recently, the IRSN generated a French geogenic radon potential map based on the interpretation of geological features. The present study analyzed the two datasets to investigate the factors influencing indoor radon concentrations using statistical modeling and to determine the optimum use of the information on geogenic radon potential that showed the best statistical association with indoor radon concentration. The results showed that the variables associated with indoor radon concentrations were geogenic radon potential, building material, year of construction, foundation type, building type and floor level. The model, which included the surrounding geogenic radon potential (i.e. the average geogenic radon potential within a disc of radius 20 km centered on the indoor radon measurement point) and variables describing house-specific factors and lifestyle explained about 20% of the overall variability of the logarithm of radon concentration. The surrounding geogenic radon potential was fairly closely associated with the local average indoor radon concentration. The prevalence of exposure to radon above specific thresholds and the average exposures to radon clearly increased with increasing classes of geogenic radon potential. Combining the two datasets enabled improved assessment of radon exposure in a given area in France. PMID- 24056051 TI - A C1 inhibitor ortholog from rock bream (Oplegnathus fasciatus): molecular perspectives of a central regulator in terms of its genomic arrangement, transcriptional profiles and anti-protease activities of recombinant peptide. AB - C1 inhibitor (C1Inh), a member of serpin superfamily, is a crucial regulator of the activation of various plasmatic cascades associated with immunity and inflammation. This study describes the identification and characterization of a C1Inh gene from rock bream Oplegnathus fasciatus (OfC1Inh) at structural, expressional and functional levels. The cDNA-(2245bp) and corresponding gDNA sequences (5.2kbp) of OfC1Inh were isolated from rock bream transcriptome- and BAC-libraries, respectively. Predicted amino acid sequence of OfC1Inh revealed a two-domain architecture composed of an N-terminal region with two Ig-like domains and a C-terminal region with a serpin domain. Tertiary model of OfC1Inh disclosed its active site topology. In the multi-exonic genomic arrangement of OfC1Inh, it consisted of eleven exons disjoined by ten introns as observed in few other fish homologs. Our comparative analysis indicated that the teleostean C1Inhs were distinct from their non-teleostean vertebrate counterparts in terms of their (1) extended N-terminal domains, (2) evolutionary divergence and (3) exon-intron distribution. The OfC1Inh had a TATA-deficient promoter with a putative initiator element, and two tandemly arranged downstream promoter elements. Several components associated with the immune and inflammatory transcriptional activation were also predicted to exist in 5' flanking region of OfC1Inh. The exclusive mRNA levels in liver and moderate levels in extra-hepatic tissues intimated the diversified importance of OfC1Inh in rock bream physiology. We also provide an evidence for the involvement of OfC1Inh in immune balance, based on its modulated transcription upon different PAMP (lipopolysaccharide and poly I:C)- or pathogen (Streptococcus iniae and rock bream irido virus)-challenges. A recombinantly expressed fusion protein [(r)OfC1Inh] was employed in demonstrating the anti protease function of OfC1Inh. The (r)OfC1Inh exhibited detectable inhibitory activity against C1 esterase and thrombin, where the anti-C1 esterase role was shown to be potentiated by heparin. Taken together, the results of this study provide the first line of evidence for the possible involvement of a teleostean C1Inh in fish immunity, based on its expressional response(s) and inhibitory properties against two enzymes involved in biological cascades. PMID- 24056052 TI - Fluorescence studies, DNA binding properties and antimicrobial activity of a dysprosium(III) complex containing 1,10-phenanthroline. AB - Luminescence and binding properties of dysprosium(III) complex containing 1,10 phenanthroline (phen), [Dy(phen)2(OH2)3Cl]Cl2?H2O with DNA has been studied by electronic absorption, emission spectroscopy and viscosity measurement. The thermodynamic studies suggest that the interaction process to be endothermic and entropically driven, which indicates that the dysprosium(III) complex might interact with DNA by a non intercalation binding mode. Additionally, the competitive fluorescence study with ethidium bromide and also the effect of iodide ion and salt concentration on fluorescence of the complex-DNA system is investigated. Experimental results indicate that the Dy(III) complex strongly binds to DNA, presumably via groove binding mode. Furthermore, the complex shows a potent antibacterial activity and DNA cleavage ability. PMID- 24056053 TI - Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. AB - Over 40% of active pharmaceutical ingredients (API) in development pipelines are poorly water-soluble drugs which limit formulation approaches, clinical application and marketability because of their low dissolution and bioavailability. Solid dispersion has been considered one of the major advancements in overcoming these issues with several successfully marketed products. A number of key references that describe state-of-the-art technologies have been collected in this review, which addresses various pharmaceutical strategies and future visions for the solubilization of poorly water-soluble drugs according to the four generations of solid dispersions. This article reviews critical aspects and recent advances in formulation, preparation and characterization of solid dispersions as well as in-depth pharmaceutical solutions to overcome some problems and issues that limit the development and marketability of solid dispersion products. PMID- 24056054 TI - In situ amorphisation of indomethacin with Eudragit(r) E during dissolution. AB - In this study, the possibility of utilising in situ crystalline-to-amorphous transformation for the delivery of poorly water soluble drugs was investigated. Compacts of physical mixtures of gamma-indomethacin (IMC) and Eudragit(r) E in 3:1, 1:1 and 1:3 (w/w) ratios were subjected to dissolution testing at pH 6.8 at which IMC but not the polymer is soluble. Compacts changed their colour from white to yellow indicating amorphisation of IMC. X-ray powder diffractometry (XRPD) confirmed the amorphisation and only one glass transition temperature was observed (58.1 degrees C, 54.4 degrees C, and 50.1 degrees C for the 3:1, 1:1 and 1:3 (w/w) drug-to-polymer ratios, respectively). Furthermore, principal component analysis of infrared spectra resulted in clustering of in situ transformed samples together with quench cooled glass solutions for each respective ratio. Subsequent dissolution testing of in situ transformed samples at pH 4.1, at which the polymer is soluble but not IMC, led to a higher dissolution rate than for quench cooled glass solution at 3:1 and 1:1 ratios, but not for the 1:3 ratio. This study showed that crystalline drug can be transformed into amorphous material in situ in the presence of a polymer, leading to the possibility of administering drugs in the amorphous state without physical instability problems during storage. PMID- 24056055 TI - The clinical efficacy of cosmeceutical application of liquid crystalline nanostructured dispersions of alpha lipoic acid as anti-wrinkle. AB - Topical 5% alpha lipoic acid (ALA) has shown efficacy in treatment of photo damaged skin. The aim of this work was to evaluate the potential of poloxamer (P407) gel as a vehicle for the novel lipid base particulate system (cubosome dispersions) of ALA. Cubosome dispersions were formulated by two different approaches, emulsification of glyceryl monoolein (GMO) and poloxamer (P407) in water followed by ultrasonication, and the dilution method using a hydrotrope. Three different concentrations of GMO were used to formulate the cubosome dispersions using the first method, 5% (D1), 10% (D2) and 15% w/w (D3). In the second technique an isotropic liquid was produced by combining GMO with ethanol, and this isotropic liquid was then diluted with a P407 solution (D4). The dispersions were characterized by zeta potential, light scattering techniques, optical and transmission electron microscopy, encapsulation efficiency and in vitro drug release. Results showed that D4 was not a uniform dispersion and that D1, D2 and D3 were uniform dispersions, in which by increasing the GMO content in the dispersion, the size of the cubosomes decreased, zeta potential became more negative, encapsulation efficiency increased up to 86.48% and the drug release rate was slower. P407 gels were prepared using the cold method. Two concentrations of P407 gel were fabricated, 20 and 30% w/w. P407 gels were loaded with either ALA or dispersions containing ALA cubosomes. P407 gels were characterized by critical gelation temperature, rheological measurements and in vitro drug release studies. Results suggested that by increasing P407 concentration, the gelation temperature decreases and viscosity increases. Drug release in both cases was found to follow the Higuchi square root model. Gel loaded with ALA cubosomes provided a significantly lower release rate than the gel loaded with the un-encapsulated ALA. A double blinded placebo controlled clinical study was conducted, aiming to evaluate the efficacy as an anti-wrinkle agent and volunteer's satisfaction upon application of topical 30% P407 gel loaded with ALA cubosomes. Results indicated reduction in facial lines, almost complete resolution of fine lines in the periorbital region and upper lip area and overall improvement in skin color and texture in most volunteers. There were no instances of irritation, peeling or other apparent adverse side effects. PMID- 24056056 TI - A novel multivariate approach using science-based calibration for direct coating thickness determination in real-time NIR process monitoring. AB - This study demonstrates an approach, using science-based calibration (SBC), for direct coating thickness determination on heart-shaped tablets in real-time. Near Infrared (NIR) spectra were collected during four full industrial pan coating operations. The tablets were coated with a thin hydroxypropyl methylcellulose (HPMC) film up to a film thickness of 28 MUm. The application of SBC permits the calibration of the NIR spectral data without using costly determined reference values. This is due to the fact that SBC combines classical methods to estimate the coating signal and statistical methods for the noise estimation. The approach enabled the use of NIR for the measurement of the film thickness increase from around 8 to 28 MUm of four independent batches in real-time. The developed model provided a spectroscopic limit of detection for the coating thickness of 0.64 +/- 0.03 MUm root-mean square (RMS). In the commonly used statistical methods for calibration, such as Partial Least Squares (PLS), sufficiently varying reference values are needed for calibration. For thin non-functional coatings this is a challenge because the quality of the model depends on the accuracy of the selected calibration standards. The obvious and simple approach of SBC eliminates many of the problems associated with the conventional statistical methods and offers an alternative for multivariate calibration. PMID- 24056057 TI - Understanding the in vivo performance of enteric coated tablets using an in vitro in silico-in vivo approach: case example diclofenac. AB - Individual pharmacokinetics after administration of enteric coated tablets are often highly variable and this has been ascribed to the interaction of the dosage form with the physiology of the gastrointestinal tract. This research aimed to explore the influence of interactions between enteric coated tablets and physiological factors such as gastric and intestinal pH as well as gastric emptying on the release of drug from the dosage form and the subsequent plasma profile, using diclofenac as a case example. A physiologically based pharmacokinetic (PBPK) model for monolithic enteric coated dosage forms was designed and coupled with biorelevant dissolution results to predict PK profiles of diclofenac from Voltaren(r) tablets in both fasted and fed humans. The paddle method was used to obtain the dissolution profiles of diclofenac in biorelevant media. The Noyes-Whitney model was employed to describe the dissolution kinetics. The PBPK model was set up using STELLA(r) software. A single unit enteric coated tablet was assumed to be emptied from stomach only with the house-keeping wave. Timing of the emptying was simulated using a random number generator to statistically estimate gastric emptying times after ingestion. The lag times and the dissolution rate used as input parameters in the STELLA(r) model were adjusted according to the pre-exposure period. The oral PK profiles were predicted for each virtual subject individually, and then the mean profiles and standard deviations were calculated. The dissolution profiles were highly affected by the period of pre-exposure in FaSSGF. A long period of pre-exposure of the tablet prolonged the lag time and decreased the dissolution rate. The results of the pharmacokinetic simulations showed that not only the mean profiles in the fasted state but also the variability could be predicted successfully using data generated for the individual virtual subjects. The results emphasize the importance of accounting for the range of pH profiles and gastrointestinal transit in the target population when predicting plasma profiles of enteric coated dosage forms and point to problems in demonstrating bioequivalence for dosage forms of this type. PMID- 24056058 TI - Quantitative on-line vs. off-line NIR analysis of fluidized bed drying with consideration of the spectral background. AB - Quantitative dehydration studies of dibasic calcium phosphate anhydrous (DCPA) in a small-scale cold-model fluidized bed dryer with process air control were conducted. Near-infrared spectroscopy (NIRS) with partial least squares regression (PLSR) was used to predict DCPAs' residual moisture content. Loss-on drying (LOD) was employed as a reference method and confirmed the actual moisture content of DCPA. First, dynamic PLSR modeling was carried out, i.e., the NIR spectra were on-line recorded and predicted throughout the drying process. Secondly, PLSR off-line modeling was performed, i.e., samples were consecutively thief-probed from the processor, put into glass vials and analyzed off-line. Furthermore, two background spectra were collected prior to the in- and off-line measurements in an attempt to increase the method's sensitivity, i.e., (i) dry DCPA that was fluidized at respective process air velocity (on-line) or inside a glass vial (off-line) and (ii) Spectralon(r)--a highly reflecting standard reference material made of fluoropolymer. Benefits and drawbacks of the in- and off-line approaches with different spectral backgrounds are discussed in detail. The results indicated that (i) the thief-probed sample amount from the processor and thus the sample weight and (ii) the downtime between thief-probing a sample and its actual analysis via NIRS and LOD can bias the moisture content predictions. PMID- 24056059 TI - Iridium-modified Si(111) surface. AB - The physical and electronic properties of Ir-modified Si(111) surface have been investigated with the help of STM (scanning tunneling microscopy) and LEED (low energy electron diffraction). The LEED pattern of the surface exhibits [Formula: see text] reconstruction. STM images show that [Formula: see text] degrees reconstruction originates from the Ir-ring clusters. STS (scanning tunneling spectroscopy) measurements on the ring clusters reveal a state located about 0.3 eV below the Fermi level. A careful analysis shows that this state originates from [Formula: see text] degrees domains of Ir-modified Si(111) surface. PMID- 24056060 TI - Systematic information processing style and perseverative worry. AB - This review examines the theoretical rationale for conceiving of systematic information processing as a proximal mechanism for perseverative worry. Systematic processing is characterised by detailed, analytical thought about issue-relevant information, and in this way, is similar to the persistent, detailed processing of information that typifies perseverative worry. We review the key features and determinants of systematic processing, and examine the application of systematic processing to perseverative worry. We argue that systematic processing is a mechanism involved in perseverative worry because (1) systematic processing is more likely to be deployed when individuals feel that they have not reached a satisfactory level of confidence in their judgement and this is similar to the worrier's striving to feel adequately prepared, to have considered every possible negative outcome/detect all potential danger, and to be sure that they will successfully cope with perceived future problems; (2) systematic processing and worry are influenced by similar psychological cognitive states and appraisals; and (3) the functional neuroanatomy underlying systematic processing is located in the same brain regions that are activated during worrying. This proposed mechanism is derived from core psychological processes and offers a number of clinical implications, including the identification of psychological states and appraisals that may benefit from therapeutic interventions for worry-based problems. PMID- 24056061 TI - Induced pluripotency for translational research. AB - The advent of induced pluripotent stem cells (iPSCs) has revolutionized the concept of cellular reprogramming and potentially will solve the immunological compatibility issues that have so far hindered the application of human pluripotent stem cells in regenerative medicine. Recent findings showed that pluripotency is defined by a state of balanced lineage potency, which can be artificially instated through various procedures, including the conventional Yamanaka strategy. As a type of pluripotent stem cell, iPSCs are subject to the usual concerns over purity of differentiated derivatives and risks of tumor formation when used for cell-based therapy, though they provide certain advantages in translational research, especially in the areas of personalized medicine, disease modeling and drug screening. iPSC-based technology, human embryonic stem cells (hESCs) and direct lineage conversion each will play distinct roles in specific aspects of translational medicine, and continue yielding surprises for scientists and the public. PMID- 24056062 TI - Identification and evolution of molecular domains involved in differentiating the cement gland-promoting activity of Otx proteins in Xenopus laevis. AB - Otx genes are a class of vertebrate homeobox genes, homologous to the orthodenticle gene of Drosophila melanogaster, that play a crucial role in anterior embryo patterning and sensory organ formation. In the frog, Xenopus laevis, at least three members of this class have been isolated: otx1, otx2 and otx5 (crx); they are involved in regulating both shared and differential processes during frog development. In particular, while otx2 and otx5 are both capable to promote cement gland (CG) formation, otx1 is not. We performed a molecular dissection of Otx5 and Otx1 proteins to characterize the functional parts of the proteins that make them differently able to promote CG formation. We show that a CG promoting domain (CGPD) is localized at the Otx5 C-terminus, and is bipartite: CGPD1 (aa210-255) is the most effective domain, while CGPD2 (aa177 209) has a lower activity. A histidine stretch disrupts CGPD1 continuity in Otx1 determining its loss of CG promoting activity; this histidine-rich region acts as an actively CG repressing domain. Another Otx1 specific domain, a serine-rich stretch, may also be involved in repressing Otx1 potential to trigger CG formation, though at a much lower level. This is the first evidence that these domains, specific of the Otx1 orthology group, play a role during development in differentiating Otx1 action compared to other Otx family members. We discuss the potential implications of their appearance in light of the evolution of Otx functional activities. PMID- 24056063 TI - Retinoic acid homeostasis regulates meiotic entry in developing anuran gonads and in Bidder's organ through Raldh2 and Cyp26b1 proteins. AB - The vitamin A (retinol) and its metabolites such as retinoic acid (RA) affect vertebrate gametogenesis. The level of RA in cells relies on the balance between its synthesis and degradation. The sex-dependent equilibrium is reached in different ways in various species. It is known that RA induces meiosis in developing gonads in mouse, chicken and urodel amphibians, but its role in anuran amphibians has not been studied. Here we show in six anuran species (Xenopus laevis, Bombina bombina, Hyla arborea, Bufo viridis, Rana arvalis and Rana temporaria) that cultured undifferentiated gonads were insensitive to RA treatment, but the RA induced ectopic meiosis in cultured larval testes. In larval testes of all studied species, the exogenous RA induced leptotene phase of I meiotic prophase in gonia, but only in H. arborea and B. viridis gonia progressed to zygotene phase. In the cultured developing ovaries, exogenous RA led to increase in the number of oocytes as compared to the control. Inhibition of either RA synthesis or RA-receptors prevented meiotic entry in larval gonads of all species. Exogenous RA rescued this inhibitory effect demonstrating that the balance in RA homeostasis plays a key role in meiotic entry in anuran gonads. The localization of two enzymes, Raldh2 and Cyp26b1, which antagonistically control RA levels and whose abundance suggests the sites of RA synthesis and degradation respectively, showed two distinct expression patterns specific for (i) X. laevis, H. arborea, R. arvalis, R. temporaria and (ii) B. bombina, B. viridis. Thus, RA, in correlation with specific expression patterns of Raldh2 and Cyp26b, induces meiosis during gonad development in anurans. In addition, in B. viridis, RA signalling seems important for development of the Bidder's organ containing oocytes both in males and females. PMID- 24056064 TI - Mutational analysis of the human MESP1 gene in patients with congenital heart disease reveals a highly variable sequence in exon 1. AB - MESP1 represents an essential transcription factor to guarantee coordinated cardiac development. The expression of MESP1 is thought to be the first sign that a cell has been committed to the cardiac lineage. We analyzed the coding sequence of MESP1 in 215 patients with congenital heart disease. Our results show that the sequence of exon 1 is highly variable with up to seven alterations in individual samples. Five base pair positions (c.157_G>C A53P, rs6496598; c.174_A>C P58P, rs28377352; c.182_T>G L61R, rs28368490; c.669_C>G F223L, rs2305440; c.687_T>G P229P, rs2305441) are particularly variable. In almost half of the samples a 12 base pair insertion after position 55 (c.165_166insGTGCCGAGCCCC P55insVPSP, rs71934166) coding for VPSP was detected which was strongly correlated with the appearance of further amino acid changes (c.157_G>C A53P, c.182_T>G L61R, c.669_C>G F223L). Two missense mutations (c.33_G>C E11D, rs190259690; c.528_A>T T176S) were detected in two patients but were absent in the controls. The assessment of the biological activity of altered MESP1 proteins in a luciferase reporter assay showed an enhanced activity of the c.33_G>C E11D mutation and a reduction of the insertion without an accompanying change of c.182_T>G L61R. The modified biological properties of mutated MESP1 proteins might be associated with the appearance of certain pathological phenotypes of congenital heart disease. PMID- 24056065 TI - Effects of intensified work-related multidisciplinary rehabilitation on occupational participation: a randomized-controlled trial in patients with chronic musculoskeletal disorders. AB - This study examined the effects of work-related multidisciplinary rehabilitation (MR) on occupational participation in patients with chronic musculoskeletal disorders. A randomized-controlled trial was carried out. The sample included patients with chronic musculoskeletal disorders and severe restrictions of work ability (n=222). Participants in the intervention group received a work-related rehabilitation programme following a comprehensive functional capacity evaluation (FCE MR). Controls completed a conventional MR. The analysis was based on 1-year follow-up data. The primary outcome was stable occupational participation (SOP), defined as employment with at most 6 months of sick leave after rehabilitation. The secondary outcomes were the duration of sick leave, employment status and the Pain Disability Index. We included 102 patients in our analysis (intervention: n=55, control: n=47). Despite randomization there were group differences. Adjusting these differences, patients of the FCE MR had 3.5 times higher odds of SOP [95% confidence interval (CI): 1.2-9.8, P=0.018]. However, there was neither a significant difference in the duration of sick leave between both groups (b= 8.0 weeks, 95% CI: -17.4 to 1.4, P=0.095) nor higher odds of employment in favour of the FCE MR after 1 year (odds ratio=2.3, 95% CI: 0.9-5.8, P=0.088). Participants in the FCE MR reported less pain-related disabilities (b=-6.5, 95% CI: -12.6 to -0.4, P=0.038). The study had a limitation in terms of group balance. However, the findings indicate that the work-related FCE MR was more effective for SOP, but did not significantly affect employment rate and sick leave duration. PMID- 24056066 TI - Receipt of HIV/STD prevention counseling by HIV-infected adults receiving medical care in the United States. AB - OBJECTIVE: Guidelines recommend risk-reduction counseling by HIV providers to all HIV-infected persons. Among HIV-infected adults receiving medical care in the United States, we estimated prevalence of exposure to three types of HIV/sexually transmitted disease (STD) risk-reduction interventions and described the characteristics of persons who received these interventions. DESIGN: Data were from the Medical Monitoring Project (MMP), a supplemental HIV surveillance system designed to produce nationally representative estimates of behavioral and clinical characteristics of HIV-infected adults receiving medical care in the United States. METHODS: Descriptive analyses were conducted to estimate the exposure to each type of HIV/STD risk-reduction intervention. Bivariate and multivariable analyses were conducted to assess associations between the selected correlates with each exposure variable. RESULTS: About 44% of participants reported a one-on-one conversation with a healthcare provider about HIV/STD prevention, 30% with a prevention program worker, 16% reported participation in a small group risk-reduction intervention, and 52% reported receiving at least one of the three interventions in the past 12 months. Minority race/ethnicity, low income, and risky sexual behavior consistently predicted greater intervention exposure. However, 39% of persons who reported risky sex did not receive any HIV/STD risk-reduction interventions. CONCLUSIONS: HIV-infected persons in care with fewer resources or those who engaged in risk behaviors were more likely to receive HIV/STD risk-reduction interventions. However, less than half of HIV infected persons in care received HIV/STD prevention counseling from their provider, an intervention that has been shown to be effective and is supported by guidelines. PMID- 24056067 TI - HIV/hepatitis C virus-coinfected patients who achieved sustained virological response are still at risk of developing hepatocellular carcinoma. AB - OBJECTIVE: To describe the frequency and the characteristics of hepatocellular carcinoma (HCC) cases that appeared in HIV/hepatitis C virus (HCV)-coinfected patients with previous sustained virological response (SVR) and to compare these cases to those diagnosed in patients without SVR. METHODS: All HIV/HCV-coinfected patients diagnosed with HCC in 26 hospitals in Spain before 31 December 2012 were analyzed. Comparisons between cases diagnosed in patients with and without previous SVR were made. RESULTS: One hundred and sixty-seven HIV/HCV-coinfected patients were diagnosed with HCC in the participant hospitals. Sixty-five (39%) of them had been previously treated against HCV. In 13 cases, HCC was diagnosed after achieving consecution of SVR, accounting for 7.8% of the overall cases. The median (Q1-Q3) elapsed time from SVR to diagnosis of HCC was 28 (20-39) months. HCC was multicentric and was complicated with portal thrombosis in nine and six patients, respectively. Comparisons with HCC cases diagnosed in patients without previous SVR only yielded a significantly higher proportion of genotype 3 infection [10 (83%) out of 13 cases versus 34 (32%) out of 107; P = 0.001)]. The median (Q1-Q3) survival of HCC was 3 (1-39) months among cases developed in patients with previous SVR, whereas it was 6 (2-20) months in the remaining individuals (P = 0.7). CONCLUSION: HIV/HCV-coinfected patients with previous SVR may develop HCC in the mid term and long term. These cases account for a significant proportion of the total cases of HCC in this setting. Our findings reinforce the need to continue surveillance of HCC with ultrasound examinations in patients with cirrhosis who respond to anti-HCV therapy. PMID- 24056069 TI - HIV-1 seroreversion in HIV-1-infected children: do genetic determinants play a role? AB - BACKGROUND: HIV-1 seroreversion in infants with vertically transmitted HIV-1 infection who started ART in the first months of life has been reported in only a subset of patients. However, the reason why most infants remain seropositive despite similar treatment response is not understood. Here, we assessed whether HIV-1 seroreversion in maternally infected infants is associated with genetic determinants. METHODS: HIV-1-infected infants with a history of documented HIV-1 seroreversion were identified throughout Germany using a standardized questionnaire. At study entry immune reconstitution and anti-HIV-1 antibody expression were monitored as clinical parameters. To search for genetic determinants high-resolution HLA genotyping was performed. In addition, the coding sequence of the chemokine receptor CCR5 was analyzed by Sanger sequencing regarding potential mutations. RESULTS: Patients showed normal numbers and frequencies of lymphocyte subpopulations. Five out of eight patients still had seronegative HIV-1 antibody status at study entry. HLA genotyping revealed the enrichment of HLA-DQB1*03 and DQB1*06 alleles within the patient cohort. Only one patient was found to carry a 32 bp-deletion within the CCR5 gene. CONCLUSION: Our results indicate that the phenotype of HIV-1 seroreversion in infants might correlate with the presence of HLA class II alleles DQB1*03 and DQB1*06. This finding supports the idea of genetic predisposition determining HIV-1 seroreversion in vertically infected infants effectively treated with ART. PMID- 24056068 TI - The magnitude of loss to follow-up of HIV-exposed infants along the prevention of mother-to-child HIV transmission continuum of care: a systematic review and meta analysis. AB - INTRODUCTION: Although prevention of mother-to-child HIV transmission (PMTCT) programs are widely implemented, many children do not benefit from them because of loss to follow-up (LTFU). We conducted a systematic review to determine the magnitude of infant/baby LTFU along the PMTCT cascade. METHODS: Eligible publications reported infant LTFU outcomes from standard care PMTCT programs (not intervention studies) at any stage of the cascade. Literature searches were conducted in Medline, Embase, Web of Knowledge, CINAHL Plus, and Maternity and Infant Care. Extracted data included setting, methods of follow-up, PMTCT regimens, and proportion and timing of LTFU. For programs in sub-Saharan Africa, random-effects meta-analysis was done using Stata v10. Because of heterogeneity, predictive intervals (PrIs; approximate 95% confidence intervals of a future study based on extent of observed heterogeneity) were computed. RESULTS: A total of 826 papers were identified; 25 publications were eligible. Studies were published from 2001 to 2012 and were mostly from sub-Saharan Africa (three were from India, one from UK and one from Ireland). There was extensive heterogeneity in findings. Eight studies reported on LTFU of pregnant HIV-positive women between antenatal care (ANC) registration and delivery, which ranged from 10.9 to 68.1%, pooled proportion 49.08% [95% confidence interval (CI) 39.6-60.9%], and PrI 22.0-100%. Fourteen studies reported LTFU of infants within 3 months of delivery, range 4.8-75%, pooled proportion 33.9% (27.6-41.5), and PrI 15.4-74.2. Children were also lost after HIV testing; this was reported in five studies, pooled estimate 45.5% (35.9-57.6), PrI 18.7-100%. Programs that actively tracked defaulters had better retention outcomes. CONCLUSION: There is unacceptable infant LTFU from PMTCT programs. Countries should incorporate defaulter-tracking as standard to improve retention. PMID- 24056070 TI - Extremely low and sustained HIV incidence among people who inject drugs in a setting of harm reduction. AB - This study created a retrospective cohort by linking repeat respondents in a large, national, annual cross-sectional sero-survey to estimate HIV incidence among people who inject drugs (PWID) in Australia. The results indicate extremely low and sustained rates of HIV incidence (0.11 per 100 person-years) over almost two decades (1995-2012). The findings demonstrate that sustained prevention of HIV transmission among PWID is possible and suggest that the early establishment and rapid scale-up of needle and syringe programmes, at a time when background prevalence was low, likely contributed to the prevention of an HIV epidemic among Australian PWID. PMID- 24056071 TI - Is preexposure prophylaxis ready for prime time use in HIV prevention research? PMID- 24056072 TI - Microarray detection and qPCR screening of potential biomarkers of Folsomia candida (Collembola: Isotomidae) exposed to Bt proteins (Cry1Ab and Cry1Ac). AB - The impact of Bt proteins on non-target arthropods is less understood than their effects on target organisms where the mechanism of toxic action is known. Here, we report the effects of two Bt proteins, Cry1Ab and Cry1Ac, on gene expression in the non-target collembolan, Folsomia candida. A customized microarray was used to study gene expression in F. candida specimens that were exposed to Cry1Ab and Cry1Ac. All selected transcripts were subsequently confirmed by qPCR. Eleven transcripts were finally verified, and three of them were annotated. The responses of all eleven transcripts were tested in specimens for both Cry1Ab and Cry1Ac at a series of concentrations. These transcripts were separated into two and three groups for Cry1Ab and Cry1Ac, respectively, depend on their expression levels. However, those eleven transcripts did not respond to the Bt proteins in Bt-rice residues. PMID- 24056073 TI - Optical manipulation of Saccharomyces cerevisiae cells reveals that green light protection against UV irradiation is favored by low Ca2+ and requires intact UPR pathway. AB - Optical manipulation of Saccharomyces cerevisiae cells with high density green photons conferred protection against the deleterious effects of UV radiation. Combining chemical screening with UV irradiation of yeast cells, it was noted that the high density green photons relied on the presence of intact unfolded protein response (UPR) pathway to exert their protective effect and that the low Ca(2+) conditions boosted the effect. UPR chemical inducers tunicamycin, dithiotreitol and calcium chelators augmented the green light effect in a synergic action against UV-induced damage. Photo-manipulation of cells was a critical factor since the maximum protection was achieved only when cells were pre-exposed to green light. PMID- 24056074 TI - Towards a critical understanding of the photosystem II repair mechanism and its regulation during stress conditions. AB - Photosystem II (PSII) is vulnerable to high light (HL) illumination resulting in photoinhibition. In addition to photoprotection mechanisms, plants have developed an efficient PSII repair mechanism to save themselves from irreversible damage to PSII under abiotic stresses including HL illumination. The phosphorylation/dephosphorylation cycle along with subsequent degradation of photodamaged D1 protein to be replaced by the insertion of a newly synthesized copy of D1 into the PSII complex, is the core function of the PSII repair cycle. The exact mechanism of this process is still under discussion. We describe the recent progress in identifying the kinases, phosphatases and proteases, and in understanding their involvement in the maintenance of thylakoid structure and the quality control of proteins by PSII repair cycle during photoinhibition. PMID- 24056075 TI - A novel ultrasensitive bioluminescent receptor-binding assay of INSL3 through chemical conjugation with nanoluciferase. AB - Insulin-like peptide 3 (INSL3) is a reproduction-related peptide hormone belonging to the insulin/relaxin superfamily, which mediates testicular descent in the male fetus, suppresses male germ cell apoptosis and promotes oocyte maturation in adults by activating the relaxin family peptide receptor 2 (RXFP2). To establish an ultrasensitive receptor-binding assay for INSL3-RXFP2 interaction studies, in the present work we labeled a recombinant INSL3 peptide with a newly developed nanoluciferase (NanoLuc) reporter through a convenient chemical conjugation approach, including the introduction of an active disulfide bond to INSL3 by chemical modification and engineering of a 6* His-Cys-NanoLuc carrying a unique exposed cysteine at the N-terminus. The bioluminescent NanoLuc-conjugated INSL3 retained high binding affinity with the target receptor RXFP2 (Kd = 2.0 +/- 0.1 nM, n = 3) and was able to sensitively monitor the receptor-binding of a variety of ligands, representing a novel ultrasensitive tracer for non radioactive receptor-binding assays. Our present chemical conjugation approach could readily be adapted for conjugation of NanoLuc with other proteins, even other macrobiomolecules, for various highly sensitive bioluminescent assays. PMID- 24056076 TI - SPSSM8: an accurate approach for predicting eight-state secondary structures of proteins. AB - Protein eight-state secondary structure prediction is challenging, but is necessary to determine protein structure and function. Here, we report the development of a novel approach, SPSSM8, to predict eight-state secondary structures of proteins accurately from sequences based on the structural position specific scoring matrix (SPSSM). The SPSSM has been successfully utilized to predict three-state secondary structures. Now we employ an eight-state SPSSM as a feature that is obtained from sequence structure alignment against a large database of 9 million sequences with putative structural information. The SPSSM8 uses a low sequence identity dataset (9062 entries) as a training set and conditional random field for the classification algorithm. The SPSSM8 achieved an average eight-state secondary structure accuracy (Q8) of 71.7% (Q3, 81.6%) for an independent testing set (463 entries), which had an improved accuracy of 10.1% and 4.6% compared with SSPro8 and CNF, respectively, and significantly improved the accuracy of eight-state secondary structure prediction. For CASP 9 dataset (92 entries) the SPSSM8 achieved a Q8 accuracy of 80.1% (Q3, 83.0%). The SPSSM8 was confirmed as an outstanding predictor for eight-state secondary structures of proteins. SPSSM8 is freely available at http://cal.tongji.edu.cn/SPSSM8. PMID- 24056077 TI - Pocket proteins pRb and p107 are required for cortical lamination independent of apoptosis. AB - Pocket proteins (pRb, p107 and p130) are well studied in their role of regulating cell cycle progression. Increasing evidence suggests that these proteins also control early differentiation and even later stages of cell maturation, such as migration. However, pocket proteins also regulate apoptosis, and many of the developmental defects in knock out models have been attributed to increased cell death. Here, we eliminate ectopic apoptosis in the developing brain through the deletion of Bax, and show that pocket proteins are required for radial migration independent of their role in cell death regulation. Following loss of pRb and p107, a population of cortical neurons fails to pass through the intermediate zone into the cortical plate. Importantly, these neurons are born at the appropriate time and this migration defect cannot be rescued by eliminating ectopic cell death. In addition, we show that pRb and p107 regulate radial migration through a cell autonomous mechanism since pRb/p107 deficient neurons fail to migrate to the correct cortical layer within a wild type brain. These results define a novel role of pocket proteins in regulating cortical lamination through a cell autonomous mechanism independent of their role in apoptosis. PMID- 24056078 TI - Inactivation of Cdc42 in neural crest cells causes craniofacial and cardiovascular morphogenesis defects. AB - Neural crest cells (NCCs) are physically responsible for craniofacial skeleton formation, pharyngeal arch artery remodeling and cardiac outflow tract septation during vertebrate development. Cdc42 (cell division cycle 42) is a Rho family small GTP-binding protein that works as a molecular switch to regulate cytoskeleton remodeling and the establishment of cell polarity. To investigate the role of Cdc42 in NCCs during embryonic development, we deleted Cdc42 in NCCs by crossing Cdc42 flox mice with Wnt1-cre mice. We found that the inactivation of Cdc42 in NCCs caused embryonic lethality with craniofacial deformities and cardiovascular developmental defects. Specifically, Cdc42 NCC knockout embryos showed fully penetrant cleft lips and short snouts. Alcian Blue and Alizarin Red staining of the cranium exhibited an unfused nasal capsule and palatine in the mutant embryos. India ink intracardiac injection analysis displayed a spectrum of cardiovascular developmental defects, including persistent truncus arteriosus, hypomorphic pulmonary arteries, interrupted aortic arches, and right-sided aortic arches. To explore the underlying mechanisms of Cdc42 in the formation of the great blood vessels, we generated Wnt1Cre-Cdc42-Rosa26 reporter mice. By beta galactosidase staining, a subpopulation of Cdc42-null NCCs was observed halting in their migration midway from the pharyngeal arches to the conotruncal cushions. Phalloidin staining revealed dispersed, shorter and disoriented stress fibers in Cdc42-null NCCs. Finally, we demonstrated that the inactivation of Cdc42 in NCCs impaired bone morphogenetic protein 2 (BMP2)-induced NCC cytoskeleton remodeling and migration. In summary, our results demonstrate that Cdc42 plays an essential role in NCC migration, and inactivation of Cdc42 in NCCs impairs craniofacial and cardiovascular development in mice. PMID- 24056079 TI - Eph:ephrin-B1 forward signaling controls fasciculation of sensory and motor axons. AB - Axon fasciculation is one of the processes controlling topographic innervation during embryonic development. While axon guidance steers extending axons in the accurate direction, axon fasciculation allows sets of co-extending axons to grow in tight bundles. The Eph:ephrin family has been involved both in axon guidance and fasciculation, yet it remains unclear how these two distinct types of responses are elicited. Herein we have characterized the role of ephrin-B1, a member of the ephrinB family in sensory and motor innervation of the limb. We show that ephrin-B1 is expressed in sensory axons and in the limb bud mesenchyme while EphB2 is expressed in motor and sensory axons. Loss of ephrin-B1 had no impact on the accurate dorso-ventral innervation of the limb by motor axons, yet EfnB1 mutants exhibited decreased fasciculation of peripheral motor and sensory nerves. Using tissue-specific excision of EfnB1 and in vitro experiments, we demonstrate that ephrin-B1 controls fasciculation of axons via a surround repulsion mechanism involving growth cone collapse of EphB2-expressing axons. Altogether, our results highlight the complex role of Eph:ephrin signaling in the development of the sensory-motor circuit innervating the limb. PMID- 24056080 TI - Comparative analysis of amino acid metabolism and transport in CHO variants with different levels of productivity. AB - Chinese hamster ovary (CHO) cells are widely used for the production of biopharmaceuticals; however, our understanding of several physiological elements that contribute to productivity is limited. One of these is amino acid transport and how its limitation and/or regulation might affect productivity. To further our understanding, we have examined the expression of 40 mammalian amino acid transporter genes during batch cultures of three CHO cell lines: a non-producer and two antibody-producing cell lines with different levels of productivity. In parallel, extracellular and intracellular levels of amino acids were quantified. The aim was to identify differences in gene regulation between cell lines and within culture. Our results show that three transporters associated with transport of taurine and beta-alanine, acidic amino acids and branched chain amino acids, are highly upregulated in both antibody-producing cell lines but not in the non-producer. Additionally, genes associated with the transport of amino acids related to the glutathione pathway (alanine, cysteine, cystine, glycine, glutamate) were found to be highly upregulated during the stationary phase of cell culture, correlating well with literature data on the importance of the pathway. Our analysis highlights potential markers for cell line selection and targets for process optimization. PMID- 24056081 TI - Metabolic flux analysis of Arthrobacter sp. CGMCC 3584 for cAMP production based on 13C tracer experiments and gas chromatography-mass spectrometry. AB - Arthrobacter sp. CGMCC 3584 are able to produce cAMP from glucose by the purine synthesis pathway via de novo or salvage biosynthesis. In order to gain an improved understanding of its metabolism, (13)C-labeling experiment and gas chromatography-mass spectrometry (GC-MS) analysis were employed to determine the metabolic network structure and estimate the intracellular fluxes. GC-MS analysis helps to reflect the activity of the intracellular pathways and reactions. The metabolic network mainly contains glycolytic and pentose phosphate pathways, the tricarboxylic acid cycle, and the inactive glyoxylate shunt. Hypoxanthine as a precursor of cAMP and sodium fluoride as an inhibitor of glycolysis were found to increase the cAMP production, as well as the flux through the PP pathway. The effects of adding hypoxanthine and sodium fluoride are discussed based on the enzyme assays and metabolic flux analysis. In conclusion, our results provide quantitative insights into how cells manipulate the metabolic network under different culture conditions and this may be of value in metabolic regulation for desirable production. PMID- 24056082 TI - Stereoselective synthesis of caffeic acid amides via enzyme-catalyzed asymmetric aminolysis reaction. AB - In this study, a new method was developed to prepare enantiopure caffeic acid amides by enzyme-catalyzed asymmetric aminolysis reaction. Methoxymethyl chloride (MOMCl) was first introduced as a protective and esterified reagent to obtain the MOM-protected caffeic acid MOM ester 1d. Aminolysis reaction occurred between 1d and (R, S)-alpha-phenylethylamine in the presence of an immobilized lipase (Novozym 435) from Candida antarctica. Compared with the methyl-protected caffeic acid methyl ester 1c, 1d as substrate improved the lipase-catalyzed reaction rate by 5.5-fold. After Novozym 435-catalyzed aminolysis reaction was established, we evaluated the effects of synthesis parameters on the catalytic activity and enantioselectivity of Novozym 435. A reaction conversion rate of 25.5% and an E value of >100 were achieved under the following optimum conditions: reaction solvent, anhydrous isooctane; reaction temperature, 70 degrees C; reaction time, 24h; ester-to-amine substrate molar ratio, 1:40; and enzyme additive amount, 40 mg. Kinetic and thermodynamic analyses were conducted to determine the main factors affecting enantiomeric discrimination. Novozym 435 still showed 80% of its initial activity after recycling five times. Highly optically pure caffeic acid amides with an enantiomeric excess of 98.5% were finally obtained by HCl deprotection. The established enzyme-catalyzed asymmetric aminolysis method in this study might be used to prepare other caffeic acid amides. PMID- 24056083 TI - Engineered fumarate sensing Escherichia coli based on novel chimeric two component system. AB - DcuS/DcuR two component system (TCS) was firstly employed for the expression of the gfp gene under the dcuB gene promoter in aerobic condition to develop high throughput screening system able to screen microorganisms producing high amount of fumarate. However, the DcuS/DcuR TCS could not produce a signal strong enough to mediate the expression of the gfp gene responding fumarate concentration. Thus, DcuS/DucR TCS was engineered by recruiting the EnvZ/OmpR system, the most studied TCS in E. coli. A chimeric DcuS/EnvZ (DcuSZ) TCS was constructed by fusing the sensor histidine kinase of DcuS with the cytoplasmic catalytic domain of EnvZ, in which the expression of the gfp gene or the ompC gene was mediated by the ompC gene promoter through the cognate response regulator, OmpR. The output signals produced by the chimeric DcuSZ TCS were enough to detect fumarate concentration quantatively, in which the expressions of the gfp gene and the ompC gene were proportional to the fumarate concentration in the medium. Moreover, principal component analysis of C4-dicarboxylates showed that DcuSZ chimera was highly specific to fumarate but could also respond to other C4-dicarboxylates, which strongly suggests that TCS-based high throughput screening system able to screen microorganisms producing target chemicals can be developed. PMID- 24056085 TI - Loss of Memo, a novel FGFR regulator, results in reduced lifespan. AB - Memo is a widely expressed 33-kDa protein required for heregulin (HRG)-, epidermal growth factor (EGF)-, and fibroblast growth factor (FGF)-induced cell motility. Studies in mouse embryonic fibroblasts, wild-type or knockout for Memo, were performed to further investigate the role of Memo downstream of FGFR. We demonstrated that Memo associates with the FGFR signalosome and is necessary for optimal activation of signaling. To uncover Memo's physiological role, Memo conditional-knockout mice were generated. These animals showed a reduced life span, increased insulin sensitivity, small stature, graying hair, alopecia, kyphosis, loss of subcutaneous fat, and loss of spermatozoa in the epididymis. Memo-knockout mice also have elevated serum levels of active vitamin D, 1,25 dihydroxyvitamin D3 (1,25(OH)2D), and calcium compared to control littermates expressing Memo. In summary, the results from in vivo and in vitro models support the hypothesis that Memo is a novel regulator of FGFR signaling with a role in controlling 1,25(OH)2D production and normal calcium homeostasis. PMID- 24056084 TI - Altered likelihood of brain activation in attention and working memory networks in patients with multiple sclerosis: an ALE meta-analysis. AB - Multiple sclerosis (MS) is a chronic neurological disease, frequently affecting attention and working memory functions. Functional imaging studies investigating those functions in MS patients are hard to compare, as they include heterogeneous patient groups and use different paradigms for cognitive testing. The aim of this study was to investigate alterations in neuronal activation between MS patients and healthy controls performing attention and working memory tasks. Two meta analyses of previously published fMRI studies investigating attention and working memory were conducted for MS patients and healthy controls, respectively. Resulting maps were contrasted to compare brain activation in patients and healthy controls. Significantly increased brain activation in the inferior parietal lobule and the dorsolateral prefrontal cortex was detected for healthy controls. In contrast, higher neuronal activation in MS patients was obtained in the left ventrolateral prefrontal cortex and the right premotor area. With this meta-analytic approach previous results of investigations examining cognitive function using fMRI are summarized and compared. Therefore a more general view on cognitive dysfunction in this heterogeneous disease is enabled. PMID- 24056086 TI - First steps for integrating sex and gender considerations into basic experimental biomedical research. AB - In recent decades there has been an increasing recognition of the need to account for sex and gender in biology and medicine, in order to develop a more comprehensive understanding of biological phenomena and to address gaps in medical knowledge that have arisen due to a generally masculine bias in research. We have noted that as basic experimental biomedical researchers, we face unique challenges to the incorporation of sex and gender in our work, and that these have remained largely unarticulated, misunderstood, and unaddressed in the literature. Here, we describe some of the specific challenges to the incorporation of sex and gender considerations in research involving cell cultures and laboratory animals. In our view, the mainstreaming of sex and gender considerations in basic biomedical research depends on an approach that will allow scientists to address these issues in ways that do not undermine our ability to pursue our fundamental scientific interests. To that end, we suggest a number of strategies that allow basic experimental researchers to feasibly and meaningfully take sex and gender into account in their work. PMID- 24056088 TI - HOXA10 mRNA expression and promoter DNA methylation in female pig offspring after in utero estradiol-17beta exposure. AB - Early exposure to environmental estrogens may exert lasting impacts on health. In rodents, homeobox A10 (HOXA10) was demonstrated to be a target of early endocrine disruption, as indicated by persistent changes in uterine HOXA10 expression and promoter DNA methylation in the offspring. This study aimed at analyzing long term effects of estradiol-17beta on porcine uterine HOXA10. Therefore, offspring were exposed in utero to low (0.05 and 10MUg/kg body weight/day) and high (1000MUg/kg body weight/day) doses, respectively. We, furthermore, investigated whether promoter DNA methylation was generally involved in regulating HOXA10 expression. Unexpectedly, the maternal estrogen exposure did not distinctly impact HOXA10 expression and promoter DNA methylation in either pre- or postpubertal offspring. Although differential HOXA10 expression was observed in endometrial tissue during the estrous cycle and the pre-implantation period, no concurrent substantial changes occurred regarding promoter DNA methylation. However, by comparing several tissues displaying larger differences in transcriptional abundance, HOXA10 expression correlated with promoter DNA methylation in prepubertal, but not postpubertal, gilts. Thus, promoter DNA methylation could affect gene expression in pigs, depending on their stage of development. Clearly, early estrogen exposure exerted other effects in pigs as known from studies in rodents. This may be due to endocrine differences as well as to species-specific peculiarities of tissue sensitivity to estradiol-17beta during critical windows of development. PMID- 24056087 TI - FE65 interacts with ADP-ribosylation factor 6 to promote neurite outgrowth. AB - FE65 is an adaptor protein that binds to the amyloid precursor protein (APP). As such, FE65 has been implicated in the pathogenesis of Alzheimer's disease. In addition, evidence suggests that FE65 is involved in brain development. It is generally believed that FE65 participates in these processes by recruiting various interacting partners to form functional complexes. Here, we show that via its first phosphotyrosine binding (PTB) domain, FE65 binds to the small GTPase ADP-ribosylation factor 6 (ARF6). FE65 preferentially binds to ARF6-GDP, and they colocalize in neuronal growth cones. Interestingly, FE65 stimulates the activation of both ARF6 and its downstream GTPase Rac1, a regulator of actin dynamics, and functions in growth cones to stimulate neurite outgrowth. We show that transfection of FE65 and/or ARF6 promotes whereas small interfering RNA knockdown of FE65 or ARF6 inhibits neurite outgrowth in cultured neurons as compared to the mock-transfected control cells. Moreover, knockdown of ARF6 attenuates FE65 stimulation of neurite outgrowth and defective neurite outgrowth seen in FE65-deficient neurons is partially corrected by ARF6 overexpression. Notably, the stimulatory effect of FE65 and ARF6 on neurite outgrowth is abrogated either by dominant-negative Rac1 or knockdown of Rac1. Thus, we identify FE65 as a novel regulator of neurite outgrowth via controlling ARF6-Rac1 signaling. PMID- 24056089 TI - Differential prospective memory profiles in frontotemporal dementia syndromes. AB - BACKGROUND: Prospective memory (PM) is the ability to remember to execute an intended action either at a future time (Time-based PM) or when a specific event occurs (Event-based PM). Previous studies demonstrate impaired PM in Alzheimer's disease (AD); however, the status of PM in frontotemporal dementia (FTD) remains unknown. OBJECTIVE: To examine PM performance and its associated cognitive mechanisms, in two subtypes of FTD: semantic dementia (SD) and the behavioral variant of FTD (bvFTD), in comparison with matched AD and control participants. METHODS: Twenty-four dementia patients (SD = 8; bvFTD = 8; AD = 8) and 12 age- and education-matched controls underwent a shortened version of the Cambridge Behavioural Prospective Memory Test, as well as a standard neuropsychological test battery. RESULTS: Compared to controls, SD patients exhibited preserved Time based PM in the context of impaired Event-based PM, with the latter strongly associated with deficits in semantic processing. In contrast, bvFTD and AD patients demonstrated global PM impairments irrespective of subscale, which strongly correlated with deficits in delayed episodic retrieval for both groups. Caregiver reports of stereotypical behaviors were associated with compromised Event-based PM in SD and Time-based PM in bvFTD, with no such relationship evident in AD. CONCLUSION: This is the first study to investigate prospective memory in FTD syndromes. A relative sparing of Time-based PM was observed in SD, in contrast with global PM deficits in bvFTD. Disrupted PM processing was found to correlate with stereotypical behaviors in FTD syndromes, a finding that we suggest is worthy of further investigation. PMID- 24056090 TI - Impact of low temperature on splicing of atypical group II introns in wheat mitochondria. AB - To investigate the impact of cold on group II intron splicing, we compared the physical forms of excised mitochondrial introns from wheat embryos germinated at room temperature and 4 degrees C. For introns which deviate from the conventional branchpoint structure, we observed predominantly heterogeneous circularized introns in the cold rather than linear polyadenylated forms arising from a hydrolytic pathway as seen at room temperature. In addition, intron-containing precursors are elevated relative to mature mRNAs upon cold treatment. Our findings indicate that low temperature growth not only reduces splicing efficiency, but also shifts the splicing biochemistry of atypical group II introns to novel, yet productive, pathways. PMID- 24056091 TI - Model-based analysis of high shear wet granulation from batch to continuous processes in pharmaceutical production--a critical review. AB - The manufacturing of pharmaceutical dosage forms, which has traditionally been a batch-wise process, is now also transformed into a series of continuous operations. Some operations such as tabletting and milling are already performed in continuous mode, while the adaptation towards a complete continuous production line is still hampered by complex steps such as granulation and drying which are considered to be too inflexible to handle potential product change-overs. Granulation is necessary in order to achieve good flowability properties and better control of drug content uniformity. This paper reviews modelling and supporting measurement tools for the high shear wet granulation (HSWG) process, which is an important granulation technique due to the inherent benefits and the suitability of this unit operation for the desired switch to continuous mode. For gaining improved insight into the complete system, particle-level mechanisms are required to be better understood, and linked with an appropriate meso- or macro scale model. A brief review has been provided to understand the mechanisms of the granulation process at micro- or particle-level such as those involving wetting and nucleation, aggregation, breakage and consolidation. Further, population balance modelling (PBM) and the discrete element method (DEM), which are the current state-of-the-art methods for granulation modelling at micro- to meso scale, are discussed. The DEM approach has a major role to play in future research as it bridges the gap between micro- and meso-scales. Furthermore, interesting developments in the measurement technologies are discussed with a focus towards inline measurements of the granulation process to obtain experimental data which are required for developing good models. Based on the current state of the developments, the review focuses on the twin-screw granulator as a device for continuous HSWG and attempts to critically evaluate the current process. As a result, a set of open research questions are identified. These questions need to be answered in the future in order to fill the knowledge gap that currently exists both at micro- and macro-scale, and which is currently limiting the further development of the process to its full potential in pharmaceutical applications. PMID- 24056092 TI - Evaluation of the light scattering and the turbidity microtiter plate-based methods for the detection of the excipient-mediated drug precipitation inhibition. AB - The excipient-mediated precipitation inhibition is classically determined by the quantification of the dissolved compound in the solution. In this study, two alternative approaches were evaluated, one is the light scattering (nephelometer) and other is the turbidity (plate reader) microtiter plate-based methods which are based on the quantification of the compound precipitate. Following the optimization of the nephelometer settings (beam focus, laser gain) and the experimental conditions, the screening of 23 excipients on the precipitation inhibition of poorly soluble fenofibrate and dipyridamole was performed. The light scattering method resulted in excellent correlation (r>0.91) between the calculated precipitation inhibitor parameters (PIPs) and the precipitation inhibition index (PI(classical)) obtained by the classical approach for fenofibrate and dipyridamole. Among the evaluated PIPs AUC100 (nephelometer) resulted in only four false positives and lack of false negatives. In the case of the turbidity-based method a good correlation of the PI(classical) was obtained for the PIP maximal optical density (OD(max), r=0.91), however, only for fenofibrate. In the case of the OD(max) (plate reader) five false positives and two false negatives were identified. In conclusion, the light scattering-based method outperformed the turbidity-based one and could be reliably used for identification of novel precipitation inhibitors. PMID- 24056093 TI - Clinical significance of postoperative changes in redundant nerve roots after decompressive laminectomy for lumbar spinal canal stenosis. AB - OBJECTIVE: The postoperative time course of redundant nerve roots (RNRs) in patients with lumbar spinal canal stenosis (LSCS) is currently unknown. The purpose of this study is to investigate the relationship between postoperative morphologic changes in detected RNRs and the clinical outcome of patients with LSCS. METHODS: A total of 33 symptomatic patients with LSCS who demonstrated RNRs on magnetic resonance imaging (MRI) were treated with decompressive laminectomy alone. On the basis of the MRI scans obtained 7 days after surgery, patients were stratified into two groups: group 1 included patients with resolution of RNRs and group 2 included patients with persistent RNRs. Comparative parameters were examined between the two groups of patients. RESULTS: We found that 24 of the 33 patients showed resolution of RNRs and 9 showed persistent RNRs. Although there was no difference in the Japanese Orthopedic Association score between the two groups before treatment, group 1 showed a greater recovery of Japanese Orthopedic Association score 1 month postoperatively. MRI demonstrated that the cross sectional area of the preoperative dural sac at the stenotic lesion was smaller in group 2 than in group 1; however, there was no difference in cross-sectional area of the postoperative dural sac between the two groups. Within 12 months, there was no evidence of RNRs in six of the nine cases in group 2. CONCLUSION: Although most patients with LSCS show postoperative resolution of RNRs detected on MRI, some show persistent RNRs postoperatively. The functional outcome of these patients remains poor even if sufficient expansion of the dural sac is achieved postoperatively. PMID- 24056094 TI - Traumatic fracture of a polymethyl methacrylate patient-specific cranioplasty implant. AB - OBJECTIVE: To present a case of a traumatic fracture of a polymethyl methacrylate (PMMA) patient-specific implant (PSI) for cranioplasty. METHODS: A 14-year-old boy with a history of right decompressive hemicraniectomy and reconstructive cranioplasty with a PMMA PSI presented after an unhelmeted bicycle accident with somnolence, confusion, seizures, left hemiparesis, and an obviously deformed cranium. RESULTS: Computed tomography scan showed a comminuted, depressed fracture of the implant and cerebral contusions. The implant was seen to be shattered, resulting in displaced, overriding fragments and significant damage to underlying brain. The patient remained neurologically stable. To minimize the number of operations, intervention was delayed while a polyetheretherketone PSI was fabricated. During surgery, it was noted that the fractured pieces of the implant had caused dural lacerations, and some pieces were embedded in brain parenchyma. The fractured PMMA was removed, and the new implant was placed. The patient remained hemiparetic and was later transferred to an inpatient rehabilitation facility. CONCLUSIONS: PMMA PSIs are commonly used for large defects and generally have good outcomes with low rates of revision. The case report described involves a shattered PMMA PSI after a traumatic impact, which resulted in hemiparesis. The question arises if this type of complication can be easily avoided with the addition of titanium onlay to restrict displacement in the event of fracture. This onlay represents a minor change of technique that could prevent migration of fracture fragments. PMID- 24056095 TI - Surgical complications of anterior cervical diskectomy and fusion for cervical degenerative disk disease: a single surgeon's experience of 1,576 patients. AB - BACKGROUND: Although anterior cervical diskectomy and fusion (ACDF) is a safe and effective procedure, the complications associated with it cannot be underestimated. The aim of this study was to highlight the potential complications associated with ACDF and the strategies to avoid them. METHODS: A total of 1576 patients was included in this retrospective study from 1995 to 2012. All patients were operated by a single surgeon, who used the standard technique. Data pertaining to the postoperative complications and mortality were collected from the database. RESULTS: The overall ACDF-related complication rate in our series was 8.4% (n = 133). Dysphagia was the most common complication encountered in 3.3 % (n = 52) of our patients. The inadvertent dural tear was encountered in 1.3% (n = 20) of our patients. Hoarseness was seen in 1.2% (n = 19) of our patients. A total of 0.88% (n = 14) of the patients had worsening of myelopathy/radiculopathy in the immediate postoperative period. Superficial wound infection occurred in 0.2% (n = 3) of our patients. Postoperative neck hematoma was seen in 0.1% (n = 2), recurrent laryngeal nerve palsy in 0.1% (n = 2), esophageal tear in 0.1% (n = 1), and graft extrusion in 0.88% (n = 14) of our cases. There was 0.1% (n = 1) mortality in our series. Of all these complications, only dysphagia was significantly correlated with 3-level ACDF as compared to 1- or 2-level ACDF (H = 12.89, df= 3, P = 0.05). CONCLUSION: ACDF is a relatively safe procedure with very low morbidity and almost no mortality. In this study, the common complications encountered were postoperative dysphagia, dural injury, and hoarseness. PMID- 24056096 TI - Predictors of outcome in patients with cervical spondylotic myelopathy undergoing surgical treatment: a survey of members from AOSpine International. AB - OBJECTIVES: To conduct a survey of the AOSpine community to determine international perceptions of key predictors of outcome in patients with cervical spondylotic myelopathy. This knowledge will guide the development of clinical prediction models and allow the alignment of clinical perceptions with evidence based reality. METHODS: A request to participate in a survey was distributed to members of AOSpine International. The primary question asked surgeons to rank eight clinical factors according to their ability to predict surgical outcome: age, preoperative severity, sex, duration of symptoms, smoking status, signs, and symptoms. Three questions were also included to address the importance of magnetic resonance imaging as a prognostic tool. RESULTS: Six hundred and eighty nine international spine professionals completed the survey, most of whom were spine surgeons. Duration of symptoms and baseline severity score were ranked as the top two predictors of outcome from all geographic locations, with the exception of Europe, which rated the presence of myelopathic symptoms more important than preoperative severity. There was international agreement that 65 years and a modified Japanese Orthopaedic Association score of 12 were the threshold age and preoperative severity above/below which there becomes a negative impact on outcome. Surgeons most frequently selected diabetes (n = 538) as the comorbidity having the most significant impact on surgical results, followed by neuromuscular disorders (n = 360). Finally, there was international consensus that magnetic resonance imaging is a valuable prognostic tool and that signal changes on T2- and T1/T2-weighted images are the most important parameters in outcome prediction. CONCLUSION: This survey summarizes surgeons' perceptions of the most important predictors of outcome and provides insight into how surgeons undertake decision making. PMID- 24056098 TI - Antimicrobial functionalization of silicone surfaces with engineered short peptides having broad spectrum antimicrobial and salt-resistant properties. AB - Catheter-associated urinary tract infections (CAUTIs) are often preceded by pathogen colonization on catheter surfaces and are a major health threat facing hospitals worldwide. Antimicrobial peptides (AMPs) are a class of new antibiotics that hold promise in curbing CAUTIs caused by antibiotic-resistant pathogens. This study aims to systematically evaluate the feasibility of immobilizing two newly engineered arginine/lysine/tryptophan-rich AMPs with broad antimicrobial spectra and salt-tolerant properties on silicone surfaces to address CAUTIs. The peptides were successfully immobilized on polydimethylsiloxane and urinary catheter surfaces via an allyl glycidyl ether (AGE) polymer brush interlayer, as confirmed by X-ray photoelectron spectroscopy and water contact angle analyses. The peptide-coated silicone surfaces exhibited excellent microbial killing activity towards bacteria and fungi in urine and in phosphate-buffered saline. Although both the soluble and immobilized peptides demonstrated membrane disruption capabilities, the latter showed a slower rate of kill, presumably due to reduced diffusivity and flexibility resulting from conjugation to the polymer brush. The synergistic effects of the AGE polymer brush and AMPs prevented biofilm formation by repelling cell adhesion. The peptide-coated surface showed no toxicity towards smooth muscle cells. The findings of this study clearly indicate the potential for the development of AMP-based coating platforms to prevent CAUTIs. PMID- 24056099 TI - Substrate specificity and function of the pheromone receptor AinR in Vibrio fischeri ES114. AB - Two distinct but interrelated pheromone-signaling systems, LuxI/LuxR and AinS/AinR, positively control bioluminescence in Vibrio fischeri. Although each system generates an acyl-homoserine lactone (AHL) signal, the protein sequences of LuxI/LuxR and AinS/AinR are unrelated. AinS and LuxI generate the pheromones N octanoyl-AHL (C8-AHL) and N-3-oxo-hexanoyl-AHL (3OC6-AHL), respectively. LuxR is a transcriptional activator that responds to 3OC6-AHL, and to a lesser extent to C8-AHL. AinR is hypothesized to respond to C8-AHL and, based on homology to Vibrio harveyi LuxN, to mediate the repression of a Qrr regulatory RNA. However, a DeltaainR mutation decreased luminescence, which was not predicted based on V. harveyi LuxN, raising the possibility of a distinct regulatory mechanism for AinR. Here we show that ainR can complement a luxN mutant, suggesting functional similarity. Moreover, in V. fischeri, we observed ainR-dependent repression of a Pqrr-lacZ transcriptional reporter in the presence of C8-AHL, consistent with its hypothesized regulatory role. The system appears quite sensitive, with a half maximal effect on a Pqrr reporter at 140 pM C8-AHL. Several other AHLs with substituted and unsubstituted acyl chains between 6 and 10 carbons also displayed an AinR-dependent effect on Pqrr-lacZ; however, AHLs with acyl chains of four carbons or 12 or more carbons lacked activity. Interestingly, 3OC6-AHL also affected expression from the qrr promoter, but this effect was largely luxR dependent, indicating a previously unknown connection between these systems. Finally, we propose a preliminary explanation for the unexpected luminescence phenotype of the DeltaainR mutant. PMID- 24056100 TI - Membrane chaperone SecDF plays a role in the secretion of Listeria monocytogenes major virulence factors. AB - Listeria monocytogenes is a Gram-positive human intracellular pathogen that infects diverse mammalian cells. Upon invasion, L. monocytogenes secretes multiple virulence factors that target host cellular processes and promote infection. It has been presumed, but was not empirically established, that the Sec translocation system is the primary mediator of this secretion. Here, we validate an important role for SecDF, a component of the Sec system, in the secretion of several critical L. monocytogenes virulence factors. A DeltasecDF mutant is demonstrated to exhibit impaired membrane translocation of listeriolysin O (LLO), PlcA, PlcB, and ActA, factors that mediate L. monocytogenes phagosomal escape and spread from cell to cell. This impaired translocation was monitored by accumulation of the factors on the bacterial membrane and by reduced activity upon secretion. This defect in secretion is shown to be associated with a severe intracellular growth defect of the DeltasecDF mutant in macrophages and a less virulent phenotype in mice, despite normal growth in laboratory medium. We further show that SecDF is upregulated when the bacteria reside in macrophage phagosomes and that it is necessary for efficient phagosomal escape. Taken together, these data support the premise that SecDF plays a role as a chaperone that facilitates the translocation of L. monocytogenes virulence factors during infection. PMID- 24056097 TI - Fibrin-based biomaterials: modulation of macroscopic properties through rational design at the molecular level. AB - Fibrinogen is one of the primary components of the coagulation cascade and rapidly forms an insoluble matrix following tissue injury. In addition to its important role in hemostasis, fibrin acts as a scaffold for tissue repair and provides important cues for directing cell phenotype following injury. Because of these properties and the ease of polymerization of the material, fibrin has been widely utilized as a biomaterial for over a century. Modifying the macroscopic properties of fibrin, such as elasticity and porosity, has been somewhat elusive until recently, yet with a molecular-level rational design approach it can now be somewhat easily modified through alterations of molecular interactions key to the protein's polymerization process. This review outlines the biochemistry of fibrin and discusses methods for modification of molecular interactions and their application to fibrin based biomaterials. PMID- 24056101 TI - Diffusible signal factor (DSF) synthase RpfF of Xylella fastidiosa is a multifunction protein also required for response to DSF. AB - Xylella fastidiosa, like related Xanthomonas species, employs an Rpf cell-cell communication system consisting of a diffusible signal factor (DSF) synthase, RpfF, and a DSF sensor, RpfC, to coordinate expression of virulence genes. While phenotypes of a DeltarpfF strain in Xanthomonas campestris could be complemented by its own DSF, the DSF produced by X. fastidiosa (XfDSF) did not restore expression of the XfDSF-dependent genes hxfA and hxfB to a DeltarpfF strain of X. fastidiosa, suggesting that RpfF is involved in XfDSF sensing or XfDSF-dependent signaling. To test this conjecture, rpfC and rpfF of X. campestris were replaced by those of X. fastidiosa, and the contribution of each gene to the induction of a X. campestris DSF-dependent gene was assessed. As in X. fastidiosa, XfDSF dependent signaling required both X. fastidiosa proteins RpfF and RpfC. RpfF repressed RpfC signaling activity, which in turn was derepressed by XfDSF. A mutated X. fastidiosa RpfF protein with two substitutions of glutamate to alanine in its active site was incapable of XfDSF production yet enabled a response to XfDSF, indicating that XfDSF production and the response to XfDSF are two separate functions in which RpfF is involved. This mutant was also hypervirulent to grape, demonstrating the antivirulence effects of XfDSF itself in X. fastidiosa. The Rpf system of X. fastidiosa is thus a novel example of a quorum sensing signal synthase that is also involved in the response to the signal molecule that it synthesizes. PMID- 24056102 TI - Listeria monocytogenes multidrug resistance transporters and cyclic di-AMP, which contribute to type I interferon induction, play a role in cell wall stress. AB - The intracellular bacterial pathogen Listeria monocytogenes activates a robust type I interferon response upon infection. This response is partially dependent on the multidrug resistance (MDR) transporter MdrM and relies on cyclic-di-AMP (c di-AMP) secretion, yet the functions of MdrM and cyclic-di-AMP that lead to this response are unknown. Here we report that it is not MdrM alone but a cohort of MDR transporters that together contribute to type I interferon induction during infection. In a search for a physiological function of these transporters, we revealed that they play a role in cell wall stress responses. A mutant with deletion of four transporter genes (DeltamdrMTAC) was found to be sensitive to sublethal concentrations of vancomycin due to an inability to produce and shed peptidoglycan under this stress. Remarkably, c-di-AMP is involved in this phenotype, as overexpression of the c-di-AMP phosphodiesterase (PdeA) resulted in increased susceptibility of the DeltamdrMTAC mutant to vancomycin, whereas overexpression of the c-di-AMP diadenylate cyclase (DacA) reduced susceptibility to this drug. These observations suggest a physiological association between c-di AMP and the MDR transporters and support the model that MDR transporters mediate c-di-AMP secretion to regulate peptidoglycan synthesis in response to cell wall stress. PMID- 24056103 TI - Characterization of the alpha- and beta-mannosidases of Porphyromonas gingivalis. AB - Mannose is an important sugar in the biology of the Gram-negative bacterium Porphyromonas gingivalis. It is a major component of the oligosaccharides attached to the Arg-gingipain cysteine proteases, the repeating units of an acidic lipopolysaccharide (A-LPS), and the core regions of both types of LPS produced by the organism (O-LPS and A-LPS) and a reported extracellular polysaccharide (EPS) isolated from spent culture medium. The organism occurs at inflamed sites in periodontal tissues, where it is exposed to host glycoproteins rich in mannose, which may be substrates for the acquisition of mannose by P. gingivalis. Five potential mannosidases were identified in the P. gingivalis W83 genome that may play a role in mannose acquisition. Four mannosidases were characterized in this study: PG0032 was a beta-mannosidase, whereas PG0902 and PG1712 were capable of hydrolyzing p-nitrophenyl alpha-d-mannopyranoside. PG1711 and PG1712 were alpha-1 -> 3 and alpha-1 -> 2 mannosidases, respectively. No enzyme function could be assigned to PG0973. alpha-1 -> 6 mannobiose was not hydrolyzed by P. gingivalis W50. EPS present in the culture supernatant was shown to be identical to yeast mannan and a component of the medium used for culturing P. gingivalis and was resistant to hydrolysis by mannosidases. Synthesis of O-LPS and A-LPS and glycosylation of the gingipains appeared to be unaffected in all mutants. Thus, alpha- and beta-mannosidases of P. gingivalis are not involved in the harnessing of mannan/mannose from the growth medium for these biosynthetic processes. P. gingivalis grown in chemically defined medium devoid of carbohydrate showed reduced alpha-mannosidase activity (25%), suggesting these enzymes are environmentally regulated. PMID- 24056104 TI - Identification of SPOR domain amino acids important for septal localization, peptidoglycan binding, and a disulfide bond in the cell division protein FtsN. AB - SPOR domains are about 75 amino acids long and probably bind septal peptidoglycan during cell division. We mutagenized 33 amino acids with surface-exposed side chains in the SPOR domain from an Escherichia coli cell division protein named FtsN. The mutant SPOR domains were fused to Tat-targeted green fluorescent protein ((TT)GFP) and tested for septal localization in live E. coli cells. Lesions at the following 5 residues reduced septal localization by a factor of 3 or more: Q251, S254, W283, R285, and I313. All of these residues map to a beta sheet in the published solution structure of FtsN(SPOR). Three of the mutant proteins (Q251E, S254E, and R285A mutants) were purified and found to be defective in binding to peptidoglycan sacculi in a cosedimentation assay. These results match closely with results from a previous study of the SPOR domain from DamX, even though these two SPOR domains share <20% amino acid identity. Taken together, these findings support the proposal that SPOR domains localize by binding to septal peptidoglycan and imply that the binding site is associated with the beta-sheet. We also show that FtsN(SPOR) contains a disulfide bond between beta-sheet residues C252 and C312. The disulfide bond contributes to protein stability, cell division, and peptidoglycan binding. PMID- 24056105 TI - A distant homologue of the FlgT protein interacts with MotB and FliL and is essential for flagellar rotation in Rhodobacter sphaeroides. AB - In this work, we describe a periplasmic protein that is essential for flagellar rotation in Rhodobacter sphaeroides. This protein is encoded upstream of flgA, and its expression is dependent on the flagellar master regulator FleQ and on the class III flagellar activator FleT. Sequence comparisons suggest that this protein is a distant homologue of FlgT. We show evidence that in R. sphaeroides, FlgT interacts with the periplasmic regions of MotB and FliL and with the flagellar protein MotF, which was recently characterized as a membrane component of the flagellum in this bacterium. In addition, the localization of green fluorescent protein (GFP)-MotF is completely dependent on FlgT. The Mot(-) phenotype of flgT cells was weakly suppressed by point mutants of MotB that presumably keep the proton channel open and efficiently suppress the Mot(-) phenotype of motF and fliL cells, indicating that FlgT could play an additional role beyond the opening of the proton channel. The presence of FlgT in purified filament-hook-basal bodies of the wild-type strain was confirmed by Western blotting, and the observation of these structures under an electron microscope showed that the basal bodies from flgT cells had lost the ring that covers the LP ring in the wild-type structure. Moreover, MotF was detected by immunoblotting in the basal bodies obtained from the wild-type strain but not from flgT cells. From these results, we suggest that FlgT forms a ring around the LP ring, which anchors MotF and stabilizes the stator complex of the flagellar motor. PMID- 24056106 TI - Aconitase-mediated posttranscriptional regulation of Helicobacter pylori peptidoglycan deacetylase. AB - Some bacterial aconitases are bifunctional proteins that function in the citric acid cycle and act as posttranscriptional regulators in response to iron levels and oxidative stress. We explore the role of aconitase (AcnB) in Helicobacter pylori as a posttranscriptional regulator of the cell wall-modifying enzyme peptidoglycan deacetylase, PgdA. Under oxidative stress, PgdA is highly expressed and confers resistance to lysozyme in wild-type cells. PgdA protein expression as well as transcript abundance is significantly decreased in an acnB mutant. In the wild type, pgdA mRNA half-life was 13 min, whereas the half-life for the acnB strain was 7 min. Based on electrophoretic mobility shift assays and RNA footprinting, the H. pylori apo-AcnB binds to the 3'-untranslated region of the pgdA RNA transcript. Some of the protected bases (from footprinting) were localized in proposed stem-loop structures. AcnB-pgdA transcript binding was abolished by the addition of iron. The acnB strain is more susceptible to lysozyme-mediated killing and was attenuated in its ability to colonize mice. The results support a model whereby apo-AcnB directly interacts with the pgdA transcript to enhance stability and increase deacetylase enzyme expression, which impacts in vivo survival. PMID- 24056107 TI - Characterization of the interaction between the chlamydial adhesin OmcB and the human host cell. AB - In a previous study, we reported that the OmcB protein from Chlamydia pneumoniae mediates adhesion of the infectious elementary body to human HEp-2 cells by interacting with heparin/heparan sulfate-like glycosaminoglycans (GAGs) via basic amino acids located in the first of a pair of XBBXBX heparin-binding motifs (K. Moelleken and J. H. Hegemann, Mol. Microbiol. 67:403-419, 2008). In the present study, we show that the basic amino acid at position 57 (arginine) in the first XBBXBX motif, the basic amino acid at position 61 (arginine) in the second motif, and another amino acid (lysine 69) C terminal to it play key roles in the interaction. In addition, we show that discrimination between heparin-dependent and -independent adhesion by C. trachomatis OmcBs is entirely dependent on three variable amino acids in the so-called variable domain C terminal to the conserved XBBXBX motif. Here, the predicted conformational change in the secondary structure induced by the proline at position 66 seems to be crucial for heparin recognition. Finally, we performed neutralization experiments using different anti-heparan sulfate antibodies to gain insight into the nature of the GAGs recognized by OmcB. The results suggest that C. trachomatis serovar L2 OmcB interacts with 6-O-sulfated domains of heparan sulfate, while C. pneumoniae OmcB apparently interacts with domains of heparan sulfate harboring a diverse subset of O-sulfations. PMID- 24056108 TI - Characterization and molecular mechanism of AroP as an aromatic amino acid and histidine transporter in Corynebacterium glutamicum. AB - Corynebacterium glutamicum is equipped with abundant membrane transporters to adapt to a changing environment. Many amino acid transporters have been identified in C. glutamicum, but histidine uptake has not been investigated in detail. Here, we identified the aromatic amino acid transporter encoded by aroP as a histidine transporter in C. glutamicum by a combination of the growth and histidine uptake features. Characterization of histidine uptake showed that AroP has a moderate affinity for histidine, with a Km value of 11.40 +/- 2.03 MUM, and histidine uptake by AroP is competitively inhibited by the aromatic amino acids. Among the four substrates, AroP exhibits a stronger preference for tryptophan than for tyrosine, phenylalanine, and histidine. Homology structure modeling and molecular docking were performed to predict the substrate binding modes and conformational changes during substrate transport. These results suggested that tryptophan is best accommodated in the binding pocket due to shape compatibility, strong hydrophobic interactions, and the lowest binding energy, which is consistent with the observed substrate preference of AroP. Furthermore, the missense mutations of the putative substrate binding sites verified that Ser24, Ala28, and Gly29 play crucial roles in substrate binding and are highly conserved in the Gram-positive bacteria. Finally, the expression of aroP is not significantly affected by extracellular histidine or aromatic amino acids, indicating that the physiological role of AroP may be correlated with the increased fitness of C. glutamicum to assimilate extracellular amino acid for avoiding the high energy cost of amino acid biosynthesis. PMID- 24056109 TI - The two CcdA proteins of Bacillus anthracis differentially affect virulence gene expression and sporulation. AB - The cytochrome c maturation system influences the expression of virulence factors in Bacillus anthracis. B. anthracis carries two copies of the ccdA gene, encoding predicted thiol-disulfide oxidoreductases that contribute to cytochrome c maturation, while the closely related organism Bacillus subtilis carries only one copy of ccdA. To investigate the roles of the two ccdA gene copies in B. anthracis, strains were constructed without each ccdA gene, and one strain was constructed without both copies simultaneously. Loss of both ccdA genes results in a reduction of cytochrome c production, an increase in virulence factor expression, and a reduction in sporulation efficiency. Complementation and expression analyses indicate that ccdA2 encodes the primary CcdA in B. anthracis, active in all three pathways. While CcdA1 retains activity in cytochrome c maturation and virulence control, it has completely lost its activity in the sporulation pathway. In support of this finding, expression of ccdA1 is strongly reduced when cells are grown under sporulation-inducing conditions. When the activities of CcdA1 and CcdA2 were analyzed in B. subtilis, neither protein retained activity in cytochrome c maturation, but CcdA2 could still function in sporulation. These observations reveal the complexities of thiol-disulfide oxidoreductase function in pathways relevant to virulence and physiology. PMID- 24056110 TI - Attenuation correction for flexible magnetic resonance coils in combined magnetic resonance/positron emission tomography imaging. AB - INTRODUCTION: Attenuation correction for magnetic resonance (MR) coils is a new challenge that came about with the development of combined MR and positron emission tomography (PET) imaging. This task is difficult because such coils are not directly visible on either PET or MR acquisitions with current combined scanners and are therefore not easily localized in the field of view. This issue becomes more evident when trying to localize flexible MR coils (eg, cardiac or body matrix coil) that change position and shape from patient to patient and from one imaging session to another. In this study, we proposed a novel method to localize and correct for the attenuation and scatter of a flexible MR cardiac coil, using MR fiducial markers placed on the surface of the coil to allow for accurate registration of a template computed tomography (CT)-based attenuation map. MATERIALS AND METHODS: To quantify the attenuation properties of the cardiac coil, a uniform cylindrical water phantom injected with 18F-fluorodeoxyglucose (18F-FDG) was imaged on a sequential MR/PET system with and without the flexible cardiac coil. After establishing the need to correct for the attenuation of the coil, we tested the feasibility of several methods to register a precomputed attenuation map to correct for the attenuation. To accomplish this, MR and CT visible markers were placed on the surface of the cardiac flexible coil. Using only the markers as a driver for registration, the CT image was registered to the reference image through a combination of rigid and deformable registration. The accuracy of several methods was compared for the deformable registration, including B-spline, thin-plate spline, elastic body spline, and volume spline. Finally, we validated our novel approach both in phantom and patient studies. RESULTS: The findings from the phantom experiments indicated that the presence of the coil resulted in a 10% reduction in measured 18F-FDG activity when compared with the phantom-only scan. Local underestimation reached 22% in regions of interest close to the coil. Various registration methods were tested, and the volume spline was deemed to be the most accurate, as measured by the Dice similarity metric. The results of our phantom experiments showed that the bias in the 18F-FDG quantification introduced by the presence of the coil could be reduced by using our registration method. An overestimation of only 1.9% of the overall activity for the phantom scan with the coil attenuation map was measured when compared with the baseline phantom scan without coil. A local overestimation of less than 3% was observed in the ROI analysis when using the proposed method to correct for the attenuation of the flexible cardiac coil. Quantitative results from the patient study agreed well with the phantom findings. CONCLUSIONS: We presented and validated an accurate method to localize and register a CT-based attenuation map to correct for the attenuation and scatter of flexible MR coils. This method may be translated to clinical use to produce quantitatively accurate measurements with the use of flexible MR coils during MR/PET imaging. PMID- 24056111 TI - Assessing lung transplantation ischemia-reperfusion injury by microcomputed tomography and ultrashort echo-time magnetic resonance imaging in a mouse model. AB - PURPOSE: Ischemia-reperfusion injury (I/R) is a common early complication after lung transplantation. The purpose of this study was to compare ultrashort echo time (UTE) sequences in magnetic resonance imaging (MRI) with a microcomputed tomography (micro-CT) reference standard for detection of I/R injury in a lung transplantation mouse model. MATERIALS AND METHODS: Six mice (C57BL/6) underwent orthotopic lung transplantation using donor grafts that were exposed to 6-hour cold ischemia. Imaging was performed within 24 hours after the transplantation with high-resolution micro-CT (tube voltage, 50 kV; current, 500 mA; aluminum filter, 0.5 mm; voxel size, 35 * 35 * 35 MUm3) and small-animal MRI at 4.7 T with a linearly polarized whole-body mouse coil. The imaging protocol comprised radial 3-dimensional UTE sequences with different echo times (repetition time, 8 milliseconds; echo time, 50/75/100/500/1500/3000/4000/5000 MUs; voxel size, 350 * 350 * 350 MUm3). Images were assessed visually and through calculation of contrast-to-noise ratio (CNR) values. Calculated S0 values and T2* transverse relaxation times (MRI) of lung parenchyma were compared with Hounsfield unit (HU) density in micro-CT images. Receiver operating characteristic curves and area under the curve values were calculated for comparison of diagnostic power. All samples underwent a histologic examination. RESULTS: The results of both UTE MRI and micro-CT showed an excellent depiction of pulmonary infiltration due to I/R injury, with MRI exhibiting a significantly higher CNR (mean [SD] CNR MRI, 19.7 [8.0]; mean [SD] CNR micro-CT, 10.3 [2.5]; P < 0.001). Measured parametrical values were as follows: mean (SD) HU, -416 (120); mean (SD) S0 value, 1655 (440); mean (SD) T2*, 895 (870) MUs for the non-transplanted right lung and mean (SD) HU, 29 (35); mean (SD) S0 value, 2310 (300); and mean (SD) T2*, 4550 (3230) MUs for the transplanted left lung. Slight infiltration could be better discriminated with micro-CT, whereas, in strong infiltration, a better contrast was provided by UTE MRI. The area under the curve values resulting from the receiver operating characteristic curve analysis were 0.99 for HU density, 0.89 for S0, 0.96 for T2*, and 0.98 for the combination of S0 and T2*. CONCLUSIONS: Results show that MRI of the lung has a similar diagnostic power compared with that of micro-CT regarding the detection of I/R injury after experimental lung transplantation. Both modalities provide complementary information in the assessment of dense and slight infiltration in the early phase after lung transplantation. Therefore, UTE MRI seems to be a promising addition to computed tomographic imaging in the assessment of I/R injury after lung transplantation. PMID- 24056113 TI - T2* mapping of articular cartilage: current status of research and first clinical applications. AB - T2* mapping is a relatively new method for the compositional assessment of the articular cartilage. Typically, a multigradient echo or an ultrashort echo time imaging technique with a range of short and very short echo times is used. In most studies, imaging is performed at a high field strength, that is, 3 and 7 T. Postprocessing includes exponential fitting of relaxation decay and manual region of-interest-based measurements of T2* times on T2* maps. Detailed analyses of T2* times of articular cartilage have shown distinct T2* components with shorter and longer T2* times. Moreover, there is a zonal distribution with a significant depthwise gradient of T2*, with relatively short times near the osteochondral junction and relatively long times at the cartilage's surface. T2* times of normal articular cartilage at the knee are, when averaged over the whole cartilage thickness and using monoexponential fitting, approximately 20 milliseconds. The results of recent studies have shown a good test-retest as well as interreader and intrareader reliabilities for T2* mapping. This article provides a descriptive review of the current literature, briefly discusses the technique itself, and provides an outlook on future research questions and possible clinical applications. PMID- 24056112 TI - Design and application of combined 8-channel transmit and 10-channel receive arrays and radiofrequency shimming for 7-T shoulder magnetic resonance imaging. AB - OBJECTIVE: The objective of the study was to investigate the feasibility of 7-T shoulder magnetic resonance imaging by developing transmit and receive radiofrequency (RF) coil arrays and exploring RF shim methods. MATERIALS AND METHODS: A mechanically flexible 8-channel transmit array and an anatomically conformable 10-channel receive array were designed and implemented. The transmit performance of various RF shim methods was assessed through local flip angle measurements in the right and left shoulders of 6 subjects. The receive performance was assessed through signal-to-noise ratio measurements using the developed 7-T coil and a baseline commercial 3-T coil. RESULTS: The 7-T transmit array driven with phase-coherent RF shim weights provided adequate B1+ efficiency and uniformity for turbo spin echo shoulder imaging. B1+ twisting that is characteristic of high-field loop coils necessitates distinct RF shim weights in the right and left shoulders. The 7-T receive array provided a 2-fold signal-to noise ratio improvement over the 3-T array in the deep articular shoulder cartilage. CONCLUSIONS: Shoulder imaging at 7-T is feasible with a custom transmit/receive array either in a single-channel transmit mode with a fixed RF shim or in a parallel transmit mode with a subject-specific RF shim. PMID- 24056114 TI - Colorectal cancer liver metastases: long-term survival and progression-free survival after thermal ablation using magnetic resonance-guided laser-induced interstitial thermotherapy in 594 patients: analysis of prognostic factors. AB - PURPOSE: The purpose of this study was the evaluation of prognostic factors for long-term survival and progression-free survival (PFS) after treatment of colorectal cancer (CRC) liver metastases with magnetic resonance-guided laser induced interstital thermotherapy (LITT). PATIENTS AND METHODS: We included 594 patients (mean age, 61.2 years) with CRC liver metastases who were treated with LITT. The statistical analysis of the long-term survival and PFS were based on the Kaplan-Meier method. The Cox regression model tested different parameters that could be of prognostic value. The tested prognostic factors were the following: sex, age, the location of primary tumor, the number of metastases, the maximal diameter and total volume of metastases and necroses, the quotient of total volumes of metastases and necroses, the time of appearance of liver metastases and location in the liver, the TNM classification of CRC, extrahepatic metastases, and neoadjuvant treatments. RESULTS: The median survival was 25 months starting from the date of the first LITT. The 1-, 2-, 3-, 4-, and 5-year survival rates were 78%, 50.1%, 28%, 16.4%, and 7.8%, respectively. The median PFS was 13 months. The 1-, 2-, 3-, 4-, and 5-year PFS rates were 51.3%, 35.4%, 30.7%, 25.4%, and 22.3%, respectively. The number of metastases and their maximal diameter were the most important prognostic factors for both long-term survival and PFS. Long-term survival was also highly influenced by the initial involvement of the lymph nodes. CONCLUSIONS: For patients treated with LITT for CRC liver metastases, the number and size of metastases, together with the initial lymph node status, are significant prognostic factors for long-term survival. PMID- 24056115 TI - Low-dose nitrite alleviates early effects of an X-ray contrast medium on renal hemodynamics and oxygenation in rats. AB - OBJECTIVE: Renal tissue hypoperfusion and hypoxia are pivotal pathophysiological elements in contrast media (CM)-induced acute kidney injury (AKI). According to a new paradigm of hypoxic vasodilation, nitrite is reduced to vasodilatory nitric oxide by hemoglobin in hypoxic areas. Here, we study the potential of low-dose nitrite administration to alleviate CM-induced AKI. MATERIALS AND METHODS: In anesthetized rats, arterial blood pressure, total renal blood flow, cortical and medullary erythrocyte flux and oxygen tension (pO2), hindquarter blood flow, and methemoglobin were measured. Nitrite was continuously infused (0.172 mg/h per kilogram of body mass for 10 minutes; thereafter, 0.057 mg/h per kilogram of body mass); control rats received isotonic saline. Hypoxic vasodilation was studied through a brief period of hypoxia (10% inspiratory oxygen fraction). Then, 1.5 mL of the CM, iodixanol of 320 mg I/mL, was injected into the thoracic aorta and the effects studied for 60 minutes. RESULTS: Nitrite infusion slightly increased methemoglobin, but it did not change per se any other parameter including arterial pressure. However, nitrite enhanced the hypoxic vasodilation in the kidney and hindquarter (by 100% and 70%, respectively) during the brief hypoxic challenge. In the control rats, CM resulted in renal tissue hypoxia mainly because of renal vasoconstriction. Medullary and cortical pO2 dropped upon CM injection and remained 30% to 40% below pre-CM level throughout the observation period. Nitrite infusion improved renal tissue oxygenation mainly by hindering CM induced renal vasoconstriction. After a small transient drop (<25% for <5 minutes), medullary and cortical pO2 was restored to values indistinguishable from pre-CM levels. CONCLUSIONS: Low-dose nitrite infusion greatly alleviates early adverse effects of CM on renal tissue oxygenation in rats. Nitrite's beneficial effect probably relies on its reduction to nitric oxide in hypoxic tissue with ensuing vasodilation. Our nitrite dose resulted in a negligible increase in methemoglobin and did not induce hypotension. Thus, low-dose nitrite infusion might prove to be a reasonably specific measure to reduce the risk for CM-induced AKI. PMID- 24056116 TI - Characterization of the intestinal and hepatic uptake/efflux transport of the magnetic resonance imaging contrast agent gadolinium-ethoxylbenzyl diethylenetriamine-pentaacetic acid. AB - OBJECTIVES: The objectives of the study were to measure the pharmacokinetics and liver enhancement of gadoxetate (gadolinium-ethoxylbenzyl-diethylenetriamine pentaacetic acid [Gd-EOB-DTPA], Eovist, Primovist) after oral and intravenous administration in wild-type and (multidrug resistance-associated protein 2) Mrp2 deficient rats and to evaluate the in vitro transport of the contrast agent via intestinal and hepatic transporter proteins. MATERIALS AND METHODS: Gadolinium ethoxylbenzyl-diethylenetriamine-pentaacetic acid-enhanced magnetic resonance imaging and pharmacokinetics of Gd-EOB-DTPA after intravenous and oral administration were evaluated in wild-type and Mrp2-deficient rats using T1 weighted magnetic resonance imaging and a validated liquid chromatography-mass spectrometry method, respectively. Cellular uptake of Gd-EOB-DTPA was measured in stably transfected human embrionic kidney 293-cells expressing oragnic anion transporting polypeptide 1A2 or organic cation transporter 3 and Madin Darby canine kidney 2-cells expressing apical sodium dependent bile acid transporter. The affinity to MRP2 and multidrug resistance-associated protein 3 was measured using inside-out vesicles. RESULTS: In vitro, Gd-EOB-DTPA was demonstrated to be a substrate for OATP1A2 (mean [SD] of the Michaelis-Menten constant [K(m)], 1.0 [0.4] mmol/L; mean [SD] of the maximal uptake rate [V(max)], 101.3 [21.1] pmol/mg per minute), MRP2 (K(m), 1.0 [0.5] mmol/L; V(max), 86.8 [31.1] pmol/mg per minute), and multidrug resistance-associated protein 3 (K(m), 1.8 [0.3] mmol/L; V(max), 116 [15.9] pmol/mg per minute) but not for the apical sodium-dependent bile acid transporter and organic cation transporter 3. After the oral administration to the wild-type animals, Gd-EOB-DTPA was considerably absorbed from the small intestine (bioavailability, approximately 17%) and predominately eliminated via feces after intravenous dosing (approximately 96%). In the Mrp2 deficient rats, oral bioavailability increased to approximately 21% and Gd-EOB DTPA was exclusively excreted into urine. Magnetic resonance enhancement of the liver was significantly prolonged in the Mrp2-deficient rats compared with the wild-type rats (mean [SD] area under the curve0-90, 36.4 [8.5] vs 14.8 [10.3] arbitary units per minute; P = 0.003; time to maximum plasma concentration, 48.6 [23.8] vs 6.0 [3.1] minutes; P = 0.001). CONCLUSIONS: The nonmetabolized Gd-EOB DTPA may have some potentials to be used as a probe-contrast agent to evaluate transporter-mediated mechanisms along the enterohepatic absorption route for drugs by functional visualization in vivo. PMID- 24056117 TI - Comparison of fat saturation techniques for single-shot fast spin echo sequences for 7-T body imaging. AB - OBJECTIVES: For T2-weighted abdominal images, homogenous fat suppression (FS) is crucial for diagnosis, but inherent B0/B1 inhomogeneities at 7 T lead to inhomogeneous FS and to tissue signal loss for most techniques. Here, 4 different FS techniques for single-shot fast spin echo were compared, whereby the recently proposed time-interleaved acquisition of modes (TIAMO) was used for the imaging portion of the sequence to reduce B1 artifacts. MATERIALS AND METHODS: Fat suppression techniques included a novel method using TIAMO (TIAMO FS: multiple fat-selective 90-degree radiofrequency pulses applied with alternating transmit radiofrequency modes), slice-selective gradient reversal (SSGR), slice-selective smaller bandwidth refocusing pulses (SSB), and the combination of SSGR and SSB with TIAMO FS. Ten volunteers were examined in 6 different ways in the following order: without any FS, with TIAMO FS, with SSGR, SSGR with preceding TIAMO FS, SSB, and SSB with preceding TIAMO FS. For evaluation of the techniques, regions of interests were placed identically for all 6 protocols per volunteer in subcutaneous fat, intra-abdominal fat, organs, and muscle. Overall image quality, artifacts, quality of subcutaneous/intra-abdominal/retroperitoneal FS, and homogeneity of FS were rated over the entire field of view by 2 experienced radiologists using a 5-point scale. RESULTS: Comparing the different FS techniques, only SSGR and SSGR combined with TIAMO FS led to a nearly homogeneous FS over the entire field of view and all slices. All other techniques showed severe FS inhomogeneities. Results of a radiologic evaluation confirmed the observations made by the quantitative analysis. CONCLUSIONS: Of the compared techniques, the most favorable was SSGR because, here, a homogeneous FS with moderate tissue signal loss of approximately 20% was achieved with no additional preparation pulses being necessary. Using this FS technique combined with TIAMO image acquisition, delineation between fat and bright liquids in single-shot fast spin echo images, which is essential for diagnosis, is possible at 7 T. PMID- 24056118 TI - Reduced interhemispheric interaction in non-autistic individuals with normal but high levels of autism traits. AB - People with autism spectrum disorder (ASD) show superior performance for tasks requiring detail-focused processing. Atypical neural connectivity and reduced interhemispheric communication are posited to underlie this cognitive advantage. Given recent conceptualization of autism as a continuum, we sought to investigate whether people with normal but high levels of autism like traits (AQ) also exhibit reduced hemispheric interaction. Sixty right-handed participants completed the AQ questionnaire (Baron-Cohen, Wheelwright, Skinner, Martin, & Clubley, 2001) and a lateralised letter matching task that assessed unilateral and bilateral performance in response to simple (physical) and complex (identity) matches. Whereas people with low self-rated AQ scores showed a bilateral advantage for the more complex task, indicating normal interhemispheric interaction, people in the high AQ group failed to show a bilateral gain for the computationally demanding stimuli. This finding of disrupted interhemispheric interaction converges with a dimensional conceptualisation of ASD, suggesting that the structural anomalies of ASD extend to non-autistic individuals with high levels of autism traits. PMID- 24056119 TI - Retinoid signaling in pathological remodeling related to cardiovascular disease. AB - Retinoids, the active derivatives of vitamin A, are critical signaling molecules in crucial biological processes such as embryonic development, the maintenance of immune function, and cellular differentiation and proliferation. Preclinical studies have shown that retinoids also regulate morphological changes during the progression of cardiovascular disease (CVD). CVD is complexly formed in a mutual chain reaction of various modern lifestyle-related risk factors such as dyslipidemia, hypertension, diabetes, and obesity. These factors induce the pathological remodeling of adipose tissue, the vasculature, and the ventricles, which are a potential target for retinoid signaling. This perspective highlights emerging topics and future prospectives on the relationship between CVD and retinoid signaling. PMID- 24056120 TI - Assay development of inducible human renal phosphate transporter Npt2A (SLC34A1) in Flp-In-Trex-HEK293 cells. AB - Hyperphosphatemia is associated with severe decline of renal function in chronic kidney disease and elevates cardiovascular mortality. Type II sodium dependent phosphate transporter 2A (Npt2A) plays a major role in renal phosphate reabsorption and could be explored as a target for anti-hyperphosphatemia therapy. Human Npt2A transporter activity was examined upon transfection into CHO, MDCK, HEK293, Flp-In-CHO and Flp-In-HEK293 cells. Only kidney-derived cells expressed functional Npt2A. HEK293 and Flp-In-HEK293 cell lines stably transfected with hNpt2A could be selected, but these cells were inactive in phosphate transport. This suggests that high-level, constitutive Npt2A expression has deleterious effects on the cell. By using the conditional promoter in the Flp In-Trex vector, functional expression of Npt2A was achieved by doxycycline induction in HEK293 cells. The EGFP tagged and non-tagged, inducible stable hNpt2A-HEK293 cell lines afforded development of a robust phosphate uptake assay mediated by hNpt2A, which can be used to screen hNpt2A inhibitors and inducers of hNpt2A expression. Using this assay, the small molecule LC-1 was identified as a potent inhibitor of hNpt2A, suggesting that it is feasible to develop potent specific hNpt2A inhibitors to control phosphate overloading for hyperphosphatemia therapy. PMID- 24056121 TI - Effects of post-resuscitation administration with sodium hydrosulfide on cardiac recovery in hypoxia-reoxygenated newborn piglets. AB - Hydrogen sulfide may protect multiple organ systems against ischemic-reperfusion injuries. It is unknown if treatment with sodium hydrosulfide (NaHS, a hydrogen sulfide donor) will improve myocardial function and minimize oxidative stress in hypoxic-reoxygenated newborn piglets. Mixed breed piglets (1-5 day, 1.5-2.5 kg) were anesthetized and acutely instrumented for the measurement of systemic, pulmonary and regional (carotid, superior mesenteric and renal) hemodynamics and blood gas parameters. The piglets were induced with normocapnic alveolar hypoxia (10-15% oxygen, 2h) followed by reoxygenation with 100% (1h) then 21% oxygen (3h). At 10 min of reoxygenation, either NaHS (10mg/kg, 5 ml) or saline (5 ml) was administered intravenously for 30 min (5 min bolus followed by 25 min of continuous infusion) in a blinded, block-randomized fashion (n = 7/group). Plasma lactate and troponin I levels and tissue markers of myocardial oxidative stress were also determined. Two hours hypoxia caused cardiogenic shock (45 +/- 3% of respective normoxic baseline), reduced regional perfusion with metabolic acidosis (pH 6.94 +/- 0.02). NaHS infusion significantly improved recovery of cardiac index (84 +/- 3% vs. 72 +/- 5% in controls), systemic oxygen delivery (84 +/- 3% vs. 72 +/- 5% in controls) and systemic oxygen consumption (102 +/- 5% vs. 84 +/- 6% in controls) at 4h of reoxygenation. NaHS had no significant effect on systemic and pulmonary blood pressures, regional blood flows, plasma lactate and troponin I levels. The myocardial glutathionine ratio was reduced in piglets treated with NaHS (vs. controls, P<0.05). Post-resuscitation administration of NaHS improves cardiac function and systemic perfusion and attenuates myocardial oxidative stress in newborn piglets following hypoxia-reoxygenation. PMID- 24056122 TI - Evaluation of the effect of kaempferol in a murine allergic rhinitis model. AB - Kaempferol (KP) is a major compound of Naju Jjok (Polygonum tinctorium Lour.). The effect of KP on allergic rhinitis (AR) has not been elucidated. Here, we report the effects and mechanisms of KP on new and predominant mediators of AR using an eosinophil cell line, Eol-1 and an ovalbumin (OVA)-induced AR mouse model. KP significantly inhibited the production of interleukin (IL)-32 and IL-8 and activation of caspase-1 in Eol-1 cells. Allergic symptoms and predominant mediators (IgE and histamine) in the KP-administered group were significantly lower than in the AR group. The levels of interferon-gamma were enhanced while the levels of IL-4 were reduced in the KP group. KP significantly reduced the levels of IL-32 and thymic stromal lymphopoietin (TSLP) compared with the AR mice. KP reduced the levels of inflammation-related proteins. In the KP administered groups, the infiltrations of eosinophils and mast cells increased by OVA were decreased. In addition, KP significantly reduced caspase-1 activity in nasal mucosa tissue of AR mice. Our findings indicate that KP has an anti allergic effect through the regulation of the production of IL-32 and TSLP and caspase-1 activity in allergic diseases including AR. PMID- 24056123 TI - Dysregulations of UDP-glucuronosyltransferases in rats with valproic acid and high fat diet induced fatty liver. AB - Both high fat diet (HFD) and valproic acid (VPA) interfere with mitochondrial beta-oxidation of fatty acids, which subsequently triggers microvesicular fatty liver and hepatic dysfunction. UDP-glucuronosyltransferases, the major phase II drug metabolism enzymes, play a pivotal role in detoxifying various exogenous and endogenous compounds. This study aimed to investigate the dysregulation patterns of major UDP-glucuronosyltransferases (UGTs) induced by VPA and/or HFD. Biochemical and histopathological results showed that chronic treatments of VPA and HFD induced fatty liver and liver dysfunction in a synergistic manner. VPA upregulated the mRNA levels of UGT1A1, 1A6, 1A7, and UGT2B1. Notably, the protein expression and enzymatic activity of UGT1A6 were significantly increased in rats treated with HFD or VPA alone, and were further enhanced by HFD and VPA co treatment. This dysregulation pattern was largely recapitulated in the in vitro HepG2 cells assay by using VPA and oleic acid treatment. Moreover, the induction of UGTs was accompanied by the increased expression of constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor alpha (PPARalpha). In line with the up-regulation of UGT1A1 and UGT1A6, urine recovery of VPA glucuronide (VPA-G) was sharply increased by VPA treatment, and the co-treatment of HFD further aggravated this change. Since VPA is necessarily prescribed for long-term and the prevalence of HFD life style nowadays, the combined effect of HFD and VPA on disturbing UGTs should take concerns in the clinics. PMID- 24056125 TI - Milestones and competency-based medical education. PMID- 24056124 TI - Tunicamycin inhibits Toll-like receptor-activated inflammation in RAW264.7 cells by suppression of NF-kappaB and c-Jun activity via a mechanism that is independent of ER-stress and N-glycosylation. AB - In this study, we investigated the effect of tunicamycin on the production of pro inflammatory molecules in RAW264.7 macrophage cells in response to lipopolysaccharide (LPS) and Toll-like receptor (TLR) agonists. Tunicamycin caused a reduction in LPS-induced nitric oxide (NO) production and expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL 1beta) and tumor necrosis factor alpha (TNF-alpha). In contrast, other ER stress inducing chemicals, such as A23187 and thapsigargin (TG), increased LPS-induced COX-2 expression and had no effect on LPS-induced iNOS, TNF-alpha or IL-1beta expression. Furthermore, the inhibitory effect of tunicamycin on LPS-induced inflammation was not influenced by salubrinal, an ER stress inhibitor, suggesting that the anti-inflammatory effect of tunicamycin is independent of ER stress. Tunicamycin also inhibited the expression of inflammatory molecule mRNAs induced by stimulation of TLR2 (with lipoteichoic acid) or TLR3 (with polyinosinic:polycytidylic acid), which do not require myeloid differentiation protein-2 (MD2) for their activation. Moreover, inhibition of LPS-induced iNOS expression was not inhibited by castanospermine, another N-glycosylation inhibitor, suggesting that the inhibitory effect of tunicamycin on LPS-induced iNOS induction is likely independent of MD2 N-glycosylation. Tunicamycin inhibited nuclear factor-kappaB (NF-kappaB) activity by suppressing LPS-induced nuclear translocation of p50 and subsequent DNA binding of p50 and p65 to the NF kappaB site of the iNOS promoter. Tunicamycin also inhibited the transcriptional activity of a cAMP-response element (CRE) reporter, possibly by inhibiting c-Jun activation. Therefore, we conclude that tunicamycin represses TLR-induced inflammation through suppression of NF-kappaB and CRE activity via a mechanism that is independent of ER-stress and N-glycosylation. PMID- 24056126 TI - Proteomic study of 'Moncada' mandarin buds from on- versus off-crop trees. AB - A proteomic analysis of buds from mandarin trees with contrasting fruit load (on- and off-crop trees) was carried out during the onset of low-temperature induction. The aim of the study was to find out more about the molecular mechanism relating to alternate bearing in Citrus and its relationship with flowering. The 'Moncada' variety (Clementine 'Oroval'x'Kara' mandarin), displaying remarkable behaviour in alternate production, was used in this study. From 2D DIGE gel, 192 spots were isolated: 97 showed increased expression in the off-crop buds as compared to the on-crop buds, while 95 exhibited enhanced expression in the on-crop buds versus the off-crop buds. These spots were identified by MALDI-MS or LC-MS-MS. The largest groups of proteins up-expressed in the off-crop buds were the proteins involved in carbohydrate and amino acid metabolism, and the proteins expressed in response to stimuli such as reactive oxygen species. The largest groups of proteins up-expressed in the on-crop buds were related to primary metabolism, oxidative stress and defence responses. Depending on their function, some of these proteins can stimulate the flowering, such as fructose-bisphosphate aldolase or leucine-rich repeat transmembrane protein kinase, while others can inhibit it, such as cytochrome c oxidase subunit II. Twenty-two other proteins with unknown functions were up-expressed in the on- or off-crop buds. PMID- 24056127 TI - Structural and functional characterization of annexin 1 from Medicago truncatula. AB - Annexins are calcium- and membrane-binding proteins that have been shown to have diverse properties such as actin, integrin and GTP binding, both in animals and plants. Recently, Medicago truncatula annexin 1 (AnnMt1) has been suggested to participate in nodulation (Nod factor signaling) and mycorrhization in legume plants. In this report we demonstrate for the first time that recombinant AnnMt1 (rec-AnnMt1) mediates membrane permeabilization to cations with conductance ranging from 16 pS to 329 pS. In agreement with other structurally determined annexins, homology modeling of AnnMt1 suggests that most of the functional determinants are found on the convex surface of the modeled structure. In conclusion, we propose a potential constitutive role of AnnMt1 in Nod factor signaling as a non-specific ion channel. PMID- 24056128 TI - Molecular cloning and expression analysis of a gene for sucrose transporter from pear (Pyrus bretschneideri Rehd.) fruit. AB - Here we report the cloning of a sucrose transporter cDNA from pear (Pyrus bretschneideri Rehd. cv 'Yali') fruit and an analysis of the expression of the gene. A cDNA clone, designated PbSUT1 was identified as a sucrose transporter cDNA from its sequence homology at the amino acid level to sucrose transporters that have been cloned from other higher plant species. PbSUT1 potentially encoded a protein of 499 amino acid residues with a predicted molecular mass of 53.4 kDa and an isoelectric point (pI) of 9.21. Phylogenetic analysis revealed that the PbSUT1 belonged to type III SUTs and was more closely related to the MdSUT1 from apple fruit. Some major facilitator superfamily (MFS)-specific sequence motifs were found in the predicted PbSUT1 peptides, and an MFS_1 domain was located at the amino acid positions of 29-447 of the sequence. A study of gene expression along fruit development showed that PbSUT1 transcripts are present at all stages but significantly increase before fruit enlargement and during the ripening process with increasing sucrose levels. In contrast, the expression levels don't change much during the period of rapid fruit growth. This work shows that sucrose transporter may play a role in the accumulation of sugars during maturation and in maintaining the internal cellular distribution. PMID- 24056129 TI - The moderating influence of nicotine and smoking on resting-state mood and EEG changes in remitted depressed patients during tryptophan depletion. AB - Comorbidity between depression and tobacco use may reflect self-medication of serotonergically mediated mood dysregulation, which has been associated with aberrant cortical activation and hemispheric asymmetry in patients with major depressive disorders (MDD). This randomized, double-blind study in 28 remitted MDD patients examined the moderating effects of acute nicotine and smoker vs. nonsmoker status on mood and EEG changes accompanying transient reductions in serotonin induced by acute tryptophan depletion (ATD). In smokers, who exhibited greater posterior high alpha power and increased left frontal low alpha power (signs of deactivation) compared to nonsmokers, ATD increased self-ratings of depressed mood and elevated left frontal and right parietal high alpha power (i.e. further cortical deactivation). Smokers were not affected by nicotine administration. In nonsmokers, ATD did not influence depression ratings, but it reduced vigor ratings and increased frontal and posterior theta power; both of which were blocked by acute nicotine. These findings indicate a role for nicotinic receptors in disordered mood. PMID- 24056130 TI - Cognitive reappraisal fails when attempting to reduce the appetitive value of food: an ERP study. AB - This event-related potential (ERP) study investigated neural correlates of cognitive reappraisal during the exposure to food cues. Thirty-three healthy, normal-weight women viewed images of high-caloric food and non-food items after an overnight fast. The participants were instructed to either passively look at the pictures, or to change (increase, decrease) the appetitive value of the food items. The P300 and the late positive potential (LPP) were higher across all conditions for food relative to non-food pictures. In the 'increase condition' the food images were rated as more appetizing and arousing than during passive viewing which was accompanied by increased amplitudes of the P300 and LPP. In contrast, the 'watch condition' and the 'decrease condition' did not differ with regard to appetite and arousal ratings as well as ERPs. Amplitudes of late positive potentials in the 'decrease condition' were positively correlated with scores on eating disorder scales indicating bulimic tendencies. The ERP data show that the appetitive value of food cues can easily be enhanced via reappraisal but is difficult to reduce, especially in women who display non-clinical forms of purging. The reduced ERP reactivity might constitute a risk factor for bulimia nervosa. Future longitudinal-prospective studies should follow up on this aspect. PMID- 24056131 TI - The use of pre- or postoperative antibiotics in surgery for appendicitis: a systematic review. AB - BACKGROUND AND AIM: The aim of this study was to review the literature regarding the use of pre- and/or postoperative antibiotics in the management of appendicitis, using data obtained from PubMed and the Cochrane Library. MATERIAL AND METHODS: A literature search was conducted using the terms "appendicitis" combined with "antibiotics." Studies were selected based on relevance for the evidence on prophylactic and postoperative treatment with regard to the route and duration of drug administration and the findings of surgery. RESULTS: Patients with acute appendicitis should receive preoperative, broad-spectrum antibiotics. The use of postoperative antibiotics is only recommended in cases of perforation, and treatment should then be given intravenously, for a minimum period of 3-5 days for adult patients, until clinical signs such as fever resolve and laboratory parameters such as C-reactive protein curve and white blood cell (WBC) start to decline. CONCLUSION: Preoperative antibiotic prophylaxis is recommended in all patients with acute appendicitis, whereas postoperative antibiotics only in cases of perforation. PMID- 24056132 TI - Does D2 plus para-aortic nodal dissection surgery offer a better survival outcome compared to D2 surgery only for gastric cancer consistently? A definite result based on a hospital population of nearly two decades. AB - BACKGROUND AND AIMS: Curative resection is the treatment of choice for gastric cancer. Although it has been concluded that D2 lymphadenectomy plus para-aortic nodal dissection does not improve survival rate in curable gastric cancer, it is unclear whether D2 plus para-aortic nodal dissection has a benefit in some groups of patients. We conducted a retrospective study in our hospital, in which we compared D2 with D2 plus para-aortic nodal dissection lymphadenectomy for gastric cancer in subgroups of each clinical characteristic in terms of long-term survival after surgery. MATERIAL AND METHODS: We selected 1792 patients who had undergone the treatment with curative intent between 1990 and 2007, 1344 in the D2 group and 448 in the D2 plus para-aortic nodal dissection group. Each procedure was verified by pathological analyses. The primary end points were 5 year overall survival. RESULTS AND CONCLUSIONS: Median follow-up periods were 50 months for patients assigned to D2 group and 54 months for patients assigned to D2 plus para-aortic nodal dissection group. Overall 5-year survival was not significantly higher in patients assigned to D2 plus para-aortic nodal dissection surgery compared to those assigned to D2 surgery (31.2% (95% confidence interval: 19.8%-42.6%) vs 26.6% (95% confidence interval: 20.3%-32.9%); log-rank p = 0.433). D2 plus para-aortic nodal dissection surgery should only be used for curable gastric cancer of T3-4 and N2 stage and should not be used for T1 disease and total gastrectomy. PMID- 24056133 TI - When are defunctioning stomas in rectal cancer surgery really reversed? Results from a population-based single center experience. AB - BACKGROUND AND AIMS: This study assessed the timing of reversal of defunctioning stoma following low anterior resection of the rectum for cancer and risk factors for a defunctioning stoma becoming permanent in patients who were not reversed. MATERIAL AND METHODS: Patients who underwent low anterior resection with defunctioning stoma during a 12-year period were assessed with regard to timing of stoma reversal. Delayed reversal was defined as >4 months after low anterior resection. Patients with a defunctioning stoma that was never reversed were assessed regarding risk factors for permanent stoma. RESULTS: A total of 134 patients were analyzed. Of 106 stoma reversals, 19% were reversed within 4 months of low anterior resection, while 81% were reversed later than 4 months. In 58% of these patients, the delay was to due to low medical priority given to this procedure. The other main reasons for delayed stoma reversal were nonsurgical complications (20%), symptomatic anastomotic leakage following low anterior resection (12%), and postoperative adjuvant chemotherapy (10%). Of all patients, 21% (28/134) ended up with a permanent stoma. Risk factors for a defunctioning stoma becoming permanent were stage IV cancer (P < 0.001) and symptomatic anastomotic leakage following low anterior resection (P < 0.001). CONCLUSION: Four in five patients experienced a delayed stoma reversal, in a majority because of the low priority given to this surgical procedure. PMID- 24056134 TI - A new mini-invasive technique in treating pediatric diaphyseal forearm fractures by bioabsorbable elastic stable intramedullary nailing: a preliminary technical report. AB - BACKGROUND AND AIM: Operative treatment is often indicated in unstable pediatric diaphyseal forearm fractures. Recently minimally invasive reduction and elastic stable intramedullary nailing have been of increasing interest, instead of open reduction and internal fixation with plates. There are several disadvantages of metallic intramedullary implants, such as soft-tissue irritation and a risk of disturbing later imaging. Thus, they are generally removed in later operations. We aimed to develop a new technique to stabilize pediatric forearm fractures by the bioabsorbable intramedullary nailing. MATERIAL AND METHODS: We developed a new, two-stage mini-invasive surgical technique to stabilize the unstable diaphyseal fractures in children. The procedure is bioabsorbable elastic stable intramedullary nailing. Ultra-high-strength bioabsorbable intramedullary nails of poly(lactide-co-glycolide) were manufactured for our purpose. The material has been widely proven to be biocompatible and stable enough for fracture treatment as screws and pins. We have used the new technique in the unstable both-bone diaphyseal forearm fractures in children between the ages of 5 and 15 years. We report the technique and our clinical experience in the series of those three cases that have been followed up for at least 12 months. The present series has been randomized for the procedure instead for titanium elastic stable intramedullary nailing, and the series represents a part of ongoing randomized trial. RESULTS: The reported cases operated by the new technique referred good union in the fractured bones and acceptable alignment in the follow-up. Removal of the implants was not required. No troubles with the procedure or implant per se were noticed, indicating good feasibility. One high-energy refracture occurred half year after the primary trauma. Traditional titanium implants were used to control the refracture. CONCLUSIONS: We report our preliminary experience of a new surgical mini-invasive procedure to stabilize the unstable pediatric forearm shaft fractures by bioabsorbable elastic stable intramedullary nailing. Our clinical experience suggests that the procedure combined with long-arm casting is feasible in treating the pediatric forearm fractures. The technique may bring benefits to handling these challenging fractures. The disadvantages of metallic implants may be avoided. In addition, removal of the implant will not be required. There was one refracture in the series, but it was due to new high energy trauma. According to our understanding, it was not related to the type of former osteosynthesis. However, ignoring the good preliminary experience, still we do not have results of the superiority of the procedure over traditional elastic stable intramedullary nailing. Our ongoing randomized multicenter study is aimed to determine its long-term outcome against the present golden standard. Nevertheless, due to encouraging preliminary results, we see it necessary to report the technique. PMID- 24056136 TI - Toward technology-supported surgical training: the potential of virtual simulators in laparoscopic surgery. AB - BACKGROUND AND AIMS: The mastery of manual skills that are indispensable for the performance of surgical tasks is a competence specific to surgery. One way of facilitating this acquisition is to move the training out of the operating room and all of its restrictions. Surgical training out of the operating room, also called simulation, has spread widely in the past decade, especially in laparoscopic and endoscopic surgery. MATERIAL AND METHODS: This review assesses the role of virtual reality (VR) simulators in laparoscopic surgery and their actual impact on technical skills. RESULTS AND CONCLUSIONS: There is a wealth of simulators, ranging from low- to high-fidelity simulators incorporating haptic feedback. They comprise basic tasks, procedural modules, and full procedures. Virtual reality simulators have shown acceptable fidelity and validity evidence. Moreover, training out of the operating room on virtual reality simulators has demonstrated its positive impact on basic skills during real laparoscopic procedures in patients. The benefit of virtual reality over simple video trainers remains unclear for teaching basic skills. However, virtual reality simulators provide automatic feedback that permitted to design structured competency-based curricula and allow deliberate practice. Finally, advanced procedures and patient specific models have been designed on virtual reality simulators, and further investigations are still awaited to appraise their educational value. PMID- 24056135 TI - Boerhaave's syndrome: lessons learned from 83 cases over three decades. AB - The authors describe their experience in the treatment of 83 Boerhaave patients. During the last few years the mortality of the disease has decreased. A successful treatment requires good treatment resources and experienced team work. The tailored open primary repair technique with fundic reinforcement, developed by the authors, is described in detail. This technique has decreased the amount of postoperative fistulation and esophageal resection. The mortality after stenting was 20%. PMID- 24056137 TI - Comparison of above-the-knee prosthetic femoro-popliteal bypass versus percutaneous transluminal angioplasty and stenting for treatment of occlusive superficial femoral artery disease. AB - BACKGROUND AND AIMS: Treatment of occlusive femoro-popliteal artery disease has changed during the last decade because of intensive development of endovascular technology. The aim of this study was to evaluate patient treated endovascularly or surgically for femoro-popliteal atherosclerotic lesions and to assess perioperative and mid-term outcome. MATERIAL AND METHODS: This is a retrospective analysis of consecutive patients who had undergone prosthetic above-the-knee femoro-popliteal bypass or percutaneous transluminal angioplasty and stenting of superficial femoral artery stenosis or occlusion at Tampere University Hospital, Finland, between January 2007 and December 2009. Patients who were alive were re evaluated in 2010. Primary and secondary patency and outcomes were assessed. RESULTS: A total of 131 patients were treated; surgically 63 patients (69 procedures) and endovascularly 68 patients (74 procedures). The mean follow-up time was 17 months (SD +/- 13 months). In the late follow-up visit, 8 (18%) patients in the bypass group suffered from claudication and 9 (20%) from critical limb ischemia. The corresponding figures for the endovascular group were 20 (36%) and 8 (20%), respectively. The primary patency was 60% at 2 years in the bypass group and 73% in the endovascular group (p = 0.092); the primary assisted patency was 62% versus 76%, respectively (p = 0.068). The secondary patency was 74% in the bypass group versus 79% in the endovascular group (p = 0.487). CONCLUSIONS: According to current results following TASC II guideline, satisfied overall mid term results can be achieved in the treatment of superficial femoral artery atherosclerotic disease. PMID- 24056138 TI - An 8-year follow-up study of 221 consecutive hip fracture patients in Finland: analysis of reoperations and their direct medical costs. AB - BACKGROUND: Some hip fracture patients need one or more reoperations because of complications following initial operative treatment. AIMS: The aim of this study was to identify all further surgical interventions in a cohort of patients with hip fractures over a period of 8 years after index fracture. Immediate direct costs of these reoperations were also calculated. MATERIAL AND METHODS: This retrospective study investigated 221 consecutive patients with hip fractures operated on at two different hospitals in southeastern Finland. The study period in hospital A was from 1 February 2003 to 31 January 2004, and in hospital B from 1 February 2003 to 30 April 2004. About 50% were femoral neck fractures, 41% trochanteric fractures, and 9% subtrochanteric fractures. Patients' medical records were checked from the hospital records and confirmed manually. Short- and long-term complications were recorded. Survival analysis was performed using a life-table method. The actual costs for reoperations and other further procedures for each patient were calculated using diagnosis-related groups-based costs for both hospitals in 2012. RESULTS: A total of 20 patients (9%) needed reoperations. Overall, 10 patients (8.9%) with a femoral neck fracture (n = 112), 8 patients (8.7%) with trochanteric fracture (n = 92), and 2 patients (10.5%) with subtrochanteric fracture (n = 19) were reoperated on. The median interval between the primary operation of the acute hip fracture (n = 20) and the first reoperation was about 300 days (range: 2 weeks to 82 months). Among the women reoperated on, the excess mortality was lower than among those undergoing a single operation. The median costs of treatment per patient with one or more reoperations were ?13,422 in hospital A (range: ?1616-?61,755), ?11,076 in hospital B (range: ?1540-?17,866), and ?12,850 in the total study group (p = 0.43). In the case of infections (3 patients), the mean costs per patient were ?28,751 (range: ?11,076-?61,755). CONCLUSIONS: Almost 10% of hip fracture patients required reoperations, and these reoperations caused significant direct costs to health care. However, direct costs account for only approximately 25% of the first year's total costs. These costs should be taken into account when evaluating the economics of hip fractures and the burden of health care. PMID- 24056139 TI - Wide excision in right-sided colon cancer is associated with decreased survival. AB - BACKGROUND AND AIMS: Nodal involvement is the most important prognostic factor in colon cancer. Although theoretically appealing, it is not known if wider mesenteric excision improves the oncological result. The aim of this retrospective study was to investigate whether wider mesenteric excision yields a superior oncological result. MATERIAL AND METHODS: Depending on the resection length, 333 cases of locally radical right-sided hemicolectomies due to adenocarcinoma were compared for perioperative morbidity and mortality, disease free survival, and long-term survival. RESULTS: Postoperative mortality was significantly higher in the quartile with the longest resections, p = 0.003. In a multivariate analysis adjusted for age, stage, emergency operation, adjuvant chemotherapy, and year of operation, a negative relationship between resection length and 5-year overall survival was noted, p = 0.01. No differences in the causes of death or in the incidence of local or distant recurrences were noted between groups. CONCLUSIONS: Wider excision in right-sided hemicolectomies was not associated with any oncological benefit but an increased postoperative mortality and a decreased 5-year overall survival. These findings may suggest consideration to perform wide mesenteric resections routinely. Further research is warranted to define which patients benefit from wider resections. PMID- 24056140 TI - Experience of structural onlay allografts for the treatment of bone deficiency in revision total hip arthroplasty. AB - BACKGROUND AND AIMS: Loss of femoral bone stock in elective revision total hip arthroplasty poses unique and substantial challenges. Structural onlay allografts may provide mechanical stability for the cementless revision prosthesis and increase bone stock. MATERIAL AND METHODS: At least one cortical onlay allograft was used in 40 elective total hip arthroplasty revisions (40 patients) to reconstruct femoral bone defects. The operations were performed between January 1999 and August 2010 in the Turku University Hospital, Finland. The mean follow up time was 52 months (range: 12-125 months). RESULTS: The allografts were incorporated into the bone tissue in 37 of 40 (92.5%) patients. Cementless revision stems healed in 36 of 40 (90.0%) patients, but these patients were not exactly the same patients whose allografts were successfully incorporated. One or more surgical complications were experienced by 14 of 40 (35.0%) patients during follow-up. In all, 4 of 40 (10.0%) patients (all women) had hip infections during follow-up. Of the 7 patients with rheumatoid arthritis, 4 (57.1%) had at least one complication. CONCLUSIONS: The use of the cortical onlay allografts provides a feasible option for restoring the integrity of the proximal femur in revision total hip arthroplasty, but the complication rate is high, particularly in female patients with rheumatoid arthritis. PMID- 24056141 TI - Closure of skin incision after thyroidectomy through a supraclavicular approach: a comparison between tissue adhesive and staples. AB - BACKGROUND: The objective of this study was to compare the effectiveness and cosmetic results of tissue adhesive or surgical staples in thyroidectomy through a supraclavicular incision. METHODS: This was a prospective, randomized study of consecutive patients undergoing thyroidectomy by a supraclavicular approach. Eligible patients were randomized into two groups: one group had the incision closed with tissue adhesive (the experimental group) and the other with surgical staples (the control group). The main outcomes included operative time, early postoperative pain measured by Visual Analog Scale, incidence of wound dehiscence and infection, perceived cosmetic outcome, and overall patient satisfaction by using Patient Satisfaction Assessment Form. RESULTS: There were 151 consecutive patients assessed for eligibility, and 132 patients were enrolled over 22 months. The clinical characteristics of the patients in the two groups were similar. Main outcomes were assessed in the first 24 h postoperatively, the first month, and the third month postoperatively. Operation time was longer in the experimental group (P = 0.027). Mean Visual Analog Scale scores for pain were lower in the experimental group in the early postoperative period (P < 0.001). No patients developed surgical site infections or wound dehiscence. Lower scores for scar assessment and higher overall satisfaction levels at the first month after surgery were found in the experimental group compared to the control group (P < 0.001). There was no significant difference between the two groups at the third month postoperatively in perceived cosmetic result (P = 0.052) or overall satisfaction (P = 0.059). CONCLUSIONS: Tissue adhesive is effective and reliable in skin closure for thyroid surgery. While this closure may take somewhat longer to perform, it leads to less postoperative pain, more acceptable wound cosmesis, and higher patient satisfaction levels in short postoperative follow-up. PMID- 24056142 TI - Technique and short-term outcomes of single-port surgery for rectal cancer: a feasibility study of 25 patients. AB - BACKGROUND AND AIMS: Although conventional laparoscopic surgery is less traumatic than open surgery, it does cause tissue trauma and multiple scar formation. The size and number of ports determine the extent of the trauma. Single-port laparoscopic surgery is assumed to minimize and perhaps eliminate the potential adverse effects of conventional laparoscopy. The aim of this study was to examine short-term outcomes of single-port laparoscopic surgery for rectal cancer. MATERIAL AND METHODS: Prospectively collected data from 25 consecutive patients who underwent single-port laparoscopic surgery for rectal cancer between January 2010 and March 2012. Perioperative data, oncological resections, and short-term outcomes were assessed. RESULTS: Male:female ratio was 10:15. Of the 25 patients, 44% had previously undergone abdominal surgery. Median body mass index was 24 kg/m(2) (range: 19-32 kg/m(2)). In all, four patients (16%) had neoadjuvant therapy. Median operating time was 260 min (range: 136-397 min). An additional port was needed in two patients, and one case was converted to hand-assisted approach. Median postoperative stay was 7 days (range: 4-39 days), and three patients (12%) were readmitted. Median lymph node harvest was 13 (range: 3-33). The surgical margins were clear in all patients. Complications were seen in six patients. CONCLUSION: Single-port laparoscopic surgery for rectal cancer can be performed in selected patients with rectal cancer without compromising oncological safety and with acceptable morbidity and mortality rates. PMID- 24056143 TI - Pleural adenosine deaminase determination: an inter-laboratory comparison is required. PMID- 24056144 TI - Paclitaxel-loaded polymeric microparticles: quantitative relationships between in vitro drug release rate and in vivo pharmacodynamics. AB - Intraperitoneal therapy (IP) has demonstrated survival advantages in patients with peritoneal cancers, but has not become a widely practiced standard-of-care in part due to local toxicity and sub-optimal drug delivery. Paclitaxel-loaded, polymeric microparticles were developed to overcome these limitations. The present study evaluated the effects of microparticle properties on paclitaxel release (extent and rate) and in vivo pharmacodynamics. In vitro paclitaxel release from microparticles with varying physical characteristics (i.e., particle size, copolymer viscosity and composition) was evaluated. A method was developed to simulate the dosing rate and cumulative dose released in the peritoneal cavity based on the in vitro release data. The relationship between the simulated drug delivery and treatment outcomes of seven microparticle compositions was studied in mice bearing IP human pancreatic tumors, and compared to that of the intravenous Cremophor micellar paclitaxel solution used off-label in previous IP studies. Paclitaxel release from polymeric microparticles in vitro was multi phasic; release was greater and more rapid from microparticles with lower polymer viscosities and smaller diameters (e.g., viscosity of 0.17 vs. 0.67 dl/g and diameter of 5-6 vs. 50-60 MUm). The simulated drug release in the peritoneal cavity linearly correlated with treatment efficacy in mice (r(2)>0.8, p<0.001). The smaller microparticles, which distribute more evenly in the peritoneal cavity compared to the large microparticles, showed greater dose efficiency. For single treatment, the microparticles demonstrated up to 2-times longer survival extension and 4-times higher dose efficiency, relative to the paclitaxel/Cremophor micellar solution. Upon repeated dosing, the paclitaxel/Cremophor micellar solution showed cumulative toxicity whereas the microparticle that yielded 2-times longer survival did not display cumulative toxicity. The efficacy of IP therapy depended on both temporal and spatial factors that were determined by the characteristics of the drug delivery system. A combination of fast- and slow-releasing microparticles with 5-6 MUm diameter provided favorable spatial distribution and optimal drug release for IP therapy. PMID- 24056146 TI - beta-Ionone derived chalcones as potent antiproliferative agents. AB - A series of beta-ionone derived chalcones were evaluated for cytotoxic activity against various human cancer cell lines using SRB dye assay. All the compounds displayed moderate to high cytotoxic effect against almost all the cancer cell lines. The results also revealed the effect of substituents of the aromatic ring on their inhibitory potential. In general, compounds bearing electron withdrawing groups such as nitro, fluoro, chloro and bromo showed more inhibitory potential than those bearing electron donating groups. The nitro substituted compound (7h) showed comparatively more inhibitory potential than other derivatives, therefore, it was further investigated for observing its effect on cell morphology in Chinese hamster ovary (CHO) cells by using phase contrast imaging, cell cycle analysis and annexin-FITC apoptosis assay. The treated cells exhibited the characteristics of apoptosis i.e. cell shrinkage, chromatin condensation and nuclear fragmentation, and induced the inhibition of cell proliferation by arresting the cells at G0 phase. PMID- 24056145 TI - Differential immunotoxicities of poly(ethylene glycol)- vs. poly(carboxybetaine) coated nanoparticles. AB - Although the careful selection of shell-forming polymers for the construction of nanoparticles is an obvious parameter to consider for shielding of core materials and their payloads, providing for prolonged circulation in vivo by limiting uptake by the immune organs, and thus, allowing accumulation at the target sites, the immunotoxicities that such shielding layers elicit is often overlooked. For instance, we have previously performed rigorous in vitro and in vivo comparisons between two sets of nanoparticles coated with either non-ionic poly(ethylene glycol) (PEG) or zwitterionic poly(carboxybetaine) (PCB), but only now report the immunotoxicity and anti-biofouling properties of both polymers, as homopolymers or nanoparticle-decorating shell, in comparison to the uncoated nanoparticles, and Cremophor-EL, a well-known low molecular weight surfactant used for formulation of several drugs. It was found that both PEG and PCB polymers could induce the expression of cytokines in vitro and in vivo, with PCB being more immunotoxic than PEG, which corroborates the in vivo pharmacokinetics and biodistribution profiles of the two sets of nanoparticles. This is the first study to report on the ability of PEG, the most commonly utilized polymer to coat nanomaterials, and PCB, an emerging zwitterionic anti-biofouling polymer, to induce the secretion of cytokines and be of potential immunotoxicity. Furthermore, we report here on the possible use of immunotoxicity assays to partially predict in vivo pharmacokinetics and biodistribution of nanomaterials. PMID- 24056147 TI - Microwave assisted synthesis of dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones; synthesis, in vitro antimicrobial and anticancer activities of novel coumarin substituted dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones. AB - The present article describes the synthesis of dihydrobenzo[4,5]imidazo[1,2 a]pyrimidin-4-one (2a-h) under microwave irradiation. The product was obtained in excellent yield (74-94%) in a shorter reaction time (2 min). These molecules (2a, b) further reacted with various substituted 4-bromomethylcoumarins (3a-f) to yield a new series of coumarin substituted dihydrobenzo[4,5]imidazo[1,2 a]pyrimidin-4-ones (4a-h). The structure of all the synthesized compounds were confirmed by spectral studies and screened for their in vitro antibacterial activity against three Gram-positive bacteria viz., Staphylococcus aureus, Enterococcus faecalis, Streptococcus mutans and three Gram-negative bacteria viz., Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa and antifungal activity against Candida albicans, Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, Fusarium oxysporum, Penicillium chrysogenum and anticancer activity against Dalton's Ascitic Lymphoma (DAL) cell line. In general, all the compounds possessed better antifungal properties than antibacterial properties. The coumarin substituted dihydrobenzo[4,5]imidazo[1,2 a]pyrimidin-4-one (4g) (R = i-Pr, R1 = 6-Cl) was found to be the most potent cytotoxic compound (88%) against Dalton's Ascitic Lymphoma cell line at the concentration of 100 MUg/mL. PMID- 24056148 TI - Effect of task-specific training on functional recovery and corticospinal tract plasticity after stroke. AB - PURPOSE: To determine the optimal timing of rehabilitation and its role in corticospinal tract (CST) plasticity after stroke. METHODS: Rats were subjected to photothrombotic infarct. The large stroke (LS) and small stroke (SS) groups were subdivided and task-specific training (TST) was initiated at 1, 5, or 14 days poststroke. Behavioral tests were performed at 2, 7, 14, 21, 28, and 35 days poststroke. The differences of axonal sprouting in the cortex, red nucleus, cerebral peduncle, and pyramid level were compared by immunohistochemistry. RESULTS: SS groups with TST starting at 1 day and 5 days showed significantly better recovery in the behavioral tests. LS group with TST starting at 5 days showed better recovery, while those with TST starting at 1 day showed worse recovery. Contralesional axonal sprouting was increased in both groups with TST starting at 5 days. However, it was decreased in the LS group with TST starting at 1 day. Transcallosal axonal sprouting from the contralesional motor cortex was increased in the LS group with TST starting at 5 days. CONCLUSIONS: Functional recovery after stroke may vary, depending on the lesion size and the timing of rehabilitation. The underlying mechanism may involve contralesional CST plasticity and transcallosal axonal sprouting. PMID- 24056149 TI - Normal hypercapnic cerebrovascular conductance in obstructive sleep apnea. AB - Both obstructive sleep apnoea (OSA) and impaired cerebrovascular reactivity (CVR) are associated with an increased risk of stroke. We therefore hypothesized that CVR would be decreased in OSA patients. Since OSA is associated with altered endothelial function and this dysfunction may in turn lead to impaired CVR, we further hypothesized that a CVR decrease could be the responsible mechanism for stroke. Middle cerebral artery blood flow velocity (MCAv) and mean arterial blood pressure (MAP) responses to hypercapnia were measured to determine cerebrovascular conductance (MCAv/MAP). Overnight changes in conductance CVR were assessed in treatment naive, otherwise healthy OSA (n=13) and non-OSA (n=9) subjects at two isoxic tensions (150 and 50mmHg). We found no significant overnight changes in CVR for either group. There were no differences in CVR between OSA and non-OSA subjects for either isoxic tension, although CVR was increased in hypoxia. PMID- 24056150 TI - Inter-individual differences in control of alveolar capillary blood volume in exercise and hypoxia. AB - We compared by non-invasive technique the adaptive response of alveolar capillary network to edemagenic conditions (exercise and high altitude [HA, PIO2 107mmHg] in subjects with different resting sea level (SL) capillary blood volume (normalized to alveolar volume, Vc/Va): Group 1 (N=10, Vc/Va=16.1+/-6.8ml/L- mean+/-SD) and Group 2 (N=10, Vc/Va=25+/-7.7). In Group 1 Vc/Va remained unchanged in HA at rest and increased during exercise at SL (26.3+/-8.6) and HA (28.75+/-10.2); in Group 2 Vc/Va significantly decreased in HA (19+/-6) and did not increase in exercise at SL and HA. We hypothesize that Group2 exerts a tight control on Vc/Va being more exposed to the risk of lung edema due to inborn greater microvascular permeability. Conversely, Group 1 appears more resistant to lung edema given the large capillary recruitment in the most edemagenic condition. The 4-fold increase in frequency dependence of respiratory resistance in Group2 in HA stems for greater proneness for lung water perturbation compared to Group 1. PMID- 24056151 TI - Cerebral sinovenous thrombosis associated with iron deficiency anemia secondary to severe menorrhagia: a case report. AB - Cerebral sinovenous thrombosis is a rare condition presenting with a wide spectrum of nonspecific symptoms that can make early diagnosis difficult. Cerebral sinovenous thrombosis has been associated with various etiologies. Iron deficiency anemia associated with cerebral sinovenous thrombosis in teenagers is rare. We present a teenage patient with complete thrombosis of the vein of Galen, straight sinus, and left internal cerebral vein associated with iron deficiency anemia due to severe menorrhagia. Mechanisms that can explain the association between iron deficiency anemia and thrombosis are discussed. PMID- 24056152 TI - A case series using a care management checklist to decrease emergency department visits and hospitalizations in children with epilepsy. AB - Each year, 1 million people are seen in an emergency department for seizures or epilepsy. We implemented a care management checklist for patients with frequent visits. A database was searched for patients with the highest number of emergency department visits and/or unplanned hospitalizations in 2011. Four patients were selected. A care management checklist was implemented in 2012. Compliance with the office visits, number of emergency department visits and/or hospitalizations, and the associated costs were tracked following implementation of the checklist for 2011 and 2012. These 4 epilepsy patients accounted for 46 visits in the year 2011 with associated health care costs of $380,209. Following a year using a care management checklist, the same patients accounted for 11 visits with a cost reduction of $188,130. Using a care management checklist was useful in these 4 epilepsy patients to decrease emergency department visits and/or unplanned hospitalizations. A limitation of this study is its small numbers. PMID- 24056153 TI - Nemaline myopathy type 2 (NEM2): two novel mutations in the nebulin (NEB) gene. AB - Nemaline myopathy is a type of the heterogeneous group of congenital myopathies. Generalized hypotonia, weakness, and delayed motor development are the main clinical features of the typical congenital form. Histopathology shows characteristic nemaline rods in the muscle biopsy. Mutations in at least 7 genes, including nebulin gene (NEB), proved to be responsible for this muscle disease. We present a boy with nemaline myopathy type 2 (NEM2) caused by compound heterozygosity for 2 novel mutations, a deletion and a duplication in the NEB gene. The deletion was inherited from the father and the duplication from the mother. Testing all family members supports genetic counseling. PMID- 24056154 TI - Clinical manifestations and treatment response of steroid in pediatric Hashimoto encephalopathy. AB - Hashimoto encephalopathy is a steroid-responsive encephalopathy associated with elevated titers of antithyroid antibodies. Clinical symptoms are characterized by behavioral and cognitive changes, speech disturbance, seizures, myoclonus, psychosis, hallucination, involuntary movements, cerebellar signs, and coma. The standard treatment is the use of corticosteroids along with the treatment of any concurrent dysthyroidism. Other options are immunoglobulins and plasmapheresis. We described symptoms and outcomes on 3 teenage girls with Hashimoto encephalopathy. Presenting symptoms were seizure or altered mental status. One patient took levothyroxine due to hypothyroidism before presentation of Hashimoto encephalopathy. After confirmation of elevated antithyroid antibodies, all patients were treated with steroids. One patient needed plasmapheresis because of the lack of response to steroids and immunoglobulins. Hashimoto encephalopathy should be considered in any patient presenting with acute or subacute unexplained encephalopathy and seizures. Even though the use of steroids is the first line of treatment, plasmapheresis can rescue steroid-resistant patients. PMID- 24056155 TI - Age-related changes in a patient with Pelizaeus-Merzbacher disease determined by repeated 1H-magnetic resonance spectroscopy. AB - A boy with Pelizaeus-Merzbacher disease underwent repeated evaluations by 3-Tesla (1)H-magnetic resonance spectroscopy (MRS). The patient showed overlap of the PLP1. Individuals selected as normal controls for (1)H-magnetic resonance spectroscopy consisted of healthy age-matched children. For (1)H-magnetic resonance spectroscopy, the center of a voxel was positioned in the right parietal lobe. (1)H-magnetic resonance spectroscopy was performed when the patient was 2, 6, 14, and 25 months old. gamma-Aminobutyric acid concentration in early childhood was increased compared with that in normal controls. However, the gamma-aminobutyric acid concentration in the Pelizaeus-Merzbacher disease patient was normalized at 14 and 25 months. No remarkable changes were observed in choline-containing compounds concentration at any time. These results suggest that the changes in metabolite concentrations during growth can reflect the pathological condition of Pelizaeus-Merzbacher disease. Furthermore, the lack of change in the choline-containing compounds concentration can be useful for differentiating Pelizaeus-Merzbacher disease from other white matter disorders. PMID- 24056156 TI - Congenital segmental lymphedema in tuberous sclerosis complex with associated subependymal giant cell astrocytomas treated with Mammalian target of rapamycin inhibitors. AB - Tuberous sclerosis complex is a genetic, multisystemic disorder characterized by circumscribed benign lesions (hamartomas) in several organs, including brain. This is the result of defects in the TSC1 and/or TSC2 tumor suppressor genes, encoding the hamartin-tuberin complex that inhibits the mammalian target of rapamycin pathway. Specific inhibitors of this pathway have been shown to reduce the volume of subependymal giant cell astrocytomas associated with tuberous sclerosis. Congenital lymphedema is rarely seen in association with tuberous sclerosis, with only a few reported cases. Although this association can be coincidental, the dysgenetic lymphatic system can represent a hamartia as a consequence of gene mutation. We describe a child with congenital lymphedema in tuberous sclerosis and associated subependymal giant cell astrocytoma who experienced lymphangitis under treatment with mammalian target of rapamycin inhibitors. Because our patient did not show worsening of lymphedema, congenital lymphedema does not seem to be a contraindication for this therapy. PMID- 24056157 TI - Intracranial arteriopathy in tuberous sclerosis complex. AB - Arterial aneurysms, mostly aortic and intracranial, have been occasionally reported in patients with tuberous sclerosis complex. Brain magnetic resonance imaging reports of 404 patients with definite and 16 patients with either probable or possible tuberous sclerosis complex were revised for intracranial aneurysms. Among these patients, brain images of 220 patients with definite and 16 with probable or possible tuberous sclerosis complex were reviewed. Intracranial aneurysms were reported in 3 of 404 patients with a definite diagnosis (0.74%) (general population: 0.35%), including 2 children. A fourth intracranial aneurysm was found in a patient with probable tuberous sclerosis complex, who did not have tubers or subependymal nodules but had clinical manifestations related to neural crest derivatives, including lymphangioleiomyomatosis and extrarenal angiomyolipomas. The authors hypothesize that neural crest dysfunction can have a major role in intracranial arteriopathy in tuberous sclerosis complex, as smooth muscle cells in the forebrain vessels are of neural crest origin. PMID- 24056158 TI - Tribolium castaneum Transformer-2 regulates sex determination and development in both males and females. AB - Tribolium castaneum Transformer (TcTra) is essential for female sex determination and maintenance through the regulation of sex-specific splicing of doublesex (dsx) pre-mRNA. In females, TcTra also regulates the sex-specific splicing of its own pre-mRNA to ensure continuous production of functional Tra protein. Transformer protein is absent in males and hence dsx pre-mRNA is spliced in a default mode. The mechanisms by which males inhibit the production of functional Tra protein are not known. Here, we report on functional characterization of transformer-2 (tra-2) gene (an ortholog of Drosophila transformer-2) in T. castaneum. RNA interference-mediated knockdown in the expression of gene coding for tra-2 in female pupae or adults resulted in the production of male-specific isoform of dsx and both female and male isoforms of tra suggesting that Tra-2 is essential for the female-specific splicing of tra and dsx pre-mRNAs. Interestingly, knockdown of tra-2 in males did not affect the splicing of dsx but resulted in the production of both female and male isoforms of tra suggesting that Tra-2 suppresses female-specific splicing of tra pre-mRNA in males. This dual regulation of sex-specific splicing of tra pre-mRNA ensures a tight regulation of sex determination and maintenance. These data suggest a critical role for Tra-2 in suppression of female sex determination cascade in males. In addition, RNAi studies showed that Tra-2 is also required for successful embryonic and larval development in both sexes. PMID- 24056159 TI - 46,XY disorder of sex development and developmental delay associated with a novel 9q33.3 microdeletion encompassing NR5A1. AB - Steroidogenic factor 1 (SF1) is a nuclear receptor encoded by the NR5A1 gene. SF1 affects both sexual and adrenal development through the regulation of target gene expression. Genotypic male and female SF1 knockout mice have adrenal and gonadal agenesis with persistent Mullerian structures and early lethality. There have been several reports of NR5A1 mutations in individuals with 46,XY complete gonadal dysgenesis (CGD) or other disorders of sex development (DSD) with or without an adrenal phenotype. To date microdeletions involving NR5A1 have been reported in only two patients with DSDs. We report a novel microdeletion encompassing NR5A1 in a patient with 46,XY DSD and developmental delay. The phenotypically female patient initially presented with mild developmental delay and dysmorphisms. Chromosome analysis revealed a 46,XY karyotype. A 1.54 Mb microdeletion of chromosome 9q33.3 including NR5A1 was detected by array CGH and confirmed by FISH. Normal maternal FISH results indicated that this was most likely a de novo event. Since most NR5A1 mutations have been ascertained through gonadal or adrenal abnormalities, the additional findings of developmental delay and minor facial dysmorphisms are possibly related to haploinsufficiency of other genes within the 1.54 Mb deleted region. This report further confirms the role of NR5A1 deletions in 46,XY DSD and reinforces the utility of aCGH in the work up of DSDs of unclear etiology. PMID- 24056160 TI - Complementary, alternative, and other noncomplete decongestive therapy treatment methods in the management of lymphedema: a systematic search and review. AB - OBJECTIVES: (1) To provide a critical analysis of the contemporary published research that pertains to complementary, alternative, and other noncomplete decongestive therapies for treatment of lymphedema (LE), and (2) to provide practical applications of that evidence to improve care of patients with or at risk for LE. TYPE: This study meets the defining criteria as a systematic search and review because it includes varied study types. All studies that met the inclusion criteria were evaluated for weight of evidence and value. LITERATURE SURVEY: The systematic search and review includes articles published in the contemporary literature (2004-2012). Publications published from 2004-2011 were retrieved from 11 major medical indices by using search terms for LE and management approaches. Literature archives were examined through 2012. Data extraction included study design, objectives pertaining to LE, number and characteristics of participants, interventions, and outcomes. Study strengths and weaknesses were summarized. Study evidence was categorized according to the Oncology Nursing Society Putting Evidence into Practice level-of-evidence guidelines after achieving consensus among the authors. No authors participated in development of nor benefitted from the review of these modality methods or devices. METHODOLOGY: Extracted data from 85 studies were reviewed in 4 subcategories: botanical, pharmaceutical, physical agent modality, and modalities of contemporary value. After review, 47 articles were excluded, which left 16 articles on botanicals and pharmaceuticals and 22 articles for physical agent modality and/or modalities of contemporary value. Pharmaceuticals were later excluded. The authors concluded that botanicals had generated sufficient studies to support a second, more specific systematic review; thus, botanicals are reported elsewhere. SYNTHESIS: It was found that limited high-level evidence was available for all categories. Well-constructed randomized controlled trials related specifically to LE were limited. Objective outcome measures over time were absent from several studies. The rationale for the use and benefits of the specific modality, as related to LE, was often anecdotal. Subject numbers were fewer than 50 for most studies. CONCLUSIONS: No interventions were ranked as "recommended for practice" based on the Putting Evidence into Practice guidelines. Two treatment modalities in 3 studies were ranked as "likely to be effective" in reducing LE or in managing secondary LE complications. Consideration should be given that many of the PAMs demonstrate long-standing support within the literature, with broad parameters for therapeutic application and benefit for secondary conditions associated with LE. However, further investigation as to their individual contributory value and the factors that contribute to their efficacy, specific to LE, has not been done. It also is significant to mention that the majority of these studies focused on breast cancer-related LE. Studies that explored treatment interventions for LE-related vascular disorders (eg, chronic venous insufficiency, congenital dysphasia, trauma) were sparse. Limitations of the literature support the recommendations for future research to further examine the level of evidence in these modalities for LE management. PMID- 24056161 TI - Total hip arthroplasty surgical approach does not alter postoperative gait mechanics one year after surgery. AB - OBJECTIVE: To investigate the differences in gait biomechanics on the basis of surgical approach 1 year after surgery. DESIGN: This was a descriptive laboratory study to investigate the side-to-side differences in walking mechanics at a self selected walking speed as well as a functional assessment 1 year after total hip arthroplasty (THA). Temporospatial, kinetic, and kinematic data as well as functional outcomes were collected. Two-way analysis of variance was used to assess for between-group differences and limb-to-limb asymmetries. SETTING: A controlled laboratory study. PARTICIPANTS: This study examined 35 patients with primary, unilateral THA. The THA surgical approaches that were used in these patients included 12 direct lateral, 18 posterior, and 11 anterolateral. All the patients were assessed 1 year after THA. Patients were excluded from the study if they had contralateral hip pain or pathology, or any prior lower extremity total joint replacements. MAIN OUTCOME MEASUREMENTS: Three-dimensional lower extremity kinematics and kinetics as well as spatiotemporal variables were collected. In addition, a series of physical performance measures were collected. RESULTS: No main effects for the physical performance measures or biomechanical variables were observed among the approach groups. Significant limb-to-limb asymmetries were observed among all the patients, with decreased sagittal plane range of motion, peak extension, and peak vertical ground reaction forces on the operative side. CONCLUSION: The results of this study indicated that no significant differences existed among the different surgical approach groups for any study variable. However, 1 year after THA, the patients demonstrated asymmetric gait patterns regardless of surgical approach, which indicated the potential need for continued intervention through physical therapy to regain normal side-to-side symmetry after THA. PMID- 24056162 TI - The concurrent validity and responsiveness of the high-level mobility assessment tool for mobility limitations in people with multitrauma orthopedic injuries. AB - OBJECTIVE: To investigate the concurrent validity, responsiveness, and ceiling effect of the revised High-Level Mobility Assessment Tool (HiMAT) in persons after orthopedic multitrauma. DESIGN: Cross-sectional sample of convenience. SETTING: A large tertiary rehabilitation hospital. PARTICIPANTS: Forty-three participants with orthopedic multitrauma lower limb injuries that resulted from motor vehicle accidents. METHODS: This study compared the concurrent validity, responsiveness, and ceiling effects of the revised HiMAT, motor subsection of the Functional Independence Measure (FIM) instrument. Performances for all participants were concurrently scored on the motor FIM, revised HiMAT, and the Lower Extremity Functional Scale (LEFS) at initial testing, and 6 and 12 weeks after the decision to fully bear weight. MAIN OUTCOME MEASUREMENTS: Revised HiMAT, motor FIM, and LEFS. RESULTS: The correlation between the revised HiMAT and the motor FIM was moderate (r = 0.49; P <.001) and partly induced by a ceiling effect in the motor FIM. After 12 weeks of full weight bearing, 51.2% of participants achieved the maximum score on the motor FIM. The correlation between the revised HiMAT and LEFS was weak (r = 0.39; P = .012), which indicated a weak relationship between self-reported mobility problems and actual performance. The revised HiMAT was more responsive than the motor FIM and the LEFS, based on the proportion of persons who exceeded the minimal detectable change score over a period of 6 and 12 weeks. CONCLUSION: The revised HiMAT is more responsive to change than the LEFS and motor FIM, and less susceptible to a ceiling effect than the motor FIM for persons with orthopedic multitrauma. It has poor-to-moderate concurrent validity with the LEFS and motor FIM, which suggests that it may be measuring a different aspect of mobility. PMID- 24056164 TI - The complement interference phenomenon as a cause for sharp fluctuations of serum anti-HLA antibody strength in kidney transplant patients. AB - The single antigen flow bead (SAFB) assay greatly improves the identification of antigenic specificity of anti-HLA alloantibodies. However, it may underestimate or miss high titer antibodies due to the prozone phenomenon caused by a competition between the fluorescent anti-IgG conjugate and serum complement, for the alloantibody. We explored this effect in our cohort of transplant candidates and transplanted recipients. Among a total of 292 and 269 patients with at least three different sera tested with class I and/or II SAFB assays respectively, we identified 9 patients (6 in class I and 3 in class II) who displayed a profound drop (>= 75%) followed by a subsequent rise (>= 100%), in strong (mean fluorescence intensity >8000) antibody levels, across an 18-month period. We postulated that such abrupt fluctuations were not explainable by naturally occurring transient desensitization. Sera were analysed with the SAFB assay using EDTA-treated serum and direct complement C1q staining, and with complement dependent cytotoxicity and flow cytometry crossmatches (CDCXM and FCXM respectively). The prozone phenomenon was involved in all cases. Because it relies on complement activation, the CDCXM was not sensitive to this phenomenon, but the FCMXM was not either, although it resembles in its principle to the SAFB assay. Four additional anti-human conjugates targeting the IgG Fc fragment or the light chains did not circumvent the SAFB drawback. Therefore, a quick decrease in antibody strength must alert against a potential risk for recipients at the time of the transplant, using virtual crossmatch strategies. A prospective pre transplant crossmatch still remains an ultimate safeguard. PMID- 24056165 TI - Prevention of human papillomavirus (HPV) infection and cervical cancer in China: how does HPV vaccination bring about benefits to Chinese women? AB - Cervical cancer is the second leading cause of cancer deaths among women in the world and more than 85% of cervical cancer cases occur in women living in developing countries. Human papillomavirus (HPV) infection is the major cause of cervical cancer. Since 2006, two prophylactic vaccines against the high-risk strains of HPV have been developed and approved in more than 100 countries around the world. However, in China, HPV vaccines are still under clinical trials for government approval. In this paper feasibility and justification of HPV vaccine introduction into China is examined by reviewing experiences in both developed and developing countries where the vaccination program has been implemented. The vaccination program has showed significant cost-effectiveness and great health and economic impacts on cervical cancer prevention and control in both high income and middle- and low-income countries. On the other hand, based on the lessons from both developed and developing countries, secondary prevention alone cannot fully play a role to reduce the incidence and the disease burden, and neither does the vaccination program. The epidemiological characteristics in China suggest an urgent need to introduce the vaccines and the geographically diversified prevalence of oncogenic HPV types as well as socioeconomic status also highlight the importance of region-driven approaches for cervical cancer prevention and control by integration of a screening and vaccination program. PMID- 24056163 TI - Characteristics of multiple and concurrent partnerships among women at high risk for HIV infection. AB - OBJECTIVES: We examined parameters of sexual partnerships, including respondents' participation in concurrency, belief that their partner had concurrent partnerships (partners' concurrency), and partnership intervals, among the 2099 women in HIV Prevention Trials Network 064, a study of women at high risk for HIV infection, in 10 U.S. communities. METHODS: We analyzed baseline survey responses about partnership dates to determine prevalence of participants' and partners' concurrency, intervals between partnerships, knowledge of whether recent partners had undergone HIV testing, and intercourse frequency during the preceding 6 months. RESULTS: Prevalence of participants' and partners' concurrency was 40% and 36%, respectively; 24% respondents had both concurrent partnerships and nonmonogamous partners. Among women with >1 partner and no concurrent partnerships themselves, the median gap between partners was 1 month. Multiple episodes of unprotected vaginal intercourse with >=2 of their most recent partners was reported by 60% of women who had both concurrent partnerships and nonmonogamous partners, 50% with only concurrent partners and no partners' concurrency, and 33% with only partners' concurrency versus 14% of women with neither type of concurrency (P < 0.0001). Women who had any involvement with concurrency were also more likely than women with no concurrency involvement to report lack of awareness of whether recent partners had undergone HIV testing (participants' concurrency 41%, partners' concurrency 40%, both participants' and partners' concurrency 48%, neither 17%; P < 0.0001). CONCLUSIONS: These network patterns and short gaps between partnerships may create substantial opportunities for HIV transmission in this sample of women at high risk for HIV infection. PMID- 24056166 TI - Measures to combat H7N9 virus infection in China: live poultry purchasing habits, poultry handling, and living conditions increase the risk of exposure to contaminated environments. AB - From March 31 to May 31, 2013, 132 cases of humans were infected with the H7N9 avian influenza virus, 39 of which resulted in death in China, which sparked global concerns about public health. Fortunately, no new case was reported in China since May 8, which seems like to make it step into a stable stage, and the emergency response to the event launched by Shanghai, Jiangsu, Zhejiang, Anhui, Jiangxi, Shandong, and Hu'nan of China have been terminated currently. However, on July 20 and August 10, two new cases were reported from two provinces--Hebei and Guangdong--where no case was reported during the period of spring of 2013. The emerged two new cases rung an alarm bell, thus, the continued public health response cannot let down its guard. Based on our before studies, we found that live poultry purchasing habits, poultry handling, and living conditions increase the risk of exposure to H7N9 virus contaminated environments in China. Due to the difficulty in changing live poultry purchasing habits and in thoroughly removing or closing live poultry markets in China, we suggest that enhanced regulation of poultry markets would be a more feasible and effective strategy to fight against H7N9 virus infection in China. Moreover, in view of the fact that frequent and inevitable contact between rural residents and poultry where rural residents lived also exists due to poultry handling and living conditions, the enhanced regulations on environmental health are also needed for free-range poultry, especially in rural areas. PMID- 24056167 TI - Advances in the study of biomarkers of idiopathic pulmonary fibrosis in Japan. AB - Idiopathic pulmonary fibrosis is an intractable disease with a median survival time of 2 to 3 years. Serum levels of Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) are useful biomarkers for idiopathic pulmonary fibrosis and they are widely used in Japan. Based on clinical use in Japan, a combination of KL-6, SPA, and SP-D is useful at diagnosing interstitial lung diseases and predicting the prognoses for patients with these diseases. However, the differential diagnosis of idiopathic pulmonary fibrosis from other interstitial lung diseases is still challenging. Several other biomarkers have been identified and are being studied in Japan. PMID- 24056168 TI - Factors affecting childhood immunization in Lao People's Democratic Republic: a cross-sectional study from nationwide, population-based, multistage cluster sampling. AB - Vaccines are one of the most important achievements in public health, and a major contributor to this success is the Expanded Programme on Immunization (EPI). The effective vaccination series of the EPI should be used by its target population. Various factors influence the utilization of the EPI vaccination series. In Lao People's Democratic Republic (Lao PDR), immunization coverage was lower than the regional average. This study evaluates risk factors affecting immunization underutilization among children five to nine years of age. It is a cross sectional study from nationwide, population-based, multistage cluster sampling. The children who have received 'standard six' antigens and those who have been partially immunized are compared. In a bivariate analysis, household occupation, maternal age, means of transportation, time to the nearest health facilities, the child's birthplace, birth attended by medical staff, and notification of vaccination date by medical staff, village authority, or megaphone were associated with vaccination status. The final multivariate logistic regression model revealed that maternal age and notification of vaccination date by the village authority increased the odds of full vaccination, while notification of vaccination date by megaphone had decreased those odds. Further detailed qualitative research may be needed to discover how maternal sociodemographic factors influence the utilization of these services. Future research needs to target younger children and must include health care provider factors related to vaccination services. PMID- 24056169 TI - An iTRAQ approach to quantitative proteome analysis of cerebrospinal fluid from patients with tuberculous meningitis. AB - To study the cerebrospinal fluid (CSF) protein profiles of tuberculous meningitis (TBM) and discover potential biomarkers for TBM, differential expression of proteins in the CSF of patients with TBM, patients with cryptococcal meningitis, and a control group were compared using isobaric tags for relative and absolute quantitation labelling (iTRAQ) coupled with 2-dimensional liquid chromatography tandem mass spectrometry (LC-MS). As a result, a total of 208 unique proteins with a molecular weight ranging from 10 KD to 135 KD were identified and quantified in CSF samples from patients with TBM. Of the proteins, 9 were expressed at levels differing 2.0 fold, 6 were up-regulated, and 3 were down regulated. These proteins appear to be involved in calcium ion binding, lipoprotein metabolism, immune response, and signal conduction. Two differentially expressed proteins were identified using ELISA. The present study represents the successful use of iTRAQ to examine CSF from patients with TBM. The differentially expressed proteins identified may be potential diagnostic biomarkers and provide valuable insight into the underlying mechanisms of TBM. This study also demonstrated that the differential protein profiles of diseases can be quickly determined using iTRAQ-LC-MS, a potential method for quantitative comparative proteomics. PMID- 24056170 TI - Sub-acute exposure to the herbicide atrazine suppresses cell immune functions in adolescent mice. AB - Atrazine (ATR), one of the most widely used herbicides worldwide, has caused a series of toxicological and environmental problems. This study sought to investigate the effects of ATR on the immune system of mice. Four-week-old female C57B l/6 mice were treated with 5, 25, and 125 mg/kg ATR for 28 days. On day 29, blood was collected and the spleen was harvested to detect lymphocyte transformation, natural killer (NK) cell activity, cellular phenotypes, and cytokines. Results indicated that the thymus and spleen weights decreased after ATR treatment, and the spleen was found to be more sensitive to ATR than the thymus. Decreases in lymphocyte transformation and NK cell activity were also observed in mice treated with 25 mg/kg ATR and 125 mg/kg ATR compared to the control group. In addition, there were also alterations of lymphocyte phenotypes in the spleen, and the percentages of CD3+ and CD4+ cells decreased in mice treated with 25 mg/kg ATR and 125 mg/kg ATR compared to the control group. Moreover, serum interleukin-4 level decreased significantly after treatment with 25 mg/kg and 125 mg/kg ATR, but ATR did not affect the expression of interleukin 2, interferon-gamma, and tumor necrosis factor-alpha. These results suggest that ATR may have induced damage in spleen cells. As ATR is an environmental contaminant, its immunosuppressive action raises concerns that it may potentiate clinical conditions such as tumors, inflammation, and infections. Thus, it needs to be carefully monitored and studied. PMID- 24056171 TI - GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression. AB - The pituitary gonadotropin hormones, FSH and LH, are essential for fertility. Containing an identical alpha-subunit (CGA), they are comprised of unique beta subunits, FSHbeta and LHbeta, respectively. These two hormones are regulated by the hypothalamic decapeptide, GnRH, which is released in a pulsatile manner from GnRH neurons located in the hypothalamus. Varying frequencies of pulsatile GnRH stimulate distinct signaling pathways and transcriptional machinery after binding to the receptor, GnRHR, on the cell surface of anterior pituitary gonadotropes. This ligand-receptor binding and activation orchestrates the synthesis and release of FSH and LH, in synergy with other effectors of gonadotropin production, such as activin, inhibin and steroids. Current research efforts aim to discover the mechanisms responsible for the decoding of the GnRH pulse signal by the gonadotrope. Modulating the response to GnRH has the potential to lead to new therapies for patients with altered gonadotropin secretion, such as those with hypothalamic amenorrhea or polycystic ovarian syndrome. PMID- 24056172 TI - Differential role of the estrogen receptors ESR1 and ESR2 on the regulation of proteins involved with proliferation and differentiation of Sertoli cells from 15 day-old rats. AB - The aim of the present study was to investigate the role of each estrogen receptors on the regulation of proteins involved with proliferation and differentiation of Sertoli cells from 15-day-old rats. Activation of ESR1 by 17beta-estradiol (E2) and ESR1-selective agonist PPT increased CCND1 expression, and this effect was dependent on NF-kB activation. E2 and the ESR2-selective agonist DPN, but not PPT, increased, in a PI3K and CREB-dependent manner, the expression of CDKN1B and the transcription factors GATA-1 and DMRT1. Analyzing the expression of ESR1 and ESR2 in different stages of development of Sertoli cells, we observed that the ESR1/ESR2 ratio decreased with age, and this ratio seems to be important to determine the end of cell proliferation and the start of cell differentiation. In Sertoli cells from 15-day-old rats, the ESR1/ESR2 ratio favors the effect of ESR1 and the activation of this receptor increased [Methyl (3)H]thymidine incorporation. We propose that in Sertoli cells from 15-day-old rats E2 modulates Sertoli cell proliferation through ESR1/NF-kB-mediated increase of CCND1, and cell cycle exit and differentiation through ESR2/CREB-mediated increase of CDKN1B, GATA-1 and DMRT1. The present study reinforces the important role of estrogen for normal testis development. PMID- 24056175 TI - New insights into the interplay between the lysine transporter LysP and the pH sensor CadC in Escherichia coli. AB - The coordination of signal transduction and substrate transport represents a sophisticated way to integrate information on metabolite fluxes into transcriptional regulation. This widely distributed process involves protein protein interactions between two integral membrane proteins. Here we report new insights into the molecular mechanism of the regulatory interplay between the lysine-specific permease LysP and the membrane-integrated pH sensor CadC, which together induce lysine-dependent adaptation of E. coli under acidic stress. In vivo analyses revealed that, in the absence of either stimulus, the two proteins form a stable association, which is modulated by lysine and low pH. In addition to its transmembrane helix, the periplasmic domain of CadC also participated in the interaction. Site-directed mutagenesis pinpointed Arg265 and Arg268 in CadC as well as Asp275 and Asp278 in LysP as potential periplasmic interaction sites. Moreover, a systematic analysis of 100 LysP variants with single-site replacements indicated that the lysine signal is transduced from co-sensor to sensor via lysine-dependent conformational changes (upon substrate binding and/or transport) of LysP. Our results suggest a scenario in which CadC is inhibited by LysP via intramembrane and periplasmic contacts under non-inducing conditions. Upon induction, lysine-dependent conformational changes in LysP transduce the lysine signal via a direct conformational coupling to CadC without resolving the interaction completely. Moreover, concomitant pH-dependent protonation of periplasmic amino acids in both proteins dissolves their electrostatic connections resulting in further destabilization of the CadC/LysP interaction. PMID- 24056174 TI - Plug-and-play pairing via defined divalent streptavidins. AB - Streptavidin is one of the most important hubs for molecular biology, either multimerizing biomolecules, bridging one molecule to another, or anchoring to a biotinylated surface/nanoparticle. Streptavidin has the advantage of rapid ultra stable binding to biotin. However, the ability of streptavidin to bind four biotinylated molecules in a heterogeneous manner is often limiting. Here, we present an efficient approach to isolate streptavidin tetramers with two biotin binding sites in a precise arrangement, cis or trans. We genetically modified specific subunits with negatively charged tags, refolded a mixture of monomers, and used ion-exchange chromatography to resolve tetramers according to the number and orientation of tags. We solved the crystal structures of cis-divalent streptavidin to 1.4A resolution and trans-divalent streptavidin to 1.6A resolution, validating the isolation strategy and explaining the behavior of the Dead streptavidin variant. cis- and trans-divalent streptavidins retained tetravalent streptavidin's high thermostability and low off-rate. These defined divalent streptavidins enabled us to uncover how streptavidin binding depends on the nature of the biotin ligand. Biotinylated DNA showed strong negative cooperativity of binding to cis-divalent but not trans-divalent streptavidin. A small biotinylated protein bound readily to cis and trans binding sites. We also solved the structure of trans-divalent streptavidin bound to biotin-4 fluorescein, showing how one ligand obstructs binding to an adjacent biotin binding site. Using a hexaglutamate tag proved a more powerful way to isolate monovalent streptavidin, for ultra-stable labeling without undesired clustering. These forms of streptavidin allow this key hub to be used with a new level of precision, for homogeneous molecular assembly. PMID- 24056173 TI - Paramyxovirus activation and inhibition of innate immune responses. AB - Paramyxoviruses represent a remarkably diverse family of enveloped nonsegmented negative-strand RNA viruses, some of which are the most ubiquitous disease causing viruses of humans and animals. This review focuses on paramyxovirus activation of innate immune pathways, the mechanisms by which these RNA viruses counteract these pathways, and the innate response to paramyxovirus infection of dendritic cells (DC). Paramyxoviruses are potent activators of extracellular complement pathways, a first line of defense that viruses must face during natural infections. We discuss mechanisms by which these viruses activate and combat complement to delay neutralization. Once cells are infected, virus replication drives type I interferon (IFN) synthesis that has the potential to induce a large number of antiviral genes. Here we describe four approaches by which paramyxoviruses limit IFN induction: by limiting synthesis of IFN-inducing aberrant viral RNAs, through targeted inhibition of RNA sensors, by providing viral decoy substrates for cellular kinase complexes, and through direct blocking of the IFN promoter. In addition, paramyxoviruses have evolved diverse mechanisms to disrupt IFN signaling pathways. We describe three general mechanisms, including targeted proteolysis of signaling factors, sequestering cellular factors, and upregulation of cellular inhibitors. DC are exceptional cells with the capacity to generate adaptive immunity through the coupling of innate immune signals and T cell activation. We discuss the importance of innate responses in DC following paramyxovirus infection and their consequences for the ability to mount and maintain antiviral T cells. PMID- 24056176 TI - Chronic skeletal unloading of the rat femur: mechanisms and functional consequences of vascular remodeling. AB - Chronic skeletal unloading diminishes hindlimb bone blood flow. The purpose of the present investigation was to determine 1) whether 7 and 14days of skeletal unloading alter femoral bone and marrow blood flow and vascular resistance during reloading, and 2) whether putative changes in bone perfusion are associated with a gross structural remodeling of the principal nutrient artery (PNA) of the femur. Six-month old male Sprague-Dawley rats were assigned to 7-d or 14-d hindlimb unloading (HU) or weight-bearing control groups. Bone perfusion was measured following 10min of standing (reloading) following the unloading treatment. Histomorphometry was used to determine PNA media wall thickness and maximal diameter. Bone blood flow, arterial pressure and PNA structural characteristics were used to calculate arterial shear stress and circumferential wall stress. During reloading, femoral perfusion was lower in the distal metaphyseal region of 7-d HU rats, and in the proximal and distal metaphyses, diaphysis and diaphyseal marrow of 14-d HU animals relative to that in control rats. Vascular resistance was also higher in all regions of the femur in 14-d HU rats during reloading relative to control animals. Intraluminal diameter of PNAs from 14-d HU rats (138+/-5MUm) was smaller than that of control PNAs (162+/ 6MUm), and medial wall thickness was thinner in PNAs from 14-d HU (14.3+/-0.6MUm) versus that of control (18.0+/-0.8MUm) rats. Decreases in both shear stress and circumferential stress occurred in the PNA with HU that later returned to control levels with the reductions in PNA maximal diameter and wall thickness, respectively. The results demonstrate that chronic skeletal unloading attenuates the ability to increase blood flow and nutrient delivery to bone and marrow with immediate acute reloading due, in part, to a remodeling of the bone resistance vasculature. PMID- 24056177 TI - Conscious thoughts from reflex-like processes: a new experimental paradigm for consciousness research. AB - The contents of our conscious mind can seem unpredictable, whimsical, and free from external control. When instructed to attend to a stimulus in a work setting, for example, one might find oneself thinking about household chores. Conscious content thus appears different in nature from reflex action. Under the appropriate conditions, reflexes occur predictably, reliably, and via external control. Despite these intuitions, theorists have proposed that, under certain conditions, conscious content resembles reflexes and arises reliably via external control. We introduce the Reflexive Imagery Task, a paradigm in which, as a function of external control, conscious content is triggered reliably and unintentionally: When instructed to not subvocalize the name of a stimulus object, participants reliably failed to suppress the set-related imagery. This stimulus-elicited content is considered 'high-level' content and, in terms of stages of processing, occurs late in the processing stream. We discuss the implications of this paradigm for consciousness research. PMID- 24056180 TI - Tumors of the nail unit. A review. Part II: acquired localized longitudinal pachyonychia and masked nail tumors. AB - This second part of the review categorizes the site-specific nail tumors, as proposed in the first part, according to their clinical presentations. Acquired localized longitudinal pachyonychia allows for the specific recognition of onychogenic nail tumor, which can be classified into 2 groups according to the predominant compartment of origin within the nail unit as follows: epithelial tumors encompassing onychocytic matricoma and onychocytic carcinoma, and fibroepithelial tumors: the so-called onychomatricoma. As onychomatricoma is neither an epithelial matrical tumor nor a tumor with a limited differentiation toward the matrix, the author proposes instead the descriptive term of panonychoma fibropapilliferum (POP). The designation of POP does convey to the surgical pathologist or the dermatopathologist the key morphological pattern of this tumor. It should be noted that the proposed term of panonychoma is analogous to the nomenclature that is well established for follicular neoplasms with differentiation toward all elements of the normal hair follicle, that is panfolliculoma. The second term fibropapilliferum is used to highlight the mixed fibroepithelial nature of this neoplasm, which forms multiple rudimentary nail units. These nail units construct multiple nail plates that join together and form a single thick nail plate. According to nail anatomy, 2 types of POP are described: POP of the apical matrix/eponychium, with a pseudo-condylomatous pattern, and POP of the ventral matrix with a foliated pattern in transverse sections and a fibrokeratoma-like pattern in the longitudinal sections. Suggestions for the evaluation and clinical management of localized longitudinal pachyonychia are proposed. On histology of a nail clipping, 2 patterns with clinical significance can be individualized. A horizontal alignment of large cavities indicates POP of the ventral matrix. A haphazard arrangement of smaller cavities in the nail plate, including an arrangement in the inferior two-thirds of the nail clipping, should prompt a biopsy of the distal ventral matrix to rule out a malignant lesion. In the setting of the "masked "nail tumor, a clinical subtype with some significance can be individualized, the subungual keratotic nodule growing rapidly. Three nail bed tumors are discussed within this latter group. Two new clinicopathological variants of subungual keratoacanthoma are described, and a new nail bed tumor is discussed: the infundibulocystic nail bed squamous cell carcinoma. The absence of striking nuclear atypia and the giant cystic to multicystic pattern distinguishes infundibulocystic nail bed squamous cell carcinoma from follicular infundibulocystic squamous cell carcinoma. The last section proposes a classification of folliculogenic nail bed tumors. The follicular microcysts of the nail bed have previously been called subungual epidermoid inclusions or onycholemmal cysts, but the term follicular microcysts of the nail bed is more pertinent, because of the multiple lines of follicular differentiation (infundibular, tricholemmal, apocrine, and sebaceous) seen in their benign and malignant counterparts. Absent in a large portion of the normal nail bed, the follicular microcysts seem to have a peculiar propensity for the formation of tumors that vary in maturity from simple follicular microcystic hyperplasia associated with acquired longitudinal melanonychia to microcystic nail bed hamartoma and microcystic nail bed carcinoma (the so-called onycholemmal carcinoma). The concluding tables emphasize the key and essential histological features required to make the diagnosis of site-specific nail tumors and guide appropriate therapy. The author proposes to categorize subungual tumors into 2 types: subungual skin tumors (including subungual skin metastasis from internal malignancies) and nail tumors. Nail tumors can be accurately classified using a combined clinical and histogenetic approach. This new and expanding group of appendageal tumors is important for both dermatologists and dermatopathologists for the potential early detection of a malignant lesion or for the avoidance of overtreatment of a benign lesion. PMID- 24056178 TI - Bone marrow-derived mesenchymal stem cells enhance angiogenesis via their alpha6beta1 integrin receptor. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) facilitate the angiogenic response of endothelial cells (ECs) within three-dimensional (3D) matrices in vivo and in engineered tissues in vitro in part through paracrine mediators and by acting as stabilizing pericytes. However, the molecular interactions between BMSCs and nascent tubules during the process of angiogenesis are not fully understood. In this study, we have used a tractable 3D co-culture model to explore the functional role of the alpha6beta1 integrin adhesion receptor on BMSCs in sprouting angiogenesis. We report that knockdown of the alpha6 integrin subunit in BMSCs significantly reduces capillary sprouting, and causes their failure to associate with the nascent vessels. Furthermore, we demonstrate that the BMSCs with attenuated alpha6 integrin proliferate at a significantly lower rate relative to either control cells expressing non-targeting shRNA or wild type BMSCs; however, despite adding more cells to compensate for this deficit in proliferation, deficient sprouting persists. Collectively, our findings demonstrate that the alpha6 integrin subunit in BMSCs is important for their ability to stimulate vessel morphogenesis. This conclusion may have important implications in the optimization of cell-based strategies to promote angiogenesis. PMID- 24056179 TI - Acute transplant glomerulopathy with monocyte rich infiltrate. AB - Acute transplant glomerulopathy refers to alloimmune mediated endothelial injury and glomerular inflammation that typically occurs early post-kidney transplantation. We report a case of a 48-year old woman with end stage renal disease from lupus nephritis who developed an unexplained rise in serum creatinine 2 months after renal transplant. As immunosuppression, she received alemtuzumab induction followed by a tacrolimus, mycophenolate mofetil and prednisone maintenance regimen. Her biopsy revealed severe glomerular endothelial injury associated with monocyte/macrophage-rich infiltrate in addition to mild acute tubulointerstitial cellular rejection. We briefly discuss acute transplant glomerulitis, its pathology and association with chronic/overt transplant glomerulopathy, C4d negative antibody-mediated rejection and the significance of monocytes in rejection. We also postulate that alemtuzumab induction may have contributed to the unusual pattern of monocyte-rich transplant glomerulitis. PMID- 24056181 TI - Plantar polypoid lesion: challenge. PMID- 24056182 TI - Dielectrophoresis: an assessment of its potential to aid the research and practice of drug discovery and delivery. AB - Dielectrophoresis (DEP) is an electrokinetic technique with proven ability to discriminate and selectively manipulate cells based on their phenotype and physiological state, without the need for biological tags and markers. The DEP response of a cell is predominantly determined by the physico-chemical properties of the plasma membrane, subtle changes of which can be detected from two so called 'cross-over' frequencies, f(xo1) and f(xo2). Membrane capacitance and structural changes can be monitored by measurement of f(xo1) at sub-megahertz frequencies, and current indications suggest that f(xo2), located above 100 MHz, is sensitive to changes of trans-membrane ion fluxes. DEP lends itself to integration in microfluidic devices and can also operate at the nanoscale to manipulate nanoparticles. Apart from measurements of f(xo1) and f(xo2), other examples where DEP could contribute to drug discovery and delivery include its ability to: enrich stem cells according to their differentiation potential, and to engineer artificial cell structures and nano-structures. PMID- 24056183 TI - When carbon nanotubes encounter the immune system: desirable and undesirable effects. AB - The role of our immune system is to bring efficient protection against invasion by foreign elements, not only pathogens but also any material it may be in contact with. Nanoparticles may enter the body and encounter the immune system either intentionally (e.g. administration for biomedical application) or not (e.g. respiratory occupational exposure). Therefore, it is of fundamental importance to get a thorough knowledge of the way they interact with immune cells and all related consequences. Among nanomaterials, carbon nanotubes (CNTs) are of special interest because of their tremendous field of applications. Consequently, their increasing production, processing and eventual incorporation into new types of composites and/or into biological systems have raised fundamental issues regarding their potential impact on health. This review aims at giving an overview of the known desirable and undesirable effects of CNTs on the immune system, i.e. beneficial modulation of immune cells by CNTs engineered for biomedical applications versus toxicity, inflammation and unwanted immune reactions triggered by CNTs themselves. PMID- 24056184 TI - Changes induced by zinc toxicity in the 2-DE protein profile of sugar beet roots. AB - Changes induced by three levels of Zn toxicity in the root proteome from Beta vulgaris were studied by two dimensional gel electrophoresis. 320 spots were consistently detected and 5, 5 and 11% of them showed significant changes in relative abundance as a result of the 50, 100 and 300MUM Zn treatments, respectively, when compared to controls (1.2MUM Zn). Forty-four spots had consistent changes between all treatments, and 93% were identified. At low and mild Zn excess, the complex I of the mitochondrial transport chain and the oxidative phosphorylation were mildly impaired, and an effort to compensate this effect by increasing glycolysis was observed. At high Zn excess, a general metabolism shutdown occurred, as denoted by decreases in the aerobic respiration and by an impairment of the defense systems against oxidative stress. Accordingly, lipid peroxidation increased as Zn supply increased. This study suggests that metabolic changes at high Zn supply reflect cell death, while changes at low and mild Zn supplies may rather explain the metabolic reprogramming occurring upon Zn toxicity. Results also suggest that Zn competition with divalent ions including Fe may contribute to many of the Zn toxicity symptoms, especially at low and moderate Zn supplies. BIOLOGICAL SIGNIFICANCE: Results in this work provide a comprehensive overview of the effects of Zn toxicity in roots of sugar beet plants. Effects at low and mild Zn excess are similar and reflect changes in the metabolism aimed to overcome this heavy metal stress, whereas effects at high Zn supply indicate a general shutdown of the metabolism and cell death. Our results indicate that Zn toxicity elicits major impairments in the oxidative stress defense systems, possibly due to Zn competition with divalent cations including Fe, in spite that Zn is not a redox active element by itself. PMID- 24056185 TI - Proteomic and metabolomic responses in hepatopancreas of Mytilus galloprovincialis challenged by Micrococcus luteus and Vibrio anguillarum. AB - The outbreak of pathogens can induce diseases and lead to massive mortalities of aquaculture animals including fish, mollusk and shrimp. In this work, the responses induced by Micrococcus luteus and Vibrio anguillarum were investigated in hepatopancreas of mussel Mytilus galloprovincialis using proteomics and metabolomics. Metabolic biomarkers demonstrated that M. luteus and V. anguillarum injections could induce osmotic stress and disturbance in energy metabolism. And the uniquely and more markedly altered metabolic biomarkers (glutamine, succinate, aspartate, glucose, ATP, homarine and tyrosine) indicated that V. anguillarum could cause more severe disturbances in osmotic regulation and energy metabolism. The differentially altered proteins meant that M. luteus and V. anguillarum induced different effects in mussels. However, the common proteomic biomarkers, arginine kinase and small heat shock protein, demonstrated that these two bacteria induced similar effects including oxidative stress and disturbance in energy metabolism in M. galloprovincialis. In addition, some metabolic biomarkers, ATP and glutamine, were confirmed by related proteins including arginine kinase, ATP synthase, nucleoside diphosphate kinase and glutamine synthetase in bacteria-challenged mussels. This study demonstrated that proteomics and metabolomics could provide an insightful view into the effects of environmental pathogens to the marine mussel M. galloprovincialis. BIOLOGICAL SIGNIFICANCE: The outbreak of pathogens can lead to diseases and massive mortalities of aquaculture animals including fish, mollusk and shrimp. The mussel M. galloprovincialis distributes widely along the Bohai coast and is popularly consumed as delicious seafood by local residents. This bivalve has become one of the important species in marine aquaculture industry in China. Therefore a study on pathogen-induced effects is necessary. In the present study, an integrated metabolomic and proteomic approach was used to elucidate the differential effects induced by the representative Gram-positive (M. luteus) and Gram-negative (V. anguillarum) bacteria in M. galloprovincialis. PMID- 24056186 TI - The peel and pulp of mango fruit: a proteomic samba. AB - Combinatorial peptide ligand libraries (CPLLs) have been adopted for investigating the proteomes of mango peel and pulp as well their peptidome content (the latter as captured with a C18 resin). The aim of this study was not only to perform the deepest investigation so far of the mango proteome, but also to assess the potential presence of allergens and of peptides endowed with biological activities. The proteins of peel and pulp have been captured under both native and denaturing extraction techniques. A total of 334 unique protein species have been identified in the peel vs. 2855 in the pulp, via capture with CPLLs at different pH values (2.2 and 7.2). PMID- 24056187 TI - Accumulation of total mercury and methylmercury in rice plants collected from different mining areas in China. AB - A total of 155 rice plants were collected from ten mining areas in three provinces of China (Hunan, Guizhou and Guangdong), where most of mercury (Hg) mining takes place in China. During the harvest season, whole rice plants were sampled and divided into root, stalk & leaf, husk and seed (brown rice), together with soil from root zone. Although the degree of Hg contamination varied significantly among different mining areas, rice seed showed the highest ability for methylmercury (MeHg) accumulation. Both concentrations of total mercury (THg) and MeHg in rice plants were significantly correlated with Hg levels in soil, indicating soil is still an important source for both inorganic mercury (IHg) and MeHg in rice plants. The obvious discrepancy between the distribution patterns of THg and MeHg reflected different pathways of IHg and MeHg accumulation. Water soluble Hg may play more important role in MeHg accumulation in rice plants. PMID- 24056188 TI - Effects of arsenate, chromate, and sulfate on arsenic and chromium uptake and translocation by arsenic hyperaccumulator Pteris vittata L. AB - We investigated effects of arsenate (AsV), chromate (CrVI) and sulfate on As and Cr uptake and translocation by arsenic hyperaccumulator Pteris vittata (PV), which was exposed to AsV, CrVI and sulfate at 0, 0.05, 0.25 or 1.25 mM for 2-wk in hydroponic system. PV was effective in accumulating large amounts of As (4598 and 1160 mg/kg in the fronds and roots at 0.05 mM AsV) and Cr (234 and 12,630 mg/kg in the fronds and roots at 0.05 mM CrVI). However, when co-present, AsV and CrVI acted as inhibitors, negatively impacting their accumulation in PV. Arsenic accumulation in the fronds was reduced by 92% and Cr by 26%, indicating reduced As and Cr translocation. However, addition of sulfate increased uptake and translocation of As by 26-28% and Cr by 1.63 fold. This experiment demonstrated that As and Cr inhibited each other in uptake and translocation by PV but sulfate enhanced As and Cr uptake and translocation by PV. PMID- 24056190 TI - Is the B6.129P2-Plg transgenic mouse an adequate treatment model for patients with ligneous conjunctivitis? PMID- 24056191 TI - Structural studies of the Trypanosoma cruzi Old Yellow Enzyme: insights into enzyme dynamics and specificity. AB - The flavoprotein old yellow enzyme of Trypanosoma cruzi (TcOYE) is an oxidoreductase that uses NAD(P)H as cofactor. This enzyme is clinically relevant due to its role in the action mechanism of some trypanocidal drugs used in the treatment of Chagas' disease by producing reactive oxygen species. In this work, the recombinant enzyme TcOYE was produced and collectively, X-ray crystallography, small angle X-ray scattering, analytical ultracentrifugation and molecular dynamics provided a detailed description of its structure, specificity and hydrodynamic behavior. The crystallographic structure at 1.27A showed a classical (alpha/beta)8 fold with the FMN prosthetic group buried at the positively-charged active-site cleft. In solution, TcOYE behaved as a globular monomer, but it exhibited a molecular envelope larger than that observed in the crystal structure, suggesting intrinsic protein flexibility. Moreover, the binding mode of beta-lapachone, a trypanocidal agent, and other naphthoquinones was investigated by molecular docking and dynamics suggesting that their binding to TcOYE are stabilized mainly by interactions with the isoalloxazine ring from FMN and residues from the active-site pocket. PMID- 24056192 TI - Highlight: tiniest of the tiny--a new low for genome size. PMID- 24056193 TI - Sleep-wake and diurnal modulation of nitric oxide in the perifornical-lateral hypothalamic area: real-time detection in freely behaving rats. AB - Nitric oxide (NO) has been implicated in the regulation of sleep. The perifornical-lateral hypothalamic area (PF-LHA) is a key wake-promoting region and contains neurons that are active during behavioral or cortical activation. Recently, we found higher levels of NO metabolites (NOx), an indirect measure of NO levels, in the PF-LHA during prolonged waking (SD). However, NO is highly reactive and diffuses rapidly and the NOx assay is not sensitive enough to detect rapid-changes in NO levels across spontaneous sleep-waking states. We used a novel Nafion(r)-modified Platinum (NF-PT) electrode for real-time detection of NO levels in the PF-LHA across sleep-wake cycles, dark-light phases, and during SD. Sprague-Dawley male rats were surgically prepared for chronic sleep-wake recording and implantation of NF-PT electrode into the PF-LHA. Electroencephalogram (EEG), electromyogram (EMG), and electrochemical current generated by NF-PT electrode were continuously acquired for 5-7days including one day with 3h of SD. In the PF-LHA, NO levels exhibited a waking>rapid eye movement (REM)>non-rapid eye movement (nonREM) sleep pattern (0.56+/-0.03MUM>0.47+/ 0.02MUM>0.42+/-0.02MUM; p<0.01). NO levels were also higher during the dark- as compared to the light-phase (0.53+/-0.03MUM vs. 0.44+/-0.02MUM; p<0.01). NO levels increased during 3h of SD as compared to undisturbed control (0.58+/ 0.04MUM vs. 0.47+/-0.01MUM; p<0.05). The findings indicate that in the PF-LHA, NO is produced during behavioral or cortical activation. Since elevated levels of NO inhibits most of the PF-LHA neurons that are active during cortical activation, these findings support a hypothesis that NO produced in conjunction with the activation of PF-LHA neurons during waking/SD, inhibits the same neuronal population to promote sleep. PMID- 24056194 TI - Guanfacine is an effective countermeasure for hypobaric hypoxia-induced cognitive decline. AB - Hypobaric hypoxia (HH), an environmental stress resulting from ascent to high altitude, affects perception, memory, judgment, and attention, resulting in degradation of many aspects of normal functioning. Alpha 2A adrenergic agonist, guanfacine proved to be beneficial in the amelioration of neurological outcomes of many neuropsychiatric disorders involving adrenergic imbalance and neurodegeneration. Adrenergic dysregulation and neuronal damage have been implicated in hypoxia-induced cognitive deficits, however, efficacy of guanfacine as a countermeasure for HH-induced cognitive decline remains to be evaluated. We, therefore, have studied the effect of this drug on the HH-induced cognitive deficits, adrenergic dysfunction and neuronal damage. Rats were exposed to HH at a simulated altitude of 25,000 feet for 7days and received an IM injection of either saline or guanfacine at a dose of 1mg/kg. Adrenergic transmission was evaluated by biomarkers i.e. norepinephrine (NE), dopamine (DA) and tyrosine hydroxylase (TH) in medial prefrontal cortex (PFC) by biochemical and immunohistochemical assays. Spine and dendritic morphology of pyramidal neurons in layer II of medial PFC was studied using Golgi-Cox staining and Neurolucida neuronal tracing. The cognitive performance was assessed by Delayed Alternation Task using a T-Maze. There was a significant reduction in HH-induced increases in NE, DA and TH levels with guanfacine treatment. Guanfacine rescued HH-induced dendritic atrophy and mushroom type spine loss. The spatial working memory deficits induced by HH were significantly ameliorated with guanfacine treatment. Furthermore, the cognitive performance showed a positive correlation with dendritic arbors and spine numbers. These results showed that the HH-induced cognitive decline is associated with adrenergic dysregulation and neuronal damage in layer II of medial PFC, and that guanfacine treatment during HH ameliorated these functional and morphological deficits. The study suggests a potential role of the alpha-2A adrenergic agonist, guanfacine, in amelioration of PFC dysfunction caused by high altitude exposure. PMID- 24056189 TI - The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor. AB - 5-Oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) is formed from the 5 lipoxygenase product 5-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) by 5 hydroxyeicosanoid dehydrogenase (5-HEDH). The cofactor NADP(+) is a limiting factor in the synthesis of 5-oxo-ETE because of its low concentrations in unperturbed cells. Activation of the respiratory burst in phagocytic cells, oxidative stress, and cell death all dramatically elevate both intracellular NADP(+) levels and 5-oxo-ETE synthesis. 5-HEDH is widely expressed in inflammatory, structural, and tumor cells. Cells devoid of 5-lipoxygenase can synthesize 5-oxo-ETE by transcellular biosynthesis using inflammatory cell derived 5-HETE. 5-Oxo-ETE is a chemoattractant for neutrophils, monocytes, and basophils and promotes the proliferation of tumor cells. However, its primary target appears to be the eosinophil, for which it is a highly potent chemoattractant. The actions of 5-oxo-ETE are mediated by the highly selective OXE receptor, which signals by activating various second messenger pathways through the release of the betagamma-dimer from Gi/o proteins to which it is coupled. Because of its potent effects on eosinophils, 5-oxo-ETE may be an important mediator in asthma, and, because of its proliferative effects, may also contribute to tumor progression. Selective OXE receptor antagonists, which are currently under development, could be useful therapeutic agents in asthma and other allergic diseases. PMID- 24056195 TI - Effects of mild TBI from repeated blast overpressure on the expression and extinction of conditioned fear in rats. AB - Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are pressing medical issues for the Warfighter. Symptoms of mTBI can overlap with those of PTSD, suggesting the possibility of a causal or mediating role of mTBI in PTSD. To address whether mTBI can exacerbate the neurobiological processes associated with traumatic stress, we evaluated the impact of mTBI from a blast overpressure (BOP) on the expression of a conditioned fear. In the rat, conditioned fear models are used to evaluate the emotional conditioning processes that are known to become dysfunctional in PTSD. Rats were first trained on a variable interval (VI), food maintained, operant conditioning task that established a general measure of performance. Inescapable electric shock (IES) was paired with an audio-visual conditioned stimulus (CS) and followed 1day later by three daily exposures to BOP (75kPa). Subsequently, the CS alone was presented once every 7days for 2months, beginning 4days following the last BOP. The CS was presented during the VI sessions allowing a concurrent measure of performance. Treatment groups (n=10, each group) received IES+BOP, IES+sham-BOP, sham-IES+BOP or sham-IES+sham-BOP. As expected, pairing the CS with IES produced a robust conditioned fear that was quantified by a suppression of responding on the VI. BOP significantly decreased the expression of the conditioned fear. No systematic short- or long-term performance deficits were observed on the VI from BOP. These results show that mTBI from BOP can affect the expression of a conditioned fear and suggests that BOP caused a decrease in inhibitory behavioral control. Continued presentation of the CS produced progressively less response suppression in both fear conditioned treatments, consistent with extinction of the conditioned fear. Taken together, these results show that mTBI from BOP can affect the expression of a conditioned fear but not necessarily in a manner that increases the conditioned fear or extends the extinction process. PMID- 24056199 TI - Environmental change and the dynamics of parasitic diseases in the Amazon. AB - The Amazonian environment is changing rapidly, due to deforestation, in the short term, and, climatic change is projected to alter its forest cover, in the next few decades. These modifications to the, environment have been altering the dynamics of infectious diseases which have natural foci in the, Amazonian biome, especially in its forest. Current land use practices which are changing the, epidemiological profile of the parasitic diseases in the region are road building; logging; mining; expansion of agriculture and cattle ranching and the building of large dams. Malaria and the cutaneous, leishmaniasis are the diseases best known for their rapid changes in response to environmental, modifications. Others such as soil-transmitted helminthiases, filarial infections and toxoplasmosis, which have part of their developmental cycles in the biophysical environment, are also expected to, change rapidly. An interdisciplinary approach and an integrated, international surveillance are needed, to manage the environmentally-driven changes in the Amazonian parasitic diseases in the near future. PMID- 24056197 TI - Drugs that prevent mouse sleep also block light-induced locomotor suppression, circadian rhythm phase shifts and the drop in core temperature. AB - Exposure of mice to a brief light stimulus during their nocturnal active phase induces several simultaneous behavioral or physiological responses, including circadian rhythm phase shifts, a drop in core body temperature (Tc), suppression of locomotor activity and sleep. Each response is triggered by light, endures for a relatively fixed interval and does not require additional light for expression. The present studies address the ability of the psychostimulant drugs, methamphetamine (MA), modafinil (MOD) or caffeine (CAF), to modify the light induced responses. Drug or vehicle (VEH) was injected at CT11 into constant dark housed mice then exposed to 5-min 100MUW/cm(2) light or no light at CT13. Controls (VEH/Light) showed approximately 60-min phase delays. In contrast, response was substantially attenuated by each drug (only 12-15min delays). Under a 12-h light:12-h dark (LD12:12) photoperiod, VEH/light-treated mice experienced a Tc drop of about 1.3 degrees C coincident with locomotor suppression and both effects were abolished by drug pre-treatment. Each drug elevated activity during the post-injection interval, but there was also evidence for CAF-induced hypoactivity in the dark prior to the photic test stimulus. CAF acutely elevated Tc; MA acutely lowered it, but both drugs reduced Tc during the early dark (ZT12.5-ZT13). The ability of the psychostimulant drugs to block the several effects of light exposure is not the result of drug-induced hyperactivity. The results raise questions concerning the manner in which drugs, activity, sleep and Tc influence behavioral and physiological responses to light. PMID- 24056196 TI - Parkinson's disease patients show impaired corrective grasp control and eye-hand coupling when reaching to grasp virtual objects. AB - The effect of Parkinson's disease (PD) on hand-eye coordination and corrective response control during reach-to-grasp tasks remains unclear. Moderately impaired PD patients (n=9) and age-matched controls (n=12) reached to and grasped a virtual rectangular object, with haptic feedback provided to the thumb and index fingertip by two 3-degree of freedom manipulanda. The object rotated unexpectedly on a minority of trials, requiring subjects to adjust their grasp aperture. On half the trials, visual feedback of finger positions disappeared during the initial phase of the reach, when feedforward mechanisms are known to guide movement. PD patients were tested without (OFF) and with (ON) medication to investigate the effects of dopamine depletion and repletion on eye-hand coordination online corrective response control. We quantified eye-hand coordination by monitoring hand kinematics and eye position during the reach. We hypothesized that if the basal ganglia are important for eye-hand coordination and online corrections to object perturbations, then PD patients tested OFF medication would show reduced eye-hand spans and impoverished arm-hand coordination responses to the perturbation, which would be further exasperated when visual feedback of the hand was removed. Strikingly, PD patients tracked their hands with their gaze, and their movements became destabilized when having to make online corrective responses to object perturbations exhibiting pauses and changes in movement direction. These impairments largely remained even when tested in the ON state, despite significant improvement on the Unified Parkinson's Disease Rating Scale. Our findings suggest that basal ganglia cortical loops are essential for mediating eye-hand coordination and adaptive online responses for reach-to-grasp movements, and that restoration of tonic levels of dopamine may not be adequate to remediate this coordinative nature of basal ganglia-modulated function. PMID- 24056200 TI - One-year postoperative morbidity associated with near-infrared-guided indocyanine green (ICG) or ICG in conjugation with human serum albumin (ICG:HSA) sentinel lymph node biopsy. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) is a standard staging procedure in breast cancer and skin melanoma patients. Radioactive colloid (RC) and blue dye are the routinely used markers for staining. The new dye used in this procedure, indocyanine green (ICG), seems to have true potential in near-infrared-guided SLNB. The aim of this study was to analyze 1-year morbidity after SLNB using RC and ICG or RC and ICG conjugated to human serum albumin (ICG:HSA) in breast cancer and skin melanoma patients. METHODS: Forty-nine patients diagnosed with breast cancer and 10 patients with skin melanoma underwent SLNB using ICG with RC and ICG:HSA with RC. A total of 47 SLNB patients without the need for additional lymphadenectomy were evaluated approximately 1 year (11-13 months) for the presence of tattoo, extremity swelling, nerve dysfunction/pain, range of motion, and stiffness. RESULTS: From the 47 patients examined, long-term morbidity was present in 3 (6.4%). In 1 patient, tattoo persisted for 11 months. Mild lymphedema was seen in 1 patient, and 1 patient exhibited minor functional deficit. CONCLUSIONS: Using ICG or ICG:HSA seems to be safe, and long-term morbidity in SLNB patients is low. However, skin discoloration may appear as it does after the use of blue dye, and an increased number of harvested nodes might be associated with an increased number of iatrogenic lymphedema. PMID- 24056201 TI - Evaluation and treatment of gastric stimulator failure in patients with gastroparesis. AB - OBJECTIVE: This study evaluates treatment of gastroparesis patients refractory to gastric electrical stimulation (GES) therapy with surgical replacement of the entire GES system. SUMMARY BACKGROUND DATA: Some patients who have symptomatic improvement with GES later develop recurrent symptoms. Some patients improve by simply altering pulse parameter settings. Others continue to have symptoms with maximized pulse parameters. For these patients, we have shown that surgical implantation of a new device and leads at a different gastric location will improve symptoms of gastroparesis. METHODS: This study evaluates 15 patients with recurrent symptoms after initial GES therapy who subsequently received a second GES system. Positive response to GES replacement therapy is evaluated by symptoms scores for vomiting, nausea, epigastric pain, early satiety, and bloating using a modified Likert score system, 0 to 4. RESULTS: Total symptom scores improved for 12 of 15 patients with GES replacement surgery. Total score for the replacement group decreased from 17.3 +/- 1.6 to 13.6 +/- 3.7 with a difference of 3.6 (P value = .017). This score is compared with that of the control group with a preoperative symptom score of 15.8 +/- 3.6 and postoperative score of 12.3 +/- 3.5 with a difference of 3.5 (P value = .011). The control group showed a 20.3% decrease in mean total symptoms score, whereas the study group showed a 22.5% decrease in mean with an absolute reduction of 2.2. CONCLUSION: Reimplantation of a GES at a new gastric location should be considered a viable option for patients who have initially failed GES therapy for gastroparesis. PMID- 24056202 TI - Incisional negative pressure therapy to prevent wound complications following cesarean section in morbidly obese women: a pilot study. AB - OBJECTIVE: We sought to evaluate the efficacy of incisional negative pressure therapy in decreasing postoperative wound complications when placed prophylactically over clean, closed incisions following cesarean section in obese patients. STUDY DESIGN: This was a retrospective cohort study comparing rates of wound complications following cesarean sections in morbidly obese women prior to and following the institution of standard use of prophylactic incisional negative pressure therapy. All women with a body mass index greater than 45 kg/m(2) undergoing cesarean section in a 2-year period in a single institution were included. The exposure was incisional negative pressure therapy, which began in September 2009, versus standard wound dressing used in the previous year. The main outcome was wound complication identified by ICD-9 codes. Demographic and wound outcomes were compared with chi(2) and t tests. Stata version 11.0 was used for all analysis. RESULTS: A total of 63 women met the inclusion criteria, 21 of whom received negative pressure wound therapy. The historical comparison and exposure groups were similar in all characteristics studied with the exceptions of length of surgery (64 vs 76 minutes, P = .03), length of labor (78 vs 261 minutes, P = .02), scheduled versus nonscheduled (77% vs 52%, P = .04), and mean age (29.5 vs 26.1 years, P = .04), respectively. There were 5 wound complications in the control group (10.4%) and none (0%) in the study group (P = .15). CONCLUSIONS: This pilot study suggests a decrease in wound complications in morbidly obese women receiving incisional negative pressure therapy following cesarean section. PMID- 24056203 TI - The development of prospective memory in young schoolchildren: the impact of ongoing task absorption, cue salience, and cue centrality. AB - This study presents evidence that 9- and 10-year-old children outperform 6- and 7 year-old children on a measure of event-based prospective memory and that retrieval-based factors systematically influence performance and age differences. All experiments revealed significant age effects in prospective memory even after controlling for ongoing task performance. In addition, the provision of a less absorbing ongoing task (Experiment 1), higher cue salience (Experiment 2), and cues appearing in the center of attention (Experiment 3) were each associated with better performance. Of particular developmental importance was an age by cue centrality (in or outside of the center of attention) interaction that emerged in Experiment 3. Thus, age effects were restricted to prospective memory cues appearing outside of the center of attention, suggesting that the development of prospective memory across early school years may be modulated by whether a cue requires overt monitoring beyond the immediate attentional context. Because whether a cue is in or outside of the center of attention might determine the amount of executive control needed in a prospective memory task, findings suggest that developing executive control resources may drive prospective memory development across primary school age. PMID- 24056204 TI - Short-term memory for serial order supports vocabulary development: new evidence from a novel word learning paradigm. AB - Although recent studies suggest a strong association between short-term memory (STM) for serial order and lexical development, the precise mechanisms linking the two domains remain to be determined. This study explored the nature of these mechanisms via a microanalysis of performance on serial order STM and novel word learning tasks. In the experiment, 6- and 7-year-old children were administered tasks maximizing STM for either item or serial order information as well as paired-associate learning tasks involving the learning of novel words, visual symbols, or familiar word pair associations. Learning abilities for novel words were specifically predicted by serial order STM abilities. A measure estimating the precision of serial order coding predicted the rate of correct repetitions and the rate of phoneme migration errors during the novel word learning process. In line with recent theoretical accounts, these results suggest that serial order STM supports vocabulary development via ordered and detailed reactivation of the novel phonological sequences that characterize new words. PMID- 24056205 TI - The novel antiepileptic drug imepitoin compares favourably to other GABA-mimetic drugs in a seizure threshold model in mice and dogs. AB - Recently, the imidazolinone derivative imepitoin has been approved for treatment of canine epilepsy. Imepitoin acts as a low-affinity partial agonist at the benzodiazepine (BZD) site of the GABAA receptor and is the first compound with such mechanism that has been developed as an antiepileptic drug (AED). This mechanism offers several advantages compared to full agonists, including less severe adverse effects and a lack of tolerance and dependence liability, which has been demonstrated in rodents, dogs, and nonhuman primates. In clinical trials in epileptic dogs, imepitoin was shown to be an effective and safe AED. Recently, seizures in dogs have been proposed as a translational platform for human therapeutic trials on new epilepsy treatments. In the present study, we compared the anticonvulsant efficacy of imepitoin, phenobarbital and the high-affinity partial BZD agonist abecarnil in the timed i.v. pentylenetetrazole (PTZ) seizure threshold test in dogs and, for comparison, in mice. Furthermore, adverse effects of treatments were compared in both species. All drugs dose-dependently increased the PTZ threshold in both species, but anticonvulsant efficacy was higher in dogs than mice. At the doses selected for this study, imepitoin was slightly less potent than phenobarbital in increasing seizure threshold, but markedly more tolerable in both species. Effective doses of imepitoin in the PTZ seizure model were in the same range as those suppressing spontaneous recurrent seizures in epileptic dogs. The study demonstrates that low-affinity partial agonists at the benzodiazepine site of the GABAA receptor, such as imepitoin, offer advantages as a new category of AEDs. PMID- 24056206 TI - Proteomics in uveal melanoma. AB - Uveal melanoma is the most common primary intraocular malignancy in adults, with an incidence of 5-7 per million per year. It is associated with the development of metastasis in about 50% of cases, and 40% of patients with uveal melanoma die of metastatic disease despite successful treatment of the primary tumour. The survival rates at 5, 10 and 15 years are 65%, 50% and 45% respectively. Unlike progress made in many other areas of cancer, uveal melanoma is still poorly understood and survival rates have remained similar over the past 25 years. Recently, advances made in molecular genetics have improved our understanding of this disease and stratification of patients into low risk and high risk for developing metastasis. However, only a limited number of studies have been performed using proteomic methods. This review will give an overview of various proteomic technologies currently employed in life sciences research, and discuss proteomic studies of uveal melanoma. PMID- 24056207 TI - The effect of simulated cataract light scatter on retinal vessel oximetry. AB - To assess the impact of light scatter, similar to that introduced by cataract on retinal vessel blood oxygen saturation measurements using poly-bead solutions of varying concentrations. Eight healthy, young, non-smoking individuals were enrolled for this study. All subjects underwent digital blood pressure measurements, assessment of non-contact intraocular pressure, pupil dilation and retinal vessel oximetry using dual wavelength photography (Oximetry Module, Imedos Systems, Germany). To simulate light scatter, cells comprising a plastic collar and two plano lenses were filled with solutions of differing concentrations (0.001, 0.002 and 0.004%) of polystyrene microspheres (Polysciences Inc., USA). The adopted light scatter model showed an artifactual increase in venous optical density ratio (p = 0.036), with the 0.004% condition producing significantly higher venous optical density ratio values when compared to images without a cell in place. Spectrophotometric analysis, and thus retinal vessel oximetry of the retinal vessels, is altered by artificial light scatter. PMID- 24056208 TI - The impact of nutritional policy on socioeconomic disparity in the unhealthy food intake among Korean adolescents. AB - The objectives of this study were to examine the trend in unhealthy food intake by socioeconomic position (SEP) and to determine whether the government's nutritional policies affect socioeconomic disparity in the food intake among adolescents. Data were from the six independent cross-sectional survey data (2006 2011) of Korea Youth Risk Behavior Web-based Survey and included 445,287 subjects aged 12-18 years. The unhealthy food intake was assessed by food frequency intake and SEP was evaluated with the family affluence scale. We observed that unhealthy food intakes decreased through the years, showing the apparent decline when nutritional policies focusing on the restriction of unhealthy foods were implemented, and the trend was all same in the different SEP groups. The pattern of unhealthy food intakes by SEP has changed before and after implementation of the policies. The intakes of carbonated beverages, fast food, and confectioneries were higher in the higher SEP group before implementation of the policies but the difference was not shown after implementation of the policies. The intake of instant noodles was consistently higher in the lower SEP group. The risk of frequent consumption of unhealthy foods was generally more decreased through the years in the higher SEP group than the lower SEP group. In conclusion, this study found the positive effect of nutritional policy on unhealthy food intake among adolescents and the high SEP group appeared to undergo greater desirable changes in dietary behaviors after implementation of nutritional policies than the low SEP group. PMID- 24056209 TI - Positive effect of mushrooms substituted for meat on body weight, body composition, and health parameters. A 1-year randomized clinical trial. AB - Reducing energy density (ED) of the diet is an important strategy for controlling obesity. This 1-year, randomized clinical trial examined the effect of substituting mushrooms for red meat ('mushroom diet'), compared to a standard diet ('meat diet'), on weight loss and maintenance among 73 obese adults (64 women, 9 men). The subjects completed anthropometric measurements and 7-day food records four times during a standardized weight loss and maintenance regimen. At the end of the 1-year trial, compared to participants on the standard diet, participants on the mushroom diet (n=36) reported lower intakes of energy (mean +/- [SE]=-123 +/- 113 kcals) and fat (-4.25 +/- 6.88 g), lost more pounds and percentage body weight (-7.03 +/- 3.34 lbs, 3.6%), achieved lower body mass index (-1.53 +/- 0.36), waist circumference (-2.6 +/- 3.5 in.) and percent total body fat (-0.85 +/- 0.53), and had lower systolic and diastolic pressure (-7.9 and 2.5 mmHg); their lipid profile and inflammatory markers also improved. After initial weight loss, subjects following the mushroom diet maintained that loss well. Those who completed the full 12-month trial still weighed a mean of 7 lbs less than baseline. Thus, encouraging adults to substitute mushrooms for red meat was a useful strategy for enhancing weight loss, weight maintenance, and health parameters. PMID- 24056210 TI - Guided growth implants for low-income to middle-income countries. PMID- 24056211 TI - The incidence of avascular necrosis of the femoral head changes with the hip abduction angle in the hip spica in treatment of developmental dislocation of the hip. PMID- 24056212 TI - Isolation and analysis of rare cells in the blood of cancer patients using a negative depletion methodology. AB - A variety of enrichment/isolation technologies exist for the characterization of rare cells in the blood of cancer patients. In this article, a negative depletion process is presented and discussed which consists of red blood cell (RBC) lysis and the subsequent removal of CD45 expressing cells through immunomagnetic depletion. Using this optimized assembly on 120 whole blood specimens, from 71 metastatic breast cancer patients, after RBC lysis, the average nucleated cell log depletion was 2.56 with a 77% recovery of the nucleated cells. The necessity of exploring different anti-CD45 antibody clones to label CD45 expressing cells in this enrichment scheme is also presented and discussed. An optimized, four color immunofluorescence staining is conducted on the cells retained after the CD45-based immunomagnetic depletion process. Different types of rare non hematopoietic cells are found in these enriched peripheral blood samples and a wide range of external and internal markers have been characterized, which demonstrates the range and heterogeneity of the rare cells. PMID- 24056213 TI - Natural products with protein tyrosine phosphatase inhibitory activity. AB - Protein tyrosine phosphatases (PTPs) play an essential role in maintaining the proper tyrosine phosphorylation state of proteins. Abnormal tyrosine phosphorylation has been implicated in diseases as diverse as type 2 diabetes, cancer, immune disorders and neurological disorders, and thus inhibitors of PTPs have been investigated as potential treatments of these diseases. Natural products are widely regarded to be privileged structures in drug discovery efforts, and are therefore a good starting point for the development of PTP inhibitors. Here we describe reported natural product PTP inhibitors as well as methods to screen for natural product PTP inhibitors using bioassay-guided fractionation. These methods are illustrated using the example of a family of bromotyrosine-derived PTP inhibitors isolated from two marine sponges. We also identify potential pitfalls and false-positives, in particular compounds that are oxidizing agents that react irreversibly with the PTP. PMID- 24056214 TI - k-Partite cliques of protein interactions: A novel subgraph topology for functional coherence analysis on PPI networks. AB - Many studies are aimed at identifying dense clusters/subgraphs from protein protein interaction (PPI) networks for protein function prediction. However, the prediction performance based on the dense clusters is actually worse than a simple guilt-by-association method using neighbor counting ideas. This indicates that the local topological structures and properties of PPI networks are still open to new theoretical investigation and empirical exploration. We introduce a novel topological structure called k-partite cliques of protein interactions-a functionally coherent but not-necessarily dense subgraph topology in PPI networks to study PPI networks. A k-partite protein clique is a maximal k-partite clique comprising two or more nonoverlapping protein subsets between any two of which full interactions are exhibited. In the detection of PPI's maximal k-partite cliques, we propose to transform PPI networks into induced K-partite graphs where edges exist only between the partites. Then, we present a maximal k-partite clique mining (MaCMik) algorithm to enumerate maximal k-partite cliques from K partite graphs. Our MaCMik algorithm is then applied to a yeast PPI network. We observed interesting and unusually high functional coherence in k-partite protein cliques-the majority of the proteins in k-partite protein cliques, especially those in the same partites, share the same functions, although k-partite protein cliques are not restricted to be dense compared with dense subgraph patterns or (quasi-)cliques. The idea of k-partite protein cliques provides a novel approach of characterizing PPI networks, and so it will help function prediction for unknown proteins. PMID- 24056215 TI - Tissue architecture, feedback regulation, and resilience to viral infection. AB - Tissue homeostasis is one of the central requirements for the existence of multicellular organisms, and is maintained by complex feedback regulatory processes. Homeostasis can be disturbed by diseases such as viruses and tumors. Here, we use mathematical models to investigate how tissue architecture influences the ability to maintain tissue homeostasis during viral infections. In particular, two different tissue designs are considered. In the first scenario, stem cells secrete negative feedback factors that influence the balance between stem cell self-renewal and differentiation. In the second scenario, those feedback factors are not produced by stem cells but by differentiated cells. The model shows a tradeoff. If feedback factors are produced by stem cells, then a viral infection will lead to a significant reduction in the number of differentiated cells leading to tissue pathology, but the number of stem cells is not affected at equilibrium. In contrast, if the feedback factors are produced by differentiated cells, a viral infection never reduces the number of tissue cells at equilibrium because the feedback mechanism compensates for virus-induced cells death. The number of stem cells, however, becomes elevated, which could increase the chance of these stem cells to accumulate mutations that can drive cancer. Interestingly, if the virus interferes with feedback factor production by cells, uncontrolled growth can occur in the presence of the virus even in the absence of genetic lesions in cells. Hence, the optimal design would be to produce feedback factors by both stem and differentiated cells in quantities that strike a balance between protecting against tissue destruction and stem cell elevation during infection. PMID- 24056216 TI - Retractor-endoscopic nerve decompression in carpal and cubital tunnel syndromes: outcomes in a small series. AB - OBJECTIVE: To present midterm to long-term results obtained in carpal tunnel release, in situ decompression, and anterior transposition of the ulnar nerve using the retractor integrated endoscope. METHODS: During the period 2000-2010, 145 patients underwent endoscopic carpal tunnel releases (n = 47), endoscopic in situ decompression of the ulnar nerve (n = 55), and endoscopic anterior transposition of the ulnar nerve (n = 52). Bilateral surgery was performed in 9 patients. Independent examinations at 24 months after surgery were used for objective results (Bishop score). Subjective results were procured using a questionnaire. RESULTS: After endoscopic carpal tunnel release, 59.6% of patients showed excellent results, 21.2% showed good results, 12.8% showed fair results, and 6.4% showed poor results according to objective scoring. In 85% of patients, subjective improvement was noted after surgery; symptoms were the same as before surgery in 12.8% of patients and were worse in 2.1% of patients after surgery. After endoscopic in situ decompression, 56.4% of patients showed excellent results on objective scoring, 32.7% showed good results, 9.1% showed fair results, and 1.8% showed poor results. On subjective questioning, 72.7% of patients reported improvement, 20% reported no change in symptoms, and 7.3% reported worse symptoms. After endoscopic anterior transposition of the ulnar nerve, 48.1% of patients showed excellent results on objective scoring, 26.9% showed good results, 23.1% showed fair results, and 1.9% showed poor results. Subjectively, 65.4% of patients reported improvement, 26.9% reported no change in symptoms, and 7.7% reported worse symptoms. Patients with symptom duration of <9 months before surgery showed better results than patients with symptom duration of >9 months. CONCLUSIONS: The retractor-endoscopic technique provides good long term results after carpal tunnel release, in situ decompression, and anterior subcutaneous transposition of the ulnar nerve. Outcomes showed some correlation to the duration of preoperative symptoms. PMID- 24056217 TI - Awake motor examination during intracranial aneurysm surgery. PMID- 24056218 TI - Outcomes after microvascular decompression for patients with trigeminal neuralgia and suspected multiple sclerosis. AB - BACKGROUND: Microvascular decompression (MVD) is an established surgical therapy for patients with idiopathic trigeminal neuralgia (TN). The role of MVD in patients with definite or suspected multiple sclerosis (MS) remains controversial. METHODS: During the period 2000-2012, 10 patients with medically refractory TN and ipsilateral brainstem T2 hyperintensity underwent MVD. In 5 patients, additional clinical features suspicious for MS were present, including prior optic neuritis (n = 2), multiple disseminated lesions (n = 3), and elevated immunoglobulin G index (n = 2). One patient had failed prior percutaneous surgery; 1 patient had Burchiel type 2 TN. Follow-up (median, 14 months) was censored at the time of additional surgery (n = 6) or last clinic visit (n = 4). RESULTS: Neurovascular compression was confirmed at surgery from the superior cerebellar artery (SCA) plus adjacent vein (n = 4), vein alone (n = 3), SCA alone (n = 2), and SCA plus anterior inferior cerebellar artery (n = 1). Initially after MVD, 8 patients (80%) were pain-free and subsequently tapered off medications for their facial pain. Pain recurred in 6 patients at a median of 4 months (range, 1-23 months). Actuarial rates of being pain-free off medications were 50% at 3 months and 15% at 2 years. In 6 patients, additional treatments were performed, including glycerol rhizotomy (n = 4), radiosurgery (n = 2), balloon compression (n = 2), and repeat MVD (n = 1). At last contact, 5 of the 6 patients who were retreated were pain-free. CONCLUSIONS: Facial pain outcomes after MVD in patients with suspected MS-related TN are poor compared with outcomes for patients with idiopathic TN. This study provides further support that many patients with MS-related TN have pain that is centrally mediated, reducing the effectiveness of procedures performed on the trigeminal root, ganglion, or divisions. PMID- 24056219 TI - The role of ultra-high field magnetic resonance imaging for track density imaging: application in neuromodulation of the brain. PMID- 24056220 TI - Use of vascular plug devices in the management of neurovascular emergencies. PMID- 24056221 TI - The carotid siphon: a historic radiographic sign, not an anatomic classification. AB - BACKGROUND: After the term carotid siphon was introduced by Moniz in 1927 to describe the radiographic appearance of the intracranial internal carotid artery (ICA), the concept gained popularity in decades following in both the anatomic and the medical literature. However, as conflicting definitions persist in the delineation of proximal and distal sites, does the term carotid siphon provide the precision needed for current anatomic and clinical studies? METHODS: A PubMed search of "carotid siphon" detected >400 articles from the anatomic and medical literature during the past 6 decades. Moniz's text and figures in his original Lancet article and a compilation of other seminal historical articles and references were reviewed to trace the use of the term carotid siphon during this period. RESULTS: Viewing the radiographic silhouette of a normal ICA, Moniz defined the carotid siphon as the series of bends and curves; an additional curvature was identified as a double siphon. Throughout Moniz's works, in text and figures, the boundaries of the carotid siphon were never delineated. Authors who followed attempted to correlate his original description of this two dimensional radiographic projection with anatomic documentation. CONCLUSIONS: Tracing the origin and usage of the term carotid siphon during 6 decades in the medical literature shows continued discrepancy rather than consensus. The term carotid siphon is historically relevant but can now be supplanted by definitive ICA classification systems, which continue to evolve in contemporary medical and anatomic communications. PMID- 24056222 TI - Prenatal diagnosis of hemimegalencephaly. AB - BACKGROUND: In recent literature, there have been case reports of prenatal diagnosis of hemimegalencephaly, an extremely rare entity characterized by enlargement of all or portions of 1 cerebral hemisphere and intractable seizures. A unique case is presented of hemimegalencephaly of a fetus diagnosed in utero. METHODS: A 27-year-old woman presented at 32 weeks' gestation for fetal magnetic resonance imaging after an abnormal fetal ultrasound. Fetal magnetic resonance imaging showed hemimegalencephaly of the left cerebral hemisphere with abnormal gyration. RESULTS: The patient was born via cesarean section at 39 weeks' gestation. He had continuous infantile spasms and partial-onset seizures starting on day 1 of life, and electroencephalography showed burst suppression. The patient's seizures were initially managed with antiepileptics, prednisolone, and a ketogenic diet; however, he was hospitalized multiple times because of status epilepticus. At 6 months of age, he underwent a successful anatomic left hemispherectomy. CONCLUSIONS: In utero diagnosis of complex developmental brain anomalies allows a multidisciplinary approach to provide optimal prenatal patient treatment and parental counseling. PMID- 24056223 TI - Pain fiber anesthetic reduces brainstem Fos after tooth extraction. AB - We recently demonstrated that pain-sensing neurons in the trigeminal system can be selectively anesthetized by co-application of QX-314 with the TRPV1 receptor agonist, capsaicin (QX cocktail). Here we examined whether this new anesthetic strategy can block the neuronal changes in the brainstem following molar tooth extraction in the rat. Adult male Sprague-Dawley rats received infiltration injection of anesthetic 10 min prior to lower molar tooth extraction. Neuronal activation was determined by immunohistochemistry for the proto-oncogene protein c-Fos in transverse sections of the trigeminal subnucleus caudalis (Sp5C). After tooth extraction, c-Fos-like immunoreactivity (Fos-LI) detected in the dorsomedial region of bilateral Sp5C was highest at 2 hrs (p < .01 vs. naive ipsilateral) and declined to pre-injury levels by 8 hrs. Pre-administration of the QX cocktail significantly reduced to sham levels Fos-LI examined 2 hrs after tooth extraction; reduced Fos-LI was also observed with the conventional local anesthetic lidocaine. Pulpal anesthesia by infiltration injection was confirmed by inhibition of the jaw-opening reflex in response to electrical tooth pulp stimulation. Our results suggest that the QX cocktail anesthetic is effective in reducing neuronal activation following tooth extraction. Thus, a selective pain fiber 'nociceptive anesthetic' strategy may provide an effective local anesthetic option for dental patients in the clinic. PMID- 24056224 TI - Calcium-phosphate-coated oral implants promote osseointegration in osteoporosis. AB - Osteoporotic conditions are anticipated to affect the osseointegration of dental implants. This study aimed to evaluate the effect of a radiofrequent magnetron sputtered calcium phosphate (CaP) coating on dental implant integration upon installment in the femoral condyles of both healthy and osteoporotic rats. At 8 weeks post-implantation, bone volume and histomorphometric bone area were lower around non-coated implants in osteoporotic rats compared with healthy rats. Interestingly, push-out tests revealed significantly enhanced implant fixation for CaP-coated compared with non-coated implants in both osteoporotic (i.e., 2.9 fold) and healthy rats (i.e., 1.5-fold), with similar implant fixation for CaP coated implants in osteoporotic conditions compared with that of non-coated implants in healthy conditions. Further, the presence of a CaP coating significantly increased bone-to-implant contact compared with that in non-coated implants in both osteoporotic (i.e., 1.3-fold) and healthy rats (i.e., 1.4-fold). Sequential administration of fluorochrome labels showed significantly increased bone dynamics close to CaP-coated implants at 3 weeks of implantation in osteoporotic conditions and significantly decreased bone dynamics in osteoporotic compared with healthy conditions. In conclusion, analysis of the data obtained demonstrated that dental implant modification with a thin CaP coating effectively improves osseointegration in both healthy and osteoporotic conditions. PMID- 24056225 TI - Bioactive nanofibrous scaffolds for regenerative endodontics. AB - Here we report the synthesis, materials characterization, antimicrobial capacity, and cytocompatibility of novel antibiotic-containing scaffolds. Metronidazole (MET) or Ciprofloxacin/(CIP) was mixed with a polydioxanone (PDS)polymer solution at 5 and 25 wt% and processed into fibers. PDS fibers served as a control. Scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), tensile testing, and high-performance liquid chromatography (HPLC) were used to assess fiber morphology, chemical structure, mechanical properties, and drug release, respectively. Antimicrobial properties were evaluated against those of Porphyromonas gingivalis/Pg and Enterococcus faecalis/Ef. Cytotoxicity was assessed in human dental pulp stem cells (hDPSCs). Statistics were performed, and significance was set at the 5% level. SEM imaging revealed a submicron fiber diameter. FTIR confirmed antibiotic incorporation. The tensile values of hydrated 25 wt% CIP scaffold were significantly lower than those of all other groups. Analysis of HPLC data confirmed gradual, sustained drug release from the scaffolds over 48 hrs. CIP-containing scaffolds significantly (p < .00001) inhibited biofilm growth of both bacteria. Conversely, MET-containing scaffolds inhibited only Pg growth. Agar diffusion confirmed the antimicrobial properties against specific bacteria for the antibiotic-containing scaffolds. Only the 25 wt% CIP-containing scaffolds were cytotoxic. Collectively, this study suggests that polymer-based antibiotic-containing electrospun scaffolds could function as a biologically safe antimicrobial drug delivery system for regenerative endodontics. PMID- 24056226 TI - GABA heteroreceptors modulate noradrenaline release in human dental pulp. AB - gamma-aminobutyric-acid-containing neurons and GABA(B) receptors have been identified in human dental pulp; however, their significance in pulpal physiology is unclear. The purpose of this study was to determine whether pre-synaptic GABAergic heteroreceptors influence the release of noradrenaline (NA). Segments of vital pulp were incubated in [(3)H]NA (0.6 MUM) and superfused with Krebs solution. GABA, a GABA(B) receptor agonist (baclofen), GABA(A and B) receptor antagonists [bicuculline and (+)-(S)-5, 5-dimethylmorpholinyl-2-acetic acid (Sch 50911), respectively], and a GABA(A) receptor-mediated Cl(-) channel inhibitor (picrotoxin) were added to the superfusion medium at least 10 min prior to the second period of stimulation (S2). Sympathetic nerves were stimulated electrically after 70 (S1) and 115 (S2) min. We determined the effects of agonists/antagonists by comparing the overflow of [(3)H]NA at S2 with that at S1 in the presence and absence of the compound. Baclofen (3 uM) inhibited the release of [(3)H]NA (IC50 = 2 uM), an action reversed by Sch 50911 (10 uM). GABA (100 uM) inhibited the release of [(3)H]NA (IC50 = 75 uM), an effect reversed by Sch 50911 (10 uM) but not by bicuculline (10 uM). However, picrotoxin (100 uM) prevented the inhibitory action of GABA. GABA(B) and GABA(A) heteroceptors mediate the release of NA from sympathetic nerves in human dental pulp in vitro. PMID- 24056228 TI - A perfusion procedure for imaging of the mouse cerebral vasculature by X-ray micro-CT. AB - BACKGROUND: Micro-CT is a novel X-ray imaging modality which can provide 3D high resolution images of the vascular network filled with contrast agent. The cerebrovascular system is a complex anatomical structure that can be imaged with contrast enhanced micro-CT. However, the morphology of the cerebrovasculature and many circulatory anastomosis in the brain result in high variations in the extent of contrast agent filling in the blood vessels and as a result, the vasculature of different subjects appear differently in the acquired images. Specifically, the posterior circulation is not consistently perfused with the contrast agent in many brain specimens and thus, many major vessels that perfuse blood to the midbrain and hindbrain are not visible in the micro-CT images acquired from these samples. NEW METHOD: In this paper, we present a modified surgical procedure of cerebral vasculature perfusion through the left ventricle with Microfil contrast agent, in order to achieve a more uniform perfusion of blood vessels throughout the brain and as a result, more consistent images of the cerebrovasculature. Our method consists of filling the posterior cerebral circulation with contrast agent, followed by the perfusion of the whole cerebrovasculature. RESULTS: Our histological results show that over 90% of the vessels in the entire brain, including the cerebellum, were filled with contrast agent. COMPARISON WITH EXISTING METHOD: Our results show that the new technique of sample perfusion decreases the variability of the posterior circulation in the cerebellum in micro CT images by 6.9%. CONCLUSIONS: This new technique of sample preparation improves the quality of cerebrovascular images. PMID- 24056227 TI - Dental pulp tissue engineering in full-length human root canals. AB - The clinical translation of stem-cell-based dental pulp regeneration will require the use of injectable scaffolds. Here, we tested the hypothesis that stem cells from exfoliated deciduous teeth (SHED) can generate a functional dental pulp when injected into full-length root canals. SHED survived and began to express putative markers of odontoblastic differentiation after 7 days when mixed with PuramatrixTM (peptide hydrogel), or after 14 days when mixed with recombinant human Collagen (rhCollagen) type I, and injected into the root canals of human premolars in vitro. Roots of human premolars injected with scaffolds (PuramatrixTM or rhCollagen) containing SHED were implanted subcutaneously into immunodeficient mice (CB-17 SCID). We observed pulp-like tissues with odontoblasts capable of generating new tubular dentin throughout the root canals. Notably, the pulp tissue engineered with SHED injected with either PuramatrixTM or rhCollagen type I presented similar cellularity and vascularization when compared with control human dental pulps. Analysis of these data, collectively, demonstrates that SHED injected into full-length human root canals differentiate into functional odontoblasts, and suggests that such a strategy might facilitate the completion of root formation in necrotic immature permanent teeth. PMID- 24056229 TI - A new, behaving, head restrained, eye movement-controlled feline model for chronic visual electrophysiological recordings. AB - BACKGROUND: Anesthetized, paralyzed domestic cats are often used as model organisms in visual neurophysiology. However, in the last few decades, behaving animal models have gathered ground in neurophysiology, due to their advantages over anesthetized, paralyzed models. NEW METHOD: In the present study a new, behaving, awake feline model is described, which is suitable for chronic visual electrophysiological recordings. Two trained, head- fixed cats were suspended in a canvas harness in a specially designed stand. The animals had been trained to fixate the center of a monitor during static and dynamic visual stimulation. Eye movements were monitored with implanted scleral coil in a magnetic field. Cell level activity was recorded with eight electrodes implanted in the caudate nucleus. RESULTS: Our two trained cats could maintain accurate fixation, even during optic flow stimulation, in an acceptance window of +/-2.5 degrees and +/ 1.5 degrees , respectively. The model has yielded accurate recordings for over two years. COMPARISON WITH EXISTING METHOD(S): To our knowledge, this is the first awake, behaving feline model with rigorous eye movement control for chronic, cell-level visual electrophysiological recordings, which has actually proven to work during a longer period. CONCLUSIONS: The new model is optimal for chronic visual electrophysiological recordings in the awake, behaving domestic cat. PMID- 24056231 TI - Effects of eye artifact removal methods on single trial P300 detection, a comparative study. AB - Electroencephalographic signals are commonly contaminated by eye artifacts, even if recorded under controlled conditions. The objective of this work was to quantitatively compare standard artifact removal methods (regression, filtered regression, Infomax, and second order blind identification (SOBI)) and two artifact identification approaches for independent component analysis (ICA) methods, i.e. ADJUST and correlation. To this end, eye artifacts were removed and the cleaned datasets were used for single trial classification of P300 (a type of event related potentials elicited using the oddball paradigm). Statistical analysis of the results confirms that the combination of Infomax and ADJUST provides a relatively better performance (0.6% improvement on average of all subject) while the combination of SOBI and correlation performs the worst. Low pass filtering the data at lower cutoffs (here 4 Hz) can also improve the classification accuracy. Without requiring any artifact reference channel, the combination of Infomax and ADJUST improves the classification performance more than the other methods for both examined filtering cutoffs, i.e., 4 Hz and 25 Hz. PMID- 24056230 TI - In situ three-dimensional reconstruction of mouse heart sympathetic innervation by two-photon excitation fluorescence imaging. AB - BACKGROUND: Sympathetic nerve wiring in the mammalian heart has remained largely unexplored. Resolving the wiring diagram of the cardiac sympathetic network would help establish the structural underpinnings of neurocardiac coupling. NEW METHOD: We used two-photon excitation fluorescence microscopy, combined with a computer assisted 3-D tracking algorithm, to map the local sympathetic circuits in living hearts from adult transgenic mice expressing enhanced green fluorescent protein (EGFP) in peripheral adrenergic neurons. RESULTS: Quantitative co-localization analyses confirmed that the intramyocardial EGFP distribution recapitulated the anatomy of the sympathetic arbor. In the left ventricular subepicardium of the uninjured heart, the sympathetic network was composed of multiple subarbors, exhibiting variable branching and looping topology. Axonal branches did not overlap with each other within their respective parental subarbor nor with neurites of annexed subarbors. The sympathetic network in the border zone of a 2 week-old myocardial infarction was characterized by substantive rewiring, which included spatially heterogeneous loss and gain of sympathetic fibers and formation of multiple, predominately nested, axon loops of widely variable circumference and geometry. COMPARISON WITH EXISTING METHODS: In contrast to mechanical tissue sectioning methods that may involve deformation of tissue and uncertainty in registration across sections, our approach preserves continuity of structure, which allows tracing of neurites over distances, and thus enables derivation of the three-dimensional and topological morphology of cardiac sympathetic nerves. CONCLUSIONS: Our assay should be of general utility to unravel the mechanisms governing sympathetic axon spacing during development and disease. PMID- 24056232 TI - Comparing thoracic and intra-nasal pressure transients to monitor active odor sampling during odor-guided decision making in the mouse. AB - BACKGROUND: Recording of physiological parameters in behaving mice has seen an immense increase over recent years driven by, for example, increased miniaturization of recording devices. One parameter particularly important for odorant-driven behaviors is the breathing frequency, since the latter dictates the rate of odorant delivery to the nasal cavity and the olfactory receptor neurons located therein. NEW METHOD: Typically, breathing patterns are monitored by either measuring the breathing-induced temperature or pressure changes in the nasal cavity. Both require the implantation of a nasal cannula and tethering of the mouse to either a cable or tubing. To avoid these limitations we used an implanted pressure sensor which reads the thoracic pressure and transmits the data telemetrically, thus making it suitable for experiments which require a freely moving animal. RESULTS: Mice performed a Go/NoGo odorant-driven behavioral task with the implanted pressure sensor, which proved to work reliably to allow recording of breathing signals over several weeks from a given animal. COMPARISON TO EXISTING METHOD(S): We simultaneously recorded the thoracic and nasal pressure changes and found that measuring the thoracic pressure change yielded similar results compared to measurements of nasal pressure changes. CONCLUSION: Telemetrically recorded breathing signals are a feasible method to monitor odorant-guided behavioral changes in breathing rates. Its advantages are most significant when recording from a freely moving animal over several weeks. The advantages and disadvantages of different methods to record breathing patterns are discussed. PMID- 24056233 TI - Simulating effects of land use policies on extent of the wildland urban interface and wildfire risk in Flathead County, Montana. AB - This study used a wildfire loss simulation model to evaluate how different land use policies are likely to influence wildfire risk in the wildland urban interface (WUI) for Flathead County, Montana. The model accounts for the complex socio-ecological interactions among climate change, economic growth, land use change and policy, homeowner mitigations, and forest treatments in Flathead County's WUI over the five 10-year subperiods comprising the future evaluation period (i.e., 2010-2059). Wildfire risk, defined as expected residential losses from wildfire [E(RLW)], depends on the number of residential properties on parcels, the probability that parcels burn, the probability of wildfire losses to residential structures on properties given the parcels on which those properties are located burn, the average percentage of wildfire-related losses in aesthetic values of residential properties, and the total value (structures plus land) of residential properties. E(RLW) for the five subperiods is simulated for 2010 (referred to as the current), moderately restrictive, and highly restrictive land use policy scenarios, a moderate economic growth scenario and the A2 greenhouse gas emissions scenario. Results demonstrate that increasingly restrictive land use policy for Flathead County significantly reduces the amount and footprint of future residential development in the WUI. In addition, shifting from the current to a moderately restrictive land use policy for Flathead County significantly reduces wildfire risk for the WUI, but shifting from the current to a highly restrictive land use policy does not significantly reduce wildfire risk in the WUI. Both the methods and results of the study can help land and wildfire managers to better manage future wildfire risk and identify residential areas having potentially high wildfire risk. PMID- 24056234 TI - Climate change and coastal environmental risk perceptions in Florida. AB - Understanding public perceptions of climate change risks is a prerequisite for effective climate communication and adaptation. Many studies of climate risk perceptions have either analyzed a general operationalization of climate change risk or employed a case-study approach of specific adaptive processes. This study takes a different approach, examining attitudes toward 17 specific, climate related coastal risks and cognitive, affective, and risk-specific predictors of risk perception. A survey of 558 undergraduates revealed that risks to the physical environment were a greater concern than economic or biological risks. Perceptions of greater physical environment risks were significantly associated with having more pro-environmental attitudes, being female, and being more Democratic-leaning. Perceptions of greater economic risks were significantly associated with having more negative environmental attitudes, being female, and being more Republican-leaning. Perceptions of greater biological risks were significantly associated with more positive environmental attitudes. The findings suggest that focusing on physical environment risks maybe more salient to this audience than communications about general climate change adaptation. The results demonstrate that climate change beliefs and risk perceptions are multifactorial and complex and are shaped by individuals' attitudes and basic beliefs. Climate risk communications need to apply this knowledge to better target cognitive and affective processes of specific audiences, rather than providing simple characterizations of risks. PMID- 24056235 TI - Musical experts recruit action-related neural structures in harmonic anomaly detection: evidence for embodied cognition in expertise. AB - Humans are extremely good at detecting anomalies in sensory input. For example, while listening to a piece of Western-style music, an anomalous key change or an out-of-key pitch is readily apparent, even to the non-musician. In this paper we investigate differences between musical experts and non-experts during musical anomaly detection. Specifically, we analyzed the electroencephalograms (EEG) of five expert cello players and five non-musicians while they listened to excerpts of J.S. Bach's Prelude from Cello Suite No. 1. All subjects were familiar with the piece, though experts also had extensive experience playing the piece. Subjects were told that anomalous musical events (AMEs) could occur at random within the excerpts of the piece and were told to report the number of AMEs after each excerpt. Furthermore, subjects were instructed to remain still while listening to the excerpts and their lack of movement was verified via visual and EEG monitoring. Experts had significantly better behavioral performance (i.e. correctly reporting AME counts) than non-experts, though both groups had mean accuracies greater than 80%. These group differences were also reflected in the EEG correlates of key-change detection post-stimulus, with experts showing more significant, greater magnitude, longer periods of, and earlier peaks in condition discriminating EEG activity than novices. Using the timing of the maximum discriminating neural correlates, we performed source reconstruction and compared significant differences between cellists and non-musicians. We found significant differences that included a slightly right lateralized motor and frontal source distribution. The right lateralized motor activation is consistent with the cortical representation of the left hand - i.e. the hand a cellist would use, while playing, to generate the anomalous key-changes. In general, these results suggest that sensory anomalies detected by experts may in fact be partially a result of an embodied cognition, with a model of the action for generating the anomaly playing a role in its detection. PMID- 24056236 TI - Levels of visuo-spatial selection: an ERP study of negative priming. AB - Usually, a probe target appearing in a recently ignored distractor location is less efficiently processed. This robust phenomenon is called (visuo-) spatial negative priming (SNP). Among other explanations, concepts of persisting or retrieved spatial inhibition play a major role. Two relevant issues were investigated using event-related brain potentials (ERPs). The first pertains to context sensitivity of inhibition: Is a probe distractor necessary for SNP? The second concerns levels of processing at which spatial inhibition operates: Does SNP affect perception, selection, and/or stimulus classification? A localization task with and without probe distractors was employed while 64-channel EEG was recorded. Obviously, SNP does not require a probe distractor; the distractor absent SNP effect was larger than the distractor-present SNP effect. Distractor present SNP had two lateralized ERP effects, N1pc amplitude reduction and N2pc amplitude increase. Smaller N1pc may indeed reflect perceptual decrement, but was inversely related to size of behavioral SNP. By contrast, only strong-SNP participants showed N2pc increase, which points to selection disadvantage due to persisting inhibition of higher-level spatial representations. Distractor-absent SNP had no N1pc/N2pc correlates; instead, reduced amplitude of a broadly distributed P300 component suggests impaired stimulus classification due to episodic retrieval of inappropriate prime information. Overall, SNP seems to emerge from relatively late stages of processing, thus challenging the idea of context-free persisting inhibition of low-level spatial representations. Furthermore, distractor-present and distractor-absent SNP are qualitatively different from each other. PMID- 24056238 TI - Hypnotic assessment based on the recurrence quantification analysis of EEG recorded in the ordinary state of consciousness. AB - The cerebral cortical correlates of the susceptibility to hypnosis in the ordinary states of consciousness have not been clarified. Aim of the study was to characterize the EEG dynamics of subjects with high (highs) and low hypnotisability (lows) through the non-linear method of Recurrence Quantification Analysis (RQA). The EEG of 16 males--8 highs and 8 lows--was monitored for 1min without instructions other than keeping the eyes closed, being silent and avoiding movements (short resting), and during 15 min of simple relaxation, that is with the instruction to relax at their best. Highs and lows were compared on the RQA measures of Determinism (DET) and Entropy (ENT), which are related to the signal determinism and complexity. In the short resting condition discriminant analysis could classify highs and lows on the basis of DET and ENT values at temporo-parietal sites. Many differences in DET and all differences in ENT disappeared during simple relaxation, although DET still separated the two groups in the earliest 6min of relaxation at temporo-parietal sites. Our RQA based approach allows to develop computer-based methods of hypnotic assessment using short-lasting, single channel EEG recordings analyzed through standard mathematical methods. PMID- 24056237 TI - Aberrant neural mediation of verbal fluency in autism spectrum disorders. AB - OBJECTIVE: Contrasts of verbal fluency and automatic speech provide an opportunity to evaluate the neural underpinnings of generativity and flexibility in autism spectrum disorders (ASD). METHOD: We used functional magnetic resonance imaging (fMRI) to contrast brain activity in high functioning ASD (n=17, mean verbal IQ=117) and neurotypical (NT; n=20, mean verbal IQ=112) adolescent and young adult males (12-23years). Participants responded to three word generation conditions: automatic speech (reciting months), category fluency, and letter fluency. RESULTS: Our paradigm closely mirrored behavioral fluency tasks by requiring overt, free recall word generation while controlling for differences in verbal output between the groups and systematically increasing the task demand. The ASD group showed reduced neural response compared to the NT participants during fluency tasks in multiple regions of left anterior and posterior cortices, and sub-cortical structures. Six of these regions fell in cortico-striatal circuits previously linked to repetitive behaviors (Langen, Durston, Kas, van Engeland, & Staal, 2011), and activity in two of them (putamen and thalamus) was negatively correlated with autism repetitive behavior symptoms in the ASD group. In addition, response in left inferior frontal gyrus was differentially modulated in the ASD, relative to the NT, group as a function of task demand. CONCLUSIONS: These data indicate a specific, atypical brain response in ASD to demanding generativity tasks that may have relevance to repetitive behavior symptoms in ASD as well as to difficulties generating original verbal responses. PMID- 24056239 TI - Functional aspects of emotions in fish. AB - There is an ongoing scientific discussion on whether fish have emotions, and if so how they experience them? The discussion has incorporated important areas such as brain anatomy and function, physiological and behavioural responses, and the cognitive abilities that fish possess. Little attention has however, been directed towards what functional aspects emotions ought to have in fish. If fish have emotions - why? The elucidation of this question and an assessment of the scientific evidences of emotions in fish in an evolutionary and functional framework would represent a valuable contribution in the discussion on whether fish are emotional creatures. Here parts of the vast amount of literature from both biology and psychology relating to the scientific field of emotions, animal emotion, and the functional aspects that emotions fulfil in the lives of humans and animals are reviewed. Subsequently, by viewing fish behaviour, physiology and cognitive abilities in the light of this functional framework it is possible to infer what functions emotions may serve in fish. This approach may contribute to the vital running discussion on the subject of emotions in fish. In fact, if it can be substantiated that emotions are likely to serve a function in fish similar to that of other higher vertebrate species, the notion that fish do have emotions will be strengthened. PMID- 24056240 TI - Effect of distracter preexposure on the reset of an internal clock. AB - Interruptions and unfamiliar events (distracters) during a timed signal disrupt (delay) timing in humans and other animals. We hypothesized that repeated exposure to a stimulus may reduce its subsequent time-disrupting properties. To test this hypothesis rats were trained in a reversed peak-interval (RPI) procedure, in which dark timing trials were separated by illuminated inter-trial intervals. Rats were then repeatedly exposed to an auditory stimulus (noise) in either dark (DARK group), or illuminated chambers (LIGHT group); control rats were not exposed to the noise (NOVEL group). Afterwards, the time-resetting properties of the noise were tested by presenting it unexpectedly during the (dark) RPI trials. The noise reset timing in NOVEL rats, but stopped timing in DARK rats, suggesting that preexposure reduces the time-resetting effects of distracters. However, in LIGHT rats, the noise stopped timing when the presented early in the RPI trial, but reset when presented late, suggesting that exposure to noise was only partly effective in overriding other relevant variables, such as distracter location. These results suggest that the effect of distracter preexposure on the reset of an internal clock depends on complex associative and temporal interactions which require further investigations. This article is part of a Special Issue entitled: Associative and Temporal Learning. PMID- 24056241 TI - How capuchin monkeys (Cebus apella) behaviorally cope with increasing delay in a self-control task. AB - Displacement activities are behavior patterns apparently irrelevant to the situation in which they are performed that facilitate transitions between behavioral states. Scratching is one of the most commonly described displacement activities in primates and is related to frustration and anxiety. In chimpanzees scratching during cognitive tasks increases with task difficulty. We analyzed behavioral data obtained from video clips on nine capuchin monkeys tested in a delay choice task, a potentially stressful self-control task where subjects choose between a small immediate and a large delayed option. Scratching, response latency, and motor impulsivity scored during the delay decreased across sessions, as capuchins became indifferent between options, whereas the bias for choosing the option placed on one side of the apparatus increased. Capuchins might have found the delay choice task less stressful over time because they shifted from slower discriminatory responses in the earlier sessions to more 'automatic', faster responses in the later sessions. However, it cannot be excluded that they habituated over time to the contingencies of the task. In contrast with previous data on chimpanzees, handedness in scratching behavior or preferential scratching on one side of the body did not emerge, but further studies are needed to corroborate this finding. PMID- 24056242 TI - Forward hysteresis and backward bifurcation caused by culling in an avian influenza model. AB - The emerging threat of a human pandemic caused by the H5N1 avian influenza virus strain magnifies the need for controlling the incidence of H5N1 infection in domestic bird populations. Culling is one of the most widely used control measures and has proved effective for isolated outbreaks. However, the socio economic impacts of mass culling, in the face of a disease which has become endemic in many regions of the world, can affect the implementation and success of culling as a control measure. We use mathematical modeling to understand the dynamics of avian influenza under different culling approaches. We incorporate culling into an SI model by considering the per capita culling rates to be general functions of the number of infected birds. Complex dynamics of the system, such as backward bifurcation and forward hysteresis, along with bi stability, are detected and analyzed for two distinct culling scenarios. In these cases, employing other control measures temporarily can drastically change the dynamics of the solutions to a more favorable outcome for disease control. PMID- 24056243 TI - Insights into potentially toxic effects of 4-aminoantipyrine on the antioxidant enzyme copper-zinc superoxide dismutase. AB - 4-Aminoantipyrine (AAP) is scarcely administered as an analgesic drug because of side effects. The residue of AAP in the environment is potentially harmful. To evaluate the toxicity of AAP from molecular level, the effects of AAP on the important antioxidant enzyme copper-zinc superoxide dismutase (Cu/ZnSOD) were explored using spectroscopic and molecular modeling methods. AAP can spontaneously bind with Cu/ZnSOD with one binding site to form AAP-Cu/ZnSOD complex through hydrogen bond and van der Waals forces. The molecular docking simulation revealed that AAP bound into the Cu/ZnSOD interface of two subdomains, which induced some conformational and microenvironmental changes of Cu/ZnSOD and further caused the inhibition of Cu/ZnSOD activity. The present study provides important insights into toxic mechanism of AAP with Cu/ZnSOD. The estimated research route can be applied to characterize interactions of enzyme systems and other pollutants and drugs. PMID- 24056244 TI - Immobilization of simulated radionuclide 133Cs+ by fly ash-based geopolymer. AB - The recent nuclear leak in Japan once again attracted people's attention to nuclear safety problems. Because of their poor thermal stability, those low-cost materials such as cement and asphalt cannot be used for the solidification of the radioactive wastes. In this work, the solidification behavior of 133Cs(+) by fly ash-based geopolymer was investigated. Leaching tests (carried out in deionized water, sulfuric acid and magnesium sulfate solutions) revealed that the geopolymer solidification had lower cumulative fraction leaching concentration (CFLC) of 133Cs(+) than that of cemented form. The thermal stability (high temperature and freeze-thaw resistance) and acid-resistance of the geopolymer were also both better than that of cement. The geopolymer solidification block can acquire a compressive strength up to 30 MPa after 2h calcination at 1000 degrees C. The morphology and mineral phases of the geopolymer and the geopolymer solidification block were characterized by SEM and XRD, and EDX analysis indicated that most of Cs associated with the amorphous geopolymer gel. These results gave encouragement for the idea that the fly ash-based geopolymer could be used as a low-cost and high-efficiency material for the immobilization of radioactive wastes. PMID- 24056245 TI - Reductive defluorination of perfluorooctanoic acid by hydrated electrons in a sulfite-mediated UV photochemical system. AB - A method for reductive degradation of perfluorooctanoic acid (PFOA) was established by using a sulfite/UV process. This process led to a PFOA removal of 100% at about 1h and a defluorination ratio of 88.5% at reaction time of 24h under N2 atmosphere, whereas the use of either UV irradiation or SO3(2-) alone induced little defluorination of PFOA under the same conditions. It was confirmed that the reductive defluorination of PFOA was achieved by hydrated electrons being generated from the photo-conversion of SO3(2-) as a mediator. Theoretical reaction kinetic analysis demonstrated that the generation of hydrated electrons was promoted by increasing either SO3(2-) concentration or solution pH, leading to the acceleration of the PFOA defluorination. Accompanying the reduction of PFOA, a small amount of short-chain perfluorocarboxylic acids, less fluorinated carboxylic acids and perfluorinated alkyl sulfonates were generated, all of which were able to be further degraded with further releasing of fluoride ions. Based on the generation, accumulation and distribution of intermediates, hydrated electrons induced defluorination pathway of PFOA was proposed in a sulfite mediated UV photochemical system. PMID- 24056246 TI - In situ determination mechanisms for the depuration of polycyclic aromatic hydrocarbons adsorbed onto the leaf surfaces of living mangrove seedlings. AB - To further increase understanding of the mechanisms responsible for air-surface exchange processes, the depuration of adsorbed individual fluorene (Flu), anthracene (Ant), phenanthrene (Phe), fluoranthene (Fla), and pyrene (Pyr) from the leaf surfaces of living Aegiceras corniculatum (Ac) and Kandelia obovata (Ko) seedlings were in situ investigated in real time using laser-induced nanosecond time-resolved fluorescence (LITRF) system. Depuration of the PAHs from the leaf surfaces of the two mangrove seedlings included a rapid and a slow phase, and both of them followed first-order kinetics. Furthermore, significant inter species and inter-chemical variability existed in terms of the elimination rates and the remaining PAHs residues during the two phases. The rapid phase mainly represented a fast volatilization, of which the volatilization rates moderately correlate with PAH molecular weight, while combined effect of volatilization and photolysis was the dominant mechanism for the slow phase. The retainment of PAHs on the leaf surfaces was associated with the plant species and physicochemical properties of PAHs, especially logKOA. PMID- 24056247 TI - Perchlorate reduction by the sulfite/ultraviolet light advanced reduction process. AB - Advanced reduction processes (ARPs) are a new class of water treatment processes that combine activation methods and reducing agents to form highly reactive reducing radicals that degrade oxidized contaminants. The combination of sulfite with low-pressure ultraviolet light (UV-L) is the most effective ARP tested to date. In this study, batch kinetic experiments were conducted to characterize the kinetics of perchlorate destruction by the sulfite/UV-L ARP. Experimental variables were pH, sulfite concentration, temperature and UV-L irradiance. The rate of perchlorate degradation by sulfite/UV-L increases with increasing pH and temperature and increases with increasing sulfite concentration to a maximum and then decreases due to lack of mixing within the reactor system used. Efficiency of perchlorate degradation was measured as a quantum yield and was observed to decrease with increasing sulfite concentration. The ultimate product of perchlorate degradation by the sulfite/UV-L ARP is chloride, but chlorate was detected as an intermediate. PMID- 24056248 TI - Soil microstructure and organic matter: keys for chlordecone sequestration. AB - Past applications of chlordecone, a persistent organochlorine pesticide, have resulted in diffuse pollution of agricultural soils, and these have become sources of contamination of cultivated crops as well as terrestrial and marine ecosystems. Chlordecone is a very stable and recalcitrant molecule, mainly present in the solid phase, and has a strong affinity for organic matter. To prevent consumer and ecosystem exposure, factors that influence chlordecone migration in the environment need to be evaluated. In this study, we measured the impact of incorporating compost on chlordecone sequestration in andosols as a possible way to reduce plant contamination. We first characterized the transfer of chlordecone from soil to plants (radish, cucumber, and lettuce). Two months after incorporation of the compost, soil-plant transfers were reduced by a factor of 1.9-15 depending on the crop. Our results showed that adding compost modified the fractal microstructure of allophane clays thus favoring chlordecone retention in andosols. The complex structure of allophane and the associated low accessibility are important characteristics governing the fate of chlordecone. These results support our proposal for an alternative strategy that is quite the opposite of total soil decontamination: chlordecone sequestration. PMID- 24056249 TI - Environmental aspects of photooxidative treatment of phenolic compounds. AB - The study was aimed at evaluation of environmental aspects on photooxidative treatment of phenolic compounds by UV/H2O2 process. Hydroxy-, chloro-, nitro- and methyl-phenols substituted in ortho and para positions were used as model pollutants. The influence of pollutant chemical structure on variations of water quality during the photooxidative treatment was investigated. In that purpose, we monitored the changes of total organic carbon (TOC); chemical oxygen demand (COD); aromaticity, measured as absorbance at 280 (A280) and 254 nm (A254); biodegradability, estimated over ratio of biochemical and chemical oxygen demand (BOD5/COD); and toxicity, estimated on inhibition of Vibrio fischeri luminescence (TU). It was found that changes of monitored parameters are influenced by the type and position of substituent. Studied pollutants share sequence in degradation pathway and consequently some of the formed by-products are the same as well. However, their distribution and the formation of specific by-products with characteristic functional groups play significant role in observed variations of water quality, which was particularly reflected in biodegradability and toxicity. The cross-correlation between recorded sum-water parameters is assessed on the basis of calculated Spearman rank coefficients. PMID- 24056250 TI - Morbidity in pediatric burns, toxic shock syndrome, and antibiotic prophylaxis: a retrospective comparative study. AB - The prophylactic use of antibiotic for pediatric burns has been suggested as a possible means of reduction of toxic shock syndrome. In our study, we review 1250 burn cases during a 16-year period (1983-1999). There was a change in protocol during this period (after 1991, all pediatric burn received prophylactic antibiotics irrespective of presentation), thus creating 2 groups: our control who received antibiotics when clinically necessary and our cases who received antibiotics as routine prophylaxis. Our results show no statistical difference between the 2 groups both in signs of morbidity and signs of potential toxic shock syndrome. We conclude that prophylactic antibiotic use is unnecessary and the use of antibiotics should be guided on a case by case basis according to symptoms. PMID- 24056251 TI - Occupational loading may not affect the association between vertebral trabecular bone and intervertebral disc narrowing. PMID- 24056252 TI - Scaling relations between trabecular bone volume fraction and microstructure at different skeletal sites. AB - In this study, we investigated the scaling relations between trabecular bone volume fraction (BV/TV) and parameters of the trabecular microstructure at different skeletal sites. Cylindrical bone samples with a diameter of 8mm were harvested from different skeletal sites of 154 human donors in vitro: 87 from the distal radius, 59/69 from the thoracic/lumbar spine, 51 from the femoral neck, and 83 from the greater trochanter. MUCT images were obtained with an isotropic spatial resolution of 26MUm. BV/TV and trabecular microstructure parameters (TbN, TbTh, TbSp, scaling indices (< > and sigma of alpha and alphaz), and Minkowski Functionals (Surface, Curvature, Euler)) were computed for each sample. The regression coefficient beta was determined for each skeletal site as the slope of a linear fit in the double-logarithmic representations of the correlations of BV/TV versus the respective microstructure parameter. Statistically significant correlation coefficients ranging from r=0.36 to r=0.97 were observed for BV/TV versus microstructure parameters, except for Curvature and Euler. The regression coefficients beta were 0.19 to 0.23 (TbN), 0.21 to 0.30 (TbTh), -0.28 to -0.24 (TbSp), 0.58 to 0.71 (Surface) and 0.12 to 0.16 (), 0.07 to 0.11 (), -0.44 to -0.30 (sigma(alpha)), and -0.39 to -0.14 (sigma(alphaz)) at the different skeletal sites. The 95% confidence intervals of beta overlapped for almost all microstructure parameters at the different skeletal sites. The scaling relations were independent of vertebral fracture status and similar for subjects aged 60-69, 70-79, and >79years. In conclusion, the bone volume fraction microstructure scaling relations showed a rather universal character. PMID- 24056253 TI - Modulation of endoplasmic reticulum chaperone GRP78 by high glucose in hippocampus of streptozotocin-induced diabetic mice and C6 astrocytic cells. AB - Diabetes mellitus is known to increase the risk of neurodegeneration, and both diseases are reported to be linked to dysfunction of endoplasmic reticulum (ER). Astrocytes are important in the defense mechanism of central nervous system (CNS), with great ability of tolerating accumulation of toxic substances and sensitivity in Ca(2+) homeostasis which are two key functions of ER. Here, we investigated the modulation of the glucose-regulated protein 78 (GRP78) in streptozotocin (STZ)-induced diabetic mice and C6 cells cultured in high glucose condition. Our results showed that more reactive astrocytes were presented in the hippocampus of STZ-induced diabetic mice. Simultaneously, decrease of GRP78 expression was found in the astrocytes of diabetic mice hippocampus. In in vitro study, C6 cells were treated with high glucose to investigate the role of high glucose in GRP78 modulation in astrocytic cells. GRP78 as well as other chaperones like GRP94, calreticulin and calnexin, transcription levels were down regulated after high glucose treatment. Also C6 cells challenged with 48h high glucose were activated, as indicated by increased level of glial fibrillary acidic protein (GFAP). Activated C6 cells simultaneously exhibited significant decrease of GRP78 level and was followed by reduced phosphorylation of Akt. Moreover, unfolded protein response was induced as an early event, which was marked by the induction of CHOP with high glucose treatment, followed by the reduction of GRP78 after 48h. Finally, the upsurge of ROS production was found in high glucose treated C6 cells and chelation of ROS could partially restore the GRP78 expression. Taken together, these data provide evidences that high glucose induced astrocytic activation in both in vivo and in vitro diabetic models, in which modulation of GRP78 would be an important event in this activation. PMID- 24056254 TI - Expression and purification of recombinant NRL-Hsp90alpha and Cdc37-CRL proteins for in vitro Hsp90/Cdc37 inhibitors screening. AB - Hsp90 has emerged as a promising target for cancer treatment. Hsp90 interacts with co-chaperone Cdc37 to mediate the conformational maturation of its kinase client proteins. Screening small molecule inhibitors targeting Hsp90/Cdc37 might be a promising strategy for further cancer therapeutic. In order to establish a recombinant protein system, the novel cloning and purification of full-length human Hsp90alpha and Cdc37 from BL21 (DE3) Escherichia coli is described here. In this work, we cloned and expressed recombinant NRL-Hsp90alpha and Cdc37-CRL that represent the full-length human Hsp90alpha and Cdc37 fused with the split Renilla luciferase (RL) protein fragments. We also expressed the full-length RL protein as a control for inhibitors screening. Moreover, we confirmed that the interaction proteins were able to complement split luciferase fragments and show the RL activity when substrate was added. In comparison, two mutations NRL Hsp90alpha (Q133A) and Cdc37 (R167A)-CRL retained only 20% of the complemented RL activities. Six small molecule compounds were tested using this recombinant system. Very interestingly, Sulforaphane, Withaferin A, Celastrol and EGCG all decreased the complemented NRL-Hsp90alpha/Cdc37-CRL activities in the concentration-dependent manner. In addition, neither Sulforaphane nor Withaferin A showed non-specific inhibition on full length RL activity. However, Celastrol and EGCG showed different RL inhibition levels. The other two compounds LBH-589 and 17-AAG showed neither NRL-Hsp90alpha/Cdc37-CRL nor RL inhibition activities. These results indicate that purified NRL-Hsp90alpha and Cdc37-CRL appeared as pure, stable and active conformation, and can be used as an in vitro bioluminescence system for Hsp90/Cdc37 inhibitors screening. PMID- 24056255 TI - Cloning, expression and N-terminal formylation of ESAT-6 of Mycobacterium tuberculosis H37Rv. AB - Bacterial protein synthesis initiates with a formyl-methionine group. Addition of the antibiotic actinonin, a known peptide deformylase inhibitor, at the time of induction of protein expression results in the retention of the formyl group by the overexpressed protein. We have demonstrated the application of this system to obtain N-formylated form of a mycobacterial secretory protein ESAT-6 which is an important target for T-cell recognition during Mycobacterium tuberculosis infection. The gene encoding the ESAT-6 of M. tuberculosis was inserted into a bacterial expression vector pET23a (+) resulting in a 6 * His-esat-6 fusion gene construction with histidine tag at its C-terminus. This recombinant plasmid was transformed into Escherichia coli strain BL21(DE3) and effectively expressed in presence or absence of a peptide deformylase inhibitor, actinonin. The expressed fusion proteins (non-formylated and N-formylated ESAT-6) found in the inclusion bodies were purified by Ni(2+)-NTA chromatography. The N-terminal formylation of ESAT-6 was confirmed by advanced proteomic techniques including MALDI-TOF mass spectrometry and 2-DE. The gene encoding ESAT-6 of M. tuberculosis was successfully cloned and expressed in E. coli. The N-terminal formylation of this protein (ESAT-6) was carried out by inducing the recombinant clone harboring the ESAT-6 gene in presence of actinonin (peptide deformylase inhibitor). PMID- 24056256 TI - One-step separation of myristoylated and nonmyristoylated retroviral matrix proteins. AB - N-terminal myristoylation of retroviral matrix proteins is essential for the targeting of the Gag polyproteins to the plasma membrane. To investigate the effect of the myristoylation on the structure and membrane binding ability of the matrix proteins, it is necessary to prepare their myristoylated forms. We present purification of myristoylated matrix proteins of the mouse mammary tumor virus and murine leukemia virus, two morphogenetically distinct retroviruses. The proteins were expressed in Escherichia coli coexpressing a yeast N myristoyltransferase. This E. coli expression system yielded a mixture of myristoylated and nonmyristoylated matrix proteins. We established efficient one step metal affinity purification that enabled to obtain pure myristoylated matrix proteins suitable for structural and functional studies. PMID- 24056257 TI - Bacteriophage T7 RNA polymerase-based expression in Pichia pastoris. AB - A novel Pichia pastoris expression vector (pEZT7) for the production of recombinant proteins employing prokaryotic bacteriophage T7 RNA polymerase (T7 RNAP) (EC 2.7.7.6) and the corresponding promoter pT7 was constructed. The gene for T7 RNAP was stably introduced into the P. pastoris chromosome 2 under control of the (endogenous) constitutive P. pastoris glyceraldehyde-3-phosphate dehydrogenase (GAP) promoter (pGAP). The gene product T7 RNAP was engineered to contain a nuclear localization signal, which directed recombinant T7 RNAP to the P. pastoris nucleus. To promote translation of uncapped T7 RNAP derived transcripts, the internal ribosomal entry site from hepatitis C virus (HCV-IRES) was inserted directly upstream of the multiple cloning site of pEZT7. A P. pastoris autonomous replicating sequence (PARS1) was integrated into pEZT7 enabling propagation and recovery of plasmids from P. pastoris. Rapid amplification of 5' complementary DNA ends (5' RACE) experiments employing the test plasmid pEZT7-EGFP revealed that transcripts indeed initiated at pT7. HCV IRES mediated translation of the latter mRNAs, however, was not observed. Surprisingly, HCV-IRES and the reverse complement of PARS1 (PARS1rc) were both found to display significant promoter activity as shown by 5' RACE. PMID- 24056258 TI - Purification and characterization of a soluble calnexin from human placenta. AB - Calreticulin (Crt) and calnexin (Cnx) are homologous endoplasmic reticulum (ER) chaperones involved in protein folding and quality control. Crt is a soluble ER luminal Mr 46 kDa protein and Cnx is a Mr 67kDa ER membrane protein. During purification of Crt from human placenta a soluble form of Cnx (sCnx) was consistently identified in a separate ion exchange chromatography peak. The sCnx was further purified and characterised. This showed that the protein had been cleaved after residue 472 (between Gln and Met), thus liberating it from the transmembrane and cytoplasmic parts of Cnx. The extraction and initial purification steps were carried out in the presence of protease inhibitors, thus ruling out that the cleavage was an artefact of the isolation procedure. This indicates that sCnx may have a physiological chaperone function similar to that of Crt. PMID- 24056259 TI - Approaches for the analysis of chlorinated lipids. AB - Leukocytes are key cellular mediators of human diseases through their role in inflammation. Identifying unique molecules produced by leukocytes may provide new biomarkers and mechanistic insights into the role of leukocytes in disease. Chlorinated lipids are generated as a result of myeloperoxidase-containing leukocyte-derived hypochlorous acid targeting the vinyl ether bond of plasmalogens. The initial product of this reaction is alpha-chlorofatty aldehyde. alpha-Chlorofatty aldehyde is both oxidized to alpha-chlorofatty acid and reduced to alpha-chlorofatty alcohol by cellular metabolism. This review focuses on the separation techniques and quantitative analysis for these chlorinated lipids. For alpha-chlorofatty acid, the negative charge of carboxylic acids is exploited to detect the chlorinated lipid species of these acids by electrospray ionization mass spectrometry in the negative ion mode. In contrast, alpha-chlorofatty aldehyde and alpha-chlorofatty alcohol are converted to pentafluorobenzyl oxime and pentafluorobenzoyl ester derivatives, which are detected by negative ion chemical ionization mass spectrometry. These two detection methods coupled with the use of stable isotope internal standards and either liquid chromatography or gas chromatography provide highly sensitive analytical approaches to measure these novel lipids. PMID- 24056260 TI - One-step reverse transcription loop mediated isothermal amplification assay for sensitive and rapid detection of Cucurbit chlorotic yellows virus. AB - A reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed for the detection of Cucurbit chlorotic yellows virus (CCYV). In this procedure, a set of four primers matching a total of six sequences in the coat protein gene region of CCYV was synthesized for the RT-LAMP assay using total RNA extracted from CCYV-infected melon leaf tissues, and the optimum reaction temperature and assay time were determined. The sensitivity assay showed that the virus was detectable in RT-LAMP reactions at dilutions of 1*10(-11), which was 10(5) times more sensitive than the RT-PCR assay. The RT-LAMP assay for CCYV and Sweet potato chlorotic stunt virus (SPCSV) exhibited high specificity for CCYV. This simple and sensitive method has potential for detection of CCYV in samples collected in the field. PMID- 24056261 TI - Application of real time RT-PCR for the genetic homogeneity and stability tests of the seed candidates for live attenuated influenza vaccine production. AB - Development and improvement of quality control tests for live attenuated vaccines are a high priority because of safety concerns. Live attenuated influenza vaccine (LAIV) viruses are 6:2 reassortants containing the hemagglutinin (HA) and neuraminidase (NA) gene segments from circulating influenza viruses to induce protective immune responses, and the six internal gene segments from a cold adapted Master Donor Virus (MDV). LAIV candidate viruses for the 2012-2013 seasons, A/Victoria/361/2011-CDC-LV1 (LV1) and B/Texas/06/2011-CDC-LV2B (LV2B), were created by classical reassortment of A/Victoria/361/2011 and MDV-A A/Leningrad/134/17/57 (H2N2) or B/Texas/06/2011 and MDV-B B/USSR/60/69. In an attempt to provide better identity and stability testing for quality control of LV1 and LV2B, sensitive real-time RT-PCR assays (rRT-PCR) were developed to detect the presence of undesired gene segments (HA and NA from MDV and the six internal genes from the seasonal influenza viruses). The sensitivity of rRT-PCR assays designed for each gene segment ranged from 0.08 to 0.8EID50 (50% of Egg Infectious Dose) per reaction for the detection of undesired genes in LV1 and from 0.1 to 1EID50 per reaction for the detection of undesired genes in LV2B. No undesired genes were detected either before or after five passages of LV1 or LV2B in eggs. The complete genome sequencing of LV1 and LV2B confirmed the results of rRT-PCR, demonstrating the utility of the new rRT-PCR assays to provide the evidence for the homogeneity of the prepared vaccine candidate. PMID- 24056262 TI - Yeast cells as a tool for analysis of HIV-1 protease susceptibility to protease inhibitors, a comparative study. AB - HIV develops drug resistance at a high rate under drug selection pressure. Resistance tests are recommended to help physicians optimize antiretroviral drug therapies. For this purpose, genotypic and phenotypic tests have been developed. In order to propose a new phenotypic test that will be less laborious, expensive, and time consuming than the standard ones, a new procedure to measure HIV-1 protease susceptibility to protease inhibitor (PIs) in Saccharomyces cerevisiae yeast cells was developed. This procedure is based on HIV-1 protease expression in yeast. While the viral protein induces yeast cell death, its inhibition by PIs in the culture medium allows the cell to grow in a dose-dependent manner. In a comparative study of standard genotypic analysis vs. yeast cell-based phenotypic tests, performed on HIV-1 protease coding DNA in 17 different plasma samples from infected individuals, a clear match was found between the results obtained using the two technologies. This suggests that the yeast-based procedure is at least as accurate as standard genotypic test in defining susceptibility to protease inhibitors. This encouraging result should be the basis for large-scale validation of the new phenotypic resistance test. PMID- 24056263 TI - Molecular data mining to improve antibody-based detection of Grapevine leafroll associated virus 1 (GLRaV-1). AB - Testing for Grapevine leafroll-associated virus 1 (GLRaV-1) is mandatory in certification schemes of propagation material within the EU. Accurate and reliable diagnostic assays are necessary for implementation of this measure. During routine detection of GLRaV-1, using double antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) and reverse transcription (RT) followed by polymerase chain reaction (PCR), evidence was obtained that positive samples could be overlooked by either or both detection methods. With the aim of improving serological detection tools for GLRaV-1, a total of 20 isolates were analyzed and 83 new complete capsid protein (CP) gene sequences were obtained. This set, together with the CP sequences available at GenBank was used for a comprehensive in silico analysis. To obtain a specific antibody able to recognize all known CP variants, conserved regions with suitable antigenicity profile were identified along the deduced CP AA sequences and a 14 AA sequence was chosen for commercial peptide synthesis and immunization. Initially polyclonal antibodies were produced and tested, followed by purification of the respective monospecific antibody and conjugation with alkaline phosphatase or fluorescein isothiocyanate (FITC). These serological tools were tested successfully on all the available positive samples and proved adequate for in situ immunoassay (ISIA). Further testing showed that the monospecific antibody could also be used in tissue print immunoblotting (TPIB), a technique that allows rapid processing of large sample sets, which is highly suitable to implement protocols ensuring that, for each vine analyzed, enough random samples are taken and processed, before certification. PMID- 24056264 TI - Surgical implantation of a mechanical valve prosthesis due to aortic stenosis in a patient after liver transplantation: case report. AB - BACKGROUND: The development of increasingly accurate immunosuppression and surgical techniques has contributed to transplantology to such an extent that patients who have undergone abdominal organ transplantations account for an increasing group in whom other diseases, including those of the cardiovascular system, have to be treated, also surgically. CASE REPORT: A 61-year-old male patient after liver transplantation was admitted to the Institute of Cardiology to undergo surgical treatment of aortic stenosis. An SJM 23-mm mechanical prosthesis was implanted into the aortic ostium. The postoperative period was without complications. On postoperative day 6, the patient was transferred to the Department of Transplantation Medicine and Nephrology to be treated further. CONCLUSIONS: Cardiosurgery procedures in liver transplant recipients involve a higher risk, which results from hemorrhagic complications requiring massive blood and blood components transfusions and repeated thoracotomy. Because of expected complications, the choice of prosthesis is difficult and should be made together by a cardiac surgeon and the patient. PMID- 24056265 TI - Anticonvulsant effect of AMP by direct activation of adenosine A1 receptor. AB - Purinergic neurotransmission mediated by adenosine (Ado) type 1 receptors (A1Rs) plays pivotal roles in negative modulation of epileptic seizures, and Ado is thought to be a key endogenous anticonvulsant. Recent evidence, however, indicates that AMP, the metabolic precursor of Ado, also activate A1Rs. Here, we evaluated the antiepileptic effects of AMP adopting in vitro and in vivo models of epilepsy. We report that AMP reversed the increase in population spike (PS) amplitude and the decrease in PS latency induced by a Mg(2+)-free extracellular solution in CA1 neurons of mouse hippocampal slices. The AMP effects were inhibited by the A1R antagonist DPCPX, but not prevented by inhibiting conversion of AMP into Ado, indicating that AMP inhibited per se sustained hippocampal excitatory neurotransmission by directly activating A1Rs. AMP also reduced seizure severity and mortality in a model of audiogenic convulsion. Of note, the anticonvulsant effects of AMP were potentiated by preventing its conversion into Ado and inhibited by DPCPX. When tested in a model of kainate-induced seizure, AMP prolonged latency of convulsions but had no effects on seizure severity and mortality. Data provide the first evidence that AMP is an endogenous anticonvulsant acting at A1Rs. PMID- 24056266 TI - Oscillatory coupling within neonatal prefrontal-hippocampal networks is independent of selective removal of GABAergic neurons in the hippocampus. AB - GABAergic neurons have been proposed to control oscillatory entrainment and cognitive processing in prefrontal-hippocampal networks. Co-activation of these networks emerges already during neonatal development, with hippocampal theta bursts driving prefrontal oscillations via axonal projections. The cellular substrate of neonatal prefrontal-hippocampal communication and in particular, the role of GABAergic neurons, is still unknown. Here, we used saporin-conjugated anti-vesicular GABA transporter antibodies to cause selective immunotoxic lesion of GABAergic neurons in the CA1 area of the hippocampus during the first postnatal week. Without affecting the somatic development of rat pups, the lesion impaired the generation of hippocampal sharp waves, but not of theta bursts during neonatal development. Moreover, the oscillatory entrainment and firing of neonatal prefrontal cortex as well as the early prefrontal-hippocampal synchrony were largely independent of GABAergic neurotransmission in the hippocampus. Thus, hippocampal interneurons are critical elements for the ontogeny of hippocampal sharp waves, but seem to not control the directed oscillatory coupling between the neonatal prefrontal cortex and hippocampus. PMID- 24056267 TI - Label-free isolation and enrichment of cells through contactless dielectrophoresis. AB - Dielectrophoresis (DEP) is the phenomenon by which polarized particles in a non uniform electric field undergo translational motion, and can be used to direct the motion of microparticles in a surface marker-independent manner. Traditionally, DEP devices include planar metallic electrodes patterned in the sample channel. This approach can be expensive and requires a specialized cleanroom environment. Recently, a contact-free approach called contactless dielectrophoresis (cDEP) has been developed. This method utilizes the classic principle of DEP while avoiding direct contact between electrodes and sample by patterning fluidic electrodes and a sample channel from a single polydimethylsiloxane (PDMS) substrate, and has application as a rapid microfluidic strategy designed to sort and enrich microparticles. Unique to this method is that the electric field is generated via fluidic electrode channels containing a highly conductive fluid, which are separated from the sample channel by a thin insulating barrier. Because metal electrodes do not directly contact the sample, electrolysis, electrode delamination, and sample contamination are avoided. Additionally, this enables an inexpensive and simple fabrication process. cDEP is thus well-suited for manipulating sensitive biological particles. The dielectrophoretic force acting upon the particles depends not only upon spatial gradients of the electric field generated by customizable design of the device geometry, but the intrinsic biophysical properties of the cell. As such, cDEP is a label-free technique that avoids depending upon surface-expressed molecular biomarkers that may be variably expressed within a population, while still allowing characterization, enrichment, and sorting of bioparticles. Here, we demonstrate the basics of fabrication and experimentation using cDEP. We explain the simple preparation of a cDEP chip using soft lithography techniques. We discuss the experimental procedure for characterizing crossover frequency of a particle or cell, the frequency at which the dielectrophoretic force is zero. Finally, we demonstrate the use of this technique for sorting a mixture of ovarian cancer cells and fluorescing microspheres (beads). PMID- 24056268 TI - Can motor control training lower the risk of injury for professional football players? AB - PURPOSE: Among injuries reported by the Australian Football League (AFL), lower limb injuries have shown the highest incidence and prevalence rates. Deficits in the muscles of the lumbopelvic region, such as a smaller size of multifidus (MF) muscle, have been related to the occurrence of lower limb injuries in the preseason in AFL players. Motor control training programs have been effective in restoring the size and control of the MF muscle, but the relationship between motor control training and occurrence of injuries has not been extensively examined. METHODS: This pre- and postintervention trial was delivered during the playing season as a panel design with three groups. The motor control program involved voluntary contractions of the MF, transversus abdominis, and pelvic floor muscles while receiving feedback from ultrasound imaging and progressed into a functional rehabilitation program. Assessments of muscle size and function were performed using magnetic resonance imaging and included the measurement of cross-sectional areas of MF, psoas, and quadratus lumborum muscles and the change in trunk cross-sectional area due to voluntarily contracting the transversus abdominis muscle. Injury data were obtained from club records. Informed consent was obtained from all study participants. RESULTS: A smaller size of the MF muscle (odds ratio [OR] = 2.38) or quadratus lumborum muscle (OR = 2.17) was predictive of lower limb injury in the playing season. At the time point when one group of players had not received the intervention (n = 14), comparisons were made with the combined groups who had received the intervention (n = 32). The risk of sustaining a severe injury was lower for those players who received the motor control intervention (OR = 0.09). CONCLUSION: Although there are many factors associated with injuries in AFL, motor control training may provide a useful addition to strategies aimed at reducing lower limb injuries. PMID- 24056269 TI - Aquatic treadmill training reduces blood pressure reactivity to physical stress. AB - PURPOSE: Endurance exercise may reduce blood pressure and improve vasodilatory capacity, thereby blunting the hypertensive response to stress. Therefore, we sought to test the efficacy of a novel model of low-impact endurance training, the aquatic treadmill (ATM), to improve blood pressure (BP) parameters. METHODS: Sixty sedentary adults were randomized to 12-wk of either ATM (n = 36 [19 males and 17 females], 41 +/- 2 yr, 173.58 +/- 1.58 cm, 93.19 +/- 3.15 kg) or land based treadmill (LTM, n = 24 [11 males, 13 females], 42 +/- 2 yr, 170.39 +/- 1.94 cm, 88.14 +/- 3.6 kg) training, three sessions per week, progressing to 500 kcal per session, 85% VO2max. The maximal Bruce treadmill test protocol was performed before and after training with BP measured before, at the end of each stage, and for 5 min after exercise testing. Twelve subjects (five ATM and seven LTM) volunteered for biopsies of the vastus lateralis before and after training, and muscle samples were assessed for endothelial nitric oxide synthase content. Data collected during exercise testing were analyzed using group by training ANCOVA repeated across training, alpha = 0.05. RESULTS: ATM but not LTM training significantly reduced resting diastolic BP (-3.2 mm Hg), exercise systolic BP (range 9-18.2 mm Hg lower for each exercise stage), diastolic BP (3.2-8.1 mm Hg), mean arterial pressure (4.8-8.3 mm Hg, lower than LTM posttraining), and pulse pressure (7.5-15 mm Hg) during stages of exercise stress and recovery (P < 0.05). In addition, an increase (+31%) in skeletal muscle endothelial nitric oxide synthase content after training (P < 0.05) occurred in only the ATM group. Body mass (-1.27 kg) and VO2max (+3.6 mL . kg(-1) . min(-1)) changes were significant for both groups (P < 0.001). CONCLUSION: ATM training can reduce BP reactivity to physical stress. PMID- 24056270 TI - Activity behaviors in schoolchildren and subsequent 5-yr change in blood pressure. AB - PURPOSE: This study aimed to establish whether time spent in sport-related physical activities and sedentary behaviors (e.g., TV viewing, videogame usage, and homework) was prospectively associated with change in blood pressure (BP) for 5 yr. METHODS: Eight hundred and twenty-one students age 6 yr at baseline (397 girls and 424 boys) were examined from 2003-2004 to 2009-2011. Children completed detailed activity questionnaires. BP was measured using a standardized protocol. RESULTS: After adjusting for age, ethnicity, parental education, parental history of hypertension, baseline height, BP, body mass index (BMI), baseline time spent in corresponding activity behavior, and change in BMI, each hour per day spent in total screen time was associated with a 0.69 and 0.59 mm Hg increase in diastolic BP (P = 0.01) and mean arterial BP (P = 0.01), respectively. In boys, each hour per day spent in TV viewing was associated with a concurrent 1.42-mm Hg increase in diastolic BP (P = 0.04) during the 5 yr. Children engaging in low sport related physical activities at baseline but who engaged in high levels of physical activity (>= 60 min . d(-1)) at follow-up (n = 154) compared with those engaging in low sport-related physical activities at both examinations (n = 305) demonstrated significantly lower mean arterial BP, 7.26 versus 9.61 mm Hg (P = 0.04). CONCLUSIONS: Time spent in physical activity and screen time could influence BP measures during childhood. PMID- 24056271 TI - Biological age and sex-related declines in physical activity during adolescence. AB - INTRODUCTION: Sex differences in the rate of decline in physical activity (PA) are most pronounced during adolescence. However, once boys and girls are aligned on biological age, sex differences in the patterns of PA become attenuated. The aim of this study was to test whether biological maturation can account for sex differences in participation in PA over time from late childhood to early adolescence. METHODS: A prospective cohort of children (N = 2100; 1064 boys) was followed from ages 11 to 14 yr, with repeated assessments of PA and anthropometry. Self-reported participation in organized and free play activities was used to track participation in PA. Biological age was measured using an estimate of years to attainment of peak height velocity. Mixed-effects models were used to test whether controlling for biological age attenuates the effect of chronological age and sex on PA. RESULTS: As expected, the rate of decline in participation in PA was greater for girls than for boys (B = -1.18, P < 0.01). In multivariable analyses, adjusting for biological age completely attenuated the effect of sex and chronological age for participation in free play activities, but not for participation in organized play. Overall, biological age was a stronger predictor of participation than chronological age. CONCLUSIONS: The effect of biological age on sex by chronological age differences may be specific to certain types of PA participation. Given the importance of maturation to participation in activity, it is suggested that public health strategies target biological not chronological age to prevent declines in PA during adolescence particularly when promoting habitual or lifestyle activity. PMID- 24056272 TI - Electron spin-lattice relaxation mechanisms of rapidly-tumbling nitroxide radicals. AB - Electron spin relaxation times at 295 K were measured at frequencies between 250 MHz and 34 GHz for perdeuterated 2,2,6,6-tetramethyl-4-piperidone-1-oxyl (PDT) in five solvents with viscosities that result in tumbling correlation times, tauR, between 4 and 50 ps and for three (14)N/(15)N pairs of nitroxides in water with tauR between 9 and 19 ps. To test the impact of structure on relaxation three additional nitroxides with tauR between 10 and 26 ps were studied. In this fast tumbling regime T2(-1)~T1(-1) at frequencies up to about 9 GHz. At 34 GHz T2( 1)>T1(-1) due to increased contributions to T2(-1) from incomplete motional averaging of g-anisotropy, and T2(-1)-T1(-1) is proportional to tauR. The contribution to T1(-1) from spin rotation is independent of frequency and decreases as tauR increases. Spin rotation dominates T1(-1) at 34 GHz for all tauR studied, and at all frequencies studied for tauR=4 ps. The contribution to T1(-1) from modulation of nitrogen hyperfine anisotropy increases as frequency decreases and as tauR increases; it dominates at low frequencies for tauR>~15 ps. The contribution from modulation of g anisotropy is significant only at 34 GHz. Inclusion of a thermally-activated process was required to account for the observation that for most of the radicals, T1(-1) was smaller at 250 MHz than at 1-2 GHz. The significant (15)N/(14)N isotope effect, the small H/D isotope effect, and the viscosity dependence of the magnitude of the contribution from the thermally-activated process suggest that it arises from intramolecular motions of the nitroxide ring that modulate the isotropic A values. PMID- 24056273 TI - Electromagnetohydrodynamic modeling of Lorentz effect imaging. AB - Lorentz Effect Imaging (LEI) is an MRI technique that has been proposed for direct imaging of neuronal activity. While promising results have been obtained in phantoms and in the human median nerve in vivo, its contrast mechanism is still not fully understood. In this paper, computational model simulations were used to investigate how electromagnetohydrodynamics (EMHD) may explain the LEI contrast. Three computational models of an electrolyte-filled phantom subject to an applied current dipole, synchronized to oscillating magnetic field gradients of an LEI protocol, were developed to determine the velocity and displacement of water molecules as well as the resulting signal loss in an MR image. The simulated images were compared to images from previous LEI phantom experiments with identical properties for different stimulus current amplitudes and polarities. The first model, which evaluated ion trajectories based on Stokes flow using different mobility values, did not generate an appreciable signal loss due to an insufficient number of water molecules associated with the ion hydration shells. The second model, which computed particle drift based on the Lorentz force of charged particles in free space, was able to approximate the magnitude, but not the distribution of signal loss observed in the experimental images. The third model, which computed EMHD based on the Lorentz force and Navier-Stokes equations for flow of a conducting fluid, provided results consistent with both the magnitude and distribution of signal loss seen in the LEI experiments. Our EMHD model further yields information on electrical potential, velocity, displacement, and pressure, which are not readily available in an experiment, thereby providing a robust means to study and optimize LEI for imaging neuronal activity in the human cortex. PMID- 24056274 TI - Cavernous sinus syndrome secondary to intracranial lymphoma in a cat. AB - Cavernous sinus syndrome is characterised by internal and external ophthalmoplegia and sensory deficits over the head due to combined deficits of the three cranial nerves (CNs) responsible for the eye movements and pupil function (CN III, IV, VI) and at least one branch of the trigeminal nerve (CN V). It has rarely been described in cats and may occur secondarily to inflammatory, infectious or neoplastic lesions within the region of the cavernous sinus on the ventral aspect of the calvarium. This report describes the clinical and magnetic resonance imaging findings in a 14-year-old domestic shorthair cat with neurological deficits compatible with cavernous sinus syndrome caused by presumptive extranodal lymphoma. Treatment with chemotherapy resulted in clinical and imaging remission. Identification of the neurological deficits in cavernous sinus syndrome allows accurate neuroanatomical localisation in order to target diagnostic imaging studies. PMID- 24056275 TI - Structural and functional characterization of the Senegalese sole (Solea senegalensis) Mx promoter. AB - Mx proteins are one of the most studied interferon-stimulated genes (ISGs). The antiviral activity against different fish viruses has been demonstrated for diverse fish Mx proteins, including the Senegalese sole (Solea senegalensis) Mx protein (SsMx). The aim of the current study is to characterize the structure and functional activity of the SsMx promoter. Several polyclonal cell populations expressing the luciferase reporter gene under the control of the SsMx promoter have been used to determine the ability of this promoter to drive the expression of the luciferase gene after poly I:C stimulation. In addition, the implication of each interferon-stimulated response element (ISRE) in the activation of the promoter has also been analysed. The genomic structure of the Senegalese sole and Japanese flounder Mx promoters (containing three ISREs) differs from the rest of the fish Mx promoters described to date. The ISRE1, the one closest to the start codon, is the main ISRE involved in the SsMx promoter activity, whereas ISRE2 and ISRE3 show a minor additive effect on this activity. Another feature differing SsMx promoter from the rest of the fish Mx promoters is the presence of a 24-bp GC island close to the ATG codon, including one Sp1 binding site, which may constitute the transcriptional start site. Furthermore, the SsMx promoter contains a gamma interferon activation site (GAS) element. PMID- 24056276 TI - Rainbow trout peptidoglycan recognition protein has an anti-inflammatory function in liver cells. AB - Peptidoglycan recognition proteins (PGRPs) are innate immune molecules that are structurally conserved through evolution in both invertebrate and vertebrate animals. PGRPs exert diverse host-defense functions both through direct antibacterial activity and through indirect effects, including the induction of antimicrobial peptides and the modulation of inflammation and immune responses. In this study, we identified the gene encoding a long form of PGRP (OmPGRP-L1) from the rainbow trout, Oncorhynchus mykiss, and investigated whether it has immunomodulating activity in a rainbow trout hepatoma cell line RTH-149 challenged with fish pathogenic bacteria. OmPGRP-L1 contains the conserved PGRP domain and the four Zn(2+)-binding amino acid residues required for amidase activity. In RTH-149 cells, OmPGRP-L1 expression was increased by bacterial stimulation. Loss-of-function and gain-of-function experiments indicated that OmPGRP-L1 is involved in the expression of pro-inflammatory cytokines. Silencing of OmPGRP-L1 in RTH-149 cells challenged with Edwardsiella tarda dramatically increased the expression of IL-1beta and TNF-alpha. In contrast, overexpression of OmPGRP-L1 or its amidase-inactive mutant OmPGRP-L1(C472S) resulted in down regulation of IL-1beta and TNF-alpha expression. When overexpressed in RTH-149 cells, OmPGRP-L1 inhibited NF-kappaB activity with or without bacterial stimulation. Collectively, these findings suggest that OmPGRP-L1 has an anti inflammatory function, independent of its amidase activity, possibly via NF kappaB inhibition in liver cells. PMID- 24056277 TI - IFN-gamma-activated lymphocytes boost nitric oxide production in grass carp monocytes/macrophages. AB - It is well known that IFN-gamma is a prime activator of nitric oxide (NO) production by monocytes/macrophages in mammals and fish. In parallel, whether IFN gamma-activated lymphocytes are associated with NO production remains unclear. In this study, grass carp monocytes/macrophages and lymphocytes from head kidney were isolated and effects of recombinant grass carp IFN-gamma (rgcIFN-gamma) on NO releases by these two cell populations were determined. Results showed that rgcIFN-gamma time- and dose-dependently increased NO production by monocytes/macrophages but not lymphocytes, which are consistent with the findings in mammals. Interestingly, rgcIFN-gamma displayed a greater stimulation on NO production in the co-cultures of monocytes/macrophages and lymphocytes when compared with that in the culture of monocytes/macrophages alone. Furthermore, the media harvested from rgcIFN-gamma-treated lymphocytes were effective in boosting NO release in monocytes/macrophages. These data suggest that secretions from rgcIFN-gamma-treated lymphocytes may be involved in the NO release by monocytes/macrophages. To address this hypothesis, effect of rgcIFN-gamma on the gene expression of inflammatory cytokines in grass carp lymphocytes was examined, showing that it consistently stimulated the mRNA expression of grass carp TNF alpha and IL-1beta but not IFN-gamma. Furthermore, treatment of rgcIFN-gamma combined with recombinant grass carp IL-1beta (rgcIL-1beta) induced a NO production by monocytes/macrophages, which was significantly higher than those induced by either cytokine alone. It provides the evidence that the cytokines secreted by the activated lymphocytes may facilitate the NO production by monocytes/macrophages. Taken together, our findings point out a new mechanism for the involvement of IFN-gamma-activated lymphocytes in the NO production by monocytes/macrophages in fish. This knowledge not only strengthens the role of IFN-gamma in immune system but also provides the evidence for the existence of a close relationship between lymphocytes and monocytes/macrophages in fish. PMID- 24056278 TI - Characterization of a 2-Cys peroxiredoxin IV in Marsupenaeus japonicus (kuruma shrimp) and its role in the anti-viral immunity. AB - Accumulating evidence suggests that peroxiredoxins (Prx) are key molecules in the pathogenesis of various infectious diseases and are potential therapeutic targets for major diseases such as cancers. In this study, we report a peroxiredoxin IV (Prx IV) in Marsupenaeus japonicus, designated as MjPrx IV, which exhibited peroxidase activity and participated in the anti-white spot syndrome virus (WSSV) immune response. MjPrx IV is a 245-amino acid polypeptide with a predicted 19 amino acid signal peptide, an Ahpc-TSA domain, and a 1-Cys PrxC domain. Phylogenetic analysis revealed that the protein belongs to the Prx IV subfamily. MjPrx IV transcripts were detected in the gills, hepatopancreas, heart, stomach, ovaries, spermary, and intestine tissues, and are upregulated in the gonads, gills and hemocytes of shrimp after WSSV challenge. The mature MjPrx IV peptide was recombinantly expressed in an Escherichia coli system. The protein exhibited peroxidase activity. Furthermore, dsRNA suppression of MjPrx IV increased WSSV replication in shrimp, whereas rMjPrx IV injection into shrimp decreased WSSV replication. These data suggest that MjPrx IV has an important role in shrimp antiviral immunity. To our knowledge, this study is the first to report a shrimp Prx IV that has anti-WSSV activity. PMID- 24056279 TI - Differential metabolic responses of clam Ruditapes philippinarum to Vibrio anguillarum and Vibrio splendidus challenges. AB - Clam Ruditapes philippinarum is one of the important marine aquaculture species in North China. However, pathogens can often cause diseases and lead to massive mortalities and economic losses of clam. In this work, we compared the metabolic responses induced by Vibrio anguillarum and Vibrio splendidus challenges towards hepatopancreas of clam using NMR-based metabolomics. Metabolic responses suggested that both V. anguillarum and V. splendidus induced disturbances in energy metabolism and osmotic regulation, oxidative and immune stresses with different mechanisms, as indicated by correspondingly differential metabolic biomarkers (e.g., amino acids, ATP, glucose, glycogen, taurine, betaine, choline and hypotaurine) and altered mRNA expression levels of related genes including ATP synthase, ATPase, glutathione peroxidase, heat shock protein 90, defensin and lysozyme. However, V. anguillarum caused more severe oxidative and immune stresses in clam hepatopancreas than V. splendidus. Our results indicated that metabolomics could be used to elucidate the biological effects of pathogens to the marine clam R. philippinarum. PMID- 24056280 TI - Long-lasting protection induced by bath vaccination against Aeromonas salmonicida subsp. salmonicida in rainbow trout. AB - For decades Aeromonas salmonicida subsp. salmonicida (from here referred to as A. salmonicida) has been recognized as the causative agent of typical furunculosis. This disease has had a major impact on aquaculture worldwide, making it a target for international research, particularly within the field of immunoprohylaxis. Initial studies attempted vaccination via oral route and immersion. However, these vaccination methods proved insufficient when compared to intraperitoneally (i.p.) injected vaccines. The focus of vaccine research regarding A. salmonicida shifted towards the i.p.-injected vaccines during the 1980's and -90's, resulting in oil-adjuvanted vaccines providing high levels of protection over longer periods of time. The majority of this research has been conducted using salmon, while rainbow trout, which is also a commercially important species, has played a much less central role. In this study, we have examined the effect of a bath vaccination using an experimental A. salmonicida bacterin. Rainbow trout were vaccinated by a 5 min bath in a formalin-inactivated bacterin. Half of these fish was booster vaccinated using 50% of the initial vaccine dose 10 weeks post primary immunization. Along with an un-vaccinated control group, the fish were challenged by waterborne infection 24 weeks post primary immunization. Both vaccinated groups showed a significantly increased survival (>93% survival) compared to a 70% survival in the un-vaccinated control group (P = 0.005 and P = 0.019 for single and dual immunizations, respectively). When comparing the survival of the single and dual immunization groups, there was no significant difference (P = 0.531). ELISA showed no significant induction of specific circulating antibodies in either vaccinated group. These results are interesting with regard to the protective mechanisms, seen in the light of previous results obtained using bath as well as i.p. vaccination against furunculosis in salmonid fishes. PMID- 24056281 TI - Thickness measurement of soft thin films on periodically patterned magnetic substrates by phase difference magnetic force microscopy. AB - The need for accurate measurement of the thickness of soft thin films is continuously encouraging the development of techniques suitable for this purpose. We propose a method through which the thickness of the film is deduced from the quantitative measurement of the contrast in the phase images of the sample surface acquired by magnetic force microscopy, provided that the film is deposited on a periodically patterned magnetic substrate. The technique is demonstrated by means of magnetic substrates obtained from standard floppy disks. Colonies of Staphylococcus aureus adherent to such substrates were used to obtain soft layers with limited lateral (a few microns) and vertical (hundreds of nanometers) size. The technique is described and its specific merits, limitations and potentialities in terms of accuracy and measurable thickness range are discussed. These parameters depend on the characteristics of the sensing tip/cantilever as well as of the substrates, the latter in terms of spatial period and homogeneity of the magnetic domains. In particular, with the substrates used in this work we evaluated an uncertainty of about 10%, a limit of detection of 50-100 nm and an upper detection limit (maximum measurable thickness) of 1 MUm, all obtained with standard lift height values (50-100 nm). Nonetheless, these parameters can be easily optimized by selecting/realizing substrates with suitable spacing and homogeneity of the magnetic domains. For example, the upper detection limit can be increased up to 25-50 MUm while the limit of detection can be reduced to a few tens of nanometers or a few nanometers. PMID- 24056282 TI - Orientation precision of TEM-based orientation mapping techniques. AB - Automatic orientation mapping is an important addition to standard capabilities of conventional transmission electron microscopy (TEM) as it facilitates investigation of crystalline materials. A number of different such mapping systems have been implemented. One of their crucial characteristics is the orientation resolution. The precision in determination of orientations and misorientations reached in practice by TEM-based automatic mapping systems is the main subject of the paper. The analysis is focused on two methods: first, using spot diffraction patterns and 'template matching', and second, using Kikuchi patterns and detection of reflections. In simple terms, for typical mapping conditions, their precisions in orientation determination with the confidence of 95% are, respectively, 1.1 degrees and 0.3 degrees . The results are illustrated by example maps of cellular structure in deformed Al, the case for which high orientation sensitivity matters. For more direct comparison, a novel approach to mapping is used: the same patterns are solved by each of the two methods. Proceeding from a classification of the mapping systems, the obtained results may serve as indicators of precisions of other TEM-based orientation mapping methods. The findings are of significance for selection of methods adequate to investigated materials. PMID- 24056283 TI - Spatiotemporal analysis of vehicle collisions involving wild boar and roe deer in NW Spain. AB - Ungulate-vehicle collisions pose a serious traffic safety hazard in the North of Spain. The understanding of underlying temporal and spatial structure of these non-random events is imperative to develop appropriate mitigation measures. This study analyses the temporal, spatial and spatiotemporal patterns of car crashes involving wild boar and roe deer in the province of Lugo (NW Spain) in the period 2006-2010 using geographic information systems (GIS) and spatial statistics. The temporal analysis--conducted at three scales: daily, weekly and seasonal- revealed that accidents are related to specific animal's life cycles and to interactions with human activities. The localization of collision points with GIS discovered the sections of the autonomic road network where accidents with the two studied species concentrate. Besides, the spatial arrangement of significant hotspots was mapped through kernel density estimation over two time scales (daily and seasonal), distinguishing among 41 sets, sequentially arranged to facilitate clustering comparison and determination of spatiotemporal risky areas. This work is of valuable help for road managers to design the appropriate mitigation measures that will improve traffic safety and animal welfare. PMID- 24056284 TI - An epidemiological study of the risk of cycling in the dark: the role of visual perception, conspicuity and alcohol use. AB - To curtail the rising numbers of cyclists seriously injured in road crashes, more insights are needed into the factors that contribute to these crashes. For instance, darkness is known to be associated with higher injury rates, but little is known about the relative influence of factors such as poor conspicuity, impaired perception and alcohol use among cyclists. To examine these factors, the present study analyzed the epidemiological crash data for three meteorological light conditions: daylight, late evening darkness and early morning darkness; for two crash types: crashes with (M-crashes) and without motorized traffic (NM crashes); and for different age groups. The relative injury rates (injury risk per distance travelled in darkness corrected for daylight injury risks for each age group) confirmed findings from earlier studies that cycling in late evening darkness is associated with higher injury rates than cycling in daylight conditions. This is the case for both crash types with only small differences between the age groups suggesting that poor conspicuity (M-crashes) and impaired perception (NM-crashes) may play a role. In comparison to late evening darkness, relative injury rates in early morning darkness are much higher. This is the case for both crash types with large differences among the age groups, suggesting that in addition to the absence of daylight also age related risk factors are at play. Support for this hypothesis was found from the analyses of hospital records, showing that the proportion of seriously injured cyclists who have been drinking is highest in early morning darkness and has strongly increased over the last decades. These insights provide input for the selection of countermeasures such as improved lighting (both street and bicycle lights) and interventions targeting alcohol use among cyclists. PMID- 24056285 TI - Estimating the effect of emergency care on early survival after traffic crashes. AB - INTRODUCTION: Traffic crash mortality is higher in rural areas, but it is unclear whether this is due to greater injury severity, time delays, or Emergency Medical Services (EMS) deficiencies. METHODS: Data from 2002-2003 were combined from the Fatality Analysis Reporting System (FARS) and an "expanded version" of the National Automotive Sampling System (NASS) Crashworthiness Data System (CDS). Weighted Cox and Weibull models for survival time (tSURV) were estimated, with time-varying covariates (TVC) having constant effects for specified time intervals following EMS arrival time (tEMS) and hospital arrival time (tHOS). The Weibull model was repeated with tSURV interval-censored to reflect uncertainty about the exact time of death, using an imputation method to accommodate interval censoring along with TVC. RESULTS: FARS contained records for 92,718 persons with fatal or incapacitating injuries, and NASS/CDS contained 5517 (weighted population of 642,716) with incapacitating injuries. All models associated mortality with increasing age, male sex, belt nonuse, higher speeds, and vehicle rollover. The interval-censored model associated EMS intervention with a beneficial effect until tEMS+30 min, but not thereafter; hospital intervention was associated with a strongly beneficial effect that increased with time. Rural location was associated with a higher baseline hazard; a 50% reduction in rural prehospital time would theoretically reduce 4-h mortality by about 7%. CONCLUSION: Rural/urban disparity in crash mortality is mostly independent of time delays and EMS effects. However, survival models with TVC support clinical intuition of a "golden hour" in EMS care, and the importance of timely transport to a hospital. PMID- 24056286 TI - The impacts of speed cameras on road accidents: an application of propensity score matching methods. AB - This paper aims to evaluate the impacts of speed limit enforcement cameras on reducing road accidents in the UK by accounting for both confounding factors and the selection of proper reference groups. The propensity score matching (PSM) method is employed to do this. A naive before and after approach and the empirical Bayes (EB) method are compared with the PSM method. A total of 771 sites and 4787 sites for the treatment and the potential reference groups respectively are observed for a period of 9 years in England. Both the PSM and the EB methods show similar results that there are significant reductions in the number of accidents of all severities at speed camera sites. It is suggested that the propensity score can be used as the criteria for selecting the reference group in before-after control studies. Speed cameras were found to be most effective in reducing accidents up to 200 meters from camera sites and no evidence of accident migration was found. PMID- 24056287 TI - Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis. AB - BACKGROUND: Numerous studies have reported that inflammation is closely associated with depression, and adjunctive non-steroidal anti-inflammatory drug (NSAID) treatment has been suggested as a novel therapeutic approach for depression. METHODS: We searched electronic databases including Medline, Embase, and the Cochrane Central Register of Controlled Trials. We only included randomized controlled trials comparing adjunctive NSAIDs with placebos for treating depressive episodes. RESULTS: Of the 654 retrieved entries, we identified four relevant studies with a total of 150 patients (75 NSAID patients and 75 placebo patients) with depressive episodes. All four studies used celecoxib as the NSAID. The patients receiving adjunctive celecoxib had significantly higher mean changes in the Hamilton Rating Scale for Depression scores between baseline and endpoint measurements compared with those receiving placebo (weighted mean difference=3.26, 95% confidence interval; CI=1.81 to 4.71). The adjunctive celecoxib group also showed better remission (odds ratio; OR=6.58, 95% CI=2.55 to 17.00) and response rates (OR=6.49, 95% CI=2.89 to 14.55) than the placebo group. The all-cause drop-out rate was more favorable for the celecoxib group than for the placebo group (OR=0.45, 95% CI=0.18 to 1.13), although the statistical significance was not statistically significant (p=0.09). CONCLUSION: Adjunctive treatment with NSAIDs, particularly celecoxib, can be a promising strategy for patients with depressive disorder. Future studies with a larger sample size and longer study duration are needed to confirm the efficacy and tolerability of NSAIDs for depression. PMID- 24056288 TI - Management of scientific information with Google Drive. AB - BACKGROUND: The amount and diversity of scientific publications requires a modern management system. By "management" we mean the process of gathering interesting information for the purpose of reading and archiving for quick access in future clinical practice and research activity. In the past, such system required physical existence of a library, either institutional or private. Nowadays in an era dominated by electronic information, it is natural to migrate entire systems to a digital form. AIM OF THE STUDY: In the following paper we describe the structure and functions of an individual electronic library system (IELiS) for the management of scientific publications based on the Google Drive service. MATERIAL AND METHODS: Architecture of the system. Architecture system consists of a central element and peripheral devices. Central element of the system is virtual Google Drive provided by Google Inc. Physical elements of the system include: tablet with Android operating system and a personal computer, both with internet access. Required software includes a program to view and edit files in PDF format for mobile devices and another to synchronize the files. RESULTS: Functioning of the system. The first step in creating a system is collection of scientific papers in PDF format and their analysis. This step is performed most frequently on a tablet. At this stage, after being read, the papers are cataloged in a system of folders and subfolders, according to individual demands. During this stage, but not exclusively, the PDF files are annotated by the reader. This allows the user to quickly track down interesting information in review or research process. Modification of the document title is performed at this stage, as well. Second element of the system is creation of a mirror database in the Google Drive virtual memory. Modified and cataloged papers are synchronized with Google Drive. At this stage, a fully functional scientific information electronic library becomes available online. The third element of the system is a periodic two-way synchronization of data between Google Drive and tablet, as occasional modification of the files with annotation or recataloging may be performed at both locations. CONCLUSIONS: The system architecture is designed to gather, catalog and analyze scientific publications. All steps are electronic, eliminating paper forms. Indexed files are available for re-reading and modification. The system allows for fast access to full-text search with additional features making research easier. Team collaboration is also possible with full control of user privileges. Particularly important is the safety of collected data. In our opinion, the system exceeds many commercially available applications in terms of functionality and versatility. PMID- 24056289 TI - Treatment of latent tuberculosis infection. AB - Treatment of latent tuberculosis (TB) infection is an important component of TB control programs in both high- and low-prevalence countries. Clinical trials of treatment of latent TB conducted over several decades have demonstrated that preventive treatment can reduce the risk of developing active TB up to 90%. Although 9 months of daily, self-administered isoniazid has been the most widely used and recommended regimen for the treatment of latent infection, other regimens such as 3 months of daily isoniazid and rifampin, or 4 months of daily rifampin alone have also been recommended and used. Most recently, a 12-dose regimen of once-weekly isoniazid and rifapentine has been shown to be noninferior to 9 months of daily isoniazid in a large and well conducted clinical trial. Adoption of such a regimen on a large scale could have significant implications for TB elimination efforts. PMID- 24056290 TI - Beneficial role of vitamin D3 in the prevention of certain respiratory diseases. AB - There is evidence of aberrations in the vitamin D-endocrine system in subjects with respiratory diseases. Vitamin D deficiency is highly prevalent in patients with respiratory diseases, and patients who receive vitamin D have significantly larger improvements in inspiratory muscle strength and maximal oxygen uptake. Studies have provided an opportunity to determine which proteins link vitamin D to respiratory pathology, including the major histocompatibility complex class II molecules, vitamin D receptor, vitamin D-binding protein, chromosome P450, Toll like receptors, poly(ADP-ribose) polymerase-1, and the reduced form of nicotinamide adenine dinucleotide phosphate. Vitamin D also exerts its effect on respiratory diseases through cell signaling mechanisms, including matrix metalloproteinases, mitogen-activated protein kinase pathways, the Wnt/beta catenin signaling pathway, prostaglandins, reactive oxygen species, and nitric oxide synthase. In conclusion, vitamin D plays a significant role in respiratory diseases. The best form of vitamin D for use in the treatment of respiratory diseases is calcitriol because it is the active metabolite of vitamin D3 and modulates inflammatory cytokine expression. Further investigation of calcitriol in respiratory diseases is needed. PMID- 24056291 TI - Factors that influence the bleeding phenotype in severe hemophilic patients. AB - Hemophilia A and B are rare, X-linked bleeding disorders resulting from a partial or total deficiency of functionally active coagulation factor VIII or factor IX, respectively. Endogenous factor levels have traditionally been used to characterize the severity of the disorder, with severe hemophilia considered as circulating levels of factor less than 1% of normal. Identifying patients with severe hemophilia is essential to effective treatment, since these patients are at highest risk of spontaneous life or limb-threatening bleeding and disability resulting from repeated joint bleeding and are most likely to benefit from prophylaxis. However, there is variability in bleeding tendency, even among patients with severe hemophilia. This article will review potential modifiers of hemophilia-associated bleeding other than endogenous factor activity, which may influence bleeding tendencies and complications in hemophilic patients considered to have severe hemophilia. These potential modifiers include physiologic factors, such as elements of the hemostatic system; pathophysiologic factors, such as hemophilic arthropathy, associated inflammation, and angiogenesis; and others, such as seasonal variation, body weight, and physical activity. PMID- 24056292 TI - The mean platelet volume is decreased in patients with mild head trauma and brain injury. AB - We planned a prospective study to assess platelet number and size in patients with or without brain injury after mild head trauma (MHT). Platelet count and mean platelet volume (MPV) were assessed in consecutive patients admitted to the emergency department with isolate MHT, as well as in healthy blood donors who served as controls. The study population consisted in 54 patients with MHT, 13 of whom (24%) with intracranial lesions suggestive for brain injury, and 339 healthy blood donors. The value of platelet count was significantly lower in patients with MHT and positive computerized tomography than in healthy controls (P = 0.014). The vales of MPV progressively decreased from healthy controls (11.1 fl) to patients with MHT and negative computerized tomography (9.8 fl; P < 0.001), and further to patients with MHT and positive computerized tomography (8.6 fl; P < 0.001). The MPV was significantly lower in patients with MHT and positive computerized tomography than in those with negative computerized tomography (P = 0.002). As compared with healthy controls, the frequency of decreased MPV values was 10-fold and 17-fold higher in MTH patients with negative and positive computerized tomography, respectively. The MPV exhibited an area under the curve of 0.74 (95% CI, 0.58 to 0.89; P < 0.001) for differentiating MHT patients with positive computerized tomography from those with negative computerized tomography. MHT patients display a larger prevalence of small and hyporeactive platelets. This observation provides a reliable basis for planning further studies to establish whether MPV may be useful for diagnostic evaluation of MHT in the emergency department. PMID- 24056293 TI - Antithrombin deficiency after prolonged asparaginase treatment in children with acute lymphoblastic leukemia. AB - Children with acute lymphoblastic leukemia (ALL) have several risk factors for deep venous thromboses (DVTs) such as central venous catheters and asparaginase (ASP), related antithrombin (AT) deficiency. After introduction of a new standard and intermediate-risk ALL treatment protocol with prolonged continuous ASP treatment, two symptomatic DVTs in 10 patients were observed at the Children's Hospital, Helsinki, Finland. To prevent further thrombotic complications yet ensuring continuous exposure to ASP, an AT substitution strategy was adopted in Helsinki. The same ALL treatment protocol is used without AT substitution in the other Nordic countries. In this retrospective study, we describe the effect of prolonged ASP treatment on AT and fibrinogen levels in children without AT substitution in Stockholm, Sweden (n = 39) and the AT substitution in children with AT activity below 0.55 kIU/l in Helsinki (n = 36, intervention group). The intervention group is compared with children treated similarly earlier in Helsinki without AT substitution (n = 10). The median lowest AT activity during the ASP treatment without AT substitution was 0.55 kIU/l. Fibrinogen level of 1.0 g/l or less was found in 14% of all routine samples during the ASP treatment. In the intervention group, 23 (64%) received AT concentrate. Two (20%) children had symptomatic DVT before initiation of the AT substitution and two (6%) thereafter. We conclude that most children are exposed to low AT activity during ASP treatment predisposing to thrombosis. The effect of prophylactic AT substitution remains unclear. PMID- 24056294 TI - Hypercoagulability in a newborn with concomitant homozygous factor V Leiden and severe homozygous protein C deficiency type 1. AB - This is a case report of a female newborn presented with skin necrotic lesions 1 week after delivery. Laboratory investigations revealed severe homozygous protein C deficiency associated with homozygous factor V Leiden, although her pregnancy and perinatal periods were otherwise uneventful, with negative family history of thrombotic or bleeding disorders. Patient stabilization was established by supportive measures and long-term administration of fresh frozen plasma and warfarin. PMID- 24056295 TI - Opposing roles of sensory and parietal cortices in awareness in a bistable motion illusion. AB - Motion-induced blindness (MIB) is a bistable visual phenomenon in which stationary disks surrounded by a moving pattern intermittently disappear from the viewer's awareness. We explored the cortical network that subserves the MIB phenomenon by targeting its constituent parts with disruptive transcranial magnetic stimulation (TMS), in the form of continuous theta burst stimulation (cTBS). Previous neuroimaging and TMS studies have implicated the right posterior parietal cortex (rPPC) in perceptual transitions such as binocular rivalry, while the visual area V5/MT has been suggested to play a key role in MIB. In this study, we found that cTBS applied to the rPPC lengthened the duration of disappearance in MIB, while cTBS applied to V5/MT shortened the duration of disappearance and decreased the frequency of disappearance in MIB. These results demonstrate a causal role for both the rPPC and V5/MT in MIB, and suggest that the rPPC is involved in shifting resources between competing functional areas, while V5/MT processing initiates and maintains MIB. PMID- 24056296 TI - Is there a left hemispheric asymmetry for tool affordance processing? AB - The perception of tools vs. other objects has been shown to activate the left premotor and somatosensory cortex, which represents object affordance associated with tool manipulability (Proverbio, Adorni, & D'Aniello, 2011). The question of whether hemispheric asymmetry depends on right hand use or is linked to a hemispheric functional specialization for fine-grained precision movement is unclear. Thus, in this paper, ERPs were recorded from 128 sites in response to the visual presentation of bidimensional (2D) pictures depicting unimanual (e.g., a hammer) and bimanual (e.g., a handlebar) tools (Study 1). Central N2 and prefrontal N400 components were much larger for bimanual than unimanual tools (over the left hemisphere for N400). SwLORETAs performed for both components showed at first the activation of the left parietal cortex (BA39) and then of the right homologous (BA40) one, for both grips but stronger for the bimanual coordination. At all times and for both grips, the left premotor cortex (BA6) was involved in coding action affordance, while only unimanual tools activated the left postcentral gyrus (BA3). In Study 2, unimanual tools were presented with an orientation congruent (standard) or incongruent to their interaction with the right hand (rotated), to manipulate affordance's quality. Standard objects elicited much larger ERP responses (namely: N1, N2, N400) than rotated tools (over the left hemisphere for N400). At the earliest stage (190-270 ms) the significant intracranial sources were of visual nature (mainly the contralateral precuneus). Regions representing motor information were not involved. Rotated tools induced a smaller activation in the STS and parahippocampal regions (possibly coding affordable biological motion and the spatial aspects of hand/object interaction), whereas rotated tools activated to a greater extent the dorsolateral prefrontal cortex (DLPF, BA9). In the later time window standard objects activated the left BA6 and the right BA40 more than rotated objects. Overall, these data suggest that viewing tools automatically activates mental representations associated with their manipulation. The left premotor cortex was found to be involved with any kind of object and grip, as early as 200 ms post stimulus, thus supporting the hypothesis of a LH asymmetry in the neural representation of grasping, within this region. The right supramarginal gyrus was also found to be crucially involved later in time. PMID- 24056297 TI - Kinematic markers dissociate error correction from sensorimotor realignment during prism adaptation. AB - This study investigated the motor control mechanisms that enable healthy individuals to adapt their pointing movements during prism exposure to a rightward optical shift. In the prism adaptation literature, two processes are typically distinguished. Strategic motor adjustments are thought to drive the pattern of rapid endpoint error correction typically observed during the early stage of prism exposure. This is distinguished from so-called 'true sensorimotor realignment', normally measured with a different pointing task, at the end of prism exposure, which reveals a compensatory leftward 'prism after-effect'. Here, we tested whether each mode of motor compensation - strategic adjustments versus 'true sensorimotor realignment' - could be distinguished, by analyzing patterns of kinematic change during prism exposure. We hypothesized that fast feedforward versus slower feedback error corrective processes would map onto two distinct phases of the reach trajectory. Specifically, we predicted that feedforward adjustments would drive rapid compensation of the initial (acceleration) phase of the reach, resulting in the rapid reduction of endpoint errors typically observed early during prism exposure. By contrast, we expected visual-proprioceptive realignment to unfold more slowly and to reflect feedback influences during the terminal (deceleration) phase of the reach. The results confirmed these hypotheses. Rapid error reduction during the early stage of prism exposure was achieved by trial-by-trial adjustments of the motor plan, which were proportional to the endpoint error feedback from the previous trial. By contrast, compensation of the terminal reach phase unfolded slowly across the duration of prism exposure. Even after 100 trials of pointing through prisms, adaptation was incomplete, with participants continuing to exhibit a small rightward shift in both the reach endpoints and in the terminal phase of reach trajectories. Individual differences in the degree of adaptation of the terminal reach phase predicted the magnitude of prism after-effects. In summary, this study identifies distinct kinematic signatures of fast strategic versus slow sensorimotor realignment processes, which combine to adjust motor performance to compensate for a prismatic shift. PMID- 24056299 TI - Microfluidic passive permeability assay using nanoliter droplet interface lipid bilayers. AB - Membrane permeability assays play an important role in assessing drug transport activities across biological membranes. However, in conventional parallel artificial membrane permeability assays (PAMPA), the membrane model used is dissimilar to biological membranes physically and chemically. Here, we describe a microfluidic passive permeability assay using droplet interface bilayers (DIBs). In a microfluidic network, nanoliter-sized donor and acceptor aqueous droplets are alternately formed in cross-flowing oil containing phospholipids. Subsequently, selective removal of oil through hydrophobic pseudo-porous sidewalls induces the contact of the lipid monolayers, creating arrayed planar DIBs between the donor and acceptor droplets. Permeation of fluorescein from the donor to the acceptor droplets was fluorometrically measured. From the measured data and a simple diffusion model we calculated the effective permeabilities of 5.1 * 10(-6) cm s(-1), 60.0 * 10(-6) cm s(-1), and 87.6 * 10(-6) cm s(-1) with donor droplets at pH values of 7.5, 6.4 and 5.4, respectively. The intrinsic permeabilities of specific monoanionic and neutral fluorescein species were obtained similarly. We also measured the permeation of caffeine in 10 min using UV microspectroscopy, obtaining a permeability of 20.8 * 10(-6) cm s(-1). With the small solution volumes, short measurement time, and ability to measure a wide range of compounds, this device has considerable potential as a platform for high throughput drug permeability assays. PMID- 24056298 TI - Improved effectiveness of performance monitoring in amateur instrumental musicians. AB - Here we report a cross-sectional study investigating the influence of instrumental music practice on the ability to monitor for and respond to processing conflicts and performance errors. Behavioural and electrophysiological indicators of response monitoring in amateur musicians with various skill levels were collected using simple conflict tasks. The results show that instrumental musicians are better able than non-musicians to detect conflicts and errors as indicated by systematic increases in the amplitude of the error-related negativity and the N200 with increasing levels of instrumental practice. Also, high levels of musical training were associated with more efficient and less reactive responses after experience of conflicts and errors as indicated by reduced post-error interference and post-conflict processing adjustments. Together, the present findings suggest that playing a musical instrument might improve the ability to monitor our behavior and adjust our responses effectively when needed. As these processes are amongst the first to be affected by cognitive aging, our evidence could promote musical activity as a realistic intervention to slow or even prevent age-related decline in frontal cortex mediated executive functioning. PMID- 24056300 TI - Giant photoluminescence emission in crystalline faceted Si grains. AB - Empowering an indirect band-gap material like Si with optical functionalities, firstly light emission, represents a huge advancement constantly pursued in the realization of any integrated photonic device. We report the demonstration of giant photoluminescence (PL) emission by a newly synthesized material consisting of crystalline faceted Si grains (fg-Si), a hundred nanometer in size, assembled in a porous and columnar configuration, without any post processing. A laser beam with wavelength 632.8 nm locally produce such a high temperature, determined on layers of a given thickness by Raman spectra, to induce giant PL radiation emission. The optical gain reaches the highest value ever, 0.14 cm/W, representing an increase of 3 orders of magnitude with respect to comparable data recently obtained in nanocrystals. Giant emission has been obtained from fg-Si deposited either on glass or on flexible, low cost, polymeric substrate opening the possibility to fabricate new devices. PMID- 24056301 TI - The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response. AB - The RAS-like GTPase RALB mediates cellular responses to nutrient availability or viral infection by respectively engaging two components of the exocyst complex, EXO84 and SEC5. RALB employs SEC5 to trigger innate immunity signalling, whereas RALB-EXO84 interaction induces autophagocytosis. How this differential interaction is achieved molecularly by the RAL GTPase remains unknown. We found that whereas GTP binding turns on RALB activity, ubiquitylation of RALB at Lys 47 tunes its activity towards a particular effector. Specifically, ubiquitylation at Lys 47 sterically inhibits RALB binding to EXO84, while facilitating its interaction with SEC5. Double-stranded RNA promotes RALB ubiquitylation and SEC5 TBK1 complex formation. In contrast, nutrient starvation induces RALB deubiquitylation by accumulation and relocalization of the deubiquitylase USP33 to RALB-positive vesicles. Deubiquitylated RALB promotes the assembly of the RALB EXO84-beclin-1 complexes driving autophagosome formation. Thus, ubiquitylation within the effector-binding domain provides the switch for the dual functions of RALB in autophagy and innate immune responses. PMID- 24056302 TI - In vivo reprogramming of astrocytes to neuroblasts in the adult brain. AB - Adult differentiated cells can be reprogrammed into pluripotent stem cells or lineage-restricted proliferating precursors in culture; however, this has not been demonstrated in vivo. Here, we show that the single transcription factor SOX2 is sufficient to reprogram resident astrocytes into proliferative neuroblasts in the adult mouse brain. These induced adult neuroblasts (iANBs) persist for months and can be generated even in aged brains. When supplied with BDNF and noggin or when the mice are treated with a histone deacetylase inhibitor, iANBs develop into electrophysiologically mature neurons, which functionally integrate into the local neural network. Our results demonstrate that adult astrocytes exhibit remarkable plasticity in vivo, a feature that might have important implications in regeneration of the central nervous system using endogenous patient-specific glial cells. PMID- 24056304 TI - Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometric analysis of intact proteins larger than 100 kDa. AB - Effectively determining masses of proteins is critical to many biological studies (e.g. for structural biology investigations). Accurate mass determination allows one to evaluate the correctness of protein primary sequences, the presence of mutations and/or post-translational modifications, the possible protein degradation, the sample homogeneity, and the degree of isotope incorporation in case of labelling (e.g. (13)C labelling). Electrospray ionisation (ESI) mass spectrometry (MS) is widely used for mass determination of denatured proteins, but its efficiency is affected by the composition of the sample buffer. In particular, the presence of salts, detergents, and contaminants severely undermines the effectiveness of protein analysis by ESI-MS. Matrix-assisted laser desorption/ionization (MALDI) MS is an attractive alternative, due to its salt tolerance and the simplicity of data acquisition and interpretation. Moreover, the mass determination of large heterogeneous proteins (bigger than 100 kDa) is easier by MALDI-MS due to the absence of overlapping high charge state distributions which are present in ESI spectra. Here we present an accessible approach for analysing proteins larger than 100 kDa by MALDI-time of flight (TOF). We illustrate the advantages of using a mixture of two matrices (i.e. 2,5 dihydroxybenzoic acid and alpha-cyano-4-hydroxycinnamic acid) and the utility of the thin layer method as approach for sample deposition. We also discuss the critical role of the matrix and solvent purity, of the standards used for calibration, of the laser energy, and of the acquisition time. Overall, we provide information necessary to a novice for analysing intact proteins larger than 100 kDa by MALDI-MS. PMID- 24056303 TI - PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions with the ER tether and the beclin 1 complex. AB - Endoplasmic reticulum (ER)-Golgi membrane transport and autophagy are intersecting trafficking pathways that are tightly regulated and crucial for homeostasis, development and disease. Here, we identify UVRAG, a beclin-1-binding autophagic factor, as a phosphatidylinositol-3-phosphate (PtdIns(3)P)-binding protein that depends on PtdIns(3)P for its ER localization. We further show that UVRAG interacts with RINT-1, and acts as an integral component of the RINT-1 containing ER tethering complex, which couples phosphoinositide metabolism to COPI-vesicle tethering. Displacement or knockdown of UVRAG profoundly disrupted COPI cargo transfer to the ER and Golgi integrity. Intriguingly, autophagy caused the dissociation of UVRAG from the ER tether, which in turn worked in concert with the Bif-1-beclin-1-PI(3)KC3 complex to mobilize Atg9 translocation for autophagosome formation. These findings identify a regulatory mechanism that coordinates Golgi-ER retrograde and autophagy-related vesicular trafficking events through physical and functional interactions between UVRAG, phosphoinositide and their regulatory factors, thereby ensuring spatiotemporal fidelity of membrane trafficking and maintenance of organelle homeostasis. PMID- 24056305 TI - Density functional study of Cu(2+)-phenylalanine complex under micro-solvation environment. AB - We present an atomistic study carried out using density functional calculations including structural relaxations and Car-Parrinello Molecular Dynamics (CPMD) simulations, aiming to investigate the structures of phenylalanine-copper (II) ([Phe-Cu](2+)) complexes and their micro-solvation processes. The structures of the [Phe-Cu](2+) complex with up to four water molecules are optimized using the B3LYP/6-311++G** model in gas phase to identify the lowest energy structures at each degree of solvation (n=0-4). It is found that the phenylalanine appears to be in the neutral form in isolated and mono-hydrated complexes, but in the zwitterionic form in other hydrated complexes (with n>=2). The most stable structures of the complexes suggest that the Cu(2+)-pi interactions are not dominant in the [Phe-Cu](2+) complexes. The present CPMD simulations of the lowest energy micro-hydrated [Phe-Cu](2+) complexes also reveal that the maximum coordination of Cu(2+) in the presence of the Phe ligand does not exceed four: the oxygen atoms from three water molecules and one carboxyl oxygen atom of Phe. Any excess water molecules will migrate to the second solvation shell. Moreover a unique structural motif, (N)H...O(3)...H2O-Cu(2+) is present in the lowest energy complexes, which is recognized to be significant in stabilizing the structures of the complexes. Extensively rich information of the structures, energetics, hydrogen bonds and dynamics of the lowest energy complexes are discussed. PMID- 24056306 TI - Exploring the effect of PARP-1 flexibility in docking studies. AB - Poly(ADP-ribose)polymerase-1 (PARP-1) is an enzyme belonging to the ADP ribosyltransferase family. A large body of works has validated PARP-1 as an attractive drug target for different therapeutic areas, including cancers and ischemia. Accordingly, sampling the conformational space of the enzyme is pivotal to understand its functions and improve structure-based drug discovery approaches. In the first part of this study we apply replica exchange molecular dynamic (REMD) simulations to sample the conformational space of the catalytic domain of PARP-1 in the ligand-bound and unbound forms. In the second part, we assess how and to what extend the emerging enzyme flexibility affects the performance of docking experiments of a library of PARP-1 inhibitors. This study pinpoints a putative key role of conformational shifts of Leu324, Tyr325 and Lys242 in opening an additional binding site pocket that affects the binding of ligands to the catalytic cleft of PARP-1. Furthermore, it highlights the improvement of the enrichment factor of active ligands obtained in docking experiments when using conformations generated with REMD simulations of ligand bound PARP-1. PMID- 24056307 TI - Short-term neonatal/prepubertal exposure of dibutyl phthalate (DBP) advanced pubertal timing and affected hypothalamic kisspeptin/GPR54 expression differently in female rats. AB - Dibutyl phthalate (DBP) had been widely used and its exposure in children has been thought to be one of the reasons causing a trend of advanced pubertal timing in girls. Puberty starts from hypothalamic gonadotropin-releasing hormone release which is controlled by many factors including neurotransmitter kisspeptin and its receptor GPR54. These neural organization or reorganization happens in hypothalamus during neonatal or prepubertal period which may be two target windows of DBP exposure. The present study was designed to determine: (1) the difference between the effects of neonatal and prepubertal DBP exposure on female pubertal timing; (2) whether kisspeptin/GPR54 expression in hypothalamus would respond to neonatal and prepubertal DBP exposure differently. Female Sprague Dawley rats were exposed by subcutaneous injection of 0.5, 5 and 50mg/kg DBP during Postnatal day (P)1-5 (neonatal) or P26-30 (prepubertal). Physiological data demonstrated that both neonatal and prepubertal DBP exposure could advance pubertal timing significantly accompanied by irregular estrous cycles but only a little gonadal impairment. Exposure-period-related difference was found significant with prepubertal exposure groups having longer estrous cycle duration, heavier at vaginal opening and having higher serum estradiol level compared with neonatal exposure groups. Molecular data showed an up-regulated trend in kisspeptin mRNA and immunoreactivity levels of hypothalamic area arcuate but a down-regulation in GPR54 mRNA expression after P1-5 DBP treatment. In P26 30 groups, kisspeptin mRNA and immunoreactivity levels tended to be lower after DBP treatment. These results demonstrated small dose of DBP could induce earlier pubertal timing in females and both neonatal and prepubertal periods were critical windows for DBP exposure. PMID- 24056308 TI - Ordered mesoporous porphyrinic carbons with very high electrocatalytic activity for the oxygen reduction reaction. AB - The high cost of the platinum-based cathode catalysts for the oxygen reduction reaction (ORR) has impeded the widespread application of polymer electrolyte fuel cells. We report on a new family of non-precious metal catalysts based on ordered mesoporous porphyrinic carbons (M-OMPC; M = Fe, Co, or FeCo) with high surface areas and tunable pore structures, which were prepared by nanocasting mesoporous silica templates with metalloporphyrin precursors. The FeCo-OMPC catalyst exhibited an excellent ORR activity in an acidic medium, higher than other non precious metal catalysts. It showed higher kinetic current at 0.9 V than Pt/C catalysts, as well as superior long-term durability and MeOH-tolerance. Density functional theory calculations in combination with extended X-ray absorption fine structure analysis revealed a weakening of the interaction between oxygen atom and FeCo-OMPC compared to Pt/C. This effect and high surface area of FeCo-OMPC appear responsible for its significantly high ORR activity. PMID- 24056310 TI - New series of hybrid fluoroferrates synthesized with triazoles: various dimensionalities and Mossbauer studies. AB - The solvothermal reactions of an equimolar mixture of FeF2 and FeF3 with Htaz (1,2,4-triazole), aqueous HF and DMF (dimethylformamide) at 120 degrees C yielded a series of new hybrid fluoroferrates (1-5). Their structures were characterized by either single crystal or powder X-ray diffraction data analysis. Both classes of hybrid networks were observed according to the Fe(n+)/Htaz/HF starting ratio: class I for 1 and 2 and class II for 3, 4 and 5. Four compounds, [Hdma].(Fe2(H2O)4F6) (1), [Hdma].(Fe2(H2O)4F6).0.5H2O (2), Fe2F5(Htaz) (3) and [Hdma].(Fe2F5(H2O)(Htaz)(taz)) (4), exhibit both Fe(II) and Fe(III) oxidation states while [Hdma].(Fe2F5(taz)2) (5) contains only Fe(III) cations. [Hdma].(Fe2(H2O)4F6) (1) and [Hdma].(Fe2(H2O)4F6).0.5H2O (2) contain anionic inorganic chains of alternating corner-sharing Fe(II) and Fe(III) octahedra; they are weakly hydrogen bonded to dimethylammonium cations [Hdma](+) which are formed by the in situ hydrolysis of DMF. The structure of Fe2F5(Htaz) (3) exhibits a three dimensional inorganic network resulting from the association of HTB planes of corner sharing Fe(II)F4N2 and Fe(III)F6 octahedra. [Hdma].(Fe2F5(H2O)(Htaz)(taz)) (4) and [Hdma].(Fe2F5(taz)2) (5) reveal two original two-dimensional sheets. In 4, the deprotonated and neutral amines connect trinuclear Fe3F10N6 units of corner-sharing octahedra and mononuclear FeN4(H2O)2 octahedra. Infinite Fe2F5(taz)2 layers in 5 are built up from dinuclear species connected by deprotonated amines along two perpendicular directions. The thermal behavior and Mossbauer spectrometry results are detailed for the first tridimensional mixed valence hybrid fluoroferrate (3). PMID- 24056309 TI - Influence of islet function on typing and prognosis of new-onset diabetes after intensive insulin therapy. AB - BACKGROUND: It is difficult in clinical practice to differentiate patients with newly diagnosed diabetes and ketosis. The aim of this study was to investigate the effect of intensive insulin therapy on islet function in patients with new onset diabetes and concomitant ketosis, and to determine the value of alternation in islet function in the typing of diabetes. MATERIAL/METHODS: A total of 206 inpatients with new-onset diabetes and ketosis were recruited after intensive insulin therapy and followed for 36 months. Patients were divided into type 1 diabetes group (Group A) and type 2 diabetes group (Group B). Islet function was compared between the 2 groups before and after intensive insulin therapy, and the influence of islet function on the typing of diabetes and the selection of therapeutic strategies is discussed. RESULTS: In group A, the AUCI, AUCC, HOMA-a cell and HOMA-IR were significantly lower than those in Group B before and after intensive insulin therapy. The sensitivity and accuracy of antibody test were at a low level in Group A. An insulin release test was done after intensive insulin therapy. Results showed that the peaks of insulin and C peptide appeared at 0.5-1 h after glucose administration in Group A, which was earlier than that before therapy, but the maximal levels were no more than 2 times those of baseline levels. In Group B, the peaks appeared at 2 h, and the maximal levels were about 10 times those of baseline levels. CONCLUSIONS: Poor islet function, incomplete recovery of islet function after intensive insulin therapy, and a short "honeymoon" period are characteristics of type 1 diabetes. Detection of diabetes related antibodies is not reliable. PMID- 24056311 TI - A theoretical study on low-lying electronic states and spectroscopic properties of PH. AB - The low-lying electronic states (X(3)?(-), a(1)Delta, b(1)Sigma(+), A(3)Pi, c(1)Pi and (5)?(-)) of the PH species correlating with the first three dissociation channels have been investigated at the MRCI+Q/aug-cc-PV5Z level of theory. Accurate adiabatic potential energy curves and spectroscopic constants (T(e), R(e), omega(e)chi(e), omega(e), B(e), D(e)) of these electronic states have been reported. Effect of the spin-orbit coupling on the A(3)Pi and (5)?(-) states of the PH has been calculated, which lead to the spin-orbit-induced predissociation of the A(3)Pi state. Electronic transition moment, Einstein coefficients and Franck-Condon factors for the A(3)Pi - X(3)?(-) system have been calculated. Dipole moment functions (MU(e)) and radiative lifetime (tau(v')) for the A(3)Pi state has also been determined. The radiative lifetime for A(3)Pi - X(3)?(-) transition is computed and compared with the available data. PMID- 24056312 TI - The investigation of the interaction between Tropicamide and bovine serum albumin by spectroscopic methods. AB - The fluorescence and ultraviolet-visible (UV-Vis) spectroscopy were explored to study the interaction between Tropicamide (TA) and bovine serum albumin (BSA) at three different temperatures (292, 301 and 310K) under imitated physiological conditions. The experimental results showed that the fluorescence quenching mechanism between TA and BSA was static quenching procedure. The binding constant (Ka), binding sites (n) were obtained. The corresponding thermodynamic parameters (DeltaH, DeltaS and DeltaG) of the interaction system were calculated at different temperatures. The results revealed that the binding process is spontaneous, hydrogen binds and vander Waals were the main force to stabilize the complex. According to Forster non-radiation energy transfer theory, the binding distance between TA and BSA was calculated to be 4.90 nm. Synchronous fluorescence spectroscopy indicated the conformation of BSA changed in the presence of TA. Furthermore, the effect of some common metal ions (Mg(2+), Ca(2+), Cu(2+), and Ni(2+)) on the binding constants between TA and BSA were examined. PMID- 24056313 TI - Spectroscopy investigation on chemo-catalytic, free radical scavenging and bactericidal properties of biogenic silver nanoparticles synthesized using Salicornia brachiata aqueous extract. AB - Nanosized silver have been widely used in many applications, such as catalysis, photonics, sensors, medicine etc. Thus, there is an increasing need to develop high-yield, low cost, non-toxic and eco-friendly procedures for the synthesis of nanoparticles. Herein, we report an efficient, green synthesis of silver nanoparticles utilizing the aqueous extract of Salicornia brachiata, a tropical plant of the Chenopodiaceae family. Silver nanoparticles have been characterized by ultraviolet-visible spectroscopy, scanning electron microscopy and transmission electron microscopy. The morphology of the particles formed consists of highly diversified shapes like spherical, rod-like, prism, triangular, pentagonal and hexagonal pattern. However, addition of sodium hydroxide to the extract produces mostly spherical particles. The stable nanoparticles obtained using this green method show remarkable catalytic activity in the reduction of 4 nitro phenol to 4-amino phenol. The reduction catalyzed by silver nanoparticles followed the first-order kinetics, with a rate constant of, 0.6*10(-2) s(-1). The bactericidal activity of the synthesized silver nanoparticles against the pathogenic bacteria, Staphylococcus aureus, Staphylococcus aureus E, Bacillus subtilis and Escherichia coli, was also explored using REMA. The obtained results showed that the minimum inhibitory concentration required to induce bactericidal effect is lower than the control antibiotic, ciprofloxacin. In addition to these, the biogenic synthesized nanoparticles also exhibited excellent free radical scavenging activity. PMID- 24056314 TI - Erythrocyte membrane fatty acid composition is related to overloaded plasma ferritin in Chinese males with angiographic coronary artery disease. AB - Not only is iron deficiency an abnormal iron status, but iron overload is also harmful for human health. It has been reported that overloaded iron stores are positively associated with increased coronary artery disease (CAD) risk, which is called the "iron-heart hypothesis". Previous studies evaluating the relationships between fatty acids (FAs) and body iron status only focused on participants with iron deficiency. However, whether FA composition is related to overloaded iron remains unclear. Therefore, this study was designed to investigate the relationships between erythrocyte membrane FA (Ery-FA) composition and overloaded body iron status as measured by plasma ferritin levels in Chinese CAD patients. A total of 446 subjects with angiographically identified CAD (mean age 63.1 years, 76.9% males) were recruited in a hospital between 2009 and 2010. Ery-FAs were measured by gas chromatography and the activities of FA desaturases, which are involved in the de novo synthesis of unsaturated FAs, were evaluated by using FA product-to-precursor ratios. Results showed that the average iron status was a bit overloaded in the population (median ferritin levels of 234.1 ng mL(-1) and 40.4% males of overload). Moreover, in males, saturated FAs (SFAs) were positively correlated (22 : 0, r = 0.182, p = 0.001; 24 : 0, r = 0.214, p < 0.001), whereas monounsaturated FAs (MUFAs) and n-6 polyunsaturated FAs (PUFAs) were negatively correlated (18 : 1n-9, r = -0.120, p = 0.028; 18 : 2n-6, r = 0.216, p < 0.001) with plasma ferritin levels. A negative correlation (r < 0, p < 0.05) between stearoyl-CoA desaturase (SCD) activity and ferritin levels was also found in males. However, all the significant associations above were not observed in females. In conclusion, the Ery-FA composition was related to overloaded plasma ferritin levels only in Chinese males with angiographic CAD, which might be linked to the change of SCD activity. The results may contribute to the understanding of the mechanism of the iron-heart hypothesis. PMID- 24056315 TI - Focal transnasal approach to the upper, middle, and lower clivus. AB - BACKGROUND: Carefully tailoring the transclival approach to the involved parts of the upper, middle, or lower clivus requires a precise understanding of the focal relationships of the clivus. OBJECTIVE: To develop an optimal classification of the upper, middle, and lower clivus and to define the extra and intracranial relationships of each clival level. METHODS: Ten cadaveric heads and 10 dry skulls were dissected using the surgical microscope and endoscope. RESULTS: The clivus is divided into upper, middle, and lower thirds by 2 endocranial landmarks: the dural pori of the abducens nerves and the dural meati of the glossopharyngeal nerves. Useful surgical landmarks exposed in the transnasal approach that aid in locating the junction of the clival divisions are the lower limit of the paraclival segment of the internal carotid artery, which is located 4.9 mm above the posterior opening of the vidian canal, and the pharyngeal tubercle. The upper, middle, and lower clival approaches provide access to the anterior midline parts of the previously described upper, middle, and lower neurovascular complexes in the posterior fossa. The nasal and nasopharyngeal relationships important in expanding the transnasal approach to the borders of the clivus are reviewed. CONCLUSION: The transclival approach can be carefully tailored to expose focal lesions in the anterior part of the posterior fossa. PMID- 24056316 TI - Mobilization of the transcavernous oculomotor nerve during basilar aneurysm surgery: biomechanical bases for better outcome. AB - BACKGROUND: The transcavernous approach adds a significant exposure advantage in basilar aneurysm surgery. However, one of its frequently reported side effects is postoperative oculomotor nerve palsy. OBJECTIVE: To present the technique of mobilizing the oculomotor nerve throughout its intracranial course and to analyze its consequences on the nerve tension and clinical outcome. METHODS: The oculomotor nerve is mobilized from its mesencephalic origin to the superior orbital fissure. Its degree of mobility, related to the imposed pulling force, was measured in 11 cadaveric nerves. Tension was mathematically deduced and compared before and after mobilizing of the cavernous segment. One hundred four patients treated for basilar aneurysms with the orbitozygomatic pretemporal transcavernous approach were followed up for a 1-year period and evaluated for postoperative oculomotor nerve palsy. RESULTS: Releasing the transcavernous segment compared to cisternal mobilization alone resulted in a significant increase in freedom of mobility from 4 to 7.9 mm (P < .001) and in a significant decrease in tension from 0.8 to 0.5 N (P = .006). Ninety-nine percent of aneurysms treated with this technique were amenable to neck clipping, and a total of 84% of patients had a good postoperative outcome (modified Rankin Scale score, 0-2). All patients showed direct postoperative palsy; however, 97% had a complete recovery by 9 months. Only 3 patients had a persistent diplopia on medial gaze, which was corrected with prism glasses. CONCLUSION: Mobilization of the transcavernous oculomotor nerve results in better maneuverability and less tension on the nerve, which lead to successful surgical treatment and favorable oculomotor outcome. PMID- 24056317 TI - Magnetic resonance imaging-guided focused laser interstitial thermal therapy for intracranial lesions: single-institution series. AB - BACKGROUND: Surgical treatments for deep-seated intracranial lesions have been limited by morbidities associated with resection. Real-time magnetic resonance imaging-guided focused laser interstitial thermal therapy (LITT) offers a minimally invasive surgical treatment option for such lesions. OBJECTIVE: To review treatments and results of patients treated with LITT for intracranial lesions at Washington University School of Medicine. METHODS: In a review of 17 prospectively recruited LITT patients (34-78 years of age; mean, 59 years), we report demographics, treatment details, postoperative imaging characteristics, and peri- and postoperative clinical courses. RESULTS: Targets included 11 gliomas, 5 brain metastases, and 1 epilepsy focus. Lesions were lobar (n = 8), thalamic/basal ganglia (n = 5), insular (n = 3), and corpus callosum (n = 1). Mean target volume was 11.6 cm, and LITT produced 93% target ablation. Patients with superficial lesions had shorter intensive care unit stays. Ten patients experienced no perioperative morbidities. Morbidities included transient aphasia, hemiparesis, hyponatremia, deep venous thrombosis, and fatal meningitis. Postoperative magnetic resonance imaging showed blood products within the lesion surrounded by new thin uniform rim of contrast enhancement and diffusion restriction. In conjunction with other therapies, LITT targets often showed stable or reduced local disease. Epilepsy focus LITT produced seizure freedom at 8 months. Preliminary overall median progression-free survival and survival from LITT in tumor patients were 7.6 and 10.9 months, respectively. However, this small cohort has not been followed for a sufficient length of time, necessitating future outcomes studies. CONCLUSION: Early peri- and postoperative clinical data demonstrate that LITT is a safe and viable ablative treatment option for intracranial lesions, and may be considered for select patients. PMID- 24056318 TI - Differences between generalized q-sampling imaging and diffusion tensor imaging in the preoperative visualization of the nerve fiber tracts within peritumoral edema in brain. AB - BACKGROUND: Diffusion tensor imaging (DTI) tractography enables the in vivo visualization of white matter tracts inside normal brain tissue, which provides the neurosurgeon important information to plan tumor resections. However, DTI is associated with restrictions in the resolution of crossing fibers in the vicinity of the tumor or in edema. We find that generalized q-sampling imaging (GQI) can overcome these difficulties and is advantageous over DTI for the tractography of the fiber bundle in peritumoral edema. OBJECTIVE: To demonstrate the differences between GQI and DTI in the preoperative mapping of fiber tractography in peritumoral edema of cerebral tumors, and discuss the clinical application of GQI in neurosurgical planning. METHODS: Five patients with brain tumors underwent 3-T magnetic resonance imaging scans, and the data were reconstructed by DTI and GQI. We adjusted the parameters and compared the differences between DTI and GQI in visualizing the fiber tracts in the peritumoral edema of cerebral tumors. RESULTS: GQI and DTI showed substantial differences in displaying the nerve fibers in the edema surrounding the tumor. The GQI tractography method could fully display existing intact fibers in the edema, whereas the fiber tracts in edema displayed by DTI tractography were incomplete, missing, or ruptured. CONCLUSION: GQI can visualize the tracts in the peritumoral edema of cerebral tumors better than DTI. Although GQI has many limitations, its future in the preoperative guidance of brain tumor lesions is promising. PMID- 24056319 TI - Life outcomes of anterior temporal lobectomy: serial long-term follow-up evaluations. AB - BACKGROUND: At 3 time points, this study examined long-term psychosocial life outcomes of individuals who underwent anterior temporal lobectomy in comparison with individuals with temporal lobe epilepsy who were medically managed. OBJECTIVE: To examine seizure frequency, employment, driving, independent living, financial independence, mental health, and quality of life at each follow-up assessment, as well as predictors of outcomes. METHODS: All participants were diagnosed with medically intractable complex partial seizures of temporal lobe origin with or without secondary generalization. A structured clinical interview was used at all 3 time points. Information was obtained regarding seizure frequency, antiepilepsy medications, employment, driving status, financial assistance, and independent living. Additionally, questions regarding quality of life, satisfaction with surgery, and the presence of depression or anxiety were included. Participants were, on average, 17 years postsurgery. RESULTS: Surgery resulted in significantly improved and sustained seizure outcomes. At the first, second, and third follow-ups, 67%, 72%, and 67% of participants in the surgery group remained seizure-free in the year before the follow-up interview. At each follow-up, 97%, 84%, and 84% reported that they would undergo surgery again. Seizure freedom predicted driving outcomes at all 3 time points, but was not a significant predictor for employment, independent living, or financial independence. Psychosocial life outcomes in the surgical group were improved and maintained over time in comparison with the medically managed group. CONCLUSION: This systematic long-term investigation provides strong support for the positive impact of anterior temporal lobectomy on psychosocial life outcomes including driving, employment, independent living, and financial independence. PMID- 24056320 TI - Long-term follow-up of blister aneurysms of the internal carotid artery. AB - BACKGROUND: Blister aneurysms of the internal carotid artery (ICA) are uncommon. There is a paucity of data on the long-term outcomes of patients. OBJECTIVE: To review our experience with the treatment of these lesions. METHODS: We retrospectively reviewed all aneurysms treated at our institution between 1994 and 2005. Relevant operative notes, radiology reports, and inpatient/outpatient records were reviewed. RESULTS: Seventeen patients (3 male, 14 female) with 18 blister aneurysms of the ICA were identified. The mean age was 44.6 years (range, 17-72; median, 42 years). Twelve patients (70.6%) presented with aneurysmal subarachnoid hemorrhage. The mean admission Glasgow Outcome Scale score was 4.3 (range, 2-5; median, 5). All patients were initially treated using microsurgical technique with direct clipping (n = 15; 83.3%) or clip-wrapping with Gore-Tex (n = 3, 16.7%). There were 4 cases of intraoperative rupture, all associated with attempted direct clipping; all 4 cases were successfully clipped. Two cases rebled post-treatment. Both rebleeding episodes were managed with endovascular stenting. Follow-up angiography was available for 14 patients and revealed a new aneurysm adjacent to the site of clipping in 1 patient and in-stent stenosis in 2. At the mean follow-up of 74.5 months (median, 73; range, 7-165), the mean Glasgow Outcome Scale score was 4.6 (range, 2-5; median, 5). CONCLUSION: Microsurgical treatment of blister aneurysms of the ICA results in excellent outcome. In the evolution of treating these friable aneurysms, we have modified our clip-wrapping technique and use this technique when direct clipping is not feasible. PMID- 24056321 TI - Urinary concentrations of metabolites of pyrethroid insecticides in textile workers, Eastern China. AB - Pyrethroid insecticides have been applied in the production of cotton, wool and textile. In order to examine whether textile workers are exposed to pyrethroid insecticides, we recruited 50 textile workers in two textile plants in Eastern China. Their urine samples were collected for the measurement of pyrethroid metabolites: cis- and trans-isomers of 2,2-dichlorovinyl-2,2-dimethylcyclopropane 1-carboxylic acid (cis-Cl2CA and trans-Cl2CA) and 3-phenoxybenzoic acid (3-PBA). Our results showed that textile workers were exposed to high levels of pyrethroid insecticides. cis-Cl2CA and 3-PBA were dominant metabolites with concentrations of 0.17-261MUg/L, while concentrations of trans-Cl2CA were in the range of 0.26 11MUg/L. Levels of three metabolites were in a descending order: cis-Cl2CA, 3 PBA, and trans-Cl2CA. Levels of the metabolites were associated with ages and job responsibilities of textile workers. Sewing workers, cutting workers, machine operators, reorganizers, and older workers were more likely in contact with pyrethroid insecticides in the textile production. trans- to cis-Cl2CA ratios might indicate that exposure of textile workers was via dermal absorption and inhalation. PMID- 24056322 TI - Development and application of an innovative expert decision support system to manage sediments and to assess environmental risk in freshwater ecosystems. AB - With the aim of supporting decision makers to manage contamination in freshwater environments, an innovative expert decision support system (EDSS) was developed. The EDSS was applied in a sediment quality assessment along the Bormida river (NW, Italy) which has been heavily contaminated by an upstream industrial site for more than a century. Sampling sites were classified by means of comparing chemical concentrations with effect-based target values (threshold and probable effect concentrations). The level of each contaminant and the combined toxic pressure were used to rank sites into three categories: (i) uncontaminated (8 sites), (ii) mildly contaminated (4) and (iii) heavily contaminated (19). In heavily contaminated sediments, an environmental risk index (EnvRI) was determined by means of integrating chemical data with ecotoxicological and ecological parameters (triad approach). In addition a sediment risk index (SedRI) was computed from combining chemical and ecotoxicological data. Eight sites exhibited EnvRI values >=0.25, the safety threshold level (range of EnvRI values: 0.14-0.31) whereas SedRI exceeded the safety threshold level at 6 sites (range of SedRI values: 0.16-0.36). At sites classified as mildly contaminated, sublethal biomarkers were integrated with chemical data into a biological vulnerability index (BVI), which exceeded the safety threshold level at one site (BVI value: 0.28). Finally, potential human risk was assessed in selected stations (11 sites) by integrating genotoxicity biomarkers (GTI index falling in the range 0.00 0.53). General conclusions drawn from the EDSS data include: (i) in sites classified as heavily contaminated, only a few exhibited some significant, yet limited, effects on biodiversity; (ii) restrictions in re-using sediments from heavily contaminated sites found little support in ecotoxicological data; (iii) in the majority of the sites classified as mildly contaminated, tested organisms exhibited low response levels; (iv) preliminary results on genotoxicity biomarkers indicate possible negative consequences for humans if exposed to river sediments from target areas. PMID- 24056323 TI - Efficient and fast sign-sensitive determination of heteronuclear coupling constants. AB - Two complementary 1D NMR approaches for the fast and easy determination of the magnitude and the sign of heteronuclear J(XH) coupling constants are proposed: The Up&Down technique relies on the direct analysis of anti-phase multiplets whereas the Left&Right technique is based on the relative displacement between separate IPAP components. PMID- 24056324 TI - A serial micropipette microfluidic device with applications to cancer cell repeated deformation studies. AB - Cells are complex viscoelastic materials that are frequently in deformed morphological states, particularly during the cancer invasion process. The ability to study cell mechanical deformability in an accessible way can be enabling in many areas of research where biomechanics is important, from cancer metastasis to immune response to stem cell differentiation. Furthermore, phenomena in biology are frequently exhibited in high multiplicity. For instance, during metastasis, cells undergoing non-proteolytic invasion squeeze through a multitude of physiological barriers, including many small pores in the dense extracellular matrix (ECM) of the tumor stroma. Therefore, it is important to perform multiple measurements of the same property even for the same cell in order to fully appreciate its dynamics and variability, especially in the high recurrence regime. We have created a simple and minimalistic micropipette system with automated operational procedures that can sample the deformation and relaxation dynamics of single-cells serially and in a parallel manner. We demonstrated its ability to elucidate the impact of an initial cell deformation event on subsequent deformations for untreated and paclitaxel treated MDA-MB-231 metastatic breast cancer cells, and we examined contributions from the cell nucleus during whole-cell micropipette experiments. Finally we developed an empirical model that characterizes the serial factor, which describes the reduction in cost for cell deformations across sequential constrictions. We performed experiments using spatial, temporal, and force scales that match physiological and biomechanical processes, thus potentially enabling a qualitatively more pertinent representation of the functional attributes of cell deformability. PMID- 24056326 TI - Bouquets, whiffs and pongs. PMID- 24056325 TI - Retinal detachment model in rodents by subretinal injection of sodium hyaluronate. AB - Subretinal injection of sodium hyaluronate is a widely accepted method of inducing retinal detachment (RD). However, the height and duration of RD or the occurrence of subretinal hemorrhage can affect photoreceptor cell death in the detached retina. Hence, it is advantageous to create reproducible RDs without subretinal hemorrhage for evaluating photoreceptor cell death. We modified a previously reported method to create bullous and persistent RDs in a reproducible location with rare occurrence of subretinal hemorrhage. The critical step of this modified method is the creation of a self-sealing scleral incision, which can prevent leakage of sodium hyaluronate after injection into the subretinal space. To make the self-sealing scleral incision, a scleral tunnel is created, followed by scleral penetration into the choroid with a 30 G needle. Although choroidal hemorrhage may occur during this step, astriction with a surgical spear reduces the rate of choroidal hemorrhage. This method allows a more reproducible and reliable model of photoreceptor death in diseases that involve RD such as rhegmatogenous RD, retinopathy of prematurity, diabetic retinopathy, central serous chorioretinopathy, and age-related macular degeneration (AMD). [corrected]. PMID- 24056333 TI - Crystal engineering: Covalent crystal growth. PMID- 24056334 TI - Carbon nanotubes: A bright future for defects. PMID- 24056335 TI - Carbene catalysis: An internal affair. PMID- 24056336 TI - Caesium chemistry: Beyond state I. PMID- 24056337 TI - Catalysis in service of main group chemistry offers a versatile approach to p block molecules and materials. AB - Catalytic reactions that enable the formation of new bonds to carbon centres play a pervasive role in the state-of-the-art synthesis of organic molecules and macromolecules. In contrast, the development of analogous processes as routes to main group compounds and materials has been much slower. Nevertheless, recent advances have led to a broad expansion of this field and now allow access to a wide range of catenated structures based on elements across the p block. These breakthroughs have already impacted areas such as hydrogen storage and transfer, functional inorganic polymers and ceramic thin films. Dehydrogenation and dehydrocoupling processes are particularly well developed and may be mediated by either transition metal or main group catalysts. Such pathways represent an increasingly attractive and convenient alternative to traditional routes, such as salt metathesis and reductive coupling reactions. An overview of this emerging area is presented in this Review with a focus on recent developments and future challenges. PMID- 24056338 TI - Constructing monocrystalline covalent organic networks by polymerization. AB - An emerging strategy for making ordered materials is modular construction, which connects preformed molecular subunits to neighbours through interactions of properly selected reactive sites. This strategy has yielded remarkable materials, including metal-organic frameworks joined by coordinative bonds, supramolecular networks linked by strong non-covalent interactions, and covalent organic frameworks in which atoms of carbon and other light elements are bonded covalently. However, the strategy has not yet produced covalently bonded organic materials in the form of large single crystals. Here we show that such materials can result from reversible self-addition polymerizations of suitably designed monomers. In particular, monomers with four tetrahedrally oriented nitroso groups polymerize to form diamondoid azodioxy networks that can be fully characterized by single-crystal X-ray diffraction. This work forges a strong new link between polymer science and supramolecular chemistry by showing how predictably ordered covalent or non-covalent structures can both be built using a single modular strategy. PMID- 24056339 TI - beta-Carbon activation of saturated carboxylic esters through N-heterocyclic carbene organocatalysis. AB - The activation of the alpha-carbons of carboxylic esters and related carbonyl compounds to generate enolate equivalents as nucleophiles is one of the most powerful strategies in organic synthesis. We reasoned that the horizons of chemical synthesis could be greatly expanded if the typically inert beta-carbons of saturated esters could be used as nucleophiles. However, despite the rather significant fundamental and practical values, direct use of the beta-carbons of saturated carbonyl compounds as nucleophiles remains elusive. Here we report the catalytic activation of simple saturated ester beta-carbons as nucleophiles (beta carbon activation) using N-heterocyclic carbene organocatalysts. The catalytically generated nucleophilic beta-carbons undergo enantioselective reactions with electrophiles such as enones and imines. Given the proven rich chemistry of ester alpha-carbons, we expect this catalytic activation mode for saturated ester beta-carbons to open a valuable new arena for new and useful reactions and synthetic strategies. PMID- 24056340 TI - Brightening of carbon nanotube photoluminescence through the incorporation of sp3 defects. AB - Semiconducting carbon nanotubes promise a broad range of potential applications in optoelectronics and imaging, but their photon-conversion efficiency is relatively low. Quantum theory suggests that nanotube photoluminescence is intrinsically inefficient because of low-lying 'dark' exciton states. Here we demonstrate the significant brightening of nanotube photoluminescence (up to 28 fold) through the creation of an optically allowed defect state that resides below the predicted energy level of the dark excitons. Emission from this new state generates a photoluminescence peak that is red-shifted by as much as 254 meV from the nanotube's original excitonic transition. We also found that the attachment of electron-withdrawing substituents to carbon nanotubes systematically drives this defect state further down the energy ladder. Our experiments show that the material's photoluminescence quantum yield increases exponentially as a function of the shifted emission energy. This work lays the foundation for chemical control of defect quantum states in low-dimensional carbon materials. PMID- 24056341 TI - Caesium in high oxidation states and as a p-block element. AB - The periodicity of the elements and the non-reactivity of the inner-shell electrons are two related principles of chemistry, rooted in the atomic shell structure. Within compounds, Group I elements, for example, invariably assume the +1 oxidation state, and their chemical properties differ completely from those of the p-block elements. These general rules govern our understanding of chemical structures and reactions. Here, first-principles calculations show that, under pressure, caesium atoms can share their 5p electrons to become formally oxidized beyond the +1 state. In the presence of fluorine and under pressure, the formation of CsF(n) (n > 1) compounds containing neutral or ionic molecules is predicted. Their geometry and bonding resemble that of isoelectronic XeF(n) molecules, showing a caesium atom that behaves chemically like a p-block element under these conditions. The calculated stability of the CsF(n) compounds shows that the inner-shell electrons can become the main components of chemical bonds. PMID- 24056342 TI - End-to-end conformational communication through a synthetic purinergic receptor by ligand-induced helicity switching. AB - The long-range communication of information, exemplified by signal transduction through membrane-bound receptors, is a central biochemical function. Reversible binding of a messenger ligand induces a local conformational change that is relayed through the receptor, inducing a chemical effect typically several nanometres from the binding site. We report a synthetic receptor mimic that transmits structural information from a boron-based ligand binding site to a spectroscopic reporter located more than 2 nm away. Reversible binding of a diol ligand to the N-terminal binding site induces a screw-sense preference in a helical oligo(aminoisobutyric acid) foldamer, which is relayed to a reporter group at the remote C-terminus, communicating information about the structure and stereochemistry of the ligand. The reversible nature of boronate esterification was exploited to switch the receptor sequentially between left- and right-handed helices, while the exquisite conformational sensitivity of the helical relay allowed the reporter to differentiate even between purine and pyrimidine nucleosides as ligands. PMID- 24056343 TI - A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling. AB - A prerequisite for successful screening campaigns in drug discovery or chemical genetics is the availability of structurally and thus functionally diverse compound libraries. Diversity-oriented synthesis (DOS) provides strategies for the generation of such libraries, of which the build/couple/pair (B/C/P) algorithm is the most frequently used. We have developed an advanced B/C/P strategy that incorporates multidimensional coupling. In this approach, structural diversity is not only defined by the nature of the building blocks employed, but also by the linking motif installed during the coupling reaction. We applied this step-efficient approach in a DOS of a library that consisted of 73 macrocyclic compounds based around 59 discrete scaffolds. The macrocycles prepared cover a broad range of different molecular shapes, as illustrated by principal moment-of-inertia analysis. This demonstrates the capability of the advanced B/C/P strategy using multidimensional coupling for the preparation of structurally diverse compound collections. PMID- 24056344 TI - Site-specific positioning of dendritic alkyl chains on DNA cages enables their geometry-dependent self-assembly. AB - Nature uses a combination of non-covalent interactions to create a hierarchy of complex systems from simple building blocks. One example is the selective association of the hydrophobic side chains that are a strong determinant of protein organization. Here, we report a parallel mode of assembly in DNA nanotechnology. Dendritic alkyl-DNA conjugates are hybridized to the edges of a DNA cube. When four amphiphiles are on one face, the hydrophobic residues of two neighbouring cubes engage in an intermolecular 'handshake', resulting in a dimer. When there are eight amphiphiles (four on the top and bottom cube faces, respectively), they engage in an intramolecular 'handshake' inside the cube. This forms the first example of a monodisperse micelle within a DNA nanostructure that encapsulates small molecules and releases them by DNA recognition. Creating a three-dimensional pattern of hydrophobic patches, like side chains in proteins, can result in specific, directed association of hydrophobic domains with orthogonal interactions to DNA base-pairing. PMID- 24056345 TI - Equilibrium between a cyclotrisilene and an isolable base adduct of a disilenyl silylene. AB - In organic chemistry, compounds with adjacent alkene and carbene functionalities (vinyl carbenes) are studied widely as fleeting intermediates and in the coordination sphere of transition metals. Stable derivatives of vinyl carbenes remain elusive, including the corresponding heavier group 14 homologues. Here we report the isolation and full characterization of a base-stabilized silicon version of a vinyl carbene that features a silicon-silicon double bond as well as a silylene functionality, coordinated by an N-heterocyclic carbene (NHC). In solution, the intensely green disilenyl silylene adduct exists in equilibrium with the corresponding silicon analogue of a cyclopropene and free NHC, which was quantified by nuclear magnetic resonance spectroscopy and ultraviolet-visible spectroscopy. The reversibility of this process raises exciting possibilities for the preparation of extended conjugated pi systems of silicon. PMID- 24056346 TI - A missing link in the transformation from asymmetric to symmetric metallofullerene cages implies a top-down fullerene formation mechanism. AB - Although fullerenes were discovered nearly three decades ago, the mechanism of their formation remains a mystery. Many versions of the classic 'bottom-up' formation mechanism have been advanced, starting with C2 units that build up to form chains and rings of carbon atoms and ultimately form those well-known isolated fullerenes (for example, I(h)-C60). In recent years, evidence from laboratory and interstellar observations has emerged to suggest a 'top-down' mechanism, whereby small isolated fullerenes are formed via shrinkage of giant fullerenes generated from graphene sheets. Here, we present molecular structural evidence for this top-down mechanism based on metal carbide metallofullerenes M2C2@C1(51383)-C84 (M = Y, Gd). We propose that the unique asymmetric C1(51383) C84 cage with destabilizing fused pentagons is a preserved 'missing link' in the top-down mechanism, and in well-established rearrangement steps can form many well-known, high-symmetry fullerene structures that account for the majority of solvent-extractable metallofullerenes. PMID- 24056348 TI - Lead between the lines. PMID- 24056349 TI - Deviations from bilinearity in multivariate voltammetric calibration models. AB - This work considers the problem of lack of bilinearity in multivariate calibration. In voltammetry this issue especially relies on the analysis of overlapping signals, which change the shape, sensitivity or shift along the potential axis, causing a significant loss of linearity. It limits the quality of many chemometric models designed for linear data. Improvement of the predictive ability of multivariate calibration models is achieved by pre-processing of the raw data. In this work we proposed the application of a technique called orthogonal signal correction (OSC). We demonstrated that orthogonal correction enables the removal of almost all non-linear effects, disturbing voltammetric signals that impede the building of effective PLS models. The methodology was presented using simulated signals, and also in determination of the nanomolar concentration of scandium in the presence of a high and changing excess of nickel. PMID- 24056347 TI - Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues. AB - The trioxacarcins are polyoxygenated, structurally complex natural products that potently inhibit the growth of cultured human cancer cells. Here we describe syntheses of trioxacarcin A, DC-45-A1 and structural analogues by late-stage stereoselective glycosylation reactions of fully functionalized, differentially protected aglycon substrates. Key issues addressed in this work include the identification of an appropriate means to activate and protect each of the two 2 deoxysugar components, trioxacarcinose A and trioxacarcinose B, as well as a viable sequencing of the glycosidic couplings. The convergent, component-based sequence we present allows for rapid construction of structurally diverse, synthetic analogues that would be inaccessible by any other means, in amounts required to support biological evaluation. Analogues that arise from the modification of four of five modular components are assembled in 11 steps or fewer. The majority of these are found to be active in antiproliferative assays using cultured human cancer cells. PMID- 24056350 TI - Bond-valence model for metal cluster compounds. I. Common lattice strains. AB - The bond-valence model was commonly considered as inappropriate to metal cluster compounds, but recently it was shown that the model provides unique information on the lattice strains and stabilization mechanisms in (TM)6-chalcohalides (TM = transition metal in the cluster). The previous study was mainly devoted to the non-uniform distribution of the anion valences (bond-valence sums) around clusters. This and the following paper focuses on two additional phenomena: (i) a steric conflict between counter-cations and the cluster-ligand framework resulting in 'common' lattice strains (this paper), and (ii) steric conflict between the small (TM)6-cluster and the large coordination polyhedron around the cluster or so-called matrix effect [the next paper; Levi et al. (2013), Acta Cryst. B69, 426-438]. It was shown that both phenomena can be well described by changes in the bond-valence parameters. The calculations were based on the structural data known to date for a variety of (TM)6-cluster compounds, Mx(TM)6Ly (TM = Nb, Mo, W and Re; M = various additional cations, L = the chalcogen and/or halogen ligands). The results were used to explain the structural peculiarities of these compounds with remarkable physical properties and the mechanisms of their stabilization. PMID- 24056351 TI - Bond-valence model for metal cluster compounds. II. Matrix effect. AB - The bond-valence model was commonly considered as inappropriate to metal cluster compounds, but recently it was shown that the model provides unique information on the lattice strains and stabilization mechanisms in (TM)6-chalcohalides, Mx(TM)6Ly (TM = transition metal, L = the chalcogen and/or halogen ligands; M = counter-cation). The previous study was mainly devoted to the non-uniform distribution of the anion valences (bond-valence sums) around clusters. This and the previous paper are focused on two additional phenomena: (i) a steric conflict between counter-cations and the cluster-ligand framework resulting in 'common' lattice strains [previous paper: Levi et al. (2013). Acta Cryst. B69, 419-425], and (ii) steric conflict between the small (TM)6-cluster and the large coordination polyhedron around the cluster or so-called matrix effect (this paper). It was shown that both phenomena can be well described by changes in the bond-valence parameters. This paper demonstrates that the matrix effect results in high strains in the TM-L bonds in most of the (TM)6-chalcohalides (TM = Nb, Mo, W and Re). In spite of this, the violations for the total TM valence are minimal, because the cluster stretching is fully or partially compensated by compression of the TM-L bonds. As a result, the influence of the matrix effect on the material stability is rather positive: it decreases the volume of the structural units and in many cases ensures a more favorable distribution of the bond valences around TM atoms, stabilizing the cluster compound. PMID- 24056352 TI - Tolerance factor for pyrochlores and related structures. AB - In this work a new empirical tolerance factor for compounds with pyrochlore structure is proposed. This suggested tolerance factor is based on experimental structural data and on the tolerance factors proposed. However, since it does not depend on the structural data, this new tolerance factor permits the prediction of some properties of these compounds directly. Also, a good structure stability field for the pyrochlore formation is observed when this tolerance factor is used. PMID- 24056353 TI - Effect of lone-pair stereoactivity on polyhedral volume and structural flexibility: application to Te(IV)O6 octahedra. AB - The Distortion Theorem implies that the irregularity of bond distances in a distorted coordination polyhedron causes an increase of mean bond distance. Examination of 40 polyhedra containing the lone-pair cation Te(IV) shows that this does not imply an increase in polyhedral volume. Volumes of these polyhedra are 10.3-23.7 A(3), compared with the 12.83 A(3) expected for a hypothetical regular octahedron. There is little correlation between volume and measures of polyhedral distortion such as quadratic elongation, bond-angle variance or vector bond valence. However, the oxygens of our polyhedra lie very close to a sphere of best fit, centred at ~ 1 A from the Te(IV) atom. The Te(IV)-centre distance is an index of lone-pair stereoactivity and is linearly related to the radius Rsph of the sphere; this is explained by a more localized lone pair repelling the anions more strongly, leading to a longer non-bonded distance between the lone pair and anions. Polyhedral volume still varies considerably for a given Rsph, because the oxygen ligands may be distributed over the whole sphere surface, or confined to a small portion of it. The uniformity of this distribution can be estimated from the distance between the sphere centre and the centroid of the O6 polyhedron. Te(IV)-centre and centroid-centre distances alone then account for 95% of the variation observed in volume for polyhedra which are topologically octahedral. Six of the polyhedra studied that are outliers are closer in shape to pentagonal pyramids than octahedra. These have short distances from the central Te(IV) cation to other Te(IV) and/or to large, polarizable cations, suggesting additional weak bonding interactions between these species and the central lone pair. The flexibility of lone-pair polyhedra is further enhanced by the ability of a single polyhedron to accommodate different cations with different degrees of lone-pair activity, which facilitates more diverse solid solution behaviour than would otherwise be the case. PMID- 24056354 TI - TiGePt--a study of Friedel differences. AB - The X-ray single-crystal diffraction intensities of the intermetallic compound TiGePt were analysed. These showed beyond doubt that the crystal structure is non centrosymmetric. The analysis revolves around the resonant-scattering contribution to differences in intensity between Friedel opposites hkl and ?bar h?bar k?bar l. The following techniques were used: R(merge) factors on the average (A) and difference (D) of Friedel opposites; statistical estimates of the resonant-scattering contribution to Friedel opposites; plots of 2A(obs) against 2A(model) and of D(obs) against D(model); the antisymmetric D-Patterson function. Moreover it was possible to show that a non-standard atomic model was unnecessary to describe TiGePt. Two data sets are compared. That measured with Ag Kalpha radiation at 295 K to a resolution of 1.25 A(-1) is less conclusive than the one measured with Mo Kalpha radiation at 100 K to the lower resolution of 0.93 A(-1). This result is probably due to the fact that the resonant scattering of Pt is larger for Mo Kalpha than for AgKalpha radiation. PMID- 24056355 TI - X-ray diffraction: a powerful tool to probe and understand the structure of nanocrystalline calcium silicate hydrates. AB - X-ray diffraction (XRD) patterns were calculated and compared to literature data with the aim of investigating the crystal structure of nanocrystalline calcium silicate hydrates (C-S-H), the main binding phase in hydrated Portland cement pastes. Published XRD patterns from C-S-H of Ca/Si ratios ranging from ~ 0.6 to ~ 1.7 are fully compatible with nanocrystalline and turbostratic tobermorite. Even at a ratio close or slightly higher than that of jennite (Ca/Si = 1.5) this latter mineral, which is required in some models to describe the structure of C-S H, is not detected in the experimental XRD patterns. The 001 basal reflection from C-S-H, positioned at ~ 13.5 A when the C-S-H structural Ca/Si ratio is low (< 0.9), shifts towards smaller d values and sharpens with increasing Ca/Si ratio, to reach ~ 11.2 A when the Ca/Si ratio is higher than 1.5. Calculations indicate that the sharpening of the 001 reflection may be related to a crystallite size along c* (i.e. a mean number of stacked layers) increasing with the C-S-H Ca/Si ratio. Such an increase would contribute to the observed shift of the 001 reflection, but fails to quantitatively explain it. It is proposed that the observed shift could result from interstratification of at least two tobermorite-like layers, one having a high and the other a low Ca/Si ratio with a basal spacing of 11.3 and 14 A, respectively. PMID- 24056356 TI - Polytypes and twins in the diamond-lonsdaleite system formed by high-pressure and high-temperature treatment of graphite. AB - As a result of the high-temperature and high-pressure treatment of graphite we obtained a powder containing diamond and lonsdaleite. The structure and properties of the powder were studied by transmission electron microscopy (TEM) and electron energy-loss spectroscopy (EELS). It was found that the synthesized material contains not only diamond nanoparticles, but also some relatively large (up to several nanometers) fragments of lonsdaleite. 4H and 6H polytypes were found in some of the diamond particles. Incoherent twin boundaries were observed in the diamond particle containing fragments of lonsdaleite. PMID- 24056357 TI - Two- and three-dimensional assembled structures constructed from amidate-bridged paddlewheel complexes with group 6 oxometallate ions. AB - Monocationic acetamidate-bridged dinuclear units are two-dimensionally connected by axially coordinating group 6 oxometallate ions in the structures [{M2(acam)4}2(M'O4)] (M = Rh, Ru; M' = Cr, Mo, W; Hacam = acetamide). In these sheet structures, dinuclear units are connected to each other by NH...O hydrogen bonds. The sheets are also connected with NH...O hydrogen bonds. Amidate-bridged dirhodium units that have bulkier alkyl groups reacted with CrO4(2-) or MoO4(2-) give three-dimensional diamondoid structures [{Rh2(pram)4}2(CrO4)] . 1.08H2O, [{Rh2(pram)4}2(MoO4)] . 2.44H2O and [{Rh2(buam)4}2(MoO4)] (Hpram = propionamide; Hbuam = butyramide). In these structures the NH group of the amidate ligands hydrogen bonds with O atoms in metallate ions. PMID- 24056358 TI - Structure and magnetic properties of a new iron(II) citrate coordination polymer. AB - The new compound [Fe(H2cit)(H2O)]n (NICS-2) is the first neutral ferrous citrate carboxylate that has been synthesized up to now. The iron citrate coordination polymer was hydrothermally synthesized and the structure was solved using single crystal X-ray diffraction. It crystallizes in an orthorhombic space group P2(1)2(1)2(1) (No. 19), with a = 5.9470 (4), b = 10.402(1) (5), c = 13.5773 (7) A, V = 839.91 (8) A(3), Z = 4. Its structure consists of one-dimensional chains of corner-sharing Fe(II)O6 octahedra that are additionally cross-linked with citrate ligands. Chains are additionally stabilized into a pseudo-three dimensional structure by hydrogen bonds. The measurement of magnetic properties revealed that the magnetic moment is almost constant above 100 K (MUeff = 5.1 uB), but decreases rapidly below this temperature most probably due to the appearance of weak antiferromagnetic interactions between Fe atoms. Additionally, analysis of Mossbauer spectra confirmed the presence of divalent Fe atoms in the structure. Thermogravimetrical and X-ray high-temperature diffraction analyses showed the thermal stability of the material up to 548 K. PMID- 24056359 TI - C6H4S2AsCl: description and interpretation of an incommensurately modulated molecular crystal structure. AB - Crystals of 2-chloro-benzo-1,3,2-dithiarsole have a strongly modulated structure that can be solved and refined with relative ease in a P(1), Z' = 17 approximate supercell but that is better described as incommensurate. Two conventional refinements (different superstructure approximations that differ in the placement of their crystallographic inversion centers) and a (3 + 1)-dimensional superspace refinement are all nearly equally successful, at least as measured by the usual agreement factors; the data integration, however, shows that the incommensurate description is preferable. The overall packing is determined by the stacking of the aromatic rings and probably by the segregation of As and Cl atoms to give short As...Cl contacts. A refinement of the average (Z' = 1) structure shows that there are two basic orientations of the C6S2 plane, but that those orientations must be correlated in several directions to avoid impossibly short intermolecular contacts. Along the modulation vector q the orientation of the C6S2 plane varies smoothly, but q is not a direction in which the molecules are in contact. Along the directions in which the molecules are in contact the orientation of the C6S2 plane alternates; there are also positional shifts. The single modulation q relieves packing problems in several different directions well enough that crystals that diffract well can be grown. PMID- 24056360 TI - Allotwinning in a molecular crystal: (1R,3S)-dimethyl 2-oxocyclohexane-1,3 dicarboxylate. AB - Two polytypic modifications of (1R,3S)-dimethyl 2-oxocyclohexane-1,3 dicarboxylate intergrow to form allotwins. One phase shows monoclinic symmetry, Cc, while the other is orthorhombic Pmc21. The structures may be considered as two different modes of superstructure ordering of an underlying, disordered structure. Considered in the same metrically orthorhombic unit cell a = 37.8883, b = 4.7233, c = 11.6835 A, the two can be conveniently distinguished by their non standard centering, Cc being represented as Xc with the centering vectors (0 0 0); (1/2 0 1/2); (1/4 1/2 3/4); (3/4 1/2 1/4); and Pmc21 as Xmc21 with the centering vectors (0 0 0); (1/2 0 0). The difference between the allotwin domains lies only in the relationship between next-nearest neighbors along the stacking direction 100 and hence the conformations and packing efficiencies are identical for both phases and all three domains. The stacking sequences for the two phases correspond to ABAB for the orthorhombic stacking and ABA'B'/AB'A'B for the two (equivalent) monoclinic stackings. The monoclinic phase dominates comprising ca 80% of the total volume. Within the monoclinic phase, the ratio between the two possible orientations is highly unbalanced (6:1) indicating relatively large domains. The allotwinning detected in this sample may appear exotic in molecular compounds, but we suggest that the rarity of such examples in the literature is a reflection of the paucity of software that can identify and handle such cases. It is easy to overlook the possibility that a complex diffraction pattern originates from allotwinning and assume that normal mono-component twinning is the cause. The underlying mechanism in this case is the formation of two-dimensional layers of molecules that allow for two equivalent, but in terms of absolute geometry, different, ways of stacking. PMID- 24056361 TI - Hydrogen-bond landscapes, geometry and energetics of squaric acid and its mono- and dianions: a Cambridge Structural Database, IsoStar and computational study. AB - As part of a programme of work to extend central-group coverage in the Cambridge Crystallographic Data Centre's (CCDC) IsoStar knowledge base of intermolecular interactions, we have studied the hydrogen-bonding abilities of squaric acid (H2SQ) and its mono- and dianions (HSQ(-) and SQ(2-)) using the Cambridge Structural Database (CSD) along with dispersion-corrected density functional theory (DFT-D) calculations for a range of hydrogen-bonded dimers. The -OH and C=O groups of H2SQ, HSQ(-) and SQ(2-) are potent donors and acceptors, as indicated by their hydrogen-bond geometries in available crystal structures in the CSD, and by the attractive energies calculated for their dimers with acetone and methanol, which were used as model acceptors and donors. The two anions have sufficient examples in the CSD for their addition as new central groups in IsoStar. It is also shown that charge- and resonance-assisted hydrogen bonds involving H2SQ and HSQ(-) are similar in strength to those made by carboxylate COO(-) acceptors, while hydrogen bonds made by the dianion SQ(2-) are somewhat stronger. The study reinforces the value of squaric acid and its anions as cocrystal formers and their actual and potential importance as isosteric replacements for carboxylic acid and carboxylate functions. PMID- 24056363 TI - "Rural health is subjective, everyone sees it differently": understandings of rural health among Australian stakeholders. AB - In Australia, a diversity of perspectives of rural health have produced a deficit discourse as well as multidisciplinary perspectives that acknowledge diversity and blend in social, cultural and public health concepts. Interviews with 48 stakeholders challenged categories of rural and remote, and discussed these concepts in different ways, but invariably marginalised Aboriginal voices. Respondents overwhelmingly used a deficit discourse to plead for more resources but also blended diverse knowledge and at times reflected a relational understanding of rurality. However, mainstream perspectives dominated Aboriginal voices and racial exclusion remains a serious challenge for rural/remote health in Australia. PMID- 24056364 TI - Contextual determinants of cardiovascular diseases: overcoming the residential trap by accounting for non-residential context and duration of exposure. AB - Multilevel neighbourhood analyses rarely account for (1) non-residential exposures and (2) duration of exposure, which have the potential to improve contextual level variance explained, model fit and strength of associations. Using cross-classified logistic regressions, we evaluate the impact of socio environmental factors at work and home on cardiovascular disease risk for 1626 adults in Toronto-Canada. In the fully-adjusted model, increased CVD risk was associated with poor food environments, lack of parks/recreational facilities, home and work proximity to a major road and noise, and working in a low-SES neighbourhood (p<0.05). Adjusting for exposure duration improved model fit and the strength of associations. PMID- 24056365 TI - Pharmacologically controlled protein switch for ON-OFF regulation of growth factor activity. AB - The precise manipulation of growth factor signaling is central to the progress of tissue engineering. Methods for direct time-resolved activation of signaling pathways through controlled receptor dimerization have been reported; however, these suffer from the risks associated with gene transfer. Here we present an alternative gene transfer-free approach in the form of a protein switch featuring pharmacologically controlled ON-OFF regulation of growth factor activity. The reversible operation of the switch enables stimulation of target processes within a defined period of time. The protein switch provides a means for both studying and manipulating signaling processes, and is thus believed to be a valuable tool for basic research as well as tissue engineering and biomedical applications. PMID- 24056366 TI - Randomized multi-centre study on the effect of training on tooth shade matching. AB - OBJECTIVES: The aim of this study was to find out whether Toothguide Trainer, TT, and Toothguide Training Box, TTB, show any training effects, independent of the shade guide chosen. METHODS: Students from four dental schools (N=78) were included in this study. The participants were randomized into a study, 42 students (age range: 19-27 years; 69% female, 31% male) and a control group of 36 students (age range: 19-30 years; 57% female, 43% male). The study group started with a double blind introduction test, followed by the TT and TTB training, finishing with the final test. The control group only passed the introduction and - after a break - the final test. Eight randomly chosen samples, seven of the Vita classical and one of the 3D-Master colour scale, were marked by barcodes. Colour matching was arranged by the Vita classical scale. RESULTS: The results of the pre- and final tests of both groups were combined. For every sample, the value DeltaE was determined. The summation of all eight samples from the introduction and final tests offered a summarized DeltaE value. The differences between introduction and final tests revealed the individual learning success. 47.6% of the study group showed statistically significant better results than the control group, 33% (p=0.031). CONCLUSION: TT and TTB show a positive effect of training on tooth shade matching independent of the colour scale used. CLINICAL SIGNIFICANCE: Visual shade taking is the most frequent clinical method for shade determination. To increase better results in visual colour matching, TT and TTB training is used. This is the first study examining the training effect of TT and TTB using Vita classical scale. PMID- 24056367 TI - Structural basis and targeting of the interaction between fibroblast growth factor-inducible 14 and tumor necrosis factor-like weak inducer of apoptosis. AB - Deregulation of the TNF-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling pathway is observed in many diseases, including inflammation, autoimmune diseases, and cancer. Activation of Fn14 signaling by TWEAK binding triggers cell invasion and survival and therefore represents an attractive pathway for therapeutic intervention. Based on structural studies of the TWEAK-binding cysteine-rich domain of Fn14, several homology models of TWEAK were built to investigate plausible modes of TWEAK-Fn14 interaction. Two promising models, centered on different anchoring residues of TWEAK (tyrosine 176 and tryptophan 231), were prioritized using a data-driven strategy. Site-directed mutagenesis of TWEAK at Tyr(176), but not Trp(231), resulted in the loss of TWEAK binding to Fn14 substantiating Tyr(176) as the anchoring residue. Importantly, mutation of TWEAK at Tyr(176) did not disrupt TWEAK trimerization but failed to induce Fn14-mediated nuclear factor kappa-light chain enhancer of activated B cell (NF-kappaB) signaling. The validated structural models were utilized in a virtual screen to design a targeted library of small molecules predicted to disrupt the TWEAK-Fn14 interaction. 129 small molecules were screened iteratively, with identification of molecules producing up to 37% inhibition of TWEAK-Fn14 binding. In summary, we present a data-driven in silico study revealing key structural elements of the TWEAK-Fn14 interaction, followed by experimental validation, serving as a guide for the design of small molecule inhibitors of the TWEAK-Fn14 ligand-receptor interaction. Our results validate the TWEAK-Fn14 interaction as a chemically tractable target and provide the foundation for further exploration utilizing chemical biology approaches focusing on validating this system as a therapeutic target in invasive cancers. PMID- 24056368 TI - Mesenchyme-specific knockout of ESET histone methyltransferase causes ectopic hypertrophy and terminal differentiation of articular chondrocytes. AB - The exact molecular mechanisms governing articular chondrocytes remain unknown in skeletal biology. In this study, we have found that ESET (an ERG-associated protein with a SET domain, also called SETDB1) histone methyltransferase is expressed in articular cartilage. To test whether ESET regulates articular chondrocytes, we carried out mesenchyme-specific deletion of the ESET gene in mice. ESET knock-out did not affect generation of articular chondrocytes during embryonic development. Two weeks after birth, there was minimal qualitative difference at the knee joints between wild-type and ESET knock-out animals. At 1 month, ectopic hypertrophy, proliferation, and apoptosis of articular chondrocytes were seen in the articular cartilage of ESET-null animals. At 3 months, additional signs of terminal differentiation such as increased alkaline phosphatase activity and an elevated level of matrix metalloproteinase (MMP)-13 were found in ESET-null cartilage. Staining for type II collagen and proteoglycan revealed that cartilage degeneration became progressively worse from 2 weeks to 12 months at the knee joints of ESET knock-out mutants. Analysis of over 14 pairs of age- and sex-matched wild-type and knock-out mice indicated that the articular chondrocyte phenotype in ESET-null mutants is 100% penetrant. Our results demonstrate that expression of ESET plays an essential role in the maintenance of articular cartilage by preventing articular chondrocytes from terminal differentiation and may have implications in joint diseases such as osteoarthritis. PMID- 24056369 TI - Transforming growth factor-beta3 (TGF-beta3) knock-in ameliorates inflammation due to TGF-beta1 deficiency while promoting glucose tolerance. AB - Three homologues of TGF-beta exist in mammals as follows: TGF-beta1, TGF-beta2, and TGF-beta3. All three proteins share high homology in their amino acid sequence, yet each TGF-beta isoform has unique heterologous motifs that are highly conserved during evolution. Although these TGF-beta proteins share similar properties in vitro, isoform-specific properties have been suggested through in vivo studies and by the unique phenotypes for each TGF-beta knock-out mouse. To test our hypothesis that each of these homologues has nonredundant functions, and to identify such isoform-specific roles, we genetically exchanged the coding sequence of the mature TGF-beta1 ligand with a sequence from TGF-beta3 using targeted recombination to create chimeric TGF-beta1/3 knock-in mice (TGF beta1(Lbeta3/Lbeta3)). In the TGF-beta1(Lbeta3/Lbeta3) mouse, localization and activation still occur through the TGF-beta1 latent associated peptide, but cell signaling is triggered through the TGF-beta3 ligand that binds to TGF-beta receptors. Unlike TGF-beta1(-/-) mice, the TGF-beta1(Lbeta3/Lbeta3) mice show neither embryonic lethality nor signs of multifocal inflammation, demonstrating that knock-in of the TGF-beta3 ligand can prevent the vasculogenesis defects and autoimmunity associated with TGF-beta1 deficiency. However, the TGF beta1(Lbeta3/Lbeta3) mice have a shortened life span and display tooth and bone defects, indicating that the TGF-beta homologues are not completely interchangeable. Remarkably, the TGF-beta1(Lbeta3/Lbeta3) mice display an improved metabolic phenotype with reduced body weight gain and enhanced glucose tolerance by induction of beneficial changes to the white adipose tissue compartment. These findings reveal both redundant and unique nonoverlapping functional diversity in TGF-beta isoform signaling that has relevance to the design of therapeutics aimed at targeting the TGF-beta pathway in human disease. PMID- 24056370 TI - Association of the yeast RNA-binding protein She2p with the tubular endoplasmic reticulum depends on membrane curvature. AB - Localization of mRNAs contributes to the generation and maintenance of cellular asymmetry in a wide range of organisms. In Saccharomyces cerevisiae, the so called locasome complex with its core components Myo4p, She2p, and She3p localizes more than 30 mRNAs to the yeast bud tip. A significant fraction of these mRNAs encodes membrane or secreted proteins. Their localization requires, besides the locasome, a functional segregation apparatus of the cortical endoplasmic reticulum (ER), including the machinery that is involved in the movement of ER tubules into the bud. Colocalization of RNA-containing particles with these tubules suggests a coordinated transport of localized mRNAs and the cortical ER to the bud. Association of localized mRNAs to the ER requires the presence of the locasome component She2p. Here we report that She2p is not only an RNA-binding protein but can specifically bind to ER-derived membranes in a membrane curvature-dependent manner in vitro. Although it does not contain any known curvature recognizing motifs, the protein shows a binding preference for liposomes with a diameter resembling that of yeast ER tubules. In addition, membrane binding depends on tetramerization of She2p. In an in vivo membrane tethering assay, She2p can target a viral peptide GFP fusion protein to the cortical ER, indicating that a fraction of She2p associates with the ER in vivo. Combining RNA- and membrane-binding features makes She2p an ideal coordinator of ER tubule and mRNA cotransport. PMID- 24056372 TI - A regeneratable and highly selective fluorescent probe for sulfide detection in aqueous solution. AB - A novel fluorescent probe based on a coumarin-dipicolylamine-Cu(2+) complex was synthesized and characterized. The probe is able to highly sensitively and selectively sense sulfide over other common anionic analytes including thiols followed by releasing ligand 1 to give a remarkable change of fluorescent intensity in aqueous solution. The probe could be regenerated by the addition of Cu(2+), and therefore the probe could be utilized repetedly to sense sulfide anions with Cu(2+) and S(2-), in turn, increased. The detection limit of the fluorescent assay for sulfide is as low as 14 nM with a rapid response time (a few seconds). Importantly, the displacement mechanism for sensing of sulfide anions was clarified through single-crystal X-ray diffraction analysis and DFT calculations. Based on this probe, a rapid, selective and sensitive fluorescence method for the detection of sulfide anions in environmental samples was established. PMID- 24056373 TI - Sleep problems in children. AB - Sleep complaints and sleep disorders are common during childhood and adolescence. The impact of not getting enough sleep may affect children's' physical health as well emotional, cognitive and social development. Insomnia, sleep-disordered breathing, parasomnias and sleep disturbances associated with medical and psychiatric disorders are some of the commonly encountered sleep disorders in this age group. Changes in sleep architecture and the amount of sleep requirement associated with each stage of development should be considered during an evaluation of sleep disorders in children. Behavioral treatments should be used initially wherever possible especially considering that most pharmacologic agents used to treat pediatric sleep disorders are off-label. In this review we address the most common sleep problems in children/adolescents as they relate to prevalence, presentation and symptoms, evaluation and management. PMID- 24056371 TI - The chemokine receptor CCR1 is constitutively active, which leads to G protein independent, beta-arrestin-mediated internalization. AB - Activation of G protein-coupled receptors by their associated ligands has been extensively studied, and increasing structural information about the molecular mechanisms underlying ligand-dependent receptor activation is beginning to emerge with the recent expansion in GPCR crystal structures. However, some GPCRs are also able to adopt active conformations in the absence of agonist binding that result in the initiation of signal transduction and receptor down-modulation. In this report, we show that the CC-type chemokine receptor 1 (CCR1) exhibits significant constitutive activity leading to a variety of cellular responses. CCR1 expression is sufficient to induce inhibition of cAMP formation, increased F actin content, and basal migration of human and murine leukocytes. The constitutive activity leads to basal phosphorylation of the receptor, recruitment of beta-arrestin-2, and subsequent receptor internalization. CCR1 concurrently engages Galphai and beta-arrestin-2 in a multiprotein complex, which may be accommodated by homo-oligomerization or receptor clustering. The data suggest the presence of two functional states for CCR1; whereas receptor coupled to Galphai functions as a canonical GPCR, albeit with high constitutive activity, the CCR1.beta-arrestin-2 complex is required for G protein-independent constitutive receptor internalization. The pertussis toxin-insensitive uptake of chemokine by the receptor suggests that the CCR1.beta-arrestin-2 complex may be related to a potential scavenging function of the receptor, which may be important for maintenance of chemokine gradients and receptor responsiveness in complex fields of chemokines during inflammation. PMID- 24056374 TI - The actual management of common arrhythmias and other ECG abnormalities in children. AB - Primary cardiac arrhythmias are much less common in infants and children than adults and the symptoms presented may be vague and nonspecific. Though true emergencies due to unstable arrhythmias in children are rare it is critical to identify and appropriately manage these arrhythmias, since when left untreated, arrhythmias may lead to cardiopulmonary compromise and arrest. Most children with a primary arrhythmia present to a pediatrician, cardiologists, or emergency physicians before being referred to a pediatric cardiologist for assessment and management. Thus, the pediatricians, cardiologists, and emergency physicians have to be able to recognize the arrhythmia and in some cases to provide the acute treatment. This article is intended to provide diagnostic and management guidelines of the most common types of arrhythmias seen in children with structurally normal hearts. PMID- 24056375 TI - Hunter syndrome (Mucopolysaccharidosis type II), severe phenotype: long term follow-up on patients undergone to hematopoietic stem cell transplantation. AB - AIM: Our study aim is the evaluation of long-term effects of hematopoietic stem cell transplantation on Italian patients with severe Hunter syndrome. METHODS: Four boys, suffering from Hunter syndrome, severe phenotype, received hematopoietic stem cell transplantation between 2 years 6 months and 2 years 11 months of age, from 1992 to 2001. A complete multidisciplinary evaluation of hematopoietic stem cell transplantation long-term effects was performed periodically. RESULTS: All patients achieved successful engraftment. Urine glycosaminoglycans excretion was reduced or normalized, and the activity of leukocyte iduronate-2-sulphatase enzyme, absent before hematopoietic stem cell transplantation, remained constant, in all patients. Dysostosis multiplex progressed over time, according to the natural evolution of the disease. Joint stiffness improved in all affected districts. Hepatosplenomegaly decreased until it disappeared. The cardiovascular involvement stayed unchanged, as well as hearing loss. Skin became hyperelastical; face features seemed less coarse if compared to the natural evolution of the disease. Cerebral white matter alterations were constant in time. On the contrary, the hematopoietic stem cell transplantation did not prove to have long-term effectiveness on neurological symptoms of Hunter syndrome. CONCLUSION: The hematopoietic stem cell transplantation was successful in slowing the progression of Hunter syndrome, and even the evolution of neurological feature of the disease was slower in the first years after this treatment. PMID- 24056376 TI - Achieving parenteral nutrition goals in the critically ill newborns: standardized better than individualized formulations? AB - AIM: The aim of this paper was to determine if the total parenteral nutrition (PN) goals for newborns in the first two weeks of lifer were better achieved with individualized prescriptions (IND-PN) or standardized formulations STD-PN prescriptions. METHODS: A retrospective study was conducted in a 16-bed polyvalent pediatric and neonatal intensive care unit in a university hospital, to compare two one-year periods, before and after a move from individualized to standardized formulations. All the prescriptions for newborns who were admitted to our unit on their first day of life and required total PN were evaluated. The primary end-point was the percentage of prescriptions full filling the PN goals defined in the written policy of our unit. RESULTS: More than 3500 prescriptions were included. The goals of PN were better achieved with STD-PN (44.0% vs. 9.4% of the prescriptions)., even after adjustment for term and birth weight. Differences between groups appeared as early as the third day of PN and remained during the first 15 days of PN. CONCLUSION: The goals of total PN were better achieved with STD-PN. Perhaps because standardized formulations contain fixed and proportional amounts of nutrients, their use results in less deviation from the established policy. PMID- 24056377 TI - [Palivizumab for respiratory syncytial virus disease]. AB - AIM: Palivizumab (Synagis, Abbott) is a humanized monoclonal antibody of IgG class currently used for prophylaxis of respiratory syncytial virus (RSV) infection. It neutralises the protein F of RSV, which allows the virus to penetrate inside the host cell and subsequently to form syncytia, causing clinical manifestations. Based on that, our aim was to assess if an early administration of palivizumab during RSV infection could positively modify the infection course, hence providing a therapeutic effect. METHODS: The study included eight infants hospitalized with a case history suggestive of severe RSV which made the use of oxygen therapy and, in five cases, mechanical ventilation necessary. The diagnosis was confirmed by the isolation of the virus in the nasopharyngeal aspirate; for all of them informed consent was obtained by the parents. All infants were treated with palivizumab (15 mg/kg i.m. in a single dose). RESULTS: All infants showed a significant clinical improvement and a fast recovery, with a consequent precocious dismissal. After 7 days, 6 infants had a negative nasopharyngeal aspirate. Palivizumab administration at the onset of RSV infection seems to work as a therapy. CONCLUSION: The limited number of the patients does not allow to formulate definitive conclusions but the present study suggests the usefulness of verifying these positive results through randomised controlled studies. PMID- 24056378 TI - [PedsQLTM 4.0 Generic Core Infant Scales Parents Report for infants (ages 13-24 months). Linguistic validation from original US English version to Italian version]. AB - AIM: The purpose of this research was to show the translation and linguistic validation of the PedsQLTM 4.0 Generic Core Infant Scales Parents Report for Infants (ages 13-24 months) from its original English version to Italian language. METHODS: The linguistic validation consists in three steps: a) different forward translations from the original US English instrument to Italian; this step includes the drawing of a "reconciliation" version (version 1); b) backward translations from the Italian reconciliation version to US English; c) patient testing: the second version of the questionnaire (obtained after the backward translations) has to be tested on a panel of a minimum of 5 respondents, throughout cognitive interviewing methodology, in order to obtain the final italian version of the PedsQLTM Parents Report for Infants (ages 13-24 months). In this report we summarize the third step of this process. To study the content validity, the applicability and comprehension of our questionnarie translation, we tested it through a qualitative methodology in a sample of parents whose children were hospitalized in Bambino Gesu Children's Hospital with two different kinds of interview: 4 parents responded to the questions posed through a "thinkaloud interview" and 3 parents responded to the questionnaire and to a "respondent debriefing" interview. RESULTS AND CONCLUSION: We modified the main question of each section and also one of the possible answer in order to maintain the Italian translation that appeared in others PedsQLTM. We did not modify the questions of each section because respondents expressed that are clearly comprehensible and easy to understand. PMID- 24056379 TI - [What new fathers know, think and do: a survey about fathering's attitudes, beliefs and behaviors in a sample of 570 men just after the birth of their newborn]. AB - AIM: The aim of this paper was to know and analyze information, attitudes and behaviors related with transformations occurring in men when they become fathers. METHODS: A self-administered questionnaire has been given out to all men whose newborns were born in the Hospitals located into Borgosesia, Ivrea, Novara, Verbania and Vercelli (Piedmont region in north west of the Italy) in the last quarter of 2006. The questionnaire was created ad hoc and filled out on the day of discharge; results underwent statistical analyses through SPSS system. RESULTS: For the duration of the research, out of 870 men who became fathers in the hospitals were involved in this study, 570 responded voluntarily to the self administered questionnaire (65.6% of the total sample). They showed a lack of information about how to take care of their newborns and the emotional turmoil of women after delivery (58% think children are blind when they are born, 52% think it is better to breastfeed newborns at fixed times and 47% ignore that mothers can enter a depression state). Eighty-eight percent of respondents were in the delivery room to see their child's birth, 56% took a leave from job to stay with mother and child in the hospital and 58% of them report the intention to take an additional 2-3 days leave after coming home from the hospital; 27% had trouble sleeping during pregnancy and are afraid not to be good fathers for their child; 90% believe that their newborn will make them change life habits. Most of the new fathers had difficulties in sharing emotions and feelings related with their status of fathers-to-be with other men. Some of these results are significantly different in older fathers, fathers having their first child and fathers with a lesser level of education. CONCLUSION: During pregnancy and in the first months after their child is born, fathers-to-be and new fathers must be considered a potential target for educational interventions aiming at promoting their parenting information and reinforcing their positive attitudes and beliefs related with their fathering status. PMID- 24056380 TI - [Congenital cytomegalovirus infection: current status and future perspectives]. AB - In recent years, infection with cytomegalovirus (CMV) was the subject of numerous studies, one side being the most frequent congenital infection in newborns and one that determines the increased incidence of sequelae distance (about one third of childhood deafness is due to CMV), and the other one of the most frequent and serious opportunistic infections in immunocompromised individuals. Of newborns with congenital infection, approximately 10% are symptomatic at birth. Of the remaining 90%, asymptomatic at birth, 10-15% will develop sequelae from a distance. Regarding the possibility of vertical transmission of the disease from mother to fetus, the debate is still open on the usefulness or not to set a screening during pregnancy in order to prevent or limit the damage caused fetal infection. Despite detailed knowledge about the epidemiology and pathogenesis of CMV disease in pregnant women, this infection remains largely unknown to most women. The opportunity of a serological screening is important, however, since more than 90% of primary CMV infection in pregnancy are asymptomatic and may remain asymptomatic in the fetus. The education on methods to prevent transmission of CMV, particularly among young women of childbearing age, must continue until an effective vaccine becomes available. In this article we summarize the current concepts regarding the epidemiology, pathogenesis, symptoms and prevention of CMV disease, with particular focus on strategies to improve awareness of the risk of CMV infection in women of childbearing age. PMID- 24056381 TI - A case of acute disseminated encephalomyelitis following influenza virus A-H1N1 infection. AB - We describe a case of acute disseminated encephalomyelitis (ADEM) occurring in a three-year old girl with influenza A (H1N1)v infection and manifesting with seizures and ataxia. The brain MRI revealed bilateral hyperintense signal changes in basal ganglia and brain stem. The patient was treated with intravenous methylprednisolone bolus followed by tapering steroids and progressively recovered without neurologic sequelae at the latest follow-up. ADEM may represent a rare postinfectious complication following novel pandemic influenza A H1N1v which should be taken into account in the differential diagnosis of associated neurologic manifestations for the specific therapeutic approach and adequate follow-up. PMID- 24056382 TI - An adolescent with persistent cervical lymphadenopathy and retropharyngeal abscess: case report. AB - Tuberculosis keeps on representing a serious threat worldwide and one of the major challenge of our century. Different strategies have been developed in order to eradicate the disease, and particular attention is paid to children, who are at great risk for developing severe manifestations and poor outcome. Age at exposure, nutritional conditions and immune status can lead to great variability of disease expressions, with subsequent difficulties in making an appropriate and rapid diagnosis. Moreover, children coming from tuberculosis-endemic areas should be carefully evaluated for M. tuberculosis infection. Here we present a infrequent manifestation of extrapulmonary tuberculosis in a 13-years-old girl coming from Latin America: a superficial persistent cervical lymphadenopathy was associated with a totally asymptomatic retropharyngeal abscess. Diagnostic approach was discussed. Treatment consisted with a combination of surgical drainage of the abscess and a prolonged combined 6-month chemotherapy. The cervical lymphadenopathy disappeared and no relapses were found during the subsequent follow up. PMID- 24056383 TI - Potential health benefits of water yam (Dioscorea alata). AB - Yam is the third most important root and tuber crop in the tropics but few species are grown as health food and/or for medicinal purposes. To ascertain the potential health benefits and alternate usage of the species, 20 varieties of Dioscorea alata (water yam) were investigated for their total dietary fiber (TDF), dry matter and amylose contents as well as selected minerals in comparison with Dioscorea rotundata, the preferred species in yam-growing areas. The TDF content varied widely ranging from 4.10 to 11.00%. The dry matter composition ranged from 19.10 to 33.80% and amylose was from 27.90 to 32.30%. In mg kg(-1), mineral contents of the varieties were from 10.10-17.60 for Zn, 10,550-20,100 for K, 83-131 for Na, 260-535 for Ca, and 390-595 for Mg. The results show significant differences (P > 0.05) among the test varieties in all the parameters determined. Generally, the test varieties had lower dry matter but higher amylose contents. TDF contents of the varieties were higher than that reported for brown rice while two varieties had comparable values to whole wheat flour. Identified varieties with higher amylose and TDF contents could be of use to diabetics and other health conscious individuals due to their slower absorption rates. Moreover, the low sodium but high potassium and TDF contents indicate the possible preventive role that D. alata could play in managing related chronic diseases. This shows the potential use of D. alata as a functional food to supplement the fiber and mineral needs of consumers. Thus, there is a need to exploit its use in food fortifications and formulations. PMID- 24056384 TI - Identification of adenine nucleotide translocase 4 inhibitors by molecular docking. AB - The protein adenine nucleotide translocase (ANT) is localized in the mitochondrial inner membrane and plays an essential role in transporting ADP into the mitochondrial matrix and ATP out from the matrix for cell utilization. In mammals there are four paralogous ANT genes, of which ANT4 is exclusively expressed in meiotic germ cells. Since ANT4 has been shown essential for spermatogenesis and male fertility in mice, inhibition of ANT4 appears to be a reasonable target for male contraceptive development. Further, in contrast to ANT1, ANT2 and ANT3 that are highly homologous to each other, ANT4 has a distinguishable amino acid sequence, which serves as a basis to develop a selective ANT4 inhibitor. In this study, we aimed to identify candidate compounds that can selectively inhibit ANT4 activity over the other ANTs. We used a structure-based method in which ANT4 was modeled then utilized as the basis for selection of compounds that interact with sites unique to ANT4. A large chemical library (>100,000 small molecules) was screened by molecular docking and effects of these compounds on ADP/ATP exchange through ANT4 were examined using yeast mitochondria expressing human ANT4. Through this, we identified one particular candidate compound, [2,2'-methanediylbis(4-nitrophenol)], which inhibits ANT4 activity with a lower IC50 than the other ANTs (5.8 MUM, 4.1 MUM, 5.1 MUM and 1.4 MUM for ANT1, 2, 3 and 4, respectively). This newly identified active lead compound and its chemical structure are expected to provide new opportunities to optimize selective ANT4 inhibitors for contraceptive purposes. PMID- 24056385 TI - Clinical evaluation of reducing acquisition time on single-photon emission computed tomography image quality using proprietary resolution recovery software. AB - INTRODUCTION: A three-dimensional model-based resolution recovery (RR) reconstruction algorithm that compensates for collimator-detector response, resulting in an improvement in reconstructed spatial resolution and signal-to noise ratio of single-photon emission computed tomography (SPECT) images, was tested. The software is said to retain image quality even with reduced acquisition time. Clinically, any improvement in patient throughput without loss of quality is to be welcomed. Furthermore, future restrictions in radiotracer supplies may add value to this type of data analysis. AIM: The aims of this study were to assess improvement in image quality using the software and to evaluate the potential of performing reduced time acquisitions for bone and parathyroid SPECT applications. MATERIALS AND METHODS: Data acquisition was performed using the local standard SPECT/CT protocols for 99mTc-hydroxymethylene diphosphonate bone and 99mTc-methoxyisobutylisonitrile parathyroid SPECT imaging. The principal modification applied was the acquisition of an eight-frame gated data set acquired using an ECG simulator with a fixed signal as the trigger. This had the effect of partitioning the data such that the effect of reduced time acquisitions could be assessed without conferring additional scanning time on the patient. The set of summed data sets was then independently reconstructed using the RR software to permit a blinded assessment of the effect of acquired counts upon reconstructed image quality as adjudged by three experienced observers. Data sets reconstructed with the RR software were compared with the local standard processing protocols; filtered back-projection and ordered-subset expectation maximization. RESULTS: Thirty SPECT studies were assessed (20 bone and 10 parathyroid). The images reconstructed with the RR algorithm showed improved image quality for both full-time and half-time acquisitions over local current processing protocols (P<0.05). CONCLUSION: The RR algorithm improved image quality compared with local processing protocols and has been introduced into routine clinical use. SPECT acquisitions are now acquired at half of the time previously required. The method of binning the data can be applied to any other camera system to evaluate the reduction in acquisition time for similar processes. The potential for dose reduction is also inherent with this approach. PMID- 24056387 TI - An iridium(III)-based lab-on-a-molecule for cysteine/homocysteine and tryptophan using triple-channel interrogation. AB - Iridium complex is a lab-on-a-molecule for recognising and quantifying cysteine/homocysteine and tryptophan in a mixture of all proteinogenic amino acids. UV-Vis and photoluminescence channels are suitable for quantification of homocysteine and cysteine in aqueous media, e.g. by emission enhancement at 606 nm, while tryptophan was selectively quantified in the electrochemiluminescence channel. PMID- 24056388 TI - Recent developments in the synthetic chemistry of technetium disulfide. AB - Technetium disulfide was prepared by reaction between the elements in a sealed tube at 450 degrees C, by reaction between Tc2(O2CCH3)5 and H2S gas in a flowing system at 450 degrees C and by reaction between K2TcCl6 and H2S gas in sulfuric acid. The samples were analysed by X-ray absorption fine structure (XAFS) spectroscopy. PMID- 24056389 TI - Does untreated post-cardiac-arrest fever counteract the benefit of therapeutic hypothermia? PMID- 24056390 TI - CREWS: improving specificity whilst maintaining sensitivity of the National Early Warning Score in patients with chronic hypoxaemia. AB - BACKGROUND: The National Early Warning Score (NEWS) is being introduced across the UK, but there are concerns about its specificity in patients with chronic hypoxaemia, such as some patients with COPD. This could lead to frequent clinically insignificant triggers and alarm fatigue. AIMS OF STUDY: To investigate whether patients with chronic hypoxaemia trigger excessively with NEWS, and to design a simple variant of NEWS for patients with chronic hypoxaemia: a Chronic Respiratory Early Warning Score (CREWS). METHODS: Data was collected from respiratory wards at two hospitals in North Wales. Components of NEWS and frequency of trigger thresholds being reached were recorded. CREWS was applied retrospectively to patients' observations. RESULTS: 196 admissions were analysed, including 78 for patients with chronic hypoxaemia. Patients with chronic hypoxaemia frequently exceeded trigger thresholds using NEWS during periods of stability/at discharge. Using CREWS, triggers during stability/at discharge were reduced from 32% of observations to 14% using a trigger threshold of a score greater than 6, and from 50% to 18% using a score greater than 5. All patients with chronic hypoxaemia who died within 30 days still reached CREWS trigger thresholds, and the area under receiver operated curves for NEWS and CREWS was comparable. CONCLUSION: CREWS is a simple variant of NEWS for patients with chronic hypoxaemia that could reduce clinically insignificant triggers and alarm fatigue, whilst still identifying the sickest patients. PMID- 24056391 TI - Use of an electronic decision support tool improves management of simulated in hospital cardiac arrest. AB - INTRODUCTION: Adherence to advanced cardiac life support (ACLS) guidelines during in-hospital cardiac arrest (IHCA) is associated with improved outcomes, but current evidence shows that sub-optimal care is common. Successful execution of such protocols during IHCA requires rapid patient assessment and the performance of a number of ordered, time-sensitive interventions. Accordingly, we sought to determine whether the use of an electronic decision support tool (DST) improves performance during high-fidelity simulations of IHCA. METHODS: After IRB approval and written informed consent was obtained, 47 senior medical students were enrolled. All participants were ACLS certified and within one month of graduation. Each participant was issued an iPod Touch device with a DST installed that contained all ACLS management algorithms. Participants managed two scenarios of IHCA and were allowed to use the DST in one scenario and prohibited from using it in the other. All participants managed the same scenarios. Simulation sessions were video recorded and graded by trained raters according to previously validated checklists. RESULTS: Performance of correct protocol steps was significantly greater with the DST than without (84.7% v 73.8%, p<0.001) and participants committed significantly fewer additional errors when using the DST (2.5 errors vs. 3.8 errors, p<0.012). CONCLUSION: Use of an electronic DST provided a significant improvement in the management of simulated IHCA by senior medical students as measured by adherence to published guidelines. PMID- 24056392 TI - Survival of resuscitated cardiac arrest patients with ST-elevation myocardial infarction (STEMI) conveyed directly to a Heart Attack Centre by ambulance clinicians. AB - OBJECTIVE: This study reports survival outcomes for patients resuscitated from out-of-hospital cardiac arrest (OHCA) subsequent to ST-elevation myocardial infarction (STEMI), and who were conveyed directly by ambulance clinicians to a specialist Heart Attack Centre for expert cardiology assessment, angiography and possible percutaneous coronary intervention (PCI). METHODS: This is a retrospective descriptive review of data sourced from the London Ambulance Service's OHCA registry over a one-year period. RESULTS: We observed excellent survival rates for our cohort of patients with 66% of patients surviving to be discharged from hospital, the majority of whom were still alive after one year. Those who survived tended to be younger, to have had a witnessed arrest in a public place with an initial cardiac rhythm of VF/VT, and to have been transported to the specialist centre more quickly than those who did not. CONCLUSION: A system allowing ambulance clinicians to autonomously convey OHCA STEMI patients who achieve a return of spontaneous circulation directly to a Heart Attack Centre is highly effective and yields excellent survival outcomes. PMID- 24056393 TI - Reply to letter: Continuous neuromuscular blockade is associated with decreased mortality in post-cardiac arrest patients--problems with the data. PMID- 24056395 TI - Continuous neuromuscular blockade is associated with decreased mortality in post cardiac arrest patients. PMID- 24056394 TI - Effect of prehospital ultrasound on clinical outcomes of non-trauma patients--a systematic review. AB - BACKGROUND: Advances in technology have made prehospital ultrasound (US) examination available. Whether US in the prehospital setting can lead to improvement in clinical outcomes is yet unclear. OBJECTIVE: The aim of this systematic review was to assess whether prehospital US improves clinical outcomes for non-trauma patients. METHOD: We conducted a systematic review on non-trauma patients who had an US examination performed in the prehospital setting. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the ISI Web of Science and the references of the included studies for additional relevant studies. We then performed a risk of bias analysis and descriptive data analysis. RESULTS: We identified 1707 unique citations and included ten studies with a total of 1068 patients undergoing prehospital US examination. Included publications ranged from case series to non-randomized, descriptive studies, and all showed a high risk of bias. The large heterogeneity between the different studies made further statistical analysis impossible. CONCLUSION: There are currently no randomized, controlled studies on the use of US for non-trauma patients in the prehospital setting. The included studies were of large heterogeneity and all showed a high risk of bias. We were thus unable to assess the effect of prehospital US on clinical outcomes. However, consistent reports suggested that US may improve patient management with respect to diagnosis, treatment, and hospital referral. PMID- 24056396 TI - Basic life support (BLS): knowledge, personal experiences, and willingness to provide BLS, among music festivals participants--a questionnaire study. PMID- 24056398 TI - Learning not to lean when you push ... some hard-pressed issues of cardiac compressions during cardiopulmonary resuscitation of neonates. PMID- 24056397 TI - Bystander-initiated CPR in an Asian metropolitan: does the socioeconomic status matter? AB - OBJECTIVES: To determine the association of neighborhood socioeconomic status (SES) with bystander-initiated cardiopulmonary resuscitation (CPR) and patient outcomes of out of hospital cardiac arrests (OHCAs) in an Asian metropolitan area. METHODS: We performed a retrospective study in a prospectively collected cohort from the Utstein registry of adult non-traumatic OHCAs in Taipei, Taiwan. Average real estate value was assessed as the first proxy of SES. Twelve administrative districts in Taipei City were categorized into low versus high SES areas to test the association. The primary outcome was bystander-initiated CPR, and the secondary outcome was patient survival status. Factors associated with bystander-initiated CPR were adjusted for in multivariate analysis. The mean household income was assessed as the second proxy of SES to validate the association. RESULTS: From January 1, 2008 to December 30, 2009, 3573 OHCAs received prehospital resuscitation in the community. Among these, 617 (17.3%) cases received bystander CPR. The proportion of bystander CPR in low-SES vs. high SES areas was 14.5% vs. 19.6% (p<0.01). Odds ratio of receiving bystander initiated CPR in low-SES areas was 0.72 (95% confidence interval: [0.60-0.88]) after adjusting for age, gender, witnessed status, public collapse, and OHCA unrecognized by the online dispatcher. Survival to discharge rate was significantly lower in low-SES areas vs. high-SES areas (4.3% vs. 6.8%; p<0.01). All results above remained consistent in the analyses by mean household income. CONCLUSIONS: Patients who experienced an OHCA in low-SES areas were less likely to receive bystander-initiated CPR, and demonstrated worse survival outcomes. PMID- 24056399 TI - A conserved motif flags acyl carrier proteins for beta-branching in polyketide synthesis. AB - Type I polyketide synthases often use programmed beta-branching, via enzymes of a 'hydroxymethylglutaryl-CoA synthase (HCS) cassette', to incorporate various side chains at the second carbon from the terminal carboxylic acid of growing polyketide backbones. We identified a strong sequence motif in acyl carrier proteins (ACPs) where beta-branching is known to occur. Substituting ACPs confirmed a correlation of ACP type with beta-branching specificity. Although these ACPs often occur in tandem, NMR analysis of tandem beta-branching ACPs indicated no ACP-ACP synergistic effects and revealed that the conserved sequence motif forms an internal core rather than an exposed patch. Modeling and mutagenesis identified ACP helix III as a probable anchor point of the ACP-HCS complex whose position is determined by the core. Mutating the core affects ACP functionality, whereas ACP-HCS interface substitutions modulate system specificity. Our method for predicting beta-carbon branching expands the potential for engineering new polyketides and lays a basis for determining specificity rules. PMID- 24056401 TI - Active hemorrhage and vascular injuries in splenic trauma: utility of the arterial phase in multidetector CT. AB - PURPOSE: To determine whether the addition of arterial phase computed tomography (CT) to the standard combination of portal venous and delayed phase imaging increases sensitivity in the diagnosis of active hemorrhage and/or contained vascular injuries in patients with splenic trauma. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant retrospective study; the requirement to obtain informed consent was waived. The study included all patients aged 15 years and older who sustained a splenic injury from blunt or penetrating trauma and who underwent CT in the arterial and portal venous phases of image acquisition during a 74-month period (September 2005 to November 2011). CT scans were reviewed by three radiologists, and a consensus interpretation was made to classify the splenic injuries according to the American Association for the Surgery of Trauma splenic injury scale. One radiologist independently recorded the presence of contained vascular injuries or active hemorrhage and the phase or phases at which these lesions were seen. Clinical outcome was assessed by reviewing medical records. The relationship between imaging findings and clinical management was assessed with the Fisher exact test. RESULTS: One hundred forty-seven patients met the inclusion criteria; 32 patients (22%) had active hemorrhage and 22 (15%) had several contained vascular injuries. In 13 of the 22 patients with contained injuries, the vascular lesion was visualized only at the arterial phase of image acquisition; the other nine contained vascular injuries were seen at all phases. Surgery or embolization was performed in 11 of the 22 patients with contained vascular injury. CONCLUSION: The arterial phase of image acquisition improves detection of traumatic contained splenic vascular injuries and should be considered to optimize detection of splenic injuries in trauma with CT. PMID- 24056400 TI - A propofol binding site on mammalian GABAA receptors identified by photolabeling. AB - Propofol is the most important intravenous general anesthetic in current clinical use. It acts by potentiating GABAA (gamma-aminobutyric acid type A) receptors, but where it binds to this receptor is not known and has been a matter of some debate. We synthesized a new propofol analog photolabeling reagent whose biological activity is very similar to that of propofol. We confirmed that this reagent labeled known propofol binding sites in human serum albumin that have been identified using X-ray crystallography. Using a combination of protiated and deuterated versions of the reagent to label mammalian receptors in intact membranes, we identified a new binding site for propofol in GABAA receptors consisting of both beta3 homopentamers and alpha1beta3 heteropentamers. The binding site is located within the beta subunit at the interface between the transmembrane domains and the extracellular domain and lies close to known determinants of anesthetic sensitivity in the transmembrane segments TM1 and TM2. PMID- 24056402 TI - Neuroendocrine tumor recurrence: diagnosis with 68Ga-DOTATATE PET/CT. AB - PURPOSE: To evaluate diagnostic performance of gallium 68-tetraazacyclododecane tetraacetic acid-octreotate ((68)Ga-DOTATATE) in detection of recurrent neuroendocrine tumors (NETs). MATERIALS AND METHODS: Approval was waived by the local ethics committee for this retrospective study. Between 2007 and 2011, 63 patients (mean age, 58 years) were examined with (68)Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) after primary NET curative resection. Reasons for PET/CT were regular follow-up examinations (n = 30), increased plasma levels of tumor markers (n = 27), or clinical suspicion of recurrence (n = 6). Final diagnosis was determined with histopathologic verification (n = 25) or clinical follow-up (n = 38). PET/CT scans were evaluated in consensus by two readers without blinding to clinical information and independently by two readers with blinding. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Final diagnosis of NET recurrence was determined in 29 patients. In three other patients, tumors of nonneuroendocrine origin were diagnosed. (68)Ga DOTATATE PET/CT helped identify NET recurrence in 26 of 29 patients (sensitivity, 90%) and exclude presence of recurrent NET in 28 of 34 patients (specificity, 82% ). PET/CT provided false-positive and false-negative results in six and three patients (PPV, 81% [26 of 32]; NPV, 90% [28 of 31]; accuracy, 86% [54 of 63]). In gastroenteropancreatic NET (n = 45), sensitivity was 94% (17 of 18); specificity was 89% (24 of 27); PPV was 85% (17 of 20); NPV was 96% (24 of 25); and accuracy was 91% (41 of 45). Two blinded readers achieved sensitivity of 79% (23 of 29) and 76% (22 of 29); specificity of 85% (29 of 34) and 94% (32 of 34) (kappa = 0.80); and accuracy of 83% and 86%. CONCLUSION: (68)Ga-DOTATATE PET/CT is accurate in detection of recurrent NET. Blinded PET/CT review markedly decreased sensitivity, underlining importance of considering clinical parameters in NET recurrence. Present results must be further validated to substantiate use of (68)Ga-DOTATATE PET/CT in routine follow-up after curative resection of NET. PMID- 24056404 TI - Illuminating radiogenomic characteristics of glioblastoma multiforme through integration of MR imaging, messenger RNA expression, and DNA copy number variation. AB - PURPOSE: To perform a multilevel radiogenomics study to elucidate the glioblastoma multiforme (GBM) magnetic resonance (MR) imaging radiogenomic signatures resulting from changes in messenger RNA (mRNA) expression and DNA copy number variation (CNV). MATERIALS AND METHODS: Radiogenomic analysis was performed at MR imaging in 23 patients with GBM in this retrospective institutional review board-approved HIPAA-compliant study. Six MR imaging features-contrast enhancement, necrosis, contrast-to-necrosis ratio, infiltrative versus edematous T2 abnormality, mass effect, and subventricular zone (SVZ) involvement-were independently evaluated and correlated with matched genomic profiles (global mRNA expression and DNA copy number profiles) in a significant manner that also accounted for multiple hypothesis testing by using gene set enrichment analysis (GSEA), resampling statistics, and analysis of variance to gain further insight into the radiogenomic signatures in patients with GBM. RESULTS: GSEA was used to identify various oncogenic pathways with MR imaging features. Correlations between 34 gene loci were identified that showed concordant variations in gene dose and mRNA expression, resulting in an MR imaging, mRNA, and CNV radiogenomic association map for GBM. A few of the identified gene-to-trait associations include association of the contrast-to necrosis ratio with KLK3 and RUNX3; association of SVZ involvement with Ras oncogene family members, such as RAP2A, and the metabolic enzyme TYMS; and association of vasogenic edema with the oncogene FOXP1 and PIK3IP1, which is a member of the PI3K signaling network. CONCLUSION: Construction of an MR imaging, mRNA, and CNV radiogenomic association map has led to identification of MR traits that are associated with some known high-grade glioma biomarkers and association with genomic biomarkers that have been identified for other malignancies but not GBM. Thus, the traits and genes identified on this map highlight new candidate radiogenomic biomarkers for further evaluation in future studies. PMID- 24056403 TI - Neural networks for nodal staging of non-small cell lung cancer with FDG PET and CT: importance of combining uptake values and sizes of nodes and primary tumor. AB - PURPOSE: To evaluate the effect of adding lymph node size to three previously explored artificial neural network (ANN) input parameters (primary tumor maximum standardized uptake value or tumor uptake, tumor size, and nodal uptake at N1, N2, and N3 stations) in the structure of the ANN. The goal was to allow the resulting ANN structure to relate lymph node uptake for size to primary tumor uptake for size in the determination of the status of nodes as human readers do. MATERIALS AND METHODS: This prospective study was approved by the institutional review board, and informed consent was obtained from all participants. The authors developed a back-propagation ANN with one hidden layer and eight processing units. The data set used to train the network included node and tumor size and uptake from 133 patients with non-small cell lung cancer with surgically proved N status. Statistical analysis was performed with the paired t test. RESULTS: The ANN correctly predicted the N stage in 99.2% of cases, compared with 72.4% for the expert reader (P < .001). In categorization of N0 and N1 versus N2 and N3 disease, the ANN performed with 99.2% accuracy versus 92.2% for the expert reader (P < .001). CONCLUSION: The ANN is 99.2% accurate in predicting surgical pathologic nodal status with use of four fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)-derived parameters. Malignant and benign inflammatory lymph nodes have overlapping appearances at FDG PET/CT but can be differentiated by ANNs when the crucial input of node size is used. PMID- 24056405 TI - Quantification of the respiratory burst response as an indicator of innate immune health in zebrafish. AB - The phagocyte respiratory burst is part of the innate immune response to pathogen infection and involves the production of reactive oxygen species (ROS). ROS are toxic and function to kill phagocytized microorganisms. In vivo quantification of phagocyte-derived ROS provides information regarding an organism's ability to mount a robust innate immune response. Here we describe a protocol to quantify and compare ROS in whole zebrafish embryos upon chemical induction of the phagocyte respiratory burst. This method makes use of a non-fluorescent compound that becomes fluorescent upon oxidation by ROS. Individual zebrafish embryos are pipetted into the wells of a microplate and incubated in this fluorogenic substrate with or without a chemical inducer of the respiratory burst. Fluorescence in each well is quantified at desired time points using a microplate reader. Fluorescence readings are adjusted to eliminate background fluorescence and then compared using an unpaired t-test. This method allows for comparison of the respiratory burst potential of zebrafish embryos at different developmental stages and in response to experimental manipulations such as protein knockdown, overexpression, or treatment with pharmacological agents. This method can also be used to monitor the respiratory burst response in whole dissected kidneys or cell preparations from kidneys of adult zebrafish and some other fish species. We believe that the relative simplicity and adaptability of this protocol will complement existing protocols and will be of interest to researchers who seek to better understand the innate immune response. PMID- 24056406 TI - The application of high-pressure treatment in the reduction of phosphate levels in breakfast sausages. AB - This study investigated effects of high pressure (HP) treatment of pork meat at 150 or 300 MPa for 5 min before manufacturing sausages on the reduction of phosphate levels and compared to sausages manufactured with untreated pork meat (control sausages). Improvement in perceived saltiness, juiciness and overall flavour was observed in sausages manufactured using HP-treated meat at 150 MPa and 0% phosphate, compared to control sausages. Sausages manufactured using meat HP-treated at 150 MPa and 0.25% phosphate (P<0.05) improved hardness of sausages. HP-treated meat at 300 MPa and 0% phosphate decreased juiciness and adhesiveness, while at 0.25% phosphate, adversely affected emulsion stability and sensory attributes. HP treatment did not affect significantly the lightness of the sausages; however, elimination of phosphate reduced (P<0.05) the yellowness, while HP treatment at 150 MPa with 0.25 or 0.5% phosphate increased (P<0.05) redness. HP reatment at 150 MPa has potential for reducing phosphate levels in sausages without significant changes in their functionality and improved acceptability. PMID- 24056407 TI - Effect of suspension method and aging time on meat quality of Chinese fattened cattle M. Longissimus dorsi. AB - Objectives of the present study were to evaluate the effects of suspension method and aging time on quality traits of Chinese fattened cattle M. Longissimus dorsi (LD). At the end of the slaughter line, the right sides of carcasses were re-hung from the pelvic bone obturator foramen, while the left sides remained hung by Achilles tendon suspension (AS). LD muscles were aged for 1, 7, 14 and 21 days and were then evaluated for quality index. Pelvic suspension (PS) significantly decreased the WBSF of beef muscle at 1 d and 7 d postmortem compared with AS. The tenderness with PS at 7 d postmortem was similar with that of AS at 14 d. Moreover, PS increased sarcomere length and decreased purge loss of LD significantly. In addition, aging time had a significant effect on pH, meat color, Warner-Bratzler shear force, and myofibril fragmentation index of LD muscle. To conclude, PS is valuable to be introduced to the beef industry in China for rapid (within 7 days) improvement of beef tenderness and decreased aging time of Chinese fattened cattle. PMID- 24056408 TI - Isolation and culture of neonatal mouse cardiomyocytes. AB - Cultured neonatal cardiomyocytes have long been used to study myofibrillogenesis and myofibrillar functions. Cultured cardiomyocytes allow for easy investigation and manipulation of biochemical pathways, and their effect on the biomechanical properties of spontaneously beating cardiomyocytes. The following 2-day protocol describes the isolation and culture of neonatal mouse cardiomyocytes. We show how to easily dissect hearts from neonates, dissociate the cardiac tissue and enrich cardiomyocytes from the cardiac cell-population. We discuss the usage of different enzyme mixes for cell-dissociation, and their effects on cell viability. The isolated cardiomyocytes can be subsequently used for a variety of morphological, electrophysiological, biochemical, cell-biological or biomechanical assays. We optimized the protocol for robustness and reproducibility, by using only commercially available solutions and enzyme mixes that show little lot-to-lot variability. We also address common problems associated with the isolation and culture of cardiomyocytes, and offer a variety of options for the optimization of isolation and culture conditions. PMID- 24056409 TI - Oligonucleotide-linked gold nanoparticle aggregates for enhanced sensitivity in lateral flow assays. AB - Lateral flow assays (LFAs) as rapid analytical techniques promise to be widely used in point-of-care (POC) diagnostics because of their affordability and simplicity. However, LFAs still suffer from low sensitivity in detection of various biomarkers, e.g., nucleic acids. In this study, we developed a simple and general one-step signal amplification strategy, which employed oligonucleotide linked gold nanoparticle (AuNP) aggregates to enhance the sensitivity in nucleic acid lateral flow (NALF) assays. Using a nucleic acid sequence of human immunodeficiency virus type 1 (HIV-1) as a model analyte, we observed that the detection limit of the developed NALF assay was 0.1 nM, which was improved by 2.5 fold compared with that of a non-signal amplification approach. The methodology described here could be used to detect a broad range of nucleic acids, and the general signal amplification approach could be potentially adopted in other types of LFAs. PMID- 24056410 TI - Blood anticoagulation and antiplatelet activity of green tea (-)-epigallocatechin (EGC) in mice. AB - EGC was prepared from green tea polyphenols through column chromatography of a polyamide (3.6 * 40 cm). Three dosages of EGC (0.25, 0.5, 1.0 g kg(-1) d(-1)) were ingested respectively by ICR mice via gavage. Compared with the control group, group EGC0.5 (dosage, 0. 5 g kg(-1) d(-1)) and group EGC1.0 (dosage, 1.0 g kg(-1) d(-1)) presented significant inhibition on platelet aggregation in mice accompanied by 18.4 and 25.6% of inhibition ratio, respectively. The bleeding times (BT) of mice in group EGC0.5 and group EGC1.0 were significantly prolonged (P < 0.01) as well as blood clotting time (BCT) in group EGC1.0 (P < 0.05). All three dosages of EGC prolonged activated partial thromboplastin time (APTT) significantly (P < 0.01), but had no prominent effect on prothrombin time (PT) and fibrinogen level which indicated that the anticoagulation of EGC could not be attributed to the level decrease of coagulation factor such as fibrinogen. The results demonstrated that EGC had prominent antiplatelet activity and blood anticoagulation in a dose-dependent manner. PMID- 24056411 TI - Integration of new genes into cellular networks, and their structural maturation. AB - It has been recently discovered that new genes can originate de novo from noncoding DNA, and several biological traits including expression or sequence composition form a continuum from noncoding sequences to conserved genes. In this article, using yeast genes I test whether the integration of new genes into cellular networks and their structural maturation shows such a continuum by analyzing their changes with gene age. I show that 1) The number of regulatory, protein-protein, and genetic interactions increases continuously with gene age, although with very different rates. New regulatory interactions emerge rapidly within a few million years, while the number of protein-protein and genetic interactions increases slowly, with a rate of 2-2.25 * 10(-8)/year and 4.8 * 10( 8)/year, respectively. 2) Gene essentiality evolves relatively quickly: the youngest essential genes appear in proto-genes ~14 MY old. 3) In contrast to interactions, the secondary structure of proteins and their robustness to mutations indicate that new genes face a bottleneck in their evolution: proto genes are characterized by high beta-strand content, high aggregation propensity, and low robustness against mutations, while conserved genes are characterized by lower strand content and higher stability, most likely due to the higher probability of gene loss among young genes and accumulation of neutral mutations. PMID- 24056412 TI - A novel intronic single nucleotide polymorphism in the myosin heavy polypeptide 4 gene is responsible for the mini-muscle phenotype characterized by major reduction in hind-limb muscle mass in mice. AB - Replicated artificial selection for high levels of voluntary wheel running in an outbred strain of mice favored an autosomal recessive allele whose primary phenotypic effect is a 50% reduction in hind-limb muscle mass. Within the High Runner (HR) lines of mice, the numerous pleiotropic effects (e.g., larger hearts, reduced total body mass and fat mass, longer hind-limb bones) of this hypothesized adaptive allele include functional characteristics that facilitate high levels of voluntary wheel running (e.g., doubling of mass-specific muscle aerobic capacity, increased fatigue resistance of isolated muscles, longer hind limb bones). Previously, we created a backcross population suitable for mapping the responsible locus. We phenotypically characterized the population and mapped the Minimsc locus to a 2.6-Mb interval on MMU11, a region containing ~100 known or predicted genes. Here, we present a novel strategy to identify the genetic variant causing the mini-muscle phenotype. Using high-density genotyping and whole-genome sequencing of key backcross individuals and HR mice with and without the mini-muscle mutation, from both recent and historical generations of the HR lines, we show that a SNP representing a C-to-T transition located in a 709-bp intron between exons 11 and 12 of the Myosin heavy polypeptide 4 (Myh4) skeletal muscle gene (position 67,244,850 on MMU11; assembly, December 2011, GRCm38/mm10; ENSMUSG00000057003) is responsible for the mini-muscle phenotype, Myh4(Minimsc). Using next-generation sequencing, our approach can be extended to identify causative mutations arising in mouse inbred lines and thus offers a great avenue to overcome one of the most challenging steps in quantitative genetics. PMID- 24056414 TI - Designed synthesis of transition metal/oxide hierarchical peapods array with the superior lithium storage performance. AB - In this report, a novel hierarchical peapoded array with Co3O4 nanoparticles encapsulated in graphitized carbon fiber is introduced for the first time. The unique peapoded structure is suitable for the excellent anode in LIBs and demonstrates enhanced rate capability, cyclability and prolonged lifespan, e.g. the specific capacity can reach up to 1150 mAh/g. All the enhanced electrochemical performance is reasonably derived from the peapod-like and aligned conformation. Furthermore, due to the specialty of the structure and the versatility of Co3O4, the composite will find more applications in specific catalysis, biomedicine, electronics, optoelectronic engineering and gas sensing. The fabrication strategy developed here is also a rational and universal approach towards peapod-like architecture and has significantly widened the specific functional material domain we created before. In our design, more peapod-like aligned samples with various nanoparticles, e.g. oxides, phosphides, even nitrides, encapsulated in graphitized carbon fibers, have been lifted on the research agenda and the results will be presented soon. PMID- 24056413 TI - Deubiquitinating enzyme Usp12 is a novel co-activator of the androgen receptor. AB - The androgen receptor (AR), a member of the nuclear receptor family, is a transcription factor involved in prostate cell growth, homeostasis, and transformation. AR is a key protein in growth and development of both normal and malignant prostate, making it a common therapeutic target in prostate cancer. AR is regulated by an interplay of multiple post-translational modifications including ubiquitination. We and others have shown that the AR is ubiquitinated by a number of E3 ubiquitin ligases, including MDM2, CHIP, and NEDD4, which can result in its proteosomal degradation or enhanced transcriptional activity. As ubiquitination of AR causes a change in AR activity or stability and impacts both survival and growth of prostate cancer cells, deubiquitination of these sites has an equally important role. Hence, deubiquitinating enzymes could offer novel therapeutic targets. We performed an siRNA screen to identify deubiquitinating enzymes that regulate AR; in that screen ubiquitin-specific protease 12 (Usp12) was identified as a novel positive regulator of AR. Usp12 is a poorly characterized protein with few known functions and requires the interaction with two cofactors, Uaf-1 and WDR20, for its enzymatic activity. In this report we demonstrate that Usp12, in complex with Uaf-1 and WDR20, deubiquitinates the AR to enhance receptor stability and transcriptional activity. Our data show that Usp12 acts in a pro-proliferative manner by stabilizing AR and enhancing its cellular function. PMID- 24056415 TI - Modelling and monitoring of integrated urban wastewater systems: review on status and perspectives. AB - While the general principles and modelling approaches for integrated management/modelling of urban water systems already present a decade ago still hold, in recent years aspects like model interfacing and wastewater treatment plant (WWTP) influent generation as complements to sewer modelling have been investigated and several new or improved systems analysis methods have become available. New/improved software tools coupled with the current high computational capacity have enabled the application of integrated modelling to several practical cases, and advancements in monitoring water quantity and quality have been substantial and now allow the collecting of data in sufficient quality and quantity to permit using integrated models for real-time applications too. Further developments are warranted in the field of data quality assurance and efficient maintenance. PMID- 24056416 TI - Combining adsorption with anodic oxidation as an innovative technique for removal and destruction of organics. AB - Coupling of adsorption with electrochemical oxidation is a novel approach to the treatment of aqueous organics that has demonstrated a number of key benefits over the individual application of these processes. This is based on a highly conducting adsorbent material, developed under the trade name NyexTM, that is able to rapidly adsorb the organics and anodically oxidise them within a single treatment unit. Successful scale up of the process (in both continuous and batch operation) has been achieved for the polishing of two separate groundwaters (one containing relatively simple petrol, diesel and their degradation products and the other with a range of more complex organics). Treatment showed that low discharge consents can be achieved, including the removal of more complex and difficult to treat compounds to below the limits of detection. Energy consumption for electrochemical regeneration was relatively low (down to 0.5 kWh/m(3)) suggesting that the process could be a practical alternative approach for effluent polishing. PMID- 24056417 TI - Multistage treatment wetland for treatment of reject waters from digested sludge dewatering. AB - The paper presents the influence of sewage composition on treatment in pilot scale facility for reject waters (RW) from sewage sludge centrifugation. The facility consisted of mechanical (two tanks with 10 d retention each) and biological parts composed of three subsurface flow reed beds working in batch. Two years of monitoring of the facility proved high efficiency removal of predominant pollutants: chemical oxygen demand (COD) 75-80%, biochemical oxygen demand (BOD) 82.2-95.5% and total nitrogen 78.7-93.9% for low ratio of BOD5/COD in discharged RW. The differences in efficiency removal were correlated with the composition of organics and nitrogen compounds rather than with concentrations. It was assumed that high concentration of colloidal fraction of Org-N and COD in discharged RW led to a decrease in efficiency removal. PMID- 24056418 TI - Spatiotemporal variation of surface water quality for decades: a case study of Huai River System, China. AB - Characterization of spatiotemporal variation of water quality is a basic environmental issue with implications for public health in China. Trends in the temporal and spatial distribution of water quality in the Huai River System (HRS) were analyzed using yearly surface water quality data collected from 1982 to 2009. Results showed that the water quality of the main stream deteriorated in the 1990s and early 2000s but has been ameliorated since 2005. The sections that were classified as severely polluted from the monitoring data were located largely in the middle reach. The water quality of HRS fluctuated during the period 1997-2009; it has improved and stabilized since 2005. In terms of spatialized frequency of serious pollution, heavily polluted regions were mostly concentrated in the area along several tributaries of the Ying, Guo and New Sui Rivers as well as the area north of Nansi Lake. These regions decreased from 1997 to 2009, especially after 2005. Our analysis indicated that water pollution in HRS had a close relation with population and primary industry during the period 1997-2009, and implied that spatiotemporal variation of surface water quality could provide a scientific foundation for human health risk assessment of the Huai River Basin. PMID- 24056419 TI - A benchmark simulation to verify an inhibition model on decay stage for nitrification. AB - Activated Sludge Models (ASMs) are widely used for biological wastewater treatment plant design, optimisation and operation. In commonly used ASMs, the nitrification process is modelled as a one-step process. However, in some process configurations, it is desirable to model the concentration of nitrite nitrogen through a two-step nitrification process. In this study, the benchmark datasets published by the Water Environment Research Foundation (WERF) were used to develop a two-step nitrification model considering the kinetics of Ammonium Oxidising Bacteria (AOB) and Nitrite Oxidising Bacteria (NOB). The WERF datasets were collected from a chemostat reactor fed about 1,000 mg-NH3-N/L synthetic influent with at different sludge retention times of 20, 10 and 5-d, whereas the pH in the reactor varied in the range of 5.8 and 8.8. Supplemental laboratory batch experiments were conducted to assess the toxicity of nitrite-N on nitrifying bacteria. These tests suggested that 500 mg-N/L of nitrite at pH 7.3 was toxic to NOB and resulted in continuous decrease in bulk oxygen uptake rate. To model this phenomenon, a poisoning model was used instead of the traditional Haldane-type inhibition model. The poisoning model for NOB and AOB with different threshold poisonings for unionised NO2-N and NH3-N concentrations could successfully reproduce the three WERF datasets. PMID- 24056420 TI - Sorption of chloramphenicol on pond sediments and the effect of coexistence Cu(II). AB - The sorption of chloramphenicol on four types of sediment and the effect of coexistence Cu(II) on the sorption were studied. Sorption isotherms and thermodynamic analysis were employed to dispose the experimental sorption data. Experimental results showed that organic matter was the dominant parameter and the coexistence of heavy metal Cu(II) could promote the sorption of chloramphenicol on four tested sediments. The adsorption parameter analysis showed sorption of chloramphenicol on the sediment was not pure distributional effects, not a strong interaction between molecule and surface, but other weak interactions. Thermodynamic parameters values such as DeltaG, DeltaH and DeltaS were all below zero, which indicated that the sorption was a spontaneous and exothermal process. PMID- 24056421 TI - Phosphorus removal in a membrane-assisted BNR process with focus on evolutions of PAOs and DPAOs. AB - A bench-scale UCT (University of Cape Town)-type membrane bioreactor (UCT-MBR) fed with low-strength synthetic wastewater was operated to investigate phosphorus removal with reference to poly-phosphate accumulating organisms (PAOs) and denitrifying poly-phosphate accumulating organisms (DPAOs). A series of kinetic assays of PAOs and DPAOs were also conducted to analyze the metabolic activities of PAOs and DPAOs. Results showed that 93% of chemical oxygen demand (COD) and 77% of total nitrogen could be removed at 0.08 kgCOD kg(-1) MLSS d(-1) and 0.015 kgN kg(-1) MLSS d(-1) loading (MLSS: mixed liquor suspended solids). Removal efficiencies of total phosphorus increased during the experimental phase, with an ultimate removal efficiency of 96.1%. Kano and Kaer increased from 1.95 and 6.29 mgPO4(3-)-P g(-1) MLSS h(-1) to 5.47 and 11.13 mgPO4(3-)-P g(-1) MLSS h(-1) for DPAOs and PAOs respectively, with the increased ratio of DPAOs to PAOs from 31 to 49% implying DPAO metabolic activity increased faster than that of PAOs during the DPAO accumulation phase. Pano-uptake increased by 6.6 mg L(-1) and the ratio of PTano-uptake to PTupt increased from 58.97 to 91.62%. The ratio of DPAOs to PAOs tended to stabilize at around 50% over time. PMID- 24056422 TI - Treatment of tapioca starch wastewater by a novel combination of physical and biological processes. AB - A pilot plant combining dissolved air flotation, anaerobic degradation in an expanded granular sludge bed (EGSB) reactor and aerobic post-treatment in a vertical flow constructed wetland has been used to treat tapioca starch wastewater for more than 2.25 years. It is demonstrated that organic matter (chemical oxygen demand by >98%), nitrogen (Kjeldahl-N by >90%) and cyanide (total cyanide by >99%) can be removed very efficiently under stable operating conditions. The removal efficiency for phosphorus is lower (total-P by 50%). The treatment concept, which includes several sustainable aspects, e.g. production of energy to be used on-site, low operation demands and minimal use of chemicals, could be interesting for small- and middle-sized tapioca processing plants. PMID- 24056423 TI - Uncertainty analysis in urban drainage modelling: should we break our back for normally distributed residuals? AB - This study presents results on the assessment of the application of a Bayesian approach to evaluate the sensitivity and uncertainty associated with urban rainfall-runoff models. The software MICA was adopted, in which the prior information about the parameters is updated to generate the parameter posterior distribution. The likelihood function adopted in MICA assumes that the residuals between the measured and modelled values have a normal distribution. This is a trait of many uncertainty/sensitivity procedures. This study compares the results from three different scenarios: (i) when normality of the residuals was checked but if they were not normal then nothing was done (unverified); (ii) normality assumption was checked, verified (using data transformations) and a weighting strategy was used that gives more importance to high flows; and (iii) normality assumption was checked and verified, but no weights were applied. The modelling implications of such scenarios were analysed in terms of model efficiency, sensitivity and uncertainty assessment. The overall results indicated that verifying the normality assumption required the models to fit a wider portion of the hydrograph, allowing a more detailed inspection of parameters and processes simulated in both models. Such an outcome provided important information about the advantages and limitations of the models' structure. PMID- 24056424 TI - Reduction of nutrient contaminants into shallow eutrophic waters through vegetated treatment beds. AB - One of the most effective mitigative approaches to eutrophication is the reduction of nutrient loading into water bodies. Bioremediation presents an economically viable and ecologically sustainable technology to nutrient pollution control taking advantage of the remarkable ability of plants and their associated microbial community to assimilate and remove nutrients from the environment. In this study, four emergent macrophytes (Cyperus haspan, Pandanus amaryllifolius, Pontederia cordata and Thalia geniculata) and two floating plants (Hygroryza aristata and Pistia stratiotes) were deployed in bank-side treatment beds and comparatively assessed for their remediative capabilities for nutrient control. P. stratiotes exhibited the highest removal efficiency for both nitrate and phosphate among the six plant species studied. Emergent macrophytes, P. amaryllifolius, C. haspan and P. cordata, were also found to be highly effective in nutrient uptake exhibiting removal efficiencies up to 100%. With the exception of T. geniculata, depletion of nutrients as a result of plant uptake significantly impeded the natural colonization of algae invariably leading to improvements in water quality in terms of turbidity and pH. Suppression of algae proliferation by T. geniculata was not preceded by a reduction in nutrient concentrations suggesting that T. geniculata may be directly inhibiting algal growth through allelopathy. PMID- 24056425 TI - KN-B removal from water by non-thermal plasma. AB - The degradation of Reactive Black 5 (KN-B) in water using double-dielectric barrier discharge (DDBD) was studied. Experimental results showed that the KN-B degradation rate increased as the initial pH decreased. Low concentrations of Fe(2+) enhanced the degradation, whereas high concentrations of Fe(2+) hindered the degradation. The results showed that DDBD did not noticeably reduce total organic carbon but did reduce the pH value and improve the biodegradability of the solution significantly. Furthermore, the UV-Vis spectra of the dye showed that the chromophore group was damaged and that the solution was decolorized after the 10-min degradation process. PMID- 24056426 TI - Estimating subcatchment runoff coefficients using weather radar and a downstream runoff sensor. AB - This paper presents a method for estimating runoff coefficients of urban drainage subcatchments based on a combination of high resolution weather radar data and flow measurements from a downstream runoff sensor. By utilising the spatial variability of the precipitation it is possible to estimate the runoff coefficients of the separate subcatchments. The method is demonstrated through a case study of an urban drainage catchment (678 ha) located in the city of Aarhus, Denmark. The study has proven that it is possible to use corresponding measurements of the relative rainfall distribution over the catchment and downstream runoff measurements to identify the runoff coefficients at subcatchment level. PMID- 24056427 TI - Struvite pellet crystallization in a high-strength nitrogen and phosphorus stream. AB - Struvite crystallization is a reliable method to recover nutrients from wastewater. Laboratory-scale experiments were conducted to investigate nutrient recovery from synthetic wastewater with high-strength orthophosphate and ammonia nitrogen by the formation of struvite pellets. Without adjusting pH, struvite crystal growth environment was achieved in ammonia-nitrogen and orthophosphate concentration ranges of 100-1,000 and 221-2,214 mg/L, respectively. The mean size of the harvested struvite pellets was in the range of 3-4 mm. pH is an important factor indicating the process supersaturation. A range of pH 6.2-9.0 was tested in order to enhance nutrient removal efficiency. The results showed although higher N, P and Mg removals were achieved at higher pH values, over 95% N, P and Mg removals were still achieved at pH of 7.6. Recycling ratio of the clarifier supernatant to influent had no significant promotion of N or P removal. PMID- 24056428 TI - Kinetics and equilibrium of the sorption of bisphenol A by carbon nanotubes from wastewater. AB - The aim of this study was to determine the sorption potential of carbon nanotubes (CNTs) to bisphenol A (BPA) contained in synthetic wastewater whose composition corresponds to biologically treated effluents. These nanotubes differed in their outer diameter, the number of graphene layers and the presence of modifying functional groups. Based on the nitrogen adsorption-desorption isotherms, mensuration of the specific surface area and pore size distribution was undertaken. The porous structure of the CNTs was bidispersive; the majority consisted of micropores, there was an average fraction of mesopores, and macropores did not occur. On the basis of common kinetics models (pseudo-first order and pseudo-second-order models), a trial of modelling the kinetics of BPA sorption onto nanotubes was undertaken. The experimental data were well fitted only to the pseudo-second-order models. The kinetics study indicated that adsorption of BPA on CNTs proceeded very fast, with the majority of the adsorbate being adsorbed in the first few seconds. The sorption capacity of nanotubes to BPA was the highest for single-walled CNTs. A decrease in the sorption potential of the nanotubes for higher pH values occurred as a result of the deprotonation of the BPA and formation of bisphenolate anions, consequently leading to a decrease of pi-pi (hydrophobic) interaction and enhancing electrostatic repulsion. Overall, these results unequivocally confirm the ideal performance and potential of nanotubes for removal of micropollutants from synthetic wastewater. Replicating the conditions occurring in real wastewater allows us to expect a high sorption of BPA in real competitive sorption systems. PMID- 24056429 TI - Analysis of the impact of low impact development on runoff from a new district in Korea. AB - An analysis of the impact of a low impact development (LID) on runoff was performed using a Storm Water Management Model 5 (SWMM5)-LID model. The SWMM5 package has been developed to facilitate the analysis of the hydrologic impacts of LID facilities. Continuous simulation of urban stormwater runoff from the district which included the LID design was conducted. In order to examine the impact of runoff in the LID district the first, second and third highest ranked flood events over the past 38 years were analyzed. The assessment estimated that a LID system under historical storm conditions would reduce peak runoff by approximately 55-66% and runoff volume by approximately 25-121% in comparison with that before the LID design. The impact on runoff was also simulated under 50, 80 and 100 year return period conditions. Under these conditions, the runoff reductions within the district were estimated to be about 6-16% (peak runoff) and 33-37% (runoff volume) in comparison with conditions prior to the LID. It is concluded from these results that LID is worthy of consideration for urban flood control in future development and as part of sewer and stormwater management planning. PMID- 24056430 TI - Preparation and characterization of C,N-codoped TiO2 photocatalyst for the degradation of diclofenac from wastewater. AB - Application of mesoporous C- and C,N-codoped TiO2 in the removal of diclofenac from water was studied. The sol-gel method was used for the preparation of the photocatalysts. The physicochemical properties of studied materials were characterized by BET (Brunauer, Emmett and Teller), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy and X-ray diffraction (XRD) methods. XPS confirmed the incorporation of nitrogen and carbon atoms into TiO2 lattice. The synthesized catalysts were effective in the removal of the studied pollutant from water and enabled reduction of the COD (chemical oxygen demand) value of the wastewater by at least 60%. The process of diclofenac photooxidation over the C,N-codoped and C-doped TiO2 photocatalysts proceeded similarly and was followed by pseudo-first order kinetics. The increase in calcination temperature resulted in the rutile fraction (5%) slightly lowering the effectiveness of treatment. The results over pure anatase structures confirmed that anatase has usually a better photocatalytic activity than rutile. The best changes in the water quality were observed during the first 50 min of treatment, but mineralization of pollutant did not lead to complete. PMID- 24056432 TI - Application of CFD modelling at a full-scale ozonation plant for the removal of micropollutants from secondary effluent. AB - Since November 2009, Germany's first full-scale ozonation plant for tertiary treatment of secondary effluent is in continuous operation. A kinetic model was developed and combined with the commercial computational fluid dynamics (CFD) software ANSYS((r)) CFX((r)) to simulate the removal of micropollutants from secondary effluents. Input data like reaction rate constants and initial concentrations of bulk components of the effluent organic matter (EfOM) were derived from experimental batch tests. Additionally, well-known correlations for the mass transfer were implemented into the simulation model. The CFD model was calibrated and validated by full-scale process data and by analytical measurements for micropollutants. The results show a good consistency of simulated values and measured data. Therewith, the validated CFD model described in this study proved to be suited for the application of secondary effluent ozonation. By implementing site-specific ozone exposition and the given reactor geometry the described CFD model can be easily adopted for similar applications. PMID- 24056431 TI - Efficient treatment of an electroplating wastewater containing heavy metal ions, cyanide, and organics by H2O2 oxidation followed by the anodic Fenton process. AB - A real electroplating wastewater, containing heavy metals, cyanide, and organic contaminants, was treated by electrocoagulation (EC), H2O2 oxidation, H2O2 pre oxidation followed by EC, and the anodic Fenton process and the efficacy of the processes was compared. Concentration of cyanide, Cu, Ni, Zn, and Cr was largely decreased by EC within 5 min. When the reaction time was extended, removal of residual cyanide, Cu, and Ni was limited. In H2O2 oxidation, the concentration of cyanide decreased from initial 75 to 12 mg L(-1) in 30 min. The effluents from the H2O2 oxidation were further treated by EC or anodic Fenton. In EC, the concentration of total cyanide, Ni, and Cu decreased to below 0.3, 0.5, and 1.5 mg L(-1), respectively. Removal efficiency of chemical oxygen demand by EC was less than 20.0%. By contrast, there was 73.5% reduction by the anodic Fenton process with 5 mM H2O2 at 30 min; this can be attributed to the oxidation induced by hydroxyl radicals generated by the reaction of H2O2 with the electrogenerated Fe(2+). Meanwhile, residual cyanide, Cu, and Ni can also be efficiently removed. Transformation of organic components in various processes was analyzed using UV visible and fluorescence excitation-emission spectra. PMID- 24056433 TI - Treatment of domestic wastewater by vertical flow constructed wetland planted with umbrella sedge and Vetiver grass. AB - The aim of this study was to investigate the efficiency of wastewater treatment by vertical flow constructed wetland systems under different hydraulic loading rates (HLR). The comparison of two types of plants, Cyperus alternifolius (Umbrella sedge) and Vetiveria zizanioides (Vetiver grass), was also conducted. In this study, six circular concrete tanks (diameter 0.8 m) were filled with fine sand and gravel to the depth of 1.23 m. Three tanks were planted with Umbrella sedge and the other three tanks were planted with Vetiver grass. Settled domestic wastewater from Chiang Mai University (chemical oxygen demand (COD), NH4(+)-N and suspended solids (SS) of 127.1, 27.4 and 29.5 mg/L on average, respectively) was intermittently applied for 45 min and rested for 3 h 15 min. The HLR of each tank was controlled at 20, 29 and 40 cm/d. It was found that the removal efficiency of the Umbrella sedge systems was higher than the Vetiver grass systems for every parameter, and the lowest HLR provided the maximum treatment efficiency. The removal efficiency of COD and nitrogen in terms of total Kjeldahl nitrogen (TKN) was 76 and 65% at 20 cm/d HLR for Umbrella sedge compared to only 67 and 56% for Vetiver grass. Nitrogen accumulation in plant biomass was also higher in Umbrella sedge than in Vetiver grass in every HLR. Umbrella sedge was thus proved to be a suitable constructed wetland plant in tropical climates. PMID- 24056434 TI - Formation, breakage and re-formation of flocs formed by cationic starch. AB - The efficiency of flocculation can be significantly improved through floc breakage and re-formation under appropriate conditions. To obtain a better understanding of the mechanisms involved and to relate floc properties to separation efficiency, the effects of mixing conditions on the formation, breakage and re-formation of flocs formed by kaolin and cationic starch were investigated through conventional jar test procedure and continuous optical monitoring. It has been found that the breakage of flocs was fully reversible and the polymer flocculant could resist strong shear; even having been sheared for four times, the flocculation index (FI) value would be higher than that of the original flocs. The results indicated flocs formed at neutral and alkaline conditions had better shear resistance than those at acidification conditions, and the mode of floc rupture was large-scale fragmentation. PMID- 24056435 TI - Assessment of E. coli partitioning behavior via both culture-based and qPCR methods. AB - Quantitative polymerase chain reaction (qPCR) offers a rapid, highly sensitive analytical alternative to the traditional culture-based techniques of microbial enumeration typically used in water quality monitoring. Before qPCR can be widely applied within surface water monitoring programs and stormwater assessment research, the relationships between microbial concentrations measured by qPCR and culture-based methods must be assessed across a range of water types. Previous studies investigating fecal indicator bacteria quantification using molecular and culture-based techniques have compared measures of total concentration, but have not examined particle-associated microorganisms, which may be more important from a transport perspective, particularly during the calibration of predictive water quality models for watershed management purposes. This study compared total, free phase, and particle-associated Escherichia coli concentrations as determined by the Colilert defined substrate method and qPCR targeting the uidA gene in stream grab samples partitioned via a calibrated centrifugation technique. Free-phase concentrations detected through qPCR were significantly higher than those detected using Colilert although total concentrations were statistically equivalent, suggesting a source of analytical bias. Although a specimen processing complex was used to identify and correct for inhibition of the qPCR reaction, high particle concentrations may have resulted in underestimation of total cell counts, particularly at low concentrations. Regardless, qPCR-based techniques will likely have an important future role in stormwater assessment and management. PMID- 24056436 TI - A quantitative speciation model for the adsorption of organic pollutants on activated carbon. AB - Granular activated carbon (GAC) is commonly used as adsorbent in water treatment plants given its high capacity for retaining organic pollutants in aqueous phase. The current knowledge on GAC behaviour is essentially empirical, and no quantitative description of the chemical relationships between GAC surface groups and pollutants has been proposed. In this paper, we describe a quantitative model for the adsorption of atrazine onto GAC surface. The model is based on results of potentiometric titrations and three types of adsorption experiments which have been carried out in order to determine the nature and distribution of the functional groups on the GAC surface, and evaluate the adsorption characteristics of GAC towards atrazine. Potentiometric titrations have indicated the existence of at least two different families of chemical groups on the GAC surface, including phenolic- and benzoic-type surface groups. Adsorption experiments with atrazine have been satisfactorily modelled with the geochemical code PhreeqC, assuming that atrazine is sorbed onto the GAC surface in equilibrium (log Ks = 5.1 +/- 0.5). Independent thermodynamic calculations suggest a possible adsorption of atrazine on a benzoic derivative. The present work opens a new approach for improving the adsorption capabilities of GAC towards organic pollutants by modifying its chemical properties. PMID- 24056437 TI - Process design for wastewater treatment: catalytic ozonation of organic pollutants. AB - Emerging micropollutants have been recently the target of interest for their potential harmful effects in the environment and their resistance to conventional water treatments. Catalytic ozonation is an advanced oxidation process consisting of the formation of highly reactive radicals from the decomposition of ozone promoted by a catalyst. Nanocarbon materials have been shown to be effective catalysts for this process, either in powder form or grown on the surface of a monolithic structure. In this work, carbon nanofibers grown on the surface of a cordierite honeycomb monolith are tested as catalyst for the ozonation of five selected micropollutants: atrazine (ATZ), bezafibrate, erythromycin, metolachlor, and nonylphenol. The process is tested both in laboratorial and real conditions. Later on, ATZ was selected as a target pollutant to further investigate the role of the catalytic material. It is shown that the inclusion of a catalyst improves the mineralization degree compared to single ozonation. PMID- 24056438 TI - Removal of nickel and zinc from single and binary metal solutions by Sargassum angustifolium. AB - The capability of Sargassum angustifolium in removing nickel (Ni) (II) and zinc (Zn) (II) from single and binary metal solution was determined. In binary solution the presence of the secondary metal inhibited the sorption of the primary metal by S. angustifolium but the inhibitory effect of Ni during sorption of Zn is stronger than the inhibitory effect of Zn in absorption of Ni. The total metal (Ni + Zn) sorbed from the binary metal solution by S. angustifolium cells always remained lower than the total sorption of individual metals from their respective single metal solutions, thereby suggesting competition between Ni(II) and Zn(II) for the common binding sites on S. angustifolium. The maximum uptake capacities of the S. angustifolium, which was collected near Bushehr, Persian Gulf, Iran in the natural form, at the optimal conditions for Ni(II) and Zn(II) ions in single metal solutions were approximately 0.71 and 0.93 mmol/g dry S. angustifolium, respectively. Under the binary system Ni(II) and Zn(II) uptake capacities were 0.41 mmol Ni/g and 0.36 mmol Zn/g, respectively. Better fitness of equilibrium metal sorption data to the Langmuir than the Freundlich model suggests multilayer adsorption of test metals onto the cell surface. PMID- 24056439 TI - Biofilm development in fixed bed biofilm reactors: experiments and simple models for engineering design purposes. AB - Biofilm development in a fixed bed biofilm reactor system performing municipal wastewater treatment was monitored aiming at accumulating colonization and maximum biofilm mass data usable in engineering practice for process design purposes. Initially a 6 month experimental period was selected for investigations where the biofilm formation and the performance of the reactors were monitored. The results were analyzed by two methods: for simple, steady-state process design purposes the maximum biofilm mass on carriers versus influent load and a time constant of the biofilm growth were determined, whereas for design approaches using dynamic models a simple biofilm mass prediction model including attachment and detachment mechanisms was selected and fitted to the experimental data. According to a detailed statistical analysis, the collected data have not allowed us to determine both the time constant of biofilm growth and the maximum biofilm mass on carriers at the same time. The observed maximum biofilm mass could be determined with a reasonable error and ranged between 438 gTS/m(2) carrier surface and 843 gTS/m(2), depending on influent load, and hydrodynamic conditions. The parallel analysis of the attachment-detachment model showed that the experimental data set allowed us to determine the attachment rate coefficient which was in the range of 0.05-0.4 m d(-1) depending on influent load and hydrodynamic conditions. PMID- 24056440 TI - High salinity wastewater treatment. AB - The shock effect, survival and ability of activated sludge to acclimatize to wastewater containing different concentrations of NaCl and Na2SO4 were investigated under laboratory conditions. To accomplish this, the potential penetration of a sewage system by seawater as a consequence of storm surge flooding was simulated. The experiments were conducted using activated sludge taken from the aeration tank of a communal wastewater treatment plant and adding different concentrations up to 40 g/L of NaCl and 4.33 g/L of Na2SO4. The effects of salinity on the activated sludge were monitored for 5 weeks based on the values of pH, dissolved oxygen, total suspended solids, volatile suspended solids, sludge volume, sludge volume index, electrokinetic potential, respirometric measurements and enzymatic activity. The addition of salt sharply reduced or completely inhibited the microbial activity in activated sludge. When salt concentrations were below 10 g/L NaCl, microorganisms were able to acclimatize in several weeks and achieve the same initial activity as in raw sludge samples. When the salt concentration was above 30 g/L NaCl, the acclimatization process was very slow or impossible. PMID- 24056441 TI - Fe(II) oxidation during acid mine drainage neutralization in a pilot-scale Sequencing Batch Reactor. AB - This study investigated Fe(II) oxidation during acid mine drainage (AMD) neutralization using CaCO3 in a pilot-scale Sequencing Batch Reactor (SBR) of hydraulic retention time (HRT) of 90 min and sludge retention time (SRT) of 360 min in the presence of air. The removal kinetics of Fe(II), of initial concentration 1,033 +/- 0 mg/L, from AMD through oxidation to Fe(III) was observed to depend on both pH and suspended solids, resulting in Fe(II) levels of 679 +/- 32, 242 +/- 64, 46 +/- 16 and 28 +/- 0 mg/L recorded after cycles 1, 2, 3 and 4 respectively, with complete Fe(II) oxidation only achieved after complete neutralization of AMD. Generally, it takes 30 min to completely oxidize Fe(II) during cycle 4, suggesting that further optimization of SBR operation based on both pH and suspended solids manipulation can result in significant reduction of the number of cycles required to achieve acceptable Fe(II) oxidation for removal as ferric hydroxide. Overall, complete removal of Fe(II) during AMD neutralization is attractive as it promotes recovery of better quality waste gypsum, key to downstream gypsum beneficiation for recovery of valuables, thereby enabling some treatment-cost recovery and prevention of environmental pollution from dumping of sludge into landfills. PMID- 24056442 TI - Potential fertilizing properties of sewage sludge treated in the sludge treatment reed beds (STRB). AB - In previous research the fertilizer value of sludge from reed beds was evaluated based on the sampling sludge on different depths from four Danish sludge treatment reed beds (STRB) after long periods of stabilization. The dewatering efficiency of sewage sludge in the STRB is comparable to mechanical dewatering. The long-term stabilization of sewage sludge progressively decreases the concentration of organic matter due to the process of humification. The aim of the work was to determine the changes of organic matter concentration, nutrients concentrations as well as speciation of selected heavy metals (Cd, Pb, Ni, Cr, Cu and Zn) in vertical profile of the sewage sludge stabilized in the STRB for 7-15 years. The analyzed sewage sludge was collected from the STRB treating sludge from four municipal wastewater treatment plants located in Denmark serving from 9,000 to 40,000 person equivalent. Analyzed heavy metals (except for Zn) were mostly bound with the most stable - residual - fraction. The most stable metals were Pb and Cr, where the share of the residual fraction exceeded 80.0%. The most mobile metal was Zn, where the share of the mobile fractions (calculated as the sum of I, II and III fractions) exceeded 85.0%. The high concentration of nitrogen and phosphorus is the decisive factor in the high valuation of sludge stabilized in the STRB as fertilizer. PMID- 24056443 TI - A green roof experimental site in the Mediterranean climate: the storm water quality issue. AB - Since 2007, the University of Genoa has been carrying out a monitoring programme to investigate the hydrologic response of green roofs in the Mediterranean climate by installing a green roof experimental site. In order to assess the influence of green roofs on the storm water runoff quality, water chemistry data have been included in the monitoring programme since 2010, providing rainfall and outflow data. For atmospheric source, the bulk deposition is collected to evaluate the role of the overall atmospheric deposition in storm water runoff quality. For subsurface outflow, a maximum of 24 composite samples are taken on an event basis, thus aiming at a full characterization of the outflow hydrograph. Water chemistry data reveal that the pollutant loads associated with green roof outflow is low; in particular, solids and metal concentrations are lower than values generally observed in storm water runoff from traditional rooftops. The concentration values of chemical oxygen demand, total dissolved solids, Fe, Ca and K measured in the subsurface outflow are significantly higher than those observed in the bulk deposition (p < 0.05). With respect to the atmospheric deposition, the green roof behaviour as a sink/source of pollutants is investigated based on both concentration and mass. PMID- 24056445 TI - Ibuprofen adsorption in four agricultural volcanic soils. AB - Ibuprofen (IB) is a high environmental risk drug and one of the most frequently prescribed in human medicine. Recently, IB has been detected in Gran Canaria in reclaimed water for irrigation and in groundwater. Adsorption was studied in four volcanic soils from three islands of the Canarian Archipelago. Once the biodegradation process has been excluded from the experimental conditions, a batch method was applied using initial concentrations of 1-5-10-20-50-100-200 mg L(-1) and two soil/water ratios (w/V): 1:5 (OECD, 2000) and 1:1. Non-linear and linearized Langmuir and Freundlich equations were well fitted. The wide IB range tested in our batch studies allowed us to measure experimental adsorption values close to the maximum adsorption capacity (S(max)) as estimated by Langmuir, making it possible thereby to validate the use of the Langmuir equation when there is a burst of contamination at high concentration. The distribution coefficient (Kd), S(max) and Retardation Factor (RF) varied from 0.04 to 0.5 kg L(-1), 4-200 mgk g(-1) and 1.2-1.9, respectively. The lowest S(max) and Kd values were found for the 1:1S/W ratio whereas most batch studies employ 1:5S/W ratios, thus obtaining higher adsorption parameters than when considering field conditions (1:1). Despite the high anion retention of andic soils, similar Kd and RF to those reported for other soils were obtained in 1:5, while high S(max) was found. Our results demonstrate that IB adsorption in volcanic areas responds not only to the soil properties commonly cited in adsorption studies, but also depends on andic properties, sorbent concentration and Dissolved Organic Carbon, the higher values of which are related to the lower Kd and S(max). The low RF and low detection frequency of the IB in groundwater suggests that a) reclaimed water irrigation is not the main source of IB, and b) the existence of some uncontrolled water disposal points in the zone. PMID- 24056444 TI - Enhanced contractility with 2-deoxy-ATP and EMD 57033 is correlated with reduced myofibril structure and twitch power in neonatal cardiomyocytes. AB - As cardiomyocytes mature, their sarcomeres and Z-band widths increase in length in order for their myofibrils to produce stronger twitch forces during a contraction. In this study, we tested the hypothesis that tensional homeostasis is affected by altering myofibril forces. To assess this hypothesis, neonatal rat cardiomyocytes were cultured on arrays of microposts to measure cellular contractility. An optical line scanning technique was used to measure the deflections in the microposts with high temporal resolution, enabling the analysis of twitch force, twitch velocity, and twitch power. Myofibril force production was elevated by vector-mediated overexpression of ribonucleotide reductase (RR) to increase cellular dATP content or by adding the inotropic agent EMD 57033 (EMD). We found that RR and EMD treatment did not affect cardiomyocyte twitch force, but it did lead to reduced twitch velocity and twitch power. Immunofluorescent analysis of alpha-actinin revealed that RR-over-expressing cardiomyocytes and EMD-treated cardiomyocytes had lower spread area, sarcomere length, and Z-band width as compared to control cells. These results indicate a correlation between myofibril structure and cardiac power. This correlation was confirmed by exposing the cells to the myosin II inhibitor blebbistatin, and then subsequently washing it out. After wash-out, cardiomyocytes exhibited a reduction in twitch force, velocity, and power due to shorter sarcomere length and Z-band widths. Our results suggest that cardiac myofibril structure is regulated by tensional homeostasis. If myofibril-generated forces in cardiomyocytes are elevated, a state of tensional homeostasis is maintained by producing sufficient twitch forces with a lower degree myofibril structure. PMID- 24056446 TI - A modeling investigation of the impact of street and building configurations on personal air pollutant exposure in isolated deep urban canyons. AB - This study evaluated the effectiveness of different configurations for two building design elements, namely building permeability and setback, proposed for mitigating air pollutant exposure problems in isolated deep canyons by using an indirect exposure approach. The indirect approach predicted the exposures of three different population subgroups (i.e. pedestrians, shop vendors and residents) by multiplying the pollutant concentrations with the duration of exposure within a specific micro-environment. In this study, the pollutant concentrations for different configurations were predicted using a computational fluid dynamics model. The model was constructed based on the Reynolds-Averaged Navier-Stokes (RANS) equations with the standard k-epsilon turbulence model. Fifty-one canyon configurations with aspect ratios of 2, 4, 6 and different building permeability values (ratio of building spacing to the building facade length) or different types of building setback (recess of a high building from the road) were examined. The findings indicated that personal exposures of shop vendors were extremely high if they were present inside a canyon without any setback or separation between buildings and when the prevailing wind was perpendicular to the canyon axis. Building separation and building setbacks were effective in reducing personal air exposures in canyons with perpendicular wind, although their effectiveness varied with different configurations. Increasing the permeability value from 0 to 10% significantly lowered the personal exposures on the different population subgroups. Likewise, the personal exposures could also be reduced by the introduction of building setbacks despite their effects being strongly influenced by the aspect ratio of a canyon. Equivalent findings were observed if the reduction in the total development floor area (the total floor area permitted to be developed within a particular site area) was also considered. These findings were employed to formulate a hierarchy decision making model to guide the planning of deep canyons in high density urban cities. PMID- 24056447 TI - Organohalogen concentrations and feeding status in Atlantic salmon (Salmo salar L.) of the Baltic Sea during the spawning run. AB - Changes in the concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in Baltic salmon muscle were studied during the spawning migration from the southern Baltic Sea to rivers flowing into the northern Gulf of Bothnia and during the spawning period. The aim was to obtain information to facilitate the arrangement of salmon fisheries such that the human dioxin intake is taken into account. The EC maximum allowable total toxic equivalent concentration (WHO TEQPCDD/F+PCB) was exceeded in the muscle of the majority of the migrating salmon, except in the Baltic Proper. The fresh-weight-based concentrations of all toxicant groups in salmon tended to be the lowest in the Baltic Proper and the Northern Quark, and all toxicant concentrations, except PCDDs and PCDFs, were significantly higher in the spawning salmon than in the salmon caught during the spawning run. The fat content of the salmon muscle decreased by 60% during the spawning run, and the lipid-based total toxicant concentrations were consequently 4.2-6.2 times higher during the spawning period than during the spawning migration. However, the toxicants were concentrated just before spawning, and thus there is no essential difference related to whether the salmon are caught in the sea or the recreational river fishery. PMID- 24056448 TI - Transport of nutrients and contaminants from ocean to island by emperor penguins from Amanda Bay, East Antarctic. AB - Penguins play important roles in the biogeochemical cycle between Antarctic Ocean and land ecosystems. The roles of emperor penguin Aptenodytes forsteri, however, are usually ignored because emperor penguin breeds in fast sea ice. In this study, we collected two sediment profiles (EPI and PI) from the N island near a large emperor penguin colony at Amanda Bay, East Antarctic and performed stable isotope and element analyses. The organic C/N ratios and carbon and nitrogen isotopes suggested an autochthonous source of organic materials for the sediments of EPI (C/N = 10.21 +/- 0.28, n = 17; delta(13)C = -13.48 +/- 0.500/00, delta(15)N = 8.35 +/- 0.550/00, n = 4) and an allochthonous source of marine derived organic materials for the sediments of PI (C/N = 6.15 +/- 0.08, delta(13)C = -26.85 +/- 0.110/00, delta(15)N = 21.21 +/- 2.020/00, n = 20). The concentrations of total phosphorus (TP), selenium (Se), mercury (Hg) and zinc (Zn) in PI sediments were much higher than those in EPI, the concentration of copper (Cu) in PI was a little lower, and the concentration of element lead (Pb) showed no difference. As measured by the geoaccumulation indexes, Zn, TP, Hg and Se were from moderately to very strongly enriched in PI, relative to local mother rock, due to the guano input from juvenile emperor penguins. Because of its high trophic level and transfer efficiency, emperor penguin can transport a large amount of nutrients and contaminants from ocean to land even with a relatively small population, and its roles in the biogeochemical cycle between ocean and terrestrial environment should not be ignored. PMID- 24056449 TI - Occurrence, fate and environmental risk assessment of endocrine disrupting compounds at the wastewater treatment works in Pietermaritzburg (South Africa). AB - Steroid hormone Endocrine Disrupting Compounds (EDCs) (natural estrogens (17-beta estradiol (E2), estrone (E1), estriol (E3), synthetic estrogen (17-alpha ethinylestradiol (EE2)), natural androgen (testosterone) (tes) and natural progestogen (progesterone) (pro)) at an activated sludge wastewater works (WWW), were quantitated using Enzyme-linked immunosorbent assay (ELISA). The steroid hormone profile in the adjacent surface water was also determined. Pro was the most abundant (41%, 408 ng/L) in the influent, followed by tes (35%, 343 ng/L) and E2 (12%, 119 ng/L). E1 was the most abundant (35%, 23 ng/L) in effluent, followed by E2 (30%, 20 ng/L) and tes (17%, 11 ng/L). Chemical removal efficiencies of the steroid hormones by the WWW averaged 92%. High removal efficiency was observed for pro (98% +/- 2) and tes (96% +/- 1), compared to natural (72-100%) and synthetic estrogen (90% +/- 3), with biodegradation being the major removal route for pro and tes. The lowest removal for E2 is in spring (65%), and maximum removal is in winter (95%). Natural (E2, E1) and synthetic estrogen (EE2) were major contributors to influent (E2 = 69%) and effluent (E2 = 73%) estrogenic potency. The estrogenic potency removal averaged 85% (range: 73 100). Risk assessment of the steroid hormones present in wastewater effluent, and surface water, indicated that EE2 and E2 pose the highest risk to human health and fish. EE2 was found to be much more resistant to biodegradation, compared to E2, in surface water. Estrone, as the breakdown product of E2 and EE2 in wastewater, appears to be suitable as an indicator of EDCs. The study suggests that a battery of tests: quantitative chemical assay, bioassay for estrogenic activity and risk assessment methods, collectively, are preferred in order to make meaningful, accurate conclusions regarding potential adverse effects of EDCs present in treated wastewater effluent or surface water, to the aquatic environment, human health, and wildlife systems. PMID- 24056450 TI - Elements uptake by metal accumulator species grown on mine tailings amended with three types of biochar. AB - Mine tailings are of great concern due to the risk their toxic inorganic elements pose to the environment. The application of biochar as an amendment may be a solution to reduce the risk of pollutant diffusion. The main purpose of the research was to verify the effects of different types of biochar produced from different feedstocks (pruning residues, fir tree pellets and manure pellets) on changing the substrate conditions to promote plant growth for the phytostabilization of mine tailings. The SEM/EDX characterization showed different structures in terms of porosity and granulosity as well as the element composition. The plants used in the pot experiment were Anthyllis vulneraria subsp. polyphylla (Dc.) Nyman, Noccaea rotundifolium (L.) Moench subsp. cepaeifolium and Poa alpina L. subsp. alpina. The biochars were applied at three doses: 0, 1.5 and 3%dw. Although to different extents, the biochars induced significant changes of the substrates in terms of pH, EC, CEC and bioavailability of the metals. The biochar from manure pellets and pruning residues reduced shoot Cd and Pb accumulations. The former also led to a higher biomass production that peaked at the1.5% dose. Biochar has great potential as an amendment for phytoremediation but its effects depend on the type of feedstock it derives from. The characteristics of the substrate to be treated are crucial for the biochar selection. PMID- 24056451 TI - Mercury in gray wolves (Canis lupus) in Alaska: increased exposure through consumption of marine prey. AB - Mercury (Hg) bioaccumulates in the tissues of organisms and biomagnifies within food-webs. Gray wolves (Canis lupus) in Alaska primarily acquire Hg through diet; therefore, comparing the extent of Hg exposure in wolves, in conjunction with stable isotopes, from interior and coastal regions of Alaska offers important insight into their feeding ecology. Liver, kidney, and skeletal muscle samples from 162 gray wolves were analyzed for total mercury (THg) concentrations and stable isotopic signatures (delta(13)C, delta(15)N, and delta(34)S). Median hepatic THg concentrations were significantly higher in wolves with coastal access compared to wolves from interior Alaska. Stable isotope ratios, in conjunction with THg concentrations, provide strong evidence that coastal wolves are utilizing marine prey representing several trophic levels. The utilization of cross-ecosystem food resources by coastal wolves is clearly contributing to increased THg exposure, and may ultimately have negative health implications for these animals. PMID- 24056452 TI - Levels and trends of toxaphene and chlordane-related pesticides in peregrine falcon eggs from South Greenland. AB - Peregrine falcon eggs were collected in South Greenland between 1986 and 2003 and analysed for 6 congeners of toxaphene and 5 chlordane-related pesticides (cis chlordane, trans-chlordane, cis-nonachlor, trans-nonachlor and oxychlordane). Oxychlordane had the highest median concentration of 1448 ng/g lipid weight (lw) or 79 ng/g wet weight (ww) of all compounds. Of the toxaphene congeners, CHB-50 was the predominant congener, with a median concentration of 215 ng/g lw (15.5 ng/g ww). Chlordane-related concentrations were comparable with results from the USA, but lower than those from Canada and Norway. Toxaphene was considerably higher than in eggs of Norwegian peregrine falcon eggs, possibly reflecting different toxaphene usage in the areas of peregrine falcon migration. Toxaphene information in birds of prey is limited and comparisons with other species indicate differences in concentrations and organochlorine pattern. Temporal trends showed significant log-linear decreases for cis-chlordane and trans chlordane, but no significant trends for other chlordanes or the toxaphene congeners, probably affected by the large variation between eggs, also of the same bird. Correlations between chlordanes and toxaphene in the Greenland peregrine falcon eggs might suggest similar sources of exposure. PMID- 24056453 TI - Development of a tetracycline-inducible gene expression system for the study of Helicobacter pylori pathogenesis. AB - Deletion mutants and animal models have been instrumental in the study of Helicobacter pylori pathogenesis. Conditional mutants, however, would enable the study of the temporal gene requirement during H. pylori colonization and chronic infection. To achieve this goal, we adapted the Escherichia coli Tn10-derived tetracycline-inducible expression system for use in H. pylori. The ureA promoter was modified by inserting one or two tet operators to generate tetracycline responsive promoters, named uPtetO, and these promoters were then fused to the reporter gfpmut2 and inserted into different loci. The expression of the tetracycline repressor (tetR) was placed under the control of one of three promoters and inserted into the chromosome. Conditional expression of green fluorescent protein (GFP) in strains harboring tetR and uPtetO-GFP was characterized by measuring GFP activity and by immunoblotting. The two tet responsive uPtetO promoters differ in strength, and induction of these promoters was inducer concentration and time dependent, with maximum expression achieved after induction for 8 to 16 h. Furthermore, the chromosomal location of the uPtetO-GFP construct and the nature of the promoter driving expression of tetR influenced the strength of the uPtetO promoters upon induction. Integration of uPtetO-GFP and tetR constructs at different genomic loci was stable in vivo and did not affect colonization. Finally, we demonstrate tetracycline-dependent induction of GFP expression in vivo during chronic infection. These results open new experimental avenues for dissecting H. pylori pathogenesis using animal models and for testing the roles of specific genes in colonization of, adaptation to, and persistence in the host. PMID- 24056454 TI - Association of a D-alanyl-D-alanine carboxypeptidase gene with the formation of aberrantly shaped cells during the induction of viable but nonculturable Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus is a halophilic Gram-negative bacterium that causes human gastroenteritis. When the viable but nonculturable (VBNC) state of this bacterium was induced by incubation at 4 degrees C in Morita minimal salt solution containing 0.5% NaCl, the rod-shaped cells became coccoid, and various aberrantly shaped intermediates were formed in the initial stage. This study examined the factors that influence the formation of these aberrantly shaped cells. The proportion of aberrantly shaped cells was not affected in a medium containing D cycloserine (50 MUg/ml) but was lower in a medium containing cephalosporin C (10 MUg/ml) than in the control medium without antibiotics. The proportion of aberrantly shaped cells was higher in a culture medium that contained 0.5% NaCl than in culture media containing 1.0 or 1.5% NaCl. The expression of 15 of 17 selected genes associated with cell wall synthesis was enhanced, and the expression of VP2468 (dacB), which encodes D-alanyl-D-alanine carboxypeptidase, was enhanced the most. The proportion of aberrantly shaped cells was significantly lower in the dacB mutant strain than in the parent strain, but the proportion was restored in the presence of the complementary dacB gene. This study suggests that disturbance of the dynamics of cell wall synthesis by enhanced expression of the VP2468 gene is associated with the formation of aberrantly shaped cells in the initial stage of induction of VBNC V. parahaemolyticus cells under specific conditions. PMID- 24056455 TI - An efficient method using Gluconacetobacter europaeus to reduce an unfavorable flavor compound, acetoin, in rice vinegar production. AB - Gluconacetobacter europaeus, one of the microorganisms most commonly used for vinegar production, produces the unfavorable flavor compound acetoin. Since acetoin reduction is important for rice vinegar production, a genetic approach was attempted to reduce acetoin produced by G. europaeus KGMA0119 using specific gene knockout without introducing exogenous antibiotic resistance genes. A uracil auxotrophic mutant with deletion of the orotate phosphoribosyltransferase gene (pyrE) was first isolated by positive selection using 5-fluoroorotic acid. The pyrE disruptant designated KGMA0704 (DeltapyrE) showed 5-fluoroorotic acid resistance. KGMA0704 and the pyrE gene were used for further gene disruption experiments as a host cell and a selectable marker, respectively. Targeted disruption of aldC or als, which encodes alpha-acetolactate decarboxylase or alpha-acetolactate synthase, was attempted in KGMA0704. The disruption of these genes was expected to result in a decrease in acetoin levels. A disruption vector harboring the pyrE marker within the targeted gene was constructed for double crossover recombination. The cells of KGMA0704 were transformed with the exogenous DNA using electroporation, and genotypic analyses of the transformants revealed the unique occurrence of targeted aldC or als gene disruption. The aldC disruptant KGMA4004 and the als disruptant KGMA5315 were cultivated, and the amount of acetoin was monitored. The acetoin level in KGMA4004 culture was significantly reduced to 0.009% (wt/vol) compared with KGMA0119 (0.042% [wt/vol]), whereas that of KGMA5315 was not affected (0.037% [wt/vol]). This indicates that aldC disruption is critical for acetoin reduction. G. europaeus KGMA4004 has clear application potential in the production of rice vinegar with less unfavorable flavor. PMID- 24056456 TI - Prevalence of diarrhea-associated virulence genes and genetic diversity in Escherichia coli isolates from fecal material of various animal hosts. AB - In order to assess the health risk associated with a given source of fecal contamination using bacterial source tracking (BST), it is important to know the occurrence of potential pathogens as a function of host. Escherichia coli isolates (n=593) from the feces of diverse animals were screened for various virulence genes: stx1 and stx2 (Shiga toxin-producing E. coli [STEC]), eae and EAF (enteropathogenic E. coli [EPEC]), STh, STp, and LT (enterotoxigenic E. coli [ETEC]), and ipaH (enteroinvasive E. coli [EIEC]). Eleven hosts were positive for only the eae (10.11%) gene, representing atypical EPEC, while two hosts were positive for both eae and EAF (1.3%), representing typical EPEC. stx1, stx2, or both stx1 and stx2 were present in 1 (0.1%,) 10 (5.56%), and 2 (1.51%) hosts, respectively, and confirmed as non-O157 by using a E. coli O157 rfb (rfbO157) TaqMan assay. STh and STp were carried by 2 hosts (2.33%) and 1 host (0.33%), respectively, while none of the hosts were positive for LT and ipaH. The repetitive element palindromic PCR (rep-PCR) fingerprint analysis identified 221 unique fingerprints with a Shannon diversity index of 2.67. Multivariate analysis of variance revealed that majority of the isolates clustered according to the year of sampling. The higher prevalence of atypical EPEC and non-O157 STEC observed in different animal hosts indicates that they can be a reservoir of these pathogens with the potential to contaminate surface water and impact human health. Therefore, we suggest that E. coli from these sources must be included while constructing known source fingerprint libraries for tracking purposes. However, the observed genetic diversity and temporal variation need to be considered since these factors can influence the accuracy of BST results. PMID- 24056457 TI - Aerobic biofilms grown from Athabasca watershed sediments are inhibited by increasing concentrations of bituminous compounds. AB - Sediments from the Athabasca River and its tributaries naturally contain bitumen at various concentrations, but the impacts of this variation on the ecology of the river are unknown. Here, we used controlled rotating biofilm reactors in which we recirculated diluted sediments containing various concentrations of bituminous compounds taken from the Athabasca River and three tributaries. Biofilms exposed to sediments having low and high concentrations of bituminous compounds were compared. The latter were 29% thinner, had a different extracellular polysaccharide composition, 67% less bacterial biomass per MUm2, 68% less cyanobacterial biomass per MUm2, 64% less algal biomass per MUm2, 13% fewer protozoa per cm2, were 21% less productive, and had a 33% reduced content in chlorophyll a per mm2 and a 20% reduction in the expression of photosynthetic genes, but they had a 23% increase in the expression of aromatic hydrocarbon degradation genes. Within the Bacteria, differences in community composition were also observed, with relatively more Alphaproteobacteria and Betaproteobacteria and less Cyanobacteria, Bacteroidetes, and Firmicutes in biofilms exposed to high concentrations of bituminous compounds. Altogether, our results suggest that biofilms that develop in the presence of higher concentrations of bituminous compounds are less productive and have lower biomass, linked to a decrease in the activities and abundance of photosynthetic organisms likely due to inhibitory effects. However, within this general inhibition, some specific microbial taxa and functional genes are stimulated because they are less sensitive to the inhibitory effects of bituminous compounds or can degrade and utilize some bitumen-associated compounds. PMID- 24056458 TI - Preadaptation to cold stress in Salmonella enterica serovar Typhimurium increases survival during subsequent acid stress exposure. AB - Salmonella is an important cause of bacterial food-borne gastroenteritis. Salmonella encounters multiple abiotic stresses during pathogen elimination methods used in food processing, and these stresses may influence its subsequent survivability within the host or in the environment. Upon ingestion, Salmonella is exposed to gastrointestinal acidity, a first line of the host innate defense system. This study tested the hypothesis that abiotic stresses encountered during food processing alter the metabolic mechanisms in Salmonella that enable survival and persistence during subsequent exposure to the host gastrointestinal acidic environment. Out of the four different abiotic stresses tested, viz., cold, peroxide, osmotic, and acid, preadaptation of the log-phase culture to cold stress (5 degrees C for 5 h) significantly enhanced survival during subsequent acid stress (pH 4.0 for 90 min). The gene expression profile of Salmonella preadapted to cold stress revealed induction of multiple genes associated with amino acid metabolism, oxidative stress, and DNA repair, while only a few of the genes in the above-mentioned stress response and repair pathways were induced upon exposure to acid stress alone. Preadaptation to cold stress decreased the NAD+/NADH ratio and hydroxyl (OH.) radical formation compared with those achieved with the exposure to acid stress alone, indicating alteration of aerobic respiration and the oxidative state of the bacteria. The results from this study suggest that preadaptation to cold stress rescues Salmonella from the deleterious effect of subsequent acid stress exposure by induction of genes involved in stress response and repair pathways, by modification of aerobic respiration, and by redox modulation. PMID- 24056459 TI - Using transcriptomics to improve butanol tolerance of Synechocystis sp. strain PCC 6803. AB - Cyanobacteria are emerging as promising hosts for production of advanced biofuels such as n-butanol and alkanes. However, cyanobacteria suffer from the same product inhibition problems as those that plague other microbial biofuel hosts. High concentrations of butanol severely reduce growth, and even small amounts can negatively affect metabolic processes. An understanding of how cyanobacteria are affected by their biofuel product can enable identification of engineering strategies for improving their tolerance. Here we used transcriptome sequencing (RNA-Seq) to assess the transcriptome response of Synechocystis sp. strain PCC 6803 to two concentrations of exogenous n-butanol. Approximately 80 transcripts were differentially expressed at 40 mg/liter butanol, and 280 transcripts were different at 1 g/liter butanol. Our results suggest a compromised cell membrane, impaired photosynthetic electron transport, and reduced biosynthesis. Accumulation of intracellular reactive oxygen species (ROS) scaled with butanol concentration. Using the physiology and transcriptomics data, we selected several genes for overexpression in an attempt to improve butanol tolerance. We found that overexpression of several proteins, notably, the small heat shock protein HspA, improved tolerance to butanol. Transcriptomics-guided engineering created more solvent-tolerant cyanobacteria strains that could be the foundation for a more productive biofuel host. PMID- 24056460 TI - Survival of bactericidal antibiotic treatment by a persister subpopulation of Listeria monocytogenes. AB - Listeria monocytogenes can cause the serious infection listeriosis, which despite antibiotic treatment has a high mortality. Understanding the response of L. monocytogenes to antibiotic exposure is therefore important to ensure treatment success. Some bacteria survive antibiotic treatment by formation of persisters, which are a dormant antibiotic-tolerant subpopulation. The purpose of this study was to determine whether L. monocytogenes can form persisters and how bacterial physiology affects the number of persisters in the population. A stationary-phase culture of L. monocytogenes was adjusted to 10(8) CFU ml(-1), and 10(3) to 10(4) CFU ml(-1) survived 72-h treatment with 100 MUg of norfloxacin ml(-1), indicating a persister subpopulation. This survival was not caused by antibiotic resistance as regrown persisters were as sensitive to norfloxacin as the parental strain. Higher numbers of persisters (10(5) to 10(6)) were surviving when older stationary phase or surface-associated cells were treated with 100 MUg of norfloxacin ml(-1). The number of persisters was similar when a DeltasigB mutant and the wild type were treated with norfloxacin, but the killing rate was higher in the DeltasigB mutant. Dormant norfloxacin persisters could be activated by the addition of fermentable carbohydrates and subsequently killed by gentamicin; however, a stable surviving subpopulation of 10(3) CFU ml(-1) remained. Nitrofurantoin that has a growth-independent mode of action was effective against both growing and dormant cells, suggesting that eradication of persisters is possible. Our study adds L. monocytogenes to the list of bacterial species capable of surviving bactericidal antibiotics in a dormant stage, and this persister phenomenon should be borne in mind when developing treatment regimens. PMID- 24056461 TI - Occurrence of pepper mild mottle virus in drinking water sources in Japan. AB - Pepper mild mottle virus (PMMoV) is a plant virus that has been recently proposed as a potential indicator of human fecal contamination of environmental waters; however, information on its geographical occurrence in surface water is still limited. We aimed to determine the seasonal and geographic occurrence of PMMoV in drinking water sources all over Japan. Between July 2008 and February 2011, 184 source water samples were collected from 30 drinking water treatment plants (DWTPs); viruses from 1 to 2 liters of each sample were concentrated by using an electronegative membrane, followed by RNA extraction and reverse transcription. Using quantitative PCR, PMMoV was detected in 140 (76%) samples, with a concentration ranging from 2.03*10(3) to 2.90*10(6) copies/liter. At least one of the samples from 27 DWTPs (n=4 or 8) was positive for PMMoV; samples from 10 of these DWTPs were always contaminated. There was a significant difference in the occurrence of PMMoV among geographical regions but not a seasonal difference. PMMoV was frequently detected in samples that were negative for human enteric virus or Escherichia coli. A phylogenetic analysis based on the partial nucleotide sequences of the PMMoV coat protein gene in 12 water samples from 9 DWTPs indicated that there are genetically diverse PMMoV strains present in drinking water sources in Japan. To our knowledge, this is the first study to demonstrate the occurrence of PMMoV in environmental waters across wide geographical regions. PMID- 24056462 TI - Components of the cultivated red seaweed Chondrus crispus enhance the immune response of Caenorhabditis elegans to Pseudomonas aeruginosa through the pmk-1, daf-2/daf-16, and skn-1 pathways. AB - Marine macroalgae are rich in bioactive compounds that can, when consumed, impart beneficial effects on animal and human health. The red seaweed Chondrus crispus has been reported to have a wide range of health-promoting activities, such as antitumor and antiviral activities. Using a Caenorhabditis elegans infection model, we show that C. crispus water extract (CCWE) enhances host immunity and suppresses the expression of quorum sensing (QS) and the virulence factors of Pseudomonas aeruginosa (strain PA14). Supplementation of nematode growth medium with CCWE induced the expression of C. elegans innate immune genes, such as irg 1, irg-2, F49F1.6, hsf-1, K05D8.5, F56D6.2, C29F3.7, F28D1.3, F38A1.5 ZK6.7, lys 1, spp-1, and abf-1, by more than 2-fold, while T20G5.7 was not affected. Additionally, CCWE suppressed the expression of PA14 QS genes and virulence factors, although it did not affect the growth of the bacteria. These effects correlated with a 28% reduction in the PA14-inflicted killing of C. elegans. Kappa-carrageenan (K-CGN), a major component of CCWE, was shown to play an important role in the enhancement of host immunity. Using C. elegans mutants, we identified that pmk-1, daf-2/daf-16, and skn-1 are essential in the K-CGN-induced host immune response. In view of the conservation of innate immune pathways between C. elegans and humans, the results of this study suggest that water soluble components of C. crispus may also play a health-promoting role in higher animals and humans. PMID- 24056463 TI - Impact of logging and forest conversion to oil palm plantations on soil bacterial communities in Borneo. AB - Tropical forests are being rapidly altered by logging and cleared for agriculture. Understanding the effects of these land use changes on soil bacteria, which constitute a large proportion of total biodiversity and perform important ecosystem functions, is a major conservation frontier. Here we studied the effects of logging history and forest conversion to oil palm plantations in Sabah, Borneo, on the soil bacterial community. We used paired-end Illumina sequencing of the 16S rRNA gene, V3 region, to compare the bacterial communities in primary, once-logged, and twice-logged forest and land converted to oil palm plantations. Bacteria were grouped into operational taxonomic units (OTUs) at the 97% similarity level, and OTU richness and local-scale alpha-diversity showed no difference between the various forest types and oil palm plantations. Focusing on the turnover of bacteria across space, true beta-diversity was higher in oil palm plantation soil than in forest soil, whereas community dissimilarity-based metrics of beta-diversity were only marginally different between habitats, suggesting that at large scales, oil palm plantation soil could have higher overall gamma-diversity than forest soil, driven by a slightly more heterogeneous community across space. Clearance of primary and logged forest for oil palm plantations did, however, significantly impact the composition of soil bacterial communities, reflecting in part the loss of some forest bacteria, whereas primary and logged forests did not differ in composition. Overall, our results suggest that the soil bacteria of tropical forest are to some extent resilient or resistant to logging but that the impacts of forest conversion to oil palm plantations are more severe. PMID- 24056465 TI - Stark contrast in denitrification and anammox across the deep Norwegian trench in the Skagerrak. AB - Environmental anaerobic ammonium oxidation (anammox) was demonstrated for the first time in 2002, using (15)N labeling, in homogenized sediment from the Skagerrak, where it accounted for up to 67% of N2 production. We returned to some of these original sites in 2010 to make measurements of nitrogen and carbon cycling under conditions more representative of those in situ, quantifying anammox and denitrification, together with oxygen penetration and consumption, in intact sediment cores. Overall, oxygen consumption and N2 production decayed with water depth, as expected, but the drop in N2 production was relatively more pronounced. Whereas we confirmed the dominance of N2 production by anammox (72% and 77%) at the two deepest sites (~700 m of water), anammox was conspicuously absent from two shallower sites (~200 m and 400 m). At the shallower sites, we could measure no anammox activity with either intact or homogeneous sediment, and quantitative PCR (16S rRNA) gave a negligible abundance of anammox bacteria in the anoxic layers. Such an absence of anammox, especially at one locale where it was originally demonstrated, is hard to reconcile. Despite the dominance of anammox at the deepest sites, anammox activity could not make up for the drop in denitrification, and assuming Redfield ratios for the organic matter being mineralized, the estimated retention of fixed N actually increased to 90% to 97% of that mineralized, whereas it was 80% to 86% at the shallower sites. PMID- 24056464 TI - Novel gene clusters and metabolic pathway involved in 3,5,6-trichloro-2-pyridinol degradation by Ralstonia sp. strain T6. AB - 3,5,6-Trichloro-2-pyridinol (TCP) is a widespread pollutant. Some bacteria and fungi have been reported to degrade TCP, but the gene clusters responsible for TCP biodegradation have not been characterized. In this study, a fragment of the reduced flavin adenine dinucleotide (FADH2)-dependent monooxygenase gene tcpA was amplified from the genomic DNA of Ralstonia sp. strain T6 with degenerate primers. The tcpA disruption mutant strain T6-DeltatcpA could not degrade TCP but could degrade the green intermediate metabolite 3,6-dihydroxypyridine-2,5-dione (DHPD), which was generated during TCP biodegradation by strain T6. The flanking sequences of tcpA were obtained by self-formed adaptor PCR. tcpRXA genes constitute a gene cluster. TcpR and TcpX are closely related to the LysR family transcriptional regulator and flavin reductase, respectively. T6-DeltatcpA-com, the complementation strain for the mutant strain T6-DeltatcpA, recovered the ability to degrade TCP, and the strain Escherichia coli DH10B-tcpRXA, which expressed the tcpRXA gene cluster, had the ability to transform TCP to DHPD, indicating that tcpA is a key gene in the initial step of TCP degradation and that TcpA dechlorinates TCP to DHPD. A library of DHPD degradation-deficient mutants of strain T6 was obtained by random transposon mutagenesis. The fragments flanking the Mariner transposon were amplified and sequenced, and the dhpRIJK gene cluster was cloned. DhpJ could transform DHPD to yield an intermediate product, 5-amino-2,4,5-trioxopentanoic acid (ATOPA), which was further degraded by DhpI. DhpR and DhpK are closely related to the AraC family transcriptional regulator and the MFS family transporter, respectively. PMID- 24056466 TI - Snf1 is a regulator of lipid accumulation in Yarrowia lipolytica. AB - In the oleaginous yeast Yarrowia lipolytica, de novo lipid synthesis and accumulation are induced under conditions of nitrogen limitation (or a high carbon-to-nitrogen ratio). The regulatory pathway responsible for this induction has not been identified. Here we report that the SNF1 pathway plays a key role in the transition from the growth phase to the oleaginous phase in Y. lipolytica. Strains with a Y. lipolytica snf1 (Ylsnf1) deletion accumulated fatty acids constitutively at levels up to 2.6-fold higher than those of the wild type. When introduced into a Y. lipolytica strain engineered to produce omega-3 eicosapentaenoic acid (EPA), Ylsnf1 deletion led to a 52% increase in EPA titers (7.6% of dry cell weight) over the control. Other components of the Y. lipolytica SNF1 pathway were also identified, and their function in limiting fatty acid accumulation is suggested by gene deletion analyses. Deletion of the gene encoding YlSnf4, YlGal83, or YlSak1 significantly increased lipid accumulation in both growth and oleaginous phases compared to the wild type. Furthermore, microarray and quantitative reverse transcription-PCR (qRT-PCR) analyses of the Ylsnf1 mutant identified significantly differentially expressed genes during de novo lipid synthesis and accumulation in Y. lipolytica. Gene ontology analysis found that these genes were highly enriched with genes involved in lipid metabolism. This work presents a new role for Snf1/AMP-activated protein kinase (AMPK) pathways in lipid accumulation in this oleaginous yeast. PMID- 24056467 TI - Dynamics of the Saccharomyces cerevisiae transcriptome during bread dough fermentation. AB - The behavior of yeast cells during industrial processes such as the production of beer, wine, and bioethanol has been extensively studied. In contrast, our knowledge about yeast physiology during solid-state processes, such as bread dough, cheese, or cocoa fermentation, remains limited. We investigated changes in the transcriptomes of three genetically distinct Saccharomyces cerevisiae strains during bread dough fermentation. Our results show that regardless of the genetic background, all three strains exhibit similar changes in expression patterns. At the onset of fermentation, expression of glucose-regulated genes changes dramatically, and the osmotic stress response is activated. The middle fermentation phase is characterized by the induction of genes involved in amino acid metabolism. Finally, at the latest time point, cells suffer from nutrient depletion and activate pathways associated with starvation and stress responses. Further analysis shows that genes regulated by the high-osmolarity glycerol (HOG) pathway, the major pathway involved in the response to osmotic stress and glycerol homeostasis, are among the most differentially expressed genes at the onset of fermentation. More importantly, deletion of HOG1 and other genes of this pathway significantly reduces the fermentation capacity. Together, our results demonstrate that cells embedded in a solid matrix such as bread dough suffer severe osmotic stress and that a proper induction of the HOG pathway is critical for optimal fermentation. PMID- 24056468 TI - Assessment of persistence of Bartonella henselae in Ctenocephalides felis. AB - Bartonella henselae (Rhizobiales: Bartonellaceae) is a Gram-negative fastidious bacterium of veterinary and zoonotic importance. The cat flea Ctenocephalides felis (Siphonaptera: Pulicidae) is the main recognized vector of B. henselae, and transmission among cats and humans occurs mainly through infected flea feces. The present study documents the use of a quantitative molecular approach to follow the daily kinetics of B. henselae within the cat flea and its excreted feces after exposure to infected blood for 48 h in an artificial membrane system. B. henselae DNA was detected in both fleas and feces for the entire life span of the fleas (i.e., 12 days) starting from 24 h after initiation of the blood meal. PMID- 24056469 TI - Fungal communities associated with the biodegradation of polyester polyurethane buried under compost at different temperatures. AB - Plastics play an essential role in the modern world due to their low cost and durability. However, accumulation of plastic waste in the environment causes wide scale pollution with long-lasting effects, making plastic waste management expensive and problematic. Polyurethanes (PUs) are heteropolymers that made up ca. 7% of the total plastic production in Europe in 2011. Polyester PUs in particular have been extensively reported as susceptible to microbial biodegradation in the environment, particularly by fungi. In this study, we investigated the impact of composting on PUs, as composting is a microbially rich process that is increasingly being used for the processing of green waste and food waste as an economically viable alternative to landfill disposal. PU coupons were incubated for 12 weeks in fresh compost at 25 degrees C, 45 degrees C, and 50 degrees C to emulate the thermophilic and maturation stages of the composting process. Incubation at all temperatures caused significant physical deterioration of the polyester PU coupons and was associated with extensive fungal colonization. Terminal restriction fragment length polymorphism (TRFLP) analysis and pyrosequencing of the fungal communities on the PU surface and in the surrounding compost revealed that the population on the surface of PU was different from the surrounding compost community, suggesting enrichment and selection. The most dominant fungi identified from the surfaces of PU coupons by pyrosequencing was Fusarium solani at 25 degrees C, while at both 45 degrees C and 50 degrees C, Candida ethanolica was the dominant species. The results of this preliminary study suggest that the composting process has the potential to biodegrade PU waste if optimized further in the future. PMID- 24056470 TI - Early and late trisporoids differentially regulate beta-carotene production and gene transcript Levels in the mucoralean fungi Blakeslea trispora and Mucor mucedo. AB - The multistep cleavage of carotenoids in Mucorales during the sexual phase results in a cocktail of trisporic acid (C18) sex pheromones. We hypothesized that the C18 trisporoid intermediates have a specific regulatory function for sex pheromone production and carotenogenesis that varies with genus/species and vegetative and sexual phases of their life cycles. Real-time quantitative PCR kinetics determined for Blakeslea trispora displayed a very high transcript turnover in the gene for carotenoid cleavage dioxygenase, tsp3, during the sexual phase. An in vivo enzyme assay and chromatographic analysis led to the identification of beta-apo-12'-carotenal as the first apocarotenoid involved in trisporic acid biosynthesis in B. trispora. Supplementation of C18 trisporoids, namely D'orenone, methyl trisporate C, and trisporin C, increased tsp3 transcripts in the plus compared to minus partners. Interestingly, the tsp1 gene, which is involved in trisporic acid biosynthesis, was downregulated compared to tsp3 irrespective of asexual or sexual phase. Only the minus partners of both B. trispora and Mucor mucedo had enhanced beta-carotene production after treatment with C20 apocarotenoids, 15 different trisporoids, and their analogues. We conclude that the apocarotenoids and trisporoids influence gene transcription and metabolite production, depending upon the fungal strain, corresponding genus, and developmental phase, representing a "chemical dialect" during sexual communication. PMID- 24056471 TI - Role of bacterial communities in the natural suppression of Rhizoctonia solani bare patch disease of wheat (Triticum aestivum L.). AB - Rhizoctonia bare patch and root rot disease of wheat, caused by Rhizoctonia solani AG-8, develops as distinct patches of stunted plants and limits the yield of direct-seeded (no-till) wheat in the Pacific Northwest of the United States. At the site of a long-term cropping systems study near Ritzville, WA, a decline in Rhizoctonia patch disease was observed over an 11-year period. Bacterial communities from bulk and rhizosphere soil of plants from inside the patches, outside the patches, and recovered patches were analyzed by using pyrosequencing with primers designed for 16S rRNA. Taxa in the class Acidobacteria and the genus Gemmatimonas were found at higher frequencies in the rhizosphere of healthy plants outside the patches than in that of diseased plants from inside the patches. Dyella and Acidobacteria subgroup Gp7 were found at higher frequencies in recovered patches. Chitinophaga, Pedobacter, Oxalobacteriaceae (Duganella and Massilia), and Chyseobacterium were found at higher frequencies in the rhizosphere of diseased plants from inside the patches. For selected taxa, trends were validated by quantitative PCR (qPCR), and observed shifts of frequencies in the rhizosphere over time were duplicated in cycling experiments in the greenhouse that involved successive plantings of wheat in Rhizoctonia-inoculated soil. Chryseobacterium soldanellicola was isolated from the rhizosphere inside the patches and exhibited significant antagonism against R. solani AG-8 in vitro and in greenhouse tests. In conclusion, we identified novel bacterial taxa that respond to conditions affecting bare patch disease symptoms and that may be involved in suppression of Rhizoctonia root rot and bare batch disease. PMID- 24056473 TI - Vertebral artery dissection caused by swinging a golf club: case report and literature review. AB - Vertebral artery (VA) dissection caused by swinging a golf club is extremely rare, and the mechanism of the dissection has not been elucidated. A 39-year-old man suddenly felt sharp neck pain and dizziness when he swung a driver while playing golf and visited our clinic. Imaging studies showed acute right cerebellar infarction and complete occlusion of the right VA at the C2 (axis) level. After 1 month of 100 mg aspirin treatment, the occluded right VA was completely recanalized and the patient became totally asymptomatic. Professional golfers look at the position of the ball on the ground or tee until completion of their follow-through. However, some amateur golfers look in the direction that the ball travels at the beginning of their follow-through. It is hypothesized that this rapid disproportionate head rotation produces VA elongation and distortion, mainly at the C2 level, causing stenosis or occlusion of the artery. PMID- 24056472 TI - Wastewater effluent impacts ammonia-oxidizing prokaryotes of the Grand River, Canada. AB - The Grand River (Ontario, Canada) is impacted by wastewater treatment plants (WWTPs) that release ammonia (NH3 and NH4+) into the river. In-river microbial communities help transform this ammonia into more oxidized compounds (e.g., NO3- or N2), although the spatial distribution and relative abundance of freshwater autotrophic ammonia-oxidizing prokaryotes (AOP) are not well characterized. This study investigated freshwater N cycling within the Grand River, focusing on sediment and water columns, both inside and outside a WWTP effluent plume. The diversity, relative abundance, and nitrification activity of AOP were investigated by denaturing gradient gel electrophoresis (DGGE), quantitative real time PCR (qPCR), and reverse transcriptase qPCR (RT-qPCR), targeting both 16S rRNA and functional genes, together with activity assays. The analysis of bacterial 16S rRNA gene fingerprints showed that the WWTP effluent strongly affected autochthonous bacterial patterns in the water column but not those associated with sediment nucleic acids. Molecular and activity data demonstrated that ammonia-oxidizing archaea (AOA) were numerically and metabolically dominant in samples taken from outside the WWTP plume, whereas ammonia-oxidizing bacteria (AOB) dominated numerically within the WWTP effluent plume. Potential nitrification rate measurements supported the dominance of AOB activity in downstream sediment. Anaerobic ammonia-oxidizing (anammox) bacteria were detected primarily in sediment nucleic acids. In-river AOA patterns were completely distinct from effluent AOA patterns. This study demonstrates the importance of combined molecular and activity-based studies for disentangling molecular signatures of wastewater effluent from autochthonous prokaryotic communities. PMID- 24056475 TI - Interaction between air pollution exposure and genes in relation to levels of inflammatory markers and risk of myocardial infarction. AB - OBJECTIVES: Air pollution exposure induces cardiovascular effects, possibly via systemic inflammation and coagulation misbalance. Genetic variation may determine individual susceptibility. Our aim was to investigate effect modification by inflammation (Interleukin6 (IL6), tumour necrosis factor-alpha (TNF-alpha)) and coagulation (fibrinogen Bbeta, plasminogen activator inhibitor-1 (PAI-1)) gene variants on the effect of long-term or short-term air pollution exposure on both blood marker levels and non-fatal myocardial infarction (MI) risk. DESIGN: Population-based case-control study with a nested case-crossover study. Gene environment interactions for short-term and long-term air pollution on blood marker levels were studied in population controls, for long-term exposure on MI risk using case-control design, and for short-term exposure on MI onset using case-crossover design. SETTING: The Stockholm Heart Epidemiology Programme (SHEEP) conducted in 1992-1994 in Stockholm, Sweden. Spatial modelling was used to assess long-term (up to 30 years retrospectively) air pollution exposure to traffic-NO2 and heating-SO2 emissions at home addresses. Urban background NO2, SO2, PM10 and O3 measurements were used to estimate short-term (up to 5 days) air pollution exposure. PARTICIPANTS: 1192 MI cases and 1506 population controls aged 45-70 years. OUTCOMES: The levels of blood markers of inflammation (IL-6, TNF alpha) and coagulation (fibrinogen, PAI-1) and MI risk. RESULTS: We observed gene environment interaction for several IL6 and TNF SNPs in relation to inflammation blood marker levels. One-year traffic-NO2 exposure was associated with higher IL 6 levels with each additional IL6-174C allele, and 1-year heating-SO2 exposure with higher levels of TNF-alpha in TNF-308AA homozygotes versus -308G carriers. Short-term air pollution exposure also interacted with IL6 and TNF in relation to marker levels. The risk of MI followed the effect on blood markers in each genotype group. CONCLUSIONS: Genetic variants in IL6 and TNF may modify effects of long-term and short-term air pollution exposure on inflammatory marker levels and MI risk. PMID- 24056476 TI - Can use of healthcare services among 15-16-year-olds predict an increased level of high school dropout? A longitudinal community study. AB - OBJECTIVES: To study associations between healthcare seeking in 15-16-year-olds and high school dropout 5 years later. DESIGN: Longitudinal community study. SETTING: Data from a comprehensive youth health survey conducted in 2000-2004, linked to data from national registries up to 2010. PARTICIPANTS: 13 964 10th grade secondary school students in six Norwegian counties. MAIN OUTCOME MEASURE: Logistic regression was used to compute ORs for high school dropout. RESULTS: The total proportion of students not completing high school 5 years after registering was 29% (girls 24%, boys 34%). Frequent attenders to school health services and youth health clinics at age 15-16 years had a higher dropout rate (37/48% and 45/71%), compared with those with no or moderate use. Adolescents referred to mental health services were also more likely to drop out (47/62%). Boys with moderate use of a general practitioner (GP) had a lower dropout rate (30%). A multiple logistic regression analysis, in which we adjusted for selected health indicators and sociodemographic background variables, revealed that seeking help from the youth health clinic and consulting mental health services, were associated with increased level of high school dropout 5 years later. Frequent attenders (>=4 contacts) had the highest odds of dropping out. Yet, boys who saw a GP and girls attending the school health services regularly over the previous year were less likely than their peers to drop out from high school. CONCLUSIONS: Adolescents who seek help at certain healthcare services can be at risk of dropping out of high school later. Health workers should pay particular attention to frequent attenders and offer follow-up when needed. However, boys who attended a GP regularly were more likely to continue to high school graduation, which may indicate a protective effect of having a regular and stable relationship with a GP. PMID- 24056477 TI - Comparison of strategies to reduce meticillin-resistant Staphylococcus aureus rates in surgical patients: a controlled multicentre intervention trial. AB - OBJECTIVE: To compare the effect of two strategies (enhanced hand hygiene vs meticillin-resistant Staphylococcus aureus (MRSA) screening and decolonisation) alone and in combination on MRSA rates in surgical wards. DESIGN: Prospective, controlled, interventional cohort study, with 6-month baseline, 12-month intervention and 6-month washout phases. SETTING: 33 surgical wards of 10 hospitals in nine countries in Europe and Israel. PARTICIPANTS: All patients admitted to the enrolled wards for more than 24 h. INTERVENTIONS: The two strategies compared were (1) enhanced hand hygiene promotion and (2) universal MRSA screening with contact precautions and decolonisation (intranasal mupirocin and chlorhexidine bathing) of MRSA carriers. Four hospitals were assigned to each intervention and two hospitals combined both strategies, using targeted MRSA screening. OUTCOME MEASURES: Monthly rates of MRSA clinical cultures per 100 susceptible patients (primary outcome) and MRSA infections per 100 admissions (secondary outcome). Planned subgroup analysis for clean surgery wards was performed. RESULTS: After adjusting for clustering and potential confounders, neither strategy when used alone was associated with significant changes in MRSA rates. Combining both strategies was associated with a reduction in the rate of MRSA clinical cultures of 12% per month (adjusted incidence rate ratios (aIRR) 0.88, 95% CI 0.79 to 0.98). In clean surgery wards, strategy 2 (MRSA screening, contact precautions and decolonisation) was associated with decreasing rates of MRSA clinical cultures (15% monthly decrease, aIRR 0.85, 95% CI 0.74 to 0.97) and MRSA infections (17% monthly decrease, aIRR 0.83, 95% CI 0.69 to 0.99). CONCLUSIONS: In surgical wards with relatively low MRSA prevalence, a combination of enhanced standard and MRSA-specific infection control approaches was required to reduce MRSA rates. Implementation of single interventions was not effective, except in clean surgery wards where MRSA screening coupled with contact precautions and decolonisation was associated with significant reductions in MRSA clinical culture and infection rates. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00685867. PMID- 24056478 TI - Reasons for readmission in an underserved high-risk population: a qualitative analysis of a series of inpatient interviews. AB - OBJECTIVE: To gather qualitative data to elucidate the reasons for readmissions in a high-risk population of underserved patients. DESIGN: We created an instrument with 27 open-ended questions based on current interventions. SETTING: Yale-New Haven Hospital. PATIENTS: Patients at the Yale Adult Primary Care Center (PCC). MEASUREMENTS: We conducted semi-structured qualitative interviews of patients who had four or more admissions in the previous 6 months and were currently readmitted to the hospital. RESULTS: We completed 17 interviews and identified themes relating to risk of readmission. We found that patients went directly to the emergency department (ED) when they experienced a change in health status without contacting their primary provider. Reasons for this included poor telephone or urgent care access and the belief that the PCC could not treat acute illness. Many patients could not name their primary provider. Conversely, every patient except one reported being able to obtain medications without undue financial burden, and every patient reported receiving adequate home care services. CONCLUSIONS: These high-risk patients were receiving the formal services that they needed, but were making the decision to go to the ED because of inadequate access to care and fragmented primary care relationships. Formal transitional care services are unlikely to be adequate in reducing readmissions without also addressing primary care access and continuity. PMID- 24056479 TI - Suicide-related events in young people following prescription of SSRIs and other antidepressants: a self-controlled case series analysis. AB - OBJECTIVES: We aimed to examine the temporal association between selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressant (TCA) prescriptions and suicide-related events in children and adolescents. DESIGN: Self-controlled case series. SETTING: Electronic health records were used from 479 general practices in The Health Improvement Network (THIN) UK primary care database from 1995 to 2009. PARTICIPANTS: 81 young people aged 10-18 years with a record of completed suicide, 1496 who attempted suicide, 1178 with suicidal ideation and 2361 with intentional self-harm. MAIN OUTCOME MEASURES: Incidence Rate Ratios (IRRs) for completed and attempted suicide, suicidal ideation and intentional self-harm. RESULTS: For non-fatal suicide-related behaviour, IRRs were similar for the time the person was prescribed either SSRIs or TCAs: IRRs increased during pre-exposure, peaked on prescription day, were stable up to the fourth prescription-week, and decreased after the prescriptions were stopped. For both types of antidepressants, IRRs were lower or similar to pre-exposure levels during the period of prescription. For SSRIs, there was an increase in the IRR for completed suicide on the day of prescription (N=5; IRR=42.5, 95% CI 4.5 to 403.4), and during the fourth week of SSRI prescription (N=2; IRR=11.3, 95% CI 1.1 to 115.6). CONCLUSIONS: We found that a very small number of young people were prescribed antidepressants and that there was an absence of a sustained increase in rates of suicide-related events in this group. There were no systematic differences between the association of TCAs and SSRIs and the incidence risk ratios for attempted suicide, suicidal ideation or intentional self-harm and, apart from the day of prescription, rates did not exceed pre exposure levels. The pattern of IRR for suicide for SSRIs was similar to that found in non-fatal suicide-related events. Our results warrant a re-evaluation of the current prescription of SSRIs in young people. We recommend the creation of a pragmatic registry for active pharmacovigilance. PMID- 24056480 TI - Risk factors for persistence of livestock-associated MRSA and environmental exposure in veal calf farmers and their family members: an observational longitudinal study. AB - OBJECTIVES: Livestock-associated methicillin-resistant Staphylococcus aureus (LA MRSA) emergence is a major public health concern. This study was aimed at assessing risk factors for persistently carrying MRSA in veal calf farmers and their family members. We also evaluate the dynamics of MRSA environmental load during the veal-calf production cycle. DESIGN: Observational, longitudinal, repeated cross-sectional study. SETTING: 52 veal calf farms in the Netherlands. PARTICIPANTS: From the end of 2010 to the end of 2011, a total of 211 farmers, family members and employees were included in the study. PRIMARY OUTCOME AND SECONDARY OUTCOME MEASURES: Nasal swabs were taken from participants on days 0, 4, 7 and week 12. A persistent MRSA carrier was defined as a person positive for MRSA on days 0, 4 and 7. Participants filled in an extensive questionnaire to identify potential risk factors and confounders. For estimation of MRSA prevalence in calves and environmental contamination, animal nasal swabs and Electrostatic Dust Collectors were taken on day 0 and week 12. RESULTS: The presence of potential animal reservoirs (free-ranging farm cats and sheep) and the level of contact with veal calves was positively associated with persistent MRSA carriage. Interestingly, at the end of the study (week 12), there was a twofold rise in animal prevalence and a significantly higher MRSA environmental load in the stables was found on farms with MRSA carriers. CONCLUSIONS: This study supports the hypothesis that environmental contamination with MRSA plays a role in the acquisition of MRSA in farmers and their household members and suggests that other animal species should also be targeted to implement effective control strategies. PMID- 24056481 TI - Cigarette pack design and adolescent smoking susceptibility: a cross-sectional survey. AB - OBJECTIVES: To compare adolescents' responses to three different styles of cigarette packaging: novelty (branded packs designed with a distinctive shape, opening style or bright colour), regular (branded pack with no special design features) and plain (brown pack with a standard shape and opening and all branding removed, aside from brand name). DESIGN: Cross-sectional in-home survey. SETTING UK PARTICIPANTS: Random location quota sample of 1025 never smokers aged 11-16 years. MAIN OUTCOME MEASURES: Susceptibility to smoking and composite measures of pack appraisal and pack receptivity derived from 11 survey items. RESULTS: Mean responses to the three pack types were negative for all survey items. However, 'novelty' packs were rated significantly less negatively than the 'regular' pack on most items, and the novelty and regular packs were rated less negatively than the 'plain' pack. For the novelty packs, logistic regressions, controlling for factors known to influence youth smoking, showed that susceptibility was associated with positive appraisal and also receptivity. For example, those receptive to the innovative Silk Cut Superslims pack were more than four times as likely to be susceptible to smoking than those not receptive to this pack (AOR=4.42, 95% CI 2.50 to 7.81, p<0.001). For the regular pack, an association was found between positive appraisal and susceptibility but not with receptivity and susceptibility. There was no association with pack appraisal or receptivity for the plain pack. CONCLUSIONS: Pack structure (shape and opening style) and colour are independently associated, not just with appreciation of and receptivity to the pack, but also with susceptibility to smoke. In other words, those who think most highly of novelty cigarette packaging are also the ones who indicate that they are most likely to go on to smoke. Plain packaging, in contrast, was found to directly reduce the appeal of smoking to adolescents. PMID- 24056482 TI - Burden of disease attributable to the Hebei Spirit oil spill in Taean, Korea. AB - OBJECTIVES: We aimed to assess the burden of disease (BOD) of the residents living in contaminated coastal area with oil spill and also analysed the BOD attributable to the oil spill by disease, age, sex and subregion. DESIGN: Health impact assessment by measuring years lived with disability (YLD) due to an oil spill. SETTING: A whole population of a community affected by an anthropogenic environmental disaster and secondary health outcome data. PARTICIPANTS: Based on the health outcome survey including 10 171 individuals (male 4354; female 5817), BOD of 66 473 populations (male 33 441; female 33 032) was measured. INTERVENTIONS: None. Observational study on the effect of a specific environmental health hazard. PRIMARY AND SECONDARY OUTCOME MEASURES: Using disability adjusted life year (DALY) method, BOD including physical and mental diseases was measured. For the BOD measurement, excess incidences of illnesses related to oil spill were estimated from the comparison of prevalence of the health outcomes between contaminated areas and reference area without contamination. RESULTS: YLD attributable to the oil spill were estimated to be 14 724 DALYs (male 7425 DALYs; female 7299 DALYs) for the year 2008. The YLD of mental diseases including post-traumatic stress disorder (PTSD) and depression for men were higher than that for women. The YLD for women was higher in asthma and allergies (rhinitis, dermatitis, conjunctivitis) than that for men. The effects of asthma and allergies were the greatest for people in their 40s, with the burden of mental illness being the greatest for those in their 20s. Proximity to the spill site was associated with increased BOD. CONCLUSIONS: An oil spill near a coastline can cause substantial adverse health effects. As the health effects of hazardous pollutants from oil spills are long-lasting, close follow-up studies are required to identify chronic health effects. PMID- 24056483 TI - A comparison of the analytical level of agreement of nine treponemal assays for syphilis and possible implications for screening algorithms. AB - OBJECTIVE: The serological diagnosis of syphilis requires the detection of two distinct antibodies, the non-treponemal and trepomenal. Center for Disease Control and Prevention (CDC) recommends screening first with a non-treponemal test such as (Rapid Plasma Reagin/Venereal Disease Research Laboratory), and then confirming those results with one of the several treponemal tests (Fluorescent Treponemal Antibody-Absorption (FTA-ABS), Enzyme Immunoassay, chemiluminescence, treponema pallidum particle agglutination (TP-PA) or Point of Care). Owing to the high volume of samples processed by some laboratories using automated systems, the screening with treponemal assays and confirming with non-treponemal tests is becoming the established norm. The purpose of this study was to evaluate eight treponemal assays using TP-PA as the predicate assay. METHODS: 290 stored serum samples were tested qualitatively according to the manufacturer's directions. RESULTS: Concordance with specimens tested as reactive or non-reactive using TP PA was: FTA-ABS 94.5-100%, Trep-Sure 100-98.9%, BioELISA 100-98.9%, INNO-LIA 99.1 99.4%, BIOLINE 100-98.9%, CAPTIA IgG 100-97.2%, Trep-ID 100-100% and LIAISON 100 99.4%. In order to properly evaluate the performance of these assays, the analytical sensitivity was determined by endpoint titration of serial dilutions of the reactive serum samples in normal sera. The median endpoint titre varied from 1:4 for FTA-ABS to 1:512 for Trep-Sure. CONCLUSIONS: The performance of the treponemal serological assays was comparable while using medium and high-titre sera. However, the varying performance on specimen dilutions suggests that there may be differences in sensitivity with low-titre sera that are more prevalent in primary and late syphilis cases. PMID- 24056484 TI - Ten years of asthma admissions to adult critical care units in England and Wales. AB - OBJECTIVES: To describe the patient demographics, outcomes and trends of admissions with acute severe asthma admitted to adult critical care units in England and Wales. DESIGN: 10-year, retrospective analysis of a national audit database. SETTING: Secondary care: adult, general critical care units in the UK. PARTICIPANTS: 830 808 admissions to adult, general critical care units. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographic data including age and sex, whether the patient was invasively ventilated or not, length of stay (LOS; both in the critical care unit and acute hospital), survival (both critical care unit and acute hospital) and time trends across the 10-year period. RESULTS: Over the 10 year period, there were 11 948 (1.4% of total) admissions with asthma to adult critical care units in England and Wales. Among them 67.5% were female and 32.5% were male (RR F:M 2.1; 95% CI 2.0 to 2.1). Median LOS in the critical care unit was 1.8 days (IQR 0.9-3.8). Median LOS in the acute hospital was 7 days (IQR 4 14). Critical care unit survival rate was 95.5%. Survival at discharge from hospital was 93.3%. There was an increase in admissions to adult critical care units by an average of 4.7% (95% CI 2.8 to 6.7)/year. CONCLUSIONS: Acute asthma represents a modest burden of work for adult critical care units in England and Wales. Demographic patterns for admission to critical care unit mirror those of severe asthma in the general adult community. The number of critical care admissions with asthma are rising, although we were unable to discern whether this represents a true increase in the incidence of acute asthma or asthma severity. PMID- 24056485 TI - Childhood happiness and violence: a retrospective study of their impacts on adult well-being. AB - OBJECTIVES: To examine the hypothesis that adult well-being is related to childhood experiences independent of current adult sociodemographic conditions. DESIGN: A cross-sectional, stratified, randomised sample survey using self assessed measures of current well-being and retrospective measures of childhood experiences. SETTING: Households in North West England (September 2012-March 2013). PARTICIPANTS: The individual with the next birthday in randomly selected households (n=11 500; compliance 89.6% of eligible households). Analysis was limited to those aged >=18 years and answering all pertinent questions (n=11 157). OUTCOMES: The primary outcome was a validated multicomponent measure of mental well-being (MWB). Additional outcomes included self-assessed life satisfaction (LS), life worth and trust in others. RESULTS: Adult MWB, LS, life worth and trust were all significantly related to childhood violence and happiness. Relationships remained after controlling for sociodemographics. Thus, compared with those with happy, non-violent childhoods, respondents with unhappy, violent childhoods had adjusted ORs (95% CI, significance) of 3.10 (2.59 to 3.71, p<0.001) for low MWB, 3.62 (2.99 to 4.38, p<0.001) for low LS, 4.13 (3.40 to 5.01, p<0.001) for low life worth and 2.62 (2.20 to 3.11, p<0.001) for low trust. The impact of unhappy but non-violent childhoods were smaller but significant (p<0.001). The modelled impact of childhood factors predicted, for instance, that among unemployed white men aged 25-39 years from the most deprived communities, 27% of those with happy non-violent childhoods would have low MWB rising to 53% of those with unhappy violent childhoods. CONCLUSIONS: Adult well-being is strongly linked to childhood experiences. The addition of well-being measures to outcomes already associated with adverse childhoods (eg, adolescent antisocial behaviour and risks of adult disease) strengthens the case for investment in interventions to improve childhood experiences. Public health systems are well placed to ensure that policy to improve adult well-being exploits the potential for this to be realised through appropriate interventions. PMID- 24056486 TI - A survey of TB knowledge among medical students in Southwest China: is the information reaching the target? AB - OBJECTIVES: Tuberculosis (TB) control in schools is a concern in low-income and middle-income countries with high TB burdens. TB knowledge is recognised as important for TB control in China, which has one of the highest TB prevalence in the world. Accordingly, National TB Control Guideline in China emphasised TB health education in schools as one of the core strategies for improving TB knowledge among the population. It was important to assess the level of TB knowledge in schools following 5-year implementation of the guideline, to determine whether the information was reaching the targets. DESIGN: A cross sectional study. METHODS AND STUDY SETTING: This survey assessed TB knowledge and access to TB-health information by questionnaire survey with 1486 undergraduates from two medical universities in Southwest China. RESULTS: Overall, the students had inadequate TB knowledge. Only 24.1%, 27.2% and 34.1% of the students had knowledge of TB symptoms of cough/blood-tinged sputum, their local TB dispensaries and free TB treatment policy, respectively. Very few (14.5%) had heard about the Directly Observed Therapy Short Course (DOTS), and only about half (54%) had ever accessed TB-health education information. Exposure to health education messages was significantly associated with increased knowledge of the five core TB knowledge as follows: classic TB symptoms of cough/blood-tinged sputum (OR (95% CI) 0.5(0.4 to 0.7)), TB modes of transmission (OR (95% CI) 0.4(0.3 to 0.5)), curability of TB (OR (95% CI) 0.6(0.5 to 0.7)), location and services provided by TB local dispensaries (OR (95% CI) 0.6(0.5 to 0.8)) and the national free TB treatment policy (OR (95% CI) 0.7(0.5 to 0.8)). CONCLUSIONS: The findings pose the question of whether it is time for a rethink of the current national and global approach to TB-health education/promotion which favours promotion of awareness on World TB Days rather than regular community sensitisation efforts. PMID- 24056487 TI - In utero exposure to antidepressant drugs and risk of attention deficit hyperactivity disorder: a nationwide Danish cohort study. AB - OBJECTIVE: To investigate whether in utero exposure to antidepressants is associated with increased risk of attention deficit hyperactivity disorder (ADHD). DESIGN: Cohort study. SETTING: Denmark. PARTICIPANTS: All Danish singletons born alive from 1996 to 2009 were included. Using national medical registries, we defined in utero exposure to antidepressants as redemption of an antidepressant prescription by the mother 30 days prior to or during pregnancy. We defined maternal former users of antidepressants as women, who had redeemed a prescription up to 30 days prior to pregnancy, and never users as women who had never redeemed a prescription. MAIN OUTCOME MEASURES: ADHD was defined as redemption of a prescription for ADHD medication or an ADHD hospital diagnosis. Children were followed through 2010, and we used proportional-hazards regression to compute adjusted HRs comparing children exposed in utero and children born to former antidepressant users with children born to never users. To adjust for confounding from family-related factors, we conducted a within-mother between pregnancy analysis comparing exposed children with unexposed siblings using conditional logistic regression. RESULTS: We identified a cohort of 877 778 children, of whom 1.7% were exposed in utero. The overall median follow-up time was 8 years; selective serotonin reuptake inhibitors were the most commonly used class of antidepressant during pregnancy (78% of users). The adjusted HR comparing children exposed to any antidepressant in utero with children born to never users was 1.2 (95% CI 1.1 to 1.4), and 1.6 (95% CI 1.5 to 1.8) comparing children born to former users to children born to never users of antidepressants. In the within-mother between-pregnancy analysis (n=867), the adjusted OR was 0.7 (95% CI 0.4 to 1.4). CONCLUSIONS: This study provides no evidence to support a causal association between in utero exposure to antidepressants and risk of ADHD. PMID- 24056488 TI - Safety during night shifts: a cross-sectional survey of junior doctors' preparation and practice. AB - OBJECTIVES: We aimed to determine whether junior doctors and trusts in the region make use of published evidence relating to best practice during night shift work that can safeguard alertness, reduce fatigue and limit mistakes. We surveyed junior doctors' preparation for and practice during night shifts, and the working and living conditions offered by hospitals for junior doctors carrying out night duties. DESIGN: Cross-sectional survey. SETTING: An anonymous online questionnaire was sent to junior doctors training within Health Education North West from 13 December 2012 to 14 February 2013. PARTICIPANTS: 32% (16/42) of trusts within Health Education North West sent the survey to 2139 junior doctor email addresses; 24.5% (524/2139) entered data into the survey. RESULTS: 91.6% of surveyed junior doctors worked night shifts. Prior to starting night shifts, 65% do not have a 'prophylactic' afternoon nap. At work, half (49%) can access a room with a reclining chair while 24% have a room with a bed. 37% 'never' achieve a 'natural break' on night shift; 53% 'never' achieve the recommended 20-45 min nap. 91% of respondents were unaware of the duration of sleep inertia that can affect alertness upon waking. When converting between day/night shifts, 2% use light lamps and 6% use non-benzodiazepine sedatives. Principal themes from free text analysis were feeling lethargic or unwell during night shifts, concern for patient and personal safety and inability to rest or take breaks. CONCLUSIONS: The trainees surveyed find night shifts difficult, yet do not/are unable to implement evidence-based recommendations to limit fatigue. Results suggest those surveyed experience a lack of rest facilities within their place of work and a demanding workload. The results may indicate the need to increase awareness of the potential benefits associated with different interventions that can help mitigate the fatigue associated with rotating shift work. PMID- 24056489 TI - Asthma related to cleaning agents: a clinical insight. AB - OBJECTIVE: To determine the agents causing asthmatic reactions during specific inhalation challenges (SICs) in workers with cleaning-related asthma symptoms and to assess the pattern of bronchial responses in order to identify the mechanisms involved in cleaning-related asthma. DESIGN: A retrospective case series analysis. SETTING: The study included all participants who completed an SIC procedure with the cleaning/disinfection products suspected of causing work related asthma over the period 1992-2011 in a tertiary centre, which is the single specialised centre of the French-speaking part of Belgium where all participants with work-related asthma are referred to for SIC. RESULTS: The review identified 44 participants who completed an SIC with cleaning/disinfection agents. Challenge exposure to the suspected cleaning agents elicited a >=20% fall in forced expiratory volume in 1 s (FEV1) in 17 (39%) participants. The cleaning products that induced a positive SIC contained quaternary ammonium compounds (n=10), glutaraldehyde (n=3), both of these agents (n=1) and ethanolamines (n=2). Positive SICs were associated with a significant decrease in the median (IQR) value of the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) from 1.4 (0.2-4.2) mg/mL at baseline to 0.5 (0.4-3.0) mg/mL after the challenge and a significant increase in sputum eosinophils from 1.8 (0.8-7.2)% at baseline to 10.0 (4.1-15.9)% 7 h after the challenge exposure while these parameters did not significantly change in participants with a negative SIC. Overall, 11 of 17 participants with positive SICs showed greater than threefold decrease in postchallenge histamine PC20 value, a >2% increase in sputum eosinophils, or both of these outcomes. CONCLUSIONS: These data indicate that a substantial proportion of workers who experience asthma symptoms related to cleaning materials show a pattern of bronchial reaction consistent with sensitiser-induced occupational asthma. The results also suggest that quaternary ammonium compounds are the principal cause of sensitiser-induced occupational asthma among cleaners. PMID- 24056490 TI - The COMPlaints After Stroke (COMPAS) study: protocol for a Dutch cohort study on poststroke subjective cognitive complaints. AB - BACKGROUND: Although many studies have assessed poststroke objective cognitive impairment, only a few have evaluated patients' subjective cognitive complaints (SCC). Although these SCC are found to be common in the early and chronic phases after stroke, knowledge about their risk factors, course over time, differences with healthy controls and their diagnostic relevance is limited. The aim of the COMPlaints After Stroke (COMPAS) study is therefore to determine the possible risk factors, prognosis, time course and predictive value of SCC in the first 2 years after stroke. METHODS AND DESIGN: A prospective cohort study is conducted in which patients are compared to non-stroke controls at 3, 6, 12 and 24 months after stroke. Approximately 300 patients are recruited from the stroke units of three hospitals in the Netherlands, while 300 controls are sought among the relatives (spouses excluded) and social networks of participants. A wide range of subjective and objective variables is assessed in both groups using interviews, questionnaires and neuropsychological assessment. The primary outcomes include SCC and objective cognitive impairment, whereas secondary outcomes are quality of life, subjective recovery and daily life functioning. ETHICS AND DISSEMINATION: The study is being carried out in agreement with the Declaration of Helsinki and the Medical Research Involving Human Subjects Act. The protocol has been approved by the medical ethics committees of the participating centres and all participants give written informed consent. The results will be published in peer reviewed journals and disseminated to the medical society and general public. DISCUSSION: The COMPAS study is the first to systematically evaluate poststroke SCC in a prospective longitudinal design, taking a wide range of subjective and objective variables into account. The results obtained can be used to accurately inform patients and their families, as well as to develop patient-tailored intervention programmes to ultimately improve stroke patient care. PMID- 24056491 TI - Cortical beta-amyloid levels and neurocognitive performance after cardiac surgery. AB - INTRODUCTION: Neurological and neurocognitive dysfunction occurs frequently in the large number of increasingly elderly patients undergoing cardiac surgery every year. Perioperative cognitive deficits have been shown to persist after discharge and up to several years after surgery. More importantly, perioperative cognitive decline is predictive of long-term cognitive dysfunction, reduced quality of life and increased mortality. The proposed mechanisms to explain the cognitive decline associated with cardiac surgery include the neurotoxic accumulation of beta-amyloid. This study will be the first to provide molecular imaging to assess the relationship between neocortical beta-amyloid deposition and postoperative cognitive dysfunction. METHODS AND ANALYSIS: 40 patients providing informed consent for participation in this Institutional Review Board approved study and undergoing cardiac (coronary artery bypass graft (CABG), valve or CABG+valve) surgery with cardiopulmonary bypass will be enrolled based on defined inclusion and exclusion criteria. At 6 weeks after surgery, participants will undergo (18)F-florbetapir positron emission tomography imaging to assess neocortical beta-amyloid burden along with a standard neurocognitive battery and blood testing for apolipoprotein E epsilon-4 genotype. RESULTS: The results will be compared to those of 40 elderly controls and 40 elderly patients with mild cognitive impairment who have previously completed (18)F-florbetapir imaging. ETHICS AND DISSEMINATION: This study has been approved by the Duke University Institutional Review Board. The results will provide novel mechanistic insights into postoperative cognitive dysfunction that will inform future studies into potential treatments or preventative therapies of long-term cognitive decline after cardiac surgery. PMID- 24056492 TI - The Smoking MUMS (Maternal Use of Medications and Safety) Study: protocol for a population-based cohort study using linked administrative data. AB - INTRODUCTION: Approximately 14% of Australian women smoke during pregnancy. Although the risk of adverse outcomes is reduced by smoking cessation, less than 35% of Australian women quit smoking spontaneously during pregnancy. Evidence for the efficacy of bupropion, varenicline or nicotine replacement therapy as smoking cessation aids in the non-pregnant population suggest that pharmacotherapy for smoking cessation is worth exploring in women of childbearing age. Currently, little is known about the utilisation, effectiveness and safety of pharmacotherapies for smoking cessation during pregnancy; neither the extent to which they are used prior to pregnancy nor whether their use has changed in response to related policy reforms. The Smoking MUMS (Maternal Use of Medications and Safety) Study will explore these issues using linked person-level data for a population-based cohort of Australian mothers. METHODS AND ANALYSIS: The cohort will be assembled by linking administrative health records for all women who gave birth in New South Wales or Western Australia since 2003 and their children, including records relating to childbirth, use of pharmaceuticals, hospital admissions, emergency department presentations and deaths. These longitudinal linked data will be used to identify utilisation of smoking cessation pharmacotherapies during and between pregnancies and to explore the associated smoking cessation rates and maternal and child health outcomes. Subgroup and temporal analyses will identify potential differences between population groups including indigenous mothers and social security recipients and track changes associated with policy reforms that have made alternative smoking cessation pharmacotherapies available. ETHICS AND DISSEMINATION: Ethical approval has been obtained for this study. To enhance the translation of the project's findings into policy and practice, policy and clinical stakeholders will be engaged through a reference group and a policy forum will be held. Outputs from the project will include scientific papers and summary reports designed for policy audiences. PMID- 24056493 TI - Phase I pilot clinical trial of antenatal maternally administered melatonin to decrease the level of oxidative stress in human pregnancies affected by pre eclampsia (PAMPR): study protocol. AB - INTRODUCTION: Pre-eclampsia is a common pregnancy condition affecting between 3% and 7% of women. Unfortunately, the exact pathophysiology of the disease is unknown and as such there are no effective treatments that exist notwithstanding prompt delivery of the fetus and culprit placenta. As many cases of pre-eclampsia occur in preterm pregnancies, it remains a significant cause of maternal and perinatal morbidity and mortality. Recently, in vitro and animal studies have highlighted the potential role of antioxidants in mitigating the effects of the disease. Melatonin is a naturally occurring antioxidant hormone and provides an excellent safety profile combined with ease of oral administration. We present the protocol for a phase I pilot clinical trial investigating the efficacy and side effects of maternal treatment with oral melatonin in pregnancies affected by preterm pre-eclampsia. METHODS AND ANALYSIS: We propose undertaking a single-arm open label clinical trial recruiting 20 women with preterm pre-eclampsia (24(+0) 35(+6) weeks). We will take baseline measurements of maternal and fetal well being, levels of oxidative stress, ultrasound Doppler studies and other biomarkers of pre-eclampsia. Women will then be given oral melatonin (10 mg) three times daily until delivery. The primary outcome will be time interval between diagnosis and delivery compared to historical controls. Secondary outcomes will compare the baseline measurements previously mentioned with twice weekly measurements during treatment and then 6 weeks postpartum. ETHICS AND DISSEMINATION: Ethical approval has been obtained from Monash Health Human Research Ethics Committee B (HREC 13076B). Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12613000476730 (ANZCTR). PMID- 24056494 TI - A population-based case-control study on social factors and risk of testicular germ cell tumours. AB - OBJECTIVES: Incidence rates for testicular cancer have risen over the last few decades. Findings of an association between the risk of testicular cancer and social factors are controversial. The association of testicular cancer and different indicators of social factors were examined in this study. DESIGN: Case control study. SETTING: Population-based multicentre study in four German regions (city states Bremen and Hamburg, the Saarland region and the city of Essen). PARTICIPANTS: The study included 797 control participants and 266 participants newly diagnosed with testicular cancer of which 167 cases were classified as seminoma and 99 as non-seminoma. The age of study participants ranged from 15 to 69 years. METHODS: Social position was classified by educational attainment level, posteducational training, occupational sectors according to Erikson Goldthorpe-Portocarrero (EGP) and the socioeconomic status (SES) on the basis of the International SocioEconomic Index of occupational status (ISEI). ORs and corresponding 95% CIs (95% CIs) were calculated for the whole study sample and for seminoma and non-seminoma separately. RESULTS: Testicular cancer risk was modestly increased among participants with an apprenticeship (OR=1.7 (95% CI 1.0 to 2.8)) or a university degree (OR=1.6 (95% CI 0.9 to 2.8)) relative to those whose education was limited to school. Analysis of occupational sectors revealed an excess risk for farmers and farm-related occupations. No clear trend was observed for the analyses according to the ISEI-scale. CONCLUSIONS: Social factors based on occupational measures were not a risk factor for testicular cancer in this study. The elevated risk in farmers and farm-related occupations warrants further research including analysis of occupational exposures. PMID- 24056495 TI - Halogen- and hydrogen-bonding triazole-functionalised porphyrin-based receptors for anion recognition. AB - Iodotriazole and triazole anion recognition groups have been integrated into a picket-fence zinc(ii)-metalloporphyrin scaffold to produce receptors for anion recognition and sensing applications. (1)H NMR and UV/visible spectroscopic investigations reveal both host systems exhibit strong anion binding affinities in a range of solvent media. Importantly, the halogen-bonding iodotriazole containing porphyrin-based host displays halide binding affinities substantially larger than the protic-functionalised analogue concomitant with a reduced strength of oxoanion complexation. PMID- 24056497 TI - A durable template for carbosilane dendrimer synthesis. AB - Many types of organosilicon dendrimers are known, but the carbosilane dendrimers are by far the most widely studied. This Viewpoint article describes the impact of a communication published in 1992 by Alexander van der Made, one of the pioneers in the field. PMID- 24056496 TI - Pharmacologic induction of epidermal melanin and protection against sunburn in a humanized mouse model. AB - Fairness of skin, UV sensitivity and skin cancer risk all correlate with the physiologic function of the melanocortin 1 receptor, a Gs-coupled signaling protein found on the surface of melanocytes. Mc1r stimulates adenylyl cyclase and cAMP production which, in turn, up-regulates melanocytic production of melanin in the skin. In order to study the mechanisms by which Mc1r signaling protects the skin against UV injury, this study relies on a mouse model with "humanized skin" based on epidermal expression of stem cell factor (Scf). K14-Scf transgenic mice retain melanocytes in the epidermis and therefore have the ability to deposit melanin in the epidermis. In this animal model, wild type Mc1r status results in robust deposition of black eumelanin pigment and a UV-protected phenotype. In contrast, K14-Scf animals with defective Mc1r signaling ability exhibit a red/blonde pigmentation, very little eumelanin in the skin and a UV-sensitive phenotype. Reasoning that eumelanin deposition might be enhanced by topical agents that mimic Mc1r signaling, we found that direct application of forskolin extract to the skin of Mc1r-defective fair-skinned mice resulted in robust eumelanin induction and UV protection (1). Here we describe the method for preparing and applying a forskolin-containing natural root extract to K14-Scf fair-skinned mice and report a method for measuring UV sensitivity by determining minimal erythematous dose (MED). Using this animal model, it is possible to study how epidermal cAMP induction and melanization of the skin affect physiologic responses to UV exposure. PMID- 24056498 TI - Risk factor analysis for capsular contracture: a 5-year Sientra study analysis using round, smooth, and textured implants for breast augmentation. AB - BACKGROUND: Although there are a few broadly agreed on contributory factors, the multifaceted causes of capsular contracture have remained unresolved for decades. This study investigates a variety of potential risk factors that contribute to capsular contracture in primary augmentation patients. METHODS: The data used for this analysis include 5109 implants in 2560 primary augmentation patients implanted by 34 surgeons based on 5-year results from Sientra's clinical study. Patients were evaluated at annual visits where the capsular contracture Baker grade was recorded. Potential risk factors, including patient attributes, implant attributes, surgery characteristics, pocket irrigation, and postsurgery characteristics, were analyzed using frequency and multivariate models. RESULTS: A total of 265 capsular contracture events in 179 patients were reported through 5 years. The overall Kaplan-Meier rate for capsular contracture was 7.6 percent by device. The unadjusted analysis showed increased odds of capsular contracture in smooth devices, periareolar incision, subglandular placement, antibiotic and steroid pocket irrigation, recommended massage, and surgical bra (p<0.05 for all). Results from the multivariate analysis, adjusting for all variables in the model, found six factors to be independently associated with capsular contracture (i.e., implant placement, implant surface, incision site, hematoma or seroma development, device size, and surgical bra; p<0.05 for all). CONCLUSION: This analysis has provided evidence that submuscular placement and textured implants, in addition to other factors, are significant in reducing the incidence of capsular contracture. PMID- 24056499 TI - RNA-seq-based comparative transcriptome analysis of the syngas-utilizing bacterium Clostridium ljungdahlii DSM 13528 grown autotrophically and heterotrophically. AB - Clostridium ljungdahlii DSM 13528 represents a promising platform organism for production of a whole variety of different biofuels and biochemicals from syngas. Although the publication of its genome gave us the first possibility to understand the molecular mechanism for carbon utilization, reports on the profiling of the transcriptome were unavailable. In this study, RNA-seq-based global transcriptome analysis was performed to compare the transcriptomes of C. ljungdahlii grown on CO-CO2 with those grown on fructose. In total, 1852 differentially expressed genes were identified, which included 366 upregulated genes and 1486 downregulated genes under CO-CO2 conditions. These up- and downregulated genes are predicted to be involved in the Wood-Ljungdahl pathway, CO2 reduction to acetic acid, fructose fermentation, central carbon metabolism and transport, and vitamin B12 synthesis. In addition, 36 small RNAs were identified, 20 of which were novel small RNAs. Quantitative real-time PCR (qRT PCR) and RT-PCR analysis of the selected functional genes and sRNA genes expression profiles were found to be consistent with the RNA-seq data. The study allowed a deeper understanding of the molecular mechanisms underlying syngas utilization and could help guide the design of rational strategies to increase the efficiency of syngas fixation in the future. PMID- 24056500 TI - Versatile multi-wavelength ultrafast fiber laser mode-locked by carbon nanotubes. AB - Multi-wavelength lasers have widespread applications (e.g. fiber telecommunications, pump-probe measurements, terahertz generation). Here, we report a nanotube-mode-locked all-fiber ultrafast oscillator emitting three wavelengths at the central wavelengths of about 1540, 1550, and 1560 nm, which are tunable by stretching fiber Bragg gratings. The output pulse duration is around 6 ps with a spectral width of ~0.5 nm, agreeing well with the numerical simulations. The triple-laser system is controlled precisely and insensitive to environmental perturbations with <0.04% amplitude fluctuation. Our method provides a simple, stable, low-cost, multi-wavelength ultrafast-pulsed source for spectroscopy, biomedical research and telecommunications. PMID- 24056501 TI - Ruthenium complexes as novel inhibitors of human islet amyloid polypeptide fibril formation. AB - Human islet amyloid polypeptide (hIAPP) can be linked to the pathology of type II diabetes. In this study, aromatic ring-containing Ru complexes were found to effectively inhibit the fibril formation of hIAPP and promote the disaggregation of formed fibrils by remarkably changing the beta-sheet components. PMID- 24056502 TI - Comparative studies on the constituents, antioxidant and anticancer activities of extracts from different varieties of corn silk. AB - The purpose of this study was to analyze the influence of varieties on the constituents, antioxidant and anticancer activities of corn silk. The contents of total phenolic and flavonoids and individual flavonoids in six corn silk varieties (Denghai6702, Delinong988, Tunyu808, Zhongdan909, Liangyu208, Jingke968) were comparatively analyzed by colourimetric methods, high performance liquid chromatography (HPLC) methods and antioxidant activities were assessed using a panel of in vitro assays, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity assay, the inhibitory effects on lipid peroxidation (MDA) assay and ferric reducing/antioxidant power (FRAP) assay, and the cytotoxicity against human prostatic carcinoma cells PC3 and breast carcinoma cells MDA-MB-231 and MCF7 were also evaluated. Results showed that Zhongdan909 exhibited the highest total phenolic content while Tunyu808 had the highest flavonoid content among the six species. Zhongdan909 showed the highest DPPH radical scavenging activity, the highest inhibitory effect on lipid peroxidation and the strongest cytotoxicity against breast carcinoma cells MCF7, while Tunyu808 exhibited the highest reducing power. There were good relationships between the total phenolic and flavonoid contents and antioxidant activities (r > 0.78) and the cytotoxicity against breast carcinoma cells MCF7 (r > 0.79). This study suggested that corn silk could be potentially used as a readily accessible source of natural antioxidants and formononetin was one of the main antioxidant constituents in corn silk. PMID- 24056503 TI - In vivo imaging of tumor angiogenesis using fluorescence confocal videomicroscopy. AB - Fibered confocal fluorescence in vivo imaging with a fiber optic bundle uses the same principle as fluorescent confocal microscopy. It can excite fluorescent in situ elements through the optical fibers, and then record some of the emitted photons, via the same optical fibers. The light source is a laser that sends the exciting light through an element within the fiber bundle and as it scans over the sample, recreates an image pixel by pixel. As this scan is very fast, by combining it with dedicated image processing software, images in real time with a frequency of 12 frames/sec can be obtained. We developed a technique to quantitatively characterize capillary morphology and function, using a confocal fluorescence videomicroscopy device. The first step in our experiment was to record 5 sec movies in the four quadrants of the tumor to visualize the capillary network. All movies were processed using software (ImageCell, Mauna Kea Technology, Paris France) that performs an automated segmentation of vessels around a chosen diameter (10 MUm in our case). Thus, we could quantify the 'functional capillary density', which is the ratio between the total vessel area and the total area of the image. This parameter was a surrogate marker for microvascular density, usually measured using pathology tools. The second step was to record movies of the tumor over 20 min to quantify leakage of the macromolecular contrast agent through the capillary wall into the interstitium. By measuring the ratio of signal intensity in the interstitium over that in the vessels, an 'index leakage' was obtained, acting as a surrogate marker for capillary permeability. PMID- 24056504 TI - Amplifying the community voice in community-academic partnerships: a summary of and commentary on a thematic issue. PMID- 24056505 TI - "I know what CBPR is, now what do i do?": Community perspectives on CBPR capacity building. AB - BACKGROUND: Community-based participatory research (CBPR) offers a promising approach for combating health disparities. CBPR capacity must be developed among academics and communities. Most published CBPR capacity development work focuses on general guidance or individual partnership development. OBJECTIVES: Herein we have reported community perspectives on community capacity-building efforts involving multiple community partners, including capacity-building outcomes and identification of facilitators and challenges. METHODS: We have presented a case study using qualitative and quantitative data from community-based organization (CBO) members of a committee guiding a university-based CBPR initiative. A survey measuring 11 CBPR capacity domains was fielded at two points. Three rounds of interviews were conducted. RESULTS: Community CBPR capacity increased over time, although there remains room for improvement. Leader commitment, CBPR resources, and hands-on CBPR experiences were identified as key facilitators. Resource limitations, difficulty integrating CBPR into organizational operations, lack of specific information, and institutional inequities were identified as challenges. Recommendations offered include continued and expanded support for sharing/co learning with academic partners and capacity-building activities and services. CONCLUSIONS: Results will inform future efforts and contribute to the understanding of capacity-building outcomes for initiatives supporting multiple CBPR partnerships. PMID- 24056507 TI - Creating a community-physical therapy partnership to increase physical activity in urban African-American adults. AB - BACKGROUND: Racial disparities in health across the United States remain, and in some cities have worsened despite increased focus at federal and local levels. One approach to addressing health inequity is community-based participatory research (CBPR). OBJECTIVES: The purpose of this paper is to describe the develop ment of an ongoing community-physical therapy partnership focused on physical activity (PA), which aims to improve the health of African-American community members and engage physical therapist (PT) students in CBPR. METHODS: Three main research projects that resulted from an initial partnership-building seed grant include (1) community focus groups, (2) training of community PA promoters, and (3) pilot investigation of PA promoter effectiveness. LESSONS LEARNED: Results from each project informed the next. Focus groups findings led to development of a PA pro moter training curriculum. PA promoters were accepted by the community, with potential to increase PA. Focus on the community issue of PA fostered and sustained the partnership. CONCLUSIONS: Community and academic partners benefitted from funding, structure, and time to create meaningful, trusting, and sustainable relationships committed to improving health. Engaging PT students with community residents provided learning opportunities that promote respect and appreciation of the social, economic, and environmental context of future patients. PMID- 24056508 TI - Beyond incentives for involvement to compensation for consultants: increasing equity in CBPR approaches. AB - BACKGROUND: Community-based participatory research (CBPR) strives for equitable collaboration among community and academic partners throughout the research process. To build the capacity of academia to function as effective research partners with communities, the North Carolina Translational and Clinical Sciences Institute (NC TraCS), home of the University of North Carolina at Chapel Hill (UNC-CH)'s Clinical and Translational Sciences Award (CTSA), developed a community engagement consulting model. This new model harnesses the expertise of community partners with CBPR experience and compensates them equitably to provide technical assistance to community-academic research partnerships. OBJECTIVES: This paper describes approaches to valuing community expertise, the importance of equitable compensation for community partners, the impact on the community partners, opportunities for institutional change, and the constraints faced in model implementation. METHODS: Community Experts (CEs) are independent contractor consultants. CEs were interviewed to evaluate their satisfaction with their engagement and compensation for their work. LESSONS LEARNED: (1) CEs have knowledge, power, and credibility to push for systems change. (2) Changes were needed within the university to facilitate successful consultation to community academic partnerships. (3) Sustaining the CE role requires staff support, continued compensation, increased opportunities for engagement, and careful consideration of position demands. (4) The role provides benefits beyond financial compensation. (5) Opportunities to gather deepened relationships within the partnership and built collective knowledge that strengthened the project. CONCLUSIONS: Leveraging CE expertise and compensating them for their role benefits both university and community. Creating a place for community expertise within academia is an important step toward equitably including the community in research. PMID- 24056509 TI - The developmental stages of a community-university partnership: the experience of Padres Informados/Jovenes Preparados. AB - BACKGROUND: Strong and sustained community-university partnerships are necessary for community-based participatory translational research. Little attention has been paid to understanding the trajectory of research partnerships from a developmental perspective. OBJECTIVE: To propose a framework describing partnership development and maturation based on Erikson's eight stages of psychosocial development and describe how our collaboration is moving through those stages. METHODS: Collaborators engaged in three rounds of iterative reflection regarding characteristics and contributors to the maturation of the Padres Informados/Jovenes Preparados (Informed Parents/Prepared Youth [PI/JP]) partnership. LESSONS LEARNED: Each stage is characterized by broad developmental partnership tasks. Conflict or tension within the partnership is often a part of achieving the associated tasks. The strengths developed at each stage prepare the partnership for challenges associated with subsequent stages. CONCLUSIONS: This framework could provide a means for partnerships to reflect on their strengths and challenges at a given time point, and to help understand why some partnerships fail whereas others achieve maturity. PMID- 24056510 TI - Rural community-academic partnership model for community engagement and partnered research. AB - BACKGROUND: A rural community-academic partnership was developed in 1997 between the Eastern Shore Area Health Education Center (ESAHEC) and the University of Maryland School of Medicine's (UMSOM) Office of Policy and Planning (OPP). The model supports partnered research, bidirectional interactions, and community and health professional education. OBJECTIVES: The primary aim was to develop a sustainable community-academic partnership that addressed health and social issues on the rural Eastern Shore. LESSONS LEARNED: Mutual respect and trust led to sustained, bidirectional interactions and communication. Community and academic partner empowerment were supported by shared grant funds. Continual refinement of the partnership and programs occurred in response to community input and qualitative and quantitative research. RESULTS: The partnership led to community empowerment, increased willingness to participate in clinical trials and biospecimen donation, leveraged grant funds, partnered research, and policies to support health and social interventions. CONCLUSIONS: This partnership model has significant benefits and demonstrates its relevance for addressing complex rural health issues. Innovative aspects of the model include shared university grants, community inclusion on research protocols, bidirectional research planning and research ethics training of partners and communities. The model is replicable in other rural areas of the United States. PMID- 24056511 TI - Community capacity building: a collaborative approach to designing a training and education model. AB - BACKGROUND: Successful community-academic research partnerships require building the capacity of both community-based organizations (CBOs) and academics to conduct collaborative research of mutual interest and benefit. Yet, information about the needs and goals of research-interested CBOs is lacking. Our partnership aimed to conduct a community research needs assessment and to use results to develop future capacity-building programs for CBOs. METHODS: Based on our review of the literature, informal interviews with research-interested CBOs and community-engaged research groups locally and nationally, we developed a needs assessment survey. Key domains of this survey included history and experience with research collaboration, interest in specific research topics, and preference for learning format and structure. We trained community health workers (CHWs) to recruit senior leaders from CBOs in New York City (NYC) and encourage them to complete an on-line survey. RESULTS: Fully 54% (33/61) of CBOs completed the needs assessment. Most (69%) reported involvement with research or evaluation in the last 2 years and 33% had some funding for research. Although 75% had collaborated with academic institutions in the past, 58% did not rate this experience well. The four areas respondents prioritized for skills building were program evaluation, developing needs assessments, building surveys, and understanding statistical analyses. They were less interested in learning to build collaborations with academics. CONCLUSIONS: A formal needs assessment of research training and educational needs of CBOs revealed that most had experience, albeit negative, with academic collaborations. CBO leaders wanted to build skills to conduct and analyze assessments and program evaluations. Our community-academic partnership is using these findings to develop a research capacity-building course. Other partnerships should consider conducting such assessments to transform the capacity of CBOs to be active research partners and leaders. PMID- 24056512 TI - External community review committee: a new strategy for engaging community stakeholders in research funding decisions. AB - BACKGROUND: Major gaps exist between what we know and what we do in clinical practice and community health programs and narrowing this gap will require substantive partnerships between academic researchers and the communities they serve. OBJECTIVES: We describe a research pilot award program that makes a unique commitment to community engagement through the addition of an External Community Review Committee to the typical research review process that gives external stakeholders decision-making power over research funding. METHODS: Whereas engaging community reviewers in discussion and rating of research proposals is not novel, the ICTR ECRC review process is distinct in that it is subsequent to peer review and uses different criteria and methodology. This method of engagement allows for the community review panel to re-rank scientifically meritorious proposals-such that proposals funded do not necessarily follow the rank order from scientific peer review. The approach taken by UW ICTR differs from those discussed in the literature that present a model of community-academic co-review. RESULTS: This article provides guidance for others interested in this model of community engagement and reviews insights gained during the evolution of this strategy; including how we addressed conflict, how the committee was able to change the pilot award program over time, and individual roles that were crucial to the success of this approach. CONCLUSIONS: The advantages of this approach include success through traditional academic metrics while achieving an innovative shared-power mechanism for community engagement which we believe is critical for narrowing the gap between knowledge and practice. PMID- 24056513 TI - Rural Oregon community perspectives: introducing community-based participatory research into a community health coalition. AB - The Community Health Improvement Partnership (CHIP) model has supported community health development in more than 100 communities nationally. In 2011, four rural Oregon CHIPs collaborated with investigators from the Oregon Rural Practice-based Research Network (ORPRN), a component of the Oregon Clinical and Translational Research Institute (OCTRI), to obtain training on research methods, develop and implement pilot research studies on childhood obesity, and explore matches with academic partners. This article summarizes the experiences of the Lincoln County CHIP, established in 2003, as it transitioned from CHIP to Community Health Improvement and Research Partnership (CHIRP). Our story and lessons learned may inform rural community-based health coalitions and academicians who are engaged in or considering Community-based participatory research (CBPR) partnerships. Utilizing existing infrastructure and relationships in community and academic settings provides an ideal starting point for rural, bidirectional research partnerships. PMID- 24056514 TI - Time, dual roles, and departments of public health: lessons learned in CBPR by an AIDS service organization. AB - Community-based participatory research (CBPR) is an important approach to inform the development and implementation of HIV/AIDS prevention and treatment strategies. However, there is a paucity of literature describing CBPR from the perspective of community-based organizations (CBOs), specifically AIDS service organizations (ASO). Focusing on the perspective of the executive director (ED) from the partnering ASO, we describe in this paper lessons learned during Project Counseling Others About Contacts and Exposures with HIV (COACH), a CBPR, qualitative study intended to examine perspectives and experiences of professionals and clients regarding partner notification (PN) for HIV. Specifically, we describe opportunities and challenges associated with the time investment, balancing a dual role of service provider and researcher, and partnering with the department of public health. This description of the perspective of the ED from the ASO and the associated lessons learned may inform the actions of other CBOs, including ASOs, considering partnering with academic institutions for CBPR. PMID- 24056515 TI - Using the Delphi and snow card techniques to build consensus among diverse community and academic stakeholders. AB - BACKGROUND: The New York University- New York City Health and Hospitals Corporation (NYU-HHC) Clinical and Translational Science Institute (CTSI) used a community-based participatory research (CBPR) and consensus-building approach among its community advisory board (CAB) and steering committee (SC) members to formulate research priorities to foster shared research collaborations. METHODS: The Delphi technique is a methodology used to generate consensus from diverse perspectives and organizational agendas through a multi-method, iterative approach to collecting data. A series of on-line surveys was conducted with CAB members to identify health and research priorities from the community perspective. Subsequently, CAB and SC members were brought together and the snow card approach was utilized to narrow to two priority areas for shared research collaborations. RESULTS: Cardiovascular disease (CVD)/obesity and mental health were identified as health disparity areas for shared research collaborations within a social determinants framework. In response, two workgroups were formed with leadership provided by three co-chairs representing the three constituents of the NYU-HHC CTSI: NYU faculty, HHC providers, and community leaders CONCLUSIONS: The Delphi approach fostered ownership and engagement with community partners because it was an iterative process that required stakeholders' input into decision making. The snow card technique allowed for organizing of a large number of discrete ideas. Results have helped to inform the overall CTSI research agenda by defining action steps, and setting an organizing framework to tackle two health disparity areas. The process helped ensure that NYUHHC CTSI research and community engagement strategies are congruent with community priorities. PMID- 24056516 TI - The development of the Bronx Community Research Review Board: a pilot feasibility project for a model of community consultation. AB - BACKGROUND: The Bronx Community Research Review Board (BxCRRB) is a community academic partnership (CAP) between the Albert Einstein College of Medicine and The Bronx Health Link (BHL). Rather than asking clinical investigators to create their own individual process de novo, we have developed an innovative, structural approach to achieve community consultation in research planning, implementation, and dissemination that involves and educates the public about research. OBJECTIVES: To collaboratively develop (1) an independent research review board of volunteer community residents and repre sentatives that tests a model of community consultation, dialogue, and "community-informed consent" by reviewing community-based research proposals; and (2) to increased understanding of and participation in clinical research in the Bronx. METHODS: (1) Recruiting members from the Health and Human Services committees of community boards, focus groups, and community health events; (2) interviewing and selecting members based on community involvement, experiences, availability, and demographics of the Bronx; (3) training members in bioethics and research methods; and (4) facilitating meetings and discussions between clinical researchers and the BxCRRB for research review and consultation. RESULTS: There is substantial interest among Bronx residents in participating in the BxCRRB. The BxCRRB provided feedback to researchers to ensure the protection of participants' rights, to improve research design by promoting increased accountability to the community, and expanded its scope to include earlier stages of the research process. CONCLUSION: The BxCRRB is a viable model for community consultation in research, but more time for implementation and evolution is needed to improve its review practices and ensure community input at all stages of the research process. PMID- 24056517 TI - Ethical engagement of communities, institutions, and providers in research: lessons from the community. PMID- 24056518 TI - ORMDL3 promotes eosinophil trafficking and activation via regulation of integrins and CD48. AB - ORM (yeast)-like protein isoform 3 (ORMDL3) has recently been identified as a candidate gene for susceptibility to asthma; however, the mechanisms by which it contributes to asthma pathogenesis are not well understood. Here we demonstrate a functional role for ORMDL3 in eosinophils in the context of allergic inflammation. Eosinophils recruited to the airways of allergen-challenged mice express ORMDL3. ORMDL3 expression in bone marrow eosinophils is localized in the endoplasmic reticulum and is induced by interleukin-3 and eotaxin-1. Overexpression of ORMDL3 in eosinophils causes increased rolling, distinct cytoskeletal rearrangement, extracellular signal-regulated kinase (1/2) phosphorylation and nuclear translocation of nuclear factor kappa B. Knockdown of ORMDL3 significantly inhibits activation-induced cell shape changes, adhesion and recruitment to sites of inflammation in vivo, combined with reduced expression of CD49d and CD18. In addition, ORMDL3 regulates interleukin-3-induced expression of CD48 and CD48-mediated eosinophil degranulation. These studies show that ORMDL3 regulates eosinophil trafficking, recruitment and degranulation, further elucidating a role for this molecule in allergic asthma and potentially other eosinophilic disorders. PMID- 24056519 TI - IL-22/IL-22R1 axis and S100A8/A9 alarmins in human osteoarthritic and rheumatoid arthritis synovial fibroblasts. AB - OBJECTIVES: Fibroblast-like synoviocytes (FLSs) are crucial players in the pathogenesis of synovitis in rheumatic diseases. Targeting FLS activation represents an approach to the development of therapeutic strategies. Our aim was to investigate whether the microenvironment of inflamed joints could modulate the expression of IL-22 and IL-22R1 on OA and RA FLSs. We also examined the effect of IL-22 on FLS activation as well as on their IL-17-related responses. METHODS: IL 22 and IL-22R1 expression was studied by RT-PCR and immunoblotting. Proliferation was measured by an ELISA kit. IL-17 receptors, p19IL-23 and alarmins were analysed by RT-PCR. IL-17 receptor expression was evaluated by flow cytometry. MMP1 and IL-23 were measured by ELISA. S100A8/A9 expression was detected by immunofluorescence and ELISA. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was quantified using a cell-based ELISA kit. RESULTS: IL 22 and IL-22R1 were expressed constitutively in FLSs. We demonstrated that S100A8 and S100A9 were synthesized in FLSs. We reported that inflammatory mediators increased the expression of the IL-22/IL-22R1 axis, amplifying FLS activation. IL 22 enhanced FLS proliferation and up-regulated MMP1 and S100A8/A9 production. STAT3 phosphorylation was induced after IL-22 treatment and the stimulatory effect of IL-22 on S100A8/A9 was reduced after the activities of Janus kinase 2 (JAK2) and JAK3 were blocked. We showed an inhibitory action of IL-22 on IL-23 and IL-17RC expression in RA FLSs and on IL-17RA in OA FLSs. CONCLUSION: Therapies based on the pharmacological disruption signalling of IL-22 could be beneficial for the treatment of rheumatic diseases. The restricted expression of IL-22R1 to non-lymphoid cells could lead to a reduction of side effects mediated by immune responses. PMID- 24056520 TI - Neutrophils produce interleukin-17B in rheumatoid synovial tissue. AB - OBJECTIVE: T helper 17 (Th17) and mast cells produce IL-17A in RA and critically contribute to the pathogenesis of RA. However, the complete IL-17 cytokine profile in RA is unknown. The aim of the study was to systematically study the expression of IL-17 family cytokines in RA. METHODS: The expression of all IL-17 cytokines in RA synovium and pannus as well as in the synovium of OA was determined using quantitative RT-PCR (qRT-PCR). IL-17A and IL-17B were immunostained. Peripheral blood neutrophils were analysed for IL-17B. The effect of IL-17B alone or in combination with TNF-alpha was tested in vitro on fibroblasts and endothelial cells. RESULTS: In all tissues IL-17B was the most expressed IL-17 family cytokine, found in lining but most strongly expressed in human neutrophil elastase containing polymorphonuclear cells. This pattern was distinct from that of IL-17A, which was found in mast cell tryptase immunoreactive cells. Circulating neutrophils contained IL-17B, verifying the in vivo results. Fibroblasts up-regulated the expression of IL-17RB, a putative receptor of IL-17B, after TNF-alpha stimulation. IL-17B significantly enhanced TNF-alpha-induced production of G-CSF and IL-6 in fibroblasts. CONCLUSION: IL 17B, which is present in synovium, may contribute to the pathogenesis of RA. IL 17B can enhance the effects of TNF-alpha on the production of cytokines and chemokines that control immune cell trafficking and neutrophil homeostasis in the inflamed tissues. PMID- 24056521 TI - Predictors of response and remission in a large cohort of rheumatoid arthritis patients treated with tocilizumab in clinical practice. AB - OBJECTIVE: The objective of this study was to identify predictors of response and remission to tocilizumab (TCZ) in RA patients seen in daily routine clinical practice. METHODS: The efficacy of TCZ was evaluated after 12 and 24 weeks of treatment by the European League Against Rheumatism (EULAR) response criteria. Regression analysis was performed to study the association between remission or EULAR response and the following characteristics: gender, age, current smokers, prior cardiovascular disease (CVD), 28-joint disease activity score (DAS28), CRP, RF or ACPA positivity, combination therapy with DMARDs and TCZ as the first biological therapy or after failure of at least one biological therapy. RESULTS: In total, 204 patients were included with a mean DAS28 score of 5.14. EULAR response and remission were obtained in 86.1% and 40% of patients, respectively, at week 24. In multiple regression analysis, a high baseline CRP level [odds ratio (OR) 4.454 (95% CI 1.446, 13.726)] was significantly associated with EULAR response at week 24 and, inversely, age >55 years [OR 0.285 (95% CI 0.086, 0.950)] and prior CVD [OR 0.305 (95% CI 0.113, 0.825)] were significantly associated with lower EULAR response at week 24. Older age was also associated with less remission at week 24 [OR 0.948 (95% CI 0.920, 0.978)]. No additional effectiveness was found when TCZ was used in combination with a DMARD or when patients were naive to biological agents. CONCLUSION: In daily practice we identified three predictors of a better response for TCZ therapy in RA: a younger age, a high baseline CRP level and no history of CVD. PMID- 24056523 TI - Effect of the counter-anion on the spin-transition properties of a family of Fe(II) tetrazole complexes, [Fe(i4tz)6]X2 (X = ClO4-, PF6-, SbF6-, BF4-). AB - The monodentate ligand 1-isobutyl-1H-tetrazole (i4tz) was used to synthesize a series of iron(II) spin-crossover (SCO) complexes with the general formula [Fe(i4tz)6]X2, where X = ClO4(-) (1), PF6(-) (2), SbF6(-) (3), or BF4(-) (4). Upon cooling, magnetic susceptibility measurements of compounds 1, 2 and 3 show a reversible one-step spin crossover (SCO) behaviour between HS (S = 2) and LS (S = 0) states without hysteresis. The ClO4(-) compound shows a gradual spin transition at T(1/2) = 208 K at a considerably higher temperature than the other compounds. The larger anions PF6(-) (T(1/2) = 114 K) and SbF6(-) (T(1/2) = 116 K) show more gradual transitions, and a "frozen-in effect" was observed after fast cooling. The crystal structure of [Fe(i4tz)6](SbF6)2 (3) was determined at 296, 200 and 100 K, revealing a reversible first-order phase transition between 200 and 100 K, accompanied by a triplication of the unit cell volume at 100 K. Temperature-dependent vibration and electronic spectroscopic measurements of compound 1 were compared with the magnetic susceptibility measurements. PMID- 24056522 TI - Microfluidic opportunities in the field of nutrition. AB - Nutrition has always been closely related to human health, which is a constant motivational force driving research in a variety of disciplines. Over the years, the rapidly emerging field of microfluidics has been pushing forward the healthcare industry with the development of microfluidic-based, point-of-care (POC) diagnostic devices. Though a great deal of work has been done in developing microfluidic platforms for disease diagnoses, potential microfluidic applications in the field of nutrition remain largely unexplored. In this Focus article, we would like to investigate the potential chances for microfluidics in the field of nutrition. We will first highlight some of the recent advances in microfluidic blood analysis systems that have the capacity to detect biomarkers of nutrition. Then we will examine existing examples of microfluidic devices for the detection of specific biomarkers of nutrition or nutrient content in food. Finally, we will discuss the challenges in this field and provide some insight into the future of applied microfluidics in nutrition. PMID- 24056524 TI - Fluorescence microscopy methods for determining the viability of bacteria in association with mammalian cells. AB - Central to the field of bacterial pathogenesis is the ability to define if and how microbes survive after exposure to eukaryotic cells. Current protocols to address these questions include colony count assays, gentamicin protection assays, and electron microscopy. Colony count and gentamicin protection assays only assess the viability of the entire bacterial population and are unable to determine individual bacterial viability. Electron microscopy can be used to determine the viability of individual bacteria and provide information regarding their localization in host cells. However, bacteria often display a range of electron densities, making assessment of viability difficult. This article outlines protocols for the use of fluorescent dyes that reveal the viability of individual bacteria inside and associated with host cells. These assays were developed originally to assess survival of Neisseria gonorrhoeae in primary human neutrophils, but should be applicable to any bacterium-host cell interaction. These protocols combine membrane-permeable fluorescent dyes (SYTO9 and 4',6 diamidino-2-phenylindole [DAPI]), which stain all bacteria, with membrane impermeable fluorescent dyes (propidium iodide and SYTOX Green), which are only accessible to nonviable bacteria. Prior to eukaryotic cell permeabilization, an antibody or fluorescent reagent is added to identify extracellular bacteria. Thus these assays discriminate the viability of bacteria adherent to and inside eukaryotic cells. A protocol is also provided for using the viability dyes in combination with fluorescent antibodies to eukaryotic cell markers, in order to determine the subcellular localization of individual bacteria. The bacterial viability dyes discussed in this article are a sensitive complement and/or alternative to traditional microbiology techniques to evaluate the viability of individual bacteria and provide information regarding where bacteria survive in host cells. PMID- 24056525 TI - Particle alignment in a viscoelastic liquid flowing in a square-shaped microchannel. AB - We demonstrate the possibility to achieve 3D particle focusing in a straight microchannel with a square cross-section by exploiting purely viscoelastic effects. Experiments are carried out by considering an elastic, constant viscosity aqueous solution of PVP (polyvinylpyrrolidone) as the suspending liquid. Several flow rates and two channel dimensions (with a fixed particle size to channel dimension ratio) are investigated. A novel technique combining particle tracking measurements and numerical simulations is used to reconstruct the position of the flowing particles over the channel cross-section. The results show that, for all the investigated experimental conditions, particles migrate towards the channel centerline. Flow-focusing is enhanced by higher flow rates. The measured particle fractions can be rescaled according to a single dimensionless parameter, as already reported in the literature for the case of cylindrical channels. The so-obtained master curve can be used as a guide to predict the required focusing length. The effect of the entrance on the focusing channel length is also addressed. Finally, analogies and discrepancies with similar previous works are discussed. PMID- 24056526 TI - Evaluation of semiautomated measurement of geographic atrophy in age-related macular degeneration by fundus autofluorescence in clinical setting. AB - PURPOSE: To assess intraobserver and interobserver agreement among physicians with different degrees of clinical experience, using a novel fundus autofluorescence semiautomated software for quantification of geographic atrophy in clinical setting. METHODS: Fundus autofluorescence frames (excitation: 488 nm; emission: 500-700 nm) of 29 eyes (20 patients; mean age, 79.6 +/- 6.2 years) with geographic atrophy secondary to age-related macular degeneration, and no signs of choroidal neovascularization, were analyzed using Region Finder, a semiautomated software embedded in Spectralis (Heidelberg Engineering, Heidelberg, Germany). For each study eye, semiautomated atrophy identification and quantification were independently performed, twice (in a 2-week time frame), by 3 readers with different degrees of clinical experience (2 fellows, and 1 resident). Intraobserver and interobserver agreements were assessed. RESULTS: Mean difference in intraobserver agreement (Bland-Altman statistics) ranged from -0.17 mm2 to 0.13 mm2. Intraobserver agreement was excellent until the geographic atrophy threshold value of 15.72 mm2. Variability correlated with the size of atrophy. Mean difference in interobserver agreement (Bland-Altman statistics) ranged from -0.25 mm2 to 0.27 mm2, with no significant difference between senior and junior readers. Multifocal lesion or foveal involvement in atrophy was not the cause of disagreement. CONCLUSION: Region Finder is a reliable tool for the identification and quantification of geographic atrophy in patients with age related macular degeneration, in a clinical setting even when performed by junior reader. PMID- 24056527 TI - Endogenous endophthalmitis in the Korean population: a six-year retrospective study. AB - PURPOSE: To identify the clinical features, treatment outcomes, and prognostic factors of endogenous endophthalmitis in multiple tertiary referral centers of South Korea over a 6-year period. METHODS: The authors conducted a retrospective review of medical records of 57 eyes of 43 patients diagnosed with endogenous endophthalmitis from January 2005 to December 2011, which was referred to tertiary referral centers. RESULTS: Fifty-seven cases of 43 patients were followed for a mean of 18.7 months (range, 0.5-50 months). The common underlying diseases were diabetes mellitus (46.5%) and liver cirrhosis (20.93%). Liver abscess (39.5%) was the most common infection source. Among prognostic factors, the initial visual acuity was associated with favorable visual outcome significantly (P < 0.001). Endogeneous endophthalmitis with gram-negative bacteria had worse visual outcomes than gram-positive bacteria or fungus (P = 0.014). CONCLUSION: Similar to the findings of previous East Asian studies, this study showed that Klebsiella pneumoniae was the most common causative organism of endogenous endophthalmitis and liver abscess was the most common infection focus. Although endogenous endophthalmitis is generally associated with poor visual acuity outcomes, the prognosis depends mainly on the initial visual acuity and the pathogen. PMID- 24056528 TI - Phase 1, dose-ranging study of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in healthy volunteers. AB - BACKGROUND: Emixustat hydrochloride (formerly ACU-4429) is a nonretinoid compound with a unique mode of action in the retinal pigment epithelium, where it modulates the biosynthesis of visual chromophore through its effect on retinal pigment epithelium-specific 65 kDa protein isomerase. This study provides clinicians with a background for understanding the pharmacokinetics and safety profile of orally administered emixustat. METHODS: This randomized, double masked, placebo-controlled Phase 1b study evaluated the pharmacokinetics, tolerability, and safety of a 14-day course of oral emixustat (5, 10, 20, 30, or 40 mg) or placebo (3:1 ratio) once daily in healthy volunteers. RESULTS: A total of 40 subjects were enrolled (mean age, 38 years; 75% male). Emixustat (n = 30) was rapidly absorbed (median T(max), 3.0-5 hours) and readily eliminated (mean t(1/2), 4.6-7.9 hours), and mean C(max) and AUC(0-24) generally increased in proportion to dose. No significant accumulation of emixustat was observed with multiple-dose administration. Ocular adverse events occurred in 67% of the subjects who received emixustat; all were considered mild and resolved after study completion. Systemic adverse events were minimal. CONCLUSION: Oral emixustat was safe and well tolerated when administered once daily for 14 days with minimal systemic adverse events reported. These data support evaluation of emixustat in subjects with geographic atrophy associated with dry age-related macular degeneration. PMID- 24056529 TI - Spectral domain optical coherence tomography characteristics of white-without pressure. PMID- 24056530 TI - Volume labeling with Alexa Fluor dyes and surface functionalization of highly sensitive fluorescent silica (SiO2) nanoparticles. AB - A new synthesis approach is described that allows the direct incorporation of fluorescent labels into the volume or body of SiO2 nanoparticles. In this process, fluorescent Alexa Fluor dyes with different emission wavelengths were covalently incorporated into the SiO2 nanoparticles during their formation by the hydrolysis of tetraethoxysilane. The dye molecules were homogeneously distributed throughout the SiO2 nanoparticles. The quantum yields of the Alexa Fluor volume labeled SiO2 nanoparticles were much higher than nanoparticles labeled using conventional organic dyes. The size of the resulting nanoparticles was controlled using microemulsion reaction media with sizes in the range of 20-100 nm and a polydispersity of <15%. In comparison with conventional surface tagged particles created by post-synthesis modification, this process maintains the physical and surface chemical properties that have the most pronounced effect on colloidal stability and interactions with their surroundings. These volume-labeled nanoparticles have proven to be extremely robust, showing excellent signal strength, negligible photobleaching, and minimal loss of functional organic components. The native or "free" surface of the volume-labeled particles can be altered to achieve a specific surface functionality without altering fluorescence. Their utility was demonstrated for visualizing the association of surface-modified fluorescent particles with cultured macrophages. Differences in particle agglomeration and cell association were clearly associated with differences in observed nanoparticle toxicity. The capacity to maintain particle fluorescence while making significant changes to surface chemistry makes these particles extremely versatile and useful for studies of particle agglomeration, uptake, and transport in environmental and biological systems. PMID- 24056531 TI - Insights into the mechanism of interaction between trehalose-conjugated beta sheet breaker peptides and Abeta(1-42) fibrils by molecular dynamics simulations. AB - An attractive strategy to contrast the Alzheimer disease (AD) is represented by the development of beta-sheet breaker peptides (BSB). beta-sheet breakers constitute a class of compounds which have shown a good efficacy in preventing the Abeta fibrillogenesis; however, their mechanism of action has not been precisely understood. In this context, we have studied the structural basis underlying the inhibitory effect of Abeta(1-42) fibrillogenesis explicated by two promising trehalose-conjugated BSB peptides using an all-atom molecular dynamics (MD) approach. Our simulations suggest that the binding on the two protofibril ends occurs through different binding modes. In particular, binding on the odd edge (chain A) is guided by a well defined hydrophobic cleft, which is common to both ligands. Moreover, targeting chain A entails a significant structure destabilization leading to a partial loss of beta structure and is an energetically favoured process. A significant contribution of the trehalose moiety to the stability of the complexes emerged from our results. The energetically favoured hydrophobic cleft detected on chain A could represent a good starting point for the design of new molecules with improved anti aggregating features. PMID- 24056532 TI - Single-cell mutational profiling and clonal phylogeny in cancer. AB - The development of cancer is a dynamic evolutionary process in which intraclonal, genetic diversity provides a substrate for clonal selection and a source of therapeutic escape. The complexity and topography of intraclonal genetic architectures have major implications for biopsy-based prognosis and for targeted therapy. High-depth, next-generation sequencing (NGS) efficiently captures the mutational load of individual tumors or biopsies. But, being a snapshot portrait of total DNA, it disguises the fundamental features of subclonal variegation of genetic lesions and of clonal phylogeny. Single-cell genetic profiling provides a potential resolution to this problem, but methods developed to date all have limitations. We present a novel solution to this challenge using leukemic cells with known mutational spectra as a tractable model. DNA from flow-sorted single cells is screened using multiplex targeted Q-PCR within a microfluidic platform allowing unbiased single-cell selection, high-throughput, and comprehensive analysis for all main varieties of genetic abnormalities: chimeric gene fusions, copy number alterations, and single-nucleotide variants. We show, in this proof of-principle study, that the method has a low error rate and can provide detailed subclonal genetic architectures and phylogenies. PMID- 24056533 TI - Handedness and language learning disability differentially distribute in progressive aphasia variants. AB - Primary progressive aphasia is a neurodegenerative clinical syndrome that presents in adulthood with an isolated, progressive language disorder. Three main clinical/anatomical variants have been described, each associated with distinctive pathology. A high frequency of neurodevelopmental learning disability in primary progressive aphasia has been reported. Because the disorder is heterogeneous with different patterns of cognitive, anatomical and biological involvement, we sought to identify whether learning disability had a predilection for one or more of the primary progressive aphasia subtypes. We screened the University of California San Francisco Memory and Aging Center's primary progressive aphasia cohort (n = 198) for history of language-related learning disability as well as hand preference, which has associations with learning disability. The study included logopenic (n = 48), non-fluent (n = 54) and semantic (n = 96) variant primary progressive aphasias. We investigated whether the presence of learning disability or non-right-handedness was associated with differential effects on demographic, neuropsychological and neuroimaging features of primary progressive aphasia. We showed that a high frequency of learning disability was present only in the logopenic group (chi(2) = 15.17, P < 0.001) and (chi(2) = 11.51, P < 0.001) compared with semantic and non-fluent populations. In this group, learning disability was associated with earlier onset of disease, more isolated language symptoms, and more focal pattern of left posterior temporoparietal atrophy. Non-right-handedness was instead over represented in the semantic group, at nearly twice the prevalence of the general population (chi(2) = 6.34, P = 0.01). Within semantic variant primary progressive aphasia the right-handed and non-right-handed cohorts appeared homogeneous on imaging, cognitive profile, and structural analysis of brain symmetry. Lastly, the non-fluent group showed no increase in learning disability or non-right handedness. Logopenic variant primary progressive aphasia and developmental dyslexia both manifest with phonological disturbances and posterior temporal involvement. Learning disability might confer vulnerability of this network to early-onset, focal Alzheimer's pathology. Left-handedness has been described as a proxy for atypical brain hemispheric lateralization. As non-right-handedness was increased only in the semantic group, anomalous lateralization mechanisms might instead be related to frontotemporal lobar degeneration with abnormal TARDBP. Taken together, this study suggests that neurodevelopmental signatures impart differential trajectories towards neurodegenerative disease. PMID- 24056534 TI - RAD51 deficiency disrupts the corticospinal lateralization of motor control. AB - Mirror movements are involuntary symmetrical movements of one side of the body that mirror voluntary movements of the other side. Congenital mirror movement disorder is a rare condition characterized by mirror movements that persist throughout adulthood in subjects with no other clinical abnormalities. The affected individuals have mirror movements predominating in the muscles that control the fingers and are unable to perform purely unimanual movements. Congenital mirror movement disorder thus provides a unique paradigm for studying the lateralization of motor control. We conducted a multimodal, controlled study of patients with congenital mirror movements associated with RAD51 haploinsufficiency (n = 7, mean age 33.3 +/- 16.8 years) by comparison with age- and gender-matched healthy volunteers (n = 14, mean age 33.9 +/- 16.1 years). We showed that patients with congenital mirror movements induced by RAD51 deficiency had: (i) an abnormal decussation of the corticospinal tract; (ii) abnormal interhemispheric inhibition and bilateral cortical activation of primary motor areas during intended unimanual movements; and (iii) an abnormal involvement of the supplementary motor area during both unimanual and bimanual movements. The lateralization of motor control thus requires a fine interplay between interhemispheric communication and corticospinal wiring. This fine interplay determines: (i) the delivery of appropriate motor plans from the supplementary motor area to the primary motor cortex; (ii) the lateralized activation of the primary motor cortex; and (iii) the unilateral transmission of the motor command to the limb involved in the intended movement. Our results also unveil an unexpected function of RAD51 in corticospinal development of the motor system. PMID- 24056535 TI - Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene. AB - Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2 Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2 Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia. PMID- 24056536 TI - Executive deficits, not processing speed relates to abnormalities in distinct prefrontal tracts in amyotrophic lateral sclerosis. AB - Cognitive impairment in amyotrophic lateral sclerosis is characterized by deficits on tests of executive function; however, the contribution of abnormal processing speed is unknown. Methods are confounded by tasks that depend on motor speed in patients with physical disability. Structural and functional magnetic resonance imaging studies have revealed multi-system cerebral involvement, with evidence of reduced white matter volume and integrity in predominant frontotemporal regions. The current study has two aims. First, to investigate whether cognitive impairments in amyotrophic lateral sclerosis are due to executive dysfunction or slowed processing speed using methodology that accommodates motor disability. This is achieved using a dual-task paradigm and tasks that manipulate stimulus presentation times and do not rely on response motor speed. Second, to identify relationships between specific cognitive impairments and the integrity of distinct white matter tracts. Thirty patients with amyotrophic lateral sclerosis and 30 age- and education-matched control subjects were administered an experimental dual-task procedure that combined a visual inspection time task and digit recall. In addition, measures of executive function (including letter fluency) and processing speed (visual inspection time and rapid serial letter identification) were administered. Integrity of white matter tracts was determined using region of interest analyses of diffusion tensor magnetic resonance imaging data. Patients with amyotrophic lateral sclerosis did not show impairments on tests of processing speed, but executive deficits were revealed once visual inspection time was combined with digit recall (dual-task) and in letter fluency. In addition to the corticospinal tracts, significant differences in fractional anisotropy and mean diffusivity were found between groups in a number of prefrontal and temporal white matter tracts including the anterior cingulate, anterior thalamic radiation, uncinate fasciculus and hippocampal portion of the cingulum bundles. Significant differences also emerged in the anterior corona radiata as well as in white matter underlying the superior, medial and inferior frontal gyri and the temporal gyri. Dual-task performance significantly correlated with fractional anisotropy measures in the middle frontal gyrus white matter and anterior corona radiata. Letter fluency indices significantly correlated with fractional anisotropy measures of the inferior frontal gyrus white matter and corpus callosum in addition to the corticospinal tracts and mean diffusivity measures in the white matter of the superior frontal gyrus. The current study demonstrates that cognitive impairment in amyotrophic lateral sclerosis is not due to generic slowing of processing speed. Moreover, different executive deficits are related to distinct prefrontal tract involvement in amyotrophic lateral sclerosis with dual-task impairment associating with dorsolateral prefrontal dysfunction and letter fluency showing greater dependence on inferolateral prefrontal dysfunction. PMID- 24056537 TI - Thalamic cholinergic innervation and postural sensory integration function in Parkinson's disease. AB - The pathophysiology of postural instability in Parkinson's disease remains poorly understood. Normal postural function depends in part on the ability of the postural control system to integrate visual, proprioceptive, and vestibular sensory information. Degeneration of cholinergic neurons in the brainstem pedunculopontine nucleus complex and their thalamic efferent terminals has been implicated in postural control deficits in Parkinson's disease. Our aim was to investigate the relationship of cholinergic terminal loss in thalamus and cortex, and nigrostriatal dopaminergic denervation, on postural sensory integration function in Parkinson's disease. We studied 124 subjects with Parkinson's disease (32 female/92 male; 65.5 +/- 7.4 years old; 6.0 +/- 4.2 years motor disease duration; modified Hoehn and Yahr mean stage 2.4 +/- 0.5) and 25 control subjects (10 female/15 male, 66.8 +/- 10.1 years old). All subjects underwent (11)C dihydrotetrabenazine vesicular monoaminergic transporter type 2 and (11)C methylpiperidin-4-yl propionate acetylcholinesterase positron emission tomography and the sensory organization test balance platform protocol. Measures of dopaminergic and cholinergic terminal integrity were obtained, i.e. striatal vesicular monoaminergic transporter type 2 binding (distribution volume ratio) and thalamic and cortical acetylcholinesterase hydrolysis rate per minute (k3), respectively. Total centre of pressure excursion (speed), a measure of total sway, and sway variability were determined for individual sensory organization test conditions. Based on normative data, principal component analysis was performed to reduce postural sensory organization functions to robust factors for regression analysis with the dopaminergic and cholinergic terminal data. Factor analysis demonstrated two factors with eigenvalues >2 that explained 52.2% of the variance, mainly reflecting postural sway during sensory organization test Conditions 1-3 and 5, respectively. Regression analysis of the Conditions 1-3 postural sway-related factor [R(2)adj = 0.123, F(5,109) = 4.2, P = 0.002] showed that decreased thalamic cholinergic innervation was associated with increased centre of pressure sway speed (beta = -0.389, t = -3.4, P = 0.001) while controlling for covariate effects of cognitive capacity and parkinsonian motor impairments. There was no significant effect of cortical cholinergic terminal deficits or striatal dopaminergic terminal deficits. This effect could only be found for the subjects with Parkinson's disease. We conclude that postural sensory integration function of subjects with Parkinson's disease is modulated by pedunculopontine nucleus-thalamic but not cortical cholinergic innervation. Impaired integrity of pedunculopontine nucleus cholinergic neurons and their thalamic efferents play a role in postural control in patients with Parkinson's disease, possibly by participating in integration of multimodal sensory input information. PMID- 24056539 TI - Oxaliplatin complexes with carnosine and its derivatives: in vitro cytotoxicity, mass spectrometric and computational studies with a focus on complex fragmentation. AB - The complexation of the Pt-based anti-cancer drug oxaliplatin (OxPt) with biological ligands other than DNA is believed to be a major cellular sink for the drug reducing its therapeutic potential and acting as a potential cause of toxicity. In this paper, the very first hypothesis driven investigation of the role of the naturally abundant cytoplasmic dipeptide ligand beta-alanyl-l histidine dipeptide (carnosine) in OxPt detoxification is presented. In vitro studies on hepatocellular carcinoma HepG2 cells suggest that carnosine may inhibit the cytotoxic action of OxPt most likely through the formation of complexes that are less cytotoxic than OxPt alone. Evidence is provided to suggest that pre-exposure of HepG2 cells to elevated levels of carnosine appears to have a lasting effect on reducing the cytotoxicity of OxPt even after the removal of the externally added carnosine. This effect, however, is likely under kinetic control as its magnitude was shown not to vary significantly with the level of carnosine exposure within the concentration range used in this study. Various mass spectrometry techniques employing electrospray ionization and chip nanospray were employed to study the interaction of oxaliplatin with carnosine as well as two of its derivatives beta-alanyl-N-methylhistidine (anserine) and N acetylcarnosine (NAC). Evidence of complexation between OxPt and each of the three ligands examined is presented. Most species observed were unambiguously assigned and compared to their theoretical isotopic patterns. Common fragmentation products due to the collisionally-activated protonated complexes of each of the ligands examined with OxPt, [M + OxPt + H](+), where M = carnosine, anserine or NAC, were reported. Density functional calculations at the B3LYP/LANL2DZ level were used to obtain structural information and relative free energies of different isomers of the observed precursor [Carnosine + OxPt + H](+) both in the gas phase and in solution as well as to probe its fragmentation, highlighting plausible fragmentation mechanisms that account for all the experimental results. Data are presented to show several binding modes between electron rich sites such as N and O centers of carnosine and the Pt metal of OxPt. Calculations were also employed to obtain proton affinities and free energies of key reactions. The proton affinities of carnosine, anserine and NAC at 298 K were calculated to be 254.4, 255.9 and 250.2 kcal mol(-1) respectively. To the best of our knowledge the proton affinities of anserine and N-acetyl carnosine are the first reported values in the literature. PMID- 24056538 TI - Connexin43 functions as a novel interacting partner of heat shock cognate protein 70. AB - Regulation of connexin43 (Cx43) expression affects cell proliferation, differentiation and apoptosis in a gap junctional intercellular communication (GJIC)-independent manner. However, the underlying mechanisms of Cx43-mediated cell cycle suppression are still poorly understood. To elucidate the molecular mechanism of Cx43-mediated cell cycle suppression, we searched for Cx43 interacting proteins by using a proteomics approach. Here, we have identified a Cx43-interacting protein, heat shock cognate protein 70 (Hsc70). We confirmed that Hsc70 directly binds to the C-terminus of Cx43, whereas Hsc54, a splice variant of Hsc70, does not, that Cx43 competes with cyclin D1 for binding to Hsc70, and that the nuclear accumulation of cyclin D1 is reduced by overexpression of Cx43 in a GJIC-independent manner, which is restored by co overexpression with Hsc70. As a result, the cell proliferation is regulated by Cx43. Our results suggest that Cx43-Hsc70 interaction probably plays a critical role during G1/S progression. PMID- 24056541 TI - The impact of in vitro digestion on bioaccessibility of polyphenols from potatoes and sweet potatoes and their influence on iron absorption by human intestinal cells. AB - The composition of potatoes as determined by chemical extraction has been described extensively. It is thus quite well known that, among other compounds, potato is rich in polyphenols, vitamins and in some minerals. This paper underlines the important role of simulated gastro-intestinal in vitro digestion in the bioaccessibility of polyphenols (chlorogenic acid and derivatives, and rutin) from potatoes and sweet potatoes and their impact on iron uptake. Concentrations of polyphenols in the flesh of two potato cultivars (Nicola, white potato, and Vitelotte, purple potato) and sweet potato were measured by Ultra Performance Liquid Chromatography after boiling and after in vitro digestion. Chemical extraction underestimates polyphenol amounts that can be released during digestion and that are actually bioaccessible. Iron uptake, as evaluated by a ferritin assay, by intestinal human cells was decreased after incubation with the intestinal phase of in vitro digestion, presumably due to the presence of polyphenols. PMID- 24056544 TI - Impaired sleep: a factor for fatigue in people with type 2 diabetes. PMID- 24056547 TI - Ushering in the new century. PMID- 24056546 TI - Assembly of nucleosomal arrays from recombinant core histones and nucleosome positioning DNA. AB - Core histone octamers that are repetitively spaced along a DNA molecule are called nucleosomal arrays. Nucleosomal arrays are obtained in one of two ways: purification from in vivo sources, or reconstitution in vitro from recombinant core histones and tandemly repeated nucleosome positioning DNA. The latter method has the benefit of allowing for the assembly of a more compositionally uniform and precisely positioned nucleosomal array. Sedimentation velocity experiments in the analytical ultracentrifuge yield information about the size and shape of macromolecules by analyzing the rate at which they migrate through solution under centrifugal force. This technique, along with atomic force microscopy, can be used for quality control, ensuring that the majority of DNA templates are saturated with nucleosomes after reconstitution. Here we describe the protocols necessary to reconstitute milligram quantities of length and compositionally defined nucleosomal arrays suitable for biochemical and biophysical studies of chromatin structure and function. PMID- 24056548 TI - Journal publishing: the changing landscape. PMID- 24056549 TI - This is hepatitis: know it, confront it. PMID- 24056550 TI - Management of haemolytic disease of the foetus & newborn: steps to improve the outcomes. PMID- 24056551 TI - Progressive multifocal leukoencephalopathy, a rare but devastating disease in AIDS patients. PMID- 24056552 TI - Use of intravenous iron sucrose for treatment of anaemia in pregnancy. PMID- 24056553 TI - Emerging & re-emerging infections in India: an overview. AB - The incidence of emerging infectious diseases in humans has increased within the recent past or threatens to increase in the near future. Over 30 new infectious agents have been detected worldwide in the last three decades; 60 per cent of these are of zoonotic origin. Developing countries such as India suffer disproportionately from the burden of infectious diseases given the confluence of existing environmental, socio-economic, and demographic factors. In the recent past, India has seen outbreaks of eight organisms of emerging and re-emerging diseases in various parts of the country, six of these are of zoonotic origin. Prevention and control of emerging infectious diseases will increasingly require the application of sophisticated epidemiologic and molecular biologic technologies, changes in human behaviour, a national policy on early detection of and rapid response to emerging infections and a plan of action. WHO has made several recommendations for national response mechanisms. Many of these are in various stages of implementation in India. However, for a country of size and population of India, the emerging infections remain a real and present danger. A meaningful response must approach the problem at the systems level. A comprehensive national strategy on infectious diseases cutting across all relevant sectors with emphasis on strengthened surveillance, rapid response, partnership building and research to guide public policy is needed. PMID- 24056554 TI - Lessons from neurolathyrism: a disease of the past & the future of Lathyrus sativus (Khesari dal). AB - Neurolathyrism is past history in India since Lathyrus sativus (khesari dal) is no longer used as a staple. A consensus has evolved that khesari dal is harmless as part of a normal diet. L-ODAP (beta-N-oxalyl-l-alpha-diamino propionic acid) the neurotoxic amino acid, from this pulse, is detoxified in humans but not in animals but still no laboratory animal is susceptible to it under acceptable feeding regimens. L-ODAP is an activator of protein kinase C and consequential crucial downstream effects such as stabilization of hypoxia inducible factor-1 (HIF-1) could be extremely conducive to humans under a variety of situations. ODAP is gradually finding a place in several patents for this reason. Homoarginine the second amino acid from L. sativus can be a better substrate for endogenous generation of nitric oxide, a crucial signaling molecule associated with the cardiovasculature and control of hypertension. These features could make L. sativus a prized commodity as a functional food for the general cardiovasculature and overcome hypoxic events and is set to change the entire perception of this pulse and neurolathyrism. PMID- 24056555 TI - New approaches & technologies of venomics to meet the challenge of human envenoming by snakebites in India. AB - The direct estimate of 46,000 snakebite deaths in India in 2005 (1 for every 2 HIV/AIDS deaths), based on verbal autopsies, renders unrealistic the total of only 47,000 snakebite deaths in the whole world in 2010, obtained indirectly as part of the "Global Burden of Disease 2010" study. Persistent underestimation of its true morbidity and mortality has made snakebite the most neglected of all the WHO's "neglected tropical diseases", downgrading its public health importance. Strategies to address this neglect should include the improvement of antivenom, the only specific antidote to envenoming. To accommodate increased understanding of geographical intraspecific variation in venom composition and the range of snake species that are medically important in India, the design of antivenoms (choice of venom sources and species coverage) should be reconsidered. Methods of preclinical and clinical testing should be improved. The relatively new science of venomics involves techniques and strategies for assessing the toxin composition of snake venoms directly through proteomics-centred approaches or indirectly via high-throughput venom gland transcriptomics and bioinformatic analysis. Antivenomics is translational venomics: a proteomics-based protocol to quantify the extent of cross-reactivity of antivenoms against homologous and heterologous venoms. These approaches could revolutionize the preclinical assessment of antivenom efficacy, leading to a new generation of antivenoms that are clinically more effective. PMID- 24056556 TI - Biomarkers for the management of pre-eclampsia in pregnant women. AB - Pre-eclampsia (PE) is a pregnancy related disorder characterized by hypertension and proteinuria noticeable after 20 wk of gestation. It is a leading cause of maternal and foetal mortality and morbidity worldwide. The aetiology of the disease is unknown, but recent studies have revealed that this disorder appears to originate in placenta and is characterized by widespread maternal endothelial dysfunction. Till date, delivery of placenta is the only cure for the disease. So, there is a need for the identification of highly specific and sensitive biochemical markers that would allow early identification of patients at risk and thus help in providing proper prenatal care. Several promising biomarkers have been proposed, alone or in combination, that may help in predicting women who are likely to develop PE. Maternal serum concentrations of these biomarkers either increase or decrease in PE during gestation. This review focuses on the various biomarkers available and their utility in predicting pre-eclampsia. PMID- 24056557 TI - Red cell alloimmunization among antenatal women attending a tertiary care hospital in south India. AB - BACKGROUND & OBJECTIVES: Detection of maternal alloimmunization against red cell antigens is vital in the management of haemolytic disease of the foetus and newborn (HDFN). This study was conducted to measure the presence of allosensitization to blood group antibodies in the antenatal women attending a tertiary care hospital and to observe the proportion of minor blood group antibodies to assess the benefit of screening for the same. METHODS: All antenatal women registered in the hospital between January 2008 and January 2009, were screened for irregular antibodies using a commercial 3-cell antibody screening panel. Antibody identification was performed on samples found positive using a commercial 11 cell-panel. RESULTS: Screening was performed on 5347 women, 339 (6.34%) of whom were Rh negative. Allosensitization was found in 79 women (1.48%; confidence interval 1.17 -1.84). In 29 of these 79 (37%) women the allo antibodies could not be identified. In the remaining 50 women, 54 antibodies were characterized. A total of 40 clinically significant antibody specificities were identified among 36 women, of whom four were Rh(D) positive. Allosensitization with clinically significant antibodies was found in 9.43 per cent (confidence interval 6.55-13.06) Rh(D) negative and in 0.08 per cent (confidence interval .02 0.2) Rh(D) positive women. Anti D was the most frequent antibody found in 8.85 per cent Rh(D) negative women. The remaining clinically significant antibodies identified included anti-C, c, E, Jk(a), Jk(b), M and S. In Rh(D) negative women, anti-D and antibodies of the Rh system contributed 83.3 and 94.4 per cent of clinically significant antibodies. However, in Rh(D) positive women, non-Rh antibodies comprised three out of four clinically significant antibodies. INTERPRETATION & CONCLUSIONS: The presence of alloimmunization in our study corroborated with data reported from India. The most frequent antibody was anti D. However, a significant fraction was non-D. Alloimmunization among Rh(D) positive women though low as compared to Rh(D) negative women, included clinically significant antibodies, and most of these were non Rh. PMID- 24056558 TI - Progressive multifocal leucoencephalopathy in HIV/AIDS: observational study from a tertiary care centre in northern India. AB - BACKGROUND & OBJECTIVES: Progressive multifocal leucoencephalopathy (PML) is seen mostly in advanced human immunodeficiency virus (HIV) infection. Little is known about the epidemiology and disease course of these patients from India. This study was aimed to determine the frequency of PML in patients with HIV/AIDS, and the clinical features and survival of these patients. METHODS: The charts of HIV/AIDS patients with PML seen over a period of five years (2006-2011) at the Antiretroviral treatment (ART) centre at a tertiary care centre in New Delhi, India, were retrospectively reviewed. RESULTS: Of 1465 patients with HIV/AIDS, 18 (1.2%) were diagnosed with PML; four were laboratory confirmed and 14 had consistent clinical and radiological features. PML was the initial presentation of HIV infection in 10 (56%) patients, and 16 (89%) patients had CD4 count less than 200/MUl. Insidious onset focal limb weakness (78%) and visual disturbance (28%) were common symptoms. Magnetic resonance imaging (MRI) of the brain revealed characteristic white matter lesions in all the patients. The estimated median survival was 7.6 months (95% CI, 0-20 months). INTERPRETATION & CONCLUSIONS: Our results show that the patients present late to access treatment with advanced immunosuppression at presentation. PML is associated with high morbidity and mortality despite institution of highly active antiretroviral therapy (HAART). There is a need to address the lacuna in diagnostic and management services for these patients in India. PMID- 24056559 TI - Intravenous iron sucrose therapy for moderate to severe anaemia in pregnancy. AB - BACKGROUND & OBJECTIVES: Iron deficiency anaemia (IDA) is the most common nutritional deficiency in pregnancy. Prophylactic oral iron is recommended during pregnancy to meet the increased requirement. In India, women become pregnant with low baseline haemoglobin level resulting in high incidence of moderate to severe anaemia in pregnancy where oral iron therapy cannot meet the requirement. Pregnant women with moderate anaemia are to be treated with parentral iron therapy. This study was undertaken to evaluate the response and effect of intravenous iron sucrose complex (ISC) given to pregnant women with IDA. METHODS: A prospective study was conducted (June 2009 to June 2011) in the department of Obstetrics & Gynecology, All India Institute of Medical Sciences, New Delhi. One hundred pregnant women with haemoglobin between 5-9 g% with diagnosed iron deficiency attending antenatal clinic were given intravenous iron sucrose complex in a dose of 200 mg twice weekly schedule after calculating the dose requirement. RESULTS: The mean haemoglobin raised from 7.63 +/- 0.61 to 11.20 +/- 0.73 g% (P<0.001) after eight wk of therapy. There was significant rise in serum ferritin levels (from 11.2 +/- 4.7 to 69 +/- 23.1 MUg/l) (P<0.001). Reticulocyte count increased significantly after two wk of starting therapy (from 1.5 +/- 0.6 to 4.6 +/- 0.8%).Other parameters including serum iron levels and red cell indices were also improved significantly. Only one woman was lost to follow up. No major side effects or anaphylactic reactions were noted during study period. INTERPRETATION & CONCLUSIONS: Parentral iron therapy was effective in increasing haemoglobin, serum ferritin and other haematological parameters in pregnant women with moderate anaemia. Intravenous iron sucrose can be used in hospital settings and tertiary urban hospitals where it can replace intramuscular therapy due to injection related side effects. Further, long-term comparative studies are required to recommend its use at peripheral level. PMID- 24056560 TI - Maternal serum median levels of alpha-foetoprotein, human chorionic gonadotropin & unconjugated estriol in second trimester in pregnant women from north-west India. AB - BACKGROUND & OBJECTIVES: Triple test as prenatal screening procedure does not form a part of routine health care of pregnant women in India. Hence, median values of triple test biomarkers are lacking for Indian population. This study was undertaken to establish population-specific medians for biomarkers viz. alpha foetoprotien (AFP), human chorionic gonadotropin (hCGbeta), and unconjugated estriol (uE3) for detection of Down's syndrome, Edward's syndrome and neural tube defects (NTDs) in pregnant women in north-west India. METHODS: Serum biomarker values were derived from 5420 pregnant women between 15-20 wk of gestation who were enrolled for triple test investigations at Department of Gynecology and Obstetrics, Government Medical College and Hospital, Chandigarh, India, between January, 2007 to December, 2009. Median values were calculated for rounded weeks using database comprising pregnancies with normal outcomes only. Simple statistical analysis and log-linear regression were used for median estimation of the biomarker values. RESULTS: The levels of the three biomarkers were found to be ranging from 1.38 to 187.00 IU/ml for AFP, 1.06 to 315 ng/ml for hCGbeta, and 0.25 to 28.5 nmol/l for uE3. The age of women ranged from 18 to 47 yr and mean weight was 57.9 +/- 9.8 kg. Data revealed that AFP, hCGbeta and uE3 medians in our study population were not significantly different from those reported from other countries or when compared ethnically. INTERPRETATION & CONCLUSION: The population-specific median values for the three biomarkers (AFP, hCGbeta, uE3) may be used as reference values during prenatal screening in Indian pregnant women. PMID- 24056561 TI - Prevalence of specific developmental disorder of scholastic skill in school students in Chandigarh, India. AB - BACKGROUND & OBJECTIVES: Several studies have been conducted in India to determine the prevalence of learning disabilities in school children which has been reported to be 3-10 per cent among students population. The present study was conducted to find out prevalence of specific developmental disorder of scholastic skills in students of classes VII to XII and to find out feasibility of screening tool in Chandigarh, India. METHODS: A cross-sectional study on school students was carried out in two phases. The students were drawn from classes VII to XII from 10 schools of Chandigarh, India. Details of academic performance of all the students was taken, subjectively from class teachers and objectively from the marks obtained in the last academic session. In phase I, 2402 students were assessed. In phase II, 108 students were randomly selected for evaluation for assessing sensitivity and specificity of screening proforma for teachers. A total of 124 students from phase I and all students in phase II were assessed in detail. Tests of intelligence (Malin's Intelligence Scale for Indian Children and Standard Progressive Matrices), and NIMHANS Index for specific learning disability (SLD) battery were administered. RESULTS: A total of 38 students were found to be having specific developmental disorder of scholastic skills in phase I, that gave a prevalence of 1.58 per cent. Majority had mixed type of errors on SLD battery. There were more boys diagnosed with specific learning disability. Teacher's screening instrument had high sensitivity (90.385) and specificity (94.68). INTERPRETATION & CONCLUSIONS: The findings of our study conducted in community, showed that specific learning disability was not identified even till later age. The screening instrument thus could be used by teachers to suspect students with specific learning disability. PMID- 24056562 TI - Evaluation of anti-inflammatory activity, effect on blood pressure & gastric tolerability of antidepressants. AB - BACKGROUND & OBJECTIVES: Antidepressants are being used as analgesics for various pain related disorders like neuropathic and non neuropathic pain. Although their analgesic activity is well recognized but anti-inflammatory potential of antidepressants is still inconclusive. Since the antidepressants are used for longer duration, it becomes important to elucidate effect of anti-depressants on blood pressure and gastric mucosa. This study was undertaken to evaluate the anti inflammatory potential of various antidepressant drugs as well as their effect on blood pressure and gastric tolerability on chronic administration in rats. METHODS: Rat paw oedema model was used for studying anti-inflammatory activity, single dose of test drug (venlafaxine 20 and 40 mg/kg, amitryptline 25 mg/kg, fluoxetine 20 mg/kg) was administered intraperitoneally 45 min prior to administration of 0.1 ml of 1 per cent carrageenan in sub-planter region. Oedema induced in test group was compared with normal saline treated control group. For studying effect on blood pressure and gastric tolerability, test drugs were administered for 14 days. Blood pressure was recorded on days 0, 7 and 14 using tail cuff method. On day 14, 4 h after drug administration, rats were sacrificed and stomach mucosa was examined for ulcerations. RESULTS: Pretreatment of rats with venlafaxine (40 mg/kg) resulted in a significant decrease in paw oedema as compared to control (2.4 +/- 0.15 to 1.1 +/- 0.16 ml, P<0.01). Similarly, in the group pretreated with fluoxetine, significant decrease in paw oedema was observed in comparison to control (P<0.05). Significant change in mean blood pressure was seen in rats pretreated with venlafaxine 40 mg/kg (126.7 +/- 4.2 to 155.2 +/- 9.7, P<0.05) and fluoxetine (143.5 +/- 2.6 to 158.3 +/- 1.2, P<0.05) on day 7. No significant difference with regard to gastric tolerability was observed among groups. INTERPRETATION & CONCLUSIONS: Our findings showed significant anti inflammatory activity of venlafaxine (40 mg/kg) and fluoxetine but these drugs were also associated with an increase in blood pressure. No significant change in mean ulcer index was observed among groups. PMID- 24056563 TI - Effect of growth factors (BMP-4/7 & bFGF) on proliferation & osteogenic differentiation of bone marrow stromal cells. AB - BACKGROUND & OBJECTIVES: BMP (bone morphogenetic protein)-4/7 and bFGF (basic fibroblast growth factor) significantly promote the osteogenic activity and the proliferation of rabbit BMSCs (bone marrow stromal cells), respectively. However, their synergistic effects on the proliferation and the differentiation of BMSCs remain unclear. In the present study, the effects of bFGF and BMP-4/7 were investigated on the proliferation and the differentiation of rat BMSCs in vitro. METHODS: BMSCs were isolated from New Zealand white rabbits and cultured to the third passage. The samples were divided into five groups according to the material implanted: (A) 80 ng/ml BMP-4/7; (B) 80 ng/ml bFGF; (C) 30 ng/ml BMP-4/7 and 30 ng/ml bFGF; (D) 50 ng/ml BMP-4/7 and 50 ng/ml bFGF; and (E) 80 ng/ml BMP 4/7 and 80 ng/ml bFGF. Cell proliferation was analyzed using methyl thiazolyl tetrazolium (MTT) assay. Alkaline phosphatase activity and osteocalcin (OC) dynamics were also measured. RESULTS: BMP-4/7 alone significantly (P<0.05) promoted the proliferation of BMSCs. At the same time, it also promoted or inhibited the osteogenic differentiation of BMSCs. The synergistic effects of BMP 4/7 and bFGF significantly promoted both the proliferation and the osteogenic differentiation of BMSCs. The treatment of the synergistic effects was dose and time dependent. INTERPRETATION & CONCLUSIONS: A rational combination of BMP-4/7 and bFGF can promote the proliferation and the osteogenic differentiation of BMSCs. In addition, the synergistic functions are effective. PMID- 24056564 TI - A sensitive & specific multiplex PCR assay for simultaneous detection of Bacillus anthracis, Yersinia pestis, Burkholderia pseudomallei & Brucella species. AB - BACKGROUND & OBJECTIVES: Bacillus anthracis, Yersinia pestis, Burkholderia pseudomallei and Brucella species are potential biowarfare agents. Classical bacteriological methods for their identification are cumbersome, time consuming and of potential risk to the handler. METHODS: We describe a sensitive and specific multiplex polymerase chain reaction (mPCR) assay involving novel primers sets for the simultaneous detection of B. anthracis, Y. pestis, B. pseudomallei and Brucella species. An additional non-competitive internal amplification control (IAC) was also included. RESULTS: The mPCR was found to be specific when tested against closely related organisms. The sensitivity of the assay in spiked blood samples was 50 colony forming units (cfus)/25 MUl reaction, for the detection of B. anthracis, Y. pestis and Brucella species; and 150 cfus/25 MUl reaction, for B. pseudomallei. The assay proved useful in correctly and promptly identifing the clinical isolates of the targeted agents recovered from patients, compared to the gold standard culture methods. INTERPRETATION & CONCLUSION: The assay described in this study showed promise to be useful in application as a routine detection cum diagnostic method for these pathogens. PMID- 24056565 TI - Development & evaluation of biotinylated DNA probe for clinical diagnosis of chikungunya infection in patients' acute phase serum & CSF samples. AB - BACKGROUND & OBJECTIVES: The resurgence of chikungunya virus (CHIKV) in the Indian Ocean Islands and India has drawn worldwide attention due to its explosive nature, high morbidity and complex clinico-pathological manifestations. The early confirmatory diagnosis of CHIKV is essential for management as well as control of unprecedented epidemics. The present study describes the development and evaluation of a highly sensitive and specific E1 structural gene specific biotinylated DNA probe for detection of chikungunya virus in clinical samples using a dot blot format. METHODS: The complementary DNA (cDNA) of CHIKV was spotted on to nylon membrane. The membrane was subjected to prehybridization and hybridization and developed using a colour development solution containing DAB chromogen. RESULTS: The CHIKV E1 specific DNA probe was highly sensitive detecting picogram levels of target nucleic acid. The comparative evaluation with SYBR Green I based real-time RT-PCR revealed 99 per cent accordance with a sensitivity and specificity of 99 and 98 per cent, respectively. The specificity of this assay was further confirmed through cross-reaction studies with confirmed dengue and Japanese encephalitis (JE) patient serum samples along with infected culture supernatant of Ross River and Saint Louis encephalitis and plasmid DNA of O'Nyong Nyong, Semlinki forest and Sindbis viruses. INTERPRETATION & CONCLUSION: The DNA probe reported in this study may be useful for specific, sensitive and confirmatory clinical diagnosis of chikungunya infection in acute phase human patient serum and CSF samples. This assay can also be used in the laboratory for quantification of viral antigen in cell culture supernatant for research purpose. PMID- 24056566 TI - Seroprevalence of anti-HCV antibodies among blood donors of north India. AB - BACKGROUND & OBJECTIVES: Transfusion of blood and blood products although considered as a life saving treatment modality, but may lead to certain infectious and non-infectious complications in the recipients. The purpose of this analysis was to monitor the seroprevalence of anti-HCV antibody in the blood donor population in a hospital based blood bank in north India, to evaluate the trends over the years (2001-2011). METHODS: Relevant information of all the blood donors who donated whole blood at the department of Transfusion Medicine, Indraprastha Apollo Hospitals, New Delhi from the January 1, 2001 to December 31, 2011 was retrieved from the departmental records. The number of donors who were found reactive for anti-HCV anatibodies was calculated. RESULTS: Of the 2,06,022 blood donors, 1,93,661 were males and 12,361 were females. The percentage of whole blood donors found seroreactive for anti-HCV antibodies was 0.39 per cent (n=795). The seroprevalence of anti-HCV in male blood donors was 0.38 per cent (n=750) and the respective seroprevalence in female blood donors was 0.36 per cent (n=45). No significant change in the trend of HCV seroprevalence was observed over the period under consideration. Maximum seroprevalence of anti-HCV was observed in the age group of 18 to 30 yr (0.41%) and the minimum in the age group of 51 to 60 yr (0.26%). INTERPRETATION & CONCLUSION: HCV seroprevalence in our study was 0.39 per cent and a decreasing trend with age was observed. No significant change in the trend of anti-HCV seroprevalence was seen over a decade. Since, no vaccine is presently available for immunization against HCV infection, transfusion transmitted HCV infection remains a potential threat to the safety of the blood supply. PMID- 24056567 TI - Larvicidal & ovicidal efficacy of Pithecellobium dulce (Roxb.) Benth. (Fabaceae) against Anopheles stephensi Liston & Aedes aegypti Linn. (Diptera: Culicidae). AB - BACKGROUND & OBJECTIVES: In view of the recently increased interest in developing plant origin insecticides as an alternative to chemical insecticide, this study was undertaken to assess the larvicidal and ovicidal potential of the crude hexane, benzene, chloroform, ethyl acetate and methanol solvent extracts from the medicinal plant Pithecellobium dulce against the mosquito vectors, Anopheles stephensi and Aedes aegypti (Diptera: Culicidae). METHODS: Larvicidal activity of P. dulce plant extracts was studied in the range of 60 to 450 mg/l against early third instar larvae of An. stephensi and Ae. aegypti in the laboratory. The larval mortality was observed after 24 h of exposure. The ovicidal activity was determined against An. stephensi and Ae. aegypti to various concentrations ranging from 100 to 750 mg/l under the laboratory conditions. Mean per cent hatchability of the eggs were observed after 48 h post treatment. RESULTS: All leaf and seed extracts showed moderate larvicidal and ovicidal effects; however, the highest larval mortality was found in methanol extract of leaf of P. dulce against the larvae of An. stephensi and Ae. aegypti with the LC50 and LC90 values 145.43, 155.78 mg/l and 251.23, 279.73 mg/l, respectively. The per cent hatchability was inversely proportional to the concentration of extract and directly proportional to the eggs. Zero hatchability was observed at 400 mg/l for leaf methanol extract and 625 mg/l for seed methanol extract of P. dulce against An. stephensi and Ae. aegypti, respectively. Compared to leaf extracts, seed extracts have low potency against the two mosquitoes. INTERPRETATION & CONCLUSIONS: The present results suggest that the leaf and seed extracts of P. dulce have the potential to be used as an ideal eco-friendly approach for the control of mosquitoes. PMID- 24056568 TI - Fluorescence in situ hybridization (FISH) using non-commercial probes in the diagnosis of clinically suspected microdeletion syndromes. AB - BACKGROUND & OBJECTIVES: Microdeletion syndromes are characterized by small (<5 Mb) chromosomal deletions in which one or more genes are involved. These are frequently associated with multiple congenital anomalies. The phenotype is the result of haploinsufficiency of genes in the critical interval. Fluorescence in situ hybridization (FISH) technique is commonly used for precise genetic diagnosis of microdeletion syndromes. This study was conducted to assess the role of FISH in the diagnosis of suspected microdeletion syndrome. METHODS: FISH was carried out on 301 clinically suspected microdeletion syndrome cases for the confirmation of clinical diagnosis using non-commercial probes. Of these, 177 cases were referred for 22q11.2 microdeletion, 42 cases were referred for William syndrome, 38 cases were referred for Prader Willi/Angelman and 44 cases were referred for other suspected microdeletion syndromes. RESULTS: FISH was confirmatory in 23 cases only (7.6%). There were 17 cases of 22q11.2 microdeletion, four cases of Prader Willi syndrome and two cases of William syndrome. INTERPRETATION & CONCLUSION: We conclude that FISH should not be the method of choice for clinically suspected microdeletion syndromes. We propose to follow strict clinical criteria for FISH testing or preferably to follow better methods (genotype first approach). Whole genome screening may be used as first line of test and FISH may be used for confirmation of screening result, screening of family members and prenatal diagnosis. PMID- 24056569 TI - Presence of virulence determinants amongst Staphylococcus aureus isolates from nasal colonization, superficial & invasive infections. PMID- 24056571 TI - Varicella pneumonia in an adult. PMID- 24056570 TI - Should pyrazinamide be preferred in tuberculosis treatment during pregnancy? PMID- 24056572 TI - Unusual localization of parathyroid carcinoma in anterior chest wall. PMID- 24056574 TI - Implementation of stable and complex biological systems through recombinase assisted genome engineering. AB - Evaluating the performance of engineered biological systems with high accuracy and precision is nearly impossible with the use of plasmids due to phenotypic noise generated by genetic instability and natural population dynamics. Minimizing this uncertainty therefore requires a paradigm shift towards engineering at the genomic level. Here, we introduce an advanced design principle for the stable installment and implementation of complex biological systems through recombinase-assisted genome engineering (RAGE). We apply this concept to the development of a robust strain of Escherichia coli capable of producing ethanol directly from brown macroalgae. RAGE significantly expedites the optimal implementation of a 34 kb heterologous pathway for alginate metabolism based on genetic background, integration locus, copy number and compatibility with two other pathway modules (alginate degradation and ethanol production). The resulting strain achieves a ~40% higher titre than its plasmid-based counterpart and enables substantial improvements in titre (~330%) and productivity (~1,200%) after 50 generations. PMID- 24056573 TI - Modulation of hydrogel nanoparticle intracellular trafficking by multivalent surface engineering with tumor targeting peptide. AB - Surface engineering of a hydrogel nanoparticle (NP) with the tumor-targeting ligand, F3 peptide, enhances both the NP's binding affinity for, and internalization by, nucleolin overexpressing tumor cells. Remarkably, the F3 functionalized NPs consistently exhibited significantly lower trafficking to the degradative lysosomes than the non-functionalized NPs, in the tumor cells, after internalization. This is attributed to the non-functionalized NPs, but not the F3 functionalized NPs, being co-internalized with Lysosome-associated Membrane Protein-1 (LAMP1) from the surface of the tumor cells. Furthermore, it is shown that the intracellular trafficking of the F3-functionalized NPs differs significantly from that of the molecular F3 peptides (untethered to NPs). This has important implications for designing effective, chemically-responsive, controlled-release and multifunctional nanodrugs for multi-drug-resistant cancers. PMID- 24056576 TI - A microfluidic device designed to induce media flow throughout pancreatic islets while limiting shear-induced damage. AB - Pancreatic islets are heavily vascularized in vivo with fenestrated endothelial cells (ECs) to facilitate blood glucose-sensing and endocrine hormone secretion. The close proximity of insulin secreting beta cells and ECs also plays a critical role in modulating the proliferation and survival of both cell types with the mechanisms governing this interaction poorly understood. Isolated islets lose EC morphology and mass over a period of days in culture prohibiting study of this interaction in vitro. The loss of ECs also limits the efficacy of islet transplant revascularization in the treatment of Type 1 diabetes. We previously showed that microfluidically driven flow positively affects beta-cell function and EC survival in culture due to enhanced transport of media into the tissue. However, holding islets stationary in media flow using a dam-wall design also resulted in reduced glucose-stimulated metabolic and Ca(2+) responses at the periphery of the tissue consistent with shear-induced damage. We have now created a device that traps islets into sequential cup-shaped nozzles. This hydrodynamic trap design limits flow velocity around the perimeter of the islet while enhancing media flow through the tissue. We demonstrate the feasibility of this device to dynamically treat and collect effluent from islets. We further show that treating islets in this device enhances EC morphology without reducing glucose-stimulate Ca(2+) responses. These data reveal a microfluidic device to study EC and endocrine cell interaction that can be further leveraged to prime islets prior to transplantation. PMID- 24056577 TI - Characterising the morphological properties and surface composition of radium contaminated particles: a means of interpreting origin and deposition. AB - Radioactive 'hot particles' that occur in the environment present specific challenges for health and environmental regulators as often their small size makes them difficult to detect, and they are easily dispersed and accidentally ingested or inhaled by members of the public. This study of nine hot particles recovered from the beach at Dalgety Bay, UK, uses a combination of gamma spectrometry, imaging microscopy and SEM-EDX in order to characterise their morphology and surface composition, thereby helping to identify their origin and source characteristics. The nine particles analysed showed great heterogeneity in their activities, physical form and elemental composition. The particle activities were dominated by (226)Ra and its daughters. Three distinct grouping of particles were identified based on their morphology (artefact, glassy and 'metal-rich'), whilst four distinct groupings (artefact, glassy, angular and porphyric, rounded and highly porous) were identified based on morphology and surface properties as seen in the SEM. Whilst the 'artefact' particles were little altered, the other particles showed evidence of incineration. All particles were in a size and/or shape class vulnerable to wind- or water-mediated transport. No correlations were found between morphology and chemical composition. SEM-EDX analysis revealed C, Si, Zn, Fe, Ca are common in the particles together with Ba, Ni, Pb, Cu, Mn and Ti. This is interpreted as the particles being derived from radium containing luminescent paint containing a Zn/S phosphor, a hydrocarbon base and other fillers and additives. Evidence of copper and steel alloys were also present in some particles, whilst one consisted of a hydrocarbon based 'capsule'. The combination of techniques employed here has enabled interpretation of the origins of the radioactive particles and given insights into the potential movement of particles within the local environment. PMID- 24056578 TI - Real-time and on-chip surface temperature sensing of GaN LED chips using PbSe quantum dots. AB - PbSe quantum dots (QDs) were employed as real-time and on-chip temperature sensors to monitor the surface temperature of GaN LED chips. The temperature dependent photoluminescence spectra were achieved and confirmed to be a good method for surface temperature sensing in a micro- to nano-region. The nanosized QD sensors did not influence the LED emission spectrum due to their infrared emission and little absorption. The surface temperature of GaN LED chips was analyzed at different working times and voltages. The temperature sensitivity characterized by the photoluminescence peak position of PbSe QDs was found to be 0.15 nm degrees C(-1) in a range of 30-120 degrees C and the precision was determined to be +/- 3 degrees C. The QD surface temperature sensors were confirmed to have good reversibility and repeatability. PMID- 24056579 TI - A new microporous carbon material synthesized via thermolysis of a porous aromatic framework embedded with an extra carbon source for low-pressure CO2 uptake. AB - Pre-introducing an extra carbon source into the porous aromatic framework of PAF 1 followed by thermolysis affords a new microporous carbon material, which demonstrates a CO2 uptake capacity of 93 cm(3) g(-1) (equivalent to 4.1 mmol g( 1) or 18.2 wt%) at 295 K and 1 bar. PMID- 24056580 TI - Profiling the triacylglyceride contents in bat integumentary lipids by preparative thin layer chromatography and MALDI-TOF mass spectrometry. AB - The mammalian integument includes sebaceous glands that secrete an oily material onto the skin surface. Sebum production is part of the innate immune system that is protective against pathogenic microbes. Abnormal sebum production and chemical composition are also a clinical symptom of specific skin diseases. Sebum contains a complex mixture of lipids, including triacylglycerides, which is species specific. The broad chemical properties exhibited by diverse lipid classes hinder the specific determination of sebum composition. Analytical techniques for lipids typically require chemical derivatizations that are labor-intensive and increase sample preparation costs. This paper describes how to extract lipids from mammalian integument, separate broad lipid classes by thin-layer chromatography, and profile the triacylglyceride contents using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. This robust method enables a direct determination of the triacylglyceride profiles among species and individuals, and it can be readily applied to any taxonomic group of mammals. PMID- 24056581 TI - Large-scale cytological profiling for functional analysis of bioactive compounds. AB - Cytological profiling (CP) is an unbiased image-based screening technique that uses automated microscopy and image analysis to profile compounds based on numerous quantifiable phenotypic features. We used CP to evaluate a library of nearly 500 compounds with documented mechanisms of action (MOAs) spanning a wide range of biological pathways. We developed informatics techniques for generating dosage-independent phenotypic "fingerprints" for each compound, and for quantifying the likelihood that a compound's CP fingerprint corresponds to its annotated MOA. We identified groups of features that distinguish classes with closely related phenotypes, such as microtubule poisons vs. HSP90 inhibitors, and DNA synthesis vs. proteasome inhibitors. We tested several cases in which cytological profiles indicated novel mechanisms, including a tyrphostin kinase inhibitor involved in mitochondrial uncoupling, novel microtubule poisons, and a nominal PPAR-gamma ligand that acts as a proteasome inhibitor, using independent biochemical assays to confirm the MOAs predicted by the CP signatures. We also applied maximal-information statistics to identify correlations between cytological features and kinase inhibitory activities by combining the CP fingerprints of 24 kinase inhibitors with published data on their specificities against a diverse panel of kinases. The resulting analysis suggests a strategy for probing the biological functions of specific kinases by compiling cytological data from inhibitors of varying specificities. PMID- 24056582 TI - On the generality of age differences in social and nonsocial decision making. AB - OBJECTIVES: Empirical work with western populations suggests that aging is associated with changes in economic decision making, including, for example, increased prosocial tendencies. We investigated the generality of age effects in social and nonsocial domains by assessing various measures of economic decision making in a rural population from Morocco. METHOD: We measured age/cohort differences using a number of economic games (risk game, time preferences game, dictator game, trust game, and public goods game) in over 700 participants ranging from 17 to 92 years of age. RESULTS: The results suggest a negative relation between age and risk taking and a concave relation between age and contribution to a public good, but no significant age trends in time preferences, altruism, trust, or trustworthiness. DISCUSSION: Our results indicate that the relationship between aging and decision making is not universal and is shaped by local culture and the type of task rather than biological factors alone. More research is needed to understand the unique age trends prevalent in specific populations and tasks. PMID- 24056583 TI - Black rice and anthocyanins induce inhibition of cholesterol absorption in vitro. AB - Black rice (Oryza sativa L.) is often associated with blood lipid control. This study systematically assessed the inhibition of cholesterol absorption in vitro by black rice and explored cholesterol-lowering compounds present in this rice. Our results indicated that black rice extracts (BRE), which were aqueous, ethanol extracts and a fraction of macroporous resin caused the reduction of cholesterol absorption by inhibiting pancreatic lipase, decreasing the micellar cholesterol solubility and suppressing cholesterol uptake in Caco-2 cells. The inhibitory activity was positively associated with anthocyanin (cyanidin-3-glucoside (Cy-3 G) and peonidin-3-glucoside (Pn-3-G)) contents of the extracts. Therefore, the cholesterol absorption inhibiting properties of anthocyanins were further explored. The IC50 values of Cy-3-G and Pn-3-G against pancreatic lipase were 42.53 +/- 4.45 and 18.13 +/- 4.22 MUg mL(-1), respectively. Kinetic analysis suggested that the enzymatic inhibitory mode of Cy-3-G and Pn-3-G belonged to the competitive type. In mixed micelles, Cy-3-G and Pn-3-G dose dependently reduced the solubility of cholesterol. Meanwhile, a potential mechanism of cholesterol reduction by anthocyanins was investigated. Results showed that anthocyanins led to precipitation of cholesterol from micellar solution, which may induce the reduction of cholesterol. In Caco-2 cells, Cy-3-G and Pn-3-G (40 MUg mL(-1)) exhibited a significant reduction in cholesterol uptake, and the degree of this reduction was almost the same as that observed in the group treated with Ezetimibe at the same concentration. These findings provide important evidence that anthocyanins may partly contribute to the inhibitory effects of black rice on cholesterol absorption, and thus may be applied for the prevention and treatment of hypercholesterolaemia. PMID- 24056584 TI - Statistical analysis of electromagnetic radiation measurements in the vicinity of GSM/UMTS base station antenna masts. AB - As a result of dense installations of public mobile base station, additional electromagnetic radiation occurs in the living environment. In order to determine the level of radio-frequency radiation generated by base stations, extensive electromagnetic field strength measurements were carried out for 664 base station locations. Base station locations were classified into three categories: indoor, masts and locations with installations on buildings. Having in mind the large percentage (47 %) of sites with antenna masts, a detailed analysis of this location category was performed, and the measurement results were presented. It was concluded that the total electric field strength in the vicinity of base station antenna masts in no case exceeded 10 V m(-1), which is quite below the International Commission on Non-Ionizing Radiation Protection reference levels. At horizontal distances >50 m from the mast bottom, the median and maximum values were <1 and 2 V m(-1), respectively. PMID- 24056585 TI - A revised model for the deposition and clearance of inhaled particles in human extra-thoracic airways. AB - The International Commission on Radiological Protection (ICRP) Task Group that developed the Human Respiratory Tract Model for Radiological Protection (HRTM) identified a lack of published information on aspects of the clearance of inhaled particles deposited in the human nasal passage. Using the results of a recent human volunteer study on the clearance of inhaled particles from the nose, a revised model of clearance from the extra-thoracic (ET) airways has been developed that addresses important issues for which simplifying assumptions had to be made in the ICRP Publication 66 HRTM ET model. This ET clearance model has been adopted by ICRP for inclusion in the revised HRTM. The derivation of the model and parameter values from the experimental data are explained. PMID- 24056586 TI - Crystalloid or colloid for goal-directed fluid therapy in colorectal surgery. AB - BACKGROUND: Goal-directed fluid therapy has been shown to improve outcomes after colorectal surgery, but the optimal type of i.v. fluid to use is yet to be established. Theoretical advantages of using hydroxyethyl starch (HES) for goal directed therapy include a reduction in the total volume of fluid required, resulting in less tissue oedema. Recent work has demonstrated that new generations of HES have a good safety profile, but their routine use in the perioperative setting has not been demonstrated to confer outcome benefit. METHODS: We randomly assigned 202 medium to high-risk patients undergoing elective colorectal surgery to receive either balanced 6% HES (130/0.4, Volulyte) or balanced crystalloid (Hartmann's solution) as haemodynamic optimization fluid. The primary outcome measure was the incidence of gastrointestinal (GI) morbidity on postoperative day 5. Secondary outcome measures included the incidence of postoperative complications, hospital length of stay, and the effect of trial fluids on coagulation and inflammation. RESULTS: No difference was seen in the number of patients who suffered GI morbidity on postoperative day 5 [30% in the HES group vs 32% in the crystalloid group; adjusted odds ratio=0.96 (0.52-1.77)]. Subjects in the crystalloid group received more fluid [median (inter-quartile ranges) 3175 (2000-3700) vs 1875 (1500-3000) ml, P<0.001] and had a higher 24 h fluid balance [+4226 (3251-5779) vs +3610 (2443-4519) ml, P<0.001]. No difference in the incidence of postoperative complications was seen between the groups. CONCLUSIONS: Goal-directed fluid therapy is possible with either crystalloid or HES. There is no evidence of a benefit in using HES over crystalloid, despite its use resulting in a lower 24 h fluid balance. PMID- 24056587 TI - Visible-light-driven photoelectrochemical and photocatalytic performances of Cr doped SrTiO3/TiO2 heterostructured nanotube arrays. AB - Well-aligned TiO2 nanotube arrays have become of increasing significance because of their unique highly ordered array structure, high specific surface area, unidirectional charge transfer and transportation features. However, their poor visible light utilization as well as the high recombination rate of photoexcited electron-hole pairs greatly limited their practical applications. Herein, we demonstrate the fabrication of visible-light-responsive heterostructured Cr-doped SrTiO3/TiO2 nanotube arrays by a simple hydrothermal method, which facilitate efficient charge separation and thus improve the photoelectrochemical as well as photocatalytic performances. PMID- 24056589 TI - Lasing and magnetic microbeads loaded with colloidal quantum dots and iron oxide nanocrystals. AB - This study investigates the feasibility of loading nanostructured lasing medium and magnetic nanocrystals in the same microbead for potential applications in bio and chemical sensing. A sequential infiltration process is proposed and tested for the preparation of magnetic and lasing microbeads by incorporating, respectively, iron oxide nanocrystals in the inner cores and colloidal quantum dots (CQDs) in the periphery regions of mesoporous silica microbeads. The co doped bead structure was confirmed by electron microscopy and energy dispersive spectroscopy. The lasing action of the CQD gain medium in the mesoporous beads was characterized with micro-photoluminescence, revealing sharp whispering gallery mode lasing signatures, whereas the distinguishing superparamagnetic property was measured from the co-doped microbeads with vibrating sample magnetometry. PMID- 24056591 TI - Treatment of irritable bowel syndrome with probiotics: growing evidence. PMID- 24056590 TI - Mutants of Cre recombinase with improved accuracy. AB - Despite rapid advances in genome engineering technologies, inserting genes into precise locations in the human genome remains an outstanding problem. It has been suggested that site-specific recombinases can be adapted towards use as transgene delivery vectors. The specificity of recombinases can be altered either with directed evolution or via fusions to modular DNA-binding domains. Unfortunately, both wild-type and altered variants often have detectable activities at off target sites. Here we use bacterial selections to identify mutations in the dimerization surface of Cre recombinase (R32V, R32M and 303GVSdup) that improve the accuracy of recombination. The mutants are functional in bacteria, in human cells and in vitro (except for 303GVSdup, which we did not purify), and have improved selectivity against both model off-target sites and the entire E. coli genome. We propose that destabilizing binding cooperativity may be a general strategy for improving the accuracy of dimeric DNA-binding proteins. PMID- 24056592 TI - Deworming conundrum - are we missing an undesirable dimension? PMID- 24056593 TI - Suicide & tuberculosis. PMID- 24056594 TI - Obesity & osteoarthritis. AB - The most significant impact of obesity on the musculoskeletal system is associated with osteoarthritis (OA), a disabling degenerative joint disorder characterized by pain, decreased mobility and negative impact on quality of life. OA pathogenesis relates to both excessive joint loading and altered biomechanical patterns together with hormonal and cytokine dysregulation. Obesity is associated with the incidence and progression of OA of both weight-bearing and non weight bearing joints, to rate of joint replacements as well as operative complications. Weight loss in OA can impart clinically significant improvements in pain and delay progression of joint structural damage. Further work is required to determine the relative contributions of mechanical and metabolic factors in the pathogenesis of OA. PMID- 24056595 TI - Prevalence of suicidal behaviour & associated factors among tuberculosis patients in public primary care in South Africa. AB - BACKGROUND & OBJECTIVES: In spite of the high prevalence of tuberculosis worldwide, there are only a few studies on its psychiatric complications such as suicidal behaviour. We undertook this study to assess the prevalence of suicidal behaviour and its associated factors among tuberculosis patients in public primary care in South Africa. METHODS: In a cross-sectional survey conducted in three provinces of South Africa new TB and new re-treatment patients were assessed within one month of anti-tuberculosis treatment. The sample included 4900 (54.5% men and women 45.5%) consecutively selected tuberculosis patients from 42 public primary care clinics in three districts in South Africa. RESULTS: A total of 322 patients (9.0%) reported suicidal ideation and 131 (3.1%) had a history of a suicide attempt. In multivariate analysis female gender [Odds Ratio (OR)= 0.56, Confidence Interval (CI)= 0.43-0.74], psychological distress (OR=2.36, CI=1.04-2.29), post-traumatic stress disorders (PTSD) (OR=4.98, CI=3.76 6.59), harmful alcohol use (OR=1.97, CI=1.25-3.09) and being a TB re-treatment patient (OR=1.76, CI=1.32-2.34) were associated with suicidal ideation, and psychological distress (OR=3.27, CI=1.51-7.10), PTSD symptoms (OR=4.48, CI=3.04 6.61) and harmful alcohol use (OR=3.01, CI=1.83-4.95) were associated with a suicide attempt. INTERPRETATION & CONCLUSIONS: Our findings suggest that co morbid illnesses of psychological distress, PTSD and harmful alcohol use and HIV infection should be assessed in TB patients under TB control programmes to prevent suicidal behaviour. Clinicians should be aware about suicidality in tuberculosis patients to reduce mortality. PMID- 24056596 TI - Antiretroviral treatment, viral load of mothers & perinatal HIV transmission in Mumbai, India. AB - BACKGROUND & OBJECTIVES: Mother-to-child transmission (MTCT) is the most significant route of HIV transmission in children below the age of 15 yr. In India, perinatal HIV transmission, even after treatment, accounts for 5.4 per cent of HIV cases. The present study was conducted to evaluate the efficacy of anti-retro viral therapy (ART) or prophylactic treatment (PT) to control maternal viral load in HIV positive women, and its effect on vertical HIV transmission to their infants. METHODS: A total of 58 HIV positive women were enrolled at the time of delivery and their plasma samples were obtained within 24 h of delivery for estimation of viral load. Viral load analysis was completed in 38 women. Infants received single dose nevirapine within 2 h of birth and zidovudine for 6 wk. At the end of 18 month follow up, HIV positive or negative status was available in 28 infants. RESULTS: Results revealed undetectable levels of viral load in 58.3 per cent of women with ART compared to 30.7 per cent of women with PT. No women on ART had viral load more than 10,000 copies/ml, whereas seven (26.9%, P=0.07) women receiving PT had this viral load. Median CD4 count of women on PT (483 cells/MUl) was high compared to the women on ART (289 cells/ MUl). At the end of 18 months follow up, only two children were HIV positive, whose mothers were on PT. One had in utero transmission; infection detected within 48 h of delivery, while the other child was infected post partum as HIV was detected at six months follow up. INTERPRETATION & CONCLUSIONS: Women who received a single dose of nevirapine during delivery had higher levels of viral load than women on ART. Combination drug therapy for pregnant women is now a standard of care in most of the western countries; use of nevirapine monotherapy at the time of delivery in our settings is not effective in controlling viral load. This highlights initiation of ART in pregnant women to control their viral load and thus to inhibit mother to child HIV transmission. PMID- 24056597 TI - Differential induction of Toll-like receptors & type 1 interferons by Sabin attenuated & wild type 1 polioviruses in human neuronal cells. AB - BACKGROUND & OBJECTIVES: Polioviruses are the causative agent of paralytic poliomyelitis. Attenuated polioviruses (Sabin oral poliovirus vaccine strains) do not replicate efficiently in neurons as compared to the wild type polioviruses and therefore do not cause disease. This study was aimed to investigate the differential host immune response to wild type 1 poliovirus (wild PV) and Sabin attenuated type 1 poliovirus (Sabin PV) in cultured human neuronal cells. METHODS: By using flow cytometry and real time PCR methods we examined host innate immune responses and compared the role of toll like receptors (TLRs) and cytoplasmic RNA helicases in cultured human neuronal cells (SK-N-SH) infected with Sabin PV and wild PV. RESULTS: Human neuronal cells expressed very low levels of TLRs constitutively. Sabin PV infection induced significantly higher expression of TLR3, TLR7 and melanoma differentiation-associated protein-5 (MDA 5) m-RNA in neuronal cells at the beginning of infection (up to 4 h) as compared to wild PV. Further, Sabin PV also induced the expression of interferon alpha/beta at early time point of infection. The induced expression of IFN alpha/beta gene by Sabin PV in neuronal cells could be suppressed by inhibiting TLR7. INTERPRETATION & CONCLUSIONS: Neuronal cell innate immune response to Sabin and wild polioviruses differ significantly for TLR3, TLR7, MDA5 and type 1 interferons. Effects of TLR7 activation and interferon production and Sabin virus replication in neuronal cells need to be actively investigated in future studies. PMID- 24056598 TI - Temporal changes of Japanese encephalitits virus in different brain regions of rat. AB - BACKGROUND & OBJECTIVES: Japanese encephalitis virus (JEV) infection results in acute encephalitic illness. The affinity of JEV to different regions of brain and temporal changes in viral load have not been studied. This study was conducted to describe localization of JEV to different regions of the brain at different stages of disease in a rat model of Japanese encephalitis (JE). METHODS: Twelve days old Wistar rats were inoculated intracerebrally with a dose of 3 x 106 pfu/ml of JEV. After 3, 6, 10 and 20 days post-inoculation, brains were dissected out and different regions of brain (cortex, striatum, thalamus and mid brain) were taken. Motor deficit was assessed by the rota rod and JEV RNA copies were evaluated using real-time PCR assay. RESULTS: There was a significant increase in motor deficit in rats inoculated with JEV compared to the controls. JEV RNA copies were present in all studied regions of the brain on days 3, 6 and 10 post inoculation. Maximum number of JEV RNA copies were present in the mid brain on days 3 and 10 post-inoculation. JEV RNA copies were not detected in any of the brain regions on day 20. INTERPRETATION & CONCLUSIONS: This study reports JEV RNA load in different brain regions of rat with higher affinity of JEV virus to thalamus and mid brain compared to other regions. PMID- 24056599 TI - Establishment of cell line from embryonic tissue of Pipistrellus ceylonicus bat species from India & its susceptibility to different viruses. AB - BACKGROUND & OBJECTIVES: Pipistrellus ceylonicus bat species is widely distributed in South Asia, with additional populations recorded in China and Southeast Asia. Bats are the natural reservoir hosts for a number of emerging zoonotic diseases. Attempts to isolate bat-borne viruses in various terrestrial mammalian cell lines have sometimes been unsuccessful. The bat cell lines are useful in isolation and propagation of many of the viruses harboured by bats. New stable bat cell lines are needed to help such investigations and to assist in the study of bat immunology and virus-host interactions. In this study we made an attempt to develop a cell line from P. ceylonicus bats. METHODS: An effort was made to establish cell line from embryo of P. ceylonicus species of bat after seeding to Dulbecco's modified eagle medium (DMEM) supplemented with 10 per cent foetal bovine serum; a primary cell line was established and designated as NIV BtEPC. Mitochondrial DNA profile analysis was done using cyt-b and ND-1 gene sequences from the cell line. Phylogenetic tree was constructed using neighbour joining algorithm for cyt-b and ND-1 genes with 1000-bootstrap replicates. RESULTS: NIV-BtEPC cell line was susceptible to Chandipura (CHPV) and novel adenovirus (BtAdv-RLM) isolated from Rousettus leschenaulti from India but did not support multiplication of a number of Bunyaviruses, Alphaviruses and Flavivirus. This might be useful for isolation of a range of viruses and investigation of unknown aetiological agents. INTERPRETATION & CONCLUSIONS: In this study, a new bat cell line was developed from P. ceylonicus. This cell line was successfully tested for the susceptibility to Chandipura and BtAdv-RLM virus isolated from bats. The approach developed and optimised in this study may be applicable to the other species of bats and this established cell line can be used to facilitate virus isolation and basic research into virus-host interaction. PMID- 24056600 TI - Increased risk of mortality among haemodialysis patients with or without prior stroke: a nationwide population-based study in Taiwan. AB - BACKGROUND & OBJECTIVES: Patients with prior stroke (PS) undergoing chronic dialysis are at a high risk of mortality. However, little is known about the cumulative risk and survival rate of dialysis patients with long-term follow up. The aim of this study was to assess risks for mortality between patients with and without PS undergoing chronic haemodialysis (HD). METHODS: The Taiwan National Health Insurance Research Database (NHRI-NHIRD-99182) was used and all adult patients (>=18 yr) with end stage renal disease (ESRD) who started maintenance HD between January 1, 1999, and December 31, 1999, were selected. The patients were followed from the first reported date of HD to the date of death, end of dialysis or December 31, 2008. A Cox's proportional hazard model was applied to identify the risk factors for all-cause mortality. RESULTS: Among 5672 HD patients, 650 patients (11.5%) had PS. A higher proportion of stroke history at baseline was found in men (52.8%) and those aged >= 55 yr (80.9%). After adjusting for age, sex and other covariates, the patients with PS were found to have a 36 per cent increased risk of mortality compared to those without PS (HR 1.36, 95% CI: 1.22 1.52). The cumulative survival rates among HD patients without PS were 96.0 per cent at the first year, 68.4 per cent at the fifth year, and 46.7 per cent at the ninth year, and 92.9, 47.3 and 23.6 per cent, respectively, in those with PS (log rank: P<0.001). INTERPRETATION & CONCLUSIONS: Our findings showed that PS was an important predictor for all-cause mortality and poor outcome in patients undergoing chronic HD. PMID- 24056601 TI - User friendliness, efficiency & spray quality of stirrup pumps versus hand compression pumps for indoor residual spraying. AB - BACKGROUND & OBJECTIVES: Indoor residual spraying (IRS) is a proven tool to reduce visceral leishmaniasis vectors in endemic villages. In India IRS is being done with stirrup pumps, whereas Nepal, Bangladesh, and other countries use compression pumps. The present study was conducted with the objectives to compare the efficiency, cost and user friendliness of stirrup and compression pumps. METHODS: The study was carried out in Gorigawan village of the Vaishali district in north Bihar and included a total population of 3259 inhabitants in 605 households. Spraying with 50 per cent DDT was done by two teams with 6 persons per team under the supervision of investigators over 5 days with each type of pump (10 days in total using 2 stirrup pumps and 3 compression pumps) by the same sprayers in an alternate way. The spraying technique was observed using an observation check list, the number of houses and room surfaces sprayed was recorded and an interview with sprayers on their satisfaction with the two types of pumps was conducted. RESULTS: On average, 65 houses were covered per day with the compression pump and 56 houses were covered with the stirrup pump. The surface area sprayed per squad per day was higher for the compression pump (4636 m2) than for the stirrup pump (4102 m2). Observation showed that it was easy to maintain the spray swath with the compression pump but very difficult with the stirrup pump. The wastage of insecticide suspension was negligible for the compression pump but high for the stirrup pump. INTERPRETATION & CONCLUSIONS: The compression pump was found to be more user friendly due to its lower weight, easier to operate, lower operation cost, higher safety and better efficiency in terms of discharge rate and higher area coverage than the stirrup pump. PMID- 24056602 TI - Molecular detection of Mycoplasma pneumoniae by quantitative real-time PCR in patients with community acquired pneumonia. AB - BACKGROUND & OBJECTIVES: Mycoplasma pneumoniae is the most important and common cause of community-acquired pneumonia (CAP). The conventional detection methods (culture and serology) lack sensitivity. PCR offers a better approach for rapid detection but is prone to carry over contamination during manipulation of amplification products. Quantitative real-time PCR (qRT-PCR) method offers an attractive alternative detection method. In the present study, qRT-PCR, PCR and serology methods were used to detect M. pneumoniae infection in cases of pneumonias and findings compared. METHODS: A total of 134 samples consisting of blood (for serology) and respiratory secretions (for PCR and qRT-PCR) from 134 patients were collected. The blood samples were tested for IgG, IgM and IgA using commercially available kits. For standardization of PCR of M. pneumoniae P1 gene was cloned in pGEMTEasy vector. Specific primers and reporter sequence were designed and procured for this fragment. The qRT-PCR assay was performed to prepare the standard curve for M. pneumoniae positive control DNA template and detection in patient samples. RESULTS: Of the 134 patients, 26 (19%) were positive for antibodies against M. pneumoniae. IgG was positive in 14.92 per cent (20) cases, IgM in 4.47 per cent (6) and IgA was positive in 5.22 per cent (7) cases. In the qRT-PCR assay 19 per cent (26) samples were positive. Of the 26 qRT PCR positive samples, nine could be detected by serology. PCR was positive for 25 samples. An extra sample negative by PCR was detected by qRT-PCR. Thus, real-time PCR assay, PCR and serology in combination could detect M. pneumoniae infection in 43 patients. INTERPRETATION & CONCLUSIONS: The study shows that 17 patients were detected by serology alone, 17 were detected by qRT-PCR only and nine patients were positive by both serology and real-time PCR. Of the 134 samples tested, 25 were positive by conventional PCR, but qRT-PCR could detect one more sample that was negative by PCR and serology. These results suggest that a combination of two or three methods may be required for reliable identification of CAP due to M. pneumoniae. PMID- 24056603 TI - Frequency & specificity of RBC alloantibodies in patients due for surgery in Iran. AB - BACKGROUND & OBJECTIVES: Red blood cell alloimmunization is common in patients receiving multiple blood transfusions. Since the probability of repeat transfusion increases with longer life expectancy, it is important to study to which extent alloimmunized patients with a history of transfusion are prone to form alloantibodies after transfusion events. The aim of this study was to retrospectively analyze the alloimmunization against RBCs among transfused patients who were to undergo elective surgery in Tehran, Iran. METHODS: A total of 3092 occasionally transfused patients, who were to undergo elective surgery, in four hospitals in Tehran were included in the study. For patients with alloantibodies, the data about sex, date of birth, history of transfusion, surgery, abortion and alloantibody specificity were collected. RESULTS: Clinically significant alloantibodies were found in 30 patients. The presence of positive antibodies in the patients for whom cross-match had been done was one per cent. Most of them had surgery history or transfusion record during the preceding year. The three most frequent alloantibodies were anti-K (23.53%), anti E (20.59%) and anti-c (17.56%). INTERPRETATION & CONCLUSIONS: The most common clinically significant alloantibodies identified in men and women were anti-K and anti-E, respectively. The most common causes of alloimmunization for men were surgery history and transfusion record and for women pregnancy. PMID- 24056604 TI - Preliminary findings on Bagaza virus (Flavivirus: Flaviviridae) growth kinetics, transmission potential & transovarial transmission in three species of mosquitoes. AB - BACKGROUND & OBJECTIVES: Bagaza virus (BAGV), a flavivirus synonymous with Israel turkey meningoencephalitis virus, has been found to circulate in India. BAGV has recently been held responsible for inducing febrile illness in humans and causing unusually high mortality to wild birds in Spain. A study was therefore, undertaken to determine its replication kinetics in certain mosquitoes and to determine vector competence and potential of the mosquitoes to transmit BAGV experimentally. METHODS: Aedes aegypti, Culex tritaeniorhynchus and Cx quinquefasciatus mosquitoes were inoculated with BAGV; samples were harvested every day and titrated in BHK-21 cell line. Vector competence and experimental transmission were determined by examining the saliva of infected mosquitoes for virus and induction of sickness in suckling mice, respectively. RESULTS: Cx. tritaeniorhynchus and Ae. aegypti mosquitoes yielded 5 log10 and 4.67 log10 TCID50/ml of virus on day 3 post-infection (PI), respectively while Cx. quinquefasciatus yielded a titre of 4 log10 TCID50/ml on day 4 PI. BAGV was detected in saliva of all the infected mosquitoes demonstrating their vector competence. Experimental transmission of BAGV to infant mice as well as transovarial transmission was demonstrated by Cx. tritaeniorhynchus but not by Ae. aegypti and Cx. quinquefasciatus mosquitoes. INTERPRETATION & CONCLUSIONS: Replication of BAGV to high titres and dissemination to saliva in three most prevalent mosquitoes in India is of immense public health importance. Though no major outbreak involving man has been reported yet, BAGV has a potential to cause outbreaks in future. PMID- 24056605 TI - Glucose & sodium chloride induced biofilm production & ica operon in clinical isolates of staphylococci. AB - BACKGROUND & OBJECTIVES: All colonizing and invasive staphylococcal isolates may not produce biofilm but may turn biofilm producers in certain situations due to change in environmental factors. This study was done to test the hypothesis that non biofilm producing clinical staphylococci isolates turn biofilm producers in presence of sodium chloride (isotonic) and high concentration of glucose, irrespective of presence or absence of ica operon. METHODS: Clinical isolates of 100 invasive, 50 colonizing and 50 commensal staphylococci were tested for biofilm production by microtiter plate method in different culture media (trypticase soy broth alone or supplemented with 0.9% NaCl/ 5 or 10% glucose). All isolates were tested for the presence of ica ADBC genes by PCR. RESULTS: Biofilm production significantly increased in the presence of glucose and saline, most, when both glucose and saline were used together. All the ica positive staphylococcal isolates and some ica negative isolates turned biofilm producer in at least one of the tested culture conditions. Those remained biofilm negative in different culture conditions were all ica negative. INTERPRETATION & CONCLUSIONS: The present results showed that the use of glucose or NaCl or combination of both enhanced biofilm producing capacity of staphylococcal isolates irrespective of presence or absence of ica operon. PMID- 24056606 TI - Seroprevalence of pandemic influenza H1N1 (2009) & seasonal influenza viruses in pigs in Maharashtra & Gujarat States, India, 2011. PMID- 24056607 TI - Regarding distance of residence in 1984 may be used as exposure surrogate for the Bhopal disaster - further observations on post-disaster epidemiology. PMID- 24056608 TI - Diagnosis of leptospirosis. PMID- 24056609 TI - Multiple brown tumours in a renal transplantation patient with hyperparathyroidism. PMID- 24056610 TI - Large B-cell lymphoma mimicking adrenal pheochromocytoma. PMID- 24056611 TI - A chemical screening procedure for glucocorticoid signaling with a zebrafish larva luciferase reporter system. AB - Glucocorticoid stress hormones and their artificial derivatives are widely used drugs to treat inflammation, but long-term treatment with glucocorticoids can lead to severe side effects. Test systems are needed to search for novel compounds influencing glucocorticoid signaling in vivo or to determine unwanted effects of compounds on the glucocorticoid signaling pathway. We have established a transgenic zebrafish assay which allows the measurement of glucocorticoid signaling activity in vivo and in real-time, the GRIZLY assay (Glucocorticoid Responsive In vivo Zebrafish Luciferase activitY). The luciferase-based assay detects effects on glucocorticoid signaling with high sensitivity and specificity, including effects by compounds that require metabolization or affect endogenous glucocorticoid production. We present here a detailed protocol for conducting chemical screens with this assay. We describe data acquisition, normalization, and analysis, placing a focus on quality control and data visualization. The assay provides a simple, time-resolved, and quantitative readout. It can be operated as a stand-alone platform, but is also easily integrated into high-throughput screening workflows. It furthermore allows for many applications beyond chemical screening, such as environmental monitoring of endocrine disruptors or stress research. PMID- 24056613 TI - Conserved residue modulates copper-binding properties through structural dynamics in human copper chaperone Atox1. AB - The human copper chaperone Atox1 plays a central role in the transport of copper in cells. It has been reported that the conserved residue Lys60 contributes to the heterocomplex stability of Atox1 with its target protein ATPase, and that the K60A mutation could diminish the copper transfer. In this work, we carried out the structure determination and dynamic analysis of Atox1 with the K60A mutation in order to elucidate the role of the conserved residue Lys60 in the copper transport. Results show that the K60A mutation results in crucial secondary structure rearrangements and side-chain orientation alteration of the metal binding residues in Atox1. Protein dynamic studies reveal that the K60A mutation leads to increased overall flexibility, and a significant difference in dynamic properties of the metal-binding sites. The structure and dynamic changes cause a decrease in the copper-binding stability of the K60A mutant. In addition, Cu(i) mediated hetero-protein interactions with ATP7A are present in the metal transfer of both Atox1 variants, although copper transfer is accompanied with smaller structural alteration in the K60A mutant. These results indicate that Lys60 is crucial in maintaining the structure and dynamic properties of Atox1. PMID- 24056614 TI - Fluorescence origin and spectral broadening mechanism in atomically precise Au8 nanoclusters. AB - Super-small Au8 nanoclusters have shown great potential to be used in bioimaging, biosensors and catalysis. Understanding the fluorescence origin and the spectral broadening mechanism is of critical importance for the applications. Here we investigate the fluorescence origin and the spectral broadening mechanism using steady state and ultrafast time-resolved spectroscopy. For the first time we clearly elucidate the broad fluorescence of Au8 nanoclusters consisting of an intrinsic band from the Au8 core and an extrinsic band from the surface fluorophores. The emission energy of the intrinsic band is in accord with the rule of E/N(1/3) and the spectral broadening originates from ultrafast dephasing due to effective electron-electron scattering. The extrinsic band has a much larger bandwidth due to massive surface fluorophores; it is the dominant mechanism for spectral broadening in Au8. In contrast to the jellium model predictions, the overall fluorescence exhibits excitation wavelength dependence. PMID- 24056615 TI - Fenton oxidation and combined Fenton-microbial treatment for remediation of crude oil contaminated soil in Assam - India. AB - The study is aimed at the remediation of soil spiked with crude oil (5%) by employing Fenton oxidation, biological treatment and combined Fenton-biological treatment. A spiked concentration of 5% crude oil was selected on the basis of contamination levels of 0-5% as found in the soil of upper Assam oil fields (India). The degradation of the aliphatic fraction (C14-C28) of the crude oil was investigated by gas chromatography. Fenton oxidation was carried out at different pH (3 to 8) in a laboratory batch reactor and maximum oxidative degradation was observed at pH 3-5. At pH 3, single Fenton oxidation resulted in 36 and 57% degradation in 5 and 10 days respectively. Biological treatment (with Fusarium solani) and combined Fenton-biological treatment were carried out with a one month incubation period. Biological treatment alone brought about 61% degradation of the crude oil while the combined process could achieve as much as 75% degradation of the aliphatic fractions of the crude oil. PMID- 24056616 TI - Synthesis, characterization and electrochemical performance of graphene decorated with 1D NiMoO4 . nH2O nanorods. AB - One-dimensional NiMoO4 . nH2O nanorods and their graphene based hybrid composite with good electrochemical properties have been synthesized by a cost effective hydrothermal procedure. The formation of the mixed metal oxide and the composite was confirmed by XRD, XPS and Raman analyses. The morphological characterizations were carried out using FESEM and TEM analyses. The materials were subjected to electrochemical characterization through cyclic voltammetry (CV), galvanostatic charge-discharge (GCD) and electrochemical impedance spectroscopy (EIS) studies with 6 M KOH as the supporting electrolyte. For NiMoO4 . nH2O, a maximum specific capacitance of 161 F g(-1) was obtained at 5 A g(-1) current density, accompanied with an energy density of 4.53 W h kg(-1) at a steady power delivery rate of 1125 W kg(-1). The high utility of the pseudocapacitive NiMoO4 . nH2O was achieved in its graphene based composite, which exhibited a high specific capacitance of 367 F g(-1) at 5 A g(-1) current density and a high energy density of 10.32 W h kg( 1) at a power density of 1125 W kg(-1) accompanied with long term cyclic stability. PMID- 24056617 TI - The liquid phase epitaxy method for the construction of oriented ZIF-8 thin films with controlled growth on functionalized surfaces. AB - Highly-oriented ZIF-8 thin films with controllable thickness were grown on an -OH functionalized Au substrate using the liquid phase epitaxy method at room temperature, as evidenced by SEM and PXRD. The adsorption-desorption properties of the resulting ZIF-8 thin film were investigated for various VOCs using the QCM technique. PMID- 24056618 TI - Alemtuzumab induction in renal transplantation permits safe steroid avoidance with tacrolimus monotherapy: a randomized controlled trial. AB - BACKGROUND: The use of alemtuzumab as induction immunosuppression for renal transplantation introduces the possibility of long-term tacrolimus monotherapy, avoiding maintenance with both corticosteroids and mycophenolate mofetil (MMF). METHODS: We conducted a single-center, prospective, open-label, randomized controlled trial comparing two steroid avoidance regimens between December 2006 and November 2010. One hundred and sixteen adult patients were randomized to either basiliximab induction followed by tacrolimus and MMF maintenance or to alemtuzumab induction followed by tacrolimus monotherapy. The primary endpoint was noninferiority of isotopic glomerular filtration rate at 1 year; secondary endpoints included patient and graft survival, incidence of delayed graft function, and incidence and severity of biopsy-proven acute rejection. RESULTS: The two groups were well matched for all baseline demographics. Isotopic glomerular filtration rate was comparable between the groups at 1 year (57+/-26 mL/min for alemtuzumab group and 53+/-21 mL/min for basiliximab group; P=0.42). Secondary endpoints were also similar between the groups. The rate of biopsy proven acute rejection by 12 months was lower in the alemtuzumab group (n=6 vs. n=14 in basiliximab arm) just reaching statistical significance (P=0.049); however, a single extra case in the alemtuzumab arm included when considering clinically treated rejection removes this significance (P=0.082). Similar rates of cardiovascular, infective, and neoplastic complications were observed in both groups. Forty-seven (81.0%) of the patients in the alemtuzumab group remained on tacrolimus monotherapy at 12 months. CONCLUSIONS: Renal transplantation with alemtuzumab induction followed by tacrolimus monotherapy leads to good graft and patient outcomes, with no major differences detected compared with basiliximab induction and tacrolimus/MMF maintenance at 1 year. PMID- 24056619 TI - Increased recipient body mass index is associated with acute rejection and other adverse outcomes after kidney transplantation. AB - BACKGROUND: Outcomes of kidney transplant recipients with increased body mass index (BMI) remain controversial. We studied the relationship between BMI and clinically relevant outcomes among kidney transplant recipients at a large center. METHODS: We performed an observational cohort study of all recipients of kidney transplants at our center from January 1, 2000 to December 31, 2010 to determine if increased BMI at transplantation is associated with adverse outcomes, including delayed graft function and biopsy-proven acute rejection (BPAR). Recipient BMI was categorized as <20, 20 to 24.9 (reference), 25 to 29.9, 30 to 34.9, and >=35 kg/m. Potential confounders were included in logistic and Cox proportional hazards models. RESULTS: A total of 1151 patients were studied. Recipient BMI of 30 to 34.9 and >=35 kg/m were associated with an increased risk of delayed graft function (odds ratio [95% confidence interval [CI], 1.92 [1.16 3.19] and 4.49 [2.24-9.00], respectively). BMI>=35 kg/m was also associated with an increased risk of BPAR (hazard ratio [HR; 95% CI], 2.43 [1.48-3.99]), all cause graft failure (HR [95% CI], 1.97 [1.09-3.56]), and death-censored graft failure (HR [95% CI], 2.43 [1.07-5.51]). Adjustment for acute rejection as a time varying covariate significantly attenuated the association with graft failure endpoints. There was no significant relation between BMI and death with graft function. CONCLUSIONS: Increased BMI at kidney transplantation is a predictor of adverse outcomes, including BPAR. The role of pretransplantation weight reduction in improving graft and patient outcomes requires further study. PMID- 24056620 TI - Defining delayed graft function after renal transplantation: simplest is best. AB - BACKGROUND: Delayed graft function (DGF) after renal transplantation can be diagnosed according to several different definitions, complicating comparison between studies that use DGF as an endpoint. This is a particular problem after transplantation with kidneys from donation after circulatory death (DCD) kidneys, because DGF is common, and its relationship to early graft failure may differ depending on the definition of DGF. METHODS: The presence of DGF in 213 donation after brain death (DBD) and 312 DCD kidney transplants from October 2005 to August 2011 was determined according to 10 different, but widely used, definitions (based on dialysis requirements, creatinine changes, or both). The relationship of DGF to graft function and graft survival was determined. RESULTS: The incidence of DGF varied widely depending on the definition used (DBD; 24% 70%: DCD; 41%-91%). For kidneys from DCD donors, development of DGF was only associated with poorer 1-year estimated glomerular filtration rate for 1 of 10 definitions of DGF, and no definition of DGF was associated with impaired graft survival. Conversely, for DBD kidneys, DGF, as defined in 9 of 10 different ways, was associated with poorer 1-year estimated glomerular filtration rate and inferior graft survival. Importantly, the predictive power for poorer transplant outcome was comparable for all definitions of DGF. CONCLUSION: No definition of DGF is superior. We suggest that the most widely used and most easily calculated definition--the use of dialysis in the first postoperative week--should be universally adopted as the definition of DGF clinically and as a study endpoint. PMID- 24056621 TI - CMV Viremia is associated with a decreased incidence of BKV reactivation after kidney and kidney-pancreas transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) and BK virus (BKV) infections can cause significant morbidity after kidney and kidney-pancreas transplant. There are limited data on the epidemiology and interactions between these two viral pathogens. METHODS: We prospectively screened 609 kidney or kidney-pancreas transplant recipients from January 2007 to June 2011 for BKV and/or CMV viremia. This included 7453 quantitative BKV polymerase chain reaction and 15,496 quantitative CMV polymerase chain reaction tests. We evaluated risk factors and timing of these infections and the impact of treatment of one infection on the other. RESULTS: Among 609 recipients, 108 (17.7%) developed CMV viremia, of which 95 (88%) were asymptomatic, 5 (5%) had CMV syndrome, and 8 (7%) developed CMV tissue invasive disease at a median of 5.6 months after transplantation. Risk factors for CMV infection using multivariable analysis were D+R- serogroup (P<=0.0001), donor age >50 years (P=0.013), and higher mean tacrolimus (P=0.0009) and mycophenolate mofetil (P=0.01) blood levels. The incidence of BKV infection in the total population was 163 of 609 (26.7%), of which 150 (92%) occurred in patents without antecedent CMV viremia. Such patients demonstrated a higher rate of subsequent BKV viremia than patients with antecedent CMV viremia (P=0.003; hazard ratio, 2.05; 95% confidence interval, 1.2-3.4). Moreover, we found that only symptomatic CMV viremia had a significant negative impact on graft survival when compared with asymptomatic CMV viremia and those without CMV viremia (relative risk, 3.5; 95% confidence interval, 1.06-8.9; P=0.04). CONCLUSION: CMV viremia may indirectly protect against subsequent BK viremia possibly due to a reduction of intensity of immunosuppression after diagnosis of CMV viremia. PMID- 24056622 TI - Predictors of graft failure and death in elderly kidney transplant recipients. AB - BACKGROUND: The upper age limit to receive a kidney transplant has progressively risen, but the outcomes of elderly (ages >=65 years) transplant recipients remain understudied. We therefore evaluated mortality, graft failure, and predictors of these outcomes in this population. METHODS: Three cohorts of recipients transplanted between 1963 and 2012 (ages <50 years [n=2900], 50-64 years [n=1218], and >=65 years [n=364] at transplantation) were compared for allograft and patient outcomes. Three similar age cohorts transplanted after 2000 (n=1410) were studied separately to address era effect. RESULTS: Death-censored graft survival was higher in recipients ages >=65 years: 5, 10, and 15 years was 90.7%, 80.4%, and 73.7%; for ages 50-64 years, it was 87.2%, 77.6%, and 71.5%; and for ages <50 years was 79.8%, 70.3%, and 60.8%. Risk factors for graft failure in those ages >=65 years included panel-reactive antibody >10%, congestive heart failure (CHF), delayed graft function, and cellular rejection. The 5-, 10-, and 15-year patient survival rate was 69.7%, 36.0%, and 14.0% for those ages >=65 years; 76.4%, 54.8%, and 34.0% for those ages 50-64 years; and 81.7%, 66.7%, and 52.2% for those ages <50 years. For the entire cohort of elderly recipients, coronary artery disease and CHF were associated with mortality, and in those recipients transplanted after 2000, the risk factors for mortality were coronary artery disease, graft failure, peripheral vascular disease, and cause of end stage renal disease listed as other. For graft failure, only CHF and cellular rejection were associated with this outcome. CONCLUSIONS: The overall outcomes of transplantation in elderly kidney transplant recipients ages >=65 years are excellent, but the risk factors for mortality and graft failure are distinctly different than those observed in younger recipients. PMID- 24056623 TI - Living-donor liver transplantation associated with higher incidence of hepatocellular carcinoma recurrence than deceased-donor liver transplantation. AB - BACKGROUND: Living-donor liver transplantation (LDLT) is becoming an important tool in hepatocellular carcinoma (HCC) treatment. However, the oncologic outcome between LDLT and deceased-donor LT (DDLT) for HCC remains controversial. This study aims to compare the HCC recurrence rates after LDLT versus DDLT. METHODS: Two hundred sixteen patients (166 LDLTs and 50 DDLTs) who underwent LT for HCC within University of California-San Francisco criteria were retrospectively reviewed. LDLT patients were divided into two groups: small living-donor graft (LDG; graft-to-recipient body weight ratio <1.0, n=59) and nonsmall LDG (graft-to recipient body weight ratio >=1.0, n=107). Patients were further stratified into low- and high-risk settings by the number of risk factors for recurrence. RESULTS: The recurrence-free survival was lower in LDLT compared with DDLT (88.6% and 80.7% vs. 96.0% and 94.0% at 1 and 5 years; P=0.045). There was no significant difference between two groups regarding the majority of clinical and tumor characteristics, with the exception of a higher proportion of microvascular invasion presence in LDLT. After the adjustment for microvascular invasion, LDLT was identified as an independent risk factor for recurrence. Moreover, recurrence free survival between small and nonsmall LDG was not statistically significant. In low-risk setting (<=1 risk factor), LDLT showed comparable outcome with DDLT. However, the risk of recurrence was higher in LDLT than DDLT in high-risk patients. CONCLUSION: In conclusion, LDLT showed poorer outcome than DDLT. This should be considered to select optimal strategy for HCC. PMID- 24056624 TI - Vascularized composite allograft transplant survival in miniature swine: is MHC tolerance sufficient for acceptance of epidermis? AB - BACKGROUND: We have previously reported that Massachusetts General Hospital miniature swine, which had accepted class I-mismatched kidneys long-term after 12 days of high-dose cyclosporine A, uniformly accepted donor-major histocompatibility complex (MHC)-matched kidneys without immunosuppression but rejected donor MHC-matched split-thickness skin grafts by day 25, without changes in renal graft function or antidonor in vitro responses. We have now tested whether this "split tolerance" would also be observed for the primarily vascularized skin of vascularized composite allografts (VCAs). METHODS: Group 1 animals (n=3) received donor MHC-matched VCAs less than 70 days after primary kidney transplant (KTx). Group 2 animals (n=3) received a second donor-matched kidney transplant followed by a donor-matched VCA more than 200 days after primary KTx. RESULTS: Animals in Group 1 lost the epidermis on days 28, 30, and 40, with all other components of the VCAs remaining viable. Histology showed cellular infiltration localized to dermal-epidermal junction. One of three recipients of VCAs in Group 2, accepted all components of the VCA, including epidermis (>200 days). The other two recipients lost only the epidermis on days 45 and 85, with survival of the remainder of the VCA long-term. CONCLUSIONS: All tissues of a VCA are accepted long-term on animals tolerant of class I-mismatched kidneys, with the exception of epidermis, the survival of which is markedly prolonged compared with split-thickness skin grafts but not indefinite. Exposure of tolerant animals to second donor-matched kidneys before VCA increases the longevity of the VCA epidermis, suggesting an increase in the immunomodulatory mechanisms associated with tolerance of the kidney. PMID- 24056625 TI - Omentum is better site than kidney capsule for growth, differentiation, and vascularization of immature porcine beta-cell implants in immunodeficient rats. AB - BACKGROUND: Rapid revascularization of islet cell implants is important for engraftment and subsequent survival and function. Development of an adequate vascular network is expected to allow adaptive growth of the beta-cell mass. The present study compares omentum and kidney capsule as sites for growth and differentiation of immature beta-cell grafts. METHODS: Perinatal porcine islet cell grafts were implanted in omentum or under kidney capsule of nondiabetic nude rats. Implants were compared over 10 weeks for their respective growth, cellular composition, number and size of beta cells, their proliferative activity, and implant blood vessel density. RESULTS: In both sites, the beta-cell volume increased fourfold between weeks 1 and 10 reflecting a rise in beta-cell number. In the omental implants, however, the cellular insulin reserves and the percent of proliferating cells were twofold higher than in kidney implants. In parallel, the blood vessel density in omental implants increased twofold, reaching a density comparable with islets in adult pig pancreas. A positive correlation was found between the percent bromodeoxyuridine-positive beta cells and the vessel density. CONCLUSIONS: Growth of the beta-cell volume proceeds similarly in the omentum and under the kidney capsule. However, the omentum leads to higher insulin reserves and an increased pool of proliferating cells, which might be related to a more extended vascular network. Our observations support the omentum as an alternative site for immature porcine islet cells, with beneficial effects on proliferation and implant revascularization. PMID- 24056626 TI - Macrophages contribute to cellular but not humoral mechanisms of acute rejection in rat renal allografts. AB - BACKGROUND: Cells of the monocyte/macrophage lineage have been implicated as effectors in acute allograft rejection based on short-term depletion studies. However, the therapeutic potential of targeting monocyte/macrophages in acute rejection is unknown. We investigated the potential of a c-fms kinase inhibitor (fms-I) in acute renal allograft rejection. METHODS: Lewis rats underwent bilateral nephrectomy and received an orthotopic Dark Agouti renal allograft. Recipients received fms-I or vehicle from the time of transplantation until being killed on day 5. RESULTS: Vehicle-treated rats developed severe allograft rejection with massive macrophage and T-cell infiltration. In contrast, fms-I substantially inhibited renal allograft dysfunction and structural damage with abrogation of macrophage and dendritic cell infiltration but had only a minor effect on the T-cell infiltrate. However, fms-I suppressed T-cell activation within the allograft, whereas systemic T- and B-cell activation was not affected. In a longer-term study to assess therapeutic potential, fms-I-treated rats developed severe antibody-mediated rejection on day 8 after transplantation. These transplants exhibited features of antibody-mediated rejection including capillaritis with thrombosis, acute tubular injury, IgG and C4d deposition, and neutrophil infiltration and activation. Interestingly, T-cell activation within these rejecting allografts remained suppressed, indicating separation of T-cell and antibody-mediated rejection. CONCLUSION: This study demonstrates the ability of c-fms kinase blockade to selectively deplete monocyte/macrophages in acute allograft rejection, although this did not result in significant prolongation of allograft survival. Furthermore, we identify contrasting roles for macrophages in cellular and humoral mechanisms of acute renal allograft rejection. PMID- 24056627 TI - Inpatient economic and mortality assessment for liver transplantation: a nationwide study of the United States data from 2005 to 2009. AB - BACKGROUND: Liver transplantation is a standard of care for treatment of end stage liver disease. The aim of this study was to evaluate resource utilization for patients admitted to the U.S. hospitals for liver transplantation from 2005 to 2009. METHODS: Nationwide inpatient sample was used. RESULTS: A total of 5527 hospital admissions were included to the study cohort approximating 27,350 procedures nationwide (compared with 32,228 reported by United Network for Organ Sharing). Approximately 75% of patients had major or extreme severity of illness (All Patient Refined Diagnosis-Related Groups). The most prevalent comorbidities were coagulopathy (36.0%), fluid and electrolyte disorders (39.8%), anemia (18.7%), and type 2 diabetes (23.8%). Furthermore, 5.1% patients died in the hospital, 80.0% were discharged routinely or to home healthcare, and 14.9% were transferred to other healthcare facilities. The mean number of inpatient procedures was 7.2, and 3.5 were minimal therapeutic. The mean length of hospitalization was 22.2 days, the mean hospital charges were $358,200, and the mean inpatient costs of liver transplantation were $114,300. In multivariate analysis, the most significant factors associated with longer stay were younger age, major or extreme severity of illness, and more procedures performed during hospitalization. Similar factors were also associated with higher cost of inpatient treatment. Inpatient mortality, however, was associated only with more severe illness and more procedures while being inversely associated with younger age and higher income. CONCLUSIONS: Liver transplantation is a life-saving procedure with significant economic burden to our society. Severity of illness is the common driver of both in hospital mortality and resource utilization. PMID- 24056629 TI - Absence of viable HCC in the native liver is an independent protective factor of tumor recurrence after liver transplantation. AB - BACKGROUND: Prognostic factors for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) are still a matter of debate. The absence of viable tumor in the native liver, due to effectiveness of pre-LT locoregional treatment or liver resection, is an intriguing prognostic factor that had never been evaluated. METHODS: Between November 2000 and December 2011, 210 LTs were performed in patients with evidence of HCC and cirrhosis. RESULTS: Fifty-three (25.2%) patients did not show any evidence of active residual HCC in the native liver (Group NVH), whereas 157 (74.8%) patients showed viable HCC (Group VH). All patients in Group NVH were treated before LT with a multimodal approach combining transarterial chemoembolization, liver resection, radiofrequency ablation, percutaneous ethanol injection, or sorafenib, whereas, in Group VH, 110 of the 157 (70.1%) patients received bridging therapy (P<0.001). HCC recurrence occurred in none of the patients in Group NVH (0%) and in 25 (15.9%) patients in Group VH (P=0.003). Liver resection was the most effective treatment in obtaining absence of HCC on liver explantation. The results of multivariate analysis showed that existence of pathologic HCC findings outside of the University of California-San Francisco criteria (P=0.001; odds ratio, 4; confidence interval, 1.7-9.2) and the presence of viable HCC (P=0.003; odds ratio, 5.9; confidence interval, 1.5-17.6) were independently associated with HCC recurrence. CONCLUSIONS: The histologic absence of viable HCC in the native liver after LT and morphologic criteria, due to the high effectiveness of pre-LT bridging treatments, is a highly positive prognostic factor against HCC recurrence after LT. PMID- 24056628 TI - Effects of preexisting autoimmunity on heart graft prolongation after donor specific transfusion and anti-CD154. AB - BACKGROUND: Alloreactive memory T cells prevent costimulatory blockade-induced heart graft survival in mice, but whether and how preexisting autoreactive T cells affect solid-organ transplants under these conditions is unknown. METHODS: We tested the impact of preexisting cardiac myosin (CM)-specific immunity on murine heart transplant recipients treated with donor-specific transfusion (DST) plus anti-CD154 monoclonal antibody MR1. RESULTS: Preimmunization with CM but not control ovalbumin abrogated the graft prolonging effects of DST/MR1, whether administered 2 weeks or more than 6 weeks before transplantation. Adoptive transfer of spleen cells from CM-immunized mice into naive recipients had similar effects. CM-specific immunity did not cross-react with donor antigens and preimmunization with CM had no impact on the survival or histology of DST/MR1 treated syngeneic heart grafts, the latter indicating that persistent autoimmunity is insufficient to cause rejection in the context of costimulatory blockade. We observed that the CM preimmunized mice produced higher frequencies of donor-reactive T cells with higher ratios of CD8/CD4Foxp3 cells, suggesting that the autoreactive memory T cells provide help for activation of alloreactive T cells despite the costimulatory blockade. CONCLUSIONS: These mechanistic insights linking autoimmunity and alloimmunity in a model of murine heart transplantation have clinical relevance to the known association between autoimmunity and an elevated risk of acute and chronic heart transplant injury in humans. PMID- 24056631 TI - Down-regulating humoral immune responses: implications for organ transplantation. AB - Alloantibody can be a major barrier to successful organ transplantation; however, therapy to control antibody production or to alter its impact on the allograft remains limited. The goal of this review is to examine the regulatory steps that are involved in the generation of alloreactive B cells, with a specific emphasis on how known mechanisms relate to clinical situations in transplant recipients. Thus, we will examine the process of activation of mature, naive B cells and how this relates to de novo antibody production. The role of long-lived plasma cells in persistent antibody production and the factors regulating their longevity will be explored. The regulation of memory B cells and their possible roles in alloimmunity also will be assessed. Finally, we will review current therapeutic approaches aimed at controlling alloantibody and assess their efficacy. By examining the pathways to antibody production mechanistically, we hope to identify important gaps in our current knowledge and gain insight into possible new therapeutic approaches to overcoming antibody in transplant patients. PMID- 24056630 TI - Impact of extracorporeal membrane oxygenation or mechanical ventilation as bridge to combined heart-lung transplantation on short-term and long-term survival. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) and mechanical ventilation (MV) can be used as a bridge to heart-lung transplantation (HLT). The goal of this study was to determine if pretransplantation ECMO or MV affects survival in HLT. METHODS: The United Network for Organ Sharing database was reviewed for all adult patients receiving HLT from 1995 to 2011. The primary outcome measured was risk-adjusted all cause mortality. RESULTS: There were 542 adult patients received HLT during the study period. Of these, 15 (2.8%) required ECMO and 22 (4.1%) required MV as a bridge to transplantation. The groups were evenly matched with regards to recipient age, recipient gender, ischemic time, donor age, and donor gender. The ECMO cohort had worse survival than the control group at 30 days (20.0% vs. 83.5%) and 5 years (20.0% vs. 47.4%; P<0.001). When compared with control, patients requiring MV had worse survival at 1 month (77.3% vs. 83.5%) and 5 years (26.5% vs. 47.4%; P<0.001). The use of ECMO (hazard ratio [HR]=3.820, 95% confidence interval [CI]=1.600-9.116; P=0.003) or MV (HR=2.011, 95% CI=1.069 3.784; P=0.030) as a bridge to transplantation was independently associated with mortality on multivariate analysis. Recipient female gender was associated with survival (HR=0.754, 95% CI=0.570-0.998; P=0.048). CONCLUSIONS: HLT recipients bridged by MV or ECMO have increased short-term and long-term mortality. Further studies are needed to optimize survival in these high-risk patients. PMID- 24056632 TI - Assessment of crosstalks between the Snf1 kinase complex and sphingolipid metabolism in S. cerevisiae via systems biology approaches. AB - Sphingolipids are essential building blocks of the plasma membranes and are highly bioactive in the regulation of diverse cellular functions and pathological processes, a fact which renders the sphingolipid metabolism an important research area. In this study, a computational framework was recruited for the reconstruction of a functional interaction network for sphingolipid metabolism in Baker's yeast, SSN. Gene Ontology (GO) annotations were integrated with functional interaction data of the BIOGRID database and the reconstructed protein interaction network was subjected to topological and descriptive analyses. SSN was of a scale-free nature, following a power law model with gamma=1.41. Prominent processes of SSN revealed that the reconstructed network encapsulated the involvement of sphingolipid metabolism in vital cellular processes such as energy homeostasis, cell growth and/or death and synthesis of building blocks. To investigate the potential of SSN for predicting signal transduction pathways regulating and/or being regulated by sphingolipid biosynthesis in yeast, a case study involving the S. cerevisiae counterpart of AMP-activated protein kinase, the Snf1 kinase complex, was conducted. The mutant strain lacking the catalytic alpha subunit, snf1Delta/snf1Delta, had elevated inositol phosphorylceramide and mannosyl-inositol phosphorylceramide levels, and decreased mannosyl-diinositol phosphorylceramide levels compared to the wild type strain, revealing that Snf1p has a regulatory role in the sphingolipid metabolism. Transcriptome data belonging to that strain available in the literature were mapped onto SSN and the correlated SSN was further investigated to evaluate the possible crosstalk machineries where sphingolipids and Snf1p function in coordination, in other words the crosstalk points between sphingolipid-mediated and Snf1 kinase signalling. The subsequent investigation of the discovered candidate crosstalk processes by performing sensitivity experiments imply a tight interconnection between sphingolipids and Snf1p in the regulation of calcineurin activity, cellular metal ion homeostasis and response to cell wall and endoplasmic reticulum stresses in yeast. PMID- 24056633 TI - Multiplex PCR assay for typing of staphylococcal cassette chromosome mec types I to V in methicillin-resistant Staphylococcus aureus. AB - Staphylococcal Cassette Chromosome mec (SCCmec) typing is a very important molecular tool for understanding the epidemiology and clonal strain relatedness of methicillin-resistant Staphylococcus aureus (MRSA), particularly with the emerging outbreaks of community-associated MRSA (CA-MRSA) occurring on a worldwide basis. Traditional PCR typing schemes classify SCCmec by targeting and identifying the individual mec and ccr gene complex types, but require the use of many primer sets and multiple individual PCR experiments. We designed and published a simple multiplex PCR assay for quick-screening of major SCCmec types and subtypes I to V, and later updated it as new sequence information became available. This simple assay targets individual SCCmec types in a single reaction, is easy to interpret and has been extensively used worldwide. However, due to the sophisticated nature of the assay and the large number of primers present in the reaction, there is the potential for difficulties while adapting this assay to individual laboratories. To facilitate the process of establishing a MRSA SCCmec assay, here we demonstrate how to set up our multiplex PCR assay, and discuss some of the vital steps and procedural nuances that make it successful. PMID- 24056634 TI - Room-temperature spin-spiral multiferroicity in high-pressure cupric oxide. AB - Multiferroic materials, in which ferroelectric and magnetic ordering coexist, are of fundamental interest for the development of multi-state memory devices that allow for electrical writing and non-destructive magnetic readout operation. The great challenge is to create multiferroic materials that operate at room temperature and have a large ferroelectric polarization P. Cupric oxide, CuO, is promising because it exhibits a significant polarization, that is, P~0.1 MUC cm( 2), for a spin-spiral multiferroic. Unfortunately, CuO is only ferroelectric in a temperature range of 20 K, from 210 to 230 K. Here, by using a combination of density functional theory and Monte Carlo calculations, we establish that pressure-driven phase competition induces a giant stabilization of the multiferroic phase of CuO, which at 20-40 GPa becomes stable in a domain larger than 300 K, from 0 to T>300 K. Thus, under high pressure, CuO is predicted to be a room-temperature multiferroic with large polarization. PMID- 24056635 TI - The in vitro effects of retrograded starch (resistant starch type 3) from lotus seed starch on the proliferation of Bifidobacterium adolescentis. AB - Prebiotics such as oligosaccharides, fructans, and resistant starch (RS) stimulate the growth of beneficial bacteria in large bowel and modify the human gastrointestinal environment. In this study, compared with glucose (GLU) and high amylose maize starch (HAMS), the in vitro effects of LRS3 and P-LRS3 (RS3 and purified RS3 prepared from lotus seed starch) on the proliferation of bifidobacteria were assessed by assessing the changes in optical density (OD), pH values, short chain fatty acid (SCFA) production, and tolerance ability to gastrointestinal conditions. Significantly higher OD values were obtained from media containing LRS3 and P-LRS3, and especially in the medium containing P-LRS3, the OD value of which reached 1.36 when the concentration of the carbon source was 20 g L(-1). Additionally, the lag phase of bifidobacteria was 8 h in the medium with LRS3 or P-LRS3, whereas it was 16 h in the medium with GLU or HAMS. What is more, a higher content of butyric acid was obtained in the P-LRS3 medium. Compared with GLU and HAMS media, bifidobacteria had a higher tolerance to gastrointestinal conditions in LRS3 and P-LRS3 media. It shows that lotus seed resistant starch, especially P-LRS3, could stimulate the growth of bifidobacteria. The rough surface of resistant starch and the SCFAs produced during fermentation might influence the proliferation of bifidobacteria. PMID- 24056638 TI - Synthesis, cellular delivery and in vivo application of dendrimer-based pH sensors. AB - The development of fluorescent indicators represented a revolution for life sciences. Genetically encoded and synthetic fluorophores with sensing abilities allowed the visualization of biologically relevant species with high spatial and temporal resolution. Synthetic dyes are of particular interest thanks to their high tunability and the wide range of measureable analytes. However, these molecules suffer several limitations related to small molecule behavior (poor solubility, difficulties in targeting, often no ratiometric imaging allowed). In this work we introduce the development of dendrimer-based sensors and present a procedure for pH measurement in vitro, in living cells and in vivo. We choose dendrimers as ideal platform for our sensors for their many desirable properties (monodispersity, tunable properties, multivalency) that made them a widely used scaffold for several biomedical devices. The conjugation of fluorescent pH indicators to the dendrimer scaffold led to an enhancement of their sensing performances. In particular dendrimers exhibit reduced cell leakage, improved intracellular targeting and allow ratiometric measurements. These novel sensors were successfully employed to measure pH in living HeLa cells and in vivo in mouse brain. PMID- 24056637 TI - Sinorhizobium meliloti Nia is a P(1B-5)-ATPase expressed in the nodule during plant symbiosis and is involved in Ni and Fe transport. AB - The P1B-ATPases are a ubiquitous family of metal transporters. These transporters are classified into subfamilies on the basis of substrate specificity, which is conferred by conserved amino acids in the last three transmembrane domains. Five subfamilies have been identified to date, and representative members of four (P1B 1 to P1B-4) have been studied. The fifth family (P1B-5), of which some members contain a C-terminal hemerythrin (Hr) domain, is less well characterized. The S. meliloti Sma1163 gene encodes for a P1B-5-ATPase, denoted Nia (Nickel-iron ATPase), that is induced by exogenous Fe(2+) and Ni(2+). The nia mutant accumulates nickel and iron, suggesting a possible role in detoxification of these two elements under free-living conditions, as well as in symbiosis, when the highest expression levels are measured. This function is supported by an inhibitory effect of Fe(2+) and Ni(2+) on the pNPPase activity, and by the ability of Nia to bind Fe(2+) in the transmembrane domain. Optical and X-ray absorption spectroscopic studies of the isolated Hr domain confirm the presence of a dinuclear iron center and suggest that this domain might function as an iron sensor. PMID- 24056639 TI - From editor's desk. PMID- 24056640 TI - Cytohistological correlation in diagnosis of lung tumors by using fiberoptic bronchoscopy: study of 200 cases. AB - BACKGROUND: Examination of specimens obtained through flexible fiberoptic bronchoscope is an important and often the initial diagnostic technique performed in patients with suspected malignant lung lesion. AIMS: To evaluate the correlation of cytological findings of bronchial washings, bronchial brushing and imprint smear of bronchial biopsy in the diagnosis of lung tumors, with histopathology of bronchial biopsy taking the latter as the confirmatory diagnostic test. MATERIALS AND METHODS: A total of 200 patients with lung mass were included in the study. Bronchial brushings were obtained from all 200 cases. In the first 100 cases, pre-biopsy bronchial washing (washing collected before the brushing and biopsy procedure) while post-biopsy washing (washing at the end of the procedure) was procured in all 200 cases. Imprint smears of bronchial biopsy were prepared in 150 cases. RESULTS: Sensitivity and specificity of brushing was 76.58% and 77.78% respectively and that of imprint smear was 81.35% and 78.12% respectively. Pre-biopsy and post-biopsy washing showed high specificity of 88.89%, but low sensitivity of 30.14 and 36.77% respectively. No significant difference was found in sensitivity between brushing and imprint smear (Chi-square; P = 0.4187); and between pre-biopsy and post-biopsy washing (Chi-square; P = 0.7982). However, there was a significant difference between sensitivity of brushing and washing (Chi-square; P = 0.0001). The sensitivity of combination of three cytological diagnostic techniques was 87.29%. CONCLUSION: Bronchial brushing and washing cytology in combination with imprint cytology aids in the diagnosis of lung tumors. Therefore, all these techniques may be used concurrently along with bronchial biopsy to diagnose lung tumors. PMID- 24056641 TI - Immunohistochemical analysis of tumor-infiltrating lymphocytes in breast carcinoma: relation to prognostic variables. AB - BACKGROUND: The role of the tumor-infiltrating lymphocytes in invasive breast cancer and its correlation with different prognostic variables were always a matter of controversy in the literature. AIM: To determine the relative density of T lymphocytes, CD4+ cells, CD8+ cells, and B lymphocytes in breast cancer and assess their relationships with clinicopathologic parameters. MATERIALS AND METHODS: Paraffin-embedded tissue sections from 48 invasive ductal carcinomas and 30 benign breast lesions were examined by means of immunohistochemistry to demonstrate CD3+, CD4+, CD8+, and CD20+. The immunophenotyped cells were semi quantitatively graded into: Absent, intermediate, and extensive. RESULTS: All lymphocyte populations were significantly more expressed in breast carcinomas than in benign lesions (P = 0.0001 for CD3+ and CD4+, P = 0.001 for CD8+, and P = 0.002 for CD20+ cells). In breast carcinoma, B and T cells were co-expressed in 33 of 48 tumors (68.8%). However, T cells were the predominant immunophenotype being noted in 81% of tumors, compared to B cells which were expressed in 50% of tumors. T cells, CD4+ and CD8+ cells were directly associated with patient's age (P = 0.004, P = 0.001, and P = 0.01, respectively). Clinical stages III and IV showed a significantly higher density of T and CD4+ lymphocytes than stage II (P = 0.004 and P = 0.009, respectively). Also, T and CD4+ cells were directly related to the histologic grade (P = 0.004 and P = 0.001, respectively). On the contrary, B lymphocytes were not related to any of the above-mentioned parameters. CONCLUSION: Although B and T lymphocytes were co-expressed in breast cancer, T lymphocytes and their subpopulations seem to have the upper hand in predicting the biological behavior. They probably promote neoplastic progression rather than acting as an antitumor immune response. PMID- 24056642 TI - Nodal mantle cell lymphoma: a descriptive study from a tertiary care center in South India. AB - INTRODUCTION: Mantle cell lymphoma (MCL) is a type of B-cell non-Hodgkin lymphoma (NHL) with distinctive morphologic, immunophenotypic and a characteristic cytogenetic abnormality, the t(11;14)(q13;q32) and overexpression of cyclin D1. The common histologic features include effaced lymphoid architecture by a monomorphic lymphoid population with a vaguely nodular, diffuse or mantle zone growth pattern. The classic cytomorphologic features include small to medium sized lymphoid cells with irregular nuclear contours and scanty cytoplasm, closely resembling centrocytes. MATERIALS AND METHODS: This retrospective study comprises 13 cases of MCL over a period of 51/2 years in our department, comprising 4% of all nodal NHL diagnosed. All cases were diagnosed on lymph node biopsy. RESULTS: The mean age of the presentation was 57 years. There was a male preponderance (M:F = 2.25:1). The disease was nodal in all cases. Most patients (84.5%) had generalized lymphadenopathy and/or hepatosplenomegaly. Bone marrow involvement was seen in 81.8% of cases. Three cases showed a nodular pattern on lymph node biopsy while remaining ten had a diffuse pattern. Immunophenotyping showed positivity for CD20, CD5 and cyclin D1 and CD23 negativity. CONCLUSION: Despite certain morphological similarity to other low-grade/intermediate-grade lymphomas, MCL has a characteristic appearance of its own. Since it is more aggressive than other low-grade lymphomas it needs to be accurately diagnosed. PMID- 24056643 TI - Chromosome 7 aneuploidy in clear cell and papillary renal cell carcinoma: detection using silver in situ hybridization technique. AB - BACKGROUND: Chromosome 7 aberrations in renal cell carcinoma (RCC) have been reported in papillary renal cell carcinoma (pRCC) and clear cell renal cell carcinoma (ccRCC). However, the implication of these anomalies on prognosis and survival is still unclear. RCC Chromosome 7 aberrations have commonly been detected by fluorescent in situ hybridization and chromogenic in situ hybridization but not silver in situ hybridization (SISH). AIM: The purpose was to report chromosome 7 aberrations in ccRCC and pRCC using SISH in paraffin embedded tissues and determine the association between the anomalies with clinical and pathological features. MATERIALS AND METHODS: Cases of ccRCC and pRCC from University Malaya Medical Centre (2001-2009) were analyzed. Chromosome 7 staining was performed using an automated SISH method and association tests between chromosomal anomalies, clinical features and survival were performed. RESULTS: SISH is a feasible technique to detect chromosome 7 aberration in RCC. Chromosome 7 aberrations with nuclear grading, staging and survival yielded no significant correlation. Surprisingly, there was a significant association between gender and chromosome 7 expressions. Though grade did not reach statistical significance for survival in our RCC cases, there was a significant correlation between overall survival with race and stage. CONCLUSION: Chromosome 7 aberrations in ccRCC showed no prognostic significance. Nevertheless, staging and grading systems that include prognostic variables could hold better promise. PMID- 24056644 TI - Spectrum of histopathologic diagnosis of lymph node biopsies: a descriptive study from a tertiary care center in South India over 51/2 years. AB - AIMS: Lymphadenopathy is a common clinical problem and biopsies undertaken to determine the cause of nodal enlargement may be neoplastic or non-neoplastic. The former are mainly lymphohematogenous malignancies and metastases while the causes of non-neoplastic lymphadenopathy are varied. This study was undertaken to determine the histopathological spectrum of lymphadenectomies. MATERIALS AND METHODS: This was a descriptive cross-sectional study wherein 1010 cases of histologically diagnosed peripheral lymph node biopsies in the Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry from January 2007 to June 2012 were reviewed. Surgical resection specimens with lymph node dissection were excluded from the study. RESULTS: Neoplastic lesions were more common comprising 53% (535 cases) and included 32.1% (324 cases) of non-Hodgkin lymphoma, 12.4% (125 cases) of Hodgkin lymphoma and 8.5% (86 cases) of metastatic lesions. The non-neoplastic lesions were 47% (475 cases), which included 21.6% (218 cases) of non-specific reactive lymphoid hyperplasia, 6.8% (69 cases) of other reactive or specific lymphoid hyperplasia, 18% (182 cases) of tuberculous lymphadenitis, 0.6% (6 cases) of other granulomatous lesions. CONCLUSIONS: Lymph node biopsy plays an important role in establishing the cause of lymphadenopathy. Among the biopsied nodes, lymphomas were the most common (44.5%) followed by non-specific reactive hyperplasia (21.6%), tuberculous lymphadenitis (18%) and metastasis (8.5%). PMID- 24056645 TI - Microcytic hypochromic anemia: should high performance liquid chromatography be used routinely for screening anemic and antenatal patients? AB - BACKGROUND: Hemoglobinopathies are the most common inherited red cell disorders worldwide. Identification of these disorders is immensely important epidemiologically and for improved management protocols. AIM AND OBJECTIVES: Our aim was to determine the prevalence of hemoglobinopathies in patients with microcytic hypochromic anemia and to assess the suitability of using high performance liquid chromatography (HPLC) routinely for screening antenatal cases and patients with anemia. MATERIALS AND METHODS: A total of 4335 cases received from Mar 2007 to Nov 2011 were studied for various hemoglobinopathies and variants on BIO RAD 'VARIANT' analyzer. RESULTS: Of the 4335 cases studied, 2119 were antenatal cases, 1710 patients with other disorders and 506 family studies. Of these, 688 cases displayed abnormal hemoglobin fractions on HPLC of which 140 were antenatal women. There were 455 cases of beta thalassemia trait, 24 beta thalassemia major, 20 thalassemia inter-media, 54 sickle cell trait, fivesickle cell disease, 21 double heterozygous beta thalassemia-sickle cell trait, nineand 4 Hb D- Punjab heterozygous and homozygous respectively, three Hb D beta Thalassemia trait, 20 and 37 Hb E homozygous and heterozygous respectively, three Hb E beta Thalassemia trait and four cases of Hb Q India. Twenty nine adults had isolated HbF elevation. CONCLUSION: Our study found a high prevalence (15.8%) of hemoglobinopathies amongst microcytic hypochromic anemia and antenatal cases. An accurate diagnosis helps in preventing unnecessary iron loading. Screening all antenatal cases with anemia helps in timely antenatal counseling, thus preventing the psychological trauma of bearing a transfusion dependent child for life. PMID- 24056646 TI - Comparison of platelet counts by sysmex XE 2100 and LH-750 with the international flow reference method in thrombocytopenic patients. AB - BACKGROUND: There are several methods for counting platelets, of which the international flow reference method (IRM) is considered to be the gold standard. We compared the platelet count given by this method to the count given by automated analyzers using other methods, such as optical fluorescence and impedance. AIMS: The aim of this study is to compare the platelet counts obtained by Sysmex XE 2100 by Impedance (Sysmex-I), optical florescence (Sysmex-O) and reported (Sysmex-R) based on the switching algorithm and LH-750 by Impedance (LH 750) with the IRM in thrombocytopenic blood samples. To calculate the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of various technologies at the clinically relevant transfusion thresholds of 10 * 10 9 /l and 20 * 10 9 /l. MATERIALS AND METHODS: A total of 118 blood samples with platelet count of <50 * 10 9 /l were selected for the study. Platelet counts of all samples were analyzed by all methods using the Sysmex analyzer, LH-750 and IRM in parallel within 6 h of collection. STATISTICAL ANALYSIS USED: Pearson correlation, bland Altman analysis, sensitivity and specificity, PPV and NPV. RESULTS AND CONCLUSIONS: Sysmex-R had the least Bias and 95% limits of agreement (95%LA) range and thus correlated best with IRM values. LH-750 had a higher Bias compared to Sysmex-O and Sysmex-R, but a strikingly similar 95% LA ensures similar results in all three methods. In fact, in the oncology subset, it had the narrowest 95% LA, which made it the best performer in this subgroup. Of the three Sysmex results, Sysmex-I had the highest bias, widest 95% LA and highest potential risk of over transfusion. Hence, Sysmex R and LH-750 were found to be reliable tools for estimation of platelet count in thrombocytopenic patients. PMID- 24056647 TI - Reference range evaluation of complete blood count parameters with emphasis on newer research parameters on the complete blood count analyzer Sysmex XE-2100. AB - Since the advent of automation in the field of hematological cell counters there has been a constant refinement of the technology and increase in the number of newer parameters available on CBC analysers. Many novel parameters are being put into routine clinical use and both clinical evaluation and monitoring critically depend on knowledge of laboratory reference ranges. Here, we present reference interval for the Sysmex XE-2100, with emphasis on the novel or newer research parameters. Blood samples from a total of 122 clinically asymptomatic and apparently healthy subjects were evaluated and a final of 100 subjects (54-M, 46 F) were included in the study. A broad spectrum of parameters available with the analyser was assessed and reference ranges for the same evaluated. PMID- 24056648 TI - Evaluation of a new tuberculosis-related interferon gamma release assay for tuberculosis infection diagnosis in Huzhou, eastern China. AB - OBJECTIVE: To compare the performance of a new tuberculosis-related interferon gamma release assay (TB-IGRA) with that of QuantiFERON-TB Gold In-Tube (QFT-GIT) for TB infection diagnosis in China. MATERIALS AND METHODS: A total of 458 active TB patients and 378 healthy individuals were enrolled. Among the 458 active TB patients, 395 had pulmonary TB and 63 had extra-pulmonary TB. The blood samples were collected from the active TB patients and health controls; then TB-IGRA and QFT-GIT were used to detect interferon gamma (IFN-gamma) levels. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value in TB infection diagnosis for active TB by the TB-IGRA were 83.4%, 94.2%, 94.5%, and 82.4%, respectively. For QFT-GIT, the sensitivity, specificity, positive predictive value, and negative predictive value in TB infection diagnosis for active TB were 81.4%, 97.1%, 97.1%, and 81.2%, respectively. CONCLUSIONS: TB-IGRA had a high sensitivity and specificity for TB infection; it could be comparable with the QFT-GIT assay. It might be a powerful assisting tool for TB infection diagnosis in the Chinese clinical setting. PMID- 24056649 TI - Importance of P53, Ki-67 expression in the differential diagnosis of benign/malignant phyllodes tumors of the breast. AB - BACKGROUND: Conventionally growth pattern, stromal overgrowth, stromal cellularity and stromal mitotic activity are the main parameters in the grading of phyllodes tumors (PTs). Recent studies revealed that both p53 and Ki-67 expressions are correlated with grade of PTs of the breast. Expression of hormone receptors and overexpression/amplification of HER2 has been studied in PTs to discover the roles of these markers as new treatment modalities. MATERIALS AND METHOD: We studied 26 PT cases. Seventeen benign and nine malignant PTs were re evaluated as regards stromal cellularity mitotic activity, p53/Ki-67 expression rates and the relation between these parameters. Estrogen receptor and progesterone receptor (ER, PR) positivity were determined by counting nuclear staining in five high-power fields. Also, the presence of any HER2 staining and staining patterns were documanted. RESULTS: Stromal cellularity, mitotic rate, p53 and Ki-67 expression rates were all correlated with benign and malignant histologic subgroups (P = 0.000-0.001). Ki-67 and p53 expressions were statistically significantly correlated with histologic subgroups, stromal cellularity and mitotic rate (P < 0.005). ER and PR expressions in the epithelial component were not statistically significant between the two groups. HER2 showed different staining patterns in the epithelial component, and there was no staining in the stromal component. CONCLUSION: Ki-67 and p53 expression rates were statistically significantly correlated with grade of mammary PTs; therefore, they can be used in the determination of tumor grade, especially for the differential diagnosis of benign and malignant tumors. Malignant and benign tumors did not differ significantly in terms of hormone receptor and HER2 expression. HER2 expression showed different patterns in the epithelial component of the PTs. PMID- 24056650 TI - Evaluation of phenotypic tests for the detection of AmpC beta-lactamase in clinical isolates of Escherichia coli. AB - BACKGROUND: AmpC beta lactamases are cephalosporinases that confer resistance to a wide range of beta lactam drugs thereby causing serious therapeautic problem. As there are no CLSI guidelines for detection of AmpC mediated resistance in Gram negative clinical isolates and it may pose a problem due to misleading results, especially so in phenotypic tests. Although cefoxitin resistance is used as a screening test, it does not reliably indicate AmpC production. MATERIALS AND METHODS: We planned a study to determine the occurrence of AmpC beta lactamase in hospital and community, clinical isolates of Escherichia coli and simultaneously evaluate different phenotypic methods for detection of AmpC beta lactamases. RESULTS: It was observed that 82.76% isolates were ESBL positive and 59% were cefoxitin screen positive. Using phenotypic confirmatory tests the occurrence of Amp C beta lactamases was found to be 40% and 39% by inhibitor based method using boronic acid (IBM) and modified three dimensional test (M3D) respectively. CONCLUSION: Both the test showed concordant result. Co-production was observed in 84.62% isolates Screening of ESBL and Amp C can be done in routine clinical microbiology laboratory using aztreonam and IBM respectively as it is a simple, rapid and technically less demanding procedure which can be used in all clinical laboratories. PMID- 24056651 TI - Evaluation of GenoType(r) MTBDRplus assay for rapid detection of drug susceptibility testing of multi-drug resistance tuberculosis in Northern India. AB - BACKGROUND: The problem of multi-drug resistance tuberculosis (MDR-TB) is growing in several hotspots throughout the world. Rapid and accurate diagnosis of MDR-TB is crucial to facilitate early treatment and to reduce its spread in the community. The aim of the present study was to evaluate the new, novel GenoType(r) MTBDRplus assay for rapid detection of drug susceptibility testing (DST) of MDR-TB cases in Northern India. MATERIALS AND METHODS: A total of 550 specimens were collected from highly suspected drug resistant from pulmonary and extra-pulmonary TB cases. All the specimens were processed by Ziehl- Neelsen staining, culture, differentiation by the GenoType(r) CM assay, first line DST using BacT/ALERT 3D system and GenoType(r) MTBDRplus assay. The concordance of the GenoType(r) MTBDRplus assay was calculated in comparison with conventional DST results. RESULTS: Overall the sensitivity for detection of rifampicin, isoniazid and MDR-TB resistance by GenoType(r) MTBDRplus assay was 98.0%, 98.4% and 98.2% respectively. Out of 55 MDR-TB strains, 45 (81.8%), 52 (94.5%) and 17 (30.9%) strains showed mutation in rpoB, katG and inhA genes respectively (P < 0.05). The most prominent mutations in rpoB, katG and inhA genes were; 37 (67.3%) in S531L, 52 (94.5%) in S315T1 and 11 (20%) in C15T regions respectively (P < 0.05). CONCLUSIONS: Our study demonstrated a high concordance between the GenoType(r) MTBDRplus assay resistance patterns and those were observed by conventional DST with good sensitivity, specificity with short turnaround times and to control new cases of MDR-TB in countries with a high prevalence of MDR-TB. PMID- 24056652 TI - Emergence of non-albicans Candida among candidal vulvovaginitis cases and study of their potential virulence factors, from a tertiary care center, North India. AB - PURPOSE: The purpose of this study was to determine the prevalence of various Candida species and study some of their virulence factors among thevulvovaginal candidiasis(VVC)patients. STUDY DESIGN AND SETTINGS: The study was conducted in a Tertiary Care University Hospital in North India. MATERIALS AND METHODS: This study was carried out prospectively for a period of 1 year. High vaginal swabs (HVSs) were collected from women in childbearing age group attending the gynecology and obstetrics out-patient departments with the complaints suggestive of vulvovaginitis. Samples were plated on Sabouraud's dextrose agar slope. Candida spp. isolated was further speciated based on microscopy, biochemical tests and culture characteristics on special media. Virulence factors of these strains were determined by biofilm formation and phospholipase activity. RESULT: A total of 464 HVS from 232 patients with the complaints of vulvovaginitis were included in this study. Following laboratory workup, 71 specimens were positive for genus Candida (30.6%). Further speciation showed 32.4% as Candida albicans, 45.07% Candida parapsilosis and 22.53% of Candida glabrata. Biofilm production was shown by 50 candidal strains (70.4%) and phospholipase activity was given by 41 candidal strains (57.74%). CONCLUSION: Our study suggests increasing prevalence of non-albicans Candida among the VVC cases along with their virulence factors. Therefore, we recommend that microbiological investigation upto species level should be mandatory to determine the emergence of non-albicans Candida as a major cause of VVC. PMID- 24056653 TI - Rubella seronegativity among health care workers in a tertiary care north Indian hospital: implications for immunization policy. AB - BACKGROUND: Rubella is traditionally considered a childhood disease but has the potential to cause outbreaks in hospital set ups. It is important to know the susceptibility status of health care workers (HCWs) as to frame guidelines for their immunization and thus prevent hospital outbreaks. PARTICIPANTS: The rubella susceptibility status of 313 HCWs working in the institute was assessed. This study was initiated after we reported an outbreak due to rubella among HCWs of our institute. MATERIALS AND METHODS: The serum samples were tested to determine Rubella IgG titres by enzyme linked immunosorbent assay (ELISA). RESULTS: Overall, 48 (15.3%) subjects were found to be negative, thereby indicating their susceptibility to infection. Out of them, 29 (60.5%) were in contact with pregnant women during the course of their employment. There is a risk of nosocomial transmission of rubella from affected HCWs to their contacts especially pregnant women as many of the rubella infections are asymptomatic. CONCLUSION: Hence, we stress the need for vaccinating the HCWs at the start of their employment to contain the spread of infection and also to reduce the risk of outbreaks in work place. PMID- 24056654 TI - Immunohistochemical expression of endothelin protein in oral squamous cell carcinoma. AB - CONTEXT: Endothelin-1 (ET-1) plays a significant role in cancer biology and is considered as a potential target for molecular therapy. Alteration of ET-1 was detected in oral squamous cell carcinoma (OSCC). AIM: To evaluate the immunohistochemical expression and distribution of ET-1 in OSCC and to correlate its expression with the degree of histopathologic differentiation as well as the regional metastatic status of OSCC. MATERIALS AND METHODS: The immunohistochemical expression and distribution of ET-1 was evaluated in total number of 30 cases of OSCC. The specimens were retrieved as formalin-fixed, paraffin-embedded blocks from the archival files. Detection of ET-1 expression in different grades of metastatic and non-metastatic OSCC was quantified using an image analyzer computer system. STATISTICAL ANALYSIS USED: Statistical software package SPSS v. 19. RESULTS: ET-1 immunoreactivity was observed in all studied specimens. On comparing optical density values for ET-1 expression in different grades of OSCC, poorly differentiated OSCC showed a significantly greater expression than moderately differentiated OSCC, which was also significantly greater than well-differentiated OSCC ( P = 0.001). Moreover, ET-1 expression was higher in metastatic OSCC than that in non-metastatic OSCC ( P = 0.018). CONCLUSIONS: Increased ET-1 expression could enhance the aggressive behavior of poorly differentiated OSCC, especially metastasis. Accordingly, ET-1 could be a therapeutic target in OSCC. PMID- 24056655 TI - Role of newer methods of diagnosing genital tuberculosis in infertile women. AB - Genital tuberculosis is an important under-diagnosed factor of infertility. A vast majority of cases are asymptomatic and diagnosing them will help in treating such patients. We conducted a retrospective study in a tertiary care hospital of Delhi with an aim to compare different methods i.e., histopathological examination (HPE), acid-fast bacilli (AFB) smears, Lowenstein-Jensen (LJ) culture, BACTEC culture and polymerase chain reaction deoxyribonucleic acid (PCR DNA) for diagnosing endometrial tuberculosis in infertile women. The data from 546 samples of endometrial biopsy histopathology, AFB smears and LJ culture was collected and then analyzed. Of these, HPE for tuberculosis was positive in 13, LJ culture in 10, AFB smear was positive in one case. BACTEC and PCR-DNA were feasible for 90 patients and PCR-DNA was positive in 20 and BACTEC in eight patients. Out of 20 patients with PCR positive results, 15 were only PCR positive and were subjected to hyster-laparoscopy and five had evidence of tuberculosis. Thus, none of the available tests can pick up all cases of genital tuberculosis, but conventional methods i.e., histopathology and LJ culture still has an important role in the diagnosis of endometrial tuberculosis in government setups where BACTEC and PCR are not performed routinely due to lack of resources. PMID- 24056656 TI - Mixed germ cell tumor of mediastinum/lung masquerading as hemangioma in fine needle biopsy. AB - The histological predominance of one component in a germ cell tumor can lead to a mistaken diagnosis. Here, we describe a mediastinal teratoma with predominant vascular proliferation (>90%) which on fine needle biopsy was diagnosed as a pulmonary hemangioma. Later, resection specimen revealed other components constituting ~4%, changing the diagnosis while illustrating theimportance of careful evaluation. A 37-year-old Caucasian male with shortness of breath, weight loss, and history of recently resolved pneumonia was diagnosed with hemangioma, after a computed tomography guided fine needle biopsy of a -16.3-cm mediastinal pulmonary mass revealed abundant benign vascular elements. Following tumor excision, ~94% of the sample exhibited predominant vascular elementsThe mass also exhibited rare focal areas of malignant epithelium in a reticular arrangement and undifferentiated pleomorphic cells associated with vascular invasion. These atypical epithelial cells were positive for CD30, pan CK, AFP, beta-HCG and CD 117, thusprocuring a diagnosis of mediastinal mixed germ cell tumor. Although mixed germ cell tumors consist of various tissue types, diagnosis can be easily overlooked if one component dominates. Therefore, obtaining adequate representative neoplasm samples, and sectioning the samples thoroughly, searching for coexisting tissue types is critical for accurate diagnosis. PMID- 24056657 TI - Granular cell tumor of the scrotum: a case report and literature review. AB - Granular cell tumors (GCTs) on the male genitalia are exceedingly rare. Solitary tumors have been reported on the penile shaft, prepuce, corpus cavernosum, glans penis, and scrotum. According to the latest serial analysis by using a MEDLINE search of the literature from January 1970 to December 2011, we identified seven reported GCTs involving the scrotum. We present a new case and perform a brief literature review. PMID- 24056658 TI - Salivary duct cyst in the upper lip: case report and review of the literature. AB - Salivary duct cyst (SDC) in an uncommon lesion of the minor salivary glands, with etiology related to obstruction of the salivary duct. It presents with a color similar to that of the mucosa, is mobile, measures between 3 and 10 mm and affects preferentially the bottom lip, floor of the mouth and the jugal mucosa. SDC have a predilection for the male and individual in elderly groups. The pathogenesis of SDC is associated with the formation of a mucous plug that causes partial or total obstruction of the salivary gland system duct, resulting in the dilation of the duct and increase in intraluminal pressure. They present clinical pathological characteristics similar to those of salivary gland tumors, making diagnosis difficult and subject to errors in treatment. It is important for the dentist to include SDC in the differential diagnosis of lesions that affect the upper lip, although it is relatively rarely found in this anatomic site. PMID- 24056659 TI - Basal like carcinoma of breast in patient with neurofibromatosis I: an association or co-existence? AB - Neurofibromatosis I (NF I), an autosomal dominant disorder is associated with increased risk of benign and malignant peripheral nerve sheath tumors and central nervous system tumors. There are only few case reports of breast carcinoma in known patients of NF I. We report a case of basal like carcinoma of the breast in a 69-year-old lady who had NF I. Considering the rare association of carcinomas with NF I and finding that both the NF I gene and a breast cancer pre-disposition gene, BRCA 1 are located in close proximity on chromosome 17q makes the association of these two conditions intriguing. PMID- 24056660 TI - Aggressive osteoblastoma in mastoid process of temporal bone with facial palsy. AB - Osteoblastoma is an uncommon primary bone tumor with a predilection for posterior elements of spine. Its occurrence in temporal bone and middle ear is extremely rare. Clinical symptoms are non-specific and cranial nerve involvement is uncommon. The cytomorphological features of osteoblastoma are not very well defined and the experience is limited to only few reports. We report an interesting and rare case of aggressive osteoblastoma, with progressive hearing loss and facial palsy, involving the mastoid process of temporal bone and middle ear along with the description of cyto-morphological features. PMID- 24056661 TI - Cytokeratin-positive interstitial reticulum cell sarcoma: extranodal presentations mimicking carcinoma. AB - Cytokeratin-positive interstitial reticulum cell (CIRC) sarcoma is a rare type of dendritic cell tumor derived from a subset of fibroblastic reticular cells. Expression of cytokeratins and extranodal location of these tumors can lead to a misdiagnosis of carcinoma. We report two cases of CIRC sarcomas primarily involving the scalp and breast. Patients were referred with an initial diagnosis of carcinoma. Case 1 underwent wide local excision of the scalp tumor with left posterolateral neck dissection. Case 2 had modified radical mastectomy for the tumor in left breast. Histopathological examination of both specimens showed an epithelioid to spindle cell malignant tumor that co-expressed CK 8, CK 18, vimentin, and smooth muscle actin. A diagnosis of CIRC sarcoma was made. Pathologists should be aware of this subset of dendritic cell sarcoma. Carcinomas, other sarcomas of the accessory dendritic cell family, and poorly differentiated malignant tumors have to be ruled out by combination of morphology, immunohistochemistry, and electron microscopic studies. PMID- 24056662 TI - Carcinosarcoma in dermoid cyst of ovary: an extremely rare malignant transformation. PMID- 24056663 TI - Disappearing bone in multiple myeloma. PMID- 24056664 TI - Pituicytoma: a case report with literature revisited. PMID- 24056665 TI - An interesting case of primary epithelial cyst of spleen. PMID- 24056666 TI - Identification of polymer types and additives in marine microplastic particles using pyrolysis-GC/MS and scanning electron microscopy. AB - Any assessment of plastic contamination in the marine environment requires knowledge of the polymer type and the additive content of microplastics. Sequential pyrolysis-gas chromatography coupled to mass spectrometry (Pyr-GC/MS) was applied to simultaneously identify polymer types of microplastic particles and associated organic plastic additives (OPAs). In addition, a scanning electron microscope equipped with an energy-dispersive X-ray microanalyser was used to identify the inorganic plastic additives (IPAs) contained in these particles. A total of ten particles, which were optically identified as potentially being plastics, were extracted from two sediment samples collected from Norderney, a North Sea island, by density separation in sodium chloride. The weights of these blue, white and transparent fragments varied between 10 and 350 MUg. Polymer types were identified by comparing the resulting pyrograms with those obtained from the pyrolysis of selected standard polymers. The particles consisted of polyethylene (PE), polypropylene, polystyrene, polyamide, chlorinated PE and chlorosulfonated PE. The polymers contained diethylhexyl phthalate, dibutyl phthalate, diethyl phthalate, diisobutyl phthalate, dimethyl phthalate, benzaldehyde and 2,4-di-tert-butylphenol. Sequential Py-GC/MS was found to be an appropriate tool for identifying marine microplastics for polymer types and OPAs. The IPAs identified were titanium dioxide nanoparticles (TiO2-NPs), barium, sulphur and zinc. When polymer-TiO2 composites are degraded in the marine environment, TiO2-NPs are probably released. Thus, marine microplastics may act as a TiO2-NP source, which has not yet been considered. PMID- 24056668 TI - Rediscovering the lost art of internal podalic version: two case reports. AB - Internal podalic version was once widely used for the management of placenta praevia. In modern obstetrics, it has been replaced by caesarean section which can lead to uterine rupture in a subsequent pregnancy. However, if the foetus is dead or very small, internal podalic version still may be carried out without major complication to avoid unnecessary caesarean section in developing countries where follow up is not satisfactory and the foetal prognosis is poor. PMID- 24056669 TI - Quasi-surgical technique for easy removal of broken tooth roots. AB - We describe a new technique for the removal of broken tooth roots utilizing existing dental equipment. PMID- 24056667 TI - Robust and specific ratiometric biosensing using a copper-free clicked quantum dot-DNA aptamer sensor. AB - We report herein the successful preparation of a compact and functional CdSe-ZnS core-shell quantum dot (QD)-DNA conjugate via highly efficient copper-free "click chemistry" (CFCC) between a dihydro-lipoic acid-polyethylene glycol-azide (DHLA PEG-N3) capped QD and a cyclooctyne modified DNA. This represents an excellent balance between the requirements of high sensitivity, robustness and specificity for the QD-FRET (Forster resonance energy transfer) based sensor as confirmed by a detailed FRET analysis on the QD-DNA conjugate, yielding a relatively short donor-acceptor distance of ~5.8 nm. We show that this CFCC clicked QD-DNA conjugate is not only able to retain the native fluorescence quantum yield (QY) of the parent DHLA-PEG-N3 capped QD, but also well-suited for robust and specific biosensing; it can directly quantitate, at the pM level, both labelled and unlabelled complementary DNA probes with a good SNP (single-nucleotide polymorphism) discrimination ability in complex media, e.g. 10% human serum via target-binding induced FRET changes between the QD donor and the dye acceptor. Furthermore, this sensor has also been successfully exploited for the detection, at the pM level, of a specific protein target (thrombin) via the encoded anti thrombin aptamer sequence in the QD-DNA conjugate. PMID- 24056670 TI - Information measure for long-range correlated sequences: the case of the 24 human chromosomes. AB - A new approach to estimate the Shannon entropy of a long-range correlated sequence is proposed. The entropy is written as the sum of two terms corresponding respectively to power-law (ordered) and exponentially (disordered) distributed blocks (clusters). The approach is illustrated on the 24 human chromosome sequences by taking the nucleotide composition as the relevant information to be encoded/decoded. Interestingly, the nucleotide composition of the ordered clusters is found, on the average, comparable to the one of the whole analyzed sequence, while that of the disordered clusters fluctuates. From the information theory standpoint, this means that the power-law correlated clusters carry the same information of the whole analysed sequence. Furthermore, the fluctuations of the nucleotide composition of the disordered clusters are linked to relevant biological properties, such as segmental duplications and gene density. PMID- 24056671 TI - Seroprevalence of human herpesvirus-8 in HIV-1 infected and uninfected individuals in Cameroon. AB - We evaluated the prevalence of HHV-8 antibodies in 516 plasma samples collected from HIV positive and negative patients from blood banks and urban areas of Cameroon. Among HIV-1 positive samples, HHV-8 seropositivity rate was 61% based on combined reactivity using both ELISA and IFA techniques. HIV negative samples showed 62% seropositivity rate for HHV-8 antibodies. Our results indicate a high HHV-8 prevalence rate in both HIV infected and uninfected individuals in Cameroon. PMID- 24056672 TI - Respiratory syncytial virus infection disrupts monolayer integrity and function in cystic fibrosis airway cells. AB - BACKGROUND: Respiratory Syncytial Virus (RSV) infection is a common contributor to pulmonary symptoms in children with cystic fibrosis (CF). Here we examined RSV infection in immortalized bronchial epithelial cells (CFBE41o-) expressing wild type (wt) or F508del cystic fibrosis transmembrane conductance regulator (CFTR), for monolayer integrity and RSV replication. METHODS: CFBE41o- monolayers expressing wt or F508del CFTR were grown on permeable supports and inoculated with RSV A2 strain. Control experiments utilized UV-inactivated RSV and heat killed RSV. Monolayer resistance and RSV production was monitored for up to six days post-infection. RESULTS: Within 24 h, a progressive decrease in monolayer resistance was observed in RSV infected F508del CFBE41o- cells, while the monolayer integrity of RSV infected wt CFTR CFBE41o- cells remained stable. RSV replication was necessary to disrupt F508del CFBE41o- monolayers as UV-irradiated and heat killed RSV had no effect on monolayer integrity, with an earlier and much more pronounced peak in RSV titer noted in F508del relative to wt CFTR expressing cells. RSV infection of wt CFBE41o- monolayers also resulted in blunting of CFTR response. CONCLUSIONS: These findings identify an enhanced sensitivity of CFBE41o- cells expressing F508del CFTR to RSV infection, replication and monolayer disruption independent of the cellular immune response, and provide a novel mechanism by which cystic fibrosis airway epithelia are susceptible to RSV-dependent injury. PMID- 24056673 TI - Development of a one-step SYBR Green I real-time RT-PCR assay for the detection and quantitation of Araraquara and Rio Mamore hantavirus. AB - Hantaviruses are members of the family Bunyaviridae and are an emerging cause of disease worldwide with high lethality in the Americas. In Brazil, the diagnosis for hantaviruses is based on immunologic techniques associated with conventional RT-PCR. A novel one-step SYBR Green real-time RT-PCR was developed for the detection and quantitation of Araraquara (ARAV) and Rio Mamore hantavirus (RIOMV). The detection limit of assay was 10 copies/MUL of RNA in vitro transcribed of segment S. The specificity of assay was evaluated by melting curve analysis, which showed that the Araraquara virus amplified product generated a melt peak at 80.83 +/- 0.89 degrees C without generating primer-dimers or non specific products. The assay was more sensitive than conventional RT-PCR and we detected two samples undetected by conventional RT-PCR. The one-step SYBR Green real-time quantitative RT-PCR is specific, sensible and reproducible, which makes it a powerful tool in both diagnostic applications and general research of ARAV and RIOMV and possibly other Brazilian hantaviruses. PMID- 24056674 TI - Chronic bee paralysis virus and Nosema ceranae experimental co-infection of winter honey bee workers (Apis mellifera L.). AB - Chronic bee paralysis virus (CBPV) is an important viral disease of adult bees which induces significant losses in honey bee colonies. Despite comprehensive research, only limited data is available from experimental infection for this virus. In the present study winter worker bees were experimentally infected in three different experiments. Bees were first inoculated per os (p/o) or per cuticle (p/c) with CBPV field strain M92/2010 in order to evaluate the virus replication in individual bees. In addition, potential synergistic effects of co infection with CBPV and Nosema ceranae (N. ceranae) on bees were investigated. In total 558 individual bees were inoculated in small cages and data were analyzed using quantitative real time RT-PCR (RT-qPCR). Our results revealed successful replication of CBPV after p/o inoculation, while it was less effective when bees were inoculated p/c. Dead bees harbored about 1,000 times higher copy numbers of the virus than live bees. Co-infection of workers with CBPV and N. ceranae using either method of virus inoculation (p/c or p/o) showed increased replication ability for CBPV. In the third experiment the effect of inoculation on bee mortality was evaluated. The highest level of bee mortality was observed in a group of bees inoculated with CBPV p/o, followed by a group of workers simultaneously inoculated with CBPV and N. ceranae p/o, followed by the group inoculated with CBPV p/c and the group with only N. ceranae p/o. The experimental infection with CBPV showed important differences after p/o or p/c inoculation in winter bees, while simultaneous infection with CBPV and N. ceranae suggesting a synergistic effect after inoculation. PMID- 24056675 TI - Palladium-catalyzed insertion of alpha,beta-unsaturated N-tosylhydrazones and trapping with carbon nucleophiles. AB - Palladium-catalyzed carbene migratory insertion-cyclization reactions were reported, delivering dihydronaphthalene and indene derivatives in moderate to good yields. A three-component cross-coupling was also developed. The reactions are easy to handle, under mild conditions and various functional groups are tolerated. PMID- 24056677 TI - Lens-free imaging of magnetic particles in DNA assays. AB - We present a novel opto-magnetic system for the fast and sensitive detection of nucleic acids. The system is based on a lens-free imaging approach resulting in a compact and cheap optical readout of surface hybridized DNA fragments. In our system magnetic particles are attracted towards the detection surface thereby completing the labeling step in less than 1 min. An optimized surface functionalization combined with magnetic manipulation was used to remove all nonspecifically bound magnetic particles from the detection surface. A lens-free image of the specifically bound magnetic particles on the detection surface was recorded by a CMOS imager. This recorded interference pattern was reconstructed in software, to represent the particle image at the focal distance, using little computational power. As a result we were able to detect DNA concentrations down to 10 pM with single particle sensitivity. The possibility of integrated sample preparation by manipulation of magnetic particles, combined with the cheap and highly compact lens-free detection makes our system an ideal candidate for point of-care diagnostic applications. PMID- 24056678 TI - In silico study on multidrug resistance conferred by I223R/H275Y double mutant neuraminidase. AB - It was recently reported that an I223R/H275Y double mutant of neuraminidase (NA) creates a multidrug-resistant form of the pandemic influenza A (H1N1) virus. However, a comprehensive understanding of the molecular mechanisms is still lacking. We conducted a systematic in silico study to explore the structural basis underlying this multidrug resistance. By molecular docking analyses and molecular dynamics (MD) simulations, we compared various biochemical and biophysical properties of the wild type, the I223R single mutant and the I223R/H275Y double mutant NA with two inhibitors, zanamivir (ZMR) and oseltamivir (G39). The binding free energy of oseltamivir with all types of NA was substantially lower than its zanamivir counterpart. On the other hand, the binding free energy of each inhibitor with wild type NA was generally higher than that with mutant NAs. MD simulation outcomes exemplify distinct patterns for oseltamivir and zanamivir with all types of NA. In particular, the stronger resistance of the double mutant NA relative to the wild and single mutant types can be ascribed to the overall looser but locally more compact structure of the former. Specifically, as a whole the double mutant NA adapts to the larger gyration radius and greater distance between charged atom groups, which is contrary to the pattern in the local binding site region. The enhanced resistance of all types of NA to oseltamivir rather than zanamivir might be accounted for similarly. We expect these findings to provide significant insights into improving inhibitors for the multidrug-resistant neuraminidase of H1N1 influenza viruses. PMID- 24056681 TI - Synthesis of hypervalent iodonium alkynyl triflates for the application of generating cyanocarbenes. AB - The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent reactions with azides to form cyanocarbene intermediates. The synthesis of hypervalent iodonium alkynyl triflates can be facile, but difficulties stem from their isolation and reactivity. In particular, the necessity to use filtration under inert atmosphere at -45 degrees C for some HIATs requires special care and equipment. Once isolated, the compounds can be stored and used in reactions with azides to form cyanocarbene intermediates. The evidence for cyanocarbene generation is shown by visible extrusion of dinitrogen as well as the characterization of products that occur from O-H insertion, sulfoxide complexation, and cyclopropanation. A side reaction of the cyanocarbene formation is the generation of a vinylidene-carbene and the conditions to control this process are discussed. There is also potential to form a hypervalent iodonium alkenyl triflate and the means of isolation and control of its generation are provided. The O-H insertion reaction involves using a HIAT, sodium azide or tetrabutylammonium azide, and methanol as solvent/substrate. The sulfoxide complexation reaction uses a HIAT, sodium azide or tetrabutylammonium azide, and dimethyl sulfoxide as solvent. The cyclopropanations can be performed with or without the use of solvent. The azide source must be tetrabutylammonium azide and the substrate shown is styrene. PMID- 24056682 TI - Complete gate control of supercurrent in graphene p-n junctions. AB - In a conventional Josephson junction of graphene, the supercurrent is not turned off even at the charge neutrality point, impeding further development of superconducting quantum information devices based on graphene. Here we fabricate bipolar Josephson junctions of graphene, in which a p-n potential barrier is formed in graphene with two closely spaced superconducting contacts, and realize supercurrent ON/OFF states using electrostatic gating only. The bipolar Josephson junctions of graphene also show fully gate-driven macroscopic quantum tunnelling behaviour of Josephson phase particles in a potential well, where the confinement energy is gate tuneable. We suggest that the supercurrent OFF state is mainly caused by a supercurrent dephasing mechanism due to a random pseudomagnetic field generated by ripples in graphene, in sharp contrast to other nanohybrid Josephson junctions. Our study may pave the way for the development of new gate-tuneable superconducting quantum information devices. PMID- 24056683 TI - Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia. AB - We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profiling and ex vivo drug sensitivity and resistance testing (DSRT) of patients' cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered five major taxonomic drug response subtypes based on DSRT profiles, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3-ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. After progression under DSRT-guided therapies, AML cells displayed significant clonal evolution and novel genomic changes potentially explaining resistance, whereas ex vivo DSRT data showed resistance to the clinically applied drugs and new vulnerabilities to previously ineffective drugs. SIGNIFICANCE: Here, we demonstrate an ISM strategy to optimize safe and effective personalized cancer therapies for individual patients as well as to understand and predict disease evolution and the next line of therapy. This approach could facilitate systematic drug repositioning of approved targeted drugs as well as help to prioritize and de-risk emerging drugs for clinical testing. PMID- 24056684 TI - Effect of selenium-enriched exopolysaccharide produced by Lactococcus lactis subsp. lactis on signaling molecules in mouse spleen lymphocytes. AB - Selenium-enriched exopolysaccharides (Se-EPS) produced by Lactococcus lactis subsp. lactis can be used as a safe and effective selenium (Se) supplement. Analysis of the Se content and monosaccharide components of Se-EPS demonstrated that it consisted of mannose, fucose, ribose, glucose, galactose, and arabinose with a molar ratio of 5.48 : 0.39 : 9.77 : 4.03 : 1.00 : 1.92, and an Se content of 183.263 MUg g(-1). The differing effects of Se-EPS and EPS on calcium channels and certain key secondary messengers in spleen lymphocytes were examined and compared. Results showed that low-dose Se-EPS, but not EPS, increased the intracellular calcium ([Ca(2+)]i) levels of mouse spleen lymphocytes. Se-EPS also increased the expression and phosphorylation of Ca(2+)-calmodulin-dependent kinase (CaMK) II in lymphocytes. In addition, increased intracellular Ca(2+) levels were also found in the cells with blocked Ca(2+) channels. We speculated that Se-EPS enhanced the activation and proliferation of lymphocytes through calcium signaling by drawing from extracellular and intracellular stores. Low dose Se-EPS also enhanced NO production, cAMP levels and PKA activity. We speculated that low-dose Se-EPS may activate certain pathways, including the calcium channel, NO, cAMP, and PKA related pathways. PMID- 24056686 TI - Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. AB - BACKGROUND: Lipoprotein(a) (Lp(a)) hyperlipoproteinemia is a major risk factor for cardiovascular disease, which is not affected by treatment of other cardiovascular risk factors. This study sought to assess the effect of chronic lipoprotein apheresis (LA) on the incidence of cardiovascular events in patients with progressive cardiovascular disease receiving maximally tolerated lipid lowering treatment. METHODS AND RESULTS: In a prospective observational multicenter study, 170 patients were investigated who commenced LA because of Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease. Patients were characterized regarding plasma lipid status, lipid-lowering drug treatment, and variants at the LPA gene locus. The incidence rates of cardiovascular events 2 years before (y-2 and y-1) and prospectively 2 years during LA treatment (y+1, y+2) were compared. The mean age of patients was 51 years at the first cardiovascular event and 57 years at the first LA. Before LA, mean low-density lipoprotein cholesterol and Lp(a) were 2.56+/-1.04 mmol.L(-1) (99.0+/-40.1 mg.dL( 1)) and Lp(a) 3.74+/-1.63 umol.L(-1) (104.9+/-45.7 mg.dL(-1)), respectively. Mean annual rates for major adverse coronary events declined from 0.41 for 2 years before LA to 0.09 for 2 years during LA (P<0.0001). Event rates including all vascular beds declined from 0.61 to 0.16 (P<0.0001). Analysis of single years revealed increasing major adverse coronary event rates from 0.30 to 0.54 (P=0.001) for y-2 to y-1 before LA, decline to 0.14 from y-1 to y+1 (P<0.0001) and to 0.05 from y+1 to y+2 (P=0.014). CONCLUSIONS: In patients with Lp(a) hyperlipoproteinemia, progressive cardiovascular disease, and maximally tolerated lipid-lowering medication, LA effectively lowered the incidence rate of cardiovascular events. CLINICAL TRIAL REGISTRATION URL: https://drks neu.uniklinik-freiburg.de. Unique identifier: DRKS00003119. PMID- 24056687 TI - Relax or contract: what's right? PMID- 24056688 TI - Right ventricular diastolic impairment in patients with pulmonary arterial hypertension. AB - BACKGROUND: The role of right ventricular (RV) diastolic stiffness in pulmonary arterial hypertension (PAH) is not well established. Therefore, we investigated the presence and possible underlying mechanisms of RV diastolic stiffness in PAH patients. METHODS AND RESULTS: Single-beat RV pressure-volume analyses were performed in 21 PAH patients and 7 control subjects to study RV diastolic stiffness. Data are presented as mean +/- SEM. RV diastolic stiffness (beta) was significantly increased in PAH patients (PAH, 0.050 +/- 0.005 versus control, 0.029 +/- 0.003; P<0.05) and was closely associated with disease severity. Subsequently, we searched for possible underlying mechanisms using RV tissue of PAH patients undergoing heart/lung transplantation and nonfailing donors. Histological analyses revealed increased cardiomyocyte cross-sectional areas (PAH, 453 +/- 31 MUm2 versus control, 218 +/- 21 MUm2; P<0.001), indicating RV hypertrophy. In addition, the amount of RV fibrosis was enhanced in PAH tissue (PAH, 9.6 +/- 0.7% versus control, 7.2 +/- 0.6%; P<0.01). To investigate the contribution of stiffening of the sarcomere (the contractile apparatus of RV cardiomyocytes) to RV diastolic stiffness, we isolated and membrane-permeabilized single RV cardiomyocytes. Passive tension at different sarcomere lengths was significantly higher in PAH patients compared with control subjects (>200%; Pinteraction <0.001), indicating stiffening of RV sarcomeres. An important regulator of sarcomeric stiffening is the sarcomeric protein titin. Therefore, we investigated titin isoform composition and phosphorylation. No alterations were observed in titin isoform composition (N2BA/N2B ratio: PAH, 0.78 +/- 0.07 versus control, 0.91 +/- 0.08), but titin phosphorylation in RV tissue of PAH patients was significantly reduced (PAH, 0.16 +/- 0.01 arbitrary units versus control, 0.20 +/- 0.01 arbitrary units; P<0.05). CONCLUSIONS: RV diastolic stiffness is significantly increased in PAH patients, with important contributions from increased collagen and intrinsic stiffening of the RV cardiomyocyte sarcomeres. PMID- 24056689 TI - Assessment and prognostic relevance of right ventricular contractile reserve in patients with severe pulmonary hypertension. AB - BACKGROUND: This study sought to analyze a new approach to assess exercise induced pulmonary artery systolic pressure (PASP) increase by means of stress Doppler echocardiography as a possible measure of right ventricular contractile reserve in patients with severe pulmonary hypertension and right heart failure. METHODS AND RESULTS: In this prospective study, patients with invasively diagnosed pulmonary arterial hypertension or inoperable chronic thromboembolic pulmonary hypertension and impaired right ventricular pump function despite a stable targeted pulmonary arterial hypertension medication underwent a broad panel of noninvasive assessments, including stress echocardiography and cardiopulmonary exercise testing. On the basis of the assumption that exercise induced PASP is a measure of right ventricular contractile reserve, patients were classified into 2 groups according to an exercise-induced PASP increase above or below the median. Patients were followed up for 3.0 +/- 1.8 years. Univariate and multivariate analyses were used for factors predicting survival. Of 124 patients, 66 were below the median exercise-induced PASP increase of 30 mm Hg (low PASP), and 58 patients were above the median (high PASP). These groups were not significantly different in terms of medication and resting hemodynamics. Low PASP was associated with a significantly lower 6-minute walking distance, peak o2 per kilogram, and 1-, 3-, and 4-year survival rates (92%, 69%, and 48%, respectively, versus 96%, 92%, and 89%). In the multivariate Cox model analysis adjusted for age and sex, PASP increase during exercise and peak o2 per kilogram remained independent prognostic markers (hazard ratio, 2.56 for peak o2 per kilogram and 2.84 for PASP increase). CONCLUSIONS: Exercise-induced PASP increase is of high clinical and prognostic relevance in pulmonary hypertension patients and may indicate right ventricular contractile reserve. Stress Doppler echocardiography may be a useful tool for prognostic assessment in pulmonary hypertension patients. PMID- 24056690 TI - Feeling lonely versus being alone: loneliness and social support among recently bereaved persons. AB - OBJECTIVES: Despite increases in social support following widowhood, loneliness is among the most frequently reported challenges of bereavement. This analysis explores the dynamic relationship between social support and loneliness among recently bereaved older adults. METHODS: Using longitudinal data from "Living After Loss" (n = 328), latent growth curve modeling was used to estimate changes in loneliness and social support during the first year and a half of bereavement among older adults aged 50+. RESULTS: Both loneliness and social support declined over the first year and a half of bereavement. Greater social support was associated with lower levels of loneliness overall, but the receipt of social support did not modify one's expression of loneliness over time. Loneliness was more highly correlated with support from friends than family. Together, social support from both friends and family accounted for 36% of the total variance in loneliness. DISCUSSION: There is conceptual and empirical overlap between the concepts of loneliness and social support, but results suggest that loneliness following widowhood cannot be remedied by interventions aimed only at increasing social support. Social support, especially that from friends, appears to be most effective if it is readily accessible and allows the newly bereaved an opportunity to express him/herself. PMID- 24056691 TI - Impact of caring for grandchildren on the health of grandparents in Taiwan. AB - OBJECTIVES: To understand how caring for grandchildren affects the physical and mental health of grandparents in Taiwan. METHOD: Grandparents aged 50 and older from 4 waves of the Taiwan Longitudinal Study on Aging (1993-2003, n = 3,711) were divided into 7 categories based on living arrangement and caregiving history. Generalized estimation equations controlling for sociodemographic characteristics and disease status were used to estimate the relationship between caregiving and 4 outcomes: self-rated physical health, mobility limitation, life satisfaction, and depressive symptoms. RESULTS: Compared with noncaregivers, long term multigenerational caregivers were more likely to report better self-rated health, higher life satisfaction, and fewer depressive symptoms. We found some evidence of reduced mobility limitations for both skipped-generation and nonresidential caregivers relative to noncaregivers. The associations in self rated health and depressive symptoms were more pronounced in long-term caregivers than among those who recently started caregiving. DISCUSSION: Improvements in self-rated health and mobility associated with caregiving support our hypothesis that caring for grandchildren can be beneficial for grandparents in Taiwan, especially for long-term multigenerational caregivers. Comparing Taiwanese grandparents across different types of caregiving shows that the associations of grandparent caregiving with health vary by living arrangement and duration. However, these findings may not be causal because caregiving and health outcomes were observed simultaneously in our data. PMID- 24056692 TI - Association between childhood school segregation and changes in adult sense of control in the African American health cohort. AB - OBJECTIVE: Cross-sectional associations between childhood school segregation and adult sense of control and physical performance have been established in the African American Health (AAH) cohort. Here we extend that work by estimating the association between childhood school segregation and 2-year changes in adult sense of control. Method. Complete data on 541 older AAH men and women were used to estimate the association between childhood school segregation and changes in the sense of control. Exposure to segregation was self-reported in 2004, and the sense of control was measured in 2008 and 2010 using Blom rank transformations of Mirowsky and Ross' 8-item scale. Declining subjective income and experiencing major life stressors between 2008 and 2010, as well as traditional covariates (demographic factors, socioeconomic status, self-rated health, racial attitudes and beliefs, and religiosity) were included for statistical adjustment. Multiple linear regression analysis with propensity score reweighting was used. RESULTS: Receiving the majority of one's primary and secondary education in segregated schools had a significant net positive association (d = 0.179; p = .029) with 2 year changes in adult sense of control. CONCLUSION: AAH participants receiving the majority of their primary and secondary educations in segregated schools appeared to have been protected, in part, from age-related declines in the sense of control. PMID- 24056693 TI - Patch clamp recordings from embryonic zebrafish Mauthner cells. AB - Mauthner cells (M-cells) are large reticulospinal neurons located in the hindbrain of teleost fish. They are key neurons involved in a characteristic behavior known as the C-start or escape response that occurs when the organism perceives a threat. The M-cell has been extensively studied in adult goldfish where it has been shown to receive a wide range of excitatory, inhibitory and neuromodulatory signals(1). We have been examining M-cell activity in embryonic zebrafish in order to study aspects of synaptic development in a vertebrate preparation. In the late 1990s Ali and colleagues developed a preparation for patch clamp recording from M-cells in zebrafish embryos, in which the CNS was largely intact(2,3,4). The objective at that time was to record synaptic activity from hindbrain neurons, spinal cord neurons and trunk skeletal muscle while maintaining functional synaptic connections within an intact brain-spinal cord preparation. This preparation is still used in our laboratory today. To examine the mechanisms underlying developmental synaptic plasticity, we record excitatory (AMPA and NMDA-mediated)(5,6) and inhibitory (GABA and glycine) synaptic currents from developing M-cells. Importantly, this unique preparation allows us to return to the same cell (M-cell) from preparation to preparation to carefully examine synaptic plasticity and neuro-development in an embryonic organism. The benefits provided by this preparation include 1) intact, functional synaptic connections onto the M-cell, 2) relatively inexpensive preparations, 3) a large supply of readily available embryos 4) the ability to return to the same cell type (i.e. M cell) in every preparation, so that synaptic development at the level of an individual cell can be examined from fish to fish, and 5) imaging of whole preparations due to the transparent nature of the embryos. PMID- 24056694 TI - Challenges in assessing release, exposure and fate of silver nanoparticles within the UK environment. AB - There are significant challenges in assessing the fate and exposure of nanoparticles (NPs) in the environment owing to the lack of information on their use, potential pathways and sinks in the environment. In order to better understand the environmental exposure of silver nanoparticles (AgNPs), we reviewed the uses and potential exposure sources of both Ag and AgNPs. The approach taken was to identify the range of products that utilise its properties, identify potential environmental release pathways and subsequent fate once released into the environment. We then compared measured environmental concentrations with modelled concentrations from our work and others. We estimate that within the United Kingdom (UK) a total quantity of 8.8 tonnes per year of AgNPs is released from products containing AgNPs and enters UK waste water systems. Sewage sludge was identified as an important receiving compartment. Agricultural land with sludge applied was estimated to have a yearly increase in AgNP concentration of 36 MUg per kg per year. Available ecotoxicity data for soil and the predicted environmental concentrations are used to perform a risk characterisation. This work highlights the on-going challenges faced when undertaking a risk assessment of AgNPs in the environment. PMID- 24056695 TI - RYB tri-colour electrochromism based on a molecular cobaloxime. AB - The three oxidation states of Co in a molecular cobaloxime were used to realise an electrochromic device displaying the red, yellow, blue (RYB) set of subtractive primary colours. A facile method for the lithographic patterning of a several micrometre thick indium tin oxide (ITO) mesoporous layer was developed, which served as the scaffold for cobaloxime adsorption. PMID- 24056696 TI - Neuroprotection and lifespan extension in Ppt1(-/-) mice by NtBuHA: therapeutic implications for INCL. AB - Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disease (LSD) that has no effective treatment. It is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 deficiency impairs the cleavage of thioester linkage in palmitoylated proteins (constituents of ceroid), preventing degradation by lysosomal hydrolases. Consequently, accumulation of lysosomal ceroid leads to INCL. Thioester linkage is cleaved by nucleophilic attack. Hydroxylamine, a potent nucleophilic cellular metabolite, may have therapeutic potential for INCL, but its toxicity precludes clinical application. We found that a hydroxylamine derivative, N-(tert-Butyl) hydroxylamine (NtBuHA), was non toxic, cleaved thioester linkage in palmitoylated proteins and mediated lysosomal ceroid depletion in cultured cells from INCL patients. In Ppt1(-/-) mice, which mimic INCL, NtBuHA crossed the blood-brain barrier, depleted lysosomal ceroid, suppressed neuronal apoptosis, slowed neurological deterioration and extended lifespan. Our findings provide a proof of concept that thioesterase-mimetic and antioxidant small molecules such as NtBuHA are potential drug targets for thioesterase deficiency diseases such as INCL. PMID- 24056698 TI - Multiple perceptible signals from a single olfactory glomerulus. AB - Glomeruli are functional units in the olfactory system. The mouse olfactory bulb contains roughly 2,000 glomeruli, each receiving inputs from olfactory sensory neurons (OSNs) that express a specific odorant receptor gene. Odors typically activate many glomeruli in complex combinatorial patterns and it is unknown which features of neuronal activity in individual glomeruli contribute to odor perception. To address this, we used optogenetics to selectively activate single, genetically identified glomeruli in behaving mice. We found that mice could perceive the stimulation of a single glomerulus. Single-glomerulus stimulation was also detected on an intense odor background. In addition, different input intensities and the timing of input relative to sniffing were discriminated through one glomerulus. Our data suggest that each glomerulus can transmit odor information using identity, intensity and temporal coding cues. These multiple modes of information transmission may enable the olfactory system to efficiently identify and localize odor sources. PMID- 24056697 TI - TAG-1-assisted progenitor elongation streamlines nuclear migration to optimize subapical crowding. AB - Neural progenitors exhibit cell cycle-dependent interkinetic nuclear migration (INM) along the apicobasal axis. Despite recent advances in understanding its underlying molecular mechanisms, the processes to which INM contributes mechanically and the regulation of INM by the apicobasally elongated morphology of progenitors remain unclear. We found that knockdown of the cell-surface molecule TAG-1 resulted in retraction of neocortical progenitors' basal processes. Highly shortened stem-like progenitors failed to undergo basalward INM and became overcrowded in the periventricular (subapical) space. Surprisingly, the overcrowded progenitors left the apical surface and migrated into basal neuronal territories. These observations, together with the results of in toto imaging and physical tests, suggest that progenitors may sense and respond to excessive mechanical stress. Although, unexpectedly, the heterotopic progenitors remained stem-like and continued to sequentially produce neurons until the late embryonic period, histogenesis was severely disrupted. Thus, INM is essential for preventing overcrowding of nuclei and their somata, thereby ensuring normal brain histogenesis. PMID- 24056699 TI - Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. AB - Rapid-eye movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus. Lateral hypothalamus melanin concentrating hormone (MCH)-expressing neurons are active during sleep, but their effects on REM sleep remain unclear. Using optogenetic tools in newly generated Tg(Pmch-cre) mice, we found that acute activation of MCH neurons (ChETA, SSFO) at the onset of REM sleep extended the duration of REM, but not non-REM, sleep episodes. In contrast, their acute silencing (eNpHR3.0, archaerhodopsin) reduced the frequency and amplitude of hippocampal theta rhythm without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA mediated inhibitory postsynaptic currents in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), and in vivo activation of MCH neuron terminals in TMN or medial septum also prolonged REM sleep episodes. Collectively, these results suggest that activation of MCH neurons maintains REM sleep, possibly through inhibition of arousal circuits in the mammalian brain. PMID- 24056701 TI - Shape control of colloidal Mn doped ZnO nanocrystals and their visible light photocatalytic properties. AB - For colloidal semiconductor nanocrystals (NCs), shape control and doping as two widely applied strategies are crucial for enhancing and manipulating their functional properties. Here we report a facile and green synthetic approach for high-quality colloidal Mn doped ZnO NCs with simultaneous control over composition, shape and optical properties. Specifically, the shape of doped ZnO NCs can be finely modulated from three dimensional (3D) tetrapods to 0D spherical nanoparticles in a single reaction scheme. The growth mechanism of doped ZnO NCs with interesting shape transition is explored. Furthermore, we demonstrate the tunable optical absorption features of Mn doped ZnO NCs by varying the Mn doping levels, and the enhanced photocatalytic performance of Mn doped ZnO NCs under visible light, which can be further optimized by delicately controlling their shapes and Mn doping concentrations. Our results provide an improved understanding of the growth mechanism of doped NCs during the growth process and can be potentially extended to ZnO NCs doped with other metal ions for various applications. PMID- 24056700 TI - Stimulus-specific enhancement of fear extinction during slow-wave sleep. AB - Sleep can strengthen memory for emotional information, but whether emotional memories can be specifically targeted and modified during sleep is unknown. In human subjects who underwent olfactory contextual fear conditioning, re-exposure to the odorant context in slow-wave sleep promoted stimulus-specific fear extinction, with parallel reductions of hippocampal activity and reorganization of amygdala ensemble patterns. Thus, fear extinction may be selectively enhanced during sleep, even without re-exposure to the feared stimulus itself. PMID- 24056702 TI - Flash photo stimulation of human neural stem cells on graphene/TiO2 heterojunction for differentiation into neurons. AB - For the application of human neural stem cells (hNSCs) in neural regeneration and brain repair, it is necessary to stimulate hNSC differentiation towards neurons rather than glia. Due to the unique properties of graphene in stem cell differentiation, here we introduce reduced graphene oxide (rGO)/TiO2 heterojunction film as a biocompatible flash photo stimulator for effective differentiation of hNSCs into neurons. Using the stimulation, the number of cell nuclei on rGO/TiO2 increased by a factor of ~1.5, while on GO/TiO2 and TiO2 it increased only ~48 and 24%, respectively. Moreover, under optimum conditions of flash photo stimulation (10 mW cm(-2) flash intensity and 15.0 mM ascorbic acid in cell culture medium) not only did the number of cell nuclei and neurons differentiated on rGO/TiO2 significantly increase (by factors of ~2.5 and 3.6), but also the number of glial cells decreased (by a factor of ~0.28). This resulted in a ~23-fold increase in the neural to glial cell ratio. Such highly accelerated differentiation was assigned to electron injection from the photoexcited TiO2 into the cells on the rGO through Ti-C and Ti-O-C bonds. The role of ascorbic acid, as a scavenger of the photoexcited holes, in flash photo stimulation was studied at various concentrations and flash intensities. PMID- 24056703 TI - High-temperature thermoelectric transport at small scales: thermal generation, transport and recombination of minority carriers. AB - Thermoelectric transport in semiconductors is usually considered under small thermal gradients and when it is dominated by the role of the majority carriers. Not much is known about effects that arise under the large thermal gradients that can be established in high-temperature, small-scale electronic devices. Here, we report a surprisingly large asymmetry in self-heating of symmetric highly doped silicon microwires with the hottest region shifted along the direction of minority carrier flow. We show that at sufficiently high temperatures and strong thermal gradients (~1 K/nm), energy transport by generation, transport and recombination of minority carriers along these structures becomes very significant and overcomes convective energy transport by majority carriers in the opposite direction. These results are important for high-temperature nanoelectronics such as emerging phase-change memory devices which also employ highly doped semiconducting materials and in which local temperatures reach ~1000 K and thermal gradients reach ~10-100 K/nm. PMID- 24056704 TI - Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs. AB - AIM: To investigate the metabolism of GLS4, a heteroaryldihydropyrimidine compound with anti-hepatitis B virus activity, in dog and human liver microsomes in vitro and evaluate the effects of ketoconazole (a potent CYP3A inhibitor) or rifampicin (a potent CYP3A inducer) on GLS4 pharmacokinetics in dogs. METHODS: Dog and human liver microsomes and CYP3A4 were incubated with [(14)C]GLS4 for 15 min and then analyzed using a HPLC-dynamic online radio flow detection method. Two groups of beagle dogs were used for in vivo studies. Group A were orally administered a single dose of GLS4 (15 mg/kg) with or without ketoconazole pretreatment (100 mg/d for 8 consecutive days). Group B were orally administered a single dose of GLS4 (15 mg/kg) with or without rifampicin pretreatment (100 mg/d for 8 consecutive days). Plasma was sampled after GLS4 dosing. GLS4 concentrations were determined by HPLC-tandem mass spectrometry. RESULTS: The metabolic profile of [(14)C]GLS4 in human and dog liver microsomes and CYP3A4 was similar. The major metabolites were morpholine N-dealkylated GLS4 and morpholine N,N-di-dealkylated GLS4. Pretreatment with ketoconazole or rifampicin significantly affected the plasma concentrations of GLS4 in dogs: ketoconazole increased the area under the concentration-time curve from 0 to infinity and peak concentration of GLS4 by 4.4 and 3.3 folds, respectively, whereas rifampicin decreased these parameters by 88.5% and 83.2%, respectively. CONCLUSION: GLS4 is a sensitive substrate of CYP3A. CYP3A inhibitors or inducers cause considerable change of GLS4 plasma concentrations in dogs, which should be considered in clinical practice. PMID- 24056705 TI - Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations. AB - AIM: To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors. METHODS: Based on the prototype model inhibitor 1, four ligands with subtle differences in the fused aromatic rings were synthesized. Quantum chemistry was employed to calculate the binding free energy for each ligand. Symmetry-adapted perturbation theory (SAPT) was used to decompose the binding energy into several fundamental forces to elucidate the determinant factors. RESULTS: Binding free energies calculated from quantum chemistry were correlated well with experimental data. SAPT calculations showed that the predominant driving force for binding was derived from a sandwich pi-pi interaction with Tyr-1230. Arg-1208 was the differentiating factor, interacting with the 6-position of the fused aromatic ring system through the backbone carbonyl with a force pattern similar to hydrogen bonding. Therefore, a hydrogen atom must be attached at the 6-position, and changing the carbon atom to nitrogen caused unfavorable electrostatic interactions. CONCLUSION: The theoretical studies have elucidated the determinant factors involved in the binding of type I inhibitors to c-Met. PMID- 24056706 TI - Pharmacokinetic evaluation of the anticancer prodrug simmitecan in different experimental animals. AB - AIM: To investigate the pharmacokinetics and disposition of simmitecan (L-P) that was a water-soluble ester prodrug of chimmitecan (L-2-Z) with potent anti-tumor activities in different experimental animals, and to assess its drug-drug interaction potential. METHODS: SD rats were injected with a single iv bolus doses of L-P (3.75, 7.5 and 15 mg/kg). The pharmacokinetics, tissue distribution, excretion and metabolism of L-P and its active metabolite L-2-Z were studied through quantitative measurements and metabolite profiling with LC/MS. The binding of L-P and L-2-Z to rat plasma proteins was examined using an ultrafiltration method. Systemic exposures of beagle dogs to L-P as well as drug distribution in tumors of the nude mice xenograft model of human hepatic cancer SMMC-7721 cells were also examined. The metabolism of L-P by liver mcirosomal carboxylesterase in vitro was investigated in different species. The effects of L P and L-2-Z on cytochrome P450 enzymes were examined using commercial screening kits. RESULTS: The in vivo biotransformation of L-P to L-2-Z showed a significant species difference, with a mean elimination half-life t1/2 of approximately 1.4 h in rats and 1.9 h in dogs. The systemic exposure levels of L-P and L-2-Z were increased in a dose-dependent manner. In rats, approximately 66% of L-P and 79% of L-2-Z were bound to plasma proteins. In rats and the nude mice bearing human hepatic cancers, most organ tissues had significantly higher concentrations of L P than the corresponding plasma levels. In the tumor tissues, the L-P levels were comparable to those of plasma, whereas the L-2-Z levels were lower than the L-P levels. In rats, L-P was eliminated mainly via biliary excretion, but metabolism played an important role in elimination of the intact L-P. Finally, L-P and L-2-Z exerted moderate inhibition on the activity of CYP3A4 in vitro. CONCLUSION: L-P and L-2-Z have relatively short elimination half-lives and L-P is mainly eliminated via biliary excretion. The species difference in the conversion of L-P to L-2-Z and potential drug-drug interactions due to inhibition of CYP3A4 should be considered in further studies. PMID- 24056708 TI - Site selectivity for protein tyrosine nitration: insights from features of structure and topological network. AB - Tyrosine nitration is a covalent post-translational modification, which regulates protein functions such as hindering tyrosine phosphorylation and affecting essential signal transductions in cells. Based on up-to-date proteomics data, tyrosine nitration appears to be a highly selective process since not all tyrosine residues in proteins or all proteins are nitrated in vivo. Quite a few investigations included the protein structural information from the RCSB PDB database, where near 100,000 high-quality three-dimensional structures are available. In this work, we analyzed the local protein structures and amino acid topological networks of the nitrated and non-nitrated tyrosine sites in nitrated proteins, including neighboring atomic distribution, amino acid pair (AAP) and amino acid triangle (AAT). It has been found that aromatic and aliphatic residues, particularly with large volume, aromatic, aliphatic, or acidic side chains, are disfavored for the nitration. After integrating these structural features and topological network features with traditional sequence features, the predictive model achieves a sensitivity of 63.30% and a specificity of 92.24%, resulting in a much better accuracy compared to the previous models with only protein sequence information. Our investigation implies that the site selectivity may stem from a more open, hydrophilic and high-pH chemical environment around the tyrosine residue. PMID- 24056709 TI - Half-metallicity of a kagome spin lattice: the case of a manganese bis-dithiolene monolayer. AB - The spin ordering in kagome lattices has long been studied in the search for real materials with a spin-liquid ground state. The synthesis of a nickel bis dichiolene complex (Ni3C12S12) nanosheet (T. Kambe et al., J. Am. Chem. Soc., 2013, 135, 2462) paved a way for realizing real two-dimensional kagome lattices. Using first-principles calculations, we predicted that a ferromagnetic kagome spin lattice with S = 3/2 on lattice vertices can be achieved in an Mn3C12S12 monolayer formed by substituting Ni with Mn atoms in nonmagnetic Ni3C12S12. Monte Carlo simulations on the basis of the Ising model suggest that it has a Curie temperature of about 212 K. A ferromagnetic Mn3C12S12 monolayer is half metallic with high carrier mobility in one spin channel and a band gap of 1.54 eV in another spin channel, which is quite promising for spintronic device applications. Additionally, a small band gap opens up at the Dirac point of the kagome bands due to the spin-orbital coupling effects, which may be implementable for achieving a quantum anomalous Hall effect. PMID- 24056707 TI - Calcineurin/NFAT pathway mediates wear particle-induced TNF-alpha release and osteoclastogenesis from mice bone marrow macrophages in vitro. AB - AIM: To investigate the roles of the calcineurin/nuclear factor of activated T cells (NFAT) pathway in regulation of wear particles-induced cytokine release and osteoclastogenesis from mouse bone marrow macrophages in vitro. METHODS: Osteoclasts were induced from mouse bone marrow macrophages (BMMs) in the presence of 100 ng/mL receptor activator of NF-kappaB ligand (RANKL). Acridine orange staining and MTT assay were used to detect the cell viability. Osteoclastogenesis was determined using TRAP staining and RT-PCR. Bone pit resorption assay was used to examine osteoclast phenotype. The expression and cellular localization of NFATc1 were examined using RT-PCR and immunofluorescent staining. The production of TNFalpha was analyzed with ELISA. RESULTS: Titanium (Ti) or polymethylmethacrylate (PMMA) particles (0.1 mg/mL) did not significantly change the viability of BMMs, but twice increased the differentiation of BMMs into mature osteoclasts, and markedly increased TNF-alpha production. The TNF alpha level in the PMMA group was significantly higher than in the Ti group (96 h). The expression of NFATc1 was found in BMMs in the presence of the wear particles and RANKL. In bone pit resorption assay, the wear particles significantly increased the resorption area and total number of resorption pits in BMMs-seeded ivory slices. Addition of 11R-VIVIT peptide (a specific inhibitor of calcineurin-mediated NFAT activation, 2.0 MUmol/L) did not significantly affect the viability of BMMs, but abolished almost all the wear particle-induced alterations in BMMs. Furthermore, VIVIT reduced TNF-alpha production much more efficiently in the PMMA group than in the Ti group (96 h). CONCLUSION: Calcineurin/NFAT pathway mediates wear particles-induced TNF-alpha release and osteoclastogenesis from BMMs. Blockade of this signaling pathway with VIVIT may provide a promising therapeutic modality for the treatment of periprosthetic osteolysis. PMID- 24056710 TI - An efficient synthesis of trisubstituted oxazoles via chemoselective O-acylations and intramolecular Wittig reactions. AB - Preparation of new types of trisubstituted oxazoles is realized via chemoselective O-acylations and intramolecular Wittig reactions with ester functionalities using in situ formed phosphorus ylides as key intermediates. A plausible reaction mechanism for this undiscovered chemistry is also proposed based on the existence of expected and rearranged isomeric oxazoles. PMID- 24056711 TI - Fluorescent proteins for live-cell imaging with super-resolution. AB - Fluorescent proteins (FPs) from the GFP family have become indispensable as marker tools for imaging live cells, tissues and entire organisms. A wide variety of these proteins have been isolated from natural sources and engineered to optimize their properties as genetically encoded markers. Here we review recent developments in this field. A special focus is placed on photoactivatable FPs, for which the fluorescence emission can be controlled by light irradiation at specific wavelengths. They enable regional optical marking in pulse-chase experiments on live cells and tissues, and they are essential marker tools for live-cell optical imaging with super-resolution. Photoconvertible FPs, which can be activated irreversibly via a photo-induced chemical reaction that either turns on their emission or changes their emission wavelength, are excellent markers for localization-based super-resolution microscopy (e.g., PALM). Patterned illumination microscopy (e.g., RESOLFT), however, requires markers that can be reversibly photoactivated many times. Photoswitchable FPs can be toggled repeatedly between a fluorescent and a non-fluorescent state by means of a light induced chromophore isomerization coupled to a protonation reaction. We discuss the mechanistic origins of the effect and illustrate how photoswitchable FPs are employed in RESOLFT imaging. For this purpose, special FP variants with low switching fatigue have been introduced in recent years. Despite nearly two decades of FP engineering by many laboratories, there is still room for further improvement of these important markers for live cell imaging. PMID- 24056712 TI - Retraction: Two novel duck antibacterial peptides, avian beta-defensins 9 and 10, with antimicrobial activity. AB - The article by Ma et al. that published in the Journal of Microbiology and Biotechnology (2009, 19: 1447-1455) was used the same data in two journal articles (Acta Veterinaria et Zootechnica Sinica, 2009, 40(9): 1320-1326, Scientia Agricultura Sinica, 2009, 42(4): 1406-1412). Therefore, the article is retracted from JMB as a misconduct of the authors. JMB as the publisher regrets for any inconvenience may have caused by the retraction to readers. PMID- 24056713 TI - The influence of glacial meltwater on alpine aquatic ecosystems: a review. AB - The recent and rapid recession of alpine glaciers over the last 150 years has major implications for associated aquatic communities. Glacial meltwater shapes many of the physical features of high altitude lakes and streams, producing turbid environments with distinctive hydrology patterns relative to nival systems. Over the past decade, numerous studies have investigated the chemical and biological effects of glacial meltwater on freshwater ecosystems. Here, we review these studies across both lake and stream ecosystems. Focusing on alpine regions mainly in the Northern Hemisphere, we present examples of how glacial meltwater can affect habitat by altering physical and chemical features of aquatic ecosystems, and review the subsequent effects on the biological structure and function of lakes and streams. Collectively or separately, these factors can drive the overall distribution, diversity and behavior of primary producers, triggering cascading effects throughout the food web. We conclude by proposing areas for future research, particularly in regions where glaciers are soon projected to disappear. PMID- 24056714 TI - Natural compounds with anti-ageing activity. AB - Ageing is a complex molecular process driven by diverse molecular pathways and biochemical events that are promoted by both environmental and genetic factors. Specifically, ageing is defined as a time-dependent decline of functional capacity and stress resistance, associated with increased chance of morbidity and mortality. These effects relate to age-related gradual accumulation of stressors that result in increasingly damaged biomolecules which eventually compromise cellular homeostasis. Nevertheless, the findings that genetic or diet interventions can increase lifespan in evolutionarily diverse organisms indicate that mortality can be postponed. Natural compounds represent an extraordinary inventory of high diversity structural scaffolds that can offer promising candidate chemical entities in the major healthcare challenge of increasing health span and/or delaying ageing. Herein, those natural compounds (either pure forms or extracts) that have been found to delay cellular senescence or in vivo ageing will be critically reviewed and summarized according to affected cellular signalling pathways. Moreover, the chemical structures of the identified natural compounds along with the profile of extracts related to their bioactive components will be presented and discussed. Finally, novel potential molecular targets for screening natural compounds for anti-ageing activity, as well as the idea that anti-ageing interventions represent a systemic approach that is also effective against age-related diseases will be discussed. PMID- 24056715 TI - Replicative mechanisms for CNV formation are error prone. AB - We investigated 67 breakpoint junctions of gene copy number gains in 31 unrelated subjects. We observed a strikingly high frequency of small deletions and insertions (29%) apparently originating from polymerase slippage events, in addition to frameshifts and point mutations in homonucleotide runs (13%), at or flanking the breakpoint junctions of complex copy number variants. These single nucleotide variants were generated concomitantly with the de novo complex genomic rearrangement (CGR) event. Our findings implicate low-fidelity, error-prone DNA polymerase activity in synthesis associated with DNA repair mechanisms as the cause of local increase in point mutation burden associated with human CGR. PMID- 24056716 TI - Arabidopsis meiotic crossover hot spots overlap with H2A.Z nucleosomes at gene promoters. AB - PRDM9 directs human meiotic crossover hot spots to intergenic sequence motifs, whereas budding yeast hot spots overlap regions of low nucleosome density (LND) in gene promoters. To investigate hot spots in plants, which lack PRDM9, we used coalescent analysis of genetic variation in Arabidopsis thaliana. Crossovers increased toward gene promoters and terminators, and hot spots were associated with active chromatin modifications, including H2A.Z, histone H3 Lys4 trimethylation (H3K4me3), LND and low DNA methylation. Hot spot-enriched A-rich and CTT-repeat DNA motifs occurred upstream and downstream, respectively, of transcriptional start sites. Crossovers were asymmetric around promoters and were most frequent over CTT-repeat motifs and H2A.Z nucleosomes. Pollen typing, segregation and cytogenetic analysis showed decreased numbers of crossovers in the arp6 H2A.Z deposition mutant at multiple scales. During meiosis, H2A.Z forms overlapping chromosomal foci with the DMC1 and RAD51 recombinases. As arp6 reduced the number of DMC1 or RAD51 foci, H2A.Z may promote the formation or processing of meiotic DNA double-strand breaks. We propose that gene chromatin ancestrally designates hot spots within eukaryotes and PRDM9 is a derived state within vertebrates. PMID- 24056717 TI - Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development. AB - The regulated proliferation and differentiation of neural stem cells before the generation and migration of neurons in the cerebral cortex are central aspects of mammalian development. Periventricular neuronal heterotopia, a specific form of mislocalization of cortical neurons, can arise from neuronal progenitors that fail to negotiate aspects of these developmental processes. Here we show that mutations in genes encoding the receptor-ligand cadherin pair DCHS1 and FAT4 lead to a recessive syndrome in humans that includes periventricular neuronal heterotopia. Reducing the expression of Dchs1 or Fat4 within mouse embryonic neuroepithelium increased progenitor cell numbers and reduced their differentiation into neurons, resulting in the heterotopic accumulation of cells below the neuronal layers in the neocortex, reminiscent of the human phenotype. These effects were countered by concurrent knockdown of Yap, a transcriptional effector of the Hippo signaling pathway. These findings implicate Dchs1 and Fat4 upstream of Yap as key regulators of mammalian neurogenesis. PMID- 24056720 TI - Monolithically integrated biophotonic lab-on-a-chip for cell culture and simultaneous pH monitoring. AB - A poly(dimethylsiloxane) biophotonic lab-on-a-chip (bioPhLoC) containing two chambers, an incubation chamber and a monitoring chamber for cell retention/proliferation and pH monitoring, respectively, is presented. The bioPhLoC monolithically integrates a filter with 3 MUm high size-exclusion microchannels, capable of efficiently trapping cells in the incubation chamber, as well as optical elements for real-time interrogation of both chambers. The integrated optical elements made possible both absorption and dispersion measurements, which were comparable to those made in a commercially available cuvette. The size-exclusion filter also showed good and stable trapping capacity when using yeast cells of variable size (between 5 and 8 MUm diameter). For cell culture applications, vascular smooth muscle cells (VSMC), with sizes between 8 and 10 MUm diameter, were used as a mammalian cell model. These cells were efficiently trapped in the incubation chamber, where they proliferated with a classical spindle-shaped morphology and a traditional hill-and-valley phenotype. During cell proliferation, pH changes in the culture medium due to cell metabolism were monitored in real time and with high precision in the monitoring chamber without interference of the measurement by cells and other (cell) debris. PMID- 24056719 TI - "Role of the B-cell receptor and the microenvironment in chronic lymphocytic leukemia''. AB - Despite significant progress in treatment, chronic lymphocytic leukemia (CLL) remains an incurable disease. Advances have been made to understand the molecular pathogenesis underlying CLL progression and treatment resistance. We here review the available evidences concerning the role of the B-cell receptor (BCR) and the tumor microenvironment interactions in CLL pathogenesis. Antigen likely has a key role in the selection of the tumoral clone, the mutational status of immunoglobulin genes is a strong prognostic predictor and BCR signaling has been postulated to have a role for CLL trafficking and interaction with the stromal microenvironment. There is also important evidence, favoring a role for the microenvironment in CLL pathogenesis. Most, if not all, proliferative events occur in the lymph nodes and bone marrow, where leukemic cells receive through microenvironment interactions survival signals aiming to avoid apoptosis and acquire favorable tumoral growing conditions. In addition, the tumoral microenvironment appears to be the site where the acquisition of additional genetic lesions in the clone occur, which should greatly influence clinical outcome. The advent of new tyrosine kinase inhibitors which seem to be able to modulate microenvironment interactions and circumvent the p53 deletion have generated significant promise by raising the possibility that they could provide significant progress in disease treatment. PMID- 24056718 TI - The landscape of somatic mutations in Down syndrome-related myeloid disorders. AB - Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%). PMID- 24056721 TI - Reciprocity of weighted networks. AB - In directed networks, reciprocal links have dramatic effects on dynamical processes, network growth, and higher-order structures such as motifs and communities. While the reciprocity of binary networks has been extensively studied, that of weighted networks is still poorly understood, implying an ever increasing gap between the availability of weighted network data and our understanding of their dyadic properties. Here we introduce a general approach to the reciprocity of weighted networks, and define quantities and null models that consistently capture empirical reciprocity patterns at different structural levels. We show that, counter-intuitively, previous reciprocity measures based on the similarity of mutual weights are uninformative. By contrast, our measures allow to consistently classify different weighted networks according to their reciprocity, track the evolution of a network's reciprocity over time, identify patterns at the level of dyads and vertices, and distinguish the effects of flux (im)balances or other (a)symmetries from a true tendency towards (anti )reciprocation. PMID- 24056722 TI - Antioxidant, antibacterial and ACE-inhibitory activity of four monofloral honeys in relation to their chemical composition. AB - Different monofloral honeys from Castilla-La Mancha (Spain) have been studied in order to determine their main functional and biological properties. Thyme honey and chestnut honey possess the highest antioxidant capacity, which is due to their high vitamin C (in thyme honey) and total polyphenolic content (in chestnut honey). On the other hand, chestnut honey showed high antimicrobial activity against Staphylococcus aureus and Escherichia coli, whilst others had no activity against S. aureus and showed very small activity against E. coli. Moreover it was found that the antimicrobial activity measured in chestnut honey was partly due to its lysozyme content. In addition the angiotensin I-converting enzyme (ACE) inhibitory activity was measured, and the ACE inhibition is one mechanism by which antihypertensive activity is exerted in vivo. All the types of honey showed some activity but chestnut honey had the highest ACE inhibitory activity. PMID- 24056723 TI - Presentation, presentation, presentation! Molecular-level insight into linker effects on glycan array screening data. AB - Changes in cell-surface glycan patterns are markers of the presence of many different disease and cancer types, offering a relatively untapped niche for glycan-targeting reagents and therapeutics in diagnosis and treatment. Of paramount importance for the success of any glycan-targeting reagent is the ability to specifically recognize the target among the plethora of different glycans that exist in the human body. The preeminent technique for defining specificity is glycan array screening, in which a glycan-binding protein (GBP) can be simultaneously screened against multiple glycans. Glycan array screening has provided unparalleled insight into GBP specificity, but data interpretation suffers from difficulties in identifying false-negative binding arising from altered glycan presentation, associated with the linker used to conjugate the glycan to the surface. In this work, we model the structure and dynamics of the linkers employed in the glycan arrays developed by the Consortium for Functional Glycomics. The modeling takes into account the physical presence and surface polarity of the array, and provides a structure-based rationalization of false negative results arising from the so-called "linker effect." The results also serve as a guide for interpreting glycan array screening data in a biological context; in particular, we show that attempts to employ natural amino acids as linkers may be prone to unexpected artifacts compromising glycan recognition. PMID- 24056725 TI - Ordered growth of topological insulator Bi2Se3 thin films on dielectric amorphous SiO2 by MBE. AB - Topological insulators (TIs) are exotic materials which have topologically protected states on the surface due to strong spin-orbit coupling. However, a lack of ordered growth of TI thin films on amorphous dielectrics and/or insulators presents a challenge for applications of TI-junctions. We report the growth of topological insulator Bi2Se3 thin films on amorphous SiO2 by molecular beam epitaxy (MBE). To achieve the ordered growth of Bi2Se3 on an amorphous surface, the formation of other phases at the interface is suppressed by Se passivation. Structural characterizations reveal that Bi2Se3 films are grown along the [001] direction with a good periodicity by the van der Waals epitaxy mechanism. A weak anti-localization effect of Bi2Se3 films grown on amorphous SiO2 shows a modulated electrical property by the gating response. Our approach for ordered growth of Bi2Se3 on an amorphous dielectric surface presents considerable advantages for TI-junctions with amorphous insulator or dielectric thin films. PMID- 24056724 TI - Functionalization of PEGylated Fe3O4 magnetic nanoparticles with tetraphosphonate cavitand for biomedical application. AB - In this contribution, Fe3O4 magnetic nanoparticles (MNPs) have been functionalized with a tetraphosphonate cavitand receptor (Tiiii), capable of complexing N-monomethylated species with high selectivity, and polyethylene glycol (PEG) via click-chemistry. The grafting process is based on MNP pre functionalization with a bifunctional phosphonic linker, 10-undecynylphosphonic acid, anchored on an iron surface through the phosphonic group. The Tiiii cavitand and the PEG modified with azide moieties have then been bonded to the resulting alkyne-functionalized MNPs through a "click" reaction. Each reaction step has been monitored by using X-ray photoelectron and FTIR spectroscopies. PEG and Tiiii functionalized MNPs have been able to load N-methyl ammonium salts such as the antitumor drug procarbazine hydrochloride and the neurotransmitter epinephrine hydrochloride and release them as free bases. In addition, the introduction of PEG moieties promoted biocompatibility of functionalized MNPs, thus allowing their use in biological environments. PMID- 24056726 TI - MR molecular imaging of prostate cancer with a small molecular CLT1 peptide targeted contrast agent. AB - Tumor extracellular matrix has abundance of cancer related proteins that can be used as biomarkers for cancer molecular imaging. In this work, we demonstrated effective MR cancer molecular imaging with a small molecular peptide targeted Gd DOTA monoamide complex as a targeted MRI contrast agent specific to clotted plasma proteins in tumor stroma. We performed the experiment of evaluating the effectiveness of the agent for non-invasive detection of prostate tumor with MRI in a mouse orthotopic PC-3 prostate cancer model. The targeted contrast agent was effective to produce significant tumor contrast enhancement at a low dose of 0.03 mmol Gd/kg. The peptide targeted MRI contrast agent is promising for MR molecular imaging of prostate tumor. PMID- 24056727 TI - The PTEN Long N-tail is intrinsically disordered: increased viability for PTEN therapy. AB - Aberrant activation of the PI3K/Akt/mTOR pathway is observed in several cancers and hyper proliferative disorders. PTEN, a tumor suppressor gene, negatively regulates the PI3K/Akt/mTOR pathway. Inhibitors of various components of this pathway are currently being used for cancer therapy. However, the use of these small molecule inhibitors remains limited due to the presence of compensatory feedback loops within the pathway such that inhibition of one oncogenic molecule often results in the activation of another oncogenic molecule resulting in the development of chemoresistance. One novel strategy that has emerged as a means to circumvent the problem of feedback signaling is by activating tumor suppressor genes that abrogate oncogenic pathways and regress tumor growth. In this regard, a newly identified isoform of the PTEN protein shows promise for use in tumors with elevated PI3K/Akt/mTOR signaling. This isoform is a translational variant of PTEN, termed as PTEN Long, and has additional 173 amino acids at its N-terminus (N-173) than normal PTEN. The N-173 region is required for PTEN secretion and transport across the body. Given the potential of this N-173 region to act as a drug delivery system for PTEN, we herein analyze the structural properties of this region. This N-173 tail has a large intrinsically disordered region (IDR) and is composed of highly charged basic residues. Further, the region is enriched in potential linear binding motifs, protein-binding sites and post-translational modifications (PTMs) indicating its probable role in PTEN function and transport across cells. An extensive analysis of this region is warranted to better exploit its structural and biophysical peculiarities to drug discovery and drug delivery applications. PMID- 24056729 TI - The brain basis of social synchrony. AB - As a social species, humans evolved to detect information from the social behavior of others. Yet, the mechanisms used to evaluate social interactions, the brain networks implicated in such recognition, and whether individual differences in own social behavior determine response to similar behavior in others remain unknown. Here we examined social synchrony as a potentially important mechanism in the evaluation of social behavior and utilized the parenting context, an evolutionarily salient setting of significant consequences for infant survival, to test this issue. The brain response of healthy postpartum mothers to three mother-infant interaction vignettes was assessed. Videos included a typical synchronous interaction and two pathological interactions of mothers diagnosed with postpartum depression and anxiety that showed marked deviations from social synchrony. Mothers' own interactions with their 4- to 6-month-old infants were videotaped and micro-coded for synchrony. Results indicated that the recognition of social synchrony involved activations in the dorsal anterior cingulate cortex (dACC), fusiform, cuneus, inferior parietal lobule, supplementary motor area and NAcc. Mother's own synchrony with her infant correlated with her dACC response to synchrony in others. Findings are consistent with models suggesting that social action underpins social recognition and highlight social synchrony and the mother infant bond as one prototypical context for studying the brain basis of social understanding. PMID- 24056730 TI - Sensitive and selective detection of Hg2+ and Cu2+ ions by fluorescent Ag nanoclusters synthesized via a hydrothermal method. AB - An easily prepared fluorescent Ag nanoclusters (Ag NCs) probe for the sensitive and selective detection of Hg(2+) and Cu(2+) ions was developed here. The Ag NCs were synthesized by using polymethacrylic acid sodium salt as a template via a convenient hydrothermal process. The as-prepared fluorescent Ag NCs were monodispersed, uniform and less than 2 nm in diameter, and can be quenched in the presence of mercury (Hg(2+)) or copper (Cu(2+)) ions. Excellent linear relationships existed between the quenching degree of the Ag NCs and the concentrations of Hg(2+) or Cu(2+) ions in the range of 10 nM to 20 MUM or 10 nM to 30 MUM, respectively. By using ethylenediaminetetraacetate (EDTA) as the masking agent of Cu(2+), Hg(2+) was exclusively detected in coexistence with Cu(2+) with high sensitivity (LOD = 10 nM), which also provided a reusable detection method for Cu(2+). Furthermore, the different quenching phenomena caused by the two metals ions such as changes in visible colour, shifts of UV absorbance peaks and changes in size of Ag NCs make it easy to distinguish between them. Therefore the easily synthesized fluorescent Ag NCs may have great potential as Hg(2+) and Cu(2+) ions sensors. PMID- 24056731 TI - Multiplex acute leukemia cytosensing using multifunctional hybrid electrochemical nanoprobes at a hierarchically nanoarchitectured electrode interface. AB - We have developed a robust, nanobiotechnology-based electrochemical cytosensing approach with high sensitivity, selectivity, and reproducibility toward the simultaneous multiplex detection and classification of both acute myeloid leukemia and acute lymphocytic leukemia cells. The construction of the electrochemical cytosensor involves the hierarchical assembly of dual aptamer functionalized, multilayered graphene-Au nanoparticle electrode interface and the utilization of hybrid electrochemical nanoprobes co-functionalized with redox tags, horseradish peroxidase, and cell-targeting nucleic acid aptamers. The hybrid nanoprobes are multifunctional, capable of specifically targeting the cells of interest, amplifying the electrochemical signals, and generating distinguishable signals for multiplex cytosensing. The as-assembled electrode interface not only greatly facilitates the interfacial electron transfer process due to its high conductivity and surface area but also exhibits excellent biocompatibility and specificity for cell recognition and adhesion. A superstructured sandwich-type sensor geometry is adopted for electrochemical cytosensing, with the cells of interest sandwiched between the nanoprobes and the electrode interface. Such an electrochemical sensing strategy allows for ultrasensitive, multiplex acute leukemia cytosensing with a detection limit as low as ~350 cells per mL and a wide linear response range from 5 * 10(2) to 1 * 10(7) cells per mL for HL-60 and CEM cells, with minimal cross-reactivity and interference from non-targeting cells. This electrochemical cytosensing approach holds great promise as a new point-of-care diagnostic tool for early detection and classification of human acute leukemia and may be readily expanded to multiplex cytosensing of other cancer cells. PMID- 24056732 TI - Protein induced fluorescence enhancement (PIFE) for probing protein-nucleic acid interactions. AB - Single molecule studies of protein-nucleic acid interactions shed light on molecular mechanisms and kinetics involved in protein binding, translocation, and unwinding of DNA and RNA substrates. In this review, we provide an overview of a single molecule fluorescence method, termed "protein induced fluorescence enhancement" (PIFE). Unlike FRET where two dyes are required, PIFE employs a single dye attached to DNA or RNA to which an unlabeled protein is applied. We discuss both ensemble and single molecule studies in which PIFE was utilized. PMID- 24056733 TI - Frictional forces between hydrophilic and hydrophobic particle coated nanostructured surfaces. AB - Friction forces have long been associated with the famous Amontons' rule that states that the friction force is linearly dependent on the applied normal load, with the proportionality constant being known as the friction coefficient. Amontons' rule is however purely phenomenological and does not in itself provide any information on why the friction coefficient is different for different material combinations. In this study, friction forces between a colloidal probe and nanostructured particle coated surfaces in an aqueous environment exhibiting different roughness length scales were measured by utilizing the atomic force microscope (AFM). The chemistry of the surfaces and the probe was varied between hydrophilic silica and hydrophobized silica. For hydrophilic silica surfaces, the friction coefficient was significantly higher for the particle coated surfaces than on the flat reference surface. All the particle coated surfaces exhibited similar friction coefficients, from which it may be concluded that the surface geometry, and not the roughness amplitude per se, influenced the measured friction. During measurements with hydrophobic surfaces, strong adhesive forces related to the formation of a bridging air cavity were evident from both normal force and friction force measurements. In contrast to the frictional forces between the hydrophilic surfaces, the friction coefficient for hydrophobic surfaces was found to depend on the surface structure and we believe that this dependence is related to the restricted movement of the three-phase line of the bridging air cavity. For measurements using a hydrophobic surface and a hydrophilic probe, the friction coefficient was significantly smaller compared to the two homogeneous systems. A layer of air or air bubbles on the hydrophobic surface working as a lubricating layer is a possible mechanism behind this observation. PMID- 24056734 TI - Use of semipermeable membrane devices (SPMDs) to characterize dissolved hydrocarbon fractions of both dispersed and undispersed oil. AB - Crude oil contamination remains a problem along coastal California and its impacts on pelagic organisms are of concern. Previous crude and dispersed oil studies showed a decrease in fish toxicity when Corexit 9500 dispersant was applied. However, observed sublethal metabolic effects were similar for both oil conditions, suggesting fish were accumulating similar dissolved hydrocarbons. This study aimed to characterize the bioavailable fraction of the water accommodated fraction (WAF) and the chemically-enhanced WAF (CEWAF) of Prudhoe Bay Crude Oil (PBCO), using semi-permeable membrane devices (SPMDs) as fish models. Seven accumulated PAHs were identified (naphthalene, 2-methylnaphthalene, 1-methylnapthalene, biphenyl, fluorene, dibenzothiophene and phenanthrene) from 24 h static exposures. Although WAF and CEWAF oil loadings differed by eight fold, accumulated dissolved concentrations among the seven PAHs differed by some three-fold. Overall, the use of SPMDs in characterizing the dissolved fraction of PBCO, has provided a better understanding of the bioavailability of crude and dispersed oil. PMID- 24056735 TI - Coordinated post-translational responses of aquaporins to abiotic and nutritional stimuli in Arabidopsis roots. AB - In plants, aquaporins play a crucial role in regulating root water transport in response to environmental and physiological cues. Controls achieved at the post translational level are thought to be of critical importance for regulating aquaporin function. To investigate the general molecular mechanisms involved, we performed, using the model species Arabidopsis, a comprehensive proteomic analysis of root aquaporins in a large set of physiological contexts. We identified nine physiological treatments that modulate root hydraulics in time frames of minutes (NO and H2O2 treatments), hours (mannitol and NaCl treatments, exposure to darkness and reversal with sucrose, phosphate supply to phosphate starved roots), or days (phosphate or nitrogen starvation). All treatments induced inhibition of root water transport except for sucrose supply to dark grown plants and phosphate resupply to phosphate-starved plants, which had opposing effects. Using a robust label-free quantitative proteomic methodology, we identified 12 of 13 plasma membrane intrinsic protein (PIP) aquaporin isoforms, 4 of the 10 tonoplast intrinsic protein isoforms, and a diversity of post-translational modifications including phosphorylation, methylation, deamidation, and acetylation. A total of 55 aquaporin peptides displayed significant changes after treatments and enabled the identification of specific and as yet unknown patterns of response to stimuli. The data show that the regulation of PIP and tonoplast intrinsic protein abundance was involved in response to a few treatments (i.e. NaCl, NO, and nitrate starvation), whereas changes in the phosphorylation status of PIP aquaporins were positively correlated to changes in root hydraulic conductivity in the whole set of treatments. The identification of in vivo deamidated forms of aquaporins and their stimulus-induced changes in abundance may reflect a new mechanism of aquaporin regulation. The overall work provides deep insights into the in vivo post-translational events triggered by environmental constraints and their possible role in regulating plant water status. PMID- 24056737 TI - Investigation of a regulatory agency enquiry into potential porcine circovirus type 1 contamination of the human rotavirus vaccine, Rotarix: approach and outcome. AB - In January 2010, porcine circovirus type 1 (PCV1) DNA was unexpectedly detected in the oral live-attenuated human rotavirus vaccine, Rotarix (GlaxoSmithKline [GSK] Vaccines) by an academic research team investigating a novel, highly sensitive analysis not routinely used for adventitious agent screening. GSK rapidly initiated an investigation to confirm the source, nature and amount of PCV1 in the vaccine manufacturing process and to assess potential clinical implications of this finding. The investigation also considered the manufacturer's inactivated poliovirus (IPV)-containing vaccines, since poliovirus vaccine strains are propagated using the same cell line as the rotavirus vaccine strain. Results confirmed the presence of PCV1 DNA and low levels of PCV1 viral particles at all stages of the Rotarix manufacturing process. PCV type 2 DNA was not detected at any stage. When tested in human cell lines, productive PCV1 infection was not observed. There was no immunological or clinical evidence of PCV1 infection in infants who had received Rotarix in clinical trials. PCV1 DNA was not detected in the IPV-containing vaccine manufacturing process beyond the purification stage. Retrospective testing confirmed the presence of PCV1 DNA in Rotarix since the initial stages of its development and in vaccine lots used in clinical studies conducted pre- and post-licensure. The acceptable safety profile observed in clinical trials of Rotarix therefore reflects exposure to PCV1 DNA. The investigation into the presence of PCV1 in Rotarix could serve as a model for risk assessment in the event of new technologies identifying adventitious agents in the manufacturing of other vaccines and biological products. PMID- 24056736 TI - Extensive post-translational modification of active and inactivated forms of endogenous p53. AB - The p53 tumor suppressor protein accumulates to very high concentrations in normal human fibroblasts infected by adenovirus type 5 mutants that cannot direct assembly of the viral E1B 55-kDa protein-containing E3 ubiquitin ligase that targets p53 for degradation. Despite high concentrations of nuclear p53, the p53 transcriptional program is not induced in these infected cells. We exploited this system to examine select post-translational modifications (PTMs) present on a transcriptionally inert population of endogenous human p53, as well as on p53 activated in response to etoposide treatment of normal human fibroblasts. These forms of p53 were purified from whole cell lysates by means of immunoaffinity chromatography and SDS-PAGE, and peptides derived from them were subjected to nano-ultra-high-performance LC-MS and MS/MS analyses on a high-resolution accurate-mass MS platform (data available via ProteomeXchange, PXD000464). We identified an unexpectedly large number of PTMs, comprising phosphorylation of Ser and Thr residues, methylation of Arg residues, and acetylation, ubiquitinylation, and methylation of Lys residues-for example, some 150 previously undescribed modifications of p53 isolated from infected cells. These modifications were distributed across all functional domains of both forms of the endogenous human p53 protein, as well as those of an orthologous population of p53 isolated from COS-1 cells. Despite the differences in activity, including greater in vitro sequence-specific DNA binding activity exhibited by p53 isolated from etoposide-treated cells, few differences were observed in the location, nature, or relative frequencies of PTMs on the two populations of human p53. Indeed, the wealth of PTMs that we have identified is consistent with a far greater degree of complex, combinatorial regulation of p53 by PTM than previously anticipated. PMID- 24056738 TI - Multiple infusions of CD20-targeted T cells and low-dose IL-2 after SCT for high risk non-Hodgkin's lymphoma: a pilot study. AB - A pilot phase I clinical trial involving 15 infusions of anti-CD3 * anti-CD20 bispecific Ab (CD20Bi)-armed anti-CD3-activated T cells (aATC) and low-dose IL-2 was conducted in three non-Hodgkin's lymphoma (NHL) patients (two high-risk and one refractory) after autologous SCT. The feasibility of T-cell expansion, safety of aATC infusions, cytotoxic immune responses and trafficking of aATC were evaluated. Three NHL patients received 15 infusions of 5 * 10(9) aATC (three infusions/week for 3 weeks and one infusion/week for 6 weeks) between days 1 and 65 after SCT with IL-2. There were no dose-limiting toxicities. Chills, fever, hypotension and malaise were the common side effects. Engraftment was delayed in one patient with a low stem cell dose. CD20Bi aATC infusions induced specific cytotoxicity directed at lymphoma targets. Endogenous peripheral blood mononuclear cells from two patients mediated anti-lymphoma cytotoxicity above preSCT background (P<0.001). (111)In labeled aATC trafficked to the lungs at 1 h and accumulated in the liver and bone marrow after 24 h. aATC infusions given over 69 days in combination with IL-2 were safe, did not inhibit engraftment, and induced endogenous cytotoxic responses directed at lymphoma targets. PMID- 24056740 TI - Reduced-intensity allogeneic stem cell transplantation for patients aged 50 years or older with B-cell ALL in remission: a retrospective study by the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation. AB - We retrospectively assessed the outcome and pretransplantation predictors of the outcome in 118 patients aged >= 50 years who received fludarabine-containing reduced-intensity allo-SCT (RIST) for B-cell ALL in the first or second CR. Eighty patients received transplants from unrelated donors. Seventy-eight patients were positive for the Ph chromosome. The median follow-up period was 18 months and the 2-year OS rate was 56%. The 2-year cumulative incidence of relapse and non-relapse mortality was 28% and 26%, respectively. The incidence of grades II-IV and III-IV acute GVHD was 46% and 24%, respectively. After 2 years, the incidence of chronic GVHD was 37%. Multivariate analysis of pretransplant factors showed that a higher white blood cell count (>= 30 * 10(9)/L) at diagnosis (hazard ratio (HR)=2.19, P=0.007) and second CR (HR=2.02, P=0.036) were significantly associated with worse OS, whereas second CR (HR=3.83, P<0.001) and related donor (HR=2.34, P=0.039) were associated with a higher incidence of relapse. Fludarabine-containing RIST may be a promising strategy for older patients with B-cell ALL in their first remission. PMID- 24056739 TI - Risk factors for ICU admission and ICU survival after allogeneic hematopoietic SCT. AB - A considerable number of patients undergoing allogeneic hematopoietic SCT (HSCT) develop post-transplant complications requiring intensive care unit (ICU) treatment. Whereas the indications and the outcome of ICU admission are well known, the risk factors leading to ICU admission are less well understood. We performed a retrospective single-center study on 250 consecutive HSCT patients analyzing the indications, risk factors and outcome of ICU admission. Of these 250 patients, 33 (13%) were admitted to the ICU. The most common indications for admission to the ICU were pulmonary complications (11, 33%), sepsis (8, 24%), neurological disorders (6, 18%) and cardiovascular problems (2, 6%). Acute GvHD and HLA mismatch were the only significant risk factors for ICU admission in multivariate analysis. Among patients admitted to the ICU, the number of organ failures correlated negatively with survival. Twenty-one (64%) patients died during the ICU stay and the 6-month mortality was 85% (27 out of 33). SAPS II score underestimated the mortality rate. In conclusion, acute GvHD and HLA mismatch were identified as risk factors for ICU admission following allogeneic HSCT. Both, short- and long-term survival of patients admitted to the ICU remains dismal and depends on the number of organ failures. PMID- 24056741 TI - Hepatitis E virus infection in a hematopoietic stem cell donor. PMID- 24056742 TI - The impact of CD34+ cell dose on engraftment after SCTs: personalized estimates based on mathematical modeling. AB - It is known that the number of transplanted cells has a significant impact on the outcome after SCT. We identify issues that cannot be addressed by conventional analysis of clinical trials and ask whether it is possible to develop a refined analysis to conclude about the outcome of individual patients given clinical trial results. To accomplish this, we propose an interdisciplinary approach based on mathematical modeling. We devise and calibrate a mathematical model of short term reconstitution and simulate treatment of large patient groups with random interindividual variation. Relating model simulations to clinical data allows quantifying the effect of transplant size on reconstitution time in the terms of patient populations and individual patients. The model confirms the existence of lower bounds on cell dose necessary for secure and efficient reconstitution but suggests that for some patient subpopulations higher thresholds might be appropriate. Simulations demonstrate that relative time gain because of increased cell dose is an 'interpersonally stable' parameter, in other words that slowly engrafting patients profit more from transplant enlargements than average cases. We propose a simple mathematical formula to approximate the effect of changes of transplant size on reconstitution time. PMID- 24056743 TI - Fludarabine Melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients. AB - This was an Australasian Bone Marrow Transplant Recipient Registry (ABMTRR)-based retrospective study assessing the outcome of Fludarabine Melphalan (FluMel) reduced-intensity conditioning between 1998 and 2008. Median follow-up was 3.4 years. There were 344 patients with a median age of 54 years (18-68). In all, 234 patients had myeloid malignancies, with AML (n=166) being the commonest indication. There were 110 lymphoid patients with non-hodgkins lymphoma (NHL) (n=64) the main indication. TRM at day 100 was 14% with no significant difference between the groups. OS and disease-free survival (DFS) were similar between myeloid and lymphoid patients (57 and 50% at 3 years, respectively). There was no difference in cumulative incidence of relapse or GVHD between groups. Multivariate analysis revealed four significant adverse risk factors for DFS: donor other than HLA-identical sibling donor, not in remission at transplant, previous autologous transplant and recipient CMV positive. Chronic GVHD was associated with improved DFS in multivariate analysis predominantly due to a marked reduction in relapse (HR:0.44, P=0.003). This study confirms that FluMel provides durable and equivalent remissions in both myeloid and lymphoid malignancies. Disease stage and chronic GVHD remain important determinants of outcome for FluMel allografting. PMID- 24056744 TI - A microfluidic device for dry sample preservation in remote settings. AB - This paper describes a microfluidic device for dry preservation of biological specimens at room temperature that incorporates chemical stabilization matrices. Long-term stabilization of samples is crucial for remote medical analysis, biosurveillance, and archiving, but the current paradigm for transporting remotely obtained samples relies on the costly "cold chain" to preserve analytes within biospecimens. We propose an alternative approach that involves the use of microfluidics to preserve samples in the dry state with stabilization matrices, developed by others, that are based on self-preservation chemistries found in nature. We describe a SlipChip-based device that allows minimally trained users to preserve samples with the three simple steps of placing a sample at an inlet, closing a lid, and slipping one layer of the device. The device fills automatically, and a pre-loaded desiccant dries the samples. Later, specimens can be rehydrated and recovered for analysis in a laboratory. This device is portable, compact, and self-contained, so it can be transported and operated by untrained users even in limited-resource settings. Features such as dead-end and sequential filling, combined with a "pumping lid" mechanism, enable precise quantification of the original sample's volume while avoiding overfilling. In addition, we demonstrated that the device can be integrated with a plasma filtration module, and we validated device operations and capabilities by testing the stability of purified RNA solutions. These features and the modularity of this platform (which facilitates integration and simplifies operation) would be applicable to other microfluidic devices beyond this application. We envision that as the field of stabilization matrices develops, microfluidic devices will be useful for cost-effectively facilitating remote analysis and biosurveillance while also opening new opportunities for diagnostics, drug development, and other medical fields. PMID- 24056745 TI - Spirulina platensis and phycocyanobilin activate atheroprotective heme oxygenase 1: a possible implication for atherogenesis. AB - Spirulina platensis, a water blue-green alga, has been associated with potent biological effects, which might have important relevance in atheroprotection. We investigated whether S. platensis or phycocyanobilin (PCB), its tetrapyrrolic chromophore, can activate atheroprotective heme oxygenase-1 (Hmox1), a key enzyme in the heme catabolic pathway responsible for generation of a potent antioxidant bilirubin, in endothelial cells and in a mouse model of atherosclerosis. In vitro experiments were performed on EA.hy926 endothelial cells exposed to extracts of S. platensis or PCB. In vivo studies were performed on ApoE-deficient mice fed a cholesterol diet and S. platensis. The effect of these treatments on Hmox1, as well as other markers of oxidative stress and endothelial dysfunction, was then investigated. Both S. platensis and PCB markedly upregulated Hmox1 in vitro, and a substantial overexpression of Hmox1 was found in aortic atherosclerotic lesions of ApoE-deficient mice fed S. platensis. In addition, S. platensis treatment led to a significant increase in Hmox1 promoter activity in the spleens of Hmox-luc transgenic mice. Furthermore, both S. platensis and PCB were able to modulate important markers of oxidative stress and endothelial dysfunction, such as eNOS, p22 NADPH oxidase subunit, and/or VCAM-1. Both S. platensis and PCB activate atheroprotective HMOX1 in endothelial cells and S. platensis increased the expression of Hmox1 in aortic atherosclerotic lesions in ApoE-deficient mice, and also in Hmox-luc transgenic mice beyond the lipid lowering effect. Therefore, activation of HMOX1 and the heme catabolic pathway may represent an important mechanism of this food supplement for the reduction of atherosclerotic disease. PMID- 24056746 TI - Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. AB - Although intergenic long noncoding RNAs (lincRNAs) have been linked to gene regulation in various tissues, little is known about lincRNA transcriptomes in the T cell lineages. Here we identified 1,524 lincRNA clusters in 42 T cell samples, from early T cell progenitors to terminally differentiated helper T cell subsets. Our analysis revealed highly dynamic and cell-specific expression patterns for lincRNAs during T cell differentiation. These lincRNAs were located in genomic regions enriched for genes that encode proteins with immunoregulatory functions. Many were bound and regulated by the key transcription factors T-bet, GATA-3, STAT4 and STAT6. We found that the lincRNA LincR-Ccr2-5'AS, together with GATA-3, was an essential component of a regulatory circuit in gene expression specific to the TH2 subset of helper T cells and was important for the migration of TH2 cells. PMID- 24056748 TI - Visible light-sensitive APTES-bound ZnO nanowire toward a potent nanoinjector sensing biomolecules in a living cell. AB - Nanoscale cell injection techniques combined with nanoscopic photoluminescence (PL) spectroscopy have been important issues in high-resolution optical biosensing, gene and drug delivery and single-cell endoscopy for medical diagnostics and therapeutics. However, the current nanoinjectors remain limited for optical biosensing and communication at the subwavelength level, requiring an optical probe such as semiconductor quantum dots, separately. Here, we show that waveguided red emission is observed at the tip of a single visible light sensitive APTES-modified ZnO nanowire (APTES-ZnO NW) and it exhibits great enhancement upon interaction with a complementary sequence-based double stranded (ds) DNA, whereas it is not significantly affected by non-complementary ds DNA. Further, the tip of a single APTES-ZnO NW can be inserted into the subcellular region of living HEK 293 cells without significant toxicity, and it can also detect the enhancement of the tip emission from subcellular regions with high spatial resolution. These results indicate that the single APTES-ZnO NW would be useful as a potent nanoinjector which can guide visible light into intracellular compartments of mammalian cells, and can also detect nanoscopic optical signal changes induced by interaction with the subcellular specific target biomolecules without separate optical probes. PMID- 24056749 TI - A fluorogenic probe for beta-galactosidase activity imaging in living cells. AB - A cell permeable fluorescence turn-on probe, AcGQCy7, was developed to image beta galactosidase activity in living cells. Once internalized by beta-galactosidase expressing cells, the probe was hydrolyzed into a highly fluorescent molecule, and the fluorescent signal was retained in mitochondria for several days. This resulted in a long-lasting and strong beta-galactosidase-dependent intracellular fluorescent signal with little background fluorescence in the culture media. PMID- 24056747 TI - The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. AB - During immune responses, T cells are subject to clonal competition, which leads to the predominant expansion of high-affinity clones; however, there is little understanding of how this process is controlled. We found here that the transcription factor IRF4 was induced in a manner dependent on affinity for the T cell antigen receptor (TCR) and acted as a dose-dependent regulator of the metabolic function of activated T cells. IRF4 regulated the expression of key molecules required for the aerobic glycolysis of effector T cells and was essential for the clonal expansion and maintenance of effector function of antigen-specific CD8(+) T cells. Thus, IRF4 is an indispensable molecular 'rheostat' that 'translates' TCR affinity into the appropriate transcriptional programs that link metabolic function with the clonal selection and effector differentiation of T cells. PMID- 24056750 TI - "Willing but unwilling": attitudinal barriers to adoption of home-based health information technology among older adults. AB - While much research focuses on adoption of electronic health-care records and other information technology among health-care providers, less research explores patient attitudes. This qualitative study examines barriers to adoption of home based health information technology, particularly personal electronic health records, among older adults. We conducted in-depth interviews (30-90 min duration) with 35 American adults, aged 46-72 years, to determine their perceptions of and attitudes toward home-based health information technology. Analysis of interview data revealed that most barriers to adoption fell under four themes: technological discomfort, privacy or security concerns, lack of relative advantage, and perceived distance from the user representation. Based on our findings, systems to promote home-based health information technology should incorporate familiar computer applications, alleviate privacy and security concerns, and align with older adults' active and engaged self-image. PMID- 24056751 TI - Family perceptions of the usability and value of chronic disease web-based patient portals. AB - The objective of this study was to understand perceptions of the usability and value of web-based patient portals among parents of children with a chronic condition (diabetes, juvenile idiopathic arthritis, and cystic fibrosis). The design was a cross-sectional telephone survey with semistructured interviews and was conducted at a tertiary children's hospital. Parent ratings of their experiences with and the value of a web-based portal and reasons for not using the portal were ascertained. Most parents agreed that the portal information was accurate, timely, and useful. Confidentiality and seeing worrisome health-related information about their child was not a major concern, and parents felt that the portal helped to improve their understanding of and ability to manage their child's condition. In conclusion, the results of this study support the notion that web-based patient portals have the potential to be a useful tool for parents of children with a chronic disease. PMID- 24056753 TI - Bio-based solvents: an emerging generation of fluids for the design of eco efficient processes in catalysis and organic chemistry. AB - Biomass and waste exhibit great potential for replacing fossil resources in the production of chemicals. The search for alternative reaction media to replace petroleum-based solvents commonly used in chemical processes is an important objective of significant environmental consequence. Recently, bio-based derivatives have been either used entirely as green solvents or utilized as pivotal ingredients for the production of innovative solvents potentially less toxic and more bio-compatible. This review presents the background and classification of these new media and highlights recent advances in their use in various areas including organic synthesis, catalysis, biotransformation and separation. The greenness, advantages and limitations of these solvents are also discussed. PMID- 24056752 TI - Test samples for optimizing STORM super-resolution microscopy. AB - STORM is a recently developed super-resolution microscopy technique with up to 10 times better resolution than standard fluorescence microscopy techniques. However, as the image is acquired in a very different way than normal, by building up an image molecule-by-molecule, there are some significant challenges for users in trying to optimize their image acquisition. In order to aid this process and gain more insight into how STORM works we present the preparation of 3 test samples and the methodology of acquiring and processing STORM super resolution images with typical resolutions of between 30-50 nm. By combining the test samples with the use of the freely available rainSTORM processing software it is possible to obtain a great deal of information about image quality and resolution. Using these metrics it is then possible to optimize the imaging procedure from the optics, to sample preparation, dye choice, buffer conditions, and image acquisition settings. We also show examples of some common problems that result in poor image quality, such as lateral drift, where the sample moves during image acquisition and density related problems resulting in the 'mislocalization' phenomenon. PMID- 24056754 TI - Assessing the relevance of building block crystallinity for tuning the stiffness of gold nanocrystal superlattices. AB - We study the influence of the size and nanocrystallinity of dodecanethiol-coated gold nanocrystals (NCs) on the stiffness of 3D self-assembled NC superlattices (called supracrystals). Using single domain and polycrystalline NCs as building blocks for supracrystals, it is shown that the stiffness of supracrystals can be tuned upon change in relative amounts of single and polycrystalline NCs. PMID- 24056755 TI - HIV: is a vaccine the answer? AB - Getting to zero: zero new HIV infections, zero deaths from AIDS-related illness, zero discrimination is the theme of World AIDS Day 2012. Given the spread of the epidemic today, getting to zero may sound difficult, but significant progress is underway. The total annual loss for the entire country due to HIV is 7% of GDP, which exceeds India's annual health expenditure in 2004. The additional loss due to loss of labor income and increased medical expenditure as measured by the external transfers, account for 5% of the country's health expenditure and 0.23% of GDP. Given that the HIV incidence rate is only 0.27% in India, these losses are quite staggering. Despite the remarkable achievements in development of anti retroviral therapies against HIV and the recent advances in new prevention technologies, the rate of new HIV infections continue to outpace efforts on HIV prevention and control. Thus, the development of a safe and effective vaccine for prevention and control of AIDS remains a global public health priority and the greatest opportunity to eventually end the AIDS pandemic. PMID- 24056756 TI - From formation mechanisms to synthetic methods toward shape-controlled oxide nanoparticles. AB - Metal oxide nanomaterials have been intensively pursued for modern science and nanotechnology. Control over the size and shape of the oxide nanoparticles enables tunability of their unique properties sought for many useful applications. This review presents a comprehensive overview of the recent advances in the shape-controlled synthesis of colloidal oxide nanoparticles. We introduce the size- and shape-dependent properties of the oxide nanoparticles along with their potential applications and subsequent descriptions of the kinetic regime concepts of the formation of the monodisperse nanocolloids. Variations of the experimental conditions including capping molecules, precursor monomer concentration, and reaction temperature/aging have been explored to control the shape of the oxide nanoparticles in wet-chemistry syntheses. The different capping molecule-assisted synthetic methods of the hydro-solvothermal route, the two-phase route, heating-up thermolysis, and reverse micelle are presented as a collection of clear examples of the regular oxide nanoparticles. We also discuss the advantages and obstacles of the synthetic methods that have proven to be controllable and reproducible. The author concludes this review with valuable portraits on working hypotheses for the shape-controlled oxide nanoparticle synthesis. PMID- 24056757 TI - Micromechanics of emergent patterns in plastic flows. AB - Crystalline solids undergo plastic deformation and subsequently flow when subjected to stresses beyond their elastic limit. In nature most crystalline solids exist in polycrystalline form. Simulating plastic flows in polycrystalline solids has wide ranging applications, from material processing to understanding intermittency of earthquake dynamics. Using phase field crystal (PFC) model we show that in sheared polycrystalline solids the atomic displacement field shows spatio-temporal heterogeneity spanning over several orders of length and time scales, similar to that in amorphous solids. The displacement field also exhibits localized quadrupolar patterns, characteristic of two dislocations of the opposite sign approaching each other. This is a signature of crystallinity at microscopic scale. Polycrystals being halfway between single crystals and amorphous solids, in terms of the degree of structural order, descriptions of solid mechanics at two widely different scales, namely continuum plastic flow and discrete dislocation dynamics turns out to be necessary here. PMID- 24056758 TI - Nanoscale structural features determined by AFM for single virus particles. AB - In this work, we propose "single-image analysis", as opposed to multi-image averaging, for extracting valuable information from AFM images of single bio particles. This approach allows us to study molecular systems imaged by AFM under general circumstances without restrictions on their structural forms. As feature exhibition is a resolution correlation, we have performed AFM imaging on surfaces of tobacco mosaic virus (TMV) to demonstrate variations of structural patterns with probing resolution. Two AFM images were acquired with the same tip at different probing resolutions in terms of pixel width, i.e., 1.95 and 0.49 nm per pixel. For assessment, we have constructed an in silico topograph based on the three-dimensional crystal structure of TMV as a reference. The prominent artifacts observed in the AFM-determined shape of TMV were attributed to tip convolutions. The width of TMV rod was systematically overestimated by ~10 nm at both probing resolutions of AFM. Nevertheless, the effects of tip convolution were less severe in vertical orientation so that the estimated height of TMV by AFM imaging was in close agreement with the in silico X-ray topograph. Using dedicated image processing algorithms, we found that at low resolution (i.e., 1.95 nm per pixel), the extracted surface features of TMV can be interpreted as a partial or full helical repeat (three complete turns with ~7.0 nm in length), while individual protein subunits (~2.5 nm) were perceivable only at high resolution. The present study shows that the scales of revealed structural features in AFM images are subject to both probing resolution and processing algorithms for image analysis. PMID- 24056759 TI - Contaminated land: can acute exposure be a significant health risk? Two case studies and associated risk assessment methods. AB - Contaminated land risk assessments generally focus on the chronic health risks, arising from long-term, low-level exposure to the contaminants, and a number of risk assessment tools are in routine use. Situations where significant acute risks might be present are not commonly encountered, and methods for risk assessment are less well established. We present two recent case studies from the northwest of England, the first an area of public open space, and the second an occupied school site, with the associated risk assessments. PMID- 24056760 TI - Intracellular delivery of top-down fabricated tunable nano-plasmonic resonators. AB - Engineered plasmonic structures fabricated using top-down technologies have demonstrated huge enhancements in the optical response of molecules, including Raman scattering. However, providing a sufficient number of such top-down fabricated nanostructures in solution has been a nontrivial task which has limited their potential in intracellular applications. Here we report the development of a protocol for the intracellular delivery of tunable nanoplasmonic resonators fabricated via scalable top-down techniques. This offers excellent possibilities towards the real-time parallel optical detection of intracellular molecular events. PMID- 24056761 TI - Catechin prodrugs and analogs: a new array of chemical entities with improved pharmacological and pharmacokinetic properties. AB - Extensive research on tea catechins, mainly (-)-epigallocatechin gallate, has shown numerous health promoting effects. However, various clinical studies demonstrated several issues associated with tea catechins which account for their poor systemic bioavailability. In order to improve pharmacological activity and bioavailability of natural tea catechins, two major strategies have been adopted to date which include synthesizing catechin analogs/prodrugs and the development of novel drug delivery systems. In this review, we provide a detailed account of novel synthetic analogs/prodrugs as well as novel drug delivery approaches used for natural tea catechins to make them therapeutically potent drug-like molecules. PMID- 24056762 TI - Hepatoprotective function of Penthorum chinense Pursh. AB - This research was to figure out the hepatoprotective constituents of Penthorum chinense Pursh, a typical species both for food and medicine, using carbon tetrachloride-induced chronic hepatotoxicity in HL-7702 cells. Cell viability, levels of microsomal enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and the concentration of malondialdehyde (MDA) were determined in homogenates of the liver cells. Results showed that the cell viability increased significantly in all test groups in a concentration-dependent manner and the content of the peroxidation product MDA decreased significantly, similar to the serum levels of hepatic enzyme biomarkers (ALT and AST). The effects of 70% ethanol extracts and Vc were better than 95% ethanol and water extracts, and the ethyl acetate extracts further obtained from 70% ethanol fraction showed the highest hepatoprotective activity, even better than Vc. The ethyl acetate fraction from 70% ethanol extracts is responsible for the hepatoprotective function of P. chinense. PMID- 24056764 TI - Activation mechanism of claudin-4 by ephrin type-A receptor 2: a molecular dynamics approach. AB - Claudin-4 is a crucial component in the tight junction which is involved in the organization of a cellular barrier. Claudin-4 is found to be up-regulated in various malignancies and is activated by forming a complex with an ephrin A2 receptor. In this computational study, we propose a rational model for the claudin-4-ephrinA2 complex which is in agreement with the experimental result. The complex model has been obtained through protein-protein docking, interface residue scanning, in silico alanine mutations and extensive molecular dynamics simulations. The docking model envisages the important residues present in the first extracellular loop of claudin-4 that plays an active role in protein protein interaction and stability. A 30 nanosecond molecular dynamics simulation of the complex revealed a higher stability by which the number of hydrogen bond interactions increased in the complex interface. Both the molecular dynamics simulations and in silico alanine mutations revealed the involvement of Lys65 (claudin-4) as one of the prime residues in the complex interface that is actively engaged in the binding mechanism with its counterpart. We postulate that the novel hotspot, Lys65 of claudin-4 can be targeted through structure based inhibitor design, which could alter the effect of the claudin-4-ephrinA2 binding mechanism in aggressive metastatic tumors. PMID- 24056763 TI - DNA damage-activated ABL-MyoD signaling contributes to DNA repair in skeletal myoblasts. AB - Previous works have established a unique function of MyoD in the control of muscle gene expression during DNA damage response in myoblasts. Phosphorylation by DNA damage-activated ABL tyrosine kinase transiently inhibits MyoD-dependent activation of transcription in response to genotoxic stress. We show here that ABL-MyoD signaling is also an essential component of the DNA repair machinery in myoblasts exposed to genotoxic stress. DNA damage promoted the recruitment of MyoD to phosphorylated Nbs1 (pNbs1)-containing repair foci, and this effect was abrogated by either ABL knockdown or the ABL kinase inhibitor imatinib. Upon DNA damage, MyoD and pNbs1 were detected on the chromatin to MyoD target genes without activating transcription. DNA damage-mediated tyrosine phosphorylation was required for MyoD recruitment to target genes, as the ABL phosphorylation resistant MyoD mutant (MyoD Y30F) failed to bind the chromatin following DNA damage, while retaining the ability to activate transcription in response to differentiation signals. Moreover, MyoD Y30F exhibited an impaired ability to promote repair in a heterologous system, as compared with MyoD wild type (WT). Consistently, MyoD-null satellite cells (SCs) displayed impaired DNA repair that was rescued by reintroduction of MyoD WT but not by MyoD Y30F. In addition, inhibition of ABL kinase prevented MyoD WT-mediated rescue of DNA repair in MyoD null SCs. These results identify an unprecedented contribution of MyoD to DNA repair and suggest that ABL-MyoD signaling coordinates DNA repair and transcription in myoblasts. PMID- 24056765 TI - How do functionalized carbon nanotubes land on, bind to and pierce through model and plasma membranes. AB - Study of the mechanisms understanding how chemically functionalized carbon nanotubes internalize into mammalian cells is important in view of their design as new tools for therapeutic and diagnostic applications. The initial contact between the nanotube and the cell membrane allows elucidation of the types of interaction that are occurring and the contribution from the types of functional groups at the nanotube surface. Here we offer a combination of experimental and theoretical evidence of the initial phases of interaction between functionalized carbon nanotubes with model and cellular membranes. Both experimental and theoretical data reveal the critical parameters to determine direct translocation of the nanotubes through the membrane into the cytoplasm as a result of three distinct processes that can be summarized as landing, piercing and uptake. PMID- 24056766 TI - Relativistic effects on acidities and basicities of Bronsted acids and bases containing gold. AB - It is usually believed that relativistic effects as described by the Dirac Schrodinger equation (relative to the classical or time-independent Schrodinger equation) are of little importance in chemistry. A closer look, however, reveals that some important and widely known properties (e.g., gold is yellow, mercury is liquid at room temperature) stem from relativistic effects. So far the influence of relativistic effects on the acid-base properties has been mostly ignored. Here we show that at least for compounds of gold such omission is completely erroneous and would lead to too high basicity and too low acidity values with errors in the range of 25-55 kcal mol(-1) (or 20 to 44 powers of ten in pK(a) units) in the gas phase. These findings have important implications for the design of new superstrong acids and bases, and for the understanding of gold-catalysed reactions. PMID- 24056767 TI - Changes in medical treatment and surgery rates in inflammatory bowel disease: a nationwide cohort study 1979-2011. AB - INTRODUCTION: Treatment possibilities have changed in inflammatory bowel disease (IBD). We assessed changes in medical treatment and surgery over time and impact of medications on risk of surgery in a population-based cohort. METHODS: 48 967 individuals were diagnosed with IBD (Crohn's disease (CD), 13 185; ulcerative colitis (UC), 35 782) during 1979-2011. Cumulative probability of receiving 5 aminosalicylic acids (5-ASA), topical, oral corticosteroids, thiopurines, and tumour necrosis factor-alpha (TNF-alpha) blockers, and of first minor or major surgery according to period of diagnosis, was estimated. Medication use and risk of surgery was examined by Cox regression. RESULTS: 5-year cumulative probability of first major surgery decreased from 44.7% in cohort (1979-1986) to 19.6% in cohort (2003-2011) (p < 0.001) for CD, and from 11.7% in cohort (1979-1986) to 7.5% in cohort (2003-2011) (p < 0.001) for UC. Minor surgery risk decreased significantly in CD. From cohort (1995-2002) to cohort (2003-2011), a significant increase in use of thiopurines and TNF-alpha blockers was observed, paralleled by a significant decrease in use of 5-ASA and corticosteroids. Comparing use of azathioprine (or oral corticosteroids) to never-use, no convincing surgery sparing effect was found. Comparing use in 3+ months of a given drug with use <3 months, only 3+ months use of oral corticosteroids reduced the risk of surgery in patients with disease duration of >1 year. CONCLUSIONS: Parallel to an increasing use of thiopurines and TNF-alpha blockers in IBD over time, a persistent significant decrease in surgery rates was observed along with a significant decrease in use of 5-ASA and corticosteroids. However, no convincing surgery sparing effect of newer medications was found. PMID- 24056768 TI - Aintree University Hospital NHS Foundation Trust v James, [2013] EWCA CIV 65. PMID- 24056769 TI - Operation of a benchtop bioreactor. AB - Fermentation systems are used to provide an optimal growth environment for many different types of cell cultures. The ability afforded by fermentors to carefully control temperature, pH, and dissolved oxygen concentrations in particular makes them essential to efficient large scale growth and expression of fermentation products. This video will briefly describe the advantages of the fermentor over the shake flask. It will also identify key components of a typical benchtop fermentation system and give basic instruction on setup of the vessel and calibration of its probes. The viewer will be familiarized with the sterilization process and shown how to inoculate the growth medium in the vessel with culture. Basic concepts of operation, sampling, and harvesting will also be demonstrated. Simple data analysis and system cleanup will also be discussed. PMID- 24056770 TI - AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. AB - In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially worsened in Akt2(-/-) but not in Akt1(-/-) mice as compared to wild-type mice. Specific deletion of Akt2 or its regulator Rictor in podocytes revealed that Akt2 has an intrinsic function in podocytes. Mechanistically, Akt2 triggers a compensatory program that involves mouse double minute 2 homolog (Mdm2), glycogen synthase kinase 3 (Gsk3) and Rac1. The defective activation of this pathway after nephron reduction leads to apoptosis and foot process effacement of the podocytes. We further show that AKT2 activation by mammalian target of rapamycin complex 2 (mTORC2) is also required for podocyte survival in human CKD. More notably, we elucidate the events underlying the adverse renal effect of sirolimus and provide a criterion for the rational use of this drug. Thus, our results disclose a new function of Akt2 and identify a potential therapeutic target for preserving glomerular function in CKD. PMID- 24056771 TI - Cellular immune correlates of protection against symptomatic pandemic influenza. AB - The role of T cells in mediating heterosubtypic protection against natural influenza illness in humans is uncertain. The 2009 H1N1 pandemic (pH1N1) provided a unique natural experiment to determine whether crossreactive cellular immunity limits symptomatic illness in antibody-naive individuals. We followed 342 healthy adults through the UK pandemic waves and correlated the responses of pre-existing T cells to the pH1N1 virus and conserved core protein epitopes with clinical outcomes after incident pH1N1 infection. Higher frequencies of pre-existing T cells to conserved CD8 epitopes were found in individuals who developed less severe illness, with total symptom score having the strongest inverse correlation with the frequency of interferon-gamma (IFN-gamma)(+) interleukin-2 (IL-2)(-) CD8(+) T cells (r = -0.6, P = 0.004). Within this functional CD8(+)IFN-gamma(+)IL 2(-) population, cells with the CD45RA(+) chemokine (C-C) receptor 7 (CCR7)(-) phenotype inversely correlated with symptom score and had lung-homing and cytotoxic potential. In the absence of crossreactive neutralizing antibodies, CD8(+) T cells specific to conserved viral epitopes correlated with crossprotection against symptomatic influenza. This protective immune correlate could guide universal influenza vaccine development. PMID- 24056772 TI - Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor. AB - Endothelial secretion of von Willebrand factor (VWF) from intracellular organelles known as Weibel-Palade bodies (WPBs) is required for platelet adhesion to the injured vessel wall. Here we demonstrate that WPBs are often found near or within autophagosomes and that endothelial autophagosomes contain abundant VWF protein. Pharmacological inhibitors of autophagy or knockdown of the essential autophagy genes Atg5 or Atg7 inhibits the in vitro secretion of VWF. Furthermore, although mice with endothelial-specific deletion of Atg7 have normal vessel architecture and capillary density, they exhibit impaired epinephrine-stimulated VWF release, reduced levels of high-molecular weight VWF multimers and a corresponding prolongation of bleeding times. Endothelial-specific deletion of Atg5 or pharmacological inhibition of autophagic flux results in a similar in vivo alteration of hemostasis. Thus, autophagy regulates endothelial VWF secretion, and transient pharmacological inhibition of autophagic flux may be a useful strategy to prevent thrombotic events. PMID- 24056774 TI - Single-crystalline metal germanate nanowire-carbon textiles as binder-free, self supported anodes for high-performance lithium storage. AB - Single-crystalline metal germanate nanowires, including SrGe4O9, BaGe4O9, and Zn2GeO4 were successfully grown on carbon textile via a simple low-cost hydrothermal method on a large scale. The as-grown germanate nanowires-carbon textiles were directly used as binder-free anodes for lithium-ion batteries, which exhibited highly reversible capacity in the range of 900-1000 mA h g(-1) at 400 mA g(-1), good cyclability (no obvious capacity decay even after 100 cycles), and excellent rate capability with a capacity of as high as 300 mA h g(-1) even at 5 A g(-1). Such excellent electrochemical performance can be ascribed to the three-dimensional interconnected conductive channels composed of the flexible carbon microfibers, which not only serve as the current collector but also buffer the volume change of the active material upon cycling. Additionally, the one dimensional nanostructures grown directly on the carbon microfibers also ensure fast charge carrier (e(-) and Li(+)) transport, large surface areas, better permeabilities, and more active sites, which also contributed to the improved electrochemical performance. PMID- 24056773 TI - CSF-1R inhibition alters macrophage polarization and blocks glioma progression. AB - Glioblastoma multiforme (GBM) comprises several molecular subtypes, including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs). Macrophages depend on colony stimulating factor-1 (CSF-1) for differentiation and survival. We used an inhibitor of the CSF-1 receptor (CSF-1R) to target TAMs in a mouse proneural GBM model, which significantly increased survival and regressed established tumors. CSF-1R blockade additionally slowed intracranial growth of patient-derived glioma xenografts. Surprisingly, TAMs were not depleted in treated mice. Instead, glioma secreted factors, including granulocyte-macrophage CSF (GM-CSF) and interferon gamma (IFN-gamma), facilitated TAM survival in the context of CSF-1R inhibition. Expression of alternatively activated M2 markers decreased in surviving TAMs, which is consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in patients with proneural GBM. Our results identify TAMs as a promising therapeutic target for proneural gliomas and establish the translational potential of CSF-1R inhibition for GBM. PMID- 24056775 TI - Gold nanoparticles functionalized with a fragment of the neural cell adhesion molecule L1 stimulate L1-mediated functions. AB - The neural cell adhesion molecule L1 is involved in nervous system development and promotes regeneration in animal models of acute and chronic injury of the adult nervous system. To translate these conducive functions into therapeutic approaches, a 22-mer peptide that encompasses a minimal and functional L1 sequence of the third fibronectin type III domain of murine L1 was identified and conjugated to gold nanoparticles (AuNPs) to obtain constructs that interact homophilically with the extracellular domain of L1 and trigger the cognate beneficial L1-mediated functions. Covalent conjugation was achieved by reacting mixtures of two cysteine-terminated forms of this L1 peptide and thiolated poly(ethylene) glycol (PEG) ligands (~2.1 kDa) with citrate stabilized AuNPs of two different sizes (~14 and 40 nm in diameter). By varying the ratio of the L1 peptide-PEG mixtures, an optimized layer composition was achieved that resulted in the expected homophilic interaction of the AuNPs. These AuNPs were stable as tested over a time period of 30 days in artificial cerebrospinal fluid and interacted with the extracellular domain of L1 on neurons and Schwann cells, as could be shown by using cells from wild-type and L1-deficient mice. In vitro, the L1-derivatized particles promoted neurite outgrowth and survival of neurons from the central and peripheral nervous system and stimulated Schwann cell process formation and proliferation. These observations raise the hope that, in combination with other therapeutic approaches, L1 peptide-functionalized AuNPs may become a useful tool to ameliorate the deficits resulting from acute and chronic injuries of the mammalian nervous system. PMID- 24056776 TI - Partial characterization, in vitro antioxidant and antiproliferative activities of patatin purified from potato fruit juice. AB - Patatin from potato fruit juice was purified by a combination of ultrafiltration and chromatographic techniques. The in vitro antioxidant and antiproliferative activity against mouse melanoma B16 cells of patatin were investigated. The results showed that the monosaccharide composition of patatin included rhamnose, mannose, glucose, and galactose with a molar ratio of 41 : 30 : 21 : 8, and patatin consisted of (1 -> 3) linked alpha-mannose, (1 -> 4) linked alpha galactose, (1 -> 4) linked beta-glucose, and (1 -> 2) linked alpha-rhamnose. Furthermore, patatin possessed significant antioxidant activities measured by scavenging of the DPPH and superoxide free radicals, notable reducing power, protective effects against hydroxyl radical-induced oxidative DNA damage and lipid peroxidation inhibitory. Moreover, patatin was identified as a potent antiproliferative agent against mouse melanoma B16 cells, causing cell cycle arrest in the G1 phase. Assays of apoptotic cells also showed that patatin treatment at concentrations of 20 mg mL(-1) resulted in a marked reduction of viable cells. These results obtained in in vitro models suggested that patatin may have potential application as a cancer chemopreventive agent and food ingredient. PMID- 24056777 TI - Distinguishing sources of HIV transmission from the distribution of newly acquired HIV infections: why is it important for HIV prevention planning? AB - OBJECTIVE: The term 'source of HIV infections' has been referred to as the source of HIV transmission. It has also been interpreted as the distribution of newly acquired HIV infections across subgroups. We illustrate the importance of distinguishing the two interpretations for HIV prevention planning. METHODS: We used a dynamical model of heterosexual HIV transmission to simulate three HIV epidemics, and estimated the sources of HIV transmission (cumulative population attributable fraction) and the single-year distribution of new HIV infections. We focused an intervention guided by the largest transmission source versus the largest single-year distribution of new HIV infections, and compared the fraction of discounted HIV infections averted over 30 years. RESULTS: The single-year distribution of newly acquired HIV infections underestimated the source of HIV transmission in the long term, when the source was unprotected sex in high-risk groups. Under equivalent and finite resources, an intervention strategy directed by the long-term transmission source was shown to achieve a greater impact than a distribution-directed strategy, particularly in the long term. CONCLUSIONS: Impact of HIV prevention strategies may vary depending on whether they are directed by the long-term transmission source or by the distribution of new HIV infections. Caution is required when interpreting the 'source of HIV infections' to avoid misusing the distribution of new HIV infections in HIV prevention planning. PMID- 24056778 TI - Highly stable monodisperse PEGylated iron oxide nanoparticle aqueous suspensions: a nontoxic tracer for homogeneous magnetic bioassays. AB - Uniformly sized and shaped iron oxide nanoparticles with a mean size of 25 nm were synthesized via decomposition of iron-oleate. High resolution transmission electron microscopy and Mossbauer spectroscopy investigations revealed that the particles are spheres primarily composed of Fe3O4 with a small fraction of FeO. From Mossbauer and static magnetization measurements, it was deduced that the particles are superparamagnetic at room temperature. The hydrophobic particles were successfully transferred into water via PEGylation using nitrodopamine as an anchoring group. IR spectroscopy and thermogravimetric analysis showed the success and efficiency of the phase transfer reaction. After PEGylation, the particles retained monodispersity and their magnetic core remained intact as proven by photon cross-correlation spectroscopy, ac susceptibility, and transmission electron microscopy. The particle aqueous suspensions revealed excellent water stability over a month of monitoring and also against temperature up to 40 degrees C. The particles exhibited a moderate cytotoxic effect on in vitro cultured bone marrow-derived macrophages and no release of inflammatory or anti-inflammatory cytokines. The PEGylated particles were functionalized with Herceptin antibodies via a conjugation chemistry, their response to a rotating magnetic field was studied using a fluxgate-based setup and was compared with the one recorded for hydrophobic and PEGylated particles. The particle phase lag rose after labeling with Herceptin, indicating the successful conjugation of Herceptin antibodies to the particles. PMID- 24056779 TI - The chromium in timberline forests in the eastern Tibetan Plateau. AB - In order to study the regional distribution, trait and possible source of chromium in the eastern Tibetan Plateau, we collected samples of xylem, bark, leaves and twigs in two parallel northwest-southeast belt transects (TA and TB) from the Hengduan Mountains. According to the Cr mean concentration, organ/tissue was split into two groups: the high-level organ/tissue (twigs: 1.476 mg kg(-1)) and the low-level organ/tissue (bark: 0.413 mg kg(-1), leaves: 0.340 mg kg(-1) and xylem: 0.194 mg kg(-1)). The mean Cr concentrations of twigs and leaves in TB samples were higher than those in the TA samples, and the mean Cr concentration in both sites gradually reduced from southeast to northwest. Both the southeasterly and southwesterly monsoons could be significant, influential factors in this connection. The top three mean Cr concentrations were S7, S1 and S8, which were closer to the developed city. Mean Cr concentrations in S3, S4 and S5, (remote, high mountains) were relatively low. The high mountains acting as a barrier to the monsoon and the distance from the big city may play important roles in the distribution of Chromium. Furthermore, the relationship between the mean Cr concentration and precipitation, timberline trees as bio-monitors of chromium pollution in polluted areas and the possible source of Cr in the eastern Tibetan Plateau are also discussed. This study may provide reliable proof of Cr contamination processes, and so help in future to prevent further Cr pollution, and also be helpful in understanding the important function of forest ecosystems in relation to atmospheric pollution and global change. To better understand the characteristics of temporal and spatial distribution of Cr concentration, we found that tree ring, fine roots and soil samples are good choices. PMID- 24056780 TI - Oxygen electrocatalysts in metal-air batteries: from aqueous to nonaqueous electrolytes. AB - With the development of renewable energy and electrified transportation, electrochemical energy storage will be more important in the future than it has ever been in the past. Although lithium-ion batteries (LIBs) are traditionally considered to be the most likeliest candidate thanks to their relatively long cycle life and high energy efficiency, their limited energy density as well as cost are still causing a bottleneck for their long-term application. Alternatively, metal-air batteries have been proposed as a very promising large scale electricity storage technology with the replacement of the intercalation reaction mechanism by the catalytic redox reaction of a light weight metal-oxygen couple. Generally, based on the electrolyte, these metal-air batteries can be divided into aqueous and nonaqueous systems, corresponding to two typical batteries of Zn-air and Li-air, respectively. The prominent feature of both batteries are their extremely high theoretical energy density, especially for nonaqueous Li-air batteries, which far exceeds the best that can be achieved with LIBs. In this review, we focus on the major obstacle of sluggish kinetics of the cathode in both batteries, and summarize the fundamentals and recent advances related to the oxygen catalyst materials. According to the electrolyte, the aqueous and nonaqueous electrocatalytic mechanisms of the oxygen reduction and evolution reactions are discussed. Subsequently, seven groups of oxygen catalysts, which have played catalytic roles in both systems, are selectively reviewed, including transition metal oxides (single-metal oxides and mixed-metal oxides), functional carbon materials (nanostructured carbons and doped carbons), metal oxide-nanocarbon hybrid materials, metal-nitrogen complexes (non-pyrolyzed and pyrolyzed), transition metal nitrides, conductive polymers, and precious metals (alloys). Nonaqueous systems have the advantages of energy density and rechargeability over aqueous systems and have gradually become the research focus of metal-air batteries. However, there are considerable challenges beyond catalysts from aqueous to nonaqueous electrolytes, which are also discussed in this review. Finally, several future research directions are proposed based on the results achieved in this field, with emphasis on nonaqueous Li-air batteries. PMID- 24056781 TI - Crawling of effector T cells on extracellular matrix: role of integrins in interstitial migration in inflamed tissues. PMID- 24056782 TI - Transcriptional remodelling in response to changing copper levels in the Wilson and Menkes disease model of Saccharomyces cerevisiae. AB - A high degree of conservation of the copper homeostasis pathway between yeast and humans makes yeast an ideal model organism for studying copper-related disorders. In this study, a system based integrative approach was used to investigate the genome-wide effects of the deletion of the yeast ortholog of Wilson and Menkes diseases encoding a Cu(2+)-transporting P-type ATPase (CCC2) in different copper containing media and to compare with the wild type. The experimental design applied in this study enabled the observation of the effect of CCC2 deletion, extracellular copper levels and interactive effects of both factors in S. cerevisiae cells. The integrative analysis of the transcriptome with the interactome and regulome further elucidated the pathways affected by the disturbance of copper homeostasis. The results demonstrated that iron homeostasis is disturbed in the absence of CCC2 under copper deficient conditions and also revealed the importance of this gene in the maintenance of iron homeostasis under high copper conditions. NAD(+) metabolism was observed to be affected both by the deletion of CCC2 and the level of bio-available extracellular copper. The regulation of glucose transporters was also affected in the absence of CCC2 and a starvation-like response was observed in a copper level dependent manner. Alterations in the amino acid metabolism and specifically in the arginine metabolic process observed at the transcriptional level provided further support through the integration of the metabolomic data. This study also highlighted pyridoxine deficiency caused by the absence of CCC2. The observation of the improvement in the respiratory capacity of CCC2 deleted cells by supplementation with pyridoxine as well as with nicotinic acid may shed light on novel therapeutic interventions for Wilson and Menkes diseases. PMID- 24056783 TI - A negative feedback of the HIF-1alpha pathway via interferon-stimulated gene 15 and ISGylation. AB - PURPOSE: The IFN-stimulated gene 15 (ISG15)- and ubiquitin-conjugation pathways play roles in mediating hypoxic and inflammatory responses. To identify interaction(s) between these two tumor microenvironments, we investigated the effect of ISG15 on the activity of the master hypoxic transcription factor HIF 1alpha. EXPERIMENTAL DESIGN: IFN and desferoxamine treatments were used to induce the expression of ISGs and HIF-1alpha, respectively. Interactions between HIF 1alpha and the ISG15 and ISGylation system were studied using knockdown of mRNA expression, immunoblotting, coimmunoprecipitation, and pull-down analyses. Effects of the ISG15 and ISGylation system on the HIF-1alpha-directed processes were examined using reporter, reverse transcription polymerase chain reaction (RT PCR), and tumorigenic growth assays. RESULTS: We found that the level of the free form of HIF-1alpha is differentially regulated by IFN treatment, and that the free ISG15 level is lower under hypoxia. Mechanism-directed studies have shown that HIF-1alpha not only interacts physically with ISG15, but is also ISGylated in multiple domains. ISG15 expression disrupts the functional dimerization of HIF 1alpha and -1beta. Subsequently, expression of the ISG15 and/or ISGylation system attenuates HIF-1alpha-mediated gene expression and tumorigenic growth. CONCLUSION: In summary, our results revealed cross-talk between inflammatory and hypoxic pathways through the ISGylation of HIF-1alpha. On the basis of these results, we propose a novel negative feedback loop for the HIF-1alpha-mediated pathway involving the regulation of HIF-1alpha via IFN-induced ISGylation. PMID- 24056784 TI - Margin-infiltrating CD20(+) B cells display an atypical memory phenotype and correlate with favorable prognosis in hepatocellular carcinoma. AB - PURPOSE: The role of infiltrating B cells in hepatocellular carcinoma has been overlooked for many years. This study is aimed to delineate the distribution, prognostic value, and functional status of B cells in human hepatocellular carcinoma. EXPERIMENTAL DESIGN: Immunohistochemistry was used to investigate the distribution and clinical significance of infiltrating CD20(+) B cells in a series of 120 patients with hepatocellular carcinoma. The results were further tested in an independent series of 200 patients with hepatocellular carcinoma. The functional status of CD20(+) B cells was determined by flow cytometry, immunofluorescence, and in vitro coculture assay. RESULTS: Infiltrating CD20(+) B cells were predominantly concentrated in the tumor invasive margin, compared with the peri- and intratumor areas. High density of margin-infiltrating B lymphocytes (MIL-B) positively correlated with small tumor size, absence of vascular invasion, and increased density of CD8(+) T cells (P < 0.05). Survival analyses revealed that increased number of MIL-Bs and their penetration through the tumor capsule were significantly associated with improved overall and recurrence-free survival, and were identified as independent prognosticators for patients with hepatocellular carcinoma (P < 0.05). Importantly, the results were further validated in another independent hepatocellular carcinoma cohort. Moreover, we found that MIL-Bs featured an atypical memory phenotype (IgD(-)IgG(+)CD27(-)CD38( )), expressed surface markers characteristic of antigen-presenting cells, possessed tumor-killing potential by producing IFN-gamma, interleukin 12p40 (IL 12p40), granzyme B, and TRAIL, and acted in cooperation with CD8(+) T cells. CONCLUSIONS: The profile of CD20(+) B cells in situ is a new predictor of prognosis for patients with hepatocellular carcinoma and provides a novel target for an optimal immunotherapy against this fatal malignancy. PMID- 24056785 TI - Evaluation of utility of pharmacokinetic studies in phase I trials of two oncology drugs. AB - PURPOSE: There are many phase I trials of oncology drug combinations, very few of which report clinically significant pharmacokinetic interactions. We hypothesized that the utility of such pharmacokinetic drug-drug interaction (DDI) studies is low in the absence of a mechanistic hypothesis. EXPERIMENTAL DESIGN: We retrospectively reviewed 152 phase I (two drug) combination studies published between 2007 and 2011. RESULTS: Only 28 (18%) studies had an implicit or explicit rationale, either inhibition/induction of a drug-metabolizing enzyme or transporter, cosubstrates for the same enzyme or transporter, potential for end organ toxicity, or protein binding. Only 12 (8%) studies demonstrated a statistically significant DDI, on the basis of change in clearance (or area under the curve) of parent drug and/or active metabolite. There was a strong association between a rationale and a demonstrable drug interaction, as only 2% of studies without a rationale demonstrated a DDI, compared with 32% of studies with a rationale (Fisher exact test; P < 10(-6)). CONCLUSION: DDI studies should not be routinely performed as part of phase I trials of oncology combinations. PMID- 24056787 TI - Technology comes to the playing field: new world of sports promises fewer injuries, better performance. PMID- 24056788 TI - Making sports safer for kids: using biomechanical devices to prevent injuries. PMID- 24056786 TI - DNA demethylating agents synergize with oncolytic HSV1 against malignant gliomas. AB - PURPOSE: Oncolytic viruses (OV) based on herpes simplex virus type 1 (HSV1) are being used in clinical trials for a variety of cancers. The OV, rQNestin34.5, uses a nestin promoter/enhancer to selectively drive robust viral replication in malignant glioma cells. We have discovered that this promoter becomes extensively methylated in infected glioma cells, reducing OV efficacy. EXPERIMENTAL DESIGN: We used demethylating drugs [5-azacytidine (5-Aza)], decitabine, or valproic acid (VPA) in both in vitro and in vivo malignant glioma models to determine if they improved the efficacy of rQNestin34.5 therapy. RESULTS: The use of demethylating agents, such as 5-Aza, improved OV replication and tumor cell lysis in vitro and, in fact, synergized pharmacologically on Chou-Talalay analysis. In vivo, the combination of the demethylating agents, 5-Aza or decitabine, with rQNestin34.5 significantly prolonged the survivorship of athymic mice harboring intracranial human glioma xenografts over single agent alone. CONCLUSION: These results, thus, provide further justification for the exploration of demethylating agents when combined with the OV, rQNestin34.5, in preclinical therapeutics and, possibly, clinical trials for malignant glioma. PMID- 24056789 TI - Moving the science of behavior change into the 21st century: novel solutions to prevent disease and promote health. PMID- 24056790 TI - Moving behavioral theories into the 21st century: technological advancements for improving quality of life. PMID- 24056791 TI - Realizing effective behavioral management of health: the metamorphosis of behavioral science methods. PMID- 24056792 TI - Frozen cells and bits: cryoelectronics advances biopreservation. PMID- 24056793 TI - A clinical roadmap for brain--neural machine interfaces: trainees' perspectives on the 2013 International Workshop. PMID- 24056794 TI - The IEEE EPICS initiative unveiled. PMID- 24056796 TI - A theoretical model for metal-graphene contact resistance using a DFT-NEGF method. AB - The contact resistance (R(c)) between graphene and metal electrodes is of crucial importance for achieving potentially high performances for graphene devices. However, previous analytical models based on Landauer's approach have failed to include the Fermi velocity difference between the graphene under the metal and the pure graphene channel. Hereby we report a theoretical model to estimate the R(c) using density-functional theory and non-equilibrium Green's function methods. Our model not only presents a clear physical picture of the metal graphene contacts, but also generates R(c) values which are in good agreement with the experimental results: 210 Omega MUm for double-sided Pd contacts compared with 403 Omega MUm for single-sided Pd contact. PMID- 24056795 TI - Synthesis of nanostructured materials in inverse miniemulsions and their applications. AB - Polymeric nanogels, inorganic nanoparticles, and organic-inorganic hybrid nanoparticles can be prepared via the inverse miniemulsion technique. Hydrophilic functional cargos, such as proteins, DNA, and macromolecular fluoresceins, may be conveniently encapsulated in these nanostructured materials. In this review, the progress of inverse miniemulsions since 2000 is summarized on the basis of the types of reactions carried out in inverse miniemulsions, including conventional free radical polymerization, controlled/living radical polymerization, polycondensation, polyaddition, anionic polymerization, catalytic oxidation reaction, sol-gel process, and precipitation reaction of inorganic precursors. In addition, the applications of the nanostructured materials synthesized in inverse miniemulsions are also reviewed. PMID- 24056797 TI - Mucocutaneous Disorders of Pediatric HIV in South West Nigeria: Surrogates for Immunologic and Virologic Indices. AB - OBJECTIVES: Nigeria has the world's highest burden of pediatric HIV. In the face of paucity of monitoring tests in Nigeria, we studied the spectrum of pediatric mucocutaneous manifestations and evaluated their clinical utility as surrogate markers for immunodeficiency and plasma viral load levels. METHODS: Cross sectional study comparing mucocutaneous manifestations in 155 HIV-positive children aged 12 weeks to 14 years with 155 HIV-negative children. Relationships between mucocutaneous manifestations in HIV-infected patients and their immunologic and virologic indices were analyzed. RESULTS: Mucocutaneous lesions were seen in 53.5% of HIV-infected children compared with 18.1% of the controls. Prevalence of lesions increased with worsening levels of immunodeficiency and increasing viral loads (P < .01). Oral candidiasis, angular stomatitis, and fluffy hair were associated with more severe degrees of immunodeficiency. CONCLUSION: Mucocutaneous disorders are common in HIV-infected children. Oral candidiasis and nutritional dermatoses can be used as surrogates for advanced or severe immunodeficiency. PMID- 24056798 TI - Coinfection with hepatitis C virus among HIV-positive people in the Kathmandu Valley, Nepal. AB - BACKGROUND: Previous research has studied the rate of hepatitis C virus (HCV) coinfection among HIV-positive people regardless of their antiretroviral therapy (ART) status. Our objectives were to measure the seroprevalence of HCV both in HIV-positive people receiving ART and in those not receiving ART and to describe the characteristics of coinfected people in the Kathmandu Valley, Nepal. METHODS: We conducted a cross-sectional survey of 319 HIV-positive people residing in the Kathmandu Valley, Nepal. We screened the participants' serum samples for HCV antibodies using the Latex Photometric Immunoassay based on third-generation assay. RESULTS: A total of 138 (43.3%) participants were HCV positive. The prevalence of HCV coinfection was 96.2% (125 of 130) among participants with lifetime injection drug use (IDU). Among participants not receiving ART, the coinfection rate was 58.1% (50 of 86) compared with 37.8% (88 of 233) among those receiving ART. In multivariable analysis, participants who reported lifetime IDU and were current smokers were more likely to have HCV coinfection. The adjusted odds ratio (AOR) of HCV coinfection for ART was decreased, although it was not statistically significant (AOR = 0.45; 95% confidence interval = 0.13-1.48). CONCLUSION: The high prevalence of HCV coinfection among both individuals receiving ART and those not receiving ART suggests that screening for HCV among HIV-positive people would be useful, in particular, for those with lifetime IDU and soon after their HIV diagnosis. PMID- 24056799 TI - Using theater of the oppressed to prevent sexual violence on college campuses. AB - Using theater of the oppressed as a practice method in sexual assault prevention interventions with college students is gaining in popularity. Theater of the oppressed interventions aims to change values and norms that perpetuate the acceptability of sexual assault and teach college students how to intervene in situations where sexual violence may occur. In this review, the author reviews the literature on using theater for social change as a prevention intervention. The aim of the article is to provide a synthesis of empirical studies investigating the effects and impact of using theater for social change in prevention education. Based upon this synthesis, implications for practice, policy, and research are provided. PMID- 24056800 TI - A totally phosphine-free synthesis of metal telluride nanocrystals by employing alkylamides to replace alkylphosphines for preparing highly reactive tellurium precursors. AB - Despite the developments in the wet chemical synthesis of high-quality semiconductor nanocrystals (NCs) with diverse elemental compositions, telluride NCs are still irreplaceable materials owing to their excellent photovoltaic and thermoelectric performances. Herein we demonstrate the dissolution of elemental tellurium (Te) in a series of alkylamides by sodium borohydride (NaBH4) reduction at relatively low temperature to produce highly reactive precursors for hot injection synthesis of telluride NCs. The capability to tune the reactivity of Te precursors by selecting injection temperature permits control of NC size over a broad range. The current preparation of Te precursors is simple, economical, and totally phosphine-free, which will promote the commercial synthesis and applications of telluride NCs. PMID- 24056801 TI - Genetically-encoded molecular probes to study G protein-coupled receptors. AB - To facilitate structural and dynamic studies of G protein-coupled receptor (GPCR) signaling complexes, new approaches are required to introduce informative probes or labels into expressed receptors that do not perturb receptor function. We used amber codon suppression technology to genetically-encode the unnatural amino acid, p-azido-L-phenylalanine (azF) at various targeted positions in GPCRs heterologously expressed in mammalian cells. The versatility of the azido group is illustrated here in different applications to study GPCRs in their native cellular environment or under detergent solubilized conditions. First, we demonstrate a cell-based targeted photocrosslinking technology to identify the residues in the ligand-binding pocket of GPCR where a tritium-labeled small molecule ligand is crosslinked to a genetically-encoded azido amino acid. We then demonstrate site-specific modification of GPCRs by the bioorthogonal Staudinger Bertozzi ligation reaction that targets the azido group using phosphine derivatives. We discuss a general strategy for targeted peptide-epitope tagging of expressed membrane proteins in-culture and its detection using a whole-cell based ELISA approach. Finally, we show that azF-GPCRs can be selectively tagged with fluorescent probes. The methodologies discussed are general, in that they can in principle be applied to any amino acid position in any expressed GPCR to interrogate active signaling complexes. PMID- 24056802 TI - Hypericin-loaded lipid nanocapsules for photodynamic cancer therapy in vitro. AB - Hypericin (Hy), a naturally occurring photosensitizer (PS), is extracted from Hypericum perforatum plants, commonly known as St. John's wort. The discovery of the in vitro and in vivo photodynamic activities of hypericin as a photosensitizer generated great interest, mainly to induce a very potent antitumoral effect. However, this compound belongs to the family of naphthodianthrones which are known to be poorly soluble in physiological solutions and produce non-fluorescent aggregates (A. Wirz et al., Pharmazie, 2002, 57, 543; A. Kubin et al., Pharmazie, 2008, 63, 263). These phenomena can reduce its efficiency as a photosensitizer for the clinical application. In the present contribution, we have prepared, characterized, and studied the photochemical properties of Hy-loaded lipid nanocapsule (LNC) formulations. The amount of singlet oxygen ((1)O2) generated was measured by the use of p-nitroso dimethylaniline (RNO) as a selective scavenger under visible light irradiation. Our results showed that Hy-loaded LNCs suppressed aggregation of Hy in aqueous media, increased its apparent solubility, and enhanced the production of singlet oxygen in comparison with free drug. Indeed, encapsulation of Hy in LNCs led to an increase of (1)O2 quantum yield to 0.29-0.44, as compared to 0.02 reported for free Hy in water. Additionally, we studied the photodynamic activity of Hy-loaded LNCs on human cervical carcinoma (HeLa) and Human Embryonic Kidney (HEK) cells. The cell viability decreased radically to 10-20% at 1 MUM, reflecting Hy-loaded LNC25 phototoxicity. PMID- 24056803 TI - Structural transitions: 'Ferroelectricity' in a metal. PMID- 24056804 TI - Thermopower enhancement by encapsulating cerium in clathrate cages. AB - The increasing worldwide energy consumption calls for the design of more efficient energy systems. Thermoelectrics could be used to convert waste heat back to useful electric energy if only more efficient materials were available. The ideal thermoelectric material combines high electrical conductivity and thermopower with low thermal conductivity. In this regard, the intermetallic type I clathrates show promise with their exceedingly low lattice thermal conductivities. Here we report the successful incorporation of cerium as a guest atom into the clathrate crystal structure. In many simpler intermetallic compounds, this rare earth element is known to lead, through the Kondo interaction, to strong correlation phenomena including the occurrence of giant thermopowers at low temperatures. Indeed, we observe a 50% enhancement of the thermopower compared with a rare-earth-free reference material. Importantly, this enhancement occurs at high temperatures and we suggest that a rattling-enhanced Kondo interaction underlies this effect. PMID- 24056805 TI - A ferroelectric-like structural transition in a metal. AB - Metals cannot exhibit ferroelectricity because static internal electric fields are screened by conduction electrons, but in 1965, Anderson and Blount predicted the possibility of a ferroelectric metal, in which a ferroelectric-like structural transition occurs in the metallic state. Up to now, no clear example of such a material has been identified. Here we report on a centrosymmetric (R3c) to non-centrosymmetric (R3c) transition in metallic LiOsO3 that is structurally equivalent to the ferroelectric transition of LiNbO3 (ref. 3). The transition involves a continuous shift in the mean position of Li(+) ions on cooling below 140 K. Its discovery realizes the scenario described in ref. 2, and establishes a new class of materials whose properties may differ from those of normal metals. PMID- 24056806 TI - Olive oil/policosanol organogels for nutraceutical and drug delivery purposes. AB - Low molecular weight organogels are semisolid systems structured by the assembly of molecules that crystallise under suitable process conditions. The inner microstructure of organogels is made up of a 3-D network, in which both an organic liquid solvent and other dispersed particles can be entrapped. In this work, olive oil organogels, structured from policosanol (a nutraceutical mixture of fatty alcohols), were studied in order to obtain the best formulation for producing a support for delivery of lipophilic agents (namely ferulic Acid) via oral administration. A rheological optimisation of the olive oil-policosanol organogel was first of all performed with Step Shear Rate Temperature Ramp tests. This provided important information on the policosanol fraction to be added to the system and on the onset of crystallisation temperature, an indirect measurement of the system melting point. It was found that a policosanol weight percentage of 0.03 was suitable to obtain contemporary semisolid organogels, consistent enough and thermally stable for human ingestion. In vitro tests on organogels loaded with ferulic acid were also carried out in order to simulate the oral intake of the nutraceutical compound. This evidenced a release mechanism determined by both erosion and diffusion; a good performance of gels and their ability to control the release rate through the degree of structuration were also observed. PMID- 24056807 TI - Zebrafish as a model for Vibrio parahaemolyticus virulence. AB - Vibrio parahaemolyticus is a Gram-negative, naturally occurring marine bacterium. Subpopulations of strains belonging to this species cause an acute self-limiting gastroenteritis in humans and, less commonly, wound infections. In vivo models to differentiate avirulent and virulent strains and evaluate the pathogenic potential of strains of this species have been largely focused on the presence of known virulence factors such as the thermostable direct haemolysin (TDH), the TDH related haemolysin (TRH) or the contributions of the type 3 secretion systems. However, virulence is likely to be multifactorial, and additional, yet to be identified factors probably contribute to virulence in this bacterium. In this study, we investigated an adult zebrafish model to assess the overall virulence of V. parahaemolyticus strains. The model could detect differences in the virulence potential of strains when animals were challenged intraperitoneally, based on survival time. Differences in survival were noted irrespective of the source of isolation of the strain (environmental or clinical) and regardless of the presence or absence of the known virulence factors TDH and TRH, suggesting the influence of additional virulence factors. The model was also effective in comparing differences in virulence between the wild-type V. parahaemolyticus strain RIMD2210633 and isogenic pilin mutants DeltapilA and DeltamshA, a double mutant DeltapilA : DeltamshA, as well as a putative chitin-binding protein mutant, DeltagbpA. PMID- 24056808 TI - Transparent, conductive, and SERS-active Au nanofiber films assembled on an amphiphilic peptide template. AB - The use of biological materials as templates for functional molecular assemblies is an active research field at the interface between chemistry, biology, and materials science. We demonstrate the formation of gold nanofiber films on beta sheet peptide domains assembled at the air/water interface. The gold deposition scheme employed a recently discovered chemical process involving spontaneous crystallization and reduction of water-soluble Au(SCN)4(1-) upon anchoring to surface-displayed amine moieties. Here we show that an interlinked network of crystalline Au nanofibers is readily formed upon incubation of the Au(iii) thiocyanate complex with the peptide monolayers. Intriguingly, the resultant films were optically transparent, enabled electrical conductivity, and displayed pronounced surface enhanced Raman spectroscopy (SERS) activity, making the approach a promising avenue for construction of nano-structured films exhibiting practical applications. PMID- 24056809 TI - Release of TiO2 from paints containing pigment-TiO2 or nano-TiO2 by weathering. AB - The release of nanomaterials from products and applications that are used by industry and consumers has only been studied to a very limited extent. The amount and the characteristics of the released particles determine the potential environmental exposure. In this work we investigated the release of Ti from paints containing pigment-TiO2 and nano-TiO2. Panels covered with paint with and without nano-TiO2 were exposed to simulated weathering by sunlight and rain in climate chambers. The same paints were also studied in small-scale leaching tests to elucidate the influence of various parameters on the release such as composition of water, type of support and UV-light. Under all conditions we only observed a very low release close to background values, less than 1.5 MUg l(-1) in the climate chamber over 113 irrigations per drying cycle and between 0.5 and 14 MUg l(-1) in the leaching tests, with the highest concentrations observed after prolonged UV-exposure. The actual release of Ti over the 113 weathering cycles was only 0.007% of the total Ti, indicating that TiO2 was strongly bound in the paint. Extraction of UV-exposed and then milled paint resulted in about 100-times larger release of Ti from the nano-TiO2 containing paint whereas the paint with only pigment-TiO2 did not show this increase. This indicated that the release of Ti from the paints is an effect of the addition of nano-TiO2, either by photocatalytic degradation of the organic paint matrix (observed by electron microscopic imaging of the paint surface) or by direct release of nano-TiO2. Our work suggests that paints containing nano-TiO2 may release only very limited amounts of materials into the environment, at least over the time-scales investigated in this work. PMID- 24056810 TI - The effect of functional MAPKAPK2 copy number variation CNV-30450 on elevating nasopharyngeal carcinoma risk is modulated by EBV infection. AB - Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) is recognized as oncogenic and simulative role on tumorigenesis by virtue of abnormal expression in cancer including nasopharyngeal carcinoma (NPC). We hypothesized that the copy number variation (CNV)-30450, which duplicates the MAPKAPK2 promoter, may affect MAPKAPK2 expression and be associated with NPC risk. In two independent case-control panels of southern and eastern Chinese with a total of 1590 NPC patients and 1979 cancer-free controls, we investigated the association between CNV-30450 and NPC risk by genotyping the CNV-30450 with the TaqMan assay, and tested its biological effect. Consistent findings were observed in the two populations, that the increased copy number of CNV-30450 was associated with increased risk of NPC (3/4-copy versus 2-copy: odds ratio = 1.28, 95% confidence interval = 1.10-1.49), in which lies a biological mechanism that the adverse genotypes enhanced the promoter activity of MAPKAPK2 and elevated MAPKAPK2 expression. Moreover, the CNV-30450 adverse genotypes significantly interacted with Epstein-Barr virus (EBV) infection on increasing NPC risk (P = 0.035), and the genotype-phenotype correlation was only significant in EBV positive cases (P = 0.037) but not in EBV-negative ones (P = 0.366). These data suggest that the functional CNV-30450 in the MAPKAPK2 promoter elevates the NPC risk with a modulation by EBV infection, which may be an indicator of susceptibility to NPC. SUMMARY: This case-control study suggests that the functional CNV-30450 in the MAPKAPK2 promoter elevates the NPC risk with a modulation by EBV infection, which may be an indicator of susceptibility to NPC. PMID- 24056811 TI - Delta insulin-like growth factor binding protein-1 (DeltaIGFBP-1): a marker of hepatic insulin resistance? AB - BACKGROUND: Insulin-like growth factor binding protein-1 (IGFBP-1) is a hepatically synthesised protein which can be used as a marker of insulin resistance. We hypothesised that the fall in serum IGFBP-1 at 2 h following a glucose load (DeltaIGFBP-10-2h) would be a more robust measure of hepatic insulin resistance than a fasting level alone. METHODS: All subjects had a standard 75 g oral GTT including IGFBP-1 and insulin measurement to enable calculation of DeltaIGFBP-10-2h, DeltaInsulin0-2h, and insulin sensitivity indices. At a second visit, subjects had a frequently sampled intravenous glucose tolerance test (FSIVGTT) in order to determine the insulin sensitivity index, Si. RESULTS: Twenty-two individuals had normal glucose tolerance (NGT) and 9 impaired fasting glucose (IFG). DeltaIGFBP-10-2h correlated with Si in total subjects (r = 0.49, p = 0.005) and NGT subjects (r = 0.50, p = 0.02) but not in IFG subjects (r = 0.43, p = 0.24). DeltaInsulin0-2h/DeltaIGFBP-10-2h correlated significantly with Si in total subjects (r = -0.68, p < 0.001) and in NGT subjects (r = -0.57, p = 0.005). Multivariate analysis was fitted using different models while keeping other explanatory variables constant. The fasting IGFBP-1 model was a better predictor of Si (beta = 0.431, p < 0.0001) than the DeltaInsulin0-2h/DeltaIGFBP10-2h model (beta = -0.185, p = 0.004). CONCLUSIONS: The dynamic indices DeltaIGFBP-10-2h and DeltaInsulin0-2h/DeltaIGFBP-10-2h appear suitable markers of (hepatic) insulin resistance with potential clinical utility. PMID- 24056812 TI - Outliers affecting cardiac troponin I measurement: comparison of a new high sensitivity assay with a contemporary assay on the Abbott ARCHITECT analyser. AB - BACKGROUND: False-positive cardiac troponin (Tn) results caused by outliers have been reported on various analytical platforms. We have compared the precision profile and outlier rate of the Abbott Diagnostics contemporary troponin I (TnI) assay with their high sensitivity (hs) TnI assay. METHODS: Three studies were conducted over a 10-month period using routine patients' samples. TnI was measured in duplicate using the contemporary TnI assay in Study 1 and Study 2 (n = 7011 and 7089) and the hs-TnI assay in Study 3 (n = 1522). Critical outliers were defined as duplicate results whose absolute difference exceeded a critical difference (CD = z x ?2 x SDAnalytical) at a probability level of 0.0005, with one of the results on the opposite side of the decision limit to its partner. RESULTS: The TnI concentration at 10% imprecision (coefficient of variation) for the contemporary TnI assay was 0.034 ug/L (Study 1) and 0.042 ug/L (Study 2), and 0.006 ug/L (6 ng/L) for the hs-TnI assay. The critical outlier rates for the contemporary TnI assay were 0.51% (Study 1) and 0.37% (Study 2) using a cut-off of 0.04 ug/L, and 0% for the hs-TnI assay using gender-specific cut-offs. CONCLUSION: The significant number of critical outliers detected using the contemporary TnI assay may pose a risk for misclassification of patients. By contrast, no critical outliers were detected using the hs-TnI assay. However, the total outlier rates for both assays were significantly higher than the expected variability of either assay. The cause of these outliers remains unclear. PMID- 24056813 TI - Stress-induced hematopoietic failure in the absence of immediate early response gene X-1 (IEX-1, IER3). AB - Expression of the immediate early response gene X-1 (IEX-1, IER3) is diminished significantly in hematopoietic stem cells in a subgroup of patients with early stage myelodysplastic syndromes, but it is not clear whether the deregulation contributes to the disease. The current study demonstrates increased apoptosis and a concomitant decrease in the number of hematopoietic stem cells lacking this early response gene. Null mutation of the gene also impeded platelet differentiation and shortened a lifespan of red blood cells. When bone marrow cells deficient in the gene were transplanted into wild-type mice, the deficient stem cells produced significantly fewer circulating platelets and red blood cells, despite their enhanced repopulation capability. Moreover, after exposure to a non-myeloablative dose of radiation, absence of the gene predisposed to thrombocytopenia, a significant decline in red blood cells, and dysplastic bone marrow morphology, typical characteristics of myelodysplastic syndromes. These findings highlight a previously unappreciated role for this early response gene in multiple differentiation steps within hematopoiesis, including thrombopoiesis, erythropoiesis and in the regulation of hematopoietic stem cell quiescence. The deficient mice offer a novel model for studying the initiation and progression of myelodysplastic syndromes as well as strategies to prevent this disorder. PMID- 24056814 TI - Response endpoints and failure-free survival after initial treatment for acute graft-versus-host disease. AB - We evaluated short-term response endpoints for acute graft-versus-host disease treatment trials. We postulated that response endpoints should correlate with reduced symptom burden and decreased subsequent treatment failure, defined as non relapse mortality, recurrent malignancy, or additional systemic treatment. The cohort included 303 consecutive patients who received initial systemic steroid treatment for acute graft-versus-host disease. Response was evaluated at day 28 after initial treatment, which in all cases preceded the onset of chronic graft versus-host disease. At day 28, 36% of patients had a complete response, 26% had a very good partial response, 10% had another degree of partial response (other partial response) and 28% had no response. As expected, the symptom burden was lower in patients with very good partial response compared to those with other partial response. The frequencies of subsequent treatment failure were similar in patients with complete and very good partial responses, but lower than in patients with other partial response or no response at day 28. The frequency of second-line treatment was lower in patients with very good partial response than in those with other partial response. Risk factors associated with a lower probability of complete or very good partial response at day 28 were unrelated or human leukocyte antigen-mismatched related donor grafts and liver or gastrointestinal involvement at onset of initial treatment. Taken together, these results suggest that endpoints in acute graft-versus-host disease treatment trials should distinguish between very good partial response and other partial response. Our results support the use of complete or very good partial response at day 28 as an appropriate short-term primary endpoint. PMID- 24056815 TI - Long-term risks after splenectomy among 8,149 cancer-free American veterans: a cohort study with up to 27 years follow-up. AB - Although preservation of the spleen following abdominal trauma and spleen preserving surgical procedures have become gold standards, about 22,000 splenectomies are still conducted annually in the USA. Infections, mostly by encapsulated organisms, are the most well-known complications following splenectomy. Recently, thrombosis and cancer have become recognized as potential adverse outcomes post-splenectomy. Among more than 4 million hospitalized USA veterans, we assessed incidence and mortality due to infections, thromboembolism, and cancer including 8,149 cancer-free veterans who underwent splenectomy with a follow-up of up to 27 years. Relative risk estimates and 95% confidence intervals were calculated using time-dependent Poisson regression methods for cohort data. Splenectomized patients had an increased risk of being hospitalized for pneumonia, meningitis, and septicemia (rate ratios=1.9-3.4); deep venous thrombosis and pulmonary embolism (rate ratios=2.2); certain solid tumors: buccal, esophagus, liver, colon, pancreas, lung, and prostate (rate ratios =1.3 1.9); and hematologic malignancies: non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and any leukemia (rate ratios =1.8-6.0). They also had an increased risk of death due to pneumonia and septicemia (rate ratios =1.6-3.0); pulmonary embolism and coronary artery disease (rate ratios =1.4-4.5); any cancer: liver, pancreas, and lung cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, and any leukemia (rate ratios =1.3-4.7). Many of the observed risks were increased more than 10 years after splenectomy. Our results underscore the importance of vaccination, surveillance, and thromboprophylaxis after splenectomy. PMID- 24056816 TI - Glutathione transferase-A2 S112T polymorphism predicts survival, transplant related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation. AB - Busulfan liver metabolism depends on glutathione, a crucial mediator of cellular and systemic stress. Here we investigated 40 polymorphisms at 27 loci involved in hepatic glutathione homeostasis, with the aim of testing their impact on the clinical outcome of 185 busulfan-conditioned allogeneic transplants. GSTA2 S112T serine allele homozygosity is an independent prognostic factor for poorer survival (RR=2.388), for increased any time- and 100-day transplant-related mortality (RR=4.912 and RR=5.185, respectively). The genotype also predicts a wider busulfan area under the concentration-time curve (1214.36 +/- 570.06 vs. 838.10 +/- 282.40 mMol*min) and higher post-transplant bilirubin serum levels (3.280 +/- 0.422 vs. 1.874+0.197 mg/dL). In vitro, busulfan elicits pro inflammatory activation (increased NF-KappaB activity and interleukin-8 expression) in human hepatoma cells. At the same time, the drug down-regulates a variety of genes involved in bilirubin liver clearance: constitutive androstane receptor, multidrug resistance-associated protein, solute carrier organic anion transporters, and even GSTA2. It is worthy of note that GSTA2 also acts as an intra-hepatic bilirubin binding protein. These data underline the prognostic value of GSTA2 genetic variability in busulfan-conditioned allotransplants and suggest a patho-physiological model in which busulfan-induced inflammation leads to the impairment of post-transplant bilirubin metabolism. PMID- 24056817 TI - Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors. AB - Allogeneic hematopoietic cell transplantation has an established role in the treatment of adults with acute lymphoblastic leukemia whose survival when recipients of grafts from adult unrelated donors approaches that of recipients of grafts from sibling donors. Our aim was to determine the role of mismatched unrelated cord blood grafts in transplantation for 802 adults with acute lymphoblastic leukemia in first or second complete remission. Using Cox regression we compared outcomes after 116 mismatched single or double cord blood transplants, 546 peripheral blood progenitor cell transplants and 140 bone marrow transplants. The characteristics of the recipients and their diseases were similar except cord blood recipients were younger, more likely to be non Caucasians and more likely to have a low white blood cell count at diagnosis. There were differences in donor-recipient human leukocyte antigen-match depending on the source of the graft. Most adult donor transplants were matched at the allele-level considering human leukocyte antigens-A, -B, -C and -DRB1. In contrast, most cord blood transplants were mismatched and considered antigen level matching; 57% were mismatched at two loci and 29% at one locus whereas only 29% of adult donor transplants were mismatched at one locus and none at two loci. There were no differences in the 3-year probabilities of survival between recipients of cord blood (44%), matched adult donor (44%) and mismatched adult donor (43%) transplants. Cord blood transplants engrafted slower and were associated with less grade 2-4 acute but similar chronic graft-versus-host disease, relapse, and transplant-related mortality. The survival of cord blood graft recipients was similar to that of recipients of matched or mismatched unrelated adult donor grafts and so cord blood should be considered a valid alternative source of stem cells for adults with acute lymphoblastic leukemia in the absence of a matched unrelated adult donor. PMID- 24056818 TI - Granulocyte colony-stimulating factor produces long-term changes in gene and microRNA expression profiles in CD34+ cells from healthy donors. AB - Granulocyte colony-stimulating factor is the most commonly used cytokine for the mobilization of hematopoietic progenitor cells from healthy donors for allogeneic stem cell transplantation. Although the administration of this cytokine is considered safe, knowledge about its long-term effects, especially in hematopoietic progenitor cells, is limited. On this background, the aim of our study was to analyze whether or not granulocyte colony-stimulating factor induces changes in gene and microRNA expression profiles in hematopoietic progenitor cells from healthy donors, and to determine whether or not these changes persist in the long-term. For this purpose, we analyzed the whole genome expression profile and the expression of 384 microRNA in CD34(+) cells isolated from peripheral blood of six healthy donors, before mobilization and at 5, 30 and 365 days after mobilization with granulocyte colony-stimulating factor. Six microRNA were differentially expressed at all time points analyzed after mobilization treatment as compared to the expression in samples obtained before exposure to the drug. In addition, 2424 genes were also differentially expressed for at least 1 year after mobilization. Of interest, 109 of these genes are targets of the differentially expressed microRNA also identified in this study. These data strongly suggest that granulocyte colony-stimulating factor modifies gene and microRNA expression profiles in hematopoietic progenitor cells from healthy donors. Remarkably, some changes are present from early time-points and persist for at least 1 year after exposure to the drug. This effect on hematopoietic progenitor cells has not been previously reported. PMID- 24056819 TI - Higher ratio immune versus constitutive proteasome level as novel indicator of sensitivity of pediatric acute leukemia cells to proteasome inhibitors. AB - The ex vivo sensitivity of pediatric leukemia cells to the proteasome inhibitor bortezomib was compared to 3 next generation proteasome inhibitors: the epoxyketone-based irreversible proteasome inhibitors carfilzomib, its orally bio available analog ONX 0912, and the immunoproteasome inhibitor ONX 0914. LC50 values were determined by MTT cytotoxicity assays for 29 childhood acute lymphoblastic leukemia and 12 acute myeloid leukemia patient samples and correlated with protein expression levels of the constitutive proteasome subunits (beta5, beta1, beta2) and their immunoproteasome counterparts (beta5i, beta1i, beta2i). Acute lymphoblastic leukemia cells were up to 5.5-fold more sensitive to proteasome inhibitors than acute myeloid leukemia cells (P<0.001) and the combination of bortezomib and dexamethasone proved additive/synergistic in the majority of patient specimens. Although total proteasome levels in acute lymphoblastic leukemia and acute myeloid leukemia cells did not differ significantly, the ratio of immuno/constitutive proteasome was markedly higher in acute lymphoblastic leukemia cells over acute myeloid leukemia cells. In both acute lymphoblastic leukemia and acute myeloid leukemia, increased ratios of beta5i/beta5, beta1i/beta1 and beta2i/beta2 correlated with increased sensitivity to proteasome inhibitors. Together, differential expression levels of constitutive and immunoproteasomes in pediatric acute lymphoblastic leukemia and acute myeloid leukemia constitute an underlying mechanism of sensitivity to bortezomib and new generation proteasome inhibitors, which may further benefit from synergistic combination therapy with drugs including glucocorticoids. PMID- 24056820 TI - Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib. AB - Ruxolitinib, a JAK1/JAK2 inhibitor, is currently the only pharmacological agent approved for the treatment of myelofibrosis. Approval was based on findings from two phase 3 trials comparing ruxolitinib with placebo (COMFORT-I) and with best available therapy (COMFORT-II) for the treatment of primary or secondary myelofibrosis. In those pivotal trials, ruxolitinib rapidly improved splenomegaly, disease-related symptoms, and quality of life and prolonged survival compared with both placebo and conventional treatments. However, for reasons that are currently unclear, there were only modest histomorphological changes in the bone marrow, and only a subset of patients had significant reductions in JAK2 V617F clonal burden. Here we describe a patient with post polycythemia vera myelofibrosis who received ruxolitinib at our institution (Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom) as part of the COMFORT-II study. While on treatment, the patient had dramatic improvements in splenomegaly and symptoms shortly after starting ruxolitinib. With longer treatment, the patient had marked reductions in JAK2 V617F allele burden, and fibrosis of the bone marrow resolved after approximately 3 years of ruxolitinib treatment. To our knowledge, this is the first detailed case report of resolution of fibrosis with a JAK1/JAK2 inhibitor. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00934544. PMID- 24056821 TI - Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation is a successful treatment for hematologic malignancies and a variety of genetic and metabolic disorders. In the period following stem cell transplantation, the immune-compromised milieu allows opportunistic pathogens to thrive. Epstein-Barr virus-associated post-transplant lymphoproliferative disease can be a life-threatening complication for transplanted patients because of suppressed T-cell-mediated immunity. We analyzed possible risk factors associated with post-transplant lymphoproliferative disease in a cohort of over 1,000 patients. The incidence of post-transplant lymphoproliferative disease was 4%. Significant risk factors identified by multivariate analysis were: human leukocyte antigen-mismatch (P<0.001), serological Epstein-Barr virus mismatch recipient-/donor+ (P<0.001), use of reduced intensity conditioning (P=0.002), acute graft-versus-host disease grade II to IV (P=0.006), pre-transplant splenectomy (P=0.008) and infusion of mesenchymal stromal cells (P=0.015). The risk of post-transplant lymphoproliferative disease has increased in more recent years, from less than 2% before 1998 to more than 6% after 2011. Additionally, we show that long-term survival of patients with post-transplant lymphoproliferative disease is poor despite initial successful treatment. The 3-year survival rate among the 40 patients with post-transplant lymphoproliferative disease was 20% as opposed to 62% among patients without post-transplant lymphoproliferative disease (P<0.001). The study identifies patients at risk of post-transplant lymphoproliferative disease after transplantation in need of pre-emptive measures. PMID- 24056822 TI - Nutrients related to the incidence of early and late age-related macular degeneration. PMID- 24056824 TI - The relevance of light in the formation of colloidal metal nanoparticles. AB - "The possibility of using colloidal silver and gold as condensors for electron storage in artificial photosynthesis has prompted the recent renewed interest in these areas." This statement by Fendler and co-workers in 1983 is even more relevant in today's science and technology. In this tutorial review we summarize research regarding the use of light in the synthesis of metallic nanoparticles. We describe how light of different energies induces a variety of chemical events that culminate in the nucleation and growth of metal nanocrystals. Light can thus be used as a handle to direct metal nanocrystal growth and improve tunability and reproducibility. PMID- 24056825 TI - Highly sensitive methane catalytic combustion micro-sensor based on mesoporous structure and nano-catalyst. AB - In order to get a methane catalytic combustion micro-sensor, two different catalytic systems used in traditional methane catalytic combustion sensors were fabricated into a mesoporous structure and their catalytic activities were investigated. In comparison, the Rh2O3-Al2O3 system can form more a uniform mesoporous structure and has a much higher specific surface area. Even more importantly, it has relatively higher catalytic activity and stability for the methane catalytic combustion reaction. After being coated on a microelectro mechanical system (MEMS) micro-heater, a catalytic combustion type methane micro sensor was fabricated. The meso-structured Rh2O3-Al2O3 hybrid based MEMS sensor demonstrated a short T90 response time, relatively high signal output, high enough signal/noise ratio for practical detecting and strong anti-poison properties. PMID- 24056826 TI - [Child sexual abuse: an irremediable hurt?]. AB - The aim of this review was to provide the state of art of child sexual abuse and its psychophysical consequences. We assessed the evidence-based literature derived from PubMed, Embase, Medline, PsychINFO databases, including a thorough analysis of what has been published in the last 5 years, not neglecting previous publications essential to the argument for their scientific validity (methodological accuracy, recruited survey). Child sexual abuse is ubiquitous both regarding victims' gender and socio-economic conditions. The important consequences linked to what they suffered--either immediately or with adolescent or adult onset--are mediated by age and family support to trauma reprocessing as well as by the frequency of repetition of the abuse or familiarity with the abuser. These factors appear to be of primary importance--both at a physical and psychic level--and may be expressed in multiple manifestations, hence it is of utmost importance to pay timely attention to possible alarm signals revealing suspected abuse suffered by any underage person. Special emphasis is addressed towards some of the consequences for which child sexual abuse is considered to be a primary cause (e.g. post-traumatic stress disorder) and the perpetuation of such abuse, both short-term as well as long-term. Poor training, regarding this field, of various professionals (pediatricians, teachers, etc.) who each day work with minors, as well as the paucity of available treatment options point to an urgent need for prevention (including in-depth diagnosis/therapy) and early intervention. PMID- 24056828 TI - Smoking, physical activity and respiratory irregularities in patients with panic disorder. AB - BACKGROUND: In the past decades different evidences suggested a relationship between panic disorder (PD) and respiration, among which the presence of different respiratory irregularities at rest in PD patients. It has been hypothesized that PD could be characterized by a dysfunction of those areas involved in the central control of respiration. The aim of the present study was to elucidate possible differences in breath-by-breath respiratory function at rest between a sample of PD patients with agoraphobia and healthy controls (HC), with particular attention to smoking and physical activity as possible relevant factors in the understanding of respiratory dynamics in PD. METHODS: Respiratory physiology was assessed in 32 PD patients and 24 HC. Respiratory rate (RR), tidal volume (VT), minute ventilation (VE), and end-tidal CO2 (pCO2) have been assessed. RESULTS: A significant diagnosis-by-smoking interaction was found for mean RR and VT. Mean pCO2 was significantly higher in active than in sedentary patients. Anxiety state did not account for the results. CONCLUSIONS: Our findings suggest an abnormal regulation of the respiratory system as a key mechanism in PD. In future studies it should be useful t o stratify data taking into account level and intensity of physical activity and smoking behaviour, as well as to consider the cardiac profile and the effect of those variables able to modulate the homeostatic brain functioning. . PMID- 24056827 TI - [Informed consent and neuromodulation techniques for psychiatric purposes: an introduction]. AB - The aim of this review was to investigate informed consent-related issues concerning vagus nerve stimulation and deep brain stimulation in the treatment of psychiatric disorders. We searched the principal medical databases for studies concerning informed consent, as well as ethical and deontological issues in psychosurgery. Data were critically analysed. We also provided guidelines for the evaluation of accuracy of the informed consent in such treatments. Despite major deontological and ethical implications, there is substantial lack of information pertaining informed consent decision-making in psychiatric patients with an indication for psychosurgery. In clinical research studies, deep brain stimulation and vagus nerve stimulation have been mainly used in drug-resistant major depressive disorder, Tourette syndrome and obsessive-compulsive disorder. Existing data on efficacy and tolerability, as well as those studies indicating the risk for incapacity in drug-resistant severe mental disorders, suggest the need to achieve a better understanding of the capacity to consent to psychosurgery in patients affected by mental disorders. Informed consent decision making in clinical trials of deep brain stimulation and vagus nerve stimulation in psychiatric patients is largely unknown and deserves further investigation. PMID- 24056829 TI - [Comorbility between anxiety and depression in patients with carcinoid tumors]. AB - BACKGROUND: People who have malignant cancer are plagued with a variety of symptoms that often severely limit their lives. In the case of carcinoid tumors, symptoms of anxiety and depression are two manifestations often associated with disturbances produced by the tumor itself and the chemicals that the tumor secretes. The aim of this study was to compare the incidence of these symptoms for gastro-entero-pancreatic (GEP) tumors and non-gastro-entero-pancreatic (non GEP). METHODS: Patients with GEP and patients with non-GEP completed the Hospital Anxiety and Depression Scale (HADS). HADS and all of its subscales were analyzed. RESULTS: Patients with GEP tended to have higher average total scores on the HADS D than those with non-GEP (p<0.08), and items in which the difference between GEP and non-GEP were statistically significant were anhedonia (p<0.05), a reduced ability to laugh and have fun (p<0.05), and the feeling of hopelessness (p<0.05). No significant differences emerged, however, in HADS-T and HADS-A scores. CONCLUSIONS: On the basis of these findings, patients with GEP are affected more than patients with non-GEP with increased levels of depressive and anxiety symptoms. What is difficult to determine, however, is whether these symptoms are related to hormone overproduction, or whether they are related to tumor-related emotional distress. PMID- 24056830 TI - [Integrated day-hospital treatment in subjects with overeating disorders]. AB - BACKGROUND: The efficacy of a multidisciplinary, intensive and integrated day hospital treatment was evaluated in a group of overeaters (bulimia nervosa, binge eating disorder, obesity without binging). METHODS: The study sample included 72 subjects consecutively admitted to DH who were evaluated at the first contact with the service, on admission, after 5 weeks of treatment, and at discharge. The primary outcome was the total score at the Eating Disorder Inventory (EDI), and the secondary outcome was change in body mass index (BMI). The effects of the duration of treatment on results were also assessed. The improvement of EDI and BMI was compared between the two groups of bingers and non-bingers. RESULTS: Four patients dropped during the treatment period. In the whole sample, both EDI and BMI improved significantly after 5 weeks (p=0.00) and continued to improve until the end of treatment (p=0.00). The duration of treatment did not have a significant impact on BMI improvement (p=0.07), but significantly affected EDI improvement (p=0.006), although only during the treatment period. No significant differences were observed between obese/overweight bingers and non-bingers in BMI improvement (p=0.41), whereas EDI improvement was higher in bingers (p=0.02). CONCLUSIONS: The relatively good compliance and the efficacy data suggest that in overeating subjects resistant to previous outpatient treatments a more intensive DH treatment may be useful. Our findings show that such a multidisciplinary therapeutic-rehabilitative treatment significantly improves both total EDI score (especially in bingers) and BMI. PMID- 24056831 TI - [Urban insecurity and fear of crime in people suffering from mental disorders: a study in 24 Mental Health Centers in Italy]. AB - AIMS: To assess in a sample of people with mental disorders: 1) fear of crime and perceived insecurity; 2) the association between fear of crime and insecurity; 3) the incidence of crimes. METHODS: Twenty-four Italian mental health centres have been invited to participate in the study from the network of the Early Career Psychiatrists' Committee of the Italian Psychiatric Association. In each participating centre, the first 20 patients consecutively accessing the mental health centre between February and April 2011 have been recruited. All patients have been assessed using validated assessment tools. RESULTS: The final sample consists of 426 patients. They are mostly female (70.1%), with a mean age of 45 years (+/- 13.5), and with a good level of education. Fifty-two percent of patients have a diagnosis of mood disorders, and 37.8% on anxiety spectrum disorders. About half of the sample declares that the most prominent feeling toward life is uncertainty. Almost all patients report to have at least one big fear, with the most frequently report being: 1) loss or death of a loved one (41.2%); 2) financial constraint (28.4%); 3) physical or mental health problems (26.5%). DISCUSSION AND CONCLUSIONS: Our results show the presence of a common sense of uncertainty among patients, probably as a result of the historical moment we are facing. It is reasonable that this attitude toward life can have a detrimental impact on patients' psychological and physical wellbeing, contributing to high levels of distress. Further studies are needed in order to clarify the possible relationship between fears, uncertainty and mental disorders. PMID- 24056832 TI - [Basic symptoms and neurocognition: preliminary comparison of first-episode psychosis vs multi-episode long-term illness]. AB - BACKGROUND: Schizophrenia is preceded by basic symptoms which may persist after long time and include subjective cognitive impairment. Furthermore, it is characterised by cognitive deficits that may deteriorate with the progression of illness. To examine the relationship between neurocognition and basic symptoms along the course of schizophrenia, we compared the cognitive performance and the basic symptoms of one population with first episode psychosis (FEP) and one with a chronic, multi-episode course (MEP). METHODS: We tested 8 FEP (5 male) and 7 MEP (7 male) in- and outpatients, for basic symptoms with the Schizophrenia Proneness Instrument-Adult version (SPI-A) and for neurocognition with Raven's Color Progressive Matrices (CPM), Rey-Osterrieth's complex figure (Rey), Corsi's and Buschke-Fuld tests, the Wisconsin Card Sorting Test (WCST), the Stroop test, and the Trail Making Test (TMT). RESULTS: FEP patients did not differ from MEP patients as for SPI-A scores. MEP patients were significantly more impaired on several subtests of Buschke-Fuld, the Rey, and the WCST with respect to FEP. Impairment on the cognitive subscale of the SPI-A correlated with non perseverative WCST errors, and on the self subscale of the SPI-A with impaired performance on the Buschke-Fuld. Further, in MEP, impairment on the body subscale of the SPI-A correlated inversely with number of categories completed of the WCST. CONCLUSIONS: Basic symptoms persist throughout the phases of schizophrenia and are relatively independent of cognitive performance. A chronic, multi-episode course is associated with increased cognitive impairment in schizophrenia. PMID- 24056833 TI - [Factor analysis and psychometric properties of the Italian version of the Neuropsychiatric Inventory-Nursing Home in an institutionalized elderly population with psychiatric comorbidity]. AB - AIM: Aim of the study was to validate the Italian version of the Neuropsychiatric Inventory-Nursing Home (NPI-NH). The evaluation of neuropsychiatric symptoms in elderly patients with cognitive impairment and/or a chronic psychiatric disorder, is an essential need in nursing home. METHODS: The Italian version of the NPI-NH was administered in 53 patients in a nursing home in Northern-Italy. RESULTS: The internal consistency of the NPI-NH reported a value (alpha=0.62) according to the literature. The inter-rater reliability was rho=0.991 and rho=0.999 for the caregiver distress. There was an almost complete overlap between the assessments of individual items ranging from (rho) 1 and 0.952. The test-retest reliability was rho=0.961 and rho=0.943 for the distress of the caregiver. Factor analysis revealed 4 factors that can explain 62.167% of the total variance: factor 1 hyperactivity, factor 2 mood, factor 3 psychosis and factor 4 withdrawal. CONCLUSIONS: The NPI-NH can be used as an instrument for follow-up of patients and as a tool to support the activities of psychiatric referring and research in nursing home because of his demonstrated psychometric validity and its ease of use. PMID- 24056834 TI - [Shy bladder syndrome]. AB - Paruresis is the inability to urinate in situations where there is perception of scrutiny, or potential scrutiny, by others. According to DSM-5, paruresis is classified as social phobia. AIM: The present study aims at offering a clinical description of the disorder in a sample of paruretics voluntarily recruited among users registered on an Italian website dedicated to people suffering from this disorder (www.paruresis.it). METHODS: Data were collected through a set of questionnaires published online, including assessment and screening measures for paruresis (Paruresis Checklist), generalized social phobia (Mini-SPIN) and depression (Beck Depression Inventory). RESULTS: 65 participants showed clinically relevant symptoms of paruresis, as suggested by a PCL score above the threshold. Mean age was 28 ys (SD= +/- 7.75 ys); most of participants were male (87.7%; N=57). Although gender differences in the clinical manifestations of the disorder appear limited, the variable mostly connected to the severity of paruresis is the presence of a further diagnosis of generalized social phobia. DISCUSSION: Paruresis is a clinical condition associated with high level of distress on which, however, there is limited knowledge among mental health professionals. PMID- 24056835 TI - [Hikikomori (?????): a culture-bound syndrome in the web 2.0 era]. AB - In 1998 the Japanese psychiatrist Tamaki Sait-o invented the term hikikomori, referring to a condition characterised by a state of social withdrawal and avoidance (education, work, friendships) combined with a persistent isolation and confinement in the own home for at least 6 months, due to various factors. Initially it undoubtedly regarded a disorder related to a specific socio-cultural context, however in the last couple of years some cases of hikikomori behaviour have also been observed in other countries far from Japan, both geographically and culturally. By way of hypothesis this diffusion can probably be attributed to the cultural revolution represented by mass communication in the internet era; in particular, it seems to be closely related to the immediateness and diffusion of web 2.0, i.e. of social networks. Therefore, we report a case of hikikomori behaviour, who was referred to our ward. M. is a 28-year-old man, who has lived the last 10 years in a state of almost complete isolation. He has maintained contacts with the outside world almost exclusively via internet. He started several therapies with psychiatrists and psychologists, without achieving significant results. The case of M. represents, to our knowledge, the first case of hikikomori described in Italy. PMID- 24056838 TI - Integrated gene co-expression network analysis in the growth phase of Mycobacterium tuberculosis reveals new potential drug targets. AB - We have carried out weighted gene co-expression network analysis of Mycobacterium tuberculosis to gain insights into gene expression architecture during log phase growth. The differentially expressed genes between at least one pair of 11 different M. tuberculosis strains as source of biological variability were used for co-expression network analysis. This data included genes with highest coefficient of variation in expression. Five distinct modules were identified using topological overlap based clustering. All the modules together showed significant enrichment in biological processes: fatty acid biosynthesis, cell membrane, intracellular membrane bound organelle, DNA replication, Quinone biosynthesis, cell shape and peptidoglycan biosynthesis, ribosome and structural constituents of ribosome and transposition. We then extracted the co-expressed connections which were supported either by transcriptional regulatory network or STRING database or high edge weight of topological overlap. The genes trpC, nadC, pitA, Rv3404c, atpA, pknA, Rv0996, purB, Rv2106 and Rv0796 emerged as top hub genes. After overlaying this network on the iNJ661 metabolic network, the reactions catalyzed by 15 highly connected metabolic genes were knocked down in silico and evaluated by Flux Balance Analysis. The results showed that in 12 out of 15 cases, in 11 more than 50% of reactions catalyzed by genes connected through co-expressed connections also had altered fluxes. The modules 'Turquoise', 'Blue' and 'Red' also showed enrichment in essential genes. We could map 152 of the previously known or proposed drug targets in these modules and identified 15 new potential drug targets based on their high degree of co expressed connections and strong correlation with module eigengenes. PMID- 24056839 TI - In vitro metabolism of the glucagon-like peptide-1 (GLP-1)-derived metabolites GLP-1(9-36)amide and GLP-1(28-36)amide in mouse and human hepatocytes. AB - Previous studies have revealed that the glucoincretin hormone glucagon-like peptide-1 (GLP-1)(7-36)amide is metabolized by dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase 24.11 (NEP) to yield GLP-1(9-36)amide and GLP-1(28 36)amide, respectively, as the principal metabolites. Contrary to the previous notion that GLP-1(7-36)amide metabolites are pharmacologically inactive, recent studies have demonstrated cardioprotective and insulinomimetic effects with both GLP-1(9-36)amide and GLP-1(28-36)amide in animals and humans. In the present work, we examined the metabolic stability of the two GLP-1(7-36)amide metabolites in cryopreserved hepatocytes, which have been used to demonstrate the in vitro insulin-like effects of GLP-1(9-36)amide and GLP-1(28-36)amide on gluconeogenesis. To examine the metabolic stability of the GLP-1(7-36)amide metabolites, a liquid chromatography-tandem mass spectrometry assay was developed for the quantitation of the intact peptides in hepatocyte incubations. GLP-1(9 36)amide and GLP-1(28-36)amide were rapidly metabolized in mouse [GLP-1(9 36)amide: t(1/2) = 52 minutes; GLP-1(28-36)amide: t(1/2) = 13 minutes] and human hepatocytes [GLP-1(9-36)amide: t(1/2) = 180 minutes; GLP-1(28-36)amide: t(1/2) = 24 minutes), yielding a variety of N-terminal cleavage products that were characterized using mass spectrometry. Metabolism at the C terminus was not observed for either peptides. The DPP-IV and NEP inhibitors diprotin A and phosphoramidon, respectively, did not induce resistance in the two peptides toward proteolytic cleavage. Overall, our in vitro findings raise the intriguing possibility that the insulinomimetic effects of GLP-1(9-36)amide and GLP-1(28 36)amide on gluconeogenesis and oxidative stress might be due, at least in part, to the actions of additional downstream metabolites, which are obtained from the enzymatic cleavage of the peptide backbone in the parent compounds. PMID- 24056837 TI - A novel CsrA titration mechanism regulates fimbrial gene expression in Salmonella typhimurium. AB - A hierarchical control of fimbrial gene expression limits laboratory grown cultures of Salmonella enterica serovar typhimurium (S. typhimurium) to the production of type I fimbriae encoded by the fimAICDHF operon. Here we show that an unlikely culprit, namely the 5'-untranslated region (5'-UTR) of a messenger (m)RNA, coordinated the regulation. Binding of CsrA to the 5'-UTR of the pefACDEF transcript was required for expression of plasmid-encoded fimbriae. The 5'-UTR of the fimAICDHF transcript cooperated with two small untranslated RNAs, termed CsrB and CsrC, in antagonizing the activity of the RNA binding protein CsrA. Through this post-transcriptional mechanism, the 5'-UTR of the fimAICDHF transcript prevented production of PefA, the major structural subunit of plasmid-encoded fimbriae. This regulatory mechanism limits the costly expression of plasmid encoded fimbriae to host environments in a mouse model. Collectively, our data suggest that the 5'-UTR of an mRNA coordinates a hierarchical control of fimbrial gene expression in S. typhimurium. PMID- 24056840 TI - Electrogeneration of platinum nanoparticles in a matrix of dendrimer-carbon nanotubes. AB - Hybrid materials with enhanced properties can now be obtained by combining nanomaterials such as carbon nanotubes and metallic nanoparticles, where the main challenge is to control fabrication conditions. In this study, we demonstrate that platinum nanoparticles (PtNps) can be electrogenerated within layer-by-layer (LbL) films of polyamidoamine (PAMAM) dendrimers and single-walled carbon nanotubes (SWCNTs), which serve as stabilizing matrices. The advantages of the possible control through electrogeneration were demonstrated with a homogeneous distribution of PtNps over the entire surface of the PAMAM/SWCNT LbL films, whose electroactive sites could be mapped using magnetic force microscopy. The Pt containing films were used as catalysts for hydrogen peroxide reduction, with a decrease in the reduction potential of 60 mV compared to a Pt film deposited onto bare ITO. By analyzing the mechanisms responsible for hydrogen peroxide reduction, we ascribed the enhanced catalytic activity to synergistic effects between platinum and carbon in the LbL films, which are promising for sensing and fuel cell applications. PMID- 24056841 TI - An individually coated near-infrared fluorescent protein as a safe and robust nanoprobe for in vivo imaging. AB - A prerequisite for in vivo fluorescence imaging is the safety of fluorescent probes. Among all fluorescent probes, fluorescent proteins (FPs) might be the safest ones, which have been widely used in biological sciences at the gene level. But FPs have not been used in vivo in the purified form yet due to the instability of proteins. Here, we individually coat near-infrared (NIR) FPs (NIRFPs) with a silica nanoshell, resulting in NIRFP@silica, one of the safest and brightest NIR fluorescent nanoprobes with a quantum yield of 0.33 for in vivo imaging. The silica shell not only protects NIRFPs from denaturation and metabolic digestion, but also enhances the quantum yield and photostability of the coated NIRFPs. When injected via the tail vein, NIRFP@silica NPs can distribute all over the mouse body, and then can be efficiently eliminated through urine in 24 h, demonstrating its potential applications as a safe and robust NIR fluorescence probe for whole body imaging. PMID- 24056842 TI - A continuous tilting of micromolds for fabricating polymeric microstructures in microinjection. AB - We demonstrate a practical design and integration of multidirectional tilted UV lithography and microinjection molding for microstructure-based microfluidic devices. The previously reported undercut (or T-profile) problem of photoresist causes the imperfect mirror image duplication of the microstructures to the Ni mold. This issue inevitably leads to the unstable molds in the production of microstructure-based microfluidic devices. This study presents a simple route for the successful fabrication of microstructure-based microfluidic devices by multidirectional tilted UV lithography. By changing slope angles of microstructures through tilting the chuck during the UV exposure, the slope angles (up to 30 degrees ) around the microstructures allow the effective prevention of the undercut problems of photoresist and facilitate easy releasing of the device with high durability. This technique can be easily used for the production of the microstructure-based microfluidic devices in microanalysis and lab-on-chip applications. PMID- 24056843 TI - 3D assembly of upconverting NaYF4 nanocrystals by AFM nanoxerography: creation of anti-counterfeiting microtags. AB - Formation of 3D close-packed assemblies of upconverting NaYF4 colloidal nanocrystals (NCs) on surfaces, by Atomic Force Microscopy (AFM) nanoxerography is presented. The surface potential of the charge patterns, the NC concentration, the polarizability of the NCs and the polarity of the dispersing solvent are identified as the key parameters controlling the assembly of NaYF4 NCs into micropatterns of the desired 3D architecture. This insight allowed us to fabricate micrometer sized Quick Response (QR) codes encoded in terms of upconversion luminescence intensity or color. Topographically hidden messages could also be readily incorporated within these microtags. This work demonstrates that AFM nanoxerography has enormous potential for generating high-security anti counterfeiting microtags. PMID- 24056844 TI - Not so transparent. PMID- 24056845 TI - Wetting translucency of graphene. PMID- 24056851 TI - Wetting: Contact with what? PMID- 24056852 TI - Bilayer graphene: A little twist with big consequences. PMID- 24056853 TI - Interface superconductivity: Pinning the critical temperature. PMID- 24056854 TI - Material witness: And the winner is.... PMID- 24056855 TI - Simultaneously capturing real-time images in two emission channels using a dual camera emission splitting system: applications to cell adhesion. AB - Multi-color immunofluorescence microscopy to detect specific molecules in the cell membrane can be coupled with parallel plate flow chamber assays to investigate mechanisms governing cell adhesion under dynamic flow conditions. For instance, cancer cells labeled with multiple fluorophores can be perfused over a potentially reactive substrate to model mechanisms of cancer metastasis. However, multi-channel single camera systems and color cameras exhibit shortcomings in image acquisition for real-time live cell analysis. To overcome these limitations, we used a dual camera emission splitting system to simultaneously capture real-time image sequences of fluorescently labeled cells in the flow chamber. Dual camera emission splitting systems filter defined wavelength ranges into two monochrome CCD cameras, thereby simultaneously capturing two spatially identical but fluorophore-specific images. Subsequently, psuedocolored one channel images are combined into a single real-time merged sequence that can reveal multiple target molecules on cells moving rapidly across a region of interest. PMID- 24056856 TI - A novel ascorbic acid sensor based on the Fe3+/Fe2+ modulated photoluminescence of CdTe quantum dots@SiO2 nanobeads. AB - In this paper, CdTe quantum dot (QD)@silica nanobeads were used as modulated photoluminescence (PL) sensors for the sensing of ascorbic acid in aqueous solution for the first time. The sensor was developed based on the different quenching effects of Fe(2+) and Fe(3+) on the PL intensity of the CdTe QD@ silica nanobeads. Firstly, the PL intensity of the CdTe QDs was quenched in the presence of Fe(3+). Although both Fe(2+) and Fe(3+) could quench the PL intensity of the CdTe QDs, the quenching efficiency were quite different for Fe(2+) and Fe(3+). The PL intensity of the CdTe QD@silica nanobeads can be quenched by about 15% after the addition of Fe(3+) (60 MUmol L(-1)), while the PL intensity of the CdTe QD@silica nanobeads can be quenched about 49% after the addition of Fe(2+) (60 MUmol L(-1)). Therefore, the PL intensity of the CdTe QD@silica nanobeads decreased significantly when Fe(3+) was reduced to Fe(2+) by ascorbic acid. To confirm the strategy of PL modulation in this sensing system, trace H2O2 was introduced to oxidize Fe(2+) to Fe(3+). As a result, the PL intensity of the CdTe QD@silica nanobeads was partly recovered. The proposed sensor could be used for ascorbic acid sensing in the concentration range of 3.33-400 MUmol L(-1), with a detection limit (3sigma) of 1.25 MUmol L(-1) The feasibility of the proposed sensor for ascorbic acid determination in tablet samples was also studied, and satisfactory results were obtained. PMID- 24056857 TI - Identification of hepatocellular carcinoma related genes with k-th shortest paths in a protein-protein interaction network. AB - Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide and one of the deadliest cancers in Asia. But at present, effective targets for HCC clinical therapy are still limited. The "guilt by association" rule suggests that interacting proteins share the same or similar functions and hence may be involved in the same pathway. This assumption can be used to identify disease related genes from protein association networks constructed from existing PPI data. Given the close association between Hepatitis B virus and Hepatitis B which may lead to HCC, here we develop a computational method to identify hepatocellular carcinoma related genes based on k-th shortest paths in the protein-protein interaction (PPI) network (we set k=1, 2 in this study). Finally, we found 33 genes whose p-values were less than 0.05, and most of them have been reported to be involved in HCC tumorigenesis and development. The results also provide a new reference for research into HCC oncogenesis and for development of new strategies for HCC clinical therapies. PMID- 24056859 TI - Synthesis and strong near-infrared fluorescence of LiLa(1-x)Nd(x)(PO3)4 nanocrystals with high doping concentrations. AB - A series of LiLa(1-x)Nd(x)(PO(3))(4) (LLNP) nanocrystals are synthesized by a combustion method for the first time. With irregular short-rod shapes and an average size of about 70 nm, the LiLa(1-x)Nd(x)(PO(3))(4) nanocrystals exhibit stronger fluorescence emission of 1.8-6.5 times in the doping concentration range of 1 mol% to 100 mol% than Nd(3+) (2.5 wt%) doped phosphate glass, and have a long lifetime of 122 MUs for the fully doped nanocrystals. Moreover, the LiLa(1 x)Nd(x)(PO(3))(4) nanocrystals show the lowest lifetime decay rate of 5.09 MUs per mol% and a quenching ratio of 10.81%. Considering the above outstanding performances, LiLa(1-x)Nd(x)(PO(3))(4) nanocrystals may have promising applications in optical amplifiers and lasers. PMID- 24056858 TI - Centrifugo-Magnetophoretic Purification of CD4+ Cells from Whole Blood Toward Future HIV/AIDS Point-of-Care Applications. AB - In medical diagnostics, detection of cells exhibiting specific phenotypes constitutes a paramount challenge. Detection technology must ensure efficient isolation of (often rare) targets while eliminating nontarget background cells. Technologies exist for such investigations, but many require high levels of expertise, expense, and multistep protocols. Increasing automation, miniaturization, and availability of such technologies is an aim of microfluidic lab-on-a-chip strategies. To this end, we present an integrated, dual-force cellular separation strategy using centrifugo-magnetophoresis. Whole blood spiked with target cells is incubated with (super-)paramagnetic microparticles that specifically bind phenotypic markers on target cells. Under rotation, all cells sediment into a chamber located opposite a co-rotating magnet. Unbound cells follow the radial vector, but under the additional attraction of the lateral magnetic field, bead-bound target cells are deflected to a designated reservoir. This multiforce separation is continuous and low loss. We demonstrate separation efficiently up to 92% for cells expressing the HIV/AIDS relevant epitope (CD4) from whole blood. Such highly selective separation systems may be deployed for accurate diagnostic cell isolations from biological samples such as blood. Furthermore, this high efficiency is delivered in a cheap and simple device, thus making it an attractive option for future deployment in resource-limited settings. PMID- 24056860 TI - IL-17A RNA aptamer: possible therapeutic potential in some cells, more than we bargained for in others? PMID- 24056862 TI - Three-dimensional confocal analysis of microglia/macrophage markers of polarization in experimental brain injury. AB - After brain stroke microglia/macrophages (M/M) undergo rapid activation with dramatic morphological and phenotypic changes that include expression of novel surface antigens and production of mediators that build up and maintain the inflammatory response. Emerging evidence indicates that M/M are highly plastic cells that can assume classic pro-inflammatory (M1) or alternative anti inflammatory (M2) activation after acute brain injury. However a complete characterization of M/M phenotype marker expression, their colocalization and temporal evolution in the injured brain is still missing. Immunofluorescence protocols specifically staining relevant markers of M/M activation can be performed in the ischemic brain. Here we present immunofluorescence-based protocols followed by three-dimensional confocal analysis as a powerful approach to investigate the pattern of localization and co-expression of M/M phenotype markers such as CD11b, CD68, Ym1, in mouse model of focal ischemia induced by permanent occlusion of the middle cerebral artery (pMCAO). Two-dimensional analysis of the stained area reveals that each marker is associated to a defined M/M morphology and has a given localization in the ischemic lesion. Patterns of M/M phenotype marker co-expression can be assessed by three-dimensional confocal imaging in the ischemic area. Images can be acquired over a defined volume (10 MUm z-axis and a 0.23 MUm step size, corresponding to a 180 x 135 x 10 MUm volume) with a sequential scanning mode to minimize bleed-through effects and avoid wavelength overlapping. Images are then processed to obtain three dimensional renderings by means of Imaris software. Solid view of three dimensional renderings allows the definition of marker expression in clusters of cells. We show that M/M have the ability to differentiate towards a multitude of phenotypes, depending on the location in the lesion site and time after injury. PMID- 24056861 TI - Plakophilin-1 protects keratinocytes from pemphigus vulgaris IgG by forming calcium-independent desmosomes. AB - Plakophilin-1 (PKP-1) is an armadillo family protein critical for desmosomal adhesion and epidermal integrity. In the autoimmune skin-blistering disease pemphigus vulgaris (PV), autoantibodies (IgG) target the desmosomal cadherin desmoglein 3 (Dsg3) and compromise keratinocyte cell-cell adhesion. Here, we report that enhanced expression of PKP-1 protects keratinocytes from PV IgG induced loss of cell-cell adhesion. PKP-1 prevents loss of Dsg3 and other desmosomal proteins from cell-cell borders and prevents alterations in desmosome ultrastructure in keratinocytes treated with PV IgG. Using a series of Dsg3 chimeras and deletion constructs, we find that PKP-1 clusters Dsg3 with the desmosomal plaque protein desmoplakin in a manner dependent on the plakoglobin binding domain of the Dsg3 tail. Furthermore, PKP-1 expression transforms desmosome adhesion from a calcium-dependent to a calcium-independent and hyperadhesive state. These results demonstrate that manipulating the expression of a single desmosomal plaque protein can block the pathogenic effects of PV IgG on keratinocyte adhesion. PMID- 24056863 TI - Role of graphene on the surface chemical reactions of BiPO4-rGO with low OH related defects. AB - Graphene has been widely introduced into photocatalysis to enhance photocatalytic performance due to its unique physical and chemical properties. However, the effect of graphene on the surface chemical reactions of photocatalysis has not been clearly researched, which is important for photocatalysis because photocatalytic reactions ultimately occur on the catalyst surface. Herein, a two step solution-phase reaction has been designed to synthesize quasi-core-shell structured BiPO4-rGO cuboids and the role of graphene on the surface chemical reactions was investigated in detail. It was found that the introduced graphene modified the process and the mechanism of the surface chemical reactions. The change mainly originates from the interaction between graphene and the adsorbed O2 molecule. Due to the electron transfer from graphene to adsorbed O2, graphene could tune the interfacial charge transport and efficiently activate molecular oxygen to form O2(-) anions as the major oxidation species instead of OH. In addition, the two-step synthesis approach could efficiently suppress the formation of OH-related defects in the lattice. As a result, the BiPO4-rGO composite exhibited superior photocatalytic activity to BiPO4 and P25, about 4.3 times that of BiPO4 and 6.9 times that of P25. PMID- 24056864 TI - Nanotextured superhydrophobic electrodes enable detection of attomolar-scale DNA concentration within a droplet by non-faradaic impedance spectroscopy. AB - Label-free, rapid detection of biomolecules in microliter volumes of highly diluted solutions (sub-femtomolar) is of essential importance for numerous applications in medical diagnostics, food safety, and chem-bio sensing for homeland security. At ultra-low concentrations, regardless of the sensitivity of the detection approach, the sensor response time is limited by physical diffusion of molecules towards the sensor surface. We have developed a fast, low cost, non faradaic impedance sensing method for detection of synthetic DNA molecules in DI water at attomolar levels by beating the diffusion limit through evaporation of a micro-liter droplet of DNA on a nanotextured superhydrophobic electrode array. Continuous monitoring of the impedance of individual droplets as a function of evaporation time is exploited to dramatically improve the sensitivity and robustness of detection. Formation of the nanostructures on the electrode surface not only increases the surface hydrophobicity, but also allows robust pinning of the droplet contact area to the sensor surface. These two features are critical for performing highly stable impedance measurements as the droplet evaporates. Using this scheme, the detection limit of conventional non-faradaic methods is improved by five orders of magnitude. The proposed platform represents a step forward towards realization of ultra-sensitive lab-on-chip biomolecule detectors for real time point-of-care application. Further works are however needed to ultimately realize the full potential of the proposed approach to appraise biological samples in complex buffer solutions rather than in DI water. PMID- 24056867 TI - Ordered and disordered packing of coronene molecules in carbon nanotubes. AB - Monte Carlo simulations of coronene molecules in single-walled carbon nanotubes (SWCNTs) and dicoronylene molecules in SWCNTs are performed. Depending on the diameter D of the encapsulating SWCNT, regimes favoring the formation of ordered, one-dimensional (1D) stacks of tilted molecules (D <= 1.7 nm for coronene@SWCNT, 1.5 nm <= D <= 1.7 nm for dicoronylene@SWCNT) and regimes with disordered molecular arrangements and increased translational mobilities enabling the thermally induced polymerization of neighboring molecules resulting in the formation of graphene nanoribbons (GNRs) are observed. The results show that the diameter of the encapsulating nanotube is a crucial parameter for the controlled synthesis of either highly ordered 1D structures or GNR precursors. PMID- 24056865 TI - RNA-seq data analysis at the gene and CDS levels provides a comprehensive view of transcriptome responses induced by 4-hydroxynonenal. AB - Reactive electrophiles produced during oxidative stress, such as 4-hydroxynonenal (HNE), are increasingly recognized as contributing factors in a variety of degenerative and inflammatory diseases. Here we used the RNA-seq technology to characterize transcriptome responses in RKO cells induced by HNE at subcytotoxic and cytotoxic doses. RNA-seq analysis rediscovered most of the differentially expressed genes reported by microarray studies and also identified novel gene responses. Interestingly, differential expression detection at the coding DNA sequence (CDS) level helped to further improve the consistency between the two technologies, suggesting the utility and importance of the CDS level analysis. RNA-seq data analysis combining gene and CDS levels yielded an informative and comprehensive picture of gradually evolving response networks with increasing HNE doses, from cell protection against oxidative injury at low dose, initiation of cell apoptosis and DNA damage at intermediate dose to significant deregulation of cellular functions at high dose. These evolving dose-dependent pathway changes, which cannot be observed by the gene level analysis alone, clearly reveal the HNE cytotoxic effect and are supported by IC50 experiments. Additionally, differential expression at the CDS level provides new insights into isoform regulation mechanisms. Taken together, our data demonstrate the power of RNA-seq to identify subtle transcriptome changes and to characterize effects induced by HNE through the generation of high-resolution data coupled with differential analysis at both gene and CDS levels. PMID- 24056866 TI - Free standing TiO2 nanotube array electrodes with an ultra-thin Al2O3 barrier layer and TiCl4 surface modification for highly efficient dye sensitized solar cells. AB - Dye sensitized solar cells were fabricated with free standing TiO2 nanotube (TNT) array films, which were prepared by template assisted atomic layer deposition (ALD) with precise wall thickness control. Efforts to improve the photovoltaic performance were made by using Al2O3 barrier layer coating in conjunction with TiCl4 surface modification. An Al2O3 thin layer was deposited on the TNT electrode by ALD to serve as the charge recombination barrier, but it suffers from the drawback of decreasing the photoelectron injection from dye into TiO2 when the barrier layer became too thick. With the TiCl4 treatment in combination with optimal thickness coating, this problem could be avoided. The co-surface treated electrode presents superior surface property with low recombination rate and good electron transport property. A high conversion efficiency of 8.62% is obtained, which is about 1.8 times that of the device without surface modifications. PMID- 24056868 TI - Chemical ecology of the marine plankton. AB - This review summarizes recent work in the chemical ecology of pelagic marine ecosystems. In order to provide a comprehensive overview of advances in the field over the period covered, we have organized this review by ecological interaction type beginning with intraspecific interactions, then interspecific interactions (including mutualism, parasitism, competition, and predation), and finally community- and ecosystem-wide interactions. PMID- 24056869 TI - Phonon spectroscopy in a Bi2Te3 nanowire array. AB - The lattice dynamics in an array of 56 nm diameter Bi2Te3 nanowires embedded in a self-ordered amorphous alumina membrane were investigated microscopically using (125)Te nuclear inelastic scattering. The element specific density of phonon states is measured on nanowires in two perpendicular orientations and the speed of sound is extracted. Combined high energy synchrotron radiation diffraction and transmission electron microscopy was carried out on the same sample and the crystallinity was investigated. The nanowires grow almost perpendicular to the c axis, partly with twinning. The average speed of sound in the 56 nm diameter Bi2Te3 nanowires is ~7% smaller with respect to bulk Bi2Te3 and a decrease in the macroscopic lattice thermal conductivity by ~13% due to nanostructuration and to the reduced speed of sound is predicted. PMID- 24056870 TI - An evaluation of the effectiveness of novel industrial by-products and organic wastes on heavy metal immobilization in Pb-Zn mine tailings. AB - The in situ immobilization of heavy metals using various easily obtainable amendments is a cost-effective and practical method in the remediation of contaminated sites. In this study, two novel industrial waste materials (sweet sorghum vinasse and medicinal herb residues), spent mushroom compost and municipal solid wastes were used as amendments to assess their potential value for the in situ immobilization of heavy metals in tailings from a Pb-Zn mine in South China. Our results demonstrate that all three freely-available organic wastes decrease the deionized water (DW)- and diethylene-triamine-pentaacetic acid (DTPA)-extractable metal concentrations, enhance the enzyme activity, reduce the metal concentration in plant tissues, and could be used for the remediation of these Pb-Zn mine tailings metals by immobilization. The municipal solid waste failed to reduce the metal concentration in tailings and plant tissues and therefore would not be a suitable immobilizing agent. The potential value of these materials as immobilizers of heavy metals and their remediation efficacy deserve further studies in large-scale field trials. PMID- 24056871 TI - Self-doping and surface plasmon modification induced visible light photocatalysis of BiOCl. AB - In this study we demonstrate that self-doping and surface plasmon resonance could endow a wide-band-gap ternary semiconductor BiOCl with remarkable visible light driven photocatalytic activity on the degradation of organic pollutants and photocurrent generation properties. The self-doped BiOCl with plasmonic silver modification was synthesized by a facile one-pot nonaqueous approach and systematically characterized using X-ray diffraction, scanning electron microscopy, transmission electron microscopy, UV-visible diffuse reflectance spectra, electron spin resonance, and X-ray photoelectron spectroscopy. The photocurrent enhancement was found to be intimately dependent on the irradiation wavelength and matched well with the intensity of the absorption of the Ag nanoparticles. Reactive species trapping experiments and electron spin resonance spectroscopy with 5,5-dimethyl-1-pyrroline-N-oxide spin-trapping adducts confirmed that more oxidative species could be generated from the photogenerated electrons due to the plasmon-excitation of the metallic Ag in the self-doped BiOCl with plasmonic silver modification, which is responsible for the great enhancement of photocatalytic activity and photocurrent. Surface photovoltage spectroscopy and time-resolved photoluminescence spectroscopy results revealed the transfer of plasmon-band-induced electrons from Ag nanoparticles into BiOCl and the acceleration effect of surface plasmon resonance-induced intense oscillating electric fields on this electron transfer. This study would not only provide direct evidence of plasmonic photocatalysis, but also shed light on the design of highly efficient metal-semiconductor composite photocatalysts. PMID- 24056872 TI - An IgE receptor mimetic peptide (PepE) protects mice from IgE mediated anaphylaxis. AB - Crosslinking of receptor-bound Immunoglobulin E (IgE) triggers immediate hypersensitivity reactions including anaphylaxis. Blocking the interaction of IgE with its high-affinity receptor, FcepsilonRI, on mast cells and basophils is an attractive strategy for the treatment of allergies. This approach has seen clinical success using the anti-IgE monoclonal antibody, omalizumab. We recently designed and characterized a novel FcepsilonRI-mimetic peptide (PepE) which contains the two key FcepsilonRI alpha-chain receptor loops known to interact with the epsilon-heavy chain of IgE, C'-E and B-C, with an optimized linker for joining them. PepE has high specificity and affinity for IgE, blocks IgE binding to FcepsilonRI and prevents IgE-induced mediator release from RBL2H3 cells. We have now investigated the biological effects of this peptide in vivo using a line of mice (BALB/c Il4raF709) very sensitive to IgE-mediated systemic anaphylaxis. IgE-deficient (IgE-/-) Il4raF709 mice were passively sensitized with the anti-DNP IgE monoclonal antibody (SPE-7) and subsequently challenged i.v. with DNP-BSA. Mice receiving a single dose of PepE prior to sensitization with SPE-7 IgE were fully protected from anaphylaxis while vehicle control-treated mice displayed strong reactions with significant core body temperature drops and elevated levels of mouse mast cell protease-1 (mMCP-1) in the serum. However, PepE had no effect on IgE-mediated anaphylaxis if given after IgE administration in IgE-/- mice, suggesting that PepE can block binding of free IgE to FcepsilonRI but cannot compete with the receptor for already bound IgE in vivo. A single dose of PepE treatment did not protect IgE sufficient mice from IgE mediated anaphylaxis. However, a 3 week long course of PepE treatment protected IgE sufficient Il4raF709 mice from body temperature drops and elevation of serum mMCP-1. Our findings establish the potential of this type of structure for blocking IgE binding to mast cells in vivo and suggest that related peptides might have the potential to attenuate clinical allergic reactions. PMID- 24056873 TI - Genetically encoded calcium indicator illuminates calcium dynamics in primary cilia. AB - Visualization of signal transduction in live primary cilia constitutes a technical challenge owing to the organelle's submicrometer dimensions and close proximity to the cell body. Using a genetically encoded calcium indicator targeted to primary cilia, we visualized calcium signaling in cilia of mouse fibroblasts and kidney cells upon chemical or mechanical stimulation with high specificity, high sensitivity and wide dynamic range. PMID- 24056874 TI - Inducible control of gene expression with destabilized Cre. AB - Acute manipulation of gene and protein function in the brain is essential for understanding the mechanisms of nervous system development, plasticity and information processing. Here we describe a technique based on a destabilized Cre recombinase (DD-Cre) whose activity is controlled by the antibiotic trimethoprim (TMP). We show that DD-Cre triggers rapid TMP-dependent recombination of loxP flanked ('floxed') alleles in mouse neurons in vivo and validate the use of this system for neurobehavioral research. PMID- 24056875 TI - Smart-seq2 for sensitive full-length transcriptome profiling in single cells. AB - Single-cell gene expression analyses hold promise for characterizing cellular heterogeneity, but current methods compromise on either the coverage, the sensitivity or the throughput. Here, we introduce Smart-seq2 with improved reverse transcription, template switching and preamplification to increase both yield and length of cDNA libraries generated from individual cells. Smart-seq2 transcriptome libraries have improved detection, coverage, bias and accuracy compared to Smart-seq libraries and are generated with off-the-shelf reagents at lower cost. PMID- 24056876 TI - Accounting for technical noise in single-cell RNA-seq experiments. AB - Single-cell RNA-seq can yield valuable insights about the variability within a population of seemingly homogeneous cells. We developed a quantitative statistical method to distinguish true biological variability from the high levels of technical noise in single-cell experiments. Our approach quantifies the statistical significance of observed cell-to-cell variability in expression strength on a gene-by-gene basis. We validate our approach using two independent data sets from Arabidopsis thaliana and Mus musculus. PMID- 24056877 TI - Silver nanoparticles induce developmental stage-specific embryonic phenotypes in zebrafish. AB - Much is anticipated from the development and deployment of nanomaterials in biological organisms, but concerns remain regarding their biocompatibility and target specificity. Here we report our study of the transport, biocompatibility and toxicity of purified and stable silver nanoparticles (Ag NPs, 13.1 +/- 2.5 nm in diameter) upon the specific developmental stages of zebrafish embryos using single NP plasmonic spectroscopy. We find that single Ag NPs passively diffuse into five different developmental stages of embryos (cleavage, early-gastrula, early-segmentation, late-segmentation, and hatching stages), showing stage independent diffusion modes and diffusion coefficients. Notably, the Ag NPs induce distinctive stage and dose-dependent phenotypes and nanotoxicity, upon their acute exposure to the Ag NPs (0-0.7 nM) for only 2 h. The late-segmentation embryos are most sensitive to the NPs with the lowest critical concentration (CNP,c << 0.02 nM) and highest percentages of cardiac abnormalities, followed by early-segmentation embryos (CNP,c < 0.02 nM), suggesting that disruption of cell differentiation by the NPs causes the most toxic effects on embryonic development. The cleavage-stage embryos treated with the NPs develop into a wide variety of phenotypes (abnormal finfold, tail/spinal cord flexure, cardiac malformation/edema, yolk sac edema, and acephaly). These organ structures are not yet developed in cleavage-stage embryos, suggesting that the earliest determinative events to create these structures are ongoing, and disrupted by NPs, which leads to the downstream effects. In contrast, the hatching embryos are most resistant to the Ag NPs, and majority of embryos (94%) develop normally, and none of them develop abnormally. Interestingly, early-gastrula embryos are less sensitive to the NPs than cleavage and segmentation stage embryos, and do not develop abnormally. These important findings suggest that the Ag NPs are not simple poisons, and they can target specific pathways in development, and potentially enable target specific study and therapy for early embryonic development. PMID- 24056878 TI - ERG9 and COQ1 disruption reveals isoprenoids biosynthesis is closely related to mitochondrial function in Saccharomyces cerevisiae. AB - Understanding in vivo regulation of isoprenoid biosynthesis is important for identifying strategies to improve carbon fluxes to desirable endproducts. To study the relevance of gene functions, substrate availability, metabolic flux, and the energetics of resource utilization for isoprenoids biosynthesis, Saccharomyces cerevisiae was co-engineered with endogenous deregulated erg9 and/or coq1 and exogenous plant genes that will lead to sesqui- and diterpene production. The flow of substrates through the MVA pathway statistically showed isoprenoids precursor levels were tightly regulated by erg9 and coq1 genes in S. cerevisiae. Physiological analysis by fluorescent probes and labeling techniques revealed elimination of the competing and/or degrading pathways by gene knockout can increase cellular stresses and change the energy metabolism. To further evaluate the role of erg9 and coq1 in the regulation of isoprenoids synthesis, heterologous terpene synthases from plants were introduced into S. cerevisiae, including the wild-type and mutant strains along with feeding of various metal cofactors under anoxic/oxic conditions. The product distribution in the strains indicated that the energy barrier could be the reason that different metal ion assisted electrophilic attacks initiated carbocation formation, carbocation stabilization, and rearrangement, incorporating exquisite regio- and stereospecificity, to generate structurally diverse products. The yeast altered in the profile of terpenoids and their precursor pools aided the mechanisms of terpenoid biosynthesis and its regulation, highlighting the need for mitochondrial function when engineering metabolic flux using assumptions based on a comprehensive network of the mitochondrial system. PMID- 24056879 TI - The NR4A orphan nuclear receptors do not confer prednisolone resistance in pediatric acute lymphoblastic leukemia. PMID- 24056880 TI - RelA and RelB cross-talk and function in Epstein-Barr virus transformed B cells. AB - In this study, we determined the respective roles of RelA and RelB NF-kappaB subunits in Epstein-Barr virus (EBV)-transformed B cells. Using different EBV immortalized B-cell models, we showed that only RelA activation increased both survival and cell growth. RelB activity was induced secondarily to RelA activation and repressed RelA DNA binding by trapping the p50 subunit. Reciprocally, RelA activation repressed RelB activity by increasing expression of its inhibitor p100. To search for such reciprocal inhibition at the transcriptional level, we studied gene expression profiles of our RelA and RelB regulatable cellular models. Ten RelA-induced genes and one RelB-regulated gene, ARNTL2, were repressed by RelB and RelA, respectively. Apart from this gene, RelB signature was included in that of RelA Functional groups of RelA-regulated genes were for control of energy metabolism, genetic instability, protection against apoptosis, cell cycle and immune response. Additional functions coregulated by RelA and/or RelB were autophagy and plasma cell differentiation. Altogether, these results demonstrate a cross-inhibition between RelA and RelB and suggest that, in fine, RelB was subordinated to RelA. In the view of future drug development, RelA appeared to be pivotal in both classical and alternative activation pathways, at least in EBV-transformed B cells. PMID- 24056882 TI - Molecular basis for solvent dependent morphologies observed on electrosprayed surfaces. AB - We study the causes of the observed tunable hydrophobicity of poly(styrene-co perfluoroalkyl ethylacrylate) electrosprayed in THF, DMF, and THF:DMF (1:1) solvents. Under the assumption that equilibrium morphologies in the solvent significantly affect the patterns observed on electrosprayed surfaces, we use atomistic and coarse-grained simulations supported by dynamic light scattering (DLS) experiments to focus on the parameters that affect the resulting morphology of superhydrophobic electrosprayed beads. The differing equilibrium chain size distributions in these solvents examined by DLS are corroborated by chain dimensions obtained via molecular dynamics simulations. Mesoscopic morphologies monitored by dissipative particle dynamics simulations explain experimental observations; in particular, the preference of the polymer for THF over DMF in the binary mixture rationalizes the dual scale roughness driven by stable microphase separation. Drying phenomena that affect resultant dual-scale roughness are described in three stages, each interpreted by concentration dependent diffusion and surface mass transfer coefficients of the solvents. Irrespective of the presence of polar groups in the structure, a conflict between the lower-boiling point solvent adhering to the polymer and the less volatile solvent abundant in the bulk leads to perfectly hydrophobic surfaces. PMID- 24056881 TI - The role of different genetic subtypes of CEBPA mutated AML. AB - The prognostic impact of mutations in the CCAAT/enhancer binding protein alpha (CEBPA) gene was evaluated in the context of concomitant molecular mutations and cytogenetic aberrations in acute myeloid leukemia (AML). CEBPA was screened in a cohort of 2296 adult AML cases. Of 244 patients (10.6%) with CEBPA mutations, 140 cases (6.1%) were single-mutated (CEBPAsm) and 104 cases (4.5%) were double mutated (CEBPAdm). Cytogenetic analysis revealed normal karyotype in 172/244 (70.5%) of CEBPAmut cases, whereas in 72/244 cases (29.5%) at least one cytogenetic aberration was detected. Concurrent molecular mutations were seen less frequently in CEBPAdm than in CEBPAsm AML cases (69.2% vs 88.6% P<0.001). In detail, the spectrum of concurrent mutations was different in both groups with the frequent occurrence of GATA1 and WT1 mutations in CEBPAdm patients. In contrast, FLT3-ITD, NPM1, ASXL1 and RUNX1 mutations were detected more frequently in CEBPAsm cases. Favorable outcome was restricted to CEBPAdm cases and remained an independent prognostic factor for a favorable outcome in multivariate analysis (hazard ratio: 0.438, P=0.020). Outcome in CEBPAsm cases strongly depended on concurrent FLT3-ITD. In conclusion, we propose that only CEBPAdm should be considered as an entity in the WHO classification of AML and should be clearly distinguished from CEBPAsm AML. PMID- 24056883 TI - Serum metabolic profiles reveal the effect of formoterol on cachexia in tumor bearing mice. AB - Cancer cachexia is a complex metabolic syndrome that cannot be fully reversed by conventional nutritional support, and leads to the progressive wasting of body tissues, particularly the loss of lean muscle mass. Formoterol, a highly selective beta2-adrenoceptor therapeutic drug, gives potential anabolic responses in the context of skeletal muscles and was widely confirmed to possess anti cachexia effects. However, the possible metabolic pathways and the metabolite changes that initiate and maintain these anabolic responses remain poorly understood. In the present study, a (1)H NMR-metabonomics model was established to investigate the metabolic features of cancer cachexia and the contribution of formoterol to serum metabolites in a mouse model bearing CT26 carcinoma cells. Among the metabolic processes found in serum, the ones associated with cancer are glycolysis and lipid lipolysis. However, the citrate cycle and amino acid metabolism are the major metabolic characteristics of cachexia. Furthermore, formoterol stimulated skeletal muscle growth, increased the body weight and altered the metabolic profile. Amino acids, ketone bodies and citrate cycle metabolites are potential biomarkers associated with these functional pathways. Taking the pathways of cancer cachexia into account, formoterol could regulate the imbalance in glycolysis, the citrate cycle, and in lipid and amino acid metabolism. Collectively, these results indicate that formoterol partially reverses the metabolic disturbances associated with cachexia. PMID- 24056884 TI - Estimation of Extreme Values and Associated Level Sets of a Regression Function via Selective Sampling. AB - We propose a new method for estimating the locations and the value of an absolute maximum (minimum) of a function from the observations contaminated by random noise. Our goal is to solve the problem under minimal regularity and shape constraints. In particular, we do not assume differentiability of a function nor that its maximum is attained at a single point. We provide tight upper and lower bounds for the performance of proposed estimators. Our method is adaptive with respect to the unknown parameters of the problem over a large class of underlying distributions. PMID- 24056885 TI - Active liquid degassing in microfluidic systems. AB - We present a method for efficient air bubble removal in microfluidic applications. Air bubbles are extracted from a liquid chamber into a vacuum chamber through a semipermeable membrane, consisting of PDMS coated with amorphous Teflon((r)) AF 1600. Whereas air is efficiently extracted through the membrane, water loss is greatly reduced by the Teflon even at elevated temperatures. We present the water loss and permeability change with the amount of added Teflon AF to the membrane. Also, we demonstrate bubble-free, multiplex DNA amplification using PCR in a PDMS microfluidic device. PMID- 24056887 TI - Colloidal chemically fabricated ZnO : Cu-based photodetector with extended UV visible detection waveband. AB - Polycrystalline ZnO : Cu-based film photodetectors with extended detection waveband (UV and visible light) were fabricated using facile colloidal chemistry and a post-annealing process. The obtained detectors are highly sensitive to visible light and can realize the response switch between UV and visible light. A native and extrinsic trap cooperatively controlled space charge limited (SCL) transport mechanism is proposed to understand this complex photoconduction behaviour. PMID- 24056888 TI - Signatures in vibrational and UV-visible absorption spectra for identifying cyclic hydrocarbons by graphene fragments. AB - To promote possible applications of graphene in molecular identification based on stacking effects, in particular in recognizing aromatic amino acids and even sequencing nucleobases in life sciences, we comprehensively study the interaction between graphene segments and different cyclic organic hydrocarbons including benzene (C6H6), cyclohexane (C6H12), benzyne (C6H4), cyclohexene (C6H10), 1,3 cyclohexadiene (C6H8(1)) and 1,4-cyclohexadiene (C6H8(2)), using the density functional tight-binding (DFTB) method. Interestingly, we find obviously different characteristics in Raman vibrational and ultraviolet visible absorption spectra of the small molecules adsorbed on the graphene sheet. Specifically, we find that both spectra involve clearly different characteristic peaks, belonging to the different small molecules upon adsorption, with the ones of ionized molecules being more substantial. Further analysis shows that the adsorptions are almost all due to the presence of dispersion energy in neutral cases and involve charge transfer from the graphene to the small molecules. In contrast, the main binding force in the ionic adsorption systems is the electronic interaction. The results present clear signatures that can be used to recognize different kinds of aromatic hydrocarbon rings on graphene sheets. We expect that our findings will be helpful for designing molecular recognition devices using graphene. PMID- 24056889 TI - Carbon doping of InSb nanowires for high-performance p-channel field-effect transistors. AB - Due to the unique physical properties, small bandgap III-V semiconductor nanowires such as InAs and InSb have been extensively studied for the next generation high-speed and high-frequency electronics. However, further CMOS applications are still limited by the lack of efficient p-doping in these nanowire materials for high-performance p-channel devices. Here, we demonstrate a simple and effective in situ doping technique in the solid-source chemical vapor deposition of InSb nanowires on amorphous substrates employing carbon dopants. The grown nanowires exhibit excellent crystallinity and uniform stoichiometric composition along the entire length of the nanowires. More importantly, the versatility of this doping scheme is illustrated by the fabrication of high performance p-channel nanowire field-effect-transistors. High electrically active carbon concentrations of ~7.5 * 10(17) cm(-3) and field-effect hole mobility of ~140 cm(2) V(-1) s(-1) are achieved which are essential for compensating the electron-rich surface layers of InSb to enable heavily p-doped and high performance device structures. All these further indicate the technological potency of this in situ doping technique as well as p-InSb nanowires for the fabrication of future CMOS electronics. PMID- 24056890 TI - Upper urinary tract tumors: how does the contrast enhancement measured in a split bolus CTU correlate to histological staging? AB - BACKGROUND: Computed tomography urography (CTU) is used widely in the work-up of patients with symptoms of urinary tract lesions. Preoperative knowledge of whether a tumor is invasive or non-invasive is important for the choice of surgery. So far there are no studies about the distinction of invasive and non invasive tumors in ureter and renal pelvis based on the enhancement measured with Hounsfield Units. PURPOSE: To examine the value of CTU using split-bolus technique to distinguish non-invasive from invasive urothelial carcinomas in the upper urinary tract. MATERIAL AND METHODS: Patients who underwent nephroureterectomy between 2006 and 2011 and who had split-bolus CTU prior to surgery were included. The images were available electronically. The attenuation values before and after administration of iodine-based contrast media were measured. The radiology, patient, and pathology records were reviewed. RESULTS: Of the 158 patients who underwent unilateral nephroureterectomy 69 fulfilled the inclusion criteria. Histopathological examination revealed 31 patients with non invasive and 38 with invasive urothelial carcinoma. Neither absolute attenuation nor change in attenuation values obtained at CTU could distinguish between invasive and non-invasive lesions. No patients had a CTU within the last year before the examination that resulted in surgery. CONCLUSION: A split-bolus CTU cannot distinguish between invasive and non-invasive urothelial tumors in the upper urinary tract, but the examination is useful to diagnose a tumor in the renal pelvis and the ureter. PMID- 24056891 TI - Coupled plasmons induce broadband circular dichroism in patternable films of silver nanoparticles with chiral ligands. AB - This contribution reports the chiro-optic response of as-cast and photopatterned films of silver nanoparticles capped with photothermally-cleavable chiral ligands. We demonstrate broadband circular dichroism in these nanoparticle films, which is not present in dispersions of the nanoparticles capped with the chiral ligands. Long wavelength circular dichroism is derived from coupling of the plasmonic bands of neighbouring silver nanoparticles. Furthermore, the chiral response is preserved in the microstructured film after photopatterning using direct two-photon absorption in the plasmonic band of the silver nanoparticles. Thus, both the as-cast and photopatterned films show circular dichroism from the UV wavelength of intrinsic absorption of the ligand, through the plasmon resonances of both the isolated silver nanoparticles and the interacting nanoparticles, which extend to the near IR. Density functional theory (DFT) calculations of model electronic complexes of a chiral ligand and a small metallic cluster suggest that the new chiral bands at the plasmonic resonances are derived from new chiral hybrid electronic states of the metal nanoparticle ligand complexes. PMID- 24056893 TI - Is there a role for bevacizumab in the treatment of glioblastoma? PMID- 24056894 TI - A review on cylindrospermopsin: the global occurrence, detection, toxicity and degradation of a potent cyanotoxin. AB - Cylindrospermopsin is an important cyanobacterial toxin found in water bodies worldwide. The ever-increasing and global occurrence of massive and prolonged blooms of cylindrospermopsin-producing cyanobacteria poses a potential threat to both human and ecosystem health. Its toxicity is associated with metabolic activation and may involve mechanisms that adversely affect a wide variety of targets in an organism. Cylindrospermopsin has been shown to be cytotoxic, dermatotoxic, genotoxic, hepatotoxic in vivo, developmentally toxic, and may be carcinogenic. Human exposure may occur through drinking water, during recreational activities and by consuming foods in which the toxin may have bioaccumulated. Drinking water shortages of sufficient quality coupled with growing human pressures and climate variability and change necessitate an integrated and sustainable water management program. This review presents an overview of the importance of cylindrospermopsin, its detection, toxicity, worldwide distribution, and lastly, its chemical and biological degradation and removal by natural processes and drinking water treatment processes. PMID- 24056895 TI - Permeabilization of adhered cells using an inert gas jet. AB - Various cell transfection techniques exist and these can be broken down to three broad categories: viral, chemical and mechanical. This protocol describes a mechanical method to temporally permeabilize adherent cells using an inert gas jet that can facilitate the transfer of normally non-permeable macromolecules into cells. We believe this technique works by imparting shear forces on the plasma membrane of adherent cells, resulting in the temporary formation of micropores. Once these pores are created, the cells are then permeable to genetic material and other biomolecules. The mechanical forces involved do run the risk of permanently damaging or detaching cells from their substrate. There is, therefore, a narrow range of inert gas dynamics where the technique is effective. An inert gas jet has proven efficient at permeabilizing various adherent cell lines including HeLa, HEK293 and human abdominal aortic endothelial cells. This protocol is appropriate for the permeabilization of adherent cells both in vitro and, as we have demonstrated, in vivo, showing it may be used for research and potentially in future clinical applications. It also has the advantage of permeabilizing cells in a spatially restrictive manner, which could prove to be a valuable research tool. PMID- 24056896 TI - Cancer-related marketing centrality motifs acting as pivot units in the human signaling network and mediating cross-talk between biological pathways. AB - Network motifs in central positions are considered to not only have more in coming and out-going connections but are also localized in an area where more paths reach the networks. These central motifs have been extensively investigated to determine their consistent functions or associations with specific function categories. However, their functional potentials in the maintenance of cross-talk between different functional communities are unclear. In this paper, we constructed an integrated human signaling network from the Pathway Interaction Database. We identified 39 essential cancer-related motifs in central roles, which we called cancer-related marketing centrality motifs, using combined centrality indices on the system level. Our results demonstrated that these cancer-related marketing centrality motifs were pivotal units in the signaling network, and could mediate cross-talk between 61 biological pathways (25 could be mediated by one motif on average), most of which were cancer-related pathways. Further analysis showed that molecules of most marketing centrality motifs were in the same or adjacent subcellular localizations, such as the motif containing PI3K, PDK1 and AKT1 in the plasma membrane, to mediate signal transduction between 32 cancer-related pathways. Finally, we analyzed the pivotal roles of cancer genes in these marketing centrality motifs in the pathogenesis of cancers, and found that non-cancer genes were potential cancer-related genes. PMID- 24056897 TI - The impact of clinical pharmacy services in China on the quality use of medicines: a systematic review in context of China's current healthcare reform. AB - INTRODUCTION: Recently, China initiated an ambitious healthcare reform aiming to provide affordable and equitable basic health care to all by 2020. To meet these goals, new policies issued by China's Ministry of Health mandate clinical pharmacy services be integrated into China's hospitals. This review aims to highlight the impact of clinical pharmacy services on the quality use of medicines in hospitals in China. METHODS: Both English and Chinese databases were used. For the English databases, Web of Science, Medline, International Pharmaceutical Abstracts and Embase were searched using the following keywords ('pharmacists' OR 'pharmacy' OR 'pharmaceutical services/pharmaceutical care') AND ('China'). For the Chinese database, Chinese Biomedical Literature Database on disc was searched using the following keywords ('clinical pharmacist' OR 'clinical pharmacy' OR 'pharmaceutical care' OR 'pharmaceutical services'). Articles were then retrieved from WanFang database and China Knowledge Resource Integrated Database. RESULTS: A total of 75 published papers were included in this review. The majority of studies were conducted in the inpatient setting (68%), which included clinical pharmacy interventions such as educating doctors and patients, evaluating and monitoring the implementation of hospital policies and/or reviewing medications on the ward. In the outpatient setting, the majority of studies conducted involved educating patients. Clinical pharmacy services frequently focused on antimicrobials (44%). More than half of these studies employed an administrative intervention alongside the clinical pharmacy service. CONCLUSION: Clinical pharmacy services in China, with its unique healthcare system and cultural nuances, appear to positively influence patient care and the appropriate use of medications. From the published literature, it is expected that clinical pharmacy services can make a strong contribution to China's healthcare reform with further governmental and educational support. PMID- 24056898 TI - Bridging the accountability divide: male circumcision planning in Rwanda as a case study in how to merge divergent operational planning approaches. AB - When voluntary medical male circumcision (MC) was confirmed as an effective tool for HIV prevention in sub-Saharan Africa in 2007, many public health policy makers and practitioners were eager to implement the intervention. How to roll out the tool as part of comprehensive strategy however was less clear. At the time, very little was known about the capacity of health systems to scale delivery of the new intervention. Today, nearly all countries prioritized for the intervention are far behind their targets. To contribute to the discourse on why this is, we develop a historical analysis of medical MC planning in sub-Saharan Africa using our own experience of this process in Rwanda. We compare our previously unpublished feasibility analysis from 2008 with international research published in 2009, which suggested how Rwanda could reduce HIV incidence through a rapid MC intervention, and Rwanda's eventual 2010 official operational plan. We trace how, in the face of uncertainty, operational plans avoided discussing the details of feasibility and focused instead on defining optimal circumcision capacity needed to achieve country level target reductions in HIV incidence. We show a distinct gap between the targets set in the official operational plan and what we determined was feasible in 2008. With actual data from the ground now available, we show our old feasibility models more closely approximate circumcision delivery rates to date. With an eye toward the future of long-term policy planning, we discuss the mechanics of how accountability gaps like this occur in global health policy making and how practitioners can better create achievable operational targets. PMID- 24056899 TI - Controllable synthesis of metal selenide heterostructures mediated by Ag2Se nanocrystals acting as catalysts. AB - Ag2Se nanocrystals were demonstrated to be novel semiconductor mediators, or in other word catalysts, for the growth of semiconductor heterostructures in solution. This is a result of the unique feature of Ag2Se as a fast ion conductor, allowing foreign cations to dissolve and then to heterogrow the second phase. Using Ag2Se nanocrystals as catalysts, dimeric metal selenide heterostructures such as Ag2Se-CdSe and Ag2Se-ZnSe, and even multi-segment heterostructures such as Ag2Se-CdSe-ZnSe and Ag2Se-ZnSe-CdSe, were successfully synthesized. Several interesting features were found in the Ag2Se based heterogrowth. At the initial stage of heterogrowth, a layer of the second phase forms on the surface of an Ag2Se nanosphere, with a curved junction interface between the two phases. With further growth of the second phase, the Ag2Se nanosphere tends to flatten the junction surface by modifying its shape from sphere to hemisphere in order to minimize the conjunct area and thus the interfacial energy. Notably, the crystallographic relationship of the two phases in the heterostructure varies with the lattice parameters of the second phase, in order to reduce the lattice mismatch at the interface. Furthermore, a small lattice mismatch at the interface results in a straight rod-like second phase, while a large lattice mismatch would induce a tortuous product. The reported results may provide a new route for developing novel selenide semiconductor heterostructures which are potentially applicable in optoelectronic, biomedical, photovoltaic and catalytic fields. PMID- 24056900 TI - Next-generation nanotechnology laboratories with simultaneous reduction of all relevant disturbances. AB - The tremendous variety of nanotechnology experiments and tools to fabricate and characterize ever-smaller structures down to molecular or even atomic scales leads to stringent demands for appropriate, so-called "silent", premises that allow such susceptible experiments to be conducted. Reducing dimensions means smaller absolute optical and electrical signal levels, and consequently reduced signal-to-noise ratios. Hence, in addition to short-range disturbances inside the laboratory, remote long-range noise sources have to be considered for next generation laboratories that aim at screening the disturbances and keeping the remaining values at utmost constancy. We present a novel laboratory concept that addresses simultaneously all the disturbances relevant for nanotechnology, namely, vibrations, electro-magnetic fields, temperature, humidity, and sound. Particular attention was paid to tackling the mutual derogation of the various measures to enable unprecedented performance of the novel research platform. PMID- 24056901 TI - Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. AB - In biological fluids, proteins bind to the surface of nanoparticles to form a coating known as the protein corona, which can critically affect the interaction of the nanoparticles with living systems. As physiological systems are highly dynamic, it is important to obtain a time-resolved knowledge of protein-corona formation, development and biological relevancy. Here we show that label-free snapshot proteomics can be used to obtain quantitative time-resolved profiles of human plasma coronas formed on silica and polystyrene nanoparticles of various size and surface functionalization. Complex time- and nanoparticle-specific coronas, which comprise almost 300 different proteins, were found to form rapidly (<0.5 minutes) and, over time, to change significantly in terms of the amount of bound protein, but not in composition. Rapid corona formation is found to affect haemolysis, thrombocyte activation, nanoparticle uptake and endothelial cell death at an early exposure time. PMID- 24056902 TI - Direct probing of the exchange interaction at buried interfaces. AB - The fundamental interactions between magnetic moments at interfaces have an important impact on the properties of layered magnetic structures. Hence, a direct probing of these interactions is highly desirable for understanding a wide range of phenomena in low-dimensional solids. Here we propose a method for probing the magnetic exchange interaction at buried interfaces using spin polarized electrons and taking advantage of the collective nature of elementary magnetic excitations (magnons). We demonstrate that, for the case of weak coupling at the interface, the low-energy magnon mode is mainly localized at the interface. Because this mode has the longest lifetime of the modes and has a finite spectral weight across the layers on top, it can be probed by electrons. A comparison of experimental data and first-principles calculations leads to the determination of the interface exchange parameters. This method may help the development of spectroscopy of buried magnetic interfaces. PMID- 24056903 TI - Nanoparticles: Tracking protein corona over time. PMID- 24056904 TI - Inhibition of Orai1-mediated Ca(2+) entry is a key mechanism of the antiproliferative action of sirolimus in human arterial smooth muscle. AB - Sirolimus (rapamycin) is used in drug-eluting stent strategies and proved clearly superior in this application compared with other immunomodulators such as pimecrolimus. The molecular basis of this action of sirolimus in the vascular system is still incompletely understood. Measurements of cell proliferation in human coronary artery smooth muscle cells (hCASM) demonstrated a higher antiproliferative activity of sirolimus compared with pimecrolimus. Although sirolimus lacks inhibitory effects on calcineurin, nuclear factor of activated T cell activation in hCASM was suppressed to a similar extent by both drugs at 10 MUM. Sirolimus, but not pimecrolimus, inhibited agonist-induced and store operated Ca(2+) entry as well as cAMP response element binding protein (CREB) phosphorylation in human arterial smooth muscle, suggesting the existence of an as-yet unrecognized inhibitory effect of sirolimus on Ca(2+) signaling and Ca(2+) dependent gene transcription. Electrophysiological experiments revealed that only sirolimus but not pimecrolimus significantly blocked the classical stromal interaction molecule/Orai-mediated, store-operated Ca(2+) current reconstituted in human embryonic kidney cells (HEK293). A link between Orai function and proliferation was confirmed by dominant-negative knockout of Orai in hCASM. Analysis of the effects of sirolimus on cell proliferation and CREB activation in an in vitro model of arterial intervention using human aorta corroborated the ability of sirolimus to suppress stent implantation-induced CREB activation in human arteries. We suggest inhibition of store-operated Ca(2+) entry based on Orai channels and the resulting suppression of Ca(2+) transcription coupling as a key mechanism underlying the antiproliferative activity of sirolimus in human arteries. This mechanism of action is specific for sirolimus and not a general feature of drugs interacting with FK506-binding proteins. PMID- 24056905 TI - Acute hyperinsulinemia increases the contraction of retinal arterioles induced by elevated blood pressure. AB - Diabetic retinopathy is accompanied by disturbances in retinal blood flow, which is assumed to be related to the diabetic metabolic dysregulation. It has previously been shown that normoinsulinemic hyperglycemia has no effect on the diameter of retinal arterioles at rest and during an increase in the arterial blood pressure induced by isometric exercise. However, the influence of hyperinsulinemia on this response has not been studied in detail. In seven normal persons, the diameter response of retinal arterioles to an increased blood pressure induced by isometric exercise, to stimulation with flickering light, and to the combination of these stimuli was studied during euglycemic normoinsulinemia (protocol N) on one examination day, and euglycemic hyperinsulinemia (protocol H) on another examination day. Isometric exercise induced significant contraction of retinal arterioles at all examinations, but during a repeated examination the diameter response was significantly reduced in the test persons following the N protocol and increased in the persons following the H protocol. Flicker stimulation induced a significant dilatation of retinal arterioles at all examinations, and the response was significantly higher during a repeated examination, irrespective of the insulin level. Repeated exposure to isometric exercise reduces contraction, whereas repeated exposure to flickering light increases dilatation of retinal arterioles in vivo. Hyperinsulinemia increases contraction of retinal arterioles induced by isometric exercise. PMID- 24056906 TI - New insights into the dynamics and morphology of P3HT:PCBM active layers in bulk heterojunctions. AB - Organic photovoltaics (OPVs) are a topic of extensive research because of their potential application in solar cells. Recent work has led to the development of a coarse-grained model for studying poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl C61-butyric acid methyl ester (PCBM) blends using molecular simulations. Here we provide further validation of the force field and use it to study the thermal annealing process of P3HT:PCBM blends. A key finding of our study is that, in contrast to a previous report, the annealing process does not converge at the short time scales reported. Rather, we find that the self-assembly of the blends is characterized by three rate dependent stages that require much longer simulations to approach convergence. Using state-of-the-art high performance computing, we are able to study annealing at length and time scales commensurate with devices used in experiments. Our simulations show different phase segregated morphologies dependent on the P3HT chain length and PCBM volume fraction in the blend. For short chain lengths, we observed a smectic morphology containing alternate P3HT and PCBM domains. In contrast, a phase segregated morphology containing domains of P3HT and PCBM distributed randomly in space is found for longer chain lengths. Theoretical arguments justifying stabilization of these morphologies due to shape anisotropy of P3HT (rod-like) and PCBM (sphere-like) are presented. Furthermore, results on the structure factor, miscibility of P3HT and PCBM, domain spacing and kinetics of phase segregation in the blends are presented in detail. Qualitative comparison of these results with published small angle neutron scattering experiments in the literature is presented and an excellent agreement is found. PMID- 24056907 TI - Flexible shrink-induced high surface area electrodes for electrochemiluminescent sensing. AB - Photolithographically defined metallic thin film on commodity shrink-wrap is leveraged to create robust electrodes. By thermally shrinking the film, electrodes are reduced by 20* in footprint for improved resolution and conductivity with >600% enhancements in electrochemically active surface area; as electrochemiluminescent sensors, they demonstrate improved limits of detection. PMID- 24056908 TI - The non-canonical Wnt ligand Wnt5a rescues morphological deficits in Prickle2 deficient hippocampal neurons. PMID- 24056909 TI - Questions about DISC1 as a genetic risk factor for schizophrenia. PMID- 24056910 TI - Combining small molecules for cell reprogramming through an interatomic analysis. AB - The knowledge available about the application and generation of induced pluripotent stem cells (iPSC) has grown since their discovery, and new techniques to enhance the reprogramming process have been described. Among the new approaches to induce iPSC that have gained great attention is the use of small molecules for reprogramming. The application of small molecules, unlike genetic manipulation, provides for control of the reprogramming process through the shifting of concentrations and the combination of different molecules. However, different researchers have reported the use of "reprogramming cocktails" with variable results and drug combinations. Thus, the proper combination of small molecules for successful and enhanced reprogramming is a matter for discussion. However, testing all potential drug combinations in different cell lineages is very costly and time-consuming. Therefore, in this article, we discuss the use of already employed molecules for iPSC generation, followed by the application of systems chemo-biology tools to create different data sets of protein-protein (PPI) and chemical-protein (CPI) interaction networks based on the knowledge of already used and new reprogramming cocktail combinations. We further analyzed the biological processes associated with PPI-CPI networks and provided new potential protein targets to be inhibited or expressed for stem cell reprogramming. In addition, we applied a new interference analysis to prospective targets that could negatively affect the classical pluripotency-associated factors (SOX2, NANOG, KLF4 and OCT4) and thus potentially improve reprogramming protocols. PMID- 24056912 TI - Isolation of human hepatocytes by a two-step collagenase perfusion procedure. AB - The liver, an organ with an exceptional regeneration capacity, carries out a wide range of functions, such as detoxification, metabolism and homeostasis. As such, hepatocytes are an important model for a large variety of research questions. In particular, the use of human hepatocytes is especially important in the fields of pharmacokinetics, toxicology, liver regeneration and translational research. Thus, this method presents a modified version of a two-step collagenase perfusion procedure to isolate hepatocytes as described by Seglen (1). Previously, hepatocytes have been isolated by mechanical methods. However, enzymatic methods have been shown to be superior as hepatocytes retain their structural integrity and function after isolation. This method presented here adapts the method designed previously for rat livers to human liver pieces and results in a large yield of hepatocytes with a viability of 77+/-10%. The main difference in this procedure is the process of cannulization of the blood vessels. Further, the method described here can also be applied to livers from other species with comparable liver or blood vessel sizes. PMID- 24056913 TI - Solution-processed Ag-doped ZnO nanowires grown on flexible polyester for nanogenerator applications. AB - The integration of ZnO nanowire-based energy harvesting devices into flexible polyesters or clothes would have a significant effect on the energy harvesting building block for harvesting the mechanical energy from human motions. Moreover, the demonstration of high output power via a doping process opens an important method for enhancing the output power. Here, we report solution-based synthesis of Ag-doped ZnO nanowires on flexible polyester substrates without using any high temperature annealing processes. Along with the structural and optical characteristics of the Ag-doped ZnO nanowires, we demonstrate the efficient features of Ag-doped nanogenerators through the measurement of a sound-driven piezoelectric energy device with an output power of 0.5 MUW, which is nearly 2.9 times that of a nanogenerator with un-doped ZnO NWs. This finding could provide the possibility of high output nanogenerators for practical applications in future portable/wearable personal displays and motion sensors. PMID- 24056914 TI - Emission behavior of hexabromocyclododecanes and polybrominated diphenyl ethers from flame-retardant-treated textiles. AB - To evaluate the emission behavior of hexabromocyclododecanes (HBCDs) and polybrominated diphenyl ethers (PBDEs) added to textile products as flame retardants, we used a small stainless steel container (7 cm i.d. * 5.5 cm height, ca. 210 cm(3)) to conduct emission tests on three upholstery textile samples at temperatures of 20, 40, 60, and 80 degrees C. The textile samples, which were intended for use in curtain manufacture and had been treated with either technical HBCD or technical DecaBDE, emitted HBCDs and PBDEs, including BDE 209, even at room temperature (20 degrees C), and the emission rates increased with increasing test temperature. These results indicate that flame-retardant-treated upholstery textiles have the potential to be major sources of brominated flame retardant contamination in indoor air and dust. The HBCD diastereomer emission profiles at the test temperatures of 20 and 40 degrees C were similar to the profiles of the original textile samples; in contrast, at the higher test temperatures, the proportion of alpha-HBCD was larger (up to 70% of the total HBCD emission) than in the original samples. At the higher test temperatures, the proportions of di- to hexa-BDEs in the emissions were clearly larger than in the original sample, suggesting that the textile products treated with technical DecaBDE could be a source of environmentally relevant PBDE congeners such as BDE 47, 99, and 100. The emission rates of HBCDs from the textiles were two orders of magnitude higher than those of PBDEs, suggesting that HBCDs volatilize more easily from textile products to the indoor environment than PBDEs. PMID- 24056915 TI - Biomimetic artificial Si compound eye surface structures with broadband and wide angle antireflection properties for Si-based optoelectronic applications. AB - We report the biomimetic artificial silicon (Si) compound eye structures for broadband and wide-angle antireflection by integrating nanostructures (NSs) into periodically patterned microstructures (p-MSs) via thermal dewetting of gold and subsequent dry etching. The truncated cone microstructures with a two-dimensional hexagonal symmetry pattern were fabricated by photolithography and dry etching processes. The desirable shape and density of the nanostructures were obtained by controlled dewetting. The incorporation of p-MSs into the NS/Si surface further reduced the surface total reflectance over a wide wavelength range of 300-1030 nm at near normal incidence, indicating the average reflectance (Ravg) and solar weighted reflectance (RSWR) values of ~ 2.5% and 2%, respectively, compared to the only NSs on the flat Si surface (i.e., Ravg ~ 4.9% and RSWR ~ 4.5%). Additionally, the resulting structure improved the angle-dependent antireflection property due to its relatively omnidirectional shape, which exhibited the Ravg < 4.3% and RSWR < 3.7% in the wavelength region of 300-1100 nm even at a high incident light angle of 70 degrees in the specular reflectance. PMID- 24056916 TI - Application of [18F]FDG in radiolabeling reactions using microfluidic technology. AB - Radiolabeling of peptides with the short-lived positron emitter fluorine-18 is usually a challenging endeavour. Conventional radiolabeling reactions mostly require fairly large amounts of peptides as labeling precursors, and extensive synthesis times. Intrinsic advantages of microfluidic technology permit to overcome these hurdles. Herein, we describe how microfluidic technology combined with [(18)F]FDG as readily available PET radiotracer allows for fast and high yielding radiolabeling reactions of peptides with fluorine-18. PMID- 24056918 TI - Hydrothermal growth of textured Ba(x)Sr(1-x)TiO3 films composed of nanowires. AB - A novel method for synthesis of Barium Strontium Titanate (BST) films with a high degree of texture is developed with a two-step hydrothermal reaction and without the need for costly equipment. The dielectric constant and ferroelectric properties of the film can be tuned by varying the Ba : Sr molar ratio of the materials. The maximum ambient temperature dielectric constant of these BST films can reach 811 when the Ba molar fraction ("x" in BaxSr1-xTiO3) is 0.71, which corresponds with the tetragonal to cubic phase transition of the solid solution. The ferroelectric behavior of the Ba0.91Sr0.09TiO3 film is confirmed by atomic force microscopy (AFM). PMID- 24056919 TI - The association of the cytoplasmic domains of interleukin 4 receptor alpha and interleukin 13 receptor alpha 2 regulates interleukin 4 signaling. AB - Interleukin-4 (IL-4) and Interleukin-13 (IL-13), key cytokines in the pathogenesis of allergic inflammatory disease, mediate their effects via a receptor composed of IL-13Ralpha1 and IL-4Ralpha. A third (decoy) receptor called IL-13Ralpha2 regulates interleukin signaling through this receptor complex. We employed a variety of biophysical and cell-based techniques to decipher the role of this decoy receptor in mediating IL-4 signaling though the IL-4Ralpha-IL 13Ralpha1 receptor complex. Surface plasmon resonance (SPR) analysis showed that IL-13Ralpha2 does not bind IL-4, and does not affect binding of IL-4 to IL 4Ralpha. These results indicate that the extracellular domains of IL-4Ralpha and IL-13Ralpha2 are not involved in the regulation of IL-4 signaling by IL 13Ralpha2. We next used a two-hybrid system to show that the cytoplasmic domains of IL-4Ralpha and IL-13Ralpha2 interact, and that the secondary structure of the IL-13Ralpha2 intracellular domain is critical for this interaction. The cellular relevance of this interaction was next investigated. BEAS-2B bronchial epithelial cells that stably express full length IL-13Ralpha2, or IL-13Ralpha2 lacking its cytoplasmic domain, were established. Over expression of IL-13Ralpha2 attenuated IL-4 and IL-13 mediated STAT6 phosphorylation. IL-13Ralpha2 lacking its cytoplasmic domain continued to attenuate IL-13-mediated signaling, but had no effect on IL-4-mediated STAT6 signaling. Our results suggest that the physical interaction between the cytoplasmic domains of IL-13Ralpha2 and IL-4Ralpha regulates IL-4 signaling through the IL-4Ralpha-IL-13Ralpha1 receptor complex. PMID- 24056920 TI - Dynamics of benzimidazole ethylphosphonate: a solid-state NMR study of anhydrous composite proton-conducting electrolytes. AB - Imidazole phosphate and phosphonate solid acids model the hydrogen-bonding networks and dynamics of the anhydrous electrolyte candidate for proton exchange membrane fuel cells. Solid-state NMR reveals that phosphate and phosphonate anion dynamics dominate the rate of long-range proton transport, and that the presence of a membrane host facilitates proton mobility, as evidenced by a decreased correlation time of the composites (80 +/- 15 ms) relative to the pristine salt (101 +/- 5 ms). Benzimidazole ethylphosphonate (Bi-ePA) is chosen as a model salt to investigate the membrane system. The hydrogen-bonding structure of Bi-ePA is established using X-ray diffraction coupled with solid-state (1)H-(1)H DQC NMR. The anion dynamics has been determined using solid-state (31)P CODEX NMR. By comparing the dynamics of ethylphosphonate groups in pristine salt and membrane salt composites, it is clear that the rotation process involves three-site exchange. Through data interpretation, a stretched exponential function is introduced with the stretching exponent, beta, ranging 0 < beta <= 1. The (31)P CODEX data for pristine salt are fitted with single exponential decay where beta = 1; however, the data for the membrane-salt composites are fitted with stretched exponential functions, where beta has a constant value of 0.5. This beta value suggests a non-Gaussian distribution of the dynamic systems in the composite sample, which is introduced by the membrane host. PMID- 24056921 TI - Design of a highly sensitive ethanol sensor using a nano-coaxial p-Co3O4/n-TiO2 heterojunction synthesized at low temperature. AB - In this paper, we describe the design, fabrication and gas-sensing tests of nano coaxial p-Co3O4/n-TiO2 heterojunction. Specifically, uniform TiO2 nanotubular arrays have been assembled by anodization and used as templates for generation of the Co3O4 one-dimensional nanorods. The structure morphology and composition of as-prepared products have been characterized by SEM, XRD, TEM, and XPS. A possible growth mechanism governing the formation of such nano-coaxial heterojunctions is proposed. The TiO2 nanotube sensor shows a normal n-type response to reducing ethanol gas, whereas TiO2-Co3O4 exhibits p-type response with excellent sensing performances. This conversion of sensing behavior can be explained by the formation of p-n heterojunction structures. A possible sensing mechanism is also illustrated, which can provide theoretical guidance for the further development of advanced gas-sensitive materials with p-n heterojunction. PMID- 24056922 TI - Mood disturbance after infection. AB - OBJECTIVE: An aetiological link between acute infection and major depression has long been hypothesized, and is increasingly gaining recognition within contemporary literature. This review aims to examine the evidence for such a link, specifically between acute, self-limiting infection and major depression, and to summarize the current understanding of pathophysiological mechanisms underlying this link. METHODS: Relevant articles were sourced via an online search of published literature from Embase, MEDLINE, PsycINFO and PubMed using a variety of search terms including mood disorder, depression, infection and inflammation. Additionally, a search for articles from the bibliographies of retrieved papers was conducted. RESULTS: Findings from retrospective studies suggest an association between infection and subsequent mood disturbance, including major depression. This association has been confirmed by studies employing prospective observational or experimental challenge designs. The available evidence supports a multifactorial basis of vulnerability towards major depression in the context of acute infection. Genetic, neuroendocrine, autonomic and psychosocial factors may interact to potentiate the likelihood of a severe and prolonged depressive response to an immunological stressor in some individuals. CONCLUSION: Mood disturbance is likely to have a host-protective role in the context of an acute sickness response to infection. However, this usually adaptive and reversible response may progress in some vulnerable individuals into a more sustained and severe pattern of behavioural and physiological changes of major depression. Further research is needed to delineate the factors that predispose, precipitate and perpetuate depression in the context of acute infective illness. Such insights will inform effective prevention and treatment strategies. PMID- 24056923 TI - A protocol for genetic induction and visualization of benign and invasive tumors in cephalic complexes of Drosophila melanogaster. AB - Drosophila has illuminated our understanding of the genetic basis of normal development and disease for the past several decades and today it continues to contribute immensely to our understanding of complex diseases (1-7). Progression of tumors from a benign to a metastatic state is a complex event (8) and has been modeled in Drosophila to help us better understand the genetic basis of this disease (9). Here I present a simple protocol to genetically induce, observe and then analyze the progression of tumors in Drosophila larvae. The tumor induction technique is based on the MARCM system (10) and exploits the cooperation between an activated oncogene, Ras(V12) and loss of cell polarity genes (scribbled, discs large and lethal giant larvae) to generate invasive tumors (9). I demonstrate how these tumors can be visualized in the intact larvae and then how these can be dissected out for further analysis. The simplified protocol presented here should make it possible for this technique to be utilized by investigators interested in understanding the role of a gene in tumor invasion. PMID- 24056924 TI - Aqueous self-assembly of poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) copolymers: disparate diblock copolymer compositions give rise to nano- and meso-scale bilayered vesicles. AB - Nanoparticles formed from diblock copolymers of FDA approved PEO and PCL have generated considerable interest as in vivo drug delivery vehicles. Herein, we report the synthesis of the most extensive family PEO-b-PCL copolymers that vary over the largest range of number-average molecular weights (Mn: 3.6-57k), PEO weight fractions (fPEO: 0.08-0.33), and PEO chain lengths (0.75-5.8k) reported to date. These polymers were synthesized in order to establish the full range of aqueous phase behaviours of these diblock copolymers and to specifically identify formulations that were able to generate bilayered vesicles (polymersomes). Cryogenic transmission electron microscopy (cryo-TEM) was utilized in order to visualize the morphology of these structures upon aqueous self-assembly of dry polymer films. Nanoscale polymersomes were formed from PEO-b-PCL copolymers over a wide range of PEO weight fractions (fPEO: 0.14-0.27) and PEO molecular weights (0.75-3.8k) after extrusion of aqueous suspensions. Comparative morphology diagrams, which describe the nature of self-assembled structures as a function of diblock copolymer molecular weight and PEO weight fraction, show that in contrast to micron-scale polymersomes, which form only from a limited range of PEO-b-PCL diblock copolymer compositions, a multiplicity of PEO-b-PCL diblock copolymer compositions are able to give rise to nanoscale vesicles. These data underscore that PEO-b-PCL compositions that spontaneously form micron-sized polymersomes, as well as those that have previously been reported to form polymersomes via a cosolvent fabrication system, provide only limited insights into the distribution of PEO-b-PCL diblocks that give rise to nanoscale vesicles. The broad range of polymersome-forming PEO-b-PCL compositions described herein suggest the ability to construct extensive families of nanoscale vesicles of varied bilayer thickness, providing the ability to tune the timescales of vesicle degradation and encapsulant release based on the intended in vivo application. PMID- 24056925 TI - Functioning of nanovalves on polymer coated mesoporous silica Nanoparticles. AB - Nanomachines activated by a pH change can be combined with polymer coatings on mesoporous silica nanoparticles to produce a new generation of nanoparticles for drug delivery that exhibits properties of both components. The nanovalves can trap cargos inside the mesoporous silica nanoparticles without premature release and only respond to specific stimuli, resulting in a high local concentration of drugs at the site of release. The polymer surface coatings can increase the cellular uptake, avoid the reticuloendothelial uptake, provide protected space for storing siRNA, and enhance the biodistribution of nanoparticles. Two nanovalve-polymer systems are designed and their successful assembly is confirmed by solid state NMR and thermogravimetric analysis. The fluorescence spectroscopy results demonstrate that the controlled release functions of the nanomachines in both of the systems are not hindered by the polymer surface coatings. These new multifunctional nanoparticles combining stimulated molecule release together with the functionality provided by the polymers produce enhanced biological properties and multi-task drug delivery applications. PMID- 24056926 TI - Improved lithium storage properties of electrospun TiO2 with tunable morphology: from porous anatase to necklace rutile. AB - Three-dimensional TiO2 with tunable morphology and crystalline phase was successfully prepared by the electrospinning technique and subsequent annealing. Porous-shaped anatase TiO2, cluster-shaped anatase TiO2, hierarchical-shaped rutile (minor) TiO2 and nano-necklace rutile (major) TiO2 were achieved at 500, 600, 700 and 800 degrees C, respectively. The mechanism of the formation of these tailored morphologies and crystallinity was investigated. Lithium insertion properties were evaluated by galvanostatic and potentiostatic modes in half-cell configurations. By combining the large surface area, open mesoporosity and stable crystalline phase, the porous-shaped anatase TiO2 exhibited the highest capacity, best rate and cycling performance among the four samples. The present results demonstrated the usefulness of three-dimensional TiO2 as an anode for lithium storage with improved electrode performance. PMID- 24056927 TI - Symbiosis: non-legumes answer the rhizobial call. PMID- 24056928 TI - Fungal genetics: the fruitful consequences of a little self-love. PMID- 24056929 TI - Bacterial physiology: a persistent magic spot. PMID- 24056931 TI - Involvement of the antioxidant system in differential sensitivity of Carcinus maenas to fenitrothion exposure. AB - Carcinus maenas is an invertebrate with worldwide distribution and high ability to adapt to different environments, which is frequently used in environmental monitoring. Despite this, it is not clear how historical exposure to moderate contamination may influence sensitivity to further chemical stress in this important decapod species. This study investigated differential responses to organophosphate fenitrothion of C. maenas from a moderately contaminated estuary and a low impacted one, using in vitro and in vivo biomarker assays. To clarify potential differences in sensitivity, a biochemical characterisation of muscle cholinesterases was first performed. The results indicated acetylcholinesterase (AChE) as the main form present in C. maenas muscle. Exposure assays revealed that crabs from the moderately contaminated site were less sensitive to fenitrothion showing lower AChE inhibition than those from the low impacted site. Other biomarker changes detected in these animals were: increased anaerobic metabolism (muscle lactate dehydrogenase), enhanced phase II biotransformation (glutathione S-transferases in the digestive gland) and antioxidant defences (i.e., activities of glutathione reductase, glutathione peroxidase and catalase, and levels of total glutathiones in the digestive gland). Altogether, the results pointed out a role for the glutathione redox system towards tolerance to fenitrothion exposure. PMID- 24056930 TI - Going back to the roots: the microbial ecology of the rhizosphere. AB - The rhizosphere is the interface between plant roots and soil where interactions among a myriad of microorganisms and invertebrates affect biogeochemical cycling, plant growth and tolerance to biotic and abiotic stress. The rhizosphere is intriguingly complex and dynamic, and understanding its ecology and evolution is key to enhancing plant productivity and ecosystem functioning. Novel insights into key factors and evolutionary processes shaping the rhizosphere microbiome will greatly benefit from integrating reductionist and systems-based approaches in both agricultural and natural ecosystems. Here, we discuss recent developments in rhizosphere research in relation to assessing the contribution of the micro- and macroflora to sustainable agriculture, nature conservation, the development of bio-energy crops and the mitigation of climate change. PMID- 24056932 TI - Controllability of the Coulomb charging energy in close-packed nanoparticle arrays. AB - We studied the electronic transport properties of metal nanoparticle arrays, particularly focused on the Coulomb charging energy. By comparison, we confirmed that it is more reasonable to estimate the Coulomb charging energy using the activation energy from the temperature-dependent zero-voltage conductance. Based on this, we systematically and comprehensively investigated the parameters that could be used to tune the Coulomb charging energy in nanoparticle arrays. We found that four parameters, including the particle core size, the inter-particle distance, the nearest neighboring number, and the dielectric constant of ligand molecules, could significantly tune the Coulomb charging energy. PMID- 24056934 TI - Discovery of new enzymes and metabolic pathways by using structure and genome context. AB - Assigning valid functions to proteins identified in genome projects is challenging: overprediction and database annotation errors are the principal concerns. We and others are developing computation-guided strategies for functional discovery with 'metabolite docking' to experimentally derived or homology-based three-dimensional structures. Bacterial metabolic pathways often are encoded by 'genome neighbourhoods' (gene clusters and/or operons), which can provide important clues for functional assignment. We recently demonstrated the synergy of docking and pathway context by 'predicting' the intermediates in the glycolytic pathway in Escherichia coli. Metabolite docking to multiple binding proteins and enzymes in the same pathway increases the reliability of in silico predictions of substrate specificities because the pathway intermediates are structurally similar. Here we report that structure-guided approaches for predicting the substrate specificities of several enzymes encoded by a bacterial gene cluster allowed the correct prediction of the in vitro activity of a structurally characterized enzyme of unknown function (PDB 2PMQ), 2-epimerization of trans-4-hydroxy-L-proline betaine (tHyp-B) and cis-4-hydroxy-D-proline betaine (cHyp-B), and also the correct identification of the catabolic pathway in which Hyp-B 2-epimerase participates. The substrate-liganded pose predicted by virtual library screening (docking) was confirmed experimentally. The enzymatic activities in the predicted pathway were confirmed by in vitro assays and genetic analyses; the intermediates were identified by metabolomics; and repression of the genes encoding the pathway by high salt concentrations was established by transcriptomics, confirming the osmolyte role of tHyp-B. This study establishes the utility of structure-guided functional predictions to enable the discovery of new metabolic pathways. PMID- 24056933 TI - Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to zygotic transition. AB - After fertilization, maternal factors direct development and trigger zygotic genome activation (ZGA) at the maternal-to-zygotic transition (MZT). In zebrafish, ZGA is required for gastrulation and clearance of maternal messenger RNAs, which is in part regulated by the conserved microRNA miR-430. However, the factors that activate the zygotic program in vertebrates are unknown. Here we show that Nanog, Pou5f1 (also called Oct4) and SoxB1 regulate zygotic gene activation in zebrafish. We identified several hundred genes directly activated by maternal factors, constituting the first wave of zygotic transcription. Ribosome profiling revealed that nanog, sox19b and pou5f1 are the most highly translated transcription factors pre-MZT. Combined loss of these factors resulted in developmental arrest before gastrulation and a failure to activate >75% of zygotic genes, including miR-430. Our results demonstrate that maternal Nanog, Pou5f1 and SoxB1 are required to initiate the zygotic developmental program and induce clearance of the maternal program by activating miR-430 expression. PMID- 24056935 TI - Hidden specificity in an apparently nonspecific RNA-binding protein. AB - Nucleic-acid-binding proteins are generally viewed as either specific or nonspecific, depending on characteristics of their binding sites in DNA or RNA. Most studies have focused on specific proteins, which identify cognate sites by binding with highest affinities to regions with defined signatures in sequence, structure or both. Proteins that bind to sites devoid of defined sequence or structure signatures are considered nonspecific. Substrate binding by these proteins is poorly understood, and it is not known to what extent seemingly nonspecific proteins discriminate between different binding sites, aside from those sequestered by nucleic acid structures. Here we systematically examine substrate binding by the apparently nonspecific RNA-binding protein C5, and find clear discrimination between different binding site variants. C5 is the protein subunit of the transfer RNA processing ribonucleoprotein enzyme RNase P from Escherichia coli. The protein binds 5' leaders of precursor tRNAs at a site without sequence or structure signatures. We measure functional binding of C5 to all possible sequence variants in its substrate binding site, using a high throughput sequencing kinetics approach (HITS-KIN) that simultaneously follows processing of thousands of RNA species. C5 binds different substrate variants with affinities varying by orders of magnitude. The distribution of functional affinities of C5 for all substrate variants resembles affinity distributions of highly specific nucleic acid binding proteins. Unlike these specific proteins, C5 does not bind its physiological RNA targets with the highest affinity, but with affinities near the median of the distribution, a region that is not associated with a sequence signature. We delineate defined rules governing substrate recognition by C5, which reveal specificity that is hidden in cellular substrates for RNase P. Our findings suggest that apparently nonspecific and specific RNA binding modes may not differ fundamentally, but represent distinct parts of common affinity distributions. PMID- 24056937 TI - Dynamics of the intrinsically disordered protein CP12 in its association with GAPDH in the green alga Chlamydomonas reinhardtii: a fuzzy complex. AB - CP12 is a widespread regulatory protein of oxygenic photosynthetic organisms that contributes to the regulation of the Calvin cycle by forming a supra-molecular complex with at least two enzymes: glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoribulokinase (PRK). CP12 shares some similarities with intrinsically disordered proteins (IDPs) depending on its redox state. In this study, site-directed spin labeling (SDSL) combined with EPR spectroscopy was used to probe the dynamic behavior of CP12 from Chlamydomonas reinhardtii upon binding to GAPDH, the first step towards ternary complex formation. The two N-terminal cysteine residues were labeled using the classical approach while the tyrosine located at the C-terminal end of CP12 was modified following an original procedure. The results show that the label grafted at the C-terminal extremity is in the vicinity of the interaction site whereas the N-terminal region remains fully disordered upon binding to GAPDH. In conclusion, GAPDH-CP12 is a fuzzy complex, in which the N-terminal region of CP12 keeps a conformational freedom in the bound form. This fuzziness could be one of the keys to facilitate binding of PRK to CP12-GAPDH and to form the ternary supra-molecular complex. PMID- 24056936 TI - Adrenaline-activated structure of beta2-adrenoceptor stabilized by an engineered nanobody. AB - G-protein-coupled receptors (GPCRs) are integral membrane proteins that have an essential role in human physiology, yet the molecular processes through which they bind to their endogenous agonists and activate effector proteins remain poorly understood. So far, it has not been possible to capture an active-state GPCR bound to its native neurotransmitter. Crystal structures of agonist-bound GPCRs have relied on the use of either exceptionally high-affinity agonists or receptor stabilization by mutagenesis. Many natural agonists such as adrenaline, which activates the beta2-adrenoceptor (beta2AR), bind with relatively low affinity, and they are often chemically unstable. Using directed evolution, we engineered a high-affinity camelid antibody fragment that stabilizes the active state of the beta2AR, and used this to obtain crystal structures of the activated receptor bound to multiple ligands. Here we present structures of the active state human beta2AR bound to three chemically distinct agonists: the ultrahigh affinity agonist BI167107, the high-affinity catecholamine agonist hydroxybenzyl isoproterenol, and the low-affinity endogenous agonist adrenaline. The crystal structures reveal a highly conserved overall ligand recognition and activation mode despite diverse ligand chemical structures and affinities that range from 100 nM to ~80 pM. Overall, the adrenaline-bound receptor structure is similar to the others, but it has substantial rearrangements in extracellular loop three and the extracellular tip of transmembrane helix 6. These structures also reveal a water-mediated hydrogen bond between two conserved tyrosines, which appears to stabilize the active state of the beta2AR and related GPCRs. PMID- 24056939 TI - Enhanced second harmonic generation from InAs nano-wing structures on silicon. AB - We demonstrate morphology-dependent second-harmonic generation (SHG) from InAs V shaped nanomembranes. We show SHG correlation with the nano-wing shape and size, experimentally quantify the SHG efficiency, and demonstrate a maximum SHG enhancement of about 500 compared to the bulk. Experimental data are supported by rigorous calculations of local electromagnetic field spectra. PMID- 24056940 TI - Sterol 3beta-glucosyltransferase biocatalysts with a range of selectivities, including selectivity for testosterone. AB - The main objectives of this work were to characterise a range of purified recombinant sterol 3beta-glucosyltransferases and show that rational sampling of the diversity that exists within sterol 3beta-glucosyltransferase sequence space can result in a range of enzyme selectivities. In our study the catalytically active domain of the Saccharomyces cerevisiae 3beta-glucosyltransferase was used to mine putative sterol 3beta-glucosyltransferases from the databases. Selected diverse sequences were expressed in and purified from Escherichia coli and shown to have different selectivities for the 3beta-hydroxysteroids ergosterol and cholesterol. Surprisingly, three enzymes were also selective for testosterone, a 17beta-hydroxysteroid. This study therefore reports for the first time sterol 3beta-glucosyltransferases with selectivity for both 3beta- and 17beta hydroxysteroids and is also the first report of recombinant 3beta glucosyltransferases with selectivity for steroids with a hydroxyl group at positions other than C-3. These enzymes could therefore find utility in the pharmaceutical industry for the green synthesis of a range of glycosylated compounds of medicinal interest. PMID- 24056941 TI - Reduced graphene oxide: firm support for catalytically active palladium nanoparticles and game changer in selective hydrogenation reactions. AB - Simultaneous decomposition and reduction of a Pd(2+) complex in the presence of graphene oxide (GO) lead to the formation of Pd(0)-nanoparticles (Pd-NPs) with average sizes of 4 nm firmly anchored on reduced graphene oxide (RGO) sheets. The Pd-NP/RGO hybrids exhibited remarkable catalytic activity and selectivity in mild hydrogenation reactions where the acidic properties of RGO play an active role and may act as an important game-changer. PMID- 24056942 TI - mRNA-mRNA duplexes that autoelicit Staufen1-mediated mRNA decay. AB - We report a new mechanism by which human mRNAs cross-talk: an Alu element in the 3' untranslated region (3' UTR) of one mRNA can base-pair with a partially complementary Alu element in the 3' UTR of a different mRNA, thereby creating a Staufen1 (STAU1)-binding site (SBS). STAU1 binding to a 3'-UTR SBS was previously shown to trigger STAU1-mediated mRNA decay (SMD) by directly recruiting the ATP dependent RNA helicase UPF1, which is also a key factor in the mechanistically related nonsense-mediated mRNA decay (NMD) pathway. In the case of a 3'-UTR SBS created by mRNA-mRNA base-pairing, we show that SMD targets both mRNAs in the duplex, provided that both mRNAs are translated. If only one mRNA is translated, then it alone is targeted for SMD. We demonstrate the functional importance of mRNA-mRNA-triggered SMD in cell migration and invasion. PMID- 24056943 TI - The structural basis of autotransporter translocation by TamA. AB - TamA is an Escherichia coli Omp85 protein involved in autotransporter biogenesis. It comprises a 16-stranded transmembrane beta-barrel and three POTRA domains. The 2.3-A crystal structure reveals that the TamA barrel is closed at the extracellular face by a conserved lid loop. The C-terminal beta-strand of the barrel forms an unusual inward kink, which weakens the lateral barrel wall and creates a gate for substrate access to the lipid bilayer. PMID- 24056946 TI - World Health Organization increases its drinking-water guideline for uranium. AB - The World Health Organization (WHO) released the fourth edition of Guidelines for Drinking-water Quality in July, 2011. In this edition, the drinking-water guideline for uranium (U) was increased to 30 MUg L(-1) despite the conclusion that "deriving a guideline value for uranium in drinking-water is complex, because the data [from exposures to humans] do not provide a clear no-effect concentration" and "Although some minor biochemical changes associated with kidney function have been reported to be correlated with uranium exposure at concentrations below 30 MUg L(-1), these findings are not consistent between studies" (WHO, Uranium in Drinking-water, Background document for development of WHO Guidelines for Drinking-water Quality, available: , accessed 13 October 2011). This paper reviews the WHO drinking-water guideline for U, from its introduction as a 2 MUg L(-1) health-based guideline in 1998 through its increase to a 30 MUg L(-1) health-based guideline in 2011. The current 30 MUg L(-1) WHO health-based drinking-water guideline was calculated using a "no-effect group" with "no evidence of renal damage [in humans] from 10 renal toxicity indicators". However, this nominal "no-effect group" was associated with increased diastolic blood pressure, systolic blood pressure, and glucose excretion in urine. In addition, the current 30 MUg L(-1) guideline may not protect children, people with predispositions to hypertension or osteoporosis, pre-existing chronic kidney disease, and anyone with a long exposure. The toxic effects of U in drinking water on laboratory animals and humans justify a re-evaluation by the WHO of its decision to increase its U drinking-water guideline. PMID- 24056944 TI - Cycles in spatial and temporal chromosomal organization driven by the circadian clock. AB - Dynamic transitions in the epigenome have been associated with regulated patterns of nuclear organization. The accumulating evidence that chromatin remodeling is implicated in circadian function prompted us to explore whether the clock may control nuclear architecture. We applied the chromosome conformation capture on chip technology in mouse embryonic fibroblasts (MEFs) to demonstrate the presence of circadian long-range interactions using the clock-controlled Dbp gene as bait. The circadian genomic interactions with Dbp were highly specific and were absent in MEFs whose clock was disrupted by ablation of the Bmal1 gene (also called Arntl). We establish that the Dbp circadian interactome contains a wide variety of genes and clock-related DNA elements. These findings reveal a previously unappreciated circadian and clock-dependent shaping of the nuclear landscape. PMID- 24056945 TI - Plasmonic nanoprobes: from chemical sensing to medical diagnostics and therapy. AB - This article provides an overview of the development and applications of plasmonics-active nanoprobes in our laboratory for chemical sensing, medical diagnostics and therapy. Molecular Sentinel nanoprobes provide a unique tool for DNA/RNA biomarker detection both in a homogeneous solution or on a chip platform for medical diagnostics. The possibility of combining spectral selectivity and high sensitivity of the surface-enhanced Raman scattering (SERS) process with the inherent molecular specificity of nanoprobes provides an important multiplex diagnostic modality. Gold nanostars can provide an excellent multi-modality platform, combining two-photon luminescence with photothermal therapy as well as Raman imaging with photodynamic therapy. Several examples of optical detection using SERS and photonics-based treatments are presented to illustrate the usefulness and potential of the plasmonic nanoprobes for theranostics, which seamlessly combines diagnostics and therapy. PMID- 24056947 TI - Structural and electrochemical studies of Sm@D3h-C74 reveal a weak metal-cage interaction and a small band gap species. AB - A metallofullerene Sm@D3h-C74 that contains a divalent rare-earth metal has been studied structurally and electrochemically. The crystallographic analysis revealed that the endohedral Sm atom is more or less motional rather than being localized at a site where the pyracylene motif is nearby. This suggests a weaker metal-pyracylene interaction in Sm@D3h-C74 relative to that in M(II)@C74 (M = Group II metal), thus confirming the importance of the metal variety. The electrochemical studies showed a major difference between the redox properties of Sm@D3h-C74 and other Sm-fullerenes and indicated a small band gap for the title compound. PMID- 24056948 TI - Identifying producers of antibacterial compounds by screening for antibiotic resistance. AB - Microbially derived natural products are major sources of antibiotics and other medicines, but discovering new antibiotic scaffolds and increasing the chemical diversity of existing ones are formidable challenges. We have designed a screen to exploit the self-protection mechanism of antibiotic producers to enrich microbial libraries for producers of selected antibiotic scaffolds. Using resistance as a discriminating criterion we increased the discovery rate of producers of both glycopeptide and ansamycin antibacterial compounds by several orders of magnitude in comparison with historical hit rates. Applying a phylogeny based screening filter for biosynthetic genes enabled the binning of producers of distinct scaffolds and resulted in the discovery of a glycopeptide antibacterial compound, pekiskomycin, with an unusual peptide scaffold. This strategy provides a means to readily sample the chemical diversity available in microbes and offers an efficient strategy for rapid discovery of microbial natural products and their associated biosynthetic enzymes. PMID- 24056949 TI - Influence of Au nanoparticles on the aggregation of amyloid-beta-(25-35) peptides. AB - The influence of Au nanoparticles (Au NPs) on the aggregation of amyloid-beta-(25 35) peptides (Abeta25-35) is investigated by atomic force microscopy and Thioflavin T fluorescence measurements. It is found that, without Au NPs, the Abeta25-35 peptides aggregate gradually from monomers and oligomers to long fibrils with the incubation time. In contrast, short protofibrils are formed quickly after Au NPs are added to the Abeta25-35 solution, which can be further aggregated to form short fibril bundles or even bundle conjunctions. To reveal the origin of Au NPs on the aggregation of Abeta25-35, electrostatic force microscopy and scanning Kelvin microscopy are employed to investigate the electrical properties of the Abeta25-35 fibrils with and without Au NPs. Due to the significant difference of the electrical properties between the Abeta25-35 fibrils and Au NPs, the locations of Au NPs inside the Abeta25-35 fibril bundles can be revealed and hence a possible influence mechanism of Au NPs on the aggregation of Abeta25-35 is suggested. PMID- 24056951 TI - Plant mediated green synthesis: modified approaches. AB - Plant mediated green synthesis of different metallic nanoparticles has emerged as one of the options for implementation of green chemistry principles, and successfully made an important contribution towards green nanotechnology. However, beyond the synthesis and application aspects, the science of green synthesis has carried some wrong perceptions in an unforeseen fashion. In this review, some of the key issues related to the green synthesis of metallic nanoparticles employing plants as reducing/capping agents have been addressed. Random selection of plants and its overall impact on the different aspects of green synthesis have been discussed. Emphasis is given to the setting of some standard selection criteria to be adopted for selecting a plant for use in green synthesis. How selection of a plant can positively or negatively influence both procedure and products of a green synthesis process is the prime concern of this article. In addition to selection, the key issue of biocompatibility associated with green synthesized metallic nanoparticles has been considered. Both selection of plant and biocompatibility were reconsidered for their minute details in terms of synthesis, analysis and data interpretation in the green synthesis approach. The key factors capable of fine tuning the core meaning of "green" in the synthesis of any metallic nanoparticles were taken into consideration. This article is an effort towards keeping the core meaning of green synthesis. PMID- 24056950 TI - Bioactive sphingolipid metabolites modulate ovarian cancer cell structural mechanics. AB - Cancer progression is associated with an increased deformability of cancer cells and reduced resistance to mechanical forces, enabling motility and invasion. This is important for metastases survival and outgrowth and as such could be a target for chemopreventive strategies. In this study, we determined the differential effects of exogenous sphingolipid metabolites on the elastic modulus of mouse ovarian surface epithelial cells as they transition to cancer. Treatment with ceramide or sphingosine-1-phosphate in non-toxic concentrations decreased the average elastic modulus by 21% (p<= 0.001) in transitional and 15% (p<= 0.02) in aggressive stages while exerting no appreciable effect on non-malignant cells. In contrast, sphingosine treatment on average increased the elastic modulus by 33% (p<= 0.0002) in aggressive cells while not affecting precursor cells. These results indicate that tumor-supporting sphingolipid metabolites act by making cells softer, while the anti-cancer metabolite sphingosine partially reverses the decreased elasticity associated with cancer progression. Thus, sphingosine may be a valid alternative to conventional chemotherapeutics in ovarian cancer prevention or treatment. PMID- 24056952 TI - Prediction of carbamylated lysine sites based on the one-class k-nearest neighbor method. AB - Protein carbamylation is one of the important post-translational modifications, which plays a pivotal role in a number of biological conditions, such as diseases, chronic renal failure and atherosclerosis. Therefore, recognition and identification of protein carbamylated sites are essential for disease treatment and prevention. Yet the mechanism of action of carbamylated lysine sites is still not realized. Thus it remains a largely unsolved challenge to uncover it, whether experimentally or theoretically. To address this problem, we have presented a computational framework for theoretically predicting and analyzing carbamylated lysine sites based on both the one-class k-nearest neighbor method and two-stage feature selection. The one-class k-nearest neighbor method requires no negative samples in training. Experimental results showed that by using 280 optimal features the presented method achieved promising performances of SN=82.50% for the jackknife test on the training set, and SN=66.67%, SP=100.00% and MCC=0.8097 for the independent test on the testing set, respectively. Further analysis of the optimal features provided insights into the mechanism of action of carbamylated lysine sites. It is anticipated that our method could be a potentially useful and essential tool for biologists to theoretically investigate carbamylated lysine sites. PMID- 24056953 TI - Recall of expressed affect during naturalistically observed interpersonal events in those with borderline personality disorder or depressive disorder. AB - We used the Electronically Activated Recorder to observe 31 individuals with either borderline personality disorder (BPD; n = 20) or a history of a depressive disorder (n = 11). The Electronically Activated Recorder yielded approximately forty-seven 50-second sound clips per day for 3 consecutive days. Recordings were coded for expressed positive affect (PA) and negative affect (NA), and coder ratings were compared to participants' reports about their PA and NA during interpersonal events. BPD participants did not differ from participants with depressive disorder in terms of their recalled levels of NA or PA across different types of interpersonal events. However, significant discrepancies between recalled and observed levels of NA and PA were found for BPD participants for all types of interpersonal events. These findings may reflect limitations in the ability of those with BPD to recall their emotional intensity during interpersonal events and may also provide some evidence for emotional invalidation experienced by those with BPD. PMID- 24056954 TI - Supramolecular aggregates of metallo-organic acids with stilbazoles. Formation of columnar mesophases and Langmuir films. AB - Supramolecular metal complexes formed through hydrogen bonding between tris(3,4,5 decyloxy)stilbazole and several metallo-organic acids of the type [Au(R)(CNC6H4CO2H)] (R = C6F5, C6F4OC10H21), [cis-[MCl2(CNC6H4COOH)2] and [trans [MI2(CNC6H4COOH)2] (M = Pd, Pt) have been synthesized. All the supramolecular palladium and platinum polycatenar aggregates display a hexagonal columnar mesophase at temperatures close to room temperature. Most of the supramolecular trisalkoxystilbazole complexes exhibit luminescent behaviour. Aggregates of [Au(C6F4OC10H21)(CNC6H4CO2H)] and [trans-[MI2(CNC6H4COOH)2] (M = Pd, Pt) form stable Langmuir films at the air-water interface. PMID- 24056955 TI - A novel method of preparing metallic Janus silica particles using supercritical carbon dioxide. AB - In this study, we demonstrate a novel fabrication method to prepare metallic Janus silica particles by embedding nanosized silica particles on a spherical polystyrene (PS) substrate in supercritical carbon dioxide (sc CO2), followed by labelling with gold nanoparticles on the exposed part of the silica colloids. To this end, three main types of Janus particles displaying two distinct surfaces are produced by recovering silica from the polystyrene template. Embedment of particles into the PS template in sc CO2 allows for precise control of the degree of embedding of particles and subsequent modification of the partially exposed particle surface. The embedding degree, as well as the final Janus balance, can be varied over a wide range through control of pressure, temperature, or treatment time of sc CO2. Hierarchical PS-silica composites and embedment are evaluated by scanning electron microscopy (SEM). Partial surface modification with gold nanoparticles is investigated by transmission electron microscopy (TEM). With this method various functionalized Janus particles with tuneable properties can be prepared by adjusting various surface modifiers and polymer substrates in the future. PMID- 24056956 TI - Non-communicable diseases in emergencies: a call to action. AB - Recent years have demonstrated the devastating health consequences of complex emergencies and natural disasters and thereby highlighted the importance of comprehensive and collaborative approaches to humanitarian responses and risk reduction. Simultaneously, noncommunicable diseases are now recognised as a real and growing threat to population health and development; a threat that is magnified by and during emergencies. Noncommunicable diseases, however, continue to receive little attention from humanitarian organisations in the acute phase of disaster and emergency response. This paper calls on all sectors to recognise and address the specific health challenges posed by noncommunicable diseases in emergencies and disaster situations. This publication aims to highlight the need for: * Increased research on morbidity and mortality patterns due to noncommunicable diseases during and following emergencies; * Raised awareness through greater advocacy for the issue and challenges of noncommunicable diseases during and following emergencies; * Incorporation of noncommunicable diseases into existing emergency-related policies, standards, and resources; * Development of technical guidelines on the clinical management of noncommunicable diseases in emergencies; * Greater integration and coordination in health service provision during and following emergencies; * Integrating noncommunicable diseases into practical and academic training of emergency workers and emergency-response coordinators. PMID- 24056957 TI - A facile one-pot route to cationic cellulose nanocrystals. AB - Pyridinium-grafted-cellulose nanocrystals were prepared by a simple one-pot reaction using 4-(1-bromoethyl/bromomethyl)benzoic acid, pyridine and cellulose nanocrystals (CNCs). The grafting consists of an esterification reaction between 4-(1-bromoethyl/bromomethyl)benzoic acid and CNCs and a nucleophilic attack on the C-Br bond of 4-(1-bromoethyl/bromomethyl)benzoic acid by pyridine. This reaction simplifies existing cationization methods, which leads to a higher grafting density while retaining the CNC crystallinity. PMID- 24056958 TI - Direct observation of rotatable uncompensated spins in the exchange bias system Co/CoO-MgO. AB - We have observed a large exchange bias field HE ~ 2460 Oe and a large coercive field HC ~ 6200 Oe at T = 2 K for Co/CoO core-shell nanoparticles (~4 nm diameter Co metal core and CoO shell with ~1 nm thickness) embedded in a non-magnetic MgO matrix. Our results are in sharp contrast to the small exchange bias and coercive field in the case of a non-magnetic Al2O3 or C matrix materials reported in previous studies. Using soft X-ray magnetic circular dichroism at the Co-L2,3 edge, we have observed a ferromagnetic signal originating from the antiferromagnetic CoO shell. This gives direct evidence for the existence of rotatable interfacial uncompensated Co spins in the nominally antiferromagnetic CoO shell, thus supporting the uncompensated spin model as a microscopic description of the exchange bias mechanism. PMID- 24056959 TI - Nanowire thermometers. AB - We report the design and demonstration of nanowire temperature reporters. Metal alloys with tunable melting points were used to create nanowires in nanopores of anodic aluminum oxide using mechanical pressure injection. When exposed to temperature above their melting points, nanowires began to break up into disconnected shorter nanorods due to Rayleigh instability. A wide range of temperature can be probed conveniently by measuring electrical resistance of nanowires. PMID- 24056960 TI - Mechanical testing at the whole-bone level of the femur in immature rats stunted by cornstarch consumption. AB - Both body weight and somatic muscle forces are the main "mechanical factors" in the determination of bone strength in the "weight-bearing bones". However, other "non-mechanical factors", such as dietary proteins, also exist, which modulate bone physiology. This study was designed to explore the mechanical behavior of the femur in post-weaning female rats stunted by feeding on cornstarch. Forty female rats aged 30 days were fed freely with one of the two diets: control (CD) and experimental (ED). CD was the standard rat laboratory diet, whereas ED was cornstarch supplemented with vitamins and minerals. Control (C) and experimental (E) animals were divided into 4 groups: C40 and E40 rats were given CD and ED, respectively, for 40 days; C105 were fed the CD for 105 days; and E40-105 were given the ED for 40 days and then the CD for the remaining experimental period (65 days). Growth of rats was assessed following Parks' model. The biomechanical structural properties of the right femur middiaphysis were estimated using a 3 point bending test. The geometric properties of both the entire bone and the cross-section were determined. The left femur was ashed and both the Ca mass and the Ca concentration were determined. Rats fed the ED failed to achieve normal weight gain. Complete catch-up was observed at the end of a 65 day period of nutritional rehabilitation. The femoral weight and length were negatively affected by the ED, as were the mid-diaphyseal cross-sectional area, the mineralized cortical area, and the cross-sectional moment of inertia. All of these parameters showed incomplete catch-up. The structural bone mechanical properties indicative of strength and stiffness were seriously negatively affected. Intrinsic material bone properties, as assessed by the modulus of elasticity and the maximal elastic stress, were within normal values. In summary, the experimental bone was weaker than the control and structurally incompetent. The considered bone was smaller than the control one, showing a significant reduction in the cross-sectional area and the moment of inertia. However, material properties as well as the ash fraction and Ca concentration were similar in E and C bones. Therefore, E bone is weaker than the C one because of its smaller bone mass, which appears to have been negatively influenced by the ED in relation to its effects on overall body mass. PMID- 24056961 TI - The receptor tyrosine kinase Axl regulates cell-cell adhesion and stemness in cutaneous squamous cell carcinoma. AB - Axl is a receptor tyrosine kinase (RTK) upregulated in various tumors including cutaneous squamous cell carcinoma (SCC). Axl expression correlates with poor prognosis and induction of epithelial-mesenchymal transition (EMT), hence we hypothesized that Axl is involved in the disruption of cell-cell adhesion to allow invasion and chemotherapy resistance of the cancer stem cell population. Cutaneous SCC cell lines with stable knockdown of Axl were generated using retroviral vectors. Axl depletion altered expression of intercellular junction molecules increasing cell-cell adhesion with downregulation of Wnt and TGFbetaR signaling. Furthermore, Axl expression correlated with the expression of putative cancer stem cell markers, CD44 and ALDH1, increased resistance to chemotherapy drugs, enhanced sphere formation ability and expression of EMT features by cancer stem cells. Axl depletion resulted in loss of tumor formation in an in vivo zebrafish xenograft model. In conclusion, these data suggest that abrogation of Axl results in loss of cancer stem cell properties indicating a role for Axl as a therapeutic target in chemotherapy-resistant cancer. PMID- 24056962 TI - miR-26a enhances miRNA biogenesis by targeting Lin28B and Zcchc11 to suppress tumor growth and metastasis. AB - Human cancers often exhibit attenuated microRNA (miRNA) biogenesis and global underexpression of miRNAs; thus, targeting the miRNA biogenesis pathway represents a novel strategy for cancer therapy. Here, we report that miR-26a enhances miRNA biogenesis, which acts as a common mechanism partially accounting for miR-26a function in diverse cancers including melanoma, prostate and liver cancer. miR-26a was broadly reduced in multiple cancers, and overexpression of miR-26a significantly suppressed tumor growth and metastasis both in vitro and in vivo, including melanoma, prostate and liver cancers. Notably, miR-26a overexpression was accompanied by global upregulation of miRNAs, especially let 7, and let-7 expression was concordant with miR-26a expression in cancer cell lines, xenograft tumors and normal human tissues, underscoring their biological relevance. We showed that miR-26a directly targeted Lin28B and Zcchc11-two critical repressors of let-7 maturation. Furthermore, we have demonstrated that Zcchc11 promoted tumor growth and metastasis, and it was prominently overexpressed in human cancers. Our findings thus provide a novel mechanism by which a miRNA acts as a modulator of miRNA biogenesis. These results also define a role of the miR-26a and Zcchc11 in tumorigenesis and metastasis and have implications to develop new strategies for cancer therapy. PMID- 24056964 TI - EIF3i promotes colon oncogenesis by regulating COX-2 protein synthesis and beta catenin activation. AB - Translational control of gene expression has recently been recognized as an important mechanism controlling cell proliferation and oncogenesis, and it mainly occurs in the initiation step of protein synthesis that involves multiple eukaryotic initiation factors (eIFs). Many eIFs have been found to have aberrant expression in human tumors and the aberrant expression may contribute to oncogenesis. However, how these previously considered house-keeping proteins are potentially oncogenic remains elusive. In this study, we investigated the expression of eIF3i in human colon cancers, tested its contribution to colon oncogenesis and determined the mechanism of eIF3i action in colon oncogenesis. We found that eIF3i expression was upregulated in both human colon adenocarcinoma and adenoma polyps as well as in model inducible colon tumorigenic cell lines. Overexpression of ectopic eIF3i in intestinal epithelial cells causes oncogenesis by directly upregulating the synthesis of cyclooxygenase-2 (COX-2) protein and activates the beta-catenin/T-cell factor 4 signaling pathway that mediates the oncogenic function of eIF3i. Together, we conclude that eIF3i is a proto-oncogene that drives colon oncogenesis by translationally upregulating COX-2 and activating the beta-catenin signaling pathway. These findings imply that proto oncogenic eIFs likely exert their tumorigenic function by regulating/altering the synthesis level of downstream tumor suppressor or oncogenes. PMID- 24056963 TI - Macrophage contact induces RhoA GTPase signaling to trigger tumor cell intravasation. AB - Most cancer patients die as a result of metastasis, thus it is important to understand the molecular mechanisms of dissemination, including intra- and extravasation. Although the mechanisms of extravasation have been vastly studied in vitro and in vivo, the process of intravasation is still unclear. Furthermore, how cells in the tumor microenvironment facilitate tumor cell intravasation is still unknown. Using high-resolution imaging, we found that macrophages enhance tumor cell intravasation upon physical contact. Macrophage and tumor cell contact induce RhoA activity in tumor cells, triggering the formation of actin-rich degradative protrusions called invadopodia, enabling tumor cells to degrade and break through matrix barriers during tumor cell transendothelial migration. Interestingly, we show that macrophage-induced invadopodium formation and tumor cell intravasation also occur in patient-derived tumor cells and in vivo models, revealing a conserved mechanism of tumor cell intravasation. Our results illustrate a novel heterotypic cell contact-mediated signaling role for RhoA, as well as yield mechanistic insight into the ability of cells within the tumor microenvironment to facilitate steps of the metastatic cascade. PMID- 24056965 TI - c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer. AB - The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self renewing phenotype independent of an epithelial-mesenchymal transition programme or regulation of conventional cancer stem cell markers. Instead, Her2 and c-Myc cooperated to induce the expression of lipoprotein lipase, which was required for proliferation and self-renewal in vitro. HER2 and MYC were frequently coamplified in breast cancer, associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in HER2(+) breast cancer patients receiving adjuvant chemotherapy (but not targeted anti-Her2 therapy), MYC amplification is associated with a poor outcome. These findings demonstrate the importance of molecular and cellular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have diagnostic and therapeutic consequences for the clinical management of HER2(+) breast cancer. PMID- 24056966 TI - A phosphatase-independent gain-of-function mutation in PTEN triggers aberrant cell growth in astrocytes through an autocrine IGF-1 loop. AB - Loss-of-function mutations in the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome10) contribute to aberrant cell growth in part through upregulation of the mitogenic IGF-1/PI3K/Akt pathway. In turn, this pathway exerts a homeostatic feedback over PTEN. Using mutagenesis analysis to explore a possible impact of this mutual control on astrocyte growth, we found that truncation of the C-terminal region of PTEN (Delta51) associates with a marked increase in NFkappaB activity, a transcription factor overactivated in astrocyte tumors. Whereas mutations of PTEN are considered to lead to a loss-of function, PTENDelta51, a truncation that comprises a region frequently mutated in human gliomas, displayed a neomorphic (gain-of-function) activity that was independent of its phosphatase activity. This gain-of-function of PTENDelta51 includes stimulation of IGF-1 synthesis through protein kinase A activation of the IGF-1 promoter. Increased IGF-1 originates an autocrine loop that activates Akt and NFkappaB. Constitutive activation of NFkappaB in PTENDelta51-expressing astrocytes leads to aberrant cell growth; astrocytes expressing this mutant PTEN generate colonies in vitro and tumors in vivo. Mutations converting a tumor suppressor such as PTEN into a tumor promoter through a gain-of-function involving IGF-1 production may further our understanding of the role played by this growth factor in glioma growth and help us define druggable targets for personalized therapy. PMID- 24056967 TI - Identification of LMX1B as a novel oncogene in human ovarian cancer. AB - Ovarian cancers are thought to result from the accumulation of multiple genetic aberrations that transform ovarian and/or fallopian tube surface epithelial cells, allowing for their abnormal growth, proliferation and metastasis. In the report presented here, we carried out genome-wide copy-number analysis using comparative genomic hybridization on a panel of mouse ovarian cancer (OVCA) cell lines previously established in our laboratory. We identified a recurrent focal amplification on mouse chromosomal region 2qB, which contains the LIM-homeodomain containing transcription factor 1B (Lmx1b) gene. LMX1B is not expressed in normal human ovary, but is expressed in many human OVCA cell lines and primary tumors. High expression of LMX1B correlates with poor outcome. To clarify the role of LMX1B in ovarian carcinogenesis, we transduced LMX1B into a panel of mouse and human OVCA cell lines and demonstrated that LMX1B strongly promotes migration of cancer cells in culture and promotes xenograft growth in nude mice. Conversely, knockdown of LMX1B in a human cell line with endogenous high expression of LMX1B inhibits cell migration in vitro and tumor growth in vivo. Microarray analysis of cells overexpressing LMX1B identified the nuclear factor (NF)-kappaB pathway as a potential mediator of tumor progression and subsequent treatment of NFkappaB inhibitor decreased the migratory capacity of these cells. Thus, our data demonstrate that LMX1B is a novel oncogene in OVCA pathogenesis. PMID- 24056968 TI - Off-on-off fluorescent chemosensor for pH measurement with a terbium(iii) complex based on a tripodal salicylic-acid derivative. AB - New Tb(iii) and Eu(iii) complexes have been synthesized as potential pH probes using a tripodal substituted-salicylic ligand (H3). Among them, this carboxylate ligand is found to be a good sensitizer for Tb(iii) emission owing to the superior match of the triplet energy level of the ligand with the (5)D4 emitting level of Tb(iii). The resulting . complex exhibited high sensitivity in the physiological pH range with significant "off-on-off" fluorescence changes in aqueous solution. Furthermore, this unique rare-earth complex has been successfully used to monitor pH variations within HeLa cells and with filter papers. PMID- 24056969 TI - Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence. AB - Mitochondria are dynamic organelles that continuously change their shape through fission and fusion. Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species (ROS) production. Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Hence, we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBEC). Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy. Senescence-associated beta-galactosidase staining and p21 Western blotting of primary HBEC were performed to evaluate cellular senescence. Mitochondrial specific superoxide production was measured by MitoSOX staining. Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins (OPA1 or Mitofusins) by small-interfering RNA transfection. N-acetylcysteine and Mito TEMPO were used as antioxidants. Mitochondria in bronchial epithelial cells were prone to be more fragmented in COPD lung tissues. CSE induced mitochondrial fragmentation and mitochondrial ROS production, which were responsible for acceleration of cellular senescence in HBEC. Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells. HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants. CSE induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production. Hence, disruption of mitochondrial dynamics may be a part of the pathogenic sequence of COPD development. PMID- 24056970 TI - Metabolic shift in lung alveolar cell mitochondria following acrolein exposure. AB - Acrolein, an alpha,beta unsaturated electrophile, is an environmental pollutant released in ambient air from diesel exhausts and cooking oils. This study examines the role of acrolein in altering mitochondrial function and metabolism in lung-specific cells. RLE-6TN, H441, and primary alveolar type II (pAT2) cells were exposed to acrolein for 4 h, and its effect on mitochondrial oxygen consumption rates was studied by XF Extracellular Flux analysis. Low-dose acrolein exposure decreased mitochondrial respiration in a dose-dependent manner because of alteration in the metabolism of glucose in all the three cell types. Acrolein inhibited glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity, leading to decreased substrate availability for mitochondrial respiration in RLE 6TN, H441, and pAT2 cells; the reduced GAPDH activity was compensated in pAT2 cells by an increase in the activity of glucose-6-phosphate dehydrogenase, the regulatory control of the pentose phosphate pathway. The decrease in pyruvate from glucose metabolism resulted in utilization of alternative sources to support mitochondrial energy production: palmitate-BSA complex increased mitochondrial respiration in RLE-6TN and pAT2 cells. The presence of palmitate in alveolar cells for surfactant biosynthesis may prove to be the alternative fuel source for mitochondrial respiration. Accordingly, a decrease in phosphatidylcholine levels and an increase in phospholipase A2 activity were found in the alveolar cells after acrolein exposure. These findings have implications for understanding the decrease in surfactant levels frequently observed in pathophysiological situations with altered lung function following exposure to environmental toxicants. PMID- 24056973 TI - Stacking of metal chelating rings with pi-systems in mononuclear complexes of copper(II) with 3,6-dichloro-2,5-dihydroxy-1,4-benzoquinone (chloranilic acid) and 2,2'-bipyridine ligands. AB - A series of four novel mononuclear complexes of copper(II) with chloranilic acid and 2,2'-bipyridine were prepared and structurally characterised by X-ray structure analysis and IR spectroscopy. The complexes exhibit square-planar, square-pyramidal and octahedral coordination. The chloranilate dianion coordinates the Cu(II) atom in a terminal bidentate o-quinone-like mode forming a mononuclear complex species. The crystal packing of the aqua complex and the complexes with crystal water molecules are defined by hydrogen bonds. However, significant contributions are from interactions involving five-membered chelate rings with both types of ligands and intermolecular pi-systems (bipyridine and chloranilate rings). The crystal packing of the complex with square planar Cu(II) coordination is dominated by interactions of the chelate rings with pi delocalised bonds and intermolecular pi-systems. The occurrence of dimorphism could be related to the different types of these interactions in the stacks. The crystal packing of the octahedral complexes of the mono- and dihydrate solvates reveal 3D-networks with pores occupied by non-coordinated bipyridine molecules. PMID- 24056971 TI - Heterogeneity of lung mononuclear phagocytes during pneumonia: contribution of chemokine receptors. AB - Bacterial pneumonia is a common and dangerous illness. Mononuclear phagocytes, which comprise monocyte, resident and recruited macrophage, and dendritic cell subsets, are critical to antimicrobial defenses, but the dynamics of their recruitment to the lungs in pneumonia is not established. We hypothesized that chemokine-mediated traffic of mononuclear phagocytes is important in defense against bacterial pneumonia. In a mouse model of Klebsiella pneumonia, circulating Ly6C(hi) and, to a lesser extent, Ly6C(lo) monocytes expanded in parallel with accumulation of inflammatory macrophages and CD11b(hi) dendritic cells and plasmacytoid dendritic cells in the lungs, whereas numbers of alveolar macrophages remained constant. CCR2 was expressed by Ly6C(hi) monocytes, recruited macrophages, and airway dendritic cells; CCR6 was prominently expressed by airway dendritic cells; and CX3CR1 was ubiquitously expressed by blood monocytes and lung CD11b(hi) dendritic cells during infection. CCR2-deficient, but not CCL2-, CX3CR1-, or CCR6-deficient animals exhibited worse outcomes of infection. The absence of CCR2 had no detectable effect on neutrophils but resulted in reduction of all subsets of lung mononuclear phagocytes in the lungs, including alveolar macrophages and airway and plasmacytoid dendritic cells. In addition, absence of CCR2 skewed the phenotype of lung mononuclear phagocytes, abrogating the appearance of M1 macrophages and TNF-producing dendritic cells in the lungs. Taken together, these data define the dynamics of mononuclear phagocytes during pneumonia. PMID- 24056974 TI - Recent developments in Cope-type hydroamination reactions of hydroxylamine and hydrazine derivatives. AB - Cope-type hydroaminations are versatile for the direct amination of alkenes, alkynes and allenes using hydroxylamines and hydrazine derivatives. These reactions occur via a concerted, 5-membered cyclic transition state that is the microscopic reverse of the Cope elimination. This article focuses on recent developments, including intermolecular variants, directed reactions, and asymmetric variants using aldehydes as tethering catalysts, and their applications in target-oriented synthesis. PMID- 24056972 TI - Salivary proteins associated with hyperglycemia in diabetes: a proteomic analysis. AB - Effective monitoring of glucose levels is necessary for patients to achieve greater control over their diabetes. However, only about a quarter of subjects with diabetes who requires close serum glucose monitoring, regularly check their serum glucose daily. One of the potential barriers to patient compliance is the blood sampling requirement. Saliva and its protein contents can be altered in subjects with diabetes, possibly due to changes in glycemic control. We propose here that salivary proteomes of subjects with diabetes may be different based on their glycemic control as reflected in A1C levels. A total of 153 subjects with type 1 or 2 diabetes were recruited. Subjects in each type of diabetes were divided into 5 groups based on their A1C levels; <7, 7-8, 8-9, 9-10, >10. To examine the global proteomic changes associated with A1C, the proteomic profiling of pooled saliva samples from each group was created using label-free quantitative proteomics. Similar proteomic analysis for individual subjects (N=4, for each group) were then applied to examine proteins that may be less abundant in pooled samples. Principle component analysis (PCA) and cluster analysis (p<0.01 and p<0.001) were used to define the proteomic differences. We, therefore, defined the salivary proteomic changes associated with A1C changes. This study demonstrates that differences exist between salivary proteomic profiles in subjects with diabetes based on the A1C levels. PMID- 24056975 TI - Assembling metal oxide nanocrystals into dense, hollow, porous nanoparticles for lithium-ion and lithium-oxygen battery application. AB - New dense hollow porous (DHP) metal oxide nanoparticles that are smaller than 100 nm and composed of Co3O4, FeOx, NiO and MnOx were prepared by densely assembling metal oxide nanocrystals based on the hard-template method using a carbon colloid as a sacrificial core. These nanoparticles are quite different from the traditional particles as their hollow interior originates from the stacking of nanocrystals rather than a spherical shell. The DHP nanoparticles preserve the intriguing properties of nanocrystals and possess desirable surface area and pore volume that enhance the active surface, which ultimately benefits applications such as lithium-ion batteries. The DHP Co3O4 nanoparticles demonstrated an enhanced capacity of 1168 mA h g(-1) at 100 mA g(-1)vs. 590 mA h g(-1) of powders and stable cycling performance greater than 250 cycles when used as an anode material. Most importantly, the electrochemical performance of DHP Co3O4 nanoparticles in a lithium-O2 battery was also investigated for the first time. A low charge potential of ~4.0 V, a high discharge voltage near 2.74 V and a long cycle ability greater than 100 cycles at a delivered capacity of 2000 mA h g(-1) (current density, 200 mA g(-1)) were observed. The performances were considerably improved compared to recent results of mesoporous Co3O4, Co3O4 nanoparticles and a composite of Co3O4/RGO and Co3O4/Pd. Therefore, it would be promising to investigate such properties of DHP nanoparticles or other hollow metal (oxide) particles for the popular lithium-air battery. PMID- 24056976 TI - Microstructural and electrochemical impedance characterization of bio functionalized ultrafine ZnS nanocrystals-reduced graphene oxide hybrid for immunosensor applications. AB - We report a mercaptopropionic acid capped ZnS nanocrystals decorated reduced graphene oxide (RGO) hybrid film on a silane modified indium-tin-oxide glass plate, as a bioelectrode for the quantitative detection of human cardiac myoglobin (Ag-cMb). The ZnS nanocrystals were anchored over electrochemically reduced GO sheets through a cross linker, 1-pyrenemethylamine hydrochloride, by carbodiimide reaction and have been characterized by scanning electron microscopy, transmission electron microscopy and energy dispersive X-ray spectroscopy. The transmission electron microscopic characterization of the ZnS RGO hybrid shows the uniform distribution of ultra-fine nanoparticles of ZnS in nano-sheets of GO throughout the material. The protein antibody, Ab-cMb, was covalently linked to ZnS-RGO nanocomposite hybrid for the fabrication of the bioelectrode. A detailed electrochemical immunosensing study has been carried out on the bioelectrode towards the detection of target Ag-cMb. The optimal fitted equivalent circuit model that matches the impedance response has been studied to delineate the biocompatibility, sensitivity and selectivity of the bioelectrode. The bioelectrode exhibited a linear electrochemical impedance response to Ag-cMb in a range of 10 ng to 1 MUg mL(-1) in PBS (pH 7.4) with a sensitivity of 177.56 Omega cm(2) per decade. The combined synergistic effects of the high surface-to volume ratio of ZnS(MPA) nanocrystals and conducting RGO has provided a dominant charge transfer characteristic (R(et)) at the lower frequency region of <10 Hz showing a good biocompatibility and enhanced impedance sensitivity towards target Ag-cMb. The impedance response sensitivity of the ZnS-RGO hybrid bioelectrode towards Ag-cMb has been found to be about 2.5 fold higher than that of a bare RGO modified bioelectrode. PMID- 24056977 TI - Biophotonic logic devices based on quantum dots and temporally-staggered Forster energy transfer relays. AB - Integrating photonic inputs/outputs into unimolecular logic devices can provide significantly increased functional complexity and the ability to expand the repertoire of available operations. Here, we build upon a system previously utilized for biosensing to assemble and prototype several increasingly sophisticated biophotonic logic devices that function based upon multistep Forster resonance energy transfer (FRET) relays. The core system combines a central semiconductor quantum dot (QD) nanoplatform with a long-lifetime Tb complex FRET donor and a near-IR organic fluorophore acceptor; the latter acts as two unique inputs for the QD-based device. The Tb complex allows for a form of temporal memory by providing unique access to a time-delayed modality as an alternate output which significantly increases the inherent computing options. Altering the device by controlling the configuration parameters with biologically based self-assembly provides input control while monitoring changes in emission output of all participants, in both a spectral and temporal-dependent manner, gives rise to two input, single output Boolean Logic operations including OR, AND, INHIBIT, XOR, NOR, NAND, along with the possibility of gate transitions. Incorporation of an enzymatic cleavage step provides for a set-reset function that can be implemented repeatedly with the same building blocks and is demonstrated with single input, single output YES and NOT gates. Potential applications for these devices are discussed in the context of their constituent parts and the richness of available signal. PMID- 24056978 TI - Mycobacterial Hsp65 potentially cross-reacts with autoantibodies of diabetes sera and also induces (in vitro) cytokine responses relevant to diabetes mellitus. AB - Diabetes mellitus is a multifactorial disease and its incidence is increasing worldwide. Among the two types of diabetes, type-2 accounts for about 90% of all diabetic cases, whereas type-1 or juvenile diabetes is less prevalent and presents with humoral immune responses against some of the autoantigens. We attempted to test whether the sera of type-1 diabetes patients cross-react with mycobacterial heat shock protein 65 (Hsp65) due to postulated epitope homologies between mycobacterial Hsp65 and an important autoantigen of type-1 diabetes, glutamic acid decarboxylase-65 (GAD65). In our study, we used either recombinant mycobacterial Hsp65 protein or synthetic peptides corresponding to some of the potential epitopes of mycobacterial Hsp65 that are shared with GAD65 or human Hsp60, and a control peptide sourced from mycobacterial Hsp65 which is not shared with GAD65, Hsp60 and other autoantigens of type-1 diabetes. The indirect ELISA results indicated that both type-1 diabetes and type-2 diabetes sera cross-react with conserved mycobacterial Hsp65 peptides and recombinant mycobacterial Hsp65 protein but do not do so with the control peptide. Our results suggest that cross reactivity of mycobacterial Hsp65 with autoantibodies of diabetes sera could be due to the presence of significantly conserved peptides between mycobacterial Hsp65 and human Hsp60 rather than between mycobacterial Hsp65 and GAD65. The treatment of human peripheral blood mononuclear cells (PBMCs) with recombinant mycobacterial Hsp65 protein or the synthetic peptides resulted in a significant increase in the secretion of cytokines such as IL-1beta, IL-8, IL-6, TNF-alpha and IL-10. Taken together, these findings point towards a dual role for mycobacterial Hsp65: in inducing autoimmunity and in inflammation, the two cardinal features of diabetes mellitus. PMID- 24056983 TI - Excellent surface-enhanced Raman scattering (SERS) based on AgFeO2 semiconductor nanoparticles. AB - A simple hydrothermal method was employed to synthesize AgFeO2 nanoparticles, which were utilized as substrates in SERS detection of Rhodamine 6G and 4 mercaptobenzoic acid. The magnetic properties of the products provided the capability of concentrating analyte molecules under an external magnetic field. The detection in aqueous solution has ensured the uniformity of the SERS signals and the reproducibility of the substrates. It was interesting that the substrates exhibited high SERS activity at Rhodamine 6G concentration of 1 * 10(-7) M with an enhancement factor of 5.1 * 10(5), showing the highest SERS effect for semiconductor substrates, which might be ascribed to the orderly orientation of AgFeO2 nanoparticles under external magnetic field. PMID- 24056979 TI - Sodium methyldithiocarbamate exerts broad inhibition of cellular signaling and expression of effector molecules of inflammation. AB - Sodium methyldithiocarbamate (SMD) is one of the most abundantly used conventional pesticides in the United States. At dosages relevant to occupational exposure, it causes major effects on the immune system in mice, including a decreased resistance to sepsis. This lab has identified some of the mechanisms of action of this compound and some of the immunological parameters affected, but the global effects have not previously been assessed. The purpose of the present study was to conduct transcriptomic analysis of the effects of SMD on lipopolysaccharide-induced expression of mediators important in innate immunity and inflammation. The results revealed broad effects on expression of transcription factors in both branches of Toll-like receptor 4 (TLR4) signaling (MyD88 and TRIF). However, TLR3 and interferon signaling pathways were decreased to a greater extent, and assessment of the effects of SMD on polyinosinic polycytidylic acid-induced cytokine and chemokine production revealed that these responses mediated by TLR3 were indeed sensitive to the effects of SMD, with inhibition occurring at lower dosages than required to inhibit responses to other immunological stimuli tested in our previous studies. In the downstream signaling pathways of these TLRs, functional analysis also revealed that NF-kappaB activation was inhibited by SMD, as indicated by gene expression analysis and a reporter construct in mice. A previously unreported effect on luteinizing hormone and follicle-stimulating hormone pathways was also observed. PMID- 24056984 TI - Acylthioureas as anion transporters: the effect of intramolecular hydrogen bonding. AB - Small molecule synthetic anion transporters may have potential application as therapeutic agents for the treatment of diseases including cystic fibrosis and cancer. Understanding the factors that can dictate the anion transport activity of such transporters is a crucial step towards their application in biological systems. In this study a series of acylthiourea anion transporters were synthesised and their anion binding and transport properties in POPC bilayers have been investigated. The transport activity of these receptors is dominated by their lipophilicity, which is in turn dependent on both substituent effects and the formation and strength of an intramolecular hydrogen bond as inferred from DFT calculations. This is in contrast to simpler thiourea systems, in which the lipophilicity depends predominantly on substituent effects alone. PMID- 24056985 TI - Growth of single-walled carbon nanotubes with large chiral angles on rhodium nanoparticles. AB - Single-walled carbon nanotubes (SWNTs) grown on rhodium (Rh) nanoparticles were demonstrated to have large chiral angles and a preference for metallic tubes. PMID- 24056986 TI - Metal-free borylative ring-opening of vinyl epoxides and aziridines. AB - A rational approach towards the borylative ring-opening of vinylepoxides and vinylaziridines, by the in situ formed MeO(-)->bis(pinacolato)diboron adduct, has been developed. The enhanced nucleophilic character of the Bpin (sp(2)) moiety from the reagent favours the SN2' conjugated B addition with the concomitant opening of the epoxide and aziridine rings. The reaction proceeds with total chemoselectivity towards the polyfunctionalised (-OH or -NHTs) allyl boronate. Theoretical calculations have determined the transition states that come from the reaction of the vinylic substrates with the activated MeO(-) >bis(pinacolato)diboron adduct, and a plausible mechanism for the organocatalytic borylative ring opening reaction has been suggested. PMID- 24056987 TI - Laulimalide and peloruside A inhibit mitosis of Saccharomyces cerevisiae by preventing microtubule depolymerisation-dependent steps in chromosome separation and nuclear positioning. AB - The activity and mechanism of action of two microtubule-stabilising agents, laulimalide and peloruside A, were investigated in Saccharomyces cerevisiae. In contrast to paclitaxel, both compounds displayed growth inhibitory activity in yeast with wild type TUB2 and were susceptible to the yeast pleiotropic drug efflux pumps, as evidenced by the increased sensitivity of a pump transcription factor knockout strain, pdr1Deltapdr3Delta. Laulimalide (IC50=3.7 MUM) was 5-fold more potent than peloruside A (IC50=19 MUM) in this knockout strain. Bud index assays and flow cytometry revealed a G2/M block as seen in mammalian cells subsequent to treatment with these compounds. Furthermore, peloruside A treatment caused an increase in the number of cells with polymerised spindle microtubules. These results indicate an anti-mitotic action of both compounds with tubulin the likely target. This conclusion was supported by laulimalide and peloruside chemogenomic profiling using a yeast deletion library in the pdr1Deltapdr3Delta background. The chemogenomic profiles of these compounds indicate that, in contrast to microtubule destabilising agents like nocodazole and benomyl, laulimalide and peloruside A inhibit mitotic processes that are reliant on microtubule depolymerisation, consistent with their ability to stabilise microtubules. Gene deletion strains hypersensitive to laulimalide and peloruside A represent possible targets for drugs that can synergize with microtubule stabilising agent and be of potential use in combination therapy for the treatment of cancer or other diseases. PMID- 24056988 TI - Triplet recombination of radical ion pairs: CIDNP effects and DFT calculations on 1,2-dicyanoethylene. AB - Radical ion pairs generated by electron transfer from photo-excited aromatic hydrocarbons to maleo- and fumaronitrile (cis- and trans-1,2-dicyanoethylene, 1) undergo back electron transfer from singlet and triplet pairs. The pair energies relative to the reactant ground states and to the triplet state, respectively, determine the competition between the recombination pathways. Cross sections through the potential surfaces of the radical anion and the triplet state of 1 have been examined by density functional theory calculations. The radical anion surface has minima in which the carbon and nitrogen skeleton is essentially planar; the central C-C bond is lengthened (weakened), but the barrier to geometric isomerization is still sizeable (31.2 kcal mol(-1)). The triplet energy surface has a minimum at a bisected geometry (plus its enantiomer); rotation of the H-C-CN segments of the triplet yields a syn-periplanar and an anti-periplanar point 9.3 kcal mol(-1) and 8.2 kcal mol(-1) above the minimum, respectively. PMID- 24056990 TI - Electrochromic properties of TiO2 nanotubes coated with electrodeposited MoO3. AB - Despite a favourable morphology, anodized and ordered TiO2 nanotubes are incapable of showing electrochromic properties in comparison to many other metal oxide counterparts. To tackle this issue, MoO3 of ~5 to 15 nm thickness was electrodeposited onto TiO2 nanotube arrays. A homogenous MoO3 coating was obtained and the crystal phase of the electrodeposited coating was determined to be alpha-MoO3. The electronic and optical augmentations of the MoO3 coated TiO2 platforms were evaluated through electrochromic measurements. The MoO3/TiO2 system showed a 4-fold increase in optical density over bare TiO2 when the thickness of the MoO3 coating was optimised. The enhancement was ascribed to (a) the alpha-MoO3 coating reducing the bandgap of the composite material, which shifted the band edge of the TiO2 platform, and subsequently increased the charge carrier transfer of the overall system and (b) the layered morphology of alpha MoO3 that increased the intercalation probability and also provided direct pathways for charge carrier transfer. PMID- 24056989 TI - Connecting microfluidic chips using a chemically inert, reversible, multichannel chip-to-world-interface. AB - In this paper we present a reusable, chemically inert, multichannel Chip-to-World Interface (CWI). The concept of this interface is based on a force fit connection similar to the hollow screw connectors known from high-performance liquid chromatography (HPLC) instruments. It allows contamination free connection of up to 100 thermoplastic tubes to microfluidic chips made from various materials e.g., epoxy polymers, glass and polydimethylsiloxane (PDMS). The spacing of the tubes is fixed whereas the outer dimensions of the CWI can be adapted to the microfluidic chip it should be used with. We demonstrate that such a CWI with 100 tubes is pressure-tight up to (at least) 630 kPa (6.3 bar) pressure and the connection easily sustains flow rates above 4 ml min(-1). The presented CWI is designed such that the fluid probed in the microfluidic chip is in direct contact only with the tube material and the material from which the microfluidic chip is made. This not only enables fluid transport without dead volume, it also ensures that CWI itself will not be contaminated or contaminate the samples being probed. Using polytetrafluoroethylene (PTFE, Teflon(r)) tubing we demonstrate that the CWI can even be used with harsh organic solvents such as dichloromethane or dimethylformamide during continuous solvent probing over several hours without damage to the CWI or leakage. This CWI therefore effectively allows using almost all types of organic solvents in microfluidic applications. PMID- 24056991 TI - Halonium-initiated double oxa-cyclization cascade as a synthetic strategy for halogenated furo[3,2-c]pyran-4-ones. AB - The reaction of 1-alkenoylcyclopropane carboxylic acids with NBS or NIS was investigated, which provides an efficient route to biologically important 7 halogenated furo[3,2-c]pyran-4-ones in a one-pot transformation. The major pathway for the formation of the O-O heterocycles was proposed as a halo-oxa cyclization, HBr elimination, cyclopropane ring-opening and recyclization (intramolecular oxa-cyclization), and bromination cascade. The double-oxa cyclization represents a novel synthetic strategy towards functionalized furo[3,2 c]pyranones. PMID- 24056993 TI - Memory and learning behaviors mimicked in nanogranular SiO2-based proton conductor gated oxide-based synaptic transistors. AB - In neuroscience, signal processing, memory and learning function are established in the brain by modifying ionic fluxes in neurons and synapses. Emulation of memory and learning behaviors of biological systems by nanoscale ionic/electronic devices is highly desirable for building neuromorphic systems or even artificial neural networks. Here, novel artificial synapses based on junctionless oxide based protonic/electronic hybrid transistors gated by nanogranular phosphorus doped SiO2-based proton-conducting films are fabricated on glass substrates by a room-temperature process. Short-term memory (STM) and long-term memory (LTM) are mimicked by tuning the pulse gate voltage amplitude. The LTM process in such an artificial synapse is due to the proton-related interfacial electrochemical reaction. Our results are highly desirable for building future neuromorphic systems or even artificial networks via electronic elements. PMID- 24056994 TI - O-GlcNAcPRED: a sensitive predictor to capture protein O-GlcNAcylation sites. AB - O-GlcNAcylation is a ubiquitous post-translational modification of proteins that is involved in the majority of cellular processes and is associated with many diseases. To reduce the workload and increase the relevance of experimental identification of protein O-GlcNAcylation sites, O-GlcNAcPRED, a support vector machine (SVM)-based model, was developed to capture potential O-GlcNAcylation sites. By virtue of the novel adapted normal distribution bi-profile Bayes (ANBPB) feature extraction method, O-GlcNAcPRED yielded a sensitivity of 80.83%, a specificity of 78.17% and an accuracy of 79.50% in jackknife cross-validation experiments. In an independent test on 38 recently experimentally identified human O-GlcNAcylated proteins with 67 O-GlcNAcylation sites, O-GlcNAcPRED captured 26 proteins and 39 sites, clearly outperforming the existing predictors, YinOYang and O-GlcNAcscan. PMID- 24056992 TI - Genetic testing strategies in newly diagnosed endometrial cancer patients aimed at reducing morbidity or mortality from lynch syndrome in the index case or her relatives. AB - Endometrial cancer is the first malignancy in 50% of women with Lynch syndrome, an autosomal dominant cancer-prone syndrome caused by germline mutations in genes encoding components of the DNA mismatch repair (MMR) pathway. These women (2-4% of all those with endometrial cancer) are at risk of metachronous colorectal cancer and other Lynch syndrome-associated cancers, and their first-degree relatives are at 50% risk of Lynch syndrome. Testing all women newly diagnosed with endometrial cancer for Lynch syndrome may have clinical utility for the index case and her relatives by alerting them to the benefits of surveillance and preventive options, primarily for colorectal cancer. The strategy involves offering germline DNA mutation testing to those whose tumour shows loss-of function of MMR protein(s) when analysed for microsatellite instability (MSI) and/or by immunohistochemisty (IHC). In endometrial tumours from unselected patients, MSI and IHC have a sensitivity of 80-100% and specificity of 60-80% for detecting a mutation in an MMR gene, though the number of suitable studies for determining clinical validity is small. The clinical validity of strategies to exclude those with false-positive tumour test results due to somatic hypermethylation of the MLH1 gene promoter has not been determined. Options include direct methylation testing, and excluding those over the age of 60 who have no concerning family history or clinical features. The clinical utility of Lynch syndrome testing for the index case depends on her age and the MMR gene mutated: the net benefit is lower for those diagnosed at older ages and with less penetrant MSH6 mutations. To date, women with these features are the majority of those diagnosed through screening unselected endometrial cancer patients but the number of studies is small. Similarly, clinical utility to relatives of the index case is higher if the family's mutation is in MLH1 or MSH2 than for MSH6 or PMS2. Gaps in current evidence include a need for large, prospective studies on unselected endometrial cancer patients, and for health-economic analysis based on appropriate assumptions. PMID- 24056995 TI - Prevalence of seropositive sheep within flocks where Schmallenberg virus infection was suspected or confirmed. PMID- 24056998 TI - Effects of graphene coating and charge injection on water adsorption of solid surfaces. AB - The adhesion and cohesion of water molecules on graphene-coated and bare copper and mica substrates under charge injection have been extensively studied by first principles calculations. Water adsorption on graphene-coated copper surface is weakened by injecting negative charges into the substrate, while enhanced by positive charges. Both negatively and positively charge injecting on graphene coated mica strengthen the adsorption between water and the surface. While the adhesive and cohesive energies of water adsorption on charged bare copper and mica exhibit similar trends and much stronger response to charge injection. The charge sensitivity of water adsorbing on positively charged surfaces is significantly weakened by the graphene coating layer, mainly due to lower interfacial charge exchange. Our results suggest a viable way to modify water adsorption on a graphene-coated surface and unveil the role of graphene as a passivation layer for the wetting of a charged substrate. PMID- 24056999 TI - Role of feedback and network architecture in controlling virulence gene expression in Bordetella. AB - Bordetella is a Gram-negative bacterium responsible for causing whooping cough in a broad range of host organisms. For successful infection, Bordetella controls expression of four distinct classes of genes (referred to as class 1, 2, 3, and 4 genes) at distinct times in the infection cycle. This control is executed by a single two-component system, BvgAS. Interestingly, the transmembrane component of the two-component system, BvgS, consists of three phospho-transfer domains leading to phosphorylation of the response regulator, BvgA. Phosphorylated BvgA then controls expression of virulence genes and also controls bvgAS transcription. In this work, we perform simulations to characterize the role of the network architecture in governing gene expression in Bordetella. Our results show that the wild-type network is locally optimal for controlling the timing of expression of the different classes of genes involved in infection. In addition, the interplay between environmental signals and positive feedback aids the bacterium identify precise conditions for and control expression of virulence genes. PMID- 24056996 TI - Enzymatic activity of CaMKII is not required for its interaction with the glutamate receptor subunit GluN2B. AB - Binding of the Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor subunit GluN2B is an important control mechanism for the regulation of synaptic strength. CaMKII binding to GluN2B and CaMKII translocation to synapses are induced by an initial Ca2+/CaM stimulus, which also activates the kinase. Indeed, several mechanistically different CaMKII inhibitors [tatCN21 and KN-93 (N-[2-[[[3-(4-chlorophenyl)-2 propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4 methoxybenzenesulphonamide)] and inactivating mutations (K42M, A302R, and T305/T306D) impair this interaction, suggesting that it requires CaMKII enzymatic activity. However, this study shows that two general kinase inhibitors, H7 [1-(5 isoquinolinylsulfonyl)-2-methylpiperazine] and staurosporine (Sta), which inhibit CaMKII activity by yet another mechanism, did not interfere with GluN2B binding in vitro or within cells. In contrast to a previous report, we found that Sta, like H7, inhibited CaMKII in an ATP-competitive manner. Nucleotide binding significantly enhances CaMKII/GluN2B binding in vitro, but the nucleotide competition by H7 or Sta did not prevent this effect and instead even mimicked it. H7 (700 uM) and Sta (2 uM) efficiently blocked enzymatic activity of CaMKII, both in vitro and within cells. However, neither H7 nor Sta prevented Ca2+ induced translocation of CaMKII to GluN2B in heterologous cells or to synapses in hippocampal neurons. Thus, activity of CaMKII (or of any other kinase inhibited by H7 or Sta) is not required for stimulation-induced GluN2B-binding or synaptic translocation of CaMKII, despite previous indication to the contrary. This shows that results with inhibitors and inhibiting mutants can be caused by structural effects independent from catalytic activity, and that detailed understanding of the mechanisms is required for their interpretation. PMID- 24057000 TI - Highly concentrated synthesis of copper-zinc-tin-sulfide nanocrystals with easily decomposable capping molecules for printed photovoltaic applications. AB - Among various candidate materials, Cu2ZnSnS4 (CZTS) is a promising earth-abundant semiconductor for low-cost thin film solar cells. We report a facile, less toxic, highly concentrated synthetic method utilizing the heretofore unrecognized, easily decomposable capping ligand of triphenylphosphate, where phase-pure, single-crystalline, and well-dispersed colloidal CZTS nanocrystals were obtained. The favorable influence of the easily decomposable capping ligand on the microstructural evolution of device-quality CZTS absorber layers was clarified based on a comparative study with commonly used oleylamine-capped CZTS nanoparticles. The resulting CZTS nanoparticles enabled us to produce a dense and crack-free absorbing layer through annealing under a N2 + H2S (4%) atmosphere, demonstrating a solar cell with an efficiency of 3.6% under AM 1.5 illumination. PMID- 24057003 TI - Asymmetric photoreaction of a diarylethene in hydrogen-bonded cocrystals with chiral molecules. AB - A photochromic diarylethene having 2-methyl-4-pyridyl groups formed chiral cocrystals with (R)- or (S)-1,1'-bi-2-naphthol (BINOL). X-ray crystal structure analysis revealed that the diarylethene forms O-H...N type hydrogen bonds with BINOL and the central hexatriene moiety is fixed in P- or M-helix conformation in the cocrystals. The diarylethene molecules underwent reversible cyclization reactions in the single-component crystal as well as in the cocrystals upon alternate irradiation with ultraviolet (UV) and visible light. In the chiral cocrystals, a highly enantioselective photocyclization reaction took place owing to the conformational confinement. PMID- 24057001 TI - Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice. AB - Lipid disorders pose therapeutic challenges. Previously we discovered that mutation of the hepatocyte beta-hydroxybutyrate transporter Slc16a6a in zebrafish causes hepatic steatosis during fasting, marked by increased hepatic triacylglycerol, but not cholesterol. This selective diversion of trapped ketogenic carbon atoms is surprising because acetate and acetoacetate can exit mitochondria and can be incorporated into both fatty acids and cholesterol in normal hepatocytes. To elucidate the mechanism of this selective diversion of carbon atoms to fatty acids, we fed wild-type and slc16a6a mutant animals high protein ketogenic diets. We find that slc16a6a mutants have decreased activity of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr), despite increased Hmgcr protein abundance and relative incorporation of mevalonate into cholesterol. These observations suggest the presence of an endogenous Hmgcr inhibitor. We took a candidate approach to identify such inhibitors. First, we found that mutant livers accumulate multiple polyunsaturated fatty acids (PUFAs) and PUFA-CoAs, and we showed that human HMGCR is inhibited by PUFA-CoAs in vitro. Second, we injected mice with an ethyl ester of the PUFA eicosapentaenoic acid and observed an acute decrease in hepatic Hmgcr activity, without alteration in Hmgcr protein abundance. These results elucidate a mechanism for PUFA-mediated cholesterol lowering through direct inhibition of Hmgcr. PMID- 24057004 TI - 3D lacunarity in multifractal analysis of breast tumor lesions in dynamic contrast-enhanced magnetic resonance imaging. AB - Dynamic contrast-enhanced magnetic resonance (DCE-MR) of the breast is especially robust for the diagnosis of cancer in high-risk women due to its high sensitivity. Its specificity may be, however, compromised since several benign masses take up contrast agent as malignant lesions do. In this paper, we propose a novel method of 3D multifractal analysis to characterize the spatial complexity (spatial arrangement of texture) of breast tumors at multiple scales. Self similar properties are extracted from the estimation of the multifractal scaling exponent for each clinical case, using lacunarity as the multifractal measure. These properties include several descriptors of the multifractal spectra reflecting the morphology and internal spatial structure of the enhanced lesions relatively to normal tissue. The results suggest that the combined multifractal characteristics can be effective to distinguish benign and malignant findings, judged by the performance of the support vector machine classification method evaluated by receiver operating characteristics with an area under the curve of 0.96. In addition, this paper confirms the presence of multifractality in DCE-MR volumes of the breast, whereby multiple degrees of self-similarity prevail at multiple scales. The proposed feature extraction and classification method have the potential to complement the interpretation of the radiologists and supply a computer-aided diagnosis system. PMID- 24057002 TI - Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice. AB - Acute inflammation in response to injury is a tightly regulated process by which subsets of leukocytes are recruited to the injured tissue and undergo behavioural changes that are essential for effective tissue repair and regeneration. The diabetic wound environment is characterised by excessive and prolonged inflammation that is linked to poor progression of healing and, in humans, the development of diabetic foot ulcers. However, the underlying mechanisms contributing to excessive inflammation remain poorly understood. Here we show in a murine model that the diabetic environment induces stable intrinsic changes in haematopoietic cells. These changes lead to a hyper-responsive phenotype to both pro-inflammatory and anti-inflammatory stimuli, producing extreme M1 and M2 polarised cells. During early wound healing, myeloid cells in diabetic mice show hyperpolarisation towards both M1 and M2 phenotypes, whereas, at late stages of healing, when non-diabetic macrophages have transitioned to an M2 phenotype, diabetic wound macrophages continue to display an M1 phenotype. Intriguingly, we show that this population predominantly consists of Gr-1(+) CD11b(+) CD14(+) cells that have been previously reported as 'inflammatory macrophages' recruited to injured tissue in the early stages of wound healing. Finally, we show that this phenomenon is directly relevant to human diabetic ulcers, for which M2 polarisation predicts healing outcome. Thus, treatments focused at targeting this inflammatory cell subset could prove beneficial for pathological tissue repair. PMID- 24057005 TI - A perceptually relevant MSE-based image quality metric. AB - Image quality metrics (IQMs), such as the mean squared error (MSE) and the structural similarity index (SSIM), are quantitative measures to approximate perceived visual quality. In this paper, through analyzing the relationship between the MSE and the SSIM under an additive noise distortion model, we propose a perceptually relevant MSE-based IQM, MSE-SSIM, which is expressed in terms of the variance of the source image and the MSE between the source and distorted images. Evaluations on three publicly available databases (LIVE, CSIQ, and TID2008) show that the proposed metric, despite requiring less computation, compares favourably in performance to several existing IQMs. In addition, due to its simplicity, MSE-SSIM is amenable for the use in a wide range of image and video tasks that involve solving an optimization problem. As an example, MSE-SSIM is used as the objective function in designing a Wiener filter that aims at optimizing the perceptual visual quality of the output. Experimental results show that the images filtered with a MSE-SSIM-optimal Wiener filter have better visual quality than those filtered with a MSE-optimal Wiener filter. PMID- 24057006 TI - Automatic inpainting scheme for video text detection and removal. AB - We present a two stage framework for automatic video text removal to detect and remove embedded video texts and fill-in their remaining regions by appropriate data. In the video text detection stage, text locations in each frame are found via an unsupervised clustering performed on the connected components produced by the stroke width transform (SWT). Since SWT needs an accurate edge map, we develop a novel edge detector which benefits from the geometric features revealed by the bandlet transform. Next, the motion patterns of the text objects of each frame are analyzed to localize video texts. The detected video text regions are removed, then the video is restored by an inpainting scheme. The proposed video inpainting approach applies spatio-temporal geometric flows extracted by bandlets to reconstruct the missing data. A 3D volume regularization algorithm, which takes advantage of bandlet bases in exploiting the anisotropic regularities, is introduced to carry out the inpainting task. The method does not need extra processes to satisfy visual consistency. The experimental results demonstrate the effectiveness of both our proposed video text detection approach and the video completion technique, and consequently the entire automatic video text removal and restoration process. PMID- 24057007 TI - Comments on "Iterative channel decoding of FEC-based multiple-description codes". AB - In a previous paper, Chang et al. presented a method for iterative decoding of FEC-based multiple description codes in image transmission. In this correspondence, we clarify that an outer interleaver used in the above research was previously proposed for the iterative decoding and optimization of product codes in image transmission. PMID- 24057008 TI - Dual catalysis by Cu(I): facile single step click and intramolecular C-O bond formation leading to triazole tethered dihydrobenzodioxines/benzoxazines/benzoxathiines/benzodioxepines. AB - Dual copper catalysis, involving two different reactions, click (alkyne-azide) and carbon-oxygen bond formation (aryl iodide-secondary alcohol) in a single step, is reported. Synthesis of novel benzodioxines (benzodioxanes), benzoxazines, benzoxathiines and benzodioxepines, which feature benzo-condensed six or seven membered rings containing two hetero-atoms attached to a 1,2,3 triazole, is described. As an extension, such compounds were also synthesised by ring opening of epoxide and cyclisation using Cu(I). All the key products have been characterized by single crystal X-ray crystallography. PMID- 24057009 TI - Cavity-enhanced optical trapping of bacteria using a silicon photonic crystal. AB - On-chip optical trapping and manipulation of cells based on the evanescent field of photonic structures is emerging as a promising technique, both in research and for applications in broader context. Relying on mass fabrication techniques, the involved integration of photonics and microfluidics allows control of both the flow of light and water on the scale of interest in single cell microbiology. In this paper, we demonstrate for the first time optical trapping of single bacteria (B. subtilis and E. coli) using photonic crystal cavities for local enhancement of the evanescent field, as opposed to the synthetic particles used so far. Three types of cavities (H0, H1 and L3) are studied, embedded in a planar photonic crystal and optimized for coupling to two collinear photonic crystal waveguides. The photonic crystals are fabricated on a silicon-on-insulator chip, onto which a fluidic channel is created as well. For each of the cavities, when pumped at the resonance wavelength (around 1550 nm), we clearly demonstrate optical trapping of bacteria, in spite of their low index contrast w.r.t. water. By tracking the confined Brownian motion of B. subtilis spores in the traps using recorded microscope observations, we derive strong in-plane trap stiffnesses of about 7.6 pN nm(-1) W(-1). The values found agree very well with calculations based on the Maxwell stress tensor for the force and finite-difference time-domain simulations of the fields for the fabricated cavity geometries. We envision that our lab-on-a chip with photonic crystal traps opens up new application directions, e.g. immobilization of single bio-objects such as mammalian cells and bacteria under controlled conditions for optical microscopy studies. PMID- 24057010 TI - Nanoscale resistive switching devices: mechanisms and modeling. AB - Resistive switching devices (also termed memristive devices or memristors) are two-terminal nonlinear dynamic electronic devices that can have broad applications in the fields of nonvolatile memory, reconfigurable logic, analog circuits, and neuromorphic computing. Current rapid advances in memristive devices in turn demand better understanding of the switching mechanism and the development of physics-based as well as simplified device models to guide future device designs and circuit-level applications. In this article, we review the physical processes behind resistive switching (memristive) phenomena and discuss the experimental and modeling efforts to explain these effects. In this article three categories of devices, in which the resistive switching effects are driven by cation migration, anion migration, and electronic effects, will be discussed. The fundamental driving forces and the stochastic nature of resistive switching will also be discussed. PMID- 24057011 TI - An enzyme-responsive system programmed for the double release of bioactive molecules through an intracellular chemical amplification process. AB - The rise of chemical biology has led to the development of sophisticated molecular devices designed to explore and manipulate biological processes. Within this framework, we developed the first chemical system programmed for the selective internalization and subsequent enzyme-catalyzed double release of bioactive compounds inside a targeted population of cells. This system is composed of five distinct units including a targeting ligand, an enzymatic trigger, a self-immolative linker and two active compounds articulated around a chemical amplifier. Designed as such, this molecular assembly is capable in an autonomous manner to recognize a selected population of cells, penetrate into the intracellular medium through endocytosis and transform a single enzymatic activation step into the release of two active units. Demonstrating that an enzyme-catalyzed amplification process can occur spontaneously under the conditions prevailing within the cells could be an important step toward the development of innovative molecular systems for a diverse range of applications spanning drug delivery, biological sensors and diagnostics. PMID- 24057012 TI - Tracking the intracellular drug release from graphene oxide using surface enhanced Raman spectroscopy. AB - We have developed a graphene oxide (GO)-based nanoplatform simultaneously loaded with a chemical drug and Ag nanoparticles (NPs), and employed it to study the drug release from GO in living cells by surface-enhanced Raman spectroscopy (SERS). In our strategy, doxorubicin (DOX), a typical model anticancer drug, was loaded onto chemically prepared GO by means of pi-pi stacking, while the Ag NPs were covalently modified onto GO. After incubation of the DOX- and Ag NPs-loaded GO with Ca Ski cells for several hours, DOX will detach from the GO in an acidic environment due to the pH-dependent pi-pi interaction between DOX and GO. Real time measurement of SERS signals of DOX using the GO loaded with Ag NPs as a SERS active substrate allows us to monitor the process of the drug release inside the living cell. The SERS results reveal that DOX is initially released from the GO surface inside the lysosomes, then escapes into the cytoplasm, and finally enters the nucleus, while GO, the nanocarrier, remains within the cytoplasm, without entering the nucleus. PMID- 24057013 TI - Hierarchical structures of AlOOH nanoflakes nested on Si nanopillars with anti reflectance and superhydrophobicity. AB - A novel method to fabricate ultra-low reflective Si surfaces with nanoscale hierarchical structures is developed by the combination of AlOOH or boehmite nanoflakes nested on plasma-etched Si nanopillars. Using CF4 plasma etching, Si surfaces are nanostructured with pillar-like structures by selective etching with self-masking by fluorocarbon residues. AlOOH nanoflakes are formed by Al thin film coating with various thicknesses and subsequent immersion in boiling water, which induces the formation of nanoscale flakes through the hydrolysis reaction. AlOOH nanoflakes are formed on Si nanopillared surfaces for hierarchical structures, which are coated with a low-surface-energy material, resulting in a higher water wetting angle of over 150 degrees and a very low contact angle hysteresis of less than 5 degrees , and implying a self-cleaning surface. Reflectance reduced to 5.18% on average on hierarchical nanostructures in comparison to 9.63% on the Si nanopillar surfaces only. We found that Si nanopillars reduced reflection for wavelengths ranging from 200 to 1200 nm while AlOOH nanoflakes reduced reflection for wavelengths longer than 600 nm. PMID- 24057014 TI - EPR as a probe of the intracellular speciation of ruthenium(III) anticancer compounds. AB - EPR (electron paramagnetic resonance) has been used to study interactions of the Ru(III) anticancer compounds imidazolium [trans-RuCl4(1H-imidazole)(DMSO-S)] (NAMI-A) and indazolium [trans-RuCl4(1H-indazole)2] (KP1019) with isolated subcellular components and whole cells of the yeast Saccharomyces cerevisiae. These studies are the first to probe the intracellular speciation of ruthenium using the EPR technique. Initially, NAMI-A and KP1019 were incubated at 30 degrees C, for time periods up to 24 hours with isolated cell wall, mitochondrial, cytoplasmic, and nuclear fractions of S. cerevisiae. EPR measurements demonstrate that NAMI-A initially forms non-coordinate interactions with each cell component. After longer incubation times these are replaced by coordinated species, particularly with cytoplasmic proteins. KP1019 shows a greater tendency to coordinate directly with cell components, demonstrating significant interactions with mitochondria and cytoplasmic proteins. Subsequently, each complex was incubated with whole cells of S. cerevisiae at 30 degrees C and whole-cell EPR measurements detected Ru(III) species in measurable concentrations even after 24 hours of incubation. Analysis of the resulting EPR spectra suggests NAMI-A interacts predominantly with cell walls, while KP1019 was found to be coordinating with both the mitochondrial and cytoplasmic protein fractions. Comparison of the signal intensity of these data with those from incubation with whole cells at 4 degrees C indicates different modes of transmembrane transport for each complex. These studies demonstrate that EPR can provide valuable insight into the oxidation state and speciation of ruthenium compounds in cellular environments. PMID- 24057015 TI - The metabolic disturbances of isoproterenol induced myocardial infarction in rats based on a tissue targeted metabonomics. AB - Myocardial infarction (MI) is a leading cause of morbidity and mortality but the precise mechanism of its pathogenesis remains obscure. To achieve the most comprehensive screening of the entire metabolome related to isoproterenol (ISO) induced-MI, we present a tissue targeted metabonomic study using an integrated approach of ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF MS) and proton nuclear magnetic resonance (1H NMR). Twenty-two metabolites were detected as potential biomarkers related to the formation of MI, and the levels of pantothenic acid (), lysoPC(18:0) (), PC(18:4(6Z,9Z,12Z,15Z)/18:0) (), taurine (), lysoPC(20:3(8Z,11Z,14Z)) (), threonine (), alanine (), creatine (), phosphocreatine (), glucose 1-phosphate (), glycine (), xanthosine (), creatinine () and glucose () were decreased significantly, while the concentrations of histamine (), L-palmitoylcarnitine (), GSSG (), inosine (), arachidonic acid (), linoelaidic acid (), 3-methylhistamine () and glycylproline () were increased significantly in the MI rats compared with the control group. The identified potential biomarkers were involved in twelve metabolic pathways and achieved the most entire metabolome contributing to the injury of the myocardial tissue. Five pathways, including taurine and hypotaurine metabolism, glycolysis, arachidonic acid metabolism, glycine, serine and threonine metabolism and histidine metabolism, were significantly influenced by ISO-treatment according to MetPA analysis and suggested that the most prominent changes included inflammation, interference of calcium dynamics, as well as alterations of energy metabolism in the pathophysiologic process of MI. These findings provided a unique perspective on localized metabolic information of ISO induced-MI, which gave us new insights into the pathogenesis of MI, discovery of targets for clinical diagnosis and treatment. PMID- 24057016 TI - A highly ordered cubic mesoporous silica/graphene nanocomposite. AB - A highly ordered cubic mesoporous silica (KIT-6)/graphene nanocomposite and 2D KIT-6 nanoflakes were synthesized using a novel synthesis methodology. The non ionic triblock copolymer, P123, played a dual role as a structure-directing agent in the formation of the cubic mesoporous structure and as a cross-linking agent between mesoporous silica and graphene. The prepared (KIT-6)/graphene nanocomposite could act as a template for the preparation of mesoporous material/graphene nanocomposites. PMID- 24057017 TI - Three-dimensional Sn-graphene anode for high-performance lithium-ion batteries. AB - Tin (Sn) has been considered as one of the most promising anode materials for high-capacity lithium-ion batteries (LIBs) due to its high energy density, abundance, and environmentally benign nature. However, the problems of fast capacity fading at prolonged cycling and poor rate capacity hinder its practical use. Herein, we report the development of a novel architecture of Sn nanoparticle decorated three-dimensional (3D) foothill-like graphene as an anode in LIBs. Electrochemical measurements demonstrated that the 3D Sn-graphene anode delivered a reversible capacity of 466 mA h g(-1) at a current density of 879 mA g(-1) (1 C) after over 4000 cycles and 794 mA h g(-1) at 293 mA g(-1) (1/3 C) after 400 cycles. The capacity at 1/3 C is over 200% that of conventional graphite anodes, suggesting that the 3D Sn-graphene structure enables a significant improvement in the overall performance of a LIB in aspects of capacity, cycle life, and rate capacity. PMID- 24057018 TI - Single-cell force spectroscopy of the medically important Staphylococcus epidermidis-Candida albicans interaction. AB - Despite the clinical importance of bacterial-fungal interactions, their molecular details are poorly understood. A hallmark of such medically important interspecies associations is the interaction between the two nosocomial pathogens Staphylococcus aureus and Candida albicans, which can lead to mixed biofilm associated infections with enhanced antibiotic resistance. Here, we use single cell force spectroscopy (SCFS) to quantify the forces engaged in bacterial-fungal co-adhesion, focusing on the poorly investigated S. epidermidis-C. albicans interaction. Force curves recorded between single bacterial and fungal germ tubes showed large adhesion forces (~5 nN) with extended rupture lengths (up to 500 nm). By contrast, bacteria poorly adhered to yeast cells, emphasizing the important role of the yeast-to-hyphae transition in mediating adhesion to bacterial cells. Analysis of mutant strains altered in cell wall composition allowed us to distinguish the main fungal components involved in adhesion, i.e. Als proteins and O-mannosylations. We suggest that the measured co-adhesion forces are involved in the formation of mixed biofilms, thus possibly as well in promoting polymicrobial infections. In the future, we anticipate that this SCFS platform will be used in nanomedicine to decipher the molecular mechanisms of a wide variety of pathogen-pathogen interactions and may help in designing novel anti-adhesion agents. PMID- 24057019 TI - Synthesis and photophysical properties of chlorins bearing 0-4 distinct meso substituents. AB - The presence of substituents at designated sites about the chlorin macrocycle can alter the spectral properties, a phenomenon that can be probed through synthesis. Prior syntheses have provided access to chlorins bearing distinct aryl substituents (individually or collectively) at the 5, 10, and 15-positions, but not the 20-position. A new Western half (5-phenyl-2,3,4,5-tetrahydro-1,3,3 trimethyldipyrrin) has been employed in condensation with an Eastern half (9 bromodipyrromethane-1-carboxaldehyde) followed by oxidative cyclization to give (5% yield) the zinc(II) 20-phenylchlorin. Condensation of the same Western half and a diaryl-substituted Eastern half provided (11% yield) the zinc(II) 5,10,20 triarylchlorin; demetalation with TFA followed by 15-bromination and Suzuki coupling gave the free base 5,10,15,20-tetraarylchlorin. Altogether, 10 new synthetic chlorins have been prepared. The near-UV (B) absorption band of the free base chlorins shifts bathochromically from 389 to 429 nm and that for the zinc chlorins from 398 to 420 nm as the number of meso-aryl rings is increased stepwise from 0-4. The long-wavelength (Q(y)) absorption band undergoes a bathochromic and hypochromic shift upon increase in number of meso-aryl groups. Regardless of the number and positions of the meso-aryl substituents (including "walking a phenyl group around the ring"), the respective fluorescence quantum yields (0.17 to 0.27) and singlet excited-state lifetimes (9.4 to 13.1 ns) are comparable among the free base chlorins and the same is true for the zinc chelates (0.057 to 0.080; 1.2 to 1.6 ns). Density functional theory calculations show that of the frontier molecular orbitals of the chlorin, the energy of the HOMO-1 is the most affected by meso-aryl substituents, undergoing progressive destabilization as the number of meso-aryl groups is increased. The availability of chlorins with 0-4 distinct meso-aryl substituents provides the individual stepping-stones to bridge the known unsubstituted chlorin and the meso tetraarylchlorins. PMID- 24057021 TI - Linking analytical chemistry Master's programs: the Franco (Pau)-Spanish (Oviedo) case. PMID- 24057020 TI - Synthesis of the C-glycoside of alpha-(D)-mannose-(1 -> 6)-(D)-myo-inositol. AB - The dimannosylatedinositol pseudotrisaccharide phospholipid of the lipoarabinomannan (LAM) component of the mycobacterial cell wall has attracted interest as a therapeutic target because of its uniqueness to mycobacteria, its assembly at an early stage in LAM biosynthesis and the immunological activity of oligosaccharides containing this subunit. Accordingly, analogues of this pseudotrisaccharide, alpha-d-mannose-(1 -> 2)-alpha-d-mannose-(1 -> 6)-d-myo inositol are of interest as mechanistic probes and drug leads. C-glycosides are of special interest because of their hydrolytic stability and conformational differences compared to O-glycosides. Herein, as a prelude to C-glycoside analogues of this pseudotrisaccharide, we describe the synthesis of the C glycoside of alpha-d-mannose-(1 -> 6)-d-myo-inositol. The synthetic strategy centers on the elaboration of a C1-linked glycal-inositol, the glycone segment of which is assembled via an oxocarbenium ion cyclization on a thioacetal-enol ether precursor that originates from "glycone" and "aglycone" components. PMID- 24057022 TI - Electrophoretically mediated microanalysis for in-capillary electrical cell lysis and fast enzyme quantification by capillary electrophoresis. AB - In this study, a novel capillary electrophoresis (CE)-based enzymatic assay was developed to evaluate enzymatic activity in whole cells. beta-Galactosidase expression was used as an example, as it is a biomarker for assessing replicative senescence in mammalian cells. It catalyzes the hydrolysis of para-nitrophenyl beta-D-galactopyranoside (PNPG) into para-nitrophenol (PNP). The CE-based assay consisted of four main steps: (1) hydrodynamic injection of whole intact cells into the capillary, (2) in-capillary lysis of these cells by using pulses of electric field (electroporation), (3) in-capillary hydrolysis of PNPG by the beta galactosidase--released from the lysed cells--by the electrophoretically mediated microanalysis (EMMA) approach, and (4) on-line detection and quantification of the PNP formed. The developed method was applied to Escherichia coli as well as to human keratinocyte cells at different replicative stages. Results obtained by CE were in excellent agreement with those obtained from off-line cell lysates which proves the efficiency of the in-capillary approach developed. This work shows for the first time that cell membranes can be disrupted in-capillary by electroporation and that the released enzyme can be subsequently quantified in the same capillary. Enzyme quantification in cells after their in-capillary lysis has never been conducted by CE. The developed CE approach is automated, economic, eco-friendly, and simple to conduct. It has attractive applications in bacteria or human cells for early disease diagnostics or insights for development in biology. PMID- 24057023 TI - Chemometric tool for identification of iron-gall inks by use of visible-near infrared fibre optic reflection spectroscopy. AB - A method has been developed for identification of corrosive iron-gall inks in historical drawings and documents. The method is based on target-factor analysis of visible-near infrared fibre optic reflection spectra (VIS-NIR FORS). A set of reference spectra was obtained from model samples of laboratory-prepared inks covering a wide range of mixing ratios of basic ink components deposited on substrates and artificially aged. As criteria for correspondence of a studied spectrum with a reference spectrum, the apparent error in target (AET) and the empirical function SPOIL according to Malinowski were used. The capability of the proposed tool to distinguish corrosive iron-gall inks from bistre and sepia inks was evaluated by use of a set of control samples of bistre, sepia, and iron-gall inks. Examples are presented of analysis of historical drawings from the 15th and 16th centuries and written documents from the 19th century. The results of analysis based on the tool were confirmed by XRF analysis and colorimetric spot analysis. PMID- 24057024 TI - Domoic acid at trace levels in lagoon waters: assessment of a method using internal standard quantification. AB - Domoic acid (DA) is a neurotoxin produced by different algae, including pennate diatoms, principally from the genus Pseudo-nitzschia, and it is the main cause of amnesic shellfish poisoning. Determination of this toxin in seawater samples is fundamental to define the real contamination risks for aquatic species. We have developed two very sensitive instrumental methods using hydrophilic interaction liquid chromatography coupled using tandem mass spectrometry in positive and negative polarity modes. Instrumental detection limits were 9 pg mL(-1) for positive and 19 pg mL(-1) for negative ionisation. A procedural method based on solid-phase extraction for the determination of dissolved DA present in seawater has been developed, and an extraction procedure was employed for the determination of the toxin in the particulate fraction. DA quantification was performed using the internal standard method to account for signals fluctuations and random errors during sample treatment. To our knowledge, this is the first study to use this quantification method for DA determination. Trueness, extraction yield, matrix effects, repeatability and procedural detection limits were evaluated during method validation. Procedural detection limits of 0.3 pg mL(-1) (positive mode) and 0.6 pg mL(-1) (negative mode) were found for the dissolved fraction, and absolute limits of 0.4 pg (positive mode) and 6.0 pg (negative mode) for particulate samples were obtained. The most sensitive method in positive mode was applied to define DA occurrence in the Venice Lagoon. Trace concentrations of domoic acid ranging from 1.5 to 16.2 pg mL(-1) were found for the first time in the Venetian environment. PMID- 24057025 TI - Integrated biological-chemical approach for the isolation and selection of polyaromatic mutagens in surface waters. AB - Many environmental mutagens, including polyaromatic compounds are present in surface waters, often in complex mixtures and at low concentrations. The present study provides and applies a novel, integrated approach to isolate polyaromatic mutagens in river water using a sample from the River Elbe. The sample was taken downstream of industrial discharges using blue rayon (BR) as a passive sampler that selectively adsorbs polyaromatic compounds and was subjected to effect directed fractionation in order to characterise the compounds causing the detected effect(s). The procedure relies on three complementary fractionation steps, the Ames fluctuation assay with strains TA98, YG1024 and YG1041 with and without S9 activation and analytical screening. Several mutagenic fractions were isolated by combining mutagenicity testing with fractionation. The enhanced mutagenicity in the nitroreductase and/or O-acetyltransferase overexpressing strains YG1024 and YG1041 strains suggested amino- and/or nitro-compounds causing mutagenicity in several fractions. Analytical screening of mutagenic fractions with LC-HRMS/MS provided a list of molecular formulas typically containing one to ten nitrogen and at least two oxygen atoms supporting the presence of amino and nitro-compounds in the mutagenic fractions. PMID- 24057026 TI - A rapid and selective method for simultaneous determination of six toxic phenolic compounds in mainstream cigarette smoke using single-drop microextraction followed by liquid chromatography-tandem mass spectrometry. AB - Cigarette smoke contains several toxic phenolic compounds, measurements of which are essential from a public health standpoint. This article describes a simple and selective analytical method for quantitative determination of six toxic phenolic compounds (phenol, catechol, resorcinol, hydroquinone, o-cresol, and p cresol) from mainstream cigarette smoke using single-drop microextraction in combination with liquid chromatography-tandem mass spectrometry. Single-drop microextraction was applied prior to analysis by liquid chromatography-tandem mass spectrometry for the extraction and preconcentration of target phenolic compounds from raw cigarette smoke extract. The effects of the extraction solvent, sampling time, solution pH, salt addition, sample agitation rate, and temperature on the extraction efficiency were examined and optimized. The identification of each analyte was established by chromatographic retention times, analyte-specific fragmentation patterns, and relative peak area ratios of two product/precursor ion pairs. Analytical parameters such as the detection limit, relative recovery, reproducibility, linearity, and enrichment factor were evaluated under the optimized experimental conditions. 1-Decanol was selected as the extraction solvent and the limits of detection were found to be in the range of 0.05-0.3 ng mL(-1) using an extraction time of 12 min. Gradient chromatographic conditions were optimized for the separation of the six phenolic compounds in a run time of 10 min including reequilibration of the column. The present method for determination of phenolic compounds from mainstream cigarette smoke is simple and specific and shows good reproducibility, with relative standard deviations less than 10% for all targeted phenolics. PMID- 24057027 TI - HRMAS NMR spectroscopy combined with chemometrics as an alternative analytical tool to control cigarette authenticity. AB - In this paper, we present for the first time the use of high-resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) spectroscopy combined with chemometrics as an alternative tool for the characterization of tobacco products from different commercial international brands as well as for the identification of counterfeits. Although cigarette filling is a very complex chemical mixture, we were able to discriminate between dark, bright, and additive-free cigarette blends belonging to six different filter-cigarette brands, commercially available, using an approach for which no extraction procedure is required. Second, we focused our study on a specific worldwide-distributed brand for which established counterfeits were available. We discriminated those from their genuine counterparts with 100% accuracy using unsupervised multivariate statistical analysis. The counterfeits that we analyzed showed a higher amount of nicotine and solanesol and a lower content of sugars, all endogenous tobacco leaf metabolites. This preliminary study demonstrates the great potential of HRMAS NMR spectroscopy to help in controlling cigarette authenticity. PMID- 24057028 TI - Biomimetic layer-by-layer Co-mineralization approach towards TiO2/Au nanosheets with high rate performance for lithium ion batteries. AB - We fabricated a sandwich-like branched-polyethyleneimine (b-PEI)/TiO2/Au/graphene oxide (GO) nanocomposite through a biomimetic layer-by-layer co-mineralization approach, and the polymer b-PEI was believed to act as both an inducing agent for the hydrolysis of titanium bis(ammonium lactato)-dihydroxide (Ti-BALDH) and a reducing agent for the reduction of HAuCl4 in the synthetic procedure. Upon organic pyrolysis in air at 500 degrees C, a TiO2/Au nanosheet was formed; and gold nanocrystals were observed uniformly dispersed on TiO2 nanosheet. Moreover, the obtained TiO2/Au nanosheets demonstrated an enhanced lithium storage performance when they are used as anode materials for lithium ion batteries (LIBs), particularly, a high capacity of 205 mA h g(-1) and 189 mA h g(-1) was obtained at 5 C and 10 C rate, respectively, indicating the high rate capability of the material. The greatly improved rate performance might be attributed from both the sheet-like nanostructure and the existence of uniformly dispersed gold nanocrystals, which facilitate electron transfer and lithium ions diffusion in the material. The result suggests that the TiO2 electrode performance can be improved through a design of sheet-like nanocomposites using a bio-inspired route, which is desirable for both "green synthesis" and application for high power LIBs, moreover, such a benign bio-inspired route can be developed into a general pathway to synthesize many other TiO2 based nanocomposites for broad applications in the fields of batteries, photoelectrochemistry, photocatalysis and dye-sensitized solar cells. PMID- 24057029 TI - Anatomic and radiographic comparison of arthroscopic suprapectoral and open subpectoral biceps tenodesis sites. AB - BACKGROUND: Arthroscopic suprapectoral and open subpectoral surgical techniques are both commonly utilized approaches for proximal biceps tenodesis of the long head of the biceps brachii. A central limitation to the widespread use of an arthroscopic approach for biceps tenodesis is that the tendon may be tenodesed too proximally in the bicipital groove, leading to persistent pain and tendinopathy. Purpose/ HYPOTHESIS: The purpose of this study was to determine the in vivo tenodesis location using arthroscopic suprapectoral and open subpectoral techniques for proximal biceps tenodesis in relation to clinically pertinent anatomic and radiographic landmarks. The null hypothesis was that arthroscopic suprapectoral biceps tenodesis would not be significantly different in terms of the location from open subpectoral biceps tenodesis. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 20 matched pairs of cadaveric shoulder specimens were randomized such that within each pair, 1 shoulder underwent a standard open subpectoral biceps tenodesis and the other underwent an arthroscopic suprapectoral tenodesis. Limited dissection and exposure of the surgical tunnel site and reference landmarks were subsequently performed, and anteroposterior and lateral radiographs were obtained. Direct measurements were performed anatomically using a digital caliper and radiographically using picture archiving and communication system (PACS) software from the proximal lip of the humeral tunnel to regional landmarks. RESULTS: Both techniques were able to place the humeral tunnel distal to the bicipital groove in all specimens. On average, the open subpectoral approach placed the tunnel 2.2 cm distal to the arthroscopic suprapectoral approach. CONCLUSION: The arthroscopic suprapectoral biceps tenodesis technique used in this study consistently placed the tenodesis tunnel distal to the bicipital groove, which may allay concerns about the bicipital groove as a pain source after this procedure. CLINICAL RELEVANCE: This anatomic study provides new information on tunnel placement in 2 biceps tenodesis techniques. In addition, it provides clinically relevant anatomic and radiographic guidelines using clinically pertinent landmarks. This information may be useful in preoperative planning, intraoperative technique, and postoperative assessment of both open subpectoral and arthroscopic suprapectoral biceps tenodesis. PMID- 24057030 TI - Acromioclavicular joint injuries in the National Football League: epidemiology and management. AB - BACKGROUND: Previous studies investigating acromioclavicular (AC) joint injuries in professional American football players have only been reported on quarterbacks during the 1980s and 1990s. These injuries have not been evaluated across all position players in the National Football League (NFL). PURPOSE: The purpose of this study was 4-fold: (1) to determine the incidence of AC joint injuries among all NFL position players; (2) to investigate whether player position, competition setting, type of play, and playing surface put an athlete at an increased risk for this type of injury; (3) to determine the incidence of operative and nonoperative management of these injuries; and (4) to compare the time missed for injuries treated nonoperatively to the time missed for injuries requiring surgical intervention. STUDY DESIGN: Descriptive epidemiological study. METHODS: All documented injuries of the AC joint were retrospectively analyzed using the NFL Injury Surveillance System (NFLISS) over a 12-season period from 2000 through 2011. The data were analyzed by the anatomic location, player position, field conditions, type of play, requirement of surgical management, days missed per injury, and injury incidence. RESULTS: Over 12 NFL seasons, there were a total of 2486 shoulder injuries, with 727 (29.2%) of these injuries involving the AC joint. The overall rate of AC joint injuries in these athletes was 26.1 injuries per 10,000 athlete exposures, with the majority of these injuries occurring during game activity on natural grass surfaces (incidence density ratio, 0.79) and most often during passing plays. These injuries occurred most frequently in defensive backs, wide receivers, and special teams players; however, the incidence of these injuries was greatest in quarterbacks (20.9 injuries per 100 players), followed by special teams players (20.7/100) and wide receivers (16.5/100). Overall, these athletes lost a mean of 9.8 days per injury, with quarterbacks losing the most time to injury (mean, 17.3 days). The majority of these injuries were low-grade AC joint sprains that were treated with nonoperative measures; only 13 (1.7%) required surgical management. Players who underwent surgical management lost a mean of 56.2 days. CONCLUSION: Shoulder injuries, particularly those of the AC joint, occur frequently in the NFL. These injuries can result in time lost but rarely require operative management. Quarterbacks had the highest incidence of injury; however, this incidence is lower than in previous investigations that evaluated these injuries during the 1980s and 1990s. PMID- 24057031 TI - Spiro-bicyclo[2.2.2]octane derivatives as paclitaxel mimetics. Synthesis and toxicity evaluation in breast cancer cell lines. AB - Paclitaxel is one of the most important anti-cancer agents introduced during the last 20 years. However, the use of paclitaxel is limited by undesirable side effects as well as the development of drug resistance. Here, we report a synthetic strategy towards spiro-bicyclo[2.2.2]octane derivatives, which includes double Michael addition and ring-closing metathesis as key synthetic steps. This strategy was used to synthesize a series of spiro-bicyclic compounds designed to be paclitaxel mimetics, which were evaluated in human breast-derived cell lines. One of these paclitaxel mimetics showed toxicity, although at higher concentrations than paclitaxel itself. In addition, two other spiro-bicyclic compounds, lacking the paclitaxel side chain, showed toxicity. PMID- 24057032 TI - Generation of embryonic stem cells and mice for duchenne research. AB - Duchenne muscular dystrophy (DMD) is a muscle-wasting disease in which muscle is continuously damaged, resulting in loss of muscle tissue and function. Antisense mediated exon skipping is a promising therapeutic approach for DMD. This method uses sequence specific antisense oligonucleotides (AONs) to reframe disrupted dystrophin transcripts. As AONs function in a sequence specific manner, human specific AONs cannot be tested in the mdx mouse, which carries a mutation in the murine Dmd gene. We have previously generated a mouse model carrying the complete human DMD gene (hDMD mouse) integrated in the mouse genome to overcome this problem. However, as this is not a disease model, it cannot be used to study the effect of AON treatment on protein level and muscle function. Therefore, our long term goal is to generate deletions in the human DMD gene in a mouse carrying the hDMD gene in an mdx background. Towards this aim, we generated a male ES cell line carrying the hDMD gene while having the mdx point mutation. Inheritance of the hDMD gene by the ES cell was confirmed both on DNA and mRNA level. Quality control of the ES cells revealed that the pluripotency marker genes Oct-4 and Nanog are well expressed and that 85% of cells have 40 chromosomes. Germ line competence of this cell line has been confirmed, and 2 mice strains were derived from this cell line and crossed back on a C57BL6 background: hDMD/mdx and mdx(BL6). PMID- 24057033 TI - Regioselective construction of 1,3-diazaheterocycle fused [1,2 a][1,8]naphthyridine derivatives via cascade reaction of quinolines with heterocyclic ketene aminals: a joint experimental-computational approach. AB - A one-step, transition-metal-free protocol, involving facile post-treatment, for the regioselective synthesis of 1,3-diazaheterocycle fused [1,2 a][1,8]naphthyridine derivatives (3) from 2-chloroquinoline-3-carbaldehydes (ClQuAlds) (1) and heterocyclic ketene aminals (HKAs) (2) was developed via a joint experimental-computational approach. The computational prediction of the reactivity of two series of synthons was applied in the process of optimizing the reaction conditions, which relied on density functional theory (DFT) calculations together with concepts of frontier molecular orbital (FMO) theory and quantitative structure-reactivity relationship (QSRR) presumptions. The combined results enabled the proposal of a pre-synthetic prediction of global reactivity. The fully consistent results of the synthetic experiments with the in silico evaluation confirmed the rationality, effectiveness, and practicability of the new strategy. Notably, the joint method is not limited to the laboratory, but has applications ranging from routine to industry. This approach is likely to yield numerous insights to accelerate HKA-related synthetic chemistry that can be extended to numerous heterocycles. It thus opens up a novel entry towards rapidly investigating the reactivity of novel synthons with unique properties, a further step towards exploiting cascade reactions by avoiding the futile waste of time and resources. PMID- 24057034 TI - Limited evidence that a brief education programme for parents of high-risk preschool children may reduce risk of internalising disorders in adolescence in girls but not boys. PMID- 24057035 TI - Review: insufficient evidence to recommend routine screening for psychological distress among people with cancer. PMID- 24057036 TI - Slow translocation of polynucleotides and their discrimination by alpha-hemolysin inside a single track-etched nanopore designed by atomic layer deposition. AB - We report the formation of a hybrid biological/artificial nanopore by the direct insertion of non-modified alpha-hemolysin at the entrance of a high aspect ratio (length/diameter) biomimetic nanopore. In this robust hybrid system, the protein exhibits the same polynucleotide discrimination properties as in the biological membrane and the polynucleotide dwell time is strongly increased. This nanopore is very promising for DNA sequencing applications where the high DNA translocation velocity and the fragility of the support are the main bottlenecks. PMID- 24057037 TI - Enhanced and directional emission of semiconductor nanowires tailored through leaky/guided modes. AB - Photoluminescence from finite semiconductor nanowires is theoretically investigated, exploring and predicting their antenna-like properties for light emission in a variety of configurations of interest in Nanophotonics. The theoretical analysis is based on the leaky/guided mode dispersion relation for infinite nanowires, which govern the local density of available electromagnetic states. Light emission from finite nanowires is then numerically investigated in various scenarios with regard to its enhancement and directionality. A simple analytical model is derived that, upon tuning leaky/guided mode coupling through dipole position/orientation and nanowire length, allows us to predict their antenna-like behavior and thus to tailor photoluminescence (including magnetic dipole transitions) at will, with regard to both enhancement/inhibition and associated radiation patterns. PMID- 24057038 TI - Monolithic 3D titania with ultrathin nanoshell structures for enhanced photocatalytic activity and recyclability. AB - Titania has attracted considerable interest for use in water purification applications due to its excellent photocatalytic activity. To further improve the efficiency of photocatalysis, numerous nanostructures (i.e. nanoparticles, nanotubes, and nanowires) have been proposed to increase the surface area of titania. Despite the high photocatalytic performance of the nanostructured titania, subsequent difficulties encountered in recollection and reuse of titania inhibit the practical application for water purification systems. Here we successfully fabricate monolithic, three dimensional (3D) nanoshell titania with high uniformity over large areas (~1 * 1 inch(2)) through proximity field nanopatterning (PnP) and low-temperature atomic layer deposition (ALD) techniques. The higher surface area of 3D nanoshell titania increases the photocatalytic performance more than three-fold relative to that of a thin film of equivalent sample size. Also, the monolithic form of titania enables it to be reused without any degradation of photocatalytic activity. The newly developed nanomaterials in this study can serve as an efficient and reusable photocatalyst for water purification systems. PMID- 24057039 TI - Comparative pharmacokinetics of subcutaneous trastuzumab administered via handheld syringe or proprietary single-use injection device in healthy males. AB - PURPOSE: To demonstrate pharmacokinetic (PK) comparability for a single dose of 600 mg subcutaneous (SC) trastuzumab, administered via a novel single-use injection device (SID) or handheld syringe in 119 randomized healthy male subjects. METHODS: The co-primary PK endpoints area under the time-concentration curve from the start of dosing to day 22 (AUC(0-21 days)) and maximum observed trastuzumab serum concentration (C(max)) were dose-normalized and body-weight adjusted, and compared using geometric mean ratios (GMRs). SID performance, injection site pain, adverse events, and antidrug antibodies (ADAs) were assessed. RESULTS: GMRs and 90 % confidence intervals (CIs) were 1.01 (0.96-1.07) for AUC(0-21 days) and 1.02 (0.96-1.10) for C(max), which fell within the prespecified bioequivalence range (0.80-1.25). No SID quality issues or failures occurred. Adverse events were mostly mild, with no deaths, adverse event-related withdrawals, or life-threatening, cardiac, or serious events reported. The ADA rate was low, and no neutralizing antibodies were detected. CONCLUSIONS: Trastuzumab SC via SID demonstrated comparable PK and safety to handheld syringe administration. SID performance was very satisfactory. PMID- 24057040 TI - An appraisal of subcutaneous trastuzumab: a new formulation meeting clinical needs. AB - Trastuzumab has deeply and radically changed the course of HER2-positive breast cancer disease. The recent development of a subcutaneous (SC) formulation of trastuzumab is an important step towards improved patients' care. SC trastuzumab at a fixed dose of 600 mg administered every 3 weeks for about 5 min provides a valid alternative to the IV, both in terms of efficacy and safety. This results in substantial time savings for patients, pharmacists, physicians and nursing staff, with a healthcare professionals' and patients' preference largely going to SC. In addition, the possibility to treat patients with poor venous access or to spare patients' venous capital when necessary may also be of interest. PMID- 24057041 TI - FOLFIRI plus bevacizumab as a first-line treatment for Japanese patients with metastatic colorectal cancer: a JACCRO CC-03 multicenter phase II study. AB - PURPOSE: The purpose of this multicenter phase II study was to evaluate the efficacy and safety of a combination of irinotecan, 5-fluorouracil (5-FU), and leucovorin (FOLFIRI) plus bevacizumab as first-line chemotherapy in Japanese patients with metastatic colorectal cancer. METHODS: Patients with metastatic colorectal cancer were eligible for enrollment. On day 1 of a 14-day cycle, patients received bevacizumab 5 mg/kg, irinotecan 150 mg/m2, and L-leucovorin 200 mg/m2 as an intravenous infusion, followed by 5-FU 400 mg/m2 as an intravenous bolus and then 5-FU 2,400 mg/m2 as an 46-h intravenous infusion. This treatment cycle was repeated. The primary endpoint was progression-free survival (PFS). RESULTS: We enrolled 40 patients, but one withdrew consent before starting treatment. The remaining 39 patients received a total of 509 cycles of FOLFIRI plus bevacizumab (median 11 per patient; range 1-30). The median PFS was 11.5 months, the median overall survival (OS) was 22.0 months, and the 1-year OS rate was 81.8 %. All 39 patients had adverse events. Grade 3 or 4 neutropenia and stomatitis occurred in 21 (53.9 %) and 4 (10.3 %) patients, respectively. CONCLUSION: Our results suggest that FOLFIRI plus bevacizumab is a clinically effective regimen with a manageable toxicity profile as first-line chemotherapy in patients with metastatic colorectal cancer. PMID- 24057043 TI - A multicenter phase II study of docetaxel, oxaliplatin, and bevacizumab in first line therapy for unresectable locally advanced or metastatic non-squamous cell histology non-small-cell lung cancer (NSCLC). AB - INTRODUCTION: Platinum-based doublets are standard of care for advanced non-small cell lung cancer (NSCLC). The combination of docetaxel and oxaliplatin has shown acceptable toxicity and encouraging activity. This phase II study aimed to determine the safety and efficacy of this doublet with bevacizumab as first-line treatment for stage IIIB/IV NSCLC. METHODS: Newly diagnosed patients >=18 years with histologically proven non-squamous NSCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) <=2 received six 21-day cycles of docetaxel, oxaliplatin, and bevacizumab followed by single-agent bevacizumab for a total of 1 year. Primary efficacy end point was radiographically documented progression free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), time to treatment failure, and safety. RESULTS: Fifty three patients were enrolled. Median age was 62.0 years, 71.7 % male, 79.2 % Caucasian. A total of 88.7 % had stage IV or recurrent disease; 94.3 % adenocarcinoma; and 94.3 % ECOG PS 0 or 1. Efficacy results are as follows: median PFS 5.6 months, ORR 30.2 % (complete response 1.9 %, partial response 28.3 %); 37.7 % stable disease; and OS 14.0 months. At least one adverse event (AE) was reported in all patients (n = 52); 98.1 % of AEs were treatment related. The most common treatment-emergent grade >=3 AEs were neutropenia (15.4 %), diarrhea (13.5 %), and fatigue (11.5 %). A serious AE was present in 32.7 %; the most common were pneumonia (7.7 %) and abdominal pain (5.8 %). Dehydration, diarrhea, febrile neutropenia, sepsis, and supraventricular tachycardia each occurred in 3.8 %. CONCLUSIONS: The addition of bevacizumab to docetaxel/oxaliplatin is effective with an acceptable safety profile in patients with chemotherapy-naive advanced NSCLC. PMID- 24057044 TI - Strategy of mutual compensation of green and red mutants of firefly luciferase identifies a mutation of the highly conservative residue E457 with a strong red shift of bioluminescence. AB - Bioluminescence spectra of firefly luciferases demonstrate highly pH-sensitive spectra changing the color from green to red light when pH is lowered from alkaline to acidic. This reflects a change of ratio of the green and red emitters in the bimodal spectra of bioluminescence. We show that the mutations strongly stabilizing green (Y35N) or red (H433Y) emission compensate each other leading to the WT color of firefly luciferase. We further used this compensating ability of Y35N to search for strong red-shifting mutations in the C-domain of firefly luciferase by random mutagenesis. The discovered mutation E457K substantially increased the contribution of the red emitter and caused a 12 nm red shift of the green emitter as well. E457 is highly conservative not only in beetle luciferases but also in a whole ANL superfamily of adenylating enzymes and forms a conservative structural hydrogen bond with V471. Our results suggest that the removal of this hydrogen bond only mildly affects luciferase properties and that most of the effect of E457K is caused by the introduction of positive charge. E457 forms a salt bridge with R534 in most ANL enzymes including pH-insensitive luciferases which is absent in pH-sensitive firefly luciferases. The mutant A534R shows that this salt bridge is not important for pH-sensitivity but considerably improves in vivo thermostability. Although E457 is located far from the oxyluciferin-binding site, the properties of the mutant E457K suggest that it affects color by influencing the AMP binding. PMID- 24057042 TI - Phase I study evaluating the combination of lapatinib (a Her2/Neu and EGFR inhibitor) and everolimus (an mTOR inhibitor) in patients with advanced cancers: South West Oncology Group (SWOG) Study S0528. AB - PURPOSE: Everolimus, an oral inhibitor of mammalian target of rapamycin, can augment the efficacy of HER inhibitors in preclinical studies. This study was conducted to determine the safety and pharmacokinetics (PK) of the combination of lapatinib, a Her1 and 2 inhibitor, and everolimus and to describe its anti-tumor activity in the Phase I setting. METHODS: In Part I, dose escalation to define the maximum tolerated dose (MTD) was performed. In Part II, PK of both drugs were analyzed to assess drug-drug interaction. RESULTS: Twenty-three evaluable patients with advanced cancers were treated on six different dose levels in Part I of the study. The dose-limiting toxicities were diarrhea, rash, mucositis, and fatigue. The MTD of the combination was 1,250 mg of lapatinib and 5 mg of everolimus once daily. In Part II of the study, 54 patients were treated with the combination at the MTD. The mean everolimus time to maximum concentration was increased by 44 %, and mean clearance was decreased by 25 % when co-administered with lapatinib, though these differences were not statistically significant. There was no significant influence on the PK of lapatinib by everolimus. Two patients achieved a partial response [thymic cancer (45+ months) and breast cancer (unconfirmed PR; 7 months)]; 11 patients attained stable disease of at least 4 months. CONCLUSIONS: Lapatinib and everolimus are well tolerated at doses of 1,250 and 5 mg po daily, respectively. Stable disease >=4 months/PR was achieved in 13 of 78 patients (17 %). PMID- 24057045 TI - Integrated plumage colour variation in relation to body condition, reproductive investment and laying date in the collared flycatcher. AB - The possible integration of different sexual ornaments into a composite system, and especially the information content of such ornament complexes, is poorly investigated. Many bird species display complex plumage coloration, but whether this represents one integrated or several independent sexual traits can be unclear. Collared flycatchers (Ficedula albicollis) display melanised and depigmented plumage areas, and the spectral features (brightness and UV chroma) of these are correlated with each other across the plumage. In a 5-year dataset of male and female plumage reflectance, we examined some of the potential information content of integrated, plumage-level colour attributes by estimating their relationships to previous and current year body condition, laying date and clutch size. Females were in better condition the year before they became darker pigmented, and males in better current year condition were also darker pigmented. Female pigment-based brightness was positively, while male structurally based brightness was negatively related to current laying date. Finally, the overall UV chroma of white plumage areas in males was positively associated with current clutch size. Our results show that higher degree of pigmentation is related to better condition, while the structural colour component is associated with some aspects of reproductive investment. These results highlight the possibility that correlated aspects of a multiple plumage ornamentation system may reflect together some aspects of individual quality, thereby functioning as a composite signal. PMID- 24057046 TI - Rhodium(iii)-catalyzed ortho-olefination of aryl phosphonates. AB - Rhodium(iii)-catalyzed C-H olefination of aryl phosphonic esters is reported for the first time. In this mild and efficient process, the phosphonic ester group is utilized successfully as a new directing group. In addition, mono-olefination for aryl phosphonates is observed using a phosphonic diamide directing group. PMID- 24057048 TI - The hexacarbonyldicobalt derivative of aspirin acts as a CO-releasing NSAID on malignant mesothelioma cells. AB - The antiproliferative activity of the aspirin derivative [2-acetoxy-(2 propynyl)benzoate]hexacarbonyldicobalt (Co-ASS) and its analogue hexacarbonyl[MU (2-ethylphenyl)methanol]dicobalt (Co-EPM) was investigated on malignant pleural mesothelioma (MPM) cell lines, having an epithelioid or a sarcomatoid phenotype. In sarcomatoid cell lines Co-ASS was more potent than Co-EPM and the prototypal metallo-drug cisplatin, and induced cell death through the intrinsic apoptotic pathway, associated with a strong NF-kappaB inhibition. In contrast, both Co-ASS and Co-EPM showed only a modest cytostatic activity against epithelioid MPM cells. Co-EPM induced an increase of senescent cells, while Co-ASS did not; the different outcomes were traced back to the organic (aspirin-like) portion of the molecule. Both Co-EPM and Co-ASS significantly reduced reactive oxygen/nitrogen species (ROS/RNS), and in turn nitrites, suggesting that the hexacarbonyldicobalt moiety may deliver CO within the cell, acting as a CO-releasing molecule (CO-RM). In perspective, Co-ASS would be better considered as a CO-NSAID agent (a CO releasing molecule retaining the NSAID properties similar to NO- and H2S-NSAIDs) than as an antitumor drug candidate. PMID- 24057047 TI - Binding structures and energies of the human neonatal Fc receptor with human Fc and its mutants by molecular modeling and dynamics simulations. AB - Homology modeling and molecular dynamics simulations have been carried out to model the detailed structures of the human neonatal Fc receptor (FcRn) binding with the wild-type Fc of human immunoglobulin G1 (IgG1) and its various mutants. Based on the modeled human FcRn-Fc binding structures, it has been proposed that the protein-protein binding interface is composed of three subsites. The first subsite is a hydrophobic core where residue I39 of human Fc can be accommodated very well, and the other two subsites are all composed of critical salt bridges between human FcRn and human Fc. All of the modeled structures and the calculated binding energies are qualitatively consistent with the available experimental data, suggesting that the modeled human FcRn-Fc binding structures are reasonable. The modeled human FcRn-Fc binding structure may be valuable for future rational design of novel mutants of human Fc and Fc-fused therapeutic proteins with a potentially higher binding affinity for human FcRn and, thus, a longer in vivo half-life in humans. PMID- 24057049 TI - High power density microbial fuel cell with flexible 3D graphene-nickel foam as anode. AB - The structure and electrical conductivity of anode play a significant role in the power generation of microbial fuel cells (MFCs). In this study, we developed a three-dimensional (3D) reduced graphene oxide-nickel (denoted as rGO-Ni) foam as an anode for MFC through controlled deposition of rGO sheets onto the nickel foam substrate. The loading amount of rGO sheets and electrode surface area can be controlled by the number of rGO loading cycles. 3D rGO-Ni foam anode provides not only a large accessible surface area for microbial colonization and electron mediators, but also a uniform macro-porous scaffold for effective mass diffusion of the culture medium. Significantly, at a steady state of the power generation, the MFC device with flexible rGO-Ni electrodes produced an optimal volumetric power density of 661 W m(-3) calculated based on the volume of anode material, or 27 W m(-3) based on the volume of the anode chamber. These values are substantially higher than that of plain nickel foam, and other conventional carbon based electrodes (e.g., carbon cloth, carbon felt, and carbon paper) measured in the same conditions. To our knowledge, this is the highest volumetric power density reported for mL-scale MFC device with a pure strain of Shewanella oneidensis MR-1. We also demonstrated that the MFC device can be operated effectively in a batch-mode at least for a week. These new 3D rGO-Ni electrodes show great promise for improving the power generation of MFC devices. PMID- 24057050 TI - Facile synthesis of carbon doped TiO2 nanowires without an external carbon source and their opto-electronic properties. AB - The present study demonstrates a simple protocol for the preparation of one dimensional (1D) oxidized titanium carbide nanowires and their opto-electronic properties. The oxidized titanium carbide nanowires (Ox-TiC-NW) are prepared from TiC nanowires (TiC-NW) that are in turn synthesized from micron sized TiC particles using the solvothermal technique. The Ox-TiC-NW is characterized by X ray diffraction, UV-Vis spectroscopy, transmission electron microscopy (TEM), scanning electron microscopy (SEM) and Raman spectroscopy. Thermal oxidation of TiC-NW yields carbon doped TiO2-NW (C-TiO2-NW), a simple methodology to obtain 1D C-TiO2-NW. Temperature dependent Raman spectra reveal characteristic bands for TiO2-NW. Electrical characterization of individual C-TiO2-NW is performed by fabricating a device structure using the focused ion beam deposition technique. The opto-electronic properties of individual C-TiO2-NW demonstrate visible light activity and the parameters obtained from photoconductivity measurements reveal very good sensitivity. This methodology opens up the possibility of using C-TiO2 NW in electronic and opto-electronic device applications. PMID- 24057051 TI - Aromatic thioglycoside inhibitors against the virulence factor LecA from Pseudomonas aeruginosa. AB - Three small families of hydrolytically stable thioaryl glycosides were prepared as inhibitors of the LecA (PA-IL) virulence factor corresponding to the carbohydrate binding lectin from the bacterial pathogen Pseudomonas aeruginosa. The monosaccharidic arylthio beta-d-galactopyranosides served as a common template for the major series that was also substituted at the O-3 position. Arylthio disaccharides from lactose and from melibiose constituted the other two series members. In spite of the fact that the natural ligand for LecA is a glycolipid of the globotriaosylceramide having an alpha-d-galactopyranoside epitope, this study illustrated that the beta-d-galactopyranoside configuration having a hydrophobic aglycon could override the requirement toward the anomeric configuration of the natural sugar. The enzyme linked lectin assay together with isothermal titration microcalorimetry established that naphthyl 1-thio-beta-d galactopyranoside () gave the best inhibition with an IC50 twenty-three times better than that of the reference methyl alpha-d-galactopyranoside. In addition it showed a KD of 6.3 MUM which was ten times better than that of the reference compound. The X-ray crystal structure of LecA with was also obtained. PMID- 24057052 TI - Structure-transfection activity relationships in a series of novel cationic lipids with heterocyclic head-groups. AB - Cationic liposomes are promising candidates for the delivery of various therapeutic nucleic acids. Here, we report a convenient synthesis of carbamate type cationic lipids with various hydrophobic domains (tetradecanol, dialkylglycerol, cholesterol) and positively charged head-groups (pyridinium, N methylimidazolium, N-methylmorpholinium) and data on the structure-transfection activity relationships. It was found that single-chain lipids possess high surface activity, which correlates with high cytotoxicity due to their ability to disrupt the cellular membrane by combined hydrophobic and electrostatic interactions. Liposomes containing these lipids also display high cytotoxicity with respect to all cell lines. Irrespective of chemical structures, all cationic lipids form liposomes with similar sizes and surface potentials. The characteristics of complexes composed of cationic liposomes and nucleic acids depend mostly on the type of nucleic acid and P/N ratios. In the case of oligodeoxyribonucleotide delivery, the transfection activity depends on the type of cationic head-group regardless of the type of hydrophobic domain: all types of cationic liposomes mediate efficient oligonucleotide transfer into 80-90% of the eukaryotic cells, and liposomes based on lipids with N-methylmorpholinium cationic head-group display the highest transfection activity. In the case of plasmid DNA and siRNA, the type of hydrophobic domain determines the transfection activity: liposomes composed of cholesterol-based lipids were the most efficient in DNA transfer, while liposomes containing glycerol-based lipids exhibited reasonable activity in siRNA delivery under serum-free conditions. PMID- 24057054 TI - Serotonin in the pathophysiology and treatment of CNS disorders. PMID- 24057053 TI - The effect of aborting ongoing movements on end point position estimation. AB - The present study investigated the impact of motor commands to abort ongoing movement on position estimation. Participants carried out visually guided reaching movements on a horizontal plane with their eyes open. By setting a mirror above their arm, however, they could not see the arm, only the start and target points. They estimated the position of their fingertip based solely on proprioception after their reaching movement was stopped before reaching the target. The participants stopped reaching as soon as they heard an auditory cue or were mechanically prevented from moving any further by an obstacle in their path. These reaching movements were carried out at two different speeds (fast or slow). It was assumed that additional motor commands to abort ongoing movement were required and that their magnitude was high, low, and zero, in the auditory fast condition, the auditory-slow condition, and both the obstacle conditions, respectively. There were two main results. (1) When the participants voluntarily stopped a fast movement in response to the auditory cue (the auditory-fast condition), they showed more underestimates than in the other three conditions. This underestimate effect was positively related to movement velocity. (2) An inverted-U-shaped bias pattern as a function of movement distance was observed consistently, except in the auditory-fast condition. These findings indicate that voluntarily stopping fast ongoing movement created a negative bias in the position estimate, supporting the idea that additional motor commands or efforts to abort planned movement are involved with the position estimation system. In addition, spatially probabilistic inference and signal-dependent noise may explain the underestimate effect of aborting ongoing movement. PMID- 24057055 TI - Tetravalent glycocyclopeptide with nanomolar affinity to wheat germ agglutinin. AB - A series of tetravalent glycocyclopeptides functionalized with GlcNAc was synthesized using copper(i)-catalysed alkyne-azide cycloaddition, oxime ligation and thiol-ene coupling. The binding ability of these compounds towards wheat germ agglutinin was studied by a competitive ELLA test and ITC experiments. While all compounds were able to inhibit WGA binding to GlcNAc-polymer coated surfaces at low concentrations, derivative 17 having an aliphatic spacer and thioether linkage was 4.9 * 10(6) times more potent on a per sugar basis than GlcNAc. This remarkably strong effect was confirmed by ITC experiments as these revealed an association constant of 9 nM for this compound, therefore presenting a gain of 200,000 times over GlcNAc. These results for compound 17 represent the highest binding properties reported for WGA. PMID- 24057057 TI - Lupus - a sea change. PMID- 24057056 TI - pH-responsive gold nanoparticles-in-liposome hybrid nanostructures for enhanced systemic tumor delivery. AB - We report a pH-responsive gold nanoparticles-in-liposome hybrid nanostructure, which effectively combines the pH-responsive assembly and surface plasmon property changes of 'smart' gold nanoparticles and enhanced systemic circulation and tumor accumulation of the PEG-grafted liposomes. PMID- 24057058 TI - Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID). AB - OBJECTIVE: The objective of this article is to evaluate the safety and clinical outcome of rituximab treatment in systemic lupus erythematosus (SLE) patients refractory to standard of care therapy in a real-life setting in Germany. METHODS: The GRAID registry included patients with different autoimmune diseases who were given off-label treatment with rituximab. Data on safety and clinical response were collected retrospectively. In SLE patients, clinical parameters included tender and swollen joint counts, fatigue, myalgia, general wellbeing, Raynaud's and the SLEDAI index. Laboratory tests included dsDNA antibody titres, complement factors, hematologic parameters and proteinuria. Finally, the investigators rated their patients as non-, partial or complete responders based on clinical grounds. RESULTS: Data from 85 SLE patients were collected, 69 female and 16 male, with a mean disease duration of 9.8 years. The mean follow-up period was 9.6 +/- 7.4 months, resulting in 66.8 patient years of observation. A complete response was reported in 37 patients (46.8%), partial response in 27 (34.2%), no response in 15 (19.0%). On average, major clinical as well as laboratory efficacy parameters improved substantially, with the SLEDAI decreasing significantly from 12.2 to 3.3 points. Concerning safety, one infusion reaction leading to discontinuation of treatment occurred. Infections were reported with a rate of 19.5 (including six severe infections) per 100 patient years. CONCLUSION: With the restrictions of a retrospective data collection, the results of this study confirm data of other registries, which suggest a favourable benefit-risk ratio of rituximab in patients with treatment-refractory SLE. PMID- 24057059 TI - Spectrum of autoantibodies for gastrointestinal autoimmune diseases in systemic lupus erythematosus patients. AB - BACKGROUND: Organ-specific autoimmune diseases may appear in patients with systemic lupus erythematosus (SLE). Gastrointestinal symptoms are well documented in SLE and may be similar to those related to autoimmune gastrointestinal diseases. OBJECTIVE: Our aim was to search for gastrointestinal organ-specific autoantibodies in 194 patients with systemic lupus and 103 healthy controls from Southern Brazil. Methods Anti-endomysium antibodies (IgA-EmA), anti-gastric parietal cells (GPC) antibodies, anti-smooth muscle antibodies (ASMA), anti mitochondrial antibodies (AMA) and anti-LKM-1 (liver-kidney microsomal) were searched for using indirect immunofluorescence in the sera of patients and controls. RESULTS: The total positivity of antibodies in SLE patients was 14.4% (28/194) and differed significantly from healthy individuals (0.97%; p<0.001). IgA-EmA was more common in lupus patients than in controls (11/194; p=0.009), and one of these patients had dermatitis herpetiformis. Clinical association revealed that IgA-EmA was more common in SLE patients with discoid lesions. The frequency of anti-GPC (p=0.10), ASMA (p=0.16) and AMA (p=0.55) did not differ significantly between groups. No patient presented LKM-1 autoantibodies. One patient presenting anti-GPC was diagnosed with atrophic gastritis and pernicious anemia. CONCLUSION: Only IgA-EmA was significantly associated with lupus and with the presence of discoid lesions. Until now, no obvious association with celiac disease has been found. PMID- 24057061 TI - Printable nanoscale metal ring arrays via vertically aligned carbon nanotube platforms. AB - This paper reports a novel and efficient strategy for fabricating sub-100 nm metal ring arrays using a simple printing process. Vertically aligned carbon nanotubes that are supported by hexagonally ordered channels of alumina matrices are used as a stamp to print nanoscale ring patterns, which is a very unique stamping platform that has never been reported. Using this strategy, uniform nanoring patterns of various metals can be directly printed onto a wide range of substrate surfaces under ambient conditions. Significantly, the size and interval of the printed nanorings can be systematically tuned by controlling the ring shaped tip dimensions of the pristine stamps. An advanced example of these printable nanoscale metal ring arrays is explicitly embodied in this work by investigation of the plasmon resonances of metal nanorings with different sizes and intervals. PMID- 24057062 TI - Synthesis of the C1-C25 southern domain of spirastrellolides B and F. AB - Synthesis of the C1-C25 ABC spiroketal ring system of spirastrellolides B and F has been executed. The synthetic strategy relied on radical cyclization, HWE olefination, (BDP)CuH conjugate reduction and spiro acetalization reactions. PMID- 24057063 TI - PBP deletion mutants of Escherichia coli exhibit irregular distribution of MreB at the deformed zones. AB - MreB is a cytoskeletal protein, which is responsible for maintaining proper cellular morphology and is essential for cell survival. Likewise, penicillin binding protein 5 (PBP5) helps in maintaining cell shape, though non-essential for survival. The contradicting feature of these two proteins paves the way for this study, wherein we attempt to draw a relation on the nature of distribution of MreB in PBP deletion mutants. The study revealed that the uniform MreB helices/patches were destabilized/disturbed at the zone of deformities of the PBP mutants, whereas the helical patterns were retained at the regions maintaining a rod shape. We interpret that MreB remains functional irrespective of its distribution being misguided by the aberrant shapes of PBP mutants. PMID- 24057064 TI - Development of intergeneric conjugal gene transfer system in Streptomyces diastatochromogenes 1628 and its application for improvement of toyocamycin production. AB - Streptomyces diastatochromogenes 1628, capable of producing toyocamycin (TM), has exhibited a potential biocontrol effect in inhibiting the development of phytopathogens in the agriculture field. In this study, an efficient transformation system was developed using the intergeneric conjugation. This was achieved by optimization of experimental parameters. Under optimal conditions, a maximal conjugation frequency of 4.1 * 10(-4) per recipient was obtained. In order to heterologously express the gene vgb encoding Vitreoscilla hemoglobin in S. diastatochromogenes 1628, we placed vgb under the control of the constitutive promoter PermE(*) and constructed plasmid pIB139-vgb. This plasmid was integrated into the chromosome of S. diastatochromogenes 1628 using intergeneric conjugation established above. Finally, strain 1628-VHB-23 with the highest TM production was screened. Results indicated that expression of vgb gene had always significantly promoted the cell growth and TM production in S. diastatochromogenes 1628 under different dissolved oxygen conditions. In particular, under the limited aerobic condition, strain 1628-VHB-23 obtained 33.3 % more DCW and produced 210 % more TM in 7-l fermentor as compared with the wild-type strain. PMID- 24057065 TI - The role of uterine manipulators in endometrial cancer recurrence after laparoscopic or robotic procedures. AB - INTRODUCTION: The evolution of minimally invasive surgery has been established and both laparoscopic- and robotic-assisted techniques can be presented as valuable alternatives to traditional approaches for the treatment of gynecological cancers, such as endometrial cancer. During laparoendoscopic procedures, the upward traction to the uterus is considered fundamental. The application of uterine manipulators in hysterectomy can facilitate diverse tasks to lead to a safe and successful surgical outcome. Some authors have raised their concern that the use of uterine manipulators might increase the incidence of tumor cell dissemination among patients with endometrial cancers. METHODS: We performed a literature search with terms related to the role of uterine manipulators in endometrial cancer recurrence in PubMed and Scopus. RESULTS: Six articles were identified dealing with this issue. Even though, the available clinical evidence suggests that the application of uterine manipulators has no clear correlation with the recurrence of the endometrial carcinoma, the existing trials are of low methodological quality. CONCLUSION: Further investigation is necessary for the clarification of the influence of the different types of uterine manipulators in cancer recurrence. PMID- 24057066 TI - [Anglicisms necessary in the clinic? The example of vestibular and oculomotor syndromes]. PMID- 24057067 TI - [How acrophobia impairs visual exploration and gait]. AB - The life-time prevalence of visual height intolerance is 28 % in the general population. More than 50 % of those affected suffer from an impairment of daily behavior and quality of life when confronted with heights. Simultaneous measurements of spontaneous eye and head movements of these subjects while looking from a balcony revealed that visual exploration of the surroundings was restricted compared to that of control subjects. Spontaneous head movements were severely diminished and saccadic eye movements were reduced. Gaze in space was preferably directed towards structures on the horizon. Those susceptible to visual height intolerance exhibited a cautious slowing of gait with small and precarious steps. Restriction of visual exploration during locomotion in a complex terrain may result in falls because obstacles can be overlooked. PMID- 24057068 TI - Large area vertical alignment of ZnO nanowires in semiconducting polymer thin films directed by magnetic fields. AB - We demonstrate the use of magnetic fields for the directed assembly of ZnO nanowires in semiconducting polymer films suitable for ordered bulk heterojunction photovoltaics. Using rotational field annealing, Co-doped ZnO nanowires with negative paramagnetic anisotropy were successfully aligned out-of plane with respect to the substrate and polymer film. PMID- 24057069 TI - Precision of high-resolution peripheral quantitative computed tomography measurement variables: influence of gender, examination site, and age. AB - High-resolution peripheral quantitative computed tomography (HR-pQCT) is increasingly being used in the research setting to assess the effects of osteoporosis treatments and disease on trabecular and cortical bone compartments. Further in-depth study of HR-pQCT measurement variables is essential to ensure study strength and statistical confidence when designing large multicenter studies. Duplicate HR-pQCT examinations of the distal radius and tibia were performed in 180 healthy men and women ages 16-18, 30-32, and >70 years. HR-pQCT images were processed using standard and extended cortical bone analysis techniques. Biomechanical properties of bone were assessed using finite element analysis. Percent root mean square coefficient of variation (RMSCV) was calculated for each measurement variable. Age, site, and gender influences on measurement variability were investigated using variance ratio tests. Smaller precision errors were observed for densitometric (0.2-5.5%) than for microstructural (1.2-7.0%), extended cortical bone (3.4-20.3%), and biomechanical (0.3-9.9%) measures at both the radius and tibia. Tibial measurements (RMSCVs = 0.2-7.4%) tended to be more precise than radial measurements (RMSCVs = 0.7 20.3%). Variability was influenced by age, site, and gender (all p < 0.05). HR pQCT measurements for the tibia were more precise than those for the radius, and this may be explained by the larger bone volumes examined and the reduced likelihood of movement artifact. The greater measurement variability observed for older volunteers may be due to the loss of bone density and microstructural integrity with age. PMID- 24057070 TI - Sphincter-sparing surgery for adenocarcinoma of the distal 3 cm of the true rectum: results after neoadjuvant therapy and minimally invasive radical surgery or local excision. AB - BACKGROUND: Ideal treatment of rectal cancer includes controlling the cancer; minimizing trauma, morbidity, and mortality; and avoiding a colostomy with preservation of adequate function. These goals become more challenging the further distal in the rectum the cancer is located. We sought to determine whether minimally invasive sphincter-preservation surgery (SPS) can accomplish good cancer control, maintaining sphincter function with minimal morbidity and mortality in rectal cancers of the distal 3 cm after receiving neoadjuvant chemoradiotherapy. METHODS: We retrospectively reviewed a prospectively maintained rectal cancer database of a single colorectal surgeon to identify all patients with cancers of the distal 3 cm undergoing SPS via a laparoscopic total mesorectal excision or transanal endoscopic microsurgery (TEM). All patients received neoadjuvant chemoradiotherapy. Patient data, including demographics, initial tumor characteristics, staging, radiation dose, perioperative morbidity and mortality, and local recurrence (LR) and survival, were analyzed. RESULTS: A total of 161 patients (108 men) underwent SPS via 3 techniques: transanal abdominal transanal proctosigmoidectomy (TATA, n = 106), TEM (n = 49), or ultralow anterior resection (LAR, n = 6). Average age was 62 years (range 22-90 years). The mean levels in rectum from the anorectal ring were as follows: TATA, 1.3 cm (range -1.0 to 3.0 cm), TEM, 1.5 cm (range -0.5 to -3.0 cm), and LAR, 2.9 cm (range 2.5-3.0 cm) (p > 0.05). Preoperative T stage was as follows: T3, n = 108 (TATA 83, TEM 20, LAR 5), T2, n = 48 (TATA 22, TEM 25, LAR 1), T1, n = 3 (TATA 1, TEM 2), and T4, n = 2 (both TEM). All patients received concomitant 5 fluorouracil-based chemotherapy and radiotherapy (mean, 5300 cGy; range 3,000 7,295 cGy). The mean estimated blood loss was 376 ml (range 10-3,600 ml). There were no mortalities. Morbidity rates were as follows: LAR, 0; TATA, 13.2%; and TEM, 32 % (wound disruption: major, 10%; minor, 16%). Pathologic staging was as follows: ypCR: uT2, 34%, and uT3, 19%. Overall LR was 3.7%. By procedure, the follow-up, LR, and KM5YAS, respectively, were: TATA, 37.9 months, 3 and 95%; TEM, 36.3 months, 6 and 88%; and LAR, 63.1 months, 0 and 75% (p > 0.05). CONCLUSIONS: This study demonstrates positive oncologic outcomes, low LR rates, and high KM5YS after minimally invasive SPS. A colostomy-free lifestyle and cancer control make the minimally invasive surgical approach an excellent treatment option for complex distal rectal cancers. PMID- 24057071 TI - Zinc-selective inhibition of the promiscuous bacterial amide-hydrolase DapE: implications of metal heterogeneity for evolution and antibiotic drug design. AB - The development of resistance to virtually all current antibiotics makes the discovery of new antimicrobial compounds with novel protein targets an urgent challenge. The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is an essential metallo-enzyme for growth and proliferation in many bacteria, acting in the desuccinylation of N-succinyl-L,L-diaminopimelic acid (SDAP) in a late stage of the anabolic pathway towards both lysine and a crucial building block of the peptidoglycan cell wall. L-Captopril, which has been shown to exhibit very promising inhibitory activity in vitro against DapE and has attractive drug-like properties, nevertheless does not target DapE in bacteria effectively. Here we show that L-captopril targets only the Zn(2+)-metallo isoform of the enzyme, whereas the Mn(2+)-enzyme, which is also a physiologically relevant isoform in bacteria, is not inhibited. Our finding provides a rationale for the failure of this promising lead-compound to exhibit any significant antibiotic activity in bacteria and underlines the importance of addressing metallo-isoform heterogeneity in future drug design. Moreover, to our knowledge, this is the first example of metallo-isoform heterogeneity in vivo that provides an evolutionary advantage to bacteria upon drug-challenge. PMID- 24057072 TI - Aptamer-conjugated Mn3O4@SiO2 core-shell nanoprobes for targeted magnetic resonance imaging. AB - The objective of this study was to evaluate the targeted T1-magnetic resonance imaging (MRI), quantitative biodistribution and toxicity of aptamer (AS411) conjugated Mn3O4@SiO2 core-shell nanoprobes (NPs) in human cervical carcinoma tumor-bearing mice. The NPs were firstly prepared by encapsulating a hydrophobic Mn3O4 core within an amino functionalized silica shell. The fluorophore rhodamine (RB) was doped into the silica shell and the amphiphilic polymer poly(ethylene glycol) (PEG) was modified on the surface of the shell to improve its biocompatibility, then the aptamer AS411 was conjugated onto the end of the PEG chains as targeting ligands. The final NPs were abbreviated as Mn3O4@SiO2(RB)-PEG Apt. By means of in vitro fluorescence confocal imaging and in vivo MRI, the NPs have been demonstrated to target cancer cells and prominent tumor aggregation effectively. The imaging results were further confirmed by a quantitative biodistribution study. In addition, histological, hematological and biochemistry analysis also proved the low toxicity of NPs in vivo. Our results showed the great potential of the Mn3O4@SiO2(RB)-PEG-Apt NPs could be used as a multifunctional nanoplatform for long-term targeted imaging and therapy of cancer. PMID- 24057073 TI - Hydrodynamics-assisted scalable production of boron nitride nanosheets and their application in improving oxygen-atom erosion resistance of polymeric composites. AB - Searching for a method for low-cost, easily manageable, and scalable production of boron nitride nanosheets (BNNSs) and exploring their novel applications are highly important. For the first time we demonstrate that a novel and effective hydrodynamics method, which involves multiple exfoliation mechanisms and thus leads to much higher yield and efficiency, can realize large-scale production of BNNSs. The exfoliation mechanisms that multiple fluid dynamics events contribute towards normal and lateral exfoliation processes could be applied to other layered materials. Up to ~95% of the prepared BNNSs are less than 3.5 nm thick with a monolayer fraction of ~37%. Compared to the conventional sonication and ball milling-based methods, the hydrodynamics method has the advantages of possessing multiple efficient ways for exfoliating BN, being low-cost and environmentally-friendly, producing high quality BNNSs in high yield and efficiency, and achieving concentrated BNNSs dispersions even in mediocre solvents. It is also shown for the first time that BNNSs can be utilized as fillers to improve the oxygen-atom erosion resistance of epoxy composites which are widely used for spacecraft in low earth orbit (LEO) where atom oxygen abounds. An addition of only 0.5 wt% BNNSs can result in a 70% decrease in the mass loss of epoxy composites after atom oxygen exposure equivalent to 160 days in an orbit of ~300 km. Overall, the demonstrated hydrodynamics method shows great potential in large-scale production of BNNSs in industry in terms of yield, efficiency, and environmental friendliness; and the innovative application of BNNSs to enhancing oxygen-atom erosion resistance of polymeric composites in space may provide a novel route for designing light spacecraft in LEO. PMID- 24057074 TI - Graphene for energy solutions and its industrialization. AB - Graphene attracts intensive interest globally across academia and industry since the award of the Nobel Prize in Physics 2010. Within the last half decade, there has been an explosion in the number of scientific publications, patents and industry projects involved in this topic. On the other hand, energy is one of the biggest challenges of this century and related to the global sustainable economy. There are many reviews on graphene and its applications in various devices, however, few of the review articles connect the intrinsic properties of graphene with its energy. The IUPAC definition of graphene refers to a single carbon layer of graphite structure and its related superlative properties. A lot of scientific results on graphene published to date are actually dealing with multi-layer graphenes or reduced graphenes from insulating graphene oxides (GO) which contain defects and contaminants from the reactions and do not possess some of the intrinsic physical properties of pristine graphene. In this review, the focus is on the most recent advances in the study of pure graphene properties and novel energy solutions based on these properties. It also includes graphene metrology and analysis of both intellectual property and the value chain for the existing and forthcoming graphene industry that may cause a new 'industry revolution' with the strong and determined support of governments and industries across the European Union, U. S., Asia and many other countries in the world. PMID- 24057075 TI - Iodine-sensitized oxidation of ferrous ions under UV and visible light: the influencing factors and reaction mechanism. AB - The sensitized oxidation of Fe(2+) ions by I2 or I3(-) in acidic aqueous solution has been examined. The reactions could occur either under UV or visible light, with the stoichiometric formation of Fe(3+) and I(-). However, the I3(-) sensitized reaction was fast and complete only in the presence of excess Fe(2+). Through a kinetics study, it becomes clear that I and I2(-) are the main reactive species for the I2 and I3(-)- sensitized oxidation of Fe(2+), respectively. Moreover, the quantum yields determined with the I2 and I3(-)-sensitized formation of Fe(3+) at 456 nm were 0.119 and 0.118, respectively. The I2 sensitized reaction was first order only in I2, and had an Arrhenius activation energy of 29.3 kJ mol(-1). It is proposed that the process of Fe(2+) oxidation by I is fast, while the rate-determining step is the formation and self recombination of I radicals. PMID- 24057076 TI - The (possibly) deceptive figures of decreased coronary heart disease mortality in Europe. PMID- 24057077 TI - Symptoms of anxiety and depression and risk of acute myocardial infarction: the HUNT 2 study. AB - AIMS: The nature of the association of depression and anxiety with risk for acute myocardial infarction (AMI) remains unclear. We aimed to study the prospective association of single and recurrent self-reported symptoms of anxiety and depression with a risk of AMI in a large Norwegian population based cohort. METHODS AND RESULTS: In the second wave of the Nord-Trondelag Health Study (HUNT2, 1995-97) baseline data on anxiety and depression symptoms, sociodemographic variables, health status including cardiovascular risk factors and common chronic disorders were registered for 57,953 adult men and women free of cardiovascular disease. The cohort was followed up during a mean (SD) 11.4 (2.9) years for a first AMI from baseline through 2008. A total of 2111 incident AMIs occurred, either identified at hospitals or by the National Cause of Death Registry. The multi-adjusted hazard ratios were 1.31 (95% CI 1.03-1.66) for symptoms of depression and 1.25 (CI 0.99-1.57) for anxiety. Two episodes of mixed symptoms of anxiety and depression (MSAD), reported 10 years apart, increased the risk for AMI by 52% (11-108%). After exclusion of the first 5 years of follow-up, the association of depression symptoms with AMI risk was attenuated. Relative risk for AMI with anxiety symptoms and MSAD weakened when participants with chronic disorders were excluded. CONCLUSION: Self-reported symptoms of depression and anxiety, especially if recurrent, were moderately associated with the risk of incident AMI. We had some indications that these associations might partly reflect reverse causation or confounding from common chronic diseases. PMID- 24057078 TI - Should axis deviation or atrial enlargement be categorised as abnormal in young athletes? The athlete's electrocardiogram: time for re-appraisal of markers of pathology. AB - AIMS: The 2010 European Society of Cardiology (ESC) guidelines for electrocardiogram (ECG) interpretation in athletes are associated with a relatively high false positive rate and warrant modification to improve the specificity without compromising sensitivity. The aim of this study was to investigate whether non-specific anomalies such as axis deviation and atrial enlargement in isolation require further assessment in highly trained young athletes. METHOD AND RESULTS: Between 2003 and 2011, 2533 athletes aged 14-35 years were investigated with 12-lead ECG and echocardiography. Electrocardiograms were analysed for non-training-related (Group 2) changes according to the 2010 ESC guidelines. Results were compared with 9997 asymptomatic controls. Of the 2533 athletes, 329 (13%) showed Group 2 ECG changes. Isolated axis deviation and isolated atrial enlargement comprised 42.6% of all Group 2 changes. Athletes revealed a slightly higher prevalence of these anomalies compared with controls (5.5 vs. 4.4%; P = 0.023). Echocardiographic evaluation of athletes and controls with isolated axis deviation or atrial enlargement (n = 579) failed to identify any major structural or functional abnormalities. Exclusion of axis deviation or atrial enlargement reduced the false positive rate from 13 to 7.5% and improved specificity from 90 to 94% with a minimal reduction in sensitivity (91-89.5%). CONCLUSION: Isolated axis deviation and atrial enlargement comprise a high burden of Group 2 changes in athletes and do not predict underlying structural cardiac disease. Exclusion of these anomalies from current ESC guidelines would improve specificity and cost-effectiveness of pre-participation screening with ECG. PMID- 24057079 TI - Triple therapy with Lactobacilli acidophili, estriol plus pelvic floor rehabilitation for symptoms of urogenital aging in postmenopausal women. AB - PURPOSE: To assess the effects of the combination of pelvic floor rehabilitation, intravaginal estriol and Lactobacillus acidophli administration on stress urinary incontinence (SUI), urogenital atrophy and recurrent urinary tract infections in postmenopausal women. METHODS: 136 postmenopausal women with urogenital aging symptoms were enrolled in this prospective randomized study. PATIENTS: randomly divided into two groups and each group consisted of 68 women. INTERVENTIONS: Subjects in the triple therapy (group I) received 1 intravaginal ovule containing 30 mcg estriol and Lactobacilli acidophili (50 mg lyophilisate containing at least 100 million live bacteria) such as once daily for 2 weeks and then two ovules once weekly for a total of 6 months as maintenance therapy plus pelvic floor rehabilitation. Subjects in the group II received one intravaginal estriol ovule (1 mg) plus pelvic floor rehabilitation in a similar regimen. MEAN OUTCOME MEASURES: We evaluated urogenital symptomatology, urine cultures, colposcopic findings, urethral cytologic findings, urethral pressure profiles and urethrocystometry before, as well as after 6 months of treatment. RESULTS: After therapy, the symptoms and signs of urogenital atrophy significantly improved in both groups. 45/59 (76.27%) of the group I and 26/63 (41.27%) of the group II referred a subjective improvement of their incontinence. In the patients treated by triple therapy with lactobacilli, estriol plus pelvic floor rehabilitation, we observed significant improvements of colposcopic findings, and there were statistically significant increases in mean maximum urethral pressure, in mean urethral closure pressure, as well as in the abdominal pressure transmission ratio to the proximal urethra. CONCLUSIONS: Our results showed that triple therapy with L. acidophili, estriol plus pelvic floor rehabilitation was effective and should be considered as first-line treatment for symptoms of urogenital aging in postmenopausal women. PMID- 24057080 TI - React or wait: which optimal culling strategy to control infectious diseases in wildlife. AB - We applied optimal control theory to an SI epidemic model to identify optimal culling strategies for diseases management in wildlife. We focused on different forms of the objective function, including linear control, quadratic control, and control with limited amount of resources. Moreover, we identified optimal solutions under different assumptions on disease-free host dynamics, namely: self regulating logistic growth, Malthusian growth, and the case of negligible demography. We showed that the correct characterization of the disease-free host growth is crucial for defining optimal disease control strategies. By analytical investigations of the model with negligible demography, we demonstrated that the optimal strategy for the linear control can be either to cull at the maximum rate at the very beginning of the epidemic (reactive culling) when the culling cost is low, or never to cull, when culling cost is high. On the other hand, in the cases of quadratic control or limited resources, we demonstrated that the optimal strategy is always reactive. Numerical analyses for hosts with logistic growth showed that, in the case of linear control, the optimal strategy is always reactive when culling cost is low. In contrast, if the culling cost is high, the optimal strategy is to delay control, i.e. not to cull at the onset of the epidemic. Finally, we showed that for diseases with the same basic reproduction number delayed control can be optimal for acute infections, i.e. characterized by high disease-induced mortality and fast dynamics, while reactive control can be optimal for chronic ones. PMID- 24057081 TI - A multi-environmental study of recent breeding progress on nitrogen use efficiency in wheat (Triticum aestivum L.). AB - KEY MESSAGE: By comparing 195 varieties in eight trials, this study assesses nitrogen use efficiency improvement in high and low nitrogen conditions in European winter wheat over the last 25 years. In a context where European agriculture practices have to deal with environmental concerns and nitrogen (N) fertiliser cost, nitrogen use efficiency (NUE) has to be improved. This study assessed genetic progress in winter wheat (Triticum aestivum L.) NUE. Two hundred and twenty-five European elite varieties were tested in four environments under two levels of N. Global genetic progress was assessed on additive genetic values and on genotype * N interaction, covering 25 years of European breeding. To avoid sampling bias, quality, precocity and plant height were added as covariates in the analyses when needed. Genotype * environment interactions were highly significant for all the traits studied to such an extent that no additive genetic effect was detected on N uptake. Genotype * N interactions were significant for yield, grain protein content (GPC), N concentration in straw, N utilisation, and NUE. Grain yield improvement (+0.45 % year(-1)) was independent of the N treatment. GPC was stable, thus grain nitrogen yield was improved (+0.39 % year( 1)). Genetic progress on N harvest index (+0.12 % year(-1)) and on N concentration in straw (-0.52 % year(-1)) possibly revealed improvement in N remobilisation. There has been an improvement of NUE additive genetic value (+0.33 % year(-1)) linked to better N utilisation (+0.20 % year(-1)). Improved yield stability was detected as a significant improvement of NUE in low compared to high N conditions. The application of these results to breeding programs is discussed. PMID- 24057082 TI - Low temperature crystallisation of mesoporous TiO2. AB - Conducting mesoporous TiO2 is rapidly gaining importance for green energy applications. To optimise performance, its porosity and crystallinity must be carefully fine-tuned. To this end, we have performed a detailed study on the temperature dependence of TiO2 crystallisation in mesoporous films. Crystal nucleation and growth of initially amorphous TiO2 derived by hydrolytic sol-gel chemistry is compared to the evolution of crystallinity from nanocrystalline building blocks obtained from non-hydrolytic sol-gel chemistry, and mixtures thereof. Our study addresses the question whether the critical temperature for crystal growth can be lowered by the addition of crystalline nucleation seeds. PMID- 24057083 TI - Diurnal temperature range may be the risk factor for respiratory tract infections among the elderly in Guangzhou, China. PMID- 24057084 TI - Effects of sudden air pressure changes on hospital admissions for cardiovascular diseases in Prague, 1994-2009. AB - Sudden weather changes have long been thought to be associated with negative impacts on human health, but relatively few studies have attempted to quantify these relationships. We use large 6-h changes in atmospheric pressure as a proxy for sudden weather changes and evaluate their association with hospital admissions for cardiovascular diseases (CVD). Winter and summer seasons and positive and negative pressure changes are analysed separately, using data for the city of Prague (population 1.2 million) over a 16-year period (1994-2009). We found that sudden pressure drops in winter are associated with significant rise in hospital admissions. Increased CVD morbidity was observed neither for pressure drops in summer nor pressure increases in any season. Analysis of synoptic weather maps shows that large pressure drops in winter are associated with strong zonal flow and rapidly moving low-pressure systems with centres over northern Europe and atmospheric fronts affecting western and central Europe. Analysis of links between passages of strong atmospheric fronts and hospital admissions, however, shows that the links disappear if weather changes are characterised by frontal passages. Sudden pressure drops in winter are associated also with significant excess CVD mortality. As climate models project strengthening of zonal circulation in winter and increased frequency of windstorms, the negative effects of such weather phenomena and their possible changes in a warmer climate of the twenty-first century need to be better understood, particularly as their importance in inducing excess morbidity and mortality in winter may increase compared to cold spells. PMID- 24057085 TI - Solitaire AB stent-assisted coiling of wide-necked intracranial aneurysms: short term results from a prospective, consecutive, European multicentric study. AB - INTRODUCTION: Solitaire AB stent-assisted coiling facilitates the endovascular treatment of wide-necked intracranial aneurysms. Solitaire Aneurysm Remodeling is the first prospective, consecutive, European multicentric study whose main objective was to evaluate the safety, short-, and long-term efficacy of the Solitaire AB stent. This first analysis is focused on the short-term results. METHODS: After exclusion of one patient, 66 Solitaire AB stents were used to treat via endovascular approach 64 aneurysms (63 patients) in seven European centers. Technical and clinical complications were recorded. A core laboratory evaluated the angiographic efficacy by using the Raymond classification scale. RESULTS: The mean width of aneurysm sac was 7.5 mm, and the mean diameter of aneurysm neck was 4.7 mm. Complete occlusion was achieved in 27 aneurysms (42.2 %); neck remnant was seen in 25 aneurysms (39.1 %) and aneurysm remnant in 12 aneurysms (18.7 %). Technical and clinical complications related to the procedure were encountered in eight patients (12.7 %). Postprocedural modification of the clinical status was observed in one patient (1.6 %). No patients died (0 %); one had a permanent deficit (1.6 %), and one had a transient deficit (1.6 %). Treatment-related mortality was 0 %, and permanent morbidity was 1.6 %. CONCLUSION: The Solitaire AB stent has an excellent rate of technical success navigation with the absence of dislodgement. The safety and short-term efficacy are comparable to those previously reported with coiling alone. Mid- and long term follow-up will be required to elucidate the impact of the Solitaire AB stent on recanalization rate. PMID- 24057087 TI - Great light absorption enhancement in a graphene photodetector integrated with a metamaterial perfect absorber. AB - A novel graphene photodetector with graphene embedded in a metamaterial perfect absorber (MPA) is proposed and its light absorption property is numerically investigated. Absorption above 40% in graphene is obtained, which is over 17 times that of a bare monolayer graphene. Both horizontally and vertically cascaded MPAs integrated with graphene are also investigated. PMID- 24057086 TI - Structure-activity relationships for biodistribution, pharmacokinetics, and excretion of atomically precise nanoclusters in a murine model. AB - The absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic (PK) properties of inorganic nanoparticles with hydrodynamic diameters between 2 and 20 nm are presently unpredictable. It is unclear whether unpredictable in vivo properties and effects arise from a subset of molecules in a nanomaterials preparation, or if the ADME/PK properties are ensemble properties of an entire preparation. Here we characterize the ADME/PK properties of atomically precise preparations of ligand protected gold nanoclusters in a murine model system. We constructed atomistic models and tested in vivo properties for five well defined compounds, based on crystallographically resolved Au25(SR)18 and Au102(SR)44 nanoclusters with different (SR) ligand shells. To rationalize unexpected distribution and excretion properties observed for several clusters in this study and others, we defined a set of atomistic structure-activity relationships (SAR) for nanoparticles, which includes previously investigated parameters such as particle hydrodynamic diameter and net charge, and new parameters such as hydrophobic surface area and surface charge density. Overall we find that small changes in particle formulation can provoke dramatic yet potentially predictable changes in ADME/PK. PMID- 24057088 TI - Vitamin E and regression of hypercholesterolemia-induced oxidative stress in kidney. AB - Hypercholesterolemia (HC) is an independent risk factor for the onset and progression of renal disease. HC induces oxidative stress (OS) in the kidney; Vitamin E (Vit.E), an antioxidant, slows the progression of OS in the kidney. This study was to investigate if Vit.E regresses the HC-induced OS, and the regression is associated with an increase in the antioxidant reserve (AR). The studies were carried out in four groups of rabbits. The kidneys were removed under anesthesia. OS and AR in the renal tissue were assessed by measuring malondialdetyde (MDA) and chemiluminescent (CL) activity, respectively. High cholesterol diet elevated the serum total cholesterol (TC), and the regular diet with or without Vit.E following a high-cholesterol diet reduced the serum TC to control levels. HC increased the MDA levels of kidney by 5.54-fold compared to control. The MDA contents of the kidneys in groups on regular diet with or without Vit.E were, respectively, 56 and 53 % lower than the control group. The CL activity in the control group was 12.15 +/- 0.73 * 10(6) RLU/mg protein. The CL activity in HC group was 45.26 % lower than that in control, indicating an increase in AR. The regular diet with or without Vit.E following high-cholesterol diet normalized the CL activity/AR. In conclusion, HC increases OS in the kidney; reduction of serum cholesterol by regular diet regresses the renal OS but Vit.E does not regress HC-induced OS in kidney. PMID- 24057089 TI - Fast preparation of an N-acetylglucosaminylated peptide segment for the chemoenzymatic synthesis of a glycoprotein. AB - A novel GlcNAc-Asn unit carrying trifluoroacetic acid (TFA)-sensitive O protecting groups was prepared. The unit was used for the solid-phase peptide synthesis (SPPS) of the N-acetylglucosaminylated emmprin (35-69) thioester via one-step deprotection by TFA combined with the N-alkylcysteine thioesterification method. This segment was used for the synthesis of the first Ig domain (22-104) of emmprin carrying GlcNAc by one-pot ligation with other segments using the thioester method. Finally, the sugar chain was elongated by transglycosylation using glycosynthase to give the Ig domain carrying the disialo- and asialo complex-type sugar chain. PMID- 24057090 TI - Comparison of tuberculosis incidence in ankylosing spondylitis and rheumatoid arthritis during tumor necrosis factor inhibitor treatment in an intermediate burden area. AB - Clinical characteristics of antitumor necrosis factor (TNF) agents-related tuberculosis (TB) in ankylosing spondylitis (AS) are not well described. The aim was to compare the incidences and the characteristics of TB in AS and rheumatoid arthritis (RA) during TNF inhibitor treatment. AS (n = 1,322) and RA (n = 3,154) patients who received medical care between January 2001 and August 2011 were enrolled. The incidence of TB in patients treated, or not, with TNF inhibitors and the clinical features associated with TB were explored. Seven patients with AS and seven with RA developed TB while receiving TNF inhibitor therapy, resulting in an incidence rate of 600.2/100,000 person-years (PYs) (95 % confidence interval (CI), 241.3-1236.3) for those with AS and 771.6/100,000 PYs (95 % CI, 310.2-1589.9) for those with RA. Incidence rate ratios for TNF inhibitor-treated vs. untreated patients were 4.87 for AS (95 % CI, 1.50-15.39; p < 0.001) and 3.61 for RA (95 % CI, 1.38-8.07; p < 0.001). Low body mass index was identified as a significant risk factor for TB in the AS group (odds ratio (OR), 13.0; p = 0.002). Extrapulmonary TB was predominant at 85.7 % during TNF inhibitor treatment. Three (42.8 %) of the AS patients, but none of the RA patients, developed TB with concomitant isoniazid. All AS patients recovered from TB whereas two of seven RA patients died. Treatment with TNF inhibitors significantly increases the risk of extrapulmonary TB in AS. Symptoms of infection should warrant clinicians to evaluate for TB during TNF inhibitor therapy in AS patients. PMID- 24057091 TI - R-R interval variation and sympathetic skin response in systemic lupus erythematosus. AB - The involvement of the autonomic nervous system is less common than that of the central and peripheral nervous system in systemic lupus erythematosus (SLE) patients. However, its involvement can negatively affect the quality of life of the patient and cause life-threatening situations. In this study, autonomic function was evaluated in SLE patients who did not show any sign of autonomic involvement using R-R interval variation (RRIV) and sympathetic skin response (SSR) electrophysiological tests. SSR was used to evaluate the sympathetic nervous system, whereas RRIV was used for the parasympathetic nervous system. We included 23 SLE patients and 21 healthy volunteers in the study. Of the 23 SLE patients, 20 (86.9 %) were female and 3 (13.1 %) were male. The age range of the patients was between 19 and 52 years, with a mean age of 32.5 +/- 9.1 years. Routine nerve conduction studies and autonomic tests were performed on patients in the electromyography (EMG) laboratory. Lower extremity SSR latencies were prolonged and a significant loss of amplitude was observed in comparison to the control group. Furthermore, deep-breath RRIV values for the patient group were significantly lower than that of the control group. Both sympathetic and parasympathetic nervous system involvement was seen in our study. In conclusion, EMG can reveal a possible underlying involvement in the absence of signs of autonomic involvement. PMID- 24057093 TI - alpha-Vinylation of amides with arylacetylenes: synthesis of allylamines under metal-free conditions. AB - A novel methodology for the alpha-vinylation of amides with arylacetylenes under metal-free conditions has been introduced. This methodology provides a new protocol to synthesize allylamines. In each product, the amount of the cis-isomer was more than that of the trans-isomer. PMID- 24057092 TI - Clinical efficacy of abatacept compared to adalimumab and tocilizumab in rheumatoid arthritis patients with high disease activity. AB - Favourable clinical results in rheumatoid arthritis (RA) patients with high disease activity (HDA) are difficult to achieve. This study evaluated the clinical efficacy of abatacept according to baseline disease activity compared to adalimumab and tocilizumab. This study included all patients registered in a Japanese multicenter registry treated with abatacept (n = 214), adalimumab (n = 175), or tocilizumab (n = 143) for 24 weeks. Clinical efficacy of abatacept in patients with HDA (DAS28-CRP > 4.1) and low and moderate disease activity was compared. Clinical efficacy of abatacept, adalimumab, and tocilizumab was compared in patients with HDA at baseline. In patients treated with abatacept, multivariate logistic regression identified HDA at baseline as an independent predictor for achieving low disease activity (LDA; DAS28-CRP < 2.7) [OR 0.26, 95 % CI 0.14-0.50] or remission (DAS28-CRP < 2.3) [OR 0.26, 95 % CI 0.12-0.56] at 24 weeks. In patients with HDA at baseline, logistic regression did not identify treatment with adalimumab or tocilizumab as independent predictors of LDA or remission compared to abatacept. Retention rates based on insufficient efficacy were significantly higher in patients treated with abatacept compared to adalimumab and lower than tocilizumab. Retention rates based on adverse events in patients treated with abatacept were significantly lower compared to tocilizumab. Clinical efficacy of abatacept was affected by baseline disease activity. There were no significant differences between the three different classes of biologics regarding clinical efficacy for treating RA patients with HDA, although definitive conclusions regarding long-term efficacy will require further research. PMID- 24057094 TI - Social smiling and its components in high-risk infant siblings without later ASD symptomatology. AB - Impaired affective expression, including social smiling, is common in children with autism spectrum disorder (ASD), and may represent an early marker for ASD in their infant siblings (Sibs-ASD). Social smiling and its component behaviors (eye contact and non-social smiling) were examined at 15 months in Sibs-ASD who demonstrated later ASD symptomatology (Sibs-ASD/AS), those who did not (Sibs ASD/NS), and low-risk controls (Sibs-TD). Both Sibs-ASD subgroups demonstrated lower levels of social smiling than Sibs-TD, suggesting that early social smiling may reflect elevated genetic vulnerability rather than a specific marker for ASD. Only the Sibs-ASD/AS demonstrated less eye contact and non-social smiling than Sibs-TD, suggesting that different processes, threshold effects, or protective factors may underlie social smiling development in the two Sibs-ASD subgroups. PMID- 24057095 TI - The host preferences of Nuttalliella namaqua (Ixodoidea: Nuttalliellidae): a generalist approach to surviving multiple host-switches. AB - Nuttalliella namaqua has been described as a "living fossil" and the closest extant species to the ancestral tick lineage. It was previously proposed that the Nuttalliella lineage parasitized reptile-like mammals in the Permian and had to switch hosts several times due to mass or host lineage extinctions. Extant hosts include girdled lizards and murid rodents. The current study extends knowledge on the extant host range of N. namaqua using gut meal analysis of field collected specimens. Nymphs and females can parasitize a variety of reptiles that includes skinks, geckos and girdled lizards. Blood-meal from a hyrax was also detected in a specimen suggesting that N. namaqua could parasitize a broader range of mammals than the previously suggested murid rodents. Rather than being host specific, N. namaqua is proposed to be a generalist and the ability to switch and parasitize multiple hosts allowed it to survive multiple mass and host lineage extinctions. PMID- 24057096 TI - Highly water-soluble multi-walled carbon nanotubes amine-functionalized by supercritical water oxidation. AB - Multi-walled carbon nanotubes (MWNTs) have been amine-functionalized by eco friendly supercritical water oxidation. The facilely functionalized MWNTs have high solubility (~84 mg L(-1)) in water and 78% transmittance at 30-fold dilution. The Tyndall effect is also shown for several liquids. PMID- 24057097 TI - Comparison of the healing mechanisms of human dry and endogenous wet traumatic eardrum perforations. AB - This prospective study aimed to assess the spontaneous healing mechanisms of human dry and endogenous wet traumatic tympanic membrane perforations (TMPs). A total of 106 patients with traumatic TMPs were included. Based on the presence or absence of endogenous bloody or watery exudates on the residual eardrum and/or at perforation margins, 73 perforations were classified as dry perforations and the remaining 33 as endogenous wet perforations. In 65 of the 73 dry perforations, centripetal migration of an epithelial layer was the first event seen during the spontaneous healing process, which was followed by growth and migration of the other two layers (i.e., the fibrous layer and the inner mucous layer). In the remaining eight dry perforation cases, outward epithelial migration was observed on the side of the perforation edge. In the 33 endogenous wet perforations, closure seemed to start with growth of the fibrous layers which were then covered by the migrating epithelium. Within the first week after injury, only 16.3 +/- 6.7 % of the perforation area healed in the dry perforation cases, whereas 82.2 +/- 13.9 % of the perforation area healed in the wet perforation cases; the difference was significant (P < 0.01). These observations suggest that different mechanisms may be involved in spontaneous healing of dry and wet traumatic TMPs in humans, thereby resulting in differences in healing time and healing outcome. PMID- 24057098 TI - Tracheostomal stenosis clinical risk factors in patients who have undergone total laryngectomy and adjuvant radiotherapy. AB - Adjuvant chemotherapy, advanced age, smoking, cardiopathies, diabetes, local infections, impaired immunocompetence, and malnutrition are potential cofactors in the genesis of aberrant wound healing and may thus play an important role in the genesis of tracheostomal stenosis. The aim of the study is to analyse the influence of the above-mentioned local and systemic risk factors in determining tracheostomal stenosis in patients who have undergone total laryngectomy and adjuvant radiotherapy. In 79 % of the cases, tracheostomal stenosis occurred within 12 months of surgery. Diabetes mellitus and local infection were the only factors that showed a statistically significant difference according to univariate and multivariate analysis. Diabetes mellitus and the related tracheostomal infection may be considered as risk factors for TS in patients who have undergone total laryngectomy and adjuvant radiotherapy. PMID- 24057099 TI - Analysis of 101 patients with severe to profound sudden unilateral hearing loss treated with explorative tympanotomy and sealing of the round window membrane. AB - The aim of this retrospective study was to evaluate the effect of sealing of the round window membrane in patients with severe to profound unilateral sudden sensorineural hearing loss (SSNHL). 101 Patients with unilateral SSNHL were treated with tympanotomy and sealing of the round window membrane if hearing did not improve after conservative treatment. Preoperative and postoperative pure tone audiograms after removal of the ear packing were evaluated. A 4-PTA (pure tone audiometry) was used as reference value. The improvement of 4-PTA was analysed; in addition, recovery was evaluated using Siegel's criteria. Mean initial hearing threshold was 101.1 dB. Eighty-one patients had a hearing threshold of 80 dB or more. The average improvement at the time of ear packing was 21.7 dB and a further average recovery of 13.4 dB was recorded in the follow up. Patients who underwent rapid tympanotomy within 5 days showed a significantly better hearing improvement than patients with delayed tympanotomy (26.9 vs. 14.0 dB, p < 0.02). Age was significantly correlated with the degree of hearing improvement. There was no significant difference of recovery between patients with detected lesions of the round window membrane and those without. Concomitant vertigo and tinnitus showed no significant effect on recovery. Tympanotomy and sealing of the round window membrane is effective in the treatment of severe to profound SSNHL. There is evidence that early surgery performed within 5 days is more effective than later surgery. The existence of a detectable lesion of the round window membrane has no significant influence on recovery. PMID- 24057100 TI - The cost associated with interstitial thermotherapy for tonsil reduction vs. standard tonsillectomy. AB - Given the high demand for tonsillectomies in children, the variety of techniques available, and the increasing need to control expenditures, it is important to analyse the costs associated with surgical procedures. The aim in the present study was to compare the cost of interstitial thermotherapy for tonsil volume reduction with conventional tonsillectomy. This was a nonrandomized, retrospective analysis at a public practice regional hospital between 2010 and 2012. Paediatric patients that underwent molecular resonance (MR)-induced tonsil thermal ablation (day case admission) were matched, according to age and concurrent surgery, to patients that underwent tonsillectomy by standard bipolar dissection (ordinary admission) during the same study period. Both groups were compared in economic terms based on operating room (OR) times, salaries, materials and hospitalization cost. Sixty-two patients were included (31 in each group). The mean ages of patients in the MR and tonsillectomy groups were 5.6 (2.7 SD) and 5.1 years (2.0 SD), respectively. A significantly lower mean surgery time (28.25 vs. 36.95 min), anaesthesia time (48.79 vs. 61.73 min), OR time (64.18 vs. 76.16 min), and OR cost (?166.60 vs. ?199.58) were found in the MR group (P < 0.05). The mean cost-per-patient was significantly higher in the MR technique when the expenses of the single-use probe and the overnight stay were, respectively, added (?408.60 vs. ?374.58, P = 0.007). The present study confirmed increased costs for interstitial thermotherapy for tonsil reduction compared to conventional tonsillectomy. Operation time and early discharge savings were eclipsed by the cost of the disposable probes. PMID- 24057101 TI - Dexamethasone contributes to the patient management after ambulatory laryngeal microsurgery by reducing sore throat. AB - This study was planned to evaluate the preventive effect of dexamethasone for sore throat after ambulatory laryngeal microsurgery. One hundred and ten patients scheduled for ambulatory laryngeal microsurgery under general anesthesia were randomly divided into two groups, group S1 and group D1. Patients in the group D1 were injected with 0.2 mg/kg of intravenous dexamethasone before the induction of anesthesia. The incidences and severities of sore throat were measured using verbal rating scale (VRS) at 1 h and through phone calls at 6 h after the operation. The patients who requested analgesics in the recovery room were measured VRS shortly before administration of medicine. The patients in group S1 and group D1 who did not receive rescue analgesics were enrolled in group S6 and group D6, respectively, and evaluated 6 h after the surgery. There were no significant differences in the incidence and severity scores of sore throat during 1 h after the end of operation between group S1 and group D1. But at 6 h, the patients in the group D6 had lower incidence of sore throat than those in group S6 significantly (P = 0.003). Furthermore, the patients in the group D6 had lower severity of sore throat than those in group S6 significantly at 6 h (P = 0.001). In conclusion, prophylactic administration of intravenous dexamethasone is appeared to have efficacy for the management of sore throat in the early post discharge period following ambulatory laryngeal microsurgery. PMID- 24057102 TI - Comparison of scalp and abdomen as split-thickness skin graft donor sites for aural stenosis repair. AB - To evaluate and compare the scalp and the abdomen as split-thickness skin graft donor sites for aural stenosis repair. A total of 34 patients with aural stenosis were included in the study. All the patients underwent meatoplasty using split thickness skin grafts. Among them, the skin graft donor site was the scalp in 11 patients and the abdomen in the other 23 patients. The surgical team followed the patients in the outpatient department for at least 6 months after surgery. Evaluations concerned healing of the donor site, hair regeneration of the donor site, survival of split-thickness skin grafts, reoccurrence of aural stenosis and hair growth in the ear canal. The incidences of reoccurrence of aural stenosis in the two groups were compared. Subjective scar evaluation of the donor sites was performed using the Patient Scar Assessment Scale (PASA). The scale items were pain, itching, color, stiffness, thickness and irregularity. All the scalp and abdominal donor sites healed well with no sign of infection. Hair regrowth and reepithelialization was observed at all the scalp donor sites. Pink discoloration was observed at the scalp donor sites in six patients 2-3 months after surgery and disappeared 6-9 months after surgery. Scars were observed at the scalp donor sites in two patients 6 months after surgery. No alopecia was observed at the scalp donor sites. The scars and pink discoloration were hidden in the hair. Scars and/or discoloration were observed at all the abdominal donor sites 12 months after surgery. All the scalp and abdominal skin grafts survived with no sign of infection. Hair growth was observed in the ear canals in two patients in the scalp group. The incidences of reoccurrence of aural stenosis were 0 % (0/23) in the abdominal group and 9.1 % (1/11) in the scalp group, respectively (Chi square test, p > 0.05). The PASA values about color, stiffness, thickness and irregularity were higher in the abdominal group than in the scalp group (Mann Whitney U test, p < 0.001). The PASA values about pain and itching were the same (Mann-Whitney U test, p > 0.05). The scalp meets most requirements of an ideal donor site of skin grafts for aural stenosis. The advantages of scalp as a donor site include easy accessibility in the operative field, simple postoperative care, low risk of infection, rapid wound healing, minimal interference with rehabilitation, and minimal scar formation. PMID- 24057104 TI - Manipulating gamma-cyclodextrin-mediated photocyclodimerization of anthracenecarboxylate by wavelength, temperature, solvent and host. AB - Wavelength effects on the enantiodifferentiating photocyclodimerization of 2 anthracenecarboxylate (AC) mediated by native and modified gamma-cyclodextrins (CDs) were examined in different solvents at varying temperatures to manipulate the photochirogenic outcomes beyond the thermodynamically determined re/si enantiotopic face selectivity upon 2 : 1 complexation of AC with CD in the ground state. Indeed, the stereochemical outcomes, i.e. syn/anti, head-to-tail/head-to head (HT/HH) and in particular enantiomer ratios, were critical functions of the irradiation wavelength, irrespective of the CD host employed. Furthermore, the wavelength effects observed strongly depended on the host structure, reaction temperature and solvent employed, for which altered stacking geometry of the complexed AC pair is thought to be responsible. By optimizing the irradiation wavelength, chiral host, temperature and solvent, an enantiomeric excess of up to 54 and -37% were achieved for chiral syn-HT and anti-HH dimers. PMID- 24057103 TI - Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration. AB - Fibroblast growth factor-2 (FGF2), also known as basic FGF, is a multi-functional growth factor. One of the 22-member FGF family, it signals through receptor tyrosine kinases encoding FGFR1-4. FGF2 activates FGFRs in cooperation with heparin or heparin sulfate proteoglycan to induce its pleiotropic effects in different tissues and organs, which include potent angiogenic effects and important roles in the differentiation and function of the central nervous system (CNS). FGF2 is crucial to development of the CNS, which explains its importance in adult neurogenesis. During development, high levels of FGF2 are detected from neurulation onwards. Moreover, developmental expression of FGF2 and its receptors is temporally and spatially regulated, concurring with development of specific brain regions including the hippocampus and substantia nigra pars compacta. In adult neurogenesis, FGF2 has been implicated based on its expression and regulation of neural stem and progenitor cells in the neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. FGFR1 signaling also modulates inflammatory signaling through the surface glycoprotein CD200, which regulates microglial activation. Because of its importance in adult neurogenesis and neuroinflammation, manipulation of FGF2/FGFR1 signaling has been a focus of therapeutic development for neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and traumatic brain injury. Novel strategies include intranasal administration of FGF2, administration of an NCAM-derived FGFR1 agonist, and chitosan-based nanoparticles for the delivery of FGF2 in pre clinical animal models. In this review, we highlight current research towards therapeutic interventions targeting FGF2/FGFR1 in neurodegenerative disorders. PMID- 24057106 TI - Comparative QTL analysis of early short-time drought tolerance in Polish fodder and malting spring barleys. AB - KEY MESSAGE: An effective approach for the further evolution of QTL markers, may be to create mapping populations for locally adapted gene pools, and to phenotype the studied trait under local conditions. Mapping populations of Polish fodder and malting spring barleys (Hordeum vulgare L.) were used to analyze traits describing short-time drought response at the seedlings stage. High-throughput genotyping (Diversity Array Technology (DArT) markers) and phenotyping techniques were used. The results showed high genetic diversity of the studied populations which allowed the creation of high-density linkage maps. There was also high diversity in the physiological responses of the barleys. Quantitative trait locus (QTL) analysis revealed 18 QTLs for nine physiological traits on all chromosomes except 1H in malting barley and 15 QTLs for five physiological traits on chromosomes 2H, 4H, 5H and 6H in fodder barley. Chromosomes 4H and 5H contained QTLs which explained most of the observed phenotypic variations in both populations. There was a major QTL for net photosynthetic rate in the malting barley located on chromosome 5H and two major QTLs for overall photochemical performance (PI) located on 5H and 7H. One major QTL related to photochemical quenching of chlorophyll fluorescence was located on chromosome 4H in fodder barley. Three QTL regions were common to both mapping populations but the corresponding regions explained different drought-induced traits. One region was for QTLs related to PSII photosynthetic activity stress index in malting barley, and the corresponding region in fodder barley was related to the water content stress index. These results are in accordance with previous studies which showed that different traits were responsible for drought tolerance variations in fodder and malting barleys. PMID- 24057105 TI - The emergence of lipid droplets in yeast: current status and experimental approaches. AB - The 'discovery' of lipid droplets as a metabolically highly active subcellular organelle has sparked great scientific interest in its research in recent years. The previous view of a rather inert storage pool of neutral lipids- triacylglycerol and sterols or steryl esters--has markedly changed. Driven by the endemic dimensions of lipid-associated disorders on the one hand, and the promising biotechnological application to generate oils ('biodiesel') from single celled organisms on the other, multiple model organisms are exploited in basic and applied research to develop a better understanding of biogenesis and metabolism of this organelle. This article summarizes the current status of LD research in yeast and experimental approaches to obtain insight into the regulatory and structural components driving lipid droplet formation and their physiological and pathophysiological roles in lipid homeostasis. PMID- 24057107 TI - Stabilization of graphene quantum dots (GQDs) by encapsulation inside zeolitic imidazolate framework nanocrystals for photoluminescence tuning. AB - Luminescent graphene quantum dots (GQDs) are encapsulated and stabilized in Zeolitic Imidazolate Framework (ZIF-8) nanocrystals. The GQDs are well confined due to the adsorption on the growing face of the ZIF-8 nanocrystals and have a profound effect on the shape of the nanocrystals from rhombic dodecahedron to spherical. Stabilizing GQDs inside the ZIF-8 nanocrystals results in tailoring of the photoluminescence emission (ca. 32 nm, bathochromic shift) of the GQD@ZIF-8 nanocrystal composite even after 3 months of aging under normal laboratory conditions. Also the water adsorption (at STP) capacity increased for the GQD@ZIF 8 composite as compared to the pristine ZIF-8. PMID- 24057109 TI - Suicide ideation in stomach cancer survivors and possible risk factors. AB - PURPOSE: Although the suicide rate of cancer survivors is higher than that of the general population, few studies have examined the potential risk factors. We assessed suicide ideation (SI) and investigated its correlates among survivors of stomach cancer, which is one of the most prevalent cancers in Korea. METHODS: We surveyed 378 stage I-III stomach cancer survivors who had been disease free for at least 1 year. The survey contained demographic questions and quality of life assessments from the European Organization for Research and Treatment of Cancer QLQ-C30 and its stomach cancer-specific module, the McGill Quality of Life Questionnaire, the Brief Fatigue Inventory, and one question from the Beck Depression Inventory. RESULTS: We found that 131/378 stomach cancer survivors (34.7 %) experienced SI. Univariate analyses showed that SI was significantly associated with income, comorbidity, smoking, and the following quality of life factors: general health status, emotional functioning, fatigue, nausea/vomiting, dyspnea, appetite loss, constipation, diarrhea, financial problems, eating restriction, anxiety, dry mouth, trouble belching, hair loss, body image, existential well-being, and social support. Multivariate logistic regression confirmed that SI was independently associated with diarrhea (adjusted odds ratio (aOR) 2.84; 95 % confidence interval (CI) 1.44-5.62), hair loss (aOR 2.77; 95 % CI 1.04-7.36), existential well-being (aOR 6.18; 95 % CI 2.91-13.1), and usual fatigue (aOR 2.29; 95 % CI 1.30-4.06). CONCLUSION: Our findings reveal a high prevalence of SI among stomach cancer survivors and identify health-related quality of life issues such as diarrhea, hair loss, existential well-being, and fatigue as important risk factors of SI. PMID- 24057112 TI - Lewis base catalyzed asymmetric substitution/Diels-Alder cascade reaction: a rapid and efficient construction of enantioenriched diverse tricyclic heterocycles. AB - The first tertiary amine catalyzed asymmetric allylic amination/cycloaddition cascade sequence has been developed, which provided a novel protocol to construct enantioenriched azapolyheterocycles under mild reaction conditions efficiently (up to 95% ee, endo/exo >20:1). PMID- 24057110 TI - Diagnostic accuracy of lipopolysaccharide-binding protein for predicting bacteremia/clinical sepsis in children with febrile neutropenia: comparison with interleukin-6, procalcitonin, and C-reactive protein. AB - PURPOSE: In febrile neutropenia (FN), no reliable marker has been identified to discriminate between severe infection and other causes of fever early in the clinical course. Since lipopolysaccharide-binding protein (LBP) has proven to be an accurate biomarker of bacteremia/clinical sepsis in critically ill non immunocompromised infants and children, we performed a prospective study to determine the diagnostic accuracy of LBP in children with FN. METHODS: Concentrations of LBP, procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) were prospectively measured on two consecutive days in 90 FN episodes experienced by 47 children. Receiver operating characteristic curve analysis was performed for each biomarker to predict bacteremia/clinical sepsis and severe sepsis. RESULTS: Eighteen of the 90 episodes were classified as bacteremia/clinical sepsis. On both days 1 and 2, all biomarkers had a low to intermediate diagnostic accuracy for sepsis, and no significant differences were found between them (area under the curve (AUC) for LBP, 0.648 and 0.714; for PCT, 0.665 and 0.744; for IL-6, 0.775 and 0.775; and for CRP, 0.695 and 0.828). Comparison of their AUCs to the AUC of maximum body temperature on admission (AUC = 0.668) also failed to show any significant differences. In severe sepsis, however, the best diagnostic accuracies were found for IL-6 and PCT (AUC 0.892 and 0.752, respectively), and these were significantly higher than those for LBP (AUC 0.566) on admission. CONCLUSIONS: On admission and 24 h later, the LBP concentration is less accurate for predicting bacteremia/clinical sepsis compared to IL-6, PCT, and CRP. PMID- 24057113 TI - Synthesis of highly functionalized macrocycles by tandem multicomponent reactions and intramolecular Sonogashira cross-coupling. AB - An efficient chemoselective process for the synthesis of 14- and 15-membered triazole-containing macrocycle compounds has been developed through the combination of two multicomponent reactions and an intramolecular Sonogashira cross-coupling reaction. PMID- 24057114 TI - Foot trajectory approximation using the pendulum model of walking. AB - Generating a natural foot trajectory is an important objective in robotic systems for rehabilitation of walking. Human walking has pendular properties, so the pendulum model of walking has been used in bipedal robots which produce rhythmic gait patterns. Whether natural foot trajectories can be produced by the pendulum model needs to be addressed as a first step towards applying the pendulum concept in gait orthosis design. This study investigated circle approximation of the foot trajectories, with focus on the geometry of the pendulum model of walking. Three able-bodied subjects walked overground at various speeds, and foot trajectories relative to the hip were analysed. Four circle approximation approaches were developed, and best-fit circle algorithms were derived to fit the trajectories of the ankle, heel and toe. The study confirmed that the ankle and heel trajectories during stance and the toe trajectory in both the stance and the swing phases during walking at various speeds could be well modelled by a rigid pendulum. All the pendulum models were centred around the hip with pendular lengths approximately equal to the segment distances from the hip. This observation provides a new approach for using the pendulum model of walking in gait orthosis design. PMID- 24057115 TI - Cellular responses to Rhipicephalus microplus infestations in pre-sensitised cattle with differing phenotypes of infestation. AB - The blue tick, Rhipicephalus microplus, threatens cattle production in most tropical and subtropical areas of the world. Delayed skin hypersensitivity reactions are thought to cause Nguni cattle to be more resistant to R. microplus than Bonsmara cattle yet the cellular mechanisms responsible for these differences have not been classified. Tick counts and inflammatory cell infiltrates in skin biopsies from feeding sites of adult R. microplus ticks were determined in 9-month-old Nguni and Bonsmara heifers to determine the cellular mechanisms responsible for tick immunity. Nguni heifers (1.7 +/- 0.03) had lower (P < 0.05) tick counts than the Bonsmaras (2.0 +/- 0.03). Parasitized sites in Nguni heifers had higher counts of basophils, mast and mononuclear cells than those in the Bonsmara heifers. Conversely, parasitized sites in Nguni heifers had lower neutrophil and eosinophil counts than those in the Bonsmara heifers. Tick count was negatively correlated with basophil and mast cell counts and positively correlated with eosinophil counts in both breeds. In the Bonsmara breed, tick count was positively correlated with mononuclear cell counts. Cellular responses to adult R. microplus infestations were different and correlated with differences in tick resistance in Nguni and Bonsmara cattle breeds. It is essential to further characterise the molecular composition of the inflammatory infiltrate elicited by adult R. microplus infestation to fully comprehend immunity to ticks in cattle. PMID- 24057116 TI - Distinct roles of neuregulin in different models of neuropathic pain. AB - The objective of the study was to investigate the role of neuregulin-ErbB signaling in neuropathic pain in different types of injury. Neuregulin-1(NRG-1) was injected into animals with either formalin-induced pain model or spared nerve injury (SNI) model. Formalin tests or paw withdrawal tests were performed to study the role of NRG-1 in neuropathic pain. siRNA specific to different erbB receptors were then introduced to test which specific signaling pathway was required for NRG-1 signaling in the different pain models. NRG-1 inhibits neuropathic pain after SNI in a dose-dependent manner, while NRG-1 aggravates formalin-induced neuropathic pain. ErbB2 and erbB4 receptors were activated after neuregulin administration. Knockdown of ErbB2 relieves the aggravation of NRG-1 on formalin-induced neuropathic pain, and knockdown of ErbB4 could relieve the inhibition of NRG-1 on neuropathic pain in the SNI model. NRG-1 has two distinct functions depending on the different receptor activation in different models of neuropathic pain. These novel findings may provide new therapeutic approaches for the treatment of neuropathic pain in different injury types. PMID- 24057117 TI - Increased fibrinogen, D-dimer and galectin-3 levels in patients with migraine. AB - There are limited studies evaluating the fibrinogen levels in patients with migraine. It remains unknown whether the levels of the haematological marker of thromboembolism, D-dimer, and the levels of galectin-3, which plays an important role in inflammation as a proinflammatory mediator, change during the attacks in patients with migraine. The present study aims to compare galectin-3, fibrinogen and D-dimer levels in patients with migraine during the attacks and interictal periods, and to compare galectin-3, fibrinogen and D-dimer levels between patients with migraine and healthy controls to investigate the role of these parameters in the pathogenesis of migraine. Fifty-nine patients with migraine and 30 age-gender matched healthy control subjects were enrolled in the study. Blood galectin-3, fibrinogen and D-dimer levels were measured in patients with migraine. Patients with migraine had higher levels of galectin-3, fibrinogen and D-dimer compared to the healthy controls (p < 0.05). No statistically significant difference was found between galectin-3 and fibrinogen levels during the attacks and interictal period in the migraine group (p > 0.05). Migraine patients had higher D-dimer levels during the attacks compared to the patients in the interictal period in the migraine group (p = 0.05). In conclusion, we found increased levels of fibrinogen, D-dimer and galectin-3 in patients with migraine compared to the healthy control group. Furthermore, we showed increased galectin 3 levels in patients with migraine, and higher D-dimer levels during migraine attacks compared to the interictal periods for the first time. These findings may be associated with the hypercoagulability and neurogenic inflammation during migraine headaches. PMID- 24057118 TI - A model of synaptic plasticity: activation of mGluR I induced long-term theta oscillations in medial septal diagonal band of rat brain slice. AB - This study aimed to establish a model of synaptic plasticity by the activation of metabotropic glutamate receptor (mGluR) I in rat medial septal diagonal band (MSDB). Electrophysiological experiment was performed to record the theta frequency oscillation activities in rat MSDB slices. The data were recorded and analyzed with Spike 2 (CED, Cambridge, UK). Application of aminocyclopentane-1, 3 dicarboxylic acid (ACPD) to MSDB slices produced theta frequency oscillations (4 12 Hz) which persisted for hours after ACPD washout, suggesting the existence of a form of synaptic plasticity in long-term oscillations (LTOs). Addition of NMDA receptor antagonist AP5 (50 MUM) caused no significant change in area power. In contrast, AMPA/Kainate receptor antagonist NBQX administration partially reduced the area power. Infusion of ZD7288, a hyperpolarization-activated channel (Ih) inhibitor, caused additional reduction to control level. Comparable effects were also observed with administration of DHPG (3, 5-dihydroxyphenylglycine) which also elicited LTOs. mGluR I activation induced theta oscillation and this activity maintained hours after drug washout. Both AMPA and hyperpolarization activated channel make an essential contribution to LTO. Our study herein established a model of synaptic plasticity. PMID- 24057119 TI - The delusion of the Master: the last days of Henry James. AB - The novelist Henry James shared with his brother William, the author of the Principles of Psychology, a deep interest in the ways in which personal identity is built through one's history and experiences. At the end of his life, Henry James suffered a vascular stroke in the right hemisphere and developed a striking identity delusion. He dictated in a perfectly clear and coherent manner two letters as if they were written by Napoleon Bonaparte. He also showed signs of reduplicative paramnesia. Negative symptoms resulting from right hemisphere damage may disrupt the feelings of "warmth and intimacy and immediacy" and the "resemblance among the parts of a continuum of feelings (especially bodily feelings)", which are the foundation of personal identity according to William James. On the other hand, a left hemisphere receiving inadequate input from the damaged right hemisphere may produce positive symptoms such as delusional, confabulatory narratives. Other fragments dictated during Henry James's final disease reveal some form of insight, if partial and disintegrated, into his condition. Thus, even when consciousness is impaired by brain damage, something of its deep nature may persist, as attested by the literary characteristics of the last fragments of the Master. PMID- 24057120 TI - Site of impaction of ureteric calculi requiring surgical intervention. AB - Textbooks describe three narrowest anatomic sites in the ureter as the most likely places for ureteral calculi to lodge, these are: the pelvi-ureteric junction (PUJ), the point where the ureters cross over the iliac vessels and the ureterovesical junction (UVJ). The purpose of this study is to determine whether calculi causing ureteric obstruction and requiring surgical treatment are found mostly at these three narrowest anatomic points of the ureter. Three hundred consecutive patients with impacted ureteric calculi who required surgical intervention were studied. The location of the impacted calculus on the day of surgical intervention was categorized according to nine predetermined levels outlined in a designed diagram based on findings on non-contrast CT of kidneys, ureters and bladder. Two peaks in stone distribution in the ureters were encountered; the first was above the ischial spine in the proximal part of the lower third ureter (84 patients, 28%), while the second was at the level between L3 and L4 lumbar vertebrae (66 patients, 22%). Overall, the location of impacted calculi was as follows, 53, 34, 10 and 3% in the lower third ureter, upper third ureter, PUJ and mid ureter, respectively. This study demonstrates two peaks of calculi distribution in the ureter where ureteric calculi become impacted: the upper ureter below the PUJ and a second in the lower ureter, more proximal than the UVJ. There was an absence of the peak in stone location over the iliac vessels, that is, the mid ureter. PMID- 24057121 TI - Antihyperglycemic effect of carvacrol in combination with rosiglitazone in high fat diet-induced type 2 diabetic C57BL/6J mice. AB - Thiazolidinediones constitute a family of antidiabetic drugs, and rosiglitasone (RSG) has an extensive usage in treating the complications of type 2 diabetes mellitus. Carvacrol (CVL), a monoterpenic phenol that occurs in many essential oils of the family Labiatae including Origanum, Satureja, Thymbra, Thymus, and Corydothymus species, possess a wide variety of pharmacological properties including antioxidant potential. We hypothesized that carvacrol in combination with RSG would prove beneficial to ameliorate the dysregulated carbohydrate metabolism in high-fat diet (HFD)-induced type 2 diabetic C57BL/6J mice. Mice were divided into six groups and fed HFD, for 10 weeks. CVL (20 mg/kg BW) and RSG (4 mg/kg BW) were administered post-orally, daily for 35 days. HFD mice showed an elevation in plasma glucose, insulin, glycosylated hemoglobin and a decrease in hemoglobin. The activities of carbohydrate metabolic enzymes such as glucose-6 phosphatase and fructose-1,6-bisphosphatase increased whereas glucokinase and glucose-6-phosphate dehydrogenase activities decreased in the liver of HFD mice. The activities of hepatic marker enzymes such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase increased in HFD mice. Combination of CVL and RSG prevented the above changes toward normalcy. Histopathological analysis of H&E stained pancreas was also in agreement with the biochemical findings. These major findings provide evidence that combination of CVL with RSG has better antidiabetic properties. PMID- 24057123 TI - Practical oxazole synthesis mediated by iodine from alpha-bromoketones and benzylamine derivatives. AB - The reagent system of I2/K2CO3 could efficiently promote the oxazole synthesis from alpha-bromoketones and benzylamine derivatives in DMF. This method was not only suitable for 2,5-diaryl oxazole synthesis but also for 2,4,5-trisubstituted oxazole and 5-alkyl/alkenyl oxazole synthesis. Furthermore, this method was successfully applied to a one-step synthesis of a natural product halfordinol in 62% yield. PMID- 24057122 TI - The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis. AB - Sepsis is one of the most common causes of mortality in intensive care units. Although sepsis-associated encephalopathy (SAE) is reported to be a leading manifestation of sepsis, its pathogenesis remains to be elucidated. In this study, we investigated whether exogenous recombinant human erythropoietin (rhEPO) could protect brain from neuronal apoptosis in the model of SAE. We showed that application of rhEPO enhanced Bcl-2, decreased Bad in lipopolysaccharide treated neuronal cultures, and improved neuronal apoptosis in hippocampus of cecal ligation and peroration rats. We also found that rhEPO increased the expression of phosphorylated AKT, and the antiapoptotic role of rhEPO could be abolished by phosphoinositide 3-kinase (PI3K)/AKT inhibitor LY294002 or SH-5. In addition, systemic sepsis inhibited the hippocampal-phosphorylated mammalian target of rapamycin (mTOR) and p70S6K (downstream substrates of PKB/AKT signaling), which were restored by administration of exogenous rhEPO. Moreover, treatment with mTOR signaling inhibitor rapamycin or transfection of mTOR siRNA reversed the neuronal protective effects of rhEPO. Finally, exogenous rhEPO rescued the emotional and spatial cognitive defects without any influence on locomotive activity. These results illustrated that exogenous rhEPO improves brain dysfunction by reducing neuronal apoptosis, and AKT/mTOR signaling is likely to be involved in this process. Application of rhEPO may serve as a potential therapy for the treatment of SAE. PMID- 24057124 TI - The persistence of ligature marks: towards a new protocol for victims of abuse and torture. AB - One of the most frequently observed lesions in clinical forensic practice concerns the patterned abrasion on skin due to constriction by various types of ligature. Detection of ligature marks and their patterns may be fundamental for reconstructing events and supporting testimony of an aggression, sexual abuse, or maltreatment. But very little actually exists in literature concerning their detectability and how long they last. This study aims at evaluating the time of persistence and detectability of skin signs left by different types of ligatures in living persons: on the arms of three volunteers, eight different ligatures were applied; 123 tests were performed, with time of contact ranging between 1 min and 2 h and 45 min. In addition, the persistence of the shape and pattern of the ligature was evaluated 15, 30, and 60 min after a 5- and 15-min compression. Polyvinyl siloxane, applied by a gun dispenser, was used to perform a cast of the skin mark. The results show that the pattern was less distinguishable with the decrease of time of contact, going from 75 % after 10 and 15 min of contact, to 45.8 % after 1 min. Above 15 min, the specific pattern was always recognizable. In addition, a progressive decrease of the detectability of the pattern with time, respectively, up to 12.5 and 37.5 % in 5- and 15-min tests was observed. This study provides useful results for the assessment of patterned injuries in forensic pathology and clinical forensic medicine, both on dead and living persons: in addition, the use of silicone casts seems to be a reliable and cheap method for easily recording and preserving the morphological profile of skin lesions. PMID- 24057125 TI - Bonding surgical incisions using a temperature-controlled laser system based on a single infrared fiber. AB - ABSTRACT. Although there has been great interest in laser heating for bonding of surgical incisions in tissues, it has not gained wide acceptance by surgeons. We argue that the main obstacle has been the lack of temperature control, which may lead to a weak bonding. We previously developed a laser bonding system based on two infrared transmitting AgBrCl fibers, one for laser heating and one for temperature control. In view of the inherent limitations of such systems observed in many animal experiments, we developed an improved system based on a single infrared fiber. Besides the decreased dimensions, this system offers many advantages over the two-fiber system. It is less sensitive to accuracy of height and tilt of the fiber distal tip above the tissue, ensuring more accurate heating that can potentially lead to stronger bonding with minimal thermal damage. The system is successfully tested in the soldering of 15 corneal incisions, ex vivo. Histopathology shows little thermal damage and good wound apposition. The average burst pressure is 100+/-30 mm Hg. These findings indicate the usefulness of the system for ophthalmic surgery as well as other surgical procedures, including endoscopic and robotic surgery. PMID- 24057126 TI - Yeast membranes and cell wall: from basics to applications. PMID- 24057128 TI - Multi-walled carbon/IF-WS2 nanoparticles with improved thermal properties. AB - A unique new class of core-shell structured composite nanoparticles, C-coated inorganic fullerene-like WS2 (IF-WS2) hollow nanoparticles, has been created for the first time in large quantities, by a continuous chemical vapour deposition method using a rotary furnace. Transmission electron microscopy and Raman characterisations of the resulting samples reveal that the composite nanoparticles exhibited a uniform shell of carbon coating, ranging from 2-5 nm on the IF-WS2 core, with little or no agglomeration. Importantly, thermogravimetric analysis and differential scanning calorimetry analysis confirm that their thermal stability against oxidation in air has been improved by about 70 degrees C, compared to the pristine IF-WS2, making these new C-coated IF-WS2 nanoparticles more attractive for critical engineering applications. PMID- 24057129 TI - Azacrown[N,S,O]-modified porphyrin sensor for detection of Ag+, Pb2+, and Cu2+. AB - One new azacrown[N,S,O]-modified metal-free porphyrin derivative, H2Por-azacrown (1), with the central tetrapyrrole moiety as signaling fluorophore and/or metal ion receptor has been designed, synthesized, and characterized. Addition of Ag(+) into this novel metal-free porphyrin compound induces a fluorescence ON-OFF process, while adding Pb(2+) leads to absorption/emission-ratiometric signals. Quite interestingly, blue-shift of the Soret band, ratiometric change of Q bands, and dual-signal changes (absorption ratio and fluorescence ON-OFF) associated with the Cu(2+) displacement from the 1-Pb(2+) system were observed upon addition of Cu(2+). These results render this H2Por-azacrown compound a porphyrin-based multi-responsive optical sensor towards Ag(+), Pb(2+), and in particular Cu(2+) with dual-mode detecting potential. PMID- 24057127 TI - Functional characterization of sucrose non-fermenting 1 protein kinase complex genes in the Ascomycete Fusarium graminearum. AB - Sucrose non-fermenting 1 (SNF1) protein kinase complex is a heterotrimer that functions in energy homeostasis in eukaryotes by regulating transcription of glucose-repressible genes. Our previous study revealed that SNF1 of the homothallic ascomycete fungus Fusarium graminearum plays important roles in vegetative growth, sexual development, and virulence. In this study, we further identified the components of the SNF1 complex in F. graminearum and characterized their functions. We found that the SNF1 complex in F. graminearum consists of one alpha subunit (FgSNF1), one beta subunit (FgGAL83), and one gamma subunit (FgSNF4). Deletion of Fggal83 and Fgsnf4 resulted in alleviated phenotype changes in vegetative growth and sexual development as compared to those of the Fgsnf1 deletion mutant. However, all of the single, double, and triple deletion mutants among Fgsnf1, Fggal83, and Fgsnf4 had similar levels of decreased virulence. In addition, there was no synergistic effect of the mutant (single, double, or triple deletions of SNF1 complex component genes) phenotypes except for sucrose utilization. In this study, we revealed that FgSNF1 is mainly required for SNF1 complex functions, and the other two SNF1 complex components have adjunctive roles with FgSNF1 in sexual development and vegetative growth but have a major role in virulence in F. graminearum. PMID- 24057130 TI - Redefining autism spectrum disorder using DSM-5: the implications of the proposed DSM-5 criteria for autism spectrum disorders. AB - A number of changes were made to pervasive developmental disorders (PDDs) in the recently released diagnostic and statistical manual of mental disorders (APA, Diagnostic and statistical manual of mental disorders, American Psychiatric Publishing, Arlington, VA, 2013). Of the 210 participants in the present study who met DSM-IV-TR criteria for a PDD [i.e., autistic disorder, Asperger's disorder and pervasive developmental disorder-not otherwise specified (PDD-NOS)], only 57.1% met DSM-5 criteria (specificity = 1.0) for autism spectrum disorder when criteria were applied concurrently during diagnostic assessment. High functioning individuals (i.e., Asperger's disorder and PDD-NOS) were less likely to meet DSM-5 criteria than those with autistic disorder. A failure to satisfy all three criteria in the social-communication domain was the most common reason for exclusion (39%). The implications of these results are discussed. PMID- 24057131 TI - Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis. AB - We performed a systematic literature search regarding maternal diabetes before and during pregnancy and the risk of autism spectrum disorders (ASD) in the offspring. Of the 178 potentially relevant articles, 12 articles including three cohort studies and nine case-control studies were included in the meta-analysis. Both the meta-analyses of cohort studies and case-control studies showed significant associations. The pooled relative risk and 95% confidence interval (CI) among cohort studies was 1.48 (1.25-1.75, p < 0.001). For case-control studies, the pooled odds ratio and 95% CI was 1.72 (1.24-2.41, p = 0.001). No indication of significant heterogeneity across studies or publication bias was observed. In conclusion, maternal diabetes was significantly associated with a greater risk of ASD in the offspring. PMID- 24057132 TI - "In the driver's seat": Parent perceptions of choice in a participant-directed medicaid waiver program for young children with autism. AB - This study investigated families' experience of choice within a participant directed Medicaid waiver program for young children with autism. Fourteen parents or grandparents participated in in-depth interviews about their experience of choosing personnel, directing in-home services, and managing the $25,000 annual allocation. Key findings included families' preference to hire providers with whom they have a prior relationship, parent empowerment and differences of opinion about parents as teachers. Professionals implementing participant directed service models could benefit from understanding the strong value parents' placed on the personalities and interpersonal skills of providers. Parents' descriptions of directing rather than merely accepting autism services revealed increased confidence in their ability to choose and manage the multiple components of their children's HCBS autism waiver program. PMID- 24057133 TI - Effects of radiation on bone. AB - Ionizing radiation produces its deleterious biologic effects by both direct (DNA strand breaks) and indirect processes (formation of free oxygen radicals). Mitotically active cells are more susceptible to the detrimental effects of ionizing radiation. These effects are most severe locally within the treatment field but can also occur systemically, possibly reflecting hormonal influences and inflammatory cytokine mediators. Specific bone complications of radiation include osteopenia, growth arrest, fracture and malignancy. Some of these complications, such as osteopenia, are reversible and severity is dose dependent. Insufficiency fractures are a common complication after radiation therapy and generally affect those bones under most physiologic stress and with the highest ratio of trabecular to cortical bone. Familiarity with the radiographic appearance of irradiated bone, including computed tomography (CT) and magnetic resonance imaging (MRI), will improve image interpretation and facilitate accurate diagnosis. PMID- 24057134 TI - Modified N-acyl-homoserine lactones as chemical probes for the elucidation of plant-microbe interactions. AB - Gram-negative bacteria often use N-acyl-homoserine lactones (AHLs) as signal molecules to monitor their local population densities and to regulate gene expression in a process called "Quorum Sensing" (QS). This cell-to-cell communication allows bacteria to adapt to environmental changes and to behave as multicellular communities. QS plays a key role in both bacterial virulence towards the host and symbiotic interactions with other organisms. Plants also perceive AHLs and respond to them with changes in gene expression or modifications in development. Herein, we report the synthesis of new AHL derivatives for the investigation and identification of AHL-interacting proteins. We show that our new compounds are still recognised by different bacteria and that a novel biotin-tagged-AHL derivative interacts with a bacterial AHL receptor. PMID- 24057135 TI - Career switch for EC-CFU to modelling. PMID- 24057137 TI - Risk stratification for diabetic eye screening. PMID- 24057136 TI - Catalase activity, allelic variations in the catalase gene and risk of kidney complications in patients with type 1 diabetes. AB - AIMS/HYPOTHESIS: Oxidative stress is involved in the pathogenesis of diabetic nephropathy. The antioxidant enzyme catalase plays a key role in redox regulation in the kidney. We investigated associations of catalase gene (CAT) polymorphisms and plasma catalase activity with diabetic nephropathy in type 1 diabetic patients. METHODS: We genotyped nine single nucleotide polymorphisms (SNPs) in the CAT region in participants from the Survival Genetic Nephropathy (SURGENE) (340 French participants, 10 year follow-up) and the Genetique de la Nephropathie Diabetique (GENEDIAB) (444 Belgian and French participants, 8 year follow-up) study cohorts. Replication was performed in a Brazilian cross-sectional cohort (n = 451). Baseline plasma catalase activity was measured in SURGENE (n = 120) and GENEDIAB (n = 391) participants. RESULTS: The A allele of rs7947841 was associated with the prevalence of incipient (OR 2.79, 95% CI 1.21, 6.24, p = 0.01) and established or advanced nephropathy (OR 5.72, 95% CI 1.62, 22.03, p = 0.007), and with the incidence of renal events, which were defined as new cases of microalbuminuria or progression to a more severe stage of nephropathy during follow-up (HR 1.82, 95% CI 1.13, 2.81, p = 0.01) in SURGENE participants. The same risk allele was associated with incipient nephropathy (OR 3.13, 95% CI 1.42, 7.24, p = 0.004) and with the incidence of end-stage renal disease (ESRD) (HR 2.11, 95% CI 1.23, 3.60, p = 0.008) in GENEDIAB participants. In both cohorts, the risk allele was associated with lower catalase activity. Associations with incipient and established or advanced nephropathy were confirmed in the replication cohort. CONCLUSIONS/INTERPRETATION: CAT variants were associated with the prevalence and incidence of diabetic nephropathy and ESRD in type 1 diabetic patients. Our results confirm the protective role of catalase against oxidative stress in the kidney. PMID- 24057138 TI - Clique size and network characteristics in hyperlink cinema. Constraints of evolved psychology. AB - Hyperlink cinema is an emergent film genre that seeks to push the boundaries of the medium in order to mirror contemporary life in the globalized community. Films in the genre thus create an interacting network across space and time in such a way as to suggest that people's lives can intersect on scales that would not have been possible without modern technologies of travel and communication. This allows us to test the hypothesis that new kinds of media might permit us to break through the natural cognitive constraints that limit the number and quality of social relationships we can manage in the conventional face-to-face world. We used network analysis to test this hypothesis with data from 12 hyperlink films, using 10 motion pictures from a more conventional film genre as a control. We found few differences between hyperlink cinema films and the control genre, and few differences between hyperlink cinema films and either the real world or classical drama (e.g., Shakespeare's plays). Conversation group size seems to be especially resilient to alteration. It seems that, despite many efficiency advantages, modern media are unable to circumvent the constraints imposed by our evolved psychology. PMID- 24057139 TI - Microbiological diagnosis of vertebral osteomyelitis: relevance of second percutaneous biopsy following initial negative biopsy and limited yield of post biopsy blood cultures. AB - The purpose of this investigation was to evaluate the microbiological diagnosis yield of post-biopsy blood cultures (PBBCs) and second percutaneous needle biopsy (PNB) following an initial negative biopsy in vertebral osteomyelitis (VO) without bacteremia. A retrospective multicenter study was performed. Patients with VO, pre-biopsy negative blood culture(s), >=1 PNB, and >=1 PBBC (0-4 h) were included. One hundred and sixty-nine PNBs (136 first and 33 following initial negative biopsy) were performed for 136 patients (median age = 58 years, sex ratio M/F = 1.9). First and second PNBs had a similar yield: 43.4 % (59/136) versus 39.4 % (13/33), respectively. Only two PBBCs (1.1 %) led to a microbiological diagnosis. The strategy with positive first PNB and second PNB following an initial negative result led to microbiological diagnosis in 79.6 % (74/93) of cases versus 44.1 % (60/136) for the strategy with only one biopsy. In the multivariate analysis, young age (odds ratio, OR [95 % confidence interval (CI)] = 0.98 [0.97; 0.99] per 1 year increase, p = 0.02) and >1 sample (OR = 2.4 ([1.3; 4.4], p = 0.007)) were independently associated with positive PNB. To optimize microbiological diagnosis in vertebral osteomyelitis, performing a second PNB (after an initial negative biopsy) could lead to a microbiological diagnosis in nearly 80 % of patients. PBBC appears to be limited in microbiological diagnosis. PMID- 24057140 TI - Population structure of methicillin-susceptible Staphylococcus aureus (MSSA) in Portugal over a 19-year period (1992-2011). AB - Despite their clinical relevance, few studies have addressed the epidemiology of methicillin-susceptible S. aureus (MSSA). In particular, it is not clear how MSSA population structure has evolved over time and how it might have been shaped by the emergence of MRSA in the community (CA-MRSA). In the present study we have evaluated the MSSA population structure over time, its geographical distribution and relatedness with MRSA in Portugal. A total of 465 MSSA from infection and colonization, collected over a 19-year period (1992-2011) in the northern, central and southern regions of Portugal were analyzed. Isolates were characterized by spa typing and multilocus-sequence typing (MLST). Isolates with predominant spa types were characterized by pulsed-field gel electrophoresis (PFGE). Isolates relatedness was analyzed by eBURST and BURP. The 172 spa types found among the 465 MSSA were grouped into 18 spa-CC (clonal complexes). Ten clonal types were more prevalent (40 %): one major clone (ST30-t012) was present in the entire study period and all over the country and the other nine were intermittently detected over time (ST5-t002, ST8-t008, ST15-t084, ST34-t166, ST72 t148, ST1-t127, ST7-t091, ST398-t571 and ST34-t136). Interestingly, three MSSA clonal types observed only after 1996 were closely related with CA-MRSA epidemic strains (ST8-t008, ST72-t148 and ST1-t127) found currently in Portugal. The MSSA population in Portugal is genetically diverse; however, some dominant clonal types have been established and widely disseminated for almost two decades. We identified MSSA isolates that were related with emergent CA-MRSA clones found in Portugal. PMID- 24057142 TI - Electrodeposited three-dimensional Ni-Si nanocable arrays as high performance anodes for lithium ion batteries. AB - A configuration of three-dimensional Ni-Si nanocable array anodes is proposed to overcome the severe volume change problem of Si during the charging-discharging process. In the fabrication process, a simple and low cost electrodeposition is employed to deposit Si instead of the common expansive vapor phase deposition methods. The optimum composite nanocable array electrode achieves a high specific capacity ~1900 mA h g(-1) at 0.05 C. After 100 cycles at 0.5 C, 88% of the initial capacity (~1300 mA h g(-1)) remains, suggesting its good capacity retention ability. The high performance of the composite nanocable electrode is attributed to its excellent adhesion of the active material on the three dimensional current collector and short ionic/electronic transport pathways during cycling. PMID- 24057141 TI - Ralstonia spp.: emerging global opportunistic pathogens. AB - The bacterial genus Ralstonia (Gram-negative non-fermenters) is becoming more prevalent in cases of infection with three bacterial species, Ralstonia pickettii, Ralstonia insidiosa and Ralstonia mannitolilytica, making up all cases reported (in the literature) to date. These organisms are prevalent in many different types of water supplies (including hospital water supplies), being well adapted to survive in low-nutrient conditions. They have been shown to cause infections, sometimes serious, such as osteomyelitis and meningitis, in hospital settings. Seventy cases of R. pickettii, 13 cases of R. mannitolilytica and three cases of R. insidiosa infection have been identified from the literature. Insight is given into the types of infections that are caused by these bacteria, the underlying conditions that are associated with these infections and potential treatments. PMID- 24057144 TI - Barriers to accessing biologic treatment for rheumatoid arthritis in Greece: the unseen impact of the fiscal crisis--the Health Outcomes Patient Environment (HOPE) study. AB - The latest regulatory change in the distribution system of biologic disease modifying, antirheumatic drugs limited their sale only through the designated pharmacies of the National Organization for Healthcare Services Provision (EOPYY) or the National Health System (NHS) hospitals, adding to the complexity of access to effective treatment for rheumatoid arthritis (RA) in Greece. The aim of this paper was to assess the barriers to access RA treatment, by recording patients', rheumatologists' and EOPYY pharmacists' experiences. One twenty-three patients, 12 rheumatologists and 27 pharmacists from Athens and other urban areas in Greece participated in the study. Three types of standardized questionnaires were used to elicit information from each group of respondents using the method of personal interview for patients and the method of postal survey for doctors and pharmacists. During the last year, 26% of patients encountered problems in accessing their rheumatologist and 49% of patients experienced difficulties in accessing their medication. Ninety-two percent of rheumatologists and 96% of pharmacists confirmed that patients experience difficulties in accessing RA medication. The most commonly reported reasons for reduced access to medical treatment were travel difficulties and long distance from doctor's clinic, as well as delays in booking an appointment. The most frequently reported barriers to access pharmaceutical treatment were difficulties in the prescription process, distance from EOPYY pharmacies and medicine shortages in NHS hospitals. The study showed that RA patients are facing increased barriers to access timely and effective treatment. Redesign of the current system of distribution ensuring the operation of additional points of sale is deemed necessary. PMID- 24057146 TI - Facile fabrication of Si mesoporous nanowires for high-capacity and long-life lithium storage. AB - Si has the second highest theoretical capacity among all the known anode materials for lithium ion batteries, whereas it is vulnerable to pulverization and crumbling upon lithiation/delithiation. Herein, Si mesoporous nanowires prepared by a scalable and cost-effective procedure are reported for the first time. Such nanowire morphology and mesoporous structure can effectively buffer the huge lithiation-induced volume expansion of Si, therefore contributing to excellent cycling stability and high-rate capability. Reversible capacities of 1826.8 and 737.4 mA h g(-1) can be obtained at 500 mA g(-1) and a very high current density of 10 A g(-1), respectively. After 1000 cycles at 2500 mA g(-1), this product still maintains a high capacity of 643.5 mA h g(-1). PMID- 24057145 TI - Pattern recognition in airflow recordings to assist in the sleep apnoea-hypopnoea syndrome diagnosis. AB - This paper aims at detecting sleep apnoea-hypopnoea syndrome (SAHS) from single channel airflow (AF) recordings. The study involves 148 subjects. Our proposal is based on estimating the apnoea-hypopnoea index (AHI) after global analysis of AF, including the investigation of respiratory rate variability (RRV). We exhaustively characterize both AF and RRV by extracting spectral, nonlinear, and statistical features. Then, the fast correlation-based filter is used to select those relevant and non-redundant. Multiple linear regression, multi-layer perceptron (MLP), and radial basis functions are fed with the features to estimate AHI. A conventional approach, based on scoring apnoeas and hypopnoeas, is also assessed for comparison purposes. An MLP model trained with AF and RRV selected features achieved the highest agreement with the true AHI (intra-class correlation coefficient = 0.849). It also showed the highest diagnostic ability, reaching 92.5 % sensitivity, 89.5 % specificity and 91.5 % accuracy. This suggests that AF and RRV can complement each other to estimate AHI and help in SAHS diagnosis. PMID- 24057147 TI - Valproic acid enhances fludarabine-induced apoptosis mediated by ROS and involving decreased AKT and ATM activation in B-cell-lymphoid neoplastic cells. AB - Histone deacetylase (HDAC) inhibitors have been shown synergize with a number of cytotoxic drugs in leukemic cells. In chronic lymphocytic leukemia (CLL), the first line therapy is based on the combination of fludarabine, a nucleoside analogue, and rituximab, an anti-CD20 monoclonal antibody, and there are presently no HDAC inhibitors are used to manage CLL. In the present study, we found that the addition of valproic acid (VPA), a HDAC inhibitor, increases cell death in B-cell-neoplasm-derived cell lines, BJAB, NALM-6 and I-83. This increased apoptosis caused release of mitochondrial cytochrome c, activation of caspases, and increased reactive oxygen species (ROS). The addition of a ROS scavenger inhibited cell death induced by the VPA-fludarabine combination. In contrast, blocking the death receptor pathway failed to inhibit VPA increased fludarabine induced apoptosis. Combination of VPA and fludarabine treatment decreased both total and phosphorylated levels of AKT, an important anti apoptotic protein, and ATM, a pivotal protein in DNA damage response. Chemical inhibition of AKT or ATM was sufficient to enhance fludarabine-induced apoptosis. We next examined patient samples from a local clinical trial where relapsed CLL patients were treated with VPA and examined the effects of VPA on AKT and ATM in vivo. After 30 days, there was a reduction in ATM levels in three out of the four patients treated, while AKT phosphorylation was reduced only in one patient. Taken together, VPA reduces ATM levels, thereby increasing ROS-dependent cell death via the mitochondrial apoptotic pathway when combined with fludarabine. PMID- 24057148 TI - Prednisolone improves walking in Japanese Duchenne muscular dystrophy patients. AB - We evaluated the long-term efficacy of prednisolone (PSL) therapy for prolonging ambulation in Japanese patients with genetically confirmed Duchenne muscular dystrophy (DMD). There were clinical trials have shown a short-term positive effect of high-dose and daily PSL on ambulation, whereas a few study showed a long-term effect. Especially in Japan, "real-life" observation was lacking. We utilized the national registry of muscular dystrophy in Japan for our retrospective study. We compared the age at loss of ambulation (LOA) between patients in PSL group and those in without-PSL group. Out of 791 patients' in the Remudy DMD/BMD registry from July 2009 to June 2012, 560 were matched with inclusion criteria. Of the 560, all were genetically confirmed DMD patients, 245 (43.8 %) of whom were treated with PSL and 315 (56.2 %) without PSL. There was no difference between the two groups regarding their mutational profile. The age at LOA was significantly greater (11 month on average) in the PSL group than in the without-PSL group (median, 132 vs. 121 months; p = 0.0002). Although strictly controlled clinical trials have shown that corticosteroid therapies achieved a marked improvement in ambulation, discontinuation of the drug due to intolerable side effects led to exclusion of clinical trial participants, which is considered as unavoidable. In our study, patients were not excluded from the PSL group, even if they discontinued the medication shortly after starting it. The results of our study may provide evidence to formulate recommendations and provide a basis for realistic expectations for PSL treatment of DMD patients in Japan, even there are certain limitations due to the retrospectively captured data in the registry. PMID- 24057149 TI - Intravenous amantadine on freezing of gait in Parkinson's disease: a randomized controlled trial. AB - To compare the effects of intravenous amantadine and placebo therapy on freezing of gait in patients with Parkinson's disease, this randomized, double-blind, placebo-controlled, multicenter trial compared the efficacy of 5 days intravenous amantadine and placebo treatments on freezing of gait in 42 subjects randomly allocated 2:1 to amantadine or placebo groups. Changes in freezing of gait questionnaire (FOG-Q) scores and in unified Parkinson's disease rating scale (UPDRS) scores, from baseline to immediately (V1) and 1 month (V2) after treatments, were assessed. Among the 42 patients (amantadine n = 29, placebo n = 13, a mean age 65.5 +/- 9.4 years and a mean FOG-Q score 17.4 +/- 3.2), 40 subjects completed treatment. There was no significant group difference on the primary outcome measure as total FOG-Q score changes at V1. However a significant beneficial effect of amantadine on freezing was seen at V2 in the UPDRS Part II freezing and FOG-Q item 3 scores, and there was significant improvement in the UPDRS Part IV total score and in the UPDRS Part II getting out of bed score in the amantadine group at both V1 and V2. There was no serious adverse event reported during the study. The intravenous amantadine therapy did not show a significant improvement on overall FOG-Q scores in patients with moderate-to severe freezing; however, it might be beneficial by attenuating freezing severity and improving patients' mobility. To prove this finding further studies with larger sample sizes are warranted in the future. PMID- 24057150 TI - Anti-GAD antibody ocular flutter: expanding the spectrum of autoimmune ocular motor disorders. PMID- 24057151 TI - Musical hallucinations after pontine ischemia: the auditory Charles Bonnet syndrome? PMID- 24057152 TI - Switching the H-bonding network of a foldamer by modulating the backbone chirality and constitutional ratio of amino acids. AB - This communication describes the folding propensity of a heterofoldamer motif featuring proline (Pro) and anthranilic acid (Ant) residues in a 1:2:1 (alpha:beta:alpha) constitutional ratio. Structural investigations unequivocally suggest that the hydrogen-bonding network of this foldamer motif can be switched between 9-membered and 6-membered by modulating the backbone chirality and constitutional ratio of the amino acid residues. PMID- 24057153 TI - Insulin degludec is not associated with a delayed or diminished response to hypoglycaemia compared with insulin glargine in type 1 diabetes: a double-blind randomised crossover study. AB - AIMS/HYPOTHESIS: Insulin degludec (Des(B30)LysB29(gamma-Glu Nepsilon hexadecandioyl) human insulin; IDeg) is a new basal insulin with an ultra-long flat action profile. The acute physiological responses to hypoglycaemia with IDeg and insulin glargine (A21Gly,B31Arg,B32Arg human insulin; IGlar) were compared. METHODS: Twenty-eight adult type 1 diabetic patients with normal hypoglycaemia awareness (age = 41 +/- 12 years, HbA1c = 7.8 +/- 0.6% [62.8 +/- 7 mmol/mol]) were randomised to once-daily IDeg or IGlar for 5 days in a two-period crossover design. Participants and research staff were blinded to group assignment. Patients were assigned the lowest available randomisation number from a set of blinded randomisation codes provided by the trial sponsor. Hypoglycaemia was induced by administering three times the usual daily insulin dose at midnight on day 5. Plasma glucose (PG) was stabilised by glucose clamp (5.5 mmol/l) for 7-9 h post dosing. Next morning, PG was allowed to decrease stepwise from 5.5 to 3.5 mmol/l (maintained for 30 min) to 2.5 mmol/l (for 15 min). PG was then increased to 3.9 mmol/l (for 120 min), before being returned to baseline. Hypoglycaemic symptom score (HSS), hypoglycaemic awareness, cognitive function, counter regulatory hormones and vital signs were assessed during each glucose plateau. The primary analysis was to compare IDeg vs IGlar with respect to HSS at nadir PG concentration (2.5 mmol/l). RESULTS: The full analysis set for treatment comparisons comprised data from all 28 exposed patients. Rates of PG decline and PG at nadir were similar for IDeg and IGlar. No treatment differences in HSS (estimated difference: 0.17 [95% CI -1.71, 2.05]; p > 0.05), cognitive function or awareness were observed at any time. Growth hormone and cortisol responses during hypoglycaemia were greater with IDeg than IGlar (AUC treatment ratio [IDeg/IGlar]: 2.44 [1.30, 4.60], p < 0.01; and 1.23 [1.01, 1.50]; p < 0.05), and adrenaline (epinephrine) responses trended higher (1.40 [0.96, 2.04], p = 0.07). The rates of recovery from hypoglycaemia were similar. CONCLUSIONS/INTERPRETATION: IDeg and IGlar elicit comparable symptomatic and cognitive responses to induced hypoglycaemia. IDeg may elicit a moderately greater endocrine response, but times to PG recovery were similar for the two insulins. TRIAL REGISTRATION: ClinicalTrials.gov NCT01002768. FUNDING: Novo Nordisk. PMID- 24057154 TI - Prediction of type 2 diabetes in women with a history of gestational diabetes using a genetic risk score. AB - AIMS/HYPOTHESIS: Women with a history of gestational diabetes mellitus (GDM) are at increased risk of future development of type 2 diabetes. Recently, over 65 genetic variants have been confirmed to be associated with diabetes. We investigated whether this genetic information could improve the prediction of future diabetes in women with GDM. METHODS: This was a prospective cohort study consisting of 395 women with GDM who were followed annually with an OGTT. A weighted genetic risk score (wGRS), consisting of 48 variants, was assessed for improving discrimination (C statistic) and risk reclassification (continuous net reclassification improvement [NRI] index) when added to clinical risk factors. RESULTS: Among the 395 women with GDM, 116 (29.4%) developed diabetes during a median follow-up period of 45 months. Women with GDM who went on to develop diabetes had a significantly higher wGRS than those who did not (9.36 +/- 0.92 vs 8.78 +/- 1.07; p < 1.56 * 10(-7)). In a complex clinical model adjusted for age, prepregnancy BMI, family history of diabetes, blood pressure, fasting glucose and fasting insulin concentration, the C statistic marginally improved from 0.741 without the wGRS to 0.775 with the wGRS (p = 0.015). The addition of the wGRS to the clinical model resulted in a modest improvement in reclassification (continuous NRI 0.430 [95% CI 0.218, 0.642]; p = 7.0 * 10(-5)). CONCLUSIONS/INTERPRETATION: In women with GDM, who are at high risk of diabetes, the wGRS was significantly associated with the future development of diabetes. Furthermore, it improved prediction over clinical risk factors. PMID- 24057156 TI - Erythemal ultraviolet solar radiation doses received by young skiers. AB - Children are a special group since epidemiological evidence indicates that excessive exposure to sunlight at an early age increases the risk of skin cancer in later life. The purpose of this study is to quantify children's UV exposure when skiing, using dosimeters (VioSpor) placed on the shoulders of 10 participants. The children received a median daily Standard Erythema Dose of 2.1 within a range of 4.9-0.71, this being approximately 35% of the calculated 24 h ambient UV radiation on the horizontal plane. According to the results obtained, young skiers are exposed to UV radiation that can potentially cause skin damage and erythema and increase the risk of skin cancer in the course of a lifetime. These findings emphasise the need for adequate protective measures against solar radiation when skiing. The results also suggest that sun-protection campaigns should be undertaken aimed at children engaged in outdoor sports, including winter activities. PMID- 24057155 TI - Case report: the use of annexin V coupled with magnetic activated cell sorting in cryopreserved spermatozoa from a male cancer survivor: healthy twin newborns after two previous ICSI failures. AB - PURPOSE: The aim of the study is to report successful outcome (live births) after sperm sorting with annexin V-MACS on cryopreserved spermatozoa with high level of sperm DNA fragmentation from a cancer patient survivor. METHODS: Cryopreserved spermatozoa were sorted with annexin V-MACS prior to ICSI. Sperm DNA fragmentation was evaluated by SCSA((r)) and TUNEL. RESULTS: The couple had two previous IVF/ICSI cycles failures using sperm cryopreserved before cancer treatment. On third ICSI cycle attempt results were as follow: pre-annexin V-MACS sperm quality: 10 * 10(6)/ml, 3.3 % progressive motility, 1 % normal forms, TUNEL: 72.5 % positive cells, SCSA((r)): 76.6 % DFI. Post-annexin V-MACS sperm quality: 2.8 * 10(6)/ml, 10 % progressive motility, TUNEL: 58.8 % positive cells. Eight metaphase II oocytes were collected, 4 fertilized, 2 embryos were transferred on day 3 and healthy twins were born (1 boy, 1 girl). CONCLUSIONS: Annexin V-MACS technique could be a potential tool to improve sperm quality on cryopreserved spermatozoa of cancer patient and improve ICSI outcome. PMID- 24057157 TI - Motility flow and growth-cone navigation analysis during in vitro neuronal development by long-term bright-field imaging. AB - A long-term live-imaging workstation to follow the development of cultured neurons during the first few days in vitro (DIV) is developed. In order to monitor neuronal polarization and axonal growth by live imaging, we built a micro incubator system that provides stable temperature, pH, and osmolarity in the culture dish under the microscope, while preserving environment sterility. We are able to image living neurons at 2 DIVs for 48 h with a temporal resolution of one frame for every 2 min. The main features of this system are its ability to adapt to every cell-culture support, to integrate in any optical microscope, because of the relatively small dimensions (9.5*6.5*2.5 cm) and low weight of the system (<200 g), and to monitor the physiological parameters in situ. Moreover, we developed an image-analysis algorithm to quantify the cell motility, in order to characterize its complex temporal-spatial pattern. The algorithm applies morphological image processing operations on the temporal variations occurring in the inspected region of interest. Here, it is used to automatically detect cellular motility in three distinct morphological regions of the neurons: around the soma, along the neurites, and in the growth cone. PMID- 24057158 TI - Neuroimaging studies in insomnia. AB - Chronic insomnia is one of the most prevalent psychiatric disorders and has a significant impact on individual's health. However, the pathophysiology of the disorder is poorly understood. The current review focuses on neuroimaging findings in insomnia. In summary, the current data suggest the following: (1) insomnia is characterized by corticolimbic overactivity during sleep and wakefulness that interferes with sleep initiation and/or maintenance; (2) insomnia patients' daytime performance is associated with a hypoactivation of task-related areas; (3) neurochemically, insomnia patients are probably characterized by reduced cortical GABA levels; (4) insomnia may be associated with abnormal brain morphometry in the frontal cortex, hippocampus and/or anterior cingulate cortex. Future investigations should include larger sample sizes or longitudinal within-subject comparisons. Other possible methodological improvements are discussed. PMID- 24057159 TI - Novel "thrifty" models of increased eating behaviour. AB - The thrifty genotype and phenotype hypotheses were developed to explain the rapid increase in diabetes and obesity in developed countries around the world. Most subsequent "thrifty" research has focused on the early developmental origins of the metabolic syndrome and cardio-metabolic disease. The goal of this manuscript is to review an emerging line of research that uses a similar thrifty framework to understand the early developmental origins of eating-related phenotypes that have primary relevance to many psychiatric disorders. Given the important role of environmental adversity in various psychiatric disorders that involve overeating, and their early age of onset, it is likely that several thrifty mechanisms are relevant in this regard. Understanding the early origins of increased eating behaviour based on a thrifty model might point the way to highly targeted preventative interventions during critical periods of development, and provide a new way of addressing these common and difficult to treat disorders. PMID- 24057160 TI - Defining psychosis: the evolution of DSM-5 schizophrenia spectrum disorders. AB - Descriptions of mental illness exist throughout recorded history. However, until the mid-twentieth century, there was no standard nosology or diagnostic standard for mental disorders. This limited understanding of these disorders and development of better treatments. As conditions such as dementia praecox and schizophrenia were being described, collaborative efforts were made in the twentieth century to develop the first Diagnostic and Statistical Manual of Mental Disorders (DSM). This review provides an overview of the history of psychiatric diagnosis with a focus on the history of schizophrenia as a diagnosis in the DSM. DSM-5 updates to diagnostic criteria for schizophrenia and related disorders are provided. Limitations to diagnostic validity and reliability are discussed in addition to changes in diagnostic approaches to schizophrenia spectrum and other psychotic disorders in an effort to improve diagnostic validity and reliability. The DSM-5 reflects the culmination of an ongoing collaborative effort to improve the diagnosis of mental disorders, and future research in Research Domain Criteria (RDoC) will help provide convergent validity when understanding and treating mental illnesses. PMID- 24057161 TI - Hemophagocytosis as the initial presentation in a patient with myelodysplastic syndrome and coexisting NK/T cell lymphoma involving bone marrow. PMID- 24057162 TI - Evaluating the efficacy and safety of apixaban, a new oral anticoagulant, using Bayesian meta-analysis. AB - Apixaban is a direct inhibitor of factor Xa, and is a potential alternative for the treatment of acute venous thromboembolism. This study sought to evaluate the efficacy and safety of apixaban versus enoxaparin. A systematic search of the literature for randomized controlled trials of apixaban thromboprophylaxis versus enoxaparin was conducted using three databases: PubMed, EMBASE, and the Cochrane library. Five studies that included a total of 12,938 patients were analyzed using Bayesian random-effects meta-analysis. To evaluate efficacy, a composite of venous thromboembolism and death during follow-up was measured. To evaluate safety, major and total bleeding events were considered. The odds ratio (OR) for the composite outcome of efficacy was 0.66 (95 % CI 0.33-1.29) for apixaban compared to enoxaparin, while there was a similar risk of major bleeding (OR 1.03, 95 % CI 0.36-3.73) and total bleeding (OR 0.92, 95 % CI 0.64-1.20). These results suggest a lack of clear superiority of apixaban relative to enoxaparin. Apixaban is an oral alternative with similar efficacy and safety to existing anticoagulant therapies. PMID- 24057164 TI - Efficient one-pot synthesis of novel and diverse tetrahydroquinolines bearing pyranopyrazoles using organocatalyzed domino Knoevenagel/hetero Diels-Alder reactions. AB - A new synthetic route to biologically interesting diverse tetrahydroquinolines bearing pyranopyrazoles was developed by reacting pyrazolones and N, N dialkylated aminobenzaldehydes in the presence of EDDA. The key strategy underlying the methodology used was the domino Knoevenagel/hetero Diels-Alder reaction. This synthetic method provides a variety of novel tetrahydroquinolines in good yields. PMID- 24057163 TI - High-sensitivity Lens culinaris agglutinin-reactive alpha-fetoprotein assay predicts early detection of hepatocellular carcinoma. AB - BACKGROUND: Prognosis of patients with hepatocellular carcinoma (HCC) remains poor because HCC is frequently diagnosed late. Therefore, regular surveillance has been recommended to detect HCC at the early stage when curative treatments can be applied. HCC biomarkers, including Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3), are widely used for surveillance in Japan. A newly developed immunoassay system measures AFP-L3 % with high sensitivity. This retrospective study aimed to evaluate clinical utility of high sensitivity AFP-L3 (hs-AFP-L3) as a predictor of early stage HCC in surveillance at a single site. METHODS: Of consecutive 2830 patients in the surveillance between 2000 and 2009, 104 HCC-developed and 104 non-HCC patients were selected by eligibility criteria and propensity score matching. Samples were obtained from the HCC patients who had blood drawn annually for 3 years prior to HCC diagnosis. RESULTS: In the present study, hs-AFP-L3 was elevated 1 year prior to diagnosis in 34.3 % of patients. The survival rate of patients with the hs-AFP-L3 >= 7 % at 1 year prior to diagnosis was significantly lower than that of patients with hs AFP-L3 < 7 %. CONCLUSIONS: Elevation of hs-AFP-L3 was early predictive of development of HCC even at low AFP levels and in absence of ultrasound findings of suspicious HCC. The hs-AFP-L3 should be added to surveillance programs with US because elevated hs-AFP-L3 may be a trigger to perform enhanced imaging modalities for confirmation of HCC. PMID- 24057165 TI - Biotransformation of methylphenylacetonitriles by Brazilian marine fungal strain Aspergillus sydowii CBMAI 934: eco-friendly reactions. AB - This study reports the biotransformation of methylphenylacetonitriles by Brazilian marine filamentous fungus Aspergillus sydowii CBMAI 934 under eco friendly reaction conditions. The phenylacetonitrile 1, 2 methylphenylacetonitrile 2, 3-methylphenylacetonitrile 3, and 4 methylphenylacetonitrile 4 were quantitatively biotransformed into 2 hydroxyphenylacetic 1a, 2-methylphenylacetic acid 2a, 3-methylphenylacetic acid 3a, and 4-methylphenylacetic acid 4a by enzymatic processes using whole cell as biocatalyst. The marine fungus A. sydowii CBMAI 934 is thus a promising biocatalyst for the preparation of important carboxylic acids under mild conditions (pH 7.5 and 32 degrees C) from nitrile compounds. PMID- 24057167 TI - Skin can control solar UVR-induced mutations through the epidermis-specific response of mutation induction suppression. AB - Skin exposure to solar ultraviolet radiation (UVR) has been a major public concern because of its genotoxicity. We established recently three action spectra of UVR biological effects using inflammation, mutagenicity, and mutation induction suppression (MIS) as indicators to evaluate UVR risk for mammalian skin. MIS is an antigenotoxic epidermis-specific response by which the increase of the mutant frequency (MF) levels off above a certain UVR dose. Here, based on these spectra, the mutation load of the skin after sunlight exposure was evaluated utilizing the spectral solar-UVR intensity data which had been measured at Tsukuba, Japan by the Japan Meteorological Agency. We estimated the daily variation of the solar-UVR effectiveness (effect per second) for the three indicators, and revealed that the effectiveness efficiency (effect per dose) of midday sunlight is 3-4-fold higher than those in the early morning and late afternoon. Based on the daily variations of mutagenicity and MIS effectiveness, we further estimated MFs induced after every one-hour sunlight exposure and reached a remarkable prediction that MFs should be suppressed to a constant level during 9:00-15:00 by MIS. The estimates agreed well with the equivalent values directly determined at Sendai, a site close to Tsukuba, although a small difference was detected for the epidermis at the dose range where the suppressed MFs were predicted. We propose the use of observed minimum inflammation/erythema doses to improve the difference. Our method could provide reliable estimates of sunlight genotoxicity to evaluate skin cancer probabilities. PMID- 24057166 TI - Comparison of protein expression profiles of the hepatopancreas in Fenneropenaeus chinensis challenged with heat-inactivated Vibrio anguillarum and white spot syndrome virus. AB - Fenneropenaeus chinensis (Chinese shrimp) culture industry, like other Penaeidae culture, has been seriously affected by the shrimp diseases caused by bacteria and virus. To better understand the mechanism of immune response of shrimp to different pathogens, proteome research approach was utilized in this study. Firstly, the soluble hepatopancreas protein samples in adult Chinese shrimp among control, heat-inactivated Vibrio-challenged and white spot syndrome virus infected groups were separated by 2-DE (pH range, 4-7; sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and pH range, 3-10; tricine-SDS PAGE). Then the differentially expressed protein spots (>=1.5-fold or <=0.67-fold averagely of controls) were analyzed by LC-ESI-MS/MS. Using Mascot online database searching algorithm and SEQUEST searching program, 48 and 49 differentially expressed protein spots were successfully identified in response to Vibrio and white spot syndrome virus infection, respectively. Based on these results, we discussed the mechanism of immune response of the shrimp and shed light on the differences between immune response of shrimp toward Vibrio and white spot syndrome virus. This study also set a basis for further analyses of some key genes in immune response of Chinese shrimp. PMID- 24057168 TI - Quadruply hydrogen-bonded heteroduplexes based on imide and urea units arrayed with ADDA/DAAD sequences. AB - A new class of imide- and urea-based hetero-strands with a quadruple ADDA/DAAD hydrogen-bond array was designed and synthesized from easily accessible starting materials. The molecular recognition between the two different strands depends highly on the substituents and the linker between neighboring hydrogen-bonds, which results in the stability of these heteroduplexes varying from 10(3) to >10(5) M(-1) in apolar solvents. In particular, an increase of the association constant by up to one order of magnitude was observed by derivatizing the ADDA arrays at the termini with electron-withdrawing groups. Molecular modelling of the representative complementary complexes reveals the binding mode of four hydrogen-bond arrays that agrees with the matched pair. PMID- 24057170 TI - Biodegradation of shrimp biowaste by marine Exiguobacterium sp. CFR26M and concomitant production of extracellular protease and antioxidant materials: production and process optimization by response surface methodology. AB - Twelve marine bacterial cultures were screened for extracellular protease activity, and the bacterium CFR26M which exhibited the highest activity on caseinate agar plate was identified as an Exiguobacterium sp. Significant amount of extracellular protease (5.9 +/- 0.3 U/ml) and antioxidant materials, measured as 2,2'-diphenyl picrylhydrazyl (DPPH) radical scavenging activity (44.4 +/- 0.5 %), was produced by CFR26M in submerged fermentation using a shrimp biowaste medium. Response surface methodology (RSM) was employed to optimize the process variables for maximum production of protease and antioxidant materials by CFR26M. Among the seven variables screened by two-level 2**(7-2) fractional factorial design, the concentration of shrimp biowaste, sugar, and phosphate was found to be significant (p <= 0.05). The optimum levels of these variables were determined by employing the central composite design (CCD) of RSM. The coefficient of determination (R (2)) values of 0.9039 and 0.8924 for protease and antioxidant, respectively, indicates the accuracy of the CCD models. The optimum levels of shrimp biowaste, sugar, and phosphate were 21.2, 10.5, and 2.3 % (w/v) for production of protease and 28.8, 12, and 0.32 % (w/v) for production of antioxidant material, respectively. The concentration of shrimp biowaste, sugar, and phosphate had linear and quadratic effect on both protease and antioxidant productions. RSM optimization yielded 6.3-fold increases in protease activity and 1.6-fold in antioxidant material production. The crude protease of CFR26M had a maximum activity at 32 +/- 2 degrees C with pH 7.6. This is the first report on the use of marine Exiguobacterium sp. for concomitant production of protease and antioxidant materials from shrimp biowaste. PMID- 24057171 TI - Novel proteins identified in the insoluble byssal matrix of the freshwater zebra mussel. AB - The freshwater zebra mussel, Dreissena polymorpha, is an invasive, biofouling species that adheres to a variety of substrates underwater, using a proteinaceous anchor called the byssus. The byssus consists of a number of threads with adhesive plaques at the tips. It contains the unusual amino acid 3, 4 dihydroxyphenylalanine (DOPA), which is believed to play an important role in adhesion, in addition to providing structural integrity to the byssus through cross-linking. Extensive DOPA cross-linking, however, renders the zebra mussel byssus highly resistant to protein extraction, and therefore limits byssal protein identification. We report here on the identification of seven novel byssal proteins in the insoluble byssal matrix following protein extraction from induced, freshly secreted byssal threads with minimal cross-linking. These proteins were identified by LC-MS/MS analysis of tryptic digests of the matrix proteins by spectrum matching against a zebra mussel cDNA library of genes unique to the mussel foot, the organ that secretes the byssus. All seven proteins were present in both the plaque and thread. Comparisons of the protein sequences revealed common features of zebra mussel byssal proteins, and several recurring sequence motifs. Although their sequences are unique, many of the proteins display similarities to marine mussel byssal proteins, as well as to adhesive and structural proteins from other species. The large expansion of the byssal proteome reported here represents an important step towards understanding zebra mussel adhesion. PMID- 24057173 TI - Photophysical behavior of new acridine(1,8)dione dyes. AB - The photophysical behavior of five acridine(1,8)dione dyes of biological interest was studied by absorption and fluorescence spectroscopy, photoacoustics and time resolved phosphorescence techniques. The results obtained in ethanol and acetonitrile solutions show that the main spectroscopic and photophysical parameters of these compounds depend strongly on both the solvent and oxygen concentrations. Oxygen completely quenched the triplet state of all dyes. In nitrogen-saturated solutions, quantum efficiencies of triplet formation in ethanol were lower than those in acetonitrile. PMID- 24057172 TI - Modulation of lipid metabolism by deep-sea water in cultured human liver (HepG2) cells. AB - It has been found that deep-sea water was associated with lower serum lipid in animal model studies. Herein, we investigated whether DSW exerted a hypolipidemic activity and further elucidated how DSW modulated lipid metabolism in HepG2 cells. Preliminary animal studies showed that DSW exhibited potency to decrease serum total cholesterol, triglycerides, and LDL cholesterol, and increase HDL cholesterol, and the hepatic lipid contents were also significantly lower in the DSW group. When DSW was added to HepG2 cells, it decreased the lipid contents of hepatocyte through the activation of AMP-activated protein kinase, thus inhibiting the synthesis of cholesterol and fatty acid. Besides, LDL receptor was upregulated by activation of sterol regulatory element-binding protein-2. In addition, the levels of apolipoprotein AI and cholesterol 7-alpha-hydroxylase were also raised. Our investigation provided mechanisms by which DSW modulated lipid metabolism and indicated that DSW was worthy of further investigation and could be developed as functional drinking water in the prevention and treatment of hypolipidemic and other lifestyle-related diseases. PMID- 24057174 TI - Overestimation of subfoveal choroidal thickness by measurement based on horizontally compressed optical coherence tomography images. PMID- 24057175 TI - Evaluation of crowded optic nerve head and small scleral canal in intrapapillary hemorrhage with adjacent peripapillary subretinal hemorrhage. AB - BACKGROUND: Intrapapillary hemorrhage with adjacent peripapillary subretinal hemorrhage (IHAPSH) is a clinical syndrome most commonly affecting myopic eyes with tilted discs that usually resolves spontaneously without treatment. Subretinal hemorrhage usually occurs peripapillary on the nasally adjacent side near the optic disc. The etiology of this condition is still unknown. The purpose of this study was to determine if a crowded optic nerve head and small scleral canal are involved in the pathogenetic mechanisms of IHAPSH. METHODS: Twelve subjects with IHAPSH diagnosed at the Affiliated Ophthalmology Hospital of the First Clinical College of Harbin Medical University and 24 control subjects were examined. The size of the inner aspect of the scleral canal and level of nerve fiber crowding of the optic nerve head were analyzed with optic nerve head analysis software packet of the Stratus Optical Coherence Tomography software and manual segmentation software. The Mann-Whitney U test and multiple comparisons (with the Bonferroni correction method) were performed. p values less than 0.002 (two-sided) were considered statistically significant. The area, perimeter, and the perimeter/area ratio of the optic disc, vertical and horizontal diameter of the inner aspect of the scleral canal, vertical integrated rim area (VIRA), and the rim area were calculated. RESULTS: The area and perimeter of the optic disc and the horizontal diameter of the inner aspect of the scleral canal were significantly lower in the affected and contralateral eyes of the subjects with IHAPSH than in the eyes of the controls. Conversely, the IHAPSH-affected and contralateral eyes had significantly higher perimeter/area ratio of the optic disc, VIRA, and rim area values than the control eyes. The VIRA and rim area were greater in the IHAPSH-affected eyes than in the contralateral eyes. CONCLUSIONS: Patients with IHAPSH have smaller optic discs and scleral canals than control subjects, with a higher level of nerve fiber crowding. PMID- 24057176 TI - Comparison of LogMAR Eye charts with angular vision for visually impaired: the Berkeley rudimentary vision test vs LogMAR One target Landolt ring Eye chart. AB - BACKGROUND: It is not common to quantify visual acuity worse than 2.0 logarithm of the minimal angle resolution (logMAR) (commensurate with decimal visual acuity 0.01) at ophthalmology clinics. Recently, the Berkeley rudimentary vision test (BRVT) was developed as a simple measurement tool of logMAR with angular vision for quantifying poor levels of visual acuity. We compared the difference between BRVT and conventional Landolt ring logMAR chart with angular vision measured by the logMAR one target Landolt ring eye chart (LogMAR LEC). METHODS: We reviewed 110 patients with best-corrected visual acuity (BCVA) in the better eye from light perception (LP) to 0.8 logMAR measured by LogMAR LEC. The reproducibility of the log MAR LEC and BRVT was evaluated on 39 eyes from 20 patients, and 33 eyes from 20 patients respectively. The comparison of logMAR between BRVT and logMAR LEC was evaluated by surveying 61 eyes from 70 patients. In addition, regardless of their BCVA, the eyes from patients with worse than 2.0 logMAR by LogMAR LEC were re-evaluated by BRVT. RESULTS: The logMAR of patients examined by BRVT or logMAR LEC did not show any significant difference between the first and second examinations, and there was a strong correlation between the examinations in both eye charts. The BRVT significantly produced better logMAR compared with logMAR LEC, and the strong correlation was shown between both eye charts. Although 35 eyes from 28 patients among 110 patients could not be quantified by logMAR LEC, 18 eyes of 35 eyes could be quantified logMAR by BRVT. CONCLUSIONS: The BRVT and logMAR LEC are reliable visual acuity measurement tools. Moreover, the BRVT is potentially effective in quantifying visual acuity of the more severe visually impaired patients. PMID- 24057177 TI - Elevated blood Hsp60, its structural similarities and cross-reactivity with thyroid molecules, and its presence on the plasma membrane of oncocytes point to the chaperonin as an immunopathogenic factor in Hashimoto's thyroiditis. AB - The role Hsp60 might play in various inflammatory and autoimmune diseases is under investigation, but little information exists pertaining to Hashimoto's thyroiditis (HT). With the aim to fill this gap, in the present work, we directed our attention to Hsp60 participation in HT pathogenesis. We found Hsp60 levels increased in the blood of HT patients compared to controls. The chaperonin was immunolocalized in thyroid tissue specimens from patients with HT, both in thyrocytes and oncocytes (Hurthle cells) with higher levels compared to controls (goiter). In oncocytes, we found Hsp60 not only in the cytoplasm but also on the plasma membrane, as shown by double immunofluorescence performed on fine needle aspiration cytology. By bioinformatics, we found regions in the Hsp60 molecule with remarkable structural similarity with the thyroglobulin (TG) and thyroid peroxidase (TPO) molecules, which supports the notion that autoantibodies against TG and TPO are likely to recognize Hsp60 on the plasma membrane of oncocytes. This was also supported by data obtained by ELISA, showing that anti-TG and anti TPO antibodies cross-react with human recombinant Hsp60. Antibody-antigen (Hsp60) reaction on the cell surface could very well mediate thyroid cell damage and destruction, perpetuating inflammation. Experiments with recombinant Hsp60 did not show stimulation of cytokine production by peripheral blood mononuclear cells from HT patients. All together, these results led us to hypothesize that Hsp60 may be an active player in HT pathogenesis via an antibody-mediated immune mechanism. PMID- 24057178 TI - Associations between endothelial nitric oxide synthase A/B, angiotensin converting enzyme I/D and serotonin transporter L/S gene polymorphisms with pulmonary hypertension in COPD patients. AB - Different biochemical pathways and cellular mechanisms play role in the pathogenesis of pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD). Alveolar hypoxia is not the only determinant of vascular remodeling, genetic factors are thought to have additive effects. We aimed to investigate the effects of endothelial nitric oxide synthase (eNOS A/B), angiotensin converting enzyme (ACE I/D) and serotonin transporter (5-HTT L/S) gene polymorphisms on development and severity of PH in COPD patients. 50 COPD patients without PH (group 1); 30 COPD patients with PH confirmed with echocardiography (group 2) and 49 healthy subjects (group 3) as control group were included to the study. eNOS A/B, ACE I/D and 5-HTT L/S gene polymorphisms and allele frequencies of COPD patients with and without PH and healthy subjects were determined. Functional parameters and echocardiographic measurements were recorded. Patients with PH were also assessed in two subgroups according to the severity of pulmonary arterial pressure (PAP). Significant differences among three groups in the distribution of 5-HTT genotype and allele frequency were present (respectively p = 0.002; p = 0.021). In group 2, LL and LS genotype rate was 93.3 % with a frequency of 71.2 % L allele and 28.3 % of S allele. 5-HTT LL genotype was present in 88.9 % of patients with PAP >=50 mmHg significantly (p = 0.012). Other genotype distributions were not significantly different between two subgroups. The results of this study can suggest that COPD patients with L allele of 5-HTT may have higher risk for the development of PH and patients with LL genotype of 5-HTT may present higher PAP. We also demonstrated that eNOS and ACE gene polymorphisms were not associated with the development and severity of PH in our study population. Further studies with larger numbers of patients are needed to explore these relationships. PMID- 24057179 TI - The genetic contribution of CIDEA polymorphisms, haplotypes and loci interaction to obesity in a Han Chinese population. AB - To investigate the association of tag-SNPs and haplotype structures of the CIDEA gene with obesity in a Han Chinese population. Five single nucleotide polymorphisms (SNPs) (rs1154588/V115F, rs4796955/SNP1, rs8092502/SNP2, rs12962340/SNP3 and rs7230480/SNP4) in the CIDEA gene were genotyped in a case control study. Genotyping was performed using the sequenom matrix-assisted laser desorption/ionization time-of-flight mass spectrometry iPLEX platform. There were significant differences between the obese and control groups in genotype distributions of V115F (P < 0.001), SNP1 (P = 0.006) and SNP2 (P = 0.005). Carriers of V115F-TT, SNP1-GG and SNP2-CC genotypes had a 2.84-fold (95 % CI 1.73 4.66), 2.19-fold (95 % CI 1.09-4.38) and 4.37-fold (95 % CI 1.21-15.08) increased risk for obesity, respectively. Haplotype analysis showed that GTTC (SNP1/SNP2/V115F/SNP4) had 1.41-fold (95 % CI 1.02-1.95) increased risk for obesity; whereas, haplotype TTGC had 0.48-fold (95 % CI 0.24-0.96) decreased risk for obesity. Using the multifactor dimensionality reduction method, the best model including SNP1, SNP2, V115F and SNP4 polymorphisms was identified with a maximum testing accuracy to 59.32 % and a perfect cross-validation consistency of 10/10 (P = 0.011). Logistic analysis indicated that there was a significant interaction between SNP1 and V115F associated with obesity. Subjects having both genotypes of SNP1/GG and V115F/TT were more susceptible to obesity in the Han Chinese population (OR 2.66, 95 %: 1.22-5.80). Genotypes of V115F/TT, SNP1/GG and SNP2/CC and haplotype GTTC of CIDEA gene were identified as risk factors for obesity in the Han Chinese population. The interaction between SNP1 and V115F could play a joint role in the development of obesity. PMID- 24057180 TI - Vascular endothelial growth factor (VEGF) gene polymorphisms and risk of head and neck cancer: a meta-analysis involving 2,444 individuals. AB - The association between vascular endothelial growth factor (VEGF) gene polymorphisms and risk of head and neck cancer (HNC) were investigated in many published studies; however, the currently available results are inconclusive. Therefore, we conducted this meta-analysis for deriving a more precise estimation of association between VEGF polymorphisms and the risk of HNC. Finally, we yield eight case-control studies involving six polymorphisms contain 2,444 individuals from PubMed, Embase, and CNKI up to January 30, 2013 (last updated on May 4, 2013). The results of meta-analysis showed that all the six polymorphisms of VEGF were not associated with risk of HNC [OR 1.25, 95 % CI (0.60-1.58) for TT vs. CC for 936 C/T; OR 1.41, 95 % CI (0.79-2.52) for GG vs. AA for -1,154 A/G; OR 0.97, 95 % CI (0.38-2.50) for CC vs. GG for 405 G/C; OR 1.44, 95 % CI (0.80-2.61) for AA vs. CC for 2,578 C/A; OR 1.27, 95 % CI (0.77-3.72) for TT vs. CC for -460 C/T; and OR 0.87, 95 % CI (0.37-2.06) for GG vs. CC for -634 G/C]. When performed subgroup analysis according to ethnicity for VEGF 936 C/T, the results suggested that it was not associated with the risk of HNC for either Asians [OR 0.84, 95 % CI (0.27-2.56) for TT vs. CC] or Caucasians [OR 2.10, 95 % CI (0.82-5.37) for TT vs. CC]. However, due to the limitations of this meta-analysis, more well designed, larger sample size, and adjusted risk factors studies are suggested to further assess the findings. PMID- 24057181 TI - Analyze association of the progesterone receptor gene polymorphism PROGINS with ovarian cancer risk. AB - Results conflict on the association between progesterone receptor gene (PRG) polymorphism PROGINS and ovarian cancer risk, despite wide-ranging investigations. We therefore performed a meta-analysis of 4,285 ovarian cancer cases and 6,257 controls from 11 published case-control studies. The strength of association between PROGINS polymorphism and ovarian cancer susceptibility was assessed using pooled odds ratios (ORs) with corresponding 95 % confidence intervals (CIs). The results suggest no significant associations exist between PROGINS polymorphisms and ovarian cancer risk in overall comparisons in all genetic models (T2T2 vs. T1T1: OR = 1.37, 95 % CI = 0.89-2.12, P = 0.15; T1T2 vs. T1T1:OR = 1.09, 95 % CI = 0.88-1.35, P = 0.41; T1T2 + T2T2 vs. T1T1:OR = 1.15, 95 % CI = 0.94-1.40, P = 0.17; T2T2 vs. T1 T1 + T1T2:OR = 1.34, 95 % CI = 0.87-2.07, P = 0.18). In conclusion, the results of this meta-analysis indicate that the PRG polymorphism PROGINS is not associated with ovarian cancer risk when multiple ethnic groups or regions were considered overall. PMID- 24057182 TI - Targeting Wnt-Frizzled signaling in cardiovascular diseases. AB - Wnts are secreted glycoproteins implicated in biological processes ranging from embryonic cardiac development to uncontrolled cell proliferation in diseased conditions. Cardiovascular disease is a major cause of morbidity and mortality worldwide. Phenotypic modulation of vascular smooth muscle cells, migration and proliferation in intimal layer and increased extracellular matrix production are some of the known hallmarks of cardiovascular pathologies. Heterogeneity associated with the binding of Wnts to their transmembrane receptors, Frizzled, and coreceptors low density lipoprotein-receptor-related protein is indeed intriguing. Nuclear-cytoplasmic shuttling of beta-catenin and activation of transcriptional factors, lymphoid enhancer factor and T cell activation factor leading to target gene activation has remained elusive. Our review highlights the emerging role of Wnt-Frizzled signaling in cardiovascular diseases. Overall, the pathway appears to be an attractive therapeutic target in identifying susceptible individuals at risk of developing restenosis/other vascular pathologies in the near future. PMID- 24057183 TI - Role of vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D level in Egyptian female patients with systemic lupus erythematosus. AB - Recently, several studies have demonstrated the role of vitamin D receptor (VDR) polymorphisms in the development of systemic lupus erythematosus (SLE). We aimed to evaluate VDR (ApaI, BsmI, and FokI) gene polymorphisms and haplotypes as a risk factors and/or activity markers for SLE, and whether they influence 25 hydroxyvitamin (25(OH) D) level. One hundred and seven SLE patients and 129 controls were enrolled in this study. Disease activity in SLE patients was assessed using Disease Activity Index. Polymorphisms of VDR gene were detected using polymerase chain reaction restriction fragment length polymorphism. Serum 25(OH) D levels were measured using ELISA. We found that ApaI AA genotype, BsmI B allele, Bb, BB genotypes, FokI F allele and FF genotype frequencies of VDR were increased in SLE group. There were significant associations of VDR ApaI AA, BsmI BB, and FokI FF genotypes with lupus nephritis and higher SLE activity scores. Moreover, serum 25(OH) D levels were increased in SLE patients carrying FokI ff genotype compared with patients carrying FF genotype. VDR haplotypes aBF and ABF were associated with SLE risk. The ABF haplotype was associated with higher SLE activity scores and lower serum 25(OH) D concentrations. We observed that the presence of leuko/lymphopenia, renal disorders, higher SLE activity scores and higher anti-dsDNA levels were accompanied by a significant decrease of serum 25(OH)D concentrations. We concluded that The VDR genes polymorphisms, haplotypes, and decreased 25(OH) D levels were associated with risk and more activity scores of SLE. PMID- 24057184 TI - Association of IL-6, TNF-alpha and IL-10 gene polymorphisms with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is a metabolic pro-inflammatory disorder characterized by chronic hyperglycemia and increased levels of circulating cytokines suggesting a causal role of inflammation in its etiology. Polymorphism of cytokine genes including interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) were studied in T2DM patients as well as in normal healthy controls. Genomic DNA was isolated from both T2DM patients and controls followed by quantification and genotyping by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) using suitable primers. The genotypic, allelic and carriage rate frequency distribution in patients and controls were analyzed by SPSS (version 15.0). Odd ratios with 95 % confidence interval was determined to describe the strength of association by logistic regression model. Double and triple combinations of genotypes were analyzed by chi(2) test. Gene-gene interaction and linkage disequilibrium tests were performed using SHEsis software. Individually, IL-6, TNF-alpha and IL-10 did not show any association. In double combination, IL-6 -597 GA and TNF-alpha -308 GG genotypes increased the risk up to 21 times and in triple combination IL-6 -597 AA, TNF-alpha -308 GG and IL-10 -592 CA increased the risk of T2DM up to 314 times. In gene-gene interaction allele 'A' of all studied polymorphisms increased the risk of T2DM up to 1.41 times. Our results suggest that individuals having a haplotype combination of AA, GG and CA for IL-6, TNF-alpha and IL-10 gene polymorphisms will have higher susceptibility and be at greater risk of developing T2DM. PMID- 24057185 TI - Upregulation of microRNA-146a was not accompanied by downregulation of pro inflammatory markers in diabetic kidney. AB - The present study was designed to evaluate whether microRNA-146a and its adapter proteins (TRAF6 and IRAK1) are involved in the pathogenesis of diabetes-induced kidney damage. Male Sprague-Dawley rats were divided into control and diabetic groups (n = 6 in each). Diabetes was induced by injection of streptozotocin (55 mg/kg; i.p.) in 12 h fasted rats. Diabetic kidney damage was diagnosed by renal hypertrophy, thickened glomerular basement membrane, widened filtration slits, mesangial expansion, as well as by elevated levels of blood urea and creatinine in diabetic rats 2 months after induction of diabetes. While the expression of NF kappaB mRNA and miR-146a were increased in diabetic kidney compared to the sham controls (p < 0.01 for both comparisons), the mRNA levels of IRAK1 and TRAF6 did not statistically reduce. The NF-kappaB activity and the concentrations of TNF alpha, IL-6 and IL-1beta in the kidney of diabetic rats were higher than the kidney of controls (p < 0.05 for TNF-alpha and NF-kappaB; p < 0.01 for IL-6 and IL-1beta). Our results indicate that the upregulation of miR-146a was not accompanied by downregulation of inflammatory mediators in diabetic kidney. It is possible that a defect in the miR-146a-mediated negative loop provides a situation for sustained activation of NF-kappaB and its targets to promote cells toward abnormalities. PMID- 24057186 TI - Effects of diethylhexyl phthalate (DEHP) given neonatally on spermatogenesis of mice. AB - We previously demonstrated that the effects of diethylhexyl phthalate (DEHP) alter reproduction function on male mice. Immature male mice were treated daily with DEHP from postnatal day 7-21, 7-35, 7-49, in a dose-dependent manner. As results, both the quality and quantity of spermatozoa were decreased in 60-day old mice. The results by RT-PCR analysis indicated that DDx3Y, Usp9Y, RBM, E1F1AY, EGF, FSHR and EGFR genes were down-regulated, and LHR, Cyp17a1 and Cyp19a1 were down-regulated in response to DEHP. These genes were selected based on their markedly increased or decreased expression levels. However, DEHP had no effect on the meiotic process and recombination levels in male mouse germ cells. Treatment with DEHP induced histopathological changes in the testes. Taken together, these results provide a new insight into the molecular mechanisms underlying the detrimental impacts of DEHP in humans and wildlife. PMID- 24057187 TI - Lack of association between the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism and the risk of benign prostatic hyperplasia in Caucasian men. AB - Glucuronidation, mediated by the UDP-glucuronosyltransferase 1A1 (UGT1A1) enzyme, is an important metabolic process during which steroids are converted to more easily excreted compounds in steroid target tissues, such as the prostate. The aim of our study was to investigate the possible correlation between UGT1A1 promoter gene polymorphism and benign prostatic hyperplasia. 421 blood samples were obtained from 138 consecutive patients diagnosed with benign prostatic hypeplasia (BPH group) and 283 healthy volunteers (control group). A(TA)6TAA promoter polymorphism of UGT1A1 gene was studied using the Fragment Analysis Software of an automated DNA sequencer and three genotypes (homozygous 7/7, heterozygous 6/7 and normal homozygous 6/6) were identified. No significant differences were observed between the BPH group and controls regarding the genotyping distribution of the three UGT1A1 promoter genotypes (P = 0.39). Also, no association was found between overall disease risk and the presence of the polymorphic homozygous genotype (TA(7)/TA)7) vs. TA(6)/TA(7) + TA(6)/TA(6)) (P = 0.31). Our data suggest that the TA repeat polymorphism of UGT1A1 is not associated with increased BPH risk susceptibility in Caucasian men. PMID- 24057188 TI - Structural development of aleurone and its function in common wheat. AB - The wheat aleurone is formed from surface endosperm cells, and its developmental status reflects its biogenesis, structural characteristics, and physiological functions. In this report, wheat caryopses at different development stages were embedded in Spurr's low-viscosity embedding medium for observation of the development of aleurone cells (ACs) by light microscopy, scanning electron microscopy, and fluorescence microscopy, respectively. According to their structures and physiological characterization, the ACs development process was divided into five stages: endosperm cellulization, spherosome formation, aleurone grain formation, filling material proliferation, and maturation. Furthermore, ACs in different parts of the caryopsis formed differently. ACs near the vascular bundle developed earlier and formed transfer cells, but other ACs formed slowly and did not form transfer cells. ACs on the caryopsis backside were a regular square shape; however, ACs in the caryopsis abdomen were mainly irregular. There were also differences in development between wheat varieties. ACs were rectangular in hard wheat but square in soft wheat. ACs were larger and showed a greater degree of filling in hard compared to soft wheat. The storage materials in ACs were different compared to inner endosperm cells (IECs). The concentrations of minerals such as sodium, magnesium, silicon, phosphorus and potassium were higher in ACs than in IECs. ACs contained many aleurone grains and spherosomes, which store lipids and mineral nutrients, respectively. The cell nucleus did not disappear and the cells were still alive during aleurone maturation. However, IECs were dead and mainly contained amyloplast and protein bodies, which store starch and protein, respectively. Overall, the above results characterized major structural features of aleurone and revealed that the wheat aleurone has mainly four functions. PMID- 24057189 TI - Polymorphisms of the bovine DKK2 and their associations with body measurement traits and meat quality traits in Qinchuan cattle. AB - The objective of this research were to detect bovine Dickkopf 2 (DKK2) gene polymorphism and analyze their associations with body measurement traits (BMT) and meat quality traits (MQT) of animals. Blood samples were taken from a total of 541 Qinchuan cattle aged from 18 to 24 months. Polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) was employed to find out DKK2 single-polymorphism nucleotide (SNPs) and to explore their possible association with BMT and MQT. Sequence analysis of DKK2 gene revealed 2 SNPs (C29 T and A169C) in 5' untranslated region (5'UTR) of exon 1.C29T and A164T SNPs are both synonymous mutation, which showed 2 genotypes namely (CC, CT) and (AA and AC), respectively. Association analysis of polymorphism with body measurement and meat quality traits at the two locus showed that there were significant effects on CT, BL, RL, PBW, BFT, LMA, and IFC. These results suggest that the DKK2 gene might have potential effects on BMT and MQT in Qinchuan cattle population and could be used for marker-assisted selection. PMID- 24057190 TI - Active management of financial conflicts of interest on the Editorial Board of CORR. PMID- 24057191 TI - The efficacy of single-stage open intramedullary nailing of neglected femur fractures. AB - BACKGROUND: Neglected femur fractures are not rare in the developing world. Treatment options include single-stage open reduction and intramedullary nailing, or open release, skeletal traction, and then second-stage open intramedullary nailing, with bone grafting. Single-stage procedures have the potential advantage of avoiding neurovascular complications secondary to acute lengthening, but they require a second operation, with potentially increased resource use and infection risk. QUESTIONS/PURPOSES: We sought to determine the (1) likelihood of union, (2) complications and reoperations, and (3) functional results with single-stage open intramedullary nailing without bone grafting in patients with neglected femur fractures. METHODS: Between January 2003 and December 2007, 17 consecutive patients presented to our practice with neglected femoral shaft fractures. All were treated with single-stage nailing without bone grafting. There were 15 men and two women with a median age of 27 years. The average time from fracture to treatment was 13 weeks (range, 4-44 weeks). Eleven patients underwent open nailing with interlocked nails and six were treated with cloverleaf Kuntscher nails. Patients were followed for a minimum of 6 months (mean, 33 months; range, 6-72 months). The mean preoperative ROM of the knee was 28 degrees (range, 10 degrees -150 degrees ) and femoral length discrepancy was 3.1 cm (range, 1-5 cm). RESULTS: All fractures united and the mean time to union was 16 weeks (range, 7 32 weeks). There were no neurologic complications secondary to acute lengthening. The mean postoperative ROM of the knee was 130 degrees (range, 60 degrees -150 degrees ). All patients were able to return to preinjury work. Sixteen patients regained their original femoral length. CONCLUSIONS: One-stage open intramedullary nailing of neglected femoral diaphyseal fractures without bone grafting was safe and effective, and obviated the need for a two-stage approach. Although the findings need to be replicated in larger numbers of patients, we believe this technique may be useful in treating patients with this injury, and may offer advantages in resource-constrained environments. PMID- 24057192 TI - Single- or two-stage revision for infected total hip arthroplasty? A systematic review of the literature. AB - BACKGROUND: The best approach for surgical treatment of an infected THA remains controversial. Two-stage revision is believed to result in lower reinfection rates but may result in significant functional impairment. Some authors now suggest that single-stage revision may provide comparable results in terms of infection eradication while providing superior functional outcomes. QUESTIONS/PURPOSES: We performed a systematic review to determine whether single- or two-stage revision for an infected THA provides lower reinfection rates and higher functional outcome scores. METHODS: We conducted a comprehensive search of PubMed and Embase, using the search string [Infection AND ("total hip replacement" OR "total hip arthroplasty") AND revision]. All studies comparing reinfection rates or functional scores for single- and two-stage revision were retrieved and reviewed. A systematic review was performed according to the PRISMA checklist. RESULTS: The initial search retrieved 1128 studies. Following strict exclusion criteria, we identified nine comparative studies comparing reinfection rates (all nine studies) or functional scores (four studies) between single- and two-stage revisions. The overall quality of studies was poor with no randomized studies being identified. Groups often varied in their baseline characteristics. There was no consensus among the studies regarding the relative incidence of reinfection between the two procedures. There was a trend toward better functional outcomes in single-stage surgery, but this reached significance in only one study. CONCLUSIONS: In appropriate patients, single-stage revision appears to be associated with similar reinfection rates when compared with two stage revision with superior functional outcomes. This concurs with earlier studies, but given the methodologic quality of the included studies, these findings should be treated with caution. High-quality randomized studies are needed to compare the two approaches to confirm these findings, and, if appropriate, to determine which patients are appropriate for single-stage revision. PMID- 24057193 TI - Serum markers of ovarian reserve and ovarian histology in adult mice treated with cyclophosphamide in pre-pubertal age. AB - PURPOSE: AMH is used to quantify the extent of follicular pool in postpubertal women, but its value after chemotherapy is unclear. We tested AMH as a marker of follicular reserve in adult mice treated with cyclophosphamide (CTX) in prepubertal age. METHODS: Mice received placebo or CTX at age 18 days. AMH and FSH were assessed on day 43, 56, and 95 of life. Ovaries were fixed in formalin, embedded in paraffin, and stained with H&E and TUNEL. Follicular apoptosis was graded. RESULTS: All mice exposed to CTX had a decreased number of follicles/mm(2) and significantly decreased AMH, but only 48 % of pubertal and 81 % of adult mice had increased FSH. Over time, there was an increase in FSH (p < 0.05), but not a concurrent decrease in AMH, while in controls, FSH remained stable and AMH decreased. There was no correlation between histological and serological markers. CONCLUSIONS: CTX administration to pre-pubertal mice caused various degrees of residual function, which were reflected by FSH, but not by AMH or by the number of ovarian follicles. AMH served as a marker of quantitative, and FSH of qualitative, residual ovarian function. PMID- 24057194 TI - Estimating the absorption coefficient of the bottom layer in four-layered turbid mediums based on the time-domain depth sensitivity of near-infrared light reflectance. AB - Expanding our previously proposed "time segment analysis" for a two-layered turbid medium, this study attempted to selectively determine the absorption coefficient (MUa) of the bottom layer in a four-layered human head model with time-domain near-infrared measurements. The difference curve in the temporal profiles of the light attenuation between an object and a reference medium, which are obtained from Monte Carlo simulations, is divided into segments along the time axis, and a slope for each segment is calculated to obtain the depth dependent MUa(MUaseg). The reduced scattering coefficient (MUs') of the reference is determined by curve fitting with the temporal point spread function derived from the analytical solution of the diffusion equation to the time-resolved reflectance of the object. The deviation of MUaseg from the actual MUa is expressed by a function of the ratio of MUaseg in an earlier time segment to that in a later segment for mediums with different optical properties and thicknesses of the upper layers. Using this function, it is possible to determine the MUa of the bottom layer in a four-layered epoxy resin-based phantom. These results suggest that the method reported here has potential for determining the MUa of the cerebral tissue in humans. PMID- 24057196 TI - Tailor-made LasR agonists modulate quorum sensing in Pseudomonas aeruginosa. AB - The primary quorum sensing system in the opportunistic pathogen Pseudomonas aeruginosa is regulated through the synthesis and secretion of N-3-oxo-dodecanoyl L-homoserine lactone (C12) which binds the transcriptional activator LasR. In this study we report the design, synthesis and biological evaluation of new analogs of C12. Analysis of the autoinducer binding site cavity of LasR revealed a positively charged cavity near the center of bound C12. Accordingly, we synthesized two piperidine-C12 diastereoisomers and tested their biological activity. Both analogs proved to be strong LasR agonists that showed a synergistic effect when presented together with the natural ligand. Moreover, binding of the analogs resulted in phenotypic changes characteristic of QS controlled receptor activation. PMID- 24057195 TI - Pediatric nephrogenic systemic fibrosis is rarely reported: a RADAR report. AB - BACKGROUND: Nephrogenic systemic fibrosis is a fibrosing disorder associated with exposure to gadolinium-based contrast agents in people with severely compromised renal function. OBJECTIVE: The purpose of this study was to determine the reported number of cases of nephrogenic systemic fibrosis in children using three distinct publicly available data sources. MATERIALS AND METHODS: We conducted systematic searches of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), the International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR) registry and published literature from January 1997 through September 2012. We contacted authors of individual published cases to obtain follow-up data. Data sets were cross-referenced to eliminate duplicate reporting. RESULTS: We identified 23 children with nephrogenic systemic fibrosis. Seventeen had documented exposure to gadolinium-based contrast agents. Six children had been reported in both the FAERS and the literature, four in the FAERS and the ICNSFR registry and five in all three data sources. CONCLUSION: Nephrogenic systemic fibrosis has been rarely reported in children. Although rules related to confidentiality limit the ability to reconcile reports, active pharmaco-vigilance using RADAR (Research on Adverse Drug events And Reports) methodology helped in establishing the number of individual pediatric cases within the three major data sources. PMID- 24057197 TI - Inorganic chemistry in a nanoreactor: Au/TiO2 nanocomposites by photolysis of a single-source precursor in miniemulsion. AB - An original synthetic route, based on the combination of a single-source precursor, UV-photodegradation and inverse w/o miniemulsion, is used to prepare Au nanoparticles (NPs) dispersed on titania. The source of the nanocomposite materials is the photolabile single-source precursor AuCl4(NH4)7[Ti2(O2)2(cit)(Hcit)]2.12H2O, which is suspended in a w/o miniemulsion consisting of different surfactant/hydrocarbon/water formulations (surfactant: sodium dodecylsulfate (SDS) or Triton X-100) and subsequently irradiated with a UV lamp to promote its decomposition in the confined space of the droplets. Gold NPs that form at room temperature are found to be crystalline, while titanium dioxide occurs as an amorphous phase. Moreover, the average crystallite size of gold NPs ranges between 20 and 24 nm when using SDS and between 26 and 40 nm in the case of Triton X-100, after 4 and 8 hours of irradiation time, respectively. Scanning and transmission electron microscopies (SEM and TEM) are used to get information about the nanocomposite morphology and nanostructure, revealing that gold NPs are uniformly distributed on the titanium oxide surface. Furthermore, X ray photoelectron spectroscopy (XPS) outcomes, besides confirming the formation of both metallic gold and titania, provide information about the high dispersion of Au NPs on the TiO2 surface. In fact, the Au : Ti atomic ratio is found to be 0.45-1.5 (1 : 2-1.5 : 1), which is higher than the value determined by starting from the precursor stoichiometry (0.25). Catalytic testing in the oxidation of 2 propanol shows that decomposition of the precursor in a miniemulsion provides a nanocomposite with enhanced activity compared to the decomposition in the aqueous phase. PMID- 24057198 TI - Answer to the letter to the editor of Svend Lings entitled "antibiotics for low back pain?" concerning "antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized controlled trial of efficacy" by Albert HB et al., Eur Spine J (2013) 22:697-707. PMID- 24057199 TI - Complications in minimally invasive percutaneous fixation of thoracic and lumbar spine fractures and tumors. AB - PURPOSE: We propose to evaluate the complication rate in minimally invasive stabilization (MIS) for spine fractures and tumors, as a common alternative to open fusion and conservative treatment. METHODS: From 2000 to 2010, 187 patients were treated by minimally invasive percutaneous fixation in 133 traumatic fractures and 54 primitive and/or secondary spine tumors. Complications were classified, according to the period of onset as intraoperative and postoperative, and according to the severity, as major and minor. RESULTS: A total of 15 complications (8 %) were recorded: 5 intraoperative (3 %), 6 early postoperative (3 %) and 4 late postoperative (2 %); 6 were minor complications (3 %) and 9 were major complications (5 %). CONCLUSIONS: Minimally invasive stabilization of selected spine pathologies appears to be a safe technique with low complication rate and high patient satisfaction. MIS reduces hospitalization and allows a fast functional recovery improving the quality of life. PMID- 24057200 TI - Anular closure device: is it necessary after discectomy? PMID- 24057201 TI - Experiences with a self-test for Dutch breast screening radiologists: lessons learnt. AB - PURPOSE: To evaluate a self-test for Dutch breast screening radiologists introduced as part of the national quality assurance programme. METHODS AND MATERIALS: A total of 144 radiologists were invited to complete a test-set of 60 screening mammograms (20 malignancies). Participants assigned findings such as location, lesion type and BI-RADS. We determined areas under the receiver operating characteristics (ROC) curves (AUC), case and lesion sensitivity and specificity, agreement (kappa) and correlation between reader characteristics and case sensitivity (Spearman correlation coefficients). RESULTS: A total of 110 radiologists completed the test (76%). Participants read a median number of 10,000 screening mammograms/year. Median AUC value was 0.93, case and lesion sensitivity was 91% and case specificity 94%. We found substantial agreement for recall (kappa = 0.77) and laterality (kappa = 0.80), moderate agreement for lesion type (kappa = 0.57) and BI-RADS (kappa = 0.45) and no correlation between case sensitivity and reader characteristics. CONCLUSION: Areas under the ROC curve, case sensitivity and lesion sensitivity were satisfactory and recall agreement was substantial. However, agreement in lesion type and BI-RADS could be improved; further education might be aimed at reducing interobserver variation in interpretation and description of abnormalities. We offered individual feedback on interpretive performance and overall feedback at group level. Future research will determine whether performance has improved. KEY POINTS: * We introduced and evaluated a self-test for Dutch breast screening radiologists. * ROC curves, case and lesion sensitivity and recall agreement were all satisfactory. * Agreement in BI-RADS interpretation and description of abnormalities could be improved. * These are areas that should be targeted with further education and training. * We offered individual feedback on interpretative performance and overall group feedback. PMID- 24057202 TI - Impact of iterative reconstruction on CT coronary calcium quantification. AB - OBJECTIVES: We evaluated the influence of sinogram-affirmed iterative reconstruction (SAFIRE) on the coronary artery calcium (CAC) score by computed tomography (CT). MATERIALS AND METHODS: Seventy patients underwent CAC imaging by 128-slice dual-source CT. CAC volume, mass and Agatston score were calculated from images reconstructed by filtered back projection (FBP) without and with incremental degrees of the SAFIRE algorithm (10-50 %). We used the repeated measuring test and the Steel-Dwass test for multiple comparisons of values and the difference ratio among different SAFIRE groups using the FBP as reference. RESULTS: The median Agatston score (range) decreased with incremental SAFIRE degrees: 163 (0.1 - 3,393.3), 158.4 (0.3 - 3,079.3), 137.7 (0.1 - 2,978.0), 120.6 (0 - 2,783.6), 102.6 (0 - 2,468.4) and 84.1 (0 - 2,186.9) for 0 % (FBP), 10 %, 20 %, 30 %, 40 % and 50 % SAFIRE, respectively (P < 0.05). In comparison with FBP, CAC volume (from 8.1 % to 47.7 %), CAC mass (from 5.3 % to 44.7 %) and CAC Agatston score (from 7.3 % to 48.4 %) all decreased with increasing SAFIRE from 10 % to 50 %, respectively (P < 0.05). High-grade SAFIRE resulted in the disappearance of detectable calcium in three cases with low calcium burden. CONCLUSION: SAFIRE noise reduction techniques significantly affected the CAC, which potentially alters perceived cardiovascular risk. PMID- 24057203 TI - External beam radiotherapy for angiographically diagnosed arteriovenous malformation involving the entire pancreas. AB - Ultrasonography of a 66-year-old man with abdominal discomfort detected an abnormality of the pancreas. Multiphase contrast-enhanced computed tomography (CT) and angiography revealed arteriovenous malformation (AVM) involving the entire pancreas. The large number of dilated and tortuous feeding arteries contraindicated surgical resection or transcatheter embolization. Hemorrhage into the main pancreatic duct occurred 1 month after diagnosis. The patient underwent external radiotherapy with a total dose of 44 Gy following a conventional fractionation schedule of 2 Gy daily for 22 days administered 5 days per week. Contrast-enhanced CT after treatment confirmed disappearance of feeding vessels and nidi with no complication. Evidence of recurrence was not detected on contrast-enhanced CT 6 months after irradiation. PMID- 24057204 TI - Adenoid cystic carcinoma of the maxillary sinus: CT and MR imaging findings. AB - OBJECTIVE: The purpose of this study was to determine whether adenoid cystic carcinomas (ACCs) of the maxillary sinus have features on CT and MR imaging. MATERIALS AND METHODS: Nine patients with histopathologically proved maxillary sinus ACCs were included. The growth pattern was classified as expansile or destructive types on the basis of CT images. CT images were also reviewed for adjacent bony defects and MR images were reviewed for tumor extension. Fluid accumulation in the ipsilateral maxillary sinus was also assessed. RESULTS: The tumors had caused adjacent bony expansion with minimal bony defects in 4 patients whereas those in the remaining 5 patients had caused extensive destruction of adjacent bones comprising the maxillary sinus walls. Nasal cavity invasion was observed in 7 patients, retroantral fat pad invasion in 5, pterygopalatine fossa invasion in 4, and orbital invasion in 3. All 4 expansile ACCs were accompanied by accumulation of a small amount of fluid in the surroundings of the tumors, which was revealed as hyperintensity on T1-weighted images. CONCLUSION: The growth pattern of maxillary sinus ACCs can be classified into an expansile type with minimal bony defects and a destructive type with extensive bony defects. PMID- 24057205 TI - L-proline catalyzed stereoselective synthesis of (E)-methyl-alpha-indol-2-yl-beta aryl/alkyl acrylates: easy access to substituted carbazoles, gamma-carbolines and prenostodione. AB - A simple, mild and robust method for the stereoselective synthesis of (E)-methyl alpha-(3-formyl-1H-indol-2-yl)-beta-aryl/alkyl-substituted acrylates via a condensation reaction of methyl 2-(3-formyl-1H-indol-2-yl)acetate with several alkyl or aryl aldehydes using L-proline (25 mol%) as a catalyst is presented for the first time. In addition, completely metal free based high yielding methods for the syntheses of highly substituted biologically important carbazoles, gamma carbolines and the marine alkaloid prenostodione have been developed through our methodology. PMID- 24057206 TI - Semivolatile compounds in schools and their influence on cognitive performance of children. AB - OBJECTIVES: WHO's Children's Environment and Health Action Plan for Europe (CEHAPE) focuses on improvements of indoor environments where children spend most of their time. To investigate the relationship between school indoor air pollutants and cognitive performance in elementary school children, a multidisciplinary study was planned in all-day schools in Austria. MATERIALS AND METHODS: In a cross-sectional study (LuKi study: Air and Children) indoor air pollutants were monitored in nine elementary all-day schools in urban and rural regions of Austria. In addition, school dust and suspended particulates (PM10, PM2.5) were measured, focusing on semivolatile compounds (e.g. phthalates, phosphororganic compounds [POC]). Health status and environmental conditions were determined by parents' questionnaire, cognitive function was measured by Standard Progressive Matrices (SPM). RESULTS: Overall, 596 children (6-8 years of age) were eligible for the study. Cognitive tests were performed in 436 children. Analysis showed significant correlations of tris(2-chlorethyl)-phosphate (TCEP) in PM10 and PM2.5 and school dust samples with cognitive performance. Cognitive performance decreased with increasing concentrations of TCEP. Furthermore, cognitive function decreased significantly with increasing CO2 levels. CONCLUSIONS: POC are widely used as plasticizers, flame retardants and floor sealing. This is the first report of a correlation between TCEP in indoor air samples and impairment of cognitive performance in school children. As a precautionary measure, it is recommended to prohibit the use of toxic chemicals and those suspected of a toxic potential in children's environments such as schools. PMID- 24057207 TI - The role of rewards and demands in burnout among surgical nurses. AB - OBJECTIVE: Job rewards have both, an intrinsic and an extrinsic motivational potential, and lead to employees' development as well as help them to achieve work goals. Rewards can balance job demands and protect from burnout. Due to changes on the labour market, new studies are needed. The aim of our study was to examine the role of demands and individual rewards (and their absence) in burnout among surgical nurses. MATERIALS AND METHODS: The study was conducted in 2009 and 2010 with 263 nurses who worked in surgical wards and clinics in hospitals in Southern Poland. The hypotheses were tested by the use of measures of demands and rewards (Effort-Reward Imbalance Questionnaire by Siegrist) and burnout syndrome (Maslach Burnout Inventory). A cross-sectional, correlational study design was applied. RESULTS: Nurses experienced the largest deficiencies in salary and prestige. Exhaustion was explained by stronger demands and lack of respect (large effect). Depersonalization was explained by stronger demands, lack of respect and greater job security (medium effect). Reduced personal achievement was explained by more demands and greater job security (small effect). CONCLUSIONS: Excessive demands and lack of esteem are key reasons for burnout among surgical nurses. Job security can increase burnout when too many resources are invested and career opportunities do not appear. These results may help to improve human resource management in the healthcare sector. PMID- 24057208 TI - Specificity of sexual arousal for sexual activities in men and women with conventional and masochistic sexual interests. AB - Prior studies consistently report that men's genital responses correspond to their sexual activity interests (consenting vs. coercive sex) whereas women's responses do not. For women, however, these results may be confounded by the sexual activities studied and lack of suitable controls. We examined the subjective and genital arousal responses of men and women with conventional (22 men and 15 women) or masochistic sexual interests (16 men and 17 women) to narratives describing conventional sex or masochistic sex. The aims of the studies were twofold: (1) to examine whether gender differences in the specificity of sexual arousal previously observed for gender also exist for sexual activity interests; and (2) to examine whether men and women with masochistic sexual interests demonstrate specificity of sexual response for their preferred sexual activities. Surprisingly, the pattern of results was very similar for men and women. Both men and women with conventional sexual interests (WCI) reported more sexual arousal, and responded more genitally, to conventional than to masochistic sex, demonstrating specificity of sexual arousal for their preferred sexual activities. Despite showing specificity for conventional sexual activities, the genital responses of WCI were still gender nonspecific. In contrast, women and men with masochistic sexual interests demonstrated nonspecific subjective and genital responses to conventional and masochistic sex. Indices of genital and subjective sexual arousal to masochistic versus conventional stimuli were positively and significantly correlated with self reported thoughts, fantasies, interests, and behaviors involving masochism. The results suggest that gender similarities in the specificity of sexual arousal for sexual activity exist despite consistent gender differences in the specificity of sexual arousal for gender. PMID- 24057209 TI - Cognitive aspects of sexual functioning: differences between East Asian-Canadian and Euro-Canadian women. AB - The purpose of this study was to investigate the sexual beliefs of female undergraduates, as well as the thoughts they experience during sexual experiences. The study aimed to determine potential differences in these variables between East Asian-Canadians and Euro-Canadians, as well as the influence of acculturation on these variables. In addition, the relationships between sexual beliefs, automatic thoughts, and specific aspects of sexual functioning were examined. Euro-Canadian (n = 77) and East Asian-Canadian (n = 123) undergraduate women completed the Sexual Dysfunctional Beliefs Questionnaire, the Sexual Modes Questionnaire, the Female Sexual Function Index, and the Vancouver Index of Acculturation. East Asian women endorsed almost all sexual beliefs assessed in this study more than did Euro-Canadian women, and endorsement of these beliefs was associated with acculturation. In addition, East Asian-Canadian and Euro-Canadian women differed in the frequency of experiencing negative automatic thoughts. Results also revealed associations between difficulties in sexual functioning, and both sexual beliefs and automatic thoughts. Together, these results provide preliminary support for the hypothesis that differences in cognitive aspects of sexuality may underlie the differences in sexual functioning previously observed between these two groups. PMID- 24057210 TI - The influence of attraction to partner on heterosexual women's sexual and relationship satisfaction in long-term relationships. AB - Previous research has consistently found that attraction is important in the formation of relationships though research on attraction in long-term relationships is less well understood. This article examined the predictive value of self-reported attraction to partner and change in attraction to partner on sexual and relationship satisfaction in 176 women in committed heterosexual relationships using online survey methodology. Participants' age ranged from 21 to 56 (M = 34.5) years and their relationship length ranged from 5 to 35 (M = 11.75) years. Hierarchical multiple regression results indicated that change in attraction to partner was the most salient predictor of sexual satisfaction, with current attraction to partner also related to women's sexual satisfaction, accounting for 20 % of the variance. Current attraction to partner was the only significant predictor of women's relationship satisfaction, accounting for 22 % of the variance. Additionally, attraction variables accounted for variance above and beyond the impact of relationship and sexual satisfaction. These findings suggest that self-reported attraction to partner is an important contributor to women's satisfaction outcomes in long-term relationships. Further studies in the area of attraction to partner that include couple dynamics and longitudinal data are encouraged and implications for therapists, clinicians, and educators are discussed. PMID- 24057211 TI - Vorarephilia: a case study in masochism and erotic consumption. AB - Vorarephilia ("vore") is an infrequently presenting paraphilia, characterized by the erotic desire to consume or be consumed by another person or creature. Few data exist on vore though several cases have been reported which appear to be consistent with basic vorarephilic interests. Because this sexual interest cannot be enacted in real life due to physical and/or legal restraints, vorarephilic fantasies are often composed in text or illustrations and shared with other members of this subculture via the Internet. Similarities with aspects of bondage/dominance sadomasochism interests, more specifically dominance and submission, are noted. The current case report describes a man with masochistic sexual interests which intersected with submissive vorarephilic fantasy. PMID- 24057212 TI - Bilateral non-arteritic ischemic optic neuropathy in a transsexual woman using excessive estrogen dosage. AB - We present a case report on a 53-year-old transsexual woman who developed acute painless vision loss in both eyes during cross-sex hormone treatment. After 10 months of cross-sex hormone treatment, she experienced total vision loss of the right eye and, 6 months later, vision loss to 20/63 in the left eye. After a full ophthalmic exam, bilateral sequential non-arteritic ischemic optic neuropathy (NA ION) was diagnosed. Extensive etiological work-up revealed no cardiac abnormalities or inherited blood-clotting disorders. A manifest self-administered overdose of transdermal estrogen treatment with serum estradiol levels of 5,765 pg/ml was possibly related to the sequential bilateral NA-ION resulting in nearly total vision loss in this transsexual woman. PMID- 24057213 TI - Human telomeres that carry an integrated copy of human herpesvirus 6 are often short and unstable, facilitating release of the viral genome from the chromosome. AB - Linear chromosomes are stabilized by telomeres, but the presence of short dysfunctional telomeres triggers cellular senescence in human somatic tissues, thus contributing to ageing. Approximately 1% of the population inherits a chromosomally integrated copy of human herpesvirus 6 (CI-HHV-6), but the consequences of integration for the virus and for the telomere with the insertion are unknown. Here we show that the telomere on the distal end of the integrated virus is frequently the shortest measured in somatic cells but not the germline. The telomere carrying the CI-HHV-6 is also prone to truncations that result in the formation of a short telomere at a novel location within the viral genome. We detected extra-chromosomal circular HHV-6 molecules, some surprisingly comprising the entire viral genome with a single fully reconstituted direct repeat region (DR) with both terminal cleavage and packaging elements (PAC1 and PAC2). Truncated CI-HHV-6 and extra-chromosomal circular molecules are likely reciprocal products that arise through excision of a telomere-loop (t-loop) formed within the CI-HHV-6 genome. In summary, we show that the CI-HHV-6 genome disrupts stability of the associated telomere and this facilitates the release of viral sequences as circular molecules, some of which have the potential to become fully functioning viruses. PMID- 24057214 TI - A general approach for discriminative de novo motif discovery from high throughput data. AB - De novo motif discovery has been an important challenge of bioinformatics for the past two decades. Since the emergence of high-throughput techniques like ChIP seq, ChIP-exo and protein-binding microarrays (PBMs), the focus of de novo motif discovery has shifted to runtime and accuracy on large data sets. For this purpose, specialized algorithms have been designed for discovering motifs in ChIP seq or PBM data. However, none of the existing approaches work perfectly for all three high-throughput techniques. In this article, we propose Dimont, a general approach for fast and accurate de novo motif discovery from high-throughput data. We demonstrate that Dimont yields a higher number of correct motifs from ChIP-seq data than any of the specialized approaches and achieves a higher accuracy for predicting PBM intensities from probe sequence than any of the approaches specifically designed for that purpose. Dimont also reports the expected motifs for several ChIP-exo data sets. Investigating differences between in vitro and in vivo binding, we find that for most transcription factors, the motifs discovered by Dimont are in good accordance between techniques, but we also find notable exceptions. We also observe that modeling intra-motif dependencies may increase accuracy, which indicates that more complex motif models are a worthwhile field of research. PMID- 24057215 TI - MiR-138 downregulates miRNA processing in HeLa cells by targeting RMND5A and decreasing Exportin-5 stability. AB - MicroRNAs (miRNAs) are a class of non-coding small RNAs that consist of ~ 22 nt and are involved in several biological processes by regulating target gene expression. MiR-138 has many biological functions and is often downregulated in cancers. Our results showed that overexpression of miR-138 downregulated target RMND5A (required for meiotic nuclear division 5 homolog A) and reduced Exportin-5 stability, which results in decreased levels of pre-miRNA nuclear export in HeLa cells. We also found that miR-138 could significantly inhibit HeLa cell migration by targeting RMND5A. Our study therefore identifies miR-138-RMND5A-Exportin-5 as a previously unknown miRNA processing regulatory pathway in HeLa cells. PMID- 24057216 TI - The tenacious recognition of yeast telomere sequence by Cdc13 is fully exerted by a single OB-fold domain. AB - Cdc13, the telomere end-binding protein from Saccharomyces cerevisiae, is a multidomain protein that specifically binds telomeric single-stranded DNA (ssDNA) with exquisitely high affinity to coordinate telomere maintenance. Recent structural and genetic data have led to the proposal that Cdc13 is the paralog of RPA70 within a telomere-specific RPA complex. Our understanding of Cdc13 structure and biochemistry has been largely restricted to studies of individual domains, precluding analysis of how each domain influences the activity of the others. To better facilitate a comparison to RPA70, we evaluated the ssDNA binding of full-length S. cerevisiae Cdc13 to its minimal substrate, Tel11. We found that, unlike RPA70 and the other known telomere end-binding proteins, the core Cdc13 ssDNA-binding activity is wholly contained within a single tight binding oligosaccharide/oligonucleotide/oligopeptide binding (OB)-fold. Because two OB-folds are implicated in dimerization, we also evaluated the relationship between dimerization and ssDNA-binding activity and found that the two activities are independent. We also find that Cdc13 binding exhibits positive cooperativity that is independent of dimerization. This study reveals that, while Cdc13 and RPA70 share similar domain topologies, the corresponding domains have evolved different and specialized functions. PMID- 24057218 TI - Traumatic Abruptio Placenta Scale (TAPS): a proposed grading system of computed tomography evaluation of placental abruption in the trauma patient. AB - Placental abruption (PA) is one of the worst possible manifestations of injury in the pregnant trauma patient with ultrasound as the current initial imaging examination of choice, despite its known limitations in placental evaluation. Pregnant patients who undergo computed tomography (CT) for evaluation of potential maternal injuries provide an additional source of imaging for placental evaluation; however, few studies have delineated normal and abnormal placental appearance, therefore resulting in insufficient placental assessments on pregnant trauma patients. Retrospective literature analysis was performed to provide a structured descriptive classification of normal and abnormal placental appearance on CT. By offering a structured system of placental appearance, radiologists will become more familiar with normal variations of the placenta as well as be able to recognize areas of abnormality, furthermore assisting in clinical management efficiency. PMID- 24057219 TI - Effect of edible sesame oil on growth of clinical isolates of Candida albicans. AB - Elderly individuals are at increased risk of oral thrush (oral candidiasis) due to decreased saliva secretion. Due to their antimicrobial properties, edible oils can be effective natural agents for oral care. The objective of the present study was to compare the effects of sesame oil, which is widely used for cooking in Asian countries, and two other edible oils on the growth of both mycelial and yeast forms of five clinical isolates of Candida albicans, a causative microorganism of oral thrush. We assessed the effect of each oil in concentrations of 0.078%, 0.156%, and 0.313% on growth of the mycelial forms of the clinical isolates over 24 hr using the crystal violet method. We also evaluated the effect of each oil on growth of the yeast forms by counting the number of viable yeast cells after culturing in the oils for 24 hr. Sesame oil inhibited the growth of both mycelial and yeast forms. Safflower and olive oil also inhibited the growth of both forms of C. albicans but to a lesser extent than sesame oil. The ability to inhibit the growth of the mycelial form correlated with sesame oil concentration. Roasting influenced growth inhibition ability and high-roasted sesame oil most effectively inhibited the yeast form. The growth inhibitory effect differed among the five isolates. We hypothesize that the sesamin and fatty acid components of sesame oil are involved in its antifungal activity. PMID- 24057217 TI - Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites. AB - We applied Illumina Human Methylation450K array to perform a genomic-scale single site resolution DNA methylation analysis in neuronal and nonneuronal (primarily glial) nuclei separated from the orbitofrontal cortex of postmortem human brain. The findings were validated using enhanced reduced representation bisulfite sequencing. We identified thousands of sites differentially methylated (DM) between neuronal and nonneuronal cells. The DM sites were depleted within CpG island-containing promoters but enriched in predicted enhancers. Classification of the DM sites into those undermethylated in neurons (neuronal type) and those undermethylated in nonneuronal cells (glial type), combined with findings of others that methylation within control elements typically negatively correlates with gene expression, yielded large sets of predicted neuron-specific and non neuron-specific genes. These sets of predicted genes were in excellent agreement with the available direct measurements of gene expression in human and mouse. We also found a distinct set of DNA methylation patterns that were unique for neuronal cells. In particular, neuronal-type differential methylation was overrepresented in CpG island shores, enriched within gene bodies but not in intergenic regions, and preferentially harbored binding motifs for a distinct set of transcription factors, including neuron-specific activity-dependent factors. Finally, non-CpG methylation was substantially more prevalent in neurons than in nonneuronal cells. PMID- 24057220 TI - A case-control study examining the effects of active versus sedentary lifestyles on measures of body iron burden and oxidative stress in postmenopausal women. AB - Approximately half of the Canadian adults have sedentary lifestyles that increase their risk of developing cardiovascular disease (CVD). Women are 10 times more likely to die from CVD than from any other disease. Their risk almost doubles with the onset of menopause, which may result in increased body iron burden and oxidative stress in sedentary women. Body iron burden may catalyze the production of cytotoxic oxygen species in vivo. We hypothesized that postmenopausal women who engage in moderate forms of aerobic exercise for at least 30 min three or more times per week would have significantly (i) lower levels of body iron burden, (ii) increased glutathione peroxidase (GPx) activity, and (iii) decreased oxidative stress in comparison to sedentary controls. An age-matched, case control study was employed to examine the effects of active (N = 25) versus sedentary (N = 25) lifestyles in women aged 55-65 years on measures of body iron burden as quantified by total serum iron, transferrin saturation, and serum ferritin levels; GPx activity; and oxidative stress as quantified by 4 hydroxynonenal, malondialdehyde, and hexanal. Measures of body iron burden were significantly elevated in sedentary women in comparison to active women (p < .001). Red cell GPx activity was higher in active women compared to sedentary women (p < .001). Measures of oxidative stress were significantly higher in sedentary versus active women (p < .001). These findings suggest that aerobic forms of exercise may mitigate the risk of developing CVD in postmenopausal women by improving antioxidant capacity and decreasing body iron burden. PMID- 24057221 TI - Associations among depression, obesity, and metabolic syndrome in young adult females. AB - Depression may be a risk factor for obesity or metabolic syndrome. The aims of this study were to determine the relationships among depression, obesity, and metabolic syndrome in young adult females as well as the role of depression in the components of metabolic syndrome. A cross-sectional study was conducted on 323 young adult females. Demographic characteristics, anthropometric measurements, and laboratory values were collected. The criteria of the Bureau of Health Promotion, Department of Health, Taiwan, were used to define metabolic syndrome. Depression was measured using the Center for Epidemiologic Studies Depression scale. The prevalence of depression in the sample was 17%, that of overweight and obesity was 17%, and that of metabolic syndrome was 6.8%. Depression showed significant associations with high body mass index (BMI), increased waist circumference and blood pressure (BP), and overweight and obesity (beta = 0.15, odds ratio [OR] = 1.17, 95% confidence interval [CI] = [1.11, 1.23], p < .001). No associations were observed between depression and metabolic syndrome (beta = -0.01, OR = 0.99, 95% CI = [0.92, 1.06], p = .69) or any of its individual components after adjustment for BMI and demographic variables. The findings show that depression was associated with increasing odds of overweight and obesity in young adult females and may also have increased the physiological risk associated with metabolic syndrome. Early detection of depression and obesity as part of metabolic syndrome is important in the health management of young adult females for decreasing the risks of cardiovascular disease and diabetes. PMID- 24057222 TI - Characterizing activity and muscle atrophy changes in rats with neuropathic pain: a pilot study. AB - The study of neuropathic pain has focused on changes within the nervous system, but little research has described systemic changes that may accompany neuropathic pain. OBJECTIVE: As part of a larger project characterizing the metabolic, activity, and musculoskeletal changes associated with neuropathic pain, the objective of the current study was to characterize changes in spontaneous activity and skeletal muscle mass using an established animal model of neuropathic pain, the chronic constriction injury (CCI) model. METHOD: Male Sprague-Dawley rats were used in this pre- and posttest quasi-experimental study. The experimental group (n = 13) received CCI surgery, while age- and weight matched rats received sham surgery (SHAM; n = 5). Thermal testing verified the presence of neuropathic pain. Spontaneous cage activity was measured gravimetrically prior to and following CCI (n = 4). Animals were euthanized and skeletal muscle was dissected and weighed to determine muscle atrophy. RESULTS: Shorter foot withdrawal latency of the ipsilateral hind limb confirmed the presence of thermal hyperalgesia in CCI rats, a sign of neuropathic pain. Weight increased in both CCI and SHAM rats. Spontaneous activity decreased following CCI ligation. Muscles of the ipsilateral hind limb weighed significantly less than contralateral hind limb muscles in CCI rats 2 and 6 weeks after surgery. In addition, CCI rats had smaller ipsilateral hind limb muscles than SHAM rats. CONCLUSION: Neuropathic pain contributes to skeletal muscle atrophy and decreases in activity in rats. PMID- 24057223 TI - Associations of schizophrenia symptoms and neurocognition with physical activity in older adults with schizophrenia. AB - BACKGROUND: Low levels of physical activity contribute to the generally poor physical health of older adults with schizophrenia. The associations linking schizophrenia symptoms, neurocognition, and physical activity are not known. Research is needed to identify the reasons for this population's lack of adequate physical activity before appropriate interventions can be designed and tested. DESIGN AND METHODS: In this cross-sectional study, 30 adults aged >=55 years with schizophrenia were assessed on symptoms (Positive and Negative Syndrome Scale), neurocognition (MATRICS Consensus Cognitive Battery), and physical activity (Sensewear ProArmband). Pearson's bivariate correlations (two-tailed) and univariate linear regression models were used to test the following hypotheses: (1) more severe schizophrenia symptoms are associated with lower levels of physical activity and (2) more severe neurocognitive deficits are associated with lower levels of physical activity. RESULTS: Higher scores on a speed-of processing test were associated with more average daily steps (p = .002) and more average daily minutes of moderate physical activity (p = .009). Higher scores on a verbal working memory task were associated with more average daily minutes of moderate physical activity (p = .05). More severe depressive symptoms were associated with more average daily minutes of sedentary activity (p = .03). CONCLUSION: Physical activity interventions for this population are imperative. In order for a physical activity intervention to be successful, it must include components to enhance cognition and diminish psychiatric symptoms. PMID- 24057224 TI - Inflammation, functional status, and weight loss during recovery from cardiac surgery in older adults: a pilot study. AB - OBJECTIVE: To determine the nutritional, inflammatory, and functional aspects of unintentional weight loss after cardiac surgery that warrant further investigation. RESEARCH METHODS AND PROCEDURES: Twenty community-dwelling adults > 65 years old undergoing cardiac surgery (coronary artery bypass graft [CABG] or CABG + valve) were recruited for this prospective longitudinal (preoperative and 4-6 weeks postdischarge) pilot study. Anthropometrics (weight, standing height, and mid-arm and calf circumference), nutritional status (Mini-Nutritional AssessmentTM [MNA]), appetite, physical performance (timed chair stand), muscle strength (hand grip) and functional status (basic and instrumental activities of daily living), and inflammatory markers (plasma leptin, ghrelin, interleukin [IL] 6, high-sensitivity[hs] C-reactive protein, and serum albumin and prealbumin) were measured. RESULTS: Participants who completed the study (n = 11 males, n = 3 females) had a mean age 70.21 +/- 4.02 years. Of these, 12 lost 3.66 +/- 1.44 kg over the study period. Weight, BMI, activities of daily living, and leptin decreased over time (p < .05). IL-6 increased over time (p < .05). Ghrelin, hs CRP, and timed chair stand increased over time in those who underwent combined procedures (p < .05). Grip strength decreased in those who developed complications (p = .004). Complications, readmission status, and lowered grip strength were found in those with low preoperative MNA scores (p < .05). CONCLUSION: After cardiac surgery, postdischarge weight loss occurs during a continued inflammatory response accompanied by decreased physical functioning and may not be a positive outcome. The impacts of weight loss, functional impairment, and inflammation during recovery on disability and frailty warrant further study. PMID- 24057225 TI - Exploring how extracellular electric field modulates neuron activity through dynamical analysis of a two-compartment neuron model. AB - To investigate how extracellular electric field modulates neuron activity, a reduced two-compartment neuron model in the presence of electric field is introduced in this study. Depending on neuronal geometric and internal coupling parameters, the behaviors of the model have been studied extensively. The neuron model can exist in quiescent state or repetitive spiking state in response to electric field stimulus. Negative electric field mainly acts as inhibitory stimulus to the neuron, positive weak electric field could modulate spiking frequency and spike timing when the neuron is already active, and positive electric fields with sufficient intensity could directly trigger neuronal spiking in the absence of other stimulations. By bifurcation analysis, it is observed that there is saddle-node on invariant circle bifurcation, supercritical Hopf bifurcation and subcritical Hopf bifurcation appearing in the obtained two parameter bifurcation diagrams. The bifurcation structures and electric field thresholds for triggering neuron firing are determined by neuronal geometric and coupling parameters. The model predicts that the neurons with a nonsymmetric morphology between soma and dendrite, are more sensitive to electric field stimulus than those with the spherical structure. These findings suggest that neuronal geometric features play a crucial role in electric field effects on the polarization of neuronal compartments. Moreover, by determining the electric field threshold of our biophysical model, we could accurately distinguish between suprathreshold and subthreshold electric fields. Our study highlights the effects of extracellular electric field on neuronal activity from the biophysical modeling point of view. These insights into the dynamical mechanism of electric field may contribute to the investigation and development of electromagnetic therapies, and the model in our study could be further extended to a neuronal network in which the effects of electric fields on network activity may be investigated. PMID- 24057226 TI - Rapid differentiation and quantification of live/dead cancer cells using differential photochemical behavior of acridine orange. AB - This paper demonstrates for the first time a simple analytical method for differentiation and quantification of dead/live cancer cells using acridine orange (AO) enabled fluorescence spectroscopic techniques. Based on the differential fluorescence (live cells fluoresce green and dead cells orange) exhibited when intercalated with AO, the live/dead cells can be easily differentiated. The optimal AO concentration for enhanced sensitive differentiation has been optimized as 0.001%. These studies offer a promising application for rapid differentiation and quantification of live/dead cells in the case of cytotoxic treatment/therapies within several minutes. PMID- 24057227 TI - Tissue distribution and subcellular localization of hyaluronan synthase isoenzymes. AB - Hyaluronan synthases (HAS) are unique plasma membrane glycosyltransferases secreting this glycosaminoglycan directly to the extracellular space. The three HAS isoenzymes (HAS1, HAS2, and HAS3) expressed in mammalian cells differ in their enzymatic properties and regulation by external stimuli, but clearly distinct functions have not been established. To overview the expression of different HAS isoenzymes during embryonic development and their subcellular localization, we immunostained mouse embryonic samples and cultured cells with HAS antibodies, correlating their distribution to hyaluronan staining. Their subcellular localization was further studied by GFP-HAS fusion proteins. Intense hyaluronan staining was observed throughout the development in the tissues of mesodermal origin, like heart and cartilages, but also for example during the maturation of kidneys and stratified epithelia. In general, staining for one or several HASs correlated with hyaluronan staining. The staining of HAS2 was most widespread, both spatially and temporally, correlating with hyaluronan staining especially in early mesenchymal tissues and heart. While epithelial cells were mostly negative for HASs, stratified epithelia became HAS positive during differentiation. All HAS isoenzymes showed cytoplasmic immunoreactivity, both in tissue sections and cultured cells, while plasma membrane staining was also detected, often in cellular extensions. HAS1 had brightest signal in Golgi, HAS3 in Golgi and microvillous protrusions, whereas most of the endogenous HAS2 immunoreactivity was localized in the ER. This differential pattern was also observed with transfected GFP-HASs. The large proportion of intracellular HASs suggests that HAS forms a reserve that is transported to the plasma membrane for rapid activation of hyaluronan synthesis. PMID- 24057229 TI - Thyroid disease in children: part 1: State-of-the-art imaging in pediatric hypothyroidism. AB - Hypothyroidism, defined as inadequate production of thyroid hormone, can be secondary to various underlying abnormalities in the pediatric population. Most frequently, hypothyroidism is related to structural abnormalities of the gland (dysgenesis), particularly in the neonatal population. However, other etiologies including intrinsic biochemical (dyshormonogenesis) and autoimmune abnormalities, as well as other rare causes, must be considered. Imaging is required to differentiate among the various etiologies of hypothyroidism and can be helpful in guiding therapy. This review aims to present an organized approach to hypothyroidism in the pediatric population, and assist the imager in guiding patient care. PMID- 24057230 TI - Thyroid disease in children: part 2 : State-of-the-art imaging in pediatric hyperthyroidism. AB - Hyperthyroidism occurs secondary to overproduction of thyroid hormone by the thyroid gland. This condition can have rather serious effects on children, and thus timely diagnosis and treatment are of utmost importance. Imaging is quite useful in the management of children with hyperthyroidism. In addition to determining the underlying pathology, radiologic exams are crucial for therapy. This article describes the underlying etiologies of pediatric hyperthyroidism and provides general information on treatment. PMID- 24057233 TI - Microscope-based near-infrared stereo-imaging system for quantifying the motion of the murine epicardial coronary arteries in vivo. AB - Atherosclerosis is a leading cause of mortality in industrialized countries. In addition to "traditional" systemic risk factors for atherosclerosis, the geometry and motion of coronary arteries may contribute to individual susceptibility to the development and progression of disease in these vessels. To be able to test this, we have developed a high-speed (~40 frames per second) microscope-based stereo-imaging system to quantify the motion of epicardial coronary arteries of mice. Using near-infrared nontargeted quantum dots as an imaging contrast agent, we synchronously acquired paired images of a surgically exposed murine heart, from which the three-dimensional geometry of the coronary arteries was reconstructed. The reconstructed geometry was tracked frame by frame through the cardiac cycle to quantify the in vivo motion of the vessel, from which displacements, curvature, and torsion parameters were derived. Illustrative results for a C57BL/6J mouse are presented. PMID- 24057234 TI - Identification of human patatin-like phospholipase domain-containing protein 1 and a mutant in human cervical cancer HeLa cells. AB - Recently members of mammalian patatin-like phospholipase domain containing (PNPLA) protein family have attracted attention for their critical roles in diverse aspects of lipid metabolism and signal pathway. Until now little has been known about the characteristics of PNPLA1. Here, the full length coding cDNA sequence of human PNPLA1 (hPNPLA1) was cloned for the first time, which encoded a polypeptide with 532 amino acids containing the whole patatin domain. Tissue expression profiles analysis showed that low mRNA levels of hPNPLA1 existed in various tissues, except high expression in the digestive system, bone marrow and spleen. Subcellular distribution of hPNPLA1 tagged with green fluorescence protein mainly localized to lipid droplets. Furthermore, a nonsense mutation of PNPLA1 in human cervical cancer HeLa cells was identified. The hPNPLA1 mutant encoded a protein of 412 amino acids without the C-terminal domain and did not colocalize to lipid droplets, which suggested that the C-terminal region of hPNPLA1 affected lipid droplet binding. These results identified hPNPLA1 and a mutant in HeLa cells, and provided insights into the structure and function of PNPLA1. PMID- 24057235 TI - Quality characteristic of spray-drying egg white powders. AB - Spray drying is a useful method for developing egg process and utilization. The objective of this study was to evaluate effects on spray drying condition of egg white. The optimized conditions were spraying flow 22 mL/min, feeding temperature 39.8 degrees C and inlet-air temperature 178.2 degrees C. Results of sulfydryl (SH) groups measurement indicated conformation structure have changed resulting in protein molecule occur S-S crosslinking phenomenon when heating. It led to free SH content decreased during spray drying process. There was almost no change of differential scanning calorimetry between fresh egg white and spray-drying egg white powder (EWP). For a given protein, the apparent SH reactivity is in turn influenced by the physico-chemical characteristics of the reactant. The phenomenon illustrated the thermal denaturation of these proteins was unrelated to their free SH contents. Color measurement was used to study browning level. EWP in optimized conditions revealed insignificant brown stain. Swelling capacity and scanning electron micrograph both proved well quality characteristic of spray drying EWP. Results suggested spray drying under the optimized conditions present suitable and alternative method for egg processing industrial implementation. Egg food industrialization needs new drying method to extend shelf-life. The purpose of the study was to provide optimal process of healthy and nutritional instant spray-drying EWP and study quality characteristic of spray-drying EWP. PMID- 24057236 TI - Tumor suppressor ING4 overexpression contributes to proliferation and invasion inhibition in gastric carcinoma by suppressing the NF-kappaB signaling pathway. AB - There is growing evidence that inhibitor of growth 4 (ING4) plays a pivotal role in development and progression of multiple different tumors; however, its precise function in gastric carcinoma remains to be elucidated. In the present study, we investigated ING4 level in gastric carcinoma tissues and cells, and preliminarily elucidated the role of ING4 in the proliferation and invasion of gastric carcinoma. The results demonstrated that expressions of ING4 mRNA and protein in gastric carcinoma tissues and cells were significantly lower than those in normal tissues and cells (P < 0.05). ING4 level in gastric carcinoma cells stably expressing ING4 was markedly higher than those in untreated group and empty vector pcDNA3.1 group (P < 0.05). Elevated ING4 level resulted in the inhibition of proliferation and invasion in three of gastric carcinoma cell lines MKN-28, SGC-7901 and MKN-45. Most notably, increased ING4 level evidently evoked the down regulation of p65, p-IkappaBalpha, MMP-9 and uPA proteins and the up-regulation of IkappaBalpha protein. Our results presented herein suggest that ING4 level elevation mediated proliferation and invasion inhibition may be tightly associated with the suppression of NF-kappaB signaling pathway. PMID- 24057237 TI - Protective effects of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate in bladder ischemia-reperfusion injury in rats. AB - The aim of the present study was to evaluate the protective effects of the NF-kB inhibition with pyrrolidine-dithiocarbamate (PDTC) in ischemia-reperfusion (I/R) injury in the rat bladder. Twenty-four Sprague-Dawley male rats were divided into three groups. Group I; (n = 8) control, group II; (n = 8) I/R group; group III (n = 8) I/R and PDTC treatment. Superoxide dismutase (SOD), catalase (CAT), and gluatathione-S-transferase (GST) enzymes was studied in bladder tissue. Lipid peroxidation (as TBARS) levels in tissue homogenate were measured with thiobarbituric acid reaction. All the slides were stained with NF-kB, p53 and HSP60 immunohistochemistry for detection genome destruction and tissue stress, respectively. Our results show that the mean TBARS levels were significantly higher in group II (p < 0.05). The TBARS levels were significantly decreased in group III compared with the group II (p < 0.05). CAT, SOD and GST activities were decreased in group II, but these enzymes levels were significantly increased in group III according to the group II (p < 0.05). Under microscopic evaluation NF kB expression increased significantly in group II compared to the group I (p < 0.05) and then decreased in group III (p < 0.05). HSP60 and p53 expression in group II was increased significantly compared with group I. Under microscopic evaluation we detected that HSP60 and p53 expression was increased significantly in group II compared with group I. In group III PDTC administration was decreased the HSP60 and p53 expression, this difference was statistically significant (p < 0.05). The results of the present study have demonstrated that NF-kB inhibition with PDTC protects and provides beneficial effects on ischemia/reperfusion stress related bladder tissue destruction. PMID- 24057238 TI - Susceptibility gene search for nephropathy and related traits in Mexican Americans. AB - The rising global epidemic of diabetic nephropathy (DN) will likely lead to increase in the prevalence of cardiovascular morbidity and mortality posing a serious burden for public health care. Despite greater understanding of the etiology of diabetes and the development of novel treatment strategies to control blood glucose levels, the prevalence and incidence rate of DN is increasing especially in minority populations including Mexican-Americans. Mexican-Americans with type 2 diabetes (T2DM) are three times more likely to develop microalbuminuria, and four times more likely to develop clinical proteinuria compared to non-Hispanic whites. Furthermore, Mexican-Americans have a sixfold increased risk of developing renal failure secondary to T2DM compared to Caucasians. Prevention and better treatment of DN should be a high priority for both health-care organizations and society at large. Pathogenesis of DN is multi factorial. Familial clustering of DN-related traits in MAs show that DN and related traits are heritable and that genes play a susceptibility role. While, there has been some progress in identifying genes which when mutated influence an individual's risk, major gene(s) responsible for DN are yet to be identified. Knowledge of the genetic causes of DN is essential for elucidation of its mechanisms, and for adequate classification, prognosis, and treatment. Self identification and collaboration among researchers with suitable genomic and clinical data for meta-analyses in Mexican-Americans is critical for progress in replicating/identifying DN risk genes in this population. This paper reviews the approaches and recent efforts made to identify genetic variants contributing to risk for DN and related phenotypes in the Mexican-American population. PMID- 24057239 TI - Association of the costimulatory molecule gene polymorphisms and active cytomegalovirus infection in hematopoietic stem cell transplant patients. AB - Determinative associations may exist between costimulatory molecule gene polymorphisms with a variety of post hematopoietic stem cell transplantation (HSCT) viral related clinical outcomes especially acute graft versus host disease (aGVHD). Therefore in this study the associations between costimulatory molecule gene polymorphisms including: cytotoxic T-lymphocyte antigen-4 (CTLA4), programmed cell death-1 (PD-1), inducible T cell costimulator (ICOS), and cluster differentiation 28 (CD28) with active cytomegalovirus (CMV) infection were evaluated in HSCT patients. The 72 allogeneic HSCT patients with and without aGVHD were enrolled in this cross sectional study between years: 2004-2011. The single nucleotide polymorphisms in loci of the costimulatory molecules including: CTLA4 gene (-318 C/T, 1722 T/C, 1661 A/G, +49 A/G), PD-1 gene (PD-1.3 A/G, PD-1.9 C/T), ICOS gene (1720 C/T), and CD28 gene (+17 C/T) were analyzed in studied HSCT patients by PCR-RFLP methods. The active CMV infection was evaluated in fresh EDTA-treated blood samples of each allogeneic HSCT patients by CMV antigenemia kit according to manufacturer's instruction. Active CMV infection was found in 11 of 72 (15.27 %) of allogeneic HSCT patients. The T allele and TT genotype of the CD28 +17 C/T were significantly higher frequency in active CMV infected allogeneic HSCT patients experienced aGVHD. The G allele and GG genotype of the CTLA4 -1661 A/G were significantly higher frequent in active CMV infected allogeneic HSCT patients experienced low grade of aGVHD. Finally, finding of significant associations between CD28 +17 C/T and CTLA4 -1661 A/G genotypes with CMV active infection in allogeneic HSCT patients experienced aGVHD emphasize on the importance of the genetic pattern of costimulatory genes in outcomes of active CMV infection in HSCT patients needs completed studies. PMID- 24057240 TI - Angiogenic and anti-angiogenic factor gene transcript level quantitation by quantitative real time PCR in patients with hepatocellular carcinoma. AB - Tumor angiogenesis, a major requirement for tumor growth and metastasis, is regulated by pro- and anti-angiogenic factors. The aim of this study was to quantify the expression of angiogenic (VEGF, HIF-1alpha, Angiopiotein-2) and anti angiogenic (endostatin, angiostatin and Thrombospondin-1) factors and to discern their clinical relevance. A total 90 patients (67 HCC, 9 cirrhosis and 14 chronic hepatitis) were enrolled in the study. Tissue transcript levels of angiogenic (VEGF, HIF-1alpha, Ang-2) and anti-angiogenic (endostatin, angiostatin and TSP-1) factors were analyzed by quantitative real time-polymerase chain reaction (qRT PCR) in the tissue samples. The tissue transcript levels of VEGF, HIF-1alpha and endostatin were found to be significantly higher in HCC in comparison to cirrhosis and chronic hepatitis. Although Ang-2, angiostatin and TSP-1 tissue transcript levels were higher in HCC group than the others groups but the difference was not statistically significant. In univariate analysis both VEGF and HIF-1alpha were found to be associated with poor survival of HCC patients. Multivariate analysis by the cox proportional hazard model revealed only VEGF as an independent factor predicting poor survival of the HCC patients. Angiogenic and anti-angiogenic factors are all highly expressed in HCC patients. Upregulation of tissue anti-angiogenic factors indicates the urgency for the alternative of anti-angiogenic therapies. PMID- 24057241 TI - Genetic characterization and authentication of Lonicera japonica Thunb. by using improved RAPD analysis. AB - In traditional medicine, Lonicera japonica (Thunb.) has a notable place, and it has been used for thousands of years in China, Japan, Korea and other East-Asian countries for treating cancer, inflammation, hepatic complications, influenza and wounds. However, the molecular or genetic characteristic of this plant is not well defined. In this study, improved random amplified polymorphic DNA (RAPD) has been employed for the genetic characterization of five varieties of L. japonica collected from different geographic locations of Southern China. A total of 147 bands of DNA fragments were obtained in RAPD-PCR by using 18 primers, and the band sizes ranged from approximately 300-2,000 bp, with 3-11 amplified bands for each primer. Based on the RAPD amplification profiles, cluster dendrogram was obtained, which showed that the similarity coefficients among five varieties of L. japonica ranged from 0.59 to 0.77. To our knowledge, this is the first report of genetic characterization of L. japonica using improved RAPD analysis which has been validated by ISSR analysis, and this characterization may be useful for the preservation of genetic diversity and Lonicera population identification. Moreover, as an option, the improved method could be employed for a variety of applications in genetic diversity and fingerprinting analyses. PMID- 24057242 TI - Association between interferon gamma +874 T>A polymorphism and acute renal allograft rejection: evidence from published studies. AB - Interferon gamma is involved in the acute rejection (AR) episodes of transplant recipients. However, results from published studies on the association of interferon gamma (IFNG) +874 T>A (rs2430561) polymorphism with AR of renal allograft are conflicting. To investigate the association between IFNG +874 T>A polymorphism with AR after renal transplantation, relevant studies were selected from PUBMED, EMBASE, Wanfang database and China National Knowledge Infrastructure until March 1st 2013. According the predesigned selection criteria, a total of 525 AR cases and 1,126 non-AR cases from 13 case-control studies were included to identify the strength of association with odds ratio (OR) and 95 % confidence intervals (95 % CI). Overall, a significant correlation between IFNG +874 T>A polymorphism and susceptibility to AR was detected (T allele vs. A allele: OR = 1.19, 95 % CI 1.02-1.38; TT/AT vs. AA: OR = 1.36, 95 % CI 1.07-1.73; TT vs. AA: OR = 1.42, 95 % CI 1.05-1.93; AT vs. AA: OR = 1.30, 95 % CI 1.01-1.68). In addition, ethnicity subgroup analysis revealed that high produce genotype (TT/AT) was associated with an increased risk of AR for Caucasians (TT/AT vs. AA: OR = 1.56, 95 % CI 1.14-2.12; TT vs. AA: OR = 1.64, 95 % CI 1.18-2.26). Furthermore, donor source subgroup analysis observed an increased risk for patients undergoing cadaveric kidney transplantation (TT/AT vs. AA: OR = 1.90, 95 % CI 1.12-3.24; TA vs. AA: OR = 2.16, 95 % CI 1.24-3.74). In conclusion, this meta-analysis suggested that IFNG +874 T>A polymorphism was associated with AR of renal transplant recipients, especially among Caucasians and those receiving cadaveric renal allograft. Additional well-designed studies with large sample size are warranted to validate our conclusion. PMID- 24057243 TI - Investigation of individual heterozygosity correlated to growth traits in Tongshan Black-boned goat. AB - Ten single nucleotide polymorphisms were used for genotyping of 176 Tongshan Black-boned goats, which are Chinese indigenous goat colony for meat production. The average individual heterozygosity was 0.292. To assess the correlations between individual heterozygosity and growth in Tongshan Black-boned goat individuals, and the potential of using individual heterozygosity as an indicator of growth, the data of growth traits, including body weight, height at withers, body length, chest girth and cannon circumference, were collected. Significant correlations were observed between individual heterozygosity and body weight, height at withers, body length, heart girth, cannon circumference (P < 0.05). All the significant regression showed positive slope with R square values ranged from 0.0251 to 0.0368. These data suggests that individual heterozygosity is positively correlated with growth traits in Tongshan Black-boned goat individuals and associative overdominance may affect Tongshan Black-boned goat growth significantly. Therefore it is possible to use individual heterozygosity as an indicator of growth. Our results also provide a strong support to the overdominance hypothesis. PMID- 24057244 TI - Detection of HbsAg and hATIII genetically modified goats (Caprahircus) by loop mediated isothermal amplification. AB - In this study, sensitive and rapid detection systems were designed using a loop mediated isothermal amplification (LAMP) method to detect the genetically modified goats. A set of 4 primers were designed for each exogenous nucleic acids HBsAg and hATIII. The DNA samples were first amplified with the outer and inner primers and released a single-stranded DNA,of which both ends were stem-loop structure. Then one inner primer hybridized with the loop, and initiated displacement synthesis in less than 1 h. The result could be visualized by both agarose gel electrophoresis and unaided eyes directly after adding SYBR GREEN 1. The detection limit of LAMP was ten copies of target molecules, indicating that LAMP was tenfold more sensitive than the classical PCR. Furthermore, all the samples of genetically modified goats were tested positively by LAMP, and the results demonstrated that the LAMP was a rapid and sensitive method for detecting the genetically modified organism. PMID- 24057245 TI - Chronic hepatitis B and IL28B rs12979860 polymorphism: preliminary study. AB - The aim of this study is to evaluate the role of IL28B rs12979860 polymorphism on pegylated interferon (peg IFN) and oral antiviral treatment in chronic hepatitis B (CHB) patients and to investigate the relationship between the severities of illness with this polymorphism. 74 CHB patients who are received treatment, 61 asymptomatic carriers and 40 healthy controls were recruited in this study. Genomic DNA of controls and patients were extracted from whole blood using High Pure PCR Template Preparation Kit (Roche, Mannheim, Germany) according to the manufacturer's instructions and stored at 4 degrees C. Genotype distribution of the IL-28B polymorphism at position -3176C/T (rs12979860) (LightMix Kit IL28B, Cat.-No. 40-0588-32 TIB MOLBIOL, Berlin, Germany) was detected by real time PCR (Roche Diagnostics, Manheim, Germany). Thirty of the patients with CHB received peg IFN-alpha treatment. There were no significant difference between groups by means of age, gender and IL28B rs12979860 polymorphism (p = 0.122, p = 0.07, p = 0.376 respectively). Patients with chronic hepatitis were categorized as grade and stage (minimal, moderate and severe) and then were analyzed for the polymorphism. There was no effect of IL28B -3176 C/T polymorphism on severity of illness (p = 0.293 for grade, p = 0.911 for stage). When the CHB treatment monitored in different time arrivals (beginning, 3th, 6th and 12th months of the treatment) in order to see if there was an effect on virological and biological response none of the genotypes of IL28B -3176C/T polymorphism altered peg IFN or oral antiviral treatment process. There are conflicting results about the role of IL28B rs12979860 polymorphism in CHB in the literature. In this preliminary study, we observed that IL28B rs12979860 polymorphism was not related with severity of illness and also was not effective on treatment response. PMID- 24057246 TI - Polymorphism of follicle stimulating hormone beta (FSHbeta) subunit gene and its association with litter traits in giant panda. AB - The different SSCP patterns of the follicle stimulating hormone beta (FSHbeta) gene amplified by three pairs of primers were sequenced. Comparisons among the three nucleotide sequences of three genotypes indicated that three base substitutions (A213T, A91G, and A89C) were detected in FSHbeta gene, which A213T substitution led to one amino acids mutation (Lys > Met), and the other two substitutions were synonymous mutations. The AA, AB and BB genotypes patterns obtained by FSHbeta primer1 had evident relation with the litter traits, but the SSCP genotypes patterns obtained by FSHbeta primer2 and primer3 had no evident relation with the litter traits in giant panda. The giant panda with AA and AB genotype had the largest litter size and multiparity rate compared with the BB genotypes (P < 0.05). We speculated that the giant pandas with the A allele have better litter traits than those with the B allele. PMID- 24057247 TI - Description of new mitochondrial genomes (Spodoptera litura, Noctuoidea and Cnaphalocrocis medinalis, Pyraloidea) and phylogenetic reconstruction of Lepidoptera with the comment on optimization schemes. AB - We newly sequenced mitochondrial genomes of Spodoptera litura and Cnaphalocrocis medinalis belonging to Lepidoptera to obtain further insight into mitochondrial genome evolution in this group and investigated the influence of optimal strategies on phylogenetic reconstruction of Lepidoptera. Estimation of p distances of each mitochondrial gene for available taxonomic levels has shown the highest value in ND6, whereas the lowest values in COI and COII at the nucleotide level, suggesting different utility of each gene for different hierarchical group when individual genes are utilized for phylogenetic analysis. Phylogenetic analyses mainly yielded the relationships (((((Bombycoidea + Geometroidea) + Noctuoidea) + Pyraloidea) + Papilionoidea) + Tortricoidea), evidencing the polyphyly of Macrolepidoptera. The Noctuoidea concordantly recovered the familial relationships (((Arctiidae + Lymantriidae) + Noctuidae) + Notodontidae). The tests of optimality strategies, such as exclusion of third codon positions, inclusion of rRNA and tRNA genes, data partitioning, RY recoding approach, and recoding nucleotides into amino acids suggested that the majority of the strategies did not substantially alter phylogenetic topologies or nodal supports, except for the sister relationship between Lycaenidae and Pieridae only in the amino acid dataset, which was in contrast to the sister relationship between Lycaenidae and Nymphalidae in Papilionoidea in the remaining datasets. PMID- 24057248 TI - Gardiquimod inhibits the expression of calcium-induced differentiation markers in HaCaT cells. AB - Toll-like receptor 7 (TLR7) is an important member in pattern recognition receptors families. TLR7 signal pathway is involved in the physiological process in many type cells, but the impact of TRL7 on differentiation in the human keratinocytes is still unknown. In this study, we investigated the expression of TLR7 in keratinocytes, and the effect of TLR7 agonist gardiquimod on the expression of calcium (Ca(2+))-induced keratinocytes differentiation markers in HaCaT cells. Immunohistochemistry and western-blotting analysis showed that TLR7 is expressed in basal keratinocytes of normal skin and in the human keratinocyte cell line HaCaT, but not expressed in the keratinocytes of psoriasis lesions. Pretreatment with gardiquimod could down-regulate Ca(2+)-induced differentiation marker expression and activate Raf-MEK-ERK and PI3K-AKT signal pathways in HaCaT cells. However, specific inhibitors studies showed that the down-regulation of the differentiation markers expression by gardiquimod was not dependent on the activation of these two pathways. TLR7 may play an important role in the pathogenesis of psoriasis through regulating the differentiation of the keratinocytes, and will give a new insight into the psoriasis. PMID- 24057249 TI - Analysis of the associations between polymorphisms in GNAS complex locus and growth, carcass and meat quality traits in pigs. AB - Imprinted genes are interesting candidates for marker assisted selection in farm animals. One of them-GNAS complex locus is engaged in obesity pathogenesis in humans and mice. In our study, we identified new polymorphism in porcine GNAS gene (variable number of CT repeats, accession number: rs196952953) and found that this polymorphism is in linkage disequilibrum with GNAS AM490165:g.324C>T. Statistical analysis (GLM procedure), performed on 552 animals (Large White n = 258 and Landrace n = 269), revealed that deduced haplotypes and GNAS AM490165:g.324C>T are associated with growth performance and a few carcass traits, but not with feed intake. We observed significant additive effects of GNAS AM490165:g.324C>T genotype and haplotype 2 (C/278 bp) on test daily gain (TDG), average daily gain (ADG), number of days on test, age of the slaughter (P < 0.01) and FCR ratio (P < 0.05). Animals with two copies of C/278 haplotype had significantly higher: TDG, ADG, lower feed:gain ratio and faster reached the weight of 100 kg. When carcass traits were considered, significant associations between GNAS AM490165:g.324C>T polymorphism, haplotype 2 (C/278) and weight of ham with and without backfat and skin (WH) (WH2), length of the carcass, height and the width of the loin, meat percentage, weight of the main cuts were identified. The significant dominance effects of GNAS AM490165:g.324C>T polymorphism and haplotype 2 on WH and WH2 were observed (P < 0.05). When the two breeds were analyzed separately significant associations were observed for most of the traits in Landrace while in Large White the same trends were present but the differences were mostly not significant. Among meat quality traits we found significant association between haplotype and IMF content in Landrace (P < 0.03). Our results show for the first time that GNAS complex locus may modulate economically important traits in pigs. PMID- 24057250 TI - Characterization of a novel Medicago sativa NAC transcription factor gene involved in response to drought stress. AB - Relying on the regulation of transcription factors, plants resist to various abiotic and biotic stresses. NAC (NAM, ATAF1/2, CUC2) are one of the largest families of plant-specific transcription factors and known to play important roles in plant development and response to environmental stresses. A new NAC gene was cloned on the basis of 503 bp EST fragment from the SSH cDNA library of Medicago sativa. It was 1,115 bp including an 816 bp ORF and encodes 271 amino acids. A highly conserved region is located from the 7th amino acid to the 315th amino acid in its N-terminal domain. The NAC protein is subcellularly localized in the nucleus of onion epidemical cells and possible functions as a transcription factor. The relative quantitative real-time RT-PCR was performed at different stress time. The results revealed that the transcription expression of NAC gene could be induced by drought, high salinity and ABA. The transgenic Arabidopsis with NAC gene has the drought tolerance better than the wild-type. PMID- 24057251 TI - Components of antioxidant system of Picrorhiza kurrooa exhibit different spatio temporal behavior. AB - Antioxidant system is one of the important factors in regulating plant growth, development and adaptation. Thus, in order to have better insights into molecular mechanisms of growth and adaptation of a plant it is prerequisite to have known the status of various components of the antioxidant system of the plant. Here we studied the status of enzymatic and non-enzymatic components of the antioxidant system of picrorhiza (Picrorhiza kurrooa). Picrorhiza is an important medicinal herb of western Himalayan region and has been listed in the Red Data Book as an endangered species. Spatio-temporal analysis of ascorbic acid and glutathione in leaf, root and rhizome during different stages of development revealed differential status of these antioxidant molecules. Of the three tissues, ascorbic acid was found to be highest in leaves and lowest in roots. Interestingly, just opposite to that, glutathione was highest in roots and lowest in leaves. Using degenerate primers based approach followed by rapid amplification of complementary DNA (cDNA) ends method, full length cDNAs of three important genes namely Picrorhiza kurrooa ascorbate peroxidase (pkapx), Picrorhiza kurrooa monodehydroascorbate reductase (pkmdhar) and Picrorhiza kurrooa glutathione reductase (pkgr) of antioxidant system were cloned from picrorhiza. Complementary DNAs of pkapx, pkmdhar and pkgr contained 1,049, 2,016 and 1,664 bp, respectively. Expression analysis showed differential spatio temporal expression of these genes. Expressions of all the three genes were found higher in roots as compared to rhizome and leaves. Temporal expression analysis of pkapx, pkmdhar and pkgr revealed differential transcript levels. Expression of pkapx exhibited negative correlation with the light intensity. Just opposite to the pkapx, expression pattern of pkgr revealed its positive correlation with light intensity. Expression pattern of pkmdhar revealed its light independent expression behavior. The findings may be useful to assess the role of cloned genes in picrorhiza growth, adaptation and can further be utilized for transgenic development for desired trait(s). PMID- 24057252 TI - Amplification and deletion of the RAPH1 gene in breast cancer patients. AB - Lamellipodin protein (Lpd), encoded by the RAPH1 gene, modulates the assembly of actin cytoskeleton through its binding to the Ena/VASPs proteins, and acts in cellular motility and lamelipodial protrusion. The region where RAPH1 gene is located (2q33) is deleted in various types of cancer and the gene expression changes in tumors when compared to normal tissues. Amplifications and deletions of the RAPH1 gene were investigated in breast carcinoma samples, in order to determine the possible relationship of the gene with breast cancer tumorigenesis and lymph node metastasis. RAPH1 gene alterations were determined by relative quantification, standard curve method using Real-time PCR technique in samples of tumor and peripheral blood from 52 patients. Regression and correlation analyses were conducted using gene alterations and clinicopathological data. All samples analyzed were altered, with 63.5 % deletion cases and 36.5 % amplification cases. The logistic regression and correlation analysis with clinicopathological data did not show significant results. The results suggest that although the RAPH1 gene was deleted or amplified in all samples, the Lpd does not seem to play a major role in tumorigenesis of mammary carcinomas and probably other proteins, also involved in the process of cellular motility and metastasis, are acting more effectively for or against the migration of breast tumor cells. PMID- 24057253 TI - VEGF +936C/T and +460C/T gene polymorphisms and oral cancer risk: a meta analysis. AB - Many studies have examined the association between the VEGF +936C/T (rs833061) and +460C/T (rs3025039) gene polymorphisms and oral cancer risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, we performed a meta-analysis. The PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases were searched for case-control studies that were published up to January 2013. Data were extracted and pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated. Ultimately, six studies were included, comprising 1006 oral cancer cases and 1016 controls. Overall, the pooled OR for VEGF +936 T allele carriers (TC + TT) versus the wild-type homozygotes (CC) was 1.28 (95 % CI 1.04 1.58; P = 0.228 for heterogeneity), the pooled OR for TT versus CC was 1.64 (95 % CI 1.34-1.98; P = 0.315 for heterogeneity), and the pooled OR for the T allele versus the C allele was 1.42 (95 % CI 1.22-1.76; P = 0.286 for heterogeneity). In the stratified analysis by ethnicity, significant risks were found among Caucasians but not Asians. However, there were no associations between VEGF +460C/T and oral cancer risk in only two of the included studies. In conclusion, this meta-analysis demonstrates that the VEGF +936 T allele may be associated with an increased risk of oral cancer, especially among Caucasian populations. PMID- 24057254 TI - Validation of reference genes for quantitative gene expression studies in Volvox carteri using real-time RT-PCR. AB - Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) is a sensitive technique for analysis of gene expression under a wide diversity of biological conditions. However, the identification of suitable reference genes is a critical factor for analysis of gene expression data. To determine potential reference genes for normalization of qRT-PCR data in the green alga Volvox carteri, the transcript levels of ten candidate reference genes were measured by qRT-PCR in three experimental sample pools containing different developmental stages, cell types and stress treatments. The expression stability of the candidate reference genes was then calculated using the algorithms geNorm, NormFinder and BestKeeper. The genes for 18S ribosomal RNA (18S) and eukaryotic translation elongation factor 1alpha2 (eef1) turned out to have the most stable expression levels among the samples both from different developmental stages and different stress treatments. The genes for the ribosomal protein L23 (rpl23) and the TATA-box binding protein (tbpA) showed equivalent transcript levels in the comparison of different cell types, and therefore, can be used as reference genes for cell-type specific gene expression analysis. Our results indicate that more than one reference gene is required for accurate normalization of qRT-PCRs in V. carteri. The reference genes in our study show a much better performance than the housekeeping genes used as a reference in previous studies. PMID- 24057255 TI - The apoptotic actions of platelets in acute ischemic stroke. AB - Stroke is a disease that affects the blood vessels that supply blood to the brain. Although platelets are implicated in the pathophysiology of stroke the mechanism is still not clear and there antiplatelet agents available for the prevention and treatment of stroke. We herein examined the relationship between the potential cytokine, TNF-alpha platelet activation and apoptosis in acute ischemic stroke patients. We selected 60 patients (mean age 57.9 +/- 10.2 years) who had not taken any antiplatelet drugs for 14 days. A group of 45 participants (mean age 51.05 +/- 9.07 years) were selected as the control group. For both the patients and for the control group, P-selectin (CD62p) and Annexin-V binding, cytochrome-c levels, caspase-3 gene expression and caspase-3 releasing and plasma TNF-alpha levels were measured in platelets. The results showed significant increase in plasma TNF-alpha and platelet Annexin-V, CD62p, cytochrome-c and caspase-3 gene expression in stroke patients compared to the control group. The data of this work suggests that inflammation may have a role in platelet apoptosis in stroke which may suggest a new aspect of the role of inflammation in the development of acute ischemic stroke. PMID- 24057256 TI - Genetic variation and phylogenetic relationship between three serow species of the genus Capricornis based on the complete mitochondrial DNA control region sequences. AB - The molecular evidence of phylogenetic status regarding the Formosan serow (Capricornis swinhoei) is not robust and little is known about the genetic diversity of the Sumatran serow (Capricornis sumatraensis), which partly is due to the hardness in sample collection. Here we determined the sequences of the complete mitochondrial DNA control region (1,014 bp) of 19 Sumatran-serow individuals. Nine new haplotypes were defined based on 78 variable sites. Combined analysis with other 32 haplotypes downloaded from the public database, including 1 Sumatran-serow, 11 Formosan-serow and 20 Japanese-serow (Capricornis crispus) haplotypes, a relatively high level of nucleotide diversity was first observed in Sumatran serow (pi = 0.0249). By comparative analysis with structural consensus sequences from other mammals, we have identified central, left and right domains and depicted the putative functional structure, including extend termination associated sequences and conserve sequence blocks, in mtDNA control region. The alignment of mtDNA control region revealed that both Sumatran and Japanese serow have two tandem repeats (TRs), but three TRs in Formosan serow. Phylogenetic analyses revealed that the Formosan serow is distinct species with the Japanese serow, but a sister group with the Sumatran serow. The divergence time estimated among three serow species revealed that Pleistocene climate changes and the uplift of Qinghai-Tibetan plateau might play an important role in the genetic differentiation of the serows. These results mainly provide the convinced evidence on the genetic relationship between three serow species. PMID- 24057257 TI - The evaluation of the usefulness of pedigree verification-dedicated SNPs for breed assignment in three polish cattle populations. AB - The breed assignment in cattle is one of the issues of molecular genetics which needs further testing and development. Although several statistical approaches have been developed to enable such application, the obtained results strongly depend on specific populations differentiation and power of markers discrimination or their informativeness. Currently, all breeding animals are being tested for parentage with the use of panel of 12 microsatellite markers, which in near future probably will be replaced by about 100 single nucleotide polymorphisms (SNPs). Despite the fact that SNPs are mainly bi-allelic, the multilocus genotypes can reach the level of polymorphism of a panel of microsatellite markers. In this study we attempted to determine the breed of origin of 741 cattle by using 120 SNPs dedicated for parentage testing and included in the BovineSNP50 BeadChip genotyping assay (Illumina). The applied Bayesian and frequency-based methods allowed such differentiation, however, the reliability of the results was not completely satisfying, suggesting that the studied markers are not the best tool for breed assignment. PMID- 24057260 TI - A computational study on the stereoselective organocatalytic epoxidation of alpha,beta-unsaturated aldehydes with hydrogen peroxide. AB - The asymmetric synthesis of vicinal diols is a very important process in organic chemistry, as it allows the preparation of a large variety of useful derivatives. One of the most interesting methods to accomplish this synthesis is the asymmetric epoxidation of activated olefins, catalysed by chiral organic or organometallic catalysts. In this paper we study, with computational tools, two possible mechanisms for the asymmetric epoxidation of conjugated aldehydes with hydrogen peroxide, catalysed by chiral pyrrolidine derivatives lacking proton donor groups. Our results indicate that the mechanism that proceeds by the initial formation of an iminium intermediate is more probable than the mechanism proceeding by general base catalysis. We also conclude that besides the oxidant role of hydrogen peroxide, it also has a very important role as a co-catalyst in the initial formation of the iminium intermediates. Moreover, epoxide formation is suggested to be a two-step process that needs the explicit participation of a hydroxyl ion. In the absence of this ion, epoxidation was calculated to be a single step process that does not explain the experimental selectivity. In contrast with the currently accepted idea, the overall calculated selectivity results mainly from the iminium formation steps and from the second step of the epoxidation reaction. PMID- 24057258 TI - MicroRNA-142-3p inhibits cell proliferation in human acute lymphoblastic leukemia by targeting the MLL-AF4 oncogene. AB - The mixed-lineage leukemia (MLL)-AF4 fusion protein encoded by the chromosomal translocation t(4;11) predicts a poorer prognosis in acute lymphoblastic leukemia (ALL) than in other MLL-associated leukemias. However, the detailed mechanism underlying regulation of MLL-AF4 expression remains largely unknown. In this study, we showed that microRNA (miR)-142-3p was significantly downregulated in ALL patients expressing MLL-AF4. Upregulation of miR-142-3p decreased MLL-AF4 expression in the RS4;11 leukemic cell line, which suggests that MLL-AF4 is a direct target of miR-142-3p. Ectopic expression of miR-142-3p remarkably suppressed cell proliferation and induced apoptosis in RS4;11 cells expressing the MLL-AF4 fusion protein. We also found that exogenous expression of miR-142-3p strongly reduced the expression of MLL-AF4 target genes such as homeobox A (HOXA)9, HOXA7, and HOXA10 in RS4;11 cells. Taken together, our results indicate that miR-142-3p functions as a growth suppressor in MLL-AF4(+) ALL, and its suppressive effects are mediated primarily through repression of MLL-AF4 expression. PMID- 24057261 TI - Strain and health implications of nurses' shift work. AB - OBJECTIVES: The study investigated whether nurses' different working schedules are associated with different levels of job-related strain, health symptoms and behavior. No reports have been accessible in the relevant literature on the possible association between shift work and job-related strain in nurses. MATERIALS AND METHODS: This was a cross-sectional study conducted at a large university hospital in North-East Italy, involving 806 nurses working in selected departments. A multilevel logistic regression was applied to assess the association between work shift conditions and selected outcomes. RESULTS: Night shifts were associated not only with higher odds of having a high Job Demand, but also with lower odds of having a high Decision Authority and consequently with a stronger likelihood of having higher levels of Job Strain (high Job Demand score >= 38 and Low Decision Authority). The night shift was associated with various symptoms, particularly exhaustion (p = 0.039) and gastric pain (p = 0.020). Nurses' working schedules did not affect their job satisfaction scores. CONCLUSIONS: It has been confirmed that night shifts are a risk factor for nurses' health perception and working night shifts carries a considerable degree of strain. This is a condition that hospital nursing managements need to consider carefully to avoid burnout in nursing personnel and prevent an excessive turnover in this profession, which is a recurring problem for health care organizations. PMID- 24057262 TI - Can empathy lead to emotional exhaustion in teachers? The mediating role of emotional labor. AB - OBJECTIVES: The present study was designed to examine the links between empathy, emotional labor (both surface and deep acting), and emotional exhaustion as well as determine if emotional labor mediates the relationship between empathy and emotional exhaustion in teachers. It was assumed that emotional labor can take two opposite directions (positive mood induction and negative mood induction). Thus, the additional aim of the study was to analyze the mediating role of mood regulation strategies in the relationship between empathy and emotional exhaustion. MATERIALS AND METHODS: A sample of 168 teachers from Lodz and its surroundings completed a set of questionnaires: Emotional Labor Scale; Mood Regulation Scales, Maslach Burnout Inventory, and Empathic Sensitivity Scale. RESULTS: The results provided mixed support for the hypotheses indicating that both types of emotional labor, negative mood induction and emotional exhaustion were positively intercorrelated. Moreover, deep acting was a significant mediator in the relationship between empathy and emotional exhaustion. The analyzed link was also mediated by negative mood induction, whereas positive mood induction did not emerge as a significant mediator. CONCLUSIONS: The study provided insight into the role of empathy and emotional labor in the development of teacher burnout. It also confirmed that deep acting and negative mood induction mediate the relationship between empathy and emotional exhaustion in teachers. PMID- 24057263 TI - Point-of-care nucleic acid detection using nanotechnology. AB - Recent developments in nanotechnology have led to significant advancements in point-of-care (POC) nucleic acid detection. The ability to sense DNA and RNA in a portable format leads to important applications for a range of settings, from on site detection in the field to bedside diagnostics, in both developing and developed countries. We review recent innovations in three key process components for nucleic acid detection: sample preparation, target amplification, and read out modalities. We discuss how the advancements realized by nanotechnology are making POC nucleic acid detection increasingly applicable for decentralized and accessible testing, in particular for the developing world. PMID- 24057264 TI - Systematic review of the effect of dynamic fixation systems compared with rigid fixation in the anterior cervical spine. AB - PURPOSE: Anterior cervical fixation is a procedure widely employed in medical practice, with different fixation systems in use. This study aimed to perform a systematic review of the literature comparing the use of rigid and dynamic cervical plates regarding the fusion rate and complications. METHODS: A search was conducted in PubMed, Lilacs, and Cochrane databases and selecting comparative studies on the use of rigid and dynamic cervical plates. Prospective randomized studies were selected to describe the final results regarding the clinical and radiological outcomes; comparative observational studies were also cited. Complications of using the dynamic cervical plate were also evaluated. RESULTS: Seven comparative studies were included in the review. Five of these were prospective and randomized studies that did not report significant differences in the clinical outcome. One study reported a faster fusion rate when dynamic cervical plate was used, and another study showed a higher fusion rate when a dynamic cervical plate was applied on multiple levels. Four studies investigated the complications of using a dynamic plate and reported that changes in the cervical curvature angle and material failure were the most frequent complications. CONCLUSIONS: There were no clinical differences between the two types of cervical fixation systems. A difference in the fusion rates could not be found at any follow-up time or in any of the studies. There was a loss of lordotic correction in the dynamic systems and a higher rate of complications in patients with a loss of lordotic correction. PMID- 24057265 TI - CuI/1,10-phen/PEG promoted decarboxylation of 2,3-diarylacrylic acids: synthesis of stilbenes under neutral and microwave conditions with an in situ generated recyclable catalyst. AB - A series of trans- or cis-stilbenes have been synthesized in good to excellent yields via a functional group-dependent decarboxylation process from the corresponding 2,3-diaryl acrylic acids in a neutral CuI/1,10-phen/PEG-400 system under microwave conditions. The in situ generation of the recyclable catalytic complex, the use of environmentally benign solvent PEG-400, the operational simplicity, the short reaction times, as well as the functional group-dependent chemo- and stereo-selectivity have made the decarboxylation process a highly efficient and applicable protocol. PMID- 24057266 TI - Impact of in-clinic follow-up visits in patients with implantable cardioverter defibrillators: demographic and socioeconomic analysis of the TARIFF study population. AB - PURPOSE: Remote monitoring of cardiac implantable electronic devices has been demonstrated to safely reduce frequency of hospital visits. Limited studies are available evaluating the economic impact. The aim of this article is to highlight the social impact and costs for the patients associated with hospital visits for routine device follow-up at the enrollment visit for the TARIFF study (NCT01075516). METHODS: TARIFF is a prospective, cohort, observational study designed to compare the costs and impact on quality of life between clinic-based and remote care device follow-up strategies. RESULTS: Two hundred nine patients (85.2 % males) were enrolled in the study; 153 patients (73.2 %) were retired, 36 (17.2 %) were active workers, 18 (8.6 %) were housewives, and 2 (1.0 %) were looking for a job. Among active workers, 63.9 % required time off from work to attend the hospital visit, while 67.0 % of all patients had to interrupt daily activities. The majority of patients spent half a day or more attending the visit. A carer accompanied 77 % of patients. Among carers, 36.6 % required time off from work, and 77.6 % had to interrupt daily activities. Median distance traveled was 36 km. The average cost of travel was 10 euros with 25 % of patients spending more than 30 euros. CONCLUSIONS: Data from patients enrolled in the TARIFF registry confirm that there are social and economic impacts to patients attending routine device checks in hospital which can be significantly reduced by using a remote monitoring strategy. PMID- 24057267 TI - Gender in urology. PMID- 24057268 TI - Linobiflavonoid inhibits human lung adenocarcinoma A549 cells: effect on tubulin protein. AB - The antitumor bioactivities of linobiflavonoid were studied through evaluating its in vitro cytotoxicity against several cell lines (A549, H1975, SMMC-7721, HEP 2 and Vero cells), with the aid of 3-(4,5)-dimethylthiazoly1)-3,5 diphenytetrazolium bromide (MTT) assay. It was found that linobiflavonoid shows more notable inhibiting activity against A549 cells, with IC50 value of 4.67 MUM. Furthermore, western blot analysis revealed that linobiflavonoid is able to increase the expression of beta-tubulin, whereas not alpha-tubulin. In virtuale simulations indicated that linobiflavonoid specifically interacts with the binding pocket which is located at the top of beta-tubulin, due to the presence of strong hydrophobic effects between the core templates and the hydrophobic surface of the tubulin protein (TB) binding site. The binding energy (E inter ) was calculated to be -140.47 kcal/mol. Results above suggest that linobiflavonoid possesses anti-A549 properties relating to beta-tubulin depolymerization inhibition. PMID- 24057269 TI - Prognostic value of HIF-1alpha expression in patients with gastric cancer. AB - The role of hypoxia-inducible factors-1 alpha (HIF-1alpha) expression in gastric cancer remains controversial. We performed a systematic review of the literature with meta-analysis. Electronic databases were used to identify published studies before December 1, 2012. Pooled hazard ratio (HR) or odds ratio (OR) with 95 % confidence interval (95 % CI) was used to estimate the strength of the association between HIF-1alpha expression and survival of gastric cancer patients. Heterogeneity and publication bias were also assessed. Final analysis of 1,268 patients from 9 eligible studies was performed. High HIF-1alpha expression was significantly correlated with poor overall survival (OS) of gastric cancer patients (HR = 2.14, 95 % CI = 1.32-3.48). Subgroup analysis indicated that HIF-1alpha over-expression had an unfavorable impact on OS in Asian patients (HR = 2.35, 95 % CI = 1.41-3.92). Moreover, up-regulation of HIF 1alpha was significantly associated with the depth of invasion (OR = 2.49, 95 % CI = 1.28-4.83), lymph node metastasis (OR = 2.15, 95 % CI = 1.27-3.66), and vascular invasion (OR = 2.23, 95 % CI = 1.20-4.14). HIF-1alpha expression might be a predicative factor of poor prognosis for gastric cancer particularly in Asia. PMID- 24057270 TI - Proteomics analysis of human brain tissue infected by street rabies virus. AB - In order to extend the knowledge of rabies pathogenesis, a two-dimensional electrophoresis/mass spectrometry based postmortem comparative proteomics analysis was carried out on human brain samples. Alteration in expression profile of several proteins was detected. Proteins related to cytoskeleton, metabolism, proteasome and immune regulatory systems showed the most changes in expression levels. Among these groups, the cytoskeleton related proteins (dynein light chain, beta-centractin, tubulin alpha-1C chain and destrin) and metabolism associated proteins (fatty acid-binding protein, macrophage migration inhibitory factor, glutamine synthetase and alpha enolase) were the main altered proteins. These alterations may be considered as an evidence of disturbances in neuronal key processes including axonal transport, synaptic activity, signaling and metabolic pathways in rabies virus infected human brain. PMID- 24057271 TI - Investigation of the common paraoxonase 1 variants with paraoxonase activity on bone fragility in Turkish patients. AB - There is increasing evidence of a biochemical link between oxidative stress and bone metabolism. Oxidative stress has been shown to be involved in bone resorption as it causes loss of bone mineral density (BMD). Paraoxonase 1 (PON1), can prevent these effects of the oxidative stress on bone formation. It has been suggested that the PON1 gene as possibly implicated in reduced BMD in bone fragility cases. It has been hypothesized that PON1 gene polymorphisms may influence both the risk of osteoporosis and osteopenia occurrence and prognosis. The aim of our study is to evaluate the relationship between PON1 polymorphisms and bone fragility development. Seventy-four osteoporotic, 121 osteopenic and 79 nonosteoporotic postmenopausal women were recruited. For detection of the polymorphisms, polymerase chain reaction-restriction fragment length polymorphism techniques have been used. BMD was measured at the lumbar spine and hip by dual energy X-ray absorptiometry. Distributions of PON1 (PON 192 and PON 55) polymorphisms in study groups were not significantly different. But, there was medium strength connection between in the osteopenic with control groups regarding PON1 55-PON1 192 haplotypes and we found a power strength connection between in the osteoporosis with control groups regarding PON1 55-PON1 192 haplotypes. Furthermore, subjects with PON1 192RR and PON1 55LL genotypes had lower PON activity values of osteoporotic subject compared to healthy control and this difference was statistically significant (p < 0.05). This result suggest that PON1 genotypes could be higher risk for osteoporosis, as determined by reduced BMD. PMID- 24057272 TI - Factors influencing law enforcement decisions to adopt an evidence-based robbery prevention program. AB - Homicide is the leading cause of workplace death among small retail and service businesses in the United States. Evidence-based programs have been shown to reduce robbery and robbery-related crimes in small retail businesses; however, reaching small businesses with programs has been difficult. As small businesses typically have no corporate backing or trade affiliation, police departments have been identified as potential vehicles for program dissemination. A national sample of 300 law enforcement agencies was surveyed to identify facilitators and barriers to adoption and sustainability of an evidence-based program. The questionnaire was developed using behavioral theory concepts and administered via telephone. Preliminary findings suggest the primary facilitators to program adoption included organizational capacity factors such as staff buy-in, dedicated personnel and financial support. Competing responsibilities was the primary barrier identified by agencies. Agency size and program complexity were identified as potential predictors of program adoption. Identifying agency and program-specific characteristics that influence program adoption by law enforcement agencies will be valuable for marketing programs to agencies that have the infrastructure to support and sustain program dissemination. Understanding these factors will optimize the reach of evidence-based strategies to small businesses. PMID- 24057273 TI - Francisella tularensis subspecies holarctica occurs in Swedish mosquitoes, persists through the developmental stages of laboratory-infected mosquitoes and is transmissible during blood feeding. AB - In Sweden, mosquitoes are considered the major vectors of the bacterium Francisella tularensis subsp. holarctica, which causes tularaemia. The aim of this study was to investigate whether mosquitoes acquire the bacterium as aquatic larvae and transmit the disease as adults. Mosquitoes sampled in a Swedish area where tularaemia is endemic (Orebro) were positive for the presence of F. tularensis deoxyribonucleic acid throughout the summer. Presence of the clinically relevant F. tularensis subsp. holarctica was confirmed in 11 out of the 14 mosquito species sampled. Experiments performed using laboratory-reared Aedes aegypti confirmed that F. tularensis subsp. holarctica was transstadially maintained from orally infected larvae to adult mosquitoes and that 25% of the adults exposed as larvae were positive for the presence of F. tularensis-specific sequences for at least 2 weeks. In addition, we found that F. tularensis subsp. holarctica was transmitted to 58% of the adult mosquitoes feeding on diseased mice. In a small-scale in vivo transmission experiment with F. tularensis subsp. holarctica-positive adult mosquitoes and susceptible mice, none of the animals developed tularaemia. However, we confirmed that there was transmission of the bacterium to blood vials by mosquitoes that had been exposed to the bacterium in the larval stage. Taken together, these results provide evidence that mosquitoes play a role in disease transmission in part of Sweden where tularaemia recurs. PMID- 24057275 TI - Using imaging to guide patient selection and performance of catheter-based mitral valve repair for mitral regurgitation. AB - Percutaneous transcatheter therapies for mitral regurgitation have found a role for patients at high operative risk with both degenerative and functional pathologies. The MitraClip therapy utilizes a catheter-based system to deliver a clip-type implant to provide apposition between anterior and posterior mitral leaflets. Key to the procedure is using imaging to guide patient selection as well as intra-procedure performance. Careful patient selection remains paramount for success with the MitraClip, with imaging determination of appropriate mitral pathology. Technical success is dependent on skill with echocardiographic imaging, with three-dimensional transesophageal echocardiography particularly valuable. PMID- 24057274 TI - Mutations in components of antiviral or microbial defense as a basis for breast cancer. AB - In-depth functional analyses of thousands of breast cancer gene mutations reveals vastly different sets of mutated genes in each of 21 different breast cancer genomes. Despite differences in which genes are mutated, innate immunity pathways and metabolic reactions supporting them are always damaged. These functions depend on many different genes. Mutations may be rare individually but each set of mutations affects some aspect of pathogen recognition and defense, especially those involving viruses. Some mutations cause a dysregulated immune response, which can also increase cancer risks. The frequency of an individual mutation may be less important than its effect on function. This work demonstrates that acquired immune deficiencies and immune dysregulation in cancer can occur because of mutations. Abnormal immune responses represent a hidden variable in breast cancer-viral association studies. Compensating for these abnormalities may open many new opportunities for cancer prevention and therapy. PMID- 24057276 TI - Surgical strategy for T2 and T3 gallbladder cancer: is extrahepatic bile duct resection always necessary? AB - PURPOSE: Resection of the extrahepatic bile duct is not performed uniformly in gallbladder cancer. The study investigated the clinical significance of resection of extrahepatic bile duct (EHBD) in T2 and T3 gallbladder cancer. METHODS: Between 2000 and 2010, 71 T2 or T3 gallbladder cancer patients who underwent R0 resection at Korea University Medical Center were included. Clinicopathological data were reviewed retrospectively. Survival analysis and comparison between EHBD resection and non-resection groups were performed. RESULTS: The 32 men and 39 women had 49 T2 tumors and 22 T3 tumors. The overall survival rate was 67.8 % at 3 years and 47.2 % at 5 years. In multivariate analysis for overall survival, lymphovascular invasion and lymph node metastasis were significant independent predictors. Comparing the patients according to EHBD resection, the EHBD resection group demonstrated significantly longer hospital stay, longer operative time, more transfusion requirement, more extensive liver resection, and less treatment of neoadjuvant therapy. Significantly higher proportions of perineural invasion and lymph node metastasis were noted in the EHBD resection group. There were no statistically significant differences in survival between the EHBD resection and non-resection groups. CONCLUSIONS: Resection of extrahepatic bile duct was not always necessary in T2 and T3 cancers. However, the patients who undergo resection of extrahepatic bile duct tended to have more aggressive tumor characteristics and undergo more aggressive surgical approach. To enhance overall survival for the patients with T2 and T3 gallbladder cancers, surgeons should try to perform R0 resection including EHBD resection. PMID- 24057277 TI - Subcutaneous dye injection for marking and identification of individual adult zebrafish (Danio rerio) in behavioral studies. AB - The zebrafish is increasingly utilized in behavioral brain research, as it offers a useful compromise between system complexity and practical simplicity. However, a potential drawback of this species in behavioral research is that individuals are difficult to distinguish. Here we describe a simple marking procedure, subcutaneous injection of color dyes, that may alleviate this problem. The procedure allowed us to successfully mark zebrafish and distinguish them for a period of more than 30 days, which is sufficiently long for most behavioral paradigms developed for this species. In addition, we also provide data suggesting that the injection-based marking does not significantly alter social interaction, as defined by the frequency of agonistic behaviors within shoals. PMID- 24057279 TI - Hair trace elementary profiles in aging rodents and primates: links to altered cell homeodynamics and disease. AB - Aging is associated with an increased incidence of pathological conditions such as neurodegeneration, cardiovascular and renal disease, and cancer. These conditions are believed to be linked to a disruption in cell homeodynamics, which is regulated by essential trace elements. In this study we used hair elementary analysis by inductively coupled plasma mass spectrometry (ICPMS) to examine age related profiles of 47 elements in both rats and common marmoset monkeys. Hair was collected from young adult (6 months) and aged (18 months) Long-Evans male rats, and young adult (2 years), middle-aged (4 years) and aged (>8 years) marmosets. The results revealed that aging reduces content levels of cobalt, potassium and selenium while content levels of aluminium, arsenic, boron, mercury, molybdenum, and titanium were elevated in aged rats. Similarly, aged marmosets showed reduced levels of cobalt and elevated levels of aluminium. Case studies in aged rats revealed that myocardial infarction was associated with elevated levels of sodium, potassium and cadmium and reduced zinc, while renal failure was linked to elevated content of potassium, chloride and boron and reduced contents of manganese. Carcinoma was linked to elevated arsenic and reduced selenium levels. These findings indicate that hair elementary profiles in healthy aging and age-related diseases reflect altered cell and organ metabolic functions. Cobalt and aluminium in particular may serve as biomarkers of aging in animal models. Thus, elementary deposition in hair may have predictive and diagnostic value in age-related pathological conditions, including cardiovascular and kidney disease and cancer. PMID- 24057280 TI - Preclinical models of stroke in aged animals with or without comorbidities: role of neuroinflammation. AB - Age is the principal nonmodifiable risk factor for stroke. Over the past 10 years, suitable models for stroke in aged rats have been established. At genetic and cellular level there are significant differences in behavioral, cytological and genomics responses to injury in old animals as compared with the young ones. Behaviorally, the aged rats have the capacity to recover after cortical infarcts albeit to a lower extent than the younger counterparts. Similarly, the increased vulnerability of the aged brain to stroke, together with a decreased interhemisphere synchrony after stroke, assessed by different experimental methods (MRI, fMRI, in vivo microscopy, EEG) leads to unfavorable recovery of physical and cognitive functions in aged people and may have a prognostic value for the recovery of stroke patients. Furthermore, in elderly, comorbidities like diabetes or arterial hypertension are associated with higher risk of stroke, increased mortality and disability, and poorer functional status and quality of life. Aging brain reacts strongly to ischemia-reperfusion injury with an early inflammatory response. The process of cellular senescence can be an important additional contributor to chronic post-stroke by creating a "primed" inflammatory environment in the brain. Overall, these pro-inflammatory reactions promote early scar formation associated with tissue fibrosis and reduce functional recovery. A better understanding of molecular factors and signaling pathways underlying the contribution of comorbidities to stroke-induced pathological sequelae, may be translated into successful treatment or prevention therapies for age-associated diseases which would improve lifespan and quality of life. PMID- 24057281 TI - Pyrrolo[2,3-d]pyrimidine synthesis through activation of N-benzyl groups by distal amides. AB - A new activation mode of CH2-benzylamino groups has been observed during the preparation of pyrrolopyrimidines from Ugi-Smiles adducts of hydroxypyrimidines. The cyclization proceeds via a formal deprotonation of the N-benzyl group followed by trapping of the resulting anion by the alkyne moiety. The key role of the vicinal amide function during the process was pointed out. PMID- 24057282 TI - Wrist drop and muscle weakness of the fingers induced by an upper cervical spine anomaly. AB - PURPOSE: This report presents a case of wrist drop and muscle weakness of the fingers as a false localizing sign induced by stenosis of the upper cervical spine caused by a bony anomaly. METHODS: A 77-year-old male complained of severe muscle weakness of the right hand. Cervical spine MRI showed a severe and sharp compression of the spinal cord from the dorsal side between C2 and C3 with intramedullary intensity changes and mild stenosis at C3/4 and C4/5. RESULTS: The patient underwent laminectomy of C2, cranial side laminotomy of C3, and laminectomy of C4. Decompression of the spinal cord was demonstrated 1 year after surgery. The patient achieved full recovery of the muscle weakness 1 year after undergoing surgery. CONCLUSIONS: The pathophysiology of false localizing signs remains controversial; however, we believe that this unusual compression pattern and level had the possibility to induce atypical myelopathies such as drop hand and finger of the unilateral hand in this case. PMID- 24057278 TI - Role of antioxidant enzymes and small molecular weight antioxidants in the pathogenesis of age-related macular degeneration (AMD). AB - Cells in aerobic condition are constantly exposed to reactive oxygen species (ROS), which may induce damage to biomolecules, including proteins, nucleic acids and lipids. In normal circumstances, the amount of ROS is counterbalanced by cellular antioxidant defence, with its main components-antioxidant enzymes, DNA repair and small molecular weight antioxidants. An imbalance between the production and neutralization of ROS by antioxidant defence is associated with oxidative stress, which plays an important role in the pathogenesis of many age related and degenerative diseases, including age-related macular degeneration (AMD), affecting the macula-the central part of the retina. The retina is especially prone to oxidative stress due to high oxygen pressure and exposure to UV and blue light promoting ROS generation. Because oxidative stress has an established role in AMD pathogenesis, proper functioning of antioxidant defence may be crucial for the occurrence and progression of this disease. Antioxidant enzymes play a major role in ROS scavenging and changes of their expression or/and activity are reported to be associated with AMD. Therefore, the enzymes in the retina along with their genes may constitute a perspective target in AMD prevention and therapy. PMID- 24057283 TI - Letter to Self-locking stitch in suture reinforcement of the laparoscopic gastric sleeve. PMID- 24057284 TI - Isolated GH deficiency due to a GHRH receptor mutation causes hip joint problems and genu valgum, and reduces size but not density of trabecular and mixed bone. AB - CONTEXT: The GH/IGF-I axis is important for bone growth, but its effects on joint function are not completely understood. Adult-onset GH-deficient individuals have often reduced bone mineral density (BMD). However, there are limited data on BMD in adult patients with untreated congenital isolated GH-deficient (IGHD). We have shown that adult IGHD individuals from the Itabaianinha, homozygous for the c.57+1G>A GHRHR mutation, have reduced bone stiffness, but BMD and joint status in this cohort are unknown. OBJECTIVE: The goal is to study BMD, joint function, and osteoarthritis score in previously untreated IGHD adults harboring the c.57+1G>A GHRHR mutation. DESIGN: This is a cross-sectional study. METHODS: Areal BMD by dual-energy X-ray absorptiometry was measured in 25 IGHD and 23 controls (CO). Volumetric BMD (vBMD) was calculated at the lumbar spine and total hip. Joint function was assessed by goniometry of elbow, hips, and knees. X-rays were used to measure the anatomic axis of knee and the severity of osteoarthritis, using a classification for osteophytes (OP) and joint space narrowing (JSN). RESULTS: Genu valgum was more prevalent in IGHD than CO. The osteoarthritis knees OP score was similar in both groups, and knees JSN score showed a trend to be higher in IGHD. The hips OP score and JSN score were higher in IGHD. Areal BMD was lower in IGHD than CO, but vBMD was similar in the two groups. Range of motion was similar in elbow, knee, and hip in IGHD and CO. CONCLUSIONS: Untreated congenital IGHD due to a GHRHR mutation causes hip joint problems and genu valgum, without apparent clinical significance, reduces bone size, but does not reduce vBMD of the lumbar spine and hip. PMID- 24057285 TI - Are cathepsin k inhibitors just another class of anti-resorptives? PMID- 24057286 TI - Observational study of natural history of small sporadic nonfunctioning pancreatic neuroendocrine tumors. AB - CONTEXT: Asymptomatic sporadic nonfunctioning, well-differentiated pancreatic neuroendocrine tumors (NF-PNETs) are increasingly diagnosed, and their management is controversial because of their overall good but heterogeneous prognosis. OBJECTIVE: The objective of the study was to assess the natural history of asymptomatic sporadic NF-PNETs smaller than 2 cm in size and the risk-benefit balance of nonoperative management. EXPERIMENTAL DESIGN: From January 2000 to June 2011, 46 patients with proven asymptomatic sporadic NF-PNETs smaller than 2 cm in size were followed up for at least 18 months with serial imaging in tertiary referral centers. RESULTS: Patients were mainly female (65%), with a median age of 60 years. Tumors were mainly located in the pancreatic head (52%), with a median lesion size of 13 mm (range 9-15). After a median follow-up of 34 months (range 24-52) and an average of four (range 3-6) serial imaging sessions, distant or nodal metastases appeared on the imaging in none of the patients. In six patients (13%), a 20% or greater increase in size was observed. Overall median tumor growth was 0.12 mm per year, and neither patients nor tumor characteristics were found to be significant predictors of tumor growth. Overall, eight patients (17%) underwent surgery after a median time from initial evaluation of 41 months (range 27-58); all resected lesions were European Neuroendocrine Tumor Society T stage 1 (n = 7) or 2 (n = 1), grade 1, node negative, with neither vascular nor peripancreatic fat invasion. CONCLUSIONS: In selected patients, nonoperative management of asymptomatic sporadic NF-PNETs smaller than 2 cm in size is safe. Larger and prospective multicentric studies with long-term follow-up are now needed to validate this wait-and-see policy. PMID- 24057287 TI - Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma. AB - CONTEXT: Mitotane is the only approved drug for treatment of adrenocortical carcinoma. Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been compared head to head. OBJECTIVE: The objective of the study was to investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens. DESIGN/SETTING: This was a prospective, open-label, multicenter trial of a predefined duration of 12 weeks. PATIENTS/INTERVENTIONS: Forty mitotane-naive patients with metastatic adrenocortical carcinoma were assigned to a predefined low- or high-dose regimen by the local investigator. Thirty-two patients could be evaluated in detail. MAIN OUTCOME MEASURE: The difference in median mitotane plasma levels between both treatment groups was measured. RESULTS: Despite a difference in mean cumulative dose (440 +/- 142 g vs 272 +/- 121 g), median maximum plasma levels were not significantly different between the two groups [high dose 14.3 mg/L (range 6.3 29.7, n = 20) vs 11.3 mg/L (range 5.5-20.0, n = 12), P = .235]. Ten of 20 patients on the high-dose regimen reached plasma concentrations of 14 mg/L or greater after 46 days (range 18-81 d) compared with 4 of 12 patients on the low dose regimen after 55 days (range 46-74 d, P = .286). All patients who reached 14 mg/L at 12 weeks displayed a level of 4.1 mg/L or greater on day 33 (100% sensitivity). There were no significant differences in frequency and severity of adverse events. Among patients not receiving concomitant chemotherapy mitotane exposure was higher in the high-dose group: 1013 +/- 494 mg/L . d vs 555 +/- 168 mg/L . d (P = .080). CONCLUSIONS: The high-dose starting regimen resulted in neither significantly different mitotane levels nor a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable. PMID- 24057288 TI - Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. AB - BACKGROUND: Aldosterone plays a detrimental role on the cardiovascular system and PA patients display a higher risk of events compared with EH. OBJECTIVES: The objectives of the study were to compare cardio- and cerebrovascular events in patients with primary aldosteronism (PA) and matched essential hypertension (EH). METHODS: We retrospectively compared the percentage of patients experiencing events at baseline and during a median follow-up of 12 years in 270 PA patients case-control matched 1:3 with EH patients and in PA subtypes [aldosterone producing adenoma (n = 57); bilateral adrenal hyperplasia (n = 213)] vs matched EH. RESULTS: A significantly higher number of PA patients experienced cardiovascular events over the entire period of the study (22.6% vs 12.7%, P < .001). At the diagnosis of PA, a higher number of patients had experienced total events (14.1% vs 8.4% EH, P = .007); furthermore, during the follow-up period, PA patients had a higher rate of events (8.5% vs 4.3% EH, P = .008). In particular, stroke and arrhythmias were more frequent in PA patients. During the follow-up, a higher percentage of PA patients developed type 2 diabetes. Parameters that were independently associated with the occurrence of all events were age, duration of hypertension, systolic blood pressure, presence of diabetes mellitus, and PA diagnosis. After division into PA subtypes, patients with either aldosterone producing adenoma or bilateral adrenal hyperplasia displayed a higher rate of events compared with the matched EH patients. CONCLUSIONS: This study demonstrates in a large population of patients the pathogenetic role of aldosterone excess in the cardiovascular system and thus the importance of early diagnosis and targeted PA treatment. PMID- 24057289 TI - Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan. AB - BACKGROUND: Agranulocytosis is a rare but serious complication of antithyroid drug (ATD) therapy. Characteristics of agranulocytosis have been reported in only a small number of patients. METHOD: We studied 754 cases of ATD-induced agranulocytosis reported over 30 years. The age distribution and sex ratio were compared with those in 12 503 untreated Graves' patients at Kuma Hospital. The annual number of new Graves' patients in Japan was estimated from the Japan Medical Data Center Data Mart-Pharmacovigilance health insurance receipt database. RESULTS: Agranulocytosis developed within 90 days after starting ATD therapy in most patients (84.5%). The methimazole dose given at onset was 25.2 +/ 12.8 mg/d (mean +/- SD). The mean age was 43.4 +/- 15.2 years, and the male to female ratio was 1:6.3. When compared with patients at Kuma Hospital, patients with agranulocytosis were older (P < .001) and more females (P < .0001). Of 211 patients with more than 1 granulocyte measurement before onset, 131 (62%) showed normal counts (>1000/MUL) within 2 weeks before onset, demonstrating real sudden onset of agranulocytosis. In contrast, some of the 20 patients with more than 4 measurements showed gradual decreases in granulocyte counts. Analysis of physician reports for 30 fatal cases revealed that some deaths might have been prevented. The number of new Graves' patients treated with ATD was estimated at about 35 000 per year, and the incidence rate of agranulocytosis was 0.1% to 0.15% in Japan. CONCLUSION: This is the largest study of agranulocytosis. Agranulocytosis tends to occur abruptly within 3 months after initiation of ATD therapy, although it develops gradually in some patients. Providing every patient with sufficient information on agranulocytosis is critical. PMID- 24057290 TI - Clinical presentation and management of children with diffuse and focal hyperinsulinism: a review of 223 cases. AB - CONTEXT: Congenital hyperinsulinism (HI) occurs in two distinct histologic forms: diffuse and focal. Distinguishing between them is essential because a pancreatectomy is curative for focal HI and palliative for diffuse HI. OBJECTIVE: The purpose of this study was to compare the presentations, treatment, and outcomes of diffuse and focal HI. DESIGN: A retrospective chart review of children who underwent pancreatectomy for hyperinsulinism from December 2004 through September 2012 was conducted. RESULTS: Based on pancreatic histology, 223 children were classified into 3 groups: diffuse (n = 97, 44%), focal (n = 114, 51%), and other (n = 12, 5%). Children with diffuse vs focal HI had significantly different mean gestational ages (38 vs 39 weeks, P < .0005) and birth weights (3963 vs 3717 g P = .012). Children with focal HI presented at an older age (0.3 vs 0 months, P < .0005) and more frequently with seizures (50 vs 25%, P < .0005). Children with diffuse HI had higher insulin levels during hypoglycemia (31.8 vs 12 MUU/mL, P < .0005) and required higher glucose infusion rates (19.2 vs 16.1 mg/kg/min, P = .002). Children with diffuse HI had a median percent pancreactectomy of 98%, and postoperatively 41% required treatment for continued hypoglycemia. Children with focal HI had a median percent pancreatectomy rate of 27%, and 94% required no treatment after surgery. CONCLUSIONS: Focal and diffuse HI present unique challenges, but the clinical differences between the 2 are subtle. Children with focal HI are at higher risk of delayed diagnosis and hypoglycemic seizures, but most are cured with surgery. In contrast, children with diffuse disease may be identified earlier, but face ongoing blood glucose abnormalities. PMID- 24057291 TI - Circulating irisin in relation to insulin resistance and the metabolic syndrome. AB - CONTEXT: Irisin, a recently identified hormone, has been proposed to regulate energy homeostasis and obesity in mice. Whether irisin levels are associated with risk of the metabolic syndrome (MetS), cardiometabolic variables, and cardiovascular disease (CVD) risk in humans remains unknown. OBJECTIVE: Our objective was to assess the associations between baseline serum irisin levels and MetS, cardiometabolic variables, and CVD risk. DESIGN, SETTING, AND SUBJECTS: We conducted a comparative cross-sectional evaluation of baseline circulating levels of the novel hormone irisin and the established adipokine adiponectin with MetS, cardiometabolic variables, and CVD risk in a sample of 151 subjects. RESULTS: Baseline irisin levels were significantly higher in subjects with MetS than in subjects without MetS. Irisin was associated negatively with adiponectin (r = 0.4, P < .001) and positively with body mass index (r = 0.22, P = .008), systolic (r = 0.17, P = .04) and diastolic (r = 0.27, P = .001) blood pressure, fasting glucose (r = 0.25, P = .002), triglycerides (r = 0.25, P = .003), and homeostasis model assessment for insulin resistance (r = 0.33, P < .001). After adjustment for potential confounders, including body mass index, subjects in the highest tertile of irisin levels were more likely to have MetS (odds ratio [OR] = 9.44, 95% confidence interval [CI] = 2.66-33.44), elevated fasting blood glucose (OR = 5.80, 95% CI = 1.72-19.60), high triglycerides (OR = 3.89, 95% CI = 1.16-13.03), and low high-density lipoprotein cholesterol (OR = 3.30, 95% CI = 1.18-9.20). Irisin was independently associated with homeostasis model assessment for insulin resistance and general Framingham risk profile in multiple linear regression analyses after adjustment for confounders. Adiponectin demonstrated the expected associations with outcomes. CONCLUSIONS: Irisin is associated with increased risk of MetS, cardiometabolic variables, and CVD in humans, indicating either increased secretion by adipose/muscle tissue and/or a compensatory increase of irisin to overcome an underlying irisin resistance in these subjects. PMID- 24057292 TI - An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities. AB - BACKGROUND: C-type natriuretic peptide (CNP)/natriuretic peptide receptor 2 (NPR2) signaling is essential for long bone growth. Enhanced CNP production caused by chromosomal translocations results in tall stature, a Marfanoid phenotype, and skeletal abnormalities. A similar phenotype was described in a family with an activating NPR2 mutation within the guanylyl cyclase domain. CASE: Here we describe an extremely tall male without skeletal deformities, with a novel NPR2 mutation (p.Arg655Cys) located in the kinase homology domain. OBJECTIVES: The objective of the study was to investigate the functional and structural effects of the NPR2 mutation. METHODS: Guanylyl cyclase activities of wild-type vs mutant NPR2 were analyzed in transfected human embryonic kidney 293 cells and in skin fibroblasts. The former were also used to study possible interactions between both isoforms. Homology modeling was performed to understand the molecular impact of the mutation. RESULTS: CNP-stimulated cGMP production by the mutant NPR2 was markedly increased in patient skin fibroblasts and transfected human embryonic kidney 293 cells. The stimulatory effects of ATP on CNP-dependent guanylyl cyclase activity were augmented, suggesting that this novel mutation enhances both the responsiveness of NPR2 to CNP and its allosteric modulation/stabilization by ATP. Coimmunoprecipitation showed that wild-type and mutant NPR2 can form stable heterodimers, suggesting a dominant-positive effect. In accordance with augmented endogenous receptor activity, plasma N-terminal pro CNP (a marker of CNP production in tissues) was reduced in the proband. CONCLUSIONS: We report the first activating mutation within the kinase homology domain of NPR2, resulting in extremely tall stature. Our observations emphasize the important role of this domain in the regulation of guanylyl cyclase activity and bone growth in response to CNP. PMID- 24057295 TI - Bronchial carcinoid and primary hyperparathyroidism. PMID- 24057293 TI - Roux-en-Y gastric bypass and sleeve gastrectomy: mechanisms of diabetes remission and role of gut hormones. AB - CONTEXT: In obese patients with type 2 diabetes (T2DM), Roux-en-Y-gastric-bypass (RYGB) and sleeve gastrectomy (SLG) improve glycemic control. OBJECTIVE: The objective of this study was to investigate the mechanisms of surgery-induced T2DM improvement and role of gastrointestinal hormones. PATIENTS, SETTING, AND INTERVENTION: In 35 patients with T2DM, we performed a mixed-meal test before and 15 days and 1 year after surgery (23 RYGB and 12 SLG). MAIN OUTCOME MEASURES: Insulin sensitivity, beta-cell function, and amylin, ghrelin, PYY, pancreatic polypeptide (PP), glucagon, and glucagon-like peptide-1 (GLP-1) responses to the meal were measured. RESULTS: T2DM remission occurred in 13 patients undergoing RYGB and in 7 patients undergoing SLG. Similarly in the RYGB and SLG groups, beta cell glucose sensitivity improved both early and long term (P < .005), whereas insulin sensitivity improved long term only (P < .006), in proportion to body mass index changes (P < .001). Early after RYGB, glucagon and GLP-1 responses to the meal increased, whereas the PP response decreased. At 1 year, PYY was increased, and PP, amylin, ghrelin, and GLP-1 were reduced. After SLG, hormonal responses were similar to those with RYGB except that PP was increased, whereas amylin was unchanged. In remitters, fasting GLP-1 was higher (P = .04), but its meal response was flat compared with that of nonremitters; postsurgery, however, the GLP-1 response was higher. Other hormone responses were similar between the 2 groups. In logistic regression, presurgery beta-cell glucose sensitivity (positive, P < .0001) and meal-stimulated GLP-1 response (negative, P = .004) were the only predictors of remission. CONCLUSIONS: RYGB and SLG have a similar impact on diabetes remission, of which baseline beta-cell glucose sensitivity and a restored GLP-1 response are the chief determinants. Other hormonal responses are the consequences of the altered gastrointestinal anatomy. PMID- 24057294 TI - Effects of pioglitazone on bone in postmenopausal women with impaired fasting glucose or impaired glucose tolerance: a randomized, double-blind, placebo controlled study. AB - CONTEXT: Meta-analyses of clinical studies have suggested an increased incidence of peripheral fractures in postmenopausal women with type 2 diabetes mellitus taking pioglitazone. The mechanism behind this apparent increase is unknown. OBJECTIVE: The objective of the study was to examine the effects of pioglitazone on bone mineral density (BMD) and turnover. DESIGN AND SETTING: Twenty-five sites (in the United States) enrolled participants in this randomized, double-blind, placebo-controlled study. PARTICIPANTS: Postmenopausal women (n = 156) with impaired fasting glucose or impaired glucose tolerance participated in the study. INTERVENTIONS: The intervention consisted of pioglitazone 30 mg/d (n = 78) or placebo (n = 78), increased to 45 mg/d after 1 month, for 12 months of treatment total, followed by 6 months of washout/follow-up. MAIN OUTCOME MEASURES: Percentage changes from baseline to month 12 and from month 12 to month18 in BMD in total proximal femur (primary end point), total body, femoral neck, lumbar spine, and radius were measured. RESULTS: Least squares mean changes from baseline to month 12 in total proximal femur BMD were -0.69% for pioglitazone and -0.14% for placebo (P = .170). No statistically significant between-group differences were observed for any BMD or bone remodeling marker end point. We observed improved glycemic control and insulin sensitivity with pioglitazone treatment. In addition, pioglitazone appeared to increase body fat, which may affect bone density measurements, especially in the lumbar spine. One pioglitazone-treated and three placebo-treated women experienced confirmed fractures. Over 18 months, one pioglitazone-treated (1.3%) and eight placebo treated women (10.3%) developed overt type 2 diabetes mellitus. The pattern and incidence of adverse events with pioglitazone were consistent with clinical experience with thiazolidinediones. CONCLUSIONS: Maximal-dose pioglitazone had no effects on BMD or bone turnover, while improving glycemic control as expected, in postmenopausal women with impaired fasting glucose or impaired glucose tolerance. PMID- 24057296 TI - Low plasma atrial natriuretic peptide: a new piece in the puzzle of polycystic ovary syndrome. AB - CONTEXT: It is believed that a dysfunction in adipose tissue plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS). Natriuretic peptides are hormones that regulate cardiovascular and body fluid homeostasis and adipose tissue metabolism. Natriuretic peptide levels are reduced in individuals with obesity and diabetes. OBJECTIVE: This study aimed to investigate whether natriuretic peptide levels are altered in women with PCOS and whether they correlate with adiponectin levels or insulin sensitivity markers. DESIGN AND SETTING: This was a cross-sectional study at a referral center in a teaching hospital. PATIENTS OR OTHER PARTICIPANTS: We evaluated 40 patients diagnosed with PCOS according to the Rotterdam criteria and 36 control women matched for age and body mass index. MAIN OUTCOME MEASURES: We measured serum adiponectin, plasma atrial natriuretic peptide (ANP), and plasma brain natriuretic peptide using enzyme immunoassays in both groups. We evaluated metabolic markers, such as fasting glucose, insulin, total cholesterol, high-density lipoprotein, low density lipoprotein, and triglycerides. In addition, we calculated the homeostasis model assessment for insulin resistance index (HOMA-IR) and the lipid accumulation product (LAP) index and tested the linear correlations between these metabolic indices and the plasma ANP and serum adiponectin concentrations. RESULTS: ANP and adiponectin were reduced in the PCOS group compared with the control group (P = 0.010 and P = 0.014, respectively). The brain natriuretic peptide concentration did not differ between the two groups (P = 0.883). There was no correlation between ANP and any of the metabolic markers. In the control group, the serum adiponectin level was inversely correlated with BMI (P = 0.011), waist circumference (P = 0.021), insulin (P = 0.013), fasting glucose (P = 0.010), homeostasis model assessment for insulin resistance index (P = 0.007), and lipid accumulation product (P = 0.022). Remarkably, none of these correlations were observed in the women with PCOS. CONCLUSION: Women with PCOS had lower ANP and adiponectin compared with controls matched for age and BMI. Thus, the mechanisms that affect ANP and adiponectin production and clearance may be altered in PCOS, regardless of adiposity. These hormones may be involved in the metabolic features of PCOS. PMID- 24057297 TI - Electrohydrodynamic direct-writing. AB - The electrohydrodynamic (EHD) direct-writing technique can be used to print solid/liquid straight/serpentine nanofibers onto a large-area substrate, in a direct, continuous, and controllable manner. It is a high-efficiency and cost effective solution-processable technique to satisfy increasing demands of large area micro/nano-manufacturing. It is ground-breaking to direct-write sub-100 nm fibers on a rigid/flexible substrate using organic materials. A comprehensive review is presented on the research and developments related to the EHD direct writing technique and print heads. Many developments have been presented to improve the controllability of the electrospun fibers to form high-resolution patterns and devices. EHD direct-writing is characterized by its non-contact, additive and reproducible processing, high resolution, and compatibility with organic materials. It combines dip-pen, inkjet, and electrospinning by providing the feasibility of controllable electrospinning for sub-100 nm nanofabrication, and overcomes the drawbacks of conventional electron-beam lithography, which is relatively slow, complicated and expensive. PMID- 24057298 TI - Rapid detection of urinary polyomavirus BK by heterodyne-based surface plasmon resonance biosensor. AB - In renal transplant patients, immunosuppressive therapy may result in the reactivation of polyomavirus BK (BKV), leading to polyomavirus-associated nephropathy (PVAN), which inevitably causes allograft failure. Since the treatment outcomes of PVAN remain unsatisfactory, early identification and continuous monitoring of BKV reactivation and reduction of immunosuppressants are essential to prevent PVAN development. The present study demonstrated that the developed dual-channel heterodyne-based surface plasmon resonance (SPR) biosensor is applicable for the rapid detection of urinary BKV. The use of a symmetrical reference channel integrated with the poly(ethylene glycol)-based low-fouling self-assembled monolayer to reduce the environmental variations and the nonspecific noise was proven to enhance the sensitivity in urinary BKV detection. Experimentally, the detection limit of the biosensor for BKV detection was estimated to be around 8500 copies/mL. In addition, urine samples from five renal transplant patients were tested to rapidly distinguish PVAN-positive and PVAN-negative renal transplant patients. By virtue of its simplicity, rapidity, and applicability, the SPR biosensor is a remarkable potential to be used for continuous clinical monitoring of BKV reactivation. PMID- 24057299 TI - In vitro determination of 6PGD enzyme activity purified from Lake Van fish (Chalcalburnus tarichii Pallas, 1811) liver exposed to pesticides. AB - In the present study, the effect of methidathion, cypermethrin, and deltamethrin pesticides on Lake Van fish (Chalcalburnus tarichii Pallas, 1811) liver 6 phosphogluconate dehydrogenase enzyme activity was investigated due to the fact that these pesticides are extensively used to improve agricultural productivity in the Van region. 2',5'-ADP Sepharose 4B affinity chromatography was used to purify 6-phosphogluconate dehydrogenase enzyme from fish liver and SDS-PAGE technique was used to control the purity of this enzyme. The in vitro effect of methidathion, cypermethrin, and deltamethrin pesticides on the enzyme activity was investigated. The enzyme was purified 1,050-fold with specific activity of 27.04 EU/mg protein. Moreover, Ki constants of methidathion, cypermethrin, and deltamethrin were to be 3.294 +/- 0.215, 0.718 +/- 0.095, and 0.084 +/- 0.009 mM respectively. The IC50 value were estimated as 9.95 * 10(-5) +/- 0.1844 * 10(-5) mM for methidathion, 1.01 * 10(-4) +/- 0.01413 * 10(-4) mM for cypermethrin, and 4.43 * 10(-6) +/- 0.05653 * 10(-6) mM for deltamethrin. In conclusion, deltamethrin inhibits the enzyme activity more than methidathion and cypermethrin. PMID- 24057301 TI - Protein oxidation: identification and utilisation of molecular markers to differentiate singlet oxygen and hydroxyl radical-mediated oxidative pathways. AB - The effect of reactive oxidation species (ROS) on tryptophan or tyrosine was investigated by qualitatively determining the major detectable oxidation products generated by hydroxyl radicals, produced by the Fenton process, or singlet oxygen, generated by exposure to green light in the presence of Rose Bengal, on these photosensitive amino acids in synthetic pentapeptides. Based on mass spectrometric analysis it would appear that the hydroxyl radical favours a pathway leading to the formation of tryptophandione-based products from tryptophan. In contrast singlet oxygen attack appears to favour the formation of kynurenine-type products from tryptophan. Specific oxidative products observed proteomically are therefore potentially able to discriminate between predominant ROS-mediated pathways. To validate these findings, a keratin-enriched extract was exposed to UVB light under aqueous conditions. The observation of the conversion of tryptophan to hydroxytryptophan in marker peptides, and the absence of singlet oxygen specific modifications, suggested that under these conditions oxidative degradation occurred primarily via hydroxyl radical attack. These observations provide the first direct proteomic evidence of the dominant photodegradation pathways in wet wool. PMID- 24057302 TI - Remarkable improvement of methylglyoxal synthase thermostability by His-His interaction. AB - Lately it has been proposed that interaction between two positively charged side chains can stabilize the folded state of proteins. To further explore this point, we studied the effect of histidine-histidine interactions on thermostability of methylglyoxal synthase from Thermus sp. GH5 (TMGS). The crystal structure of TMGS revealed that His23, Arg22, and Phe19 are in close distance and form a surface loop. Here, two modified enzymes were produced by site-directed mutagenesis (SDM); one of them, one histidine (TMGS-HH(O)), and another two histidines (TMGS HHH(O)) were inserted between Arg22 and His23 (H(O)). In comparison with the wild type, TMGS-HH(O) thermostability increased remarkably, whereas TMGS-HHH(O) was very unstable. To explore the role of His23 in the observed phenomenon, the original His23 in TMGS-HHH(O) was replaced with Ala (TMGS-HHA). Our data showed that the half-life of TMGS-HHA decreased in relation to the wild type. However, its half-life increased in comparison with TMGS-HHH(O). These results demonstrated that histidine-histidine interactions at position 23 in TMGS-HH(O) probably have the main role in TMGS thermostability. PMID- 24057303 TI - Production of rhamsan gum using a two-stage pH control strategy by Sphingomonas sp. CGMCC 6833. AB - In this paper, the production of rhamsan gum from Sphingomonas sp. CGMCC 6833 at different pH values was investigated. Based on kinetic analysis, a two-stage strategy for pH control was proposed. During the first 10 h, pH was controlled at 7.5 to maintain high specific cell growth rate and specific glucose consumption rate. After 10 h, pH decreased naturally to 7.0; this value was retained to maintain high specific rhamsan gum formation rate. Using this method, the maximum concentration and productivity of rhamsan gum reached 18.56 +/- 1.68 g/L and 0.290 +/- 0.026 g/L/h, which are 12.83 and 12.84 % higher than the optimum results obtained at natural pH, respectively. PMID- 24057304 TI - Characterization of a layered methylene blue/vanadium oxide nanocomposite and its application in a reagentless H2O2 biosensor. AB - Layered nanocomposite of methylene blue (MB)-intercalated vanadium oxide was obtained through a simple hydrothermal synthesis method using MB, V2O5, and NaI as starting materials. The intercalation reaction was proven to be successful using X-ray diffraction pattern. The MB-V2O5 nanocomposite was characterized using a scanning electron micrograph, infrared spectra, thermogravimetric analysis, UV spectra, and electrochemical measurements. The intercalated MB cations showed a fine diffusion-controlled electrochemical redox process and facilitated the immobilized horseradish peroxidase's (HRP) good catalytic reduction upon H2O2. The as-prepared MB-V2O5/HRP biosensor showed a linear response to H2O2 over a range from 2.0 * 10(-6) to 9.5 * 10(-5) M with a detection limit of 9.7 * 10(-7) M (S/N ratio = 3). PMID- 24057305 TI - Ruthenium- and rhodium-catalyzed oxidative alkylation of C-H bonds: efficient access to beta-aryl ketones. AB - Ruthenium- and rhodium-catalyzed oxidative couplings between versatile directed aromatic C-H bonds and allylic alcohols have been achieved. This method provides efficient synthesis of functional beta-aryl ketones and aldehydes in good to excellent yields, and the carbonyl group in the desired products was a significant synthon for organic synthesis. PMID- 24057308 TI - Medicine, the Law and traffic accidents. PMID- 24057309 TI - Civil aircraft accident investigation. AB - This talk reviews some historic aircraft accidents and some more recent. It reflects on the division of accident causes, considering mechanical failures and aircrew failures, and on aircrew training. Investigation results may lead to improved aircraft design, and to appropriate crew training. PMID- 24057310 TI - Patients' responsibilities for their health. AB - Our modern societies have always given special prominence to patients' rights, but rarely acknowledged the existence of their responsibilities. However, rights have to be fully balanced with obligations. Patients are not only duty-bound by the traditional relationship they have with medical professionals, but also by their role in society through healthcare. Nowadays, as societies cannot afford irresponsible behaviour from the public in health care systems, more attention has been paid to patients' duties. These do not just have moral consequences, but also legal ones. Can a patient be held responsible for a bad outcome in a medical treatment? Recent debates have shown that this question is a global problem and it therefore requires an international overview. Such a study will help to clarify patients' duties and show how the legal system deals with them and what has been done so far to engage more patients in their own health. PMID- 24057311 TI - Cut wrists, electrocution and subsequent drowning in a water drum: an unusual combination of methods in complex suicide. AB - A 25-year-old male was found dead in a water drum inside the bathroom of his house one morning. Autopsy revealed a fatal right wrist cut, superficial cuts on middle phalanx of left index finger and features of ante mortem drowning. Investigation revealed the victim was an alcoholic and was depressed due to financial problems. On the previous night, under the influence of alcohol, he first tried to commit suicide by cutting wrist with razor blades, but death was not immediate. He then attempted electrocuting himself by touching a live wire, inside the bathroom, which failed and finally he drowned in a water drum. The victim had left a message, written with his blood on the floor of the room, reflecting his suicidal intentions. In complex suicide, many bizarre methods are used, but this combination of methods is unusual and not found in available forensic literature. PMID- 24057312 TI - Clinical trials with subjects unable to give consent: some ethical-legal paradoxes. AB - The Italian Data Protection Authority recently authorised a US pharmaceutical company and an Italian hospital to use the personal data of people without capacity to make their own decisions, including those with no legal representation, within the framework of a specific clinical trial although this is not legal under current Italian legislation. This action effectively acknowledged the validity of consent given by persons with family ties to patients, or those in hospitals caring for patients, in contrast with Italian legislation which regards as valid only consent that is given by a legally appointed guardian. This article considers the present state of the regulations governing trials involving incapacitated adults, the paradoxes generated by the discrepancy between the authorisation granted by the Authority and current legislation, and (possible) future developments. PMID- 24057313 TI - Accidental strangulation by a hot belt: an occupational medico-legal case report. AB - Death due to strangulation is generally considered homicidal unless proved otherwise. Here a case of accidental strangulation by a faulty machine is presented and discussed where the deceased was strangled by a heated rubber belt of a rice mill machine. The ligature mark was an assortment of abrasion and dermo epidermal burns. The term "thermal ligature strangulation" is proposed for such an occurrence. PMID- 24057314 TI - Drivers under the influence of drugs of abuse: quantification of cocaine and impaired driving. AB - In recent years, the interest in oral fluid as a biological matrix has significantly increased, particularly for detecting driving under the influence of drugs. In this study, the concentration of cocaine and its relationship with clinical symptoms in drivers suspected of driving under the influence of drugs was evaluated. A total of 154 samples of oral fluid, which tested positive for cocaine in previous immunoassay screening, Cozart Drug Detector System, were confirmed using gas chromatography/mass spectrometry method. In Catalonia, during 2007-2010, there were 1791 samples positive for cocaine among a total of 3468 samples taken from drivers who tested positive for any drug of abuse. The evaluation of clinical symptoms was through a questionnaire that was filled in by the police officers who collected the samples. The mean concentration of cocaine was 4.11 mg/l and median concentration was 0.38 mg/l (range 0.01-345.64 mg/l). Clinical impairment symptoms such as motor coordination, walking, speech, mood and state of pupils were not significant. The testing of oral fluids presents fewer ethical problems than blood or urine. PMID- 24057318 TI - Neuronal oscillations in Golgi cells and Purkinje cells are accompanied by decreases in Shannon information entropy. AB - Neuronal oscillations have been shown to contribute to the function of the cerebral cortex by coordinating the neuronal activities of distant cortical regions via a temporal synchronization of neuronal discharge patterns. This can occur regardless whether these regions are linked by cortico-cortical pathways or not. Less is known concerning the role of neuronal oscillations in the cerebellum. Golgi cells and Purkinje cells are both principal cell types in the cerebellum. Purkinje cells are the sole output cells of the cerebellar cortex while Golgi cells contribute to information processing at the input stage of the cerebellar cortex. Both cell types have large cell bodies, as well as dendritic structures, that can generate large currents. The discharge patterns of both these cell types also exhibit oscillations. In view of the massive afferent information conveyed by the mossy fiber-granule cell system to different and distant areas of the cerebellar cortex, it is relevant to inquire the role of cerebellar neuronal oscillations in information processing. In this study, we compared the discharge patterns of Golgi cells and Purkinje cells in conscious rats and in rats anesthetized with urethane. We assessed neuronal oscillations by analyzing the regularity in the timing of individual spikes within a spike train by using autocorrelograms and fast-Fourier transform. We measured the differences in neuronal oscillations and the amount of information content in a spike train (defined by Shannon entropy processed per unit time) in rats under anesthesia and in conscious, awake rats. Our findings indicated that anesthesia caused more prominent neuronal oscillations in both Golgi cells and Purkinje cells accompanied by decreases in Shannon information entropy in their spike trains. PMID- 24057319 TI - A comparative North American experience of robotic thyroidectomy in a thyroid cancer population. AB - PURPOSE: This study seeks to explore the efficacy of robotic thyroidectomy in treating a North American population with differentiated thyroid cancer (DTC) as compared with the conventional cervical approach. METHODS: A retrospective analysis of our prospectively collected thyroid surgery database was performed. We included all consecutive patients that underwent thyroidectomy for the treatment of well-differentiated thyroid cancer, performed by a single surgeon. RESULTS: Twenty-four robotic transaxillary and 35 conventional thyroidectomy procedures were performed. Average size of the tumor was 1.1 +/- 0.2 cm in the robotic group and 1.7 +/- 0.3 cm in the cervical group (p = 0.16). Average total operative time for the robotic group was 133 +/- 65.4 and 119.7 +/- 22.5 min in the cervical group (p = 0.34). No robotic cases required conversion. One patient required reoperation for recurrent disease at 24 months follow-up. Both groups had similar blood loss (p = 0.37) and all margins were negative for malignancy on permanent pathology. All patients were discharged home within 24 h. Postoperative stimulated thyroglobulin levels were similar for the two groups (p = 0.82). CONCLUSIONS: Our experience with robotic transaxillary thyroidectomy confirms this technique is feasible. It is possible to achieve a safe and effective oncologic result in a select group of North American patients with DTC. PMID- 24057320 TI - Current therapeutic strategies for childhood hepatic malignant tumors. AB - The two main malignant hepatic tumors in children are hepatoblastomas (HBLs) and hepatocellular carcinomas (HCCs). The past two decades have brought significant improvement to the outcomes of children diagnosed with malignant hepatic tumors, especially HBL, due to improvements in diagnosis and treatment. Histological diagnosis is essential for differential diagnosis of these tumors. In surgery, liver resection has become a safe and secure technique because of progress in anatomical knowledge and surgical dissection; also liver transplantation has become widely used for unresectable tumors. Moreover, the introduction of effective chemotherapeutic regimens has significantly improved the survival of children with HBL due to an increase in the number of patients ultimately undergoing tumor resection, and a reduction in the incidence of post-surgical recurrence. These improvements are the result of multicenter cooperative trials conducted by the Japanese Study Group for Pediatric Liver Tumor, the Children's Oncology Group, and the International Childhood Liver Tumor Strategy Group, including work of the German Association of Pediatric Hematology and Oncology. This paper summarizes the results of these studies and calls on the current international collaboration study called the Children's Hepatic Tumors International Collaboration Project to establish global clinical research on childhood hepatic malignant tumors. PMID- 24057321 TI - Chemical modification for improving activity and stability of lipase B from Candida antarctica with imidazolium-functional ionic liquids. AB - Various imidazolium-functional ionic liquids (ILs) composed of different cations and anions were grafted onto Candida antarctica lipase B (CALB) through lysine coupling, and 4-6 of the 9 primary amino groups of the lysine residues were modified. The catalytic activity and stability were investigated in a p nitrophenyl palmitate hydrolysis reaction. After modification, CALB was activated and achieved a high catalytic efficiency in the aqueous phase (e.g., [HOOCMMIm][Cl] modification showed a 1.5-fold increase in the catalytic efficiency). The thermostability and organic solvent tolerance were significantly increased with the ILs modification (e.g., [HOOCBMIm][Cl] owned kosmotropic cation and chaotropic anion modification showed a 7-fold thermostability increase at 70 degrees C, 1-fold increase in 50% aqueous dimethylformamide and 5-fold increase in 50% aqueous methanol). Conformation changes were confirmed by fluorescence spectroscopy, circular dichroism spectroscopy and attenuated total reflection Fourier transform infrared spectroscopy. PMID- 24057322 TI - Response of archaeal communities to oil spill in bioturbated mudflat sediments. AB - The response of archaeal community to oil spill with the combined effect of the bioturbation activity of the polychaetes Hediste diversicolor was determined in mudflat sediments from the Aber-Benoit basin (Brittany, French Atlantic coast), maintained in microcosms. The dynamics of the archaeal community was monitored by combining comparative terminal restriction fragment length polymorphism (T-RFLP) fingerprints and sequence library analyses based on 16S rRNA genes and 16S cDNA. Methanogens were also followed by targeting the mcrA gene. Crenarchaeota were always detected in all communities irrespective of the addition of H. diversicolor and/or oil. In the presence of oil, modifications of archaeal community structures were observed. These modifications were more pronounced when H. diversicolor was added resulting in a more diverse community especially for the Euryarchaeota and Thaumarchaeota. The analysis of mcrA transcripts showed a specific structure for each condition since the beginning of the experiment. Overall, oiled microcosms showed different communities irrespective of H. diversicolor addition, while similar hydrocarbon removal capacities were observed. PMID- 24057323 TI - Release and consumption of D-amino acids during growth of marine prokaryotes. AB - Analysis of the composition of the marine-dissolved organic matter has highlighted the importance of D-amino acids, whose origin is attributed mainly to the remains of bacterial peptidoglycan released as a result of grazing or viral lysis. However, very few studies have focused on the active release of D-amino acids by bacteria. With this purpose, we measured the concentration of dissolved amino acids in both enantiomeric forms with two levels of complexity: axenic cultures of Vibrio furnissii and Vibrio alginolyticus and microcosms created from marine microbial assemblages (Biscay Bay, Cantabrian Sea) with and without heterotrophic nanoflagellates (HNFs). Axenic cultures showed that only D-Ala was significantly released and accumulated in the medium up to a concentration of 120 nM, probably as a consequence of the rearrangement of peptidoglycan. The marine microbial assemblages showed that only two D-amino acids significantly accumulated in the environment, D-Ala and D-aspartic acid (Asp), in both the absence and presence of HNFs. The D/L ratio increased during the incubation and reached maximum values of 3.0 to 4.3 for Ala and 0.4 to 10.6 for Asp and correlated with prokaryotic and HNF abundance as well as the rate of prokaryotic thymidine and leucine incorporation. Prokaryotes preferentially consumed L-amino acids, but the relative uptake rates of D-Ala significantly increased in the growth phase. These results demonstrate that bacteria can release and consume D amino acids at high rates during growth, even in the absence of viruses and grazers, highlighting the importance of bacteria as producers of dissolved organic matter (DOM) in the sea. PMID- 24057324 TI - Natural history and role of radiation in patients with supratentorial and infratentorial WHO grade II ependymomas: results from a population-based study. AB - Patients with World Health Organization (WHO) grade II supratentorial ependymomas are commonly observed after gross total resection (GTR), although supporting data are limited. We sought to characterize the natural history of such tumors. We used the Surveillance, Epidemiology, and End Results program to identify 112 patients ages 0-77 diagnosed with WHO grade II ependymomas between 1988 and 2007, of whom 63 (56 %) and 49 (44 %) had supratentorial and infratentorial primaries, respectively. Inclusion criteria were strict to ensure patient homogeneity. Of 33 patients with supratentorial tumors after GTR, 18 (55 %) received adjuvant radiation therapy and 15 (45 %) did not. Ependymoma-specific mortality (ESM) was the primary endpoint. With a median follow up of 4.5 years, only 1 of 33 patients with supratentorial ependymoma died of their disease after GTR; the 5-year estimate of ESM in this population was 3.3 % (95 % CI 0.2-14.8 %). Among patients with infratentorial ependymomas after GTR, the 5-year estimate of ESM was 8.7 % (95 % CI 1.4-24.6 %). In patients with subtotally resected tumors, 5-year estimates of ESM in patients with supratentorial and infratentorial primaries were 20.1 % (95 % CI 8.0-36.2 %) and 12.3 % (95 % CI 2.9-28.8 %), respectively. Among the whole cohort, on both univariable and multivariable regression, extent of resection was predictive of ESM, while tumor location and use of radiation were not. After GTR, patients with WHO grade II supratentorial ependymomas have a very favorable natural history with low associated cancer-specific mortality. Observation, with radiation reserved as a salvage option, may be a reasonable postoperative strategy in this population. PMID- 24057325 TI - Prognostic value of Musashi-1 in gliomas. AB - The aim of this study was to investigate the prognostic value of the RNA-binding protein Musashi-1 in adult patients with primary gliomas. Musashi-1 has been suggested to be a cancer stem cell-related marker in gliomas, and high levels of Musashi-1 have been associated with high tumor grades and hence poor prognosis. Samples of 241 gliomas diagnosed between 2005 and 2009 were stained with an anti Musashi-1 antibody using a fluorescent staining protocol followed by automated image acquisition and processing. Musashi-1 area fraction and intensity in cytoplasm and in nuclei were quantified by systematic random sampling in 2 % of the vital tumor area. In WHO grade III tumors high levels of Musashi-1 were associated with poor survival in multivariate analysis (HR 3.39, p = 0.02). We identified a sub-population of glioblastoma (GBM) patients with high levels of Musashi-1 and a superior prognosis (HR 0.65, p = 0.038). In addition patients with high levels of Musashi-1 benefitted most from post-surgical treatment, indicating that Musashi-1 may be a predictive marker in GBMs. In conclusion, our results suggest that high levels of Musashi-1 are associated with poor survival in patients with WHO grade III tumors and that Musashi-1 may be a predictive marker in GBMs, although further validation is needed. We find the combination of immunofluorescence and automated quantitation to be a feasible, robust, and reproducible approach for quantitative biomarker studies. PMID- 24057326 TI - The differential diagnosis of pilocytic astrocytoma with atypical features and malignant glioma: an analysis of 16 cases with emphasis on distinguishing molecular features. AB - Rare pilocytic astrocytomas (PA) have atypical histologic and clinicoradiologic features that raise the differential diagnosis of glioblastoma. Whether ancillary studies can supplement histopathologic examination in placing these cases accurately on the spectrum of WHO Grade I PA to higher-grade glioma is not always clear, partly because these cases are not common. Here, ten PAs with atypical clinicoradiologic and histologic features and six pediatric glioblastoma multiforme (pGBMs) were analyzed for BRAF V600E, IDH1, IDH2, and TP53 mutations. Ki-67, p53, and p16 protein expression were also examined by immunohistochemistry. BRAF-KIAA1549 fusion status was assessed in the PA subgroup. The rate of BRAF-KIAA1549 fusion was high in these PAs (5/7 tumors) including four extracerebellar examples. A single BRAF V600E mutation was identified in the fusion-negative extracerebellar PA of a very young child who succumbed to the disease. TP53 mutations were present only in malignant gliomas, including three pGBMs and one case designated as PA with anaplastic features (with consultation opinion of pGBM). IDH1 and IDH2 were wild type in all cases, consistent with earlier findings that IDH mutations are not typical in high-grade gliomas of patients <=14 years of age. Immunohistochemical studies showed substantial overlap in Ki-67 labeling indices, an imperfect correlation between p53 labeling and TP53 mutation status, and complete p16 loss in only two pGBMs but in no PAs. These results suggest that (a) BRAF-KIAA1549 fusion may be common in PAs with atypical clinicoradiologic and histologic features, including those at extracerebellar sites, (b) BRAF V600E mutation is uncommon in extracerebellar PAs, and (c) TP53 mutation analysis remains a valuable tool in identifying childhood gliomas that will likely behave in a malignant fashion. PMID- 24057327 TI - Linear fusigen as the major hydroxamate siderophore of the ectomycorrhizal Basidiomycota Laccaria laccata and Laccaria bicolor. AB - A screening for siderophores produced by the ectomycorrhizal fungi Laccaria laccata and Laccaria bicolor in synthetic low iron medium revealed the release of several different hydroxamate siderophores of which four major siderophores could be identified by high resolution mass spectrometry. While ferricrocin, coprogen and triacetylfusarinine C were assigned as well as other known fungal siderophores, a major peak of the siderophore mixture revealed an average molecular mass of 797 for the iron-loaded compound. High resolution mass spectrometry indicated an absolute mass of m/z = 798.30973 ([M + H](+)). With a relative error of Delta = 0.56 ppm this corresponds to linear fusigen (C33H52N6O13Fe; MW = 797.3). The production of large amounts of linear fusigen by these basidiomycetous mycorrhizal fungi may possibly explain the observed suppression of plant pathogenic Fusarium species. For comparative purposes Fusarium roseum was included in this study as a well known producer of cyclic and linear fusigen. PMID- 24057328 TI - Acid-catalyzed reactions of 3-hydroxy-2-oxindoles with electron-rich substrates: synthesis of 2-oxindoles with all-carbon quaternary center. AB - A Lewis acid catalyzed reaction of in situ generated 2H-indol-2-one () with various 2pi and other electron-rich substrates has been developed. A variety of electron-rich substrates such as allyl/methallyltrimethylsilane, phenylacetylene, styrenes, acetophenone, and indoles have been used. The methodology provides a straightforward approach for the synthesis of 2-oxindoles with an all-carbon quaternary center at the pseudobenzylic position. PMID- 24057329 TI - Profound first-degree atrioventricular block. PMID- 24057330 TI - Primary signet ring cell carcinoma of the lung: a rare subtype. AB - Signet ring cell carcinoma (SRCC) is a subtype of adenocarcinoma. It can arise in different organs including stomach, colon, bladder, prostate and breast. The vast majority of SRCC found in the pulmonary system is metastatic. Primary disease to the lungs is rare. The main feature of this type of malignancy is mucin-producing cells. It has been reported that out of 3500 cases of pulmonary adenocarcinoma, five cases had features of SRCC. PMID- 24057331 TI - Metastasis of diffuse hepatocellular carcinoma to an extremely unusual site. AB - Hepatocellular carcinoma is a common and aggressive malignancy the world over. Metastasis commonly occurs in lungs, bone, lymph node and adrenals. Skeletal muscle metastases from any primary is a rare occurrence, those occurring from hepatocellular carcinoma even more so. We present a case of a 61-year-old man presenting with hepatocellular carcinoma with synchronous symptomatic metastasis to the skeletal muscle. This article discusses approach to hepatocellular carcinoma with skeletal muscle metastases aetiopathogenesis, differential diagnosis and approach to treatment. PMID- 24057332 TI - Lessons learnt from managing an avulsion fracture of the tibial tubercle extending into the tibial physis. AB - Acute avulsions of the tibial tubercle apophysis are uncommon, with reported incidence of 0.4-2.7% of all physeal injuries. In our case the extent of the injury was not realised at first presentation and initial internal fixation was attempted. At first outpatient follow-up, repeat radiographs indicated the fracture was not reduced and further CT imaging requested. The three-dimensional CT reconstructed images provide considerably more information on the fracture pattern and retrospectively these may have been helpful during the initial procedure. Therefore we would recommend obtaining a preoperative CT scan if extension of the fracture into the tibial physis is suspected. During the second procedure arthroscopy was tried to aid fracture reduction, but visualisation of the anterior articular surface under the anterior horns of the menisci was difficult through the anterior portals with a standard 30 degrees arthroscope and we further recommend having a 70 degrees scope available to ensure optimal visualisation. PMID- 24057333 TI - Pycnodysostosis with novel gene mutation and severe obstructive sleep apnoea: management of a complex case. AB - Pycnodysostosis is a rare genetic disease. Impaired osteoclastic function is the basis for typical phenotypic features and bone fragility. The main differential diagnosis is osteopetrosis, also associated with altered bone remodelling, but with a more severe prognosis. We describe the case of an 8-year-old boy who presented life-threatening obstructive sleep apnoea successfully managed with non invasive ventilation. Haematological overlap phenotype included anaemia and altered bone marrow, more common in osteopetrosis. Molecular analysis of the CTSK gene revealed a mutation not previously described in the literature. PMID- 24057334 TI - Challenges in imaging and histopathological assessment of a giant cell tumour with secondary aneurysmal cyst in the patella. AB - The patella is an uncommon site for all primary and metastatic bone tumours and primary intra-osseous tumours of the patella are very rare. A majority of the patella tumours are benign. We report a patient with a sudden onset swelling and pain of the right knee following a staircase fall. The plain radiograph showed an expansile multiseptated patella lesion and it was further assessed with an MRI. The radiological findings and the initial histopathological features from a limited sample were suggestive of a primary aneurysmal bone cyst. However, the final histopathological diagnosis from a more adequate specimen was a giant cell tumour with a secondary aneurysmal bone cyst. PMID- 24057335 TI - Left-sided Poland's syndrome in a girl with rare associations like spina bifida and diaphragmatic hernia. AB - Poland's syndrome is a rare congenital anomaly characterised by partial or complete absence of sternocostal head of pectoralis major muscle and anomalies of ipsilateral hand and digits. Other associated anomalies involving anterior thoracic wall, breast, diaphragm and vertebrae have also been reported in various cases. We report a case of a 10-year-old girl, with features of left-sided Poland's syndrome associated with spina bifida, dextroposition of the heart and left-sided diaphragmatic hernia. These are rare associations of Poland's syndrome. She was investigated with chest X-ray, contrast-enhanced CT of the thorax, ultrasonography of abdomen and echocardiography which helped in arriving at an accurate diagnosis and assessing all the associated abnormalities. PMID- 24057336 TI - Upper cervical cord enterogenous cyst mimicking transient ischaemic attacks. AB - A 76-year-old woman presenting with tetraparesis, left-sided hemisensory loss and occasional neck pain was urgently admitted to our department. A cervical spine MRI scan revealed a partially cystic lesion compressing the cord at the C2-4 level. The lesion was surgically excised. The histopathological diagnosis was that of an enterogenous cyst. No postoperative complications were noted and the patient significantly recovered from the preoperative tetraparesis. Eleven months before surgery, a waxing and waning presentation of the myelopathic signs with normal neuroradiological findings on a non-contrast-enhanced head CT scan, had unfortunately led to the misdiagnosis of transient ischaemic attacks and ischaemic stroke which delayed the treatment of an essentially benign disease the total surgical excision of which not only is usually curative but also improves the preoperative signs and symptoms. PMID- 24057337 TI - Nanodiamond molecular imaging with enhanced contrast and expanded field of view. AB - Nanodiamond imaging is a new molecular imaging modality that takes advantage of nitrogen-vacancy (NV) centers in nanodiamonds to image a distribution of nanodiamonds with high sensitivity and high spatial resolution. Since nanodiamonds are nontoxic and are easily conjugated to biomolecules, nanodiamond imaging can potentially elicit physiological information from within a living organism. The position of the nanodiamonds is measured using optically detected electron spin resonance of the NVs. In a previous paper, we described a proof-of principle nanodiamond imaging system with the ability to image in two dimensions over a 1*1 cm field of view and demonstrated imaging within scattering tissue. Here, we describe a second-generation nanodiamond imaging system with a field of view of 30*200 mm, and with three-dimensional imaging potential. The new system has a comparable spatial resolution of 1.2 mm FWHM and a sensitivity (in terms of the concentration of carbon atoms in a mm3 voxel) of 1.6 mM mm3 Hz-1/2, a 3-dB improvement relative to the old system. We show that imaging at 2.872 GHz versus imaging at 2.869 GHz offers a 1.73* improvement in sensitivity with only a 20% decrease in resolution and motivate this by describing the observed lineshape starting from the NV spin Hamiltonian. PMID- 24057338 TI - [Correction of pronounced plagiocephaly with orthosis : results of a prospective follow-up control]. AB - For the treatment of pronounced deformational plagiocephaly in infants different therapeutic options are under discussion in the literature. This article presents a prospective observational study of 45 infants enrolled with distinct plagiocephaly and treated with a custom-made helmet orthosis. Treatment with the helmet orthosis was indicated by a difference in the skull diagonals of more than 0.5 cm or a cranial vault asymmetry (CVA) index > 3.5. The follow-up results were controlled with the help of a mobile spatial laser scanner and the CVA index and the skull deformity were measured. The average duration of treatment was 131 days. The CVA index improved from 9.95 to a normal value of 3.35 (median) and the skull deformity improved from 1.3 cm to 0.5 cm (median). The only side effects observed were easily treatable pressure marks. The results of this study reveal that pronounced deformational plagiocephaly can be successfully treated with a custom-made helmet orthosis and closely controlled monitoring. PMID- 24057339 TI - A novel strategy to construct high performance lithium-ion cells using one dimensional electrospun nanofibers, electrodes and separators. AB - We successfully demonstrated the performance of novel, one-dimensional electrospun nanofibers as cathode, anode and separator-cum-electrolyte in full cell Li-ion configuration. The cathode, LiMn2O4 delivered excellent cycle life over 800 cycles at current density of 150 mA g(-1) with capacity retention of ~93% in half-cell assembly (Li/LiMn2O4). Under the same current rate, the anode, anatase phase TiO2, rendered ~77% initial reversible capacity after 500 cycles in half-cell configuration (Li/TiO2). Gelled electrospun PVdF-HFP exhibits liquid like conductivity of ~3.2 mS cm(-1) at ambient temperature conditions (30 degrees C). For the first time, a full-cell is fabricated with enitrely electrospun one-dimensional materials by adjusting the mass loading of cathode with respect to anode in the presence of gelled PVdF-HFP membrane as a separator cum-electrolyte. Full-cell LiMn2O4|gelled PVdF-HFP|TiO2 delivered good capacity characteristics and excellent cyclability with an operating potential of ~2.2 V at a current density of 150 mA g(-1). Under harsh conditions (16 C rate), the full-cell showed a very stable capacity behavior with good calendar life. This clearly showed that electrospinning is an efficient technique for producing high performance electro-active materials to fabricate a high performance Li-ion assembly for commercialization without compromising the eco-friendliness and raw material cost. PMID- 24057340 TI - Bone bruise patterns in knee injuries: where are they found? AB - PURPOSE: Bone bruise represents an entity of occult bone lesions that can occur in the knee, causing knee pain and tenderness clinically. The aim of this study was to investigate the incidence and pattern of bone bruising seen in the anterior cruciate ligament (ACL) injury cohort, the non-ACL injury cohort, and between both cohorts. METHODS: We reviewed 710 knee magnetic resonance imagings performed over a 6-month period. Eighty-eight patients with prior history of a knee injury were identified. The mechanism of injury and other clinical findings was noted. RESULTS: Among these 88 patients, 58 patients had an associated ACL injury (31 had isolated ACL injuries; 27 had combined ACL and other ligamentous injuries). Among the 30 who had non-ACL injuries, 15 had either an MCL, LCL, or PCL injury. The remaining 15 patients had no associated ligament injury. With an ACL injury, the most common bone bruise sites are the lateral femur (74%) and lateral tibia (64%). Without an ACL injury, the pattern of bruising was more common in the lateral femur (69%) and medial tibia (37%). CONCLUSION: Bone bruises are important as previous studies have shown that they can cause persistent knee pain. Our study has shown that there are differences in pattern of bone bruising in knee injuries with or without ACL injuries. PMID- 24057341 TI - Effects of tirofiban maintenance duration on myocardial perfusion defect severity in anterior myocardial infarction. AB - INTRODUCTION: Percutaneous coronary intervention (PCI) does not often produce optimal results, despite restoration of coronary blood flow at myocardial recovery, because of impaired microvascular perfusion. This study aimed to investigate and evaluate with (99m)Tc-sestamibi scan whether the results of PCI can be changed by maintenance infusion of tirofiban for 24 or 48 h in patients presenting with anterior ST-elevation myocardial infarction (STEMI). METHODS: The study included 84 patients with anterior STEMI who were candidates for primary PCI and whose occlusion was in the proximal or mid-left anterior descending artery. Patients were given 25 MUg/kg/3 min tirofiban and randomized to receive maintenance infusion at 0.15 MUg/kg/min for 24 or 48 h. A resting (99m)Tc sestamibi scan was performed on the 5th day post-procedure before discharge. The primary efficacy endpoint was a patient's score on a 5-point scoring system for perfusion defect severity. Major adverse cardiac events (MACE) were defined as death from any cause, re-infarction, and clinically driven target-vessel revascularization within the first 6 months. RESULTS: Baseline characteristics of the patients were similar in the two infusion groups (n = 42 per group). There was no significant difference in the symptom onset-to-presentation time or door to-balloon time between the two groups. With the exception of basal anteroseptal and basal anterior segments, significant reductions were obtained on the 5-point scoring system for perfusion defect severity in segments and in the summed rest scores. No significant differences were observed between the two groups in the incidence of MACE at 6 months. The safety profile did not differ between 24 and 48 h infusions of tirofiban. CONCLUSION: The use of tirofiban, when administered at a high bolus dose and maintained for 48 h, was safe and significantly reduced perfusion defect severity in patients with anterior STEMI presenting early after symptom onset and undergoing primary PCI. PMID- 24057342 TI - Visible light photoredox atom transfer Ueno-Stork reaction. AB - A visible light-promoted atom transfer Ueno-Stork reaction was developed using Ir(ppy)2(dtb-bpy)PF6 as the sensitizer. 2-Iodoethyl propargyl ethers or 2 iodoethyl allyl ethers were used as the radical precursors to construct tetrahydrofuran-containing fused [6,5] and [5,5] bicyclic frameworks. PMID- 24057343 TI - Congenital long QT syndrome with compound mutations in the KCNH2 gene. AB - Congenital long QT syndrome is a genetic disorder encompassing a family of mutations that can lead to aberrant ventricular electrical activity. We report on two brothers with long QT syndrome caused by compound mutations in the KCNH2 gene inherited from parents who had no prolonged QT interval on electrocardiography. The proband had syncope, and his elder brother suffered from ventricular fibrillation. Genetic testing revealed that both brothers had multiple mutations in the KCNH2 gene, including a missense mutation of C1474T (exon 6) as well as a frameshift/nonsense mutation, resulting from the insertion of 25 nucleotides, which caused an altered amino acid sequence beginning at codon 302 and a premature termination codon (i.e., TAG) at codon 339 (exon 4). Family genetic screening found that their father had the same frameshift mutation, and their mother and sister had the same missense mutation, in the KCNH2 gene. However, these other family members were asymptomatic, with normal QT intervals on electrocardiography. These results suggest that compound mutations in the KCNH2 gene inherited independently from the parents made the phenotypes of their sons more severe. PMID- 24057345 TI - European database for mechanical circulatory support gets into its stride. PMID- 24057344 TI - Plasma urokinase antigen and C-reactive protein predict angina recurrence after coronary angioplasty. AB - This study evaluates the predictive value of several biochemical indices of the coagulation-fibrinolysis system, platelet function, and inflammatory state for angina recurrence after successful percutaneous transluminal coronary angioplasty (PTCA). We measured preprocedural and follow-up plasma levels of C-reactive protein (CRP), fibrinogen, and urokinase plasminogen activator antigen (uPA), plasminogen activator inhibitor-1 (PAI-1) activity, tissue plasminogen activator activity, and adenosine diphosphate-induced platelet aggregation in 53 patients with chronic stable angina who underwent successful elective PTCA of single hemodynamically significant lesions in coronary arteries. All patients were followed up for 12 months after PTCA. The Cox proportional hazards model was used to assess the association of variables with angina recurrence rate. At the end of the follow-up, 16 patients had angina recurrence. Among 36 clinical, biochemical, and angiographic variables, the duration of stable angina more than 12 months before PTCA (chi (2) = 5.73; P = 0.02, hazard ratio (HR) 3.7, 95 % confidence interval (CI) 1.26-10.6), high baseline levels of CRP (>7 mg/l) (chi (2) = 8.34; P = 0.004, HR 2.9, 95 % CI 1.4-5.9), uPA antigen baseline (>1 ng/ml) (chi (2) = 17.11; P = 0.0001, HR 11.5, 95 % CI 3.6-36.7) and 48 h after PTCA (chi (2) = 15.73; P = 0.0001, HR 8.8, 95 % CI 3.01-25.96), baseline PAI-1 activity (>18 IU/ml) (chi (2) = 9.37; P = 0.002, HR 7.6, 95 % CI 2.07-27.84) were significant predictors of recurrent angina by univariate analyses. According to stepwise multivariate analyses, only the levels of plasma uPA antigen and serum CRP were shown to be significant independent predictors of angina recurrence (multivariate uPA chi (2) = 8.22, P = 0.004, HR 6.2, 95 % CI 1.78-21.67; CRP chi (2) = 4.09, P = 0.04, HR 1.9, 95 % CI 1.02-3.68). High preprocedural plasma uPA and serum CRP levels are indicative of angina recurrence after successful PTCA, and are valuable for the prognosis of restenosis. PMID- 24057346 TI - A man with recurrent syncope. PMID- 24057347 TI - Carotid stenosis management: a review for the internist. AB - Stroke is one of the most important causes of mortality and morbidity worldwide and, for a long time, was the leading cause of death in developed countries. Atherothrombotic carotid stenosis is one of the most important etiologies behind this event. If properly recognized and treated, lives can be saved, as well as long-term disabilities prevented. With population aging and improvements in surgical and clinical care, patients with several comorbidities will be referred for revascularization procedures more frequently, posing a challenge for physicians. The purpose of this review is to provide internists and clinicians with information based on several studies so they can offer to their patients, the best evidence-based care, indicating appropriate medical therapy, as well as referral to a vascular surgeon, or what contraindicates endarterectomy or angioplasty, depending on individual characteristics. PMID- 24057350 TI - Visible-light-induced, copper(I)-catalysed C-N coupling between o phenylenediamine and terminal alkynes: one-pot synthesis of 3-phenyl-2-hydroxy quinoxalines. AB - Visible-light-initiated aerobic direct C-N coupling between o-phenylenediamines and terminal acetylenes was performed using simple copper(I) chloride as a catalyst for the synthesis of quinoxaline derivatives. The current method works well for a wide range of electron rich as well as electron poor group-substituted o-phenylenediamines and phenylacetylenes. The key component in the reaction is the direct photo-excitation of in situ generated copper arylacetylide (lambda(abs) = 420-480 nm). Moreover, as compared to the literature reports (thermal process), the current photochemical method is simple, mild, high yielding, and more viable towards the construction of biologically important quinoxaline derivatives from easily accessible raw materials, without the need of ligands and strong oxidants. PMID- 24057348 TI - Glucocorticoid mediates the transcription of OAT-PG, a kidney-specific prostaglandin transporter. AB - OAT-PG is a kidney-specific prostaglandin transporter and exclusively expressed at the basolateral membrane of proximal tubules in rodent kidneys. We previously reported that OAT-PG was dominantly expressed in the male kidney similar to the other SLC22 family proteins as organic anion transporter (OAT) 1 and OAT3. Recently, Wegner et al. revealed that a transcription factor, B-cell CLL/lymphoma 6 (BCL6), is associated with the male-dominant expressions of OAT1 and OAT3 in the rat kidney. Here, we performed the luciferase assay to investigate whether OAT-PG is also transcriptionally regulated by BCL6. However, the promoter activity of OAT-PG was not directly affected by BCL6 overexpression nor the testosterone treatment, suggesting that different regulatory mechanisms underlie the male-dominant transcriptional regulation of OAT-PG compared to those of OAT1 and OAT3. We newly found that adrenalectomy (Adx) of male rat caused a significant reduction of OAT-PG expression without any significant changes in the OAT1 and OAT3 expressions, and it was recovered by the dexamethasone administration. Furthermore, the renocortical PGE2 concentration was markedly increased in Adx male rat, concomitant with the downregulation of OAT-PG, and it was reduced to the basal level by dexamethasone treatment. In the luciferase assay, dexamethasone stimulated OAT-PG promoter activity but not OAT1. The luciferase activity responsiveness to dexamethasone was significantly reduced by the deletion of glucocorticoid response elements in the OAT-PG promoter region. These results suggest that glucocorticoid plays an important role in the regulation of the renocortical PGE2 concentration by the transcriptional regulation of OAT-PG in the rat kidney. PMID- 24057351 TI - In silico comparison of low- and high-risk human papillomavirus proteins. AB - Human papillomavirus (HPV) is an important pathogen which is classified into two, high- and low-risk groups. The proteins of high-risk and low-risk HPV types have different functions. Therefore, there is a need to develop a computational method for predicting these two groups. In the present study, the physiochemical properties of all early (E1, E2, E4, E5, E6, and E7) and late (L1 and L2) proteins in high- and low-risk HPV types have been studied. The concept of receiver operating characteristic analysis and support vector machines methods has been used for comparison of high- and low-risk HPV types. The results demonstrate that amino acid composition, physiochemical, and secondary structure of E2 protein are significantly different between these two groups. The results demonstrate that in silico properties can create useful information to predict high-risk and low-risk HPV types. PMID- 24057349 TI - Functional TRPV and TRPM channels in human preadipocytes. AB - Preadipocytes are widely used as an in vitro model to investigate proliferation, adipogenic differentiation, and lipodystrophy; however, cellular physiology and biology are not fully understood in human preadipocytes. The present study was to investigate the expression of transient receptor potential (TRP) channels in human preadipocytes and their potential roles in regulating proliferation and adipogenic differentiation using approaches of confocal microscopy, whole-cell patch voltage-clamp, reverse transcription polymerase chain reaction, Western blot, etc. We found that TRPV2, TRPV4, and TRPM7 channels were abundantly expressed in human preadipocytes. The intracellular Ca(2+) transient activated by the TRPV2 activator probenecid was reversed or prevented by ruthenium red, a TRPV2 blocker. The TRPV4 channel activator, 4alpha-phorbol 12-13-dicaprinate, enhanced intracellular Ca(2+) oscillations, and the effect was inhibited by the TRPV4 blocker RN-1734. TRPM7 current was recorded with dialysis of Mg(2+)-free pipette solution, which was inhibited by the TRP channel blocker 2 aminoethoxydiphenyl borate and enhanced by acidic extracellular pH. Silencing TRPV2 or TRPM7, but not TRPV4, significantly reduced cell proliferation via inhibiting cyclin D1, cyclin E, and p-ERK1/2. Interestingly, individually silencing these three channels decreased adipogenic differentiation of human preadipocytes by reducing p-Akt kinase. Our results demonstrate for the first time that functional TRPV2, TRPV4, and TRPM7 channels are abundantly expressed in human preadipocytes. TRPV2 and TRPM7, but not TRPV4, regulate cell proliferation via activating cyclin D1, cyclin E, and p-ERK1/2, while they are all involved in adipogenesis in human preadipocytes via phosphorylating Akt kinase. PMID- 24057352 TI - Visual mismatch negativity and categorization. AB - Visual mismatch negativity (vMMN) component of event-related potentials is elicited by stimuli violating the category rule of stimulus sequences, even if such stimuli are outside the focus of attention. Category-related vMMN emerges to colors, and color-related vMMN is sensitive to language-related effects. A higher order perceptual category, bilateral symmetry is also represented in the memory processes underlying vMMN. As a relatively large body of research shows, violating the emotional category of human faces elicits vMMN. Another face related category sensitive to the violation of regular presentation is gender. Finally, vMMN was elicited to the laterality of hands. As results on category related vMMN show, stimulus representation in the non-conscious change detection system is fairly complex, and it is not restricted to the registration of elementary perceptual regularities. PMID- 24057353 TI - Alpha angle correction in femoroacetabular impingement. AB - PURPOSE: The predictive value of the alpha angle, currently the most validated magnetic resonance imaging parameter for CAM-impingement FAI, remains to be systematically evaluated in the orthopaedic literature. A systematic review was conducted to determine whether alpha angle correction influences clinical outcomes in patients with FAI. METHODS: We searched three databases (MEDLINE, EMBASE and PubMed) for English clinical studies published up to August 2012, reporting surgical correction of the alpha angle in patients with a primary diagnosis of FAI. Two independent assessors reviewed eligible studies. Where applicable, the Newcastle-Ottawa Scale was used to perform a quality assessment. Descriptive statistics are presented. RESULTS: Of the 1,103 studies initially retrieved, 14 fulfilled our eligibility criteria. Majority of studies (86 %) were case-control designs, with no randomized controlled trials. Variability existed in the surgical techniques and modalities used to measure pre- and post-operative alpha angles. All 14 studies reported a mean measured post-operative restoration of a normal alpha angle (equal to or less than 55 degrees ). Failure due to inadequate osseous correction was cited in 3/14 included studies. Correction resulted in significant improvements in range of motion and patient Visual Analog Scales, non-arthritic hip scores, Harris Hip Scores and the short-form-12. CONCLUSION: Based on this review, there is evidence supporting that precise surgical restoration of the alpha angle in CAM-type FAI to a minimum of less than 55 degrees will lead to improved patient outcomes. The alpha angle is a good predictor of outcome and represents a simple, reproducible and inexpensive guide that can be used intra-operatively and post-operatively. PMID- 24057354 TI - Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering. AB - PURPOSE: Tendon injuries vary from acute rupture to chronic tendinopathy. For an optimal treatment of either condition, a profound knowledge is essential. Therefore, this article shall give an overview of physiology, biology, and pathology of tendon healing and state of the art in tendon bioengineering. METHODS: For a preferably comprehensive survey, the current literature listed in PubMed and published in English peer-reviewed journals (March 2013) was systematically reviewed for tendon healing and tendon bioengineering including cytokine modulation, autologous sources of growth factors, biomaterials, gene therapy, and cell-based therapy. No differentiation was made between clinical and preclinical in vitro investigations. RESULTS: Tendon healing happens in certain stadiums of inflammation, formation, and remodelling. An additional process of "collagen recycling" close to the healing site has been described recently. With increasing comprehension of physiology and pathology of tendon healing, several promising approaches in tendon bioengineering using growth factors, biomaterials, gene therapy, or cell-based therapy are described. However, only some of these are already used routinely in clinics. CONCLUSION: Strong and resistant tendons are crucial for a healthy musculoskeletal system. The new approaches in tendon bioengineering are promising to aid physiological tendon healing and thus resulting in a stronger and more resistant tendon after injury. The growing knowledge in this field will need to be further taken into clinical studies so that especially those patients with prolonged courses, revision surgery, or chronic tendinopathy and high-demanding patients, i.e., professional athletes would benefit. LEVEL OF EVIDENCE: II. PMID- 24057356 TI - Transanal endoscopic microsurgery for giant polyps of the rectum. AB - BACKGROUND: The potential for malignancy in rectal polyps increases with the size of the polyp, and unexpected malignancy is reported in up to 39 % of large rectal adenomas. Transanal endoscopic microsurgery (TEM) offers the possibility of an en bloc full-thickness excision for lesions in the rectum. We present our results with TEM in the removal of giant polyps equal or greater than 4 cm in diameter. METHODS: In the period between 1998 and 2012, TEM was performed in 39 patients with rectal polyps measuring at least 4 cm in diameter. Transrectal ultrasound and/or magnetic resonance imaging of the rectum was used when cancer was suspected. RESULTS: The polyp was removed with en bloc full-thickness excision in 77 % (n = 30). The preoperative diagnosis was benign rectal adenoma in 89.7 % (n = 35). The median size of the polyps was 30 cm(2) (range 16-100 cm(2)). Postoperative complications included bleeding in 4 patients (10.3 %). Histological examination showed unexpected cancer in 4 patients (10.3 %). TEM was curative in 2 of these patients, and the other 2 underwent further surgery. Recurrences occurred in 10 patients (25.6 %) and consisted of 5 adenomas and 5 adenocarcinomas. In 5 patients, these recurrences were treated with endoscopic removal or re-TEM. The remaining 5 underwent total mesorectal excision and/or chemotherapy. CONCLUSIONS: Full-thickness TEM provides a safe and efficient treatment for excision of giant polyps. In case of unexpected cancer, TEM can be curative. Local recurrence can be often treated with a second TEM procedure. PMID- 24057357 TI - Simultaneous laparoscopic resection of primary colorectal cancer and associated liver metastases: a systematic review. AB - As many as 25 % of colorectal cancer (CRC) patients have liver metastases at presentation. However, the optimal strategy for resectable synchronous colorectal liver metastasis remains controversial. Despite the increasing use of laparoscopy in colorectal and liver resections, combined laparoscopic resection of the primary CRC and synchronous liver metastasis is rarely performed. The potential benefits of this approach are the possibility to perform a radical operation with small incisions, earlier recovery, and reduction in costs. The aim of this study was to review the literature on feasibility and short-term results of simultaneous laparoscopic resection. We conducted a systematic search of all articles published until February 2013. Search terms included: hepatectomy [Mesh], "liver resection," laparoscopy [Mesh], hand-assisted laparoscopy [Mesh], surgical procedures, minimally invasive [Mesh], colectomy [Mesh], colorectal neoplasms [Mesh], and "colorectal resections." No randomized trials are available. All data have been reported as case reports, case series, or case control studies. Thirty-nine minimally invasive simultaneous resections were identified in 14 different articles. There were 9 (23 %) major hepatic resections. The most performed liver resection was left lateral sectionectomy in 26 (67 %) patients. Colorectal resections included low rectal resections with total mesorectal excision, right and left hemicolectomies, and anterior resections. Despite the lack of high-quality evidence, the laparoscopic combined procedure appeared to be feasible and safe, even with major hepatectomies. Good patient selection and refined surgical technique are the keys to successful simultaneous resection. Simultaneous left lateral sectionectomy associated with colorectal resection should be routinely proposed. PMID- 24057358 TI - Handling Arabidopsis plants: growth, preservation of seeds, transformation, and genetic crosses. AB - Growing healthy plants is essential for the advancement of Arabidopsis thaliana (Arabidopsis) research. Over the last 20 years, the Arabidopsis Biological Resource Center (ABRC) has collected and developed a series of best-practice protocols, some of which are presented in this chapter. Arabidopsis can be grown in a variety of locations, growth media, and environmental conditions. Most laboratory accessions and their mutant or transgenic derivatives flower after 4-5 weeks and set seeds after 7-8 weeks, under standard growth conditions (soil, long day, 23 oC). Some mutant genotypes, natural accessions, and Arabidopsis relatives require strict control of growth conditions best provided by growth rooms, chambers, or incubators. Other lines can be grown in less-controlled greenhouse settings. Although the majority of lines can be grown in soil, certain experimental purposes require utilization of sterile solid or liquid growth media. These include the selection of primary transformants, identification of homozygous lethal individuals in a segregating population, or bulking of a large amount of plant material. The importance of controlling, observing, and recording growth conditions is emphasized and appropriate equipment required to perform monitoring of these conditions is listed. Proper conditions for seed harvesting and preservation, as well as seed quality control, are also described. Plant transformation and genetic crosses, two of the methods that revolutionized Arabidopsis genetics, are introduced as well. PMID- 24057359 TI - Using Arabidopsis-related model species (ARMS): growth, genetic transformation, and comparative genomics. AB - The Arabidopsis-related model species (ARMS) Thellungiella salsuginea and Thellungiella parvula have generated broad interest in salt stress research. While general growth characteristics of these species are similar to Arabidopsis, some aspects of their life cycle require particular attention in order to obtain healthy plants, with a large production of seeds in a relatively short time. This chapter describes basic procedures for growth, maintenance, and Agrobacterium mediated transformation of ARMS. Where appropriate, differences in requirements between Thellungiella spp. and Arabidopsis are highlighted, along with basic growth requirements of other less studied candidate model species. Current techniques for comparative genomics analysis between Arabidopsis and ARMS are also described in detail. PMID- 24057360 TI - Growing Arabidopsis in vitro: cell suspensions, in vitro culture, and regeneration. AB - An understanding of basic methods in Arabidopsis tissue culture is beneficial for any laboratory working on this model plant. Tissue culture refers to the aseptic growth of cells, organs, or plants in a controlled environment, in which physical, nutrient, and hormonal conditions can all be easily manipulated and monitored. The methodology facilitates the production of a large number of plants that are genetically identical over a relatively short growth period. Techniques, including callus production, cell suspension cultures, and plant regeneration, are all indispensable tools for the study of cellular biochemical and molecular processes. Plant regeneration is a key technology for successful stable plant transformation, while cell suspension cultures can be exploited for metabolite profiling and mining. In this chapter we report methods for the successful and highly efficient in vitro regeneration of plants and production of stable cell suspension lines from leaf explants of both Arabidopsis thaliana and Arabidopsis halleri. PMID- 24057361 TI - Arabidopsis database and stock resources. AB - The volume of Arabidopsis information has increased enormously in recent years as a result of the sequencing of the reference genome and other large-scale functional genomics projects. Much of the data is stored in public databases, where data are organized, analyzed, and made freely accessible to the research community. These databases are resources that researchers can utilize for making predictions and developing testable hypotheses. The methods in this chapter describe ways to access and utilize Arabidopsis data and genomic resources found in databases and stock centers. PMID- 24057362 TI - Bioinformatic tools in Arabidopsis research. AB - Bioinformatic tools are an increasingly important resource for Arabidopsis researchers. With them, it is possible to rapidly query the large data sets covering genomes, transcriptomes, proteomes, epigenomes, and other "omes" that have been generated in the past decade. Often these tools can be used to generate quality hypotheses at the click of a mouse. In this chapter, we cover the use of bioinformatic tools for examining gene expression and coexpression patterns, performing promoter analyses, looking for functional classification enrichment for sets of genes, and investigating protein-protein interactions. We also introduce bioinformatic tools that allow integration of data from several sources for improved hypothesis generation. PMID- 24057363 TI - Exploiting natural variation in Arabidopsis. AB - Natural variation for many traits is present within the species Arabidopsis thaliana. This chapter describes the use of natural variation to elucidate genes underlying the regulation of quantitative traits. It deals with the development and use of mapping populations, the detection and handling of genetic markers, the phenotyping of quantitative traits, and, finally, QTL analyses. The focus of the chapter is on the use and development of recombinant inbred lines, but other types of segregating populations, including genome-wide association mapping in natural populations, are also discussed. PMID- 24057364 TI - Grafting in Arabidopsis. AB - Grafting provides a simple way to generate chimeric plants with regions of different genotypes and thus to assess the cell autonomy of gene action. The technique of grafting has been widely used in other species, but in Arabidopsis, its small size makes the process rather more demanding. However, there are now several well-established grafting procedures available, which we described here, and their use has already contributed greatly to understanding of such processes as shoot branching control, flowering, disease resistance, and systemic silencing. PMID- 24057365 TI - Agrobacterium tumefaciens-mediated transient transformation of Arabidopsis thaliana leaves. AB - Transient assays provide a convenient alternative to stable transformation. Compared to the generation of stably transformed plants, agroinfiltration is more rapid, and samples can be analyzed a few days after inoculation. Nevertheless, at difference of tobacco and other plant species, Arabidopsis thaliana remains recalcitrant to routine transient assays. In this chapter, we describe a transient expression assay using simple infiltration of intact Arabidopsis leaves with Agrobacterium tumefaciens carrying a plasmid expressing a reporter fluorescent protein. In this protocol, Agrobacterium aggressiveness was increased by a prolonged treatment in an induction medium deficient in nutrients and containing acetosyringone. Besides, Arabidopsis plants were cultivated in intermediate photoperiod (12 h light-12 h dark) to promote leaf growth. PMID- 24057366 TI - iTILLING: personalized mutation screening. AB - One powerful approach to studying gene function is to analyze the phenotype of an organism carrying a mutant allele of a gene of interest. In order to use this experimental approach, one must have the ability to easily isolate individual organisms carrying desired mutations. A widely used method for accomplishing this task in plants and other organisms is a procedure called TILLING. A traditional TILLING project has at its foundation an ordered mutant population produced by treating seeds with a chemical mutagen. From this mutagenized seed, thousands of individual mutant lines are produced, and corresponding DNA samples are collected. For several plant species, publicly accessible screening facilities have been established that perform mutant screens on a gene-by-gene basis in response to customer requests using PCR and heteroduplex detection methods. The iTILLING method described in this chapter represents an individualized version of the TILLING process. Performing a traditional TILLING experiment requires a large investment in time and resources to establish the well-ordered mutant population. By contrast, iTILLING is a low-investment alternative that provides the individual research lab with a practical solution to mutation screening. The main difference between the two approaches is that iTILLING is not based on the establishment of a durable, organized mutant population. Instead, a system for growing Arabidopsis seedlings in 96-well plates is used to produce an ephemeral mutant population for screening. Because the intention is not to develop a long term resource, a considerable savings in time and money is realized when using iTILLING as compared to traditional TILLING. iTILLING is not intended to serve as a replacement to traditional TILLING. Rather, iTILLING provides a strategy by which custom mutagenesis screens can be performed by individual labs using unique genetic backgrounds that are of specific interest to that research group. PMID- 24057367 TI - Tailor-made mutations in Arabidopsis using zinc finger nucleases. AB - Zinc finger nucleases (ZFNs) are proteins engineered to make site-specific double strand breaks (DSBs) in a DNA sequence of interest. Imprecise repair of the ZFN induced DSBs by the nonhomologous end-joining (NHEJ) pathway results in a spectrum of mutations, such as nucleotide substitutions, insertions, and deletions. Here we describe a method for targeted mutagenesis in Arabidopsis with ZFNs, which are engineered by context-dependent assembly (CoDA). This ZFN-induced mutagenesis method is an alternative to other currently available gene knockout or knockdown technologies and is useful for reverse genetic studies. PMID- 24057368 TI - The use of artificial microRNA technology to control gene expression in Arabidopsis thaliana. AB - In plants, double-stranded RNA (dsRNA) is an effective trigger of RNA silencing, and several classes of endogenous small RNA (sRNA), processed from dsRNA substrates by DICER-like (DCL) endonucleases, are essential in controlling gene expression. One such sRNA class, the microRNAs (miRNAs) control the expression of closely related genes to regulate all aspects of plant development, including the determination of leaf shape, leaf polarity, flowering time, and floral identity. A single miRNA sRNA silencing signal is processed from a long precursor transcript of nonprotein-coding RNA, termed the primary miRNA (pri-miRNA). A region of the pri-miRNA is partially self-complementary allowing the transcript to fold back onto itself to form a stem-loop structure of imperfectly dsRNA. Artificial miRNA (amiRNA) technology uses endogenous pri-miRNAs, in which the miRNA and miRNA* (passenger strand of the miRNA duplex) sequences have been replaced with corresponding amiRNA/amiRNA* sequences that direct highly efficient RNA silencing of the targeted gene. Here, we describe the rules for amiRNA design, as well as outline the PCR and bacterial cloning procedures involved in the construction of an amiRNA plant expression vector to control target gene expression in Arabidopsis thaliana. PMID- 24057369 TI - Generation and identification of Arabidopsis EMS mutants. AB - EMS mutant analysis is a routine experiment to identify new players in a specific biological process or signaling pathway using forward genetics. It begins with the generation of mutants by treating Arabidopsis seeds with EMS. A mutant with a phenotype of interest (mpi) is obtained by screening plants of the M2 generation under a specific condition. Once the phenotype of the mpi is confirmed in the next generation, map-based cloning is performed to locate the mpi mutation. During the map-based cloning, mpi plants (Arabidopsis Columbia-0 (Col-0) ecotype background) are first crossed with Arabidopsis Landsberg erecta (Ler) ecotype, and the presence or absence of the phenotype in the F1 hybrids indicates whether the mpi is recessive or dominant. F2 plants with phenotypes similar to the mpi, if the mpi is recessive, or those without the phenotype, if the mpi is dominant, are used as the mapping population. As few as 24 such plants are selected for rough mapping. After finding one marker (MA) linked to the mpi locus or mutant phenotype, more markers near MA are tested to identify recombinants. The recombinants indicate the interval in which the mpi is located. Additional recombinants and molecular markers are then required to narrow down the interval. This is an iterative process of narrowing down the mapping interval until no further recombinants or molecular markers are available. The genes in the mapping interval are then sequenced to look for the mutation. In the last step, the wild type or mutated gene is cloned to generate binary constructs. Complementation or recapitulation provides the most convincing evidence in determining the mutation that causes the phenotype of the mpi. Here, we describe the procedures for generating mutants with EMS and analyzing EMS mutations by map-based cloning. PMID- 24057370 TI - Generation and characterization of Arabidopsis T-DNA insertion mutants. AB - Transfer DNA (T-DNA) insertion mutants are often used in forward and reverse genetics to reveal the molecular mechanisms of a particular biological process in plants. To generate T-DNA insertion mutants, T-DNA must be inserted randomly in the genome through transformation mediated by Agrobacterium tumefaciens. During generation of a T-DNA insertion mutant, Agrobacterium competent cells are first prepared and plasmids containing the T-DNA introduced into Agrobacterium cells. Agrobacterium containing T-DNA vectors are then used to transform T-DNA into Arabidopsis. After screening and identifying T-DNA insertion mutants with interesting phenotypes, genomic DNA is extracted from the mutants and used to isolate the T-DNA flanking sequences. To finally determine the mutated genes causing the specific phenotype in the T-DNA insertion mutants, cosegregation analysis and complementation or recapitulation analysis are needed. In this chapter, we describe detailed protocols for generation and characterization of T DNA insertion mutants. PMID- 24057371 TI - Identification of EMS-induced causal mutations in Arabidopsis thaliana by next generation sequencing. AB - Emerging next-generation sequencing (NGS) technologies are powerful tools for the identification of causal mutations underlying phenotypes of interest in Arabidopsis thaliana. Based on a methodology termed bulked segregant analysis (BSA), whole-genome sequencing data are derived from pooled F2 segregants after crossing a mutant to a different polymorphic accession and are analyzed for single nucleotide polymorphisms (SNPs). Then, a genome region spanning the causal mutation site is narrowed down by linkage analysis of SNPs in the accessions used to produce the F1 generation. Next, candidate SNPs for the causative mutation are extracted by filtering the linked SNPs using multiple appropriate criteria. Effects of each candidate SNP on the function of the corresponding gene are evaluated to identify the causal mutation, and its validity is then confirmed by independent criteria. This chapter describes the identification by NGS analysis of causal recessive mutations derived from EMS mutagenesis. PMID- 24057372 TI - Arabidopsis transformation with large bacterial artificial chromosomes. AB - The study of a gene's function requires, in many cases, the ability to reintroduce the gene of interest or its modified version back into the organism of choice. One potential caveat of this approach is that not only the coding region but also the regulatory sequences of a gene should be included in the corresponding transgenic construct. Even in species with well-annotated genomes, such as Arabidopsis, it is nearly impossible to predict which sequences are responsible for the proper expression of a gene. One way to circumvent this problem is to utilize a large fragment of genomic DNA that contains the coding region of the gene of interest and at least 5-10 kb of flanking genomic sequences. To facilitate these types of experiments, libraries harboring large genomic DNA fragments in binary vectors have been constructed for Arabidopsis and several other plant species. Working with these large clones, however, requires some special precautions. In this chapter, we describe the experimental procedures and extra cautionary measures involved in the identification of the clone containing the gene of interest, its transfer from E. coli to Agrobacterium, and the generation, verification, and analysis of the corresponding transgenic plants. PMID- 24057373 TI - Global DNA methylation analysis using methyl-sensitive amplification polymorphism (MSAP). AB - DNA methylation is a crucial epigenetic process which helps control gene transcription activity in eukaryotes. Information regarding the methylation status of a regulatory sequence of a particular gene provides important knowledge of this transcriptional control. DNA methylation can be detected using several methods, including sodium bisulfite sequencing and restriction digestion using methylation-sensitive endonucleases. Methyl-Sensitive Amplification Polymorphism (MSAP) is a technique used to study the global DNA methylation status of an organism and hence to distinguish between two individuals based on the DNA methylation status determined by the differential digestion pattern. Therefore, this technique is a useful method for DNA methylation mapping and positional cloning of differentially methylated genes. In this technique, genomic DNA is first digested with a methylation-sensitive restriction enzyme such as HpaII, and then the DNA fragments are ligated to adaptors in order to facilitate their amplification. Digestion using a methylation-insensitive isoschizomer of HpaII, MspI is used in a parallel digestion reaction as a loading control in the experiment. Subsequently, these fragments are selectively amplified by fluorescently labeled primers. PCR products from different individuals are compared, and once an interesting polymorphic locus is recognized, the desired DNA fragment can be isolated from a denaturing polyacrylamide gel, sequenced and identified based on DNA sequence similarity to other sequences available in the database. We will use analysis of met1, ddm1, and atmbd9 mutants and wild-type plants treated with a cytidine analogue, 5-azaC, or zebularine to demonstrate how to assess the genetic modulation of DNA methylation in Arabidopsis. It should be noted that despite the fact that MSAP is a reliable technique used to fish for polymorphic methylated loci, its power is limited to the restriction recognition sites of the enzymes used in the genomic DNA digestion. PMID- 24057374 TI - Next-generation mapping of genetic mutations using bulk population sequencing. AB - Next-generation sequencing platforms have made it possible to very rapidly map genetic mutations in Arabidopsis using whole-genome resequencing against pooled members of an F2 mapping population. In the case of recessive mutations, all individuals expressing the phenotype will be homozygous for the mutant genome at the locus responsible for the phenotype, while all other loci segregate roughly equally for both parental lines due to recombination. Importantly, genomic regions flanking the recessive mutation will be in linkage disequilibrium and therefore also be homozygous due to genetic hitchhiking. This information can be exploited to quickly and effectively identify the causal mutation. To this end, sequence data generated from members of the pooled population exhibiting the mutant phenotype are first aligned to the reference genome. Polymorphisms between the mutant and mapping line are then identified and used to determine the homozygous, nonrecombinant region harboring the mutation. Polymorphisms in the identified region are filtered to provide a short list of markers potentially responsible for the phenotype of interest, which is followed by validation at the bench. Although the focus of recent studies has been on the mapping of point mutations exhibiting recessive phenotypes, the techniques employed can be extended to incorporate more complicated scenarios such as dominant mutations and those caused by insertions or deletions in genomic sequence. This chapter describes detailed procedures for performing next-generation mapping against an Arabidopsis mutant and discusses how different mutations might be approached. PMID- 24057375 TI - Chemical fingerprinting of Arabidopsis using Fourier transform infrared (FT-IR) spectroscopic approaches. AB - Fourier transform infrared (FT-IR) spectroscopy is a fast, sensitive, inexpensive, and nondestructive technique for chemical profiling of plant materials. In this chapter we discuss the instrumental setup, the basic principles of analysis, and the possibilities for and limitations of obtaining qualitative and semiquantitative information by FT-IR spectroscopy. We provide detailed protocols for four fully customizable techniques: (1) Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS): a sensitive and high-throughput technique for powders; (2) attenuated total reflectance (ATR) spectroscopy: a technique that requires no sample preparation and can be used for solid samples as well as for cell cultures; (3) microspectroscopy using a single element (SE) detector: a technique used for analyzing sections at low spatial resolution; and (4) microspectroscopy using a focal plane array (FPA) detector: a technique for rapid chemical profiling of plant sections at cellular resolution. Sample preparation, measurement, and data analysis steps are listed for each of the techniques to help the user collect the best quality spectra and prepare them for subsequent multivariate analysis. PMID- 24057376 TI - A pipeline for 15N metabolic labeling and phosphoproteome analysis in Arabidopsis thaliana. AB - Within the past two decades, the biological application of mass spectrometric technology has seen great advances in terms of innovations in hardware, software, and reagents. Concurrently, the burgeoning field of proteomics has followed closely (Yates et al., Annu Rev Biomed Eng 11:49-79, 2009)-and with it, importantly, the ability to globally assay altered levels of posttranslational modifications in response to a variety of stimuli. Though many posttranslational modifications have been described, a major focus of these efforts has been protein-level phosphorylation of serine, threonine, and tyrosine residues (Schreiber et al., Proteomics 8:4416-4432, 2008). The desire to examine changes across signal transduction cascades and networks in their entirety using a single mass spectrometric analysis accounts for this push-namely, preservation and enrichment of the transient yet informative phosphoryl side group. Analyzing global changes in phosphorylation allows inferences surrounding cascades/networks as a whole to be made. Towards this same end, much work has explored ways to permit quantitation and combine experimental samples such that more than one replicate or experimental condition can be identically processed and analyzed, cutting down on experimental and instrument variability, in addition to instrument run time. One such technique that has emerged is metabolic labeling (Gouw et al., Mol Cell Proteomics 9:11-24, 2010), wherein biological samples are labeled in living cells with nonradioactive heavy isotopes such as (15)N or (13)C. Since metabolic labeling in living organisms allows one to combine the material to be processed at the earliest possible step, before the tissue is homogenized, it provides a unique and excellent method for comparing experimental samples in a high-throughput, reproducible fashion with minimal technical variability. This chapter describes a pipeline used for labeling living Arabidopsis thaliana plants with nitrogen-15 ((15)N) and how this can be used, in conjunction with a technique for enrichment of phosphorylated peptides (phosphopeptides), to determine changes in A. thaliana's phosphoproteome on an untargeted, global scale. PMID- 24057377 TI - Gene expression profiling using DNA microarrays. AB - In Arabidopsis research, microarrays have typically been employed for the measurement of gene expression under different conditions. Microarray analysis is often used to analyze the effects of the expression of wild-type genes (control) versus mutants, the effects of varying environmental conditions, and the effects of hormones. In addition, microarray analysis is used to analyze differences in gene expression between growth stages and tissues. Other array applications include comparative genomic hybridization, chromatin immunoprecipitation, mutation detection, and genotyping. This chapter focuses on gene expression profiling, which is typically performed by the competitive hybridization of two samples, each labeled with a fluorescent dye such as cyanine 3-CTP or cyanine 5 CTP. We describe the steps, from RNA purification to data analysis, that are involved in obtaining data from DNA microarrays. PMID- 24057378 TI - Forward chemical genetic screening. AB - Chemical genetics utilizes small molecules to perturb biological processes. Unlike conventional genetics methods, which involve the alteration of genetic information mostly with lasting effects, chemical genetics allows temporary and reversible alterations of biological processes. Furthermore, it enables the alteration of biological processes in a dose-dependent manner, providing an advantage over conventional genetics. In the present chapter, the general procedures of forward chemical genetic screening are described. Forward chemical genetic screening can be performed in three steps. The first step involves the identification of small molecules that induce phenotypic or physiological changes in a biological system from a chemical library. In the second step, cellular targets that interact with the isolated chemical, which are mostly proteins, are identified. Although several methods can be applied in the second step, the most common one is affinity pull-down assay using a target protein that binds to the isolated compound. However, affinity pull-down of a target protein is a formidable barrier in forward chemical genetics. We introduced a tagged chemical library approach that significantly facilitates the identification of target proteins. The third step consists of the validation of the target protein, which should include the assessment of target specificity. This step is critical because small molecules often show pleiotropic effects due to low specificity. The specificity test may include a competition assay using cold competitors and a genetic study using mutants or transgenic lines modified for the cellular target. PMID- 24057379 TI - Highly reproducible ChIP-on-chip analysis to identify genome-wide protein binding and chromatin status in Arabidopsis thaliana. AB - Gene activity is regulated via chromatin dynamics in eukaryotes. In plants, alterations of histone modifications are correlated with gene regulation for development, vernalization, and abiotic stress responses. Using ChIP, ChIP-on chip, and ChIP-seq analyses, the direct binding regions of transcription factors and alterations of histone modifications can be identified on a genome-wide level. We have established reliable and reproducible ChIP and ChIP-on-chip methods that have been optimized for the Arabidopsis model system. These methods are not only useful for identifying the direct binding of transcription factors and chromatin status but also for scanning the regulatory network in Arabidopsis. PMID- 24057380 TI - Fluorescence microscopy. AB - Optical microscopy has developed as an indispensable tool for Arabidopsis cell biology. This is due to the high sensitivity, good spatial resolution, minimal invasiveness, and availability of autofluorescent proteins, which can be specifically fused to a distinct protein of interest. In this chapter, we introduce the theoretical concepts of fluorescence emission necessary to accomplish quantitative and functional cell biology using optical microscopy. The main focus lies on spectroscopic techniques, which, in addition to intensity based studies, provide functional insight into cellular processes. PMID- 24057381 TI - Immunocytochemical fluorescent in situ visualization of proteins in Arabidopsis. AB - The understanding of cellular and subcellular functions often relies on the ability to visualize proteins as close as possible to their endogenous locations. A number of immunocytochemical techniques have been developed to detect proteins in situ using specific antibodies raised against proteins of interest. Here, we describe in detail two protocols commonly, successfully employed in Arabidopsis research. The first allows for immunolocalization of proteins in whole-mount Arabidopsis roots without the need for physical sectioning. The second allows for immunolocalization of proteins on semi-thin microtome sections of wax-embedded swamples. This approach is particularly useful when sectioning of Arabidopsis roots or other thicker plant organs is required for immunolocalization. We provide step-by-step protocols with extensive troubleshooting for both the whole mount and sectioning protocols. Furthermore, critical steps, advantages, and limitations of the two protocols described here are discussed. PMID- 24057382 TI - High-pressure freezing and freeze substitution of Arabidopsis for electron microscopy. AB - The objectives of electron microscopy ultrastructural studies are to examine cellular architecture and relate the cell's structural machinery to dynamic functional roles. This aspiration is difficult to achieve if specimens have not been adequately preserved in a "living state"; hence specimen preparation is of the utmost importance for the success of any electron micrographic study. High pressure freezing (HPF)/freeze substitution (FS) has long been recognized as the primer technique for the preservation of ultrastructure in biological samples. In most cases a basic HPF/freeze substitution protocol is sufficient to obtain superior ultrastructural preservation and structural contrast, which allows one to use more advanced microscopy techniques such as 3D electron tomography. However, for plant tissues, which have a thick cell wall, large water-filled vacuoles, and air spaces (all of which are detrimental to cryopreservation), these basic HPF/FS protocols often yield undesirable results. In particular, ice crystal artifacts and the staining of membrane systems are often poorly or negatively stained, which make 3D segmentation of a tomogram difficult. To overcome these problems, various aspects of the HPF/FS protocol can be altered, including the cryo-filler(s) used, freeze substitution cocktail, and the resin infiltration process. This chapter will describe these modifications for the preparation of plant tissues for routine electron microscopic studies, immunocytochemistry, and 3D tomographic electron imaging. PMID- 24057383 TI - Applications of fluorescent marker proteins in plant cell biology. AB - Over the past decade, confocal microscopy and the ever-expanding toolchest of fluorescent protein (xFP) markers and technologies have become routine methods for the biological laboratory. A common use of xFP fluorophores is in localizing proteins and the subcellular structures with which they associate, including analyzing their distribution and dynamics and the interactions of proteins in vivo. Additionally, a number of so-called optical highlighters have proven especially useful in analyzing the kinetics of these processes in pulse-chase studies of protein relocation(s) following an experimental challenge. Here we focus on exemplary methods in transformation and live-cell imaging in plant cells, with the expectation that researchers will find these and the accompanying resources useful as a starting point in developing their own expertise. PMID- 24057384 TI - Flow cytometry and sorting in Arabidopsis. AB - Flow cytometry, and the accompanying technology of cell sorting, represents an established and valuable experimental platform for the analysis of cellular populations. Applications involving higher plants, which started to emerge around 30 years ago, are now widely employed both to provide unique information regarding fundamental questions in basic and applied bioscience and to advance agricultural productivity in practical ways. Further developments of this platform are being actively pursued, promising additional advances in our understanding of the interactions of cells within the complex tissues and organs. Higher plants offer unique challenges in terms of flow cytometric analysis, first since their organs and tissues are, almost without exception, three-dimensional assemblies of different cell types and second that their individual cells are generally larger than those of mammals. This chapter focuses on the use of flow cytometry and cell sorting with the model species Arabidopsis thaliana, in particular addressing (1) fluorescence in vivo labeling of specific cell types, (2) fluorescence-activated sorting of protoplasts and nuclei, and (3) transcriptome analyses using sorted protoplasts and nuclei. PMID- 24057385 TI - Live imaging of Arabidopsis development. AB - Live cell imaging is an essential methodology for studying the structure, dynamics, and functions of cells in a living plant under normal or stressed growth conditions. Arabidopsis thaliana is perfectly amenable to various live microscopy techniques. In this chapter, we provide guidelines to design live imaging experiments. We discuss specifically the respective advantage of each microscopy technique, the choice of reporter, and the preparation of the sample. Detailed protocols for imaging of shoot and roots are provided. PMID- 24057386 TI - Arabidopsis organelle isolation and characterization. AB - The subcellular energy organelles (chloroplast, mitochondria, and peroxisome) in plants are responsible for major metabolic processes including photosynthesis, photorespiration, oxidative phosphorylation, beta-oxidation, and the tricarboxylic acid cycle. Arabidopsis thaliana provides a considerable challenge to organellar researchers that have traditionally focused their methods on the use of larger plants and storage organs from which organelles are relatively easy to isolate. In contrast, the small size and lack of abundant heterotrophic organs in Arabidopsis thaliana means that many traditional techniques have required significant modification to yield enough isolated organelles for experimentation. However, these challenges are balanced by the advantages of working in an organism that has such a wide array of publically available genetic resources. Here we present methods for the isolation of chloroplasts, mitochondria and peroxisomes from Arabidopsis thaliana plants and heterotrophic cell cultures as well as a number of commonly used assays to assess their functional integrity and purity. PMID- 24057387 TI - Analysis of subcellular metabolite distributions within Arabidopsis thaliana leaf tissue: a primer for subcellular metabolomics. AB - Every biological organism relies for its proper function on interactions between a multitude of molecular entities like RNA, proteins, and metabolites. The comprehensive measurement and the analysis of all these entities would therefore provide the basis for our functional and mechanistic understanding of most biological processes. Next to their amount and identity, it is most crucial to also gain information about the subcellular distribution and the flux of the measured compounds between the cellular compartments. That is, we want to understand not only the individual functions of cellular components but also their functional implications within the whole organism. While the analysis of macromolecules like DNA, RNA, and proteins is quite established and robust, analytical techniques for small metabolites, which are prone to diffusion and degradation processes, provide a host of unsolved challenges. The major limitations here are the metabolite conversion and relocation processes. In this protocol we describe a methodological workflow which includes a nonaqueous fractionation method, a fractionated two-phase liquid/liquid extraction protocol, and a software package, which together allow extracting and analyzing starch, proteins, and especially polar and lipophilic metabolites from a single sample towards the estimation of their subcellular distributions. PMID- 24057388 TI - Hormone profiling. AB - Phytohormones are low molecular weight compounds that are produced by plants to regulate growth and development and also in response to biotic and abiotic stresses. The quantitative analysis of these molecules, which is essential for a better understanding of their physiological functions, is still particularly challenging due to their very low abundance in plant tissues. In this chapter, a rapid, sensitive, and accurate method for the quantification of acidic plant hormones is described. A fast and simple extraction procedure without purification or derivatization was devised, followed by optimized ultrahigh pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. The analytical procedure was validated in terms of selectivity, sensitivity, linearity, precision, recovery, and matrix effects. This protocol facilitates the high-throughput analysis of the main plant hormones and is applicable as a routine tool for a wide range of research fields such as plant-pathogen interactions, mutant screening, or plant development. PMID- 24057389 TI - Purification of protein complexes and characterization of protein-protein interactions. AB - In plants and all other multicellular organisms, both the intra- and extracellular environments are filled with dynamic biomolecular interactions that control many biological processes. Most of these interactions are biochemical in nature and often exist between proteins. For instance, many protein-protein interactions assist in sustained cellular homeostasis but also allow for rapid intracellular communication in response to stimuli. Thus, the discovery and validation of protein-protein interactions, and the consequent formation of protein complexes, is an integral and essential component of plant biology research. The ability to efficiently and accurately determine existing protein networks is necessary to further our understanding of plant biology. However, discovering protein networks represents a challenge for both present and future researchers. Here we have outlined several straightforward methods aimed at first discovering protein-protein interactions and then characterizing them utilizing additional approaches. We first describe methods for rate-zonal centrifugation, in vitro binding assays, and co-immunoprecipitation experiments in the context of discovering novel protein-protein interactions. Next, we discuss methods for characterizing and validating these interactions using alternative approaches: yeast two-hybrid, in vitro pull-down assays, and bimolecular fluorescence complementation (BiFC). Obviously each of these methods need not be performed in parallel; rather our goal was to describe several approaches, some of which may be more appropriate for increasingly specialized laboratory environments. PMID- 24057391 TI - The split-ubiquitin system for the analysis of three-component interactions. AB - Protein-protein interactions are vital to all living cells. Many different in vivo and in vitro approaches are published which enable detection and determination of interactions between two proteins. However, most of these techniques are not designed to test for multi-protein interactions although oligomeric protein complexes are probably more likely to be the status quo in vivo than simple binary interactions. This chapter describes how a well established system for detection of protein-protein interactions can be exploited for assaying and screening of different kinds of oligomeric interactions. The split-ubiquitin bridge assay (SUB) is based on the split-ubiquitin system and enables detection of trimeric protein complexes. SUB assays can be used to check several putative interaction couples and to screen for novel interaction partners in different ways. PMID- 24057392 TI - RNA-binding protein immunoprecipitation from whole-cell extracts. AB - RNA-based regulation is increasingly recognized as an important factor shaping the cellular transcriptome. RNA-binding proteins that interact with cis regulatory motifs within pre-mRNAs determine the fate of their targets. Understanding posttranscriptional networks controlled by an RNA-binding protein requires the identification of its immediate in vivo targets. Here we describe RNA immunoprecipitation in Arabidopsis thaliana. Transgenic plants expressing an RNA-binding protein fused to green fluorescent protein are treated with formaldehyde to "trap" RNAs in complexes with their physiological protein partners. A whole-cell extract is subjected to immunoprecipitation with an antibody against the GFP tag. In parallel, a mock immunoprecipitation is performed using an unrelated antibody. Coprecipitated RNAs are eluted from the immunoprecipitate and identified via real-time PCR. Enrichment relative to immunoprecipitation from plants expressing GFP only and mock immunoprecipitation with an unrelated antibody indicates specific binding. PMID- 24057390 TI - Protein fragment bimolecular fluorescence complementation analyses for the in vivo study of protein-protein interactions and cellular protein complex localizations. AB - The analyses of protein-protein interactions are crucial for understanding cellular processes including signal transduction, protein trafficking, and movement. Protein fragment complementation assays are based on the reconstitution of protein function when non-active protein fragments are brought together by interacting proteins that were genetically fused to these protein fragments. Bimolecular fluorescence complementation (BiFC) relies on the reconstitution of fluorescent proteins and enables both the analysis of protein-protein interactions and the visualization of protein complex formations in vivo. Transient expression of proteins is a convenient approach to study protein functions in planta or in other organisms and minimizes the need for time consuming generation of stably expressing transgenic organisms. Here we describe protocols for BiFC analyses in Nicotiana benthamiana and Arabidopsis thaliana leaves transiently transformed by Agrobacterium infiltration. Further, we discuss different BiFC applications and provide examples for proper BiFC analyses in planta. PMID- 24057393 TI - High-throughput analysis of protein-DNA binding affinity. AB - Sequence-specific protein-DNA interactions mediate most regulatory processes underlying gene expression, such as transcriptional regulation by transcription factors (TFs) or chromatin organization. Current knowledge about DNA-binding specificities of TFs is based mostly on low- to medium-throughput methodologies that are time-consuming and often fail to identify DNA motifs recognized by a TF with lower affinity but retaining biological relevance. The use of protein binding microarrays (PBMs) offers a high-throughput alternative for the identification of protein-DNA specificities. PBM consists in an array of pseudorandomized DNA sequences that are optimized to include all the possible 10- or 11-mer DNA sequences, allowing the determination of binding specificities of most eukaryotic TFs. PBMs that can be synthesized by several manufacturing companies as single-stranded DNA are converted into double-stranded in a simple primer extension reaction. The protein of interest fused to an epitope tag is then incubated onto the PBM, and specific DNA-protein complexes are revealed in a series of immunological reactions coupled to a fluorophore. After scanning and quantifying PBMs, specific DNA motifs recognized by the protein are identified with ready-to-use scripts, generating comprehensive but accessible information about the DNA-binding specificity of the protein. This chapter describes detailed procedures for preparation of double-stranded PBMs, incubation with recombinant protein, and detection of protein-DNA complexes. Finally, we outline some cues for evaluating the biological role of DNA motifs obtained in vitro. PMID- 24057394 TI - Hemostatic efficacy of a traditional medicinal plant extract (Ankaferd Blood Stopper) in bleeding control. AB - The aim of this study is to assess the in vivo hemostatic effect of Ankaferd Blood Stopper (ABS) on rats using a tail bleeding model. Wistar rats were randomized into 4 groups of 9 each: group 1, control, no pretreatment, irrigated with saline; group 2, no pretreatment, irrigated with ABS; group 3, control, heparin pretreatment, irrigated with saline; and group 4, heparin pretreatment, irrigated with ABS. To control bleeding, compressive dressings were placed after instilling 1 mL of either ABS or saline to the bleeding area. Without heparin pretreatment, ABS shortened hemostasis time by 1.57 minutes and reduced the amount of bleeding by 0.85 g. With heparin pretreatment, ABS shortened hemostasis time by 3.29 minutes and reduced the amount of bleeding by 1.32 g. The ABS was more effective than saline irrigation for treating tail tip bleeding in rats, with or without heparin pretreatment, while also using a compressive dressing. PMID- 24057395 TI - Primary thrombophilia in Mexico X: a prospective study of the treatment of the sticky platelet syndrome. AB - INTRODUCTION: The sticky platelet syndrome (SPS) is a common cause of thrombosis. There are no prospective studies concerning treatment. OBJECTIVE: To analyze changes in platelet hyperaggregability of patients with SPS who were given antiplatelet drugs and to assess its association with rethrombosis. METHODS: A total of 55 patients with a history of thrombosis and SPS phenotype were prospectively studied before and after treatment with aspirin and/or clopidogrel. RESULTS: Patients were followed for 1 to 129 months, median 13. Of 55 patients, 40 received aspirin, 13 received aspirin + clopidogrel, and 2 received only clopidogrel. The platelet aggregation response to adenosine diphosphate and epinephrine significantly diminished after treatment, and only 2 patients developed rethrombosis 52 and 129 months after starting therapy, with the freedom from rethrombosis rate of the patients being 96.4% at 129 months. CONCLUSION: Using antiplatelet drugs, the platelet hyperreactivity of patients with the SPS phenotype was reverted; and this translated into a substantial decrease in the rethrombosis rate. PMID- 24057396 TI - Practical management of rivaroxaban for the treatment of venous thromboembolism. AB - Traditional anticoagulants, such as low-molecular-weight heparin and vitamin K antagonists, have been the mainstay for the treatment of venous thromboembolism (VTE) in the hospital setting and after discharge. These anticoagulants are effective but are associated with some limitations that may lead to their underuse. Based on the results of the EINSTEIN clinical trial program, the oral, direct factor Xa inhibitor rivaroxaban is approved for the treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE) and for the prevention of recurrent VTE. The single-drug approach with rivaroxaban is now available in both the hospital and the outpatient settings and may overcome some of the limitations of traditional agents. This review provides hospital physicians with an overview of the practical management of rivaroxaban and a critical evaluation of its use for the treatment of DVT and PE, including in specific clinical settings and special patient populations. PMID- 24057397 TI - New protocol for detection of intron 22 inversion mutation from cases with hemophilia A. AB - BACKGROUND: Hemophilia A is a X-linked recessive bleeding disorder characterized by qualitative and quantitative deficiency of factor VIII resulting from heterogeneous mutations in the factor VIII gene located in the Xq28 region. Intron 22 inversion (Inv22) mutation is one of the major causes of the protein alteration in factor VIII; its frequency is 40% to 50% in severe patients. Long polymerase chain reaction (PCR) and inverse PCR (I-PCR) have been used for the detection of Inv22 mutation. OBJECTIVE: Development of new protocol for detection of Inv22 mutation. METHOD: We have designed a new method for the detection of Inv22 mutation in complementary DNA (cDNA) of patients. Real-time PCR targeting exons 21 to 22, 22 to 23, and 23 to 24 of factor VIII gene were used in cases with hemophilia A. Samples that were inversion positive by this new method were cross-checked by the conventional I-PCR method. We observed that region between exons 22 and 23 could not be amplified, while in negative cases and controls a 480 bp product is obtained. RESULT: The method was validated in 20 cases with severe hemophilia A by the new cDNA method, and 8 cases were inversion positive, whereas 12 were negative cases. The findings were confirmed by standard I-PCR method. Complete correlation was observed. CONCLUSION: Conventional long PCR and I-PCR methods are work intensive, prolonged, and sometimes difficult to be standardize. The cDNA method is short, involves 3 short-segment amplifications, and is easy to reproduce. PMID- 24057398 TI - The relationship between eosinophil and cardiac syndrome X. AB - AIM: The pathophysiology of cardiac syndrome X (CSX) has not been clearly identified, although multiple abnormalities including microvascular spasm, endothelial dysfunction, and atherothrombosis have been reported. It is known that eosinophils play an important role in vasoconstruction and thrombosis. We aimed to compare the eosinophil counts in patients with CSX versus controls. MATERIALS AND METHODS: This study included 50 patients with CSX (20 male, mean age 50.42 +/- 9.6 years) and 30 control persons (10 male, mean age 49.16.11 +/- 9.2 years). These participants underwent concurrent routine biochemical tests, and their eosinophil counts were obtained on whole blood count. These parameters were compared between groups. RESULTS: Baseline characteristics of the study groups were comparable. Patients with CSX had a higher eosinophil count and mean platelet volume (MPV) value than the controls (339.4 +/- 188 vs 132.7 +/- 75 and 8.8 +/- 0.2 vs 7.2 +/- 0.1 fL; P < .001, respectively). CONCLUSION: As a result, our study revealed a relationship between eosinophil count and MPV in patients with CSX. PMID- 24057399 TI - Neutrophil-lymphocyte ratio may predict left atrial thrombus in patients with nonvalvular atrial fibrillation. AB - OBJECTIVE: Neutrophil-lymphocyte ratio (NLR) has been associated with poor outcomes in patients with cardiovascular diseases. We aimed to compare NLRs among patients with nonvalvular atrial fibrillation (AF) with or without left atrial (LA) thrombus. METHODS: A total of 309 (70.1 +/- 9.8 years, 49% male) patients with nonvalvular AF have undergone transoesophageal echocardiography (TEE) to assess the presence of LA thrombus. Baseline NLR was measured by dividing neutrophil count to lymphocyte count. RESULTS: Left atrial thrombus was detected in 32 (10.3%) of 309 patients. Mean NLR (2.2 +/- 1.0 vs 2.7 +/- 1.1, P = .026) was significantly higher among patients with LA thrombus compared to patients without LA thrombus. On multivariate analysis, NLR (odds ratio 1.59, 95% confidence interval 0.87-4.18; P < .02) was an independent risk factor for the presence of LA thrombus in patients with nonvalvular AF. CONCLUSION: Neutrophil lymphocyte ratio, an emerging marker of inflammation, was independently associated with the presence of LA thrombus in patients with nonvalvular AF. PMID- 24057400 TI - Neurite outgrowth of PC12 cells by 4'-O-beta-D-glucopyranosyl-3',4 dimethoxychalcone from Brassica rapa L. 'hidabeni' was enhanced by pretreatment with p38MAPK inhibitor. AB - The cellular effects of eleven compounds including chalcone glycosides isolated from Brassica rapa L. 'hidabeni' and their synthetic derivatives were studied in rat pheochromocytoma PC12 cells. Of the compounds tested, 4'-O-beta-D glucopyranosyl-3',4-dimethoxychalcone (A2) significantly increased the levels of the phosphorylated forms of extracellular signal-regulated kinases 1/2 (ERK 1/2), p38 mitogen-activated protein kinase (p38MAPK), and stress-activated protein kinases/Jun amino-terminal kinases (JNK/SAPK), but it did not affect Akt. Nerve growth factor (NGF), a well-known neurotrophic factor, increased the levels of phosphorylated ERK1/2, JNK/SAPK, and Akt but not p38MAPK, which may mediate marked neurite outgrowth. Signals evoked by A2 shared common characteristics with those induced by NGF; therefore, we evaluated the neuritogenic activity of A2 and found it induced only weak neurite outgrowth. However, this effect was enhanced by pre-treatment with a p38MAPK inhibitor, suggesting that the phosphorylation of p38MAPK down-regulated neurite outgrowth. From the results of this study, it was found that A2 in combination with a p38MAPK inhibitor can induce NGF-like effects. Hence, a combination of chalcone glycosides containing A2 and a p38MAPK inhibitor increases the likelihood that chalcone glycosides could be put to practical use in the form of drugs or alternative medicines to maintain neural health. PMID- 24057401 TI - One-pot approach to functional nucleosides possessing a fluorescent group using nucleobase-exchange reaction by thymidine phosphorylase. AB - Herein, we describe beta-selective coupling between a modified uracil and a deoxyribose to produce functionalized nucleosides catalyzed by thymidine phosphorylase derived from Escherichia coli. This enzyme mediates nucleobase exchange reactions to convert unnatural nucleosides possessing a large functional group such as a fluorescent molecule, coumarin or pyrene, linked via an alkyl chain at the C5 position of uracil. 5-(Coumarin-7-oxyhex-5-yn)uracil (C4U) displayed 57.2% conversion at 40% DMSO concentration in 1.0 mM phosphate buffer pH 6.8 to transfer thymidine to an unnatural nucleoside with C4U as the base. In the case of using 5-(pyren-1-methyloxyhex-5-yn)uracil (P4U) as the substrate, TP also could catalyse the reaction to generate a product with a very large functional group at 50% DMSO concentration (21.6% conversion). We carried out docking simulations using MF myPrest for the modified uracil bound to the active site of TP. The uracil moiety of the substrate binds to the active site of TP, with the fluorescent moiety linked to the C5 position of the nucleobase located outside the surface of the enzyme. As a consequence, the bulky fluorescent moiety binding to uracil has little influence on the coupling reaction. PMID- 24057402 TI - Characterization of propionate CoA-transferase from Ralstonia eutropha H16. AB - In this study, a propionate CoA-transferase (H16_A2718; EC 2.8.3.1) from Ralstonia eutropha H16 (Pct(Re)) was characterized in detail. Glu342 was identified as catalytically active amino acid residue via site-directed mutagenesis. Activity of Pct(Re) was irreversibly lost after the treatment with NaBH4 in the presence of acetyl-CoA as it is shown for all CoA-transferases from class I, thereby confirming the formation of the covalent enzyme-CoA intermediate by Pct(Re). In addition to already known CoA acceptors for Pct Re such as 3 hydroxypropionate, 3-hydroxybutyrate, acrylate, succinate, lactate, butyrate, crotonate and 4-hydroxybutyrate, it was found that glycolate, chloropropionate, acetoacetate, valerate, trans-2,3-pentenoate, isovalerate, hexanoate, octanoate and trans-2,3-octenoate formed also corresponding CoA-thioesters after incubation with acetyl-CoA and Pct(Re). Isobutyrate was found to be preferentially used as CoA acceptor amongst other carboxylates tested in this study. In contrast, no products were detected with acetyl-CoA and formiate, bromopropionate, glycine, pyruvate, 2-hydroxybutyrate, malonate, fumarate, itaconate, beta-alanine, gamma aminobutyrate, levulate, glutarate or adipate as potential CoA acceptor. Amongst CoA donors, butyryl-CoA, crotonyl-CoA, 3-hydroxybutyryl-CoA, isobutyryl-CoA, succinyl-CoA and valeryl-CoA apart from already known propionyl-CoA and acetyl CoA could also donate CoA to acetate. The highest rate of the reaction was observed with 3-hydroxybutyryl-CoA (2.5 MUmol mg-1 min-1). K(m) values for propionyl-CoA, acetyl-CoA, acetate and 3-hydroxybutyrate were 0.3, 0.6, 4.5 and 4.3 mM, respectively. The rather broad substrate range might be a good starting point for enzyme engineering approaches and for the application of Pct(Re) in biotechnological polyester production. PMID- 24057403 TI - Stable overproducer of hepatitis B surface antigen in the methylotrophic yeast Hansenula polymorpha due to multiple integration of heterologous auxotrophic selective markers and defect in peroxisome biogenesis. AB - Two methods of multicopy integrant selection in the methylotrophic yeast Hansenula polymorpha based on the use of heterologous yeast auxotrophic genes have been used to isolate effective overproducers of hepatitis B surface antigen (HBsAg). One selection marker was described earlier for this yeast, the Saccharomyces cerevisiae URA3 gene, whereas the second selection marker was developed by us, the Pichia pastoris ADE1 gene with shortened native promoter. Sequential use of both selection markers produced stable transformants containing up to 30 integration cassettes with HBsAg gene. Deletion of PEX3 gene coding for peroxine involved in the early step of peroxisome formation substantially increased the production of HBsAg in glucose medium as compared to the parental strain. Maximal production of HBsAg in Deltapex3 strain was nearly 8-9% of the total cell protein. PMID- 24057405 TI - Streptavidin-biotin technology: improvements and innovations in chemical and biological applications. AB - Streptavidin and its homologs (together referred to as streptavidin) are widely used in molecular science owing to their highly selective and stable interaction with biotin. Other factors also contribute to the popularity of the streptavidin biotin system, including the stability of the protein and various chemical and enzymatic biotinylation methods available for use with different experimental designs. The technology has enjoyed a renaissance of a sort in recent years, as new streptavidin variants are engineered to complement native proteins and novel methods of introducing selective biotinylation are developed for in vitro and in vivo applications. There have been notable developments in the areas of catalysis, cell biology, and proteomics in addition to continued applications in the more established areas of detection, labeling and drug delivery. This review summarizes recent advances in streptavidin engineering and new applications based on the streptavidin-biotin interaction. PMID- 24057404 TI - Culturable rare Actinomycetes: diversity, isolation and marine natural product discovery. AB - Rare Actinomycetes from underexplored marine environments are targeted in drug discovery studies due to the Actinomycetes' potentially huge resource of structurally diverse natural products with unusual biological activity. Of all marine bacteria, 10 % are Actinomycetes, which have proven an outstanding and fascinating resource for new and potent bioactive molecules. Past and present efforts in the isolation of rare Actinomycetes from underexplored diverse natural habitats have resulted in the isolation of about 220 rare Actinomycete genera of which more than 50 taxa have been reported to be the producers of 2,500 bioactive compounds. That amount represents greater than 25 % of the total Actinomycetes metabolites, demonstrating that selective isolation methods are being developed and extensively applied. Due to the high rediscovery rate of known compounds from Actinomycetes, a renewed interest in the development of new antimicrobial agents from rare and novel Actinomycetes is urgently required to combat the increasing number of multidrug-resistant human pathogens. To facilitate that discovery, this review updates all selective isolation media including pretreatment and enrichment methods for the isolation of marine rare Actinomycetes. In addition, this review demonstrates that discovering new compounds with novel scaffolds can be increased by intensive efforts in isolating and screening rare marine genera of Actinomycetes. Between 2007 and mid-2013, 80 new rare Actinomycete species were reported from marine habitats. They belong to 23 rare families, of which three are novel, and 20 novel genera. Of them, the family Micromonosporaceae is dominant as a producer of promising chemical diversity. PMID- 24057406 TI - Rhodococcus lactonase with organophosphate hydrolase (OPH) activity and His6 tagged OPH with lactonase activity: evolutionary proximity of the enzymes and new possibilities in their application. AB - Decontamination of soils with complex pollution using natural strains of microorganisms is a matter of great importance. Here we report that oil-oxidizing bacteria Rhodococcus erythropolis AC-1514D and Rhodococcus ruber AC-1513D can degrade various organophosphorous pesticides (OP). Cell-mediated degradation of five different OP is apparently associated with the presence of N-acylhomoserine lactonase, which is pronouncedly similar (46-50 %) to the well-known enzyme organophosphate hydrolase (OPH), a hydrolysis catalyst for a wide variety of organophosphorous compounds. Additionally, we demonstrated the high lactonase activity of hexahistidine-tagged organophosphate hydrolase (His6-OPH) with respect to various N-acylhomoserine lactones, and we determined the catalytic constants of His6-OPH towards these compounds. These experimental data and theoretical analysis confirmed the hypothesis about the evolutionary proximity of OPH and lactonases. Using Rhodococcus cells, we carried out effective simultaneous biodegradation of pesticide paraoxon (88 mg/kg) and oil hydrocarbon hexadecane (6.3 g/kg) in the soil. Furthermore, the discovered high lactonase activity of His6-OPH offers new possibilities for developing an efficient strategy of combating resistant populations of Gram-negative bacterial cells. PMID- 24057407 TI - Family and neighborhood correlates of overweight and obesogenic behaviors among Chinese children. AB - BACKGROUND: The prevalence of childhood obesity is increasing rapidly in China. However, research on its modifiable environmental determinants to inform preventive interventions is limited. PURPOSE: This paper reports a cross sectional study that aimed to identify family and neighborhood environmental correlates of overweight and related health behavior among Chinese primary school aged children in urban areas. METHODS: Routinely collected height and weight data of third year students (8-10 years) from four primary schools in socioeconomically distinct districts of two southern cities of China was obtained. Using the WHO 2007 reference values, children were categorized into overweight/obese or non-overweight. Parents of the same children completed a questionnaire, comprising mainly validated questions, about family and perceived neighborhood environments, parental physical activity habits, and the child's dietary and physical activity patterns. Multiple logistic regression analysis was performed to examine the association between these environmental factors and childhood overweight or whether or not the child engages in at least 1 h daily moderate to vigorous physical activity. Multiple linear regression analysis was undertaken to examine the association between environmental factors and the frequency of consumption of unhealthy snacks, fruit, and vegetables in children. RESULTS: Data on 497 children were available. Children who were mainly cared for by their grandparents were over twice as likely to be overweight/obese (adjusted OR 2.03; 95% CI 1.19-3.47) and to have higher consumption of unhealthy snacks and sugar-added drinks (B = 2.13, 95% CI 0.87-3.40), compared with children who were mainly cared for by their parents or other adult. Children who lived with at least two grandparents in the household were at higher risk for being overweight/obese than children who lived without any grandparent (adjusted OR 1.72; 95% CI 1.00-2.94). No evidence was found for associations between perceived neighborhood environmental characteristics and child's weight status and obesogenic behaviors in this study. CONCLUSIONS: Children's family environment, particularly the living-in grandparents, should be targeted in future preventive interventions among China's southern urban populations. PMID- 24057408 TI - Influence of municipal- and individual-level socioeconomic conditions on mortality in Japan. AB - BACKGROUND: The health effect of area socioeconomic conditions has been evident especially in Western countries; however, limited research has focused on the effect of municipal-level socioeconomic conditions, especially in Asia. PURPOSE: Multilevel research using data from the Japan Collaborative Cohort Study, a large cohort study followed from 1990 to 2006, was conducted to examine individual as well as municipal socioeconomic conditions on risk of death, adjusting for each other. METHOD: We included 24,460 men and 32,649 women aged 40 to 65 years at baseline in 35 municipalities as our study population. Primary predictors were municipal socioeconomic conditions (proportion of college graduates, per capita income, unemployment rate, and proportion of households receiving public assistance) and individual socioeconomic conditions (education level and occupation). RESULTS: Among men, the multilevel logistic estimate (standard errors) of proportion of college graduates and unemployment rate for mortality from cardiovascular disease were -0.399 (0.094) and -0.343 (0.122), respectively. Among women, the multilevel logistic estimate (standard errors) of proportion of college graduates and per capita annual income for mortality from injuries were 0.386 (0.171) and -1.069 (0.407). Individual education level and occupation were associated with all-cause mortality, in particular, mortality from cardiovascular disease or injuries. Interactions between individual education level and indicators of municipal socioeconomic conditions were observed for mortality from cancer and cardiovascular disease among men and mortality from injuries among women. CONCLUSION: Municipal and individual socioeconomic conditions were independently and interactively associated with premature death; this suggests that reducing social inequalities in health demands a focus on municipal conditions in addition to those of individuals. PMID- 24057409 TI - Dangerous agent or saviour? HPV vaccine representations on online discussion forums in Romania. AB - PURPOSE: Whereas Romanian health officials have launched two national human papillomavirus (HPV) vaccination campaigns, the uptake rate remained insignificant. Understanding local perceptions of the vaccine is necessary, as they could inform future educational programmes. Given that social media provide new opportunities to communicate about vaccination, this paper sought to explore the public's constructions of the HPV vaccine as they were expressed on Internet discussion forums. METHODS: Twenty discussion forums, with a total sample size of 2,240 comments (2007-2012), were included. We conducted a thematic analysis with a focus on language, informed by a discourse analytic approach. RESULTS: Positive discourses relying on evidence-based arguments or cancer-related experiences battled with negative discourses that focused mostly on pseudo-scientific information and affect-based testimonials. Both camps made use of appeals to authority in order to provide powerful messages. Critics expressed high levels of mistrust in the health system and perceived the vaccine as dangerous, as part of a conspiracy, as unnecessary or as a promoter of promiscuity. By contrast, supporters considered the HPV vaccine to be helpful and criticized the irrationality of opponents. Ambivalence and uncertainty also emerged, along with criticism toward the suboptimal organization of the vaccination programmes. Findings highlight ways in which views about the vaccine are embedded in broader perspectives about science, the national medical system, society development and economic inequality. CONCLUSION: Online posts are likely to elicit fear and doubts around vaccination, which in turn may impair decisions. Findings indicate that targeted education campaigns are needed in order to address public concerns about vaccination. PMID- 24057410 TI - Vascular risk factor burden, atherosclerosis, and functional dependence in old age: a population-based study. AB - BACKGROUND: Vascular risk factors such as hypertension and obesity have been associated with physical limitations among older adults. PURPOSE: The purpose of this study is to examine whether individual and aggregated vascular risk factors (VRFs) are associated with functional dependence and to what extent carotid atherosclerosis (CAS) or peripheral artery disease (PAD) may mediate the possible associations of aggregated VRFs with functional dependence. METHOD: This cross sectional study included 1,451 community-living participants aged >=60 years in the Confucius Hometown Aging Project of China. Data on demographic features, hypertension, high total cholesterol, obesity, smoking, physical inactivity, diabetes, CAS, PAD, and cardiovascular diseases (CVDs) were collected through an interview, a clinical examination, and laboratory tests. Functional dependence was defined as being dependent in at least one activity in the personal or instrumental activities of daily living. Data were analyzed using multiple logistic models controlling for potential confounders. We used the mediation model to explore the potential mediating effect of CAS and PAD on the associations of aggregated VRFs with functional dependence. RESULTS: Of the 1,451 participants, 222 (15.3%) had functional dependence. The likelihood of functional dependence increased linearly with increasing number of VRFs (hypertension, high total cholesterol, abdominal obesity, and physical inactivity) (p for trend <0.002). Mediation analysis showed that controlling for demographics and CVDs up to 11% of the total association of functional dependence with clustering VRFs was mediated by CAS and PAD. CONCLUSION: Aggregation of multiple VRFs is associated with an increased likelihood of functional dependence among Chinese older adults; the association is partially mediated by carotid and peripheral artery atherosclerosis independently of CVDs. PMID- 24057411 TI - Differential isotope-labeling for Leu and Val residues in a protein by E. coli cellular expression using stereo-specifically methyl labeled amino acids. AB - The (1)H-(13)C HMQC signals of the (13)CH3 moieties of Ile, Leu, and Val residues, in an otherwise deuterated background, exhibit narrow line-widths, and thus are useful for investigating the structures and dynamics of larger proteins. This approach, named methyl TROSY, is economical as compared to laborious methods using chemically synthesized site- and stereo-specifically isotope-labeled amino acids, such as stereo-array isotope labeling amino acids, since moderately priced, commercially available isotope-labeled alpha-keto acid precursors can be used to prepare the necessary protein samples. The Ile delta1-methyls can be selectively labeled, using isotope-labeled alpha-ketobutyrates as precursors. However, it is still difficult to prepare a residue-selectively Leu and Val labeled protein, since these residues share a common biosynthetic intermediate, alpha-ketoisovalerate. Another hindering drawback in using the alpha ketoisovalerate precursor is the lack of stereo-selectivity for Leu and Val methyls. Here we present a differential labeling method for Leu and Val residues, using four kinds of stereo-specifically (13)CH3-labeled [U-(2)H;(15)N]-leucine and -valine, which can be efficiently incorporated into a protein using Escherichia coli cellular expression. The method allows the differential labeling of Leu and Val residues with any combination of stereo-specifically isotope labeled prochiral methyls. Since relatively small amounts of labeled leucine and valine are required to prepare the NMR samples; i.e., 2 and 10 mg/100 mL of culture for leucine and valine, respectively, with sufficient isotope incorporation efficiency, this approach will be a good alternative to the precursor methods. The feasibility of the method is demonstrated for 82 kDa malate synthase G. PMID- 24057412 TI - Silent destruction of aortic and mitral valve by Klebsiella pneumoniae endocarditis. AB - Klebsiella endocarditis rarely affects the native valve especially in the immunocompromised and the elderly. We report a case of Klebsiella endocarditis in a 60-year-old man who had a nidus of infection on the aortic valve which led to severe aortic regurgitation. This possibly spread to the anterior mitral leaflet (AML) leading to AML perforation therefore causing moderate mitral regurgitation. The reason for this suspicion was that there was perforation of the AML in the absence of vegetation. Noteworthy is that he was asymptomatic apart from generalised fatigue. This case draws our attention to the nature of Klebsiella valvular affection due to the fact that it had bitten the aortic and mitral valve silently and compelled the patient to undergo double valve replacement without having a prolonged duration of symptomatic illness thereby calling for high suspicion especially in individuals in the extremes of ages where the symptoms are less-guiding than the signs. PMID- 24057413 TI - Essential palatal tremor with hemifacial and vocal cord tremor. PMID- 24057414 TI - Synthesis of charged bis-heteroaryl donor-acceptor (D-A+) NLO-phores coupling (pi deficient-pi-excessive) heteroaromatic rings. AB - Charged chromophores based on heteroaromatic cations were prepared by reaction of alkylazinium salts with N-heteroarylstannanes under Stille conditions. This approach provides easy access to potential single donor D-A(+) chromophores in which the acceptor moiety A(+) is the pyridinium cation and the donors are different pi-excessive N-heterocycles. The beta hyperpolarizabilities were measured in hyper-Rayleigh scattering experiments and the experimental data are supported by a theoretical analysis that combines a variety of computational procedures, including density functional theory and correlated Hartree-Fock-based methods. In some chromophores, the absence of a bridge between donor and acceptor fragments increases the NLO properties. PMID- 24057416 TI - Trastuzumab: a review of its use in HER2-positive advanced gastric cancer. AB - Trastuzumab (Herceptin((r))) is a humanized monoclonal antibody that binds selectively to human epidermal growth factor 2 (HER2), interfering with its downstream cancer-promoting effects. This article focuses on the efficacy and tolerability of trastuzumab in HER2-positive advanced gastric cancer. The potential of trastuzumab as a cytotoxic for use in gastric cancer was confirmed by in vitro studies in HER2-positive gastric cancer cell lines and gastric cancer xenograft models. In a randomized, controlled, open-label, multinational trial in patients with HER2-positive advanced gastric cancer, trastuzumab plus chemotherapy (cisplatin plus capecitabine or 5-fluorouracil) was significantly more efficacious than chemotherapy alone, in terms of a longer median overall survival (13.8 vs. 11.1 months in the chemotherapy alone group) [primary endpoint], a longer median progression-free survival, and a higher response rate. Trastuzumab was efficacious across patient subgroups, although stronger effects were observed in a subgroup with high HER2 overexpression (immunohistochemistry 2+/fluorescence in-situ hybridization positive or immunohistochemistry 3+). There was a slightly higher tolerability burden in the trastuzumab plus chemotherapy group than with chemotherapy alone, based on small between-group numerical differences in rates of common gastrointestinal and general adverse events. Most individual adverse events reported in this trial were at a grade 1 or 2 level of severity. However, in both treatment groups approximately half of the haematological adverse were at a grade 3 or 4 level of severity, with no marked between-group differences. Trastuzumab in combination with cisplatin and a fluoropyrimidine is an effective regimen for patients with HER2-positive advanced gastric cancer, has acceptable tolerability and represents an important advance in the treatment of gastric cancer. PMID- 24057417 TI - Eating frequency and risk of colorectal cancer. AB - PURPOSE: Eating frequency is a modifiable aspect of dietary behavior that may affect risk of colorectal cancer (CRC). Although most previous case-control studies indicate a positive association, two prospective studies suggest an inverse association between eating frequency and CRC risk, with evidence of effect modification by diet composition. We examined the association between eating frequency and CRC in a large, prospective cohort study, and explored whether this relationship was modified by sex, coffee consumption, or dietary glycemic load. METHODS: Between 2000 and 2002, 67,912 western Washington residents aged 50-76 reported average daily meal and snack frequency using a mailed questionnaire as part of the vitamins and lifestyle study. Participants were followed for CRC through linkage with SEER through 2008, over which time 409 CRC cases developed. Hazard Ratios and 95 % Confidence Intervals were obtained using Cox regression. RESULTS: In age- and sex-adjusted models higher (5+ times/d) vs. lower (1-2 times/d) eating frequency was associated with a HR of 0.62 (95 % CI 0.43-0.88, Ptrend = 0.001). However, following further adjustment for BMI, race/ethnicity, alcohol, and other known CRC risk factors, the relationship was no longer statistically significant (HR: 0.76; 95 % CI 0.51, 1.14). No effect modification was observed by sex (Pinteraction = 0.45), coffee consumption (Pinteraction = 0.44), or dietary glycemic load (Pinteraction = 0.90). In subgroup analyses by tumor site, higher vs. lower eating frequency was associated with lower risk for colon (HR 0.65 95 % CI 0.39-1.07, Ptrend = 0.04), but not rectal cancers (HR = 1.08 95 % CI 0.54-2.18, Ptrend = 0.94). CONCLUSION: The weak inverse association observed between eating frequency and CRC is consistent with findings from other prospective studies. Modification of this relationship by diet quality and participant characteristics should be considered in the future studies. PMID- 24057415 TI - Update on the management of postoperative nausea and vomiting. AB - New antiemetic drug developments, formulations, guidelines, risk evaluation, and controversies have occurred in the area of postoperative nausea and vomiting (PONV). These developments have helped improve our understanding of the prevention and treatment of PONV in the postanesthesia care unit and after discharge home or to the hospital ward. Antiemetic drug research has resulted in the introduction of the second-generation 5-hydroxytryptamine-3 (5-HT3) receptor antagonist palonosetron and the neurokinin-1 (NK-1) receptor antagonist aprepitant, as well as new data on existing antiemetics. The next frontier and need for further nausea and vomiting research and therapy is the area of postdischarge nausea and vomiting after the patient is discharged home from phase II of the ambulatory stepdown unit or to the hospital ward. Antiemetic drug selection depends on efficacy, cost, safety, and ease of dosing. Safety concerns have arisen regarding the side effects of antiemetics, specifically their effect on the ECG with prolongation of the QTc interval by the butyrophenones and the first-generation 5-HT3 receptor antagonist class of antiemetics. The impact of pharmocogenetics on antiemetic drug metabolism and their resulting efficacy has been correlated with genetic makeup affecting drug response. A discussion of ethics in PONV research has been initiated by the meta-analysis of PONV studies. To help guide antiemetic selection and PONV therapy for clinical practitioners, the Society of Ambulatory Anesthesia (SAMBA) PONV consensus guidelines have been introduced and updated. PMID- 24057418 TI - Jellyfish envenomation in an ocean swimmer. PMID- 24057420 TI - Cerebellopontine angle oligodendroglioma in a child: first case report. AB - The reported incidence of oligodendrogliomas in the paediatric population is less than 1 %. The posterior fossa is a rare location, with the vast majority arising in the cerebral hemispheres. We report the first paediatric case of a WHO grade II oligodendroglioma arising in the cerebellopontine angle (CPA). CPA oligodendrogliomas in children appear to behave aggressively and adjuvant therapy must be considered early; especially when complete resection cannot be achieved. PMID- 24057419 TI - Is there a clinical role for oxidative stress biomarkers in atherosclerotic diseases? AB - Growing evidences suggest that reactive oxidant species (ROS) are involved in the pathogenesis and progression of the atherosclerotic diseases. Markers assessing the oxidation of LDL and formation of eicosanoids, such as isoprostanes, were among the first that were analyzed. More recently, new biomarkers, such as endogenous secretory receptor for AGEs have been suggested to play an oxidative role in specific atherosclerotic settings, such as diabetes. Unfortunately, clinical trials included cross-sectional as well as retrospective and prospective studies which provide inconclusive results. Thus, clear evidence that oxidative biomarkers can improve risk stratification in addition to the common used atherosclerotic risk factors is still lacking. The analysis of oxidative stress focused on enzymatic systems generating ROS. The most studied enzymes were NADPH oxidase and myeloperoxidase (MPO). Experimental and clinical studies suggest that both enzymes may be implicated in promoting atherosclerotic disease. Novel laboratory methodologies have been, therefore, developed to study NADPH oxidase and MPO in patients with stable atherosclerosis as well in patients with acute coronary syndrome and cerebrovascular accident. This review will report on the more relevant studies in which the clinical application of the oxidative biomarkers was evaluated. PMID- 24057421 TI - Photosolvolysis of bulky (4-hydroxyphenyl)naphthalene derivatives. AB - Six new naphthylphenols , bearing bulky hydroxymethyl substituents on the naphthalene, were synthesized and their photoreactivity was investigated by preparative irradiation, fluorescence measurements, and laser flash photolysis. All derivatives (in S1) undergo deprotonation of the phenolic OH in the aqueous solution. Also, fluorescence quenching with HClO4 in the pH range 2-4 indicates that can be protonated in S1. Formation of QMs most probably takes place sequentially, triggered by the phenol deprotonation. However, with the present data, a mechanism that involves simultaneous deprotonation and the loss of OH(-) cannot be ruled out. Photodehydration takes place only for , , and , delivering the corresponding QMs which react with nucleophilic solvents giving the corresponding photosolvolysis products. The other less likely option for the formation of the observed solvolysis products from , , and may involve some radical species. Photodehydration of and was not observed which may be due to the anticipated high energy of the corresponding sterically-congested and . The most efficient photosolvolyses were observed for the 2,6-substituted naphthalenes. PMID- 24057422 TI - Unconstrained arthroplasty in type II valgus knees: posterior stabilized or cruciate retaining? AB - PURPOSE: Type II valgus knees are defined by medial collateral ligament laxity. This paper studies the results of posterior stabilized (PS) and cruciate retaining (CR) knee implants in type II valgus knees. METHODS: From 1999 to 2009, there were 100 type II valgus knees in 95 patients eligible for study (63 PS, 37 CR). Patients had prospectively collected clinical data up to 2 years after surgery. RESULTS: At 24 months after surgery, the CR group had reduced range of motion (PS: median 126.0 degrees , CR: median 114 degrees ; n.s.) and a marginally but statistically significant increased valgus alignment (PS: median 5 degrees , CR: median 6 degrees ; p = 0.011). Despite this, both groups produced equal and marked improvements in SF-36, function score and knee score of the Knee Society score, and Oxford knee score. CONCLUSIONS: Overall, both PS and CR implants performed equally well in type II valgus knees at 24 months post operatively. Further longer-term studies would be warranted to assess for late instability. LEVEL OF EVIDENCE: Retrospective, Level III. PMID- 24057423 TI - Arthroscopic repair of massive, contracted, immobile tears using interval slides: clinical and MRI structural follow-up. AB - PURPOSE: The purpose of this study was to determine clinical and structural outcomes of arthroscopic repair of massive, contracted, immobile rotator cuff tears using interval slides. METHODS: Eleven patients who had rotator cuff tears that were irreparable using standard mobilization techniques, but were repaired using interval slides were reviewed. Patients were evaluated at mean 25.2 months (+/-10.3) post-operatively utilizing a standardized clinical examination and by magnetic resonance imaging (MRI). RESULTS: American Shoulder and Elbow Surgeons (ASES) and Simple Shoulder Test (SST) scores improved significantly (ASES p = 0.0001; SST p = 0.0001) from pre- to post-operative. Range of motion in forward elevation and external rotation increased from pre- to post-operative, though not significantly. Strength via manual muscle testing improved on forward elevation (p = 0.001) and external rotation (p = 0.007) from pre- to post-operative. Post operative MRI demonstrated massive re-tearing to the original size in 6 patients (55 %) and intact rotator cuffs with tissue spanning the defects in 5 (45 %) patients. CONCLUSIONS: In patients with massive, contracted, immobile tears, an interval slide technique may be utilized as a salvage procedure. Arthroscopic repair of massive, contracted, immobile rotator cuff tears using interval slide techniques can lead to good clinical and satisfactory structural outcomes. LEVEL OF EVIDENCE: IV. PMID- 24057424 TI - Newborn car bed testing in a community hospital: implementing the American Academy of Pediatrics recommendations. AB - OBJECTIVE: This study was designed to describe our experience in implementing the American Academy of Pediatrics (AAP) recommendation to test infants in a car bed if they fail a car seat challenge test. STUDY DESIGN: Car seat challenge testing was performed for 90 minutes or the anticipated duration of the trip home, whichever was longer. Based on the pulse oximetry saturation values (90-92% or < 90%) two categories of test failure were used. Infants who failed in the car seat were tested in the car bed. Testing took place in both the normal newborn nursery (NBN) and special care nursery (SCN). NBN babies who failed in the car bed were transferred to our SCN for additional assessment and management. RESULTS: A total of 197 infants were tested in car seats out of which 177 (89.8%) passed the test. Of the 20 infants who failed, 16 passed the car bed challenge test on the first attempt and were discharged in those devices. All infants who failed the car bed challenge were NBN patients. CONCLUSIONS: Using 93% as the acceptable lower limit of oxygenation we successfully implemented the AAP recommendations for car bed challenge testing in our nursery. PMID- 24057425 TI - Productivity and selenium concentrations in egg and tissue of laying quails fed selenium from hydroponically produced selenium-enriched kale sprout (Brassica oleracea var. alboglabra L.). AB - This study aimed to determine the effectiveness of Se from hydroponically produced Se-enriched kale sprout (HPSeKS) on productive performance, egg quality, and Se concentrations in egg and tissue of laying quails. Two-hundred quails, 63 days of age, were divided into four groups. Each group consisted of five replicates and each replicate had ten birds, according to a completely randomized design. The experiment lasted for 6 weeks. The dietary treatments were T1 (control diet), T2 (control diet plus 0.2 mg Se/kg from sodium selenite), T3 (control diet plus 0.2 mg Se/kg from Se-enriched yeast), T4 (control diet plus 0.2 mg Se/kg from HPSeKS). The findings revealed that productive performance and egg quality of quails were not altered (p > 0.05) by Se sources. Whole egg Se concentrations of quails fed Se from HPSeKS and Se-enriched yeast were higher (p < 0.05) than that of quails fed the control diet. Breast muscle Se concentrations in quails fed Se from HPSeKS were higher (p < 0.05) than that of quails fed Se from sodium selenite and Se-enriched yeast. Heart tissue Se concentrations of quails fed Se from Se-enriched yeast and HPSeKS were similar (p > 0.05), but higher (p < 0.05) than that of quails fed Se from sodium selenite. The results reveal that Se from HPSeKS did not change the performance and egg quality of quails. The effectiveness of Se from HPSeKS was comparable to that of Se-enriched yeast, which was higher than that of Se from sodium selenite. PMID- 24057426 TI - The median local analgesic dose of intrathecal bupivacaine with hydromorphone for labour: a double-blind randomized controlled trial. AB - PURPOSE: Neuraxial hydromorphone has been reported to provide rapid onset of labour analgesia, effective segmental pain relief, and a longer duration of action than commonly used lipophilic opioids. This study was conducted to test the hypothesis that intrathecal hydromorphone reduces the dose requirement for intrathecal bupivacaine to induce rapid analgesia for women in the first stage of labour. METHODS: In this double-blind randomized controlled sequential allocation trial, 88 labouring parturients received combined spinal-epidural analgesia at 2 6 cm cervical dilation. Participants received intrathecal bupivacaine alone or bupivacaine plus hydromorphone 100 MUg with the bupivacaine dose determined using up-down sequential allocation. An effective dose was defined as a visual analogue pain score of <=10 mm (on a 100-mm pain scale) reported within 20 min of injection. The median effective doses were calculated using the formula of Dixon and Massey and verified using isotonic regression. RESULTS: A decrease was observed in the median local analgesic doses (effective dose [ED50]) estimated according to the formulas of Dixon and Massey, with a between-group difference of -0.45 mg. The precision of the estimate was wide-ranging (95% confidence interval -1.23 to 0.33), so no definitive conclusion can be drawn. CONCLUSION: Further research is needed to determine whether or not intrathecal hydromorphone 100 MUg changes the dose of intrathecal bupivacaine required to induce labour analgesia within 20 min. TRIAL REGISTRATION: The trial was conducted in 2007 prior to widespread acceptance of the standard for clinical trial registration. PMID- 24057427 TI - Airway management: judgment and communication more than gadgets. PMID- 24057428 TI - Endurance training is feasible in severely disabled patients with progressive multiple sclerosis. AB - This study tested whether upper-body endurance training (ET) is feasible and can be performed at sufficient intensity to induce cardiovascular adaptations in severely disabled patients with progressive multiple sclerosis (MS). Eleven progressive MS patients (6.5 <= EDSS <= 8.0) scheduled for a four-week inpatient rehabilitation program were randomized to a control group (CON, n = 5) that received standard individualized MS rehabilitation or an intervention group (EXE, n = 6) that in addition received 10 sessions of predominantly upper-body ET. One patient dropped out of the EXE group (drop-out rate: 1/6~17%) and no adverse events were recorded. The EXE group completed on average 9.3+/-0.8 sessions (~96.0+/-5%). During the ET sessions an average heart rate of 93.9+/ 9.3beats*min(-1) were sustained corresponding to 91.6+/-6.8% of the maximal pre intervention heart rate. In the EXE group a trend toward a time*group interaction was seen for VO2peak (p = 0.06). ET is feasible in severely disabled patients with progressive MS and it can probably be performed at sufficient intensity to induce cardiovascular adaptations. PMID- 24057429 TI - Circulating dendritic cells of multiple sclerosis patients are proinflammatory and their frequency is correlated with MS-associated genetic risk factors. AB - BACKGROUND: The role of the adaptive immune system and more specifically T cells in the pathogenesis of multiple sclerosis (MS) has been studied extensively. Emerging evidence suggests that dendritic cells (DCs), which are innate immune cells, also contribute to MS. OBJECTIVES: This study aimed to characterize circulating DC populations in MS and to investigate the contribution of MS associated genetic risk factors to DCs. METHODS: Ex vivo analysis of conventional (cDCs) and plasmacytoid DCs (pDCs) was carried out on peripheral blood of MS patients (n = 110) and age- and gender-matched healthy controls (n = 112). RESULTS: Circulating pDCs were significantly decreased in patients with chronic progressive MS compared to relapsing-remitting MS and healthy controls. While no differences in cDCs frequency were found between the different study groups, HLA DRB1*1501(+) MS patients and patients not carrying the protective IL-7Ralpha haplotype 2 have reduced frequencies of circulating cDCs and pDCs, respectively. MS-derived DCs showed enhanced IL-12p70 production upon TLR ligation and had an increased expression of the migratory molecules CCR5 and CCR7 as well as an enhanced in vitro chemotaxis. CONCLUSION: DCs in MS are in a pro-inflammatory state, have a migratory phenotype and are affected by genetic risk factors, thereby contributing to pathogenic responses. PMID- 24057430 TI - Multiple Sclerosis Outcome Assessments Consortium: Genesis and initial project plan. AB - The need for improved clinical outcome measures in multiple sclerosis trials has been recognized for two decades, but only recently has the Food and Drug Administration (FDA) created a pathway for qualification of new clinician reported outcome (ClinRO) assessments. Additionally, drug development in multiple sclerosis (MS) has been extraordinarily active, with numerous disease-modifying drugs now on the market. This shifting therapeutic landscape, along with the unmet need for drugs to treat the progressive forms of MS and the changing expectations of clinicians, patients, and payers, have led to the call for more sensitive and meaningful disability progression measures. In response to these drivers, the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was launched. A public-private partnership, MSOAC aims to accelerate the development of new therapies for MS by generating new tools for measuring outcomes in clinical trials. At the first annual MSOAC/FDA meeting, a regulatory path was outlined for qualifying a new tool for assessing efficacy in registration trials of MS. The European Medicines Agency (EMA) and FDA will provide parallel consultation and review. The consensus approach with engagement by all of the stakeholders, prominently including patients with MS, should also increase acceptance of the measure by clinicians and patients. PMID- 24057432 TI - Outcomes of repair of complete atrioventricular septal defect in the current era. AB - OBJECTIVES: We sought to evaluate the surgical outcomes of the repair of complete atrioventricular septal defects (cAVSDs) in our institution in the current era. METHODS: From 2000 to 2011, 138 patients underwent definitive repair of cAVSD. Repair was performed using a two-patch technique in 92.0% of patients and one patch technique in 2.2%, and the ventricular septal component was closed directly in 5.8% of patients. RESULTS: Operative mortality was 1.4% (2 of 138). Overall mortality was 5.8% (8 of 138). Follow-up was 96% complete. Freedom from reoperation was 84.3% (95% CI 77.1-91.5%) at 8 years. Age >6 months at repair was associated with higher rates of reoperation (P = 0.001; HR 6.85; 95% CI 2.30 20.44). However, operating at <6 months of age was associated with longer intensive care unit stay (P = 0.019; median 2.7 vs 1.4 days), mechanical ventilation (P = 0.001; median 1.7 vs 0.9 days) and postoperative hospital stay (P = 0.016; median 8 vs 5 days). Moderate or greater left atrioventricular valvular regurgitation (LAVVR) at discharge was a risk factor for reoperation (P < 0.001; HR 10.85; 95% CI 3.75-31.40). CONCLUSIONS: Repair of cAVSD carries low mortality, but a moderate reoperation rate. An optimal time for repair of the cAVSD is between 3 and 6 months of age. Repair prior to 3 months of age and the need for cleft closure were associated with a higher degree of LAVVR at discharge. Greater LAVVR at discharge is a risk factor for reoperation regardless of age at initial repair. In the current era, Down's syndrome is not a risk factor for reoperation. PMID- 24057431 TI - Biosynthesis of the carbohydrate moieties of arabinogalactan proteins by membrane bound beta-glucuronosyltransferases from radish primary roots. AB - A membrane fraction from etiolated 6-day-old primary radish roots (Raphanus sativus L. var hortensis) contained beta-glucuronosyltransferases (GlcATs) involved in the synthesis of the carbohydrate moieties of arabinogalactan proteins (AGPs). The GlcATs transferred [(14)C]GlcA from UDP-[(14)C]GlcA on to beta-(1 -> 3)-galactan as an exogenous acceptor substrate, giving a specific activity of 50-150 pmol min(-1) (mg protein)(-1). The enzyme specimen also catalyzed the transfer of [(14)C]GlcA on to an enzymatically modified AGP from mature radish root. Analysis of the transfer products revealed that the transfer of [(14)C]GlcA occurred preferentially on to consecutive (1 -> 3)-linked beta-Gal chains as well as single branched beta-(1 -> 6)-Gal residues through beta-(1 -> 6) linkages, producing branched acidic side chains. The enzymes also transferred [(14)C]GlcA residues on to several oligosaccharides, such as beta-(1 -> 6)- and beta-(1 -> 3)-galactotrioses. A trisaccharide, alpha-L-Araf-(1 -> 3)-beta-Gal-(1 > 6)-Gal, was a good acceptor, yielding a branched tetrasaccharide, alpha-L-Araf (1 -> 3)[beta-GlcA-(1 -> 6)]-beta-Gal-(1 -> 6)-Gal. We report the first in vitro assay system for beta-GlcATs involved in the AG synthesis as a step toward full characterization and cloning. PMID- 24057433 TI - ZY-1, a novel nicotinic analog, promotes proliferation and migration of adult hippocampal neural stem/progenitor cells. AB - Neural stem/progenitor cells (NSPCs) of the subgranular zone have been implicated in cognitive processes, which represent a potentially important source of regenerative medicine for the treatment of neurodegenerative diseases such as Alzheimer's disease (AD). In our previous studies, ZY-1, a novel nicotinic analog, improved cognitive function in transgenic mice model of AD. However, the effect of ZY-1 on the NSPCs remains unclear. Here, we show that ZY-1 significantly increased proliferation and migration of NSPCs, but failed to affect NSPCs differentiation in vitro. Furthermore, during the proliferative period, ZY-1 enhanced intracellular reactive oxygen species (ROS) levels. Meanwhile, ZY-1 also inhibited the levels of Abeta42-induced ROS. Our data indicate that ZY-1 regulates adult hippocampal neurogenesis in vitro, at least partly due to modulating intracellular ROS levels. These results, taken together with those of our previous studies, suggest that ZY-1 might have a potential therapeutic effect for the treatment of AD. PMID- 24057434 TI - Thai community pharmacist involvement in weight management in primary care to improve patient's outcomes. AB - BACKGROUND: The community pharmacist has significant potential to assist in providing health advice aimed at the improvement outcomes pertaining to weight management, however, up to now, evidence regarding its effectiveness has been inconclusive. In Thailand, community pharmacy involvement in weight management is a novel idea and therefore needs an evaluation of its effectiveness. OBJECTIVE: To examine essential outcomes, comparing the pharmacist's interventions with a routine weight management service provided at a primary care unit (PCU). SETTING: Maha Sarakham province, Thailand. METHODS: A randomized controlled trial was designed involving sixty-six obese patients randomly assigned to either the control group or the experimental group. Participants in the control group received group counselling from the PCU staff as usual, while those participants in the experimental group received one-on-one advice from a community pharmacist along with the weight loss handbook for self-study. Both groups were followed up and clinical outcomes were monitored four times at weeks 0, 4, 8, and 16. Eating behaviours and knowledge about overweight and obesity were measured twice, at weeks 0 and 16. MAIN OUTCOME MEASURE: Clinical outcomes included weight, waist circumference, body mass index, measured by standard medical devices. Eating behaviours were measured by the theory of planned behaviour (TPB) questionnaire. Knowledge was measured by a questionnaire focusing on the subjects' level of understanding regarding overweight and obesity issues. RESULTS: Neither group showed improvement in clinical outcomes. The TPB average sum score significantly increased from baseline in the experimental group in terms of intention to perform healthy dieting behaviour, subjective norm, behavioural beliefs, normative beliefs, and control beliefs. (P < 0.05) In the control group, scores increased significantly from the baseline only for behavioural beliefs. (P < 0.05) Moreover, the knowledge score in experimental group increased significantly from 6.42 +/- 1.94 to 8.75 +/- 0.68 (P < 0.05). CONCLUSION: Thai community pharmacists can help to improve both eating behaviour and knowledge about weight and obesity among obese patients. However, since the effect on clinical outcomes is unclear, a long-term study is still needed. PMID- 24057435 TI - Australian community pharmacists' awareness and practice in supporting secondary prevention of cardiovascular disease. AB - BACKGROUND: Pharmacists are well placed to identify, prevent and resolve medicine related problems as well as monitor the effectiveness of treatments in cardiovascular disease (CVD). Pharmacists' interventions in CVD secondary prevention have been shown to improve outcomes for clients with established CVD. OBJECTIVE: To explore the scope of pharmacists' activities in supporting CVD secondary prevention. SETTING: Community pharmacies in New South Wales, Australia. METHODS: Twenty-one in-depth, semi-structured interviews with a range of community pharmacists were conducted. All interviews were audio-recorded and transcribed ad verbatim. Data were analyzed using a 'grounded-theory' approach by applying methods of constant comparison. MAIN OUTCOME MEASURE: Community pharmacists' awareness and current practice in supporting secondary prevention of CVD. RESULTS: Four key themes identified included 'awareness', 'patient counselling', 'patient monitoring', and 'perceptions of the role of pharmacists in CVD secondary prevention'. The pharmacists demonstrated a moderate understanding of CVD secondary prevention. There was considerable variability in the scope of practice among the participants, ranging from counselling only about medicines to providing continuity of care. A minority of pharmacists who had negative beliefs about their roles in CVD secondary prevention offered limited support to their clients. The majority of pharmacists, however, believed that they have an important role to play in supporting clients with established CVD. CONCLUSION: Community pharmacists in Australia make a contribution to the care of clients with established CVD despite the gap in their knowledge and understanding of CVD secondary prevention. The scope of practice in CVD secondary prevention ranged from only counselling about medicines to offering continuity of care. The extent of pharmacists' involvement in offering disease management appears to be influenced by their beliefs regarding what is required within their scope of practice. PMID- 24057436 TI - 2,6,9-Triazabicyclo[3.3.1]nonanes as overlooked amino-modification products by acrolein. AB - The reaction of several primary amines with acrolein smoothly provided the corresponding 2,6,9-triazabicyclo[3.3.1]nonanes through a formal [4 + 4] reaction of the intermediary unsaturated imines. The reactivity profiles in aqueous media and the results from cytotoxic activity assays suggested that the caged products may be relevant in biological systems and may contribute to the mechanisms underlying the oxidative stress response to acrolein. PMID- 24057439 TI - Surface chondromyxoid fibroma of the distal ulna: unusual tumor, site, and age. AB - Chondromyxoid fibroma (CMF) is a rare benign cartilage congener tumor comprising less than 1 % of primary bone tumors. Although the age range is wide, it is most commonly seen in the second and third decades. The most frequent location of CMF is in the long tubular bones of the lower extremities, particularly the proximal tibia and distal femur. Although the majority of chondromyxoid fibromas present as intramedullary tumors, a subgroup of chondromyxoid fibromas arising as surface lesions of the bone has recently been described. These are associated with an older mean age and an increased incidence of matrix calcifications. Chondromyxoid fibromas are rare in the distal ulna. We report a CMF presenting as a surface lesion of the distal metaphysis of the left ulna in a 41-year-old woman. We reviewed the literature on chondromyxoid fibromas involving the ulna and found that out of 22 cases, 1 was in the distal ulna, 13 in the proximal ulna, and in the remaining 8 the ulnar sites were unspecified. No case of chondromyxoid fibroma in the published literature had been designated as a surface lesion. Our own unpublished data include 70 chondromyxoid fibromas, 4 of which are in the ulna. Two of these are in the distal portion. PMID- 24057438 TI - alpha-[11C] methyl-L tryptophan-PET as a surrogate for interictal cerebral serotonin synthesis in migraine without aura. AB - BACKGROUND: Alteration in central serotonin biology has been implicated in migraine, and serotonin (5-HT) agonists have been available for more than a decade in the treatment of that condition. OBJECTIVES: To test this hypothesis, we studied in vivo using positron-emission tomography (PET) and alpha-[(11)C] methyl-L-tryptophan (alpha-[(11)C]MTrp) as a surrogate marker of cerebral 5-HT synthetic rate before and after administration of eletriptan in migraine and control subjects. METHODS: Six nonmenopausal female migraine subjects with migraine without aura (MoA) and six nonmenopausal age-matched female control subjects were scanned at baseline and after oral administration of 40 mg of eletriptan. Migraine subjects at the time of PET had to have been headache free for a minimum of three days. Images of (alpha-[(11)C]MTrp) brain trapping were colocalized with individual MRI images in three dimensions and analyzed. RESULTS: There was no difference in baseline cerebral global 5-HT synthesis between migraine and control subjects. After administration of eletriptan, there was a striking global reduction in cerebral 5-HT synthesis (K*) in the migraine group and in 22 regions of interest (ROIs). In control subjects, no significant changes were found in global cerebral 5-HT synthesis (K*) or in any of the ROIs. CONCLUSIONS: These findings suggest in migraine an interictal alteration in the regulation mechanisms of cerebral 5-HT synthesis. PMID- 24057440 TI - Peroneal tendon abnormalities in subjects with an enlarged peroneal tubercle. AB - OBJECTIVE: To examine the association between inframalleolar peroneal tendon abnormalities and an enlarged peroneal tubercle. MATERIALS AND METHODS: Two independent readers evaluated consecutive ankle MR imaging studies to classify inframalleolar peroneal tendon findings as normal, tenosynovitis, partial tear or complete tear. The size and morphology of the peroneal tubercle was also recorded. We performed statistical analyses for inter-observer agreement and to assess differences in peroneal tubercle size between groups with and without peroneal tendon abnormalities. RESULTS: The study group comprised 121 subjects (mean age, 45.5 years) of whom 28% (34 out of 121) had lateral ankle symptoms. The peroneal tubercle was absent in 56% of subjects (68 out of 121). In subjects with a peroneal tubercle (>0 mm), the mean size was 3.5 mm (37% triangular and 7% plateau-shaped). Male subjects had significantly larger mean peroneal tubercle size than female subjects (2.1 +/- 2.5 vs 1.2 +/- 1.9 mm, P = 0.04). Overall, 26% (32 out of 121) of subjects had some peroneal tendon abnormality: 17% (20 out of 121) had tenosynovitis and 17 % (20 out of 121) had partial thickness tears. The peroneal tubercle size was significantly larger in subjects with peroneal tendon partial tears (P = 0.036), tenosynovitis (P < 0.001), and when both abnormalities were present (P = 0.007). ROC statistic showed 73% sensitivity and 74% specificity for detection of partial tears for peroneal tubercle size >=4.3 mm. CONCLUSION: Our study shows a significantly larger peroneal tubercle in subjects with inframalleolar peroneal tendon abnormalities. A cut-off of 4.3 mm showed good sensitivity and specificity for the presence of partial tears of the peroneal tendon. PMID- 24057441 TI - Human papillomavirus-associated plantar epidermoid cysts: MR and US imaging appearance. AB - Epidermoid cysts are epithelial cysts that present as slow-growing intradermal or subcutaneous lesions. While recent epidemiological studies have isolated human papillomavirus (HPV) from plantar epidermoid cysts, imaging findings in HPV associated epidermoid cysts have not been previously reported. We describe imaging findings in two patients with HPV-associated plantar epidermoid cysts. Magnetic resonance (MR) imaging and ultrasonography (US) showed linear arrangement of several adjacent globular cysts. This appearance is hypothesized to result from HPV-associated eccrine duct metaplasia leading to cyst formation and later traumatic rupture leading to formation of multiple adjacent cystic components. It may be useful to suggest assessing the presence of HPV antigen in plantar lesions having these imaging findings. PMID- 24057443 TI - Strain-promoted retro-Dieckmann-type condensation on [2.2.2]- and [2.2.1]bicyclic systems: a fragmentation reaction for the preparation of functionalized heterocycles and carbocycles. AB - The fragmentation reaction of differently functionalized [2.2.2]- and [2.2.1]bicyclic systems that leads to substituted five membered heterocycles and five/six membered carbocycles is broadly studied. This reaction is carried out through a retro-Dieckmann-type condensation on strained [2.2.1]bicyclic beta ketosulfones and their counterparts beta-ketoesters under very mild catalytic acid or basic conditions and short reaction times. The same reaction is also achieved on [2.2.2]bicyclic beta-ketosulfones requiring harsher reaction conditions. PMID- 24057444 TI - Solution structure of human Ca(2+)-bound S100A12. PMID- 24057447 TI - Evidence on dye clustering in the sensitization of TiO2 by aluminum phthalocyanine. AB - As previous studies have shown, the photocatalytic reduction of Cr(VI) to Cr(III) in the presence of 4-chlorophenol can be carried out efficiently under visible irradiation using TiO2 modified with hydroxoaluminum-tricarboxymonoamide phthalocyanine (AlTCPc) in spite of the high aggregation tendency of the dye. In the present work, photocurrent and absorption spectra of AlTCPc modified TiO2 films are studied together with absorption and fluorescence of the dye in solution as a function of the concentration of the dye to clarify (a) the role of aggregates and the nature of the species responsible for electron injection into the semiconductor and (b) the reasons why, as reported earlier, the photocatalytic activity is nearly independent of dye loading at constant TiO2 mass. Results are consistent with the presence of AlTCPc clusters with similar properties both on the TiO2 surface and in H2O-DMSO solution. The actual photoactive species is the monomeric dye electronically coupled to the semiconductor. Monomer concentration depends only slightly on AlTCPc analytical concentration, in a way similar to surfactant monomers in micellar equilibrium, thus explaining the independence of photocatalytic activity on dye concentration. PMID- 24057446 TI - Aging induces tissue-specific changes in cholesterol metabolism in rat brain and liver. AB - Disturbance of cholesterol homeostasis in the brain is coupled to age-related brain dysfunction. In the present work, we studied the relationship between aging and cholesterol metabolism in two brain regions, the cortex and hippocampus, as well as in the sera and liver of 6-, 12-, 18- and 24-month-old male Wistar rats. Using gas chromatography-mass spectrometry, we undertook a comparative analysis of the concentrations of cholesterol, its precursors and metabolites, as well as dietary-derived phytosterols. During aging, the concentrations of the three cholesterol precursors examined (lanosterol, lathosterol and desmosterol) were unchanged in the cortex, except for desmosterol which decreased (44 %) in 18 month-old rats. In the hippocampus, aging was associated with a significant reduction in lanosterol and lathosterol concentrations at 24 months (28 and 25 %, respectively), as well as by a significant decrease of desmosterol concentration at 18 and 24 months (36 and 51 %, respectively). In contrast, in the liver we detected age-induced increases in lanosterol and lathosterol concentrations, and no change in desmosterol concentration. The amounts of these sterols were lower than in the brain regions. In the cortex and hippocampus, desmosterol was the predominant cholesterol precursor. In the liver, lathosterol was the most abundant precursor. This ratio remained stable during aging. The most striking effect of aging observed in our study was a significant decrease in desmosterol concentration in the hippocampus which could reflect age-related reduced synaptic plasticity, thus representing one of the detrimental effects of advanced age. PMID- 24057448 TI - Serial three-dimensional optical coherence tomography assessment of strut coverage and intraluminal structures after drug-eluting stent implantation. AB - Understanding of intraluminal structure and distribution of uncovered struts after drug-eluting stent implantation are limited by only 2-dimensional (2D) optical coherence tomography (OCT) images. We compared tissue coverage with 3 dimensional (3D) OCT and 2D quantitative analyses, and changes in intraluminal structure immediately after (baseline) everolimus-eluting stent (EES) implantation and at follow-up. The 2D analyses of uncovered struts ratio and tissue coverage thickness at a 0.5-mm interval were compared to 3D-OCT images and visually classified for the degree of tissue coverage. The difference in tissue coverage at baseline and follow-up after EES implantation was evaluated with tissue coverage scores (TCS) calculated by the 3D-OCT classification (Grade 0-3). 3D-OCT classifications were negatively correlated with uncovered-to-total struts (r = -0.864, P < 0.001) and positively correlated with tissue coverage thickness (r = 0.905, P < 0.001). Follow-up TCS was greater than baseline TCS (0.2 +/- 0.4 vs. 1.4 +/- 0.5, P < 0.001). Moreover, changes in intraluminal structures and longitudinal distribution of uncovered struts were assessed. Incomplete stent appositions, in-stent dissections, and thrombi were decreased at follow-up, indicating progressive arterial healing. The distribution of uncovered-to-total struts could be assessed by 3D-OCT, which was related to 2D analysis. Significant correlations between 3D-OCT classifications and quantitative analyses were shown. The classification and visual assessment of intraluminal structures by 3D-OCT were useful in evaluating arterial healing after EES implantation. PMID- 24057449 TI - A case of intermittent claudication associated with the Angio-SealTM vascular closure device after carotid artery stenting. AB - We report a case of intermittent claudication caused by the use of Angio-SealTM vascular closure device after carotid artery stenting. This device is widely used for hemostasis at the femoral arterial puncture site. It allows early ambulation of patients and reduces labor for manual compression. However, various vascular complications have been reported. Physicians need to know the unique structure of this device and possible complications arising after deployment. PMID- 24057451 TI - Neuroglobin involvement in the course of arsenic toxicity in rat cerebellar granule neurons. AB - Exposure to arsenic in drinking water results in a widespread environmental problem in the world, and the brain is a major target. Neuroglobin is a vertebrate heme protein regarded as playing neuroprotective role in hypoxia or oxidative stress. In this study, we investigated the toxic effects of sodium arsenite (NaAsO2) on primary cultured rat cerebellar granule neurons (CGNs) and detected neuroglobin (Ngb) expression in rat CGNs exposed to NaAsO2. Our results show that apoptosis was obviously induced by NaAsO2 treatment in rat CGNs by annexin V-fluorescein isothiocyanate assay. Intracellular reactive oxygen species generation increased significantly in the cells exposed to NaAsO2, and the apoptotic effects could be partially reversed by antioxidant N-acetyl-L-cysteine. Ngb protein and mRNA expression were significantly downregulated in rat CGNs shortly after NaAsO2 exposure and then upregulated after a longer time of exposure. Furthermore, mRNA expression changed more than protein expression and the toxic effect of NaAsO2 on Ngb expression is dose dependent. Higher Ngb expression was also detected in rat cerebellum, but not in other parts (cerebrum, hippocampus, and midbrain) of the brain exposed to NaAsO2 for 16 weeks. Taken together, cytotoxic effects of NaAsO2 on rat CGNs is induced at least partly by oxidative stress and Ngb may influence the course of arsenic toxicity in rat CGNs and rat cerebellum. PMID- 24057452 TI - Comorbid personality disorders and violent behavior in psychotic patients. AB - Schizophrenia without any comorbidity confers a modest, but statistically significant elevation of the risk for violence. That risk is considerably increased by comorbid antisocial personality disorder or psychopathy as well as by comorbid substance use disorders. These comorbidities are frequent. Conduct disorder and conduct disorder symptoms elevate the risk for aggressive behavior in patients with schizophrenia. Violence among adults with schizophrenia may follow at least two distinct pathways-one associated with premorbid conditions, including antisocial conduct, and another associated with the acute psychopathology of schizophrenia. Aggressive behavior in bipolar disorder occurs mainly during manic episodes, but it remains elevated in euthymic patients in comparison with controls. The risk of violent behavior is increased by comorbidity with borderline personality disorder, antisocial personality disorder, and substance use disorders. These comorbidities are frequent. Borderline personality disorder and bipolar disorder are related in their phenomenology and response to medication. These two disorders share a tendency to impulsiveness, and impulsive behavior, including impulsive aggression, is particularly expressed when they co-occur. PMID- 24057453 TI - Reducing the risk of harm from intravenous potassium: a multi-factorial approach in the haematology setting. AB - AIMS: To describe the implementation of safety systems for the use of intravenous potassium chloride in haematology patients. METHODS: We assessed the use of intravenous potassium in a haematology ward at a tertiary hospital. Initially, we prospectively analysed the prescribing and administration of intravenous potassium to all patients over a two-week period. To complement this data, we retrospectively analysed all clinical incidents involving intravenous potassium and the dispensing patterns of potassium ampoules for the past 12 months. Drawing on evidence and recommendations from international safety literature, gaps in the safe use of potassium were identified, and a multi-factorial approach to system change was implemented. RESULTS: A total of 18 patients were analysed with 90 intravenous bags of potassium prepared on the ward using 624 ampoules. We identified multiple opportunities for error and a lack of standardisation of therapy. The following safety systems were introduced: (i) a new prescribing and monitoring form that included dose calculation, prescriber support and pre printed orders; (ii) removal of potassium ampoules and introduction of premixed bags; (iii) independent double checking by nursing staff at point of administration; (iv) dedicated labelling of intravenous lines; (v) extensive clinician training supported by guidelines; and (vi) introduction of 'smart pump' infusion software. The number of incidents significantly reduced from 23 to 9 (p < 0.001), and the number of ampoules dispensed reduced from 10,100 to 0. CONCLUSIONS: A multi-factorial approach to the safe prescribing, dispensing and administration of intravenous potassium has reduced the potential for patient harm in the haematology setting. PMID- 24057455 TI - The effect of donor-modification in organic light-harvesting motifs: triphenylamine donors appended with polymerisable thienyl subunits. AB - A family of seven organic triphenylamine-based dyes suitable for dye-sensitized solar cell (DSSC) applications is reported. The donor portion of these dyes has been systematically modified using polymerisable thienyl subunits. The physicochemical properties and device performance are discussed with device efficiencies ranging from 5.51 to 6.65%. PMID- 24057454 TI - Schizophrenia-like phenotype of polysialyltransferase ST8SIA2-deficient mice. AB - Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is crucial for nervous system development and brain plasticity. PolySia attachment is catalyzed by the polysialyltransferases (polySTs) ST8SIA2 and ST8SIA4, two enzymes with distinct but also common functions during neurodevelopment and in the adult brain. A growing body of evidence links aberrant levels of NCAM and polySia as well as variation in the ST8SIA2 gene to neuropsychiatric disorders, including schizophrenia. To investigate whether polyST deficiency might cause a schizophrenia-like phenotype, St8sia2 (-/-) mice, St8sia4 (-/-) mice and their wildtype littermates were assessed neuroanatomically and subjected to tests of cognition and sensorimotor functions. St8sia2 (-/-) but not St8sia4 (-/-) mice displayed enlarged lateral ventricles and a size reduction of the thalamus accompanied by a smaller internal capsule and a highly disorganized pattern of fibers connecting thalamus and cortex. Reduced levels of the vesicular glutamate transporter VGLUT2 pointed towards compromised glutamatergic thalamocortical input into the frontal cortex of St8sia2 (-/-) mice. Both polyST-deficient lines were impaired in short- and long-term recognition memory, but only St8sia2 (-/-) mice displayed impaired working memory and deficits in prepulse inhibition. Furthermore, only the St8sia2 (-/-) mice exhibited anhedonic behavior and increased sensitivity to amphetamine induced hyperlocomotion. These results reveal that reduced polysialylation in St8sia2 (-/-) mice leads to pathological brain development and schizophrenia-like behavior. We therefore propose that genetic variation in ST8SIA2 has the potential to confer a neurodevelopmental predisposition to schizophrenia. PMID- 24057456 TI - SPECT/CT for imaging of the spine and pelvis in clinical routine: a physician's perspective of the adoption of SPECT/CT in a clinical setting with a focus on trauma surgery. AB - Injuries of the axial skeleton are an important field of work within orthopaedic surgery and traumatology. Most lesions following trauma may be diagnosed by means of conventional plain radiography, computed tomography or magnetic resonance imaging. However, for some aspects SPECT/ CT can be helpful even in a trauma setting. In particular, the combination of highly sensitive but nonspecific scintigraphy with nonsensitive but highly specific computed tomography makes it particularly useful in anatomically complex regions such as the pelvis and spine. From a trauma surgeon's point of view, the four main indications for nuclear medicine imaging are the detection of (occult) fractures, and the imaging of inflammatory bone and joint diseases, chronic diseases and postoperative complications such as instability of instrumentation or implants. The aim of the present review was to give an overview of the adoption of SPECT/CT in a clinical setting. PMID- 24057457 TI - Combined 18F-fluoride and 18F-FDG PET/CT: a response based on actual data from prospective studies. PMID- 24057460 TI - The paediatric surgeon and prenatal diagnosis : Editorial. PMID- 24057459 TI - The association of 18F-FDG PET/CT parameters with survival in malignant pleural mesothelioma. AB - PURPOSE: Malignant pleural mesothelioma (MPM) is a disease with poor prognosis despite multimodal therapy but there is variation in survival between patients. Prognostic information is therefore potentially valuable in managing patients, particularly in the context of clinical trials where patients could be stratified according to risk. Therefore we have evaluated the prognostic ability of parameters derived from baseline 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT). METHODS: In order to determine the relationships between metabolic activity and prognosis we reviewed all (18)F-FDG PET/CT scans used for pretreatment staging of MPM patients in our institution between January 2005 and December 2011 (n = 60) and measured standardised uptake values (SUV) including mean, maximum and peak values, metabolic tumour volume (MTV) and total lesion glycolysis (TLG). Overall survival (OS) or time to last censor was recorded, as well as histological subtypes. RESULTS: Median follow-up was 12.7 months (1.9-60.9) and median OS was 14.1 months (1.9-54.9). By univariable analysis histological subtype (p = 0.013), TLG (p = 0.024) and MTV (p = 0.038) were significantly associated with OS and SUVmax was borderline (p = 0.051). On multivariable analysis histological subtype and TLG were associated with OS but at borderline statistical significance (p = 0.060 and 0.058, respectively). No statistically significant differences in any PET parameters were found between the epithelioid and non-epithelioid histological subtypes. CONCLUSION: (18)F-FDG PET/CT parameters that take into account functional volume (MTV, TLG) show significant associations with survival in patients with MPM before adjusting for histological subtype and are worthy of further evaluation to determine their ability to stratify patients in clinical trials. PMID- 24057461 TI - Abdominal wall defects in the era of prenatal diagnosis. AB - In order to study the effects of prenatal diagnosis, we reviewed all 141 cases of abdominal wall defects (AWD) seen in our institution since 1980. In the period up to the end of 1994, 65 AWDs were diagnosed at the Department of Obstetric Ultrasound and another 76 infants were born with an AWD, 44 with omphalocele (prenatal diagnosis 29), 21 with a cord hernia (prenatal diagnosis 4), and 76 with gastroschisis (prenatal diagnosis 32). In the prenatal diagnosis group the frequency of cesarean section was 48%, in the postnatal diagnosis group 13%. In the omphalocele group, the pregnancy was terminated in 12 cases and there were 10 intrauterine deaths. A further 10 babies died in the first days of life, so that only 12 came to operation; 6 survived. At least 27 of the 44 infants had other severe anomalies. Omphalocele has a poor prognosis that is not improved by prenatal diagnosis, so that termination is a reasonable option. In the cord hernia group 1 patient died because of a cardiac anomaly; all the others had primary closure without complications. In the gastroschisis group, the pregnancy was terminated in 7 cases and there were 2 intrauterine and 2 neonatal deaths. Sixty-five infants were operated upon immediately after birth, 50 (77%) with primary closure and 15 in two stages. Four died after primary closure (8%) and 4 after a silastic silo (27%). The overall mortality was 12.3%. Postoperative intestinal morbidity was assessed by the period until total enteral nutrition could be established, which was from 8 to 185 days (median 17 days). The unfavorable prognostic factors were intestinal thickening and staged closure. Neither prenatal diagnosis nor mode of delivery could be shown to have any effect on mortality or morbidity. PMID- 24057462 TI - Prenatal ultrasonographic detection of abdominal and pelvic tumors: impact on management. AB - An abdominal or pelvic tumor in very seldom detected in a prenatal ultrasound examination. The most commonly detected tumors are, in order of decreasing frequency, sacrococcygeal teratomas, neuroblastomas and kidney tumors. According to the present state of the art, diagnosis of a sacrococcygeal teratoma only leads to specific monitoring of the pregnancy, because an early delivery or delivery by cesarean section will be necessary in some cases to improve the prognosis of child and/or mother. For other types of tumors investigations and actions should be delayed until after birth. PMID- 24057463 TI - Urodynamics in boys after prenatally diagnosed vesicoureteric reflux. AB - Over the years, several theories have been presented regarding the pathogenesis of vesicoureteral reflux (VUR) in children without neurological disease or posterior urethral valves. Primary VUR is one of many fetal uropathies detectable by prenatal sonography. Thirteen boys with a prenatal diagnosis of hydronephrosis and postnatally demonstrated VUR had a urodynamic evaluation carried out at the age of 1 to 26 weeks. The renal function was evaluated by renography and estimation of glomerular filtration rate. Maximum detrusor pressure at voiding was significantly higher in the group of patients with VUR and impaired renal function compared to: (1) reflux patients with bilateral normal renal function; and (2) "normal" controls. Patients with normal bilateral renal and bladder function had a low risk of urinary tract infection during the period of follow-up (1 to 6 years). Early urodynamic studies in infants with VUR are important in order to clarify the pathogenesis of reflux and plan treatment strategy. PMID- 24057464 TI - Follow-up of prenatally diagnosed unilateral hydronephrosis. AB - Based on previous experience with prenatally diagnosed unilateral hydronephrosis, we found that the primary indications for surgical intervention should be symptoms or functional impairment of the hydronephrotic kidney. Nonoperative management of neonates without symptoms and with normal function of the affected kidney was proposed. However, the strategy of treatment after prenatally diagnosed hydronephrosis is still controversial. We studied 28 consecutive children with suspected unilateral pelviureteral junction obstruction and a normal contralateral kidney. The overall follow-up period varied between 2.5 months and 6 years (median 2 years). Eleven children had normal function of the hydronephrotic kidney and were managed nonoperatively throughout the follow-up period. None of these demonstrated any symptoms and the renal function remained normal. A further 4 children with normal function of the affected kidney were managed nonoperatively, but later had a pyeloplasty performed because of either symptoms or deterioration of renal function. Eleven children had a pyeloplasty performed after the first renography showed that the hydronephrotic kidney provided less than 40% of total renal function. The age at pyeloplasty was 3 weeks- 7 months (median 6 weeks). In all cases but 1 the function of the affected kidney improved. Two patients with impaired hydronephrotic renal function were not operated upon. Our results indicate no need to change the strategy of treatment. PMID- 24057465 TI - Traumatic pancreatic fistula in children: early management with a somatostatin analogue and drainage. AB - The management of a high-output pancreatic fistula is often difficult, and can be even more challenging in the pediatric patient. Octreotide acetate (OA) (Sandostatin, Sandoz, East Hanover, NJ) has served to facilitate the treatment of this difficult problem, but experience has been limited to adults. Somatostatin is a hormone that decreases the production of pancreatic exocrine and endocrine secretions. The use of the long-acting somatostatin analogue, OA, has reduced pancreatic fistula output and facilitated resolution of pancreatic fistulae in adults. This report summarizes the IV use of OA and external drainage in the complete resolution of high-output traumatic pancreatic fistulae in three pediatric patients. The treatment was well tolerated without side effects, and resulted in a dramatic decrease in the amount of fistula drainage within the first 24 to 48 h. OA can be safely administered IV (5-10 MUg/kg per day) and is valuable in the management of traumatic pancreatic fistula in children. PMID- 24057466 TI - Splenectomy and acute splenic sequestration crises in sickle cell disease. AB - Acute splenic sequestration crises (ASSC) is one of the complications of sickle cell disease (SCD) that can be life-threatening due to loss of blood volume. Over a 5-year period, we have treated 19 patients ranging in age from 4 to 32 years with ASSC. There were 14 males and 5 females; 17 had homozygous SCD and the other 2 had sickle thalassemia. Two patients presented with severe anemia and acute circulatory collapse; 1 of them developed residual weakness of his limbs and decreased visual acuity. Nine patients underwent splenectomy after major episodes of sequestration while the remaining 10 had recurrent minor episodes of sequestration. The clinical features and the role of splenectomy are discussed. PMID- 24057467 TI - Histometry and three-dimensional image reconstruction of the lung in congenital diaphragmatic hernia. AB - A small lung capacity, hypoplasia of the airway system, and abnormalities of the pulmonary artery system have been demonstrated as pathologic characteristics of congenital diaphragmatic hernia, but opinions have differed on the degree of hypoplasia of the acinus and terminal airspace. In this study, acinar size, mean wall thickness of the terminal airspace, an surface area of the terminal airspace were histometrically evaluated in four clinical cases. In addition, the pulmonary artery system was investigated by computerized three dimensional image reconstruction. Hypoplasia of the lung acinus and terminal airspace was observed in all four cases, and hypoplasia was more marked as lung capacity decreased. Thickening of the walls of pulmonary arterioles was confirmed, and previously undescribed abnormal branching of the pulmonary artery was recorded. PMID- 24057468 TI - Peptidergic innervation of the internal anal sphincter in Hirschsprung's disease. AB - The pathophysiology of the impaired sphincter function in Hirschsprung's disease is still unclear. The peptidergic innervation of the aganglionic large intestine is known to be disturbed. The present study analyzes the peptidergic innervation of the aganglionic internal anal sphincter (IAS) in comparison with that of the circular layer of ganglionic and aganglionic large intestine. Immunoreactivity for the following substances was analyzed: vasoactive intestinal polypeptide (VIP), substance P (SP), met-enkephalin (ENK), calcitonin gene-related peptide (CGRP), somatostatin (SOM), and neuropeptide Y (NPY). All patients were operated upon with Soave's endorectal pull-through technique and a posterior partial myectomy of the IAS. For comparison, specimens of resected IAS from adult patients operated upon for rectal cancer as well as autopsy specimens from a 2 year-old child were analyzed. Differences in the density of nerve fibers between the ganglionic and aganglionic large intestine were in accordance with previous studies. In sections of normoganglionic IAS moderately dense networks of nerve fibers immunoreactive for NPY, SOM, and VIP were observed. The occurrence of NPY and SOM was somewhat more frequent here compared to the colonic circular muscle coat, whereas the opposite was seen for VIP. In aganglionic IAS abundant nerve fibers immunoreactive for NPY, SOM, and VIP were observed. Only a few SP-, CGRP-, and ENK-immunoreactive fibers were found in normal and aganglionic IAS. It is concluded that there were moderate differences in the peptidergic innervation of the aganglionic IAS as compared to the normal ganglionic IAS and the circular muscle coat of the ganglionic and aganglionic large intestine. PMID- 24057469 TI - Effects of bupivacaine infiltration on beta-endorphin and cortisol release and postoperative pain following inguinal herniorrhaphy in children. AB - This study was undertaken to investigate the effects of bupivacaine on beta endorphin (BE) and cortisol (C) release and postoperative pain in children. Thirty children aged 1 month to 2 years undergoing outpatient inguinal hernia under general anesthesia were randomized into three groups. Wound infiltration in group 1 patients (precisional group) was performed with 0.5 ml/ kg 0.25% bupivacaine following anesthesia induction but prior to surgery. Group 2 patients (postincisional group) had wound infiltration with bupivacaine following repair of the hernia but before skin closure. Group 3 patients (control group) did not receive any local anesthetic. In the post-anesthesia care unit (PACU) objective pain assessments were performed every 5 min using a standardized ten-point objective pain scale. Plasma C concentrations increased at the end of the operation in all groups, but this increase was significant only in the control group (P < 0.001). There was no significant difference between the pre- and postincisional groups with regard to pre- and postoperative C alterations (P > 0.05). Although plasma BE concentrations increased significantly at the end of the operation in the control group (P < 0.001), no significant difference was found between pre- and postoperative values in the infiltration groups. There was a more marked difference in BE release between the preincisional and control groups (P < 0.001) than the postincisional group (P < 0.05). Although the objective pain scores were not statistically different upon PACU arrival, the patients in the infiltration groups achieved a pain score of 0 much more quickly than those in the control group (P < 0.05). These findings suggest that wound infiltration with bupivacaine decreases the stress response to surgery and postoperative pain. PMID- 24057470 TI - Giant purulent mesenteric cyst. AB - Infected intra-abdominal cystic lymphangiomas are very rare. We report a case of a purulent mesenteric cyst, histologically a cystic lymphangioma, w which developed in a 1-year-old girl who presented with marked abdominal distension and high fever. Magnetic resonance imaging revealed that the huge cystic lesion occupied the entire peritoneal cavity. It originated from the mesocolon. It was removed completely, and contained sticky pus at the base where the right fallopian tube penetrated it, which indicated the focus of infection. This may be the first report of a purulent mesenteric cyst in which the route of infection was suspected. PMID- 24057471 TI - Isolated torsion of the fallopian tube in a premenarchal girl : Case report and review of the literature. AB - A case is reported of an isolated torsion of the left fallopian tube in a 12-year old premenarchal girl, and the relevant literature is reviewed. This would seem to be an infrequent cause of acute abdominal pain in girls, and is rarely diagnosed preoperatively. The correct treatment is detorsion of a viable tube, or salpingectomy if ischaemia and necrosis have occurred. PMID- 24057472 TI - Association of ambiguous genitalia with VATER anomalies and its significance in management. AB - Tracheo-oesophageal fistula, oesophageal atresia, and imperforate anus are known to be associated with renal anomalies - the VATER complex. The occurrence of ambiguous genitalia with this collection of anomalies has not previously been highlighted. We report two cases occurring 15 years apart; both had renal agenesis and neither was salvagealble from a renal or pulmonary viewpoint. Preoperative ultrasound examination of the renal tract should be performed in all babies born with the VATER complex and ambiguous genitalia; this will prevent unnecessary surgery. PMID- 24057473 TI - Neuroblastoma arising from the celiac ganglion. AB - Neuroblastoma from the celiac ganglion (CG) is rare, accounting for only 1.4% (2 out of 144 cases) of all neuroblastomas. This is a case report of two infants with neuroblastoma from the CG detected by mass screening. Imaging techniques revealed a tumor in front of the aorta with involvement of the celiac axis and its main branches, which was confirmed at operation. Although incision of the tumour capsule was required to preserve the vessels, the outcome of these patients was good with disease-free survival of 2 and 12 years, respectively. PMID- 24057474 TI - Extraosseous chondroma presenting as a midline neck mass in a child. AB - We report an extraosseous chondroma (EC) presenting as a painless midline neck mass in a healthy 3-year-old boy. EC is a benign tumor of the soft tissues; malignant degeneration has not been observed and recurrence is unusual (5%-18%). The treatment of choice is local excision. With this report, EC can be included and considered in the assessment of any firm, smooth subcutaneous mass. PMID- 24057475 TI - Non-ossifying fibroma of the spine. AB - Non-ossifying fibroma of the spine is a rare disease: three cases have been reported in adults. We report a 17-year-old boy who had an asymptomatic osteolytic lesion of the body of the 1st lumbar vertebra. There were several radiolucent areas with sclerotic margins. The radiologic diagnosis of a non ossifying fibroma was made. The histologic findings confirmed the diagnosis. Four years after the initial examination, the 1st lumbar vertebra appeared almost normal. PMID- 24057476 TI - Modified Kasai's procedure for a choledochal cyst with a very narrow hilar duct. AB - Excision has been widely recognized as the treatment of choice for choledochal cysts. For biliary reconstruction after cyst excision, we have strongly recommended hepaticoenterostomy at the hepatic hilum with a wide anastomotic stoma to prevent postoperative cholangitis. However, we recently treated two infants in whom a wide anastomotic stoma could not be made due to a narrow hilar duct. Therefore, a hepatic portojejunostomy with Roux-en-Y anastomosis (Kasai's procedure) was performed after cyst excision in both case to permit free drainage of bile. The mucosa of the hilar duct was everted and fixed to the liver parenchyma to prevent stricture formation. Both babies have done well since the surgery. PMID- 24057477 TI - Tl(+) induces both cationic and transition pore permeability in the inner membrane of rat heart mitochondria. AB - Effects of Tl(+) were studied in experiments with isolated rat heart mitochondria (RHM) injected into 400 mOsm medium containing TlNO3 and a nitrate salt (KNO3 or NH4NO3) or TlNO3 and sucrose. Tl(+) increased permeability of the inner membrane of the RHM to K(+) and H(+). This manifested as an increase of the non-energized RHM swelling, in the order of sucrose < K(+) < NH4 (+), respectively. After succinate administration, the swollen RHM contracted. The Tl(+)-induced opening of the mitochondrial permeability pore (MPTP) in Ca(2+)-loaded rat heart mitochondria increased both the swelling and the inner membrane potential dissipation, as well as decreased basal state and 2,4-dinitrophenol-stimulated respiration. These effects of Tl(+) were suppressed by the MPTP inhibitors (cyclosporine A, ADP, bongkrekic acid, and n-ethylmaleimide), activated in the presence of the MPTP inducer (carboxyatractyloside) or mitoKATP inhibitor (5 hydroxydecanoate), but were not altered in the presence of mitoKATP agonists (diazoxide or pinacidil). We suggest that the greater sensitivity of heart and striated muscles, versus liver, to thallium salts in vivo can result in more vigorous Tl(+) effects on muscle cell mitochondria. PMID- 24057478 TI - Policy decisions on endocrine disruptors should be based on science across disciplines: a response to Dietrich et al. PMID- 24057479 TI - Impact of nutrition on muscle mass, strength, and performance in older adults: response to Scott and Jones. PMID- 24057480 TI - Prevalence of causes of secondary osteoporosis and contribution to lower bone mineral density in HIV-infected patients. AB - SUMMARY: Eighty-one percent of human immunodeficiency virus (HIV)-infected patients had one or more of seven evaluated causes of secondary osteoporosis, and this rate increases with age. The type and number of causes were associated with a lower bone mineral density (BMD), and with an increased rate of osteopenia/osteoporosis, regardless of age and body mass index. INTRODUCTION: The objective of this study was to determine whether factors of secondary osteoporosis were associated with lower BMD in HIV. METHODS: This was a cross sectional study of 285 HIV-infected patients (25 % females) evaluating the impact of seven different factors of reduced BMD: hyperthyroidism, diabetes, chronic viral hepatitis, chronic kidney disease (CKD), hypovitaminosis D, secondary hyperparathyroidism, and hypogonadism. Dual-energy X-ray absorptiometry scan of the femoral neck was obtained at the clinical visit. RESULTS: Mean age was 45.7 years; osteopenia and osteoporosis were diagnosed in 38 and 6 %, respectively. Overall, 230 patients (81 %) had secondary factors; 107 (38 %) had only 1 cause, 94 (33 %) had 2, and 28 (10 %) had 3 or more, predominantly vitamin D deficiency in 61 %, hepatitis C virus coinfection in 45 %, and secondary hyperparathyroidism in 27 %. The number of secondary factors was closely related to a lower BMD, which is statistically significant for patients having >=2 causes (0.77 vs 0.73 g/cm(2), p = 0.02). The rate of osteopenia ranged from 36 % without any cause to 57 % with three or more, osteoporosis from 0 to 19 %, and Z-score <-2 SD from 0 to 27 %, respectively. In a multivariate linear regression, adjusting by age, body mass index, and HIV-related factors, the number of secondary factors was independently associated with a lower BMD (beta coefficient -0.134; p = 0.02), mainly due to patients with hepatitis C virus (HCV) coinfection, secondary hyperparathyroidism, and CKD. CONCLUSIONS: A high prevalence of secondary causes of osteoporosis is observed in HIV-infected patients, and its type and cumulative number determine a lower BMD, after adjusting by age and body mass index. PMID- 24057482 TI - Impact of nutrition on muscle mass, strength, and performance in older adults. PMID- 24057483 TI - The legend of the "tooth fairy". PMID- 24057481 TI - Osteoporosis epidemiology in UK Biobank: a unique opportunity for international researchers. PMID- 24057484 TI - Strategy adopts a One Health approach to antimicrobial resistance. PMID- 24057485 TI - FSA outlines measures to stamp out Campylobacter in UK poultry. PMID- 24057489 TI - Government responds to EFRACom on dangerous dogs legislation. PMID- 24057490 TI - Confusion over horse passports. PMID- 24057491 TI - Cats helping police with their inquiries. PMID- 24057493 TI - Study reveals bovine origin for human MRSA strain. PMID- 24057494 TI - New research centre for poultry health. PMID- 24057495 TI - 'Bling with bite' - the rise of status and weapon dogs. AB - Simon Harding looks into what motivates people to own 'status' or 'weapon' dogs, and why numbers are increasing. PMID- 24057496 TI - Cataract surgery restores penguin's sight. PMID- 24057497 TI - Has horsepox become extinct? AB - Mystery surrounds the extent to which horsepox virus may have contributed to the vaccinia virus used to eradicate smallpox. With few documented cases of horsepox in recent years it may never be solved, says Jose Esparza, who seeks to raise awareness of the potential historical and scientific importance of identifying new cases. PMID- 24057498 TI - Chlortetracycline in calf milk replacer. PMID- 24057499 TI - Risk of disease spread from meat and meat products. PMID- 24057500 TI - Cisplatin chemotherapy for the treatment of canker. PMID- 24057501 TI - Bovine viral diarrhoea initiative in Wales. PMID- 24057503 TI - Cisplatin chemotherapy for the treatment of canker. Veronika Apprich and Theresia Licka comment. PMID- 24057504 TI - Proteomic analysis of tomato (Lycopersicum esculentum var. cerasifarm) expressing the HBsAg gene by 2-dimensional difference gel electrophoresis. AB - In a previous study, an HBsAg gene-bearing transgenic tomato line was made available and it exhibited notable physiological alterations compared with the non-transgenic tomato (control). In particular, leaves of the transgenic plants were fleshy and dark. We hypothesized that a change in leaf proteins of the transgenic plants account for the observed phenotypes. In this study, total protein content in leaves of the transgenic plants was analyzed by 2-dimensional difference gel electrophoresis. A total number of 700 protein spots were detected on silver-stained gels, of which 368 protein spots were matched between the control and sample gels. Among these matched proteins, the expression levels of 122 proteins in the transgenic plants were upregulated while those of the rest were downregulated. In addition, 25 abundant proteins (value ratio > 2.0) on silver-stained gels were analyzed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Sixteen differentially expressed proteins were identified, of which 13 were predicted to be involved in cell division, energy metabolism, protein synthesis and processing. The possible roles of these proteins in the transgenic tomato strain have been discussed. Taken together, our data indicate that significant alterations in protein expression occur in transgenic tomatoes bearing the HBsAg gene. Our findings will help broaden our knowledge of the mechanism by which exogenously expressed genes lead to phenotypic alterations in transgenic plants. PMID- 24057506 TI - Editorial comments: Is multiple sclerosis a neurodegenerative or inflammatory disease? PMID- 24057505 TI - Increases in CSF dopamine in HIV patients are due to the dopamine transporter 10/10-repeat allele which is more frequent in HIV-infected individuals. AB - Dysfunction of dopaminergic neurotransmission has been implicated in HIV infection. We showed previously increased dopamine (DA) levels in CSF of therapy naive HIV patients and an inverse correlation between CSF DA and CD4 counts in the periphery, suggesting adverse effects of high levels of DA on HIV infection. In the current study including a total of 167 HIV-positive and negative donors from Germany and South Africa (SA), we investigated the mechanistic background for the increase of CSF DA in HIV individuals. Interestingly, we found that the DAT 10/10-repeat allele is present more frequently within HIV individuals than in uninfected subjects. Logistic regression analysis adjusted for gender and ethnicity showed an odds ratio for HIV infection in DAT 10/10 allele carriers of 3.93 (95% CI 1.72-8.96; p = 0.001, Fishers exact test). 42.6% HIV-infected patients harbored the DAT 10/10 allele compared to only 10.5% uninfected DAT 10/10 carriers in SA (odds ratio 6.31), whereas 68.1 versus 40.9%, respectively, in Germany (odds ratio 3.08). Subjects homozygous for the 10-repeat allele had higher amounts of CSF DA and reduced DAT mRNA expression but similar disease severity compared with those carrying other DAT genotypes. These intriguing and novel findings show the mutual interaction between DA and HIV, suggesting caution in the interpretation of CNS DA alterations in HIV infection solely as a secondary phenomenon to the virus and open the door for larger studies investigating consequences of the DAT functional polymorphism on HIV epidemiology and progression of disease. PMID- 24057507 TI - Is MS an inflammatory or primary degenerative disease? AB - Multiple sclerosis (MS) is characterized by multiple areas of inflammation, demyelination and neurodegeneration. Multiple molecular and cellular components mediate neuroinflammation in MS. They involve: adhesion molecules, chemokines, cytokines, matalloproteases and the following cells: CD4+ T cells, CD8+ T cells, B cells, microglia and macrophages. Infiltrating Th1 CD4+ T cells secrete proinflammatory cytokines. They stimulate the release of chemokines, expression of adhesion molecules and can be factors that cause damage to the myelin sheath and axons. Chemokines stimulate integrin activation, mediate leukocyte locomotion on endothelial cells and participate in transendothelial migration. CD8+ cells can directly damage axons. B cells are involved in the production of antibodies which can participate in demyelination. B cells can also function as antigen presenting cells and contribute to T cell activation. Neuroinflammation is not only present in relapsing-remitting MS, but also in the secondary and primary progressive forms of the disease. The association between inflammation consisting of T cells, B cells, plasma cells and macrophages and axonal injury exists in MS patients including the progressive forms of the disease. The above association does not exclude the possibility that neurodegeneration can exist independently from inflammation. Very little inflammation is seen in cortical MS plaques. Anti inflammatory therapies with different mode of action change the course of MS. Anti-inflammatory and immunomodulatory treatments are beneficial in the early relapsing stage of MS, but these treatments are ineffective in secondary progressive and primary progressive MS. In the stage of progressive MS, inflammation becomes trapped behind a closed or repaired blood-brain barrier. In such a situation current immunomodulatory, immunosuppressive or anti-inflammatory treatments might not reach this inflammatory process to exert a beneficial effect. PMID- 24057509 TI - Chemiluminescent 2,6-diphenylimidazo[1,2-a]pyrazin-3(7H)-ones: a new entry to Cypridina luciferin analogues. AB - An investigation of the chemiluminescent properties of 2,6-diphenylimidazo[1,2 a]pyrazin-3(7H)-one derivatives (1), having substituted phenyl groups, is described. Among the derivatives 1, the 6-[4-(dimethylamino)phenyl] derivatives (1a,d-f) gave a high quantum yield (Phi(CL) >= 0.0025) in diglyme/acetate buffer, which is a model reaction condition for the Cypridina bioluminescence. Their efficient chemiluminescence is mainly caused by the electronic effect of the substituent at C6. In particular, the electron-donating 4-(dimethylamino)phenyl group at C6 of 1a,d-f plays an essential role in increasing the chemiexcitation efficiency (PhiS) by the charge transfer-induced luminescence (CTIL) mechanism. The results provide useful information for designing new Cypridina luciferin analogues showing efficient chemiluminescence. PMID- 24057508 TI - Chemo-sensitisation of HeLa cells to etoposide by a benzoxazine in the absence of DNA-PK inhibition. AB - The benzoaxines have been developed from structurally similar chromones as specific inhibitors of the PI3K family to sensitize cancer cells to the effects of chemotherapeutic agents; most have been shown to do this through specific inhibition of DNA-PK and DNA repair mechanisms. In this study we examined the benzoxazine, 2-((3-methoxybut-3en-2-yl)amino)-8methyl-4H-benzo[1,3]oxazin-4one (LTUSI54). This compound had no DNA-PK or PI3K inhibitory activity but still sensitized HeLa cells to the effects of Etoposide. LTUSI54 works synergistically with Etoposide to inhibit growth of HeLa cells and sub G1 analysis indicates that this is not due to an increase in apoptosis. LTUSI54 neither enhances DSB formation due to Etoposide nor does it delay the repair of such damage. Cell cycle analysis shows a clear G2 block with Etoposide alone while, in combination with LTUSI54 there is an additional S phase arrest. Phospho-kinase analysis indicated that LTUSI54 engages key regulators of cell cycle progression, specifically p38alpha, p53 and ERK 1/2. From our results we hypothesize that LTUSI54 is promoting the cell cycle arrest through activation of p38alpha pathways, independent of p53 mechanisms. This results in a decrease in p53 phosphorylation and hence, restricted apoptosis. Changes in cell number appear to be the result of p38alpha pathways disrupting cell cycle progression, at the S and G2 checkpoints. Further investigation into the finer mechanisms by which LTUSI54 effects cell cycle progression would be of great interest in assessing this compound as a chemosensitising agent. PMID- 24057510 TI - Urinary n-acetyl-beta-d-glucosaminidase excretion: an indicator of neuropathy in type 2 diabetes. AB - The established marker for tubular damage, urinary n-acetyl-beta-d glucosaminidase is significantly increased in type 1 and 2 diabetes patients and is related to albuminuria and other diabetic complications. In this cross sectional study of type 2 diabetes patients with a history of albuminuria, we studied the relationship between excretion of n-acetyl-beta-d-glucosaminidase in urine and diabetic neuropathy.160 type 2 diabetes patients were screened for diabetic peripheral neuropathy and cardiovascular autonomic neuropathy. N-acetyl beta-d-glucosaminidase excretion was detected in 24 h urine samples.Urinary excretion of n-acetyl-beta-d-glucosaminidase correlated significantly with glucose control (fasting glucose r=0.18; p=0.04; HbA1c r=0.20; p=0.02) and urine albumin excretion (r=0.22; p=0.01). Binary regression analyses showed that increased urinary n-acetyl-beta-d-glucosaminidase concentration is an independent predictor for presence of clinical symptoms of peripheral neuropathy (OR 1.8 [95%CI 1.2-2.74] and vibration deficiency [OR 1.7; 95% CI 1.2-2.66]. There was also a significant negative association between urinary n-acetyl-beta-d glucosaminidase and E/I-Ratio (r=-0.21, p<0.02) as well as the 30:15-Ratio (r= 0.24; p<0.01) of heart rate variability. Furthermore, increased n-acetyl-beta-d glucosaminidase excretion independently predicted cardiovascular autonomic diabetic neuropathy with an OR for decreased E/I-Ratio of 1.7 [95%CI 1.1-2.75]; (p<0.02) and 30:15-Ratio:OR 2.4 [95% CI 1.26-4.45]; (p<0.01).Urinary n-acetyl beta-d-glucosami-nidase excretion is an independent marker for diabetic peripheral and cardiovascular autonomic neuropathy in type 2 diabetic patients. PMID- 24057511 TI - The effect of simvastatin treatment on plasma steroid levels in females with non classic congenital adrenal hyperplasia. AB - Non-classic congenital adrenal hyperplasia (NC-CAH) is one of the most frequent genetic disorders and its presence often results in androgen excess. 4 females with coexisting symptomatic NC-CAH and isolated hypercholesterolemia and 11 sex- and weight-matched control subjects with elevated cholesterol but normal steroid levels, participating in our study, were treated with simvastatin (20 mg daily). Throughout the whole period of simvastatin treatment, plasma levels of 17 hydroxyprogesterone, testosterone, androstendione and dehydroepiandrosterone sulfate in patients with NC-CAH remained lower compared with baseline, but increased in 2 patients after withdrawal of this drug. No changes in plasma steroids were observed in simvastatin-treated control subjects. Our findings suggest that simvastatin treatment may bring some benefits to symptomatic female patients with NC-CAH. PMID- 24057512 TI - Immunotherapy for mold allergy. AB - The objective of this article is to review the available studies regarding mold immunotherapy. A literature search was conducted in MEDLINE to identify peer reviewed articles related to mold immunotherapy using the following keywords: mold, allergy, asthma, and immunotherapy. In addition, references cited within these articles were also reviewed. Articles were selected based on their relevance to the topic. Allergic responses to inhaled mold antigens are a recognized factor in allergic rhinitis and asthma. There are significant problems with respect to the production of relevant allergen material for the diagnosis and treatment of mold allergy with immunotherapy. Mold allergens contain proteases and should not be mixed with other allergens for immunotherapy. Most of the immunotherapy studies focus on two molds, Alternaria and Cladosporium. There is a lack of randomized placebo-controlled trials when evaluating the efficacy of mold immunotherapy with trials only focusing on immunotherapy to Alternaria and Cladosporium. Additional studies are needed regarding mold allergy and immunotherapy focusing on which molds are important for causing allergic disease. PMID- 24057516 TI - Toll-like receptors' pathway disturbances are associated with increased susceptibility to infections in humans. AB - Toll-like receptors (TLRs) sense microbial products and play an important role in innate immunity. Currently, 11 members of TLRs have been identified in humans, with important function in host defense in early steps of the inflammatory response. TLRs are present in the plasma membrane (TLR1, TLR2, TLR4, TLR5, TLR6) and endosome (TLR3, TLR7, TLR8, TLR9) of leukocytes. TLRs and IL-1R are a family of receptors related to the innate immune response that contain an intracellular domain known as the Toll-IL-1R (TIR) domain that recruits the TIR-containing cytosolic adapters MyD88, TRIF, TIRAP and TRAM. The classical pathway results in the activation of both nuclear factor kappaB and MAPKs via the IRAK complex, with two active kinases (IRAK-1 and IRAK-4) and two non-catalytic subunits (IRAK-2 and IRAK-3/M). The classical pro-inflammatory TLR signaling pathway leads to the synthesis of inflammatory cytokines and chemokines, such as IL-1beta, IL-6, IL-8, IL-12 and TNF-alpha. In humans, genetic defects have been identified that impair signaling of the TLR pathway and this may result in recurrent pyogenic infections, as well as virus and fungi infections. In this review, we discuss the main mechanisms of microbial recognition and the defects involving TLRs. PMID- 24057517 TI - Gastroschisis and omphalocele : Editorial comment. PMID- 24057513 TI - Anti-inflammatory effects of Retama monosperma in acute ulcerative colitis in rats. AB - Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic intestinal disorder resultant from a dysfunctional epithelial, innate and adaptive immune response to intestinal microorganisms. Current IBD treatment presents limitations in both efficacy and safety that stimulated for new active drugs. Retama spp. have been traditionally used in the Mediterranean region in treatment of pain and inflammation. In this study, the anti-inflammatory and protective properties of a standardised aqueous extract from Retama monosperma (RmE) was evaluated in vivo, by intra-colonic administration of trinitrobenzene sulfonic acid (TNBS) in rats as a Crohn's disease model. The qualitative and quantitative analysis of flavonoids from RmE was performed by high-performance liquid chromatography-tandem mass spectrometry. Oral administration of RmE diminished the severity and extension of the intestinal injuries induced by TNBS. In addition, RmE increased mucus production in goblet cells in colon mucosa, decreased neutrophil infiltration and cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) overexpression. Similarly, RmE significantly reduced p38 mitogen-activated protein kinase activation, preventing the inhibitory protein IkappaB degradation in colonic mucosa. RmE anti-inflammatory effects seem to be related to impairment of neutrophil function and COX-2 and iNOS down-regulation possibly through p38 MAPK and nuclear transcription factor kappa B signalling pathways. These results suggest that RmE might contribute to the development of new pharmaceutical products for inflammatory bowel disease. PMID- 24057515 TI - Differential influenza H1N1-specific humoral and cellular response kinetics in kidney transplant patients. AB - Renal transplant recipients (RTR) are considered at high risk for influenza associated complications due to immunosuppression. The efficacy of standard influenza vaccination in RTRs is unclear. Hence, we evaluated activation of the adaptive immunity by the pandemic influenza A(H1N1) 2009 (A(H1N1)pdm09) vaccine in RTRs as compared to healthy controls. To determine cross-reactivity and/or bystander activation, seasonal trivalent influenza vaccine and tetanus/diphteria toxoid (TT/DT) vaccine-specific T cells along with allospecific T cells were quantified before and after A(H1N1)pdm09 vaccination. Vaccination-induced alloimmunity was additionally determined by quantifying serum creatinine and proinflammatory protein IP-10. Contrary to healthy controls, RTRs required a booster vaccination to achieve seroconversion (13.3 % day 21; 90 % day 90). In contrast to humoral immunity, sufficient A(H1N1)pdm09-specific T-cell responses were mounted in RTRs already after the first immunization with a magnitude comparable with healthy controls. Interestingly, vaccination simultaneously boosted T cells reacting to seasonal flu but not to TT/DT, suggesting cross activation. No alloimmune effects were recorded. In conclusion, protective antibody responses required booster vaccination. However, sufficient cellular immunity is established already after the first vaccination, demonstrating differential kinetics of humoral and cellular immunity. PMID- 24057518 TI - The pathogenesis of omphalocele and gastroschisis : An unsolved problem. AB - The embryology of gastroschisis and omphalocele remains a matter of speculation. Most authors still assume that they represent separate entities with a different pathology and embryology. In contrast, others feel that gastrochisis is simply the end-result of a ruptured omphalocele. Reviewing the current literature on the normal and abnormal embryology of the anterior abdominal wall, it becomes obvious that appropriate embryological knowledge of these processes is still missing. Animal models are not at hand that would allow clear definitions of morphological changes unique to either malformation. Nevertheless, our own observations of the pathological anatomy of these anomalies lead us to believe that the abdominal wall defects are the result of disturbed development of the embryonic umbilicus. This includes gastroschisis, which is more likely a ruptured small omphalocele than a developmental entity of its own. In our view, the common ventral abdominal wall defects fall into two main categories: (1) large omphaloceles; and (2) small omphaloceles, with gastroschisis as a subentity of this lesion. PMID- 24057519 TI - Prenatal diagnosis and management of gastroschisis and omphalocele. AB - Prenatal diagnosis of gastroschisis (GS) and omphalocele (OC) has allowed improved antenatal and perinatal management. It was the aim of this study to compare prenatal findings and assess fetal outcome. Twenty-four fetus with GS and 33 with OC were diagnosed prenatally. Maternal serum alpha-protein (MSAFP), sonographic (US), and perinatal data were analyzed. The average maternal age for GS was younger than for OC (24 vs. 30 years). The median MSAFP values were 7.7 multiples of median for GS and 3.6 for OC. The initial US diagnosis was made at 22 weeks for GS and at 19 weeks for OC. A pathological karyotype was observed in 4% of the fetuses with GS and 33% with OC. The mortality of fetuses with OC was twice as high as that of those with GS. Accurate prenatal diagnosis of GS and OC as well as their differentiation are of crucial importance for both counselling of the parents and the resulting antenatal consequences, and provide the basis for optimal interdisciplinary co-operation at a perinatal tertiary-care center. PMID- 24057520 TI - The influence of gastroschisis on plasmatic coagulation, humoral immunity, and C reactive protein. AB - Around the 30th week of gestation, patients with gastroschisis (GS) develop chronic inflammatory reactions on the serosal surface of the eventrated loops of intestine that lead to severe hyperfibrinogenemia and hypercoagulability, particularly if they are born prematurely. This result was found on comparison of coagulation studies from 12 patients with GS with those of 4 patients with omphalocele and of healthy premature babies and term infants. Furthermore, the patients with GS showed marked hypogammaglobulinemia, which might also be responsible for the increased numbers of infections complicating the course of this disease. The hypercoagulability increases the risk of thromboembolic complications and disseminated intravascular coagulation, particularly in combination with the surgical closure of the abdominal wall that is undertaken postnatally or with perinatal complications such as asphyxia. Prophylactic therapy with low-dose heparin is indicated. PMID- 24057521 TI - Treatment of congenital abdominal wall defects -a 25-year review of 132 patients. AB - The outcome data of 132 patients treated at the Department of Pediatric Surgery in Mainz during the last 25 years were reviewed. Prenatal diagnosis of abdominal wall defects (AWDs) and associated malformations led to increasing selection of the patient population. The aim of primary closure of the abdominal wall can be achieved more frequently in gastroschisis (GS) than omphalocele (OC), while the postoperative course is more complicated and of longer duration in GS. Delayed or secondary closure extended the hospitalization period but had no negative effects on the outcome. Reoperations or planned secondary operations were performed in 23 patients with GS and 14 with OC. Early mortality was 15/55 for OC and 21/77 for GS over the period of 25 years. In recent years, a drastic reduction in mortality has occurred, and mortality is now mainly due to additional malformations. Further development and quality of life are not significantly reduced after survival of an isolated AWD. Malpositioning of parenchymatous organs after closure of AWDs has to be considered during pregnancy and abdominal operations. PMID- 24057522 TI - The pivotal role of the surgeon in the results achieved in gastroschisis. AB - A single neonatal surgical unit treated 42 cases of gastroschisis over a 12-year period (1981-1993). The surgical management of each case was individualised, but every attempt was made to perform a primary repair when possible, based on the premise that this strategy gave the best outcome. The eviscerated intestine was evaluated with the patient under general anaesthesia. Serosal peel was not removed and intestinal atresias were not repaired. Gangrenous intestine was resected. The contents of the bowel were emptied proximally via a large naso gastric tube and distally via the anus with warm saline lavage. The anterior abdominal wall was stretched and then reduction of the prolapse attempted. Following maximal enlargement of the peritoneal cavity, it was left to the operator to decide whether primary repair was possible and, indeed, permissible in each instance. Staged repairs necessitated the use of silastic pouches. Respiratory and intestinal insufficiency were managed by intermittent positive pressure ventilation and total parenteral nutrition (TPN). Over one-half of the cases (24 of 42) were under 2.5 kg at birth. Intra-uterine growth retardation was unusual. Ten babies were delivered for obstetrical indications by Caesarean section: 50% were pre-term and in 4 pre-natal diagnosis of a ventral abdominal wall anomaly had been made. The transmural defects were all sited at the umbilicus and were to the right of a consolidated cord in 41 instances. Midgut necrosis due to torsion was encountered in 1 case; 3 further cases with intestinal atresia occurred. Primary closure was obtained in 30 (71%) of the cases reviewed. A prosthetic pouch was used in 12 patients for on everage 10 days in 10 uncomplicated cases. The average length of time in days of tertiary care given to 25 uncomplicated cases treated by primary fascial closure was: ventilatory support 4; intensive care treatment 8; and nutritional source TPN 20. There were 5 deaths (12%): 1 was unpreventable due to prenatal intestinal infarction; 2 were due to abdominal compartment syndrome with renal failure, and, intestinal ischaemia complicating primary and planned staged repairs; 1 caused by intestinal infarction due to torsion of bowel in a pouch; and 1 due to invasive infection. The role played by the strategy taken by the surgeon in the management of gastroschisis is crucial to the outcome. The creation of a compartment-like syndrome produced uncorrectable complications in this series of cases in both primary and staged abdominal wall closures. Minor degrees of this complication proved to be reversible in some patients, which was the reason for the wait-and see attitude adopted in the management of this problem, often with fatal outcome. Where intra-peritoneal pressure monitoring is not used, the operating surgeon relies on unscientific observations for decision-making at the operating table. The time from birth to operation in 25 of the reviewed cases was on average 5 1/2 h. Of this group, 20 were outborn babies. This is unsatisfactory, but as shown by this review, even in the absence of prenatal management, which should ensure prompt repair, satisfactory results are still possible. PMID- 24057523 TI - Intraoperative vascular assessment for estimation of risk in primary closure of omphalocele and gastroschisis. AB - Surgical repair of anterior abdominal wall defects is often complicated by a discrepancy between the eviscerated organs and the intra-abdominal space available. Primary closure of the abdominal wall may result in increased intra abdominal pressure and consecutive circulatory impairment. We report the results of a retrospective and consecutive prospective study evaluating the influence of different witameters on mortality and morbidity in children with gastroschitis and omphalocele. Both studies demonstrated that real-time sonographic investigations, intraoperative Doppler duplex sonography, and colour-coded Doppler sonography provide the oppurtunity to collect objective intraoperative data. Our data indicate that intraoperative vascular assessment facilitates the discrimination between infants who benefit from primary closure and those in whom a staged repair is the treatment of choice. PMID- 24057524 TI - Amnion as a prosthetic material in congenital defects. AB - In pediatric surgery, amniotic membranes taken from autologous placenta are occasionally used as an implant in cases of large ventral abdominal clefts. The questions arise, which part of this organ should be used and how to use it in the recipient organism. Amniotic membranes consist anatomically of amnion and chorion, which are of fetal origin, and maternal decidua. In our experimental studies, we used the fetal parts of the amniotic membrane as an implant in a standardized rat model and investigated the utilization and possible foreign-body reaction (FBR) induced. Fifteen, 30, and 90 days after implantation the macroscopic appearance, light microscopy, and immunohistology of the specimens were examined. Adhesions to parenchymal organs and omentum were present irrespective of the side facing the abdominal cavity. Amnion induced a rapid FBR that diminished with time. Chorion and parts of the amnion were resorbed within the examined period after infiltration with recipient cells and neovascularization. Our studies have shown that for best results, only amnion in its anatomical definition and parts of the chorion should be prefered as an implant. PMID- 24057525 TI - Use of amniotic grafts in the repair of gastroschisis. AB - This article describes the use of amniotic grafts (AG) in the repair of large abdominal wall defects in newborns with gastroschisis. From 1988 to 1995, 22 newborns with gastroschisis underwent surgical repair. In 12 primary closure (PC) was performed; in 10 the abdominal wall defect was covered with an AG. A double layer of AG was used and the graft was additionally covered with a silastic silo in 8 cases. The overall mortality was 14%; 3 children died from necrotizing enterocolitis or sepsis after AG. However, the difference in mortality of newborns with PC versus AG was not statistically significant. Patient characteristics, the postoperative courses, nd the frequency of complications were similar after PC and AG. It is concluded that AG has no negative impact on the postoperative course and yields a low overall mortality. In our opinion there are several advantages in using the AG technique: it is an autoplastic material that is readily available without costs, reefing and removal is unnecessary, and there is a potentially low rate of adhesions. PMID- 24057526 TI - The effect of mode of delivery on outcome in fetuses with gastroschisis. AB - The postoperative course in neonates with gastroschisis after successful surgical repair is complicated by prolonged ileus. Elective cesarean section (CS) has been advocated to limit damage to the bowel due to labor and compression in the narrow birth canal and to prevent retrograde infection. We reviewed the records of 58 infants with gastroschisis treated between 1977 and 1993; 12 were delivered by CS for obstetrical reasons and 46 were delivered vaginally (V). Mortality was higher in the CS group (V = 1/46, CS = 4/12). Both groups differed significantly with respect to birth weight and gestational age; gestational age, however, had no influence on morbidity and mortality. Primary contamination was significantly lower in the CS group (V = 29/42, CS = 3/12). However, no difference was found regarding infectious complications. No complications could be attributed directly to the mode of delivery. Since these data do not show any significant advantages of CS on morbidity and mortality, we do not recommend CS for fetuses with gastroschisis diagnosed prenatally. PMID- 24057527 TI - Late follow-up in patients with gastroschisis : Gastroesophageal reflux is common. AB - During a 16-year period, 60 neonates with gastroschisis were treated at the Department of Pediatric Surgery in Graz; 6 died and 54 (90%) survived. A questionnaire was sent to 45 patients, who were called for a medical examination; 31 patients (69%) came to follow-up, 26 of whom reported minor abdominal problems that could be related to gastroesophageal reflux (GER). Fifteen agreed to 24-h esophageal pH monitoring and/or upper gastrointestinal series; in 7 pathological GER could be demonstrated. Manometric studies in 6 patients revealed a motility disorder of the esophagus. Only 4 children were concerned by a disfiguring scar or the absence of a navel. Heigtt and weight were within normal limits and the children had developed normally. PMID- 24057528 TI - Management of coexisting coarctation of the aorta and oesophageal atresia. AB - The combination of neonatal coarctation of the aorta (CoA) and oesophageal atresia (oA) is rare and the optimum approach to surgical correction uncertain. Of 84 consecutive neonates with CoA over an 8-year period, 2 had coexisting oA. We consider that CoA repair by subclavian flap should be performed first to improve the environment for healing of the oesophageal anastomosis. A carefully co-ordinated approach between paediatric and cardiac surgical teams is recommended. PMID- 24057529 TI - Surgical management of large breast tumors in the adolescent. AB - The management of adolescent females with giant cystosarcoma phylloides remains controversial. Since in this age group the overwhelming majority of these neoplasms are benign, aesthetic outcome is as important as adequate tumor resection. Traditional, treatment has been wide local excision, which may lead to substantial breast deformity. In addition, inadequate planning with improper incision placement may result in visible scarring and impair immediate or subsequent breast reconstruction. The treatment of four adolescent females with large breast masses using breast-sparing techniques is discussed. PMID- 24057530 TI - Pulmonary sequestrations detected by antenatal ultrasound. AB - We present three cases of abdominal and abdomino-thoracic extra-lobar pulmonary sequestrations detected by antenatal ultrasound (US) over a 12-month period. In addition, we briefly refer to a case previously described. A cystic mass was demonstrated in the left upper abdomen of the fetus in all four cases, with two extending into the thorax. The diagnosis was confirmed postnatally by fine-needle biopsy and later excision of the mass. In all four cases the lesion did not interfere with the pregnancy, and only one child demonstrated transient effects of mild pulmonary hypoplasia. Review of the antenatal scans showed that in each case the sequestration did not appear to grow during the pregnancy, with a relative decrease in size. Extra-lobar sequestration should always be considered in the differential diagnosis of an abdominal mass diagnosed on antenatal US, especially if cystic and extending from the abdomen through the diaphragm into the mediastinum. Although abdominal sequestrations are rare in comparison to thoracic lesions at postnatal diagnosis, they represent 21 of the 40 published series of pulmonary sequestrations diagnosed on antenatal US. PMID- 24057531 TI - Congenital intrathoracic stomach. AB - This paper reviews the presentation and management for congenital intrathoracic stomach (CIS). The features that distinguish CIS from congenital short oesophagus and acquired oesophageal shortening are emphasised. The study is based on a retrospective review of six patients treated between 1988 and 1994. The four youngest presented with vomiting and the older two with respiratory symptoms. Chest radiographs were abnormal in every case, although the precise diagnosis was confirmed by barium meal. All cases were repaired through an abdominal approach; in each case the oesophagus was of sufficient length to allow the stomach to lie below the diaphragm. CIS is an uncommon condition. The most frequent cause is a large hiatus hernia, and the transabdominal route is the most satisfactory approach for operative repair. PMID- 24057532 TI - Transthoracic endoscopic sympathectomy for primary palmar hyperhidrosis in children. AB - Primary palmar hyperhidrosis often starts in childhood. It usually causes academic and social disabling at the age children begin primary school. This study included 65 children (44 girls and 21 boys, mean age 13.5 years) who underwent one-stage bilateral transthoracic endoscopic sympathectomy. The proper sympathetic segment was visualized in almost all cases and electrocautery ablation was performed. The immediate postoperative course was uneventful in all cases and no major morbidity was encountered. Horner's syndrome did not occur in any case. All patients were discharged the day of surgery or after an overnight stay. The duration of follow-up was from 6 months to 3 years. Although compensatory sweating was found in 40% of the patients, long-term satisfaction was reported in 63 cases (96%). This procedure is effective, simple, and is recommended as the method of choice for surgical treatment of severe upper extremity hyperhidrosis in children. PMID- 24057533 TI - Congenital eventration of the diaphragm - 45 years' perspective. AB - Fifty-five children with congenital eventration of the diaphragm were operated upon in a single tertiary-care children's hospital during the 45-year period from 1948 to 1992. The study was divided into three periods: 1948-1962, 1963-1977, 1978-1992. There were 14 patients in the first group, 26 in the second, and 15 in the third. Children later in the series presented earlier and with more acute symptoms. Mortality was related to severe pulmonary hypoplasia and associated anomalies, especially chromosomal defects: 14% during the first period, 27% during the second, and 7% during the third. PMID- 24057534 TI - Proliferation of intrahepatic bile-duct epithelium in biliary atresia : A useful predictor of clinical outcome. AB - Proliferating cell nuclear antigen (PCNA) and transforming growth factor alpha (TGFalpha) are considered as markers of cell proliferation. The expression of PCNA and TGFalpha was evaluated immunohistochemically using anti-PCNA antibody and TGFalpha in 31 patients with biliary atresia (BA) (15 jaundice-free and 16 with persistent jaundice) and 6 control infants. The labeling indices (LI) for PCNA- and TGFalpha-positive bile-duct epithelium in BA were 14.1+/-14.0% and 51.4+/-33.7%, respectively, which was significantly higher than in the controls (P <0.01). In BA, the number of PCNA-immunoreactive cells was higher in the peripheral bile ductules than in the central bile ducts of the portal tract (P <0.01). LI was not related to patient age at the time of hepatic portoenterostomy in two groups divided at the age of 60 days. Patients in the persistent jaundice group had greater expression of PCNA and TGFalpha (21.7+/-16.0% and 76.9+/-20.7%, respectively) compared to those in the jaundice-free group (6.0+/-2.7% and 24.3+/ 20.9%, P <0.001). PCNA and TGFalpha expression in the bile-duct epithelium of the portal tract was closely related to prognosis in BA patients, and thus could be useful as a prognostic marker. PMID- 24057535 TI - The management of choledochal cysts in the newborn. AB - Choledochal cysts are now being diagnosed before birth on routine maternal sonography (US). There is no report in the literature outlining the management of newborns with choledochal cysts, many of whom are asymptomatic. Our study details the diagnosis, treatment and outcome of six such children, four girls and two boys. Five had antenatal US revealing cystic abdominal masses. One had intermittent vomiting and US suggested a choledochal cyst. Four of six had normal serum bilirubin levels; two had elevations. In five babies the choledochal cyst was correctly diagnosed from the preoperative studies; in one the preoperative diagnosis was an ovarian cyst. The children underwent an operation at an average of 6 weeks of age (range 5 days to 17 weeks). At exploration, cholangiography showed Alonso-Lej type I cysts in all cases. Treatment consisted of resection of the cyst with Roux-en-Y choledochojejunostomy in five and with a valved jejunal choledochoduodenal conduit in one. In no case was the dissection of the choledochal cyst off the portal vein and hepatic artery difficult. There were no intra- or early postoperative complications. Mean hospital stay was 8 days (range 5 to 9 days). Presently, all 6 patients have normal bilirubin levels at an average length of follow-up of 35 months (range 16 to 70 months) after operation. We conclude that operative treatment of choledochal cysts in early infancy, even in asymptomatic children, is safe and effective and may prevent serious complications later in life. PMID- 24057536 TI - Surgical treatment of achalasia in children: is an added antireflux procedure necessary? AB - Between 1975 and 1994, nine patients with achalasia were treated surgically at the Department of Pediatric Surgery, Ege University Hospital. The mean age was 8.3 years; there were 4 boys and 5 girls; and dysphagia was the leading symptom. There was also significant growth retardation in most of the patients. A modified Heller's myotomy was performed in all cases via a transthoracic approach without an antireflux procedure. In one patient the myotomy resulted in significant gastroesophageal reflux, but this could be controlled medically. This patient also needed esophageal balloon dilatation twice after the operation. Symptoms were relieved dramatically in the rest of the patients after surgery. We conclude that an additional antireflux procedure need only be performed when the esophagomyotomy is done incorrectly (an unnecessarily long incision extended onto the stomach), but is otherwise unnecessary. PMID- 24057538 TI - Is routine stenting necessary in pyeloplasty? AB - Although the evaluation of surgical procedures for the repair of ureteropelvic junction obstruction continues, open pyeloplasty is still the gold standard in the management of pediatric cases. The use of stents in open pyeloplasty is subject to discussion among pediatric urologists. To clarify this question on the basis of our experience, we retrospectively reviewed our 28 stented and 15 unstented pediatric pyeloplasty operations in terms of hospital stay, early and late complications, and success rates. While there were no differences between both groups in terms of early and late complications and success rates, hospital stay favored the unstented cases. We have concluded that routine stenting in pyeloplasty is not necessary unless a perfect anastomosis is accomplished. PMID- 24057537 TI - Abdominal tuberculosis in Indian children. AB - During the period 1980-1991, 166 cases (121 surgically explored and 45 treated conservatively) of abdominal tuberculosis in children were encountered at the Children's Hospital, Institute of Medical Sciences, Banaras Hindu University. Various types of presentations and their management are discussed in the light of pertinent literature. PMID- 24057539 TI - Exophytic urinary bladder lesions in childhood. AB - A retrospective study of the clinical presentation, diagnosis, and treatment of eight patients whose common characteristic was an exophytic, solid urinary bladder lesion (botryoid rhabdomyosarcoma, transitional-cell carcinoma, nephrogenic adenoma, cystitis cystica, von Brunn's nests, hemangioma, and squamous-cell metaplasia) is presented. Exophytic bladder lesions, some of which are of great importance, are rare entities in childhood and present nonspecific clinical pictures. Therefore, whenever a space-occupying lesion is detected on a complementary study of the lower urinary tract, the differential diagnosis should be considered. Advantages of each of the currently available diagnostic methods are discussed and the essential role of cystoscopy is stressed. PMID- 24057540 TI - Ureterocystoplasty with renal preservation in young infants. AB - To assess the outcome of ureterocystoplasty (UCP) with renal preservation in infants, three infants had a UCP with preservation of the ipsilateral kidney, including one who had a ureteropyeloplasty and one who had a UCP using a previously reimplanted ureter. All three had complication-free improvement in bladder volume and compliance. UCP thus produces an augmented bladder and can be performed as part of a transureteropyeloplasty and following ureteric reimplantation. PMID- 24057541 TI - Metabolic consequences of sigmoidocystoplasty in children. AB - Recent reports have shown that metabolic acidosis is a possible complication in patients who undergo augmentation enterocystoplasty. We studied 30 patients with neurogenic bladder who underwent sigmoidocystoplasty. Follow-up ranged from 1 to 10 years; all the patients showed normal renal function. We found significant hyperchloremic acidosis in 10% and borderline acidosis in 27% of the patients. Abnormalities of calcium and phosphorus balance were noted in 16.5% and 43% of the patients respectively, and more frequently in acidolic patients, which might be the result of activation of the bony buffers and might cause delayed growth in children. Close follow-up of all patients with enterocystoplasty is required, and oral bicarbonate is indicated when acidosis is detected. PMID- 24057542 TI - Epidural metastasis in chemoresistant Wilms' tumor with perilobar nephroblastomatosis. AB - An 8-year-old boy with vertebral and epidural metastases was diagnosed with Wilms' tumor associated with perilobar nephroblastomatosis (NB) based on histologic examination. During combined chemotherapy with vincristine, actinomycin D, doxorubicin, and cyclophosphamide (NWTS-3 J protocol), a rapid increase in tumor size was observed. The treatment was replaced with etoposide and carboplatin (JET regimen). A transient response was sustained for 5 months during this chemotherapy. However, regrowth of the tumor was observed and the patient died 11 months after the initial chemotherapy. PMID- 24057544 TI - Central venous catheter tip position and malfunction in a paediatric oncology unit. AB - An audit of 151 central venous catheters (CVCs) in 118 children with malignant disease was carried out over 20 months. The types included 31 valved silastic (Groshong), 58 non-valved silastic (Hickman), and 62 non-valved polyurethane (Cuff Cath) CVCs. There was no difference between the three groups with regard to the clinical diagnosis. The mean patient age at catheter insertion was 5.5 years and the mean weight 21.6 kg. None of the catheter types were associated with an increased risk of problems at insertion, migration, mechanical damage, blockage, sampling, or catheter infection. The incidence of catheter infection was 1.4/1,000 catheter days. Exit-site infection was less frequent with Groshong CVCs (P <0.05), which were in situ for the shortest period. The risk of problems with blood sampling was significantly increased in those catheters whose tip was sited outside the right atrium (P <0.005). For the 60 CVCs removed electively, the mean duration in situ was similar for all catheter types; 43 were removed following a problem. Of these, Groshong catheters were in situ for the shortest period (P = 0.05), probably as a result of delayed anchoring of the cuff. The tip position was the single most important determinant in the correct functioning of CVCs, irrespective of the type of catheter. Intraoperative screening of the tip position at catheter insertion is therefore mandatory for optimal catheter functioning. PMID- 24057543 TI - Totally implantable vascular access devices in 131 pediatric oncology patients. AB - The use of totally implantable vascular access devices (TIVAD) has gained acceptance in oncology patients, with lower overall complications and maintenance costs than percutaneous silastic catheters. We inserted 135 TIVAD in 131 selected pediatric oncology patients (mean age 8.9 years) for chemotherapy of 68 solid tumors, 39 leukemias, and 24 lymphomas. Patients were required to have an absolute neutrophil count of 1,000/MUl prior to TIVAD insertion. The cumulative duration of access was 45,098 days, with a mean of 334 days per device (range 5 to 981 days). At the time of review, 53 (39%) TIVAD were functioning without complication, 69 (51%) were removed at the end of therapy or were functioning at the time of death, and 13 (9.6%) were removed due to complications. Complications (n = 23) included 12 episodes of septicemia and 4 pocket infections for an infection rate of 11.8% (1 in 2,819 access days). Infections were more common in patients with leukemia compared to all others (P <0.001). Coagulase-negative staphylococci were isolated in 10 of the 16 infections; 7 infections resolved with antibiotic therapy. Mechanical complications were associated with 7 (5.2%) devices (1 in 6,443 access days). These data suggest that in selected non neutropenic pediatric oncology patients, TIVAD can be utilized with minimal morbidity in the delivery of long-term chemotherapy. PMID- 24057545 TI - Horner's syndrome and bilateral esophageal duplications. AB - Bilateral esophageal duplications are exceptionally rare. A 3-month-old male presented with a left-sided Horner's syndrome. Upon further investigation, bilateral upper thoracic masses with an air-fluid level within the right-sided mass were found. Sequential thoracotomies at 1-week intervals confirmed the presence of bilateral esophageal duplications. At 1 year of age the patient is growing normally and is asymptomatic except for a persistent Horner's syndrome. We believe this to be the first case of bilateral esophageal duplication cysts presenting with Horner's syndrome. PMID- 24057546 TI - Successful management of a chylothorax in infancy using a pleurectomy. AB - The management of chylothorax is described in three infants. Because none of them had had a direct injury to the thoracic duct, it was suspected that the chylothoraces had a significant chance of recurrence after simple ligation of the duct. To avoid recurrence, formal stripping of the parietal pleura was performed using a technique not previously reported in the literature. The operation was simple to perform and resulted in resolution of the chylothorax in all infants. The three cases and details of the surgical procedure are described. PMID- 24057547 TI - Familial occurrence of congenital diaphragmatic hernia : Father-to-son inheritance. AB - Familial occurrence of congenital diaphragmatic hernia is rare. This is only the second case of parent-to-child inheritance and the first case of father-to-son inheritance. The available data point toward a multifactorial mode of genetic transmission. PMID- 24057548 TI - Superior ectopic thoracic kidney. AB - A 9-month-old boy with a respiratory tract infection was found to have a mass in the left chest posteriorly. This proved to be a superior ectopic thoracic kidney, which was easily identifiable on ultrasonography. The case is reported to stress the importance of recognizing thoracic kidneys in order to avoid unnecessary invasive investigations and/or thoracotomy. PMID- 24057549 TI - Pancreatic tumors in children. AB - Pancreatic tumors rarely present in childhood. Diagnostic difficulty and inappropriate treatment may occur due to the variable clinical appearance of the illness. A 26-year audit (1968-1994) at this institution showed five patients ranging in age from 5 to 14 years who were operated upon for pancreatic tumors, four of which were malignant. In two cases primary resection of the tumor was possible and in the remaining three, after establishing the histopathologic diagnosis, chemo- and radiotherapy were used. Three of the five children are still alive; the mean follow-up was 9 years. PMID- 24057550 TI - Cystic teratoma of the pancreas. AB - Cystic teratoma of the pancreas is an extremely rare entity: only 11 cases have been described so far in the world literature. We report the 12th case, in a 4 month-old girl. PMID- 24057551 TI - Meckel's diverticulitis caused by roundworm incarceration. AB - Meckel's diverticulitis (MD) may occur de novo or may result from a foreign body in the diverticulum. A case is reported where MD was caused by incarceration of a roundworm. There do not appear to be previous documented reports of this condition. PMID- 24057552 TI - Association of a bleeding Meckel's diverticulum with upper thoracic vertebral anomalies and tetralogy of Fallot. AB - A 14-month-old child presented with recurrent episodes of melaena, upper thoracic hemivertebrae, and tetralogy of Fallot. The presence of the upper thoracic hemivertebrae led to the suspicion of intestinal duplication. However, technetium (Tc99m) scintigraphy revealed a Meckel's diverticulum. Following laparotomy and excision of the diverticulum, the histopathological examination confirmed the diagnosis. PMID- 24057553 TI - Unique presentation of heterotopic pancreatic tissue arising from small-bowel mesentery. AB - Heterotopic pancreatic tissue in the small-bowel mesentery is an extremely rare anomaly: no such case has been reported in the English literature. We report a 5 year-old boy in whom the aberrant tissue formed a retroperitoneal cyst. The condition was further complicated by a ventral pancreatic duct defect. The unique clinical manifestations and difficulty in making the diagnosis are discussed. PMID- 24057554 TI - Recurrent spontaneous perforation of intestinal lymphoma. AB - The possibility of intestinal lymphoma should be kept in mind when operating upon an immunodeficient child with an intestinal perforation without apparent reason; the phenomenon can recur during the post-operative period without being recognized early. PMID- 24057555 TI - Femoral artery embolus post-appendicectomy in a 12-year-old boy. AB - A 12-year-old male presented with an acutely ischaemic leg following a laparotomy for a pelvic abscess secondary to acute appendicitis. A femoral angiogram revealed an embolus at the popliteal artery. Urgent embolectomy was performed with restoration of normal arterial flow. Subsequent investigation revealed a patent foramen ovale. We believe this case represents a paradoxical embolus from a primary pelvic vein thrombosis dislodged at the time of laparotomy. PMID- 24057556 TI - Diphallus associated with a third ectopic urethra. AB - A case of diphallus is reported in a Saudi male born with two independent phalli with two urethras, the right urethra being joined by a third urethra opening on the perineum. In addition, the child had an absent right 1st rib, a 3rd thoracic hemivertebra, an absent left kidney, and a spinal lipoma. PMID- 24057557 TI - Paraurethral (Skene's duct) cysts in the newborn resolve spontaneously. AB - Paraurethral or Skene's duct cysts in the newborn period and early childhood are readily identified by their characteristic appearance -round, yellow- or orange coloured swellings beside and distorting the urethral orifice. Clinical examination should be followed by sonography of the urinary tract. Natural resolution is the likely outcome and early surgery is not necessary. PMID- 24057558 TI - Acute promyelocytic leukemia presenting as Fournier's syndrome in infancy. AB - Fournier's syndrome (FS) is occassionaly encountered in surgical practice. We report a 4-month-old female with acute promyelocytic leukemia (APL) presenting as FS. This case is interesting in two aspects: the early onset of the APL and its presentation as FS, which is the first such case reported in the literature. PMID- 24057559 TI - Constrictive amniotic bands: a case report. AB - Constrictive amniotic bands are circular depressions of the soft tissue of the digits, limbs, chest, abdomen, face, or scalp. A newborn with a constrictive amniotic band of the lower limb is presented. The pathogenesis, clinical manifestations, and treatment are discussed. PMID- 24057560 TI - Suppurative myositis in children. AB - Three cases are reported of pyogenic (non-tuberculous) myositis involving the ilio-psoas and/or iliacus muscles in children presenting to John Hunter Hospital, Newcastle, Australia, in a 12-month period. In one, cultures grew Haemophilus influenzae type B and in the other two Staphylococcus aureus was isolated. Biopsy of the abscess cavity from the second child confirmed an antecedent haematoma as the underlying cause. The third had underlying sacroiliac septic arthritis with a history of antecedent trauma. The classification, investigation, and treatment of myositis is discussed. PMID- 24057561 TI - Complete supernumerary leg in association with mesodermal abnormalities - a 16 year follow-up and literature review. AB - A male with a complete third leg in association with genito-urinary, anorectal, and colonic defects and an Arnold-Chiari malformation is described at birth and at 16 years of age following surgery. A short review of similar cases over the last century is presented and reference made to reported induction of similar abnormalities in vertebrates. PMID- 24057562 TI - Oronasopharyngeal teratomas. AB - Oronasopharyngeal teratomas are rare tumours that usually present in the neonatal period with airway obstruction. Management should include prompt establishment of the airway and early excision. Complete excision is recommended, which may require more than one operation, but multilating surgery should be avoided as the malignant potential of these tumours is extremely low. We describe our experience with three patients along with a literature review. PMID- 24057563 TI - Giant thoracolumbosacral teratoma in an infant. AB - A case of sacrococcygeal teratoma with unusually high intraspinal extension is reported and the symptomatology and treatment are discussed. A 7-month-old male presented at birth with a prominent mass of the right gluteal region preventing him from straightening his legs and causing undue effort during defecation. Magnetic resonance T1-weighted imaging revealed a thoracolumbosacrococcygeal, partly cystic tumor with intraspinal extension up to the mid-thoracic spine. During two-staged surgery, a cystic tumor containing fragments of hair, teeth, and bone and adherent to its surroundings was completely removed. The histologic examination confirmed the presence of a benign teratoma. A neurogenic bladder of the lower-motor-neuron type and constipation improved spontaneously. No further neurological deficits before and during a 3-year postoperative follow-up period were recorded. PMID- 24057564 TI - Pelvic ganglioneuroblastoma totally excised using posterior sagittal and abdominal approach. AB - Neuroblastoma usually presents as an upper abdominal mass arising from the adrenal gland. Recent experience with neuroblastoma of the spermatic cord, bladder, and pelvis demonstrates the propensity of this tumor to arise in unusual areas. A 1-year-old boy was admitted with pollakiuria, acute urinary retention, and chronic constipation. Computed tomographic and ultrasonographic examinations revealed a 5*5.5*4-cm pelvic mass, which was totally excised using a posterior sagittal and abdominal approach. The pathologic diagnosis was ganglioneuroblastoma and 1-year follow-up was uneventful. PMID- 24057565 TI - Reply. PMID- 24057566 TI - Laparoscopic splenectomy for hereditary spherocytosis. PMID- 24057567 TI - Errata. PMID- 24057569 TI - The Second Balkan Congress of Nuclear Medicine. PMID- 24057570 TI - Primary care physicians' knowledge of and confidence in their referrals for special education services in 3- to 5-year-old children. AB - BACKGROUND: Children 3 to 5 years old with developmental delays are eligible for special education services. OBJECTIVE: To assess primary care physicians' (PCPs) knowledge, attitudes, and practices regarding their referrals to the special education system on behalf of children 3 to 5 years old. DESIGN/METHODS: Mail survey of 400 office-based general pediatricians and 414 family physicians in Michigan, fielded in fall 2012 and winter 2013, with a response rate of 44%. The 4-page survey included knowledge questions about special education eligibility, PCPs' role in accessing school-based services, and self-confidence in ability to help patients access these services. RESULTS: PCPs neither fully understood requirements for special education services nor were they very confident in identifying 3- to 5-year-old children eligible for special education services. CONCLUSIONS: PCPs recognize interacting with special education as a relative weakness, and they may be accepting of interventions to improve their knowledge and skills. PMID- 24057571 TI - PI3K signaling mediates diverse regulation of ATF4 expression for the survival of HK-2 cells exposed to cadmium. AB - Cadmium exposure causes endoplasmic reticulum (ER) stress and accumulation of activating transcription factor 4 (ATF4), an ER stress marker. To elucidate the role of phosphatidylinositol-3-kinase (PI3K) signaling in this process, we examined the effects of PI3K signaling on cadmium chloride (CdCl2) exposure induced ATF4 expression in HK-2 human renal proximal tubular cells. ATF4 knockdown by siRNA enhanced CdCl2-induced cellular damage, indicating a cytoprotective function of ATF4. Treatment with LY294002, a PI3K inhibitor, suppressed CdCl2-induced ATF4 expression and Akt phosphorylation at Thr308 with little effect on phosphorylation of eukaryotic translation initiation factor 2 subunit alpha at Ser51. Activation of PI3K signaling with epidermal growth factor treatment enhanced CdCl2-induced Akt phosphorylation and ATF4 expression. Suppression of CdCl2-induced ATF4 expression by LY294002 treatment was markedly blocked by cycloheximide, a translation inhibitor, but not by MG-132, a proteasome inhibitor, or actinomycin D, a transcription inhibitor. CdCl2 exposure also induced phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448, glycogen synthase kinase-3alpha (GSK-3alpha) at Ser21, GSK-3beta at Ser9, and 90 kDa ribosomal S6 kinase 2 (RSK2) at Ser227 in HK-2 cells. Treatment with rapamycin, an mTOR inhibitor, MK2206, an Akt inhibitor, and BI-D1870, a RSK inhibitor, partially suppressed CdCl2-induced ATF4 expression. Conversely, SB216763, a GSK-3 inhibitor, markedly inhibited the potency of LY294002 to suppress CdCl2-induced ATF4 expression. These results suggest that PI3K signaling diversely regulates the expression of ATF4 in a translation-dependent manner via downstream molecules, including mTOR, GSK-3alpha/beta, and RSK2, and plays a role in protecting HK-2 cells from cadmium-induced damage. PMID- 24057572 TI - In vitro kinetics of nerve agent degradation by fresh frozen plasma (FFP). AB - Great efforts have been undertaken in the last decades to develop new oximes to reactivate acetylcholinesterase inhibited by organophosphorus compounds (OP). So far, a broad-spectrum oxime effective against structurally diverse OP is still missing, and alternative approaches, e.g. stoichiometric and catalytic scavengers, are under investigation. Fresh frozen plasma (FFP) has been used in human OP pesticide poisoning which prompted us to investigate the in vitro kinetics of OP nerve agent degradation by FFP. Degradation was rapid and calcium dependent with the G-type nerve agents tabun, sarin, soman and cyclosarin with half-lives from 5 to 28 min. Substantially longer and calcium-independent degradation half-lives of 23-33 h were determined with the V-type nerve agents CVX, VR and VX. However, at all the tested conditions, the degradation of V-type nerve agents was several-fold faster than spontaneous hydrolysis. Albumin did not accelerate the degradation of nerve agents. In conclusion, the fast degradation of G-type nerve agents by FFP might be a promising tool, but would require transfusion shortly after poisoning. FFP does not seem to be suitable for detoxifying relevant agent concentrations in case of human poisoning by V-type nerve agents. PMID- 24057574 TI - Serologic autoantibodies as diagnostic cancer biomarkers--a review. AB - Current diagnostic techniques used for the early detection of cancers are successful but subject to detection bias. A recent focus lies in the development of more accurate diagnostic tools. An increase in serologic autoantibody levels has been shown to precede the development of cancer disease symptoms. Therefore, autoantibody levels in patient blood serum have been proposed as diagnostic biomarkers for early-stage diagnosis of cancers. Their clinical application has, however, been hindered by low sensitivity, specificity, and low predictive value scores. These scores have been shown to improve when panels of multiple diagnostic autoantibody biomarkers are used. A five-marker biomarker panel has been shown to increase the sensitivity of prostate cancer diagnosis to 95% as compared with 12.2% for prostate-specific antigen alone. New potential biomarker panels were also discovered for lung, colon, and stomach cancer diagnosis with sensitivity of 76%, 65.4%, and 50.8%, respectively. Studies in breast and liver cancer, however, seem to favor single markers, namely alpha-2-HS-glycoprotein and des-gamma-carboxyprothrombin with sensitivities of 79% and 89% for the early detection of the cancers. The aim of this review is to discuss the relevance of autoantibodies in cancer diagnosis and to outline the current methodologies used in the detection of autoantibodies. The review concludes with a discussion of the autoantibodies currently used in the diagnosis of cancers of the prostate, breast, lung, colon, stomach, and liver. A discussion of the potential future use of autoantibodies as diagnostic cancer biomarkers is also included in this review. PMID- 24057573 TI - Direct analysis of tobacco-specific nitrosamine NNK and its metabolite NNAL in human urine by LC-MS/MS: evidence of linkage to methylated DNA lesions. AB - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its urinary metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), are the most investigated carcinogenic biomarkers of tobacco-specific nitrosamines. Here, we report the development of a sensitive and selective assay based on liquid chromatography tandem mass spectrometry (LC-MS/MS) to simultaneously measure urinary NNK and NNAL. With the use of isotope internal standards and online solid-phase extraction, urine samples were directly analyzed without prior sample purification. The detection limits of this method were 0.13 and 0.19 pg on column for NNK and NNAL, respectively. Inter- and intra-day imprecision was <10 %. Mean recovery of NNK and NNAL in urine was 99-100 %. This method was applied to measure urinary NNK and NNAL in 101 smokers and 40 nonsmokers to assess tobacco exposure. Urinary nicotine, cotinine, N3-methyladenine (N3-MeA), and N7 methylguanine (N7-MeG) were also measured by isotope-dilution LC-MS/MS methods. The results showed that urinary NNK was not observed in all smokers. Urinary free NNAL (0.10 +/- 0.09 ng/mg creatinine) and total NNAL (0.17 +/- 0.14 ng/mg creatinine) were detected in all smokers. Urinary concentrations of NNAL were significantly correlated with nicotine, cotinine, N3-MeA, and N7-MeG in smokers (P < 0.001). This method enables the direct and simultaneous measurement of NNK and NNAL in urine using only 50 MUL of urine. This study first demonstrated in human that urinary tobacco-specific nitrosamines metabolite (NNAL) are highly correlated with their resulting methylated DNA lesions in urine, which may help to substantiate an increased cancer risk associated with tobacco smoke exposure. PMID- 24057575 TI - Factorial validity and invariance of four psychosocial constructs of colorectal cancer screening: does screening experience matter? AB - BACKGROUND: Few studies have examined the psychometric properties and invariance of scales measuring constructs relevant to colorectal cancer screening (CRCS). We sought to: (i) evaluate the factorial validity of four core constructs associated with CRCS (benefits, barriers, self-efficacy, and optimism); and (ii) examine measurement invariance by screening status (currently screened, overdue, never screened). METHODS: We used baseline survey data from a longitudinal behavioral intervention trial to increase CRCS among U.S. veterans. Respondents were classified as currently screened (n = 3,498), overdue (n = 418), and never screened (n = 1,277). The measurement model was developed using a random half of the sample and then validated with the second half of the sample and the full baseline sample (n = 5,193). Single- and multi-group confirmatory factor analysis was used to examine measurement invariance by screening status. RESULTS: The four factor measurement model demonstrated good fit. Factor loadings, item intercepts, and residual item variance and covariance were invariant when comparing participants never screened and overdue for CRCS, indicating strict measurement invariance. All factor loadings were invariant among the currently screened and overdue groups. Only the benefits scale was invariant across current screeners and never screeners. Non-invariant items were primarily from the barriers scale. CONCLUSION: Our findings provide additional support for the construct validity of scales of CRCS benefits, barriers, self-efficacy, and optimism. A greater understanding of the differences between current and never screeners may improve measurement invariance. IMPACT: Measures of benefits, barriers, self-efficacy, and optimism may be used to specify intervention targets and effectively assess change pre- and post-intervention across screening groups. PMID- 24057576 TI - From amputation to limb salvage reconstruction: evolution and role of the endoprosthesis in musculoskeletal oncology. AB - In 1943, Austin Moore developed the first endoprosthesis fashioned from Vitallium, providing the first alternative to traditional amputation as primary treatment of bone tumors. The success of the Vitallium endoprosthesis has since then led to the development of new materials and designs further advancing limb salvage and reconstructive surgery. Combined with the advent of chemotherapy use and imaging advances, conservative treatment of musculoskeletal tumors has expanded greatly. As the implantable options increased with the development of the Lewis expandable adjustable prosthesis and the noninvasive Phenix Growing prosthesis, receiving the diagnosis of a bone tumor no longer equates to automatic limb loss. Our review details the history and development of endoprostheses throughout orthopedic oncology in the treatment of musculoskeletal tumors. PMID- 24057577 TI - Responses of herbivore and predatory mites to tomato plants exposed to jasmonic acid seed treatment. AB - Jasmonic acid (JA) signalling can influence plant defense and the production of plant volatiles that mediate interactions with insects. Here, we tested whether a JA seed treatment could alter direct and indirect defenses. First, oviposition levels of herbivorous mites, Tetranychus urticae, on JA seed-treated and control tomato plants were compared. They were not significantly different on tomato cv. 'Moneymaker', however, there was a significant reduction in oviposition on treated plants in additional experiments with cv. 'Carousel'. Second, responses of predatory mites, Phytoseiulus persimilis, were assessed in a Y-tube olfactometer. Volatiles from JA seed-treated tomato cv. 'Moneymaker' plants were significantly more attractive than volatiles from control plants. Volatiles collected from plants were analysed by GC/MS, and samples from JA seed-treated plants contained more methyl salicylate and (E,E)-4,8,12-trimethyl-1,3,7,11 tridecatetraene (TMTT) than samples from control plants. Our results indicate that JA seed treatment can make tomato plants more attractive to predatory mites, but that direct effects on herbivorous mites are variable and cultivar dependent. PMID- 24057589 TI - Breastfeeding is natural but not always easy: intervention for common medical problems of breastfeeding mothers - a review of the scientific evidence. AB - Natural processes do not always function perfectly. In breastfeeding, problems are encountered in up to 80% of mother-infant dyads. Altogether, in Western societies, the difficulties reduce the breastfeeding rate within the first months drastically. To deal with the problems of breastfeeding efficiently requires a profound understanding of its physiology, as well as of its psychological and social determinants. This review focuses on the current knowledge of breastfeeding physiology, only touching the psychosocial factors, which are included in the promotion strategies. Subsequently, it scrutinizes definitions, incidences, prevention, and treatment of breastfeeding problems faced most frequently by nursing mothers and their consultants. Not all measures used in counseling mothers and not all treatments for the most common medical problems withstand a careful evaluation on the basis of current scientific data. However, applying proven prevention strategies will significantly improve the well being of mothers and their infants, and may contribute to an affective attitude that increases the success, frequency, and duration of breastfeeding. PMID- 24057591 TI - Clinical expression of familial Williams-Beuren syndrome in a Turkish family. AB - Williams-Beuren syndrome (WBS) is a rare genetic disorder characterized by distinctive facial features, intellectual disability with a typical neurobehavioral profile, cardiovascular anomalies, and occasional infantile hypercalcemia. Majority of cases occur sporadically, and only a few cases of familial WBS have been reported. Although pre- and post-natal growth retardation is a common clinical feature of the syndrome, growth hormone deficiency is detected only in a few patients. To our knowledge, there has only been one report about familial Williams-Beuren syndrome in the Turkish population. Here, we report on the three molecular cytogenetically confirmed familial Williams-Beuren syndromes detected in a family with familial short stature. The father, daughter, and son analyzed with clinical and laboratory findings, and reasons of the short stature in Williams-Beuren syndrome are discussed through the literature. PMID- 24057590 TI - The relationship between thyroid dose and diagnosis of primary hypothyroidism in pediatric brain tumor patients receiving craniospinal irradiation. AB - PURPOSE: The aim of this work is to determine if a relationship exists between thyroid dose and incidence of primary hypothyroidism (PH) in children undergoing craniospinal irradiation (CSI). METHODS: A total of 22 patients received CSI with evaluable thyroid dose information. All patients received concurrent chemotherapy and 21 patients (95%) received adjuvant chemotherapy. Median follow-up was 42.9 months. RESULTS: The incidence of PH in our cohort was 59% at a median time after radiotherapy of 3.5 years (range: 8 months to 7.5 years). Mean thyroid dose appeared to best predict for PH, with a median of 2080 cGy for patients with PH versus 1736 cGy for children without PH (p=0.057). There was no association between the rate of PH and sex, age, CSI dose, minimum thyroid dose and maximum thyroid dose. CONCLUSIONS: A relationship may exist between the mean thyroid dose and incidence of PH in patients undergoing CSI. Thus, new strategies to protect the thyroid gland may be warranted. PMID- 24057592 TI - Marine-Lenhart syndrome in a young girl. AB - Graves' disease is the most common reason of hyperthyroidism in children. Graves' disease with accompanying functioning nodules is defined as Marine-Lenhart syndrome. This syndrome has not been described in children before. Here, a 15 year-old girl with Graves' disease and a coexisting cold nodule is presented. A thyroid scan showed diffuse uptake of Tc-99m pertechnatate in both lobes and decreased uptake in accordance with the left lobe nodule. The nodule was histologically diagnosed as benign. The patient was diagnosed with type 1 diabetes mellitus and polyglandular autoimmune syndrome during clinical follow up. The differential diagnoses of Graves' disease with coexisting nodules should include the Marine-Lenhart syndrome. Treatment options should be determined taking this rare condition into account. PMID- 24057593 TI - Factors influencing neonatal thyroid-stimulating hormone concentrations as a measure of population iodine status. AB - BACKGROUND: The World Health Organization (WHO) has recommended measurement of neonatal thyroid-stimulating hormone (TSH) as a marker of population iodine status. A population is considered iodine sufficient when <3% of neonatal blood samples collected 3-4 days after birth have TSH concentrations >5 mIU/L. However, changes in technology and clinical practices have opened the WHO criteria to various interpretations. AIM: This study aimed to investigate the effects of time of sampling, weight, and sex on neonatal TSH concentrations by analyzing neonatal TSH data, based on the WHO criteria for population iodine sufficiency. METHODS: We analyzed the Western Australian (WA) Newborn Screening Program records for 198,826 babies born in WA between 2005 and 2011, to determine the relationship between neonatal TSH concentrations and time of sampling, weight, and sex. RESULTS: The proportion of TSH results above the WHO cut-off was higher for samples collected 48-72 h after birth rather than later, for males, for birth weights below 2500 g, and when a cut-off of 5.0 mIU/L was used. CONCLUSION: Following changes in newborn screening protocols and earlier collection of blood samples, the WHO criteria appear inappropriate. We recommend that WHO revise current guidelines regarding use of neonatal TSH for monitoring population iodine status. PMID- 24057594 TI - Roasting and lipid binding provide allergenic and proteolytic stability to the peanut allergen Ara h 8. AB - Abstract Ara h 8 is the peanut allergen homologous to the birch pollen allergen Bet v 1. Because Bet v 1 has been shown to bind lipophilic ligands, the aim of this investigation was to determine the impact of lipid binding and roasting on the Ara h 8 structure and their influences on allergenicity. For the characterization of natural Ara h 8 (nAra h 8) from roasted and unroasted peanuts, circular dichroism spectroscopy, hydrophobic binding assay, immunohistochemistry, and immunoblot with sera of peanut allergic patients were performed and compared with results from recombinant Ara h 8 (rAra h 8) and Bet v 1. rAra h 8 displayed stronger hydrophobicity than rBet v 1. Patients' sera showed IgE reactivity with rAra h 8 and nAra h 8 from roasted peanuts, whereas fewer sera recognized nAra h 8 from unroasted peanuts. Simulated gastric digestion experiments demonstrated low proteolytic stability of rAra h 8, whereas the stability of nAra h 8 was increasingly higher in unroasted and roasted peanuts. The results demonstrate that IgE reactivity and thermal and proteolytic stability are reinforced in nAra h 8 after roasting, most likely due to Maillard reactions, lipid oxidations, and lipophilic associations. These aspects must be considered when estimating the allergenicity of Bet v 1-homologous proteins. PMID- 24057595 TI - The relationship between estimated average glucose and fasting plasma glucose. AB - BACKGROUND: Estimated average glucose (eAG) is a value calculated from hemoglobin A1c (HbA1c) that reflects average glycemic status over the preceding few months. A linear relationship between HbA1c and eAG was demonstrated by the International HbA1c-Derived Average Glucose (ADAG) Trial in 2008. We investigated the relationship between fasting plasma glucose (FPG) and eAG. METHODS: This retrospective study was conducted by reviewing the medical records of 6443 subjects, including 5567 diabetic patients and 876 non-diabetic subjects. The levels of HbA1c and FPG were reviewed and eAG was calculated using the regression equation published by the ADAG trial: eAGmmol/L=1.59*HbA1c(NGSP, %) 2.59[eAGmg/dL= 28.7*HbA1c(NGSP, %)-46.7]. RESULTS: In all subjects, FPG showed a moderate correlation with eAG (r=0.672, p<0.001). When diabetic and non-diabetic subjects were divided into subgroups according to FPG level, the correlation between eAG and FPG decreased in both diabetic [FPG >=10.0 mmol/L (180 mg/dL), r=0.425; FPG 7.2-9.9 mmol/L (130-179 mg/dL), r=0.373; FPG <7.2 mmol/L (130 mg/dL), r=0.202] and non-diabetic [FPG 5.6-6.9 mmol/L (100-125 mg/dL), r=0.363; FPG <5.6 mmol/L (100 mg/dL), r=0.186] subgroups as the FPG level decreased. The differences between eAG and FPG were statistically significant (p<0.001). Only 81% (4487/5567) of diabetic patients had a lower FPG level than eAG level. CONCLUSIONS: Our results suggest that the relationship between eAG and FPG may depend on glycemic control, thereby enhancing our understanding of eAG. PMID- 24057596 TI - Tackling metabolic syndrome by functional foods. AB - The metabolic syndrome is one of the most vibrant and widely prevailing health concerns worldwide. It is characterized by several metabolic abnormalities, which involve obesity, insulin resistance, dyslipidemia, enhanced oxidative stress; hypertension and increased pro-inflammatory state that ultimate contribute towards poor health. The prevalence of metabolic syndrome in Pakistan according to different definitions is reported to be from 18 % to 46 %. Fifty percent of Pakistani population is at high risk of metabolic syndrome as being hypertensive. In studying dyslipidemia in Pakistan, hypertriglyceridemia is found in 27-54 % of the population, whereas 68-81 % has low levels of high-density lipoprotein (HDL). Population likes to eat healthier diet without changing their fundamental dietary pattern. Nutrition science has moved on from the classical concepts of avoiding nutrient deficiencies and basic nutritional adequacy to the concept of positive or optimal nutrition. Many traditional food products including fruits, vegetables, flaxseed, oat, barley, whole grains, soy and milk have been found to contain component with potential health benefits. Nowadays, functional foods are used in the prevention and amelioration of several chronic diseases, such as the metabolic syndrome. The relation of the consumption of certain functional foods and the improvement in health status is regulated through health claims. This review focuses on the different features of the metabolic syndrome and the influence of functional foods on these aspects, involving dyslipidemia, improvement of insulin sensitivity, serum lipid profile, antioxidant status, anti inflammatory status and weight management of humans. PMID- 24057597 TI - Genetic models of PGC-1 and glucose metabolism and homeostasis. AB - Type II diabetes and its complications are a tremendous health burden throughout the world. Our understanding of the changes that lead to glucose imbalance and insulin resistance and ultimately diabetes remain incompletely understood. Many signaling and transcriptional pathways have been identified as being important to maintain normal glucose balance, including that of the peroxisome proliferator activated receptor gamma coactivator (PGC-1) family. This family of transcriptional coactivators strongly regulates mitochondrial and metabolic biology in numerous organs. The use of genetic models of PGC-1s, including both tissue-specific overexpression and knock-out models, has helped to reveal the specific roles that these coactivators play in each tissue. This review will thus focus on the PGC-1s and recently developed genetic rodent models that have highlighted the importance of these molecules in maintaining normal glucose homeostasis. PMID- 24057598 TI - New strategies in the management of Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an acute and usually monophasic, neurological, demyelinating disease. Although most patients have good outcomes without sequelae after conventional plasma exchange and intravenous immunoglobulin therapy, 20% of patients continue to have severe disease and 5% die of their disease. Therefore, there is an obvious need for more acceptable and efficacious therapies. Experimental autoimmune neuritis (EAN) is the classical animal model for GBS. As there is no specific drug for GBS, several drugs targeting the humoral and cellular components of the immune response have been used to treat EAN in the endeavour to find new treatment alternatives for GBS. This review focused on some new strategies for GBS, which have been reported but have not yet been widely used, and on the main drugs which have been investigated in EAN. PMID- 24057599 TI - Fatal aortotracheal fistula combined with aortoesophageal fistula in an infant with double aortic arch: a warning. AB - This report describes a 2-month-old male infant with a double aortic arch (DAA) complicated by aortoesophageal fistula (AEF) and aortotracheal fistula (ATF). He was intubated with an endotracheal tube at birth because of neonatal asphyxia. A nasogastric tube was also placed for gastric decompression and milk feeding. On the 74th day of birth, he had massive upper gastrointestinal hemorrhage associated with shock, and was referred to our hospital. Although emergent surgery controlled the bleeding from AEF, he suffered cardiac arrest due to massive bleeding from ATF 5 h after surgery, and died on the 9th postoperative day. Physicians should be aware that prolonged endotracheal and nasogastric intubation predispose to the development of not only esophageal erosion but also more lethal tracheal erosion. In addition to the importance of early diagnosis and prompt surgery for DAA, appropriate preoperative respiratory management is emphasized to prevent similar occurrences in the future. PMID- 24057600 TI - Overcoming the perceived barriers to health care access among single mothers in coastal Kenya. AB - OBJECTIVES: This study assesses the effects of a comprehensive empowerment intervention on barriers to health care access for single mothers in coastal Kenya. METHODS: We surveyed 41 single mothers who completed a pilot empowerment program and 60 single mothers who had not yet initiated the program. Comparisons were made using bivariate tests of association and logistic regression. RESULTS: Women in the pilot program were less likely to report transportation costs (OR = 0.26; 95 % CI [0.11-0.59], p = 0.001) and hospital fees (OR = 0.22 [0.10-0.49], p < 0.001) as barriers. Pilot program mothers were more likely to visit a public hospital for their children (OR = 4.38; [1.58-12.1], p = 0.004) and self (OR = 4.70; [1.54-14.4], p = 0.007) when ill. CONCLUSIONS: Empowerment programs can alleviate perceived barriers to health care among vulnerable populations. PMID- 24057601 TI - Theoretical fingerprinting of the photophysical properties of four firefly bioluminophores. AB - The photophysical properties of four bare firefly bioluminophores were studied in vacuo by means of a density functional theory approach. The objective of this work was to fingerprint the excited-state properties of these molecules without perturbations of the microenvironment (either solution or enzyme active site). It is known that intermolecular interactions formed between the light-emitter and active site molecules govern the bioluminescence multicolor tuning mechanism. However, it is difficult to disentangle the numerous active site-oxyluciferin interactions and understand the effect exerted by each one of these interactions on the color of light emitted. Thus, the study of these isolated bioluminophores allows us to obtain their intrinsic photophysics properties, which can serve as a reference in studies aiming to understand the role of perturbations from the microenvironment. PMID- 24057603 TI - [Development and Evaluation of a Health Promotion Programme for Low-Qualified Workers with Special Attention to Transfer]. AB - A health promotion programme for low-qualified workers was developed with focus on resource and stress management (ReSuM) and with special attention to transfer. ReSuM is a multiplier concept and combines a team intervention for low-qualified workers with an intervention for their supervisors. The effectiveness and efficiency were successfully evaluated within a comprehensive evaluation strategy. PMID- 24057602 TI - Bt rice expressing Cry2Aa does not cause direct detrimental effects on larvae of Chrysoperla sinica. AB - To assess the potential effects of Cry2Aa-expressing insect-resistant Bt rice on Chrysoperla sinica larvae, we conducted two tritrophic bioassays using a non target (Laodelphax striatellus) and a target herbivore (Chilo suppressalis) as prey. None of the tested life-table parameters of C. sinica did differ when fed with L. striatellus nymphs reared on either Bt or control rice plants. Similarly, C. sinica larval survival and development were not affected when fed C. suppressalis larvae that were reared on Cry2Aa-contained artificial diet compared to those fed control diet. However, the 7-day larval weight was significantly decreased in the Bt treatment and none of the C. sinica larvae developed to the adult stage. To clarify whether the observed effects were due to the direct toxicity of Cry2Aa or prey-quality mediated, we conducted a dietary exposure assay in which the toxicity of Cry2Aa to C. sinica larvae was tested. Potassium arsenate (PA) was included as a positive control. None of the tested life-table parameters of C. sinica was adversely affected when fed Cry2Aa at 500 MUg/ml sucrose solution. In contrast, C. sinica larvae were adversely affected by feeding on sucrose solution containing PA. In the feeding assays, exposure of C. sinica larvae to Cry2Aa was confirmed by ELISA. Our results demonstrate that C. sinica larvae are not sensitive to Cry2Aa at concentrations exceeding the levels that the larvae may encounter in Bt rice fields. Consequently the detrimental effects observed in the tritrophic studies using Bt rice-fed C. suppressalis as prey can be attributed to the decreased prey quality due to the sensitivity of C. suppressalis larvae to Cry2Aa. PMID- 24057604 TI - ABO blood group and risk of peripheral arterial thrombosis in patients with atrial fibrillation: a single center survey. PMID- 24057605 TI - Cangrelor for patients undergoing percutaneous coronary intervention: evidence from a meta-analysis of randomized trials. AB - Cangrelor is a new parenteral adenosine diphosphate P2Y12 receptor inhibitor with rapid, profound and reversible inhibition of platelet activity. The aim of this meta-analysis was to evaluate efficacy and safety of this new agent in patients undergoing percutaneous coronary intervention (PCI). We searched PubMed, Cochrane Library, EMBASE, Web of Science and CINAHL databases from the inception through April 2013. Randomized controlled trials (RCTs) comparing cangrelor with control (clopidogrel/placebo) were selected. We used the random-effects models to calculate the risk ratio. The primary efficacy outcome was risk of myocardial infarction, and the primary safety outcome was TIMI major bleeding at 48 h. Three RCTs included a total of 25,107 participants. Effects of Cangrelor were not different against comparators for myocardial infarction (MI) (Risk ratio [RR] 0.94, 95% confidence interval [CI] 0.78-1.13) and all-cause mortality (RR 0.72, 95% CI 0.36-1.43). However, cangrelor significantly reduced the risk of ischemia driven revascularization (RR 0.72, 95% CI 0.52-0.98), stent thrombosis (RR 0.60, 95% CI 0.44-0.82) and Q wave MI (RR 0.53, 95% CI 0.30-0.92) without causing extra major bleeding (Thrombolysis in Myocardial infarction criteria) and severe or life-threatening bleeding (Global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries criteria). Separate analysis against only clopidogrel also showed similar findings except Q wave MI outcome. Use of cangrelor during PCI might reduce the risk of ischemia-driven revascularization and stent thrombosis, without causing extra major bleeding. PMID- 24057616 TI - Synthesis of 3H-pyrrolo[2,3-c]quinolin-4(5H)-ones via Pd-catalyzed cross-coupling reaction and cyclization. AB - Biologically active 3H-pyrrolo[2,3-c]quinolin-4(5H)-ones have been synthesized in an efficient and concise manner utilizing readily available 4-hydroxyquinolin 2(1H)-ones as the starting material. The key strategy relies on the construction of the pyrrole ring through the palladium catalyzed sequential cross-coupling reaction and cyclization process. PMID- 24057618 TI - Oesophageal substitution : Editorial comment. PMID- 24057617 TI - Bifunctional primary amine-thioureas in asymmetric organocatalysis. AB - Research disclosed since the demonstration of the first examples of primary amine thiourea organocatalysis in 2006 has shown that primary amine-based thioureas can successfully catalyze a diverse variety of highly enantioselective transformations providing a wide range of versatile organic compounds. Recent remarkable progress with these chiral catalysts is summarized in this review. PMID- 24057619 TI - Esophageal reconstruction by elongation of the lesser gastric curvature. AB - Long-gap esophageal atresias (EA) generally require surgical substitution using colon, jejunum, or a portion of the stomach. In these procedures, as in total gastric pull-up operations, the distal portion of the esophagus is sacrificed. Experimental studies on cadaver stomachs have shown that retrosternal transfer of the distal esophagus with preservation of all esophageal portions is possible when the lesser curvature is incised diagonally, provided the collateral circulation via the left gastric artery (LGA) is preserved. A tension-free esophageal anastomosis is then carried out intrathoracically or cervically. This technique was employed successfully in eight children. In two cases ligation of the LGA alone was sufficient; in six an additional incision in the lesser curvature was required to achieve adequate length. This procedure is advantageous in that all portions of the esophagus are preserved and, due to the retrosternal position, a thoracotomy is unnecessary. The morbidity is significantly lower than that associated with all the other substitution techniques. The main complications included cervical anastomotic leaks, which closed spontaneously, and stenoses that required bouginage. There was no mortality. From our experience to date, it can be concluded that esophageal anastomosis is possible in long-gap EA after incising the lesser gastric curvature, and that substitution plasties can be avoided. PMID- 24057620 TI - Gastric transposition for oesophageal replacement. AB - Eighty-three gastric transpositions for oesophageal replacement were carried out over the 15-year period 1981-1995. The vast majority of patients underwent the replacement procedure for oesophageal atresia (OA) (56), 35 following failed or abandoned attempts at primary anastomosis, and 21 for isolated atresia. Caustic oesophageal strictures constituted the next largest group (14). The favoured method of transposition was via the posterior mediastinal route without thoracotomy (n = 50). There were 6 deaths in this series (7.2%); 12% of patients developed anastomotic leaks, all of which healed spontaneously, and 12% developed strictures that responded to dilatation/s alone. Establishing oral feeding was the most common problem, especially in infants with OA who had not been sham-fed. The majority of patients have achieved satisfactory growth at medium-term follow up and 64% have an excellent and 24% a satisfactory outcome at follow-up of up to 14 years. PMID- 24057621 TI - The reversed gastric tube for esophageal replacement in children. AB - The reversed gastric tube provides a relatively simple method of esophageal replacement in children. A thirty year experience of this technique is described together with the long-term results in 34 patients. Complications such as anastomotic leakage and stricturing have responded well to treatment and only one patient died. The reversed gastric tube remains a useful alternative to other methods of esophageal substitution. PMID- 24057622 TI - Esophageal substitution with colon - the Waterston operation. AB - Twenty-three interpleural (Waterston) colon replacements of the esophagus are reported, 21 for esophageal atresia and 2 for corrosive strictures. Twenty patients are alive with an intact replacement; 17 are swallowing well and 3 have some dysphagia. Two grafts were converted to reverse gastric tubes, 1 for venous infarction and the other because of difficult vascular anatomy. One child died from disseminated intravascular coagulation following gastroenteritis shortly after successful completion of the interposition. Technical details of the operation are described. The need for replacement has been much less in recent years because of improved surgical techniques for esophageal atresia, particularly elective ventilation and the upper pouch flap operation. Recognition that corrosive and reflux strictures, if a dilatable channel can be maintained, will improve if dilatation is persevered with for 2 years may avoid the need for replacement. PMID- 24057623 TI - Oesophageal substitution by jejunal free graft: follow-up data and an evaluation. AB - We have developed a new technique for oesophageal substitution using a jejunal free graft and now present a 3-5 year follow-up study of five infants who had this procedure performed for long gap oesophageal atresia. Swallowing is excellent in two, good in two and fair in one. We conclude that jejunal interposition, though technically difficult, can produce excellent results and we particularly recommend this technique, when the oesophageal substitute has to reach high in the thorax or to the neck. PMID- 24057624 TI - Anatomy of the extrinsic nerve supply of the oesophagus in oesophageal atresia of the common type. AB - Cadaver dissections of the oesophagus were carried out to evaluate its extrinsic nerve supply in oesophageal atresia (OA) with distal tracheo-oesophageal fistula. In OA the atresia occurs at an anatomic watershed in the oesophagus. Proximal to the atresia, the oesophageal wall contains striated muscle. There is a known change in the type of muscle that forms the oesophagus as it descends through the chest. As a continuation of the pharynx, its wall is made up entirely of striated muscle, which is gradually replaced by smooth muscle. What percentage of the wall proximal to an atresia is normally striated is not known. Distal to the atresia the oesophagus is a smooth-muscle tube that receives its extrinsic motor nerve supply from the vagal nerves. These specific nerve fibres have their central origin in the dorsal nucleus of the vagus and are part of the autonomic nervous system. They appear to reach the oesophagus with its blood supply in an ordered but random manner. As the autonomic nervous system does not supply striated muscles, fibres of the vagal nerves that supply the proximal pouch must be somatic nerves. This is confirmed, as this portion of the oesophagus is shown to be supplied by the recurrent laryngeal nerves, which contain fibres that have their origin in the nucleus ambiguous. These nerves are bilateral and reach the oesophageal wall in a segmental fashion; this supply is continuous with that of the pharynx. As the oesophagus proximal to an atresia anatomically belongs to the pharynx, it is called the pharyngeal oesophagus. For a similar reason, the distal segment is named the gastric oesophagus. This anatomy is of practical importance to the surgeon. PMID- 24057625 TI - Periodic bile cultures and irrigation of the external jejunostomy for cholangitis in biliary atresia. AB - We retrospectively investigated the use of periodic bile cultures and irrigation of the external jejunostomy for prevention or treatment of postoperative cholangitis in 11 infants who had undergone the Suruga II modification with external jejunostomy for biliary atresia. Periodic cultures obtained from bile in the external jejunostomy were done weekly in all patients. Staphylococci were first cultured 1 week after operation, followed by intestinal flora such as enterococci, Pseudomonas, Klebsiella, or Enterobacter. Most of the cultures revealed two or more microorganisms. Susceptibility testing indicated the effective antibiotics for the treatment of each case of cholangitis. Therefore, periodic bile cultures and irrigation of the external jejunostomy provide important information for prevention or treatment of postoperative cholangitis, especially in the early postoperative period. PMID- 24057626 TI - The umbilicus in gastroschisis: aesthetic considerations. AB - Preservation of the umbilical cord attachment (UCA) in gastroschisis (GS) is still not routine practice. In a prospective series of 36 children with GS, it was always possible to preserve the UCA, even in those undergoing a temporary silo and delayed closure. Reconstruction by 'umbilical cord capping' left no additional scar and achieved a normal abdominal wall. Mild cellulitis in 3 infants resolved on antibiotics, and an initial umbilical weakness in 7 did not require additional surgery. We conclude that preservation of the UCA should be an integral part of surgical technique for all infants with GS. Reconstruction by 'umbilical cord capping' alone achieves an unscarred abdominal wall with an umbilicus of normal shape and position. PMID- 24057627 TI - The value of sodium pertechnetate Tc99m scans in the diagnosis of Meckel's diverticulum. AB - A retrospective study was conducted of our experience with sodium pertechnetate Tc99m scans for diagnosing suspected Meckel's diverticula. Seventy-seven cases scanned between 1979 and 1994 were reviewed. Eighty per cent of the group presented with bleeding per rectum, 12% with pain, and 6.5% with anaemia. Ten scans were positive with 7 true-positive and 3 false-positive. Of the 67 negative scans, 3 were false-negatives. There were six Meckel's diverticuli and four duplication cysts between the true-positive and false-negative groups. All presented with major gastrointestinal (GI) bleeding and gastric mucosa was identified on histology. The three false-positive cases had inappropriate laparotomies on the basis of scan results. The test sensitivity was 70% with a specificity of 95%, giving an overall accuracy of 92%. The Meckel's scan is a useful investigation for GI bleeding in children. Surgical intervention should be guided by the full clinical picture and the scan, rather than the scan result alone. PMID- 24057628 TI - A modified operation for Hirschsprung's disease: Posterior longitudinal anorectal split with a "heart-shaped" anastomosis. AB - A variety of complications can arise after the definitive pull-through operation for Hirschsprung's disease. Among these are constipation and soiling, which may be due to mismanagement of the internal anal sphincter. In order to prevent these complications, we developed an improved operative procedure based on preservation of the anterior anorectum that utilizes a posterior longitudinal split with an oblique anastomosis. Forty patients underwent this procedure over a 4-year period; adequate follow-up was obtained in 34 cases. Mean age at operation was 13 months (range 3 months to 7 years). A primary pull-through without a colostomy was performed in 38 of the 40 patients. The results showed excellent preservation of function, with a mean follow-up of 5 years and 7 months. There was no occurrence of spastic stenosis of the internal sphincter, no incontinence, and minimal constipation or soiling. PMID- 24057629 TI - Megacystis - microcolon - intestinal hypoperistalsis syndrome. AB - Two non-related female neonates with the megacystis-microcolon-intestinal hypoperistalsis syndrome are described. One presented with a family history of a similar condition. In one child no intestinal peristalsis was observed, while in the other decreased peristalsis with occasional rectal evacuation occurred. Both had fatal outcomes. These two cases demonstrate the wide variation in the clinical course of this rare and fatal syndrome. PMID- 24057630 TI - Autologous gastro-intestinal reconstruction: the composite ileo-colic loop. AB - A reproducible technique was developed experimentally in pigs for construction of a 'composite bowel tube' (CBT) made up of ileal mucosa that was grafted to a mucosally denuded colonic muscle surface vascularised by the colonic mesentery. Macroscopic and microscopic studies at terminal laparotomy revealed a viable, mucosally lined, patent peristaltic loop of bowel in six of the eight animals. Two animals died after sloughing the grafted mucosa. In vivo absorption studies, using l-alanine as an index of amino acid absorption, showed a transport pattern through the grafted mucosa of the composite ileo-colic loop appropriate to ileum when compared with controls. The CBT constitutes another autologous gastro intestinal reconstructive technique for redistribution of available absorptive mucosa over a longer intestinal length, and may therefore be of benefit in the management of the short-bowel syndrome. PMID- 24057631 TI - The use of gastrocystoplasty in patients with bladder exstrophy. AB - The authors report the use of a stomach segment vascularized via the right gastroepiploic artery in order to increased bladder capacity in 18 patients with bladder exstrophy. The morphological and functional results were good in 15 patients (83.4%); 13 (72.2%) continue to use intermittent catheterization to empty the bladder, while 5 (27.7%) have spontaneous voiding. Seven patients are completely continent, 8 partially continent (<3 h), and 2 are still incontinent. We encountered no metabolic complications and no patient complained of mucus production. Ten patients had a dysuria-hematuria syndrome, 8 only slight and 2 marked. We believe that even though gastrocystoplasty is a valid alternative compared with other tissues used to date for bladder augmentation, attention should be paid to this new pathological sequela, which has proved to occur quite frequently, as seen from the long- and short-term follow-up of patients who have had this operation. PMID- 24057632 TI - Evolution of urodynamic patterns in posterior urethral valves. AB - A retrospective, long-term urodynamic study was performed in order to follow the evolution of the urodynamic patterns in 55 unselected patients previously affected by posterior urethral valves (PUV). The mean maximum cystometric capacity (MCC) values progressively increased over time and, on long-term follow up, were just above 2 standard deviations (SD). The mean compliance values were clearly reduced in the first urodynamic studies after valve ablation, and only after a mean of 5 years follow-up did they approach the lower limits of normal. The small compliance and capacity (SCC) group showed two trends of evolution: a more numerous subgroup tended toward progressive normalization while a second subgroup (<20%) showed mean compliance values below normal limits, with reduced ( 2 SD) MCC persisting at long-term follow-up. The number of patients in this group decreased over time. In contrast, we were able to show a significant increase in patients with myogenic failure. In this group scheduled voiding using the Valsava maneuver in conjunction with a regimen of double or triple micturition was usually succesful in modifying the course, normalizing MCC, reducing residual urine, and also eliminating incontinence. Finally, initial urodynamic investigations in the fulguration and vesicostomy groups showed a much higher percentage of SCC bladders in the latter group (83.5% vs. 35%). However, at long term examinations the urodynamic parameters were nearly identical in both groups, showing that temporary bladder defunctionalization does bot adversely affect future detrusor activity. No direct relationship between urodynamic abnormalities and renal insufficiency could be shown, however, the majority of patients with reduced glomerular filtration rates still showed urodynamic dysfunction at long term follow-up. In the authors' opinion, serial urodynamic investigations in association with serial evaluation of the evolution of upper urinary tract and renal function are mandatory for correct PUV management and provide useful guidelines for avoiding incorrect treatment and obtaining better long-term results. PMID- 24057633 TI - Testicular maldescent and maldevelopment in fetal rats prenatally exposed to nitrofen. AB - In the rat model of nitrofen-induced congenital diaphragmatic hernia, we found the testicles in a high abdominal position in many male animals, and undertook to investigate whether the teratogen interferes with testicular descent and development. Male fetuses from time-mated Wistar rats treated intragastrically with 100 mg nitrofen dissolved in oil on day 9.5 of gestation were compared with control fetuses from mothers receiving only vehicle. The litters were recovered by cesarean section on days 17, 19, and 21 of gestation; the position of the testicles in male animals was recorded, and their volume was measured prior to histological assessment of mean tubular diameter, number of germ cells per tubule, and degree of collagenization of the tunica albuginea. Testicular maldescent was present in 100% of nitrofen-exposed fetuses on the 17th gestational day, 77% of those recovered on day 19, and 41% of those near term (21st day), whereas all control animals but 1 had "descended" gonads on all three days. Testicular volume was significantly decreased in treated fetuses on the 21st gestational day, and the mean tubular diameter was significantly decreased in all three age groups. Experimental and control animals had similar numbers of germ cells per tubule. The albuginea layer had apparently normal collagen content in all groups. These findings suggest that prenatal exposure to nitrofen interferes with both transabdominal descent of the testicle (transinguinal descent is postnatal in the rodent) and its normal development. Previous evidence and the present results authorize speculation on the possible role of nitrofen induced prenatal thyroid hypofunction in the pathogenesis of maldescent and maldevelopment in this model, since thyroid hormones act directly on Sertoli cells, which secrete mullerian inhibiting substance, which is likely responsible for transabdominal descent. PMID- 24057634 TI - Fertility and unilateral undescended testis in the rat model. AB - Fertility potential in patients with unilateral (UL) undescended testis is a debated topic. An experimental study was done in rats by surgically creating a UL undescended testis and studying its effect on their potential to father offspring when housed with female rats. No difference in fertility potential was observed in the various groups in this study. Since fertility was tested immediately after the rats became mature, it could be possible that fertility might decrease if the rats were tested in later adulthood. We conclude that experimentally created UL undescended testis does not cause damage sufficient to result in infertility in young adult rats. Also discussed is the significance of this finding in relation to UL undescended testis in humans. PMID- 24057635 TI - Regional lymphadenitis following BCG vaccination. AB - A cluster of cases of lymphadenitis occurred in Dublin following vaccination with a newly introduced Copenhagen 1331 strain of Bacille Calmette-Guerin (BCG) vaccine during 1989. All cases of BCG lymphadenitis presenting to paediatric surgical clinics over an 11-year period were reviewed to determine the optimum treatment for this problem. Seventeen patients are included, 16 of whom received vaccine in the newborn period; 1 received BCG at 8 months. Nine were treated by initial operation, 6 with antituberculous drugs, and 2 were observed without specific therapy. All but 1 of the medically treated patients and both patients who received observation only required operation for failure to resolve or progression of disease. The best results were obtained with excision and primary closure. We conclude that although sponteneous resolution occurs in a majority of all cases of BCG lymphadenitis in infants, in those patients with more severe disease who require surgical referral, a short trial of anti-microbial therapy is indicated. Patients who fail to improve or develop complications are then best treated by surgical excision of the involved nodes. PMID- 24057636 TI - Nitric oxide avoids the need for a second course of ECMO in congenital diaphragmatic hernia. AB - Inhaled nitric oxide was effectively used to avoid the need for a second course of extracorporeal membrane oxygenation (ECMO) in a neonate with a congenital diaphragmatic hernia and recurrent pulmonary hypertension following ECMO. PMID- 24057637 TI - Anomalous pancreaticobiliary ductal junction without dilatation of the choledochus. AB - A case of anomalous pancreaticobiliary ductal junction is reported in which the choledochus was not dilated but had significant histopathologic changes in its wall. This case suggests that early operative resection of the choledochus is indicated even if choledochal dilatation is minimal in order to prevent the occurrence of carcinoma in the long term. PMID- 24057638 TI - Complete pelviureteric junction obstruction following a diuretic renal scan. AB - A 13-day-old neonate with a single functioning, hydronephrotic kidney developed complete pelviureteric junction (PUJ) obstruction and anuria following a diuretic radionuclide renal scan. Urgent pyeloplasty resulted in a favourable outcome. Possible dynamics of the obstruction are discussed. Monitoring urine output after diuretic renal scans, especially in infants with a single functioning kidney and PUJ obstruction, is of paramount importance. PMID- 24057639 TI - Penile strangulation injuries. AB - Penile tourniquet injury is probably not a rare entity. Various objects can cause penile strangulation, which may lead to severe injury. Three penile strangulation injuries are presented, one due to thread and two to hair. There were urethral fistulas in two cases. All patients were circumcised and had enuresis nocturna. They were treated successfully. In enuretic patients, it should be kept in mind that there may be a strangulation that can cause penile edema or ulceration and even a urethral fistula. PMID- 24057640 TI - An unusual case of testicular ectopia. AB - A testis is termed ectopic when it lies outside the normal line of descent. A case of testicular ectopia in which the testicle was located cranial and lateral to the internal ring dorsal to the external oblique muscle is reported in a 2 month-old boy. This highly aberrant ectopic testis was treated successfully by orchiopexy; as far as we know, this is the second such case in the literature. PMID- 24057641 TI - Identification and surgical management of cystic retroperitoneal lymphangioma in children. AB - Retroperitoneal lymphangiomas are rare, benign cystic structures that are best evaluated with computed tomography and ultrasound. Preoperative diagnosis is often difficult, in part because there is little to distinguish them from other cystic masses and because the lesion is often not considered on the differential diagnosis. Surgery may be required as both a diagnostic and therapeutic measure. The cysts may be asymptomatic for years and then present because of compression of surrounding structures or pain. The treatment is as complete surgical excision as is possible. Bowel cleansing should be done preoperatively. The long-term results are excellent when total excision or near-total excision with marsupialization is accomplished. PMID- 24057642 TI - Magnetic resonance appearance in a case of lipoblastomatosis. AB - Lipoblastoma-lipoblastomatosis represents a rare, benign tumorous proliferation of adipocytes and their mesenchymal precursor cells. Seen almost exclusively in early childhood, it should be considered in the differential diagnosis of any rapidly expanding soft-tissue mass. We present a case of lipoblastomatosis and its magnetic resonance appearance, which has not been previously described. PMID- 24057643 TI - Intraoperative scrotal expansion before prosthesis insertion. AB - The use of an intraoperative sustained limited expansion (ISLE) tissue expander before placing a testicular prosthesis in a hypoplastic scrotum is described. PMID- 24057644 TI - [Complementary medicine in cancer patients under treatment in Marrakech, Morocco: a prospective study]. AB - Use of complementary and alternative medicine (CAM) is very frequent in cancer patients. The aims of this study were to analyze the frequency, the reasons of use of CAM in patients with a cancer treated in a Moroccan oncology department. We included in this study 400 patients. An anonymous questionnaire was proposed to patients during treatment. Over 384 analyzable questionnaires, 71% of patients were using CAM. The most frequent method was religious therapy (60%). The second one was herbal medicine (36%). The main reason for using CAM was reducing psychic pain in 53%, and boosting the immune system in 32%. Adverse effects were reported in 2% of cases. Only 5% of patients discussed CAM with their doctors. The cost of CAM was less than 100 Euros in 88% of cases. To optimize the patient-physician relationship and to avoid a propensity to unproved treatments, accurate and adequate communication is necessary. PMID- 24057645 TI - May non-metastatic clinically localized castration-resistant prostate cancer after primary androgen ablation benefit from salvage prostate radiotherapy? AB - PURPOSE: A proportion of patients with localized prostate cancer is still treated with primary androgen deprivation therapy (PADT) alone. Some of these patients may develop a PSA rising despite castration. The purpose of this study was to retrospectively evaluate the potential benefit of external beam radiotherapy (EBRT) in this cohort. METHODS: Forty-two patients presenting a non-metastatic castration-resistant prostate cancer after PADT were referred to our institution and underwent RT between June 2003 and July 2011. Biochemical failure (BF) after EBRT was defined according to Phoenix criteria (nadir + 2 ng/mL "at call"). Median RT dose was 78 Gy. RESULTS: Median duration of PADT was 54 months (range 10.2-181 months). Median follow-up after EBRT was 53 months. Twenty-one patients had BF after EBRT (median time 27.4 months): 13 presented with loco-regional and/or distant metastases, while in 8 patients, a PSA rise only was observed. Ten patients died of prostate cancer (and no patient died of causes other than prostate cancer). Five-year biochemical disease-free survival (bDFS), distant metastases-free survival (DMFS) and cancer-specific survival (CSS) were, respectively, 39.4, 60 and 65 %. On multivariate analysis, GS, nadir PSA (nPSA) and a pre-EBRT PSA <=5 ng/mL significantly affected bDFS, while Gleason score (GS) and T stage significantly affected distant metastases onset. No factors affected CSS at multivariate analysis. CONCLUSIONS: EBRT may be a suitable therapeutic option, able to provide an excellent loco-regional control and to obtain a systemic disease control in up to 60 % of patients at 5 years, especially in patients presenting with lower Gleason score and T stage at diagnosis and lower pre-RT PSA and nPSA post-RT. PMID- 24057646 TI - Comparison of metastatic lymph node ratio staging system with the 7th AJCC system for colorectal cancer. AB - PURPOSE: To evaluate the prognostic value and staging accuracy of the metastatic lymph node ratio (rN) staging system for colorectal cancer. METHODS: A total of 1,127 patients with colorectal cancer who underwent curative surgery between 2000 and 2011 at our institute were analyzed. Lymph nodes status was assigned according to American Joint Committee on Cancer (AJCC) pN system and rN system. Patients with colon cancer (group 1, n = 652) and rectal cancer (group 2, n = 475) were analyzed separately. RESULTS: The rN staging system was generated using 0.2 and 0.6 as the cutoff values of lymph node ratio and then compared with AJCC pN stages. Linear regression model revealed that the number of retrieved lymph node was related to number of metastatic lymph nodes. After a median follow-up of 46 months, the 5-year survival rates of patients with more than 12 lymph nodes (LNs) retrieved were better than cases with fewer than 12 LNs, while the differences were not obvious in rN classification. CONCLUSIONS: The rN category is a better prognostic tool than the AJCC pN category for colorectal cancer patients after curative surgery. PMID- 24057649 TI - Pro-senescence therapy for hepatocellular carcinoma. PMID- 24057647 TI - Effect of the tyrosine kinase inhibitor nilotinib in patients with hypereosinophilic syndrome/chronic eosinophilic leukemia: analysis of the phase 2, open-label, single-arm A2101 study. AB - PURPOSE: Hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) are characterized by sustained overproduction of eosinophils and organ dysfunction. CEL involves the presence of clonal genetic markers, such as a fusion of FIP1-like 1 protein and platelet-derived growth factor receptor alpha (FIP1L1-PDGFRalpha, or F/P) or PDGFRalpha-activating mutations. METHODS: Sixteen patients with HES/CEL were enrolled in the phase 2 nilotinib registration trial (NCT00109707) and treated with nilotinib 400 mg twice daily. The median duration of treatment was 95 days (range 3-1,079). RESULTS: Twelve patients had HES: 1 achieved a complete hematologic response (CHR), 3 achieved stable disease, 3 had progressive disease, and 5 were not evaluable for response. Four patients had CEL: 2 with the F/P fusion and 2 with PDGFRalpha-activating mutations. Both patients with an F/P fusion achieved a CHR; 1 also achieved a complete molecular response (CMR). Of the 2 patients with PDGFRalpha-activating mutations, 1 had stable disease and the other achieved CMR. At 24 months, overall survival in the HES group was 75.0 % (95 % CI 50.5-100.0) and no patients in the CEL group died. Median survival was not yet reached after a median follow-up of 32 months. The most common grade 3/4 hematologic laboratory abnormalities were lymphocytopenia (31.3 %) and neutropenia (25.0 %). The most common drug-related nonhematologic grade 3/4 adverse event was pruritus, which occurred in 2 patients (12.5 %). CONCLUSIONS: Nilotinib 400 mg twice daily was effective in some patients with HES/CEL regardless of F/P mutation status, and the safety profile was consistent with other nilotinib studies. PMID- 24057651 TI - Fe(III)-photocatalytic partial oxidation of benzyl alcohol to benzaldehyde under UV-solar simulated radiation. AB - A great deal of interest is recorded among researchers in the identification of new catalytic systems that make possible the selective oxidation of organic species in the presence of non-toxic solvents, primarily water, through the use of inexpensive catalysts. The possibility to selectively oxidize benzyl alcohol to benzaldehyde is studied in the present work by using ferric ions as homogeneous catalysts and oxygen as an oxidant under UV-solar simulated radiation. Due to the possibility that Fe(III) aquo-complex photolysis could generate undesired reactive OH radicals with the consequent occurrence of side reactions, most of the runs are carried out at pH = 0.5 at which these events have a reduced incidence. The results indicate that benzyl alcohol can be partially converted into benzaldehyde with yield and selectivity values higher than 40% and 80% respectively for the conditions adopted, with a minor occurrence of benzoic acid formation. Reaction schemes to account for the experimental observations are provided. PMID- 24057650 TI - Effects of tobacco smoke exposure in childhood on atopic diseases. AB - Although the smoking prevalence in the United States continues to decline since the Surgeon General's first report in 1964, certain vulnerable populations continue to be disproportionately affected by the adverse consequences of tobacco smoke exposure. Children are particularly vulnerable to exposure and are likely to suffer from both short- and long-term adverse consequences after early life tobacco smoke exposure. An overwhelming amount of evidence supports an association between asthma development and tobacco smoke exposure, and evidence is mounting that tobacco smoke exposure may also increase risk of IgE sensitization. This manuscript will review the effects of tobacco smoke exposure in childhood on the development of asthma and allergic sensitization, and will review practical strategies to assist motivated parents with smoking cessation. PMID- 24057652 TI - The prevalence and incidence of Parkinson's disease in China: a systematic review and meta-analysis. AB - Parkinson's disease (PD) is a chronic neurodegenerative disorder affecting older individuals. There is inconsistent evidence about the prevalence and incidence of PD in China at present. The aim of the meta-analysis was to estimate the prevalence and incidence of PD and its relation to age, gender, and stage in China. The literature search was conducted using PubMed, EMBASE, Chinese Biological Medical Literature database (CBM), Chinese National Knowledge Infrastructure database (CNKI), Chinese Wanfang and Chongqing VIP database for studies investigating the prevalence and incidence of PD in China from the commencement of the database until August 2012; both English and Chinese publications were included. We estimated the prevalence and incidence of PD using meta-analysis. Thirteen eligible articles were collected. The results showed that the pooled prevalence and incidence of PD were 2 per 100,000 population and 797 per 100,000 person-years. A higher prevalence of PD was found in males than in females (OR 1.29, 95 % CI 1.05-1.57). The prevalence of PD increased with age: the highest was 1,663 per 100,000 in those aged 80 and older. The overall prevalence of PD is lower in China than in developed countries, but the incidence is higher than in some developed countries. Overall, the prevalence of PD appears to increase with age and there are sex differences evident in Chinese individuals. PMID- 24057654 TI - Supramolecular Study on the Interaction Between Ofloxacin and Methyl beta Cyclodextrin by Fluorescence Spectroscopy and its Analytical Application. AB - The supramolecular interaction of ofloxacin (Oflo) and methyl beta-cyclodextrin (Mbeta-CD) has been examined by UV-vis, IR and fluorescence spectroscopy. The formation of inclusion complex has been confirmed based on the changes of the spectral properties. The results showed that Mbeta-CD reacted with Oflo to form an inclusion complex. The Oflo and Mbeta-CD complex formed a host-guest complex in 1:1 stoichiometry and inclusion constant (K = 7.8 * 10(-3) L mol(-1)) was ascertained by the typical double reciprocal plots. Furthermore, the thermodynamic parameters (?H degrees , ?S degrees and ?G degrees ) associated with the inclusion process were also determined. In addition, solid inclusion complex was synthesized. Based on the significant enhancement of the fluorescence intensity of Oflo produced through complex formation, a simple, accurate, rapid and highly sensitive spectrofluorometric method for the determination of Oflo in pharmaceutical formulation was developed. The measurement of relative fluorescence intensity was carried out at 497 nm with excitation at 296 nm. The factors affecting the inclusion complex formation were studied and optimized. Under the optimum reaction conditions, linear relationships with good correlation coefficients (0.9995) were in the concentration range of 50-350 ng/mL for spectrofluorimetry. The limit of detection (LOD) was 11.5 ng/mL. The proposed method was successfully applied to the analysis of Oflo in pharmaceutical preparation. PMID- 24057655 TI - Fluorescence Properties and Electrochemical Behavior of Some Schiff Bases Derived from N-Aminopyrimidine. AB - A series of Schiff bases (L 1 , L 2 and L 3) were prepared by refluxing aromatic aldehydes with N-Aminopyrimidine derivatives in methanol and ethanol. The structures of synthesized compounds were characterized by FTIR, (1)H NMR, (13)C NMR and microanalysis. The electrochemical behaviors of the Schiff base ligands were also discussed. Moreover, the evaluation of absorption and emission properties of the structures were carried out in five different solvents. The products show visible absorption maxima in the range of 304-576 nm, and emission maxima from 636 to 736 nm in all solvents tested. PMID- 24057656 TI - Anterior knee pain after total knee arthroplasty: a narrative review. AB - Anterior knee pain is one of the most common causes of persistent problems after implantation of a total knee replacement. It can occur in patients with or without patellar resurfacing. As a result of the surgical procedure itself many changes can occur which may affect the delicate interplay of the joint partners in the patello-femoral joint. Functional causes of anterior knee pain can be distinguished from mechanical causes. The functional causes concern disorders of inter- and intramuscular coordination, which can be attributed to preoperative osteoarthritis. Research about anterior knee pain has shown that not only the thigh muscles but also the hip and trunk stabilising muscles may be responsible for the development of a dynamic valgus malalignment. Dynamic valgus may be a causative factor for patellar maltracking. The mechanical causes of patello femoral problems after knee replacement can be distinguished according to whether they increase instability in the joint, increase joint pressure or whether they affect the muscular lever arms. These causes include offset errors, oversizing, rotational errors of femoral or tibial component, instability, maltracking and chondrolysis, patella baja and aseptic loosening. In these cases, reoperation or revision is often necessary. PMID- 24057657 TI - Comparison of anterior cervical fusion by titanium mesh cage versus nano hydroxyapatite/polyamide cage following single-level corpectomy. AB - PURPOSE: The titanium mesh cage (TMC) is a typical metal cage device which has been widely used in cervical reconstruction for decades. Nano hydroxyapatite/polyamide-66 (n-HA/PA66) cage is a novel biomimetic non-metal cage device growing in popularity in many medical centres in recent years. There has been no comparison of the efficacy between these two anterior reconstructing cages. The purpose of this study was to compare the radiographic and clinical outcomes of these two different devices. METHODS: Sixty-seven eligible patients with single-level ACCF using TMC or n-HA/PA66 cage for cervical degenerative diseases, with four-year minimum follow-up, were included in this prospective non randomised comparative study. Their radiographic (cage subsidence, fusion status, segmental sagittal alignment [SSA]) and clinical (VAS and JOA scales) data before surgery and at each follow-up was recorded completely. RESULTS: The fusion rate of the n-HA/PA66 group was higher than TMC at one year after surgery (94% vs. 84%) though their finial fusion rates were similar (97% vs. 94%). Finial n HA/PA66 cage subsidence was 1.5 mm with 6% of severe subsidence over three millimetres, which was significantly lower than the respective 2.9 mm and 22% of TMC (P < 0.0001). Lastly, SSA, VAS and JOA in TMC group were worse than in the n HA/PA66 group (P = 0.235, 0.034 and 0.007, respectively). CONCLUSIONS: The n HA/PA66 cage is associated with earlier radiographic fusion, less subsidence and better clinical results than TMC within four years after one-level ACCF. With the added benefit of radiolucency, the n-HA/PA66 cage may be superior to TMC in anterior cervical construction. PMID- 24057659 TI - Early visuomotor integration processes induce LTP/LTD-like plasticity in the human motor cortex. AB - To investigate whether visuomotor integration processes induce long-term potentiation (LTP) and depression (LTD)-like plasticity in the primary motor cortex (M1), we designed a new paired associative stimulation (PAS) protocol coupling left primary visual area (V1) activation achieved by hemifield visual evoked potentials (VEPs) and transcranial magnetic stimulation (TMS) over the left M1, at specific interstimulus intervals (ISIs), delivered at 1 Hz (V-PAS). Before and after V-PAS, we measured motor evoked potentials (MEPs). To clarify the mechanisms underlying V-PAS, we tested the effect of 1-Hz repetitive TMS (rTMS), 0.25-Hz V-PAS and rTMS, and a shorter 0.25-Hz V-PAS protocol. To examine V-PAS with contralateral V1 activation, we delivered V-PAS activating the right V1. To clarify whether V-PAS increases V1 activity or parieto- and premotor-to-M1 connectivity, before and after V-PAS, we examined VEPs and MEPs evoked by paired pulse techniques. V-PAS increased, decreased, or left MEPs unchanged according to the ISI used. After 1-Hz rTMS MEPs decreased. Although 0.25-Hz rTMS elicited no aftereffect, 0.25-Hz V-PAS modulated MEPs according to the ISI used. The short 0.25-Hz V-PAS protocol left MEPs unchanged. Contralateral V-PAS inhibited MEPs. After V-PAS, VEPs remained unchanged and the premotor-to-M1 inhibitory connections decreased. V-PAS induces M1 LTP/LTD-like plasticity by activating premotor-to-motor connections. PMID- 24057658 TI - Treatment strategies for the surgical complications of thoracic spinal stenosis: a retrospective analysis of two hundred and eighty three cases. AB - PURPOSE: Our aim was to investigate the causes of and treatment strategies for surgical complications of thoracic spinal stenosis. METHODS: Between May 1990 and May 2010, 283 patients with thoracic spinal stenosis were treated in our department. Three physicians were assigned to patient follow-up. Patient medical records and radiographs were reviewed. Complications were categorised as perioperative, mid- to long-term and donor-site. RESULTS: Follow-up was completed for 254 patients; 249 patients survived. Follow-up time ranged from one to 19 years, with a mean of six years and two months. There were 107 cases with complications an incidence rate of 42.1%. Eleven cases were pulmonary infection, seven transient nerve-root injury, three pulmonary injury and one vertebral canal haematoma, all of which resolved. Thirteen cases of spinal cord injury postoperatively were treated using dehydration and corticosteroid therapy; eight recovered to the preoperation level, and five deteriorated. Eleven cases resulted in dural injury, and four led to cerebrospinal fluid leakage. There were five cases of wound-fat liquefaction and one of wound infection. Seven cases with deep venous thrombosis of the lower limb resolved by elevating the affected limb and administration of low-molecular-weight dextran. Seven cases of delayed wound healing recovered following change of dressings and antibiotic administration. Four cases of delayed bone-graft fusion recovered by extending the external fixation time. One case of bone-graft absorption was treated by iliac bone grafting and bracing. Two cases of internal fixation breakage were treated by removing the internal fixation. CONCLUSIONS: Thoracic spinal stenosis surgery may result in various complications but has a good prognosis with proper treatment. The key points in reducing complications are the surgeon's familiarity with operative imperatives and the appropriate surgical approach. PMID- 24057660 TI - Intra-cardiac erosion of a pectus bar. PMID- 24057661 TI - Use of speckle strain to assess left ventricular responses to cardiotoxic chemotherapy and cardioprotection. AB - AIMS: The variability of ejection fraction (EF) poses a problem in the assessment of left ventricular (LV) function in patients receiving potentially cardiotoxic chemotherapy. We sought to use global longitudinal strain (GLS) to compare LV responses to various cardiotoxic chemotherapy regimens and to examine the response to cardioprotection with beta-blockers (BB) in patients showing subclinical myocardial damage. METHODS AND RESULTS: We studied 159 patients (49 +/- 14 year, 127 women) receiving anthracycline (group A, n = 53, 46 +/- 17 year), trastuzumab (group T, n = 61, 53 +/- 12 year), or trastuzumab after anthracyclines (group AT, n = 45, 46 +/- 9 year). LV indices [ejection fraction (EF), mitral annular systolic velocity, and GLS] were measured at baseline and follow-up (7 +/- 7 months). Patients who decreased GLS by >=11% were followed for another 6 months; initiation of BB was at the discretion of the clinician. Anthracycline dose was similar between group A and group AT (213 +/- 118 vs. 216 +/- 47 mg/m(2), P = 0.85). Although DeltaEF was similar among the groups, attenuation of GLS was the greatest in group AT (group A, 0.7 +/- 2.8% shortening; T, 1.1 +/- 2.7%; and AT, 2.0 +/- 2.3%; P = 0.003, after adjustment). Of 52 patients who decreased GLS by >=-11%, 24 were treated with BB and 28 were not. GLS improved in BB groups (from -17.6 +/- 2.3 to -19.8 +/- 2.6%, P < 0.001) but not in non-BB groups (from -18.0 +/- 2.0 to -19.0 +/- 3.0%, P = 0.08). Effects of BB were similar with all regimens. CONCLUSIONS: GLS is an effective parameter for identifying systolic dysfunction (which appears worst with combined anthracycline and trastuzumab therapy) and responds to cardioprotection in patients administered beta-blockers. PMID- 24057662 TI - The autopsy of Reinhard Heydrich. PMID- 24057663 TI - Henssge nomogram typesetting error. PMID- 24057664 TI - Using a neural network approach and time series data from an international monitoring station in the Yellow Sea for modeling marine ecosystems. AB - The international marine ecological safety monitoring demonstration station in the Yellow Sea was developed as a collaborative project between China and Russia. It is a nonprofit technical workstation designed as a facility for marine scientific research for public welfare. By undertaking long-term monitoring of the marine environment and automatic data collection, this station will provide valuable information for marine ecological protection and disaster prevention and reduction. The results of some initial research by scientists at the research station into predictive modeling of marine ecological environments and early warning are described in this paper. Marine ecological processes are influenced by many factors including hydrological and meteorological conditions, biological factors, and human activities. Consequently, it is very difficult to incorporate all these influences and their interactions in a deterministic or analysis model. A prediction model integrating a time series prediction approach with neural network nonlinear modeling is proposed for marine ecological parameters. The model explores the natural fluctuations in marine ecological parameters by learning from the latest observed data automatically, and then predicting future values of the parameter. The model is updated in a "rolling" fashion with new observed data from the monitoring station. Prediction experiments results showed that the neural network prediction model based on time series data is effective for marine ecological prediction and can be used for the development of early warning systems. PMID- 24057665 TI - Modeling hourly dissolved oxygen concentration (DO) using two different adaptive neuro-fuzzy inference systems (ANFIS): a comparative study. AB - This article presents a comparison of two adaptive neuro-fuzzy inference systems (ANFIS)-based neuro-fuzzy models applied for modeling dissolved oxygen (DO) concentration. The two models are developed using experimental data collected from the bottom (USGS station no: 420615121533601) and top (USGS station no: 420615121533600) stations at Klamath River at site KRS12a nr Rock Quarry, Oregon, USA. The input variables used for the ANFIS models are water pH, temperature, specific conductance, and sensor depth. Two ANFIS-based neuro-fuzzy systems are presented. The two neuro-fuzzy systems are: (1) grid partition-based fuzzy inference system, named ANFIS_GRID, and (2) subtractive-clustering-based fuzzy inference system, named ANFIS_SUB. In both models, 60 % of the data set was randomly assigned to the training set, 20 % to the validation set, and 20 % to the test set. The ANFIS results are compared with multiple linear regression models. The system proposed in this paper shows a novelty approach with regard to the usage of ANFIS models for DO concentration modeling. PMID- 24057666 TI - Multivariate assessment of polycyclic aromatic hydrocarbons in surface sediments of the Beijiang, a tributary of the Pearl River in Southern China. AB - To estimate the severity of polycyclic aromatic hydrocarbon (PAH) contamination in the upper sediment of the Beijiang River, 42 sediment samples were analyzed for the presence of 16 key PAHs using gas chromatography-mass spectrometry. The concentrations of PAH in the sediment ranged from 44 to 8,921 ng g(-1) dry weight. The four- to six-ring PAHs, contributing >50% to PAHs in 34 of the 42 sites, were the dominant species. Based on a principal component analysis, combined with multivariate linear regression, it became clear that the most important contributors of PAH were fossil fuel combustion (48%), diesel emissions plus oil spillage (33%), and coke combustion (19%). The surface sediments of Beijiang River were grossly contaminated by PAHs mainly derived from combustion. PMID- 24057667 TI - Mineral contents of the head, caudal, central fleshy part, and spinal columns of some fishes. AB - In the experiment, mineral contents of the head, caudal, central fleshy part, and spinal columns of fishes were determined by inductively coupled plasma atomic emission spectrometry. The Ca content of base fleshy part ranged from 1,682 to 5,505 mg/kg. The Ca contents of central fleshy part were found between 104 and 428 mg/kg. This value was found between 5,582 and 7,368 in the spinal column parts. The K content in general ranged from 2,411 (Carassius gibellio) and 4,419 mg/kg (Scomber scombrus). The highest potassium was found on the central fleshy part and ranged between 3,214 and 4,419. The P content was found mostly on the bones and it range between 28,833 and 34,726. The least phosphor amount was found on the central fleshy part. While the Cd content ranges between 0.019 ppm and 0.104 mg/kg, Cr content changed between 1.32 and 4.20 ppm. PMID- 24057668 TI - Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation. AB - RASopathies are syndromes caused by gain-of-function mutations in the Ras signaling pathway. One of these conditions, Costello syndrome (CS), is typically caused by an activating de novo germline mutation in HRAS and is characterized by a wide range of cardiac, musculoskeletal, dermatological and developmental abnormalities. We report that a majority of individuals with CS have hypo mineralization of enamel, the outer covering of teeth, and that similar defects are present in a CS mouse model. Comprehensive analysis of the mouse model revealed that ameloblasts, the cells that generate enamel, lacked polarity, and the ameloblast progenitor cells were hyperproliferative. Ras signals through two main effector cascades, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways. To determine through which pathway Ras affects enamel formation, inhibitors targeting either PI3K or MEK 1 and 2 (MEK 1/2), kinases in the MAPK pathway, were utilized. MEK1/2 inhibition rescued the hypo-mineralized enamel, normalized the ameloblast polarity defect and restored normal progenitor cell proliferation. In contrast, PI3K inhibition only corrected the progenitor cell proliferation phenotype. We demonstrate for the first time the central role of Ras signaling in enamel formation in CS individuals and present the mouse incisor as a model system to dissect the roles of the Ras effector pathways in vivo. PMID- 24057669 TI - Reversibility of neuropathology in Tay-Sachs-related diseases. AB - The GM2 gangliosidoses are progressive neurodegenerative disorders due to defects in the lysosomal beta-N-acetylhexosaminidase system. Accumulation of beta hexosaminidases A and B substrates is presumed to cause this fatal condition. An authentic mouse model of Sandhoff disease (SD) with pathological characteristics resembling those noted in infantile GM2 gangliosidosis has been described. We have shown that expression of beta-hexosaminidase by intracranial delivery of recombinant adeno-associated viral vectors to young adult SD mice can prevent many features of the disease and extends lifespan. To investigate the nature of the neurological injury in GM2 gangliosidosis and the extent of its reversibility, we have examined the evolution of disease in the SD mouse; we have moreover explored the effects of gene transfer delivered at key times during the course of the illness. Here we report greatly increased survival only when the therapeutic genes are expressed either before the disease is apparent or during its early manifestations. However, irrespective of when treatment was administered, widespread and abundant expression of beta-hexosaminidase with consequent clearance of glycoconjugates, alpha-synuclein and ubiquitinated proteins, and abrogation of inflammatory responses and neuronal loss was observed. We also show that defects in myelination occur in early life and cannot be easily resolved when treatment is given to the adult brain. These results indicate that there is a limited temporal opportunity in which function and survival can be improved-but regardless of resolution of the cardinal pathological features of GM2 gangliosidosis, a point is reached when functional deterioration and death cannot be prevented. PMID- 24057670 TI - Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia. AB - Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's rho = 0.743, P = 1.05 * 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual. PMID- 24057671 TI - Genome-wide association study of ancestry-specific TB risk in the South African Coloured population. AB - The worldwide burden of tuberculosis (TB) remains an enormous problem, and is particularly severe in the admixed South African Coloured (SAC) population residing in the Western Cape. Despite evidence from twin studies suggesting a strong genetic component to TB resistance, only a few loci have been identified to date. In this work, we conduct a genome-wide association study (GWAS), meta analysis and trans-ethnic fine mapping to attempt the replication of previously identified TB susceptibility loci. Our GWAS results confirm the WT1 chr11 susceptibility locus (rs2057178: odds ratio = 0.62, P = 2.71e(-06)) previously identified by Thye et al., but fail to replicate previously identified polymorphisms in the TLR8 gene and locus 18q11.2. Our study demonstrates that the genetic contribution to TB risk varies between continental populations, and illustrates the value of including admixed populations in studies of TB risk and other complex phenotypes. Our evaluation of local ancestry based on the real and simulated data demonstrates that case-only admixture mapping is currently impractical in multi-way admixed populations, such as the SAC, due to spurious deviations in average local ancestry generated by current local ancestry inference methods. This study provides insights into identifying disease genes and ancestry-specific disease risk in multi-way admixed populations. PMID- 24057673 TI - Genetic associations with expression for genes implicated in GWAS studies for atherosclerotic cardiovascular disease and blood phenotypes. AB - Genome-wide association studies (GWAS) have uncovered many genetic associations for cardiovascular disease (CVD). However, data are limited regarding causal genetic variants within implicated loci. We sought to identify regulatory variants (cis- and trans-eQTLs) affecting expression levels of 93 genes selected by their proximity to SNPs with significant associations in prior GWAS for CVD traits. Expression levels were measured by qRT-PCR in leukocytes from 1846 Framingham Heart Study participants. An additive genetic model was applied to 2.5 million imputed SNPs for each gene. Approximately 45% of genes (N = 38) harbored at least one cis-eSNP after a regional multiple-test adjustment. Applying a more rigorous significance threshold (P < 5 * 10(-8)), we found the expression level of 10 genes was significantly associated with more than one cis-eSNP. The top cis eSNPs for 7 of these 10 genes exhibited moderate-to-strong association with >= 1 CVD clinical phenotypes. Several eSNPs or proxy SNPs (r(2) = 1) were replicated by other eQTL studies. After adjusting for the lead GWAS SNPs for the 10 genes, expression variances explained by top cis-eSNPs were attenuated markedly for LPL, FADS2 and C6orf184, suggesting a shared genetic basis for the GWAS and expression trait. A significant association between cis-eSNPs, gene expression and lipid levels was discovered for LPL and C6orf184. In conclusion, strong cis-acting variants are localized within nearly half of the GWAS loci studied, with particularly strong evidence for a regulatory role of the top GWAS SNP for expression of LPL, FADS2 and C6orf184. PMID- 24057675 TI - Survey of otolaryngology services in Central America: need for a comprehensive intervention. AB - In the developing world, there exists a scarcity of services and training in otolaryngology, audiology, and speech therapy, which is reflected by the gap between health care delivery in high-income countries and low-income countries. We surveyed, by questionnaire, the countries of Central America, except for Belize, because of the lack of otolaryngology services, on the following issues: availability of otolaryngology, audiology, and speech therapy services and equipment; otolaryngologist, audiologist, and speech therapist training; and availability of services in rural areas. Surveys were distributed via email and by hand at the 2011 Central American Congress of Otolaryngology, in San Salvador, El Salvador, to otolaryngologists, audiologists, and speech therapists. Not to our surprise, there is a shortfall in services and training in all three professions. The data collected and presented in this commentary will provide a basis by which change might take place. PMID- 24057674 TI - Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence. AB - Previous findings have demonstrated that variants in nicotinic receptor genes are associated with nicotine, alcohol and cocaine dependence. Because of the substantial comorbidity, it has often been unclear whether a variant is associated with multiple substances or whether the association is actually with a single substance. To investigate the possible contribution of rare variants to the development of substance dependencies other than nicotine dependence, specifically alcohol and cocaine dependence, we undertook pooled sequencing of the coding regions and flanking sequence of CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 in 287 African American and 1028 European American individuals from the Collaborative Study of the Genetics of Alcoholism (COGA). All members of families for whom any individual was sequenced (2504 African Americans and 7318 European Americans) were then genotyped for all variants identified by sequencing. For each gene, we then tested for association using FamSKAT. For European Americans, we find increased DSM-IV cocaine dependence symptoms (FamSKAT P = 2 * 10(-4)) and increased DSM-IV alcohol dependence symptoms (FamSKAT P = 5 * 10(-4)) among carriers of missense variants in CHRNB3. Additionally, one variant (rs149775276; H329Y) shows association with both cocaine dependence symptoms (P = 7.4 * 10(-5), beta = 2.04) and alcohol dependence symptoms (P = 2.6 * 10(-4), beta = 2.04). For African Americans, we find decreased cocaine dependence symptoms among carriers of missense variants in CHRNA3 (FamSKAT P = 0.005). Replication in an independent sample supports the role of rare variants in CHRNB3 and alcohol dependence (P = 0.006). These are the first results to implicate rare variants in CHRNB3 or CHRNA3 in risk for alcohol dependence or cocaine dependence. PMID- 24057676 TI - Evaluating the effects of a 532-nm fiber-based KTP laser on transoral laser surgery supplies. AB - OBJECTIVE: The KTP laser has become commonplace in transoral head and neck surgery. The interactions of this laser with commonly used supplies in transoral surgery have not been formally examined. This study evaluates the effects of the KTP laser on surgical supplies. STUDY DESIGN: Experimental study. SETTING: The study was conducted in an empty operating room at a university-affiliated medical center. METHODS: An Aura XP 532-nm KTP laser with a 600-nm fiber was used in pulsed and continuous modes. The beam was focused at the shaft and balloon of 3 "laser-safe" endotracheal tubes (ETTs), a polyvinyl chloride (PVC) ETT, and a Codman surgical patty. Time to penetrate was recorded. Results The KTP laser beam was unable to penetrate any of the laser-resistant ETTs. It did react with the black number markings on the PVC ETT by producing sparks but was unable to penetrate the shaft of the ETT. The KTP laser was nonreactive with all ETT cuffs except in 1 of 3 trials with the outer balloon cuff of a Rusch Lasertubus ETT when the laser was used in a continuous mode. The KTP laser caused the production of a flame upon contact with the blue radiopaque strip of the surgical patty, even when the patty was wet. CONCLUSION: This study demonstrates that a number of safe ETT options may be used during transoral laser microsurgery with a KTP laser. In addition, Codman surgical patties are shown to be a significant fire risk in KTP laser surgery. PMID- 24057678 TI - Do life-events that obese inpatients think happened to them soon before their subjective problematic weight gain have an effect on their current psychopathology over and beyond BMI and binge eating? AB - The present study had two aims: (1) to investigate life-events that obese inpatients think happened to them during the 6 months preceding their subjective problematic weight gain and (2) to evaluate the associations of such life-events with psychopathology controlling for the effects of gender, age, BMI and binge eating in a large sample of obese inpatients referred to hospital for weight-loss treatment. The analysis used cross-sectional data on 2,900 obese adults from the hospital database. Psychopathology was assessed with the SCL-90 questionnaire, binge eating was evaluated with the Bulimic Investigatory Test, Edinburgh (BITE) and life-events were retrospectively assessed with a pre-defined self-report checklist asking patients to select the events that occurred to them in the 6 months preceding their problematic weight gain. Multivariate analysis of covariance was used to test the association between a pre-defined classification of patients according to the kind of life-events ("no event", "undefined events", "negative events" and "mixed events") with psychopathology controlling for gender, age, BMI and binge eating. The life-events factor was significantly associated with psychopathology even after adjusting for the effects of gender, age, BMI and binge eating. A significant linear trend was evident so that obese patients who reported both negative and undefined events or only negative events had higher levels of psychopathology than patients reporting only undefined events or no event. Though these findings should be considered with caution due to the subjective recall of problematic weight gain and the retrospective assessment of life-events, future studies investigating the link between obesity and psychopathology should not ignore the role of negative life-events that obese patients think happened to them before weight gain. PMID- 24057679 TI - Stereotypical images and implicit weight bias in overweight/obese people. AB - PURPOSE: In this brief report, an unanswered question in implicit weight bias research is addressed: Is weight bias stronger when obese and thin people are pictured engaging in stereotype consistent behaviors (e.g., obese-watching TV/eating junk food; thin-exercising/eating healthy) as opposed to the converse? METHODS: Implicit Associations Test (IAT) data were collected from two samples of overweight/obese adults participating in weight loss treatment. Both samples completed two IATs. In one IAT, obese and thin people were pictured engaging in stereotype consistent behaviors (e.g., obese-watching TV/eating junk food; thin exercising/eating healthy). In the second IAT, obese and thin people were pictured engaging in stereotype inconsistent behaviors (e.g., obese exercising/eating healthy; thin-watching TV/eating junk food). RESULTS: Implicit weight bias was evident regardless of whether participants viewed stereotype consistent or inconsistent pictures. However, implicit bias was significantly stronger for stereotype consistent compared to stereotype inconsistent images. CONCLUSION: Implicit anti-fat attitudes may be connected to the way in which people with obesity are portrayed. PMID- 24057680 TI - A pilot study of blood epinephrine levels and CREB phosphorylation in men undergoing prostate biopsies. AB - PURPOSE: In mouse models of prostate cancer, increased epinephrine levels accelerated tumor growth via the beta2-adrenoreceptor/PKA signaling pathway. It is unknown, however, whether men experience increased epinephrine levels sufficient to activate the beta2-adrenoreceptor/PKA pathway in the prostate gland. We measured epinephrine levels in blood samples collected immediately prior to prostate biopsies and measured phosphorylation of S133CREB (PKA site), S112BAD, T202/Y204ERK, and S473 Akt in prostate biopsy tissue samples. METHODS: Tissue samples and 3 ml of blood were obtained from men (n = 20) recruited from the patients scheduled for prostate biopsies. Epinephrine levels were measured by ELISA. Proteins were extracted from biopsied tissue, and protein phosphorylation was measured by Western blotting with phospho-specific antibodies. Pearson and Spearman's rank correlations were analyzed to assess relationships between blood epinephrine levels and phosphorylation of CREB, BAD, AKT, and ERK. RESULTS: Epinephrine levels above 1 nM were detected in 5 of 20 patients. A strong positive correlation was observed between increased epinephrine levels and CREB phosphorylation. In contrast, no correlation was observed between epinephrine levels and phosphorylation of ERK, BAD, or AKT. CONCLUSION: Our results suggest that increased blood epinephrine levels activate the beta2-adrenoreceptor/PKA signaling pathway in human prostate glands. These results will inform future studies to examine whether beta2-selective blockers can inhibit activation of the epinephrine/ADRB2/PKA pathway in prostate tumors of men with increased epinephrine levels and explore the use of beta2-selective blockers as adjuvant therapy for prostate cancer. PMID- 24057672 TI - Genetic comorbidities in Parkinson's disease. AB - Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain. PMID- 24057681 TI - A comparison of epididymectomy with vasectomy reversal for the surgical treatment of postvasectomy pain syndrome. AB - PURPOSE: To compare the outcome of epididymectomy and vasectomy reversal (VR) in patients with postvasectomy pain syndrome (PVPS) who required surgical treatment. METHODS: A total of 50 patients with PVPS who underwent epididymectomy or VR between January 2000 and January 2010 were included retrospectively. Of these, 36 (72.0%) patients completed the study questionnaire. These 36 patients completed the questionnaire either during attendance at the outpatient clinic or during a telephone interview. Twenty patients (22 cases) underwent epididymectomy, and sixteen patients (17 cases) underwent VR. Analyses were performed for (1) preoperative clinical findings, (2) preoperative and postoperative visual analogue pain scale (VAPS) scores, (3) patency and pregnancy rate in VR group, and (4) patient satisfaction with surgical treatment. RESULTS: The mean age was 48.28 +/- 11.27 years, and the mean period of follow-up was 3.58 years (0.15 10.03). The mean VAPS score was 6.78 +/- 0.93 preoperatively and 1.13 +/- 0.72 postoperatively (p < 0.001). The difference in the mean preoperative and postoperative VAPS scores was 6.00 +/- 1.34 (3-8) in the epididymectomy group and 5.50 +/- 1.03 (4-8) in the VR group. However, this difference was not statistically significant (p = 0.227). No significant difference in satisfaction with surgical outcome was observed between the epididymectomy and the VR groups (p = 0.124). CONCLUSIONS: In PVPS patients requiring surgical treatment, no significant difference was observed between the epididymectomy and VR groups in either the reduction in pain or the degree of patient satisfaction with surgical outcome. Selection of the optimal surgical procedure may be dependent on specific patient characteristics. PMID- 24057682 TI - Survival of incident patients on high-volume online hemodiafiltration compared to low-volume online hemodiafiltration and high-flux hemodialysis. AB - BACKGROUND: Hemodiafiltration is becoming a preferred treatment modality for dialysis patients in many countries. The volume of substitution fluid delivered has been indicated as an independent mortality risk factor. The aim of this study is to compare patient survival on three different treatment modalities: high-flux hemodialysis, low-volume online HDF (oHDF) and high-volume oHDF. METHODS: Incident hemodialysis and oHDF patients treated in 13 NephroCare centers in Bosnia and Herzegovina, Serbia and Slovenia between January 1, 2007, and December 31, 2011, were included in this epidemiological cohort study. High-volume oHDF was defined as substitution volume higher than the median substitution volume infused, otherwise low-volume. Main predictor was treatment modality at baseline and in time-dependent model. Other predictors were age, gender, diabetes mellitus, cerebrovascular accident, arrhythmia, hemoglobin and C-reactive protein. RESULTS: Four hundred and forty-two patients were included in the study. Median substitution fluid volume was 20.4 L. Mean difference between the oHDF groups in substitution fluid volume was 8.3 +/- 5.2 L [95 % confidence intervals (95 % CI) 7.1-9.5, p < 0.0001]. The unadjusted hazard ratios (HR) with 95 % CI compared to high-flux HD were 0.87 (0.5-1.5) for low-volume oHDF and 0.29 (0.13 0.63) for high-volume oHDF. After the adjustment for covariates, the HR for patients on low-volume oHDF remained statistically insignificant compared to high flux HD (0.84; 95 % CI 0.46-1.53), while patients on high-volume oHDF showed a marked and significantly lower HR (0.29; 95 % CI 0.13-0.68) than patients on high flux HD in baseline model. While this effect failed to reach significance in the time-dependent model (HR 0.477; 95 % CI 0.196-1.161), possibly due to an inadequate sample size here, the consistency of results in both models supports the robustness of the findings. After switching from high-flux hemodialysis to oHDF, mean hemoglobin and albumin levels did not change significantly. Mean erythropoietin resistance index (ERI) and erythropoiesis stimulating agents (ESA) consumption decreased significantly (p = 0.02, p = 0.03, respectively). CONCLUSIONS: The median substitution volume used in these three countries for post-dilutional oHDF is 20.4 L. oHDF is associated with significant reductions in ERI and ESA consumption. Only high-volume oHDF is associated with improved survival compared to high-flux hemodialysis. PMID- 24057683 TI - Influence of the lysine on the calcium oxalate renal calculi. AB - Plasma levels and urinary excretions of amino acid lysine were estimated by high performance liquid chromatography in 15 control subjects and 56 stone formers (SFs) with calcium oxalate (CaOX) urolithiasis. Data demonstrated clearly that there is a general tendency toward decreased lysine's excretions in above 40% of SFs. Moreover, it was found that DL-lysine, a normal physiological constituent of urine, acts at increased concentrations as a dissolving agent with respect to CaOX and CaOX calculi. The kinetics of dissolution of crystalline calcium oxalate calculi in physiological solutions containing DL-lysine at different concentrations is studied, using the change in the Archimedean weight of samples immersed in the solution. The possible effect of lysine as a natural regulator of CaOX supersaturation and crystallization in human urine is also discussed. PMID- 24057684 TI - The impact of tumor size on outcomes in patients with upper urinary tract urothelial carcinoma. AB - PURPOSE: To investigate the association between tumor size and clinicopathologic factors and outcomes of upper urinary tract urothelial carcinoma (UTUC) in patients treated surgically for UTUC. METHODS: A single-center series of 235 consecutive patients who were treated surgically for UTUC between January 1999 and December 2011 was evaluated. Patients with a history of muscle-invasive urothelial carcinoma of the urinary bladder, those who received neoadjuvant therapies, and those with previous contralateral UTUC were excluded. Bladder-only recurrence, any recurrence, and cancer-specific mortality after surgery were analyzed. Recurrence-free probabilities and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method and Cox regression analyses. RESULTS: Tumor size was significantly associated with age of the patient (P = 0.001), tumor location (P < 0.0001), tumor multifocality (P = 0.005), higher tumor stage (P < 0.0001), higher tumor grade (P = 0.038), lymphovascular invasion (P = 0.002), and mode of operation (P = 0.001). Tumor size was not associated with bladder-only recurrence (HR 0.91; 95% CI 0.46-1.80; P = 0.79). The Kaplan-Meier method showed that tumor size >3 cm was significantly associated with worse CSS (P = 0.006, log rank). The 5-year CSS for patients with tumor size <= 3 cm was 70.1% and for patients with tumor size >3 cm was 56.1%. Tumor size was not associated with cancer-specific survival in multivariable analysis (HR 1.53; 95% CI 0.89-2.61; P = 0.12). CONCLUSIONS: Tumor size >3 cm was associated with a lower 5-year CSS at Kaplan-Meier analysis, but was not an independent predictor of CSS, bladder-only recurrence, and any recurrence-free survival at multivariable analysis. PMID- 24057685 TI - A short story of Klotho and FGF23: a deuce of dark side or the savior? AB - Fibroblast growth factor 23 (FGF23) is an osteocyte and osteoblast derived peptide hormone, which requires Klotho as a cofactor for its biologic actions. FGF23 acts as a phosphaturic agent and it is capable of reducing serum inorganic phosphate (Pi) via direct inhibition of renal NaPi-2a transporter in the proximal tubuli, as well as indirectly, via the suppression of calcitriol synthesis. In patients with chronic kidney disease (CKD), circulating FGF23 levels are markedly elevated, while Klotho production is decreased. Experimental observations indicating that lack of activities of both Klotho and FGF23 may cause decreased life span, premature aging and accelerated atherosclerosis and generalized vascular calcifications have raised the question whether FGF23 could be a new risk factor and predictor of cardiovascular (CV) disease in both renal and non renal patient groups. Clinical studies, however, have yielded conflicting results. Some of these studies have found that serum FGF23 is independently associated with mortality and CV events in CKD patients, while others have failed to show any relationship. Furthermore, some studies have even suggested that FGF23 may have a protective role against vascular calcifications and CV disease. Thus, there is clearly a need for further research in this area, and special interest should be paid to the physiologic consequences of high FGF23/low Klotho state, which is typical for patients with CKD. PMID- 24057687 TI - Performance of the Lausanne questionnaire and the 2010 European Society of Cardiology criteria for ECG interpretation in athletes. AB - BACKGROUND: In recent years various proposals and subsequent changes have been made to improve pre-participation screening (PPS) methods. This study examines the Lausanne questionnaire and the old and new ESC criteria for a positive electrocardiogram (ECG) in athletes. DESIGN: Retrospective cohort study. METHODS: All consecutive students undergoing a PPS between January and July 2011 were included. The screening consisted of the Lausanne questionnaire, a physical examination, and a 12-lead ECG. RESULTS: A total of 561 students were screened. A total of 310 students (55%) answered positively to one or more of the Lausanne questions and 49 (9%) of these abnormalities were assessed as medically relevant. Physical examination was abnormal in nine (1.6%) students. In total, 120 (21%) ECGs were found positive following the old criteria. According to the new criteria, 68 (12%) ECGs were found positive. Four (already known) congenital cardiac disorders and four new diagnoses were found. When using the new ECG criteria, two out of four new cardiovascular diagnoses would have been missed. CONCLUSIONS: The use of the Lausanne questionnaire provides many irrelevant findings causing unnecessary positive screening outcomes. With the new ESC criteria for a positive 12-lead ECG in athletes, the number of false-positive screenings greatly decrease: however, at the cost of an increase in the number of false-negatives. To reach a conclusive judgment on the cost:benefit ratio of PPS, it is necessary to have a validated discriminating questionnaire, specific medical knowledge of PPS and clear definitions of a normal and abnormal 12-lead ECG in athletes. PMID- 24057686 TI - Exercise training is safe after coronary stenting: a prospective multicentre study. AB - BACKGROUND: Data on the safety of exercise training after coronary stenting are scarce. DESIGN: This is a prospective cohort study of 3132 patients with coronary stenting within the last 12 months, recruited by 44 cardiac rehabilitation centres; patients were included in a cardiac rehabilitation programme with training sessions 3-5 days a week. Cardiac rehabilitation was defined as early rehabilitation when starting <1 month after coronary stenting and as late rehabilitation when starting later. METHODS: Rate of acute coronary syndrome (ACS) after coronary stenting was estimated according to time to training session. ACS was defined as related to exercise when it occurs during or within the hour after an exercise stress test or a training session. All ACS were documented by an angiographic control. RESULTS: Overall 5016 stents (41.4% drug eluting stents) were implanted in 3132 patients aged 56.5 +/- 12.9 years (84.7% men) with a median of 1 stent (range 1-8) per patient. Indication of coronary senting was ACS (86.4%), angina pectoris (8.6%), and silent ischaemia (5%). Combined antiplatelet treatment was used in 97.2% of the patients. Overall rate of ACS after coronary stenting was 2.9/1000 patients, corresponding to 1.7 complications out of 10(6) patient-hours of exercise. There were four stent thromboses related to exercise (1.2/1000 patients, 0.8/10(6) patient-hours of exercise): two in the early rehabilitation group (days 9 and 11), and two in the late rehabilitation group (days 77 and 228). CONCLUSIONS: Exercise training seems safe and there is no justification to delay cardiac rehabilitation after coronary stenting. PMID- 24057689 TI - Treatment of distal fingertip degloving injuries using a cross-finger flap based on the dorsal branch of the proper digital artery at the middle phalanx. AB - This study reports our experience with reconstruction of distal fingertip degloving injuries using a single cross-finger flap based on the dorsal branch of the proper digital artery at the middle phalanx. From January 2009 to October 2011, 18 patients (18 fingers) presented with distal fingertip degloving injuries and were treated with this technique. The mean size of the soft tissue defects was 4.5 cm in length and 2.0 cm in width. The mean size of the cross-finger flaps was 4.7 * 2.1 cm. In the series, all flaps survived completely. No complication was reported, and no further flap debunking procedure was required. At the mean follow-up period of 20.5 months (range, 12-48 mo), the mean static two-point discrimination was 6.3 mm (range, 5-9 mm) of the reconstructed finger pulp. The total range of active motion of the proximal and the distal interphalangeal joints of the donor fingers were 105 and 77.4 degrees, respectively. The cross finger flap based on the dorsal branch of the proper digital artery at the middle phalanx is a reliable and simple method in reconstruction of distal degloving injuries of the finger. PMID- 24057688 TI - Systematic echocardiography is not efficacious when screening an ethnically diverse cohort of athletes in West Asia. AB - BACKGROUND: The clinical and economic value of including systematic echocardiography (ECHO) alongside the 12-lead electrocardiograpm (ECG) when undertaking pre-participation screening in athletes has not been examined, yet several sporting organistations recommend its inclusion. DESIGN: To examine the efficacy of systematic ECHO alongside the ECG, to identify sudden cardiac death (SCD) disease and to provide a cost-analysis of a government-funded pre participation screening programme. METHODS: A total 1628 athletes presented for cardiological consultation, ECG, and ECHO as standard, with further cardiac examinations performed if necessary to confirm or exclude pathology. The efficacy of systematic ECHO was compared to an ECG-led programme, with ECHO reserved as a follow-up examination. RESULTS: To screen 1628 athletes with ECG and ECHO cost US$743,996. There were 54 24-h-blood pressure/ECG Holter recordings, 62 exercise tests, 25 CMRs, two electrophysiological studies, and two genetic tests, which cost US$67,734: total US$811,730. Eight athletes (0.5%) were identified with hypertrophic cardiomyopathy (HCM) and two (0.1%) with Wolff-Parkinson-White syndrome. The cost per identifed athlete was US$81,173. All 10 athletes presented an abnormal ECG. No athlete diagnosed with HCM was identified by ECHO in isolation. When adopting a ECG-led screening protocol, 15% of athletes required ECHO as a follow-up examination, resulting in a US$380,600 cost reduction (47% saving), with the cost per diagnosis reduced to US$43,113. CONCLUSIONS: Athletes diagnosed with a disease associated with SCD were identified via an abnormal ECG and/or physical examination, personal symptoms, or family history. Screening athletes with systematic ECHO is not economically or clinically effective. PMID- 24057690 TI - Standardized templates for shaping the fibula free flap in mandible reconstruction. AB - Conversion of the straight fibula bone flap into the parabolic mandible shape can be performed using customized acrylic templates made from a 1:1 mandible computed tomography scan and lateral cephalogram. The premise of the current study is to objectively quantify the variability in a series of acrylic templates used for mandible reconstruction to assess the feasibility of creating a standardized template.In this study acrylic templates of 48 consecutive adult dentate patients who underwent fibula flap mandible reconstruction from 1994 to 1999 were evaluated. Osteotomy angles for the mandibular angle, midbody and parasymphysis, and length of each bony segment were determined using a metric ruler and protractor. Values were reported as means +/- standard deviation.The mean mandibular angle measured 122.6 +/- 6.4 degrees, while the midbody and parasymphysis angles were 153 +/- 4.5 degrees and 130 +/- 4.2 degrees, respectively. Mean bone segment lengths were: ramus 64.5 +/- 9.8 mm, distal body 47.6 +/- 4.2 mm, mesial body 40.6 +/- 3.2 mm, and symphysis 18.5 +/- 2.2 mm.It was concluded that the evaluation of patient acrylic templates used in a series of mandible reconstructions demonstrates osteotomy angles vary minimally (3-5%). Bone segment lengths vary from 10 to 15%, suggesting heterogeneity in mandible size. A standard template can be used to shape the fibula in most mandible reconstructions eliminating the need for routine preoperative imaging or costly fabricated computer-aided design/computer-aided manufacturing cutting guides. PMID- 24057691 TI - Knowledge and awareness of prostate cancer among the general public in Burkina Faso. AB - The lack of awareness about prostate cancer and other prostate-related issues has been identified as a cause of low survival and higher mortality rates among black men. The aim of this study is to assess the knowledge of prostate cancer (PCa) among men in the general public, in the main city of Burkina Faso (Ouagadougou). The targeted population was black African men aged 25 years and older, with no history of PCa. Six hundred men who provided informed consent were invited to participate in a PCa knowledge questionnaire through face-to-face interviews. The questionnaire was composed of multiple-choice items designed to ascertain participant's characteristics (age, profession, and level of education) and knowledge of prostate and PCa (risk factors, diagnosis tests, and curative treatments). The average age of men was 42 (min 25, max 80), and 63% reported primary school or less. Sixty-two percent admitted they did not know the terms prostate and prostate cancer. Only two respondents (0.3%) cited race as a risk factor, when 90 (15%) perceived too much sexual activity as a risk factor. A majority of respondents (70.3%, n = 422) stated that they were unaware of any diagnosis tests for PCa. The level of education was strongly correlated with PCa knowledge (p < 0.001). Men in the city of Ouagadougou have poor knowledge of PCa. Educational interventions should target the entire populations to improve self informed decision about early diagnostic possibilities of PCa. PMID- 24057692 TI - Advantages of wordless instructions on how to complete a fecal immunochemical test: lessons from patient advisory council members of a federally qualified health center. AB - Some patients face difficulty understanding instructions for completing the fecal immunochemical test (FIT), a self-administered test to screen for colorectal cancer. We sought to develop and test low-literacy instructions for completing the FIT. Working in partnership with a Latino-serving Federally Qualified Health Center (FQHC) in the Portland Metro area, we developed and tested low-literacy instructions for completing the FIT; the instructions contained seven words (mail within 3 days; Devolver dentro de 3 dias). We conducted focus groups of Spanish speaking patients on the advisory council of our partnering FQHC organization, and we gathered feedback from the project's advisory board members and clinic staff. We mailed a FIT kit to each patient, along with either (a) instructions written in English and Spanish, consisting of 415 words; or (b) low-literacy "wordless" instructions. We asked patients to complete the test before providing feedback. Our qualitative assessment showed that the wordless instructions were preferred over instructions consisting of words. Wordless instructions might aid efforts to raise the rates of colorectal cancer screening among low-literacy and non-English-speaking populations. PMID- 24057693 TI - Iron deficiency and cardiovascular disease: an updated review of the evidence. AB - Body iron status has been suggested to be related to the development of cardiovascular disease (CVD). Biologically plausible mechanisms for this association have been described, however epidemiological studies on iron status and CVD risk have provided conflicting results. The lack of consistency is likely explained by differences in the study design, the measures used for the assessment of iron status, the definition of outcomes, and adjustment for confounders. To help clarify the available evidence, we report a systematic review of published cross-sectional, longitudinal, and intervention studies evaluating the relationship between different measures of iron status and CVD risk. The most likely scenario that emerges from the available studies is that, in the reference range, iron status has a neutral effect. Extreme conditions of iron deficiency, as well as of iron overload, are associated with modestly increased CVD risk, although with different proposed mechanisms. PMID- 24057694 TI - Glyconanoparticles for the plasmonic detection and discrimination between human and avian influenza virus. AB - A plasmonic bioassay for the specific detection of human influenza virus has been developed based on gold nanoparticles functionalised with a designed and synthesised thiolated trivalent alpha2,6-thio-linked sialic acid derivative. The glyconanoparticles consist of the thiolated trivalent alpha2,6-thio-linked sialic acid derivative and a thiolated polyethylene glycol (PEG) derivative self assembled onto the gold surface. Varying ratios of the trivalent alpha2,6-thio linked sialic acid ligand and the PEG ligand were used; a ratio of 25:75 was found to be optimum for the detection of human influenza virus X31 (H3N2). In the presence of the influenza virus a solution of the glyconanoparticles aggregate following the binding of the trivalent alpha2,6-thio-linked sialic acid ligand to the haemagglutinin on the surface of the virus. The aggregation of the glycoparticles with the influenza virus induces a colour change of the solution within 30 min. Non-purified influenza virus in allantoic fluid was successfully detected using the functionalised glyconanoparticles. A comparison between the trivalent and a monovalent alpha2,6-thio-linked sialic acid functionalised nanoparticles confirmed that more rapid results, with greater sensitivity, were achieved using the trivalent ligand for the detection of the X31 virus. Importantly, the glyconanoparticles were able to discriminate between human (alpha2,6 binding) and avian (alpha2,3 binding) RG14 (H5N1) influenza virus highlighting the binding specificity of the trivalent alpha2,6-thio-linked sialic acid ligand. PMID- 24057696 TI - Factors affecting the drinking behavior of black howler monkeys (Alouatta pigra). AB - Water is essential for animals, and is particularly critical for thermoregulation. Animals obtain water from three main sources, free water, water contained in food, and water produced in the body during metabolism. Howler monkeys (Alouatta spp.) spend a small proportion of their time drinking water and some populations have not been observed drinking, suggesting they obtain most of their water requirements in food or by metabolism. However, when howler monkeys have been observed drinking there is evidence suggesting the drinking is associated with low precipitation, temperature, and fruit consumption, and high mature leaf consumption, although it remains unclear which factors determine drinking by this genus. In this study we tested the hypothesis that drinking by howler monkeys results from increased hydration requirements in drier climates and from lower consumption of foods rich in water (e.g., new leaves, fruit). We tested this hypothesis by comparative analysis of 14 groups of Yucatan black howler monkeys (A. pigra) living under different climatic conditions. From April 2005 to November 2008 we collected a total of 3,747.2 focal observation hours of the feeding and drinking behavior of 60 individuals, with data on ambient temperature and rainfall. Individuals spent more time drinking when they lived in habitats with higher maximum temperature and when they consumed more mature leaves. For this species, therefore, drinking seems to be linked to heat stress and a low availability of water in ingested food. PMID- 24057695 TI - A combination of praziquantel and the traditional medicinal plant Thunbergia laurifolia on Opisthorchis viverrini infection and cholangiocarcinoma in a hamster model. AB - Cholangiocarcinoma (CCA) associated by Opisthorchis viverrini remains a health problem in Southeast Asia including Thailand. At present, there is still no efficient treatment for CCA. Thunbergia laurifolia is a traditionally used medicinal plant; its aqueous leave extract possesses the antioxidant activity and anti-inflammatory on hamster opisthorchiasis had been reported previously. Here, we demonstrate the combined effects of the T. laurifolia extract plus antihelminthic drug, praziquantel (PZ) on hamsters with opisthorchiasis and hamsters with opisthorchiasis related-cholangiocarcinoma through light microscopic observations of histopathological changes, as well as liver function tests for alanine transaminase (ALT) and alkaline phosphatase, and kidney function tests for blood urea nitrogen and creatinine. Results showed T. laurifolia extract combined with praziquantel reduced inflammatory cell aggregation and inhibiting CCA development, which were correlated to the serum ALT level. These present studies suggest that administration of T. laurifolia after praziquantel treatment clearly improve the hepatobiliary system and could reduce the risk of subsequent CCA development in human. PMID- 24057697 TI - Hemangioma and vascular malformations : Editorial. PMID- 24057698 TI - Vascular cutaneous anomalies in children: malformations and hemangiomas. AB - The vast majority of cutaneous vascular anomalies in infants and children are either malformations or hemangiomas. Vascular malformations are subgrouped, based on channel morphology and rheology: slow-flow (capillary, lymphatic, venous, or combined-complex types) and fast-flow malformations (ectasia, aneurysm, fistula, or arteriovenous anomalies). Noninvasive radiologic techniques, especially ultrasonography with Doppler flow studies and magnetic resonance imaging, serve to document the extent and flow characteristics. Management depends on the type of malformation: laser for capillary malformations; surgical excision for lymphatic malformations; compression, sclerotherapy, and resection for venous malformations; and embolization and/or surgical resection for arteriovenous fistulae/malformations. Hemangiomas are the most common tumors of infancy. The life cycle is divided into three phases: proliferating, involuting, and involuted. Most hemangiomas do not require treatment, although drug therapy is indicated for endangering or life-threatening hemangiomas. Corticosteroids (either systemic or local) and alpha-2a interferon are currently the most effective agents. Surgical resection of problematic hemangiomas can be undertaken during infancy, the preschool years, or childhood. PMID- 24057699 TI - Vascular malformations: a review of 10 years' management in a university hospital. AB - In order to gain insight into the management of patients with vascular malformations (VM) in the University Hospital Nijmegen in the past 10 years, 151 cases managed by different specialists were reviewed. To avoid the usual confusion in terminology, all recorded diagnoses were reclassified according to the biological classification of Mulliken. The sex distribution was equal; 79% of the malformations were diagnosed at birth or in the 1st year of life. The median time between presentation and consultation was 3 years. Sixty-two lymphatic, 26 venous, 24 capillary, 1 arterial, and 38 combined malformations (8 arteriovenous, 30 others) were found. The head and neck region was most frequently involved, followed by the lower and upper limbs and trunk. The pediatric surgeon was the most frequently consulted specialist. Confusing, mutually incompatible terminology and a wide variety of different diagnostic techniques and treatments had been used by the different specialists. To improve the management of patients with vascular malformations, the use of a uniform classification, an increase in basic investigations, and the development and evaluation of protocols for diagnosis and treatment by multidisciplinary teams are necessary. PMID- 24057700 TI - Laser options for vascular lesions in childhood. AB - To determine which laser can be used for a vascular lesion, the different working mechanisms of the individual lasers must first be understood. The localization and diameter of the vessels to be treated define whether a certain laser is appropriate for that lesion. For teleangiectasias and port-wine stains the pulsed dye laser works without scarring. Hemangiomas respond only when flat and superficial. Deeper lesions can only be reached with the ND-Yag laser. PMID- 24057701 TI - The current management of cervico-cephalic venous malformations. AB - Venous malformations are often detected at birth and progressively increase in size if not treated. They can have severe aesthetic and functional consequences. Our purpose is to evaluate therapeutic results with Ethibloc. From 1982 to 1994, we have been using Ethibloc injections under fluoroscopic control in a group of 421 patients with malformations in cervicofacial veins. The diagnosis was made on the basis of clinical examinations as well as by using CT and MRI. In addition, 40 patients had a diagnostic angiogram. The therapeutic procedure consisted of direct puncture and opacification of venous the basis of lakes before injection of Ethibloc. Two hundred patients have been analyzed. In 139 patients treated with Ethibloc alone, the venous malformations were reduced significantly in size in 64%, while we obtained good results in 67% of the 61 patients treated with a combined procedure (Ethibloc followed by surgical excision). In those, Ethibloc effectively prevented extensive blood loss during surgery and delineated the malformations. Minor complications occurred such as fever or aseptic superficial abscesses. Ethibloc is safe, has no neurotoxicity, is efficient can be repeated many times and facilitates surgery. It must be used as the therapy of choice in venous malformations. PMID- 24057702 TI - Surgical treatment of hemangiomas and vascular malformations in functional areas. AB - Hemangiomas and vascular malformations (VM) in functional areas can be treated by a variety of methods. Because of the natural involution of hemangiomas, a non agressive approach is recommended. Active therapy is necessary only in cases where a function is affected such as vision, respiration, hearing, and feeding. Psychological problems can be an indication for early excision, and psychological/cosmetic reasons in the presence of fibrofatty tissue residues when the hemangioma has been involuted for late excision. In contrast to hemangiomas, no involution is to be expected for VMs, so that therapy depends mainly on the occurrence of functional problems and/or serious complications. Surgical excision still has a place, however, the indications are limited. PMID- 24057704 TI - Aspiration of pins : A hazard of tradition in Oman. AB - Forty-six patients were admitted over a 3-year period after having inhaled a pin; 43 were females in the age range 8-17 years. Most of the patients had only minimal symptoms; only 2 presented with respiratory infections. Aspiration into the left bronchial tree occurred in 22 patients and into the right in 15. Extraction by means of rigid bronchoscopy was succesful in 40 patients (87%) while 6 (13%) required a thoracotomy. PMID- 24057703 TI - Factors contributing to poor results of treatment of esophageal atresia in developing countries. AB - The results of treatment of 341 consecutive cases of esophageal atresia/tracheoesophageal fistula over an 11-year period have been analyzed to determine the factors resulting in a poorer prognosis of these cases in a developing country; 121 neonates in the first 6-year period are compared with 220 in the last 5 years. In the latter group only 8% were in Waterston's group A; 46% reached the hospital within 24 h of birth, 13% were normothermic on presentation, 70% had a chest infection, and 28% had major associated malformations. This was similar to the preceding 6-year period. In the last 5 years the overall mortality was 58%, compared to 67% in the preceding 6 years. Despite improvement in survival in the last 5 years, the overall survival is far inferior to that reported from the developed countries. The factors resulting in poorer results have been analyzed and remedial actions suggested. PMID- 24057705 TI - Histopathology of bile ducts in F1 rats hybridized from parents with different major histocompatibility antigens, undergoing inoculation with maternal strain lymphocytes during the fetal period. AB - In 1979, Seemayer suggested that biliary atresia (BA) might represent maternal or postnatally induced graft-versus-host reactions in which the liver is the principal target for aggressor lymphocytes. We attempted to produce perinatal graft-versus-host disease (GVHD) models to clarify the causal relationship between BA and GVHD. F1 rats were hybridized from parents with different major histocompatibility antigens: inbred strain maternal Lewis (LEW) and paternal Brown Norway (BN). F1 hybrid rats between 16 and 18 days' gestational age (term: 21 days) were given a single intrahepatic inoculation of mixed lymphocytes (1 * 10(7)/ml) from spleen and peripheral blood of female LEW rats. Forty-seven (25.6%) of 184 F1 hybrid rats receiving lymphocyte inoculation were born alive. They were killed immediately after birth or between 1 and 65 days of age for histologic examination. Abnormalities of the intrahepatic bile ducts were noted in 16 (84.2%) of 19 rats, while 3 (60%) of 5 showed abnormalities of the extrahepatic bile ducts. Main histological features involved periductal lymphoid cell infiltration and intraepithelial lymphoid cell invasion as well as epithelial degeneration. The histologic changes corresponded to those in GVHD, and furthermore showed common findings observed in BA. PMID- 24057707 TI - Management of traumatic pancreatic pseudocysts in children. AB - Eight children with pancreatic injuries after blunt abdominal trauma are presented. One patient with pancreatitis without complications was treated successfully with medication; seven (87.5%) developed pseudocysts, which resolved spontaneously with conservative treatment in four cases (57.1%). Non-resolving pseudocysts in 3 patients finally required surgical intervention. Pseudocysts that resolve spontaneously and those that require surgical intervention can be distinguished. The two groups showed different time sequences in both serum amylase values and pseudocyst size. Analyses of these clinical data revealed three factors with significant predictive value. On the basis of these findings, a new management strategy for traumatic pancreatic pseudocysts in children is proposed. The cyst is likely to resolve spontaneously in cases showing any two or more of the following factors: (1) cyst presentation after day 6; (2) maximum serum amylase below 1,600 IU/l; and (3) serum amylase below 600 IU/l on day 20. However, early surgical intervention is required in the presence of two or more of the following: (1) cyst presentation before day 4; (2) maximum serum amylase above 1,900 IU/l; or (3) serum amylase above 1,200 IU/l on day 20. PMID- 24057706 TI - Bacterial translocation in chronic portal hypertensive and common bile duct ligated growing rats. AB - Spontaneous bacteremias and infectious complications occur in patients with chronic portal hypertension (PH) and obstructive jaundice, and most of these infections are caused by indigenous intestinal bacteria translocating to regional lymph nodes and the systemic circulation. The aim of this study was to investigate bacterial translocation (BT) at two stages: (1) isolated chronic PH; and (2) obstructive jaundice. Four-week-old male rats were either subjected to sham laparotomy (SL) or to pH or common bile duct ligation (CBDL). After 4 weeks, animals were weighed and the portal pressure was measured. Samples from the portal vein (PV), vena cava, liver, spleen, mesenteric lymph nodes (MLN), and ileum were obtained for bacteriologic cultures. Specimens from the liver, jejunum, and ileum were taken for histologic examination. Portal pressure increased from 7.4+/-0.3 to 20.5+/-0.6 mmHg in PH and CBDL animals (P <0.01). Bacterial cultures obtained from the ileum showed significant bacterial overgrowth (P <0.01) in pH and CBDL rats (1.3+/-0.8 * 10(4) after SL; 1.2+/-0.6 * 10(5) in PH and 1.9+/-0.6 * 10(6) in CBDL). BT occured in 10% of SL animals to the MLN and spleen. In PH animals 23% positive cultures were found, almost all due to BT to the PV, vena cava, and liver. CBDL resulted in a BT rate of 47%, mainly by translocation to the PV, liver, and MLN (P <0.05 vs. SL). Histomorphologically, the jejunum and ileum were normal in all three groups. These results suggest that in growing PH and CBDL rats intestinal bacterial overgrowth with significant BT occurs, and the incidence of BT seems to be related to the amount of bacteria colonizing the intestinal tract. PMID- 24057708 TI - Pentoxifylline attenuates ischemia/reperfusion injury to the small intestine in the rat. AB - There is a large body of evidence that neutrophils may play an important role in the mucosal injury that follows ischemia of the intestine. Pentoxifylline (PTF), a methylxanthine derivative, prevents leukocyte adherence to vascular endothelium and restores intestinal blood flow following hemorrhagic shock and sepsis. The purpose of this study was to evaluate the protective properties of PTF in an ischemia-reperfusion model of the intestine and whether its action is mediated through tissue neutrophils as assessed by myeloperoxidase (MPO) determination. Intestinal ischemia of either 1 or 2 h was induced in rats by clamping the superior mesenteric artery, followed by a 17-min reperfusion period. PTF (25 mg/kg) or saline solution was injected IP 10 min prior to ischemia. Multiple bowel samples were harvested at the end of the reperfusion period and evaluated for histology and tissue MPO. PTF significantly changed the resultant histologic damage to the intestinal mucosa exerted by prolonged ischemia of 1 and 2 h duration, although the beneficial effect of PTF in this animal model was independent of the number of tissue neutrophils as assessed by tissue MPO levels. Pretreatment with PTF can thus reduce the histologic damage caused by prolonged ischemia to the intestine. PMID- 24057709 TI - Postoperative medium-term follow-up of patients with bilateral, massive primary vesicorenal reflux and reduced renal function at presentation. AB - We report the results of a medium-term follow-up study of 52 patients with bilateral, massive primary vesicorenal reflux (PVRR) with renal damage at presentation. Ten infants between 2 and 5 months of age, with a total of 19 renal units, had a temporary vesicostomy followed by ureteral reimplantation after 12 15 months; 42 patients with 81 renal units had primary ureteral reimplantation. The postoperative observation period covered 9.5 years on average (20 months - 21.5 years). The study showed that: (1) urinary specific gravity remained reduced in about 61% of patients; (2) proteinuria improved significantly, in a direct proportion to the favorable evolution of renal function; (3) the frequency of acute pyelonephritis decreased significantly from 98% to 23%. Postoperatively, 27 patients (51%) had one or more episodes of urinary tract infection (UTI) and 12 (23.0%) still had episodes of acute pyelonephritis. (4) At follow-up 7 patients (13.5%) had stable hypertension, while 3 others had unstable hypertension (19.2%); 8 had chronic renal insufficiency or end-stage renal disease. When only adolescents more than 12 years old were considered, the incidence of hypertension increased to 34.4% (10.29). (5) Some renal scarring developed despite successful antireflux surgery, and parenchymal growth, which was severely impaired prior to surgery, restarted although it remained below - 2 standard deviations from the mean. (6) In the overall series glomerular filtration rates (GFR) significantly improved after successful surgery. However, this improvement was much more evident in patients operated upon within the 1st year of life and in those who had had a temporary vesicostomy. In the subgroup of patients operated upon after 6 years of age, successful surgery had no effect on the further decline of renal function when this was already severely compromised. We conclude that early antireflux surgery or, in selected cases, temporary vesicostomy followed by ureteral reimplantation was effective in significantly improving GFR and sharply decreasing febrile UTIs in patients with massive bilateral PVRR and renal damage at presentation. PMID- 24057710 TI - Evolution of upper urinary tract and renal function in patients with posterior urethral valves. AB - From January 1972 to June 1993, 166 patients with posterior urethral valves (PUV) were treated in our surgical department, 59 with a milder form of PUV (upper urinary tract [UUT] complication rate 29%) and 107 with a severer form (UUT complication rate 96.3%). Only the latter group was studied for long-term (mean 9.3 years) evaluation of the UUT and renal function. A temporary vesicostomy was the primary treatment in 25 patients. Indications for temporary diversion were very young age and/or low birth weight, severe and bilateral UUT complications, and severe renal damage. All the other patients were treated by primary endoscopic valve fulguration. After removal of the lower urinary tract obstruction, vesicorenal reflux (VRR) resolved spontaneously or was ameliorated in 59.2% of the renal units. Spontaneous normalization or evident amelioration were found at long-term follow-up in nearly 70% of dilated, non-refluxing ureters. Ureteral reimplantation was performed on 41 of the 202 dilated or refluxing ureters (surgical rate 20.3%). The surgical failure rate requiring reoperation was 5% (2/41). The prerequisite for successful reimplantation was a large-capacity, stable, and compliant bladder. Ten nephroureterectomies were carried out for unilateral, massive VRR and renal dysplasia; 1 late nephrectomy was performed for arterial hypertension. The evolution of renal function showed statistically significant overall improvement, which was more evident in patients diagnosed and treated in the 1st month of life (P = 0.000) than in those treated between 1 and 12 months (P = 0.004) or after 1 year of age (P = 0.025). Renal function considerably improved in the vesicostomy group (P = 0.000). Thirteen patients (12.4%) are now either dead (2) or have end-stage renal disease (6) or chronic renal insufficiency evolving toward end-stage renal disease (5); 5 of these 13 were treated by vesicostomy in the first days or months of life, and at presentation the glomerular filtration rate (GFR) was less than 25 ml/min . 1.73 m(2). Determination of basic GFR and, even more, functional renal reserve is relevant in predicting the long-term evolution. In the author's opinion, vesicostomy is the procedure of choice in very ill newborns or infants. Aggressive management with early surgical reconstruction is rarely justified, because frequently UUT complications resolve spontaneously or clearly improve, and their surgical treatment has limited and very precise indications. PMID- 24057711 TI - Management of urethral strictures in children. AB - We report the results of a long-term follow-up study in 78 children with urethral strictures. The ages ranged from 1 month to 20 years and the follow-up from 8 months to 15 years (average 5.9 years). Balloon dilation was the primary treatment in 66 patients. Manipulative management (balloon dilation and endoscopic urethrotomy) was performed in 68 cases and was successful in 55. There were no complications. Balloon dilation alone provided an 80% success rate (53/66). Twenty-two patients were treated by one-stage urethroplasty, with an overall 95.5% success rate. The surgical repair was performed in 12 patients as a secondary procedure after failure of conservative treatment. Our data do not support the rather poor results usually reported in the pediatric literature associated with the balloon dilation technique. PMID- 24057712 TI - Vesicostomy in childhood: indications and results. AB - The authors report their experience with 27 patients who underwent cutaneous vesicostomy (CV) diversion for either lower tract disorders or obstruction. The indications for CV included 18 cases of neurogenic bladder, 3 pseudo-prune belly syndrome, 3 bladder exstrophy, 2 vesicoureteral reflux, and 1 posterior urethral valves. A Lapides-type technique with minor changes was performed in all cases. Improvement of renal function occurred after CV in all but 3 patients (11.1%). No early surgical complications were observed. Late complications occurred in 8 patients (29.6%): 4 (14.8%) had a stomal stenosis and 4 (14.8%) urinary tract infections. The overall revision rate was 7.4%. We believe this technique is simple to perform, tubeless, easy to manage, and readly reversible. Our experience tends to confirm CV to be an easy, effective, and reversible means to treat children and infants with selected pathology of the lower urinary tract. Results and complications are discussed. PMID- 24057713 TI - The transpuboperineal approach for repair of traumatic strictures of the posterior urethra in children. AB - Strictures of the posterior urethra resulting from pelvic fractures in children pose a formidable challenge due to the limitations of perineal exposure. With the transpubic approach, direct access to the involved anatomy is obtained. This technique, combined with perineal mobilization of the distal urethra, allows the performance of a tension-free anastomosis. The use of an omental pedicle wrap graft seems to add safety to the procedure. It is particularly suited for long strictures and after failure of the transperineal approaches. The results reported in the literature are remarkably good. There are no reports of orthopedic sequelae in children. Sexual potency and continence do not seem to be adversely affected. We present two cases successfully operated upon by this technique. PMID- 24057714 TI - Semen quality and gonadotropin levels in patients operated upon for cryptorchidism. AB - In a long-term follow-up study we compared preoperative testicular position, age at orchiopexy, and morphology of testicular biopsies investigated at orchiopexy to sperm analysis results, testicular volume, and serum follicle-stimulating hormone and luteinizing hormone levels at follow-up in 46 men with a history of surgical correction of cryptorchidism in childhood. They had undergone orchiopexy at age 1.5-12.0 years, 24 for unilateral and 22 for bilateral cryptorchidism. Eleven (46%) of the 24 patients with unilateral and 7 (32%) of the 22 with bilateral undescended testes had a normal sperm analysis, whereas in men with impaired spermiogenesis oligo-asthenozoospermia was the predominant feature. Three (13.6%) patients with bilateral cryptorchidism showed azoospermia, but none of the patients with unilateral cryptorchidism did. Neither the age at orchiopexy nor the average germ-cell count per cross-sectioned seminiferous tubule of testicular biopsies examined at orchiopexy correlated significantly with subsequent sperm analysis results or gonadotropin levels at follow-up. The pretreatment testicular position ("testicular position value") has a high prognostic value for prediction of subsequent sperm analysis results and serum gonadotropin levels. PMID- 24057715 TI - The extended Mathieu procedure in coronal, distal penile, and midshaft hypospadias repair. AB - The Mathieu procedure was adequately modified for glanular, coronal, and midshaft hypospadias variants with chordee and/or urethral hypoplasia in order to anatomically reconstruct the penis. A total of 129 patients aged 12 months to 22 years with coronal (35.7%), distal penile (51.9%), and midshaft (12.4%) hypospadias were operated upon. Chordee was found in 33.3% and distal urethral hypoplasia in 15.5% of the patients. The ventral flap was based anatomically on the external meatus, the glans was made pyramidal with an apical external meatus, the prepuce was resutured, and the neurethra was buried deeply within the glans. In patients with distal urethral hypoplasia the external meatus was incised proximally; in chordee the urethral plate was mobilized off the corpora cavernosa. Fistulas were uncommon (3.4%) in the primarily operated patients. The external meatus was always apical, and no stenosis was demonstrated at follow-up. The prepuce was reconstructed in 71.5% of patients. The extended Mathieu procedure appears recommendable for all coronal, distal penile, and midshaft variants regardless of associated anomalies of the penis. It also seems suitable for secondary repairs. The prepuce can be reconstructed in the majority of patients. The complication rate is significantly low compared to other methods, and the extended Mathieu operation is a good teaching tool with a high success rate and versatility. PMID- 24057716 TI - Surgical complications of the haemolytic uraemic syndrome. AB - During the first outbreak of haemolytic uraemic syndrome (HUS) to be reported in Australia, 22 children were admitted to the Women's and Children's Hospital, Adelaide. The outbreak was caused by an entero-haemorrhagic Escherichia coli strain (EHEC) of serotype 011:H-, a strain rarely implicated as a cause for HUS. In all 22 patients, the onset of HUS was preceded by a gastrointestinal (GI) prodrome. All patients had diarrhoea. In 17 (73%), the diarrhoea became bloody; in 20 (86%) there was vomiting; in 15 (65%) there was abdominal pain; and in 12 (50%) all three symptoms were present. Abdominal symptoms continued to complicate the course of 4 patients. Two of these underwent exploratory laparotomy, both had gangrenous colon excised, and both survived. The 2 remaining patients were successfully treated non-operatively. One further patient underwent appendicectomy before the diagnosis of HUS was made. There was 1 death during this epidemic. In patients with HUS and GI involvement, optimal surgical management requires careful consideration of the indications for, and the timing of, surgical intervention. PMID- 24057717 TI - Treatment of an aggressive haemangiomatous lesion with alpha-interferon. AB - We report an infant who presented with an aggressive haemangiomatous lesion of the right thigh that was treated successfully with alpha-interferon. PMID- 24057718 TI - Ketamine : A safe and effective anesthetic agent for children in the developing world. AB - Ketamine is used extensively in the developing world (DW) because of its effectiveness, availability, relatively low cost, and presumed safety. This report is a prospective, objective assessment of the efficacy and safety of ketamine when used as the sole anesthetic agent in a general medical practice hospital in the DW in children less than 16 years of age undergoing nonemergent operative procedures. Children undergoing laparotomy, thoracotomy, or craniotomy were excluded. Data analysis included serial arterial hemoglobin saturation (SpO2) and pulse rate, amount of ketamine utilized, adequacy of anesthesia, and perioperative complications. One hundred thirty-one children undergoing a total of 210 anesthetics were studied. The level of anesthesia was adequate in all cases. The SpO2 dropped below 90% in 40 (19%) children, below 85% in 25 (12%), and below 80% in 13 (6%). SpO2 drops occurred significantly (P = 0.004) more often after IM than after IV injection. All drops in SpO2 were abrupt without premonitory signs. Thirty-three (82.5%) of these 40 children responded readily to airway manipulation with a jaw thrust, and only 7 (3.3% of the total series) required face-mask O2. None required intubation or positive-pressure ventilation. Transient laryngospasm occurred in 1 child, but there were no other complications. In particular, there was no mortality, apnea, emesis, excessive salivation, or significant early or delayed emergence phenomena. Ketamine is quite effective when used as the sole anesthetic agent in DW children. It is relatively safe, but hypoxemia may go undetected unless technologically sophisticated monitoring equipment is available. Proper suction and ventilatory support equipment should be readily available prior to ketamine injection. The first step when hypoxemia is detected is simple airway manipulation, followed by oxygen administration by face mask if needed. Rarely will intubation be indicated. Ketamine is also a good drug for the management of pediatric emergency department procedures in the United States, but all children in these more developed centers should be monitored with a pulse oximeter, since a significant number of children have a precipitous drop in SpO2. PMID- 24057719 TI - Primary hyperparathyroidism in children. AB - Primary hyperparathyroidism is an uncommon condition in childhood that is easily amenable to surgical treatment with excellent results. Pathologically, the parathyroid glands may show generalized hyperplasia or, more commonly, adenoma formation, the latter frequently being seen in adolescence. Two girls with solitary parathyroid adenomas and predominantly skeletal manifestations resembling rickets are reported, underlining the need to suspect and appropriately investigate these children. The literature on the subject is reviewed. PMID- 24057720 TI - Neonatal pulmonary blastoma. AB - A thoracic mass was identified on a routine ultrasound (US) examination in the 30th week of gestation. A postnatal chest radiograph, US, and computed tomography demonstrated a well-delineated, solid, cystic tumor in the left lower lobe. The mass was excised and a diagnosis of pulmonary blastoma (PB) was made on pathologic examination. The patient is alive and free of disease 8 years after the operation. PB is a rare primary neoplasm of the lung, adults being more frequently affected than children. This case appears to be the third neonatal PB reported and one of the few long-term survivors. PMID- 24057721 TI - Hepatobiliary cystadenoma with hyaline stroma : A pediatric case associated with multiple hemangiomas. AB - The authors describe a case of hepatobiliary cystadenoma and its pathogenetic, histopathologic, and clinical aspects and point out its association with multiple hemangiomas. PMID- 24057722 TI - Multiloculated epidermoid cyst of the liver. AB - Epidermoid cysts of the liver are extremely rare and have been described in both children and adults. Their etiology remains an enigma, and several theories have been suggested as to their origin. Due to their possible malignant potential, early detection and resection are mandatory whether the cysts are unilocular or multilocular. PMID- 24057723 TI - Omental cysts: an unusual cause of abdominal distension in children. AB - Congenital cystic lesions arising in the omentum are a rare finding in the paediatric age group. They are difficult to diagnose preoperatively as they have few distinct features; the diagnosis is often confirmed only at lalaparotomy. They are thought to arise due to a developmental abnormality of the lymphatic system. Two cases are presented and the literature reviewed. The treatment of choice is complete resection. Long-term follow-up is unnecessary due to their benign nature. PMID- 24057724 TI - Mechanical obstruction of a Roux-Y limb : A rare cause of recurrent jaundice after apparently succesfuul surgery for biliary atresia. AB - Two cases of mechanical obstruction of the defunctionalized limb of a Roux-en-Y loop of a bilioenteric conduit are reported. Both patients developed recurrent jaundice and acholic stools after apparently successful surgery for biliary atresia, and were initially diagnosed as having ascending cholangitis. However, the symptoms failed to respond to conservative treatment. At surgery, a mechanical obstruction of the Roux-Y limb due to adhesions was found. The jaundice disappeared and the stool color became normal after lysis of the adhesions. PMID- 24057725 TI - Duodenal duplication with bile duct obstruction and keratinaceous casts. AB - We report an unusual case of duodenal duplication presenting in a newborn with duodenal and bile duct obstruction. The duplication and biliary tract were filled with keratinaceous casts. To our knowledge, such an association has not been previously reported; this case demonstrates the importance of confirming bile duct patency during operations to remove duodenal duplications. PMID- 24057726 TI - Sequestrated tubular duplication of the ileum. AB - Duplication of the small bowel is uncommon, and a sequestrated tubular duplication of the ileum that is isolated from the normal bowel and mesentry has not been previously described in the literature. We report one case of such a sequestrated duplication. PMID- 24057727 TI - Successful treatment of congenital chylous ascites with a somatostatin analogue. AB - Congenital chylous ascites (CCA) results from maldevelopment of the intra abdominal lymphatic system. Newborns present with respiratory distress and abdominal distention. Medical treatment of CCA is often prolonged. A newborn with CCA was treated with octreotide, a somatostatin analogue, resulting in rapid and complete resolution of the ascites. PMID- 24057728 TI - Carcinoid syndrome. AB - The authors report a rate case of carcinoid syndrome (CS) in a 12-year-old child that was caused by a carcinoid tumor located in the ileum that had metastasized mainly to the liver. After resection of the primary tumor, treatment with octreotide and polychemotherapy (five monthly cycles of 5-flourouracil, epidoxorubicin, and deticene) was ineffective for both reducing the metastatic liver disease and controlling the clinical symptoms. The patient's poor prognosis led the authors to perform a liver transplantation. The results of liver transplantation in patients with metastatic liver disease are generally not good. However, neuroendocrine tumors seem to be an exception due to their slow growth. At present, the child is in complete clinical and laboratory remission 4 months after transplantation. To the best of our knowledge, only 5 cases of CS have been reported to date in children. PMID- 24057729 TI - Ascariasis presenting as massive gastrointestinal bleeding. AB - A 2-year-old boy presented with massive hematemesis and hematochezia for 1 day; an ascarid was removed from his jejunum at laparotomy. Multiple duodenal and jejunal mucosal erosions were found on panendoscopy through an enterotomy. The causes of mucosal erosions made by ascarids are discussed briefly. PMID- 24057730 TI - Massive gastrointestinal bleeding associated with hookworm infestation in a child: case report. AB - We report a rare case of massive haematochezia due to hookworm infestation that required two laparotomies before the cause of bleeding could be diagnosed. The need to consider this parasite as a possible cause of gut bleeding in endemic countries is stressed, as early recognition may avoid unnecessary investigations and surgical interventions. PMID- 24057731 TI - Complete duplication of the hindgut, penis, and lower urinary tract. AB - A 1-day-old male with complete duplication of the caudal gut from the terminal ileum to the anus with a normal, midline-localized anus and an imperforate right sided anus with a rectourethral fistula and a skin dimple is presented. He also had complete duplication of the bladder urethra, and penis (true diphallus), an umbilical hernia, spina bifida occulta covered by skin containing a capillary hemangioma, and separation of the symphysis pubis. This case represents caudal twinning with duplication of the hindgut, genitalia, and lower urinary tract. PMID- 24057732 TI - Prenatal ultrasonograms showing a reduced amniotic cavity in a patient with. AB - Multiple genitourinary, anorectal, and limb anomalies are described in association with the presence of intrauterine compression in a male newborn. Bilateral hydronephrosis, and imperforate anus with a rectourethral fistula, a posterior urethral valve, a left undescended testis, a bifid scrotum, a short prepuce, and flexible clubfeet were all noted in one of twin boys. Furthermore, a strikingly smal amniotic cavity was demonstrated at 7 weeks' gestation by ultrasonograms and pressure pits on the ankles were also seen after birth, features suggestive of intrauterine spatial compression. It is postulated that the early intrauterine compression inhibited the normal development of the fetus, causing the multiple anomalies. The conditions observed in this case are considered compatible with the concepts previously proposed by Stephens et al. PMID- 24057733 TI - Posterior sagittal rectoplasty for rectal atresia: a definitive approach. AB - Two infants with rectal atresia were successfully treated by end-to-end anastomosis via a posterior sagittal approach with a covering colostomy. The first child had previously undergone numerous local procedures in an attempt to correct the anomaly. PMID- 24057734 TI - Urogenital sinus with sinorectal H-fistula - a hitherto undescribed anorectal anomaly. AB - In a urogenital sinus anomaly, the urethra and vagina are conjoint for a variable distance and the anorectum is usually intact and complete. We report a case of a urogenital sinus with a fistula between the rectum and the sinus. The anomaly was successfully repaired at 2.5 years of age through a midline muscle-splitting incision in the anterior perineum. The anterior wall of the anorectum was divided in the line of the incision in order to deal with the fistula. Repair was done in layers. PMID- 24057735 TI - Incomplete diphallus: correction in one stage. AB - We report a patient with an anorectal malformation and an abnormal penis with an isolated prepuce, double glans, and two corpora cavernosa. A right main urethra opened into the bladder neck; the right meatus was hypospadiac. The proximal end of the left accessory urethra opened into the right prostatic urethra and the left meatus was orthotopic. Severe chordee and normal urinary flow through both meatuses were present. At the age of 4 years, the diphallus was corrected. Both corpora cavernosa were dissected and the urethra was reconstructed, lengthening the right urethra with a 2.5-cm fragment of left urethra as a free graft excised from the emergence point and joined to the main urethra pasteriorly. The right urethra, whose meatus was hypospadiac and lateral, was dissected until a medial course was obtained. The glans was reconstructed using the lateral aspect of each glans; both medial aspects were extirpated. To correct the urethral trajectory, the urethra was fixed to the tip of the glans. A penis with two corpora cavernosa, a single glans, and a complete urethra with a meatus at the tip of the glans was obtained. The prepuce was reconstructed from the dorsal redundant aspect. The postoperative course was satisfactory. PMID- 24057736 TI - A rare association of diphallus, colonic duplications, ileal atresia, and an anorectal malformation. AB - Diphallus is a rare congenital anomaly that is often associated with various other anomalies of the midline structures of the posterior portion of the body. We report a unique case of a 1-day-old male with complete diphallus, incomplete bilateral tubular duplications of the colon, ileal atresia, and an anorectal malformation. PMID- 24057737 TI - Needle track recurrence after biopsy of non-metastatic Wilms tumour. AB - A 2-year-old girl presented with a left-sided Wilms tumour. She was randomised to have a needle biopsy and preoperative chemotherapy according to the United Kingdom Children's Cancer Study Group (UKCCSG) protocol, a trial of preoperative chemotherapy in biopsy-proven Wilms tumour versus immediate nephrectomy (UK 9101). A nephrectomy was performed 6 weeks later. Six months later she presented with an abdominal wall recurrence at the needle biopsy site, which was resected. The value of needle biopsy in localised Wilms tumour is debated. PMID- 24057738 TI - Carcinoma of the rectum in children. AB - Two cases of carcinoma of the rectum in children (10 and 11 years old) are presented. Both cases presented as acute intestinal obstruction with the history of bleeding per rectum, constipation, abdominal distention, and loss of weight and appetite. Carcinoma of the colon and rectum in children is rare. Its clinical, pathologic, and biological characteristics are different than those of adults. The prognosis is poorer in children, the reason for which is explained, and its management is briefly discussed. PMID- 24057739 TI - Lumbar teratoma with intraspinal extension. AB - Teratomas are childhood tumours especially notable for their diversity of anatomic locations and biological behaviour. We present an extremely rare occurrence of a lumbar teratoma with intraspinal extension. The importance of thorough preoperative evaluation and magnetic resonance imaging for tumours in this location is also emphasised. PMID- 24057740 TI - Extrarenal rhabdoid tumour presenting as a congenital subcutaneous mass. AB - Extrarenal malignant rhabdoid tumour is a rare neoplasm of childhood. A congenital example has only been reported once previously, presenting as a facial mass. We report a second congenital case with the tumour over the right shoulder in which postoperative investigations revealed multiple hepatic metastases proving fatal at 51 days, with adjuvent therapy felt inappropriate. PMID- 24057741 TI - Benign mesenteric lipoblastoma. AB - An unusual case of benign intraperitoneal lipoblastoma in a 10-months-old girl is presented. Cytologically and histologically, the tumor had no malignant features. By means of DNA cytometry, it was regarded as diploid without signs of malignancy and of low proliferative potential. The tumor was treated by complete surgical excision. PMID- 24057742 TI - Juvenile xanthogranuloma: three cases. AB - Juvenile xanthogranuloma (JX) is a regressing fibrous histiocytoma occurring during infancy and characterized by cutaneous papules and nodules and less often by additional lesions in deep tissue and organs. It has a special place among childhood masses by presenting different outcomes and spontaneous regression. We report three cases of JX that were detected after birth and resected. PMID- 24057743 TI - Fundoplication with anastomotic wrap : A modification of a Nissen procedure to achieve permanence. AB - Gastric fundoplication is an accepted treatment for disabling or life-threatening gastro-oesophageal reflux in childhood, and a modified Nissen's procedure is most commonly used. Wrap failure is a common complication and occurs most frequently and earliest in neurologically impaired children. To obviate this complication, the procedure was modified by anastomosis of the two limbs of the fundal wrap. The maintenance of the wrap then relies on healing and physical union of the stomach wall, rather than on sutures that eventually cut out, leading to recurrence of reflux. The procedure has been performed in four neurologically impaired children, in three after failure of a previous Nissen procedure. There has been one complication, an adhesive bowel obstruction, and follow-up is too short to assess the ultimate results. PMID- 24057744 TI - An easy method for adjusting a silo for delayed closure of gastroschisis. AB - A method is described permitting rapid and safe tucks and adjustments to be made to a silo in staged reduction of an anterior abdominal wall defect. PMID- 24057745 TI - Early definitive surgery for total colon aganglionosis: Duhamel procedure with right colon patch graft using GIA stapler. AB - A report is presented of an infant with total colon aganglionosis (TCA) with ileal involvement in whom a modified Duhamel procedure was used accompanied by a right colon patch graft 12 cm in length using a GIA-90 stapler at 3 months of age. The patient with TCA is usually treated by an initial diverting ileostomy followed by a definitive operation performed several months later. However, the management during the ileostomy period is associated with a variety of problems. In to minimize the resulting complications, we developed a procedure to allow a much earlier definitive operation. PMID- 24057746 TI - Plug the lung until it grows, a new method to treat congenital diaphragmatic hernia in utero. PMID- 24057747 TI - Long-term results following repair of neonatal abdominal wall defects with Gore Tex. PMID- 24057748 TI - Posterior mediastinal teratomas. PMID- 24057749 TI - TAPS procedure for correcting ventral chordee. PMID- 24057750 TI - Retroperitoneal pseudocyst: an explanation. PMID- 24057751 TI - Crossed Intra-abdominal "gonadal" ectopia? PMID- 24057752 TI - Parental awareness and dental attendance of children among African immigrants. AB - To assess parental awareness of their child's dental status and the relationship between parental awareness and children's dental attendance. Participants were children aged 6 years or younger and their African parents who had lived in Canada for up to 10 years. Demographics and parents' perceived dental status were collected. Children's normative dental status was determined by dental examinations. 125 pairs of parents and children aged 21-72 months were included. 52% of the children never had a dental visit. Dental status of 44% of children was rated as good by parents, among them, 56% had dental decay. Parental assessments did not coincide with the clinical assessments of 62% of children. No correlation was found between parental awareness and children's dental attendance. Children of African immigrants are at high risk for developing severe dental decay because of low parental awareness and lack of regular dental visits. PMID- 24057753 TI - A review of the dental caries status of ethnic minority children in China. AB - China has 55 ethnic minority groups comprised of 113 million persons, or 7.0% of total population. Dental caries is a major health problem for children in China, and national oral health surveys currently report dental caries based on geographical location rather than by ethnic group. This study reviews the literature on dental caries in ethnic minority children in China. Publications were retrieved in Chinese and English from five electronic databases; thirty eight studies from 1983 to 2012 met inclusion criteria and described 25 ethnic minority groups. Primary dentition median caries prevalence and experience were higher (51% and dmft = 3.0, respectively) than permanent dentition caries prevalence and experience (39% and DMFT = 0.8). Median caries prevalence was highest (80%) for permanent dentition among aggregated ethnic minorities with population greater than 1 million. More work and research is needed to expand dental caries prevention and treatment measures for ethnic minority child populations in China. PMID- 24057754 TI - 'Upenamide: trials and tribulations. AB - The complex macrocycle 'upenamide was isolated in 2000, stimulating significant effort from synthetic chemists to complete its total synthesis and verify its structure. Progress made by several groups is detailed, culminating in the synthesis of both of the proposed structures of this unique natural product, neither of which matched the natural material according to spectroscopic analysis. The evolution of the synthetic route and the development of associated methodologies are described. PMID- 24057755 TI - In vitro response of pre-osteoblastic cells to laser microgrooved PEEK. AB - Polyetheretherketone (PEEK) is currently being used in implants as an alternative to titanium, due to its mechanical properties, cytocompatibility and inertness. Several studies have demonstrated that certain patterning on the implants promotes the oriented cell growth of osteoblasts, favouring the formation of bone tissue. This patterning improves the implant's osteointegration in the bone and its mechanical stability. Therefore, the objective of this work is to micro structure PEEK by laser radiation and to carry out an exhaustive study of the orientation of pre-osteoblast cells that grow on this material. Parallel microgrooves were obtained using an ArF excimer laser coupled with a mask projection unit with distances of 25, 50, 75 and 100 um between grooves. The cell growth on these PEEK surfaces was studied, in order to compare the effect of different distances between grooves on the biological response of MC3T3-E1 pre osteoblastic cells. Preferential cell orientation was observed for all studied distances, which was more pronounced in the 25 and 50 um ones. PMID- 24057756 TI - The prevalence of neutralising antibodies to chimpanzee adenovirus type 6 and type 7 in healthy adult volunteers, patients with chronic hepatitis B and patients with primary hepatocellular carcinoma in China. AB - The presence of neutralising antibodies (NAbs) against adenovirus in the population is a major hurdle preventing the effective use of replication defective adenoviruses (Ads) as candidates for gene therapy and vaccine vectors for many diseases. Only a few studies have described the epidemiology of pre existing immunity to chimpanzee Ads in China. To assess the prevalence of NAbs to chimpanzee adenovirus serotypes 6 and 7 (AdC6 and AdC7), we enrolled 998 healthy participants from five regions in China as well as 196 chronic hepatitis B virus (HBV) patients and 193 primary hepatocellular carcinoma (HCC) patients from Chongqing, China. The total seroprevalence rates of AdC6 and AdC7 NAbs in the healthy participants were 12.22 % (122/998) (95 % confidence interval [CI], 10.34 14.40 %) and 13.13 % (131/998) (95 % CI, 11.17-15.36 %), respectively. The seroprevalence rates of AdC6 and AdC7 NAbs in the HBV patients were 21.43 % (42/196) (95 % CI, 16.26-27.69 %) and 25.51 % (50/196) (95 % CI, 19.92-32.04 %), respectively. The seroprevalence rates of AdC6 and AdC7 NAbs in the HCC patients were 27.46 % (53/193) (95 % CI, 21.65-34.15 %) and 31.09 % (60/193) (95 % CI, 24.98-37.93 %), respectively. The seroprevalence rates of these Ads were not associated with age and gender. The present study may provide useful insights for developing future AdC-based vaccines and gene therapies. PMID- 24057757 TI - Evaluation of neutralizing efficacy of monoclonal antibodies specific for 2009 pandemic H1N1 influenza A virus in vitro and in vivo. AB - Pandemic influenza A virus (H1N1) 2009 poses a serious public-health challenge worldwide. To characterize the neutralizing epitopes of this virus, we generated a panel of eight monoclonal antibodies (mAbs) against the HA of the A/California/07/2009 virus. The antibodies were specific for the 2009 pdm H1N1 HA, as the antibodies displayed HA-specific ELISA, hemagglutination inhibition (HAI) and neutralization activity. One mAb (mAb12) showed significantly higher HAI and neutralizing titers than the other mAbs. We mapped the antigenic epitopes of the HA by characterizing escape mutants of a 2009 H1N1 vaccine strain (NYMC X 179A). The amino acid changes suggested that these eight mAbs recognized HA antigenic epitopes located in the Sa, Sb, Ca1 and Ca2 sites. Passive immunization with mAbs showed that mAb12 displayed more efficient neutralizing activity in vivo than the other mAbs. mAb12 was also found to be protective, both prophylactically and therapeutically, against a lethal viral challenge in mice. In addition, a single injection of 10 mg/kg mAb12 outperformed a 5-day course of treatment with oseltamivir (10 mg/kg/day by gavage) with respect to both prophylaxis and treatment of lethal viral infection. Taken together, our results showed that mouse-origin mAbs displayed neutralizing effectiveness in vitro and in vivo. One mAb in particular (mAb12) recognized an epitope within the Sb site and demonstrated outstanding neutralizing effectiveness. PMID- 24057758 TI - Proteomic profiling of sea bass muscle by two-dimensional gel electrophoresis and tandem mass spectrometry. AB - In this study, the proteome profile of European sea bass (Dicentrarchus labrax) muscle was analyzed using two-dimensional electrophoresis (2-DE) and tandem mass spectrometry with the aim of providing a more detailed characterization of its specific protein expression profile. A highly populated and well-resolved 2-DE map of the sea bass muscle tissue was generated, and the corresponding protein identity was provided for a total of 49 abundant protein spots. Upon Ingenuity Pathway Analysis, the proteins mapped in the sea bass muscle profile were mostly related to glycolysis and to the muscle myofibril structure, together with other biological activities crucial to fish muscle metabolism and contraction, and therefore to fish locomotor performance. The data presented in this work provide important and novel information on the sea bass muscle tissue-specific protein expression, which can be useful for future studies aimed to improve seafood traceability, food safety/risk management and authentication analysis. This work is also important for understanding the proteome map of the sea bass toward establishing the animal as a potential model for muscular studies. PMID- 24057759 TI - [Pain, agitation and delirium. Amended 2013 guidelines of the American College of Critical Care Medicine]. AB - BACKGROUND: Intensive care patients regularly feel pain, not only during intensive care therapeutic measures but also when resting. The associated negative physiological and psychological sequelae can be serious and protracted in intensive care patients. Acute pain is predestined for the development of persistant neuropathic pain. AIM: This study informs the readership on the contents of the amended 2013 guidelines of the American College of Critical Care Medicine (ACCCM) on pain, agitation and delirium and presents strategies for implementation of the guidelines. MATERIAL AND METHODS: The focus of the amended recommendations is to give recommendations for treatment, in particular with respect to practical implementation of evidence-based scientific knowledge in the daily routine of intensive care wards. RESULTS: The fundamental principles which are summarized in these guidelines are: the regular collation of pain, measurement of depth of sedation and delirium with valid and reliable measurement instruments, an adequate and preemptive analgesia, administration of sedatives only when necessary and titration of sedatives so that patients remain responsive and are able to react. CONCLUSION: The amended version of the guidelines is intended to achieve a high acceptance and clinical implementation in intensive care medical teams and therefore to improve the outcome of intensive care patients by optimized therapy. PMID- 24057760 TI - [Postoperative pain management after minimally invasive hysterectomy: thoracic epidural analgesia versus intravenous patient-controlled analgesia]. AB - BACKGROUND: In view of the development of innovative and non-traumatic surgical techniques, postoperative pain management should be carried out depending on the invasiveness of the intervention. In the present study two analgesic strategies were compared in patients undergoing minimally invasive hysterectomy: epidural analgesia (EDA) and intravenous patient-controlled analgesia (iv-PCA). MATERIAL AND METHODS: For this prospective case controlled study 60 women with benign uterine diseases undergoing vaginal hysterectomy (VH) or laparoscopically assisted vaginal hysterectomy (LAVH) were enrolled. Patients were divided for analysis into two groups (n=30 each) according to the postoperative analgesic strategy (EDA group versus iv-PCA group). A matched-pair analysis was applied (matching criteria: risk assessment, surgeon and age of patient) to minimize the differences between both groups. Patients were evaluated with respect to the extent of pain determined by a numeric rating scale (NRS 0-10 scale), analgesic consumption, rate of postoperative nausea and vomiting (PONV), mobilization from bed, oral intake of nutrition, complications, duration of stay in the recovery room as well as hospital stay and health-related quality of life (SF-36 Health Survey; collected before and 6 weeks after surgery). RESULTS: Laparoscopically assisted removal of the uterus was carried out in 22 women and by vaginal hysterectomy in 38 women. No significant differences between the study groups were seen in the duration of surgery (iv-PCA 58 +/- 25 min versus EDA 60 +/- 26 min). Demographic data of both groups as well as intraoperative hemodynamic and respiratory parameters were comparable to a great extent. Compared to the iv-PCA group, women in the EDA group showed lower NRS values (p<0.01): recovery room admission 4.7 +/- 2.5 iv-PCA vs. 0.9 +/- 1.3 EDA, recovery room discharge 3.8 +/- 1.8 iv-PCA vs. 1.0 +/- 1.2 EDA, day of surgery at 8 p.m. 5.0 +/- 2.1 iv-PCA vs. 1.8 +/- 2.3 EDA and first postoperative day at 8 a.m. 3.5 +/- 1.7 iv-PCA vs. 1.9 +/- 2.2 EDA. In addition, less PONV (iv-PCA 9/30 vs. EDA 1/30, p<0.01), less shivering (iv-PCA 8/30 vs. EDA 2/30, p<0.05), reduced fatigue (iv-PCA 26/30 vs. EDA 9/30, p<0.05) and a lower consumption of analgesics were found. Average postoperative requirement for piritramide in the iv-PCA group was 7 mg (range 0 24 mg) on the day of surgery and 5 mg (0-39 mg) on the first postoperative day. In the EDA group no opiate medication was given postoperatively (p<0.01). Duration of stay in the recovery room was shorter in the EDA group (71 +/- 32 min vs. 50 +/- 13 min, p<0.05). Hospital stay was 5 days on average in both groups. There were no surgical complications or epidural catheter-related complications. Because of urinary retention catheterization of the bladder had to be made in 3 patients of the iv-PCA group and 13 patients of the EDA group (p<0.05). Furthermore, the possibility to take a shower postoperatively was restricted in the EDA group because the epidural catheter was in place and thereby hygiene concerns. Regarding the early oral nutritional intake as well as postoperative mobilization, no significant differences between groups were found. In comparison with the preoperative status, the results regarding health-related quality of life were significantly better for both groups after a follow-up of 6 weeks (p<0.01); however, this effect was especially pronounced in the EDA group (p<0.05). CONCLUSIONS: To reduce the number of patients suffering from postoperative pain a procedure-specific pain management should be developed. The results of this study have shown that even in minimally invasive surgery, such as vaginal hysterectomy and laparoscopically assisted vaginal hysterectomy there are some advantages for epidural analgesia compared to intravenous patient-controlled analgesia. In particular reduced pain intensity, lower need for analgesics and reduced occurrence of PONV can lead to excellent patient comfort, fast recovery as well as positive effects on health-related quality of life. However, there are also some disadvantages such as an increased rate of urinary retention and restriction of mobility. PMID- 24057761 TI - [Traumatic dissection of the carotid artery: challenges for diagnostics and therapy illustrated by a case example]. AB - Traumatic dissection of the carotid artery is an easily overlooked consequence of trauma with notable morbidity and mortality which can be observed in up to 4% of cases involving multiple trauma. Certain mechanisms and patterns of injury as well as specific symptoms should serve as indicators of a dissection and should therefore result in further diagnostic measures. An early diagnosis is of major relevance. This report describes the case of a 45-year-old victim of a traffic accident who showed symptoms of a dissection which had initially not been diagnosed. PMID- 24057762 TI - GPCR activation: protonation and membrane potential. AB - GPCR proteins represent the largest family of signaling membrane proteins in eukaryotic cells. Their importance to basic cell biology, human diseases, and pharmaceutical interventions is well established. Many crystal structures of GPCR proteins have been reported in both active and inactive conformations. These data indicate that agonist binding alone is not sufficient to trigger the conformational change of GPCRs necessary for binding of downstream G-proteins, yet other essential factors remain elusive. Based on analysis of available GPCR crystal structures, we identified a potential conformational switch around the conserved Asp2.50, which consistently shows distinct conformations between inactive and active states. Combining the structural information with the current literature, we propose an energy-coupling mechanism, in which the interaction between a charge change of the GPCR protein and the membrane potential of the living cell plays a key role for GPCR activation. PMID- 24057763 TI - Effect of alpha7 nicotinic acetylcholine receptor agonists on attentional set shifting impairment in rats. AB - RATIONALE: Attentional set shifting, a measure of executive function, is impaired in schizophrenia patients. Current standard of care has little therapeutic benefit for treating cognitive dysfunction in schizophrenia; therefore, novel drugs and animal models for testing novel therapies are needed. The NMDA receptor antagonist, MK-801, produces deficits in a rat maze-based set-shifting paradigm, an effect which parallels deficits observed on tests of executive function in schizophrenia patients. Alpha7 nicotinic acetylcholine receptor (nAChR) agonists, currently under clinical development by several companies, show promise in treating cognitive symptoms in schizophrenia patients and can improve cognition in various animal models. OBJECTIVES: The objectives of the present study were to determine whether the MK-801 deficit in set shifting could be reproduced in a drug discovery setting and to determine whether cognitive improvement could be detected for the first time in this task with alpha7 nAChR agonists. RESULTS: The data presented here replicate findings that a systemic injection of the NMDA receptor antagonist MK-801 can induce a deficit in set shifting in rats. Furthermore, the deficit could be reversed by the atypical antipsychotic clozapine as well as by several alpha7 nAch receptor agonists (SSR-180711, PNU 282987, GTS-21) with varying in vitro properties. CONCLUSIONS: Results indicate that the MK-801 set-shift assay is a useful preclinical tool for measuring prefrontal cortical function in rodents and can be used to identify novel mechanisms for the potential treatment of cognitive deficits in schizophrenia. PMID- 24057765 TI - Pneumomediastinum and pulmonary interstitial emphysema after tracheal taser injury. PMID- 24057766 TI - Anaemia in a renal allograft recipient: an unusual cause. PMID- 24057767 TI - Management and outcomes of penile fracture: 10 years' experience from a tertiary care center. AB - OBJECTIVES: To evaluate our experience on diagnosis and management of penile fractures. MATERIALS AND METHODS: This retrospective study included 31 patients who were treated for penile fracture between 2002 and 2012. We analyzed the etiology of penile fracture, concomitant pathologies such as urethral injury, deep or superficial dorsal vein ruptures, treatment modalities (surgery or conservative treatment) and complications of treatment modalities. RESULTS: The mean age of the patients was 32 years (range, 23-47 years). In 27 patients (87%), the cause of penile fracture was sexual intercourse. Patients presented with swelling, pain and popping or cracking sound in penis. The diagnosis of penile fracture was established clinically in all of the patients. There were no urethral injuries or dorsal vein ruptures. Ten patients who refused surgical treatment were treated conservatively and remaining 21 patients with early surgical intervention. Among conservatively treated patients, two suffered from erectile dysfunction, two from painful erection and another two from penile curvature. No serious complications such as erectile dysfunction, penile curvature or painful erection were observed in surgically treated patients. CONCLUSION: Penile fracture can be diagnosed easily with history and physical examination, and favorable functional results can be achieved with early surgical repair. PMID- 24057764 TI - Self-injurious behaviour in autistic children: a neuro-developmental theory of social and environmental isolation. AB - RATIONALE: Self-injurious behaviour is not one of the three core symptoms that define autism. However, children on the autism spectrum appear to be particularly vulnerable. Afflicted children typically slap their faces, punch or bang their heads, and bite or pinch themselves. These behaviours can be extremely destructive, and they interfere with normal social and educational activities. However, the neurobiological mechanisms that confer vulnerability in children with autism have not been adequately described. OBJECTIVES: This review explores behavioural and neurobiological characteristics of children with autism that may be relevant for an increased understanding of their vulnerability for self injurious behaviour. METHODS: Behavioural characteristics that are co-morbid for self-injurious behaviour in children with autism are examined. In addition, the contributions of social and environmental deprivation in self-injurious institutionalized orphans, isolated rhesus macaques, and additional animal models are reviewed. RESULTS: There is extensive evidence that social and environmental deprivation promotes self-injurious behaviour in both humans (including children with autism) and animal models. Moreover, there are multiple lines of convergent neuroanatomical, neurophysiological, and neurochemical data that draw parallels between self-injurious children with autism and environmentally deprived humans and animals. CONCLUSIONS: A hypothesis is presented that describes how the core symptoms of autism make these children particularly vulnerable for self-injurious behaviour. Relevant neurodevelopmental pathology is described in cortical, limbic, and basal ganglia brain regions, and additional research is suggested. PMID- 24057768 TI - Increasingly twisted push-pull oligothiophenes and their planarization in confined space. AB - A series of systematically deplanarized push-pull oligothiophenes is designed and synthesized to determine the perfect twist for maximal spectroscopic response to their planarization within lipid bilayer membranes. Weak deplanarization naturally gives weak shifts, but strong deplanarization also gives weak shifts because planarization becomes impossible. Intermediate deplanarization turns out to be ideal. The shifts found in response to chromophore planarization are not as dramatic as with lobsters during cooking but sufficient to discriminate solid ordered and liquid-disordered membranes with the naked eye. PMID- 24057769 TI - The treatment of hypertension during pregnancy: when should blood pressure medications be started? AB - Hypertensive pregnancy disorders (HPD) are important causes of maternal and fetal morbidity and mortality worldwide. In addition, a history of HPD has been associated with an increased risk for maternal cardiovascular disease later in life, possibly because of irreversible vascular and metabolic changes that persist beyond the affected pregnancies. Therefore, treatment of HPD may not only improve immediate pregnancy outcomes, but also maternal long-term cardiovascular health. Unlike the recommendations for hypertension treatment in the general population, treatment recommendations for HPD have not changed substantially for more than 2 decades. This is particularly true for mild to moderate hypertension in pregnancy, defined as a blood pressure of 140-159/90-109 mm Hg. This review focuses on the goals of therapy, treatment strategies, and new developments in the field of HPD that should be taken into account when considering blood pressure targets and pharmacologic options for treatment of hypertension in pregnant women. PMID- 24057770 TI - Exercise: friend or foe in adult congenital heart disease? AB - Exercise training is beneficial in healthy adults as well as patients with acquired cardiovascular disease such as coronary artery disease and heart failure. While a reduced exercise capacity is common in adults with congenital heart disease, it is not clear if these patients stand to benefit from exercise training or if it could be potentially detrimental. International recommendations encourage regular exercise in these patients but the evidence base is limited. Data from cardiopulmonary exercise testing suggest a relatively low risk of adverse events during exercise in adults with congenital heart disease. This is also supported by studies investigating the mode of death in this patient group, reporting that only a minority of patients die during exercise. Regarding the benefits of exercise training in adults with congenital heart disease only a few studies with relatively small sample sizes are available pointing to beneficial effects in selected patients. Encouragingly, in none of these short-term studies were detrimental effects observed. Therefore, adult congenital heart disease patients should not be categorically discouraged from physical activity or from participating in non-competitive sports. However, individual exercise prescriptions should be based on a comprehensive assessment of the underlying cardiac condition, possible sequelae, cardiac function, arrhythmias, pulmonary hypertension, and aortic dimensions. Furthermore, the intensity of exercise should be adapted to individual exercise capacity. PMID- 24057771 TI - Screening for and management of elevated Lp(a). AB - While lipoprotein(a) (Lp(a)) has long been an intriguing subject for basic researchers and clinicians alike, it is only recently that this unique cardiovascular risk factor has begun to be broadly utilized as part of risk prediction. This has dovetailed with the recognition, from genetic studies, that Lp(a) is indeed causal for atherothrombotic disease rather than being merely a marker. Yet, significant questions remain the subject of ongoing study including: what patients groups benefit the most from determination of plasma Lp(a) concentrations; how can elevated plasma Lp(a) concentrations be most effectively managed; does reduction in plasma Lp(a) concentrations reduce risk for atherothrombotic events; and what is the molecular mechanism or mechanisms underlying the risk attributed to elevated Lp(a)? This review summarizes recent progress in genetic studies, basic laboratory research, and epidemiology with a focus on how Lp(a) might be incorporated into clinical practice. PMID- 24057772 TI - Medication adherence in patients with diabetes and dyslipidemia: associated factors and strategies for improvement. AB - Dyslipidemia and diabetes mellitus are commonly coincident, and together contribute to the development of atherosclerotic disease. Medication therapy is the mainstay of treatment for dyslipidemia. Optimal medication therapy for dyslipidemia in patients with diabetes reduces cardiovascular events but necessitates patients take multiple medications. As a result, sub-optimal adherence to medication therapy is common. Factors contributing to medication non adherence in patients taking multiple medications are complex and can be grouped into patient-, social and economic-, medication therapy-, and health provider and health system-related factors. Strategies aimed at improving medication adherence may target the patient, health care providers, or health systems. Recent data suggest medication non-adherence contributes to racial health disparities. In addition, health literacy, cost-related medication non-adherence, and patient beliefs regarding medication therapy have all been recently described as factors affecting medication adherence. Data from within the last year support an important role for regular contact between patients and health care providers to effectively address these factors. Cost-related barriers to medication adherence have recently been addressed through examination of health system approaches to decreasing cost-related non-adherence. PMID- 24057773 TI - Cather-based approaches to stroke prevention in atrial fibrillation. AB - The left atrial appendage (LAA) is a prominent source of cardioembolic stroke in patients with nonvalvular atrial fibrillation (AF). While systemic anticoagulation is the common therapeutic choice, these medications carry many contraindications and possible complications. Epicardial and endovascular techniques for occlusion of LAA have been explored and early clinical data is accumulating. In the coming years, this data will help guide the management of AF patients at risk of bleeding as well as potentially become first-line therapy to reduce the risk of thromboembolic stroke. The purpose of this article is to review current endovascular and epicardial catheter based LAA occlusion devices and the clinical data supporting their use. PMID- 24057775 TI - Development of a CZE method for the quantification of pseudoephedrine and cetirizine. AB - Pseudoephedrine and cetirizine have been combined in dosage forms with more therapeutic benefits when compared with single-drug treatment. The current manuscript reports the development of the first capillary zone electrophoresis (CZE) assay method for that combination. The effects of pH and buffer concentration on resolution, noise, migration time and peak area were examined employing experimental design approach. The analytes were electropherographed into a 50.2 cm-long and 50 um i.d. fused-silica capillary column using 10 mmol/L borate at pH 8.3 with a potential of 25 kV at 25 degrees C and UV detection at 214 nm. The method was successfully validated in order to verify its suitability for pharmaceutical analysis for the purposes of quality control. Over previous high-performance liquid chromatographic methods, the current CZE method features the benefits of the use of cost-effective electrolyte, besides high sample throughput (11 samples/h). Furthermore, other analytical results including linear dynamic ranges, recovery (96.9-98.1%), intra- and interday precision (relative standard deviation <= 1.70%) as well as the limits of detection and quantification (<=2.65 ug/mL) were all satisfactory for the intended purpose. PMID- 24057774 TI - The evolving role of cardiac troponin in the evaluation of cardiac disorders. AB - Due to their tissue specificity and ease of detection, the cardiac troponins (cTn) have emerged as the most important and most utilized biomarkers for the diagnosis of acute myocardial infarction (AMI). The recent achievement of greater sensitivity by cTn assay systems, however, has resulted in the detection of cTn in a wide array of medical conditions, highlighting myocardial cellular necrosis as a feature in several, seemingly unrelated medical conditions, yet complicating the interpretation of a positive test. Since elevated cTn levels are associated with worse clinical outcomes and, thereby, influence medical decisions, careful consideration should be given to the method by which these biomarkers are measured, the patient population on which the test is being applied, and applicable thresholds based on particular clinical conditions. The objective of this review is to trace the clinical evolution of the cTn biomarker from a test for AMI to a general marker of myocardial cellular necrosis with clinically important prognostic information. PMID- 24057776 TI - Antidepressant-induced tardive syndrome: a retrospective epidemiological study. AB - INTRODUCTION: The impact of using antidepressant on the occurrence of tardive syndrome is rarely studied. Here we aimed to investigate the prevalence of various types of antidepressant induced tardive syndrome. METHODS: This study was conducted by means of a retrospective survey. Subjects receiving antidepressant(s) for over 6 months, but no other agents that may cause involuntary movements, were consecutively recruited. Tardive syndrome was evaluated in every included subject. Possible confounding medical conditions were carefully ruled out. RESULTS: Of the 158 included subjects, 22 (14.0 %) were found to have at least one tardive syndrome. The prevalence of subtypes of tardive syndromes was: tardive dystonia: 10.8 %, tardive dykinesia: 3.2 %, tardive tremor: 1.3 %, tardive parkinsonism: 1.3 %, tardive tics: 1.3 %, tardive sensory syndrome: 1.3 %, and tardive myoclonus: 0.6 %. Using serotonin norepinephrine reuptake inhibitors and previous marital status significantly increase the risk of tardive syndrome. DISCUSSION: This study showed that antidepressants may induce various types of tardive syndrome, of which tardive dystonia is the predominant form. Clinicians should be cautious of this infrequent but distressing adverse effect when using antidepressants. PMID- 24057777 TI - Animal research in pediatric surgery : Editorial. PMID- 24057778 TI - Ethical issues: impact of the animal rights movement on surgical research. AB - The aggressive militancy of many animal rights or "antivivisectionist" groups is causing great consternation but little action on the part of medical and surgical researchers. Pediatric surgeons are particularly affected, since issues of tissue healing, growth and development, and organ or total-body responses to surgical insults must be established in the live organism, usually in animal models that cannot be replaced by other methods. Investigators have been threatened physically; laboratories have been vandalized and valuable data destroyed. Biomedical researchers have been called "animal-Nazis." The proliferation of animal rights groups such as the Animal Liberation Front (ALF) and People for the Ethical Treatment of Animals (PETA) have prompted the birth of pro-research organizations such as "Putting People First" and the "incurably ill For Animal Research" (iiFAR). The result of this pro and con activity is an extraordinary amount of time and expense devoted to cover the cost of new regulations and laboratory security (approximately $ 1.5 billion in the U. S. alone) at the expense of research budgets, adding to the increasing shortage of research funding. This situation has created dilemmas for the surgeon involved in basic animal research: is it worth taking personal risks to develop new techniques? Is it ethical to allow these fears to hinder progress in surgery? Should we do away with animal research entirely and test new techniques directly on children? Would that be ethical? These questions are difficult to answer, but must be addressed if we expect medicine to progress. PMID- 24057779 TI - Narrowing the embryologic window of the adriamycin-induced fetal rat model of esophageal atresia and tracheoesophageal fistula. AB - We recently reported on a new fetal rat model of esophageal atresia (EA) with tracheoesophageal fistula (TEF) induced by prenatal exposure to adriamycin (1.75 mg/kg i. p. injected daily to the pregnant dam from the 6th to 9th gestational days). With this treatment regime, many fetuses were resorbed and the number of associated malformations was very high. The present study demonstrates that similar doses of the drug administered only on the 8th and 9th gestational days allow higher fetal survival (9.7 ? 3.9 vs. 6.8 ? 4.7 fetuses per litter, P < 0.01) with a similar incidence of EA-TEF (41.2% vs. 56.4%, n. s.) and decreased occurence of associated anorectal and genitourinary malformations. Since this model is an instrument for further investigation of the disturbed cellular and morphogenetic events leading to EA and TEF, the narrowing of the embryologic window obtained by the present study will allow better focusing of the research on the critical period of time involved. PMID- 24057780 TI - Increased intracellular levels of calcitonin gene-related peptide-like immunoreactivity in pulmonary endocrine cells in an experimental model of congenital diaphragmatic hernia. AB - A congenital diaphragmatic hernia (CDH) model was induced in pregnant rats following administration of 100 mg nitrofen. The fetuses were stored and fixed in Bouin's solution for 24 h after caesarean section at term. After fixation, the lungs were dissected out. Immunostaining of the CDH lungs and controls with rabbit anti-rat calcitonin gene-related peptide (CGRP) antibody at "optimal" and "supraoptimal" dilution levels was obtained by examining the intensity of staining with a series of dilutions of the antisera from 1: 1,000 to 1: 20,000. Supraoptimal dilution detects variations in antigen concentration that may be masked if the routine optimal dilution is used. Immunostaining of the lung by antisera to platelet-derived growth factor (PDGF) and alpha-smooth-muscle actin (ASMA) was performed to examine vascular remodelling. The number of CGRP immunoreactive cells was significantly (P <0.001) greater in the lungs of CDH rats (n = 26) (0.74 +-0.19 NEB [neuroepithelial bodies]/mm(2); mean +- SEM) compared with controls (n = 21) (0.30+-0.16 NEB/mm(2)) seen at supraoptimal dilution (1:20,000). Since CGRP is a vasodilator, this could have important implications in the development of pulmonary hypertension. The pattern of ASMA and PDGF immunostaining was similar in CDH lungs and controls, and therefore, vascular remodelling is not a feature of CDH lungs in fetuses delivered by caesarean section and not exposed to hypoxia. PMID- 24057781 TI - Bacterial translocation, intestinal morphology, and enzyme activities after ileal ischemia in newborn piglets. AB - Intestinal ischemia was created after a limited laparotomy by ligation of the terminal mesenteric vessels in the last 10 cm of distal ileum in 2-day-old piglets. Five groups (each n = 15) were studied: 1 (unoperated control group, killed on day 4), 2 (sham control with laparotomy, killed on day 4), 3 (ischemia, killed on day 4), 4 (ischemia, killed on day 9), and 5 (unoperated control on day 9, not killed). All animals in groups 1, 2 and 5 survived. Two animals in group 3 and 1 in group 4 died (peritonitis and distal ileal perforation). In animals killed on day 9, less weight gain was observed in group 4 compared to the unoperated controls. Macroscopically, no alteration was found at laparotomy in the animals in group 1, whereas in group 2, 1 animal showed beginning peritonitis and another some degree of peritoneal adhesions in group 3, 1 piglet had an intestinal perforation and 4 had intestinal distention above the ischemic loop. In group 4, 7 animals had dilatation of the upper loops, 4 a complete stricture, and 3 peritonitis with complete necrosis of the distal ileum. Microscopic examination revealed severe lesions of the ischemic area in groups 3 and 4 and mild lesions of the upper loop. The kidney was contaminated by translocation of gram-positive cocci in 36% of cases in group 2. Germ carriage for staphylococci was estimated at 80% in the terminal ileum of animals in group 3 versus 8.3% in group 2. In groups 3 and 4, the translocation rate was 30% in the kidney and 40% in the liver. Low disaccharidase activities were found in ischemic areas in groups 3 and 4, with no difference in activity in the upper loops. PMID- 24057782 TI - Cultured urothelium in sheep bladder augmentation. AB - In search of alternatives for urothelial-lined augmentation or reconstruction of the urinary bladder, this study combined the application of seromuscular gastrointestinal (GI) segments with the use of in-vitro cultured, autologous urothelial cells in a sheep model. A cell culture system was set up for establishment and expansion of urothelial cells out of small biopsies from bladder mucosa. A biodegradable carrier made of lactidcaprolactoncopolymer was introduced, allowing upside-down transplantation of cell cultures in vivo. Bladder mucosal biopsies were taken from 14 sheep (mean weight 13.3 kg) with an average yield of 3.5*10(5) viable cells/cm(2) after trypsinization. Primary low density cultures grew to confluence within 5-7 days. Secondary cultures were established on the biodegradable film and were available a week later. They were transplanted onto demucosalized segments of stomach (group 1) or colon (group 2) in 5 animals each, followed by bladder incorporation in clam fashion. The earliest specimens, demonstrating survival and some proliferation of the cultured urothelium in both groups, were obtained 13 days postoperatively. To exclude urothelial regrowth, a temporary pouch grafted with cultured urothelium was created in 2 more sheep of each group. Biopsies were taken after 2 and 3 weeks, respectively, when the reopened pouch was integrated into the bladder (delayed augmentation). In these pouches, adherence and proliferation of urothelial cells could not be demonstrated. Limited radiologic and urodynamic investigations after 5-6-month follow-up revealed good shape, capacity, and compliance of the primarily augmented bladders only. The results indicate that urothelial cell cultures can be established and applied in vivo. Despite upside-down transplantation, they are able to survive on seromuscular segments in an autologous setting. The bladder environment is necessary to promote complete covering of the seromuscular segments. Based on our histologic findings, the share of both resident bladder urothelium and transplanted cells in the formation of the final urothelial lining remains uncertain. Morphologic and urodynamic follow-up data indicate that this process can be accelerated by the transplanted urothelial cells, reducing fibrotic changes of the GI segments. The functional quality of the augmented bladder seemed to improve compared to results after seromuscular augmentation alone. PMID- 24057783 TI - Long-gap oesophageal atresia. AB - The various options for the management of long-gap oesophageal atresia are discussed. Of 89 infants treated, 27 had isolated atresia, 6 distal atresia with proximal fistula, and 56 atresia with distal fistula. The preferred approach for the former two groups was oesophageal replacement via gastric transposition. Recently, delayed primary anastomosis has been attempted after 6-12 weeks. For wide-gap atresia with distal fistula, primary anastomosis under marked or extreme tension with elective paralysis and mechanical ventilation for 5 days postoperatively achieved highly successful results in 39 infants. There were no major anastomotic disruptions and only 7 minor leaks. Strictures developed in 72% of cases and gastro-oesophageal reflux in 54%, 66% of whom required antireflux surgery. There was only 1 death in the 43 patients undergoing oesophageal replacement (none after gastric transposition, n = 34). A highly satisfactory outcome was achieved in 85%-90% of infants undergoing a replacement procedure. PMID- 24057784 TI - Twenty-four-hour venoarterial extracorporeal membrane oxygenation without systemic heparinization in dogs. AB - Venoarterial extracorporeal membrane oxygenation (ECMO) was performed in five dogs without systemic heparinization to assess the feasibility of heparin-free ECMO. The surfaces of the inverted hollow-fiber-type oxygenator and circuit of the ECMO system were coated with heparin by the endpoint-attached (covalent bonded) technique. No heparin was administered to the animal except for a small dose to maintain patency of the arterial line (1 IU/h). ECMO was run for 24 h at a pump flow of 50 ml/kg . min and was successful throughout the experiment in four of the five dogs. Scanning electron microscopy did not detect any blood clots in the oxygenator or circuit except for inside and outside the cannulas that were not coated with heparin in the carotid artery and jugular vein. Activated clotting time (ACT), fibrinogen, and anti-thrombin III (AT-III) activity remained within the normal physiological range. Serum heparin concentrations were low throughout the experiment, indicating minimal heparin release. Platelet levels decreased and fibrinopeptide B beta15-42 (FPB beta15-42) increased significantly after 6 h ECMO. D-dimer levels did not change throughout the experiment. ECMO was discontinued in one case after successful a 23-h run because of macroscopic clot formation at the oxygenator blood inlet. ACT had suddenly increased to 160 s approximately 1 h prior to this clot formation. These results suggest that the amount of systemic heparinization required can be substantially reduced by a heparin-coated ECMO system. Total abolishment of heparin administration in pediatric venoarterial ECMO may be possible by refinement of this technique. Monitoring of AT-III and FPB beta15-42 in addition to ACT may be useful for early diagnosis of latent but ongoing coagulopathies during ECMO. PMID- 24057785 TI - Cholelithiasis in children with sickle cell disease. AB - Abdominal ultrasonography was performed on 305 children with sickle cell disease (SCD) (285 SS and 20 S-beta-thalassemia) to establish the prevalence of cholelithiasis in Saudi children with SCD. Their ages ranged from 1 to 18 years (mean 10.45 years). Gallstones were demonstrated in 60 children, giving a prevalence of 19.7%. An additional 50 patients (16.4%) had only biliary sludge. The youngest patient with gallstones was 3 years old. There was a correlation between the presence of gallstones and increasing age. Patients with gallstones were also found to have higher serum bilirubin levels, but their hemoglobin, hematocrit, reticulocyte count, hemoglobin S, and hemoglobin F levels were not significantly different from those of patients without gallstones. PMID- 24057786 TI - Reconstruction for duodenal atresia: tapered or non-tapered duodenoplasty? AB - The short-term outcome of surgery for congenital duodenal stenosis or atresia has been evaluated by studying the case-notes of 37 patients treated between 1988 and 1993. Eighteen underwent 'tapered' duodeno-duodenostomy; biliary complications occurred in 3 and 1 developed an adhesive intestinal obstruction. Transient post operative vomiting occurred in 1 other patient. Nineteen patients underwent non tapered duodeno-duodenostomy. One die 19 days post-operatively; 1 developed an intra-peritoneal abscess and another an adhesive intestinal obstruction. Transient post-operative vomiting occurred in 3 other patients. Full intra gastric feeding was achieved between a mean of 13 and 14 days in both groups. There was no advantage to either technique with regard to the time of establishment of full intra-gastric feeding. Although there were surgical complications in both groups, it appears that tapered duodenoplasty carries a considerable risk of incidental biliary injury. PMID- 24057787 TI - The omentum-pedicled intestinal segment: an experimental model for bowel lengthening. AB - Various experiments designed to increase the absorptive surface of the intestine to minimize dependence on total parenteral nutrition in short-bowel syndromes have been challenged by the limitations of the vascular supply to the gut. We have investigated the feasibility of small-bowel lengthening in a rabbit model by creating a neo-mesentery for a segment of jejunum. In this method the serosa of the antimesenteric aspect of the jejunum is removed and a flap of omentum is attached to this surface. Intestinal segments were separated from their original mesentery after 5, 6, and 7 weeks of omental revascularization and specimens examined histologically 24 h after vascular division. Our data support the hypothesis that intestinal segments with both omental and mesenteric pedicles are viable and that the small bowel can be divided longitudinally and remodelled for elongation with the vascular support of the two distinct sources. PMID- 24057788 TI - Initial experience with one-stage endorectal pull-through procedures for Hirschsprung's disease. AB - To evaluate our experience with one-stage endorectal pull-through (ERPT) procedures (without colostomy) for Hirschsprung's disease (HD), we compared 7 such patients to a cohrt of 20 consecutive patients undergoing EROT folowing colostomy. Reasons for exclusion from hte cohort group included: (1) bowel obstruction requiring operation before 1 month of age; (2) presentation with enterocolitis (EC), intestinal perforation, or massive fecal distension; (3) long segment disease; or (4) severe associated anomalies. The 7 male patients in the single-stage ERPT group first presented at a median age of 16 days (4 days-2.5 years) and were managed by regular digital dilation or colonic irrigation for between 1 and 6 months (median 2 months) prior to surgery. Single-stage procedures were performed at a median age and weight of 4 months (2 months-2.5 years) and 6.4 kg (4.5-13.8 kg), respectively Median hospitalization for these patients was 9 dyas. Postoperative complications occurred in 2 patients (29%), and included anastomotic stricture requiring outpatient dilation, and 1 case or recurrent EC that responded to a course of anal dilations. The cohort group (14 M, 6 F) presented at a median of 15 months. All underwent colostomy as a primary procedure. ERPT was deferred until a median age of 21 months, and the hospitalization after pull-through averaged 10 dyas (20 days including stay after colostomy). Four patient (20%) developed complications requiring reoperation following the initial colostomy. Complications after ERPT occurred in 5 patients (25%) and included 1 death from fulminant Hirschsprung's EC. Other complications included 1 anastomotic stricture and 2 mucosal prolapses requiring anoplasty. Long-term functional results were similar in both groups. Despit our limited experience, we conclude that one-stage ERPT can be safely performed in infants, including those under 3 months of age, with rectosigmoid HD. Total duration of hospitalization is reduced and colostomy complications are avoided. Functional outcome appears to be comparable between patients treated in one or two stages. PMID- 24057789 TI - A selective approach to the treatment of acute scrotum in children. AB - To determine a reliable clinical approach to the problem of acute scrotum (AS) in children and identify patients who require emergent surgical intervention, 65 boys with the diagnosis of AS were studied. The mean age was 11 years. Acute orchitis/epididymitis was diagnosed in 42 (64.6%), torsion of the testis in 12 (18.5%), and torsion of the appendix testis in 5 (7.7%). A testicular radionuclide scan was the most reliable diagnostic tool, being positive in all 12 cases of torsion of the testis. Eighteen patients underwent scrotal exploration. Detorsion and bilateral orchidopexy was performed in 12, excision of a necrotic appendix testis in 5, and evacuation of a scrotal hematoma in 1. The outcome of the involved testis at follow-up examination was excellent, with only 1 child developing testicular atrophy. This study stresses the reliability of the selective approach for the treatment of the AS in children. PMID- 24057790 TI - Preoperative sonography of the inguinal canal prevents unnecessary contralateral exploration. AB - The need for contralateral inguinal exploration in children during unilateral inguinal hernia repair remains controversial. We questioned whether an elective preoperative sonographic examination of the contralateral inguinal canal was accurate enough to prevent unnecessary exploration of the asymptotic side. Sonography (US) of the groins was performed randomly in 200 out of 600 patients awaiting unilateral hernia repair over a 1.5-year period during 1990-1991. The patients and their medical records were reviewed in 1994, 3-4 years following surgery. Four hundred infants and children underwent unilateral inguinal hernia repair without preoperative US, based on the clinical diagnosis (group I). Of the remaining 200, 160 (group II)_ had the clinical diagnosis confirmed by US. Forty patients with US evidence of a contralateral hernia or hydrocele (group III) were excluded from the study. At follow-up after 3-4 years, 26 patients in group I presented with a hernia in the opposite groin 2 weeks to 2 years following surgery. The incidence of a subsequent contralateral hernia in patients under 1 year, 1-2 years, and older than 2 years was 7.3%, 9.6%, and 4.5%, respectively. None of the patients in group II presented with a clinically evident hernia during the follow-up period. These findings suggest that US is a readily available, non-invasive, and accurate method of preoperative evaluation of the groins. Our policy of contralateral exploration based on the US findings was shown to be reliable in preventing unnecessary surgical exploration of the unaffected inguinal canal. PMID- 24057791 TI - Coincidence of congenital cystic adenomatoid malformation and extralobar sequestration of the lung in a newborn. AB - We present a rare case of coincidence of an extralobar sequestration with a congenital cystic adenomatoid malformation of the lung in a newborn. The symptoms, diagnostic features, and therapy are described and the etiology and classification are briefly discussed. PMID- 24057792 TI - The Rapunzel syndrome: case report and review of the literature. AB - We report a case of a gastric trichobezoar (TB) extending throughout the small bowel in a child. The possibility of a TB causing an epigastric mass should be borne in mind, and ultrasonography could be used to support such a diagnosis. These bezoars should be considered to possibly have extensions for which there may be no preoperative or endoscopic evidence. Their complete operative removal is required. A psychiatric consultation and long-term follow-up are necessary, as recurrence of trichophagia and eventually the TB could occur. PMID- 24057793 TI - Excision of a choledochal cyst and simultaneous hepatic lateral segmentectomy. AB - We treated a 4-year-old girl with a choledochal cyst (CC) with bilateral intrahepatic involvement. A severe stricture between the enormously dilated left intrahepatic bile duct and the dilated common hepatic duct was found; this necessitated prophylactic hepatic lateral segmentectomy together with excision of the CC to avoid possible stone formation in the cystically dilated left intrahepatic duct. The choice of the combined procedures was based upon long-term results of other patients in our experience. This is the first such procedure to be reported. PMID- 24057794 TI - Infarcted intestinal volvulus detected by prenatal ultrasonography. AB - This article describes a prenatal ultrasonographic finding of an infarcted intestinal volvulus. Ultrasonography showed polyhydramnios, multiple dilated intestinal loops, increased transverse abdominal area, and ascites. After cesarean section due to premature rupture of membranes and fetal distress, derotation of the infarcted volvulus caused postoperative thrombocytopenia, hyperkalemia, and acidosis and a subsequent resection was required. A high output of intestinal juice from the jejunostomy caused severe hypovolemia and electrolyte imbalance with resultant death. Increased transverse abdominal area caused by marked intestinal dilatation, ascites, fetal distress, and hydrops fetalis may suggest an infarcted intestinal volvulus. PMID- 24057795 TI - Neonatal intussusception as a presenting sign of Hirschsprung's disease. AB - A case of ileocecal intussusception as a presenting sign of Hirschsprung's disease in the neonatal period is presented with a review of the literature. PMID- 24057796 TI - Nissen-type colonic bladder wall ureteral wraparound for reimplantation in a complex reconstructive case. AB - We have applied a technique patterned after the Nissen gastroesophageal fundoplication to accomplish an antireflux mechanism in a girl who had had several failed operations that left her with a microbladder augmented with colon and both ureters replaced by small bowel and implanted without any antireflux procedure. Anchoring of the wrapped colonic bladder wall to the ureteral musculature and the addition of a psoas hitch were important in assuring the success of the procedure. This technique can be utilized in similar cases as a tool to prevent reflux and avoid the need for more complex surgical treatment. PMID- 24057797 TI - Neonatal inguinoscrotal hematocele. AB - Neonatal inguinoscrotal lesion, or hematocele of neonates, is attributed to trauma from the plastic clamp used to ligate the umbilical cord immediately after delivery. The pathogenesis is thought to be related to two factors: incorrect clamping technique, in which the clamp is eccentric or too distal, and the infant's position, lying over the clamp. This is a rare event that usually appears on the 2nd day of life, with very few reports recorded in the literature. The lesion does not have any complications, but may be easily confused with testicular torsion. We present two cases and review the literature. PMID- 24057799 TI - Letters to the editor. PMID- 24057798 TI - A simple alternative to circumcision. AB - Circumcision is overperformed in the United Kingdom. An alternative procedure, dorsal incision of the prepuce, was performed in 40 boys whose foreskins were nonretractable and showed a tight preputial band on retraction at operation with no scarring. The procedure was quick, simple, and effective at producing a retractable foreskin. A good cosmetic result was achieved. There were no complications in this group of patients. The procedure is recommended as an alternative to circumcision. PMID- 24057801 TI - Duration of plague (Yersinia pestis) outbreaks in black-tailed prairie dog (Cynomys ludovicianus) colonies of northern Colorado. AB - Plague, caused by the bacterium Yersinia pestis, triggers die-offs in colonies of black-tailed prairie dogs (Cynomys ludovicianus), but the time-frame of plague activity is not well understood. We document plague activity in fleas from prairie dogs and their burrows on three prairie dog colonies that suffered die offs. We demonstrate that Y. pestis transmission occurs over periods from several months to over a year in prairie dog populations before observed die-offs. PMID- 24057800 TI - A unified GMDR method for detecting gene-gene interactions in family and unrelated samples with application to nicotine dependence. AB - Gene-gene and gene-environment interactions govern a substantial portion of the variation in complex traits and diseases. In convention, a set of either unrelated or family samples are used in detection of such interactions; even when both kinds of data are available, the unrelated and the family samples are analyzed separately, potentially leading to loss in statistical power. In this report, to detect gene-gene interactions we propose a generalized multifactor dimensionality reduction method that unifies analyses of nuclear families and unrelated subjects within the same statistical framework. We used principal components as genetic background controls against population stratification, and when sibling data are included, within-family control were used to correct for potential spurious association at the tested loci. Through comprehensive simulations, we demonstrate that the proposed method can remarkably increase power by pooling unrelated and offspring's samples together as compared with individual analysis strategies and the Fisher's combining p value method while it retains a controlled type I error rate in the presence of population structure. In application to a real dataset, we detected one significant tetragenic interaction among CHRNA4, CHRNB2, BDNF, and NTRK2 associated with nicotine dependence in the Study of Addiction: Genetics and Environment sample, suggesting the biological role of these genes in nicotine dependence development. PMID- 24057802 TI - Pre-emptive national monitoring plan for detecting the amphibian chytrid fungus in Madagascar. PMID- 24057804 TI - Linking the historical roots of environmental conservation with human and wildlife health. AB - We examine the historical and philosophical roots of environmental stewardship and how they relate to conservation and human health. Concern for the environment in the United States derives from two distinct historical ideologies that we term ''green'' and ''brown'' environmentalism. We propose a modern-day synthesis of these ideologies that recognizes that environmental degradation and the emergence of zoonotic and epizootic diseases, affecting both humans and wildlife (i.e., pathogen pollution), are interconnected. This interconnection provides a compelling new reason to protect and preserve biodiversity. PMID- 24057805 TI - Cultural and social influences on adolescent smoking dissipate by emerging adulthood among Hispanics in Southern California. AB - The aim of the present study was to identify risk factors for smoking among Hispanic adolescents and determine whether these factors continued to influence smoking into emerging adulthood. Data were drawn from 932 Hispanics in the greater Los Angeles area who were surveyed in high school in 2007 and then again in emerging adulthood from 2010 to 2012. Logistic regression assessed the associations between predictors in adolescence and smoking in adolescence while an order one transition logistic model assessed predictors in adolescence and smoking in emerging adulthood. Adult and sibling smoking status, perceptions of smoking, perceived discrimination, and fatalism all influenced smoking in adolescence but not in emerging adulthood. Once Hispanics reach emerging adulthood different tactics to reduce smoking will be needed and are where future research should be directed. PMID- 24057806 TI - Health related lifestyle and preventive medical care of rural Spanish women compared to their urban counterparts. AB - The objective of this work is to study the differences in health related behavior, habits and preventive health care attendance between women living in rural areas and their metropolitan counterparts in Spain. We analyzed health related behavior (such as leisure time physical activity, smoking, alcohol use and other health related dietary patterns) and preventive medical attendance (gynecological attendance, mammography frequency, flu vaccinations, cholesterol and blood pressure checks) in a total of 17,833 women older than 16 from the Spanish National Health Survey 2006. A multinomial logistic regression model was employed to compare groups (adjusted for age and social class). The main findings of this study is that the likelihood of receiving and attending to preventive public health care services was significantly lower for women in medium-sized urban or rural and remote locations than those living in metropolitan areas, as well as differences in health-related lifestyle behaviours. PMID- 24057807 TI - Efficacy of population structure analysis with breeding populations and inbred lines. AB - The objective was to assess by simulation the efficacy of population structure analysis in plant breeding. Twelve populations and 300 inbred lines were simulated and genotyped using 100 microsatellite loci. The experimental material included populations with and without admixture, ancestry relationship and linkage disequilibrium, and with distinct levels of genetic differentiation and effective sizes. The analyses were performed using Structure software and employed all available models. For all the group number (K) tested, for both populations and inbred lines, the admixture model with correlated allelic frequencies provided the highest value for the logarithm of the marginal likelihood. Fitting appropriate model and using adequate sample size for individuals and markers, Structure was effective in identifying the correct population structure, migrants and individuals with genome from distinct populations. The linkage model did not result in an improvement in clustering relative to the admixture model with correlated allelic frequencies. The inclusion of prior information did not change the results; for some K values the analyses showed slight higher values of the marginal likelihood. The reduction in the number of individuals and markers negatively affected the results. There was a high variation in the most probable K value between the evaluated methods. PMID- 24057808 TI - Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials. AB - Beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of the branched-chain amino acid leucine, is extensively used by athletes and bodybuilders in order to increase strength, muscle mass and exercise performance. We performed a systematic review of the clinical literature on the effectiveness of HMB supplementation in healthy and pathological conditions (i.e. training programs, aging, acute and chronic diseases, and after bariatric surgery). We reviewed all clinical trials indexed in Medline that tested HMB supplementation as well as all the experimental data regarding HMB intracellular mechanisms of action. Search terms included: randomized controlled trials, controlled clinical trials, single- and double-blind method, HMB, proteolytic pathways, muscle atrophy, cachexia, and training. We found out 13 studies testing HMB in healthy young trained subjects, 11 in healthy young untrained subjects, 9 in patients affected by chronic diseases (i.e. cancer, HIV, chronic obstructive pulmonary disease), and 6 in elderly subjects. The indexed studies support that HMB is effective in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. Most of the selected studies showed the effectiveness of HMB in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. The usual dose of 3 g/day may be routinely recommended to maintain or improve muscle mass and function in health and disease. The safety profile of HMB is unequivocal. Further, well-designed clinical studies are needed to confirm effectiveness and mode of action of HMB, particularly in pathological conditions. PMID- 24057809 TI - Preparation and characterization of a hydrogel carrier to deliver gatifloxacin and its application as a therapeutic contact lens for bacterial keratitis therapy. AB - A soft and biocompatible hydrogel exhibiting a higher loading and the sustained release of gatifloxacin (GFLX) was developed as the potential matrix to fabricate a therapeutic contact lens for curing bacterial keratitis. 2-hydroxyethyl methacrylate (HEMA) and five other kinds of vinyl monomers with different side groups were used as co-monomers. Copolymerization took place in a cornea shaped mould via the gradient temperature-elevating method. The results of drug loading and in vitro release experiments showed that P(HEMA-co-MAA) achieved the highest drug loading of 11.78+/-0.77 ug mg(-1) among the obtained hydrogels, as well as a slow release. In addition, its physical properties and cytocompatibility were also proved suitable and safe for wearing on the eye surface. In animal experiments, a rat model of bacterial keratitis was established and employed to evaluate the clinical results of certain treatments employing obtained hydrogels; saline and GFLX eye drops were used as negative and positive controls, respectively. Corneal abscess and opacity caused by epithelial erosion and stromal ulceration were almost healed after wearing the drug loaded P(HEMA-co MAA) hydrogel for 48 h. Its excellent antibacterial effect was also confirmed by testing the bacterial activity in tear extraction via the streak line method. PMID- 24057810 TI - Traumatic cleft earlobe repair: using a double triangular flap for differently sized components on either side of the cleft. AB - Numerous techniques, including double opposing Z-plasty, have been introduced to repair traumatic cleft earlobes and break the linear scar. Even with multiple operative methods available for repairing traumatic cleft earlobe, notable scar contractures and dimpling of the earlobe border remain in some cases. The authors noted patients with different sized components on either side of the traumatized earlobe. For these patients, the authors utilized epithelialized skin to elevate two small triangular flaps from the larger component of the cleft earlobe and transferred them to the smaller component to augment the volume and elongate the scar. There was minimal tissue loss and dissection. Five patients with an asymmetrical secondary cleft earlobe with different sized components underwent lobe repair via this method, and there was no scar contracture or dimpling after at least 6 months of follow-up. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24057811 TI - Effect of pregabalin and dexamethasone addition to multimodal analgesia on postoperative analgesia following rhinoplasty surgery. AB - BACKGROUND: We investigated the effect of a combination of pregabalin and dexamethasone, when used as part of a multimodal analgesic regimen, on pain control after rhinoplasty operations. METHODS: Sixty patients were enrolled in this study. They were randomly assigned into three groups: Group C (placebo + placebo), Group P (pregabalin + placebo), and Group PD (pregabalin + dexamethasone). Patients received either pregabalin 300 mg orally 1 h before surgery, dexamethasone 8 mg intravenously during induction, or placebo according to their allocation. Postoperative pain was treated with intravenous patient controlled analgesia (tramadol, 20-mg bolus dose, 45-min lockout time). The numeric rating scale (NRS), side effects, and consumption of tramadol, pethidine, and ondansetron were assessed. RESULTS: The median NRS scores at 0, 1, and 6 h after surgery were significantly higher in Group C than in Group PD (p < 0.001 for all). The 24-h consumption of tramadol and pethidine was significantly reduced in Groups P and PD compared to Group C (p < 0.01 and p < 0.01). The total tramadol consumption was decreased by 54.5 % in Group P and 81.9 % in Group PD compared to Group C (p < 0.001 for both). The incidence of nausea was higher in Group C than in Groups P and PD between the postoperative 0-2 and 0-24-h periods (p < 0.05 for both). The frequency of blurred vision was significantly higher in Groups P and PD than in Group C within the 0-24-h period (p < 0.05 for both). CONCLUSION: We found that the addition of a single dose of pregabalin and dexamethasone to multimodal analgesia in rhinoplasty surgeries provided efficient analgesia and thus decreased opioid consumption. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24057812 TI - Validity of exchangeable solute balance as a measure of blood volume in neurologically injured adults. AB - BACKGROUND: Daily weight (DW) and examination of fluid balances (FB) are commonly used in assessments of extracellular fluid (ECF) and circulating blood volume (BV). We hypothesized that a calculated total body exchangeable solute, the main determinant of the ECF, would have high agreement and correlation with actual BV. METHODS: The University of Washington IRB approved the study. We included a sample of consecutive adult patients in whom a BV was measured, while in the neuroscience intensive care units of a large academic medical center. BV was measured as part of routine care using iodinated (131)I albumin injection and the BVA-100 (Daxor Corp, New York, NY, USA). Total body exchangeable solute was estimated at the time of BV measurement by multiplying the calculated total body water by the sum of the sodium plus potassium and chloride measured in plasma. The correlation between the change in DW, FB (adjusted for insensible fluid loss), exchangeable solute, and BV was performed using linear regression with adjustment for number of days between admit and BV measurement, and capillary leak. Errors were computed using robust variance estimation. RESULTS: 55 patients had BV tests available, and 43 of them had subarachnoid hemorrhage. Total body exchangeable solute strongly correlated with BV (r = 0.75, 95% CI 0.63-0.84, p < 0.01 for Na(+)/K(+), and r = 0.71, 95% CI 0.58-0.81, p < 0.01 for Cl(-)). DW (r = 0.21) and FB (r = 0.11) were not correlated with BV. CONCLUSIONS: Total body exchangeable solute appears to be a valid and reliable measure of BV and can be calculated using information readily available at the bedside. The value of having this information automatically calculated and available at the bedside should be explored. PMID- 24057814 TI - DNA methylation biomarkers as diagnostic and prognostic tools in colorectal cancer. AB - Colorectal cancer (CRC) is the third most common type of cancer and is responsible for 9 % of cancer deaths in both men and women in the USA for 2013. It is a heterogenous disease, and its three classification types are microsatellite instability, chromosomal instability, and CpG island methylator phenotype. Biomarkers are molecules, which can be used as indicators of cancer. They have the potential to achieve great sensitivities and specificities in diagnosis and prognosis of CRC. DNA methylation biomarkers are epigenetic markers, more specifically genes that become silenced after aberrant methylation of their promoter in CRC. Some methylation biomarkers like SEPT9 (ColoVantage(r)) and vimentin (ColoSure(TM)) are already commercially available. Other blood and fecal-based biomarkers are currently under investigation and clinical studies so that they can be used in the near future. Biomarker panels are also currently being studied since they show great potential in diagnosis as they can combine robust biomarkers to achieve even greater sensitivities than single markers. Finally, methylation-sensitive microRNAs (miRNAs) are very promising markers, and their investigation as biomarkers, is only at primitive stage. PMID- 24057813 TI - The role of interleukin-6 in the evolution of ovarian cancer: clinical and prognostic implications--a review. AB - An increasing number of studies emphasize the role of inflammation and metabolic changes in the induction of cancer-related symptoms, which can affect cancer evolution and prognosis. These changes result from the interactions between the tumor and the host. To date, however, markers of this peculiar condition, which can help clinicians to manage patients better, have still not been identified with certainty. Epithelial ovarian cancer (EOC) appears to be particularly appropriate to study these interactions because of its biological characteristics, its peculiar evolution, and the relevant scientific evidence available. Immunosuppression, anemia, depression, and weight loss affect the evolution of EOC and appear to be directly related to the immune-metabolic changes. In light of the aforementioned evidence, our review will focus on interleukin-6 (IL-6) and its role as potential marker of the patients' immune metabolic status, to better monitor disease outcome and identify the most appropriate therapeutic strategy in EOC. Furthermore, leptin will be discussed as a sensor of the changes of energy metabolism induced by IL-6. PMID- 24057815 TI - Amphetamine and cocaine suppress social play behavior in rats through distinct mechanisms. AB - RATIONALE: Social play behavior is a characteristic form of social behavior displayed by juvenile and adolescent mammals. This social play behavior is highly rewarding and of major importance for social and cognitive development. Social play is known to be modulated by neurotransmitter systems involved in reward and motivation. Interestingly, psychostimulant drugs, such as amphetamine and cocaine, profoundly suppress social play, but the neural mechanisms underlying these effects remain to be elucidated. OBJECTIVE: In this study, we investigated the pharmacological underpinnings of amphetamine- and cocaine-induced suppression of social play behavior in rats. RESULTS: The play-suppressant effects of amphetamine were antagonized by the alpha-2 adrenoreceptor antagonist RX821002 but not by the dopamine receptor antagonist alpha-flupenthixol. Remarkably, the effects of cocaine on social play were not antagonized by alpha-2 noradrenergic, dopaminergic, or serotonergic receptor antagonists, administered either alone or in combination. The effects of a subeffective dose of cocaine were enhanced by a combination of subeffective doses of the serotonin reuptake inhibitor fluoxetine, the dopamine reuptake inhibitor GBR12909, and the noradrenaline reuptake inhibitor atomoxetine. CONCLUSIONS: Amphetamine, like methylphenidate, exerts its play-suppressant effect through alpha-2 noradrenergic receptors. On the other hand, cocaine reduces social play by simultaneous increases in dopamine, noradrenaline, and serotonin neurotransmission. In conclusion, psychostimulant drugs with different pharmacological profiles suppress social play behavior through distinct mechanisms. These data contribute to our understanding of the neural mechanisms of social behavior during an important developmental period, and of the deleterious effects of psychostimulant exposure thereon. PMID- 24057817 TI - Terry D. Fife, MD. PMID- 24057818 TI - Neuro-otology. Preface. PMID- 24057816 TI - Behavioral effects of dopamine receptor inactivation in the caudate-putamen of preweanling rats: role of the D2 receptor. AB - RATIONALE: Inactivating dopamine (DA) receptors in the caudate-putamen (CPu) attenuates basal and DA agonist-induced behaviors of adult rats while paradoxically increasing the locomotor activity of preweanling rats. OBJECTIVE: The purpose of this study was to determine (a) whether D1 or D2 receptor inactivation is responsible for the elevated locomotion shown by preweanling rats and (b) whether DA receptor inactivation produces a general state in which any locomotor-activating drug will cause a potentiated behavioral response. METHODS: Dimethyl sulfoxide (DMSO) or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was bilaterally infused into the CPu on postnatal day (PD) 17. In experiment 1, DA receptors were selectively protected from EEDQ-induced alkylation by pretreating rats with D1 and/or D2 antagonists. On PD 18, rats received bilateral microinjections of the DA agonist R(-)-propylnorapomorphine into the dorsal CPu, and locomotor activity was measured for 40 min. In subsequent experiments, the locomotion of DMSO- and EEDQ-pretreated rats was assessed after intraCPu infusions of the selective DA agonists SKF82958 and quinpirole, the partial agonist terguride, or after systemic administration of nonDAergic compounds. RESULTS: Experiment 1 showed that EEDQ's ability to enhance the locomotor activity of preweanling rats was primarily due to the inactivation of D2 receptors. Consistent with this finding, only drugs that directly or indirectly stimulated D2 receptors produced a potentiated locomotor response in EEDQ-treated rats. CONCLUSIONS: These results show that DA receptor inactivation causes dramatically different behavioral effects in preweanling and adult rats, thus providing additional evidence that the D2 receptor system is not functionally mature by the end of the preweanling period. PMID- 24057819 TI - Acute continuous vertigo. AB - Acute continuous vertigo presentations are among the most feared presentations in medicine. Although a self-limited disorder is the typical cause, a life threatening stroke can also occur. Differentiating a self-limited disorder from a life-threatening stroke can be a challenge. Routinely collected information--such as stroke risk factors and findings on the general neurologic examination--is not likely to enable the clinician to discriminate between these causes. A focused oculomotor examination is a necessary component of the assessment, but is underused in routine care. The author describes the challenges to diagnosing stroke in cases of acute continuous vertigo and provides an approach to inform decision making at the bedside. Future research is necessary to validate clinical decision support, assess generalizability, and demonstrate its impact on meaningful outcomes. PMID- 24057820 TI - Vertigo due to posterior circulation stroke. AB - Stroke in the distribution of the posterior circulation may present as acute onset spontaneous vertigo and imbalance. Although vertigo due to posterior circulation stroke is usually associated with other neurologic symptoms or signs, small infarcts in the cerebellum or brainstem can present with vertigo without other localizing symptoms. Approximately 17% of patients with isolated posterior inferior cerebellar artery territory infarction presented with isolated vertigo, nystagmus, and postural unsteadiness. A head impulse test can differentiate acute isolated vertigo associated with cerebellar stroke from more benign disorders involving the inner ear. Sometimes acute isolated audiovestibular loss can be the initial symptom of impending posterior circulation ischemic stroke (particularly within the territory of the anterior inferior cerebellar artery). In this case, evaluation of isolated audiovestibular loss may prevent the progression of acute vertigo and hearing loss into more widespread areas of infarction in the posterior circulation. In this article, the clinical syndromes and signs of acute vestibular syndrome due to posterior circulation stroke involving the brainstem and cerebellum are summarized. PMID- 24057821 TI - Vestibular neuritis. AB - Vestibular neuritis is the most common cause of acute spontaneous vertigo. Vestibular neuritis is ascribed to acute unilateral loss of vestibular function, probably due to reactivation of herpes simplex virus in the vestibular ganglia. The diagnostic hallmarks of vestibular neuritis are spontaneous horizontal torsional nystagmus beating away from the lesion side, abnormal head impulse test for the involved semicircular canals, ipsilesional caloric paresis, decreased responses of vestibular-evoked myogenic potentials during stimulation of the affected ear, and unsteadiness with a falling tendency toward the lesion side. Vestibular neuritis preferentially involves the superior vestibular labyrinth and its afferents. Accordingly, the function of the posterior semicircular canal and saccule, which constitute the inferior vestibular labyrinth, is mostly spared in vestibular neuritis. However, because the rare subtype of inferior vestibular neuritis lacks the typical features of vestibular neuritis, it may be misdiagnosed as a central vestibular disorder. Even in the patient with the typical pattern of spontaneous nystagmus observed in vestibular neuritis, brain imaging is indicated when the patient has unprecedented headache, negative head impulse test, severe unsteadiness, or no recovery within 1 to 2 days. Symptomatic medication is indicated only during the acute phase to relieve the vertigo and nausea/vomiting. Vestibular rehabilitation hastens the recovery. The efficacy of topical and systemic steroids requires further validation. PMID- 24057822 TI - Bilateral vestibular loss. AB - Bilateral vestibular loss is a rare cause of visual disturbance (oscillopsia) and imbalance. When severe, the most common cause is iatrogenic-gentamicin ototoxicity. Bilateral loss is easily diagnosed at the bedside with the dynamic illegible E test. If this test is omitted, it can easily be misdiagnosed as a cerebellar syndrome. Treatment is largely supportive. Care should be taken to avoid medications that suppress vestibular function, and to encourage activity. PMID- 24057823 TI - Benign paroxysmal positional vertigo. AB - Benign paroxysmal positional vertigo (BPPV) is the most common and the most effectively treated vestibular disorder. The prevailing pathomechanism is canalolithiasis, which is otoconia falling in one of the semicircular canals where they move in response to changes of the head position, triggering excitation of the vestibular receptors of the affected canal. In the majority of patients with BPPV, the posterior canal is affected by canalolithiasis and there are two highly effective therapeutic maneuvers for treatment. About 20% of patients present with lithiasis of the horizontal or anterior canal. The author focuses on recent advances in diagnosis and treatment of the more rare variants of BPPV. PMID- 24057824 TI - Vestibular migraine. AB - Vestibular migraine presents with attacks of spontaneous or positional vertigo, head motion-induced vertigo, and visual vertigo lasting 5 minutes to 3 days. The recent classification of vestibular migraine, jointly proposed by the Barany Society and the International Headache Society, allows identification of vestibular migraine and probable vestibular migraine based on explicit criteria. The diagnosis is based on symptom type, severity and duration, a history of migraine, temporal association of migraine symptoms with vertigo attacks, and exclusion of other causes. Because headache is often absent during acute attacks, other migraine features such as photophobia or auras have to be specifically inquired about. During acute attacks, one may find central spontaneous or positional nystagmus, and less commonly, unilateral vestibular hypofunction. In the symptom-free interval, vestibular testing adds little to the diagnosis as findings are mostly minor and nonspecific. The pathophysiology of vestibular migraine is unknown, but several mechanisms link the trigeminal system, which is activated during migraine attacks, and the vestibular system. Treatment includes antiemetics for severe acute attacks, pharmacological migraine prophylaxis, and lifestyle changes. PMID- 24057825 TI - Vertigo and dizziness from environmental motion: visual vertigo, motion sickness, and drivers' disorientation. AB - The normal vestibular system may be adversely affected by environmental challenges which have characteristics that are unfamiliar or ambiguous in the patterns of sensory stimulation they provide. A disordered vestibular system lends susceptibility even to quotidian environmental experiences as the sufferer becomes dependent on potentially misleading, nonvestibular sensory stimuli. In both cases, the sequelae may be vertigo, incoordination, imbalance, and unpleasant autonomic responses. Common environmental motion conditions include visual vertigo, motion sickness, and motorists' disorientation. The core therapy for visual vertigo, motion sickness, and drivers' disorientation is progressive desensitization within a cognitive framework of reassurance and explanation, plus anxiolytic tactics and autogenic control of autonomic symptoms. PMID- 24057826 TI - Otolithic disease: clinical features and the role of vestibular evoked myogenic potentials. AB - Through selective tests of the function of the canal and otolith sense organs, it is possible to assert that patient conditions are purely otolithic and that the canals are not involved. The video head impulse test selectively tests each semicircular canal; the ocular vestibular-evoked myogenic potential to 500 Hz Fz (Fz is the location on the forehead in the midline at the hairline) bone conducted vibration (BCV) selectively tests the utricular macula and the cervical vestibular-evoked myogenic potential to 500 Hz Fz BCV selectively tests the saccular macula. The development of new specific tests of otolith function has shown that some patients may have specific deficits of just otolithic function. In the authors' experience, patients who complain strongly of postural unsteadiness should be suspected to have otolithic deficits. They may also have vertigo and in some cases have spontaneous nystagmus of peripheral origin, even though their semicircular canal function is normal. The prognosis for such patients is good. They usually appear to regain their postural stability spontaneously over weeks (or longer), even though they still have an otolithic deficit as shown by objective tests when they are free of symptoms. It is not known what procedures may accelerate the recovery of otolith function. PMID- 24057827 TI - Posttraumatic vertigo and dizziness. AB - Dizziness and vertigo are common symptoms following minor head trauma. Although these symptoms resolve within a few weeks in many patients, in some the symptoms may last much longer and impede ability to return to work and full functioning. Causes of persisting or recurrent dizziness may include benign paroxysmal positional vertigo, so-called labyrinthine concussion, unilateral vestibular nerve injury or damage to the utricle or saccule, perilymphatic fistula, or less commonly traumatic endolymphatic hydrops. Some dizziness after head trauma is due to nonlabyrinthine causes that may be related to structural or microstructural central nervous system injury or to more complicated interactions between migraine, generalized anxiety, and issues related to patients self-perception, predisposing psychological states, and environmental and stress-related factors. In this article, the authors review both the inner ear causes of dizziness after concussion and also the current understanding of chronic postconcussive dizziness when no peripheral vestibular cause can be identified. PMID- 24057828 TI - Clinical characteristics of cervicogenic-related dizziness and vertigo. AB - Cervical vertigo has long been a controversial entity and its very existence as a medical entity has advocates and opponents. Supporters of cervical vertigo claim that its actual prevalence is underestimated due to the overestimation of other diagnostic categories in clinics. Furthermore, different pathophysiological mechanisms have been attributed to cervical vertigo. Here the authors discuss the clinical characteristics of rotational vertebral artery vertigo, postwhiplash vertigo, proprioceptive cervical vertigo, and cervicogenic vertigo of old age. A clinical entity named subclinical vertebrobasilar insufficiency appears in the context of cervical osteoarticular changes. Migraine-associated vertigo may explain why some patients suffering from cervical pain have vertigo while others do not. PMID- 24057829 TI - Tinnitus: diagnostic approach leading to treatment. AB - Optimal care for a patient with tinnitus begins with identifying the cause of the tinnitus. Once the cause has been identified then an appropriate treatment plan can be initiated. In this article, the author reviews how to identify the tinnitus etiology and its treatment.The workup begins with the patient's description of the percept because in some cases, the quality of the tinnitus will make the diagnosis (e.g., clicking, which is readily suppressed pharmacologically); in other cases, it will give direction in the diagnostic evaluation (e.g., pulsatile). With the exception of a small dural arteriovenous malformation, the source of objective pulsatile tinnitus can be determined without conventional cerebral angiography. If the diagnostic workup is unrevealing and the pulsations are not suppressed with somatic testing, then eighth nerve vascular compression becomes the likely etiology, especially if there is some clicking also heard, no matter how minor.The two major causes of tinnitus are hearing loss and myofascial disorders of the head and neck. Moreover, the two can combine and cause tinnitus even though either condition alone would not have caused tinnitus. Although the tinnitus of hearing loss is not easily treatable, the tinnitus from myofascial disorders is often responsive to an optimized myofascial treatment program. Hyperacusis, a frequent accompaniment of tinnitus, and its treatment are discussed. PMID- 24057830 TI - Causes of imbalance and abnormal gait that may be misdiagnosed. AB - Disorders of gait and balance are common in medicine and often lead to referral for neurologic evaluation. Because the maintenance of balance and normal gait are mediated by complex neurologic pathways as well as musculoskeletal, metabolic, and behavioral considerations, the list of possible contributing causes is very large. Much of the time, the history and neurologic examination reveal the underlying cause or causes. There are instances, however, when there are limited neurologic findings, as well as no structural abnormalities on brain or spine magnetic resonance imaging studies to explain the imbalance or gait difficulty. In this article, selected disorders that may be overlooked in the neurologic examination and imaging studies are reviewed. Possible causes of imbalance include occult drug-induced ataxia, autoimmune ataxia, ataxia associated with tremor, bilateral vestibular hypofunction, and spastic or dystonic gait disorders with normal imaging. PMID- 24057831 TI - Vestibular rehabilitation: rationale and indications. AB - Treatment options of the patient with dizziness include medication, rehabilitation with physical therapy, surgery, counseling, and reassurance. Here the authors discuss vestibular rehabilitation for patients with benign paroxysmal positional vertigo (BPPV), unilateral vestibular loss or hypofunction, and bilateral vestibular loss/hypofunction. They describe the different mechanisms for recovery with vestibular rehabilitation, the exercises that are used, and which ones are best. An exhaustive literature review on clinical outcomes with the best research publications for BPPV, unilateral vestibular loss/hypofunction, and bilateral vestibular loss/hypofunction is presented. For BPPV, the authors also summarize the evidence-based review practice parameters published in Neurology by Fife et al. (2008) and review all relevant articles published since then. PMID- 24057832 TI - Pharmacotherapy of vestibular disorders and nystagmus. AB - Vertigo and dizziness are with a life-time prevalence of ~30% among the most common symptoms and are often associated with nystagmus or other oculomotor disorders. The prerequisite for a successful treatment is a precise diagnosis of the underlying disorder. In this overview, the current pharmacological treatment options for peripheral and central vestibular, cerebellar, and oculomotor disorders including nystagmus are described. There are basically seven groups of drugs that can be used (the "7 As"): antiemetics; anti-inflammatory, anti Meniere's, and antimigraine medications; antidepressants, anticonvulsants, and aminopyridines. In acute vestibular neuritis, recovery of the peripheral vestibular function can be improved by treatment with oral corticosteroids. In Meniere's disease, a long-term high-dose treatment with betahistine dihydrochloride (at least 48 mg three times daily) had a significant effect on the frequency of the attacks; the underlying mode of action is evidently an increase in inner-ear blood flow. The use of aminopyridines is a well-established therapeutic principle in the treatment of downbeat and upbeat nystagmus as well as episodic ataxia type 2 and cerebellar gait disorders. As was shown in animal experiments, these potassium channel blockers increase the activity and excitability and normalize irregular firing of cerebellar Purkinje cells. They evidently augment the inhibitory influence of these cells on vestibular and deep cerebellar nuclei. A few studies showed that baclofen improves periodic alternating nystagmus; gabapentin and memantine improve pendular and infantile nystagmus. However, many other eye-movement disorders such as ocular flutter, opsoclonus, central positioning, and see-saw nystagmus are still difficult to treat. Although substantial progress has been made, further state-of-the-art trials must still be performed on many vestibular and oculomotor disorders, namely Meniere's disease, vestibular paroxysmia, vestibular migraine, and many forms of central eye-movement disorders. PMID- 24057833 TI - Threat assessment and locomotion: clinical applications of an integrated model of anxiety and postural control. AB - Interactions between anxiety and vestibular symptoms have been described since the late 1800s. Typically, they have been conceptualized as bidirectional effects of one condition on the other (i.e., anxiety disorders as a cause of vestibular symptoms and vestibular disorders as a cause of anxiety symptoms). Over the past 30 years, however, a steady progression of neurophysiological investigations of gait and stance under conditions of postural threat, neuroanatomical studies of connections between threat assessment and vestibular pathways in the brain, and clinical research on anxiety-related vestibular conditions has offered the building blocks of a more integrated model. In this newer concept, threat assessment is an integral component of spatial perception, postural control, and locomotion in health and disease. It is not imposed on the vestibular system from the outside or simply reactive to vestibular dysfunction, but an inherently necessary part of every aspect of mobility. In this article, the authors review evidence that supports this model and then use it to examine common neurotologic conditions in which anxiety-related processes play important roles-fear of falling, primary and secondary anxiety disorders in patients with vestibular symptoms, and chronic subjective dizziness. PMID- 24057837 TI - Congenital diaphragmatic hernia: an ongoing debate : Editorial. PMID- 24057836 TI - Home blood pressure monitoring is better predictor of cardiovascular disease and target organ damage than office blood pressure: a systematic review and meta analysis. AB - The available, albeit rare, evidence indicates the superiority of home- over office blood pressure monitoring (HBPM vs OBP) to predict cardiovascular (CV) outcomes. We performed a systematic review to update the efficacy of HBPM vs OBP as predictors of all-cause mortality, CV death, and target organ damage. Two reviewers independently performed the literature search in various databases. A meta-analysis with a fixed-effect model was conducted, and the heterogeneity and inconsistency indices were assessed. The search identified 291 articles, of which 10 were eligible for inclusion in the study, and five articles published in 2012 were included in the meta-analysis. A previous meta-analysis showed the superiority of HBPM over OBP to predict all-cause mortality, CV mortality, and CV events. The meta-analysis of articles published in 2012 identified that HBPM was also a better predictor of proteinuria than OBP. In conclusion, the results of our systematic review and meta-analysis confirm that HBPM is a better predictor of CV outcomes and target organ damage than OBP. PMID- 24057835 TI - Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities. AB - The existence of pleiotropy in disorders with multi-organ involvement can suggest therapeutic targets that could ameliorate overall disease severity. Here we assessed pleiotropy of modifier genes in cystic fibrosis (CF). CF, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects the lungs, liver, pancreas and intestines. However, modifier genes contribute to variable disease severity across affected organs, even in individuals with the same CFTR genotype. We sought to determine whether SLC26A9, SLC9A3 and SLC6A14, that contribute to meconium ileus in CF, are pleiotropic for other early-affecting CF co-morbidities. In the Canadian CF population, we assessed evidence for pleiotropic effects on (1) pediatric lung disease severity (n = 815), (2) age at first acquisition of Pseudomonas aeruginosa (P. aeruginosa) (n = 730), and (3) prenatal pancreatic damage measured by immunoreactive trypsinogen (n = 126). A multiple-phenotype analytic strategy assessed evidence for pleiotropy in the presence of phenotypic correlation. We required the same alleles to be associated with detrimental effects. SLC26A9 was pleiotropic for meconium ileus and pancreatic damage (p = 0.002 at rs7512462), SLC9A3 for meconium ileus and lung disease (p = 1.5 * 10(-6) at rs17563161), and SLC6A14 for meconium ileus and both lung disease and age at first P. aeruginosa infection (p = 0.0002 and p = 0.006 at rs3788766, respectively). The meconium ileus risk alleles in SLC26A9, SLC9A3 and SLC6A14 are pleiotropic, increasing risk for other early CF co-morbidities. Furthermore, co-morbidities affecting the same organ tended to associate with the same genes. The existence of pleiotropy within this single disorder suggests that complementary therapeutic strategies to augment solute transport will benefit multiple CF-associated tissues. PMID- 24057838 TI - Prenatal diagnosis of congenital diaphragmatic hernia and pulmonary hypoplasia and therapeutic strategy. AB - The outcome of fetuses with congenital diaphragmatic hernia (CDH) has been reported to be fatal when pulmonary hypoplasia (PH) is severe. As an indicator of PH, we attempted to measure the lung-thorax transverse area ratio (L/T) using ultrasonic echography. Immediate postnatal surgery was performed using high frequency oscillatory ventilation (HFOV) and sometimes followed by extracorporeal membrane oxygenation (ECMO). Eighteen fetuses were treated and 14 survived. L/T correlated well with the best preductal arterial blood gas data before surgical reduction during manual ventilation and HFOV, while preductal PO2 and alveolar arterial oxygen differences from patients managed with HFOV were better than those in patients with manual ventilation. Although L/T also correlated with the duration of O2 therapy and hospitalization in survivors without major anomalies, there was no significant difference between L/T in survivors and nonsurvivors. Because delayed institution of ECMO and complications related to ECMO management seemed to be a major cause of death in non-survivors, the unsalvageable L/T due to PH was estimated to be below 0.06 for HFOV and below 0.1 for conventional ventilation based on the correlation between L/T and preductal P02. These results suggest that L/T is a useful indicator of PH in patients with CDH and also that HFOV is advantageous in treating CDH with PH. The advantage of prenatal diagnosis in predicting unsalvageable L/Ts, should be considered in the therapeutic strategy. PMID- 24057839 TI - Effect of intrauterine repair of diaphragmatic hernia on the accompanying pulmonary hypoplasia in the fetal rabbit. AB - Severe pulmonary hypoplasia precluding the sustenance of life is often found in newborns with prenatally diagnosed congenital diaphragmatic hernia (CDH). In utero repair of the hernia it is thought to be the sole method of salvaging these patients. To study the efficacy and feasibility of in utero repair of CDH, diaphragmatic hernias (DH) were produced successfully in 81 of 90 fetal rabbits by diaphragmatic perforation via a left thoracotomy at 22 days' gestation (term = 31 days). The DHs were repaired successfully in 25 of 50 fetal rabbits at 26 days' gestation. The rabbits with repaired and non-repaired DHs and their litter mates (the control group) were delivered at 29 days' gestation by cesarean section. Some of the rabbits were killed and subjected to measurements of body and lung weight, determination of the DNA and surfactant (disaturated phosphatidylcholine; DSPC) contents of the lungs, and light and electron microscopic examination of the lung. Some newborn rabbits underwent endotracheal intubation and measurement of pressure-volume curves and pulmonary compliance. The total lung/body weight ratios and total lung DNA contents in the repair group were greater than those in the non-repair Group (P <0.01). There were no differences among the three groups in regard to body weight. When compared with the control group, both the repair and non-repair groups had increased DSPC content (P <0.01 andP <0.05, respectively), although there was no difference between the repair and non-repair groups. Histologically, the thickness of the terminal air spaces was smaller and the size of the lung acini was larger in the repair group than the non-repair group. Electron-microscopically, the number of type 11 lung cells in both the repair and nonrepair groups tended to be larger than that in the control group. When compared with the non-repair group, the repair group showed increased values for pressure-volume curves (P <0.01) and pulmonary compliance (P <0.01). In conclusion, in utero repair of CDHs is effective in improving the hypoplasticity of the lung accompanying this lesion. PMID- 24057840 TI - Congenital diaphragmatic hernia: lung compliance after antenatal tracheal obstruction or surgical correction of the defect. AB - Fetal lambs with diaphragmatic herniae (CDH) created surgically at 73 days' gestation were subjected to three different forms of intrauterine correction: silastic patch correction of the diaphragmatic defect plus an abdominal patch at 101 days gestation; an intrathoracic "silo" at 101 days; and a tracheal "plug" obstruction at 101 or 129 days. At 143 days' gestation (term 145-149 days), the lambs were delivered by caesarean section and ventilated for 30 min before undergoing respiratory compliance measurements. These results were compared to those of normal lambs and animals with uncorrected herniae. The total respiratory system compliance values in those groups undergoing corrections were remarkably similar: those with any form of correction had a significant improvement (P < 0.05) compared to those with herniae and no correction (patch = 1.57 = +/- 0.182 ml/cm H2O; silo = 1.53 +/- 0.179; plug at 101 days = 1.66 +/- 0.311; plug at 129 days = 2.00 +/- 0,175; without correction = 0.62 +/- 0.073). None, however, reached the values of those with normal lungs: 2.72 +/- 0.223 (P < 0.05). This improvement in compliance in all corrected groups suggests that fetal tracheal obstruction is as effective as the two more invasive forms of open fetal surgery carried out in this study and, as this procedure lends itself to surgery through a small uterine incision or "minimally invasive" surgery, it may be the procedure of choice to reduce the incidence of preterm labour for those human fetuses undergoing antenatal correction of a CDH.bb. PMID- 24057841 TI - How often is extracorporeal membrane oxygenation needed in cases of congenital diaphragmatic hernia? AB - Some newborns with congenital diaphragmatic hernia (CDH) and severe pulmonary hypertension cannot be saved by conventional treatment and may obtain some benefit from extracorporeal membrane oxygenation (ECMO) as a bridging measure until adequate hematosis is possible. Early prediction of the insufficiency of "optimal" assistance is still unclear; we reviewed our recent experience with CDH patients in an attempt to evaluate the real need for ECMO in our institution. Between 1987 and 1994, 47 newborns with CDH manifested in the first 24 h were treated with maximal ventilatory assistance (including high-frequency ventilation in 12 cases) and vasoactive drugs prior to surgical repair. In order to summarize the ventilatory and blood-gas parameters, we determined oxygenation index (OI) and ventilatory index (VI) and compared the results in survivors and nonsurvivors. Overall survival was 60% (2 cases of Fryns' syndrome were excluded from analysis). OI was 10.3+/-5.7 (mean +/- SD) for survivors and 46.2 +/- 37.8 for nonsurvivors (P < 0.01). VI was 460.9+/-303 and 1,532+/-500.6, respectively (P <0.01). Bayesian analysis and receiver operating characteristic curves enabled us to select a threshold value of OI of 20 as the best means of predicting survival in our current conditions (sensitivity: 0.7, specificity: 0.83). The generally accepted figure of 40 had a sensitivity of 1 but a specificity of only 0.44. For VI, the best threshold value was 1,100 (sensitivity: 0.93, specificity: 0.94), whereas the generally used figure of 1,000 had 0.89 and 1, respectively. According to our results, with our current management conditions, approximately 50% of our CDH patients might have obtained some benefit from ECMO. PMID- 24057842 TI - Entry criteria for extracorporeal membrane oxygenation In neonates with congenital diaphragmatic hernia treated with high-frequency oscillatory ventilation. AB - Although respiratory management with high-frequency oscillatory ventilation (HFOV) has generally been used for neonates with congenital diaphragmatic hernia (CDH), entry criteria for extracorporeal membrane oxygenation (ECMO) based on data from patients who underwent HFOV have not yet been reported. To establish entry criteria for ECMO in such patients, we retrospectively studied 36 neonates with CDH treated by HFOV in our institutions between 1986 and 1994. From the admission records, preductal and postductal arterial blood gas data and HFOV ventilation conditions for 72 h after admission were extracted. Oxygenation index (01) and alveolar-arterial oxygen gradient (A-aD02) time interval combinations were calculated. Patients were divided into two groups: candidates for ECMO (n = 22) who underwent ECMO (n = 18) or died without ECMO (n = 4); and non-candidates (n = 14), who survived without ECMO. Blood gas data in patients placed on ECMO were comparable to those in patients who died without ECMO: mean pre- and postductal OI for 4 h > 30, postductal A-aD02 >=620 mmHg for 4 h, postductal A aD02 >=580 mmHg for 8 h, and postductal A-aD02 ?550 mmHg for 12 h showed better sensitivity with a specificity of more than 90% compared to entry criteria that had previously been used in our institutions: a postductal OI >40 for 4 h and postductal A-aDO2 >=610 mmHg for 8 h. In addition, a combination of preand postductal OI >30 for 4 h indicated a sensitivity of 95.5% and a specificity of 92.9%. PMID- 24057843 TI - Ten years' experience in the management of cervical teratomas. AB - Five patients with cervical teratoma were seen between 1982 and 1992 in the Maternity and Children's Hospital, Riyadh, Saudi Arabia. All presented with a cervical mass at birth. Their weights ranged between 2.6 and 3.5 kg (average 3.1 kg); all were full-term babies, three girls and two boys. Three cases were diagnosed antenatally; three had a history of maternal hydramnios; three presented with severe respiratory distress at birth and needed endotracheal intubation. All patients underwent surgical treatment except one who died before surgical intervention because of severe respiratory distress. Surgery included complete resection of the tumor. The postoperative courses were uneventful. The histopathology of the tumor showed tissue from all three germ layers. Over 3-11 years of follow-up, none of the patients showed signs of recurrence. Postoperative thyroid function tests and serum alpha-fetoprotein showed no abnormalities. We conclude that antenatal diagnosis help to reduce the morbidity and mortality due to upper airway obstruction. Surgery is safe and represents the only way of treating this tumor. PMID- 24057844 TI - Use of Vicryl mesh to support the esophageal wall after circular myotomy (Livaditis procedure) in long-gap esophageal atresia - an experimental study. AB - Circular esophageal myotomy (CEM) is currently a well-accepted technique for elongation of the upper esophageal pouch in cases of long-gap esophageal atresia (EA). Esophageal pseudodiverticulum is a frequent and perhaps underreported sequela of this technique, characterized by ballooning or outpouching of the esophageal mucosa in the myotomized area. The present study was designed to seek a supplement for the CEM technique in order to avoid possible pseudodiverticulum formation in the myotomized area. We created an animal model to simulate the anatomic conditions present after primary repair of EA facilitated by CEM. Three groups of dogs underwent either cervical (1 group) or thoracic (2 groups) esophageal myectomy. In the cervical and first thoracic groups, the denuded mucosa was left without any support. In the second thoracic group, the denuded mucosal area was wrapped with polyglactin 910 (Vicryl) mesh. In all three groups the esophagus was narrowed by a Marlex mesh ring 3 cm distal to the myectomized zone, simulating a condition resulting from anastomotic narrowing. The dogs underwent barium swallows under fluoroscopy at different postoperative periods and were killed 4 or 6 months after surgery. The esophagi were removed for gross and radiologic investigation under maximal insufflation as well as for histologic assessment. The proposed canine model proved to be useful for study of the myectomized esophagus, mimicking the anatomy and conditions after CEM in long-gap EA repair. Wrapping the denuded mucosa with Vicryl mesh fortified the weakened esophageal wall, thus diminishing the likelihood of future pseudodiverticulum development. In light of the simplicity of the technique and the absence of any evident risk or complications, we recommend that the use of Vicryl mesh wrap be considered during CEM to reinforce the esophageal wall. PMID- 24057845 TI - Retained esophageal foreign bodies in children. AB - Foreign-body (FB) ingestion is common in children. Retained FBs in the esophagus can produce serious complications. We report five children with retained esophageal FBs: one presented with massive hematemesis due to an esophago-carotid fistula and the others had FB impaction above esophageal strictures. The hazards of impaction of small FBs above the strictures and delayed referral are highlighted. PMID- 24057846 TI - The effect of polycythemic hyperviscosity on ischemic bowel necrosis. AB - It is known that polycythemia decreases the fluidity of the blood and impairs tissue perfusion due to red-cell sludging in the microcirculation. In this study, the effect of polycythemic hyperviscosity (PH) on bowel necrosis was evaluated in an experimental model of intestinal ischemia. Twenty-eight Wistar albino rats (90 170 g) were divided into two groups: group 1 was transfused to create hyperviscosity and then intestinal ischemia was produced (n = 16); in group 2 ischemia was produced without transfusion (n = 12). Intestinal ischemia was produced by clamping the superior mesenteric artery and the collateral arcades of the right colic artery for 30 min. Gross and histopathologic evaluations were performed by either immediate necropsy or relaparotomy 24 h later. Microscopic findings were graded from 0 to 3 according to the degree of ischemic changes. In group 1, 2 animals (12.5%) died before 24 h postoperatively; coagulation necrosis with grade 2 or 3 ischemic changes was observed in 10 animals (62.5%). In group 2 only a few hypertrophied Peyer's patches and capillary dilation were found, and all histopathologic changes were between grades 0 and 1. The difference between the histopathologic gradings of the two groups was significant (P < 0.001). It appears that in addition to reduced splanchnic blood flow, a secondary effect of PH is needed to induce ischemic coagulation necrosis. PH of the newborn must be considered a risk factor for necrotizing enterocolitis, so-called spontaneous intestinal perforations, and even intestinal atresia. PMID- 24057847 TI - Paediatric adrenocortical neoplasia - a study of 25 cases. AB - We reviewed our experience of 25 children with adrenocortical tumours from January 1980 to December 1994. Their ages ranged from 7 months to 15 years; there were 16 girls and 9 boys. Truncal obesity, moon facies, hypertension, and virilisation were the most common clinical features. Establishment of the diagnosis of Cushing's syndrome was accomplished by hormonal and radiological studies. Eighteen patients had adrenocortical carcinomas, but 2 of them refused operation; 7 had adrenocortical adenomas. Twenty-three patients were treated by surgery; 6 with carcinomas are still alive after periods of 6 months to 3 years. The results of treatment of adrenocortical carcinoma have been poor, but the prognosis is excellent for benign lesions. PMID- 24057848 TI - In support of early surgical repair of ureteropelvic junction obstruction. AB - Ureteropelvic junction (UPJ) obstruction is the most common urinary tract obstruction in children. Maternal ultrasonography has resulted in early diagnosis of an increasing number of neonatal cases, allowing repair of hydronephrotic kidneys before complications occur. We favor early treatment of congenital hydronephrosis, which should be performed prior to 6 months of age based on evidence of UPJ obstruction, increased pyelocaliceal dilatation, parenchymal thinning, contralateral normal kidney hypertrophy, and functional deterioration. One should not wait for evidence of progressive renal damage before making a diagnosis of obstruction. This therapeutic approach is supported by a review of the most relevant literature published on the subject and our clinical experience. None of the standard tests for measuring obstruction are ideal; hence, we recommend that the results of the different diagnostic procedures for UPJ obstruction should be examined collectively. PMID- 24057849 TI - Rectal atresia: pathogenesis and operative treatment. AB - Rectal atresia (RA) with a normal anus is a rare anomaly mostly described as part of a series of anorectal malformations. Most authors believe it to be an acquired lesion with a vascular genesis. One of the arguments quoted is the lack of other congenital anomalies. Several operative procedures are recommended for this lesion. We describe four patients with RA who had other significant congenital anomalies; two other cases were found in the literature. A lack of other congenital anomalies in patients with RA does not seem to be a strong argument for an acquired lesion. All four patients were treated by a posterior sagittal approach with good functional results. PMID- 24057850 TI - Antegrade balloon dilation of postoperative ureterovesical junction obstruction in children. AB - Obstruction of the ureterovesical junction is an uncommon but well-recognized complication of ureteral reimplantation that traditionally has been treated by surgical correction [1, 5-9]. We report our experience with antegrade balloon dilation (ABD) of these strictures in two children. Obstruction was confirmed by diuretic renogram and pressure perfusion studies prior to ABD. Clinical follow-up was done at 3 months and 14 months, and ultrasonographic studies revealed resolution of the hydronephrosis. In addition, diuretic renograms showed complete washout of radiotracer. Morbidity was limited to episodes of pyelonephritis that readily responded to medical management. ABD of ureteral strictures is a relatively simple procedure with a potential for a high success rate and low morbidity. This modality should be considered as the first line of treatment in patients with distal ureteral obstruction after reimplantation. PMID- 24057851 TI - Incidence of urological anomalies in children with urinary tract infections in India. AB - A total of 2,970 infants and children with symptoms suggestive of urinary tract infection (UTI) were investigated. Diagnosis was based on clinical, microbiological, radiological, and sometimes endoscopic investigations. Quantitative culture of an uncontaminated sample of urine is the most sensitive screening test. An additional 548 children had positive physical findings such as enlarged kidneys and/or bladder and were excluded from this study. There were 2,970 children with urinary symptoms but no definite positive physical findings, and this group is discussed in detail; 73% (2,168) were boys and 27% (802) were girls. The commonest presenting symptoms were frequency of micturition, enuresis, and straining on voiding. One hundred sixty-six had significant bacteriuria and were fully investigated. Only 148 children completed the investigations and treatment; 130 had an underlying structural abnormality causing stasis of urine. It is well known that removal of the cause of the stasis will help to prevent further infections in most patients, and also reduces the effects of back pressure on the upper tracts. This study illustrates: (1) the importance of proper urine culture technique; (2) the high incidence (88%) of structural abnormalities causing UTI in children; and (3) the importance of investigating all children with proven UTI to determine the cause of stasis. In India, the patterns of UTIs and their causes are markedly different from those published in the English literature. PMID- 24057852 TI - Pediatric surgical missions in Bangladesh. AB - Bangladesh is one of the poorest countries in the world, with a population of more than 120 million people living in a territory of only 55,000 square miles. Pediatric surgery is not recognized as an independent branch of surgery: the Dhaka Shishu Hospital is the only pediatric hospital in the country. Sponsored by the World Organization for Pediatric Surgery in Emerging Countries and Azienda Ospedaliera di Parma, the authors performed four surgical missions in Bangladesh in the city of Khulna from 1991 to 1995. During these missions 395 operations were performed on children with general surgical urological, or maxillofacial problems. Besides the humanitarian significance of these missions, it is very edifying for a Western surgeon to observe the natural evolution of untreated congenital malformations. PMID- 24057853 TI - Pre- and postnatal treatment of a pulmonary sequestration presenting as a unilateral hydrothorax. AB - We report a case of a neonatal sequestration diagnosed antenatally as a progressive left hydrothorax when ultrasound (US) was done at 30 weeks' gestation for polyhydramnios. Postnatal US and computed tomography failed to demonstrate any lesion; magnetic resonance imaging showed a spherical mass in the left chest adjacent to the left lower lobe. At the age of 4 weeks a thoracotomy was performed and the mass was excised. Pulmonary sequestrations may present with a pleural effusion and polyhydramnios as a part of non-immune hydrops fetalis. In our case hydrops was prevented by insertion of a pleuro-amniotic shunt. PMID- 24057854 TI - Ileocolic intussusception: an unusual complication in a newborn with intestinal neuronal dysplasia. AB - Intestinal neuronal dysplasia type B (IND B) represents a congenital malformation of the enteric nervous system causing disorders of intestinal motility, e. g., chronic constipation. We report a newborn who primarily suffered from intussusception and peritonitis. He required a subtotal colectomy for gangrene, but since IND B had not been expected at this time, no specific immunhistochemical workup for IND was initiated. Following recurrent episodes of ileus and subileus within the next years, colonic biopsies were taken and histotopochemical staining revealed IND B. The remaining colon required resection; an ileorectostomy was performed and the patient is now asymptomatic. This case report discusses the causality of IND B for intussusception and stresses that in newborn patients the clinical presentation may be misleading, and adequate histochemical evaluation is essential for early detection. PMID- 24057855 TI - Anal canal duplication in childhood. AB - Anal canal duplication is an extremely rare abnormality. Two cases in children are reported; in both cases, the orifice of the duplicate tubular structure was located just behind the normal anus and ran along the posterior side of the anal canal without communication with the anorectum. Complete removal of the duplication was performed through a perineal approach. Histology revealed a squamous lining with a smooth-muscle component around the cavity, with mucus secreting transitional epithelium. Anal ducts with apocrine secretion and lymphocyte infiltration were also observed. The postoperative clinical courses were uneventful with satisfactory anal function. We collected nine similar cases from the literature. The term "anal canal duplication" is proposed based on common clinical features and pathology. PMID- 24057856 TI - Sirenomelia: the mermaid syndrome. AB - Sirenomelia, or mermaid syndrome, is the extreme form of caudal regression syndrome. We present another case of this fascinating anomaly with fused lower limbs, absent external genitalia, and absent genitourinary system. The patient could not be salvaged because of bilateral renal agenesis. Detailed autopsy findings and a review of the literature are presented. PMID- 24057857 TI - Reduction of gangrenous small bowel by taxis on an inguinal hernia. AB - Reduction of gangrenous small bowel by taxis on an inguinal hernia is an extremely rare event. We present a case in which this occurred, leading to a bowel obstruction and urgent laparotomy. PMID- 24057858 TI - Expressions of tumor necrosis factor-alpha, its receptor I, II and receptor associated factor 2 in the porcine corpus luteum during the estrous cycle and early pregnancy. AB - We examined the gene and protein levels of tumor necrosis factor (TNF)-alpha, its receptors (types I and II, designated TNF-RI and TNF-RII, respectively), TNF receptor-associated factor 2 (TRAF2) and morphological features in the porcine corpus luteum (CL), on Days 13 and 17 (Day 0 = the last day of estrus) of the estrous cycle or of early pregnancy. Gene expression levels of TNF-alpha, TNF-RI, TNF-RII and TRAF2 were unaffected by the day or reproductive status. TNF-alpha concentration was significantly higher in the CL on Day 17 of pregnancy than on Day 13 of pregnancy and on day 17 of the estrous cycle. The TNF-RI protein level was significantly higher in the CL on Days 13 and 17 of pregnancy than those of the estrous cycle, significantly increasing on Day 17 compared with those on Day 13 in pregnancy. In relation to TNF-RII protein levels, although there were no change during pregnancy, there was a tendency (P = 0.0524) to up-regulate as pregnancy proceeded. In estrous cycle, TNF-RII protein levels decreased significantly as luteolysis proceeded. TRAF2 protein level was significantly higher in the CL on Days 13 and 17 of pregnancy than during estrous. There were few apoptotic bodies in the CL between Days 13 and 17 of pregnancy than during esrous. There were few apoptotic bodies in the CL between Days 13 and 17 of pregnancy. The number of apoptotic bodies was much greater than the CL on Day 17 of the estrous than those of pregnancy. Thus, the TNF-alpha and TNF-RI and TNF RII pathways including the TRAF2 protein, known to control of cell differentiation, tissue renewal and apoptosis, might participate in maintaining the porcine CL during early pregnancy. PMID- 24057859 TI - Comparative analysis of innate immune response following in vitro stimulation of sheep and goat peripheral blood mononuclear cells with bluetongue virus - serotype 23. AB - Bluetongue is an infectious disease caused by bluetongue virus (BTV), which affects sheep, goat, cattle and certain wild ruminants. However severe clinical signs are usually seen with significant mortality in sheep than cattle and goat. To date, comparative studies on innate immune responses of sheep and goat infected with BTV is lacking. In this study, we compared the innate immune response of sheep and goat by infecting the peripheral blood mononuclear cells (PBMCs) with BTV serotype 23. In our study, we observed that sheep PBMCs supports higher virus replication than goat PBMCs. To delineate the role of innate immune response in differential viral replication observed in this study, we examined TLR3 (Receptor for dsRNA virus) mRNA expression and cytokine profiles (IL-1beta, Il-6, IL-8, Il-10, IL-12p40, TNF-alpha, IFN-gamma and IFN-alpha) following Poly I:C (TLR3 ligand) stimulation and BTV 23 infection. In our present study, sheep PBMCs had significantly higher TLR3 mRNA levels, TLR3 specific ligand (Poly I:C) stimulation resulted in increased levels of IFN-gamma at transcriptional and translational levels along with IL-8 and IL-10 at transcriptional levels. Whereas, the levels of TNF-alpha was higher in goat PBMCs at transcriptional levels. BTV infected sheep PBMCs expressed significantly higher levels of IFN gamma at transcriptional and translational levels along with IL-6, IL-8 and IL-10 at transcriptional levels. Whereas the expression levels of TNF-alpha and IFN alpha at transcriptional and translational levels were significantly high in goat PBMCs. To examine the potential factor for consistent increase in the expression of TNF-alpha, we sequenced the promoter region of TNF-alpha and identified a total of five single nucleotide polymorphisms (SNP) and one indel in goat TNF alpha promoter region. Luciferase assay for transcriptional activity of the promoter showed that goat TNF-alpha has significantly enhanced transcriptional activity in comparison with sheep TNF-alpha promoter. Altogether, our data suggests that the expression levels of TNF-alpha and IFN-alpha and/or IL-10 plays crucial role in replication of BTV 23. PMID- 24057860 TI - Endovascular management of an acquired aortobronchial fistula following aortic bypass for coarctation. AB - Aortobronchial fistula (ABF) in the setting of aortic coarctation repair is very rare but uniformly fatal if untreated. Endovascular stenting of the descending aorta is now the first-choice approach for ABF presenting with haemoptysis and offers a less-invasive technique with improved outcomes, compared with open repair. We report a case of late ABF occurring following bypass for aortic coarctation. Management focused on two key manoeuvres: use of a covered endovascular stent to occlude the aortic bypass thus controlling the fistula and dilatation and stenting of native coarctation. PMID- 24057861 TI - Outcomes following cardiac surgery in patients with preoperative renal dialysis. AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was that whether patients who are dependent on chronic dialysis have higher morbidity and mortality rates than the general population when undergoing cardiac surgery. These patients often require surgery in view of their heightened risk of cardiac disease. Altogether 278 relevant papers were identified using the below mentioned search, 16 papers represented the best evidence to answer the question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. Dialysis-dependent (DD) patients undergoing coronary artery bypass grafting (CABG) or valve replacement have higher morbidity but acceptable outcomes. There is some evidence to show that outcomes after off pump coronary artery bypass grafting (OPCAB) are better than after on-pump coronary artery bypass grafting (ONCAB) and that results are worse in DD patients with diabetic nephropathy. Patients undergoing combined procedures have a higher mortality. PMID- 24057862 TI - Surgical algorithm for heterogeneous bilateral quadruple pulmonary nodules. AB - A 65-year old female with no history of smoking reported experiencing 6 months of tightness in the chest. Chest computed tomography showed two pulmonary nodules in the left upper lobe (one in S3 segment, the other in S4 segment), one nodule in the left lower lobe and a ground-glass opacity (GGO) in the right upper lobe. Synchronous bilateral thoracoscopic wedge resections of the lung were performed to investigate the nodules. Intraoperative frozen section pathology revealed that the two nodules in the left upper lobe were malignant, the nodule in the left lower lobe was a benign lesion and the GGO in the right upper lobe was an atypical adenomatous hyperplasia. As a result, a left upper lobectomy with lymph node dissection was performed. The final pathological diagnosis of the nodule in the left S3 segment was well differentiated adenocarcinoma (pT1bN0M0, IA), the nodule in the left S4 segment was moderately to poorly differentiated adenocarcinoma (pT1aN0M0, IA), the nodule in the left lower lobe was cryptococcal granuloma and the GGO in the right upper lobe was adenocarcinoma in situ. The patient is currently following a favourable course in her recovery. Here, we would like to share the surgical algorithm used for the treatment of heterogeneous bilateral quadruple pulmonary nodules. PMID- 24057863 TI - Cardiovascular pharmacology core reviews: aspirin. AB - Acetylsalicylic acid, or aspirin, is perhaps the most well-studied drug in human history, but controversy persists regarding both optimal dose and its use in the primary prevention of atherothrombotic events. This article reviews the following: the effect of aspirin upon the cyclooxygenase pathway; clinical trials of aspirin for both secondary and primary prevention; prospective and retrospective studies of aspirin dose; the potential interaction between aspirin and ticagrelor; and the concept of aspirin resistance. It concludes with a review of major society guidelines regarding aspirin and offers a perspective on the evidence-based use of aspirin in clinical practice. PMID- 24057864 TI - Curcumin protects mice from coxsackievirus B3-induced myocarditis by inhibiting the phosphatidylinositol 3 kinase/Akt/nuclear factor-kappaB pathway. AB - Viral myocarditis is an inflammation of the myocardium, and coxsackievirus B3 (CVB3) is one of the most important etiologic agents. Curcumin is an active ingredient of Curcumin longa, which has been used as a traditional Chinese herb for the treatment of various inflammatory diseases. The aim of this study was to explore the therapeutic effect of curcumin on CVB3-induced myocarditis and the underlying mechanism. Our results showed that treatment with curcumin could significantly attenuate CVB3-induced myocarditis, as demonstrated by improved weight loss, increased survival rate, reduced serological level cardiac enzymes, and improved heart histopathology. Of importance, curcumin administration was revealed to significantly reduce the systemic and local myocardial expression of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin (IL) 6, and IL-1beta, in the CVB3-infected mice. Further study showed that curcumin treatment significantly inhibited the CVB3-induced activation of nuclear factor kappaB (NF-kappaB), a key transcription factor in the pathogenesis of inflammation, in a phosphatidylinositol 3 kinase (PI3K)/Akt pathway-dependent manner. These data indicate that curcumin has protective effect against CVB3 induced myocarditis by inhibiting PI3K/Akt/NF-kappaB signaling pathway and thus reducing the inflammatory response. PMID- 24057865 TI - Combination of D942 with curcumin protects cardiomyocytes from ischemic damage through promoting autophagy. AB - Myocardial ischemia is one of the main causes of sudden cardiac death. Autophagy has been demonstrated to protect cardiomyocytes from ischemia/reperfusion (I/R) induced damage. A small molecule compound 5-(3-(4-(2-(4 fluorophenyl)ethoxy)phenyl)propyl)furan-2-carboxylic acid (D942) has been previously shown to specifically activate adenosine monophosphate-activated protein kinase (AMPK) in cancer cells. Another reagent, curcumin, has been shown to inhibit mammalian target of rapamycin (mTOR) signal pathway in tumor cells. Since AMPK signaling induces autophagy, while mTOR signaling inhibits autophagy, here we tested the potential protective efficacy of D942 with curcumin for cardiomyocytes under oxygen-glucose deprivation and reoxygenation (OGD/R). Mouse neonatal cardiomyocytes were treated with D942 and curcumin after being subjected to OGD/R. Cell survival and autophagy-related signal pathways were measured after treatment. Our data indicated both D942 and curcumin enhanced cell survival after OGD/R. The D942 and curcumin induced autophagy in cardiomyocytes through activating AMPK pathway or inhibiting mTOR signaling. Induction of autophagy by D942 and curcumin was the cause of cardioprotection, since inhibition of autophagy abolished the protective efficacy. Furthermore, combination treatment with D942 and curcumin profoundly upregulated autophagy after OGD/R and significantly promoted cell survival. Treatment with D942 and curcumin significantly upregulated autophagy in a murine myocardial I/R model. Taken together, our research suggests that D942 and curcumin could be promising therapeutic agents for myocardial I/R. PMID- 24057867 TI - Predicting the elastic properties of selective laser sintered PCL/beta-TCP bone scaffold materials using computational modelling. AB - This study assesses the ability of finite element (FE) models to capture the mechanical behaviour of sintered orthopaedic scaffold materials. Individual scaffold struts were fabricated from a 50:50 wt% poly-epsilon-caprolactone (PCL)/beta-tricalcium phosphate (beta-TCP) blend, using selective laser sintering. The tensile elastic modulus of single struts was determined experimentally. High resolution FE models of single struts were generated from micro-CT scans (28.8 MUm resolution) and an effective strut elastic modulus was calculated from tensile loading simulations. Three material assignment methods were employed: (1) homogeneous PCL elastic constants, (2) composite PCL/beta-TCP elastic constants based on rule of mixtures, and (3) heterogeneous distribution of micromechanically-determined elastic constants. In comparison with experimental results, the use of homogeneous PCL properties gave a good estimate of strut modulus; however it is not sufficiently representative of the real material as it neglects the beta-TCP phase. The rule of mixtures method significantly overestimated strut modulus, while there was no significant difference between strut modulus evaluated using the micromechanically-determined elastic constants and experimentally evaluated strut modulus. These results indicate that the multi-scale approach of linking micromechanical modelling of the sintered scaffold material with macroscale modelling gives an accurate prediction of the mechanical behaviour of the sintered structure. PMID- 24057866 TI - Changes in fucosylation of human seminal IgG and secretory component of IgA in leukocytospermic patients. AB - Our study compares the status of human seminal plasma immunoglobulin G (IgG) and IgA secretory component (SC) fucosylation between infertile leukocytospermic and normal, fertile normozoospermic patients. The seminal IgG and SC are decorated with AAL-reactive core fucose, and antennary UEA- and LTA-reactive fucose of Lewis(y) and Lewis(x) structures, respectively. However, a correlation between IgG core fucosylation and IgG concentration (r = -0.52; p < 0.0003) was observed. The IgG present in leukocytospermic samples is characterized by lower expression of core fucose than in the normal group (0.82 +/- 0.3 AU and 1.2 +/- 0.3 AU, respectively; p < 0.002). In seminal plasma the SC is present in two forms: 78 kDa and 63-kDa. The present study has also shown a higher AAL and LTA specific reactivity of glycans expressed in 63-kDa SC, in comparison to 78-kDa SC, in the normal group. In leukocytospermia, the values of specific lectin reactivity for core fucose, fucose alpha(1-2)- and alpha(1-3)- linked, were similar for both SC bands. Moreover, the present study has shown that in leukocytospermic samples the mean concentrations of IgG and S-IgA are twice as high (131.68 +/- 102.6 mg/l and 36 +/- 27 mg/l, respectively) as in the normal group (67.68 +/- 29.2 mg/l; p < 0.02, and 19 +/- 18 mg/l, p < 0.019, respectively). The analysis of IgG and SC fucosylation status and the determination of IgG and S-IgA concentrations in seminal plasma might constitute a valuable diagnosis tools for the evaluation of male infertility associated with leukocytospermia with accompanying inflammation. PMID- 24057868 TI - Maternal anxiety disorders prior to conception, psychopathology during pregnancy and early infants' development: a prospective-longitudinal study. AB - Family-genetic studies suggest that anxiety disorders run in families and that mechanisms of familial transmission might act as early as during pregnancy. The aims of the Maternal Anxiety in Relation to Infant Development (MARI) Study are to prospectively investigate the course of pregnancy in women with and without anxiety disorders prior to conception from early pregnancy to postpartum focussing on (a) maternal psychopathology, (b) maternal perinatal health, and (c) offspring outcomes that are supposed to be early indicators/ antecendents for later anxiety disorders. The MARI Study is a prospective-longitudinal study program with seven waves of assessment: T1 (baseline: week 10 to 12 of gestation), T2 (week 22 to 24 of gestation), T3 (week 35 to 37 of gestation), T4 (10 days postpartum), T5 (2 months postpartum), T6 (4 months postpartum), and T7 (16 months postpartum). Overall, N = 306 pregnant women were enrolled during early pregnancy (T1) and allocated to one of the following initial diagnostic groups: no AD: no anxiety nor depressive disorder prior to pregnancy (N = 109), pure D: pure depressive disorder(s) prior to pregnancy (N = 48), pure A: pure anxiety disorder(s) prior to pregnancy (N = 84), and comorbid AD: comorbid anxiety and depressive disorders prior to pregnancy (N = 65). Overall, N = 284 mothers could be retained until T6 (retention rate: 92.8 %) and N = 274 until T7 (retention rate: 89.5 %). Clinical and psychosocial measures were used including a standardized diagnostic interview (CIDI-V) with dimensional scales and standardized observation paradigms (mother-infant-relationship, infant temperament and neuropsychological development). Dimensional anxiety and depression liability indices were developed to reflect the severity of anxiety and depressive disorders prior to pregnancy and to ease longitudinal modelling. Findings from this study will contribute to improved knowledge about the natural course of anxiety disorders during transition to parenthood and associated outcomes that are assumed to be early indicators of later psychopathology in the offspring. Results are expected to provide new insights into mechanisms of familial transmission and clues for targeted prevention and early intervention. PMID- 24057869 TI - Prenatal depressive symptoms and abnormalities of glucose tolerance during pregnancy among Hispanic women. AB - The aim of this study is to prospectively examine the association between maternal depressive symptoms in early pregnancy and risk of abnormal glucose tolerance (AGT) and impaired glucose tolerance (IGT) in mid-pregnancy. We evaluated this association among 934 participants in Proyecto Buena Salud, a prospective cohort study of Hispanic (predominantly Puerto Rican) women in Western Massachusetts. Depressive symptoms were assessed in early pregnancy using the 10-item Edinburgh Postnatal Depression Scale. Scores >=13 indicated at least probable minor depression and scores >=15 indicated probable major depression. AGT and IGT were diagnosed using American Diabetes Association criteria. In early pregnancy, 247 (26.5 %) participants experienced at least minor depression and 163 (17.4 %) experienced major depression. A total of 123 (13.2 %) were classified with AGT and 56 (6.0 %) were classified with IGT. In fully-adjusted models, the odds ratio for AGT associated with minor depression was 1.20 (95 % CI 0.77-1.89) and for major depression was 1.34 (95 % CI 0.81-2.23). The odds ratio for IGT associated with minor depression was 1.22 (95 % CI 0.62-2.40) and for major depression was 1.53 (95 % CI 0.73-3.22). We did not observe an association with continuous screening glucose measures. Findings in this prospective cohort of Hispanic women did not indicate a statistically significant association between minor or major depression in early pregnancy and AGT or screening glucose values in mid-pregnancy. Due to the small number of cases of IGT, our ability to evaluate the association between depression and IGT risk was constrained. PMID- 24057870 TI - Non-familial synchronous double primary malignancies of the gallbladder and rectum. PMID- 24057871 TI - Process evaluation of a multidisciplinary care program for patients undergoing gynaecological surgery. AB - PURPOSE: This study describes the process evaluation of an innovative multidisciplinary care program for patients undergoing benign gynaecologic surgery. This care program aims at improving recovery and preventing delayed return to work and consists of two steps: (1) an interactive e-health intervention for all participants, and (2) integrated clinical and occupational care management for those participants whose sick leave exceeds 10 weeks. METHODS: Eligible for this study were employed women aged between 18-65 years scheduled for a laparoscopic adnexal surgery and/or hysterectomy. Data were collected from patients, their supervisors and their gynaecologists, by means of electronic questionnaires during a 6 month follow-up period and an automatically generated, detailed weblog of the patient web portal ( www.ikherstel.nl ). Investigated process measures included: reach, dose delivered, dose received, and fidelity. In addition, attitudes towards the intervention were explored among all stakeholders. RESULTS: 215 patients enrolled in the study and accounted to a reach of 60.2 % (215/357). All intervention group patients used their account at least once and total time spent on the patient web portal was almost 2 h for each patient (median 118 min, IQR 64-173 min). Most patients visited the website several times (median 11 times, IQR 6-16). Perceived effectiveness among patients was high (74 %). In addition, gynaecologists (76 %) and employers (61 %) were satisfied with the web portal as well. Implementation of the second step of the intervention was suboptimal. Motivating patients to consent to additional guidance and developing an accurate return-to-work-prognosis were two important obstacles. CONCLUSIONS: The results of this study indicate good feasibility for implementation on a broad scale of the e-health intervention for patients undergoing benign gynaecological surgery. To enhance the implementation of the second step of the perioperative care program, adaptations in the integrated care protocol are needed. PMID- 24057872 TI - Enhanced osteogenic activity of a poly(butylene succinate)/calcium phosphate composite by simple alkaline hydrolysis. AB - Bone engineering offers the prospect of alternative therapies for clinically relevant skeletal defects. Poly(butylene succinate) (PBSu) is a biodegradable and biocompatible polyester which may possess some limitations in clinical use due to its hydrophobicity. In order to overcome these limitations and increase the bioactivity, a simple and convenient surface hydrolysis of PBSu, PBSu/hydroxyapatite and PBSu/beta-tricalcium phosphate (TCP) films was performed. The resulting surfaces (i.e., HPBSu, HPBSu/HA and HPBSu/TCP) were tested for their physicochemical property, biocompatibility and osteogenic potency. The results showed that surface hydrolysis significantly increased surface roughness and hydrophilicity of the composites, with the HPBSu/TCP possessing the most pronounced results. All the materials appeared to be biocompatible and supported in vitro growth and osteoblast differentiation of hMSCs, and the alkaline hydrolysis significantly enhanced the hMSC cell proliferation and the osteogenic potency of PBSu/TCP compared with the non-hydrolyzed sample. In conclusion, the HPBSu/TCP possessed better hydrophilicity, biocompatibility and osteogenic potency in vitro, suggesting that this simple and convenient alkaline hydrolysis could be used to augment the biological property of PBSu-based composites for bone engineering in vivo. PMID- 24057873 TI - Meniscus repair and regeneration: review on current methods and research potential. AB - Meniscus regeneration is an unsolved clinical challenge. Despite the wide acceptance of the degenerative consequences of meniscectomy, no surgical procedure has succeeded to date in regenerating a functional and long-lasting meniscal fibrocartilage. Research proposed a number of experimental approaches encompassing all the typical strategies of regenerative medicine: cell-free scaffolds, gene therapy, intra-articular delivery of progenitor cells, biological glues for enhanced bonding of reparable tears, partial and total tissue engineered meniscus replacement. None of these approaches has been completely successful and can be considered suitable for all patients, as meniscal tears require specific and patient-related treatments depending on the size and type of lesion. Recent advances in cell biology, biomaterial science and bioengineering (e.g., bioreactors) have now the potential to drive meniscus regeneration into a series of clinically relevant strategies. In this tutorial paper, the clinical need for meniscus regeneration strategies will be explained, and past and current experimental studies on meniscus regeneration will be reported. PMID- 24057874 TI - Coxsackievirus and adenovirus receptor-positive cells compose the putative stem/progenitor cell niches in the marginal cell layer and parenchyma of the rat anterior pituitary. AB - The pituitary gland is a slow generative tissue but actively responds to demands by changing homeostasis. The marginal cell layer (MCL) facing the residual lumen has long been indicated as a stem/progenitor cell niche of the pituitary. On the other hand, the coxsackievirus and adenovirus receptor (CAR), which localizes at the tight-junction of the polarized epithelium, is known to participate in the development, differentiation and regeneration of specified tissues. The present study attempts to characterize the cells lining the MCL during pituitary development by immunohistochemistry of CAR. Consequently, we found that CAR localizes in an apical surface of the single cell layer facing the oral cavity in the invaginating oral epithelium on rat embryonic day (E) 11.5. On E13.5, when this single layer constructs the MCL in the pituitary primordium Rathke's pouch, CAR-positive cells occupied the MCL and this localization pattern of CAR was persistently maintained throughout life. Moreover, clusters of CAR-positive cells were also found in the parenchyma. CAR-positive cells were positive for stem/progenitor cell markers sex-determining region Y-box 2 (SOX2) and epithelial calcium-dependent adhesion (E-cadherin). However, prior to the postnatal growth wave, cells positive for CAR in the basolateral surface constructed multiple cell layers beneath the MCL and cell-type transition to a putative migratory cell phenotype by fading of SOX2 and E-cadherin occurred, suggesting the composition of new putative niches in the parenchyma. These data, together with our previous reports, suggest that CAR-positive cells are pituitary stem/progenitor cells and compose putative stem/progenitor cell niches in the MCL and parenchyma. PMID- 24057875 TI - New facets of keratin K77: interspecies variations of expression and different intracellular location in embryonic and adult skin of humans and mice. AB - The differential expression of keratins is central to the formation of various epithelia and their appendages. Structurally, the type II keratin K77 is closely related to K1, the prototypical type II keratin of the suprabasal epidermis. Here, we perform a developmental study on K77 expression in human and murine skin. In both species, K77 is expressed in the suprabasal fetal epidermis. While K77 appears after K1 in the human epidermis, the opposite is true for the murine tissue. This species-specific pattern of expression is also found in conventional and organotypic cultures of human and murine keratinocytes. Ultrastructure investigation shows that, in contrast to K77 intermediate filaments of mice, those of the human ortholog are not attached to desmosomes. After birth, K77 disappears without deleterious consequences from human epidermis while it is maintained in the adult mouse epidermis, where its presence has so far gone unnoticed. After targeted Krt1 gene deletion in mice, K77 is normally expressed but fails to functionally replace K1. Besides the epidermis, both human and mouse K77 are present in luminal duct cells of eccrine sweat glands. The demonstration of a K77 ortholog in platypus but not in non-mammalian vertebrates identifies K77 as an evolutionarily ancient component of the mammalian integument that has evolved different patterns of intracellular distribution and adult tissue expression in primates. PMID- 24057876 TI - Co-localization of serine/threonine kinase 33 (Stk33) and vimentin in the hypothalamus. AB - We investigate the immunoreactivity of serine/threonine kinase 33 (Stk33) and of vimentin in the brain of mouse, rat and hamster. Using a Stk33-specific polyclonal antibody, we show by immunofluorescence staining that Stk33 is present in a variety of brain regions. We found a strong staining in the ependymal lining of all cerebral ventricles and the central canal of the spinal cord as well as in hypothalamic tanycytes. Stk33 immunoreactivity was also found in circumventricular organs such as the area postrema, subfornical organ and pituitary and pineal glands. Double-immunostaining experiments with antibodies against Stk33 and vimentin showed a striking colocalization of Stk33 and vimentin. As shown previously, Stk33 phosphorylates recombinant vimentin in vitro. Co-immunoprecipitation experiments and co-sedimentation assays indicate that Stk33 and vimentin are associated in vivo and that this association does not depend on further interacting partners (Brauksiepe et al. in BMC Biochem 9:25, 2008). This indicates that Stk33 is involved in the dynamics of vimentin polymerization/depolymerization. Since in tanycytes the vimentin expression is regulated by the photoperiod (Kameda et al. in Cell Tissue Res 314:251-262, 2003), we determine whether this also holds true for Stk33. We study hypothalamic sections from adult Djungarian hamsters (Phodopus sungorus) held under either long photoperiods (L:D 16:8 h) or short photoperiods (L:D 8:16 h) for 2 months. In addition, we examine whether age-dependent changes in Stk33 protein content exist. Our results show that Stk33 in tanycytes is regulated by the photoperiod as is the case for vimentin. Stk33 may participate in photoperiodic regulation of the endocrine system. PMID- 24057878 TI - alpha-ENaC in bullfrog embryo: expression in cement gland, gills and skin. AB - The epithelial sodium channel (ENaC) is involved in Na(+) responses such as Na(+) absorption and salt taste. The alpha ENaC subunit (alpha-ENaC) is expressed in the skin of both the adult and larval (tadpole) bullfrog. alpha-ENaC expression in the developing bullfrog embryo has not been previously investigated. In this study, the expression of alpha-ENaC at various stages (Sts.) of bullfrog embryonic development is assessed by western blot and immunofluorescence analysis. Bullfrog alpha-ENaC (alpha-fENaC) protein was detected by western blot in embryos at Sts. (Gosner/Shumway) 19, 21 and 25. Immunofluorescence studies indicate that alpha-fENaC was localized to the embryonic cement glands at St. 18 (muscular response), St. 19 (heart beat) and St. 21 (mouth open and/or cornea transparent), to the external gills at St. 21 and to the outermost cell-layer of the skin at St. 25 (operculum complete). The function(s) of ENaC in these embryonic structures remain to be elucidated. PMID- 24057877 TI - Control of Sertoli cell metabolism by sex steroid hormones is mediated through modulation in glycolysis-related transporters and enzymes. AB - Sertoli cells (SCs) glucose metabolism is crucial for spermatogenesis since developing germ cells consume lactate produced by SCs as their main energy source. Recently, androgens and estrogens have been implicated in SCs energy metabolism modulation, although the molecular mechanisms remained undisclosed. Here, we report the effect of sex steroid hormones on key points of cultured rat SCs glycolytic pathway. We used primary cultures of immature rat SCs treated with 17beta-estradiol (E2) or 5alpha-dihydrotestosterone (DHT). The transcript levels of glucose transporters (GLUTs), phosphofructokinase 1 (PFK-1) and lactate dehydrogenase C (LDH C) were analyzed after 25 and 50 h of culture by qPCR. Protein levels of GLUTs, PFK-1, LDH and monocarboxylate transporter 4 (MCT4) after 25 and 50 h were determined by western blot and LDH activity was also assessed. Our results show that both E2 and DHT downregulated the transcript levels of PFK-1, GLUT1 and GLUT3 after 50 h. However, only DHT-treated cells presented a downregulation of LDH C transcript levels. Interestingly, the protein levels of these enzymes and transporters remained unaltered except in DHT-treated cells that presented a significant decrease on GLUT1 protein levels evidencing a possible site for the regulation of SCs glucose metabolism by androgens. Taken together, our results provide evidence that sex steroid hormones action in SCs energy metabolism is mediated through modulation in glycolysis-related transporters and enzymes, particularly at the transcriptional level. DHT decreased GLUT1 protein levels and increased LDH activity after 25 h, evidencing key points for this hormone action in the regulation of SCs metabolism. PMID- 24057879 TI - Proceedings of the XXXIInd Seminar of the French-Speaking Society for Theoretical Biology; Saint-Flour (Cantal), France, 10-13 June, 2012. PMID- 24057881 TI - XRCC1 polymorphisms and cervical cancer risk: an updated meta-analysis. AB - X-ray repair cross complementing 1 (XRCC1) plays a key role in DNA repair, genetic instability and tumorigenesis. A series of epidemiological studies have examined associations between XRCC1 polymorphisms and cervical cancer risk, but the findings remain inconclusive. We searched three electronic databases (MEDLINE, EMBASE and CNKI) for studies on the association between XRCC1 polymorphisms and cervical cancer risk published before June 2013. Pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated to estimate risk associations. A total of 28 case-control studies from 15 publications with 5,890 cervical cancer cases and 7,626 controls were identified. There was a significant association between rs25487 and cervical cancer risk in Asian populations (Dominant model: OR = 1.25, 95 % CI =1.04-1.50, P = 0.051 for heterogeneity test). After excluding three studies deviated from Hardy-Weinberg equilibrium, we observed a significant association of rs1799782 with cervical cancer risk in all populations and in Asian populations (Recessive model: OR = 1.62 and 1.72, 95 % CI = 1.22-2.14 and 1.29-2.30, P = 0.090 and 0.266 for heterogeneity test, respectively). However, there was no significant association between rs25489 and cervical cancer risk. These findings were further confirmed by false-positive report probability analysis. No publication bias was found by using the funnel plot and Egger's test. This meta-analysis provides strongly statistical evidence for the association between rs1799782 and cervical cancer risk, as well as its association with rs25487 only in Asian populations. However, single large, well designed prospective studies are needed to confirm these findings. PMID- 24057883 TI - Complete genome sequence of a novel monopartite begomovirus infecting sweet potato in China. AB - The complete genome sequence of a new monopartite begomovirus isolate SC-1 was obtained from sweet potato samples in Sichuan province, China. The viral genome consists of 2,764 nucleotides (nt) and encodes two open reading frames (ORFs) called AV1 and AV2 genes in the viral-sense strand and four ORFs (AC1-AC4) in the complementary-sense strand. Sequence comparisons revealed that it shared the highest level of nt sequence identity (81.2 %) with Sweet potato leaf curl Georgia virus (AF326775). Phylogenetic analysis showed that the SC-1 genome was in a separate clade from other 29 begomovirus isolates. Thus, the SC-1 isolate is a novel species according to the demarcation criteria of species in the genus Begomovirus, for which the name "Sweet potato leaf curl China Sichuan Virus" (SPLCCSV) is proposed. Recombination analysis suggests that SPLCCSV has sequences derived from recombination between Sweet potato leaf curl virus (SPLCV) isolate GZ01 (JX286653) and SPLCV isolate Merremia N4 (DQ644563). PMID- 24057882 TI - Alteration in apoptosis and cell cycle by celecoxib and/or fish oil in 7,12 dimethyl benzene (alpha) anthracene-induced mammary carcinogenesis. AB - Cyclooxygenase (COX)-2 inhibition by nonsteroidal anti-inflammatory drugs is a useful approach for cancer prevention but has several side effects. A novel approach combining these chemopreventive agents at low doses with dietary elements has been suggested to augment their effects and reduce side effects. Dietary fats, particularly, n-3 polyunsaturated fatty acids (PUFA) also exert cancer chemopreventive effect mediated through COX-2 inhibition. Therefore, the present study was designed to investigate the effect of combined dosage of celecoxib and n-3 PUFA-rich fish oil in experimental mammary carcinogenesis. Female Wistar rats were distributed into control and DMBA-treated groups. The groups were further subdivided based on pretreatment with celecoxib and/or fish oil. The animals were maintained for 90 days before sacrifice. To analyze the role of redox signaling, the two mediators, reactive oxygen species and calcium, and their effects on c-myc expression were evaluated. The chemopreventive effect was assessed by measurement of cell proliferation, apoptosis, and p53 in isolated mammary epithelial cells. Increased redox signaling with enhanced c-myc, p53 expression, and augmented apoptotic and proliferative rate were observed in carcinogen-treated animals. Pretreatment of carcinogen-treated animals with celecoxib and/or fish oil altered redox signaling with reduced c-myc, p53 expression, apoptosis, and proliferation. However, a combination dosage of celecoxib and fish oil had a better chemopreventive effect. The results suggest that a combination of celecoxib and fish oil is more effective in the chemoprevention of experimental mammary carcinogenesis, and this effect can be attributed to the modification of redox signaling. PMID- 24057884 TI - New Neuro-Oncology Practice journal to launch in 2014. PMID- 24057886 TI - Surgical resection of epidural disease improves local control following postoperative spine stereotactic body radiotherapy. AB - BACKGROUND: Spine stereotactic body radiotherapy (SBRT) is increasingly being applied to the postoperative spine metastases patient. Our aim was to identify clinical and dosimetric predictors of local control (LC) and survival. METHODS: Eighty patients treated between October 2008 and February 2012 with postoperative SBRT were identified from our prospective database and retrospectively reviewed. RESULTS: The median follow-up was 8.3 months. Thirty-five patients (44%) were treated with 18-26 Gy in 1 or 2 fractions, and 45 patients (56%) with 18-40 Gy in 3-5 fractions. Twenty-one local failures (26%) were observed, and the 1-year LC and overall survival (OS) rates were 84% and 64%, respectively. The most common site of failure was within the epidural space (15/21, 71%). Multivariate proportional hazards analysis identified systemic therapy post-SBRT as the only significant predictor of OS (P = .02) and treatment with 18-26 Gy/1 or 2 fractions (P = .02) and a postoperative epidural disease grade of 0 or 1 (0, no epidural disease; 1, epidural disease that compresses dura only, P = .003) as significant predictors of LC. Subset analysis for only those patients (n = 48/80) with high-grade preoperative epidural disease (cord deformed) indicated significantly greater LC rates when surgically downgraded to 0/1 vs 2 (P = .0009). CONCLUSIONS: Postoperative SBRT with high total doses ranging from 18 to 26 Gy delivered in 1-2 fractions predicted superior LC, as did postoperative epidural grade. PMID- 24057888 TI - Abstracts of the 11th International Symposium on VIP, PACAP and Related Peptides. August 27-31, 2013. Pecs, Hungary. PMID- 24057885 TI - Mitochondrial protein ATPase family, AAA domain containing 3A correlates with radioresistance in glioblastoma. AB - BACKGROUND: ATPase-family, AAA domain containing 3A (ATAD3A) is located on human chromosome 1p36.33, and high endogenous expression may associate with radio- and chemosensitivity. This study was conducted to investigate the significance of ATAD3A in glioblastoma multiforme (GBM). METHODS: Clinical significance of ATAD3A expression was assessed by immunohistochemistry in 67 GBM specimens, and prognostic value was assessed in 32 GBM patients statistically. To investigate in vitro phenotypic effects of ATAD3A, cell viability was measured using a clonogenic survival assay under either knockdown or ectopic expression of ATAD3A in GBM cell lines. The effects of ATAD3A knockdown on targeted DNA repair associated proteins in T98G cells were evaluated using immunofluorescence and Western blotting. RESULTS: Clinically, high expression of ATAD3A was independent of O(6)-DNA methylguanine-methyltransferase methylation status and correlated with worse prognosis. In vitro, high ATAD3A-expressing T98G cells were more resistant to radiation-induced cell death compared with control and low endogenous ATAD3A U87MG cells. After silencing ATAD3A, T98G cells became more sensitive to radiation. On the other hand, enforced ATAD3A expression in U87MG cells exhibited increased radioresistance. ATAD3A may coordinate with aldo-keto reductase genes and participate in bioactivation or detoxication of temozolomide. Surprisingly, deficient DNA repair after irradiation was observed in T98G/ATAD3A knockdown as a result of decreased nuclear ataxia telangiectasia mutated kinase and histones H2AX and H3, which was also evidenced by the sustained elevation of poly (ADP-ribose) polymerase prior to and after radiation treatment. CONCLUSION: Our data suggest that high expression of ATAD3A is an independent biomarker for radioresistance in GBM. ATAD3A could be a potential target for therapy. PMID- 24057889 TI - Involvement of protease-activated receptor 2 in nociceptive behavior in a rat model of bone cancer. AB - Treatment for bone cancer pain remains a clinical challenge due to a poor understanding of the underlying mechanisms. Protease-activated receptor 2 (PAR2), a receptor for inflammatory proteases, has been implicated in nociceptive signaling under both normal and pathologic pain states. However, little is known of the role of PAR2 in cancer-induced bone pain. Here we investigated the potential role of PAR2 in a rat model of bone cancer pain. The model of bone cancer pain was induced by inoculating Walker 256 into the tibia bone cavity of rats and verified by X-ray imaging, pathology, and behavior assessments. The rats with bone cancer exhibited marked mechanical allodynia, thermal hyperalgesia, and signs of spontaneous nocifensive behavior. Subcutaneous administration of the PAR2 antagonist FSLLRY-NH2 almost completely abolished mechanical allodynia and thermal hyperalgesia but had no effects on spontaneous pain behavior in the rats with bone cancer. Immunohistochemical study revealed that the expression of PAR2 was significantly increased in large- and medium-sized dorsal root ganglia (DRG) neurons but not in small-sized neurons after Walker 256 inoculation. These results suggest that the increased expression of PAR2 in the DRG may contribute to the development of mechanical allodynia and thermal hyperalgesia associated with bone cancer rats. PAR2 might become a novel target for the treatment of pain in patients with bone cancer. PMID- 24057891 TI - Transcription dynamics of inducible genes modulated by negative regulations. AB - Gene transcription is a stochastic process in single cells, in which genes transit randomly between active and inactive states. Transcription of many inducible genes is also tightly regulated: It is often stimulated by extracellular signals, activated through signal transduction pathways and later repressed by negative regulations. In this work, we study the nonlinear dynamics of the mean transcription level of inducible genes modulated by the interplay of the intrinsic transcriptional randomness and the repression by negative regulations. In our model, we integrate negative regulations into gene activation process, and make the conventional assumption on the production and degradation of transcripts. We show that, whether or not the basal transcription is temporarily terminated when cells are stimulated, the mean transcription level grows in the typical up and down pattern commonly observed in immune response genes. With the help of numerical simulations, we clarify the delicate impact of the system parameters on the transcription dynamics, and demonstrate how our model generates the distinct temporal gene-induction patterns in mouse fibroblasts discerned in recent experiments. PMID- 24057890 TI - Interaction of different antidepressants with acute and chronic methadone in mice, and possible clinical implications. AB - We studied the interaction of a single dose of different antidepressant medications with a single (acute) dose or implanted mini-pump (chronic) methadone administration in mice, using the hotplate assay. For the acute experiment, subthreshold doses of six antidepressant drugs were administered separately with a single dose of methadone. The addition of a subthreshold dose of desipramine or clomipramine to methadone produced significant augmentation of the methadone effect with each drug (p < 0.05). Fluvoxamine given at a fixed subthreshold dose induced a synergistic effect only with a low methadone dose. Escitalopram, reboxetine and venlafaxine given separately, each at a fixed subthreshold dose, induced no interaction. Possible clinical implications of these findings are that while escitalopram, reboxetine and venlafaxine do not affect methadone's antinociception in mice and are safe to be given together with methadone when indicated, fluvoxamine, clomipramine and desipramine considerably augment methadone-induced effects and should be avoided in this population due to the risk of inducing opiate overdose. For the chromic experiment, when a subthreshold dose of either escitalopram, desipramine or clomipramine was injected to mice following 2 weeks of methadone administration with the mini-pump, none of the antidepressant drugs strengthened methadone's analgesic effect. Further studies are needed before possible clinical implications can be drawn. PMID- 24057893 TI - Enhanced chemoresistance of squamous carcinoma cells grown in 3D cryogenic electrospun scaffolds. AB - It is critically important to study head and neck squamous cell carcinoma tumorigenic mechanisms in order to gain a better understanding of tumor development, progression, and treatment. Unfortunately, a representative three dimensional (3D) model for these evaluations has yet to be developed. The purpose of this study was to replicate tumor extracellular matrix (ECM) morphology utilizing electrospinning technology. First, the tumor ECM was evaluated by decellularizing tumor samples and analyzing the fibrous structure of the ECM by scanning electron microscopy. Cryogenic electrospun silk scaffolds were then fabricated to mimic the tumor ECM, and were found to be similar in fiber orientation and fiber dimensions to the native tumor ECM. Tumor cells were cultured on these ECM mimicking scaffolds and compared to an in vivo model of the same derivative human tumor in terms of proliferation and differentiation. The tumor cells in the 3D model show similar phenotypes to those found in vivo, contrasting to the same cells grown in two-dimensional (2D) culture. The sensitivity of the tumor cells to paclitaxel was compared between 2D culture and 3D culture. The results indicate that increased drug concentrations, orders of magnitude higher than the IC90 for 2D culture, had minimal effects on HN12 cell viability in the 3D model. In conclusion, an in vitro tumor model has been developed that will allow for a better understanding of tumor biology and aid chemotherapeutic drug development and accurate evaluation of drug efficacy. PMID- 24057894 TI - Does progressive resistance strength training as additional training have any measured effect on functional outcomes in older hospitalized patients? A single blinded randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of progressive resistance strength training as additional training measured on functional outcomes in older hospitalized patients. DESIGN: A single-blinded randomized controlled trial. SETTING: Department of Geriatric Rehabilitation in university hospital. PARTICIPANTS: A sample of 71 patients were successively included and randomized either to the treatment group (TG) (n = 36) or the control group (CG) (n = 35). Fifteen participants dropped out (TG n = 7; CG n = 8), leaving 56 participants with a mean age of 79 (SD 7). INTERVENTION: Participants in the treatment group were treated in groups with progressive resistance strength training in addition to standard care. Progressive resistance strength training of the lower extremities was performed in three sets of 12-15 repetitions, intensity 60-70% of one repetition maximum, in four 50-minute sessions per week. MAIN MEASURES: The effect was evaluated by timed up & go test, 30-second chair-stand test, 10-m walk test, three tasks (transfer, walking, stairs) of the Barthel Index, and use of walking aids. RESULTS: Significant improvements in the 10-m walk test (P < 0.01) and Barthel Index (walking) (P = 0.01) were demonstrated within the treatment group but not in the control group. Both groups had significant improvements in timed up & go, 30-second chair-stand (modified) and Barthel Index (transfer and walking). No significant difference was found between groups except for the Barthel Index (stairs) (P = 0.05). Analysis by the mixed-effects model showed that the treatment group improved more than the control group in all outcome variables. CONCLUSION: The results indicate that for older hospitalized patients progressive resistance strength training as additional training may have an effect compared to standard care, but no statistically significant effects were demonstrated when measured by functional outcomes. PMID- 24057896 TI - Role of serum holotranscobalamin (holoTC) in the diagnosis of patients with low serum cobalamin. Comparison with methylmalonic acid and homocysteine. AB - Plasma holotranscobalamin (holoTC) transports active cobalamin. Decreased levels of holoTC have been considered to be the earliest marker of cobalamin (Cbl) deficiency. In this work, holoTC was evaluated in low or borderline serum Cbl (LB12) and a concordance analysis was carried out with methylmalonic acid (MMA) and homocysteine (Hcy). Levels of Cbl, holoTC, MMA, and Hcy were investigated in a reference group in 106 patients with LB12 (<=200 pmol/l) and in 27 with folate deficiency (FOL). HoloTC levels were evaluated by an automated immunoassay (Active B12, Abbott Lab, Abbott Park, IL, USA). Lower levels of holoTC were observed in both LB12 and FOL groups (reference group vs LB12; p < 0.0001. Reference group vs FOL; p = 0.002). HoloTC levels were lower in LB12 than in FOL (p = 0.001). In LB12, concordance between Hcy and MMA was 82.1 % (chi-square test, p < 0.001; Kappa Index, 0.64, p < 0.0001). Concordance between Hcy and holoTC was 62 % (chi-square test, p = 0.006; Kappa index, 0.245, p = 0.006). Concordance between holoTC and MMA was 55.6 % (p = 0.233). Some cases with LB12 and elevated MMA did not show decreased holoTC. By contrast, MMA and Hcy were not increased in some patients with low holoTC and LB12. In conclusion, levels of holoTC were decreased in LB12 and FOL. In LB12 patients, holoTC concordance with MMA was poor. MMA/Hcy levels were not increased in a significant number of subjects with LB12 and low holoTC. This profile was found in iron deficiency. The significance of these changes remains to be clarified. PMID- 24057897 TI - How closely related are allergic rhinitis, asthma, and chronic sinusitis? PMID- 24057895 TI - How does renal denervation lower blood pressure and when should this technique be considered for the treatment of hypertension? AB - Resistant hypertension poses significant health concerns. There are strong demands for new safe therapeutics to control resistant hypertension, while addressing its common causes, specifically poor compliance to lifelong polypharmacy, lifestyle modification and physician inertia. The sympathetic nervous system plays a significant pathophysiological role in hypertension. Surgical sympathectomy for blood pressure reduction is an old but extremely efficacious therapeutic concept, since abandoned, with the dawn of safer contemporary pharmacology era. Recently, clinical studies have revealed promising results for safe and sustained blood pressure reduction with percutaneous renal sympathetic denervation. This is a novel, minimally-invasive, device-based therapy, specifically targeting and ablating the renal artery nerves with radiofrequency waves, without permanent implantation. There are also reported additional benefits in related comorbidities, such as impaired glucose metabolism, renal impairment, left ventricular hypertrophy, heart failure, and others. This review will focus on how selective renal sympathetic denervation works, as well as its present and potential therapeutic indications. PMID- 24057898 TI - Medial canal fibrosis. PMID- 24057899 TI - Progressive blindness caused by an unusual sphenoid sinus dehiscence. PMID- 24057900 TI - Correction of the severely deviated septum: extracorporeal septoplasty. PMID- 24057901 TI - Larynx: nodules and polyps. PMID- 24057902 TI - Paraganglioma presenting as cholesterol granuloma of the petrous apex. AB - We report the unique finding of a petrous apex cholesterol granuloma associated with a paraganglioma, also known as a glomus jugulare tumor, in a 52-year-old woman who presented to our department with pulsatile tinnitus, hearing loss, aural fullness, and disequilibrium. She had been treated for a petrous apex cholesterol granuloma 20 years earlier, at which time she had undergone drainage of the granuloma via subtotal petrous apicectomy. When she came to our facility approximately 20 years later, she had signs and symptoms consistent with a jugular paraganglioma, which was likely to have been present at the time of her initial presentation for the cholesterol granuloma. In fact, microscopic bleeding from the paraganglioma might have led to the formation of the cholesterol granuloma. The metachronous presentation of these two entities, which to our knowledge has not been reported previously in the literature, indicates the potential association of paragangliomas with the formation of cholesterol granulomas of the petrous apex. PMID- 24057903 TI - Hemangiopericytoma of the parapharyngeal space. AB - Hemangiopericytomas of the head and neck are rarely found in the parapharyngeal space. We report the case of a 53-year-old woman who presented with a globus sensation in her throat. Imaging detected a left submucosal oropharyngeal mass that extended into the prestyloid parapharyngeal space. The tumor was surgically excised en bloc. Histopathologic examination identified it as a hemangiopericytoma. We discuss the diagnosis and management of this rare entity. PMID- 24057904 TI - Features of sequential CT and US-guided biopsy in recurrent Kikuchi disease of the neck: a case report. AB - A 26-year-old woman presented with recurrent Kikuchi disease 7 years after her initial episode. Computed tomography (CT) and ultrasonography demonstrated enlarged lymph nodes with extensive necrosis at the same site as the initial episode. Cytologic and histologic examinations were not conclusive. CT performed 1 month later demonstrated a complete resolution of the lymphadenopathy, which confirmed the diagnosis of recurrent Kikuchi disease. Care must be taken to avoid misdiagnosis of recurrent Kikuchi disease as tuberculous lymphadenitis. PMID- 24057905 TI - Practical applications of in-office fiberoptic transnasal esophagoscopy in the initial evaluation of patients with squamous cell cancer of the head and neck. AB - We conducted a study to analyze the effectiveness of transnasal esophagoscopy (TNE) as an alternative to operative endoscopy (OE) for the evaluation of primary head and neck cancers and for the surveillance of synchronous esophageal cancers. Our study population was made up of 96 consecutively presenting patients-75 men and 21 women, aged 45 to 88 years (mean: 64)-who were treated at our institution for squamous cell cancer of the head and neck. Of this group, 42 patients had been evaluated with TNE and 54 with OE. More OEs were performed in patients with an unknown primary (26 vs. 3). Incidental findings on TNE included 3 cases of gastritis, 2 cases each of hiatal hernia and esophagitis, 1 case of Barrett esophagus, and 1 inlet patch. No incidental findings were reported during OE. Primary cancers were biopsied by TNE through a port on the endoscope in 4 patients; 2 of these cancers were in the tongue base, 1 in the hypopharynx, and 1 in the aryepiglottic fold. After the initial visit, patients in the TNE group waited significantly fewer days for their endoscopy than did those in the OE group (median: 6.5 vs. 16; p < 0.05). Conversely, patients in the OE group waited significantly fewer days for treatment following endoscopy (median: 12 vs. 20; p < 0.05). However, there was no significant difference between the TNE patients and the OE patients in the total number of days comprising their entire course of management, from the initial visit to definite treatment (median: 27.5 and 33 days, respectively; p = 0.7). We conclude that TNE is a reasonable alternative to OE for the initial screening for synchronous esophageal cancers in patients with squamous cancers of the head and neck. OE is preferred for the initial workup of unknown primary cancers and for large tongue base cancers. The rate of detection of clinically relevant incidental findings is higher with TNE. Biopsy is possible during TNE for all subsites within the upper aerodigestive tract. PMID- 24057906 TI - Comparison of clinical differences between patients with allergic rhinitis and nonallergic rhinitis. AB - We conducted a retrospective study to investigate the clinical differences between subtypes of rhinitis patients. Our findings were based on a detailed history and nasal examination. The study population was made up of 910 patients who had at least two rhinitis symptoms. These patients were categorized into one of three rhinitis groups: nonallergic rhinitis (NAR), seasonal allergic rhinitis (SAR), and perennial allergic rhinitis (PAR); there were 212 patients (23.3%) in the NAR group, 473 (52.0%) in the SAR group, and 225 (24.7%) in the PAR group. In addition to demographic data, we compiled information on the season when each patient presented, specific symptoms and their triggers, parental history, associated allergic diseases (e.g., skin, lung, and eye allergies), and nasal examination findings. The SAR patients represented the youngest of the three groups. Most SAR patients presented in spring and summer, and this group had the highest incidence of eye itchiness, pharyngeal itchiness, eye redness, and palatal itchiness. In terms of triggering factors, a visit to a green area was significantly more common in the SAR patients, while detergent odor, sudden temperature change, and cold air were significantly more common in the NAR patients. On nasal examination, a pale nasal mucosa was significantly more common in the NAR group. In clinical practice, it is crucial to differentiate between allergic and nonallergic rhinitis. We conclude that relevant information from the history can predict allergic rhinitis. Future studies of prevalence should take into consideration the important findings of our study, including the significance of age and the seasonality of exacerbation of rhinitis symptoms. PMID- 24057907 TI - An unusual case of angiolymphoid hyperplasia with eosinophilia of the nose. AB - Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare benign vascular lesion that most commonly involves the ear and preauricular area. We report the case of a 38-year-old man who presented with a progressively enlarging mass of the left nasal vestibule. The lesion was diagnosed as a nasal ALHE and treated with surgical excision. There were no complications. PMID- 24057908 TI - Thyroglossal duct cyst carcinoma: case report and review of the literature. AB - Well-differentiated thyroid carcinoma of a thyroglossal duct cyst (TGDC) is a rare entity, found in about 1% of all TGDCs. Diagnosis is usually made incidentally after a Sistrunk procedure. Options for further therapy include total thyroidectomy, T4 suppression therapy, and radioactive iodine ablation. In a patient with a normal-appearing thyroid gland and no evidence of metastatic disease, the treatment course is controversial. The recent literature emphasizes the identification of risk factors that may prompt the clinician to pursue more aggressive treatment. We present the case of a 35-year-old woman who was found to have a 1-cm midline neck mass that showed atypical cells on fine-needle aspiration. Histologic analysis after a Sistrunk procedure revealed a small focus of papillary carcinoma within the TGDC. The patient subsequently underwent total thyroidectomy with no evidence of carcinoma on histologic examination. PMID- 24057909 TI - Endometrial carcinoma metastatic to the retromolar pad. AB - Metastatic carcinoma from the female genitalia to the oral mucosa is exceptionally rare, with only 11 such cases having been previously reported in the English-language literature. We describe a new case in a 65-year-old woman with a history of endometrial carcinoma who presented with swelling of the retromolar pad. Radiographic examination showed slight opacities and irregular trabecular bone in the left posterior mandible. Following an incisional biopsy, histologic examination and immunohistochemical studies revealed glandular adenocarcinoma with positivity for progesterone receptor, estrogen receptor, and cytokeratin 7. The patient was referred to her primary care physician for comprehensive treatment. This case illustrates the value of considering cancer metastasis in the differential diagnosis of an oral swelling, particularly in a patient with a history of cancer. PMID- 24057910 TI - A case of a nasal polyp originating in the cribriform plate. AB - Nasal polyps were once believed to originate in sinus cavities, and from there to pass through ostia and into the nasal cavity. However, data gained from subsequent anatomic studies revealed that they can actually originate in numerous locations in the sinonasal area. We report a case of a nasal polyp that originated in the cribriform plate, which is a very rare site of origin for a nasal polyp. PMID- 24057911 TI - Acantholytic squamous cell carcinoma of the maxilla: unusual location and aggressive behavior of a rare histologic variant. AB - Acantholytic squamous cell carcinoma (ASCC) of the mucosal membranes has been documented sporadically. The highly aggressive behavior of a mucosal ASCC arising in the oral cavity has been recently reported. To the best of our knowledge, only 1 autopsy case of maxillary ASCC previously has been reported in the literature. We present what we believe is only the second case of maxillary ASCC. Our goal is to emphasize the aggressive behavior of this tumor in order to add weight to the argument that the prognosis is poor. PMID- 24057912 TI - Calcific tendinitis of the prevertebral space: a case report. AB - Calcific prevertebral tendinitis is a self-limiting inflammatory condition of the prevertebral space that involves the insertion of the longus colli tendon. Understanding this condition and its characteristic imaging findings is essential for early diagnosis and differentiation of the disorder from other acute conditions. We describe a case of a 40-year-old patient who presented to the emergency department with severe odynophagia and exhibited the computed tomography findings necessary to confirm this disease. PMID- 24057913 TI - Vocal fold atrophy after paralysis. PMID- 24057914 TI - Extranasopharyngeal angiofibroma originating in the inferior turbinate. PMID- 24057915 TI - Ice-cream stick injury resembling torus palatinus. PMID- 24057916 TI - Lymphoepithelial carcinoma of the parotid gland, a very unusual tumor: case report and review. AB - Lymphoepithelial carcinoma (LEC) of the parotid gland is rare. When it does occur, it is usually seen in Asians and Greenland Eskimos. An association with Epstein-Barr virus (EBV) infection has been documented. We report a case of EBV associated LEC of the parotid gland in a 30-year-old Chinese woman. The patient underwent a total parotidectomy with preservation of the facial nerve, followed by postoperative radiotherapy. She recovered well without complications or recurrence. We present this case in view of the rarity of LEC, which has prevented extensive study of its clinical course, optimal treatment options, and overall prognosis. PMID- 24057917 TI - A general method for modeling population dynamics and its applications. AB - Studying populations, be it a microbe colony or mankind, is important for understanding how complex systems evolve and exist. Such knowledge also often provides insights into evolution, history and different aspects of human life. By and large, populations' prosperity and decline is about transformation of certain resources into quantity and other characteristics of populations through growth, replication, expansion and acquisition of resources. We introduce a general model of population change, applicable to different types of populations, which interconnects numerous factors influencing population dynamics, such as nutrient influx and nutrient consumption, reproduction period, reproduction rate, etc. It is also possible to take into account specific growth features of individual organisms. We considered two recently discovered distinct growth scenarios: first, when organisms do not change their grown mass regardless of nutrients availability, and the second when organisms can reduce their grown mass by several times in a nutritionally poor environment. We found that nutrient supply and reproduction period are two major factors influencing the shape of population growth curves. There is also a difference in population dynamics between these two groups. Organisms belonging to the second group are significantly more adaptive to reduction of nutrients and far more resistant to extinction. Also, such organisms have substantially more frequent and lesser in amplitude fluctuations of population quantity for the same periodic nutrient supply (compared to the first group). Proposed model allows adequately describing virtually any possible growth scenario, including complex ones with periodic and irregular nutrient supply and other changing parameters, which present approaches cannot do. PMID- 24057918 TI - Metal-binding ability of VIP1: a bZIP protein in Arabidopsis thaliana. AB - VirE2-interacting protein 1 (VIP1) is an Arabidopsis thaliana bZIP transcription factor which regulates pathogen responses and rehydration responses. VIP1 has transcriptional activation potential, DNA-binding ability, and a nuclear cytoplasmic shuttling property. These functions are possibly regulated by cofactors and/or post-translational modifications. During an investigation of the functions of VIP1, we discovered that VIP1 can react with an Ni2+-activated derivative of horseradish peroxidase, HisProbe-HRP, suggesting that VIP1 can bind Ni2+. Using truncated versions and mutated versions of VIP1, the Ni2+-binding region was narrowed. Using VIP1 H145Q and H145R mutants, which have H -> Q and H > R mutations at the amino acid position 145 of VIP1, a trihistidine site at the amino acid position 144-146 was confirmed to be responsible for the Ni2+-binding ability. Immobilized-metal affinity chromatography (IMAC) suggested that VIP1 can bind Zn2+ and Co2+ as well as Ni2+, which is consistent with the known metal chelating property of polyhistidine. In IMAC, the levels of purified VIP1 were not significantly different between denaturing and non-denaturing conditions, suggesting that the trihistidine is located on the surface of the native form of VIP1. In gel shift assays, VIP1-dependent decreases of electrophoretic mobilities of DNA probes were further decreased by Co2+. Among wild-type VIP1 and the H145Q and H145R mutants, H145R was the least sensitive to the effect of Co2+ in the gel shift assays. These results suggest that the Co2+ and the metal-binding site of VIP1 affect the interaction between VIP1 and DNA. PMID- 24057919 TI - Randomized clinical evaluation of a light-cured base material for complete dentures. AB - OBJECTIVES: The purpose of this study was to compare plaque adhesion, tissue reaction, and technical complications for complete dentures based on visible light-cured resin (VLCR) or on conventional poly(methyl methacrylate) (PMMA). MATERIALS AND METHODS: A stratified randomized cohort study was designed with 52 patients treated with a complete denture in the maxilla (n = 28), the mandible (n = 2), or both (n = 22). Seventy-four dentures were manufactured, 38 of PMMA and 36 of VLCR. Investigators and patients were unaware of the nature of the denture base material. Plaque adhesion, tissue reaction, and technical complications were investigated 4 weeks after denture insertion (baseline). Recall investigations were performed after 6, 12, and 24 months. RESULTS: After 6, 12, and 24 months, plaque adhesion was significantly higher for VLCR dentures than for PMMA dentures. Tissue reaction was comparable for both groups, however. After 6, 12, and 24 months, need for repair was significantly greater for VLCR prostheses. The mean number of additional aftercare sessions per patient after 24 months was 50 % higher for VLCR than for PMMA. CONCLUSIONS: Good oral hygiene must be established by patients treated with VLCR dentures, to remove biofilm from these dentures. Increased aftercare must also be taken into account when this material is used. CLINICAL RELEVANCE: VLCR might be a viable alternative to PMMA for patients with allergic reactions to residual monomer or benzoyl peroxide. PMID- 24057920 TI - Regulation of docosahexaenoic acid production by Schizochytrium sp.: effect of nitrogen addition. AB - Docosahexaenoic acid (DHA) percentage in total fatty acids (TFAs) is an important index in DHA microbial production. In this study, the change of DHA percentage in response to fermentation stages and the strategies to increase DHA percentage were investigated. Two kinds of conventional nitrogen sources, monosodium glutamate (MSG) and ammonium sulfate (AS), were tested to regulate DHA synthesis. Results showed that MSG addition could accelerate the substrate consumption rate but inhibit lipid accumulation, while AS addition could increase DHA percentage in TFAs effectively but extend fermentation period slightly. Finally, the AS addition strategy was successfully applied in 7,000-L fermentor and DHA percentage in TFAs and DHA yield reached 46.06 % and 18.48 g/L, which was 19.54 and 17.41 % higher than that of no-addition strategy. This would provide guidance for the large-scale production of the other similar polyunsaturated fatty acid, and give insight into the nitrogen metabolism in oil-producing microorganisms. PMID- 24057921 TI - Simultaneous wastewater treatment, electricity generation and biomass production by an immobilized photosynthetic algal microbial fuel cell. AB - A photosynthetic algal microbial fuel cell (PAMFC) was constructed by the introduction of immobilized microalgae (Chlorella vulgaris) into the cathode chamber of microbial fuel cells to fulfill electricity generation, biomass production and wastewater treatment. The immobilization conditions, including the concentration of immobilized matrix, initial inoculation concentration and cross linking time, were investigated both for the growth of C. vulgaris and power generation. It performed the best at 5 % sodium alginate and 2 % calcium chloride as immobilization matrix, initial inoculation concentration of 10(6) cell/mL and cross-linking time of 4 h. Our findings indicated that C. vulgaris immobilization was an effective and promising approach to improve the performance of PAMFC, and after optimization the power density and Coulombic efficiency improved by 258 and 88.4 %, respectively. Important parameters such as temperature and light intensity were optimized on the performance. PAMFC could achieve a COD removal efficiency of 92.1 %, and simultaneously the maximum power density reached 2,572.8 mW/m(3) and the Coulombic efficiency was 14.1 %, under the light intensity of 5,000 lux and temperature at 25 degrees C. PMID- 24057922 TI - Endogenous subventricular zone neural progenitors contribute to the formation and hyperexcitability of experimental model of focal microgyria. AB - Microgyria is associated with epilepsy and due to developmental disruption of neuronal migration. However, the role of endogenous subventricular zone-derived neural progenitors (SDNPs) in formation and hyperexcitability has not been fully elucidated. Here, we establish a neonatal cortex freeze-lesion (FL) model, which was considered as a model for focal microgyria, and simultaneously label SDNPs by CM-DiI. Morphological investigation showed that SDNPs migrated into FL and differentiated into neuronal and glia cell types, suggesting the involvement of endogenous SDNPs in the formation of FL-induced microgyria. Patch-clamp recordings in CM-DiI positive (CM-DiI(+)) pyramidal neurons within FL indicated an increase in frequency of spontaneous action potentials, while the resting membrane potential did not differ from the controls. We also found that spontaneous excitatory postsynaptic currents (EPSCs) increased in frequency but not in amplitude compared with controls. The evoked EPSCs showed a significant increase of 10-90% in rise time and decay time in the CM-DiI(+) neurons. Moreover, paired-pulse facilitation was dramatically larger in CM-DiI(+) pyramidal neurons. Western blotting data showed that AMPA and NMDA receptors were increased to some extent in the FL cortex compared with controls, and the NMDA/AMPA ratio of eEPSCs at CM-DiI(+) pyramidal neurons was significantly increased. Taken together, our findings provide novel evidence for the contribution of endogenous SDNPs in the formation and epileptogenicity of FL induced focal microgyria. PMID- 24057923 TI - Premiere use of IntegraTM artificial skin to close an extensive fetal skin defect during open in utero repair of myelomeningocele. AB - BACKGROUND: There are fetuses demonstrating very large myelomeningocele lesion which can not be covered with autochothonous skin. MATERIAL AND METHODS: We use IntegraTM artificial skin for intrauterine coverage of the back lesion. A reverse latissimus dorsi flap was used postnatally to reinforce the repair site. CONCLUSION: IntegraTM appears to be a suitable coverage for large soft tissue defects in utero. Moreover, a postnatal reverse latissimus dorsi flap appears to markedly strengthen tissue coverage over a spinal cord rescued in utero. PMID- 24057924 TI - Intra-abdominal (Type IV) sacrococcygeal teratoma presenting with buttock hemangioma. AB - Sacrococcygeal teratoma is the most common type of extragonadal germ cell tumor in infants and young children. Sacrococcygeal teratomas can uncommonly present in an intra-abdominal fashion, with minimal clinical findings. Dermatologic lesions overlying the vertebrae or buttocks are often associated with sacrococcygeal teratoma and may be the only clue to their presence. Here, we report a case of an intra-abdominal sacrococcygeal teratoma presenting with an anatomically separate buttock hemangioma. PMID- 24057925 TI - Comparative outcomes of rituximab-based systemic therapy and splenectomy in splenic marginal zone lymphoma. AB - Despite diagnostic and therapeutic advances, the majority of patients with splenic marginal zone lymphoma (SMZL) are still treated with splenectomy. We analyzed survival outcomes after surgery or rituximab-based systemic therapy in the Surveillance Epidemiology and End Results-Medicare database, using inverse probability of treatment weighting to minimize treatment selection bias. From the 657 recorded cases diagnosed between 2000 and 2007, with a median age of 77 years, we selected 227 eligible patients treated with splenectomy (68 %), rituximab alone (23 %), or in combination with chemotherapy (9 %) within 2 years from diagnosis. No significant difference between the groups was observed in the cumulative incidence of lymphoma-related death (LRD) at 3 years (19.6 % with systemic therapy and 17.3 % with splenectomy; hazard ratio [HR], 1.04; 95 % confidence interval [CI], 0.56-1.92; P = 0.90) or in the overall survival (HR, 1.01; 95 % CI, 0.66-1.55; P = 0.95). The 90-day mortality after splenectomy was 7.1 %. The rates of hospitalizations, infections, transfusions, and cardiovascular or thromboembolic events were higher after combination chemoimmunotherapy than after splenectomy. Conversely, there was no significant difference in most complications between groups treated with splenectomy or rituximab alone. The cumulative incidence of LRD after single-agent rituximab at 3 years was 18.7 % (95 % CI, 8.6-31.7). In conclusion, in SMZL patients over the age of 65 years, the risk of LRD and overall survival are similar with systemic therapy or splenectomy as initial therapy. Single-agent rituximab may offer the most favorable risk/benefit ratio in this population. PMID- 24057926 TI - Thymol inhibits LPS-stimulated inflammatory response via down-regulation of NF kappaB and MAPK signaling pathways in mouse mammary epithelial cells. AB - Thymol is a natural monoterpene phenol primarily found in thyme, oregano, and tangerine peel. It has been shown to possess anti-inflammatory property both in vivo and in vitro. In the present paper, we studied the anti-inflammatory effect of thymol in lipopolysaccharide (LPS)-stimulated mouse mammary epithelial cells (mMECs). The mMECs were stimulated with LPS in the presence or absence of thymol (10, 20, 40 MUg/mL). The concentrations of tumor necrosis factor alpha (TNF alpha), interleukin (IL)-6, and IL-1beta in the supernatants of culture were determined using enzyme-linked immunosorbent assay. Cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), nuclear factor-kappaB (NF-kappaB), and inhibitor protein of NF-kappaB (IkappaBalpha) were measured using western blot. The results showed that thymol markedly inhibited the production of TNF alpha and IL-6 in LPS-stimulated mMECs. The expression of iNOS and COX-2 was also suppressed by thymol in a dose-dependent manner. Furthermore, thymol blocked the phosphorylation of IkappaBalpha, NF-kappaB p65, ERK, JNK, and p38 mitogen activated protein kinases (MAPKs) in LPS-stimulated mMECs. These results indicate that thymol exerted anti-inflammatory property in LPS-stimulated mMECs by interfering the activation of NF-kappaB and MAPK signaling pathways. Thereby, thymol may be a potential therapeutic agent against mastitis. PMID- 24057927 TI - Utilization of blood glucose data in patient education. AB - Many studies have tested clinical and behavioral approaches for improving glycemic control in people with diabetes. We reviewed studies to identify how blood glucose (BG) values have been used in patient-focused clinical research and interventions. We sought to describe the frequency that BG values have been the focus of patient education research and to characterize the different methods to integrate BG into an intervention, the approaches implemented to support patient education, and behavior change, and the nature of communication about BG values. Thirty-four eligible studies were identified that included patient education using BG values. Information regarding the study and intervention characteristics include: (1) characteristics of the study sample, (2) how BG values were obtained, (3) use of a graphical interface for BG values, (4) use of a BG log, (5) BG interpretation and regimen adjustments, (6) recommended actions to patient, (7) modality of intervention, and (8) intervention communication schedule. The review demonstrated that new BG technologies provide outstanding opportunities for greater access to BG data, and for patient support and intervention. However, it also indicated a need to improve and expand support for people with diabetes in their daily use of BG values to maintain and improve glycemic control. In order to make the most sustainable impact on behavior, generalizable skills such as problem solving need to be integrated into BG education. PMID- 24057928 TI - Efficacy of sequential use of fluoxetine for smoking cessation in elevated depressive symptom smokers. AB - INTRODUCTION: Fluoxetine, a selective serotonin reuptake inhibitor, was examined in the treatment of smokers with elevated depressive symptoms. Specifically, this randomized, open-label clinical trial was designed to evaluate the efficacy of three logical, real-world alternatives for providing smoking cessation treatment to smokers with elevated depressive symptoms. METHODS: In a sample of 216 smokers (mean Center for Epidemiological Studies Depression Scale score = 11.41), participants were randomly assigned to (a) transdermal nicotine patch (TNP), beginning on quit date and continuing for 8 weeks thereafter; (b) standard administration of antidepressant pharmacotherapy with fluoxetine (20mg), beginning 2 weeks before quit date and continuing for 8 weeks following quit date + TNP (ST-FLUOX); or (c) sequential administration of fluoxetine (20mg), beginning 8 weeks before quit date and continuing for 8 weeks following quit date + TNP (SEQ-FLUOX). All participants received 5 sessions of brief behavioral smoking cessation treatment. RESULTS: Findings indicate that SEQ-FLUOX resulted in significantly higher point prevalence abstinence than ST-FLUOX at 6-month follow-up (OR = 2.35; 95% CI = 1.10-5.02, p < .03), a difference that was reduced at the 12-month assessment. Furthermore, sequential fluoxetine treatment, compared with standard fluoxetine treatment, resulted in significantly lower levels of depressive symptoms throughout smoking cessation treatment (p < .025) and significantly lower nicotine withdrawal-related negative affect (p < .004) immediately after quitting. CONCLUSIONS: Findings suggest that if one is going to prescribe fluoxetine for smoking cessation in smokers with elevated depressive symptoms, it is best to begin prescribing fluoxetine well before the target quit date. PMID- 24057929 TI - Expression of HAX-1 in human colorectal cancer and its clinical significance. AB - Colorectal cancer (CRC) remains one of the most common cancers worldwide. HS1 associated protein X-1 (HAX-1) has been highlighted as an important marker in many types of cancers. However, little is known about the role of HAX-1 in CRC. The aim of this study was to analyze the correlation of HAX-1 expression with the clinicopathological features of CRC. The protein and mRNA levels of HAX-1 were examined by immunohistochemistry (IHC) and real-time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) in CRC tissues and adjacent noncancerous tissues. Survival curves were made with follow-up data. The relations of the prognosis with clinical and pathological characteristics were analyzed. Using IHC and RT-qPCR, we showed that HAX-1 expression was significantly higher in CRC tissues than in adjacent noncancerous tissues (P < 0.05). High HAX-1 expression was significantly associated with lymph node metastasis (P = 0.034) and tumor (T) node (N) metastasis (M) stage (P = 0.028) of patients with CRC. The Kaplan-Meier survival curves indicated that overall survival was significantly worse in CRC patients with HAX-1 overexpression. Multivariate analysis showed that high HAX-1 expression was an independent predictor of overall survival. In conclusion, our data for the first time provide a basis for the concept that overexpression of HAX-1 may contribute to the malignant progression of CRC and predict poor prognosis for patients with this disease. HAX-1 might be an important marker for tumor progression and prognosis, as well as a potential therapeutic target of CRC. PMID- 24057930 TI - Moving the bar to the right place: positioning interventions in HIV prevention. PMID- 24057931 TI - Measures of condom and safer sex social norms and stigma towards HIV/AIDS among Beijing MSM. AB - Social norms around condom use and safe sex as well as HIV/AIDS stigma are used to identify persons at higher risk for HIV. These measures have been developed and tested in a variety of settings and populations. While efforts have been undertaken to develop context specific measures of these domains among Chinese MSM, the feasibility of using existing measures is unknown. A survey of MSM, based on respondent-driven sampling, was conducted in Beijing. Existing measures of condom social norms, attitudes towards safer sex and HIV/AIDS stigma were piloted. Internal consistency of all measures was high. As expected higher levels of condom social norms and positive attitudes towards safer sex were associated with condom use. HIV/AIDS stigma and discrimination had a significant relationship with never having an HIV test and lack of discussion of HIV/AIDS with male partners. Correlates of low condom social norms were age, education, employment and resident status. Existing measures of condom social norms, attitudes towards safer sex and HIV/AIDS stigma appear to be appropriate for use among Chinese MSM. Using existing measures as opposed to developing new measures has the potential to expedite investigations into psychosocial correlates of HIV risk behavior. PMID- 24057932 TI - Prevalence and correlates of sexual partner concurrency among Australian gay men aged 18-39 years. AB - Mathematical models predict higher rates of HIV and sexually transmitted infections (STIs) in populations with higher rates of concurrent sexual partnerships. Although gay men and other men who have sex with men (MSM) have disproportionately high rates of HIV/STIs, little is known about the prevalence and correlates of sexual concurrency in these populations. This paper reports findings from a national community-based survey of 1,034 Australian gay identified men aged 18-39 years, who gave detailed information about their sexual partners over the past 12 months. In all, 237 (23 %) reported two or more concurrent sexual partners. For their most recent period of concurrency, 44 % reported three or more partners and 66 % reported unprotected sex with one or more of their partners. A multivariate logistic regression found sexual concurrency was significantly more likely among men on higher incomes (P = 0.02), who first had anal sex at a relatively young age (P = 0.03), and who reported a large number of partners in the past 12 months (P < 0.001). Age, education, HIV status, and other sociodemographic and sexual behavior variables were not significant correlates. However, men who reported sexual concurrency were significantly more likely to have been diagnosed with an STI in the past 12 months (P = 0.04). Findings from this study suggest sexual concurrency is common among younger Australian gay men. With many of these men not always using condoms, health agencies should consider the potential impact of concurrency on HIV/STI epidemics among gay men and other MSM. PMID- 24057933 TI - HIV testing among heterosexuals at elevated risk for HIV in the District of Columbia: has anything changed over time? AB - The District of Columbia launched a routine HIV testing initiative in 2006. We examined HIV testing behaviors among heterosexuals at risk for HIV over time using CDC National HIV Behavioral Surveillance data from Washington, DC for the heterosexual cycles from 2006 to 2007 (Cycle 1) and 2010 (Cycle 2). Past year and past 2-year HIV testing across study cycles were compared using Chi square tests. Weighted multivariable logistic regression identified correlates of past year testing. The majority of participants across both cycles were black and female. Cycle 1 participants were significantly more likely to have >=4 partners in the past year, casual sex partners, and have anal sex at last sexual encounter (p < 0.05). Lifetime testing was high, and individuals from Cycle 2 versus Cycle 1 were more likely to have been tested in the past 2 years. There were no significant differences in past year testing or being offered the HIV test at last health care visit by cycle. Independent correlates of past year testing were seeing a health care provider in the past year and using condoms at last vaginal sex. In conclusion, although past year testing did not differ between the two data collection years, the proportion of heterosexuals testing in the past 2 years was higher in Cycle 2 versus Cycle 1, suggesting successful expansion of HIV testing between the two time periods. PMID- 24057934 TI - Assessing appearance-related disturbances in HIV-infected men who have sex with men (MSM): psychometrics of the body change and distress questionnaire-short form (ABCD-SF). AB - Appearance-related disturbances are common among HIV-infected MSM; however, to date, there have been limited options in the valid assessment of this construct. The aim of the current study was to assess the structural, internal, and convergent validity of the assessment of body change distress questionnaire (ABCD) and its short version. Exploratory and confirmatory factor analyses indicated that both versions fit the data well. Four subfactors were revealed measuring the following body disturbance constructs: (1) negative affect about appearance, (2) HIV health-related outcomes and stigma, (3) eating and exercise confusion, and (4) ART non-adherence. The subfactors and total scores revealed bivariate associations with salient health outcomes, including depressive symptoms, HIV sexual transmission risk behaviors, and ART non-adherence. The ABCD and its short form, offer valid means to assess varied aspects of body image disturbance among HIV-infected MSM, and require modest participant burden. PMID- 24057935 TI - Imaging in retina units: changes observed during the last 12 years. AB - PURPOSE: The last decade has seen many improvements in the imaging of the choroids, retina, and vitreous. However, there are no available data about changes in the practice of imaging in retina units. The present study was therefore undertaken to document the 12-year changes in this practice in retina units in France, particularly the relative changes in the distribution of the different imaging methods. METHODS: This retrospective study was performed in 4 different retina units considered to be representative of retina units in France. They comprise 2 departments of ophthalmology in university-based hospitals in Paris and Nantes, one in a non-university-based general hospital in Orleans, and one private tertiary care clinical center located in Paris. The annual numbers for the different retinal imaging methods performed in the 4 units between 2000 and 2011 were recorded, analyzed, and compared. RESULTS: The total of images performed increased during the last decade, from 16,084 in 2000 to 76,318 in 2011. The distribution of the imaging techniques performed each year changed significantly during this period (p<0.0001, chi2 test): the share of fluorescein angiography decreased from 78.7% in 2000 to 7.0% in 2011. During this period, the share of indocyanine green angiography also dropped from 11.3% to 1.3%. The share of optical coherence tomography increased from 26.4% in 2003 to 53.4% in 2012. CONCLUSIONS: The present study documents the increasing share of noninvasive imaging and the decreasing share of angiography in retina units over the last 12 years. PMID- 24057936 TI - Posterior iris-claw aphakic intraocular lens implantation in subluxated lenses due to Marfan syndrome. AB - PURPOSE: To evaluate the indications, visual outcomes, and complication rate after posterior implantation of an iris-claw aphakic intraocular lens (IOL) in subluxated lenses due to Marfan syndrome. METHODS: Eyes without adequate capsular support had posterior chamber iris-claw aphakic IOL implantation between 2006 and 2012. RESULTS: This retrospective cohort study comprised 13 eyes of 10 patients (7 female, 3 male; mean age +/- standard deviation, 34.7 +/- 19.6; range 9-61 years). The mean follow-up was 37 months (range 6-74 months). The mean final postoperative best-corrected visual acuity was significantly (0.24 +/- 0.36 logMAR) better at the last follow-up than 1 day preoperatively (0.72 +/- 0.46 logMAR) (p<0.05). There was no significant change in intraocular pressure before and after surgery. The mean endothelial cell density decreased from 2793 +/- 478 cells/mm2 preoperatively to 2637 +/- 612 cells/mm2 at last follow-up, representing a mean endothelial cell loss of 5.6%. Complications included early transient postoperative hypotony in 2 eyes (15.4%), slight persistent pupil ovalization in 1 eye (7.7%), and retinal detachment in 1 eye (7.7%). CONCLUSIONS: The posterior implantation technique of aphakic iris-claw IOL provided good visual outcomes with a favorable complication rate and can be used as a reasonable alternative in subluxated lenses due to Marfan syndrome without adequate capsular support. PMID- 24057937 TI - Supracor hyperopia and presbyopia correction: 6-month results. AB - PURPOSE: To investigate refractive and visual outcomes and complications of the Supracor procedure to treat presbyopia. METHODS: A total of 123 eyes from 68 presbyopic patients with hyperopia were enrolled in this prospective, nonrandomized, clinical trial. The Supracor procedure was performed using the Technolas excimer laser 217P (Technolas Perfect Vision GmbH). Follow-up eye examinations were performed at postoperative day 1, month 1, and month 6. RESULTS: All 123 surgeries were uneventful. At 6 months postoperatively, uncorrected distance visual acuity was 20/20 or better in 27 (22.0%) eyes and 20/25 or better in 45 (36.6%) eyes. At 6 months postoperatively, 35 (28.5%) eyes lost 1 line and 13 (10.6%) eyes lost 2 lines of corrected distance visual acuity (CDVA). At 6 months postoperatively, uncorrected near visual acuity was 20/20 or better in 95 (77.2%) eyes and 20/25 or better in 110 (89.4%) eyes. At 6 months postoperatively, 6 (4.9%) eyes lost 1 line of corrected near visual acuity. CONCLUSIONS: The Supracor presbyopia procedure showed good near visual acuity outcomes over 6 months follow-up but loss of CDVA occurred in 39.1% of eyes. PMID- 24057938 TI - Optical and visual simulation of standard and modified spherical aberration implantable Collamer lens post myopic LASIK surgery. AB - PURPOSE: To evaluate the visual quality achieved in patients undergoing standard or modified implantable Collamer lens (ICL) to correct residual myopic error after laser-assisted in situ keratomileusis (LASIK) surgery. METHODS: The adaptive optics visual simulator was used to simulate LASIK surgery of moderate and high myopia with a myopic regression corrected by a standard and modified ICL. Visual acuity (VA) and contrast sensitivity (CS) were measured in 14 subjects at 3- and 4.5-mm pupil. Point spread function and simulated retinal images were calculated. RESULTS: Comparing LASIK plus standard ICL and LASIK plus modified ICL simulations, for moderate myopia, VA improvement was less than 1 line in all VA contrasts and both pupils evaluated. No statistically significant differences were found in CS between the simulations at any spatial frequency evaluated and for 3-mm pupil (p>0.05), but differences were significant at 4.5-mm pupil (p<0.05). For high myopia, the VA improvement was less than 1 line at 3-mm pupil, although it increased 2 or more lines at 4.5-mm pupil. Statistically significant differences were found in CS between the simulations for all spatial frequencies and both pupils evaluated (p<0.05), except for low and medium spatial frequencies at 3-mm pupil (p>0.05). CONCLUSIONS: These outcomes suggest that an ICL is a good option to correct the myopic residual error after myopic LASIK. When the ICL's spherical aberration is modified, the post-LASIK eyes of high myopia are the most benefited, as these eyes are more aberrated than after moderate myopic LASIK. PMID- 24057939 TI - Retractor plication versus retractor plication and lateral tarsal strip for eyelid entropion correction. AB - PURPOSE: Involutional entropion is a common lower lid malposition. Addressing both the horizontal and the vertical lower eyelid laxity in patients with involutional entropion seems to have a more long-lasting effect on maintaining lower eyelid stability; however, there is some disagreement as to which approach is the best surgical intervention. The aim of this study was to determine differences in the surgical outcome of Jones retractor plication (JRP) alone versus Jones retractor plication with a lateral tarsal strip (JRP + LTS) for the treatment of involutional entropion. METHODS: A retrospective case series comparison of 118 patients with primary involutional lower eyelid entropion was performed. Jones retractor plication alone was performed in 61 patients, and JRP + LTS in 57 patients. The baseline characteristics of the 2 groups were similar. Patients were retrospectively evaluated from a retrospective case-note review 3 weeks and 6, 12, 18, and 24 months postoperatively. Successful surgery was defined as a normal eyelid position. RESULTS: A total of 115 patients fulfilled the inclusion criteria, 60 in the JRP group and 55 in the JRP + LTS group. Ten patients (16.5%) in the JRP group and 2 patients (3.5%) in the JRP + LTS group had a recurrence of the entropion at or before their 24-month follow-up visit (p = 0.03). CONCLUSIONS: These data provide strong evidence that the success rate at 24 months is higher in patients treated with the JRP + LTS procedure compared with JRP alone. PMID- 24057941 TI - Real-time measurement of quorum-sensing signal autoinducer 3OC6HSL by a FRET based nanosensor. AB - Quorum sensing (QS) is involved in many important biological functions such as luminescence, antibiotic production, and biofilm formation. The autoinducer N-(3 oxo-hexanoyl)-L-homoserine lactone (3OC6HSL) plays a significant role in the QS system of the marine bacterium Vibrio fischeri. Tracing 3OC6HSL would be significant in studies related to QS signal transduction. Traditional detection of QS signaling molecules has relied on bacterial reporter strains and high performance liquid chromatography, which are time consuming and have low sensitivity. Because 3OC6HSL binding to LuxR from V. fischeri causes a conformational change, we developed a genetically encoded biosensor based on Forster resonance energy transfer (FRET) by inserting LuxR between the FRET pair YFP/CFP. The detection limit of the sensor was 100 MUM. We attained an optimized sensor with 70 % Deltaratio increase by screening different hydrophobic linkers, and demonstrated the feasibility of this sensor for visualizing 3OC6HSL both in vitro and in vivo. PMID- 24057940 TI - Locking versus nonlocking plates in mandibular reconstruction with fibular graft- a biomechanical ex vivo study. AB - OBJECTIVES: The main goal of the present study was to compare the biomechanical stability of locking plates and conventional miniplate combinations in human mandibles reconstructed with fibular grafts. MATERIALS AND METHODS: A specially developed and well-proven testing device reproduced the in vivo loading conditions on the mandible. Cadaveric human mandibles (n = 12) reconstructed with harvested human fibular bone grafts were divided into two groups, and different osteosynthesis systems were applied using two lines of plates per osteotomy. On the test apparatus, the specimens were stressed to failure, and interfragmentary movement was monitored and quantified with a contact-free optical measurement system. RESULTS: The relevant interfragmentary movement results from a Euclidean summary calculation which considered all three spatial angles around the axes. Using values up to a maximum load of 300 N, the conventional six-hole miniplates (profile 1.0) had an average value of 7.45 degrees +/- 1.46 degrees , and the locking six-hole plates (profile 1.3) had an average value of 12.16 degrees +/- 2.37 degrees for rotational interfragmentary movement. The miniplate system exhibited a significantly superior performance in fixation compared to the fixed angle system (p < 0.05). CONCLUSION: According to these biomechanical experiments, both osteosynthesis devices provided sufficient stabilization at loads of up to 300 N. The six-hole miniplate system provided better stabilization of the osteotomy gap for mandibles reconstructed with fibular grafts. CLINICAL RELEVANCE: The osteosynthesis system is essential for primary stability and the avoidance of pseudarthrosis formation. This study demonstrates that the miniplates provide sufficient stabilization and offers a method to improve fixation in reconstructed mandibles. PMID- 24057942 TI - Who funds their health savings account and why? AB - Health savings account (HSA) enrollment has increased markedly in the last several years, but little is known about the factors affecting account funding decisions. We use a unique data set containing from a bank that exclusively services HSA funds linked to health status, benefit design, plan coverage, and enrollee characteristics from a very large national health insurance company to examine the factors associated with HSA contribution. We found that even small employer contributions had an apparently large effect on the decision to open an account: the account-opening rate was 50 % higher when employers contributed to the account. Conditional on opening an HSA, employee contributions were negatively associated with the amount of employer contribution, contributions rose with age, income, education, and health care need. PMID- 24057943 TI - Group fitness activities for the elderly: an innovative approach to reduce falls and injuries. AB - AIM: The aim of this study was to examine the opportunity to adopt, for the elderly, already validated function ability tests to better understand how to prevent falls and injuries and to better plan group fitness activities like ballroom dance classes (e.g., Valzer, Polka, Mazurka). METHODS: A cross-sectional study was conducted. The Berg Balance Scale (BBS) and the Barthel Index (BI) were administered and the occurrence of falls during the previous 2 years was evaluated by anamnesis. One hundred and twenty-two elderly subjects living in Palermo city participated to the study. According to the anamnesis, subjects were divided into two groups: experimental group (EG) and control group (CG). The EG consisted of 75 subjects attending classes of ballroom dancing (73.0 +/- 5.6 years 26.1 +/- 3.9 BMI), while the CG included 47 volunteers (74.3 +/- 5.4 years, 26.8 +/- 4.4 BMI). A threshold of 70 % for both scales (BBS-70 and BI-70 %) was set, according to the aims of the study. STATISTICA software was adopted to perform an unpaired t test. A P value lower than 0.05 was considered to be statistically relevant. RESULTS: The BI and BBS of CG were 76.7 +/- 33.08 and 30.9 +/- 14.9, respectively, while the BI and BBS of EG were 98.1 +/- 6.9 and 50.5 +/- 54. In EG the BBS-70 % showed 96.0 % of cases compared to 27.6 % of the CG. The BI showed a similar trend to BBS. In EG the BI-70 % showed 98.6 % of cases, while the BI-70 % of CG showed 70.2 % of cases. Moreover, only 36.0 % of EG reported falls previously, while CG reported 53.2 % of falls during the same period of time. CONCLUSION: The BBS seems to be a valid and reliable tool able to be adopted also by professionals of the ballroom dancing sector (e.g., Valzer, Polka and Mazurka classes). Instructors may evaluate the functional ability of their attendees through BBS to easily obtain more information and better plan ballroom dance classes. Moreover, we highlight that these conclusions need to be supported by other studies with different cohorts and a larger population scale. PMID- 24057944 TI - Cross-language perception of Cantonese vowels spoken by native and non-native speakers. AB - This study examined the effect of native language background on listeners' perception of native and non-native vowels spoken by native (Hong Kong Cantonese) and non-native (Mandarin and Australian English) speakers. They completed discrimination and an identification task with and without visual cues in clear and noisy conditions. Results indicated that visual cues did not facilitate perception, and performance was better in clear than in noisy conditions. More importantly, the Cantonese talker's vowels were the easiest to discriminate, and the Mandarin talker's vowels were as intelligible as the native talkers' speech. These results supported the interlanguage speech native intelligibility benefit patterns proposed by Hayes-Harb et al. (J Phonetics 36:664-679, 2008). The Mandarin and English listeners' identification patterns were similar to those of the Cantonese listeners, suggesting that they might have assimilated Cantonese vowels to their closest native vowels. In addition, listeners' perceptual patterns were consistent with the principles of Best's Perceptual Assimilation Model (Best in Speech perception and linguistic experience: issues in cross language research. York Press, Timonium, 1995). PMID- 24057946 TI - Elastic properties of liquid and solid argon in nanopores. AB - We have measured sorption isotherms and determined the intrinsic longitudinal elastic modulus beta(Ar,ads) of nanoconfined material via ultrasonic measurements combined with a special effective medium analysis. In the liquid regime the adsorbate only contributes to the measured effective properties when the pores are completely filled and the modulus is bulklike. At partial fillings its contribution is cancelled out by the high compressibility of the vapour phase. In contrast, at lower temperatures frozen argon as well as underlying liquid surface layers cause a linear increase of the effective longitudinal modulus upon filling. During sorption the contribution of the liquid surface layers near the pore wall beta(Ar,surf) increases with the thickness of the solid layers reaching the bulk value beta(Ar,liquid) only in the limit of complete pore filling. We interpret this effect as due to the gradual stiffening of the solid argon membrane. The measurements and their analysis show that longitudinal ultrasonic waves are well suited to the study of the elastic properties and liquid-solid phase transitions in porous systems. This method should also help to detect the influence of nanoconfinement on elastic properties in further research. PMID- 24057948 TI - A transconceptual model of empowerment and resilience: divergence, convergence and interactions in kindred community concepts. AB - Resilience and empowerment are widely employed concepts in community psychology and other social sciences. Although empowerment is more closely associated with community psychology, both concepts hone to community psychology's strengths based values, recognizing, respecting, and promoting local capacity and positive outcomes. Both concepts also have been critiqued for lacking clear consensus regarding definition, operationalization, and measurement (Cattaneo and Chapman in Am Psychol 65(7):646-659, 2010; Luthar et al. in Child Dev 71(3):543-562, 2000). This deficiency is reflected in the wide ranging applications of each term independently, and is particularly concerning when the terms are used together or interchangeably. Theoretical work on these concepts' boundaries and interaction is lacking. This paper builds on the authors' prior work operationalizing the processes and outcomes of each concept (Brodsky et al. in Am J Community Psychol 47(3-4):217-235, 2011; Cattaneo and Chapman in Am Psychol 65(7):646-659, 2010; Cattaneo and Goodman in Psychol Violence, in press) to present a combined transconceptual model illuminating the divergence, convergence, and interactions between the two. Both resilience and empowerment are fueled by unsatisfying states, but are differentiated by, among other things, internally (resilience) versus externally (empowerment) focused change goals. Goal determinants include context, power differentials, and other risks and resources. These concepts have the potential to facilitate each other, and understanding their interaction can better inform community psychologists' work with marginalized populations. PMID- 24057947 TI - Incretin-based therapies: focus on effects beyond glycemic control alone. AB - Type 2 diabetes is associated with a high prevalence of comorbidities resulting from hypertension, dyslipidemia, and hyperglycemia. Inadequate management of these risk factors will eventually result in detrimental health consequences. Thus, the effect of a drug on factors such as weight, cardiovascular (CV) risk factors, and adherence is important to consider. A review was undertaken of the recent medical literature describing the extraglycemic characteristics of the two classes of incretin-based therapies-glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors. PubMed searches were performed to identify published data on incretin therapies that describe their effects on CV risk factors, CV events, and factors related to medication adherence. The maintenance or loss of weight associated with the use of GLP-1RAs and DPP-4 inhibitors is well described in the medical literature. These agents also appear to be associated with a modest decrease in blood pressure and a reduced risk of CV events. In addition, several characteristics of incretin therapies may improve rates of medication adherence, such as generally favorable tolerability profiles (particularly with DPP-4 inhibitors), the availability of formulations that simplify treatment regimens, and a low risk for hypoglycemia. The literature on incretin therapies describes a number of clinical characteristics that are relevant to the management of extraglycemic risk factors. As part of a holistic treatment strategy, these properties constitute important considerations for tailoring therapy to individual patients with type 2 diabetes. PMID- 24057949 TI - Onset of neuromuscular blockade: more than just the time to get there. PMID- 24057950 TI - New insights about the use of tranexamic acid in children undergoing cardiac surgery: from pharmacokinetics to pharmacodynamics. PMID- 24057951 TI - Sevoflurane and its role in the development of chronic postsurgical pain: where is the smoking gun? PMID- 24057952 TI - Does isoflurane or isoflurane plus hyperoxia induce apoptotic cell death? PMID- 24057953 TI - Real-time 3-dimensional transesophageal echocardiography: improvements in intraoperative mitral valve imaging. PMID- 24057954 TI - Time to reconsider the landmark technique for internal jugular vein cannulation. PMID- 24057958 TI - Nordic research on per- and polyfluoroalkyl substances (PFASs). PMID- 24057959 TI - Synthesis and characterization of nanocrystalline TiO2 with application as photoactive coating on stones. AB - Self-cleaning photocatalytic coatings for biocalcarenite stones, based on TiO2 nanoparticles obtained by sol-gel processes at different pH values and also adding gold particles, have been investigated. The selected test material is a biocalcarenite named "pietra di Lecce" (Lecce stone), outcropping in Southern Italy. Scanning electron microscopy with energy-dispersive X-ray spectroscopy, transmission electron microscopy, X-ray diffraction, and Raman investigations were carried out to characterize the TiO2 nanoparticles and coatings. Nanocrystalline anatase and, to a lesser extent, brookite phases are obtained. Photocatalytic activity of the TiO2 sols and of the coatings on "pietra di Lecce" was assessed under ultraviolet irradiation, monitoring methyl orange (MeO) dye degradation as a function of time. To evaluate the harmlessness of the treatment, colorimetric tests and water absorption by capillarity were performed. The results show good photodegradation rates for titania nanosols, particularly when putting in Au particles, whereas a satisfactory chromatic compatibility between the sol and the surface of the calcarenite is found only without Au addition. HIGHLIGHTS: Sols of nanocrystalline titania at different pH values and with Au particles were prepared and characterized. Satisfactory photodegradation of MeO by the sols in solution and on calcarenite-coated surfaces is obtained. The addition of Au particles improves the photodegradation activity but gives poor chromatic results on "pietra di Lecce." PMID- 24057960 TI - Assessment of (222)Rn emanation from ore body and backfill tailings in low-grade underground uranium mine. AB - This paper presents a comparative study of (222)Rn emanation from the ore and backfill tailings in an underground uranium mine located at Jaduguda, India. The effects of surface area, porosity, (226)Ra and moisture contents on (222)Rn emanation rate were examined. The study revealed that the bulk porosity of backfill tailings is more than two orders of magnitude than that of the ore. The geometric mean radon emanation rates from the ore body and backfill tailings were found to be 10.01 * 10(-3) and 1.03 Bq m(-2) s(-1), respectively. Significant positive linear correlations between (222)Rn emanation rate and the (226)Ra content of ore and tailings were observed. For normalised (226)Ra content, the (222)Rn emanation rate from tailings was found to be 283 times higher than the ore due to higher bulk porosity and surface area. The relative radon emanation from the tailings with moisture fraction of 0.14 was found to be 2.4 times higher than the oven-dried tailings. The study suggested that the mill tailings used as a backfill material significantly contributes to radon emanation as compared to the ore body itself and the (226)Ra content and bulk porosity are the dominant factors for radon emanation into the mine atmosphere. PMID- 24057961 TI - Longevity of rodenticide bait pellets in a tropical environment following a rat eradication program. AB - Invasive rodents (primarily Rattus spp.) are responsible for loss of biodiversity in island ecosystems worldwide. Large-scale rodenticide applications are typically used to eradicate rats and restore ecological communities. In tropical ecosystems, environmental conditions rapidly degrade baits and competition for baits by non-target animals can result in eradication failure. Our objective was to evaluate persistence of rodenticide baits during a rat eradication program on Palmyra Atoll; a remote tropical atoll with intense competition for resources by land crabs. Following aerial application, bait condition was monitored in four terrestrial environments and in the canopy foliage of coconut palms. Ten circular PVC hoops were fixed in place in each of Palmyra's four primary terrestrial habitats and five rodenticide pellets were placed in each hoop. Five coconut palms were selected in three distinct regions of the atoll. One rodenticide pellet was placed on each of five palm fronds in each coconut palm. Fresh baits were placed in all monitoring locations after each broadcast bait application. Bait condition and survival was monitored for 7 days after the first bait application and 6 days after second application. Bait survival curves differed between applications at most monitoring sites, suggesting a decrease in overall rat activity as a result of rodenticide treatment. One terrestrial site showed near 100 % bait survival after both applications, likely due to low localized rat and crab densities. Median days to pellet disappearance were one and two days for the first and second application, respectively. Differences in survival curves were not detected in canopy sites between bait applications. Median days to pellet disappearance in canopy sites were 2 and 4 days for the first and second application, respectively. Frequent rainfall likely contributed to rapid degradation of bait pellets in coconut palm fronds. PMID- 24057962 TI - Release of vanadium from oxidized sediments: insights from different extraction and leaching procedures. AB - Although the attention for vanadium (V) as a potentially harmful element is growing and some countries adopted threshold values for V in soils, sediments, groundwater, or surface water, V is generally of little importance in environmental legislation and the knowledge about the behavior of V in the environment is still limited. In the present study, the release of V from oxidized sediments, sediment-derived soils, and certified reference materials was investigated by means of several types of leaching tests and extractions that are frequently used for soil and sediment characterization. The pHstat leaching tests and single and sequential extractions applied in this study show that V generally displays a very limited actual and potential mobility in sediment. "Mobile" V concentrations, as estimated by the amount of V released by a single extraction with CaCl2 0.01 mol L(-1), were low, even in the most contaminated sediment samples. Only under strongly acidifying conditions (pH 2), such as in the case of ingestion of soil or sediment or in accidental spills, a substantial release of V can be expected. PMID- 24057964 TI - The role of bacterial consortium and organic amendment in Cu and Fe isotope fractionation in plants on a polluted mine site. AB - Copper and iron isotope fractionation by plant uptake and translocation is a matter of current research. As a way to apply the use of Cu and Fe stable isotopes in the phytoremediation of contaminated sites, the effects of organic amendment and microbial addition in a mine-spoiled soil seeded with Helianthus annuus in pot experiments and field trials were studied. Results show that the addition of a microbial consortium of ten bacterial strains has an influence on Cu and Fe isotope fractionation by the uptake and translocation in pot experiments, with an increase in average of 0.99 0/00 for the delta(65)Cu values from soil to roots. In the field trial, the amendment with the addition of bacteria and mycorrhiza as single and double inoculation enriches the leaves in (65)Cu compared to the soil. As a result of the same trial, the delta(56)Fe values in the leaves are lower than those from the bulk soil, although some differences are seen according to the amendment used. Siderophores, possibly released by the bacterial consortium, can be responsible for this change in the Cu and Fe fractionation. The overall isotopic fractionation trend for Cu and Fe does not vary for pot and field experiments with or without bacteria. However, variations in specific metabolic pathways related to metal-organic complexation and weathering can modify particular isotopic signatures. PMID- 24057963 TI - Styrofoam debris as a potential carrier of mercury within ecosystems. AB - The present paper falls within the trend of research into interactions between various pollutants emitted anthropogenically into the environment and focuses on mercury and styrofoam debris. The study covers part of the Southern Baltic's drainage area. Apart from styrofoam and beach sand, the research involved mosses, which are bioindicators of atmospheric metal pollution. The research has shown that mercury present in the environment becomes associated with styrofoam debris. The median for mercury concentrations in virgin styrofoam samples (0.23 ng g(-1) dry weight (d.w.)) and in beach sand samples (0.69 ng g(-1) d.w.) was an order of magnitude lower than in the styrofoam debris (5.20 ng g(-1) d.w.). The highest mercury content observed in styrofoam debris (3,863 ng g(-1) d.w.) exceeded the standards for bottom sediment and soil. The binding of mercury to styrofoam debris takes place in water, and presumably also through contact with the ground. A significant role in this process was played by biotic factors, such as the presence of biofilm and abiotic ones, such as solar radiation and the transformations of mercury forms related to it. As a result, mercury content in styrofoam debris underwent seasonal changes, peaking in summertime. Furthermore, the regional changes of mercury content in the studied debris seem to reflect the pollution levels of the environment. PMID- 24057965 TI - Dichlobenil and 2,6-dichlorobenzamide (BAM) dissipation in topsoil and deposits from groundwater environment within the boreal region in southern Finland. AB - BAM (2,6-dichlorobenzamide) is a metabolite of pesticide dichlobenil and a common groundwater contaminant. Dichlobenil and BAM half-lives were determined in five Finnish subsurface deposits and in topsoil. Aerobic and anaerobic conditions with sterilized controls were included in this 1.4-year incubation experiment. In subsurface deposits, dichlobenil half-life varied from 157 days to no degradation and that of BAM from 314 days to no degradation. Microbes and oxygen enhanced dichlobenil and BAM dissipation rates in some deposits. However, dichlobenil and BAM concentrations were most significantly affected by deposit characteristics, especially carbon and nitrogen amounts. Also low pH, cadmium, iron, zinc, manganese and lead correlated with low dichlobenil and/or BAM concentrations. In mineral topsoil, dissipation was faster with half-lives of 41-54 days for dichlobenil, and 182-261 days for BAM. Dichlobenil was depleted completely in surface soil, but BAM was not dissipated below 55-81 % of the initial concentration. Generally, dichlobenil and BAM dissipation in samples from the northern boreal region was similar to that reported for the temperate region. BAM was persistent in topsoil and subsurface deposits, indicating long-term persistence problems in groundwater also within the northern boreal region. PMID- 24057966 TI - Novel degradation pathway of 4-chloro-2-aminophenol via 4-chlorocatechol in Burkholderia sp. RKJ 800. AB - Burkholderia sp. RKJ 800 utilized 4-chloro-2-aminophenol (4C2AP) as the sole carbon and energy source and degraded it with release of chloride and ammonium ions. The metabolic pathway of degradation of 4C2AP was studied and a novel intermediate, 4-chlorocatechol was identified as a major degradation product of 4C2AP using high-performance liquid chromatography and gas chromatography-mass spectrometry. Enzyme activities for 4C2AP-deaminase and 4-chlorocatechol-1,2 dioxygenase were detected in the crude extracts of the 4C2AP-induced cells of strain RKJ 800. The activity of the 4C2AP-deaminase confirmed the formation of 4 chlorocatechol from 4C2AP and the 4-chlorocatechol-1,2-dioxygenase activity suggested the cleavage of 4-chlorocatechol into 3-chloro-cis,cis-muconate. On the basis of the identified metabolites, we have proposed a novel degradation pathway of 4C2AP for Burkholderia sp. RKJ 800. Furthermore, the potential of Burkholderia sp. RKJ 800 to degrade 4C2AP in soil was also investigated using microcosm studies under laboratory conditions. The results of microcosm studies conclude that Burkholderia sp. RKJ 800 was able to degrade 4C2AP in soil and may be used to remediate 4C2AP-contaminated site. This is the first report of (1) the formation of 4-chlorocatechol and 3-chloro-cis,cis-muconate in the degradation pathway of 4C2AP and (2) bioremediation of 4C2AP by any bacterium. PMID- 24057967 TI - Evaluation of effectiveness of integrated intervention in autistic children. AB - OBJECTIVES: To assess the effectiveness of integrated therapy over the past 3 y on the recipient autistic children and its correlation with the following variables - age at admission, duration of therapy given and initial severity of symptoms. METHODS: The index study was a retrospective study with 18 autistic children as subjects; the maximum duration of intervention was 3 y. The integrated approach consisted of special education using principles of applied behavior analysis, occupational and speech therapy. The progress records, the occupational therapy and the speech therapy progress reports were tabulated as data. The Childhood Autism Rating Scale (Schopler, Reichler and Renner, 1986) was used for evaluation of severity of symptoms at admission and in present day. The data was then compared and analyzed. RESULTS: The present study showed significant positive results. Only few domains requiring very high integrated cognitive and sensorimotor functioning showed non-significant results. Age at intervention correlated negatively and, duration of therapy given and initial severity of symptoms correlated positively with effectiveness of therapy. CONCLUSIONS: Continuous feedback and modification of the therapy is required to maintain performance and develop target interventions for problematic areas identified. Longitudinal as well as comparative studies are required to better understand the benefits of integrated approach. PMID- 24057968 TI - Acute motor axonal neuropathy in HIV infection. PMID- 24057969 TI - Tuberculosis spine presenting as multiple skip lesions and non-contiguous paraspinal abscesses: an atypical presentation. PMID- 24057971 TI - Inflammatory granulomas: most common cause of acute symptomatic focal seizures. PMID- 24057970 TI - Gammaglobulin treatment in an unusual meningococcal case. PMID- 24057972 TI - Isolated sinusitis of lateral recesses of sphenoid sinus. PMID- 24057973 TI - Evaluation of structural anomalies of kidney and urinary tract in children with Down syndrome. PMID- 24057975 TI - Axillary artery to right atrium bypass for hemodialysis in a patient with difficult vascular access. PMID- 24057974 TI - Imaging psychogenic movement disorders. AB - The neurobiological basis of psychogenic movement disorders (PMDs) has been elusive, and they remain difficult to treat. In the last few years, functional neuroimaging studies have provided insight into their pathophysiology and neural correlates. Here, we review the various methodological approaches that have been used in both clinical and research practice to address neural correlates of functional disorders. We then review the dominant hypotheses generated from the literature on psychogenic paralysis. Overall, these studies emphasize abnormalities in the prefrontal and anterior cingulate cortices. Recently, functional neuroimaging has been used to specifically examine PMDs. These studies have addressed a major point of controversy: whether higher frontal brain areas are directly responsible for inhibiting motor areas or whether they reflect modulation by attentional and/or emotional processes. In addition to elucidating the mechanism and cause, recent work has also explored the lack of agency that characterizes PMDs. We describe the results and implications of the results of these imaging studies and discuss possible interpretations. PMID- 24057976 TI - Effect of surface hydroxyls on dimethyl ether synthesis over the gamma-Al2O3 in liquid paraffin: a computational study. AB - In a recent paper (Zuo et al., Appl Catal A 408:130-136, 2011), the mechanism of dimethyl ether (DME) synthesis from methanol dehydration over gamma-Al2O3 (110) was studied using density functional theory (DFT). Using the same method, the effect of surface hydroxyls on gamma-Al2O3 in liquid paraffin during DME synthesis from methanol dehydration is investigated. It is found that DME is mainly formed from two adsorbed CH3O groups via methanol dehydrogenation on both dehydrated and hydrated gamma-Al2O3 in liquid paraffin. No close correlation between catalytic activity and acid intensity was found. Before and after water adsorption at typical catalytic conditions (e.g., 553 K), the reaction rate is not obviously changed on gamma-Al2O3(100) surface in liquid paraffin, but the reaction rate decreases by about 11 times on the (110) in liquid paraffin. Considering the area of the (110) and (100) surfaces under actual conditions, the catalytic activity decreased mainly because the Al3 sites on the (110) surface gradually become inactive. Catalytic activity decreased mainly due to surface hydrophilicity. The calculated results were consistent with the experiment. PMID- 24057977 TI - Focus in honor of Josh Coon, recipient of the 2012 Biemann medal. PMID- 24057978 TI - New LIC vectors for production of proteins from genes containing rare codons. AB - In the effort to produce proteins coded by diverse genomes, structural genomics projects often must express genes containing codons that are rare in the production strain. To address this problem, genes expressing tRNAs corresponding to those codons are typically coexpressed from a second plasmid in the host strain, or from genes incorporated into production plasmids. Here we describe the modification of a series of LIC pMCSG vectors currently used in the high throughput (HTP) production of proteins to include crucial tRNA genes covering rare codons for Arg (AGG/AGA) and Ile (AUA). We also present variants of these new vectors that allow analysis of ligand binding or co-expression of multiple proteins introduced through two independent LIC steps. Additionally, to accommodate the cloning of multiple large proteins, the size of the plasmids was reduced by approximately one kilobase through the removal of non-essential DNA from the base vector. Production of proteins from core vectors of this series validated the desired enhanced capabilities: higher yields of proteins expressed from genes with rare codons occurred in most cases, biotinylated derivatives enabled detailed automated ligand binding analysis, and multiple proteins introduced by dual LIC cloning were expressed successfully and in near balanced stoichiometry, allowing tandem purification of interacting proteins. PMID- 24057979 TI - Role of ghrelin-induced phosphatidylinositol 3-kinase activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori. AB - A peptide hormone, ghrelin, is recognized as an important modulator of gastric mucosal inflammatory responses to Helicobacter pylori through the regulation of Src/Akt-dependent activation of constitutive nitric oxide synthase (cNOS) by phosphorylation. In this study, we report on the role of phosphatidylinositol 3 kinase (PI3K) in the processes of Src/Akt activation in gastric mucosal cells exposed to H. pylori LPS. We demonstrate that cNOS activation through phosphorylation induced by ghrelin is associated with PI3K activation which occurs upstream of cSrc, and that PI3K is required for cSrc activation of Akt. We show further that ghrelin-induced activation of PI3K, as well as that of Src and Akt, was susceptible to suppression by the inhibitors of phospholipase C (U73122) and protein kinase C (BIM). Both these inhibitors also blocked the ghrelin induced membrane translocation of PI3K and cSrc, whereas the inhibitor of PI3K (LY294002) blocked only the membrane translocation of cSrc. Collectively, our findings suggest that the modulatory influence of ghrelin in countering gastric mucosal responses to H. pylori LPS relies on PI3K activation that depends on PLC/PKC signaling pathway, and that PI3K activity is required for the induction of cSrc/Akt activation. PMID- 24057980 TI - Accumulation of polycyclic aromatic hydrocarbons (PAHs) on the spider webs in the vicinity of road traffic emissions. AB - Studies focused on the possible use of spider webs as environmental pollution indicators. This was a first time ever attempt to use webs as indicators of polycyclic aromatic hydrocarbons (PAHs) pollution. The aim of the study was (a) to evaluate whether webs are able to accumulate PM-associated road traffic emissions and be analyzed for organic toxics such as PAHs, (b) to assess if the distance from emission sources could have an influence on the accumulation level of pollutants, and (c) to determine types of pollution sources responsible for a structure of monitoring data set. Webs of four species from the family Agelenidae were sampled for PAHs presence. Data from vehicle traffic sites (i.e., road tunnel, arterial surface road, underground parking) and from railway traffic sites (i.e., two railway viaducts) in the city of Wroclaw (Southwest of Poland) showed a significantly higher mean concentrations of PAHs than the reference site 1 (municipal water supply works). We also found a significant differences at sites differed by the distance from emission sources. The result of PCA analysis suggested three important sources of pollution. We conclude that spider webs despite of some limitations proved useful indicators of road traffic emissions; they could be even more reliable compared to use of bioindicators whose activity is often limited by a lack of water and sun. PMID- 24057982 TI - Burkholderia caballeronis sp. nov., a nitrogen fixing species isolated from tomato (Lycopersicon esculentum) with the ability to effectively nodulate Phaseolus vulgaris. AB - During a survey of Burkholderia species with potential use in agrobiotechnology, a group of 12 strains was isolated from the rhizosphere and rhizoplane of tomato plants growing in Mexico (Nepantla, Mexico State). A phylogenetic analysis of 16S rRNA gene sequences showed that the strains are related to Burkholderia kururiensis and Burkholderia mimosarum (97.4 and 97.1 %, respectively). However, they induced effective nitrogen-fixing nodules on roots of Phaseolus vulgaris. Based on polyphasic taxonomy, the group of strains represents a novel species for which the name Burkholderia caballeronis sp. nov. is proposed. The type species is TNe-841(T) (= LMG 26416(T) = CIP 110324(T)). PMID- 24057981 TI - A proposal to unify two subspecies of Staphylococcus equorum: Staphylococcus equorum subsp. equorum and Staphylococcus equorum subsp. linens. AB - Twelve isolates from jeotgal, a Korean high-salt-fermented seafood, identified as Staphylococcus equorum were compared by phenotypic and genotypic methods to determine their precise taxonomic identities at the subspecies level. Four strains and three strains had complete 16S rRNA gene sequence matches with S. equorum subsp. equorum DSM 20674(T) and S. equorum subsp. linens DSM 15097(T), respectively. Five strains showed 99.9 % identity with the sequences of both type strains. In our DNA-DNA hybridization analyses among two type strains and two isolates, the similarities were over 72 % and were higher than the similarities presented at the subspecies proposal. Physiological characteristics such as sugar utilization, beta-galactosidase activity, novobiocin resistance and salt tolerance, which were adopted for subspecies separation, could not be applied to assign the isolates to a taxonomic unit. Antibiotic susceptibility, hemolytic activity, biofilm formation and protein profiles did not present markers to divide the isolates into either of the subspecies. Multilocus sequence typing of the sequences of the 16S rRNA gene and five housekeeping genes did not produce any coherent relationship among the isolates and type strains. Repetitive element PCR fingerprinting using ERIC (enterobacterial repetitive intergenic consensus) primers classified 12 isolates to three genotypes, and the genotypes of both type strains coincided with two isolates expressing different characteristics. Based on these phenotypic and genotypic analyses results, we propose to unify the present two subspecies of S. equorum into one species, S. equorum. PMID- 24057983 TI - Non-linear dynamics of carbon and hydrogen isotopic signatures based on a biological kinetic model of nitrite-dependent methane oxidation by "Candidatus Methylomirabilis oxyfera". AB - System dynamics of nitrite-dependent anaerobic methane oxidation (N-DAMO) in a "Candidatus Methylomirabilis oxyfera" culture are described using a mathematical model based on chemical kinetics, microbial growth dynamics and equations for (13)C and (2)H isotopic fractionation. Experimental data for the N-DAMO model were taken from Rasigraf et al. (2012), who studied N-DAMO in a batch culture of "Ca. M. oxyfera" started at two different conditions with varying methane, nitrite and biomass concentrations. In the model, instead of using concentrations of each isotopologue ((12)C and (13)C, (1)H and (2)H), total concentrations and respective isotope ratios were considered as variables. The empirical Monod equations, which included methane and nitrite as two rate-limiting substrates, a threshold methane concentration CH 4min below which there was no biomass growth, and the same kinetic coefficients for the separate batch experiments, fitted the experimental data much better than apparent first-order kinetics that required rather different kinetic coefficients for the two experiments. Non-linear dynamics of (13)C and (2)H isotopic signatures were obtained based on the N-DAMO model. It was shown that rate limitation by methane or nitrite concentrations significantly affected the dynamics of carbon and hydrogen isotopic signatures. Fractionation rate increased at higher initial biomass concentration. The non linear N-DAMO model satisfactorily described experimental data presented in the two-dimensional plot of hydrogen versus carbon stable isotopic signatures. PMID- 24057984 TI - Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma. AB - BACKGROUND: Colorectal mucinous adenocarcinoma (MC) has been associated with impaired prognosis compared with nonmucinous adenocarcinoma (NMC). Response to palliative chemotherapy is poor in metastatic disease, but the benefit of adjuvant chemotherapeutic treatment has never been assessed in large patient groups. This study analyses overall survival and efficacy of adjuvant chemotherapy in terms of survival in patients following radical resection for MC. PATIENTS AND METHODS: This population-based study involved 27 251 unselected patients diagnosed with colorectal carcinoma between 1990 and 2010 and recorded in a prospective pathology-based registry. Kaplan-Meier analysis and log-rank testing were used to estimate survival. Cox proportional hazard model was used to calculate multivariate hazard ratios for death. RESULTS: MC was found in 12.3% (N = 3052) of colorectal tumors with a different distribution compared with NMC, with 24.4% located in the rectum and 54.3% in the proximal colon (versus 38.0% and 30.6%), P < 0.0001. NMC was more often classified as stage I disease than MC (20.5% versus 10.9%), P < 0.0001. After adjustments for covariates, MC was associated with a higher risk of death only when located in the rectum [hazard ratio 1.22; 95% confidence interval (CI) 1.11-1.34]. Multivariate regression analysis showed a similar survival after adjuvant chemotherapy for stage III MC and NMC patients. CONCLUSIONS: The poor prognosis for MC is only present in rectal cancer. In the adjuvant setting, there is no difference in the efficacy of chemotherapy between MC and NMC; therefore, current adjuvant treatment recommendations should not take histology into account. PMID- 24057987 TI - Cheilitis granulomatosa: a review. AB - Cheilitis granulomatosa (CG) is a cosmetically disturbing and persistent idiopathic lip swelling. It is one manifestation of orofacial granulomatosis (OFG), which is a clinical entity describing facial and oral swelling in the setting of non-caseating granulomatous inflammation and in the absence of systemic disease such as Crohn's disease and sarcoidosis. CG can occur by itself or as part of the Melkersson-Rosenthal syndrome, which includes facial palsy and a plicated tongue. Other proposed causes of OFG include dietary allergens such as cinnamon and benzoates. Similar orofacial swelling may be an early manifestation of Crohn's disease or sarcoidosis, and so clinical history is important in diagnosis. The cause of CG has not been wholly elucidated, but a current hypothesis holds that a random influx of inflammatory cells is responsible. Other granulomatous and edematous causes of lip swelling must be investigated prior to diagnosis. Options for treatment include dietary modifications, antibiotics, systemic or intralesional corticosteroids, and surgery, although treatment is not always necessary. CG should be considered in the differential of persistent lip swelling. PMID- 24057988 TI - Chest physiotherapy for pneumonia in children. AB - BACKGROUND: Pneumonia is an inflammatory lung disease and it is the greatest cause of deaths in children younger than five years of age worldwide. Chest physiotherapy is widely used in the treatment of pneumonia because it can help to eliminate inflammatory exudates and tracheobronchial secretions, remove airway obstructions, reduce airway resistance, enhance gas exchange and reduce the work of breathing. Thus, chest physiotherapy may contribute to patient recovery as an adjuvant treatment even though its indication remains controversial. OBJECTIVES: To assess the effectiveness of chest physiotherapy in relation to time until clinical resolution in children (from birth up to 18 years old) of either gender with any type of pneumonia. SEARCH METHODS: We searched CENTRAL 2013, Issue 4; MEDLINE (1946 to May week 4, 2013); EMBASE (1974 to May 2013); CINAHL (1981 to May 2013); LILACS (1982 to May 2013); Web of Science (1950 to May 2013); and PEDro (1950 to May 2013).We consulted the ClinicalTrials.gov and the WHO ICTRP registers to identify planned, ongoing and unpublished trials. We consulted the reference lists of relevant articles found by the electronic searches for additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared chest physiotherapy of any type with no chest physiotherapy in children with pneumonia. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies to be included in the review, assessed trial quality and extracted data. MAIN RESULTS: Three RCTs involving 255 inpatient children are included in the review. They addressed conventional chest physiotherapy, positive expiratory pressure and continuous positive airway pressure. The following outcomes were measured: duration of hospital stay, time to clinical resolution (observing the following parameters: fever, chest indrawing, nasal flaring, tachypnoea and peripheral oxygen saturation levels), change in adventitious sounds, change in chest X-ray and duration of cough in days. Two of the included studies found a significant improvement in respiratory rate and oxygen saturation whereas the other included study failed to show that standardised respiratory physiotherapy and positive expiratory pressure decrease the time to clinical resolution and the duration of hospital stay. No adverse effects related to the interventions were described. Due to the different characteristics of the trials, such as the duration of treatment, levels of severity, types of pneumonia and the techniques used in children with pneumonia, as well as differences in their statistical presentation, we were not able to pool data. Two included studies had an overall low risk of bias whereas one included study had an overall unclear risk of bias. AUTHORS' CONCLUSIONS: Our review does not provide conclusive evidence to justify the use of chest physiotherapy in children with pneumonia due to a lack of data. The number of included studies is small and they differed in their statistical presentation. PMID- 24057989 TI - Social capital and hypertension in rural Haitian women. AB - Hypertension is a major global public health risk and significant precursor to cardiovascular disease, stroke, diabetes and maternal mortality. A possible strategy to reduce chronic disease in resource-poor areas is social intervention. Research into the possible relationship of social determinants and disease is needed to determine appropriate social interventions. This study aims to determine the association between social capital and hypertension in rural Haitian women. From June to August 2005, 306 women, ages 18-49, who attended one of Hopital Albert Schweitzer's five rural dispensaries as patients or accompanying patients, were interviewed. Individual interviews on social capital, demographics and anthropometrics were conducted. SAS statistical package was used to analyze the data. Groups/networks, personal empowerment, collective action/cooperation and trust components significantly decreased the likelihood of hypertension in multivariate analysis. In an additive model, the ranked index of social capital indicated that each social capital component score above the conceptual midpoint showed a 41 % reduction in the likelihood of hypertension. The findings suggest that interventions aimed to increase components of social capital may significantly lower hypertension. PMID- 24057990 TI - Maternal influenza vaccination: evaluation of a patient-centered pamphlet designed to increase uptake in pregnancy. AB - We developed and tested a theoretically-based pamphlet entitled 'Influenza in Pregnancy,' specifically designed to increase pregnant women's knowledge, reduce barriers to maternal vaccination, and subsequently improve vaccine uptake. A randomized control trial was conducted on pregnant women (n = 135) at three locations in Connecticut during the 2011-2012 season to evaluate the impact of the patient-centered pamphlet. The women were randomized to one of three groups: the pamphlet; pamphlet/benefit statement (vaccinating the pregnant woman also benefits the young infant); or control. A Chi square analysis compared the intervention with control using the primary outcome of vaccination. A secondary outcome of the perceptions of health beliefs of maternal vaccination were measured through General Linear Model/ANOVA model for repeated measures. Overall 66.9% (89/133) were vaccinated. Both the pamphlet group 72.9% (35/48) (chi2 = 6.81, df = 1 p = .009), and the pamphlet/benefit statement group 86.1% (31/36) (chi2 = 13.74, df = 1, p < .001), had significantly higher vaccine uptake than the control group 46.9% (23/49). The potential barrier, perception of vaccine safety (F = 4.973, df = 2, p < .01), and benefit of vaccination to mother and infant (F = 6.690, df = 2, p < .01) significantly improved for the intervention groups compared to control group. The pamphlet significantly increased the pregnant women's perceptions of the safety and benefit of the vaccine, and the overall uptake. PMID- 24057991 TI - Early childhood healthy and obese weight status: potentially protective benefits of breastfeeding and delaying solid foods. AB - The aim of this study was to assess the relationship between breastfeeding and postponing introduction to solid food (SF) on children's obesity and healthy weight status (WS), at 2 and 4 years. Drawing upon a nationally representative sample of children from the Early Childhood Longitudinal Study-Birth Cohort, we estimated the magnitude of the relationship between children's WS and early feeding practices. Contingency tables and multinomial logistic regression were used to analyze obese and healthy WS for breastfed and never breastfed children and examine three timing categories for SF introduction. With both percentages and odds, breastfeeding and delaying introduction to SF until 4 months were associated with lower obesity rates and higher, healthy WS rates (typically 5 10%). Analyses of feeding practice combinations revealed that when children were not breastfed, obesity odds decreased when SF introduction was postponed until 4 months. Obesity odds were further reduced when SF delay was combined with breastfeeding. Consistent increases in healthy WS were also observed. Benefits were stable across both follow-up periods. Breastfeeding and delaying complementary foods yielded consistently and substantially lower likelihood of obesity and greater probability of healthy WS. Health policies targeting early feeding practices represent promising interventions to decrease preschool obesity and promote healthy WS. PMID- 24057992 TI - WIC participation and breastfeeding in South Carolina: updates from PRAMS 2009 2010. AB - Few studies examined breastfeeding initiation and duration among mothers who were eligible for the Women Infants Children (WIC) program and did not participate. This study is sought to understand the role of WIC participation and poverty level in breastfeeding initiation and duration in South Carolina. The data came from the 2009-2010 South Carolina Pregnancy Risk Assessment Monitoring System (unweighted N = 1,796). All participants were classified as WIC participants, income-eligible non-WIC participants, and income-ineligible non-WIC participants. Logistic regression models were used to analyze the association between breastfeeding initiation and WIC participation. The Kaplan-Meier method and Cox proportional hazards models were used to determine whether the continuation of breastfeeding and hazards of discontinuing breastfeeding differed by WIC participation groups. In South Carolina, two out of three women (67.2%) initiated breastfeeding. The breastfeeding initiation rate was higher among income ineligible (84.0%) and income-eligible (78.9%) non-WIC participants than among WIC participants (55.5%). Compared to WIC participants, both income-ineligible [odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.2-4.0] and income-eligible (OR = 2.6, 95% CI 1.1-4.3) non-WIC participants were more likely to initiate breastfeeding. Among mothers who already initiated breastfeeding, after adjusting covariates, the hazard ratios for weaning within 34 weeks postpartum were not significantly different by WIC participation groups. This study confirmed WIC participants were less likely to initiate breastfeeding. Once initiated, WIC participation did not significantly impact breastfeeding duration in the early postpartum period. Poverty status may not play an important role in explaining disparities in breastfeeding initiation between WIC and non-WIC participants. PMID- 24057993 TI - Obituary for Andrea Coda. PMID- 24057994 TI - Cigarette rod length and its impact on serum cotinine and urinary total NNAL levels, NHANES 2007-2010. AB - INTRODUCTION: Research suggests that smokers of slim, long, or ultralong cigarettes may have a perception of reduced harm from their own brand. This study compared serum cotinine and urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanonol (NNAL) levels among smokers of regular-sized (68-72mm), king-sized (79 88mm), and long (94-101mm) or ultralong (110-121mm) cigarettes. METHODS: Nationally representative data from the 2007-2008 and 2009-2010 National Health and Nutrition Examination Survey were analyzed for 3,699 current smokers aged >=20 years. Biomarker levels were summarized using geometric means (GMs). Multivariate linear regression analyses were performed to assess the effect of cigarette rod length on log-transformed serum cotinine and creatinine-adjusted urinary total NNAL levels. RESULTS: The GM of serum cotinine level was higher among smokers of long/ultralong cigarettes (263.15ng/ml) compared with smokers of regular-sized (173.13ng/ml) or king-sized (213.79ng/ml) cigarettes. Similarly, the GM of creatinine-adjusted NNAL levels was higher among smokers of long/ultralong cigarettes (0.48ng NNAL/mg of creatinine) compared with smokers of regular-sized (0.34ng NNAL/mg of creatinine) or king-sized (0.33ng NNAL/mg of creatinine) cigarettes. After adjusting for potential confounders, mean cotinine and NNAL levels were both significantly higher among smokers of long/ultralong cigarettes compared with levels observed in smokers of either regular-sized or king-sized cigarettes. However, no significant differences were observed between smokers of regular-sized and king-sized cigarettes in mean levels of cotinine or NNAL. CONCLUSIONS: Significantly elevated tobacco biomarker levels were observed among smokers of long/ultralong cigarettes compared with smokers of regular-sized or king-sized cigarettes. This underscores the need to educate the public about the dangers of all tobacco products. PMID- 24057995 TI - Advancing cessation research by integrating EMA and geospatial methodologies: associations between tobacco retail outlets and real-time smoking urges during a quit attempt. AB - INTRODUCTION: Residential tobacco retail outlet (TRO) density and proximity have been associated with smoking behaviors. More research is needed to understand the mechanisms underlying these relations and their potential relevance outside of the residential setting. This study integrates ecological momentary assessment (EMA) and geo-location tracking to explore real-time associations between exposure to TROs and smoking urges among 47 economically disadvantaged smokers in a cessation trial (59.6% female; 36.2% White). METHODS: EMA data were collected for 1 week postquit via smartphone, which recorded smoking urge strength <= 4 random times daily along with real-time participant location data. For each assessment, the participants' proximity to the closest TRO and the density of TROs surrounding the participant were calculated. Linear mixed model regressions examined associations between TRO variables and smoking urges and whether relations varied based on participants' distance from their home. Covariates included sociodemographics, prequit tobacco dependence, treatment group, and daily smoking status. RESULTS: Main effects were nonsignificant; however, the interaction between TRO proximity and distance from home was considered significant (p = .056). Specifically, closer proximity to TROs was associated with stronger smoking urges <= 1 mile of home (p = .001) but not >1 mile from home (p = .307). Significant associations were attributable to assessments completed at participants' home addresses. All density analyses were nonsignificant. CONCLUSIONS: Technological challenges encountered in this study resulted in a significant amount of missing data, highlighting the preliminary nature of these findings and limiting the inferences that can be drawn. However, results suggest that closer residential proximity to tobacco outlets may trigger stronger urges to smoke among economically disadvantaged smokers trying to quit, perhaps due to enhanced cigarette availability and accessibility. Therefore, limiting tobacco sales in close proximity to residential areas may complement existing tobacco control efforts and facilitate cessation. PMID- 24057996 TI - Topiramate for smoking cessation: a randomized, placebo-controlled pilot study. AB - INTRODUCTION: Topiramate (TOP) blocks glutamate receptors and facilitates GABA (gamma-aminobutyric acid) neurotransmission, effects that may facilitate smoking cessation. We compared the effects of behavioral counseling combined with (a) TOP, (b) TOP/nicotine patch (TOP/NIC), or (c) placebo (PLC) for smoking cessation. METHODS: We conducted a 10-week randomized trial in which subjects and research personnel were blinded to TOP versus PLC but not to the TOP/NIC patch condition. In groups receiving TOP, the medication dosage was titrated gradually up to 200 mg/day. The smoking quit date (QD) was scheduled after 2 weeks of medication treatment. NIC (21 mg) was started on the QD in subjects randomized to the TOP/NIC condition. The main outcome measure was the end-of-treatment, 4-week continuous abstinence rate (CAR; biochemically confirmed). RESULTS: Fifty-seven subjects were randomized to treatment. The 4-week CAR was 1 of 19 (5%) in the PLC group, 5 of 19 (26%) in the TOP group, and 7 of 19 (37%) in the TOP/NIC group (p = .056). Pairwise comparisons showed a difference between TOP/NIC and PLC (p = .042) and a nonsignificant difference between TOP and PLC (p = .18). The PLC group gained 0.37 lb/week, the TOP group lost 0.41 lb/week, and the TOP/NIC group lost 0.07 lb/week (p = .004). Pairwise comparisons showed a difference between TOP and PLC (p < .001) and between TOP/NIC and PLC groups (p = .035). Paresthesia was more frequent in subjects on TOP than PLC (p = .011). CONCLUSIONS: TOP, alone or in combination with the NIC, resulted in a numerically higher quit rate than PLC and decreased weight. A larger, PLC-controlled trial is needed to confirm these findings. PMID- 24057997 TI - Metrics matter: the case of assessing the importance of non-communicable diseases for the poor. PMID- 24057998 TI - Household organophosphorus pesticide use and Parkinson's disease. AB - BACKGROUND: Household pesticide use is widespread in the USA. Since the 1970s, organophosphorus chemicals (OPs) have been common active ingredients in these products. Parkinson's disease (PD) has been linked to pesticide exposures but little is known about the contributions of chronic exposures to household pesticides. Here we investigate whether long-term use of household pesticides, especially those containing OPs, increases the odds of PD. METHODS: In a population-based case-control study, we assessed frequency of household pesticide use for 357 cases and 807 controls, relying on the California Department of Pesticide Regulation product label database to identify ingredients in reported household pesticide products and the Pesticide Action Network pesticide database of chemical ingredients. Using logistic regression we estimated the effects of household pesticide use. RESULTS: Frequent use of any household pesticide increased the odds of PD by 47% [odds ratio (OR)=1.47, (95% confidence interval (CI): 1.13, 1.92)]; frequent use of products containing OPs increased the odds of PD more strongly by 71% [OR=1.71, (95% CI: 1.21, 2.41)] and frequent organothiophosphate use almost doubled the odds of PD. Sensitivity analyses showed that estimated effects were independent of other pesticide exposures (ambient and occupational) and the largest odds ratios were estimated for frequent OP users who were carriers of the 192QQ paraoxonase genetic variant related to slower detoxification of OPs. CONCLUSIONS: We provide evidence that household use of OP pesticides is associated with an increased risk of developing PD. PMID- 24057999 TI - Exhaled carbon monoxide and its associations with smoking, indoor household air pollution and chronic respiratory diseases among 512,000 Chinese adults. AB - BACKGROUND: Exhaled carbon monoxide (COex) level is positively associated with tobacco smoking and exposure to smoke from biomass/coal burning. Relatively little is known about its determinants in China despite the population having a high prevalence of smoking and use of biomass/coal. METHODS: The China Kadoorie Biobank includes 512,000 participants aged 30-79 years recruited from 10 diverse regions. We used linear regression and logistic regression methods to assess the associations of COex level with smoking, exposures to indoor household air pollution and prevalent chronic respiratory conditions among never smokers, both overall and by seasons, regions and smoking status. RESULTS: The overall COex level (ppm) was much higher in current smokers than in never smokers (men: 11.5 vs 3.7; women: 9.3 vs 3.2). Among current smokers, it was higher among those who smoked more and inhaled more deeply. Among never smokers, mean COex was positively associated with levels of exposures to passive smoking and to biomass/coal burning, especially in rural areas and during winter. The odds ratios (OR) and 95% confidence interval (CI) of air flow obstruction (FEV1/FVC ratio<0.7) for never smokers with COex at 7-14 and >=14 ppm, compared with those having COex<7, were 1.38 (1.31-1.45) and 1.65 (1.52-1.80), respectively (Ptrend<0.001). Prevalence of other self-reported chronic respiratory conditions was also higher among people with elevated COex (P<0.05). CONCLUSION: In adult Chinese, COex can be used as a biomarker for assessing current smoking and overall exposure to indoor household air pollution in combination with questionnaires. PMID- 24058000 TI - Maternal pre-pregnancy body mass index and offspring attention deficit hyperactivity disorder: a population-based cohort study using a sibling comparison design. AB - BACKGROUND: High maternal pre-pregnancy body mass index (BMI) is associated with increased risk of offspring attention deficit hyperactivity disorder (ADHD). However, the role of unmeasured familial confounding for this association remains unclear. METHODS: We conducted a population-based cohort study via linkage of Swedish national and regional registers to investigate maternal pre-pregnancy BMI (underweight: BMI <18.5; overweight: 25<= BMI <30; obesity: BMI >=30) in relation to offspring ADHD. We followed 673 632 individuals born in Sweden between 1992 and 2000, with prospectively collected information on maternal pre-pregnancy BMI, until they received an ADHD diagnosis or ADHD medication, death, emigration or 31 December 2009. Hazard ratios (HRs) were estimated by Cox proportional hazards models. Stratified Cox proportional hazards models were applied to data on full siblings to control for unmeasured familial confounding. RESULTS: At the population level, pre-pregnancy overweight/obesity was associated with increased risk of offspring ADHD (HR(overweight) = 1.23, 95% CI = 1.18-1.27, P = 0.01; HR(obesity) = 1.64, 95% CI = 1.57-1.73, P = 0.01), after adjustment for measured covariates. In full sibling comparisons, however, previously observed associations no longer remained (HR(overweight) = 0.98, 95% CI = 0.83-1.16, P = 0.82; HR(obesity) = 1.15, 95% CI = 0.85-1.56, P = 0.38). CONCLUSIONS: The results suggested that the association between maternal pre-pregnancy overweight/obesity and offspring ADHD could be ascribed to unmeasured familial confounding. PMID- 24058002 TI - Linking quality of healthcare and health-related quality of life of patients with type 2 diabetes: an evaluative study in Mexican family practice. AB - OBJECTIVE: To assess the association between quality of care and health-related quality of life among type 2 diabetes patients. DESIGN: A cross-sectional study assessing the association between quality of care and quality of life using multiple linear regression analysis. SETTING: Family medicine clinics (FMC) (n = 39) of the Mexican Institute of Social Security (IMSS) in Mexico City. PARTICIPANTS: Type 2 diabetes patients (n = 312), older than 19 years. MAIN OUTCOME MEASURE(S): Health-related quality of life was measured using the MOS Short-Form-12 (SF-12); quality of healthcare was measured as the percentage of recommended care received under each of four domains: early detection of diabetes complications, non-pharmacological treatment, pharmacological treatment and health outcomes. RESULTS: The average quality of life score was 41.4 points on the physical component and 47.9 points on the mental component. Assessment of the quality of care revealed deficiencies. The average percentages of recommended care received were 21.9 for health outcomes and 56.6 for early detection of diabetes complications and pharmacological treatment; for every 10 percent additional points on the pharmacological treatment component, quality of life improved by 0.4 points on the physical component (coefficient 0.04, 95% confidence intervals 0.01-0.07). CONCLUSIONS: There was a positive association between the quality of pharmacological care and the physical component of quality of life. The quality of healthcare for type 2 diabetes patients in FMC of the IMSS in Mexico City is not optimal. PMID- 24058003 TI - Just good care? The palliative care of those with non-malignant disease. PMID- 24058004 TI - Noninvasive ventilation and end of life in motor neuron disease. PMID- 24058005 TI - Use of non-invasive ventilation at end of life. PMID- 24058006 TI - Metrics for describing soft-tissue artefact and its effect on pose, size, and shape of marker clusters. AB - In human movement analysis based on stereophotogrammetry, bone pose is reconstructed by observing a cluster of skin markers. Each marker undergoes a displacement relative to the underlying bone that is regarded as an artefact (soft-tissue artefact, STA) since it affects accuracy in bone pose estimation. This paper proposes a set of metrics for the statistical description of the STA and its effects on cluster pose, size, and shape, with the intent of contributing to a clearer knowledge of its characteristics, and consequently of setting the bases for the development of more accurate bone pose estimators than presently available. Skin marker clusters behave as deformable bodies in motion relative to the underlying bone. Their motion can be described, based on Procrustes analysis, as the composition of four independent transformations: translation and rotation (rigid motion, RM), and change in size and shape (nonrigid motion, NRM). Statistical parameters describing the time histories of both the individual marker STA and the cluster transformations listed earlier were defined. For demonstration purposes, data collected ex vivo were used. The lower limbs of three cadavers were made to undergo movements with prevailing flexion-extension components. Femur pose was accurately measured using pin markers and the movement of twelve thigh skin markers observed relative to it. The STAs of all possible clusters of four skin markers were analysed. RM and NRM exhibited similar magnitudes and therefore impact on bone pose estimation. Thus bone pose estimators should not account for NRM only, as is normally the case, but also for RM. PMID- 24058007 TI - Real-time, simultaneous myoelectric control using force and position-based training paradigms. AB - In this paper, the simultaneous real-time control of multiple degrees of freedom (DOF) for myoelectric systems is investigated. The goal of this study, in which ten able-bodied subjects participated, was to directly compare three control paradigms of constrained (force targeted), unconstrained (position targeted) and resisted unconstrained (position targeted) limb contractions. Artificial neural networks (ANNs) were trained for simultaneous myoelectric control of the three degrees of freedom (DOFs) (wrist flexion-extension, abduction-adduction, and pronation-supination) using mirrored bilateral contractions. In the resisted unconstrained experiment, some resistance to movement was provided using flexible wrist braces in order to increase the required level of muscle activation. The force, in constrained experiments, and position, in unconstrained and resisted unconstrained experiments, were measured. The three protocols were compared off line using estimation accuracies (R2) and online using a real-time computer-based target acquisition test. The constrained control paradigm outperformed the unconstrained method in the abduction-adduction DOF (R(constrained)2 = 90.8 +/- 0.6, R(unconstrained)2 = 85.6 +/- 1.6) and pronation-supination DOF (R(constrained)2 = 88.5 +/- 0.9, R(unconstrained)2 = 82.3 +/- 1.6), but no significant difference was found in the flexion-extension DOF. The constrained control method outperformed unconstrained control in two real-time testing metrics including completion time and path efficiency. The constrained method results, however, were not significantly different than those of the resisted unconstrained method (with braces) in both off-line and real-time tests. This suggests that the quality of control using constrained and unconstrained contraction-based myoelectric schemes is not appreciably different when using comparable l- vels of muscle activation. PMID- 24058008 TI - Cardiac electrophysiological activation pattern estimation from images using a patient-specific database of synthetic image sequences. AB - While abnormal patterns of cardiac electrophysiological activation are at the origin of important cardiovascular diseases (e.g., arrhythmia, asynchrony), the only clinically available method to observe detailed left ventricular endocardial surface activation pattern is through invasive catheter mapping. However, this electrophysiological activation controls the onset of the mechanical contraction; therefore, important information about the electrophysiology could be deduced from the detailed observation of the resulting motion patterns. In this paper, we present the study of this inverse cardiac electrokinematic relationship. The objective is to predict the activation pattern knowing the cardiac motion from the analysis of cardiac image sequences. To achieve this, we propose to create a rich patient-specific database of synthetic time series of the cardiac images using simulations of a personalized cardiac electromechanical model, in order to study this complex relationship between electrical activity and kinematic patterns in the context of this specific patient. We use this database to train a machine-learning algorithm which estimates the depolarization times of each cardiac segment from global and regional kinematic descriptors based on displacements or strains and their derivatives. Finally, we use this learning to estimate the patient's electrical activation times using the acquired clinical images. Experiments on the inverse electrokinematic learning are demonstrated on synthetic sequences and are evaluated on clinical data with promising results. The error calculated between our prediction and the invasive intracardiac mapping ground truth is relatively small (around 10 ms for ischemic patients and 20 ms for nonischemic patient). This approach suggests the possibility of noninvasive electrophysiological pattern estimation using cardiac motion imaging. PMID- 24058009 TI - A speedy hybrid BCI spelling approach combining P300 and SSVEP. AB - This study proposes a novel hybrid brain-computer interface (BCI) approach for increasing the spelling speed. In this approach, the P300 and steady-state visually evoked potential (SSVEP) detection mechanisms are devised and integrated so that the two brain signals can be used for spelling simultaneously. Specifically, the target item is identified by 2-D coordinates that are realized by the two brain patterns. The subarea/location and row/column speedy spelling paradigms were designed based on this approach. The results obtained for 14 healthy subjects demonstrate that the average online practical information transfer rate, including the time of break between selections and error correcting, achieved using our approach was 53.06 bits/min. The pilot studies suggest that our BCI approach could achieve higher spelling speed compared with the conventional P300 and SSVEP spellers. PMID- 24058010 TI - Real-Time Adaptive Apnea and Hypopnea Event Detection Methodology for Portable Sleep Apnea Monitoring Devices. AB - This paper presents a novel real-time adaptive sleep apnea monitoring methodology, suitable for portable devices used in home care applications. The proposed method identifies apnea/hypopnea events with the help of oronasal airflow signal and aimed to meet clinical standards in the assessment mechanism of apnea severity. It uses a strategically combined adaptive two stage classifier model to detect apnea or hypopnea events on the basis of personalized breathing patterns. For the detection of events, optimum set of time, frequency, and nonlinear measures, extracted from overlapping segments of typical 8 s were fed to support vector machine-based classifiers model to identify the possible origin of the segments, i.e., whether from normal or abnormal (apnea/hypopnea) episodes, and then the decision of the classifier model on the time sequenced successive segments have been used to detect an event. The performance of the proposed real time algorithm is validated on clinical tests online. Average accuracies of hypopnea, apnea, and combined event detection when compared with polysomnography based respective indices on unseen subjects during online tests were found to be 91.8%, 94.9%, and 96.5%, respectively, which are quite acceptable. PMID- 24058011 TI - Amorphous regions-of-interest projection method for simplified longitudinal comparison of dynamic regions in cancer imaging. AB - Tumors are typically analyzed as a single unit, despite their biologically heterogeneous nature. This limits correlations that can be drawn between regional variation and treatment outcome. Furthermore, despite the availability of high resolution 3-D medical imaging techniques, local outcomes, (e.g., tumor growth), are not easily measured. This paper proposes a method that uses streamlines to divide a 3-D region of interest (e.g., tumor) into units where local properties can be measured over the paths of growth. The parameters such as directional length and mean intensity can be measured locally at sequential time points and then compared. The method is evaluated on synthetic objects, simulated tumors, and medical images of brain tumors. The evaluations suggest that the method is suitable for mapping amorphous dynamic objects. PMID- 24058012 TI - A Neuro-Fuzzy Approach for Medical Image Fusion. AB - This paper addresses a novel approach to the multimodal medical image fusion (MIF) problem, employing multiscale geometric analysis of the nonsubsampled contourlet transform and fuzzy-adaptive reduced pulse-coupled neural network (RPCNN). The linking strengths of the RPCNNs' neurons are adaptively set by modeling them as the fuzzy membership values, representing their significance in the corresponding source image. Use of the RPCNN with a less complex structure and having less number of parameters leads to computational efficiency-an important requirement of point-of-care health care technologies. The proposed scheme is free from the common shortcomings of the state-of-the-art MIF techniques: contrast reduction, loss of image fine details, and unwanted image degradations, etc. Subjective and objective evaluations show better performance of this new approach compared to the existing techniques. PMID- 24058013 TI - A mathematical model of cellular metabolism during ischemic stroke and hypothermia. AB - Stroke is a major cause of death and disability worldwide. Therapeutic hypothermia is a potentially useful neuroprotective treatment. A mathematical model of brain metabolism during stroke is extended here to simulate the effect of hypothermia on cell survival. Temperature decreases were set to reduce chemical reaction rates and slow diffusion through ion channels according to the Q10 rule. Heat delivery to tissues was set to depend on metabolic heat generation rate and perfusion. Two cooling methods, scalp and vascular, were simulated to approximate temperature variation in the brain during treatment. Cell death was assumed to occur at continued cell membrane depolarization. Simulations showed that hypothermia to 34.5 degrees C induced within 1-1.5 h of stroke onset could extend cell survival time by at least 5 h in tissue with perfusion reduced by 80% of normal. There was good agreement between simulated metabolite dynamics and those reported in rat model studies. PMID- 24058014 TI - Detecting diabetes mellitus and nonproliferative diabetic retinopathy using tongue color, texture, and geometry features. AB - Diabetes mellitus (DM) and its complications leading to diabetic retinopathy (DR) are soon to become one of the 21st century's major health problems. This represents a huge financial burden to healthcare officials and governments. To combat this approaching epidemic, this paper proposes a noninvasive method to detect DM and nonproliferative diabetic retinopathy (NPDR), the initial stage of DR based on three groups of features extracted from tongue images. They include color, texture, and geometry. A noninvasive capture device with image correction first captures the tongue images. A tongue color gamut is established with 12 colors representing the tongue color features. The texture values of eight blocks strategically located on the tongue surface, with the additional mean of all eight blocks are used to characterize the nine tongue texture features. Finally, 13 features extracted from tongue images based on measurements, distances, areas, and their ratios represent the geometry features. Applying a combination of the 34 features, the proposed method can separate Healthy/DM tongues as well as NPDR/DM-sans NPDR (DM samples without NPDR) tongues using features from each of the three groups with average accuracies of 80.52% and 80.33%, respectively. This is on a database consisting of 130 Healthy and 296 DM samples, where 29 of those in DM are NPDR. PMID- 24058015 TI - Launch of a checklist for reporting longitudinal observational drug studies in rheumatology: a EULAR extension of STROBE guidelines based on experience from biologics registries. PMID- 24058016 TI - Response to 'Evidence in Support of the Validity of the TNF Brake Hypothesis' by Maksymowych. PMID- 24058017 TI - Linguistic Analysis of Laser Speckle Contrast Images Recorded at Rest and During Biological Zero: Comparison With Laser Doppler Flowmetry Data. AB - Laser speckle contrast imaging (LSCI) is a newly commercialized imaging modality to monitor microvascular blood flow. Contrary to the well-known laser Doppler flowmetry (LDF), LSCI has the advantage of giving a full-field image of surface blood flow using simple instrumentation. However, laser speckle contrast images are not fully understood yet and their link with LDF signals still has to be studied. To quantify the similarity between LSCI and LDF symbolic sequences, we propose to use, for the first time, the index adapted from linguistic analysis and information theory proposed by Yang For this purpose, LSCI and LDF data were recorded simultaneously on the forearm of healthy subjects, at rest and during a vascular occlusion (biological zero). We show that there are different dynamical patterns for LSCI and LDF data, and the distances between these patterns differ through the space scales explored. Moreover, our results suggest that these different dynamical patterns could be linked to blood flow. The quantitative metric used herein therefore provides new information on LSCI and brings knowledge on links between LSCI and LDF. PMID- 24058018 TI - A Flexible Method for Multi-Material Decomposition of Dual-Energy CT Images. AB - The ability of dual-energy computed-tomographic (CT) systems to determine the concentration of constituent materials in a mixture, known as material decomposition, is the basis for many of dual-energy CT's clinical applications. However, the complex composition of tissues and organs in the human body poses a challenge for many material decomposition methods, which assume the presence of only two, or at most three, materials in the mixture. We developed a flexible, model-based method that extends dual-energy CT's core material decomposition capability to handle more complex situations, in which it is necessary to disambiguate among and quantify the concentration of a larger number of materials. The proposed method, named multi-material decomposition (MMD), was used to develop two image analysis algorithms. The first was virtual unenhancement (VUE), which digitally removes the effect of contrast agents from contrast-enhanced dual-energy CT exams. VUE has the ability to reduce patient dose and improve clinical workflow, and can be used in a number of clinical applications such as CT urography and CT angiography. The second algorithm developed was liver-fat quantification (LFQ), which accurately quantifies the fat concentration in the liver from dual-energy CT exams. LFQ can form the basis of a clinical application targeting the diagnosis and treatment of fatty liver disease. Using image data collected from a cohort consisting of 50 patients and from phantoms, the application of MMD to VUE and LFQ yielded quantitatively accurate results when compared against gold standards. Furthermore, consistent results were obtained across all phases of imaging (contrast-free and contrast enhanced). This is of particular importance since most clinical protocols for abdominal imaging with CT call for multi-phase imaging. We conclude that MMD can successfully form the basis of a number of dual-energy CT image analysis algorithms, and has the potential to improve the clinical utility of dual-energy CT in disease management. PMID- 24058019 TI - Generating Synthetic Mammograms From Reconstructed Tomosynthesis Volumes. AB - Digital breast tomosynthesis (DBT) is a promising 3-D modality that may replace mammography in the future. However, lesion search is likely to require more time in DBT volumes, while comparisons between views from different projections and prior exams might be harder to make. This may make screening with DBT cumbersome. A solution may be provided by synthesizing 2-D mammograms from DBT, which may then be used to guide the search for abnormalities. In this work we focus on synthesizing mammograms in which masses and architectural distortions are optimally visualized. Our approach first determines relevant points in a DBT volume with a computer-aided detection system and then renders a mammogram from the intersection of a surface fitted through these points and the DBT volume. The method was evaluated in a pilot observer study where three readers reported mass findings in 87 patients (25 malignant, 62 normal) for which both DBT and digital mammograms were available. We found that on average, diagnostic accuracy in the synthetic mammograms was higher (Az=0.85) than in conventional mammograms (Az=0.81), although the difference was not statistically significant. Preliminary results suggest that the synthesized mammograms are an acceptable alternative for real mammograms regarding the detection of mass lesions. PMID- 24058020 TI - Automated characterization of breast lesions imaged with an ultrafast DCE-MR protocol. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the breast has become an invaluable tool in the clinical work-up of patients suspected of having breast carcinoma. The purpose of this study is to introduce novel features extracted from the kinetics of contrast agent uptake imaged by a short (100 s) view-sharing MRI protocol, and to investigate how these features measure up to commonly used features for regular DCE-MRI of the breast. Performance is measured with a computer aided diagnosis (CADx) system aimed at distinguishing benign from malignant lesions. A bi-temporal breast MRI protocol was used. This protocol produces five regular, high spatial-resolution T1-weighted acquisitions interleaved with a series of 20 ultrafast view-sharing acquisitions during contrast agent uptake. We measure and compare the performances of morphological and kinetic features derived from both the regular DCE-MRI sequence and the ultrafast view-sharing sequence with four different classifiers. The classification performance of kinetics derived from the short (100 s) ultrafast acquisition starting with contrast agent administration, is significantly higher than the performance of kinetics derived from a much lengthier (510 s), commonly used 3-D gradient echo acquisition. When combined with morphology information all classifiers show a higher performance for the ultrafast acquisition (two out of four results are significantly better). PMID- 24058021 TI - Automatic Detection and Segmentation of Crohn's Disease Tissues From Abdominal MRI. AB - We propose an information processing pipeline for segmenting parts of the bowel in abdominal magnetic resonance images that are affected with Crohn's disease. Given a magnetic resonance imaging test volume, it is first oversegmented into supervoxels and each supervoxel is analyzed to detect presence of Crohn's disease using random forest (RF) classifiers. The supervoxels identified as containing diseased tissues define the volume of interest (VOI). All voxels within the VOI are further investigated to segment the diseased region. Probability maps are generated for each voxel using a second set of RF classifiers which give the probabilities of each voxel being diseased, normal or background. The negative log-likelihood of these maps are used as penalty costs in a graph cut segmentation framework. Low level features like intensity statistics, texture anisotropy and curvature asymmetry, and high level context features are used at different stages. Smoothness constraints are imposed based on semantic information (importance of each feature to the classification task) derived from the second set of learned RF classifiers. Experimental results show that our method achieves high segmentation accuracy with Dice metric values of 0.90 +/- 0.04 and Hausdorff distance of 7.3 +/- 0.8 mm. Semantic information and context features are an integral part of our method and are robust to different levels of added noise. PMID- 24058022 TI - Magnetic Resonance Image Example-Based Contrast Synthesis. AB - The performance of image analysis algorithms applied to magnetic resonance images is strongly influenced by the pulse sequences used to acquire the images. Algorithms are typically optimized for a targeted tissue contrast obtained from a particular implementation of a pulse sequence on a specific scanner. There are many practical situations, including multi-institution trials, rapid emergency scans, and scientific use of historical data, where the images are not acquired according to an optimal protocol or the desired tissue contrast is entirely missing. This paper introduces an image restoration technique that recovers images with both the desired tissue contrast and a normalized intensity profile. This is done using patches in the acquired images and an atlas containing patches of the acquired and desired tissue contrasts. The method is an example-based approach relying on sparse reconstruction from image patches. Its performance in demonstrated using several examples, including image intensity normalization, missing tissue contrast recovery, automatic segmentation, and multimodal registration. These examples demonstrate potential practical uses and also illustrate limitations of our approach. PMID- 24058023 TI - Volumetric optoacoustic imaging with multi-bandwidth deconvolution. AB - Optoacoustic (photoacoustic) imaging based on cylindrically focused 1-D transducer arrays comes with powerful characteristics in visualizing optical contrast. Parallel reading of multiple detectors arranged around a tissue cross section enables capturing data for generating images of this plane within micro seconds. Dedicated small animals scanners and handheld systems using 1-D cylindrically focused ultrasound transducer arrays have demonstrated real-time cross-sectional imaging and high in-plane resolution. Yet, the resolution achieved along the axis perpendicular to the focal plane, i.e., the elevation resolution, is determined by the focusing capacities of the detector and is typically lower than the in-plane resolution. Herein, we investigated whether deconvolution of the sensitivity field of the transducer could lead to tangible image improvements. We showcase the findings on experimental measurements from phantoms and animals and discuss the features and the limitations of the approach in improving resolution along the elevation dimension. PMID- 24058024 TI - Model-Based Iterative Reconstruction for Dual-Energy X-Ray CT Using a Joint Quadratic Likelihood Model. AB - Dual-energy X-ray CT (DECT) has the potential to improve contrast and reduce artifacts as compared to traditional CT. Moreover, by applying model-based iterative reconstruction (MBIR) to dual-energy data, one might also expect to reduce noise and improve resolution. However, the direct implementation of dual energy MBIR requires the use of a nonlinear forward model, which increases both complexity and computation. Alternatively, simplified forward models have been used which treat the material-decomposed channels separately, but these approaches do not fully account for the statistical dependencies in the channels. In this paper, we present a method for joint dual-energy MBIR (JDE-MBIR), which simplifies the forward model while still accounting for the complete statistical dependency in the material-decomposed sinogram components. The JDE-MBIR approach works by using a quadratic approximation to the polychromatic log-likelihood and a simple but exact nonnegativity constraint in the image domain. We demonstrate that our method is particularly effective when the DECT system uses fast kVp switching, since in this case the model accounts for the inaccuracy of interpolated sinogram entries. Both phantom and clinical results show that the proposed model produces images that compare favorably in quality to previous decomposition-based methods, including FBP and other statistical iterative approaches. PMID- 24058025 TI - Distinguishing texture edges from object boundaries in video. AB - One of the most fundamental problems in image processing and computer vision is the inherent ambiguity that exists between texture edges and object boundaries in real-world images and video. Despite this ambiguity, many applications in computer vision and image processing often use image edge strength with the assumption that these edges approximate object depth boundaries. However, this assumption is often invalidated by real world data, and this discrepancy is a significant limitation in many of today's image processing methods. We address this issue by introducing a simple, low-level, and patch-consistency assumption that leverages the extra information present in video data to resolve this ambiguity. Through analyzing how well patches can be modeled by simple transformations over time, we can obtain an indication of which image edges correspond to texture edges versus object boundaries. Our approach is simple to implement and has the potential to improve a wide range of image and video-based applications by suppressing the detrimental effects of strong texture edges on regularization terms. We validate our approach by presenting results on a variety of scene types and directly incorporating our augmented edge map into existing image segmentation and optical flow applications, showing results that better correspond to object boundaries. PMID- 24058027 TI - Design of non-linear kernel dictionaries for object recognition. AB - In this paper, we present dictionary learning methods for sparse signal representations in a high dimensional feature space. Using the kernel method, we describe how the well known dictionary learning approaches, such as the method of optimal directions and KSVD, can be made nonlinear. We analyze their kernel constructions and demonstrate their effectiveness through several experiments on classification problems. It is shown that nonlinear dictionary learning approaches can provide significantly better performance compared with their linear counterparts and kernel principal component analysis, especially when the data is corrupted by different types of degradations. PMID- 24058026 TI - Automatic segmentation of the left atrium from MR images via variational region growing with a moments-based shape prior. AB - The planning and evaluation of left atrial ablation procedures are commonly based on the segmentation of the left atrium, which is a challenging task due to large anatomical variations. In this paper, we propose an automatic approach for segmenting the left atrium from magnetic resonance imagery. The segmentation problem is formulated as a problem in variational region growing. In particular, the method starts locally by searching for a seed region of the left atrium from an MR slice. A global constraint is imposed by applying a shape prior to the left atrium represented by Zernike moments. The overall growing process is guided by the robust statistics of intensities from the seed region along with the shape prior to capture the entire atrial region. The robustness and accuracy of our approach are demonstrated by experimental results from 64 human MR images. PMID- 24058028 TI - Fast video shot boundary detection based on SVD and pattern matching. AB - Video shot boundary detection (SBD) is the first and essential step for content based video management and structural analysis. Great efforts have been paid to develop SBD algorithms for years. However, the high computational cost in the SBD becomes a block for further applications such as video indexing, browsing, retrieval, and representation. Motivated by the requirement of the real-time interactive applications, a unified fast SBD scheme is proposed in this paper. We adopted a candidate segment selection and singular value decomposition (SVD) to speed up the SBD. Initially, the positions of the shot boundaries and lengths of gradual transitions are predicted using adaptive thresholds and most non-boundary frames are discarded at the same time. Only the candidate segments that may contain the shot boundaries are preserved for further detection. Then, for all frames in each candidate segment, their color histograms in the hue-saturation value) space are extracted, forming a frame-feature matrix. The SVD is then performed on the frame-feature matrices of all candidate segments to reduce the feature dimension. The refined feature vector of each frame in the candidate segments is obtained as a new metric for boundary detection. Finally, cut and gradual transitions are identified using our pattern matching method based on a new similarity measurement. Experiments on TRECVID 2001 test data and other video materials show that the proposed scheme can achieve a high detection speed and excellent accuracy compared with recent SBD schemes. PMID- 24058029 TI - Two dimensional array imaging with beam steered data. AB - This paper discusses different approaches used for millimeter wave imaging of 2D objects. Imaging of a 2D object requires reflected wave data to be collected across two distinct dimensions. In this paper, we propose a reconstruction method that uses narrowband waveforms along with 2D beam steering. The beam is steered in azimuthal and elevation direction, which forms the two distinct dimensions required for the reconstruction. The reconstruction technique uses inverse Fourier transform along with amplitude and phase correction factors. In addition, this reconstruction technique does not require interpolation of the data in either wavenumber or spatial domain. Use of the 2D beam steering offers better performance in the presence of noise compared with the existing methods, such as switched array imaging system. Effects of radio-frequency impairments such as quantization of the phase of beam steering weights and timing jitter, which add to phase noise, are analyzed. PMID- 24058030 TI - Noise estimation from digital step-model signal. AB - This paper addresses the noise estimation in the digital domain and proposes a noise estimator based on the step signal model. It is efficient for any distribution of noise because it does not rely only on the smallest amplitudes in the signal or image. The proposed approach uses polarized/directional derivatives and a nonlinear combination of these derivatives to estimate the noise distribution (e.g., Gaussian, Poisson, speckle, etc.). The moments of this measured distribution can be computed and are also calculated theoretically on the basis of noise distribution models. The 1D performances are detailed, and as this paper is mostly dedicated to image processing, a 2D extension is proposed. The 2D performances for several noise distributions and noise models are presented and are compared with selected other methods. PMID- 24058032 TI - A rule-based decision-making diagnosis system to evaluate arteriovenous shunt stenosis for hemodialysis treatment of patients using fuzzy petri nets. AB - This paper proposes a rule-based decision-making diagnosis system to evaluate arteriovenous shunt (AVS) stenosis for long-term hemodialysis treatment of patients using fuzzy petri nets (FPNs). AVS stenoses are often associated with blood sounds, resulting from turbulent flow over the narrowed blood vessel. Phonoangiography provides a noninvasive technique to monitor the sounds of the AVS. Since the power spectra changes in frequency and amplitude with the degree of AVS stenosis, it is difficult to make a human-made decision to judge the degree using a combination of those variances. The Burg autoregressive (AR) method is used to estimate the frequency spectra of a phonoangiographic signal and identify the characteristic frequencies. A rule-based decision-making method, FPNs, is designed as a decision-making system to evaluate the degree of stenosis (DOS) in routine examinations. For 42 long-term follow-up patients, the examination results show the proposed diagnosis system has greater efficiency in evaluating AVS stenosis. PMID- 24058031 TI - An evaluation of cardiorespiratory and movement features with respect to sleep stage classification. AB - Polysomnography (PSG) is considered the gold standard to assess sleep accurately, but it can be expensive, time-consuming, and uncomfortable, specifically in long term sleep studies. Actigraphy, on the other hand, is both cheap and userfriendly, but depending on the application lacks detail and accuracy. Our aim was to evaluate cardiorespiratory and movement signals in discriminating between wake, rapid-eye-movement (REM), light (N1N2), and deep (N3) sleep. The dataset comprised 85 nights of PSG from a healthy population. Starting from a total of 750 characteristic variables (features), problem-specific subsets of 40 features were forwardly selected using the combination of a wrapper method (Cohen's kappa statistic on radial basis function (RBF)-kernel support vector machine (SVM) classifier) and filter method (minimum redundancy maximum relevance criterion on mutual information). Final classification was performed using an RBF-kernel SVM. Non-subject-specific wake versus sleep classification resulted in a Cohen's kappa value of 0.695, while REM versus NREM resulted in 0.558 and N3 versus N1N2 in 0.553. The broad pool of initial features gave insight in which features discriminated best between the different classes. The classification results demonstrate the possibility of making long-term sleep monitoring more widely available. PMID- 24058033 TI - Modeling cell-cell interactions in regulating multiple myeloma initiating cell fate. AB - Cancer initiating cells have been documented in multiple myeloma and believed to be a key factor that initiates and drives tumor growth, differentiation,metastasis, and recurrence of the diseases. Although myeloma initiating cells (MICs) are likely to share many properties of normal stem cells, the underlying mechanisms regulating the fate of MICs are largely unknown. Studies designed to explore such communication are urgently needed to enhance our ability to predict the fate decisions of ICs (self-renewal, differentiation, and proliferation). In this study, we developed a novel system to understand the intercellular communication between MICs and their niche by seamlessly integrating experimental data and mathematical model. We first designed dynamic cell culture experiments and collected three types of cells (side population cells, progenitor cells, and mature myeloma cells) under various cultural conditions with flow cytometry. Then we developed a lineage model with ordinary differential equations by considering secreted factors, self-renewal, differentiation, and other biological functions of those cells, to model the cell cell interactions among the three cell types. Particle swarm optimization was employed to estimate the model parameters by fitting the experimental data to the lineage model. The theoretical results show that the correlation coefficient analysis can reflect the feedback loops among the three cell types, the intercellular feedback signaling can regulate cell population dynamics, and the culture strategies can decide cell growth. This study provides a basic framework of studying cell-cell interactions in regulating MICs fate. PMID- 24058034 TI - Red blood cell tracking using optical flow methods. AB - The investigation of microcirculation is an important task in biomedical and physiological research because the microcirculation information, such as flow velocity and vessel density, is critical to monitor human conditions and develop effective therapies of some diseases. As one of the tasks of the microcirculation study, red blood cell (RBC) tracking presents an effective approach to estimate some parameters in microcirculation. The common method for RBC tracking is based on spatiotemporal image analysis, which requires the image to have high qualification and cells should have fixed velocity. Besides, for in vivo cell tracking, cells may disappear in some frames, image series may have spatial and temporal distortions, and vessel distribution can be complex, which increase the difficulties of RBC tracking. In this paper, we propose an optical flow method to track RBCs. It attempts to describe the local motion for each visible point in the frames using a local displacement vector field. We utilize it to calculate the displacement of a cell in two adjacent frames. Additionally, another optical flow-based method, scale invariant feature transform (SIFT) flow, is also presented. The experimental results show that optical flow is quite robust to the case where the velocity of cell is unstable, while SIFT flow works well when there is a large displacement of the cell between two adjacent frames. Our proposed methods outperform other methods when doing in vivo cell tracking, which can be used to estimate the blood flow directly and help to evaluate other parameters in microcirculation. PMID- 24058035 TI - Models and methods for quantitative analysis of surface-enhanced Raman spectra. AB - The quantitative analysis of surface-enhanced Raman spectra using scattering nanoparticles has shown the potential and promising applications in in vivo molecular imaging. The diverse approaches have been used for quantitative analysis of Raman pectra information, which can be categorized as direct classical least squares models, full spectrum multivariate calibration models, selected multivariate calibration models, and latent variable regression (LVR) models. However, the working principle of these methods in the Raman spectra application remains poorly understood and a clear picture of the overall performance of each model is missing. Based on the characteristics of the Raman spectra, in this paper, we first provide the theoretical foundation of the aforementioned commonly used models and show why the LVR models are more suitable for quantitative analysis of the Raman spectra. Then, we demonstrate the fundamental connections and differences between different LVR methods, such as principal component regression, reduced-rank regression, partial least square regression (PLSR), canonical correlation regression, and robust canonical analysis, by comparing their objective functions and constraints.We further prove that PLSR is literally a blend of multivariate calibration and feature extraction model that relates concentrations of nanotags to spectrum intensity. These features (a.k.a. latent variables) satisfy two purposes: the best representation of the predictor matrix and correlation with the response matrix. These illustrations give a new understanding of the traditional PLSR and explain why PLSR exceeds other methods in quantitative analysis of the Raman spectra problem. In the end, all the methods are tested on the Raman spectra datasets with different evaluation criteria to evaluate their performance. PMID- 24058036 TI - Knowledge-assisted sequential pattern analysis with heuristic parameter tuning for labor contraction prediction. AB - The optimal dosing regimen of remifentanil for relieving labor pain should achieve maximal efficacy during contractions and little effect between contractions. Toward such a need, we propose a knowledge-assisted sequential pattern analysis with heuristic parameter tuning to predict the changes in intrauterine pressure,which indicates the occurrence of labor contractions. This enables giving the drug shortly before each contraction starts. Asequential association rule mining based patient selection strategy is designed to dynamically select data for training regression models. A novel heuristic parameter tuning method is proposed to decide the appropriate value ranges and searching strategies for both the regularization factor and the Gaussian kernel parameter of leastsquares support vector machine with radial basis function (RBF) kernel, which is used as the regression model for time series prediction. The parameter tuning method utilizes information extracted from the training dataset, and it is adaptive to the characteristics of time series. The promising experimental results show that the proposed framework is able to achieve the lowest prediction errors as compared to some existing methods. PMID- 24058037 TI - Local and global preserving semisupervised dimensionality reduction based on random subspace for cancer classification. AB - Precise cancer classification is essential to the successful diagnosis and treatment of cancers. Although semisupervised dimensionality reduction approaches perform very well on clean datasets, the topology of the neighborhood constructed with most existing approaches is unstable in the presence of high-dimensional data with noise. In order to solve this problem, a novel local and global preserving semisupervised dimensionality reduction based on random subspace algorithm marked as RSLGSSDR, which utilizes random subspace for semisupervised dimensionality reduction, is proposed. The algorithm first designs multiple diverse graphs on different random subspace of datasets and then fuses these graphs into a mixture graph on which dimensionality reduction is performed. As themixture graph is constructed in lower dimensionality, it can ease the issues on graph construction on highdimensional samples such that it can hold complicated geometric distribution of datasets as the diversity of random subspaces. Experimental results on public gene expression datasets demonstrate that the proposed RSLGSSDR not only has superior recognition performance to competitive methods, but also is robust against a wide range of values of input parameters. PMID- 24058038 TI - Semantics driven approach for knowledge acquisition from EMRs. AB - Semantic computing technologies have matured to be applicable to many critical domains such as national security, life sciences, and health care. However, the key to their success is the availability of a rich domain knowledge base. The creation and refinement of domain knowledge bases pose difficult challenges. The existing knowledge bases in the health care domain are rich in taxonomic relationships, but they lack nontaxonomic (domain) relationships. In this paper, we describe a semiautomatic technique for enriching existing domain knowledge bases with causal relationships gleaned from Electronic Medical Records (EMR) data. We determine missing causal relationships between domain concepts by validating domain knowledge against EMR data sources and leveraging semantic based techniques to derive plausible relationships that can rectify knowledge gaps. Our evaluation demonstrates that semantic techniques can be employed to improve the efficiency of knowledge acquisition. PMID- 24058039 TI - A spatiotemporal-based scheme for efficient registration-based segmentation of thoracic 4-D MRI. AB - Dynamic three-dimensional (3-D) (four-dimensional, 4-D) magnetic resonance (MR) imaging is gaining importance in the study of pulmonary motion for respiratory diseases and pulmonary tumor motion for radiotherapy. To perform quantitative analysis using 4-D MR images, segmentation of anatomical structures such as the lung and pulmonary tumor is required. Manual segmentation of entire thoracic 4-D MRI data that typically contains many 3-D volumes acquired over several breathing cycles is extremely tedious, time consuming, and suffers high user variability. This requires the development of new automated segmentation schemes for 4-D MRI data segmentation. Registration-based segmentation technique that uses automatic registration methods for segmentation has been shown to be an accurate method to segment structures for 4-D data series. However, directly applying registration based segmentation to segment 4-D MRI series lacks efficiency. Here we propose an automated 4-D registration-based segmentation scheme that is based on spatiotemporal information for the segmentation of thoracic 4-D MR lung images. The proposed scheme saved up to 95% of computation amount while achieving comparable accurate segmentations compared to directly applying registration based segmentation to 4-D dataset. The scheme facilitates rapid 3-D/4-D visualization of the lung and tumor motion and potentially the tracking of tumor during radiation delivery. PMID- 24058040 TI - Compressed sensing technology-based spectral estimation of heart rate variability using the integral pulse frequency modulation model. AB - In this paper, a compressed sensing (CS)-based spectral estimation of heart rate variability (HRV) using the integral pulse frequency modulation (IPFM) model is introduced. Previous research in the literature indicated that the IPFM model is widely accepted as a functional description of the cardiac pacemaker, and thus, very useful in modeling the mechanism by which the autonomic nervous system modulates the heart rate (HR). On the other hand, recently CS becomes an emerging technology that has attracted great attention since it is capable of acquiring and reconstructing signals that are considered sparse or compressible, even when the number of measurements is small. Using the IPFM model, we here present a CS based algorithm for deriving the amplitude spectrum of the modulating signal for HRV assessments. In fact, the application of the CS method into HRV spectral estimation is unprecedented. Numerical results produced by a real RR database of PhysioNet demonstrated that the proposed approach can robustly provide high fidelity HRV spectral estimates, even under the situation of a degree of incompleteness in the RR data caused by ectopic or missing beats. PMID- 24058041 TI - Optimization of heartbeat detection in fiber-optic unobtrusive measurements by using maximum a posteriori probability estimation. AB - This paper deals with an optimized heartbeat detection multimethod by using maximum a posteriori probability (MAP). The approach was derived for unobtrusive fiber-optic measurements of cardiac activity. Multiple independent detection methods were selected and characterized by their delays and variability referring to cardiac electrical excitation (R waves). Validation of the approach was performed in two experiments involving 24 participants: 10 interferometric signals were recorded at rest, 14 with variable heart rate after physical exercise. The proposed MAP heartbeat detection was assessed by a cross validation in 250 iterations. Obtained results show the overall efficiency, which was estimated by a product of the sensitivity, precision, and variability of heartbeat detections, yields 97.04 +/- 3.36% for the experiment with physical exercise and 97.07 +/- 4.49% at rest. The method's accuracy guarantees that the heartbeat detections differ for 22 +/- 5 ms and 22 +/- 3 ms from the ECG reference in the two types of experiments, respectively. PMID- 24058042 TI - Detecting periods of eating during free-living by tracking wrist motion. AB - This paper is motivated by the growing prevalence of obesity, a health problem affecting over 500 million people. Measurements of energy intake are commonly used for the study and treatment of obesity. However, the most widely used tools rely upon self-report and require a considerable manual effort, leading to underreporting of consumption, noncompliance, and discontinued use over the long term. The purpose of this paper is to describe a new method that uses a watch like configuration of sensors to continuously track wrist motion throughout the day and automatically detect periods of eating. Our method uses the novel idea that meals tend to be preceded and succeeded by the periods of vigorous wrist motion. We describe an algorithm that segments and classifies such periods as eating or noneating activities. We also evaluate our method on a large dataset (43 subjects, 449 total h of data, containing 116 periods of eating) collected during free-living. Our results show an accuracy of 81% for detecting eating at 1 s resolution in comparison to manually marked event logs of periods eating. These results indicate that vigorous wrist motion is a useful indicator for identifying the boundaries of eating activities, and that our method should prove useful in the continued development of body-worn sensor tools for monitoring energy intake. PMID- 24058043 TI - Using evolutional properties of gene networks in understanding survival prognosis of glioblastoma. AB - Previously, we investigated survival prognosis of glioblastoma by applying a gene regulatory approach to a human glioblastoma dataset. Here, we further extend our understanding of survival prognosis of glioblastoma by refining the network inference technique we apply to the glioblastoma dataset with the intent of uncovering further topological properties of the networks. For this study, we modify the approach by specifically looking at both positive and negative correlations separately, as opposed to absolute correlations. There is great interest in applying mathematical modeling approaches to cancer cell line datasets to generate network models of gene regulatory interactions. Analysis of these networks using graph theory metrics can identify genes of interest. The principal approach for modeling microarray datasets has been to group all the cell lines together into one overall network, and then, analyze this network as a whole. As per the previous study, we categorize a human glioblastoma cell line dataset into five categories based on survival data, and analyze each category separately using both negative and positive correlation networks constructed using a modified version of the WGCNA algorithm. Using this approach, we identified a number of genes as being important across different survival stages of the glioblastoma cell lines. PMID- 24058044 TI - Characterization of physical activity in COPD patients: validation of a robust algorithm for actigraphic measurements in living situations. AB - We have developed robust embedded algorithms for the real-time classification of activity detected by our wearable inertial device. We collected 224 h of accelerometric signals from 28 subjects [22 suffering from chronic obstructive pulmonary disease (COPD)] to develop and then evaluate our algorithms. We describe the process for determining the most robust parameters of the algorithms. Our results with COPD patients show the feasibility of conducting real-time classification of their activities in everyday situations, with high fidelity. PMID- 24058045 TI - Social voting advice applications-definitions, challenges, datasets and evaluation. AB - Voting advice applications (VAAs) are online tools that have become increasingly popular and purportedly aid users in deciding which party/candidate to vote for during an election. In this paper we present an innovation to current VAA design which is based on the introduction of a social network element. We refer to this new type of online tool as a social voting advice application (SVAA). SVAAs extend VAAs by providing (a) community-based recommendations, (b) comparison of users' political opinions, and (c) a channel of user communication. In addition, SVAAs enriched with data mining modules, can operate as citizen sensors recording the sentiment of the electorate on issues and candidates. Drawing on VAA datasets generated by the Preference Matcher research consortium, we evaluate the results of the first VAA-Choose4Greece-which incorporated social voting features and was launched during the landmark Greek national elections of 2012. We demonstrate how an SVAA can provide community based features and, at the same time, serve as a citizen sensor. Evaluation of the proposed techniques is realized on a series of datasets collected from various VAAs, including Choose4Greece. The collection is made available online in order to promote research in the field. PMID- 24058046 TI - Exemplar-based human action pose correction. AB - The launch of Xbox Kinect has built a very successful computer vision product and made a big impact on the gaming industry. This sheds lights onto a wide variety of potential applications related to action recognition. The accurate estimation of human poses from the depth image is universally a critical step. However, existing pose estimation systems exhibit failures when facing severe occlusion. In this paper, we propose an exemplar-based method to learn to correct the initially estimated poses. We learn an inhomogeneous systematic bias by leveraging the exemplar information within a specific human action domain. Furthermore, as an extension, we learn a conditional model by incorporation of pose tags to further increase the accuracy of pose correction. In the experiments, significant improvements on both joint-based skeleton correction and tag prediction are observed over the contemporary approaches, including what is delivered by the current Kinect system. Our experiments for the facial landmark correction also illustrate that our algorithm can improve the accuracy of other detection/estimation systems. PMID- 24058047 TI - Multiscale asymmetric orthogonal wavelet kernel for linear programming support vector learning and nonlinear dynamic systems identification. AB - Support vector regression for approximating nonlinear dynamic systems is more delicate than the approximation of indicator functions in support vector classification, particularly for systems that involve multitudes of time scales in their sampled data. The kernel used for support vector learning determines the class of functions from which a support vector machine can draw its solution, and the choice of kernel significantly influences the performance of a support vector machine. In this paper, to bridge the gap between wavelet multiresolution analysis and kernel learning, the closed-form orthogonal wavelet is exploited to construct new multiscale asymmetric orthogonal wavelet kernels for linear programming support vector learning. The closed-form multiscale orthogonal wavelet kernel provides a systematic framework to implement multiscale kernel learning via dyadic dilations and also enables us to represent complex nonlinear dynamics effectively. To demonstrate the superiority of the proposed multiscale wavelet kernel in identifying complex nonlinear dynamic systems, two case studies are presented that aim at building parallel models on benchmark datasets. The development of parallel models that address the long-term/mid-term prediction issue is more intricate and challenging than the identification of series parallel models where only one-step ahead prediction is required. Simulation results illustrate the effectiveness of the proposed multiscale kernel learning. PMID- 24058048 TI - C-Leg(r) improves function and quality of life in an adolescent traumatic trans femoral amputee: a case study. AB - BACKGROUND AND AIMS: (1) To demonstrate that a 13-year-old male can be successfully fitted with a C-Leg(r) microprocessor-controlled knee. (2) To use validated outcome measurement tools to assess change in mobility, physical function, fatigue and quality of life after fitting. CASE DESCRIPTION AND METHODS: A 13-year-old unilateral traumatic trans-femoral amputee was studied pre C-Leg fitting and 2 weeks and 10 months post C-Leg fitting. FINDINGS AND OUTCOMES: The 6-Minute Walk Test improved by 33% from 360 to 480 m. PedsQLTM Multidimensional Fatigue Scale improved by 32% from 68 to 90, and PedsQLTM Quality of Life Scale improved 14 points, with minimal clinically important difference of 4.36 points. CONCLUSION: In this case, the provision of a microprocessor-controlled knee in the context of a new prosthesis with new socket system produced improvements for the patient in walking speed, fatigue and quality of life. CLINICAL RELEVANCE: This case report shows that n = 1 methodology can be used to demonstrate clinical improvement in an adolescent subject when using an intervention (C-Leg) which is not supported in this age group by published evidence. PMID- 24058049 TI - Information theory applications for biological sequence analysis. AB - Information theory (IT) addresses the analysis of communication systems and has been widely applied in molecular biology. In particular, alignment-free sequence analysis and comparison greatly benefited from concepts derived from IT, such as entropy and mutual information. This review covers several aspects of IT applications, ranging from genome global analysis and comparison, including block entropy estimation and resolution-free metrics based on iterative maps, to local analysis, comprising the classification of motifs, prediction of transcription factor binding sites and sequence characterization based on linguistic complexity and entropic profiles. IT has also been applied to high-level correlations that combine DNA, RNA or protein features with sequence-independent properties, such as gene mapping and phenotype analysis, and has also provided models based on communication systems theory to describe information transmission channels at the cell level and also during evolutionary processes. While not exhaustive, this review attempts to categorize existing methods and to indicate their relation with broader transversal topics such as genomic signatures, data compression and complexity, time series analysis and phylogenetic classification, providing a resource for future developments in this promising area. PMID- 24058050 TI - Climate and dengue transmission: evidence and implications. AB - BACKGROUND: Climate influences dengue ecology by affecting vector dynamics, agent development, and mosquito/human interactions. Although these relationships are known, the impact climate change will have on transmission is unclear. Climate driven statistical and process-based models are being used to refine our knowledge of these relationships and predict the effects of projected climate change on dengue fever occurrence, but results have been inconsistent. OBJECTIVE: We sought to identify major climatic influences on dengue virus ecology and to evaluate the ability of climate-based dengue models to describe associations between climate and dengue, simulate outbreaks, and project the impacts of climate change. METHODS: We reviewed the evidence for direct and indirect relationships between climate and dengue generated from laboratory studies, field studies, and statistical analyses of associations between vectors, dengue fever incidence, and climate conditions. We assessed the potential contribution of climate-driven, process-based dengue models and provide suggestions to improve their performance. RESULTS AND DISCUSSION: Relationships between climate variables and factors that influence dengue transmission are complex. A climate variable may increase dengue transmission potential through one aspect of the system while simultaneously decreasing transmission potential through another. This complexity may at least partly explain inconsistencies in statistical associations between dengue and climate. Process-based models can account for the complex dynamics but often omit important aspects of dengue ecology, notably virus development and host-species interactions. CONCLUSION: Synthesizing and applying current knowledge of climatic effects on all aspects of dengue virus ecology will help direct future research and enable better projections of climate change effects on dengue incidence. PMID- 24058051 TI - Titrated oral misoprostol for augmenting labour to improve maternal and neonatal outcomes. AB - BACKGROUND: Labour dystocia is associated with a number of adverse maternal and neonatal outcomes. Augmentation of labour is a commonly used intervention in cases of labour dystocia. Misoprostol is an inexpensive and stable prostaglandin E1 analogue that can be administered orally, vaginally, sublingually or rectally. Misoprostol has proven to be effective at stimulating uterine contractions although it can have serious, and even life-threatening side-effects. Titration refers to the process of adjusting the dose, frequency, or both, of a medication on the basis of frequent review to achieve optimal outcomes. Studies have reported on a range of misoprostol titration regimens used for labour induction and titrated misoprostol may potentially be effective and safe for augmentation of labour. OBJECTIVES: To examine the effects and safety of titrated oral misoprostol compared with placebo, oxytocin, other interventions, or no active treatment, in women with labour dystocia. SEARCH METHODS: The Trials Search Co ordinator of the Cochrane Pregnancy and Childbirth Group searched the Cochrane Pregnancy and Childbirth Group's Trials Register; date of search: 29 May 2013. We also searched the reference lists of retrieved studies SELECTION CRITERIA: Randomised trials (including quasi-randomised and cluster-randomised trials) comparing titrated oral misoprostol with placebo, other interventions (e.g. oxytocin, other prostaglandins), or no treatment in women requiring augmentation of labour were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility for inclusion, carried out data extraction and assessed risk of bias in included studies. Data were entered by one author and checked for accuracy. MAIN RESULTS: We included two randomised trials with a total of 581 women each comparing different regimens of titrated oral misoprostol with intravenous oxytocin. One study compared 20 mcg doses of misoprostol dissolved in water (repeated every hour up to four hours, after which the dose was increased to 40 mcg per hour up to a maximum total dose of 1600 mcg), while the second study gave women 75 mcg doses (repeated after four hours provided there were no adverse effects observed).Neither trial reported maternal death, severe maternal morbidity, or fetal/neonatal mortality outcomes, and only a few fetal/neonatal morbidity outcomes were considered, none of which were significantly different between groups. For several outcomes (such as maternal side-effects, instrumental birth, maternal blood transfusion for hypovolaemia and epidural analgesia), the number of events was generally too low for sufficient statistical power to be achieved. Maternal satisfaction was not reported in either trial. One trial reported a slight reduction in the median duration of labour from the start of augmentation to vaginal delivery in the oxytocin group.Neither trial reported significantly higher rates of caesarean section (CS) in the oral misoprostol group. Rates of vaginal delivery within 12 and 24 hours of commencing augmentation were not significantly different in the trial using a 20 mcg misoprostol dose. Neither trial had significantly higher rates of uterine hyperstimulation with fetal heart rate changes in the titrated oral misoprostol group. However, the rates of this outcome varied so greatly between the two studies as to suggest that other factors were at play. The only significant differences between groups related to uterine hyperstimulation (without fetal heart rate changes), and results were not consistent in the two trials. In the trial examining the higher dose of misoprostol, more women in the misoprostol group experienced hyperstimulation of labour measured over a 10-minute period compared with those receiving oxytocin (risk ratio (RR) 1.17, 95% confidence interval (CI) 1.02 to 1.35, 350 women). In the study examining the lower titrated dose of misoprostol, there was a lower incidence of tachysystole when labour was augmented with titrated oral misoprostol than with oxytocin (RR 0.39, 95% CI 0.17 to 0.91, 231 women) with no occurrences of hypertonus in either group of women. AUTHORS' CONCLUSIONS: Important uncertainties still exist on the safety and acceptability of titrated oral misoprostol compared with intravenous oxytocin regimens in women with dystocia following spontaneous onset of labour. Although in facilities where electronic oxytocin infusion is not available, low-dose titrated misoprostol may offer a better alternative to an uncontrolled oxytocin infusion to avoid hyperstimulation. Further research is needed in both high- and low-resource settings More trials should be conducted to evaluate the effect of a standard titration oral misoprostol regimen, both following spontaneous labour and labour induction. Comparisons with other augmentation methods are also warranted, as are any effects on women's birth experiences. PMID- 24058053 TI - Abstracts of the 45th Congress of the International Society of Paediatric Oncology (SIOP) 2013. Hong Kong, China. September 25-28, 2013. PMID- 24058052 TI - Insulin resistance and environmental pollutants: experimental evidence and future perspectives. AB - BACKGROUND: The metabolic disruptor hypothesis postulates that environmental pollutants may be risk factors for metabolic diseases. Because insulin resistance is involved in most metabolic diseases and current health care prevention programs predominantly target insulin resistance or risk factors thereof, a critical analysis of the role of pollutants in insulin resistance might be important for future management of metabolic diseases. OBJECTIVES: We aimed to critically review the available information linking pollutant exposure to insulin resistance and to open the discussion on future perspectives for metabolic disruptor identification and prioritization strategies. METHODS: We searched PubMed and Web of Science for experimental studies reporting on linkages between environmental pollutants and insulin resistance and identified a total of 23 studies as the prime literature. DISCUSSION: Recent studies specifically designed to investigate the effect of pollutants on insulin sensitivity show a potential causation of insulin resistance. Based on these studies, a summary of viable test systems and end points can be composed, allowing insight into what is missing and what is needed to create a standardized insulin resistance toxicity testing strategy. CONCLUSIONS: It is clear that current research predominantly relies on top-down identification of insulin resistance-inducing metabolic disruptors and that the development of dedicated in vitro or ex vivo screens to allow animal sparing and time- and cost-effective bottom-up screening is a major future research need. PMID- 24058055 TI - customProDB: an R package to generate customized protein databases from RNA-Seq data for proteomics search. AB - Database search is the most widely used approach for peptide and protein identification in mass spectrometry-based proteomics studies. Our previous study showed that sample-specific protein databases derived from RNA-Seq data can better approximate the real protein pools in the samples and thus improve protein identification. More importantly, single nucleotide variations, short insertion and deletions and novel junctions identified from RNA-Seq data make protein database more complete and sample-specific. Here, we report an R package customProDB that enables the easy generation of customized databases from RNA-Seq data for proteomics search. This work bridges genomics and proteomics studies and facilitates cross-omics data integration. AVAILABILITY AND IMPLEMENTATION: customProDB and related documents are freely available at http://bioconductor.org/packages/2.13/bioc/html/customProDB.html. PMID- 24058054 TI - Disruption of aryl hydrocarbon receptor homeostatic levels during embryonic stem cell differentiation alters expression of homeobox transcription factors that control cardiomyogenesis. AB - BACKGROUND: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of xenobiotic detoxification genes and is a critical mediator of gene-environment interactions. Many AHR target genes identified by genome-wide gene expression profiling have morphogenetic functions, suggesting that AHR may play a role in embryonic development. OBJECTIVES: To characterize the developmental functions of the AHR, we studied the consequences of AHR activation by the agonist 2,3,7,8 tetrachlorodibenzo-p-doxin (TCDD), and the result of its repression by the antagonists 6,2,4-trimethoxyflavone and CH 223191 or by short-hairpin RNA (shRNA) mediated Ahr knockdown during spontaneous differentiation of embryonic stem (ES) cells into cardiomyocytes. METHODS: We generated an AHR-positive cardiomyocyte lineage differentiated from mouse ES cells that expresses puromycin resistance and enhanced green fluorescent protein (eGFP) under the control of the Cyp1a1 (cytochrome P450 1a1) promoter. We used RNA sequencing (RNA.Seq) to analyze temporal trajectories of TCDD-dependent global gene expression in these cells during differentiation. RESULTS: Activation, inhibition, and knockdown of Ahr significantly inhibited the formation of contractile cardiomyocyte nodes. Global expression analysis of AHR-positive cells showed that activation of the AHR/TCDD axis disrupted the concerted expression of genes that regulate multiple signaling pathways involved in cardiac and neural morphogenesis and differentiation, including dozens of genes encoding homeobox transcription factors and Polycomb and trithorax group proteins. CONCLUSIONS: Disruption of AHR expression levels resulted in gene expression changes that perturbed cardiomyocyte differentiation. The main function of the AHR during development appears to be the coordination of a complex regulatory network responsible for attainment and maintenance of cardiovascular homeostasis. PMID- 24058056 TI - Design and analysis of large-scale biological rhythm studies: a comparison of algorithms for detecting periodic signals in biological data. AB - MOTIVATION: To discover and study periodic processes in biological systems, we sought to identify periodic patterns in their gene expression data. We surveyed a large number of available methods for identifying periodicity in time series data and chose representatives of different mathematical perspectives that performed well on both synthetic data and biological data. Synthetic data were used to evaluate how each algorithm responds to different curve shapes, periods, phase shifts, noise levels and sampling rates. The biological datasets we tested represent a variety of periodic processes from different organisms, including the cell cycle and metabolic cycle in Saccharomyces cerevisiae, circadian rhythms in Mus musculus and the root clock in Arabidopsis thaliana. RESULTS: From these results, we discovered that each algorithm had different strengths. Based on our findings, we make recommendations for selecting and applying these methods depending on the nature of the data and the periodic patterns of interest. Additionally, these results can also be used to inform the design of large-scale biological rhythm experiments so that the resulting data can be used with these algorithms to detect periodic signals more effectively. PMID- 24058057 TI - Single assay-wide variance experimental (SAVE) design for high-throughput screening. AB - MOTIVATION: Advantages of statistical testing of high-throughput screens include P-values, which provide objective benchmarks of compound activity, and false discovery rate estimation. The cost of replication required for statistical testing, however, may often be prohibitive. We introduce the single assay-wide variance experimental (SAVE) design whereby a small replicated subset of an entire screen is used to derive empirical Bayes random error estimates, which are applied to the remaining majority of unreplicated measurements. RESULTS: The SAVE design is able to generate P-values comparable with those generated with full replication data. It performs almost as well as the random variance model t-test with duplicate data and outperforms the commonly used Z-scores with unreplicated data and the standard t-test. We illustrate the approach with simulated data and with experimental small molecule and small interfering RNA screens. The SAVE design provides substantial performance improvements over unreplicated screens with only slight increases in cost. PMID- 24058058 TI - Exploring variation-aware contig graphs for (comparative) metagenomics using MaryGold. AB - MOTIVATION: Although many tools are available to study variation and its impact in single genomes, there is a lack of algorithms for finding such variation in metagenomes. This hampers the interpretation of metagenomics sequencing datasets, which are increasingly acquired in research on the (human) microbiome, in environmental studies and in the study of processes in the production of foods and beverages. Existing algorithms often depend on the use of reference genomes, which pose a problem when a metagenome of a priori unknown strain composition is studied. In this article, we develop a method to perform reference-free detection and visual exploration of genomic variation, both within a single metagenome and between metagenomes. RESULTS: We present the MaryGold algorithm and its implementation, which efficiently detects bubble structures in contig graphs using graph decomposition. These bubbles represent variable genomic regions in closely related strains in metagenomic samples. The variation found is presented in a condensed Circos-based visualization, which allows for easy exploration and interpretation of the found variation. We validated the algorithm on two simulated datasets containing three respectively seven Escherichia coli genomes and showed that finding allelic variation in these genomes improves assemblies. Additionally, we applied MaryGold to publicly available real metagenomic datasets, enabling us to find within-sample genomic variation in the metagenomes of a kimchi fermentation process, the microbiome of a premature infant and in microbial communities living on acid mine drainage. Moreover, we used MaryGold for between-sample variation detection and exploration by comparing sequencing data sampled at different time points for both of these datasets. AVAILABILITY: MaryGold has been written in C++ and Python and can be downloaded from http://bioinformatics.tudelft.nl/software PMID- 24058060 TI - Ultrafast transient absorption studies of hematite nanoparticles: the effect of particle shape on exciton dynamics. AB - Much progress has been made in using hematite (alpha-Fe2 O3 ) as a potentially practical and sustainable material for applications such as solar-energy conversion and photoelectrochemical (PEC) water splitting; however, recent studies have shown that the performance can be limited by a very short charge carrier diffusion length or exciton lifetime. In this study, we performed ultrafast studies on hematite nanoparticles of different shapes to determine the possible influence of particle shape on the exciton dynamics. Nanorice, multifaceted spheroidal nanoparticles, faceted nanocubes, and faceted nanorhombohedra were synthesized and characterized by using SEM and XRD techniques. Their exciton dynamics were investigated by using femtosecond transient absorption (TA) spectroscopy. Although the TA spectral features differ for the four samples studied, their decay profiles are similar, which can be fitted with time constants of 1-3 ps, approximately 25 ps, and a slow nanosecond component extending beyond the experimental time window that was measured (2 ns). The results indicate that the overall exciton lifetime is weakly dependent on the shape of the hematite nanoparticles, even though the overall optical absorption and scattering are influenced by the particle shape. This study suggests that other strategies need to be developed to increase the exciton lifetime or to lengthen the exciton diffusion length in hematite nanostructures. PMID- 24058061 TI - Nonverbal expressions of status and system legitimacy: an interactive influence on race bias. AB - A voluminous literature has examined how primates respond to nonverbal expressions of status, such as taking the high ground, expanding one's posture, and tilting one's head. We extend this research to human intergroup processes in general and interracial processes in particular. Perceivers may be sensitive to whether racial group status is reflected in group members' nonverbal expressions of status. We hypothesized that people who support the current status hierarchy would prefer racial groups whose members exhibit status-appropriate nonverbal behavior over racial groups whose members do not exhibit such behavior. People who reject the status quo should exhibit the opposite pattern. These hypotheses were supported in three studies using self-report (Study 1) and reaction time (Studies 2 and 3) measures of racial bias and two different status cues (vertical position and head tilt). For perceivers who supported the status quo, high-status cues (in comparison with low-status cues) increased preferences for White people over Black people. For perceivers who rejected the status quo, the opposite pattern was observed. PMID- 24058062 TI - The number of fatalities drives disaster aid: increasing sensitivity to people in need. AB - In the studies reported here, an analysis of financial donations in response to natural disasters showed that the amount of money allocated for humanitarian aid depends on the number of fatalities but not on the number of survivors who are affected by the disaster (i.e., the actual beneficiaries of the aid). On the basis of the experimental evidence, we discuss the underlying cause and provide guidelines to increase sensitivity to people in need. PMID- 24058063 TI - Sustained striatal activity predicts eudaimonic well-being and cortisol output. AB - Eudaimonic well-being-a sense of purpose, meaning, and engagement with life-is protective against psychopathology and predicts physical health, including lower levels of the stress hormone cortisol. Although it has been suggested that the ability to engage the neural circuitry of reward may promote well-being and mediate the relationship between well-being and health, this hypothesis has remained untested. To test this hypothesis, we had participants view positive, neutral, and negative images while fMRI data were collected. Individuals with sustained activity in the striatum and dorsolateral prefrontal cortex to positive stimuli over the course of the scan session reported greater well-being and had lower cortisol output. This suggests that sustained engagement of reward circuitry in response to positive events underlies well-being and adaptive regulation of the hypothalamic-pituitary-adrenal axis. PMID- 24058064 TI - When truth is personally inconvenient, attitudes change: the impact of extreme weather on implicit support for green politicians and explicit climate-change beliefs. AB - A naturalistic investigation of New Jersey residents, both before and after they experienced Hurricanes Irene and Sandy, examined support for politicians committed or opposed to policies designed to combat climate change. At Time 1, before both hurricanes, participants showed negative implicit attitudes toward a green politician, but at Time 2, after the hurricanes, participants drawn from the same cohort showed a reversed automatic preference. Moreover, those who were significantly affected by Hurricane Sandy were especially likely to implicitly prefer the green politician, and implicit attitudes were the best predictor of voting after the storms, whereas explicit climate-change beliefs was the best predictor before the storms. In concert, the results suggest that direct experience with extreme weather can increase pro-environmentalism, and further support conceptualizing affective experiences as a source of implicit attitudes. PMID- 24058066 TI - The development of episodic memory: items, contexts, and relations. AB - Episodic memory involves the formation of relational structures that bind information about the stimuli people experience to the contexts in which they experience them. The ability to form and retain such structures may be at the core of the development of episodic memory. In the first experiment reported here, 4- and 7-year-olds were presented with paired-associate learning tasks requiring memory structures of different complexity. A multinomial-processing tree model was applied to estimate the use of different structures in the two age groups. The use of two-way list-context-to-target structures and three-way structures was found to increase between the ages of 4 and 7. Experiment 2 demonstrated that the ability to form increasingly complex relational memory structures develops between the ages of 4 and 7 years and that this development extends well into adulthood. These results have important implications for theories of memory development. PMID- 24058067 TI - Genes for emotion-enhanced remembering are linked to enhanced perceiving. AB - Emotionally enhanced memory and susceptibility to intrusive memories after trauma have been linked to a deletion variant (i.e., a form of a gene in which certain amino acids are missing) of ADRA2B, the gene encoding subtype B of the alpha2 adrenergic receptor, which influences norepinephrine activity. We examined in 207 participants whether variations in this gene are responsible for individual differences in affective influences on initial encoding that alter perceptual awareness. We examined the attentional blink, an attentional impairment during rapid serial visual presentation, for negatively arousing, positively arousing, and neutral target words. Overall, the attentional blink was reduced for emotional targets for ADRA2B-deletion carriers and noncarriers alike, which reveals emotional sparing (i.e., reduction of the attentional impairment for words that are emotionally significant). However, deletion carriers demonstrated a further, more pronounced emotional sparing for negative targets. This finding demonstrates a contribution of genetics to individual differences in the emotional subjectivity of perception, which in turn may be linked to biases in later memory. PMID- 24058065 TI - Emotional distractors can enhance attention. AB - The deleterious effects of emotional distractors on attention have been well demonstrated. However, it is unclear whether emotional distractors inevitably disrupt task-relevant attention. In the research reported here, the impact of the valence and arousal of distracting emotional stimuli and individual differences in anxiety on task-relevant processing were examined using multilevel modeling. Consistent with prior literature, results showed that high-arousal negative distractors, compared with positive and neutral distractors, were associated with poorer task-relevant attention. However, low-arousal negative distractors were associated with better task-relevant performance than were positive and neutral distractors. Furthermore, these effects were accentuated by individual differences in worry. These findings challenge assumptions that distraction and worry must be minimized for augmented attentional performance. Overall, these results emphasize the importance of taking into account emotional dimensions of arousal and valence as well as individual differences in anxiety when examining attention in the presence of emotional distractors. PMID- 24058068 TI - Why neoliberal values of self-enhancement lead to cheating in higher education: a motivational account. AB - The significant number of financial and academic frauds hitting the headlines is paralleled by high rates of cheating in schools. Does adherence to the neoliberal values that underpin our economic and academic systems predict acceptance of cheating? Four studies revealed that adherence to neoliberal values of self enhancement-power and achievement-predicts the motivation to gain social approval; this motivation, in turn, favors the adoption of context-specific competitive performance-approach goals, which predict the condoning of cheating. An experimental study showed that when participants were exposed to a source promoting the values of universalism and benevolence (self-transcendence values, the normative opposite of self-enhancement values), self-enhancement adherence ceased to predict the condoning of cheating. Most important, a classroom-based study addressed the core question of cheating behavior, revealing that adherence to self-enhancement values indeed predicted actual cheating behavior. These results point to the relevance of diagnosing societal values as social causes of cheating. PMID- 24058069 TI - A sense of "deja vu"? PMID- 24058070 TI - What is microNRA and should interventionalists be aware of it? PMID- 24058071 TI - Transcatheter aortic valve replacement: many roads lead to Rome...but the implantation technique makes the difference! PMID- 24058072 TI - Plasma miR-126 as a potential marker predicting major adverse cardiac events in dual antiplatelet-treated patients after percutaneous coronary intervention. AB - AIMS: Antiplatelet treatment can cause a change in plasma levels of platelet microRNAs (miRNAs). However, it is not clear whether the plasma level of platelet miRNAs can predict clinical outcomes of antiplatelet treatment. The present study aimed to evaluate the association of plasma miR-16, miR%E2%80%9121, miR-126, miR 26b, and miR-223 with the risk of clinical outcomes in dual antiplatelet-treated patients after percutaneous coronary intervention (PCI). METHODS AND RESULTS: A total of 491 Han Chinese patients who had received PCI and dual antiplatelet therapy were sequentially recruited to the study and followed for up to one year. Plasma concentrations of five candidate miRNAs early the next morning after PCI were determined by quantitative reverse transcription PCR. The effect of the plasma miRNA level on major adverse cardiovascular events (MACE) within one year and bleeding within six months were assessed. We found that a higher plasma miR 126 level was significantly associated with a higher risk in terms of time-to MACE. When compared with the plasma miR-126 level in the first three quartiles, the hazard ratio (HR) for the plasma miR-126 level in the fourth quartile was 2.61 (95% CI: 1.32-5.18, p=0.006). Multivariable Cox regression analysis showed that diabetes mellitus, ejection fraction, hypertension and a higher plasma miR 126 level were independent risk factors for MACE. Plasma miR-223 level was not an independent predictive marker for MACE. There was no significant association between the level of five plasma miRNAs and bleeding events during six-month follow-up. CONCLUSIONS: Based on these results, we suggest that plasma miR-126 could be a potential marker for predicting major adverse cardiac events in patients after PCI. PMID- 24058073 TI - Optimisation of transcatheter aortic balloon-expandable valve deployment: the two step inflation technique. AB - AIMS: To evaluate the two-step inflation technique aimed at achieving optimal valve implantation depth (defined as 40% of prosthesis height extending below the lower sinus border on angiography) during balloon-expandable transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: Between September 2010 and March 2013, 103 patients (67 females, mean age 80.9+/-5.6 years) were treated with the Edwards SAPIEN XT prosthesis using the two-step inflation technique. Implantation depth was measured on angiography. A historical control group (treated with Edwards SAPIEN) was used for comparison (n=20). Deviation from the defined optimum implantation depth (expressed as a percentage of stent frame height) was significantly less in the study group versus controls (7.0 [3.4-14.1]% vs. 13.9 [5.4-18.9]%; p=0.048). Valve placement was graded "as intended"/"within range"/"out of range" (defined as <=10%, >10% but <=20% and >20% deviation, respectively) in 66%/22%/12% of the study group and 35%/40%/25% of historical controls (p=0.02). Corrections in valve position were made in 20 procedures (20%), resulting in placement as intended in 16 cases (80%), with highest efficacy in the transapical and direct aortic approaches. CONCLUSIONS: The two step inflation technique improves valve placement towards optimal implantation depth and may thereby prevent adverse events due to malpositioning. PMID- 24058074 TI - Current treatment and outcome of coronary in-stent restenosis in Sweden: a report from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). AB - AIMS: The aim of this study was to evaluate treatment of coronary in-stent restenosis (ISR). METHODS AND RESULTS: We investigated interventions for ISR and the occurrence of re-restenosis in the Swedish Angiography and Angioplasty Registry (SCAAR). From January 1st 2005 to March 3rd 2012, 212,166 coronary segments were treated and 7,806 restenoses analysed. During seven years of follow up 1,079 re-restenoses were registered on clinically driven angiography. For BMS ISR the adjusted risk of re-restenosis was significantly lower with DES (adjusted hazard ratio [HR] 0.71, 95% confidence interval [CI]: 0.61-0.82), tended to be lower with DEB (HR 0.84, 95% CI: 0.62-1.16), but higher with BMS (HR 1.24, 95% CI: 1.0-1.55) as compared to balloon angioplasty. For DES-ISR a new DES was associated with a significantly lower adjusted risk of re-restenosis (HR 0.80, 95% CI: 0.66-0.99), and a similar but non-significant reduction with DEB (HR 0.86, 95% CI: 0.57-1.30) and BMS (HR 0.81, 95% CI: 0.53-1.24) compared to balloon angioplasty. For DES-ISR a DES with a different drug was not more effective than a DES with the same drug. CONCLUSIONS: ISR in BMS should be treated with DES or DEB while the optimal treatment of ISR in DES remains to be proven. PMID- 24058075 TI - Three-year clinical results of the Axxess Biolimus A9 eluting bifurcation stent system: the DIVERGE study. AB - AIMS: To report the three-year clinical outcome of the AxxessTM stent, a nitinol self-expanding Biolimus A9TM eluting stent for treatment of de novo coronary bifurcation lesions. The Axxess stent is a new-generation drug-eluting stent that might offer advantages in terms of improved clinical outcomes and safety profile in bifurcation lesion stenting. METHODS AND RESULTS: The DIVERGE study was a multicentre, prospective, single-arm trial. The primary endpoint was the cumulative rate of major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction (MI), and ischaemia-driven target lesion revascularisation (TLR) at one, two and three years. Secondary safety endpoints were cumulative stent thrombosis (ST). A total of 302 patients were included across 14 sites: 77.4% had a true bifurcation lesion, with the left anterior descending/diagonal as target vessel in 80.8%. The Axxess stent was placed in 299 patients (99.0%) and scored as optimal in 93.0%. Two hundred and ninety-eight patients (98.7%) returned for the three-year follow-up. The MACE rate was 9.3% at one year, 14.0% at two years and 16.1% at three years. Individual components at three years were 10.1% for ischaemia-driven TLR, 3.0% for death (2.0% cardiac death), and 7.4% for MI. In the secondary safety endpoint at three years, a total of seven patients (2.3%) had ST with six (2.0%) definite and two (0.7%) probable ST events. CONCLUSIONS: The present large study of the Axxess stent reports a good cumulative MACE rate during three years of long-term follow-up. The Axxess stent offers a promising treatment strategy for bifurcation lesions. PMID- 24058076 TI - No indication for an unexpected high rate of coronary artery aneurysms after angioplasty with drug-coated balloons. AB - AIMS: Coronary artery aneurysms (CAA) are a rare complication after percutaneous coronary intervention (PCI) and are reported with an incidence of 0.6% to 3.9%. While in recent years the use of paclitaxel drug-coated balloons (DCB) has increased, so far no CAA formation after DCB intervention has been reported. METHODS AND RESULTS: During the years 2010 and 2011 we used DCBs in 704 PCIs. Follow-up angiography was scheduled at four months in all patients and has so far been achieved in 380 PCIs. In three patients we found development of a CAA at the former PCI site within four months of observation. Aneurysm length varied between 8.4 mm and 13 mm and lumina increased 58% to 131%. Retrospectively all patients with CAA development showed small intimal dissection partially with tiny persisting contrast bands parallel to the lumen according to type B and type C of the NHLBI classification after PCI. CONCLUSIONS: CAA formation after DCB intervention was found in three out of 380 PCIs with DCB, consistent with an incidence of 0.8%. Thus, PCI with DCB does not cause an unexpectedly high rate of coronary artery aneurysms. PMID- 24058077 TI - Drug-coated balloons for de novo coronary lesions: results from the Valentines II trial. AB - AIMS: This study aimed to evaluate the safety and efficacy of using the second generation DIOR drug-coated balloons (DCB) as an adjunct to plain old balloon angioplasty (POBA) for the treatment of de novo coronary lesions. METHODS AND RESULTS: Valentines II was designed as a prospective, multicentre, multinational, web-based registry. Eligible patients with stable or unstable angina, and/or documented ischaemia on stress testing with de novo lesions of >50% stenosis were prospectively enrolled. Patients underwent POBA followed by DCB treatment. In cases of suboptimal angiographic success (Thrombolysis In Myocardial Infarction [TIMI] flow <3 and/or residual stenosis of >30%), additional bail-out bare metal stenting (BMS) was left at the operator's discretion. The primary endpoint was major adverse cardiac events (MACE; all-cause death, myocardial infarction [MI], target vessel revascularisation [TVR] and vessel thrombosis) at six to nine months. A subset of patients underwent angiographic follow-up. One hundred and nine lesions in 103 patients were treated. Mean age was 62.6+/-10.2 years; 79.6% were men. Lesion stenosis at baseline and post treatment was 83.3+/-9.5% and 10.4+/-10.6%, respectively. Procedural success was 99%. Coronary dissections occurred in 14.7%, and bail-out BMS implantation was required in 13 patients (11.9%). Mean follow-up was 7.5 months; follow-up rate was 99%. Cumulative MACE at follow-up was 8.7%, with 1% all-cause death, 1% MI, 6.9% overall TVR, of which 2.9% were target lesion revascularisations, and no vessel thrombosis. Angiographic follow-up on a subset of patients (n=35) demonstrated late luminal loss of 0.38+/-0.39 mm for both the in-balloon and in-segment analyses. CONCLUSIONS: The Valentines II trial demonstrates the feasibility of using a second-generation DIOR DCB as adjunct to POBA in de novo coronary lesions. This approach achieved high procedural success with acceptable rates of bail-out stenting and low MACE rates at mid-term follow-up, and offers an attractive alternative for revascularisation of patients who are unsuitable candidates for drug-eluting stents. PMID- 24058078 TI - Treatment of small coronary arteries with a paclitaxel-coated balloon catheter in the PEPCAD I study: are lesions clinically stable from 12 to 36 months? AB - AIMS: The one-year outcome of lesions in small coronary arteries by using a paclitaxel-iopromide-coated (3 ug/mm2) balloon catheter (DCB) has yielded good six-month angiographic and one-year clinical data. We now report the three-year clinical follow-up. METHODS AND RESULTS: One hundred and twenty patients with >70% stenoses <22 mm in length in small coronary vessels (vessel diameter: 2.25 2.8 mm) were treated with the DCB. The primary endpoint was angiographic in segment late lumen loss. The secondary endpoints encompassed all other angiographic and clinical data up to three years post intervention. In total 82/120 (68.3%) patients with a vessel diameter of 2.35+/-0.19 mm were treated with the DCB only, and 32/120 (26.7%) patients required additional bare metal stent (BMS) deployment. Both the 12- and 36-month major adverse cardiac event rates were 5/82 (6.1%) for DCB only and 12/32 (37.5%) for DCB+BMS, primarily due to the need for target lesion revascularisation in 4/82 (4.9%) patients and 9/32 (28.1%) (p<0.001) patients, respectively. Total MACE rate after 36 months was 18/120 (15%; intention-to-treat). CONCLUSIONS: Treatment of small vessel coronary artery disease with a paclitaxel-iopromide-coated balloon exhibited good six month angiographic and one-year clinical data that persisted during the three year follow-up period. Randomised trials will clarify its role as an alternative to drug-eluting stents in the treatment of small vessel coronary artery disease. (ClinicalTrials.gov Identifier: NCT00404144). PMID- 24058079 TI - Initial clinical experience with the GORE septal occluder for the treatment of atrial septal defects and patent foramen ovale. AB - AIMS: To describe the initial experience with the GORE(r) septal occluder (GSO), a new septal occluder for the treatment of atrial septal defects (ASD) and patent foramen ovale (PFO). METHODS AND RESULTS: This was a prospective single-centre review of patients undergoing percutaneous closure for a PFO or ASD with the GSO. A clinical evaluation and follow-up echocardiography were performed at three months with transoesophageal echocardiography (TEE) in case of PFO and transthoracic echocardiography (TTE) in ASDs. Between July 2011 and February 2012, thirty-eight patients underwent PFO (n=29) or ASD (n=9) closure with the GSO using TEE (n=36, 94.7%) or intracardiac echocardiography (n=2, 5.3%) guidance. In PFOs, three-month TEE was available in 24 patients and showed no residual shunt in 18 (75%), bubble shunt in two (8.3%) and bubble shunt after Valsalva in four (16.7%). In ASDs, three-month TTE showed no shunt in eight patients (88.8%) and residual shunt in one patient (11.2%). There was no device embolisation, air embolism, procedure-related stroke or pericardial effusion. No neurological events occurred during the follow-up period. CONCLUSIONS: This initial experience with the new GSO device has demonstrated acceptable safety with no procedural complications and acceptable efficacy with low rates of residual shunting at three-month follow-up. PMID- 24058080 TI - Emergency transseptal transcatheter mitral valve-in-valve implantation. AB - AIMS: We report a case of emergency transcatheter heart valve implantation in a failing mitral bioprosthesis via a transseptal access complicated by the atrial migration of a prosthesis. METHODS AND RESULTS: A 42-year-old woman was referred for stenotic failure of a mitral bioprosthesis. A transapical valve-in-valve implantation was initially planned. However, due to sudden haemodynamic deterioration, an emergency transseptal implantation via a femoral venous access was undertaken. Following cardiac arrest, the procedure was performed with extracorporeal membrane oxygenation (ECMO), and was complicated by the migration of a valve, which was left moving freely in the left atrium. A second valve was successfully implanted in the mitral bioprosthesis. Following initial clinical recovery, there was a sudden recurrence of heart failure due to entrapment of the migrated valve in the implanted valve in a "reverse position", which was dislodged percutaneously in an emergency procedure. The valve later migrated into the left atrial appendage. Immediate outcome was uneventful, but the patient suddenly died six months later. CONCLUSIONS: Transseptal transcatheter mitral valve-in-valve implantation is feasible, even in an emergency setting with ECMO. Valve migration in the left atrium may occur and lead to late entrapment in a "reverse position", with significant haemodynamic consequences. PMID- 24058081 TI - Tools and Techniques--Clinical: the transaortic approach through a mini sternotomy using the self-expandable CoreValve Revalving System. PMID- 24058082 TI - How should I treat severe paravalvular leakage after TAVI? PMID- 24058083 TI - A plea for caution: transcatheter aortic valve implantation using the Medtronic CoreValveTM prosthesis without balloon predilatation. PMID- 24058084 TI - In memoriam Professor Gyorgy Adam (1922-2013). PMID- 24058085 TI - Corrected QT interval in white young healthy women: should the norms be updated? AB - The electrocardiographic QT interval duration is a frequently studied ECG parameter. The aim of this study was to compare the quantitative influence of nine QTc formulae and discuss the duration of QT/QTc normal values. The QTc duration was calculated from manually measured QT intervals and heart rate of the Frank XYZ electrocardiograms in 138 white young healthy Slovak women (18-24 years, 690 primary ECG measurements). Dispersion of the QT/QTc interval values was not Gaussian (Shapiro-Wilk test) in most cases. The course of the measured QT regression lines were -1.9186 HR + 511.13 ms or 0.1504RR + 245.72 ms. Median QTc duration in ms was decreasing in this sequence: Bazett 407.04, Fridericia 394.61, Hodges 393.27, Rautaharju and Arrowood 368.79, Framingham-Sagie 368.78, Lecocq 368.70, Sarma 368.66, and Malik 338.70. No QTc value above 440 ms was found after Hodges' correction only. The differences of median QTc values were significant (P < 0.01) in most possible combinations (Kruskal-Wallis test). We recommend using the QTc formula created from observed persons only and updating the QT interval norms. So-called "ideal" QTc models from other not examined persons are methodically incorrect and may produce the misleading results. The frequently used Bazett formula is appropriate for orientation only. PMID- 24058086 TI - Effect of age on the contractile response of the rat carotid artery in the presence of sympathetic drugs and L-NAME. AB - For evaluating the age-related change in noradrenaline (NA)-induced contraction of isolated rat carotid artery (CA), the effect of alpha and beta adrenoreceptor (AR) blockers and the role of nitric oxide (NO) were investigated. METHODS: Concentration-response curves to NA (10-10-10-4 M) and alpha1 agonist phenylephrine (PE; 10-10-10-5 M) were constructed in isolated CA rings from young and middle-aged rats. The effects of nitric oxide synthase (NOS) inhibitor (L NAME; 100 MUM), alpha1-AR antagonist (prazosin; 0.1 MUM), alpha2-AR antagonist (yohimbine; 0.1 MUM) and beta-AR antagonist (propranolol; 1 MUM) on NA-induced contraction of isolated CA rings were examined. In CA rings preconstricted with NA, the responses to alpha2-AR agonist (clonidine; 10-7-10-5 M), beta-AR agonist (isoprenaline; 10-8-10-5 M),), sodium nitroprusside (SNP; 10-9-10-5 M) were assessed. RESULTS: The maximum contractile response of CA to NA and to PE was higher in younger than in middle-aged rats. Prazosin reduced the contractile response to NA in both groups, while propranolol, yohimbine and L-NAME did not affect NA-induced contraction in either of them. Clonidine, isoprenaline and SNP produced a dose-dependent vasorelaxation of CA rings, isoprenaline-induced vasodilatation was lower in middle-aged rats, while there was no difference in clonidine or SNP-induced relaxant effect between the two groups. CONCLUSIONS: NA induced contraction of isolated rat CA rings is decreased in old rats, this is related to alpha1-AR. beta-AR mediated dilatation was compromised in middle-aged rats (endothelium-dependent). alpha2-AR and SNP-mediated dilator effect seems to be unchanged. PMID- 24058087 TI - The effect of Des-Arg9-bradykinin and bradykinin-potentiating peptide C on isolated rat hearts. AB - OBJECTIVES: Des-Arg9-bradykinin and bradykinin-potentiating peptide C (BPPC) may contribute to the regulation of cardiovascular function. Therefore, we studied effects of these peptides on coronary perfusion pressure (CPP), heart rate, left ventricular developed pressure (LVDP) and maximum rate of increase of left ventricular pressure (+dP/dtmax). METHODS: The isolated rat hearts were perfused with modified Krebs-Henseleit solution. RESULTS: Infusion of 10, 100 and 1000 nM Des-Arg9-bradykinin decreased CPP (-13.6, -14.8 and -19.0%), LVDP (-16.5, -21.0 and -30.7%) and +dP/dtmax (-11.8, -17.8 and -23.7%), respectively (p < 0.001). Ten or 100 nM Des-Arg9-bradykinin did not alter heart rate, but 1000 nM increased it (+11.3%, p < 0.01). One, 10 and 100 nM BBPC reduced CPP (-16.3, -28.5 and 47.5%), LVDP (-12.6, -19.6 and -21.3%) and +dP/dtmax (-8.7, -18.6 and -20.3%), respectively (p < 0.001). BPPC increased heart rate at 1 nM (+9.6%, p < 0.05 ) and at 10 nM (+14.2%, p < 0.01), however 100 nM decreased it (-15.3%, p < 0.001). CONCLUSIONS: This study evidences that Des-Arg9-bradykinin and BPPC possess vasodilatory effect with modest negative inotropic action. Furthermore, high-dose of Des-Arg9-bradykinin and low-dose of BPPC may produce a tachycardic action, but high dose of BBPC may cause a bradycardic action. PMID- 24058088 TI - Performance enhancing genetic variants, oxygen uptake, heart rate, blood pressure and body mass index of elite high altitude mountaineers. AB - AIM: To analyse and compare the ACE (angiotensin-converting enzyme), ACTN3 (actinin-3) and AMPD1 (adenosine monophosphate deaminase 1) genetic variants, oxygen uptake (VO2max), heart rate (HR), blood pressure (BP) and body mass index (BMI) of elite high altitude mountaineers and average athletes. METHODS: Elite Bulgarian alpinists (n = 5) and control group of athletes (n = 72) were recruited. VO2max was measured using a treadmill graded protocol. HR, BP and BMI were recorded. Genotyping was done by polymerase chain reaction (PCR) amplification followed by agarose gel electrophoresis. Chi2-test and Fisher's exact test were used for statistical analysis. RESULTS: Alpinists showed significantly higher frequencies of 60% ACE I allele (p = 0.002), 50% ACTN3 X allele (p = 0.032) and 30% AMPD1 T allele (p = 0.003) compared to controls - 39%, 36%, 13%, respectively. ACE ID genotype prevalence and null DD genotype were observed in mountaineers. Higher absolute VO2max, but no differences in VO2max ml kg-1 min-1, HR, oxygen pulse, blood pressure and BMI were found. CONCLUSIONS: The ID genotype and higher frequencies of ACE I allele could contribute to successful high altitude ascents in mountaineers. The genetic make-up of the two mountaineers who made the summit of Mt Everest was distinctive, revealing ACE ID genotype, mutant ACTN3 XX and AMPD1 TT genotypes. PMID- 24058089 TI - Postprandial effects of two Chinese liquors on selected cardiovascular disease risk factors in young men. AB - The aim of this study was to investigate postprandial effects of two Chinese liquors on s elected cardiovascular disease risk factors in humans. Sixteen healthy men were randomized into three groups in a three-way crossover study: tea flavor liquor (TFL), traditional Chinese liquor (TCL) and water control (WC). Every subject consumed 60 mL of either liquor (45% (v/v) ethanol) or water together with a high-fat meal, respectively. Compared with baseline, serum uric acid was significantly increased in TFL group (0.5-hour: P = 0.012; 1-hour: P = 0.001; 2-hour: P = 0.008) and it was significantly decreased in WC group (1-hour: P = 0.001; 2-hour: P = 0.001; 4-hour: P < 0.001), while uric acid was non significantly increased in the TCL group. High-sensitive C-reactive protein (hs CRP) was significantly increased in the TCL (P = 0.014) and WC (P = 0.008) groups at postprandial 4 hours compared with baseline. There was no significant difference between groups during the postprandial period for these two parameters or other biochemical parameters. In conclusion, both liquors increased postprandial uric acid, and no significant difference was observed for the effects of TFL and TCL on the measured biochemical parameters. PMID- 24058090 TI - Running economy and body composition between competitive and recreational level distance runners. AB - The aim of the present study was to compare running economy between competitive and recreational level athletes at their individual ventilatory thresholds on track and to compare body composition parameters that are related to the individual running economy measured on track. We performed a cross-sectional analysis of a total 45 male runners classified as competitive runners (CR; n = 28) and recreational runners (RR; n = 17). All runners performed an incremental test on treadmill until voluntary exhaustion and at least 48 h later a 2 * 2000 m test at indoor track with intensities according to ventilatory threshold 1, ventilator threshold 2. During the running tests, athletes wore portable oxygen analyzer. Body composition was measured with Dual energy X-ray absorptiometry (DXA) method. Running economy at the first ventilatory threshold was not significantly related to any of the measured body composition values or leg mass ratios either in the competitive or in the recreational runners group. This study showed that there was no difference in the running economy between distance runners with different performance level when running on track, while there was a difference in the second ventilatory threshold speed in different groups of distance runners. Differences in running economy between competitive and recreational athletes cannot be explained by body composition and/or different leg mass ratios. PMID- 24058091 TI - Comparison of physiological and acid-base balance response during uphill, level and downhill running performed at constant velocity. AB - The purpose of this study was to compare the physiological and the acid-base balance response to running at various slope angles. Ten healthy men 22.3 +/- 1.56 years old participated in the study. The study consisted of completing the graded test until exhaustion and three 45-minute runs. For the first 30 minutes, runs were performed with an intensity of approximately 50% VO2max, while in the final 15 minutes the slope angle of treadmill was adjusted (0 degrees ; +4.5 degrees ; -4.5 degrees ), and a fixed velocity of running was maintained. During concentric exercise, a significant increase in the levels of physiological indicators was reported; during eccentric exercise, a significant decrease in the level of the analyzed indicators was observed. Level running did not cause significant changes in the indicators of acid-base balance. The indicators of acid-base balance changed significantly in the case of concentric muscle work (in comparison to level running) and after the eccentric work, significant and beneficial changes were observed in most of the biochemical indicators. The downhill run can be used for a partial regeneration of the body during exercise, because during this kind of effort an improvement of running economy was observed, and this type of effort did not impair the acid-base balance of body. PMID- 24058092 TI - Concentric and eccentric: muscle contraction or exercise? PMID- 24058093 TI - Comment to the "letter to the editor-concentric and eccentric: muscle contraction or exercise?" : types of muscle contractions and exercises: what is the proper terminology? PMID- 24058094 TI - Visual Reaction TimeTM as a predictor of sexual offense recidivism. AB - In this study, we investigated the use of Visual Reaction TimeTM (VRTTM) for sexual interest in children to predict recidivism of sexual offenses among men who sexually abused children and men with other sexually deviant behaviors. The authors hypothesized that study participants with a higher VRTTM to stimuli of children would be more likely to sexually reoffend compared with those with a lower VRTTM to stimuli of children. Participants included 621 adult males on parole or probation for acting on a range of sexual paraphilias who sought outpatient treatment or evaluation at two separate therapists' practices. Sample 1 consisted of 284 adult males followed up (by the lead author) during a 15-year period, while Sample 2 consisted of 337 adult males followed up (by the second author) during a 7-year period. A discrete-time hazard model found VRTTM to children to be significantly related to sexual recidivism. The researchers found that VRTTM to children measured at intake held up in its predictive ability over a 15-year period. When the participants were divided into three groups based on their VRTTM, of the 97 participants who measured at least one standard deviation lower than the mean VRTTM, 0% reoffended. The 432 participants in the medium VRTTM group had an estimated recidivism rate of 7% after 15 years and the 92 participants who measured at least one standard deviation higher than the mean had an estimated recidivism rate of 27%. PMID- 24058095 TI - The impact of saddle embolism on the major adverse event rate of patients with non-high-risk pulmonary embolism. AB - OBJECTIVE: Wider application of CT angiography (CTA) improves the diagnosis of acute pulmonary embolism (PE). It also permits the visualisation of saddle embolism (SE), namely thrombi, which are located at the bifurcation of the main pulmonary artery. The aim of this study was to assess the prevalence of SE and whether SE predicts a complicated clinical course in patients with non-high-risk PE. METHODS: In total, 297 consecutive patients with non-high-risk PE confirmed using CTA in the emergency department were studied. The presence of SE and its ability to predict the occurrence of major adverse events (MAEs) within 1 month were determined. RESULTS: Of the 297 patients, 27 (9.1%) had an SE. The overall mortality at 1 month was 12.5%; no significant difference was observed between the SE and non-SE groups (18.5% vs 11.9%, p=0.32). However, patients with SE were more likely to receive thrombolytic therapy (29.6% vs 8.1%, p<0.01) and had significantly more MAEs (59.3% vs 25.6%, p<0.01). CONCLUSION: At the time of diagnosis, SE, as determined using CTA, is associated with the development of MAE within 1 month. It may be a simple method for risk stratification of patients with non-high-risk PE. ADVANCES IN KNOWLEDGE: The prognosis of patients with SE, especially those who are haemodynamically stable, is unclear. This study shows that patients with SE, determined with CTA, is associated with the development of MAE. PMID- 24058096 TI - [Editor's commentary: Clinical use of somatostatin]. PMID- 24058097 TI - [Drug therapy for acromegaly]. AB - Prolonged overproduction of growth hormone, like insulin-like growth factor-1 hypersecretion leads to acromegaly in adults. This is associated with several co morbidities and increased mortality. Despite typical clinical features and modern diagnostic tools, it often takes years to diagnose from the onset of the disease. The aims of the treatment are to reduce or control tumour growth, inhibit growth hormone hypersecretion, normalize insulin-like growth factor-1 levels, treat co morbidities and, therefore, reduce mortality. There are three approaches for therapy: surgery, medical management (dopamine agonists, somatostatin analogues and growth hormone receptor antagonist), and radiotherapy. Efficient therapy of the disease is based on the appropriate multidisciplinary team management. The review provides a summary of medical treatment for acromegaly. PMID- 24058098 TI - [Somatostatin and the digestive system. Clinical experiences]. AB - The effect of somatostatin on the gastrointestinal tract is complex; it inhibits the release of gastrointestinal hormones, the exocrine function of the stomach, pancreas and bile, decreases motility and influences absorption as well. Based on these diverse effects there was an increased expectation towards the success of somatostatin therapy in various gastrointestinal disorders. The preconditions for somatostatin treatment was created by the development of long acting somatostatin analogues (octreotide, lanreotide). During the last twenty-five years large trials clarified the role of somatostatin analogues in the treatment of various gastrointestinal diseases. This study summarizes shortly these results. Somatostatin analogue treatment could be effective in various pathological conditions of the gastrointestinal tract, however, this therapeutic modality became a part of the clinical routine only in neuroendocrine tumours and adjuvant treatment of oesophageal variceal bleeding and pancreatic fistulas. PMID- 24058099 TI - [Genetics of neuroendocrine tumours, hereditary tumour syndromes]. AB - Neuroendocrine tumours occur in some hereditary tumour syndromes, and the molecular pathophysiological mechanisms involved in these are also important in their sporadic counterparts which representing the majority of neuroendocrine tumours. These syndromes include multiple endocrine neoplasia type 1, von Hippel Lindau syndrome, neurofibromatosis type 1 and tuberous sclerosis. All these follow an autosomal dominant inheritance. The primarily affected molecular pathways are Ras-MAPK signalling, hypoxia induced factor 1alpha, and mTOR signalling that are also involved in sporadic tumours and may even represent potential molecular targets of therapy. In this review, the major characteristics of hereditary tumour syndromes, their molecular genetics and the pathophysiological mechanisms involved in sporadic tumours are discussed. PMID- 24058100 TI - [Diagnosis and treatment options of neuroendocrine tumours]. AB - Neuroendocrine neoplasms belong to the group of rare tumours. Their clinical importance may be highlighted by their high prevalence despite low incidence. Since survival rate is similar to other progressive neoplastic diseases in metastatic cases, early recognition and appropriate therapy of these neoplasms are equally important. Classification of neuroendocrine tumours is based on their pathologic characteristics according to the 2010 WHO recommendation. Non functioning tumours cause local symptoms due to their mass effect, while functioning tumours produce well-defined endocrine syndromes. Among laboratory tests, serum chromogranin-A is considered the most important biomarker of both non-functioning and functioning neuroendocrine tumours. Localization of these tumours includes the use of conventional diagnostic imaging, endoscopic examinations, and functional imaging studies. With respect to treatment, elimination of the primary tumour remains one of the most important issues. In advanced cases of the disease metastasectomy, interventional radiologic methods, medical treatment and endoradiotherapy can be used. The aim of this review is to summarize briefly the symptoms, diagnostic methods and treatment options of neuroendocrine tumours. PMID- 24058101 TI - [Drug therapy for neuroendocrine tumours]. AB - The author aims to review the established medical treatment options of neuroendocrine tumours, which have expanded greatly in recent years and present the most important aspects to be considered in planning patients' management. Medical treatment is usually considered in advanced stages of these tumours, as well as in cases of hormone overproduction. Somatostatin analogues have been known to be effective in alleviating hormone excess syndromes, especially carcinoid syndrome for the past 25 years. There is a convincing evidence that the somatostatin analogue octreotide is useful as an antitumor agent, at least in well-differentiated small intestinal neuroendocrine tumours and probably also in those of pancreatic origin. Interferons may be also used and the indications for their use may be almost the same. Optimal patient selection is mandatory for the use of cytotoxic chemotherapy. Streptozotocin- and, recently, temozolomide-based chemotherapies should be considered in progressive phases of well differentiated (G1/G2) pancreatic neuroendocrine tumours. A cisplatin-etoposide combination is the first choice for the treatment of G3 neuroendocrine carcinomas of any origin. Recently, the mammalian target of rapamycin inhibitor everolimus and the combined tyrosine kinase inhibitor sunitinib were registered for the treatment of G1/G2 pancreatic neuroendocrine tumours. The most recent drug treatment recommendations and therapeutic algorithms to improve systemic therapy in patients with neuroendocrine tumours are summarized and novel drug candidates with particular potential for future management of these tumours are outlined. PMID- 24058102 TI - [New considerations in the surgical treatment of pancreatic neuroendocrine tumours]. AB - Except insulinomas, pancreatic neuroendocrine tumours are malignant in more than 50% of cases. Treatment of these tumours should be directed against the tumours and the excess of hormones produced by the tumours. Surgical treatment may reduce the mortality and morbidity of patients and, in case of localized lesions, may result in a definitive cure. The aim of this review is to summarize novel developments in the surgical treatment of pancreatic neuroendocrine tumours, including those related to metastatic diseases and MEN1 syndrome. PMID- 24058104 TI - A socio-psychological perspective on community participation in health during the Unidad Popular government: Santiago de Chile, from 1970 to 1973. AB - Community participation in health has conventionally been described and analysed from a non-historical perspective, neglecting the central role that disadvantaged communities have played in the construction of health institutions in our societies, alienating collective health from its historical subject. From a socio psychological perspective, this study explores the experiences of community participation in health during the Unidad Popular government in Santiago de Chile from 1970 to 1973, evidencing a radical pedagogical process inside poor urban settlements, aimed to transform Chilean classist health institutions. These findings contribute to a critical understanding of community participation in health, conceived as a dialectic and transformative action. PMID- 24058103 TI - The Functional Well-Being Scale: a measure of functioning loss due to well-being related barriers. AB - The objective of this study was to develop the Pro-Change Functional Well-Being Scale, a measure that provides an informative evaluation of general functioning loss due to well-being-related barriers. Exploratory and confirmatory analyses on data from 642 individuals supported a one-factor solution with good model fit. A strong positive correlation existed between the Pro-Change Functional Well-Being Scale and Well-Being Assessment for Productivity. Initial construct validity was demonstrated by predictable relationships between functioning loss and other measures of health and well-being. This initial psychometric evidence suggests that the Pro-Change Functional Well-Being Scale is a reliable and valid assessment of functioning loss due to common well-being-related barriers. PMID- 24058105 TI - HIV/AIDS, beersellers and critical community health psychology in Cambodia: a case study. AB - This case study illustrates a participatory framework for confronting critical community health issues using 'grass-roots' research-guided community-defined interventions. Ongoing work in Cambodia has culturally adapted research, theory and practice for particular, local health-promotion responses to HIV/AIDS, alcohol abuse and other challenges in the community of Siem Reap. For resource poor communities in Cambodia, we recycle such 'older' concepts as 'empowerment' and 'action research'. We re-imagine community health psychology, when confronted with 'critical', life-and-death issues, as adjusting its research and practices to local, particular ontological and epistemological urgencies of trauma, morbidity and mortality. PMID- 24058106 TI - Moving images: psychoanalytically informed visual methods in documenting the lives of women migrants and asylum seekers. AB - While feminist arts-based projects have gained legitimacy, theory guiding the use of visual images in field research has lagged. Drawing on psychoanalytic-feminist theory and participatory action research methods, the article presents a study carried out with women refugee and asylum seekers that focuses on their experiences in seeking a place of safety in the United Kingdom. The aim was to produce through photography and videography a collective account of asylum as a daily process. In discussing the study, the authors provide a psychoanalytic framework for working through ethical, political, and methodological dilemmas in the use of visual imagery in feminist research. PMID- 24058107 TI - Patient neglect in 21st century health-care institutions: a community health psychology perspective. AB - Despite the technological and organisational advances of 21st century health-care systems, care scandals and burgeoning complaints from patients have raised concerns about patient neglect in hospitals. This article reviews the concept of patient neglect and the role of community health psychology in understanding its occurrence. Patient neglect has previously been conceptualised as a problem associated with hospital staff attitudes and behaviours, with regulation and training cited as solutions. Yet, a community health psychology perspective shows that the wider symbolic, material and relational aspects of care are crucial for understanding why patient neglect occurs and for outlining new solutions to augment existing interventions. PMID- 24058108 TI - Beyond ideal speech situations: adapting to communication asymmetries in health care. AB - Inclusive, unconstrained and honest communication is widely advocated as beneficial and ethical. We critically explore this assumption by reflecting upon our research in acute care, informal care and public health. Using Habermas' ideals of dialogue to conceptualise ideal speech, we concur with observations that health care is often characterised by intractable exclusions and constraints. Rather than advocating implementing the ideals of dialogue, however, we examine how people adapt to these difficult and intransigent contexts. Non ideal contexts, we find, sometimes call for non-ideal responses. Deception and furthering personal interests, and thus departing from the ideals of dialogue, can be adaptive responses. PMID- 24058109 TI - Risky eating behaviors and beliefs among adolescent girls. AB - This study investigated the prevalence of weight control and binge eating behaviors in a sample of 767 adolescent girls aged 16-20 years, and the differences between adolescents with and without altered eating behaviors regarding anthropometric and body image variables and beliefs associated with eating disorders. Adolescents who engaged in unhealthy strategies were found to be at a higher risk of eating disorders, since these behaviors were accompanied by higher levels of drive for thinness and body dissatisfaction, as well as by beliefs associated with the importance of weight and body shape as a means of personal and social acceptance. PMID- 24058110 TI - Participatory research with youth: idealising safe social spaces or building transformative links in difficult environments? AB - Freire's theory of social change informs analysis of youth-focused participatory research, with researchers describing links between participation and young people's critical thinking. There is less analysis of how youth move from the safe social space of a participatory research project to take health-promoting action in difficult real-world contexts. This article analyses a project conducted with Papua New Guinean youth, disrupting assumptions that critical thinking inevitably leads to critical action on health. Findings suggest the need to shift the focus of participatory research from supporting 'safe social spaces' to supporting 'transformative action in context' to concretely contribute to improving youth health. PMID- 24058111 TI - Community organizing practices in a globalizing era: building power for health equity at the community level. AB - In the postindustrial era, global economic processes have constrained the ability of local agencies, service providers, and civic groups to respond to systemic challenges in public health. Community health psychology can benefit by focusing on interventions through mediating structures that develop innovative methods of leveraging power in the context of globalizing economic forces. Promising methods include careful analysis of power within targeted policy domains and developing strategic alliances with others, so as to exercise social power to affect policy change. The case of ISAIAH, an organizing group based in Minnesota, illustrates innovative avenues for intervention in the context of globalization. PMID- 24058112 TI - Looking within and beyond the community: lessons learned by researching, theorising and acting to address urban poverty and health. AB - Urban poverty and health inequalities are inextricably intertwined. By working in partnership with service providers and communities to address urban poverty, we can enhance the wellness of people in need. This article reflects on lessons learned from the Family100 project that explores the everyday lives, frustrations and dilemmas faced by 100 families living in poverty in Auckland. Lessons learned support the need to bring the experiences and lived realities of families to the fore in public deliberations about community and societal responses to urban poverty and health inequality. PMID- 24058113 TI - Short health anxiety inventory: factor structure and psychometric properties in Spanish adolescents. AB - The Short Health Anxiety Inventory is a common screening tool for assessing health anxiety among adolescents; however, its psychometric properties and internal structure have not been evaluated within a Spanish-speaking population. The goodness of fit of four models of the latent structure of the Short Health Anxiety Inventory was tested by using confirmatory factor analysis in a sample of 832 Spanish secondary school adolescents. Based on these results, the reliability of the original two-factor model was tested. Differences in health anxiety by gender and age were also examined. The results support use of the Spanish version of the Short Health Anxiety Inventory by researchers and clinicians among Spanish adolescents. PMID- 24058114 TI - Challenging empowerment: AIDS-affected South African children and the need for a multi-level relational approach. AB - Critics of empowerment have highlighted the concept's mutability, focus on individual transformation, one-dimensionality and challenges of operationalisation. Relating these critiques to children's empowerment raises new challenges. Drawing on scholarship on children's subjecthood and exercise of power, alongside empirical research with children affected by AIDS, I argue that empowerment envisaged as individual self-transformation and increased capacity to act independently offers little basis for progressive change. Rather it is essential to adopt a relational approach that recognises the need to transform power relationships at multiple levels. This analysis has implications for our wider understanding of empowerment in the 21st century. PMID- 24058115 TI - The relationship between transformational teaching and adolescent physical activity: the mediating roles of personal and relational efficacy beliefs. AB - The purpose of this study was to examine the extent to which transformational teaching, exhibited by secondary school physical education teachers, predicts within-class physical activity and leisure-time physical activity among adolescents. The study used a prospective observational design and involved data collected from 874 Grade 10 adolescents (M age = 15.41, (SD) = .61). Through use of structural equation modeling, the results revealed that adolescents' perceptions of transformational teaching were positively related to within-class physical activity and leisure-time physical activity, and these effects were mediated by adolescents' estimation of their teacher's confidence in their abilities (i.e. relation-inferred self-efficacy) and self-efficacy beliefs. PMID- 24058116 TI - Being healthy in unhealthy places: health tactics in a homeless lifeworld. AB - Street life can compromise a person's health. In response, homeless people exert considerable agency in attempts to preserve their health. Drawing on ethnographic research in central Auckland, this article explores the ways in which a homeless man maintains his health. We consider the tactics Clinton develops to maintain his health and to gain respite while living on the streets, an unhealthy place. Of particular note are the ways in which he works to transform a 'landscape of despair' into a 'landscape of care'. The case of Clinton foregrounds the fundamentally emplaced and relational nature of homeless peoples' health. PMID- 24058117 TI - Measuring Illness beliefs in neurodegenerative disease: why we need to be specific. AB - Positive perceptions of illness are typically associated with good health outcomes. However, this may not be true for all domains of illness perception in neurodegenerative diseases because of their progressive incurable nature. The appropriateness of current measures of illness belief in these conditions is not known. The validity and reliability of the Illness Perception Questionnaire Revised was evaluated in 215 participants with Parkinson's disease. A confirmatory factor analysis supported the structure of the Illness Perception Questionnaire-Revised with the exception of the treatment control domain. It is important to consider the nature of neurodegenerative diseases and limits of symptom control when planning interventions. PMID- 24058118 TI - Theorising beyond the individual: adherence to antiretroviral therapy in resource constrained societies. AB - Adherence to antiretroviral therapy, while often conceptualised as an individual or community-level concern, needs to be understood in the context of political and historical developments that have characterised many resource-constrained societies. This article identifies some of these dimensions of antiretroviral therapy adherence in South Africa and outlines the implications for community health psychology in taking this perspective. Using the conceptual apparatus of therapeutic citizenship, we demonstrate the importance of historical, political and other structural barriers to adherence. We conclude by examining the implications of these debates for community health psychology that go beyond the individual as the unit of intervention and analysis. PMID- 24058119 TI - The role of schools in promoting inclusive communities in contexts of diversity. AB - Against the background of evidence for links between ill-health and prejudice, in this article we discuss how to promote inclusive communities in contexts of diversity. A brief critical overview of dominant psychological approaches to prejudice reduction reveals the apolitical nature of these approaches, and thus, we argue for a more contextual and political model on how to promote inclusive communities. Drawing on examples of different school practices on cultural diversity from across England, we argue that we need to develop a perspective that connects local contexts of everyday practice, resistance and agency to the institutional and structural realities of prejudice. PMID- 24058120 TI - Patient and public involvement in health research: ethical imperative and/or radical challenge? AB - Patient and public involvement in health research, including mental health research, is promoted by research funders in England. However, it is poorly conceptualised. One argument is that patient and public involvement in research is an ethical imperative because those who research is for should have a stake in how it is done. This could be developed through concepts of citizenship and democratic science. More strongly, it can be argued that changing the knowledge producers will change knowledge itself. Starting with feminist standpoint epistemology, it is argued that a political conceptualisation best captures the new knowledge that marginalised health groups can produce. PMID- 24058121 TI - Factorial invariance of pregnancy-specific anxiety dimensions across nulliparous and parous pregnant women. AB - The 10-item version of the Pregnancy-Related Anxiety Questionnaire-Revised was developed based on a sample of nulliparous women. Whether this measure is also a valuable tool for future research on pregnancy-specific anxiety is unclear. Our study tested for invariance of this measure across nulliparous women and parous women by using a dataset of 6004 women pregnant up to 35 weeks. Results showed that whereas the factor structure of the 10-item version of the Pregnancy-Related Anxiety Questionnaire-Revised was noninvariant, removing item 8 from the measure created a measure with invariant factor loadings that can be used for all pregnant women. PMID- 24058122 TI - Effects of self-construal and its relationship with subjective well-being across cultures. AB - The purpose of this study is to test cross-cultural predictions of the associations between goal pursuits and subjective well-being among 601 college students (200 in Japan and 401 in the United States). The results indicated that interdependence in all cultures was associated with socially oriented subjective well-being. In the United States, it was also correlated with social goal pursuit. However, independence in the United States correlated with individual oriented subjective well-being, while in Hawaii, it also correlated with hedonic goal pursuit. Discussion of these results and their implications are provided. PMID- 24058123 TI - A queer-theoretical approach to community health psychology. AB - Queer-theoretical resources offer ways of productively rethinking how central concepts such as 'person-context', 'identity' and 'difference' may be understood for community health psychologists. This would require going beyond consideration of the problems with which queer theory is popularly associated to cautiously engage with the aspects of this work relevant to the promotion of collective practice and engaging with processes of marginalisation. In this article, we will draw upon and illustrate the queer-theoretical concepts of 'performativity' and 'cultural intelligibility' before moving towards a preliminary mapping of what a queer-informed approach to community health psychology might involve. PMID- 24058124 TI - Understanding medical students' views of chronic fatigue syndrome: a qualitative study. AB - Chronic fatigue syndrome receives little attention in the medical curriculum. This study explores UK medical students' knowledge of and attitudes towards chronic fatigue syndrome. Semi-structured interviews (average length 22 minutes) were conducted with 21 participants (7 females and 14 males) in years 3 (n = 4), 4 (n = 11) and 5 (n = 6) of their studies. Inductive thematic analysis taking a realist perspective produced three themes: limited knowledge, influences on attitudes and training needs. Students acquired their knowledge and attitudes largely from informal sources and expressed difficulty understanding chronic fatigue syndrome within a traditional biomedical framework. Incorporating teaching about chronic fatigue syndrome into the medical curriculum within the context of a biopsychosocial understanding of illness could encourage more positive attitudes towards chronic fatigue syndrome. PMID- 24058125 TI - Secondary traumatization and self-rated health among wives of former prisoners of war: the moderating role of marital adjustment. AB - We investigated the relationships between secondary traumatization, marital adjustment, and self-rated health among wives of former prisoners of war. Participants were Israeli wives of former prisoners of war (N = 116) and a matched control group of wives of combat veterans (N = 56). Wives of former prisoners of war reported worse self-rated health compared to the control group of wives of combat veterans. Wives of former prisoners of war also reported higher levels of secondary traumatization, and marital adjustment moderated the relationship between wives' secondary traumatization and their general health. The experience of living with former prisoners of war who might also suffer from posttraumatic stress disorder is associated with wives' own psychological and self-rated health outcomes. PMID- 24058126 TI - Psychosocial functioning in adults with beta-thalassaemia major: evidence for resilience. AB - Our aims were to compare the psychosocial functioning of a sample of adults with beta-thalassaemia major to that of a control sample and to examine the protective role of quality of relationship with parents during adolescence and perceived quality of care. A total of 85 Italian beta-thalassaemia major participants and 73 controls completed an ad hoc questionnaire. Compared with controls, beta thalassaemia major participants did not differ on relationships with significant others and coping strategies. Beta-thalassaemia major participants reported higher scores on job satisfaction, self-esteem and self-description. The relationship with parents during adolescence and the perceived quality of care significantly predicted higher well-being and psychosocial functioning. PMID- 24058127 TI - Barriers to and acceptability of provider-initiated HIV testing and counselling and adopting HIV-prevention behaviours in rural Uganda: a qualitative study. AB - In Uganda, a nationwide scale-up of provider-initiated HIV testing and counselling presents an opportunity to deliver HIV-prevention services to large numbers of people. In a rural Ugandan hospital, focus group discussions and key informant interviews were conducted with outpatients receiving provider-initiated HIV testing and counselling and staff to explore the HIV-prevention information, motivation and behavioural skills strengths and weaknesses, and community-level and structural barriers to provider-initiated HIV testing and counselling acceptability and HIV prevention among this population. Strengths and weakness occurred at all levels, and results suggest brief client-centred interventions during provider-initiated HIV testing and counselling may be an effective approach to increase prevention behaviours in outpatient settings. PMID- 24058128 TI - Media exposure and smoking intention in adolescents: a moderated mediation analysis from a cultivation perspective. AB - The study tested a moderated mediation model to examine the mechanisms underlying the link between media exposure and adolescent smoking intention by utilizing a modification of cultivation theory. A total of 12,586 non-current smoker adolescents in California were included in the analysis. Results showed that media exposure was positively related to smoking intention via perceived prevalence of peer smoking when friend disapproval of cigarette use was low. This study contributes to a better understanding of the mechanisms regarding the media effects on smoking intention, but the findings should be interpreted with caution due to the small effect size. PMID- 24058130 TI - The TFOS International Workshop on Contact Lens Discomfort: report of the subcommittee on epidemiology. PMID- 24058131 TI - The TFOS International Workshop on Contact Lens Discomfort: report of the management and therapy subcommittee. PMID- 24058133 TI - The TFOS International Workshop on Contact Lens Discomfort: report of the contact lens interactions with the ocular surface and adnexa subcommittee. PMID- 24058132 TI - The TFOS International Workshop on Contact Lens Discomfort: report of the subcommittee on clinical trial design and outcomes. PMID- 24058134 TI - The TFOS International Workshop on Contact Lens Discomfort: report of the definition and classification subcommittee. PMID- 24058135 TI - The TFOS International Workshop on Contact Lens Discomfort: executive summary. PMID- 24058136 TI - The TFOS International Workshop on Contact Lens Discomfort: introduction. PMID- 24058138 TI - The TFOS International Workshop on Contact Lens Discomfort: report of the contact lens materials, design, and care subcommittee. PMID- 24058139 TI - The TFOS International Workshop on Contact Lens Discomfort: report of the contact lens interactions with the tear film subcommittee. PMID- 24058140 TI - Photo quiz: young girl with cough, headache, and visual loss. PMID- 24058143 TI - Did greater burial depth increase the seed size of domesticated legumes? AB - The independent domestication of crop plants in several regions of the world formed the basis of human civilizations, and attracts considerable interest from archaeologists and biologists. Selection under cultivation led to a suite of domestication traits which distinguish crops from their wild progenitors, including larger seeds in most seed crops. This selection may be classified as 'conscious' or 'unconscious' selection according to whether humans were aware of the changes that they were driving. The hypothesis that human cultivation buried seeds deeper than natural dispersal, exerting unconscious selection favouring larger seeds with greater reserves, was tested. Using a comparative approach, accessions of eight grain legumes, originating from independent domestication centres across several continents, were sampled. Seeds were planted at different depths in a controlled environment, and seedling emergence scored for 5 weeks after sowing. Domestication in all species was associated with increased seed mass. In three species, greater mass was not correlated with increased ability to emerge from depth. In five species, emergence depth did correlate with mass, suggesting that selection during domestication may have acted on emergence depth. However, domestication only had a significant effect in two of these species (lentil and mung bean), and the increase in depth was no more than predicted by a cube-root allometric relationship with seed mass. The results do not support the hypothesis that burial under cultivation was a general selection mechanism for increased seed mass during the domestication of grain legumes, but it may have acted in particular species or regions. PMID- 24058145 TI - Cell wall polysaccharides are mislocalized to the Vacuole in echidna mutants. AB - During cell wall biosynthesis, the Golgi apparatus is the platform for cell wall matrix biosynthesis and the site of packaging, of both matrix polysaccharides and proteins, into secretory vesicles with the correct targeting information. The objective of this study was to dissect the post-Golgi trafficking of cell wall polysaccharides using echidna as a vesicle traffic mutant of Arabidopsis thaliana and the pectin-secreting cells of the seed coat as a model system. ECHIDNA encodes a trans-Golgi network (TGN)-localized protein, which was previously shown to be required for proper structure and function of the secretory pathway. In echidna mutants, some cell wall matrix polysaccharides accumulate inside cells, rather than being secreted to the apoplast. In this study, live cell imaging of fluorescent protein markers as well as transmission electron microscopy (TEM)/immunoTEM of cryofixed seed coat cells were used to examine the consequences of TGN disorganization in echidna mutants under conditions of high polysaccharide production and secretion. While in wild-type seed coat cells, pectin is secreted to the apical surface, in echidna, polysaccharides accumulate in post-Golgi vesicles, the central lytic vacuole and endoplasmic reticulum derived bodies. In contrast, proteins were partially mistargeted to internal multilamellar membranes in echidna. These results suggest that while secretion of both cell wall polysaccharides and proteins at the TGN requires ECHIDNA, different vesicle trafficking components may mediate downstream events in their secretion from the TGN. PMID- 24058146 TI - Cell type-specific transcriptome of Brassicaceae stigmatic papilla cells from a combination of laser microdissection and RNA sequencing. AB - Pollination is an early and critical step in plant reproduction, leading to successful fertilization. It consists of many sequential processes, including adhesion of pollen grains onto the surface of stigmatic papilla cells, foot formation to strengthen pollen-stigma interaction, pollen hydration and germination, and pollen tube elongation and penetration. We have focused on an examination of the expressed genes in papilla cells, to increase understanding of the molecular systems of pollination. From three representative species of Brassicaceae (Arabidopsis thaliana, A. halleri and Brassica rapa), stigmatic papilla cells were isolated precisely by laser microdissection, and cell type specific gene expression in papilla cells was determined by RNA sequencing. As a result, 17,240, 19,260 and 21,026 unigenes were defined in papilla cells of A. thaliana, A. halleri and B. rapa, respectively, and, among these, 12,311 genes were common to all three species. Among the17,240 genes predicted in A. thaliana, one-third were papilla specific while approximately half of the genes were detected in all tissues examined. Bioinformatics analysis revealed that genes related to a wide range of reproduction and development functions are expressed in papilla cells, particularly metabolism, transcription and membrane-mediated information exchange. These results reflect the conserved features of general cellular function and also the specific reproductive role of papilla cells, highlighting a complex cellular system regulated by a diverse range of molecules in these cells. This study provides fundamental biological knowledge to dissect the molecular mechanisms of pollination in papilla cells and will shed light on our understanding of plant reproduction mechanisms. PMID- 24058147 TI - Two DYW subclass PPR proteins are involved in RNA editing of ccmFc and atp9 transcripts in the moss Physcomitrella patens: first complete set of PPR editing factors in plant mitochondria. AB - The moss Physcomitrella patens has 11 RNA editing sites in mitochondrial transcripts. We previously identified six DYW subclass pentatricopeptide repeat (PPR) proteins as RNA editing factors for nine out of 11 sites. In this study, we identified two novel DYW subclass PPR proteins, PpPPR_65 and PpPPR_98, as RNA editing factors. Disruption of the PpPPR_65 gene resulted in a complete loss of RNA editing at two neighboring sites, ccmFc-C103 and ccmFc-C122, in the mitochondrial ccmFc transcript. To confirm this result, we further generated PpPPR_65 knockdown (KD) mutants by an inducible RNA interference (RNAi) system. The generated RNAi lines displayed reduced levels of RNA editing at both ccmFc C103 and ccmFc-C122 sites. Next, we characterized the function of PpPPR_98 by constructing a KD mutant of PpPPR_98 expression. The KD mutant showed a 30% reduction in the level of atp9-C92 editing. When PpPPR_98 cDNA was introduced into the KD mutant, RNA editing levels were restored to the wild-type level. This indicates that PpPPR_98 is an editing factor for the atp9-C92 site. The recombinant PpPPR_98 protein bound to the upstream sequence of the editing site that was created by splicing of atp9 transcript. This suggests that atp9 RNA editing occurs after splicing of atp9 transcript. Our present and previous data provide the first evidence that all 11 known editing events require at least eight DYW subclass PPR proteins in the moss mitochondria. PMID- 24058149 TI - Aquaporins and leaf hydraulics: poplar sheds new light. AB - To help understand leaf hydraulic conductance (Kleaf) modulation under high irradiance, well-watered poplars (Populus trichocarpa Torr. & Gray ex Hook and Populus nigra L.) were studied diurnally at molecular and ecophysiological scales. Transcriptional and translational modulations of plasma membrane intrinsic protein (PIP) aquaporins were evaluated in leaf samples during diurnal time courses. Among the 15 poplar PIP genes, a subset of two PIP1s and seven PIP2s are precociously induced within the first hour of the photoperiod concomitantly with a Kleaf increase. Since expression patterns were cyclic and reproducible over several days, we hypothesized that endogenous signals could be involved in PIP transcriptional regulation. To address this question, plants were submitted to forced darkness during their subjective photoperiod and compared with their control counterparts, which showed that some PIP1s and PIP2s have circadian regulation while others did not. Promoter analysis revealed that a large number of hormone, light, stress response and circadian elements are present. Finally, involvement of aquaporins is supported by the reduction of Kleaf by HgCl2 treatment. PMID- 24058148 TI - Nitrogen-dependent regulation of de novo cytokinin biosynthesis in rice: the role of glutamine metabolism as an additional signal. AB - Cytokinin activity in plants is closely related to nitrogen availability, and an Arabidopsis gene for adenosine phosphate-isopentenyltransferase (IPT), IPT3, is regulated by inorganic nitrogen sources in a nitrate-specific manner. In this study, we have identified another regulatory system of cytokinin de novo biosynthesis in response to nitrogen status. In rice, OsIPT4, OsIPT5, OsIPT7 and OsIPT8 were up-regulated in response to exogenously applied nitrate and ammonium, with accompanying accumulation of cytokinins. Pre-treatment of roots with l methionine sulfoximine, a potent inhibitor of glutamine synthetase, abolished the nitrate- and ammonium-dependent induction of OsIPT4 and OsIPT5, while glutamine application induced their expression. Thus, neither nitrate nor ammonium, but glutamine or a related metabolite, is essential for the induction of these IPT genes in rice. On the other hand, glutamine-dependent induction of IPT3 occurs in Arabidopsis, at least to some extent. In transgenic lines repressing the expression of OsIPT4, which is the dominant IPT in rice roots, the nitrogen dependent increase of cytokinin in the xylem sap was significantly reduced, and seedling shoot growth was retarded despite sufficient nitrogen. We conclude that plants possess multiple regulation systems for nitrogen-dependent cytokinin biosynthesis to modulate growth in response to nitrogen availability. PMID- 24058150 TI - Ionomic responses and correlations between elements and metabolites under salt stress in wild and cultivated barley. AB - A thorough understanding of ionic detoxification and homeostasis is imperative for improvement of salt tolerance in crops. However, the homeostasis of elements and their relationship to metabolites under salt stress have not been fully elucidated in plants. In this study, Tibetan wild barley accessions, XZ16 and XZ169, differing in salt tolerance, and a salt-tolerant cultivar CM72 were used to investigate ionomic profile changes in tissues in response to 150 and 300 mM NaCl at the germination and seedling stages. At the germination stage, the contents of Ca and Fe significantly decreased in roots, while K and S contents increased, and Ca and Mg contents decreased in shoots, after 10 d of treatment. At the seedling stage, the contents of K, Mg, P and Mn in roots and of K, Ca, Mg and S in shoots decreased significantly after 21 d of treatment. Moreover, Na had a significant negative correlation with metabolites involved in glycolysis, alpha ketoglutaric acid, maleic acid and alanine in roots, and metabolites associated with the tricarboxylic acid (TCA) cycle, sucrose, polyols and aspartate in leaves. The salt-tolerant genotypes XZ16 and CM72 showed a lower Na content in tissues, and less reduction in Zn and Cu in roots, of Ca, Mg and S in leaves, and shoot DW than the sensitive genotype XZ169, when exposed to a higher salt level. The results indicated that restriction of Na accumulation and rearrangement of nutrient elements and metabolites in barley tissues are possibly attributable to development of salt tolerance. PMID- 24058151 TI - A single-cell bioluminescence imaging system for monitoring cellular gene expression in a plant body. AB - Gene expression is a fundamental cellular process and expression dynamics are of great interest in life science. We succeeded in monitoring cellular gene expression in a duckweed plant, Lemna gibba, using bioluminescent reporters. Using particle bombardment, epidermal and mesophyll cells were transfected with the luciferase gene (luc+) under the control of a constitutive [Cauliflower mosaic virus 35S (CaMV35S)] and a rhythmic [Arabidopsis thaliana CIRCADIAN CLOCK ASSOCIATED 1 (AtCCA1)] promoter. Bioluminescence images were captured using an EM CCD (electron multiply charged couple device) camera. Luminescent spots of the transfected cells in the plant body were quantitatively measured at the single cell level. Luminescence intensities varied over a 1,000-fold range among CaMV35S::luc+-transfected cells in the same plant body and showed a log-normal like frequency distribution. We monitored cellular gene expression under light dark conditions by capturing bioluminescence images every hour. Luminescence traces of >=50 individual cells in a frond were successfully obtained in each monitoring procedure. Rhythmic and constitutive luminescence behaviors were observed in cells transfected with AtCCA1::luc+ and CaMV35S::luc+, respectively. Diurnal rhythms were observed in every AtCCA1::luc+-introduced cell with traceable luminescence, and slight differences were detected in their rhythmic waveforms. Thus the single-cell bioluminescence monitoring system was useful for the characterization of cellular gene expression in a plant body. PMID- 24058137 TI - The TFOS International Workshop on Contact Lens Discomfort: report of the subcommittee on neurobiology. AB - This report characterizes the neurobiology of the ocular surface and highlights relevant mechanisms that may underpin contact lens-related discomfort. While there is limited evidence for the mechanisms involved in contact lens-related discomfort, neurobiological mechanisms in dry eye disease, the inflammatory pathway, the effect of hyperosmolarity on ocular surface nociceptors, and subsequent sensory processing of ocular pain and discomfort have been at least partly elucidated and are presented herein to provide insight in this new arena. The stimulus to the ocular surface from a contact lens is likely to be complex and multifactorial, including components of osmolarity, solution effects, desiccation, thermal effects, inflammation, friction, and mechanical stimulation. Sensory input will arise from stimulation of the lid margin, palpebral and bulbar conjunctiva, and the cornea. PMID- 24058152 TI - Image-based monitoring system for green algal Haematococcus pluvialis (Chlorophyceae) cells during culture. AB - The green microalga Haematococcus pluvialis accumulates the red pigment astaxanthin accompanied by morphological changes under stress conditions, including nutrient depletion, continuous light and high temperature. To investigate the physiological state of the algal cells, we developed the digital image-processing software called HaematoCalMorph. The software automatically outputs 25 single-cell measurements of cell morphology and pigments based on color, bright-field microscopic images. Compared with manual inspection, the output values of cell shape were reliable and reproducible. The estimated pigment content fits the values calculated by conventional methods. Using a random forests classifier, we were able to distinguish flagellated cells from immotile cells and detect their transient appearance in culture. By performing principal components analysis, we also successfully monitored time-dependent morphological and colorimetric changes in culture. Thus, combined with multivariate statistical techniques, the software proves useful for studying cellular responses to various conditions as well as for monitoring population dynamics in culture. PMID- 24058153 TI - In memoriam: Elwood Jensen (1920-2012). PMID- 24058154 TI - A tag to track short chain fatty acid sensors. PMID- 24058155 TI - Regulation of hepatic glucose production by Gq-coupled receptors: potential new targets for treatment of type 2 diabetes. PMID- 24058156 TI - Therapeutic interventions into early stages of follicle maturation: a new treatment paradigm after over 50 years of modern infertility therapy. PMID- 24058157 TI - Arabidopsis actin-depolymerizing factor7 severs actin filaments and regulates actin cable turnover to promote normal pollen tube growth. AB - Actin filaments are often arranged into higher-order structures, such as the longitudinal actin cables that generate the reverse fountain cytoplasmic streaming pattern present in pollen tubes. While several actin binding proteins have been implicated in the generation of these cables, the mechanisms that regulate their dynamic turnover remain largely unknown. Here, we show that Arabidopsis thaliana actin-depolymerizing factor7 (ADF7) is required for turnover of longitudinal actin cables. In vitro biochemical analyses revealed that ADF7 is a typical ADF that prefers ADP-G-actin over ATP-G-actin. ADF7 inhibits nucleotide exchange on actin and severs filaments, but its filament severing and depolymerizing activities are less potent than those of the vegetative ADF1. ADF7 primarily decorates longitudinal actin cables in the shanks of pollen tubes. Consistent with this localization pattern, the severing frequency and depolymerization rate of filaments significantly decreased, while their maximum lifetime significantly increased, in adf7 pollen tube shanks. Furthermore, an ADF7-enhanced green fluorescent protein fusion with defective severing activity but normal G-actin binding activity could not complement adf7, providing compelling evidence that the severing activity of ADF7 is vital for its in vivo functions. These observations suggest that ADF7 evolved to promote turnover of longitudinal actin cables by severing actin filaments in pollen tubes. PMID- 24058158 TI - Dynamic expression of imprinted genes associates with maternally controlled nutrient allocation during maize endosperm development. AB - In angiosperms, the endosperm provides nutrients for embryogenesis and seed germination and is the primary tissue where gene imprinting occurs. To identify the imprintome of early developing maize (Zea mays) endosperm, we performed high throughput transcriptome sequencing of whole kernels at 0, 3, and 5 d after pollination (DAP) and endosperms at 7, 10, and 15 DAP, using B73 by Mo17 reciprocal crosses. We observed gradually increased expression of paternal transcripts in 3- and 5-DAP kernels. In 7-DAP endosperm, the majority of the genes tested reached a 2:1 maternal versus paternal ratio, suggesting that paternal genes are nearly fully activated by 7 DAP. A total of 116, 234, and 63 genes exhibiting parent-specific expression were identified at 7, 10, and 15 DAP, respectively. The largest proportion of paternally expressed genes was at 7 DAP, mainly due to the significantly deviated parental allele expression ratio of these genes at this stage, while nearly 80% of the maternally expressed genes (MEGs) were specific to 10 DAP and were primarily attributed to sharply increased expression levels compared with the other stages. Gene ontology enrichment analysis of the imprinted genes suggested that 10-DAP endosperm-specific MEGs are involved in nutrient uptake and allocation and the auxin signaling pathway, coincident with the onset of starch and storage protein accumulation. PMID- 24058159 TI - Histone deacetylase complex1 expression level titrates plant growth and abscisic acid sensitivity in Arabidopsis. AB - Histone deacetylation regulates gene expression during plant stress responses and is therefore an interesting target for epigenetic manipulation of stress sensitivity in plants. Unfortunately, overexpression of the core enzymes (histone deacetylases [HDACs]) has either been ineffective or has caused pleiotropic morphological abnormalities. In yeast and mammals, HDACs operate within multiprotein complexes. Searching for putative components of plant HDAC complexes, we identified a gene with partial homology to a functionally uncharacterized member of the yeast complex, which we called Histone Deacetylation Complex1 (HDC1). HDC1 is encoded by a single-copy gene in the genomes of model plants and crops and therefore presents an attractive target for biotechnology. Here, we present a functional characterization of HDC1 in Arabidopsis thaliana. We show that HDC1 is a ubiquitously expressed nuclear protein that interacts with at least two deacetylases (HDA6 and HDA19), promotes histone deacetylation, and attenuates derepression of genes under water stress. The fast-growing HDC1-overexpressing plants outperformed wild-type plants not only on well-watered soil but also when water supply was reduced. Our findings identify HDC1 as a rate-limiting component of the histone deacetylation machinery and as an attractive tool for increasing germination rate and biomass production of plants. PMID- 24058161 TI - Allelic diversity and molecular characterization of puroindoline genes in five diploid species of the Aegilops genus. AB - Grain hardness is an important quality trait in wheat. This trait is related to the variation in, and the presence of, puroindolines (PINA and PINB). This variation can be increased by the allelic polymorphism present in the Aegilops species that are related to wheat. This study evaluated allelic Pina and Pinb gene variability in five diploid species of the Aegilops genus, along with the molecular characterization of the main allelic variants found in each species. This polymorphism resulted in 16 alleles for the Pina gene and 24 alleles for the Pinb gene, of which 10 and 17, respectively, were novel. Diverse mutations were detected in the deduced mature proteins of these alleles, which could influence the hardness characteristics of these proteins. This study shows that the diploid species of the Aegilops genus could be a good source of genetic variability for both Pina and Pinb genes, which could be used in breeding programmes to extend the range of different textures in wheat. PMID- 24058160 TI - Metabolic analysis of kiwifruit (Actinidia deliciosa) berries from extreme genotypes reveals hallmarks for fruit starch metabolism. AB - Tomato, melon, grape, peach, and strawberry primarily accumulate soluble sugars during fruit development. In contrast, kiwifruit (Actinidia Lindl. spp.) and banana store a large amount of starch that is released as soluble sugars only after the fruit has reached maturity. By integrating metabolites measured by gas chromatography-mass spectrometry, enzyme activities measured by a robot-based platform, and transcript data sets during fruit development of Actinidia deliciosa genotypes contrasting in starch concentration and size, this study identified the metabolic changes occurring during kiwifruit development, including the metabolic hallmarks of starch accumulation and turnover. At cell division, a rise in glucose (Glc) concentration was associated with neutral invertase (NI) activity, and the decline of both Glc and NI activity defined the transition to the cell expansion and starch accumulation phase. The high transcript levels of beta-amylase 9 (BAM9) during cell division, prior to net starch accumulation, and the correlation between sucrose phosphate synthase (SPS) activity and sucrose suggest the occurrence of sucrose cycling and starch turnover. ADP-Glc pyrophosphorylase (AGPase) is identified as a key enzyme for starch accumulation in kiwifruit berries, as high-starch genotypes had 2- to 5 fold higher AGPase activity, which was maintained over a longer period of time and was also associated with enhanced and extended transcription of the AGPase large subunit 4 (APL4). The data also revealed that SPS and galactinol might affect kiwifruit starch accumulation, and suggest that phloem unloading into kiwifruit is symplastic. These results are relevant to the genetic improvement of quality traits such as sweetness and sugar/acid balance in a range of fruit species. PMID- 24058162 TI - Characterization and genetic dissection of resistance to spotted alfalfa aphid (Therioaphis trifolii) in Medicago truncatula. AB - Aphids cause significant yield losses in agricultural crops worldwide. Medicago truncatula, a model legume, cultivated pasture species in Australia and close relative of alfalfa (Medicago sativa), was used to study the defence response against Therioaphis trifolii f. maculate [spotted alfalfa aphid (SAA)]. Aphid performance and plant damage were compared among three accessions. A20 is highly susceptible, A17 has moderate resistance, and Jester is strongly resistant. Subsequent analyses using A17 and A20, reciprocal F1s and an A17*A20 recombinant inbred line (RIL) population revealed that this moderate resistance is phloem mediated and involves antibiosis and tolerance but not antixenosis. Electrical penetration graph analysis also identified a novel waveform termed extended potential drop, which occurred following SAA infestation of M. truncatula. Genetic dissection using the RIL population revealed three quantitative trait loci on chromosomes 3, 6, and 7 involved in distinct modes of aphid defence including antibiosis and tolerance. An antibiosis locus resides on linkage group 3 (LG3) and is derived from A17, whereas a plant tolerance and antibiosis locus resides on LG6 and is derived from A20, which exhibits strong temporary tolerance. The loci identified reside in regions harbouring classical resistance genes, and introgression of these loci in current medic cultivars may help provide durable resistance to SAA, while elucidation of their molecular mechanisms may provide valuable insight into other aphid-plant interactions. PMID- 24058163 TI - Pharyngeal airway dimensions: a cephalometric, growth-study-based analysis of physiological variations in children aged 6-17. AB - OBJECTIVE: The aim was to assess pharyngeal airway dimensions and physiological changes based on lateral cephalometric radiographs from healthy untreated children aged 6-17 years. MATERIALS/METHODS: The sample consisted of 880 lateral cephalograms (412 females and 468 males) of the Zurich Craniofacial Growth Study. Statistical analyses on cephalometric measurements of airway dimensions (distances 'p': shortest distance between soft palate and posterior pharyngeal wall and 't': shortest distance between tongue and posterior pharyngeal wall) and craniofacial parameters were performed. To disclose differences between different age groups, a Kruskal-Wallis test was applied. The influence of gender on 'p' and 't' was analysed by a Mann-Whitney U-test for each age group separately. The Spearman correlation was computed in order to investigate associations between craniofacial parameters. Variables associated with 'p' and 't' were chosen for multiple regression model investigation. RESULTS: The results demonstrated high interindividual variations. A slight influence of age on 'p' (P = 0.034) could be attested (+1.03 mm) but not on 't' (P = 0.208). With the exception of the 9-year age group, no significant differences between the genders were found. Correlation analysis revealed several statistically significant correlations between 't' or 'p' and antero-posterior cephalometric variables. All correlation coefficients were, however, very low and the adjusted coefficient of determination also revealed the regression model to be very weak. CONCLUSIONS: The high interindividual variations of 'p' and 't' render the use of reference values problematic. Contrary to other craniofacial structures, neither age-related changes nor sexual dimorphism were found for 'p' and 't'. Any associations to antero-posterior cephalometric characteristics seem low. PMID- 24058164 TI - Speciation and distribution of arsenic in the nonhyperaccumulator macrophyte Ceratophyllum demersum. AB - Although arsenic (As) is a common pollutant worldwide, many questions about As metabolism in nonhyperaccumulator plants remain. Concentration- and tissue dependent speciation and distribution of As was analyzed in the aquatic plant Ceratophyllum demersum to understand As metabolism in nonhyperaccumulator plants. Speciation was analyzed chromatographically (high-performance liquid chromatography-[inductively coupled plasma-mass spectrometry]-[electrospray ionization-mass spectrometry]) in whole-plant extracts and by tissue-resolution confocal x-ray absorption near-edge spectroscopy in intact shock-frozen hydrated leaves, which were also used for analyzing cellular element distribution through x-ray fluorescence. Chromatography revealed up to 20 As-containing species binding more than 60% of accumulated As. Of these, eight were identified as thiol bound (phytochelatins [PCs], glutathione, and cysteine) species, including three newly identified complexes: Cys-As(III)-PC2, Cys-As-(GS)2, and GS-As(III)-desgly PC2. Confocal x-ray absorption near-edge spectroscopy showed arsenate, arsenite, As-(GS)3, and As-PCs with varying ratios in various tissues. The epidermis of mature leaves contained the highest proportion of thiol (mostly PC)-bound As, while in younger leaves, a lower proportion of As was thiol bound. At higher As concentrations, the percentage of unbound arsenite increased in the vein and mesophyll of young mature leaves. At the same time, x-ray fluorescence showed an increase of total As in the vein and mesophyll but not in the epidermis of young mature leaves, while this was reversed for zinc distribution. Thus, As toxicity was correlated with a change in As distribution pattern and As species rather than a general increase in many tissues. PMID- 24058165 TI - Functional characterization of the plastidial 3-phosphoglycerate dehydrogenase family in Arabidopsis. AB - This work contributes to unraveling the role of the phosphorylated pathway of serine (Ser) biosynthesis in Arabidopsis (Arabidopsis thaliana) by functionally characterizing genes coding for the first enzyme of this pathway, 3 phosphoglycerate dehydrogenase (PGDH). We identified two Arabidopsis plastid localized PGDH genes (3-PGDH and EMBRYO SAC DEVELOPMENT ARREST9 [EDA9]) with a high percentage of amino acid identity with a previously identified PGDH. All three genes displayed a different expression pattern indicating that they are not functionally redundant. pgdh and 3-pgdh mutants presented no drastic visual phenotypes, but eda9 displayed delayed embryo development, leading to aborted embryos that could be classified as early curled cotyledons. The embryo-lethal phenotype of eda9 was complemented with an EDA9 complementary DNA under the control of a 35S promoter (Pro-35S:EDA9). However, this construct, which is poorly expressed in the anther tapetum, did not complement mutant fertility. Microspore development in eda9.1eda9.1 Pro-35S:EDA9 was arrested at the polarized stage. Pollen from these lines lacked tryphine in the interstices of the exine layer, displayed shrunken and collapsed forms, and were unable to germinate when cultured in vitro. A metabolomic analysis of PGDH mutant and overexpressing plants revealed that all three PGDH family genes can regulate Ser homeostasis, with PGDH being quantitatively the most important in the process of Ser biosynthesis at the whole-plant level. By contrast, the essential role of EDA9 could be related to its expression in very specific cell types. We demonstrate the crucial role of EDA9 in embryo and pollen development, suggesting that the phosphorylated pathway of Ser biosynthesis is an important link connecting primary metabolism with development. PMID- 24058166 TI - The roots of folk biology. PMID- 24058167 TI - Lung epithelial branching program antagonizes alveolar differentiation. AB - Mammalian organs, including the lung and kidney, often adopt a branched structure to achieve high efficiency and capacity of their physiological functions. Formation of a functional lung requires two developmental processes: branching morphogenesis, which builds a tree-like tubular network, and alveolar differentiation, which generates specialized epithelial cells for gas exchange. Much progress has been made to understand each of the two processes individually; however, it is not clear whether the two processes are coordinated and how they are deployed at the correct time and location. Here we show that an epithelial branching morphogenesis program antagonizes alveolar differentiation in the mouse lung. We find a negative correlation between branching morphogenesis and alveolar differentiation temporally, spatially, and evolutionarily. Gain-of-function experiments show that hyperactive small GTPase Kras expands the branching program and also suppresses molecular and cellular differentiation of alveolar cells. Loss-of-function experiments show that SRY-box containing gene 9 (Sox9) functions downstream of Fibroblast growth factor (Fgf)/Kras to promote branching and also suppresses premature initiation of alveolar differentiation. We thus propose that lung epithelial progenitors continuously balance between branching morphogenesis and alveolar differentiation, and such a balance is mediated by dual-function regulators, including Kras and Sox9. The resulting temporal delay of differentiation by the branching program may provide new insights to lung immaturity in preterm neonates and the increase in organ complexity during evolution. PMID- 24058169 TI - Evidence of intraflagellar transport and apical complex formation in a free living relative of the apicomplexa. AB - Since its first description, Chromera velia has attracted keen interest as the closest free-living relative of parasitic Apicomplexa. The life cycle of this unicellular alga is complex and involves a motile biflagellate form. Flagella are thought to be formed in the cytoplasm, a rare phenomenon shared with Plasmodium in which the canonical mode of flagellar assembly, intraflagellar transport, is dispensed with. Here we demonstrate the expression of intraflagellar transport components in C. velia, answering the question of whether this organism has the potential to assemble flagella via the canonical route. We have developed and characterized a culturing protocol that favors the generation of flagellate forms. From this, we have determined a marked shift in the mode of daughter cell production from two to four daughter cells per division as a function of time after passage. We conduct an ultrastructural examination of the C. velia flagellate form by using serial TEM and show that flagellar biogenesis in C. velia occurs prior to cytokinesis. We demonstrate a close association of the flagellar apparatus with a complex system of apical structures, including a micropore, a conoid, and a complex endomembrane system reminiscent of the apical complex of parasitic apicomplexans. Recent work has begun to elucidate the possible flagellar origins of the apical complex, and we show that in C. velia these structures are contemporaneous within a single cell and share multiple connections. We propose that C. velia therefore represents a vital piece in the puzzle of the origins of the apical complex. PMID- 24058170 TI - Interaction maps of the Saccharomyces cerevisiae ESCRT-III protein Snf7. AB - The Saccharomyces cerevisiae ESCRT-III protein Snf7 is part of an intricate interaction network at the endosomal membrane. Interaction maps of Snf7 were established by measuring the degree of binding of individual binding partners to putative binding motifs along the Snf7 sequence by glutathione S-transferase (GST) pulldown. For each interaction partner, distinct binding profiles were obtained. The following observations were made. The ESCRT-III subunits Vps20 and Vps24 showed a complementary binding pattern, suggesting a model for the series of events in the ESCRT-III functional cycle. Vps4 bound to individual Snf7 motifs but not to full-length Snf7. This suggests that Vps4 does not bind to the closed conformation of Snf7. We also demonstrate for the first time that the ALIX/Bro1 homologue Rim20 binds to the alpha6 helix of Snf7. Analysis of a Snf7 alpha6 deletion mutant showed that the alpha6 helix is crucial for binding of Bro1 and Rim20 in vivo and is indispensable for the multivesicular body (MVB)-sorting and Rim-signaling functions of Snf7. The Snf7Deltaalpha6 protein still appeared to be incorporated into ESCRT-III complexes at the endosomal membrane, but disassembly of the complex seemed to be defective. In summary, our study argues against the view that the ESCRT cycle is governed by single one-to-one interactions between individual components and emphasizes the network character of the ESCRT interactions. PMID- 24058171 TI - Bidirectional-genetics platform, a dual-purpose mutagenesis strategy for filamentous fungi. AB - Rapidly increasing fungal genome sequences call for efficient ways of generating mutants to translate quickly gene sequences into their functions. A reverse genetic strategy via targeted gene replacement (TGR) has been inefficient for many filamentous fungi due to dominant production of undesirable ectopic transformants. Although large-scale random insertional mutagenesis via transformation (i.e., forward genetics) facilitates high-throughput uncovering of novel genes of interest, generating a huge number of transformants, which is necessary to ensure the likelihood of mutagenizing most genes, is time-consuming. We propose a new strategy, entitled the Bidirectional-Genetics (BiG) platform, which combines both forward and reverse genetic strategies by recycling ectopic transformants derived from TGR as a source for random insertional mutants. The BiG platform was evaluated using the rice blast fungus Magnaporthe oryzae as a model. Over 10% of >1,000 M. oryzae ectopic transformants, generated during disruption of specific genes, displayed abnormality in vegetative growth, pigmentation, and/or asexual reproduction. In this pool of putative mutants, we isolated insertional mutants with mutations in three genes involved in histidine biosynthesis (MoHIS5), vegetative growth (MoVPS74), or conidiophore formation (MoFRQ) (where "Mo" indicates "M. oryzae"), supporting the utility of this platform for systematic gene function studies. PMID- 24058172 TI - Characterization of three ammonium transporters of the glomeromycotan fungus Geosiphon pyriformis. AB - Members of the Glomeromycota form the arbuscular mycorrhiza (AM) symbiosis. They supply plants with inorganic nutrients, including nitrogen, from the soil. To gain insight into transporters potentially facilitating nitrogen transport processes, ammonium transporters (AMTs) of Geosiphon pyriformis, a glomeromycotan fungus forming a symbiosis with cyanobacteria, were studied. Three AMT genes were identified, and all three were expressed in the symbiotic stage. The localization and functional characterization of the proteins in a heterologous yeast system revealed distinct characteristics for each of them. AMT1 of G. pyriformis (GpAMT1) and GpAMT2 were both plasma membrane localized, but only GpAMT1 transported ammonium. Neither protein transported the ammonium analogue methylammonium. Unexpectedly, GpAMT3 was localized in the vacuolar membrane, and it has as-yet-unknown transport characteristics. An unusual cysteine residue in the AMT signature of GpAMT2 and GpAMT3 was identified, and the corresponding residue was demonstrated to play an important role in ammonium transport. Surprisingly, each of the three AMTs of G. pyriformis had very distinct features. The localization of an AMT in the yeast vacuolar membrane is novel, as is the described amino acid residue that clearly influences ammonium transport. The AMT characteristics might reflect adaptations to the lifestyle of glomeromycotan fungi. PMID- 24058173 TI - Brain tumour mimics and chameleons. AB - The timely diagnosis of a brain tumour is crucial to optimising outcome in a group of patients with limited survival. Several common neurological conditions mimic brain tumours, causing concern to patient and physician until the correct diagnosis becomes clear. In addition, atypical presentations of brain tumours may cause diagnostic confusion, acting as chameleons and delaying correct workup and treatment. This review focuses on the important mimics and chameleons encountered in clinical practice, aiming to illustrate the wide range of clinical neurology encountered in this specialty and to provide guidance on reaching the correct diagnosis. PMID- 24058174 TI - Abr, a negative regulator of Rac, attenuates cockroach allergen-induced asthma in a mouse model. AB - Abr deactivates Ras-related C3 botulinum toxin substrate (Rac), a master molecular switch that positively regulates many immune cell functions, by converting it to its GDP-bound conformation. In this article, we report that, in the absence of Abr function, cockroach allergen (CRA)-immunized mice experienced a fatal asthma attack when challenged with CRA. The asthma in abr(-/-) mice was characterized by increased pulmonary mucus production, elevated serum IgE, and leukocyte airway infiltration. Decreased pulmonary compliance was further documented by increased airway resistance upon methacholine challenge. Peribronchial and bronchoalveolar lavage eosinophils, key cells associated with allergic asthma, were increased in abr(-/-) mice, but adoptive transfer of this cell type from immunized mice to naive controls, followed by CRA challenge, showed that eosinophils are not primarily responsible for differences in airway resistance between controls and abr-null mutants. CD4(+) T cell numbers in the airways of CRA-challenged abr(-/-) mice also were significantly increased compared with controls, as were the Th2 T cell-secreted cytokines IL-4 and IL-5 in total lung. Interestingly, when control and abr(-/-) CD4(+) T cells from CRA immunized mice were transferred to wild-type animals, airway resistance upon challenge with CRA was significantly higher in mice transplanted with T cells lacking Abr function. CD4(+) T cells from CRA-immunized and challenged abr(-/-) mice contained elevated levels of activated GTP-bound Rac compared with wild-type controls. Functionally, abr(-/-) CD4(+) T cells from CRA-exposed mice showed significantly enhanced chemotaxis toward CCL21. These results identify Abr regulated CD4(+) T cell migration as an important component of severe CRA-evoked allergic asthma in mice. PMID- 24058176 TI - Defining CD8+ T cell determinants during human viral infection in populations of Asian ethnicity. AB - The identification of virus-specific CD8(+) T cell determinants is a fundamental requirement for our understanding of viral disease pathogenesis. T cell epitope mapping strategies increasingly rely on algorithms that predict the binding of peptides to MHC molecules. There is, however, little information on the reliability of predictive algorithms in the context of human populations, in particular, for those expressing HLA class I molecules for which there are limited experimental data available. In this study, we evaluate the ability of NetMHCpan to predict antiviral CD8(+) T cell epitopes that we identified with a traditional approach in patients of Asian ethnicity infected with Dengue virus, hepatitis B virus, or severe acute respiratory syndrome coronavirus. We experimentally demonstrate that the predictive power of algorithms defining peptide-MHC interaction directly correlates with the amount of training data on which the predictive algorithm has been constructed. These results highlight the limited applicability of the NetMHCpan algorithm for populations expressing HLA molecules for which there are little or no experimental binding data, such as those of Asian ethnicity. PMID- 24058175 TI - Role of the Igh intronic enhancer EMU in clonal selection at the pre-B to immature B cell transition. AB - We previously described a checkpoint for allelic exclusion that occurs at the pre B cell to immature B cell transition and is dependent upon the IgH intronic enhancer, EMU. We now provide evidence that the breach in allelic exclusion associated with EMU deletion results from decreased IgMU levels that make it difficult for emerging BCRs to reach the signaling threshold required for positive selection into the immature B cell compartment. We show that this compartment is smaller in mice carrying an EMU-deficient, but functional, IgH allele (VHDelta(a)). Pre-B cells in such mice produce ~ 50% wild-type levels of IgMU (mRNA and protein), and this is associated with diminished signals, as measured by phosphorylation of pre-BCR/BCR downstream signaling proteins. Providing EMU-deficient mice with a preassembled VL gene led not only to a larger immature B cell compartment but also to a decrease in "double-producers," suggesting that H chain/L chain combinations with superior signaling properties can overcome the signaling defect associated with low IgMU-chain and can eliminate the selective advantage of "double-producers" that achieve higher IgMU chain levels through expression of a second IgH allele. Finally, we found that "double-producers" in EMU-deficient mice include a subpopulation with autoreactive BCRs. We infer that BCRs with IgH chain from the EMU-deficient allele are ignored during negative selection owing to their comparatively low density. In summary, these studies show that EMU's effect on IgH levels at the pre-B cell to immature B cell transition strongly influences allelic exclusion, the breadth of the mature BCR repertoire, and the emergence of autoimmune B cells. PMID- 24058178 TI - Double deficiency for RORgammat and T-bet drives Th2-mediated allograft rejection in mice. AB - Although Th1, Th2, and Th17 cells are thought to be major effector cells in adaptive alloimmune responses, their respective contribution to allograft rejection remains unclear. To precisely address this, we used mice genetically modified for the Th1 and Th17 hallmark transcription factors T-bet and RORgammat, respectively, which allowed us to study the alloreactive role of each subset in an experimental transplant setting. We found that in a fully mismatched heterotopic mouse heart transplantation model, T cells deficient for T-bet (prone to Th17 differentiation) versus RORgammat (prone to Th1 differentiation) rejected allografts at a more accelerated rate, indicating a predominance of Th17- over Th1-driven alloimmunity. Importantly, T cells doubly deficient for both T-bet and RORgammat differentiated into alloreactive GATA-3-expressing Th2 cells, which promptly induced allograft rejection characterized by a Th2-type intragraft expression profile and eosinophilic infiltration. Mechanistically, Th2-mediated allograft rejection was contingent on IL-4, as its neutralization significantly prolonged allograft survival by reducing intragraft expression of Th2 effector molecules and eosinophilic allograft infiltration. Moreover, under IL-4 neutralizing conditions, alloreactive double-deficient T cells upregulated Eomesodermin (Eomes) and IFN-gamma, but not GATA-3. Thus, in the absence of T-bet and RORgammat, Eomes may salvage Th1-mediated alloimmunity that underlies IL-4 neutralization-resistant allograft rejection. We summarize that, whereas Th17 cells predictably promote allograft rejection, IL-4-producing GATA-3(+) Th2 cells, which are generally thought to protect allogeneic transplants, may actually be potent facilitators of organ transplant rejection in the absence of T bet and RORgammat. Moreover, Eomes may rescue Th1-mediated allograft rejection in the absence of IL-4, T-bet, and RORgammat. PMID- 24058177 TI - The host environment is responsible for aging-related functional NK cell deficiency. AB - NK cells play an important role in immunity against infection and tumors. Aging related functional NK cell deficiency is well documented in humans and mice. However, the mechanism for this is poorly understood. Using an adoptive transfer approach in mice, we found that NK cells from both young and aged mice responded vigorously to priming by pathogen-derived products after being cotransferred into young mice. In contrast, NK cells from young mice responded poorly to priming by pathogen-derived products after being transferred to aged mice. In addition to defects in NK cell priming, maturation of NK cells under steady-state conditions is also impaired in aged mice, resulting in a decreased proportion of CD27(-) mature NK cells. We found that bone marrow from young and aged mice gave rise to CD27(-) mature NK cells similarly in young mixed bone marrow chimeric mice. Furthermore, by using a novel bone marrow transfer approach without irradiation, we found that after being transferred to aged mice, bone marrow from young mice gave rise to NK cells with maturation defects. Finally, we found that aging related functional NK cell deficiency was completely reversed by injecting soluble IL-15/IL-15Ralpha complexes. In contrast, blockade of IL-10 signaling, which broadly augments inflammatory responses to pathogen-derived products, had little effect on aging-related defects in NK cell priming. These data demonstrate that the aged host environment is responsible for aging-related functional NK cell deficiency. Additionally, our data suggest that IL-15 receptor agonists may be useful tools in treating aging-related functional NK cell deficiency. PMID- 24058179 TI - The effect of a nurse-led integrated chronic care approach on quality of life in patients with atrial fibrillation. AB - AIMS: Quality of life (QoL) is often impaired in patients with atrial fibrillation (AF). A novel nurse-led integrated chronic care approach demonstrated superiority compared with usual care in terms of cardiovascular hospitalization and mortality. Consequently, we hypothesized that this approach may also improve QoL and AF-related knowledge, which in turn may positively correlate with QoL. METHODS AND RESULTS: In this randomized controlled trial, 712 patients were randomly assigned to nurse-led care vs. usual care. Nurse-led care consisted of guidelines-based, software supported care, supervised by cardiologists. Usual care was provided by cardiologists in the regular outpatient setting. Quality of life was assessed by means of the Medical Outcomes Study 36 Item Short-Form Survey (SF-36). The Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety and depression scores. The AF knowledge scale was used to gain an insight into the patients' AF knowledge levels. Baseline QoL scores were relatively high in both groups, with median scores ranging from 55 to 100. Quality of life significantly improved over time in both groups with no significant differences between the two groups. Atrial fibrillation-related knowledge improved over time and was significantly higher at follow-up in the intervention group, compared with the usual care group (8.23 +/- 2.16 vs. 7.66 +/ 2.09; P < 0.05). Quality of life was correlated with gender (rs: -5.819 to 2.960), anxiety (rs: -0.746 to -0.277), depression (rs: -0.596 to -0.395), and knowledge (rs: 0.145-0.245), expressed in Spearman's rank correlation coefficient (rs). CONCLUSION: Quality of life including anxiety and depression improved over time, regardless of the treatment group. The AF-related knowledge level was better in the nurse-led care group at follow-up. Trial registration information: Clinicaltrials.gov identifier number: NCT00753259. PMID- 24058180 TI - Cavo-tricuspid isthmus radiofrequency ablation using a novel remote navigation catheter system in patients with typical atrial flutter. AB - AIMS: A new remote catheter system (AMIGOTM Remote Catheter System) compatible with conventional ablation catheters is now commercially available but no data about its performance in clinical use during ablation have been reported. This study evaluates the feasibility, efficacy, and safety of cavo-tricuspid isthmus (CTI) ablation with this system in patients with typical atrial flutter (AFl). METHODS AND RESULTS: Sixty patients with typical AFl underwent CTI ablation using the new remote catheter navigation system with 8 mm tip or irrigated catheters in three centres following each centre's routine practice. The endpoint was stable bidirectional CTI block. CTI ablation was successful in 98% of patients. Ablation was completed manually in one patient. The overall procedure, fluoroscopy, and radiofrequency times (median +/- standard deviation, range) were 123 +/- 42 (50 250), 24 +/- 13 (3-82), and 10 +/- 8 (1.17-43.3) min, respectively. Three patients had vascular complications not requiring surgical intervention. There were no complications related to the remote catheter manipulation system. CONCLUSION: Cavo-tricuspid isthmus ablation for typical AFl can be safely and effectively performed with the AMIGOTM. The learning curve seems to be short even for physicians with limited ablation experience. PMID- 24058181 TI - Risk prediction of ventricular arrhythmias and myocardial function in Lamin A/C mutation positive subjects. AB - AIMS: Mutations in the Lamin A/C gene may cause atrioventricular block, supraventricular arrhythmias, ventricular arrhythmias (VA), and dilated cardiomyopathy. We aimed to explore the predictors and the mechanisms of VA in Lamin A/C mutation-positive subjects. METHODS AND RESULTS: We included 41 Lamin A/C mutation-positive subjects. PR-interval and occurrence of VA were recorded. Left ventricular (LV) myocardial function was assessed as ejection fraction and speckle tracking longitudinal strain by echocardiography. Magnetic resonance imaging was performed to assess fibrosis in a selection of subjects. Ventricular arrhythmias were documented in 21 patients (51%). Prolonged PR-interval was the best predictor of VA (P < 0.001). Myocardial function by strain was reduced in the interventricular septum compared with the rest of the LV segments (-16.7% vs. -18.7%, P = 0.001) and correlated to PR-interval (R = 0.41, P = 0.03). Myocardial fibrosis was found exclusively in the interventricular septum and only in patients with VA (P = 0.007). PR-interval was longer in patients with septal fibrosis compared with those without (320 +/- 66 vs. 177 +/- 40 ms, P < 0.001). CONCLUSION: Prolonged PR-interval was the best predictor of VA in Lamin A/C mutation-positive subjects. Electrical, mechanical, and structural cardiac properties were related in these subjects. Myocardial function was most reduced in the interventricular septum and correlated to prolonged PR-interval. Myocardial septal fibrosis was associated with prolonged PR-interval and VA. Localized fibrosis in the interventricular septum may be the mechanism behind reduced septal function, atrioventricular block and VA in Lamin A/C mutation positive subjects. PMID- 24058182 TI - Do implantable cardioverter defibrillators improve survival in patients with chronic kidney disease at high risk of sudden cardiac death? A meta-analysis of observational studies. AB - AIMS: Prospective randomized clinical trials show that implantable cardioverter defibrillators (ICDs) can reduce the risk of total mortality in select populations. However, data regarding patients with chronic kidney disease (CKD) are inconclusive. The aim of this study was to evaluate if ICDs affect total mortality in CKD patients at high risk of sudden cardiac death. METHODS AND RESULTS: Two separate meta-analyses were performed to (i) assess the effect of ICD on all-cause mortality in CKD patients at high risk of sudden cardiac death and (ii) assess the effect of CKD on all-cause mortality in patients who already had an ICD for primary or secondary prevention purposes. Medline and EMBASE were searched from 1966 to 2013. A manual search by cross-referencing was performed. Five observational studies with 17 460 CKD patients considered at high risk of sudden cardiac death were included to evaluate the effect of ICDs on patients with severe CKD. Patients with ICD implants had a reduction in all-cause mortality (adjusted hazard ratio (HR) = 0.65, 95% confidence interval (CI) = 0.47 0.91, P < 0.05) compared with a matched control group. Based on 15 observational studies with 5233 patients as part of our second comparison that evaluated the effect of CKD on patients who received an ICD, CKD was associated with higher mortality risk (HR = 2.86, 95% CI = 1.91-4.27, P < 0.05) despite an ICD. CONCLUSION: The meta-analysis indicates that for patients undergoing ICD implant, CKD is associated with greater risk of dying. However, ICD placement reduces mortality in CKD patients at high risk of sudden cardiac death. PMID- 24058183 TI - Clinical context and outcome of carotid sinus syndrome diagnosed by means of the 'method of symptoms'. AB - AIMS: The prevalence and outcome of carotid sinus syndrome (CSS) reported in the literature vary owing to differences in indications and methods of carotid sinus massage (CSM). METHODS AND RESULTS: We performed CSM on all patients aged 40 years and above with unexplained syncope after the initial evaluation. Carotid sinus massage was performed in the supine and standing positions on both sides for 10 s during continuous electrocardiogram and blood pressure monitoring; CSS was diagnosed in the event of an abnormal response to CSM in association with reproduction of spontaneous symptoms ('method of symptoms'). From July 2005 to July 2012, CSS was found in 164 (8.8%) of 1855 patients (mean age 77 +/- 9 years, 73% males): 81% had an asystolic reflex (mean pause 7.6 +/- 2.2 s) and 19% a vasodepressor reflex (mean lowest systolic blood pressure 65 +/- 15 mmHg). Potential multifactorial causes of syncope (orthostatic hypotension, bundle branch block, bradycardia, tachyarrhythmias) were found in 74% of patients. One hundred forty-one patients received the proper care [advice on lifestyle measures in all, discontinuation (#40) or reduction (#17) of antihypertensive drugs, pacemaker implantation (#57)] and were followed up for 39 +/- 25 months. Syncope recurred in 23 patients; the actuarial syncopal recurrence rate was 7% at 1 year and 26% at 5 years. Total syncopal episodes decreased from 91 per year during the 2 years before evaluation to 21 episodes per year during follow-up (P = 0.001). On Cox proportional-hazards regression, a mixed or vasodepressor response to tilt testing was the only independent predictor of syncopal recurrence (hazard ratio = 1.8; P = 0.01). CONCLUSION: Carotid sinus massage by means of the 'method of symptoms' indentifies a clinical syndrome with definite features and outcome. A treatment strategy involving lifestyle measures, reduction of antihypertensive drugs and cardiac pacing when appropriate is effective in reducing the syncopal recurrence rate. PMID- 24058184 TI - Differential impact of the economic recession on alcohol use among white British adults, 2004-2010. AB - BACKGROUND: Unlike other west European countries, there is a long-term trend of rising alcohol consumption and mortality in England. Whether drinking will rise or fall during the current recession is widely debated. We examined how the recession affected alcohol use in adults in England using individual-level data. METHODS: We analysed a nationally representative sample of non-institutionalized white persons aged 20-60 years from seven waves of the Health Survey for England, 2004-2010 (n = 36 525), to assess trends in alcohol use and frequency before, during and after the recession and in association with unemployment, correcting for possible changes in sample composition and socio-demographic confounders. The primary analysis compared 2006/7 with 2008/9, following the official onset of the UK recession in early 2008. RESULTS: During England's recession, there was a significant decrease in frequent drinking defined as drinking four or more days in the past week (27.1% in 2006 to 23.9% in 2009, P < 0.001), the number of units of alcohol imbibed on the heaviest drinking day (P < 0.01) and the number of days that individuals reported drinking over the past seven days (P < 0.01). However, among current drinkers who were unemployed there was a significantly elevated risk of binge drinking in 2009 and 2010 (odds ratio = 1.64, 95% confidence interval: 1.22-2.19, P = 0.001) that was not previously observed in 2004-2008 (1.03, 0.76-1.41; test for effect heterogeneity: P = 0.036). CONCLUSIONS: England's recession was associated with less hazardous drinking among the population overall, but with rises in binge drinking among a smaller high-risk group of unemployed drinkers. PMID- 24058185 TI - Deep brain stimulation and autonomic control. AB - NEW FINDINGS: What is the topic of this review? This article reviews data from studies on human participants and animal models showing how electrical stimulation in deep brain structures (deep brain stimulation) can influence autonomic function. What advances does it highlight? Focusing on the control of the cardiovascular system and bladder function, it highlights the potential for development of deep brain stimulation as a new treatment option for patients with autonomic dysfunction. Deep brain stimulation (DBS) in humans has come of age as a tool to treat movement disorders including Parkinson's disease tremor and dystonia as well as a panoply of other disease states including headache, epilepsy, obesity, eating disorders, depression, obsessive compulsive disorder, Tourette's syndrome, addiction and chronic pain. Increasingly, practitioners of DBS are reporting autonomic side effects, which intriguingly, sometimes result in improved autonomic function. Focussing on the effects of stimulation at periaqueductal and periventricular sites on cardiovascular function and control of micturition, this review shows that data obtained from studies in animals is now being confirmed in humans. Lowering of blood pressure and improved baroreflex function can be evoked in humans by DBS at these midbrain sites as well as increased bladder capacity. The findings highlight the tantalizing possibility that DBS could be developed for treatment of dysfunctional autonomic states in humans. PMID- 24058186 TI - Cardiovascular control from cardiac and pulmonary vascular receptors. AB - NEW FINDINGS: What is the topic of this review? The purpose of this review is to summarize present knowledge of the function of the afferent nerves arising from the heart and the coronary and pulmonary arteries. Although there is abundant evidence that atrial receptor stimulation influences heart rate and urine flow, with little or no effect elsewhere, and that ventricular receptors are strongly excited only by chemical stimuli, there is still the erroneous belief that they act as a homogeneous group causing cardiovascular depression. What advances does it highlight? Coronary receptors deserve to be recognized as a potentially important additional group of baroreceptors. Stimulation of pulmonary arterial baroreceptors at physiological pressures causes reflex vasoconstriction and could have a hitherto unacknowledged important role in cardiovascular control, for example in exercise. Although there has been a tendency to regard cardiac and pulmonary receptors as a single population of 'cardiopulmonary receptors', this cannot be justified as the various receptor types all induce their own particular pattern of responses. Stimulation of atrial receptors increases activity in sympathetic nerves to the sino-atrial node, causing tachycardia, but there is no effect on activity to the myocardium or to most blood vessels. Renal nerve activity, however, is decreased, and secretion of antidiuretic hormone is inhibited, causing diuresis. Ventricular receptors induce a powerful depressor response, but only in response to abnormal chemical stimulation and possibly to myocardial injury. Coronary arterial receptors function as baroreceptors, but have a lower threshold and a more prolonged effect than other baroreceptors. Pulmonary arterial baroreceptors induce vasoconstriction and respiratory stimulation at physiological pressures and may be of importance in mediating some of the responses to exercise, as well as in hypoxic conditions. PMID- 24058187 TI - A word of caution concerning the use of Nnt-mutated C57BL/6 mice substrains as experimental models to study metabolism and mitochondrial pathophysiology. PMID- 24058188 TI - ATP in the locus coeruleus as a modulator of cardiorespiratory control in unanaesthetized male rats. AB - Locus coeruleus (LC) noradrenergic neurons are chemosensitive to CO2 and pH in mammals and amphibians and are involved in the CO2-related drive to breathe. Purinergic neuromodulation in the LC is of particular interest because ATP acts as a neuromodulator in brainstem regions involved in cardiovascular and respiratory regulation, such as the LC. ATP acting on LC P2 receptors influences the release of noradrenaline. Thus, the goal of the present study was to investigate the role of LC purinergic neuromodulation of ventilatory and cardiovascular responses in normocapnic and hypercapnic conditions in unanaesthetized male Wistar rats. We assessed the purinergic modulation of cardiorespiratory systems by microinjecting an ATP P2X receptor agonist [alpha,beta-methylene ATP (alpha,beta-meATP), 0.5 or 1 nmol in 40 nl] and two non selective P2 receptor antagonists [pyridoxalphosphate-6-azophenyl-2',4' disulfonic acid (PPADS), 0.5 or 1 nmol in 40 nl; and suramin, 1 nmol in 40 nl] into the LC. Pulmonary ventilation (measured by plethysmography), mean arterial pressure (MAP) and heart rate (HR) were determined before and after unilateral microinjection (40 nl) of alpha,beta-meATP, PPADS, suramin or 0.9% saline (vehicle) into the LC. These measurements were made during a 60 min exposure to normocapnic conditions or a 30 min exposure to 7% CO2. Subsequently, animals undergoing pharmacological treatment were subjected to a 30 min exposure to normocapnic conditions as a recovery period. In normocapnic conditions, alpha,beta-meATP did not affect any parameter, whereas PPADS decreased respiratory frequency and increased MAP and HR. Suramin increased MAP and HR but did not change ventilation. Moreover, hypercapnic conditions induced an increase in ventilation and a decrease in HR in all groups. In hypercapnic conditions, alpha,beta-meATP increased ventilation but did not change cardiovascular parameters, whereas PPADS increased MAP but did not alter ventilation, and suramin increased both ventilation and MAP. Thus, our data suggest that purinergic signalling, specifically through P2 receptors, in the LC plays an important role in cardiorespiratory control in normocapnic and hypercapnic conditions in unanaesthetized rats. PMID- 24058189 TI - Acute acetaminophen (paracetamol) ingestion improves time to exhaustion during exercise in the heat. AB - Acetaminophen (paracetamol) is a commonly used over-the-counter analgesic and antipyretic and has previously been shown to improve exercise performance through a reduction in perceived pain. This study sought to establish whether its antipyretic action may also improve exercise capacity in the heat by moderating the increase in core temperature. On separate days, 11 recreationally active participants completed two experimental time-to-exhaustion trials on a cycle ergometer in hot conditions (30 degrees C, 50% relative humidity) after ingesting a placebo control or an oral dose of acetaminophen in a randomized, double-blind design. Following acetaminophen ingestion, participants cycled for a significantly longer period of time (acetaminophen, 23 +/- 15 min versus placebo, 19 +/- 13 min; P = 0.005; 95% confidence interval = 90-379 s), and this was accompanied by significantly lower core (-0.15 degrees C), skin (-0.47 degrees C) and body temperatures (0.19 degrees C; P < 0.05). In the acetaminophen condition, participants also reported significantly lower ratings of thermal sensation ( 0.39; P = 0.015), but no significant change in heart rate was observed (P > 0.05). This is the first study to demonstrate that an acute dose of acetaminophen can improve cycling capacity in hot conditions, and that this may be due to the observed reduction in core, skin and body temperature and the subjective perception of thermal comfort. These findings suggest that acetaminophen may reduce the thermoregulatory strain elicited from exercise, thus improving time to exhaustion. PMID- 24058190 TI - The many faces of TRAF molecules in immune regulation. PMID- 24058191 TI - Inhibitory receptors and their mode of action: key insights from NK cells. PMID- 24058192 TI - Pillars article: Recruitment of tyrosine phosphatase HCP by the killer cell inhibitory receptor. Immunity. 1996. 4: 77-85. PMID- 24058193 TI - IL-21-producing Th cells in immunity and autoimmunity. AB - IL-21 is a member of the common gamma-chain signaling family of cytokines. Analyses of the behavior of immune cells in response to IL-21 in vitro and studies of mice deficient in IL-21 or its receptor indicate that IL-21 has a role in lymphocyte activation, proliferation, differentiation, and survival. IL-21 producing CD4(+) Th cells constitute a broad array of helper subtypes including T follicular helper cells and Th17 cells. Both autocrine and paracrine utilization of IL-21 contributes to the overall signal transduction pathways of the Ag receptor to influence the growth and survival of lymphocytes. The redundancy that IL-21 exhibits in lymphoid organs during immune responses is in stark contrast to the evidence that pharmacological neutralization of this cytokine can halt inflammation in nonlymphoid organs where IL-21 becomes the dominant voice. PMID- 24058200 TI - Successful use of dydrogesterone as maintenance therapy in recurrent endometrial stromal sarcoma: a case report. AB - Endometrial stromal sarcoma is known to be a hormone-dependent tumor. Efficacy of hormonal therapy including high-dose progestins, aromatase inhibitors or gonadotropin-releasing hormone analogs has been reported. We report a case of recurrent endometrial stromal sarcoma, the tumor cells of which were strongly positive for CD10, estrogen and progesterone receptors. Although almost all of the pelvic tumors infiltrating the rectum or pelvic side wall remained, the patient is alive with slight disease 9 years and 6 months after the initial failure. During the treatment period of 4 years and 3 months, the patient was treated exclusively with dydrogesterone at a daily dose of 10 mg and the tumor clinically disappeared. Dydrogesterone at a daily dose of 10 mg may be effective in treating low-grade endometrial stromal sarcoma. PMID- 24058202 TI - Age, gender and tumour size predict work capacity after surgical treatment of vestibular schwannomas. AB - AIMS: The aim of the present study was to identify predictive factors for outcome after surgery of vestibular schwannomas. DESIGN: This is a retrospective study with partially collected prospective data of patients who were surgically treated for vestibular schwannomas at a single institution from 1979 to 2000. Patients with recurrent tumours, NF2 and those incapable of answering questionnaires were excluded from the study. The short form 36 (SF36) questionnaire and a specific questionnaire regarding neurological status, work status and independent life (IL) status were sent to all eligible patients. PATIENTS AND METHODS: The questionnaires were sent to 430 eligible patients (out of 537) and 395 (93%) responded. Scores for work capacity (WC) and IL were compared with SF36 scores as outcome estimates. Patients were divided into two groups (<64, >=64-years-old) in order to assess them for either WC or IL. Putative preoperative and postoperative predictive factors were tested in univariate and multivariable regression analysis for the outcome scores of WC, IL and SF36. RESULTS: In the group <64 years, age, gender and tumour diameter were independent predictive factors for postoperative WC in multivariate analysis. A high-risk group was identified in women with age >50 years and tumour diameter >25 mm. In patients >=64, gender and tumour diameter were significant predictive factors for IL in univariate analysis. Perioperative and postoperative objective factors as length of surgery, blood loss and complications did not predict outcome in the multivariable analysis for any age group. Patients' assessment of change in balance function was the only neurological factor that showed significance both in univariate and multivariable analysis in both age cohorts. While SF36 scores were lower in surgically treated patients in relation to normograms for the general population, they did not correlate significantly to WC and IL. CONCLUSIONS: The SF36 questionnaire did not correlate to outcome measures as WC and IL in patients undergoing surgery for vestibular schwannomas. Women and patients above 50 years with larger tumours have a high risk for reduced WC after surgical treatment. These results question the validity of quality of life scores in assessment of outcome after surgery of benign skullbase lesions. PMID- 24058201 TI - Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis. AB - Angiopoietin-like 3 (ANGPTL3) regulates lipoprotein metabolism by modulating extracellular lipases. Loss-of function mutations in ANGPTL3 gene cause familial combined hypolipidemia (FHBL2). The mode of inheritance and hepatic and vascular consequences of FHBL2 have not been fully elucidated. To get further insights on these aspects, we reevaluated the clinical and the biochemical characteristics of all reported cases of FHBL2. One hundred fifteen FHBL2 individuals carrying 13 different mutations in the ANGPTL3 gene (14 homozygotes, 8 compound heterozygotes, and 93 heterozygotes) and 402 controls were considered. Carriers of two mutant alleles had undetectable plasma levels of ANGPTL3 protein, whereas heterozygotes showed a reduction ranging from 34% to 88%, according to genotype. Compared with controls, homozygotes as well as heterozygotes showed a significant reduction of all plasma lipoproteins, while no difference in lipoprotein(a) [Lp(a)] levels was detected between groups. The prevalence of fatty liver was not different in FHBL2 subjects compared with controls. Notably, diabetes mellitus and cardiovascular disease were absent among homozygotes. FHBL2 trait is inherited in a codominant manner, and the lipid-lowering effect of two ANGPTL3 mutant alleles was more than four times larger than that of one mutant allele. No changes in Lp(a) were detected in FHBL2. Furthermore, our analysis confirmed that FHBL2 is not associated with adverse clinical sequelae. The possibility that FHBL2 confers lower risk of diabetes and cardiovascular disease warrants more detailed investigation. PMID- 24058203 TI - Are Drugs Substitutes or Complements for Intensive (and Expensive) Medical Treatment. PMID- 24058204 TI - Racial Discrimination, Ethnic-Racial Socialization, and Crime: A Micro sociological Model of Risk and Resilience. AB - Dominant theoretical explanations of racial disparities in criminal offending overlook a key risk factor associated with race: interpersonal racial discrimination. Building on recent studies that analyze race and crime at the micro-level, we specify a social psychological model linking personal experiences with racial discrimination to an increased risk of offending. We add to this model a consideration of an adaptive facet of African American culture: ethnic racial socialization, and explore whether two forms-cultural socialization and preparation for bias-provide resilience to the criminogenic effects of interpersonal racial discrimination. Using panel data from several hundred African American male youth from the Family and Community Health Study, we find that racial discrimination is positively associated with increased crime in large part by augmenting depression, hostile views of relationships, and disengagement from conventional norms. Results also indicate that preparation for bias significantly reduces the effects of discrimination on crime, primarily by reducing the effects of these social psychological mediators on offending. Cultural socialization has a less influential but beneficial effect. Finally, we show that the more general parenting context within which preparation for bias takes place influences its protective effects. PMID- 24058206 TI - Transport-Constrained Extensions of Collision and Track Length Estimators for Solutions of Radiative Transport Problems. AB - In this paper we develop novel extensions of collision and track lengh estimators for the complete space-angle solutions of radiative transport problems. We derive the relevant equations, prove that our new estimators are unbiased, and compare their performance with that of more conventional ) estimators. Such comparisons based on numerical solutions of simple one dimensional slab problems indicate the the potential superiority of the new estimators for a wide variety of more general transport problems. PMID- 24058207 TI - A Diffuse Interface Model with Immiscibility Preservation. AB - A new, simple, and computationally efficient interface capturing scheme based on a diffuse interface approach is presented for simulation of compressible multiphase flows. Multi-fluid interfaces are represented using field variables (interface functions) with associated transport equations that are augmented, with respect to an established formulation, to enforce a selected interface thickness. The resulting interface region can be set just thick enough to be resolved by the underlying mesh and numerical method, yet thin enough to provide an efficient model for dynamics of well-resolved scales. A key advance in the present method is that the interface regularization is asymptotically compatible with the thermodynamic mixture laws of the mixture model upon which it is constructed. It incorporates first-order pressure and velocity non-equilibrium effects while preserving interface conditions for equilibrium flows, even within the thin diffused mixture region. We first quantify the improved convergence of this formulation in some widely used one-dimensional configurations, then show that it enables fundamentally better simulations of bubble dynamics. Demonstrations include both a spherical bubble collapse, which is shown to maintain excellent symmetry despite the Cartesian mesh, and a jetting bubble collapse adjacent a wall. Comparisons show that without the new formulation the jet is suppressed by numerical diffusion leading to qualitatively incorrect results. PMID- 24058205 TI - Advances in Polymer and Polymeric Nanostructures for Protein Conjugation. AB - Linear polymers have been considered the best molecular structures for the formation of efficient protein conjugates due to their biological advantages, synthetic convenience and ease of functionalization. In recent years, much attention has been dedicated to develop synthetic strategies that produce the most control over protein conjugation utilizing linear polymers as scaffolds. As a result, different conjugate models, such as semitelechelic, homotelechelic, heterotelechelic and branched or star polymer conjugates, have been obtained that take advantage of these well-controlled synthetic strategies. Development of protein conjugates using nanostructures and the formation of said nanostructures from protein-polymer bioconjugates are other areas in the protein bioconjugation field. Although several polymer-protein technologies have been developed from these discoveries, few review articles have focused on the design and function of these polymers and nanostructures. This review will highlight some recent advances in protein-linear polymer technologies that employ protein covalent conjugation and successful protein-nanostructure bioconjugates (covalent conjugation as well) that have shown great potential for biological applications. PMID- 24058208 TI - Marital Conflict Behaviors and Implications for Divorce over 16 Years. AB - This study examined self-reported marital conflict behaviors and their implications for divorce. Husbands and wives (N = 373 couples; 47% White American, 53% Black American) reported conflict behaviors in years 1, 3, 7, and 16 of their marriages. Individual behaviors (e.g., destructive behaviors) and patterns of behaviors between partners (e.g., withdrawal-constructive) in Year 1 predicted higher divorce rates. Wives' destructive and withdrawal behaviors decreased over time, whereas husbands' conflict behaviors remained stable. Husbands reported more constructive and less destructive behaviors than wives and Black American couples reported more withdrawal than White American couples. Findings support behavioral theories of marriage demonstrating that conflict behaviors predict divorce and accommodation theories indicating that conflict behaviors become less negative over time. PMID- 24058209 TI - Structural characterization of amphiphilic homopolymer micelles using light scattering, SANS, and cryo-TEM. AB - We report the aqueous solution self-assembly of a series of poly(N isopropylacrylamide) (PNIPAM) polymers end-functionalized with a hydrophobic sulfur-carbon-sulfur (SCS) pincer ligand. Although the hydrophobic ligand accounted for <5 wt% of the overall homopolymer mass, the polymers self-assembled into well-defined spherical micelles in aqueous solution, and these micelles are potential precursors to solution-assembled nanoreactors for small molecule catalysis applications. The micelle structural details were investigated using light scattering, cryogenic transmission electron microscopy (cryo-TEM), and small angle neutron scattering (SANS). Radial density profiles extracted from the cryo-TEM micrographs suggested that the PNIPAM chains formed a diffuse corona with a radially decreasing corona density profile and provided valuable a priori information about the micelle structure for SANS data modeling. SANS analysis indicated a similar profile in which the corona surrounded a small hydrophobic core containing the pincer ligand. The similarity between the SANS and cryo-TEM results demonstrated that detailed information about the micelle density profile can be obtained directly from cryo-TEM and highlighted the complementary use of scattering and cryo-TEM in the structural characterization of solution assemblies, such as the SCS pincer-functionalized homopolymers described here. PMID- 24058210 TI - Quantitative analysis of generation and branch defects in G5 poly(amidoamine) dendrimer. AB - Although methods have been developed to synthesize and isolate generation 5 (G5) PAMAM dendrimers containing precise numbers of ligands per polymer particle, the presence of skeletal and generational defects in this material can substantially hamper the process. Here we provide a quantitative analysis of G5 PAMAM dendrimer defects via high performance liquid chromatography, potentiometric titration, mass spectrometry, size exclusion chromatography, and nuclear magnetic resonance. We identified, isolated, and characterized the major structural defects of G5 dendrimer, trailing generations, and dimer, trimer, and tetramer species. We determine that the G5 material present in the as-received mixture contains 93 arms on average. We have developed two model systems capable of generating the experimentally observed mass range and polydispersity at defect rates of 8-15%. PMID- 24058211 TI - Season of Birth and Later Outcomes: Old Questions, New Answers. AB - Season of birth is associated with later outcomes; what drives this association remains unclear. We consider a new explanation: variation in maternal characteristics. We document large changes in maternal characteristics for births throughout the year; winter births are disproportionally realized by teenagers and the unmarried. Family background controls explain nearly half of season-of birth's relation to adult outcomes. Seasonality in maternal characteristics is driven by women trying to conceive; we find no seasonality among unwanted births. Prior seasonality-in-fertility research focuses on conditions at conception; here expected conditions at birth drive variation in maternal characteristics while conditions at conception are unimportant. PMID- 24058212 TI - Dielectric Boundary Force in Molecular Solvation with the Poisson-Boltzmann Free Energy: A Shape Derivative Approach. AB - In an implicit-solvent description of molecular solvation, the electrostatic free energy is given through the electrostatic potential. This potential solves a boundary-value problem of the Poisson-Boltzmann equation in which the dielectric coefficient changes across the solute-solvent interface-the dielectric boundary. The dielectric boundary force acting on such a boundary is the negative first variation of the electrostatic free energy with respect to the location change of the boundary. In this work, the concept of shape derivative is used to define such variations and formulas of the dielectric boundary force are derived. It is shown that such a force is always in the direction toward the charged solute molecules. PMID- 24058213 TI - Variational Implicit Solvation with Solute Molecular Mechanics: From Diffuse Interface to Sharp-Interface Models. AB - Central in a variational implicit-solvent description of biomolecular solvation is an effective free-energy functional of the solute atomic positions and the solute-solvent interface (i.e., the dielectric boundary). The free-energy functional couples together the solute molecular mechanical interaction energy, the solute-solvent interfacial energy, the solute-solvent van der Waals interaction energy, and the electrostatic energy. In recent years, the sharp interface version of the variational implicit-solvent model has been developed and used for numerical computations of molecular solvation. In this work, we propose a diffuse-interface version of the variational implicit-solvent model with solute molecular mechanics. We also analyze both the sharp-interface and diffuse-interface models. We prove the existence of free-energy minimizers and obtain their bounds. We also prove the convergence of the diffuse-interface model to the sharp-interface model in the sense of Gamma-convergence. We further discuss properties of sharp-interface free-energy minimizers, the boundary conditions and the coupling of the Poisson-Boltzmann equation in the diffuse interface model, and the convergence of forces from diffuse-interface to sharp interface descriptions. Our analysis relies on the previous works on the problem of minimizing surface areas and on our observations on the coupling between solute molecular mechanical interactions with the continuum solvent. Our studies justify rigorously the self consistency of the proposed diffuse-interface variational models of implicit solvation. PMID- 24058214 TI - Easily Constructed Microscale Spectroelectrochemical Cell. AB - The design and performance of an easily constructed cell for microscale spectroelectrochemical analysis is described. A cation exchange polymer film, Nafion, was used as a salt bridge to provide ionic contact between a small sample well containing a coiled wire working electrode and separate, larger wells housing reference and auxiliary electrodes. The cell was evaluated using aqueous ferri/ferrocyanide as a test system and shown to be capable of relatively sensitive visible absorption measurements (path lengths on the order of millimeters) and reasonably rapid bulk electrolysis (~ 5 min) of samples in the 1 to 5 MUL volume range. Minor alterations to the cell design are cited that could allow for analysis of sub-microliter volumes, rapid multi-sample analysis, and measurements in the ultraviolet spectral region. PMID- 24058215 TI - Concise enantioselective synthesis of diospongins A and B. AB - Ether transfer methodology is capable of stereoselectively generating 1,3-diol mono- and diethers in good yield. Surprisingly, allylic and benzylic substrates provide none of the desired products when exposed to previously optimized conditions of iodine monochloride. Herein, second-generation activation conditions for ether transfer have been developed that circumvents undesired side reactions for these substrates. The application of this chemistry to the enantioselective synthesis of diospongins A and B has now been accomplished. PMID- 24058216 TI - Preparation of Aryl-Susbstituted 2-Oxyindoles by Superelectrophilic Chemistry. AB - A series of pyridyl-substituted 3-hydroxy-2-oxyindoles have been prepared and reacted with arenes in superacid promoted Friedel-Crafts reactions. The product aryl-substituted 2-oxyindoles are formed in generally good yields. With substituted arenes such as toluene, bromobenzene, or ethyl salicylate, the Friedel-Crafts reactions occur with excellent regioselectivity. A mechanism is proposed involving dicationic, superelectrophilic species leading to the electrophilic aromatic substitution chemistry. PMID- 24058217 TI - A mild synthesis of N-functionalised bromomaleimides, thiomaleimides and bromopyridazinediones. AB - Bromomaleimides are useful building blocks in synthesis and powerful reagents for the selective chemical modification of proteins. A mild new synthesis of these reagents is described, along with the convenient transferability of the approach to dithiomaleimides and bromopyridazinediones. PMID- 24058219 TI - EFFICIENT ESTIMATION IN SUFFICIENT DIMENSION REDUCTION. AB - We develop an efficient estimation procedure for identifying and estimating the central subspace. Using a new way of parameterization, we convert the problem of identifying the central subspace to the problem of estimating a finite dimensional parameter in a semiparametric model. This conversion allows us to derive an efficient estimator which reaches the optimal semiparametric efficiency bound. The resulting efficient estimator can exhaustively estimate the central subspace without imposing any distributional assumptions. Our proposed efficient estimation also provides a possibility for making inference of parameters that uniquely identify the central subspace. We conduct simulation studies and a real data analysis to demonstrate the finite sample performance in comparison with several existing methods. PMID- 24058218 TI - Effects of pH and ionic strength on the thermodynamics of human serum albumin photosensitizer binding. AB - Fluorescence spectroscopy was used to measure the effects of pH and ionic strength on thermodynamic parameters governing the interaction of human serum albumin with zinc phthalocyanine tetrasulfonic acid. Fluorescence emission of zinc phthalocyanine increases at 686 nm with increasing concentrations of the protein. The non-linear correlation between protein concentration and emission of the photosensitizer was fitted using Chipman's analysis to calculate the binding affinities. The standard enthalpy and entropy changes were estimated from van't Hoff analysis of data that were acquired from temperature ramping studies. Results show that reaction is primarily driven by solution dynamics and that the change in enthalpy for the system becomes increasingly unfavorable with increasing pH and ionic strength. The effect of ionic strength on the entropy change for binding is shown to be significantly greater than the effects of pH. The interplay between entropy and enthalpy changes is demonstrated. PMID- 24058220 TI - Tetrahedron-based orthogonal simultaneous scan for cone-beam computed tomography. AB - In this article, a cone-beam computed tomography scanning mode is designed using four x-ray sources and a spherical sample. The x-ray sources are mounted at the vertices of a regular tetrahedron. On the circumsphere of the tetrahedron, four detection panels are mounted opposite of each vertex. To avoid x-ray interference, the largest half angle of each x-ray cone beam is 27 degrees 22', while the radius of the largest ball fully covered by all the cone beams is 0.460, when the radius of the circumsphere is 1. A proposed scanning scheme consists of two rotations about orthogonal axes, such that, each quarter turn provides sufficient data for theoretically exact and stable reconstruction. This design can be used in biomedical or industrial settings, such as when a sequence of reconstructions of an object is desired. PMID- 24058221 TI - Evaluation of Data Entry Errors and Data Changes to an Electronic Data Capture Clinical Trial Database. AB - Monitoring of clinical trials includes several disciplines, stakeholders, and skill sets. The aim of the present study was to identify database changes and data entry errors to an electronic data capture (EDC) clinical trial database, and to access the impact of the changes. To accomblish the aim, Target e*CRF was used as the EDC tool for a multinational, dose-finding, multicenter, double blind, randomized, parallel, placebo-controlled trial to investigate efficacy and safety of a new treatment in men with lower urinary tract symptoms associated with benign prostatic hyperplasia. The main errors observed were simple transcription errors from the paper source documents to the EDC database. This observation was to be expected, since every transaction has an inherant error rate. What and how to monitor must be assessed within the risk-based monitoring section of the comprehensive data monitoring plan. With the advent of direct data entry, and the elimination of the requirement to transcribe from a paper source record to an EDC system, error rates should go down dramatically. In addition, protocol violations and data outside the normal range can be identified at the time of data entry and not days, weeks, and months after the fact. PMID- 24058222 TI - Partially ordered mixed hidden Markov model for the disablement process of older adults. AB - At both the individual and societal levels, the health and economic burden of disability in older adults is enormous in developed countries, including the U.S. Recent studies have revealed that the disablement process in older adults often comprises episodic periods of impaired functioning and periods that are relatively free of disability, amid a secular and natural trend of decline in functioning. Rather than an irreversible, progressive event that is analogous to a chronic disease, disability is better conceptualized and mathematically modeled as states that do not necessarily follow a strict linear order of good-to-bad. Statistical tools, including Markov models, which allow bidirectional transition between states, and random effects models, which allow individual-specific rate of secular decline, are pertinent. In this paper, we propose a mixed effects, multivariate, hidden Markov model to handle partially ordered disability states. The model generalizes the continuation ratio model for ordinal data in the generalized linear model literature and provides a formal framework for testing the effects of risk factors and/or an intervention on the transitions between different disability states. Under a generalization of the proportional odds ratio assumption, the proposed model circumvents the problem of a potentially large number of parameters when the number of states and the number of covariates are substantial. We describe a maximum likelihood method for estimating the partially ordered, mixed effects model and show how the model can be applied to a longitudinal data set that consists of N = 2,903 older adults followed for 10 years in the Health Aging and Body Composition Study. We further statistically test the effects of various risk factors upon the probabilities of transition into various severe disability states. The result can be used to inform geriatric and public health science researchers who study the disablement process. PMID- 24058223 TI - EFFECTIVELY SELECTING A TARGET POPULATION FOR A FUTURE COMPARATIVE STUDY. AB - When comparing a new treatment with a control in a randomized clinical study, the treatment effect is generally assessed by evaluating a summary measure over a specific study population. The success of the trial heavily depends on the choice of such a population. In this paper, we show a systematic, effective way to identify a promising population, for which the new treatment is expected to have a desired benefit, utilizing the data from a current study involving similar comparator treatments. Specifically, using the existing data, we first create a parametric scoring system as a function of multiple multiple baseline covariates to estimate subject-specific treatment differences. Based on this scoring system, we specify a desired level of treatment difference and obtain a subgroup of patients, defined as those whose estimated scores exceed this threshold. An empirically calibrated threshold-specific treatment difference curve across a range of score values is constructed. The subpopulation of patients satisfying any given level of treatment benefit can then be identified accordingly. To avoid bias due to overoptimism, we utilize a cross-training-evaluation method for implementing the above two-step procedure. We then show how to select the best scoring system among all competing models. Furthermore, for cases in which only a single pre-specified working model is involved, inference procedures are proposed for the average treatment difference over a range of score values using the entire data set, and are justified theoretically and numerically. Lastly, the proposals are illustrated with the data from two clinical trials in treating HIV and cardiovascular diseases. Note that if we are not interested in designing a new study for comparing similar treatments, the new procedure can also be quite useful for the management of future patients, so that treatment may be targeted towards those who would receive nontrivial benefits to compensate for the risk or cost of the new treatment. PMID- 24058224 TI - Kernel Continuum Regression. AB - The continuum regression technique provides an appealing regression framework connecting ordinary least squares, partial least squares and principal component regression in one family. It offers some insight on the underlying regression model for a given application. Moreover, it helps to provide deep understanding of various regression techniques. Despite the useful framework, however, the current development on continuum regression is only for linear regression. In many applications, nonlinear regression is necessary. The extension of continuum regression from linear models to nonlinear models using kernel learning is considered. The proposed kernel continuum regression technique is quite general and can handle very flexible regression model estimation. An efficient algorithm is developed for fast implementation. Numerical examples have demonstrated the usefulness of the proposed technique. PMID- 24058225 TI - Older Adults' Trait Impressions of Faces Are Sensitive to Subtle Resemblance to Emotions. AB - Younger adults (YA) attribute emotion-related traits to people whose neutral facial structure resembles an emotion (emotion overgeneralization). The fact that older adults (OA) show deficits in accurately labeling basic emotions suggests that they may be relatively insensitive to variations in the emotion resemblance of neutral expression faces that underlie emotion overgeneralization effects. On the other hand, the fact that OA, like YA, show a 'pop-out' effect for anger, more quickly locating an angry than a happy face in a neutral array, suggests that both age groups may be equally sensitive to emotion resemblance. We used computer modeling to assess the degree to which neutral faces objectively resembled emotions and assessed whether that resemblance predicted trait impressions. We found that both OA and YA showed anger and surprise overgeneralization in ratings of danger and naivete, respectively, with no significant differences in the strength of the effects for the two age groups. These findings suggest that well-documented OA deficits on emotion recognition tasks may be more due to processing demands than to an insensitivity to the social affordances of emotion expressions. PMID- 24058226 TI - MARRIAGE AND MEN'S WEALTH ACCUMULATION IN THE UNITED STATES, 1860-1870. AB - This paper explores how changes in marital status affected men's wealth accumulation in mid-nineteenth-century America, using a longitudinal sample of Union Army veterans linked to the 1860 and 1870 census manuscript schedules. Controlling for the endogeneity of wealth and marital selection, this paper provides strong evidence that marriage had positive effects on men's wealth accumulation, whereas ending a marriage had negative effects. The estimated wealth premium on married men is about 60 percent per marital year. This substantial wealth premium is closely related to wives' specializing in household production, and farmers and craftsmen economically benefited from the unpaid labor of their wives. PMID- 24058227 TI - STABILITY OF THE INTERIOR PROBLEM FOR POLYNOMIAL REGION OF INTEREST. AB - In many practical applications, it is desirable to solve the interior problem of tomography without requiring knowledge of the attenuation function fa on an open set within the region of interest (ROI). It was proved recently that the interior problem has a unique solution if fa is assumed to be piecewise polynomial on the ROI. In this paper, we tackle the related question of stability. It is well-known that lambda tomography allows one to stably recover the locations and values of the jumps of fa inside the ROI from only the local data. Hence, we consider here only the case of a polynomial, rather than piecewise polynomial, fa on the ROI. Assuming that the degree of the polynomial is known, along with some other fairly mild assumptions on fa , we prove a stability estimate for the interior problem. Additionally, we prove the following general uniqueness result. If there is an open set U on which fa is the restriction of a real-analytic function, then fa is uniquely determined by only the line integrals through U. It turns out that two known uniqueness theorems are corollaries of this result. PMID- 24058228 TI - The impact of impaired semantic knowledge on spontaneous iconic gesture production. AB - BACKGROUND: Previous research has found that people with aphasia produce more spontaneous iconic gesture than control participants, especially during word finding difficulties. There is some evidence that impaired semantic knowledge impacts on the diversity of gestural handshapes, as well as the frequency of gesture production. However, no previous research has explored how impaired semantic knowledge impacts on the frequency and type of iconic gestures produced during fluent speech compared with those produced during word-finding difficulties. AIMS: To explore the impact of impaired semantic knowledge on the frequency and type of iconic gestures produced during fluent speech and those produced during word-finding difficulties. METHODS & PROCEDURES: A group of 29 participants with aphasia and 29 control participants were video recorded describing a cartoon they had just watched. All iconic gestures were tagged and coded as either "manner," "path only," "shape outline" or "other". These gestures were then separated into either those occurring during fluent speech or those occurring during a word-finding difficulty. The relationships between semantic knowledge and gesture frequency and form were then investigated in the two different conditions. OUTCOMES & RESULTS: As expected, the participants with aphasia produced a higher frequency of iconic gestures than the control participants, but when the iconic gestures produced during word-finding difficulties were removed from the analysis, the frequency of iconic gesture was not significantly different between the groups. While there was not a significant relationship between the frequency of iconic gestures produced during fluent speech and semantic knowledge, there was a significant positive correlation between semantic knowledge and the proportion of word-finding difficulties that contained gesture. There was also a significant positive correlation between the speakers' semantic knowledge and the proportion of gestures that were produced during fluent speech that were classified as "manner". Finally while not significant, there was a positive trend between semantic knowledge of objects and the production of "shape outline" gestures during word-finding difficulties for objects. CONCLUSIONS: The results indicate that impaired semantic knowledge in aphasia impacts on both the iconic gestures produced during fluent speech and those produced during word-finding difficulties but in different ways. These results shed new light on the relationship between impaired language and iconic co-speech gesture production and also suggest that analysis of iconic gesture may be a useful addition to clinical assessment. PMID- 24058230 TI - Ultraslow dynamics in asymmetric block copolymers with nanospherical domains. AB - Low shear rate and low frequency measurements focused on the extremely slow dynamics of a three-dimensional body-centered cubic (BCC) structure of an asymmetric block copolymer under nanophase-separated conditions. The material studied was poly(styrene-b-ethylene-co-butylene-b-styrene) swollen in a hydrocarbon oil selective for the midblock. Transient viscosities during start-up of shear flow at extremely low shear rates are governed by very long relaxation times and by a modulus that is nearly the same as the plateau modulus obtained from oscillatory shear experiments. Only at extremely low shear rates a zero shear viscosity could be attained. Its very high value is close to the viscosity calculated from stress relaxation experiments. The steady shear viscosity decreases by several orders of magnitude when increasing the shear rate. SAXS experiments on samples sheared even at very low rates indicated loss of the BCC order that was present in the annealed samples before shearing. The SAXS profile recorded on such a sample showed a first-order maximum followed by a broad shoulder indicating a liquid-like short-range order of PS nanospheres in the swollen EB matrix. PMID- 24058231 TI - A site-directed spin-labeling study of surfactants in polymer-clay nanocomposites. AB - Polymer-clay nanocomposites exhibit much improved mechanical, physical, and chemical properties compared to the pure polymer. The interaction of polymer and organically modified silicates is mainly influenced by the surfactant layer in the system. To investigate the structure and dynamics of this surfactant layer, various electron paramagnetic spectroscopy (EPR) techniques were applied. Continuous wave EPR experiments showed a temperature-dependent heterogeneous mobility of the surfactant layer in organoclay as well as a difference in dynamics along the alkyl chain. Intercalation of polystyrene causes a significant slowdown in surfactant dynamics. Electron spin echo envelope modulation indicates a closer contact of the polymer with the mid of the surfactant tail than with the end of the tail. From the obtained data the picture of flatly lying surfactants on clay platelets with a mobility gradient along their alkyl chains can be drawn. PMID- 24058229 TI - Using E-Z Reader to examine the concurrent development of eye-movement control and reading skill. AB - Compared to skilled adult readers, children typically make more fixations that are longer in duration, shorter saccades, and more regressions, thus reading more slowly (Blythe & Joseph, 2011). Recent attempts to understand the reasons for these differences have discovered some similarities (e.g., children and adults target their saccades similarly; Joseph, Liversedge, Blythe, White, & Rayner, 2009) and some differences (e.g., children's fixation durations are more affected by lexical variables; Blythe, Liversedge, Joseph, White, & Rayner, 2009) that have yet to be explained. In this article, the E-Z Reader model of eye-movement control in reading (Reichle, 2011; Reichle, Pollatsek, Fisher, & Rayner, 1998) is used to simulate various eye-movement phenomena in adults vs. children in order to evaluate hypotheses about the concurrent development of reading skill and eye movement behavior. These simulations suggest that the primary difference between children and adults is their rate of lexical processing, and that different rates of (post-lexical) language processing may also contribute to some phenomena (e.g., children's slower detection of semantic anomalies; Joseph et al., 2008). The theoretical implications of this hypothesis are discussed, including possible alternative accounts of these developmental changes, how reading skill and eye movements change across the entire lifespan (e.g., college-aged vs. older readers), and individual differences in reading ability. PMID- 24058232 TI - Preparation of silver-poly(acrylamide-co-methacrylic acid) composite microspheres with patterned surface structures. AB - Acrylamide (AM) and methacrylic acid (MAA) copolymer microgels were prepared by a reverse suspension polymerization technique. The microgels were used as templates for the preparation of silver-poly(acrylamide-co-methacrylic acid) [Ag-P(AM-co MAA)] composite microspheres. The surface structures of the microspheres prepared in this way are characterized by zigzag-like structures. It was found that the composition of the microgels, the nature and dosage of surfactants, the quantity of the metal, and even the reduction methods employed have a significant effect upon the surface structures of the microspheres. X-ray diffraction analysis confirmed that Ag formed during the process is in a crystal state of a face centered cubic structure. PMID- 24058233 TI - The effect of polymers on the phase behavior of balanced microemulsions: diblock copolymer and comb-polymers. AB - The effect of some amphipilic diblock-copolymers and comb-polymers on a balanced Winsor III microemulsion system is investigated with the quaternary system n octyl-beta-d-glucoside/1-octanol/n-octane/D2O as basis system. The diblock copolymers are polyethyleneoxide-co-polydodecenoxide (PEO x PEDODO y ) and polyethyleneoxide-co-polybutyleneoxide (PEO x PEBU y ), constituted of a straight chain hydrophilic part and a bulky hydrophobic part. Addition of the diblock copolymer leads to an enhancement of the swelling of the middle phase by uptake of water and oil; a maximum boosting factor of 6 was obtained for PEO111PEDODO25. Nuclear magnetic resonance diffusometry yields the self-diffusion coefficients of all the components in the system. The diffusion experiments provide information on how the microstructure of the bicontinuous microemulsion changes upon addition of the polymers. The reduced self-diffusion coefficients of water and oil are sensitive to the type of polymer that is incorporated in the film. For the diblock-copolymers, as mainly used here, the reduced self-diffusion coefficient of oil and water will respond to how the polymer bends the film. When the film bends away from water, the reduced self-diffusion of the water will increase, whereas the oil diffusion will decrease due to the film acting as a barrier, hindering free diffusion. The self-diffusion coefficient of the polymer and surfactant are similar in magnitude and both decrease slightly with increasing polymer concentration. PMID- 24058234 TI - Non-ionic amphiphilic block copolymers by RAFT-polymerization and their self organization. AB - Water-soluble, amphiphilic diblock copolymers were synthesized by reversible addition fragmentation chain transfer polymerization. They consist of poly(butyl acrylate) as hydrophobic block with a low glass transition temperature and three different nonionic water-soluble blocks, namely, the classical hydrophilic block poly(dimethylacrylamide), the strongly hydrophilic poly(acryloyloxyethyl methylsulfoxide), and the thermally sensitive poly(N-acryloylpyrrolidine). Aqueous micellar solutions of the block copolymers were prepared and characterized by static and dynamic light scattering analysis (DLS and SLS). No critical micelle concentration could be detected. The micellization was thermodynamically favored, although kinetically slow, exhibiting a marked dependence on the preparation conditions. The polymers formed micelles with a hydrodynamic diameter from 20 to 100 nm, which were stable upon dilution. The micellar size was correlated with the composition of the block copolymers and their overall molar mass. The micelles formed with the two most hydrophilic blocks were particularly stable upon temperature cycles, whereas the thermally sensitive poly(N-acryloylpyrrolidine) block showed a temperature-induced precipitation. According to combined SLS and DLS analysis, the micelles exhibited an elongated shape such as rods or worms. It should be noted that the block copolymers with the most hydrophilic poly(sulfoxide) block formed inverse micelles in certain organic solvents. PMID- 24058235 TI - Polystyrene latex particles coated with crosslinked poly(N-isopropylacrylamide). AB - Thermoresponsive colloidal particles were prepared by seeded precipitation polymerization of N-isopropylacrylamide (NIPAM) in the presence of a crosslinking monomer, N,N-methylenebisacrylamide (MBA), using polystyrene latex particles (ca. 50 nm in diameter) as seeds in aqueous dispersion. Phase transitions of the prepared poly(N-isopropylacrylamide), PNIPAM, shells on polystyrene cores were studied in comparison to colloidal PNIPAM microgel particles, in H2O and/or in D2O by dynamic light scattering, microcalorimetry and by 1H NMR spectroscopy including the measurements of spin-lattice (T1) and spin-spin (T2) relaxation times for the protons of PNIPAM. As expected, the seed particles grew in hydrodynamic size during the crosslinking polymerization of NIPAM, and a larger NIPAM to seed mass ratio in the polymerization batch led to a larger increase of particle size indicating a product coated with a thicker PNIPAM shell. Broader microcalorimetric endotherms of dehydration were observed for crosslinked PNIPAM on the solid cores compared to the PNIPAM microgels and also an increase of the transition temperature was observed. The calorimetric results were complemented by the NMR spectroscopy data of the 1H-signal intensities upon heating in D2O, showing that the phase transition of crosslinked PNIPAM on polystyrene core shifts towards higher temperatures when compared to the microgels, and also that the temperature range of the transition is broader. PMID- 24058236 TI - Preparation, structural, and optical features of two-dimensional cross-linked DNA/gold-nanoparticle conjugates. AB - The formation and the optical features of two-dimensional aggregates formed by DNA-directed immobilization and cross-linking of bifunctional DNA-gold nanoparticles at flat gold substrates are analyzed. The samples are structurally characterized by atomic force microscopy to evaluate the particle size, the particle densities, and the degree of aggregation. The optical characteristics determined by UV/visible measurements are correlated with the structural features observed. PMID- 24058237 TI - Electroosmotic flow velocity measurements in a square microchannel. AB - Experiments were performed using a microparticle image velocimetry (MPIV) for 2D velocity distributions of electroosmotically driven flows in a 40-mm-long microchannel with a square cross section of 200*200 MUm. Electroosmotic flow (EOF) bulk fluid velocity measurements were made in a range of streamwise electric field strengths from 5 to 25 kV/m. A series of seed particle calibration tests can be made in a 200*120*24,000-MUm untreated polydimethyl siloxane (PDMS channel incorporating MPIV to determine the electrophoretic mobilities in aqueous buffer solutions of 1* TAE, 1* TBE, 10 mM NaCl, and 10 mM borate. A linear/nonlinear (due to Joule heating) flow rate increase with applied field was obtained and compared with those of previous studies. A parametric study, with extensive measurements, was performed with different electric field strength and buffer solution concentration under a constant zeta potential at wall for each buffer. The characteristics of EOF in square microchannels were thus investigated. Finally, a composite correlation of the relevant parameters was developed in the form of [Formula: see text] within +/-1% accuracy for 99% of the experimental data. PMID- 24058238 TI - Effect of thiol-containing monomer on the preparation of temperature-sensitive hydrogel microspheres. AB - The main objective of this study is to prepare, thermally, sensitive microgel particles bearing thiol groups via precipitation polymerization of N isopropylacrylamide (NIPAM), methylenebisacrylamide (MBA) and vinylbenzylisothiouronium chloride (VBIC) using 2-2'-azobis(2-amidinopropane) dihydrochloride (V50) as initiator. The influence of various parameters has been investigated as a systematic study to point out the role of each reactant on polymerization conversion, and consequently, on particles and water-soluble polymer formation. The final microgel particles were characterized with respect to particle size and swelling ability. The aim of this paper is to complete our first short communication; Macromolecular symposia, 2000. 150: p. 283-290. PMID- 24058239 TI - Negatively charged hyperbranched polyether-based polyelectrolytes. AB - The preparation of carboxylated hyperbranched polyglycerols of narrow polydispersity was achieved by modification (78-90%) of the hydroxyl end groups via Michael addition of acrylonitrile, followed by hydrolysis. High conversion could only be achieved for low molecular weight starting materials (520 and 1,030 g mol-1). The solution properties of the resulting materials were investigated by dynamic light scattering (DLS), showing the formation of large aggregates with size depending on the pH value. After deposition on a negatively charged mica surface, the structures observed by atomic force microscope (AFM) show the coexistence of aggregates and single macromolecules. Most interesting, in the case of the lower molecular weight sample (PG 520 g mol-1), extended and ordered terrace structures were formed, which are unprecedented for hyperbranched polymers and are of interest for surface modification in general. PMID- 24058240 TI - Anomalous small-angle X-ray scattering: analyzing correlations and fluctuations in polyelectrolytes. AB - We review recent structural investigations done by anomalous small-angle X-ray scattering (ASAXS). ASAXS uses the dependence of the scattering length of a given element if the energy of the incident X-ray beam is near the absorption edge of this element. The analysis of the ASAXS data leads to three partial intensities. We show that the comparison of these three partial intensities leads to valuable information in fluctuating systems. This has been demonstrated from data derived from recent molecular dynamics simulations of charged colloidal spheres. Moreover, it is shown that the three partial intensities can be obtained from experimental ASAXS data indeed. As an example for this analysis, we discuss recent ASAXS data referring to rod-like polyelectrolytes. These polyelectrolytes consist of a stiff poly(p-phenylene) backbone with attached charged groups that are balanced by bromine counterions. The three partial intensities can be determined experimentally and compared to the prediction of the Poisson-Boltzmann cell model. Quantitative agreement is found demonstrating the strong correlation of the counterions to the rod-like macroion. ASAXS is thus shown to furnish information not available by the conventional small-angle scattering experiment. PMID- 24058241 TI - Microwave-assisted synthesis and micellization behavior of soy-based copoly(2 oxazoline)s. AB - Polymers based on renewable resources are promising candidates for replacing common organic polymers, and thus, for reducing oil consumption. In this contribution we report the microwave-assisted synthesis of block and statistical copolymers from 2-ethyl-2-oxazoline and 2-"soy alkyl"-2-oxazoline via a cationic ring-opening polymerization mechanism. The synthesized copolymers were characterized by gel permeation chromatography and 1H-NMR spectroscopy. The micellization of these amphiphilic copolymers was investigated by dynamic light scattering and atomic force microscopy to examine the effect of hydrophobic block length and monomer distribution on the resulting micellar characteristics. PMID- 24058242 TI - Estimation of distribution state of carboxyl groups within submicron-sized, carboxylated polymer particle with isothermal titration calorimeter. AB - A novel technique to estimate the distribution state of carboxyl groups within submicron-sized, carboxylated polymer particles was proposed. For the purpose, carboxyl groups in two kinds of butyl methacrylate-methacrylic acid copolymer emulsion, which were prepared by emulsion copolymerizations with different monomer addition methods, were titrated by isothermal titration calorimetry with an extremely small amount (ca. 2 mg) of the particles. PMID- 24058243 TI - The elastic properties of single double-stranded DNA chains of different lengths as measured with optical tweezers. AB - Optical tweezers are microscopic tools with extraordinary precision in the determination of the position (+/-2 nm) of a colloid (diameter: ~2.0 MUm) in 3D space and in the measurement of small forces in the range between 0.1 and 100 pN (pN=10-12 N). Experiments are reported in which single double-stranded (ds)-DNA chains of different length [2,000 base pairs (bp), 3,000, 4,000, and 6,000 bp] are spanned between two colloidal particles by use of appropriate molecular linkers. For the forces applied (<=40 pN) a fully reversible and well reproducible force-extension dependence is found. The data can be well described by both the worm-like chain model or by an approach developed by R. G. Winkler. For the resulting persistence length, a pronounced dependence on the ionic concentration in the surrounding medium is found. PMID- 24058244 TI - Branched trichain sulfosuccinates as novel water in CO2 dispersants. AB - A series of highly branched trichain sulfosuccinate surfactants have been synthesized and studied in condensed CO2 and aqueous environments. Aqueous critical micelle concentrations (CMCs) showed a general trend of increasing CMC with decreasing chain length, whereas increased branching appeared to increase solubility in CO2 and aid the dispersion of water. Near infrared spectra confirmed observed cloud with a large increase in solubility above the cloud pressures in this solvent. PMID- 24058245 TI - A 1H NMR study of 1,4-bis(N-hexadecyl-N, N-dimethylammonium)butane dibromide/sodium anthranilate system: spherical to rod-shaped transition. AB - The effect of addition of sodium anthranilate to 5 mM micellar solutions of gemini surfactant 1,4-bis(N-hexadecyl-N,N-dimethylammonium)butane dibromide is investigated by 1H NMR. The solubilization site of anthranilate anion near the micellar surface is inferred. In the micelles, the An- ions intercalate among the surfactant headgroups producing morphological changes. PMID- 24058246 TI - Control on shape, porosity and surface hydrophilicity of hematite particles by using polymers. AB - The shape, porosity, and surface hydrophilicity of hematite particles formed from a forced hydrolysis reaction of acidic FeCl3 solution were controlled by using a trace of polymers (0.001 and 0.003 wt%). The spherical particles were produced on the systems with polyvinyl alcohol (PVA) and polyaspartic acid (PAS). In the case of polyacryl amide (PAAm), slightly small spherical particles were precipitated at 0.003 wt%. However, polyacrylic acid (PAAc) and poly-gamma-glutamic acid (PGA) gave ellipsoidal particles. This morphological change on hematite particles depended on the order of functional groups of polymers as -OH<-CONH2<-COOH<-COOH and ?C=O, corresponding to the order in extent of polymer molecules for complexation to Fe3+ ions and adsorption onto particle surface. Accompanying this order, the hematite particles produced were changed from less porous to microporous. On the other hand, only the system with 0.003 wt% of PAAm produced mesoporous hematite particles. Choosing the kinds of polymers also controlled the ultramicroporosity and surface hydrophilicity of the particles. PMID- 24058248 TI - Assessment of learning style in a sample of saudi medical students. AB - CONFLICT OF INTEREST: NONE DECLARED. BACKGROUND: By knowing the different students' learning styles, teachers can plan their instruction carefully in ways that are capitalized on student preferences. The current research is done to determine specific learning styles of students. METHOD: This cross sectional study was conducted in Al Ahsa College of Medicine from 2011 to 2012. A sample of 518 students completed a questionnaire based on Kolb inventory (LSI 2) to determine their learning style. A spreadsheet was prepared to compute all the information to get the cumulative scores of learning abilities and identify the learning styles. RESULTS: The mean values of the learning abilities; active experimentation (AE), reflective observation (RO), abstract conceptualizing (AC) or concrete experience (CE) for male students were 35, 28, 30 and 26 respectively while they were 31, 30, 31 and 29 respectively for female students. There were significant difference between male and female students regarding the mean values of AE-RO (6.7 vs 1.5) and AC-CE (4.1 vs 2.1). This indicated that the style of male students were more convergent and accommodating than those of female students. The female had more assimilating and divergent styles. CONCLUSION: Learning style in Saudi medical students showed difference between males and females in the early college years. Most male students had convergent and accommodating learning styles, while the female dominant learning styles were divergent and assimilating. Planning and implementation of instruction need to consider these findings. PMID- 24058247 TI - Controllable immobilization of polyacrylamide onto glass slide: synthesis and characterization. AB - A novel route was introduced to synthesize dense polyacrylamide (PAM) onto the glass slide surface. To investigate the surface chemistry of the PAM on the glass slides, X-ray photoelectron spectroscopy (XPS) was utilized to obtain detailed chemical state information on the PAM layer constituents. The XPS peak data were consistent with the presented model of the PAM on the glass slide surface. Scanning electron microscopy and atomic force microscope data indicated the presence of PAM on the glass slides, which consist of nodules. The results showed that PAM was successfully immobilized onto glass slides with a two-tier structure under aqueous condition and a monolayer structure under anhydrous condition. Compared with those under aqueous condition, the controllability of the molecular layer on glass slides and the reproducibility under anhydrous condition were much better, which makes anhydrous condition an advisable condition for the study of the reaction mechanisms of glass slides modified by PAM. PMID- 24058249 TI - Survey of keyword adjustment of published articles medical subject headings in journal of mazandaran university of medical sciences (2009-2010). AB - CONFLICT OF INTEREST: NONE DECLARED. INTRODUCTION: Keywords are the most important tools for Information retrieval. They are usually used for retrieval of articles based on contents of information reserved from printed and electronic resources. Retrieval of appropriate keywords from Medical Subject Headings (MeSH) can impact with exact, correctness and short time on information retrieval. Regarding the above mentioned matters, this study was done to compare the Latin keywords was in the articles published in the Journal of Mazandaran University of Medical Sciences. METHOD: This is a descriptive study. The data were extracted from the key words of Englsih abstracts of articles published in the years 2009 2010 in the Journal of Mazandaran University of Medical Sciences by census method. Checklist of data collection is designed, based on research objectives and literature review which has face validity. Compliance rate in this study was to determine if the keywords cited in this article as a full subject of the main subject headings in a MeSH (Bold and the selected word) is a perfect adjustment. If keywords were cited in the article but the main heading is not discussed in the following main topics to be discussed with reference to See and See related it has considered has partial adjustment. RESULTS: Out of 148 articles published in 12 issues in proposed time of studying, 72 research papers were analyzed. The average numbers of authors in each article were 4 +/- 1. Results showed that most of specialty papers 42 (58. 4%), belonging to the (Department of Clinical Sciences) School of Medicine, 11 (15.3%) Basic Science, 6(8.4%) Pharmacy, Nursing and Midwifery 5(6.9%), 4(5.5%) Health, paramedical Sciences 3(4.2%), and non medical article 1(1.3%) school of medicine. In general, results showed that 80 (30%) of key words have been used to complete the adjustment. Also, only 1(1.4%) had complete adjustment with all the MeSH key words and in 8 articles(11.4%) key words of had no adjustment with MeSH. CONCLUSION: The results showed that only 17 articles could be retrieved if the search words are selected from the MeSH. In this case the expected 100% of published articles titles at this university the validity of exchange of research projects which is something noteworthy. The lack of correlation between number of authors and matching of Keywords with MeSH, may mean all of the papers' authors did not take part in writing and it is understanding that only one author wrote the paper. PMID- 24058250 TI - Awareness and using of medical students about mobile health technology in clinical areas. AB - CONFLICT OF INTEREST: NONE DECLARED. INTRODUCTION: Necessity of data transmission and getting contact with specialists is so evident in impassable regions. In order to solve such problems, there are different solutions one of which is mobile health technology. Being small and user-friendly, easy to enter data and having low expense are some of its advantages. This study aims to define the association between awareness of medical students in clinical stage about mobile health technology application and the rate of their using this technology in educational hospital of Isfahan in 2011. METHOD: The study is a cross-sectional analytical application research. Sixty medical students were selected as samples from a society of 240 medical students. A researcher-made questionnaire was used. The questionnaire included 21 multiple choice and 15 yes no questions, which were corrected to reach a score. A researcher-made checklist with 5-fold Likert scale was used to define the rate of applying such technology. The reliability of questionnaire was confirmed through a test-retest. The collected data were analyzed with the help of SPSS software in descriptive and deductive statistics level. FINDINGS: The highest percentage of awareness about mobile health technology among medical students in the clinical stage of Azzahra educational hospital is 45.6 in nature areas, and their lowest percentage of awareness is 17.8 in the infrastructure area. In addition, their mean awareness of all areas is 54.4. The highest percentage of using mobile health technology by medical students is 14.6 in the education area, and their lowest percentage of usage is 6.8 in the treatment area. Their mean usage of all areas is 9.4 as well. CONCLUSION: The rate of awareness and application of mobile health technology is not favorable. Except for treatment, there is no significant association between the rate of awareness and application of mobile health technology. PMID- 24058251 TI - Scientific production of medical sciences universities in north of iran. AB - CONFLICT OF INTEREST: NONE DECLARED. INTRODUCTION: The study of the scientific evidence citation production by famous databases of the world is one of the important indicators to evaluate and rank the universities. The study at investigating the scientific production of Northern Iran Medical Sciences Universities in Scopus from 2005 through 2010. METHOD: This survey used scientometrics technique. The samples under studies were the scientific products of four northern Iran Medical universities. RESULTS: Viewpoints quantity of the Scientific Products Mazandaran University of Medical Sciences stands first and of Babol University of Medical Sciences ranks the end, but from the viewpoints of quality of scientific products of considering the H-Index and the number of cited papers the Mazandaran University of Medical Sciences is a head from the other universities under study. From the viewpoints of subject of the papers, the highest scientific products belonged to the faculty of Pharmacy affiliated to Mazandaran University of Medial Sciences, but the three other universities for the genetics and biochemistry. CONCLUSION: Results showed that the Mazandaran University of Medical Sciences as compared to the other understudies universities ranks higher for the number of articles, cited articles, number of hard work authors and H-Index of Scopus database from 2005 through 2010. PMID- 24058252 TI - Initial values of donor hematocrit and efficiency of plateletpheresis. AB - CONFLICT OF INTEREST: NONE DECLARED. INTRODUCTION: The collection of platelets by apheresis is considered as a very great progress in transfusion medicine. A larger yield (total number of collected platelets) is obtained if the donor has a greater number of initial platelets and if the separation is done in a shorter time. One of the parameters is also the efficiency of the platelet collection (expressed in percentage) on the value of which different factors may have direct or indirect influence. AIMS: To calculate the efficiency of platelet collection with the separator Fenval Baxter AMICUS and to compare the efficiency of platelet collection with this separator in relation to the initial value of donor hematocrit. DONORS AND METHODS: The donors who participated in this study were divided into groups according to the value of the donor's 'hematocrit before separation. Group C consisted of donors whose initial value of the hematocrit was lower or equal to 46%. Group D consisted of donors whose initial value of the hematocrit was higher than 46%. The process was carried out on Fenval Baxter AMICUS. The expected efficiency of the collection was obtained by dividing the total number of collected cells by the expected total number of processed cells, i.e. the total number of cells passed through the equipment. RESULTS: In the 258 separations which satisfied the fixed criteria were men in 226 cases (87.6%) and women in 32 (12.4%). There is a statically significant difference in the platelet value between the groups and this value is higher in group D than in group C. The average value of platelets before separation was 46.66. The range of minimal and maximal value is from 38.8 to 52.4 +/-2.78. The initial value of hematocrits of the donor does not intervene in the length of the separation, but it has a significant effect on the efficiency of the platelet collection. Increases in the number of hematocrits significantly decrease the efficiency of platelet collection. In practice it means that we can base on this fact make a better selection of donors. In this kind selection, one should prefer a donor with a higher number of initial platelets and lower levels of hematocrits. In that way we can collect a more important yield, have a shorter length of separation and increase the efficiency of platelet collection. Its advantage is as well medical because of a more important yield but also financial because of the decrease of the length of the separation and the increase in efficiency. Key words: value of hematocrits, donors, apheresis, platelets, efficiency. PMID- 24058253 TI - United in prevention-electrocardiographic screening for chronic obstructive pulmonary disease. AB - CONFLICT OF INTEREST: NONE DECLARED. INTRODUCTION: P-wave abnormalities on the resting electrocardiogram have been associated with cardiovascular or pulmonary disease. So far, "Gothic" P wave and verticalization of the frontal plane axis is related to lung disease, particularly obstructive lung disease. AIM: We tested if inverted P wave in AVl as a lone criteria of P wave axis >70 degrees could be screening tool for emphysema. MATERIAL AND METHOD: 1095 routine electrocardiograms (ECGs) were reviewed which yielded 478 (82,1%) ECGs with vertical P-axis in sinus rhythm. Charts were reviewed for the diagnosis of COPD and emphysema based on medical history and pulmonary function tests. CONCLUSION: Electrocardiogram is very effective screening tool not only in cardiovascular field but in chronic obstructive pulmonary disease. The verticality of the P axis is usually immediately apparent, making electrocardiogram rapid screening test for emphysema. PMID- 24058254 TI - Barriers for Adopting Electronic Health Records (EHRs) by Physicians. AB - CONFLICT OF INTEREST: NONE DECLARED. INTRODUCTION: Electronic Medical Records (EMRs) are computerized medical information systems that collect, store and display patient information. They are means to create legible and organized recordings and to access clinical information about individual patients. Despite of the positive effects of the EMRs usage in medical practices, the adoption rate of such systems is still low and meets resistance from physicians. The EHRs represent an essential tool for improving both in the safety and quality of health care, though physicians must actively use these systems to accrue the benefits. This study was unsystematic-review. AIM: The aim of this study was to express barriers perceived y physicians to the adoption of the EHRs. METHOD OF THE STUDY: This study was non-systematic reviewed which the literature was searched on barriers perceived by physicians to the adoption of Electronic Health Records (EHRs) with the help of library, books, conference proceedings, data bank, and also searches engines available at Google, Google scholar. DISCUSSION: FOR OUR SEARCHES, WE EMPLOYED THE FOLLOWING KEYWORDS AND THEIR COMBINATIONS: physicians, electronic medical record, electronic health record, barrier, and adoption in the searching areas of title, keywords, abstract, and full text. In this study, more than 100 articles and reports were collected and 27 of them were selected based on their relevancy. Electronic health record use requires the presence of certain user and system attributes, support from others, and numerous organizational and environment facilitators. PMID- 24058255 TI - The role of robotics in ovarian transposition. AB - CONFLICT OF INTEREST: NONE DECLARED The preservation of ovarian function in young patients after radical hysterectomy has an important role at the post-oncologic management and preserves life quality. Ovarian transposition is a technique in order to avoid irreversible damage to the ovaries caused by irradiation. The principal surgical ways in the transposition of the ovaries is both through laparotomy and laparoscopy. Recently, the application of the robotic technology on this method seems to be promising. We performed a literature search with terms related to robotic surgery and ovarian transposition in Pubmed and Scopus. Two articles were identified dealing with this technique. Robotic assisted ovarian transposition is presented and the possible advantages and disadvantages of such a technique are discussed. PMID- 24058256 TI - Choledochal cyst - presentation and treatment in an adult. AB - CONFLICT OF INTEREST: NONE DECLARED Choledochal cyst is a congenital cystic dilation of a part of bile duct that occurs most commonly in the main part of common bile duct. Diagnosis of choledochal cyst is concluded upon disproportionate expansion of extrahepatic bile duct. Symptom trias are: abdominal pain, jaundice and abdominal mass represent clinical guideline signs of diagnosis. Furthermore, hepato-biliary diseases in adults can conceal the primary condition. In addition to this, ultrasound, CT, MRI, cholangiopancreatography (ERCP), transhepatic percutane cholangiography (PTC) guide us for a detailed examination in order to verify the diagnosis. Active endoscopic cholangiography represents an important technique that provides needed anatomic solution and details in diagnosis of choledochal cyst. PMID- 24058257 TI - Giant mature adrenal cystic teratoma in an infant. AB - CONFLICT OF INTEREST: NONE DECLARED. INTRODUCTION: Teratomas are derived from embryonic tissues that are typically found in the gonadal and sacrococcygeal regions of adults and children. Primary teratomas in the retroperitoneum are very rare in infant and primary adrenal teratomas are extremely rare. Early diagnosis and surgical resection are important for effective treatment. CASE REPORT: We report here the case of a histologically unusual adrenal teratomas detected on computed tomography during the workup of abdominal distension 3-mounth-old male infant. The evaluation and treatment of this condition and a review of the literature are included in this paper. PMID- 24058258 TI - Ambivalent Sexism and Power-Related Gender-role Ideology in Marriage. AB - Glick-Fiske's (1996) Ambivalent Sexism Inventory(ASI) and a new Gender-Role Ideology in Marriage (GRIM) inventory examine ambivalent sexism toward women, predicting power-related, gender-role beliefs about mate selection and marriage norms. Mainland Chinese, 552, and 252 U.S. undergraduates participated. Results indicated that Chinese and men most endorsed hostile sexism; Chinese women more than U.S. women accepted benevolent sexism. Both Chinese genders prefer home oriented mates (women especially seeking a provider and upholding him; men especially endorsing male-success/female-housework, male dominance, and possibly violence). Both U.S. genders prefer considerate mates (men especially seeking an attractive one). Despite gender and culture differences in means, ASI-GRIM correlations replicate across those subgroups: Benevolence predicts initial mate selection; hostility predicts subsequent marriage norms. PMID- 24058259 TI - Laser Wavelength Dependence of Background Fluorescence in Raman Spectroscopic Analysis of Synovial Fluid from Symptomatic Joints. AB - Gout is a disease process where the nucleation and growth of crystals in the synovial fluid of joints elicit painful arthritis-like symptoms. Raman spectroscopy is evolving as a potential diagnostic tool in identifying such crystals; however, attainment of sufficient Raman signal while overcoming the background fluorescence remains as a major challenge. The current study focused on assessing whether excitation in 532-700 nm range will provide greater signal intensity than the standard 785 nm while not being impeded by background fluorescence. We characterized the fluorescence spectra, absorption spectra and Raman spectra of synovial fluid from patients who presented "gout-like symptoms" (symptomatic) and controls (asymptomatic). A digestion and filtration method was developed to isolate crystals from synovial fluid while reducing the organic burden. Spectral profile and photobleaching dynamics during Raman spectroscopy were observed under an excitation wavelength range spanning 532 to 785 nm. Absorbance and fluorescence profiles indicated the digestion and filtration worked effectively to extract crystals from symptomatic synovial fluid without introducing additional fluorescence. Raman spectral analyses at 532 nm, 660 nm, 690 nm and 785 nm indicated that both asymptomatic and symptomatic samples had significant levels of fluorescence at excitation wavelengths below 700 nm, which either hindered the collection of Raman signal or necessitated prolonged durations of photobleaching. Raman-based diagnostics were more feasible at the longest excitation wavelength of 785 nm without employing photobleaching. This study further demonstrated that a near-infrared OEM based lower-cost Raman system at 785 nm excitation has sufficient sensitivity to identify crystals isolated from the synovial fluid. In conclusion, while lower excitation wavelengths provide greater signal, the fluorescence necessitates near-infrared wavelengths for Raman analysis of crystal species observed in synovial aspirates. PMID- 24058260 TI - Social learning about levels of perinatal and infant mortality in Niakhar, Senegal. PMID- 24058261 TI - Giving and Receiving Emotional Support Online: Communication Competence as a Moderator of Psychosocial Benefits for Women with Breast Cancer. AB - This study examines the moderating role of emotional communication competence in the relationship between computer-mediated social support (CMSS) group participation, specifically giving and receiving emotional support, and psychological health outcomes. Data were collected as part of randomized clinical trials for women diagnosed with breast cancer within the last 2 months. Expression and reception of emotional support was assessed by tracking and coding the 18,064 messages that 236 patients posted and read in CMSS groups. The final data used in the analysis was created by merging (a) computer-aided content analysis of discussion posts, (b) action log data analysis of system usage, and (c) baseline and six-month surveys collected to assess change. Results of this study demonstrate that emotional communication competence moderates the effects of expression and reception of emotional support on psychological quality of life and breast cancer-related concerns in both desired and undesired ways. Giving and receiving emotional support in CMSS groups has positive effects on emotional well being for breast cancer patients with higher emotional communication, while the same exchanges have detrimental impacts on emotional well-being for those with lower emotional communication competence. The theoretical and practical implications for future research are discussed. PMID- 24058262 TI - The Daily Heterosexist Experiences Questionnaire: Measuring Minority Stress Among Lesbian, Gay, Bisexual, and Transgender Adults. AB - The authors conducted a three-phase, mixed-methods study to develop a self-report measure assessing the unique aspects of minority stress for lesbian, gay, bisexual, and transgender adults. The Daily Heterosexist Experiences Questionnaire has 50 items and nine subscales with acceptable internal reliability, and construct and concurrent validity. Mean sexual orientation and gender differences were found. PMID- 24058263 TI - Common Prediction Equations Overestimate Measured Resting Metabolic Rate in Young Hispanic Women. AB - The accuracy of 6 resting metabolic rate (RMR) prediction equations to indirect calorimetry was compared in 38 Hispanic women (age = 30 +/- 7 years; body mass index = 28.9 +/- 7.2 kg/m2; body fat = 42% +/- 8%). Paired t tests examined differences between predicted and measured RMR; significance defined as P < 0.05. Bias and agreement were displayed using Bland-Altman plots. Accuracy was defined when the predicted RMR was +/- 10% of the measured RMR. Data were analyzed with SPSS (version 19). Only the equation of Owen et al was not significantly different from the measured RMR (1336 +/- 142 and 1322 +/- 203 kcal/d, respectively). The equation of Owen et al was accurate for 84.2% of women; RMR prediction equations had limited applicability for young Hispanic women. PMID- 24058264 TI - New evidence on the validity of the Arnett Caregiver Interaction Scale: Results from the Early Childhood Longitudinal Study-Birth Cohort. AB - The Arnett Caregiver Interaction Scale (CIS) has been widely used in research studies to measure the quality of caregiver-child interactions. The scale was modeled on a well-established theory of parenting, but there are few psychometric studies of its validity. We applied factor analyses and item response theory methods to assess the psychometric properties of the Arnett CIS in a national sample of toddlers in home-based care and preschoolers in center-based care from the Early Childhood Longitudinal Study-Birth Cohort. We found that a bifactor structure (one common factor and a second set of specific factors) best fits the data. In the Arnett CIS, the bifactor model distinguishes a common substantive dimension from two methodological dimensions (for positively and negatively oriented items). Despite the good fit of this model, the items are skewed (most teachers/caregivers display positive interactions with children) and, as a result, the Arnett CIS is not well suited to distinguish between caregivers who are "highly" versus "moderately" positive in their interactions with children, according to the items on the scale. Regression-adjusted associations between the Arnett CIS and child outcomes are small, especially for preschoolers in centers. We encourage future scale development work on measures of child care quality by early childhood scholars. PMID- 24058265 TI - Are People Overoptimistic about the Effects of Heavy Drinking? AB - We test whether heavy or binge drinkers are overly optimistic about probabilities of adverse consequences from these activities or are relatively accurate about these probabilities. Using data from a survey in eight cities, we evaluate the relationship between subjective beliefs and drinking. We assess accuracy of beliefs about several outcomes of heavy/binge drinking: reduced longevity, liver disease onset, link between alcohol consumption and Driving While Intoxicated (DWI), probability of an accident after drinking, accuracy of beliefs about encountering intoxicated drivers on the road, and legal consequences of DWI ranging from being stopped to receiving fines and jail terms. Overall, there is no empirical support for the optimism bias hypothesis. We do find that persons consuming a lot of alcohol tend to be more overconfident about their driving abilities and ability to handle alcohol. However, such overconfidence does not translate into over-optimism about consequences of high levels of alcohol consumption. PMID- 24058267 TI - Viscous damping and spring force calculation of regularly perforated MEMS microstructures in the Stokes' approximation. AB - There are a number of applications for microstructure devices consisting of a regular pattern of perforations, and many of these utilize fluid damping. For the analysis of viscous damping and for calculating the spring force in some cases, it is possible to take advantage of the regular hole pattern by assuming periodicity. Here a model is developed to determine these quantities based on the solution of the Stokes' equations for the air flow. Viscous damping is directly related to thermal-mechanical noise. As a result, the design of perforated microstructures with minimal viscous damping is of real practical importance. A method is developed to calculate the damping coefficient in microstructures with periodic perforations. The result can be used to minimize squeeze film damping. Since micromachined devices have finite dimensions, the periodic model for the perforated microstructure has to be associated with the calculation of some frame (edge) corrections. Analysis of the edge corrections has also been performed. Results from analytical formulas and numerical simulations match very well with published measured data. PMID- 24058266 TI - Parent and Multidisciplinary Provider Perspectives on Earliest Intervention for Children at Risk for Autism Spectrum Disorders. AB - Early identification and treatment of Autism Spectrum Disorder (ASD) in children younger than age 3 years is becoming an increasingly common area of concern and study. Research suggests that systematic, early intervention can significantly improve outcomes and reduce the cost of caring for children with ASD through the lifespan. Therefore, it is imperative that evidence-based practices (EBPs) for this young age group are translated effectively into community settings. One method of promoting EBPs and developing capacity for implementation is active collaboration between researchers and community stakeholders. This requires a precise understanding of the perspectives of stakeholders regarding the benefits and barriers of specific practices and early intervention in general. In the current study, we gathered feedback from families and a multidisciplinary group of community providers regarding early intervention values for infants/toddlers at risk for ASD and their families through focus groups. The opinions and values of the community sample were examined using mixed qualitative and quantitative methods to facilitate efforts to build long-term capacity for implementing efficacious ASD intervention for children younger than 3 years. Results indicated that, the values of community providers and parents were highly similar and were aligned with EBP strategies. Recommendations for translating EBPs for this population into community settings are discussed. PMID- 24058268 TI - Total Synthesis of (+/-)-Dragmacidin E: Problems Solved and Lessons Learned. AB - (+/-)-Dragmacidin E was synthesized in 25 steps from commercially available 7 (benzyloxy)indole. Key transformations in this sponge metabolite's preparation include (a) a Witkop cyclization to establish the bridging indole core, (b) cyclo dehydrative pyrazinone formation to unite the two indole-bearing components, and (c) late-stage guanidine installation via chemoselective carbonyl activation. PMID- 24058269 TI - Continuous-Wave Stimulated Raman Scattering (cwSRS) Microscopy. AB - Stimulated Raman scattering (SRS) microscopy is a powerful tool for chemically sensitive non-invasive optical imaging. However, ultrafast laser sources, which are currently employed, are still expensive and require substantial maintenance to provide temporal overlap and spectral tuning. SRS imaging, which utilizes continuous-wave laser sources, has a major advantage, as it eliminates the cell damage due to exposure to the high-intensity light radiation, while substantially reducing the cost and complexity of the set-up. As a proof-of-principle, we demonstrate microscopic imaging of dimethyl sulfoxide using two independent, commonly used lasers, a diode-pumped, intracavity doubled 532-nm laser and a He Ne laser operating at 632.8-nm. PMID- 24058271 TI - How histopathology can contribute to an understanding of defense mechanisms against cryptococci. AB - Invasive fungal infections, particularly those considered opportunistic, have become a common and significant complication of procedures performed in advanced contemporary medicine. Among such infections, cryptococcosis, which is usually caused by infection with Cryptococcus neoformans and Cryptococcus gattii, is particularly problematic because this fungal infection occurs in immunocompromised and apparently immunocompetent individuals. It has been largely accepted that Cryptococcus species are recognized by cellular receptors and that Th1-type immune responses play an important role in defense mechanisms against the yeast. However, the interaction between the yeast and host tissue varies depending on the characteristics of the yeast and the immune status of the host. To gain a better understanding of the pathophysiology of cryptococcosis, we wish to emphasize the usefulness of histopathological examinations, because it allowed more detailed information of an extremely complex interaction between the causative yeasts and tissue response. In the present review, we describe the pathophysiology of cryptococcosis as largely revealed in our previous histopathological investigations of the experimental infection. PMID- 24058270 TI - Stimulation of MMP-1 and CCL2 by NAMPT in PDL cells. AB - Periodontitis is an inflammatory disease caused by pathogenic microorganisms and characterized by the destruction of the periodontium. Obese individuals have an increased risk of periodontitis, and elevated circulating levels of adipokines, such as nicotinamide phosphoribosyltransferase (NAMPT), may be a pathomechanistic link between both diseases. The aim of this in vitro study was to examine the regulation of periodontal ligament (PDL) cells by NAMPT and its production under inflammatory and infectious conditions. NAMPT caused a significant upregulation of 9 genes and downregulation of 3 genes, as analyzed by microarray analysis. Eight of these genes could be confirmed by real-time PCR: NAMPT induced a significant upregulation of EGR1, MMP-1, SYT7, ITPKA, CCL2, NTM, IGF2BP3, and NRP1. NAMPT also increased significantly the MMP-1 and CCL2 protein synthesis. NAMPT was significantly induced by interleukin-1 beta and the periodontal microorganism P. gingivalis. NAMPT may contribute to periodontitis through upregulation of MMP-1 and CCL2 in PDL cells. Increased NAMPT levels, as found in obesity, may therefore represent a mechanism whereby obesity could confer an increased risk of periodontitis. Furthermore, microbial and inflammatory signals may enhance the NAMPT synthesis in PDL cells and thereby contribute to the increased gingival and serum levels of this adipokine, as found in periodontitis. PMID- 24058273 TI - Problems for the Book of Problems? Diagnosing Mental Health Disorders Among Youth. AB - As an introduction to the Special Issue that includes a series of articles on comorbid mental health conditions among youth, some issues pertinent to the diagnostic system are considered. The discussion of illustrative issues that affect the diagnoses of mental health problems among youth includes reminders to consider the source, the time frame, what's normal, the situation, the data, and the effect of changing diagnostic criteria. We support the DSM and ICD efforts to continue to develop as instruments by relying on the data. PMID- 24058274 TI - Volume Measures Using a Digital Image Analysis System are Reliable in Diabetic Foot Ulcers. AB - Reliable measures of wound size are critical to wound healing research and clinical management. Measurement of full-thickness wounds is increasingly being done using digital images and photogrammetric software, such as VeVMD (Vista Medical, Winnipeg, Manitoba, Canada), to estimate wound volume. The reliability of VeVMD in determining wound volume is unknown. The present study sought to examine the reliability of wound volume measurements obtained using VeVMD. METHODS: A cross-sectional study of adults with full-thickness, neuropathic, diabetic foot ulcers (DFU) at 2 sites in the US Midwest was undertaken. Ulcer images were obtained, stored, and used to obtain measures of wound volume using VeVMD. Four raters independently completed wound measures, and then repeated these measures 2 weeks after the first measurement. Raters were blinded to the comparison measurements. Inter- and intra-rater correlations were computed. RESULTS: Thirty-three enrolled subjects with 33 DFU were included in the analyses. Inter-rater reliability was 0.745 and intra-rater reliability was 0.868. Four ulcers showed noticeably less agreement between raters; these ulcers had small, but deeply recessed areas, resulting in differences in defining the wound margin. When these 4 ulcers were removed, inter- and intra-rater reliabilities were excellent (0.970 and 0.981, respectively). CONCLUSION: Reliabilities of volume measurements obtained with VeVMD were acceptable in DFU, even when raters had different definitions of the ulcer margin or changed their definition from time to time. However, conclusions cannot be drawn regarding the performance of VeVMD in other wound types. PMID- 24058275 TI - Magic-Angle-Spinning NMR Magnet Development: Field Analysis and Prototypes. AB - We are currently working on a program to complete a 1.5 T/75 mm RT bore magic angle-spinning nuclear magnetic resonance magnet. The magic-angle-spinning magnet comprises a z-axis 0.866-T solenoid and an x-axis 1.225-T dipole, each to be wound with NbTi wire and operated at 4.2 K in persistent mode. A combination of the fields creates a 1.5-T field pointed at 54.74 degrees (magic angle) from the rotation (z) axis. In the first year of this 3-year program, we have completed magnetic analysis and design of both coils. Also, using a winding machine of our own design and fabrication, we have wound several prototype dipole coils with NbTi wire. As part of this development, we have repeatedly made successful persistent NbTi-NbTi joints with this multifilamentary NbTi wire. PMID- 24058272 TI - Contribution of lung macrophages to the inflammatory responses induced by exposure to air pollutants. AB - Large population cohort studies have indicated an association between exposure to particulate matter and cardiopulmonary morbidity and mortality. The inhalation of toxic environmental particles and gases impacts the innate and adaptive defense systems of the lung. Lung macrophages play a critically important role in the recognition and processing of any inhaled foreign material such as pathogens or particulate matter. Alveolar macrophages and lung epithelial cells are the predominant cells that process and remove inhaled particulate matter from the lung. Cooperatively, they produce proinflammatory mediators when exposed to atmospheric particles. These mediators produce integrated local (lung, controlled predominantly by epithelial cells) and systemic (bone marrow and vascular system, controlled predominantly by macrophages) inflammatory responses. The systemic response results in an increase in the release of leukocytes from the bone marrow and an increased production of acute phase proteins from the liver, with both factors impacting blood vessels and leading to destabilization of existing atherosclerotic plaques. This review focuses on lung macrophages and their role in orchestrating the inflammatory responses induced by exposure to air pollutants. PMID- 24058276 TI - EXPONENTIAL TIME DIFFERENCING FOR HODGKIN-HUXLEY-LIKE ODES. AB - Several authors have proposed the use of exponential time differencing (ETD) for Hodgkin-Huxley-like partial and ordinary differential equations (PDEs and ODEs). For Hodgkin-Huxley-like PDEs, ETD is attractive because it can deal effectively with the stiffness issues that diffusion gives rise to. However, large neuronal networks are often simulated assuming "space-clamped" neurons, i.e., using the Hodgkin-Huxley ODEs, in which there are no diffusion terms. Our goal is to clarify whether ETD is a good idea even in that case. We present a numerical comparison of first- and second-order ETD with standard explicit time-stepping schemes (Euler's method, the midpoint method, and the classical fourth-order Runge-Kutta method). We find that in the standard schemes, the stable computation of the very rapid rising phase of the action potential often forces time steps of a small fraction of a millisecond. This can result in an expensive calculation yielding greater overall accuracy than needed. Although it is tempting at first to try to address this issue with adaptive or fully implicit time-stepping, we argue that neither is effective here. The main advantage of ETD for Hodgkin Huxley-like systems of ODEs is that it allows underresolution of the rising phase of the action potential without causing instability, using time steps on the order of one millisecond. When high quantitative accuracy is not necessary and perhaps, because of modeling inaccuracies, not even useful, ETD allows much faster simulations than standard explicit time-stepping schemes. The second-order ETD scheme is found to be substantially more accurate than the first-order one even for large values of Deltat. PMID- 24058277 TI - Particle Filters and Occlusion Handling for Rigid 2D-3D Pose Tracking. AB - In this paper, we address the problem of 2D-3D pose estimation. Specifically, we propose an approach to jointly track a rigid object in a 2D image sequence and to estimate its pose (position and orientation) in 3D space. We revisit a joint 2D segmentation/3D pose estimation technique, and then extend the framework by incorporating a particle filter to robustly track the object in a challenging environment, and by developing an occlusion detection and handling scheme to continuously track the object in the presence of occlusions. In particular, we focus on partial occlusions that prevent the tracker from extracting an exact region properties of the object, which plays a pivotal role for region-based tracking methods in maintaining the track. To this end, a dynamical choice of how to invoke the objective functional is performed online based on the degree of dependencies between predictions and measurements of the system in accordance with the degree of occlusion and the variation of the object's pose. This scheme provides the robustness to deal with occlusions of an obstacle with different statistical properties from that of the object of interest. Experimental results demonstrate the practical applicability and robustness of the proposed method in several challenging scenarios. PMID- 24058278 TI - 2D/3D Image Registration using Regression Learning. AB - In computer vision and image analysis, image registration between 2D projections and a 3D image that achieves high accuracy and near real-time computation is challenging. In this paper, we propose a novel method that can rapidly detect an object's 3D rigid motion or deformation from a 2D projection image or a small set thereof. The method is called CLARET (Correction via Limited-Angle Residues in External Beam Therapy) and consists of two stages: registration preceded by shape space and regression learning. In the registration stage, linear operators are used to iteratively estimate the motion/deformation parameters based on the current intensity residue between the target projec-tion(s) and the digitally reconstructed radiograph(s) (DRRs) of the estimated 3D image. The method determines the linear operators via a two-step learning process. First, it builds a low-order parametric model of the image region's motion/deformation shape space from its prior 3D images. Second, using learning-time samples produced from the 3D images, it formulates the relationships between the model parameters and the co-varying 2D projection intensity residues by multi-scale linear regressions. The calculated multi-scale regression matrices yield the coarse-to-fine linear operators used in estimating the model parameters from the 2D projection intensity residues in the registration. The method's application to Image-guided Radiation Therapy (IGRT) requires only a few seconds and yields good results in localizing a tumor under rigid motion in the head and neck and under respiratory deformation in the lung, using one treatment-time imaging 2D projection or a small set thereof. PMID- 24058279 TI - Prognostic value of resting pulmonary function in heart failure. AB - BACKGROUND: The heart and lungs are intimately linked anatomically and physiologically, and, as a result, heart failure (HF) patients often develop changes in pulmonary function. This study examined the prognostic value of resting pulmonary function (PF) in HF. METHODS AND RESULTS: In all, 134 HF patients (enrolled from January 1, 1999 Through December 31, 2005; ejection fraction (EF) = 29% +/- 11%; mean age = 55 +/- 12 years; 65% male) were followed for 67 +/- 34 months with death/transplant confirmed via the Social Security Index and Mayo Clinic registry. PF included forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), diffusing capacity of the lungs for carbon monoxide (DLCO), and alveolar volume (VA). Patients were divided in tertiles according to PF with survival analysis via log-rank Mantel-Cox test with chi square analysis. Groups for FVC included (1) >96%, (2) 96% to 81%, and (3) <81% predicted (chi-square = 18.9, P < 0.001). Bonferroni correction for multiple comparisons (BC) suggested differences between groups 1 and 3 (P < 0.001) and 2 and 3 (P = 0.008). Groups for FEV1 included (1) >94%, (2) 94% to 77%, and (3) <77% predicted (chi-square = 17.3, P <0.001). BC suggested differences between groups 1 and 3 (P <0.001). Groups for DLCO included (1) >90%, (2) 90% to 75%, and (3) <75% predicted (chi-square = 11.9, P = 0.003). BC suggested differences between groups 1 and 3 (P < 0.001). Groups for VA included (1) >97%, (2) 97% to 87%, and (3) <87% predicted (Chi-square = 8.5, P = 0.01). BC suggested differences between groups 1 and 2 (P = 0.014) and 1 and 3 (P = 0.003). CONCLUSIONS: In a well-defined cohort of HF patients, resting measures of PF are predictive of all-cause mortality. PMID- 24058280 TI - Nonparametric Spatial Models for Extremes: Application to Extreme Temperature Data. AB - Estimating the probability of extreme temperature events is difficult because of limited records across time and the need to extrapolate the distributions of these events, as opposed to just the mean, to locations where observations are not available. Another related issue is the need to characterize the uncertainty in the estimated probability of extreme events at different locations. Although the tools for statistical modeling of univariate extremes are well-developed, extending these tools to model spatial extreme data is an active area of research. In this paper, in order to make inference about spatial extreme events, we introduce a new nonparametric model for extremes. We present a Dirichlet-based copula model that is a flexible alternative to parametric copula models such as the normal and t-copula. The proposed modelling approach is fitted using a Bayesian framework that allow us to take into account different sources of uncertainty in the data and models. We apply our methods to annual maximum temperature values in the east-south-central United States. PMID- 24058281 TI - The compression of deaths above the mode. AB - Kannisto (2001) has shown that as the frequency distribution of ages at death has shifted to the right, the age distribution of deaths above the modal age has become more compressed. In order to further investigate this old-age mortality compression, we adopt the simple logistic model with two parameters, which is known to fit data on old-age mortality well (Thatcher 1999). Based on the model, we show that three key measures of old-age mortality (the modal age of adult deaths, the life expectancy at the modal age, and the standard deviation of ages at death above the mode) can be estimated fairly accurately from death rates at only two suitably chosen high ages (70 and 90 in this study). The distribution of deaths above the modal age becomes compressed when the logits of death rates fall more at the lower age than at the higher age. Our analysis of mortality time series in six countries, using the logistic model, endorsed Kannisto's conclusion. Some possible reasons for the compression are discussed. PMID- 24058282 TI - Arthur Roger Thatcher's contributions to longevity research: A Reflexion. PMID- 24058283 TI - Dyspnea Management in Early Stage Lung Cancer: A Palliative Perspective. PMID- 24058284 TI - Stability of a cosmetic multiple emulsion loaded with green tea extract. AB - Multiple emulsions are excellent and exciting potential systems for the delivery of useful cosmetic agents. The work describes stability of a multiple emulsion for cosmetic purpose, loaded with extract of Camellia sinensis L. (Theaceae) in concentration of 5%. The formulation constitutes of cetyl dimethicone copolyol and polyoxyethylene (20) cetyl ether as emulsifiers and was characterised and monitored for various physicochemical aspects. Centrifugation has no devastating effect on physical destabilization/phase separation observed for 30 days. Mean globule sizes of multiple droplets were found in the range of 10.29 +/- 4.4 MUm to 12.77 +/- 5.1 MUm and of inner droplets were in the range of 0.8 +/- 0.4 MUm to 1.6 +/- 0.8 MUm. All samples exhibited shear thinning behavior with increase in shear stress. The results of the present study indicate that multiple emulsions can be used as carrier of 5% Camellia sinensis L. extract to enhance desired effects. The developed physically and chemically stable system is an effective system for targeting skin layers; however, long-term stability at elevated temperatures may be needed with suitable modifications, if required. PMID- 24058285 TI - Energy-efficient data gathering scheme based on broadcast transmissions in wireless sensor networks. AB - Improving energy efficiency is the most important challenge in wireless sensor networks. Because sensing information is correlated in many sensor network applications, some previous works have proposed ideas that reduce the energy consumption of the network by exploiting the spatial correlation between sensed information. In this paper, we propose a distributed data compression framework that exploits the broadcasting characteristic of the wireless medium to improve energy efficiency. We analyze the performance of the proposed framework numerically and compare it with the performance of previous works using simulation. The proposed scheme performs better when the sensing information is correlated. PMID- 24058287 TI - Nonoscillatory central schemes for hyperbolic systems of conservation laws in three-space dimensions. AB - We extend a family of high-resolution, semidiscrete central schemes for hyperbolic systems of conservation laws to three-space dimensions. Details of the schemes, their implementation, and properties are presented together with results from several prototypical applications of hyperbolic conservation laws including a nonlinear scalar equation, the Euler equations of gas dynamics, and the ideal magnetohydrodynamic equations. Parallel scaling analysis and grid-independent results including contours and isosurfaces of density and velocity and magnetic field vectors are shown in this study, confirming the ability of these types of solvers to approximate the solutions of hyperbolic equations efficiently and accurately. PMID- 24058286 TI - Denervation as a common mechanism underlying different pulmonary vein isolation strategies for paroxysmal atrial fibrillation: evidenced by heart rate variability after ablation. AB - BACKGROUNDS: Segmental and circumferential pulmonary vein isolations (SPVI and CPVI) have been demonstrated to be effective therapies for paroxysmal atrial fibrillation (PAF). PVI is well established as the endpoint of different ablation techniques, whereas it may not completely account for the long-term success. METHODS: 181 drug-refractory symptomatic PAF patients were referred for segmental or circumferential PVI (SPVI = 67; CPVI = 114). Heart rate variability (HRV) was assessed before and after the final ablation. RESULTS: After following up for 62.23 +/- 12.75 months, patients underwent 1.41 +/- 0.68 procedures in average, and the success rates in SPVI and CPVI groups were comparable. 119 patients were free from AF recurrence (SPVI-S, n = 43; CPVI-S, n = 76). 56 patients had recurrent episodes (SPVI-R, n = 21; CPVI-R, n = 35). Either ablation technique decreased HRV significantly. Postablation SDNN and rMSSD were significantly lower in SPVI-S and CPVI-S subgroups than in SPVI-R and CPVI-R subgroups (SPVI-S versus SPVI-R: SDNN 91.8 +/- 32.6 versus 111.5 +/- 36.2 ms, rMSSD 47.4 +/- 32.3 versus 55.2 +/- 35.2 ms; CPVI-S versus CPVI-R: SDNN 83.0 +/- 35.6 versus 101.0 +/- 40.7 ms, rMSSD 41.1 +/- 22.9 versus 59.2 +/- 44.8 ms; all P < 0.05). Attenuation of SDNN and rMSSD remained for 12 months in SPVI-S and CPVI-S subgroups, whereas it recovered earlier in SPVI-R and CPVI-R subgroups. Multivariate logistic regression analysis identified SDNN as the only predictor of long-term success. CONCLUSIONS: Beyond PVI, denervation may be a common mechanism underlying different ablation strategies for PAF. PMID- 24058288 TI - Effects of an undergraduate HIV/AIDS course on students' HIV risk. AB - This study utilizes a quasi-experimental pre- and post-test survey design to examine the effects of a course, called HIV/AIDS: Science, Behavior, and Society, on undergraduate students' HIV knowledge, attitudes and risky sexual behaviors. With the assistance of social work faculty the course incorporates experiential learning pedagogy and a transdisciplinary perspective. Although the course was not designed as a prevention program, the theory of health behavior suggests the incorporation of experiential learning will impact crucial HIV/AIDS attitudes and behaviors. When regression models were applied, relative to the comparison group (N = 111), the HIV/AIDS class students (N = 79) reported an increase in post-test HIV knowledge, perceived susceptibility to HIV among females, and a reduction of risky sexual attitudes among sexually active students. PMID- 24058289 TI - LONG-TERM MONITORING OF THE PHYSICOCHEMICAL PROPERTIES OF SILICA-BASED NANOPARTICLES ON THE RATE OF ENDOCYTOSIS AND EXOCYTOSIS AND CONSEQUENCES OF CELL DIVISION. AB - Nanomaterials are diverse in size, shape and charge and these differences likely alter their physicochemical properties in biological systems. We have investigated how these properties alter the initial and long-term dynamics of endocytosis, cell viability, cell division, exocytosis, and interaction with a collagen extracellular matrix using silica-based fluorescent nanoparticles and the murine pre-osteoblast cell line, MC3T3-E1. Three surface modified nanoparticles were analyzed: positively charged (PTMA), negatively charged (OH), and neutrally charged polyethylene glycol (PEG). Positively charged PTMA-modified nanoparticles demonstrated the most rapid uptake, within 2 hours, while PEG modified and negatively charged OH nanoparticles demonstrated slower uptake. Cell viability was >80% irrespective of nanoparticle surface charge suggesting a general lack of toxicity. Long-term monitoring of fluorescent intensity revealed that nanoparticles were passed to daughter cells during mitotic cell division with a corresponding decrease in fluorescent intensity. These data suggest that irrespective of surface charge silica nanoparticles have the potential to internalize into osteoblasts, albeit with different kinetics. Furthermore, long lived nanoparticles have the potential to be transferred to daughter cells during mitosis and can be maintained for weeks intracellularly or within a collagen matrix without toxicity and limited exocytosis. PMID- 24058290 TI - FLUORESCENCE KINETICS OF COMPLEX FORMATION BETWEEN HUMAN SERUM ALBUMIN AND ZINC PHTHALOCYANINE TETRASULFONIC ACID. AB - Stopped-flow fluorescence was employed to measure the dissociation constant, activation energy, and frequency factor for zinc phthalocyanine tetrasulfonic acid binding to human serum albumin. A pseudo 1st order "Isolation Method" was used to measure temperature dependent rate constants at pH 7.00. Binding was followed by a relatively large emission signal that indicated the formation of a protein-ligand complex. The dissociation constant, activation energy and frequency factor were 3.3 (+/-0.3)*10-5 (M), 4.5 (+/-0.2)*104 J/mol, and 1.1 (+/ 0.1)*108 min-1 respectively. PMID- 24058291 TI - THERMODYNAMIC CHARACTERIZATION OF METAL PHTHALOCYANINES-HUMAN SERUM ALBUMIN INTERACTIONS. AB - The temperature dependence of the binding constants for human serum albumin and sulfonated metal-phthalocyanines were estimated by fluorescence spectroscopy. Stern-Volmer's analysis and Chipman's fits provided binding data for van't Hoff calculations of the thermodynamic parameters governing these interactions. Results show that the formations of the HSA- phthalocyanine complexes are favorable processes by both the DeltaH degrees and DeltaS degrees . However, the formation of HSA-AIPcS4 has a stronger dependence than HSA-ZnPcS 4on DeltaS degrees . PMID- 24058292 TI - Spatially explicit data: stewardship and ethical challenges in science. AB - Scholarly communication is at an unprecedented turning point created in part by the increasing saliency of data stewardship and data sharing. Formal data management plans represent a new emphasis in research, enabling access to data at higher volumes and more quickly, and the potential for replication and augmentation of existing research. Data sharing has recently transformed the practice, scope, content, and applicability of research in several disciplines, in particular in relation to spatially specific data. This lends exciting potentiality, but the most effective ways in which to implement such changes, particularly for disciplines involving human subjects and other sensitive information, demand consideration. Data management plans, stewardship, and sharing, impart distinctive technical, sociological, and ethical challenges that remain to be adequately identified and remedied. Here, we consider these and propose potential solutions for their amelioration. PMID- 24058293 TI - Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors. AB - Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distinct site. There is growing evidence that allosteric cooperativity can be communicated by modulation of protein dynamics without conformational change. The mechanisms, however, for communicating dynamic fluctuations between sites are debated. We provide a foundational theory for how allostery can occur as a function of low-frequency dynamics without a change in structure. We have generated coarse-grained models that describe the protein backbone motions of the CRP/FNR family transcription factors, CAP of Escherichia coli and GlxR of Corynebacterium glutamicum. The latter we demonstrate as a new exemplar for allostery without conformation change. We observe that binding the first molecule of cAMP ligand is correlated with modulation of the global normal modes and negative cooperativity for binding the second cAMP ligand without a change in mean structure. The theory makes key experimental predictions that are tested through an analysis of variant proteins by structural biology and isothermal calorimetry. Quantifying allostery as a free energy landscape revealed a protein "design space" that identified the inter- and intramolecular regulatory parameters that frame CRP/FNR family allostery. Furthermore, through analyzing CAP variants from diverse species, we demonstrate an evolutionary selection pressure to conserve residues crucial for allosteric control. This finding provides a link between the position of CRP/FNR transcription factors within the allosteric free energy landscapes and evolutionary selection pressures. Our study therefore reveals significant features of the mechanistic basis for allostery. Changes in low-frequency dynamics correlate with allosteric effects on ligand binding without the requirement for a defined spatial pathway. In addition to evolving suitable three-dimensional structures, CRP/FNR family transcription factors have been selected to occupy a dynamic space that fine-tunes biological activity and thus establishes the means to engineer allosteric mechanisms driven by low-frequency dynamics. PMID- 24058294 TI - Integrated conformational and lipid-sensing regulation of endosomal ArfGEF BRAG2. AB - The mechanisms whereby guanine nucleotide exchange factors (GEFs) coordinate their subcellular targeting to their activation of small GTPases remain poorly understood. Here we analyzed how membranes control the efficiency of human BRAG2, an ArfGEF involved in receptor endocytosis, Wnt signaling, and tumor invasion. The crystal structure of an Arf1-BRAG2 complex that mimics a membrane-bound intermediate revealed an atypical PH domain that is constitutively anchored to the catalytic Sec7 domain and interacts with Arf. Combined with the quantitative analysis of BRAG2 exchange activity reconstituted on membranes, we find that this PH domain potentiates nucleotide exchange by about 2,000-fold by cumulative conformational and membrane-targeting contributions. Furthermore, it restricts BRAG2 activity to negatively charged membranes without phosphoinositide specificity, using a positively charged surface peripheral to but excluding the canonical lipid-binding pocket. This suggests a model of BRAG2 regulation along the early endosomal pathway that expands the repertoire of GEF regulatory mechanisms. Notably, it departs from the auto-inhibitory and feedback loop paradigm emerging from studies of SOS and cytohesins. It also uncovers a novel mechanism of unspecific lipid-sensing by PH domains that may allow sustained binding to maturating membranes. PMID- 24058296 TI - Expanding the regulatory repertoire of GEFs. PMID- 24058295 TI - Unisexual and heterosexual meiotic reproduction generate aneuploidy and phenotypic diversity de novo in the yeast Cryptococcus neoformans. AB - Aneuploidy is known to be deleterious and underlies several common human diseases, including cancer and genetic disorders such as trisomy 21 in Down's syndrome. In contrast, aneuploidy can also be advantageous and in fungi confers antifungal drug resistance and enables rapid adaptive evolution. We report here that sexual reproduction generates phenotypic and genotypic diversity in the human pathogenic yeast Cryptococcus neoformans, which is globally distributed and commonly infects individuals with compromised immunity, such as HIV/AIDS patients, causing life-threatening meningoencephalitis. C. neoformans has a defined a-alpha opposite sexual cycle; however, >99% of isolates are of the alpha mating type. Interestingly, alpha cells can undergo alpha-alpha unisexual reproduction, even involving genotypically identical cells. A central question is: Why would cells mate with themselves given that sex is costly and typically serves to admix preexisting genetic diversity from genetically divergent parents? In this study, we demonstrate that alpha-alpha unisexual reproduction frequently generates phenotypic diversity, and the majority of these variant progeny are aneuploid. Aneuploidy is responsible for the observed phenotypic changes, as chromosome loss restoring euploidy results in a wild-type phenotype. Other genetic changes, including diploidization, chromosome length polymorphisms, SNPs, and indels, were also generated. Phenotypic/genotypic changes were not observed following asexual mitotic reproduction. Aneuploidy was also detected in progeny from a-alpha opposite-sex congenic mating; thus, both homothallic and heterothallic sexual reproduction can generate phenotypic diversity de novo. Our study suggests that the ability to undergo unisexual reproduction may be an evolutionary strategy for eukaryotic microbial pathogens, enabling de novo genotypic and phenotypic plasticity and facilitating rapid adaptation to novel environments. PMID- 24058297 TI - A bipartite molecular module controls cell death activation in the Basal cell lineage of plant embryos. AB - Plant zygote divides asymmetrically into an apical cell that develops into the embryo proper and a basal cell that generates the suspensor, a vital organ functioning as a conduit of nutrients and growth factors to the embryo proper. After the suspensor has fulfilled its function, it is removed by programmed cell death (PCD) at the late stages of embryogenesis. The molecular trigger of this PCD is unknown. Here we use tobacco (Nicotiana tabacum) embryogenesis as a model system to demonstrate that the mechanism triggering suspensor PCD is based on the antagonistic action of two proteins: a protease inhibitor, cystatin NtCYS, and its target, cathepsin H-like protease NtCP14. NtCYS is expressed in the basal cell of the proembryo, where encoded cystatin binds to and inhibits NtCP14, thereby preventing precocious onset of PCD. The anti-cell death effect of NtCYS is transcriptionally regulated and is repressed at the 32-celled embryo stage, leading to increased NtCP14 activity and initiation of PCD. Silencing of NtCYS or overexpression of NtCP14 induces precocious cell death in the basal cell lineage causing embryonic arrest and seed abortion. Conversely, overexpression of NtCYS or silencing of NtCP14 leads to profound delay of suspensor PCD. Our results demonstrate that NtCYS-mediated inhibition of NtCP14 protease acts as a bipartite molecular module to control initiation of PCD in the basal cell lineage of plant embryos. PMID- 24058298 TI - The fate of the plant embryo's suspensor: balancing life and death. PMID- 24058299 TI - Transnational tobacco company interests in smokeless tobacco in Europe: analysis of internal industry documents and contemporary industry materials. AB - BACKGROUND: European Union (EU) legislation bans the sale of snus, a smokeless tobacco (SLT) which is considerably less harmful than smoking, in all EU countries other than Sweden. To inform the current review of this legislation, this paper aims to explore transnational tobacco company (TTC) interests in SLT and pure nicotine in Europe from the 1970s to the present, comparing them with TTCs' public claims of support for harm reduction. METHODS AND RESULTS: Internal tobacco industry documents (in total 416 documents dating from 1971 to 2009), obtained via searching the online Legacy Tobacco Documents Library, were analysed using a hermeneutic approach. This library comprises documents obtained via litigation in the US and does not include documents from Imperial Tobacco, Japan Tobacco International, or Swedish Match. To help overcome this limitation and provide more recent data, we triangulated our documentary findings with contemporary documentation including TTC investor presentations. The analysis demonstrates that British American Tobacco explored SLT opportunities in Europe from 1971 driven by regulatory threats and health concerns, both likely to impact cigarette sales negatively, and the potential to create a new form of tobacco use among those no longer interested in taking up smoking. Young people were a key target. TTCs did not, however, make SLT investments until 2002, a time when EU cigarette volumes started declining, smoke-free legislation was being introduced, and public health became interested in harm reduction. All TTCs have now invested in snus (and recently in pure nicotine), yet both early and recent snus test markets appear to have failed, and little evidence was found in TTCs' corporate materials that snus is central to their business strategy. CONCLUSIONS: There is clear evidence that BAT's early interest in introducing SLT in Europe was based on the potential for creating an alternative form of tobacco use in light of declining cigarette sales and social restrictions on smoking, with young people a key target. We conclude that by investing in snus, and recently nicotine, TTCs have eliminated competition between cigarettes and lower-risk products, thus helping maintain the current market balance in favour of (highly profitable) cigarettes while ensuring TTCs' long-term future should cigarette sales decline further and profit margins be eroded. Please see later in the article for the Editors' Summary. PMID- 24058300 TI - Adherence to antiretroviral prophylaxis for HIV prevention: a substudy cohort within a clinical trial of serodiscordant couples in East Africa. AB - BACKGROUND: Randomized clinical trials of oral antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention have widely divergent efficacy estimates, ranging from 0% to 75%. These discrepancies are likely due to differences in adherence. To our knowledge, no studies to date have examined the impact of improving adherence through monitoring and/or intervention, which may increase PrEP efficacy, or reported on objective behavioral measures of adherence, which can inform PrEP effectiveness and implementation. METHODS AND FINDINGS: Within the Partners PrEP Study (a randomized placebo-controlled trial of oral tenofovir and emtricitabine/tenofovir among HIV-uninfected members of serodiscordant couples in Kenya and Uganda), we collected objective measures of PrEP adherence using unannounced home-based pill counts and electronic pill bottle monitoring. Participants received individual and couples-based adherence counseling at PrEP initiation and throughout the study; counseling was intensified if unannounced pill count adherence fell to <80%. Participants were followed monthly to provide study medication, adherence counseling, and HIV testing. A total of 1,147 HIV uninfected participants were enrolled: 53% were male, median age was 34 years, and median partnership duration was 8.5 years. Fourteen HIV infections occurred among adherence study participants--all of whom were assigned to placebo (PrEP efficacy = 100%, 95% confidence interval 83.7%-100%, p<0.001). Median adherence was 99.1% (interquartile range [IQR] 96.9%-100%) by unannounced pill counts and 97.2% (90.6%-100%) by electronic monitoring over 807 person-years. Report of no sex or sex with another person besides the study partner, younger age, and heavy alcohol use were associated with <80% adherence; the first 6 months of PrEP use and polygamous marriage were associated with >80% adherence. Study limitations include potential shortcomings of the adherence measures and use of a convenience sample within the substudy cohort. CONCLUSIONS: The high PrEP adherence achieved in the setting of active adherence monitoring and counseling support was associated with a high degree of protection from HIV acquisition by the HIV uninfected partner in heterosexual serodiscordant couples. Low PrEP adherence was associated with sexual behavior, alcohol use, younger age, and length of PrEP use. Please see later in the article for the Editors' Summary. PMID- 24058301 TI - Feasibility of mass vaccination campaign with oral cholera vaccines in response to an outbreak in Guinea. PMID- 24058302 TI - Toward Improved Description of DNA Backbone: Revisiting Epsilon and Zeta Torsion Force Field Parameters. AB - We present a refinement of the backbone torsion parameters epsilon and zeta of the Cornell et al. AMBER force field for DNA simulations. The new parameters, denoted as epsilonzetaOL1, were derived from quantum-mechanical calculations with inclusion of conformation-dependent solvation effects according to the recently reported methodology (J. Chem. Theory Comput. 2012, 7(9), 2886-2902). The performance of the refined parameters was analyzed by means of extended molecular dynamics (MD) simulations for several representative systems. The results showed that the epsilonzetaOL1 refinement improves the backbone description of B-DNA double helices and G-DNA stem. In B-DNA simulations, we observed an average increase of the helical twist and narrowing of the major groove, thus achieving better agreement with X-ray and solution NMR data. The balance between populations of BI and BII backbone substates was shifted towards the BII state, in better agreement with ensemble-refined solution experimental results. Furthermore, the refined parameters decreased the backbone RMS deviations in B DNA MD simulations. In the antiparallel guanine quadruplex (G-DNA) the epsilonzetaOL1 modification improved the description of non-canonical alpha/gamma backbone substates, which were shown to be coupled to the epsilon/zeta torsion potential. Thus, the refinement is suggested as a possible alternative to the current epsilon/zeta torsion potential, which may enable more accurate modeling of nucleic acids. However, long-term testing is recommended before its routine application in DNA simulations. PMID- 24058303 TI - Depression, Readiness for Change, and Treatment Among Court-Mandated DUI Offenders. AB - OBJECTIVE: The current study is part of a larger study that was designed to evaluate the impact of brief interventions on subsequent alcohol and drug use of individuals convicted of driving under the influence (DUI). This element considers the interaction of depression levels with treatment on subsequent substance use and problems related to substance use. METHODS: Subjects were referred to the Research Institute on Addictions from various courts in the Western New York area for clinical evaluation and treatment referral, if further treatment was indicated. A total of 765 individuals were referred to the program, with 549 agreeing to participate. Participants were assessed at baseline using a number of different measures, with depression and readiness to change among them. A follow-up assessment took place 18-24 months following the baseline, with subsequent treatment experiences being one of the primary measures of interest for this study. A total of 443 participants were successfully interviewed at follow-up. RESULTS: The high depression group had greater readiness to change and a greater likelihood of entering treatment than the low depression group (p's < .001). ANCOVAs showed depression by treatment interactions for drug problem severity, drug use, DUI risk, alcohol expectancies, abstinence self-efficacy, and psychiatric distress (all p's < .05). Furthermore, the treated high depression group made the largest positive gains across all outcomes (all p's < .01). CONCLUSIONS: The readiness to change, treatment entry, and ANCOVA results, all support Wells-Parker and her colleagues' approach that depression may be a strong indicator of DUI offenders' readiness to change their substance use behavior. PMID- 24058304 TI - Parental permission and child assent in research on children. AB - Grounded on the ethical principle of respect for persons, parental permission and child assent function together to protect the child and to foster the development of the child's self-determination. Although both parental permission and child assent involve the same components of information sharing, comprehension, and voluntariness, how these three components are understood and operationalized should differ depending on the developmental level of the child. For example, the amount of information that a child must comprehend to provide meaningful and developmentally appropriate child assent (or dissent) should be allowed to vary with the age and maturity of the child. By understanding child assent together with the important protections of parental permission, child assent does not need to be burdened with the same informational and process requirements. As a result, the age (as a proxy for developmental stage) at which a child is deemed capable of assent would be lower (i.e., 5 to 7 years old). By assuming a lack of capacity, the potential arises to dishonor and disregard a child's wishes by failing to solicit meaningful assent or dissent. Further research needs to be done on how best to obtain truly informed and voluntary parental permission and child assent for research participation. PMID- 24058305 TI - Research ethics and intellectual disability: broadening the debates. AB - This article examines the ethical issues surrounding the inclusion of people with intellectual disabilities as research subjects. It explores subject selection, competence, risk and benefits, and authority through three tensions that emerge when considering these concepts in the context of the Disability Rights Movement and critical disability scholarship. These tensions are defined as the double dangers of inclusion and exclusion; the challenges of defining competence and risk in terms of individuals vs. groups; and the conflicts that arise when pursuing the dual goals of amelioration and elimination of disabilities. Though these tensions are not resolved, they underscore the importance of researchers engaging with critical disability perspectives in order to navigate these complex ethical questions. PMID- 24058306 TI - Conducting research with human subjects in international settings: ethical considerations. AB - Biomedical research in international settings is undergoing expansive growth and may potentially result in far-reaching benefits, such as direction of research resources toward solving basic health care needs of world populations. However, key ethical concerns surround this expansion and must be carefully considered by international researchers. International research is impacted by differences in language, culture, regulatory structures, financial resources, and possibly ethical standards. Local community leadership involvement in the planning stages of research is imperative. Especially in resource-poor countries, the research agenda must be designed to address local needs and provide local benefit. Capacity strengthening efforts, aimed at improving institutional support for ethical conduct of human subjects research, must continue to be supported by wealthier nations. PMID- 24058307 TI - Deceit and transparency in placebo research. AB - Studies designed to elicit the full strength of the placebo effect differ from those in which the placebo effect represents a nuisance factor to be accounted for in order to establish the efficacy of a treatment. In the latter, informed consent is the rule; in the first, while consent may be informed in some narrow sense of the word, deception is common. However, the trickery of placebo experimentation goes beyond straightforward lies to include the use of crafty ambiguities, half-truths, and deliberate omissions in scripts read to the subjects of these studies. As words come to resemble therapeutic agents in their own right, it is only to be expected that researchers would methodically exploit verbal effects to evoke the responses they are looking for. Even experiments in which placebo is disclosed as placebo have used language in leading and misleading ways. Such studies are conducted in the hope of yielding results that might translate into clinical practice, but it should be noted that good clinical practice has a placebo value of its own--that is, confers a benefit over and beyond the specific effects of treatments--even if nothing like a sugar pill is administered. PMID- 24058308 TI - Organ donation after acute brain death: addressing limitations of time and resources in the emergency department. AB - It is not unusual for emergency physicians to quickly identify whether a patient would have wanted to be resuscitated or intubated in a cardiac arrest situation, but patients' other preferences for end-of-life care or organ donation are less commonly ascertained in the emergency department. Typically, the decision process regarding such goals at end of life may be "deferred" to the intensive care unit. We present a case illustrative of the complexity of discussing organ donation in the emergency department and suggest that patients who die in the emergency department should be afforded the respect and consideration provided in other parts of the hospital, including facilitation of organ transplantation. As circulatory determination of death becomes a more common antecedent to organ transplantation, specific questions may arise in the emergency department setting. When in the emergency department, how should organ donation be addressed and by whom? Should temporary organ preservation be initiated in the setting of uncertainty regarding a patient's wishes? To better facilitate discussions about organ donation when they arise in emergency settings, we propose increased coordination between organ procurement organizations and emergency physicians to improve awareness of organ transplantation. PMID- 24058309 TI - Strategies for dealing with missing data in clinical trials: from design to analysis. AB - Randomized clinical trials are the gold standard for evaluating interventions as randomized assignment equalizes known and unknown characteristics between intervention groups. However, when participants miss visits, the ability to conduct an intent-to-treat analysis and draw conclusions about a causal link is compromised. As guidance to those performing clinical trials, this review is a non-technical overview of the consequences of missing data and a prescription for its treatment beyond the typical analytic approaches to the entire research process. Examples of bias from incorrect analysis with missing data and discussion of the advantages/disadvantages of analytic methods are given. As no single analysis is definitive when missing data occurs, strategies for its prevention throughout the course of a trial are presented. We aim to convey an appreciation for how missing data influences results and an understanding of the need for careful consideration of missing data during the design, planning, conduct, and analytic stages. PMID- 24058310 TI - Direct-to-consumer genetic testing: a comprehensive view. AB - Direct-to-consumer (DTC) genetic testing refers to testing sold directly to consumers via the Internet, television, or other marketing venues without involving health care professionals. As the recent Supreme Court ruling eliminated the patentability of human genes, this rapidly evolving segment in the laboratory testing industry is starting to attract increasing scrutiny by government, scientists, consumers, and other interested parties. This article provides a panoramic view of the DTC genetic testing industry, including reasons for seeking DTC testing services, benefits and concerns associated with the industry, and potential development and prospects of this relatively new market under the current regulatory environment. PMID- 24058312 TI - Damage control surgery in a <1 kg neonate: a brief report. AB - Damage control surgery is a feasible and successful approach for the management of unstable neonates with intra-abdominal catastrophes, including liver injuries. We report the case of a premature infant with a liver injury secondary to the placement of an umbilical vein catheter who was successfully managed using damage control surgery techniques. PMID- 24058313 TI - Reflections on a life in biomedicine: leading change. AB - Dr. Elizabeth Nabel delivered the following presentation as the Lee E. Farr Lecturer on May 7, 2013, which served as the culmination of the annual Student Research Day at Yale School of Medicine. Dr. Nabel is President of the Brigham and Women's Hospital in Boston, Massachusetts, and Professor of Medicine at Harvard Medical School. Her lecture to Yale medical students portrayed her own personal and professional journey through medicine as a series of opportunities. Dr. Nabel focused on the roles and responsibilities of physicians to recognize need and to make change through focused advocacy. PMID- 24058311 TI - High-resolution optical tweezers for single-molecule manipulation. AB - Forces hold everything together and determine its structure and dynamics. In particular, tiny forces of 1-100 piconewtons govern the structures and dynamics of biomacromolecules. These forces enable folding, assembly, conformational fluctuations, or directional movements of biomacromolecules over sub-nanometer to micron distances. Optical tweezers have become a revolutionary tool to probe the forces, structures, and dynamics associated with biomacromolecules at a single molecule level with unprecedented resolution. In this review, we introduce the basic principles of optical tweezers and their latest applications in studies of protein folding and molecular motors. We describe the folding dynamics of two strong coiled coil proteins, the GCN4-derived protein pIL and the SNARE complex. Both complexes show multiple folding intermediates and pathways. ATP-dependent chromatin remodeling complexes translocate DNA to remodel chromatin structures. The detailed DNA translocation properties of such molecular motors have recently been characterized by optical tweezers, which are reviewed here. Finally, several future developments and applications of optical tweezers are discussed. These past and future applications demonstrate the unique advantages of high-resolution optical tweezers in quantitatively characterizing complex multi-scale dynamics of biomacromolecules. PMID- 24058314 TI - Growing into my white coat: improving the patient-provider relationship through diverse patient interviews. AB - The "Patient Diversity" assignment is an integral component for all medical and other health care professional students rotating through the Surgery clerkship at the Yale School of Medicine. Students are instructed to interview a surgical patient who is of a varied social or cultural background to identify how psychosocial factors impact patient coping strategies. In the process, students often appreciate how health care providers' own social and cultural backgrounds similarly shape their sentiments and reactions in patient care. In this interview with a 26-year-old surgical patient, one student strives to come to terms with her personal insecurities in patient interactions and seeks to overcome them through open conversation and honest introspection. By working to acknowledge and understand patient diversity, health care providers can enhance understanding of their patients' conditions and form more trustful and empathic relationships with both their patients and colleagues. PMID- 24058315 TI - Health care politics and policy: the business of medicine: a course for physician leaders. AB - This article is a condensed and edited version of a speech delivered to the business of medicine: A Course for Physician Leaders symposium presented by Yale New Haven Hospital and the Medical Directors Leadership Council at Yale University in November 2012 and drawn from Politics, Health, and Health Care: Selected Essays by Theodore R. Marmor and Rudolf Klein [1]. It faithfully reflects the major argument delivered, but it does not include the typical range of citations in a journal article. The material presented here reflects more than 40 years of teaching a course variously described as Political Analysis and Management, Policy and Political Analysis, and The Politics of Policy. The aim of all of these efforts is to inform audiences about the necessity of understanding political conflict in any arena, not least of which is the complex and costly world of medical care. PMID- 24058316 TI - What is a hospital? Future roles and prospects for success: the business of medicine: a course for physician leaders. AB - As hospitals consolidate and take on more financial and clinical risk, they face numerous obstacles. While the past can provide answers to solving many of the challenges, some issues are new and require innovative approaches. This article, from a speech delivered to The Business of Medicine: A Course for Physician Leaders symposium presented by Yale-New Haven Hospital and the Medical Directors Leadership Council at Yale University in November 2012, discusses the models for these hospital organizations and the pitfalls they will face in coordinating care. The insights will help these systems overcome potential problems and enhance their chances of success. PMID- 24058317 TI - StemCONN: realizing the promise: StemConn 2013. AB - On April 3, 2013, the fourth biennial StemCONN conference took place at the Omni Hotel at Yale in New Haven, Connecticut. This conference featured talks by scientists from across the country who are currently at the forefront of stem cell research, as well as talks by Edison Liu, President and CEO of the Jackson Laboratory, and Jonathan Rotherberg, PhD, a Yale alumnus and Ion Torrent Systems Founder and CEO. The conference highlighted the importance of stem cell research to both science and medicine and emphasized the necessity of continued government funding for this research, both in Connecticut and nationwide. PMID- 24058318 TI - Helping science and drug development to succeed through pharma-academia partnerships: Yale Healthcare Conference 2013. AB - The theme of the 2013 Yale Healthcare Conference was "Partnerships in Healthcare: Cultivating Collaborative Solutions." The April conference brought together leaders across several sectors of health care, including academic research, pharmaceuticals, information technology, policy, and life sciences investing. In particular, the breakout session titled "Taking R&D Back to School: The Rise of Pharma-Academia Alliances" centered on the partnerships between academic institutions and pharmaceutical companies. Attendees of the session included members of the pharmaceutical industry, academic researchers, and physicians, as well as graduate and professional students. The discussion was led by Dr. Thomas Lynch of Yale University. Several topics emerged from the discussion, including resources for scientific discovery and the management of competing interests in collaborations between academia and the pharmaceutical industry. PMID- 24058322 TI - Workplace Stress, Organizational Factors and EAP Utilization. AB - This study examined relationships between workplace stress, organizational factors and use of EAP counseling services delivered by network providers in a large, privately-insured population. Claims data were linked to measures of workplace stress, focus on wellness/prevention, EAP promotion, and EAP activities for health care plan enrollees from 26 employers. The association of external environment and work organization variables with use of EAP counseling services was examined. Higher levels of EAP promotion and worksite activities were associated with greater likelihood of service use. Greater focus on wellness/prevention and unusual and significant stress were associated with lower likelihood of service use. Results provide stakeholders with insights on approaches to increasing utilization of EAP services. PMID- 24058323 TI - Children's and adults' intuitions about who can own things. AB - The understanding that people can own certain things is essential for activities such as trading, lending, sharing, and use of currency. In two studies, children in grades K, 2, and 4 (N = 118) and adults (N = 40) were asked to identify whether four kinds of individuals could be owners: typical humans, non-human animals, artifacts, and atypical humans (e.g., individuals who were sleeping or unable to move). Participants in all age groups attributed ownership to typical humans most often, non-human animals less often, and artifacts least often. In a third study, children and adults (N = 240) attributed property rights to individuals who were awake, asleep, or tied up, but children continued to deny that these rights extend to atypical humans. Although both children and adults use an ontological boundary to guide their ownership attributions, concepts of owners change significantly over the course of development. PMID- 24058320 TI - Quantitative models of the dose-response and time course of inhalational anthrax in humans. AB - Anthrax poses a community health risk due to accidental or intentional aerosol release. Reliable quantitative dose-response analyses are required to estimate the magnitude and timeline of potential consequences and the effect of public health intervention strategies under specific scenarios. Analyses of available data from exposures and infections of humans and non-human primates are often contradictory. We review existing quantitative inhalational anthrax dose-response models in light of criteria we propose for a model to be useful and defensible. To satisfy these criteria, we extend an existing mechanistic competing-risks model to create a novel Exposure-Infection-Symptomatic illness-Death (EISD) model and use experimental non-human primate data and human epidemiological data to optimize parameter values. The best fit to these data leads to estimates of a dose leading to infection in 50% of susceptible humans (ID50) of 11,000 spores (95% confidence interval 7,200-17,000), ID10 of 1,700 (1,100-2,600), and ID1 of 160 (100-250). These estimates suggest that use of a threshold to human infection of 600 spores (as suggested in the literature) underestimates the infectivity of low doses, while an existing estimate of a 1% infection rate for a single spore overestimates low dose infectivity. We estimate the median time from exposure to onset of symptoms (incubation period) among untreated cases to be 9.9 days (7.7 13.1) for exposure to ID50, 11.8 days (9.5-15.0) for ID10, and 12.1 days (9.9 15.3) for ID1. Our model is the first to provide incubation period estimates that are independently consistent with data from the largest known human outbreak. This model refines previous estimates of the distribution of early onset cases after a release and provides support for the recommended 60-day course of prophylactic antibiotic treatment for individuals exposed to low doses. PMID- 24058324 TI - The Effects of Family Stressors on Substance Use Initiation in Adolescence. AB - Smoking and drinking are critical problems in adolescence that have long-term adverse impacts on health and socio-economic factors. We examine the extent to which family stresses influence the timing of initiation of smoking and drinking. Using national panel data from the National Educational Longitudinal Study (NELS) we capitalize on the survey design and use school-level fixed effects that control for the local environments, including prices of cigarettes and alcohol. In addition, we narrow our control group to classmates who will experience a similar stressor in the future. We find that a composite measure of family stressors when young increases the likelihood of initiating tobacco and alcohol use, with much of the impact attributable to parental divorce. In our baseline estimates, the composite stress measure is associated with a 30% increase in the likelihood of smoking and a 20% increase in drinking. When we control for multiple sources of confounding, the impact shrinks and remains significant for smoking but not for drinking. We conclude that studies which do not control for confounding are likely to significantly overestimate the impact of family stress on substance use. Our approach helps to move the literature forward by separating causal results from spurious associations. PMID- 24058325 TI - The Andrews' Principles of Risk, Need, and Responsivity as Applied in Drug Abuse Treatment Programs: Meta-Analysis of Crime and Drug Use Outcomes. AB - OBJECTIVES: The purpose of the present meta-analysis was to answer the question: Can the Andrews principles of risk, needs, and responsivity, originally developed for programs that treat offenders, be extended to programs that treat drug abusers? METHODS: Drawing from a dataset that included 243 independent comparisons, we conducted random-effects meta-regression and ANOVA-analog meta analyses to test the Andrews principles by averaging crime and drug use outcomes over a diverse set of programs for drug abuse problems. RESULTS: For crime outcomes, in the meta-regressions the point estimates for each of the principles were substantial, consistent with previous studies of the Andrews principles. There was also a substantial point estimate for programs exhibiting a greater number of the principles. However, almost all of the 95% confidence intervals included the zero point. For drug use outcomes, in the meta-regressions the point estimates for each of the principles was approximately zero; however, the point estimate for programs exhibiting a greater number of the principles was somewhat positive. All of the estimates for the drug use principles had confidence intervals that included the zero point. CONCLUSIONS: This study supports previous findings from primary research studies targeting the Andrews principles that those principles are effective in reducing crime outcomes, here in meta-analytic research focused on drug treatment programs. By contrast, programs that follow the principles appear to have very little effect on drug use outcomes. Primary research studies that experimentally test the Andrews principles in drug treatment programs are recommended. PMID- 24058326 TI - Mechanical Imaging - a Technology for 3-D Visualization and Characterization of Soft Tissue Abnormalities. A Review. AB - Mechanical Imaging (MI) is a branch of Elastography. MI differs from conventional ultrasonic and MR elastography in that it evaluates soft tissue mechanical structure using stress data rather than dynamic or static strain data. MI closely mimics manual palpation because the MI probe with a force sensor array attached to its tip acts as a palpating finger. MI is intrinsically a three-dimensional imaging modality because the surface stress patterns obtained at different levels of tissue compression are defined by three-dimensional mechanical structure of the tissue. This review presents the biomechanical basis of MI and its applications for breast cancer screening, and the differentiation of benign and malignant lesions, the visualization and evaluation of prostate conditions, and for the characterization of vaginal wall elasticity. PMID- 24058327 TI - Development of a tobacco cessation intervention for Alaska Native youth. AB - Tobacco cessation treatments have not been evaluated among Alaska Native (AN) adolescents. This pilot study evaluated the feasibility and acceptability of a targeted cessation intervention developed for AN youth. Intervention components were informed by prior focus groups assessing treatment preferences among AN youth, a social cognitive theoretical framework and feedback obtained from a teen advisory group. The intervention consisted of a weekend program where youth traveled by small airplane from their villages to stay overnight with other adolescents who quit tobacco use together. The program included recreational activities, talking circles, personal stories from elders and teen advisors, and cognitive behavioral counseling. Two intervention pilots were conducted from October 2010 to January 2011 using a non-randomized, uncontrolled study design with assessments at baseline and six-week follow-up. One village in Western Alaska was selected for each pilot with a targeted enrollment of 10 adolescents each. Participants were recruited for each pilot within five days, but recruitment challenges and ''lessons learned'' are described. The first pilot enrolled nine adolescents (all female) aged 13-16 years; all nine attended the intervention program and 78% (7/9) completed follow-up. The second pilot enrolled 12 adolescents (eight females, four males) aged 12-17 years, of which seven attended the intervention program. Six of these seven participants (86%) completed follow-up. In both pilots, participants rated the intervention as highly acceptable. A targeted cessation intervention was feasible and acceptable to AN youth. The intervention will be tested for efficacy in a subsequent randomized controlled trial. PMID- 24058328 TI - Slowly degradable porous silk microfabricated scaffolds for vascularized tissue formation. AB - There is critical clinical demand for tissue-engineered (TE), three-dimensional (3D) constructs for tissue repair and organ replacements. Current efforts toward this goal are prone to necrosis at the core of larger constructs because of limited oxygen and nutrient diffusion. Therefore, critically sized 3D TE constructs demand an immediate vascular system for sustained tissue function upon implantation. To address this challenge the goal of this project was to develop a strategy to incorporate microchannels into a porous silk TE scaffold that could be fabricated reproducibly using microfabrication and soft lithography. Silk is a suitable biopolymer material for this application because it is mechanically robust, biocompatible, slowly degrades in vivo, and has been used in a variety of TE constructs. We report the fabrication of a silk-based TE scaffold that contains an embedded network of porous microchannels. Enclosed porous microchannels support endothelial lumen formation, a critical step toward development of the vascular niche, while the porous scaffold surrounding the microchannels supports tissue formation, demonstrated using human mesenchymal stem cells. This approach for fabricating vascularized TE constructs is advantageous compared to previous systems, which lack porosity and biodegradability or degrade too rapidly to sustain tissue structure and function. The broader impact of this research will enable the systemic study and development of complex, critically-sized engineered tissues, from regenerative medicine to in vitro tissue models of disease states. PMID- 24058329 TI - Biocompatibility Assessment of Novel Bioresorbable Alloys Mg-Zn-Se and Mg-Zn-Cu for Endovascular Applications: In- Vitro Studies. AB - Previous studies have shown that using biodegradable magnesium alloys such as Mg Zn and Mg-Zn-Al possess the appropriate mechanical properties and biocompatibility to serve in a multitude of biological applications ranging from endovascular to orthopedic and fixation devices. The objective of this study was to evaluate the biocompatibility of novel as-cast magnesium alloys Mg-1Zn-1Cu wt.% and Mg-1Zn-1Se wt.% as potential implantable biomedical materials, and compare their biologically effective properties to a binary Mg-Zn alloy. The cytotoxicity of these experimental alloys was evaluated using a tetrazolium based MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) 2H-tetrazolium) assay and a lactate dehydrogenase membrane integrity assay (LDH). The MTS assay was performed on extract solutions obtained from a 30-day period of alloy immersion and agitation in simulated body fluid to evaluate the major degradation products eluted from the alloy materials. Human foreskin fibroblast cell growth on the experimental magnesium alloys was evaluated for a 72 hour period, and cell death was quantified by measuring lactate dehydrogenase concentrations. Both Mg-Zn-Se and Mg-Zn-Cu alloys exhibit low cytotoxicity levels which are suitable for biomaterial applications. The Mg-Zn-Cu alloy was found to completely degrade within 72 hours, resulting in lower human foreskin fibroblast cell viability. The Mg-Zn-Se alloy was shown to be less cytotoxic than both the Mg-Zn-Cu and Mg-Zn alloys. PMID- 24058330 TI - Finding a roadmap to achieve large neuromorphic hardware systems. AB - Neuromorphic systems are gaining increasing importance in an era where CMOS digital computing techniques are reaching physical limits. These silicon systems mimic extremely energy efficient neural computing structures, potentially both for solving engineering applications as well as understanding neural computation. Toward this end, the authors provide a glimpse at what the technology evolution roadmap looks like for these systems so that Neuromorphic engineers may gain the same benefit of anticipation and foresight that IC designers gained from Moore's law many years ago. Scaling of energy efficiency, performance, and size will be discussed as well as how the implementation and application space of Neuromorphic systems are expected to evolve over time. PMID- 24058331 TI - Instrumentation bias in the use and evaluation of scientific software: recommendations for reproducible practices in the computational sciences. PMID- 24058333 TI - A new in vivo model of pantothenate kinase-associated neurodegeneration reveals a surprising role for transcriptional regulation in pathogenesis. AB - Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a neurodegenerative disorder with a poorly understood molecular mechanism. It is caused by mutations in Pantothenate Kinase, the first enzyme in the Coenzyme A (CoA) biosynthetic pathway. Here, we developed a Drosophila model of PKAN (tim-fbl flies) that allows us to continuously monitor the modeled disease in the brain. In tim-fbl flies, downregulation of fumble, the Drosophila PanK homologue in the cells containing a circadian clock results in characteristic features of PKAN such as developmental lethality, hypersensitivity to oxidative stress, and diminished life span. Despite quasi-normal circadian transcriptional rhythms, tim-fbl flies display brain-specific aberrant circadian locomotor rhythms, and a unique transcriptional signature. Comparison with expression data from flies exposed to paraquat demonstrates that, as previously suggested, pathways others than oxidative stress are affected by PANK downregulation. Surprisingly we found a significant decrease in the expression of key components of the photoreceptor recycling pathways, which could lead to retinal degeneration, a hallmark of PKAN. Importantly, these defects are not accompanied by changes in structural components in eye genes suggesting that changes in gene expression in the eye precede and may cause the retinal degeneration. Indeed tim-fbl flies have diminished response to light transitions, and their altered day/night patterns of activity demonstrates defects in light perception. This suggest that retinal lesions are not solely due to oxidative stress and demonstrates a role for the transcriptional response to CoA deficiency underlying the defects observed in dPanK deficient flies. Moreover, in the present study we developed a new fly model that can be applied to other diseases and that allows the assessment of neurodegeneration in the brains of living flies. PMID- 24058334 TI - Miro, MCU, and calcium: bridging our understanding of mitochondrial movement in axons. AB - Neurons are extremely polarized structures with long axons and dendrites, which require proper distribution of mitochondria and maintenance of mitochondrial dynamics for neuronal functions and survival. Indeed, recent studies show that various neurological disorders are linked to mitochondrial transport in neurons. Mitochondrial anterograde transport is believed to deliver metabolic energy to synaptic terminals where energy demands are high, while mitochondrial retrograde transport is required to repair or remove damaged mitochondria in axons. It has been suggested that Ca(2) (+) plays a key role in regulating mitochondrial transport by altering the configuration of mitochondrial protein, miro. However, molecular mechanisms that regulate mitochondrial transport in neurons still are not well characterized. In this review, we will discuss the roles of miro in mitochondrial transport and how the recently identified components of the mitochondrial calcium uniporter add to our current model of mitochondrial mobility regulation. PMID- 24058332 TI - Fatting the brain: a brief of recent research. AB - Fatty acids are of paramount importance to all cells, since they provide energy, function as signaling molecules, and sustain structural integrity of cellular membranes. In the nervous system, where fatty acids are found in huge amounts, they participate in its development and maintenance throughout life. Growing evidence strongly indicates that fatty acids in their own right are also implicated in pathological conditions, including neurodegenerative diseases, mental disorders, stroke, and trauma. In this review, we focus on recent studies that demonstrate the relationships between fatty acids and function and dysfunction of the nervous system. Fatty acids stimulate gene expression and neuronal activity, boost synaptogenesis and neurogenesis, and prevent neuroinflammation and apoptosis. By doing so, they promote brain development, ameliorate cognitive functions, serve as anti-depressants and anti-convulsants, bestow protection against traumatic insults, and enhance repairing processes. On the other hand, unbalance between different fatty acid families or excess of some of them generate deleterious side effects, which limit the translatability of successful results in experimental settings into effective therapeutic strategies for humans. Despite these constraints, there exists realistic evidence to consider that nutritional therapies based on fatty acids can be of benefit to several currently incurable nervous system diseases. PMID- 24058335 TI - Circulating cell-free microRNA as biomarkers for screening, diagnosis and monitoring of neurodegenerative diseases and other neurologic pathologies. AB - Many neurodegenerative diseases, such as Alzheimer's disease, Parkinson disease, vascular and frontotemporal dementias, as well as other chronic neurological pathologies, are characterized by slow development with a long asymptomatic period followed by a stage with mild clinical symptoms. As a consequence, these serious pathologies are diagnosed late in the course of a disease, when massive death of neurons has already occurred and effective therapeutic intervention is problematic. Thus, the development of screening tests capable of detecting neurodegenerative diseases during early, preferably asymptomatic, stages is a high unmet need. Since such tests are to be used for screening of large populations, they should be non-invasive and relatively inexpensive. Further, while subjects identified by screening tests can be further tested with more invasive and expensive methods, e.g., analysis of cerebrospinal fluid or imaging techniques, to be of practical utility screening tests should have high sensitivity and specificity. In this review, we discuss advantages and disadvantages of various approaches to developing screening tests based on analysis of circulating cell-free microRNA (miRNA). Applications of circulating miRNA-based tests for diagnosis of acute and chronic brain pathologies, for research of normal brain aging, and for disease and treatment monitoring are also discussed. PMID- 24058337 TI - Neudesin is involved in anxiety behavior: structural and neurochemical correlates. AB - Neudesin (also known as neuron derived neurotrophic factor, Nenf) is a scarcely studied putative non-canonical neurotrophic factor. In order to understand its function in the brain, we performed an extensive behavioral characterization (motor, emotional, and cognitive dimensions) of neudesin-null mice. The absence of neudesin leads to an anxious-like behavior as assessed in the elevated plus maze (EPM), light/dark box (LDB) and novelty suppressed feeding (NSF) tests, but not in the acoustic startle (AS) test. This anxious phenotype is associated with reduced dopaminergic input and impoverished dendritic arborizations in the dentate gyrus granule neurons of the ventral hippocampus. Interestingly, shorter dendrites are also observed in the bed nucleus of the stria terminalis (BNST) of neudesin-null mice. These findings lead us to suggest that neudesin is a novel relevant player in the maintenance of the anxiety circuitry. PMID- 24058338 TI - Introduction to the special topic: a multidisciplinary approach to motor learning and sensorimotor adaptation. PMID- 24058339 TI - Why non-invasive brain stimulation should not be used in military and security services. PMID- 24058336 TI - Memory reconsolidation in aversive and appetitive settings. AB - Memory reconsolidation has been observed across species and in a number of behavioral paradigms. The majority of memory reconsolidation studies have been carried out in Pavlovian fear conditioning and other aversive memory settings, with potential implications for the treatment of post-traumatic stress disorder. However, there is a growing literature on memory reconsolidation in appetitive reward-related memory paradigms, including translational models of drug addiction. While there appears to be substantial similarity in the basic phenomenon and underlying mechanisms of memory reconsolidation across unconditioned stimulus valence, there are also notable discrepancies. These arise both when comparing aversive to appetitive paradigms and also across different paradigms within the same valence of memory. We review the demonstration of memory reconsolidation across different aversive and appetitive memory paradigms, the commonalities and differences in underlying mechanisms and the conditions under which each memory undergoes reconsolidation. We focus particularly on whether principles derived from the aversive literature are applicable to appetitive settings, and also whether the expanding literature in appetitive paradigms is informative for fear memory reconsolidation. PMID- 24058340 TI - A biological security motivation system for potential threats: are there implications for policy-making? AB - Research indicates that there is a specially adapted, hard-wired brain circuit, the security motivation system, which evolved to manage potential threats, such as the possibility of contamination or predation. The existence of this system may have important implications for policy-making related to security. The system is sensitive to partial, uncertain cues of potential danger, detection of which activates a persistent, potent motivational state of wariness or anxiety. This state motivates behaviors to probe the potential danger, such as checking, and to correct for it, such as washing. Engagement in these behaviors serves as the terminating feedback for the activation of the system. Because security motivation theory makes predictions about what kinds of stimuli activate security motivation and what conditions terminate it, the theory may have applications both in understanding how policy-makers can best influence others, such as the public, and also in understanding the behavior of policy-makers themselves. PMID- 24058341 TI - The primacy of social over visual perspective-taking. AB - In this article, we argue for the developmental primacy of social over visual perspective-taking. In our terminology, social perspective-taking involves some understanding of another person's preferences, goals, intentions etc. which can be discerned from temporally extended interactions, including dialog. As is evidenced by their successful performance on various reference disambiguation tasks, infants in their second year of life first begin to develop such skills. They can, for example, determine which of two or more objects another is referring to based on previously expressed preferences or the distinct quality with which these objects were jointly explored. The pattern of findings from developmental research further indicates that this ability emerges sooner than analogous forms of visual perspective-taking. Our explanatory account of this developmental sequence highlights the primary importance of joint attention and the formation of common ground with others. Before children can develop an awareness of what exactly is seen or how an object appears from a particular viewpoint, they must learn to share attention and build common "experiential" ground. Learning about others' as well as one's own "snapshot" perspectives in a literal, i.e., optical sense of the term, is a secondary step that affords an abstraction from all (prior) pragmatic involvement with objects. PMID- 24058342 TI - Efficient neural codes can lead to spurious synchronization. PMID- 24058343 TI - Relation of neuropathology with cognitive decline among older persons without dementia. AB - OBJECTIVE: Although it is now widely accepted that dementia has a long preclinical phase during which neuropathology accumulates and cognition declines, little is known about the relation of neuropathology with the longitudinal rate of change in cognition among older persons without dementia. We quantified the burden of the neuropathologies of the three most common causes of dementia [i.e., Alzheimer's disease (AD), cerebrovascular disease (CVD), and Lewy body disease (LBD)] and examined their relation with cognitive decline in a large cohort of persons without dementia proximate to death. METHODS: A total of 467 deceased participants without dementia from two longitudinal clinical-pathologic studies, Rush Memory and Aging Project and Religious Orders Study, completed a mean of 7 annual evaluations including 17 cognitive tests. Neuropathologic examinations provided quantitative measures of AD (i.e., amyloid load, tangle density), CVD (i.e., macroscopic infarcts, microinfarcts), and neocortical Lewy bodies. Random coefficient models were used to examine the relation of the neuropathologies with rates of global cognitive decline as well as decline in four specific cognitive systems. RESULTS: At autopsy, 82% of persons without dementia had amyloid, 100% had tangles, 29% had macroscopic infarcts, 25% had microinfarcts, and 6% had neocortical Lewy bodies. Global cognition declined a mean of 0.034 unit per year (SE = 0.003, p < 0.001). In separate analyses, amyloid, tangles (p-values <0.001) and neocortical Lewy bodies (p = 0.015) were associated with an increased rate of global cognitive decline; macroscopic infarcts and microinfarcts were not. Further, when analyzed simultaneously, amyloid, tangles, and neocortical Lewy bodies remained associated with global cognitive decline (p-values <0.024). Finally, measures of AD were associated with decline in three of four systems, including episodic memory (i.e., tangles), semantic memory (i.e., amyloid and tangles), and working memory (i.e., amyloid). Lewy bodies also were associated with decline in three of four systems (i.e., semantic memory, working memory, and perceptual speed). INTERPRETATION: The neuropathologies of the common causes of dementia, particularly AD and neocortical LBD, are associated with decline in multiple cognitive abilities among older persons without dementia. PMID- 24058345 TI - A European approach to clinical investigator training. AB - A better education and training of clinical investigators and their teams is one of the factors that could foster the development of clinical research in Europe, a key objective of the Innovative Medicines Initiative (IMI). PharmaTrain (an IMI programme on training in medicines development), and European Clinical Research Infrastructures Network (ECRIN) have joined forces to address this issue. An advisory group composed of representatives of universities, pharmaceutical companies and other organisations met four times between June 2011 and July 2012. This resulted in a position paper proposing a strategy to improve and harmonize clinical investigator training in Europe, and including a detailed syllabus and list of learning outcomes. Major recommendations are the establishment of minimal and mutually recognized certification requirement for investigators throughout the EU and the creation of a European platform to provide a suitable course and examination infrastructure. PMID- 24058346 TI - Blood flow restriction pressure recommendations: a tale of two cuffs. PMID- 24058347 TI - "XXIst century odyssey of Medicine" stem cells and their future. PMID- 24058344 TI - Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target? AB - Our knowledge of the pathophysiology of affect dysregulation has progressively increased, but the pharmacological treatments remain inadequate. Here, we summarize the current literature on deficits in somatostatin, an inhibitory modulatory neuropeptide, in major depression and other neurological disorders that also include mood disturbances. We focus on direct evidence in the human postmortem brain, and review rodent genetic and pharmacological studies probing the role of the somatostatin system in relation to mood. We also briefly go over pharmacological developments targeting the somatostatin system in peripheral organs and discuss the challenges of targeting the brain somatostatin system. Finally, the fact that somatostatin deficits are frequently observed across neurological disorders suggests a selective cellular vulnerability of somatostatin-expressing neurons. Potential cell intrinsic factors mediating those changes are discussed, including nitric oxide induced oxidative stress, mitochondrial dysfunction, high inflammatory response, high demand for neurotrophic environment, and overall aging processes. Together, based on the co localization of somatostatin with gamma-aminobutyric acid (GABA), its presence in dendritic-targeting GABA neuron subtypes, and its temporal-specific function, we discuss the possibility that deficits in somatostatin play a central role in cortical local inhibitory circuit deficits leading to abnormal corticolimbic network activity and clinical mood symptoms across neurological disorders. PMID- 24058348 TI - Can Psychiatry be Misused Again? PMID- 24058349 TI - Spoken word recognition without a TRACE. AB - How do we map the rapid input of spoken language onto phonological and lexical representations over time? Attempts at psychologically-tractable computational models of spoken word recognition tend either to ignore time or to transform the temporal input into a spatial representation. TRACE, a connectionist model with broad and deep coverage of speech perception and spoken word recognition phenomena, takes the latter approach, using exclusively time-specific units at every level of representation. TRACE reduplicates featural, phonemic, and lexical inputs at every time step in a large memory trace, with rich interconnections (excitatory forward and backward connections between levels and inhibitory links within levels). As the length of the memory trace is increased, or as the phoneme and lexical inventory of the model is increased to a realistic size, this reduplication of time- (temporal position) specific units leads to a dramatic proliferation of units and connections, begging the question of whether a more efficient approach is possible. Our starting point is the observation that models of visual object recognition-including visual word recognition-have grappled with the problem of spatial invariance, and arrived at solutions other than a fully reduplicative strategy like that of TRACE. This inspires a new model of spoken word recognition that combines time-specific phoneme representations similar to those in TRACE with higher-level representations based on string kernels: temporally independent (time invariant) diphone and lexical units. This reduces the number of necessary units and connections by several orders of magnitude relative to TRACE. Critically, we compare the new model to TRACE on a set of key phenomena, demonstrating that the new model inherits much of the behavior of TRACE and that the drastic computational savings do not come at the cost of explanatory power. PMID- 24058350 TI - Understanding less than nothing: children's neural response to negative numbers shifts across age and accuracy. AB - We examined the brain activity underlying the development of our understanding of negative numbers, which are amounts lacking direct physical counterparts. Children performed a paired comparison task with positive and negative numbers during an fMRI session. As previously shown in adults, both pre-instruction fifth graders and post-instruction seventh-graders demonstrated typical behavioral and neural distance effects to negative numbers, where response times and parietal and frontal activity increased as comparison distance decreased. We then determined the factors impacting the distance effect in each age group. Behaviorally, the fifth-grader distance effect for negatives was significantly predicted only by positive comparison accuracy, indicating that children who were generally better at working with numbers were better at comparing negatives. In seventh-graders, negative number comparison accuracy significantly predicted their negative number distance effect, indicating that children who were better at working with negative numbers demonstrated a more typical distance effect. Across children, as age increased, the negative number distance effect increased in the bilateral IPS and decreased frontally, indicating a frontoparietal shift consistent with previous numerical development literature. In contrast, as negative comparison task accuracy increased, the parietal distance effect increased in the left IPS and decreased in the right, possibly indicating a change from an approximate understanding of negatives' values to a more exact, precise representation (particularly supported by the left IPS) with increasing expertise. These shifts separately indicate the effects of increasing maturity generally in numeric processing and specifically in negative number understanding. PMID- 24058352 TI - Adaptive control of human action: the role of outcome representations and reward signals. AB - The present paper aims to advance the understanding of the control of human behavior by integrating two lines of literature that so far have led separate lives. First, one line of literature is concerned with the ideomotor principle of human behavior, according to which actions are represented in terms of their outcomes. The second line of literature mainly considers the role of reward signals in adaptive control. Here, we offer a combined perspective on how outcome representations and reward signals work together to modulate adaptive control processes. We propose that reward signals signify the value of outcome representations and facilitate the recruitment of control resources in situations where behavior needs to be maintained or adapted to attain the represented outcome. We discuss recent research demonstrating how adaptive control of goal directed behavior may emerge when outcome representations are co-activated with positive reward signals. PMID- 24058353 TI - Moderating variables of music training-induced neuroplasticity: a review and discussion. AB - A large body of literature now exists to substantiate the long-held idea that musicians' brains differ structurally and functionally from non-musicians' brains. These differences include changes in volume, morphology, density, connectivity, and function across many regions of the brain. In addition to the extensive literature that investigates these differences cross-sectionally by comparing musicians and non-musicians, longitudinal studies have demonstrated the causal influence of music training on the brain across the lifespan. However, there is a large degree of inconsistency in the findings, with discordance between studies, laboratories, and techniques. A review of this literature highlights a number of variables that appear to moderate the relationship between music training and brain structure and function. These include age at commencement of training, sex, absolute pitch (AP), type of training, and instrument of training. These moderating variables may account for previously unexplained discrepancies in the existing literature, and we propose that future studies carefully consider research designs and methodologies that control for these variables. PMID- 24058354 TI - Gaming science: the "Gamification" of scientific thinking. AB - Science is critically important for advancing economics, health, and social well being in the twenty-first century. A scientifically literate workforce is one that is well-suited to meet the challenges of an information economy. However, scientific thinking skills do not routinely develop and must be scaffolded via educational and cultural tools. In this paper we outline a rationale for why we believe that video games have the potential to be exploited for gain in science education. The premise we entertain is that several classes of video games can be viewed as a type of cultural tool that is capable of supporting three key elements of scientific literacy: content knowledge, process skills, and understanding the nature of science. We argue that there are three classes of mechanisms through which video games can support scientific thinking. First, there are a number of motivational scaffolds, such as feedback, rewards, and flow states that engage students relative to traditional cultural learning tools. Second, there are a number of cognitive scaffolds, such as simulations and embedded reasoning skills that compensate for the limitations of the individual cognitive system. Third, fully developed scientific thinking requires metacognition, and video games provide metacognitive scaffolding in the form of constrained learning and identity adoption. We conclude by outlining a series of recommendations for integrating games and game elements in science education and provide suggestions for evaluating their effectiveness. PMID- 24058351 TI - The inevitable contrast: Conscious vs. unconscious processes in action control. PMID- 24058355 TI - Individual differences in motives, preferences, and pathology in video games: the gaming attitudes, motives, and experiences scales (GAMES). AB - A new measure of individual habits and preferences in video game use is developed in order to better study the risk factors of pathological game use (i.e., excessively frequent or prolonged use, sometimes called "game addiction"). This measure was distributed to internet message boards for game enthusiasts and to college undergraduates. An exploratory factor analysis identified 9 factors: Story, Violent Catharsis, Violent Reward, Social Interaction, Escapism, Loss Sensitivity, Customization, Grinding, and Autonomy. These factors demonstrated excellent fit in a subsequent confirmatory factor analysis, and, importantly, were found to reliably discriminate between inter-individual game preferences (e.g., Super Mario Brothers as compared to Call of Duty). Moreover, three factors were significantly related to pathological game use: the use of games to escape daily life, the use of games as a social outlet, and positive attitudes toward the steady accumulation of in-game rewards. The current research identifies individual preferences and motives relevant to understanding video game players' evaluations of different games and risk factors for pathological video game use. PMID- 24058357 TI - Normative preconditions for the assessment of mental disorder. AB - The debate about the relevance of values for the concept of a mental disorder has quite a long history. In the light of newer insights into neuroscience and molecular biology it is necessary to re-evaluate this issue. Since the medical model in previous decades was more of a confession rather than evidence based, one could assume that it is-due to scientific progress-currently becoming the one and only bedrock of psychiatry. This article argues that this would be a misapprehension of the normative constitution of the assessment of human behavior. The claim made here is twofold: First, whether something is a mental disease can only be determined on the mental level. This is so because we can only call behavior deviant by comparing it to non-deviant behavior, i.e., by using norms regarding behavior. Second, from this it follows that psychiatric disorders cannot be completely reduced to the physical level even if mental processes and states as such might be completely reducible to brain functions. PMID- 24058356 TI - What would my avatar do? Gaming, pathology, and risky decision making. AB - Recent work has revealed a relationship between pathological video game use and increased impulsivity among children and adolescents. A few studies have also demonstrated increased risk-taking outside of the video game environment following game play, but this work has largely focused on one genre of video games (i.e., racing). Motivated by these findings, the aim of the current study was to examine the relationship between pathological and non-pathological video game use, impulsivity, and risky decision making. The current study also investigated the relationship between experience with two of the most popular genres of video games [i.e., first-person shooter (FPS) and strategy] and risky decision making. Consistent with previous work, ~7% of the current sample of college-aged adults met criteria for pathological video game use. The number of hours spent gaming per week was associated with increased impulsivity on a self report measure and on the temporal discounting (TD) task. This relationship was sensitive to the genre of video game; specifically, experience with FPS games was positively correlated with impulsivity, while experience with strategy games was negatively correlated with impulsivity. Hours per week and pathological symptoms predicted greater risk-taking in the risk task and the Iowa Gambling task, accompanied by worse overall performance, indicating that even when risky choices did not pay off, individuals who spent more time gaming and endorsed more symptoms of pathological gaming continued to make these choices. Based on these data, we suggest that the presence of pathological symptoms and the genre of video game (e.g., FPS, strategy) may be important factors in determining how the amount of game experience relates to impulsivity and risky-decision making. PMID- 24058358 TI - Neural dynamics of audiovisual speech integration under variable listening conditions: an individual participant analysis. AB - Speech perception engages both auditory and visual modalities. Limitations of traditional accuracy-only approaches in the investigation of audiovisual speech perception have motivated the use of new methodologies. In an audiovisual speech identification task, we utilized capacity (Townsend and Nozawa, 1995), a dynamic measure of efficiency, to quantify audiovisual integration. Capacity was used to compare RT distributions from audiovisual trials to RT distributions from auditory-only and visual-only trials across three listening conditions: clear auditory signal, S/N ratio of -12 dB, and S/N ratio of -18 dB. The purpose was to obtain EEG recordings in conjunction with capacity to investigate how a late ERP co-varies with integration efficiency. Results showed efficient audiovisual integration for low auditory S/N ratios, but inefficient audiovisual integration when the auditory signal was clear. The ERP analyses showed evidence for greater audiovisual amplitude compared to the unisensory signals for lower auditory S/N ratios (higher capacity/efficiency) compared to the high S/N ratio (low capacity/inefficient integration). The data are consistent with an interactive framework of integration, where auditory recognition is influenced by speech reading as a function of signal clarity. PMID- 24058360 TI - Plant soil interactions alter carbon cycling in an upland grassland soil. AB - Soil carbon (C) storage is dependent upon the complex dynamics of fresh and native organic matter cycling, which are regulated by plant and soil-microbial activities. A fundamental challenge exists to link microbial biodiversity with plant-soil C cycling processes to elucidate the underlying mechanisms regulating soil carbon. To address this, we contrasted vegetated grassland soils with bare soils, which had been plant-free for 3 years, using stable isotope ((13)C) labeled substrate assays and molecular analyses of bacterial communities. Vegetated soils had higher C and N contents, biomass, and substrate-specific respiration rates. Conversely, following substrate addition unlabeled, native soil C cycling was accelerated in bare soil and retarded in vegetated soil; indicative of differential priming effects. Functional differences were reflected in bacterial biodiversity with Alphaproteobacteria and Acidobacteria dominating vegetated and bare soils, respectively. Significant isotopic enrichment of soil RNA was found after substrate addition and rates varied according to substrate type. However, assimilation was independent of plant presence which, in contrast to large differences in (13)CO2 respiration rates, indicated greater substrate C use efficiency in bare, Acidobacteria-dominated soils. Stable isotope probing (SIP) revealed most community members had utilized substrates with little evidence for competitive outgrowth of sub-populations. Our findings support theories on how plant-mediated soil resource availability affects the turnover of different pools of soil carbon, and we further identify a potential role of soil microbial biodiversity. Specifically we conclude that emerging theories on the life histories of dominant soil taxa can be invoked to explain changes in soil carbon cycling linked to resource availability, and that there is a strong case for considering microbial biodiversity in future studies investigating the turnover of different pools of soil carbon. PMID- 24058359 TI - Roles of NAC transcription factors in the regulation of biotic and abiotic stress responses in plants. AB - NAC transcription factors are one of the largest families of transcriptional regulators in plants, and members of the NAC gene family have been suggested to play important roles in the regulation of the transcriptional reprogramming associated with plant stress responses. A phylogenetic analysis of NAC genes, with a focus on rice and Arabidopsis, was performed. Herein, we present an overview of the regulation of the stress responsive NAC SNAC/(IX) group of genes that are implicated in the resistance to different stresses. SNAC factors have important roles for the control of biotic and abiotic stresses tolerance and that their overexpression can improve stress tolerance via biotechnological approaches. We also review the recent progress in elucidating the roles of NAC transcription factors in plant biotic and abiotic stresses. Modification of the expression pattern of transcription factor genes and/or changes in their activity contribute to the elaboration of various signaling pathways and regulatory networks. However, a single NAC gene often responds to several stress factors, and their protein products may participate in the regulation of several seemingly disparate processes as negative or positive regulators. Additionally, the NAC proteins function via auto-regulation or cross-regulation is extensively found among NAC genes. These observations assist in the understanding of the complex mechanisms of signaling and transcriptional reprogramming controlled by NAC proteins. PMID- 24058361 TI - Quantification of viral infection dynamics in animal experiments. AB - Analyzing the time-course of several viral infections using mathematical models based on experimental data can provide important quantitative insights regarding infection dynamics. Over the past decade, the importance and significance of mathematical modeling has been gaining recognition among virologists. In the near future, many animal models of human-specific infections and experimental data from high-throughput techniques will become available. This will provide us with the opportunity to develop new quantitative approaches, combining experimental and mathematical analyses. In this paper, we review the various quantitative analyses of viral infections and discuss their possible applications. PMID- 24058362 TI - Southern rice black-streaked dwarf virus: a white-backed planthopper-transmitted fijivirus threatening rice production in Asia. AB - Southern rice black-streaked dwarf virus (SRBSDV), a non-enveloped icosahedral virus with a genome of 10 double-stranded RNA segments, is a novel species in the genus Fijivirus (family Reoviridae) first recognized in 2008. Rice plants infected with this virus exhibit symptoms similar to those caused by Rice black streaked dwarf virus. Since 2009, the virus has rapidly spread and caused serious rice losses in East and Southeast Asia. Significant progress has been made in recent years in understanding this disease, especially about the functions of the viral genes, rice-virus-insect interactions, and epidemiology and control measures. The virus can be efficiently transmitted by the white-backed planthopper (WBPH, Sogatella furcifera) in a persistent circulative propagative manner but cannot be transmitted by the brown planthopper (Nilaparvata lugens) and small brown planthopper (Laodelphax striatellus). Rice, maize, Chinese sorghum (Coix lacryma-jobi) and other grass weeds can be infected via WBPH. However, only rice plays a major role in the virus infection cycle because of the vector's preference. In Southeast Asia, WBPH is a long-distance migratory rice pest. The disease cycle can be described as follows: SRBSDV and its WBPH vector overwinter in warm tropical or sub-tropical areas; viruliferous WBPH adults carry the virus from south to north via long-distance migration in early spring, transmit the virus to rice seedlings in the newly colonized areas, and lay eggs on the infected seedlings; the next generation of WBPHs propagate on infected seedlings, become viruliferous, disperse, and cause new disease outbreaks. Several molecular and serological methods have been developed to detect SRBSDV in plant tissues and individual insects. Control measures based on protection from WBPH, including seedbed coverage, chemical seed treatments, and chemical spraying of seedlings, have proven effective in China. PMID- 24058364 TI - Thioredoxin ameliorates cutaneous inflammation by regulating the epithelial production and release of pro-inflammatory cytokines. AB - Human thioredoxin-1 (TRX) is a 12-kDa protein with redox-active dithiol in the active site -Cys-Gly-Pro-Cys-. It has been demonstrated that systemic administration and transgenic overexpression of TRX ameliorate inflammation in various animal models, but its anti-inflammatory mechanism is not well characterized. We investigated the anti-inflammatory effects of topically applied recombinant human TRX (rhTRX) in a murine irritant contact dermatitis (ICD) induced by croton oil. Topically applied rhTRX was distributed only in the skin tissues under both non-inflammatory and inflammatory conditions, and significantly suppressed the inflammatory response by inhibiting the production of cytokines and chemokines, such as TNF-alpha, Il-1beta, IL-6, CXCL-1, and MCP 1. In an in vitro study, rhTRX also significantly inhibited the formation of cytokines and chemokines produced by keratinocytes after exposure to croton oil and phorbol 12-myristate 13-acetate. These results indicate that TRX prevents skin inflammation via the inhibition of local formation of inflammatory cytokines and chemokines. As a promising new approach, local application of TRX may be useful for the treatment of various skin and mucosal inflammatory disorders. PMID- 24058363 TI - Highlights on distinctive structural and functional properties of HTLV Tax proteins. AB - Human T cell leukemia viruses (HTLVs) are complex human retroviruses of the Deltaretrovirus genus. Four types have been identified thus far, with HTLV-1 and HTLV-2 much more prevalent than HTLV-3 or HTLV-4. HTLV-1 and HTLV-2 possess strictly related genomic structures, but differ significantly in pathogenicity, as HTLV-1 is the causative agent of adult T cell leukemia and of HTLV-associated myelopathy/tropical spastic paraparesis, whereas HTLV-2 is not associated with neoplasia. HTLVs code for a protein named Tax that is responsible for enhancing viral expression and drives cell transformation. Much effort has been invested to dissect the impact of Tax on signal transduction pathways and to identify functional differences between the HTLV Tax proteins that may explain the distinct oncogenic potential of HTLV-1 and HTLV-2. This review summarizes our current knowledge of Tax-1 and Tax-2 with emphasis on their structure, role in activation of the NF-kappaB (nuclear factor kappa-B) pathway, and interactions with host factors. PMID- 24058365 TI - The role of nitric oxide in the interaction of Arabidopsis thaliana with the biotrophic fungi, Golovinomyces orontii and Erysiphe pisi. AB - Powdery mildews are a diverse group of pathogenic fungi that can infect a large number of plant species, including many economically important crops. However, basic and applied research on these devastating diseases has been hampered by the obligate biotrophic lifestyle of the pathogens, which require living host cells for growth and reproduction, and lacking genetic and molecular tools for important host plants. The establishment of Arabidopsis thaliana as a host of different powdery mildew species allowed pursuing new strategies to study the molecular mechanisms governing these complex plant-pathogen interactions. Nitric oxide (NO) has emerged as an important signaling molecule in plants, which is produced upon infection and involved in activation of plant immune responses. However, the source and pathway of NO production and its precise function in the regulatory network of reactions leading to resistance is still unknown. We studied the response of Arabidopsis thaliana to infection with the adapted powdery mildew, Golovinomyces orontii (compatible interaction) and the non adapted, Erysiphe pisi (incompatible interaction). We observed that NO accumulated rapidly and transiently at infection sites and we established a correlation between the resistance phenotype and the amount and timing of NO production. Arabidopsis mutants with defective immune response accumulated lower NO levels compared to wild type. Conversely, increased NO levels, generated by treatment with chemicals or expression of a NO-synthesizing enzyme, resulted in enhanced resistance, but only sustained NO production prevented excessive leaf colonization by the fungus, which was not achieved by a short NO burst although this reduced the initial penetration success. By contrast, lowered NO levels did not impair the ultimate resistance phenotype. Although our results suggest a function of NO in mediating plant immune responses, a direct impact on pathogen growth and development cannot be excluded. PMID- 24058366 TI - Heritability of pulmonary function estimated from pedigree and whole-genome markers. AB - Asthma and chronic obstructive pulmonary disease (COPD) are major worldwide health problems. Pulmonary function testing is a useful diagnostic tool for these diseases, and is known to be influenced by genetic and environmental factors. Previous studies have demonstrated that a substantial proportion of the variation in pulmonary function phenotypes can be explained by familial relationships. The availability of whole-genome single nucleotide polymorphism (SNP) data enables us to further evaluate the extent to which genetic factors account for variation in pulmonary function and to compare pedigree- to SNP-based estimates of heritability. Here, we employ methods developed in the animal breeding field to estimate the heritability of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the ratio of these two measures (FEV1/FVC) among subjects in the Framingham Heart Study dataset. We compare heritability estimates based on pedigree-based relationships to those based on genome-wide SNPs. We find that, in a family-based study, estimates of heritability using SNP data are nearly identical to estimates based on pedigree information, and range from 0.50 for FEV1 to 0.66 for FEV1/FVC. Therefore, we conclude that genetic factors account for a sizable proportion of inter-individual differences in pulmonary function, and that estimates of heritability based on SNP data are nearly identical to estimates based on pedigree data. Finally, our findings suggest a higher heritability for FEV1/FVC compared to either FEV1 or FVC. PMID- 24058367 TI - (Epi)genetics of pregnancy-associated diseases. AB - This review describes the current knowledge regarding genetics and epigenetics of pregnancy-associated diseases with placental origin. We discuss the effect on genetic linkage analyses when the fetal genotype determines the maternal phenotype. Secondly, the genes identified by genome-wide linkage studies to be associated with pre-eclampsia (ACVR2A, STOX1) and the HELLP-syndrome (LINC-HELLP) are discussed regarding their potential functions in the etiology of disease. Furthermore, susceptibility genes identified by candidate gene approaches (e.g., CORIN) are described. Next, we focus on the additional challenges that come when epigenetics also play a role in disease inheritance. We discuss the maternal transmission of the chromosome 10q22 pre-eclampsia linkage region containing the STOX1 gene and provide further evidence for the role of epigenetics in pre eclampsia based on the cdkn1c mouse model of pre-eclampsia. Finally, we provide recommendations to unravel the genetics of pregnancy-associated diseases, specifically regarding clear definitions of patient groups and sufficient patient numbers, and the potential usefulness of (epi)genetic data in early non-invasive biomarker development. PMID- 24058368 TI - A FINITE ELEMENT METHOD FOR ELASTICITY INTERFACE PROBLEMS WITH LOCALLY MODIFIED TRIANGULATIONS. AB - A finite element method for elasticity systems with discontinuities in the coefficients and the flux across an arbitrary interface is proposed in this paper. The method is based on a Cartesian mesh with local modifications to the mesh. The total degrees of the freedom of the finite element method remains the same as that of the Cartesian mesh. The local modifications lead to a quasi uniform body-fitted mesh from the original Cartesian mesh. The standard finite element theory and implementation are applicable. Numerical examples that involve discontinuous material coefficients and non-homogeneous jump in the flux across the interface demonstrate the efficiency of the proposed method. PMID- 24058369 TI - Hepatoprotective Effect of Fermented Soybean (Nutrient Enriched Soybean Tempeh) against Alcohol-Induced Liver Damage in Mice. AB - Recently, soybean tempeh has received great attention due to many advantages such as higher nutritional value, lower production cost, and shorter fermentation time. In this study, the in vivo hepatoprotective and antioxidant effects of nutrient enriched soybean tempeh (NESTE) were determined. NESTE fermentation process which involved anaerobic incubation was previously proclaimed to increase the content of amino acids and antioxidant properties remarkably. The evaluation of histological sections, serum biochemical markers (aspartate aminotransferase (AST), alanine aminotransferase (ALT), and cholesterol and triglycerides (TG)), liver immune response level (nitric oxide (NO)) and liver antioxidant level (superoxide dismutase (SOD), ferric reducing antioxidant power (FRAP), and malondialdehyde (MDA)) was conducted in order to compare the effects of nonfermented soybean extract (SBE) and fermented soybean extract (NESTE) on alcohol-induced liver damage in mice. Results demonstrated that 1000 mg/kg of NESTE can significantly reduce the levels of AST, ALT, cholesterol, TG, MDA, and NO. On the other hand, it also raised the level of SOD and FRAP. Furthermore, the histological examination on 1000 mg/kg NESTE treatment group showed that this extract was capable of recovering the damaged hepatocytes to their normal structures. Thus, it can be concluded that NESTE produced through fermentation process was able to enhance hepatoprotective and antioxidant effects in vivo. PMID- 24058370 TI - Effect of bee venom acupuncture on oxaliplatin-induced cold allodynia in rats. AB - Oxaliplatin, a chemotherapy drug, often leads to neuropathic cold allodynia after a single administration. Bee venom acupuncture (BVA) has been used in Korea to relieve various pain symptoms and is shown to have a potent antiallodynic effect in nerve-injured rats. We examined whether BVA relieves oxaliplatin-induced cold allodynia and which endogenous analgesic system is implicated. The cold allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) was evaluated by immersing the rat's tail into cold water (4 degrees C) and measuring the withdrawal latency. BVA (1.0 mg/kg, s.c.) at Yaoyangguan (GV3), Quchi (LI11), or Zusanli (ST36) acupoints significantly reduced cold allodynia with the longest effect being shown in the GV3 group. Conversely, a high dose of BVA (2.5 mg/kg) at GV3 did not show a significant antiallodynic effect. Phentolamine ( alpha -adrenergic antagonist, 2 mg/kg, i.p.) partially blocked the relieving effect of BVA on allodynia, whereas naloxone (opioid antagonist, 2 mg/kg, i.p.) did not. We further confirmed that an intrathecal administration of idazoxan ( alpha 2 adrenergic antagonist, 50 MU g) blocked the BVA-induced anti-allodynic effect. These results indicate that BVA alleviates oxaliplatin-induced cold allodynia in rats, at least partly, through activation of the noradrenergic system. Thus, BVA might be a potential therapeutic option in oxaliplatin-induced neuropathy. PMID- 24058371 TI - Matrine Inhibits Infiltration of the Inflammatory Gr1(hi) Monocyte Subset in Injured Mouse Liver through Inhibition of Monocyte Chemoattractant Protein-1. AB - Matrine (Mat) is a major alkaloid extracted from Sophora flavescens Ait, an herb which is used in the traditional Chinese medicine for treatment of inflammation, cancer, and other diseases. The present study examined the impact of Mat on the CCl4-induced hepatic infiltration of Gr1(hi) monocytes to explore the possible mechanisms underlying its anti-inflammatory and antifibrotic effects. The results indicated that Mat protected mice from acute liver injury induced by single intraperitoneal injection of CCl4 and attenuated liver fibrosis induced by repeated CCl4 injection. Meanwhile, the infiltrations of Gr1(hi) monocytes in both acute and chronic injured livers were all inhibited, and the enhanced hepatic expression of MCP-1 was suppressed. Cellular experiments demonstrated that Mat directly inhibited MCP-1 production in both nonparenchymal cells and hepatic stellate cells derived from CCl4-injured livers. Transwell chemotaxis assays showed that Mat significantly inhibited the chemotactic activity of MCP-1. These results suggest that the anti-inflammatory and antifibrotic effects of Mat could be contributed, at least in part, to its prevention of Gr1(hi) monocyte infiltration into the injured livers and inhibition of MCP-1 production and activity. These findings extend our understanding of the mechanisms underlying the anti-inflammatory and antifibrotic effects of Mat. PMID- 24058372 TI - Lingmao Formula Combined with Entecavir for HBeAg-Positive Chronic Hepatitis B Patients with Mildly Elevated Alanine Aminotransferase: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial. AB - Objective. To determine the efficacy and safety of Lingmao Formula combined with entecavir for HBeAg-positive chronic hepatitis B patients with mildly elevated alanine aminotransferase (ALT). Methods. 301 patients were randomly assigned to receive Lingmao Formula combined with entecavir (treatment group) or placebo combined with entecavir (control group) for 52 weeks. The outcomes of interest included the reduction of serum HBV DNA level, HBeAg loss, HBeAg seroconversion, ALT normalization, and histological improvement. Results. The mean decrease of serum HBV DNA level from baseline and the percentage of patients who had reduction in serum HBV DNA level >=2 lg copies/mL in treatment group were significantly greater than that in control group (5.5 versus 5.4 lg copies/mL, P = 0.010; 98.5% versus 92.6%, P = 0.019). The percentage of HBeAg loss in treatment group was 22.8%, which was much higher than a percentage of 12.6% in control group (P = 0.038). There was no significant difference between the two groups in histological improvement. Safety was similar in the two groups. Conclusions. The combination of Lingmao Formula with entecavir could result in significant decrease of serum HBV DNA and increase of HBeAg loss for HBeAg positive chronic hepatitis B patients with mildly elevated ALT without any serious adverse events. Clinical trial registration number is ChiCTR-TRC 09000594. PMID- 24058374 TI - Coniferyl Ferulate, a Strong Inhibitor of Glutathione S-Transferase Isolated from Radix Angelicae sinensis, Reverses Multidrug Resistance and Downregulates P Glycoprotein. AB - Glutathione S-transferase (GST) is the key enzyme in multidrug resistance (MDR) of tumour. Inhibition of the expression or activity of GST has emerged as a promising therapeutic strategy for the reversal of MDR. Coniferyl ferulate (CF), isolated from the root of Angelica sinensis (Oliv.) Diels (Radix Angelicae sinensis, RAS), showed strong inhibition of human placental GST. Its 50% inhibition concentration (IC50) was 0.3 MU M, which was greater than a known GSTP1-1 inhibitor, ethacrynic acid (EA), using the established high-throughput screening model. Kinetic analysis and computational docking were used to examine the mechanism of GST inhibition by CF. Computational docking found that CF could be fully docked into the gorge of GSTP1-1. The further exploration of the mechanisms showed that CF was a reversible noncompetitive inhibitor with respect to GSH and CDNB, and it has much less cytotoxicity. Apoptosis and the expression of P-gp mRNA were evaluated in the MDR positive B-MD-C1 (ADR+/+) cell line to investigate the MDR reversal effect of CF. Moreover, CF showed strong apoptogenic activity and could markedly decrease the overexpressed P-gp. The results demonstrated that CF could inhibit GST activity in a concentration-dependent manner and showed a potential MDR reversal effect for antitumour adjuvant therapy. PMID- 24058373 TI - Synergistic Action of Flavonoids, Baicalein, and Daidzein in Estrogenic and Neuroprotective Effects: A Development of Potential Health Products and Therapeutic Drugs against Alzheimer's Disease. AB - Despite the classical hormonal effect, estrogen has been reported to mediate neuroprotection in the brain, which leads to the searching of estrogen-like substances for treating neurodegenerative diseases. Flavonoids, a group of natural compounds, are well known to possess estrogenic effects and used to substitute estrogen, that is, phytoestrogen. Flavonoid serves as one of the potential targets for the development of natural supplements and therapeutic drugs against different diseases. The neuroprotection activity of flavonoids was chosen for a possible development of anti-Alzheimer's drugs or food supplements. The estrogenic activity of two flavonoids, baicalein and daidzein, were demonstrated by their strong abilities in stimulating estrogen receptor phosphorylation and transcriptional activation of estrogen responsive element in MCF-7 breast cells. The neuroprotection effects of flavonoids against beta amyloid (A beta ) were revealed by their inhibition effects on in vitro A beta aggregation and A beta -induced cytotoxicity in PC12 neuronal cells. More importantly, the estrogenic and neuroprotective activities of individual flavonoid could be further enhanced by the cotreatment in the cultures. Taken together, this synergistic effect of baicalein and daidzein might serve as a method to improve the therapeutic efficacy of different flavonoids against A beta , which might be crucial in developing those flavonoidsin treating Alzheimer's disease in the future. PMID- 24058375 TI - A network study of chinese medicine xuesaitong injection to elucidate a complex mode of action with multicompound, multitarget, and multipathway. AB - Chinese medicine has evolved from thousands of years of empirical applications and experiences of combating diseases. It has become widely recognized that the Chinese medicine acts through complex mechanisms featured as multicompound, multitarget and multipathway. However, there is still a lack of systematic experimental studies to elucidate the mechanisms of Chinese medicine. In this study, the differentially expressed genes (DEGs) were identified from myocardial infarction rat model treated with Xuesaitong Injection (XST), a Chinese medicine consisting of the total saponins from Panax notoginseng (Burk.) F. H. Chen (Chinese Sanqi). A network-based approach was developed to combine DEGs related to cardiovascular diseases (CVD) with lines of evidence from the literature mining to investigate the mechanism of action (MOA) of XST on antimyocardial infarction. A compound-target-pathway network of XST was constructed by connecting compounds to DEGs validated with literature lines of evidence and the pathways that are functionally enriched. Seventy potential targets of XST were identified in this study, of which 32 were experimentally validated either by our in vitro assays or by CVD-related literatures. This study provided for the first time a network view on the complex MOA of antimyocardial infarction through multiple targets and pathways. PMID- 24058376 TI - TCM Zheng Classification and Clinical Trials. PMID- 24058377 TI - Clitocybe nuda Activates Dendritic Cells and Acts as a DNA Vaccine Adjuvant. AB - This work represents the first evaluation of the effects of water extract of C. nuda (WE-CN), an edible mushroom, on murine bone marrow-derived dendritic cells (BMDCs) and the potential pathway through which the effects are mediated. Our experimental results show that WE-CN could induce phenotypic maturation of DCs, as shown by the increased expression of MHC and costimulatory molecules. In addition, it also induced the proinflammatory cytokines expression on DCs and enhanced both the proliferation and IFN- gamma secretion of allogenic T cells. Therefore, since WE-CN did not induce maturation of DCs generated from mice with mutated TLR-4 or TLR-2, suggesting that TLR4 and TLR2 might function as membrane receptors for WE-CN. Moreover, the mechanism of action of WE-CN may be mediated by increased phosphorylation of ERK, p38, and JNK mitogen-activated protein kinase (MAPK) and increased NF- kappa B p65 activity, which are important signaling molecules downstream of TLR-4 and TLR-2. Finally, coimmunization of mice with WE-CN and a HER-2/neu DNA vaccine induced a HER-2/neu-specific Th1 response that resulted in significant inhibition of HER-2/neu overexpressing mouse bladder tumor (MBT-2) growth. These data suggest that WE-CN induces DC maturation through TLR-4 and/or TLR-2 and that WE-CN can be used as an adjuvant in cancer vaccine immunotherapy. PMID- 24058378 TI - An ultra-thin Schottky diode as a transmission particle detector for biological microbeams. AB - We fabricated ultrathin metal-semiconductor Schottky diodes for use as transmission particle detectors in the biological microbeam at Columbia University's Radiological Research Accelerator Facility (RARAF). The RARAF microbeam can deliver a precise dose of ionizing radiation in cell nuclei with sub-micron precision. To ensure an accurate delivery of charged particles, the facility currently uses a commercial charged-particle detector placed after the sample. We present here a transmission detector that will be placed between the particle accelerator and the biological specimen, allowing the irradiation of samples that would otherwise block radiation from reaching a detector behind the sample. Four detectors were fabricated with co-planar gold and aluminum electrodes thermally evaporated onto etched n-type crystalline silicon substrates, with device thicknesses ranging from 8.5 MUm - 13.5 MUm. We show coincident detections and pulse-height distributions of charged particles in both the transmission detector and the commercial detector above it. Detections are demonstrated at a range of operating conditions, including incoming particle type, count rate, and beam location on the detectors. The 13.5 MUm detector is shown to work best to detect 2.7 MeV protons (H+), and the 8.5 MUm detector is shown to work best to detect 5.4 MeV alpha particles (4He++). The development of a transmission detector enables a range of new experiments to take place at RARAF on radiation-stopping samples such as thick tissues, targets that need immersion microscopy, and integrated microfluidic devices for handling larger quantities of cells and small organisms. PMID- 24058379 TI - Varieties of Resilience in MIDUS. AB - Population-based studies of health typically focus on psychosocial contributors to illness and disease. We examine findings from a national longitudinal study of American adults, known as MIDUS (Midlife in the U.S.) to examine the role of psychosocial factors in promoting resilience, defined as the maintenance, recovery, or improvement in health following challenge. Classic studies of resilience are briefly noted, followed by a look at three categories of resilience in MIDUS. The first pertains to having good health and well-being in the face of low socioeconomic standing. The second pertains to maintaining good health and well-being despite the challenges that accompany aging. The third pertains to resilience in the face of targeted life challenges such as abuse in childhood, loss of spouse in adulthood, or having cancer. Across each area, we summarize evidence of positive health, and where possible, highlight protective influences that account for such salubrious outcomes. We conclude with opportunities for future research in MIDUS such as examining cultural and genetic influences on resilience as well as utilizing laboratory challenge data to illuminate underlying mechanisms. PMID- 24058381 TI - Wii Tennis Play for Low-Income African American Adolescents' Energy Expenditure. AB - Exergames, which are video games that require gross motor activity, are popular activities that produce energy expenditure. Seventy-four low-income African American 12- to 18-year-old adolescents were randomly assigned to a 30-minute condition: 1) solitary Wii tennis exergame play against virtual peers; 2) social Wii tennis exergame play against a real peer; or 3) control group with sedentary computer activity. Adolescents were tested for caloric expenditure after exposure to treatment conditions as well as on a tennis court using Actical accelerometers. Adolescents who played the social exergame against a peer expended significantly more energy than those who played alone. Both exergame groups expended more energy than the control group. Adolescents who played the social exergame also expended comparable calories to actual tennis court play during a simulated lesson. Exergames, then, could promote physical activity, thereby becoming a tool to combat the obesity crisis that is affecting many youth. PMID- 24058380 TI - Advances in our Understanding of the Pathophysiology, Detection and Management of Cerebral Amyloid Angiopathy. AB - Cerebral amyloid angiopathy (CAA) is pathologically defined as the deposition of amyloid protein, most commonly the amyloid beta peptide (Abeta), primarily within the media and adventitia of small and medium-sized arteries of the leptomeninges, cerebral and cerebellar cortex. This deposition likely reflects an imbalance between Abeta production and clearance within the brain and leads to weakening of the overall structure of brain small vessels, predisposing patients tolobar intracerebral haemorrhage (ICH), brain ischaemia and cognitive decline. CAA is associated with markers of small vessel disease, like lobar microbleeds and white matter hyperintensities on magnetic resonance imaging. Therefore, it can be now be diagnosed during life with reasonable accuracy by clinical and neuroimaging criteria. Despite the lack of a specific treatment for this condition, the detection of CAA may help in the management of patients, regarding the prevention of major haemorrhagic complications and genetic counselling. This review discusses recent advances in our understanding of the pathophysiology, detection and management of CAA. PMID- 24058383 TI - JOCB Bulletin. PMID- 24058382 TI - An Interface-Fitted Finite Element Level Set Method with Application to Solidification and Solvation. AB - A new finite element level set method is developed to simulate the interface motion. The normal velocity of the moving interface can depend on both the local geometry, such as the curvature, and the external force such as that due to the flux from both sides of the interface of a material whose concentration is governed by a diffusion equation. The key idea of the method is to use an interface-fitted finite element mesh. Such an approximation of the interface allows an accurate calculation of the solution to the diffusion equation. The interface-fitted mesh is constructed from a base mesh, a uniform finite element mesh, at each time step to explicitly locate the interface and separate regions defined by the interface. Several new level set techniques are developed in the framework of finite element methods. These include a simple finite element method for approximating the curvature, a new method for the extension of normal velocity, and a finite element least-squares method for the reinitialization of level set functions. Application of the method to the classical solidification problem captures the dendrites. The method is also applied to the the molecular solvation to determine optimal solute-solvent interfaces of solvation systems. PMID- 24058385 TI - User-centered development of a smart phone mobile application delivering personalized real-time advice on sun protection. AB - Smart phones are changing health communication for Americans. User-centered production of a mobile application for sun protection is reported. Focus groups (n = 16 adults) provided input on the mobile application concept. Four rounds of usability testing were conducted with 22 adults to develop the interface. An iterative programming procedure moved from a specification document to the final mobile application, named Solar Cell. Adults desired a variety of sun protection advice, identified few barriers to use and were willing to input personal data. The Solar Cell prototype was improved from round 1 (seven of 12 tasks completed) to round 2 (11 of 12 task completed) of usability testing and was interoperable across handsets and networks. The fully produced version was revised during testing. Adults rated Solar Cell as highly user friendly (mean = 5.06). The user centered process produced a mobile application that should help many adults manage sun safety. PMID- 24058384 TI - Statistical and Computational Methods for High-Throughput Sequencing Data Analysis of Alternative Splicing. AB - The burgeoning field of high-throughput sequencing significantly improves our ability to understand the complexity of transcriptomes. Alternative splicing, as one of the most important driving forces for transcriptome diversity, can now be studied at an unprecedent resolution. Efficient and powerful computational and statistical methods are in urgent need to facilitate the characterization and quantification of alternative splicing events. Here we discuss methods in splice junction read mapping, and methods in exon-centric or isoform-centric quantification of alternative splicing. In addition, we discuss HITS-CLIP and splicing QTL analyses which are novel high-throughput sequencing based approaches in the dissection of splicing regulation. PMID- 24058386 TI - The Longitudinal Relationship Between Satisfaction with Transitional Care and Social and Emotional Quality of Life Among Chronically Ill Adolescents. AB - This study aimed to identify the relationship between satisfaction with transitional care and quality of life of chronically ill adolescents over time. This longitudinal study included adolescents with type I diabetes, juvenile idiopathic arthritis (JIA), and neuromuscular disorders (NMD). At baseline 138 respondents (response rate 31 %) filled in a questionnaire and 188 about 1 year later (response rate 43 %). Analysis of variance showed that adolescents with diabetes reported the highest physical quality of life, followed in order by those with NMD and JIA (p <= 0.01). Adolescents with diabetes reported the highest social quality of life, followed in order by those with JIA and NMD (both at p <= 0.001). Univariate analyses showed that satisfaction with transitional care at T0 was significantly related to emotional and physical quality of life at T1 (both at p <= 0.05). At T1, satisfaction with transitional care was significantly related to the emotional, physical, and social domains of quality of life (all at p <= 0.001). Multiple regression analyses revealed that satisfaction with transitional care at T1 was related to emotional (beta -0.20; p <= 0.05) and social (beta -0.35; p <= 0.01) quality of life domains over time. This indicates that lower gap scores, which measured differences between 'best care' and 'current care,' are associated with better social and emotional quality of life in this sample of adolescents. Satisfaction with transitional care and social and emotional quality of life are related over time. PMID- 24058387 TI - Relationship between Uric Acid Levels and Diagnostic and Prognostic Outcomes in Acute Heart Failure. AB - OBJECTIVES: We evaluated the association of plasma uric acid alone and in combination with b-type natriuretic peptide (BNP) for emergency department (ED) diagnosis and 30-day prognosis in patients evaluated for acute heart failure (AHF). METHODS: We prospectively enrolled 322 adult ED patients with suspected AHF. Wilcoxon rank sum test, multivariable logistic regression and likelihood ratio (LR) tests were used for statistical analyses. RESULTS: Uric acid's diagnostic utility was poor and failed to show significant associations with 30 day clinical outcomes. Uric acid also did not add significantly to BNP results. CONCLUSION: Among ED patients with suspected AHF, uric acid has poor diagnostic and prognostic utility. PMID- 24058388 TI - Patterns of care in older patients with squamous cell carcinoma of the head and neck: a surveillance, epidemiology, and end results-medicare analysis. AB - BACKGROUND: There is growing evidence in the literature that older patients may not benefit from more intensive therapy for head and neck squamous cell carcinoma (HNSCC). A growing number of patients with HNSCC are age 65 years or older; however, much of the evidence base informing treatment decisions is based on substantially younger and healthier clinical trial populations. The purpose of this study was to assess the patterns of care of older HNSCC patients to better understand how age is associated with treatment decisions. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (1992-2007), we identified patients with non-metastatic HNSCC (n = 10,867) and categorized them by treatment: surgery vs. non-surgery and chemoradiotherapy (CRT) vs. radiotherapy (RT). Multivariate logistic regression models were used to identify variables associated with the receipt of surgery and CRT. RESULTS: Increasing age was associated with decreased odds of receiving CRT (OR = 0.94; 95% CI 0.93-0.94) but not surgery (OR 1.00; 95% CI 0.99-1.00). Co-morbidity and race were not associated with receipt of either surgery or CRT. Utilization of CRT increased while surgery decreased between 1992 and 2007. CONCLUSION: Age may influence the receipt of CRT for older HNSCC patients. There has been an increasing trend in the receipt of CRT and a decrease in primary surgery. PMID- 24058389 TI - Cancer Treatment in Malawi: A Disease of Palliation. AB - BACKGROUND: Worldwide, new cancer cases will nearly double in the next 20 years while disproportionately affecting low and middle income countries (LMICs). Cancer outcomes in LMICs also remain bleaker than other regions of the world. Despite this, little is known about cancer epidemiology and surgical treatment in LMICs. To address this we sought to describe the characteristics of cancer patients presenting to the Surgery Department at Kamuzu Central Hospital in Lilongwe, Malawi. METHODS: We conducted a retrospective review of adult (18 years or older) surgical oncology services at Kamuzu Central Hospital in Lilongwe, Malawi from 2007 - 2010. Data obtained from the operating theatre logs included patient demographics, indication for operative procedure, procedure performed, and operative procedures (curative, palliative, or staging). RESULTS: Of all the general surgery procedures performed during this time period (7,076 in total), 16% (406 cases) involved cancer therapy. The mean age of male and female patients in this study population was 52 years and 47 years, respectively. Breast cancer, colorectal cancer, gastric cancer, and melanoma were the most common cancers among women, whereas prostate, colorectal, pancreatic, and, gastric were the most common cancers in men. Although more than 50% of breast cancer operations were performed with curative intent, most procedures were palliative including prostate cancer (98%), colorectal cancer (69%), gastric cancer (71%), and pancreatic cancer (94%). Patients with colorectal, gastric, esophageal, pancreatic, and breast cancer presented at surprisingly young ages. CONCLUSION: The paucity of procedures with curative intent and young age at presentation reveals that many Malawians miss opportunities for cure and many potential years of life are lost. Though KCH now has pathology services, a cancer registry and a surgical training program, the focus of surgical care remains palliative. Further research should address other methods of increasing early cancer detection and treatment in such populations. PMID- 24058390 TI - Cardiorespiratory Fitness in Women with and without Lymphedema following Breast Cancer Treatment. AB - Following breast cancer (BC) treatment, many women develop impairments that may impact cardiorespiratory (CR) fitness. The aims of this study were to 1) evaluate CR fitness in women following BC treatment, 2) evaluate differences in CR fitness in those with and without breast cancer-related lymphedema (BCRL) and compare these to age-matched norms, and 3) evaluate the contribution of predictor variables to CR fitness. 136 women post-BC treatment completed testing: 67 with BCRL, and 69 without. VO2 peak was lower in participants compared to published healthy age-matched norms. VO2 peak was statistically significantly lower in women with BCRL. Age, BMI, meeting recommended exercise criteria, and DASH scores explained 50% of the variance in VO2 peak (R=0.708, p<0.001). Following BC treatment CR fitness may be impaired, more-so in women with BCRL. This should be considered when providing rehabilitation for women following BC treatment as cardiorespiratory fitness has linked to improved health outcomes and survivorship. PMID- 24058396 TI - Retraction: Eafs control erythroid cell fate by regulating c-myb expression through Wnt signaling. PMID- 24058397 TI - A consistency-based feature selection method allied with linear SVMs for HIV-1 protease cleavage site prediction. AB - BACKGROUND: Predicting type-1 Human Immunodeficiency Virus (HIV-1) protease cleavage site in protein molecules and determining its specificity is an important task which has attracted considerable attention in the research community. Achievements in this area are expected to result in effective drug design (especially for HIV-1 protease inhibitors) against this life-threatening virus. However, some drawbacks (like the shortage of the available training data and the high dimensionality of the feature space) turn this task into a difficult classification problem. Thus, various machine learning techniques, and specifically several classification methods have been proposed in order to increase the accuracy of the classification model. In addition, for several classification problems, which are characterized by having few samples and many features, selecting the most relevant features is a major factor for increasing classification accuracy. RESULTS: We propose for HIV-1 data a consistency-based feature selection approach in conjunction with recursive feature elimination of support vector machines (SVMs). We used various classifiers for evaluating the results obtained from the feature selection process. We further demonstrated the effectiveness of our proposed method by comparing it with a state-of-the-art feature selection method applied on HIV-1 data, and we evaluated the reported results based on attributes which have been selected from different combinations. CONCLUSION: Applying feature selection on training data before realizing the classification task seems to be a reasonable data-mining process when working with types of data similar to HIV-1. On HIV-1 data, some feature selection or extraction operations in conjunction with different classifiers have been tested and noteworthy outcomes have been reported. These facts motivate for the work presented in this paper. SOFTWARE AVAILABILITY: The software is available at http://ozyer.etu.edu.tr/c-fs-svm.rar. The software can be downloaded at esnag.etu.edu.tr/software/hiv_cleavage_site_prediction.rar; you will find a readme file which explains how to set the software in order to work. PMID- 24058398 TI - At grammatical faculty of language, flies outsmart men. AB - Using a symbolic dynamics and a surrogate data approach, we show that the language exhibited by common fruit flies Drosophila ('D.') during courtship is as grammatically complex as the most complex human-spoken modern languages. This finding emerges from the study of fifty high-speed courtship videos (generally of several minutes duration) that were visually frame-by-frame dissected into 37 fundamental behavioral elements. From the symbolic dynamics of these elements, the courtship-generating language was determined with extreme confidence (significance level > 0.95). The languages categorization in terms of position in Chomsky's hierarchical language classification allows to compare Drosophila's body language not only with computer's compiler languages, but also with human spoken languages. Drosophila's body language emerges to be at least as powerful as the languages spoken by humans. PMID- 24058399 TI - Programmatically selected multidrug-resistant strains drive the emergence of extensively drug-resistant tuberculosis in South Africa. AB - BACKGROUND: South Africa shows one of the highest global burdens of multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). Since 2002, MDR-TB in South Africa has been treated by a standardized combination therapy, which until 2010 included ofloxacin, kanamycin, ethionamide, ethambutol and pyrazinamide. Since 2010, ethambutol has been replaced by cycloserine or terizidone. The effect of standardized treatment on the acquisition of XDR-TB is not currently known. METHODS: We genetically characterized a random sample of 4,667 patient isolates of drug-sensitive, MDR and XDR-TB cases collected from three South African provinces, namely, the Western Cape, Eastern Cape and KwaZulu Natal. Drug resistance patterns of a subset of isolates were analyzed for the presence of commonly observed resistance mutations. RESULTS: Our analyses revealed a strong association between distinct strain genotypes and the emergence of XDR-TB in three neighbouring provinces of South Africa. Strains predominant in XDR-TB increased in proportion by more than 20-fold from drug-sensitive to XDR-TB and accounted for up to 95% of the XDR-TB cases. A high degree of clustering for drug resistance mutation patterns was detected. For example, the largest cluster of XDR-TB associated strains in the Eastern Cape, affecting more than 40% of all MDR patients in this province, harboured identical mutations concurrently conferring resistance to isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, ethionamide, kanamycin, amikacin and capreomycin. CONCLUSIONS: XDR TB associated genotypes in South Africa probably were programmatically selected as a result of the standard treatment regimen being ineffective in preventing their transmission. Our findings call for an immediate adaptation of standard treatment regimens for M/XDR-TB in South Africa. PMID- 24058400 TI - Hidden Markov models: the best models for forager movements? AB - One major challenge in the emerging field of movement ecology is the inference of behavioural modes from movement patterns. This has been mainly addressed through Hidden Markov models (HMMs). We propose here to evaluate two sets of alternative and state-of-the-art modelling approaches. First, we consider hidden semi-Markov models (HSMMs). They may better represent the behavioural dynamics of foragers since they explicitly model the duration of the behavioural modes. Second, we consider discriminative models which state the inference of behavioural modes as a classification issue, and may take better advantage of multivariate and non linear combinations of movement pattern descriptors. For this work, we use a dataset of >200 trips from human foragers, Peruvian fishermen targeting anchovy. Their movements were recorded through a Vessel Monitoring System (~1 record per hour), while their behavioural modes (fishing, searching and cruising) were reported by on-board observers. We compare the efficiency of hidden Markov, hidden semi-Markov, and three discriminative models (random forests, artificial neural networks and support vector machines) for inferring the fishermen behavioural modes, using a cross-validation procedure. HSMMs show the highest accuracy (80%), significantly outperforming HMMs and discriminative models. Simulations show that data with higher temporal resolution, HSMMs reach nearly 100% of accuracy. Our results demonstrate to what extent the sequential nature of movement is critical for accurately inferring behavioural modes from a trajectory and we strongly recommend the use of HSMMs for such purpose. In addition, this work opens perspectives on the use of hybrid HSMM-discriminative models, where a discriminative setting for the observation process of HSMMs could greatly improve inference performance. PMID- 24058401 TI - Network-level structural abnormalities of cerebral cortex in type 1 diabetes mellitus. AB - Type 1 diabetes mellitus (T1DM) usually begins in childhood and adolescence and causes lifelong damage to several major organs including the brain. Despite increasing evidence of T1DM-induced structural deficits in cortical regions implicated in higher cognitive and emotional functions, little is known whether and how the structural connectivity between these regions is altered in the T1DM brain. Using inter-regional covariance of cortical thickness measurements from high-resolution T1-weighted magnetic resonance data, we examined the topological organizations of cortical structural networks in 81 T1DM patients and 38 healthy subjects. We found a relative absence of hierarchically high-level hubs in the prefrontal lobe of T1DM patients, which suggests ineffective top-down control of the prefrontal cortex in T1DM. Furthermore, inter-network connections between the strategic/executive control system and systems subserving other cortical functions including language and mnemonic/emotional processing were also less integrated in T1DM patients than in healthy individuals. The current results provide structural evidence for T1DM-related dysfunctional cortical organization, which specifically underlie the top-down cognitive control of language, memory, and emotion. PMID- 24058402 TI - Phototoxic action spectrum on a retinal pigment epithelium model of age-related macular degeneration exposed to sunlight normalized conditions. AB - Among the identified risk factors of age-related macular degeneration, sunlight is known to induce cumulative damage to the retina. A photosensitive derivative of the visual pigment, N-retinylidene-N-retinylethanolamine (A2E), may be involved in this phototoxicity. The high energy visible light between 380 nm and 500 nm (blue light) is incriminated. Our aim was to define the most toxic wavelengths in the blue-green range on an in vitro model of the disease. Primary cultures of porcine retinal pigment epithelium cells were incubated for 6 hours with different A2E concentrations and exposed for 18 hours to 10 nm illumination bands centered from 380 to 520 nm in 10 nm increments. Light irradiances were normalized with respect to the natural sunlight reaching the retina. Six hours after light exposure, cell viability, necrosis and apoptosis were assessed using the Apotox-Glo TriplexTM assay. Retinal pigment epithelium cells incubated with A2E displayed fluorescent bodies within the cytoplasm. Their absorption and emission spectra were similar to those of A2E. Exposure to 10 nm illumination bands induced a loss in cell viability with a dose dependence upon A2E concentrations. Irrespective of A2E concentration, the loss of cell viability was maximal for wavelengths from 415 to 455 nm. Cell viability decrease was correlated to an increase in cell apoptosis indicated by caspase-3/7 activities in the same spectral range. No light-elicited necrosis was measured as compared to control cells maintained in darkness. Our results defined the precise spectrum of light retinal toxicity in physiological irradiance conditions on an in vitro model of age-related macular degeneration. Surprisingly, a narrow bandwidth in blue light generated the greatest phototoxic risk to retinal pigment epithelium cells. This phototoxic spectrum may be advantageously valued in designing selective photoprotection ophthalmic filters, without disrupting essential visual and non-visual functions of the eye. PMID- 24058403 TI - Association study of polymorphisms in selenoprotein genes and Kashin-Beck disease and serum selenium/iodine concentration in a Tibetan population. AB - BACKGROUND: Kashin-Beck disease is a kind of degenerative osteoarthropathy. Genetic factors may play an important role in the pathogenesis of KBD. OBJECTIVE: To investigate the association of the selenoprotein genes GPX1 (rs1050450, rs1800668, and rs3811699), TrxR2 (rs5748469), and DIO2 (rs225014) with Kashin Beck disease (KBD) in a Tibetan population and to investigate the association of these SNPs with the serum iodine/selenium concentration in the Tibetan population. DESIGN: Five SNPs including rs1050450, rs1800668, and rs3811699 in the GPX1 gene, rs5748469 in the TrxR2 gene, and rs225014 in the DIO2 gene were analyzed in Tibetan KBD patients and controls using the SNaPshot method. P trend values of the SNPs were calculated using an additive model. RESULTS: None of the five SNPs in the three genes showed a significant association with KBD. Haplotypes TCC, TTC and TTT of rs1050450, rs1800668 and rs3811699 in GPX1 showed a significant association with KBD and controls with P value of 0.0421, 5.0E-4 and 0.0066, respectively. The GPX1 gene (rs1050450) showed a potential significant association with the iodine concentration in the Tibetan study population (P = 0.02726). However, no such association was detected with the selenium concentration (P = 0.2849). CONCLUSIONS: In this study, we showed that single SNPs in the genes GPX1 (rs1050450, rs1800668 and rs3811699), TrxR2 (rs5748469), and DIO2 (rs225014) may not be significantly associated with KBD in a Tibetan population. However, haplotype analysis of SNPs rs1050450, rs1800668 and rs3811699 in GPX1 gene showed a significant association with KBD. The results suggested that GPX1 gene play a protective role in the susceptivity of KBD in Tibetans. Furthermore, the GPX1 gene (rs1050450) may be significantly associated with the serum iodine concentration in Tibetans. PMID- 24058404 TI - Demographic variation between colour patterns in a temperate protogynous hermaphrodite, the ballan wrasse Labrus bergylta. AB - Fish populations are often treated as homogeneous units in typical fishery management, thereby tacitly ignoring potential intraspecific variation which can lead to imprecise management rules. However, intraspecific variation in life history traits is widespread and related to a variety of factors. We investigated the comparative age-based demography of the two main colour patterns of Labrus bergylta (plain and spotted, which coexist in sympatry), a commercially valuable resource in the NE Atlantic. Individuals were aged based on otolith readings after validating the annual periodicity of annuli deposition. The relationships between the otolith weight and fish age and between otolith length and fish length were strong but differed between colour patterns. The fit of the growth models to the age and length data resulted in divergent growth curves between colour morphotypes and between sexes. Males and spotted individuals attained larger mean asymptotic sizes (Linf ) than females and plain individuals, respectively, but converged to them more slowly (smaller k). Estimates of mortality based on catch curves from two independent datasets provided a global total mortality (Z) of 0.35 yr(-1), although Z was larger in plain and female individuals. Overall, the results of this research have direct implications for management of L. bergylta and, as a precautionary measure, we recommend considering both colour patterns as two different management units. PMID- 24058405 TI - Variable behavior of iPSCs derived from CML patients for response to TKI and hematopoietic differentiation. AB - Chronic myeloid leukemia disease (CML) found effective therapy by treating patients with tyrosine kinase inhibitors (TKI), which suppress the BCR-ABL1 oncogene activity. However, the majority of patients achieving remission with TKI still have molecular evidences of disease persistence. Various mechanisms have been proposed to explain the disease persistence and recurrence. One of the hypotheses is that the primitive leukemic stem cells (LSCs) can survive in the presence of TKI. Understanding the mechanisms leading to TKI resistance of the LSCs in CML is a critical issue but is limited by availability of cells from patients. We generated induced pluripotent stem cells (iPSCs) derived from CD34+ blood cells isolated from CML patients (CML-iPSCs) as a model for studying LSCs survival in the presence of TKI and the mechanisms supporting TKI resistance. Interestingly, CML-iPSCs resisted to TKI treatment and their survival did not depend on BCR-ABL1, as for primitive LSCs. Induction of hematopoietic differentiation of CML-iPSC clones was reduced compared to normal clones. Hematopoietic progenitors obtained from iPSCs partially recovered TKI sensitivity. Notably, different CML-iPSCs obtained from the same CML patients were heterogeneous, in terms of BCR-ABL1 level and proliferation. Thus, several clones of CML-iPSCs are a powerful model to decipher all the mechanisms leading to LSC survival following TKI therapy and are a promising tool for testing new therapeutic agents. PMID- 24058406 TI - Elevated alpha-synuclein impairs innate immune cell function and provides a potential peripheral biomarker for Parkinson's disease. AB - Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of alpha-synuclein due to genetic multiplication or point mutations leads to early onset disease. While alpha-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of alpha synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC alpha-synuclein transgenic mice, which overexpress alpha synuclein under regulation of its own promoter, express alpha-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure alpha-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of alpha-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal alpha-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased alpha-synuclein and altered phagocytosis may provide a useful biomarker for human PD. PMID- 24058407 TI - Piwi genes are dispensable for normal hematopoiesis in mice. AB - Hematopoietic stem cells (HSC) must engage in a life-long balance between self renewal and differentiation to sustain hematopoiesis. The highly conserved PIWI protein family regulates proliferative states of stem cells and their progeny in diverse organisms. A Human piwi gene (for clarity, the non-italicized "piwi" refers to the gene subfamily), HIWI (PIWIL1), is expressed in CD34+ stem/progenitor cells and transient expression of HIWI in a human leukemia cell line drastically reduces cell proliferation, implying the potential function of these proteins in hematopoiesis. Here, we report that one of the three piwi genes in mice, Miwi2 (Piwil4), is expressed in primitive hematopoetic cell types within the bone marrow. Mice with a global deletion of all three piwi genes, Miwi, Mili, and Miwi2, are able to maintain long-term hematopoiesis with no observable effect on the homeostatic HSC compartment in adult mice. The PIWI-deficient hematopoetic cells are capable of normal lineage reconstitution after competitive transplantation. We further show that the three piwi genes are dispensable during hematopoietic recovery after myeloablative stress by 5-FU. Collectively, our data suggest that the function of the piwi gene subfamily is not required for normal adult hematopoiesis. PMID- 24058408 TI - Soil respiration and organic carbon dynamics with grassland conversions to woodlands in temperate china. AB - Soils are the largest terrestrial carbon store and soil respiration is the second largest flux in ecosystem carbon cycling. Across China's temperate region, climatic changes and human activities have frequently caused the transformation of grasslands to woodlands. However, the effect of this transition on soil respiration and soil organic carbon (SOC) dynamics remains uncertain in this area. In this study, we measured in situ soil respiration and SOC storage over a two-year period (Jan. 2007-Dec. 2008) from five characteristic vegetation types in a forest-steppe ecotone of temperate China, including grassland (GR), shrubland (SH), as well as in evergreen coniferous (EC), deciduous coniferous (DC) and deciduous broadleaved forest (DB), to evaluate the changes of soil respiration and SOC storage with grassland conversions to diverse types of woodlands. Annual soil respiration increased by 3%, 6%, 14%, and 22% after the conversion from GR to EC, SH, DC, and DB, respectively. The variation in soil respiration among different vegetation types could be well explained by SOC and soil total nitrogen content. Despite higher soil respiration in woodlands, SOC storage and residence time increased in the upper 20 cm of soil. Our results suggest that the differences in soil environmental conditions, especially soil substrate availability, influenced the level of annual soil respiration produced by different vegetation types. Moreover, shifts from grassland to woody plant dominance resulted in increased SOC storage. Given the widespread increase in woody plant abundance caused by climate change and large-scale afforestation programs, the soils are expected to accumulate and store increased amounts of organic carbon in temperate areas of China. PMID- 24058409 TI - Enhancer/promoter activities of the long/middle wavelength-sensitive opsins of vertebrates mediated by thyroid hormone receptor beta2 and COUP-TFII. AB - Cone photopigments (opsins) are crucial elements of, and the first detection module in, color vision. Individual opsins have different wavelength sensitivity patterns, and the temporal and spatial expression patterns of opsins are unique and stringently regulated. Long and middle wavelength-sensitive (L/M) opsins are of the same phylogenetic type. Although the roles of thyroid hormone/TRbeta2 and COUP-TFs in the transcriptional regulation of L/M opsins have been explored, the detailed mechanisms, including the target sequence in the enhancer of L/M opsins, have not been revealed. We aimed to reveal molecular mechanisms of L/M opsins in vertebrates. Using several human red opsin enhancer/promoter-luciferase reporter constructs, we found that TRbeta2 increased luciferase activities through the 5' UTR and intron 3-4 region, whereas the presence of T3 affected only the intron 3 4 region-dependent luciferase activity. Furthermore, COUP-TFII suppressed intron 3-4 region-dependent luciferase activities. However, luciferase expression driven by the mouse M opsin intron 3-4 region was only slightly increased by TRbeta2, and rather enhanced by COUP-TFII. To determine whether these differential responses reflect differences between primates and rodents, we examined the enhancer/promoter region of the red opsin of the common marmoset. Interestingly, while TRbeta2 increased 5'-UTR- or intron 3-4 region-driven luciferase expression, as observed for the human red opsin, expression of the latter luciferase was not suppressed by COUP-TFII. In fact, immunostaining of common marmoset retinal sections revealed expression of COUP-TFII and red opsin in the cone cells. PMID- 24058410 TI - Comparative evaluation of six commercialized multiplex PCR kits for the diagnosis of respiratory infections. AB - The molecular diagnosis of respiratory infection can be performed using different commercial multiplex-based PCR kits whose performances have been previously compared individually to those of conventional techniques. This study compared the practicability and the diagnostic performances of six CE-marked kits available in 2011 on the French market, including 2 detecting viruses and atypical bacteria (from Pathofinder and Seegene companies) and 4 detecting only viruses (from Abbott, Genomica, Qiagen and Seegene companies). The respective sensitivity, specificity, accuracy and agreement of each multiplex technique were calculated by comparison to commercial duplex PCR tests (Argene/bioMerieux) used as gold standard. Eighty-eight respiratory specimens with no pathogen (n = 11), single infections (n = 33) or co-infections (n = 44) were selected to cover 9 viruses or groups of viruses and 3 atypical bacteria. All samples were extracted using the NUCLISENS(r) easyMAGTM instrument (bioMerieux). The overall sensitivity ranged from 56.25% to 91.67% for viruses and was below 50% with both tests for bacteria. The overall specificity was excellent (>94% for all pathogens). For each tested kit, the overall agreement with the reference test was strong for viruses (kappa test >0.60) and moderate for bacteria. After the extraction step, the hands-on time varied from 50 min to 2h30 and the complete results were available in 2h30 to 9 h. The spectrum of tested agents and the technology used to reveal the PCR products as well as the laboratory organization are determinant for the selection of a kit. PMID- 24058411 TI - Osteoprotegerin in exosome-like vesicles from human cultured tubular cells and urine. AB - Urinary exosomes have been proposed as potential diagnostic tools. TNF superfamily cytokines and receptors may be present in exosomes and are expressed by proximal tubular cells. We have now studied the expression of selected TNF superfamily proteins in exosome-like vesicles from cultured human proximal tubular cells and human urine and have identified additional proteins in these vesicles by LC-MS/MS proteomics. Human proximal tubular cells constitutively released exosome-like vesicles that did not contain the TNF superfamily cytokines TRAIL or TWEAK. However, exosome-like vesicles contained osteoprotegerin (OPG), a TNF receptor superfamily protein, as assessed by Western blot, ELISA or selected reaction monitoring by nLC-(QQQ)MS/MS. Twenty-one additional proteins were identified in tubular cell exosome-like vesicles, including one (vitamin D binding protein) that had not been previously reported in exosome-like vesicles. Twelve were extracellular matrix proteins, including the basement membrane proteins type IV collagen, nidogen-1, agrin and fibulin-1. Urine from chronic kidney disease patients contained a higher amount of exosomal protein and exosomal OPG than urine from healthy volunteers. Specifically OPG was increased in autosomal dominant polycystic kidney disease urinary exosome-like vesicles and expressed by cystic epithelium in vivo. In conclusion, OPG is present in exosome like vesicles secreted by proximal tubular epithelial cells and isolated from Chronic Kidney Disease urine. PMID- 24058412 TI - Cardiac myocyte diversity and a fibroblast network in the junctional region of the zebrafish heart revealed by transmission and serial block-face scanning electron microscopy. AB - The zebrafish has emerged as an important model of heart development and regeneration. While the structural characteristics of the developing and adult zebrafish ventricle have been previously studied, little attention has been paid to the nature of the interface between the compact and spongy myocardium. Here we describe how these two distinct layers are structurally and functionally integrated. We demonstrate by transmission electron microscopy that this interface is complex and composed primarily of a junctional region occupied by collagen, as well as a population of fibroblasts that form a highly complex network. We also describe a continuum of uniquely flattened transitional cardiac myocytes that form a circumferential plate upon which the radially-oriented luminal trabeculae are anchored. In addition, we have uncovered within the transitional ring a subpopulation of markedly electron dense cardiac myocytes. At discrete intervals the transitional cardiac myocytes form contact bridges across the junctional space that are stabilized through localized desmosomes and fascia adherentes junctions with adjacent compact cardiac myocytes. Finally using serial block-face scanning electron microscopy, segmentation and volume reconstruction, we confirm the three-dimensional nature of the junctional region as well as the presence of the sheet-like fibroblast network. These ultrastructural studies demonstrate the previously unrecognized complexity with which the compact and spongy layers are structurally integrated, and provide a new basis for understanding development and regeneration in the zebrafish heart. PMID- 24058413 TI - Hyaluronic acid oligosaccharides suppress TLR3-dependent cytokine expression in a TLR4-dependent manner. AB - The release of endogenous molecules from the skin after injury has been proposed to influence inflammation. Recent studies have found that pro-inflammatory signals can be generated by damaged endogenous self-RNA, and this event is detected by TLR3. Conversely, release of endogenous fragments of hyaluronic acid (HA) after injury has been proposed to inhibit LPS induced inflammation driven by TLR4. In this study we investigated if HA oligomers could also influence inflammation mediated by TLR3. A tetramer form of HA (oligo-HA) was added to MH-S cells (mouse alveolar macrophage cell line) that were then activated by poly(I:C). ELISA analysis of culture supernatants showed that the presence of oligo-HA suppressed the poly(I:C) induced release of IL-6 and TNFalpha. IL-6 mRNA expression was also suppressed as measured by quantitative RT-PCR. To determine the mechanism of action for oligo-HA to inhibit poly(I:C), macrophages derived from wild-type (WT), Tlr2-/- or Tlr4-/- mice were treated with oligo-HA and poly(I:C). Similar to WT cells, Tlr2-/- macrophages were inhibited by oligo-HA and retained suppression of cytokine release. In contrast, Tlr4-/- macrophages lost the capacity to be suppressed by oligo-HA. An increase in Traf1 (TLR negative regulator) mRNA was observed after oligo-HA treatment of WT but not in Tlr4-/- macrophages, and oligo-HA did not suppress cytokine responsiveness in Traf1-/- macrophages. These results show that oligo-HA acts through TLR4 and TRAF1 to inhibit TLR3-dependent inflammation. This observation illustrates the complex immunomodulatory action of endogenous products released after injury. PMID- 24058414 TI - Knockdown of human TCF4 affects multiple signaling pathways involved in cell survival, epithelial to mesenchymal transition and neuronal differentiation. AB - Haploinsufficiency of TCF4 causes Pitt-Hopkins syndrome (PTHS): a severe form of mental retardation with phenotypic similarities to Angelman, Mowat-Wilson and Rett syndromes. Genome-wide association studies have also found that common variants in TCF4 are associated with an increased risk of schizophrenia. Although TCF4 is transcription factor, little is known about TCF4-regulated processes in the brain. In this study we used genome-wide expression profiling to determine the effects of acute TCF4 knockdown on gene expression in SH-SY5Y neuroblastoma cells. We identified 1204 gene expression changes (494 upregulated, 710 downregulated) in TCF4 knockdown cells. Pathway and enrichment analysis on the differentially expressed genes in TCF4-knockdown cells identified an over representation of genes involved in TGF-beta signaling, epithelial to mesenchymal transition (EMT) and apoptosis. Among the most significantly differentially expressed genes were the EMT regulators, SNAI2 and DEC1 and the proneural genes, NEUROG2 and ASCL1. Altered expression of several mental retardation genes such as UBE3A (Angelman Syndrome), ZEB2 (Mowat-Wilson Syndrome) and MEF2C was also found in TCF4-depleted cells. These data suggest that TCF4 regulates a number of convergent signaling pathways involved in cell differentiation and survival in addition to a subset of clinically important mental retardation genes. PMID- 24058428 TI - Retraction: Small-molecule quinolinol inhibitor identified provides protection against BoNT/A in mice. PMID- 24058416 TI - Structure of the HHARI catalytic domain shows glimpses of a HECT E3 ligase. AB - The ubiquitin-signaling pathway utilizes E1 activating, E2 conjugating, and E3 ligase enzymes to sequentially transfer the small modifier protein ubiquitin to a substrate protein. During the last step of this cascade different types of E3 ligases either act as scaffolds to recruit an E2 enzyme and substrate (RING), or form an ubiquitin-thioester intermediate prior to transferring ubiquitin to a substrate (HECT). The RING-inBetweenRING-RING (RBR) proteins constitute a unique group of E3 ubiquitin ligases that includes the Human Homologue of Drosophila Ariadne (HHARI). These E3 ligases are proposed to use a hybrid RING/HECT mechanism whereby the enzyme uses facets of both the RING and HECT enzymes to transfer ubiquitin to a substrate. We now present the solution structure of the HHARI RING2 domain, the key portion of this E3 ligase required for the RING/HECT hybrid mechanism. The structure shows the domain possesses two Zn2+-binding sites and a single exposed cysteine used for ubiquitin catalysis. A structural comparison of the RING2 domain with the HECT E3 ligase NEDD4 reveals a near mirror image of the cysteine and histidine residues in the catalytic site. Further, a tandem pair of aromatic residues exists near the C-terminus of the HHARI RING2 domain that is conserved in other RBR E3 ligases. One of these aromatic residues is remotely located from the catalytic site that is reminiscent of the location found in HECT E3 enzymes where it is used for ubiquitin catalysis. These observations provide an initial structural rationale for the RING/HECT hybrid mechanism for ubiquitination used by the RBR E3 ligases. PMID- 24058415 TI - Molecular typing and virulence characteristic of methicillin-resistant Staphylococcus aureus isolates from pediatric patients in Bucaramanga, Colombia. AB - BACKGROUND: Staphylococcus aureus is among the most common global nosocomial pathogens. The emergence and spread of methicillin-resistant Staphylococcus aureus (MRSA) is a public health problem worldwide that causes nosocomial and community infections. The goals of this study were to establish the clonal complexes (CC) of the isolates of MRSA obtained from pediatric patients in a university hospital in Colombia and to investigate its molecular characteristics based on the virulence genes and the genes of staphylococcal toxins and adhesins. METHODS: A total of 53 MRSA isolates from pediatric patients with local or systemic infections were collected. The MRSA isolates were typed based on the SCCmec, MLST, spa and agr genes. The molecular characterization included the detection of Panton-Valentine Leukocidin, superantigenic and exfoliative toxins, and adhesin genes. The correlation between the molecular types identified and the profile of virulence factors was determined for all isolates. RESULTS: Four CC were identified, including CC8, CC5, CC80 and CC78. The ST8-MRSA-IVc-agrI was the predominant clone among the isolates, followed by the ST5-MRSA-I-agrII and ST5 MRSA-IVc-agrII clones. Twelve spa types were identified, of which t10796 and t10799 were new repeat sequences. The isolates were carriers of toxin genes, and hlg (100%), sek (92%) and pvl (88%) were the most frequent. Ten toxin gene profiles were observed, and the most frequent were seq-sek-hlg (22.6%), sek-hlg (22.6%), seb-seq-sek-hlg (18.9%) and seb-sek-hlg (15.1%). The adhesion genes were present in most of the MRSA isolates, including the following: clf-A (89%), clf-B (87%), fnb-A (83%) and ica (83%). The majority of the strains carried SCCmec-IVc and were identified as causing nosocomial infection. No significant association between a molecular type and the virulence factors was found. CONCLUSION: Four major MRSA clone complexes were identified among the isolates. ST8-MRSA-IVc-agrI pvl+ (USA300-LV) was the most frequent, confirming the presence of community associated MRSA in Colombian hospitals. PMID- 24058437 TI - Coffee agroforests remain beneficial for neotropical bird community conservation across seasons. AB - Coffee agroforestry systems and secondary forests have been shown to support similar bird communities but comparing these habitat types are challenged by potential biases due to differences in detectability between habitats. Furthermore, seasonal dynamics may influence bird communities differently in different habitat types and therefore seasonal effects should be considered in comparisons. To address these issues, we incorporated seasonal effects and factors potentially affecting bird detectability into models to compare avian community composition and dynamics between coffee agroforests and secondary forest fragments. In particular, we modeled community composition and community dynamics of bird functional groups based on habitat type (coffee agroforest vs. secondary forest) and season while accounting for variation in capture probability (i.e. detectability). The models we used estimated capture probability to be similar between habitat types for each dietary guild, but omnivores had a lower capture probability than frugivores and insectivores. Although apparent species richness was higher in coffee agroforest than secondary forest, model results indicated that omnivores and insectivores were more common in secondary forest when accounting for heterogeneity in capture probability. Our results largely support the notion that shade-coffee can serve as a surrogate habitat for secondary forest with respect to avian communities. Small coffee agroforests embedded within the typical tropical countryside matrix of secondary forest patches and small-scale agriculture, therefore, may host avian communities that resemble those of surrounding secondary forest, and may serve as viable corridors linking patches of forest within these landscapes. This information is an important step toward effective landscape-scale conservation in Neotropical agricultural landscapes. PMID- 24058438 TI - Curcumin prevents replication of respiratory syncytial virus and the epithelial responses to it in human nasal epithelial cells. AB - The human nasal epithelium is the first line of defense during respiratory virus infection. Respiratory syncytial virus (RSV) is the major cause of bronchitis, asthma and severe lower respiratory tract disease in infants and young children. We previously reported in human nasal epithelial cells (HNECs), the replication and budding of RSV and the epithelial responses, including release of proinflammatory cytokines and enhancement of the tight junctions, are in part regulated via an NF-kappaB pathway. In this study, we investigated the effects of the NF-kappaB in HNECs infected with RSV. Curcumin prevented the replication and budding of RSV and the epithelial responses to it without cytotoxicity. Furthermore, the upregulation of the epithelial barrier function caused by infection with RSV was enhanced by curcumin. Curcumin also has wide pharmacokinetic effects as an inhibitor of NF-kappaB, eIF-2alpha dephosphorylation, proteasome and COX2. RSV-infected HNECs were treated with the eIF-2alpha dephosphorylation blocker salubrinal and the proteasome inhibitor MG132, and inhibitors of COX1 and COX2. Treatment with salubrinal, MG132 and COX2 inhibitor, like curcumin, prevented the replication of RSV and the epithelial responses, and treatment with salubrinal and MG132 enhanced the upregulation of tight junction molecules induced by infection with RSV. These results suggest that curcumin can prevent the replication of RSV and the epithelial responses to it without cytotoxicity and may act as therapy for severe lower respiratory tract disease in infants and young children caused by RSV infection. PMID- 24058439 TI - The opportunistic pathogen Propionibacterium acnes: insights into typing, human disease, clonal diversification and CAMP factor evolution. AB - We previously described a Multilocus Sequence Typing (MLST) scheme based on eight genes that facilitates population genetic and evolutionary analysis of P. acnes. While MLST is a portable method for unambiguous typing of bacteria, it is expensive and labour intensive. Against this background, we now describe a refined version of this scheme based on two housekeeping (aroE; guaA) and two putative virulence (tly; camp2) genes (MLST4) that correctly predicted the phylogroup (IA1, IA2, IB, IC, II, III), clonal complex (CC) and sequence type (ST) (novel or described) status for 91% isolates (n = 372) via cross-referencing of the four gene allelic profiles to the full eight gene versions available in the MLST database (http://pubmlst.org/pacnes/). Even in the small number of cases where specific STs were not completely resolved, the MLST4 method still correctly determined phylogroup and CC membership. Examination of nucleotide changes within all the MLST loci provides evidence that point mutations generate new alleles approximately 1.5 times as frequently as recombination; although the latter still plays an important role in the bacterium's evolution. The secreted/cell associated 'virulence' factors tly and camp2 show no clear evidence of episodic or pervasive positive selection and have diversified at a rate similar to housekeeping loci. The co-evolution of these genes with the core genome might also indicate a role in commensal/normal existence constraining their diversity and preventing their loss from the P. acnes population. The possibility that members of the expanded CAMP factor protein family, including camp2, may have been lost from other propionibacteria, but not P. acnes, would further argue for a possible role in niche/host adaption leading to their retention within the genome. These evolutionary insights may prove important for discussions surrounding camp2 as an immunotherapy target for acne, and the effect such treatments may have on commensal lineages. PMID- 24058440 TI - Fusion protein vaccines targeting two tumor antigens generate synergistic anti tumor effects. AB - INTRODUCTION: Human papillomavirus (HPV) has been consistently implicated in causing several kinds of malignancies, and two HPV oncogenes, E6 and E7, represent two potential target antigens for cancer vaccines. We developed two fusion protein vaccines, PE(DeltaIII)/E6 and PE(DeltaIII)/E7 by targeting these two tumor antigens to test whether a combination of two fusion proteins can generate more potent anti-tumor effects than a single fusion protein. MATERIALS AND METHODS: In vivo antitumor effects including preventive, therapeutic, and antibody depletion experiments were performed. In vitro assays including intracellular cytokine staining and ELISA for Ab responses were also performed. RESULTS: PE(DeltaIII)/E6+PE(DeltaIII)/E7 generated both stronger E6 and E7 specific immunity. Only 60% of the tumor protective effect was observed in the PE(DeltaIII)/E6 group compared to 100% in the PE(DeltaIII)/E7 and PE(DeltaIII)/E6+PE(DeltaIII)/E7 groups. Mice vaccinated with the PE(DeltaIII)/E6+PE(DeltaIII)/E7 fusion proteins had a smaller subcutaneous tumor size than those vaccinated with PE(DeltaIII)/E6 or PE(DeltaIII)/E7 fusion proteins alone. CONCLUSION: Fusion protein vaccines targeting both E6 and E7 tumor antigens generated more potent immunotherapeutic effects than E6 or E7 tumor antigens alone. This novel strategy of targeting two tumor antigens together can promote the development of cancer vaccines and immunotherapy in HPV related malignancies. PMID- 24058441 TI - Crocins with high levels of sugar conjugation contribute to the yellow colours of early-spring flowering crocus tepals. AB - Crocus sativus is the source of saffron spice, the processed stigma which accumulates glucosylated apocarotenoids known as crocins. Crocins are found in the stigmas of other Crocuses, determining the colourations observed from pale yellow to dark red. By contrast, tepals in Crocus species display a wider diversity of colours which range from purple, blue, yellow to white. In this study, we investigated whether the contribution of crocins to colour extends from stigmas to the tepals of yellow Crocus species. Tepals from seven species were analysed by UPLC-PDA and ESI-Q-TOF-MS/MS revealing for the first time the presence of highly glucosylated crocins in this tissue. beta-carotene was found to be the precursor of these crocins and some of them were found to contain rhamnose, never before reported. When crocin profiles from tepals were compared with those from stigmas, clear differences were found, including the presence of new apocarotenoids in stigmas. Furthermore, each species showed a characteristic profile which was not correlated with the phylogenetic relationship among species. While gene expression analysis in tepals of genes involved in carotenoid metabolism showed that phytoene synthase was a key enzyme in apocarotenoid biosynthesis in tepals. Expression of a crocetin glucosyltransferase, previously identified in saffron, was detected in all the samples. The presence of crocins in tepals is compatible with the role of chromophores to attract pollinators. The identification of tepals as new sources of crocins is of special interest given their wide range of applications in medicine, cosmetics and colouring industries. PMID- 24058442 TI - Metabolic signature of electrosurgical liver dissection. AB - BACKGROUND AND AIMS: High frequency electrosurgery has a key role in the broadening application of liver surgery. Its molecular signature, i.e. the metabolites evolving from electrocauterization which may inhibit hepatic wound healing, have not been systematically studied. METHODS: Human liver samples were thus obtained during surgery before and after electrosurgical dissection and subjected to a two-stage metabolomic screening experiment (discovery sample: N = 18, replication sample: N = 20) using gas chromatography/mass spectrometry. RESULTS: In a set of 208 chemically defined metabolites, electrosurgical dissection lead to a distinct metabolic signature resulting in a separation in the first two dimensions of a principal components analysis. Six metabolites including glycolic acid, azelaic acid, 2-n-pentylfuran, dihydroactinidiolide, 2 butenal and n-pentanal were consistently increased after electrosurgery meeting the discovery (p<2.0 * 10(-4)) and the replication thresholds (p<3.5 * 10(-3)). Azelaic acid, a lipid peroxidation product from the fragmentation of abundant sn 2 linoleoyl residues, was most abundant and increased 8.1-fold after electrosurgical liver dissection (preplication = 1.6 * 10(-4)). The corresponding phospholipid hexadecyl azelaoyl glycerophosphocholine inhibited wound healing and tissue remodelling in scratch- and proliferation assays of hepatic stellate cells and cholangiocytes, and caused apoptosis dose-dependently in vitro, which may explain in part the tissue damage due to electrosurgery. CONCLUSION: Hepatic electrosurgery generates a metabolic signature with characteristic lipid peroxidation products. Among these, azelaic acid shows a dose-dependent toxicity in liver cells and inhibits wound healing. These observations potentially pave the way for pharmacological intervention prior liver surgery to modify the metabolic response and prevent postoperative complications. PMID- 24058444 TI - A macrophysiological analysis of energetic constraints on geographic range size in mammals. AB - Physiological processes are essential for understanding the distribution and abundance of organisms, and recently, with widespread attention to climate change, physiology has been ushered back to the forefront of ecological thinking. We present a macrophysiological analysis of the energetics of geographic range size using combined data on body size, basal metabolic rate (BMR), phylogeny and range properties for 574 species of mammals. We propose three mechanisms by which interspecific variation in BMR should relate positively to geographic range size: (i) Thermal Plasticity Hypothesis, (ii) Activity Levels/Dispersal Hypothesis, and (iii) Energy Constraint Hypothesis. Although each mechanism predicts a positive correlation between BMR and range size, they can be further distinguished based on the shape of the relationship they predict. We found evidence for the predicted positive relationship in two dimensions of energetics: (i) the absolute, mass-dependent dimension (BMR) and (ii) the relative, mass-independent dimension (MIBMR). The shapes of both relationships were similar and most consistent with that expected from the Energy Constraint Hypothesis, which was proposed previously to explain the classic macroecological relationship between range size and body size in mammals and birds. The fact that this pattern holds in the MIBMR dimension indicates that species with supra-allometric metabolic rates require among the largest ranges, above and beyond the increasing energy demands that accrue as an allometric consequence of large body size. The relationship is most evident at high latitudes north of the Tropics, where large ranges and elevated MIBMR are most common. Our results suggest that species that are most vulnerable to extinction from range size reductions are both large bodied and have elevated MIBMR, but also, that smaller species with elevated MIBMR are at heightened risk. We also provide insights into the global latitudinal trends in range size and MIBMR and more general issues of phylogenetic and geographic scale. PMID- 24058445 TI - Enhancement of collective immunity in Tokyo metropolitan area by selective vaccination against an emerging influenza pandemic. AB - Vaccination is a preventive measure against influenza that does not require placing restrictions on social activities. However, since the stockpile of vaccine that can be prepared before the arrival of an emerging pandemic strain is generally quite limited, one has to select priority target groups to which the first stockpile is distributed. In this paper, we study a simulation-based priority target selection method with the goal of enhancing the collective immunity of the whole population. To model the region in which the disease spreads, we consider an urban area composed of suburbs and central areas connected by a single commuter train line. Human activity is modelled following an agent-based approach. The degree to which collective immunity is enhanced is judged by the attack rate in unvaccinated people. The simulation results show that if students and office workers are given exclusive priority in the first three months, the attack rate can be reduced from [Formula: see text] in the baseline case down to 1-2%. In contrast, random vaccination only slightly reduces the attack rate. It should be noted that giving preference to active social groups does not mean sacrificing those at high risk, which corresponds to the elderly in our simulation model. Compared with the random administration of vaccine to all social groups, this design successfully reduces the attack rate across all age groups. PMID- 24058443 TI - An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population. AB - PURPOSE: We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer. PATIENTS AND METHODS: Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates. RESULTS: Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84-2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19-1.76]), obesity (body mass index >30 kg/m(2)) (OR: 1.26 [1.09 1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13-2.18], case-control OR: 1.80 [1.40-2.32]), family history of pancreatic cancer (OR: 1.60 [1.20 2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10-1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97-2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19-1.40]), rs401681(5p15.33) (OR: 1.18 [1.10-1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18 1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk. CONCLUSION: Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors. PMID- 24058446 TI - Reliable reference genes for normalization of gene expression in cucumber grown under different nitrogen nutrition. AB - In plants, nitrogen is the most important nutritional factor limiting the yield of cultivated crops. Since nitrogen is essential for synthesis of nucleotides, amino acids and proteins, studies on gene expression in plants cultivated under different nitrogen availability require particularly careful selection of suitable reference genes which are not affected by nitrogen limitation. Therefore, the objective of this study was to select the most reliable reference genes for qPCR analysis of target cucumber genes under varying nitrogen source and availability. Among twelve candidate cucumber genes used in this study, five are highly homologous to the commonly used internal controls, whereas seven novel candidates were previously identified through the query of the cucumber genome. The expression of putative reference genes and the target CsNRT1.1 gene was analyzed in roots, stems and leaves of cucumbers grown under nitrogen deprivation, varying nitrate availability or different sources of nitrogen (glutamate, glutamine or NH3). The stability of candidate genes expression significantly varied depending on the tissue type and nitrogen supply. However, in most of the outputs genes encoding CACS, TIP41, F-box protein and EFalpha proved to be the most suitable for normalization of CsNRT1.1 expression. In addition, our results suggest the inclusion of 3 or 4 references to obtain highly reliable results of target genes expression in all cucumber organs under nitrogen related stress. PMID- 24058447 TI - Is the masked priming same-different task a pure measure of prelexical processing? AB - To study prelexical processes involved in visual word recognition a task is needed that only operates at the level of abstract letter identities. The masked priming same-different task has been purported to do this, as the same pattern of priming is shown for words and nonwords. However, studies using this task have consistently found a processing advantage for words over nonwords, indicating a lexicality effect. We investigated the locus of this word advantage. Experiment 1 used conventional visually-presented reference stimuli to test previous accounts of the lexicality effect. Results rule out the use of different strategies, or strength of representations, for words and nonwords. No interaction was shown between prime type and word type, but a consistent word advantage was found. Experiment 2 used novel auditorally-presented reference stimuli to restrict nonword matching to the sublexical level. This abolished scrambled priming for nonwords, but not words. Overall this suggests the processing advantage for words over nonwords results from activation of whole-word, lexical representations. Furthermore, the number of shared open-bigrams between primes and targets could account for scrambled priming effects. These results have important implications for models of orthographic processing and studies that have used this task to investigate prelexical processes. PMID- 24058448 TI - Orai3 constitutes a native store-operated calcium entry that regulates non small cell lung adenocarcinoma cell proliferation. AB - Orai channels have been associated with cell proliferation, survival and metastasis in several cancers. The present study investigates the expression and the role of Orai3 in cell proliferation in non-small cell lung cancer (NSCLC). We show that Orai3 is over-expressed in cancer tissues as compared to the non tumoral ones. Furthermore, Orai3 staining is stronger in high grade tumors. Pharmacological inhibition or knockdown of Orai3 significantly reduced store operated calcium entry (SOCE), inhibited cell proliferation and arrested cells of two NSCLC cell lines in G0/G1 phase. These effects were concomitant with a down regulation of cyclin D1, cyclin E, CDK4 and CDK2 expression. Moreover, Orai3 silencing decreased Akt phosphorylation levels. In conclusion, Orai3 constitutes a native SOCE pathway in NSCLC that controls cell proliferation and cell cycle progression likely via Akt pathway. PMID- 24058449 TI - First definition of reference intervals of liver function tests in China: a large population-based multi-center study about healthy adults. AB - BACKGROUND: Reference intervals of Liver function tests are very important for the screening, diagnosis, treatment, and monitoring of liver diseases. We aim to establish common reference intervals of liver function tests specifically for the Chinese adult population. METHODS: A total of 3210 individuals (20-79 years) were enrolled in six representative geographical regions in China. Analytes of ALT, AST, GGT, ALP, total protein, albumin and total bilirubin were measured using three analytical systems mainly used in China. The newly established reference intervals were based on the results of traceability or multiple systems, and then validated in 21 large hospitals located nationwide qualified by the National External Quality Assessment (EQA) of China. RESULTS: We had been established reference intervals of the seven liver function tests for the Chinese adult population and found there were apparent variances of reference values for the variables for partitioning analysis such as gender(ALT, GGT, total bilirubin), age(ALP, albumin) and region(total protein). More than 86% of the 21 laboratories passed the validation in all subgroup of reference intervals and overall about 95.3% to 98.8% of the 1220 validation results fell within the range of the new reference interval for all liver function tests. In comparison with the currently recommended reference intervals in China, the single side observed proportions of out of range of reference values from our study for most of the tests deviated significantly from the nominal 2.5% such as total bilirubin (15.2%), ALP (0.2%), albumin (0.0%). Most of reference intervals in our study were obviously different from that of other races. CONCLUSION: These used reference intervals are no longer applicable for the current Chinese population. We have established common reference intervals of liver function tests that are defined specifically for Chinese population and can be universally used among EQA-approved laboratories located all over China. PMID- 24058450 TI - Immunization against GAD induces antibody binding to GAD-independent antigens and brainstem GABAergic neuronal loss. AB - Stiff person syndrome (SPS) is a highly-disabling neurological disorder of the CNS characterized by progressive muscular rigidity and spasms. In approximately 60-80% of patients there are autoantibodies to glutamic acid decarboxylase (GAD), the enzyme that synthesizes gamma-amino butyric acid (GABA), the predominant inhibitory neurotransmitter of the CNS. Although GAD is intracellular, it is thought that autoimmunity to GAD65 may play a role in the development of SPS. To test this hypothesis, we immunized mice, that expressed enhanced green fluorescent protein (EGFP) under the GAD65 promoter, with either GAD65 (n = 13) or phosphate buffered saline (PBS) (n = 13). Immunization with GAD65 resulted in autoantibodies that immunoprecipitated GAD, bound to CNS tissue in a highly characteristic pattern, and surprisingly bound not only to GAD intracellularly but also to the surface of cerebellar neurons in culture. Moreover, immunization resulted in immunoglobulin diffusion into the brainstem, and a partial loss of GAD-EGFP expressing cells in the brainstem. Although immunization with GAD65 did not produce any behavioral abnormality in the mice, the induction of neuronal surface antibodies and the trend towards loss of GABAergic neurons in the brainstem, supports a role for humoral autoimmunity in the pathogenesis of SPS and suggests that the mechanisms may involve spread to antigens expressed on the surface of these neurons. PMID- 24058451 TI - Association of renal biomarkers with 3-month and 1-year outcomes among critically ill acute stroke patients. AB - BACKGROUND: The comparative relationships of widely recognized biomarkers of renal injury with short-term and long-term outcomes among critically ill acute stroke patients are unknown. We evaluated the impact of baseline albuminuria [urine albumin-creatinine ratio (UACR) >= 30 mg/g] or low estimated glomerular filtration rate (eGFR<60 ml/min per 1.73 m(2)) on stroke patients admitted to the intensive care unit (ICU). METHODS: We reviewed data on consecutive stroke patients admitted to a hospital ICU in Taiwan from September 2007 to August 2010 and followed-up for 1 year. Baseline UACR was categorized into <30 mg/g (normal), 30-299 mg/g (microalbuminuria), and >= 300 mg/g (macroalbuminuria), while eGFR was divided into >= 60, 45-59, and <45 ml/min per 1.73 m(2). The outcome measure was death or disability at 3-month and 1-year after stroke onset, assessed by dichotomizing the modified Rankin Scale at 3-6 versus 0-2. RESULTS: Of 184 consecutive patients, 153 (83%) met study entry criteria. Mean age was 67.9 years and median admission NIHSS score was 16. Among the renal biomarkers, only macroalbuminuria was associated with poorer 3-month outcome (OR 8.44, 95% CI 1.38 to 51.74, P = 0.021) and 1-year outcome (OR 18.06, 95% CI 2.59 to 125.94, P = 0.003) after adjustment of relevant covariates. When ischemic and hemorrhagic stroke were analyzed separately, macroalbuminuria was associated with poorer 1 year outcome among ischemic (OR 17.10, 95% CI 1.04 to 280.07, P = 0.047) and hemorrhagic stroke patients (OR 1951.57, 95% CI 1.07 to 3561662.85, P = 0.048), respectively, after adjustment of relevant covariates and hematoma volume. CONCLUSIONS: Presence of macroalbuminuria indicates poor 3-month and 1-year outcomes among critically ill acute stroke patients. PMID- 24058452 TI - Role of recently migrated monocytes in cigarette smoke-induced lung inflammation in different strain of mice. AB - This study investigates the role of proinflammatory monocytes recruited from blood circulation and recovered in bronchoalveolar lavage (BAL) fluid in mediating the lung damage in a model of acute cigarette smoke (CS)-induced lung inflammation in two strains of mice with different susceptibility to develop emphysema (susceptible -C57BL/6J and non susceptible -129S2/SvHsd). Exposure to whole-body CS for 3 consecutive research cigarettes in one single day induced acute inflammation in the lung of mice. Analysis of BAL fluid showed more influx of recently migrated monocytes at 72 h after CS-exposition in susceptible compared to non susceptible mice. It correlated with an increase in MMP-12 and TNF-alpha protein levels in the lung tissue, and with an increment of NF-kappaB translocation to the nucleus measured by electrophoretic mobility shift assay in C57BL/6J mice. To determine the functional role of these proinflammatory monocytes in mediating CS-induced airway inflammation, alveolar macrophages and blood monocytes were transiently removed by pretreatment with intratracheal and intravenous liposome-encapsulated CL2MDP, given 2 and 4 days prior to CS exposure and their repopulation was studied. Monocytes/macrophages were maximally depleted 48 h after last liposome application and subsequently recently migrated monocytes reappeared in BAL fluid of susceptible mice at 72 h after CS exposure. Recently migrated monocytes influx to the lung correlated with an increase in the MMP-12 protein level in the lung tissue, indicating that the increase in proinflammatory monocytes is associated with a major tissue damaging. Therefore our data confirm that the recruitment of proinflammatory recently migrated monocytes from the blood are responsible for the increase in MMP-12 and has an important role in the pathogenesis of lung disease induced by acute lung inflammation. These results could contribute to understanding the different susceptibility to CS of these strains of mice. PMID- 24058453 TI - Small-scale intraspecific life history variation in herbivorous spider mites (Tetranychus pacificus) is associated with host plant cultivar. AB - Life history variation is a general feature of arthropod systems, but is rarely included in models of field or laboratory data. Most studies assume that local processes occur identically across individuals, ignoring any genetic or phenotypic variation in life history traits. In this study, we tested whether field populations of Pacific spider mites (Tetranychus pacificus) on grapevines (Vitis vinifera) display significant intraspecific life history variation associated with host plant cultivar. To address this question we collected individuals from sympatric vineyard populations where either Zinfandel or Chardonnay were grown. We then conducted a "common garden experiment" of mites on bean plants (Phaseolus lunatus) in the laboratory. Assay populations were sampled non-destructively with digital photography to quantify development times, survival, and reproductive rates. Two classes of models were fit to the data: standard generalized linear mixed models and a time-to-event model, common in survival analysis, that allowed for interval-censored data and hierarchical random effects. We found a significant effect of cultivar on development time in both GLMM and time-to-event analyses, a slight cultivar effect on juvenile survival, and no effect on reproductive rate. There were shorter development times and a trend towards higher juvenile survival in populations from Zinfandel vineyards compared to those from Chardonnay vineyards. Lines of the same species, originating from field populations on different host plant cultivars, expressed different development times and slightly different survival rates when reared on a common host plant in a common environment. PMID- 24058455 TI - Molecular phylogeny and biogeography of the Hawaiian craneflies Dicranomyia (Diptera: Limoniidae). AB - The Hawaiian Diptera offer an opportunity to compare patterns of diversification across large and small endemic radiations with varying species richness and levels of single island endemism. The craneflies (Limoniidae: Dicranomyia) represent a small radiation of 13 described species that have diversified within the Hawaiian Islands. We used Bayesian and maximum likelihood approaches to generate a molecular phylogeny of the Hawaiian Dicranomyia using a combination of nuclear and mitochondrial loci, estimated divergence times and reconstructed ancestral ranges. Divergence time estimation and ancestral range reconstruction suggest that the colonization that led to most of the diversity within the craneflies arrived prior to the formation of Kauai and demonstrates that the two major clades within that radiation contrast sharply in their patterns of diversification. PMID- 24058454 TI - Vitellogenin from the silkworm, Bombyx mori: an effective anti-bacterial agent. AB - Silkworm, Bombyx mori, vitellogenin (Vg) was isolated from perivisceral fat body of day 3 of pupa. Both Vg subunits were co-purified as verified by mass spectrometry and immunoblot. Purified Vg responded to specific tests for major posttranslational modifications on native gels indicating its nature as lipo glyco-phosphoprotein. The Vg fraction had strong antibacterial activity against Gram negative bacterium Escherichia coli and Gram positive bacterium Bacillus subtilis. Microscopic images showed binding of Vg to bacterial cells and their destruction. When infected silkworm larvae were treated with purified Vg they survived the full life cycle in contrast to untreated animals. This result showed that Vg has the ability to inhibit the proliferation of bacteria in the silkworm fluid system without disturbing the regular metabolism of the host. PMID- 24058456 TI - Bilinguals use language-control brain areas more than monolinguals to perform non linguistic switching tasks. AB - We tested the hypothesis that early bilinguals use language-control brain areas more than monolinguals when performing non-linguistic executive control tasks. We do so by exploring the brain activity of early bilinguals and monolinguals in a task-switching paradigm using an embedded critical trial design. Crucially, the task was designed such that the behavioural performance of the two groups was comparable, allowing then to have a safer comparison between the corresponding brain activity in the two groups. Despite the lack of behavioural differences between both groups, early bilinguals used language-control areas--such as left caudate, and left inferior and middle frontal gyri--more than monolinguals, when performing the switching task. Results offer direct support for the notion that, early bilingualism exerts an effect in the neural circuitry responsible for executive control. This effect partially involves the recruitment of brain areas involved in language control when performing domain-general executive control tasks, highlighting the cross-talk between these two domains. PMID- 24058457 TI - Ultrasonic incisions produce less inflammatory mediator response during early healing than electrosurgical incisions. AB - As the use of laparoscopic surgery has become more widespread in recent years, the need has increased for minimally-invasive surgical devices that effectively cut and coagulate tissue with reduced tissue trauma. Although electrosurgery (ES) has been used for many generations, newly-developed ultrasonic devices (HARMONIC(r) Blade, HB) have been shown at a macroscopic level to offer better coagulation with less thermally-induced tissue damage. We sought to understand the differences between ES and HB at a microscopic level by comparing mRNA transcript and protein responses at the 3-day timepoint to incisions made by the devices in subcutaneous fat tissue in a porcine model. Samples were also assessed via histological examination. ES-incised tissue had more than twice as many differentially-expressed genes as HB (2,548 vs 1,264 respectively), and more differentially-expressed proteins (508 vs 432) compared to control (untreated) tissue. Evaluation of molecular functions using Gene Ontology showed that gene expression changes for the energized devices reflected the start of wound healing, including immune response and inflammation, while protein expression showed a slightly earlier stage, with some remnants of hemostasis. For both transcripts and proteins, ES exhibited a greater response than HB, especially in inflammatory mediators. These findings were in qualitative agreement with histological results. This study has shown that transcriptomics and proteomics can monitor the wound healing response following surgery and can differentiate between surgical devices. In agreement with clinical observations, electrosurgery was shown to incur a greater inflammatory immune response than an ultrasonic device during initial iatrogenic wound healing. PMID- 24058458 TI - Ionization constants pKa of cardiolipin. AB - Cardiolipin is a phospholipid found in the inner mitochondrial membrane and in bacteria, and it is associated with many physiological functions. Cardiolipin has a dimeric structure consisting of two phosphatidyl residues connected by a glycerol bridge and four acyl chains, and therefore it can carry two negative charges. The pKa values of the phosphate groups have previously been reported to differ widely with pKa1 = 2.8 and pKa2 = 7.5-9.5. Still, there are several examples of experimental observations from cardiolipin-containing systems that do not fit with this dissociation behavior. Therefore, we have carried out pH titration and titration calorimetric experiments on two synthetic cardiolipins, 1,1',2,2'-tetradecanoyl cardiolipin, CL (C14:0), and 1,1',2,2'-tetraoctadecenoyl cardiolipin, CL (C18:1). Our results show that both behave as strong dibasic acids with pKa1 about the same as the first pKa of phosphoric acid, 2.15, and pKa2 about one unit larger. The characterization of the acidic properties of cardiolipin is crucial for the understanding of the molecular organization in self-assembled systems that contain cardiolipin, and for their biological function. PMID- 24058459 TI - Metabolic profiles and free radical scavenging activity of Cordyceps bassiana fruiting bodies according to developmental stage. AB - The metabolic profiles of Cordyceps bassiana according to fruiting body developmental stage were investigated using gas chromatography-mass spectrometry. We were able to detect 62 metabolites, including 48 metabolites from 70% methanol extracts and 14 metabolites from 100% n-hexane extracts. These metabolites were classified as alcohols, amino acids, organic acids, phosphoric acids, purine nucleosides and bases, sugars, saturated fatty acids, unsaturated fatty acids, or fatty amides. Significant changes in metabolite levels were found according to developmental stage. Relative levels of amino acids, purine nucleosides, and sugars were higher in development stage 3 than in the other stages. Among the amino acids, valine, isoleucine, lysine, histidine, glutamine, and aspartic acid, which are associated with ABC transporters and aminoacyl-tRNA biosynthesis, also showed higher levels in stage 3 samples. The free radical scavenging activities, which were significantly higher in stage 3 than in the other stages, showed a positive correlation with purine nucleoside metabolites such as adenosine, guanosine, and inosine. These results not only show metabolic profiles, but also suggest the metabolic pathways associated with fruiting body development stages in cultivated C. bassiana. PMID- 24058460 TI - An Hinfinity strategy for strain estimation in ultrasound elastography using biomechanical modeling constraint. AB - The purpose of ultrasound elastography is to identify lesions by reconstructing the hardness characteristics of tissue reconstructed from ultrasound data. Conventional quasi-static ultrasound elastography is easily applied to obtain axial strain components along the compression direction, with the results inverted to represent the distribution of tissue hardness under the assumption of constant internal stresses. However, previous works of quasi-static ultrasound elastography have found it difficult to obtain the lateral and shear strain components, due to the poor lateral resolution of conventional ultrasound probes. The physical nature of the strain field is a continuous vector field, which should be fully described by the axial, lateral, and shear strain components, and the clinical value of lateral and shear strain components of deformed tissue is gradually being recognized by both engineers and clinicians. Therefore, a biomechanical-model-constrained filtering framework is proposed here for recovering a full displacement field at a high spatial resolution from the noisy ultrasound data. In our implementation, after the biomechanical model constraint is integrated into the state-space equation, both the axial and lateral displacement components can be recovered at a high spatial resolution from the noisy displacement measurements using a robust Hinfinity filter, which only requires knowledge of the worst-case noise levels in the measurements. All of the strain components can then be calculated by applying a gradient operator to the recovered displacement field. Numerical experiments on synthetic data demonstrated the robustness and effectiveness of our approach, and experiments on phantom data and in-vivo clinical data also produced satisfying results. PMID- 24058461 TI - Plasma ceramide and glucosylceramide metabolism is altered in sporadic Parkinson's disease and associated with cognitive impairment: a pilot study. AB - BACKGROUND: Mutations in the gene coding for glucocerebrosidase (GBA), which metabolizes glucosylceramide (a monohexosylceramide) into glucose and ceramide, is the most common genetic risk factor for sporadic Parkinson's disease (PD). GBA mutation carriers are more likely to have an earlier age of onset and to develop cognitive impairment and dementia. We hypothesized that plasma levels of lipids involved in ceramide metabolism would also be altered in PD non-GBA mutation carriers and associated with worse cognition. METHODS: Plasma ceramide, monohexosylceramide, and lactosylceramide levels in 26 cognitively normal PD patients, 26 PD patients with cognitive impairment or dementia, and 5 cognitively normal non-PD controls were determined by LC/ESI/MS/MS. RESULTS: Levels of all lipid species were higher in PD patients versus controls. Among PD patients, levels of ceramide C16:0, C18:0, C20:0, C22:0, and C24:1 and monohexosylceramide C16:0, C20:0 and C24:0 species were higher (all P<0.05) in those with versus without cognitive impairment. CONCLUSION: These results suggest that plasma ceramide and monohexosylceramide metabolism is altered in PD non-GBA mutation carriers and that higher levels are associated with worse cognition. Additional studies with larger sample sizes, including cognitively normal controls, are needed to confirm these findings. PMID- 24058462 TI - Pseudomonas aeruginosa utilizes the type III secreted toxin ExoS to avoid acidified compartments within epithelial cells. AB - Invasive Pseudomonas aeruginosa (PA) can enter epithelial cells wherein they mediate formation of plasma membrane bleb-niches for intracellular compartmentalization. This phenotype, and capacity for intracellular replication, requires the ADP-ribosyltransferase (ADPr) activity of ExoS, a PA type III secretion system (T3SS) effector protein. Thus, PA T3SS mutants lack these capacities and instead traffic to perinuclear vacuoles. Here, we tested the hypothesis that the T3SS, via the ADPr activity of ExoS, allows PA to evade acidic vacuoles that otherwise suppress its intracellular viability. The acidification state of bacteria-occupied vacuoles within infected corneal epithelial cells was studied using LysoTracker to visualize acidic, lysosomal vacuoles. Steady state analysis showed that within cells wild-type PAO1 localized to both membrane bleb-niches and vacuoles, while both exsA (transcriptional activator) and popB (effector translocation) T3SS mutants were only found in vacuoles. The acidification state of occupied vacuoles suggested a relationship with ExoS expression, i.e. vacuoles occupied by the exsA mutant (unable to express ExoS) were more often acidified than either popB mutant or wild-type PAO1 occupied vacuoles (p < 0.001). An exoS-gfp reporter construct pJNE05 confirmed that high exoS transcriptional output coincided with low occupation of acidified vacuoles, and vice versa, for both popB mutants and wild-type bacteria. Complementation of a triple effector null mutant of PAO1 with exoS (pUCPexoS) reduced the number of acidified bacteria-occupied vacuoles per cell; pUCPexoSE381D which lacks ADPr activity did not. The H(+)-ATPase inhibitor bafilomycin rescued intracellular replication to wild-type levels for exsA mutants, showing its viability is suppressed by vacuolar acidification. Taken together, the data show that the mechanism by which ExoS ADPr activity allows intracellular replication by PA involves suppression of vacuolar acidification. They also show that variability in ExoS expression by wild-type PA inside cells can differentially influence the fate of individual intracellular bacteria, even within the same cell. PMID- 24058464 TI - Non-invasive measurement of frog skin reflectivity in high spatial resolution using a dual hyperspectral approach. AB - BACKGROUND: Most spectral data for the amphibian integument are limited to the visible spectrum of light and have been collected using point measurements with low spatial resolution. In the present study a dual camera setup consisting of two push broom hyperspectral imaging systems was employed, which produces reflectance images between 400 and 2500 nm with high spectral and spatial resolution and a high dynamic range. METHODOLOGY/PRINCIPAL FINDINGS: We briefly introduce the system and document the high efficiency of this technique analyzing exemplarily the spectral reflectivity of the integument of three arboreal anuran species (Litoria caerulea, Agalychnis callidryas and Hyla arborea), all of which appear green to the human eye. The imaging setup generates a high number of spectral bands within seconds and allows non-invasive characterization of spectral characteristics with relatively high working distance. Despite the comparatively uniform coloration, spectral reflectivity between 700 and 1100 nm differed markedly among the species. In contrast to H. arborea, L. caerulea and A. callidryas showed reflection in this range. For all three species, reflectivity above 1100 nm is primarily defined by water absorption. Furthermore, the high resolution allowed examining even small structures such as fingers and toes, which in A. callidryas showed an increased reflectivity in the near infrared part of the spectrum. CONCLUSION/SIGNIFICANCE: Hyperspectral imaging was found to be a very useful alternative technique combining the spectral resolution of spectrometric measurements with a higher spatial resolution. In addition, we used Digital Infrared/Red-Edge Photography as new simple method to roughly determine the near infrared reflectivity of frog specimens in field, where hyperspectral imaging is typically difficult. PMID- 24058463 TI - Fusarium oxysporum f.sp. ciceri race 1 induced redox state alterations are coupled to downstream defense signaling in root tissues of chickpea (Cicer arietinum L.). AB - Reactive oxygen species are known to play pivotal roles in pathogen perception, recognition and downstream defense signaling. But, how these redox alarms coordinate in planta into a defensive network is still intangible. Present study illustrates the role of Fusarium oxysporum f.sp ciceri Race1 (Foc1) induced redox responsive transcripts in regulating downstream defense signaling in chickpea. Confocal microscopic studies highlighted pathogen invasion and colonization accompanied by tissue damage and deposition of callose degraded products at the xylem vessels of infected roots of chickpea plants. Such depositions led to the clogging of xylem vessels in compatible hosts while the resistant plants were devoid of such obstructions. Lipid peroxidation assays also indicated fungal induced membrane injury. Cell shrinkage and gradual nuclear adpression appeared as interesting features marking fungal ingress. Quantitative real time polymerase chain reaction exhibited differential expression patterns of redox regulators, cellular transporters and transcription factors during Foc1 progression. Network analysis showed redox regulators, cellular transporters and transcription factors to coordinate into a well orchestrated defensive network with sugars acting as internal signal modulators. Respiratory burst oxidase homologue, cationic peroxidase, vacuolar sorting receptor, polyol transporter, sucrose synthase, and zinc finger domain containing transcription factor appeared as key molecular candidates controlling important hubs of the defense network. Functional characterization of these hub controllers may prove to be promising in understanding chickpea-Foc1 interaction and developing the case study as a model for looking into the complexities of wilt diseases of other important crop legumes. PMID- 24058465 TI - Averting HIV infections in New York City: a modeling approach estimating the future impact of additional behavioral and biomedical HIV prevention strategies. AB - BACKGROUND: New York City (NYC) remains an epicenter of the HIV epidemic in the United States. Given the variety of evidence-based HIV prevention strategies available and the significant resources required to implement each of them, comparative studies are needed to identify how to maximize the number of HIV cases prevented most economically. METHODS: A new model of HIV disease transmission was developed integrating information from a previously validated micro-simulation HIV disease progression model. Specification and parameterization of the model and its inputs, including the intervention portfolio, intervention effects and costs were conducted through a collaborative process between the academic modeling team and the NYC Department of Health and Mental Hygiene. The model projects the impact of different prevention strategies, or portfolios of prevention strategies, on the HIV epidemic in NYC. RESULTS: Ten unique interventions were able to provide a prevention benefit at an annual program cost of less than $360,000, the threshold for consideration as a cost saving intervention (because of offsets by future HIV treatment costs averted). An optimized portfolio of these specific interventions could result in up to a 34% reduction in new HIV infections over the next 20 years. The cost-per infection averted of the portfolio was estimated to be $106,378; the total cost was in excess of $2 billion (over the 20 year period, or approximately $100 million per year, on average). The cost-savings of prevented infections was estimated at more than $5 billion (or approximately $250 million per year, on average). CONCLUSIONS: Optimal implementation of a portfolio of evidence-based interventions can have a substantial, favorable impact on the ongoing HIV epidemic in NYC and provide future cost-saving despite significant initial costs. PMID- 24058466 TI - Categorical dimensions of human odor descriptor space revealed by non-negative matrix factorization. AB - In contrast to most other sensory modalities, the basic perceptual dimensions of olfaction remain unclear. Here, we use non-negative matrix factorization (NMF)--a dimensionality reduction technique--to uncover structure in a panel of odor profiles, with each odor defined as a point in multi-dimensional descriptor space. The properties of NMF are favorable for the analysis of such lexical and perceptual data, and lead to a high-dimensional account of odor space. We further provide evidence that odor dimensions apply categorically. That is, odor space is not occupied homogenously, but rather in a discrete and intrinsically clustered manner. We discuss the potential implications of these results for the neural coding of odors, as well as for developing classifiers on larger datasets that may be useful for predicting perceptual qualities from chemical structures. PMID- 24058467 TI - Heteroplasmy in the mitochondrial genomes of human lice and ticks revealed by high throughput sequencing. AB - The typical mitochondrial (mt) genomes of bilateral animals consist of 37 genes on a single circular chromosome. The mt genomes of the human body louse, Pediculus humanus, and the human head louse, Pediculus capitis, however, are extensively fragmented and contain 20 minichromosomes, with one to three genes on each minichromosome. Heteroplasmy, i.e. nucleotide polymorphisms in the mt genome within individuals, has been shown to be significantly higher in the mt cox1 gene of human lice than in humans and other animals that have the typical mt genomes. To understand whether the extent of heteroplasmy in human lice is associated with mt genome fragmentation, we sequenced the entire coding regions of all of the mt minichromosomes of six human body lice and six human head lice from Ethiopia, China and France with an Illumina HiSeq platform. For comparison, we also sequenced the entire coding regions of the mt genomes of seven species of ticks, which have the typical mitochondrial genome organization of bilateral animals. We found that the level of heteroplasmy varies significantly both among the human lice and among the ticks. The human lice from Ethiopia have significantly higher level of heteroplasmy than those from China and France (Pt<0.05). The tick, Amblyomma cajennense, has significantly higher level of heteroplasmy than other ticks (Pt<0.05). Our results indicate that heteroplasmy level can be substantially variable within a species and among closely related species, and does not appear to be determined by single factors such as genome fragmentation. PMID- 24058468 TI - Entamoeba histolytica contains an occludin-like protein that can alter colonic epithelial barrier function. AB - The exact mechanism by which Entamoeba histolytica disrupts the human colonic epithelium and invades the mucosa has yet to be clearly elucidated. E. histolytica produces a diverse array of putative virulent factors such as glycosidase, cysteine proteinases and amebapore that can modulate and/or disrupt epithelial barrier functions. However, it is currently thought that E. histolytica produces numerous other molecules and strategies to disrupt colonic mucosal defenses. In this study, we document a putative mechanism whereby the parasite alters the integrity of human epithelium by expressing a cognate tight junction protein of the host. We detected this protein as "occludin-like" as revealed by immunoblotting and immunoprecipitation studies and visualization by confocal microscopy using antibodies highly specific for human occludin. We propose that E. histolytica occludin-like protein might displace mucosal epithelial occludin-occludin tight junction interactions resulting in epithelial disruption analogous to sub mucosal human dendritic cells sampling luminal contents. These results indicate that E. histolytica occludin is a putative virulent component that can play a role in the pathogenesis of intestinal amebiasis. PMID- 24058469 TI - Superior cross-species reference genes: a blueberry case study. AB - The advent of affordable Next Generation Sequencing technologies has had major impact on studies of many crop species, where access to genomic technologies and genome-scale data sets has been extremely limited until now. The recent development of genomic resources in blueberry will enable the application of high throughput gene expression approaches that should relatively quickly increase our understanding of blueberry physiology. These studies, however, require a highly accurate and robust workflow and make necessary the identification of reference genes with high expression stability for correct target gene normalization. To create a set of superior reference genes for blueberry expression analyses, we mined a publicly available transcriptome data set from blueberry for orthologs to a set of Arabidopsis genes that showed the most stable expression in a developmental series. In total, the expression stability of 13 putative reference genes was evaluated by qPCR and a set of new references with high stability values across a developmental series in fruits and floral buds of blueberry were identified. We also demonstrated the need to use at least two, preferably three, reference genes to avoid inconsistencies in results, even when superior reference genes are used. The new references identified here provide a valuable resource for accurate normalization of gene expression in Vaccinium spp. and may be useful for other members of the Ericaceae family as well. PMID- 24058470 TI - Conservation priorities in a biodiversity hotspot: analysis of narrow endemic plant species in New Caledonia. AB - New Caledonia is a global biodiversity hotspot facing extreme environmental degradation. Given the urgent need for conservation prioritisation, we have made a first-pass quantitative assessment of the distribution of Narrow Endemic Species (NES) in the flora to identify species and sites that are potentially important for conservation action. We assessed the distributional status of all angiosperm and gymnosperm species using data from taxonomic descriptions and herbarium samples. We characterised species as being NES if they occurred in 3 or fewer locations. In total, 635 of the 2930 assessed species were classed as NES, of which only 150 have been subjected to the IUCN conservation assessment. As the distributional patterns of un-assessed species from one or two locations correspond well with assessed species which have been classified as Critically Endangered or Endangered respectively, we suggest that our distributional data can be used to prioritise species for IUCN assessment. We also used the distributional data to produce a map of "Hotspots of Plant Narrow Endemism" (HPNE). Combined, we used these data to evaluate the coincidence of NES with mining activities (a major source of threat on New Caledonia) and also areas of conservation protection. This is to identify species and locations in most urgent need of further conservation assessment and subsequent action. Finally, we grouped the NES based on the environments they occurred in and modelled the habitat distribution of these groups with a Maximum Entropy Species Distribution Model (MaxEnt). The NES were separable into three different groups based primarily on geological differences. The distribution of the habitat types for each group coincide partially with the HPNE described above and also indicates some areas which have high habitat suitability but few recorded NES. Some of these areas may represent under-sampled hotspots of narrow endemism and are priorities for further field work. PMID- 24058471 TI - Cerebroside C increases tolerance to chilling injury and alters lipid composition in wheat roots. AB - Chilling tolerance was increased in seed germination and root growth of wheat seedlings grown in media containing 20 ug/mL cerebroside C (CC), isolated from the endophytic Phyllosticta sp. TG78. Seeds treated with 20 ug/mL CC at 4 degrees C expressed the higher germination rate (77.78%), potential (23.46%), index (3.44) and the shorter germination time (6.19 d); root growth was also significantly improved by 13.76% in length, 13.44% in fresh weight and 6.88% in dry mass compared to controls. During the cultivation process at 4 degrees C for three days and the followed 24 h at 25 degrees C, lipid peroxidation, expressed by malondialdehyde (MDA) content and relative membrane permeability (RMP) was significantly reduced in CC-treated roots; activities of lipoxygenase (LOX), phospholipid C (PLC) and phospholipid D (PLD) were inhibited by 13.62-62.26%, 13.54-63.93% and 13.90-61.17%, respectively; unsaturation degree of fatty acids was enhanced through detecting the contents of CC-induced linoleic acid, linolenic acid, palmitic acid and stearic acid using GC-MS; capacities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were individually increased by 7.69-46.06%, 3.37-37.96%, and -7.00-178.07%. These results suggest that increased chilling tolerance may be due, in part, to the reduction of lipid peroxidation and alternation of lipid composition of roots in the presence of CC. PMID- 24058472 TI - A comparison of job satisfaction of community health workers before and after local comprehensive medical care reform: a typical field investigation in Central China. AB - BACKGROUND: The government of China promulgated new medical care reform policies in March 2009. After that, provincial-level governments launched new medical care reform which focusing on local comprehensive medical care reform (LCMR). Anhui Province is an example of an area affected by LCMR, in which the LCMR was started in October 2009 and implemented in June 2010. The objective of this study was to compare the job satisfaction (JS) of community health workers (CHWs) before and after the reform in Anhui Province. METHODS: A baseline survey was carried out among 813 community health workers (CHWs) of 57 community health centers (CHCs) (response rate: 94.1%) and an effect evaluation survey among 536 CHWs of 30 CHCs (response rate: 92.3%) in 2009 and 2012 respectively. A self-completion questionnaire was used to assess the JS of the CHWs (by the job satisfaction scale, JSS). RESULTS: The average scores of total JS and satisfaction with pay, contingent rewards, operating procedures and communication in the effect evaluation survey were statistically significantly higher than those of the baseline survey (P<0.05). The average score of satisfaction with promotion (2.55 +/- 1.008) in the effect evaluation survey was statistically significantly lower than that in the baseline survey (2.71 +/- 0.730) (P=0.002). In both surveys, the average scores of satisfaction with pay, benefits and promotion were statistically significantly lower than the others (all P<0.05). CONCLUSIONS: After two years' implementation of the LCMR, CHWs' total JS have a small improvement. However, CHWs have lower satisfaction in the dimensions of pay, promotion and benefits dimensions before and after the LCMR. Therefore, policy makers should take corresponding measures to raise work reward of CHWs and pay more attention to CHWs' professional development to further increase their JS. PMID- 24058473 TI - Efficient TALEN construction for Bombyx mori gene targeting. AB - Engineered nucleases are artificial enzymes able to introduce double stranded breaks at desired genomic locations. The double stranded breaks start the error prone repair process of non-homologous end-joining (NHEJ), which eventually leads to the induction of mutations at target sites. We showed earlier that ZFNs and TALENs are able to induce NHEJ mutations in the B. mori genome. In order to optimize our mutagenesis protocol, we modified one of the reported truncated TALEN scaffolds and optimized it for use in the B. mori embryo. We also established a novel B. mori somatic cell assay suitable for the preselection of highly efficient TALENs directly in the B. mori model system. We compared the efficiency of several TALEN pairs based on three different frameworks using the BmBLOS2 gene. The new active TALENs show one order of magnitude higher efficiency than those we used previously. We confirmed the utility of our improved protocol by mutagenesis of the autosomal gene, red egg (Bm-re) and showed that it allows obtaining homozygous mutants in G1. Our procedure minimizes the chance of failure in B. mori gene targeting experiments. PMID- 24058475 TI - The effect of polychlorinated biphenyls on the song of two passerine species. AB - Polychlorinated biphenyls (PCBs) are synthetic chemical pollutants with demonstrated detrimental toxic and developmental effects on humans and wildlife. Laboratory studies suggest that PCBs influence behavior due to their effects on endocrine and neurological systems, yet little is known about the behavioral consequences of sublethal PCB exposure in the field. Additionally, specific PCB congener data (in contrast to total PCB load) is necessary to understand the possible effects of PCBs in living organisms since number and position of chlorine substitution in a PCB molecule dictates the toxicity and chemical fate of individual PCB congeners. We non-lethally investigated total PCB loads, congener specific PCB profiles, and songs of black-capped chickadees (Poecile atricapillus) and song sparrows (Melospiza melodia) along a historical PCB gradient at the Hudson River in New York State. Our results indicate that black capped chickadees and song sparrows have higher total blood PCBs in regions with higher historic PCB contamination. The two bird species varied substantially in their congener-specific PCB profiles; within sites, song sparrows showed a significantly higher proportion of lower chlorinated PCBs, while black-capped chickadees had higher proportions of highly chlorinated PCBs. In areas of PCB pollution, the species-specific identity signal in black-capped chickadee song varied significantly, while variation in song sparrow trill performance was best predicted by the mono-ortho PCB load. Thus, PCBs may affect song production, an important component of communication in birds. In conclusion, we suggest that the ramifications of changes in song quality for bird populations may extend the toxic effects of environmental PCB pollution. PMID- 24058474 TI - Validating the InterVA model to estimate the burden of mortality from verbal autopsy data: a population-based cross-sectional study. AB - BACKGROUND: In countries with incomplete or no vital registration systems, verbal autopsy data are often reviewed by physicians in order to assign the probable cause of death. But in addition to being time and energy consuming, the method is liable to produce inconsistent results. The aim of this study is to validate the InterVA model for estimating the burden of mortality from verbal autopsy data by using physician review as a reference standard. METHODS AND FINDINGS: A population-based cross-sectional study was conducted from March to April, 2012. All adults aged >= 14 years and died between 01 January, 2010 and 15 February, 2012 were included in the study. The verbal autopsy interviews were reviewed by the InterVA model and physicians to estimate cause-specific mortality fractions. Cohen's kappa statistic, sensitivity, specificity, positive predictive value, and negative predictive value were applied to compare the agreement between the InterVA model and the physician review. A total of 408 adult deaths were studied. There was a general similarity and just slight differences between the InterVA model and the physicians in assigning cause-specific mortality. Both approaches showed an overall agreement in 298 (73%) cases [kappa = 0.49, 95% CI: 0.37-0.60]. The observed sensitivities and specificities across causes of death categories varied from 13.3% to 81.9% and 77.7% to 99.5%, respectively. CONCLUSIONS: In understanding the burden of disease and setting health intervention priorities in areas that lack reliable vital registration systems, an accurate analysis of verbal autopsies is essential. Therefore, users should be aware of the suboptimal performance of the InterVA model. Similar validation studies need to be undertaken considering the limitation of the physician review as gold standard since physicians may misinterpret some of the verbal autopsy data and finally reach a wrong conclusion of the cause of death. PMID- 24058476 TI - The estimation of prevalence, incidence, and residual risk of transfusion transmitted human hepatitis B infection from blood donated at the Anhui blood center, China, from 2009 to 2011. AB - BACKGROUND: The high prevalence of hepatitis B virus (HBV) among the Chinese population poses a threat to blood safety; however, few studies have examined epidemiological data regarding HBV infection of Chinese blood donors. The present study investigated the demographic characteristics of blood donors at the Anhui blood center in China, the prevalence, incidence, and residual risk (RR) associated with hepatitis B surface antigen (HBsAg) expression in terms of transfusion transmitted HBV (TTHBV) infections. METHODS: The demographic characteristics and HBV status of people who donated blood at the Anhui blood center between 2009 and 2011 were retrospectively analyzed. The incidence of HBV was estimated through HBsAg yield approach. The window period model was then used to estimate the RR of TTHBV infection. RESULTS: The typical donor at the Anhui blood center was a first-time volunteer, aged less than 25 years, unmarried, of Han ethnicity, and with an education below high school level. The prevalence of HBV infection among repeat donors, first-time donors, and all donors was 28.9, 127.2 and 82.1 per 100,000, respectively. The incidence estimate was 333.9 per 10(5) person-years. Using an infectious window period of 59 days, the RR for HBV was estimated to be 1 in 1853 between 2009 and 2011. CONCLUSIONS: The incidence and RR of HBV in Chinese blood donors are much higher than those of donors in developed countries. This is because sensitive ELISAs and nucleic acid tests are not available in China. Further work is needed to improve both the safety and availability of blood products in China. PMID- 24058477 TI - Ovariectomy increases the participation of hyperpolarizing mechanisms in the relaxation of rat aorta. AB - This study examines the downstream NO release pathway and the contribution of different vasodilator mediators in the acetylcholine-induced response in rat aorta 5-months after the loss of ovarian function. Aortic segments from ovariectomized and control female Sprague-Dawley rats were used to measure: the levels of superoxide anion, the superoxide dismutases (SODs) activity, the cGMP formation, the cGMP-dependent protein kinase (PKG) activity and the involvement of NO, cGMP, hydrogen peroxide and hyperpolarizing mechanisms in the ACh-induced relaxation. The results showed that ovariectomy did not alter ACh-induced relaxation; incubation with L-NAME, a NO synthase inhibitor, decreased the ACh induced response to a lesser extent in aorta from ovariectomized than from control rats, while ODQ, a guanylate cyclase inhibitor, decreased that response to a similar extent; the blockade of hyperpolarizing mechanisms, by precontracting arteries with KCl, decreased the ACh-induced response to a greater extent in aortas from ovariectomized than those from control rats; catalase, that decomposes hydrogen peroxide, decreased the ACh-induced response only in aorta from ovariectomized rats. In addition, ovariectomy increased superoxide anion levels and SODs activity, decreased cGMP formation and increased PKG activity. Despite the increased superoxide anion and decreased cGMP in aorta from ovariectomized rats, ACh-induced relaxation is maintained by the existence of hyperpolarizing mechanisms in which hydrogen peroxide participates. The greater contribution of hydrogen peroxide in ACh-induced relaxation is due to increased SOD activity, in an attempt to compensate for increased superoxide anion formation. Increased PKG activity could represent a redundant mechanism to ensure vasodilator function in the aorta of ovariectomized rats. PMID- 24058478 TI - When overweight is the normal weight: an examination of obesity using a social media internet database. AB - Using a large social media database, Yahoo Answers, we explored postings to an online forum in which posters asked whether their height and weight qualify themselves as "skinny," "thin," "fat," or "obese" over time and across forum topics. We used these data to better understand whether a higher-than-average body mass index (BMI) in one's county might, in some ways, be protective for one's mental and physical health. For instance, we explored whether higher proportions of obese people in one's county predicts lower levels of bullying or "am I fat?" questions from those with a normal BMI relative to his/her actual BMI. Most women asking whether they were themselves fat/obese were not actually fat/obese. Both men and women who were actually overweight/obese were significantly more likely in the future to ask for advice about bullying than thinner individuals. Moreover, as mean county-level BMI increased, bullying decreased and then increased again (in a U-shape curve). Regardless of where they lived, posters who asked "am I fat?" who had a BMI in the healthy range were more likely than other posters to subsequently post on health problems, but the proportions of such posters also declined greatly as county-level BMI increased. Our findings suggest that obese people residing in counties with higher levels of BMI may have better physical and mental health than obese people living in counties with lower levels of BMI by some measures, but these improvements are modest. PMID- 24058479 TI - Inhibition of Fas-associated death domain-containing protein (FADD) protects against myocardial ischemia/reperfusion injury in a heart failure mouse model. AB - AIM: As technological interventions treating acute myocardial infarction (MI) improve, post-ischemic heart failure increasingly threatens patient health. The aim of the current study was to test whether FADD could be a potential target of gene therapy in the treatment of heart failure. METHODS: Cardiomyocyte-specific FADD knockout mice along with non-transgenic littermates (NLC) were subjected to 30 minutes myocardial ischemia followed by 7 days of reperfusion or 6 weeks of permanent myocardial ischemia via the ligation of left main descending coronary artery. Cardiac function were evaluated by echocardiography and left ventricular (LV) catheterization and cardiomyocyte death was measured by Evans blue-TTC staining, TUNEL staining, and caspase-3, -8, and -9 activities. In vitro, H9C2 cells transfected with ether scramble siRNA or FADD siRNA were stressed with chelerythrin for 30 min and cleaved caspase-3 was assessed. RESULTS: FADD expression was significantly decreased in FADD knockout mice compared to NLC. Ischemia/reperfusion (I/R) upregulated FADD expression in NLC mice, but not in FADD knockout mice at the early time. FADD deletion significantly attenuated I/R induced cardiac dysfunction, decreased myocardial necrosis, and inhibited cardiomyocyte apoptosis. Furthermore, in 6 weeks long term permanent ischemia model, FADD deletion significantly reduced the infarct size (from 41.20 +/- 3.90% in NLC to 26.83 +/- 4.17% in FADD deletion), attenuated myocardial remodeling, improved cardiac function and improved survival. In vitro, FADD knockdown significantly reduced chelerythrin-induced the level of cleaved caspase-3. CONCLUSION: Taken together, our results suggest FADD plays a critical role in post-ischemic heart failure. Inhibition of FADD retards heart failure progression. Our data supports the further investigation of FADD as a potential target for genetic manipulation in the treatment of heart failure. PMID- 24058480 TI - SOD mRNA and MDA expression in rectus femoris muscle of rats with different eccentric exercise programs and time points. AB - PURPOSE: Although superoxide dismutase (SOD) and malondialdehyde (MDA) affect Delayed Onset Muscle Soreness (DOMS), their effects are unclear in rectus femoris muscles (RFM) of rats with different eccentric exercise programs and time points. The purpose of this study is to investigate the effects of the various eccentric exercise programs at different time points on the SOD mRNA expression and MDA using rat as the animal model. METHODS: 248 male rats were randomly divided into 4 groups: control group (CTL, n = 8), once-only exercise group (OEG, n = 80), continuous exercise group (CEG, n = 80), and intermittent exercise group (IEG, n = 80). Each exercise group was divided into 10 subgroups that exercised 0.5 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, or 168 h. Rats were sacrificed and their SOD mRNA expression, and MDA concentrations of skeletal muscle tissue were measured. RESULTS: The specimen in all eccentric exercise programs showed increased RFM SOD1 mRNA expression levels at 0.5 h (P<0.05), and decreased RFM SOD3 mRNA expression at 0.5 h (P<0.05). The continuous eccentric exercise (CE) significantly enhanced muscle SOD2 mRNA level at 0.5 h (P<0.05). After once-only eccentric exercise (OE), SOD1, SOD2, and SOD3 mRNA expression significantly increased at 96 h, whereas MDA concentrations decreased at 96 h. After CE, the correlation coefficients of SOD1, SOD2, SOD3 mRNA expression levels and MDA concentrations were -0.814, -0.763, -0.845 (all P<0.05) at 12 h. CONCLUSION: Regular eccentric exercise, especially CE could enhance SOD1 and SOD2 mRNA expression in acute stage and the SOD2 mRNA expression correlates to MDA concentration in vivo, which may improve the oxidative adaption ability of skeletal muscles. PMID- 24058481 TI - Wnt11b is involved in cilia-mediated symmetry breakage during Xenopus left-right development. AB - Breakage of bilateral symmetry in amphibian embryos depends on the development of a ciliated epithelium at the gastrocoel roof during early neurulation. Motile cilia at the gastrocoel roof plate (GRP) give rise to leftward flow of extracellular fluids. Flow is required for asymmetric gene expression and organ morphogenesis. Wnt signaling has previously been involved in two steps, Wnt/beta catenin mediated induction of Foxj1, a regulator of motile cilia, and Wnt/planar cell polarity (PCP) dependent cilia polarization to the posterior pole of cells. We have studied Wnt11b in the context of laterality determination, as this ligand was reported to activate canonical and non-canonical Wnt signaling. Wnt11b was found to be expressed in the so-called superficial mesoderm (SM), from which the GRP derives. Surprisingly, Foxj1 was only marginally affected in loss-of-function experiments, indicating that another ligand acts in this early step of laterality specification. Wnt11b was required, however, for polarization of GRP cilia and GRP morphogenesis, in line with the known function of Wnt/PCP in cilia-driven leftward flow. In addition Xnr1 and Coco expression in the lateral-most GRP cells, which sense flow and generate the first asymmetric signal, was attenuated in morphants, involving Wnt signaling in yet another process related to symmetry breakage in Xenopus. PMID- 24058482 TI - Broad MICA/B expression in the small bowel mucosa: a link between cellular stress and celiac disease. AB - The MICA/B genes (MHC class I chain related genes A and B) encode for non conventional class I HLA molecules which have no role in antigen presentation. MICA/B are up-regulated by different stress conditions such as heat-shock, oxidative stress, neoplasic transformation and viral infection. Particularly, MICA/B are expressed in enterocytes where they can mediate enterocyte apoptosis when recognised by the activating NKG2D receptor present on intraepithelial lymphocytes. This mechanism was suggested to play a major pathogenic role in active celiac disease (CD). Due to the importance of MICA/B in CD pathogenesis we studied their expression in duodenal tissue from CD patients. By immunofluorescence confocal microscopy and flow cytometry we established that MICA/B was mainly intracellularly located in enterocytes. In addition, we identified MICA/B(+) T cells in both the intraepithelial and lamina propria compartments. We also found MICA/B(+) B cells, plasma cells and some macrophages in the lamina propria. The pattern of MICA/B staining in mucosal tissue in severe enteropathy was similar to that found in in vitro models of cellular stress. In such models, MICA/B were located in stress granules that are associated to the oxidative and ER stress response observed in active CD enteropathy. Our results suggest that expression of MICA/B in the intestinal mucosa of CD patients is linked to disregulation of mucosa homeostasis in which the stress response plays an active role. PMID- 24058484 TI - On the socio-sexual behaviour of the extinct Ursid Indarctos arctoides: an approach based on its baculum size and morphology. AB - The fossil bacula, or os penis, constitutes a rare subject of study due to its scarcity in the fossil record. In the present paper we describe five bacula attributed to the bear Indarctos arctoides Deperet, 1895 from the Batallones-3 site (Madrid Basin, Spain). Both the length and morphology of this fossil bacula enabled us to make interpretative approaches to a series of ecological and ethological characters of this bear. Thus, we suggest that I. arctoides could have had prolonged periods of intromission and/or maintenance of intromission during the post-ejaculatory intervals, a multi-male mating system and large home range sizes and/or lower population density. Its size might also have helped females to choose from among the available males. PMID- 24058483 TI - SNP discovery by illumina-based transcriptome sequencing of the olive and the genetic characterization of Turkish olive genotypes revealed by AFLP, SSR and SNP markers. AB - BACKGROUND: The olive tree (Olea europaea L.) is a diploid (2n = 2x = 46) outcrossing species mainly grown in the Mediterranean area, where it is the most important oil-producing crop. Because of its economic, cultural and ecological importance, various DNA markers have been used in the olive to characterize and elucidate homonyms, synonyms and unknown accessions. However, a comprehensive characterization and a full sequence of its transcriptome are unavailable, leading to the importance of an efficient large-scale single nucleotide polymorphism (SNP) discovery in olive. The objectives of this study were (1) to discover olive SNPs using next-generation sequencing and to identify SNP primers for cultivar identification and (2) to characterize 96 olive genotypes originating from different regions of Turkey. METHODOLOGY/PRINCIPAL FINDINGS: Next-generation sequencing technology was used with five distinct olive genotypes and generated cDNA, producing 126,542,413 reads using an Illumina Genome Analyzer IIx. Following quality and size trimming, the high-quality reads were assembled into 22,052 contigs with an average length of 1,321 bases and 45 singletons. The SNPs were filtered and 2,987 high-quality putative SNP primers were identified. The assembled sequences and singletons were subjected to BLAST similarity searches and annotated with a Gene Ontology identifier. To identify the 96 olive genotypes, these SNP primers were applied to the genotypes in combination with amplified fragment length polymorphism (AFLP) and simple sequence repeats (SSR) markers. CONCLUSIONS/SIGNIFICANCE: This study marks the highest number of SNP markers discovered to date from olive genotypes using transcriptome sequencing. The developed SNP markers will provide a useful source for molecular genetic studies, such as genetic diversity and characterization, high density quantitative trait locus (QTL) analysis, association mapping and map-based gene cloning in the olive. High levels of genetic variation among Turkish olive genotypes revealed by SNPs, AFLPs and SSRs allowed us to characterize the Turkish olive genotype. PMID- 24058485 TI - Genotyping Candida albicans from Candida leukoplakia and non-Candida leukoplakia shows no enrichment of multilocus sequence typing clades but enrichment of ABC genotype C in Candida leukoplakia. AB - Oral leukoplakias are histopathologically-diagnosed as Candida leukoplakia or non Candida leukoplakia by the presence or absence of hyphae in the superficial epithelium. Candida leukoplakia lesions have significantly increased malignant potential. Candida albicans is the most prevalent fungal species associated with oral leukoplakia and may contribute to malignant transformation of Candida leukoplakia. To date, no detailed population analysis of C. albicans isolates from oral leukoplakia patients has been undertaken. This study investigated whether specific C. albicans genotypes were associated with Candida leukoplakia and non-Candida leukoplakia in a cohort of Irish patients. Patients with histopathologically-defined Candida leukoplakia (n = 31) or non-Candida leukoplakia (n = 47) were screened for Candida species by culture of oral rinse and lesional swab samples. Selected C. albicans isolates from Candida leukoplakia patients (n = 25), non-Candida leukoplakia patients (n = 19) and oral carriage isolates from age and sex matched healthy subjects without leukoplakia (n = 34) were subjected to multilocus sequence typing (MLST) and ABC genotyping. MLST revealed that the clade distribution of C. albicans from both Candida leukoplakia and non-Candida leukoplakia lesions overlapped with the corresponding clade distributions of oral carriage isolates and global reference isolates from the MLST database indicating no enrichment of leukoplakia-associated clones. Oral leukoplakia isolates were significantly enriched with ABC genotype C (12/44, 27.3%), particularly Candida leukoplakia isolates (9/25, 36%), relative to oral carriage isolates (3/34, 8.8%). Genotype C oral leukoplakia isolates were distributed in MLST clades 1,3,4,5,8,9 and 15, whereas genotype C oral carriage isolates were distributed in MLST clades 4 and 11. PMID- 24058486 TI - Transcriptional and microscopic analyses of citrus stem and root responses to Candidatus Liberibacter asiaticus infection. AB - Huanglongbing (HLB) is the most destructive disease that affects citrus worldwide. The disease has been associated with Candidatus Liberibacter. HLB diseased citrus plants develop a multitude of symptoms including zinc and copper deficiencies, blotchy mottle, corky veins, stunting, and twig dieback. Ca. L. asiaticus infection also seriously affects the roots. Previous study focused on gene expression of leaves and fruit to Ca. L. asiaticus infection. In this study, we compared the gene expression levels of stems and roots of healthy plants with those in Ca. L. asiaticus infected plants using microarrays. Affymetrix microarray analysis showed a total of 988 genes were significantly altered in expression, of which 885 were in the stems, and 111 in the roots. Of these, 551 and 56 were up-regulated, while 334 and 55 were down-regulated in the stem and root samples of HLB diseased trees compared to healthy plants, respectively. Dramatic differences in the transcriptional responses were observed between citrus stems and roots to Ca. L. asiaticus infection, with only 8 genes affected in both the roots and stems. The affected genes are involved in diverse cellular functions, including carbohydrate metabolism, cell wall biogenesis, biotic and abiotic stress responses, signaling and transcriptional factors, transportation, cell organization, protein modification and degradation, development, hormone signaling, metal handling, and redox. Microscopy analysis showed the depletion of starch in the roots of the infected plants but not in healthy plants. Collapse and thickening of cell walls were observed in HLB affected roots, but not as severe as in the stems. This study provides insight into the host response of the stems and roots to Ca. L. asiaticus infection. PMID- 24058487 TI - Effect of radiation dose-rate on hematopoietic cell engraftment in adult zebrafish. AB - Although exceptionally high radiation dose-rates are currently attaining clinical feasibility, there have been relatively few studies reporting the biological consequences of these dose-rates in hematopoietic cell transplant (HCT). In zebrafish models of HCT, preconditioning before transplant is typically achieved through radiation alone. We report the comparison of outcomes in adult zebrafish irradiated with 20 Gy at either 25 or 800 cGy/min in the context of experimental HCT. In non-transplanted irradiated fish we observed no substantial differences between dose-rate groups as assessed by fish mortality, cell death in the kidney, endogenous hematopoietic reconstitution, or gene expression levels of p53 and ddb2 (damage-specific DNA binding protein 2) in the kidney. However, following HCT, recipients conditioned with the higher dose rate showed significantly improved donor-derived engraftment at 9 days post transplant (p <= 0.0001), and improved engraftment persisted at 31 days post transplant. Analysis for sdf-1a expression, as well as transplant of hematopoietic cells from cxcr4b -/- zebrafish, (odysseus), cumulatively suggest that the sdf-1a/cxcr4b axis is not required of donor-derived cells for the observed dose-rate effect on engraftment. Overall, the adult zebrafish model of HCT indicates that exceptionally high radiation dose-rates can impact HCT outcome, and offers a new system for radiobiological and mechanistic interrogation of this phenomenon. Key words: Radiation dose rate, Total Marrow Irradiation (TMI), Total body irradiation (TBI), SDF-1, Zebrafish, hematopoietic cell transplant. PMID- 24058488 TI - Mild anastomotic stenosis in patient-specific CABG model may enhance graft patency: a new hypothesis. AB - It is well known that flow patterns at the anastomosis of coronary artery bypass graft (CABG) are complex and may affect the long-term patency. Various attempts at optimal designs of anastomosis have not improved long-term patency. Here, we hypothesize that mild anastomotic stenosis (area stenosis of about 40-60%) may be adaptive to enhance the hemodynamic conditions, which may contribute to slower progression of atherosclerosis. We further hypothesize that proximal/distal sites to the stenosis have converse changes that may be a risk factor for the diffuse expansion of atherosclerosis from the site of stenosis. Twelve (12) patient specific models with various stenotic degrees were extracted from computed tomography images using a validated segmentation software package. A 3-D finite element model was used to compute flow patterns including wall shear stress (WSS) and its spatial and temporal gradients (WSS gradient, WSSG, and oscillatory shear index, OSI). The flow simulations showed that mild anastomotic stenosis significantly increased WSS (>15 dynes . cm(-2)) and decreased OSI (<0.02) to result in a more uniform distribution of hemodynamic parameters inside anastomosis albeit proximal/distal sites to the stenosis have a decrease of WSS (<4 dynes . cm(-2)). These findings have significant implications for graft adaptation and long-term patency. PMID- 24058489 TI - Surviving in mountain climate refugia: new insights from the genetic diversity and structure of the relict shrub Myrtus nivellei (Myrtaceae) in the Sahara Desert. AB - The identification of past glacial refugia has become a key topic for conservation under environmental change, since they contribute importantly to shaping current patterns of biodiversity. However, little attention has been paid so far to interglacial refugia despite their key role for the survival of relict species currently occurring in climate refugia. Here, we focus on the genetic consequences of range contraction on the relict populations of the evergreen shrub Myrtus nivellei, endemic in the Saharan mountains since at least the end of the last Green Sahara period, around 5.5 ka B.P. Multilocus genotypes (nuclear microsatellites and AFLP) were obtained from 215 individuals collected from 23 wadis (temporary rivers) in the three main mountain ranges in southern Algeria (the Hoggar, Tassili n'Ajjer and Tassili n'Immidir ranges). Identical genotypes were found in several plants growing far apart within the same wadis, a pattern taken as evidence of clonality. Multivariate analyses and Bayesian clustering revealed that genetic diversity was mainly structured among the mountain ranges, while low isolation by distance was observed within each mountain range. The range contraction induced by the last episode of aridification has likely increased the genetic isolation of the populations of M. nivellei, without greatly affecting the genetic diversity of the species as a whole. The pattern of genetic diversity observed here suggests that high connectivity may have prevailed during humid periods, which is consistent with recent paleoenvironmental reconstructions. PMID- 24058490 TI - Prevalence of anemia among adults with newly diagnosed HIV/AIDS in China. AB - BACKGROUND: The prevalence of anemia among antiretroviral-naive HIV-infected patients in China has not been well characterized. We conducted a cross-sectional study to estimate the prevalence of anemia among Chinese adults with newly diagnosed HIV/AIDS. METHODS: One thousand nine hundred and forty-eight newly diagnosed HIV-infected patients in China were selected during 2009 and 2010. Serum samples obtained from each individual were collected to measure hemoglobin levels. Demographics and medical histories were recorded. Factors associated with the presence of anemia were analysed by logistic regression. RESULTS: Among the 1948 patients, 75.8% were male. Median age was 40 years (range: 18-80 years). The overall prevalence of anemia among HIV-infected patients was 51.9% (51.5% among men, 53.2% among women). The prevalences of mild anemia, of moderate anemia, of severe anemia were 32.4%, 17.0%, and 2.5%, respectively. The prevalence of anemia was higher among ethnic minority patients than among the Han patients (70.9% versus 45.9%). The prevalence of anemia increased with increasing age (49.6%, 53.5% and 60.1% among patients who were 18-39, 40-59, and >= 60 years of age respectively) and with decreasing CD4 count (14.0%, 22.4%, 50.7%, and 74.6% among patients with CD4 count of >= 350, 200-349, 50-199, and <50 cells/mm(3) respectively). The logistic regression analysis showed that older age, lower CD4 count and minority ethnicity were significantly associated with an increased risk of anemia. CONCLUSIONS: Anemia is highly prevalent among Chinese adults with newly diagnosed HIV/AIDS, but severe anemia is less prevalent in this population. Older age, lower CD4 count and minority ethnicity are associated with an increased risk of anemia. PMID- 24058491 TI - The trophy hunting of African lions: scale, current management practices and factors undermining sustainability. AB - The trophy hunting of lions Panthera leo is contentious due to uncertainty concerning conservation impacts and because of highly polarised opinions about the practice. African lions are hunted across at least ~558,000 km(2), which comprises 27-32% of the lion range in countries where trophy hunting of the species is permitted. Consequently, trophy hunting has potential to impart significant positive or negative impacts on lions. Several studies have demonstrated that excessive trophy harvests have driven lion population declines. There have been several attempts by protectionist non-governmental organisations to reduce or preclude trophy hunting via restrictions on the import and export of lion trophies. We document the management of lion hunting in Africa and highlight challenges which need addressing to achieve sustainability. Problems include: unscientific bases for quota setting; excessive quotas and off-takes in some countries; fixed quotas which encourage over-harvest; and lack of restrictions on the age of lions that can be hunted. Key interventions needed to make lion hunting more sustainable, include implementation of: enforced age restrictions; improved trophy monitoring; adaptive management of quotas and a minimum length of lion hunts of at least 21 days. Some range states have made important steps towards implementing such improved management and off-takes have fallen steeply in recent years. For example age restrictions have been introduced in Tanzania and in Niassa in Mozambique, and are being considered for Benin and Zimbabwe, several states have reduced quotas, and Zimbabwe is implementing trophy monitoring. However, further reforms are needed to ensure sustainability and reduce conservation problems associated with the practice while allowing retention of associated financial incentives for conservation. PMID- 24058492 TI - May salivary gland secretory proteins from hematophagous leeches (Hirudo verbana) reach pharmacologically relevant concentrations in the vertebrate host? AB - Saliva of hematophagous leeches (Hirudo sp.) contains bioactive proteins which allow the leech proper feeding and storage of ingested blood, but may also exert effects in the host. Leech therapy is used to treat many different ailments in humans, although only a small fraction of salivary proteins are characterized yet. Moreover, we do not know whether complete transfer of salivary proteins stored in the unicellular salivary glands in a leech to the host during feeding may generate concentrations that are sufficiently high to affect physiological processes in the host. Our 3D reconstruction of a portion of internal leech tissue from histological sections revealed that one leech contains approx. 37,000 salivary gland cells. Using tissue slices from pig liver and mouse skeletal muscle for reference, we obtained data for protein densities in leech salivary gland cells. As individual salivary cells are voluminous (67,000 um(3)) and the stored proteins are densely packed (approx. 500 ug/mm(3)), we extrapolated that a single leech may contain up to 1.2 mg of salivary proteins. Analyzing protein extracts of unfed or fed leeches by 2D electrophoresis, we calculated the relative molar amounts of individual salivary proteins in the mass range of 17-60 kDa which may be released from a single leech during feeding. Distribution of these salivary proteins in the host (assumed plasma volume of 5 l) may result in concentrations of individual compounds between 3 and 236 pmol/l. Such concentrations seem sufficiently high to exert biochemical interactions with target molecules in the host. PMID- 24058493 TI - Altered metabolites in the plasma of autism spectrum disorder: a capillary electrophoresis time-of-flight mass spectroscopy study. AB - Clinical diagnosis and severity of autism spectrum disorders (ASD) are determined by trained clinicians based on clinical evaluations of observed behaviors. As such, this approach is inevitably dependent on the expertise and subjective assessment of those administering the clinical evaluations. There is a need to identify objective biological markers associated with diagnosis or clinical severity of the disorder. To identify novel candidate metabolites as potential biomarkers for ASD, the current study applied capillary electrophoresis time-of flight mass spectroscopy (CE-TOFMS) for high-throughput profiling of metabolite levels in the plasma of 25 psychotropic-naive adult males with high-functioning ASD and 28 age-matched typically-developed control subjects. Ten ASD participants and ten age-matched controls were assigned in the first exploration set, while 15 ASD participants and 18 controls were included in the second replication set. By CE-TOFMS analysis, a total of 143 metabolites were detected in the plasma of the first set. Of these, 17 metabolites showed significantly different relative areas between the ASD participants and the controls (p<0.05). Of the 17 metabolites, we consistently found that the ASD participants had significantly high plasma levels of arginine (p = 0.024) and taurine (p = 0.018), and significantly low levels of 5-oxoproline (p<0.001) and lactic acid (p = 0.031) compared with the controls in the second sample set. Further confirmatory analysis using quantification of absolute metabolite concentrations supported the robustness of high arginine (p = 0.001) and low lactic acid (p = 0.003) in the combined sample (n = 53). The present study identified deviated plasma metabolite levels associated with oxidative stress and mitochondrial dysfunction in individuals with ASD. PMID- 24058494 TI - Syndromic surveillance for influenza in the emergency department-A systematic review. AB - The science of surveillance is rapidly evolving due to changes in public health information and preparedness as national security issues, new information technologies and health reform. As the Emergency Department has become a much more utilized venue for acute care, it has also become a more attractive data source for disease surveillance. In recent years, influenza surveillance from the Emergency Department has increased in scope and breadth and has resulted in innovative and increasingly accepted methods of surveillance for influenza and influenza-like-illness (ILI). We undertook a systematic review of published Emergency Department-based influenza and ILI syndromic surveillance systems. A PubMed search using the keywords "syndromic", "surveillance", "influenza" and "emergency" was performed. Manuscripts were included in the analysis if they described (1) data from an Emergency Department (2) surveillance of influenza or ILI and (3) syndromic or clinical data. Meeting abstracts were excluded. The references of included manuscripts were examined for additional studies. A total of 38 manuscripts met the inclusion criteria, describing 24 discrete syndromic surveillance systems. Emergency Department-based influenza syndromic surveillance has been described worldwide. A wide variety of clinical data was used for surveillance, including chief complaint/presentation, preliminary or discharge diagnosis, free text analysis of the entire medical record, Google flu trends, calls to teletriage and help lines, ambulance dispatch calls, case reports of H1N1 in the media, markers of ED crowding, admission and Left Without Being Seen rates. Syndromes used to capture influenza rates were nearly always related to ILI (i.e. fever +/- a respiratory or constitutional complaint), however, other syndromes used for surveillance included fever alone, "respiratory complaint" and seizure. Two very large surveillance networks, the North American DiSTRIBuTE network and the European Triple S system have collected large-scale Emergency Department-based influenza and ILI syndromic surveillance data. Syndromic surveillance for influenza and ILI from the Emergency Department is becoming more prevalent as a measure of yearly influenza outbreaks. PMID- 24058495 TI - Molecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against CDKs: insights for rational drug design. AB - Cyclin-dependent kinases (CDKs) belong to the CMGC subfamily of protein kinases and play crucial roles in eukaryotic cell division cycle. At least seven different CDKs have been reported to be implicated in the cell cycle regulation in vertebrates. These CDKs are highly homologous and contain a conserved catalytic core. This makes the design of inhibitors specific for a particular CDK difficult. There is, however, growing need for CDK5 specific inhibitors to treat various neurodegenerative diseases. Recently, cis-substituted cyclobutyl-4 aminoimidazole inhibitors have been identified as potent CDK5 inhibitors that gave up to 30-fold selectivity over CDK2. Available IC50 values also indicate a higher potency of this class of inhibitors over commercially available drugs, such as roscovitine. To understand the molecular basis of higher potency and selectivity of these inhibitors, here, we present molecular dynamics simulation results of CDK5/p25 and CDK2/CyclinE complexed with a series of cyclobutyl substituted imidazole inhibitors and roscovitine. The atomic details of the stereospecificity and selectivity of these inhibitors are obtained from energetics and binding characteristics to the CDK binding pocket. The study not only complements the experimental findings, but also provides a wealth of detailed information that could help the structure-based drug designing processes. PMID- 24058496 TI - Adjuvant chemotherapy, a valuable alternative option in selected patients with cervical cancer. AB - Radiotherapy is the standard treatment for cervical cancer, but causes radiotherapy-induced complications. Recently, chemotherapy has been more extensively utilized. Here, we perform a large-scale comparison of chemotherapy and radiotherapy. From 2002 to 2008, 2,268 patients were grouped according to adjuvant radiotherapy or chemotherapy before and/or after surgery, and we compared the 5-year overall survival (OS) and disease-free survival (DFS) rates, recurrence rates, side effects, quality of life (QoL), and sexual activity. There were no significant differences between the treatment groups for the 5-year OS and DFS rates (OS: p = 0.053, DFS: p = 0.095), although marginally improved outcomes were observed in the chemotherapy group (OS: 86.5% vs. 82.8%; DFS: 84.5% vs. 81.4%). However, patients with early-stage disease, clinical response, and younger age had increased 5-year OS and DFS rates following chemotherapy compared to radiotherapy (p<0.05). The chemotherapy group exhibited significantly lower 5 year recurrence and distant failure rates compared to the radiotherapy group (p<0.001 and p = 0.007, respectively). Nausea and vomiting were the most frequent short-term complications of chemotherapy, whereas bowel and urinary complications were more frequent in the radiotherapy group. Compared to the chemotherapy group, patients who received radiotherapy reported a lower QoL, less frequent sexual activity, and more severe menopausal symptoms (p<0.05). Cervical cancer patients treated with chemotherapy, especially those with early-stage disease, clinical responses, and younger ages, have more positive outcomes, fewer complications, better QoL and sexual activity, suggesting that chemotherapy may be a valuable alternative option for selected patients. PMID- 24058497 TI - Toll-like receptor 4-mediated nuclear factor kappa B activation is essential for sensing exogenous oxidants to propagate and maintain oxidative/nitrosative cellular stress. AB - The mechanism(s) by which cells can sense exogenous oxidants that may contribute to intracellular oxidative/nitrosative stress is not clear. The objective of this study was to determine how cells might respond to exogenous oxidants to potentially initiate, propagate and/or maintain inflammation associated with many human diseases through NF-kappaB activation. First, we used HEK-Blue cells that are stably transfected with mouse toll-like receptor 4 (mTLR4) or mouse TLR2. These cells also express optimized secreted embryonic alkaline phosphatase (SEAP) reporter gene under the control of a promoter inducible by NF-kappaB transcription factor. These cells were challenged with their respective receptor specific ligands, different pro-oxidants and/or inhibitors that act at different levels of the receptor signaling pathways. A neutralizing antibody directed against TLR4 inhibited responses to both TLR4-specific agonist and a prooxidant, which confirmed that both agents act through TLR4. We used the level of SEAP released into the culture media due to NF-kappaB activation as a measure of TLR4 or TLR2 stimulation. Pro-oxidants evoked increased release of SEAP from HEK-Blue mTLR4 cells at a much lower concentration compared with release from the HEK-Blue mTLR2 cells. Specific TLR4 signaling pathway inhibitors and oxidant scavengers (anti-oxidants) significantly attenuated oxidant-induced SEAP release by TLR4 stimulation. Furthermore, a novel pro-oxidant that decays to produce the same reactants as activated phagocytes induced inflammatory pain responses in the mouse orofacial region with increased TLR4 expression, and IL-1beta and TNFalpha tissue levels. EUK-134, a synthetic serum-stable scavenger of oxidative species decreased these effects. Our data provide in vitro and related in vivo evidence that exogenous oxidants can induce and maintain inflammation by acting mainly through a TLR4-dependent pathway, with implications in many chronic human ailments. PMID- 24058498 TI - Development of recombinant antigen array for simultaneous detection of viral antibodies. AB - Protein microarrays have been developed to study antibody reactivity against a large number of antigens, demonstrating extensive perspective for clinical application. We developed a viral antigen array by spotting four recombinant antigens and synthetic peptide, including glycoprotein G of herpes simplex virus (HSV) type 1 and 2, phosphoprotein 150 of cytomegalovirus (CMV), Rubella virus (RV) core plus glycoprotein E1 and E2 as well as a E1 peptide with the optimal concentrations on activated glass slides to simultaneously detect IgG and IgM against HSV1, HSV2, CMV and RV in clinical specimens of sera and cerebrospinal fluids (CSFs). The positive reference sera were initially used to measure the sensitivity and specificity of the array with the optimal conditions. Then clinical specimens of 144 sera and 93 CSFs were tested for IgG and IgM antibodies directed against HSV1, HSV2, CMV and RV by the antigen array. Specificity of the antigen array for viral antibodies detection was satisfying compared to commercial ELISA kits but sensitivity of the array varied relying on quality and antigenic epitopes of the spotting antigens. In short, the recombinant antigen array has potential to simultaneous detect multiple viral antibodies using minute amount (3 ul) of samples, which holds the particularly advantage to detect viral antibodies in clinical CSFs being suspicious of neonatal meningitis and encephalitis. PMID- 24058499 TI - Increase or decrease hydrogen sulfide exert opposite lipolysis, but reduce global insulin resistance in high fatty diet induced obese mice. AB - OBJECTIVE: Adipose tissue expressed endogenous cystathionine gamma lyase (CSE)/hydrogen sulfide (H2S) system. H2S precursor inhibited catecholamine stimulated lipolysis. Thus, we hypothesized that CSE/H2S system regulates lipolysis which contributed to the pathogenesis of insulin resistance. METHODS: We treated rat adipocyte with DL-propargylglycine (PAG, a CSE inhibitor), L cysteine (an H2S precursor) plus pyridoxial phosphate (co-enzyme) or the H2S chronic release donor GYY4137, then the glycerol level was assayed for assessing the lipolysis. Then, the effects of PAG and GYY4137 on insulin resistance in high fatty diet (HFD) induced obese mice were investigated. RESULTS: Here, we found that PAG time-dependently increased basal or isoproterenol stimulated lipolysis. However, L-cysteine plus pyridoxial phosphate or GYY4137 significantly reduced it. PAG increased phosphorylated protein kinase A substrate, perilipin 1 and hormone sensitive lipase, but L-cysteine and GYY4137 decreased the parameters. In HFD induced obese mice, PAG increased adipose basal lipolysis, thus blunted fat mass increase, resulting in lowering insulin resistance evidenced by reduction of fasting glucose, insulin level, HOMA index, oral glucose tolerance test (OGTT) curve area and elevating the insulin tolerance test (ITT) response. GYY4137 inhibited lipolysis in vivo without increasing fat mass, but also ameliorated the insulin resistance in HFD mice. CONCLUSION: These results implicated that inhibition endogenous CSE/H2S system in adipocytes increased lipolysis by a protein kinase A-perilipin/hormone-sensitive lipase pathway, thus blunted fat mass increase and reduced insulin resistance in obese mice; giving H2S donor decreased lipolysis, also reduced insulin resistance induced by HFD. Our data showed that increase or decrease H2S induced opposite lipolysis, but had the same effect on insulin resistance. The paradoxical regulation may be resulted from different action of H2S on metabolic and endocrine function in adipocyte. PMID- 24058500 TI - Analysis of enhanced current-generating mechanism of Geobacter sulfurreducens strain via model-driven metabolism simulation. AB - Microbial fuel cells (MFCs) are a class of ideal technologies that function via anaerobic respiration of electricigens, which bring current generation and environmental restoration together. An in-depth understanding of microbial metabolism is of great importance in engineering microbes to further improve their respiration. We employed flux balance analysis and selected Fe(iii) as a substitute for the electrode to simulate current-generating metabolism of Geobacter sulfurreducens PCA with a fixed acetate uptake rate. Simulation results indicated the fluxes of reactions directing acetate towards dissimilation to generate electrons increased under the suboptimal growth condition, resulting in an increase in the respiration rate and a decrease in the growth rate. The results revealed the competitive relationship between oxidative respiration and cell growth during the metabolism of microbe current generation. The results helped us quantitatively understand why microbes growing slowly have the potential to make good use of fuel in MFCs. At the same time, slow growth does not necessarily result in speedy respiration. Alternative respirations may exist under the same growth state due to redundant pathways in the metabolic network. The big difference between the maximum and minimum respiration mainly results from the total formate secretion. With iterative flux variability analysis, a relatively ideal model of variant of G. sulfurreducens PCA was reconstructed by deleting several enzymes in the wild model, which could reach simultaneous suboptimal growth and maximum respiration. Under this ideal condition, flux towards extracellular electron transfer rather than for biosynthesis is beneficial for the conversion of organic matter to electricity without large accumulations of biomass and electricigens may maximize utilization of limited fuel. Our simulations will provide an insight into the enhanced current generating mechanism and identify theoretical range of respiration rates for guiding strain improvement in MFCs. PMID- 24058501 TI - An analysis of the Athetis lepigone transcriptome from four developmental stages. AB - Athetis lepigone Moschler (Lepidoptera: Noctuidae) has recently become an important insect pest of maize (Zea mays) crops in China. In order to understand the characteristics of the different developmental stages of this pest, we used Illumina short-read sequences to perform de novo transcriptome assembly and gene expression analysis for egg, larva, pupa and adult developmental stages. We obtained 10.08 Gb of raw data from Illumina sequencing and recovered 81,356 unigenes longer than 100 bp through a de novo assembly. The total sequence length reached 49.75 Mb with 858 bp of N50 and an average unigene length of 612 bp. Annotation analysis of predicted proteins indicate that 33,736 unigenes (41.47% of total unigenes) are matches to genes in the Genbank Nr database. The unigene sequences were subjected to GO, COG and KEGG functional classification. A large number of differentially expressed genes were recovered by pairwise comparison of the four developmental stages. The most dramatic differences in gene expression were found in the transitions from one stage to another stage. Some of these differentially expressed genes are related to cuticle and wing formation as well as the growth and development. We identified more than 2,500 microsatellite markers that may be used for population studies of A. lepigone. This study lays the foundation for further research on population genetics and gene function analysis in A. lepigone. PMID- 24058503 TI - UVB radiation as a potential selective factor favoring microcystin producing bloom forming Cyanobacteria. AB - Due to the stratospheric ozone depletion, several organisms will become exposed to increased biologically active UVB (280-320 nm) radiation, not only at polar but also at temperate and tropical latitudes. Bloom forming cyanobacteria are exposed to UVB radiation on a mass scale, particularly during the surface bloom and scum formation that can persist for long periods of time. All buoyant species of cyanobacteria are at least periodically exposed to higher irradiation during their vertical migration to the surface that usually occurs several times a day. The aim of this study is to assess the influence on cyanobacteria of UVB radiation at realistic environmental intensities. The effects of two UVB intensities of 0.5 and 0.99 W/m(2) in up to 0.5 cm water depth were studied in vitro on Microcystis aeruginosa strains, two microcystin producing and one non producing. After UVB exposure their ability to proliferate was estimated by cell counting, while cell fitness and integrity were evaluated using light microscopy, autofluorescence and immunofluorescence. Gene damage was assessed by TUNEL assay and SYBR Green staining of the nucleoide area. We conclude that UVB exposure causes damage to the genetic material, cytoskeletal elements, higher sedimentation rates and consequent cell death. In contrast to microcystin producers (PCC7806 and FACHB905), the microcystin non-producing strain PCC7005 is more susceptible to the deleterious effects of radiation, with weak recovery ability. The ecological relevance of the results is discussed using data from eleven years' continuous UVB radiation measurements within the area of Ljubljana city (Slovenia, Central Europe). Our results suggest that increased solar radiation in temperate latitudes can have its strongest effect during cyanobacterial bloom formation in spring and early summer. UVB radiation in this period may significantly influence strain composition of cyanobacterial blooms in favor of microcystin producers. PMID- 24058502 TI - Risk factors for moderate and severe persistent pain in patients undergoing total knee and hip arthroplasty: a prospective predictive study. AB - Persistent post-surgical pain (PPSP) is a major clinical problem with significant individual, social and health care costs. The aim of this study was to examine the joint role of demographic, clinical and psychological risk factors in the development of moderate and severe PPSP after Total Knee and Hip Arthroplasty (TKA and THA, respectively). This was a prospective study wherein a consecutive sample of 92 patients were assessed 24 hours before (T1), 48 hours after (T2) and 4-6 months (T3) after surgery. Hierarchical logistic regression analyses were performed to identify predictors of moderate and severe levels of PPSP. Four to six months after TKA and THA, 54 patients (58.7%) reported none or mild pain (Numerical Rating Scale: NRS <= 3), whereas 38 (41.3%) reported moderate to severe pain (NRS >3). In the final multivariate hierarchical logistic regression analyses, illness representations concerning the condition leading to surgery (osteoarthritis), such as a chronic timeline perception of the disease, emerged as a significant predictor of PPSP. Additionally, post-surgical anxiety also showed a predictive role in the development of PPSP. Pre-surgical pain was the most significant clinical predictive factor and, as expected, undergoing TKA was associated with greater odds of PPSP development than THA. The findings on PPSP predictors after major joint arthroplasties can guide clinical practice in terms of considering cognitive and emotional factors, together with clinical factors, in planning acute pain management before and after surgery. PMID- 24058504 TI - Thiourea, a ROS scavenger, regulates source-to-sink relationship to enhance crop yield and oil content in Brassica juncea (L.). AB - In the present agricultural scenario, the major thrust is to increase crop productivity so as to ensure sustainability. In an earlier study, foliar application of thiourea (TU; a non physiological thiol based ROS scavenger) has been demonstrated to enhance the stress tolerance and yield of different crops under field condition. Towards this endeavor, present work deals with the effect of TU on photosynthetic efficiency and source-to-sink relationship of Indian mustard (Brassica juncea) for understanding its mode of action. The application of TU increased the efficiency of both PSI and PSII photosystems and vegetative growth of plant. The comparative analysis of sucrose to starch ratio and expression level of sugar transporters confirmed the higher source and sink strength in response to TU treatment. The biochemical evidence in support of this was derived from higher activities of sucrose phosphate synthase and fructose-1,6 bis-phosphatase at source; and sucrose synthase and different classes of invertases at both source and sink. This indicated an overall increase in photoassimilate level at sink. An additional contribution through pod photosynthesis was confirmed through the analysis of phosphoenol pyruvate carboxylase enzyme activity and level of organic acids. The increased photoassimilate level was also co-ordinated with acetyl coA carboxylase mediated oil biosynthesis. All these changes were ultimately reflected in the form of 10 and 20% increase in total yield and oil content, respectively under TU treatment as compared to control. Additionally, no change was observed in oil composition of seeds derived from TU treated plants. The study thus signifies the co ordinated regulation of key steps of photosynthesis and source-to-sink relationship through the external application of TU resulting in increased crop yield and oil content. PMID- 24058505 TI - The association of health and income in the elderly: experience from a southern state of Brazil. AB - OBJECTIVES: In high income, developed countries, health status tends to improve as income increases, but primarily through the 50(th)-66(th) percentile of income. It is unclear whether the same limitation holds in middle income countries, and for both general assessments of health and specific conditions. METHODS: Data were obtained from Brazil, a middle income country. In-person interviews with a representative sample of community residents age >= 60 (N=6963), in the southern state of Rio Grande do Sul, obtained information on demographic characteristics including household income and number of persons supported, general health status (self-rated health, functional status), depression, and seven physician-diagnosed, self-reported health conditions. Analyses used household income (adjusted for number supported and economies of scale) together with higher order income terms, and controlled for demographics and comorbidities, to ascertain nonlinearity between income and general and specific health measures. RESULTS: In fully controlled analyses income was associated with general measures of health (linearly with self-rated health, nonlinearly with functional status). For specific health measures there was a consistent linear association with depression, pulmonary disorders, renal disorders, and sensory impairment. For musculoskeletal, cardiovascular (negative association), and gastrointestinal disorders this association no longer held when comorbidities were controlled. There was no association with diabetes. CONCLUSION: Contrary to findings in high income countries, the association of household-size-adjusted income with health was generally linear, sometimes negative, and sometimes absent when comorbidities were controlled. PMID- 24058506 TI - Genetic effects on DNA methylation and its potential relevance for obesity in Mexican Americans. AB - Several studies have identified effects of genetic variation on DNA methylation patterns and associated heritability, with research primarily focused on Caucasian individuals. In this paper, we examine the evidence for genetic effects on DNA methylation in a Mexican American cohort, a population burdened by a high prevalence of obesity. Using an Illumina-based platform and following stringent quality control procedures, we assessed a total of 395 CpG sites in peripheral blood samples obtained from 183 Mexican American individuals for evidence of heritability, proximal genetic regulation and association with age, sex and obesity measures (i.e. waist circumference and body mass index). We identified 16 CpG sites (~4%) that were significantly heritable after Bonferroni correction for multiple testing and 27 CpG sites (~6.9%) that showed evidence of genetic effects. Six CpG sites (~2%) were associated with age, primarily exhibiting positive relationships, including CpG sites in two genes that have been implicated in previous genome-wide methylation studies of age (FZD9 and MYOD1). In addition, we identified significant associations between three CpG sites (~1%) and sex, including DNA methylation in CASP6, a gene that may respond to estradiol treatment, and in HSD17B12, which encodes a sex steroid hormone. Although we did not identify any significant associations between DNA methylation and the obesity measures, several nominally significant results were observed in genes related to adipogenesis, obesity, energy homeostasis and glucose homeostasis (ARHGAP9, CDKN2A, FRZB, HOXA5, JAK3, MEST, NPY, PEG3 and SMARCB1). In conclusion, we were able to replicate several findings from previous studies in our Mexican American cohort, supporting an important role for genetic effects on DNA methylation. In addition, we found a significant influence of age and sex on DNA methylation, and report on trend-level, novel associations between DNA methylation and measures of obesity. PMID- 24058508 TI - In silico approach for predicting toxicity of peptides and proteins. AB - BACKGROUND: Over the past few decades, scientific research has been focused on developing peptide/protein-based therapies to treat various diseases. With the several advantages over small molecules, including high specificity, high penetration, ease of manufacturing, peptides have emerged as promising therapeutic molecules against many diseases. However, one of the bottlenecks in peptide/protein-based therapy is their toxicity. Therefore, in the present study, we developed in silico models for predicting toxicity of peptides and proteins. DESCRIPTION: We obtained toxic peptides having 35 or fewer residues from various databases for developing prediction models. Non-toxic or random peptides were obtained from SwissProt and TrEMBL. It was observed that certain residues like Cys, His, Asn, and Pro are abundant as well as preferred at various positions in toxic peptides. We developed models based on machine learning technique and quantitative matrix using various properties of peptides for predicting toxicity of peptides. The performance of dipeptide-based model in terms of accuracy was 94.50% with MCC 0.88. In addition, various motifs were extracted from the toxic peptides and this information was combined with dipeptide-based model for developing a hybrid model. In order to evaluate the over-optimization of the best model based on dipeptide composition, we evaluated its performance on independent datasets and achieved accuracy around 90%. Based on above study, a web server, ToxinPred has been developed, which would be helpful in predicting (i) toxicity or non-toxicity of peptides, (ii) minimum mutations in peptides for increasing or decreasing their toxicity, and (iii) toxic regions in proteins. CONCLUSION: ToxinPred is a unique in silico method of its kind, which will be useful in predicting toxicity of peptides/proteins. In addition, it will be useful in designing least toxic peptides and discovering toxic regions in proteins. We hope that the development of ToxinPred will provide momentum to peptide/protein-based drug discovery (http://crdd.osdd.net/raghava/toxinpred/). PMID- 24058507 TI - The conservation and application of three hypothetical protein coding gene for direct detection of Mycobacterium tuberculosis in sputum specimens. AB - BACKGROUND: Accurate and early diagnosis of tuberculosis (TB) is of major importance in the control of TB. One of the most important technical advances in diagnosis of tuberculosis is the development of nucleic acid amplification (NAA) tests. However, the choice of the target sequence remains controversial in NAA tests. Recently, interesting alternatives have been found in hypothetical protein coding sequences from mycobacterial genome. METHODOLOGY/PRINCIPAL FINDINGS: To obtain rational biomarker for TB diagnosis, the conservation of three hypothetical genes was firstly evaluated in 714 mycobacterial strains. The results showed that SCAR1 (Sequenced Characterized Amplified Region) based on Rv0264c coding gene showed the highest conservation (99.8%) and SCAR2 based on Rv1508c gene showed the secondary high conservation (99.7%) in M. tuberculosis (MTB) strains. SCAR3 based on Rv2135c gene (3.2%) and IS6110 (8%) showed relatively high deletion rate in MTB strains. Secondly, three SCAR markers were evaluated in 307 clinical sputum from patients in whom TB was suspected or patients with diseases other than TB. The amplification of IS6110 and 16SrRNA sequences together with both clinical and bacteriological identification was as a protocol to evaluate the efficacy of SCAR markers. The sensitivities and specificities, positive predictive value (PPV) and negative predictive value (NPV) of all NAA tests were higher than those of bacteriological detection. In four NAA tests, IS6110 and SCAR3 showed the highest PPV (100%) and low NPV (70% and 68.8%, respectively), and SCAR1 and SCAR2 showed the relatively high PPV and NPV (97% and 82.6%, 95.6% and 88.8%, respectively). CONCLUSIONS/SIGNIFICANCE: Our result indicated that SCAR1 and SCAR2 with a high degree of sequence conservation represent efficient and promising alternatives as NAA test targets in identification of MTB. Moreover, the targets developed from this study may provide more alternative targets for the development of a multisite system to effectively detect MTB in samples. PMID- 24058509 TI - Reproductive isolation between host races of Phytomyza glabricola on Ilex coriacea and I. glabra. AB - Recently diverged taxa often show discordance in genetic divergence among genomic loci, where some loci show strong divergence and others show none at all. Genetic studies alone cannot distinguish among the possible mechanisms but experimental studies on other aspects of divergence may provide guidance in the inference of causes of observed discordances. In this study, we used no-choice mating trials to test for the presence of reproductive isolation between host races of the leaf mining fly, Phytomyza glabricola on its two holly host species, Ilex coriacea and I. glabra. These trials inform our effort to determine the cause of significant differences in the degree of divergence of nuclear and mitochondrial loci of flies collected from the two host plants. We present evidence of reproductive isolation between host races in a controlled greenhouse setting: significantly more mate pairs consisting of flies from the same host plant species produced offspring than inter-host mate pairs, which produced no offspring. We also tested whether the presence of the natal or non-natal host plant affects reproductive success. Flies collected from I. coriacea were more likely to produce offspring when in the presence of the natal host, whereas the presence or absence of either the natal or non-natal host had no effect on flies collected from I. glabra. The results indicate discordant patterns of nuclear and mitochondrial divergence among host races of P. glabricola are likely due to incomplete lineage sorting, and the host races may be well on their way to becoming biological species. PMID- 24058510 TI - Aquaporin-3 and aquaporin-4 are sorted differently and separately in the trans Golgi network. AB - Aquaporin-3 (AQP3) and aquaporin-4 (AQP4) are homologous proteins expressed in the basolateral plasma membrane of kidney collecting duct principal cells, where they mediate the exit pathway for apically reabsorbed water. Although both proteins are localized to the same plasma membrane domain, it is unknown if they are sorted together in the Golgi, or arrive in the same or different vesicles at the plasma membrane. We addressed these questions using high resolution deconvolution imaging, spinning disk and laser scanning confocal microscopy of cells expressing AQP3 and AQP4. AQP3 and AQP4 were observed mostly in separate post-Golgi carriers, and spinning disk microscopy showed that most of AQP3 and AQP4 were delivered to the plasma membrane in separate vesicles. In contrast, VSV G and LDL-R, two well-characterized basolateral proteins, co-localized to a high degree in the same post-Golgi carriers, indicating that the differential sorting of AQP3 and AQP4 is specific and regulated. Significantly, a chimeric AQP3 containing the AQP4 cytoplasmic tails co-localized with AQP4 in post-Golgi vesicles. These results indicate that AQP3 and AQP4 are separated into different post-Golgi carriers based on different cytoplasmic domain sorting signals, and are then delivered separately to the plasma membrane. PMID- 24058511 TI - Transcriptional profiling of human monocytes identifies the inhibitory receptor CD300a as regulator of transendothelial migration. AB - Local inflammatory responses are characterized by the recruitment of circulating leukocytes from the blood to sites of inflammation, a process requiring the directed migration of leukocytes across the vessel wall and hence a penetration of the endothelial lining. To identify underlying signalling events and novel factors involved in these processes we screened for genes differentially expressed in human monocytes following their adhesion to and passage through an endothelial monolayer. Functional annotation clustering of the genes identified revealed an overrepresentation of those associated with inflammation/immune response, in particular early monocyte to macrophage differentiation. Among the gene products so far not implicated in monocyte transendothelial migration was the inhibitory immune receptor CD300a. CD300a mRNA and protein levels were upregulated following transmigration and engagement of the receptor by anti CD300a antibodies markedly reduced monocyte transendothelial migration. In contrast, siRNA mediated downregulation of CD300a in human monocytes increased their rate of migration. CD300a colocalized and cosedimented with actin filaments and, when activated, caused F-actin cytoskeleton alterations. Thus, monocyte transendothelial migration is accompanied by an elevation of CD300a which serves an inhibitory function possibly required for termination of the actual transmigration. PMID- 24058512 TI - Measuring fast-temporal sediment fluxes with an analogue acoustic sensor: a wind tunnel study. AB - In aeolian research, field measurements are important for studying complex wind driven processes for land management evaluation and model validation. Consequently, there have been many devices developed, tested, and applied to investigate a range of aeolian-based phenomena. However, determining the most effective application and data analysis techniques is widely debated in the literature. Here we investigate the effectiveness of two different sediment traps (the BEST trap and the MWAC catcher) in measuring vertical sediment flux. The study was performed in a wind tunnel with sediment fluxes characterized using saltiphones. Contrary to most studies, we used the analogue output of five saltiphones mounted on top of each other to determine the total kinetic energy, which was then used to calculate aeolian sediment budgets. Absolute sediment losses during the experiments were determined using a balance located beneath the test tray. Test runs were conducted with different sand sizes and at different wind speeds. The efficiency of the two traps did not vary with the wind speed or sediment size but was affected by both the experimental setup (position of the lowest trap above the surface and number of traps in the saltation layer) and the technique used to calculate the sediment flux. Despite this, good agreement was found between sediment losses calculated from the saltiphone and those measured using the balance. The results of this study provide a framework for measuring sediment fluxes at small time resolution (seconds to milliseconds) in the field. PMID- 24058513 TI - Molecular characterization of circulating respiratory syncytial virus (RSV) genotypes in Gilgit Baltistan Province of Pakistan during 2011-2012 winter season. AB - Respiratory syncytial virus (RSV) is the major cause of acute lower respiratory tract infections in young children, but very little is known about its epidemiology and circulating genotypes in Pakistan. This study analyzed the epidemiological and molecular characteristics of RSV genotypes detected in Pakistani children less than 2 years of age with acute respiratory tract infections (ARIs) in a tertiary care hospital in Gilgit Baltistan (GB) province during 2011-12 winter season. RSV was detected in 75 out of 105 children presenting with acute respiratory infection. Male infants between 2-6 months age made up the highest percentage of RSV positive cases. Epidemiological factors such as pre-maturity, mean weight, clinical features and diagnosis when compared between RSV positive and negative groups were found to be statistically insignificant. Phylogenetic analysis classified all 75 of the RSV strains into 71 strains of subgroups A and 4 strains of subgroup B, respectively. Strains belonging to subgroups A and B were further subdivided into NA1/GA2 and BA, respectively. The nucleotide and deduced amino acid sequence identities were relatively high among these strains (>90%). Both RSV-A and RSV-B isolates had two potential N-glycosylation sites in HVR2 of G protein and with heavy O glycosylation of serine and threonine residues (G scores of 0.5-0.7). This report highlights the significance of RSV as a dominant viral etiologic agent of pediatric ARIs, and need for continued molecular epidemiological surveys for early detection of prevalent strains and newly emerging genotypes to understand epidemiology of RSV infections in various regions of Pakistan. PMID- 24058514 TI - PET reveals inflammation around calcified Taenia solium granulomas with perilesional edema. AB - OBJECTIVE: Neurocysticercosis, an infection with the larval form of the tapeworm, Taeniasolium, is the cause of 29% of epilepsy in endemic regions. Epilepsy in this population is mostly associated with calcified granulomas; at the time of seizure recurrence 50% of those with calcifications demonstrate transient surrounding perilesional edema. Whether edema is consequence of the seizure, or a result of host inflammation directed against parasite antigens or other processes is unknown. To investigate whether perilesional edema is due to inflammation, we imaged a marker of neuroinflammation, translocater protein (TSPO), using positron emission tomography (PET) and the selective ligand (11)C-PBR28. METHODS: In nine patients with perilesional edema, degenerating cyst or both, PET findings were compared to the corresponding magnetic resonance images. Degenerating cysts were also studied because unlike perilesional edema, degenerating cysts are known to have inflammation. In three of the nine patients, changes in (11)C-PBR28 binding were also studied over time. (11)C-PBR28 binding was compared to the contralateral un-affected region. RESULTS: (11)C-PBR28 binding increased by a mean of 13% in perilesional edema or degenerating cysts (P = 0.0005, n = 13 in nine patients). Among these 13 lesions, perilesional edema (n=10) showed a slightly smaller increase of 10% compared to the contralateral side (P = 0.005) than the three degenerating cysts. In five lesions with perilesional edema in which repeated measurements of (11)C-PBR28 binding were done, increased binding lasted for 2-9 months. CONCLUSIONS: Increased TSPO in perilesional edema indicates an inflammatory etiology. The long duration of increased TSPO binding after resolution of the original perilesional edema and the pattern of periodic episodes is consistent with intermittent exacerbation from a continued baseline presence of low level inflammation. Novel anti-inflammatory measures may be useful in the prevention or treatment of seizures in this population. PMID- 24058515 TI - Association of insulin resistance with chronic kidney disease in non-diabetic subjects with normal weight. AB - OBJECTIVE: To the best of our knowledge, the association of insulin resistance (IR) with chronic kidney disease (CKD) has not been well studied in normal-weight individuals. The aim of this study is to examine whether IR is associated with CKD in non-diabetic subjects with normal weight. We also examine whether the presence of obesity modifies the association of IR with CKD. METHODS: Data were drawn from a cross-sectional survey in China. Both estimated glomerular filtration rate and urinary albumin to creatinine ratio were used as markers of CKD. Logistic regression models and the quartiles of homeostatic model assessment of insulin resistance were used to explore the associations of IR with CKD in entire cohort, normal-weight and overweight/obese subpopulations. RESULTS: In normal-weight subpopulation, the prevalence of IR and metabolic syndrome were 11.11% and 8.99%, respectively. In the entire cohort, the highest quartile HOMA insulin resistance had a 70% increased risk for CKD (RR 1.70, 95% CI 1.07, 2.71, P=0.03, comparing the highest to the lowest quartile). However, when adding obesity to the model, the association was abolished. IR was associated with CKD in overweight/obese subpopulation but not in normal-weight subpopulation. CONCLUSION: IR and MetS in normal-weight individuals is common in the Chinese population. IR is associated with CKD in overweight/obese subpopulation but not in normal-weight subpopulation and the presence of obesity modifies the association of IR with CKD. PMID- 24058516 TI - Alkaline pH Is a signal for optimal production and secretion of the heat labile toxin, LT in enterotoxigenic Escherichia coli (ETEC). AB - Enterotoxigenic Escherichia coli (ETEC) cause secretory diarrhea in children and travelers to endemic areas. ETEC spreads through the fecal-oral route. After ingestion, ETEC passes through the stomach and duodenum before it colonizes the lower part of the small intestine, exposing bacteria to a wide range of pH and environmental conditions. This study aimed to determine the impact of external pH and activity of the Cyclic AMP receptor protein (CRP) on the regulation of production and secretion of heat labile (LT) enterotoxin. ETEC strain E2863wt and its isogenic mutant E2863DeltaCRP were grown in LBK media buffered to pH 5, 7 and 9. GM1 ELISA, cDNA and cAMP analyses were carried out on bacterial pellet and supernatant samples derived from 3 and 5 hours growth and from overnight cultures. We confirm that CRP is a repressor of LT transcription and production as has been shown before but we show for the first time that CRP is a positive regulator of LT secretion both in vitro and in vivo. LT secretion increased at neutral to alkaline pH compared to acidic pH 5 where secretion was completely inhibited. At pH 9 secretion of LT was optimal resulting in 600 percent increase of secreted LT compared to unbuffered LBK media. This effect was not due to membrane leakage since the bacteria were viable at pH 9. The results indicate that the transition to the alkaline duodenum and/or exposure to high pH close to the epithelium as well as activation of the global transcription factor CRP are signals that induce secretion of the LT toxin in ETEC. PMID- 24058517 TI - Molecular detection of peripheral blood breast cancer mRNA transcripts as a surrogate biomarker for circulating tumor cells. AB - Circulating tumor cells (CTCs) are becoming a scientifically recognized indicator of primary tumors and/or metastasis. These cells can now be accurately detected and characterized as the result of technological advances. We analyzed the presence of CTCs in the peripheral blood of patients with metastatic breast cancer by real-time reverse-transcription PCR (RT-qPCR) using a panel of selected genes. The analysis of a single marker, without an EpCAM based enrichment approach, allowed the positive identification of 35% of the metastatic breast cancer patients. The analysis of five genes (SCGB2, TFF1, TFF3, Muc1, KRT20) performed in all the samples increased the detection to 61%. We describe a sensitive, reproducible and easy to implement approach to characterize CTC in patients with metastasic breast cancer. PMID- 24058518 TI - GOMoDo: A GPCRs online modeling and docking webserver. AB - G-protein coupled receptors (GPCRs) are a superfamily of cell signaling membrane proteins that include >750 members in the human genome alone. They are the largest family of drug targets. The vast diversity and relevance of GPCRs contrasts with the paucity of structures available: only 21 unique GPCR structures have been experimentally determined as of the beginning of 2013. User friendly modeling and small molecule docking tools are thus in great demand. While both GPCR structural predictions and docking servers exist separately, with GOMoDo (GPCR Online Modeling and Docking), we provide a web server to seamlessly model GPCR structures and dock ligands to the models in a single consistent pipeline. GOMoDo can automatically perform template choice, homology modeling and either blind or information-driven docking by combining together proven, state of the art bioinformatic tools. The web server gives the user the possibility of guiding the whole procedure. The GOMoDo server is freely accessible at http://molsim.sci.univr.it/gomodo. PMID- 24058520 TI - Punishment sensitivity predicts the impact of punishment on cognitive control. AB - Cognitive control theories predict enhanced conflict adaptation after punishment. However, no such effect was found in previous work. In the present study, we demonstrate in a flanker task how behavioural adjustments following punishment signals are highly dependent on punishment sensitivity (as measured by the Behavioural Inhibition System (BIS) scale): Whereas low punishment-sensitive participants do show increased conflict adaptation after punishment, high punishment-sensitive participants show no such modulation. Interestingly, participants with a high punishment-sensitivity showed an overall reaction time increase after punishments. Our results stress the role of individual differences in explaining motivational modulations of cognitive control. PMID- 24058519 TI - Development of novel 123I-labeled pyridyl benzofuran derivatives for SPECT imaging of beta-amyloid plaques in Alzheimer's disease. AB - Imaging of beta-amyloid (Abeta) plaques in the brain may facilitate the diagnosis of cerebral beta-amyloidosis, risk prediction of Alzheimer's disease (AD), and effectiveness of anti-amyloid therapies. The purpose of this study was to evaluate novel (123)I-labeled pyridyl benzofuran derivatives as SPECT probes for Abeta imaging. The formation of a pyridyl benzofuran backbone was accomplished by Suzuki coupling. [(123)I/(125)I]-labeled pyridyl benzofuran derivatives were readily prepared by an iododestannylation reaction. In vitro Abeta binding assays were carried out using Abeta(1-42) aggregates and postmortem human brain sections. Biodistribution experiments were conducted in normal mice at 2, 10, 30, and 60 min postinjection. Abeta labeling in vivo was evaluated by small-animal SPECT/CT in Tg2576 transgenic mice injected with [(123)I]8. Ex vivo autoradiography of the brain sections was performed after SPECT/CT. Iodinated pyridyl benzofuran derivatives showed excellent affinity for Abeta(1-42) aggregates (2.4 to 10.3 nM) and intensely labeled Abeta plaques in autoradiographs of postmortem AD brain sections. In biodistribution experiments using normal mice, all these derivatives displayed high initial uptake (4.03 5.49% ID/g at 10 min). [(125)I]8 displayed the quickest clearance from the brain (1.30% ID/g at 60 min). SPECT/CT with [(123)I]8 revealed higher uptake of radioactivity in the Tg2576 mouse brain than the wild-type mouse brain. Ex vivo autoradiography showed in vivo binding of [(123)I]8 to Abeta plaques in the Tg2576 mouse brain. These combined results warrant further investigation of [(123)I]8 as a SPECT imaging agent for visualizing Abeta plaques in the AD brain. PMID- 24058521 TI - Biological evaluation of the copper/low-density polyethylene nanocomposite intrauterine device. AB - Devices and materials intended for clinical applications as medical and implant devices should be evaluated to determine their biocompatibility in physiological systems. This article presents results from cytotoxicity assay of L929 mouse fibroblasts culture, tests for skin irritation, intracutaneous reactivity and sensitization, and material implantation tests for the novel copper/low-density polyethylene nanocomposite intrauterine device (nano-Cu/LDPE IUD) with potential for future clinical utilization. Cytotoxicity test in vitro was conducted to evaluate the change in morphology, growth and proliferation of cultured L929 mouse fibroblasts, which in vivo examination for skin irritation (n = 6) and intracutaneous reactivity (n = 6) were carried out to explore the irritant behavior in New Zealand White rabbits. Skin sensitization was implemented to evaluate the potential skin sensitizing in Hartley guinea pigs (n = 35). The materials were implanted into the spinal muscle of rabbits (n = 9). The cytotoxicity grade of the nano-Cu/LDPE IUD was 0-1, suggested that the composite was nontoxic or mildly cytotoxic; no irritation reaction and skin sensitization were identified in any animals of specific extracts prepared from the material under test; similarly to the control sides, the inflammatory reaction was observed in the rabbits living tissue of the implanted material in intramuscular implantation assay. They indicated that the novel composite intrauterine device presented potential for this type of application because they meet the requirements of the standard practices recommended for evaluating the biological reactivity. The nano-Cu/LDPE IUD has good biocompatibility, which is biologically safe for the clinical research as a novel contraceptive device. PMID- 24058522 TI - Therapeutic outcome of fluorescence cystoscopy guided transurethral resection in patients with non-muscle invasive bladder cancer: a meta-analysis of randomized controlled trials. AB - OBJECTIVES: To conduct a meta-analysis of randomized controlled trials (RCTs) to assess the therapeutic outcome of fluorescence cystoscopy (FC) guided transurethral resection (TUR) in non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: Relevant RCTs were identified from electronic database (MEDLINE, Embase and the Cochrane Library). The proceedings of relevant congress were also searched. The primary parameters were recurrence rate, the time to fist recurrence, recurrence free survival rate (RFS) and progression rate. RESULTS: 12 RCTs including 2258 patients, which were identified for analysis in our study. Our study showed that the FC group have lower recurrence rate than the white light cystoscopy (WLC) group with statistically significant difference (OR: 0.5; p<0.00001). The time of the FC group first recurrence delayed significantly 7.39 weeks than WLC group (MD: 7.39 weeks; p<0.0001). There was a statistically significant difference in favor of FC in RFS at 1 yr (HR: 0.69; p<0.00001) and 2 yrs (HR: 0.65; p=0.0004). However, the FC group cannot significantly reduce the rate of progression into muscle invasive bladder cancer compared with the WLC group (OR: 0.85; p=0.39). CONCLUSIONS: FC guided TUR was demonstrated to be an effective procedure for delaying recurrence of NMIBC. Unfortunately, FC guided TUR could not significantly decrease the rate of progression into muscle invasive bladder cancer. PMID- 24058523 TI - Normative data of the EORTC QLQ-C30 for the German population: a population-based survey. AB - AIM: The aim of the present study was to generate up-to-date normative data for health-related quality of life (QoL) measured with the "European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ C30)" in a random sample of the population in Northern Germany. METHODS: We conducted a population-based survey of a random sample of 10,000 persons aged 16 years or older. The postal questionnaire included questions regarding lifetime prevalence of common diseases and quality of life. EORTC QLQ-C30 scales were scored according to standard procedures. The results were stratified for age and sex. RESULTS: The questionnaire was completed by 4,684 (47%) of 9,928 eligible persons. Mean age of the participants was 51.7 years (standard deviation: 18.5) and 57% were females. Missing values for the EORTC QLQ-C30 scales and items were sparse (minimum: 0.2%, maximum: 1.5%). Self-reported health related QoL varied by age and sex. Generally, men reported better functioning and fewer symptoms than women. In both sexes function declined and symptoms increased with increasing age. Symptoms most frequently reported were fatigue, pain and insomnia. Compared to the German reference data published in 2001 our participants scored more than 10 points higher on the latter three scales/items. The most frequently reported diseases were hypertension (36%), hyperlipidemia (26%) and arthritis (30%). Lifetime prevalence of depression was 16% in women and 11% in men. CONCLUSION: Our study participants are representative for the German general population with regard to age, sex and education. Of special interest is the high proportion of participants reporting depression which is also mirrored by high fatigue, pain and insomnia scores. The normative data provided should be used as comparison health-related QoL data when evaluating the QoL in German cancer patients. PMID- 24058524 TI - Label retaining cells (LRCs) with myoepithelial characteristic from the proximal acinar region define stem cells in the sweat gland. AB - Slow cycling is a common feature shared among several stem cells (SCs) identified in adult tissues including hair follicle and cornea. Recently, existence of unipotent SCs in basal and lumenal layers of sweat gland (SG) has been described and label retaining cells (LRCs) have also been localized in SGs; however, whether these LRCs possess SCs characteristic has not been investigated further. Here, we used a H2BGFP LRCs system for in vivo detection of infrequently dividing cells. This system allowed us to specifically localize and isolate SCs with label retention and myoepithelial characteristics restricted to the SG proximal acinar region. Using an alternative genetic approach, we demonstrated that SG LRCs expressed keratin 15 (K15) in the acinar region and lineage tracing determined that K15 labeled cells contributed long term to the SG structure but not to epidermal homeostasis. Surprisingly, wound healing experiments did not activate proximal acinar SG cells to participate in epidermal healing. Instead, predominantly non-LRCs in the SG duct actively divided, whereas the majority of SG LRCs remained quiescent. However, when we further challenged the system under more favorable isolated wound healing conditions, we were able to trigger normally quiescent acinar LRCs to trans-differentiate into the epidermis and adopt its long term fate. In addition, dissociated SG cells were able to regenerate SGs and, surprisingly, hair follicles demonstrating their in vivo plasticity. By determining the gene expression profile of isolated SG LRCs and non-LRCs in vivo, we identified several Bone Morphogenetic Protein (BMP) pathway genes to be up-regulated and confirmed a functional requirement for BMP receptor 1A (BMPR1A)-mediated signaling in SG formation. Our data highlight the existence of SG stem cells (SGSCs) and their primary importance in SG homeostasis. It also emphasizes SGSCs as an alternative source of cells in wound healing and their plasticity for regenerating different skin appendages. PMID- 24058525 TI - Diabetes protects from prostate cancer by downregulating androgen receptor: new insights from LNCaP cells and PAC120 mouse model. AB - Type 2 diabetes has been associated with decreased risk of prostate cancer in observational studies, and this inverse association has been recently confirmed in several large cohort studies. However the mechanisms involved in this protective effect remain to be elucidated. The aim of the present study was to explore whether different features of type 2 diabetes (hyperinsulinemia, hyperglycemia and tumor necrosis factor alpha [TNF-alpha]) protect against the development of prostate cancer. For this purpose LNCaP cells were used for in vitro experiments and nude mice in which PAC120 (hormone-dependent human prostate cancer) xenografts had been implanted were used for in vivo examinations. We provide evidence that increasing glucose concentrations downregulate androgen receptor (AR) mRNA and protein levels through NF-kappaB activation in LNCaP cells. Moreover, there was a synergic effect of glucose and TNFalpha in downregulating the AR in LNCaP cells. By contrast, insulin had no effect on AR regulation. In vivo experiments showed that streptozotocin-induced diabetes (STZ DM) produces tumor growth retardation and a significant reduction in AR expression in PAC120 prostate cancer mice. In conclusion, our results suggest that hyperglycemia and TNF-alpha play an important role in protecting against prostate cancer by reducing androgen receptor levels via NF-kappaB. PMID- 24058526 TI - Genome-wide meta-analysis of systolic blood pressure in children with sickle cell disease. AB - In pediatric sickle cell disease (SCD) patients, it has been reported that higher systolic blood pressure (SBP) is associated with increased risk of a silent cerebral infarction (SCI). SCI is a major cause of neurologic morbidity in children with SCD, and blood pressure is a potential modulator of clinical manifestations of SCD; however, the risk factors underlying these complications are not well characterized. The aim of this study was to identify genetic variants that influence SBP in an African American population in the setting of SCD, and explore the use of SBP as an endo-phenotype for SCI. We conducted a genome-wide meta-analysis for SBP using two SCD cohorts, as well as a candidate screen based on published SBP loci. A total of 1,617 patients were analyzed, and while no SNP reached genome-wide significance (P-value<5.0 x 10(-8)), a number of suggestive candidate loci were identified. The most significant SNP, rs7952106 (P value=8.57 x 10(-7)), was in the DRD2 locus on chromosome 11. In a gene-based association analysis, MIR4301 (micro-RNA4301), which resides in an intron of DRD2, was the most significant gene (P-value=5.2 x 10(-5)). Examining 27 of the previously reported SBP associated SNPs, 4 SNPs were nominally significant. A genetic risk score was constructed to assess the aggregated genetic effect of the published SBP variants, demonstrating a significant association (P=0.05). In addition, we also assessed whether these variants are associated with SCI, validating the use of SBP as an endo-phenotype for SCI. Three SNPs were nominally associated, and only rs2357790 (5' CACNB2) was significant for both SBP and SCI. None of these SNPs retained significance after Bonferroni correction. Taken together, our results suggest the importance of DRD2 genetic variation in the modulation of SBP, and extend the aggregated importance of previously reported SNPs in the modulation of SBP in an African American cohort, more specifically in children with SCD. PMID- 24058527 TI - Chronic pain with neuropathic characteristics in diabetic patients: a French cross-sectional study. AB - OBJECTIVE: Our aim was to estimate the prevalence of distal chronic pain with neuropathic characteristics in patients with type 1 and type 2 diabetes mellitus and its impact on quality of life, mood, anxiety, sleep and healthcare utilization. METHODS: In total, 885 patients were screened and 766 diabetic patients (38.7% with type 1 diabetes mellitus, 44.8% women, mean age: 57.2 +/- 14.9 years) were enrolled consecutively over a three-month period in this observational study by 85 diabetes specialists working in a hospital department or in private practice. All the patients completed a series of questionnaires for the detection of chronic pain (i.e. daily pain for more than three months) in the lower limbs and assessment of health-related quality of life (Medical Outcomes Short Form 12 scale), sleep disturbances (MOS sleep scale), depression and anxiety (Hospital Anxiety and Depression scale). Patients with chronic pain were also assessed with the 7-item DN4-interview questionnaire, the monofilament test and the Michigan Neuropathy Screening Instrument (MNSI). RESULTS: The overall prevalence of chronic pain with neuropathic characteristics was 20.3% [95% CI 17.4-23.1]. The MNSI examination score suggested that pain was related to polyneuropathy, in 80.1% of these patients (89.5% of those with bilateral pain). Patients with chronic pain had a poorer quality of life and more sleep disturbances, anxiety and depression than patients without pain and the presence of neuropathic characteristics was predictive of such impairments. Only 38.6% of the patients had received appropriate treatment for neuropathic pain. CONCLUSIONS: Chronic pain with neuropathic characteristics concerns one in five diabetic patients, has a significant impact on quality of life and is not adequately managed. The close correlation between the DN4 questionnaire and MNSI results suggests that screening tools for neuropathic pain could be used in daily practice for the identification of painful diabetic polyneuropathy. PMID- 24058528 TI - Direct cloning of isogenic murine DNA in yeast and relevance of isogenicity for targeting in embryonic stem cells. AB - Efficient gene targeting in embryonic stem cells requires that modifying DNA sequences are identical to those in the targeted chromosomal locus. Yet, there is a paucity of isogenic genomic clones for human cell lines and PCR amplification cannot be used in many mutation-sensitive applications. Here, we describe a novel method for the direct cloning of genomic DNA into a targeting vector, pRTVIR, using oligonucleotide-directed homologous recombination in yeast. We demonstrate the applicability of the method by constructing functional targeting vectors for mammalian genes Uhrf1 and Gfap. Whereas the isogenic targeting of the gene Uhrf1 showed a substantial increase in targeting efficiency compared to non-isogenic DNA in mouse E14 cells, E14-derived DNA performed better than the isogenic DNA in JM8 cells for both Uhrf1 and Gfap. Analysis of 70 C57BL/6-derived targeting vectors electroporated in JM8 and E14 cell lines in parallel showed a clear dependence on isogenicity for targeting, but for three genes isogenic DNA was found to be inhibitory. In summary, this study provides a straightforward methodological approach for the direct generation of isogenic gene targeting vectors. PMID- 24058529 TI - Molecular analysis of the processes of surface brown spot (SBS) formation in pear fruit (Pyrus bretschneideri Rehd. cv. Dangshansuli) by de novo transcriptome assembly. AB - Browning disorder, which usually occurs post-harvest in pears subjected to long term storage, can cause browning of the pear flesh and/or core. In 2011, investigators in China found a novel type of brown spot (designated as surface brown spot, SBS) in pre-harvest 'Dangshansuli' pears (Pyrus bretschneideri Rehd.). SBS has a large impact on the exterior quality of the pears. Interestingly, the brown coloration was only found on the peel and not the flesh or the core. In this paper, de novo transcriptome analysis of the exocarp of pears with SBS using Illumina sequencing showed that SBS up-regulated the expression of genes related to oxidative phosphorylation, phenolic compound synthesis and polyphenoloxidase (PPO), and SBS was associated with inhibition of primary and secondary metabolism genes. Ca(2+)-sensor proteins might be involved in the signal transduction that occurs during the process of SBS formation, and this signaling is likely to be regulated by H2O2, abscisic acid (ABA) and gibberellic acid (GA3). Phytohormone and mineral element analyses confirmed that GA3, ABA, H2O2 and Ca(2+) contribute to SBS formation. In addition to the seasonal characteristics, low levels of O2 and Ca(2+) in the fruit are potential causes of the browning response due to exposure to oxidative stress, oxidative reductive imbalance and the accumulation of reactive oxygen species (ROS), which affected the membrane integrity. Disruption of the membranes allows for PPO and phenolic compounds to come into contact, and the phenolic compounds are oxidized to form the browning pigments. PMID- 24058530 TI - Effects of ascent to high altitude on human antimycobacterial immunity. AB - BACKGROUND: Tuberculosis infection, disease and mortality are all less common at high than low altitude and ascent to high altitude was historically recommended for treatment. The immunological and mycobacterial mechanisms underlying the association between altitude and tuberculosis are unclear. We studied the effects of altitude on mycobacteria and antimycobacterial immunity. METHODS: Antimycobacterial immunity was assayed in 15 healthy adults residing at low altitude before and after they ascended to 3400 meters; and in 47 long-term high altitude residents. Antimycobacterial immunity was assessed as the extent to which participants' whole blood supported or restricted growth of genetically modified luminescent Bacille Calmette-Guerin (BCG) mycobacteria during 96 hours incubation. We developed a simplified whole blood assay that could be used by a technician in a low-technology setting. We used this to compare mycobacterial growth in participants' whole blood versus positive-control culture broth and versus negative-control plasma. RESULTS: Measurements of mycobacterial luminescence predicted the number of mycobacterial colonies cultured six weeks later. At low altitude, mycobacteria grew in blood at similar rates to positive control culture broth whereas ascent to high altitude was associated with restriction (p <= 0.002) of mycobacterial growth to be 4-times less than in culture broth. At low altitude, mycobacteria grew in blood 25-times more than negative-control plasma whereas ascent to high altitude was associated with restriction (p <= 0.01) of mycobacterial growth to be only 6-times more than in plasma. There was no evidence of differences in antimycobacterial immunity at high altitude between people who had recently ascended to high altitude versus long-term high-altitude residents. CONCLUSIONS: An assay of luminescent mycobacterial growth in whole blood was adapted and found to be feasible in low resource settings. This demonstrated that ascent to or residence at high altitude was associated with decreased mycobacterial growth in whole blood relative to controls, consistent with altitude-related augmentation of antimycobacterial cellular immunity. PMID- 24058531 TI - Stress responsive proteins are actively regulated during rice (Oryza sativa) embryogenesis as indicated by quantitative proteomics analysis. AB - Embryogenesis is the initial step in a plant's life, and the molecular changes that occur during embryonic development are largely unknown. To explore the relevant molecular events, we used the isobaric tags for relative and absolute quantification (iTRAQ) coupled with the shotgun proteomics technique (iTRAQ/Shotgun) to study the proteomic changes of rice embryos during embryogenesis. For the first time, a total of 2 165 unique proteins were identified in rice embryos, and the abundances of 867 proteins were actively changed based on the statistical evaluation of the quantitative MS/MS signals. The quantitative data were then confirmed using multiple reactions monitoring (MRM) and were also supported by our previous study based on two-dimensional gel electrophoresis (2 DE). Using the proteome at 6 days after pollination (DAP) as a reference, cluster analysis of these differential proteins throughout rice embryogenesis revealed that 25% were up-regulated and 75% were down-regulated. Gene Ontology (GO) analysis implicated that most of the up-regulated proteins were functionally categorized as stress responsive, mainly including heat shock-, lipid transfer-, and reactive oxygen species-related proteins. The stress responsive proteins were thus postulated to play an important role during seed maturation. PMID- 24058532 TI - Detection of phospho-sites generated by protein kinase CK2 in CFTR: mechanistic aspects of Thr1471 phosphorylation. AB - By mass spectrometry analysis of mouse Cystic Fibrosis Transmembrane-conductance Regulator (mCFTR) expressed in yeast we have detected 21 phosphopeptides accounting for 22 potential phospho-residues, 12 of which could be unambiguously assigned. Most are conserved in human CFTR (hCFTR) and the majority cluster in the Regulatory Domain, lying within consensus sequences for PKA, as identified in previous mammalian studies. This validates our yeast expression model. A number of phospho-residues were novel and human conserved, notably mouse Ser670, Ser723, Ser737, and Thr1467, that all lie in acidic sequences, compatible with their phosphorylation by protein kinase CK2. Thr1467 is localized in the C-terminal tail, embedded in a functionally important and very acidic sequence (EETEEE) which displays an optimal consensus for protein kinase CK2. Herein, we show that Thr1467, homologous to human Thr1471 is readily phosphorylated by CK2. Indeed a 42 amino acid peptide encompassing the C-terminal segment of human CFTR is readily phosphorylated at Thr1471 with favorable kinetics (Km 1.7 uM) by CK2 holoenzyme, but neither by its isolated catalytic subunit nor by other acidophilic Ser/Thr kinases (CK1, PLK2/3, GCK/FAM20C). Our finding that by treating CFTR expressing BHK cells with the very specific CK2 inhibitor CX4945, newly synthesized wild type CFTR (and even more its Phe508del mutant) accumulates more abundantly than in the absence of CK2 inhibitor, supports the conclusion that phosphorylation of CFTR by CK2 correlates with decreased stability of the protein. PMID- 24058533 TI - Ca2+ influx and tyrosine kinases trigger Bordetella adenylate cyclase toxin (ACT) endocytosis. Cell physiology and expression of the CD11b/CD18 integrin major determinants of the entry route. AB - Humans infected with Bordetella pertussis, the whooping cough bacterium, show evidences of impaired host defenses. This pathogenic bacterium produces a unique adenylate cyclase toxin (ACT) which enters human phagocytes and catalyzes the unregulated formation of cAMP, hampering important bactericidal functions of these immune cells that eventually cause cell death by apoptosis and/or necrosis. Additionally, ACT permeabilizes cells through pore formation in the target cell membrane. Recently, we demonstrated that ACT is internalised into macrophages together with other membrane components, such as the integrin CD11b/CD18 (CR3), its receptor in these immune cells, and GM1. The goal of this study was to determine whether ACT uptake is restricted to receptor-bearing macrophages or on the contrary may also take place into cells devoid of receptor and gain more insights on the signalling involved. Here, we show that ACT is rapidly eliminated from the cell membrane of either CR3-positive as negative cells, though through different entry routes, which depends in part, on the target cell physiology and characteristics. ACT-induced Ca(2+) influx and activation of non-receptor Tyr kinases into the target cell appear to be common master denominators in the different endocytic strategies activated by this toxin. Very importantly, we show that, upon incubation with ACT, target cells are capable of repairing the cell membrane, which suggests the mounting of an anti-toxin cell repair-response, very likely involving the toxin elimination from the cell surface. PMID- 24058534 TI - Next-generation sequencing of HIV-1 RNA genomes: determination of error rates and minimizing artificial recombination. AB - Next-generation sequencing (NGS) is a valuable tool for the detection and quantification of HIV-1 variants in vivo. However, these technologies require detailed characterization and control of artificially induced errors to be applicable for accurate haplotype reconstruction. To investigate the occurrence of substitutions, insertions, and deletions at the individual steps of RT-PCR and NGS, 454 pyrosequencing was performed on amplified and non-amplified HIV-1 genomes. Artificial recombination was explored by mixing five different HIV-1 clonal strains (5-virus-mix) and applying different RT-PCR conditions followed by 454 pyrosequencing. Error rates ranged from 0.04-0.66% and were similar in amplified and non-amplified samples. Discrepancies were observed between forward and reverse reads, indicating that most errors were introduced during the pyrosequencing step. Using the 5-virus-mix, non-optimized, standard RT-PCR conditions introduced artificial recombinants in a fraction of at least 30% of the reads that subsequently led to an underestimation of true haplotype frequencies. We minimized the fraction of recombinants down to 0.9-2.6% by optimized, artifact-reducing RT-PCR conditions. This approach enabled correct haplotype reconstruction and frequency estimations consistent with reference data obtained by single genome amplification. RT-PCR conditions are crucial for correct frequency estimation and analysis of haplotypes in heterogeneous virus populations. We developed an RT-PCR procedure to generate NGS data useful for reliable haplotype reconstruction and quantification. PMID- 24058535 TI - Runx1 is critical for PTH-induced onset of mesenchymal progenitor cell chondrogenic differentiation. AB - Parathyroid hormone (PTH) plays a critical role in the regulation of chondrogenesis. In this study, we have found for the first time that Runt-related transcription factor 1 (Runx1) contributes to PTH-induced chondrogenesis. Upon PTH treatment, limb bud mesenchymal progenitor cells in micromass culture showed an enhanced chondrogenesis, which was associated with a significant increase of chondrogenic marker gene expression, such as type II collagen and type X collagen. Runx1 was also exclusively expressed in cells treated with PTH at the onset stage of chondrogenesis. Knockdown of Runx1 completely blunted PTH-mediated chondrogenesis. Furthermore, PTH induced Runx1 expression and chondrogenesis were markedly reduced by inhibition of protein kinase A (PKA) signaling. Taken together, our present study indicates that chondrogenesis induced by PTH in mesenchymal progenitor cells is mediated by Runx1, which involves the activation of PKA. These data provide a novel insight into understanding the molecular mechanisms behind PTH-enhanced cartilage regeneration. PMID- 24058536 TI - Pathogenic mouse hepatitis virus or poly(I:C) induce IL-33 in hepatocytes in murine models of hepatitis. AB - The IL-33/ST2 axis is known to be involved in liver pathologies. Although, the IL 33 levels increased in sera of viral hepatitis patients in human, the cellular sources of IL-33 in viral hepatitis remained obscure. Therefore, we aimed to investigate the expression of IL-33 in murine fulminant hepatitis induced by a Toll like receptor (TLR3) viral mimetic, poly(I:C) or by pathogenic mouse hepatitis virus (L2-MHV3). The administration of poly(I:C) plus D-galactosamine (D-GalN) in mice led to acute liver injury associated with the induction of IL-33 expression in liver sinusoidal endothelial cells (LSEC) and vascular endothelial cells (VEC), while the administration of poly(I:C) alone led to hepatocyte specific IL-33 expression in addition to vascular IL-33 expression. The hepatocyte-specific IL-33 expression was down-regulated in NK-depleted poly(I:C) treated mice suggesting a partial regulation of IL-33 by NK cells. The CD1d KO (NKT deficient) mice showed hepatoprotection against poly(I:C)-induced hepatitis in association with increased number of IL-33 expressing hepatocytes in CD1d KO mice than WT controls. These results suggest that hepatocyte-specific IL-33 expression in poly(I:C) induced liver injury was partially dependent of NK cells and with limited role of NKT cells. In parallel, the L2-MHV3 infection in mice induced fulminant hepatitis associated with up-regulated IL-33 expression as well as pro-inflammatory cytokine microenvironment in liver. The LSEC and VEC expressed inducible expression of IL-33 following L2-MHV3 infection but the hepatocyte-specific IL-33 expression was only evident between 24 to 32h of post infection. In conclusion, the alarmin cytokine IL-33 was over-expressed during fulminant hepatitis in mice with LSEC, VEC and hepatocytes as potential sources of IL-33. PMID- 24058537 TI - Effects of elaidic acid on lipid metabolism in HepG2 cells, investigated by an integrated approach of lipidomics, transcriptomics and proteomics. AB - Trans fatty acid consumption in the human diet can cause adverse health effects, such as cardiovascular disease, which is associated with higher total cholesterol, a higher low density lipoprotein-cholesterol level and a decreased high density lipoprotein-cholesterol level. The aim of the study was to elucidate the hepatic response to the most abundant trans fatty acid in the human diet, elaidic acid, to help explain clinical findings on the relationship between trans fatty acids and cardiovascular disease. The human HepG2 cell line was used as a model to investigate the hepatic response to elaidic acid in a combined proteomic, transcriptomic and lipidomic approach. We found many of the proteins responsible for cholesterol synthesis up-regulated together with several proteins involved in the esterification and hepatic import/export of cholesterol. Furthermore, a profound remodeling of the cellular membrane occurred at the phospholipid level. Our findings contribute to the explanation on how trans fatty acids from the diet can cause modifications in plasma cholesterol levels by inducing abundance changes in several hepatic proteins and the hepatic membrane composition. PMID- 24058538 TI - Contribution of toll-like receptor 2 to the innate response against Staphylococcus aureus infection in mice. AB - Staphylococcus aureus is a common pathogen that causes a wide range of infectious diseases. The function of TLRs, specifically TLR2, during S. aureus infection is still debated. In this study, we investigated the extent to which TLR2 contributes to the host innate response against the bacterial infection using TLR2-deficient mice. Intravenous inoculation with S. aureus resulted in all TLR2 deficient mice dying within 4 d, along with a high bacterial burden in the livers. However, histological examination showed the same degree of macrophage and neutrophil accumulation in the livers of infected TLR2-deficient mice as that in infected wild-type (WT) mice. TLR2-deficient mouse macrophages also showed normal phagocytic activity, although they failed to express CD36 that appeared on the surface of WT mouse cells upon challenge with heat-killed S. aureus. These data indicate that TLR2, as well as CD36, does not directly affect S. aureus clearance and that CD36 expression on macrophages depends on the presence of TLR2. In vivo infection with S. aureus caused significantly elevated production of TNF-alpha and IL-6 in the livers and blood of TLR2-deficient mice compared with those in WT mice, while the hepatic and serum levels of IL-10 decreased in these mice. In contrast, lower expression of IL-6 and IL-10, but not of TNF alpha, at both the gene and protein levels was found in TLR2-deficient mouse macrophages compared to that in WT mouse cells, in response to challenge with heat-killed S. aureus. These findings suggest that the S. aureus-induced pro inflammatory cytokine response is not dependent on macrophages and that TLR2 deficiency results in decreased IL-10 release by macrophages, which contributes to dysregulated cytokine balance, impaired bacterial clearance, and mouse death. Therefore, TLR2 possesses a protective function during S. aureus infection by regulating pro- and anti-inflammatory cytokine responses. PMID- 24058539 TI - Loose binding of the DF axis with the A3B3 complex stimulates the initial activity of Enterococcus hirae V1-ATPase. AB - Vacuolar ATPases (V-ATPases) function as proton pumps in various cellular membrane systems. The hydrophilic V1 portion of the V-ATPase is a rotary motor, in which a central-axis DF complex rotates inside a hexagonally arranged catalytic A3B3 complex by using ATP hydrolysis energy. We have previously reported crystal structures of Enterococcushirae V-ATPase A3B3 and A3B3DF (V1) complexes; the result suggested that the DF axis induces structural changes in the A3B3 complex through extensive protein-protein interactions. In this study, we mutated 10 residues at the interface between A3B3 and DF complexes and examined the ATPase activities of the mutated V1 complexes as well as the binding affinities between the mutated A3B3 and DF complexes. Surprisingly, several V1 mutants showed higher initial ATPase activities than wild-type V1-ATPase, whereas these mutated A3B3 and DF complexes showed decreased binding affinities for each other. However, the high ATP hydrolysis activities of the mutants decreased faster over time than the activity of the wild-type V1 complex, suggesting that the mutants were unstable in the reaction because the mutant A3B3 and DF complexes bound each other more weakly. These findings suggest that strong interaction between the DF complex and A3B3 complex lowers ATPase activity, but also that the tight binding is responsible for the stable ATPase activity of the complex. PMID- 24058541 TI - The role of N-glycosylation in folding, trafficking, and functionality of lysosomal protein CLN5. AB - CLN5 is a soluble lysosomal protein with unknown function. Mutations in CLN5 lead to neuronal ceroid lipofuscinosis, a group of inherited neurodegenerative disorders that mainly affect children. CLN5 has eight potential N-glycosylation sites based on the Asn-X-Thr/Ser consensus sequence. Through site-directed mutagenesis of individual asparagine residues to glutamine on each of the N glycosylation consensus sites, we showed that all eight putative N-glycosylation sites are utilized in vivo. Additionally, localization studies showed that the lack of N-glycosylation on certain sites (N179, N252, N304, or N320) caused CLN5 retention in the endoplasmic reticulum, indicating that glycosylation is important for protein folding. Interestingly, one particular mutant, N401Q, is mislocalized to the Golgi, suggesting that N401 is not important for protein folding but essential for CLN5 trafficking to the lysosome. Finally, we analyzed several patient mutations in which N-glycosylation is affected. The N192S patient mutant is localized to the lysosome, indicating that this mutant has a functional defect in the lysosome. Our results suggest that there are functional differences in various N-glycosylation sites of CLN5 which affect folding, trafficking, and lysosomal function of CLN5. PMID- 24058542 TI - Fluorescent advanced glycation end products and their soluble receptor: the birth of new plasmatic biomarkers for risk stratification of acute coronary syndrome. AB - OBJECTIVE: Advanced glycation end products (AGEs) have pathophysiological implications in cardiovascular diseases. The aim of our study was to evaluate the prognostic value of fluorescent AGEs and its soluble receptor (sRAGE) in the context of acute coronary syndrome (ACS), both in-hospital phase and follow-up period. METHODS: A prospective clinical study was performed in patients with debut's ACS. The endpoints were the development of cardiac events (cardiac deaths, re-infarction and new-onset heart failure) during in-hospital phase and follow-up period (366 days, inter-quartile range: 273-519 days). 215 consecutive ACS patients admitted to the coronary care unit (62.7+/-13.0 years, 24.2% female) were included. 47.4% had a diagnosis of ST segment elevation myocardial infarction. AGEs and sRAGE were analysed by fluorescence spectroscopy and competitive ELISA, respectively. Risk scores (GRACE, TIMI, PURSUIT) were calculated retrospectively using prospective data. The complexity of coronary artery disease was evaluated by SYNTAX score. RESULTS: The mean fluorescent AGEs and sRAGE levels were 57.7+/-45.1 AU and 1045.4+/-850.0 pg/mL, respectively. 19 patients presented cardiac events during in-hospital phase and 29 during the follow-up. In-hospital cardiac events were significantly associated with higher sRAGE levels (p = 0.001), but not long-term cardiac events (p = 0.365). Regarding fluorescent AGE the opposite happened. After multivariate analysis correcting by gender, left ventricular ejection fraction, glucose levels, haemoglobin, GRACE and SYNTAX scores, sRAGE was significantly associated with in-hospital prognosis, whereas fluorescent AGEs was significantly associated with long-term prognosis. CONCLUSIONS: We conclude that elevated values of sRAGE are associated with worse in-hospital prognosis, whereas high fluorescent AGE levels are associated with more follow-up events. PMID- 24058540 TI - Plasticity of blood- and lymphatic endothelial cells and marker identification. AB - The distinction between lymphatic and blood vessels is biologically fundamental. Here we wanted to rigorously analyze the universal applicability of vascular markers and characteristics of the two widely used vascular model systems human microvascular endothelial cell line-1 (HMEC-1) and telomerase-immortalized microvascular endothelial cell line (TIME). Therefore we studied the protein expression and functional properties of the endothelial cell lines HMEC-1 and TIME by flow cytometry and in vitro flow assays. We then performed microarray analyses of the gene expression in these two cell lines and compared them to primary endothelial cells. Using bioinformatics we then defined 39 new, more universal, endothelial-type specific markers from 47 primary endothelial microarray datasets and validated them using immunohistochemistry with normal and pathological tissues. We surprisingly found that both HMEC-1 and TIME are hybrid blood- and lymphatic cells. In addition, we discovered great discrepancies in the previous identifications of blood- and lymphatic endothelium-specific genes. Hence we identified and validated new, universally applicable vascular markers. Summarizing, the hybrid blood-lymphatic endothelial phenotype of HMEC-1 and TIME is indicative of plasticity in the gene expression of immortalized endothelial cell lines. Moreover, we identified new, stable, vessel-type specific markers for blood- and lymphatic endothelium, useful for basic research and clinical diagnostics. PMID- 24058543 TI - Microstructural and compositional features of the fibrous and hyaline cartilage on the medial tibial plateau imply a unique role for the hopping locomotion of kangaroo. AB - Hopping provides efficient and energy saving locomotion for kangaroos, but it results in great forces in the knee joints. A previous study has suggested that a unique fibrous cartilage in the central region of the tibial cartilage could serve to decrease the peak stresses generated within kangaroo tibiofemoral joints. However, the influences of the microstructure, composition and mechanical properties of the central fibrous and peripheral hyaline cartilage on the function of the knee joints are still to be defined. The present study showed that the fibrous cartilage was thicker and had a lower chondrocyte density than the hyaline cartilage. Despite having a higher PG content in the middle and deep zones, the fibrous cartilage had an inferior compressive strength compared to the peripheral hyaline cartilage. The fibrous cartilage had a complex three dimensional collagen meshwork with collagen bundles parallel to the surface in the superficial zone, and with collagen bundles both parallel and perpendicular to the surface in the middle and deep zones. The collagen in the hyaline cartilage displayed a typical Benninghoff structure, with collagen fibres parallel to the surface in the superficial zone and collagen fibres perpendicular to the surface in the deep zone. Elastin fibres were found throughout the entire tissue depth of the fibrous cartilage and displayed a similar alignment to the adjacent collagen bundles. In comparison, the elastin fibres in the hyaline cartilage were confined within the superficial zone. This study examined for the first time the fibrillary structure, PG content and compressive properties of the central fibrous cartilage pad and peripheral hyaline cartilage within the kangaroo medial tibial plateau. It provided insights into the microstructure and composition of the fibrous and peripheral hyaline cartilage in relation to the unique mechanical properties of the tissues to provide for the normal activities of kangaroos. PMID- 24058544 TI - Lessons from an evaluation of a provincial-level smoking control policy in Shanghai, China. AB - BACKGROUND: The Shanghai Public Places Smoking Control Legislation was implemented in March 2010 as the first provincial-level legislation promoting smoke-free public places in China. OBJECTIVE: To evaluate the compliance with this policy as well as its impact on exposure to secondhand smoke (SHS), respiratory symptoms, and related attitudes among employees in five kinds of workplaces (schools, kindergartens, hospitals, hotels, and shopping malls). METHODS: A cross-sectional survey was conducted six months before and then six months after the policy was implemented. Five types of occupational employees from 52 work settings were surveyed anonymously using multistage stratified cluster sampling. RESULTS: Six months after implementation, 82% of the participants agreed that "legislation is enforced most of the time". The percentage of self-reported exposure to secondhand smoke declined from round up to 49% to 36%. High compliance rates were achieved in schools and kindergartens (above 90%), with less compliance in hotels and shopping malls (about 70%). Accordingly, prevalence of exposure to SHS was low in schools and kindergartens (less than 10%) and high in hotels and shopping malls (40% and above). The prevalence of respiratory and sensory symptoms (e.g., red or irritated eyes) among employees decreased from 83% to 67%. CONCLUSIONS: Initial positive effects were achieved after the implementation of Shanghai Smoking Control legislation including decreased exposure to SHS. However, compliance with the policies was a considerable problem in some settings. Further evaluation of such policy implementation should be conducted to inform strategies for increasing compliance in the future. PMID- 24058545 TI - Resequencing of Treponema pallidum ssp. pallidum strains Nichols and SS14: correction of sequencing errors resulted in increased separation of syphilis treponeme subclusters. AB - BACKGROUND: Treponema pallidum ssp. pallidum (TPA), the causative agent of syphilis, is a highly clonal bacterium showing minimal genetic variability in the genome sequence of individual strains. Nevertheless, genetically characterized syphilis strains can be clearly divided into two groups, Nichols-like strains and SS14-like strains. TPA Nichols and SS14 strains were completely sequenced in 1998 and 2008, respectively. Since publication of their complete genome sequences, a number of sequencing errors in each genome have been reported. Therefore, we have resequenced TPA Nichols and SS14 strains using next-generation sequencing techniques. METHODOLOGY/PRINCIPAL FINDINGS: The genomes of TPA strains Nichols and SS14 were resequenced using the 454 and Illumina sequencing methods that have a combined average coverage higher than 90x. In the TPA strain Nichols genome, 134 errors were identified (25 substitutions and 109 indels), and 102 of them affected protein sequences. In the TPA SS14 genome, a total of 191 errors were identified (85 substitutions and 106 indels) and 136 of them affected protein sequences. A set of new intrastrain heterogenic regions in the TPA SS14 genome were identified including the tprD gene, where both tprD and tprD2 alleles were found. The resequenced genomes of both TPA Nichols and SS14 strains clustered more closely with related strains (i.e. strains belonging to same syphilis treponeme subcluster). At the same time, groups of Nichols-like and SS14-like strains were found to be more distantly related. CONCLUSION/SIGNIFICANCE: We identified errors in 11.5% of all annotated genes and, after correction, we found a significant impact on the predicted proteomes of both Nichols and SS14 strains. Corrections of these errors resulted in protein elongations, truncations, fusions and indels in more than 11% of all annotated proteins. Moreover, it became more evident that syphilis is caused by treponemes belonging to two separate genetic subclusters. PMID- 24058546 TI - A population model of integrative cardiovascular physiology. AB - We present a small integrative model of human cardiovascular physiology. The model is population-based; rather than using best fit parameter values, we used a variant of the Metropolis algorithm to produce distributions for the parameters most associated with model sensitivity. The population is built by sampling from these distributions to create the model coefficients. The resulting models were then subjected to a hemorrhage. The population was separated into those that lost less than 15 mmHg arterial pressure (compensators), and those that lost more (decompensators). The populations were parametrically analyzed to determine baseline conditions correlating with compensation and decompensation. Analysis included single variable correlation, graphical time series analysis, and support vector machine (SVM) classification. Most variables were seen to correlate with propensity for circulatory collapse, but not sufficiently to effect reasonable classification by any single variable. Time series analysis indicated a single significant measure, the stressed blood volume, as predicting collapse in situ, but measurement of this quantity is clinically impossible. SVM uncovered a collection of variables and parameters that, when taken together, provided useful rubrics for classification. Due to the probabilistic origins of the method, multiple classifications were attempted, resulting in an average of 3.5 variables necessary to construct classification. The most common variables used were systemic compliance, baseline baroreceptor signal strength and total peripheral resistance, providing predictive ability exceeding 90%. The methods presented are suitable for use in any deterministic mathematical model. PMID- 24058547 TI - Depersonalization disorder: disconnection of cognitive evaluation from autonomic responses to emotional stimuli. AB - BACKGROUND: Patients with depersonalization disorder (DPD) typically complain about emotional detachment. Previous studies found reduced autonomic responsiveness to emotional stimuli for DPD patients as compared to patients with anxiety disorders. We aimed to investigate autonomic responsiveness to emotional auditory stimuli of DPD patients as compared to patient controls. Furthermore, we examined the modulatory effect of mindful breathing on these responses as well as on depersonalization intensity. METHODS: 22 DPD patients and 15 patient controls balanced for severity of depression and anxiety, age, sex and education, were compared regarding 1) electrodermal and heart rate data during a resting period, and 2) autonomic responses and cognitive appraisal of standardized acoustic affective stimuli in two conditions (normal listening and mindful breathing). RESULTS: DPD patients rated the emotional sounds as significantly more neutral as compared to patient controls and standardized norm ratings. At the same time, however, they responded more strongly to acoustic emotional stimuli and their electrodermal response pattern was more modulated by valence and arousal as compared to patient controls. Mindful breathing reduced severity of depersonalization in DPD patients and increased the arousal modulation of electrodermal responses in the whole sample. Finally, DPD patients showed an increased electrodermal lability in the rest period as compared to patient controls. CONCLUSIONS: These findings demonstrated that the cognitive evaluation of emotional sounds in DPD patients is disconnected from their autonomic responses to those emotional stimuli. The increased electrodermal lability in DPD may reflect increased introversion and cognitive control of emotional impulses. The findings have important psychotherapeutic implications. PMID- 24058548 TI - Autoantibodies to estrogen receptor alpha in systemic sclerosis (SSc) as pathogenetic determinants and markers of progression. AB - Systemic sclerosis (SSc) is a multisystem autoimmune disease of unknown etiology characterized by inflammation, autoantibody production, and fibrosis. It predominantly affects women, this suggesting that female sex hormones such as estrogens may play a role in disease pathogenesis. However, up to date, the role of estrogens in SSc has been scarcely explored. The activity of estrogens is mediated either by transcription activity of the intracellular estrogen receptors (ER), ERalpha and ERbeta, or by membrane-associated ER. Since the presence of autoantibodies to ERalpha and their role as estrogen agonists interfering with T lymphocyte homeostasis were demonstrated in other autoimmune diseases, we wanted to ascertain whether anti-ERalpha antibodies were detectable in sera from patients with SSc. We detected anti-ERalpha antibody serum immunoreactivity in 42% of patients with SSc (30 out of 71 analyzed). Importantly, a significant association was found between anti-ERalpha antibody values and key clinical parameters of disease activity and severity. Fittingly, anti-ERalpha antibody levels were also significantly associated with alterations of immunological features of SSc patients, including increased T cell apoptotic susceptibility and changes in T regulatory cells (Treg) homeostasis. In particular, the percentage of activated Treg (CD4(+)CD45RA(-) FoxP3(bright)CD25(bright)) was significantly higher in anti-ERalpha antibody positive patients than in anti-ERalpha antibody negative patients. Taken together our data clearly indicate that anti-ERalpha antibodies, probably via the involvement of membrane-associated ER, can represent: i) promising markers for SSc progression but, also, ii) functional modulators of the SSc patients' immune system. PMID- 24058549 TI - The non-structural NS1 protein unique to respiratory syncytial virus: a two-state folding monomer in quasi-equilibrium with a stable spherical oligomer. AB - Human respiratory syncytial virus (hRSV) is a major infectious agent that cause pediatric respiratory disease worldwide. Considered one of the main virulence factors of hRSV, NS1 is known to suppress type I interferon response and signaling, thus favoring immune evasion. This, together with the fact that NS1 is unique to hRSV among paramyxoviruses, and that has no homology within databases, prompted us to investigate its conformational stability, equilibria and folding. Temperature cooperatively induces conformational changes leading to soluble spherical oligomers (NS1SOs) with amyloid-like or repetitive beta-sheet structures. The onset of the thermal transition is 45 degrees C, and the oligomerization rate is increased by 25-fold from 40 to 46 degrees C. Conformational stability analyzed by chemical perturbation of the NS1 monomer shows a two-state, highly reversible and cooperative unfolding, with a denaturant midpoint of 3.8 M, and a free energy change of 9.6+/-0.9 kcal?mol(-1). However, two transitions were observed in the chemical perturbation of NS1SOs: the first, from 2.0 to 3.0 M of denaturant, corresponds to a conformational transition and dissociation of the oligomers to the native monomer, indicating a substantial energy barrier. The second transition (2.0 to 3.5 M denaturant) corresponds to full unfolding of the native NS1 monomer. In addition, different cosolvent perturbations converged on the formation of beta-sheet enriched soluble oligomeric species, with secondary structure resembling those obtained after mild temperature treatment. Thus, a unique protein without homologs, structure or mechanistic information may switch between monomers and oligomers in conditions compatible with the cellular environment and be potentially modulated by crowding or compartmentalization. NS1 may act as a reservoir for increased levels and impact on protein turnover. PMID- 24058550 TI - Allosteric coupling between the intracellular coupling helix 4 and regulatory sites of the first nucleotide-binding domain of CFTR. AB - Cystic fibrosis is caused by mutations in CFTR (cystic fibrosis transmembrane conductance regulator), leading to folding and processing defects and to chloride channel gating misfunction. CFTR is regulated by ATP binding to its cytoplasmic nucleotide-binding domains, NBD1 and NBD2, and by phosphorylation of the NBD1 regulatory insert (RI) and the regulatory extension (RE)/R region. These regulatory effects are transmitted to the rest of the channel via NBD interactions with intracellular domain coupling helices (CL), particularly CL4. Using a sensitive method for detecting inter-residue correlations between chemical shift changes in NMR spectra, an allosteric network was revealed within NBD1, with a construct lacking RI. The CL4-binding site couples to the RI deletion site and the C-terminal residues of NBD1 that precede the R region in full-length CFTR. Titration of CL4 peptide into NBD1 perturbs the conformational ensemble in these sites with similar titration patterns observed in F508del, the major CF-causing mutant, and in suppressor mutants F494N, V510D and Q637R NBD1, as well as in a CL4-NBD1 fusion construct. Reciprocally, the C-terminal mutation, Q637R, perturbs dynamics in these three sites. This allosteric network suggests a mechanism synthesizing diverse regulatory NBD1 interactions and provides biophysical evidence for the allosteric coupling required for CFTR function. PMID- 24058551 TI - Alternative treatments for indoor residual spraying for malaria control in a village with pyrethroid- and DDT-resistant vectors in the Gambia. AB - BACKGROUND: Malaria vector control is threatened by resistance to pyrethroids, the only class of insecticides used for treating bed nets. The second major vector control method is indoor residual spraying with pyrethroids or the organochloride DDT. However, resistance to pyrethroids frequently confers resistance to DDT. Therefore, alternative insecticides are urgently needed. METHODOLOGY/PRINCIPAL FINDINGS: Insecticide resistance and the efficacy of indoor residual spraying with different insecticides was determined in a Gambian village. Resistance of local vectors to pyrethroids and DDT was high (31% and 46% mortality, respectively) while resistance to bendiocarb and pirimiphos methyl was low (88% and 100% mortality, respectively). The vectors were predominantly Anopheles gambiae s.s. with 94% of them having the putative resistant genotype kdr 1014F. Four groups of eight residential compounds were each sprayed with either (1) bendiocarb, a carbamate, (2) DDT, an organochlorine, (3) microencapsulated pirimiphos methyl, an organophosphate, or (4) left unsprayed. All insecticides tested showed high residual activity up to five months after application. Mosquito house entry, estimated by light traps, was similar in all houses with metal roofs, but was significantly less in IRS houses with thatched roofs (p=0.02). Residents participating in focus group discussions indicated that IRS was considered a necessary nuisance and also may decrease the use of long lasting insecticidal nets. CONCLUSION/SIGNIFICANCE: Bendiocarb and microencapsulated pirimiphos methyl are viable alternatives for indoor residual spraying where resistance to pyrethroids and DDT is high and may assist in the management of pyrethroid resistance. PMID- 24058552 TI - Impact of living environment on 2-year mortality in elderly maintenance hemodialysis patients. AB - BACKGROUND: Studies on risk factors of mortality in elderly patients with hemodialysis usually focus on comorbidities, nutrition, and inflammation. Discussion on the correlation between living environment and mortality of these patients is limited. METHODS: A total of 256 elderly hemodialysis patients participated in this 2-year prospective observational study. The subjects were divided into 2 subgroups based on whether they were living in Taipei Basin (n = 63) or not (n = 193). Demographic, hematological, nutritional, inflammatory, biochemical, and dialysis-related data were obtained for cross-sectional analysis. Causes of death and mortality rates were also analyzed for each subgroup. RESULTS: Patients in the basin group had a higher incidence of combined protein-energy wasting and inflammation than those in the around basin group. At the end of the 2-year follow-up, 68 patients had died. Univariate binary logistic regression analysis revealed that a very advanced age, basin group, serum albumin levels, serum creatinine levels, non-anuria, and the complications of stroke and CAD were associated with 2-year mortality. Meanwhile, log high-sensitivity C reactive protein (hs-CRP) levels were not associated with 2-year mortality. Multivariate Cox regression analysis revealed that basin group, serum albumin levels, and the complications of stroke and CAD were significant risk factors for 2-year mortality in these patients. CONCLUSION: The results of this study indicate that factors such as living in the Taipei Basin with higher air pollutant levels in elderly hemodialysis patients is associated with protein energy wasting and inflammation, as well as 2-year mortality. These findings suggest that among this population, living environment is as important as comorbidities and nutrition. Furthermore, air pollution should be getting more attention especially in the overcrowding Basin topography. PMID- 24058553 TI - H(2)S inhibits hyperglycemia-induced intrarenal renin-angiotensin system activation via attenuation of reactive oxygen species generation. AB - Decrease in endogenous hydrogen sulfide (H2S) was reported to participate in the pathogenesis of diabetic nephropathy (DN). This study is aimed at exploring the relationship between the abnormalities in H2S metabolism, hyperglycemia-induced oxidative stress and the activation of intrarenal renin-angiotensin system (RAS). Cultured renal mesangial cells (MCs) and streptozotocin (STZ) induced diabetic rats were used for the studies. The expressions of angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II (Ang II) type I receptor (AT1), transforming growth factor-beta1 (TGF-beta1) and collagen IV were measured by real time PCR and Western blot. Reactive oxygen species (ROS) production was assessed by fluorescent probe assays. Cell proliferation was analyzed by 5'-bromo 2'-deoxyuridine incorporation assay. Ang II concentration was measured by an enzyme immunoassay. AGT, ACE and AT1 receptor mRNA levels and Ang II concentration were increased in high glucose (HG) -treated MCs, the cell proliferation rate and the production of TGF-beta1 and of collagen IV productions were also increased. The NADPH oxidase inhibitor diphenylenechloride iodonium (DPI) was able to reverse the HG-induced RAS activation and the changes in cell proliferation and collagen synthesis. Supplementation of H2S attenuated HG induced elevations in ROS and RAS activation. Blockade on H2S biosynthesis from cystathione-gamma-lyase (CSE) by DL-propargylglycine (PPG) resulted in effects similar to that of HG treatment. In STZ-induced diabetic rats, the changes in RAS were also reversed by H2S supplementation without affecting blood glucose concentration. These data suggested that the decrease in H2S under hyperglycemic condition leads to an imbalance between oxidative and reductive species. The increased oxidative species results in intrarenal RAS activation, which, in turn, contributes to the pathogenesis of renal dysfunction. PMID- 24058555 TI - The 3' untranslated region of the cyclin B mRNA is not sufficient to enhance the synthesis of cyclin B during a mitotic block in human cells. AB - Antimitotic agents are frequently used to treat solid tumors and hematologic malignancies. However, one major limitation of antimitotic approaches is mitotic slippage, which is driven by slow degradation of cyclin B during a mitotic block. The extent to which cyclin B levels decline is proposed to be governed by an equilibrium between cyclin B synthesis and degradation. It was recently shown that the 3' untranslated region (UTR) of the murine cyclin B mRNA contributes to the synthesis of cyclin B during mitosis in murine cells. Using a novel live-cell imaging-based technique allowing us to study synthesis and degradation of cyclin B simultaneously at the single cell level, we tested here the role of the human cyclin B 3'UTR in regulating cyclin B synthesis during mitosis in human cells. We observed that the cyclin B 3'UTR was not sufficient to enhance cyclin B synthesis in human U2Os, HeLa or hTERT RPE-1 cells. A better understanding of how the equilibrium of cyclin B is regulated in mitosis may contribute to the development of improved therapeutic approaches to prevent mitotic slippage in cancer cells treated with antimitotic agents. PMID- 24058554 TI - Quantification of anti-aggregation activity of chaperones: a test-system based on dithiothreitol-induced aggregation of bovine serum albumin. AB - The methodology for quantification of the anti-aggregation activity of protein and chemical chaperones has been elaborated. The applicability of this methodology was demonstrated using a test-system based on dithiothreitol-induced aggregation of bovine serum albumin at 45 degrees C as an example. Methods for calculating the initial rate of bovine serum albumin aggregation (v agg) have been discussed. The comparison of the dependences of v agg on concentrations of intact and cross-linked alpha-crystallin allowed us to make a conclusion that a non-linear character of the dependence of v agg on concentration of intact alpha crystallin was due to the dynamic mobility of the quaternary structure of alpha crystallin and polydispersity of the alpha-crystallin-target protein complexes. To characterize the anti-aggregation activity of the chemical chaperones (arginine, arginine ethyl ester, arginine amide and proline), the semi-saturation concentration [L]0.5 was used. Among the chemical chaperones studied, arginine ethyl ester and arginine amide reveal the highest anti-aggregation activity ([L]0.5 = 53 and 58 mM, respectively). PMID- 24058556 TI - Increased endoplasmic reticulum stress response is involved in clopidogrel induced apoptosis of gastric epithelial cells. AB - BACKGROUND: The widespread use of clopidogrel alone or in combination with aspirin may result in gastrointestinal mucosal injury, clinically represented as recurrent ulceration and bleeding complications. Our recent work suggested that clopidogrel significantly induced human gastric epithelial cell (GES-1) apoptosis and disrupted gastric mucosal barrier, and that a p38 MAPK inhibitor could attenuate such injury. However, their exact mechanisms are largely unknown. METHODS: The GES-1 cells were used as a model system, the effects of clopidogrel on the whole gene expression profile were evaluated by human gene expression microarray and gene ontology analysis, changes of the mRNA and protein expression were determined by real-time PCR and Western blot analysis, and cell viability and apoptosis were measured by MTT assay and flow cytometry analysis, respectively. RESULTS: Gene microarray analysis identified 79 genes that were differentially expressed (P<0.05 and fold-change >3) when cells were treated with or without clopidogrel. Gene ontology analysis revealed that response to stress and cell apoptosis dysfunction were ranked in the top 10 cellular events being affected, and that the major components of endoplasmic reticulum stress-mediated apoptosis pathway - CHOP and TRIB3- were up-regulated in a concentration- and time-dependent manner when cells were treated with clopidogrel. Pathway analysis demonstrated that multiple MAPK kinases were phosphorylated in clopidogrel treated GES-1 cells, but that only SB-203580 (a p38-specific MAPK inhibitor) attenuated cell apoptosis and CHOP over-expression, both of which were induced by clopidogrel. CONCLUSIONS: Increased endoplasmic reticulum stress response is involved in clopidogrel-induced gastric mucosal injury, acting through p38 MAPK activation. PMID- 24058557 TI - Methylglyoxal induces platelet hyperaggregation and reduces thrombus stability by activating PKC and inhibiting PI3K/Akt pathway. AB - Diabetes is characterized by a dysregulation of glucose homeostasis and platelets from patients with diabetes are known to be hyper-reactive and contribute to the accelerated development of vascular diseases. Since many of the deleterious effects of glucose have been attributed to its metabolite methylgyloxal (MG) rather than to hyperglycemia itself, the aim of the present study was to characterize the effects of MG on platelet function. Washed human platelets were pre-incubated for 15 min with MG and platelet aggregation, adhesion on matrix coated slides and signaling (Western blot) were assessed ex vivo. In vivo, the effect of MG on thrombus formation was determined using the FeCl3-induced carotid artery injury model. MG potentiated thrombin-induced platelet aggregation and dense granule release, but inhibited platelet spreading on fibronectin and collagen. In vivo, MG accelerated thrombus formation but decreased thrombus stability. At the molecular level, MG increased intracellular Ca(2+) and activated classical PKCs at the same time as inhibiting PI3K/Akt and the beta3 integrin outside-in signaling. In conclusion, these findings indicate that the enhanced MG concentration measured in diabetic patients can directly contribute to the platelet dysfunction associated with diabetes characterized by hyperaggregability and reduced thrombus stability. PMID- 24058558 TI - Promoting colonization in metastatic HCC cells by modulation of autophagy. AB - BACKGROUND: Autophagy is an important adaptive survival mechanism, which has been postulated to be involved in cancer metastasis. The purpose of this study was to investigate autophagy in metastasis of hepatocellular carcinoma (HCC). METHODS: Immunohistochemical analysis of autophagic activity in metastatic and paired primary HCC tissues using LC3 as autophagosome marker was performed in samples from 216 HCC patients diagnosed with metastasis (including 158 intravascular, 42 intrabiliary, 8 lymph node, 4 bone and 4 lung metastases). Then a mouse model of pulmonary metastasis was established using a highly metastatic HCC cell line (HCCLM3). Autophagy in pulmonary metastases and paired primary tumors were analyzed by LC3 immunohistochemistry, transmission electron microscopy (TEM) and western blot analysis. Further, mouse model of pulmonary metastasis and in vitro cell migration, invasion and detachment models were established using a stable GFP-LC3-expressing HCCLM3 cell line (HCCLM3-GFP-LC3). Autophagic alterations during metastatic colonization, migration, invasion and detachment were determined by GFP-LC3 analysis and western blot analysis. RESULTS: LC3 immunohistochemistry of metastases and primary tumors from HCC patients revealed significantly higher LC3 expression in metastases than primary HCC, which suggested a higher level of autophagy in HCC metastases. Further immunohistochemical, TEM, western blot and in vivo GFP-LC3 analyses of lung metastases and primary tumors in mouse model of pulmonary metastasis confirmed that metastatic colonies displayed higher level of autophagy than primary tumors and the early metastatic colonies displayed highest level. The dynamic monitoring of autophagy in cell migration, invasion and detachment showed that autophagy did not significantly alter in those processes. CONCLUSIONS: Autophagy is activated in metastatic colonization but not in invasion, migration and detachment of HCC cells. Autophagy may play a role in HCC metastasis via promoting metastatic colonization of HCC cells. PMID- 24058560 TI - Impacts of temperature on primary productivity and respiration in naturally structured macroalgal assemblages. AB - Rising global temperatures caused by human-mediated change has already triggered significant responses in organismal physiology, distribution and ecosystem functioning. Although the effects of rising temperature on the physiology of individual organisms are well understood, the effect on community-wide processes has remained elusive. The fixation of carbon via primary productivity is an essential ecosystem function and any shifts in the balance of primary productivity and respiration could alter the carbon balance of ecosystems. Here we show through a series of tests that respiration of naturally structured algal assemblages in southern New Zealand greatly increases with rising temperature, with implications for net primary productivity (NPP). The NPP of in situ macroalgal assemblages was minimally affected by natural temperature variation, possibly through photo-acclimation or temperature acclimation responses, but respiration rates and compensating irradiance were negatively affected. However, laboratory experiments testing the impacts of rising temperature on several photosynthetic parameters showed a decline in NPP, increasing respiration rates and increasing compensating irradiance. The respiration Q10 of laboratory assemblages (the difference in metabolic rates over 10 degrees C) averaged 2.9 compared to a Q10 of 2 often seen in other autotrophs. However, gross primary productivity (GPP) Q10 averaged 2, indicating that respiration was more severely affected by rising temperature. Furthermore, combined high irradiance and high temperature caused photoinhibition in the laboratory, and resulted in 50% lower NPP at high irradiance. Our study shows that communities may be more severely affected by rising global temperatures than would be expected by responses of individual species. In particular, enhanced respiration rates and rising compensation points have the potential to greatly affect the carbon balance of macroalgal assemblages through declines in sub-canopy NPP, the impacts of which may be exacerbated over longer time-scales and could result in declines in sub canopy species richness and abundance. PMID- 24058559 TI - An FtsH protease is recruited to the mitochondrion of Plasmodium falciparum. AB - The two organelles, apicoplast and mitochondrion, of the malaria parasite Plasmodium falciparum have unique morphology in liver and blood stages; they undergo complex branching and looping prior to division and segregation into daughter merozoites. Little is known about the molecular processes and proteins involved in organelle biogenesis in the parasite. We report the identification of an AAA+/FtsH protease homolog (PfFtsH1) that exhibits ATP- and Zn(2+)-dependent protease activity. PfFtsH1 undergoes processing, forms oligomeric assemblies, and is associated with the membrane fraction of the parasite cell. Generation of a transfectant parasite line with hemagglutinin-tagged PfFtsH1, and immunofluorescence assay with anti-PfFtsH1 Ab demonstrated that the protein localises to P. falciparum mitochondria. Phylogenetic analysis and the single transmembrane region identifiable in PfFtsH1 suggest that it is an i-AAA like inner mitochondrial membrane protein. Expression of PfFtsH1 in Escherichia coli converted a fraction of bacterial cells into division-defective filamentous forms implying a sequestering effect of the Plasmodium factor on the bacterial homolog, indicative of functional conservation with EcFtsH. These results identify a membrane-associated mitochondrial AAA+/FtsH protease as a candidate regulatory protein for organelle biogenesis in P. falciparum. PMID- 24058561 TI - ALDH2 genotype has no effect on salivary acetaldehyde without the presence of ethanol in the systemic circulation. AB - BACKGROUND: Acetaldehyde associated with alcoholic beverages was recently classified as carcinogenic (Group 1) to humans based on uniform epidemiological and biochemical evidence. ALDH2 (aldehyde dehydrogenase 2) deficient alcohol consumers are exposed to high concentrations of salivary acetaldehyde and have an increased risk of upper digestive tract cancer. However, this interaction is not seen among ALDH2 deficient non-drinkers or rare drinkers, regardless of their smoking status or consumption of edibles containing ethanol or acetaldehyde. Therefore, the aim of this study was to examine the effect of the ALDH2 genotype on the exposure to locally formed acetaldehyde via the saliva without ethanol ingestion. METHODS: The ALDH2 genotypes of 17 subjects were determined by PCR RFLP. The subjects rinsed out their mouths with 5 ml of 40 vol% alcohol for 5 seconds. Salivary ethanol and acetaldehyde levels were measured by gas chromatography. RESULTS: Acetaldehyde reached mutagenic levels rapidly and the exposure continued for up to 20 minutes. The mean salivary acetaldehyde concentrations did not differ between ALDH2 genotypes. CONCLUSIONS: For ALDH2 deficient subjects, an elevated exposure to endogenously formed acetaldehyde requires the presence of ethanol in the systemic circulation. IMPACT: Our findings provide a logical explanation for how there is an increased incidence of upper digestive tract cancers among ALDH2 deficient alcohol drinkers, but not among those ALDH2 deficient subjects who are locally exposed to acetaldehyde without bloodborne ethanol being delivered to the saliva. Thus, ALDH2 deficient alcohol drinkers provide a human model for increased local exposure to acetaldehyde derived from the salivary glands. PMID- 24058563 TI - Utilization of replication-competent XMRV reporter-viruses reveals severe viral restriction in primary human cells. AB - The gammaretrovirus termed xenotropic murine leukemia virus-related virus (XMRV) was described to be isolated from prostate cancer tissue biopsies and from blood of patients suffering from chronic fatigue syndrome. However, many studies failed to detect XMRV and to verify these disease associations. Data suggesting the contamination of specimens in particular by PCR-based methods and recent reports demonstrating XMRV generation via recombination of two murine leukemia virus precursors raised serious doubts about XMRV being a genuine human pathogen. To elucidate cell tropism of XMRV, we generated replication competent XMRV reporter viruses encoding a green fluorescent protein or a secretable luciferase as tools to analyze virus infection of human cell lines or primary human cells. Transfection of proviral DNAs into LNCaP prostate cancer cells resulted in readily detectably reporter gene expression and production of progeny virus. Inoculation of known XMRV susceptible target cells revealed that these virions were infectious and expressed the reporter gene, allowing for a fast and highly sensitive quantification of XMRV infection. Both reporter viruses were capable of establishing a spreading infection in LNCaP and Raji B cells and could be easily passaged. However, after inoculation of primary human blood cells such as CD4 T cells, macrophages or dendritic cells, infection rates were very low, and a spreading infection was never established. In line with these results we found that supernatants derived from these XMRV infected primary cell types did not contain infectious virus. Thus, although XMRV efficiently replicated in some human cell lines, all tested primary cells were largely refractory to XMRV infection and did not support viral spread. Our results provide further evidence that XMRV is not a human pathogen. PMID- 24058562 TI - Hydrogen sulfide preconditioning protects rat liver against ischemia/reperfusion injury by activating Akt-GSK-3beta signaling and inhibiting mitochondrial permeability transition. AB - Hydrogen sulfide (H2S) is the third most common endogenously produced gaseous signaling molecule, but its impact on hepatic ischemia/reperfusion (I/R) injury, especially on mitochondrial function, remains unclear. In this study, rats were randomized into Sham, I/R, ischemia preconditioning (IPC) or sodium hydrosulfide (NaHS, an H2S donor) preconditioning groups. To establish a model of segmental (70%) warm hepatic ischemia, the hepatic artery, left portal vein and median liver lobes were occluded for 60 min and then unclamped to allow reperfusion. Preconditioning with 12.5, 25 or 50 MUmol/kg NaHS prior to the I/R insult significantly increased serum H2S levels, and, similar to IPC, NaHS preconditioning decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the plasma and prevented hepatocytes from undergoing I/R-induced necrosis. Moreover, a sub-toxic dose of NaHS (25 MUmol/kg) did not disrupt the systemic hemodynamics but dramatically inhibited mitochondrial permeability transition pore (MPTP) opening and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that NaHS preconditioning markedly increased the expression of phosphorylated protein kinase B (p-Akt), phosphorylated glycogen synthase kinase-3 beta (p-GSK-3beta) and B-cell lymphoma-2 (Bcl-2) and decreased the release of mitochondrial cytochrome c and cleaved caspase-3/9 levels. Therefore, NaHS administration prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through the inhibition of MPTP opening and the activation of Akt-GSK-3beta signaling. Furthermore, this study provides experimental evidence for the clinical use of H2S to reduce liver damage after perioperative I/R injury. PMID- 24058564 TI - Fetal functional brain age assessed from universal developmental indices obtained from neuro-vegetative activity patterns. AB - Fetal brain development involves the development of the neuro-vegetative (autonomic) control that is mediated by the autonomic nervous system (ANS). Disturbances of the fetal brain development have implications for diseases in later postnatal life. In that context, the fetal functional brain age can be altered. Universal principles of developmental biology applied to patterns of autonomic control may allow a functional age assessment. The work aims at the development of a fetal autonomic brain age score (fABAS) based on heart rate patterns. We analysed n = 113 recordings in quiet sleep, n = 286 in active sleep, and n = 29 in active awakeness from normals. We estimated fABAS from magnetocardiographic recordings (21.4-40.3 weeks of gestation) preclassified in quiet sleep (n = 113, 63 females) and active sleep (n = 286, 145 females) state by cross-validated multivariate linear regression models in a cross-sectional study. According to universal system developmental principles, we included indices that address increasing fluctuation range, increasing complexity, and pattern formation (skewness, power spectral ratio VLF/LF, pNN5). The resulting models constituted fABAS. fABAS explained 66/63% (coefficient of determination R(2) of training and validation set) of the variance by age in quiet, while 51/50% in active sleep. By means of a logistic regression model using fluctuation range and fetal age, quiet and active sleep were automatically reclassified (94.3/93.1% correct classifications). We did not find relevant gender differences. We conclude that functional brain age can be assessed based on universal developmental indices obtained from autonomic control patterns. fABAS reflect normal complex functional brain maturation. The presented normative data are supplemented by an explorative study of 19 fetuses compromised by intrauterine growth restriction. We observed a shift in the state distribution towards active awakeness. The lower WGA dependent fABAS values found in active sleep may reflect alterations in the universal developmental indices, namely fluctuation amplitude, complexity, and pattern formation that constitute fABAS. PMID- 24058565 TI - Z-score linear discriminant analysis for EEG based brain-computer interfaces. AB - Linear discriminant analysis (LDA) is one of the most popular classification algorithms for brain-computer interfaces (BCI). LDA assumes Gaussian distribution of the data, with equal covariance matrices for the concerned classes, however, the assumption is not usually held in actual BCI applications, where the heteroscedastic class distributions are usually observed. This paper proposes an enhanced version of LDA, namely z-score linear discriminant analysis (Z-LDA), which introduces a new decision boundary definition strategy to handle with the heteroscedastic class distributions. Z-LDA defines decision boundary through z score utilizing both mean and standard deviation information of the projected data, which can adaptively adjust the decision boundary to fit for heteroscedastic distribution situation. Results derived from both simulation dataset and two actual BCI datasets consistently show that Z-LDA achieves significantly higher average classification accuracies than conventional LDA, indicating the superiority of the new proposed decision boundary definition strategy. PMID- 24058566 TI - Direct regulation of cytochrome c oxidase by calcium ions. AB - Cytochrome c oxidase from bovine heart binds Ca(2+) reversibly at a specific Cation Binding Site located near the outer face of the mitochondrial membrane. Ca(2+) shifts the absorption spectrum of heme a, which allowed previously to determine the kinetics and equilibrium characteristics of the binding. However, no effect of Ca(2+) on the functional characteristics of cytochrome oxidase was revealed earlier. Here we report that Ca(2+) inhibits cytochrome oxidase activity of isolated bovine heart enzyme by 50-60% with Ki of ~1 uM, close to Kd of calcium binding with the oxidase determined spectrophotometrically. The inhibition is observed only at low, but physiologically relevant, turnover rates of the enzyme (~10 s(-1) or less). No inhibitory effect of Ca(2+) is observed under conventional conditions of cytochrome c oxidase activity assays (turnover number >100 s(-1) at pH 8), which may explain why the effect was not noticed earlier. The inhibition is specific for Ca(2+) and is reversed by EGTA. Na(+) ions that compete with Ca(2+) for binding with the Cation Binding Site, do not affect significantly activity of the enzyme but counteract the inhibitory effect of Ca(2+). The Ca(2+)-induced inhibition of cytochrome c oxidase is observed also with the uncoupled mitochondria from several rat tissues. At the same time, calcium ions do not inhibit activity of the homologous bacterial cytochrome oxidases. Possible mechanisms of the inhibition are discussed as well as potential physiological role of Ca(2+) binding with cytochrome oxidase. Ca(2+)- binding at the Cation Binding Site is proposed to inhibit proton-transfer through the exit part of the proton conducting pathway H in the mammalian oxidases. PMID- 24058567 TI - Transglutaminase 2 overexpression in tumor stroma identifies invasive ductal carcinomas of breast at high risk of recurrence. AB - INTRODUCTION: Molecular markers for predicting breast cancer patients at high risk of recurrence are urgently needed for more effective disease management. The impact of alterations in extracellular matrix components on tumor aggressiveness is under intense investigation. Overexpression of Transglutaminase 2 (TG2), a multifunctional enzyme, in cancer cells impacts epithelial mesenchymal transition, growth, invasion and interactions with tumor microenvironment. The objective of our study is to determine the clinical relevance of stromal TG2 overexpression and explore its potential to identify breast cancers at high risk of recurrence. METHODS: This retrospective study is based on immunohistochemical analysis of TG2 expression in normal breast tissues (n = 40) and breast cancers (n = 253) with clinical, pathological and follow-up data available for up to 12 years. TG2 expression was correlated with clinical and pathological parameters as well as disease free survival (DFS) of breast cancer patients. RESULTS: Stromal TG2 overexpression was observed in 114/253 (45.0%) breast cancer tissues as compared to breast normal tissues. Among invasive ductal carcinomas (IDC) of the breast, 97/168 (57.7%) showed strong TG2 expression in tumor stroma. Importantly, IDC patients showing stromal TG2 accumulation had significantly reduced DFS (mean DFS = 110 months) in comparison with patients showing low expression (mean DFS = 130 months) in Kaplan-Meier survival analysis (p<0.001). In Cox multivariate regression analysis, stromal TG2 accumulation was an independent risk factor for recurrence (p = 0.006, Hazard's ratio, H.R. = 3.79). Notably, these breast cancer patients also showed immunostaining of N-epsilon gamma-glutamyl lysine amino residues in tumor stroma demonstrating the transamidating activity of TG2. CONCLUSIONS: Accumulation of TG2 in tumor stroma is an independent risk factor for identifying breast cancer patients at high risk of recurrence. TG2 overexpression in tumor stroma may serve as a predictor of poor prognosis for IDC of the breast. PMID- 24058568 TI - Circulating antibody and memory B-Cell responses to C. difficile toxins A and B in patients with C. difficile-associated diarrhoea, inflammatory bowel disease and cystic fibrosis. AB - C. difficile infection (CDI) is rarely reported in cystic fibrosis (CF) patients despite frequent hospitalisations and antibiotic usage. Conversely, the prevalence of CDI in inflammatory bowel disease (IBD) has received increased attention. We investigated components of the IgG-specific humoral immune response to C. difficile toxins A and B in patients with C. difficile-associated diarrhoea (CDAD), IBD patients with CDI, CF patients and healthy controls. Serum anti-toxin IgG was determined by ELISA. Circulating antigen-activated B-cells were investigated using Alexa Fluor 488-labelled toxin A and assessed by flow cytometry. Following induction of differentiation of memory B-cells, toxin A- and B-specific antibody secreting cells (ASCs) were quantified using ELISpot. We present the first data showing levels of serum anti-toxin A and B antibodies were significantly higher in patients with CF (without a history of CDI) than in CDAD patients and were stably maintained over time. Notably, the CDAD patients were significantly older than the CF patients. We also show that circulating toxin A specific memory B-cells (IgD-negative) can be detected in CDAD patients [0.92 (0.09-1.78)%], and were prominent (5.64%, 1.14%) in two CF patients who were asymptomatic carriers of C. difficile. There was correlation between toxin A- and B-specific ASCs, with significantly higher proportions of the latter seen. In some with CDAD, high serum antibody levels were seen to only one of the two toxins. Mucosal secretion of toxin-specific IgG was detected in an additional group of IBD patients with no history of CDI. We conclude that enhanced and stable humoral immune responses to toxins A and B may protect CF and some IBD patients against CDI. The impaired ability to generate strong and/or sustained toxin-specific antibody and memory B-cell responses may increase susceptibility of older patients to CDI and highlight the need to investigate the role of immune senescence in future studies. PMID- 24058569 TI - Leucine-rich alpha2-glycoprotein is a novel biomarker of neurodegenerative disease in human cerebrospinal fluid and causes neurodegeneration in mouse cerebral cortex. AB - Leucine-rich alpha2-glycoprotein (LRG) is a protein induced by inflammation. It contains a leucine-rich repeat (LRR) structure and easily binds with other molecules. However, the function of LRG in the brain during aging and neurodegenerative diseases has not been investigated. Here, we measured human LRG (hLRG) concentration in the cerebrospinal fluid (CSF) and observed hLRG expression in post-mortem human cerebral cortex. We then generated transgenic (Tg) mice that over-expressed mouse LRG (mLRG) in the brain to examine the effects of mLRG accumulation. Finally, we examined protein-protein interactions using a protein microarray method to screen proteins with a high affinity for hLRG. The CSF concentration of hLRG increases with age and is significantly higher in patients with Parkinson's disease with dementia (PDD) and progressive supranuclear palsy (PSP) than in healthy elderly people, idiopathic normal pressure hydrocephalus (iNPH) patients, and individuals with Alzheimer's disease (AD). Tg mice exhibited neuronal degeneration and neuronal decline. Accumulation of LRG in the brains of PDD and PSP patients is not a primary etiological factor, but it is thought to be one of the causes of neurodegeneration. It is anticipated that hLRG CSF levels will be a useful biomarker for the early diagnosis of PDD and PSP. PMID- 24058570 TI - Differential joint-specific corticospinal tract projections within the cervical enlargement. AB - The motor cortex represents muscle and joint control and projects to spinal cord interneurons and-in many primates, including humans-motoneurons, via the corticospinal tract (CST). To examine these spinal CST anatomical mechanisms, we determined if motor cortex sites controlling individual forelimb joints project differentially to distinct cervical spinal cord territories, defined regionally and by the locations of putative last-order interneurons that were transneuronally labeled by intramuscular injection of pseudorabies virus. Motor cortex joint-specific sites were identified using intracortical-microstimulation. CST segmental termination fields from joint-specific sites, determined using anterograde tracers, comprised a high density core of terminations that was consistent between animals and a surrounding lower density projection that was more variable. Core terminations from shoulder, elbow, and wrist control sites overlapped in the medial dorsal horn and intermediate zone at C5/C6 but were separated at C7/C8. Shoulder sites preferentially terminated dorsally, in the dorsal horn; wrist/digit sites, more ventrally in the intermediate zone; and elbow sites, medially in the dorsal horn and intermediate zone. Pseudorabies virus injected in shoulder, elbow, or wrist muscles labeled overlapping populations of predominantly muscle-specific putative premotor interneurons, at a survival time for disynaptic transfer from muscle. At C5/C6, CST core projections from all joint zones were located medial to regions of densely labeled last-order interneurons, irrespective of injected muscle. At C7/C8 wrist CST core projections overlapped the densest interneuron territory, which was located in the lateral intermediate zone. In contrast, elbow CST core projections were located medial to the densest interneuron territories, and shoulder CST core projections were located dorsally and only partially overlapped the densest interneuron territory. Our findings show a surprising fractionation of CST terminations in the caudal cervical enlargement that may be organized to engage different spinal premotor circuits for distal and proximal joint control. PMID- 24058571 TI - Potential role of mesenchymal stem cells in alleviating intestinal ischemia/reperfusion impairment. AB - BACKGROUND: Transplantation of bone marrow mesenchymal stem cells (MSCs) provides a promising therapeutic efficiency for a variety of disorders caused by ischemia or reperfusion impairment. We have previously demonstrated the efficacy of MSCs in mitigating intestinal ischemia/reperfusion (I/R) injuries in rats, but the mechanism by which MSCs engraft ameliorates I/R injuries has largely been unknown. The present study aimed at investigating probable mechanisms by which MSCs exert their function. METHODS: Male donor derived rat MSCs were implanted into intestine of female recipient rat by direct submucosal injection after superior mesenteric artery clamping and unclamping. The homed MSCs were detected by Y chromosome in situ hybridization probe, and the tumor necrosis factor-alpha (TNF-alpha) content in intestinal mucosa was determined by ELISA. Expression of proliferative cell nuclear antigen (PCNA) in bowel mucosa was assayed by real time PCR and intestinal mucosa expression of phosphorylation extracellular signal regulated kinase (pERK1/2) and nuclear factor-kappaB (NF-kappaB) were evaluated by western blot. RESULTS: Four and seven days after MSCs transplantation, the TNF alpha content of bowel mucosa in MSCs group was significantly lower than that in saline group. The PCNA in bowel mucosa showed higher expression in MSCs treated group than the saline group, both at 4 and 7 days after cell transplantation. The expression of intestinal mucosal pERK1/2 in MSCs treated group was markedly higher than that in saline group, and the expression of NF-kappaB in MSCs treated group was noticeably decreased than that in saline group at 4 and 7 days post MSCs transplantation. CONCLUSION: The present investigation provides novel evidence that MSCs have the potential to reduce intestinal I/R injuries probably due to their ability to accelerate cell proliferation and decrease the inflammatory response within intestinal mucosa after ischemia and reperfusion. PMID- 24058572 TI - Relationship between differential hepatic microRNA expression and decreased hepatic cytochrome P450 3A activity in cirrhosis. AB - BACKGROUND AND AIM: Liver cirrhosis is associated with decreased hepatic cytochrome P4503A (CYP3A) activity but the pathogenesis of this phenomenon is not well elucidated. In this study, we examined if certain microRNAs (miRNA) are associated with decreased hepatic CYP3A activity in cirrhosis. METHODS: Hepatic CYP3A activity and miRNA microarray expression profiles were measured in cirrhotic (n=28) and normal (n=12) liver tissue. Hepatic CYP3A activity was measured via midazolam hydroxylation in human liver microsomes. Additionally, hepatic CYP3A4 protein concentration and the expression of CYP3A4 mRNA were measured. Analyses were conducted to identify miRNAs which were differentially expressed between two groups but also were significantly associated with lower hepatic CYP3A activity. RESULTS: Hepatic CYP3A activity in cirrhotic livers was 1.7-fold lower than in the normal livers (0.28 +/- 0.06 vs. 0.47 +/- 0.07mL* min( 1)*mg protein(-1) (mean +/- SEM), P=0.02). Six microRNAs (miR-155, miR-454, miR 582-5p, let-7f-1*, miR-181d, and miR-500) had >1.2-fold increase in cirrhotic livers and also had significant negative correlation with hepatic CYP3A activity (range of r = -0.44 to -0.52, P <0.05). Notably, miR-155, a known regulator of liver inflammation, had the highest fold increase in cirrhotic livers (2.2-fold, P=4.16E-08) and significantly correlated with hepatic CYP3A activity (r=-0.50, P=0.017). The relative expression (2(-DeltaDeltaCt) mean +/- SEM) of hepatic CYP3A4 mRNA was significantly higher in cirrhotic livers (21.76 +/- 2.65 vs. 5.91 +/- 1.29, P=2.04E-07) but their levels did not significantly correlate with hepatic CYP3A activity (r=-0.43, P=0.08). CONCLUSION: The strong association between certain miRNAs, notably miR-155, and lower hepatic CYP3A activity suggest that altered miRNA expression may regulate hepatic CYP3A activity. PMID- 24058573 TI - Genomewide variation in an introgression line of rice-Zizania revealed by whole genome re-sequencing. AB - BACKGROUND: Hybridization between genetically diverged organisms is known as an important avenue that drives plant genome evolution. The possible outcomes of hybridization would be the occurrences of genetic instabilities in the resultant hybrids. It remained under-investigated however whether pollination by alien pollens of a closely related but sexually "incompatible" species could evoke genomic changes and to what extent it may result in phenotypic novelties in the derived progenies. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have re sequenced the genomes of Oryza sativa ssp. japonica cv. Matsumae and one of its derived introgressant RZ35 that was obtained from an introgressive hybridization between Matsumae and Zizanialatifolia Griseb. in general, 131 millions 90 base pair (bp) paired-end reads were generated which covered 13.2 and 21.9 folds of the Matsumae and RZ35 genomes, respectively. Relative to Matsumae, a total of 41,724 homozygous single nucleotide polymorphisms (SNPs) and 17,839 homozygous insertions/deletions (indels) were identified in RZ35, of which 3,797 SNPs were nonsynonymous mutations. Furthermore, rampant mobilization of transposable elements (TEs) was found in the RZ35 genome. The results of pathogen inoculation revealed that RZ35 exhibited enhanced resistance to blast relative to Matsumae. Notably, one nonsynonymous mutation was found in the known blast resistance gene Pid3/Pi25 and real-time quantitative (q) RT-PCR analysis revealed constitutive up regulation of its expression, suggesting both altered function and expression of Pid3/Pi25 may be responsible for the enhanced resistance to rice blast by RZ35. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that introgressive hybridization by Zizania has provoked genomewide, extensive genomic changes in the rice genome, and some of which have resulted in important phenotypic novelties. These findings suggest that introgressive hybridization by alien pollens of even a sexually incompatible species may represent a potent means to generate novel genetic diversities, and which may have played relevant roles in plant evolution and can be manipulated for crop improvements. PMID- 24058574 TI - A longitudinal study of motor, oculomotor and cognitive function in progressive supranuclear palsy. AB - OBJECTIVE: We studied the annual change in measures of motor, oculomotor and cognitive function in progressive supranuclear palsy. This had twin objectives, to assess the potential for clinical parameters to monitor disease progression in clinical trials and to illuminate the progression of pathophysiology. METHODS: Twenty three patients with progressive supranuclear palsy (Richardson's syndrome) were compared to 22 matched controls at baseline and 16 of these patients compared at baseline and one year using: the progressive supranuclear palsy rating scale; the unified Parkinson's disease rating scale; the revised Addenbrooke's cognitive examination; the frontal assessment battery; the cubes section of the visual object and space perception battery; the Hayling and Brixton executive tests; and saccadic latencies. RESULTS: Patients were significantly impaired in all domains at baseline. However, cognitive performance was maintained over a year on the majority of tests. The unified Parkinson's disease rating scale, saccadic latency and progressive supranuclear palsy rating scale deteriorated over a year, with the latter showing the largest change. Power estimates indicate that using the progressive supranuclear palsy rating scale as an outcome measure in a clinical trial would require 45 patients per arm, to identify a 50% reduction in rate of decline with 80% power. CONCLUSIONS: Motor, oculomotor and cognitive domains deteriorate at different rates in progressive supranuclear palsy. This may be due to differential degeneration of their respective cortical-subcortical circuits, and has major implications for the selection of outcome measures in clinical trials due to wide variation in sensitivity to annual rates of decline. PMID- 24058575 TI - Aminergic control of social status in crayfish agonistic encounters. AB - Using pairings of male crayfish Procambarus clarkii with a 3-7% difference in size, we confirmed that physically larger crayfish were more likely to win encounters (winning probability of over 80%). Despite a physical disadvantage, small winners of the first pairings were more likely to win their subsequent conflicts with larger naive animals (winning probability was about 70%). By contrast, the losers of the first pairings rarely won their subsequent conflicts with smaller naive animals (winning probability of 6%). These winner and loser effects were mimicked by injection of serotonin and octopamine. Serotonin injected naive small crayfish were more likely to win in pairings with untreated larger naive crayfish (winning probability of over 60%), while octopamine injected naive large animals were beaten by untreated smaller naive animals (winning probability of 20%). Furthermore, the winner effects of dominant crayfish were cancelled by the injection of mianserin, an antagonist of serotonin receptors and were reinforced by the injection of fluoxetin, serotonin reuptake inhibitor, just after the establishment of social order of the first pairings. Injection of octopamine channel blockers, phentolamine and epinastine, by contrast, cancelled the loser effects. These results strongly suggested that serotonin and octopamine were responsible for winner and loser effects, respectively. PMID- 24058576 TI - Hepatitis C virus replication and Golgi function in brefeldin a-resistant hepatoma-derived cells. AB - Recent reports indicate that the replication of hepatitis C virus (HCV) depends on the GBF1-Arf1-COP-I pathway. We generated Huh-7-derived cell lines resistant to brefeldin A (BFA), which is an inhibitor of this pathway. The resistant cell lines could be sorted into two phenotypes regarding BFA-induced toxicity, inhibition of albumin secretion, and inhibition of HCV infection. Two cell lines were more than 100 times more resistant to BFA than the parental Huh-7 cells in these 3 assays. This resistant phenotype was correlated with the presence of a point mutation in the Sec7 domain of GBF1, which is known to impair the binding of BFA. Surprisingly, the morphology of the cis-Golgi of these cells remained sensitive to BFA at concentrations of the drug that allowed albumin secretion, indicating a dichotomy between the phenotypes of secretion and Golgi morphology. Cells of the second group were about 10 times more resistant than parental Huh-7 cells to the BFA-induced toxicity. The EC50 for albumin secretion was only 1.5 1.8 fold higher in these cells than in Huh-7 cells. However their level of secretion in the presence of inhibitory doses of BFA was 5 to 15 times higher. Despite this partially effective secretory pathway in the presence of BFA, the HCV infection was almost as sensitive to BFA as in Huh-7 cells. This suggests that the function of GBF1 in HCV replication does not simply reflect its role of regulator of the secretory pathway of the host cell. Thus, our results confirm the involvement of GBF1 in HCV replication, and suggest that GBF1 might fulfill another function, in addition to the regulation of the secretory pathway, during HCV replication. PMID- 24058577 TI - Chronic psychological stress induces the accumulation of myeloid-derived suppressor cells in mice. AB - Chronic psychological stress has been shown to adversely impact immune system functions and compromise host defenses against various infections. However, the underlying mechanisms remain elusive. Recent studies have demonstrated that myeloid-derived suppressor cells (MDSCs) play an important role in regulating immunity. It is of interest to explore whether or not chronic psychological stress plays immunosuppressive functions partially by inducing MDSCs accumulation. In this work, we report that chronic psychological stress led to the accumulation of CD11b+Gr1+ cells in the bone marrow of BALB/c mice. Repeated beta-agonist infusion showed no such effect. However, beta-adrenergic blockade, but not glucocorticoids blockade, partially reversed the accumulation of CD11b+Gr1+ cells under the condition of chronic psychological stress, suggesting catecholamines collaborate with other factors to induce the accumulation. Further exploration indicates that cyclooxygenase 2 (COX-2)-prostaglandin E2 (PGE2) loop might act downstream to induce the accumulation. A majority of the accumulated CD11b+Gr1+ cells were Ly6G+Ly6C(low) immature neutrophils, which inhibited cytokine release of macrophages as well as T cell responsiveness. Moreover, the accumulated CD11b+Gr1+ cells under the condition of chronic psychological stress expressed multiple inhibitory molecules. Taken together, our data demonstrate for the first time that chronic psychological stress induces MDSCs accumulation in mice, which can contribute to immunosuppression. PMID- 24058578 TI - Temporal dynamics of abundance and composition of nitrogen-fixing communities across agricultural soils. AB - BACKGROUND: Despite the fact that the fixation of nitrogen is one of the most significant nutrient processes in the terrestrial ecosystem, a thorough study of the spatial and temporal patterns in the abundance and distribution of N-fixing communities has been missing so far. METHODOLOGY/PRINCIPAL FINDINGS: In order to understand the dynamics of diazotrophic communities and their resilience to external changes, we quantified the abundance and characterized the bacterial community structures based on the nifH gene, using real-time PCR, PCR-DGGE and 454-pyrosequencing, across four representative Dutch soils during one growing season. In general, higher nifH gene copy numbers were observed in soils with higher pH than in those with lower pH, but lower numbers were related to increased nitrate and ammonium levels. Results from nifH gene pyrosequencing confirmed the observed PCR-DGGE patterns, which indicated that the N fixers are highly dynamic across time, shifting around 60%. Forward selection on CCA analysis identified N availability as the main driver of these variations, as well as of the evenness of the communities, leading to very unequal communities. Moreover, deep sequencing of the nifH gene revealed that sandy soils (B and D) had the lowest percentage of shared OTUs across time, compared with clayey soils (G and K), indicating the presence of a community under constant change. Cosmopolitan nifH species (present throughout the season) were affiliated with Bradyrhizobium, Azospirillum and Methylocistis, whereas other species increased their abundances progressively over time, when appropriate conditions were met, as was notably the case for Paenibacilus and Burkholderia. CONCLUSIONS: Our study provides the first in-depth pyrosequencing analysis of the N-fixing community at both spatial and temporal scales, providing insights into the cosmopolitan and specific portions of the nitrogen fixing bacterial communities in soil. PMID- 24058579 TI - Optimizing sampling design to deal with mist-net avoidance in Amazonian birds and bats. AB - Mist netting is a widely used technique to sample bird and bat assemblages. However, captures often decline with time because animals learn and avoid the locations of nets. This avoidance or net shyness can substantially decrease sampling efficiency. We quantified the day-to-day decline in captures of Amazonian birds and bats with mist nets set at the same location for four consecutive days. We also evaluated how net avoidance influences the efficiency of surveys under different logistic scenarios using re-sampling techniques. Net avoidance caused substantial declines in bird and bat captures, although more accentuated in the latter. Most of the decline occurred between the first and second days of netting: 28% in birds and 47% in bats. Captures of commoner species were more affected. The numbers of species detected also declined. Moving nets daily to minimize the avoidance effect increased captures by 30% in birds and 70% in bats. However, moving the location of nets may cause a reduction in netting time and captures. When moving the nets caused the loss of one netting day it was no longer advantageous to move the nets frequently. In bird surveys that could even decrease the number of individuals captured and species detected. Net avoidance can greatly affect sampling efficiency but adjustments in survey design can minimize this. Whenever nets can be moved without losing netting time and the objective is to capture many individuals, they should be moved daily. If the main objective is to survey species present then nets should still be moved for bats, but not for birds. However, if relocating nets causes a significant loss of netting time, moving them to reduce effects of shyness will not improve sampling efficiency in either group. Overall, our findings can improve the design of mist netting sampling strategies in other tropical areas. PMID- 24058580 TI - Sequence recombination and conservation of Varroa destructor virus-1 and deformed wing virus in field collected honey bees (Apis mellifera). AB - We sequenced small (s) RNAs from field collected honeybees (Apis mellifera) and bumblebees (Bombuspascuorum) using the Illumina technology. The sRNA reads were assembled and resulting contigs were used to search for virus homologues in GenBank. Matches with Varroadestructor virus-1 (VDV1) and Deformed wing virus (DWV) genomic sequences were obtained for A. mellifera but not B. pascuorum. Further analyses suggested that the prevalent virus population was composed of VDV-1 and a chimera of 5'-DWV-VDV1-DWV-3'. The recombination junctions in the chimera genomes were confirmed by using RT-PCR, cDNA cloning and Sanger sequencing. We then focused on conserved short fragments (CSF, size > 25 nt) in the virus genomes by using GenBank sequences and the deep sequencing data obtained in this study. The majority of CSF sites confirmed conservation at both between-species (GenBank sequences) and within-population (dataset of this study) levels. However, conserved nucleotide positions in the GenBank sequences might be variable at the within-population level. High mutation rates (Pi>10%) were observed at a number of sites using the deep sequencing data, suggesting that sequence conservation might not always be maintained at the population level. Virus-host interactions and strategies for developing RNAi treatments against VDV1/DWV infections are discussed. PMID- 24058581 TI - Repetitive concussive traumatic brain injury interacts with post-injury foot shock stress to worsen social and depression-like behavior in mice. AB - The debilitating effects of repetitive concussive traumatic brain injury (rcTBI) have been increasingly recognized in both military and civilian populations. rcTBI may result in significant neurological, cognitive, and affective sequelae, and is often followed by physical and/or psychological post-injury stressors that may exacerbate the effects of the injury and prolong the recovery period for injured patients. However, the consequences of post-injury stressors and their subsequent effects on social and emotional behavior in the context of rcTBI have been relatively little studied in animal models. Here, we use a mouse model of rcTBI with two closed-skull blunt impacts 24 hours apart and social and emotional behavior testing to examine the consequences of a stressor (foot shock fear conditioning) following brain injury (rcTBI). rcTBI alone did not affect cued or contextual fear conditioning or extinction compared to uninjured sham animals. In the sucrose preference test, rcTBI animals had decreased preference for sucrose, an anhedonia-like behavior, regardless of whether they experienced foot shock stress or were non-shocked controls. However, rcTBI and post-injury foot shock stress had synergistic effects in tests of social recognition and depression-like behavior. In the social recognition test, animals with both injury and shock were more impaired than either non-shocked injured mice or shocked but uninjured mice. In the tail suspension test, injured mice had increased depression-like behavior compared with uninjured mice, and shock stress worsened the depression-like behavior only in the injured mice with no effect in the uninjured mice. These results provide a model of subtle emotional behavioral deficits after combined concussive brain injury and stress, and may provide a platform for testing treatment and prevention strategies for social behavior deficits and mood disorders that are tailored to patients with traumatic brain injury. PMID- 24058582 TI - A computational study of the glycine-rich loop of mitochondrial processing peptidase. AB - An all atomic, non-restrained molecular dynamics (MD) simulation in explicit water was used to study in detail the structural features of the highly conserved glycine-rich loop (GRL) of the alpha-subunit of the yeast mitochondrial processing peptidase (MPP) and its importance for the tertiary and quaternary conformation of MPP. Wild-type and GRL-deleted MPP structures were studied using non-restrained MD simulations, both in the presence and the absence of a substrate in the peptidase active site. Targeted MD simulations were employed to study the mechanism of substrate translocation from the GRL to the active site. We demonstrate that the natural conformational flexibility of the GRL is crucial for the substrate translocation process from outside the enzyme towards the MPP active site. We show that the alpha-helical conformation of the substrate is important not only during its initial interaction with MPP (i.e. substrate recognition), but also later, at least during the first third of the substrate translocation trajectory. Further, we show that the substrate remains in contact with the GRL during the whole first half of the translocation trajectory and that hydrophobic interactions play a major role. Finally, we conclude that the GRL acts as a precisely balanced structural element, holding the MPP subunits in a partially closed conformation regardless the presence or absence of a substrate in the active site. PMID- 24058583 TI - Point mutations in the transmembrane region of the clic1 ion channel selectively modify its biophysical properties. AB - Chloride intracellular Channel 1 (CLIC1) is a metamorphic protein that changes from a soluble cytoplasmic protein into a transmembrane protein. Once inserted into membranes, CLIC1 multimerises and is able to form chloride selective ion channels. Whilst CLIC1 behaves as an ion channel both in cells and in artificial lipid bilayers, its structure in the soluble form has led to some uncertainty as to whether it really is an ion channel protein. CLIC1 has a single putative transmembrane region that contains only two charged residues: arginine 29 (Arg29) and lysine 37 (Lys37). As charged residues are likely to have a key role in ion channel function, we hypothesized that mutating them to neutral alanine to generate K37A and R29A CLIC1 would alter the electrophysiological characteristics of CLIC1. By using three different electrophysiological approaches: i) single channel Tip-Dip in artificial bilayers using soluble recombinant CLIC1, ii) cell attached and iii) whole-cell patch clamp recordings in transiently transfected HEK cells, we determined that the K37A mutation altered the single-channel conductance while the R29A mutation affected the single-channel open probability in response to variation in membrane potential. Our results show that mutation of the two charged amino acids (K37 and R29) in the putative transmembrane region of CLIC1 alters the biophysical properties of the ion channel in both artificial bilayers and cells. Hence these charged residues are directly involved in regulating its ion channel activity. This strongly suggests that, despite its unusual structure, CLIC1 itself is able to form a chloride ion channel. PMID- 24058584 TI - Reactivation of estrogen receptor alpha by vorinostat sensitizes mesenchymal-like triple-negative breast cancer to aminoflavone, a ligand of the aryl hydrocarbon receptor. AB - OBJECTIVE: Aminoflavone (AF) acts as a ligand of the aryl hydrocarbon receptor (AhR). Expression of estrogen receptor alpha (ERalpha) and AhR-mediated transcriptional induction of CYP1A1 can sensitize breast cancer cells to AF. The objective of this study was to investigate the combined antitumor effect of AF and the histone deacetylase inhibitor vorinostat for treating mesenchymal-like triple-negative breast cancer (TNBC) as well as the underlying mechanisms of such treatment. METHODS: In vitro antiproliferative activity of AFP464 (AF prodrug) in breast cancer cell lines was evaluated by MTS assay. In vitro, the combined effect of AFP464 and vorinostat on cell proliferation was assessed by the Chou Talalay method. In vivo, antitumor activity of AFP464, given alone and in combination with vorinostat, was studied using TNBC xenograft models. Knockdown of ERalpha was performed using specific, small-interfering RNA. Western blot, quantitative RT-PCR, immunofluorescence, and immunohistochemical staining were performed to study the mechanisms underlying the combined antitumor effect. RESULTS: Luminal and basal A subtype breast cancer cell lines were sensitive to AFP464, whereas basal B subtype or mesenchymal-like TNBC cells were resistant. Vorinostat sensitized mesenchymal-like TNBC MDA-MB-231 and Hs578T cells to AFP464. It also potentiated the antitumor activity of AFP464 in a xenograft model using MDA-MB-231 cells. In vitro and in vivo mechanistic studies suggested that vorinostat reactivated ERalpha expression and restored AhR-mediated transcriptional induction of CYP1A1. CONCLUSION: The response of breast cancer cells to AF or AFP464 was associated with their gene expression profile. Vorinostat sensitized mesenchymal-like TNBC to AF, at least in part, by reactivating ERalpha expression and restoring the responsiveness of AhR to AF. PMID- 24058586 TI - Quantitative evaluation of 3D mouse behaviors and motor function in the open field after spinal cord injury using markerless motion tracking. AB - Thousands of scientists strive to identify cellular mechanisms that could lead to breakthroughs in developing ameliorative treatments for debilitating neural and muscular conditions such as spinal cord injury (SCI). Most studies use rodent models to test hypotheses, and these are all limited by the methods available to evaluate animal motor function. This study's goal was to develop a behavioral and locomotor assessment system in a murine model of SCI that enables quantitative kinematic measurements to be made automatically in the open-field by applying markerless motion tracking approaches. Three-dimensional movements of eight naive, five mild, five moderate, and four severe SCI mice were recorded using 10 cameras (100 Hz). Background subtraction was used in each video frame to identify the animal's silhouette, and the 3D shape at each time was reconstructed using shape-from-silhouette. The reconstructed volume was divided into front and back halves using k-means clustering. The animal's front Center of Volume (CoV) height and whole-body CoV speed were calculated and used to automatically classify animal behaviors including directed locomotion, exploratory locomotion, meandering, standing, and rearing. More detailed analyses of CoV height, speed, and lateral deviation during directed locomotion revealed behavioral differences and functional impairments in animals with mild, moderate, and severe SCI when compared with naive animals. Naive animals displayed the widest variety of behaviors including rearing and crossing the center of the open-field, the fastest speeds, and tallest rear CoV heights. SCI reduced the range of behaviors, and decreased speed (r = .70 p<.005) and rear CoV height (r = .65 p<.01) were significantly correlated with greater lesion size. This markerless tracking approach is a first step toward fundamentally changing how rodent movement studies are conducted. By providing scientists with sensitive, quantitative measurement methods, subjectivity and human error is reduced, potentially providing insights leading to breakthroughs in treating human disease. PMID- 24058585 TI - Seasonality of Kawasaki disease: a global perspective. AB - BACKGROUND: Understanding global seasonal patterns of Kawasaki disease (KD) may provide insight into the etiology of this vasculitis that is now the most common cause of acquired heart disease in children in developed countries worldwide. METHODS: Data from 1970-2012 from 25 countries distributed over the globe were analyzed for seasonality. The number of KD cases from each location was normalized to minimize the influence of greater numbers from certain locations. The presence of seasonal variation of KD at the individual locations was evaluated using three different tests: time series modeling, spectral analysis, and a Monte Carlo technique. RESULTS: A defined seasonal structure emerged demonstrating broad coherence in fluctuations in KD cases across the Northern Hemisphere extra-tropical latitudes. In the extra-tropical latitudes of the Northern Hemisphere, KD case numbers were highest in January through March and approximately 40% higher than in the months of lowest case numbers from August through October. Datasets were much sparser in the tropics and the Southern Hemisphere extra-tropics and statistical significance of the seasonality tests was weak, but suggested a maximum in May through June, with approximately 30% higher number of cases than in the least active months of February, March and October. The seasonal pattern in the Northern Hemisphere extra-tropics was consistent across the first and second halves of the sample period. CONCLUSION: Using the first global KD time series, analysis of sites located in the Northern Hemisphere extra-tropics revealed statistically significant and consistent seasonal fluctuations in KD case numbers with high numbers in winter and low numbers in late summer and fall. Neither the tropics nor the Southern Hemisphere extra-tropics registered a statistically significant aggregate seasonal cycle. These data suggest a seasonal exposure to a KD agent that operates over large geographic regions and is concentrated during winter months in the Northern Hemisphere extra-tropics. PMID- 24058587 TI - Drug screening identifies niclosamide as an inhibitor of breast cancer stem-like cells. AB - The primary cause of death from breast cancer is the progressive growth of tumors and resistance to conventional therapies. It is currently believed that recurrent cancer is repopulated according to a recently proposed cancer stem cell hypothesis. New therapeutic strategies that specifically target cancer stem-like cells may represent a new avenue of cancer therapy. We aimed to discover novel compounds that target breast cancer stem-like cells. We used a dye-exclusion method to isolate side population (SP) cancer cells and, subsequently, subjected these SP cells to a sphere formation assay to generate SP spheres (SPS) from breast cancer cell lines. Surface markers, stemness genes, and tumorigenicity were used to test stem properties. We performed a high-throughput drug screening using these SPS. The effects of candidate compounds were assessed in vitro and in vivo. We successfully generated breast cancer SPS with stem-like properties. These SPS were enriched for CD44(high) (2.8-fold) and CD24(low) (4-fold) cells. OCT4 and ABCG2 were overexpressed in SPS. Moreover, SPS grew tumors at a density of 10(3), whereas an equivalent number of parental cells did not initiate tumor formation. A clinically approved drug, niclosamide, was identified from the LOPAC chemical library of 1,258 compounds. Niclosamide downregulated stem pathways, inhibited the formation of spheroids, and induced apoptosis in breast cancer SPS. Animal studies also confirmed this therapeutic effect. The results of this proof of-principle study may facilitate the development of new breast cancer therapies in the near future. The extension of niclosamide clinical trials is warranted. PMID- 24058588 TI - Preclinical development of a novel class of CXCR4 antagonist impairing solid tumors growth and metastases. AB - The CXCR4/CXCL12 axis plays a role in cancer metastases, stem cell mobilization and chemosensitization. Proof of concept for efficient CXCR4 inhibition has been demonstrated in stem cell mobilization prior to autologous transplantation in hematological malignancies. Nevertheless CXCR4 inhibitors suitable for prolonged use as required for anticancer therapy are not available. To develop new CXCR4 antagonists a rational, ligand-based approach was taken, distinct from the more commonly used development strategy. A three amino acid motif (Ar-Ar-X) in CXCL12, also found in the reverse orientation (X-Ar-Ar) in the vMIP-II inhibitory chemokine formed the core of nineteen cyclic peptides evaluated for inhibition of CXCR4-dependent migration, binding, P-ERK1/2-induction and calcium efflux. Peptides R, S and I were chosen for evaluation in in vivo models of lung metastases (B16-CXCR4 and KTM2 murine osteosarcoma cells) and growth of a renal cells xenograft. Peptides R, S, and T significantly reduced the association of the 12G5-CXCR4 antibody to the receptor and inhibited CXCL12-induced calcium efflux. The four peptides efficiently inhibited CXCL12-dependent migration at concentrations as low as 10 nM and delayed CXCL12-mediated wound healing in PES43 human melanoma cells. Intraperitoneal treatment with peptides R, I or S drastically reduced the number of B16-CXCR4-derived lung metastases in C57/BL mice. KTM2 osteosarcoma lung metastases were also reduced in Balb/C mice following CXCR4 inhibition. All three peptides significantly inhibited subcutaneous growth of SN12C-EGFP renal cancer cells. A novel class of CXCR4 inhibitory peptides was discovered. Three peptides, R, I and S inhibited lung metastases and primary tumor growth and will be evaluated as anticancer agents. PMID- 24058589 TI - The hierarchical process of differentiation of long-lived antibody-secreting cells is dependent on integrated signals derived from antigen and IL-17A. AB - Switched CD19-positive memory B cells purified from mice with chronic immune response against Thalassophrynenattereri venom proteins were cultured with venom or cytokines. Our results confirm the existence of a hierarchic process of differentiation: activated memory B cells progressively acquire increasing levels of CD138 and decreasing levels of CD45R/B220 to finally arrive at ASC with B220(neg) phenotype, which are IgG1-secreting cells. Only Bmem from peritoneal cavity or bone marrow of VTn immunized mice presented the capacity to generate ASC functionally active. IL-17A or IL-21/IL-23/IL-33 improves the ability of venom to induce intracellular IgG of peritoneal derived-ASC. Cognate stimulation with venom and IL-17A is sufficient to down-regulate the expression of CD45R/B220. BAFF-R is up-regulated in splenic or medullar derived-ASC stimulated by venom, CpG or cytokines. Only splenic derived-ASC up-regulate Bcl-2 expression after CpG or the combination of IL-21/IL-23/IL-33 stimulation. Finally, the activation of ASC for IgG1 secretion is triggered by venom proteins in peritoneal cavity and by IL-17A in medullar niche. These results show the importance of the integration of signals downstream of BCR and IL17-A receptors in modulating ASC differentiation, focusing in the microenvironment niche of their generation. PMID- 24058590 TI - Characterization of the mouse neuroinvasiveness of selected European strains of West Nile virus. AB - West Nile virus (WNV) has caused outbreaks and sporadic infections in Central, Eastern and Mediterranean Europe for over 45 years. Most strains responsible for the European and Mediterranean basin outbreaks are classified as lineage 1. In recent years, WNV strains belonging to lineage 1 and 2 have been causing outbreaks of neuroinvasive disease in humans in countries such as Italy, Hungary and Greece, while mass mortality among birds was not reported. This study characterizes three European strains of WNV isolated in Italy (FIN and Ita09) and Hungary (578/10) in terms of in vitro replication kinetics on neuroblastoma cells, LD50 values in C57BL/6 mice, median day mortality, cumulative mortality, concentration of virus in the brain and spinal cord, and the response to infection in the brain. Overall, the results indicate that strains circulating in Europe belonging to both lineage 1 and 2 are highly virulent and that Ita09 and 578/10 are more neurovirulent compared to the FIN strain. PMID- 24058591 TI - Doping control using high and ultra-high resolution mass spectrometry based non targeted metabolomics-a case study of salbutamol and budesonide abuse. AB - We have detected differences in metabolite levels between doped athletes, clean athletes, and volunteers (non athletes). This outcome is obtained by comparing results of measurements from two analytical platforms: UHPLC-QTOF/MS and FT ICR/MS. Twenty-seven urine samples tested positive for glucocorticoids or beta-2 agonists and twenty samples coming from volunteers and clean athletes were analyzed with the two different mass spectrometry approaches using both positive and negative electrospray ionization modes. Urine is a highly complex matrix containing thousands of metabolites having different chemical properties and a high dynamic range. We used multivariate analysis techniques to unravel this huge data set. Thus, the several groups we created were studied by Principal Components Analysis (PCA) and Partial Least Square regression (PLS-DA and OPLS) in the search of discriminating m/z values. The selected variables were annotated and placed on pathway by using MassTRIX. PMID- 24058592 TI - Brachial artery constriction during brachial artery reactivity testing predicts major adverse clinical outcomes in women with suspected myocardial ischemia: results from the NHLBI-sponsored women's ischemia Syndrome Evaluation (WISE) Study. AB - BACKGROUND: Limited brachial artery (BA) flow-mediated dilation during brachial artery reactivity testing (BART) has been linked to increased cardiovascular risk. We report on the phenomenon of BA constriction (BAC) following hyperemia. OBJECTIVES: To determine whether BAC predicts adverse CV outcomes and/or mortality in the women's ischemic Syndrome Evaluation Study (WISE). Further, as a secondary objective we sought to determine the risk factors associated with BAC. METHODS: We performed BART on 377 women with chest pain referred for coronary angiography and followed for a median of 9.5 years. Forearm ischemia was induced with 4 minutes occlusion by a cuff placed distal to the BA and inflated to 40mm Hg > systolic pressure. BAC was defined as >4.8% artery constriction following release of the cuff. The main outcome was major adverse events (MACE) including all-cause mortality, non-fatal MI, non-fatal stroke, or hospitalization for heart failure. RESULTS: BA diameter change ranged from -20.6% to +44.9%, and 41 (11%) women experienced BAC. Obstructive CAD and traditional CAD risk factors were not predictive of BAC. Overall, 39% of women with BAC experienced MACE vs. 22% without BAC (p=0.004). In multivariate Cox proportional hazards regression, BAC was a significant independent predictor of MACE (p=0.018) when adjusting for obstructive CAD and traditional risk factors. CONCLUSIONS: BAC predicts almost double the risk for major adverse events compared to patients without BAC. This risk was not accounted for by CAD or traditional risk factors. The novel risk marker of BAC requires further investigation in women. PMID- 24058593 TI - Trans-kingdom horizontal DNA transfer from bacteria to yeast is highly plastic due to natural polymorphisms in auxiliary nonessential recipient genes. AB - With the rapid accumulation of genomic information from various eukaryotes in the last decade, genes proposed to have been derived from recent horizontal gene transfer (HGT) events have been reported even in non-phagotrophic unicellular and multicellular organisms, but the molecular pathways underlying HGT remain to be explained. The development of in vitro HGT detection systems, which permit the molecular and genetic analyses of donor and recipient organisms and quantify HGT, are helpful in order to gain insight into mechanisms that may contribute to contemporary HGT events or may have contributed to past HGT events. We applied a horizontal DNA transfer system model based on conjugal gene transfer called trans kingdom conjugation (TKC) from the prokaryote Escherichia coli to the eukaryote Saccharomyces cerevisiae, and assessed whether and to what extent genetic variations in the eukaryotic recipient affect its receptivity to TKC. Strains from a collection of 4,823 knock-out mutants of S. cerevisiae MAT-alpha haploids were tested for their individual TKC receptivity. Two types of mutants, an ssd1 mutant and respiratory mutants, which are also found in experimental strains and in nature widely, were identified as highly receptive mutants. The TKC efficiency for spontaneously accrued petite (rho (-/0)) mutants of the functional allele (SSD1-V) strain showed increased receptivity. The TKC efficiency of the ssd1Delta mutant was 36% for bacterial conjugation, while that of the petite/ssd1Delta double mutants was even higher (220% in average) compared to bacterial conjugation. This increased TKC receptivity was also observed when other conjugal transfer systems were applied and the donor bacterium was changed to Agrobacterium tumefaciens. These results support the idea that the genomes of certain eukaryotes have been exposed to exogenous DNA more frequently and continuously than previously thought. PMID- 24058594 TI - The overexpression of scaffolding protein NEDD9 promotes migration and invasion in cervical cancer via tyrosine phosphorylated FAK and SRC. AB - NEDD9, a focal adhesion scaffolding protein, has been recently proposed to regulate invasion and metastasis in some cancer types, but unknown in cervical cancer. The aim of this study was to determine if NEDD9 was involved in the progression and metastasis of cervical cancer. The experimental results showed NEDD9 protein was overexpressed in cervical cancer compared with normal cervical epithelium tissues. Overexpression of NEDD9 was correlated with histological grading, lymph node metastasis, and FIGO stage of cervical cancer. Silencing NEDD9 resulted in tyrosine dephosphorylation of FAK and SRC oncoproteins, and decreased cell migration and invasion in the cervical carcinoma SiHa and HeLa cells. Overexpression of NEDD9 led to tyrosine phosphorylation of FAK and SRC oncoproteins, and increased cell migration and invasion. Moreover, tyrosine phosphorylation of NEDD9 was significantly decreased via suppressing tyrosine phosphorylation of FAK or SRC, suggesting a positive feedback loop of tyrosine phosphorylation between NEDD9 and FAK or SRC. In addition, our data showed that silencing NEDD9 decreased Vimentin expression and increased E-cadherin expression in cervical cancer cells, and vice versa. E-cadherin was subject to regulation of NEDD9, FAK and SRC, but altered neither tyrosine-phosphorylated nor total NEDD9. Our findings suggest that NEDD9 is overexpressed in cervical cancer tissues and cells, and overexpressed NEDD9 promotes migration and invasion in cervical carcinoma cells, probably via a positive feedback loop of tyrosine phosphorylation between NEDD9 and FAK or SRC. PMID- 24058595 TI - TLR2 mediates Helicobacter pylori-induced tolerogenic immune response in mice. AB - We have shown that Helicobacter pylori induces tolerogenic programming of dendritic cells and inhibits the host immune response. Toll-like receptors (TLRs) represent a class of transmembrane pattern recognition receptors essential for microbial recognition and control of the innate immune response. In this study, we examined the role of TLRs in mediating H. pylori tolerogenic programming of dendritic cells and their impact on anti-H. pylori immunity using C57BL/6 wild type and TLR2-knockout (TLR2KO) mice. We analyzed the response of TLR2KO bone marrow-derived dendritic cells (BMDCs) to H. pylori SS1 stimulation and the outcome of chronic H. pylori infection in TLR2KO mice. We showed that H. pylori stimulated BMDCs upregulated the expression of TLR2, but not TLR4, TLR5, or TLR9. H. pylori-stimulated BMDCs from TLRKO mice induced lower Treg and Th17 responses, but a higher IFN-gamma response compared to H. pylori-stimulated BMDCs from wild type mice. In vivo analyses following an H. pylori infection of 2 months duration showed a lower degree of gastric H. pylori colonization in TLR2KO mice and more severe gastric immunopathology compared to WT mice. The gastric mucosa of the infected TLR2KO mice showed a lower mRNA expression of Foxp3, IL-10, and IL-17A, but higher expression of IFN-gamma compared to the gastric mRNA expression in infected wild-type mice. Moreover, the H. pylori-specific Th1 response was higher and the Treg and Th17 responses were lower in the spleens of infected TLR2KO mice compared to infected WT mice. Our data indicate that H. pylori mediates immune tolerance through TLR2-derived signals and inhibits Th1 immunity, thus evading host defense. TLR2 may be an important target in the modulation of the host response to H. pylori. PMID- 24058596 TI - Effects of fully open-air [CO2] elevation on leaf photosynthesis and ultrastructure of Isatis indigotica fort. AB - Traditional Chinese medicine relies heavily on herbs, yet there is no information on how these herb plants would respond to climate change. In order to gain insight into such response, we studied the effect of elevated [CO2] on Isatis indigotica Fort, one of the most popular Chinese herb plants. The changes in leaf photosynthesis, chlorophyll fluorescence, leaf ultrastructure and biomass yield in response to elevated [CO2] (550+/-19 umol mol(-1)) were determined at the Free Air Carbon dioxide Enrichment (FACE) experimental facility in North China. Photosynthetic ability of I. indigotica was improved under elevated [CO2]. Elevated [CO2] increased net photosynthetic rate (P N), water use efficiency (WUE) and maximum rate of electron transport (J max) of upper most fully-expended leaves, but not stomatal conductance (gs), transpiration ratio (Tr) and maximum velocity of carboxylation (V c,max). Elevated [CO2] significantly increased leaf intrinsic efficiency of PSII (Fv'/Fm') and quantum yield of PSII(PhiPS II ), but decreased leaf non-photochemical quenching (NPQ), and did not affect leaf proportion of open PSII reaction centers (qP) and maximum quantum efficiency of PSII (Fv/Fm). The structural chloroplast membrane, grana layer and stroma thylakoid membranes were intact under elevated [CO2], though more starch grains were accumulated within the chloroplasts than that of under ambient [CO2]. While the yield of I. indigotica was higher due to the improved photosynthesis under elevated [CO2], the content of adenosine, one of the functional ingredients in indigowoad root was not affected. PMID- 24058597 TI - Identification of six novel PTH1R mutations in families with a history of primary failure of tooth eruption. AB - Primary Failure of tooth Eruption (PFE) is a non-syndromic disorder which can be caused by mutations in the parathyroid hormone receptor 1 gene (PTH1R). Traditionally, the disorder has been identified clinically based on post-emergent failure of eruption of permanent molars. However, patients with PTH1R mutations will not benefit from surgical and/or orthodontic treatment and it is therefore clinically important to establish whether a given failure of tooth eruption is caused by a PTH1R defect or not. We analyzed the PTH1R gene in six patients clinically diagnosed with PFE, all of which had undergone surgical and/or orthodontic interventions, and identified novel PTH1R mutations in all. Four of the six mutations were predicted to abolish correct mRNA maturation either through introduction of premature stop codons (c.947C>A and c.1082G>A), or by altering correct mRNA splicing (c.544-26_544-23del and c.989G>T). The latter was validated by transfection of minigenes. The six novel mutations expand the mutation spectrum for PFE from eight to 14 pathogenic mutations. Loss-of-function mutations in PTH1R are also associated with recessively inherited Blomstrand chondrodysplasia. We compiled all published PTH1R mutations and identified a mutational overlap between Blomstrand chondrodysplasia and PFE. The results suggest that a genetic approach to preclinical diagnosis will have important implication for surgical and orthodontic treatment of patients with failure of tooth eruption. PMID- 24058598 TI - Toxic effects of silica nanoparticles on zebrafish embryos and larvae. AB - Silica nanoparticles (SiNPs) have been widely used in biomedical and biotechnological applications. Environmental exposure to nanomaterials is inevitable as they become part of our daily life. Therefore, it is necessary to investigate the possible toxic effects of SiNPs exposure. In this study, zebrafish embryos were treated with SiNPs (25, 50, 100, 200 ug/mL) during 4-96 hours post fertilization (hpf). Mortality, hatching rate, malformation and whole embryo cellular death were detected. We also measured the larval behavior to analyze whether SiNPs had adverse effects on larvae locomotor activity. The results showed that as the exposure dosages increasing, the hatching rate of zebrafish embryos was decreased while the mortality and cell death were increased. Exposure to SiNPs caused embryonic malformations, including pericardial edema, yolk sac edema, tail and head malformation. The larval behavior testing showed that the total swimming distance was decreased in a dose dependent manner. The lower dose (25 and 50 ug/mL SiNPs) produced substantial hyperactivity while the higher doses (100 and 200 ug/mL SiNPs) elicited remarkably hypoactivity in dark periods. In summary, our data indicated that SiNPs caused embryonic developmental toxicity, resulted in persistent effects on larval behavior. PMID- 24058599 TI - Utilization of cervical cancer screening services and trends in screening positivity rates in a 'screen-and-treat' program integrated with HIV/AIDS care in Zambia. AB - BACKGROUND: In the absence of stand-alone infrastructures for delivering cervical cancer screening services, efforts are underway in sub-Saharan Africa to dovetail screening with ongoing vertical health initiatives like HIV/AIDS care programs. Yet, evidence demonstrating the utilization of cervical cancer prevention services in such integrated programs by women of the general population is lacking. METHODS: We analyzed program operations data from the Cervical Cancer Prevention Program in Zambia (CCPPZ), the largest public sector programs of its kind in sub-Saharan Africa. We evaluated patterns of utilization of screening services by HIV serostatus, examined contemporaneous trends in screening outcomes, and used multivariable modeling to identify factors associated with screening test positivity. RESULTS: Between January 2006 and April 2011, CCPPZ services were utilized by 56,247 women who underwent cervical cancer screening with visual inspection with acetic acid (VIA), aided by digital cervicography. The proportion of women accessing these services who were HIV-seropositive declined from 54% to 23% between 2006-2010, which coincided with increasing proportions of HIV-seronegative women (from 22% to 38%) and women whose HIV serostatus was unknown (from 24% to 39%) (all p-for trend<0.001). The rates of VIA screening positivity declined from 47% to 17% during the same period (p-for trend <0.001), and this decline was consistent across all HIV serostatus categories. After adjusting for demographic and sexual/reproductive factors, HIV seropositive women were more than twice as likely (Odds ratio 2.62, 95% CI 2.49, 2.76) to screen VIA-positive than HIV-seronegative women. CONCLUSIONS: This is the first 'real world' demonstration in a public sector implementation program in a sub-Saharan African setting that with successful program scale-up efforts, nurse-led cervical cancer screening programs targeting women with HIV can expand and serve all women, regardless of HIV serostatus. Screening program performance can improve with adequate emphasis on training, quality control, and telemedicine support for nurse-providers in clinical decision making. PMID- 24058600 TI - Tonic and phasic smooth muscle contraction is not regulated by the PKCalpha - CPI 17 pathway in swine stomach antrum and fundus. AB - Regulation of myosin light chain phosphatase (MLCP) via protein kinase C (PKC) and the 17 kDa PKC-potentiated inhibitor of myosin light chain phosphatase (CPI 17) has been reported as a Ca(2+) sensitization signaling pathway in smooth muscle (SM), and thus may be involved in tonic vs. phasic contractions. This study examined the protein expression and spatial-temporal distribution of PKCalpha and CPI-17 in intact SM tissues. KCl or carbachol (CCh) stimulation of tonic stomach fundus SM generates a sustained contraction while the phasic stomach antrum generates a transient contraction. In addition, the tonic fundus generates greater relative force than phasic antrum with 1 uM phorbol 12, 13 dibutyrate (PDBu) stimulation which is reported to activate the PKCalpha - CPI-17 pathway. Western blot analyses demonstrated that this contractile difference was not caused by a difference in the protein expression of PKCalpha or CPI-17 between these two tissues. Immunohistochemical results show that the distribution of PKCalpha in the longitudinal and circular layers of the fundus and antrum do not differ, being predominantly localized near the SM cell plasma membrane. Stimulation of either tissue with 1 uM PDBu or 1 uM CCh does not alter this peripheral PKCalpha distribution. There are no differences between these two tissues for the CPI-17 distribution, but unlike the PKCalpha distribution, CPI-17 appears to be diffusely distributed throughout the cytoplasm under relaxed tissue conditions but shifts to a primarily peripheral distribution at the plasma membrane with stimulation of the tissues with 1 uM PDBu or 1 uM CCh. Results from double labeling show that neither PKCalpha nor CPI-17 co-localize at the adherens junction (vinculin/talin) at the membrane but they do co-localize with each other and with caveoli (caveolin) at the membrane. This lack of difference suggests that the PKCalpha - CPI-17 pathway is not responsible for the tonic vs. phasic contractions observed in stomach fundus and antrum. PMID- 24058601 TI - Empathic fear responses in mice are triggered by recognition of a shared experience. AB - Empathy is an important psychological capacity that involves the ability to recognize and share emotions with others. In humans, empathy for others is facilitated by having had a similar prior experience. It increases with the intensity of distress that observers believe is occurring to others, and is associated with acute emotional responses to witnessing others' distress. We sought to develop a relatively simple and fast mouse model of human empathy that resembled these characteristics. We modeled empathy by measuring the freezing of observer mice to observing the footshock of a subject mouse. Observer mice froze to subject footshocks only when they had a similar shock experience 24 hours earlier. Moreover, this freezing increased with the number of footshocks given to the subject and it was accentuated within seconds after footshock delivery. Freezing was not seen in naive observers or in experienced observers that observed a subject who was spared footshock. Observers did not freeze to a subject's footshock when they had experienced a swim stress 24 hours prior, demonstrating a specific effect for shared experience, as opposed to a generalized stressor in eliciting observer mouse freezing. We propose that this two-day experimental protocol resembles many aspects of human empathy in a mouse model that is amenable to transgenic analysis of neural substrates for empathy and its impairment in certain clinical disorders. PMID- 24058602 TI - Challenges and implications of routine depression screening for depression in chronic disease and multimorbidity: a cross sectional study. AB - BACKGROUND: Depression screening in chronic disease is advocated but its impact on routine practice is uncertain. We examine the effects of a programme of incentivised depression screening in chronic disease within a UK primary care setting. METHODS AND FINDINGS: Cross sectional analysis of anonymised, routinely collected data (2008-9) from family practices in Scotland serving a population of circa 1.8 million. Primary care registered patients with at least one of three chronic diseases, coronary heart disease, diabetes and stroke, underwent incentivised depression screening using the Hospital Anxiety and Depression Score (HADS). 125143 patients were identified with at least one chronic disease. 10670 (8.5%) were under treatment for depression and exempt from screening. Of remaining, HADS were recorded for 35537 (31.1%) patients. 7080 (19.9% of screened) had raised HADS (>=8); majority had indications of mild depression with HADS between 8 and 10. Over 6 months, 572 (8%) of those with raised HADS (>=8) were initiated on antidepressants, while 696 (2.4%) patients with normal HADS (<8) were also initiated on antidepressants (relative risk of antidepressant initiation with raised HADS 3.3 (CI 2.97-3.67), p value <0.0001). Of those with multimorbidity who were screened, 24.3% had raised HADS (>=8). A raised HADS was more likely in females, socioeconomically deprived, multimorbid or younger (18 44) individuals. Females and 45-64 years old were more likely to receive antidepressants. LIMITATIONS: retrospective study of routinely collected data. CONCLUSIONS: Despite incentivisation, only a minority of patients underwent depression screening, suggesting that systematic depression screening in chronic disease can be difficult to achieve in routine practice. Targeting those at greatest risk such as the multimorbid or using simpler screening methods may be more effective. Raised HADS was associated with higher number of new antidepressant prescriptions which has significant resource implications. The clinical benefits of such screening remain uncertain and merits investigation. PMID- 24058603 TI - Predictive value of BRCA1, ERCC1, ATP7B, PKM2, TOPOI, TOPOmicron-IIA, TOPOIIB and C-MYC genes in patients with small cell lung cancer (SCLC) who received first line therapy with cisplatin and etoposide. AB - BACKGROUND: The aim of the study was to evaluate the predictive value of genes involved in the action of cisplatin-etoposide in Small Cell Lung Cancer (SCLC). METHODS: 184 SCLC patients' primary tumour samples were analyzed for ERCCI, BRCA1, ATP7B, PKM2 TOPOI, TOPOIIA, TOPOIIB and C-MYC mRNA expression. All patients were treated with cisplatin-etoposide. RESULTS: The patients' median age was 63 years and 120 (65%) had extended stage, 75 (41%) had increased LDH serum levels and 131 (71%) an ECOG performance status was 0-1. Patients with limited stage, whose tumours expressed high ERCC1 (p=0.028), PKM2 (p=0.046), TOPOI (p=0.008), TOPOIIA (p=0.002) and TOPOIIB (p<0.001) mRNA had a shorter Progression Free Survival (PFS). In limited stage patients, high expression of ERCC1 (p=0.014), PKM2 (p=0.026), TOPOIIA (p=0.021) and TOPOIIB (p=0.019) was correlated with decreased median overall survival (mOS) while in patients with extended stage, only high TOPOIIB expression had a negative impact on Os (p=0.035). The favorable expression signature expression signature (low expression of ERCC1, PKM2, TOPOIIA and TOPOIIB) was correlated with significantly better PFS and Os in both LS-SCLC (p<0.001 and p=0.007, respectively) and ES-SCLC (p=0.007 and (p=0.011, respectively) group. The unfavorable expression signature was an independent predictor for poor PFS (HR: 3.18; p=0.002 and HR: 3.14; p=0.021) and Os (HR: 4.35; p=0.001and HR: 3.32; p=0.019) in both limited and extended stage, respectively. CONCLUSIONS: Single gene's expression analysis as well as the integrated analysis of ERCC1, PKM2, TOPOIIA and TOPOIIB may predict treatment outcome in patients with SCLC. These findings should be further validated in a prospective study. PMID- 24058604 TI - STE20/SPS1-related proline/alanine-rich kinase is involved in plasticity of GABA signaling function in a mouse model of acquired epilepsy. AB - The intracellular concentration of chloride ([Cl(-)]i) determines the strength and polarity of GABA neurotransmission. STE20/SPS1-related proline/alanine-rich kinase (SPAK) is known as an indirect regulator of [Cl(-)]i for its activation of Na-K-2 Cl(-)co-transporters (NKCC) and inhibition of K-Cl(-)co-transporters (KCC) in many organs. NKCC1 or KCC2 expression changes have been demonstrated previously in the hippocampal neurons of mice with pilocarpine-induced status epilepticus (PISE). However, it remains unclear whether SPAK modulates [Cl(-)]i via NKCC1 or KCC2 in the brain. Also, there are no data clearly characterizing SPAK expression in cortical or hippocampal neurons or confirming an association between SPAK and epilepsy. In the present study, we examined SPAK expression and co-expression with NKCC1 and KCC2 in the hippocampal neurons of mice with PISE, and we investigated alterations in SPAK expression in the hippocampus of such mice. Significant increases in SPAK mRNA and protein levels were detected during various stages of PISE in the PISE mice in comparison to levels in age-matched sham (control) and blank treatment (control) mice. SPAK and NKCC1 expression increased in vitro, while KCC2 was down-regulated in hippocampal neurons following hypoxic conditioning. However, SPAK overexpression did not influence the expression levels of NKCC1 or KCC2. Using co-immunoprecipitation, we determined that the intensity of interaction between SPAK and NKCC1 and between SPAK and KCC2 increased markedly after oxygen-deprivation, whereas SPAK overexpression strengthened the relationships. The [Cl(-)]i of hippocampal neurons changed in a corresponding manner under the different conditions. Our data suggests that SPAK is involved in the plasticity of GABA signaling function in acquired epilepsy via adjustment of [Cl(-)]i in hippocampal neurons. PMID- 24058605 TI - Plant-based assessment of inherent soil productivity and contributions to China's cereal crop yield increase since 1980. AB - OBJECTIVE: China's food production has increased 6-fold during the past half century, thanks to increased yields resulting from the management intensification, accomplished through greater inputs of fertilizer, water, new crop strains, and other Green Revolution's technologies. Yet, changes in underlying quality of soils and their effects on yield increase remain to be determined. Here, we provide a first attempt to quantify historical changes in inherent soil productivity and their contributions to the increase in yield. METHODS: The assessment was conducted based on data-set derived from 7410 on-farm trials, 8 long-term experiments and an inventory of soil organic matter concentrations of arable land. RESULTS: Results show that even without organic and inorganic fertilizer addition crop yield from on-farm trials conducted in the 2000s was significantly higher compared with those in the 1980s - the increase ranged from 0.73 to 1.76 Mg/ha for China's major irrigated cereal-based cropping systems. The increase in on-farm yield in control plot since 1980s was due primarily to the enhancement of soil-related factors, and reflected inherent soil productivity improvement. The latter led to higher and stable yield with adoption of improved management practices, and contributed 43% to the increase in yield for wheat and 22% for maize in the north China, and, 31%, 35% and 22% for early and late rice in south China and for single rice crop in the Yangtze River Basin since 1980. CONCLUSIONS: Thus, without an improvement in inherent soil productivity, the 'Agricultural Miracle in China' would not have happened. A comprehensive strategy of inherent soil productivity improvement in China, accomplished through combining engineering-based measures with biological approaches, may be an important lesson for the developing world. We propose that advancing food security in 21st century for both China and other parts of world will depend on continuously improving inherent soil productivity. PMID- 24058606 TI - Effect of saline injection mixing on accuracy of conductance lumen sizing of peripheral vessels. AB - Transient displacement of blood in vessel lumen with saline injection is necessary in the conductance method for measurement of arterial cross-sectional area (CSA). The displacement of blood is dictated by the interactions between arterial flow hemodynamics and saline injection dynamics. The objective of the present study is to understand how the accuracy of conductance measurements is affected by the saline injection. Computational simulations were performed to assess the error in predictions of arterial CSA using conductance measurements over a range of peripheral artery diameters (i.e., 4, 7, and 10 mm) with an introducing catheter (6 Fr.) for various blood flow and saline injection rates. The simulation results were validated using the conductance measurements of the phantoms with known diameters (i.e., 7 and 10 mm). The results demonstrated that a minimum ratio of saline injection rate to blood flow rate of 3 is needed to fully displace the blood and result in accurate measurement of CSA for the peripheral artery sizes considered. Furthermore, the error was shown to be minimized as the detection electrodes are positioned between the distal to the mixing zone induced by saline injection and far downstream (4-8 cm from the injection catheter tip). The present study shows that even for the large peripheral arteries (7-10 mm) where mixing can occur, an appropriate injection rate and detection position can produce accurate measurement of lumen size. PMID- 24058607 TI - Role of PINCH and its partner tumor suppressor Rsu-1 in regulating liver size and tumorigenesis. AB - Particularly interesting new cysteine-histidine-rich protein (PINCH) protein is part of the ternary complex known as the IPP (integrin linked kinase (ILK)-PINCH Parvin-alpha) complex. PINCH itself binds to ILK and to another protein known as Rsu-1 (Ras suppressor 1). We generated PINCH 1 and PINCH 2 Double knockout mice (referred as PINCH DKO mice). PINCH2 elimination was systemic whereas PINCH1 elimination was targeted to hepatocytes. The genetically modified mice were born normal. The mice were sacrificed at different ages after birth. Soon after birth, they developed abnormal hepatic histology characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells and increased deposition of extracellular matrix. After a sustained and prolonged proliferation of all epithelial components, proliferation subsided and final liver weight by the end of 30 weeks in livers with PINCH DKO deficient hepatocytes was 40% larger than the control mice. The livers of the PINCH DKO mice were also very stiff due to increased ECM deposition throughout the liver, with no observed nodularity. Mice developed liver cancer by one year. These mice regenerated normally when subjected to 70% partial hepatectomy and did not show any termination defect. Ras suppressor 1 (Rsu-1) protein, the binding partner of PINCH is frequently deleted in human liver cancers. Rsu-1 expression is dramatically decreased in PINCH DKO mouse livers. Increased expression of Rsu-1 suppressed cell proliferation and migration in HCC cell lines. These changes were brought about not by affecting activation of Ras (as its name suggests) but by suppression of Ras downstream signaling via RhoGTPase proteins. In conclusion, our studies suggest that removal of PINCH results in enlargement of liver and tumorigenesis. Decreased levels of Rsu-1, a partner for PINCH and a protein often deleted in human liver cancer, may play an important role in the development of the observed phenotype. PMID- 24058608 TI - GSTCD and INTS12 regulation and expression in the human lung. AB - Genome-Wide Association Study (GWAS) meta-analyses have identified a strong association signal for lung function, which maps to a region on 4q24 containing two oppositely transcribed genes: glutathione S-transferase, C-terminal domain containing (GSTCD) and integrator complex subunit 12 (INTS12). Both genes were found to be expressed in a range of human airway cell types. The promoter regions and transcription start sites were determined in mRNA from human lung and a novel splice variant was identified for each gene. We obtained the following evidence for GSTCD and INTS12 co-regulation and expression: (i) correlated mRNA expression was observed both via Q-PCR and in a lung expression quantitative trait loci (eQTL) study, (ii) induction of both GSTCD and INTS12 mRNA expression in human airway smooth muscle cells was seen in response to TGFbeta1, (iii) a lung eQTL study revealed that both GSTCD and INTS12 mRNA levels positively correlate with percent predicted FEV1, and (iv) FEV1 GWAS associated SNPs in 4q24 were found to act as an eQTL for INTS12 in a number of tissues. In fixed sections of human lung tissue, GSTCD protein expression was ubiquitous, whereas INTS12 expression was predominantly in epithelial cells and pneumocytes. During human fetal lung development, GSTCD protein expression was observed to be highest at the earlier pseudoglandular stage (10-12 weeks) compared with the later canalicular stage (17 19 weeks), whereas INTS12 expression levels did not alter throughout these stages. Knowledge of the transcriptional and translational regulation and expression of GSTCD and INTS12 provides important insights into the potential role of these genes in determining lung function. Future work is warranted to fully define the functions of INTS12 and GSTCD. PMID- 24058609 TI - The ins and outs of the BCCAo model for chronic hypoperfusion: a multimodal and longitudinal MRI approach. AB - Cerebral hypoperfusion induced by bilateral common carotid artery occlusion (BCCAo) in rodents has been proposed as an experimental model of white matter damage and vascular dementia. However, the histopathological and behavioral alterations reported in this model are variable and a full characterization of the dynamic alterations is not available. Here we implemented a longitudinal multimodal magnetic resonance imaging (MRI) design, including time-of-flight angiography, high resolution T1-weighted images, T2 relaxometry mapping, diffusion tensor imaging, and cerebral blood flow measurements up to 12 weeks after BCCAo or sham-operation in Wistar rats. Changes in MRI were related to behavioral performance in executive function tasks and histopathological alterations in the same animals. MRI frequently (70%) showed various degrees of acute ischemic lesions, ranging from very small to large subcortical infarctions. Independently, delayed MRI changes were also apparent. The patterns of MRI alterations were related to either ischemic necrosis or gliosis. Progressive microstructural changes revealed by diffusion tensor imaging in white matter were confirmed by observation of myelinated fiber degeneration, including severe optic tract degeneration. The latter interfered with the visually cued learning paradigms used to test executive functions. Independently of brain damage, BCCAo induced progressive arteriogenesis in the vertebrobasilar tree, a process that was associated with blood flow recovery after 12 weeks. The structural alterations found in the basilar artery were compatible with compensatory adaptive changes driven by shear stress. In summary, BCCAo in rats induces specific signatures in multimodal MRI that are compatible with various types of histological lesion and with marked adaptive arteriogenesis. PMID- 24058610 TI - Mechanical ventilation enhances HMGB1 expression in an LPS-induced lung injury model. AB - BACKGROUND: Mechanical ventilation (MV) can augment inflammatory response in lipopolysaccharide (LPS) challenged lungs. High mobility group box 1 protein (HMGB1) is a pro-inflammatory mediator in ventilator-induced lung injury, but its mechanisms are not well defined. This study investigated the role of HMGB1 in lung inflammation in response to the combination of MV and LPS treatment. METHODS: Forty-eight male Sprague-Dawley rats were randomized to one of four groups: sham control; LPS treatment; mechanical ventilation; mechanical ventilation with LPS treatment. Mechanically ventilated animals received 10 ml/kg tidal volumes at a rate of 40 breaths/min for 4 h. In the HMGB1-blockade study, sixteen rats were randomly assigned to HMGB1 antibody group or control antibody group and animals were subjected to MV+LPS as described above. A549 cells were pre-incubated with different signal inhibitors before subjected to 4 h of cyclic stretch. Lung wet/dry weight (W/D) ratio, total protein and IgG concentration, number of neutrophils in bronchoalveolar lavage fluid (BALF), and lung histological changes were examined. The levels of interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2) and HMGB1 in BALF were measured using ELISA. Real-time quantitative PCR and Western blot were used to analyze mRNA and protein expression of HMGB1. Western blot were employed to analyze the activation of IkappaB-alpha, NF-kappaB, JNK, ERK, and p38. RESULTS: MV significantly augmented LPS-induced lung injury and HMGB1 expression, which was correlated with the increase in IL-1beta, IL-6 and MIP-2 levels in BALF. In vivo, intratracheally administration of HMGB1 antibody significantly attenuated pulmonary inflammatory injury. In vitro experiments showed cyclic stretch induced HMGB1 expression through signaling pathways including p38 and NF-kappaB. CONCLUSIONS: The findings indicated that moderate tidal volume MV augmented LPS induced lung injury by up-regulating HMGB1. The mechanism of HMGB1-mediated lung injury is likely to be signaling through p38 and NF-kappaB pathways. PMID- 24058611 TI - Non-high-density lipoprotein cholesterol on the risks of stroke: a result from the Kailuan study. AB - AIMS: To prospectively explore the association between non-high-density lipoprotein cholesterol (non-HDLC) and the risks of stroke and its subtypes. METHODS: A total of 95,916 participants (18-98 years old; 76,354 men and 19,562 women) from a Chinese urban community who were free of myocardial infarction and stroke at baseline time point (2006-2007) were eligible and enrolled in the study. The serum non-HDLC levels of participants were determined by subtracting the high-density lipoprotein cholesterol (HDLC) from total serum cholesterol. The primary outcome was the first occurrence of stroke, which was diagnosed according to the World Health Organization criteria and classified into three subtypes: ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. The Cox proportional hazards models were used to estimate risk of stroke and its subtypes. RESULTS: During the four-year follow-up, we identified 1614 stroke events (1,156 ischemic, 416 intracerebral hemorrhagic and 42 subarachnoid hemorrhagic). Statistical analyses showed that hazard ratios (HR) (95% Confidence Interval: CI) of serum Non-HDLC level for total and subtypes of stroke were: 1.08 (1.03-1.12) (total), 1.10 (1.05-1.16) (ischemic), 1.03 (0.96-1.10) (intracerebral hemorrhage) and 0.83 (0.66-1.05) (subarachnoid hemorrhage). HR for non-HDLC refers to the increase per each 20 mg/dl. For total and ischemic stroke, the risks were significantly higher in the fourth and fifth quintiles of non-HDLC concentrations compared to the first quintile after adjusting the confounding factors (total stroke: 4(th) quintile HR=1.33 (1.12-1.59); 5(th) quintile HR = 1.36 (1.15-1.62); ischemic stroke: 4(th) quintile HR =1.34 (1.09-1.66); 5(th) quintile HR = 1.53 (1.24-1.88)). CONCLUSIONS: Our data suggest that serum non HDLC level is an independent risk factor for total and ischemic stroke, and that higher serum non-HDLC concentrations are associated with increased risks for total stroke and ischemic stroke, but not for intracerebral and subarachnoid hemorrhage. PMID- 24058612 TI - Clinical features and surgical management of spinal osteoblastoma: a retrospective study in 18 cases. AB - OBJECTIVES: To investigate the clinical manifestation and surgical outcome of spinal osteoblastoma. METHODS: From June 2006 to July 2011, 18 patients with spinal osteoblastoma treated surgically were analyzed retrospectively. There were 11 males and 7 females with an average age of 27.5 years(range, 16-38 years). The tumors were located at C5 in 7, C6 in 6, C7 in 3, C6-T1 1 in 1 and T11 in 1. Based on WBB classification, 16 were 1-3 or 10-12 and 2 were 4-9 and 1-3. 18 operations had been performed with en bloc resection. A posterior approach was used for 16 patients, and a combined posterior and anterior approach was used for 2 patients. Reconstruction using instrumentation and fusion was performed using spinal instrumentation in 13 patients. We used visual analogue scales (VAS) to evaluate the change of pain before and after the operation, and the McCormick System to assess functional status of the spine. Imaging test was used to review the stability and recurrence rate of spine cord, and the confluence of graft bones. RESULTS: All cases were followed up for 24-80 months (average, 38.4 months). The average surgical time was 120.8 minutes (range, 80-220 minutes), with the average intraoperative blood loss of 520 ml (range, 300-1200 ml). During the follow-up period, the VAS grade reduced from 6.46+/-1.32 to 2.26+/-1.05 (P <0.05). 15 patients had neurological function improved and 3 remained no change which was evaluated by McCormick scale for spinal function status at final follow up. CONCLUSIONS: Spinal osteoblastoma has its own specific radiographic features. There is some recurrence in simple curettage of tumor lesion. The thoroughly en bloc resection of tumor or spondylectomy, bone fusion and strong in Ter fixation are the key points for successful surgical treatment. PMID- 24058613 TI - TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity. AB - Regulatory T cells (Tregs) maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR). T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3 Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO) mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 (+) Tregs into Rag2(-/-) mice revealed that TRAF6-deficient Tregs converted into Foxp3(-) cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3(+) to Foxp3(-) (exFoxp3 cells) was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs. PMID- 24058614 TI - Timing of malaria infection during pregnancy has characteristic maternal, infant and placental outcomes. AB - We conducted a clinical study of pregnant women in Blantyre, Malawi to determine the effect of the timing of malaria infection during pregnancy on maternal, infant and placental outcomes. Women were enrolled in their first or second trimester of their first or second pregnancy and followed every four weeks until delivery. Three doses of sulfadoxine-pyrimethamine were given for intermittent preventive treatment for malaria, and all episodes of parasitemia were treated according to the national guidelines. Placentas were collected at delivery and examined for malaria parasites and pigment by histology. Pregnant women had 0.6 episodes of malaria per person year of follow up. Almost all episodes of malaria were detected at enrollment and malaria infection during the follow up period was rare. Malaria and anemia at the first antenatal visit were independently associated with an increased risk of placental malaria detected at delivery. When all episodes of malaria were treated with effective antimalarial medication, only peripheral malaria infection at the time of delivery was associated with adverse maternal and infant outcomes. One quarter of the analyzed placentas had evidence of malaria infection. Placental histology was 78% sensitive and 89% specific for peripheral malaria infection during pregnancy. This study suggests that in this setting of high antifolate drug resistance, three doses of sulfadoxine pyrimethamine maintain some efficacy in suppressing microscopically detectable parasitemia, although placental infection remains frequent. Even in this urban setting, a large proportion of women have malaria infection at the time of their first antenatal care visit. Interventions to control malaria early and aggressive case detection are required to limit the detrimental effects of pregnancy associated malaria. PMID- 24058615 TI - Aging and calorie restriction oppositely affect mitochondrial biogenesis through TFAM binding at both origins of mitochondrial DNA replication in rat liver. AB - Aging affects mitochondria in a tissue-specific manner. Calorie restriction (CR) is, so far, the only intervention able to delay or prevent the onset of several age-related changes also in mitochondria. Using livers from middle age (18-month old), 28-month-old and 32-month-old ad libitum-fed and 28-month-old calorie restricted rats we found an age-related decrease in mitochondrial DNA (mtDNA) content and mitochondrial transcription factor A (TFAM) amount, fully prevented by CR. We revealed also an age-related decrease, completely prevented by CR, for the proteins PGC-1alpha NRF-1 and cytochrome c oxidase subunit IV, supporting the efficiency of CR to forestall the age-related decrease in mitochondrial biogenesis. Furthermore, CR counteracted the age-related increase in oxidative damage to proteins, represented by the increased amount of oxidized peroxiredoxins (PRX-SO3) in the ad libitum-fed animals. An unexpected age-related decrease in the mitochondrial proteins peroxiredoxin III (Prx III) and superoxide dismutase 2 (SOD2), usually induced by increased ROS and involved in mitochondrial biogenesis, suggested a prevailing relevance of the age-reduced mitochondrial biogenesis above the induction by ROS in the regulation of expression of these genes with aging. The partial prevention of the decrease in Prx III and SOD2 proteins by CR also supported the preservation of mitochondrial biogenesis in the anti-aging action of CR. To investigate further the age- and CR related effects on mitochondrial biogenesis we analyzed the in vivo binding of TFAM to specific mtDNA regions and demonstrated a marked increase in the TFAM bound amounts of mtDNA at both origins of replication with aging, fully prevented by CR. A novel, positive correlation between the paired amounts of TFAM-bound mtDNA at these sub-regions was found in the joined middle age ad libitum-fed and 28-month-old calorie-restricted groups, but not in the 28-month-old ad libitum fed counterpart suggesting a quite different modulation of TFAM binding at both origins of replication in aging and CR. PMID- 24058616 TI - Low control over palatable food intake in rats is associated with habitual behavior and relapse vulnerability: individual differences. AB - The worldwide obesity epidemic poses an enormous and growing threat to public health. However, the neurobehavioral mechanisms of overeating and obesity are incompletely understood. It has been proposed that addiction-like processes may underlie certain forms of obesity, in particular those associated with binge eating disorder. To investigate the role of addiction-like processes in obesity, we adapted a model of cocaine addiction-like behavior in rats responding for highly palatable food. Here, we tested whether rats responding for highly palatable chocolate Ensure would come to show three criteria of addiction-like behavior, i.e., high motivation, continued seeking despite signaled non availability and persistence of seeking despite aversive consequences. We also investigated whether exposure to a binge model (a diet consisting of alternating periods of limited food access and access to highly palatable food), promotes the appearance of food addiction-like behavior. Our data show substantial individual differences in control over palatable food seeking and taking, but no distinct subgroup of animals showing addiction-like behavior could be identified. Instead, we observed a wide range extending from low to very high control over palatable food intake. Exposure to the binge model did not affect control over palatable food seeking and taking, however. Animals that showed low control over palatable food intake (i.e., scored high on the three criteria for addiction-like behavior) were less sensitive to devaluation of the food reward and more prone to food induced reinstatement of extinguished responding, indicating that control over palatable food intake is associated with habitual food intake and vulnerability to relapse. In conclusion, we present an animal model to assess control over food seeking and taking. Since diminished control over food intake is a major factor in the development of obesity, understanding its behavioral and neural underpinnings may facilitate improved management of the obesity epidemic. PMID- 24058618 TI - Caught in the middle: combined impacts of shark removal and coral loss on the fish communities of coral reefs. AB - Due to human activities, marine and terrestrial ecosystems face a future where disturbances are predicted to occur at a frequency and severity unprecedented in the recent past. Of particular concern is the ability of systems to recover where multiple stressors act simultaneously. We examine this issue in the context of a coral reef ecosystem where increases in stressors, such as fisheries, benthic degradation, cyclones and coral bleaching, are occurring at global scales. By utilizing long-term (decadal) monitoring programs, we examined the combined effects of chronic (removal of sharks) and pulse (cyclones, bleaching) disturbances on the trophic structure of coral reef fishes at two isolated atoll systems off the coast of northwest Australia. We provide evidence consistent with the hypothesis that the loss of sharks can have an impact that propagates down the food chain, potentially contributing to mesopredator release and altering the numbers of primary consumers. Simultaneously, we show how the effects of bottom up processes of bleaching and cyclones appear to propagate up the food chain through herbivores, planktivores and corallivores, but do not affect carnivores. Because their presence may promote the abundance of herbivores, the removal of sharks by fishing has implications for both natural and anthropogenic disturbances involving the loss of corals, as herbivores are critical to the progress and outcome of coral recovery. PMID- 24058617 TI - Bile salts affect expression of Escherichia coli O157:H7 genes for virulence and iron acquisition, and promote growth under iron limiting conditions. AB - Bile salts exhibit potent antibacterial properties, acting as detergents to disrupt cell membranes and as DNA-damaging agents. Although bacteria inhabiting the intestinal tract are able to resist bile's antimicrobial effects, relatively little is known about how bile influences virulence of enteric pathogens. Escherichia coli O157:H7 is an important pathogen of humans, capable of causing severe diarrhea and more serious sequelae. In this study, the transcriptome response of E. coli O157:H7 to bile was determined. Bile exposure induced significant changes in mRNA levels of genes related to virulence potential, including a reduction of mRNA for the 41 genes making up the locus of enterocyte effacement (LEE) pathogenicity island. Bile treatment had an unusual effect on mRNA levels for the entire flagella-chemotaxis regulon, resulting in two- to four fold increases in mRNA levels for genes associated with the flagella hook-basal body structure, but a two-fold decrease for "late" flagella genes associated with the flagella filament, stator motor, and chemotaxis. Bile salts also caused increased mRNA levels for seventeen genes associated with iron scavenging and metabolism, and counteracted the inhibitory effect of the iron chelating agent 2,2'-dipyridyl on growth of E. coli O157:H7. These findings suggest that E. coli O157:H7 may use bile as an environmental signal to adapt to changing conditions associated with the small intestine, including adaptation to an iron-scarce environment. PMID- 24058619 TI - MR monitoring of minimally invasive delivery of mesenchymal stem cells into the porcine intervertebral disc. AB - PURPOSE: Bone marrow stem cell therapy is a new, attractive therapeutic approach for treatment of intervertebral disc (IVD) degeneration; however, leakage and backflow of transplanted cells into the structures surrounding the disc may lead to the formation of undesirable osteophytes. The purpose of this study was to develop a technique for minimally invasive and accurate delivery of stem cells. METHODS: Porcine mesenchymal stem cells (MSCs) were labeled with superparamagnetic iron oxide nanoparticles (SPIO, Molday ION rhodamine) and first injected into the explanted swine lumbar IVD, followed by ex vivo 3T MRI. After having determined sufficient sensitivity, IVD degeneration was then induced in swine (n=3) by laser-evaporation. 3 x 10(6) SPIO-labeled cells embedded within hydrogel were injected in 2 doses using a transcutaneous cannula and an epidural anesthesia catheter. T2-weighted MR images were obtained at 3T before and immediately after cell infusion. Two weeks after injection, histological examination was performed for detection of transplanted cells. RESULTS: MSCs were efficiently labeled with Molday ION rhodamine. Cells could be readily detected in the injected vertebral tissue explants as distinct hypointensities with sufficient sensitivity. MR monitoring indicated that the MSCs were successfully delivered into the IVD in vivo, which was confirmed by iron-positive Prussian Blue staining of the tissue within the IVD. CONCLUSION: We have developed a technique for non-invasive monitoring of minimally invasive stem delivery into the IVD at 3T. By using a large animal model mimicking the anatomy of IVD in humans, the present results indicate that this procedure may be clinically feasible. PMID- 24058620 TI - Disruption of 5-HT2A receptor-PDZ protein interactions alleviates mechanical hypersensitivity in carrageenan-induced inflammation in rats. AB - Despite common pathophysiological mechanisms, inflammatory and neuropathic pain do not respond equally to the analgesic effect of antidepressants, except for selective serotonin reuptake inhibitors (SSRIs), which show a limited efficacy in both conditions. We previously demonstrated that an interfering peptide (TAT 2ASCV) disrupting the interaction between 5-HT2A receptors and its associated PDZ proteins (e.g. PSD-95) reveals a 5-HT2A receptor-mediated anti-hyperalgesic effect and enhances the efficacy of fluoxetine (a SSRI) in diabetic neuropathic pain conditions in rats. Here, we have examined whether the same strategy would be useful to treat inflammatory pain. Sub-chronic inflammatory pain was induced by injecting lambda-carrageenan (100 ul, 2%) into the left hind paw of the rat. Mechanical hyperalgesia was assessed after acute treatment with TAT-2ASCV or/and fluoxetine (SSRI) 2.5 h after lambda-carrageenan injection. Possible changes in the level of 5-HT2A receptors and its associated PDZ protein PSD-95 upon inflammation induction were quantified by Western blotting in dorsal horn spinal cord. Administration of TAT-2ASCV peptide (100 ng/rat, intrathecally) but not fluoxetine (10 mg/kg, intraperitoneally) relieves mechanical hyperalgesia (paw pressure test) in inflamed rats. This anti-hyperalgesic effect involves spinal 5 HT2A receptors and GABAergic interneurons as it is abolished by a 5-HT2A antagonist (M100907, 150 ng/rat, intrathecally) and a GABAA antagonist, (bicuculline, 3 ug/rat, intrathecally). We also found a decreased expression of 5 HT2A receptors in the dorsal spinal cord of inflamed animals which could not be rescued by TAT-2ASCV injection, while the amount of PSD-95 was not affected by inflammatory pain. Finally, the coadministration of fluoxetine does not further enhance the anti-hyperalgesic effect of TAT-2ASCV peptide. This study reveals a role of the interactions between 5-HT2A receptors and PDZ proteins in the pathophysiological pathways of inflammatory pain and opens new perspectives in its control thanks to molecules disrupting 5-HT2A receptor/PDZ protein interactions. PMID- 24058621 TI - Genetics of type III Bartter syndrome in Spain, proposed diagnostic algorithm. AB - The p.Ala204Thr mutation (exon 7) of the CLCNKB gene is a "founder" mutation that causes most of type III Bartter syndrome cases in Spain. We performed genetic analysis of the CLCNKB gene, which encodes for the chloride channel protein ClC Kb, in a cohort of 26 affected patients from 23 families. The diagnostic algorithm was: first, detection of the p.Ala204Thr mutation; second, detecting large deletions or duplications by Multiplex Ligation-dependent Probe Amplification and Quantitative Multiplex PCR of Short Fluorescent Fragments; and third, sequencing of the coding and flanking regions of the whole CLCNKB gene. In our genetic diagnosis, 20 families presented with the p.Ala204Thr mutation. Of those, 15 patients (15 families) were homozygous (57.7% of overall patients). Another 8 patients (5 families) were compound heterozygous for the founder mutation together with a second one. Thus, 3 patients (2 siblings) presented with the c. -19-?_2053+? del deletion (comprising the entire gene); one patient carried the p.Val170Met mutation (exon 6); and 4 patients (3 siblings) presented with the novel p.Glu442Gly mutation (exon 14). On the other hand, another two patients carried two novel mutations in compound heterozygosis: one presented the p.Ile398_Thr401del mutation (exon 12) associated with the c. -19-?_2053+? del deletion, and the other one carried the c.1756+1G>A splice-site mutation (exon 16) as well as the already described p.Ala210Val change (exon 7). One case turned out to be negative in our genetic screening. In addition, 51 relatives were found to be heterozygous carriers of the described CLCNKB mutations. In conclusion, different mutations cause type III Bartter syndrome in Spain. The high prevalence of the p.Ala204Thr in Spanish families thus justifies an initial screen for this mutation. However, should it not be detected further investigation of the CLCNKB gene is warranted in clinically diagnosed families. PMID- 24058622 TI - Vascular surgery, microsurgery and supramicrosurgery for treatment of chronic diabetic foot ulcers to prevent amputations. AB - INTRODUCTION: Diabetic foot ulcers occur in approximately 2,5% of patients suffering from diabetes and may lead to major infections and amputation. Such ulcers are responsible for a prolonged period of hospitalization and co- morbidities caused by infected diabetic foot ulcers. Small, superficial ulcers can be treated by special conservative means. However, exposed bones or tendons require surgical intervention in order to prevent osteomyelitis. In many cases reconstructive surgery is necessary, sometimes in combination with revascularization of the foot. There are studies on non surgical treatment of the diabetic foot ulcer. Most of them include patients, classified Wagner 1-2 without infection. Patients presenting Wagner 3D and 4D however are at a higher risk of amputation. The evolution of microsurgery has extended the possibilities of limb salvage. Perforator based flaps can minimize the donorsite morbidity. PATIENTS AND METHODS: 41 patients were treated with free tissue transfer for diabetic foot syndrome and chronic defects. 44 microvascular flaps were needed. The average age of patients was 64.3 years. 18 patients needed revascularization. 3 patients needed 2 microvascular flaps. In 6 cases supramicrosurgical technique was used. RESULTS: There were 2 flap losses leading to amputation. 4 other patients required amputation within 6 months postoperatively due to severe infection or bypass failure. Another 4 patients died within one year after reconstruction. The remaining patients were ambulated. DISCUSSION: Large defects of the foot can be treated by free microvascular myocutaneous or fasciocutaneous tissue transfer. If however, small defects, exposing bones or tendons, are not eligible for local flaps, small free microvascular flaps can be applied. These flaps cause a very low donor site morbidity. Arterialized venous flaps are another option for defect closure. Amputation means reduction of quality of life and can lead to an increased mortality postoperatively. PMID- 24058624 TI - Arabidopsis C-terminal domain phosphatase-like 1 functions in miRNA accumulation and DNA methylation. AB - Arabidopsis CTD-PHOSPHATASE-LIKE 1 (CPL1) is a protein phosphatase that can dephosphorylate RNA polymerase II C-terminal domain (CTD). Unlike typical CTD phosphatases, CPL1 contains a double-stranded (ds) RNA-binding motif (dsRBM) and has been implicated for gene regulation mediated by dsRNA-dependent pathways. We investigated the role of CPL1 and its dsRBMs in various gene silencing pathways. Genetic interaction analyses revealed that cpl1 was able to partially suppress transcriptional gene silencing and DNA hypermethylation phenotype of ros1 suggesting CPL1 is involved in the RNA-directed DNA methylation pathway without reducing siRNA production. By contrast, cpl1 reduced some miRNA levels at the level of processing. Indeed, CPL1 protein interacted with proteins important for miRNA biogenesis, suggesting that CPL1 regulates miRNA processing. These results suggest that CPL1 regulates DNA methylation via a miRNA-dependent pathway. PMID- 24058623 TI - The impact of ovariectomy on calcium homeostasis and myofilament calcium sensitivity in the aging mouse heart. AB - This study determined whether deficiency of ovarian estrogen starting very early in life promoted age-associated Ca(2+) dysregulation and contractile dysfunction in isolated ventricular myocytes. Myocytes were isolated from anesthetized C57BL/6 female mice. Animals received an ovariectomy or sham-operation at one month and were aged to ~24 months. Excitation-contraction coupling parameters were compared in fura-2 loaded myocytes (37 degrees C). While Ca(2+) transients were larger and faster in field-stimulated myocytes from ovariectomized mice, ovariectomy had no effect on peak fractional shortening. Similarly, ovariectomy had no effect on fractional shortening measured in vivo by echocardiography (values were 60.5 +/- 2.9 vs. 60.3 +/- 2.5% in sham and ovariectomized, respectively; n=5 mice/group). Ovariectomy did decrease myofilament Ca(2+) sensitivity, as evidenced by a 26% increase in the Ca(2+) required to activate actomyosin MgATPase in ovariectomized hearts. Larger Ca(2+) transients were attributable to a 48% increase in peak Ca(2+) current, along with an increase in the amplitude, width and frequency of Ca(2+) sparks measured in fluo-4 loaded myocytes. These changes in Ca(2+) handling were not due to increased expression of Ca(2+) channels (Cav1.2), sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) or Na(+)-Ca(2+) exchanger in ovariectomized hearts. However, ovariectomy increased sarcoplasmic reticulum Ca(2+) stores by ~90% and promoted spontaneous Ca(2+) release from the sarcoplasmic reticulum when compared to sham controls. These observations demonstrate that long-term ovariectomy promotes intracellular Ca(2+) dysregulation, reduces myofilament Ca(2+) sensitivity and increases spontaneous Ca(2+) release in the aging female heart. PMID- 24058625 TI - Role of human metapneumovirus, influenza A virus and respiratory syncytial virus in causing WHO-defined severe pneumonia in children in a developing country. AB - OBJECTIVE: The role of respiratory viruses in causing severe, life threatening pneumonia in children in developing countries is not well established. Our study aims to determine the role of human metapneumovirus (HMPV), influenza A virus and respiratory syncytial virus (RSV) in children, aged 6 weeks to 2 years, hospitalized with WHO defined severe pneumonia (tachypnea plus any general danger sign or chest in-drawing) at a public sector hospital in Karachi, Pakistan. METHODS: This study was conducted from November 2010 to September 2011 at Abbassi Shaheed Hospital, a large public tertiary care hospital in Karachi, Pakistan. Children admitted with WHO-defined severe pneumonia were enrolled and throat swabs were obtained to detect respiratory viruses using real time RT-PCR. Chest x rays of all subjects were obtained and independently interpreted by two radiologists to diagnose radiologic pneumonia. RESULTS: 169 children were enrolled. HMPV was detected in 24 (14.2%), influenza A virus in 9 (5.3%) and RSV in 30 (17.8%) children admitted with severe pneumonia. Of 9 patients with influenza A, 8 tested positive for H1N1. Viral etiology was found in 18% of radiologically confirmed pneumonia. HMPV infections peaked in February and April, influenza A was prevalent in January, June and November and RSV infections were most prevalent from June to September. CONCLUSION: HMPV, influenza A and RSV are common causes of WHO-defined severe pneumonia in hospitalized children in Karachi. Knowledge regarding the viral etiology of pediatric pneumonia and individual viral seasonality can help in the recommendation and implementation of appropriate management strategies. PMID- 24058626 TI - Skin equivalent tissue-engineered construct: co-cultured fibroblasts/ keratinocytes on 3D matrices of sericin hope cocoons. AB - The development of effective and alternative tissue-engineered skin replacements to autografts, allografts and xenografts has became a clinical requirement due to the problems related to source of donor tissue and the perceived risk of disease transmission. In the present study 3D tissue engineered construct of sericin is developed using co-culture of keratinocytes on the upper surface of the fabricated matrices and with fibroblasts on lower surface. Sericin is obtained from "Sericin Hope" silkworm of Bombyx mori mutant and is extracted from cocoons by autoclave. Porous sericin matrices are prepared by freeze dried method using genipin as crosslinker. The matrices are characterized biochemically and biophysically. The cell proliferation and viability of co-cultured fibroblasts and keratinocytes on matrices for at least 28 days are observed by live/dead assay, Alamar blue assay, and by dual fluorescent staining. The growth of the fibroblasts and keratinocytes in co-culture is correlated with the expression level of TGF-beta, b-FGF and IL-8 in the cultured supernatants by enzyme-linked immunosorbent assay. The histological analysis further demonstrates a multi layered stratified epidermal layer of uninhibited keratinocytes in co-cultured constructs. Presence of involucrin, collagen IV and the fibroblast surface protein in immuno-histochemical stained sections of co-cultured matrices indicates the significance of paracrine signaling between keratinocytes and fibroblasts in the expression of extracellular matrix protein for dermal repair. No significant amount of pro inflammatory cytokines (TNF-alpha, IL-1beta and nitric oxide) production are evidenced when macrophages grown on the sericin matrices. The results all together depict the potentiality of sericin 3D matrices as skin equivalent tissue engineered construct in wound repair. PMID- 24058627 TI - Enhanced cardiac function in Gravin mutant mice involves alterations in the beta adrenergic receptor signaling cascade. AB - Gravin, an A-kinase anchoring protein, targets protein kinase A (PKA), protein kinase C (PKC), calcineurin and other signaling molecules to the beta2-adrenergic receptor (beta2-AR). Gravin mediates desensitization/resensitization of the receptor by facilitating its phosphorylation by PKA and PKC. The role of gravin in beta-AR mediated regulation of cardiac function is unclear. The purpose of this study was to determine the effect of acute beta-AR stimulation on cardiac contractility in mice lacking functional gravin. Using echocardiographic analysis, we observed that contractility parameters such as left ventricular fractional shortening and ejection fraction were increased in gravin mutant (gravin-t/t) animals lacking functional protein compared to wild-type (WT) animals both at baseline and following acute isoproterenol (ISO) administration. In isolated gravin-t/t cardiomyocytes, we observed increased cell shortening fraction and decreased intracellular Ca(2+) in response to 1 umol/L ISO stimulation. These physiological responses occurred in the presence of decreased beta2-AR phosphorylation in gravin-t/t hearts, where PKA-dependent beta2-AR phosphorylation has been shown to lead to receptor desensitization. cAMP production, PKA activity and phosphorylation of phospholamban and troponin I was comparable in WT and gravin-t/t hearts both with and without ISO stimulation. However, cardiac myosin binding protein C (cMyBPC) phosphorylation site at position 273 was significantly increased in gravin-t/t versus WT hearts, in the absence of ISO. Additionally, the cardioprotective heat shock protein 20 (Hsp20) was significantly more phosphorylated in gravin-t/t versus WT hearts, in response to ISO. Our results suggest that disruption of gravin's scaffold mediated signaling is able to increase baseline cardiac function as well as to augment contractility in response to acute beta-AR stimulation by decreasing beta2-AR phosphorylation and thus attenuating receptor desensitization and perhaps by altering PKA localization to increase the phosphorylation of cMyBPC and the nonclassical PKA substrate Hsp20. PMID- 24058628 TI - Identification and characterization of a novel Plasmodium falciparum adhesin involved in erythrocyte invasion. AB - Malaria remains a major health problem worldwide. All clinical symptoms of malaria are attributed to the asexual blood stages of the parasite life cycle. Proteins resident in apical organelles and present on the surface of P. falciparum merozoites are considered promising candidates for the development of blood stage malaria vaccines. In the present study, we have identified and characterized a microneme associated antigen, PfMA [PlasmoDB Gene ID: PF3D7_0316000, PFC0700c]. The gene was selected by applying a set of screening criteria such as transcriptional upregulation at late schizogony, inter-species conservation and the presence of signal sequence or transmembrane domains. The gene sequence of PfMA was found to be conserved amongst various Plasmodium species. We experimentally demonstrated that the transcript for PfMA was expressed only in the late blood stages of parasite consistent with a putative role in erythrocyte invasion. PfMA was localized by immunofluorescence and immuno electron microscopy to be in the micronemes, an apical organelle of merozoites. The functional role of the PfMA protein in erythrocyte invasion was identified as a parasite adhesin involved in direct attachment with the target erythrocyte. PfMA was demonstrated to bind erythrocytes in a sialic acid independent, chymotrypsin and trypsin resistant manner and its antibodies inhibited P. falciparum erythrocyte invasion. Invasion of erythrocytes is a complex multistep process that involves a number of redundant ligand-receptor interactions many of which still remain unknown and even uncharacterized. Our work has identified and characterized a novel P. falciparum adhesin involved in erythrocyte invasion. PMID- 24058629 TI - Characteristics of HPV-specific antibody responses induced by infection and vaccination: cross-reactivity, neutralizing activity, avidity and IgG subclasses. AB - OBJECTIVES: In order to assess HPV-specific IgG characteristics, we evaluated multiple aspects of the humoral antibody response that will provide insight in the HPV humoral immune response induced by HPV infection and vaccination. METHODS: Cross-reactivity of HPV-specific antibodies induced by infection or vaccination was assessed with VLP16 or 18 inhibition using a VLP-based multiplex immunoassay (MIA) for HPV16, 18, 31, 33, 45, 52 and 58. HPV16/18 specific IgG1-4 subclasses and avidity were determined with the VLP-MIA in sera after HPV infection and after vaccination. Neutralizing antibodies were determined in a small subset of single-seropositive and multi-seropositive naturally derived antibodies. RESULTS: Naturally derived antibodies from single-positive sera were highly genotype-specific as homologue VLP-inhibition percentages varied between 78-94%. In multi-positive sera, cross-reactive antibodies were observed both within and between alpha7 and alpha9 species. After vaccination, cross-reactive antibodies were mainly species-specific. Avidity of vaccine-derived HPV-specific antibodies was 3 times higher than that of antibodies induced by HPV infection (p<0.0001). IgG1 and IgG3 were found to be the predominant subclasses observed after HPV infection and vaccination. In the small subset tested, the number of single-positive sera with neutralizing capacity was higher than of multi-positive sera. CONCLUSION: Naturally derived HPV-specific antibodies from single-positive samples showed different characteristics in terms of cross-reactivity and neutralizing capacity compared with antibodies from multi-positive sera. Post vaccination, HPV antibody avidity was approximately 3 times higher than antibody avidity induced by HPV infection. Therefore, antibody avidity might be a potential surrogate of protection. PMID- 24058630 TI - Simultaneous activation of Kras and inactivation of p53 induces soft tissue sarcoma and bladder urothelial hyperplasia. AB - The development of the Cre recombinase-controlled (Cre/LoxP) technique allows the manipulation of specific tumorigenic genes, temporarily and spatially. Our original intention of this study was to investigate the role of Kras and p53 in the development of urinary bladder cancer. First, to validate the effect of intravesical delivery on Cre recombination (Adeno-Cre), we examined activity and expression of beta-galactosidase in the bladder of control ROSA transgenic mice. The results confirmed specific recombination as evidenced by beta-galactosidase activity in the bladder urothelium of these mice. Then, we administered the same adenovirus into the bladder of double transgenic Kras(LSLG12D/+). p53(fl/fl) mice. The virus solution was held in place by a distal urethral retention suture for 2 hours. To our surprise, there was a rapid development of a spindle-cell tumor with sarcoma characteristics near the suture site, within the pelvic area but outside the urinary track. Since we did not see any detectable beta galactosidase in the area outside of the bladder in the validating (control) experiment, we interpreted that this sarcoma formation was likely due to transduction by Adeno-Cre in the soft tissue of the suture site. To avoid the loss of skin integrity associated with the retention suture, we transitioned to an alternative technique without suture to retain the Adeno-Cre into the bladder cavity. Interestingly, although multiple Adeno-Cre treatments were applied, only urothelial hyperplasia but not carcinogenesis was observed in the subsequent experiments of up to 6 months. In conclusion, we observed that the simultaneous inactivation of p53 and activation of Kras induces quick formation of spindle cell sarcoma in the soft tissues adjacent to the bladder but slow formation of urothelial hyperplasia inside the bladder. These results strongly suggest that the effect of oncogene regulation to produce either hyperplasia or carcinogenesis greatly depends on the tissue type. PMID- 24058631 TI - Exploring anti-bacterial compounds against intracellular Legionella. AB - Legionella pneumophila is a ubiquitous fresh-water bacterium which reproduces within its erstwhile predators, environmental amoeba, by subverting the normal pathway of phagocytosis and degradation. The molecular mechanisms which confer resistance to amoeba are apparently conserved and also allow replication within macrophages. Thus, L. pneumophila can act as an 'accidental' human pathogen and cause a severe pneumonia known as Legionnaires' disease. The intracellular localisation of L. pneumophila protects it from some antibiotics, and this fact must be taken into account to develop new anti-bacterial compounds. In addition, the intracellular lifestyle of L. pneumophila may render the bacteria susceptible to compounds diminishing bacterial virulence and decreasing intracellular survival and replication of this pathogen. The development of a single infection cycle intracellular replication assay using GFP-producing L. pneumophila and Acanthamoebacastellanii amoeba is reported here. This fluorescence-based assay allows for continuous monitoring of intracellular replication rates, revealing the effect of bacterial gene deletions or drug treatment. To examine how perturbations of the host cell affect L. pneumophila replication, several known host-targeting compounds were tested, including modulators of cytoskeletal dynamics, vesicle scission and Ras GTPase localisation. Our results reveal a hitherto unrealized potential antibiotic property of the beta-lactone-based Ras depalmitoylation inhibitor palmostatin M, but not the closely related inhibitor palmostatin B. Further characterisation indicated that this compound caused specific growth inhibition of Legionella and Mycobacterium species, suggesting that it may act on a common bacterial target. PMID- 24058632 TI - Community level offset of rain use- and transpiration efficiency for a heavily grazed ecosystem in inner Mongolia grassland. AB - Water use efficiency (WUE) is a key indicator to assess ecosystem adaptation to water stress. Rain use efficiency (RUE) is usually used as a proxy for WUE due to lack of transpiration data. Furthermore, RUE based on aboveground primary productivity (RUEANPP) is used to evaluate whole plant water use because root production data is often missing as well. However, it is controversial as to whether RUE is a reliable parameter to elucidate transpiration efficiency (TE), and whether RUEANPP is a suitable proxy for RUE of the whole plant basis. The experiment was conducted at three differently managed sites in the Inner Mongolia steppe: a site fenced since 1979 (UG79), a winter grazing site (WG) and a heavily grazed site (HG). Site HG had consistent lowest RUEANPP and RUE based on total net primary productivity (RUENPP). RUEANPP is a relatively good proxy at sites UG79 and WG, but less reliable for site HG. Similarly, RUEANPP is good predictor of transpiration efficiency based on aboveground net primary productivity (TEANPP) at sites UG79 and WG but not for site HG. However, if total net primary productivity is considered, RUENPP is good predictor of transpiration efficiency based on total net primary productivity (TENPP) for all sites. Although our measurements indicate decreased plant transpiration and consequentially decreasing RUE under heavy grazing, productivity was relatively compensated for with a higher TE. This offset between RUE and TE was even enhanced under water limited conditions and more evident when belowground net primary productivity (BNNP) was included. These findings suggest that BNPP should be considered when studies fucus on WUE of more intensively used grasslands. The consideration of the whole plant perspective and "real" WUE would partially revise our picture of system performance and therefore might affect the discussion on the C sequestration and resilience potential of ecosystems. PMID- 24058633 TI - Forearm posture and mobility in quadrupedal dinosaurs. AB - Quadrupedality evolved four independent times in dinosaurs; however, the constraints associated with these transitions in limb anatomy and function remain poorly understood, in particular the evolution of forearm posture and rotational ability (i.e., active pronation and supination). Results of previous qualitative studies are inconsistent, likely due to an inability to quantitatively assess the likelihood of their conclusions. We attempt to quantify antebrachial posture and mobility using the radius bone because its morphology is distinct between extant sprawled taxa with a limited active pronation ability and parasagittal taxa that have an enhanced ability to actively pronate the manus. We used a sliding semi landmark, outline-based geometric morphometric approach of the proximal radial head and a measurement of the angle of curvature of the radius in a sample of 189 mammals, 49 dinosaurs, 35 squamates, 16 birds, and 5 crocodilians. Our results of radial head morphology showed that quadrupedal ceratopsians, bipedal non hadrosaurid ornithopods, and theropods had limited pronation/supination ability, and sauropodomorphs have unique radial head morphology that likely allowed limited rotational ability. However, the curvature of the radius showed that no dinosaurian clade had the ability to cross the radius about the ulna, suggesting parallel antebrachial elements for all quadrupedal dinosaurs. We conclude that the bipedal origins of all quadrupedal dinosaur clades could have allowed for greater disparity in forelimb posture than previously appreciated, and future studies on dinosaur posture should not limit their classifications to the overly simplistic extant dichotomy. PMID- 24058634 TI - Matrix intensification alters avian functional group composition in adjacent rainforest fragments. AB - Conversion of farmland land-use matrices to surface mining is an increasing threat to the habitat quality of forest remnants and their constituent biota, with consequences for ecosystem functionality. We evaluated the effects of matrix type on bird community composition and the abundance and evenness within avian functional groups in south-west Ghana. We hypothesized that surface mining near remnants may result in a shift in functional composition of avifaunal communities, potentially disrupting ecological processes within tropical forest ecosystems. Matrix intensification and proximity to the remnant edge strongly influenced the abundance of members of several functional guilds. Obligate frugivores, strict terrestrial insectivores, lower and upper strata birds, and insect gleaners were most negatively affected by adjacent mining matrices, suggesting certain ecosystem processes such as seed dispersal may be disrupted by landscape change in this region. Evenness of these functional guilds was also lower in remnants adjacent to surface mining, regardless of the distance from remnant edge, with the exception of strict terrestrial insectivores. These shifts suggest matrix intensification can influence avian functional group composition and related ecosystem-level processes in adjacent forest remnants. The management of matrix habitat quality near and within mine concessions is important for improving efforts to preserveavian biodiversity in landscapes undergoing intensification such as through increased surface mining. PMID- 24058635 TI - Triiodothyronine increases mRNA and protein leptin levels in short time in 3T3-L1 adipocytes by PI3K pathway activation. AB - The present study aimed to examine the effects of thyroid hormone (TH), more precisely triiodothyronine (T3), on the modulation of leptin mRNA expression and the involvement of the phosphatidyl inositol 3 kinase (PI3K) signaling pathway in adipocytes, 3T3-L1, cell culture. We examined the involvement of this pathway in mediating TH effects by treating 3T3-L1 adipocytes with physiological (P=10nM) or supraphysiological (SI=100 nM) T3 dose during one hour (short time), in the absence or the presence of PI3K inhibitor (LY294002). The absence of any treatment was considered the control group (C). RT-qPCR was used for mRNA expression analyzes. For data analyzes ANOVA complemented with Tukey's test was used at 5% significance. T3 increased leptin mRNA expression in P (2.26 +/- 0.36, p< 0.001), SI (1.99 +/-0.22, p< 0.01) compared to C group (1+/- 0.18). This increase was completely abrogated by LY294002 in P (1.31+/-0.05, p< 0.001) and SI (1.33+/-0.31, p< 0.05). Western blotting confirmed these results at protein level, indicating the PI3K pathway dependency. To examine whether leptin is directly induced by T3, we used the translation inhibitor cycloheximide (CHX). In P, the presence of CHX maintained the levels mRNA leptin, but was completely abrogated in SI (1.14+/-0.09, p> 0.001). These results demonstrate that the activation of the PI3K signaling pathway has a role in TH-mediated direct and indirect leptin gene expression in 3T3-L1 adipocytes. PMID- 24058637 TI - Fine structure of the male reproductive system and reproductive behavior of Lutzomyia longipalpis sandflies (Diptera: Psychodidae: Phlebotominae). AB - BACKGROUND: The male reproductive system of insects can have several tissues responsible for the secretion of seminal fluid proteins (SFPs), such as testes, accessory glands, seminal vesicles, ejaculatory duct and ejaculatory bulb. The SFPs are transferred during mating and can induce several physiological and behavioral changes in females, such as increase in oviposition and decrease in sexual receptivity after copulation. The phlebotomine Lutzomyia longipalpis is the main vector of visceral leishmaniasis. Despite its medical importance, little is known about its reproductive biology. Here we present morphological aspects of the male L. longipalpis reproductive system by light, scanning and transmission electron microscopy, and compare the mating frequency of both virgin and previously mated females. RESULTS: The male L. longipalpis reproductive system is comprised by a pair of oval-shaped testes linked to a seminal vesicle by vasa deferentia. It follows an ejaculatory duct with an ejaculatory pump (a large bulb enveloped by muscles and associated to tracheas). The terminal endings of the vasa deferentia are inserted into the seminal vesicle by invaginations of the seminal vesicle wall, which is composed by a single layer of gland cells, with well-developed endoplasmic reticulum profiles and secretion granules. Our data suggest that the seminal vesicle acts both as a spermatozoa reservoir and as an accessory gland. Mating experiments support this hypothesis, revealing a decrease in mating frequency after copulation that indicates the effect of putative SFPs. CONCLUSION: Ultrastructural features of the L. longipalpis male seminal vesicle indicated its possible role as an accessory gland. Behavioral observations revealed a reduction in mating frequency of copulated females. Together with transcriptome analyses from male sandfly reproductive organs identifying ESTs encoding orthologs of SFPs, these data indicate the presence of putative L. longipalpis SFPs reducing sexual mating frequency of copulated females. PMID- 24058636 TI - Associations between 25-hydroxyvitamin D and immunologic, metabolic, inflammatory markers in treatment-naive HIV-infected persons: the ANRS CO9 "COPANA" cohort study. AB - OBJECTIVES: Low 25(OH)D has been associated with dyslipidemia, insulin resistance and inflammation in both general and HIV-infected (mostly treated) populations. We investigated these associations in antiretroviral-naive HIV-infected persons. DESIGN: We measured plasma 25(OH)D, metabolic, immunologic and inflammatory markers in 355 persons (204 Whites, 151 Blacks) at enrollment in the ANRS COPANA cohort. METHODS: 25(OH)D levels were categorized <10 ng/mL (severe deficiency) and <20 ng/mL (deficiency). Statistical analyses were adjusted for sampling season, ethnicity and the interaction between season and ethnicity. RESULTS: 25(OH)D insufficiency (<30 ng/mL), deficiency (<20 ng/mL) and severe deficiency (<10 ng/mL) were highly prevalent (93%, 67% and 24% of patients, respectively). Blacks had significantly lower 25(OH)D than Whites (median: 13 vs. 17 ng/mL, P<0.001), with markedly less pronounced seasonal variation. Smoking and drinking alcohol were associated with having a 25 OHD level<10 ng/mL. In patients with 25(OH)D<10 ng/mL, the proportion of persons with a CD4 count<100/mm(3) was higher than in patients with 25(OH)D>=10 ng/mL (18.8% vs. 10.7%, P = 0.04). Persons with 25 OHD<10 ng/mL had higher levels of hsCRP (1.60 mg/L [IQR: 0.59-5.76] vs. 1.27 mg/L [0.58-3,39], P = 0.03) and resistin (16.81 ng/L [IQR: 13.82-25.74] vs. 11.56 ng/L [IQR: 8.87-20.46], P = 0.02), and, among Blacks only, sTNFR2 (2.92 ng/mL [2.31-4.13] vs. 2.67 ng/mL, [1.90-3.23], P = 0.04). The strength and significance of the association between CD4<100/mm(3) and 25 OHD<10 ng/mL were reduced after adjustment on sTNFR1, sTNFR2, and hsCRP levels. In multivariate analysis, a CD4 count <100/mm(3), resistin concentration and smoking were independently associated with 25(OH)D<10 ng/mL. CONCLUSIONS: Severe vitamin D deficiency was associated with low CD4 counts and increased markers of inflammation in ARV-naive HIV-infected persons. PMID- 24058639 TI - Fli1 represses transcription of the human alpha2(I) collagen gene by recruitment of the HDAC1/p300 complex. AB - Fli1, a member of the Ets transcription factor family, is a key repressor of the human alpha2(I) collagen (COL1A2) gene. Although our previous studies have delineated that TGF-beta induces displacement of Fli1 from the COL1A2 promoter through sequential post-translational modifications, the detailed mechanism by which Fli1 functions as a potent transcriptional repressor of the COL1A2 gene has not been fully investigated. To address this issue, we carried out a series of experiments especially focusing on protein-protein interaction and epigenetic transcriptional regulation. The combination of tandem affinity purification and mass spectrometry identified HDAC1 as a Fli1 interacting protein. Under quiescent conditions, HDAC1 induced deacetylation of Fli1 resulting in an increase of Fli1 DNA binding ability and p300 enhanced this process by promoting the formation of a Fli1-HDAC1-p300 complex. TGF-beta-induced phosphorylation of Fli1 at threonine 312 led to disassembly of this protein complex. In quiescent dermal fibroblasts Fli1, HDAC1, and p300 occupied the -404 to -237 region, including the Fli1 binding site, of the COL1A2 promoter. TGF-beta induced Fli1 and HDAC1 dissociation from the COL1A2 promoter, while promoting Ets1 and p300 recruitment. Furthermore, acetylation levels of histone H3 around the Fli1 binding site in the COL1A2 promoter inversely correlated with the DNA occupancy of Fli1 and HDAC1, while positively correlating with that of Ets1 and p300. In the functional studies, HDAC1 overexpression magnified the inhibitory effect of Fli1 on the COL1A2 promoter. Moreover, pharmacological blockade of HDAC1 by entinostat enhanced collagen production in dermal fibroblasts. Collectively, these results indicate that under quiescent conditions Fli1 recruits HDAC1/p300 to the COL1A2 promoter and suppresses the expression of the COL1A2 gene by chromatin remodeling through histone deacetylation. TGF-beta-dependent phosphorylation of Fli1 at threonine 312 is a critical step regulating the remodeling of the Fli1 transcription repressor complex, leading to transcriptional activation of the COL1A2 gene. PMID- 24058638 TI - Risky behavior in gambling tasks in individuals with ADHD--a systematic literature review. AB - OBJECTIVE: The aim of this review was to gain insight into the relationship between Attention deficit hyperactivity disorder (ADHD) and risky performance in gambling tasks and to identify any potential alternate explanatory factors. METHODS: PsycINFO, PubMed, and Web of Knowledge were searched for relevant literature comparing individuals with ADHD to normal controls (NCs) in relation to their risky performance on a gambling task. In total, fourteen studies in children/adolescents and eleven studies in adults were included in the review. RESULTS: Half of the studies looking at children/adolescents with ADHD found evidence that they run more risks on gambling tasks when compared to NCs. Only a minority of the studies on adults with ADHD reported aberrant risky behavior. The effect sizes ranged from small to large for both age groups and the outcome pattern did not differ between studies that applied an implicit or explicit gambling task. Two studies demonstrated that comorbid oppositional defiant disorder (ODD) and conduct disorder (CD) increased risky behavior in ADHD. Limited and/or inconsistent evidence was found that comorbid internalizing disorders (IDs), ADHD subtype, methylphenidate use, and different forms of reward influenced the outcomes. CONCLUSION: The evidence for increased risky performance of individuals with ADHD on gambling tasks is mixed, but is stronger for children/adolescents with ADHD than for adults with ADHD, which may point to developmental changes in reward and/or penalty sensitivity or a publication bias for positive findings in children/adolescents. The literature suggests that comorbid ODD/CD is a risk factor in ADHD for increased risky behavior. Comorbid IDs, ADHD subtype, methylphenidate use, and the form of reward received may affect risky performance in gambling tasks; however, these factors need further examination. Finally, the implications of the findings for ADHD models and the ecological validity of gambling tasks are discussed. PMID- 24058640 TI - Evaluation of node-inhomogeneity effects on the functional brain network properties using an anatomy-constrained hierarchical brain parcellation. AB - To investigate functional brain networks, many graph-theoretical studies have defined nodes in a graph using an anatomical atlas with about a hundred partitions. Although use of anatomical node definition is popular due to its convenience, functional inhomogeneity within each node may lead to bias or systematic errors in the graph analysis. The current study was aimed to show functional inhomogeneity of a node defined by an anatomical atlas and to show its effects on the graph topology. For this purpose, we compared functional connectivity defined using 138 resting state fMRI data among 90 cerebral nodes from the automated anatomical labeling (AAL), which is an anatomical atlas, and among 372 cerebral nodes defined using a functional connectivity-based atlas as a ground truth, which was obtained using anatomy-constrained hierarchical modularity optimization algorithm (AHMO) that we proposed to evaluate the graph properties for anatomically defined nodes. We found that functional inhomogeneity in the anatomical parcellation induced significant biases in estimating both functional connectivity and graph-theoretical network properties. We also found very high linearity in major global network properties and nodal strength at all brain regions between anatomical atlas and functional atlas with reasonable network-forming thresholds for graph construction. However, some nodal properties such as betweenness centrality did not show significant linearity in some regions. The current study suggests that the use of anatomical atlas may be biased due to its inhomogeneity, but may generally be used in most neuroimaging studies when a single atlas is used for analysis. PMID- 24058641 TI - Mode of genetic inheritance modifies the association of head circumference and autism-related symptoms: a cross-sectional study. AB - BACKGROUND: Frequently individuals with autism spectrum disorder (ASD) have been noted with a larger head circumference (HC) than their typical developing peers. Biologic hypotheses suggest that an overly rapid brain growth leads to the core symptoms of ASD by impairing connectivity. Literature is divided however where deleterious, protective and null associations of HC with ASD symptoms in individuals with ASD have been found. METHOD: Individuals (n = 1,416) from the Autism Genetic Resource Exchange with ASD were examined for associations of HC with ASD like symptoms. Mixed models controlling for sex, age, race/ethnicity, simplex/multiplex status and accounting for correlations between siblings were used. Interactions by simplex/multiplex were explored. Adjustments for height in a sub-population with available data were explored as well. RESULTS: A Significant interaction term (p = 0.03) suggested that the effect of HC was dependent on whether the individual was simplex or multiplex. In simplex individuals at mean age (8.9 years) 1 cm increase in head circumference was associated with a 24% increase in the odds of a high social diagnostic score from the Autism Diagnostic Interview-Revised (odds ratio = 1.24, p = 0.01). There was no association in multiplex individuals. Additionally, individuals classified with a non-verbal IQ <70 were 90% simplex and had a significantly increased head circumference (0.7 cm p = 0.03) relative to a mid-range non-verbal IQ group. Interestingly, children classified with a >110 non-verbal IQ also had an increased HC (0.4 cm p = 0.04), relative to a mid-range non-verbal IQ group, and were 90% multiplex. HC effects do not appear to be confounded by height, however, larger samples with height information are needed. CONCLUSION: The potential link between brain growth and autism like symptoms is complex and could depend on specific etiologies. Further investigations accounting for a likely mode of inheritance will help identify an ASD subtype related to HC. PMID- 24058642 TI - Co-variation of depressive mood and locomotor dynamics evaluated by ecological momentary assessment in healthy humans. AB - Computerized ecological momentary assessment (EMA) is widely accepted as a "gold standard" method for capturing momentary symptoms repeatedly experienced in daily life. Although many studies have addressed the within-individual temporal variations in momentary symptoms compared with simultaneously measured external criteria, their concurrent associations, specifically with continuous physiological measures, have not been rigorously examined. Therefore, in the present study, we first examined the variations in momentary symptoms by validating the associations among self-reported symptoms measured simultaneously (depressive mood, anxious mood, and fatigue) and then investigated covariant properties between the symptoms (especially, depressive mood) and local statistics of locomotor activity as the external objective criteria obtained continuously. Healthy subjects (N = 85) from three different populations (adolescents, undergraduates, and office workers) wore a watch-type computer device equipped with EMA software for recording the momentary symptoms experienced by the subjects. Locomotor activity data were also continuously obtained by using an actigraph built into the device. Multilevel modeling analysis confirmed convergent associations by showing positive correlations among momentary symptoms. The increased intermittency of locomotor activity, characterized by a combination of reduced activity with occasional bursts, appeared concurrently with the worsening of depressive mood. Further, this association remained statistically unchanged across groups regardless of group differences in age, lifestyle, and occupation. These results indicate that the temporal variations in the momentary symptoms are not random but reflect the underlying changes in psychophysiological variables in daily life. In addition, our findings on the concurrent changes in depressive mood and locomotor activity may contribute to the continuous estimation of changes in depressive mood and early detection of depressive disorders. PMID- 24058643 TI - Modeling individual subtests of the WAIS IV with multiple latent factors. AB - Performance on a cognitive test can be viewed either as measuring a unitary function or as reflecting the operation of multiple factors. Individual subtests in batteries designed to measure human abilities are commonly modeled as a single latent factor. Several latent factors are then used to model groups of subtests. However these latent factors are not independent as they are related through hierarchical or oblique structures. As a result, the simple structure of subtest performance results in complex latent factors. The present study used structural equation modeling to evaluate several multidimensional models of the Wechsler Adult Intelligence Scales-fourth edition (WAIS-IV) subtests. Multidimensional models of subtest performance provided better model fit as compared to several previously proposed one dimensional models. These multidimensional models also generalized well to new samples of populations differing in age from that used to estimate the model parameters. Overall these results show that models that describe subtests as multidimensional functions of uncorrelated factors provided a better fit to the WAIS-IV correlations than models that describe subtests as one dimensional functions of correlated factors. There appears to be a trade-off in modeling subtests as one dimensional and modeling with homogeneous latent traits. More consideration should be given to models that include multiple uncorrelated latent factors as determinants of the performance on a given subtest. These results support the view that performance on any given cognitive test is potentially the result of multiple factors. Simple structure may be too simple. PMID- 24058644 TI - Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells. AB - Macrophages are cells with many important functions in both innate and adaptive immune responses and have been shown to play a complex role in tumor progression since they harbour both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. In many human cancers, infiltrating macrophages have been associated with a poor patient prognosis, and therefore suggested to be mainly of an M2 phenotype. However, we and others have previously shown that increased macrophage density in colorectal cancer (CRC) instead is correlated with an improved prognosis. It is an intriguing question if the different roles played by macrophages in various cancers could be explained by variations in the balance between M1 and M2 macrophage attributes, driven by tumor- or organ specific factors in the tumor microenvironment of individual cancers. Here, we utilized an in vitro cell culture system of macrophage differentiation to compare differences and similarities in the phenotype (morphology, antigen-presentation, migration, endocytosis, and expression of cytokine and chemokine genes) between M1/M2 and tumor activated macrophages (TAMs), that could explain the positive role of macrophages in CRC. We found that secreted factors from CRC cells induced TAMs of a "mixed" M1/M2 phenotype, which in turn could contribute to a "good inflammatory response". This suggests that re-education of macrophages might allow for important therapeutic advances in the treatment of human cancer. PMID- 24058645 TI - Kinetics of germination of individual spores of Geobacillus stearothermophilus as measured by raman spectroscopy and differential interference contrast microscopy. AB - Geobacillus stearothermophilus is a gram-positive, thermophilic bacterium, spores of which are very heat resistant. Raman spectroscopy and differential interference contrast microscopy were used to monitor the kinetics of germination of individual spores of G. stearothermophilus at different temperatures, and major conclusions from this work were as follows. 1) The CaDPA level of individual G. stearothermophilus spores was similar to that of Bacillus spores. However, the Raman spectra of protein amide bands suggested there are differences in protein structure in spores of G. stearothermophilus and Bacillus species. 2) During nutrient germination of G. stearothermophilus spores, CaDPA was released beginning after a lag time (T(lag)) between addition of nutrient germinants and initiation of CaDPA release. CaDPA release was complete at T(release), and DT(release) (T(release) - T(lag)) was 1-2 min. 3) Activation by heat or sodium nitrite was essential for efficient nutrient germination of G. stearothermophilus spores, primarily by decreasing T(lag) values. 4) Values of T(lag) and T(release) were heterogeneous among individual spores, but DT(release) values were relatively constant. 5) Temperature had major effects on nutrient germination of G. stearothermophilus spores, as at temperatures below 65 degrees C, average T(lag) values increased significantly. 6) G. stearothermophilus spore germination with exogenous CaDPA or dodecylamine was fastest at 65 degrees C, with longer T(lag) values at lower temperatures. 7) Decoating of G. stearothermophilus spores slowed nutrient germination slightly and CaDPA germination significantly, but increased dodecylamine germination markedly. These results indicate that the dynamics and heterogeneity of the germination of individual G. stearothermophilus spores are generally similar to that of Bacillus species. PMID- 24058646 TI - Heterogeneity of the MDCK cell line and its applicability for influenza virus research. AB - Single-cell clones have been established from the MDCK cell line, characterized for their morphology and evaluated for their suitability for influenza virus research. Three discrete cell morphotypes were identified using light microscopy. Besides morphological features, the cell types can be distinguished by the level of expression of surface glycans recognized by peanut agglutinin (PNA). All clones were susceptible to infection by influenza viruses of different subtypes of influenza A virus (H1N1, H1N1pdm09, H3N2, H5N1) and influenza B virus, and all possessed on their surface terminally sialylated glycans with both types of glycosidic linkage (alpha2-3 and alpha2-6). The Type-1 cell lines were able to support a multicycle replication of influenza A and B viruses without help of an exogenous trypsin. In contrast, cell lines exhibiting Type-2 morphology were unable to support multicycle replication of influenza A viruses without trypsin supplementation. Western blot analysis of the hemagglutinin of H1N1 strains demonstrated that Type-2 cells were deficient in production of proteolytically activated hemagglutinin (no cleavage between HA1/HA2 was observed). HA1/HA2 cleavage of influenza B viruses in the Type-2 cells was also significantly impaired, but not completely abrogated, producing sufficient amount of activated HA to support efficient virus replication without trypsin. In contrast, all clones of Type-1 cells were able to produce proteolytically activated hemagglutinin of influenza A and B viruses. However, the growth kinetics and plaque size of influenza A viruses varied significantly in different clones. Influenza B virus also showed different plaque size, with the biggest plaque formation in the Type-2 cells, although the growth kinetics and peak infectivity titers were similar in all clones. Taken together, the study demonstrates that the population of original MDCK cells is represented by various types of cells that differ in their capacities to support replication of influenza A and B viruses. PMID- 24058647 TI - Mechanistic insight into the relationship between N-terminal acetylation of alpha synuclein and fibril formation rates by NMR and fluorescence. AB - Aggregation of alpha-synuclein (alphaSyn), the primary protein component in Lewy body inclusions of patients with Parkinson's disease, arises when the normally soluble intrinsically disordered protein converts to amyloid fibrils. In this work, we provide a mechanistic view of the role of N-terminal acetylation on fibrillation by first establishing a quantitative relationship between monomer secondary structural propensity and fibril assembly kinetics, and secondly by demonstrating in the N-terminal acetylated form of the early onset A53T mutation, that N-terminal transient helices formed and/or inhibited by N-terminal acetylation modulate the fibril assembly rates. Using NMR chemical shifts and fluorescence experiments, we report that secondary structural propensity in residues 5-8, 14-31, and 50-57 are highly correlated to fibril growth rate. A four-way comparison of secondary structure propensity and fibril growth rates of N-terminally acetylated A53T and WT alphaSyn with non-acetylated A53T and WT alphaSyn present novel mechanistic insight into the role of N-terminal acetylation in amyloid fibril formation. We show that N-terminal acetylation inhibits the formation of the "fibrillation promoting" transient helix at residues 14-31 resulting from the A53T mutation in the non-acetylated variant and supports the formation of the "fibrillation inhibiting" transient helix in residues 1-12 thereby resulting in slower fibrillation rates relative to the previously studied non-acetylated A53T variant. Our results highlight the critical interplay of the region-specific transient secondary structure of the N terminal region with fibrillation, and the inhibitory role of the N-terminal acetyl group in fibril formation. PMID- 24058648 TI - Gastroprotection studies of Schiff base zinc (II) derivative complex against acute superficial hemorrhagic mucosal lesions in rats. AB - BACKGROUND: The study was carried out to assess the gastroprotective effect of the zinc (II) complex against ethanol-induced acute hemorrhagic lesions in rats. METHODOLOGY/PRINCIPAL FINDING: The animals received their respective pre treatments dissolved in tween 20 (5% v/v), orally. Ethanol (95% v/v) was orally administrated to induce superficial hemorrhagic mucosal lesions. Omeprazole (5.790*10(-5) M/kg) was used as a reference medicine. The pre-treatment with the zinc (II) complex (2.181*10(-5) and 4.362*10(-5) M/kg) protected the gastric mucosa similar to the reference control. They significantly increased the activity levels of nitric oxide, catalase, superoxide dismutase, glutathione and prostaglandin E2, and decreased the level of malondialdehyde. The histology assessments confirmed the protection through remarkable reduction of mucosal lesions and increased the production of gastric mucosa. Immunohistochemistry and western blot analysis indicated that the complex might induced Hsp70 up regulation and Bax down-regulation. The complex moderately increased the gastroprotectiveness in fine fettle. The acute toxicity approved the non-toxic characteristic of the complex (<87.241*10(-5) M/kg). CONCLUSION/SIGNIFICANCE: The gastroprotective effect of the zinc (II) complex was mainly through its antioxidant activity, enzymatic stimulation of prostaglandins E2, and up regulation of Hsp70. The gastric wall mucus was also a remarkable protective mechanism. PMID- 24058649 TI - Heterogeneity of estrogen receptor expression in circulating tumor cells from metastatic breast cancer patients. AB - BACKGROUND: Endocrine treatment is the most preferable systemic treatment in metastatic breast cancer patients that have had an estrogen receptor (ER) positive primary tumor or metastatic lesions, however, approximately 20% of these patients do not benefit from the therapy and demonstrate further metastatic progress. One reason for failure of endocrine therapy might be the heterogeneity of ER expression in tumor cells spreading from the primary tumor to distant sites which is reflected in detectable circulating tumor cells (CTCs). METHODS: A sensitive and specific staining protocol for ER, keratin 8/18/19, CD45 was established. Peripheral blood from 35 metastatic breast cancer patients with ER positive primary tumors was tested for the presence of CTCs. Keratin 8/18/19 and DAPI positive but CD45 negative cells were classified as CTCs and evaluated for ER staining. Subsequently, eight individual CTCs from four index patients (2 CTCs per patient) were isolated and underwent whole genome amplification and ESR1 gene mutation analysis. RESULTS: CTCs were detected in blood of 16 from 35 analyzed patients (46%), with a median of 3 CTCs/7.5 ml. In total, ER-negative CTCs were detected in 11/16 (69%) of the CTC positive cases, including blood samples with only ER-negative CTCs (19%) and samples with both ER-positive and ER-negative CTCs (50%). No correlation was found between the intensity and/or percentage of ER staining in the primary tumor with the number and ER status of CTCs of the same patient. ESR1 gene mutations were not found. CONCLUSION: CTCs frequently lack ER expression in metastatic breast cancer patients with ER-positive primary tumors and show a considerable intra-patient heterogeneity, which may reflect a mechanism to escape endocrine therapy. Provided single cell analysis did not support a role of ESR1 mutations in this process. PMID- 24058650 TI - The electro-oxidation of ethylene glycol on platinum over a wide pH range: oscillations and temperature effects. AB - We report a comprehensive study of the electro-oxidation of ethylene glycol (EG) on platinum with emphasis on the effects exerted by the electrolyte pH, the EG concentration, and temperature, under both regular and oscillatory conditions. We extracted and discussed parameters such as voltammetric activity, reaction orders (with respect to [EG]), oscillation's amplitude, frequency and waveform, and the evolution of the mean electrode potential at six pH values from 0 to 14. In addition, we obtained the apparent activation energies under several different conditions. Overall, we observed that increasing the electrolyte pH results in a discontinuous transition in most properties studied under both voltammetric and oscillatory regimes. As a relevant result in this direction, we found that the increase in the reaction order with pH is mediated by a minimum (~ 0) at pH = 12. Furthermore, the solution pH strongly affects all features investigated, c.f. the considerable increase in the oscillatory frequency and the decrease in the, oscillatory, activation energy as the pH increase. We suggest that adsorbed CO is probably the main surface-blocking species at low pH, and its absence at high pH is likely to be the main reason behind the differences observed. The size of the parameter region investigated and the amount of comparable parameters and properties presented in this study, as well as the discussion that followed illustrate the strategy of combining investigations under conventional and oscillatory regimes of electrocatalytic systems. PMID- 24058651 TI - Prognostic value of HIFs expression in head and neck cancer: a systematic review. AB - BACKGROUND: Tumor hypoxia plays a fundamental role in resistance to therapy and disease progression. A number of studies have assessed the prognostic role of HIFs expression in head and neck cancer (HNC), but no consistent outcomes are reported. METHODOLOGY: A systematical search was performed to search relevant literatures in PubMed, Web of Science and ISI Web of Knowledge databases. The patients' clinical characteristics and survival outcome were extracted. The correlation between HIFs expression and prognosis was analyzed. PRINCIPAL FINDINGS: A total of 28 studies assessed the association between HIFs and HNC survival, the result showed that overexpressed HIFs was significantly associated with increase of mortality risk (HR = 2.12; 95% CI: 1.52-2.94; I(2) 74%). Subgroup analysis on different HIF isoforms with OS indicated that both HIF 1alpha and HIF-2alpha were associated with worse prognosis. The pooled HRs were 1.72(95% CI 1.34-2.20; I(2) 70.7%) and 1.79(95% CI: 1.42-2.27, I(2) 0%). Further subgroup analysis was performed by different geographical locations, disease subtype, stage, types of variate analysis and cut-off value. The results revealed that overexpressed HIF-1alpha was significantly associated with poor prognosis in Asian patients (HR = 2.34; 95% CI: 1.76-3.1; I(2) 48.9%), but not in European patients (HR = 1.13; 95% CI: 0.77-1.66; I(2) 78.3%). Furthermore, HIF-1alpha overexpression was significantly associated with worse OS in oral carcinoma (HR = 2.1; 95% CI: 1.11-3.97; I(2) 81.7%), nasopharyngeal carcinoma (HR = 2.07; 95% CI:1.23-3.49; I(2) 22.5%) and oropharynx carcinoma (HR = 1.76; 95% CI:1.05-2.97; I(2) 61%), but not in laryngeal carcinoma (HR = 1.38; 95% CI: 0.87-2.19; I(2) 62.5%). We also found that the prognostic value of HIF-1alpha overexpression existed only when using staining and percentage as positive definition (HR = 1.82; 95% CI 1.42-2.33; I(2) 9.9%). CONCLUSIONS: This study showed that overexpressed HIFs were significantly associated with increase of mortality risk. Subgroup analysis revealed that overexpressed HIF-1alpha was significantly associated with worse prognosis of HNC in Asian countries. Additionally, HIF 1alpha had different prognostic value in different HNC disease subtypes. PMID- 24058652 TI - Feasibility and reproducibility of left ventricular rotation by speckle tracking echocardiography in elderly individuals and the impact of different software. AB - BACKGROUND: Changes in ventricular rotation measured by two-dimensional speckle tracking echocardiography (2DSTE) are early indicators of cardiac disease. Data on the clinical feasibility of this important measure are scarce and there is no information on the comparability of different software versions. We assessed the feasibility, reproducibility and within patient temporal variability of 2DSTE in a large community based sample of older adults. We additionally compared 2DSTE results to those generated by 3DSTE. METHODS AND RESULTS: 1408 participants underwent transthoracic echocardiography. Using Philips Qlab 8.1 peak LV rotation at either the base or the apex was analysable in 432 (31%) participants. Peak twist measurements were achieved in 274 (20%) participants. 66 participants were randomly selected for the reproducibility study. 20 additional participants had scans 4-6 weeks apart for temporal variability and 3D echocardiography to assess the agreement between 2DSTE and 3DSTE. Reproducibility was evaluated using the intraclass coefficient of correlation (ICC). Better reproducibility for rotation and twist were obtained when measured at the endocardium, and when using more recent software versions, Peak twist and rotation were significantly different using two versions of the same software. Agreement with 3DSTE was better using newer software. CONCLUSION: Feasibility of 2DSTE is low in this cohort of elderly individuals severely limiting its utility in clinical settings. However if high quality images can be acquired assessment of ventricular rotation by 2DSTE is reproducible. Caution should be taken when comparing measurements of ventricular rotation by software from different vendors or different versions of software from the same vendor. PMID- 24058653 TI - Characterization of four type IV pilin homologues in Stigmatella aurantiaca DSM17044 by heterologous expression in Myxococcus xanthus. AB - As prokaryotic models for multicellular development, Stigmatella aurantiaca and Myxococcus xanthus share many similarities in terms of social behaviors, such as gliding motility. Our current understanding of myxobacterial grouped-cell motilities comes mainly from the research on M. xanthus, which shows that filamentous type IV pili (TFP), composed of type IV pilin (also called PilA protein) subunits, are the key apparatus for social motility (S-motility). However, little is known about the pilin protein in S. aurantiaca. We cloned and sequenced four genes (pilA(Sa1~4)) from S. aurantiaca DSM17044 that are homologous to pilA(Mx) (pilA gene in M. xanthus DK1622). The homology and similarities among pilA(Sa) proteins and other myxobacterial homologues were systematically analyzed. To determine their potential biological functions, the four pilA(Sa) genes were expressed in M. xanthus DK10410 (DeltapilA(Mx)), which did not restore S-motility on soft agar or EPS production to host cells. After further analysis of the motile behaviors in a methylcellulose solution, the M. xanthus strains were categorized into three types. YL6101, carrying pilA(Sa1), and YL6104, carrying pilA(Sa4), produced stable but unretractable surface pili; YL6102, carrying pilA(Sa2), produced stable surface pili and exhibited reduced TFP-dependent motility in methylcellulose; YL6103, carrying pilA(Sa3), produced unstable surface pili. Based on these findings, we propose that pilA(Sa2) might be responsible for the type IV pilin production involved in group motility in S. aurantiaca DSM17044. After examining the developmental processes, it was suggested that the expression of PilA(Sa4) protein might have positive effects on the fruiting body formation of M. xanthus DK10410 cells. Moreover, the formation of fruiting body in M. xanthus cells with stable exogenous TFPSa were compensated by mixing them with S. aurantiaca DSM17044 cells. Our results shed some light on the features and functions of type IV pilin homologues in S. aurantiaca. PMID- 24058655 TI - Plasma concentrations of efavirenz and nevirapine among HIV-infected patients with immunological failure attending a tertiary hospital in North-western Tanzania. AB - BACKGROUND: Sub-therapeutic and supra-therapeutic plasma concentrations of antriretrovirals are the significant causes of treatment failure and toxicity respectively among HIV-infected patients. We conducted this study to determine the pattern of efavirenz and nevirapine plasma drug concentrations among adult HIV-infected patients with immunological failure attending at a tertiary hospital in North-western Tanzania. MATERIALS AND METHODS: A cross-sectional study was conducted among adult HIV-infected patients with immunological failure who have been on either efavirenz or nevirapine based antiretroviral regimen for more than 6 months. Patients were serially enrolled through routine Care and Treatment Clinic (CTC) activities. Plasma drug concentrations for efavirenz and nevirapine were determined by high performance liquid chromatography (HPLC) and Gas Chromatography (GC) respectively. Demographic, clinical and laboratory data such as viral load and CD4 counts were collected. Data analysis was done using STATA 12. RESULTS: Of the 152 patients with immunological failure enrolled, the sub therapeutic, therapeutic and supra-therapeutic plasma antiretroviral drug concentrations were found in 43/152 (28.3%), 76/152 (50.0%) and 33/152 (21.7%) respectively. Half of the patients were outside therapeutic window with either sub-therapeutic or supra-therapeutic plasma ARV drug concentrations. There was a significant difference in distribution of ARV adherence (p-value<0.001), NRTI backbone (p-value = 0.039), HIV stage (p-value = 0.026) and viral load (p-value = 0.007) within sub-therapeutic, therapeutic and supra-therapeutic ARV plasma drug concentrations. CONCLUSION: There is a wide inter-individual variability of plasma ARV concentrations among HIV patients with immunological failure, with a large proportion of patients being outside therapeutic window. This variability is significant based on ARV adherence, NRTI backbone, viral load and HIV stage. Routine therapeutic drug monitoring (TDM) could assist identifying these patients early and making timely correction to avoid virological failure, poor immunological outcome and prevent associated drug toxicities. Nonetheless, ARV adherence should be strictly emphasized on HIV patients with immunological failure. PMID- 24058654 TI - Inducible CYP2J2 and its product 11,12-EET promotes bacterial phagocytosis: a role for CYP2J2 deficiency in the pathogenesis of Crohn's disease? AB - The epoxygenase CYP2J2 has an emerging role in inflammation and vascular biology. The role of CYP2J2 in phagocytosis is not known and its regulation in human inflammatory diseases is poorly understood. Here we investigated the role of CYP2J2 in bacterial phagocytosis and its expression in monocytes from healthy controls and Crohns disease patients. CYP2J2 is anti-inflammatory in human peripheral blood monocytes. Bacterial LPS induced CYP2J2 mRNA and protein. The CYP2J2 arachidonic acid products 11,12-EET and 14,15-EET inhibited LPS induced TNFalpha release. THP-1 monocytes were transformed into macrophages by 48h incubation with phorbol 12-myristate 13-acetate. Epoxygenase inhibition using a non-selective inhibitor SKF525A or a selective CYP2J2 inhibitor Compound 4, inhibited E. coli particle phagocytosis, which could be specifically reversed by 11,12-EET. Moreover, epoxygenase inhibition reduced the expression of phagocytosis receptors CD11b and CD68. CD11b also mediates L. monocytogenes phagocytosis. Similar, to E. coli bioparticle phagocytosis, epoxygenase inhibition also reduced intracellular levels of L. monocytogenes, which could be reversed by co-incubation with 11,12-EET. Disrupted bacterial clearance is a hallmark of Crohn's disease. Unlike macrophages from control donors, macrophages from Crohn's disease patients showed no induction of CYP2J2 in response to E. coli. These results demonstrate that CYP2J2 mediates bacterial phagocytosis in macrophages, and implicates a defect in the CYP2J2 pathway may regulate bacterial clearance in Crohn's disease. PMID- 24058656 TI - Video game telemetry as a critical tool in the study of complex skill learning. AB - Cognitive science has long shown interest in expertise, in part because prediction and control of expert development would have immense practical value. Most studies in this area investigate expertise by comparing experts with novices. The reliance on contrastive samples in studies of human expertise only yields deep insight into development where differences are important throughout skill acquisition. This reliance may be pernicious where the predictive importance of variables is not constant across levels of expertise. Before the development of sophisticated machine learning tools for data mining larger samples, and indeed, before such samples were available, it was difficult to test the implicit assumption of static variable importance in expertise development. To investigate if this reliance may have imposed critical restrictions on the understanding of complex skill development, we adopted an alternative method, the online acquisition of telemetry data from a common daily activity for many: video gaming. Using measures of cognitive-motor, attentional, and perceptual processing extracted from game data from 3360 Real-Time Strategy players at 7 different levels of expertise, we identified 12 variables relevant to expertise. We show that the static variable importance assumption is false--the predictive importance of these variables shifted as the levels of expertise increased--and, at least in our dataset, that a contrastive approach would have been misleading. The finding that variable importance is not static across levels of expertise suggests that large, diverse datasets of sustained cognitive-motor performance are crucial for an understanding of expertise in real-world contexts. We also identify plausible cognitive markers of expertise. PMID- 24058657 TI - Infants help a non-human agent. AB - Young children can be motivated to help adults by sympathetic concern based upon empathy, but the underlying mechanisms are unknown. One account of empathy-based sympathetic helping in adults states that it arises due to direct-matching mirror system mechanisms which allow the observer to vicariously experience the situation of the individual in need of help. This mechanism could not account for helping of a geometric-shape agent lacking human-isomorphic body-parts. Here 17 month-olds observed a ball-shaped non-human agent trying to reach a goal but failing because it was blocked by a barrier. Infants helped the agent by lifting it over the barrier. They performed this action less frequently in a control condition in which the barrier could not be construed as blocking the agent. Direct matching is therefore not required for motivating helping in infants, indicating that at least some of our early helpful tendencies do not depend on human-specific mechanisms. Empathy-based mechanisms that do not require direct matching provide one plausible basis for the observed helping. A second possibility is that rather than being based on empathy, the observed helping occurred as a result of a goal-contagion process in which the infants were primed with the unfulfilled goal. PMID- 24058658 TI - Uterine endoplasmic reticulum stress and its unfolded protein response may regulate caspase 3 activation in the pregnant mouse uterus. AB - We have previously proposed that uterine caspase-3 may modulate uterine contractility in a gestationally regulated fashion. The objective of this study was to determine the mechanism by which uterine caspase-3 is activated and consequently controlled in the pregnant uterus across gestation. Utilizing the mouse uterus as our gestational model we examined the intrinsic and extrinsic apoptotic signaling pathways and the endoplasmic reticulum stress response as potential activators of uterine caspase-3 at the transcriptional and translational level. Our study revealed robust activation of the uterine myocyte endoplasmic reticulum stress response and its adaptive unfolded protein response during pregnancy coinciding respectively with increased uterine caspase-3 activity and its withdrawal to term. In contrast the intrinsic and extrinsic apoptotic signaling pathways remained inactive across gestation. We speculate that physiological stimuli experienced by the pregnant uterus likely potentiates the uterine myocyte endoplasmic reticulum stress response resulting in elevated caspase-3 activation, which is isolated to the pregnant mouse myometrium. However as term approaches, activation of an elevated adaptive unfolded protein response acts to limit the endoplasmic reticulum stress response inhibiting caspase-3 resulting in its decline towards term. We speculate that these events have the capacity to regulate gestational length in a caspase-3 dependent manner. PMID- 24058659 TI - Spatial distribution of DARPP-32 in dendritic spines. AB - The phosphoprotein DARPP-32 (dopamine and cyclic adenosine 3', 5'-monophosphate regulated phosphoprotein, 32 kDa) is an important component in the molecular regulation of postsynaptic signaling in neostriatum. Despite the importance of this phosphoprotein, there is as yet little known about the nanoscale distribution of DARPP-32. In this study we applied superresolution stimulated emission depletion microscopy (STED) to assess the expression and distribution of DARPP-32 in striatal neurons. Primary culture of striatal neurons were immunofluorescently labeled for DARPP-32 with Alexa-594 and for the dopamine D1 receptor (D1R) with atto-647N. Dual-color STED microscopy revealed discrete localizations of DARPP-32 and D1R in the spine structure, with clustered distributions in both head and neck. Dissected spine structures reveal that the DARPP-32 signal rarely overlapped with the D1R signal. The D1R receptor is positioned in an "aggregated" manner primarily in the spine head and to some extent in the neck, while DARPP-32 forms several neighboring small nanoclusters spanning the whole spine structure. The DARPP-32 clusters have a mean size of 52 +/- 6 nm, which is close to the resolution limit of the microscope and corresponds to the physical size of a few individual phosphoprotein immunocomplexes. Dissection of synaptic proteins using superresolution microscopy gives possibilities to reveal in better detail biologically relevant information, as compared to diffraction-limited microscopy. In this work, the dissected postsynaptic topology of the DARPP-32 phosphoprotein provides strong evidence for a compartmentalized and confined distribution in dendritic spines. The protein topology and the relatively low copy number of phosphoprotein provides a conception of DARPP-32's possibilities to fine-tune the regulation of synaptic signaling, which should have an impact on the performance of the neuronal circuits in which it is expressed. PMID- 24058660 TI - Validity and reproducibility of a food frequency questionnaire as a measure of recent dietary intake in young adults. AB - This research assessed the relative validity and reproducibility of the Dietary Questionnaire for Epidemiological Studies (DQESV2) over one month in young adults, given the lack of concise and convenient instruments for assessing recent dietary intake in this population. Participants were recruited from a large Australian university (N = 102; 35% male; age 18-34 years; body mass index 16-37 kg/m(2)). Five one-day weighed food records (WFR) were administered over one month followed by the DQESV2. Estimates for nutrients (energy, protein, total fat, saturated fat, carbohydrate, sugars, dietary fibre, and alcohol) and fruit and vegetable servings were compared between methods using correlation coefficients, 95% limits of agreement, and quintile classifications. One week later, a second DQESV2 was completed by n = 77 of the participants to assess reproducibility using intra-class correlations (ICC) and weighted kappa. Comparing methods, all nutrients and fruit and vegetable servings showed significant positive correlations (P<0.05) except protein intake in males; over 60% of participants were within one quintile classification except total fat and dietary fibre intakes in males (55% and 56%, respectively); and differences in nutrient and food intakes between methods were all within +/-20% of the mean WFR values except alcohol intake in females. Between first and second administrations of the DQESV2 all ICC coefficients were positive (P<0.01) and weighted kappa coefficients ranged from 0.54 for fruit servings (including fruit juice) in males to 0.91 for protein intake in females. Over a one month period, the DQESV2 demonstrated good reproducibility for the studied nutrients and for fruit and vegetable servings and provided a valid measure of the studied nutrients, except alcohol in females, and of fruit servings (including fruit juice) in both genders, at the group level in this young adult population. PMID- 24058661 TI - Scattering of light by colloidal aluminosilicate particles produces the unusual sky-blue color of Rio Celeste (Tenorio volcano complex, Costa Rica). AB - Rio Celeste (Sky-Blue River) in Tenorio National Park (Costa Rica), a river that derives from the confluence and mixing of two colorless streams--Rio Buenavista (Buenavista River) and Quebrada Agria (Sour Creek)--is renowned in Costa Rica because it presents an atypical intense sky-blue color. Although various explanations have been proposed for this unusual hue of Rio Celeste, no exhaustive tests have been undertaken; the reasons hence remain unclear. To understand this color phenomenon, we examined the physico-chemical properties of Rio Celeste and of the two streams from which it is derived. Chemical analysis of those streams with ion-exchange chromatography (IC) and inductively coupled plasma atomic emission spectroscopy (ICP-OES) made us discard the hypothesis that the origin of the hue is due to colored chemical species. Our tests revealed that the origin of this coloration phenomenon is physical, due to suspended aluminosilicate particles (with diameters distributed around 566 nm according to a lognormal distribution) that produce Mie scattering. The color originates after mixing of two colorless streams because of the enlargement (by aggregation) of suspended aluminosilicate particles in the Rio Buenavista stream due to a decrease of pH on mixing with the acidic Quebrada Agria. We postulate a chemical mechanism for this process, supported by experimental evidence of dynamic light scattering (DLS), zeta potential measurements, X-ray diffraction and scanning electron microscopy (SEM) with energy-dispersive spectra (EDS). Theoretical modeling of the Mie scattering yielded a strong coincidence between the observed color and the simulated one. PMID- 24058662 TI - Ambient air toxics and asthma prevalence among a representative sample of US kindergarten-age children. AB - BACKGROUND: Criteria pollutants have been associated with exacerbation of children's asthma, but the role of air toxics in relation to asthma is less clear. Our objective was to evaluate whether exposure to outdoor air toxics in early childhood increased asthma risk or severity. METHODS: Air toxics exposure was estimated using the 2002 National Air toxics Assessment (NATA) and linked to longitudinal data (n=6950) from a representative sample of US children born in 2001 and followed through kindergarten-age in the Early Child Longitudinal Study Birth Cohort (ECLS-B). RESULTS: Overall, 17.7% of 5.5 year-olds had ever been told by a healthcare professional they had asthma, and 6.8% had been hospitalized or visited an emergency room for an asthma attack. Higher rates of asthma were observed among boys (20.1%), low-income (24.8%), and non-Hispanic black children (30.0%) (p<=0.05). Air toxics exposure was greater for minority race/ethnicity (p<0.0001), low income (p<0.0001), non-rural area (p<0.001). Across all analyses, greater air toxics exposure, as represented by total NATA respiratory hazard index, or when limited to respiratory hazard index from onroad mobile sources or diesel PM, was not associated with a greater prevalence of asthma or hospitalizations (p trend >0.05). In adjusted logistic regression models, children exposed to the highest respiratory hazard index were not more likely to have asthma compared to those exposed to the lowest respiratory hazard index of total, onroad sources, or diesel PM. CONCLUSIONS: Early childhood exposure to outdoor air toxics in a national sample has not previously been studied relative to children's asthma. Within the constraints of the study, we found no evidence that early childhood exposure to outdoor air toxics increased risk for asthma. As has been previously reported, it is evident that there are environmental justice and disparity concerns for exposure to air toxics and asthma prevalence in US children. PMID- 24058663 TI - Deletion of LRP5 in VLDLR knockout mice inhibits retinal neovascularization. AB - The development and maintenance of retinal vasculature require a precise balance between pro-angiogenic and anti-angiogenic factors. However, mechanisms underlying normal homeostasis of retinal vasculature and pathological changes of disrupted retinal vessel development are not fully understood. Recent studies of the low-density lipoprotein receptor-related protein 5 (LRP5) and the very low density lipoprotein receptor (VLDLR) mutant mice indicate that LRP5 mediates a pro-angiogenic signal while VLDLR mediates an anti-angiogenic signal in retinal vasculature. Mice with a loss of LRP5 display underdeveloped intraretinal vasculature associated with endothelial cell (EC) clustering and failed EC migration into deep retinal layers. In contrast, VLDLR knockout mice show overgrown intraretinal vasculature and subretinal neovascularization. To understand the mechanisms for the opposite retinal vascular abnormalities between LRP5 and VLDLR mutant mice and to test how a loss of LRP5 perturbs subretinal neovascularization caused by a loss of VLDLR, we have generated and characterized the retinal vasculature in LRP5/VLDLR double knockout (DKO) mice. Our data show that DKO mice develop substantial EC clustering without subretinal neovascularization. The absence of subretinal neovascularization in DKO mice is associated with inhibited migration of ECs into the photoreceptor cell layer. In addition, the transcription level of Slc38a5, which encodes a Muller cell specific glutamine transporter, is significantly reduced in DKO mice, similar to previously reported changes in LRP5 single knockout mice. Thus, LRP5 signaling is a prerequisite for neovascularization in VLDLR knockout mice. LRP5 may be an effective target for inhibiting intraretinal neovascularization. PMID- 24058664 TI - Functional traits reveal processes driving natural afforestation at large spatial scales. AB - An understanding of the processes governing natural afforestation over large spatial scales is vital for enhancing forest carbon sequestration. Models of tree species occurrence probability in non-forest vegetation could potentially identify the primary variables determining natural afforestation. However, inferring processes governing afforestation using tree species occurrence is potentially problematic, since it is impossible to know whether observed occurrences are due to recruitment or persistence of existing trees following disturbance. Plant functional traits have the potential to reveal the processes by which key environmental and land cover variables influence afforestation. We used 10,061 survey plots to identify the primary environmental and land cover variables influencing tree occurrence probability in non-forest vegetation in New Zealand. We also examined how these variables influenced diversity of functional traits linked to plant ecological strategy and dispersal ability. Mean annual temperature was the most important environmental predictor of tree occurrence. Local woody cover and distance to forest were the most important land cover variables. Relationships between these variables and ecological strategy traits revealed a trade-off between ability to compete for light and colonize sites that were marginal for tree occurrence. Biotically dispersed species occurred less frequently with declining temperature and local woody cover, suggesting that abiotic stress limited their establishment and that biotic dispersal did not increase ability to colonize non-woody vegetation. Functional diversity for ecological strategy traits declined with declining temperature and woody cover and increasing distance to forest. Functional diversity for dispersal traits showed the opposite trend. This suggests that low temperatures and woody cover and high distance to forest may limit tree species establishment through filtering on ecological strategy traits, but not on dispersal traits. This study shows that 'snapshot' survey plot data, combined with functional trait data, may reveal the processes driving tree species establishment in non-forest vegetation over large spatial scales. PMID- 24058665 TI - Monocyte exosomes stimulate the osteogenic gene expression of mesenchymal stem cells. AB - Inflammation and regeneration at the implant-bone interface are intimately coupled via cell-cell communication. In contrast to the prevailing view that monocytes/macrophages orchestrate mesenchymal stem cells (MSCs) and progenitor cells via the secretion of soluble factors, we examined whether communication between these different cell types also occurs via exosomes. LPS-stimulated human monocytes released exosomes, positive for CD9, CD63, CD81, Tsg101 and Hsp70, as determined by flow cytometry and Western blot. These exosomes also contained wide size distribution of RNA, including RNA in the size of microRNAs. The exosomes were shown to interact with human mesenchymal stem cells. After 24 h of culture, a considerable portion of the MSCs had internalised PKH67-labelled exosomes. Furthermore, after 72 h, the gene expression of the osteogenic markers runt related transcription factor 2 (RUNX2) and bone morphogenetic protein-2 (BMP-2) had increased in comparison with control medium, whereas no significant difference in osteocalcin (OC) expression was demonstrated. The present results show that, under given experimental conditions, monocytes communicate with MSCs via exosomes, resulting in the uptake of exosomes in MSCs and the stimulation of osteogenic differentiation. The present observations suggest that exosomes constitute an additional mode of cell-cell signalling with an effect on MSC differentiation during the transition from injury and inflammation to bone regeneration. PMID- 24058666 TI - Abundance and survival of Pacific humpback whales in a proposed critical habitat area. AB - Humpback whales (Megaptera novaeangliae) were hunted commercially in Canada's Pacific region until 1966. Depleted to an estimated 1,400 individuals throughout the North Pacific, humpback whales are listed as Threatened under Canada's Species at Risk Act (SARA) and Endangered under the US Endangered Species Act. We conducted an 8-year photo-identification study to monitor humpback whale usage of a coastal fjord system in British Columbia (BC), Canada that was recently proposed as candidate critical habitat for the species under SARA. This participatory research program built collaborations among First Nations, environmental non-governmental organizations and academics. The study site, including the territorial waters of Gitga'at First Nation, is an important summertime feeding destination for migratory humpback whales, but is small relative to the population's range. We estimated abundance and survivorship using mark-recapture methods using photographs of naturally marked individuals. Abundance of humpback whales in the region was large, relative to the site's size, and generally increased throughout the study period. The resulting estimate of adult survivorship (0.979, 95% CI: 0.914, 0.995) is at the high end of previously reported estimates. A high rate of resights provides new evidence for inter-annual site fidelity to these local waters. Habitat characteristics of our study area are considered ecologically significant and unique, and this should be considered as regulatory agencies consider proposals for high-volume crude oil and liquefied natural gas tanker traffic through the area. Monitoring population recovery of a highly mobile, migratory species is daunting for low-cost, community-led science. Focusing on a small, important subset of the animals' range can make this challenge more tractable. Given low statistical power and high variability, our community is considering simpler ecological indicators of population health, such as the number of individuals harmed or killed each year by human activities, including ship strikes and entanglement in fishing gear. PMID- 24058667 TI - Earlier visual N1 latencies in expert video-game players: a temporal basis of enhanced visuospatial performance? AB - Increasing behavioural evidence suggests that expert video game players (VGPs) show enhanced visual attention and visuospatial abilities, but what underlies these enhancements remains unclear. We administered the Poffenberger paradigm with concurrent electroencephalogram (EEG) recording to assess occipital N1 latencies and interhemispheric transfer time (IHTT) in expert VGPs. Participants comprised 15 right-handed male expert VGPs and 16 non-VGP controls matched for age, handedness, IQ and years of education. Expert VGPs began playing before age 10, had a minimum 8 years experience, and maintained playtime of at least 20 hours per week over the last 6 months. Non-VGPs had little-to-no game play experience (maximum 1.5 years). Participants responded to checkerboard stimuli presented to the left and right visual fields while 128-channel EEG was recorded. Expert VGPs responded significantly more quickly than non-VGPs. Expert VGPs also had significantly earlier occipital N1s in direct visual pathways (the hemisphere contralateral to the visual field in which the stimulus was presented). IHTT was calculated by comparing the latencies of occipital N1 components between hemispheres. No significant between-group differences in electrophysiological estimates of IHTT were found. Shorter N1 latencies may enable expert VGPs to discriminate attended visual stimuli significantly earlier than non-VGPs and contribute to faster responding in visual tasks. As successful video-game play requires precise, time pressured, bimanual motor movements in response to complex visual stimuli, which in this sample began during early childhood, these differences may reflect the experience and training involved during the development of video-game expertise, but training studies are needed to test this prediction. PMID- 24058668 TI - Mice infected with low-virulence strains of Toxoplasma gondii lose their innate aversion to cat urine, even after extensive parasite clearance. AB - Toxoplasma gondii chronic infection in rodent secondary hosts has been reported to lead to a loss of innate, hard-wired fear toward cats, its primary host. However the generality of this response across T. gondii strains and the underlying mechanism for this pathogen-mediated behavioral change remain unknown. To begin exploring these questions, we evaluated the effects of infection with two previously uninvestigated isolates from the three major North American clonal lineages of T. gondii, Type III and an attenuated strain of Type I. Using an hour long open field activity assay optimized for this purpose, we measured mouse aversion toward predator and non-predator urines. We show that loss of innate aversion of cat urine is a general trait caused by infection with any of the three major clonal lineages of parasite. Surprisingly, we found that infection with the attenuated Type I parasite results in sustained loss of aversion at times post infection when neither parasite nor ongoing brain inflammation were detectable. This suggests that T. gondii-mediated interruption of mouse innate aversion toward cat urine may occur during early acute infection in a permanent manner, not requiring persistence of parasite cysts or continuing brain inflammation. PMID- 24058669 TI - Human brain activity patterns beyond the isoelectric line of extreme deep coma. AB - The electroencephalogram (EEG) reflects brain electrical activity. A flat (isoelectric) EEG, which is usually recorded during very deep coma, is considered to be a turning point between a living brain and a deceased brain. Therefore the isoelectric EEG constitutes, together with evidence of irreversible structural brain damage, one of the criteria for the assessment of brain death. In this study we use EEG recordings for humans on the one hand, and on the other hand double simultaneous intracellular recordings in the cortex and hippocampus, combined with EEG, in cats. They serve to demonstrate that a novel brain phenomenon is observable in both humans and animals during coma that is deeper than the one reflected by the isoelectric EEG, and that this state is characterized by brain activity generated within the hippocampal formation. This new state was induced either by medication applied to postanoxic coma (in human) or by application of high doses of anesthesia (isoflurane in animals) leading to an EEG activity of quasi-rhythmic sharp waves which henceforth we propose to call nu-complexes (Nu-complexes). Using simultaneous intracellular recordings in vivo in the cortex and hippocampus (especially in the CA3 region) we demonstrate that nu-complexes arise in the hippocampus and are subsequently transmitted to the cortex. The genesis of a hippocampal nu-complex depends upon another hippocampal activity, known as ripple activity, which is not overtly detectable at the cortical level. Based on our observations, we propose a scenario of how self oscillations in hippocampal neurons can lead to a whole brain phenomenon during coma. PMID- 24058670 TI - Characterizing immunoglobulin repertoire from whole blood by a personal genome sequencer. AB - In human immune system, V(D)J recombination produces an enormously large repertoire of immunoglobulins (Ig) so that they can tackle different antigens from bacteria, viruses and tumor cells. Several studies have demonstrated the utility of next-generation sequencers such as Roche 454 and Illumina Genome Analyzer to characterize the repertoire of immunoglobulins. However, these techniques typically require separation of B cell population from whole blood and require a few weeks for running the sequencers, so it may not be practical to implement them in clinical settings. Recently, the Ion Torrent personal genome sequencer has emerged as a tabletop personal genome sequencer that can be operated in a time-efficient and cost-effective manner. In this study, we explored the technical feasibility to use multiplex PCR for amplifying V(D)J recombination for IgH, directly from whole blood, then sequence the amplicons by the Ion Torrent sequencer. The whole process including data generation and analysis can be completed in one day. We tested the method in a pilot study on patients with benign, atypical and malignant meningiomas. Despite the noisy data, we were able to compare the samples by their usage frequencies of the V segment, as well as their somatic hypermutation rates. In summary, our study suggested that it is technically feasible to perform clinical monitoring of V(D)J recombination within a day by personal genome sequencers. PMID- 24058672 TI - In vitro and ex vivo evaluations on transdermal delivery of the HIV inhibitor IQP 0410. AB - The aim of this study was to investigate the physicochemical and in vitro/ex vivo characteristics of the pyrmidinedione IQP-0410 formulated into transdermal films. IQP-0410 is a potent therapeutic anti-HIV nonnucleoside reverse transcriptase inhibitor that would be subjected to extensive first pass metabolism, through conventional oral administration. Therefore, IQP-0410 was formulated into ethyl cellulose/HPMC-based transdermal films via solvent casting. In mano evaluations were performed to evaluate gross physical characteristics. In vitro release studies were performed in both Franz cells and USP-4 dissolution vessels. Ex vivo release and permeability assays were performed on human epidermal tissue models, and the permeated IQP-0410 was collected for in vitro HIV-1 efficacy assays in CEM-SS cells and PBMCs. Film formulation D3 resulted in pliable, strong transdermal films that were loaded with 2% (w/w) IQP-0410. Composed of 60% (w/w) ethyl cellulose and 20% (w/w) HPMC, the films contained < 1.2% (w/w) of water and were hygroscopic resulting in significant swelling under humid conditions. The water permeable nature of the film resulted in complete in vitro dissolution and drug release in 26 hours. When applied to ex vivo epidermal tissues, the films were non-toxic to the tissue and also were non-toxic to HIV target cells used in the in vitro efficacy assays. Over a 3 day application, the films delivered IQP 0410 through the skin tissue at a zero-order rate of 0.94 +/- 0.06 ug/cm(2)/hr with 134 +/- 14.7 uM collected in the basal media. The delivered IQP-0410 resulted in in vitro EC50 values against HIV-1 of 2.56 +/- 0.40 nM (CEM-SS) and 0.58 +/- 0.03 nM (PBMC). The film formulation demonstrated no significant deviation from target values when packaged in foil pouches under standard and accelerated environmental conditions. It was concluded that the transdermal film formulation was a potentially viable method of administering IQP-0410 that warrants further development. PMID- 24058671 TI - Mutation of the light-induced yellow leaf 1 gene, which encodes a geranylgeranyl reductase, affects chlorophyll biosynthesis and light sensitivity in rice. AB - Chlorophylls (Chls) are crucial for capturing light energy for photosynthesis. Although several genes responsible for Chl biosynthesis were characterized in rice (Oryza sativa), the genetic properties of the hydrogenating enzyme involved in the final step of Chl synthesis remain unknown. In this study, we characterized a rice light-induced yellow leaf 1-1 (lyl1-1) mutant that is hypersensitive to high-light and defective in the Chl synthesis. Light-shading experiment suggested that the yellowing of lyl1-1 is light-induced. Map-based cloning of LYL1 revealed that it encodes a geranylgeranyl reductase. The mutation of LYL1 led to the majority of Chl molecules are conjugated with an unsaturated geranylgeraniol side chain. LYL1 is the firstly defined gene involved in the reduction step from Chl-geranylgeranylated (Chl(GG)) and geranylgeranyl pyrophosphate (GGPP) to Chl-phytol (Chl(Phy)) and phytyl pyrophosphate (PPP) in rice. LYL1 can be induced by light and suppressed by darkness which is consistent with its potential biological functions. Additionally, the lyl1-1 mutant suffered from severe photooxidative damage and displayed a drastic reduction in the levels of alpha-tocopherol and photosynthetic proteins. We concluded that LYL1 also plays an important role in response to high-light in rice. PMID- 24058674 TI - Nocturnal hypoxia in ALS is related to cognitive dysfunction and can occur as clusters of desaturations. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that leads to progressive weakness of the respiratory and limb muscles. Consequently, most patients with ALS exhibit progressive hypoventilation, which worsens during sleep. The aim of this study was to evaluate the relationship between nocturnal hypoxia and cognitive dysfunction and to assess the pattern of nocturnal hypoxia in patients with ALS. METHOD: Twenty-five patients with definite or probable ALS underwent neuropsychologic testing, nocturnal pulse oximetry, and capnography. Patients were grouped according to the presence of nocturnal hypoxia (SpO2<95% for >=10% of the night) and their clinical characteristics and cognitive function were compared. RESULTS: Compared to patients without nocturnal hypoxia, those with nocturnal hypoxia (n = 10, 40%) had poor memory retention (p = 0.039) and retrieval efficiency (p = 0.045). A cluster-of-desaturation pattern was identified in 7 patients (70%) in the Hypoxia Group. CONCLUSIONS: These results suggest that nocturnal hypoxia can be related to cognitive dysfunction in ALS. In addition, a considerable number of patients with ALS may be exposed to repeated episodes of deoxygenation-reoxygenation (a cluster-of-desaturation pattern) during sleep, which could be associated with the generation of reactive oxygen species. Further studies are required to define the exact causal relationships between these phenomena, the exact manifestations of nocturnal cluster-of-desaturation patterns, and the effect of clusters of desaturation on ALS progression. PMID- 24058673 TI - Hedgehog/GLI signaling activates suppressor of cytokine signaling 1 (SOCS1) in epidermal and neural tumor cells. AB - Sustained hedgehog (Hh) signaling mediated by the GLI transcription factors is implicated in many types of cancer. Identification of Hh/GLI target genes modulating the activity of other pathways involved in tumor development promise to open new ways for better understanding of tumor development and maintenance. Here we show that SOCS1 is a direct target of Hh/GLI signaling in human keratinocytes and medulloblastoma cells. SOCS1 is a potent inhibitor of interferon gamma (IFN-y)/STAT1 signaling. IFN-u/STAT1 signaling can induce cell cycle arrest, apoptosis and anti-tumor immunity. The transcription factors GLI1 and GLI2 activate the SOCS1 promoter, which contains five putative GLI binding sites, and GLI2 binding to the promoter was shown by chromatin immunoprecipitation. Consistent with a role of GLI in SOCS1 regulation, STAT1 phosphorylation is reduced in cells with active Hh/GLI signaling and IFN-u/STAT1 target gene activation is decreased. Furthermore, IFN-u signaling is restored by shRNA mediated knock down of SOCS1. Here, we identify SOCS1 as a novel Hh/GLI target gene, indicating a negative role of Hh/GLI pathway in IFN-y/STAT1 signaling. PMID- 24058675 TI - Long-term outcomes in patients with early stage nodular lymphocyte-predominant Hodgkin's lymphoma treated with radiotherapy. AB - PURPOSE: Radiation therapy (RT) is commonly used as definitive treatment for early-stage nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL). We evaluated the cause-specific survival (CSS), overall survival (OS), and second malignancy (SM) rates in patients with early-stage NLPHL treated with RT. METHODS AND MATERIALS: Patients with stage I-II NLPHL between 1988 and 2009 who underwent RT were selected from the Surveillance, Epidemiology and End Results database. Univariate analysis (UVA) for CSS and Os was performed using the Kaplan-Meier method and included age, gender, involved site, year of diagnosis, presence of B symptoms, and extranodal involvement (ENI). Multivariable analysis (MVA) was performed using Cox Proportional Hazards modeling and included the above clinical variables. SM were classified as RT-related or non-RT-related. Freedom from SM and freedom from RT-related SM were determined using the Kaplan-Meier method. RESULTS: The study cohort included 469 patients. Median age was 37 years. The most common involved sites were the head and neck (36%), axilla/arm (26%), and multiple lymph node regions (18%). Sixty-eight percent had stage I disease, 70% were male, 4% had ENI, and 7% had B-symptoms. Median follow-up was 6 years. Ten year CSS and Os were 98% and 88%, respectively. On UVA, none of the covariates was associated with CSS. Increasing age (p<0.01) and female gender (p<0.01) were associated with worse Os. On MVA, older age (p<0.01), female gender (p=0.04), multiple regions of involvement (p=0.03), stage I disease (p=0.02), and presence of B-symptoms (p=0.02) were associated with worse Os. Ten-year freedom from SM and freedom from RT-related SM were 89% and 99%, respectively. CONCLUSIONS: This is the largest series to evaluate the outcomes of stage I-II NLPHL patients treated with RT and found that this patient population has an excellent long-term prognosis and a low rate of RT-related second malignancies. PMID- 24058677 TI - Dual p38/JNK mitogen activated protein kinase inhibitors prevent ozone-induced airway hyperreactivity in guinea pigs. AB - Ozone exposure causes airway hyperreactivity and increases hospitalizations resulting from pulmonary complications. Ozone reacts with the epithelial lining fluid and airway epithelium to produce reactive oxygen species and lipid peroxidation products, which then activate cell signaling pathways, including the mitogen activated protein kinase (MAPK) pathway. Both p38 and c-Jun NH2 terminal kinase (JNK) are MAPK family members that are activated by cellular stress and inflammation. To test the contribution of both p38 and JNK MAPK to ozone-induced airway hyperreactivity, guinea pigs were pretreated with dual p38 and JNK MAPK inhibitors (30 mg/kg, i.p.) 60 minutes before exposure to 2 ppm ozone or filtered air for 4 hours. One day later airway reactivity was measured in anesthetized animals. Ozone caused airway hyperreactivity one day post-exposure, and blocking p38 and JNK MAPK completely prevented ozone-induced airway hyperreactivity. Blocking p38 and JNK MAPK also suppressed parasympathetic nerve activity in air exposed animals, suggesting p38 and JNK MAPK contribute to acetylcholine release by airway parasympathetic nerves. Ozone inhibited neuronal M2 muscarinic receptors and blocking both p38 and JNK prevented M2 receptor dysfunction. Neutrophil influx into bronchoalveolar lavage was not affected by MAPK inhibitors. Thus p38 and JNK MAPK mediate ozone-induced airway hyperreactivity through multiple mechanisms including prevention of neuronal M2 receptor dysfunction. PMID- 24058678 TI - Diabetes and perinatal mortality in twin pregnancies. AB - BACKGROUND: Diabetes in pregnancy has been associated with a paradoxically reduced risk of neonatal death in twin pregnancies. Risk "shift" may be a concern in that the reduction in neonatal deaths may be due to an increase in fetal deaths (stillbirths). This study aimed to clarify the impact of diabetes on the risk of perinatal death (neonatal death plus stillbirth) in twin pregnancies. METHODS: This was a retrospective cohort study of twin births using the largest available dataset on twin births (the U.S. matched multiple birth data 1995-2000; 19,676 neonates from diabetic pregnancies, 541,481 from non-diabetic pregnancies). Cox proportional hazard models were applied to estimate the adjusted hazard ratios (aHR) of perinatal death accounting for twin cluster-level dependence. RESULTS: Comparing diabetic versus non-diabetic twin pregnancies, overall perinatal mortality rate was counterintuitively lower [2.1% versus 3.3%, aHR 0.70 (95% confidence intervals 0.63-0.78)]. Individually, both stillbirth and neonatal mortality rates were lower in diabetic pregnancies, but we identified significant differences by gestational age and birth weight. Diabetes was associated with a survival benefit in pregnancies completed before 32 weeks [aHR 0.55 (0.48-0.63)] or with birth weight <1500 g [aHR 0.61 (0.53-0.69)]. In contrast, diabetes was associated with an elevated risk of perinatal death in pregnancies delivered between 32 and 36 weeks [aHR 1.38 (1.10-1.72)] or with birth weight >=2500 g [aHR 2.20 (1.55-3.13)]. CONCLUSIONS: Diabetes in pregnancy appears to be "protective" against perinatal death in twin pregnancies ending in very preterm or very low birth weight births. Prospective studies are required to clarify whether these patterns of risk are real, or they are artifacts of unmeasured confounders. Additional data correlating these outcomes with the types of diabetes in pregnancy are also needed to distinguish the effects of pre gestational vs. gestational diabetes. PMID- 24058676 TI - Analysis of the host transcriptome from demyelinating spinal cord of murine coronavirus-infected mice. AB - Persistent infection of the mouse central nervous system (CNS) with mouse hepatitis virus (MHV) induces a demyelinating disease pathologically similar to multiple sclerosis and is therefore used as a model system. There is little information regarding the host factors that correlate with and contribute to MHV induced demyelination. Here, we detail the genes and pathways associated with MHV induced demyelinating disease in the spinal cord. High-throughput sequencing of the host transcriptome revealed that demyelination is accompanied by numerous transcriptional changes indicative of immune infiltration as well as changes in the cytokine milieu and lipid metabolism. We found evidence that a Th1-biased cytokine/chemokine response and eicosanoid-derived inflammation accompany persistent MHV infection and that antigen presentation is ongoing. Interestingly, increased expression of genes involved in lipid transport, processing, and catabolism, including some with known roles in neurodegenerative diseases, coincided with demyelination. Lastly, expression of several genes involved in osteoclast or bone-resident macrophage function, most notably TREM2 and DAP12, was upregulated in persistently infected mouse spinal cord. This study highlights the complexity of the host antiviral response, which accompany MHV-induced demyelination, and further supports previous findings that MHV-induced demyelination is immune-mediated. Interestingly, these data suggest a parallel between bone reabsorption by osteoclasts and myelin debris clearance by microglia in the bone and the CNS, respectively. To our knowledge, this is the first report of using an RNA-seq approach to study the host CNS response to persistent viral infection. PMID- 24058679 TI - Long-term survival of dental implants placed in the grafted maxillary sinus: systematic review and meta-analysis of treatment modalities. AB - BACKGROUND: A prevalent modality to increase the amount of available bone prior to implantation is grafting of the maxillary sinus. Multiple factors such as the surgical technique, moment of implant placement as well as grafting materials and membranes are known to affect implant survival. However, the role of different factor combinations and associated reciprocal effects remain unclear. Conventional statistical methods do not consider inconsistency of study designs and do not take covariables into account. Hence, a systematic research and meta analysis was conducted to investigate the influence of various treatment modalities on implant survival in the grafted maxillary sinus. MATERIALS AND METHODS: A meta-analysis was conducted according to the PRISMA guidelines. Articles published from 1980 through January 2013 were electronically and manually searched in MEDLINE (Ovid), the Cochrane Register of Controlled Trials, the Database of Abstracts of Effects, and the Cochrane Database of Systematic Reviews. Clinical reports on single intervention sinus augmentation with root form implants, a minimum of 10 patients and 6 months of loading were eligible for inclusion if implant survival was stated or calculable. Results were calculated by non-parametric univariate Kaplan-Meier analysis and Bayesian multivariate interval-censored Cox regression. RESULTS: A total of 122 publications on 16268 endosseous implants placed in grafted maxillary sinus were included. The treatment parameters surgical approach, grafting material and implant type showed no selective preference. However, application of membranes showed a significantly reduced hazard-ratio, independent of other co-factors. CONCLUSIONS: The use of membranes is the most significant factor to achieve long-term implant survival in sinus augmentation procedures. More data exceeding 3 years follow-up are needed to address prospective confounding and improve clinical evidence. PMID- 24058680 TI - Biodistribution and subcellular localization of an unnatural boron-containing amino acid (cis-ABCPC) by imaging secondary ion mass spectrometry for neutron capture therapy of melanomas and gliomas. AB - The development of new boron-delivery agents is a high priority for improving the effectiveness of boron neutron capture therapy. In the present study, 1-amino-3 borono-cyclopentanecarboxylic acid (cis-ABCPC) as a mixture of its L- and D enantiomers was evaluated in vivo using the B16 melanoma model for the human tumor and the F98 rat glioma as a model for human gliomas. A secondary ion mass spectrometry (SIMS) based imaging instrument, CAMECA IMS 3F SIMS Ion Microscope, was used for quantitative imaging of boron at 500 nm spatial resolution. Both in vivo and in vitro studies in melanoma models demonstrated that boron was localized in the cytoplasm and nuclei with some cell-to-cell variability. Uptake of cis-ABCPC in B16 cells was time dependent with a 7.5:1 partitioning ratio of boron between cell nuclei and the nutrient medium after 4 hrs. incubation. Furthermore, cis-ABCPC delivered boron to cells in all phases of the cell cycle, including S-phase. In vivo SIMS studies using the F98 rat glioma model revealed an 8:1 boron partitioning ratio between the main tumor mass and normal brain tissue with a 5:1 ratio between infiltrating tumor cells and contiguous normal brain. Since cis-ABCPC is water soluble and can cross the blood-brain-barrier via the L-type amino acid transporters (LAT), it may accumulate preferentially in infiltrating tumor cells in normal brain due to up-regulation of LAT in high grade gliomas. Once trapped inside the tumor cell, cis-ABCPC cannot be metabolized and remains either in a free pool or bound to cell matrix components. The significant improvement in boron uptake by both the main tumor mass and infiltrating tumor cells compared to those reported in animal and clinical studies of p-boronophenylalanine strongly suggest that cis-ABCPC has the potential to become a novel new boron delivery agent for neutron capture therapy of gliomas and melanomas. PMID- 24058681 TI - Are routinely collected NHS administrative records suitable for endpoint identification in clinical trials? Evidence from the West of Scotland Coronary Prevention Study. AB - BACKGROUND: Routinely collected electronic patient records are already widely used in epidemiological research. In this work we investigated the potential for using them to identify endpoints in clinical trials. METHODS: The events recorded in the West of Scotland Coronary Prevention Study (WOSCOPS), a large clinical trial of pravastatin in middle-aged hypercholesterolaemic men in the 1990s, were compared with those in the record-linked deaths and hospitalisations records routinely collected in Scotland. RESULTS: We matched 99% of fatal study events by date. We showed excellent matching (97%) of the causes of fatal endpoint events and good matching (>80% for first events) of the causes of nonfatal endpoint events with a slightly lower rate of mismatching of record linkage than study events (19% of first study myocardial infarctions (MI) and 4% of first record linkage MIs not matched as MI). We also investigated the matching of non-endpoint events and showed a good level of matching, with >78% of first stroke/TIA events being matched as stroke/TIA. The primary reasons for mismatches were record linkage data recording readmissions for procedures or previous events, differences between the diagnoses in the routinely collected data and the conclusions of the clinical trial expert adjudication committee, events occurring outside Scotland and therefore being missed by record linkage data, miscoding of cardiac events in hospitalisations data as 'unspecified chest pain', some general miscoding in the record linkage data and some record linkage errors. CONCLUSIONS: We conclude that routinely collected data could be used for recording cardiovascular endpoints in clinical trials and would give very similar results to rigorously collected clinical trial data, in countries with unified health systems such as Scotland. The endpoint types would need to be carefully thought through and an expert endpoint adjudication committee should be involved. PMID- 24058682 TI - Phosphorylation at serines 216 and 221 is important for Drosophila HeT-A Gag protein stability. AB - Telomeres from Drosophila appear to be very different from those of other organisms - in size and the mechanism of their maintenance. In the absence of the enzyme telomerase, Drosophila telomeres are maintained by retrotransposition of three elements, HeT-A, TART, and TAHRE, but details of their transposition mechanisms are not known. Here we characterized some biochemical characteristics of the HeT-A Gag protein encoded by the HeT-A element to understand this mechanism. The HeT-A Gag protein when overexpressed in S2 cells was localized to the nucleus but was resistant to high salt, detergents and nuclease extraction treatments. Analysis of the HeT-A Gag protein by tandem mass spectrophotometry revealed that serines 216 and 221 are phosphorylated. Substituting these serines with alanine or aspartic acid by site-directed mutagenesis did not result in any changes in HeT-A Gag translocation across the nucleus, suggesting that phosphorylation of these sites is not associated with HeT-A Gag translocation, but time course experiments showed that these phosphorylation sites are important for Gag-protein stability. PMID- 24058683 TI - New insights into the binding and catalytic mechanisms of Bacillus thuringiensis lactonase: insights into B. thuringiensis AiiA mechanism. AB - The lactonase enzyme (AiiA) produced by Bacillus thuringiensis serves to degrade autoinducer-1 (AI-1) signaling molecules in what is an evolved mechanism by which to compete with other bacteria. Bioassays have been previously performed to determine whether the AI-1 aliphatic tail lengths have any effect on AiiA's bioactivity, however, data to date are conflicting. Additionally, specific residue contributions to the catalytic activity of AiiA provide for some interesting questions. For example, it has been proposed that Y194 serves to provide an oxyanion hole to AI-1 which is curious given the fact the substrate spans two Zn(2+) ions. These ions might conceivably provide enough charge to promote both ligand stability and the carbonyl activation necessary to drive a nucleophilic attack. To investigate these questions, multiple molecular dynamics simulations were performed across a family of seven acylated homoserine lactones (AHL) along with their associated intermediate and product states. Distance analyses and interaction energy analyses were performed to investigate current bioassay data. Our simulations are consistent with experimental studies showing that AiiA degrades AHLs in a tail length independent manner. However, the presence of the tail is required for activity. Also, the putative oxyanion hole function of Y194 toward the substrate is not observed in any of the reactant or product state simulation trajectories, but does seem to show efficacy in stabilizing the intermediate state. Last, we argue through ionization state analyses, that the proton shuttling necessary for catalytic activity might be mediated by both water and substrate-based intra-molecular proton transfer. Based on this argument, an alternate catalytic mechanism is proposed. PMID- 24058684 TI - Caffeine alters anaerobic distribution and pacing during a 4000-m cycling time trial. AB - The purpose of the present study was to investigate the effects of caffeine ingestion on pacing strategy and energy expenditure during a 4000-m cycling time trial (TT). Eight recreationally-trained male cyclists volunteered and performed a maximal incremental test and a familiarization test on their first and second visits, respectively. On the third and fourth visits, the participants performed a 4000-m cycling TT after ingesting capsules containing either caffeine (5 mg.kg( 1) of body weight, CAF) or cellulose (PLA). The tests were applied in a double blind, randomized, repeated-measures, cross-over design. When compared to PLA, CAF ingestion increased mean power output [219.1+/-18.6 vs. 232.8+/-21.4 W; effect size (ES) = 0.60 (95% CI = 0.05 to 1.16), p = 0.034] and reduced the total time [419+/-13 vs. 409+/-12 s; ES = -0.71 (95% CI = -0.09 to -1.13), p = 0.026]. Furthermore, anaerobic contribution during the 2200-, 2400-, and 2600-m intervals was significantly greater in CAF than in PLA (p<0.05). However, the mean anaerobic [64.9+/-20.1 vs. 57.3+/-17.5 W] and aerobic [167.9+/-4.3 vs. 161.8+/-11.2 W] contributions were similar between conditions (p>0.05). Similarly, there were no significant differences between CAF and PLA for anaerobic work (26363+/-7361 vs. 23888+/-6795 J), aerobic work (68709+/-2118 vs. 67739+/-3912 J), or total work (95245+/-8593 vs. 91789+/-7709 J), respectively. There was no difference for integrated electromyography, blood lactate concentration, heart rate, and ratings of perceived exertion between the conditions. These results suggest that caffeine increases the anaerobic contribution in the middle of the time trial, resulting in enhanced overall performance. PMID- 24058685 TI - Gallbladder gallstone disease is associated with newly diagnosed coronary artery atherosclerotic disease: a cross-sectional study. AB - BACKGROUND AND AIMS: The association between gallstone disease and coronary artery atherosclerotic disease (CAD) remains unclear. To clarify their relationship, patients with CAD newly diagnosed by coronary angiography were investigated in this cross-sectional study. METHODS: The study cohort consisted of 1,270 patients undergoing coronary angiography for the first time between January 2007 and September 2011. Patients with >=50% diameter stenosis in any major coronary artery on coronary angiography were defined as being CAD positive (n = 766) and those with no stenosis as CAD negative (n = 504). Multivariate logistic regression was used to investigate the relationship between gallstone disease and CAD. The odds ratios (OR) of factors associated with CAD were calculated. In addition, CAD-positive and CAD-negative patients were matched one to-one by age, gender and metabolic syndrome (MetS), and the association between gallbladder disease and CAD was determined. RESULTS: The prevalence of gallstone disease was significantly higher in CAD-positive than in CAD negative patients (149/766 [19.5%] vs 57/504 [11.3%], P<0.01). Gallstone disease was significantly associated with CAD (adjusted OR = 1.59, 95% confidence interval [CI] 1.10-2.31). Following matched pairing of 320 patients per group, gallstone disease remained significantly associated with CAD (adjusted OR = 1.69, 95% CI: 1.08-2.65). CONCLUSION: Gallstone disease is strongly associated with CAD diagnosed by coronary angiography. PMID- 24058686 TI - Epidemiology and population structure of serotypes 1, 5 and 7f carried by children in Portugal from 1996-2010 before introduction of the 10-valent and 13 valent pneumococcal conjugate vaccines. AB - Among the over 90 serotypes of Streptococcus pneumoniae described, serotypes 1, 5, and 7F account for a significant proportion of invasive disease worldwide and are now covered by the most recent 10- and 13-valent pneumococcal conjugate vaccines (PCVs). The epidemiology of these serotypes in carriage remains poorly studied because they are rarely detected. We aimed to gain insights into the epidemiology and population structure of serotypes 1, 5 and 7F carried by children in Portugal before PCV10 and PCV13 became widely used. Isolates obtained in cross-sectional studies carried out over a 15-year period (1996-2010) were retrospectively pooled and characterized. Of 5,123 pneumococci obtained, 70 were associated with serotypes 1 (n = 21), 5 (n = 7), and 7F (n = 42). The highest prevalence detected was 3.3% for serotype 1 in 2006, 1% for serotype 5 in 2009, and 3.3% for serotype 7F in 2006; Serotype 1 was associated with PMEN international clones Sweden(1)-28(ST306) and Sweden(1)-40(ST304); serotype 5 was associated with Colombia(5)-19(ST289); and serotype 7F was associated with Netherlands(7F)-39(ST191). All these isolates were fully susceptible. Most carriers of serotypes 1 (86%), 5 (86%), and 7F (91%) were older than two years but a significant association with older age was only observed for serotype 7F (p = 0.006). Evidence for cross-transmission was obtained. In conclusion, we were able to detect and characterize the rarely carried serotypes 1, 5, and 7F among healthy children in Portugal. These data will constitute an important baseline for upcoming surveillance studies aimed to establish the impact of novel PCVs targeting these serotypes in carriage. PMID- 24058688 TI - An intragenic SRF-dependent regulatory motif directs cardiac-specific microRNA-1 1/133a-2 expression. AB - Transcriptional regulation is essential for any gene expression including microRNA expression. MiR-1-1 and miR-133a-2 are essential microRNAs (miRs) involved in cardiac and skeletal muscle development and diseases. Early studies reveal two regulatory enhancers, an upstream and an intragenic, that direct the miR-1-1 and miR-133a-2 transcripts. In this study, we identify a unique serum response factor (SRF) binding motif within the enhancer through bioinformatic approaches. This motif is evolutionarily conserved and is present in a range of organisms from yeast, flies, to humans. We provide evidence to demonstrate that this regulatory motif is SRF-dependent in vitro by electrophoretic mobility shift assay, luciferase activity assay, and endogenous chromatin immunoprecipitation assay followed by DNA sequence confirmation, and in vivo by transgenic lacZ reporter mouse studies. Importantly, our transgenic mice indicate that this motif is indispensable for the expression of miR1-1/133a-2 in the heart, but not necessary in skeletal muscle, while the enhancer is sufficient for miR1-1/133a-2 gene expression in both tissues. The mutation of the motif alone completely abolishes miR-1-1/133a-2 gene expression in the animal heart, but not in the skeletal muscle. Our findings reveal an additional architecture of regulatory complex directing miR-1-1/133a-1 gene expression, and demonstrate how this intragenic enhancer differentially manages the expression of the two miRs in the heart and skeletal muscle, respectively. PMID- 24058687 TI - A fully human inhibitory monoclonal antibody to the Wnt receptor RYK. AB - RYK is an unusual member of the receptor tyrosine kinase (RTK) family that is classified as a putative pseudokinase. RYK regulates fundamental biological processes including cell differentiation, migration and target selection, axon outgrowth and pathfinding by transducing signals across the plasma membrane in response to the high affinity binding of Wnt family ligands to its extracellular Wnt inhibitory factor (WIF) domain. Here we report the generation and initial characterization of a fully human inhibitory monoclonal antibody to the human RYK WIF domain. From a naive human single chain fragment variable (scFv) phage display library, we identified anti-RYK WIF domain-specific scFvs then screened for those that could compete with Wnt3a for binding. Production of a fully human IgG1kappa from an inhibitory scFv yielded a monoclonal antibody that inhibits Wnt5a-responsive RYK function in a neurite outgrowth assay. This antibody will have immediate applications for modulating RYK function in a range of settings including development and adult homeostasis, with significant potential for therapeutic use in human pathologies. PMID- 24058689 TI - Dual regulation of the lin-14 target mRNA by the lin-4 miRNA. AB - microRNAs (miRNAs) are ~22 nt regulatory RNAs that in animals typically bind with partial complementarity to sequences in the 3' untranslated (UTR) regions of target mRNAs, to induce a decrease in the production of the encoded protein. The relative contributions of translational inhibition of intact mRNAs and degradation of mRNAs caused by binding of the miRNA vary; for many genetically validated miRNA targets, translational repression has been implicated, whereas some analyses of other miRNA targets have revealed only modest translational repression and more significant mRNA destabilization. In Caenorhabditis elegans, the lin-4 miRNA accumulates during early larval development, binds to target elements in the lin-14 mRNA, and causes a sharp decrease in the abundance of LIN 14 protein. Here, we monitor the dynamics of lin-14 mRNA and protein as well as lin-4 miRNA levels in finely staged animals during early larval development. We find complex regulation of lin-14, with the abundance of lin-14 mRNA initially modestly declining followed by fluctuation but little further decline of lin-14 mRNA levels accompanied by continuing and more dramatic decline in LIN-14 protein abundance. We show that the translational inhibition of lin-14 is dependent on binding of the lin-4 miRNA to multiple lin-4 complementary sites in the lin-14 3'UTR. Our results point to the importance of translational inhibition in silencing of lin-14 by the lin-4 miRNA. PMID- 24058690 TI - Molecular analysis of a mutated FSH receptor detected in a patient with spontaneous ovarian hyperstimulation syndrome. AB - Spontaneous ovarian hyperstimulation syndrome (sOHSS) is a rare event that may result from a FSH-producing pituitary adenoma (FSHoma), activating mutations of the FSH receptor (FSHR), and cross-reactivity of the FSHR to elevated hCG and TSH in the setting of pregnancy or hypothyroidism. The objective of this study was to investigate whether an aberrant FSHR was present in a woman with sOHSS and a non surgically diagnosed FSHoma whose serum FSH levels and FSH bioactivity were nearly normal. Sequencing of the patient's FSHR gene revealed a heterozygous novel missense mutation c. 1536G>A resulting in an amino acid substitution M512I. We asked whether this mutant FSHR affected FSHR-mediated signaling pathways involving cAMP/protein kinase A (PKA), phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog kinase (SRC)/ p42/p44 extracellular signal-regulated protein kinases (ERK1/2). Thus, 293T cells expressing wild-type (FSHRwt), the mutant FSHR (FSHRmt), or both (FSHRwt/mt) were treated with FSH and subjected to measurements of intracellular cAMP, cAMP-induced CRE (cAMP response element)-mediated luciferase assays and immunoblot analyses of phosphorylated PI3K and ERK1/2. There were no differences in luciferase activities or phosphorylation levels of ERK1/2 among FSHRwt, FSHRmt cells and FSHwt/mt cells. However, FSHRmt cells showed a significant reduction in both cAMP production and PI3K phosphorylation levels with unchanged phosphorylation of ERK1/2 upon FSH stimulation in comparison to FSHwt cells. Also, FSH treatment did not provoke PI3K phosphorylation in FSHwt/mt cells. These results indicate that the novel missense M512I FSHR mutation identified herein did not participate in hyperactivation of FSHR-mediated signaling pathways but rather in hypoactivation of the FSH-mediated PI3K/AKT pathway. Thus, this study demonstrates a new functional property of this novel mutatnt FSHR, which, however, might not be involved in the pathogenesis of sOHSS in this FSHoma patient. PMID- 24058691 TI - Prosocial bonuses increase employee satisfaction and team performance. AB - In three field studies, we explore the impact of providing employees and teammates with prosocial bonuses, a novel type of bonus spent on others rather than on oneself. In Experiment 1, we show that prosocial bonuses in the form of donations to charity lead to happier and more satisfied employees at an Australian bank. In Experiments 2a and 2b, we show that prosocial bonuses in the form of expenditures on teammates lead to better performance in both sports teams in Canada and pharmaceutical sales teams in Belgium. These results suggest that a minor adjustment to employee bonuses--shifting the focus from the self to others- can produce measurable benefits for employees and organizations. PMID- 24058692 TI - Expression and function of scleraxis in the developing auditory system. AB - A study of genes expressed in the developing inner ear identified the bHLH transcription factor Scleraxis (Scx) in the developing cochlea. Previous work has demonstrated an essential role for Scx in the differentiation and development of tendons, ligaments and cells of chondrogenic lineage. Expression in the cochlea has been shown previously, however the functional role for Scx in the cochlea is unknown. Using a Scx-GFP reporter mouse line we examined the spatial and temporal patterns of Scx expression in the developing cochlea between embryonic day 13.5 and postnatal day 25. Embryonically, Scx is expressed broadly throughout the cochlear duct and surrounding mesenchyme and at postnatal ages becomes restricted to the inner hair cells and the interdental cells of the spiral limbus. Deletion of Scx results in hearing impairment indicated by elevated auditory brainstem response (ABR) thresholds and diminished distortion product otoacoustic emission (DPOAE) amplitudes, across a range of frequencies. No changes in either gross cochlear morphology or expression of the Scx target genes Col2A, Bmp4 or Sox9 were observed in Scx(-/-) mutants, suggesting that the auditory defects observed in these animals may be a result of unidentified Scx-dependent processes within the cochlea. PMID- 24058693 TI - Contribution of S6K1/MAPK signaling pathways in the response to oxidative stress: activation of RSK and MSK by hydrogen peroxide. AB - Cells respond to different kind of stress through the coordinated activation of signaling pathways such as MAPK or p53. To find which molecular mechanisms are involved, we need to understand their cell adaptation. The ribosomal protein, S6 kinase 1 (S6K1), is a common downstream target of signaling by hormonal or nutritional stress. Here, we investigated the initial contribution of S6K1/MAPK signaling pathways in the cell response to oxidative stress produced by hydrogen peroxide (H2O2). To analyze S6K1 activation, we used the commercial anti-phospho Thr389-S6K1 antibody most frequently mentioned in the bibliography. We found that this antibody detected an 80-90 kDa protein that was rapidly phosphorylated in response to H2O2 in several human cells. Unexpectedly, this phosphorylation was insensitive to both mTOR and PI3K inhibitors, and knock-down experiments showed that this protein was not S6K1. RSK and MSK proteins were candidate targets of this phosphorylation. We demonstrated that H2O2 stimulated phosphorylation of RSK and MSK kinases at residues that are homologous to Thr389 in S6K1. This phosphorylation required the activity of either p38 or ERK MAP kinases. Kinase assays showed activation of RSK and MSK by H2O2. Experiments with mouse embryonic fibroblasts from p38 animals' knockout confirmed these observations. Altogether, these findings show that the S6K1 signaling pathway is not activated under these conditions, clarify previous observations probably misinterpreted by non-specific detection of proteins RSK and MSK by the anti-phospho-Thr389-S6K1 antibody, and demonstrate the specific activation of MAPK signaling pathways through ERK/p38/RSK/MSK by H2O2. PMID- 24058694 TI - Preferred habitat of breeding birds may be compromised by climate change: unexpected effects of an exceptionally cold, wet spring. AB - Previous studies of the consequences for breeding birds of climate change have explored how their populations may respond to increasing temperatures. However, few have considered the likely outcome of predicted extreme conditions and the relative vulnerability of populations in different habitats. Here, we compare phenology and breeding success in great tits and blue tits over a 10 year period, including the extremely harsh conditions during spring 2012, at three sites in eastern England--mixed deciduous woodland, riparian and urban habitat. Production, measured as brood biomass, was significantly lower in 2012 compared with the previous 9 years, with the decrease in productivity relatively greatest in woodland habitat. Production was related to hatch delay, i.e. birds not initiating incubation immediately after clutch completion, which was more common in 2012 than in previous years. The best predictor of hatch delay was daytime temperature (not nighttime minimum temperature) and rainfall, which convincingly reflected low growth and activity of caterpillar prey. We found that birds breeding in riparian and urban habitats were less vulnerable to the extremes of weather than those breeding in mixed deciduous woodland. PMID- 24058695 TI - Sliding over the blocks in enzyme-free RNA copying--one-pot primer extension in ice. AB - Template-directed polymerization of RNA in the absence of enzymes is the basis for an information transfer in the 'RNA-world' hypothesis and in novel nucleic acid based technology. Previous investigations established that only cytidine rich strands are efficient templates in bulk aqueous solutions while a few specific sequences completely block the extension of hybridized primers. We show that a eutectic water/ice system can support Pb(2+)/Mg(2+)-ion catalyzed extension of a primer across such sequences, i.e. AA, AU and AG, in a one-pot synthesis. Using mixtures of imidazole activated nucleotide 5'-monophosphates, the two first "blocking" residues could be passed during template-directed polymerization, i.e., formation of triply extended products containing a high fraction of faithful copies was demonstrated. Across the AG sequence, a mismatch sequence was formed in similar amounts to the correct product due to U.G wobble pairing. Thus, the template-directed extension occurs both across pyrimidine and purine rich sequences and insertions of pyrimidines did not inhibit the subsequent insertions. Products were mainly formed with 2'-5'-phosphodiester linkages, however, the abundance of 3'-5'-linkages was higher than previously reported for pyrimidine insertions. When enzyme-free, template-directed RNA polymerization is performed in a eutectic water ice environment, various intrinsic reaction limitations observed in bulk solution can then be overcome. PMID- 24058696 TI - HIV-1 Nef sequence and functional compartmentalization in the gut is not due to differential cytotoxic T lymphocyte selective pressure. AB - The gut is the largest lymphoid organ in the body and a site of active HIV-1 replication and immune surveillance. The gut is a reservoir of persistent infection in some individuals with fully suppressed plasma viremia on combination antiretroviral therapy (cART) although the cause of this persistence is unknown. The HIV-1 accessory protein Nef contributes to persistence through multiple functions including immune evasion and increasing infectivity. Previous studies showed that Nef's function is shaped by cytotoxic T lymphocyte (CTL) responses and that there are distinct populations of Nef within tissue compartments. We asked whether Nef's sequence and/or function are compartmentalized in the gut and how compartmentalization relates to local CTL immune responses. Primary nef quasispecies from paired plasma and sigmoid colon biopsies from chronically infected subjects not on therapy were sequenced and cloned into Env(-) Vpu(-) pseudotyped reporter viruses. CTL responses were mapped by IFN-gamma ELISpot using expanded CD8+ cells from blood and gut with pools of overlapping peptides covering the entire HIV proteome. CD4 and MHC Class I Nef-mediated downregulation was measured by flow cytometry. Multiple tests indicated compartmentalization of nef sequences in 5 of 8 subjects. There was also compartmentalization of function with MHC Class I downregulation relatively well preserved, but significant loss of CD4 downregulation specifically by gut quasispecies in 5 of 7 subjects. There was no compartmentalization of CTL responses in 6 of 8 subjects, and the selective pressure on quasispecies correlated with the magnitude CTL response regardless of location. These results demonstrate that Nef adapts via diverse pathways to local selective pressures within gut mucosa, which may be predominated by factors other than CTL responses such as target cell availability. The finding of a functionally distinct population within gut mucosa offers some insight into how HIV-1 may persist in the gut despite fully suppressed plasma viremia on cART. PMID- 24058697 TI - E-readers are more effective than paper for some with dyslexia. AB - E-readers are fast rivaling print as a dominant method for reading. Because they offer accessibility options that are impossible in print, they are potentially beneficial for those with impairments, such as dyslexia. Yet, little is known about how the use of these devices influences reading in those who struggle. Here, we observe reading comprehension and speed in 103 high school students with dyslexia. Reading on paper was compared with reading on a small handheld e-reader device, formatted to display few words per line. We found that use of the device significantly improved speed and comprehension, when compared with traditional presentations on paper for specific subsets of these individuals: Those who struggled most with phoneme decoding or efficient sight word reading read more rapidly using the device, and those with limited VA Spans gained in comprehension. Prior eye tracking studies demonstrated that short lines facilitate reading in dyslexia, suggesting that it is the use of short lines (and not the device per se) that leads to the observed benefits. We propose that these findings may be understood as a consequence of visual attention deficits, in some with dyslexia, that make it difficult to allocate attention to uncrowded text near fixation, as the gaze advances during reading. Short lines ameliorate this by guiding attention to the uncrowded span. PMID- 24058699 TI - Population ecology of free-roaming cats and interference competition by coyotes in urban parks. AB - Free-roaming cats are a common element of urban landscapes worldwide, often causing controversy regarding their impacts on ecological systems and public health. We monitored cats within natural habitat fragments in the Chicago metropolitan area to characterize population demographics, disease prevalence, movement patterns and habitat selection, in addition to assessing the possible influence of coyotes on cats. The population was dominated by adults of both sexes, and 24% of adults were in reproductive condition. Annual survival rate was relatively high (S=0.70, SE=0.10), with vehicles and predation the primary causes of death. Size of annual home range varied by sex, but not reproductive status or body weight. We observed partitioning of the landscape by cats and coyotes, with little interspecific overlap between core areas of activity. Coyotes selected for natural habitats whereas cats selected for developed areas such as residences. Free-roaming cats were in better condition than we predicted, but their use of natural habitat fragments, and presumably their ecological impact, appeared to be limited by coyotes through intraguild competition. PMID- 24058698 TI - The noninvasive retro-mode imaging modality of confocal scanning laser ophthalmoscopy in polypoidal choroidal vasculopathy: a preliminary application. AB - PURPOSE: To evaluate the validity of the novel and noninvasive retro-mode imaging modality of confocal scanning laser ophthalmoscopy (cSLO) for detecting the morphological features of polypoidal choroidal vasculopathy (PCV). DESIGN: Prospective, observational, consecutive case series. METHODS: Twenty-six patients (29 eyes) with PCV were enrolled in this study. All patients underwent comprehensive ophthalmologic examinations and imaging studies, including retro mode imaging, fundus autofluorescence (FAF), fundus photography, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA) and spectral domain optical coherence tomography (SD-OCT). We investigated the retro-mode images and compared the results with those of SD-OCT, FFA and ICGA. RESULTS: In the 29 PCV eyes, the retro-mode images clearly revealed polypoidal lesions in 27 (93.1%) eyes as well as branching vascular networks in 16 (55.2%) eyes. Others findings, including pigment epithelial detachment (PED) in 20 (69.0%) eyes, neuroretinal detachment (NRD) in 3 (10.3%) eyes, cystoid macular edema (CME) in 3 (10.3%) eyes, drusen in 4 (13.8%) eyes and minute granular changes of the retinal pigment epithelium (RPE) in 12 (41.3%) eyes, were also clearly visualized. When we compared the results with those of SD-OCT, FFA and ICGA, there was no significant difference between ICGA and retro-mode imaging for finding polypoidal lesions and (or) branching choroidal vascular networks (P>0.05). However, the rate of PED detection was significantly better with retro-mode imaging than with the ICGA (P<0.05). The differences were not statistically significant between SD OCT and retro-mode imaging for detecting PED, NRD, CME, drusen and minute granular RPE changes (P>0.05). The differences were not statistically significant between FFA and retro-mode imaging for detecting PED, NRD, CME (P>0.05). CONCLUSIONS: The novel and noninvasive retro-mode imaging by cSLO is able to clearly visualize the morphological features of PCV. PMID- 24058700 TI - 1H-NMR-based metabonomic studies on the anti-depressant effect of genipin in the chronic unpredictable mild stress rat model. AB - The purpose of this work was to investigate the anti-depressant effect of genipin and its mechanisms using (1)H-NMR spectroscopy and multivariate data analysis on a chronic unpredictable mild stress (CUMS) rat model. Rat serum and urine were analyzed by nuclear magnetic resonance (NMR)-based metabonomics after oral administration of either genipin or saline for 2 weeks. Significant differences in the metabolic profile of the CUMS-treated group and the control group were observed, which were consistent with the results of behavioral tests. Metabolic effects of CUMS included decreases in serum trimetlylamine oxide (TMAO) and beta hydroxybutyric acid (beta-HB), and increases in lipid, lactate, alanine and N acetyl-glycoproteins. In urine, decreases in creatinine and betaine were observed, while citrate, trimethylamine (TMA) and dimethylamine were increased. These changes suggest that depression may be associated with gut microbes, energy metabolism and glycometabolism. Genipin showed the best anti-depressive effects at a dose of 100 mg/kg in rats. These results indicate that metabonomic approaches could be powerful tools for the investigation of the biochemical changes in pathological conditions or drug treatment. PMID- 24058701 TI - Regulation of sumo mRNA during endoplasmic reticulum stress. AB - The unfolded protein response (UPR) is a collection of pathways that maintains the protein secretory pathway during the many physiological and pathological conditions that cause stress in the endoplasmic reticulum (ER). The UPR is mediated in part by Ire1, an ER transmembrane kinase and endoribonuclease that is activated when misfolded proteins accumulate in the ER. Ire1's nuclease initiates the cytosolic splicing of the mRNA encoding X-box binding protein (Xbp1), a potent transcription factor that then upregulates genes responsible for restoring ER function. This same nuclease is responsible for the degradation of many other mRNAs that are localized to the ER, through Regulated Ire1 Dependent Decay (RIDD). Here we show that Smt3, a homolog of small ubiquitin-like modifier (sumo), is a non-canonical RIDD target in Drosophila S2 cells. Unlike other RIDD targets, the sumo transcript does not stably associate with the ER membrane, but instead relies on an Xbp1-like stem loop and a second UPR mediator, Perk, for its degradation during stress. PMID- 24058702 TI - Epsilon PKC increases brain mitochondrial SIRT1 protein levels via heat shock protein 90 following ischemic preconditioning in rats. AB - Ischemic preconditioning is a neuroprotective mechanism whereby a sublethal ischemic exposure is protective against a subsequent lethal ischemic attack. We previously demonstrated that SIRT1, a nuclear localized stress-activated deacetylase, is vital for ischemic preconditioning neuroprotection. However, a recent study demonstrated that SIRT1 can also localize to the mitochondria. Mitochondrial localized SIRT1 may allow for a direct protection of mitochondria following ischemic preconditioning. The objective of this study was to determine whether ischemic preconditioning increases brain mitochondrial SIRT1 protein levels and to determine the role of PKCE and HSP90 in targeting SIRT1 to the mitochondria. Here we report that preconditioning rats, with 2 min of global cerebral ischemia, induces a delayed increase in non-synaptic mitochondrial SIRT1 protein levels which was not observed in synaptic mitochondria. This increase in mitochondrial SIRT1 protein was found to occur only in neuronal cells and was mediated by PKCepsilon activation. Inhibition of HSP90, a protein chaperone involved in mitochondrial protein import, prevented preconditioning induced increases in mitochondrial SIRT1 and PKCepsilon protein. Our work provides new insights into a possible direct role of SIRT1 in modulating mitochondrial function under both normal and stress conditions, and to a possible role of mitochondrial SIRT1 in activating preconditioning induced ischemic tolerance. PMID- 24058703 TI - Role of S-palmitoylation on IFITM5 for the interaction with FKBP11 in osteoblast cells. AB - Recently, one of the interferon-induced transmembrane (IFITM) family proteins, IFITM3, has become an important target for the activity against influenza A (H1N1) virus infection. In this protein, a post-translational modification by fatty acids covalently attached to cysteine, termed S-palmitoylation, plays a crucial role for the antiviral activity. IFITM3 possesses three cysteine residues for the S-palmitoylation in the first transmembrane (TM1) domain and in the cytoplasmic (CP) loop. Because these cysteines are well conserved in the mammalian IFITM family proteins, the S-palmitoylation on these cysteines is significant for their functions. IFITM5 is another IFITM family protein and interacts with the FK506-binding protein 11 (FKBP11) to form a higher-order complex in osteoblast cells, which induces the expression of immunologically relevant genes. In this study, we investigated the role played by S palmitoylation of IFITM5 in its interaction with FKBP11 in the cells, because this interaction is a key process for the gene expression. Our investigations using an established reporter, 17-octadecynoic acid (17-ODYA), and an inhibitor for the S-palmitoylation, 2-bromopalmitic acid (2BP), revealed that IFITM5 was S palmitoylated in addition to IFITM3. Specifically, we found that cysteine residues in the TM1 domain and in the CP loop were S-palmitoylated in IFITM5. Then, we revealed by immunoprecipitation and western blot analyses that the interaction of IFITM5 with FKBP11 was inhibited in the presence of 2BP. The mutant lacking the S-palmitoylation site in the TM1 domain lost the interaction with FKBP11. These results indicate that the S-palmitoylation on IFITM5 promotes the interaction with FKBP11. Finally, we investigated bone nodule formation in osteoblast cells in the presence of 2BP, because IFITM5 was originally identified as a bone formation factor. The experiment resulted in a morphological aberration of the bone nodule. This also indicated that the S-palmitoylation contributes to bone formation. PMID- 24058705 TI - Spatial and temporal patterns of eastern Australia subtropical coral communities. AB - Despite increases in the frequency and intensity of disturbances on coral reefs over the past few decades, the response of subtropical coral assemblages to climate change is poorly understood. To address this knowledge gap on Australian reefs and provide a baseline for future comparisons, we quantified spatial (10 100's of kilometres) and temporal (decadal) patterns of benthic assemblages across a latitudinal gradient along the east Australian coastline (23.5 degrees S to 31.5 degrees S). Benthic community composition was quantified at six locations from the southern Great Barrier Reef, Queensland (Heron Reef, 23.5 degrees S, 152 degrees E) to northern New South Wales (31 degrees S, 153.1 degrees E) and at Lord Howe Island (31.5 degrees S, 159.1 degrees E). Our results indicate significant latitudinal differences in benthic assemblages, while community composition at some sites was more similar to those hundreds of kilometres away than to that of neighbouring reefs. A general trend was observed with decreasing cover of Acroporidae with increasing latitude, corresponding with an increasing cover of Pocilloporidae and Dendrophylliidae. Heron Reef comprised a high proportion of Acropora corals (43% total coral cover) and coralline algae (44%). In contrast, high-latitude reefs were dominated by mixed coral assemblages (0-52%) and high macroalgal cover (16-27%). Decadal comparisons of high-latitude reefs showed regional stability of benthic assemblages (9 out of 11 assemblages remained stable at > 75% similarity), during a period of warming oceans (0.15 0.24 degrees C per decade). Such temporal stability suggests that eastern Australian subtropical communities may be more resistant than tropical reef communities that have experienced assembly shifts caused by perturbations associated with recent global climate change. Despite the clear differences in the structure of coral assemblages evident in our spatial surveys, we suggest that the temporal stability of high-latitude reefs may provide a limited refuge for tropical coral populations in an increasingly uncertain future. PMID- 24058704 TI - Avoidance of apoptosis in embryonic cells of the annual killifish Austrofundulus limnaeus exposed to anoxia. AB - Embryos of the annual killifish Austrofunduluslimnaeus have unequalled ability among vertebrates to survive long-term anoxia. Surprisingly, these embryos can survive for months in anoxia despite a large-scale decrease in ATP levels during the initial hours of anoxic exposure. These conditions are known to trigger apoptotic cell death in mammalian cells as a result of ischemia or anoxia. Anoxia induced induction of apoptosis was investigated in four developmental stages of A. limnaeus that differ in their tolerance of anoxia, and thus may respond to anoxia uniquely. Exposure to staurosporine was used to determine if A. limnaeus cells were competent to enter apoptosis via cues other than anoxia. Apoptotic cells were identified by TUNEL assays and by measuring caspase 3/7 activity. Exposure to 48 hr of anoxia did not induce an increase in TUNEL-positive cells and generally did not lead to an increase in caspase 3/7 activity. However, treatment of anoxic embryos with 10 MUM staurosporine resulted in a significant increase in caspase 3/7 activity in both normoxic and anoxic embryos. These results suggest that apoptosis is avoided in embryos of A. limnaeus following exposure to anoxia at least in part by mechanisms that prevent the activation of caspase 3/7 activity. While this mechanism remains unknown, it may be triggered by a protein kinase that can be experimentally inhibited by staurosporine. PMID- 24058706 TI - Deployment and post-deployment experiences in OEF/OIF veterans: relationship to gray matter volume. AB - BACKGROUND: Combat-related PTSD has been associated with reduced gray matter volume in regions of the prefrontal and temporal cortex, hippocampus, insula, and amygdala. However, the relationship between gray matter volume and specific deployment and post-deployment experiences has not been investigated. The aim of this study was to delineate how such experiences may contribute to structural brain changes for combat veterans. METHODS: Operation Iraqi Freedom/Operation Enduring Freedom veterans (N = 32) completed magnetic resonance imaging, the Deployment Risk and Resilience Inventory, Alcohol Use Disorders Identification Test, and Clinical Administered PTSD Scale. Voxel-wise Huber robust multiple regressions were used to quantify the relationship between gray matter volume and deployment experiences (combat experiences, military social support) and post deployment symptoms (PTSD, alcohol use). RESULTS: There was an interaction between severity of combat experiences and military social support for orbitofrontal gyrus gray matter volume. Specifically, individuals with more orbitofrontal gyrus gray matter volume reported less combat experiences and higher unit support. Individuals with more severe PTSD symptoms showed reduced gray matter volume within a large temporal region (inferior temporal and parahippocampal gyrus). CONCLUSIONS: The identified association between unit support and orbitofrontal gyrus volume supports two potential resilience mechanisms to be delineated with future longitudinal studies. First, individuals with larger orbitofrontal gyrus may engage in greater quality of social interactions and thus experience combat as less stressful. Second, individuals who experience greater unit support may preserve a larger orbitofrontal gyrus, serving to "protect" them from aversive consequences of combat. PMID- 24058707 TI - Factors regulating early life history dispersal of Atlantic cod (Gadus morhua) from coastal Newfoundland. AB - To understand coastal dispersal dynamics of Atlantic cod (Gadus morhua), we examined spatiotemporal egg and larval abundance patterns in coastal Newfoundland. In recent decades, Smith Sound, Trinity Bay has supported the largest known overwintering spawning aggregation of Atlantic cod in the region. We estimated spawning and dispersal characteristics for the Smith Sound-Trinity Bay system by fitting ichthyoplankton abundance data to environmentally-driven, simplified box models. Results show protracted spawning, with sharply increased egg production in early July, and limited dispersal from the Sound. The model for the entire spawning season indicates egg export from Smith Sound is 13%*day(-1) with a net mortality of 27%*day(-1). Eggs and larvae are consistently found in western Trinity Bay with little advection from the system. These patterns mirror particle tracking models that suggest residence times of 10-20 days, and circulation models indicating local gyres in Trinity Bay that act in concert with upwelling dynamics to retain eggs and larvae. Our results are among the first quantitative dispersal estimates from Smith Sound, linking this spawning stock to the adjacent coastal waters. These results illustrate the biophysical interplay regulating dispersal and connectivity originating from inshore spawning of coastal northwest Atlantic. PMID- 24058708 TI - Tomato spotted wilt virus benefits a non-vector arthropod, Tetranychus urticae, by modulating different plant responses in tomato. AB - The interaction between plant viruses and non-vector arthropod herbivores is poorly understood. However, there is accumulating evidence that plant viruses can impact fitness of non-vector herbivores. In this study, we used oligonucleotide microarrays, phytohormone, and total free amino acid analyses to characterize the molecular mechanisms underlying the interaction between Tomato spotted wilt virus (TSWV) and a non-vector arthropod, twospotted spider mite (Tetranychusurticae), on tomato plants, Solanumlycopersicum. Twospotted spider mites showed increased preference for and fecundity on TSWV-infected plants compared to mock-inoculated plants. Transcriptome profiles of TSWV-infected plants indicated significant up regulation of salicylic acid (SA)-related genes, but no apparent down-regulation of jasmonic acid (JA)-related genes which could potentially confer induced resistance against TSM. This suggests that there was no antagonistic crosstalk between the signaling pathways to influence the interaction between TSWV and spider mites. In fact, SA- and JA-related genes were up-regulated when plants were challenged with both TSWV and the herbivore. TSWV infection resulted in down regulation of cell wall-related genes and photosynthesis-associated genes, which may contribute to host plant susceptibility. There was a three-fold increase in total free amino acid content in virus-infected plants compared to mock inoculated plants. Total free amino acid content is critical for arthropod nutrition and may, in part, explain the apparent positive indirect effect of TSWV on spider mites. Taken together, these data suggest that the mechanism(s) of increased host suitability of TSWV-infected plants to non-vector herbivores is complex and likely involves several plant biochemical processes. PMID- 24058709 TI - NSD1 mitigates caspase-1 activation by listeriolysin O in macrophages. AB - Mammals and plants share pathogen-sensing systems named nod-like receptors (NLRs). Some NLRs form the inflammasome, a protein scaffold that regulates the secretion of interleukin (IL)-1beta and IL-18 by cleaving catalytically inactive substrates into mature cytokines. Here, we show an immune conservation between plant and mammalian NLRs and demonstrate that the murine nuclear receptor binding SET domain protein 1 (NSD1), a protein that bears similarity to the NLR regulator enhanced downy mildew 2 (EDM2) in Arabidopsis, diminishes caspase-1 activity during extracellular stimulation with Listeria monocytogenes listeriolysin O (LLO). EDM2 is known to regulate plant developmental processes, whereas NSD1 is associated with developmental disorders. We observed that NSD1 neither affects nuclear factor (NF)-kappaB signaling nor regulates NLRP3 inflammasome gene expression at the chromatin, transcriptional or translational level during LLO stimulation of macrophages. Silencing of Nsd1 followed by LLO stimulation led to increased caspase-1 activation, enhanced post-translational maturation of IL 1beta and IL-18 and elevated pyroptosis, a form of cell death associated with inflammation. Furthermore, treatment of macrophages with LLO(W492A), which lacks hemolytic activity due to a tryptophan to alanine substitution in the undecapeptide motif, indicates the importance of functional LLO for NSD1 regulation of the NLRP3 inflammasome. Taken together, our results indicate that NLR signaling in plants may be used for gene discovery in mammals. PMID- 24058710 TI - The G32E functional variant reduces activity of PPARD by nuclear export and post translational modification in pigs. AB - Peroxisome proliferator-activated receptor beta/delta (PPARD) is a crucial and multifaceted determinant of diverse biological functions including lipid metabolism, embryonic development, inflammatory response, wound healing and cancer. Recently, we proposed a novel function of porcine PPARD (sPPARD) in external ear development. A missense mutation (G32E) in an evolutionary conservative domain of sPPARD remarkably increases external ear size in pigs. Here, we investigated the underlying molecular mechanism of the causal mutation at the cellular level. Using a luciferase reporter system, we showed that the G32E substitution reduced transcription activity of sPPARD in a ligand-dependent manner. By comparison of the subcellular localization of wild-type and mutated sPPARD in both PK-15 cells and pinna cartilage-derived primary chondrocytes, we found that the G32E substitution promoted CRM-1 mediated nuclear exportation of sPPARD. With the surface plasmon resonance technology, we further revealed that the G32E substitution had negligible effect on its ligand binding affinity. Finally, we used co-immunoprecipitation and luciferase reporter assays to show that the G32E substitution greatly reduced ubiquitination level by blocking ubiquitination of the crucial A/B domain and consequently decreased transcription activity of sPPARD. Taken together, our findings strongly support that G32E is a functional variant that plays a key role in biological activity of sPPARD, which advances our understanding of the underlying mechanism of sPPARD G32E for ear size in pigs. PMID- 24058711 TI - Role of injured pancreatic extract promotes bone marrow-derived mesenchymal stem cells efficiently differentiate into insulin-producing cells. AB - Mesenchymal stem cells (MSCs) can be successfully induced to differentiate into insulin-producing cells (IPCs) by a variety of small molecules and cytokines in vitro. However, problems remain, such as low transdifferentiation efficiency and poor maturity of trans-differentiated cells. The damaged pancreatic cells secreted a large amount of soluble proteins, which were able to promote pancreative islet regeneration and MSCs differentiation. In this study, we utilized the rat injured pancreatic tissue extract to modulate rat bone marrow derived MSCs differentiation into IPCs by the traditional two-step induction. Our results showed that injured pancreatic tissue extract could effectively promote the trans-differentiation efficiency and maturity of IPCs by the traditional induction. Moreover, IPCs were able to release more insulin in a glucose dependent manner and ameliorate better the diabetic conditions of streptozotocin (STZ)-treated rats. Our study provides a new strategy to induce an efficient and directional differentiation of MSCs into IPCs. PMID- 24058712 TI - Rats and seabirds: effects of egg size on predation risk and the potential of conditioned taste aversion as a mitigation method. AB - Seabirds nesting on islands are threatened by invasive rodents, such as mice and rats, which may attack eggs, chicks and even adults. The low feasibility of rat eradications on many islands makes the development of alternate control plans necessary. We used a combination of field experiments on a Mediterranean island invaded by black rats (Rattusrattus) to evaluate (1) the predation risk posed to different-sized seabird eggs and (2), the potential of two deterrent methods (electronic and chemical) to reduce its impact. Rats were able to consume eggs of all sizes (12 to 68 g), but survival increased 13 times from the smallest to the largest eggs (which also had more resistant eggshells). Extrapolation to seabird eggs suggests that the smallest species (Hydrobatespelagicus) suffer the most severe predation risk, but even the largest (Larusmichahellis) could suffer >60% mortality. Nest attack was not reduced by the deterrents. However, chemical deterrence (conditioned taste aversion by lithium chloride) slowed the increase in predation rate over time, which resulted in a three-fold increase in egg survival to predation as compared to both control and electronic deterrence. At the end of the experimental period, this effect was confirmed by a treatment swap, which showed that conferred protection remains at least 15 days after cessation of the treatment. Results indicate that small seabird species are likely to suffer severe rates of nest predation by rats and that conditioned taste aversion, but not electronic repellents, may represent a suitable method to protect colonies when eradication or control is not feasible or cost-effective. PMID- 24058713 TI - Feasibility of using Clinical Element Models (CEM) to standardize phenotype variables in the database of genotypes and phenotypes (dbGaP). AB - The database of Genotypes and Phenotypes (dbGaP) contains various types of data generated from genome-wide association studies (GWAS). These data can be used to facilitate novel scientific discoveries and to reduce cost and time for exploratory research. However, idiosyncrasies and inconsistencies in phenotype variable names are a major barrier to reusing these data. We addressed these challenges in standardizing phenotype variables by formalizing their descriptions using Clinical Element Models (CEM). Designed to represent clinical data, CEMs were highly expressive and thus were able to represent a majority (77.5%) of the 215 phenotype variable descriptions. However, their high expressivity also made it difficult to directly apply them to research data such as phenotype variables in dbGaP. Our study suggested that simplification of the template models makes it more straightforward to formally represent the key semantics of phenotype variables. PMID- 24058714 TI - The S-layer homology domain-containing protein SlhA from Paenibacillus alvei CCM 2051(T) is important for swarming and biofilm formation. AB - BACKGROUND: Swarming and biofilm formation have been studied for a variety of bacteria. While this is well investigated for Gram-negative bacteria, less is known about Gram-positive bacteria, including Paenibacillus alvei, a secondary invader of diseased honeybee colonies infected with Melissococcus pluton, the causative agent of European foulbrood (EFB). METHODOLOGY: Paenibacillus alvei CCM 2051(T) is a Gram-positive bacterium which was recently shown to employ S-layer homology (SLH) domains as cell wall targeting modules to display proteins on its cell surface. This study deals with the newly identified 1335-amino acid protein SlhA from P. alvei which carries at the C-terminus three consecutive SLH-motifs containing the predicted binding sequences SRGE, VRQD, and LRGD instead of the common TRAE motif. Based on the proof of cell surface location of SlhA by fluorescence microscopy using a SlhA-GFP chimera, the binding mechanism was investigated in an in vitro assay. To unravel a putative function of the SlhA protein, a knockout mutant was constructed. Experimental data indicated that one SLH domain is sufficient for anchoring of SlhA to the cell surface, and the SLH domains of SlhA recognize both the peptidoglycan and the secondary cell wall polymer in vitro. This is in agreement with previous data from the S-layer protein SpaA, pinpointing a wider utilization of that mechanism for cell surface display of proteins in P. alvei. Compared to the wild-type bacterium DeltaslhA revealed changed colony morphology, loss of swarming motility and impaired biofilm formation. The phenotype was similar to that of the flagella knockout Deltahag, possibly due to reduced EPS production influencing the functionality of the flagella of DeltaslhA. CONCLUSION: This study demonstrates the involvement of the SLH domain-containing protein SlhA in swarming and biofilm formation of P. alvei CCM 2051(T). PMID- 24058715 TI - Differential reports of suicidal ideation and attempts of questioning adults compared to heterosexual, lesbian, gay, and bisexual individuals. AB - Many sexual minority individuals attempt suicide each year, but little is known about the suicidality of individuals who are questioning their sexual orientation. This study assessed suicidal ideation and attempts of questioning individuals compared to lesbian/gay, bisexual, and heterosexual individuals. This cross-sectional study enrolled participants (N = 2,841) from a community health center. Questioning (OR = 4.286, 95% CI [2.119-8.671]), lesbian/gay (OR = 3.024, 95% CI [2.351-3.890]), and bisexual (OR = 4.389, 95% CI [2.942-6.575]) individuals had significantly greater odds of considering suicide compared to heterosexuals. However, questioning individuals had non-significant odds of attempting suicide compared to heterosexuals. We discuss possible explanations for these findings. PMID- 24058716 TI - Do functional keratin dressings accelerate epithelialization in human partial thickness wounds? A randomized controlled trial on skin graft donor sites. AB - OBJECTIVE: To determine if the experimental (keratin-based) dressing accelerates epithelialization rates during healing of partial-thickness wounds, relative to a Standard Care dressing. METHOD: A randomized control trial was conducted using a Standard Care dressing side by side with the experimental dressing on a sample (n=26) of partial-thickness donor site wounds. The proximal/distal placement of the control and treatment was randomized. Percentage epithelialization after approximately 7 days was estimated from which time to fully epithelialize can be inferred. Patients were grouped into "young" (<=50 y/o) and "old" (>50 y/o). RESULTS: For the "old" patients (n=15), the median epithelialization percentage at 7 days is 5% and was significantly (P=.023) greater for the experimental dressing. For the "young" patients (n=11), the median epithelialization percentage at 7 days was 80% and there is no significant difference between the experimental and Standard Care control dressings. CONCLUSIONS: The experimental dressing significantly increases the rate of epithelialization of acute, traumatic partial-thickness wounds in older patients. We suggest that the dressing may be clinically useful in similar situations where epithelialization may be delayed because of patient or wound characteristics. PMID- 24058717 TI - CASE REPORT Successful Treatment of a Rare Massive Dabska Tumor. AB - OBJECTIVE: The Dabska tumor is a rare low-grade angiosarcoma first described in 1969 by Maria Dabska. Approximately 30 cases of varying presentations have been reported since its initial description. METHODS: We describe a case of a 23-year old woman presenting with a massive recurrent left flank hemangioendothelioma, at final resection diagnosed to be an endovascular papillary angioendothelioma (Dabska tumor). The sheer size of the tumor necessitated reconstructive surgery. RESULTS: Successful abdominal reconstruction after radical resection of a Dabska tumor was achieved using local fasciocutaneous-type flaps. CONCLUSION: To our knowledge, this is the first case report describing reconstructive surgery following resection of an abdominal Dabska tumor. PMID- 24058718 TI - Indications and outcomes of the components separation technique in the repair of complex abdominal wall hernias: experience from the cambridge plastic surgery department. AB - OBJECTIVES: The components separation technique (CST) is a widely described abdominal wall reconstructive technique. There have, however, been no UK reports of its use, prompting the present review. METHODS: Between 2008 and 2012, 13 patients who underwent this procedure by a single plastic surgeon (C.M.M.) were retrospectively evaluated. The indications, operative details, and clinical outcomes were recorded. RESULTS: There were 7 women and 6 men in the series with a mean age of 53 years (range: 30-80). Patients were referred from a variety of specialties, often as a last resort. The commonest indication for CST was herniation following abdominal surgery. All operations except 1 were jointly performed with general surgeons (for bowel resection, stoma reversal, and hernia dissection). The operations lasted a mean of 5 hours (range: 3-8 hours). There were no major intra- and postoperative problems, except in 1 patient who developed intra-abdominal compartment syndrome, secondary to massive hemorrhage. All patients were satisfied with the cosmetic improvement in their abdominal contours. None of the patients have developed a clinical recurrence after a mean follow-up of 16 months (range: 3-38 months). CONCLUSIONS: The components separation technique is an effective method of treating large recalcitrant hernias but appears to be underutilized in the United Kingdom. The management of large abdominal wall defects requires a multidisciplinary approach, with input across a variety of specialities. Liaison with plastic surgery teams should be encouraged at an early stage and the CST should be more widely considered when presented with seemingly intractable abdominal wall defects. PMID- 24058719 TI - Dual pedicle mastopexy technique for reorientation of volume and shape after subglandular and submuscular breast implant removal. AB - BACKGROUND: The purpose of this article was to report our experience in achieving satisfactory breast shape and volume using dual pedicle mastopexy technique after subglandular and submuscular breast implant removal. METHODS: Breast implant related problems in 51 breasts included capsular contracture (Baker grade III IV), 76%; implant rupture/bleed, 41%; breasts undergoing repeat surgery more than once, 22%. The size of the breast implants removed ranged from 240 to 525 cc (average size: 320 +/- 65 cc) (saline-filled, 40%; silicone-filled, 60%; subglandular, 40%; submuscular, 60%). Capsulectomy, implant removal, and dual pedicle mastopexy were performed for reconfiguration of breast shape and reorientation of volume. RESULTS: Mean follow-up was 14.5 months. On average, 65.0% of breast implant volume was achieved. There was 1-cup reduction in brassiere size in 21 patients, and the cup size remained the same in 5 patients. Postoperative pain scores were no pain or mild pain in 26 patients who initially in the preoperative evaluation reported having mild pain (11), moderate pain (12), and severe pain (3). Overall patient satisfaction scores were 3 (neutral) in 1 patient, 4 (satisfied) in 12 patients, and 5 (very satisfied) in 13 patients. CONCLUSION: The dual pedicle mastopexytechnique provided a reliable way of reorienting breast volume and configuring breast shape in patients who opted to have implants removed without replacement. The results demonstrated that a pleasing outcome could be obtained using the described technique with additional benefits of elimination of breast tenderness and discomfort secondary to implant removal and/or capsulectomy. PMID- 24058720 TI - The effect of semantic context on speech intelligibility in reverberant rooms. AB - Although it is well known that semantic context affects speech intelligibility and that different reverberant rooms affect speech intelligibility differentially, these effects have seldom been studied together. Revised SPIN sentences in a background of Gaussian noise in simulated rooms with reverberation time (T60) of 1 and 0.25 s were used. The carrier phrase and the target word of the speech stimuli were manipulated to be either in the same room or in different rooms. As expected, intelligibility of predictable sentences was higher compared to unpredictable sentences-the context effect. The context effect was higher in the low-reverberant room as compared to the high-reverberant room. When the carrier phrase and target words were in different rooms, the context effect was higher when the carrier phrase was in the low-reverberant room and target word in the high-reverberant room. For predictable sentences, changing the target word from high-reverberation to low reverberation with a high reverberant carrier increased intelligibility. However, with a low-reverberant carrier and different rooms for the target word, there was no change in intelligibility. Overall, it could be concluded that there is an interaction between semantic context and room acoustics for speech intelligibility. PMID- 24058722 TI - Episodic HIV Risk Behavior Can Greatly Amplify HIV Prevalence and the Fraction of Transmissions from Acute HIV Infection. AB - A deterministic compartmental model was explored that relaxed the unrealistic assumption in most HIV transmission models that behaviors of individuals are constant over time. A simple model was formulated to better explain the effects observed. Individuals had a high and a low contact rate and went back and forth between them. This episodic risk behavior interacted with the short period of high transmissibility during acute HIV infection to cause dramatic increases in prevalence as the differences between high and low contact rates increased and as the duration of high risk better matched the duration of acute HIV infection. These same changes caused a considerable increase in the fraction of all transmissions that occurred during acute infection. These strong changes occurred despite a constant total number of contacts and a constant total transmission potential from acute infection. Two phenomena played a strong role in generating these effects. First, people were infected more often during their high contact rate phase and they remained with high contact rates during the highly contagious acute infection stage. Second, when individuals with previously low contact rates moved into an episodic high-risk period, they were more likely to be susceptible and thus provided more high contact rate susceptible individuals who could get infected. These phenomena make test and treat control strategies less effective and could cause some behavioral interventions to increase transmission. Signature effects on genetic patterns between HIV strains could make it possible to determine whether these episodic risk effects are acting in a population. PMID- 24058723 TI - Visual Discomfort with Stereo 3D Displays when the Head is Not Upright. AB - Properly constructed stereoscopic images are aligned vertically on the display screen, so on-screen binocular disparities are strictly horizontal. If the viewer's inter-ocular axis is also horizontal, he/she makes horizontal vergence eye movements to fuse the stereoscopic image. However, if the viewer's head is rolled to the side, the on-screen disparities now have horizontal and vertical components at the eyes. Thus, the viewer must make horizontal and vertical vergence movements to binocularly fuse the two images. Vertical vergence movements occur naturally, but they are usually quite small. Much larger movements are required when viewing stereoscopic images with the head rotated to the side. We asked whether the vertical vergence eye movements required to fuse stereoscopic images when the head is rolled cause visual discomfort. We also asked whether the ability to see stereoscopic depth is compromised with head roll. To answer these questions, we conducted behavioral experiments in which we simulated head roll by rotating the stereo display clockwise or counter-clockwise while the viewer's head remained upright relative to gravity. While viewing the stimulus, subjects performed a psychophysical task. Visual discomfort increased significantly with the amount of stimulus roll and with the magnitude of on screen horizontal disparity. The ability to perceive stereoscopic depth also declined with increasing roll and on-screen disparity. The magnitude of both effects was proportional to the magnitude of the induced vertical disparity. We conclude that head roll is a significant cause of viewer discomfort and that it also adversely affects the perception of depth from stereoscopic displays. PMID- 24058721 TI - Oxidative stress and nucleic acid oxidation in patients with chronic kidney disease. AB - Patients with chronic kidney disease (CKD) have high cardiovascular mortality and morbidity and a high risk for developing malignancy. Excessive oxidative stress is thought to play a major role in elevating these risks by increasing oxidative nucleic acid damage. Oxidative stress results from an imbalance between reactive oxygen/nitrogen species (RONS) production and antioxidant defense mechanisms and can cause vascular and tissue injuries as well as nucleic acid damage in CKD patients. The increased production of RONS, impaired nonenzymatic or enzymatic antioxidant defense mechanisms, and other risk factors including gene polymorphisms, uremic toxins (indoxyl sulfate), deficiency of arylesterase/paraoxonase, hyperhomocysteinemia, dialysis-associated membrane bioincompatibility, and endotoxin in patients with CKD can inhibit normal cell function by damaging cell lipids, arachidonic acid derivatives, carbohydrates, proteins, amino acids, and nucleic acids. Several clinical biomarkers and techniques have been used to detect the antioxidant status and oxidative stress/oxidative nucleic acid damage associated with long-term complications such as inflammation, atherosclerosis, amyloidosis, and malignancy in CKD patients. Antioxidant therapies have been studied to reduce the oxidative stress and nucleic acid oxidation in patients with CKD, including alpha-tocopherol, N acetylcysteine, ascorbic acid, glutathione, folic acid, bardoxolone methyl, angiotensin-converting enzyme inhibitor, and providing better dialysis strategies. This paper provides an overview of radical production, antioxidant defence, pathogenesis and biomarkers of oxidative stress in patients with CKD, and possible antioxidant therapies. PMID- 24058724 TI - Design and exploratory neuropharmacological evaluation of novel thyrotropin releasing hormone analogs and their brain-targeting bioprecursor prodrugs. AB - Efforts to take advantage of the beneficial activities of thyrotropin-releasing hormone (TRH) in the brain are hampered by its poor metabolic stability and lack of adequate central nervous system bioavailability. We report here novel and metabolically stable analogs that we derived from TRH by replacing its amino terminal pyroglutamyl (pGlu) residue with pyridinium-containing moieties. Exploratory studies have shown that the resultant compounds were successfully delivered into the mouse brain after systemic administration via their bioprecursor prodrugs, where they manifested neuropharmacological responses characteristic of the endogenous parent peptide. On the other hand, the loss of potency compared to TRH in a model testing antidepressant-like effect with a simultaneous preservation of analeptic activity has been observed, when pGlu was replaced with trigonelloyl residue. This finding may indicate an opportunity for designing TRH analogs with potential selectivity towards cholinergic effects. PMID- 24058725 TI - Family environment and adult resilience: contributions of positive parenting and the oxytocin receptor gene. AB - BACKGROUND: Abundant research shows that childhood adversity increases the risk for adult psychopathology while research on influences of positive family environment on risk for psychopathology is limited. Similarly, a growing body of research examines genetic and gene by environment predictors of psychopathology, yet such research on predictors of resilience is sparse. OBJECTIVES: We examined the role of positive factors in childhood family environment (CFE) and the OXTR rs53576 genotype in predicting levels of adult resilient coping and positive affect. We also examined whether the relationship between positive factors in the CFEs and adult resilient coping and positive affect varied across OXTR rs53576 genotype. METHODS: We gathered self-report data on childhood environment, trauma history, and adult resilience and positive affect in a sample of 971 African American adults. RESULTS: We found that positive CFE was positively associated with higher levels of resilient coping and positive affect in adulthood after controlling for childhood maltreatment, other trauma, and symptoms of posttraumatic stress disorder. We did not find a direct effect of OXTR 53576 on a combined resilient coping/positive-affect-dependent variable, but we did find an interaction of OXTR rs53576 with family environment. CONCLUSIONS: Our data suggest that even in the face of adversity, positive aspects of the family environment may contribute to resilience. These results highlight the importance of considering protective developmental experiences and the interaction of such experiences with genetic variants in risk and resilience research. PMID- 24058726 TI - Heterobimetallic Complexes with MIII-(MU-OH)-MII Cores (MIII = Fe, Mn, Ga; MII = Ca, Sr, and Ba): Structural, Kinetic, and Redox Properties. AB - The effects of redox-inactive metal ions on dioxygen activation were explored using a new FeII complex containing a tripodal ligand with 3 sulfonamido groups. This iron complex exhibited a faster initial rate for the reduction of O2 than its MnII analog. Increases in initial rates were also observed in the presence of group 2 metal ions for both the FeII and MnII complexes, which followed the trend NMe4+ < BaII < CaII = SrII. These studies led to the isolation of heterobimetallic complexes containing FeIII-(MU-OH)-MII cores (MII = Ca, Sr, and Ba) and one with a [SrII(OH)MnIII]+ motif. The analogous [CaII(OH)GaIII]+ complex was also prepared and its solid state molecular structure is nearly identical to that of the [CaII(OH)FeIII]+ system. Nuclear magnetic resonance studies indicated that the diamagnetic [CaII(OH)GaIII]+ complex retained its structure in solution. Electrochemical measurements on the heterobimetallic systems revealed similar one electron reduction potentials for the [CaII(OH)FeIII]+ and [SrII(OH)FeIII]+ complexes, which were more positive than the potential observed for [BaII(OH)FeIII]+. Similar results were obtained for the heterobimetallic MnII complexes. These findings suggest that Lewis acidity is not the only factor to consider when evaluating the effects of group 2 ions on redox processes, including those within the oxygen-evolving complex of Photosystem II. PMID- 24058727 TI - Lipid-coated nanoscale coordination polymers for targeted cisplatin delivery. AB - Nanoscale coordination polymers (NCPs) containing a Pt(IV) cisplatin prodrug, disuccinatocisplatin, were formed by a surfactant-templated synthesis and were shown to have a prodrug loading of 8.2 wt% and a diameter of ~133 nm by dynamic light scattering. These NCPs were stabilized by coating with a DOPC/cholesterol/DSPE-Peg2K lipid layer; a release profile in phosphate buffered saline showed an initial drug release of ~25% within the first hour and no more release observed up to 192 h. The NCP was rendered target-specific for sigma receptors by addition of an AA-DSPE-Peg2K conjugate (AA = anisamide) in the lipid formulation. The AA-containing NCP showed a statistically significant decrease in IC50 (inhibitory concentration, 50%) compared to the non-targeted NCP. Enhanced uptake of the AA-containing NCP was further supported by confocal microscopy and competitive binding assays. PMID- 24058728 TI - Nucleic Acid-directed Self-assembly of Multifunctional Gold Nanoparticle Imaging Agents. AB - Gold nanoparticles have attracted much interest as a platform for development of multifunctional imaging and therapeutic agents. Multifunctionalized gold nanoparticles are generally constructed by covalent assembly of a gold core with thiolated ligands. In this study, we have assembled multifunctionalized gold nanoparticles in one step by nucleic acid hybridization of ODN (oligodeoxynucleotide)-derivatized gold nanoparticles with a library of pre functionalized complementary PNAs (peptide nucleic acids). The PNAs were functionalized by conjugation with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid) for chelating 64Cu for PET imaging, PEG (polyethylene glycol) for conferring stealth properties, and Cy5 for fluorescent imaging. The resulting nanoparticles showed good stability both in vitro and in vivo showing biodistribution behavior in a mouse that would be expected for a PEGylated gold nanoparticle rather than that for the radiolabelled PNA used in its assembly. PMID- 24058730 TI - Azadioxatriangulenium (ADOTA+): A long fluorescence lifetime fluorophore for large biomolecule binding assay. AB - Of the many optical bioassays available, sensing by fluorescence anisotropy have great advantages as it provides a sensitive, instrumentally simple, ratiometric method of detection. However, it is hampered by a severe limitation as the emission lifetime of the label needs to be comparable to the correlation lifetime (tumbling time) of the biomolecule which is labelled. For proteins of moderate size this is in the order of 20-200 ns, which due to practical issues currently limits the choice of labels to the dansyl-type dyes and certain aromatics dyes. These have the significant drawback of UV/blue absorption and emission as well as an often significant solvent sensitivity. Here, we report the synthesis and characterization of a new fluorescent label for high molecular weight biomolecules assay based on the azadioxatriangulenium motif. The NHS ester of the long fluorescence lifetime, red emitting fluorophore: azadioxatriangulenium (ADOTA-NHS) was conjugated to anti-rabbit Immunoglobulin G (antiIgG). The long fluorescence lifetime was exploited to determine the correlation time of the high molecular weight antibody and its complex with rabbit Immuniglobulin G (IgG) with steady-state fluorescence anisotropy and time-resolved methods: solution phase immuno-assay was performed following either steady-state or time-resolved fluorescence anisotropy. By performing a variable temperature experiment it was determined that the binding of the ligand resulted in an increase in correlation time by more than 75 %, and a change in the steady-state anisotropy increase of 18%. The results show that the triangulenium class of dyes can be used in anisotropy assay for detecting binding events involving biomolecules of far larger size than what is possible with the other red emitting organic dyes. PMID- 24058729 TI - Development of IgG4-related disease in a patient diagnosed with idiopathic membranous nephropathy. AB - We report a case of IgG4-related disease (IgG4-RD) diagnosed after 3 years of follow-up for idiopathic membranous nephropathy (MN). MN has been considered as glomerular lesion of IgG4-related kidney diseases in recent years and was diagnosed simultaneously with or after a diagnosis of IgG4-RD in previously reported cases. In the present case, IgG4-RD developed 3 years after the diagnosis of idiopathic MN, indicating a possible relationship between idiopathic MN and IgG4-RD through common underlying mechanisms of development. PMID- 24058731 TI - Comparative evaluation of impact of Zn and ZnO nanoparticles on brine shrimp (Artemia salina) larvae: effects of particle size and solubility on toxicity. AB - Brine shrimp (Artemia salina) larvae were exposed to different sizes of zinc (Zn) and zinc oxide (ZnO) nanoparticles (NPs) to evaluate their toxicity in marine aquatic ecosystems. Acute exposure was conducted in seawater with 10, 50 and 100 mg L(-1) concentrations of the NPs for 24 h and 96 h. Phase contrast microscope images confirmed the accumulation of the NPs inside the guts. Artemia were unable to eliminate the ingested particles, which was thought to be due to the formation of massive particles in the guts. Although the suspensions of the NPs did not exhibit any significant acute toxicity within 24 h, mortalities increased remarkably in 96 h and escalated with increasing concentration of NP suspension to 42% for Zn NPs (40-60 nm) (LC50~ 100 mg L(-1)) and to about 34% for ZnO NPs (10-30 nm) (LC50 > 100 mg L(-1)). The suspensions of Zn NPs were more toxic to Artemia than those of ZnO NPs under comparable regimes. This effect was attributed to higher Zn(2+) levels (ca. up to 8.9 mg L(-1)) released to the medium from Zn NPs in comparison to that measured in the suspensions of ZnO NPs (ca. 5.5 mg L(-1)). In addition, the size of the nanopowders appeared to contribute to the observed toxicities. Although the suspensions possessed aggregates of comparable sizes, smaller Zn NPs (40-60 nm) were relatively more toxic than larger Zn NPs (80-100 nm). Likewise, the suspensions of 10-30 nm ZnO NPs caused higher toxicity than those of 200 nm ZnO NPs. Lipid peroxidation levels were substantially higher in 96 h (p < 0.05), indicating that the toxic effects were due to the oxidative stress. PMID- 24058732 TI - Impacts of Active Urea Secretion into Pars Recta on Urine Concentration and Urea Excretion Rate. AB - It has been observed experimentally that early distal tubular urea flow exceeds urea delivery by the proximal convoluted tubule to the pars recta and loop of Henle. Moreover, the fractional excretion of urea in the urine may exceed values compatible with the reabsorption known to occur in the proximal convoluted tubule in the cortex. A likely explanation for these observations is that urea may be actively secreted into the pars recta, as proposed in a few studies. However, this hypothesis has yet to be demonstrated experimentally. In this study, we used a mathematical model of the renal medulla of the rat kidney to investigate the impacts of active urea secretion in the intrarenal handling of urea and in the urine concentrating ability. The model represents only the outer and inner medullary zones, with the actions taking place in the cortex incorporated via boundary conditions. Blood flow in the model vasculature is divided into plasma and red blood cell compartments. We compared urea flow rates and other related model variables without and with the hypothetical active urea secretion in the pars recta. The simulation suggests that active urea secretion induces a "urea selective" improvement in urine concentrating ability by enhancing the efficiency of urea excretion without requiring a higher urine flow rate, and with only modest changes in the excretion of other solutes. These results should encourage experimental studies in order to assess the existence of an active urea secretion in the rodent kidney. PMID- 24058733 TI - Cellulase and Xylanase Production by Penicillium echinulatum in Submerged Media Containing Cellulose Amended with Sorbitol. AB - The present work investigated the use of sorbitol as a soluble carbon source, in association with cellulose, to produce cellulases and xylanases in submerged cultures of Penicillium echinulatum 9A02S1. Because cellulose is an insoluble carbon source, in cellulase production, there are some problems with rheology and oxygen transfer. The submerged fermentations containing media composed of 0, 0.25, 0.5, 0.75, and 1% (w/v) sorbitol and cellulose that were added at different times during the cultivation; 0.2% (w/v) soy bran; 0.1% (w/v) wheat bran; and a solution of salts. The highest filter paper activity (FPA) (1.95 +/- 0.04 IU.mL(-1)) was obtained on the seventh day in the medium containing 0.5% (w/v) sorbitol and 0.5% (w/v) cellulose added 24 h after the start of cultivation. However, the CMCases showed an activity peak on the sixth day (9.99 +/- 0.75 IU.mL(-1)) in the medium containing 0.75% (w/v) sorbitol and 0.75% (w/v) cellulose added after 12 h of cultivation. The xylanases showed the highest activity in the medium with 0.75% (w/v) sorbitol and 0.25% (w/v) cellulose added 36 h after the start of cultivation. This strategy enables the reduction of the cellulose concentration, which in high concentrations can cause rheological and oxygen transfer problems. PMID- 24058734 TI - Cognitive Vulnerabilities and Depression in Young Adults: An ROC Curves Analysis. AB - Objectives and Methods. The aim of the present study was to evaluate, by means of receiver operating characteristic (ROC) curves, whether cognitive vulnerabilities (CV), as measured by three well-known instruments (the Beck Hopelessness Scale, BHS; the Life Orientation Test-Revised, LOT-R; and the Attitudes Toward Self Revised, ATS-R), independently discriminate between subjects with different severities of depression. Participants were 467 young adults (336 females and 131 males), recruited from the general population. The subjects were also administered the Beck Depression Inventory-II (BDI-II). Results. Four first-order (BHS Optimism/Low Standard; BHS Pessimism; Generalized Self-Criticism; and LOT Optimism) and two higher-order factors (Pessimism/Negative Attitudes Toward Self, Optimism) were extracted using Principal Axis Factoring analysis. Although all first-order and second-order factors were able to discriminate individuals with different depression severities, the Pessimism factor had the best performance in discriminating individuals with moderate to severe depression from those with lower depression severity. Conclusion. In the screening of young adults at risk of depression, clinicians have to pay particular attention to the expression of pessimism about the future. PMID- 24058735 TI - Epigenetic alterations and an increased frequency of micronuclei in women with fibromyalgia. AB - Fibromyalgia (FM), characterized by chronic widespread pain, fatigue, and cognitive/mood disturbances, leads to reduced workplace productivity and increased healthcare expenses. To determine if acquired epigenetic/genetic changes are associated with FM, we compared the frequency of spontaneously occurring micronuclei (MN) and genome-wide methylation patterns in women with FM (n = 10) to those seen in comparably aged healthy controls (n = 42 (MN); n = 8 (methylation)). The mean (sd) MN frequency of women with FM (51.4 (21.9)) was significantly higher than that of controls (15.8 (8.5)) (chi (2) = 45.552; df = 1; P = 1.49 * 10(-11)). Significant differences (n = 69 sites) in methylation patterns were observed between cases and controls considering a 5% false discovery rate. The majority of differentially methylated (DM) sites (91%) were attributable to increased values in the women with FM. The DM sites included significant biological clusters involved in neuron differentiation/nervous system development, skeletal/organ system development, and chromatin compaction. Genes associated with DM sites whose function has particular relevance to FM included BDNF, NAT15, HDAC4, PRKCA, RTN1, and PRKG1. Results support the need for future research to further examine the potential role of epigenetic and acquired chromosomal alterations as a possible biological mechanism underlying FM. PMID- 24058737 TI - How Noninvasive Haemoglobin Measurement with Pulse CO-Oximetry Can Change Your Practice: An Expert Review. AB - Trauma related haemorrhagic anaemia is rarely diagnosed by physical examination alone but typically includes measurement of blood haemoglobin, one of the most frequently ordered laboratory tests. Recently, noninvasive technologies have been developed that allow haemoglobin to be measured immediately without the need for intravenous access or having to take venous, arterial, or capillary blood. Moreover, with these technologies haemoglobin can be continuously measured in patients with active bleeding, to guide the start and stop of blood transfusions and to detect occult bleeding. Recent studies on the accuracy of the devices showed promising results in terms of accuracy of hemoglobin measurement compared to laboratory determination. The present review gives an overview on the technology itself and reviews the current literature on the subject. PMID- 24058738 TI - Percentage of deaths attributable to poor cardiovascular health lifestyle factors: Findings from the Aerobics Center Longitudinal Study. AB - PURPOSE: We assessed the effects of the four newly defined American Heart Association (AHA) lifestyle factors on mortality by examining the associated population attributable fractions (PAFs) of these factors. METHODS: Slightly modified AHA cardiovascular health factors (smoking, BMI, cardiorespiratory fitness, and diet) were measured among 11,240 (24% women) participants from the Aerobics Center Longitudinal Study between 1987 and 1999. The cohort was followed to December 31, 2003 or death. PAFs were calculated as the proportionate reduction in death attributable to identified risk factors. RESULTS: During an average 12 years of follow-up, 268 deaths occurred. Low fitness had the highest PAFs at the 5th, 10th, and 15th year of follow-up, respectively: 6.6%, 6.4%, and 5.5%. Current smokers had the second highest PAFs at the 5th, 10th, and 15th year of follow-up, respectively: 5.4%, 5.2%, and 5.0%. Additional adjusting for other confounders in the model did not change the above associations. The PAFs for overweight or obesity and unhealthy diet were not significant in the current analyses. CONCLUSIONS: Assuming a causal relationship between smoking, low fitness and mortality, avoidance of both would have prevented 13% of the deaths in the current population. Preventive interventions to increase physical activity and stop smoking would most likely promote longevity. PMID- 24058736 TI - Inflammation, cerebral vasospasm, and evolving theories of delayed cerebral ischemia. AB - Cerebral vasospasm (CVS) is a potentially lethal complication of aneurysmal subarachnoid hemorrhage (aSAH). Recently, the symptomatic presentation of CVS has been termed delayed cerebral ischemia (DCI), occurring as early as 3-4 days after the sentinel bleed. For the past 5-6 decades, scientific research has promulgated the theory that cerebral vasospasm plays a primary role in the pathology of DCI and subsequently delayed ischemic neurological decline (DIND). Approximately 70% of patients develop CVS after aSAH with 50% long-term morbidity rates. The exact etiology of CVS is unknown; however, a well-described theory involves an antecedent inflammatory cascade with alterations of intracellular calcium dynamics and nitric oxide fluxes, though the intricacies of this inflammatory theory are currently unknown. Consequently, there have been few advances in the clinical treatment of this patient cohort, and morbidity remains high. Identification of intermediaries in the inflammatory cascade can provide insight into newer clinical interventions in the prevention and management of cerebral vasospasm and will hopefully prevent neurological decline. In this review, we discuss current theories implicating the inflammatory cascade in the development of CVS and potential treatment targets. PMID- 24058740 TI - Severe Intraperitoneal Haemorrhage following Suprapubic Catheter Insertion in a Patient Treated with Iloprost. AB - Suprapubic catheter (SPC) insertion is a common urological procedure, performed both in the elective and emergency settings. The authors present an unusual case of severe intraperitoneal bleeding following the insertion of an SPC under direct vision, where the use of prostacyclin analogue may have been a contributing factor. PMID- 24058739 TI - Undiagnosed Chronic Granulomatous Disease, Burkholderia cepacia complex Pneumonia, and Acquired Hemophagocytic Lymphohistiocytosis: A Deadly Association. AB - Background. Chronic granulomatous disease is a rare inherited disorder of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The clinical course of the disease is marked by recurrent infections, including Burkholderia cepacia complex infection. Case Report. Here we report the case of a 21-year-old male hospitalized for a Burkholderia cepacia complex pneumonia. Despite the broad spectrum antibiotic treatment, fever continued and patient's condition worsened. Anemia and thrombocytopenia developed together with hypofibrinogenemia. The patient died of multiple organ dysfunction 17 days after his admission. Autopsy revealed hemophagocytosis, suggesting the diagnosis of acquired hemophagocytic lymphohistiocytosis. DNA analysis showed a deletion in the p47phox gene, confirming the diagnosis of autosomal recessive chronic granulomatous disease. Discussion. In addition to chronic granulomatous disease, recent findings have demonstrated that Burkholderia cepacia complex can decrease activity of the NADPH oxidase. Interestingly, hemophagocytic lymphohistiocytosis is characterized by an impaired function of the T-cell mediated inflammation which is partly regulated by the NADPH oxidase. Physicians should therefore pay particular attention to this deadly association. PMID- 24058741 TI - A rare prostatic diagnosis of an old man: a pure prostatic leiomyoma. AB - A pure leiomyoma of the prostate is a rare benign tumor. An 82-year-old man was referred to our urology department with gross hematuria and complete urinary retention. Examination revealed a benign prostatic hyperplasia. Transrectal ultrasound showed a prostate of 125 mL. Serum PSA was 1.9 ug/L. A simple retropubic prostatectomy was performed. Histopathological examination showed a pure leiomyoma of the prostate, without the presence of glandular prostate tissue. The diagnosis, characteristics, and treatment of this tumor are described. PMID- 24058742 TI - Physicians' Use of Patients' Daily Reports of Quality of Life to Evaluate Treatment Response in Phase I Cancer Trials. AB - For cancer patients on Phase I trials, one of the most important physician decisions is whether or not patients are deriving benefit from therapy. With an increasing number of cytostatic treatment agents, the criteria to determine patient response to Phase I treatment has become harder to define. Physicians are increasingly looking to patient-reported outcomes (PROs) such as quality of life (QOL) to help evaluate treatment response. Electronic daily diary (EDD) devices can be used by patients to report their QOL over extended periods of time, thereby providing a more accurate picture of how patients are affected by treatment on a daily basis. However, questions remain about how to integrate this patient-reported information into decisions about Phase I treatment. This study investigated how physicians use patients' daily QOL reports to evaluate patient response to Phase I treatment. Data were collected over a 4-month period from Phase I patients (N = 30) and physicians (N = 3) in an NCI-designated comprehensive cancer center. Patients completed daily QOL reports using EDD devices and physicians were provided with a summary of patients' QOL before each visit. After the visit, doctors recorded their treatment decision and also rated the importance of four biomedical factors (Toxicity, Imaging, Labs, and Performance Status) and QOL in their treatment decision for that visit. Although physicians rated QOL as being very important in evaluating treatment response, in practice, when predictors of their decisions were analyzed, results showed they relied exclusively on biomedical data (Toxicity, Imaging) to make Phase I treatment decisions. Questions remain about the utility and effective integration of QOL and biomedical data in clinical decision-making processes in Phase I clinical trials. PMID- 24058743 TI - Loss of Neuronal Phenotype and Neurodegeneration: Effects of T Lymphocytes and Brain Interleukin-2. AB - Loss of neuronal phenotype and reversal of neuronal atrophy have been demonstrated in different models of central nervous system (CNS) injury. These processes may be generalizable to different types of brain neurons and circuitry. The idea that some injured neurons may lose their phenotype and/or atrophy with the potential to rejuvenate is a remarkable and potentially promising form of neuronal plasticity that is not well understood. In this paper, we present some of our laboratory's basic neuroimmunology research showing that peripheral T cells entering the CNS, and brain-derived interleukin-2 (IL-2), play significant roles in these intriguing processes. Our findings suggest, for example, that T cell immunosenesence could be involved in related processes of brain aging and contribute to neurodegenerative disease. Neuroimmunological approaches may provide new insights into yet undiscovered factors and brain mechanisms that regulate changes in neuronal integrity associated with aging and disease. Such findings could have important implications for discovering more effective strategies for treating patients with neurotrauma and neurodegenerative diseases (e.g., Alzheimer's disease). PMID- 24058744 TI - The beginning of the STAT: Letter from the Editor. PMID- 24058745 TI - The JAK-STAT pathway at 20. PMID- 24058746 TI - Wheezing and itching: The requirement for STAT proteins in allergic inflammation. AB - The development of allergic inflammation requires the orchestration of gene expression from the inflamed tissue and from the infiltrating immune cells. Since many of the cytokines that promote allergic inflammation signal through hematopoietin family receptors, the Signal Transducer and Activator of Transcription (STAT) family have obligate roles in pro-allergic cytokine-induced gene regulation in multiple cell types. In this review, we summarize work defining the contribution of each of the STAT family members to the development of allergic inflammation, using data from mouse models of allergic inflammation, studies on patient samples and correlations with single nucleotide polymorphisms in STAT genes. PMID- 24058748 TI - Comparative evolutionary genomics of the STAT family of transcription factors. AB - The STAT signaling pathway is one of the seven common pathways that govern cell fate decisions during animal development. Comparative genomics revealed multiple incidences of stat gene duplications throughout metazoan evolutionary history. While pseudogenization is a frequent fate of duplicated genes, many of these STAT duplications evolved into novel genes through rapid sequence diversification and neofunctionalization. Additionally, the core of STAT gene regulatory networks, comprising stat1 through 4, stat5 and stat6, arose early in vertebrate evolution, probably through the two whole genome duplication events that occurred after the split of Cephalochordates but before the rise of Chondrichthyes. While another complete genome duplication event took place during the evolution of bony fish after their separation from the tetrapods about 450 million years ago (Mya), modern fish have only one set of these core stats, suggesting the rapid loss of most duplicated stat genes. The two stat5 genes in mammals likely arose from a duplication event in early Eutherian evolution, a period from about 310 Mya at the avian-mammal divergence to the separation of marsupials from other mammals about 130 Mya. These analyses indicate that whole genome duplications and gene duplications by unequal chromosomal crossing over were likely the major mechanisms underlying the evolution of STATs. PMID- 24058747 TI - STAT5-mediated self-renewal of normal hematopoietic and leukemic stem cells. AB - The level of transcription factor activity critically regulates cell fate decisions such as hematopoietic stem cell self-renewal and differentiation. The balance between hematopoietic stem cell self-renewal and differentiation needs to be tightly controlled, as a shift toward differentiation might exhaust the stem cell pool, while a shift toward self-renewal might mark the onset of leukemic transformation. A number of transcription factors have been proposed to be critically involved in governing stem cell fate and lineage commitment, such as Hox transcription factors, c-Myc, Notch1, beta-catenin, C/ebpalpha, Pu.1 and STAT5. It is therefore no surprise that dysregulation of these transcription factors can also contribute to the development of leukemias. This review will discuss the role of STAT5 in both normal and leukemic hematopoietic stem cells as well as mechanisms by which STAT5 might contribute to the development of human leukemias. PMID- 24058749 TI - Modulation of human JAK-STAT pathway signaling by functionally conserved regulators. AB - Both the core JAK-STAT pathway components and their in vivo roles have been widely conserved between vertebrates and invertebrate models such as Drosophila melanogaster. Misregulation of JAK-STAT pathway activity has also been identified as a key factor in the development of multiple human malignancies. Recently, whole genome RNA interference (RNAi) screens in cultured Drosophila cells have identified both positively and negatively acting JAK-STAT pathway regulators. Here, we describe the analysis of 73 human genes representing homologs of 56 Drosophila genes originally identified by genome-wide RNAi screening as regulators of JAK-STAT signaling. Using assays for human STAT1 and STAT3 protein levels and phosphorylation status, as well as assays measuring the expression of endogenous STAT1 and STAT3 transcriptional targets, we have tested siRNAs targeting these 73 human genes and have identified potential JAK-STAT pathway regulatory roles in 69 (95%) of these. The genes identified represent a wide range of human JAK-STAT pathway regulators and include genes not previously known to modulate this signaling cascade. These results underline the value of model system based approaches for the identification of pathway regulators and have led to the identification of loci whose misregulation may ultimately be implicated in JAK-STAT pathway-mediated human disease. PMID- 24058750 TI - A membrane penetrating peptide aptamer inhibits STAT3 function and suppresses the growth of STAT3 addicted tumor cells. AB - Cancer cells are characterized by the aberrant activation of signaling pathways governing proliferation, survival, angiogenesis, migration and immune evasion. These processes are partially regulated by the transcription factor STAT3. This factor is inappropriately activated in diverse tumor types. Since tumor cells can become dependent on its persistent activation, STAT3 is a favorable drug target. Here, we describe the functional characterization of the recombinant STAT3 inhibitor, rS3-PA. This inhibitor is based on a 20 amino acid peptide which specifically interacts with the dimerization domain of STAT3. It is integrated into a thioredoxin scaffold and fused to a protein transduction domain. Protein gel blot and immunofluorescence analyses showed that rS3-PA is efficiently taken up by cells via an endocytosis independent mechanism. Intracellularly, it reduces the phosphorylation of STAT3 and enhances its degradation. This leads to the downregulation of STAT3 target gene expression on the mRNA and protein levels. Subsequently, tumor cell proliferation, survival and migration and the induction of angiogenesis are inhibited. In contrast, normal cells remain unaffected. Systemic administration of rS3-PA at doses of 7.5 mg/kg reduced P-STAT3 levels and significantly inhibited tumor growth up to 35% in a glioblastoma xenograft mouse model. PMID- 24058751 TI - STAT signaling in the pathogenesis and treatment of myeloid malignancies. AB - STAT transcription factors play a critical role in mediating the effects of cytokines on myeloid cells. As STAT target genes control key processes such as survival, proliferation and self-renewal, it is not surprising that constitutive activation of STATs, particularly STAT3 and STAT5, are common events in many myeloid tumors. STATs are activated both by mutant tyrosine kinases as well as other pathogenic events, and continued activation of STATs is common in the setting of resistance to kinase inhibitors. Thus, the targeting of STATs, alone or in combination with other drugs, will likely have increasing importance for cancer therapy. PMID- 24058753 TI - STAT5 fits the RISK profile for cardioprotection. AB - How wonderful would it be if there were a simple, cheap, safe, non-invasive treatment that could be administered to a patient to protect their organs from ischemia and reperfusion? Such a treatment might be used to protect the organs during temporary loss of blood flow, as occurs for example during a heart attack or stroke. As unlikely as this may sound, such a treatment has indeed been discovered, although research into the mechanism is only just beginning. A recent paper by Heusch et al. in Circulation Research has taken the first step in this direction, as explained below. PMID- 24058754 TI - The interplay between inhibition of JAK2 and HSP90. AB - A recent article by Weigert et al. published in The Journal of Experimental Medicine described the in vitro generation of synthetic mutations in Janus kinase 2 (JAK 2) that decreased the potency of JAK2 (or JAK1/JAK2) inhibitors in artificial systems. The authors found that heat shock protein 90 (HSP90) inhibitors circumvented the potency shift and suggested that HSP90 inhibition may abrogate JAK inhibitor resistance in these experimental systems. However, the clinical relevance of these laboratory-generated JAK2 mutations, which have not been identified to-date in patients treated with JAK inhibitors, and the therapeutic potential of HSP90 inhibitors in diseases involving aberrant JAK-STAT signaling remain to be determined. PMID- 24058752 TI - STAT1 and STAT3 in tumorigenesis: A matter of balance. AB - The transcription factors STAT1 and STAT3 appear to play opposite roles in tumorigenesis. While STAT3 promotes cell survival/proliferation, motility and immune tolerance and is considered as an oncogene, STAT1 mostly triggers anti proliferative and pro-apoptotic responses while enhancing anti-tumor immunity. Despite being activated downstream of common cytokine and growth factor receptors, their activation is reciprocally regulated and perturbation in their balanced expression or phosphorylation levels may re-direct cytokine/growth factor signals from proliferative to apoptotic, or from inflammatory to anti inflammatory. Here we review the functional canonical and non-canonical effects of STAT1 and STAT3 activation in tumorigenesis and their potential cross regulation mechanisms. PMID- 24058755 TI - Production of IL-17: What's STAT got to do with it? AB - Th17 cells are important mediators of autoimmunity, yet the mechanisms by which they are controlled are not fully understood. Studies in mice, including a recent article in Nature Immunology by Yang et al., show that IL-2 is an important inhibitory factor for the differentiation of Th17 cells, inducing phosphorylation of STAT5, which outcompetes STAT3 binding at the IL-17 locus. In humans however, IL-2 appears to be crucial for Th17 differentiation, yet inhibits the expansion of antigen-specific Th17 clones, again via a STAT5 mechanism. Here we discuss how the article by Yang et al. offers a novel mechanism to explain how changes in the balance of different cytokines in the inflammatory environment may alter the stability or phenotype of regulatory T cells and T helper cell subsets. PMID- 24058756 TI - Angiotensin II induces cell growth and IL-6 mRNA expression through the JAK2 STAT3 pathway in rat cerebellar astrocytes. AB - The pleiotrophic effects of angiotensin II (Ang II) play important roles in astrocyte growth and inflammatory responses. We investigated whether Ang II induces astrocyte growth and interleukin-6 (IL-6) mRNA expression in rat cerebellar astrocytes through Janus kinase 2-signal transduction activator of transcription (JAK2-STAT3). Ang II increased JAK2 and STAT3 phosphorylation in a time- and a dose-dependent manner. One hundred nanomolar Ang II induced maximal phosphorylation of both JAK2 and STAT3 between 15 min and 30 min. The Ang II mediated phosphorylation of both JAK2 and STAT3 was blocked by AG490, a selective JAK2 inhibitor. Losartan, a selective AT1 receptor antagonist, inhibited Ang II mediated JAK2 and STAT3 phosphorylation, while pretreatment with an AT2 receptor blocker, PD123319, was ineffective. Ang II increased the mRNA expression of IL-6 in a concentration-and time-dependent manner. Maximal IL-6 mRNA expression occurred with 100 nM Ang II, and the peak effect occurred in a biphasic manner at 3 h and between 12 and 24 h. Moreover, pretreatments with AG490 attenuated Ang II induced IL-6 mRNA levels, and Ang II-induced astrocyte growth. This study has demonstrated that Ang II induced the phosphorylation of both JAK2 and STAT3 via the AT1 receptor in cerebellar astrocytes. In addition, our results suggest that JAK2 and STAT3 are upstream signals that mediate Ang II-induced IL-6 mRNA expression and astrocyte growth. These findings represent a novel non-classical mechanism of Ang II signaling in cerebellar astrocytes. PMID- 24058757 TI - JAK-STAT: Getting to the heart of the matter. PMID- 24058758 TI - High density lipoprotein/sphingosine-1-phosphate-induced cardioprotection: Role of STAT3 as part of the SAFE pathway. AB - High density lipoprotein (HDL) cholesterol has beneficial effects beyond its atheroprotective function in reverse cholesterol transport, including cardioprotection against ischemia reperfusion (IR) injuries. Two major constituents of HDL, namely the structural protein apolipoprotein AI (apoAI) and the sphingolipid sphingosine-1-phosphate (S1P) appear to contribute to this cardioprotective effect via the activation of intrinsic prosurvival signaling pathways that still remain to be clarified. Recently, a powerful prosurvival signaling pathway, termed the survivor activating factor enhancement (SAFE) pathway, which involves the activation of signal transducer and activator of transcription 3 (STAT3) and tumor necrosis factor alpha (TNF), has been shown to protect against ischemia-reperfusion injuries. The present review summarizes the evidence for the roles of HDL and S1P in cardioprotection and discusses the signaling pathways that have been implicated. It thus provides support for our contention that S1P should be considered in potential formulations of reconstituted HDL (reHDL) that may be tested for cardioprotection against coronary artery disease via the activation of the SAFE pathway. PMID- 24058759 TI - STAT transcription in the ischemic heart. AB - All seven STAT proteins are expressed in the heart, and in this review we will focus on their contribution to cardiac physiology and to ischemic heart disease and its consequences. A substantial literature has focused on the roles of STAT1 and STAT3 in ischemic heart disease, where, at least in the acute phase, they appear to have a yin-yang relationship. STAT1 contributes to the loss of irreplaceable cardiac myocytes both by increasing apoptosis and by reducing cardioprotective autophagy. In contrast, STAT3 is cardioprotective, since STAT3 deficient mice have larger infarcts following ischemic injury, and a number of cardioprotective agents have been shown to act, at least partly, through STAT3 activation. STAT3 is also absolutely required for preconditioning-a process where periods of brief ischemia protect against a subsequent or previous prolonged ischemic episode. Prolonged activation of STAT3, however, is strongly implicated in the post-infarction remodeling of the heart which leads to heart failure, where, possibly together with STAT5, it augments activation of the renin angiotensin system. PMID- 24058760 TI - Roles of STATs signaling in cardiovascular diseases. AB - In cardiac and many other systems, chronic stress activates avfamily of structurally and functionally conserved receptors and their downstream signaling molecules that entail tyrosine, serine or threonine phosphorylation to transfer the messages to the genetic machinery. However, the activation of the Janus kinases (JAKs) and their downstream signal transducer and activator of transcription (STATs) proteins is both characteristic of and unique to cytokine and growth factor signaling which plays a central role in heart physiology. Dysregulation of JAK-STAT signaling is associated with various cardiovascular diseases. The molecular signaling and specificity of the JAK-STAT pathway are modulated at many levels by distinct regulatory proteins. Here, we review recent studies on the regulation of the STAT signaling pathway that will enhance our ability to design rational therapeutic strategies for stress-induced heart failure. PMID- 24058761 TI - JAK-STAT signaling in cardiomyogenesis of cardiac stem cells. AB - Recently various kinds of cardiac stem/progenitor cells have been identified and suggested to be involved in cardiac repair and regeneration in injured myocardium. In this review, we focus on the roles of JAK-STAT signaling in cardiac stem/progenitor cells in cardiomyogenesis. JAK-STAT signaling plays important roles in the differentiation of stem cells into cardiac lineage cells. The activation of JAK-STAT signal elicits the mobilization of mesenchymal stem cells as well, contributing to the maintenance of cardiac function. Thus we propose that JAK-STAT could be a target signaling pathway in cardiac regenerative therapy. PMID- 24058762 TI - The JAK-STAT pathway in hypertrophic stress signaling and genomic stress response. AB - The JAK-STAT signaling pathway plays a central role in transducing stress and growth signals in the hypertrophic heart. Unlike most signal transducers, JAKs and STATs signal in a number of different ways, both within the JAK-STAT pathway and in collaboration with other signaling pathways. In this review, we discuss how IL-6 activates cells lacking IL-6 receptors through trans-signaling and examine JAK-STAT pathway interaction with GPCR-linked pathways both within and between cells. Finally, we discuss recent studies showing how the JAK-STAT pathway can intersect with a general transcriptional regulatory mechanism to effect transcription of STAT-dependent stress response genes. PMID- 24058763 TI - STAT3 regulation of and by microRNAs in development and disease. AB - MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs acting at the post-transcriptional level where they promote mRNA degradation and block protein translation. Recent findings suggest that complex transcriptional and post transcriptional circuits control miRNAs. STAT3 has emerged as an important regulator of their expression and biogenesis and, in turn, STAT3 signaling pathways are controlled by distinct miRNAs. We summarize the current knowledge on STAT3 mediated processing of individual miRNAs and contrariwise, the modulation of the STAT3 pathway by miRNAs in development and in pathophysiological conditions such as immune processes, infection, cancer, cardiovascular disease and pulmonary hypertension. PMID- 24058764 TI - The spectrum of STAT functions in mammary gland development. AB - The signal transducer and activator of transcription (STAT) family of transcription factors have a spectrum of functions in mammary gland development. In some cases these roles parallel those of STATs in other organ systems, while in other instances the function of individual STATs in the mammary gland is specific to this tissue. In the immune system, STAT6 is associated with differentiation of T helper cells, while in the mammary gland, it has a fundamental role in the commitment of luminal epithelial cells to the alveolar lineage. STAT5A is required for the production of luminal progenitor cells from mammary stem cells and is essential for the differentiation of milk producing alveolar cells during pregnancy. By contrast, the initiation of regression following weaning heralds a dramatic and specific activation of STAT3, reflecting its pivotal role in the regulation of cell death and tissue remodeling during mammary involution. Although it has been demonstrated that STAT1 is regulated during a mammary developmental cycle, it is not yet determined whether it has a specific, non-redundant function. Thus, the mammary gland constitutes an unusual example of an adult organ in which different STATs are sequentially activated to orchestrate the processes of functional differentiation, cell death and tissue remodeling. PMID- 24058765 TI - Infection-induced IL-10 and JAK-STAT: A review of the molecular circuitry controlling immune hyperactivity in response to pathogenic microbes. AB - Generation of effective immune responses against pathogenic microbes depends on a fine balance between pro- and anti-inflammatory responses. Interleukin-10 (IL-10) is essential in regulating this balance and has garnered renewed interest recently as a modulator of the response to infection at the JAK-STAT signaling axis of host responses. Here, we examine how IL-10 functions as the "master regulator" of immune responses through JAK-STAT, and provide a perspective from recent insights on bacterial, protozoan, and viral infection model systems. Pattern recognition and subsequent molecular events that drive activation of IL 10-associated JAK-STAT circuitry are reviewed and the implications for microbial pathogenesis are discussed. PMID- 24058766 TI - Ubiquitin-mediated regulation of JAK-STAT signaling in embryonic stem cells. AB - LIF activates several intracellular signaling pathways including JAK-STAT, PI3K/AKT and MAPK pathways. LIF is an important cytokine for maintenance of pluripotency and self-renewal of mouse ES cells. The JAK-STAT signal plays a key role in maintenance of the pluripotency of ESCs. Recent evidence shows that several post-translational modifications regulate activation or inhibition of intracellular signal transductions. The JAK-STAT signal is also modulated by several modifications including phosphorylation, acetylation and ubiquitination. In this review, we discuss regulation of the LIF-mediated-JAK-STAT signaling pathway that contributes to self-renewal of pluripotent ESCs. PMID- 24058767 TI - Functions of the Drosophila JAK-STAT pathway: Lessons from stem cells. AB - JAK-STAT signaling has been proposed to act in numerous stem cells in a variety of organisms. Here we provide an overview of its roles in three well characterized stem cell populations in Drosophila, in the intestine, lymph gland and testis. In flies, there is a single JAK and a single STAT, which has made the genetic dissection of pathway function considerably easier and facilitated the analysis of communication between stem cells, their niches and offspring. Studies in flies have revealed roles for this pathway as diverse as regulating bona fide intrinsic self-renewal, integrating response to environmental cues that control quiescence and promoting mitogenic responses to stress. PMID- 24058768 TI - The JAK-STAT pathway and hematopoietic stem cells from the JAK2 V617F perspective. AB - Janus kinases (JAKs) are non-receptor tyrosine kinases essential for activation of signaling mediated by cytokine receptors that lack catalytic activity, including receptors for erythropoietin, thrombopoietin, most interleukins and interferon. Upon hormone binding, JAKs phosphorylate tyrosine residues in the receptor cytoplasmic domains and in JAKs themselves leading to recruitment and activation of downstream signaling proteins such as signal transducer and activator of transcription (STAT). The JAK-STAT pathway is important for functional hematopoiesis and several activating mutations in JAK proteins have recently been described as underlying cause of blood disorders. One of the best studied examples is the JAK2 V617F mutant which is found in 95% of polycythemia vera patients and 50% of patients suffering from essential thrombocythemia and primary myelofibrosis. Much effort has been made to understand how the JAK2 V617F affects hematopoietic stem cell (HSC) renewal and lineage differentiation, since convincing evidence has been provided to support the notion that the mutation is acquired at the HSC level. We discuss several in vivo models that support contrary conclusions with respect to the advantage given to HSCs by JAK2 V617F. Moreover, we provide the current knowledge about STAT5 activation and its link to HSC expansion as well as amplification of the erythroid compartment. Evidence for both JAK2 V617F mutated HSCs exhibiting skewed differentiation potential and for amplification occurring after erythroid commitment has been provided, and we will discuss whether this evidence is relevant for the disease. PMID- 24058769 TI - JAK2-STAT3 signaling: A novel function and a novel mechanism. AB - The function of JAK-STAT signaling in the central nervous system has been widely studied in the context of neural cell development and differentiation and in neuronal and glial responses to CNS injury. A study published recently in Neuron by Nicolas et al. now demonstrates that the JAK2-STAT3 pathway also plays an important role in the regulation of synaptic transmission. By using a combination of biochemical, pharmacological and genetic approaches they show that induction of long-term depression (LTD), an activity-dependent rapid and long-lasting decrease in synaptic strength, via NMDA receptors depends on STAT3 activation by JAK2 that can be localized specifically to postsynaptic structures. Most interestingly, they find that induction of LTD requires STAT3 phosphorylation and dimerization but is independent of nuclear translocation and transcriptional activity of STAT3. Although it remains to be clarified how NMDA receptor-mediated postsynaptic processes lead to JAK2-STAT3 activation and how this in turn translates into persistent changes in synaptic strength, these results provide evidence for a novel mechanism of signal transduction. PMID- 24058770 TI - PKM2, STAT3 and HIF-1alpha: The Warburg's vicious circle. AB - The M2 isoform of pyruvate kinase, highly expressed in tumor cells, is known to engage a feed forward loop with the glycolysis master transcription factor HIF 1alpha. Gao and co-authors recently showed that dimeric PKM2 localizes to the nucleus in highly proliferating cancer cells, where it regulates in vivo growth by acting as a protein kinase and directly activating STAT3. STAT3 is therefore a novel player of the PKM2/HIF-1alpha feedback loop, since HIF-induced PKM2 activates STAT3 that in turn induces HIF-1alpha expression. These findings have profound implications for understanding the complex connections between gene regulation, metabolism, survival and proliferation in cancer. PMID- 24058771 TI - Role of STAT1 in the breast. AB - Signal transducer and activator of transcription-1 (STAT1) plays a role in the transduction of stress and cytokine responses, DNA damage, and activation of B and T cell immune responses. The ability of STAT1 to act as a pro- or anti apoptotic signaling molecule depends upon the cellular environment and stimulus. Post-translational modifications provide the main method of control over the function of STAT1, however, recent data in the breast has shown that loss of STAT1 from both the tumor and the surrounding mammary epithelium greatly influence the development and response to treatment of breast cancers. Here, we discuss the recent findings of Chan et al. in Breast Cancer Research who described a new role for STAT1 in the development of estrogen receptor (ER) positive and progesterone receptor (PR)-positive luminal breast cancers. PMID- 24058772 TI - Necroptosis: STAT3 kills? AB - TNF-induced necroptosis is caused by the activation of RIPK1 and the subsequent production of reactive oxygen species in the mitochondria, although the intermittent molecules of the signaling pathway responsible for this ROS-mediated type of programmed necrosis have not yet been identified. A recent article by Shulga and Pastorino in the Journal of Cell Science identifies RIPK1 as the mediator of STAT3 Ser727 phosphorylation, which leads to the translocation of the latter into the mitochondria via its interaction with GRIM-19, a member of the mitochondrial complex I. Here we discuss how the findings of the Shulga and Pastorino study shed light onto the involvement of STAT3 in necroptosis. PMID- 24058773 TI - Acetylation and sumoylation control STAT5 activation antagonistically. AB - STAT5 proteins are activated by tyrosine phosphorylation, but recently further post-translation modifications such as serine/threonine phosphorylation, acetylation at lysine residues or sumoylation in close vicinity of the critical tyrosine residue have been reported. Here, we discuss new findings on impaired STAT5 signaling in lymphocytes isolated from a SUMO-specific protease knockout mouse (SENP1(-/-)), which results in sumoylated STAT5 and abolishes tyrosine phosphorylation. Van Nguyen and colleagues examined acetylation and sumoylation of STAT5 and found that both modifications act antagonistically to control tyrosine phosphorylation of STAT5. PMID- 24058774 TI - Matters of the heart. AB - What does it take to make a heart? Even in the fruit fly, in which matters of the heart don't extend to either pop music or pulp fiction, making a heart requires big decisions and processes of surprising complexity. PMID- 24058775 TI - Determinants of the extent and duration of STAT3 signaling. AB - Multiple molecular mechanisms have been identified that are responsible for the deregulation of the quantitative aspects of JAK-STAT signaling. These mechanisms enhance the extent and the duration of, e.g., STAT3 activation and have profound consequences on the phenotypes of the affected cells. The fine tuning of STAT3 signaling is required to maintain its physiological functions and its deregulation is associated with diverse pathological states. Deregulation can be exerted by the gain of function of components mediating the activation of STAT3 or the loss of function of molecules involved in the deactivation steps of STAT3. Gain of function mutations can involve tyrosine kinases that phosphorylate STAT3, mutations in cytokine and growth factor receptors causing their ligand independent activation, mutations in STAT3 that enhance and prolong its tyrosine phosphorylation and the autocrine or paracrine production and secretion of cytokines, most notably IL-6. Diminished deactivation of phosphorylated STAT3 can be due to the reduced expression of tyrosine phosphatases, inactivating mutations in these enzymes, silencing or functional inactivation of SOCS molecules, post transcriptional inhibition of PIAS3 expression or deletion mutations in the lymphocyte adaptor protein, LNK. STAT3 variants that exhibit autonomous transactivation potential have been detected in 40% of patients with T-cell large granular lymphocytic leukemia in clonally expanded CD8(+) T cells. These patients also were preferentially affected by neutropenia and rheumatoid disorders and the results suggest that activating STAT3 mutations in T lymphocytes could be a cause of autoimmune diseases. PMID- 24058776 TI - Is suppression of cyst growth in PKD enough to preserve renal function?: STAT6 inhibition is a novel promising target. AB - The autosomal dominant form of polycystic kidney disease (ADPKD) is one of the most frequent monogenic disorders and the most frequent among inherited kidney disorders. In fact it has a prevalence in the population of about 1/1,000 individuals, therefore it does not even satisfy the definition for rare diseases. It is mainly characterized by the formation of multiple cysts filled with fluid that over time develop in number and size leading to the distraction of the structure and function of the kidneys and eventually leading to chronic kidney disease/end stage kidney disease (CKD/ESKD), usually between the 4th and 7th decade of life. There are two known forms of the autosomal dominant type of polycystic kidney disease, type 1 and type 2, caused by mutations in the PKD1 and PKD2 genes, located on chromosomes 16 and 4 respectively. The polycystin 1 protein, encoded by PKD1 and mutated in ~85% of patients, is a huge protein of 4,302 amino acids with multiple transmembrane domains, 200 residues intracytoplasmic part and a huge extracellular part with multiple Ig-like PKD repeats, which probably acts as a receptor to an unknown ligand. Polycystin 1 has been shown to interact with and participate in multiple signal transduction pathways, including the G-protein coupled receptor, cAMP pathway, Wnt, mTOR, MAPK/ERK, AP1 and JAK-STAT pathway, while its intracytoplasmic C-terminal domain has been shown to be cleaved and translocated to the nucleus where it plays a role in gene transcription, in concert with P100 and STAT6.(1.) PMID- 24058777 TI - STAT3 signaling in pulmonary arterial hypertension. AB - Pulmonary artery hypertension (PAH) is a proliferative disorder associated with enhanced pulmonary artery smooth muscle cell proliferation and suppressed apoptosis. The sustainability of this phenotype requires the activation of pro survival transcription factor like the signal transducers and activators of transcription-3 (STAT3). Using multidisciplinary and translational approaches, we and others have demonstrated that STAT3 activation in both human and experimental models of PAH accounts for the modulation of the expression of several proteins already known as implicated in PAH pathogenesis, as well as for signal transduction to other transcription factors. Furthermore, recent data demonstrated that STAT3 could be therapeutically targeted in different animal models and some molecules are actually in clinical trials for cancer or PAH treatment. PMID- 24058778 TI - SOCS3: A novel therapeutic target for cardioprotection. AB - The suppressors of cytokine signaling (SOCS) family of proteins are cytokine inducible inhibitors of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT) signaling pathways. Among the family, SOCS1 and SOCS3 potently suppress cytokine actions by inhibiting JAK kinase activities. The generation of mice lacking individual SOCS genes has been instrumental in defining the role of individual SOCS proteins in specific cytokine pathways in vivo; SOCS1 is an essential negative regulator of interferon-gamma (IFNgamma) and SOCS3 is an essential negative regulator of leukemia inhibitory factor (LIF). JAK STAT3 activating cytokines have exhibited cardioprotective roles in the heart. The cardiac-specific deletion of SOCS3 enhances the activation of cardioprotective signaling pathways, inhibits myocardial apoptosis and fibrosis and results in the inhibition of left ventricular remodeling after myocardial infarction (MI). We propose that myocardial SOCS3 is a key determinant of left ventricular remodeling after MI, and SOCS3 may serve as a novel therapeutic target to prevent left ventricular remodeling after MI. In this review, we discuss the signaling pathways mediated by JAK-STAT and SOCS proteins and their roles in the development of myocardial injury under stress (e.g., pressure overload, viral infection and ischemia). PMID- 24058779 TI - STAT1 as a central mediator of IFNgamma and TLR4 signal integration in vascular dysfunction. AB - Atherosclerosis is characterized by early endothelial dysfunction and altered vascular smooth muscle cells (VSMCs) contractility. The forming atheroma is a site of excessive production of cytokines and inflammatory ligands by various cell types that mediate inflammation and immune responses. Key factors contributing to early stages of plaque development are IFNgamma and TLR4. This review provides insight in the differential STAT1-dependent signal integration between IFNgamma and TLR4 signals in vascular cells and atheroma interacting immune cells. This results in increased leukocyte attraction and adhesion and VSMC proliferation and migration, which are important characteristics of EC dysfunction and early triggers of atherosclerosis. PMID- 24058781 TI - The STAT3-DNMT1 connection. AB - Gene activity is regulated by transcriptional and epigenetic mechanisms. A paper in 2005 by Zhang et al.(1) showed that STAT3 binds to the DNA methyl transferase, DNMT1 and their data indicated that STAT3 may cause epigenetic gene silencing by targeting DNMT1 to the PTPN6 promoter. Now, a paper by Lee et al.(2) has fleshed out the mechanism. They provide evidence that acetylation of STAT3 regulates the binding of DNMT1, CpG DNA methylation and regulation of several genes, including that encoding the estrogen receptor alpha (ESR1) in breast cancer cells. PMID- 24058780 TI - JAK-STAT and the renin-angiotensin system: The role of the JAK-STAT pathway in blood pressure and intrarenal renin-angiotensin system regulation. AB - The renin-angiotensin system (RAS) plays important roles in blood pressure control and tissue disease. An inappropriate local angiotensin II elevation in the kidneys leads to the development of hypertension, tissue damage and chronic injury. Studies have demonstrated that the JAK-STAT pathway mediates angiotensin II-triggered gene transcription. The JAK-STAT pathway in turn, acting as an amplifying system, contributes to further intrarenal RAS activation. These observations prompt the suggestion that the JAK-STAT pathway may be of importance in elucidating the mechanisms RAS-associated tissue injury. Accordingly, this review provides a brief overview of the interactions between the JAK-STAT pathway and the RAS, specifically the RAS expressed in the kidneys. PMID- 24058782 TI - Targeting STATs for cancer therapy: "Undruggable" no more. AB - We are in the midst of an exciting transition in the treatment of cancers, from the empirically developed non-specifically cytotoxic drugs to the era of rationally derived molecularly targeted therapies. Over the past 15 years, our understanding of the mutations that drive cancer pathogenesis has grown enormously, which has rapidly led to the development of drugs to target the associated gene products. Almost all of this focus has been on kinases, largely tyrosine kinases that are activated by translocations, point mutations, insertions and deletions. Although this approach will continue to bear fruit for some time, there is increasing evidence that the returns will be diminishing. First, dominant activating mutations in kinases are less frequent then initially expected particularly in common human cancers, and thus the number of patient whose tumors have suitable targets may be limited. The second cause for concern is the rapid development of resistance that often occurs, arising either from mutations in the target kinase or activation of a parallel pathway. Thus, the desire to target a common convergence point of multiple pathways that directly contributes to the oncogenic phenotype is highly desirable. This goal has led to consideration of transcription factors as therapeutic targets. PMID- 24058783 TI - The consequences of selective inhibition of signal transducer and activator of transcription 3 (STAT3) tyrosine705 phosphorylation by phosphopeptide mimetic prodrugs targeting the Src homology 2 (SH2) domain. AB - Herein we review our progress on the development of phosphopeptide-based prodrugs targeting the SH2 domain of STAT3 to prevent recruitment to cytokine and growth factor receptors, activation, nuclear translocation and transcription of genes involved in cancer. We developed high affinity phosphopeptides (K I = 46-200 nM). Corresponding prodrugs inhibited constitutive and IL-6 induced Tyr705 phosphorylation at 0.5-1 MUM in a variety of human cancer cell lines. They were not cytotoxic at 5 MUM in vitro but they inhibited tumor growth in a human xenograft breast cancer model in mice, accompanied by reduced VEGF expression and angiogenesis. PMID- 24058784 TI - Alternative ways of modulating JAK-STAT pathway: Looking beyond phosphorylation. AB - Most attempts to develop inhibitors of STAT transcription factors target either activating phosphorylation of tyrosine residue or SH2 domains. However, all six domains of STATs are highly conserved between the species and play important roles in the function of this family of transcription factors. STATs are involved in numerous protein-protein interactions that are likely to regulate and fine tune transcriptional activity. Targeting these interactions can provide plentiful opportunities for the discovery of novel drug candidates and powerful chemical biology tools. Using N-terminal domains as an example we describe alternative rational approaches to the development of modulators of JAK-STAT signaling. PMID- 24058785 TI - Nucleic acid-based approaches to STAT inhibition. AB - Silencing of abnormally activated genes can be accomplished in a highly specific manner using nucleic acid based approaches. The focus of this review includes the different nucleic acid based inhibition strategies such as antisense oligodeoxynucleotides, small interfering RNA (siRNA), dominant-negative constructs, G-quartet oligonucleotides and decoy oligonucleotides, their mechanism of action and the effectiveness of these approaches to targeting the STAT (signal transducer and activator of transcription) proteins in cancer. Among the STAT proteins, especially STAT3, followed by STAT5, are the most frequently activated oncogenic STATs, which have emerged as plausible therapeutic cancer targets. Both STAT3 and STAT5 have been shown to regulate numerous oncogenic signaling pathways including proliferation, survival, angiogenesis and migration/invasion. PMID- 24058786 TI - Screening approaches to generating STAT inhibitors: Allowing the hits to identify the targets. AB - STAT transcription factors are regulators of critical cellular processes such as proliferation, survival, and self-renewal. While the activity of these proteins is tightly regulated under physiological conditions, they can become constitutively activated in a broad range of human cancers. This inappropriate STAT activation leads to enhanced transcription of genes that can directly lead to the malignant phenotype. Since STATs are largely dispensable for normal cell function, this has raised the possibility that STATs might be key targets for cancer therapy. Although a number of structure-based strategies have been used to develop STAT inhibitors, an alternate approach is to use cell-based assays that make use of the transcriptional function of STATs. Employing these systems, one can screen large chemical libraries to identify compounds that specifically block the function of a given STAT. This approach can lead to the identification of compounds that inhibit STATs by a variety of mechanisms, and can suggest novel targets for therapy. This type of functional screening strategy has already identified a drug that potently inhibits STAT3, and which is now being evaluated in a clinical trial for patients with chronic lymphocytic leukemia. PMID- 24058787 TI - Evolution of the JAK-STAT pathway. AB - The JAK-STAT pathway represents a finely tuned orchestra capable of rapidly facilitating an exquisite symphony of responses from a complex array of extracellular signals. This review explores the evolution of the JAK-STAT pathway: the origins of the individual domains from which it is constructed, the formation of individual components from these basic building blocks, the assembly of the components into a functional pathway, and the subsequent reiteration of this basic template to fulfill a variety of roles downstream of cytokine receptors. PMID- 24058788 TI - STAT3 inhibitors for cancer therapy: Have all roads been explored? AB - The signal transducer and activator of transcription STAT3 is a transcription factor which plays a key role in normal cell growth and is constitutively activated in about 70% of solid and hematological cancers. Activated STAT3 is phosphorylated on tyrosine and forms a dimer through phosphotyrosine/src homology 2 (SH2) domain interaction. The dimer enters the nucleus via interaction with importins and binds target genes. Inhibition of STAT3 results in the death of tumor cells, this indicates that it is a valuable target for anticancer strategies; a view that is corroborated by recent findings of activating mutations within the gene. Yet, there is still only a small number of STAT3 direct inhibitors; in addition, the high similarity of STAT3 with STAT1, another STAT family member mostly oriented toward apoptosis, cell death and defense against pathogens, requires that STAT3-inhibitors have no effect on STAT1. Specific STAT3 direct inhibitors consist of SH2 ligands, including G quartet oligodeoxynucleotides (ODN) and small molecules, they induce cell death in tumor cells in which STAT3 is activated. STAT3 can also be inhibited by decoy ODNs (dODN), which bind STAT3 and induce cell death. A specific STAT3 dODN which does not interfere with STAT1-mediated interferon-induced cell death has been designed pointing to the STAT3 DBD as a target for specific inhibition. Comprehensive analysis of this region is in progress in the laboratory to design DBD-targeting STAT3 inhibitors with STAT3/STAT1 discriminating ability. PMID- 24058790 TI - Circulating miRNAs as new activators of the JAK-STAT3 pathway. AB - Cell communication is well known to rely on direct contacts or on secreted factors that bind to receptors located on the surface of their target cells. In addition to this classical pathway, recent results have shown that cells produce microvesicles that contain functional DNA, RNA and proteins that can be directly transferred to recipient cells. This induces proliferation, differentiation or cell death to the same extent as classical soluble factors. New data obtained from the laboratory of Napoleone Ferrara show that these microvesicles also contain miRNAs that can induce angiogenic activities in neighboring endothelial cells. When secreted from cancer cells, these miRNA-loaded vesicles penetrate recipient cells where they activate the JAK-STAT pathway. This represents a new type of intercellular signaling and a new way of activating the STAT transcription factors that could be of interest for the design of cancer treatments. PMID- 24058789 TI - The role of JAK-STAT signaling within the CNS. AB - JAK-STAT is an efficient and highly regulated system mainly dedicated to the regulation of gene expression. Primarily identified as functioning in hematopoietic cells, its role has been found critical in all cell types, including neurons. This review will focus on JAK-STAT functions in the mature central nervous system. Our recent research suggests the intriguing possibility of a non-nuclear role of STAT3 during synaptic plasticity. Dysregulation of the JAK-STAT pathway in inflammation, cancer and neurodegenerative diseases positions it at the heart of most brain disorders, highlighting the importance to understand how it can influence the fate and functions of brain cells. PMID- 24058791 TI - STAT3 activation: A key factor in tumor immunoescape. AB - Cancer growth is controlled by cancer cells (cell intrinsic phenomenon), but also by the immune cells in the tumor microenvironment (cell extrinsic phenomenon). Thus cancer progression is mediated by the activation of transcription programs responsible for cancer cell proliferation, but also induced proliferation/activation of immunosuppressive cells such as Th17, Treg or myeloid derived suppressor cells (MDSCs). One of the key transcription factors involved in these pathways is the signal transducer and activator of transcription 3 (STAT3). In this review we will focus on STAT3 activation in immune cells, and how it impacts on tumor progression. PMID- 24058792 TI - TLR7 inhibition: A novel strategy for pancreatic cancer treatment? AB - PANCREATIC DUCTAL ADENOCARCINOMA IS ASSOCIATED WITH A POOR PROGNOSIS: For local disease, the 5-y survival rate is approximately 20% and median survival in locally advanced disease is only about 10 mo. Carcinogenesis is associated with chronic inflammation showing that innate immunity can be a double-edged sword. Here, we discuss recent findings of Ochi et al. in The Journal of Clinical Investigation who described a novel role for TLR7 in the development and progression of pancreatic cancer through interference with cell cycle regulation and by activation of multiple cell signaling pathways. Of note, inhibition of TLR7 signaling in a mouse p48Cre;Kras(G12D) pancreatic cancer model protected against tumor progression thus paving the road for TLR-blocking strategies to combat tumors. PMID- 24058793 TI - STAT heterodimers in immunity: A mixed message or a unique signal? AB - Cytokine signals are essential for generating a robust and specialized immune response. These signals are typically transmitted via canonical STAT homodimers. However, the number of STAT molecules utilized by cytokine signaling cascades within immune cells are limited, and so the mechanism used to deliver complex signals remains elusive. Heterodimerization of STAT proteins is one potential mechanism for signals to be modified downstream of the receptor and may play an important role in dictating the targets of specific cytokine signaling. In this review, we discuss our current understanding of the prevalence of STAT heterodimers, how they are formed and what their physiologic role may be in vivo. PMID- 24058794 TI - Interleukin-2 and STAT5 in regulatory T cell development and function. AB - Interleukin-2 and its downstream target STAT5 have effects on many aspects of immune function. This has been perhaps best documented in regulatory T cells. In this review we summarize the initial findings supporting a role for IL2 and STAT5 in regulatory T cell development and outline more recent studies describing how this critical signaling pathway entrains regulatory T cell differentiation and affects regulatory T cell function. PMID- 24058795 TI - Changing partners at the dance: Variations in STAT concentrations for shaping cytokine function and immune responses to viral infections. AB - Differential use of cellular and molecular components shapes immune responses, but understanding of how these are regulated to promote defense and health during infections is still incomplete. Examples include signaling from members of the Janus activated kinase-signal transducer and activator of transcription (JAK STAT) cytokine family. Following receptor stimulation, individual JAK-STAT cytokines have preferences for particular key STAT molecules to lead to specific cellular responses. Certain of these cytokines, however, can conditionally activate alternative STATs as well as elicit pleiotropic and paradoxical effects. Studies examining basal and infection conditions are revealing intrinsic and induced cellular differences in various intracellular STAT concentrations to control the biological consequences of cytokine exposure. The system can be likened to changing partners at a dance based on competition and relative availability, and sets a framework for understanding the particular conditions promoting subset biological functions of cytokines as needed during evolving immune responses to infections. PMID- 24058796 TI - Cytokine signaling in the differentiation of innate effector cells. AB - Innate effector cells, including innate effector cells of myeloid and lymphoid lineages, are crucial components of various types of immune responses. Bone marrow progenitors differentiate into many subsets of innate effector cells after receiving instructional signals often provided by cytokines. Signal transducer and activator of transcription (STATs) have been shown to be essential in the differentiation of various types of innate effector cells. In this review, we focus specifically on the differentiation of innate effector cells, particularly the role of cytokine signaling in the differentiation of innate effector cells. PMID- 24058797 TI - A rapid conformational rearrangement of STAT1 dimers is required for termination rather than for amplification of interferon-gamma signaling. AB - Sequence-specific binding of STAT1 (signal transducer and activator of transcription 1) transcription factor to palindromic promoter elements, termed gamma-activated sites (GAS), and an extended spatial reorientation between two dimer configurations are key events in the interferon signaling pathway. Although the DNA-binding domain of STAT1 is engaged in both processes, how the conformational change from a parallel to an antiparallel dimer configuration affects cytokine-induced target gene activation is unknown. In order to study the impact of the conformational shift on gene expression, we generated a STAT1 point mutant with a structurally altered architecture of the DNA-binding domain and characterized the resulting mutant (F364A) in cells stimulated with interferon gamma. Here, we report that substituting alanine for phenylalanine at position 364 resulted in reduced affinity to GAS sites and, additionally, a decreased dephosphorylation rate by the inactivating Tc45 phosphatase. The mutant had no defect in cooperative DNA binding and displayed normal kinetics of interferon gamma-induced nuclear accumulation, despite its elevated level of tyrosine phosphorylation. By assessing the transcriptional activity of the mutant, we found a strikingly robust expression of known interferon-gamma-driven target genes, indicating that an impaired stability of the antiparallel dimer configuration can compensate for a reduced affinity to GAS sites. However, the mutant followed changes in ligand-induced receptor activation more slowly than the wild-type molecule, as demonstrated by its elevated phospho-STAT1 concentration following addition of the kinase inhibitor staurosporine to interferon-pretreated cells. This finding showed that the DNA-binding mutant F364A had partially lost its ability to terminate signal transmission rapidly. Thus, the coupling of high-affinity GAS binding to a rapid exchange from a parallel to an antiparallel dimer conformation is not necessarily required for optimal signal amplification, but rather allows for a dynamic signal response and ensures high adaptability to changes in signal input. PMID- 24058798 TI - STAT2: A shape-shifting anti-viral super STAT. AB - STAT2 is unique among the STAT family of transcription factors in that its activation is driven predominantly by only two classes of cell surface receptors: Type I and III interferon receptors. As such, STAT2 plays a critical role in host defenses against viral infections. Viruses have evolved to target STAT2 by either inhibiting its expression, blocking its activity, or by targeting it for degradation. Consequently, these viral onslaughts have driven remarkable divergence in the STAT2 gene across species that is not observed in other STAT family members. Thus, the evolution of STAT2 may preserve its activity and protect each species in the face of an ever-changing viral community. PMID- 24058800 TI - Therapeutic targeting of STAT pathways in CNS autoimmune diseases. AB - Signal transducers and activators of transcription (STATs) transduce extracellular signals that regulate the initiation, duration and intensity of immune responses. However, unbridled activation of STATs by pro-inflammatory cytokines or growth factors contributes to pathogenic autoimmunity. In this review, we briefly discuss STAT pathways that promote the development and expansion of T cells that mediate two CNS inflammatory diseases, multiple sclerosis (MS) and uveitis. Particular focus is on animal models of MS and uveitis and new approaches to the treatment of CNS autoimmune diseases based on therapeutic targeting of Th17 cells and STAT pathways. PMID- 24058801 TI - STAT signaling in inflammation. PMID- 24058799 TI - The regulation of inflammation by interferons and their STATs. AB - Interferons (IFN) are subdivided into type I IFN (IFN-I, here synonymous with IFN alpha/beta), type II (IFN-gamma) and type III IFN (IFN-III/IFN-lambda) that reprogram nuclear gene expression through STATs 1 and 2 by forming STAT1 dimers (mainly IFN-gamma) or the ISGF3 complex, a STAT1-STAT2-IRF9 heterotrimer (IFN-I and IFN-III). Dominant IFN activities in the immune system are to protect cells from viral replication and to activate macrophages for enhanced effector function. However, the impact of IFN and their STATs on the immune system stretches far beyond these activities and includes the control of inflammation. The goal of this review is to give an overview of the different facets of the inflammatory process that show regulatory input by IFN/STAT. PMID- 24058803 TI - Why should we care about fly tumors?: The case of JAK-STAT and EGFR cooperation in oncogenesis. AB - Drosophila is proving to be a valuable model for studying aggressive tumors induced by the combined activation of EGFR and JAK-STAT signaling. Here we summarize some of the most recent data showing that tissue damage and the modulation of common pathway regulators are at the heart tumor progression and metastasis. PMID- 24058802 TI - Identification of STAT target genes in adipocytes. AB - Adipocytes play important roles in lipid storage, energy homeostasis and whole body insulin sensitivity. Studies in the last two decades have identified the hormones and cytokines that activate specific STATs in adipocytes in vitro and in vivo. Five of the seven STAT family members are expressed in adipocyte (STATs 1, 3, 5A, 5B and 6). Many transcription factors, including STATs, have been shown to play an important role in adipose tissue development and function. This review will summarize the importance of adipocytes, indicate the cytokines and hormones that utilize the JAK-STAT signaling pathway in fat cells and focus on the identification of STAT target genes in mature adipocytes. To date, specific target genes have been identified for STATs, 1, 5A and 5B, but not for STATs 3 and 6. PMID- 24058804 TI - Making milk: A new link between STAT5 and Akt1. AB - The transcription factor STAT5A is essential for two processes during mammary gland development. First, it controls the development of luminal progenitor cells from stem cells(1) and second, it has a role during pregnancy where it is required for alveologenesis(2) (,) (3) the production of clusters of luminal cells that synthesize and secrete milk during lactation. Thus, deletion of STAT5A in late pregnancy results in lactation failure. Alveologenesis requires the proliferation of a different lineage of luminal epithelial cells in response to the pregnancy hormones progesterone and prolactin, the latter of which activates STAT5. Prolactin is required additionally during lactation to ensure adequate milk production and the transcription of several milk protein genes has been shown to be regulated by STAT5.(4) (,) (5) On the other hand, the PI3K/Akt pathway is essential for the synthesis of other milk components such as lipids and lactose.(6) In recent elegant work from Lewis Chodosh's laboratory, published in Genes and Development, these two pathways are now shown to be directly linked.(7) More specifically, it is shown that the PI3K/Akt pathway induces autocrine prolactin production and that this is required for the initiation of lactation. PMID- 24058805 TI - JAK-STAT pathway and myogenic differentiation. AB - Myogenic differentiation plays an important role in muscle regeneration and is regulated by two transcription factor families, MRFs and MEF2, which induce differentiation of myoblasts through expression of the muscle-specific gene, myogenin. In addition, many intracellular signaling pathways are also involved in myogenic differentiation, including p38 MAPK, ERK/MAPK and PI3K/AKT. The JAK-STAT pathway is activated by various cytokines and positively or negatively regulates the differentiation of myoblasts. JAK1 plays a notable role in proliferation; whereas, JAK2 and JAK3 function mainly in differentiation. The STATs, molecules downstream of JAK, regulate myogenesis. With JAK1, STAT1 promotes proliferation, while STAT3 has a dual effect on proliferation and differentiation. The JAK-STAT negative regulator, SOCS, is also associated with myogenesis; although, its role is controversial. In this review, we will discuss the role of the JAK-STAT pathway on myogenic differentiation. PMID- 24058806 TI - The tumor suppressor function of STAT1 in breast cancer. AB - The anti-tumor function of STAT1 through its capacity to control the immune system and promote tumor immune surveillance has been well understood. However, little is known about cell autonomous (i.e., tumor cell-specific) functions of STAT1 in tumor formation. Recent studies have provided strong evidence that STAT1 suppresses mouse mammary gland tumorigenesis by both, immune regulatory and tumor cell-specific functions of STAT1. Specifically, STAT1 deficiency in the mouse mammary gland inhibits ErbB2/Neu-mediated tumorigenesis and contributes to spontaneous formation of estrogen receptor alpha (ER alpha)-positive as well as ER alpha-negative tumors closely resembling human disease. Herein, we review the anti-tumor functions of STAT1 revealed from investigations of murine breast cancer models and from characterization of the signaling properties of STAT1 in human breast tumor cells. The significance of STAT1 in breast cancer is underscored by studies proposing a prognostic value for the expression and/or phosphorylation of STAT1 for specific molecular types of breast cancer. Furthermore, STAT1 dependent transcription is proposed to contribute to therapeutic responses by modulating the efficacy of chemotherapeutic drugs and the development of drug resistance. PMID- 24058807 TI - STAT3 and the Hyper-IgE syndrome: Clinical presentation, genetic origin, pathogenesis, novel findings and remaining uncertainties. AB - During recent years a number of primary immunodeficiencies resulting from impaired function of JAK-STAT molecules have been described. One of these is the Hyper-IgE syndrome (HIES) characterized by elevated IgE levels, eczema, recurrent staphylococcal skin and pulmonary infections and pleiotropic somatic manifestations. In 2007 the genetic basis of HIES was revealed by identification of dominant negative STAT3 mutations in HIES patients. Subsequently impaired function of Tyk2 and DOCK8 have been implicated in milder forms of HIES. Since STAT3 acts as a central transcription factor downstream of multiple cytokine and growth factor receptors and thus regulates antimicrobial responses and cell survival, impaired STAT3 function results in immunodeficiency and in some cases tumorigenesis. However, as the immunological and molecular basis of HIES is being unraveled, important biological and immunological insight into JAK-STAT signaling is emerging that may have implications for our understanding of the pathogenesis and clinical management of patients with HIES. PMID- 24058808 TI - Regulation of STATs by polycystin-1 and their role in polycystic kidney disease. AB - Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disease caused by mutations in the gene coding for polycystin-1 (PC1). PC1 can regulate STAT transcription factors by a novel, dual mechanism. STAT3 and STAT6 are aberrantly activated in renal cysts. Genetic and pharmacological approaches to inhibit STAT3 or STAT6 have led to promising results in ADPKD mouse models. Here, we review current findings that lead to a model of PC1 as a key regulator of STAT signaling in renal tubule cells. We discuss how PC1 may orchestrate appropriate epithelial responses to renal injury, and how this system may lead to aberrant STAT activation in ADPKD thereby causing inappropriate activation of tissue repair programs that culminate in renal cyst growth and fibrosis. PMID- 24058810 TI - Mutual cytokine crosstalk between colon cancer cells and microenvironment initiates development of distant metastases. AB - Tumor growth and cancer development are considered clear examples of Darwinian selection, whereby random mutational events in heterogeneous cancer cell populations that best fit the selective microenvironment are preferred.(1) As a result, cancer cells evolve resistance to apoptosis, hide from immune surveillance and acquire the ability to invade other organs. Cancer cells, however, are not necessarily passive subjects of selection; they can actively subvert the host tissue to provide a favorable habitat for their growth. Recent findings by Calon et al. convincingly demonstrate that transforming growth factor beta-induced secretion of interleukin 11 by tumor stromal fibroblasts is a necessary prerequisite for the development of distant metastases in colorectal carcinoma. Thus, understanding the complex molecular feedback loops between cancer cells and the surrounding microenvironment (i.e., the tumor-associated stroma or invaded host tissue) should aid the identification of useful molecular targets for improving clinical management of advanced metastatic cancers. PMID- 24058809 TI - JAK-STAT and feeding. AB - The regulation of energy balance requires a complex system to homeostatically maintain the adult body at a precise set point. The central nervous system, particularly the hypothalamus, plays a key role in integrating a variety of signals that can relay information about the body's energy stores. As part of this system, numerous cytokines and hormones contribute to the regulation of food intake and energy homeostasis. Cytokines, and some hormones, are known to act through JAK-STAT intracellular signaling pathways. The hormone leptin, which plays a vital role in appetite regulation, signals through the JAK-STAT pathway, and it is through this involvement that the JAK-STAT pathway has become an established component in the mechanisms regulating food intake within the body. Emerging research, however, is now showing that this involvement of JAK-STAT is not limited to its activation by leptin. Furthermore, while the JAK-STAT pathway may simply act to transmit the anorectic signal of circulating factors, this intracellular signaling pathway may also become impaired when normal regulation of energy balance is disrupted. Thus, altered JAK-STAT signaling may contribute to the breakdown of the normal homeostatic mechanisms maintaining body weight in obesity. PMID- 24058811 TI - CCL2 at the crossroad of cancer metastasis. AB - Primary tumors can affect organ functions, either mechanically when they grow to a considerable size or via production of hormones. However, mortality of cancer patients is in most cases due to formation of secondary growths.(1) (,) (2) Consequently, various drugs are currently employed in clinical trials to impair specific steps of cancer metastasis such as mesenchymal or amoeboid cell migration, intravasation and/or colonization.(2) From the clinical point of view, targeting late metastatic processes such as extravasation or colonization might be required for cancer patients that bear already dormant micrometastases in their capillaries which have left behind earlier metastatic steps. Development of such drugs needs characterization of molecular targets implicated in distinct steps of cancer metastasis. PMID- 24058812 TI - Targeting the tumor microenvironment: JAK-STAT3 signaling. AB - Persistent JAK-STAT3 signaling is implicated in many aspects of tumorigenesis. Apart from its tumor-intrinsic effects, STAT3 also exerts tumor-extrinsic effects, supporting tumor survival and metastasis. These involve the regulation of paracrine cytokine signaling, alterations in metastatic sites rendering these permissive for the growth of cancer cells and subversion of host immune responses to create an immunosuppressive environment. Targeting this signaling pathway is considered a novel promising therapeutic approach, especially in the context of tumor immunity. In this article, we will review to what extent JAK-STAT3-targeted therapies affect the tumor microenvironment and whether the observed effects underlie responsiveness to therapy. PMID- 24058814 TI - Egr2 and Egr3 are the unique regulators for systemic autoimmunity. AB - Systemic autoimmunity is characterized by widespread inflammation, autoantibody production and immune complex deposition. The regulatory mechanisms for the systemic autoimmunity are not fully understood. A paper by Li et al. revealed that Egr2 and Egr3, transcription factors required for T-cell anergy, are the regulators for systemic autoimmune disease. They showed evidence that Egr2 and Egr3 control cytokine productions and cell proliferation via SOCS and Batf regulation. PMID- 24058813 TI - Mechanisms of chronic JAK-STAT3-SOCS3 signaling in obesity. AB - Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathways are critical for the maintenance of homeostatic and developmental processes; however, deregulation and chronic activation of JAK STAT3 results in numerous diseases. Among others, obesity is currently being intensively studied. In obesity, chronic JAK-STAT3 is activated by the CNS by increased circulating leptin levels leading to the development of leptin resistance, whereas in the peripheral organs chronic IL-6-induced JAK-STAT3 impairs insulin action. We report the consequences of chronic JAK-STAT3 induced signaling as present under obese conditions in the main metabolic organs. PMID- 24058816 TI - Introducing Worm: The journal. PMID- 24058815 TI - Anti-STAT6 CTL activity in Stat6 (-/-) mice: A cautionary tale. AB - The generation of germline gene mutations in mice has been an invaluable tool for experimental biology. However, studying immune responses that develop in the absence of a specific protein that could alter thymic selection complicates experimental interpretations. We observed that CD8(+) T cells from Stat6 (-/-) mice displayed "autoreactivity" to STAT6-expressing cells, associated with specific STAT6 peptides binding to MHC class I molecules. These results suggest caution in interpreting experiments where STAT6-expressing cells are transferred into Stat6 (-/-) mice, or where adoptive transfer of Stat6 (-/-) lymphocytes is performed. Our results further highlight additional considerations when studying immune responses involving cell transfer into gene-deficient mice. PMID- 24058817 TI - Reduced muscle contraction and a relaxed posture during sleep-like Lethargus. AB - Sleep is characterized by reduced muscle activity resulting in reduced movement and a typical posture compatible with relaxed muscles. Prior to each molt, C. elegans larvae go through a phase of behavioral quiescence called Lethargus. Lethargus has sleep-like properties, but a specific posture has not yet been described. Do C. elegans larvae relax their muscles during sleep and do they assume a typical posture? We measured worm posture and body wall muscle activity using calcium imaging across the sleep-wake-like cycle. We found that worms were less curved and had less muscle activity during the sleep-like state. We conclude that during Lethargus, muscle activity is reduced, resulting in a relaxed body posture typical for a sleep-like state. PMID- 24058818 TI - WormBase: Annotating many nematode genomes. AB - WormBase (www.wormbase.org) has been serving the scientific community for over 11 years as the central repository for genomic and genetic information for the soil nematode Caenorhabditis elegans. The resource has evolved from its beginnings as a database housing the genomic sequence and genetic and physical maps of a single species, and now represents the breadth and diversity of nematode research, currently serving genome sequence and annotation for around 20 nematodes. In this article, we focus on WormBase's role of genome sequence annotation, describing how we annotate and integrate data from a growing collection of nematode species and strains. We also review our approaches to sequence curation, and discuss the impact on annotation quality of large functional genomics projects such as modENCODE. PMID- 24058819 TI - New techniques and tools in 2011. PMID- 24058820 TI - A method for measuring fatty acid oxidation in C. elegans. AB - The nematode C. elegans has during the past decade proven to be a valuable model organism to identify and examine molecular mechanisms regulating lipid storage and metabolism. While the primary approach has been to identify genes and pathways conferring alterations in lipid accumulation, only a few recent studies have recognized the central role of fatty acid degradation in cellular lipid homeostasis. In the present study, we show how complete oxidation of fatty acids can be determined in live C. elegans by examining oxidation of tritium-labeled fatty acids to tritiated H2O that can be measured by scintillation counting. Treating animals with sodium azide, an inhibitor of the electron transport chain, reduced (3)H2O production to approximately 15%, while boiling of animals prior to assay completely blocked the production of labeled water. We demonstrate that worms fed different bacterial strains exhibit different fatty acid oxidation rates. We show that starvation results in increased fatty acid oxidation, which is independent of the transcription factor NHR-49. On the contrary, fatty acid oxidation is reduced to approximately 70% in animals lacking the worm homolog of the insulin receptor, DAF-2. Hence, the present methodology can be used to delineate the role of specific genes and pathways in the regulation of beta oxidation in C. elegans. PMID- 24058821 TI - Thermotaxis of C. elegans as a model for temperature perception, neural information processing and neural plasticity. AB - Thermotaxis is a model to elucidate how nervous systems sense and memorize environmental conditions to regulate behavioral strategies in Caenorhabditis elegans. The genetic and neural imaging analyses revealed molecular and cellular bases of this experience-dependent behavior. Surprisingly, thermosensory neurons themselves memorize the sensed temperatures. Recently developed techniques for optical manipulation of neuronal activity have facilitated the revelation that there is a sophisticated information flow between sensory neurons and interneurons. Further studies on thermotaxis will allow us to understand the fundamental logics of neural processing from sensory perceptions to behavioral outputs. PMID- 24058822 TI - Toward 959 nematode genomes. AB - The sequencing of the complete genome of the nematode Caenorhabditis elegans was a landmark achievement and ushered in a new era of whole-organism, systems analyses of the biology of this powerful model organism. The success of the C. elegans genome sequencing project also inspired communities working on other organisms to approach genome sequencing of their species. The phylum Nematoda is rich and diverse and of interest to a wide range of research fields from basic biology through ecology and parasitic disease. For all these communities, it is now clear that access to genome scale data will be key to advancing understanding, and in the case of parasites, developing new ways to control or cure diseases. The advent of second-generation sequencing technologies, improvements in computing algorithms and infrastructure and growth in bioinformatics and genomics literacy is making the addition of genome sequencing to the research goals of any nematode research program a less daunting prospect. To inspire, promote and coordinate genomic sequencing across the diversity of the phylum, we have launched a community wiki and the 959 Nematode Genomes initiative (www.nematodegenomes.org/). Just as the deciphering of the developmental lineage of the 959 cells of the adult hermaphrodite C. elegans was the gateway to broad advances in biomedical science, we hope that a nematode phylogeny with (at least) 959 sequenced species will underpin further advances in understanding the origins of parasitism, the dynamics of genomic change and the adaptations that have made Nematoda one of the most successful animal phyla. PMID- 24058823 TI - On the morphogenesis of glial compartments in the sensory organs of Caenorhabditis elegans. AB - Glial cells surround neuronal endings and isolate them within specialized compartments. This architecture is found at synapses in the central nervous system, as well as at receptive endings of sensory neurons. Recent studies are beginning to uncover the contributions of glial compartments to the functions of the ensheathed neurons. However, the cellular and molecular processes that guide compartment morphogenesis remain unknown. The main sensory organ of Caenorhabditis elegans, the amphid, provides an experimentally tractable setting in which to address the mechanisms underlying glial compartment formation. Amphid development is stereotyped and amphid structure is easily assayed. We recently uncovered a molecular tug of war that regulates the size of the amphid sensory compartment. The Nemo-like kinase LIT-1 interacts with the glial cytoskeleton to promote compartment growth, a process that also involves components of the retromer complex, while the Patched-related transmembrane protein DAF-6 keeps this expansion in check. Here we discuss how regulation of secretion by the cytoskeleton could guide the sculpting of glial compartments. PMID- 24058824 TI - The G protein regulator AGS-3 allows C. elegans to alter behaviors in response to food deprivation. AB - Behavioral responses to food deprivation are a fundamental aspect of nervous system function in all animals. In humans, these behavioral responses prevent dieting from being an effective remedy for obesity. Several signaling molecules in the mammalian brain act through G proteins of the Galphai/o family to mediate responses to food restriction. The mechanisms for neural response to food deprivation may be conserved across species, allowing the power of genetic model organisms to generate insights relevant to the problem of human obesity. In a recent study, we found that C. elegans uses Galphao signaling to mediate a number of behavioral changes that occur after food deprivation. Food deprivation causes biochemical changes in the G Protein Regulator (GPR) domain protein AGS-3 and AGS 3, together with the guanine nucleotide exchange factor RIC-8, activates Galphao signaling to alter food-seeking behavior. These proteins are all conserved in the human brain. Thus the study of behavioral responses to food deprivation in C. elegans may reveal the details of conserved molecular mechanisms underlying neural responses to food deprivation. PMID- 24058825 TI - How worms survive desiccation: Trehalose pro water. AB - While life requires water, many organisms, known as anhydrobiotes, can survive in the absence of water for extended periods of time. Although discovered 300 years ago, we know very little about the fascinating phenomenon of anhydrobiosis. In this paper, we summarize our previous findings on the desiccation tolerance of the Caenorhabditis elegans dauer larva. A special emphasis is given to the role of trehalose in protecting membranes against desiccation. We also propose a simple mechanism for this process. PMID- 24058826 TI - Quantitative proteomics by amino acid labeling identifies novel NHR-49 regulated proteins in C. elegans. AB - Stable isotope labeling by amino acids combined with mass spectrometry is a widely used methodology to quantitatively examine metabolic and signaling pathways in yeast, fruit flies, plants, cell cultures and mice. However, only metabolic labeling using (15)N has been applied to examine such events in the nematode Caenorhabditis elegans. We have recently shown that C. elegans can be completely labeled with heavy-labeled lysine by feeding worms on prelabeled lysine auxotroph Escherichia coli for just one generation. We applied this methodology to examine the organismal response to functional loss or RNAi mediated knock down of the transcription factor NHR-49, and found numerous proteins involved in lipid metabolism to be downregulated, which is consistent with its previously proposed function as a transcriptional regulator of fatty acid metabolism. The combined use of quantitative proteomics and selective gene knockdown by RNAi provides a powerful tool with broad implications for C. elegans biology. PMID- 24058827 TI - A cellular funicular: A hydrodynamic coupling between the anterior- and posterior directed cytoplasmic flows. AB - Organelles inside cells move to position themselves at the right place at the right time. A mechanism for generating active force exists for each of such directed organelle movements. In our recent study on cytoplasmic streaming in the Caenorhabditis elegans one-cell embryo, we demonstrated that an anterior-directed force generated by myosin could drive not only anterior-directed cortical flow but also posterior-directed cytoplasmic flow. This coupling of flows in opposing directions is mediated by the hydrodynamic properties of the cytoplasm. This work provided a good example of an active force generation mechanism that drives organelle movements in two opposite directions inside the cell, just as a funicular moves up and down a slope. Interestingly, the funicular-like coupling of intracellular movements is also seen in our recent studies on centrosome positioning in the C. elegans embryo and on interkinetic nuclear movement during mouse neurogenesis. Thus, funicular-like coupling may be a general strategy used repeatedly in cells. The use of the funicular-like coupling seems advantageous because it is efficient, as one active force generation mechanism can drive movements in two directions, and also because the two movements can be coordinated to have similar speeds. PMID- 24058828 TI - Epigenetic memory of longevity in Caenorhabditis elegans. AB - A recent study by Greer et al. in the nematode C. elegans has shown transgenerational epigenetic inheritance of longevity in the descendants of worms deficient for subunits of a complex responsible for histone H3 lysine 4 trimethylation (H3K4me3). In this commentary, we discuss the implications of this epigenetic memory of longevity and the potential mechanisms underlying this phenomenon. The transgenerational inheritance of longevity could result from heritable depletion of H3K4me3 at particular aging-regulating gene loci that would only be progressively replenished. The epigenetic memory of longevity could also be explained by the transgenerational transmission of other molecules, for example other proteins or non-coding RNAs. The discovery of an epigenetic memory of longevity in worms raises the intriguing possibility that environmental cues modulating longevity in ancestors might affect subsequent generations in a non Mendelian manner. Another remaining intriguing question is whether transgenerational inheritance of longevity also exists in other species, including mammals. PMID- 24058829 TI - Our evolving view of Wnt signaling in C. elegans: If two's company and three's a crowd, is four really necessary? AB - In this commentary, we discuss how our recent paper by Yang et al. contributes a new wrinkle to the already somewhat curious Wnt signaling pathway in C. elegans. We begin with a historical perspective on the Wnt pathway in the worm, followed by a summary of the key salient point from Yang et al., 2011, namely demonstration of mutually inhibitory binding of a beta-catenin SYS-1 to the N terminus and another beta-catenin WRM-1 to the C-terminus of the TCF protein POP 1, and a plausible structural explanation for these differential binding specificities. The mutually inhibitory binding creates one population of POP-1 that is bound by WRM-1, phosphorylated by the NLK kinase and exported from the nucleus, and another bound by coactivator SYS-1 that remains in the nucleus. We speculate on the evolutionary history of the four beta-catenins in C. elegans and suggest a possible link between multiple beta-catenin gene duplications and the requirement to reduce nuclear POP-1 levels to activate Wnt target genes. PMID- 24058830 TI - Body size change in various nematodes depending on bacterial food, sex and growth temperature. AB - We previously reported significant body size change in the nematode Caenorhabditis elegans, depending on the food strain of E. coli. Here, we examined this body size change in 11 other nematode species as well, and found that it is common to most of these nematodes. Furthermore, this food-dependent body size change is influenced by sex and growth temperature. PMID- 24058831 TI - Phenotypic plasticity in nematodes: Evolutionary and ecological significance. AB - Model systems, including C. elegans, have been successfully studied to understand the genetic control of development. A genotype's phenotype determines its evolutionary fitness in natural environments, which are typically harsh, heterogeneous and dynamic. Phenotypic plasticity, the process by which one genome can produce different phenotypes in response to the environment, allows genotypes to better match their phenotype to their environment. Phenotypic plasticity is rife among nematodes, seen both as differences among life-cycles stages, perhaps best exemplified by parasitic nematodes, as well as developmental choices, such as shown by the C. elegans dauer/non-dauer developmental choice. Understanding the genetic basis of phenotypically plastic traits will probably explain the function of many genes whose function still remains unclear. Understanding the adaptive benefits of phenotypically plastic traits requires that we understand how plasticity differs among genotypes, and the effects of this in diverse, different environments. PMID- 24058832 TI - Finding a niche for seam cells? AB - The C. elegans neuroectodermal seam cells provide a tractable and well established model for studying the stem cell mode of division, due to the reiterative asymmetric divisions occurring during larval development. They are, however, not generally considered to be 'true' stem cells, owing to their eventual terminal differentiation and the lack of a defined stem cell niche-a microenvironment that promotes the proliferation and prevents the differentiation of the stem cells that reside within. Here, we discuss the concept of the niche in relation to the seam, with reference to our recent findings suggesting that the stem-like properties of the seam cells are maintained at least in part through protection from differentiation signals emanating from the surrounding hypodermal syncytium. Determining the applicability of the niche concept will require definition of these signals and will have important implications for the status of seam cells in the context of stem cell biology. PMID- 24058833 TI - Nuclear positioning in the gonadal distal tip cells of C. elegans. AB - Morphogenesis of the hermaphrodite gonad of Caenorhabditis elegans is directed by the U-shaped migration of the gonadal leader cells, which are called distal tip cells (DTCs). The nuclei of migrating DTCs are always positioned at the leading edge of the cells, even as these cells turn dorsally to contact the hypodermis and intestine. When the DTCs turn dorsally, VAB-10B1/spectraplakin acts in nuclear translocation by regulating the polarized growth of microtubules. The function of spectraplakin in nuclear positioning may be evolutionarily conserved. Here we discuss the possible reason for leading-edge positioning of the DTC nucleus. PMID- 24058834 TI - Collaborative homologous pairing during C. elegans meiosis. AB - In preparation for meiotic chromosome segregation, homologous chromosomes need to pair, synapse (i.e., assemble the synaptonemal complex, SC), and then recombine to generate a physical linkage (i.e., chiasma) between them. In many organisms meiotic pairing capacity distributed along the entire chromosome length supports presynaptic alignment. In contrast, the prevailing model for C. elegans proposes that presynaptic homologous pairing is performed solely by a master pairing-site, the pairing center (PC). In this model, the remaining chromosomal regions (the non-PC regions) are not actively involved in presynaptic pairing, and the SC assembling from the PC aligns the homologous chromosomes along non-PC regions and holds them together. Our recent work, however, demonstrates that C. elegans chromosomes establish presynaptic alignment along the entire chromosome length, suggesting that the non-PC regions are also actively involved in the presynaptic pairing process. Furthermore, we have also discovered that the chromodomain protein MRG-1 facilitates this presynaptic non-PC pairing. The phenotype of the mrg-1 mutant indicates that the PC and the non-PC collaborate in successful pairing and synapsis. Therefore, homologous pairing mechanisms in C. elegans possibly share more similarity with those in other organisms than previously thought. Here, we elaborate on these observations and discuss a hypothetical model for presynaptic pairing in C. elegans based on our novel findings. PMID- 24058835 TI - Planar polarity genes and inhibition of supernumerary neurites. AB - Planar cell polarity (PCP) genes have recently emerged as important players in sculpting neuronal connections. The bipolar VC neurons display stereotypical differences in axon extension along the anterior-posterior (AP) body axis: VC1-3 and VC6 polarize along the AP axis while VC4 and VC5 polarize along the orthogonal left-right (LR) axis generated by the developing vulva. vang-1 and prkl-1, the worm orthologs of Van Gogh and Prickle, are required to restrict the polarity of neurite emergence to a specific tissue axis. vang-1 and prkl-1 loss results in ectopic VC4 and VC5 neurites extending inappropriately along the AP axis. Conversely, prkl-1 overexpression in VC neurons suppresses neurite formation. These findings suggest that a PCP-like pathway acts to silence or antagonize neuronal responses to polarity cues that would otherwise be permissive for neurite growth. PMID- 24058836 TI - A connectivity model for the locomotor network of Caenorhabditis elegans. AB - Recently, we described a new method for representing and analyzing the connectivity of a motoneuronal network. We used it to deduce a connectivity model for the neuromuscular network that generates locomotion in the nematode Caenorhabditis elegans. The network regulates muscle contraction and for this reason we used the location or function of body wall muscles to map every element (neuron or muscle cell) in a new framework, namely the peri-motor space. The previously published connectivity data for C. elegans locomotion network are incomplete; in particular, the connectivity of motoneurons in the posterior half of the animal is missing or partial. When we analyzed the connectivity data for motoneurons in the anterior half, we detected repeating patterns which we named iterativity. We analyzed the iterativity of each class of motoneuron and statistically validated that it is higher than expected by chance. We could then extrapolate the iteration into the posterior half. Here we will explain the new terms and elaborate on the process of analysis and the features of the new connectivity model. PMID- 24058837 TI - Endogenous RNAi and adaptation to environment in C. elegans. AB - The contributions of short RNAs to the control of repetitive elements are well documented in animals and plants. Here, the role of endogenous RNAi and AF10 homolog ZFP-1 in the adaptation of C. elegans to the environment is discussed. First, modulation of insulin signaling through regulation of transcription of the PDK-1 kinase (Mansisidor et al., PLoS Genetics, 2011) is reviewed. Second, an siRNA-based natural selection model is proposed in which variation in endogenous siRNA pools between individuals is subject to natural selection similarly to DNA based genetic variation. The value of C. elegans for the research of siRNA-based epigenetic variation and adaptation is highlighted. PMID- 24058839 TI - In this Issue of Worm. PMID- 24058838 TI - The wounded worm: Using C. elegans to understand the molecular basis of skin wound healing. AB - The ability to heal wounds is an ancient and conserved function of epidermal epithelial layers. The importance of skin wound healing to human life and biology has long been evident, however many of the molecular mechanisms underlying wound repair remain little understood. In the past several years, analysis of the C. elegans innate immune response to fungal infection of the epidermis has led to investigations of the ability of the C. elegans skin to respond to damage. In a recent paper we used live imaging to investigate the cell biological basis of wound repair in the adult C. elegans epidermis. We found that needle or laser injury of the skin triggers a large and sustained increase in epidermal calcium. Epidermal calcium signals appear to specifically promote actin-dependent processes of wound closure. The innate immune and wound closure responses act in parallel to promote survival after injury. Our findings indicate that wounding triggers multiple signals in the C. elegans skin. C. elegans offers a tractable model to dissect how epidermal epithelia activate coordinated responses to repair damage. PMID- 24058840 TI - A seminal fluid protease activates sperm motility in C. elegans males. AB - Seminal fluid factors have been shown to play a significant role in fertility in many animals. However, little is known about the contributions of seminal fluid to male fertility in C. elegans. In this commentary, we summarize our recent finding of a seminal fluid sperm activator, the serine protease TRY-5. TRY-5 is required for males to activate sperm, yet surprisingly it is not required for male fertility, likely due to redundancy with an activator present in hermaphrodites. TRY-5 is transferred to hermaphrodites during mating in a series of distinct release events just prior to transfer of sperm. Thus, we propose a model in which TRY-5 cleaves sperm cell surface proteins to trigger sperm maturation. We discuss other possible roles for seminal fluid factors in C. elegans and prospects for using TRY-5 as a marker for studies of male mating behavior and seminal fluid secretion. PMID- 24058841 TI - Regulation of tubulin glutamylation plays cell-specific roles in the function and stability of sensory cilia. AB - Microtubules (MTs) are post-translationally modified, but the functions of post translational modifications (PTMs) have in many cases remained unknown. Most PTMs, such as polyglutamylation, occur on the protruding C-terminal tail (CTT) of tubulins, are reversible, and have been proposed to play a role in regulation of MT-associated proteins (MAPs), molecular motors, and MT-severing proteins. Several PTM enzymes have been identified, including a carboxypeptidase in mice known as CCP1, which reduces polyglutamylation on the CTT of MTs, and causes cell specific neurodegeneration when mutated. PMID- 24058842 TI - Speculations on the activation of ROS generation in C. elegans innate immune signaling. AB - We recently published work demonstrating that ROS (reactive oxygen species) generated by the dual oxidase, Ce-Duox1/BLI-3, in response to infection in Caenorhabditis elegans activates the transcription factor SKN-1, initiating a protective response. Moreover, we showed that the crucial innate immune pathway, p38 MAPK signaling, was responsible for relaying the activating signal. In this commentary, we speculate on the signaling pathway upstream of Ce-Duox1/BLI-3 that triggers its activity. Specifically, we hypothesize that a G-protein signaling pathway comprising Galphaq - PLCbeta - TPA-1 - DKF-2 activates Ce-Duox1/BLI-3. Our rationale is based on work showing that these components are connected to p38 MAPK signaling and innate immunity in the worm, and investigations in other organisms demonstrating that some of these components are involved in dual oxidase activation. PMID- 24058843 TI - The transcription factor VAB-23 links vulval cell fate specification and morphogenesis. AB - During organogenesis, individual cells must commit to and execute specific cell fates. However, the molecular mechanisms linking cell fate specification to fate execution and morphogenesis remain a largely unexplored area in developmental biology. The Caenorhabditis elegans vulva is an excellent model to dissect the molecular pathways linking cell fate specification and execution during organogenesis. We have recently identified a conserved nuclear zinc finger transcription factor called VAB-23 that plays essential roles during vulval torid formation in the larva and ventral epidermal closure in the embryo. VAB-23 regulates the transcription of specific target genes including smp-1 Semaphorin. EGFR/RAS/MAPK signaling upregulates via the HOX protein LIN-39 the expression of VAB-23 in the 1 degrees vulval cell lineage, indicating that cell fate specification and execution are temporally overlapping and tightly linked processes. Here, we discuss the roles of VAB-23 in morphogenesis and the implications of its regulation on the spatio-temporal control of organogenesis. PMID- 24058844 TI - Necrotic cell death and neurodegeneration: The involvement of endocytosis and intracellular trafficking. AB - Necrosis, one of the two main types of cell death, contributes critically in many devastating pathological conditions in human, including stroke, ischemia, trauma and neurodegenerative diseases. However, unlike apoptosis, the molecular mechanisms underlying necrotic cell death and neurodegeneration are poorly understood. Caenorhabditis elegans offers a powerful platform for a thorough and systematic dissection of the molecular basis of necrotic cell death. Similarly to humans, neuronal necrosis can be induced by several well-characterized genetic lesions and by adverse environmental conditions in the nematode. The availability of precisely-defined C. elegans neurodegeneration models provides a unique opportunity for comprehensive delineation of the cellular and molecular mechanisms mediating necrotic cell death. Through genetic dissection of such models, we recently uncovered an unexpected requirement for specific proteins involved in endocytosis and intracellular trafficking, in the execution of necrosis. Moreover, initiation of necrotic cell death is accompanied by a sharp increase in the formation of early and recycling endosomes, which subsequently disintegrate during the final stage of cell death. These findings implicate endocytic and intracellular trafficking processes in the cellular destruction during necrosis. Indeed, endocytosis synergizes with two other essential cellular processes, autophagy and lysosomal proteolysis to facilitate necrotic neurodegeneration. In this commentary, we consider the contribution of endocytosis and intracellular trafficking to cell injury and discuss the crosstalk between these processes and other molecular mechanisms that mediate necrosis. PMID- 24058845 TI - Should I stay or should I go? AB - Most animals inhabit environments in which resources are heterogeneous and distributed in patches. A fundamental question in behavioral ecology is how an animal feeding on a particular food patch, and hence depleting it, decides when it is optimal to leave the patch in search of a richer one. Optimal foraging has been extensively studied and modeled in animals not amenable to molecular and neuronal manipulation. Recently, however, we and others have begun to elucidate at a mechanistic level how food patch leaving decisions are made. We found that C. elegans leaves food with increasing probability as food patches become depleted. Therefore, despite its artificial laboratory environment, its behavior conforms to the optimal foraging theory, which allowed us to genetically dissect the behavior. Here we expand our discussion on some of these findings, in particular how metabolism, oxygen and carbon dioxide regulate C. elegans food leaving behavior. PMID- 24058846 TI - In this issue of Worm. PMID- 24058847 TI - Reproductive isolation in Caenorhabditis briggsae: Dysgenic interactions between maternal- and zygotic-effect loci result in a delayed development phenotype. AB - In sexual species, speciation occurs through the accumulation of genetic barriers to gene flow. In Caenorhabditis briggsae, one such barrier impedes gene flow between temperate strains and the tropical AF16 strain. Up to 20% of F2 progeny derived from crosses of AF16 to strains from the temperate clade exhibit a delayed development phenotype. This phenotype, which results from dysgenic interactions between maternal- and zygyotic-effect loci, causes a ~21% decrease in the intrinsic growth rate. The maternal-effect requires contributions from both parental genotypes. The dysgenic maternal-effect allele appears to be fixed in the temperate clade of C. briggsae and appears to have arisen between 700 and 15,000 y ago. The dysgenic zygotic allele appears to be present only in AF16 and also may be of recent origin. PMID- 24058848 TI - G-proteins: Fighting infection on two fronts. AB - Animals have evolved multiple strategies for coping with the presence of pathogenic microbes. The best characterized is the immune response where animals activate their physical and cellular defenses to respond to invading microorganisms. However, behavioral changes can also be triggered by exposure to microbes and play an important role in defending many species, including humans, from pathogen attack. In our recent study we demonstrate that, following infection, C. elegans uses the same G-protein signaling pathway in neurons and epithelial cells to coordinate avoidance behaviors and immune responses. Coordination of these responses allows animals to mount an immune response to the immediate threat while simultaneously taking action to remove the pathogen, however, the complicated nature of the mammalian brain and immune system has made it difficult to identify the molecular mechanisms mediating these interactions. With its simple, well described, nervous system and a rapidly growing understanding of its immune system, C. elegans has emerged as an excellent model to study the mechanisms by which animals recognize pathogens and coordinate behavioral and immune responses to infection. PMID- 24058849 TI - The interaction of octopamine and neuropeptides to slow aversive responses in C. elegans mimics the modulation of chronic pain in mammals. AB - Octopamine (OA) appears to function as the invertebrate counterpart of norepinephrine (NE) in the modulation of a number of key behaviors. In C. elegans, OA signaling is complex, mediated by at least three distinct alpha adrenergic-like receptors and appears to activate more global peptidergic signaling cascades that have the potential to dramatically amplify the octopaminergic signal. These OA-dependent peptidergic signaling cascades involve an array of neuropeptides that activate receptors throughout the nervous system and have the potential to both directly and indirectly modulate locomotory decision-making. In this commentary we highlight the use of C. elegans as a model to expand our understanding of noradrenergic signaling in mammals, specifically as it relates to the role of NE in anti-nociception. PMID- 24058850 TI - Preparing a discreet escape: Microsporidia reorganize host cytoskeleton prior to non-lytic exit from C. elegans intestinal cells. AB - Intracellular pathogens commonly invade and replicate inside of intestinal cells and exit from these cells is a crucial step in pathogen transmission. For convenience, studies of intracellular pathogens are often conducted using in vitro cell culture systems, which unfortunately lack important features of polarized, intact intestinal epithelial cells. The nematode C. elegans provides a tractable system to study intracellular pathogens in vivo, where features of differentiated epithelial cells are easily visualized. In a recent paper, we used C. elegans as a host organism to study the exit strategy of Nematocida parisii, a naturally occurring intracellular pathogen in the microsporidia phylum. We showed that N. parisii remodels the C. elegans host cytoskeleton, and then exits host cells in an actin-dependent, non-lytic fashion. These findings illuminate key details about the transmission of microsporidia, which are poorly understood but ubiquitous pathogens. More generally, these findings have implications for exit strategies used by other intracellular pathogens that also infect epithelial cells. PMID- 24058851 TI - Try to disarm the intruder or kill him! AB - RNA interference and transgene-mediated cosuppression are trans-generational silencing mechanisms acting both at a post-transcriptional and epigenetic level. We have recently shown that both these procedures, which share several common factors and are commonly used to phenocopy gene deletions, also induce germ-line DNA damage and apoptosis. These observations shed new light on the cross-talk between different pathways devoted to the protection of genome stability in germ cells. PMID- 24058852 TI - Autophagy in endosomal mutants: Desperately seeking to survive. AB - The endosomal and autophagic pathways are essential for the degradation and renewal of cellular components. After a complex maturation process, both pathways converge to their final destination, the lysosome. A close link between these two pathways was described along the last decade, notably through the analysis of ESCRT mutants. Although in mammals ESCRT mutants are unable to complete autophagic maturation due to the lack of fusion with the endolysosomal system, the role of ESCRT in the autophagic process still remains an open issue. Using C. elegans, we recently showed that blockage of the endosomal maturation triggers the induction of autophagic activity in ESCRT mutant.(1) This increase of autophagic flux is an attempt to correct cellular defects and promote the survival of mutant animals. PMID- 24058854 TI - C. elegans survivors without telomerase. AB - In most eukaryotic organisms with a linear genome, the telomerase complex is essential for telomere maintenance and, thus, for genomic integrity. Proper telomerase function in stem and germ cell populations counteracts replication dependent telomere shortening. On the other hand, repression of telomerase expression in most somatic tissues limits the proliferative potential of these cells through the induction of a permanent cell cycle arrest termed senescence upon critical telomere erosion. Thus, senescence, induced by telomere shortening and subsequent DNA damage signaling, is an essential tumor suppressive mechanism, emphasized by the fact that repression of telomerase is lost in about 90% of cancers, endowing them with unlimited proliferative potential. In 10% of cancers telomeres are maintained using the recombination-based alternative mechanism of telomere lengthening (ALT). To date, ALT and ALT-like mechanisms have only been described in the context of individual cells such as cancer cells and yeast. Now, several "survivor" strains of the nematode Caenorhabditis elegans have been generated that can propagate despite mutations of the telomerase gene. These nematode strains represent the first multi-cellular organism with canonical telomerase that can survive in the absence of a functional telomerase pathway. PMID- 24058853 TI - Toward a unified model of developmental timing: A "molting" approach. AB - Animal development requires temporal coordination between recurrent processes and sequential events, but the underlying timing mechanisms are not yet understood. The molting cycle of C. elegans provides an ideal system to study this basic problem. We recently characterized LIN-42, which is related to the circadian clock protein PERIOD, as a key component of the developmental timer underlying rhythmic molting cycles. In this context, LIN-42 coordinates epithelial stem cell dynamics with progression of the molting cycle. Repeated actions of LIN-42 may enable the reprogramming of seam cell temporal fates, while stage-specific actions of LIN-42 and other heterochronic genes select fates appropriate for upcoming, rather than passing, life stages. Here, we discuss the possible configuration of the molting timer, which may include interconnected positive and negative regulatory loops among lin-42, conserved nuclear hormone receptors such as NHR-23 and -25, and the let-7 family of microRNAs. Physiological and environmental conditions may modulate the activities of particular components of this molting timer. Finding that LIN-42 regulates both a sleep-like behavioral state and epidermal stem cell dynamics further supports the model of functional conservation between LIN-42 and mammalian PERIOD proteins. The molting timer may therefore represent a primitive form of a central biological clock and provide a general paradigm for the integration of rhythmic and developmental processes. PMID- 24058855 TI - The evolutionary role of males in C. elegans. AB - Although the nematode worm Caenorhabditis elegans reproduces primarily as a self fertilizing hermaphrodite, males are maintained in natural populations at low frequency. In this commentary, I discuss the evolutionary forces that maintain males and the role males might play in this mating system. PMID- 24058856 TI - The impact of mitochondrial oxidative stress on bile acid-like molecules in C. elegans provides a new perspective on human metabolic diseases. AB - C. elegans is a model used to study cholesterol metabolism and the functions of its metabolites. Several studies have reported that, in worms, cholesterol is not a structural component of the membrane as it is in vertebrates. However, as in other animals, it is used for the synthesis of steroid hormones that regulate physiological processes such as dauer formation, molting and defecation. After cholesterol is taken up by the gut, mechanisms of transport of cholesterol between tissues in C. elegans involve lipoproteins, as in mammals. A recent study shows that both cholesterol uptake and lipoprotein metabolism in C. elegans are regulated by molecules whose activities, biosynthesis, and secretion strongly resemble those of mammalian bile acids, which are metabolites of cholesterol that act on metabolism in a variety of ways. Importantly, it was found that oxidative stress upsets the regulation of the synthesis of these molecules. Given the known function of mammalian bile acids as metabolic regulators of lipid and glucose homeostasis, future investigations of the biology of C. elegans bile acid-like molecules could provide information on the etiology of human metabolic disorders that are characterized by elevated oxidative stress. PMID- 24058857 TI - Managing intracellular transport. AB - Formation and normal function of neuronal synapses are intimately dependent on the delivery to and removal of biological materials from synapses by the intracellular transport machinery. Indeed, defects in intracellular transport contribute to the development and aggravation of neurodegenerative disorders. Despite its importance, regulatory mechanisms underlying this machinery remain poorly defined. We recently uncovered a phosphorylation-regulated mechanism that controls FEZ1-mediated Kinesin-1-based delivery of Stx1 into neuronal axons. Using C. elegans as a model organism to investigate transport defects, we show that FEZ1 mutations resulted in abnormal Stx1 aggregation in neuronal cell bodies and axons. This phenomenon closely resembles transport defects observed in neurodegenerative disorders. Importantly, diminished transport due to mutations of FEZ1 and Kinesin-1 were concomitant with increased accumulation of autophagosomes. Here, we discuss the significance of our findings in a broader context in relation to regulation of Kinesin-mediated transport and neurodegenerative disorders. PMID- 24058858 TI - The pharynx of the nematode C. elegans: A model system for the study of motor control. AB - Motor control is a complex process that requires interplay among the nervous system, muscles and environment. The simple anatomy, well-characterized muscle movements and ample resources for molecular and cellular dissection make the pharynx of the nematode C. elegans an attractive model system for the study of motor control. The C. elegans pharynx shows two clear muscle movements that are essential for food intake, pharyngeal pumping and isthmus peristalsis. Here, we review our recent findings on the mechanism by which food activates the feeding motions. To understand this process, we characterized the behavior of the feeding motions in response to serotonin, an endogenous pharyngeal pumping activator whose action is triggered by food. We found that: (1) the timing of onset and frequencies of the two feeding motions are distinct; (2) isthmus peristalsis is selectively coupled to the preceding pump; (3) like food, serotonin activates isthmus peristalsis as well as pharyngeal pumping. By genetic analysis, we showed that two separate neural pathways activate the two feeding motions explaining the differences between the two feeding motions. We also proposed a model that explains how the two feeding motions are separately controlled, yet coupled by the interaction between the nervous system and the muscles in the pharynx. Finally, we briefly discuss future approaches to further understand the mechanism that couples the two feeding motions in C. elegans and to possibly understand evolution of motor control in the pharynx by expanding findings in C. elegans to other nematode species. PMID- 24058859 TI - PAR-5 is a PARty hub in the germline: Multitask proteins in development and disease. AB - As our understanding of how molecular machineries work expands, an increasing number of proteins that appear as regulators of different processes have been identified. These proteins are hubs within and among functional networks. The 14 3-3 protein family is involved in multiple cellular pathways and, therefore, influences signaling in several disease processes, from neurobiological disorders to cancer. As a consequence, 14-3-3 proteins are currently being investigated as therapeutic targets. Moreover, 14-3-3 protein levels have been associated with resistance to chemotherapies. There are seven 14-3-3 genes in humans, while Caenorhabditis elegans only possesses two, namely par-5 and ftt-2. Among the C. elegans scientific community, par-5 is mainly recognized as one of the par genes that is essential for the asymmetric first cell division in the embryo. However, a recent study from our laboratory describes roles of par-5 in germ cell proliferation and in the cellular response to DNA damage induced by genotoxic agents. In this review, we explore the broad functionality of 14-3-3 proteins in C. elegans and comment on the potential use of worms for launching a drugs/modifiers discovery platform for the therapeutic regulation of 14-3-3 function in cancer. PMID- 24058860 TI - MicroRNAs that interfere with RNAi. AB - A recent study by Massirer et al. in the nematode C. elegans has shown that a family of microRNAs (miRNAs), miR-35-41, regulates the efficiency of RNA interference (RNAi), revealing a new connection between these small RNA pathways. In this commentary, we discuss the potential mechanisms for cross regulation in the miRNA and RNAi pathways and the implications for gene expression. While miRNAs are genetically encoded, the small interfering RNAs (siRNAs) that function in RNAi can originate from processing of exogenous dsRNA (exo-RNAi) or from the production of siRNAs from endogenous transcripts (endo-RNAi). These small RNA pathways involve Dicer and Argonaute proteins and typically use antisense base pairing to target mRNAs for downregulated expression. The discovery that loss of miR-35-41 results in enhanced exo-RNAi sensitivity and reduced endo-RNAi effectiveness suggests that these miRNAs normally help balance the RNAi pathways. The effect of mir-35-41 on RNAi is largely through lin-35, the C. elegans homolog of the tumor suppressor Retinoblastoma (Rb) gene. lin-35/Rb previously has been shown to regulate RNAi sensitivity through unclear mechanisms and the new finding that accumulation of LIN-35/Rb protein is dependent on miR-35-41 adds another layer of complexity to this process. The utilization of miRNAs to control the responsiveness of RNAi exemplifies the cross-regulation embedded in small RNA directed pathways. PMID- 24058861 TI - Meta-Boolean models of asymmetric division patterns in the C. elegans intestinal lineage: Implications for the posterior boundary of intestinal twist. AB - The intestine of Caenorhabditis elegans is derived from 20 cells that are organized into nine intestinal rings. During embryogenesis, three of the rings rotate approximately 90 degrees in a process known as intestinal twist. The underlying mechanisms for this morphological event are not fully known, but it has been demonstrated that both left-right and anterior-posterior asymmetry is required for intestinal twist to occur. We have recently presented a rule-based meta-Boolean tree model intended to describe complex lineages. In this report we apply this model to the E lineage of C. elegans, specifically targeting the asymmetric anterior-posterior division patterns within the lineage. The resulting model indicates that cells with the same factor concentration are located next to each other in the intestine regardless of lineage origin. In addition, the shift in factor concentrations coincides with the boundary for intestinal twist. When modeling lit-1 mutant data according to the same principle, the factor distributions in each cell are altered, yet the concurrence between the shift in concentration and intestinal twist remains. This pattern suggests that intestinal twist is controlled by a threshold mechanism. In the current paper we present the factor concentrations for all possible combinations of symmetric and asymmetric divisions in the E lineage and relate these to the potential threshold by studying existing data for wild-type and mutant embryos. Finally, we discuss how the resulting models can serve as a basis for experimental design in order to reveal the underlying mechanisms of intestinal twist. PMID- 24058862 TI - Vesicular sorting controls the polarity of expanding membranes in the C. elegans intestine. AB - Biological tubes consist of polarized epithelial cells with apical membranes building the central lumen and basolateral membranes contacting adjacent cells or the extracellular matrix. Cellular polarity requires distinct inputs from outside the cell, e.g., the matrix, inside the cell, e.g., vesicular trafficking and the plasma membrane and its junctions.(1) Many highly conserved polarity cues have been identified, but their integration during the complex process of polarized tissue and organ morphogenesis is not well understood. It is assumed that plasma membrane-associated polarity determinants, such as the partitioning-defective (PAR) complex, define plasma membrane domain identities, whereas vesicular trafficking delivers membrane components to these domains, but lacks the ability to define them. In vitro studies on lumenal membrane biogenesis in mammalian cell lines now indicate that trafficking could contribute to defining membrane domains by targeting the polarity determinants, e.g., the PARs, themselves.(2) This possibility suggests a mechanism for PARs' asymmetric distribution on membranes and places vesicle-associated polarity cues upstream of membrane-associated polarity determinants. In such an upstream position, trafficking might even direct multiple membrane components, not only polarity determinants, an original concept of polarized plasma membrane biogenesis(3) (,) (4)that was largely abandoned due to the failure to identify a molecularly defined intrinsic vesicular sorting mechanism. Our two recent studies on C. elegans intestinal tubulogenesis reveal that glycosphingolipids (GSLs) and the well-recognized vesicle components clathrin and its AP-1 adaptor are required for targeting multiple apical molecules, including polarity regulators, to the expanding apical/lumenal membrane.(5) (,) (6) These findings support GSLs' long-proposed role in in vivo polarized epithelial membrane biogenesis and development and identify a novel function in apical polarity for classical post-Golgi vesicle components. They are also compatible with a vesicle-intrinsic sorting mechanism during membrane biogenesis and suggest a model for how vesicles could acquire apical directionality during the assembly of the functionally critical polarized lumenal surfaces of epithelial tubes. PMID- 24058863 TI - Effects of mutations in mitochondrial dynamics-related genes on the mitochondrial response to ultraviolet C radiation in developing Caenorhabditis elegans. AB - We recently found that genes involved in mitochondrial dynamics and autophagy are required for removal of UVC-induced mitochondrial DNA damage. However, drp-1 and pink-1, unlike the autophagy and fusion genes tested, were not necessary for larval development after exposure. We hypothesized that increased fusion resulting from mutations in these genes facilitated recovery of mitochondrial function. In this work, we investigated this hypothesis by studying the effects of fis-1, fis-2, drp-1 and pink-1 mutations on mitochondrial responses to UVC exposure including ATP levels, mitochondrial DNA copy number, larval development and mitochondrial morphology. Our results suggest that mutations that promote highly networked mitochondria have the capacity to lessen the effects of mitochondrial genotoxicants on the function of this organelle. PMID- 24058865 TI - In this issue of Worm. PMID- 24058864 TI - Depletion of the ER chaperone ENPL-1 sensitizes C. elegans to the anticancer drug cisplatin. AB - Cisplatin is an essential chemotherapeutic drug in the treatment of many cancers. Its use, however, is limited by the development of resistance in many tumors. The ability to re-sensitize resistant tumors could significantly strengthen cisplatin therapy in patients. Caenorhabditis elegans is a suitable model for studying the cytoplasmic role of cisplatin in tumor cells. We have previously shown that the ATPase ASNA-1 has similar roles as a factor governing cisplatin sensitivity in mammalian tumor cells and C. elegans. Here we study the endoplasmic reticulum (ER) resident chaperone ENPL-1/GRP94 and find that its depletion makes worms sensitive to cisplatin. Elevated ER stress levels in enpl-1 mutants is the likely cause of this sensitivity because a correlation can be made between cisplatin sensitivity and the high ER stress levels. We also find that asna-1 mutants have elevated unfolded protein response (UPR) activity and that the intrinsically cisplatin resistant wild-type worms become sensitive when ER stress is high. We conclude that enpl-1 is a cisplatin sensitizing factor and suggest that manipulation of its levels or of UPR activity will enhance the effects of cisplatin based cancer therapy. PMID- 24058866 TI - Catalytic-independent roles of UTX-1 in C. elegans development. AB - We recently analyzed the functional roles of UTX-1 during development. utx-1 is an essential gene required for the correct embryonic and post-embryonic development of C. elegans, and it displays an H3K27me3 demethylase activity. Rescue experiments demonstrated that the enzymatic activity of UTX-1 is not relevant for its role in development. The phenotypes associated with loss of UTX 1 might, instead, be a result of compromised functions of an UTX-1-containing complex. Here we discuss the possible mechanisms by which UTX-1 contributes to normal development. PMID- 24058867 TI - Neuronal repair: Apoptotic proteins make good. AB - The potential of the central nervous system (CNS) to regenerate is regulated by a complex interaction of neuronal intrinsic and extrinsic factors that remain poorly understood. Significant research has been dedicated to identifying these factors to facilitate design of therapies that will treat the functional impairment associated with CNS injuries. Over the last decade, the development of in vivo laser severing of single axons in C. elegans has established an invaluable model for the genetic identification of novel regeneration factors. In a recent study we report the unexpected identification of the core apoptotic proteins CED-4/Apaf-1 and the executioner caspase CED-3 as important factors that promote early events in regeneration in C. elegans. Other upstream regulators of apoptosis do not influence regeneration, indicating the existence of a novel mechanism for activation of CED-4 and CED-3 in neuronal repair. CED-4 and CED-3 function downstream of injury-induced calcium transients and appear to act through the conserved DLK-1 pathway to promote regeneration. We propose a working model for calcium-dependent localized activation of CED-4 and CED-3 caspase and discuss questions raised including mechanisms for spatially regulating activated CED-3 and the possible substrates that it might cleave to initiate regeneration. PMID- 24058868 TI - Everything in moderation: Proteolytic regulation of centrosome duplication. AB - The presence of too many or too few centrosomes at mitosis can disrupt the timely formation of a bipolar spindle and may lead to aneuploidy and cancer. Strict control of centrosome duplication is therefore crucial. Centrosome duplication must occur once per cell cycle and the number of new centrioles made must be tightly controlled. The importance of protein degradation for the orderly progression of the cell cycle has long been recognized, but until recently the role of proteolysis in the regulation of centrosome duplication had not been appreciated. Recent evidence suggests that restricting protein levels so that a single new centriole is built next to each pre-existing centriole is one way in which centrosome duplication is controlled. Here we discuss our recent finding that the SCF ubiquitin ligase complex regulates centrosome duplication in C. elegans in the larger context of the proteolytic regulation of centrosome duplication. PMID- 24058869 TI - Entwined engrams: The evolution of associative and non-associative learning. AB - The nematode Caenorhabditis elegans displays a surprisingly sophisticated behavioral repertoire that includes the utilization of both associative and non associative forms of learning. Elucidating the molecular basis of learning remains a fundamental, yet daunting, challenge of modern neuroscience. In Pereira and van der Kooy (ref. 2), we described the use of a two input-two output stimuli system to dissociate between associative and non-associative learning and between memory acquisition and retrieval processes. Briefly, one finding indicated that after training with the odorant isoamyl alcohol (IsoA), we could preferentially retrieve either associative or non-associative memory with a choice of either a benzaldehyde (Bnz) or IsoA retrieval stimulus, respectively. Here, we describe how that apparently enigmatic molecular cross wiring of the two forms of memory examined could represent an evolutionary relic of the ancient divergence between non-associative and associative learning. In addition, we extrapolate on the utility and subtleties of using such a system to dissociate and decipher the components of memory in C. elegans. PMID- 24058870 TI - Interaction between quality control systems for ER protein folding and RNA biogenesis. AB - The endoplasmic reticulum (ER) is the intracellular organelle responsible for the synthesis, folding and assembly of proteins destined for secretion and the endomembrane system of the cell. ER quality control (ERQC) is an intensively studied surveillance mechanism that selectively degrades misfolded proteins to ensure that only properly folded proteins exit the ER en route to the Golgi compartment. Proper protein folding is indispensable for the differentiation and function of cells that secrete high levels of protein and defects in protein folding are implicated in many pathologies, including metabolic, genetic, neurodegenerative and inflammatory diseases. Accumulation of misfolded proteins in the ER activates an adaptive set of signaling pathways, collectively known as the unfolded protein response (UPR), to resolve protein misfolding and restore ER homeostasis. Nonsense-mediated RNA decay (NMD) is an RNA surveillance system that selectively degrades nascent mRNAs containing premature termination codons (PTCs). Recently, we used a genetic screen to identify genes that interact with UPR signaling in C. elegans. These studies identified NMD-associated genes that are required for ER protein folding homeostasis. These findings link the quality control systems required for ER protein folding and RNA biogenesis, provide new insights into mechanisms of ERQC and have implications on diseases of ER dysfunction and therapeutic approaches based on NMD inhibition. Here, we discuss the biological significance of these findings and future directions for study. PMID- 24058872 TI - Histone H1 and heterochromatin protein 1 (HP1) regulate specific gene expression and not global transcription. AB - The highly conserved Hox transcription factors define positional identity along the anterior-posterior body axis during development. Inappropriate expression of Hox genes causes homeotic transformation, which leads to abnormal development of a specific region or segment. C. elegans offers an excellent model for studying factors required for the establishment of the spatially-restricted expression of Hox genes. We have recently identified chromatin factors, including a linker histone (H1) variant, HIS-24 and heterochromatin protein 1 (HP1) homolog, HPL-2, which contribute to the regulation of specific Hox gene expression through their binding to the repressive mark, H3K27me3. Furthermore, HIS-24 and HPL-2 act in a parallel pathway as members of the evolutionally conserved Polycomb group (PcG) silencing complex, MES-2/3/6. By microarray analysis, we found that HIS-24 and HPL-2 are not global transcriptional repressors as suggested by early studies, but rather are fine tuners of selected genes. Here, we discuss how HIS-24 and HPL 2 are responsible for the repression of specific genes in C. elegans. We suggest possible mechanisms for such an unanticipated function of an individual H1 variant and HP1 in the transcriptional repression of Hox genes. PMID- 24058871 TI - Co-occurrence of tetraspanin and ROS generators: Conservation in protein cross linking and other developmental processes. AB - The nematode exoskeleton, commonly called the cuticle, is a highly structured extracellular matrix mainly composed of collagen. Secreted collagen molecules from the underlying epidermal cells are cross-linked via their tyrosyl residues. Reactive oxygen species (ROS) are required for the cross-linking reaction to produce tyrosyl radicals. The conserved ROS generator enzyme in C. elegans, BLI 3/CeDUOX1, a homolog of dual oxidases (DUOXs), is responsible for production of hydrogen peroxide. The ROS generation system must be properly controlled since ROS are highly reactive molecules that irreversibly inhibit the functions of cellular components such as nucleic acids and proteins. We recently reported that the ROS generation system directed by BLI-3 requires the tetraspanin protein, TSP 15. Herein we outline the process of cuticle development with a focus on the molecular roles of TSP-15 in the BLI-3 system. We also propose the co-occurrence of tetraspanin and ROS generators by convergent evolution. PMID- 24058873 TI - Ancient neuromodulation by vasopressin/oxytocin-related peptides. AB - Neuropeptidergic signaling is widely adopted by animals for the regulation of physiology and behavior in a rapidly changing environment. The vasopressin/oxytocin neuropeptide family originates from an ancestral peptide precursor in the antecedent of protostomian and deuterostomian animals. In vertebrates, vasopressin and oxytocin have both hormonal effects on peripheral target tissues, such as in the regulation of reproduction and water balance, and neuromodulatory actions in the central nervous system controlling social behavior and cognition. The recent identification of vasopressin/oxytocin-related signaling in C. elegans reveals that this peptidergic system is widespread among nematodes. Genetic analysis of the C. elegans nematocin system denotes vasopressin/oxytocin-like peptides as ancient neuromodulators of neuronal circuits involved in reproductive behavior and associative learning, whereas former invertebrate studies focused on conserved peripheral actions of this peptide family. Nematocin provides neuromodulatory input into the gustatory plasticity circuit as well as into distinct male mating circuits to generate a coherent mating behavior. Molecular interactions are comparable to those underlying vasopressin- and oxytocin-mediated effects in the mammalian brain. Understanding how the vasopressin/oxytocin family fine-tunes neuronal circuits for social behavior, learning and memory poses a major challenge. Functional conservation of these effects in nematodes and most likely in other invertebrates enables the development of future models to help answering this question. PMID- 24058874 TI - Virgin Caenorhabditis remanei females are attracted to a coital pheromone released by con-specific copulating males. AB - The gonochoristic soil nematode Caenorhabditis remanei strictly requires copulation for species propagation. Males of this species are sexually promiscuous with females of other species; therefore, we asked in this study whether virgin C. remanei females display evidence of mate choice. We digitally recorded and measured the locomotor behaviors of one or more virgin females in the presence of a single male on a 5 mm diameter mating lawn. We observed that initially only the male modifies his locomotor trajectory to another animal on the mating lawn; the virgin females showed no locomotor bias toward the mate searching male. However, once a male started to copulate, females in the vicinity altered their movement trajectories toward the copulating couple. Newly inseminated females are refractive to the coital signal, but partially regain their attraction to copulating males after 24 h. We found only copulating males with an intact gonad can attract females, and that the coital signal can be broadcasted at least 1.5 mm through the air. Unlike males, which are also attracted to hetero-specific females, virgin C. remanei females will only crawl toward a copulating con-specific male. We suggest that Caenorhabditis females use the coital signal as a pheromone to identify a vigorous male of their own species. PMID- 24058876 TI - In this issue of Worm. PMID- 24058875 TI - A microfluidic phenotype analysis system reveals function of sensory and dopaminergic neuron signaling in C. elegans electrotactic swimming behavior. AB - The nematode (worm) C. elegans is a leading multicellular animal model to study neuronal-basis of behavior. Worms respond to a wide range of stimuli and exhibit characteristic movement patterns. Here we describe the use of a microfluidics setup to probe neuronal activity that relies on the innate response of C. elegans to swim toward the cathode in the presence of a DC electric field (termed "electrotaxis"). Using this setup, we examined mutants affecting sensory and dopaminergic neurons and found that their electrotactic responses were defective. Such animals moved with reduced speed (35-80% slower than controls) with intermittent pauses, abnormal turning and slower body bends. A similar phenotype was observed in worms treated with neurotoxins 6-OHDA (6- hydroxy dopamine), MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine) and rotenone (20-60% slower). We also found that neurotoxin effects could be suppressed by pre-exposing worms to a known neuroprotective compound acetaminophen. Collectively, these results show that microfluidic electrotaxis can identify alterations in dopamine and amphid neuronal signaling based on swimming responses of C. elegans. Further characterization has revealed that the electrotactic swimming response is highly sensitive and reliable in detecting neuronal abnormalities. Thus, our microfluidics setup could be used to dissect neuronal function and toxin-induced neurodegeneration. Among other applications, the setup promises to facilitate genetic and chemical screenings to identify factors that mediate neuronal signaling and neuroprotection. PMID- 24058877 TI - Direct-to-Consumer Genetic Testing and Personal Genomics Services: A Review of Recent Empirical Studies. AB - Direct-to-consumer genetic testing (DTC-GT) has sparked much controversy and undergone dramatic changes in its brief history. Debates over appropriate health policies regarding DTC-GT would benefit from empirical research on its benefits, harms, and limitations. We review the recent literature (2011-present) and summarize findings across (1) content analyses of DTC-GT websites, (2) studies of consumer perspectives and experiences, and (3) surveys of relevant health care providers. Findings suggest that neither the health benefits envisioned by DTC-GT proponents (e.g., significant improvements in positive health behaviors) nor the worst fears expressed by its critics (e.g., catastrophic psychological distress and misunderstanding of test results, undue burden on the health care system) have materialized to date. However, research in this area is in its early stages and possesses numerous key limitations. We note needs for future studies to illuminate the impact of DTC-GT and thereby guide practice and policy regarding this rapidly evolving approach to personal genomics. PMID- 24058878 TI - ABT-737, a small molecule Bcl-2/Bcl-xL antagonist, increases antimitotic-mediated apoptosis in human prostate cancer cells. AB - Castration-resistant prostate cancer (CRPC) expresses high levels of the anti apoptotic proteins Bcl-2, Bcl-xL and Mcl-1, resulting in resistance to apoptosis and association with poor prognosis. Docetaxel, an antimitotic drug that is the first-line treatment strategy for CRPC, is known to provide a small survival benefit. However, docetaxel chemotherapy alone is not enough to counteract the high levels of Bcl-2/Bcl-xL/Mcl-1 present in CRPC. ABT-737 is a small molecule that binds to Bcl-2/Bcl-xL (but not Mcl-1) with high affinity and disrupts their interaction with pro-apoptotic Bax/Bak, thus enhancing apoptosis. Our results indicate that ABT-737 can sensitize androgen-dependent LNCaP and CRPC PC3 cells to docetaxel- and to the novel antimitotic ENMD-1198-mediated caspase-dependent apoptosis. CRPC DU145 cells, however, are more resistant to ABT-737 because they are Bax null and not because they express the highest levels of anti-apoptotic Mcl-1 (associated with ABT-737 resistance). Knockdown of Bax or Bak in LNCaP indicates that ABT-737-induced antimitotic enhancement of apoptosis is more dependent on the levels of Bax than Bak. Furthermore, we find that the ability of docetaxel to increase cyclin B1/Cdk1-mediated phosphorylation of Bcl-2/Bcl-xL and decrease Mcl-1 is required for ABT-737 to enhance apoptosis in PC3 cells, as determined by addition of Cdk1 inhibitor purvalanol A and expression of shRNA specific for cyclin B1. Overall, our data suggests that the high levels of anti apoptotic proteins in Bax-expressing CRPC cells can be overcome by targeting Bcl 2/Bcl-xL with ABT-737 and Mcl-1 with antimitotics. PMID- 24058879 TI - A systematic review of methods for studying consumer health YouTube videos, with implications for systematic reviews. AB - Background. YouTube is an increasingly important medium for consumer health information - with content provided by healthcare professionals, government and non-government organizations, industry, and consumers themselves. It is a rapidly developing area of study for healthcare researchers. We examine the methods used in reviews of YouTube consumer health videos to identify trends and best practices. Methods and Materials. Published reviews of consumer-oriented health related YouTube videos were identified through PubMed. Data extracted from these studies included type of journal, topic, characteristics of the search, methods of review including number of reviewers and method to achieve consensus between reviewers, inclusion and exclusion criteria, characteristics of the videos reported, ethical oversight, and follow-up. Results. Thirty-three studies were identified. Most were recent and published in specialty journals. Typically, these included more than 100 videos, and were examined by multiple reviewers. Most studies described characteristics of the videos, number of views, and sometime characteristics of the viewers. Accuracy of portrayal of the health issue under consideration was a common focus. Conclusion. Optimal transparency and reproducibility of studies of YouTube health-related videos can be achieved by following guidance designed for systematic review reporting, with attention to several elements specific to the video medium. Particularly when seeking to replicate consumer viewing behavior, investigators should consider the method used to select search terms, and use a snowballing rather than a sequential screening approach. Discontinuation protocols for online screening of relevance ranked search results is an area identified for further development. PMID- 24058880 TI - Do N-arachidonyl-glycine (NA-glycine) and 2-arachidonoyl glycerol (2-AG) share mode of action and the binding site on the beta2 subunit of GABAA receptors? AB - NA-glycine is an endogenous lipid molecule with analgesic properties, which is structurally similar to the endocannabinoids 2-AG and anandamide but does not interact with cannabinoid receptors. NA-glycine has been suggested to act at the G-protein coupled receptors GPR18 and GPR92. Recently, we have described that NA glycine can also modulate recombinant alpha1beta2gamma2 GABAA receptors. Here we characterize in more detail this modulation and investigate the relationship of its binding site with that of the endocannabinoid 2-AG. PMID- 24058881 TI - Estradiol differentially affects auditory recognition and learning according to photoperiodic state in the adult male songbird, European starling (Sturnus vulgaris). AB - Changes in hormones can affect many types of learning in vertebrates. Adults experience fluctuations in a multitude of hormones over a temporal scale, from local, rapid action to more long-term, seasonal changes. Endocrine changes during development can affect behavioral outcomes in adulthood, but how learning is affected in adults by hormone fluctuations experienced during adulthood is less understood. Previous reports have implicated the sex steroid hormone estradiol (E2) in both male and female vertebrate cognitive functioning. Here, we examined the effects of E2 on auditory recognition and learning in male European starlings (Sturnus vulgaris). European starlings are photoperiodic, seasonally breeding songbirds that undergo different periods of reproductive activity according to annual changes in day length. We simulated these reproductive periods, specifically 1. photosensitivity, 2. photostimulation, and 3. photorefractoriness in captive birds by altering day length. During each period, we manipulated circulating E2 and examined multiple measures of learning. To manipulate circulating E2, we used subcutaneous implants containing either 17-beta E2 and/or fadrozole (FAD), a highly specific aromatase inhibitor that suppresses E2 production in the body and the brain, and measured the latency for birds to learn and respond to short, male conspecific song segments (motifs). We report that photostimulated birds given E2 had higher response rates and responded with better accuracy than those given saline controls or FAD. Conversely, photosensitive, animals treated with E2 responded with less accuracy than those given FAD. These results demonstrate how circulating E2 and photoperiod can interact to shape auditory recognition and learning in adults, driving it in opposite directions in different states. PMID- 24058882 TI - Hypoxia-inducible C-to-U coding RNA editing downregulates SDHB in monocytes. AB - Background. RNA editing is a post-transcriptional regulatory mechanism that can alter the coding sequences of certain genes in response to physiological demands. We previously identified C-to-U RNA editing (C136U, R46X) which inactivates a small fraction of succinate dehydrogenase (SDH; mitochondrial complex II) subunit B gene (SDHB) mRNAs in normal steady-state peripheral blood mononuclear cells (PBMCs). SDH is a heterotetrameric tumor suppressor complex which when mutated causes paraganglioma tumors that are characterized by constitutive activation of hypoxia inducible pathways. Here, we studied regulation, extent and cell type origin of SDHB RNA editing. Methods. We used short-term cultured PBMCs obtained from random healthy platelet donors, performed monocyte enrichment by cold aggregation, employed a novel allele-specific quantitative PCR method, flow cytometry, immunologic cell separation, gene expression microarray, database analysis and high-throughput RNA sequencing. Results. While the editing rate is low in uncultured monocyte-enriched PBMCs (average rate 2.0%, range 0.4%-6.3%, n = 42), it is markedly upregulated upon exposure to 1% oxygen tension (average rate 18.2%, range 2.8%-49.4%, n = 14) and during normoxic macrophage differentiation in the presence of serum (average rate 10.1%, range 2.7%-18.8%, n = 17). The normoxic induction of SDHB RNA editing was associated with the development of dense adherent aggregates of monocytes in culture. CD14-positive monocyte isolation increased the percentages of C136U transcripts by 1.25-fold in normoxic cultures (n = 5) and 1.68-fold in hypoxic cultures (n = 4). CD14 negative lymphocytes showed no evidence of SDHB editing. The SDHB genomic DNA remained wild-type during increased RNA editing. Microarray analysis showed expression changes in wound healing and immune response pathway genes as the editing rate increased in normoxic cultures. High-throughput sequencing of SDHB and SDHD transcripts confirmed the induction of C136U RNA editing in normoxic cultures but showed no additional verifiable coding edits. Analysis of SDHB RNA sequence data from 16 normal human tissues from the Illumina Body Map and from 45 samples representing 23 different cell types from the ENCODE projects confirmed the occurrence of site-specific C136U editing in whole blood (1.7%) and two primary CD14+ monocyte samples (1.9% and 2.6%). In contrast, the other cell types showed an average of 0.2% and 0.1% C136U editing rates in the two databases, respectively. Conclusions. These findings demonstrate that C-to-U coding RNA editing of certain genes is dynamically induced by physiologically relevant environmental factors and suggest that epigenetic downregulation of SDHB by site specific RNA editing plays a role in hypoxia adaptation in monocytes. PMID- 24058883 TI - Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines. AB - Objectives. Marijuana is the most commonly used illicit drug during pregnancy. Due to high lipophilicity, cannabinoids can easily penetrate physiological barriers like the human placenta and jeopardize the developing fetus. We evaluated the impact of cannabidiol (CBD), a major non-psychoactive cannabinoid, on P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) expression, and P-gp function in a placental model, BeWo and Jar choriocarcinoma cell lines (using P-gp induced MCF7 cells (MCF7/P-gp) for comparison). Study design. Following the establishment of the basal expression of these transporters in the membrane fraction of all three cell lines, P-gp and BCRP protein and mRNA levels were determined following chronic (24-72 h) exposure to CBD, by Western Blot and qPCR. CBD impact on P-gp efflux function was examined by uptake of specific P-gp fluorescent substrates (calcein-AM, DiOC2(3) and rhodamine123(rh123)). Cyclosporine A (CsA) served as a positive control. Results. Chronic exposure to CBD resulted in significant changes in the protein and mRNA levels of both transporters. While P-gp was down-regulated, BCRP levels were up-regulated in the choriocarcinoma cell lines. CBD had a remarkably different influence on P-gp and BCRP expression in MCF7/P-gp cells, demonstrating that these are cell type specific effects. P-gp dependent efflux (of calcein, DiOC2(3) and rh123) was inhibited upon short-term exposure to CBD. Conclusions. Our study shows that CBD might alter P-gp and BCRP expression in the human placenta, and inhibit P-gp efflux function. We conclude that marijuana use during pregnancy may reduce placental protective functions and change its morphological and physiological characteristics. PMID- 24058884 TI - The affective profiles in the USA: happiness, depression, life satisfaction, and happiness-increasing strategies. AB - Background. The affective profiles model categorizes individuals as self fulfilling (high positive affect, low negative affect), high affective (high positive affect, high negative affect), low affective (low positive affect, low negative affect), and self-destructive (low positive affect, high negative affect). The model has been used extensively among Swedes to discern differences between profiles regarding happiness, depression, and also life satisfaction. The aim of the present study was to investigate such differences in a sample of residents of the USA. The study also investigated differences between profiles with regard to happiness-increasing strategies. Methods. In Study I, 900 participants reported affect (Positive Affect Negative Affect Schedule; PANAS) and happiness (Happiness-Depression Scale). In Study II, 500 participants self reported affect (PANAS), life satisfaction (Satisfaction With Life Scale), and how often they used specific strategies to increase their own happiness (Happiness-Increasing Strategies Scales). Results. The results showed that, compared to the other profiles, self-fulfilling individuals were less depressed, happier, and more satisfied with their lives. Nevertheless, self-destructive individuals were more depressed, unhappier, and less satisfied than all other profiles. The self-fulfilling individuals tended to use strategies related to agentic (e.g., instrumental goal-pursuit), communal (e.g., social affiliation), and spiritual (e.g., religion) values when pursuing happiness. Conclusion. These differences suggest that promoting positive emotions can positively influence a depressive-to-happy state as well as increasing life satisfaction. Moreover, the present study shows that pursuing happiness through strategies guided by agency, communion, and spirituality is related to a self-fulfilling experience described as high positive affect and low negative affect. PMID- 24058885 TI - Abundance-weighted phylogenetic diversity measures distinguish microbial community states and are robust to sampling depth. AB - In microbial ecology studies, the most commonly used ways of investigating alpha (within-sample) diversity are either to apply non-phylogenetic measures such as Simpson's index to Operational Taxonomic Unit (OTU) groupings, or to use classical phylogenetic diversity (PD), which is not abundance-weighted. Although alpha diversity measures that use abundance information in a phylogenetic framework do exist, they are not widely used within the microbial ecology community. The performance of abundance-weighted phylogenetic diversity measures compared to classical discrete measures has not been explored, and the behavior of these measures under rarefaction (sub-sampling) is not yet clear. In this paper we compare the ability of various alpha diversity measures to distinguish between different community states in the human microbiome for three different datasets. We also present and compare a novel one-parameter family of alpha diversity measures, BWPDtheta, that interpolates between classical phylogenetic diversity (PD) and an abundance-weighted extension of PD. Additionally, we examine the sensitivity of these phylogenetic diversity measures to sampling, via computational experiments and by deriving a closed form solution for the expectation of phylogenetic quadratic entropy under re-sampling. On the three datasets, a phylogenetic measure always performed best, and two abundance weighted phylogenetic diversity measures were the only measures ranking in the top four across all datasets. OTU-based measures, on the other hand, are less effective in distinguishing community types. In addition, abundance-weighted phylogenetic diversity measures are less sensitive to differing sampling intensity than their unweighted counterparts. Based on these results we encourage the use of abundance-weighted phylogenetic diversity measures, especially for cases such as microbial ecology where species delimitation is difficult. PMID- 24058886 TI - Matching based on biological categories in Orangutans (Pongo abelii) and a Gorilla (Gorilla gorilla gorilla). AB - Following a series of experiments in which six orangutans and one gorilla discriminated photographs of different animal species in a two-choice touch screen procedure, Vonk & MacDonald (2002) and Vonk & MacDonald (2004) concluded that orangutans, but not the gorilla, seemed to learn intermediate level category discriminations, such as primates versus non-primates, more rapidly than they learned concrete level discriminations, such as orangutans versus humans. In the current experiments, four of the same orangutans and the gorilla were presented with delayed matching-to-sample tasks in which they were rewarded for matching photos of different members of the same primate species; golden lion tamarins, Japanese macaques, and proboscis monkeys, or family; gibbons, lemurs (Experiment 1), and subsequently for matching photos of different species within the following classes: birds, reptiles, insects, mammals, and fish (Experiment 2). Members of both Great Ape species were rapidly able to match the photos at levels above chance. Orangutans matched images from both category levels spontaneously whereas the gorilla showed effects of learning to match intermediate level categories. The results show that biological knowledge is not necessary to form natural categories at both concrete and intermediate levels. PMID- 24058887 TI - BD-Func: a streamlined algorithm for predicting activation and inhibition of pathways. AB - BD-Func (BiDirectional FUNCtional enrichment) is an algorithm that calculates functional enrichment by comparing lists of pre-defined genes that are known to be activated versus inhibited in a pathway or by a regulatory molecule. This paper shows that BD-Func can correctly predict cell line alternations and patient characteristics with accuracy comparable to popular algorithms, with a significantly faster run-time. BD-Func can compare scores for individual samples across multiple groups as well as provide predictive statistics and receiver operating characteristic (ROC) plots to quantify the accuracy of the signature associated with a binary phenotypic variable. BD-Func facilitates collaboration and reproducibility by encouraging users to share novel molecular signatures in the BD-Func discussion group, which is where the novel progesterone receptor and LBH589 signatures from this paper can be found. The novel LBH589 signature presented in this paper also serves as a case study showing how a custom signature using cell line data can accurately predict activity in vivo. This software is available to download at https://sourceforge.net/projects/bdfunc/. PMID- 24058888 TI - Masticatory biomechanics of the Laotian rock rat, Laonastes aenigmamus, and the function of the zygomaticomandibularis muscle. AB - The Laotian rock rat, Laonastes aenigmamus, is one of the most recently discovered species of rodent, and displays a cranial morphology that is highly specialised. The rostrum of L. aenigmamus is exceptionally elongate and bears a large attachment site for the infraorbital portion of the zygomaticomandibularis muscle (IOZM), which is particularly well-developed in this species. In this study, we used finite element analysis to investigate the biomechanical performance of the Laotian rock rat cranium and to elucidate the function of the IOZM. A finite element model of the skull of L. aenigmamus was constructed and solved for biting on each of the teeth (incisors, premolar and molars). Further load cases were created and solved in which the origin of the IOZM had been moved anteriorly and posteriorly along the rostrum. Finally, a set of load cases were produced in which the IOZM was removed entirely, and its force was redistributed between the remaining masticatory muscles. The analysis showed that, during biting, the most stressed areas of the skull were the zygomatic and orbital regions. Compared to other rodents, L. aenigmamus is highly efficient at incisor gnawing, but less efficient at molar chewing. However, a relatively constant bite force across the molar tooth row may be an adaptation to folivory. Movement of the origin of the IOZM had little on the patterns of von Mises stresses, or the overall stress experienced by the cranium. However, removal of the IOZM had a substantial effect on the total deformation experienced by the skull. In addition, the positioning and presence of the IOZM had large impact on bite force. Moving the IOZM origin to the anterior tip of the rostrum led to a substantially reduced bite force at all teeth. This was hypothesised to be a result of the increasing horizontal component to the pull of this muscle as it is moved anteriorly along the rostrum. Removal of the IOZM also resulted in reduced bite force, even when the total input muscle force was maintained at the same level. It was thus concluded that the function of the IOZM in L. aenigmamus is to increase bite force whilst reducing cranial deformation. If the IOZM can be shown to have this function in other rodent groups, this may help explain the evolution of this muscle, and may also provide an understanding of why it has evolved independently several times within rodents. PMID- 24058889 TI - 2-D Fused Image Reconstruction approach for Microwave Tomography: a theoretical assessment using FDTD Model. AB - This paper describes an efficient two-dimensional fused image reconstruction approach for Microwave Tomography (MWT). Finite Difference Time Domain (FDTD) models were created for a viable MWT experimental system having the transceivers modelled using thin wire approximation with resistive voltage sources. Born Iterative and Distorted Born Iterative methods have been employed for image reconstruction with the extremity imaging being done using a differential imaging technique. The forward solver in the imaging algorithm employs the FDTD method of solving the time domain Maxwell's equations with the regularisation parameter computed using a stochastic approach. The algorithm is tested with 10% noise inclusion and successful image reconstruction has been shown implying its robustness. PMID- 24058890 TI - Initial Development and Validation of the Mexican Intercultural Competence Scale. AB - The current project sought to develop the Mexican Intercultural Competence Scale (MICS), which assesses group-specific skills and attributes that facilitate effective cultural interactions, among adults of Mexican descent. Study 1 involved an Exploratory Factor Analysis (N = 184) that identified five factors including Ambition/Perseverance, Networking, the Traditional Latino Culture, Family Relationships, and Communication. In Study 2, a Confirmatory Factor Analysis provided evidence for the 5-factor model for adults of Mexican origin living in the Midwest (N = 341) region of the U.S. The general findings are discussed in terms of a competence-based formulation of cultural adaptation and include theoretical and clinical implications. PMID- 24058891 TI - Hyperglycaemia and oxidative stress upregulate HSP60 & HSP70 expression in HeLa cells. AB - Heat Shock Proteins 60 & 70 (HSP60 & HSP70) are intracellular protein that has been shown to be present at elevated levels in systemic circulation in Type 2 Diabetes mellitus (T2DM) patients. Conditions that lead to its secretion, and the mechanism of its translocation from cells, have not yet been defined. The aim of this study was to determine if specific cell stressors associated with T2DM, namely hyperglycaemia and oxidative stress, result in the upregulation of HSP60 in human cells in vitro. Human HeLa cells were grown in media supplemented with 100 mM glucose, 200 MUM hydrogen peroxide (H2O2), and 50 MUM sodium azide. Initially, the effect of these treatments on cell growth rate was examined, with each treatment significantly inhibiting growth rate. LDH and MTT assays were also used to successfully demonstrate that these treatments do not significantly increase cell lysis, but do significantly impair mitochondrial dehydrogenase activity. To confirm this mitochondria specific form of inhibition, DCFDA assay were used to investigate any increases in intracellular reactive oxygen species (ROS) generation. All three treatments resulted in significantly increased ROS generation, with greater ROS production occurring with a greater exposure time. Interestingly, when the protein levels of HSP60 and HSP70 were measured after 3 and 7 days of exposure of the HeLa cells to 100 mM glucose, 200 MUM H2O2, and 50 MUM sodium azide significant induction of these two molecular stress proteins were observed ranging from 2.43-5.08 fold compared to untreated control cells. PMID- 24058892 TI - Improvement of innate immune responses and defense activity in tiger shrimp (Penaeus monodon Fab.) by intramuscular administration of the outer membrane protein Vibrio alginolyticus. AB - The Outer Membrane Protein (OMP) of Vibrio alginolyticus cell wall was administered intramuscularly (IM) to the tiger shrimp (Penaeus monodon Fab.) at 10, 20, 30 MUg/kg bw. After 14 days infection, the tiger shrimps were challenged with 10(7) bacterial density of Vibrio harveyi for 24 hours. The total haemocyte count (THC), differential haemocyte count (DHC) and amount of total protein plasma (TPP), superoxide dismutase and protease enzyme activity were monitored. The results showed that intramuscular administration of OMP enhanced an immunomodulatory effect and protection against V. harveyi. The beneficial effect of OMP on the tiger shrimp is dose-dependent and OMP-20 MUg/kg bw is an optimal dose after two times of boosters for 14 days against V. harveyi infection. PMID- 24058893 TI - pPCV, a versatile vector for cloning PCR products. AB - The efficiency of PCR product cloning depends on the nature of the DNA polymerase employed because amplicons may have blunt-ends or 3' adenosines overhangs. Therefore, for amplicon cloning, available commercial vectors are either blunt ended or have a single 3' overhanging thymidine. The aim of this work was to offer in a single vector the ability to clone both types of PCR products. For that purpose, a minimal polylinker was designed to include restriction sites for EcoRV and XcmI which enable direct cloning of amplicons bearing blunt-ends or A overhangs, respectively, still offering blue/white selection. When tested, the resulting vector, pPCV, presented high efficiency cloning of both types of amplicons. PMID- 24058894 TI - Smoking cessation in community pharmacy practice-a clinical information needs analysis. AB - BACKGROUND: With the emerging role of pharmacists in implementing smoking cessation services and the recent evidence about smoking cessation pharmacotherapies, a needs analysis to assess baseline knowledge about current smoking cessation practice is needed; hence, training and development in this area can target possible 'gaps'. OBJECTIVE: This study aimed at exploring pharmacy students' knowledge about and attitudes toward smoking cessation, as compared to practicing community pharmacists and smoking cessation educators. The overall objective was to uncover underlying 'gaps' in pharmacy-based smoking cessation practice, particularly clinical gaps. SETTING: Final-year pharmacy students at the University of Sydney, practicing community pharmacists and smoking cessation educators in Australia. METHOD: As no previous standard pharmacist-focused smoking cessation knowledge questionnaires exist, a review of the literature informed the development of such a questionnaire. The questionnaire was administered to a cohort of fourth-year pharmacy students at the University of Sydney, practicing pharmacists and smoking cessation educators. Data analysis was performed using Predictive Analytics SoftWare (PASW(r) Statistics 18). Mean total scores, independent t-tests, analysis of variances and exploratory factor analysis were performed. MAIN OUTCOME MEASURE: To determine areas of major clinical deficits about current evidence related to smoking cessation interventions at the pharmacy level. RESULTS: Responses from 250 students, 51 pharmacists and 20 educators were obtained. Smoking educators scored significantly higher than pharmacists and students (P < .05), while score differences in the latter two groups were not statistically significant (P > .05). All groups scored high on 'general' knowledge questions as compared to specialised pharmacologic and pharmacotherapeutic questions. All respondents demonstrated positive attitudes toward the implications of smoking cessation. Factor analysis of the 24-item knowledge section extracted 12 items loading on 5 factors accounting for 53% of the total variance. CONCLUSIONS: The results provide a valid indication of 'gaps' in the practice of up-to-date smoking cessation services among Australian pharmacy professionals, particularly in clinical expertise areas involving assessment of nicotine dependence and indications, dosages, adverse effects, contraindications, drug interactions and combinations of available pharmacotherapies. These gaps should be addressed, and the results should inform the design, implementation and evaluation of a pharmacy based educational training program targeting current clinical issues in smoking cessation. PMID- 24058895 TI - Powerline bioactivity - more than magnetism. AB - BACKGROUND: Previous work on the possible public health impact of electricity utilization has mostly considered low frequency electromagnetic fields, particularly those associated with high voltage overhead powerlines, but no generally accepted biological mechanism has been proposed. The present study seeks to expand the area of debate to include airborne electroactivity. FINDINGS: From a literature survey it is concluded that there is statistically significant published evidence consistent with the involvement of airborne electroactive agents in the powerline proximity modulation of some cytokine activity. Attention is drawn to overhead line fault associated corona discharge action as a source of potentially bioactive agents deserving careful study in view of the widespread close residential proximity to overhead power distribution lines in many countries. Particular attention is given to the role of electricity access associated faults as a possible explanation for the high childhood leukaemia rates in certain districts of Mexico City. CONCLUSIONS: Despite more than 30 years research worldwide there is no generally accepted biological mechanism to explain the adverse health impact of overhead powerline residential proximity. Expanding the area of consideration to include airborne electroactivity may provide the basis for a plausible outline model of such a mechanism. More attention should be given to this research area. PMID- 24058896 TI - Prediction of the muscle strength by the muscle thickness and hardness using ultrasound muscle hardness meter. AB - PURPOSES: The present study investigated whether a combination of the thickness and hardness of muscles without muscle tension can be used to estimate muscle strength during knee extension in adult males and females. METHODS: Seventy-two males and thirty-three females, whose ages ranged from 18 to 35 years, participated in this study. We measured muscle thickness and hardness in the right anterior region of the thigh (rectus femoris muscle and vastus intermedius muscle) without muscle tension using an ultrasound muscle hardness meter, and the maximal voluntary isometric contraction of right knee extension (MVIC). The changing ratios (%) of the tissue thickness before compression to those during compression (compression ratio) are calculated as an index of the hardness. Higher ratio indicates a harder muscle compared with that of other individuals showing the same muscle thickness. RESULTS: In male group, although the MVIC had significantly positive correlation to both muscle thickness (r=0.412, p<0.01) and compression ratio (r=0.233, p<0.05), their variables also had correlation mutually. In the female group, the MVIC has significantly positive correlation to only compression ratio (r=0.499, p<0.01), not muscle thickness (r=0.225, n.s.). On multiple linear regression analysis, the combination of two parameters (muscle thickness and compression ratio) allowed more accurate estimation of MVIC (r=0.573, p<0.01) in the female group. CONCLUSION: These findings suggested that the combination of muscle thickness and hardness is capable of effectively estimating muscle strength especially in females. PMID- 24058897 TI - Prenatal Chlamydia trachomatis infection increases the risk of preeclampsia. AB - The relationship between Chlamydia trachomatis (CT) and preeclampsia was examined longitudinally among 205 cases and 423 normotensive controls nested within the Collaborative Perinatal Project. Antibodies were analyzed at a first prenatal visit (mean 14.2 weeks) and at delivery. Prenatal infections were identified as IgG/IgM seroconversion or a four-fold rise in IgG antibody titers. Although serological evidence of incident prenatal CT infection was uncommon (n=9, 1.4%) in this general pregnant population, infected women were more likely to develop preeclampsia, after adjustment for maternal age, body mass index, smoking status, race and time between blood draws (ORadj 7.2, 95% CI 1.3 - 39.7). PMID- 24058898 TI - Traditional Knowledge of Western Herbal Medicine and Complex Systems Science. AB - Traditional knowledge of Western herbal medicine (WHM) supports experiential approaches to healing that have evolved over time. This is evident in the use of polyherb formulations comprised of crude plant parts, individually tailored to treat the cause of dysfunction and imbalance by addressing the whole person holistically. The challenge for WHM is to integrate science with traditional knowledge that is a foundation of the practice of WHM. The purpose of this paper is to provide a plausible theoretical hypothesis by applying complex systems science to WHM, illustrating how medicinal plants are complex, adaptive, environmentally interactive systems exhibiting synergy and nonlinear healing causality. This paper explores the conceptual congruence between medicinal plants and humans as complex systems coherently coupled through recurrent interaction. Complex systems science provides the theoretical tenets that explain traditional knowledge of medicinal plants while supporting clinical practice and expanding research and documentation of WHM. PMID- 24058899 TI - Symmetry Concerns as a Symptom of Body Dysmorphic Disorder. AB - Symmetry obsessions are a common symptom of obsessive-compulsive disorder (OCD) and have several demographic and clinical correlates. Appearance-related symmetry concerns appear common in body dysmorphic disorder (BDD); however, no published studies have examined this topic. This study examined the clinical features, prevalence, and correlates of symmetry concerns involving physical appearance in two BDD samples (N=160 and N=115). More than 25% of participants in each sample reported symmetry concerns for a body part with which they were preoccupied (total of 18 body parts in sample 1 and 18 in sample 2). In sample 1, BDD participants with appearance-related symmetry concerns were older than those without appearance-related symmetry concerns. In sample 2, those with appearance related symmetry concerns reported poorer mental health-related quality of life, were more likely to have experienced lifetime suicidal ideation, had better BDD related insight, and were less likely to have a lifetime eating disorder. In both samples, participants with appearance-related symmetry concerns were more likely to have lifetime OCD but not OCD-related symmetry obsessions. Thus, symmetry is a common appearance concern in BDD that is associated with comorbid OCD but not with OCD symmetry concerns specifically, suggesting that symmetry concerns may have a different mechanism/pathophysiology in BDD versus OCD. PMID- 24058900 TI - Food allergy and increased asthma morbidity in a School-based Inner-City Asthma Study. AB - BACKGROUND: Children with asthma have increased prevalence of food allergies. The relationship between food allergy and asthma morbidity is unclear. OBJECTIVE: We aimed to investigate the presence of food allergy as an independent risk factor for increased asthma morbidity by using the School Inner-City Asthma Study, a prospective study that evaluates risk factors and asthma morbidity among urban children. METHODS: We prospectively surveyed, from inner-city schools, 300 children with physician-diagnosed asthma, followed by clinical evaluation. Food allergies were reported, which included symptoms experienced within 1 hour of food ingestion. Asthma morbidity, pulmonary function, and resource utilization were compared between children with food allergies and those without. RESULTS: Seventy-three of 300 children with asthma (24%) surveyed had physician-diagnosed food allergy, and 36 (12%) had multiple food allergies. Those with any food allergy independently had increased risk of hospitalization (OR [odds ratio] 2.35 [95% CI, 1.30-4.24]; P = .005) and use of controller medication (OR 1.99 [95% CI, 1.06-3.74]; P = .03). Those with multiple food allergies also had an independently higher risk of hospitalization in the past year (OR 4.10 [95% CI, 1.47-11.45]; P = .007), asthma-related hospitalization (OR 3.52 [95% CI, 1.12 11.03]; P = .03), controller medication use (OR 2.38 [95% CI, 1.00-5.66]; P = .05), and more provider visits (median, 4.5 vs 3.0; P = .008). Furthermore, lung function was significantly lower (percent predicted FEV1 and FEV1/FVC ratios) in both food allergy category groups. CONCLUSIONS: Food allergy is highly prevalent in inner-city school-aged children with asthma. Children with food allergies have increased asthma morbidity and health resource utilization with decreased lung function, and this association is stronger in those with multiple food allergies. PMID- 24058902 TI - Pre-clinical studies of epigenetic therapies targeting histone modifiers in lung cancer. AB - Treatment options for lung cancer patients have been generally limited to standard therapies or targeted interventions which involve a small number of known mutations. Although the targeted therapies are initially successful, they most often result in drug resistance, relapse, and mortality. We now know that the complexity of lung cancer comes not only from genomic changes, but also from aberrant epigenetic regulatory events. Epigenetic therapies have shown promise as single agents in the treatment of hematological malignancies but have yet to meet this expectation in solid tumors thus fostering researchers to pursue new approaches in the development and use of epigenetic interventions. Here, we review some recent pre-clinical findings involving the use of drugs targeting histone modifying enzymes both as single agents and as co-therapies against lung cancer. A greater understanding of the impact of these epigenetic compounds in lung cancer signaling is needed and further evaluation in vivo is warranted in several cases based on the pre-clinical activity of a subset of compounds discussed in this review, including drugs co-targeting HDACs and EGF receptor, targeting Brd4 and targeting Jumonji histone demethylases. PMID- 24058903 TI - Transport of ixodid ticks and tick-borne pathogens by migratory birds. AB - Birds, particularly passerines, can be parasitized by Ixodid ticks, which may be infected with tick-borne pathogens, like Borrelia spp., Babesia spp., Anaplasma, Rickettsia/Coxiella, and tick-borne encephalitis virus. The prevalence of ticks on birds varies over years, season, locality and different bird species. The prevalence of ticks on different species depends mainly on the degree of feeding on the ground. In Europe, the Turdus spp., especially the blackbird, Turdus merula, appears to be most important for harboring ticks. Birds can easily cross barriers, like fences, mountains, glaciers, desserts and oceans, which would stop mammals, and they can move much faster than the wingless hosts. Birds can potentially transport tick-borne pathogens by transporting infected ticks, by being infected with tick-borne pathogens and transmit the pathogens to the ticks, and possibly act as hosts for transfer of pathogens between ticks through co feeding. Knowledge of the bird migration routes and of the spatial distribution of tick species and tick-borne pathogens is crucial for understanding the possible impact of birds as spreaders of ticks and tick-borne pathogens. Successful colonization of new tick species or introduction of new tick-borne pathogens will depend on suitable climate, vegetation and hosts. Although it has never been demonstrated that a new tick species, or a new tick pathogen, actually has been established in a new locality after being seeded there by birds, evidence strongly suggests that this could occur. PMID- 24058901 TI - DNA damage tolerance: a double-edged sword guarding the genome. AB - Preservation of genome integrity is an essential process for cell homeostasis. During the course of life of a single cell, the genome is constantly damaged by endogenous and exogenous agents. To ensure genome stability, cells use a global signaling network, namely the DNA damage response (DDR) to sense and repair DNA damage. DDR senses different types of DNA damage and coordinates a response that includes activation of transcription, cell cycle control, DNA repair pathways, apoptosis, senescence, and cell death. Despite several repair mechanisms that repair different types of DNA lesions, it is likely that the replication machinery would still encounter lesions that are mis-repaired or not repaired. Replication of damaged genome would result in high frequency of fork collapse and genome instability. In this scenario, the cells employ the DNA damage tolerance (DDT) pathway that recruits a specialized low fidelity translesion synthesis (TLS) polymerase to bypass the lesions for repair at a later time point. Thus, DDT is not a repair pathway per se, but provides a mechanism to tolerate DNA lesions during replication thereby increasing survival and preventing genome instability. Paradoxically, DDT process is also associated with increased mutagenesis, which can in turn drive the cell to cancer development. Thus, DDT process functions as a double-edged sword guarding the genome. In this review, we will discuss the replication stress induced DNA damage-signaling cascade, the stabilization and rescue of stalled replication forks by the DDT pathway and the effect of the DDT pathway on cancer. PMID- 24058904 TI - Optimal control of gene regulatory networks with effectiveness of multiple drugs: a Boolean network approach. AB - Developing control theory of gene regulatory networks is one of the significant topics in the field of systems biology, and it is expected to apply the obtained results to gene therapy technologies in the future. In this paper, a control method using a Boolean network (BN) is studied. A BN is widely used as a model of gene regulatory networks, and gene expression is expressed by a binary value (0 or 1). In the control problem, we assume that the concentration level of a part of genes is arbitrarily determined as the control input. However, there are cases that no gene satisfying this assumption exists, and it is important to consider structural control via external stimuli. Furthermore, these controls are realized by multiple drugs, and it is also important to consider multiple effects such as duration of effect and side effects. In this paper, we propose a BN model with two types of the control inputs and an optimal control method with duration of drug effectiveness. First, a BN model and duration of drug effectiveness are discussed. Next, the optimal control problem is formulated and is reduced to an integer linear programming problem. Finally, numerical simulations are shown. PMID- 24058905 TI - Population abundance of potentially pathogenic organisms in intestinal microbiome of jungle crow (Corvus macrorhynchos) shown with 16S rRNA gene-based microbial community analysis. AB - Jungle Crows (Corvus macrorhynchos) prefer human habitats because of their versatility in feeding accompanied with human food consumption. Therefore, it is important from a public health viewpoint to characterize their intestinal microbiota. However, no studies have been involved in molecular characterization of the microbiota based on huge and reliable number of data acquisition. In this study, 16S rRNA gene-based microbial community analysis coupled with the next generation DNA sequencing techniques was applied to the taxonomic classification of intestinal microbiome for three jungle crows. Clustering of the reads into 130 operational taxonomic units showed that at least 70% of analyzed sequences for each crow were highly homologous to Eimeria sp., which belongs to the protozoan phylum Apicomplexa. The microbiotas of three crows also contained potentially pathogenic bacteria with significant percentages, such as the genera Campylobacter and Brachyspira. Thus, the profiling of a large number of 16S rRNA gene sequences in crow intestinal microbiomes revealed the high-frequency existence or vestige of potentially pathogenic microorganisms. PMID- 24058907 TI - Evidence for the treatment of osteoporosis with vitamin D in residential care and in the community dwelling elderly. AB - INTRODUCTION: Vitamin D is common treatment for osteoporosis. Both age >70 years and living in residential care are associated with increased fracture risk. Community dwelling elderly are a heterogeneous group who may have more similatiry with residential care groups than younger community dwelling counterparts. AIMS: To review the evidence for cholecalciferol or ergocalciferol tretment of osteoporosis in either community dwelling patients aged >=70 years of age, or redidential care patients. Secondly endpoints were changes in bone mineral denisty, and in bone turnover markers. METHODS: We performed a literature search using search terms for osteoporosis and vitamin D. Treatment for at least one year was required. RESULTS: Only one residential care study using cholecalciferol, showed non-vertebral and hip fracture reduction in vitamin D deficient subjects. In the community setting one quasi randomised study using ergocalciferol showed reduction in total but not hip or non-vertebral fracture, and a second randomised study showed increased hip fracture risk. Three studies reported increases in hip bone mineral denisty. DISCUSSION: A minority of studies demonstrated a fracture benefit form vitamin D and one suggested possible harm in a community setting. Current practice should be to only offer this treatment to subjects identified as deficient. PMID- 24058906 TI - Sporadic cerebral cavernous malformations: report of further mutations of CCM genes in 40 Italian patients. AB - Cerebral cavernous malformations (CCMs) are vascular lesions characterized by abnormally enlarged capillary cavities, affecting the central nervous system. CCMs can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (K-Rev interaction trapped 1 (KRIT1)), CCM2 (MGC4607), and CCM3 (PDCD10). CCMs occur as a single or multiple malformations that can lead to seizures, focal neurological deficits, hemorrhagic stroke, and headache. However, patients are frequently asymptomatic. In our previous mutation screening, performed in a cohort of 95 Italian patients, both sporadic and familial, we have identified several mutations in CCM genes, three of which in three distinct sporadic patients. In this study, representing further molecular screening of the three CCM genes, in a south Italian cohort of CCM patients enrolled by us in the last three years, we report the identification of other four new mutations in 40 sporadic patients with either single or multiple CCM. PMID- 24058908 TI - A qualitative study of barriers to enrollment into free HIV care: perspectives of never-in-care HIV-positive patients and providers in Rakai, Uganda. AB - BACKGROUND: Early entry into HIV care is low in Sub-Saharan Africa. In Rakai, about a third (31.5%) of HIV-positive clients who knew their serostatus did not enroll into free care services. This qualitative study explored barriers to entry into care from HIV-positive clients who had never enrolled in care and HIV care providers. METHODS: We conducted 48 in-depth interviews among HIV-infected individuals aged 15-49 years, who had not entered care within six months of result receipt and referral for free care. Key-informant interviews were conducted with 12 providers. Interviews were audio-recorded and transcripts subjected to thematic content analysis based on the health belief model. RESULTS: Barriers to using HIV care included fear of stigma and HIV disclosure, women's lack of support from male partners, demanding work schedules, and high transport costs. Programmatic barriers included fear of antiretroviral drug side effects, long waiting and travel times, and inadequate staff respect for patients. Denial of HIV status, belief in spiritual healing, and absence of AIDS symptoms were also barriers. CONCLUSION: Targeted interventions to combat stigma, strengthen couple counseling and health education programs, address gender inequalities, and implement patient-friendly and flexible clinic service hours are needed to address barriers to HIV care. PMID- 24058909 TI - Endometrial polyps in women affected by levothyroxine-treated hypothyroidism- histological features, immunohistochemical findings, and possible explanation of etiopathogenic mechanism: a pilot study. AB - The aim of the study was to investigate the possible overexpression of estrogen (ERs) and progesterone (PRs) receptors both in EPs glandular and stromal cells in postmenopausal women with levothyroxine-treated hypothyroidism in comparison to EPs detected in women with physiological thyroid hormone levels. During the study period (January-February 2013) 22 patients were eligible (12 treated, 10 controls). The two groups were homogenous for general, EPs sonographic and hysteroscopic features. None of the cases of atypia was found. Immunohistochemistry showed that the two groups were similar for ERs and PRs intensity rates in EPs glandular cells despite a trend of ERs percentage expression more than 60% in 2/3 of treated patients versus 1/3 of controls. In stromal EPs components, ERs intensity was high positive in 10 (83,3%) treated cases while it was high positive in 1 control (10%). Percentage of ERs stromal expression showed a different trend between the two groups despite a borderline statistical significance. Our hypothesis is based on a possible double action of hypothyroidism and thyroxine intake: the subclinical TSH increased levels and its possible circadian oscillation could stimulate the endometrial TSHRs (increasing type 2 DIO activity); the circulating levels of exogenous thyroxine could be locally metabolized in active form by type 2 DIO stimulating ERs. PMID- 24058910 TI - Serum proteome analysis in patients with rheumatoid arthritis receiving therapy with tocilizumab: an anti-interleukin-6 receptor antibody. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disorder of the synovial membrane that results in the destruction of bone and cartilage in affected joints. Tocilizumab is a biological agent and an anti-interleukin-6 (IL-6) receptor monoclonal antibody that blocks IL-6-mediated inflammatory processes in RA patients. In order to identify novel disease-related proteins and candidate biomarkers, we analyzed the changes in the serum proteome profiles of patients with RA who were treated with tocilizumab. Serum samples were collected from the RA patients before and after tocilizumab treatment. Following immunodepletion of major proteins, the proteins were digested and labeled with isobaric tag, iTRAQ reagent. The proteins were identified and quantified using liquid chromatography tandem mass spectrometry. Among a total of 311 proteins identified, seven were decreased and 16 were increased by tocilizumab treatment. Although some of the proteins are known to be related to RA, several are currently unknown with respect to their relationship to RA and may be involved in the development of this disease. This study is the first to perform a comparative serum proteomic analysis of RA patients treated with tocilizumab. Our results may contribute to the identification of novel disease-related proteins and enhance the understanding of the pathogenesis of RA. PMID- 24058911 TI - Thermal stability of glucokinases in Thermoanaerobacter tengcongensis. AB - In the genome of Thermoanaerobacter tengcongensis, three genes belonging to ROK (Repressor, ORF, and Kinase) family are annotated as glucokinases (GLKs). Using enzyme assays, the three GLKs were identified as ATP-dependent GLK (ATP-GLK), ADP dependent GLK (ADP-GLK), and N-acetyl-glucosamine/mannosamine kinase (glu/man NacK). The kinetic properties of the three GLKs such as K(m), V(max), optimal pH, and temperature were characterized, demonstrating that these enzymes performed the specific functions against varied substrates and under different temperatures. The abundance of ATP-GLK was attenuated when culture temperature was elevated and was almost undetectable at 80 degrees C, whereas the ADP-GLK abundance was insensitive to temperature changes. Using degradation assays, ATP GLK was found to have significantly faster degradation than ADP-GLK at 80 degrees C. Co-immunoprecipitation results revealed that heat shock protein 60 (HSP60) could interact with ATP-GLK and ADP-GLK at 60 and 75 degrees C, whereas at 80 degrees C, the interaction was only effectively with ADP-GLK but not ATP-GLK. The functions of GLKs in T. tengcongensis are temperature dependent, likely regulated through interactions with HSP60. PMID- 24058912 TI - Magnetic resonance imaging of cardiovascular fibrosis and inflammation: from clinical practice to animal studies and back. AB - Late gadolinium enhancement is the technique of choice for detecting myocardial fibrosis. Although this technique is used in a wide range of cardiovascular pathologies, ischemic cardiomyopathy and the workup for myocarditis and other cardiomyopathies make up a significant proportion of the total indications. Multiple studies during the last decade have demonstrated its utility to adequately characterize myocardial tissue and offer diagnostic and prognostic information. Recent T1 mapping techniques aim to overcome the limitations of late gadolinium enhancement to assess diffuse fibrosis. 19F magnetic resonance has recently emerged as a promising technique for the assessment of inflammation. In the following review we will discuss the basic aspects of fibrosis assessment with MR and its utility for diagnostic and prognostic evaluation. We will also address the topic of cardiovascular inflammation imaging with 19F as a potential new development that may broaden the indications for MR in the future. PMID- 24058913 TI - Solid lipid nanoparticles of guggul lipid as drug carrier for transdermal drug delivery. AB - Diclofenac sodium loaded solid lipid nanoparticles (SLNs) were formulated using guggul lipid as major lipid component and analyzed for physical parameters, permeation profile, and anti-inflammatory activity. The SLNs were prepared using melt-emulsion sonication/low temperature-solidification method and characterized for physical parameters, in vitro drug release, and accelerated stability studies, and formulated into gel. Respective gels were compared with a commercial emulgel (CEG) and plain carbopol gel containing drug (CG) for ex vivo and in vivo drug permeation and anti-inflammatory activity. The SLNs were stable with optimum physical parameters. GMS nanoparticle 1 (GMN-1) and stearic acid nanoparticle 1 (SAN-1) gave the highest in vitro drug release. Guggul lipid nanoparticle gel 3 (GLNG-3) showed 104.68 times higher drug content than CEG in receptor fluid. The enhancement ratio of GLNG-3 was 39.43 with respect to CG. GLNG-3 showed almost 8.12 times higher C(max) than CEG at 4 hours. The AUC value of GLNG-3 was 15.28 times higher than the AUC of CEG. GLNG-3 showed edema inhibition up to 69.47% in the first hour. Physicochemical properties of major lipid component govern the properties of SLN. SLN made up of guggul lipid showed good physical properties with acceptable stability. Furthermore, it showed a controlled drug release profile along with a promising permeation profile. PMID- 24058914 TI - Sustainability at the edge of chaos: its limits and possibilities in public health. AB - This paper critically reviews the expanding literature on applications of sustainability to healthcare policy and planning. It argues that the concept has been overgeneralized and has become a buzzword masking disparate agendas. It ignores the insights of the newest generation of systems theory on complex systems on the ubiquity of far-from-equilibrium conditions. Yet, a central meaning often ascribed to sustainability is the level continuation of healthcare programs and their institutionalization. Sustainability is only coherent in health care when it is more narrowly delimited to involve public health and treated as only one of several evaluative criteria that informs not only the continuation of programs but more often their expansion or contraction as needs dynamically change. PMID- 24058916 TI - Quality of life after stapled hemorrhoidopexy: a prospective observational study. AB - OBJECTIVE: The objective of the study was to assess the change in quality of life (QOL) of patients undergoing stapled hemorrhoidopexy (SH) using WHO Quality of Life-BREF (WHOQOL-BREF) questionnaire. METHODS: The study sample comprised patients with symptomatic II, III, and IV degree hemorrhoids, undergoing SH. The patients were asked to complete WHOQOL-BREF questionnaire before and one month following the surgery. RESULT: There were 20 patients in the study group. The postoperative pain score measured by visual analogue scale at six hours postoperatively was 7.60 +/- 1.23, which reduced to 0.70 +/- 0.92 at 24 hours. The items in the WHOQOL-BREF had high-internal consistency or reliability as shown by high Cronbach's alpha coefficient which was 0.82 and 0.90 for pre- and postoperative questionnaires. There was significant improvement in the overall perception of QOL and health, and in physical and psychological domains. There was modest improvement in environmental domain, while no change was noted in social domain. CONCLUSION: SH improved the quality of life of patients treated for hemorrhoids. PMID- 24058915 TI - Possible future monoclonal antibody (mAb)-based therapy against arbovirus infections. AB - More than 150 arboviruses belonging to different families are known to infect humans, causing endemic infections as well as epidemic outbreaks. Effective vaccines to limit the occurrence of some of these infections have been licensed, while for the others several new immunogens are under development mostly for their improvements concerning safety and effectiveness profiles. On the other hand, specific and effective antiviral drugs are not yet available, posing an urgent medical need in particular for emergency cases. Neutralizing monoclonal antibodies (mAbs) have been demonstrated to be effective in the treatment of several infectious diseases as well as in preliminary in vitro and in vivo models of arbovirus-related infections. Given their specific antiviral activity as well tolerated molecules with limited side effects, mAbs could represent a new therapeutic approach for the development of an effective treatment, as well as useful tools in the study of the host-virus interplay and in the development of more effective immunogens. However, before their use as candidate therapeutics, possible hurdles (e.g., Ab-dependent enhancement of infection, occurrence of viral escape variants) must be carefully evaluated. In this review are described the main arboviruses infecting humans and candidate mAbs to be possibly used in a future passive immunotherapy. PMID- 24058917 TI - Rapid purification and procoagulant and platelet aggregating activities of Rhombeobin: a thrombin-like/gyroxin-like enzyme from Lachesis muta rhombeata snake venom. AB - We report a rapid purification method using one-step chromatography of SVSP Rhombeobin (LMR-47) from Lachesis muta rhombeata venom and its procoagulant activities and effects on platelet aggregation. The venom was fractionated by a single chromatographic step in RP-HPLC on a C8 Discovery BIO Wide Pore, showing high degree of molecular homogeneity with molecular mass of 47035.49 Da. Rhombeobin showed amidolytic activity upon BA rho NA, with a broad optimum pH (7 10) and was stable in solution up to 60 degrees C. The amidolytic activity was inhibited by serine proteinase inhibitors and reducing agents, but not chelating agents. Rhombeobin showed high coagulant activity on mice plasma and bovine fibrinogen. The deduced amino acid sequence of Rhombeobin showed homology with other SVSPs, especially with LM-TL (L. m. muta) and Gyroxin (C. d. terrificus). Rhombeobin acts, in vitro, as a strong procoagulant enzyme on mice citrated plasma, shortening the APTT and PT tests in adose-dependent manner. The protein showed, "ex vivo", a strong defibrinogenating effect with 1 ug/animal. Lower doses activated the intrinsic and extrinsic coagulation pathways and impaired the platelet aggregation induced by ADP. Thus, this is the first report of a venom component that produces a venom-induced consumptive coagulopathy (VICC). PMID- 24058918 TI - Optimization of sulfide/sulfite pretreatment of lignocellulosic biomass for lactic acid production. AB - Potential of sodium sulfide and sodium sulfite, in the presence of sodium hydroxide was investigated to pretreat the corncob (CC), bagasse (BG), water hyacinth and rice husk (RH) for maximum digestibility. Response Surface Methodology was employed for the optimization of pretreatment factors such as temperature, time and concentration of Na2S and Na2SO3, which had high coefficient of determination (R2) along with low probability value (P), indicating the reliable predictability of the model. At optimized conditions, Na2S and Na2SO3 remove up to 97% lignin, from WH and RH, along with removal of hemicellulose (up to 93%) during pretreatment providing maximum cellulose, while in BG and CC; 75.0% and 90.0% reduction in lignin and hemicellulose was observed. Saccharification efficiency of RH, WH, BG and CC after treatment with 1.0% Na2S at 130 degrees C for 2.3-3.0 h was 79.40, 85.93, 87.70, and 88.43%, respectively. WH treated with Na2SO3 showed higher hydrolysis yield (86.34%) as compared to Na2S while other biomass substrates showed 2.0-3.0% less yield with Na2SO3. Resulting sugars were evaluated as substrate for lactic acid production, yielding 26.48, 25.36, 31.73, and 30.31 gL-1 of lactic acid with 76.0, 76.0, 86.0, and 83.0% conversion yield from CC, BG, WH, and RH hydrolyzate, respectively. PMID- 24058920 TI - Comparative analysis of context-dependent mutagenesis using human and mouse models. AB - Substitution rates strongly depend on their nucleotide context. One of the most studied examples is the excess of C > T mutations in the CG context in various groups of organisms, including vertebrates. Studies on the molecular mechanisms underlying this mutation regularity have provided insights into evolution, mutagenesis, and cancer development. Recently several other hypermutable motifs were identified in the human genome. There is an increased frequency of T > C mutations in the second position of the words ATTG and ATAG and an increased frequency of A > C mutations in the first position of the word ACAA. For a better understanding of evolution, it is of interest whether these mutation regularities are human specific or present in other vertebrates, as their presence might affect the validity of currently used substitution models and molecular clocks. A comprehensive analysis of mutagenesis in 4 bp mutation contexts requires a vast amount of mutation data. Such data may be derived from the comparisons of individual genomes or from single nucleotide polymorphism (SNP) databases. Using this approach, we performed a systematical comparison of mutation regularities within 2-4 bp contexts in Mus musculus and Homo sapiens and uncovered that even closely related organisms may have notable differences in context-dependent mutation regularities. PMID- 24058919 TI - Effects of an alpha7 nicotinic receptor agonist and stress on spatial memory in an animal model of Alzheimer's disease. AB - The aim of the present study was to test the effects of PNU-282987 on spatial learning and memory and hippocampal neurogenesis in both intact and chronically stressed transgenic mice. Transgenic mice with susceptibility to Alzheimer's disease (AD) under immobilization stress and not-stressed animals receiving 0 and 1 mg/kg of PNU-282987 (PNU) were evaluated in a water maze task. The effects of PNU and stress on proliferation of new cells in the hippocampus of these animals were also assessed. The latency to escape the platform was significantly higher in transgenic stressed mice compared to those in the wild stressed group, as well as in transgenic animals without PNU compared to control wild group. On retention of the task, differences emerged on stressed wild animals, PNU wild group, and stressed wild mice receiving PNU. However, no significant differences were detected on new cell proliferation. The results of the present study did not show any impact of stress in acquisition of a spatial task both in wild and transgenic mice. No clear effects of PNU on acquisition of a spatial task in transgenic mice with susceptibility to AD were detected. Although PNU and stress effects were detected on retention of the task in wild animals, no changes were noted in transgenic mice. PMID- 24058921 TI - Quantitative trait locus linkage analysis in a large Amish pedigree identifies novel candidate loci for erythrocyte traits. AB - We characterized a large Amish pedigree and, in 384 pedigree members, analyzed the genetic variance components with covariate screen as well as genome-wide quantitative trait locus (QTL) linkage analysis of red blood cell count (RBC), hemoglobin (HB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), platelet count (PLT), and white blood cell count (WBC) using SOLAR. Age and gender were found to be significant covariates in many CBC traits. We obtained significant heritability estimates for RBC, MCV, MCH, MCHC, RDW, PLT, and WBC. We report four candidate loci with LOD scores above 2.0: 6q25 (MCH), 9q33 (WBC), 10p12 (RDW), and 20q13 (MCV). We also report eleven candidate loci with LOD scores between 1.5 and < 2.0. Bivariate linkage analysis of MCV and MCH on chromosome 20 resulted in a higher maximum LOD score of 3.14. Linkage signals on chromosomes 4q28, 6p22, 6q25, and 20q13 are concomitant with previously reported QTL. All other linkage signals reported herein represent novel evidence of candidate QTL. Interestingly rs1800562, the most common causal variant of hereditary hemochromatosis in HFE (6p22) was associated with MCH and MCHC in this family. Linkage studies like the one presented here will allow investigators to focus the search for rare variants amidst the noise encountered in the large amounts of data generated by whole genome sequencing. PMID- 24058923 TI - Efficient Recursive Algorithms for Computing the Mean Diffusion Tensor and Applications to DTI Segmentation? AB - Computation of the mean of a collection of symmetric positive definite (SPD) matrices is a fundamental ingredient of many algorithms in diffusion tensor image (DTI) processing. For instance, in DTI segmentation, clustering, etc. In this paper, we present novel recursive algorithms for computing the mean of a set of diffusion tensors using several distance/divergence measures commonly used in DTI segmentation and clustering such as the Riemannian distance and symmetrized Kullback-Leibler divergence. To the best of our knowledge, to date, there are no recursive algorithms for computing the mean using these measures in literature. Recursive algorithms lead to a gain in computation time of several orders in magnitude over existing non-recursive algorithms. The key contributions of this paper are: (i) we present novel theoretical results on a recursive estimator for Karcher expectation in the space of SPD matrices, which in effect is a proof of the law of large numbers (with some restrictions) for the manifold of SPD matrices. (ii) We also present a recursive version of the symmetrized KL divergence for computing the mean of a collection of SPD matrices. (iii) We present comparative timing results for computing the mean of a group of SPD matrices (diffusion tensors) depicting the gains in compute time using the proposed recursive algorithms over existing non-recursive counter parts. Finally, we also show results on gains in compute times obtained by applying these recursive algorithms to the task of DTI segmentation. PMID- 24058922 TI - Motor Neurons Exhibit Sustained Loss of Atrophy Reversal in Immunodeficent Mice. AB - Our lab showed previously that whereas a substantial portion of chronically resected facial motor neurons reside in an atrophied state that can be reversed at 14 days following reinjury in wild-type (WT) mice, atrophy reversal was altered in immunodeficient mice. It was unclear, however, if the abnormal response at day 14 post-reinjury in immunodeficient mice might be due to differences in the kinetics of the reversal response or impaired regeneration. We sought to address this question, and test our working hypothesis that the normal regeneration of atrophied motor neurons is dependent on normal adaptive immunity, by comparing WT and immunodeficient recombination activating gene-2 knockout (RAG2-KO) mice that lack a mature T and B lymphocytes, at 3 and 28 days following reinjury. In WT mice, facial motor neurons that were resected for 10 weeks and subsequently reinjured for 3 days were able to regain fully an apparent 40% loss of countable neurons, and nearly 45% of that robust increase in neurons was sustained at 28 days post-reinjury in the WT mice. By contrast, at both 3 and 28 days post-reinjury RAG2-KO mice failed to show any increase in neuronal number. Size measurements showed that the surviving neurons of WT and RAG2-KO mice exhibited substantial motor neuron hypertrophy at 3 days post-reinjury, and similar levels of normal size motor neurons by 28 days post-reinjury. Among the WT mice, small numbers of T lymphocytes where found in the reinjured facial motor nucleus (FMN), and were significantly higher at 3 days, but not 28 days, in the reinjury compared to sham-reinjury groups. No differences were seen between the WT and RAG2-KO mice in overall microglial cell activity using CD11b expression following reinjury. These data suggest that many resected motor neurons did not survive the initial resection in RAG2-KO mice, whereas in WT mice they atrophied and could be restimulated by reinjury to regenerate their phenotype. Moreover, they indicate that normal T cell function, or some yet unknown function of the RAG2 gene in the brain, is essential for activating regeneration programs of atrophied motor neurons - programs with therapeutic potential for modifying neuroplasticity. PMID- 24058924 TI - Molecular depth profiling of organic photovoltaic heterojunction layers by ToF SIMS: comparative evaluation of three sputtering beams. AB - With the recent developments in secondary ion mass spectrometry (SIMS), it is now possible to obtain molecular depth profiles and 3D molecular images of organic thin films, i.e. SIMS depth profiles where the molecular information of the mass spectrum is retained through the sputtering of the sample. Several approaches have been proposed for "damageless" profiling, including the sputtering with SF5(+) and C60(+) clusters, low energy Cs(+) ions and, more recently, large noble gas clusters (Ar500-5000(+)). In this article, we evaluate the merits of these different approaches for the in depth analysis of organic photovoltaic heterojunctions involving poly(3-hexylthiophene) (P3HT) as the electron donor and [6,6]-phenyl C61 butyric acid methyl ester (PCBM) as the acceptor. It is demonstrated that the use of 30 keV C60(3+) and 500 eV Cs(+) (500 eV per atom) leads to strong artifacts for layers in which the fullerene derivative PCBM is involved, related to crosslinking and topography development. In comparison, the profiles obtained using 10 keV Ar1700(+) (~6 eV per atom) do not indicate any sign of artifacts and reveal fine compositional details in the blends. However, increasing the energy of the Ar cluster beam beyond that value leads to irreversible damage and failure of the molecular depth profiling. The profile qualities, apparent interface widths and sputtering yields are analyzed in detail. On the grounds of these experiments and recent molecular dynamics simulations, the discussion addresses the issues of damage and crater formation induced by the sputtering and the analysis ions in such radiation-sensitive materials, and their effects on the profile quality and the depth resolution. Solutions are proposed to optimize the depth resolution using either large Ar clusters or low energy cesium projectiles for sputtering and/or analysis. PMID- 24058925 TI - Label-free fluorescence probe based on structure-switching aptamer for the detection of interferon gamma. AB - A novel label-free fluorescence probe based on structure-switching aptamer was developed for the detection of interferon-gamma (IFN-gamma). In this work, a single stranded DNA (ssDNA) with G-rich sequence (aptamer) was folded into secondary G-quadruplex structures in the presence of Na(+) and Mg(2+), thiazole orange (TO) was then intercalated into the G-quadruplex structures, resulting in a high fluorescence emission. The target combined with its aptamer, disrupts G quadruplex structure and releases TO, resulting in a reduction of fluorescence. Using IFN-gamma as the model target, the proposed fluorescence probe shows a linear range from 3.0 to 120 nM with a detection limit of 2.0 nM. The proposed strategy avoids complicated covalent modifications or chemical labeling, and thus offers advantages of simplicity and cost efficiency. PMID- 24058926 TI - The evolution of species recognition signals. PMID- 24058927 TI - Proteases hold the key to an exclusive mutualism. AB - Mutualisms, cooperative interactions between species, generally involve an economic exchange: species exchange commodities that are cheap for them to provide, for ones that cannot be obtained affordably or at all. But these associations can only succeed if effective partners can be enticed to interact. In some mutualisms, partners can actively seek one another out. However, plants, which use mutualists for a wide array of essential life history functions, do not have this option. Instead, natural selection has repeatedly favoured the evolution of rewards - nutritional substances (such as sugar-rich nectar and fleshy fruit) with which plants attract certain organisms whose feeding activities can then be co-opted for their own benefit. The trouble with rewards, however, is that they are usually also attractive to organisms that confer no benefits at all. Losing rewards to 'exploiters' makes a plant immediately less attractive to the mutualists it requires; if the reward cannot be renewed quickly (or at all), then mutualistic service is precluded entirely. Thus, it is in plants' interests to either restrict rewards to only the most beneficial partners or somehow punish or deter exploiters. Yet, at least in cases where the rewards are highly nutritious, we can expect counter-selection for exploiter traits that permit them to skirt such control. How, then, can mutualisms persist? In this issue, Orona-Tamayo et al. () describe a remarkable adaptation that safeguards one particularly costly reward from nonmutualists. Their study helps to explain the evolutionary success of an iconic interaction and illuminates one way in which mutualism as a whole can persist in the face of exploitation. PMID- 24058928 TI - Next-generation QTL mapping: crowdsourcing SNPs, without pedigrees. AB - For many molecular ecologists, the mantra and mission of the field of ecological genomics could be encapsulated by the phrase 'to find the genes that matter' (Mitchell-Olds ; Rockman ). This phrase of course refers to the early hope and current increasing success in the search for genes whose variation underlies phenotypic variation and fitness in natural populations. In the years since the modern incarnation of the field of ecological genomics, many would agree that the low-hanging fruit has, at least in principle, been plucked: we now have several elegant examples of genes whose variation influences key adaptive traits in natural populations, and these examples have revealed important insights into the architecture of adaptive variation (Hoekstra et al. ; Shapiro et al. ; Chan et al. ). But how well will these early examples, often involving single genes of large effect on discrete or near-discrete phenotypes, represent the dynamics of adaptive change for the totality of phenotypes in nature? Will traits exhibiting continuous rather than discrete variation in natural populations have as simple a genetic basis as these early examples suggest (Prasad et al. ; Rockman )? Two papers in this issue (Robinson et al. ; Santure et al. ) not only suggest answers to these questions but also provide useful extensions of statistical approaches for ecological geneticists to study the genetics of continuous variation in nature. Together these papers, by the same research groups studying evolution in a natural population of Great Tits (Parus major), provide a glimpse of what we should expect as the field begins to dissect the genetic basis of what is arguably the most common type of variation in nature, and how genome-wide surveys of variation can be applied to natural populations without pedigrees. PMID- 24058929 TI - Reply to A. Surbone et al. PMID- 24058930 TI - Reply to P.J. Leary et al. PMID- 24058931 TI - Reply to K.S. Wilson et al. PMID- 24058932 TI - Immune response in spirlins (Alburnoides bipunctatus, Bloch 1782) infested by Ligula intestinalis parasite. AB - Ligula intestinalis parasite is a cestode that can cause remarkable damages to fishes. SDS-PAGE is one of the methods that can be used to determine the immune serum band polymorphism and immune responses in fishes infested by Ligula intestinalis. This study reports the results of an investigation conducted using SDS-PAGE focusing on immune serum band polymorphism and on the reaction of the immune system in spirlins (Alburnoides bipunctatus) infested by pleurocercoids of Ligula intestinalis parasite. Serum samples from infested spirlins revealed a polymorphism band which differed from that reported in sera of roaches (Rutilus rutilus), a species of the same Cyprinidae family. PMID- 24058933 TI - Author's reply: To PMID 22824608. PMID- 24058934 TI - Climate change: A patchwork of emissions cuts. PMID- 24058935 TI - History: Pushing the climate frontier. PMID- 24058936 TI - Small steps toward a better treatment for chronic hepatitis C infection: mericitabine, pegylated interferon, and ribavirin in the PROPEL and JUMP-C trials. PMID- 24058937 TI - Lab life: Battle zone. PMID- 24058938 TI - The final assessment. PMID- 24058941 TI - Author response. PMID- 24058939 TI - Spooked. PMID- 24058943 TI - [Practical note to electron microscopy]. PMID- 24058942 TI - The alphabet of sport science research starts with Q. PMID- 24058945 TI - [Not Available]. PMID- 24058944 TI - [Not Available]. PMID- 24058946 TI - [Not Available]. PMID- 24058947 TI - Experts: to crack down on violence in the ED, establish a robust system of reporting, educating staff. AB - Researchers say that most ED personnel will experience some form of physical or verbal violence at some point in their careers. However, when such incidents are regularly reported, the patients involved can be flagged in a hospital's computer system, making future events involving the same patients much less likely. Further, when ED personnel are alert to the clues that a patient or family member is becoming agitated, early intervention can usually prevent the situation from escalating to violence. About one-half of all ED personnel will experience a physical assault, and 97%-100% will experience verbal abuse during their careers, according to research. A first step in developing a strategy for dealing with violence is to educate ED personnel about what constitutes workplace violence so that all such incidents can be reported. Experts say many ED workers fail to recognize some instances of violence, based on the intent of the person involved. However, intent should not be a factor, they say. In many cases, empathy and good customer service skills can prevent tense situations from escalating to violence, but experts say that it is important to intervene at the first sign of agitation. ED administrators should gather input from frontline staff on how to most effectively derail instances of violence. PMID- 24058948 TI - In a dynamic health care environment, take steps to fully leverage case managers in the ED. AB - In an effort to create more capacity while also improving the patient experience, the University of Virginia Medical Center (UVAMC) in Charlottesville, VA, has taken steps to better leverage case managers in the ED. Under the new approach, case managers work alongside clinicians on the floor. They step in when added resources are needed or services need to be arranged before discharge. Administrators say the new ED case manager role has helped UVAMC reduce medically unnecessary length-of-stay by 34 minutes, enabling the hospital to see up to 4,000 additional patients per year. The ED-based case managers learn of patients who may benefit from their involvement by regularly participating in flow rounds with clinicians on the floor. Administrators are eyeing future improvements from the approach, including a concentrated effort to reduce visits to the ED by frequent utilizers. PMID- 24058949 TI - ED accreditation update. Hospitals put on notice: alarm management is a top priority for 2014. AB - Establishing alarm management as a new National Patient Safety Goal (NPSG), The Joint Commission (TJC) is calling on hospitals to make the issue a safety priority, and to begin establishing policies and procedures designed to minimize alarm fatigue among clinical staff. Beginning on January 1,2014, hospitals need to begin identifying the most important alarm signals to manage based on input from staff as well as factors such as patient risk, and the potential for harm as demonstrated by the device's history. By January 1,2016, hospitals need to have policies and procedures in place for managing alarms identified in the first phase of the NPSG's requirements. Also, staff and independent licensed practitioners need to be educated about the purpose and proper operation of alarm systems that they are responsible for. PMID- 24058950 TI - Pilot study: an ED-based HIV screening program can be more productive when combined with a peer referral program. AB - In a pilot study, researchers at the University of Cincinnati have found that when a peer referral program is combined with an ED-based HIV screening program, more cases of undiagnosed HIV can be detected, providing a preventive health benefit to the community. However, more studies are needed to determine how to best capitalize on the yield of ED-based screening programs, and to get better estimates on the potential benefits of combining social networking programs with screening programs. Dedicated testers and a streamlined process for enabling patients to be signed in as outpatients rather than ED patients were key aspects of the program. To reach into the social networks of patients who tested positive for HIV or were at high risk, program staff provided them with coupons for free HIV testing that they could pass on to their friends and partners. In particular, program staff targeted any companions or partners of patients who were in the ED with them when they came in for testing. Between May and September of 2011, 466 patients were tested, with four patients testing positive for HIV. Among participants in the testing/peer-referral program, 34% had no prior visit to the ED, and 69% had never been tested by the ED-based HIV testing program. PMID- 24058951 TI - Earthshaking proposal from CMS may change how ED visits are billed. PMID- 24058952 TI - [To the Editors: Historical occurrences of various diseases in Hungary]. PMID- 24058953 TI - The first themed issue for the Journal. Preface. PMID- 24058954 TI - [History of stomatogenetic teaching from the view of a geneticist]. PMID- 24058955 TI - Response to letter regarding article, "Bilateral internal mammary artery grafting enhances survival in diabetic patients: a 30-year follow-up of propensity score matched cohorts". PMID- 24058956 TI - Reply to Wang et al.: Snow cover and air temperature affect the rate of changes in spring phenology in the Tibetan Plateau. PMID- 24058957 TI - Reply to Carnicer et al.: Environmental heterogeneity reduces breeding bird richness in Catalonia by increasing extinction rates. PMID- 24058958 TI - Reply to Kline et al.: Cropland data layer provides a valid assessment of recent grassland conversion in the Western Corn Belt. PMID- 24058959 TI - [Current problems in medical parasitology]. PMID- 24058960 TI - Dosimetric promise versus cost: critics question proton therapy. PMID- 24058962 TI - Combination chemotherapy for lung cancer patients. PMID- 24058961 TI - Carcinogenicity of some drugs and herbal products. PMID- 24058963 TI - Targeting the B-cell signalling pathway in CLL and MCL. PMID- 24058964 TI - Artifacts marr the genetic signature of cancer. PMID- 24058965 TI - India urged to reverse dextropropoxyphene ban. PMID- 24058966 TI - Lenalidomide as first-line therapy for elderly CLL patients. PMID- 24058967 TI - Afatinib monotherapy in EGFR-mutant lung adenocarcinoma. PMID- 24058968 TI - Cigarette packaging--EU progress, UK stalls. PMID- 24058969 TI - Arsenic trioxide combination improves survival in APL. PMID- 24058970 TI - Virus-fighting protein causes mutations in cancers. PMID- 24058971 TI - Maintenance therapy improves survival of NSCLC patients. PMID- 24058972 TI - [Staphylococcal exotoxins are not a trigger for antrochoanal polyps]. PMID- 24058973 TI - Heritable genetic changes in the open. PMID- 24058974 TI - The author file: Anne-Claude Gingras. PMID- 24058975 TI - Points of view: Storytelling. PMID- 24058976 TI - Fishing for fluorescent proteins. PMID- 24058977 TI - The pull of a cell. PMID- 24058978 TI - Protein GPS. PMID- 24058979 TI - Engineering to find function. PMID- 24058980 TI - Missing the target? PMID- 24058981 TI - [Punch biopsy as an alternative to surgical biopsy]. PMID- 24058982 TI - Retraction notice to "Hopf bifurcation stability in Hopfield neural networks" [Neural Networks 36 (2012) 51-58]. PMID- 24058983 TI - [3D MRI for the representation of fat infiltration in the lumbar muscles]. PMID- 24058984 TI - [Linear contrast enhancement of the thrombus improved prognosis of PCI]. PMID- 24058985 TI - [Non-ionic contrast agent gadobutrol preference clarified]. PMID- 24058986 TI - [Adapted radiation and contrast doses for age-specific risks]. PMID- 24058987 TI - [Is successful localization of herniated discs closed?]. PMID- 24058988 TI - [A one-time MRI reduced the incidence of metachronous contralateral tumors?]. PMID- 24058989 TI - [CT-guided fine needle aspiration biopsy]. PMID- 24058990 TI - [MDCT angiography: Individualized contrast medium administration]. PMID- 24058991 TI - [Diagnostic laparoscopy is as essential as CT for staging]. PMID- 24058992 TI - [Prevention with the Salivagramm]. PMID- 24058993 TI - [Cross-sectoral pain treatment. Reply]. PMID- 24058994 TI - Report criticizes management of wild horses: herds continue to grow at fast pace. PMID- 24058995 TI - Most NIH research chimps to be retired. PMID- 24058996 TI - Disease risks change since SARS. PMID- 24058997 TI - Fighting a deadly pig disease. Industry, veterinarians trying to contain PED virus, new to the US. PMID- 24058998 TI - Lincoln Memorial gets green light from AVMA council: 85 students anticipated for fall 2014. PMID- 24058999 TI - The authors respond. PMID- 24059000 TI - Surgical versus nonsurgical management for overweight dogs with cranial cruciate ligament rupture. PMID- 24059001 TI - Use of marijuana in complementary and alternative veterinary medicine. PMID- 24059002 TI - Additional variables identified as significant return of spontaneous circulation in cardiac arrest and resuscitation. PMID- 24059003 TI - Improving the quality of reporting a cohort study. PMID- 24059004 TI - Peroneal nerve palsy after rapid weight loss due to uncontrolled diet in a patient treated with oral isotretinoin. PMID- 24059005 TI - Protecting uninsured patients from high hospital charges: lessons from California. AB - Key findings. (1) In 1997, the amount California hospitals billed uninsured patients was more than twice the amount hospitals received from Medicare for the same services. By 2010, billed charges had grown to be five times what Medicare paid, which trans-lated into a gap of more than $10,000 per day in the hospital. (2) Five years after the passage of the state's Hospital Fair Pricing Act, most California hospitals had financial assistance policies in place to make care more affordable for the state's uninsured population. (3) As of 2011, 81 percent of California hospitals reported charging low-income uninsured patients prices that were at or below Medicare rates. (4) While not required by the law, nearly all California hospitals reported offering free care to uninsured patients with incomes at or below 100 percent of poverty. PMID- 24059006 TI - Serum visfatin levels should be evaluated with further markers of endolthelial inflamation. PMID- 24059007 TI - Medicare program; obtaining final Medicare secondary conditional payment amounts via web portal. Interim final rule with comment period. AB - This interim final rule with comment period specifies the process and timeline for expanding CMS' existing Medicare Secondary Payer (MSP) Web portal to conform to section 201 of the Medicare IVIG and Strengthening Medicare and Repaying Taxpayers Act of 2012 (the SMART Act). The interim final rule specifies a timeline for developing a multifactor authentication solution to securely permit authorized users other than the beneficiary to access CMS' MSP conditional payment amounts and claims detail information via the MSP Web portal. It also requires that we add functionality to the existing MSP Web portal that permits users to: notify us that the specified case is approaching settlement; obtain time and date stamped final conditional payment summary forms and amounts before reaching settlement; and ensure that relatedness disputes and any other discrepancies are addressed within 11 business days of receipt of dispute documentation. PMID- 24059008 TI - [My 40-year studies on vertigo]. PMID- 24059009 TI - [On the special issue on "surgical treatment of severe heart failure"]. PMID- 24059010 TI - Serum gamma-glutamyltransferase and the burden of atherosclerosis in patients with acute coronary syndrome. PMID- 24059011 TI - Authors reply. PMID- 24059012 TI - [Not Available]. PMID- 24059013 TI - [Not Available]. PMID- 24059014 TI - Multimodal imaging approach to intracardiac masses for proper diagnosis, measurement, and definitive surgery. PMID- 24059015 TI - [My technique. Management of the pulmonary artery in the pericardium (left)]. PMID- 24059016 TI - Authors reply. PMID- 24059017 TI - [Clinical investigations and first case series of Takotsubo cardiomyopathy]. PMID- 24059018 TI - [Double-sleeve lingual segment resection]. PMID- 24059020 TI - [Use of iPad to facilitate the work of thoracic surgeons. Use of the "cloud"]. PMID- 24059019 TI - [Imaging diagnosis. Q & A: A raised lesion at the entry to the right lobar bronchus]. PMID- 24059021 TI - The accuracy of IOL power calculation formulas for eyes of axial length exceeding 24.5 mm. AB - PURPOSE: To compare the accuracy of different IOL power calculation formulas for eyes of axial length exceeding 24.5 mm. MATERIAL AND METHODS: 61 patients were examined, whose ocular axial lenght ranged between 24.51 mm and 26.72 mm. Preoperatively, the IOL power for each patient was calculated using six different formulas (SRK II, SRK/T, Binkhorst, Hoffer Q, Holladay 1, and Haigis). The power of the actually implanted IOL was based on Holladay 1 formula. Visual acuity was measured using Snellen chart on the 30th postoperative day. RESULTS: 54 patients (88.5%) achieved full visual acuity (1.0 on Snellen chart) after cataract surgery. If other power calculation formulas were used for the actual IOL, this would be achieved respectively in: SRK/T - 39 patients (63.9%), Hoffer O - 22 patients (36.1%), Binkhorst - 21 patients (34.4%), Haigis - 7 patients (11.5%), SRK II - 5 patients (8.2%). CONCLUSIONS: 1. Holladay 1 formula is recommended for intraocular lens power calculation for eyes of axial length exceeding 24.5 mm. 2. SRK/T formula also seems to be satisfactory for these cases. PMID- 24059022 TI - Association between the 25129A > C polymorphism of the nuclear respiratory factor 2 gene and age-related macular degeneration. AB - PURPOSE: Oxidative stress belongs to the main factors of pathogenesis of age related macular degeneration, characterized by the damage to the retinal pigment epithelium cells and photoreceptors. Retinal pigment epithelium cells are rich in mitochondria, producing large amount of reactive oxygen species, which are by products of the activity of the respiratory chain. The distribution in the activity of the chain may be evoked by the release of cytochrome C from the mitochondrion to the cytoplasm. This process may activated by nuclear respiratory factor 2, Nrf2, which is encoded by a highly polymorphic gene. In this study we examined the association between age-related macular degeneration risk and the 25129A > C polymorphism of the gene encoding nuclear respiratory factor 2 (rs12594956). MATERIAL AND METHODS: Genotypes were determined in DNA from peripheral blood lymphocytes of 281 patients with age-related macular degeneration (181 with wet form of the disease and 101 with its dry form), and 105 controls by PCR-restriction fragment length polymorphism. RESULTS: A weak association (OR 1.96; p = 0.023) between the C/C genotype of the 25129A > C polymorphism and the occurrence of age-related macular degeneration was found. A stronger association was observed between dry age-related macular degeneration occurrence and the C/C genotype of the polymorphism (OR 2.23; p = 0.018). The A/C genotype decreased the risk of age-related macular degeneration and its dry form (OR 0.51; p = 0.023 and 0.44; p = 0.018, respectively). Potential risk factors such as age, gender, smoking habit, living environment (rural or urban) and family status of age-related macular degeneration increased the risk of AMD associated with the C/C genotype (OR 2.52; p = 0.012). CONCLUSIONS: The 25129A > C polymorphism of the NRF2 gene may be associated with age-related macular degeneration. mitochondria, reactive oxygen species, gene polymorphism, NRF2 gene, age-related macular degeneration - AMD. PMID- 24059023 TI - [Analysis of risk factors of choroidal melanoma extraocular extension]. AB - PURPOSE: To report the risk factors for extraocular extension of uveal melanoma. MATERIAL AND METHODS: A retrospective study of 1144 enucleated eyes with ciliary body or/and choroidal melanoma. RESULTS: Extraocular extension or intrascleral invasion was found in 170 patients (14.86%), the nodular extraocular extension in 71 (6.20%). Extraocular extension was more common in older patients (> 50), large and medium size tumors, located close to the optic disc and mixed type. PMID- 24059024 TI - [Choroidal melanoma--routes of extraocular extension]. AB - PURPOSE: To report the routs of extraocular extension of uveal melanoma. MATERIAL AND METHODS: A retrospective study of 170 enucleated eyes with uveal melanoma and deep intrascleral tumor invasion and/or nodular extrascleral extension. RESULTS: The routes of passages by sclera were natural channels: ciliary arteries, ciliary nerves, optic nerve, vortex veins, aqueous channels and intrascleral melanoma invasion. PMID- 24059025 TI - [Dry eye disease in patients treated with antidepressants]. AB - PURPOSE: Dry eye disease is defined as a multifactorial disease of tears and ocular surfaces that causes discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. This study aimed to determine dry eye findings in patients with depression. MATERIAL AND METHODS: There were 40 patients with depression aged 18-65 years old. A comprehensive ophthalmic examination, including intraocular pressure and dry eye tests, was performed. RESULTS: Among patients with depression 24 patients (70%) had dry eye syndrome. Compared with patients who did not have dry eye, the patients with dry eye were significantly older than the patients without dry eye (44 years old and 36 years old, respectively). Time in duration of depression in patients with depression and with dry eye lasted over 54 months and time of taking antidepressants was longer than 18 months and was significant, in comparing to the patients without dry eye (36 months and 10 months, respectively). CONCLUSIONS: Dry eye is frequent disease in patients with depression, especially in older patients, who have longer duration of depression, and taking antidepressant medication for a longer period of time. Using of antidepressant may be cosidered as potential cause of dry eye syndrome. PMID- 24059026 TI - [Alterations in tears aqueous layer during cytostatics treatment]. AB - PURPOSE: The aim of the study was to evaluate tears secretion, pH and lysozyme activity in tears aqueous layer during chemotherapy in lung, breast and bowel cancer. MATERIAL AND METHODS: 36 patients were enrolled to the study. Depending on the type of cancer and type of chemotherapy patients were divided into three groups. Group I (12 patients) diagnosed with non-small-cell lung cancer treated with PE schema (cisplatin, etoposide), Group II (12 patients) with breast cancer treated with FAC schema (fluorouracil, doxorubicin, cyclophosphamide), Group III (12 patients) with bowel cancer treated with FU/LV schema (fluorouracil, leucovorin). In all the patients: Schirmer's I test, pH measurements and lysozyme test were performed. Patients were examined before chemotherapy, after 2nd, 4th, 6th cycle. RESULTS: In group I and II lowering of tears secretion (p < 0.001) was revealed. In group III there was higher tears secretion (p < 0.001). PH was lowered after 2nd chemotherapy course in group I and II. In further treatment pH value were in the same lower level as after the second course. In group III there was higher pH--more alkaline (p < 0.001) after 2nd cycle of treatment and it was on the same level to the end of the examination process. Lowering of lysozyme activity in the tears film in all groups (p < 0.001) was established. The higher alterations of the lysozyme activity were observed in group treated with FAC schema. CONCLUSIONS: Cytostatic treatment has major influence on tears aqueous layer causing alterations of tears secretions. PH alterations depending on type of chemotherapy was observed. Lowering of lysozyme activity in tears was observed. All the deteriorations aggravate with duration of chemotherapy. Alterations of tears film parameters during chemotherapy may influence upon eye surface homeostasis and infectious complication. tears aqueous layer, Schirmer's test, lysozyme activity, tears pH. PMID- 24059027 TI - [Evaluate central corneal thickness in patients from Podbeskidzie area in adult patients]. AB - OBJECTIVE: The aim of this study was to evaluate central corneal thickness in patients from Podbeskidzie area and to determine percentage of patients requiring correction of the intraocular pressure measured with Goldmann applanation tonometer. METHODS: We analyzed results of measurements of the central corneal thickness in 365 patients (242 females, 123 males). The study population was divided by gender and by age into 3 groups of people under 40, between 40 and 60 and over 60 years of age. The measurements of central corneal thickness were performed with ultrasonic pachymeter. RESULTS: Mean corneal thickness in examined eyes was 563.0 +/- 38.1 microm. There was no statistically significant difference in central corneal thickness between men and women (F = 0.10; p = 0.71) but there was significant difference between group of age (F = 28.4; p = < 0.001) and was interaction between gender and group of age under 40, between 40 and 60 and over 60 years of age (F = 4.60; p < 0.05). There was statistically significant difference between women and men in the group 40-60 years of age (p < 0.01). Among women there were statistically significant differences in corneal thickness among all age groups (p < 0.01), among men between group of age over 60 and under 40 and between 40-60 years of age (p < 0.001). CONCLUSIONS: 1. Measurement of central corneal thickness is necessary in order to obtain correct values of intraocular pressure measured with Goldmann applanation tonometer in 80% of patients. 2. In people over 60 year of age, especially in women, are expectet to have thinner corneas than younger individuals and it is useful to repeat measurement of central corneal thickness. PMID- 24059028 TI - [Comparison of Heidelberg retinal tomography and spectral domain optical coherence tomography examinations for detection of glaucoma]. AB - PURPOSE: To compare the diagnostic ability of Heidelberg Retina Tomograph 3 and Spectral Domain Optical Coherence Tomography Copernicus in detection of optic disc changes in glaucomatous patients. MATERIAL AND METHODS: Retrospective analysis of 24 eyes of 24 subjects with primary open angle glaucoma. All individuals had complete ophthalmic examination, Heidelberg Retina Tomograph 3 and Spectral Domain Optical Coherence Tomography examinations performed. Measurements in Spectral Domain Optical Coherence Tomography were obtained both automatically (Spectral Domain Optical Coherence Tomography software) and manually. Following diameters were analyzed: disc area, cup area, cup volume, C to D ratio (C/D ratio) and circumpapillary retinal nerve fiber layer thickness. RESULTS: Disc area, cup area, cup volume were classified as within normal limits more often in Spectral Domain Optical Coherence Tomography printouts than in Heidelberg Retina Tomograph (75%, 63% and 83% in SD-OCT auto, 70%, 57% and 83% in SD-OCT manu vs. 58%, 37% and 33% in Heidelberg Retina Tomograph, respectively). C/D ratio was increased in 23 eyes (96%) in Heidelberg Retina Tomograph compared to 14 eyes (58%) in SD-OCT auto and 12 eyes (52%) in SD-OCT manu. Retinal nerve fiber layer thickness was significantly lower in Spectral Domain Optical Coherence Tomography (both auto and manu 96% vs. 58% in Heidelberg Retina Tomograph). According to the Moorfields Regresion Analysis classification from Heidelberg Retina Tomograph, 21 eyes were diagnosed as glaucomatous (88%). CONCLUSIONS: Although there was poor agreement in optic disc measurements between the two methods, both had high sensitivity in detection of glaucomatous optic disc changes (96% when retinal nerve fiber layer thickness measured by Spectral Domain Optical Coherence Tomography compared to 88% for Moorfield regresion analysis in Heidelberg Retina Tomograph). The sensitivity of diagnostic ability increases when both, Heidelberg Retina Tomograph and Spectral Domain Optical Coherence Tomography are performed. PMID- 24059029 TI - [An assessment of the usefulness of the POLWROCHROM pupillometer to study the pupil light reflex to chromatic stimuli taking into account the intrinsically photosensitive retinal ganglion cells activity]. AB - PURPOSE: The pupillary light reflex is a useful diagnostic tool used to assess the function of the eye and the visual system. The increased interest in testing the pupillary light reflex is the discovery that the intrinsically photosensitive retinal ganglion cells are involved in the reflex physiology. The aim of this study was to evaluate the usefulness of POLWROCHROM pupillometer, developed at the Wroclaw University of Technology, to study the pupillary light reflex to chromatic stimuli taking into account the photosensitive retinal ganglion cells activity. MATERIAL AND METHODS: The pupillary light reflex to 10 sec. light pulse were recorded. In the experiment, a long wavelength (640 nm bandwidth) red light and a short wavelength (470 nm bandwidth) blue light were used at 2 different light luminance levels (10 cd/m2 and 100 cd/m2). RESULTS: The greatest pupil response is obtained for short wavelength (blue) light at a high luminance level, whereas the markedly lower pupil response was obtained for long (red) wavelength light at a low luminance level. CONCLUSIONS: The observed sensitivity of the pupillary light reflex response to color and intensity of the light stimulus was similar to known from literature the results of in vitro photosensitive retinal ganglion cells electrophysiological activity study. The described system and measurement technique can provide a new tool in testing the pupillary light reflex to chromatic stimuli enabling the assessment of photosensitive retinal ganglion cells activity and identification of pupillary light reflex components derived from photoreceptors and ganglion cells, and therefore may become a clinical pupil test which allows differentiation between disorders affecting photoreceptors and those affecting retinal ganglion cells. PMID- 24059030 TI - Exophthalmos as a first manifestation of the systemic spread of small cell lung cancer. AB - Small cell lung cancer is characterized by rapid growth and early metastases. The most frequent locations of the secondary lesions include adrenal glands, brain, liver, and skeleton. On initial diagnosis, up to 70% of patients with small cell lung cancer have metastases. Metastases to the eye or orbit developed approximately 0.7-12% of patients with lung cancer. Clinical signs and symptoms of orbital metastases may include exophthalmos, diplopia, pain, limited ocular motility, blurred vision, swollen eyelid, conjunctival hyperemia and edema, increased ocular pressure and papilledema. Here, we report a rare case of exophthalmos as the first manifestation of a metastatic tumor of orbit due to small cell lung cancer. PMID- 24059031 TI - [Optical coherence tomography in monitoring of choroidal folds after surgical excision of ethmoidal myxoma]. AB - PURPOSE: We describe a case of choroidal folds coexisting with ethmoidal myxoma and the evolution of folds after tumor excision. Choroidal folds can occure in the case of intraorbital pathology. Optical coherence tomography is usefull in diagnosis and monitoring of these folds. MATERIAL AND METHODS: 45 years old woman was reffered to our clinic because of visal disturbances in her right eye. Visual acuity of right eye was 0.5, of the left eye 1.0. Intraocular pressure of both eyes was within normal limits. Biomicroscopic evaluation of the right eye revealed no changes in anterior segment but choroidal folds in posterior segment were evident. The left eye was normal. Computer tomography of the orbit documented the presence of tumor within the right ethmoid. The tumor was excised surgically and its myxoidal nature was confirmed. RESULTS: 3 months after that intervention retinal profile in posterior pole in optical coherence tomography was normal and visual acuity of right eye improved by 1 line in Snellen chart. CONCLUSIONS: Choroidal folds caused by ethmoidal myxoma can disapper after surgical excison of tumor. Optical coherence tomography is very useful in documentation of these changes. PMID- 24059032 TI - [A case of clinical manifestation of X-linked retinoschisis--in the one eye, and choroidal neovascularisation--in the second eye, in two family members]. AB - PURPOSE: Description of long-time observation of X-linked retinoschisis coexisting with choroidal neovascularization in two brothers. MATERIAL AND METHODS: 27-year-old man reported sudden visual impairment in one eye. The same symptoms had patient's brother. Ophthalmic examination and imaging studies were performed. RESULTS: The diagnosis was made based on clinical features and imaging examinations. CONCLUSIONS: This case is unusual. At present there is no effective therapy. PMID- 24059033 TI - Electrophysiological tests in evaluation of glaucoma and ocular hypertension treatment--up to date knowledge. A review. AB - PURPOSE: On the basis of the literature data to assess the efficacy of the electrophysiological tests (pattern electroretinogram, multifocal electroretinogram and multifocal visual evoked potentials) in evaluation of retinal ganglion cells function in glaucomatous and ocular hypertension eyes, after intraocular pressure reduction. MATERIAL AND METHODS: Data published in the literature available at the Pub Med library between 1964-2012. RESULTS: Several results of studies suggest, that steady-state pattern electroretinogram reveals significant improvement of retinal ganglion cells function after treatment with timolol, acatazolamide, beta-blockers and prostaglandin analogues. Multifocal electroretinograms' changes, after lowering the intraocular pressure by trabeculectomy, were confirmed in only one study, There were no statistically significant correlations between changes in intraocular pressure reduction and multifocal visual evoked potentials. CONCLUSIONS: Steady state pattern electroretinogram is the most commonly used electrophysiological test in evaluating the results of glaucoma and ocular hypertension treatment. PMID- 24059034 TI - [Mucopolysaccharidosis and organ of sight]. AB - Mucopolysaccharidoses are a group of genetically determined storage diseases in which lysosomal enzyme deficiency leads to a vast accumulation of glycosaminoglycans in tissues. Depending on the sort of deficient enzyme MPS are divided into the types marked with Roman numerals. Clinical symptoms are caused by the involvement of the nervous, respiratory, visceral and skeletal system, organ of hearing and sight. Ocular manifestations result in significant visual impairment. Ophthalmic symptoms include corneal opacification, glaucoma, optic nerve swelling and retinopathy. Modern methods for the treatment involving enzyme replacement therapy and bone marrow transplantation significantly improved the prognosis in many cases. This article presents a brief description of mucopolysaccharidoses, concentrating mainly on ocular symptoms and their possible treatments. PMID- 24059035 TI - [Adam Bednarski (1869-1941)--professor of ophthalmology in Lviv]. AB - Adam Bednarski (1869-1941). Prominent Polish ophthalmologist, a student of professor Wiktor Boleslaw Wicherkiewicz. A professor and the head of the department of ophthalmology in Lviv. The author of about 50 works in ophthalmology and the history of medicine, published in Polish, German, and French. He prepared the first study of the history of Polish ophthalmology from the 13th to the18th century. He also studied the history of the use of herbs in medicine; on the basis of the old herbaria he described the herbal treatment and remedies in the 16th and 17th centuries. He also described the origin and the development of eyeglasses. He published several papers on intraocular foreign bodies and their removal. He described the case of gyrate atrophy of the choroid and the retina, which was one of the first such descriptions in the world. He also wrote several works on the vascular pathologies of the retina, pathologies of the lens and the orbit, neuroophtalmology and children's blindness Adam Bednarski, Medical University in Lvov, history of ophthalmology. PMID- 24059036 TI - [3D region growing algorithm driven by morphological dilation for airway tree segmentation in image guided therapy]. AB - The precise three-dimensional (3-D) segmentation of airway from CT image is essential for the image-guided therapy, which helps avoid a serious airway injury. We proposed a new segmentation algorithm for the calculation. Firstly, region growing method was employed to segment the main bronchioles (rough segmentation). And then region growing driven by morphology dilation was used to expand the airway region, where centerline of airway tree was extracted. Terminal bronchia (fine segmentation) were segmented along the centerline. Ultimately, rough and fine segmentation results are combined by a logical OR as final airway tree. Quantitative comparisons with 6 sets of manual segmentation results showed that the algorithm could be used to segment up to 9 bronchia, and the average branch sensitivity of 6th was 63.5%, meeting the requirement of airway tree in the image-guided therapy. PMID- 24059037 TI - [Applicability of the two-compartment coaxial cylindrical model for ambulatory measuring of cardiac output with spot-electrodes]. AB - The principle of ambulatory cardiac output (CO) measuring technique is introduced in this paper. Experimental studies about the applicability of the two compartment coaxial cylindrical model for ambulatory measurement of cardiac output with spot-electrodes have been carried out with using our newly-developed multi-channel impedance mapping system. The key factors using a spot-electrode array instead of a conventional band-electrode array for non-invasive CO) measurement are elaborated. The variations of the electric impedance pulsatile component (deltaZ waveform) and the two kinds of typical modes of deltaZ distributions measured by six electrodes on the midsternal (midian) line from the medial portion at the level of clavicle to the portion above the xiphisternum are discussed. The applicability of the two-compartment coaxial cylindrical model for ambulatory measurement of CO with spot-electrodes is analyzed. Synthesizing the deltaZ distributions and their typical changing models on the midsternal (midian) line during blood inflowing into aorta is the optimal positions of a pair of spot electrodes for voltage pick-up at the level of clavicle for the upper electrode and the position at the level of nipple for the lower electrode when spot electrode is being used to measure non-invasive CO. PMID- 24059038 TI - [Automatic segmentation of clustered breast cancer cells based on modified watershed algorithm and concavity points searching]. AB - As a common malignant tumor, breast cancer has seriously affected women's physical and psychological health even threatened their lives. Breast cancer has even begun to show a gradual trend of high incidence in some places in the world. As a kind of common pathological assist diagnosis technique, immunohistochemical technique plays an important role in the diagnosis of breast cancer. Usually, Pathologists isolate positive cells from the stained specimen which were processed by immunohistochemical technique and calculate the ratio of positive cells which is a core indicator of breast cancer in diagnosis. In this paper, we present a new algorithm which was based on modified watershed algorithm and concavity points searching to identify the positive cells and segment the clustered cells automatically, and then realize automatic counting. By comparison of the results of our experiments with those of other methods, our method can exactly segment the clustered cells without losing any geometrical cell features and give the exact number of separating cells. PMID- 24059039 TI - [A simulation study for the effect of acid concentration and temperture on sick sinus syndrome]. AB - The effective therapeutics for the sinoatrial node (SAN) pacemaker dysfunction induced by SCN5A gene mutation this is still being explored recently. In this study, a two-dimensional experimental model of rabbit SAN-atrial cell system which proposed by Zhang et al., was used as a prototype, the gene mutation was considered, and effects of both the acid concentration and temperature were also introduced. The effects of acid concentration and temperature on sick sinus syndrome (SSS) at the tissue level were investigated by simulation. The results showed that the SAN abnormal pacemaker could be caused by the reduction of I(Na), which is induced by the two mutations of T220I and delF1617. The results also showed that if we properly adjusted the acid concentration and temperature of the system, not only could we increase the relevant currents, but also could we increase I(Na) which reduced by gene mutations, so that the pacemaking behavior of SAN tissue could return to normal state from abnormalities. The above simulation results imply that the abnormal pacemaking of SAN system may closely relate to the gene mutation of ion channel mutations, and the acid concentration and temperature may play a modulatory role. Our study could be useful for clinical medical diagnosis and therapy of cardiac disease. PMID- 24059040 TI - [The comparison of the extraction of beta wave from EEG between FFT and wavelet transform]. AB - In order to choose a fast and efficient real-time method in beta wave information extraction, we compared the result and the efficiency of the information separation of both fast Fourier transform (FFT) and wavelet transform of EEG beta band in the present paper. Our work provides the basis for the EEG data come from the real-time health assessment of 3DTV. We took the EEGs of 5 healthy volunteers before, after and during the process of watching 3DTV and meanwhile recorded the results. The trends of the relative energy and the time cost of two methods were compared by using both the FFT and wavelet packet transform (WPT) which was to extract the feature of EEG beta wave. It demonstrated that (1) Results of the two methods were consistent in the trends of watching 3DTV; (2) Results of the differences in two methods were consistent before and after watching 3DTV; (3) FFT took less time than the wavelet transform in the same case. It is concluded that the results of both FFT and Wavelet transform are consistent in feature extraction of EEG, and a fast method to work with the large quantities of EEG data obtained in the experiments can be offered in the future. PMID- 24059041 TI - [Detection of epileptic spike wave in EEG signals based on morphological component analysis]. AB - This paper proposed a morphological component analysis (MCA) method, which is based on sparse representation, to detect the spike wave in electroencephalogram (EEG) signals. It takes the advantage of MCA being able to extract the background waves and the spike waves from the EEG signals, respectively,as the dictionaries and chooses the discrete cosine transform (DCT) and the daubechies order 4 wavelet (db4) transformation as the dictionaries of MCA to detect the spike waves from the epileptic EEG. The experiment results showed that the MCA could detect epileptic spike waves in EEG signals very effectively, and it yielded high selectivity of 89.01% and sensitivity of 90.71%. As a feature extraction/decomposition algorithm, MCA can be used to extract the spike waves from EEG signals. PMID- 24059042 TI - [MR spectroscopy of amygdala: investigation of methodology]. AB - This study was aimed to optimize the methods of magnetic resonance spectroscopy (MRS) to improve its quality in amygdala. Forty-three volunteers were examined at right and left amygdala using stimulated-echo acquisition mode (STEAM), and point resolved spectroscopy series (PRESS) with and without saturation bands. The Cr SNR, water-suppression level, water full width at half maximum (FWHM) and RMS noise of three sequences were compared. The results showed that (1) the Cr-SNR and water-suppression lelvel of PRESS with saturation bands were better than that of PRESS without saturation bands and STEAM (P<0.001); (2) the left and right RMS noise was significantly different both using PRESS with saturation bands and using STEAM (P<0.05); (3) there was a positive, significant correlation between Cr-SNR and voxel size (P<0.05). Therefore, PRESS with saturation bands is better than PRESS without saturation bands or STEAM for the spectroscopy of amygdala. It is also useful to make the voxel as big as possible to improve the spectral quality. PMID- 24059043 TI - [Research on compatibility of prescription of TCP based on the principle of attribute hierarchical graph]. AB - On the basis of the theory of formal concept analysis (FCA), a new method for generation of an attribute hierarchical graph is proposed in this paper. This method can solve the problems of how to mine and express classification knowledge and rules in compatibility of prescription. In this paper, we view prescriptions as objects that possess certain attributes of the named drugs. First, the formal context is established based on theory. Then optimization of the original formal context and extracts the connotation and extension of the concept are followed, constructing attribute hierarchical graph. Finally, useful knowledge from the hierarchical diagram of attributes based on the way of knowledge representation is mined. The result showed that the method for discovering Traditional Chinese Prescription (TCP) diagnostic knowledge is feasible and effectual for small samples. The research of large samples is 13th open question of FCA. It is an international subject to be studied urgently. PMID- 24059044 TI - [An implantable micro-device using wireless power transmission for measuring aortic aneurysm sac pressure]. AB - In order to detect endoleaks after endovascular aneurysm repair (EVAR), we developed an implantable micro-device based on wireless power transmission to measure aortic aneurysm sac pressure. The implantable micro-device is composed of a miniature wireless pressure sensor, an energy transmitting coil, a data recorder and a data processing platform. Power transmission without interconnecting wires is performed by a transmitting coil and a receiving coil. The coupling efficiency of wireless power transmission depends on the coupling coefficient between the transmitting coil and the receiving coil. With theoretical analysis and experimental study, we optimized the geometry of the receiving coil to increase the coupling coefficient. In order to keep efficiency balance and satisfy the maximizing conditions, we designed a closed loop power transmission circuit, including a receiving voltage feedback module based on wireless communication. The closed loop improved the stability and reliability of transmission energy. The prototype of the micro-device has been developed and the experiment has been performed. The experiments showed that the micro-device was feasible and valid. For normal operation, the distance between the transmitting coil and the receiving coil is smaller than 8cm. Besides, the distance between the micro-device and the data recorder is within 50cm. PMID- 24059045 TI - [The appearance test of a molar tooth with phase shift shadow moire]. AB - Modern photo-mechanics testing techniques are widely used in industrial circles and academic circles. In order to solve the problem of biomedical engineering, shadow moire method is used in oral and dental area in our study. A molar tooth was tested by phase shift shadow moire method. Through testing molar tooth, the results show that shadow moire method could be used for measuring the appearance of the oral area and concave and convex parts of molar tooth could also be distinguished and shown by interference patterns. The characteristics of shadow moirh are that it does't need exerting load on the specimen and could realize non contact measurement. PMID- 24059046 TI - [Research on video measuring method of knee joint angle based on cross ratio invariability]. AB - With an un-calibrated camera a new method is proposed in this paper to measure dynamically the bending angle of knee-joint based on cross ratio invariability. Firstly, by video image processing technique, we detected 25 circular objectives distributed in the aided measurement tool and determined their geometric centers in the video frame respectively. Then we further computed the extending direction of thigh and shank by detecting position of two rectangular targets tied on them. Finally, using of the principle of cross ratio invariability in Projection Geometry, we could realize real-time dynamic measurement of the bending angle of knee-joint based on the method. Experiments have proved that the measurement precision of the introduced approach could satisfy basic requirements of clinical applications. PMID- 24059047 TI - [Experimental research on heart rate variability analysis with application of acquisition system of R peak of electrocardiosignal based on sound card]. AB - This study designed an audio signal acquisition system to achieve real-time detection of R peak for heart rate variability (HRV) analysis, substituting ECG specific data acquisition board with sound card. It is proved that the R peak with low frequency can be gathered by sound card. The comparison with PowerLab signal acquisition system has shown that the acquisition system of R peak could accurately detect the R peak. The R peak detected by sound card and PowerLab signal acquisition system completely overlap each other, while RR intervals has no difference. The HRV analysis was accurate and reliable with the RR interval from sound card. This low cost, high performance, strong compatibility and easy upgraded acquisition system of R peak compared with the traditional data acquisition board has the value of practical uses and might have broad applications in the future. PMID- 24059048 TI - [A new wavelet image de-noising method based on new threshold function]. AB - In order to improve image de-noising effect,a new threshold function de-noising method based on wavelet analysis was proposed, which can overcome the continuity problem of the hard-threshold function, and eliminate the constant deviation of the soft one by constructing a new threshold function. Experimental results showed that the new threshold function could obtain higher peak signal to noise ratio (PSNR) in image de-nosing. A better denoising effect could be obtained compared with the hard-threshold function, the soft one, the semi-soft one, the cubic polynomial interpolation semi-soft one, and the asymptotic semi-soft one. PMID- 24059050 TI - [Analysis of the evolution of esophageal tumor volume in radiotherapy process using a mathematical model]. AB - The volume change of tumor during radiotherapy processes indirectly reflects the short-term efficacy and the quality of radiotherapy planning. We analyzed clinical data of radiotherapy using a mathematical model in our study. First, we selected eight esophageal carcinoma patients with only using 3DRT and conventional dose fractionation schemes. And then we observed and measured the change of tumor volume during the radiotherapy. Based on the LQ model, repopulation and re-oxygenation in 4Rs, and the kinetics of doomed tumor disintegration, we established the mathematical model of tumor evolution in radiotherapy. And then we used the model to analyze the clinical trial data about esophageal carcinoma with radiotherapy. It was proved that the results of the model almost coincided with the clinical trial data. According to the analysis results, we could get the related radiobiology parameters to estimate biological effective dose and repopulation of patients. The mathematical model could provide reference for assessment of prognosis and further scheme of treatment. PMID- 24059049 TI - [Assessment of left ventricular systolic function with magnetic resonance imaging: comparison with that of echocardiography]. AB - This study is designed to test the agreement in measuring left ventricular systolic function between transthoracic two-dimensional echocardiography (2DTTE) and "gold standard" of non-invasive cardiac imaging, magnetic resonance imaging (CMRI) and their impacts on the classification of patients according to the left ventricular ejection fraction (EF). 32 patients who were suspected with heart disease were evaluated by CMRI and 2DTTE examinations. End diastolic volume (EDV), end systolic volume (ESV), EF and left ventricular function category were then calculated and compared. There was no significant difference (P=0.504) for EDV, while ESV of CMRI was significantly higher than that of 2DTTE (P=0.049), and EF of CMRI was significantly lower than that of 2DTTE (P= 0.018). There was no significant difference (P=0.077) in left ventricular functional category. Bland Altman analysis of LV volumetric data and EF measurements showed a good agreement between two methods. The 2DTTE over-estimated I (n=5) or II (n=1) degrees of functional classification when compared with the CMRI. Both CMRI and 2DTTE are of great clinical value in evaluating left ventricular systolic function, while CMR may be more beneficial to patients with abnormal LV functions. PMID- 24059051 TI - [HPLC method to determine DEHP released into blood from a disposable extracorporeal circulation tube]. AB - We used blood as leaching medium, simulating clinical operation under maximum condition, to develop Liquid-phase extraction- High Performance Liquid Chromatography (HPLC) method for determination of plasticizer Di-(2 ethylhexyl)phthalate (DEHP) released from Disposable Extracorporeal Circulation Tube in order to lay the foundation of risk analysis of this product. The characteristic wavelength of DEHP in methanol was detected. Acetonitrile was added to the leaching blood in proportion and extracted DEHP from blood. The methodology for HPLC to quantify DEHP was established and the DEHP amount released from this disposable extracorporeal circulation tube was measured. The experiments showed good results as follows. The characteristic wavelength of DEHP was 272nm. The concentration of DEHP (5-250 microg/mL) kept good linear relationship with peak area (r=0.9999). Method sensitivity was 1 microg/mL. Precisions showed RSD<5%. The adding standard extraction Recovery Rates of 25, 100 and 250 microg DEHP standard were 61.91 +/- 3.32)%, (69.38 +/- 0.55)% and (68.47 +/- 1.15)%. The DEHP maximum amounts released from 3 sets of this disposable extracorporeal circulation tube were 204.14, 106.30 and 165.34 mg/set. Our Liquid-phase Extraction-HPLC method showed high accuracy and precision, and relatively stable recovery rate. Its operation was also convenient. PMID- 24059052 TI - [Design of an anesthesia and micro-environment information management system in mobile operating room]. AB - We have designed a mobile operating room information management system. The system is composed of a client and a server. A client, consisting of a PC, medical equipments, PLC and sensors, provides the acquisition and processing of anesthesia and micro-environment data. A server is a powerful computer that stores the data of the system. The client gathers the medical device data by using the C/S mode, and analyzes the obtained HL7 messages through the class library call. The client collects the micro-environment information with PLC, and finishes the data reading with the OPC technology. Experiment results showed that the designed system could manage the patient anesthesia and micro-environment information well, and improve the efficiency of the doctors' works and the digital level of the mobile operating room. PMID- 24059053 TI - [Study of mechanical effects of the EVA glove on finger base with finite element modeling]. AB - The hand strength of astronauts, when they are outside the space capsule, is highly influenced by the residual pressure (the pressure difference between inside pressure and outside one of the suit) of extravehicular activity spacesuit glove and the pressure exerted by braided fabric. The hand strength decreases significantly on extravehicular activity, severely reducing the operation efficiency. To measure mechanical influence caused by spacesuit glove on muscle tendon and joints, the present paper analyzes the movement anatomy and biomechanical characteristics of gripping, and then proposes a grip model. With phalangeal joint simplified as hinges, seven muscles as a finger grip energy unit, the Hill muscle model was used to compute the effects. We also used ANSYS in this study to establish a 3-D finite element model of an index finger which included both bones and muscles with glove, and then we verified the model. This model was applied to calculate the muscle stress in various situations of bare hands or hands wearing gloves in three different sizes. The results showed that in order to achieve normal grip strength with the influence caused by superfluous press, the finger's muscle stress should be increased to 5.4 times of that in normal situation, with most of the finger grip strength used to overcome the influence of superfluous pressure. When the gap between the finger surface and the glove is smaller, the mechanical influence which superfluous press made will decrease. The results would provide a theoretical basis for the design of the EVA Glove. PMID- 24059054 TI - [Response of a finite element model of the pelvis to different side impact loads]. AB - The pelvis is one of the most likely affected areas of the human body in case of side impact, especially while people suffer from motor vehicle crashes. With the investigation of pelvis injury on side impact, the injury biomechanical behavior of pelvis can be found, and the data can help design the vehicle security devices to keep the safety of the occupants. In this study, a finite element (FE) model of an isolated human pelvis was used to study the pelvic dynamic response under different side impact conditions. Fracture threshold was established by applying lateral loads of 1000, 2000, 3000, 4000 and 5000 N, respectively, to the articular surface of the right acetabulum. It was observed that the smaller the lateral loads were, the smaller the von Mises stress and the displacement in the direction of impact were. It was also found that the failure threshold load was near 3000 N, based on the fact that the peak stress would not exceed the average compressive strength of the cortical bone. It could well be concluded that with better design of car-door and hip-pad so that the side impact force was brought down to 3000 N or lower, the pelvis would not be injured. PMID- 24059055 TI - [Gene expressions of LOXs and MMPs of the ACL fibroblasts cells co-cultured with synovial cells]. AB - The progress of research on the the anterior cruciate ligament (ACL) wound healing demonstrates that the synovial tissue in the knee joint plays a very important role in the healing process of injured ACL. Therefore, the molecular response mechanisms of lysyl oxidase (LOX) and matrix metalloproteina (MMP) in normal/injured ACL fibroblast cells could be considered to perform the major analysis function of injured ACL healing mechanism. The mRNA expressions of LOXs and MMPs and the activity expressions of MMP-2 in ACL fibroblasts co-cultured with synovial cells were analyzed by quantitative real-time PCR and zymography. The results showed that co-culture could regulate the mRNA expressions of LOXs and MMPs in the ACL fibroblasts cells. These results suggest that the differential expressions of LOXs and MMP-1, 2, 3 in co-cultured ACL indicate that interaction crosstalk do exist between ACL cells and synovial cells and provide a theoretical basis for subsequent exploration of the mechanisms and treatment of ACL injury and repair. PMID- 24059056 TI - [Regulation of chondrosarcoma cell growth using synthesized hydrogels with different electric charges]. AB - To develop standard in vitro chondrosarcoma models, we synthesized three hydrogels (i. e., PDMAAm, PNaAMPS and PMETAC) and investigated the influence of Young's modulus, swelling ratio and electric charges on the behavior of chondrosarcoma cells seeded on the hydrogels, including morphology, adhesion and aggregation. Results showed that the morphology of chondrosarcoma cells at 6h was dependent on the charges of hydrogels; cells present spindle-shaped and round shaped morphology on negative charged and neutral hydrogel, respectively, while no cells spreaded on positive charged hydrogel. Chondrosarcoma cells formed aggregates on neutral PDMAAm after further culture. The hydrogels can be synthesized easily and has the characteristics of ease at use with defined components, which holds great potential for developing standard chondrosarcoma models in vitro. PMID- 24059057 TI - [Effect of hydroxyapatite nanoparticles on MII-stage porcine oocytes vitrification and the study of its mechanism]. AB - Nano-cryopreservation may become a new way in the next generation of cryopreservation technology. However, research using nanoparticles in oocytes vitrification has not been reported in the literature. In this study, HA nanoparticles with different diameters were added into cryoprotectant and M II stage porcine oocytes were vitrified by Cryotop. The results showed that nanoparticles improved the survival rate of cryopreserved M II-stage porcine oocytes, but the difference between nanoparticles with different diameters of was not significant. In order to study the mechanism of nano-cryopreservation, the cooling rate of cryoprotectant was measured by ultra-fast temperature measurement system and the melting enthalpy of cryoprotectant was measured by differential scanning calorimeter (DSC). The results showed that the adding of nanoparitcles could not increase the cooling rate of cryoprotectant, but could decreases the amount of ice crystals during freezing and warming. Therefore, the mechanical injury within and outside cells might be effectively reduced. PMID- 24059058 TI - [Study of the preparation of silk fibroin gel and its morphology as drug release matrix in vitro and in vivo]. AB - Silk fibroin (SF)/sodium alginate (SA) hydrogels can be used as drug injection materials. Homogenate was prepared by centrifugation of the pig myocardial extracellular matrix (PMM) and its modification of SF gel material. This paper observes and compares the different components SF, SF/SA, SF/SA/PMM to illustrate the SF/SA/PMM ternary material as a drug delivery composition material. This ternary material can shorten the gel time, and can make the gel form to be maintained better. Meanwhile, it makes the internal structure of the gel looser so that the hole wall becomes thinner and more conducive to the drug release. In addition, it has good biocompatibility proved by pathological analysis, and is able to enhance the mesenchymal stem cells growth activity, which has great significance in carrying out drug control release. PMID- 24059059 TI - [The effect of heme oxygenase-1 on BMSCs damaged by high-concentration glucose]. AB - This investigation was aimed to explore whether over-expression of 27heme oxygenase-1 (HO-1) could protect bone marrow mesenchymal stem cells(BMSCs)against injury induced by high-concentration glucose. We cultured BMSCs in high concentration glucose medium, and up-regulated or inhibited HO-1 expression in BMSCs through its agonist or inhibitor. We detected the ability of BMSCs proliferation and secretion respectively by MTT and enzyme-linked immunosorbnent assay (ELISA). Then we detected the effect of BMSCs conditions medium on proliferation and migration of human umbilical vein endothelial cells (HUVECs) through scratch experiments and transwell assay. It was found that HO-1 over expression could not only promote BMSCs proliferation, but also promote secretion of vascular endothelial growth factor (VEGF), and could further accelerate the proliferation and migration of HUVECs. It could be well concluded that HO-1-over expressing BMSCs can not only inhibit damage induced by high-concentration glucose, but can promote the proliferation and migration of vascular endothelial cells through paracrine as well. The result indicated that HO-1-over-expressing BMSCs played an important role in the treatment of diabetic vascular complication. PMID- 24059060 TI - [Influence of endogenous TgAb upon serum Tg measurement results and Tg positive rate in patients with differentiated thyroid carcinoma]. AB - The first aim of this study was to compare the serum thyroglobulin (Tg) positive rate between differentiated thyroid carcinoma (DTC) patients with positive thyroglobulin antibody (TgAb) and patients with negative TgAb. The second aim of this study was to investigate the correlation between serum Tg value and antithyroglobulin (TgAb) concentration of patients with DTC. We collected the serum Tg value and TgAb concentration of patients with DTC after thyroid ablation by operation and radioiodine therapy retrospectively. Then we investigated the Tg positive rate of DTC patients with positive TgAb and patients with negative TgAb separately. The scatter diagram between serum Tg value and TgAb concentration of DTC patients was performed to analyze their potential relationship. As a result, among 252 patients with DTC after thyroid ablation, 7 of 47 patients (14.89%) with positive TgAb (>115 IU/mL) had positive serum Tg (>10 microg/L), and 61 of 205 (29.76%) patients with negative TgAb (<115 IU/mL) had positive serum Tg. Eighty three of the 252 patients with DTC had accurate serum Tg and TgAb concentration. No correlation between serum Tg value and TgAb concentration was found among these Eighty three patients. Thus, it may be concluded that positive TgAb could cause much more TgAb interference in serum Tg value than negative TgAb could because of a different quality of TgAb. Serum Tg value is not correlated with serum TgAb concentration in patients with DTC after thyroid ablation. PMID- 24059061 TI - [Expression of hippocampus Klotho protein and insulin-like growth factor-1 in rats with dementia]. AB - This study aims to assess the expression of Klotho and insulin-like growth factor 1 (IGF-1) and the association between Klotho and IGF-1 in rats with dementia model. Thirty rats were randomly divided into three groups. Morris water maze was used to investigate the learning and memory functions, and enzyme linked immunosorbent assay was used to analyze the levels of Klotho and IGF-1. Klotho and IGF-1 levels in the model group were lower than those in other 2 groups. Morris water maze test showed that the model group had longer escape latency times and shorter step platform times compared to other groups. Line correlation model demonstrated that Klotho level was positively correlated with IGF-1 level in rats with dementia (P= 0. 029). The levels of Klotho and IGF-1 both reduced at hippocampus in rats with dementia model, suggesting that it may be a close relationship between Klotho and IGF-1 in the pathogenesis of dementia. PMID- 24059062 TI - [Studies on expression, purification, crystal growth and optimization of putative transcription factor LytR from Streptococcus pneumoniae]. AB - The aim of the present study was to obtain the crystal of transcription factor LytR of streptococcus pneumoniae for X-ray crystal structure and function analysis. The LytR gene of D39 strains from Streptococcus pneumoniae (S. pn) was cloned into the prokaryotic expression vector pET32a(+), then overexpression was obtained in the E. coli BL21 (DE3) through transformation of the recombinant plasmid that had been verified by colony PCR and sequencing. Soluble fusion protein with His-tag highly expressed by the induction of 0.5 mmol/L IPTG and was purified by a three step procedure, the purity of the purified LytR recombinant protein was over 90%. Preliminary screening of crystallization conditions was performed using the hanging-drop vapour-diffusing method with Hampton Crystal screen and PEG screen kits. The protein crystals X-ray diffraction data were collected from a single crystal and more stick crystals whose X-ray diffraction reached 4.0 A were obtained. These works laid the foundation for further research on the 3D structure of putative transcription factor LytR and its biological aspects. PMID- 24059063 TI - [Study on immunogenicity elicited by a recombinant vaccine of rBCG-Rv3133c to fight against dormancy Mycobacterium tuberculosis]. AB - To obtain a vaccine to defend from dormancy Mycobacterium tuberculosis, we constructed the recombinant Bacilli Calmette-Guerin (BCG) vaccine with Rv3133c encoding dormancy-correlated transcriptional regulatory protein DosR in Mycobacterium tuberculosis as a target gene, and evaluated its immunogenicity in BALB/c mice. In this study, we constructed the recombinant plasmids of rpMV361 Rv3133c using gene colon technology. We then transformed BCG strains with above mentioned plasmids to obtain recombinant vaccine of rBCG-Rv3133c. We used the rBCG strains successfully constructed to vaccinate in BALB/c mice. 30d and 180d after immunization, the specific antibody titers were determined to investigate humoral responses induced by recombinant vaccine. We detected changes of splenocyte subsets of CD4+T, CD8+ T cells and cytokine of IFN-gamma secreted by splenocytes for evaluation of cellular immune responses. The results showed that the rBCG-Rv3133c was able to induce higher levels of antibody titer, stronger proliferative responses and higher IFN-gamma production comparing with BCG vaccine. The results also suggested that this recombinant vaccine was a more efficacious tuberculosis vaccine for further study. PMID- 24059064 TI - [Purification and biological osteoinductive activity analysis of recombinant human bone morphogenetic protein 9 by eukaryotic expression]. AB - The present paper is aimed to explore the biological osteoinductive activity of recombinant human bone morphogenetic protein 9 (rhBMP-9) by various biological technologies. In this study, we firstly obtained hBMP-9 cDNA by PCR and inserted it into vector pcDNA4/His Max to reconstruct hBMP-9 eukaryotic expression vector pcDNA4/His Max-BMP-9. Recombinant Chinese hamster ovary (rCHO) cell line expressing high-level rhBMP-9 was reconstructed by co-transfecting the expression vectors pcDNA4/His* Max-hBMP-9 and plasmid pSV2-dhfr into dihydrofolate reductase (dhfr)-deficient CHO cells and the subsequent gene amplification by the methotrexate. We finally obtained a monoclonal cell line expressing the highest level protein. We purified the medium after culturing the highest-producing monoclonal by Ni-NTA His-Bind Resin columns and concentrated to by a Centricon 50 at 4 degrees C and stored at 70 degrees C until it was used. Western blot and SDS PAGE analyses showed a specific band of about 32kD in pro-region lane and a specific band of about 50kD in pro-region complex lane. Biological activities of rhBMP-9 were tested by colorimetric determination and histochemical staining of Alkaline Phosphatase (ALP) Activity, osteocalcin and oesteopontin for C3H10 T1/2 cells, which were stimulated culture by different concentration (20, 50, 100 microg/mL) of rhBMP-9. The results showed that the rhBMP-9 could induce osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro, and were proportional to the amount. This study can provide experimental data for further tests in vivo and clinical applications. PMID- 24059065 TI - [Antiviral effects of dual-target antisense LNA by cationic liposomes in transgenic mice]. AB - This paper is aimed to investigate the inhibitory effects of hepatitis B virus (HBV) preC and C genes-specific antisense locked nucleic acid (LNA) on HBV replication and expression in transgenic mice. The antisense LNA, which was complementary to the preC and C gene region of HBV, was designed, synthesized, and injected into transgenic mice via the tail vein. Serum HBV DNA was tested with real-time PCR, and Serum HBsAg was tested with time-resolved fluorescence immune assay (TRFIA). Then the expression of HBcAg in the liver was detected with immuneohistochemistry. Serum ALB, ALT, BUN and CRea were measured with an antomatic biochemicall analyzer. It was found that 5 days after LNA injection, serum HBV DNA levels in the dual-target group were reduced by 53.72%, and serum HBsAg levels were decreased by 71.57%. These values were significantly higher than those in the control groups (P<0.05) and the expression levels of HBcAg in the liver were significantly lower than those in the control groups (P<0.05). The result also showed that there were no significant differences discovered in serum ALB, ALT, BUN and CR between the experiment groups and the control groups. The present study provides that antisense LNA targeting to both preC and C genes has shown strong inhibition on HBV replication and expression in transgenic mice, and stronger than target at single gene site. PMID- 24059066 TI - [Effect of ovariectomy on rat behavior and hippocampal neuronal nitric oxide synthase and electroacupuncture intervention role]. AB - In order to explore the possible mechanism of EA (Electroacupuncture) in improving cognitive impairment, the present study was to research the effect of EA on the behavior and expression of the hippocampal neuronal nitric oxide synthase (nNOS) protein of the ovariectomized rats. Forty female SD rats were randomly and equally divided into four groups: sham group (ovarian fat around removal), model group (ovariectomy), sham EA group (sham EA stimulation after ovariectomy) and EA group (EA stimulation after ovariectomy). Two weeks after the ovariectomy, EA and sham EA were applied continuously for 3 months. In the experiment, Morris water maze was used to test the ability of spatial learning and memory, while enzyme-linked immuno sorbent assay (ELISA) and Western blot (WB) were used to detect the concentration of serum estradiol (E2) and relative expression of nNOS protein. The results showed that the escape latency of the EA and sham EA groups was shortened and the number of platform-crossing was significantly increased. The concentration of serum E2 and the expression of nNOS protein in both EA group and sham EA group were significantly elevated compared to those in the model group, while increment in the EA group was more significant (P<0.01). It could be concluded that from above experimental results, EA could be capable of improving learning and memory in ovariectomized rats by promoting the expression of nNOS protein through increasing the concentration of estrogen. PMID- 24059067 TI - [Design and realization of X-ray TUBE HEAD control system in the CBCT system]. AB - Cone beam computer tomography (CBCT) has advantages of high precision, low radiation and high image quality. It has been developing quickly since it was applied clinically. In order to control X-ray TUBE HEAD effectively in Dental CBCT, X-ray TUBE HEAD Control System was designed and realized in this study. This control system is the core of CBTC system, which includes the communication between CBCT system and computer, the control of X-ray tube head by CBCT system main control board and the synchronization between main control board and the flat panel detector. Control circuit of the control system and corresponding operating software were designed with PIC16F877A as the core. This control system has been put into use in current CBCT system successfully. PMID- 24059068 TI - [Self-adaptive beamforming method based on plane wave ultrasound imaging]. AB - In order to improve the resolution, contrast and frame rate of ultrasound imaging, it is necessary to design an adaptive beamforming method for plane wave ultrasound imaging. An optimized minimum variance algorithm that suits plane wave ultrasound imaging was proposed, based on the traditional minimum variance algorithm that combines with the subband beamforming as well as the forward backward spatial smoothing method in the frequency domain. To verify the effectiveness of the improved algorithm, the matlab software was used. Simulation results showed that full width at half maximum and peak side-lobe level of Optimized MV, Conventional MV, DAS boxcar, and Linear scan methods were 0.08, 0.36, 0.92, 1.42 dB, and -41.1, - 37.3, -16.9, - 34.1 dB, respectively. The improved algorithm can significantly improve the image resolution and contrast, particularly applicable to plane wave ultrasound imaging, compared with the conventional minimum variance algorithm and traditional delay-and-sum method. PMID- 24059069 TI - [Research of the influences on the electromagnetic fields by the pelvic tissues in the design of the radio frequency coils]. AB - In the present study, the effect of the electromagnetic field, induced by radio frequency (RF) coils and coupled with the pelvic tissues, was calculated with the method of finite difference time domain (FDTD). Using the established electromagnetic model of human pelvis region, the simulation was implemented. The imaging uniformity was quantitatively calculated and scaled with the values of the percentage image uniformity (PIU). The electromagnetic model was derived from the anatomical data of human pelvic region and loaded into the simulation. The results showed that the homogeneity of the magnetic fields was severely damaged due to the coupling between the RF coil and the human tissues when loaded with the human pelvis in the Birdcage RF coils at 3T. The research results set a basis meaningful for the design of RF coils. PMID- 24059070 TI - [Investigation on bioactive protection of LEA protein for insulin by molecular simulation in the low-temperature drying process]. AB - Nowadays various protein medicines are increasingly playing significant roles in the treatment of many diseases, but the bioactive structures of such kinds of protein medicines are unstable because they are heat sensitive. Therefore, it is very important to explore a protective method and to explain the protective mechanism of protein medicines. In the present research, insulin was chosen as a heat-sensitive protein medicine, and a Group 3 late embryogenesis abundant (LEA) protein was chosen as its bioactive protectant during desiccation. The results of replica exchange molecular dynamics simulation suggest that comparing with insulin without any protection, the bioactive 3D structure and secondary structure of the insulin protected by LEA protein were preserved very well. All analyzing results proved that the LEA protein was a good bioactive protectant for heat sensitive protein medicines. PMID- 24059071 TI - [The detection of non-stationary T-wave alternans: a modified correlation method]. AB - T-wave alternans (TWA) refers to a phenomenon appearing in the surface electrocardiograph (ECG) as a consistent fluctuation in morphology and amplitude of the T wave on an "every-other-beat" basis. Correlation method (CM) has a certain ability to detect the non-stationary TWA, but it is very sensitive to noise. In this paper we propose a modified correlation method to ensure a stable and accurate detection of non-stationary TWA. Compared to the CM, the method modifies the judge condition and uses the linear fitting to limit the noise to gain the ability of detecting of non-stationary TWA. Our simulation and clinical data assessment study demonstrates the improved performance of the proposed algorithm. PMID- 24059072 TI - [The construction and the expression of V5 epitope fused human androgen receptor vector in the yeast cell]. AB - When we try to establish the gene recombinant yeast cell to screen the androgenic endocrine disruptors, the key procedure is the androgen receptor (AR) expression in the yeast cell. For this purpose, we obtained the GPD (glyceraldehyde-3 phosphote dehydrogenase) promoter from the yeast genosome of W303-1A using PCR system and inserting it into Swa I and BamH I sites of pYestrp2. The new constructed vector was named pGPD. The V5 epitope tag DNA with a 5'-BamH I and a 3'-EcoR I sticky end was cloned into the corresponding site of the pGPD vector to yield the vector of pGPDV5. The 2 723 bp full length AR ORF amplified by PCR from pcDNA3.1/AR was fused to V5 epitope tag DNA in pGPDV5 to give the AR yeast expression vector of pGPDV5/AR. This fused vector was transformed into the yeast cell (W303-1A). Western blot was used to detect the V5 fused protein of AR, in the protocol of which the primary monoclonal antibody (IgG(2a)) of mouse anti-V5 and the polyclonal secondary antibody of goat anti-mouse (IgG) linked to horseradish peroxidase (HRP) were used to detect the specific protein in the given sample of the transformed yeast extract. The result showed that the fused protein of AR was expressed successfully in the yeast cell. PMID- 24059073 TI - [The finite element analysis of polyetheretherketone/hydroxyapatite/carbon fiber cage]. AB - To compare the bio-mechanical characteristics of cages of two types, i. e., polyetheretherketone/ hydroxyapatite/carbon fiber (PEEK/HA/CF) and titanium combined with internal pedicle screw fixation in lumbar model, and to provide experimental evidences for clinical application, we constructed a three dimensional finite element model of an intact L2-L4 segment by using computer tomography scans of a healthy male. The three-dimensional finite element models of an intact L2-L4 segment and single cage plus bilateral vertebral pedicle screw fixation were established. The angular motion of fused segment and stress distribution in the bone graft and cage and L3 inferior endplate under different loads were recorded. The result showed that the peak Von Mises stresses of the bone graft of PEEK/HA/CF group were at least 2.2 time as that of titanium group. The peak Von Mises stresses of L3 inferior endplate of the titanium group were at least 2. 3 times as that of PEEK/HA/CF group. These stresses were concentrated at places where the cage interfaced with the endplate. The angular variation of the titanium group showed similarity to PEEK/HA/CF group. The PEEK/HA/CF cage could provide stability similar to that of titanium cage in the presence of posterior instrumentation. It could increase the load transfer through the bone graft and promote the bone fusion. It could also reduce the stresses in endplates adjacent to the cage and reduce the subsidence of the cage. PMID- 24059074 TI - [Bio-detection techniques based on magnetic signal of nanoparticles]. AB - This article summarizes biological detection techniques based on magnetic signal of magnetic nanoparticles and the research progress of these techniques in biomedicine. Biological detection based on magnetic nanoparticles is faster, more accurate and more convenient compared to traditional optical techniques and causes much attention. It can be classified into giant magneto resistive biosensor (GMR), magnetic relaxation switch (based on T2 relaxation time), AC susceptibility (based on Brownian relaxation) and magnetic lateral flow immunoassay. These techniques can be combined with nanotechnology, microfluidics, immunoassay and bio-chips and have wide application prospects in clinical diagnosis, biological detection, environmental monitoring and food security areas. PMID- 24059075 TI - [Study on diabetes-induced cognitive impairment]. AB - The diabetes-induced cognitive impairment complications have serious effects on the patients' lives, and there is an enormous and financial burden on patients, their families and society as a whole. This review investigates the current research status of diabetes-induced cognitive impairment from different view points including molecular, models, clinics and electrophysiology. The relationship between diabetes and cognitive function and developments of research are hereby summarized. And finally, future issues of diabetes-induced cognitive impairments are pointed out, and the effective rehabilitation methods should be considered. PMID- 24059076 TI - [Progress of research on interaction between bone marrow mensenchymal stem cell and other intra-bone marrow cells]. AB - Bone marrow mensenchymal stem cells (BM-MSCs) are capable of supporting the survival, differentiation and migration of hematopoietic stem cell, and have a profound application prospect in transplantation and treatment of graft-versus host disease (GVHD). This review aims to illustrate the interaction between BM MSCs and other intra-bone marrow cells, including hematopoietic stem cells, endothelial cells and osteoblasts. The investigation of their regulating mechanism will help better understanding of the BM-MSCs' role in hematopoiesis. PMID- 24059077 TI - [Novel therapeutic strategies for treatment of hepatocellular carcinoma: targeting intervention on liver cancer stem cells]. AB - Hepatocellular carcinoma (HCC) is one of the most common human malignant tumors worldwide; it is also hard to prevent its metastasis and recurrence by traditional treatments. Up to now, how to prevent and treat HCC is still a challenging problem in clinic. Cancer stem cells (CSCs) are cells within malignant tumor that possess the capacity to self-renew and differentiate to lead to the heterogeneous lineages of cancer cells that comprise the tumor, and are the root to cause metastasis, recurrence and bad prognosis of the cancer. Targeting CSCs is a novel therapeutic strategy for management and treatment of the cancer. In recent years, targeting intervention on liver cancer stem cells (LCSCs) gradually became a novel strategy for HCC treatment, and some exciting research results in the treatment of HCC were also achieved. In this review, we introduce the biological characteristics of LCSCs and highlight the therapeutic strategies for hepatocellular carcinoma by targeting intervention on LCSCs. PMID- 24059078 TI - [Principles of photoplethysmography and its applications in physiological measurements]. AB - The electro-optic technique of measuring the cardiovascular pulse wave, known as photoplethysmography (PPG), is clinically utilised for noninvasive characterisation of physiological components by dynamic monitoring of tissue optical absorption. Non-invasive PPG technology has been used in a wide range of individual, home or public health monitoring. The application of PPG has become one of the hot topics in the fields of biomedical engineering recently. This paper reviews the optical origins of PPG signal, the feature of PPG technology, the applications of PPG in physiological measurements and its development in the future. PMID- 24059079 TI - [Prolongation of QT interval and evaluation of safety of drugs]. AB - People pay more and more attention to the prolongation of QT interval caused by drugs because it could probably result in lethal arrhythmia. This article introduces mechanisms, risk factors and guidelines for QT interval, and also reviews drugs withdrawal from the market due to the results of prolongations of QT interval. It discusses as well the value of new drugs in the QT interval for the evaluation of safety. PMID- 24059080 TI - Antibacterial and bioactive alpha- and beta-chitin hydrogel/nanobioactive glass ceramic/nano silver composite scaffolds for periodontal regeneration. AB - Alveolar bone loss and bone defects are the commonly encountered periodontal problems. Large defects do not heal spontaneously and thus require surgical interventions with bone substitutes. Bone grafts have the disadvantages of eliciting an immunologic response with subsequent graft rejection. The success rate of Guided Tissue Regeneration (GTR) is variable because of high susceptibility to infection. Thus emerged the important role of synthetic biomaterials and hence for this purpose we developed a nanocomposite scaffold, using alpha- and beta-chitin hydrogel with bioactive glass ceramic nanoparticles (nBGC) and silver nanoparticles (nAg) by lyophilization technique (aalpha and beta-chitin hydrogel/nBGC/nAg nanocomposite scaffold). The prepared nanoparticles and nanocomposite scaffolds were characterized. In addition, the porosity, swelling, mechanical properties, antibacterial activity, in vitro degradation and biomineralization, cell viability, cell attachment and cell proliferation ability of the prepared composite scaffolds were also evaluated. The results showed that alpha- and beta-chitin/nBGC/nAg composite scaffolds were porous and have the capacity to absorb fluids and swell. The composite scaffolds also showed enhanced antibacterial activity, bioactivity and controlled degradation in comparison to the control scaffolds. Cell viability studies proved the non-toxic nature of the nanocomposite scaffolds. Cell attachment and cell proliferation studies revealed the attachment and spreading nature of cells. All these studies revealed that, these antibacterial nanocomposite scaffolds could be a promising approach for the management of periodontal defects. PMID- 24059081 TI - Sweeter but deadlier: decoupling size, charge and capping effects in carbohydrate coated bactericidal silver nanoparticles. AB - Silver nanoparticles are widely used due to their biomedical-antibacterial applications. At the same time, the stabilization of these nanoparticles is challenging and may be made using polymeric carbohydrates, based on the practice of avoiding toxic chemicals and undesirable residues. In this study, we synthesized silver nanoparticles (AgNPs) which were stabilized by carbohydrates (potato starch and chitosan) and characterized by UV-Vis spectroscopy, zeta potential and transmission electron microscopy techniques. Bactericidal efficiency of AgNPs capped with different carbohydrates was tested demonstrating that the synthesized materials were able to inhibit the growth of two clinical/medical relevant bacteria strains (Escherichia coil and Staphylococcus aureus). AgNPs stabilized by chitosan presented enhanced bactericidal activity if compared to the ones synthesized in presence of potato starch. This difference is mainly attributed to the known antibacterial properties of chitosan associated to overall positive charge of the nanoparticles capped by this polymer. Those nanoparticles obtained in presence of starch presented minor bactericidal effects since the starch-capping agent is not able to contribute to the avoidance of bacteria growth and confers a quasi-neutral charge to the nanoparticle. PMID- 24059082 TI - Photoluminescence and X-ray excited luminescence from glutathione-stabilized gold nanoparticles. AB - Au nanoparticles coated with glutathione (GSH) were prepared by the heat-assisted reduction of Au(I)-thiol complex at 1:1 or 5:4 molar ratio of Au to GSH. The 1:1 sample has three emissions at 610, 645 and 800 nm while the 5:4 sample has a dominant emission at 800 nm but the two emissions at 610 and 645 nm are very weak. It was found in separations that the 610 and 645 nm emissions are closely related while the 800 nm emission behaves in a different way. By adding NaOH, the 800 nm emission decreases while the red emission increases in intensity at low concentration, but both the red and the NIRL emissions are quenched at high concentrations. The luminescence lifetimes of the red emissions were on the nanosecond time scale while the 800 nm emission was on the microsecond time scale. Based on these observations, it is concluded that the red emission is from a single excited states while the 800 nm emission is originated from surface states. Also, for the first time, X-ray excited luminescence is reported here from Au nanoparticles and the applications of these nanoparticles for cell imaging is also investigated. PMID- 24059083 TI - The influence of laser-induced 3-D titania nanofibrous platforms on cell behavior. AB - The current challenge in tissue engineering is to design a platform that can provide appropriate topography and suitable surface chemistry to encourage desired cellular activities and to guide 3-D tissue regeneration. Compared with traditional cell culture materials, 3-D nanofibrous platforms offer a superior environment for promoting cell functions by mimicking the architecture of extracellular matrix (ECM). In this study, we present a technique to engineer freestanding 3-D titania nanofibrous structures on titanium substrates using femtosecond laser processing. The crystallinity, surface adhesion, and surface energy of the synthesized nanostructures are discussed. The effects of synthesized nanoarchitectures on the proliferation, morphology, and viability of MC3T3-E1 mouse osteoblast-like cells and NIH 3T3 mouse embryonic fibroblasts are investigated. The nanofibrous structures show high surface energy and hydrophilicity. The results from in vitro studies reveal that the titania nanofibrous architectures possess excellent biocompatibility and significantly enhances proliferation of both cell lines compared to untreated titanium specimens. Study of the cell morphology shows dynamic cell migration and attachment on the titania nanofibrous architecture. The bioactivity and biocompatibility of the engineered 3-D nanostructures suggest noticeable perspective for developing bio-functionalized scaffolds and implantable materials in regenerative medicine and clinical tissue engineering. PMID- 24059084 TI - Novel pH-sensitive micelles generated by star-shape copolymers containing zwitterionic sulfobetaine for efficient cellular internalization. AB - pH-sensitive micelles are considered promising carriers for tumor targeted drug delivery. In this study, novel pH-sensitive star-shape copolymers of amphiphilic poly(epsilon-caprolactone)-b-poly(N, N-diethylaminoethyl methacrylate)-r-poly(N (3-sulfopropyl)-N-methacryloxyethy-N, N-diethylammoniumbetaine) (4sPCLDEAS) are designed and synthesized with the combination of ring opening polymerization (ROP) and atom radical transferpolymerization (ATRP). The structure of the copolymers is characterized by proton nuclear magnetic resonance spectra (1HNMR). The poly(N-(3-sulfopropyl)-N-methacryloxyethy-N, N-diethylammoniumbetaine) segment is used instead of poly(ethylene glycol) (PEG) as hydrophilic block in the copolymers to form polymeric micelles. The micelles present spherical shape, narrow size distribution, and are reponsive to the acidity. The CMC of the micelles is as low as 1 x 10(-3) mg mL(-1). Doxorubin (DOX) is efficiently encapsulated in the micelles and the drug release is pH dependant. The cytotoxicity as well as the intracellular drug delivery of the micelles are investigated. The micelles are nontoxic to human cervical carcinoma (Hela) cells. The DOX-loaded micelles are internalized in Hela cells efficiently, which are better than that of hydrophilic doxorubicin hydrochloride (DOX x HCl). These pH sensitive micelles are potential promising carriers for anti-cancer drug delivery. PMID- 24059085 TI - Surface stabilized efavirenz nanoparticles for oral bioavailability enhancement. AB - The aim of the present study was to prepare surface stabilized nanoparticles for oral bioavailability enhancement of efavirenz (EFZ). EFZ nanoparticles (EFZ-NPs) were prepared by combination of anti-solvent precipitation and high pressure homogenization technique, using hydroxy propyl methyl cellulose as stabilizer which resulted in formation of EFZ-NPs of average particle size -350 nm with excellent particles size distribution (< 0.2). EFZ-NPs were freeze dried using trehalose as cryoprotectant and found to be quite stable against storage at 25 +/ 2 degrees C/60 +/- 5% RH and 40 +/- 2 degrees C/75 +/- 5% RH as evidenced from particle size, particle size distribution and drug content. EFZ-NPs demonstrated an increase in saturation solubility by 5.16 folds in comparison with free EFZ. In vitro dissolution studies established advantage of EFZ-NPs over free EFZ as more than 75% drug was dissolved within 5 min in case of EFZ-NPs while it was approx 20% in case of free EFZ. In vivo pharmacokinetic studies further confirmed the potential of EFZ-NPs as 2.02 folds increase in peak plasma concentration and 2.29 folds increase in AUC(0-infinity) were observed in comparison to free EFZ. The In vitro-In vivo relationship of the formulations further suggested higher correlation coefficient of 0.9995 for EFZ-NPs in Levys plot as compared to 0.8726 for free EFZ. PMID- 24059086 TI - Direct patterning of free standing three dimensional silicon nanofibrous network to facilitate multi-dimensional growth of fibroblasts and osteoblasts. AB - The advent of tissue engineering has invigorated interest in novel tissue regeneration matrices. An ideal matrix that simulates the natural extra cellular matrix (ECM) should be nanoscale, with three dimensionally interconnected nanofibers which cannot be generated by current methods such as electrospinning. Furthermore, certain biocompatible materials like silicon cannot be electrospun. We present a novel MHz laser synthesis method that permits sub-100 nm scale structures on any material, including silicon, that mimic the natural ECM. Owing to its three dimensional interlinked nature, the nanofibrous substrate is shown to guide the osteoblasts and fibroblasts to grow not only planarly to the surface, as is true for conventional scaffolds, but also expand and grow upward vertically. This method of synthesis demonstrates promise for novel three dimensional (3D) scaffolds that can assist in tissue and bone regeneration and a myriad of other applications such as drug delivery and biosensing. PMID- 24059087 TI - Increasing cellular uptake of mesoporous silica nanoparticles in human embryonic kidney cell line 293T cells by using Lipofectamine 2000. AB - Mesoporous silica nanoparticles (MSNs) are ideal nanocarriers that have recently gained attention in important bioapplications such as drug, gene, and protein delivery. The efficacy of endocytosis greatly affects the biological functions of MSNs. In the present study, we investigated the effect of cationic liposomes of Lipofectamine 2000 on cellular uptake of MSNs and the cytotoxicity of cationic liposomes combining with MSNs both in vitro and in vivo. Therefore, mesoporous silica nanoparticles with an average diameter of 130 nm and negative surface charge were synthesized and characterized. The possible role of Lipofectamine 2000 in cellular uptake of MSNs was evaluated in human embryonic kidney cell line 293T cells by transmission electron microscopy (TEM) and with inductively coupled plasma (ICP) analysis. The toxicities of liposomes combining with MSNs were tested in vitro via cell apoptosis assay and MTT cell viability assay, and in vivo by histological examination of six organs of mice after intravenous injection. The endocytosis efficiency of MSNs in human embryonic kidney 293T cells was greatly increased using Lipofectamine 2000 compared with controls (P < 0.001). No apparent in vitro or in vivo cytotoxicity was found for Lipofectamine 2000 combining with MSNs. Our data indicate that cationic liposomes of Lipofectamine 2000 has the potential to greatly increase cellular uptake of MSNs with negative surface charge in human renal 293T cells without apparent toxicity. PMID- 24059088 TI - Cytotoxicity and cell interaction studies of bioadhesive poly(anhydride) nanoparticles for oral antigen/drug delivery. AB - The use of bioadhesive polymers as nanodevices has emerged as a promising strategy for oral delivery of therapeutics. In this regard, poly(anhydride) nanoparticles have shown great potential for oral drug delivery and vaccine purposes. However, despite extensive research into the biomedical and pharmaceutical applications of poly(anhydride) nanoparticles, there are no studies to evaluate the interaction of these nanoparticles at a cellular level. Therefore, the main objectives of this study were to evaluate the cytotoxicity as well as the cell interaction of different poly(anhydride) nanoparticles: conventional (NP), nanoparticles containing 2-hydroxypropyl-beta-cyclodextrin (NP HPCD) and nanoparticles coated with poly(ethylene glycol) 6000 (PEG-NP). For this purpose, nanoparticles were prepared by solvent displacement method and labelled with BSA-FITC. Nanoparticles displayed a size about 175 nm with negative surface charge. Cytotoxicity studies were developed by MTS and LDH assays in HepG2 and Caco-2 cells. Results showed that only in HepG2 cells, NP and NP-HPCD induced significant cytotoxicity at the highest concentrations (1 and 2 mg/mL) and incubation times (48 and 72 h) tested. Studies to discriminate between cytoadhesion and cytoinvasion were performed at 4 degrees C and 37 degrees C in Caco-2 cell line as intestinal cell model. Nanoparticles showed cytoadhesion to the cell surface but not internalization; PEG-NP was the most bioadhesive followed by NP-HPCD and NP as demonstrated by flow cytometry. Finally, cellular localization of particles by fluorescence confocal microscopy confirmed the association of these nanoparticles with cells. Thus, this study demonstrated the safety of NP, NP-HPCD and PEG-NP at cellular level and its bioadhesive properties within cells. PMID- 24059089 TI - Biocompatibility testing of single-walled carbon nanotubes on murine preosteoblasts: higher osteoblastic differentiation with BMP-9 than with BMP-2. AB - Carbon nanotubes (CNTs) have been used in orthopaedic applications because of their exceptional mechanical properties. However, the influence of CNTs on the behaviour of bone-forming cells and on the ability of these cells to respond to growth factors, such as bone morphogenetic proteins (BMPs), remains poorly known. Therefore, in the present study, single-walled CNTs (SWCNTs) were synthesised using an induction thermal plasma process and purified using a multistep procedure. The impact of these purified SWCNTs on the Smad activation, cell proliferation and differentiation, with or without BMP-2 and BMP-9 (1.92 nM), was also studied using western blot, mitochondrial enzymatic activity, TUNEL, RT-PCR and alkaline phosphatase activity analyses. Pre-treatment of MC3T3-E1 preosteoblasts with SWCNTs accelerated the Smad1/5/8 activation, induced by both BMP-2 and BMP-9, within 15 min. It also slightly affected their proliferation at 48 h without apoptosis. Interestingly, at 72 h, BMP-9 favoured the differentiation of MC3T3-E1 preosteoblasts pretreated with SWCNTs to a larger extent than BMP-2 did. Therefore, the combination of BMP-9 with SWCNTs appears to be a promising avenue for bone applications. PMID- 24059090 TI - Guided bone regeneration using a flexible hydroxyapatite patch. AB - Guided bone regeneration (GBR) is a new method of promoting new bone formation by blocking the proliferation of regenerated connective tissue or providing additional interventions such as direct drug delivery and mechanical support. This in vivo study of bone regeneration in radius compound fractures in rabbits was conducted using a highly flexible scaffold of nanoscale hydroxyapatite (nHAp)/chitosan, termed a "bone patch". A solidification-assisted compression (SAC) method was utilized to fabricate the bone patch, and its in vivo cytotoxicity, bio-absorption, and bone regeneration capacity were evaluated. Four weeks after implantation, new bone formation with abundant active osteoblasts and incompleted degradation of chitosan in the patch were observed without any regeneration of connective tissue, compared with the corresponding implant without a patch. X-ray images showed that the radius with the bone patch had higher opacity than that of the control, which was consistent with the results obtained via histological analysis. Evidently, the nHAp-embedded bone-patch scaffold has considerable potential for application in the field of orthopedics of bone regeneration. PMID- 24059091 TI - Enhancement of osteoinduction by continual simvastatin release from poly(lactic co-glycolic acid)-hydroxyapatite-simvastatin nano-fibrous scaffold. AB - Simvastatin is considered as a stimulator for bone formation. However, the half life for simvastatin is generally 2 hours, which means, it is difficult to maintain biologically active simvastatin in vivo. To overcome this limitation, we created a system to slowly release simvastatin in vitro and in vivo. We constructed a poly(lactic-co-glycolic acid)/hydroxyapatite nano-fibrous scaffold to carry simvastatin. Releasing assays showed that simvastatin was released from poly(lactic-co-glycolic acid)/hydroxyapatite/simvastatin quickly within - 15 days, and small amounts continued to be released through day 56 (experiments terminated). MTT assays demonstrated that both poly(lactic-co-glycolic acid)/hydroxyapatite and poly(lactic-co-glycolic acid)/hydroxyapatite/simvastatin promoted MC3T3-E1 cell proliferation. However, Alkaline phosphatase assays showed that only poly(lactic-co-glycolic acid)/hydroxyapatite/simvastatin scaffold significantly promoted the osteogenic differentiation of MC3T3-E1 cells in vitro on day 14. To further test in vivo, we created calvaria bone defect models and implanted either poly(lactic-co-glycolic acid)/hydroxyapatite or poly(lactic-co glycolic acid)/hydroxyapatite/simvastatin. After 4 or 8 weeks post-implantation, the results indicated that poly(lactic-co-glycolic acid)/hydroxyapatite/simvastatin scaffold induced bone formation more efficiently than poly(lactic-co-glycolic acid)/hydroxyapatite alone. Our data demonstrates that poly(lactic-co-glycolic acid)/hydroxyapatite/simvastatin has the potential to aid in healing bone defects and promoting bone regeneration in the future although we still need to optimize this complex to efficiently promote bone regeneration. PMID- 24059092 TI - Extraction, purification and nanoformulation of natural phycocyanin (from Klamath algae) for dermal and deeper soft tissue delivery. AB - This study focuses on the extraction and isolation of a natural anti-inflammatory phycocyanin and its nanoformulation in innovative and efficient vesicular carriers able to improve its delivery to the skin. C-phycocyanin was successfully isolated from a commercial dry extract (AfaMax) of blue-green Klamath algae. Protein extraction and purity were confirmed by gel electrophoresis (SDS PAGE), MALDI top-down sequencing, Liquid Chromatography/Mass Spectrometry, and UV absorption. Purified C-phycocyanin was then encapsulated in different phospholipid vesicles: liposomes, ethosomes and Penetration Enhancer containing Vesicles (PEVs), the latter containing the penetration enhancer propylene glycol or Transcutol P. The main colloidal characteristics of the systems were assessed, showing spherical vesicles around 100 nm, negatively charged, with different lamellarity depending on the formulation composition. An in depth investigation on vesicle geometrical properties and morphology was carried out by Small and Wide-Angle X-ray Scattering. Further, the ability of rhodamine-labelled vesicles to allow fluorescent phycocyanin penetration and distribution through human skin was evaluated by Confocal Laser Scanning Microscopy, while a complete picture of vesicle-treated skin architecture was gained using Scanning Electron Microscopy. Results indicate that PEVs, especially propylene glycol containing vesicles, are promising carriers for the delivery of the high molecular weight protein phycocyanin to the deep skin layers. PMID- 24059093 TI - Evaluation of antitumor activity and development of solid lipid nanoparticles of metronidazole analogue. AB - Nitroheterocyclic compounds have received considerable interest as hypoxia selective cytotoxins (HSC) for cancer treatment. In the present study, we investigated antitumor activity of an iodide analogue of metronidazole, 1-(2 iodoethyl)-2-methyl-5-nitroimidazole (MTZ-I), using Swiss mice bearing solid Ehrlich tumor. MTZ-I showed potent anti-cancer activity at a dose of 40 mg/kg. MTZ-I loaded solid lipid nanoparticles (SLN) were developed as an alternative colloidal carrier system to enhance tumor drug uptake. SLN were characterized for particle size, polydispersity index, zeta potential and entrapment efficiency. In addition, the influence of presence of the cationic lipid stearylamine (STE) on stability of formulation was assessed. The results of DSC study showed that MTZ-I exhibited interaction with STE. PMID- 24059094 TI - Solid-phase hybridization efficiency improvement on the magnetic nanoparticle surface by using dextran as molecular arms. AB - For reducing the steric hindrance and nonspecific binding of the target DNA, the dextran was used as molecular arms to be immobilized on the surface of magnetic nanoparticles (MNPs). Magnetic separation was used in preparation of dextran-MNPs (DMNPs). Aspartic acid and aminated DNA probe were successively modified on the dextran immobilized on the surface of MNPs. These probe-DMNPs were successfully applied to detect biotin-labeled PCR product of E. coli O157:H7 genome by hybridization. Then the complexes were bonded with streptavidin-modified alkaline phosphatase (ALP-SA). Finally the chemiluminescent signals were detected by adding 3-(2-spiroadamantane)-4-methoxy-4- (3-phosphoryloxy) phenyl-1,2-dioxetane (AMPPD). The results showed that this method had a good specificity, and higher sensitivity than that when only MNPs were used as solid carriers. PMID- 24059095 TI - Limited inhibitory effects of non-steroidal antiinflammatory drugs on in vitro osteogenic differentiation in canine cells. AB - Cyclooxygenase (COX)-2 participates essentially in bone healing, demonstrated by COX-2 knockout mice that showed delayed fracture repair. Considerable controversy still exists on inhibitory effects of COX-2 inhibitors on bone healing in clinical cases. To assess stage-dependent effects of short-term treatment of COX 2 inhibitors on osteogenic differentiation, a canine POS osteosarcoma cell line which spontaneously differentiates into osteoblastic cell was exposed to COX-2 inhibitors such as carprofen and meloxicam for 72 hours during three different stages of osteoblast differentiation, including day 0 to 3 (pre-osteoblastic stage), day 4 to 7 (transitional stage) and day 8 to 11 (mature osteoblastic stage). As osteogenic markers, expression of alkaline phosphatase (ALP) was estimated by analysis of mRNA expression, enzymatic activity and ALP staining, and expression of osteocalcin was estimated by analysis of mRNA expression after the drug treatments. Calcified matrix formation was finally observed by von Kossa staining on day 14. Expressions of ALP showed no significant suppression by carprofen and meloxicam during all three stages. However, expressions of osteocalcin mRNA and non-calcified nodule formations were delayed by carprofen and meloxicam during transitional stage. Nevertheless, fully calcified nodule formation was observed in all experimental groups during post-medication period. These results indicate that short-term treatment of carprofen and meloxicam would reversibly suppress the differentiation of osteoblasts. PMID- 24059096 TI - C-X-C chemokine receptor type 4 and cytokine expressions in cows of a dairy herd with high prevalence of calves persistently infected with bovine viral diarrhea virus. AB - Animals persistently infected (PI) with bovine viral diarrhea virus (BVDV) play an important role in the spread of BVDV. Alteration of maternal C-X-C chemokine receptor type 4 (CXCR4) expression has been suspected as closely concerned with the production of PI calves. It is not clear what the influence of CXCR4 response to the prevalence of PI calves. We have previously reported a dairy herd with high prevalence of PI calves within a short period having a single origin of infection. CXCR4 and cytokine expressions in cows of this herd were investigated. There were no significant differences in CXCR4 and cytokine expressions between the dams of PI calves and the dams of non PI calves in the herd. In the comparison among the herds, CXCR4 expressions in the PI producing herds were significantly lower than the BVDV-free herd. Moreover, CXCR4 expressions in the high prevalence herd and the low prevalence herd were similar. These findings among herds corresponded with the previously reported experimental production of persistent infection with BVDV in cows. Based on the cytokine profile of these herds, IL-10 was significantly higher in the high prevalence herd and the BVDV free herd. The combination of low expression of CXCR4 and high expression of IL 10 might be closely concerned with some bias for the production of PI calves. PMID- 24059097 TI - Antibodies to H5 subtype avian influenza virus and Japanese encephalitis virus in northern pintails (Anas acuta) sampled in Japan. AB - Blood samples from 105 northern pintails (Anas acuta) captured on Hokkaido, Japan were tested for antibodies to avian influenza virus (AIV), Japanese encephalitis virus (JEV), and West Nile virus (WNV) to assess possible involvement of this species in the spread of economically important and potentially zoonotic pathogens. Antibodies to AIV were detected in 64 of 105 samples (61%). Of the 64 positives, 95% and 81% inhibited agglutination of two different H5 AIV antigens (H5N1 and H5N9), respectively. Antibodies to JEV and WNV were detected in five (5%) and none of the samples, respectively. Results provide evidence for prior exposure of migrating northern pintails to H5 AIV which couldhave implications for viral shedding and disease occurrence. Results also provide evidence for limited involvement of this species in the transmission and spread of flaviviruses during spring migration. PMID- 24059098 TI - [The effects of di-(2-ethylhexyl) phthalate (DEHP) in testosterone synthesis and its molecular mechanisms in the fetal testis of male mouse by organ culture in vitro]. AB - OBJECTIVE: To investigate the effects of DEHP in testosterone synthesis and the related genes expression in the fetal testis of male mouse by organ culture in vitro. METHODS: The testis tissues were cultured in infiltrating type rotating device for 72 hours. The culture and gas were changed every 24 hours. The testis tissues were divided into the DMSO control group and four DEHP groups (the terminal concentration were 0.1, 1.0, 10.0, 100.0 micromol/L). The testosterone levels in the cultured medium were measured by radioimmunoassay, the INHBbeta levels were measured by Elisa, the gene expressions related with testosterone synthesis were detected by real-time PCR, the morphological changes of cultured testis were observed by HE staining under optical microscope, the expressions of related proteins were measured by immunohistochemistry. RESULTS: Compared to the control group, the levels of testosterone synthesis in 0.1, 1.0, 10.0 micromol/L groups were increased, but decreased in 100.0 micromol/ L group which were exposed in DEHP for 48 hours and 72 hours. There was an increase of INHBbeta synthesis in 0.1 and 1.0 micromol/L groups, but a decrease in 10.0 and 100.0 micromol/L groups. The gene expressions of 3beta-HSD, P450c17, P450Scc, vimentin were significantly decreased compared to that of control group especially in 1.0 and 10.0 micromol/L groups (P < 0.05), but the expressions of INHBbeta had no significant changes. There were no apparent morphological changes in testis tissue by HE staining. A significant increase of the three proteins (3beta-HSD, P450c17, P450Scc) and a significant decrease of vimentin were observed in 10.0 and 100.0 micromol/L groups (P < 0.05). CONCLUSION: DEHP exposure can affect the testosterone synthesis in the fetal testis of male mouse. The regulation of gene expression involving in testosterone synthesis might be the mechanism. PMID- 24059099 TI - [Influence of fetal bovine serum protein concentration in adipose tissue extract on adipogenic differentiation of adipose derived stem cells]. AB - OBJECTIVE: To observe whether fetal bovine serum (FBS) will affect the adipogenic ability of adipose derived stem cells (ADSCs) induced by adipose tissue extract (ATE), and to explore the effects of different FBS protein concentrations in ATE on adipogenic ability, cell proliferation and migration of ADSCs. METHODS: Rat ADSCs were cultured, passaged, and then subjected to osteogenic and neural induction. The adipose explants were cultured in culture medium with or without FBS, then ATE was collected to induce passage four (P4)-ADSCs, which were subsequently detected with oil red staining on the 7th day and the adipogenic ratio was calculated. Different concentrations of ATE without FBS (100 microg/mL, 250 microg/mL and 500 microg/mL) were used to induce P4-ADSCs before the adipogenic events, and the adipogenic ratio of each concentration group was observed. The effect of different protein concentrations on ADSCs proliferation and migration was also observed. RESULTS: Alizarin red staining and NF immunofluorescence staining were positive after the osteogenic and neural induction of cultured ADSCs. Either ATE with or without FBS was able to induce adipogenic differentiation of ADSCs on the 3rd day and there was no significant differences of adipogenic differentiation between ATE with FBS and without FBS on the 7th day. The adipogenic ratio of 500 microg/mL group was higher than that of 100 pg/mL group and 250 microg/mL group (P < 0.05). After two days of induction, all the three different protein concentrations could inhibit cell proliferation, and different protein concentrations in ATE had no effect on the migration of ADSCs. CONCLUSION: ATE obtained from culture medium without FBS has no effect on adipogenic capacity of ADSCs in a short period of time. The adipogenic ratio of ADSCs is associated with protein concentration in ATE. PMID- 24059100 TI - [Expression of non-secretory CXCL16 and its impact on biological characteristics in breast cancer cell lines]. AB - OBJECTIVE: To detect the expression of non-secretory CXCL16 and its impact on malignant biological behaviors in breast cancer cell lines. METHODS: RT-PCR was carried out to examine the expression of CXCL16 mRNA in breast cancer cell lines with different aggressiveness SK-BR-3, MCF-7, MDA-MB-231, MDA-MB-435S and human mammary normal epithelial cell; MCF-10A. The eukaryotic expression plasmid of CXCL16 was transfected into MDA-MB-231 cells and overexpression of CXCL16 was confirmed by Real time PCR and Western blot. Boyden Chamber assay was used to determine cell migration and invasion, while MTT assay was performed to determine cell proliferation. RESULTS: Among four breast cancer cell lines, CXCL16 mRNA was highly expressed in MCF-7, lowly expressed in MDA-MB-231, while MCF-10A faintly expressed CXCL16. Overexpression of CXCL16 led to a decrease in cell migration, invasion but not proliferation in MDA-MB-231 cells. CONCLUSION: Expression of non secretory CXCL16 is associated with aggressiveness of breast cancer cell lines, and CXCL16 expression inhibits cell migration and invasion in vitro. PMID- 24059101 TI - [Effects of intrauterine cigarette smoking exposure on expression of 3 mercaptopyruvate sulfurtransferase in medulla oblongata of neonatal rats]. AB - OBJECTIVE: To investigate the expression of 3-mercaptopyruvate sulfurtransferase (3MST) in medulla oblongata of neonatal rats and effects of intrauterine cigarette exposure on its expression. METHODS: Sprague Dawley pregnant rats were randomly divided into 2 groups, control group and cigarette smoke exposure group (n = 8). 3MST mRNA and protein expression in medulla oblongata of neonatal rats were analysed by RT-PCR and Western blot, respectively, and the expression of 3MST in the neurons of respiratory-related nuclei in medulla oblongata of neonatal rats was investigated with immunohistochemical technique. RESULTS: The RT-PCR and Western blot analyses showed that 3MST mRNA and protein were expressed in the medulla oblogata of neonatal rats and intrauterine cigarette exposure promoted their expression (P < 0.05). Immunohistochemical staining indicated that 3MST existed in the neurons of pre-Botzinger complex (pre-BotC), hypoglossal nucleus (12N), ambiguous nucleus (Amb), facial nucleus (FN) and nucleus tractus solitarius (NTS) in control group of the animals and the mean optical densities of 3MST-positive neurons in the pre-BotC, 12N, Amb and FN, but not NTS, were significantly increased in cigarette smoke exposure group (P < 0.05). CONCLUSIONS: 3MST exists in the neurons of medullary respiratory nuclei of neonatal rats and its expression can be up-regulated by intrauterine cigarette exposure, suggesting that the 3MST-H2S pathway may be involved in protection of medullary respiratory centers against injury induced by intrauterine cigarette exposure. PMID- 24059102 TI - [Effect of RAAS antagonist on the expression of gap junction cx43 in myocardium of spontaneously hypertensive rat]. AB - OBJECTIVE To investigate the expression of gap junction protein Cx43 in the cardiac muscle of spontaneous hypertensive rat and the effects of various antagonists against renin angiotensin aldosterone system (RAAS) on Cx43 expression. METHODS 70 spontaneous hypertensive rats of 8-week age, 200-gram weight were separated into 7 groups, as hypertension, ramipril, telmisartan, eplerenone, ramipril + telmisartan, telmisartan + eplerenone, and ramipril+eplerenone treatment group. Another 10 healthy Wistar rats of the same age and weight were used as control group. All the rats were given intragastric administration at 8 a. m. every morning, and measured arteria caudilis pressure at 0, 4 and 8 week, respectively. 8 weeks later, all the rats were sacrificed, and the hearts were taken to measure the weight of left ventricle and the ratio of left ventricle to body weight. Myocardial fibrosis was observed by H&E staining of paraffin embedded sections, and Cx43 expression was examined by RT PCR and western blot. RESULTS: The arteria caudilis pressure of spontaneous hypertensive rats was significantly higher than that of healthy control Wistar rats (P < 0.01). The decreased blood pressure was observed in RAAS antagonists treated rats, compared with hypertension group (P < 0.05). The combined treatment of telmisartan and eplerenone had the best effect of lowering blood pressure. Moreover, the weight of left ventricle, the ratio of left ventricle to body weight, myocardial fibrosis and angiotensin 11 were all prominently decreased in telmisartan and eplerenone combination group (P < 0.01). The expression of Cx43 in spontaneous hypertensive rats was significantly lower than that of healthy control Wistar rats (P < 0.01). Increased Cx43 expression was observed in RAAS antagonists treated rats, compared with hypertension group (P < 0.05). CONCLUSION: The expression of gap junction protein Cx43 was significantly down regulated in spontaneous hypertensive rats, while RAAS antagonists increased Cx43 expression. The combination of telmisartan and eplerenone effectively recovered the expression of Cx43 and probably reversed hypertension. PMID- 24059103 TI - [Effect of PEGylation of alpha-Momorcharin against its hepatotoxicity in rats]. AB - OBJECTIVE: To explore the effect of PEGylation of alpha-Momorcharin (alpha-MMC), one of ribosome-inactivating proteins from bitter melon seed, against its hepatotoxicity in rats. METHODS: SD rats were randomized into NS group, alpha-MMC treated groups, and alpha-MMC-PEG treated groups. The doses of alpha-MMC and alpha-MMC-PEG were high, middle, and low dose (6.25, 2.08, 0.70 mg/kg). The rats were given different dose of alpha-MMC, or alpha-MMC-PEG via caudal vein every other day for consecutive 28 days and then left for 14 days recovery. The general condition of animals was observed, blood and liver samples were collected for liver function study and pathological examination on day 28 after initiation of administration and on day 14 after withdrawal. RESULTS: On day 28 after initiation of administration, the liver function damages were found in high-dose and middle-dose of alpha-MMC treated groups, such as the decreasing of ALB, increasing of GLB, A/G ratio decreasing and the dose-dependant increasing of AST, BIL and CHO. The pathological changes of hepatotoxicity were also observed in these two groups, including the massive hepatocyte, swelling degeneration, inflammatory cell infiltration, congestion and diffusive necrosis. However, the liver function and pathological changes in alpha-MMC-PEG treated groups were better than those in alpha-MMC treated groups. CONCLUSION: PEGylation could reduce the hepatotoxicity of alpha-MMC to rats. PMID- 24059104 TI - [Effects of Fukang oral liquid on the prevention of intrauterine adhesion and expressions of TGF-beta1, PAI-1 and MMP-9 in endometrium of rats]. AB - OBJECTIVE: To investigate the preventing effect of Fukang oral liquid (fuk) in intrauterine adhesions and its effects on the expression of TGFbeta-1, PAI-1 and MMP-9 in endometrium of rats with intrauterine adhesions. METHODS: 50 female wistar rats were divided into high, medium, low dose of Fukang oral liquid group (Hfuk, Mfuk, Lfuk), blank control group (Bcon), and model control group (Mcon) (n = 10 in each group). The rats in Hfuk, Mfuk and Lfuk groups were treated with intragastric administration of 4 mL, 2 mL and 1 mL Fukang Oral Liquid per day, while the rats in Mcon group and Bcon group received 2 mL physiological saline intragastric administration per day. All of rats were executed on 10th day and the sample of endometrium was harvested for the study of histology and morphology and the expression of TGFbeta-1, PAI-1 and MMP-9. RESULTS: Under the light microscope, the organizational structure of the uterine cavity and uterine wall was clear in Bcon group, the uterine cavity disappeared in Mcon group, and the layers structure remained normal arrangement in three fuk treated groups. TGFbeta 1 and PAI-1 protein expressions in Hfuk, Mfuk, Lfuk groups were less than those in Mcon group (P < 0.001), but MMP-9 protein expressions were higher. (P < 0.001). CONCLUSION: Fukang oral liquid show preventing effect on IUA, the mechanism may be related to its effects on the expressions of TGF-beta1, PAI-1, and MMP-9 in the endometrium. PMID- 24059105 TI - [Effect of cyclooxygenase-2 inhibitor on CD4+ CD25+ regulatory T cells in mouse hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the effect of celecoxib on regulatory T cells (Treg) in mouse hepatocellular carcinoma (HCC). METHODS: Total of 40 mice was divided into two subgroups, normal animal groups include control and celecoxib group, HCC groups include control and celecoxib group. 30 mg/kg of celecoxib were given daily for 24 days for celecoxib groups. All mice were sacrificed after 24 days treatment and the removed tumor weight were measured. By detecting CD4 and CD25 with flow cytometry, the level of Treg in peripheral blood was determined. The expressions of Forkhead/winged helix transcription factor-3 (Foxp3) protein in the tumor infiltrating lymphocytes (TILs) and cyclooxygenase-2 (COX-2) protein in tumor tissue were measured by immunohistochemistry techniques. RESULTS: The mean weight of tumor in celecoxib group is much lower than that of control group [(0.82 +/- 0.30) g vs. (1.41 +/- 0.63) g, P < 0.05]. The percentage of Treg in total CD4+ T cells isolated from the peripheral blood of HCC animals in control group was higher than that of normal control group [(4.26 +/- 0.89)% vs. (3.01 +/ 0.65)%, P < 0.05]. After treatment with celecoxib, the percentage of Treg was decreased [(3.04 +/- 0.74)% vs. (4.26 +/- 0.89)%, P < 0.053 and the percentage of Foxp3 positive cell in TILs was also decreased [(8.87 +/- 3.72)% vs. (30.78 +/- 9.26)%, P < or = 0.05]. The tumor tissue COX-2 protein expression in celecoxib group was lower than in that of control group [IOD (2.90 +/- 1.030) vs. (6.63 +/- 2.279), P < 0.01)] and the changing of COX-2 in tumor tissue was according to Treg in the peripheral blood. CONCLUSION: Treg cells are increased in the peripheral blood of HCC mice and COX-2 inhibitor could decrease the percentage of Treg cell in the peripheral blood or TILs. PMID- 24059106 TI - [Expression and its clinical significance of AMP-activated protein kinase in esophageal squamous cell carcinoma]. AB - OBJECTIVE: To investigate the expression and its possible function of AMP activated protein kinase (AMPK) in the occurrence of esophageal squamous cell carcinoma (ESCC). METHODS: The tissue samples were collected from 40 fresh ESCC and 40 normal esophagus, and the expression of AMPK downstream substrates p-ACC and ACC were tested by Western-blot, then the correlations of p-ACC and ACC expression to the clinicopathologic characterisics were analyzed. RESULTS: The expression of p-ACC in ESCC was lower than that in normal tissues, with significant statistical difference (P < 0.05). The down-regulation ratio of p-ACC in poorly-differentiated ESCC was 81.8% (9/11), which was significantly higher than that in moderately and well-differentiated ESCC (3.5%, 1/29). There was no correlation of p-ACC down-regulation with age, gender, TNM stage and lymph node metastasis (P > 0.05). CONCLUSION: The expression of p-ACC was down-regulation in ESCC, and the down-regulation is associated with tumor cell differentiation. PMID- 24059107 TI - [Effects of emulsified isoflurane preconditioning on LPS-induced acute lung injury in rats]. AB - OBJECTIVE: To investigate the effects of emulsified isoflurane preconditioning on LPS-induced acute lung injury in rats. METHODS: Acute lung injury was induced by the administration of LPS 8 mg/kg intravenously in male Sprague-Dawley rats. The ratswere randomly assigned to 4 groups: LPS-induced acute lung injury group (LPS, n = 10); emulsified Isoflurane Preconditioning group (EISO, n = 10); Intralipid pre-treated group (INT, n = 10), and saline pre-reated control group (CON, n = 5). In the later 3 groups, 2 mL/kg NS, IL and EISO were infused intravenously for 30 min before the administration of LPS respectively. The animals were then observed for 5 hours. The mean arterial blood pressure(MAP) and heart rate(HR) were monitored hourly. Arterial blood gas (ABG) was measured for oxygenation index (OI) at the end of 5h. The blood samples were taken for the measurements of plasma tumor necrosis factor-alpha (TNF-alpha) and interleukin-6(IL-6). The lungs were removed for the measurements of wet/dry (W/D) weight ratio, as well as the levels of malondialdehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO). RESULTS: The OI of group CON was 435 +/- 30, group LPS 225 +/- 49, group EISO 367 +/- 41, and group INT 267 +/- 41. Compared with group CON, OI and pulmonary SOD activity significantly decreased while plasma TNF-alpha, IL-6 concentration and pulmonary MDA level, MPO activity increased in LPS, EISO and INT groups. The plasma TNF-alpha, IL-6 concentration, pulmonary MDA level and pulmonary MPO activity of group EISO were lower while OI and pulmonary SOD activity were higher than those of group LPS. CONCLUSION: The emulsified isoflurane pretreatment can ameliorate LPS-induced acute lung injury in rats. PMID- 24059108 TI - [Signal transducer and activator of transcription 4 gene polymorphisms associated with dilated cardiomyopathy in Chinese Han population]. AB - OBJECTIVE: To investigate the association between signal transducer and activator of transcription 4 (STAT4) gene polymorphism and dilated cardiomyopathy (DCM). METHODS: Two single nucleotide polymorphisms (SNP) (rs7574865 and rs11889341) in STAT4 gene were determined using PCR-RFLP method. The genotype and allele frequencies of these two SNPs were compared between 294 DCM patients and 334 normal controls to test whether SNPs in STAT4 was associated with DCM. RESULTS: Compared to healthy controls, the frequency of GG genotype (55.8% in patients vs. 47.9% in controls, P = 0.039) and the G allele in rs11889341 (76.4% in patients vs. 70.7% in controls, P = 0.023) were significantly increased in D C M patients. We found that increased DCM risk is associated with CC+AC genotypes of rs574865 (94.2% in patients vs. 89.2% in controls, P = 0.025). No significant difference was observed in the distribution of allele frequency in rs7874865 between DCM patients and the controls. CONCLUSION: SNPs in STAT4 gene is associated with DCM. G allele and GG genotype in rs11889341, and CC+AC genotypes in rs7574865, may be associated with significantly increased risk of DCM. PMID- 24059109 TI - [Association between SNP rs12740374 and acute ischemic stroke in Chinese Han population]. AB - OBJECTIVE: To investigate the association between single nucleotide polymorphism (SNP) rs12740374 and acute ischemic stroke in Chinese Han population. METHODS: All subjects (778 ischemic stroke patients and 602 controls) were genotyped using ligation detection reaction (LDR). We analyzed the differences among all genotypes in two groups, as well as the association between rs12740374 and low density lipoprotein cholesterol (LDL-C). RESULTS: All three genotypes (GG, GT, TT) of rs12740374 were found in both stroke and control group. After adjusting for risk factors, although there was a trend that participants with a minor allele T of rs12740374 (GT/TT) had lower LDL-C concentration, no significant association was found between rs12740374 and ischemic stroke, and also no significant association between different genotypes and LDL-C was found. CONCLUSION: SNPs of rs12740374 was not significantly associated with ischemic stroke in the Chinese Han population. PMID- 24059110 TI - [The study of esophageal cancer risk associated with polymorphisms of DNA damage repair genes XRCC4 and RAD51]. AB - OBJECTIVE: Investigate the association between genetic polymorphism of DSBs repair gene XRCC4, RAD51 and susceptibility to esophageal cancer (EC). METHODS: A hospital based case-control study with 123 EC cases and 61 controls in a Chinese population was conducted. PCR-RFLP was applied to investigate the genotype of XRCC4 promoter G-1394T (rs6869366) and RAD51-G135C and then statistical analysis was conducted by calculating the adjusted odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: A significant difference of XRCC4-1394 polymorphism was observed between EC cases and controls (P < 0.05). Carriers of the XRCC4 rs6869366 G allele (GC+GG) were at a higher risk of developing EC with the TT genotype as reference (OR = 3.022, 95% CI = 1.487-6.142, P = 0.002). When GG served as the reference group of RAD51-G135C allele, variant genotype (GC and CC) had a significant increased risk of lung cancer (OR = 3.643, 95% CI = 1.501-8. 842, P < 0.05). CONCLUSION: Our findings indicated that genetic variants in DNA repair pathways may be involved in esophageal tumorigenesis. XRCC4 G-1394T and RAD51-G135C conferred risk for the process of developing EC. PMID- 24059111 TI - [Association of CYP3A5 and MDR1 genetic polymorphisms with the blood concentration of tacrolimus in Chinese liver and renal transplant recipients]. AB - OBJECTIVE: To investigate the association of CYP3A5 and MDR1 genetic polymorphisms with the concentration/ dose (C/D) ratio of tacrolimus for the feasibility of individualized medication. METHODS: The concentration of tacrolimus was detected by enzyme-multiplied immunoassay technique, and was adjusted by weight and dosage to C/D ratios. The single nucleotide polymorphisms of CYP3A5 A6986G and MDR1 C3435T, G2677T/ A, T1236C were determined by TaqMan RT PCR. The differences of C/D ratio were compared among all of the genotype groups. RESULTS: There were 5 cases with CYP3A5 *1/*1, 22 cases with CYP3A5 *1/*3, and 33 cases with CYP3A5 *3/*3. The C/D ratios of the patients with at least one CYP3A5 *1 allele (130.40 +/- 53.94) was significantly lower than those with CYP3A5 *3/*3 (198.12 +/- 90.80) (P < 0.01). For MDR1, there were 22, 23 and 15 recipients carried C/C, C/T and T/T respectively in C3435T, and 8, 32 and 20 recipients carried T/T, T/ C and C/C respectively in T1236C. The carriers with G/G, G/T, G/A, T/A, T/T were 9, 24, 5, 8 and 14 respectively in G2677T/A. No significant difference was found in the C/D ratios of tacrolimus among different MDR1 genotypes. CONCLUSIONS: Determination of CYP3A5 genotype could help individualize tacrolimus dose regimen prospectively. The patients with CYP3A5 *3 *3 require less dose of tacrolimus to reach the same concentrations comparing with the patients with at least one CYP3A5 * 1 allele. PMID- 24059112 TI - [Image quality adapted thoracic diameters in CT coronary artery imaging]. AB - OBJECTIVE: To evaluate the correlation between image quality and thoracic diameters, anteroposterior diameter (AP) and right-left diameter (RL) for the optimization of reducing radiation dose in coronary artery imaging with Dual source CT. METHODS: 118 patients underwent CT coronary artery imaging (CTCA) were divided into two groups (A and B) according to body mass index (BMI). There were 58 patients in group A with BMI values > or = 25 kg/m2 and < 30 kg/m2; and 60 patients in group B with BMI values < 25 kg/m2. Scan parameters: collimation 64 X 0.6 mm, reconstruction slice thickness 0.75 mm, reconstructin interval 0.7 mm, FOV 150-180 mm, the pitch adjusted according to heart rate automatically. CT imagings were obtained with tube voltage 100 kV, tube current 330 mAs (group A) and 100 kV, tube current 220 mAs (group B). The contrast-noise ratio (CNR), signal to noise ratio (SNR), as well as blind correlation test score values were calculated to establish the relationship among BMI, AP, RL and CNR, SNR. RESULTS: RL of five levels in groups of A, B were correlated to CNRa (P < 0.05). In group A and B (except iii, iv level of Group A), AP were associated with CNRa (P < 0.05). In addition to ii, iv level of group A, v level of group B, BMI were associated with CNRa (P < 0.05). The correlation coefficient of CNRa and RL of group A except ii level was greater than that of CNRa and AP. The correlation coefficient of CNRa, SNRa and RL of group B was greater than that of CNRa, SNRa and AP. Except iii level, the correlation coefficient of CNRa, SNRa and AP of group A was greater than that of CNRa, SNRa and BMI. Except ii level, the correlation coefficient of CNRa and AP of group B was greater than that of CNRa and BMI. CONCLUSION: Thoracic diameter of RL can be used as a guider to select the appropriate scan protocol in the coronary imaging acqusition with dual-source CT. PMID- 24059113 TI - [The risk factors of ventilator-associated pneumonia in newborn and the changes of isolated pathogens]. AB - OBJECTIVE: To study the risk factors of ventilator-associated pneumonia (VAP) in newborn and the profiles of isolated pathogens. METHODS: The clinical data of 179 neonates in the previous group (from December 2005 to December 2008) and 331 neonates in the present group (from January 2009 to January 2012) admitted into the neonatal intensive care unit (NICU) and received mechanical ventilation for equal or longer than 48 hours were respectively reviewed and analyzed,and their isolated pathogen profile and drug sensitivity were also compared in two groups. RESULTS: The incidence of VAP in the previous group and the present group were 22.35% and 20.24% respectively, no significant difference between two groups (P > 0.05) was observed. Gram-negative bacteria was the main pathogens (93.40%), the first 5 common pathogens in the previous group were Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter aerogenes. However, the first 5 of isolated gram-negative pathogens in the present group were somewhat different from the previous group, which were Klebsiella pneumoniae, Acinetobacter baumannii, Enterobacter cloacae, Escherichia coli and Enterobacter aerogenes. The drug sensitivity test showed that these pathogens had a general decline in sensitivities to commonly used antibiotics, of which the carbapenem antibiotic drug sensitivity decreased significantly, there was statistically significant difference between the previous group and the present group (P < 0.05). The risk factors of VAP include the duration of mechanical ventilation (OR = 5.680, 95% CI: 2.867-11.253), the frequency of tracheal intubation (OR = 2.219, 95% CI: 1.037- 4.748), birth weight (OR = 2. 127, 95% CI: 1.067-4.238) and neonatal asphyxia (OR = 2.025, 95% CI: 1.079-3.799) as well as the duration of hospital stay (OR = 2.012, 95% CI: 1.215-3.967). CONCLUSIONS: According to the data in our hospital, the main pathogenic bacteria of VAP were gram-negative pathogens, which showed a general decline in sensitivities to commonly used antibiotics. The incidence of VAP was closely related to the duration of mechanical ventilation, the frequency of intubation, birth weight and the hospitalization as well as the neonatal asphyxia. PMID- 24059114 TI - [Serum leptin, adiponectin, visfatin levels in adult GHD patients and correlation studies]. AB - OBJECTIVE: To investigate the change of leptin, adiponectin and visfatin levels in adult growth hormone deficiency (GHD) patients, and its relationship with other indicators. METHODS: 40 adult GHD patients (19 males) entered the observation group with 36 cases of healthy individuals (18 males) as the control group. Basic information (height, body mass, waistline, hipline etc.) was collected from both groups. Fasting venous blood samples were collected to measure the leptin, adiponectin and visfatin levels. RESULTS: The GHD group had a higher waist to hip ratio, and higher levels of cholesterol, triglyceride (TG), low density lipoprotein cholesterol (LDL-C), leptin, adiponectin and visfatin, but lower levels of growth hormone (GH), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3) and dehydroepiandrosterone sulfate (DHEA-S) when campared with that of the control group (P < 0.05). Logistic regression analysis demonstrated that adult GHD patients are associated with elevated levels of visfatin (OR = 1. 430, P < 0.05). CONCLUSION: Our study implied that adult GHD patients are associated with elevated levels of visfatin. PMID- 24059115 TI - [The relationship between hyperinsulinemia and hypokalemic periodic paralysis in overweight/obesity subjects]. AB - OBJECTIVE: To study the relationship between hyperinsulinemia and primary periodic paralysis in overweight/obesity people. METHODS: Overweight/obesity people with primary hypokalemic periodic paralysis were administrated as disease group. Serum potassium, insulin and glucose were analyzed at different time (0 h, 1 h, 2 h, 3 h, 4 h) after taking 100 g carbohydrates and the results were compared with that of control group matched by gender, age and body mass index (BMI). RESULTS: (1) Males were much more than females in disease group (14 males and 2 females), the onset age ranged from 20 to 50 years old. (2) Both the highest insulin level and the lowest potassium level appeared at one hour after taking the carbohydrates. And the highest insulin level of disease group was significant higher than that of control group. (3) The area under the curve of insulin and insulin/potassium of disease group was significant higher than that of control group. CONCLUSION: The postprandial hyperinsulinemia was an important factor in overweight/obesity people with hypokalemic periodic paralysis. PMID- 24059116 TI - [Study the effects of neuroplasticity on major depression disorder in rTMS combined with antidepressant treatments]. AB - OBJECTIVE: To explore the effects of neuroplasticity on major depression disorder (MDD) with event related potentials (ERPs) of mismatch negativity (MMN) and sensory gating potentials P50 for repetitive transcranial magnetic stimulation (rTMS) combined with antidepressant treatments. METHODS: A total of 159 patients with MDD randomly divided into two groups: 75 patients in group A was administrated rTMS treatment for 2 weeks (15 days), and continues to give antidepressant of selective serotonin reuptake inhibitor (SSRI) regularly. 84 patients in group B was consistently administered the similar antidepressant. The 24-item Hamilton Depression Scale (HAMD-24), MMN latency, S1-P50 amplitude, S2 P50 amplitude and S2-P50/S1-P50 amplitude ratio, and the percentages of abnormal P50 (S2-P50/S1-P50 > or = 0.5) were assessed and measured before treatment, at the 2nd and the 10th weekend after treatment in two treatment groups. Meanwhile, 90 normal control cases was set up as control group (group C). Results At 2th and 10th week after treatment, the HAMD-24 scores were reduced remarkably than those before treatment in group A and B (P < 0.001), and the scores in group A was lower than that in group B (P < 0.001). MMN latencies and S-P50 amplitudes after treatment in group A were significant shorter and lower than those before treatment in group A and after treatment in group B (P < 0.05) (except for intergroup comparison of S2-P50, amplitude after treatment weeks). No significant difference was found in S2-P50/S1-P50 ratio ( except for after treatment 2 weeks ) and percentage of abnormal P50 between group A after treatment and group C (P > 0.05). There were no statistical significance difference of ERPs between after treatment 2 weeks and 10 weeks in group A (P > 0.05). No statistical differences of ERPs between before and after treatment in group B (P > 0.05) was observed. CONCLUSION: rTMS combined with antidepressant therapy was superior to single antidepressant treatment, and marked improved automatic processing and sensory gating of the brain senior functional electrical physiological index. rTMS might induce effects of long-term potentiation/long-term depression like plasticity on brain, and keep brain function in a dynamic stability and balance. MMN and P50 maybe become neuroplasticity index reflecting relevant the brain senior function. PMID- 24059117 TI - [Epidemiological analysis of selected congenital limb malformations in Hengyang]. AB - OBJECTIVE: To describe the epidemiological characteristics of selected congenital limb malformations (CLM) in newborns of Hengyang. METHODS: During the period of 2008-2010, cluster sampling survey was adopted to investigate the congenital limb malformations of neonates born to women resident in Hengyang, including Nanyue District, Zhuhui District, Changning City and Hengshan County. Each newborn was examined for the screening of CLM after birth. Limb malformations were grouped into the isolated (ILM) and the syndromic (SLM) form, depending on associated malformations of the affected. Prevalence rates, CLM spectrum and clinical manifestations were analyzed. RESULTS: A total of 170 CLM cases were identified among 52,307 newborns during the study period, resulting overall rate of 32.50/10(4). The rates for isolated and syndromic CLM were 28.29 and 4.21 per 10 000 births respectively. The rates for polydactyly, congenital talipes equinovarus, syndactyly and limb reduction defects were 13.00/10(4), 9.56/10(4), 5.16/10(4) and 3.63/10(4), respectively. No significant difference in rates of overall CLM or specified CLM was observed across urban-rural, gender and maternal age groups. Of the cases affected by polydactyly, syndactyly and limb reduction defects, malformation involved upper limbs, lower limbs and the both accounted for 68.14%, 14.16% and 17.70%. Preterm birth, low birth-weight, still birth and neonatal death were observed more frequently in syndromic cases than in isolated patients. CONCLUSION: The high CLM prevalence rate and fatality rate in Hengyang suggest that effective measures should be taken to prevent malformations and to improve survival of the affected. PMID- 24059118 TI - [An descriptive epidemiological study on congenital clubfoot in China during 2001 to 2010]. AB - OBJECTIVE: To understand the trend of prevalence of congenital clubfoot and its epidemiological characterisitics in China during 2001 to 2010. METHODS: The data of the perinatal children with congenital clubfoot from 2001 to 2010 in the birth defects monitoring program were collected and analyzed, and the perinatal children were defined from the pregnancy of 28 weeks to postnatal 7 days, including live births, fetal deaths and stillbirths. SPSS16.0 software was used to analyze the data. RESULTS: A total of 4,233 cases were identified with congenital clubfoot among 8 273 382 births, with a prevalence of 5.12/10(4). There was no increasing trend or decreasing trend on the prevalence of congenital clubfoot to be found in China during 2001 to 2010 (chi2 = 2. 43, P > 0.05). The prevalence of congenital clubfoot in urban and rural areas was 4.90 and 5.43 per 10 000 births respectively. The prevalence of congenital clubfoot in male and female babies was 5.31 and 4.3 per 10,000 births respectively. The prevalence of congenital clubfoot in west, middle and east region was 7.00, 4.52 and 4.27 per 10,000 births respectively. The prevalence of congenital clubfoot in south and north region was 5. 82 and 4. 34 per 10,000 births respectively. The difference between them is statistically significant (P < 0.05). The distribution of affected area between male and female was not significantly different (chi2 = 1.74, P < 0.05). CONCLUSION: There was no increasing or decreasing trend on the prevalence of congenital clubfoot to be found in China during 2001 to 2010. The prevalence of congenital clubfoot in China was found with regional differences and gender differences. The prevalence of congenital clubfoot in Chinese population is greater than foreign populations. PMID- 24059119 TI - [Development of the comprehensive geriatric assessment scale for Chinese elderly]. AB - OBJECTIVE: To establish a comprehensive geriatric assessment scale which fit the situations of Chinese old people most, and to provide an evaluation tool for the proposal and intervention of functional health problems for the elderly. METHODS: The comprehensive geriatric assessment scale was produced by Delphi method combing with Chinese cultural background, some methods such as literature review and experts evaluation were conducted. The manuscript of this questionnaire was developed through Delphi and pre-experiment. Then the manuscript questionnaires were used among 300 old people, to analyze and assess the reliability, validity and reactivity. RESULTS: The experiment analysis demonstrated that the total Cronbach alpha coefficient was 0. 909 and that of each index ranged from 0.718 0.960, most of the dimension-related coefficients were over 0.5. The construct validity was validated by factor analysis and the cumulative contribution rate was up to 76.88%. Results of non-parametric test on reactivity showed that the differences of total scores and each dimension' scores and substitute scores between the elderly from different institutions were statistically significant (P < 0.01). CONCLUSION: The comprehensive geriatric assessment scale owns a reasonable reliability, validity and reactivity, and this scale can be used as an evaluation instrument for the finding and intervention of the elder's health problems. PMID- 24059120 TI - [The hot point and controversy of clinical measures in critical are medicine]. AB - With its powerful ability to monitoring and support of organs, the survival rate of critically ill patients has been improved significantly by critical care medicine. Critical ill patients centralized in ICU accepted the treatments given by multidisciplinary team as a mode have played a very important role, especially during the rescue of victims in public health emergencies and natural disasters. Changings of the measures of monitoring and support are always along with the development of the critical care medicine. Fluid therapy is the most core measures in ICU, but there is a significant contradiction between positive fluid therapy and patient's impaired organ compensatory ability. The premise of appropriate fluid therapy is continuous and accurate evaluation of the hemodynamic status of critical ill patients. The variation of peak velocity of common carotid artery measured by bedside ultrasound can estimate the volume status of the SICU patients accurately. This method has high feasibility and accuracy and easy to be handled by the residents of ICU. The non-C. difficile associated nosocomial diarrhea even fatal enteritis in ICU can be caused by Klebsiella oxytoca and Clostridium perfringens. Although this kind of incidence occurs in a relatively low rate, it always associates with severe diseases and poor outcome. Analgesia and sedation had become routine measures in ICU. There is still great controversy in some of the sedation protocol, such as sedation level and wake up daily. More and more evidence-based data suggested taking appropriate sedation targeting to individuals, and the protocol should be integrated with the dealing of pain, anxiety and delirium. PMID- 24059121 TI - [Influence of 20% lipid emulsion on drug concentration, distribution volume and pharmacology effect of continuous infusion of propofol in rabbits]. AB - OBJECTIVE: To investigate the influence of 20% lipid emulsion on drug plasma concentration, distribution volume and pharmacology effect of propofol administered with constant rate intravenous infusion in rabbits. METHODS: Propofol was intravenously administrated at a constant rate of 70 mg/(kg x h) in propofol group (P group, n = 8), low rate lipid group (L group, n = 8), high rate lipid group (H group, n = 8) and saline group (S group, n = 8) within 2 h. After 60 min, different agents were administrated in L group (20% lipid emulsion with rate of 0.3 mL/(kg x h)), H group (20% lipid emulsion with rate of 15 mL/(kg x h)), S group (saline with rate of 15 mL/(kg x h)) for another 60 min respectively. Blood samples were taken to measure the plasma concentration and calculate the pharmacokinetic parameters at the following time points: 30, 60, 65, 70, 80, 90, 120 min after the start of propofol infusion and 10, 20, 30, 60, 120, 180 min after the termination of propofol infusion. Brain tissues were also taken to measure propofol concentration. Related information about vital signs and pharmaceutical effects were recorded. RESULTS: High rate lipid infusion was associated with elevated propofol plasma concentration and reduced volume of distribution. The volume of distribution based on the terminal phase (V): P group, (34.56 +/- 16.11) mL; L group, (33.37 +/- 29.87) mL; H group,(7.29 +/- 3.20) mL; S group,(35.46 +/- 13.58) mL; P < 0.05). The volume of distribution at steady state (Vss): P group, (11.13 +/- 3.21) mL; L group, (13.87 +/- 4.09) mL; H group, (4.82 +/- 1.46) mL; S group, (11.61 +/- 4.11) mL P < 0.05)). Painful stimulation existences were higher at 90,120 min and the mean arterial pressure and heart rate were higher in H group (P < 0.05). The propofol concentration in brain tissue was lower in H group at 120 min (P < 0.05). CONCLUSION: Amelioration of pharmacology effect of propofol with high rate lipid infusion is associated with reduced V, Vss, elevated propofol plasma concentration and lowered propofol brain tissue concentration. 20% lipid will not influence these indice when infused with low rate, indicating that lipid in TPN will not change the sedation effects of propofol. PMID- 24059122 TI - [Measurement of peak velocity variation of common carotid artery with bedside ultrasound to estimate preload in surgery ICU]. AB - OBJECTIVE: To investigate the feasibility and accuracy of bedside ultrasound measuring peak velocity variation of common carotid artery to estimate preload of the patients in surgery ICU. METHODS: In this prospective cohort study, SICU patients with sinus rhythm and positive pressure ventilation were included. The peak velocity variation in common carotid artery (delta V peak) during each respiratory circle was measured by ICU resident with short-term training and experienced attending songrapher. Stroke volume before and after the fluid challenge was also measured by the experienced songrapher as the gold standard of fluid responsiveness. Then the ROC, feasibility and accuracy of the diagnosis trial were analyzed. RESULTS: There were 46 patients included. The peak velocity variation of common carotid artery measured by the attending (delta V peak) is highly related with delta SV (r1 = 0.76, P < 0.05). Area under the receiver operating characteristic curve was 0.95 (P < 0.05). The peak velocity variation of common carotid artery (delta V peak) > 12.1% predicted fluid responsiveness with sensitivity of 90.9%, specificity of 83.3%, positive predictive value of 83.3% and negative predictive value of 90.9%. The peak velocity variation of common carotid artery measured by the resident (delta V peak2) were highly related with delta V peak1 (R2 = 0.68, P < 0.05), the AUC was 0.94. CONCLUSION: Measurement of peak velocity variation of common carotid artery with bedside ultrasound can accurately estimate the volume status of the patients in surgery ICU, and it is easy to be performed by the residents of ICU. PMID- 24059123 TI - [Risk factors and therapy strategies of acute pulmonary edema in critically ill patients with multiple trauma]. AB - OBJECTIVE: To analyze the risk factors and therapy strategies of acute pulmonary edema (APE) in critically ill patients with multiple trauma. METHODS: We conducted a retrospective analysis with the clinical date of all the critically ill patients with multiple trauma treated in General ICU from Jan. 2009 to Jan. 2012. We compared the clinical characteristics of the patients with or without onset of APE. The patients with APE were divided into young group (< or = 55 yr.) or elderly group (> 55 yr.), then the clinical data were analyzed between the two groups, including the level of hemoglobin (Hb), mean arterial pressure (MAP), central venous pressure (CVP), serum albumin (A1b), as well as complications, liquid balance during 1 week, 3 d, 1 d before the onset of APE. RESULTS: Among the 284 patients with multiple trauma, APE was detected in 47 patients (16.5%) for 68 times, 29 (61.7%) in young group and 18 (38.3%) in elderly group. The ratio of acute renal failure (ARF) and systematic infection were significantly higher in the patients with APE (P < 0.05). Hb, MAP, CVP, A1b and the ratio of ARF, severe infection, extremity lost were not statistically different (P > 0.05) between young and elderly group, while the ratio of primary heart disease was significantly higher in elderly group (P < 0.05). The net balance of liquid during 1 week, 3 d and 1 d before the onset of APE was significantly higher in young group (P < 0.05). CONCLUSION: Mutiple Trauma patients with ARF are prone to encounter APE on the exist of infection and overburden of liquid; young patients tend to develop APE followed by liquid overburden,while elderly patients tend to develop APE because of poor primary heart condition even with more cautious fluid infusion. PMID- 24059124 TI - [Risk factors for massive ascites after living donor liver transplantation in adult and impact of massive ascites on patient survival]. AB - OBJECTIVE: To analyze the risk factors relate to massive ascites after the living donor liver transplantation (LDLT) in adult and the impact of massive ascites on patient survival. METHODS: Clinical data of 105 adult patients undergone LDLT from 2005 to 2011 in West China Hospital were retrospectively analyzed. The risk factors for massive ascites were firstly determined with univariate analysis, then with two logistic regression analysis if P< 0.1 by univariate analysis. Kaplan-Meier survival curve was used to investigate the association between massive ascites and patient survival. RESULTS: The average amount of ascites within seven days postoperatively in 105 LDLT cases was 5 362 mL (766 mL per day), and massive ascites developed in 27 patients (25.7%). The variables, including receptor age, liver disease, preoperative MELD score, Child-Pugh score, preoperative ascites, preoperative INR, preoperative total bilirubin, preoperative serum albumin, operative time, postoperative SOFA score, postoperative total bilirubin, showed significant difference between massive ascites group and non-massive ascites group. Another variable that P < 0.1 was graft to recipient weight ratio (GRWR) (P = 0.069). The two logistic regression showed that preoperative ascites (OR = 3.33, P < 0.001), postoperative SOFA score (OR = 1.25, P = 0.027) were independent risk factors for massive ascites after LDLT. The results of Kaplan-Meier analysis showed that the 3-month, 6-month, 1 year survival rates of control group were 89.6%, 81.2%, 79.5% respectively, and those rates of massive ascites group were 80.8%, 80.8%, 74.1% respectively. The survival of the patients who developed massive ascites after LDLT was reduced when compared with control group, but it was not statistically significant. CONCLUSION: Preoperative ascites, postoperative SOFA score were independent risk factors for massive ascites after LDLT. The impact of massive ascites on patients survival need further investigation. PMID- 24059125 TI - [Nosocomial diarrhea in intensive care unit: other than Clostridium difficile]. AB - OBJECTIVE: To investigate the incidence and clinical features of non-Clostridium difficile (C. difficile) associated nosocomial diarrhea in intensive care unit (ICU) caused by Klebsiella oxytoca and Clostridium perfringens. METHODS: The faeces of 102 patients with non-C. difficile associated nosocomial diarrhea in ICU of West China Hospital, were collected during April to November, 2012. The target bacterial genes were detected by PCR amplification and sequencing, including toxic gene pehX of Klebsiella oxytoca, species-specific 16S rRNA gene and toxic gene cpa and cpe of Clostridium perfringens, species-specific 16S rRNA gene with mapA and toxic gene hipO of Campylobacter jejuni. Clinical features of the patients with positive results were summarized. RESULTS: Among 102 patients with non-C. difficile associated nosocomial diarrhea, 4 patients (3.9%) were detected with toxic Klebsiella oxytoca while 4 patients (3.9%) were detected with toxic Clostridium perfringens. No toxic Campylobacter jejuni was detected. Most of the patients had severe underlying diseases and poor final outcome, accepted potent antibiotics which disturbed intestinal flora obviously.. CONCLUSION: Non C. difficile associated nosocomial diarrhea in ICU caused by Klebsiella oxytoca is and Clostridium perfringens is associated with severe diseases and poor outcome, but the incidence in our hospital is relatively low in our hospital. PMID- 24059126 TI - [The use of human papillomavirus genotying kit based on gene chip technology for detecting and typing of human papillomavirus]. AB - OBJECTIVE: To evaluate a new human papillomavirus (HPV) genotyping technique based on gene chip technology (HPG) for HPV genotyping and its clinical efficacy. METHODS: HPV genotyping (HPG) test, hybrid capture II (HC2) test and DNA sequencing assay were performed in 151 patients aged 20-75 years with diagnosis of chronic cervicitis or abnormal vaginal bleeding. The cervical specimens were collected from cervical epithelium. All the cervical samples were analyzed by the HPG test, HC2 test and DNA sequencing. The clinical efficacy of the HPG test was analyzed. RESULTS: The consistent rate between HPG test and HC2 test was 87.42% (kappa = 0.75, P < 0.05). When DNA sequencing assay was regarding as the final test result, the sensitivity and specificity of HPG test for high risk HPV were 100% and 96.49%, respectively. The consistent rate between HPG test and direct DNA sequencing was 98.70% (kappa = 0.97, P < 0.05). The most common six HPV genotypes detected by HPG test were HPV 16 (13.25%), 58 (11.92%), 52 (11.92%), 31 (6.62%) 39 (5.96%), 33 (5.96%) in descending order of frequency. The incidence of multiple-types infection detected by HPG test was 23.84%. CONCLUSION: HPG test is a rapid and accurate test for HPV genotyping which could detect 29 types of HPV infection at one time. It is suitable for cervical HPV infection screening in clinic. PMID- 24059127 TI - [Monitoring renal microcirculation perfusion alteration with contrast-enhanced ultrasound during cardiopulmonary bypass]. AB - OBJECTIVE: To investigate the monitoring of renal microcirculation perfusion alteration with contrast-enhanced ultrasound (CEU) during cardiopulmonary bypass (CPB). METHODS: Renal microcirculation perfusion before and during CPB was assessed by CEU. Time-intensity curve (TIC) were derived from three region of interest (ROI) using QLAB post-analysis software. Parameters such as TIC curve wash in slope (A), area under curve (AUC), peak intensity (DPI) as well as time to peak intensity (TTP) were then calculated. RESULTS: Contrast-enhanced ultrasound showed a significant reduction (or elongation) of perfusion parameter (A, AUC, DPI, TTP) in all three regions (superficial cortex, deep cortex and medulla) during cardiopulmonary bypass in comparison with normal cardiac cycle. CONCLUSION: Cardiopulmonary bypass (CPB) has a dramatic impact on renal microcirculation in pediatric patients which manifest as global reduction in renal perfusion as well as significant region perfusion difference. Contrast enhanced ultrasound (CEU) could detect the renal microcirculation alteration during CPB. PMID- 24059128 TI - [Value of three-dimensional speckle-tracking echocardiography and the novel area strain in detecting wall motion abnormalities of coronary artery diseases]. AB - OBJECTIVE: To investigate the value of three-dimensional speckle tracking echocardiography (3DSTE) and the novel areas train (AS) in detecting wall motion abnormalities caused by coronary artery diseases. METHODS: Conventional and 3D echocardiography was done on forty-six patients suspected with coronary heart diseases, immediately before they received cardiac catheterization. Segmental wall-motion score (WMS) and WMS index (WMSI) were assessed on conventional two dimensional (2D) images, and strain-derived parameters were analyzed by speckle tracking technique based on 3D images. The accuracy of echocardiographic parameters to assess the regional myocardial ischemia was tested against coronary angiography results using ROC curve analysis and linear regression. RESULTS: Compared with controls, patients with severe coronary stenosis (> or = ;70% coronary stenosis) had lower left ventricular ejection fraction, higher WMSI and lower global strains. ROC curve analysis demonstrated that segmental WMS had relatively poor sensitivity for regional myocardial ischemia and infarction. The segmental strains measured using 3DSTE provided accurate assessment of the regional wall motion abnormalities. The segmental area strain > -25% yielded the best sensitivity and specificity for detecting the ischemic and infracted segments among all four strain parameters. CONCLUSION: 3DSTE provides a swift and accurate assessment of regional myocardial motion. The novel area strain derived by 3DSTE is an accurate and reproducible index for regional wall motion abnormality. PMID- 24059129 TI - [Research on the effect of extract of dentin matrix on the differentiation of dental pulp cells]. AB - OBJECTIVE: To investigate the effects of human treated dentin matrix (hTDM) extracellular matrix molecules on odontogenetic and neural differentiation of human dental pulp cells (hDPCs) with an aim to find an effective method to collect extracellular matrix molecules to contribute to reparation dental-pulp complex with dentin defects. METHODS: hDPCs were obtained and biological characteristics such as source of cells and multi-differentiation potentials were assessed using immunofluorescence and flow cytometry. Fabrication of hTDM extracts and hDPCs was induced with it for 1 week. The odontogenetic differentiation associated genes were tested by qRT-PCR. Results qRT-PCR results showed that cells were higher expression of odontogenetic differentiation associated genes ALP, OPN, OCN, BSP, DMP-1, DSP, beta-III tubulin. CONCLUSION: The method of extracting extracellular matrix molecules from dentin matrix was effective. The extract liquid provides a suitable microenvironment for odontogenetic and neural differentiation of hDPCs and contributes to reparation dental-pulp complex. PMID- 24059130 TI - [Joint diagnostic value of four temperature sensation tests in elderly patients with type 2 diabetic peripheral neuropathy]. AB - OBJECTIVE: To explore the joint diagnostic value of four temperature sensation tests in elderly patients with type 2 diabetic peripheral neuropathy. METHODS: Thermal sensory analyzer-II were applied to measure cool sensation (CS), warm sensation (WS), cold pain sensation (CP)and heat pain sensation (HP) of 308 elderly patients with type 2 diabetes. Logistic regression model was adopted to create the new variable Temp4 from four temperature sensation tests to diagnose type 2 diabetic peripheral neuropathy. The ROC curve analysis was used to determine the best cut-off points of the four temperature sensation and Temp4, and the diagnostic value of it was evaluated. RESULTS: The means of temperature sensation tests of the diabetic peripheral neuropathy (DPN) group were significantly different from those of the non-DPN group (P < 0.05). According to the current reference intervals of the four temperature sensation tests to diagnose the DPN, the sensitivity of WS test was the highest, and the value was 0.710; but the specificity, positive predictive value, negative predictive value, Youden index, diagnostic accuracy and Kappa value of cold sensation test were the highest, and the values were 0.842, 0.746, 0.799, 0.528, 77.92% and 0.535, respectively; the Kappa values of the other three temperature sensation tests were all greater than 0.4 (P < 0.05). The area under the ROC curve of the new variable Temp4 was 0.93 (95% CI 0.91-0.96), and was larger than the four temperature sensation tests (P < 0.05). The sensitivity, specificity, Youden index and diagnostic accuracy of Temp4 were 0.823, 0.897, 0.719 and 86.69%, respectively. The new best cut-off points of the CS test, WS test, CP test, HP test and Temp4 was 27.5 degrees C, 34.7 degrees C, 20.5 degrees C, 43.5 degrees C and 0.416, respectively. CONCLUSION: The results of the four temperature sensation quantitative tests were in good agreementand could be applied to diagnose DPN; the new variable Temp4 could be used for diagnosis of DPN with a higher diagnostic accuracy. PMID- 24059131 TI - [Efficiency of postoperative ovulation induction on infertile women with minimal mild endometriosis]. AB - OBJECTIVE: To investigate the efficacy of timely ovulation induction on Infertility women with minimal-mild endometriosis (EMS) after laparoscopy combined with hysteroscopy. METHODS: A randomized controlled trial was performed on 132 infertility women diagnosed with minimal-mild EMS according to r-AFS by laparoscopy. They were divided into two groups after operations. The experimental group (n = 68) was administrated timely ovulation induction with clomiphene citrate tablets at the first menstrual cycle post-operation and given conceive guidance. The control group (n = 64) was treated with expectant treatment only. All the patients were followed up for 18 months after the surgery. Pregnancy rates and pregnancy outcomes within 1 year post-operation were compared between the two groups. RESULTS: During the follow up period, there were 6 cases lost. At 3 months after surgery, pregnancy rates (PR) in the experimental group and the control group were 37.88%, 21.67% respectively; the PR at 4-6 months were 29.27%, 19.15% in the two groups respectively. The less-than-6-months PR in the experimental group (56.06%) was significantly higher than that of the control group (36.67%) (P < 0.05), and also higher than the PR of 7-12 months post operation in the same group (P < 0.05). Significant difference was found for the abortion rate between the ovulation induction group (12.19%) and the control group (26.92%) (P < 0.05). CONCLUSION: Timely ovulation induction after laparoscopic surgery combined with hysteroscopy could significantly increase pregnancy rate and reduce abortion rate in infertility patients with minimal-mild endometriosis. PMID- 24059132 TI - [Risk factors of acute-phase response following the first-dose administration of zoledronic acid in the treatment of osteoporosis]. AB - OBJECTIVE: To explore the risk factors of acute-phase response (APR) following the first-dose administration of zoledronic acid in the treatment of osteoporosis. METHODS: We reviewed the clinical data of the patients receiving the first use of zoledronic acid 5 mg treatment of osteoporosis from January 2009 to November 2012, and divided the patients into acute phase response group (APR+) and no response group (APR-). The age, body mass index (BMI), concomitant medications, comorbidities, laboratory parameters between the two groups were compared and analyzed. RESULTS: A total of 178 patients were eligible for inclusion in the study, of which 108 patients experienced APR. In APR group, there were 80 (44. 9%) patients developed fever, 14 (9. 6%) chills, 48 (27.0%) musculoskeletal pain, 19 (10.7%) gastrointestinal symptoms, 10 (5.6%) headache and dizziness, 7 (3.9%) palpitation,and 3 (1.7%) rash. APR was more common in the patients with higher baseline tartrate-resistant acid phosphatase 5b (TRACP-5b) and new-onset vertebral compression fractures (new-onset VCF). Stepwise logistic regression showed that the odds ratio (OR) of APR in higher baseline TRACP-5b and new VCF was 3. 3 and 2. 5 respectively. CONCLUSION: The first use of zoledronic acid in the treatment of osteoporosis appears high incidence of APR. High TRACP 5b levels and new vertebral fracture are risk factors for APR. PMID- 24059134 TI - [The application of nasopharyngeal airway in nurosurgery patients during anesthesia recovery]. AB - OBJECTIVE: To evaluate safety and effectiveness of nasopharyngeal airway used for neurosurgery patients during the anesthesia recovery period. METHODS: A total of 60 patients (ASAI-II), aged between 25 to 67 years old, who were scheduled to undergo elective neurosurgery operation under general anesthesia, were randomly divided into the oropharyngeal airway group (group O) and the nasopharyngeal airway group (group N), with 30 cases in each group. After respiratory recovery was satisfactory at the end of operation, endotracheal tube was extubated under deep anesthesia. Afterwards, oropharyngeal airway was intubated in group O, and nasopharyngeal airway was intubated in group N. BP and HR before induction (T0), before airway intubation (T1), at 1 min (T2) and 5 min (T3) after airway intubation were recorded. Meanwhile, one-time success rate of airway intubation, the airway retention time, the times of airway regulation due to location change and the change of respiration and circulation in each groups during airway retention period were recorded. In addition, adverse reactions during airway retention period and tolerance scores of patients in both groups were recorded. RESULTS: BP and HR in group N at T1 and T2 increased significantly compared with T0 (P < 0.05), Compared with T1, BP and HR increased significantly at T2 in group N (P < 0.05). Compared with T1 and T2, the same index reduced significantly at T3 (P < 0.05). BP and HR in group N were significantly higher than those in group O at T2 (P < 0.05). Airway retention time in group N was significantly longer than that in group O [(137.4 +/- 18.32) min vs. (64.2 +/- 8.25) min, P < 0.053; the times of airway location regulation in group N was less than that in group O (0.34 +/- 0.21 vs. 2.80 +/- 0.54) (P < 0.05). During airway retention period the incidence of BP and HR exceeding the base value by 15% in group O was higher than that in group N (80.0% vs. 46.7%)(P < 0.01), and the incidence of SPO2 less than 95% in group O was higher than that in group N (26.7% vs. 6.7%) (P < 0.05). The incidence of nausea, upper airway obstruction and restlessness in group O was significantly higher than that in group N (P < 0.05). Moreover, airway tolerance score of patients in group N was significantly better than that in group O (P < 0.05). CONCLUSION: Nasopharyngeal airway could better maintain unobstructed upper airway in neurosurgery patients during the anesthesia recovery period with advantages such as small circulatory effect, good tolerance and fewer complications. PMID- 24059133 TI - [Comparison of platinum-containing doublet chemotherapy and liposome paclitaxel monotherapy for the treatment of elderly patients with advanced non-small cell lung cancer]. AB - OBJECTIVE: Given controversy remains on monotherapy and combinatory chemotherapy in elderly patients (> or = 70 years) with advanced non-small cell lung cancer (NSCLC), we conducted this study to compare the safety and efficacy of liposome paclitaxel and platinum-containing doublets. METHODS: From January 2007 to March 2009, totally 65 patients (age > or = 70 years) with pathologically confirmed NSCLC were enrolled. 33 patients received liposome paclitaxel monotherapy (monotherapy group) and 32 patients received platinum-containing doublets chemotherapy (combinatory group). RESULTS: No CR was observed in all patients. Both groups had similar objective response rate (ORR) (6.1% vs. 15.6%, P = 0.399). However, a statistically significant higher disease control rate (DCR) (65. 6%) was observed in he combinatory group when compared with that of monotherapy group (39.4%, P = 0.034). The combinatory group had longer time-to progression (TTP) (94 days, 95% CI: 60-127 days) than the monotherapy group (51 days, 95% CI: 22-79 days, P = 0.046). The median overall survival days in the combinatory group was 524 days (95% CI: 146-901 days) where as in the monotherapy group only 146 days (95% CI 32-259 days) (P = 0.001). The most common adverse reactions were myelosuppression, gastrointestinal reactions and elevated transaminase in the monotherapy group, while those were myelosuppression, gastrointestinal reactions and infection in the combinatory group. Generally there was no significant difference in the adverse reaction, except grade 3-4 thrombocytopenia (P = 0.004). It should be addressed that 1 patient (3.0%) in the monotherapy group had an onset of severe infection, while the number rose to 5 (15.6%) in the combinatory group (P = 0.079). CONCLUSION: Platinum-containing doublet chemotherapy achieved a higher response rate, longer time-to-progression and overall survival compared with liposome paclitaxel monotherapy in the treatment of elderly patients with advanced NSCLC. However thrombocytopenia and severe infection should be monitored for the combinatory chemotherapy. PMID- 24059135 TI - [Frontiers of autism]. PMID- 24059136 TI - [Details of the proposed law regarding treatment without consent]. PMID- 24059137 TI - [The end of life: conclusions of the ethics committee]. PMID- 24059138 TI - [New hypotheses of the origin of bipolar disorders]. PMID- 24059139 TI - [A gerontopsychiatric clinica at Garches (92)]. PMID- 24059140 TI - [From the happiness of inventing to the pleasure of creating]. PMID- 24059141 TI - [The margin of autonomy of nurses in psychiatry: for a clinical approach in the institution]. AB - In care units, nurses operate in working environments which offer them a margin of autonomy. When they seize upon this opportunity, they invent therapeutics tools. Their creativity as well as the pleasure given in the care contributes to the clinical dynamics within the institution. PMID- 24059142 TI - [Institution, primary nurse and projective identification]. AB - Ayoung bipolar patient admitted to day hospital care questions the importance of institutional networking. His history, his behaviour and his words unsettle the thinking of the primary nurse. The support of the institution and the clinical work established around the patient are a reminder of the importance of the team in patient management. PMID- 24059143 TI - [Being a long-term patient: chronicity and institutional clinic approach]. AB - Some patients, especially schizophrenics, are hospitalised for a long time in psychiatric units. Evolving in a subjective and discontinued space-time, these "chronic" patients destabilise the professionals who support them in their daily life and in their "projects". Community psychiatry settles chronicity inside health care function by ensuring these patients are offered continuity as well as the layout of a subjective pathway. PMID- 24059144 TI - [A caregiver-patient meeting or reading between the lines in the institution]. AB - Faced with unsettling institutional changes, the creation of a caregiver-patient meeting can have unexpected effects. It opens up possibilities of things to say and work on. This space leads the nurse to re-question care and gives back to the psychotic patient a place in the institution. PMID- 24059145 TI - [Towards a clinical approach in institutions in order to enable dreams]. AB - Care protocols and their proliferation tend to dampen the enthusiasm of professionals in their daily practice. An institution's clinical approach must be designed in terms of admission in order notto leave madness on the threshold of care. Trusting the enthusiasm and desire of nurses means favouring creativity within practices. PMID- 24059147 TI - [The clinic in the institution. Bibliography]. PMID- 24059146 TI - [A therapy bar: a concrete example of treatment]. AB - The existence of a therapy bar within cares structure offers an alternative meeting place for patients and caregivers. This care tool boosts the clinic approach within the institution and favours exchanges. Here, patients offload other things than during a formal interview. This commitment from the caregivers and patients is a strong sign of the fight against chronicisation. A review. PMID- 24059148 TI - [Support in addictology: hydrotherapy]. AB - Hydrotherapy is a corporal mediation treatment used with patients with addictions by the Mayenne centre for addiction support therapy and prevention. A demonstration of the benefit of hydrotherapy for these patients through a patient's case. PMID- 24059149 TI - [Clinical consequences of modernity]. AB - When they receive patients in their treatment centre, clinicians witness symptoms which are sometimes very closely related to the inclusion within hypermodernity of hyperbole and instantaneousness. A study of the question of contemporary violence through an analytical explanation of the relationship between the subject and the object. PMID- 24059150 TI - [Georges Daumezon]. PMID- 24059151 TI - Healthcare's data revolution: How data is changing the industry and reshaping HIM's roles. PMID- 24059152 TI - Leading innovation in enterprise information governance. PMID- 24059153 TI - Data migration lessons learned: One facility relates hard-learned best practices after migrating to a new EHR. PMID- 24059154 TI - The good, bad, and reality of offshore coding: Some turn to distant shores to fill US coding demands. PMID- 24059155 TI - Adapting BA practices to meet the Omnibus Rule. PMID- 24059156 TI - Small hospital uses data for big improvements. PMID- 24059157 TI - Show me the data: From data exchange to data aggregation, HIM has role to play. PMID- 24059158 TI - HIM's role in managing big data: Turning data collected by an EHR into information. PMID- 24059159 TI - Performing a breach risk assessment. PMID- 24059160 TI - Managing and mapping coded ICD-9-CM data to ICD-10-CM/PCS. PMID- 24059162 TI - Tracking how healthcare professionals see health information. PMID- 24059161 TI - Coding root operations with ICD-10-PCS: understanding transplantation, reattachment, transfer, and reposition. PMID- 24059163 TI - [Development of a photoacoustic spectroscopy system for the measurement of absorption coefficient of atmospheric aerosols]. AB - In the present paper, the authors focus on the effect of the resonance frequency shift due to the changes in temperature and humidity on the PA signal, present several methods to control the noise derived form gas flow and vibration from the sampling pump. Based on the efforts mentioned above, a detection limit of 1.4 x 10(-8) W x cm(-1) x Hz(-1/2) was achieved for the measurement of atmospheric aerosols absorption coefficient. During the experiments, the PA cell was calibrated with the absorption of standard NO2 gas at 532 nm and the atmospheric aerosols were measured continuously. The measurement results show that the PAS is suitable for the real-time measurement of the absorption coefficient of atmospheric aerosols in their natural suspended state. PMID- 24059164 TI - [Spectroscopy parameters of Ho3+ in Ho3+ : FOG and Ho3+ : FOV]. AB - In the present paper, the absorption spectra of Ho3+ (0.5 mol%)-doped oxyfluoride glass (FOG) sample and Ho3+ (0.5 mol%)-doped oxyfluoride vitroceramics (FOV) sample were measured through experiment. The authors calculated the intensity parameters omega 2, 4, 6 of the two materials according to J-O theory, and analyzed the possible reason for the difference between the two materials on the intensity parameters. After that the authors calculated oscillator strength, spontaneous radiative transition rate, branching ratio and integrated emission cross section and some other spectroscopic parameters of several excited states and then made a comparative analysis of the two materials based on these spectroscopic parameters. The authors found that the oscillator strength of trivalent holmium iron in FOV is about the same with the oscillator strength in YAlO3 and is similar to oscillator strength in FOG, while slightly larger than in that LBTAF and much larger than that in LaF3 and ZBLAN. By analyzing the calculated spectroscopic parameters, it can be found that some transitions, especially 5I7 --> 5I8, 5F5 --> 5I8 etc., have a relatively large oscillator strengths(larger than 10(-6)) and large integrated emission cross sections(larger than 10(-18) cm). These transitions have the conditions to form laser passages, so they are worth a lot of attention. At last, application prospects of several strong luminescence transitions were concluded. PMID- 24059165 TI - [The estimation of cirrus cloud particulate shape using combined simulation and a three-wavelength lidar measurement]. AB - The global occurrence of cirrus clouds can reach as high as 30%, whose scattering properties are essential impact on the climatic model, radiative transfer, and remote sensing. Their scattering properties are determined by the ice crystal shape, size distribution, refractive index and so on. Retrieval of the backscattering color ratios of cirrus cloud using a 355, 532 and 1 064 nm three wavelength lidar, combined with the simulation of the three backscattering color ratios of different ice crystal shape, the shape of the lidar-measured ice crystal can be estimated. The results indicate that the shape of cirrus cloud over Hefei city is mostly composed by aggregates. PMID- 24059166 TI - [Effect of ionic liquid [bmim][PF6] on the transient photolysis behavior of xanthone]. AB - The transient photochemical behavior of xanthone (XAN) in 1-butyl-3-methyl imidazolium hexafluoride phosphate ionic liquid ([bmim][PF6]) or binary mixed solution with acetonitrile (MeCN) was investigated by nano-second laser photolysis techniques. The spectral blue shift of 3XAN* was observed in the neat [bmim][PF6] or IL/MeCN mixture solution compared to MeCN solution. And the yield was also increased. Moreover, the energy transfer rate constant of XAN and naphthalene (NAP) was affected by the concentrations of ionic liquid. The values decreased rapidly with increasing VIL. For example, the values were 1.2 x 10(10) mol x L(-1) x s(-1) in MeCN, and 1.1 x 10(8) mol x L(-1) x s(-1) in [bmim][PF6], respectively. The photo-induced electron transfer between XAN and N,N dimethylaniline was also investigated by changing the concentrations of [bmim][PF6] in binary solution. PMID- 24059167 TI - [Characterization of thermal denaturation process of proteinase K by spectrometry]. AB - The effect of different temperatures on the activity and conformational changes of proteinase K was studied. Methods Proteinase K was treated with different temperatures, then denatured natural substrate casein was used to assay enzyme activity, steady-state and time-resolved fluorescence spectroscopy was used to study tertiary structure, and circular dichroism was used to study secondary structure. Results show with the temperature rising from 25 to 65 degrees C, the enzyme activity and half-life of proteinase K dropped, maximum emission wavelength red shifted from 335 to 354 nm with fluorescence intensity decreasing. Synchronous fluorescence intensity of tryptophan residues decreased and that of tyrosine residues increased. Fluorescence lifetime of tryptophan residues reduced from 4. 427 1 to 4. 032 4 ns and the fraction of alpha-helix dropped. It was concluded that it is simple and accurate to use steady-state/time-resolved fluorescence spectroscopy and circular dichroism to investigate thermal stability of proteinase K. Thermal denaturation of proteinase K followed a three-state process. Fluorescence intensity of proteinase K was affected by fluorescence resonance energy transfer from tyrosine to tryptophan residues. The alpha-helix was the main structure to maintain conformational stability of enzyme active site of proteinase K. PMID- 24059168 TI - [Vibrational temperature of plasma plume in atmospheric pressure air]. AB - A tri-electrode discharge device was designed in a dielectric barrier discharge configurations to generate a fairly large volume plasma plume in atmospheric pressure air. The discharge characteristics of the plasma plume were investigated by an optical method. The discharge emission from the plasma plume was collected by a photomultiplier tube. It was found that the number of discharge pulse per cycle of the applied voltage increased with increasing the peak value of the applied voltage. The emission spectra of the plasma plume were collected by a spectrometer. The vibrational temperature was calculated by fitting the experimental data to the theoretical one. Results showed that the vibrational temperature of the plasma plume decreases with increasing the U(p). Spatially resolved measurement of the vibrational temperature was also conducted on the plasma plume with the same method. Results showed that the vibrational temperature increases firstly and then decreases with increasing distance from the nozzle. The vibrational temperature reachs its maximum when the distance is 5.4 mm from the nozzle. These experimental phenomena were analyzed qualitatively based on the discharge theory. These results have important significance for the industrial applications of the plasma plume in atmospheric pressure air. PMID- 24059169 TI - [Influence of Bi3+ doping on properties of CaMoO4 : Eu3+ phosphors]. AB - Europium doped CaMoO4 and bismuth co-doped CaMoO4 : Eu3+ phosphors were prepared via microemulsion-hydrothermal method. The structure, morphology and luminescence properties of samples were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM) and fluorescence spectroscopy, respectively. The XRD patterns of as-prepared samples were in agreement with the PDF # 29-0351 of CaMoO4, which indicated that the phosphor possessed tetragonal crystal structure. SEM images showed that the samples were basically flake in shape and their average size was 1.5-2.5 microm. The critical molar concentration of activator (Eu3+) in CaMoO4 : Eu3+ was 5%, and the predominant peak of CaMoO4 : Eu3+ located at 616 nm, corresponding to the 5D0 -->7 F2 electronic dipole transition of Eu3+. The photoluminescence color can be tuned from orange-yellow (0.514, 0.537) to white (0.339, 0.333) by adjusting the doping concentrations of Eu3+ ions. To enhance the red emission intensity of Eu3+, Bi3+ was used to co-dope CaMoO4 : Eu3+ as sensitizers. When the concentration of Bi3+ is 3%, luminescence intensity was maximum. The chromaticity coordinates (CIE) varied from orange (0.497, 0.347) to red (0.585, 0.349) with increasing the content of Bi3+. PMID- 24059170 TI - [Properties of phosphorescent organic light-emitting diodes with different doping order on light emitting layer]. AB - Utilizing GIr1(green) and R-4B(red) phosphorescent dye, organic light-emitting diodes with different doping orders on red and green light-emitting layers were fabricated. The authors investigated the luminescent properties of devices combined with the effect of electron (TCTA) and hole (BCP) blocking layer. The results showed that the great impacts on spectrum, light efficiency, luminance and luminescent color were produced based on different doping order, and the authros also found the strong emission peak at the interface of the BCP and CBP layer. With the use of the red and green doping type, 0.527 mA x cm(-2), 104 cd x m(-2), 19.75 cd x A(-1) and (0.371 7, 0.576 8) could be reached, respectively. The reasons were that on the one hand, because of large difference between energy levels of host material CBP and doping material GIr1, R-4B, and charge trapping and hopping via dopants were the main mechanism of change; on the other hand, for the different energy levels between dopants and blocking layers, the doping sequence could affect barrier distribution, and then affect the electric field distribution. PMID- 24059171 TI - [Influence of BCP on efficiency of red phosphorescent electroluminescent device]. AB - The present paper uses the R-4B as phosphor dopant, the main body was CBP, regulation carrier composite layer was BCP, and the device structure was ITO/MoO3 (30)/NPB (40)/TCTA (10)/CBP : R-4B(6%)(15)/BCP(chi)/CBP : R-4B(6%) (15)/BCP(10)/Alq3 (40)/LiF/Al. In the device, chi was the thickness of the BCP with five different thickness of the device. At the same time, another contrast device was made, which had been optimized at MoO3 without regulated BCP layer. The result shows that the luminous area was 1.18 cm2, BCP was 4, MoO3 was 30 nm, its performance was the best, light voltage was 4 V, maximum efficiency was 18. 9 cd x A(-1), its corresponding EL main peak was at 612 nm, and color coordinates was (0.643, 0.353), getting stable and high efficient red phosphor OLED devices. PMID- 24059172 TI - [Optical properties research of NH4NO3 by Fourier transform infrared spectroscopy]. AB - In the present paper, the infrared spectrum of aerosol and NH4 NO3 was analysed and compared, and the result showed that the infrared spectral features of aerosol are consistent with that of NH4 NO3. The absorption coefficient alpha and the mass absorption cross section kappa of NO3- was calculated by the transmissivity of NO3- in NH4 NO3 according to Beer-Lambert law. Then the imaginary part of the complex refractive index was calculated through alpha. The real part of the complex refractive index was derived from the K-K(Kramers Kroning) relationship. It has important significance for further research on the scattering and absorption characteristics of the different composition of the atmospheric aerosol through analysing the results of the experiment. PMID- 24059173 TI - [Study on soil carbon estimation by on-the-go near-infrared spectra and partial least squares regression with variable selection]. AB - The present paper tried to evaluate the effectiveness and improvement of variable selection before modeling with partial least squares regression (PLSR). Based on the independent test dataset, and compared with the PLSR model derived from all spectral variables, the prediction accuracy by modeling after variable selection has been improved. Thus, the results showed that variable selection was beneficial and necessary for soil carbon modeling by on-the-go NIRS. UVE (uninformative variable elimination) and UVE-SPA (successive projection algorithm) could perform effective variable selection and created promising models, and SPA and GA-PLS (genetic algorithm PLS) failed to make appropriate models. For synergy interval PLS (siPLS), change in interval number and number of interval for modeling could affect the prediction accuracy obviously. Promising models could be made by selecting appropriate interval number and number of interval for modeling, and siPLS could achieve similar prediction accuracy to UVE or UVE-SPA, and the shortcoming was that siPLS required a lot of computing time to find optimal combination of intervals for modeling. PMID- 24059174 TI - [Influence of measurement errors of radiation in NIR bands on water atmospheric correction]. AB - For standard algorithm of atmospheric correction of water, the ratio of two near infrared (NIR) channels is selected to determine an aerosol model, and then aerosol radiation at every wavelength is accordingly estimated by extrapolation. The uncertainty of radiation measurement in NIR bands will play important part in the accuracy of water-leaving reflectance. In the present research, erroneous expressions were derived mathematically in order to see the error propagation from NIR bands. The errors distribution of water-leaving reflectance was thoroughly studied. The results show that the bigger the errors of measurement are made, the bigger the errors of water-leaving reflectance are retrieved, with sometimes the NIR band errors canceling out. Moreover, the higher the values of aerosol optical depth or the more the component of small particles in aerosol, the bigger the errors that appear during retrieval. PMID- 24059176 TI - [The research on the identification of some polygonatum crude drugs by Fourier transform infrared spectrometry]. AB - The common peak ratio and variant peak ratio were calculated by FTIR spectroscopy of six medicinal plants of polygonatum. The index sequence of common peak ratio and variant peak ratio of six medicinal plants was established and the FTIR spectroscopy was analyzed by cluster analysis, which indicated the sibship of the six medicinal plants, polygonati rhizoma, polygonati odorati rhizoma and their adulterant such as Polygonatum filipes Merr., Polygonatum macropodium Turcz. and Polygonatum humile Fisch Ex Maxim. could be identified by comparing second derivative spectrum of the samples. FTIR with good characteristics such as simple and rapid procedures, nondestructive testing, small amount of sample required, good reproducibility and specificity of fingerprint, provides a new method for identification of polygonati rhizoma, polygonati odorati rhizoma and their adulterant. PMID- 24059175 TI - [Effect of the near infrared spectrum resolution on the nitrogen content model in green tea]. AB - The effect of different resolutions(2, 4, 6, 8, 16 cm(-1)) on the near infrared spectrogram and nitrogen content model for green tea was studied. Test results showed that instrument resolution could influence the spectra quality. The higher the resolution was, the richer the information would be, but the noise would increase. With lower resolution, spectrogram would be much more smooth, but get seriously distorted, and prediction accuracy would decrease at the same time. The partial least squares model was built after spectral pretreatment. When resolution was 4 cm(-1), the RMSEP value of external validation set was 0.054 6, which was obviously lower than others. The Corr. Coeff. was 0.998 2. Its prediction performance was the best and the prediction accuracy better. STDEV and RSD were 0.020 and 0.334 respectively. Resolution 4 cm(-1) for near infrared spectrometer collecting green tea samples was the optimal resolution. This research can provide a reference for parameters selection when collecting green tea spectra with near infrared spectrometer, improve the stability and prediction performance of the model and promote the application and promotion of the near infrared spectroscopy for tea. PMID- 24059177 TI - [Miniature near-infrared fibre optic spectrometer for the quantitative detection of protein and fat in milk powder]. AB - The method based on miniature near-infrared spectrometer combined with Y fiber optic probe to detect the protein and fat in milk powder by diffuse reflectance spectroscopy in the wavelength range of 900-1 700 nm was proposed. By selecting the appropriate spectral bands, the correction models of protein and fat were established with partial least squares algorithm using Unscrambler 9.7 Chemometrics software. The determination coefficients R2 of the correction modes are 0.987 and 0.986 for protein and fat respectively, and the root mean square errors RMSEC are 0.385 and 0.419 respectively. Using these correction models to predict the protein and fat contents with 30 sets of forecast sample data, the prediction standard deviation is SEP(Protein) = 0.751 for protein, and is SEP(Fat) = 1.109 for fat. The results indicate that these correction models have prediction capability with unknown samples and meet the on line requirements. PMID- 24059178 TI - [Determination of chlorogenic acid, rutin, scopoletin and total polyphenol in tobacco by Fourier transform near infrared spectroscopy]. AB - The objective of the present study was to investigate the feasibility of predicting chlorogenic acid, rutin, scopoletin and total polyphenol in tobacco by Fourier transform near-infrared (FT-NIR) spectroscopy. The partial least squares(PLS) regression method, second derivative and Norris derivative filter were applied in the NIR spectroscopy prediction of chlorogenic acid, rutin, scopoletin and total polyphenol in the range of 7 500 to 4 000 cm(-1). For chlorogenic acid, rutin, scopoletin and total polyphenol, the determination coefficients were 0.976 6, 0.941 9, 0.957 1 and 0.966 6, respectively. The SEP/SEC values for them were < 1.2, and the SD/SEP values for them were > 2. The root mean square error of cross validation (RMSECV) of the four calibration models were 1.938 9, 1.046 2, 0.047 9 and 2.745 2, respectively. NIR spectroscopy was compared with the conventional methods. The results show that the two methods showed no significant difference at the significant level of 0.05. NIR spectroscopy technology can accurately analyze chlorogenic acid, rutin, scopoletin and total polyphenol in tobacco. PMID- 24059179 TI - [Quantization determination study of micro-Raman spectroscopy of methemoglobin induced by sodium nitrite]. AB - In the present study, Raman spectral characteristics of methemoglobin (MetHb) induced by sodium nitrite (NaNO2) were investigated. Hemoglobin (Hb) was oxidated to MetHb with NaNO2, the Raman spectral specific changes of MetHb was studied by determining the Raman spectral changes of methemoglobin/total hemoglobin of different ratios, and the Raman intensities of methemoglobin/total hemoglobin of different ratios at 1 586, 1 605 and 1 637 cm(-1) were linearly fitted to realize its quantitative detection. The results show that the completely oxidized MetHb can be obtained when the molar ratio of NaNO2 to Hb is 3.5 : 1 whose Raman characteristic peaks are at around 499, 1 340, 1 562 and 1 622 cm(-1), and that the linear fitting correlation coefficients R2 of the Raman intensities of methemoglobin/total hemoglobin of different ratios at 1 586, 1 605 and 1 637 cm( 1) are 0.972 84, 0.997 97 and 0.991 26 respectively, which shows a good linear relationship. This study indicates that the Raman spectrums of MetHb induced by NaNO2 have characteristic differences when compared with normal Hb, that the locations and intensities of Raman characteristic peaks change correspondingly with the alterations of the ratios of methemoglobin/total hemoglobin, and that there are linear correlations between the ratios and their corresponding Raman intensities, which would provide theoretical bases for the clinical Raman spectral detection and quantitative study of methemoglobinemia. PMID- 24059180 TI - [Application of polarized Raman spectroscopy in the research on molecule conformation]. AB - In the present paper, the carbon tetrachloride (CCl4) is the main object of study. According to the calculation of the degree of depolarization, the authors can understand CCl4 crystal vibration. With the comparison between the calculated theoretical value and the experimental value, we are sure that our work is accurate. PMID- 24059181 TI - [Green synthesis of silver nanoparticles and their application in SERS]. AB - In the present paper, we have successfully synthesized silver nancomparticles by reducing of silver nitrate in alkaline solution via 60 degrees C water bath for 20 minutes with the use of tyrosine, a nontoxic and green macromolecule, as a reducing and stabilizing agent. The formation of silver nanoparticles was observed visually by color change of the solutions (from faint yellow to brown yellow). The morphologies of the Ag NPs were characterized by UV-Vis absorption spectroscopy and transmission electron microscopy (TEM). The UV-Vis absorption peak of silver nanoparticles located at 412 nm. The TEM image of silver nanoparticles indicated that the diameters of nanospheres are mainly in the range 15-25 nm. In order to evaluate the SERS activity of the silver nancomparticles, crystal violet and folic acid were used as the Raman probe molecule. The experimental results indicated that there are two ascendancies, firstly, the approach is convenient and the reaction condition is facile, secondly, tyrosine is a water-soluble, nontoxic and biodegradable macromolecule, which makes this approach provide a green strategy to prepare Ag NPs. Significantly, the synthesized Ag NPs exhibits good surface enhanced Raman scattering (SERS) activity as SERS substrates to detect crystal violet and folic acid in aqueous solution. PMID- 24059182 TI - [Effect of straw incorporation on three-dimensional fluorescence spectrum of dissolved organic matter in arid loess]. AB - The three-dimensional fluorescence spectrum was used to investigate the fluorescence characterization of dissolved organic matter (DOM) before and after straw incorporation in arid loess, and the variation of humification degree and Pb(II) speciation were illustrated. The results showed that the fluorescence peaks of loess appears at the regions of lambda(ex/em) = 240-270/280-340 and lambda(ex/em) = 325/450, referred as UV fulvic-like fluorescence, and visible fulvic-like and humic-like fluorescence, respectively. After straw incorporation for 60 days, the intensity of UV fulvic-like fluorescence peaks increases, and novel humic-like fluorescence peaks appears around the region of lambda(ex/em) = 250/440 and lambda(ex/em) = 320-350/350-400. The longer time of straw incorporation would accelerate the humification degree of loess and decrease the bioactivity of Pb(II). The three-dimensional fluorescence spectrum is appropriate for characterization identification of DOM in arid loess before and after straw incorporation. PMID- 24059183 TI - [Studies on fluorescence spectral characteristics of fulvic acid (FA) from Xingkai Lake sediments]. AB - Four samples (sample No. HXXD, HXXX, HXDX and HXDB) were taken from Xingkai Lake Sediments in Heilongjiang province and fluorescence spectral characteristics of Fulvic acid (FA) from sediments were studied. Conventional and excitation emission matrix (EEM) all indicated that FA from HXXD sediment exhibited primary peaks at longer wavelengths. The analysis of fluorescence characteristic parameters indicated that the degree of humification of FA from all sample points were in the order: HXXD > HXDX > HXDB > HXXX. Fluorescence index (f450/500) suggested that FA from HXXD mainly originated from terrestrial sources, while the FA from other samples mainly originated from aquatic organism sources and terrestrial sources. Based on EEM fluorescence regional integration (FIR), the percent fluorescence responses (P(i, n)) of five regions in 3EEMs was calculated. The distributions of P(V, n) (humic acid-like region) and P(III, n) (fulvic acid like region) were the largest in all samples. The conclusion of the degree of humification of FA based on FIR was consistent with the analysis of conventional fluorescence parameters. The correlation analysis showed that, gamma(A, C) was significantly correlative with P(V, n)/P(III, n), (P(V, n) + P(III, n))/(P(I, n) + P(II, n) + P(III, n)) and P(V, n). The results suggest that gamma(A, C) index is a reasonable tool for assessing humification degree of FA from Xingkai Lake sediments. PMID- 24059184 TI - [Effect of REE on growth of bacteria and fluorescence spectrum of DNA]. AB - Growth curve of bacteria treated by the rare earth elements and calmodulin inhibitor (chlorpromazine) was studied, and the effect of REE on calf thymus-DNA and intracellular DNA in bacteria was studied by fluorescence spectrum. The results showed that the logarithmic phase of growth and fission of bacteria can be advanced by REE, so they grew faster than contrast. At the same time, Bacillus subtilis was found bigger by SEM. But growth and fission was inhibited by chlorpromazine, indicating that the mechanism about growth and fission of bacteria by REE was connected with calmodulin inhibitor. Fluorescence of ct-DNA can be enhanced by REE. But intracellular DNA in bacteria was different, it can be enhanced by Ce(NO3)3, quenched by La(NO3)3. So we think that the function of REE to biological materials was very complicated. PMID- 24059187 TI - [Quantitative analysis of protein concentration by absorption peak integration method of UV spectroscopy--taking alkaline phosphatase as an example]. AB - Adsorption of alkaline phosphatase (APase) on minerals (goethite, montmorillonite) and sediments from Taihu Lake was studied. However, the concentration of alkaline phosphatase in the supernatant cannot be analyzed by the adsorption at 280 nm due to that the UV spectroscopy was changed. Quantitative analysis of alkaline phosphatase in the supernatant by the absorption peak (252-305 nm) integration method of UV spectroscopy was developed. This method determined the concentrations of alkaline phosphatase well. Compared to the results of Bradford, the absorption peak integration method can determine the concentrations of supernatant fast, conveniently, and accurately. This method can also be applied to other protein solution analysis and similar experiments. The drawbacks of traditional single wavelength method (280nm) were overcome to some extent based on the method of absorption peak integration. PMID- 24059189 TI - [Modeling continuous scaling of NDVI based on fractal theory]. AB - Scale effect was one of the very important scientific problems of remote sensing. The scale effect of quantitative remote sensing can be used to study retrievals' relationship between different-resolution images, and its research became an effective way to confront the challenges, such as validation of quantitative remote sensing products et al. Traditional up-scaling methods cannot describe scale changing features of retrievals on entire series of scales; meanwhile, they are faced with serious parameters correction issues because of imaging parameters' variation of different sensors, such as geometrical correction, spectral correction, etc. Utilizing single sensor image, fractal methodology was utilized to solve these problems. Taking NDVI (computed by land surface radiance) as example and based on Enhanced Thematic Mapper Plus (ETM+) image, a scheme was proposed to model continuous scaling of retrievals. Then the experimental results indicated that: (a) For NDVI, scale effect existed, and it could be described by fractal model of continuous scaling; (2) The fractal method was suitable for validation of NDVI. All of these proved that fractal was an effective methodology of studying scaling of quantitative remote sensing. PMID- 24059188 TI - [Study on the UV-quantitative analysis of theabrownins in Pu-Erh tea]. AB - An UV-quantitative analysis method for the theabrownin (TB) in Pu-erh tea and its derived products was established in the present study. The results showed that the Pu-erh tea shows characteristic absorption at the wavelength of 270 nm, which can be used as wavelength for the content determination of TB. The preparation methods of standard TB and standard curve were also established. The determination results show that the method is simple, the results have certain credibility, and the established method can be used for the determination of TB in Pu-erh tea and its derived products. PMID- 24059190 TI - [Noninvasive medical imaging system for tissue classification using RGB LED and micro-spectroscopy]. AB - As skin is the exterior organ of human body, cosmetic industry advances year by year. To reveal the details of skin tissue, threedimensional medical imaging is required. Based on the idea of "readout instead of write", a new scheme named spectral classification imaging (SCI) is proposed in the present study to reduce the invasiveness by applying the reflection spectra of the sample points for three-dimensional medical imaging. Broad-band light source and the spectrometer were employed to collect the spectra curves of scanned region, which were classified into several tissue types by their cross-correlations. A colorful tissue tomography can finally be obtained by filling in each image pixel the color indicating the corresponding tissue type. The lateral/longitudinal resolutions and penetration depth were analyzed to characterize the SCI system. The lateral resolution is based on the source's diffraction limit, the longitudinal resolution is by its depth-of-focus, and the penetration depth is equivalent to its skin depth. The imaging results of an amethyst of 0.6 mm (chi direction) x 0.6 mm (y-direction) with a total of 120 x 120 pixels per frame and a guppy fish of 3.2 mm (chi-direction) x 2.4 mm (y-direction) of 160 x 120 pixels, are presented to show the image quality. The effects of the cross correlation coefficient and the number of source wavelengths on the imaging results were explored. The value of cross-correlation threshold determines the required time for imaging, the resulted number of tissue groups, and the variety of tissue colors in the imaging result. Owing to its virtual noninvasiveness and easy configuration, the SCI system is highly promising for practical uses. RGB LEDs possess merits of broad bandwidth, low cost, long lifetime, small volume, and are ready to be integrated into a multi-color source module. Replacing the wide-band light source and the spectrometer module with a composite RGB LED with discrete wavelengths and a micro-spectrometer for spectra retrieval, the system has great potential to be minimized as a hand-held product for noninvasive medical imaging. It leads to reduced use of non-eco-friendly cosmetics and extended advance of cosmetic dermatology. PMID- 24059191 TI - [Theoretical research on a high Q factor elliptical differential photoacoustic resonator]. AB - The sensitivity of photoacoustic (PA) sensors strongly depends on the characteristic of PA cell. In the present paper, a novel elliptical differential PA cell was proposed to enhance the signal noise ratio of PA system. An acoustic characteristic mathematic model was built and the acoustic characteristic of PA cell was simulated with COMSOL software. The result shows that peak pressures would occur at the two ends of major axis with a pi phase difference when the mixed modes in the cross section of elliptical cell have odd azimuthal nodes along the minor axis. When the half major axis is less than 4 cm, the resonant frequency could be greater than 10kHz and the Q factor could achieve 1 835. Differential detection of PA signal could be realized and the common mode environment noise would be suppressed effectively. The signal noise ratio can be enhanced and high sensitivity detection could be achieved with this high Q factor elliptical differential cell. PMID- 24059192 TI - [Application of rational ant colony optimization to improve the reproducibility degree of laser three-dimensional copy]. AB - Three-dimensional (3D) copying of artificial ears and pistol printing are pushing laser three-dimensional copying technique to a new page. Laser three-dimensional scanning is a fresh field in laser application, and plays an irreplaceable part in three-dimensional copying. Its accuracy is the highest among all present copying techniques. Reproducibility degree marks the agreement of copied object with the original object on geometry, being the most important index property in laser three-dimensional copying technique. In the present paper, the error of laser three-dimensional copying was analyzed. The conclusion is that the data processing to the point cloud of laser scanning is the key technique to reduce the error and increase the reproducibility degree. The main innovation of this paper is as follows. On the basis of traditional ant colony optimization, rational ant colony optimization algorithm proposed by the author was applied to the laser three-dimensional copying as a new algorithm, and was put into practice. Compared with customary algorithm, rational ant colony optimization algorithm shows distinct advantages in data processing of laser three-dimensional copying, reducing the error and increasing the reproducibility degree of the copy. PMID- 24059193 TI - [Distribution characteristics of soil heavy metals in bamboo forest of Phyllostachys edulis on lead-zinc orefield]. AB - The woodland and farmland soil nearby lead-zinc mine has been polluted seriously due to the mining. Bamboo forest of Phyllostachys edulis has high economic value and is distributed widely in China. The Phyllostachys edulis forest nearby lead zinc mine was selected, and the distribution characteristics of main heavy metal Cu, Zn, Pb and Cd in soil were studied. The result showed that the concentration of Cu, Zn, Pb and Cd in bamboo rhizome zone reached 38.10-50.87, 92.24-137.75, 32.04-46.22 and 0.03-0.35 mg x kg(-1) respectively, which was lower than that in non-rhizome zone soil significantly. This result indicated that the distribution and concentration of heavy metals in soil were influenced partly by bamboo developed rhizome-root system and human frequent tending management. About the influence of distance from pollution source and slope position, the heavy metals content in soil showed a decreasing trend as the distance increased, and for most elements, the content in soil of the middle slope position was high, and was a little lower in upper slope position. PMID- 24059194 TI - [Study of prediction models for oil thickness based on spectral curve]. AB - Nowdays, oil spill accidents on sea occur frequently. It is a practical topic to estimate the amount of spilled oil, which is helpful for the subsequent processing and loss assessment. With the rapid development of hyperspectral remote sensing technology, estimating the oil thickness becomes possible. Firstly, a series of oil thicknesses are tested with the AvaSpec Spectrometer to get their corresponding spectral curves. And then the characteristics of the spectral curve are extracted to analyze their relationship with the oil thickness. The study shows that the oil thickness has large correlation with variables based on hyperspectral positions such as R(g), R(o), and vegetation indexes such as RDVI, TVI and Haboudane. Curve fitting, BP neural network and SVD iteration method were chosen to build the prediction models for oil thicknesses. Finally, the analysis and evaluation of each estimating model are provided. PMID- 24059195 TI - [Correlation of visual spectral response with aging and its effect on color discrimination]. AB - The variation in normal observers' color perception and discrimination will occur with the aging effect. The authors carried out a psychophysical experiment with the method of binocular observational technique. Three observers at the age of 21, 32 and 58 were organized to match the 9 printed color samples on EIZO monitor with the repetition of 7 times. Groups of data for cross-media color matching with different age were established to investigate the response of photoreceptor cells. The results indicated that with the aging effect the chroma of the matched color will decrease obviously and the spectral response of the blue channel will decrease for blue and purple colors. The results validate the prediction of CIEPO06 model to some extent and provide some theoretical basis and experimental supports for the application of color reproduction and the color evaluation of the products related to age. PMID- 24059196 TI - [Backscattering characteristics of Amphidinium carterae Hulburt]. AB - Variability of the backscattering characteristics of the alga amphidinium carterae hulburt and its interpretation were examined using the measured data performed during July 2012 in the laboratory. The results indicated that the backscattering coefficient has the characteristic of spectral variability, and was highly power correlated with the chlorophyll concentration, the minimum of the correlation coefficient reached up to 0.96; otherwise, the shape of the particulate backscattering coefficient spectra was also changed from the low chlorophyll concentration to the higher concentration because of the influence of chlorophyll absorption. At the same time, the authors got another value of the particulate backscattering ratio ranging between 0.006 4 and 0.011 6 at 620 nm, although a global increase in particulate backscattering ratio with growing chlorophyll concentration was also visible, but the regularity is not obviously especially at the higher chlorophyll concentration and unlike backscattering coefficient, the spectral shapes of the backscattering ratio remained constant. The authors also found that particle density was one of the main factors controlling the variability of particles backscattering ratio for the pure algal water, and the authors fit a power law function to them and the correlation coefficient at 620 nm was as high as 0.98. PMID- 24059197 TI - [Study on reflectance spectra morphological character of the hyperspectral mixed pixels at different component proportion]. AB - Under the experimental condition, the hyperspectral reflectance spectra of the mixed pixel of lotus and water body were acquired using the multi-angles dichotic reflex platform and ASD spectrum instrument. The reflectance spectral morphological character index variation of the hyperspectral mixed pixel at different component proportion was analyzed. The conclusions are as follows: the correlation between these morphological indexes was obvious, and the best morphological index was chosen by removing the index whose R2 was greater than 0.5 (R is correlation coefficient); the variation of different morphological index was obvious; the cluster analysis shows that there was a critical value in the progress of the transformation from the pure pixel (water) to mixed pixel. If the proportion was less than the critical value, the reflectance spectra reflected the reflection characteristics of pure pixel; otherwise, it was the reflection of characteristics of mixed pixel. PMID- 24059198 TI - [Research on the atmospheric correction for ZY-3 MUX image]. AB - The resolution of the ZY-3 MUX data is 5.8 meter, which is used to the subject classification. It is very difficult to use the dark target method for the atmosphere correction due to the lack of near infrared band in ZY-3 MUX data. The present paper uses the atmospheric correction coefficient look-up table (LUT) constructed by the radiation transmission model 6S based on the aerosol optical depth retrieved from the MODIS data for the atmospheric correction of ZY-3 image. To validate the results, the paper compares the surface spectral curves of the gypsum mine and Gobi and the NDVI values from the corrected and TOA reflectance, the relative error of the atmosphere corrected and the ground-based surface reflectance is less than 6%; the atmospheric correction increases the difference between vegetation NDVI and other features NDVI, highlights vegetation monitoring application ability. PMID- 24059199 TI - [Analysis of sensitive spectral bands for burning status detection using hyper spectral images of Tiangong-01]. AB - To obtain the sensitive spectral bands for detection of information on 4 kinds of burning status, i. e. flaming, smoldering, smoke, and fire scar, with satellite data, analysis was conducted to identify suitable satellite spectral bands for detection of information on these 4 kinds of burning status by using hyper spectrum images of Tiangong-01 (TG-01) and employing a method combining statistics and spectral analysis. The results show that: in the hyper-spectral images of TG-01, the spectral bands differ obviously for detection of these 4 kinds of burning status; in all hyper-spectral short-wave infrared channels, the reflectance of flaming is higher than that of all other 3 kinds of burning status, and the reflectance of smoke is the lowest; the reflectance of smoke is higher than that of all other 3 kinds of burning status in the channels corresponding to hyper-spectral visible near-infrared and panchromatic sensors. For spectral band selection, more suitable spectral bands for flaming detection are 1 000.0-1 956.0 and 2 020.0-2 400.0 nm; the suitable spectral bands for identifying smoldering are 930.0-1 000.0 and 1 084.0-2 400.0 nm; the suitable spectral bands for smoke detection is in 400.0-920.0 nm; for fire scar detection, it is suitable to select bands with central wavelengths of 900.0-930.0 and 1 300.0-2 400.0 nm, and then to combine them to construct a detection model. PMID- 24059200 TI - [Remote sensing image segmentation based on a multiresolution region granularity analysis method]. AB - Remote sensing image has abundant granularity information. In order to utilize this information, a multiresolution region granularity analysis method is proposed in the present paper for image segmentation The proposed method firstly uses the mean shift to obtain the initial oversegmented regions at each resolution of the image, and then extracts the granularity information based on the region size and the region context, the Markov random field is employed to provide the final segmentation result by modeling the spectrum information and the granularity information. The SPOT5 remote sensing images of Pingshuo and the aerial image of Taizhou were tested to evaluate the proposed method. Compared with other spectrum-based methods, our method shows a better performance and results improved the segmentation accuracy. PMID- 24059201 TI - [Research on remote sensing monitoring of soil salinization based on measured hyperspectral and EM38 data]. AB - In the present study, the delta oasis between the Weigan River and the Kuqa River was selected as our study area. Firstly, the measured hyperspectral data related to different soil salinization extent was combined with electromagnetic induction instrument (EM38) in order to establish a soil salinization monitoring model; Secondly, by using the scaling transformation method, the model was adopted to calibrate the soil salinity index calculated from Landsat-TM images. Thirdly, the calibrated Landsat-TM images were used for the retrieval of regional soil salinity, and the retrieved data was verified based on the measured data. We found that at wavelengths of 456, 533, 686 and 1 373 nm, the interpretated data of EM38 were highly correlated with soil spectral reflectance (obtained via first order differentiation transformation of the spectra). Additionally, the soil salinity index model constructed from the combination of 456, 686 and 1 373 nm waveband was the best model among the different saliniza tion monitoring models. The authors' conclusion is that with R2 = 0.799 3 (p < 0.01), extracting the salinity information at regional scale by combining the electromagnetic and multispectral data performed better than those monitoring models with only salinity index extracted from multispectral remote sensing method (R2 = 0.587 4, p < 0 01). Our findings provides scientific bases for the future studies related to more accurate monitoring and prediction of soil salinization. PMID- 24059202 TI - [Nondestructive discrimination of waxed apples based on hyperspectral imaging technology]. AB - The potential of hyperspectral imaging technology was evaluated for discriminating three types of waxed apples. Three types of apples smeared with fruit wax, with industrial wax, and not waxed respectively were imaged by a hyperspectral imaging system with a spectral range of 308-1 024 nm. ENVI software processing platform was used for extracting hyperspectral image object of diffuse reflection spectral response characteristics. Eighty four of 126 apple samples were selected randomly as calibration set and the rest were prediction set. After different preprocess, the related mathematical models were established by using the partial least squares (PLS), the least squares support vector machine (LS SVM) and BP neural network methods and so on. The results showed that the model of MSC-SPA-LSSVM was the best to discriminate three kinds of waxed apples with 100%, 100% and 92.86% correct prediction respectively. PMID- 24059203 TI - [Retrieval method for estimating snow depth using hyperspectral data in snowmelt period]. AB - The snow surface reflectance spectra with different depth in snowmelt period and snow depth data were measured and its correlation was analyzed. The characteristic absorption band data of the valley with higher correlation were used to establish a single band snow depth regression model. The highest contribution rate of the band was selected as the input variable of the neural network model to retrieve snow depth. The results show that in Juntang Lake area, near 1 022, 1 241 and 1 492 nm exists characteristic absorption valley of snow, and compared to estimation accuracy of the single-band inversion of snow depth model (R2 = 0.53), ANN-BP model has a higher inversion level, and determination coefficient (R2 = 0.86, RMSE = 0.67) was obtained with 4 nodes in hidden layers, indicating that ANN-BP model can greatly improve the ability of inversion of snow depth with hyperspectral data. PMID- 24059204 TI - [Research on hyperspectral remote sensing inversion of barrier factors in saline alkaline land use]. AB - In the present paper, the meliorated saline-alkaline land by mixing sand in the north of Shaanxi province was chosen as the study area. The growth situation of the corn in the study area was measured, and soil samples and hyperspectral data were collected. The barrier factors for saline-alkaline land use were obtained by analysing the properties of soil samples. And the hyperspectral characteristics of the barrier factors were studied to elicit the quantitative inverse model, and the accuracy was verified. The study results indicated that the salt content in soil was the primary factor restricting the saline-alkaline land use, and capillary porosity was also the barrier factor because of its good correlation with the salt content. The precisions of quantitative inverse model of salt content and capillary porosity with hyperspectral data were good (the determinate coefficients R2 were 0.938 and 0.973). The test result with testing points showed that there were good correlations between the measured value and predicted value of salt content and capillary porosity (the slope was near to 1, and R2 was 0.840 4 and 0.796 5), the accuracy was good. It is of great promotion for guiding the saline-alkaline land consolidation and use that the barrier factors for saline alkaline land use were interpreted quantitatively by hyperspectral data. PMID- 24059205 TI - [Application of argon-nitrogen mixed gas inductively coupled plasma in elements and isotopes analysis]. AB - To improve the precision and accuracy of elements and isotopes analysis in traditional Ar-ICP, the addition of nitrogen in ICP has been widely used. The present review focused on the discussions of the basic physical and chemical properties of the Ar-N2 mixed gas inductively coupled plasma and the mechanisms of the special nature of Ar-N2 mixed gas plasma. The applications of Ar-N2 inductively coupled plasma in spectral analysis and mass spectrometry analysis in the past 40 years were summarized. The authors also give an overall outlook on the application of this technology. PMID- 24059206 TI - [Comparison of fluorescence spectroscopy and plasma-mass spectrometry results of the Meso/Cenozoic basic rocks in SE China and its geo-implication]. AB - With comparison of the fluorescence spectroscopy and plasma-mass spectroscopy analysis results of the Meso/Cenozoic basic rocks of SE China, the authors found that the average SiO2 content of the Mesozoic basic rocks in this area is about 50%, while that of the Cenozoic basic rocks is about 43%. The former belongs to the basic group and the later to the ultrabasic group in igneous rock classification. Cenozoic basalts, accompanied with high magnesium content and low silica-alumina component, are obviously basic or ultrabasic rocks. Distinctive difference in the content of trace elements and of REE is also presented between the Mesozoic and the Cenozoic basic rocks. Distribution models of both trace elements and REE of the Mesozoic basic rocks are similar to those of the upper crust, and the models of the Cenozoic basic rocks are like those of OIB, indicating that basic rocks of the Cenozoic and OIB should originate from the mantle while that of the Mesozoic is from the bottom part of the upper crust with relationship to the evolution of the Mesozoic crustal magma layer of this area. PMID- 24059207 TI - [Study on trace elements of lake sediments by ICP-AES and XRF core scanning]. AB - It is the first time to study sediment of Toson lake in Qaidam Basin. Trace elements including Cd, Cr, Cu, Zn and Pb in lake sediment were measured by ICP AES method, studied and optimized from different resolution methods respectively, and finally determined a optimum pretreatment system for sediment of Toson lake, namely, HCl-HNO3-HF-HClO4-H2O2 system in the proportions of 5 : 5 : 5 : 1 : 1 was determined. At the same time, the data measured by XRF core scanning were compared, the use of moisture content correction method was analyzed, and the influence of the moisture content on the scanning method was discussed. The results showed that, compared to the background value, the contents of Cd and Zn were a little higher, the content of Cr, Cu and Pb was within the background value limits. XRF core scanning was controlled by sediment elements as well as water content in sediment to some extent. The results by the two methods showed a significant positive correlation, with the correlation coefficient up to 0.673 0.925, and they have a great comparability. PMID- 24059208 TI - [Study on the determination of 14 inorganic elements in coffee by inductively coupled plasma mass spectrometry]. AB - Samples of coffee were digested by microwave digestion, and inorganic elements amounts of Na, Mg, P, Ca, Cr, Mn, Fe, Co, Cu, Zn, As, Se, Mo and Pb in sample solutions were determined by inductively coupled plasma mass spectrometry (ICP MS). HNO3 + H2O2 was used to achieve the complete decomposition of the organic matrix in a closed-vessel microwave oven. The working parameters of the instrument were optimized. The results showed that the relative standard deviation (RSD) was less than 3.84% for all the elements, and the recovery was found to be 92.00% -106.52% by adding standard recovery experiment. This method was simple, sensitive and precise and can perform simultaneous multi-elements determination of coffee, which could satisfy the sample examination request and provide scientific rationale for determining inorganic elements of coffee. PMID- 24059209 TI - [Determination of ru, rh and Pd in 30% trialkyl phosphine oxide (TRPO)-kerosene by inductively coupled plasma-atomic emission spectrum (ICP-AES)]. AB - The determination method of Ru, Rh and Pd in 30% TRPO-kerosene ICP-AES was studied by using aqueous calibration reference solution and choosing ethanol as diluent. The effects of the contents of 30% TRPO-kerosene and aqueous solution and the concentration of HNO3 in 30% TRPO-kerosene on the intensities of Ru, Rh and Pd were described. The optimized condition for preparing samples and calibration solutions was chosen as follows: The contents of 30% TRPO-kerosene and aqueous phase were 10% (V/V) and 5% (V/V) respectively and the concentration of HNO3 30% TRPO-kerosene was 0.20 mol x L(-1). The determination method of Au, Ru and Pd was set up according to the above condition. The detection limit, precision and recovery ratio of Ru, Rh and Pd are well. The method is not only used in determination of Au, Ru and Pd in 30% TRPO-kerosene, but also used in other organic phases. PMID- 24059210 TI - [Study on the simultaneous determintion of various components in cement samples by inductive coupled plasma-atomic emission spectrometry]. AB - A simple and rapid method for determination of CaO, MgO, Fe2O3, Al2O3 and TiO2 in cement samples by inductive coupled plasma-atomic emission spectrometry (ICP-AES) was developed. In order to carry out the analysis, the cement samples were dissolved with mixed aqua regia, hydrofluoric acid, perchloric acid, hydrochloric acid, and the standard solution was prepared by a series of standard cement samples. The matrix interference and the mutual interference of elements under test were studied by ICP-AES. The detection limits are in the range of 3.79 x 10( 4)-1.07 x 10(-2) microg x mL(-1). The recovery rates and relative standard deviations (RSD) of the method are in the range of 87.5%-105.6% and less than 1% respectively. Research results show that the method can meet the requirements of rapid chemical analysis for cement. PMID- 24059211 TI - [Analysis of X-ray fluorescence spectroscopy and plasma mass spectrometry of the Guidong granite body and its implications to granite evolution]. AB - The Guidong composite granite body (CGB) located in the north Guangdong Province consists of numerous rock bodies formed respectively in the early and late Jurassic and early Cretaceous. Analysis of the granites of different period with X-ray fluorescence spectroscopy and plasma mass spectrometry indicates: (1) From the top of a granite body downwards, the felsic components of rock decrease, while the mafic and sigmaREE, LREE/HREE, (La/Yb)N, as well as delta Eu value increase, suggesting the material differentiation in the in-situ melting of crustal rocks and crystallisation of magma; (2) From old to young of the different period granite-massifs in the Guidong CGB, the felsic compositions totally decrease, and the mafic components, sigmaEE, LREE/HREE, (La/Yb)N, and delta Eu value increase as well, implying multiple crustal melting (remelting) events in the Mesozoic in this area; and (3) Primitive mantle-normalized spider diagram for trace elements of Guidong CGB suggests high maturity of the crust involved in the in-situ melting. PMID- 24059212 TI - [Infrared spectra and XRD characteristics of alunite in the Zijinshan gold-copper deposit]. AB - The structural characteristics and composition of alunite in the Zijinshan gold copper deposit were studied by infrared absorption spectroscopy and X-ray powder diffraction analysis. The results show that infrared spectral absorption peaks, the growth degree of crystal faces (006) and (004), and crystal cell parameters of the alunite display gradually decreasing trend from the crater to northwest along the metallogenic belt. Combined with electron probe analysis results, we go further and obtain that the alunite mainly belongs to potassium alunite, and the characteristics of infrared spectra and XRD of the alunite mainly have relation to the content of potassium of the alunite in different parts of volcanic mechanism. Near the crater, with higher temperature, it is helpful for the isomorphism replacement between sodium and potassium, the content of sodium is higher and the content of potassium is lower relatively in the alunite; and away from the crater, the temperature is relatively lower, it is against the isomorphism replacement between sodium and potassium, the content of sodium is lower, and the content of potassium is higher relatively in the alunite. PMID- 24059213 TI - [Study on the traditional lime mortar from the memorial archway in the southern Anhui province]. AB - The traditional lime mortar was investigated by means of scanning electron microscope (SEM), X-ray diffractometry and Fourier transform infrared spectrometry (FTIR). The results show that the mortar from the memorial archway in the southern Anhui province was the organic-inorganic composite materials composed of lime with tung oil or sticky rice. It was found that the excellent performance of the tung oil-lime mortar can be explained by the compact lamellar organic-inorganic composite structure that was produced by carbonization reaction of lime, cross-linking reactions of tung oil and oxygen and complexing reaction of Ca2+ and -COO-. The compact micro-structure of sticky rice-lime mortar, which was produced due to carbonation process of lime controlled by amylopectin, should be the cause of the good performance of this kind of organic-inorganic mortar. PMID- 24059214 TI - [Mineralogical and spectral characteristics of copper pectolite]. AB - Copper pectolite, a type of pectolite with blue stripes, is a rare gem material with a great market prospect. Mineralogy and genesis were investigated using X ray diffraction (XRD), Fourier infrared absorption spectroscopy (FTIR), Raman spectroscopy (Raman), scanning electron microscopes (SEM) and ultraviolet-visible spectrometer(UV-VIS) to understand the mineralogical compositions and characteristics of the parts with different color. XRD, FTIR and Raman result showed that copper pectolite is composed of pectolite and minor calcite, consistent with the result of SEM. FTIR showed that an obvious band at 1 500 cm( 1) with 883 and 710 cm(-1) occurred on the white part that contain minor calcite, while the band was absent on the blue part. UV-Vis absorption spectroscopy analysis showed that the blue part has 640 nm absorption band in the UV area that indicates containing elements Cu. The different mineralogical compositions of the white and blue part indicate their different geological conditions. PMID- 24059215 TI - [Impact and improvement of the mechanical shutter on large-array filter-type multispectral imaging system]. AB - The present paper analyzes the impact of mechanical shutter on the spectral image acquisition and processing of large-array filter-type multispectral imaging system. The final image quality relies highly on the mechanical shutter due to the fluctuation at exposure time. The conventional mechanical shutter's structure and driving method was analyzed to find out the key fact for its poor stability. An improved method of mechanical transmission and circuit driving was proposed. Laboratory experiments showed that with the improved design strategy, the maximum rate of change between adjacent exposures was reduced from 15.05% to 0.96%, which is a great improvement of the exposure time stability. Field test was also carried out and the results show that the combined color images are closer to the realistic targets and no abrupt color change iwas found. It's of great significance for practical application in multispectral image process, interpretation and target identification. PMID- 24059216 TI - [Imaging quality evaluation of computational imaging spectrometry]. AB - As a novel imaging spectrometry, computational imaging spectrometry (CIS) has the advantages of high throughput, snapshot imaging etc. However, there is little research on imaging quality evaluation of CIS system. In the present paper, a quantitive evaluation method for imaging quality of CIS system was presented. ISO 12233 chart was used as the objective source, and then imaging and reconstruction of the spatial-spectral information was provided. Calculating modulation transfer functions (MTFs) for the reconstructed images was considered as the criterion of the imaging quality evaluation of CIS system. The result shows that MTFs for single-frame sampling decrease rapidly with the aliasing spectral number increasing. When the number of the aliasing spectra is 9, MTF for the reconstructed image decreases by 50% compared to the original scene. This work helps better understand the pros and cons of CIS system and arrange the aliasing spectral number reasonably to reconstruct the object scene precisely. PMID- 24059217 TI - [Optical path difference in off-plane quasi-Littrow dispersion mountings]. AB - The present paper analyzes the relative relation between the meridian and sagittal rays in off-plane quasi-Littrow (OP-QL) dispersion mountings. It's concluded that the off-plane angle will cause the rotation of the beam and result in the mismatch between the sagittal beams on different optical elements. Therefore the total optical path difference (OPD) should be an accumulation of corresponding beams instead of the sagittal beam of each element itself. Then, a directional derivative based method is put forward to calculate the OPD for spherical mirrors in various directions. Based on the method, the numerical OPD for OP-QL mountings is solved. Finally, this methodology is validated with both echelette and echelle examples. PMID- 24059218 TI - [General calculation method of diffraction efficiency of concave blazed gratings]. AB - In order to make diffraction energy of concave gratings more concentrated in the desired order, the present paper puts forward that the concave blazed grating with variable groove angles could be fabricated on the concave substrates by mechanical ruling method, and the theoretical method of simultaneously calculating the diffraction efficiency in the main section and non-main section is deduced by using Fresnel-Kirchhoff's diffraction formula, which makes up the shortage of the diffraction efficiency calculated only in the main section. Finally, the diffraction efficiency curves varied with wavelength is simulated by Matlab software, and the variation laws of the diffraction efficiency are compared for different production methods and application parameters, which provides a valuable reference for the design and production of the concave gratings. PMID- 24059219 TI - [Study on the characteristics of radiance calibration using nonuniformity extended source]. AB - Integrating sphere and diffuser are always used as extended source, and they have different effects on radiance calibration of imaging spectrometer with parameter difference. In the present paper, a mathematical model based on the theory of radiative transfer and calibration principle is founded to calculate the irradiance and calibration coefficients on CCD, taking relatively poor uniformity lights-board calibration system for example. The effects of the nonuniformity on the calibration was analyzed, which makes up the correlation of calibration coefficient matrix under ideal and unideal situation. The results show that the nonuniformity makes the viewing angle and the position of the point of intersection of the optical axis and the diffuse reflection plate have relatively large effects on calibration, while the observing distance's effect is small; under different viewing angles, a deviation value can be found that makes the calibration results closest to the desired results. So, the calibration error can be reduced by choosing appropriate deviation value. PMID- 24059220 TI - [Hadamard transform spectral imager of adaptive spectral resolution based on DMD]. AB - Digital micro-mirror device (DMD) can be controlled to form Hadamard encoding masks flexibly and efficiently. A kind of Hadamard transform spectral imager of adaptive spectral resolution based on DMD is proposed. The structure and the working principle of the instrument are described and the implementation method of adaptive spectral resolution is analyzed. It can adjust the spectral resolution according to the target and the observational requirements, and a reasonable compromise can be reached between the spectral accuracy and the computation of data. It not only meets the requirements of the target classification and recognition, but also improves the speed of data transmission and processing. PMID- 24059221 TI - [A novel scheme SVR(HAAR) for automatically estimating stellar atmospheric parameters from spectrum]. AB - A novel scheme SVR(Haar) is proposed in the present work for automatically estimating the physical parameters of stellar spectra. The observed spectrum is disturbed usually by noise which is caused by the universe radiation, the atmosphere and observation equipment. Furthermore, the noise usually is the component of the spectrum with higher frequency. Therefore, we propose to extract features with Haar wavelet by removing higher frequency components. Researches show that this procedure can improve the accuracy of the estimation. Secondly, the support vector regression model is employed for estimating physical parameters of the stellar spectra. In this method, the epsilon insensitive domain techniques can further improve the probability to the slight distortion of the spectrum from imperfect calibration, and enhance the robustness of the proposed scheme. To check the effectiveness of the proposed scheme SVR(Haar), we did experiments extensively on authoritative simulated stellar spectra and real spectra observed by SLOAN, and compared it with the typical methods in the literature. The results show that the SVR (Haar) is better than the principal component analysis and non-parametric regression model in the literature. PMID- 24059222 TI - Biocompatibility effects of biologically synthesized graphene in primary mouse embryonic fibroblast cells. AB - Due to unique properties and unlimited possible applications, graphene has attracted abundant interest in the areas of nanobiotechnology. Recently, much work has focused on the synthesis and properties of graphene. Here we show that a successful reduction of graphene oxide (GO) using spinach leaf extract (SLE) as a simultaneous reducing and stabilizing agent. The as-prepared SLE-reduced graphene oxide (S-rGO) was characterized by ultraviolet-visible spectroscopy and Fourier transform infrared spectroscopy. Dynamic light scattering technique was used to determine the average size of GO and S-rGO. Scanning electron microscopy and atomic force microscopy images provide clear surface morphological evidence for the formation of graphene. The resulting S-rGO has a mostly single-layer structure, is stable, and has significant water solubility. In addition, the biocompatibility of graphene was investigated using cell viability, leakage of lactate dehydrogenase and alkaline phosphatase activity in primary mouse embryonic fibroblast (PMEFs) cells. The results suggest that the biologically synthesized graphene has significant biocompatibility with PMEF cells, even at a higher concentration of 100 MUg/mL. This method uses a 'green', natural reductant and is free of additional stabilizing reagents; therefore, it is an environmentally friendly, simple, and cost-effective method for the fabrication of soluble graphene. This study could open up a promising view for substitution of hydrazine by a safe, biocompatible, and powerful reduction for the efficient deoxygenation of GO, especially in large-scale production and potential biomedical applications. PMID- 24059223 TI - Pharmacophore-based 3DQSAR and molecular docking studies to identify new non peptidic inhibitors of cathepsin S. AB - Cathepsin S (CatS) is one of the 11 cysteine protease cathepsins which are expressed predominantly in antigen presenting cells (APC) namely B cells, macrophages and dendritic cells. CatS has been implicated in a wide range of diseases such as rheumatoid arthritis, multiple sclerosis, neuropathic pain and allergic disorders. In the present study, pharmacophore mapping studies followed by 3D QSAR analysis was undertaken for a large set of 161 molecules reported to be non-covalent binding and non-peptidic inhibitors of CatS. The activity range (IC50) of these compounds was between 2 picomolar to 100 nanomolar. A five point pharmacophore model with three hydrogen bond acceptors (A), one hydrogen bond donor (D) and one hydrophobic (H) group as pharmacophoric features was developed. The generated model showed reasonable predictive power, with a correlation coefficient Q(2) of 0.607. The model was further confirmed by an external test set validation that showed statistically significant parameters r(2) value of 0.840 with the R(2)p value of 0.812 and r(2)m value of 0.530. Validated model was then used to identify six diverse non-peptidic scaffolds from a commercial structure database by the analyses of parameters such as pharmacophore fitness, docking score, interacting amino acids and ADME properties to achieve prototypical lead compounds. PMID- 24059224 TI - Effect of resveratrol and tiron on the inactivation of glyceraldehyde-3- phosphate dehydrogenase induced by superoxide anion radical. AB - Protein damage mediated by oxidation has been associated with aging and age related diseases, in particular neurodegenerative diseases. The protein that is known to be one of the major targets of oxidative stress is glyceraldehyde- 3 phosphate dehydrogenase. GAPDH is believed to play a key role in certain neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Several recent studies have suggested that a wide range of variety of polyphenols including resveratrol may have neuroprotective effects. Here, we present data that clearly indicate the prooxidative properties of resveratrol and tiron in the inactivation of GAPDH induced by the superoxide anion generated via xanthine oxidase mediated oxidation of xanthine. Generated in the studied system tiron and resveratrol radicals are much more efficient in the inactivation of GAPDH than the superoxide anion alone. The analysis of CD spectra of protein exposed to the tiron and resveratrol radicals revealed little effect on the secondary structure of GAPDH. In both cases reduction of α-helical structure was followed by the increase in beta-sheet conformation. Thus, the most probable mechanism of inactivation of GAPDH in the studied system is oxidation of cysteine residues in the catalytic center of the enzyme. Finally, molecular modeling of the resveratrol - GAPDH and tiron - GAPDH complexes showed potential binding sites for those antioxidants with binding affinity -45 kcal/mol and -48 kcal/mol respectively. PMID- 24059225 TI - MK-0626, a dipeptidyl peptidase-4 inhibitor, improves neovascularization by increasing both the number of circulating endothelial progenitor cells and endothelial nitric oxide synthetase expression. AB - Current treatment modalities for critical limb ischemia (CLI) are of limited benefit; therefore, advances in therapeutic vasculogenesis may open an important new avenue for the treatment of CLI. This study examines the therapeutic potential of the DPP-4 inhibitor MK-0626 as a regulator of vasculogenesis in vivo. MK-0626 was administered daily to C57CL/B6 mice and eGFP-labeled bone marrow-transplanted ICR mice that had undergone hind limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neo vasculogenesis and the number of circulating endothelial progenitor cells (EPCs), respectively. Cell surface markers of EPCs and the level of endothelial nitric oxide synthase (eNOS) were studied in the vessels. Mice that received MK-0626 had an elevated level of glucagon- like peptide-1 (GLP-1) and a decreased level of dipeptidyl peptidase-4 (DPP-4) in their plasma, in addition to an ischemia induced increase in the level of stromal cell-derived factor-1 (SDF-1). In C57CL/B6 mice, blood flow in the ischemic limb was significantly improved by treatment with MK-0626. The number of circulating EPCs and both the synthesis and phosphorylation of eNOS were also increased in ischemic thigh muscle after MK 0626 treatment. In contrast, similar effects of MK-0626 were not observed in B6.129P2-Nos3(tm1Unc)/J mice (an eNOS knockout mouse). Additionally, MK-0626 treatment promoted the mobilization and homing of EPCs to ischemic tissue in eGFP transgenic mouse bone marrow-transplanted ICR mice. We conclude that both the number of circulating EPCs and neo-vasculogenesis are increased in response to DPP-4 inhibitor treatment and that this occurs via an eNOS-dependent mechanism. The results highlight the therapeutic vasculogenesis potential of the DPP-4 inhibitor MK-0626 using a hind limb ischemia mouse model. PMID- 24059226 TI - Ellipticines as DNA-targeted chemotherapeutics. AB - The anti-tumor therapeutic ellipticine and its derivatives act as potent anticancer agents via a combined mechanism involving cell cycle arrest and induction of apoptosis. Cell death induced by ellipticine has been shown to engage a p53-dependent pathway, cell cycle arrest, interaction with several kinases and induction of the mitochondrial pathway of apoptotic cell death. Cell cycle arrest was shown to result from DNA damage caused by a variety of tumor chemotherapeutic agents; this is also the case for ellipticines. The prevalent DNA-mediated mechanisms of anti-tumor, mutagenic and cytotoxic activities of ellipticine are (i) intercalation into DNA, (ii) inhibition of DNA topoisomerase II activity, and (iii) covalent binding to DNA in vitro and in vivo after enzymatic activation by cytochrome P450 and/or peroxidase enzymes The mechanism leading to apoptosis by ellipticine is thought to also be associated with DNA damage, by inhibition of topoisomerase II and the covalent modification of DNA. In addition, the formation of ellipticine-DNA adducts ultimately can mutate cancer cells or initiate cell death. The aim of this review is to summarize our knowledge on the molecular mechanisms with the aim to explain the effectiveness of ellipticines as DNA-targeted chemotherapeutics in cancer cells. PMID- 24059227 TI - Therapeutic reflections in cholesterol homeostasis and gallstone disease: a review. AB - Cholesterol gallstone disease is one of the most prevalent and the most costly digestive diseases in Western countries. Its pathogenesis is a complex paradigm resulting from the interaction of genetic factors, hepatic hypersecretion of cholesterol, increased intestinal absorption of cholesterol, a constantly "supersaturated" bile, crystallization of biliary cholesterol, and gallbladder stasis. De novo cholesterol biosynthesis, biliary cholesterol output, and intestinal cholesterol absorption are therefore key steps involved in cholesterol homeostasis. Establishing the right pharmacological therapy for cholesterol gallstones is of major importance in Western healthcare systems. Certain drugs might independently influence cholesterol gallstone formation by blocking the 3 hydroxy-3-methylglutaryl-coenzyme A reductase and inhibiting cholesterol biosynthesis in the liver (statins) or blocking cholesterol absorption in the small intestine apical membrane by specifically inhibiting the Niemann-Pick C1 like 1 protein (ezetimibe). This review will focus on the possibility that statins and ezetimibe, by acting at different levels of cholesterol homeostasis, might represent novel therapeutic approaches to prevent cholesterol gallstones in selected subjects at risk. PMID- 24059228 TI - Does erythropoietin always win? AB - The synthesis of recombinant human erythropoietin has marked a turning point in the treatment of anaemia secondary to chronic kidney disease. However, the potentially fatal cardio- and cerebrovascular complications of the intake of high doses of ESAs (erythropoiesis-stimulating agents), such as those observed in athletes who resort to doping, reason out the ever-prevalent debate concerning the balance between the risks and benefits of ESA administration for therapeutic purposes. Hence, there is still a discussion as to what values haemoglobin should ideally be maintained at. Additional concerns arise in cancer patients due to the ability of erythropoietin to act as an angiogenic and, in general, as a cell growth factor, because this might favour the progression of neoplastic disease. We summarized the prominent points of the latest guidelines on the management of anaemia in nephropathic patients, also identifying the possible risks that may result from the tendency to aim at too low haemoglobin levels. PMID- 24059229 TI - P-glycoprotein and vacuolar ATPase synergistically confer anthracycline resistance to fission yeast and human cells. AB - Drug resistance is a major hurdle to the success of chemotherapy. The permeability glycoprotein (P-gp) is an important factor dictating drug access to the cells, as it controls the efflux of chemotherapeutic agents against the concentration gradient. Pmd1, a P-gp-like protein, was recently isolated as a doxorubicin resistance gene in fission yeast. Although the null mutant of pmd1 (Deltapmd1) exhibited sensitivity to doxorubicin, it showed an unexpectedly high resistance to the drug at relatively high concentrations. The data presented here suggest that this is due to the presence of cooperative processes that can complement and counteract drug cytotoxicity in the absence of Pmd1. One such factor, Rav1, is an essential factor in controlling the assembly of the pH regulating transporter vacuolar-ATPase (V-ATPase) in fission yeast. The simultaneous disruption of Pmd1 and Rav1 resulted in a prominent accumulation of doxorubicin in the cytoplasm of cells, accompanied by a decline in cell viability. With concurrent treatment of pharmacological inhibitors in human cervical cancer cells, P-gp and V-ATPase were further shown to act synergistically to sensitize cells to doxorubicin also in the human cells. Furthermore, a novel Cornichon-like protein SPAC2C4.05 (herein named as Cor1) was demonstrated for the first time to be involved in the interaction with P-gp and V ATPase to counteract doxorubicin-dependent cytotoxicity. Therefore this study identified a molecular cooperation between multiple membrane transporter proteins that confers chemoresistance to cells against the chemical insult of doxorubicin. Interestingly, this network exhibited differential effects to doxorubicin as compared with its close epimeric analog epirubicin, suggestive of the intricacy of the drug response regulated by this synergistic interaction. A model is discussed on how the versatility of this network can differentiate closely related chemical drug structures yet allow for the robustness to counteract a vast range of drugs. PMID- 24059230 TI - Recent trends in the design, synthesis and biological exploration of beta lactams. AB - Since the discovery of penicillin, natural and synthetic beta-lactams have aroused great interest not only as sources of effective antibacterial agents but also as specific inhibitors of proteases responsible for various non-bacterial pathological processes. This interest was reflected in our review published in Current Medicinal Chemistry in 2003. The present article summarises new data published during the last decade dedicated to the design, synthesis and biological exploration of new beta-lactams with anti-inflammatory, antiviral, anticancer and other activities based on the inhibition of human leukocyte elastase, porcine pancreatic elastase, tryptase, chymase, human cytomegalovirus protease, fatty acid amide hydrolase, protein phosphatase methylesterase-1, serine protease responsible for tumor proliferation, cysteine proteases, matrix metalloproteinases, human 20s proteasome, human immunodeficiency virus, cholesterol absorption, human fatty acid synthase, bacterial RNase A and Leishmania D-mannosyl phosphate transferase. Antitumor effect was achieved also by new beta-lactams activating apoptosis-specific poly(ADP-ribose) polymerase or participating in DNA intercalation. PMID- 24059231 TI - New fabrication and applications of carbohydrate arrays. AB - Carbohydrate arrays are used as high-throughput screening platforms to study the carbohydrate-mediated recognition events for glycobiology. The polysaccharide arrays are easy to fabricate by non-covalently or covalently immobilizing polysaccharides onto array surfaces because polysaccharides have hydrophobic interactions. Oligosaccharides must be derived and covalently or non-covalently immobilized onto array surfaces to fabricate oligosaccharide arrays because they have hydrophilic interactions. At the moment, carbohydrate arrays are mainly used to study the carbohydrate-protein interactions and carbohydrate-binding lectins or antibodies, which are possible to be applied to clinics and diagnoses. This review mainly summed up the new fabrication strategies of carbohydrate arrays and their applications in recent four years. PMID- 24059232 TI - Adenosine A(2A) receptor antagonists as Positron Emission Tomography (PET) tracers. AB - The adenosine A(2A) receptor (A(2A)R) is highly concentrated in the striatum, and a therapeutic target for Parkinson's disorder (PD) and Huntington's disease. High affinity and selective radiolabeled A(2A)R antagonists can be important research and diagnostic tools for PD. Positron Emission Tomography (PET) can play an important role by measuring radiolabeled A(2A) antagonists non-invasively in the brain. However, till date no complete review on A(2A)R PET ligands is available. The present article has been therefore focused on available PET tracers for A(2A)R and their detailed biological evaluation in rodents, nonhuman primates and humans. Drug design and development by molecular modeling including new lead structures that are potential candidates for radiolabeling and mapping of cerebral A(2A)Rs is discussed in the present article. A brief overview of functions of adenosine in health and disease, including the relevance of A(2A)R for PD has also been presented. PMID- 24059233 TI - VEGF signal system: the application of antiangiogenesis. AB - Among the numerous endogenous promoters of angiogenesis, vascular endothelia growth factor (VEGF) plays a leading role in angiogenesis, which has huge impact on proliferation, survival, migration and permeability of tumor cells. VEGF signal system also becomes remarkable anticancer targets, including VEGF, vascular endothelia growth factor receptor (VEGFR), and VEGF downstream signal pathways. So far, there has been many clinical or approved anticancer drugs that directly or indireactly interfere with VEGF signal system applied in the treatment of various tumors and other diseases associated with pathological angiogenesis. Various kinds of antiangiogenic agents which inhibit VEGF and VEGFR have been developed and discovered gradually, including antibodies, ribozymes and small molecule inhibitors. Meanwhile, the investigation into antiangiogenic agents which block certain signal proteins of VEGF downstream signal pathways attracts the attention of medicinal chemists and enriches the application of antiangiogenic agents. This review will interpret the mysterious VEGF signal system from its molecular structure and probe to the mechanism of the combination of VEGF and its receptors. Furthermore, the detail of VEGF signal pathways will be introduced comprehensively and methodically. In addition, some up-to-date clinical or approved anticancer agents will be clearly tabulated. The binding modes of different kinase inhibitors will be used to explain the SAR of the small molecule inhibitors. Finally, in order to make the readers master VEGF signal system completely, some novel targets and inhibitors which block the downstream signal pathways of VEGF are plainly stated. PMID- 24059234 TI - Enantiospecific synthesis of heterocycles linked to purines: different apoptosis modulation of enantiomers in breast cancer cells. AB - The issue of chiral drug is now a major theme in the design, discovery and development of new drugs. It has been shown for many pharmaceuticals that only one enantiomer contains the desired activity, and the synthesis of such drug molecules in their optically pure form is becoming increasingly important. Mitsunobu reaction was carried out between (R)- and (S)-3,4-dihydro-2H-1,5 benzoxathiepin-3-ol and purines under microwave irradiation. A contraction into a six-membered ring takes place with concomitant inversion at the stereocentre with excellent enatiomeric excesses giving rise to the homochiral 9-(2,3-dihydro-1,4 benzoxathiin-3-ylmethyl)-9H-purines. The anti-tumour activity of all enantiomers is reported against the caspase-3-deficient MCF-7 and the wild type SKBR-3 human breast cancer cells. The most active homochiral compound displays an IC50 of 1.85 MUM and induces inhibition of the translation initiation factor eIF2alpha. All homochiral compounds included in this study show different apoptotic effects between both enantiomers with levels up to 99%. We have analyzed caspase-mediated apoptotic pathways on enantiomers and racemates. We have found a homochiral derivative that activates the canonical intrinsic caspase-8/caspase-3 apoptotic pathway on the MCF-7 cells, and a racemic compound that induces caspase-2 activation. Moreover, we demonstrate the involvement of caspase activation during cell death induced by these compounds in SKBR-3 cells. PMID- 24059235 TI - Farnesyltransferase inhibitors: a comprehensive review based on quantitative structural analysis. AB - Farnesyltransferase inhibitors (FTIs) have mainly been used in cancer therapy. However, more recently, investigations on these inhibitors revealed that FTIs can be used for the treatment of other diseases such as Progeria, P. falciparum resistant malaria, Trypnosomatid, etc. Hence the development of novel FTIs is an important task for the drug discovery program. Initially, numerous peptidomimetic FTIs were developed from the template of CAAX (CVIM was the first pharmacophore model used as a peptidomimetic). Later, many non-peptidomimetic FTIs have been discovered with the structural modification of the peptidomimetics. The structural analysis of those developed FTIs by various researchers suggested that the presence of a heterocycle or a polar group in place of the thiol group is required for interaction with the Zn(2+) ion. The bulky naphthyl, quinolinyl, phenyl, phenothazine, etc in this position provide better hydrophobicity to the molecules which interact with the aromatic amino acid moieties in the hydrophobic pocket. A hydrophilic region with polar groups is necessary for the polar or hydrogen bonding interactions with the amino acids or water molecules in the active site. Many FTIs have been isolated from natural products, which possessed inhibitory activity against farnesyltransferase (FTase). Among them, pepticinnamin E (9R), fusidienol (9T), gliotoxin (9V), cylindrol A (9X), etc possessed potential FTase inhibitory activities and their structural features are comparable to those of the synthetic molecules. The clinical studies progressing on FTIs showed that tipifarnib in combination with bortezomib is used for the treatment of patients with advanced acute leukemias. Successful phase I and II studies are undergoing for tipifarnib alone or in combination with other drugs/radiation for the treatment of multiple myeloma, AML, breast cancer, mantle cell lymphoma, solid tumors, non-small cell lung cancer (NSCLC), pancreatic cancer, glioblastoma, etc. Phase I pharmacokinetic (maximum tolerated dose, toxicity) and pharmacodynamic studies of AZD3409 (an orally active double prodrug) is progressing on patients with solid malignancies taking 500 mg once a day. A phase II study is undergoing on lonafarnib alone and in combination with zoledronic acid and pravastatin for the treatment of Hutchinson-Gilford Progeria syndrome (HGPS) and progeroid laminopathies. Lonafarnib therapy improved cardiovascular status of children with HGPS, by improved peripheral arterial stiffness, bone structure and audiological status in the patients. Other important FTIs such as BMS-214662, LB42908, LB42708, etc are under clinical studies for the treatment of various cancers. This review concluded that the quantitative structural analysis report with an elaborative study on the natural product compounds provides ideas for development of novel molecules for the FTase inhibitory activity. The fragment based analysis is also needed to select the substituents, which provides significant inhibitory activities and can also have good pharmacokinetic properties in the clinical studies. PMID- 24059236 TI - Chemokines and chemokine receptors blockers as new drugs for the treatment of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response of the lung to noxious particles or gases. The cellular inflammatory response in COPD is characterised by an increased number of inflammatory cells in the lungs. Although the molecular and cellular mechanisms responsible for the development of COPD are not well understood; several mediators are assumed to regulate the activation and recruitment of these inflammatory cells into the lung of COPD patients particularly those belonging to the chemokine family. Inhibitors or blockers of chemokine and chemokine receptors are therefore of great interest as potential novel therapies for COPD and many are now in clinical development. A high degree of redundancy exists in the chemokine network and inhibition of a single chemokine or receptor may not be sufficient to block the inflammatory response. Despite this, animal studies suggest a strong rationale for inhibiting the chemokine network in COPD. As such, every leading pharmaceutical company maintains a significant interest in developing agents that regulate leukocyte navigation as potential anti inflammatory drugs. Drugs and antibodies targeting chemokines and their receptors are generally still in early stages of development and the results of clinical trial are awaited with great interest. These agents may not only provide improved management of COPD but also, importantly, indicate proof-of-concept to further clarify the role of chemokines in the pathophysiology of COPD. PMID- 24059237 TI - Radiotracers for molecular imaging of cyclooxygenase-2 (COX-2) enzyme. AB - Cyclooxygenase (COX) enzyme is responsible for the formation of important biological mediators including prostaglandins, prostacyclin and thromboxane to trigger many physiological and patho-physiological responses. COXs exist in two distinct isoforms, a constitutively expressed form (COX-1) and an inducible form (COX-2). COX-2 is involved in the body's response to inflammation and pain. Moreover, it has also been shown that COX-2 is overexpressed in many human cancers, and that COX-2 is involved in various neurodegenerative diseases such as Parkinson's and Alzheimer's disease. COX-2 inhibitors are among the most widely used therapeutics for the treatment of chronic and acute pain and inflammation. Non-invasive monitoring of COX-2 functional expression by means of nuclear molecular imaging techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT) might provide unique opportunities to obtain data on COX-2 expression levels during disease manifestation and progression to study potential roles of COX-2 under various pathological conditions. The present review summarizes recent research efforts directed to the design and synthesis of radiotracers as molecular probes with special emphasis on COX-2 imaging. PMID- 24059238 TI - Interaction of small cationic peptides with intact basement membranes. A study using intrinsic optical signals of chick retinas. AB - Cationic peptides (polylysines and polyarginines) are being developed as drug delivery systems to nuclei. Therefore, a detailed description of tissue response changes upon the application of cationic peptides over intact basement membranes of excitable tissue is of interest in pharmacology. In this paper we examine the effects of two naturally occurring cationic peptides protamine (polyarginine) and crotamine (polylysine) on the optical profiles of retinal spreading depression waves (RSDs). This intrinsic optical signal (IOS), recorded non-invasively, provides information about dissipation of electrochemical gradients within the tissue and its metabolic consequences. Protamine at nanomolar range brought the tissue excitability to collapse without any signs of acute toxicity whereas crotamine, a known myotoxin from rattlesnake, decreased the tissue transparency and changed markedly the optical profiles of RSDs. Also, fluorescent crotamine was incorporated to Muller cells in a few minutes, suggesting a close membrane interaction. The optical changes brought about by crotamine were easily washed off. By contrast, the excitability collapse in presence of protamine lasted for at least two hours. CONCLUSIONS: we concluded that crotamine has fusogenic properties that alters ion transport in excitable tissue. Protamine effect seems to be similar to its effect on basement membrane of epithelium due to its property of making heteropolymers with heparan sulfate. The clinical syndrome expressed in mice after crotamine injection suggested excitotoxic CNS effects confirmed by the isolated retina experiments. PMID- 24059239 TI - Alzheimer's disease and oxidative stress: a review. AB - Alzheimer's disease (AD) is a neurodegenerative disorder with no known cure and rapid rise in incidence. The predominant cognitive impairment is currently treated using cognitive enhancers like cholinesterase inhibitors. The two molecular hallmarks of AD are amyloid plaques created from an amyloid precursor protein and hyperphosphorylated tau protein that is deposited as neurofibrillary tangles inside neurons. A number of pathological mechanisms follow or precede these formations. Alteration in mitochondrial function and deposition of heavy metals are reported. The disease progression is enhanced by oxidative stress. However, the role of oxidative stress is not universally accepted. The current review covers and discusses the basic evidence and role of oxidative stress in AD development. PMID- 24059240 TI - Isoform selective voltage-gated sodium channel modulators and the therapy of pain. AB - Voltage-gated sodium channels are large transmembrane protein complexes responsible for the propagation and transmission of electrical impulses through nerve, muscle and endocrine cells and cell systems. Dysregulated expression and/or functional changes of ion channel isoforms are found in many associated pathological conditions. In such cases, modulation of voltage gated sodium channels (Na(V) channels) is a recognised approach in medicinal chemistry. Multiple small-molecule active compounds are used for a plethora of Na(V) channel linked indications, for example epilepsy and CNS disorders, arrhythmia, stroke and pain states such as congenital analgesia/hyperalgesia and neuropathic pain. As existent Na(V) channel modulators suffer mainly from selectivity issues and thus exert significant side effects, novel and selective Na(V) channel modulators would be beneficial. Consequently, the increased research on voltage-gated sodium channels has led to a large number of novel compounds that exploit classic binding site selectivity with state-dependence or functional selectivity. Such compounds offer selective targeting and new possibilities for studying the physiology of Na(V) channels and pathophysiology of the associated ailment conditions. This review consolidates the recent literature on Na(V) 1.3, 1.7 and 1.8 channel isoform selective and/or state-dependent modulators. In particular, their structure-activity relationship is illustrated, especially in the context of selectivity on a particular isoform, and their applicability in the therapy of neuropathic pain is described. PMID- 24059241 TI - Thioflavin-S staining of bacterial inclusion bodies for the fast, simple, and inexpensive screening of amyloid aggregation inhibitors. AB - Amyloid aggregation is linked to a large number of human disorders, from neurodegenerative diseases as Alzheimer's disease (AD) or spongiform encephalopathies to non-neuropathic localized diseases as type II diabetes and cataracts. Because the formation of insoluble inclusion bodies (IBs) during recombinant protein production in bacteria has been recently shown to share mechanistic features with amyloid self-assembly, bacteria have emerged as a tool to study amyloid aggregation. Herein we present a fast, simple, inexpensive and quantitative method for the screening of potential anti-aggregating drugs. This method is based on monitoring the changes in the binding of thioflavin-S to intracellular IBs in intact Eschericchia coli cells in the presence of small chemical compounds. This in vivo technique fairly recapitulates previous in vitro data. Here we mainly use the Alzheimer's related beta-amyloid peptide as a model system, but the technique can be easily implemented for screening inhibitors relevant for other conformational diseases simply by changing the recombinant amyloid protein target. Indeed, we show that this methodology can be also applied to the evaluation of inhibitors of the aggregation of tau protein, another amyloidogenic protein with a key role in AD. PMID- 24059242 TI - Studies on Brassica carinata seed. 2. Carbohydrate molecular structure in relation to carbohydrate chemical profile, energy values, and biodegradation characteristics. AB - The objectives of this study were to investigate (1) the carbohydrate chemical profile, (2) the energy values, (3) the rumen neutral detergent fiber (NDF) degradation kinetics, (4) the carbohydrate-related functional group structural features using a Fourier transform infrared (FTIR) spectroscopic technique with attenuated total reflectance (ATR), and (5) the correlations between carbohydrate intrinsic structural features and nutritional profiles in three strains of Brassica carinata in yellow and brown seed coats, with comparison to canola seed as a reference. The results showed that yellow B. carinata strains 111000EM and AAC A100 were lower for contents of neutral detergent fiber (NDF), acid detergent fiber (ADF), acid detergent lignin (ADL), and carbohydrate (CHO) and higher for contents of total digestible nutrients (TDN), energy values, and effective degradable NDF (EDNDF) than brown-seeded 110915EM. In comparison, brown canola seed (Brassica napus L.) had more fiber content and less EDNDF. Also, carinata strains showed significantly different IR intensities in structural carbohydrate (SCHO), cellulosic compounds (CELC), and total CHO profiles. These structural variations might be one of the possible reasons for various fiber profile and biodegradation characteristics for ruminants in oilseeds. However, multivariate analyses within carbohydrate regions indicated there were still some structural relationships among the four oilseed samples. Moreover, the correlation study showed that the changes of CELC and CHO peak intensities were highly related with some changes in CHO chemical profile, energy values, and in situ NDF degradation kinetics in B. carinata and canola seeds. Further study with a large sample size is still necessary to figure out whether CHO molecular spectral information could be used to predict nutrient values and biological behavior in oilseeds. PMID- 24059243 TI - Rational design of a colorimetric pH sensor from a soluble retinoic acid chaperone. AB - Reengineering of cellular retinoic acid binding protein II (CRABPII) to be capable of binding retinal as a protonated Schiff base is described. Through rational alterations of the binding pocket, electrostatic perturbations of the embedded retinylidene chromophore that favor delocalization of the iminium charge lead to exquisite control in the regulation of chromophoric absorption properties, spanning the visible spectrum (474-640 nm). The pKa of the retinylidene protonated Schiff base was modulated from 2.4 to 8.1, giving rise to a set of proteins of varying colors and pH sensitivities. These proteins were used to demonstrate a concentration-independent, ratiometric pH sensor. PMID- 24059245 TI - Engineering of monodisperse mesoporous titania beads for photocatalytic applications. AB - The properties of monodisperse mesoporous TiO2 beads were readily tuned by varying the temperature (500-800 degrees C) and time (2-24 h) of calcination for solvothermally treated hexadecylamine/TiO2 hybrid assemblies. The crystal properties (crystal phase, crystallite size, and crystallinity), surface and pore properties (surface hydroxyl groups, surface area, porosity, and pore size), and diameter of the beads were significantly altered with these changes in calcination conditions. These properties played an important role in determining the photocatalytic activity of the materials, which was assessed by monitoring the photodegradation of a methylene blue solution under ultraviolet light. The maximum activity was achieved with the materials that were calcined at 650 degrees C for 2-8 h with a bead diameter around 700 nm. High activity was attributed to the balance of high crystallinty of the anatase phase, high porosity and large surface area. The size of the beads made separation easy for the reuse of the material after reaction. The synthesis-properties-photocatalytic activity relationships of these monodisperse mesoporous TiO2 beads have been established. PMID- 24059244 TI - Integrated genomic analysis of triple-negative breast cancers reveals novel microRNAs associated with clinical and molecular phenotypes and sheds light on the pathways they control. AB - BACKGROUND: This study focuses on the analysis of miRNAs expression data in a cohort of 181 well characterised breast cancer samples composed primarily of triple-negative (ER/PR/HER2-negative) tumours with associated genome-wide DNA and mRNA data, extensive patient follow-up and pathological information. RESULTS: We identified 7 miRNAs associated with prognosis in the triple-negative tumours and an additional 7 when the analysis was extended to the set of all ER-negative cases. miRNAs linked to an unfavourable prognosis were associated with a broad spectrum of motility mechanisms involved in the invasion of stromal tissues, such as cell-adhesion, growth factor-mediated signalling pathways, interaction with the extracellular matrix and cytoskeleton remodelling. When we compared different intrinsic molecular subtypes we found 46 miRNAs that were specifically expressed in one or more intrinsic subtypes. Integrated genomic analyses indicated these miRNAs to be influenced by DNA genomic aberrations and to have an overall influence on the expression levels of their predicted targets. Among others, our analyses highlighted the role of miR-17-92 and miR-106b-25, two polycistronic miRNA clusters with known oncogenic functions. We showed that their basal-like subtype specific up-regulation is influenced by increased DNA copy number and contributes to the transcriptional phenotype as well as the activation of oncogenic pathways in basal-like tumours. CONCLUSIONS: This study analyses previously unreported miRNA, mRNA and DNA data and integrates these with pathological and clinical information, from a well-annotated cohort of breast cancers enriched for triple-negative subtypes. It provides a conceptual framework, as well as integrative methods and system-level results and contributes to elucidate the role of miRNAs as biomarkers and modulators of oncogenic processes in these types of tumours. PMID- 24059246 TI - Influence of endothelin-1 and nitric oxide on left ventricular remodelling in patients on peritoneal dialysis. AB - BACKGROUND: Left ventricular hypertrophy is the most common structural cardiac alteration in chronic dialysis patients. The aim of this study was to determine the possible association of endotelin-1 (ET-1) and nitric oxide (NO) with parameters of echocardiography in order to assess their participation in left ventricular (LV) remodeling in patients on peritoneal dialysis (PD). METHODS: This prospective longitudinal study included 40 PD patients. Serum levels of ET-1 and NO baseline and after 12 months of PD treatment were measured and compared with echocardiography parameters done at the same time of PD treatment. Linear regression analysis was used to detect independent correlations of variables. RESULTS: Mean ET-1 serum concentration decreased significantly after 12 months of PD treatment compared to baseline values (p < 0.01). NO serum concentration increased significantly 12 months after treatment compared to baseline values (p < 0.01). Left ventricular hypertrophy (LVH) was observed in 72.5% of patients at baseline with significant reduction in LV mass index after 12 months of PD treatment (p < 0.001). On linear regression analysis serum concentration of ET-1 was independent predictors of LV mass index, as well as NO at the end of observed period. CONCLUSIONS: According to our data ET-1 and NO are independently related to the process of left ventricular remodeling in PD patients. PMID- 24059247 TI - Multivariate matching pursuit in optimal Gabor dictionaries: theory and software with interface for EEG/MEG via Svarog. AB - BACKGROUND: Matching pursuit algorithm (MP), especially with recent multivariate extensions, offers unique advantages in analysis of EEG and MEG. METHODS: We propose a novel construction of an optimal Gabor dictionary, based upon the metrics introduced in this paper. We implement this construction in a freely available software for MP decomposition of multivariate time series, with a user friendly interface via the Svarog package (Signal Viewer, Analyzer and Recorder On GPL, http://braintech.pl/svarog), and provide a hands-on introduction to its application to EEG. Finally, we describe numerical and mathematical optimizations used in this implementation. RESULTS: Optimal Gabor dictionaries, based on the metric introduced in this paper, for the first time allowed for a priori assessment of maximum one-step error of the MP algorithm. Variants of multivariate MP, implemented in the accompanying software, are organized according to the mathematical properties of the algorithms, relevant in the light of EEG/MEG analysis. Some of these variants have been successfully applied to both multichannel and multitrial EEG and MEG in previous studies, improving preprocessing for EEG/MEG inverse solutions and parameterization of evoked potentials in single trials; we mention also ongoing work and possible novel applications. CONCLUSIONS: Mathematical results presented in this paper improve our understanding of the basics of the MP algorithm. Simple introduction of its properties and advantages, together with the accompanying stable and user friendly Open Source software package, pave the way for a widespread and reproducible analysis of multivariate EEG and MEG time series and novel applications, while retaining a high degree of compatibility with the traditional, visual analysis of EEG. PMID- 24059248 TI - Additional role of second washing specimen obtained during single bronchoscopy session in diagnosis of pulmonary tuberculosis. AB - BACKGROUND: Flexible bronchoscopy with bronchial washing is a useful procedure for diagnosis of pulmonary tuberculosis (TB), when a patient cannot produce sputum spontaneously or when sputum smears are negative. However, the benefit of gaining serial bronchial washing specimens for diagnosis of TB has not yet been studied. Therefore, we conducted a retrospective study to determine the diagnostic utility of additional bronchial washing specimens for the diagnosis of pulmonary TB in suspected patients. METHODS: A retrospective analysis was performed on 174 patients [sputum smear-negative, n = 95 (55%); lack of sputum specimen, n = 79 (45%)] who received flexible bronchoscopy with two bronchial washing specimens with microbiological confirmation of pulmonary TB in Samsung Medical Center, between January, 2010 and December, 2011. RESULTS: Pulmonary TB was diagnosed by first bronchial washing specimen in 141 patients (81%) out of 174 enrolled patients, and an additional bronchial washing specimen established diagnosis exclusively in 22 (13%) patients. Smear for acid-fast bacilli (AFB) was positive in 46 patients (26%) for the first bronchial washing specimen. Thirteen patients (7%) were positive only on smear of an additional bronchial washing specimen. Combined smear positivity of the first and second bronchial washing specimens was significantly higher compared to first bronchial washing specimen alone [Total cases: 59 (34%) vs. 46 (26%), p < 0.001; cases for smear negative sputum: 25 (26%) vs. 18 (19%), p = 0.016; cases for poor expectoration: 34 (43%) vs. 28 (35%), p = 0.031]. The diagnostic yield determined by culture was also significantly higher in combination of the first and second bronchial washing specimens compared to the first bronchial washing. [Total cases: 163 (94%) vs. 141 (81%), p < 0.001; cases for smear negative sputum: 86 (91%) vs. 73 (77%), p < 0.001; cases for poor expectoration: 77 (98%) vs. 68 (86%), p = 0.004]. CONCLUSIONS: Obtaining an additional bronchial washing specimen could be a beneficial and considerable option for diagnosis of TB in patients with smear negative sputum or who cannot produce sputum samples. PMID- 24059249 TI - Self-assembly of KxWO3 nanowires into nanosheets by an oriented attachment mechanism. AB - The KxWO3 nanosheets consisting of superfine nanowires were successfully synthesized in ambient air. The detailed electron microscopy and X-ray diffraction investigations imply that the nanosheets were obtained by self assembly of the ordered nanowires with exposed {0110}H facets. The sheet morphology is closely related with the growth conditions including temperature and time, etc. A possible mechanism based on the oriented attachment of neighboring nanowires for the formation of nanosheets is proposed. Our results shed light on the interfacial characteristics of self-assembled KxWO3 nanowires and can serve as guidance to the future design of relevant two-dimensional structures for various electrical and optical applications. PMID- 24059250 TI - Assessing and presenting summaries of evidence in Cochrane Reviews. AB - Cochrane Reviews are intended to help providers, practitioners and patients make informed decisions about health care. The goal of the Cochrane Applicability and Recommendation Methods Group (ARMG) is to develop approaches, strategies and guidance that facilitate the uptake of information from Cochrane Reviews and their use by a wide audience with specific focus on developers of recommendations and on healthcare decision makers. This paper is part of a series highlighting developments in systematic review methodology in the 20 years since the establishment of The Cochrane Collaboration, and its aim is to present current work and highlight future developments in assessing and presenting summaries of evidence, with special focus on Summary of Findings (SoF) tables and Plain Language Summaries.A SoF table provides a concise and transparent summary of the key findings of a review in a tabular format. Several studies have shown that SoF tables improve accessibility and understanding of Cochrane Reviews.The ARMG and GRADE Working Group are working on further development of the SoF tables, for example by evaluating the degree of acceptable flexibility beyond standard presentation of SoF tables, developing SoF tables for diagnostic test accuracy reviews and interactive SoF tables (iSoF).The plain language summary (PLS) is the other main building block for dissemination of review results to end-users. The PLS aims to summarize the results of a review in such a way that health care consumers can readily understand them. Current efforts include the development of a standardized language to describe statistical results, based on effect size and quality of supporting evidence.Producing high quality PLS and SoF tables and making them compatible and linked would make it easier to produce dissemination products targeting different audiences (for example, providers, health policy makers, guideline developers).Current issues of debate include optimal presentation formats of SoF tables, the training required to produce SoF tables, and the extent to which the authors of Cochrane Reviews should provide explicit guidance to target audiences of patients, clinicians and policy-makers. PMID- 24059251 TI - Carbon monoxide exposures in New York City following Hurricane Sandy in 2012. AB - CONTEXT: On October 29, 2012, Hurricane Sandy made landfall and devastated New York's metropolitan area, causing widespread damage to homes and the utility infrastructure. Eight days later, snow and freezing temperatures from a nor'easter storm delayed utility restoration. OBJECTIVE: To examine carbon monoxide (CO) exposures in the 2 weeks following Hurricane Sandy. Methods. This was a retrospective review of prospectively collected, standardized, and de identified data sets. CO exposures and poisonings identified from two electronic surveillance systems, the New York City Poison Control Center (NYCPCC) and New York City's Syndromic Surveillance Unit, were compared with CO exposures from identical dates in 2008-2011. Data collected from the poison center included exposure type, CO source, poisoning type, treatment, and outcomes. Data collected from the Syndromic Surveillance Unit cases, which were identified by CO-related chief complaints presenting to NYC hospitals, included visit date and time, and patient demographics. RESULTS: Four hundred thirty-seven CO exposures were reported to the NYCPCC, 355 from NYC callers, and the remainder from surrounding counties, which represented a significant increase when compared with CO exposures from identical dates in the preceding 4 years (p < 0.001). The total cases that were reported to the NYCPCC in 2008, 2009, 2010, and 2011 were 18, 13, 24, and 61, respectively. Excluding a single apartment fire that occurred (n = 311), the more common sources of CO were grilling indoors (26.2%) and generators (17.5%). Syndromic surveillance captured 70 cases; 6 cases were captured by both data sets. CONCLUSIONS: CO exposures following weather-related disasters are a significant public health concern, and the use of fuel-burning equipment is a clear source of storm-related morbidity and mortality. Multiple real-time epidemiologic surveillance tools are useful in estimating the prevalence of CO exposure and poisoning and are necessary to assist public health efforts to prevent CO poisoning during and after disasters. PMID- 24059252 TI - Racial/ethnic minority and low-income hotspots and their geographic proximity to integrated care providers. AB - BACKGROUND: The high prevalence of mental health issues among clients attending substance abuse treatment (SAT) has pressured treatment providers to develop integrated substance abuse and mental health care. However, access to integrated care is limited to certain communities. Racial and ethnic minority and low-income communities may not have access to needed integrated care in large urban areas. Because the main principle of health care reform is to expand health insurance to low-income individuals to improve access to care and reduce health disparities among minorities, it is necessary to understand the extent to which integrated care is geographically accessible in minority and low-income communities. METHODS: National Survey of Substance Abuse Treatment Services data from 2010 were used to examine geographic availability of facilities offering integration of mental health services in SAT programs in Los Angeles County, California. Using geographic information systems (GIS), service areas were constructed for each facility (N = 402 facilities; 104 offering integrated services) representing the surrounding area within a 10-minute drive. Spatial autocorrelation analyses were used to derive hot spots (or clusters) of census tracts with high concentrations of African American, Asian, Latino, and low-income households. Access to integrated care was reflected by the hot spot coverage of each facility, i.e., the proportion of its service area that overlapped with each type of hot spot. RESULTS: GIS analysis suggested that ethnic and low-income communities have limited access to facilities offering integrated care; only one fourth of SAT providers offered integrated care. Regression analysis showed facilities whose service areas overlapped more with Latino hot spots were less likely to offer integrated care, as well as a potential interaction effect between Latino and high-poverty hot spots. CONCLUSION: Despite significant pressure to enhance access to integrated services, ethnic and racial minority communities are disadvantaged in terms of proximity to this type of care. These findings can inform health care policy to increase geographic access to integrated care for the increasing number of clients with public health insurance. PMID- 24059253 TI - The contribution of moral disengagement in mediating individual tendencies toward aggression and violence. AB - This study examines the role of moral disengagement in fostering engagement in aggression and violence through adolescence to young adulthood in accordance with a design in which the study of individual differences and of their relations is instrumental to address underlying intraindividual structures and process conducive to detrimental conduct. Participants were 345 young adults (52% females) who were followed across 4 time periods (T1 M age = 17 years to T4 M age = 25 years). The longitudinal relations among irritability, hostile rumination, and moral disengagement attest to a conceptual model in which moral disengagement is crucial in giving access to action to aggressive tendencies. Findings suggest that irritability and hostile rumination contributed to the development of each other reciprocally and significantly across time. While hostile rumination and moral disengagement significantly mediated the relation between irritability and violence, moral disengagement significantly mediated the relation between hostile rumination and violence. PMID- 24059254 TI - Benefits of training visuospatial working memory in young-old and old-old. AB - The purpose of the present study was to test the efficacy of a visuospatial working memory (WM) training in terms of its transfer effects and maintenance effects, in the young-old and old-old. Forty young-old and 40 old-old adults took part in the study. Twenty participants in each age group received training with a visuospatial WM task, whereas the others served as active controls and completed alternative activities. Training benefits were examined, considering (a) the specific training-related gains in a visuospatial WM task (criterion); and (b) the transfer effects on measures of verbal WM, visuospatial short-term memory, inhibition, processing speed, and reasoning. Maintenance of training benefits was also assessed after 8 months. Results showed that the trained groups (both young old and old-old), but not the control groups, performed better in the WM measures and preserved these gains after 8 months. Some transfer effects were found, but only in the young-old-trained participants, and they were not maintained at the follow-up. These results are discussed in terms of the efficacy of WM training for older adults when a visuospatial modality is used. PMID- 24059255 TI - Executed and imagined bimanual movements: a study across different ages. AB - Movements with both hands are essential to our everyday life, and it has been shown that performing asymmetric bimanual movements produces an interference effect between hands. There have been many studies--using varying methods- investigating the development of bimanual movements that show that this skill continues to evolve during childhood and adolescence. In the current study we used a spatial bimanual task to delineate the development of bimanual movements not only during different stages of childhood but also during late stages of adulthood. Furthermore, we used the same task as a window to observe the involvement of motor imagery through the same age groups. For this study we recruited participants from 4 different age groups and asked them to perform congruent and noncongruent bimanual movements in a Real condition, where participants moved both hands, and in an Imagery condition, where they had to imagine 1 hand's movements while actually using the other hand. Our results showed that, with actual movement execution, the interference between motor programs of the 2 hands is higher in children (6-10 years old) than in younger adults (20-30 years old), while it tends to increase again in the elderly adults (60-80 years old). Interestingly, in the Imagery condition, the interference was present only among 10-year-old and 20- to 30-year-old participants, suggesting that motor imagery, not yet developed in young children and compromised by age in the elderly subjects, did not modulate motor performance in these last 2 groups. PMID- 24059256 TI - Age-related differences in altruism across adulthood: making personal financial gain versus contributing to the public good. AB - Four studies utilizing different methodological approaches investigated adult age related differences in altruism (i.e., contributions to the public good) and the self-centered value of increasing personal wealth. In Study 1, data from the World Values Survey (World Values Survey Association, 2009) provided 1st evidence of a negative association between age and the self-reported wish to be rich. Ecological concerns, a form of contributing to the public good, were positively related to age. Study 2 investigated whether these values are expressed behaviorally when participants solved a complex problem that allowed striving for monetary gains or contributing to a public good. Confirming hypotheses, young adults' strategies were consistent with the aim of optimizing personal financial gain, and older adults' strategies with the aim to contribute to the public good. Studies 3 and 4 showed that older adults were more likely than younger and middle aged adults to donate money to a good cause than to keep it for themselves. Study 4 manipulated participants' future time perspective as a factor potentially contributing to age-related differences. Partly confirming hypotheses, a longer time perspective reduced donations by older adults, but a shorter time perspective did not increase donations by younger adults. These studies suggest that older adults not only report valuing contributions to the public good more highly but also are more likely to behave altruistically than younger adults. All studies used cross-sectional designs that prevent a strict test of developmental trajectories but rather provide age-related differences at 1 point in time, representing a 1st step in investigating adult age-related differences in altruism. PMID- 24059257 TI - Does a risky outcome of antenatal screening test indicate oxidative stress? AB - OBJECTIVE: The study aimed to investigate a possible relationship between second trimester aneuploidiy screening results and oxidative stress in foetal amnion and maternal serum. METHODS: Concerning the outcome of the second-trimester screening test, 50 pregnant women of high risk were included in the experimental group, whereas 50 pregnant women with normal scores who wished to proceed with the amniocentesis procedure due to advanced maternal age and counselling were included in the control group. The biochemical parameters of total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) were measured in the amniotic fluid samples and maternal serum samples. RESULTS: OSI in the maternal serum samples, as well as TAS and TOS in the amniotic fluid, was significantly higher in the control group compared to the experimental group (p < 0.001, p = 0.047, p = 0.005, respectively). There was no significant difference in the TAS and TOS in the maternal serum samples or the OSI in the amniotic fluid between the groups. CONCLUSIONS: The results indicate that the positivity of the screening test is not significantly correlated with oxidative stress, a factor regarded as a pathological mechanism in various diseases. Potential maternal anxiety could underlie the elevated oxidative stress in the control group. PMID- 24059258 TI - Zinc coordination spheres in protein structures. AB - Zinc metalloproteins are one of the most abundant and structurally diverse proteins in nature. In these proteins, the Zn(II) ion possesses a multifunctional role as it stabilizes the fold of small zinc fingers, catalyzes essential reactions in enzymes of all six classes, or assists in the formation of biological oligomers. Previously, a number of database surveys have been conducted on zinc proteins to gain broader insights into their rich coordination chemistry. However, many of these surveys suffer from severe flaws and misinterpretations or are otherwise limited. To provide a more comprehensive, up to-date picture on zinc coordination environments in proteins, zinc containing protein structures deposited in the Protein Data Bank (PDB) were analyzed in detail. A statistical analysis in terms of zinc coordinating amino acids, metal to-ligand bond lengths, coordination number, and structural classification was performed, revealing coordination spheres from classical tetrahedral cysteine/histidine binding sites to more complex binuclear sites with carboxylated lysine residues. According to the results, coordination spheres of hundreds of crystal structures in the PDB could be misinterpreted due to symmetry related molecules or missing electron densities for ligands. The analysis also revealed increasing average metal-to-ligand bond length as a function of crystallographic resolution, which should be taken into account when interrogating metal ion binding sites. Moreover, one-third of the zinc ions present in crystal structures are artifacts, merely aiding crystal formation and packing with no biological significance. Our analysis provides solid evidence that a minimal stable zinc coordination sphere is made up by four ligands and adopts a tetrahedral coordination geometry. PMID- 24059259 TI - The nature of verbal memory impairment in multiple sclerosis: a list-learning and meta-analytic study. AB - The primary purpose of this study was to test the hypothesis that multiple sclerosis (MS) patients have impaired acquisition rather than a retrieval deficit. Verbal memory impairment in MS was examined in 53 relapsing-remitting MS patients and 31 healthy controls (HC), and in a meta-analysis of studies that examined memory functioning in MS with list-learning tasks. The MS group demonstrated significantly lower acquisition and delayed recall performance than the HC group, and the meta-analysis revealed that the largest effect sizes were obtained for acquisition measures relative to delayed recall and recognition. Our data argue against a retrieval deficit as the sole explanation for verbal memory impairment in MS, and make a consistent case for the position that deficient acquisition contributes to the memory dysfunction of MS patients. Deficient acquisition may result from demyelination in relevant white matter tracts that reduces encoding efficiency as a result of impaired speed of information processing. PMID- 24059262 TI - Identification of autoantigens in body fluids by combining pull-downs and organic precipitations of intact immune complexes with quantitative label-free mass spectrometry. AB - Most autoimmune diseases are multifactorial diseases and are caused by the immunological reaction against a number of autoantigens. Key for understanding autoimmune pathologies is the knowledge of the targeted autoantigens, both initially and during disease progression. We present an approach for autoantigen identification based on isolation of intact autoantibody-antigen complexes from body fluids. After organic precipitation of high molecular weight proteins and free immunoglobulins, released autoantigens were identified by quantitative label free liquid chromatography mass spectrometry. We confirmed feasibility of target enrichment and identification from highly complex body fluid proteomes by spiking of a predefined antibody-antigen complex at low level of abundance. As a proof of principle, we studied the blinding disease autoimmune uveitis, which is caused by autoreactive T-cells attacking the inner eye and is accompanied by autoantibodies. We identified three novel autoantigens in the spontaneous animal model equine recurrent uveitis (secreted acidic phosphoprotein osteopontin, extracellular matrix protein 1, and metalloproteinase inhibitor 2) and confirmed the presence of the corresponding autoantibodies in 15-25% of patient samples by enzyme-linked immunosorbent assay. Thus, this workflow led to the identification of novel autoantigens in autoimmune uveitis and may provide a versatile and useful tool to identify autoantigens in other autoimmune diseases in the future. PMID- 24059263 TI - Effect of mold treatment by solvent on PDMS molding into nanoholes. AB - Polydimethylsiloxane (PDMS) is the most popular and versatile material for soft lithography due to its flexibility and easy fabrication by molding process. However, for nanoscale patterns, it is challenging to fill uncured PDMS into the holes or trenches on the master mold that is coated with a silane anti-adhesion layer needed for clean demolding. PDMS filling was previously found to be facilitated by diluting it with toluene or hexane, which was attributed to the great reduction of viscosity for diluted PDMS. Here, we suggest that the reason behind the improved filling for diluted PDMS is that the diluent solvent increases in situ the surface energy of the silane-treated mold and thus the wetting of PDMS to the mold surface. We treated the master mold surface (that was already coated with a silane anti-adhesion monolayer) with toluene or hexane, and found that the filling by undiluted PMDS into the nanoscale holes on the master mold was improved despite the high viscosity of the undiluted PDMS. A simple estimation based on capillary filing into a channel also gives a filling time on the millisecond scale, which implies that the viscosity of PMDS should not be the limiting factor. We achieved a hole filling down to sub-200-nm diameter that is smaller than those of the previous studies using regular Sylgard PDMS (not hard PDMS, Dow Corning Corporation, Midland, MI, USA). However, we are not able to explain using a simple argument based on wetting property why smaller, e.g., sub 100-nm holes, cannot be filled, for which we suggested a few possible factors for its explanation. PMID- 24059264 TI - Genetic diversity in black South Africans from Soweto. AB - BACKGROUND: Due to the unparalleled genetic diversity of its peoples, Africa is attracting growing research attention. Several African populations have been assessed in global initiatives such as the International HapMap and 1000 Genomes Projects. Notably excluded, however, is the southern Africa region, which is inhabited predominantly by southeastern Bantu-speakers, currently suffering under the dual burden of infectious and non-communicable diseases. Limited reference data for these individuals hampers medical research and prevents thorough understanding of the underlying population substructure. Here, we present the most detailed exploration, to date, of genetic diversity in 94 unrelated southeastern Bantu-speaking South Africans, resident in urban Soweto (Johannesburg). RESULTS: Participants were typed for ~4.3 million SNPs using the Illumina Omni5 beadchip. PCA and ADMIXTURE plots were used to compare the observed variation with that seen in selected populations worldwide. Results indicated that Sowetans, and other southeastern Bantu-speakers, are a clearly distinct group from other African populations previously investigated, reflecting a unique genetic history with small, but significant contributions from diverse sources. To assess the suitability of our sample as representative of Sowetans, we compared our results to participants in a larger rheumatoid arthritis case control study. The control group showed good clustering with our sample, but among the cases were individuals who demonstrated notable admixture. CONCLUSIONS: Sowetan population structure appears unique compared to other black Africans, and may have clinical implications. Our data represent a suitable reference set for southeastern Bantu-speakers, on par with a HapMap type reference population, and constitute a prelude to the Southern African Human Genome Programme. PMID- 24059265 TI - Detecting chronotype differences associated to latitude: a comparison between Horne--Ostberg and Munich Chronotype questionnaires. AB - BACKGROUND: Chronotype, phase preference to perform activities during a 24-hour day, represents distinct circadian temporal organization of living organisms. Morning and evening types can be identified by questionnaires such as Horne and Ostberg (HO) and Munich Chronotype Questionnaire (MCTQ). Environmental factors, such as different light-dark cycles experienced at different latitudes, interact with the organisms' circadian timekeeping system. Therefore, chronotype is expected to vary as a result of different geographical locations. AIM: To identify differences in chronotype distribution in populations of two Brazilian cities, Natal and Sao Paulo, located at different latitudes. SUBJECTS AND METHODS: Two specific questionnaires, the Horne and Ostberg Questionnaire (HO) and the Munich Chronotype Questionnaire (MCTQ), were used to identify chronotypes of undergraduate students from Sao Paulo and Natal. RESULTS: The comparison of the curve distributions of HO and MCTQ scores between both cities allowed one to observe that, while HO curves of Sao Paulo and Natal overlapped, MCTQ curves showed a clear shift towards eveningness in Sao Paulo. CONCLUSION: This experiment confirmed results from previous studies that the farther away from the equator, the longer the delay of the sleep phase. It was also concluded that MCTQ is better at detecting this phenomenon. PMID- 24059266 TI - Anti-HIV-1 activity, protease inhibition and safety profile of extracts prepared from Rhus parviflora. AB - BACKGROUND: In the present study, extracts prepared from the leaves of Rhus parviflora Roxb. (Anacardiaceae) were evaluated for their anti-HIV activity, which have been traditionally used for the treatment of neurological disorders such as anxiety, insomnia and epilepsy. METHODS: Aqueous and 50% ethanolic extracts prepared from leaves of the plant were tested for their cytotoxicity and anti-HIV property using reporter gene based assays as well as human peripheral blood lymphocytes (PBLs). Further these extracts were evaluated for their ability to inhibit HIV-1 reverse transcriptase (RT) and protease activity. Safety profile of the extracts was determined on viability of Lactobacillus sp., secretion of pro-inflammatory cytokines by vaginal keratinocytes and transepithelial resistance. RESULTS: Both aqueous (IC50 = 15 MUg/ml) and 50% ethanolic (IC50 = 26 MUg/ml) extracts prepared from leaves of R. parviflora showed anti-HIV activity in TZM-bl cells wherein the virus was treated with the extracts prior to infection. Further, both the extracts also inhibited virus load in HIV infected CEM-GFP cells and human PBLs. The anti-HIV activity is mediated through inhibition of HIV-1 protease activity. Both the extracts did not disturb the integrity of monolayer formed by intestinal epithelial Caco-2 cells. The extracts when tested up to 100 MUg/ml did not significantly reduce the viability of L. plantarum, L. fermentum, L. rhamnosus and L. casei. The extracts (100 MUg/ml) did not reveal any cytotoxic effect on vaginal keratinocytes (Vk2/E6E7). Levels of pro-inflammatory cytokines secreted by Vk2/E6E7 cells treated with both the plant extracts were within the non-inflammatory range. CONCLUSIONS: The studies reported herein showed in vitro anti-HIV activity and preliminary safety profile of the extracts prepared from the leaves of R. parviflora. PMID- 24059267 TI - Detection of the V1016G mutation in the voltage-gated sodium channel gene of Aedes aegypti (Diptera: Culicidae) by allele-specific PCR assay, and its distribution and effect on deltamethrin resistance in Thailand. AB - BACKGROUND: Resistance to pyrethroid insecticides is widespread among populations of Aedes aegypti, the main vector for the dengue virus. Several different point mutations within the voltage-gated sodium channel (VGSC) gene contribute to such resistance. A mutation at position 1016 in domain II, segment 6 of the VGSC gene in Ae. aegypti leads to a valine to glycine substitution (V1016G) that confers resistance to deltamethrin. METHODS: This study developed and utilized an allele specific PCR (AS-PCR) assay that could be used to detect the V1016G mutation. The assay was validated against a number of sequenced DNA samples of known genotype and was determined to be in complete agreement. Larvae and pupae were collected from various localities throughout Thailand. Samples were reared to adulthood and their resistance status against deltamethrin was determined by standard WHO susceptibility bioassays. Deltamethrin-resistant and susceptible insects were then genotyped for the V1016G mutation. Additionally, some samples were genotyped for a second mutation at position 1534 in domain III (F1534C) which is also known to confer pyrethroid resistance. RESULTS: The bioassay results revealed an overall mortality of 77.6%. Homozygous 1016G individuals survived at higher rates than either heterozygous or wild-type (1016 V) mosquitoes. The 1016G mutation was significantly and positively associated with deltamethrin resistance and was widely distributed throughout Thailand. Interestingly, wild-type 1016 V mosquitoes tested were homozygous for the 1534C mutation, and all heterozygous mosquitoes were also heterozygous for 1534C. Mutant homozygous (G/G) mosquitoes expressed the wild-type (F/F) at position 1534. However, the presence of the 1534C mutation was not associated with deltamethrin resistance. CONCLUSIONS: Our bioassay results indicate that all populations sampled display some degree of resistance to deltamethrin. Homozygous 1016G mosquitoes were far likelier to survive such exposure. However, resistance in some populations cannot be explained due to kdr mutations and indicates that other resistance mechanisms are operating. The presence of this mutation alone does not fully explain the resistance phenotype we see among Thai Ae. aegypti populations. PMID- 24059268 TI - Dual lipidation of the brain-specific Cdc42 isoform regulates its functional properties. AB - Cdc42 (cell division cycle 42) is a member of the Rho GTPase family which regulates a variety of cellular activities by controlling actin cytoskeleton and gene expression. Cdc42 is expressed in the form of two splice variants. The canonical Cdc42 isoform is prenylated (Cdc42-prenyl), whereas the brainspecific isoform can be palmitoylated (Cdc42-palm). In the present study we have demonstrated palmitoylation of endogenous Cdc42 in rodent and human brains and identified Cys(188) and Cys(189) as acylation sites of Cdc42-palm. Moreover, we have shown that Cys(188) can also be prenylated. Analysis of acylation-deficient mutants revealed that lipidation of Cys(188) is essential for proper membrane binding of Cdc42-palm as well as for Cdc42-mediated regulation of gene transcription and induction of densely packed filopodia in neuroblastoma cells. We also found that Cdc42-prenyl is a dominant splice variant in a wide range of commonly used cell lines as well as in the cerebellum, whereas Cdc42-palm is the main Cdc42 isoform in hippocampus, where it is critically involved in the formation of dendritic filopodia and spines. Replacement of endogenous Cdc42 by its acylation-deficient mutants revealed the importance of Cdc42-palm lipidation for its morphogenic and synaptogenic effects in neurons. These findings demonstrate that dual lipidation of Cdc42-palm represents an important regulator of morphogenic signalling in hippocampal neurons. PMID- 24059269 TI - First-principles molecular dynamics simulation of atmospherically relevant anion solvation in supercooled water droplet. AB - We present a comprehensive first-principles Born-Oppenheimer molecular dynamics (BOMD) simulation study of halide anion solvation in a deeply supercooled water droplet (with diameter ~1.8 nm). We show that larger halide anions Br(-) and I(-) show "outer-layer surface preference", whereas F(-) exhibits bulk preference. Contrary to behavior of other halide anions, Cl(-) in the water droplet appears to exhibit no strong tendency of surface or bulk preference at either the supercooled or ambient condition, a phenomenon not previously reported in the literature. BOMD simulation indicates that fully hydrated complex of F(-) is mainly five-fold coordinated (showing square pyramid structure), whereas Cl(-), Br(-) and I(-) hydrated complexes are either five- or six-fold coordinated (showing sandwich-like structure). Among Cl(-), Br(-) and I(-) anions, BOMD simulation indicates that I(-) exhibits the largest diffusion coefficient despite its largest size. However, computed resident time of the four halide ions suggests that Br(-) can approach from the interior to the surface of the water droplet at a much faster rate than I(-) and Cl(-). PMID- 24059270 TI - Cost-effectiveness analysis of scalp cooling to reduce chemotherapy-induced alopecia. AB - BACKGROUND: Alopecia is a frequently occurring side effect of chemotherapy that often can be prevented by cooling the scalp during the infusion. This study compared effects and costs of scalp cooling with usual general oncological care, i.e. purchasing a wig or head cover. MATERIAL AND METHODS: Scalp-cooled patients (n = 160) were compared with non-scalp-cooled patients (n = 86) at 15 Dutch hospitals. Patients were enrolled prior to anthracycline and/or taxane-based chemotherapy for several types of cancer between 2007 and 2008. Cost effectiveness of scalp cooling compared with that of usual care was determined by the ratio of costs to quality adjusted life years (QALYs). Costs for scalp cooling (machines and nursing time), hair dressers, wigs and head covers were estimated from a societal perspective. QALYs were measured using the Short Form 36. RESULTS: Scalp cooling reduced the use of a wig or head cover by 40%, but wigs were still purchased unnecessarily by 38% of scalp-cooled patients. Average societal costs decreased therefore only by ?269 per patient due to scalp cooling (p = 0.02). Given the eligibility for scalp cooling at the time, the insignificant difference in QALYs resulted from a balance of the benefits for those patients with successful scalp cooling and those without success. For the Dutch, given the generally accepted threshold of willingness to pay for a QALY (between ?20 000 and ?40 000), scalp cooling was cost-effective, therefore justifying the choice of scalp cooling or purchasing a wig or head cover. CONCLUSION: Given the right indication, cost-effectiveness might be improved further by postponing wig and head cover purchases, by improving scalp cooling efficacy, as well as using the scalp cooling capacity more intensively. PMID- 24059271 TI - Normobaric hyperoxia preconditioning ameliorates cisplatin nephrotoxicity. AB - BACKGROUND: Cisplatin is a potent anticancer drug, but its nephrotoxicity limits the clinical use of it. To reduce the Cisplatin-induced nephrotoxicity, various interventions have been implicated. The aim of this study was to examine whether preconditioning with normobaric hyperoxia would prevent Cisplatin-induced nephrotoxicity in patient with solid tumor. METHODS: In a prospective study, 80 adult patients with solid tumor who were treated with Cisplatin between February 2011 and December 2011 were included. Forty-three patients were exposed to pure oxygen via non-rebreathing reservoir mask which increased the provided oxygen rate to 60% oxygen for 2 hours at 48, 24, and 6 hours before intravenous administration of Cisplatin and 37 patients received only Cisplatin as a control group. Estimated glomerular filtration rate (eGFR) calculated in all patients on day 1 before and on days 1, 3, 6, 30 after Cisplatin exposures. RESULTS: Patients treated with Cisplatin and 60% oxygen showed a mild improvement in eGFR and mild reduction of serum creatinine after 30 days with statistically mild significant differences (p = 0.048). CONCLUSION: This study showed that normobaric and intermittent precondition of 60% oxygen prior to Cisplatin treatment had an acute transient adverse effect on renal function; however, the improvement of renal function will be seen after 30 days. Thus, it may help to prevent Cisplatin nephrotoxicity. PMID- 24059272 TI - Transporting integrated primary care to the private sector: addressing the business challenges. AB - The primary care literature provides some useful information and several project examples for clinicians attempting to develop an integrated care practice, but prior discussion has been based largely on projects developed in government funded or HMO systems. The current paper focuses on the business challenges of establishing an integrated care practice in a private, fee-for-service setting. Despite increasing commitment to the concept of the medical home, which embraces behavioral health care, physicians in the private sector remain cautious about proposed practice changes such as integrated care. There are additional obstacles that can impede successful implementation of integrated primary care in the private sector. The authors identify five major challenges and suggest potential strategies to address these challenges, drawing, in part, on their experience with a 4-year integrated primary care demonstration project. PMID- 24059273 TI - E-Health innovations, collaboration, and healthcare disparities: developing criteria for culturally competent evaluation. AB - E-Health alters how health care clinicians, institutions, patients, caregivers, families, advocates, and researchers collaborate. Few guidelines exist to evaluate the impact of social technologies on furthering family health and even less on their capacity to ameliorate health disparities. Health social media tools that help develop, sustain, and strengthen the collaborative health agenda may prove useful to ameliorate health care inequities; the linkage should not, however, be taken for granted. In this article we propose a classification of emerging social technologies in health care with the purpose of developing evaluative criteria that assess their ability to foster collaboration and positively impact health care equity. The findings are based on systematic Internet ethnographic observations, a qualitative analysis of e-health tool exemplars, and a review of the literature. To triangulate data collection and analysis, the research team consulted with social media health care experts in making recommendations for evaluation criteria. Selected cases illustrate the analytical conclusions. Lines of research that are needed to accurately rate and reliably measure the ability of social media e-health offerings to address health disparities are proposed. PMID- 24059274 TI - Effects of different models of integrated collaborative care in a family medicine residency program. AB - Integrated collaborative care (ICC) combines medical and behavioral health services in the primary care setting. Our family medicine residency program implemented care across three different models of integration over five years, allowing retrospective, cohort evaluation of the changes in behavioral health services and patient outcomes for depression. We identified three time periods representing increasing levels of services: Colocation of behavioral health services in 2004-05 (CL), primary care behavioral health model (behavioral health providers embedded in primary care) in 2009 (PCBH), and a blended model of PCBH and care management for depression in early 2010 (BM). All adult patient charts (n = 552) with PHQ9 scores >=10 were analyzed for number of provider contacts (physician and behavioral health) and changes in scores during the 12-week follow up. The percent of patients receiving adequate care (>=3 provider contacts in 12 weeks) improved from 43.5% (CL) to 55.1% (PCBH) to 60.6% (BM; Pearson chi-square, p = .02). Forty-two percent of patients in BM achieved remission (PHQ9 <= 4), 25.2% in PCBH and 12% in CL (Pearson chi-square, p = .02). The Blended Model resulted in better access to behavioral health care and outcomes for patients with depression symptoms. PMID- 24059275 TI - Hispanic children and the obesity epidemic: exploring the role of abuelas. AB - This study evaluated the rate of Hispanic children who have grandparents involved in caretaking and whether grandparents' involvement had a negative impact on feeding practices, children's physical activity, and body mass index (BMI). One hundred and 99 children and their parents were recruited at an elementary school. Parents completed a questionnaire regarding their children's grandparents' involvement as caretakers and the feeding and physical activity practices of that grandparent when with the child. Children's height and weight were measured and zBMI scores were calculated. Forty-three percent of parents reported that there was a grandparent involved in their child's caretaking. Grandparents served a protective role on zBMI for youth of Hispanic descent, except for the Cuban subgroup. There was no relationship between grandparent involvement and feeding and physical activity behaviors. In some cases grandparents may serve a protective function for childhood obesity. These results highlight the need for future research on grandparents and children's health, especially among Hispanic subgroups. PMID- 24059278 TI - Allicin induces anti-human liver cancer cells through the p53 gene modulating apoptosis and autophagy. AB - Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer globally and ranks first among the cancer-related mortalities in Taiwan. This study aims to understand the modes of cell death mechanism induced by allicin, a major phytochemical of crushed garlic, in human hepatoma cells. Our earlier study indicated that allicin induced autophagic cell death in human HCC Hep G2 (p53(wild type)) cells, whereas in the present study, allicin induced apoptotic cell death through caspase-dependent and caspase-independent pathways by reactive oxygen species (ROS) overproduction in human HCC Hep 3B (p53(mutation)) cells. To gain insight into the cell death mechanism in p53 knocked down Hep G2, we silenced the p53 gene using siRNA-mediated silencing. Allicin treatment induced apoptotic cell death in p53 knocked down Hep G2 cells similar to that of Hep 3B cells. These results suggest that allicin induced cell death in human hepatoma cells through either autophagy or apoptosis and might be a potential novel complementary gene therapeutic agent for the treatment of apoptosis-resistant cancer cells. PMID- 24059279 TI - Racism as a determinant of health: a protocol for conducting a systematic review and meta-analysis. AB - BACKGROUND: Racism is increasingly recognized as a key determinant of health. A growing body of epidemiological evidence shows strong associations between self reported racism and poor health outcomes across diverse minority groups in developed countries. While the relationship between racism and health has received increasing attention over the last two decades, a comprehensive meta analysis focused on the health effects of racism has yet to be conducted. The aim of this review protocol is to provide a structure from which to conduct a systematic review and meta-analysis of studies that assess the relationship between racism and health. METHODS: This research will consist of a systematic review and meta-analysis. Studies will be considered for review if they are empirical studies reporting quantitative data on the association between racism and health for adults and/or children of all ages from any racial/ethnic/cultural groups. Outcome measures will include general health and well-being, physical health, mental health, healthcare use and health behaviors. Scientific databases (for example, Medline) will be searched using a comprehensive search strategy and reference lists will be manually searched for relevant studies. In addition, use of online search engines (for example, Google Scholar), key websites, and personal contact with experts will also be undertaken. Screening of search results and extraction of data from included studies will be independently conducted by at least two authors, including assessment of inter-rater reliability. Studies included in the review will be appraised for quality using tools tailored to each study design. Summary statistics of study characteristics and findings will be compiled and findings synthesized in a narrative summary as well as a meta-analysis. DISCUSSION: This review aims to examine associations between reported racism and health outcomes. This comprehensive and systematic review and meta-analysis of empirical research will provide a rigorous and reliable evidence base for future research, policy and practice, including information on the extent of available evidence for a range of racial/ethnic minority groups. PMID- 24059280 TI - Effect of gamma radiation and accelerated aging on the mechanical and thermal behavior of HDPE/HA nano-composites for bone tissue regeneration. AB - BACKGROUND: The replacement of hard tissues demands biocompatible and sometimes bioactive materials with properties similar to those of bone. Nano-composites made of biocompatible polymers and bioactive inorganic nano particles such as HDPE/HA have attracted attention as permanent bone substitutes due to their excellent mechanical properties and biocompatibility. METHOD: The HDPE/HA nano composite is prepared using melt blending at different HA loading ratios. For evaluation of the degradation by radiation, gamma rays of 35 kGy, and 70 kGy were used to irradiate the samples at room temperature in vacuum. The effects of accelerated ageing after gamma irradiation on morphological, mechanical and thermal properties of HDPE/HA nano-composites were measured. RESULTS: In Vitro test results showed that the HDPE and all HDPE/HA nano-composites do not exhibit any cytotoxicity to WISH cell line. The results also indicated that the tensile properties of HDPE/HA nano-composite increased with increasing the HA content except fracture strain decreased. The dynamic mechanical analysis (DMA) results showed that the storage and loss moduli increased with increasing the HA ratio and the testing frequency. Finally, it is remarked that all properties of HDPE/HA is dependent on the irradiation dose and accelerated aging. CONCLUSION: Based on the experimental results, it is found that the addition of 10%, 20% and 30% HA increases the HDPE stiffness by 23%, 44 and 59% respectively. At the same time, the G' increased from 2.25E11 MPa for neat HDPE to 4.7E11 MPa when 30% HA was added to the polymer matrix. Also, significant improvements in these properties have been observed due to irradiation. Finally, the overall properties of HDPE and its nano-composite properties significantly decreased due to aging and should be taken into consideration in the design of bone substitutes. It is attributed that the developed HDPE/HA nano-composites could be a good alternative material for bone tissue regeneration due to their acceptable properties. PMID- 24059281 TI - Optimization of the fabrication of novel stealth PLA-based nanoparticles by dispersion polymerization using D-optimal mixture design. AB - PURPOSE: Nanoparticle size is important in drug delivery. Clearance of nanoparticles by cells of the reticuloendothelial system has been reported to increase with increase in particle size. Further, nanoparticles should be small enough to avoid lung or spleen filtering effects. Endocytosis and accumulation in tumor tissue by the enhanced permeability and retention effect are also processes that are influenced by particle size. We present the results of studies designed to optimize cross-linked biodegradable stealth polymeric nanoparticles fabricated by dispersion polymerization. METHODS: Nanoparticles were fabricated using different amounts of macromonomer, initiators, crosslinking agent and stabilizer in a dioxane/DMSO/water solvent system. Confirmation of nanoparticle formation was by scanning electron microscopy (SEM). Particle size was measured by dynamic light scattering (DLS). D-optimal mixture statistical experimental design was used for the experimental runs, followed by model generation (Scheffe polynomial) and optimization with the aid of a computer software. Model verification was done by comparing particle size data of some suggested solutions to the predicted particle sizes. RESULTS AND CONCLUSION: Data showed that average particle sizes follow the same trend as predicted by the model. Negative terms in the model corresponding to the cross-linking agent and stabilizer indicate the important factors for minimizing particle size. PMID- 24059282 TI - Preparation and characterization of curcumin thermosensitive hydrogels for intratumoral injection treatment. AB - OBJECTIVES: This paper describes the development and optimization of curcumin thermosensitive hydrogels (CTH), a kind of gel injection for intratumoral injection treatment. METHODS: Aimed at increasing the content and stability of effective components, an optimal formulation of CTH was chosen based on the results from orthogonal tests and the optimal pH was determined by stability test. To investigate the hydrogels drug release in vitro, residence time by RP HPLC and therapeutic effects on ascitic hepatocarcinoma cell strain with high metastasis potential in lymphatic system (HCA-F) solid tumors in mice. KEY FINDINGS: The selected optimal formulation of CTH was: 0.2% curcumin, 20% poloxamer 407, 4% poloxamer 188, 8% polyethylene glycol 400, 12% 1,2-propanediol and pH was 6.0. The drug release determined by RP-HPLC fit to the Higuchi model. The residence time of CTH was longer than the curcumin suspensions. Intratumoral injection of the CTH can effectively inhibit the growth of HCA-F solid tumors in mice. CONCLUSIONS: The CTH prepared in this test demonstrates proper gel temperature and viscosity. It improves the solubility of curcumin with a relatively long period of drug release in vitro and residence time. Intratumoral injection of the CTH can effectively inhibit the growth of HCA-F solid tumors in mice. PMID- 24059283 TI - Simple coating with pH-responsive polymer-functionalized silica nanoparticles of mixed sizes for controlled surface properties. AB - Different-sized silica nanoparticles (SiNPs) were functionalized by pH-responsive poly(2-(diisopropylamino)ethyl methacrylate) (PDP) via surface-initiated atom transfer radical polymerization (ATRP). The functionalized PDP-SiNPs were used to coat glass surfaces, polymeric nanofibers, and paper via simple coating methods such as dip, cast, and spray coating. A PDP-SiNPs mixture having different sizes was found to change the surface properties of the substrates remarkably, compared to one containing PDP-SiNPs with uniform sizes. High surface roughness was achieved with very little coating materials, which is beneficial from an economical point of view. Moreover, adsorption/desorption of PDP-SiNPs onto/from the substrates could be controlled by changing solution pH due to the protonation/deprotonation of the PDP. The surface properties of the coated substrates were analyzed by contact angle (CA) measurement, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). This inexpensive system provides a simple, quick, and effective approach to changing the surface properties of substrates that could be exploited for large-scale surface modification. PMID- 24059284 TI - Correlation between iron stores and QTc dispersion in chronic ambulatory peritoneal dialysis patients. AB - AIM: We aimed to investigate the QT dispersion and corrected QT (QTc) dispersion which are suggested as the signals of ventricular arrhythmias, in patients on maintenance CAPD and to evaluate the correlation between iron stores and these electrocardiographic parameters. MATERIALS AND METHOD: Fifty-eight patients on maintenance CAPD and 19 healthy age- and sex-matched adults without cardiac disease were included. The PD patients were divided into two groups according to whether their computerized measurements of QTc dispersion were longer than 65 ms. RESULTS: Although QT interval was statistically significantly shorter in control group (34 +/- 28 vs. 43 +/- 34 ms; p < 0.05), there was no significant difference in regards to the QTc, QT dispersion and QTc dispersion between two groups. PD patients with QTc dispersion longer than 65 ms had higher levels of serum ferritin (p = 0.038) and transferrin saturation (TSAT; p = 0.022) than the others. QTc dispersion were positively correlated with ferritin (r = 0.469, p < 0.01) and TSAT (r = 0.430, p < 0.01) in CAPD patients. CONCLUSION: Although prolonged QTc, QT dispersion and QTc dispersion were suggested as the markers of ventricular arrhythmias we did not find any significant difference in regards to these parameters between control patients and CAPD patients. But the high body iron stores in these patients increase the risk of increased QT dispersion. The concern over iron overload in dialysis patients is not only because of its oxidative toxicity, but also its precipitation of arrhythmias, which may be measured by the surrogate marker of QTc dispersion. PMID- 24059285 TI - Maximum parsimony xor haplotyping by sparse dictionary selection. AB - BACKGROUND: Xor-genotype is a cost-effective alternative to the genotype sequence of an individual. Recent methods developed for haplotype inference have aimed at finding the solution based on xor-genotype data. Given the xor-genotypes of a group of unrelated individuals, it is possible to infer the haplotype pairs for each individual with the aid of a small number of regular genotypes. RESULTS: We propose a framework of maximum parsimony inference of haplotypes based on the search of a sparse dictionary, and we present a greedy method that can effectively infer the haplotype pairs given a set of xor-genotypes augmented by a small number of regular genotypes. We test the performance of the proposed approach on synthetic data sets with different number of individuals and SNPs, and compare the performances with the state-of-the-art xor-haplotyping methods PPXH and XOR-HAPLOGEN. CONCLUSIONS: Experimental results show good inference qualities for the proposed method under all circumstances, especially on large data sets. Results on a real database, CFTR, also demonstrate significantly better performance. The proposed algorithm is also capable of finding accurate solutions with missing data and/or typing errors. PMID- 24059287 TI - Pressure induced crossover between a ferromagnetic and a canted antiferromagnetic state for [bis(pentamethylcyclopentadienyl)-iron(III)][tetracyanoethenide], [FeCp2*][TCNE]. AB - The reversible hydrostatic pressure dependent DC magnetic behavior of the ferromagnetically ordered electron transfer salt [Fe(III)Cp2*](*+)[TCNE](*-) (Cp* = pentamethylcyclopentadienide; TCNE = tetracyanoethylene) was studied up to 12.2 kbar. A significant departure from the ambient pressure ferromagnetic behavior was observed under pressure. The temperature dependent magnetization data were typical of a ferromagnet at ambient pressure but exhibited an extreme reduction with increasing applied pressure, while metamagnetic-like behavior was evident in the field dependent magnetization data at 4.2 kbar and above. Hence, the decrease of the intermolecular separations due to increasing pressure enhances the nearest neighbor couplings, leading to an increase in magnetic ordering temperature, T(c). Furthermore, the presence of a metamagnetic-like behavior suggests an increase of the antiferromagnetic contribution to the interchain interactions. The low field magnetization data indicate that spin canting is induced by pressure, leading to a canted antiferromagnetic phase with a much lower magnetization than the low-pressure ferromagnetic state. This unprecedented magnetic behavior is consistent with the field, temperature, and pressure dependences of the magnetization below 20 K. PMID- 24059286 TI - KIR3DS1/L1 and HLA-Bw4-80I are associated with HIV disease progression among HIV typical progressors and long-term nonprogressors. AB - BACKGROUND: Natural killer (NK) cells have emerged as pivotal players in innate immunity, especially in the defense against viral infections and tumors. Killer immunoglobulin-like receptors (KIRs)--an important recognition receptor expressed on the surface of NK cells--regulate the inhibition and/or activation of NK cells after interacting with human leukocyte antigen (HLA) class I ligands. Various KIR genes might impact the prognosis of many different diseases. The implications of KIR-HLA interaction in HIV disease progression remains poorly understood. METHODS: Here, we studied KIR genotypes, mRNA levels, HLA genotypes, CD4+ T cell counts and viral loads in our cohort of Human Immunodeficiency Virus (HIV) infected individuals, a group that includes HIV long-term nonprogressors (LTNPs) and typical progressors (TPs). RESULTS: We found that the frequency of KIR3DS1/L1 heterozygotes with HLA-Bw4-80I gene was much higher in LTNPs than in TPs (P = 0.001) and that the KIR3DL1 homozygotes without HLA-Bw4-80I gene had higher viral loads and lower CD4+ T cell counts (P = 0.014 and P = 0.021, respectively). Our study also confirmed that homozygosity for the HLA-Bw6 allele was associated with rapid disease progression. In addition to the aforementioned results on the DNA level, we observed that higher level expression of KIR3DS1 mRNA was in LTNP group, and that higher level expression of KIR3DL1 mRNA was in TP group. CONCLUSIONS: Our data suggest that different KIR-HLA genotypes and different levels of transcripts associate with HIV disease progression. PMID- 24059288 TI - Acute and chronic nephrotoxicity of platinum nanoparticles in mice. AB - Platinum nanoparticles are being utilized in various industrial applications, including in catalysis, cosmetics, and dietary supplements. Although reducing the size of the nanoparticles improves the physicochemical properties and provides useful performance characteristics, the safety of the material remains a major concern. The aim of the present study was to evaluate the biological effects of platinum particles less than 1 nm in size (snPt1). In mice administered with a single intravenous dose of snPt1, histological analysis revealed necrosis of tubular epithelial cells and urinary casts in the kidney, without obvious toxic effects in the lung, spleen, and heart. These mice exhibited dose-dependent elevation of blood urea nitrogen, an indicator of kidney damage. Direct application of snPt1 to in vitro cultures of renal cells induced significant cytotoxicity. In mice administered for 4 weeks with twice-weekly intraperitoneal snPt1, histological analysis of the kidney revealed urinary casts, tubular atrophy, and inflammatory cell accumulation. Notably, these toxic effects were not observed in mice injected with 8-nm platinum particles, either by single- or multiple-dose administration. Our findings suggest that exposure to platinum particles of less than 1 nm in size may induce nephrotoxicity and disrupt some kidney functions. However, this toxicity may be reduced by increasing the nanoparticle size. PMID- 24059289 TI - Development of a theory-based instrument to identify barriers and levers to best hand hygiene practice among healthcare practitioners. AB - BACKGROUND: A theoretical approach to assessing the barriers and levers to evidence-based practice (EBP) with subsequent tailoring of theoretically informed strategies to address these may go some way to positively influencing the delay in implementing research findings into practice. Hand hygiene is one such example of EBP, chosen for this study due to its importance in preventing death through healthcare associated infections (HCAI). The development of an instrument to assess barriers and levers to hand hygiene and to allow the subsequent tailoring of theoretically informed implementation strategies is reported here. METHODS: A comprehensive list of barriers and levers to hand hygiene were categorised to the Theoretical Domains Framework (TDF) in a Delphi survey. These items formed the basis of an instrument that was tested to establish validity and reliability. The relationship between self-reported compliance with hand hygiene and barriers and levers to hand hygiene was also examined along with compliance according to where the barriers and levers fit within the domains of the TDF framework. RESULTS: A 33-item instrument that tested well for internal consistency (alpha = 0.84) and construct validity (chi2/df = 1.9 [p < 0.01], RMSEA = 0.05 and CFA = 0.84) was developed. The relationship between self-reported compliance with hand hygiene moderately correlated with barriers identified by participants (total barrier score) (r = 0.41, n = 276, p <0.001). The greater the number of barriers reported, the lower the level of compliance. A one-way between groups multivariate analysis of variance was performed to investigate differences between those adopting high or low compliance with hand hygiene. Compliance was highest for this sample of participants among practitioners with high levels of motivation, strong beliefs about capabilities, when there were positive social influences, when hand hygiene was central to participants' sense of professional identity and was easier to remember to do. CONCLUSIONS: This study has produced encouraging findings suggesting the potential for improved hand hygiene and resulting effects on the human and financial costs of healthcare associated infection. This study identifies a further potential use for the TDF. PMID- 24059290 TI - The new 3D/4D based spatio-temporal imaging correlation (STIC) in fetal echocardiography: a promising tool for the future. AB - Congenital heart disease is the commonest congenital anomaly. It is much more common than chromosomal malformations and spinal defects. Its estimated incidence is about 4-13 per 1000 live births. Congenital heart disease is a significant cause of fetal mortality and morbidity. Antenatal diagnosis of congenital heart disease is extremely difficult and requires extensive training and expertise. The detection rate of congenital heart disease is very variable and it ranged from 35 to 86% in most studies. In the light of the above, the introduction of the new 3D/4D based spatio-temporal Image Correlation (STIC) is highly welcomed to improve antenatal detection of congenital heart disease. STIC is an automated device incorporated into the ultrasound probe and has the capacity to perform slow sweep to acquire a single 3-dimensional (3D) volume. This acquired volume is composed of a great number of 2-dimension (2D) frames. This volume can be analyzed and reanalyzed as required to demonstrate all the required cardiac views. It also provides the examiner with the ability to review all images in a looped cine sequence. This technology has the ability to improve our ability to examine the fetal heart in the acquired volume and decrease examination time. Using this technique you can share the information and consult colleagues both at your clinical sitting or remotely using the internet. PMID- 24059291 TI - Short communication: molecular epidemiology of HIV type 1 infection in northern Greece (2009-2010): evidence of a transmission cluster of HIV type 1 subtype A1 drug-resistant strains among men who have sex with men. AB - A prospective molecular epidemiology study of HIV-1 infection was conducted in newly diagnosed and antiretroviral-naive patients in Northern Greece between 2009 and 2010 using a predefined enrolling strategy. Phylogenetic trees of the pol sequences obtained in this study with reference sequences indicated that subtypes B and A1 were the most common subtypes present and accounted for 44.9% and 42.9%, respectively, followed by subtype C (3.1%), CRF02_AG (4.1%), CRF04_cpx (2.0%), and subtypes CRF01_01, F1, and G (1.0%). A high rate of clustered transmission of subtype A1-resistant strains to reverse transcriptase (RT) inhibitors was observed among men having sex with men. Indeed, 15 out of 17 study subjects (88.2%) infected with transmitted drug resistance (TDR) strains were implicated in transmission clusters, 10 of whom (66.7%) were men who have sex with men (MSM), and were also infected with subsubtype A1 strains. The main cluster within subtype A1 (I) included eight men reporting having sex with men from Thessaloniki infected with dual-class RT-resistant strains carrying both T215C and Y181C mutations. PMID- 24059292 TI - Cost-effectiveness of a nurse-based intervention (AIMS) to improve adherence among HIV-infected patients: design of a multi-centre randomised controlled trial. AB - BACKGROUND: Non-adherence to HIV-treatment can have a negative impact on patients treatment success rates, quality of life, infectiousness, and life expectancy. Few adherence interventions have shown positive effects on adherence and/or virologic outcomes. The theory- and evidence-based Adherence Improving self Management Strategy (AIMS) is an intervention that has been demonstrated to improve adherence and viral suppression rates in a randomised controlled trial. However, evidence of its cost-effectiveness is lacking. Following a recent review suggesting that cost-effectiveness evaluations of adherence interventions for chronic diseases are rare, and that the methodology of such evaluations is poorly described in the literature, this manuscript presents the study protocol for a multi-centre trial evaluating the effectiveness and cost-effectiveness of AIMS among a heterogeneous sample of patients. METHODS/DESIGN: The study uses a multi centre randomised controlled trial design to compare the AIMS intervention to usual care from a societal perspective. Embedded in this RCT is a trial-based and model-based economic evaluation. A planned number of 230 HIV-infected patients are randomised to receive either AIMS or usual care. The relevant outcomes include changes in adherence, plasma viral load, quality of life, and societal costs. The time horizon for the trial-based economic evaluation is 12-15 months. Costs and effects are extrapolated to a lifetime horizon for the model-based economic evaluation. DISCUSSION: The present multicentre RCT is designed to provide sound methodological evidence regarding the effectiveness and cost effectiveness of a nurse-based counselling intervention (AIMS) to support treatment adherence among a large and heterogeneous sample of HIV-infected patients in the Netherlands. The objective of the current paper is to describe the trial protocol in sufficient detail to allow full evaluation of the quality of the study design. It is anticipated that, if proven cost-effective, AIMS can contribute to improved evidence-based counselling guidelines for HIV-nurses and other health care professionals. TRIAL REGISTRATION: The study has been registered on clinicaltrials.gov (Identifier: NCT01429142). PMID- 24059293 TI - Positive and negative phosphorylation regulates RIP1- and RIP3-induced programmed necrosis. AB - Programmed necrosis or necroptosis is controlled by the action of two serine/threonine kinases, RIP1 (receptor-interacting serine/threonine protein kinase 1; also known as RIPK1) and RIP3. The phosphorylation of RIP1 and RIP3 is critical for assembly of the necrosome, an amyloid-like complex that initiates transmission of the pro-necrotic signal. In the present study, we used site directed mutagenesis to systematically examine the effects of putative phosphoacceptor sites on RIP1 and RIP3 on TNF (tumour necrosis factor)-induced programmed necrosis. We found that mutation of individual serine residues in the kinase domain of RIP1 had little effect on RIP1 kinase activity and TNF-induced programmed necrosis. Surprisingly, an alanine residue substitution for Ser(89) enhanced RIP1 kinase activity and TNF-induced programmed necrosis without affecting RIP1-RIP3 necrosome formation. This indicates that Ser(89) is an inhibitory phosphoacceptor site that can dampen the pro-necrotic function of RIP1. In addition, we show that a phosphomimetic mutant of RIP3, S204D, led to programmed necrosis that was refractory to RIP1 siRNA and insensitive to necrostatin-1 inhibition. Our results show that programmed necrosis is regulated by positive and inhibitory phosphorylation events. PMID- 24059294 TI - Monocyte chemoattractant protein-1 -2518G/A gene polymorphism and the risk of nephropathy in type 2 diabetes mellitus among Asians: a meta-analysis. AB - The association between monocyte chemoattractant protein-1 (MCP-1) -2518G/A gene polymorphism and the risk of nephropathy in type 2 diabetes mellitus (T2DM) remains controversial. A meta-analysis was conducted to assess the association of MCP-1 -2518G/A gene polymorphism with the risk of nephropathy in T2DM. Eight studies were included in our meta-analysis by searching electronic databases according to predefined criteria. No significant association between G allele, GG genotype, or AA genotype and the onset of nephropathy in T2DM was observed among Asians. GA genotype was significantly associated with nephropathy risk in T2DM among Asians (p = 0.024). MCP-1 -2518G/A gene polymorphism was not associated with nephropathy risk in T2DM among Chinese, Koreans, and Turks. For Indians, G allele and AA genotype were not associated with nephropathy risk in T2DM, GG genotype was associated with a lower risk of nephropathy in T2DM (p = 0.017), GA genotype was associated with the susceptibility of nephropathy in T2DM (p = 0.029). In conclusions, GA genotype might be a risk factor for the onset of nephropathy in T2DM among Asians, particularly Indians; GG genotype seems to be a protective factor against the susceptibility of nephropathy in T2DM among Indians. PMID- 24059295 TI - Current view from Alzheimer disease to type 2 diabetes mellitus. AB - Alzheimer's disease (AD) is a neurodegenerative disorder that leads to memory problems. It has been associated with type 2 diabetes mellitus at both the molecular and biochemical level. Pancreatic cells have molecular similarities to the brain at the transcriptomic and proteomic levels. Several genes have been reported to be responsible for both AD and diabetes. Currently, no proper treatment is available but various therapeutic approaches are utilized worldwide for the management of these disorders and may be nanoparticles and herbal treatment of Bacopa monnieri will make promise for the treatment of AD in future. The formation of amyloids in neurons and the formation of amylin in pancreatic cells are potential links between these two disorders, which can be silent killers. PMID- 24059296 TI - Current acetylcholinesterase-inhibitors: a neuroinformatics perspective. AB - This review presents a concise update on the inhibitors of the neuroenzyme, acetylcholinesterase (AChE; EC 3.1.1.7). AChE is a serine protease, which hydrolyses the neurotransmitter, acetylcholine into acetate and choline thereby terminating neurotransmission. Molecular interactions (mode of binding to the target enzyme), clinical applications and limitations have been summarized for each of the inhibitors discussed. Traditional inhibitors (e.g. physostigmine, tacrine, donepezil, rivastigmine etc.) as well as novel inhibitors like various physostigmine-derivatives have been covered. This is followed by a short glimpse on inhibitors derived from nature (e.g. Huperzine A and B, Galangin). Also, a discussion on 'hybrid of pre-existing drugs' has been incorporated. Furthermore, current status of therapeutic applications of AChEinhibitors has also been summarized. PMID- 24059298 TI - An association of virus infection with type 2 diabetes and Alzheimer's disease. AB - Diabetes mellitus type 2 is a metabolic disorder characterized by high blood glucose due to insulin deficiency or resistance. Alzheimer's disease (AD) is a complex neurodegenerative disease leading to irreversible loss of neurons, intellectual abilities, memory and reasoning. The worldwide prevalence of diabetes and AD in elderly population is a major public health concern. Interestingly, both health issues are unraveling the puzzling links. The clinico pathological relationship between diabetes and AD has been reported at genomic and proteomic levels. The association of virus infection in type 2 diabetes mellitus and AD has been reported in few recent studies, some have shown direct evidence of virus infection in diabetes and AD while other have shown that diabetes increases the risk of developing AD. This review aims to summarize the association of few common viruses like Hepatitis C Virus and Herpes Simplex Virus 1 which affects both these two age-related devastating diseases. We also discuss the pathological links of Influenza virus, Cytomegalovirus, West Nile virus, Enterovirus, Herpes Simplex Virus-2, Hepatitis viruses in diabetes and Influenza virus, Picornavirus and Borna disease virus in AD. Establishing such relationships and defining their common pathogenesis and patho-physiological mechanisms may lead to new concepts and paths for developing novel preventive strategies and pharmacological treatment options for diabetes and AD. This study may aid in future for the identification of a single or a panel of likely blood based viral biomarkers for early diagnosis of diabetes and AD with high sensitivity and specificity. PMID- 24059299 TI - Molecular interaction of human brain acetylcholinesterase with a natural inhibitor huperzine-B: an enzoinformatics approach. AB - The present study emphasizes the molecular interactions between human brain acetylcholinesterase (AChE) and the natural ligand Huperzine-B and its comparison to 'AChE-Tolserine interactions'. Docking between Huperzine-B and AChE was performed using 'Autodock4.2'. Hydrophobic interactions and hydrogen bonds both play an equally important role in the correct positioning of Huperzine-B within the 'catalytic site' of AChE to permit docking. However, docking of Tolserine to AChE is largely dominated by hydrophobic interactions. Such information may aid in the design of versatile AChE-inhibitors, and is expected to aid in safe clinical use of Huperzine-B. Scope still remains in the determination of the three-dimensional structure of AChE-Huperzine-B complex by X-ray crystallography to validate the described data. Furthermore, this study confirms that Huperzine-B is a more efficient inhibitor of human brain AChE compared to tolserine with reference to Ki and DeltaG values. PMID- 24059300 TI - Prediction of comparative inhibition efficiency for a novel natural ligand, galangin against human brain acetylcholinesterase, butyrylcholinesterase and 5 lipoxygenase: a neuroinformatics study. AB - The present study elucidates molecular interactions of human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and 5-lipoxygenase (5-LPO) with a novel natural ligand Galangin (GAL); and also with the well-known ligands Bisnorcymserine (BNC) and Cymserine for comparison. Docking between these ligands and enzymes were performed using 'Autodock4.2'. It was found that hydrophobic interactions play an important role in the correct positioning of BNC within the 'catalytic site' of AChE, BuChE and 5-LPO to permit docking while hydrogen bonds are significant in case of cymserine for the same. However, only polar interactions are significant in the correct positioning of GAL within the 'catalytic site' of AChE, BuChE and 5-LPO to permit docking. Such information may aid in the design of versatile AChE, BuChE and 5 LPO-inhibitors, and is expected to aid in safe clinical use of above ligands. Scope still remains in the determination of the three-dimensional structure of AChE-GAL, BuChE-GAL and 5-LPO GAL complex by X-ray crystallography to certify the described data. Moreover, the present study confirms that GAL is a more efficient inhibitor of human brain AChE compared to BNC and cymserine, while in case of 5-LPO and human brain BuChE, BNC is a more efficient inhibitor compared to GAL and cymserine with reference to DeltaG and Ki values. PMID- 24059301 TI - Structural and functional characterization of pathogenic non- synonymous genetic mutations of human insulin-degrading enzyme by in silico methods. AB - Insulin-degrading enzyme (IDE) is a key protease involved in degrading insulin and amyloid peptides in human body. Several non-synonymous genetic mutations of IDE gene have been recently associated with susceptibility to both diabetes and Alzheimer's diseases. However, the consequence of these mutations on the structure of IDE protein and its substrate binding characteristics is not well elucidated. The computational investigation of genetic mutation consequences on structural level of protein is recently found to be an effective alternate to traditional in vivo and in vitro approaches. Hence, by using a combination of empirical rule and support vector machine based in silico algorithms, this study was able to identify that the pathogenic nonsynonymous genetic mutations corresponding to p.I54F, p.P122T, p.T533R, p.P581A and p.Y609A have more potential role in structural and functional deviations of IDE activity. Moreover, molecular modeling and secondary structure analysis have also confirmed their impact on the stability and secondary properties of IDE protein. The molecular docking analysis of IDE with combinational substrates has revealed that peptide inhibitors compared to small non-peptide inhibitor molecules possess good inhibitory activity towards mutant IDE. This finding may pave a way to design novel potential small peptide inhibitors for mutant IDE. Additionally by un translated region (UTR) scanning analysis, two regulatory pathogenic genetic mutations i.e., rs5786997 (3' UTR) and rs4646954 (5' UTR), which can influence the translation pattern of IDE gene through sequence alteration of upstream-Open Reading Frame and Internal Ribosome Entry Site elements were identified. Our findings are expected to help in narrowing down the number of IDE genetic variants to be screened for disease association studies and also to select better competitive inhibitors for IDE related diseases. PMID- 24059302 TI - Invokana (Canagliflozin) as a dual inhibitor of acetylcholinesterase and sodium glucose co-transporter 2: advancement in Alzheimer's disease- diabetes type 2 linkage via an enzoinformatics study. AB - Acetylcholinesterase (AChE) is a primary target for Alzheimer's therapy while recently sodium glucose cotransporter 2 (SGLT2) has gained importance as a potential target for Type 2 Diabetes Mellitus (T2DM) therapy. The present study emphasizes the molecular interactions between a new Food and Drug Administration (FDA) approved antidiabetic drug 'Invokana' (chemically known as Canagliflozin) with AChE and SGLT2 to establish a link between the treatment of T2DM and Alzheimer's Disease (AD). Docking study was performed using 'Autodock4.2'. Both hydrophobic and pi-pi interactions play an important role in the correct positioning of Canagliflozin within SGLT2 and catalytic site (CAS) of AChE to permit docking. Free energy of binding (DeltaG) for 'Canagliflozin-SGLT2' interaction and 'Canagliflozin - CAS domain of AChE' interaction were found to be -10.03 kcal/mol and -9.40 kcal/mol, respectively. During 'Canagliflozin-SGLT2' interaction, Canagliflozin was found to interact with the most important amino acid residue Q457 of SGLT2. This residue is known for its interaction with glucose during reabsorption in kidney. However, 'Canagliflozin-CAS domain of AChE' interaction revealed that out of the three amino acids constituting the catalytic triad (S203, H447 and E334), two amino acid residues (S203 and H447) interact with Canagliflozin. Hence, Invokana (Canagliflozin) might act as a potent dual inhibitor of AChE and SGLT2. However, scope still remains in the determination of the three-dimensional structure of SGLT2-Canagliflozin and AChE Canagliflozin complexes by X-ray crystallography to validate the described data. Since the development of diabetes is associated with AD, the design of new AChE inhibitors based on antidiabetic drug scaffolds would be particularly beneficial. Moreover, the present computational study reveals that Invokana (Canagliflozin) is expected to form the basis of a future dual therapy against diabetes associated neurological disorders. PMID- 24059303 TI - A nanotechnological approach to the management of Alzheimer disease and type 2 diabetes. AB - Alzheimer's disease (AD) and type 2 diabetes (T2D) are both prevalent in older individuals and have gained significant attention due to alarming rates of increase. The high incidences of these diseases pose a great socioeconomic burden and cause major public health concerns worldwide. A number of studies have established potential links between AD and T2D, supporting the hypothesis that T2D is linked with an increased risk of AD and that controlling diabetes could have a positive impact on the prevention of AD. At present, both diseases lack precise diagnostic approaches for early intervention and effective cure. Further, the currently available diagnostic tools for AD screening are insufficiently sensitive and robust for preventive measures. Although several drugs are used for the treatment of both these diseases, none of these drugs offers complete remission of the disease, merely symptomatic relief. Moreover, these drugs have limited efficacy because of problems such as conventional drug delivery systems beyond the blood brain barrier, a lack of target specificity and diminished potency. From this perspective, the emerging field of nanotechnology has offered new techniques and tools to overcome these challenges. In this review, we discuss the direct and indirect limitations of existing therapies and describe alternative potential nanotechnological approaches that could be utilized to overcome these limitations. New insight in the field of nanomedicine is necessary for early diagnosis, the development of novel drug therapies, the action of drugs and prevention, as well as for gaining an in-depth understanding of the complex biology of both diseases. PMID- 24059304 TI - Bacteriophage--a common divergent therapeutic approach for Alzheimer's disease and type II diabetes mellitus. AB - Alzheimer's disease, the most important neurodegenerative disorder, is an irreversible, age-dependent disease of the brain characterized by problems in progressive impairments in memory, language, reasoning, behavior and visuospatial skills. It is characterized by the deposition of amyloid beta peptide, forming compact fibrillar plaques and neurofibrillary tau tangles. Another major and much more prevalent cause of morbidity and mortality in world is diabetes especially type 2 diabetes mellitus. It is caused by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. Chronic wounds caused by antibiotic resistant bacterial infections that fail to heal are a common complication of diabetes mellitus and the most frequent reason for nontraumatic lower limb amputation. Holistically, these two diseases are linked at molecular level but the exact mechanism is a topic of debate. Bacteriophages are viruses infecting bacteria and lack ability to infect mammalian cells. They are neither causative agent for Alzheimer's disease or type 2 diabetes mellitus nor involved in their pathogenicity but promises for a novel divergent therapeutic approach. The great versatility of the phage system has led to the development of improved phage delivery vectors, as well as immunomodulation of anti-amyloid beta peptide response. Phages could also constitute valuable prophylaxis against bacterial infections, especially in immunocompromised patients like in the case of diabetes. Patients having diabetes have a high risk of developing foot ulcers which are difficult to be treated by antibiotics alone due to ever increasing antibiotic resistance strains. Combination therapy based on multiple phage and broad spectrum antibiotics holds great promise. The potential therapeutic phage therapy arises from its lack of natural tropism for mammalian cells, resulting in no adverse effects. PMID- 24059305 TI - Molecular interaction of acetylcholinesterase with carnosic acid derivatives: a neuroinformatics study. AB - Alzheimer's disease is a progressive degenerative disease of the brain marked by gradual and irreversible declines in cognitive functions. Acetylcholinesterase (AChE) plays a biological role in the termination of nerve impulse transmissions at cholinergic synapses by rapid hydrolysis of its substrate, "acetylcholine". The deficit level of acetylcholine leads to deprived nerve impulse transmission. Thus the cholinesterase inhibitors would reverse the deficit in acetylcholine level and consequently may reverse the memory impairments, which is characteristic of the Alzheimer's disease. The molecular interactions between AChE and Carnosic acid, a well known antioxidant substance found in the leaves of the rosemary plant has always been an area of interest. Here in this study we have performed in silico approach to identify carnosic acid derivatives having the potential of being a possible drug candidate against AChE. The best candidates were selected on the basis of the results of different scoring functions. PMID- 24059306 TI - Diabetes of the brain: computational approaches and interventional strategies. AB - Diabetes mellitus (DM) is characterized by hyperglycemia either due to deficient insulin production (Type 1 Diabetes mellitus) or peripheral insulin resistance of the cells (Type 2 Diabetes mellitus). Both Type 1 Diabetes mellitus and Type 2 Diabetes mellitus are more prevalent and efforts are directed to actively control these metabolic syndromes. Currently, Alzheimer's disease (AD), is gaining popularity as 'Type 3 diabetes' or 'Diabetes of the brain' and it is now evident that this neurodegenerative disease has multiple shared pathology with DM. Alarming is the fact that the incidence of AD might double within the next two decades, and this is certain to cause devastating effects not only to the afflicted individual or the family, but also to the global economy. Methods to either delay the onset or inhibit the progression of AD are therefore necessary. Progressive dementia, increased deposition of amyloid- beta protein, neurofibrillary tangles and neuritic plaques in the brain are some of the hallmarks of AD. More understanding of the disease at the cellular and molecular level will enable identifying the possible targets for intervention and pave way for either development of novel or modification of the existing therapeutic options. In this work we have performed semantic data mining analysis on a large collection of most recently published data and identified an updated list of common genes expressed in DM and AD. Functional analysis of these genes revealed both existing and missing links involved in a bigger network associated with both disease conditions. Thus we argue that computational analysis methods help not only in understanding the mechanistic links but also in narrowing down precise targets (genes, proteins, metabolites and signalling pathways) and provide the base for both disease intervention and development of therapeutic options. PMID- 24059307 TI - Does Parkinson's disease and type-2 diabetes mellitus present common pathophysiological mechanisms and treatments? AB - Parkinson's disease (PD) is the second most common neurodegenerative disease afflicting about 1% of people over 65 years old and 4-5% of people over 85 years. It is proposed that a cascade of deleterious factors is set in motion within that neuron made not of one, but rather of multiple factors such as free radicals, excitotoxicity, neuroinflammation, and apoptosis to cite only some of the most salient. In this scenario, chronic systemic inflammation, as well as impaired mitochondrial metabolism, have also been suspected of playing a role in the development of type-2 diabetes, and the possibility of a shared pathophysiology of PD and type-2 diabetes has been proposed. The discussion about the interactions between PD and type-2 diabetes mellitus began in the 1960's and there is still controversy. Insulin and dopamine may exert reciprocal regulation hence; hypoinsulinemia induced by streptozotocin decreased the amounts of dopamine transporter and tyrosine hydroxylase transcripts in the substantia nigra pars compacta. Accordingly, dopamine depletion in the striatum is able to decreases insulin signaling in basal ganglia, indicating that, perhaps, PD may be considered as a risk factor for the development of type-2 diabetes mellitus. In this sense, it is described that peroxisome proliferator-activated receptor gamma, ATP-sensitive K(+) channels, AMP-activated protein kinase, glucagon-like peptide-1 and dipeptidyl peptidase-4 are important therapeutic targets for PD and reinforces the association with diabetes. Therefore, the objective of the present review is to contextualize the mutual pathophysiological interactions between PD and type-2 diabetes mellitus, as well as the potential common treatments. PMID- 24059308 TI - Establishing genomic/transcriptomic links between Alzheimer's disease and type 2 diabetes mellitus by meta-analysis approach. AB - Meta-analysis methods exist for combining multiple microarray datasets. However, there are a wide range of issues associated with microarray meta-analysis and a limited ability to compare the performance of different metaanalysis methods. Using cDNA microarray technology (Partek Genomics Suite 6.6) and global pathway analysis with Ingenuity Pathway Analysis tool (IPA, Inc), we examined the transcript level in type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) patients and controls. To understand the molecular link between T2DM and AD, we compared the gene expression pattern and pathway involved. Microarray analysis identified 235 differentially expressed genes between T2DM patients and controls; and 834 between AD and controls at two fold change and a false discovery rate of 0.05. Significantly changed expression of "myeloid leukemia cell differentiation protein 1; RAS guanyl releasing protein 1; S100 calcium-binding protein A8; prostaglandin- endoperoxide synthase 2; parvalbumin; endoplasmic reticulum aminopeptidase 1; phosphoglycerate kinase 1; Eukaryotic translation initiation factor 3 subunit F; Interleukin-1 beta; tubulin, beta 2A; glycine receptor alpha 1 and ribosomal protein S24" genes were highly associated with T2DM, whereas "neuronal differentiation 6; G-protein coupled receptor 83; phosphoserine phosphatase; bobby sox homolog or HMG box -containing protein 2; Glutathione S transferase theta 1; alpha-2-glycoprotein 1 zinc-binding; Heat shock 70kDa protein 1B; transportin 1, Acidic leucine-rich nuclear phosphoprotein 32 family member B; Nuclear factor of activated T-cells 5; inositol 1,4,5-trisphosphate 3 kinase B; prenylcysteine oxidase 1 like" were found to be strongly related with AD. We also found a set of differentially expressed genes; "ARP2 actin-related protein 2; Cell division control protein 42; cytoplasmic polyadenylation element binding protein 4; Early growth response protein 1; ectonucleotide pyrophosphatase/phosphodiesterase 5; folate receptor 1; glutamate-ammonia ligase; hydroxy-3-methylglutaryl-Coenzyme A reductase; 3-hydroxy-3- methylglutaryl-CoA synthase; interleukin 1 receptor- like 1; leukemia inhibitory factor receptor; metastasis associated lung adenocarcinoma transcript 1; pyruvate dehydrogenase kinase, isozyme 4; phosphoserine phosphatase, parvalbumin, and tubulin, beta 2A" to be present in both dataset. Altered regulation of intracellular signaling pathways, including Ephrin receptor, liver X receptor/ retinoid X receptor; interleukin 6; insulinlike growth factor 1; interleukin 10 and 14-3-3-mediated signaling pathways were associated with T2DM as well as Alzheimer-type pathology. Our findings implicate diabetic disorders in the pathogenesis of AD, and provide a basis for future candidate studies based on specific pathways. PMID- 24059310 TI - How do periodontal infections affect the onset and progression of Alzheimer's disease? AB - Chronic infection can cause slow progressive dementia, cortical atrophy and amyloid deposition in the atrophic form of general paresis. Due to the fact that specific bacterial ligands can increase the expression of proinflammatory molecules that can activate innate and adaptive immune systems, inflammation may play a significant role in the pathogenesis of Alzheimer's disease (AD). Furthermore, there is a significant association between AD and various types of spirochete. Periodontitis is a prevalent and persistent peripheral infection that is associated with gram-negative anaerobic bacteria and is capable of showing localized and systemic infections in the host. Periodontal disease related pathogens and their inflammatory products contribute to systemic inflammation and the pathogenesis of AD. In this minireview, we propose a hypothetical link between periodontitis, type 2 diabetes and AD. We also present the possible mechanistic links between periodontitis-related inflammation, type 2 diabetes and AD. Since this condition is treatable, periodontitis may be a readily-modifiable risk factor for AD. PMID- 24059309 TI - Alzheimer disease and type 2 diabetes mellitus: the link to tyrosine hydroxylase and probable nutritional strategies. AB - Alzheimer disease (AD) and type 2 diabetes mellitus (T2DM) are chronic health disorders that affect millions of people around the world. According to recent studies, there are molecular similarities in the inflammatory pathways involved in both AD and T2DM, which opens a new avenue for researchers with different perspectives to target the cause of these diseases rather than their obvious symptoms. Several links between inflammation, cardiovascular disease, T2DM and central nervous system disorders such as AD and Parkinson's disease have been elucidated. Mutations in the hippocampal-beta-amyloid precursor protein gene in genetically high-risk individuals have been shown to cause the early onset of AD symptoms. The overexpression of beta-amyloid protein in the hippocampal region and the synaptotoxicity that occurs as a result have been considered a typical feature of AD and leads to neuronal loss and cognitive decline. However, the identity of the cellular components that cause the late onset of the disease seen in the majority of the cases is still unknown. Synaptic insults associated with neuronal dysfunction may involve several cascades and molecules, one of which has been hypothesized to be tyrosine hydroxylase (TH). The axons of the noradrenergic cells that project to the hippocampus appear to be affected by the beta-amyloid protein, which subsequently contributes to TH loss in Alzheimer brain cells. In this review, we attempt to shed light on the important mechanisms involved in AD as well as T2DM such as inflammatory factors, abnormalities in the insulin signaling system and the possible role of the endocrine enzyme TH. PMID- 24059311 TI - A possible link of gut microbiota alteration in type 2 diabetes and Alzheimer's disease pathogenicity: an update. AB - Imbalances in gut microbiota are associated with metabolic disorder, which are a group of obesity-related metabolic abnormalities that increase an individual's risk of developing type 2 diabetes (T2D) and Alzheimer's disease (AD). Although a number of risk factors have been postulated that may trigger the development of AD, the root cause of this disease is still a matter of debate. This review further investigates the etiology of AD by accumulating the current role played by gut microbiota in human, and trying to establish an inter-link between T2D and AD pathogenesis. There is a growing body of evidence which suggests that obesity is associated with alteration in the normal gut flora, reduced bacterial diversity, metabolic pathways and altered representation of bacterial genes. Obesity and T2D are considered to be induced as a result of changes within the composition of gut microbiota. The evidence gathered so far clearly advocates the involvement of gut microbes in causing obesity, a state of chronic and low-grade inflammation. Hence, understanding the microbiota of the gut is significant in relation to inflammation, as it is a key contributor for diabetes which has a direct relation to the AD pathogenesis. Comparative analysis of gut microbiota may enable further novel insight into the complex biology of AD, which is very important in order to take preventive measure such as early diagnosis, identification of new therapeutic targets and development of novel drugs. PMID- 24059312 TI - Commentary: research highlights: Inflammation, demyelination and neurodegeneration: risky buddies in multiple sclerosis. PMID- 24059313 TI - Role of gut microbiota in obesity, type 2 diabetes and Alzheimer's disease. AB - In recent years, there is a growing interest in research to investigate the importance of gut microbiome in health and diseases. This opens a new area of research for the role of microbial flora of the human gut in inflammation, energy homeostasis, pathogenesis of obesity and other associated disorders. Recent studies propose association of the gut microbiome with development of obesity and metabolic syndromes, such as type 2 diabetes mellitus (T2DM). The T2DM is a metabolic disease that is mainly caused by obesity-linked insulin resistance. The vascular effects of obesity appears to play a role in the development of Alzheimer's disease (AD) that is one of the rapidly growing diseases of a late stage of life all over the world. Studies from both humans and mice models have been demonstrated the engagement of gut microbial flora in the pathogenesis of obesity and host metabolism. The aim of this review is to discuss the current findings that may explain the cascade of gut microbial flora participation in the development of obesity, T2DM and further initiation of AD. In addition, the available data regarding the mechanisms that have been proposed to elucidate the role of gut microbiota in weight gain and possible cause of T2DM and AD have been examined. PMID- 24059314 TI - Autophagy dysfunction and its link to Alzheimer's disease and type II diabetes mellitus. AB - Epidemiological data testifies the increasing incidence of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Some associations were made between occidental lifestyle and development of these pathologies, moreover AD and T2DM are linked since each pathology is a causative risk factor for the other. Interestingly, autophagy, a catabolic pathway whose efficiency declines with age is importantly impaired in the affected tissues. Autophagy regulation is dependent of cell metabolic status and consequently on the 5'AMP-activated protein kinase (AMPK) and mammalian target of rapamycin signaling pathways. These pathways are altered with aging and molecular, pharmacological and physiological interventions increase lifespan in various organismal models and favours healthy aging diminishing the occurrence of age-related diseases such as diabetes, cancer, cardiovascular and neurodegenerative pathologies. Decreasing calorie intake has been known for a long time to have a beneficial effect on longevity and health. Some drug agonists of AMPK are known to mimic these effects such as metformin or resveratrol, a polyphenol extracted from plants and present in red wine, a component of the French paradox related diet. In this review, we present the epidemiological and pathogenesis links existing between AD and T2DM with an insight into the perturbations of the autophagic process highlighting the crucial role of the AMPK in development of age and metabolic related diseases. Hence, in a last part we will discuss the possible interventions susceptible to combat both T2DM and AD. PMID- 24059315 TI - Alzheimer's and type 2 diabetes treatment via common enzyme targeting. AB - Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two devastating diseases that are currently incurable. Epidemiological, clinical and pathological evidence has confirmed the co-existence of these two disorders. Moreover, there has been promising progress made in the identification of the pathological linkage between T2DM and AD in the last decade. Hence, developing common treatment strategies for these diseases is important. Currently, enzyme targeting is a potential strategy to cure many diseases. In this communication, we tried to summarize the single enzymetargeted therapeutic approach for the treatment of AD and T2DM. This field of research continues to be active and progressive in identifying many promising enzymes that are involved in both diseases. Based on this review article, we also believe that enzyme inhibition is a promising and reliable strategy for the treatment of many incurable diseases. In the future, we expect that the scientific community will be able to develop common enzyme inhibitors for the treatment of both AD and T2DM. PMID- 24059316 TI - Proteomics approaches to understand linkage between Alzheimer's disease and type 2 diabetes mellitus. AB - Alzheimer's disease (AD) is a progressive neurological disease of the brain leading to the irreversible loss of neurons and intellectual abilities. Diabetes mellitus type 2 (T2DM) is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. The prevalence of AD and T2DM is increasing at an alarming rate and has become a major public health concern worldwide. The clinico-pathological relationship between AD and T2DM has been debated for more than a decade. Recent epidemiological studies have provided direct evidence that T2DM is a strong risk factor for AD and numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD as compared with healthy individuals. The underlying biological mechanisms that link the development of diabetes with AD are not fully understood and therefore are worth intensive research. The existence of proteomic links between AD and diabetes is an important topic currently under active debate. An understanding of the complex association between diabetes and AD is necessary for the development of novel drug therapies and lifestyle guidelines aimed at the treatment and/or prevention of these diseases. This review aims to summarize what is currently known about the biological and especially proteomic relationships and similarities between these two age-related devastating diseases of modern day life. This study may also aid in future for the identification of a single or a panel of potential blood-based protein biomarkers for early diagnosis of AD and T2DM with high sensitivity and specificity. PMID- 24059317 TI - A neuroinformatics study describing molecular interaction of Cisplatin with acetylcholinesterase: a plausible cause for anticancer drug induced neurotoxicity. AB - Several chemotherapeutic drugs are known to cause significant clinical neurotoxicity, which can result in the early cessation of treatment. To identify and develop more effective means of neuroprotection it is important to understand the toxicity of these drugs at the molecular and cellular levels. This study describes molecular interactions between human brain acetylcholinesterase (AChE) and the well-known anti-neoplastic drug, Cisplatin. Docking between Cisplatin and AChE was performed using 'GOLD 5.0' and accessible surface area of protein before and after ligand binding was calculated by NACCESS version 2.1.1. Hydrophobic interactions and hydrogen bonds both play an equally important role in the correct positioning of Cisplatin within the 'acyl pocket' as well as 'catalytic site' of AChE to permit docking. Gold fitness score of 'Cisplatin- acyl domain of AChE' interaction and 'Cisplatin-CAS domain of AChE' interaction were 38.78 and 39.91, respectively and free binding energy was found to be -5.82 Kcal/mol and 5.79 Kcal/mol, respectively. During 'Cisplatin-CAS site of AChE enzyme' interaction, it was found that out of the three amino acids constituting the catalytic triad (S203, H447 and E334), two amino acid residues namely S203 and H447 interact with Cisplatin by hydrogen bonding and hydrophobic interaction, respectively. The values for 'accessible surface area' for the amino acid residues H447 and S203 were found to be reduced by 14.398 A(2) and 3.894 A(2), respectively after interaction with Cisplatin. Hence, Cisplatin might act as a potent inhibitor of AChE. Scope still remains in the determination of the three dimensional structure of AChE-Cisplatin complex by X-ray crystallography to validate the described data. Moreover, such information may aid in the design of versatile AChE-inhibitors, and is expected to aid in safe clinical use of Cisplatin. PMID- 24059318 TI - The role of neuronal insulin/insulin-like growth factor-1 signaling for the pathogenesis of Alzheimer's disease: possible therapeutic implications. AB - Recent data suggest that brains of patients with Alzheimer's disease (AD) are insulin and insulin-like growth factor-1 (IGF-1) resistant. So far, there have been two different approaches to investigate possible therapeutic implications of modulating cerebral insulin/IGF-1 signaling (IIS) in AD. One approach is peripheral or intranasal administration of insulin or IGF-1. Intranasal and peripheral insulin administration has been shown to improve memory in patients with AD. Additionally, peripheral IGF-1 administration resulted in decreased amyloid-beta (Abeta) levels in brains of AD mouse models accompanied by elevated Abeta levels in the cerebrospinal fluid (CSF). Insulin and IGF-1 regulate multicargotransporters influencing trafficking of several molecules including Abeta from the brain to the blood as well as to the CSF and possibly vice versa. Furthermore, insulin and related peptides regulate neurovascular coupling changing regional blood flow. Thus, positive effects of peripheral insulin/IGF-1 administration on AD pathology might be due to changes in the blood-brain-barrier (BBB) and/or in the transport between the CSF/blood and the brain. Clinical and experimental data suggest that increased serum insulin and IGF-1 levels do not necessarily correlate with an upregulation of neuronal insulin/IGF-1 receptor signaling. Therefore, the second approach in investigating the role of neuronal IIS for the pathogenesis of AD analyzes knockout mice lacking components of the IIS in AD models. Haploinsufficiency of the IGF- 1 receptor (IGF-1R) (IGF-1R(+/-) mice) as well as neuronal deficiency of the insulin receptor (IR) (nIR(-/-) mice) or IGF-1R (nIGF-1R(-/-) mice) leads to delayed Abeta accumulation when crossed with mouse models for AD. Furthermore, insulin receptor substrate (IRS)-2 knockout mice (IRS-2(-/-) mice) show reduced Abeta levels in an Alzheimer background. These data suggest beneficial effects of decreased neuronal IIS on Alzheimer-pathology and question the therapeutic outcome of long-term administration of insulin or IGF-1 in patients with AD. Whether the observed phenomenon of cerebral insulin and IGF-1 resistance even at an early stage of Alzheimer's disease is cause, consequence or possibly counter-regulation to AD pathology needs further investigation and should lead to critical discussions. The current review discusses the pros and cons of targeting insulin/IGF-1 signaling as therapeutic approach for AD. PMID- 24059319 TI - Genomic linkage between Alzheimer's disease and type 2 diabetes. AB - Alzheimer's disease (AD) is a major health concern that affects nearly every society worldwide. The disease is an irreversible, progressive and age-related neurodegenerative disorder. It is characterized by impaired cognitive function and the diffuse deposition of amyloid plaques and neurofibrillary tangles. The causes of AD and the underlying mechanisms that trigger the onset of the disease are still a matter of debate. Several epidemiological studies have shown that the development of AD is associated with type 2 diabetes mellitus (T2D). In this review, we provide evidence for the link between T2D and AD, highlighting the critical role of insulin in the pathogenesis of these diseases, and we provide information on the genes that might be involved in the interplay between these two disorders. New insight into the complex biology of AD is necessary for the early diagnosis of the disease, the development of novel drug therapies and the prevention of these health issues. PMID- 24059320 TI - Insulin-degrading enzyme: a link between Alzheimer's and type 2 diabetes mellitus. AB - Enzymes play a very vital role in maintaining the homeostasis inside the body. Improper functioning of enzymes is associated with many diseases. Insulin degrading enzyme (IDE), a ubiquitously expressed zinc metalloprotease, is believed to act as a junction point of Type 2 Diabetes and Alzheimer's disease. Recent studies provide inkling for the use of IDE as a potential target hence the design of its regulators would be a viable approach towards treatment of these diseases. This review provides an overview of the IDE structure and function; a relationship is drawn between IDE, Type 2 Diabetes mellitus and Alzheimer's disease and the approaches that make IDE a potential target, are discussed. PMID- 24059321 TI - Common cellular and molecular mechanisms underlying Alzheimer's disease and type 2 diabetes: a knowledge-driven approach. AB - The relationship between the two age-related diseases namely, Alzheimer's disease (AD) and type II diabetes mellitus (T2DM), is gaining much attention in research because of the alarming forecast on both increasing incidence and economic burden. Recent research studies have identified some of the existing links, between AD and T2DM, such as the dysfunctional glucose metabolism and insulin signaling, stress and inflammation, defective protein processing and the role of advanced glycation end products. It is, therefore, crucial to understand the cellular and molecular mechanisms to identify the common linking mechanisms involved in the pathogenesis of both AD and T2DM. Genome wide association studies may lead to identification of novel targets and provide clues for possible interventional strategies to limit the progression of these two age-related diseases. Hence, the purpose of the present review is to provide an update, on the various possible linking cellular and molecular mechanisms, including our experience on the use of high throughput applications to investigate the molecular mechanisms underneath the neurodegeneration in animal models. Besides, using this knowledge-driven approach, we discuss how the current technological advancements can effectively be used to identify possible associations between these age-related diseases. PMID- 24059323 TI - Molecular linkages between diabetes and Alzheimer's disease: current scenario and future prospects. AB - After the revolutionary Rotterdam study that suggested there was an increased risk of developing Alzheimer's disease (AD) in patients with type-2 diabetes mellitus (T2DM), a number of studies have provided direct evidence for the linkage between AD and T2DM. In recent years, AD is considered as a neuroendocrine disorder, also referred as type-3 diabetes. There is a growing list of evidence to suggest that, in addition to impaired insulin signaling, there are a number of additional factors that may act as mechanistic links between AD and T2DM. These factors mainly include hypercholesterolemia, dyslipidemia, hypercystinemia, inflammation, impaired insulin signaling and impaired central nervous response to the adipose tissue-derived hormone leptin. Increased cholesterol plays a crucial role in the abnormal metabolism of the amyloid precursor protein, leading to the accumulation of beta-amyloid. In addition to impaired insulin signaling, diabetes has been found to accelerate the appearance of cerebrovascular inflammation and beta-amyloid peptide (Abeta) deposition. Increased oxidative stress and production of advanced glycation end products are other probable marker linkages. However, the details of many of these molecular links still require extensive investigation. It is possible that a number of common molecular linkages exist between T2DM and AD. Understanding and analyzing the various molecular linkages between AD and T2DM may shed light on new tools that can be used for the early diagnosis and treatment of AD and also accelerate the identification of T2DM patients who are at high risk of AD. PMID- 24059322 TI - Exploring N(1)-p-fluorobenzyl-cymserine as an inhibitor of 5-lipoxygenase as a candidate for type 2 diabetes and neurodegenerative disorder treatment. AB - Developing a single selective ligand to a target relevant to two mechanistically interlinked diseases, such as type 2 diabetes mellitus (T2DM) and a neurodegenerative disorder, like Parkinson's disease or Alzheimer's disease, provides the potential for an effective treatment that may impact both. The enzyme 5-lipoxygenase (5-LOX) has been revealed responsible for producing fatty acid molecules, leukotrienes. These leukotrienes are known to produce inflammatory responses in asthma and allergic reactions, to induce a reduction of tyrosine hydroxylase in brain, and are involved in the development of cardiac strokes, obesity and type 2 diabetes. N(1)-p-fluorobenzyl-cymserine (FBC), an analogue of cymserine and a known cholineterase inhibitor, was evaluated for inhibition of pleiotropic 5-LOX in our study. The stable 3D structure of 5-LOX was obtained from the Protein Data Bank (PDB) database and was implied for homology modeling of four reported mutant models. Each generated model was submitted to the Protein Model Database (PMDB) and employed for measuring inhibition and ligand efficiency of FBC with support of molecular docking. For each model, normal as well as mutant, FBC yielded remarkable inhibition constant values, with exothermic free binding energies. The current study revealed a highly reactive narrow fissure near the non-heme iron binding pocket of 5-LOX that contains residues crucial for 5-LOX stability and FBC binding. Investigating the binding of FBC with stabilized and destabilized 5-LOX structures confirmed it as a candidate therapeutic inhibitor worthy of assessment in preclinical models of T2DM and neurodegeneration. PMID- 24059324 TI - Fighting Alzheimer's disease and type 2 diabetes: pathological links and treatment strategies. AB - The incidence of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) with associated serious complications continues to grow rapidly especially in developed countries. Emerging evidence indicates that AD and T2DM share some common risk factors with comparable pathological features including insulin resistance, amyloidogenesis, glucocorticoid imbalance, inflammation, mitochondrial function and oxidative stress. T2DM has been identified as a risk factor for AD. It has even been hypothesized that AD might be "type 3 diabetes". In addition to amyloid precursor protein processing and tau phosphorylation, commonalities between T2DM and AD in molecular mechanisms provide clues to the identification of novel therapeutic targets such as glucagon-like peptide 1, butyrylcholinesterase, and receptor for advanced glycosylation end products. Although several classes of anti-diabetic drugs are available, achieving long term glycaemic control without side effects is often challenging. This review summarizes recent evidence for the pathological links, common therapeutic targets, currently the U.S. Food and Drug Administration approved and potential future therapies, giving special attention to ongoing clinical trials of antidiabetic drugs in AD patients and common therapeutic strategies in the management of both AD and T2DM. PMID- 24059325 TI - A molecular bridge: connecting type 2 diabetes and Alzheimer's disease. AB - Type 2 diabetes (T2D) and Alzheimer's disease (AD) are complex diseases commonly associated with aging. Accumulating evidence indicates a connection between these two diseases at the molecular level. Much of what we currently know about T2D and AD is derived from in vivo and in vitro studies. However, further research and characterization of molecules is necessary to establish a strong connection between T2D and AD. In silico studies play a major role in finding non-evident patterns of gene expression and gene network connectivity. In this review, we give a brief introduction to T2D and AD and then describe the risk factors and molecules that are commonly associated with these diseases. Finally, we discuss the future directions and applications of bioinformatics that can provide greater insight into the relationship between these two diseases. Analysis and integration of high-throughput data on genomics, transcriptomics, proteomics and metabolomics from normal and disease tissues would be very useful to improve our understanding of the mechanism behind disease initiation and the connection between these two diseases. We encourage researchers to use bioinformatics approaches to identify genes and their regulatory pathways that are commonly affected in T2D and AD, as these genes and pathways could be potential biomarkers and targets for disease treatment. PMID- 24059326 TI - Structural evidence for a two-regime photobleaching mechanism in a reversibly switchable fluorescent protein. AB - Photobleaching, the irreversible photodestruction of a chromophore, severely limits the use of fluorescent proteins (FPs) in optical microscopy. Yet, the mechanisms that govern photobleaching remain poorly understood. In Reversibly Switchable Fluorescent Proteins (RSFPs), a class of FPs that can be repeatedly photoswitched between nonfluorescent and fluorescent states, photobleaching limits the achievable number of switching cycles, a process known as photofatigue. We investigated the photofatigue mechanisms in the protein IrisFP using combined X-ray crystallography, optical in crystallo spectroscopy, mass spectrometry and modeling approaches. At laser-light intensities typical of conventional wide-field fluorescence microscopy, an oxygen-dependent photobleaching pathway was evidenced. Structural modifications induced by singlet oxygen production within the chromophore pocket revealed the oxidation of two sulfur-containing residues, Met159 and Cys171, locking the chromophore in a nonfluorescent protonated state. At laser-light intensities typical of localization-based nanoscopy (>0.1 kW/cm(2)), a completely different, oxygen independent photobleaching pathway was found to take place. The conserved Glu212 underwent decarboxylation concomitantly with an extensive rearrangement of the H bond network around the chromophore, and an sp(2)-to-sp(3) hybridization change of the carbon atom bridging the chromophore cyclic moieties was observed. This two-regime photobleaching mechanism is likely to be a common feature in RSFPs from Anthozoan species, which typically share high structural and sequence identity with IrisFP. In addition, our results suggest that, when such FPs are used, the illumination conditions employed in localization-based super-resolution microscopy might generate less cytotoxicity than those of standard wide-field microscopy at constant absorbed light-dose. Finally, our data will facilitate the rational design of FPs displaying enhanced photoresistance. PMID- 24059327 TI - Targeted radionuclide therapy--an overview. AB - Radionuclide therapy (RNT) based on the concept of delivering cytotoxic levels of radiation to disease sites is one of the rapidly growing fields of nuclear medicine. Unlike conventional external beam therapy, RNT targets diseases at the cellular level rather than on a gross anatomical level. This concept is a blend of a tracer moiety that mediates a site specific accumulation followed by induction of cytotoxicity with the short-range biological effectiveness of particulate radiations. Knowledge of the biochemical reactions taking place at cellular levels has stimulated the development of sophisticated molecular carriers, catalyzing a shift towards using more specific targeting radiolabelled agents. There is also improved understanding of factors of importance for choice of appropriate radionuclides based on availability, the types of emissions, linear energy transfer (LET), and physical half-life. This article discusses the applications of radionuclide therapy for treatment of cancer as well as other diseases. The primary objective of this review is to provide an overview on the role of radionuclide therapy in the treatment of different diseases such as polycythaemia, thyroid malignancies, metastatic bone pain, radiation synovectomy, hepatocellular carcinoma (HCC), neuroendocrine tumors (NETs), non-Hodgkin's lymphoma (NHL) and others. In addition, recent developments on the systematic approach in designing treatment regimens as well as recent progress, challenges and future perspectives are discussed. An examination of the progress of radionuclide therapy indicates that although a rapid stride has been made for treating hematological tumors, the development for treating solid tumors has, so far, been limited. However, the emergence of novel tumor-specific targeting agents coupled with successful characterization of new target structures would be expected to pave the way for future treatment for such tumors. PMID- 24059329 TI - Immunophenotype of Dental Implant-Associated Peripheral Giant Cell Reparative Granuloma in a Representative Case Report. AB - We report the case of a 74-year-old white male patient who had worn an overdenture for the previous 6 years, retained by 4 screwed implants and a bar, who presented with an exophytic multilobed lesion of 2.5 * 2.0 cm on the anterior aspect of 1 implant neck, which was surrounded by pink-reddish tissue. All of the soft tissue around the implant was removed until the periosteum was reached. Histologic examination of the lamina propria revealed a cellular proliferation with imprecise boundaries, dense stromal component composed of spindle- to round shaped mononucleated cells (fibroblasts and monocytes/macrophages), abundant multinucleated giant cells surrounding microscopic hemorrhagic foci, and deposits of hemosiderin; the diagnosis was peripheral giant-cell reparative granuloma (PGCG). Giant cells share the immunohistochemical expression of monocyte/macrophage markers (CD68, calprotectin [Mc387]) and osteoclastic cell markers (tartrate-resistant acid phosphatase, cathepsin K, and microphthalmia associated transcription factor). After 6 months of follow-up, no bone resorption or recurrence of implant loss was observed. There have been only 12 case reports on dental implant-associated PGCG. Research results to date indicate that there may be little difference in immunophenotype among the giant cells of PGCG, central giant cell reparative granuloma, and peri-implant osteolysis. In conclusion, the immunohistochemical study confirms an osteoclast like giant cells phenotype differentiation in PGCG. PMID- 24059328 TI - The effect of avian blood on Leishmania development in Phlebotomus duboscqi. AB - BACKGROUND: The development of pathogens transmitted by haematophagous invertebrate vectors is closely connected with the digestion of bloodmeals and is thus affected by midgut enzymatic activity. Some studies have demonstrated that avian blood inhibits Leishmania major infection in the Old World vector Phlebotomus papatasi; however, this effect has never been observed in the New World vectors of the genus Lutzomyia infected by other Leishmania species. Therefore, our study was focused on the effect of chicken blood on bloodmeal digestion and the development of Leishmania major in its natural vector Phlebotomus duboscqi, i.e. in a vector-parasite combination where the effect of blood is assumed. In addition, we tested the effect of avian blood on midgut trypsin activity and the influence of repeated feedings on the susceptibility of sand flies to Leishmania infection. METHODS: Phlebotomus duboscqi females were infected by rabbit blood containing L. major and either before or after the infection fed on chickens or mice. The individual guts were checked microscopically for presence and localization of Leishmania, parasite numbers were detected by Q-PCR. In addition, midgut trypsin activity was studied. RESULTS: Sand fly females fed on chicken blood had significantly lower midgut trypsin activity and delayed egg development compared to those fed on rabbits. On the other hand, there was no effect detected of avian blood on parasite development within the sand fly gut: similar infection rates and parasite loads were observed in P. duboscqi females infected by L. major and fed on chickens or mouse one or six days later. Similarly, previous blood feeding of sand flies on chickens or mice did not show any differences in subsequent Leishmania infections, and there was equal susceptibility of P. duboscqi to L. major infection during the first and second bloodmeals. CONCLUSION: In spite of the fact that avian blood affects trypsin activity and the oocyte development of sand flies, no effect of chicken blood was observed on the development of L. major in P. duboscqi. Our study unambiguously shows that sand fly feeding on avian hosts is not harmful to Leishmania parasites within the sand fly midgut. PMID- 24059330 TI - Biological strategies to enhance rotator cuff healing. AB - Rotator cuff tear causes a high rate of morbidity. After surgical repair, the presence of a scar tissue reduces tendon biomechanical properties. Emerging strategies for enhancing tendon healing are growth factors, cytokines, gene therapy and tissue engineering. However their efficacy has to be proved. Growth factors help the process of tendon healing by aiding cells chemotaxis, differentiation and proliferation. Numerous growth factors, including the bone morphogenetic proteins and platelet-derived growth factor can be found during the early healing process of a rotator cuff repair. Growth factors are delivered to the repair site using tissue-engineered scaffolding, coated sutures, or dissolved in a fibrin sealant. Platelet-rich plasma is an autologous concentration of platelets and contains an high density of growth factors. There is some evidence that platelet-rich plasma may improve pain and recovery of function in a short time period, but it does not improve healing rates in rotator cuff. Thus the routine use of platelet-rich plasma in rotator cuff repair is not recommended. The addition of mesenchymal stem cells to scaffolds can lead to the production of a better quality healing tissue. Gene therapy is a gene transfer from a cell into another, in order to over-express the gene required. In this way, cultures of stem cells can over-express growth factors. Better understanding of the mechanisms of physiological tendon healing can promote the correct use of these new biological therapies for a better healing tissue. PMID- 24059331 TI - Modulation of prion by small molecules: from monovalent to bivalent and multivalent ligands. AB - Prion diseases are fatal neurodegenerative disorders that affect humans and animals and for which no pharmacological treatment is available. Compounds consisting of two identical moieties joined via an appropriate spacer (i.e. bivalent compounds) have turned out to be effective tools to prevent prion fibril formation and exhibit an improved biological profile with regard to the corresponding monovalent derivatives. In this review we discuss the importance of the bivalent strategy as a viable approach to design new chemical entities to combat prion diseases. PMID- 24059332 TI - Thienyl pyrimidine derivatives with PrP(Sc) oligomer-inducing activity are a promising tool to study prions. AB - Transmissible spongiform encephalopathies (TSEs), also called prion diseases, are fatal, infectious, genetic or sporadic neurodegenerative disorders of humans and animals. In humans, TSEs are represented by Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia and Kuru. In animals, the most prominent prion diseases are scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) of cattle and chronic wasting disease (CWD) of deer and elk. A critical event in prion diseases is the accumulation in the central nervous system (CNS) of the abnormally folded PrP(Sc) protein that is the protease-resistant isoform of a normal cellular protein encoded by the host and called PrP(C). PrP(Sc) (also known as rPrP(Sc) or PrP27-30) represents the main marker of prion diseases and is routinely used in the reference method for the diagnosis of prion diseases. Most of the therapeutic strategies developed so far aimed at identifying compounds that diminish the levels of PrP(Sc), with variable success when tested in vivo. In this review, we present an alternative approach in which small molecules that induce PrP(Sc) oligomers are identified. By using virtual and cellular screenings, we found several thienyl pyrimidine compounds that trigger PrP(Sc) oligomerization and trap prion infectivity. PMID- 24059334 TI - Animal models for testing anti-prion drugs. AB - Prion diseases belong to a group of fatal infectious diseases with no effective therapies available. Throughout the last 35 years, less than 50 different drugs have been tested in different experimental animal models without hopeful results. An important limitation when searching for new drugs is the existence of appropriate models of the disease. The three different possible origins of prion diseases require the existence of different animal models for testing anti-prion compounds. Wild type, over-expressing transgenic mice and other more sophisticated animal models have been used to evaluate a diversity of compounds which some of them were previously tested in different in vitro experimental models. The complexity of prion diseases will require more pre-screening studies, reliable sporadic (or spontaneous) animal models and accurate chemical modifications of the selected compounds before having an effective therapy against human prion diseases. This review is intended to put on display the more relevant animal models that have been used in the search of new antiprion therapies and describe some possible procedures when handling chemical compounds presumed to have anti-prion activity prior to testing them in animal models. PMID- 24059333 TI - Amyloid-binding compounds and their anti-prion potency. AB - Prion diseases, or transmissible spongiform encephalopathies, are characterized by abnormal prion protein accumulation in the brain. Abnormal prion proteins, having properties of amyloids when extracted from the brain, are observed as amyloid plaque deposits in the brain in some prion diseases such as variant Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker syndrome. This article reviews amyloid-binding compounds from the perspective of their usefulness for diagnosis and therapy of prion diseases. Styrylbenzoazole derivatives and phenylhydrazine derivatives are recently developed amyloid binding compounds that present benefits for prion-disease-related medicinal applications. For instance, styrylbenzoazole derivative BF-227, currently used as an amyloid imaging probe of positron emission tomography in Alzheimer disease, is useful also for the diagnosis of Gerstmann-Straussler-Scheinker syndrome. A phenylhydrazine derivative, compB, has remarkable prophylactic effects on intracerebrally infected animals with certain prion strains, even when administered orally. These amyloid-binding compounds, however, are not applicable to prion strains or prion diseases of all types. For example, amyloid-binding compounds are ineffective for inhibiting prion strains such as 263K. They are not feasible for detecting abnormal prion protein accumulation in the brain for prion diseases having no amyloid plaques. To elucidate the limitations of amyloid binding compounds, further investigation is necessary to clarify the binding mode of the compounds to abnormal prion protein structures at an atomic level. PMID- 24059335 TI - Hybrid molecules synergistically acting against protein aggregation diseases. AB - An emerging common feature of the age-associated neurodegenerative disorders like Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) is the ability of many disease-associated protein aggregates to induce conversion of a normal counterpart conformer leading to an acceleration of disease progression. Curative pharmacotherapy has not been achieved so far despite successes in elucidating pathomechanisms. Here, we review the pharmaceutical strategy of generating hybrid compounds, i.e. compounds consisting of several independently acting moieties with synergistic effects, on key molecular players in AD and CJD. For prion diseases, we review hybrid compounds consisting of two different heterocyclic compounds, their synergistic effects on prion replication in a cell culture model and their ability to prolong survival of experimentally prion-infected mice in vivo. While a combination therapy of several antiprion compounds including quinacrine, clomipramine, simvastatin and tocopherol prolonged survival time to 10-25%, administration of hybrid compound quinpramine alone, a chimera of acridine and iminodibenzyl scaffolds, led to 10% survival time extension. For AD, we review a hybrid compound consisting of an Abeta recognizing D-peptide fused to a small molecule beta-sheet breaker, an aminopyrazole. This molecule was able to diminish Abeta oligomers in cell culture and significantly decrease synaptotoxicity as measured by miniature excitatory postsynaptic responses in vitro. Hybrid compounds can dramatically increase potency of their single moieties and lead to novel functions when they act in a simultaneous or sequential manner thereby revealing synergistic properties. Their systematic generation combining different classes of compounds from peptides to small molecules has the potential to significantly accelerate drug discovery. PMID- 24059336 TI - Therapy in prion diseases. AB - In the last two decades, knowledge of the neurobiology of prion diseases or transmissible spongiform encephalopathies (TSE) has significantly advanced, but a successful therapy to stop or delay the progression of these disorders remains one of the most challenging goals of biomedical research. Several obstacles to this achievement are in common with other neurodegenerative disorders: difficulties to move from experimental level to clinical stage; appropriate timing of intervention; correct set up of clinical trial. Also in terms of molecular bases of disease, TSE and the other neurodegenerative disorders associated with protein misfolding such as Alzheimer, Parkinson and Huntington diseases, share a central pathogenic role of soluble small aggregates, named oligomers, considered the culprit of neuronal dysfunction: accordingly, these disorders could by termed oligomeropathies. However, the rapid progression of TSE, together with their clinical and molecular heterogeneity, make the therapeutic approach particularly problematic. The main target of the antiprion strategy has been the pathological form of the cellular prion protein (PrP(C)) termed PrP(Sc), invariably associated with the diseases. Several compounds have been found to affect PrP(Sc) formation or enhance its clearance in in vitro models, and prolong survival in experimental animals. However, few of them such as quinacrine and pentosan polysulfate have reached the clinical evaluation; more recently, we have conducted a clinical trial with doxycycline in patients with Creutzfeldt-Jakob disease without satisfactory results. In experimental conditions, active and passive immunization with antibodies against PrP and mucosal vaccination have shown to protect from peripheral infection. Other studies have proposed new potentially effective molecules targeting PrP oligomers. Furthermore, the possibility to interfere with PrP(C) to PrP(Sc) conversion by an active control of PrP(C) is another interesting approach emerging from experimental studies. However, in common with the other oligomeropathies, early diagnosis allowing to treat at risk population in a preclinical stage represent the more realistic perspective for efficient TSE therapy. PMID- 24059337 TI - Prion chemical biology: on the road to therapeutics? AB - Prion diseases, also known as transmissible spongiform encephalopathies (TSEs) are infectious and fatal neurodegenerative diseases. So far, there is no therapy available with clinical efficacy. A detailed survey on the discovery of major classes of small molecule antiprion compounds is documented in this review in the hope that it may shine some light on the future direction of drug discovery against prion and other neurodegenerative diseases. PMID- 24059338 TI - Logical design of medical chaperone for prion diseases. AB - A strategy of logical drug design (LDD) and its application to prion diseases are reviewed. LDD is primarily based on the localizability of a hot spot which initiates structural instability in the target protein. It is also based on the regulability of the hot spot by small compounds, their designabilty by a computer, their organic synthesizability and the specificity of their functions once administered to the biological organisms. Unification of localizability, regulability, producibility and specificity is the central theme of LDD. Theoretical foundation of LDD based on quantum theories is initially outlined. The localizability using nuclear magnetic resonance (NMR), the regulability by a medical chaperone, the synthesizability, and the functional specificity accomplished thus far, are then described. PMID- 24059339 TI - Computational studies on the prion protein. AB - Prion diseases are rare neurodegenerative diseases characterized by the conversion of the prion protein from its native state (PrP(C)) towards the so called 'scrapie form', rich in beta-strands. Computational approaches, here briefly reviewed, are instrumental to understand the intrinsic instability of PrP(C) fold and how the latter is affected by mutations, binding of metals as well as by different environmental conditions, such as pH and temperature. These studies also provide a structural basis for the binding of anti-prion compounds, which may block the conversion to the scrapie form and, consequently, may inhibit fibril formation. PMID- 24059340 TI - NMR structural studies of human cellular prion proteins. AB - Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the conformational conversion of the cellular prion protein, PrP(C), into a pathological form known as prion or PrP(Sc). They can be classified into sporadic, inherited and infectious forms. Spontaneous generation of PrP(Sc) in inherited forms of prion diseases is caused by mutations in the human prion protein gene (PRNP). A major goal in prion biology is unraveling the molecular mechanism by which PrP(C) misfolds and leads to development of diseases. Structural characterization of various human PrP (HuPrP) variants may be helpful for better understanding of the earliest stages of the conformational changes leading to spontaneous generation of prions. Here, we review the results of the recent high-resolution nuclear magnetic resonance (NMR) structural studies on HuPrPs with pathological Q212P and V210I mutations linked with Gerstmann-Straussler-Scheinker (GSS) syndrome and familial Creutzfeldt-Jakob disease (fCJD), respectively, and HuPrP carrying naturally occurring E219K polymorphism considered to protect against sporadic CJD (sCJD). We describe subtle local differences between the three-dimensional (3D) structures of HuPrP mutants and the wild-type (WT) protein, providing new insights into the possible key structural determinants underlying conversion of PrP(C) into PrP(Sc). Also highlighted are the most recent findings from NMR studies about the effect of pH on the structural features of HuPrP with V210I mutation. PMID- 24059341 TI - Strain specificity and drug resistance in anti-prion therapy. AB - Prion diseases are a group of fatal neurodegenerative diseases caused by the misfolding of cellular prion protein (PrP(C)) into pathogenic conformers (PrP(Sc)). Although no effective therapies for prion diseases are currently available, a number of small molecule inhibitors have been identified that are capable of reducing or eliminating PrP(Sc) in prion infected cells. However, recent experiments have shown that upon sustained treatment, prions have the capacity to evolve into drug resistant conformations. These studies suggest that the mechanism of prion strain adaptation involves rare conformational conversions followed by competitive selection among the heterogeneous pool of PrP(Sc) conformers. The plasticity of prion conformers makes PrP(Sc) a particularly challenging drug target and suggests that combination drug therapies or targeting of PrP(C) may be required for effective therapy. In this review, we highlight recent literature that demonstrate the phenomenon of prion drug resistance and strain specificity, and discuss potential ramifications for therapeutic efforts against prion diseases. PMID- 24059343 TI - The influence of passivation and photovoltaic properties of alpha-Si:H coverage on silicon nanowire array solar cells. AB - Silicon nanowire (SiNW) arrays for radial p-n junction solar cells offer potential advantages of light trapping effects and quick charge collection. Nevertheless, lower open circuit voltages (Voc) lead to lower energy conversion efficiencies. In such cases, the performance of the solar cells depends critically on the quality of the SiNW interfaces. In this study, SiNW core-shell solar cells have been fabricated by growing crystalline silicon (c-Si) nanowires via the metal-assisted chemical etching method and by depositing hydrogenated amorphous silicon (alpha-Si:H) via the plasma-enhanced chemical vapor deposition (PECVD) method. The influence of deposition parameters on the coverage and, consequently, the passivation and photovoltaic properties of alpha-Si:H layers on SiNW solar cells have been analyzed. PMID- 24059344 TI - Syntheses of pentanuclear group 6 iridium clusters by core expansion of tetranuclear clusters with Ir(CO)2(eta5-C5Me4R) (R = H, Me). AB - Metal cluster core expansion at tetrahedral group 6-group 9 mixed-metal clusters MIr3(MU-CO)3(CO)8(eta(5)-L) (M = W, Mo, L = C5H5; M = Mo, L = C5Me5) with the iridium capping reagents Ir(CO)2(eta(5)-L') (L' = C5Me5, C5Me4H) in refluxing toluene afforded the trigonal-bipyramidal clusters MIr4(MU-CO)3(CO)7(eta(5) C5H5)(eta(5)-L') (M = Mo, L' = C5Me5, 1a; M = W, L' = C5Me5, 1b; M = Mo, L' = C5Me4H, 1c; M = W, L' = C5Me4H, 1d) and MoIr4(MU3-H)(MU-CO)2(MU-eta(1):eta(5) CH2C5Me4)(CO)7(eta(5)-C5Me5) (2). Related reactions with M2Ir2(MU CO)3(CO)7(eta(5)-L)2 (M = W, Mo, L = C5H5; M = Mo, L = C5Me5) afforded M2Ir3(MU CO)3(CO)6(eta(5)-C5H5)2(eta(5)-L') (M = Mo, L' = C5Me5, 3a; M = W, L' = C5Me5, 3b; M = Mo, L' = C5Me4H, 3c; M = W, L' = C5Me4H, 3d), W2Ir3(MU-CO)4(CO)5(eta(5) C5H5)2(eta(5)-C5Me4H) (4), and Mo2Ir3(MU-CO)3(CO)6(eta(5)-C5Me5)3 (5). Single crystal X-ray diffraction studies of 1a-1d, 2, 3a-3d, and 4 confirmed their molecular structures, including the MU-eta(1):eta(5)-CH2C5Me4 ligand at hydrido cluster 2, derived from a C-H bond activation of one of the methyl groups. Density functional theory (DFT) studies were employed to suggest the structure of 5. The redox behavior of the new clusters was examined through cyclic voltammetry; all clusters exhibit oxidation and reduction processes (with respect to the resting state), with the oxidation processes being the more reversible, and increasingly so on decreasing Ir content of the clusters, replacing W by Mo, and increasing alkylation of the cyclopentadienyl ligands. In situ IR and UV-vis near-IR spectroelectrochemical studies of the reversible oxidation processes in 1a and 3a were undertaken, with the spectra of the former suggesting progression to an all-terminal CO geometry concomitant with the first oxidation and a significant structural change upon the second oxidation step. DFT studies of 1a revealed that its crystallographically-confirmed Mo-equatorial core geometry is essentially isoenergetic with a possible Mo-apical isomer, and identified several bridging CO structures for the charged states. PMID- 24059345 TI - Blood total carbon dioxide content and bicarbonate can be used together to predict blood pH correctly in venous blood samples. AB - Blood gas analyses are needed to reveal any kind of acid-base imbalance in some patients. Traditionally, arterial punctures are performed to obtain the blood samples for blood gas analyses. Arterial puncture is not a completely safe procedure. It may cause serious problems including arterial thrombosis, arteriovenous fistula, pseudoaneurysms and hematoma. In this retrospective reviewing, it was aimed to yield novel formulations to predict the blood pH only from CtCO2 and HCO3 values which can easily be measured in venous blood samples obtained for other diagnostic and follow-up purposes. PMID- 24059346 TI - The evaluating self-management and educational support in severely obese patients awaiting multidisciplinary bariatric care (EVOLUTION) trial: rationale and design. AB - BACKGROUND: In Canada, demand for multidisciplinary bariatric (obesity) care far outstrips capacity. Consequently, prolonged wait times exist and contribute to substantial health impairments.A supportive, educational intervention (with in person and web-based versions) designed to enhance the self-management skills of patients wait-listed for multidisciplinary bariatric medical and surgical care has been variably implemented across Alberta, Canada. However, its effectiveness has not been evaluated. Our objectives were: 1. To determine if this program improves clinical and humanistic outcomes and is cost-effective compared to a control intervention; and 2. To compare the effectiveness and cost-effectiveness of in-person group-based versus web-based care. We hypothesize that both the web based and in-person programs will reduce body weight and improve outcomes compared to the control group. Furthermore, we hypothesize that the in-person version will be more effective but more costly than the web-based version. METHODS/DESIGN: This pragmatic, prospective controlled trial will enrol 660 wait listed subjects (220 per study arm) from regional bariatric programs in Alberta and randomly assign them to: 1. an in-person, group-based intervention (9 modules delivered over 10 sessions); 2. a web-based intervention (13 modules); and 3. controls who will receive mailed literature. Subjects will have three months to review the content assigned to them (the intervention period) after which they will immediately enter the weight management clinic. Data will be collected at baseline and every 3 months for 9 months (study end), including: 1. Clinical [5% weight loss responders (primary outcome), absolute and % weight losses, changes in obesity-related comorbidities]; 2. Humanistic (health related quality of life, patient satisfaction, depression, and self-efficacy); and 3. Economic (incremental costs and utilities and cost per change in BMI assessed from the third party health care payor perspective) outcomes. Covariate-adjusted baseline to-nine-month change-scores will be compared between groups for each outcome using linear regression for continuous outcomes and logistic regression for dichotomous ones. DISCUSSION: Our findings will determine whether this intervention is effective and cost-effective compared to controls and if online or in-person care delivery is preferred. This information will be useful for clinicians, health-service providers and policy makers and should be generalizable to similar publically-funded bariatric care programs. TRIAL REGISTRATION: Trial Identifier: NCT01860131. PMID- 24059349 TI - Total ileocolic intussusception with rectal prolapse presenting in an adult: a case report and review of the literature. AB - INTRODUCTION: Intussusception is rarely encountered in adults, accounting for just 5% of all occurrences and 1% of bowel obstructions. In up to 90% of episodes of adult intussusceptions, operative intervention is required secondary to pathological lead points. Prior to the current report, only three cases of total ileocolic intussusception with rectal prolapse in adults have been described in the world literature, making it an important contribution to surgical knowledge. In addition to a discussion of disease etiology, this review outlines sound diagnostic and therapeutic principles in the successful management of this rare emergent surgical condition. CASE PRESENTATION AND LITERATURE REVIEW: In this case report, we will present a rare case of total ileocolic intussusception with rectal prolapse in a 22 year-old female without antecedent history. She had both a lead point in the cecum, as well as a highly mobile, intraperitoneal colon. Lead points have been found in only half of the reported cases, including this one. In addition, colonic laxity may enable this phenomenon, being attributed to the loss of zygosis during the embryological period, in which there is persistence of the ascending and descending mesocolons and lack of apposition to the retroperitoneum. The diagnostic work-up, operative strategy and pathological findings are discussed. The three previous cases reported in the English-language medical literature were reviewed. CONCLUSIONS: Adult intussusception, while uncommon, may be encountered in an acute surgical setting and optimal outcomes depend on a high index of suspicion and expeditious management. Embryological divergence may contribute to the even rarer variant of total ileocolic intussusception with rectal prolapse. PMID- 24059347 TI - SDF-1alpha in glycan nanoparticles exhibits full activity and reduces pulmonary hypertension in rats. AB - To establish a homing signal in the lung to recruit circulating stem cells for tissue repair, we formulated a nanoparticle, SDF-1alpha NP, by complexing SDF 1alpha with dextran sulfate and chitosan. The data show that SDF-1alpha was barely released from the nanoparticles over an extended period of time in vitro (3% in 7 days at 37 degrees C); however, incorporated SDF-1alpha exhibited full chemotactic activity and receptor activation compared to its free form. The nanoparticles were not endocytosed after incubation with Jurkat cells. When aerosolized into the lungs of rats, SDF-1alpha NP displayed a greater retention time compared to free SDF-1alpha (64 vs 2% remaining at 16 h). In a rat model of monocrotaline-induced lung injury, SDF-1alpha NP, but not free form SDF-1alpha, was found to reduce pulmonary hypertension. These data suggest that the nanoparticle formulation protected SDF-1alpha from rapid clearance in the lung and sustained its biological function in vivo. PMID- 24059348 TI - Transcriptional reprogramming and chromatin remodeling accompanies Oct4 and Nanog silencing in mouse trophoblast lineage. AB - In mouse blastocysts, CDX2 plays a key role in silencing Oct4 and Nanog expression in the trophectoderm (TE) lineage. However, the underlying transcriptional and chromatin-based changes that are associated with CDX2 mediated repression are poorly understood. To address this, a Cdx2-inducible mouse embryonic stem (ES) cell line was utilized as a model system. Induction of Cdx2 expression resulted in a decrease in Oct4/Nanog expression, an increase in TE markers, and differentiation into trophoblast-like stem (TS-like) cells within 48 to 120 h. Consistent with the down-regulation of Oct4 and Nanog transcripts, a time-dependent increase in CDX2 binding and a decrease in RNA polymerase II (RNAPII) and OCT4 binding was observed within 48 h (P<0.05). To test whether transcriptionally active epigenetic marks were erased during differentiation, histone H3K9/14 acetylation and two of its epigenetic modifiers were evaluated. Accordingly, a significant decrease in histone H3K9/14 acetylation and loss of p300 and HDAC1 binding at the Oct4 and Nanog regulatory elements was observed by 48 h. Accompanying these changes, there was a significant increase in total histone H3 and a loss of chromatin accessibility at both the Oct4 and Nanog regulatory elements (P<0.05), indicative of chromatin remodeling. Lastly, DNA methylation analysis revealed that methylation did not occur at Oct4 and Nanog until 96 to 120 h after induction of CDX2. In conclusion, our results show that silencing of Oct4 and Nanog is facilitated by sequential changes in transcription factor binding, histone acetylation, chromatin remodeling, and DNA methylation at core regulatory elements. PMID- 24059350 TI - Comparative methylomics between domesticated and wild silkworms implies possible epigenetic influences on silkworm domestication. AB - BACKGROUND: In contrast to wild species, which have typically evolved phenotypes over long periods of natural selection, domesticates rapidly gained human preferred agronomic traits in a relatively short-time frame via artificial selection. Under domesticated conditions, many traits can be observed that cannot only be due to environmental alteration. In the case of silkworms, aside from genetic divergence, whether epigenetic divergence played a role in domestication is an unanswered question. The silkworm is still an enigma in that it has two DNA methyltransferases (DNMT1 and DNMT2) but their functionality is unknown. Even in particular the functionality of the widely distributed DNMT1 remains unknown in insects in general. RESULTS: By embryonic RNA interference, we reveal that knockdown of silkworm Dnmt1 caused decreased hatchability, providing the first direct experimental evidence of functional significance of insect Dnmt1. In the light of this fact and those that DNA methylation is correlated with gene expression in silkworms and some agronomic traits in domesticated organisms are not stable, we comprehensively compare silk gland methylomes of 3 domesticated (Bombyx mori) and 4 wild (Bombyx mandarina) silkworms to identify differentially methylated genes between the two. We observed 2-fold more differentiated methylated cytosinces (mCs) in domesticated silkworms as compared to their wild counterparts, suggesting a trend of increasing DNA methylation during domestication. Further study of more domesticated and wild silkworms narrowed down the domesticates' epimutations, and we were able to identify a number of differential genes. One such gene showing demethyaltion in domesticates correspondently displays lower gene expression, and more interestingly, has experienced selective sweep. A methylation-increased gene seems to result in higher expression in domesticates and the function of its Drosophila homolog was previously found to be essential for cell volume regulation, indicating a possible correlation with the enlargement of silk glands in domesticated silkworms. CONCLUSIONS: Our results imply epigenetic influences at work during domestication, which gives insight into long time historical controversies regarding acquired inheritance. PMID- 24059351 TI - Application of fluorescently labeled tracer technique for detection of natural active macromolecules in Chinese medicine. AB - Active substances in traditional Chinese Medicine (TCM) contain not only a variety of small molecules, but also many other macromolecules (TCMMs), such as proteins, peptides and polysaccharides. Active TCMM can achieve good therapeutic effects by regulating the body's overall function with lower side effects. This review summarized the literatures published in recent years on the application of fluorescently labeled tracer technique for detection of natural active macromolecules in TCM. Classified by fluorescent markers, applications of fluorescein, rhodamine, and quantum dots (QDs) in TCMM active tracer are reviewed, and the methods and principles of TCMM fluorescent marker are illustrated. Studies on active TCMMs and their action mechanism are quite difficult due to a multitarget, multicomponent, and multipath system of TCM. However, the development of fluorescently labeled active tracer technique (FLATT) provides this research with new tools. Traditional fluorescent markers have many deficiencies, such as easily quenched, short luminous cycle, and intrinsic toxicity. Relatively, FLATT has many obvious advantages, and its application in TCMM is still at the early stage. In order to improve the overall level of fluorescence labeling in TCMM active tracer, the improvement on FLATT's detection sensitivity and biological affinity is urgent and critical to allow study of these interesting molecules. PMID- 24059352 TI - Using image mapping towards biomedical and biological data sharing. AB - : Image-based data integration in eHealth and life sciences is typically concerned with the method used for anatomical space mapping, needed to retrieve, compare and analyse large volumes of biomedical data. In mapping one image onto another image, a mechanism is used to match and find the corresponding spatial regions which have the same meaning between the source and the matching image. Image-based data integration is useful for integrating data of various information structures. Here we discuss a broad range of issues related to data integration of various information structures, review exemplary work on image representation and mapping, and discuss the challenges that these techniques may bring. PMID- 24059353 TI - Comprehensive two-dimensional liquid chromatography of stereoregular poly(methyl methacrylates) for tacticity and molar mass analysis. AB - For the first time, stereoregular poly(methyl methacrylates) (PMMAs) were separated according to tacticity on a carbon-based stationary phase using solvent gradient interaction chromatography (SGIC). This stationary phase provides superior separation capabilities, enabling the baseline separation of highly isotactic and syndiotactic PMMAs of different molar masses. Two-dimensional liquid chromatography was performed with the SGIC method separating, according to tacticity in the first dimension coupled to size-exclusion chromatography separating according to molar mass in the second dimension, thus providing comprehensive information on both microstructure and molar mass. PMID- 24059354 TI - Isolated effect of geometry on mitral valve function for in silico model development. AB - Computational models for the heart's mitral valve (MV) exhibit several uncertainties that may be reduced by further developing these models using ground truth data-sets. This study generated a ground-truth data-set by quantifying the effects of isolated mitral annular flattening, symmetric annular dilatation, symmetric papillary muscle (PM) displacement and asymmetric PM displacement on leaflet coaptation, mitral regurgitation (MR) and anterior leaflet strain. MVs were mounted in an in vitro left heart simulator and tested under pulsatile haemodynamics. Mitral leaflet coaptation length, coaptation depth, tenting area, MR volume, MR jet direction and anterior leaflet strain in the radial and circumferential directions were successfully quantified at increasing levels of geometric distortion. From these data, increase in the levels of isolated PM displacement resulted in the greatest mean change in coaptation depth (70% increase), tenting area (150% increase) and radial leaflet strain (37% increase) while annular dilatation resulted in the largest mean change in coaptation length (50% decrease) and regurgitation volume (134% increase). Regurgitant jets were centrally located for symmetric annular dilatation and symmetric PM displacement. Asymmetric PM displacement resulted in asymmetrically directed jets. Peak changes in anterior leaflet strain in the circumferential direction were smaller and exhibited non-significant differences across the tested conditions. When used together, this ground-truth data-set may be used to parametrically evaluate and develop modelling assumptions for both the MV leaflets and subvalvular apparatus. This novel data may improve MV computational models and provide a platform for the development of future surgical planning tools. PMID- 24059355 TI - Latent tuberculosis infection and associated risk factors among undergraduate healthcare students in Italy: a cross-sectional study. AB - BACKGROUND: The screening of both healthcare workers and students attending teaching hospitals for latent tuberculosis infection (LTBI) is recommended in hospitals of many countries with a low-incidence of TB, including Italy, as a fundamental tool of tuberculosis (TB) control programs. The aim of the study was to estimate the prevalence of LTBI and evaluate the main risk-factors associated with this condition in a cohort of healthcare Italian students. METHODS: In a cross-sectional study, performed between January and May 2012, 881 undergraduate students attending the Medical, Nursing, Pediatric Nursing and Midwifery Schools of the University of Genoa, trained at the IRCCS San Martino-IST Teaching Hospital of Genoa, were actively called to undergo the Tuberculin Skin Test (TST). All the TST positive cases were also tested with an Interferon-Gamma Release Assay (IGRA) to confirm the diagnosis of LTBI. A standardized questionnaire was collected for risk-assessment analysis. RESULTS: Seven hundred and thirty-three (83.2%) subjects underwent TST testing. The prevalence of TST positives was 1.4%, and in 4 (0.5%) out of 10 TST positive cases LTBI diagnosis was confirmed by IGRA. No difference in the prevalence of subjects who tested positive to TST emerged between pre-clinical (n = 138) and clinical (n = 595) students. No statistically significant association between TST positivity and age, gender, and BCG vaccination was observed. The main independent variable associated with TST positivity was to be born in a country with a high TB incidence (i.e., >=20 cases per 100,000 population) (adjusted OR 102.80, 95% CI 18.09-584.04, p < 0.001). CONCLUSIONS: The prevalence of LTBI among healthcare students resulted very low. The only significant association between TST positivity and potential risk factors was to be born in high TB incidence areas. In countries with a low incidence of TB, the screening programs of healthcare students before clinical training can be useful for the early identification and treatment of the sporadic cases of LTBI. PMID- 24059356 TI - Polydopamine microcapsules with different wall structures prepared by a template mediated method for enzyme immobilization. AB - Microcapsules with diverse wall structures may exhibit different performance in specific applications. In the present study, three kinds of mussel-inspired polydopamine (PDA) microcapsules with different wall structures have been prepared by a template-mediated method. More specifically, three types of CaCO3 microspheres (poly(allylamine hydrochloride), (PAH)-doped CaCO3; pure-CaCO3; and poly(styrene sulfonate sodium), (PSS)-doped CaCO3) were synthesized as sacrificial templates, which were then treated by dopamine to obtain the corresponding PDA-CaCO3 microspheres. Through treating these microspheres with disodium ethylene diamine tetraacetic acid (EDTA-2Na) to remove CaCO3, three types of PDA microcapsules were acquired: that was (1) PAH-PDA microcapsule with a thick (~600 nm) and highly porous capsule wall composed of interconnected networks, (2) pure-PDA microcapsule with a thick (~600 nm) and less porous capsule wall, (3) PSS-PDA microcapsule with a thin (~70 nm) and dense capsule wall. Several characterizations confirmed that a higher degree in porosity and interconnectivity of the capsule wall would lead to a higher mass transfer coefficient. When serving as the carrier for catalase (CAT) immobilization, these enzyme-encapsulated PDA microcapsules showed distinct structure-related activity and stability. In particular, PAH-PDA microcapsules with a wall of highly interconnected networks displayed several significant advantages, including increases in enzyme encapsulation efficiency and enzyme activity/stability and a decrease in enzyme leaching in comparison with other two types of PDA microcapsules. Besides, this hierarchically structured PAH-PDA microcapsule may find other promising applications in biocatalysis, biosensors, drug delivery, etc. PMID- 24059358 TI - "I Just bought my residents iPads... now what?" The integration of mobile devices into radiology resident education. AB - OBJECTIVE: This article describes how mobile technologies can improve the way we teach radiology and offers ideas to bridge the clinical gap with technology. CONCLUSION: Radiology programs across the country are purchasing iPads and other mobile devices for their residents. Many programs, however, do not have a concrete vision for how a mobile device can enhance the learning environment. PMID- 24059359 TI - Cost-effectiveness of a novel blood-pool contrast agent in the setting of chest pain evaluation in an emergency department. AB - OBJECTIVE: We evaluated three diagnostic strategies with the objective of comparing the current standard of care for individuals presenting acute chest pain and no history of coronary artery disease (CAD) with a novel diagnostic strategy using an emerging technology (blood-pool contrast agent [BPCA]) to identify the potential benefits and cost reductions. MATERIALS AND METHODS: A decision analytic model of diagnostic strategies and outcomes using a BPCA and a conventional agent for CT angiography (CTA) in patients with acute chest pain was built. The model was used to evaluate three diagnostic strategies: CTA using a BPCA followed by invasive coronary angiography (ICA), CTA using a conventional agent followed by ICA, and ICA alone. RESULTS: The use of the two CTA-based triage tests before ICA in a population with a CAD prevalence of less than 47% was predicted to be more cost-effective than ICA alone. Using the base-case values and a cost premium for BPCA over the conventional CT agent (cost of BPCA ~ 5* that of a conventional agent) showed that CTA with a BPCA before ICA resulted in the most cost-effective strategy; the other strategies were ruled out by simple dominance. The model strongly depends on the rates of complications from the diagnostic tests included in the model. In a population with an elevated risk of contrast-induced nephropathy (CIN), a significant premium cost per BPCA dose still resulted in the alternative whereby CTA using BPCA was more cost-effective than CTA using a conventional agent. A similar effect was observed for potential complications resulting from the BPCA injection. Conversely, in the presence of a similar complication rate from BPCA, the diagnostic strategy of CTA using a conventional agent would be the optimal alternative. CONCLUSION: BPCAs could have a significant impact in the diagnosis of acute chest pain, in particular for populations with high incidences of CIN. In addition, a BPCA strategy could garner further savings if currently excluded phenomena including renal disease and incidental findings were included in the decision model. PMID- 24059360 TI - Detection of implants and other objects using a ferromagnetic detection system: implications for patient screening before MRI. AB - OBJECTIVE: Ferromagnetic detection systems have been used to prevent accidents related to external ferromagnetic objects (e.g., pocket knives, hearing aids, and so on). If a ferromagnetic implant was missed during MRI screening, the ability to use a ferromagnetic detection system to discover the object in a patient before MRI could potentially avoid a serious injury, which has important implications for patient safety. Therefore, the purpose of this investigation was to use a ferromagnetic detection system to assess implants and other objects that may be encountered in patients referred for MRI procedures. MATERIALS AND METHODS: A "pillar-type" ferromagnetic detection system was used to evaluate 67 different implants and other objects (pulse generators [n = 43], electronic devices [n = 5], stents [n = 6], CSF shunt valves [n = 3], orthopedic implants [n = 3], bullets [n = 4], and others [n = 3]) that were attached to a volunteer subject's body to approximate a realistic in situ location. The subject with the test item approached the ferromagnetic detection system, rotated in front of it four times, and withdrew while the alarms were monitored and recorded. RESULTS: There were 58 true-positive, four true-negative, no false-positive, and five false-negative findings. Thus, the sensitivity was 92% and the specificity was 100%. CONCLUSIONS: These results indicated that, besides being used to identify external ferromagnetic objects, this ferromagnetic detection system may be a useful tool to screen patients referred for MRI examinations who may have implanted or embedded items. Further investigation to determine the use of this ferromagnetic detection system to detect additional implants in the clinical setting is warranted. PMID- 24059361 TI - Palliative procedures for the interventional oncologist. AB - OBJECTIVE: The purpose of this article is to present our experience using multimodality interventional radiologic techniques for the treatment of cancer related pain across a spectrum of abnormalities. CONCLUSION: Percutaneous imaging guided thermal ablation has emerged as a safe and efficacious treatment for painful osseous metastases. The implementation of interventional thermal ablative techniques for the treatment of intractable pain secondary to malignancy can be further expanded to include transcatheter and combination procedures. PMID- 24059362 TI - MDCT evaluation of aortic root surgical complications. AB - OBJECTIVE: CT is the primary imaging modality used after aortic root repair. Distinction of normal findings from postoperative complications is imperative and requires optimization of acquisition parameters and interpretation with advanced postprocessing tools. CONCLUSION: After aortic root surgery, findings can be categorized as complications within the aorta, complications outside the aorta, and benign postoperative changes. Distinction of normal findings from postoperative complications requires proper CT technique and an understanding of CT findings that require intervention. PMID- 24059363 TI - CT angiography of the upper extremity arterial system: Part 1-Anatomy, technique, and use in trauma patients. AB - OBJECTIVE: In this article, we focus on the arterial anatomy of the upper extremities, the technical aspects of upper extremity CT angiography (CTA), and CTA use in trauma patients. CONCLUSION: CTA using modern MDCT scanners has evolved into a highly accurate noninvasive diagnostic tool for the evaluation of patients with abnormalities of the upper extremity arterial system. PMID- 24059364 TI - CT angiography of the upper extremity arterial system: Part 2- Clinical applications beyond trauma patients. AB - OBJECTIVE: CT angiography using modern MDCT scanners has evolved into a highly accurate noninvasive diagnostic tool for the evaluation of patients with pathologic abnormalities of the upper extremity arterial system. CONCLUSION: Here we focus on the use of this modality in patients with nontraumatic vascular pathologic abnormalities. PMID- 24059365 TI - Serial CT findings of nodular bronchiectatic Mycobacterium avium complex pulmonary disease with antibiotic treatment. AB - OBJECTIVE: The objective of our study was to analyze the serial CT findings of patients with the nodular bronchiectatic form of Mycobacterium avium complex (MAC) pulmonary disease treated with antibiotic therapy. MATERIALS AND METHODS: Between January 2005 and December 2009, MAC lung disease was diagnosed in 475 patients at a single tertiary referral hospital. Of the 475 patients, 339 had a CT pattern of disease consistent with the nodular bronchiectatic form. Among these 339 patients, 110 patients treated with a combination of antibiotics for 1 year were selected for this study. Two independent chest radiologists reviewed retrospectively the chest CT scans of 101 patients (M. avium disease [n = 57] and M. intracellulare disease [n = 44]) in whom serial CT scans had been obtained at the beginning of and at 12 months after standardized therapy. Each CT study was assessed for the presence and extent of lung parenchymal abnormalities (maximum score, 30). RESULTS: After 12 months of antibiotic therapy, 84 patients (83%) had a decrease in the overall CT score, three (3%) had an increase, and 14 (14%) had no change in disease extent. The decrease in total CT score was statistically significant (overall score difference, 2.54; p < 0.0001). Cellular bronchiolitis showed the largest decrease in extent (difference in mean pre and posttreatment scores, -1.02, -1.07, and -0.94 for MAC, M. avium, and M. intracellulare diseases, respectively). Before treatment, patients with M. intracellulare disease showed more extensive disease than patients with M. avium disease (total CT score, 13.31 vs 11.10; p = 0.025). CONCLUSION: In the nodular bronchiectatic form of MAC pulmonary disease, lung parenchymal abnormalities show a significant decrease in extent on CT after antibiotic treatment and the decrease is mainly related to the improvement of cellular bronchiolitis. PMID- 24059366 TI - Imaging features of carcinoid tumors of the gastrointestinal tract. AB - OBJECTIVE: Recent studies have provided a better understanding of the biologic behavior of gastrointestinal carcinoid tumors. This article focusing on imaging of gastrointestinal carcinoids will emphasize epidemiology, molecular biology, taxonomy, histopathology, and management. CONCLUSION: Gastrointestinal carcinoids are a biologically heterogeneous group of tumors, with variable clinical presentation and biologic behavior. Imaging can play an important role in multidisciplinary identification and management of this disease. PMID- 24059367 TI - Noncathartic CT colonography: Image quality assessment and performance and in a screening cohort. AB - OBJECTIVE: Cathartic bowel preparation is a major barrier for colorectal cancer screening. We examined noncathartic CT colonography (CTC) quality and performance using four similar bowel-tagging regimens in an asymptomatic screening cohort. SUBJECTS AND METHODS: This prospective study included 564 asymptomatic subjects who underwent noncathartic CTC without dietary modification but with 21 g of barium with or without iodinated oral contrast material (four regimens). The quality of tagging with oral agents was evaluated. A gastrointestinal radiologist evaluated examinations using primary 2D search supplemented by electronic cleansing (EC) and 3D problem solving. Results were compared with complete colonoscopy findings after bowel purgation and with retrospective unblinded evaluation in 556 of the 564 (99%) subjects. RESULTS: Of the 556 subjects, 7% (37/556) and 3% (16/556) of patients had 52 and 20 adenomatous polyps >= 6 and >= 10 mm, respectively. The addition of iodine significantly improved the percentage of labeled stool (p <= 0.0002) and specificity (80% vs 89-93%, respectively; p = 0.046). The overall sensitivity of noncathartic CTC for adenomatous polyps >= 6 mm was 76% (28/37; 95% CI, 59-88%), which is similar to the sensitivity of the iodinated regimens with most patients (sensitivity: 231 patients, 74% [14/19; 95% CI, 49-91%]; 229 patients, 80% [12/15; 95% CI, 52-96%]). The negative predictive value was 98% (481/490), and the lone cancer was detected (0.2%, 1/556). EC was thought to improve conspicuity of 10 of 21 visible polyps >= 10 mm. CONCLUSION: In this prospective study of asymptomatic subjects, the per-patient sensitivity of noncathartic CTC for detecting adenomas >= 6 mm was approximately 76%. Inclusion of oral iodine contrast material improves examination specificity and the percentage of labeled stool. EC may improve polyp conspicuity. PMID- 24059368 TI - Hepatocellular carcinoma: perfusion quantification with dynamic contrast-enhanced MRI. AB - OBJECTIVE: The objective of our study was to report our initial experience with dynamic contrast-enhanced MRI (DCE-MRI) for perfusion quantification of hepatocellular carcinoma (HCC) and surrounding liver. SUBJECTS AND METHODS: DCE MRI of the liver was prospectively performed on 31 patients with HCC (male-female ratio, 26:5; mean age, 61 years; age range, 41-83 years). A dynamic coronal 3D FLASH sequence was performed at 1.5 T before and after injection of gadolinium based contrast agent with an average temporal resolution of 3.8 seconds. Regions of interest were drawn on the abdominal aorta, portal vein, liver parenchyma, and HCC lesions by two observers in consensus. Time-activity curves were analyzed using a dual-input single-compartment model. The following perfusion parameters were obtained: arterial flow, portal venous flow, arterial fraction, distribution volume, and mean transit time (MTT). RESULTS: Thirty-three HCCs (mean size, 3.9 cm; range, 1.1-12.6 cm) were evaluated in 26 patients. When compared with liver parenchyma, HCC showed significantly higher arterial hepatic blood flow and arterial fraction (p < 0.0001) and significantly lower distribution volume and portal venous hepatic blood flow (p < 0.0001-0.023), with no difference in MTT. Untreated HCCs (n = 16) had a higher arterial fraction and lower portal venous hepatic blood flow value than chemoembolized HCCs (n = 17, p < 0.04). CONCLUSION: DCE-MRI can be used to quantify perfusion metrics of HCC and liver parenchyma and to assess perfusion changes after HCC chemoembolization. PMID- 24059369 TI - Imatinib and beyond in gastrointestinal stromal tumors: A radiologist's perspective. AB - OBJECTIVE: The purpose of this article is to review the decade-long experience with imatinib and other molecular targeted agents in the treatment of gastrointestinal stromal tumor (GIST). CONCLUSION: Tremendous progress has been made in the medical management of GIST since the inception of imatinib, and imaging has played a key role in understanding the typical and atypical responses of GIST to molecular targeted therapies. PMID- 24059371 TI - Multimodality imaging findings of pheochromocytoma with associated clinical and biochemical features in 53 patients with histologically confirmed tumors. AB - OBJECTIVE: The purpose of this study was to determine the spectrum of imaging appearances of pheochromocytoma and the associated clinical and biochemical features. MATERIALS AND METHODS: In this retrospective study, a citywide pathology database (2000-2011) was searched to identify the records of patients with pheochromocytoma. The search yielded the cases of 53 patients (28 men, 25 women; mean age, 50 years). The institutional PACS and radiology information system records, hospital charts, and the provincial electronic health records of these patients were reviewed. Imaging appearances and clinical and biochemical features related to pheochromocytomas were recorded. RESULTS: One chart was not available for review. In the 52 cases analyzed, 40 of the patients had symptoms: 31 patients had hypertension; 10 had the triad of palpitations, diaphoresis, and headaches; and all had elevated urinary metanephrine concentrations. Seven patients had a familial syndrome, and five had bilateral pheochromocytomas. One patient had an extraadrenal pheochromocytoma, and five had malignant tumors. The mean size of pheochromocytomas was 4.0 cm. Most pheochromocytomas were heterogeneous (CT, 56%; MRI, 65%; ultrasound, 45%) and were MIBG positive (90%). Eleven of 34 (32%) pheochromocytomas had T2 signal intensity greater than that of the spleen. Most pheochromocytomas were less enhancing than the spleen (CT, 85%; MRI, 71%). Contrast-enhanced CT was performed on 33 tumors, of which 20 enhanced less than the spleen and 8 showed similar enhancement to the spleen; contrast enhanced MRI was performed on 24 tumors, of which 12 enhanced less than the spleen and 5 showed similar enhancement to the spleen. Predominant cystic change was found in 4 of 20 (20%) ultrasound, 9 of 41 (22%) CT, and 11 of 34 (32%) MRI examinations. Eight of 34 (24%) pheochromocytomas were hemorrhagic, two (5%) had calcifications, and three of six were PET positive. Two cystic pheochromocytomas and one lipid-containing pheochromocytoma were misdiagnosed as adrenal adenomas. CONCLUSION: Most pheochromocytomas were heterogeneous at imaging, were MIBG positive, accompanied elevated urinary metanephrine concentrations, and were symptomatic. High T2 signal intensity was found in approximately one third of solid tumors. Atypical imaging features included homogeneity, cystic change, hemorrhage, intense enhancement, calcifications, intracellular lipid, bilaterality, and malignancy. PMID- 24059370 TI - Update on the management of gastroenteropancreatic neuroendocrine tumors with emphasis on the role of imaging. AB - OBJECTIVE: The purposes of this article are to review the current management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) based on the 2012 National Comprehensive Cancer Network guidelines and to describe the role of imaging in a multidisciplinary approach. CONCLUSION: The management of GEP-NETs has become complex, requiring a multidisciplinary approach. The World Health Organization classification of GEP-NETs has been revised; the U.S. Food and Drug Administration has approved molecular targeted agents (sunitinib, everolimus) for the treatment of pancreatic NETs; and the National Comprehensive Cancer Network clinical practice guidelines have been updated. PMID- 24059372 TI - MDCT of adrenal masses: Can dual-phase enhancement patterns be used to differentiate adenoma and pheochromocytoma? AB - OBJECTIVE: The purpose of this study was to compare enhancement of adrenal adenomas and pheochromocytomas during dual-phase (arterial and venous phases) CT performed with currently used MDCT protocols with the goal of defining enhancement patterns predictive of pathologic findings. MATERIALS AND METHODS: Pathologically proven pheochromocytomas were retrospectively compared with adrenal adenomas. Inclusion criteria for adenomas, collected by searching the radiology database, were confirmatory adrenal CT (unenhanced with or without washout) and absence of clinical indicators of pheochromocytoma. A fellowship trained attending radiologist blinded to the pathologic diagnosis reviewed existing images from dual-phase IV contrast-enhanced CT examinations to measure enhancement of adrenal lesions and characterize the appearance (homogeneous versus heterogeneous). Student t test analysis was performed to compare arterial and venous phase enhancement levels. RESULTS: The findings in 39 patients with 41 adenomas were compared with those in 10 patients with 12 pheochromocytomas. Mean arterial and venous enhancement of adenomas at 37 HU (-6 to 85 HU) and 60 HU (16 133 HU) was significantly lower than that of pheochromocytomas at 104 HU (42-190 HU) and 119 HU (61-195 HU) (p < 0.001). No adenoma was more than 85-HU enhancing in the arterial phase, and 58% of pheochromocytomas were more than 110-HU enhancing. Most adenomas (85%) were more enhancing in the venous phase. No adenoma was more enhancing in the arterial phase, but 25% (3/12) of pheochromocytomas were. Most (58%) pheochromocytomas were heterogeneous in appearance, compared with 22% of adenomas. CONCLUSION: For indeterminate adrenal masses identified at dual-phase IV contrast-enhanced CT, higher enhancement during the arterial phase, arterial phase enhancement levels greater than 110 HU, and lesion heterogeneity should prompt consideration of pheochromocytoma. PMID- 24059373 TI - Utility of diffusional kurtosis imaging as a marker of adverse pathologic outcomes among prostate cancer active surveillance candidates undergoing radical prostatectomy. AB - OBJECTIVE: The purpose of this study was to compare findings at nongaussian diffusional kurtosis imaging and conventional diffusion-weighted MRI as markers of adverse pathologic outcomes among prostate cancer patients who are active surveillance candidates and choose to undergo prostatectomy. MATERIALS AND METHODS: Fifty-eight active surveillance candidates (prostate-specific antigen concentration, < 10 ng/mL; clinical tumor category less than T2a; Gleason score, 3 + 3; <= 25% of biopsy cores positive for tumor; <= 50% tumor involvement of any individual core; <= 20% tumor involvement across all cores) who underwent prostatectomy and preoperative 3-T MRI including diffusional kurtosis imaging (b values, 0, 500, 1000, 1500, and 2000 s/mm(2)) were included. Adverse pathologic features at prostatectomy were defined using two schemes of varying stringency. One scheme (less stringent) was presence of a Gleason score greater than 6 or extracapsular extension (n = 19). The other scheme (more stringent) was presence of a Gleason score greater than 6, extracapsular extension, or an index tumor 10 mm or larger (n = 35). Parametric maps displaying standard apparent diffusion coefficient (ADC), kurtosis (K) representing nongaussian diffusion behavior, and diffusion (D) representing a diffusion coefficient adjusted for nongaussian (kurtosis) behavior were reviewed, and the most abnormal region was recorded for each metric. Associations between these metrics and the presence of adverse final pathologic findings were assessed with unpaired Student t tests and receiver operating characteristic analyses. RESULTS: For both schemes, only D was significantly lower in patients with adverse final pathologic findings (p = 0.006, p = 0.025). K tended to be greater in patients with adverse final pathologic findings for the more stringent scheme (p = 0.072). ADC was not significantly different in the presence of adverse final pathologic findings for either scheme (p = 0.357, p = 0.383). With either scheme, D had a larger area under the receiver operating characteristics curve (AUC) for predicting adverse final pathologic results (AUC, 0.691 and 0.743) than did ADC (AUC, 0.569 and 0.655) or K (AUC, 0.617 and 0.714), but the difference was not significant (p = 0.183, p = 0.734). CONCLUSION: Preliminary results suggest that diffusional kurtosis imaging findings may have more value than findings at conventional diffusion-weighted MRI as a marker of adverse final pathologic outcome among active surveillance candidates. PMID- 24059374 TI - Role of CT in the assessment of muscular venous branch invasion in patients with renal cell carcinoma. AB - OBJECTIVE: The purpose of this article is to determine whether the relationship between a renal cell carcinoma and the renal sinus fat on contrast-enhanced CT could predict muscular venous branch invasion and the type of surgery needed. MATERIALS AND METHODS: A total of 115 consecutive patients underwent pre operative contrast-enhanced CT between August 2011 and December 2011. Without access to histopathologic information, on nephrographic phase contrast-enhanced CT images, two radiologists independently determined whether the renal tumor was in contact with the renal sinus fat or separated from the renal sinus fat. Interreader agreements and performance characteristics of imaging tests were calculated, and histopathologic analysis served as the standard of reference. RESULTS: Histopathologic analysis identified 115 renal tumors, 90% (103/115) of which were renal cell carcinomas. Thirty-nine percent (31/80) of renal cell carcinomas that abutted the renal sinus fat on CT displayed muscular venous branch invasion on histopathologic analysis. Patients with renal cell carcinomas separated from the renal sinus fat were more likely to undergo partial nephrectomies (96% [22/23]; p = 0.013). Sensitivity and specificity for the identification of muscular venous branch invasion on CT were 94% (95% CI, 80-99%) and 30% (20-42%), respectively. Interreader agreement of visual assessment was excellent (kappa = 0.87; 95% CI, 0.81-0.92). CONCLUSION: If a renal cell carcinoma was separated from the renal sinus fat on CT, the likelihood of muscular venous branch invasion being identified by histopathologic analysis was significantly decreased, and the patient was more likely to undergo a partial nephrectomy. PMID- 24059375 TI - Structured feedback from referring physicians: a novel approach to quality improvement in radiology reporting. AB - OBJECTIVE: There is considerable interest in improving radiology reporting practices through peer review, and the inclusion of structured feedback from referring physicians may improve this process. The purpose of this article is to evaluate the feasibility of this type of novel peer-review system. MATERIALS AND METHODS: Five referring physicians from our institution participated as reviewers. Reports from abdominal CT, chest CT, brain MRI, and abdominal ultrasound were eligible for review if the indication was "abdominal pain," "shortness of breath," "headache," and "pain," respectively. Reports were excluded if the examinations were normal or ordered as follow-up. Forty-eight reports (12 from each group) were then selected at random and distributed to the referring physicians along with the clinical scenario and an evaluation form for each examination. RESULTS: The reports were found to be clinically useful (average, 3.8 on a 1-5 scale), allowing for good confidence in clinical decision making (average, 3.7). The most common problems were unclear language, typographical errors, and reports that did not answer the clinical question. Of the reports, 35.4% contained recommendations for further diagnosis or treatment, and 84.7% of these recommendations were deemed clinically appropriate. The participating physicians thought that the results of 31.2% of the examinations should have been directly communicated to the ordering provider. CONCLUSION: Radiology reports and recommendations were clinically useful, even though problems with language, typographical errors, answering the clinical question, and direct communication of examination results were identified. Structured feedback from referring physicians is a novel approach to the peer-review process that may identify problems that go unnoticed by the radiologist, thereby improving reporting practices. PMID- 24059376 TI - Continuous monitoring of CT dose indexes at Dubai Hospital. AB - OBJECTIVE: Experience of continuous monitoring and control of patient doses in CT in Dubai Hospital over a period of approximately 4 years (January 2008 through August 2011) is presented. MATERIALS AND METHODS: Dose measurements-in particular, weighted and volumetric CT dose index, dose-length product (DLP), and estimated effective dose-were regularly monitored using head (16 cm diameter) and body (32 cm diameter) CT phantoms. Patient radiation dose indexes were manually recorded during 2008 for common CT examinations: head, chest, and abdomen and pelvis scans. In 2009-2011, these CT dose data were recorded within the radiology information system and the PACS. Dose reduction actions were taken while maintaining a watch on image quality. The effects of these factors were monitored through change in average DLP on a monthly basis and third quartile annually. Adapted diagnostic reference levels were used for comparison. RESULTS: The reduction in adult dose indexes in 2010 as compared with 2008 was 52%, 16.4%, and 34.8% for head, chest, and abdomen and pelvis examinations, respectively. For the pediatric group, the reduction was 45.23%, 39.6%, and 43.34% for head, chest, and abdomen and pelvis examinations, respectively. CONCLUSION: Substantial reduction in DLP for common examinations of adults and children is shown through a program of continuous monitoring and action. The results indicate the need to introduce local diagnostic reference levels to substitute for the adapted ones. PMID- 24059377 TI - Imaging-guided subacromial therapeutic injections: prospective study comparing abnormalities on conventional radiography with patient outcomes. AB - OBJECTIVE: The purpose of this study was to compare abnormalities detected on conventional shoulder radiography with improvement in pain and shoulder function after subacromial injections. SUBJECTS AND METHODS: We conducted a prospective outcomes study including 98 consecutive patients after fluoroscopy-guided subacromial injections who returned outcome questionnaires and who underwent routine shoulder radiography. Numeric pain rating scale (NRS) data were collected before and, along with patient global impression of change (PGIC) data, at 1 week and 1 month after injection. Outcome differences were assessed using the Student t test and Mann-Whitney U test. Logistic regression analysis was done, including radiographic variables compared with the outcome improvement. The odds ratios with 95% CIs were identified for the significant predictors. RESULTS: A significant difference in overall improvement was found depending on the posterior acromial slope. Patients with a slope of more than 36 degrees had significantly lower NRS and PGIC scores at 1 week and 1 month (p < 0.025) compared with those with a slope of 36 degrees or less, with 86.4% of patients with a slope of more than 36 degrees reporting significant improvement at 1 month. This was the only variable linked with improvement in the logistic regression analysis, with an odds ratio of 2.16 (95% CI, 1.11-4.22). Patients with calcific tendinitis had significantly lower NRS scores at both 1 week and 1 month (p = 0.03 and 0.05, respectively) and PGIC scores at 1 week (p = 0.05). CONCLUSION: A posterior acromial slope of more than 36 degrees and the presence of calcific tendinitis on conventional shoulder radiography are associated with better outcomes. Patients with a slope of more than 36 degrees showed the best improvement. PMID- 24059378 TI - Candida spondylitis: Comparison of MRI findings with bacterial and tuberculous causes. AB - OBJECTIVE: Candida spondylitis is relatively uncommon and is usually encountered as an opportunistic infection. We analyzed the MRI characteristics of biopsy proven cases of Candida spondylitis, and compared the findings with bacterial or tuberculous spondylitis. MATERIALS AND METHODS: The study included patients with infectious spondylitis who underwent MRI and biopsy from 1998 to 2011 (60 patients; mean age 56 +/- 18 years). MR images were analyzed with respect to the number of involved vertebrae, contrast enhancement pattern, signal intensity of spinal inflammatory masses on T2-weighted imaging, paraspinal abscess size, intervertebral disk destruction, subligamentous spread, and skip lesions. The Fisher exact test and analysis of variance were used for statistical analysis. RESULTS: There were 10 cases of Candida spondylitis, and 29 and 21 cases of bacterial and tuberculous spondylitis, respectively. On MRI, disk destruction was seen in 50%, 93%, and 30% of Candida, bacterial, and tuberculous cases, respectively. Subligamentous spread of infection was noted in 22%, 10%, and 85%. Paraspinal inflammatory masses were seen in 100%, 100%, and 76%, and abscesses in 100%, 66%, and 90%, of Candida, bacterial, and tuberculous cases, respectively. Paraspinal inflammatory masses contained low T2 signal intensity portions in 80%, 21%, and 67%, and skip lesions were seen in 0%, 10%, and 14%, respectively. Small abscesses were noted in 100%, 76%, and 35% of Candida, bacteria, and tuberculosis infections, respectively. Candida involved 2.3 +/- 0.4 vertebrae compared with 2.3 +/- 0.9 and 3.0 +/- 1.7 in bacterial and tuberculous, respectively. Differences in the three groups were statistically significant (p < 0.05) except for the number of involved vertebrae, and skip lesions. CONCLUSION: Candida spondylitis can be suspected when infectious lesions contain low-signal spinal inflammatory masses on T2-weighted imaging, small paraspinal abscesses, and in immunocompromised patients. PMID- 24059379 TI - Utility of dual-energy CT virtual keV monochromatic series for the assessment of spinal transpedicular hardware-bone interface. AB - OBJECTIVE: Our aim was to evaluate the utility of dual-energy CT (DECT) virtual kilo-electron volt (keV) monochromatic images for the visualization of the transpedicular screw-bone interface after spinal fusion. MATERIALS AND METHODS: This retrospective study included postfusion spine CT studies performed from October 2011 through April 2012 on a dual-energy 64-MDCT unit (Discovery CT750 HD). Studies were postprocessed on an Advantage Windows workstation (version 4.4) by two neuroradiologists with creation of monochromatic images from 40 to 140 keV. Each reader graded the screw-bone interfaces on the 70-keV images (used for clinical interpretation) and on the monochromatic series using a 5-point scale (1 [uninterpretable] to 5 [excellent]). The grades of the interfaces were compared using the Wilcoxon signed rank test to detect differences between the 70-keV image and the monochromatic series. RESULTS: Ninety-two transpedicular screws in 10 patients were studied. Significant improvement in the visibility of the hardware-bone interface was seen on the monochromatic series compared with the 70 keV images: The median grade for the monochromatic series was 4 (range, 2-5) for both readers, whereas the median grade for the 70-keV images was 3 (range, 2-4) for reader 1 and 2 (range, 2-3) for reader 2 (both, p < 0.001). The interobserver agreement using weighted kappa was 0.51 for grading screw-bone interface visualization. The volume CT dose index was 29.5 mGy in all patients and the mean dose-length product was 805.2 mGy * cm. CONCLUSION: Monochromatic images generated on gemstone spectral DECT are beneficial in the reduction of metallic streak artifact and enable better visualization of the hardware-bone interface than the 70-keV series in patients treated with spinal transpedicular screw fixation. PMID- 24059380 TI - Imaging of blunt vascular neck injuries: a review of screening and imaging modalities. AB - OBJECTIVE: We will review the epidemiology of blunt cerebrovascular injuries (BCVIs) and the rationale for screening. Current imaging modalities used to screen for BCVIs will be discussed with an emphasis on CT angiography. CONCLUSION: Screening for BCVIs can decrease rates of postinjury complications, such as stroke. The use of standardized screening criteria and the appropriate imaging modalities can allow early detection of BCVIs and effective intervention. PMID- 24059381 TI - Imaging of blunt vascular neck injuries: a clinical perspective. AB - OBJECTIVE: We will review the common injuries and anatomic distributions of blunt cerebrovascular injuries (BCVIs) of the neck, explain the grading criteria, and discuss the corresponding management. Artifacts associated with BCVI on CT will also be examined. CONCLUSION: Identifying common injury patterns and anatomic distributions associated with BCVI can help decide the grade and management earlier and reduce the risk for potential complications. Recognizing the common artifacts associated with BCVI helps the reader successfully recognize a true BCVI. PMID- 24059382 TI - Fat-water interface on susceptibility-weighted imaging and gradient-echo imaging: comparison of phantoms to intracranial lipomas. AB - OBJECTIVE: In a clinical setting, lipoma can sometime show low signal intensity on susceptibility-weighted imaging (SWI) mimicking hemorrhage. The purpose of this study was to evaluate the fat-water interface chemical-shift artifacts between SWI and T2*-weighted imaging with a phantom study and evaluate SWI in lipoma cases. MATERIALS AND METHODS: SWI, magnitude, high-pass filtered phase, and T2*-weighted imaging of a lard-water phantom were evaluated in the in-phase, out-of phase, and standard partially out-of-phase TE settings used for clinical 3 T SWI (19.7, 20.9, and 20.0 ms, respectively) to identify the most prominent fat water interface low signal. SWI of five cases of CNS lipoma were retrospectively evaluated by two neuroradiologists. RESULTS: TE at 19.7 ms (in-phase) showed the minimum fat-water interface low signal in the phase-encoding direction on magnitude, high-pass filtered phase, and SWI. TE at 20.9 ms (out-of-phase) showed the maximum fat-water interface in the phase-encoding direction on magnitude, high-pass filtered phase, and SWI. TE at 20.0 ms (partially out-of-phase) showed more fat-water interface low signal on SWI than on T2*-weighted imaging, especially in the phase-encoding direction. All lipomas in the five patients showed high signal intensity with surrounding peripheral dark rim on SWI. CONCLUSION: Fat-water interface is more prominent on the standard TE setting used for clinical SWI (20.0 ms) than that of T2*-weighted imaging and shows a characteristic surrounding peripheral low-signal-intensity rim in lipoma. Knowing the fat-water appearance on SWI is important to avoid misinterpreting intracranial lipomas as hemorrhages. PMID- 24059383 TI - PET angiography: Application of early dynamic PET/CT to the evaluation of arteries. AB - OBJECTIVE: Early dynamic PET/CT is primarily used for oncologic perfusion studies. The purpose of this article is to show how the modality can be applied for angiography with data reconstructed in time-based frames for direct visualization of arterial vessels. CONCLUSION: Our initial data suggest that PET angiography can be used to establish patency and delineate relevant stenoses and occlusions. It therefore may be a useful complement to conventional angiography. PMID- 24059384 TI - Intermittent testicular torsion in the pediatric patient: sonographic indicators of a difficult diagnosis. AB - OBJECTIVE: The purpose of this study was to determine whether intermittent testicular torsion, defined as the sudden onset of unilateral scrotal pain of short duration with spontaneous resolution, has sonographic indicators that can be used to establish the diagnosis. MATERIALS AND METHODS: A retrospective search for pediatric patients presenting with suspected intermittent testicular torsion over a 2-year period was performed. The sonographic findings, medical records for clinical presentation, surgical outcomes, and comorbidities relevant to intermittent testicular torsion were reviewed. RESULTS: Analysis was performed on two separate categories for intermittent testicular torsion: total patient episodes (n = 19) and surgical cases (n = 10), with a total of 15 patients with 1.26 episodes per patient. Of the 19 episodes of intermittent testicular torsion, 63% (12) had either absent flow followed by normal to increased flow (n = 6, p = 0.18) or increased testicular flow (n = 6), 26% (5) had normal flow, and 10.5% (2) had decreased flow. Of the total episodes of intermittent testicular torsion, 79% (15) had a whirlpool sign or pseudomass, 10.5% (2) had neither a whirlpool sign or pseudomass but a "boggy" thickened cord, and 10.5% (2) had a normal appearance of the spermatic cord with no pseudomass. CONCLUSION: The whirlpool sign or an abnormal boggy cord and pseudomass formation below the twisted spermatic cord were both significant findings to support a diagnosis of intermittent testicular torsion. Although change from no perfusion to perfusion during the examination was not statistically significant in our cases, when present it led to the correct diagnosis in each case. PMID- 24059385 TI - JOURNAL CLUB: Is screening MRI indicated for women with a personal history of breast cancer? Analysis based on biopsy results. AB - OBJECTIVE: American College of Radiology and Society of Breast Imaging guidelines call for routine breast MRI screening only for women with the highest risk profiles for development of breast cancer, suggesting that screening of women at lower risk might result in an increased frequency of false-positive biopsy results. The purpose of this study was to test this assumption by comparing MRI guided biopsy outcomes of lesions detected at MRI screening of women with a personal history of breast cancer with outcomes among women with genetic or familial high risk. MATERIALS AND METHODS: Outcomes of 130 MRI-guided biopsies were analyzed. One group consisted of women with hereditary (genetic or familial) risk, and the other group consisted of women with a personal history of breast cancer. Biopsies were performed with a 9-gauge vacuum-assisted device or surgically after MRI localization. RESULTS: Of 130 MRI-guided biopsies, 20 (15%) yielded malignant histologic findings, 14 (11%) yielded high-risk lesions, and 96 (74%) had benign findings. There was a slightly higher malignancy rate for the personal-risk group (19%) compared with the hereditary-risk group (13.5%). There also was a slightly higher combined rate of malignancy and high-risk lesions (34% vs 22%) with no statistically significant difference (p < 0.25, p < 0.12). Patients in the hereditary-risk group were younger (44 +/- 1.2 vs 54 +/- 1.7 years; p < 0.001) than those in the personal-risk group. CONCLUSION: Our preliminary data show no difference between the two risk groups with respect to probability of an MRI-guided biopsy result of malignancy, calling into question the proposed assumption. Further prospective studies of the role of MRI screening combined with MRI-guided biopsy when required for patients with previously treated localized breast cancer may be indicated. PMID- 24059386 TI - Columnar cell lesions without atypia initially diagnosed on breast needle biopsies: is imaging follow-up enough? AB - OBJECTIVE: The purpose of this study was to evaluate the underestimation rate and predictive factor of underestimation of columnar cell lesions (CCLs) without atypia diagnosed through breast core needle biopsies (CNBs). MATERIALS AND METHODS: From January 2007 through December 2011, 141 CCLs without atypia, including columnar cell change and columnar cell hyperplasia, were diagnosed in 138 women by CNB. Excisional (n = 16) or imaging follow-up (n = 125) findings were available in all cases. On a per-lesion basis, the underestimation rate and predictive factor of underestimation were evaluated. RESULTS: Among the 16 surgically excised lesions, there were two malignancies (one ductal carcinoma in situ and one invasive ductal carcinoma) and one lobular carcinoma in situ. Overall, the pooled underestimation rate of malignancy was 1.4% (2/141). With regard to lesion variables, the mean lesion size was significantly larger in the underestimation group of CCLs (p = 0.007). Fine pleomorphic morphology of microcalcifications (p < 0.001), the distribution of the microcalcifications (p = 0.007), BI-RADS final assessment (p = 0.001), and imaging-pathologic correlation (p < 0.001) were significantly associated with underestimation. Multivariate analysis showed that fine pleomorphic morphology of microcalcifications (p < 0.0001) was an independent predictor of underestimation in 58 lesions with microcalcifications on mammography. CONCLUSION: The overall underestimation rate of malignancy was 1.4%. Imaging follow-up is reasonable for CCLs without atypia at CNB, especially in small lesions with less suspicious imaging findings. Fine pleomorphic microcalcifications and higher BI-RADS category might be helpful in the prediction of underestimation of a high-risk lesion or malignancy. PMID- 24059388 TI - Esophageal abnormalities in pediatric patients. PMID- 24059389 TI - Common blind spots on chest CT: where are they all hiding? Part 1-airways, lungs, and pleura. PMID- 24059390 TI - Ultrasound as a tool for preoperative planning, monitoring, and interventions in dialysis arteriovenous access. AB - OBJECTIVE: The rising prevalence of end-stage renal disease has resulted in increasing focus on delivery of vascular access care for hemodialysis. Duplex Doppler ultrasound, with its unique ability to reliably evaluate both structural and functional aspects of the peripheral vessels, is the preferred imaging modality for access planning and follow-up. CONCLUSION: This article will review how ultrasound is currently used to evaluate patients pre-, intra-, and postoperatively for vascular access. PMID- 24059391 TI - Noninvasive vascular imaging in abdominal solid organ transplantation. AB - OBJECTIVE: In this article, we focus on the vascular complications related to liver, pancreas, and kidney transplantation. CONCLUSION: Long term allograft survival of solid organ transplantation depends on early intervention of complications. Noninvasive imaging with ultrasound, CT, and MRI allows accurate diagnosis of complications and aids in treatment planning. PMID- 24059392 TI - Ten frequently asked questions about MRI evaluation of soft-tissue vascular anomalies. AB - OBJECTIVE: The objective of this article was to address 10 frequently asked questions that radiologists face when planning, performing, and interpreting an MRI study in a patient with a soft-tissue vascular anomaly. CONCLUSION: MRI permits a comprehensive assessment of vascular anomalies. It is important for radiologists to be familiar with the classification and correct nomenclature of vascular anomalies as well as the MRI protocol and distinct imaging findings of the different vascular malformations and tumors. PMID- 24059393 TI - Multiacquisition T1-mapping MRI during tidal respiration for quantification of myocardial T1 in swine with heart failure. AB - OBJECTIVE: The purpose of this article is to evaluate a free-breathing pulse sequence to quantify myocardial T1 changes in a swine model of tachycardia induced heart failure. MATERIALS AND METHODS: Yorkshire swine were implanted with pacemakers and were ventricularly paced at 200 beats/min to induce heart failure. Animals were scanned twice with a 1.5-T MRI scanner, once at baseline and once at heart failure. A T1-mapping sequence was performed during tidal respiration before and 5 minutes after the administration of a gadolinium-chelate contrast agent. T1-mapping values were compared between the baseline and heart failure scans. The percentage of fibrosis of heart failure myocardial tissue was compared with similar left ventricular tissue from control animals using trichrome blue histologic analysis. RESULTS: In the study cohort, differences were found between the baseline and heart failure T1-mapping values before the administration of contrast agent (960 +/- 96 and 726 +/- 94 ms, respectively; p = 0.02) and after contrast agent administration (546 +/- 180 and 300 +/- 171 ms, respectively; p = 0.005). The animals with heart failure also had a difference histologically in the percentage of myocardial collagen compared with tissue from healthy control animals (control, 5.4% +/- 1.0%; heart failure, 9.4% +/- 1.6%; p < 0.001). CONCLUSION: The proposed T1-mapping technique can quantify diffuse myocardial changes associated with heart failure without the use of a contrast agent and without breath-holding. These T1 changes appear to be associated with increases in the percentage of myocardial collagen that in this study were not detected by traditional myocardial delayed enhancement imaging. T1 mapping may be a useful technique for detecting early but clinically significant myocardial fibrosis. PMID- 24059394 TI - Prediction of lobar collateral ventilation in 25 patients with severe emphysema by fissure analysis with CT. AB - OBJECTIVE: Reducing pulmonary volume through implantation of endobronchial valves is a major interest to improve exercise tolerance and survival in patients with severe emphysema. The primary aim of this study was to evaluate how well CT determined fissure integrity predicts interlobar collateral ventilation. The secondary objective was to show whether there is a relationship between the size of fissural defects and the presence of collateral ventilation. MATERIALS AND METHODS: Thirty patients with heterogeneous emphysema (postbronchodilator forced expiratory volume in 1 second [FEV1] = 20-50% predicted and > 50% of emphysema in a lobe) underwent collateral ventilation measurements with a catheter through an occlusive balloon within this target lobe during flexible endoscopy. Two senior thoracic radiologists studied the fissures on thoracic high-resolution CT. RESULTS: Collateral ventilation was successfully measured in 37 target lobes in 25 patients. The fissures surrounding the 37 target lobes were evaluated on CT. For the detection of collateral ventilation, the presence of a fissural defect on CT has a sensitivity, specificity, positive predictive value, and negative predictive value of 95%, 44%, 69%, and 88%, respectively. There was a statistically significant difference in the area of the defect between patients with collateral ventilation and those without collateral ventilation (p = 0.04). CONCLUSION: Analysis of pulmonary fissures using CT is useful before endoscopic volume reduction because results are well correlated to endoscopic measurements of collateral ventilation. Further study with clinical outcomes is mandatory to determine if and when one test or the other or both should be used in patient selection. PMID- 24059395 TI - In search of venous thromboembolism: the first 2913 years. AB - OBJECTIVE: Venous thromboembolism was first described in India around 600-900 BC. It was not until the 17th through 19th centuries that Western researchers began to understand the anatomy, physiology, and pathology of deep venous thrombosis and pulmonary embolism. Roentgen's discovery of x-rays in 1895 led to the first objective imaging. CONCLUSION: Currently, scintigraphy, helical CT, MRI, and sonography provide accurate in vivo images. These high-quality images have forced clinicians to reevaluate many preimaging assumptions about and treatments for venous thromboembolism. PMID- 24059396 TI - Intrabiliary growth of colorectal liver metastasis: spectrum of imaging findings and implications for surgical management. AB - OBJECTIVE: The propensity for colorectal liver metastasis to invade the biliary tree is increasingly recognized, placing particular emphasis on the risk of postoperative recurrence. This article illustrates the spectrum of imaging findings when colorectal metastasis invades the biliary tree. CONCLUSION: Knowledge of the imaging features of intrabiliary invasion by colorectal liver metastasis improves the quality of preoperative staging and is crucial in an era in which nonanatomic wedge resection and radiofrequency ablation are routinely performed. PMID- 24059397 TI - Appendiceal mucocele: A diagnostic dilemma in differentiating malignant from benign lesions with CT. AB - OBJECTIVE: The purpose of this study was to assess the feasibility of using CT to differentiate malignant from benign lesions in patients with pathologically confirmed appendiceal mucoceles. MATERIALS AND METHODS: CT scans of 18 consecutively registered patients (11 men, seven women; age range, 21-78 years) with pathologically confirmed appendiceal mucocele were reviewed retrospectively. Patients were classified into three groups according to pathologic results: nonneoplastic mucocele (n = 3), mucinous cystadenoma (n = 10), and mucinous cystadenocarcinoma (n = 5). The nonneoplastic and mucinous cystadenoma groups were formed into a benign group, and the mucinous cystadenocarcinoma constituted the malignant group. Two experienced radiologists working in consensus assessed the shape, short diameter, density, contour, and wall thickness of the masses. The presence of calcifications, internal septations, soft-tissue thickening, periappendiceal fat stranding, intraperitoneal free fluid and pseudomyxoma peritonei were also evaluated. The CT results were compared for malignant and benign appendiceal mucoceles. RESULTS: CT showed statistically significant differences in wall irregularity and soft-tissue thickening between malignant and benign cases (p < 0.05). Short diameter of mucoceles, attenuation of intraluminal contents, maximal wall thickness, calcifications, internal septations, periappendiceal fat stranding, intraperitoneal free fluid, and pseudomyxoma peritonei in the lesions did not differ significantly between the benign and malignant groups (p > 0.05). CONCLUSION: Differentiating malignant from benign mucoceles can be difficult with CT. Irregular walls and soft-tissue thickening are features most likely to be associated with malignancy. PMID- 24059398 TI - MRI arterial enhancement fraction in hepatic fibrosis and cirrhosis. AB - OBJECTIVE: Fibrosis leads to altered liver hemodynamics. The arterial enhancement fraction, which is defined as the ratio of hepatic arterial perfusion to the total hepatic perfusion, can provide noninvasive assessment of hepatic perfusion. The aim of this study was to show that the arterial enhancement fraction values correlate with histopathologic stage of liver fibrosis, thus providing a reliable noninvasive radiologic alternative to liver biopsy for the detection and staging of hepatic fibrosis. MATERIALS AND METHODS: We evaluated hepatic fibrosis stage (denoted by Metavir score [F]) and arterial enhancement fraction of patients who underwent standard triphasic liver MRI and liver biopsy within 1 year from January 2005 to December 2010. Prototype software was used to calculate the arterial enhancement fraction. Statistical analysis included nonparametric tests and area under the receiver operating characteristic curve (AUC). RESULTS: One hundred fourteen patients (69 men and 45 women; median age, 52.5 years) were divided into groups according to the Metavir score. The mean arterial enhancement fraction was 24.2% +/- 11.6% for F0, 35.2% +/- 18.7% for F1, 30.2% +/- 12.5% for F2, 37.5% +/- 16.4% for F3, and 59.8% +/- 16.6% for F4. The mean arterial enhancement fraction values differed significantly between Metavir scores (p < 0.001) and showed a positive correlation with Metavir score (r = 0.693; p < 0.001). The optimal mean arterial enhancement fraction cutoffs were 32.96% or more (AUC = 0.8343) for detection of mild fibrosis, 33.33% or more (AUC = 0.8524) for detection of moderate fibrosis, 38.43% or more (AUC = 0.8819) for detection of severe fibrosis, and 45.76% or more (AUC = 0.9161) for detection of cirrhosis. CONCLUSION: Arterial enhancement fraction using triple-phase MRI can provide a reliable noninvasive method to assess hepatic fibrosis. PMID- 24059399 TI - Gadoxetate disodium-enhanced MRI of mass-forming intrahepatic cholangiocarcinomas: imaging-histologic correlation. AB - OBJECTIVE: The purpose of this study was to describe the enhancement patterns of mass-forming intrahepatic cholangiocarcinomas on gadoxetate disodium-enhanced MR images using imaging-histologic correlation. MATERIALS AND METHODS: We retrospectively evaluated the preoperative gadoxetate disodium-enhanced MR images of 19 patients with mass-forming intrahepatic cholangiocarcinomas. Two readers independently interpreted enhancement patterns on arterial (globally high, rimlike), dynamic (washout, progressive), and hepatobiliary (target, nontarget) phase images. Dynamic enhancement was categorized as washout (hypoenhancement on later phase compared with arterial phase images) or progressive (persistent or gradually increased enhancement). Tumor enhancement ratio and tumor-to-liver signal difference curves were analyzed. The enhancement patterns were correlated with the extent of stromal fibrosis within the tumors. RESULTS: Rimlike arterial enhancement (89%, reader 1; 84%, reader 2) and a progressive dynamic pattern (89%, both readers) were predominant. Tumor enhancement ratio increased gradually from the arterial to the equilibrium phase then decreased in the hepatobiliary phase, but the tumor signal intensities were lower than liver signal intensity in all phases. The two lesions that both readers considered to have globally high arterial enhancement and a washout dynamic pattern presented with minimal or scattered stromal fibrosis. Target appearance in the hepatobiliary phase (reader 1, 42%; reader 2, 47%) was more commonly seen in tumors with central stromal fibrosis (reader 1, p = 0.025; reader 2, p = 0.001). CONCLUSION: Mass-forming intrahepatic cholangiocarcinomas may be characterized by rimlike enhancement and a progressive dynamic pattern on gadoxetate disodium-enhanced MR images, and these features seem related to the extent of stromal fibrosis in the tumor. Furthermore, mass-forming intrahepatic cholangiocarcinomas may have a pseudowashout pattern on gadoxetate disodium-enhanced MR images because of progressive background liver enhancement. Therefore, radiologists need to be aware of this pattern as a possible pitfall. PMID- 24059400 TI - Comparison of interreader reproducibility of the prostate imaging reporting and data system and likert scales for evaluation of multiparametric prostate MRI. AB - OBJECTIVE: The objective of our study was to compare interreader reproducibility of the recently proposed "Prostate Imaging Reporting and Data System," or "PI RADS," scale incorporating fixed criteria and a standard Likert scale based on overall impression for prostate cancer localization using multiparametric MRI. MATERIALS AND METHODS: Fifty-five patients who underwent a 3-T prostate MRI examination using a pelvic phased-array coil and incorporating T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast-enhanced imaging were included in the study. Three radiologists (6, 4, and 1 year of experience) independently scored 18 regions (12 in the peripheral zone [PZ] and six in the transition zone [TZ]) using PI-RADS (range, 3-15) and Likert (range, 1-5) scales, which were based on fixed criteria and overall impression, respectively. Interreader reproducibility was evaluated using the concordance correlation coefficient (CCC), which assesses exact agreement between scores (minimal, < 0.2; poor, 0.2-<0.4; moderate, 0.4-<0.6; strong, 0.6-<0.8; almost perfect, >= 0.8). RESULTS: Agreement between experienced readers was strong in the PZ and TZ combined and in the PZ for both the PI-RADS and Likert scales (CCC = 0.608 0.677), moderate in the TZ for the Likert scale (CCC = 0.519), and poor in the TZ for PI-RADS (CCC = 0.376). Agreement between experienced and inexperienced readers was moderate to poor in the PZ and TZ combined for PI-RADS (CCC = 0.340 0.477), moderate in the PZ and TZ combined for the Likert scale (CCC = 0.471 0.497), moderate in the PZ for PI-RADS and Likert scales (CCC = 0.472-0.542), minimal to poor in the TZ for PI-RADS (CCC = 0.094-0.283), and poor in the TZ for the Likert scale (CCC = 0.287-0.400). CONCLUSION: Interreader reproducibility tended to be higher for relatively experienced readers than for less experienced readers and to be higher in the PZ than in the TZ. For the relatively experienced readers, reproducibility was similar for PI-RADS and Likert scales in the PZ but was somewhat higher for the Likert scale than for PI-RADS in the TZ. PMID- 24059401 TI - Appropriateness of imaging studies ordered by emergency medicine residents: results of an online survey. AB - OBJECTIVE: The purpose of this study is to determine the proficiency of emergency medicine residents in selecting appropriate radiologic examinations for specific clinical scenarios and to ascertain whether their training improves competency in this area over the course of their residency. MATERIALS AND METHODS: An online multiple-choice questionnaire was created. It included 10 clinical scenarios excerpted from the American College of Radiology Appropriateness Criteria guidelines and instructed residents to select the most appropriate initial imaging study. A link and invitation to the survey were e-mailed to the residency program directors and coordinators of all American Council for Graduate Medical Education-accredited emergency medicine residency training programs with the request that they be forwarded to their current residents. Responses were graded, with correct answers derived from the American College of Radiology guidelines. Results were stratified by year of emergency medicine training, and an analysis of variance was performed. RESULTS: A total of 583 residents from at least 77 different emergency medicine residency training programs completed the survey. Overall, the average number of questions answered correctly was 7.1 of 10 (SD, 1.2). First-through fourth-year residents averaged 6.9 (SD, 1.3), 7.1 (SD, 1.2), 7.1 (SD, 1.1), and 7.5 (SD, 1.1) correct answers, respectively. Analysis of variance found no significant difference between the scores of the four classes (p = 0.09). CONCLUSION: Emergency medicine residents do not show significant improvement over the course of their residency in their ability to choose appropriate imaging studies. This finding suggests that there is a role for more rigorous focused instruction to better familiarize residents with appropriateness guidelines for diagnostic imaging selection. PMID- 24059402 TI - Electronic noise in CT detectors: Impact on image noise and artifacts. AB - OBJECTIVE: The objective of our study was to evaluate in phantoms the differences in CT image noise and artifact level between two types of commercial CT detectors: one with distributed electronics (conventional) and one with integrated electronics intended to decrease system electronic noise. MATERIALS AND METHODS: Cylindric water phantoms of 20, 30, and 40 cm in diameter were scanned using two CT scanners, one equipped with integrated detector electronics and one with distributed detector electronics. All other scanning parameters were identical. Scans were acquired at four tube potentials and 10 tube currents. Semianthropomorphic phantoms were scanned to mimic the shoulder and abdominal regions. Images of two patients were also selected to show the clinical values of the integrated detector. RESULTS: Reduction of image noise with the integrated detector depended on phantom size, tube potential, and tube current. Scans that had low detected signal had the greatest reductions in noise, up to 40% for a 30 cm phantom scanned using 80 kV. This noise reduction translated into up to 50% in dose reduction to achieve equivalent image noise. Streak artifacts through regions of high attenuation were reduced by up to 45% on scans obtained using the integrated detector. Patient images also showed superior image quality for the integrated detector. CONCLUSION: For the same applied radiation level, the use of integrated electronics in a CT detector showed a substantially reduced level of electronic noise, resulting in reductions in image noise and artifacts, compared with detectors having distributed electronics. PMID- 24059403 TI - Engaging Hill-Sachs lesion: is there an association between this lesion and findings on MRI? AB - OBJECTIVE: The objective of our study was to see whether there is an association between engagement on physical examination and the location or size of a Hill Sachs lesion and the presence and degree of glenoid bone loss as assessed on MRI. MATERIALS AND METHODS: Thirty-three consecutive patients (32 males and one female) with a history of anterior shoulder dislocation who underwent preoperative MRI and arthroscopy at our institution and were tested for engagement on physical examination over a 9-month period were included in the study. Two blinded readers reviewed each study independently and documented the presence and size of the Hill-Sachs lesion, location of the Hill-Sachs lesion with a modified biceps angle, and presence and size of glenoid bone loss. Statistical analysis included the Mann-Whitney, logistic regression, Pearson correlation, and intraclass correlation tests. RESULTS: Eleven patients had evidence of an engaging Hill-Sachs lesion on physical examination and 22 did not. There was no statistically significant difference between any of the dimensions or overall area of the Hill-Sachs lesion when comparing the group with an engaging Hill-Sachs lesion and the group with a nonengaging lesion (surface area, 3.60 vs 3.23 cm(3), respectively; p = 0.272). There was a trend for a larger biceps angle in the engaging group without a statistically significant difference (mean, 154.5 degrees vs 143.9 degrees ; p = 0.069). There was a statistically significant difference in the amount of glenoid bone loss in the engaging group compared with the nonengaging group (mean, 20.2% vs 6.0%; p = 0.001). CONCLUSION: There is a significant association between an engaging Hill-Sachs lesion on physical examination and the degree of glenoid bone loss as well as a trend toward increased engagement with more medially oriented Hill-Sachs lesions. These findings show the importance of considering both the Hill-Sachs lesion and glenoid bone loss when evaluating patients with engagement. PMID- 24059404 TI - MDCT in the assessment of laryngeal trauma: value of 2D multiplanar and 3D reconstructions. AB - OBJECTIVE: The purpose of this study was to analyze fracture patterns and related effects of laryngeal trauma and to assess the value of 2D multiplanar reformation (MPR) and 3D reconstruction. MATERIALS AND METHODS: Among 4222 consecutively registered trauma patients who underwent emergency MDCT, 38 patients had presented with laryngeal trauma. Axial, 2D MPR, 3D volume-rendered, and virtual endoscopic images were analyzed retrospectively by two blinded observers according to predefined criteria. Laryngeal fractures, soft-tissue injuries, and airway compromise were evaluated and correlated with clinical, endoscopic, surgical, and follow-up findings. RESULTS: Fifty-nine fractures (37 thyroid, 13 cricoid, nine arytenoid) were present in 38 patients. They were isolated in 21 (55%) patients. The other 17 (45%) patients had additional injuries to the neck, face, brain, chest, or abdomen. Laryngeal fractures were bilateral in 31 (82%) patients and were associated with hyoid bone fractures in nine (24%) patients. Arytenoid luxation was present in eight cartilages. Axial imaging missed 7 of 59 (12%) laryngeal fractures, six of eight (75%) arytenoid luxations, and four of nine (44%) hyoid bone fractures. Additional 2D MPR imaging missed 5 of 59 (8%) laryngeal fractures, five of eight (62.5%) arytenoid luxations, and two of nine (22%) hyoid bone fractures, whereas 3D volume-rendered images depicted them all. Virtual endoscopy and 3D volume rendering added diagnostic accuracy with respect to the length, width, shape, and spatial orientation of fractures in 22 of 38 (58%) patients; arytenoid luxation in six of eight (75%) luxations; and the evaluation of airway narrowing in 19 of 38 (50%) patients. Three-dimensional volume rendering was not of additional value in evaluation of the cricoid cartilage. CONCLUSION: The use of 2D MPR and 3D volume rendering with or without virtual endoscopy improved assessment of thyroid and hyoid bone fractures, arytenoid luxations, and laryngotracheal narrowing, providing helpful data for optimal management. PMID- 24059405 TI - Primary gynecologic lymphoma: imaging findings. AB - OBJECTIVE: The purpose of this article is to review the imaging features, particularly on MR images, useful in identifying primary gynecologic lymphoma. CONCLUSION: Primary gynecologic lymphoma is rare. Nonetheless, the distinction between primary and secondary involvement is important because of critical differences in prognosis and treatment. The prospective diagnosis of primary gynecologic lymphoma enables immediate chemotherapy or radiation therapy and avoids unnecessary surgery, which delays treatment. Diagnostic imaging can be key in differentiating lymphoma from the far more common pelvic malignancies. PMID- 24059406 TI - Medicolegal-malpractice and ethical issues in radiology: Recommending additional and follow-up radiologic examinations. PMID- 24059407 TI - Medicolegal-malpractice and ethical issues in radiology: Disclaimers on reports. PMID- 24059408 TI - Imaging self-referral: here we go again. PMID- 24059409 TI - Imaging self-referral: here we go again. Reply. PMID- 24059410 TI - Low-dose CT angiography: which contrast medium? PMID- 24059411 TI - Low-dose CT angiography: which contrast medium? Reply. PMID- 24059412 TI - Anaphylactic shock due to vitamin K in a newborn and review of literature. AB - Newborn infants are born with an immature innate immunity. They are less likely to develop anaphylaxis since their immune system is weaker than older infants and children. There are only a few reports of side effects after vitamin K injection in neonates although prophylaxis against hemorrhagic disease of the newborn with this drug has been in routine practice in all over the world for many years. We herein report a case of anaphylactic shock developing after the intramuscular administration of vitamin K1 in a newborn. To our knowledge, this patient is the first case of neonatal anaphylactic shock developing due to intramuscular administration of vitamin K1. We suggest the clinicians should be aware of this possibility of potentially fatal adverse effect occurring with intramuscular administration of vitamin K1. PMID- 24059413 TI - [Critical Medicine: past, present and future]. PMID- 24059414 TI - [Analysis of risk factors affecting prognosis of exertional heat stroke]. AB - OBJECTIVE: To determine prognostic risk factors of exertional heat stroke (EHS). METHODS: Sixty-nine patients who met the case definition of EHS at ten military hospitals from June 2002 to August 2012 were enrolled in this retrospective study. The clinical data and prognosis was observed, including rhabdomyolysis (RM), disseminated intravascular coagulation (DIC), acute kidney injury (AKI), hepatosis, epilepsy, shock, arrhythmia, multiple organ dysfunction syndrome (MODS) and consciousness disorder. A logistic regression analysis was made to look for the significant risk factors, and its accuracy and reliability were tested and verified by statistical equation. RESULTS: There were 69 patients with EHS in the study, and 18 (26.09%) were dead. The independent prognostic factors were identified as DIC and AKI [DIC odds ratio (OR)=94.994, 95% confidence interval (95%CI) 3.837-2352.031, P=0.005; AKI OR=90.871, 95%CI 2.079-3971.995, P=0.019]. The mortality was 16.67% (3/18) when any one factor exist; the mortality was 93.75% (15/16) when two factors exist (sensibility was 83.33%; with specificity of 98.03%, positive predictive value of 93.75%, negative predictive value of 94.34%, and accuracy of 94.20%). CONCLUSIONS: Among all the clinical parameters, the major risk factors affecting prognosis of EHS included DIC and AKI. The mortality might go very high if both two risk factors exist. PMID- 24059415 TI - [Prognostic significance of serum lactic acid in evaluation of acute paraquat poisoning patients]. AB - OBJECTIVE: To discuss the role of serum lactic acid (Lac) level in evaluation of prognosis of acute paraquat poisoning (APP) patients. METHODS: Clinical data from 168 APP patients were retrospectively analyzed. The serum Lac level and the plasma paraquat concentrations at admission were collected, and the severity index of paraquat poisoning (SIPP) were calculated. The patients were divided into <10, 10-50, >=50 h*mg*L(-1) groups on the basis of SIPP. The correlation between Lac and SIPP was analyzed, as well as the role in evaluating prognosis. RESULTS: The higher the SIPP level, the higher the Lac level [2.00 (1.50, 2.83) mmol/L, 3.10 (1.73, 5.15) mmol/L, 8.95 (5.90, 13.10) mmol/L, all P<0.05]; Lac was correlated positively with SIPP (r=0.569, P<0.05). The higher the SIPP, the higher the mortality of patients [17.4% (15/86), 61.5% (24/39), 97.7% (42/43), all P<0.05]. The survival days of SIPP>=50 h*mg*L(-1) group was shorter than that in SIPP<10 h*mg*L(-1) group and 10-50 h*mg*L(-1) group [2.0 (1.0, 3.0) days vs. 9.0 (4.0, 11.0) days and 5.0 (3.0, 10.0) days, both P<0.05]. A negative correlation was found between Lac, SIPP and survival days in non-survivors (r1= 0.778, r2=-0.621, both P<0.05). Logistic regression analyses showed either Lac or SIPP was of prognostic significance [odds ratio (OR) of Lac: 1.758, 95% confidence interval (95%CI) 1.278-2.417;OR of SIPP: 1.063,95%CI 1.025-1.103, both P=0.001]. The area under the receiver operating characteristic curve (ROC curve) of Lac, SIPP and prognosis were 0.885 and 0.897 respectively (both P<0.05), Lac>=3.35 mmol/L was the best cut-off value, the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and accuracy for predicting the death were 74.07%, 90.80%, 88.24%, 79.00%, 8.056, 0.286 and 82.74% respectively; the evaluation value was closed to SIPP>=13.83 h*mg*L(-1) (77.78%, 91.95%, 90.00%, 81.63%, 9.677, 0.242 and 85.12%, respectively). CONCLUSIONS: The change in serum Lac level has evaluation value of the severity and prognosis for APP patients, and Lac>=3.35 mmol/L can be made as a simple and easy indicator for prognosis of APP patients. PMID- 24059416 TI - [Variations in expressions of periostin and related factors in early stage of wound healing and scar remodeling in rats]. AB - OBJECTIVE: To investigate the expressions of periostin (PN), angiopoietin-1 (Ang 1), vascular epithelial growth factor (VEGF) and fetal liver kinase-1 (Flk-1) during the processes of scar formation and modulation in rat cutaneous wounds and probe into their roles in wound healing and scaring. METHODS: Eighty-two male Sprague-Dawley (SD) rats were randomly divided into 10 groups with 8-9 rats in each group. Two 2 cm*2 cm full-thickness excisional wounds in the back were created in each rat. The wound surface was observed, and the healing area was measured. The pathological change was observed after hematoxylin and eosin (HE) staining. The expressions of PN, Ang-1, VEGF and Flk-1 in wound surface scar at 4 8 weeks were determined with immunohistochemistry. The expressions of PN, Ang-1 and VEGF were determined by Western blotting. The normal skin was served as control. RESULTS: HE staining showed that the wound surface tissue had healed with epithelization at 4-8 weeks. Immunohistochemistry results showed that there was no significant difference in Flk-1 expression between wound surface tissue and normal skin. The PN expression (A value/MUm(2)) in wound surface tissue was significantly lower than that in normal skin at 5 weeks (2.43+/-0.44 vs. 4.24+/ 0.50, P<0.05), and the expression of Ang-1 and VEGF (A value/MUm(2)) at 4, 5, 6, 8 weeks was significantly lower than that in normal skin (Ang-1: 3.51+/-0.93, 3.10+/-0.57, 2.77+/-0.59, 2.77+/-1.26 vs. 4.89+/-0.48; VEGF: 1.76+/-0.68, 1.75+/ 0.49, 1.99+/-0.42, 1.94+/-0.86 vs. 4.86+/-1.63, all P<0.05). In wound surface scar, PN and Flk-1 positive signal was found in cell, and the Ang-1 and VEGF positive signal in extracellular matrix. Western blotting data demonstrated that the expressions of PN, Ang-1 and VEGF peaked at the 10th day after excision with increases to 7.90-22.56 folds compared with normal skin (PN: 2.45+/-1.51 vs. 0.31+/-0.19, Ang-1: 18.43+/-15.20 vs. 1.53+/-1.42, VEGF: 6.09+/-4.66 vs. 0.27+/ 0.13, P<0.05 or P<0.01), and then followed with a decrease. CONCLUSIONS: PN, Ang 1, VEGF and Flk-1 are transiently overexpressed in early stage of full-thickness cutaneous wound healing in rats. Their expressions vary in wounds and scars. They participate in the healing of full-thickness cutaneous wounds together and may be essential for the proliferation stage during wound healing. PMID- 24059417 TI - [Effect mechanism of NOD like receptor signaling pathway on intestinal mucosal barrier of rat during early phase of acute intra-abdominal infection]. AB - OBJECTIVE: To initially investigate the expressing regularity and effect of enterocyte NOD like receptors on gut mucosal barrier during early phase of acute intra-abdominal infection. METHODS: Sprague-Dawley (SD) rats were randomly allocated into control group (n=6) and experimental group (n=24). Acute intra abdominal infection model was induced by cecal ligation and puncture (CLP). The level of NOD2 and NOD like receptor 3 (NLRP3) mRNA expression in gut mucosa was determined using fluorescent polymerase chain reaction (PCR); the expression of caspase-1 and tight junction protein was determined by Western blotting; the activity of nuclear factor-KappaB (NF-KappaB) was determined by electrophoretic mobility shift assay (EMSA); the level of serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) was determined by enzyme linked immunosorbent assay (ELISA). The dead cell percentage of enterocyte was observed by terminal deoxynucleotidyl transferase mediated nick end labeling, and the gut mucosal permeability using an in situ loop preparation of gut with fluorescence isothiocyanate-conjugated dextran was determined. RESULTS: NOD2 mRNA expression was quickly increased to a very high apex at 2 hours after operation, compared with the control group, the difference was statistically significant (75.50+/ 13.03 vs. 1.00+/-0.00, P<0.01), and quickly descended at 6 hours, and then slowing descended. The expression of NLRP3 mRNA was decreased at 2 hours after the operation, then increased gradually, and peaked at 12 hours, which was significantly higher than that in control group (4.03+/-0.71 vs. 1.00+/ 0.00,P<0.05). The level of caspase-1 was significantly higher than that in control group at 2 hours (3.56+/-0.14 vs. 2.10+/-0.11,P<0.01) and then gradually increased. The levels of Occludin, ZO-1 and Claudin-4 were obviously lowered than that in control group at 2-6 hours (2 hours Occludin: 7.24+/-1.13 vs. 12.72+/ 1.34, 6 hours ZO-1: 0.47+/-0.09 vs. 1.57+/-0.17, 2 hours Claudin-4: 1.63+/-0.28 vs. 3.40+/-0.34, P<0.05 or P<0.01), and then all slowly decreased. The activity of NF-KappaB was quickly increased at 2 hours, obviously higher than that in control group (24.85+/-0.57 vs. 12.42+/-0.73, P<0.01), and then slowly decreased at a state of high expression. The expression of IL-6 in experimental group had a peak at 6 hours (compared with the control group, 3088.07+/-330.03 vs. 26.19+/ 7.58,P<0.01), and then slowly decreased. The level of TNF-alpha was significantly higher than that in control group at 2 hours (110.75+/-19.18 vs. 7.86+/ 3.58,P<0.01), and then gradually increased. The percentage of dead enterocyte was higher than that in control group with infection progress (0.12+/-0.02 vs. 0.03+/ 0.01,P<0.05), and then gradually increased, so mucosal permeability was gradually increased too. Compared with the control group, the difference was statistically significant through 2 hours [glucosans: (35.75+/-4.66)% vs. (2.84+/-0.35)%, P<0.01]. The relevance analysis showed that NLRP3 have a little higher correlation with mucosal permeability and caspase-1 protein expression than other targets. Caspase-1 had a strong correlation with the percentage of dead cell, TNF alpha and gut mucosal permeability. Gut mucosal permeability had highest correlation with the expression of caspase-1 protein. CONCLUSIONS: The data of our study suggested that NOD2 and NLRP3 take role in early phase of intra abdominal infection, the huge wave of the expression level of NOD2 hinted that it was feed backed by some accurate mechanism in case of its express was too strong or too weak. The correlation of NLRP3, caspase-1, and percentage of dead cell imply they maybe have some extent of causation, and the percentage of dead cell in gut mucosa was as important as tight junction protein in maintaining the function of intestinal mucosal barrier. PMID- 24059418 TI - [The role of nitric oxide on the dysfunction of intestinal motility in rats subjected to hemorrhagic shock]. AB - OBJECTIVE: To determine the role of nitric oxide (NO) in intestinal motility dysfunction in rats subjected to hemorrhagic shock (HS). METHODS: Sixteen male Wistar rats were randomly and equally divided into two groups. The HS model of rat was induced by bleeding from femoral artery. After animal models were made, different inducers were added, and duodenum samples were harvested for the determination of contractile response to acetylcholine (ACh) in vitro, activities of inducible nitric oxide synthase (iNOS), contents of NO in tissue, and morphological changes. RESULTS: The spontaneous contraction of intestinal smooth muscle and contractile response induced by ACh were significantly decreased at 180 minutes in HS group, compared with control group, the contractile response induced by ACh of intestinal smooth muscle was decreased by almost 60% (0.40+/ 0.11 g*mm(-2)*s(-1) vs. 1.00+/-0.20 g*mm(-2)*s(-1), P<0.01). The inhibitor of iNOS N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) could significantly restore the suppressed contractile response of smooth muscle strips obtained from HS rats (0.97+/-0.25 vs. 0.40+/-0.11, P<0.01). Moreover, the inhibitor of soluble guanylyl cyclase 1H-[1,2,4] Oxadiazolo [4,3-a] quinoxalin-1 one (ODQ) also improved the contractility of HS muscle strips significantly (0.79+/-0.17 vs. 0.40+/-0.11, P<0.01). But the blocker of ATP-sensitive potassium channel glibenclamide had no effect on the contractility of HS muscle strips (0.47+/-0.14 vs. 0.40+/-0.11, P>0.05). Compared with those of control group, iNOS activities (2.295+/-0.310 U/g vs. 1.319+/-0.322 U/g) and NO contents (2.880+/ 0.353 MUmol/g vs. 1.505+/-0.387 MUmol/g) in duodenum of HS rats were both significantly increased (both P<0.01). Under light microscopy, the most significant morphological change in duodenum following HS was the infiltration of obvious inflammatory cells. CONCLUSIONS: The NO produced by the overexpression of iNOS induced by HS involves in the motility dysfunction of intestine through the mechanism of cyclic guanosine monophosphate (cGMP) system. Moreover, NO-mediated infiltration of inflammatory cells in tissue may also contribute to the development of motility dysfunction of intestine following HS. PMID- 24059419 TI - [The effect of Xuebijing on liver translationally controlled tumor protein expression in Acinetobacter baumannii sepsis rats]. AB - OBJECTIVE: To study the effect of Xuebijing on liver expressing translationally controlled tumor protein (TCTP) in Acinetobacter baumannii sepsis rats. METHODS: Among 42 healthy adult male Wistar rats of clean grade, 6 rats were randomly selected as the control group, others were randomly divided into two groups by the method of random digits table: sepsis group(n=18), Xuebijing group(n=18). Sepsis model was established through intraperitoneal injecting Acinetobacter baumannii suspension, and the Xuebijing injection was administrated through caudal vein 30 minutes later in Xuebijing group. After making model for 6, 12 and 24 hours, 6 rats were randomly selected from sepsis group and Xuebijing group, and then the rats were sacrificed, liver tissue samples were extracted for hematoxylin and eosin (HE) staining. Pathological changes of the liver were observed, and immunohistochemical analysis of liver tissue TCTP expression positive cells and the expression of TCTP in liver cells were detected by Western blotting method. RESULTS: HE staining of liver indicated that it was inflammatory injured in sepsis group, and inflammation decreased in Xuebijing group. Immunohistochemistry results showed that, compared with the control group, TCTP positive cells expression score at 6, 12 and 24 hours in sepsis group were significantly increased (7.33+/-0.82, 10.67+/-1.21, 7.67+/-1.21 vs. 2.50+/-1.05, all P<0.05). Compared with sepsis group, liver tissue TCTP positive cells expression score at 6, 12 and 24 hours in Xuebijing group (5.83+/-0.75, 7.50+/ 1.05, 5.67+/-1.37) were significantly decreased (all P<0.05). Western blotting results showed that, compared with the control group, TCTP expression at 6, 12 and 24 hours in sepsis group were significantly increased (1.94+/-0.59, 3.20+/ 0.72, 1.96+/-0.55 vs. 0.93+/-0.24, all P<0.05); compared with sepsis group, TCTP expression at 6, 12 and 24 hours in Xuebijing group (1.38+/-0.36, 2.03+/-0.49, 1.30+/-0.30) were significantly decreased (all P<0.05). CONCLUSIONS: Xuebijing can reduce inflammatory injury in liver of rats with Acinetobacter baumannii sepsis, and its mechanism may be associated with reduced hepatic cells expressed TCTP. PMID- 24059420 TI - [Pediatric nitrite poisoning caused repeated cardiac arrest]. PMID- 24059421 TI - [Risk factors and early diagnosis of acute kidney injury in patients with sepsis]. AB - OBJECTIVE: To analyze related risk factors of sepsis complicated acute kidney injury (AKI), and to explore the precaution equation for early clinical diagnosis. METHODS: A retrospective review of patients with sepsis complicating AKI admitted to intensive care unit (ICU) of Affiliated Hospital of Binzhou Medical University from April 2011 to April 2013 were enrolled. Fifty-eight sepsis patients without AKI were enrolled as control. Eleven indexes including age, mean arterial pressure (MAP) score, sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE II) score, 24-hour urine volume, 24-hour net liquid intake score, serum creatinine (SCr) score, blood urea nitrogen (BUN), oxygenation index, blood lactic acid score and plasma albumin were collected as possible risk factors for AKI in sepsis patients. The risk factors and calculation of the critical value were analyzed by multiple factor logistic regression analysis. RESULTS: Nine factors with statistical significance for AKI in sepsis patients analyzed with univariate analysis were substituted in logistic regression model including MAP score, SOFA score, APACHEII score, 24-hour urine volume, 24-hour net liquid intake score, SCr score, BUN, oxygenation index, blood lactic acid score. After variable screening SCr score, MAP score, 24-hour net liquid intake score and blood lactic acid score were substituted in regression equation: Y=0.237X1 + 0.139X2 + 0.057X3 + 0.051X4 (X1, X2, X3, X4 typified SCr score, MAP score, blood lactic acid score and 24 hour net liquid intake score), F=125.897, P=0.000. The diagnostic cutoff appeared as 0.778. The sensitivity, the specificity, the Youden index, positive predictive value and negative predictive value were 80%, 100%, 0.8, 100% and 74%, respectively. CONCLUSIONS: SCr score, MAP score, blood lactic acid score and 24 hour net liquid intake score were risk factors of sepsis complicating AKI. When the value higher than 0.778 from regression equation Y=0.237X1 + 0.139X2 + 0.057X3 + 0.051X4, it hinted there was risk related to AKI in sepsis patients. The equation can help the clinicians diagnose sepsis and AKI earlier. PMID- 24059422 TI - [Screening type II alveolar epithelial cell apoptosis related microRNA]. AB - OBJECTIVE: To screen type II alveolar epithelial cell (AECII) apoptosis related microRNA (miRNA) with gene chip technology, provide a new strategy for the prevention and treatment of hyperoxia-induced acute lung injury(HALI). METHODS: AECII of male Sprague-Dawley (SD) rats was primarily cultured for 36 hours, then exposed to 0.5 mmol/L H2O2 to establish apoptosis model. Transmission electron microscope (TEM) was used to identify AECII and to observe apoptosis cell morphology. Before and after H2O2 injury for 2.5, 6, 12 and 24 hours, fluorescence-activated cell sorting (FACS) was employed to detect apoptosis rate. Additionally, gene chip technology and real time polymerase chain reaction (RT PCR) were used to screen and verify apoptosis related miRNA respectively. RESULTS: Microvilli and osmiophilic multilamellar body were found under TEM, which were the characteristic structure of AECII. This proved that the cells cultured were AECII. After H2O2 injury for 24 hours, cytoplasmic retraction, chromatin condensation and margination, microvilli and osmiophilic multilamellar body disappearance could be found under TEM. Compared with the blank control group, the apoptosis rate of AECII was significantly increased after exposed to 0.5 mmol/L H2O2, and gradually increased with time [the early apoptosis rate before and after H2O2 injury for 2.5, 6, 12 and 24 hours were (9.43+/-1.02)%, (18.38+/-2.91)%, (28.57+/-1.18)%, (35.83+/-2.66)% and (57.68+/-2.22)%, respectively, all P<0.05]. Compared with before H2O2 injury, cells at 24 hours accompanied a significantly changed miRNA expression profiling, in which apoptosis related miRNA had been screened, they were rno-miR-449a-5p, rno-miR 34b/c-5p, rno-miR-200a/c-3p, rno-miR-146a-5p, rno-miR-141-3p, rno-miR-21-5p, rno miR-375-3p, rno-miR-29b-3p, rno-miR-214-5p, rno-miR-210-5p and rno-miR-214-3p,and the results of RT-PCR were consistent with the gene chip results. CONCLUSIONS: Screened out AECII apoptosis related miRNA, and miR-34 family may play a key role in AECII apoptosis regulation. Rno-miR-21-5p may be an important anti-apoptotic gene in AECII apoptosis regulation. PMID- 24059423 TI - [Study of traditional Chinese medicine syndrome on multiple organ dysfunction syndrome in the elderly]. AB - OBJECTIVE: To statistically analyze the clinical data from patients with multiple organ dysfunction syndrome in the elderly (MODSE), and to investigate the distribution pattern of traditional Chinese medicine (TCM) syndromes. METHODS: TCM data of 200 patients with MODSE was collected on 1, 3 and 7 days after diagnosis. Using 134 symptoms as observation indexes, clustering analysis was used to analyze the TCM symptoms and syndromes of these patients. RESULTS: In accordance with Diagnostic efficacy of standard TCM Syndrome, Diagnostics of TCM, State Standard of the People's Republic of China: clinical diagnose and treat Terminology of TCM, expert group differentiate on the professional knowledge and clinical manifestation and 7 types of TCM syndrome were selected. Among all syndrome types, there were 134 (22.3%) cases of phlegm stagnation with the largest population, 113 cases (18.8%) of toxic heat flourishing, 97 cases (16.2%) of damp-heat accumulation, 85 cases (14.2%) of qi-deficiency, 67 cases (11.2%) of both yin and yang deficiency, 55 cases (9.2%) of fu being filled and substances could not pass through, and 48 cases (8.1%) of qi stagnation and blood stasis. CONCLUSIONS: This preliminary study found 7 primary types of TCM syndrome in patients with MODSE, including syndrome of phlegm stagnation, toxic heat flourishing, accumulation of damp-heat, qi-deficiency, both yin and yang deficiency, fu being filled and substances could not pass through and qi stagnation and blood stasis. The most common syndrome is phlegm stagnation and deficiency, phlegm, blood stasis, toxic are the main etiology and pathology of the disease. PMID- 24059424 TI - [Effect of sengstaken-blakemore tube combined with suction catheter in esophageal varices bleeding patients]. PMID- 24059425 TI - [Invention and clinical application of modified one-time teeth cushion]. PMID- 24059426 TI - [Electroversion treatment of paroxysmal supraventricular tachycardia caused by aconitum poisoning:a case report]. PMID- 24059427 TI - [A study about the clinical significance of cardiac QTc interval for predicting the mortality and prognostic of acute organophosphate poisoning]. PMID- 24059428 TI - [Nursing care of patients with bile leakage post orthotopic liver transplantation by the peritoneal lavage and drainage]. PMID- 24059429 TI - [The application value of portable bedside ultrasound in abdominal closed blunt trauma of sudden accident in the spot]. PMID- 24059430 TI - [Intestinal obstruction and necrosis caused by lumianling poisoning: a case report]. PMID- 24059431 TI - [A case of septic shock and multiple organ injury induced by urinary tract infection with Morganella morganii subsp. morganii]. PMID- 24059432 TI - [Research progress in the pathogenesis of central nervous system on severe heat stroke]. PMID- 24059433 TI - [Advances in non-cultivation technology of microorganism and study on intestinal microecology]. PMID- 24059434 TI - Solid-phase electrochemical reduction of graphene oxide films in alkaline solution. AB - Graphene oxide (GO) film was evaporated onto graphite and used as an electrode to produce electrochemically reduced graphene oxide (ERGO) films by electrochemical reduction in 6 M KOH solution through voltammetric cycling. Fourier transformed infrared and Raman spectroscopy confirmed the presence of ERGO. Electrochemical impedance spectroscopy characterization of ERGO and GO films in ferrocyanide/ferricyanide redox couple with 0.1 M KCl supporting electrolyte gave results that are in accordance with previous reports. Based on the EIS results, ERGO shows higher capacitance and lower charge transfer resistance compared to GO. PMID- 24059436 TI - Malaria's many mates: past, present, and future of the systematics of the order Haemosporida. AB - Malaria has been one of the most important diseases of humans throughout history and continues to be a major public health concern. The 5 species of Plasmodium that cause the disease in humans are part of the order Haemosporida, a diverse group of parasites that all have heteroxenous life cycles, alternating between a vertebrate host and a free-flying, blood-feeding dipteran vector. Traditionally, the identification and taxonomy of these parasites relied heavily on life-history characteristics, basic morphological features, and the host species infected. However, molecular approaches to resolving the phylogeny of the group have sometimes challenged many of these traditional hypotheses. One of the greatest debates has concerned the origin of the most virulent of the human-infecting parasites, Plasmodium falciparum, with early results suggesting a close relationship with an avian parasite. Subsequent phylogenetic studies placed it firmly within the mammalian clade instead, but the avian origin hypothesis has been revived with recent genome-based analyses. The rooting of the tree of Haemosporida has also been inconsistent, and the various topologies that result certainly affect our interpretation of the history of the group. There is clearly a pressing need to obtain a much more complete degree of taxon sampling of haemosporidians, as well as a greater number of characters before confidence can be placed in any hypothesis regarding the evolutionary history of the order. There are numerous challenges moving forward, particularly for generating complete genome sequences of avian and saurian parasites. PMID- 24059435 TI - Solution structures of the Bacillus cereus metallo-beta-lactamase BcII and its complex with the broad spectrum inhibitor R-thiomandelic acid. AB - Metallo-beta-lactamases, enzymes which inactivate beta-lactam antibiotics, are of increasing biological and clinical significance as a source of antibiotic resistance in pathogenic bacteria. In the present study we describe the high resolution solution NMR structures of the Bacillus cereus metallo-beta-lactamase BcII and of its complex with R-thiomandelic acid, a broad-spectrum inhibitor of metallo-beta-lactamases. This is the first reported solution structure of any metallo-beta-lactamase. There are differences between the solution structure of the free enzyme and previously reported crystal structures in the loops flanking the active site, which are important for substrate and inhibitor binding and catalysis. The binding of R-thiomandelic acid and the roles of active-site residues are defined in detail. Changes in the enzyme structure upon inhibitor binding clarify the role of the mobile beta3-beta4 loop. Comparisons with other metallo-beta-lactamases highlight the roles of individual amino-acid residues in the active site and the beta3-beta4 loop in inhibitor binding and provide information on the basis of structure-activity relationships among metallo-beta lactamase inhibitors. PMID- 24059438 TI - Giant electroactive M4L6 tetrahedral host self-assembled with Fe(II) vertices and perylene bisimide dye edges. AB - Self-assembly of octahedral Fe(II) ions and linear perylene bisimide (PBI) dyes with 2,2'-bipyridine groups covalently attached at the imide positions quantitatively yields an Fe4(PBI)6 tetrahedron by the directional bonding approach. With an edge length of 3.9 nm and estimated internal volume >950 A(3), tetrahedron T is one of the largest M4L6 tetrahedra ever reported. Importantly, many of the desirable photo- and electroactive properties of the PBI ligands are transferred to the nanoscale metallosupramolecule. Tetrahedron T absorbs strongly across the visible spectrum out to 650 nm and exhibits a total of 7 highly reversible electrochemical oxidation and reduction waves spanning a 3.0 V range. This facile cycling of 34 electrons between +18 and -16 charged species is likely enabled due to the porous nature of the tetrahedron that allows the necessary counterions to freely flow in and out of the host. Host-guest encapsulation of C60 by T in acetonitrile was studied by (13)C NMR spectroscopy, UV-vis spectroscopy, and ESI-MS, confirming that the tetrahedron is a suitable host for large, functional guest molecules. PMID- 24059437 TI - Structural equation modeling of parasympathetic and sympathetic response to traffic air pollution in a repeated measures study. AB - BACKGROUND: Traffic-related air pollution has been associated to a range of adverse health impacts, including decreased heart rate variability (HRV). The association between traffic-related pollution and HRV, however, has varied by traffic-related or HRV marker as well as by study, suggesting the need for a more comprehensive and integrative approach to examining air pollution-mediated biological impacts on these outcomes. In a Bayesian framework, we examined the effect of traffic pollution on HRV using structural equation models (SEMs) and looked at effect modification by participant characteristics. METHODS: We studied measurements of 5 HRV markers [high frequency (HF), low frequency (LF), 5-min standard deviation of normal-to-normal intervals (SDNN), square root of the mean squared differences of successive normal-to-normal intervals (rMSSD), and LF/HF ratio (LF/HF)] for 700 elderly men from the Normative Aging Study. Using SEMs, we fit a latent variable for traffic pollution that is reflected by levels of carbon monoxide, nitrogen monoxide, nitrogen dioxide, and black carbon (BC) to estimate its effect on latent variable for parasympathetic tone that included HF, SDNN and rMSSD, and the sympathetic tone marker, LF/HF. Exposure periods were assessed using 4-, 24-, 48-, 72-hour moving average pre-visit. We compared our main effect findings using SEMs with those obtained using linear mixed models. RESULTS: Traffic pollution was not associated with mean parasympathetic tone and LF/HF for all examined moving averages. In Bayesian linear mixed models, however, BC was related to increased LF/HF, an inter quartile range (IQR) increase in BC was associated with a 6.5% (95% posterior interval (PI): -0.7%, 14.2%) increase in mean LF/HF 24-hours later. The strongest association observed was for the 4-hour moving average (10.1%; 95% PI: 3.0%, 17.6%). The effect of traffic on parasympathetic tone was stronger among diabetic as compared to non-diabetic participants. Specifically, an IQR increase in traffic pollution in the 48-hr prior to the clinic visit was associated with a 44.3% (95% PI: -67.7%, -4.2%) lower mean parasympathetic tone among diabetics, and a 7.7% (95% PI: -18.0%, 41.4%) higher mean parasympathetic tone among non-diabetics. CONCLUSIONS: BC was associated with adverse changes LF/HF in the elderly. Traffic pollution may decrease parasympathetic tone among diabetic elderly. PMID- 24059439 TI - Ion implantation of graphene-toward IC compatible technologies. AB - Doping of graphene via low energy ion implantation could open possibilities for fabrication of nanometer-scale patterned graphene-based devices as well as for graphene functionalization compatible with large-scale integrated semiconductor technology. Using advanced electron microscopy/spectroscopy methods, we show for the first time directly that graphene can be doped with B and N via ion implantation and that the retention is in good agreement with predictions from calculation-based literature values. Atomic resolution high-angle dark field imaging (HAADF) combined with single-atom electron energy loss (EEL) spectroscopy reveals that for sufficiently low implantation energies ions are predominantly substitutionally incorporated into the graphene lattice with a very small fraction residing in defect-related sites. PMID- 24059440 TI - Pheochromocytoma presenting with rhabdomyolysis and acute renal failure: a case report. AB - Rhabdomyolysis ranges from an asymptomatic illness with elevated creatine kinase levels to a life-threatening condition associated with extreme elevations in creatine kinase, electrolyte imbalances, acute renal failure, and disseminated intravascular coagulation. The most common causes are crush injury, overexertion, alcohol abuse, certain medicines, and toxic substances. A number of electrolyte abnormalities and endocrinopathies, including hypothyroidism, thyrotoxicosis, diabetic ketoacidosis, nonketotic hyperosmolar state, and hyperaldosteronism, cause rhabdomyolysis. Rhabdomyolysis and acute renal failure are unusual manifestations of pheochromocytoma. There are a few case reports with pheochromocytoma presenting rhabdomyolysis and acute renal failure. Herein, we report a case with pheochromocytoma crisis presenting with rhabdomyolysis and acute renal failure. PMID- 24059441 TI - Simulations suggest possible novel membrane pore structure. AB - Amphiphilic proteins and peptides can induce the formation of stable and metastable pores in membranes. Using coarse-grained simulations, we have studied the factors that affect structure of peptide-stabilized pores. Our simulations are able to reproduce the formation of the well-known barrel-stave or toroidal pores, but in addition, we find evidence for a novel "double-belt" pore structure: in this structure the peptides that coat the membrane pore are oriented parallel to the membrane plane. To check the predictions of our coarse grained model, we have performed more detailed simulations, using the MARTINI force field. These simulations show that the double-belt structure is stable up to at least the microsecond time scale. PMID- 24059443 TI - Effects of interactive metronome therapy on cognitive functioning after blast related brain injury: a randomized controlled pilot trial. AB - OBJECTIVE: We report preliminary findings on the efficacy of interactive metronome (IM) therapy for the remediation of cognitive difficulties in soldiers with persisting cognitive complaints following blast-related mild-to-moderate traumatic brain injury (TBI). METHOD: Forty-six of a planned sample of 50 active duty soldiers with persistent cognitive complaints following a documented history of blast-related TBI of mild-to-moderate severity were randomly assigned to receive either standard rehabilitation care (SRC) or SRC plus a 15-session standardized course of IM therapy. Primary outcome measures were Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Index Scores. Secondary outcome measures included selected subtests from the Delis-Kaplan Executive Functioning System (Trail Making Test and Color-Word Interference) and the Wechsler Adult Intelligence Scale-Fourth Edition (Symbol Search, Digit-Symbol Coding, Digit Span, and Letter-Number Sequencing) as well as the Integrated Visual and Auditory Continuous Performance Test. RESULTS: Significant group differences (SRC vs. IM) were observed for RBANS Attention (p = .044), Immediate Memory (p = .019), and Delayed Memory (p = .031) indices in unadjusted analyses, with the IM group showing significantly greater improvement at Time 2 than the SRC group, with effect sizes in the medium-to-large range in the adjusted analyses for each outcome (Cohen's d = 0.511, 0.768, and 0.527, respectively). Though not all were statistically significant, effects in 21 of 26 cognitive outcome measures were consistently in favor of the IM treatment group (binomial probability = .00098). CONCLUSION: The addition of IM therapy to SRC appears to have a positive effect on neuropsychological outcomes for soldiers who have sustained mild-to-moderate TBI and have persistent cognitive complaints after the period for expected recovery has passed. PMID- 24059442 TI - Chlorinated biphenyl quinones and phenyl-2,5-benzoquinone differentially modify the catalytic activity of human hydroxysteroid sulfotransferase hSULT2A1. AB - Human hydroxysteroid sulfotransferase (hSULT2A1) catalyzes the sulfation of a broad range of environmental chemicals, drugs, and other xenobiotics in addition to endogenous compounds that include hydroxysteroids and bile acids. Polychlorinated biphenyls (PCBs) are persistent environmental contaminants, and oxidized metabolites of PCBs may play significant roles in the etiology of their adverse health effects. Quinones derived from the oxidative metabolism of PCBs (PCB-quinones) react with nucleophilic sites in proteins and also undergo redox cycling to generate reactive oxygen species. This, along with the sensitivity of hSULT2A1 to oxidative modification at cysteine residues, led us to hypothesize that electrophilic PCB-quinones react with hSULT2A1 to alter its catalytic function. Thus, we examined the effects of four phenylbenzoquinones on the ability of hSULT2A1 to catalyze the sulfation of the endogenous substrate, dehydroepiandrosterone (DHEA). The quinones studied were 2'-chlorophenyl-2,5 benzoquinone (2'-Cl-BQ), 4'-chlorophenyl-2,5-benzoquinone (4'-Cl-BQ), 4' chlorophenyl-3,6-dichloro-2,5-benzoquinone (3,6,4'-triCl-BQ), and phenyl-2,5 benzoquinone (PBQ). At all concentrations examined, pretreatment of hSULT2A1 with the PCB-quinones decreased the catalytic activity of hSULT2A1. Pretreatment with low concentrations of PBQ, however, increased the catalytic activity of the enzyme, while higher concentrations inhibited catalysis. A decrease in substrate inhibition with DHEA was seen following preincubation of hSULT2A1 with all of the quinones. Proteolytic digestion of the enzyme followed by LC/MS analysis indicated PCB-quinone- and PBQ-adducts at Cys55 and Cys199, as well as oxidation products at methionines in the protein. Equilibrium binding experiments and molecular modeling suggested that changes due to these modifications may affect the nucleotide binding site and the entrance to the sulfuryl acceptor binding site of hSULT2A1. PMID- 24059444 TI - Meeting an "impossible challenge" in semantic dementia: outstanding performance in numerical Sudoku and quantitative number knowledge. AB - OBJECTIVE: This study describes a follow-up investigation of numerical abilities and visuospatial memory in a patient suffering from semantic dementia whose progressive decline of semantic memory variably affected different types of knowledge. Crucially, we investigated in detail her outstanding performance with Sudoku that has been only anecdotally reported in the previous literature. METHOD: We tested spatial cognition and memory, body representation, number processing, calculation, and Sudoku tasks, and we compared the patient's performance with that of matched controls. RESULTS: In agreement with the neuroanatomical data, showing substantial sparing of the parietal lobes in the face of severe atrophy of the temporal (and frontal) regions, we report full preservation of skills known to be supported by intact parietal-basal ganglia networks, and impaired knowledge related to long-term stored declarative information mediated by temporal regions. Performance in tasks sensitive to parietal dysfunction (such as right-left orientation, finger gnosis, writing, and visuospatial memory) was normal; within the numerical domain, preserved quantity based number knowledge dissociated from increasing difficulties with nonquantitative number knowledge (such as knowledge of encyclopedic and personal number facts) and arithmetic facts knowledge. CONCLUSIONS: This case confirms the relation between numbers and space, and, although indirectly, their anatomical correlates, underlining which abilities are preserved in the case of severe semantic loss. In addition, although Sudoku is not inherently numerical, the patient was able to solve even the most difficult pattern, provided that it required digits and not letters, showing that digits have, in any case, a specific status. PMID- 24059445 TI - Aerobic fitness and the attentional blink in preadolescent children. AB - OBJECTIVE: Given the growing concern that children in today's industrialized and technologically advanced society are becoming more sedentary and less fit, a greater understanding of the extent to which aerobic fitness relates to brain health and cognition during development is of increasing importance. Accordingly, this study sought to use neuroelectric and behavioral measures during an attentional blink task to examine the temporal dynamics of attention as a function of children's aerobic fitness. METHOD: Using a cross-sectional design, response accuracy and event-related brain potentials were assessed in preadolescent children with different levels of aerobic fitness. RESULTS: Results indicated that higher fit children exhibited greater task performance and better attentional resources distribution, as measured via the P3 component, compared to lower fit children. CONCLUSION: These findings indicate that aerobic fitness may benefit aspects of cognitive health that involve temporal dynamics of attentional processes during preadolescent maturation. PMID- 24059446 TI - Predictive performance of comorbidity measures in administrative databases for diabetes cohorts. AB - BACKGROUND: The performance of comorbidity measures for predicting mortality in chronic disease populations and using ICD-9 diagnosis codes in administrative health data has been investigated in several studies, but less is known about predictive performance with ICD-10 data and for other health outcomes. This study investigated predictive performance of five comorbidity measures for population based diabetes cohorts in administrative data. The objectives were to evaluate performance for: (a) disease-specific and general health outcomes, (b) data based on the ICD-9 and ICD-10 diagnoses, and (c) different age groups. METHODS: Performance was investigated for heart attack, stroke, amputation, renal disease, hospitalization, and death in all-age and age-specific cohorts. Hospital records, physician billing claims, and prescription drug records from one Canadian province were used to identify diabetes cohorts and measure comorbidity. The data were analysed using multiple logistic regression models and summarized using measures of discrimination, accuracy, and fit. RESULTS: In Cohort 1 (n = 29,058), for which only ICD-9 diagnoses were recorded in administrative data, the Elixhauser index showed good or excellent prediction for amputation, renal disease, and death and performed better than the Charlson index. Number of diagnoses was a good predictor of hospitalization. Similar results were obtained for Cohort 2 (n = 41,925), in which both ICD-9 and ICD-10 diagnoses were recorded in administrative data, although predictive performance was sometimes higher. For age-specific models of mortality, the Elixhauser index resulted in the largest improvement in predictive performance in all but the youngest age group. CONCLUSIONS: Cohort age and the health outcome under investigation, but not the diagnosis coding system, may influence the predictive performance of comorbidity measure for studies about diabetes populations using administrative health data. PMID- 24059447 TI - The in vitro and in vivo effects of a low-molecular-weight fucoidan on the osteogenic capacity of human adipose-derived stromal cells. AB - Human adipose-derived stromal cells (hASCs) may hold potential for bone tissue engineering. Osteogenic differentiation of these cells is crucial to bone formation. Low-molecular-weight fucoidan (LMWF) is a sulfated polysaccharide that potentiates several growth factors, including pro-angiogenic growth factors. To investigate whether hASC preconditioning with LMWF promoted bone repair, we compared the effects of LMWF and low-molecular-weight heparin on hASC phenotype and osteogenic differentiation. LMWF did not modify the stem-cell phenotype of hASCs but enhanced their osteogenic differentiation (formation of calcium deposits, increased activity and expression of alkaline phosphatase, and increased expression of osteopontin and runt-related transcription factor 2). However, when hASCs were exposed to LMWF before their adhesion to biphasic calcium phosphate particles and implantation in a bone-growth mouse model, no bone formation was apparent after 5 or 8 weeks, probably due to cell death. In conclusion, LMWF may hold promise for enhancing the osteogenic differentiation of hASCs before their implantation. However, concomitant vascularization would be required to enhance bone formation. PMID- 24059448 TI - Associations between social participation and subjective quality of life for adults with moderate to severe traumatic brain injury. AB - PURPOSE: To examine the association between social participation and subjective quality of life (SQOL) for non-employed, community-dwelling adults with moderate to severe traumatic brain injury (TBI) at 1 year or greater post-injury. METHOD: A correlational study was conducted involving 46 participants. Social participation was measured using the Community Integration Questionnaire, Social Provisions Scale and the Adult Subjective Assessment of Participation. SQOL was measured using the Quality of Life and Health Questionnaire, Abdel-Khalek Happiness Scale and UCLA Loneliness Scale. RESULTS: Higher levels of happiness and global quality of life were each associated with higher levels of enjoyment, satisfaction with performance and higher proportion of activities performed with others. Lower levels of loneliness were associated with higher levels of general social integration and higher levels of perceived social supports. There were no associations found between SQOL and the objective social participation measures of diversity, frequency (intensity) or proportion of activities performed outside of home. CONCLUSIONS: Findings contribute to the TBI literature in showing that it is: (a) the more subjective and not objectively measured nature of participation that is associated with SQOL and (b) positive and negative aspects of quality of life show different relationships with social participation variables. Implications for Rehabilitation A high proportion of individuals with traumatic brain injury (TBI) experiences reduced involvement in social participation (involvement in social and leisure activities and within a social network) and low subjective quality of life (SQOL). This study suggests that, by simply increasing the variety and frequency of social and leisure activities, there may be no positive influences on SQOL. Instead, this study suggests that, to increase SQOL, it is important to increase opportunities for individuals to participate with others and also to enhance their subjective experience of social and leisure activities. The large variance obtained of scores for social participation and SQOL provide a reminder to clinicians to maintain an individualized approach when working with individuals with TBI. PMID- 24059450 TI - The impact of academic calendar cycle on coronary artery bypass outcomes: a comparison of teaching and non-teaching hospitals. AB - BACKGROUND: The commencement of new academic cycle in July is presumed to be associated with poor patient outcomes, although supportive evidence is limited for cardiac surgery patients. We sought to determine if the new academic cycle affected the outcomes of patients undergoing Coronary Artery Bypass Grafting. METHODS: A retrospective analysis was performed on 10-year nationwide in-hospital data from 1998-2007. Only patients who underwent CABG in the first and final academic 3-month calendar quarter were included. Generalized multivariate regression was used to assess indicators of hospital quality of care such as risk adjusted mortality, total complications and "failure to rescue" (FTOR) - defined as death after a complication. RESULTS: Of the 1,056,865 CABG operations performed in the selected calendar quarters, 698,942 were at teaching hospitals. The risk-adjusted mortality, complications and FTOR were higher in the beginning of the academic year [Odds ratio = 1.14, 1.04 and 1.19 respectively; p < 0.001 for all] irrespective of teaching status. However, teaching status was associated with lower mortality (OR 0.9) despite a higher complication rate (OR 1.02); [p < 0.05 for both]. The July Effect thus contributed to only a 2.4% higher FTOR in teaching hospitals compared to 19% in non teaching hospitals. CONCLUSIONS: The July Effect is reflective of an overall increase in morbidity in all hospitals at the beginning of the academic cycle and it had a pronounced effect in non teaching hospitals. Teaching hospitals were associated with lower mortality despite higher complication rates in the beginning of the academic cycle compared to non-teaching hospitals. The July effect thus cannot be attributed to presence of trainees alone. ULTRAMINI ABSTRACT: This study compares the July effect in teaching and non-teaching hospitals and demonstrates that this effect is not unique to teaching hospitals for CABG patients. In fact, teaching hospitals have somewhat better outcomes at the beginning of the academic cycle and the July effect is a much broader seasonal variation. PMID- 24059449 TI - Histone deacetylase inhibition rescues gene knockout levels achieved with integrase-defective lentiviral vectors encoding zinc-finger nucleases. AB - Zinc-finger nucleases (ZFNs) work as dimers to induce double-stranded DNA breaks (DSBs) at predefined chromosomal positions. In doing so, they constitute powerful triggers to edit and to interrogate the function of genomic sequences in higher eukaryotes. A preferred route to introduce ZFNs into somatic cells relies on their cotransduction with two integrase-defective lentiviral vectors (IDLVs) each encoding a monomer of a functional heterodimeric pair. The episomal nature of IDLVs diminishes the risk of genotoxicity and ensures the strict transient expression profile necessary to minimize deleterious effects associated with long term ZFN activity. However, by deploying IDLVs and conventional lentiviral vectors encoding HPRT1- or eGFP-specific ZFNs, we report that DSB formation at target alleles is limited after IDLV-mediated ZFN transfer. This IDLV-specific underperformance stems, to a great extent, from the activity of chromatin remodeling histone deacetylases (HDACs). Importantly, the prototypic and U.S. Food and Drug Administration-approved inhibitors of metal-dependent HDACs, trichostatin A and vorinostat, respectively, did not hinder illegitimate recombination-mediated repair of targeted chromosomal DSBs. This allowed rescuing IDLV-mediated site-directed mutagenesis to levels approaching those achieved by using their isogenic chromosomally integrating counterparts. Hence, HDAC inhibition constitutes an efficacious expedient to incorporate in genome-editing strategies based on transient IDLV-mediated ZFN expression. Finally, we compared two of the most commonly used readout systems to measure targeted gene knockout activities based on restriction and mismatch-sensitive endonucleases. These experiments indicate that these enzymatic assays display a similar performance. PMID- 24059451 TI - Sensitive single particle method for characterizing rapid rotational and translational diffusion and aspect ratio of anisotropic nanoparticles and its application in immunoassays. AB - In this article, we reported a new and sensitive method for characterizing rapid rotational and translational diffusion of gold nanoparticles (GNPs) and gold nanorods (GNRs) by resonance light scattering correlation spectroscopy (RLSCS). The RLSCS is a new single nanoparticle method, and its principle is based on measuring the resonance light scattering fluctuations in a highly focused volume due to Brownian motion of single particles, which resembles fluorescence correlation spectroscopy (FCS). On the basis of the theory of FCS, we first developed a model for rotational and translational diffusion and aspect ratio of nanoparticles in the RLSCS system. Then, we investigated the effects of certain factors such as the wavelength of illumination light and viscosity of solution using GNPs and GNRs as model samples and discovered that the polarization anisotropy and the scattering light intensity of GNPs and GNRs were significantly dependent on the wavelengths of illumination light. Using the 632.8 nm He-Ne laser as a light source, which was close to the resonance scattering band, we successfully obtained the translational and rotational diffusion coefficients and aspect ratios of anisotropic nanoparticles by the RLSCS method. The results obtained by this new method were in good agreement with transmission electron microscopy and theoretical calculation. Furthermore, the homogeneous sandwich immunoreaction was investigated using the antibody-modified GNPs as the probes. The changes in translational diffusion behaviors and aspect ratios of GNPs in immunoreaction were observed by the RLSCS method. By these changes, we can develop a new homogeneous immunoassay. Our preliminary results illustrated that the RLSCS method was a powerful tool for characterizing rapid rotational and translational diffusion behaviors of anisotropic nanoparticles in solution. We believe that the RLSCS method exhibits the wide applications in biological science especially in vivo study on the interaction of nanoparticles and biomolecules. PMID- 24059453 TI - Airway transplantation: a challenge for regenerative medicine. AB - After more than 50 years of research, airway transplantation remains a major challenge in the fields of thoracic surgery and regenerative medicine. Five principal types of tracheobronchial substitutes, including synthetic prostheses, bioprostheses, allografts, autografts and bioengineered conduits have been evaluated experimentally in numerous studies. However, none of these works have provided a standardized technique for the replacement of the airways. More recently, few clinical attempts have offered encouraging results with ex vivo or stem cell-based engineered airways and tracheal allografts implanted after heterotopic revascularization. In 1997, we proposed a novel approach: the use of aortic grafts as a biological matrix for extensive airway reconstruction. In vivo regeneration of epithelium and cartilage were demonstrated in animal models. This led to the first human applications using cryopreserved aortic allografts that present key advantages because they are available in tissue banks and do not require immunosuppressive therapy. Favorable results obtained in pioneering cases have to be confirmed in larger series of patients with extensive tracheobronchial diseases. PMID- 24059454 TI - Transparent luminescent hyperbranched epoxy/carbon oxide dot nanocomposites with outstanding toughness and ductility. AB - A luminescent transparent hyperbranched epoxy nanocomposite with previously unachieved outstanding toughness and elasticity has been created by incorporation of a very small amount of carbon oxide nanodots. The nanocomposites of the hyperbranched epoxy with carbon oxide dots at different dose levels (0.1, 0.5, and 1.0 wt %) have been prepared by an ex situ solution technique followed by curing with poly(amido-amine) at 100 degrees C. Different characterizations and evaluations of mechanical and optical properties of the nanocomposites have been performed. The toughness (area under the stress-strain curve) of the pristine system has been improved dramatically by 750% with only 0.5 wt % carbon oxide dots. The tensile strength has been enhanced from 38 to 46 MPa, whereas the elongation at break improved noticeably from 15 to 45%. Excellent adhesive strength combined with transparency and photoluminescent behavior renders these materials highly interesting as functional films in optical devices like light emitting diodes and UV light detection systems as well as in anticounterfeiting applications. PMID- 24059452 TI - CD38 in the nucleus accumbens and oxytocin are related to paternal behavior in mice. AB - BACKGROUND: Mammalian sires participate in infant care. We previously demonstrated that sires of a strain of nonmonogamous laboratory mice initiate parental retrieval behavior in response to olfactory and auditory signals from the dam during isolation in a new environment. This behavior is rapidly lost in the absence of such signals when the sires are caged alone. The neural circuitry and hormones that control paternal behavior are not well-understood. CD38, a membrane glycoprotein, catalyzes synthesis of cyclic ADP-ribose and facilitates oxytocin (OT) secretion due to cyclic ADP-ribose-dependent increases in cytosolic free calcium concentrations in oxytocinergic neurons in the hypothalamus. In this paper, we studied CD38 in the nucleus accumbens (NAcc) and the role of OT on paternal pup retrieval behavior using CD38 knockout (CD38-/-) mice of the ICR strain. RESULTS: CD38-/- sires failed to retrieve when they were reunited with their pups after isolation together with the mate dams, but not with pup, in a novel cage for 10 min. CD38-/- sires treated with a single subcutaneous injection of OT exhibited recovery in the retrieval events when caged with CD38-/- dams treated with OT. We introduced human CD38 in the NAcc of CD38-/- sires using a lentiviral infection technique and examined the effects of local expression of CD38. Pairs of knockout dams treated with OT and sires expressing CD38 in the NAcc showed more retrieval (83% of wild-type sire levels). Complete recovery of retrieval was obtained in sires with the expression of CD38 in the NAcc in combination with OT administration. Other paternal behaviors, including pup grooming, crouching and huddling, were also more common in CD38-/- sires with CD38 expression in the NAcc compared with those in CD38-/- sires without CD38 expression in the NAcc. CONCLUSIONS: CD38 in the NAcc and OT are critical in paternal behavior. PMID- 24059456 TI - In vitro evaluation of encapsulated primary rat hepatocytes pre- and post cryopreservation at -80 degrees C and in liquid nitrogen. AB - Encapsulation techniques have the potential to protect hepatocytes from cryoinjury. In this study, we comparatively evaluated the viability and metabolic function of primary rat hepatocytes encapsulated in calcium alginate microbeads, in chitosan tripolyphosphate beads, and in three-layered alginate-chitosan alginate (ACA) microcapsules, before and after cryopreservation at -80 degrees C and in liquid nitrogen (LN2) for 1 and 3 months. Findings demonstrated that LN2 was atop of -80 degrees C in regard to preservation of viability (> 90%) and hepatic functions. LN2-cryopreserved hepatocytes encapsulated in ACA microcapsules retained metabolic function post-thawing, with > 90% of the albumin, total protein and urea syntheses activities, and > 80% of oxidative function. PMID- 24059455 TI - Comprehensive transcriptomic study on horse gram (Macrotyloma uniflorum): De novo assembly, functional characterization and comparative analysis in relation to drought stress. AB - BACKGROUND: Drought tolerance is an attribute maintained in plants by cross-talk between multiple and cascading metabolic pathways. Without a sequenced genome available for horse gram, it is difficult to comprehend such complex networks and intercalated genes associated with drought tolerance of horse gram (Macrotyloma uniflorum). Therefore, de novo transcriptome discovery and associated analyses was done for this highly drought tolerant yet under exploited legume to decipher its genetic makeup. RESULTS: Eight samples comprising of shoot and root tissues of two horse gram genotypes (drought-sensitive; M-191 and drought-tolerant; M 249) were used for comparison under control and polyethylene glycol-induced drought stress conditions. Using Illumina sequencing technology, a total of 229,297,896 paired end read pairs were generated and utilized for de novo assembly of horse gram. Significant BLAST hits were obtained for 26,045 transcripts while, 3,558 transcripts had no hits but contained important conserved domains. A total of 21,887 unigenes were identified. SSRs containing sequences covered 16.25% of the transcriptome with predominant tri- and mono nucleotides (43%). The total GC content of the transcriptome was found to be 43.44%. Under Gene Ontology response to stimulus, DNA binding and catalytic activity was highly expressed during drought stress conditions. Serine/threonine protein kinase was found to dominate in Enzyme Classification while pathways belonging to ribosome metabolism followed by plant pathogen interaction and plant hormone signal transduction were predominant in Kyoto Encyclopedia of Genes and Genomes analysis. Independent search on plant metabolic network pathways suggested valine degradation, gluconeogenesis and purine nucleotide degradation to be highly influenced under drought stress in horse gram. Transcription factors belonging to NAC, MYB-related, and WRKY families were found highly represented under drought stress. qRT-PCR validated the expression profile for 9 out of 10 genes analyzed in response to drought stress. CONCLUSIONS: De novo transcriptome discovery and analysis has generated enormous information over horse gram genomics. The genes and pathways identified suggest efficient regulation leading to active adaptation as a basal defense response against drought stress by horse gram. The knowledge generated can be further utilized for exploring other underexploited plants for stress responsive genes and improving plant tolerance. PMID- 24059457 TI - Distribution of congenital anomalies in a neonatal intensive care unit in Turkey. AB - BACKGROUND: Congenital anomalies are one of the important reasons of mortality and morbidity in newborns. The aim of this study is to determine the incidence, distribution and the mortality of the congenital anomalies in a single neonatal intensive care unit (NICU) from Turkey. METHOD: A retrospective analysis was performed between 2005 and 2012 in NICU using a computerized database. Variables including the type of anomaly, antenatal and postnatal history, gestational age, birth weight, consanguinity and other demographic, clinical and related laboratory variables were extracted from the computerized database using ICD-10 codes. Congenital anomalies were classified according to involved organ systems and also classified as single and multiple anomalies. RESULTS: A total of 1024 newborns with congenital anomaly (CA) (13.7%) were identified among the 7450 hospitalized newborns in NICU. The most affected system was the cardiovascular system (68.8%). Most of the anomalies (67.1%) were single anomalies. Of all, 59.4% had single major, 7.7% had single minor, 9% had single major plus single minor, 18.4% had multiple major and 2% had multiple minor anomalies. On the other hand, 96.3, 1.9, 0.1 and 1.7% of the newborns had malformation, deformation, disruption and dysplasia, respectively. Chromosomal analysis was only performed 24.8% of the newborns with CA and among them, 65.3% of these were in normal limits. The most frequently detected chromosomal abnormality was trisomy 21. Overall, mortality rate was 15.5% among the newborns with CA. CONCLUSION: In conclusion, the most common and mortal CA was cardio-vascular malformations in our hospital. The overall prevalence of cardio-vascular malformations among the newborn was higher than previously reported studies in Turkey. Further, studies with larger sample size are needed to determine CA in Turkey. PMID- 24059459 TI - Repurposed drugs in metabolic disorders. AB - Drug repurposing (drug repositioning, drug reprofiling, drug retasking) gains increasing importance as the development of new drugs becomes increasingly expensive. Though only a few compounds have been approved for new indications in the field of metabolic disorders, there are a number of substances which have the potential to become reprofiled in a new indication. Generally, reprofiled drugs for metabolic disorders can be classified in three groups. Group A contains those of which both, the original and repurposed indication, concern metabolic disorders. Group B comprises drugs, which were originally approved for non metabolic disorders but show beneficial effects for metabolic disorders after repurposing. Group C comprises drugs, which were originally approved for metabolic disorders and are effective for non-metabolic disorders in their repurposed indication. Repurposed drugs in the field of metabolic disorders of group A include tetra-hydrobiopterin, originally indicated for phenylketonuria and now also approved for tetrahydrobiopterindeficiency, coenzyme-Q, originally approved for primary coenzyme-Q deficiency and reprofiled for statin-myopathy, and colesevelam, originally approved to reduce elevated low-density lipoprotein (LDL)-cholesterol (LDL-C) and now being approved for type-2-diabetes. An example of group C is phenylbutyrate, which was originally approved for urea-cycle disorders and meanwhile gained approval for progressive familial intrahepatic cholestasis type 2 due to mutations in the ABCB11 gene. Still additional compounds used to treat metabolic (non-metabolic) disorders show promising effects in non-metabolic (metabolic disorders) after repurposing in cell and tissue models. Future investigations will need to identify which candidate drugs may leave the pipeline status to acquire approval for new indications. PMID- 24059458 TI - Contribution of different pneumococcal virulence factors to experimental meningitis in mice. AB - BACKGROUND: Pneumococcal meningitis (PM) is a life-threatening disease with a high case-fatality rate and elevated risk for serious neurological sequelae. In this study, we investigated the contribution of three major virulence factors of Streptococcus pneumoniae, the capsule, pneumococcal surface protein A (PspA) and C (PspC), to the pathogenesis of experimental PM. METHODS: Mice were challenged by the intracranial route with the serotype 4 TIGR4 strain (wt) and three isogenic mutants devoid of PspA, PspC, and the capsule. Survival, bacterial counts, and brain histology were carried out. To study the interaction between S. pneumoniae mutants and microglia, phagocytosis and survival experiments were performed using the BV2 mouse microglial cell line. RESULTS: Virulence of the PspC mutant was comparable to that of TIGR4. In contrast, survival of animals challenged with the PspA mutant was significantly increased compared with the wt, and the mutant was also impaired at replicating in the brain and blood of infected mice. Brain histology indicated that all strains, except for the unencapsulated mutant, caused PM. Analysis of inflammation and damage in the brain of mice infected with TIGR4 or its unencapsulated mutant demonstrated that the rough strain was unable to induce inflammation and neuronal injury, even at high challenge doses. Results with BV2 cells showed no differences in phagocytic uptake between wt and mutants. In survival assays, however, the PspA mutant showed significantly reduced survival in microglia compared with the wt. CONCLUSIONS: PspA contributed to PM pathogenesis possibly by interacting with microglia at early infection stages, while PspC had limited importance in the disease. The rough mutant did not cause brain inflammation, neuronal damage or mouse death, strengthening the key role of the capsule in PM. PMID- 24059460 TI - Repurposed drugs for the treatment of schizophrenia and bipolar disorders. AB - Characteristic symptoms of schizophrenia and bipolar disorders have been described and classified about a century ago. Each of these disorders may cause considerable impairment reflecting substantial alterations in cognition, perception, and mood. Though both disease concepts are well established, psychopharmacological treatment strategies, involving first- and second generation antipsychotics, benzodiazepines and mood stabilizing drugs, often fail to keep their purported alleviating effects on respective characteristic symptom spectra, producing unsatisfactory patient responses. While drug profiles may differ concerning the underlying mechanism of action, the breadth of treatment options remains limited. Besides developing new drugs with different mechanisms of action, side-effect profile and efficacy, it has to be emphasized that repurposed drugs might serve as alternative or adjuvant treatment options for patients, who continue to poorly respond to standard treatment algorithms. Here, we review the current evidence of selected drugs whose repurposed use might expand the range of treatment options for schizophrenia and bipolar disorders. PMID- 24059461 TI - Drug repositioning for treatment of movement disorders: from serendipity to rational discovery strategies. AB - Movement disorders are a heterogeneous group of both common and rare neurological conditions characterized by abnormalities of motor functions and movement patterns. This work overviews recent successes and ongoing studies of repositioning relating to this disease group, which underscores the challenge of integrating the voluminous and heterogeneous findings required for making suitable drug repositioning decisions. In silico drug repositioning methods hold the promise of automated fusion of heterogeneous information sources, but the controllable, flexible and transparent incorporation of the expertise of medicinal chemists throughout the repositioning process remains an open challenge. In support of a more systematic approach toward repositioning, we summarize the application of a computational repurposing method based on statistically rooted knowledge fusion. To foster the spread of this technique, we provide a step-by-step guide to the complete workflow, together with a case study in Parkinson's disease. PMID- 24059463 TI - Discovering new treatments for Alzheimer's disease by repurposing approved medications. AB - Alzheimer's disease (AD) is the most common cause of dementia and a major cause of morbidity and mortality. The greatest risk factor for AD is age and as many countries are experiencing an aging population, the expected rise in AD threatens to have serious medical and socioeconomic impact in the coming decades. The only approved medications for AD are symptomatic and there are no currently available disease modifying treatments. Hence, a disease modifying treatment is desperately needed for AD not only for proper care and management of affected patients, but also to reduce society's socioeconomic burden. Developing novel compounds for any indication is a time, effort, and money consuming endeavor and most treatments never make it to market. Other research and development strategies are needed, especially for the treatment of AD. We provide a review of the current literature in assessing possibilities of repurposing medications currently used for non-AD indications. Many different compounds from many different pharmacological classes have already been studied in an AD context. We provide a "pragmatic drug repurposing score" for each of these compounds based on type of studies conducted, number of possible mechanisms of action, efficacy in AD and other neurodegenerative disease studies, tolerability profile, and their ability to cross the blood brain barrier. The current data suggest several compounds worthy of further study as treatments for AD. Compounds with the highest scores include lithium, minocycline, exenatide, valproic acid, methylene blue, and nicotine. PMID- 24059462 TI - Drug repurposing: translational pharmacology, chemistry, computers and the clinic. AB - The process of discovering a pharmacological compound that elicits a desired clinical effect with minimal side effects is a challenge. Prior to the advent of high-performance computing and large-scale screening technologies, drug discovery was largely a serendipitous endeavor, as in the case of thalidomide for erythema nodosum leprosum or cancer drugs in general derived from flora located in far reaching geographic locations. More recently, de novo drug discovery has become a more rationalized process where drug-target-effect hypotheses are formulated on the basis of already known compounds/protein targets and their structures. Although this approach is hypothesis-driven, the actual success has been very low, contributing to the soaring costs of research and development as well as the diminished pharmaceutical pipeline in the United States. In this review, we discuss the evolution in computational pharmacology as the next generation of successful drug discovery and implementation in the clinic where high-performance computing (HPC) is used to generate and validate drug-target-effect hypotheses completely in silico. The use of HPC would decrease development time and errors while increasing productivity prior to in vitro, animal and human testing. We highlight approaches in chemoinformatics, bioinformatics as well as network biopharmacology to illustrate potential avenues from which to design clinically efficacious drugs. We further discuss the implications of combining these approaches into an integrative methodology for high-accuracy computational predictions within the context of drug repositioning for the efficient streamlining of currently approved drugs back into clinical trials for possible new indications. PMID- 24059464 TI - Calcium antagonists: a ready prescription for treating infectious diseases? AB - Emergence of new and medically resistant pathogenic microbes continues to escalate toward worldwide public health, wild habitat, and commercial crop and livestock catastrophes. Attempts at solving this problem with sophisticated modern biotechnologies, such as smart vaccines and microbicidal and microbistatic drugs that precisely target parasitic bacteria, fungi, and protozoa, remain promising without major clinical and industrial successes. However, discovery of a more immediate, broad spectrum prophylaxis beyond conventional epidemiological approaches might take no longer than the time required to fill a prescription at your neighborhood pharmacy. Findings from a growing body of research suggest calcium antagonists, long approved and marketed for various human cardiovascular and neurological indications, may produce safe, efficacious antimicrobial effects. As a general category of drugs, calcium antagonists include compounds that disrupt passage of Ca(2+) molecules across cell membranes and walls, sequestration and mobilization of free intracellular Ca(2+), and downstream binding proteins and sensors of Ca(2+)-dependent regulatory pathways important for proper cell function. Administration of calcium antagonists alone at current therapeutically relevant doses and schedules, or with synergistic compounds and additional antimicrobial medications, figures to enhance host immunoprotection by directly altering pathogen infection sequences, life cycles, homeostasis, antibiotic tolerances, and numerous other infective, survival, and reproductive processes. Short of being miracle drugs, calcium antagonists are welcome old drugs with new tricks capable of controlling some of the most virulent and pervasive global infectious diseases of plants, animals, and humans, including Chagas' disease, malaria, and tuberculosis. PMID- 24059465 TI - Minocycline repurposing in critical illness: focus on stroke. AB - Stroke is a devastating disease associated with high morbidity and mortality. Despite the approved indication of systemic thrombolytic therapy in the United States for the acute management of ischemic stroke, its use is limited given a strict eligibility criteria and a risk for hemorrhagic transformation as a feared adverse effect. Many agents have been studied without success for neuroprotection in patients with stroke to reduce vascular injury and improve long-term functional outcomes. Minocycline is a tetracycline antibiotic that shows promise for its neuroprotective effects in multiple animal models and three human trials. It affects multiple pathways to reduce apoptosis, neuroinflammation, infarct size, and vascular injury. The aim of this review is to discuss current evidence for minocycline from pre-clinical and early clinical trials and its potential role in neuroprotection in patients with acute ischemic stroke. PMID- 24059466 TI - New therapeutic bearings for repositioned drugs. PMID- 24059467 TI - Electronic spectroscopy of toluene in helium nanodroplets: evidence for a long lived excited state. AB - Optical excitation of toluene to the S1 electronic state in helium nanodroplets is found to alter the rate of production of the fragment ions C7H7(+) and C5H5(+) when the droplets are subjected to subsequent electron ionization. The optical excitation process reduces the abundance of C7H7(+) ions delivered into the gas phase, whereas C5H5(+) ions become more abundant beyond a minimum droplet size. This process contrasts with normal optical depletion spectroscopy, where the optical absorption of a molecular dopant in a helium nanodroplet shrinks the helium droplet, and thus, the electron impact cross-sections because of dissipation of the absorbed energy by evaporative loss of helium atoms. The observations here are interpreted in terms of formation of an excited state in the neutral molecule, which survives for several hundred MUs. This long-lived excited state, which is assumed to be the lowest triplet electronic state, shows different cross-sections for production of C7H7(+) and C5H5(+) relative to the S0 state. PMID- 24059468 TI - Short- and long-term effects of a maternal low-protein diet on ventilation, O2/CO2 chemoreception and arterial blood pressure in male rat offspring. AB - Maternal undernutrition increases the risk of adult arterial hypertension. The present study investigated the short- and long-term effects of a maternal low protein diet on respiratory rhythm, O2/CO2 chemosensitivity and arterial blood pressure (ABP) of the offspring. Male Wistar rats were divided into two groups according to their mothers' diets during gestation and lactation: control (NP, 17% of casein) and low-protein (LP, 8% of casein) groups. Direct measurements of ABP, respiratory frequency (RF), tidal volume (V T) and ventilation (VE), as well as hypercapnia (7% CO2) and hypoxia (7% O2) evoked respiratory responses were recorded from the awake male offspring at the 30th and 90th days of life. Blood samples were collected for the analyses of protein, creatinine and urea concentrations. The LP offspring had impaired body weight and length throughout the experiment. At 30 d of age, the LP rats showed a reduction in the concentrations of total serum protein (approximately 24%). ABP in the LP rats was similar to that in the NP rats at 30 d of age, but it was 20% higher at 90 d of age. With respect to ventilatory parameters, the LP rats showed enhanced RF (approximately 34%) and VE (approximately 34%) at 30 d of age, which was associated with increased ventilatory responses to hypercapnia (approximately 21% in VE) and hypoxia (approximately 82% in VE). At 90 d of age, the VE values and CO2/O2 chemosensitivity of the LP rats were restored to the control range, but the RF values remained elevated. The present data show that a perinatal LP diet alters respiratory rhythm and O2/CO2 chemosensitivity at early ages, which may be a predisposing factor for increased ABP at adulthood. PMID- 24059469 TI - Tunable cytotoxicity of rhodamine 6G via anion variations. AB - Chemotherapeutic agents with low toxicity to normal tissues are a major goal in cancer research. In this regard, the therapeutic activities of cationic dyes, such as rhodamine 6G, toward cancer cells have been studied for decades with observed toxicities toward normal and cancer cells. Herein, we report rhodamine 6G-based organic salts with varying counteranions that are stable under physiological conditions, display excellent fluorescence photostability, and more importantly have tunable chemotherapeutic properties. Our in vitro studies indicate that the hydrophobic compounds of this series allow production of nanoparticles which are nontoxic to normal cells and toxic to cancer cells. Furthermore, the anions, in combination with cations such as sodium, were observed to be nontoxic to both normal and cancer cells. To the best of our knowledge, this is the first demonstration that both the cation and anion play an extremely important and cooperative role in the antitumor properties of these compounds. PMID- 24059470 TI - Current-voltage characterization of individual as-grown nanowires using a scanning tunneling microscope. AB - Utilizing semiconductor nanowires for (opto)electronics requires exact knowledge of their current-voltage properties. We report accurate on-top imaging and I-V characterization of individual as-grown nanowires, using a subnanometer resolution scanning tunneling microscope with no need for additional microscopy tools, thus allowing versatile application. We form Ohmic contacts to InP and InAs nanowires without any sample processing, followed by quantitative measurements of diameter dependent I-V properties with a very small spread in measured values compared to standard techniques. PMID- 24059471 TI - Viral phylogeny in court: the unusual case of the Valencian anesthetist. AB - A large and complex outbreak of hepatitis C virus in Valencia, Spain that began 25 years ago led to the prosecution and conviction of an anesthetist who was accused of infecting hundreds of his patients. Evolutionary analyses of viral gene sequences were presented as evidence in the trial, and these are now described in detail by Gonzalez-Candelas and colleagues in a paper published in BMC Biology. Their study illustrates the challenges and opportunities that arise from the use of phylogenetic inference in criminal trials concerning virus transmission. PMID- 24059473 TI - Understanding the recognition of Lewis X by anti-Le(x) monoclonal antibodies. AB - The recognition of the Le(x) antigen by the anti-Le(x) monoclonal antibody (mAb) SH1 was studied by ELISA using a panel of 4"-modified Le(x) analogues. We confirmed that these analogues maintained the stacked conformation adopted by natural Le(x) antigen using 1D ROESY experiments and measuring intramolecular distances. Our binding studies show that the 4-OH" of galactose behaves as an H bond donor to an electronegative amino acid side chain in the SH1 binding site. While removal of this H-bond leads to reduced inhibition, disturbing the hydrophobic alpha face of the beta-galactosyl residue leads to complete loss of binding to SH1. We compared our results to the crystal structure of the Fab fragment of anti-Le(x) mAb 291-2G3-A complexed with Le(x) (PDB entry 1UZ8 ). While no H-bond involving the 4-OH" was described, hydrophobic interactions between a tryptophan residue and the beta-galactoside alpha face are observed. We conclude that the hydrophobic alpha face that is uniquely displayed by beta galactosyl residues is essential to the recognition of the Le(x) antigen by anti Le(x) antibodies. PMID- 24059474 TI - The brief experiential avoidance questionnaire: development and initial validation. AB - The 62-item Multidimensional Experiential Avoidance Questionnaire (MEAQ) was recently developed to assess a broad range of experiential avoidance (EA) content. However, practical clinical and research considerations made a briefer measure of EA desirable. Using items from the original 62-item MEAQ, a 15-item scale was created that tapped content from each of the MEAQ's six dimensions. Items were selected on the basis of their performance in 3 samples: undergraduates (n = 363), psychiatric outpatients (n = 265), and community adults (n = 215). These items were then evaluated using 2 additional samples (314 undergraduates and 201 psychiatric outpatients) and cross-validated in 2 new, independent samples (283 undergraduates and 295 community adults). The resulting measure (Brief Experiential Avoidance Questionnaire; BEAQ) demonstrated good internal consistency. It also exhibited strong convergence with respect to each of the MEAQ's 6 dimensions. The BEAQ demonstrated expected associations with measures of avoidance, psychopathology, and quality of life and was distinguishable from negative affectivity and neuroticism. PMID- 24059472 TI - Acute Rho-kinase inhibition improves coronary dysfunction in vivo, in the early diabetic microcirculation. AB - OBJECTIVES: Activation of RhoA/Rho-kinase (ROCK) is increasingly implicated in acute vasospasm and chronic vasoconstriction in major organ systems. Therefore we aimed to ascertain whether an increase in ROCK activity plays a role in the deterioration of coronary vascular function in early stage diabetes. METHODS: Synchrotron radiation microangiography was used to determine in vivo coronary responses in diabetic (3 weeks post streptozotocin 65 mg/kg ip) and vehicle treated male Sprague-Dawley rats (n = 8 and 6). Changes in vessel number and calibre during vasodilator stimulation before and after blockade of nitric oxide synthase and cyclooxygenase were compared between rats. Acute responses to ROCK inhibitor, fasudil (10 mg/kg iv) was evaluated. Further, perivascular and myocardial fibrosis, arterial intimal thickening were assessed by histology, and capillary density, nitrotyrosine and ROCK1/2 expressions were evaluated by immunohistochemical staining. RESULTS: Diabetic rats had significantly elevated plasma glucose (P < 0.001 vs control), but did not differ in fibrotic scores, media to lumen ratio, capillary density or baseline visible vessel number or calibre. Responses to acetylcholine and sodium nitroprusside stimulation were similar between groups. However, in comparison to control rats the diabetic rats showed more segmental constrictions during blockade, which were not completely alleviated by acetylcholine, but were alleviated by fasudil. Further, second order vessel branches in diabetic rats were significantly more dilated relative to baseline (37% vs 12% increase, P < 0.05) after fasudil treatment compared to control rats, while visible vessel number increased in both groups. ROCK2 expression was borderline greater in diabetic rat hearts (P < 0.053). CONCLUSIONS: We found that ahead of the reported decline in coronary endothelial vasodilator function in diabetic rats there was moderate elevation in ROCK expression, more widespread segmental constriction when nitric oxide and prostacyclin production were inhibited and notably, increased calibre in second and third order small arteries-arterioles following ROCK inhibition. Based on nitrotyrosine staining oxidative stress was not significantly elevated in early diabetic rats. We conclude that tonic ROCK mediated vasoconstriction contributes to coronary vasomotor tone in early diabetes. PMID- 24059475 TI - State Mindfulness Scale (SMS): development and initial validation. AB - The goal of the present research was to develop and test a novel conceptual model and corresponding measure of state mindfulness-the State Mindfulness Scale (SMS). We developed the SMS to reflect traditional Buddhist and contemporary psychological science models of mindfulness not similarly reflected in extant published measures of the construct. Study 1 exploratory and confirmatory factor analyses supported a higher order 2-factor solution encompassing 1 second-order state mindfulness factor, and 2 first-order factors, one reflecting state mindfulness of bodily sensations and the other state mindfulness of mental events. Study 2 provided cross-sectional evidence of the convergent, discriminant, and incremental convergent validity of SMS scores with respect to other measures of state and trait mindfulness. Study 3, a randomized control experimental mindfulness intervention study, yielded a number of key findings with respect to SMS stability as a function of time and context, construct validity, incremental sensitivity to change in state mindfulness over time, and incremental predictive criterion-related validity. Findings are discussed with respect to the potential contribution of the SMS to the study of mindfulness as a statelike mental behavior, biopsychobehavioral research on the mechanisms of mindfulness, and clinical evaluation of mindfulness. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 24059476 TI - The emotion regulation questionnaire: validation of the ERQ-9 in two community samples. AB - The 10-item Emotion Regulation Questionnaire (ERQ) was developed by Gross and John (2003) to measure the habitual use of 2 emotion regulation strategies: reappraisal and suppression. Several studies using student samples have provided validation for the ERQ, although the only article (Wiltink et al., 2011) that evaluated the ERQ in a community sample was unable to replicate the original factor structure. Before using the ERQ in non-student samples, it is important to validate the scale in a sample broadly representative of the adult population and to determine the influence of demographic variables. The current study examined the psychometric properties of the ERQ in 2 community samples (Australia, N = 550; United Kingdom, N = 483; 17-95 years of age) using confirmatory analysis. The original ERQ factor structure was not supported by either the Australian or United Kingdom samples. However, with the removal of 1 item, a strong model fit was obtained for both samples (9-item ERQ [ERQ-9]). Using measurement invariance tests, the revised ERQ-9 was found to be equivalent across the samples and demographics (age, gender, and education). Gender, depression, anxiety, and stress were the only factors that were significantly associated with reappraisal and suppression use. Overall, the ERQ-9 provides better fit of the data than the 10-item ERQ. The utility of this measure is enhanced by the provision of normative data for males and females. PMID- 24059477 TI - Testing measurement invariance of the protective behavioral strategies scale in college men and women. AB - This study tested whether the measurement parameters of the Protective Behavioral Strategies Scale (PBSS; Martens et al., 2005) were equivalent for men and women in a college student sample. Multi-group confirmatory factor analyses tested whether a similar 3-factor latent structure was shared across gender groups and whether item origins (i.e., thresholds) and the strength of associations between individual items and latent factors (i.e., factor loadings) were equivalent across gender groups. Multiple indicators multiple causes (MIMIC) models tested whether gender differences in measurement parameters were explained by drinking patterns among college men and women. Results evidenced significant measurement bias (i.e., non-invariant measurement parameters) across gender groups at both the factor structure and individual item level. In addition, MIMIC models suggested that gender differences in item loadings and thresholds were not better explained by discrepancies in drinking patterns among male and female college students. Findings indicate that gender differences in latent factor scores may reflect measurement bias rather than true mean differences between gender groups, restricting meaningful comparisons of PBSS scores between college men and women. Implications for the assessment of specific strategies as well as clinical interventions among college students that include components on protective behavioral strategies are discussed. PMID- 24059478 TI - A case of focal segmental glomerulosclerosis syndrome secondary to high-altitude polycythemia. AB - In recent years, focal segmental glomerulosclerosis has become the commonest cause of the nephrotic syndrome seen in adults. Secondary focal segmental glomerulosclerosis is observed when glomerular workload is increased. We report a case of focal segmental glomerulosclerosis with nephrotic syndrome secondary to high-altitude polycythemia (HAPC). Our case points out that for patients with focal segmental glomerulosclerosis, who presented with nephrotic syndrome secondary to HAPC, treatments for HAPC are crucial for the reduction of proteinuria and renal protection instead of glucocorticoid and immunosuppressive drugs. PMID- 24059480 TI - Sam's story: how AboutFace is helping people with facial differences. PMID- 24059479 TI - Effects of two different strategies of fluid administration on inflammatory mediators, plasma electrolytes and acid/base disorders in patients undergoing major abdominal surgery: a randomized double blind study. AB - BACKGROUND: Administration of normal saline might increase circulating levels of pro-inflammatory cytokines and may cause variation of plasmatic electrolytic and hyperchloremic acidosis, which in turn can impair renal function. Hence the use of balanced solutions could influence the inflammatory cascade triggered by the surgical procedures, the plasmatic electrolyte concentration, the acid-base equilibrium, and the renal function. METHODS: This is a double blind randomized trial. Forty patients undergoing major abdominal surgery (bowel cancer) were allocated in two groups, the balanced solution (BS) group in which the fluids administered were balanced solutions (colloids and crystalloids); and the unbalanced solution (UBS) group in which the fluids administered were unbalanced solutions (colloids and crystalloids). Measurements were performed after anaesthesia induction (T0), at the end of surgery (T1), within 2 h after surgery (T2) and 24 h after the beginning of surgery (T3). The following data were collected: 1) active matrix metalloproteinase 9 (MMP-9) and its tissue inhibitor (TIMP-1), IL-6, IL-8, IL-10; 2) blood gases variables; 3) electrolytes, albumin, total serum protein and the strong ion difference; 4) neutrophil gelatinase associated lipocalin (NGAL) from urinary sample. RESULTS: The BS group exhibited higher circulating level of IL-10 and TIMP-1 and lower level of active MMP-9. The UBS group experienced hypercloremia, hypocalcemia, hypomagnesemia, worse acid base equilibrium and higher level of NGAL. CONCLUSIONS: The use of balanced solutions was responsible of less alteration of plasmatic electrolytes, acid-base equilibrium, kidney function and it might be associated with an early anti inflammatory mechanisms triggering. TRIAL REGISTRATION: ClinicalTrials.gov (Ref: NCT01320891). PMID- 24059481 TI - The use of pink porcelain to manage a malposed anterior implant: case report. AB - Pink porcelain was used in a custom zirconia abutment with a zirconia implant supported anterior crown to compensate for a malposed anterior implant with horizontal bone deficiency and lack of keratinized tissue. This clinical procedure was able to reduce abutment height, mask the horizontal defect and create a symmetrical and esthetic effect. PMID- 24059482 TI - Dentistry needs to address the cost of care. PMID- 24059483 TI - Response from Dr. Peter Doig. PMID- 24059484 TI - Studying abroad, practising in Canada. PMID- 24059485 TI - New resources for providing care to older adults. PMID- 24059486 TI - CDA and CIHR partner to promote health equity for Aboriginal Canadians. PMID- 24059488 TI - Nova Scotia invests in oral health. PMID- 24059489 TI - Dental volunteerism: is the current model working? PMID- 24059490 TI - Pulpitis (reversible/irreversible). PMID- 24059491 TI - Primary extranodal B-cell non-Hodgkin lymphoma mimicking an endodontic lesion: report of 2 cases. AB - Intrabony oral non-Hodgkin lymphoma (NHL) is rare. We report 2 cases of NHL of the maxilla that initially presented as apical abscesses in endodontically treated teeth. Radiographic findings were nondescript, but tissue biopsy revealed diffuse large B-cell NHL in both instances. No other sites of disease were found. Both patients were treated by chemotherapy and radiation with good results. As primary NHL of the maxilla can mimic a dental inflammatory lesion, tissue biopsy is mandatory in cases where symptoms do not resolve after specific treatment. PMID- 24059492 TI - Failure of root canal treatment misdiagnosed as neuropathic pain: case report. AB - A patient presented with long-standing symptoms of neuropathic pain in the upper jaw. There were no signs of infection, and the patient had been told by several dentists and physicians that there was no evidence of any pathology. Investigations eventually revealed the source of the problem as failure of root canal treatment. Diagnosis of neuropathic pain (and other orofacial neurogenic disorders) is often a process of exclusion, and this case underscores the need for clinicians to eliminate all possible causes before reaching that conclusion. PMID- 24059493 TI - Substrate-integrated hollow waveguides: a new level of integration in mid infrared gas sensing. AB - A new generation of hollow waveguide (HWG) gas cells of unprecedented compact dimensions facilitating low sample volumes suitable for broad- and narrow-band mid-infrared (MIR; 2.5-20 MUm) sensing applications is reported: the substrate integrated hollow waveguide (iHWG). iHWGs are layered structures providing light guiding channels integrated into a solid-state substrate material, which are competitive if not superior in performance to conventional leaky-mode fiber optic silica HWGs having similar optical pathlengths. In particular, the provided flexibility in device and optical design and the wide variety of manufacturing strategies, substrate materials, access to the optical channel, and optical coating options highlight the advantages of iHWGs in terms of robustness, compactness, and cost-effectiveness. Finally, the unmatched modularity of this novel waveguide approach facilitates tailoring iHWGs to almost any kind of gas sensor technology providing adaptability to the specific demands of a wide range of sensing scenarios. Device fabrication is demonstrated for the example of a yin yang-shaped gold-coated iHWG fabricated within an aluminum substrate with a footprint of only 75 mm * 50 mm * 12 mm (L * W * H), yet providing a nominal optical absorption path length of more than 22 cm. The analytical utility of this device for advanced MIR gas sensing applications is demonstrated for the gaseous constituents butane, carbon dioxide, cyclopropane, isobutylene, and methane. PMID- 24059494 TI - Effect of NR3C2 genetic polymorphisms on the blood pressure response to enalapril treatment. AB - AIM: The mineralocorticoid receptor (MR; also known as NR3C2) plays important roles in the modulation of blood pressure. The effect of NR3C2 polymorphisms on antihypertensive response to enalapril was investigated. PATIENTS & METHODS: Two hundred and seventy nine essential hypertension patients treated with enalapril were genotyped for two NR3C2 tagSNPs, rs5522 and rs2070950, by Sequenom MassArrayTM technology. RESULTS: The reductions in diastolic blood pressure (DBP) were significantly greater in AA homozygotes compared with AG+GG genotype carriers for the rs5522 polymorphism (p = 0.009), and the reductions in DBP were greater in GG homozygotes compared with GC+CC genotype carriers for the rs2070950 polymorphism, with marginal significance (p = 0.065). Stepwise multiple regression analysis indicated that significant predictors of DBP reduction were baseline DBP (p < 0.001), waist:hip ratio (p = 0.001) and rs5522 genotype (p = 0.003). CONCLUSION: NR3C2 rs5522 affects blood pressure response to enalapril treatment and may serve as a useful pharmacogenomic marker of antihypertensive response to enalapril in essential hypertension patients. PMID- 24059495 TI - Simtomax, a novel point of care test for coeliac disease. AB - INTRODUCTION: Coeliac disease is an autoimmune condition resulting from an abnormal reaction to dietary gluten leading to small bowel villous atrophy. International prevalence studies suggest that coeliac disease affects 1% of the adult population. However, despite its high prevalence, large numbers of patients go undiagnosed. One method of increasing detection rates would be to introduce a quick screening test in the form of a finger-prick blood test. AREAS COVERED: There are currently four available point-of-care tests (POCTs) available for use by health professionals. This diagnostic evaluation will review the evidence for the use of POCTs in coeliac disease including Simtomax a novel test for deamidated gliadin peptides and total IgA level. EXPERT OPINION: An accurate POCT has the potential to increase the rates of diagnosis of coeliac disease if used effectively as part of a case finding approach in primary or secondary care. Evidence for the use of Simtomax is currently fairly limited only drawing comparison with laboratory serology rather than the gold standard of histology and it has only been trialled in high-risk populations. However, results to date are encouraging and further research into this area is required. PMID- 24059496 TI - Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. AB - Autophagy is an intracellular degradation pathway essential for cellular and energy homoeostasis. It functions in the clearance of misfolded proteins and damaged organelles, as well as recycling of cytosolic components during starvation to compensate for nutrient deprivation. This process is regulated by mTOR (mammalian target of rapamycin)-dependent and mTOR-independent pathways that are amenable to chemical perturbations. Several small molecules modulating autophagy have been identified that have potential therapeutic application in diverse human diseases, including neurodegeneration. Neurodegeneration-associated aggregation-prone proteins are predominantly degraded by autophagy and therefore stimulating this process with chemical inducers is beneficial in a wide range of transgenic disease models. Emerging evidence indicates that compromised autophagy contributes to the aetiology of various neurodegenerative diseases related to protein conformational disorders by causing the accumulation of mutant proteins and cellular toxicity. Combining the knowledge of autophagy dysfunction and the mechanism of drug action may thus be rational for designing targeted therapy. The present review describes the cellular signalling pathways regulating mammalian autophagy and highlights the potential therapeutic application of autophagy inducers in neurodegenerative disorders. PMID- 24059497 TI - NextGen protein design. AB - Protein engineering is at an exciting stage because designed protein-protein interactions are being used in many applications. For instance, three designed proteins are now in clinical trials. Although there have been many successes over the last decade, protein engineering still faces numerous challenges. Often, designs do not work as anticipated and they still require substantial redesign. The present review focuses on the successes, the challenges and the limitations of rational protein design today. PMID- 24059498 TI - Engineering chimaeric proteins from fold fragments: 'hopeful monsters' in protein design. AB - Modern highly complex proteins evolved from much simpler and less specialized subunits. The same concept can be applied in protein engineering to construct new well-folded proteins. Hybrid proteins or chimaeras can be built from contemporary protein fragments through illegitimate recombination. Even parts from different globular folds can be fitted together using rational design methodologies. Furthermore, intrinsic functional properties encoded in the fold fragments allow rapid adaptation of the new proteins and thus provide interesting starting scaffolds for further redesign. PMID- 24059500 TI - Opportunities for bioprocess monitoring using FRET biosensors. AB - Bioprocess monitoring is used to track the progress of a cell culture and ensure that the product quality is maintained. Current schemes for monitoring metabolism rely on offline measurements of samples of the extracellular medium. However, in the era of synthetic biology, it is now possible to design and implement biosensors that consist of biological macromolecules and are able to report on the intracellular environment of cells. The use of fluorescent reporter signals allows non-invasive, non-destructive and online monitoring of the culture, which reduces the delay between measurement and any necessary intervention. The present mini-review focuses on protein-based biosensors that utilize FRET as the signal transduction mechanism. The mechanism of FRET, which utilizes the ratio of emission intensity at two wavelengths, has an inherent advantage of being ratiometric, meaning that small differences in the experimental set-up or biosensor expression level can be normalized away. This allows for more reliable quantitative estimation of the concentration of the target molecule. Existing FRET biosensors that are of potential interest to bioprocess monitoring include those developed for primary metabolites, redox potential, pH and product formation. For target molecules where a biosensor has not yet been developed, some candidate binding domains can be identified from the existing biological databases. However, the remaining challenge is to make the process of developing a FRET biosensor faster and more efficient. PMID- 24059499 TI - Using anchoring motifs for the computational design of protein-protein interactions. AB - The computer-based design of PPIs (protein-protein interactions) is a challenging problem because large desolvation and entropic penalties must be overcome by the creation of favourable hydrophobic and polar contacts at the target interface. Indeed, many computationally designed interactions fail to form when tested in the laboratory. In the present article, we highlight strategies our laboratory has been pursuing to make interface design more tractable. Our general approach has been to make use of structural motifs found in native proteins that are predisposed to interact with a particular binding geometry, and then further bolster these anchor points with favourable hydrophobic contacts. We describe the use of three different anchor points, i.e. beta-strand pairing, metal binding and the docking of alpha-helix into a groove, to successfully design new interfaces. In several cases, high-resolution crystal structures show that the design models closely match the experimental structure. In addition, we have tested the use of buried hydrogen-bond networks as a source of affinity and specificity at interfaces. In these cases, the designed complexes did not form, highlighting the challenges associated with designing buried polar interactions. PMID- 24059501 TI - Repeat protein engineering: creating functional nanostructures/biomaterials from modular building blocks. AB - There is enormous interest in molecular self-assembly and the development of biological systems to form smart nanostructures for biotechnology (so-called 'bottom-up fabrications'). Repeat proteins are ideal choices for development of such systems as they: (i) possess a relatively simple relationship between sequence, structure and function; (ii) are modular and non-globular in structure; (iii) act as diverse scaffolds for the mediation of a diverse range of protein protein interactions; and (iv) have been extensively studied and successfully engineered and designed. In the present review, we summarize recent advances in the use of engineered repeat proteins in the self-assembly of novel materials, nanostructures and biosensors. In particular, we show that repeat proteins are excellent monomeric programmable building blocks that can be triggered to associate into a range of morphologies and can readily be engineered as stimuli responsive biofunctional materials. PMID- 24059502 TI - Evolving protocells to prototissues: rational design of a missing link. AB - Realization of a functional artificial cell, the so-called protocell, is a major challenge posed by synthetic biology. A subsequent goal is to use the protocellular units for the bottom-up assembly of prototissues. There is, however, a looming chasm in our knowledge between protocells and prototissues. In the present paper, we give a brief overview of the work on protocells to date, followed by a discussion on the rational design of key structural elements specific to linking two protocellular bilayers. We propose that designing synthetic parts capable of simultaneous insertion into two bilayers may be crucial in the hierarchical assembly of protocells into a functional prototissue. PMID- 24059503 TI - Predicting affinity- and specificity-enhancing mutations at protein-protein interfaces. AB - Manipulations of PPIs (protein-protein interactions) are important for many biological applications such as synthetic biology and drug design. Combinatorial methods have been traditionally used for such manipulations, failing, however, to explain the effects achieved. We developed a computational method for prediction of changes in free energy of binding due to mutation that bring about deeper understanding of the molecular forces underlying binding interactions. Our method could be used for computational scanning of binding interfaces and subsequent analysis of the interfacial sequence optimality. The computational method was validated in two biological systems. Computational saturated mutagenesis of a high-affinity complex between an enzyme AChE (acetylcholinesterase) and a snake toxin Fas (fasciculin) revealed the optimal nature of this interface with only a few predicted affinity-enhancing mutations. Binding measurements confirmed high optimality of this interface and identified a few mutations that could further improve interaction fitness. Computational interface scanning of a medium affinity complex between TIMP-2 (tissue inhibitor of metalloproteinases-2) and MMP (matrix metalloproteinase) 14 revealed a non-optimal nature of the binding interface with multiple mutations predicted to stabilize the complex. Experimental results corroborated our computational predictions, identifying a large number of mutations that improve the binding affinity for this interaction and some mutations that enhance binding specificity. Overall, our computational protocol greatly facilitates the discovery of affinity- and specificity-enhancing mutations and thus could be applied for design of potent and highly specific inhibitors of any PPI. PMID- 24059504 TI - The antiviral lectin cyanovirin-N: probing multivalency and glycan recognition through experimental and computational approaches. AB - CVN (cyanovirin-N), a small lectin isolated from cyanobacteria, exemplifies a novel class of anti-HIV agents that act by binding to the highly glycosylated envelope protein gp120 (glycoprotein 120), resulting in inhibition of the crucial viral entry step. In the present review, we summarize recent work in our laboratory and others towards determining the crucial role of multivalency in the antiviral activity, and we discuss features that contribute to the high specificity and affinity for the glycan ligand observed in CVN. An integrated approach that encompasses structural determination, mutagenesis analysis and computational work holds particular promise to clarify aspects of the interactions between CVN and glycans. PMID- 24059505 TI - Genetically encoding phenyl azide chemistry: new uses and ideas for classical biochemistry. AB - Introducing new physicochemical properties into proteins through genetically encoded Uaa (unnatural amino acid) incorporation can lead to the generation of proteins with novel properties not normally accessible with the 20 natural amino acids. Phenyl azide chemistry represents one such useful addition to the protein repertoire. Classically used in biochemistry as a non-specific photochemical protein cross-linker, genetically encoding phenyl azide chemistry at selected residues provides more powerful routes to post-translationally modify protein function in situ. The two main routes are modulation by light (optogenetics) and site-specific bio-orthogonal modification (bioconjugation) via Click chemistry. In the present article, we discuss both approaches and their influence on protein function. PMID- 24059506 TI - Optobiology: optical control of biological processes via protein engineering. AB - Enabling optical control over biological processes is a defining goal of the new field of optogenetics. Control of membrane voltage by natural rhodopsin family ion channels has found widespread acceptance in neuroscience, due to the fact that these natural proteins control membrane voltage without further engineering. In contrast, optical control of intracellular biological processes has been a fragmented effort, with various laboratories engineering light-responsive properties into proteins in different manners. In the present article, we review the various systems that have been developed for controlling protein functions with light based on vertebrate rhodopsins, plant photoregulatory proteins and, most recently, the photoswitchable fluorescent protein Dronpa. By allowing biology to be controlled with spatiotemporal specificity and tunable dynamics, light-controllable proteins will find applications in the understanding of cellular and organismal biology and in synthetic biology. PMID- 24059507 TI - ProxiMAX randomization: a new technology for non-degenerate saturation mutagenesis of contiguous codons. AB - Back in 2003, we published 'MAX' randomization, a process of non-degenerate saturation mutagenesis using exactly 20 codons (one for each amino acid) or else any required subset of those 20 codons. 'MAX' randomization saturates codons located in isolated positions within a protein, as might be required in enzyme engineering, or else on one face of an alpha-helix, as in zinc-finger engineering. Since that time, we have been asked for an equivalent process that can saturate multiple contiguous codons in a non-degenerate manner. We have now developed 'ProxiMAX' randomization, which does just that: generating DNA cassettes for saturation mutagenesis without degeneracy or bias. Offering an alternative to trinucleotide phosphoramidite chemistry, ProxiMAX randomization uses nothing more sophisticated than unmodified oligonucleotides and standard molecular biology reagents. Thus it requires no specialized chemistry, reagents or equipment, and simply relies on a process of saturation cycling comprising ligation, amplification and digestion for each cycle. The process can encode both unbiased representation of selected amino acids or else encode them in predefined ratios. Each saturated position can be defined independently of the others. We demonstrate accurate saturation of up to 11 contiguous codons. As such, ProxiMAX randomization is particularly relevant to antibody engineering. PMID- 24059508 TI - Rewiring cell signalling through chimaeric regulatory protein engineering. AB - Bacterial cells continuously sense and respond to their environment using their inherent signalling and gene regulatory networks. Cells are equipped with parallel signalling pathways, which can specifically cope with individual input signals, while interconnectivities between pathways lead to an enhanced complexity of regulatory responses that enable sophisticated adaptation. In principle, any cell signalling pathway may be rewired to respond to non-cognate signals by exchanging and recombining their underlying cognate signalling components. In the present article, we review the engineering strategies and use of chimaeric regulatory proteins in cell signalling pathways, especially the TCS (two-component signalling) system in bacteria, to achieve novel customized signalling or regulatory functions. We envisage that engineered chimaeric regulatory proteins can play an important role to aid both forward and reverse engineering of biological systems for many desired applications. PMID- 24059509 TI - Rational design of FRET sensor proteins based on mutually exclusive domain interactions. AB - Proteins that switch between distinct conformational states are ideal to monitor and control molecular processes within the complexity of biological systems. Inspired by the modular architecture of natural signalling proteins, our group explores generic design strategies for the construction of FRET-based sensor proteins and other protein switches. In the present article, I show that designing FRET sensors based on mutually exclusive domain interactions provides a robust method to engineer sensors with predictable properties and an inherently large change in emission ratio. The modularity of this approach should make it easily transferable to other applications of protein switches in fields ranging from synthetic biology, optogenetics and molecular diagnostics. PMID- 24059510 TI - Half a century of molecular bioenergetics. AB - Molecular bioenergetics deals with the construction, function and regulation of the powerhouses of life. The present overview sketches scenes and actors, farsighted goals and daring hypotheses, meticulous tool-making, painstaking benchwork, lucky discovery, serious scepticism, emphatic believing and strong characters with weak and others with hard arguments, told from a personal, admittedly limited, perspective. Bioenergetics will blossom further with the search focused on both where there is bright light for ever-finer detail and the obvious dark spots for surprise and discovery. PMID- 24059512 TI - Role of cryo-ET in membrane bioenergetics research. AB - To truly understand bioenergetic processes such as ATP synthesis, membrane-bound substrate transport or flagellar rotation, systems need to be analysed in a cellular context. Cryo-ET (cryo-electron tomography) is an essential part of this process, as it is currently the only technique which can directly determine the spatial organization of proteins at the level of both the cell and the individual protein complexes. The need to assess bioenergetic processes at a cellular level is becoming more and more apparent with the increasing interest in mitochondrial diseases. In recent years, cryo-ET has contributed significantly to our understanding of the molecular organization of mitochondria and chloroplasts. The present mini-review first describes the technique of cryo-ET and then discusses its role in membrane bioenergetics specifically in chloroplasts and mitochondrial research. PMID- 24059511 TI - Spotlighting motors and controls of single FoF1-ATP synthase. AB - Subunit rotation is the mechanochemical intermediate for the catalytic activity of the membrane enzyme FoF1-ATP synthase. smFRET (single-molecule FRET) studies have provided insights into the step sizes of the F1 and Fo motors, internal transient elastic energy storage and controls of the motors. To develop and interpret smFRET experiments, atomic structural information is required. The recent F1 structure of the Escherichia coli enzyme with the epsilon-subunit in an inhibitory conformation initiated a study for real-time monitoring of the conformational changes of epsilon. The present mini-review summarizes smFRET rotation experiments and previews new smFRET data on the conformational changes of the CTD (C-terminal domain) of epsilon in the E. coli enzyme. PMID- 24059513 TI - Methods to analyse composition and dynamics of macromolecular complexes. AB - Macromolecular complexes are involved in a broad spectrum of cellular processes including protein biosynthesis, protein secretion and degradation, metabolism, DNA replication and repair, and signal transduction along with other important biological processes. The analysis of protein complexes in health and disease is important to gain insights into cellular physiology and pathophysiology. In the last few decades, research has focused on the identification and the dynamics of macromolecular complexes. Several techniques have been developed to isolate native protein complexes from cells and tissues to allow further characterization by microscopic and proteomic analysis. In the present paper, we provide a brief overview of proteomic methods that can be used to identify protein-protein interactions, focusing on recent developments to study the entire complexome of a biological sample. PMID- 24059514 TI - IR signatures of the metal centres of bovine cytochrome c oxidase: assignments and redox-linkage. AB - Assignments of IR bands of reduced minus oxidized IR difference spectra of bovine and related cytochrome c oxidases are reviewed and their linkages to specific metal centres are assessed. To aid this, redox-poised difference spectra in the presence of cyanide or carbon monoxide are presented. These ligands fix the redox states of either haem a3 alone or haem a3 and CuB respectively, while allowing redox cycling of the remaining centres. PMID- 24059515 TI - Electrode assemblies composed of redox cascades from microbial respiratory electron transfer chains. AB - Respiratory and photosynthetic electron transfer chains are dependent on vectorial electron transfer through a series of redox proteins. Examples include electron transfer from NapC to NapAB nitrate reductase in Paracoccus denitrificans and from CymA to Fcc3 (flavocytochrome c3) fumarate reductase in Shewanella oneidensis MR-1. In the present article, we demonstrate that graphite electrodes can serve as surfaces for the stepwise adsorption of NapC and NapAB, and the stepwise adsorption of CymA and Fcc3. Aspects of the catalytic properties of these assemblies are different from those of NapAB and Fcc3 adsorbed in isolation. We propose that this is due to the formation of NapC-NapAB and of CymA Fcc3 complexes that are capable of supporting vectorial electron transfer. PMID- 24059516 TI - Metabolic engineering of cyanobacteria for the production of hydrogen from water. AB - Requirements concerning the construction of a minimal photosynthetic design cell with direct coupling of water-splitting photosynthesis and H2 production are discussed in the present paper. Starting from a cyanobacterial model cell, Synechocystis PCC 6803, potentials and possible limitations are outlined and realization strategies are presented. In extension, the limits of efficiency of all major biological components can be approached in a semi-artificial system consisting of two electrochemically coupled half-cells without the physiological constraints of a living cell. PMID- 24059517 TI - Dynamic structural science: recent developments in time-resolved spectroscopy and X-ray crystallography. AB - To understand the mechanism of biological processes, time-resolved methodologies are required to investigate how functionality is linked to changes in molecular structure. A number of spectroscopic techniques are available that probe local structural rearrangements with high temporal resolution. However, for macromolecules, these techniques do not yield an overall high-resolution description of the structure. Time-resolved X-ray crystallographic methods exist, but, due to both instrument availability and stringent sample requirements, they have not been widely applied to macromolecular systems, especially for time resolutions below 1 s. Recently, there has been a resurgent interest in time resolved structural science, fuelled by the recognition that both chemical and life scientists face many of the same challenges. In the present article, we review the current state-of-the-art in dynamic structural science, highlighting applications to enzymes. We also look to the future and discuss current method developments with the potential to widen access to time-resolved studies across discipline boundaries. PMID- 24059518 TI - A long road towards the structure of respiratory complex I, a giant molecular proton pump. AB - Complex I (NADH:ubiquinone oxidoreductase) is central to cellular energy production, being the first and largest enzyme of the respiratory chain in mitochondria. It couples electron transfer from NADH to ubiquinone with proton translocation across the inner mitochondrial membrane and is involved in a wide range of human neurodegenerative disorders. Mammalian complex I is composed of 44 different subunits, whereas the 'minimal' bacterial version contains 14 highly conserved 'core' subunits. The L-shaped assembly consists of hydrophilic and membrane domains. We have determined all known atomic structures of complex I, starting from the hydrophilic domain of Thermus thermophilus enzyme (eight subunits, nine Fe-S clusters), followed by the membrane domains of the Escherichia coli (six subunits, 55 transmembrane helices) and T. thermophilus (seven subunits, 64 transmembrane helices) enzymes, and finally culminating in a recent crystal structure of the entire intact complex I from T. thermophilus (536 kDa, 16 subunits, nine Fe-S clusters, 64 transmembrane helices). The structure suggests an unusual and unique coupling mechanism via long-range conformational changes. Determination of the structure of the entire complex was possible only through this step-by-step approach, building on from smaller subcomplexes towards the entire assembly. Large membrane proteins are notoriously difficult to crystallize, and so various non-standard and sometimes counterintuitive approaches were employed in order to achieve crystal diffraction to high resolution and solve the structures. These steps, as well as the implications from the final structure, are discussed in the present review. PMID- 24059519 TI - Accessory subunits of mitochondrial complex I. AB - Mitochondrial complex I has a molecular mass of almost 1 MDa and comprises more than 40 polypeptides. Fourteen central subunits harbour the bioenergetic core functions. We are only beginning to understand the significance of the numerous accessory subunits. The present review addresses the role of accessory subunits for assembly, stability and regulation of complex I and for cellular functions not directly associated with redox-linked proton translocation. PMID- 24059520 TI - Cation transport by the respiratory NADH:quinone oxidoreductase (complex I): facts and hypotheses. AB - The respiratory complex I (electrogenic NADH:quinone oxidoreductase) has been considered to act exclusively as a H+ pump. This was questioned when the search for the NADH-driven respiratory Na+ pump in Klebsiella pneumoniae initiated by Peter Dimroth led to the discovery of a Na+-translocating complex in this enterobacterium. The 3D structures of complex I from different organisms support the idea that the mechanism of cation transport by complex I involves conformational changes of the membrane-bound NuoL, NuoM and NuoN subunits. In vitro methods to follow Na+ transport were compared with in vivo approaches to test whether complex I, or its individual NuoL, NuoM or NuoN subunits, extrude Na+ from the cytoplasm to the periplasm of bacterial host cells. The truncated NuoL subunit of the Escherichia coli complex I which comprises amino acids 1-369 exhibits Na+ transport activity in vitro. This observation, together with an analysis of putative cation channels in NuoL, suggests that there exists in NuoL at least one continuous pathway for cations lined by amino acid residues from transmembrane segments 3, 4, 5, 7 and 8. Finally, we discuss recent studies on Na+ transport by mitochondrial complex I with respect to its putative role in the cycling of Na+ ions across the inner mitochondrial membrane. PMID- 24059521 TI - Assembly of the Escherichia coli FoF1 ATP synthase involves distinct subcomplex formation. AB - The ATP synthase (FoF1) of Escherichia coli couples the translocation of protons across the cytoplasmic membrane by Fo to ATP synthesis or hydrolysis in F1. Whereas good knowledge of the nanostructure and the rotary mechanism of the ATP synthase is at hand, the assembly pathway of the 22 polypeptide chains present in a stoichiometry of ab2c10alpha3beta3gammadeltaepsilon has so far not received sufficient attention. In our studies, mutants that synthesize different sets of FoF1 subunits allowed the characterization of individually formed stable subcomplexes. Furthermore, the development of a time-delayed in vivo assembly system enabled the subsequent synthesis of particular missing subunits to allow the formation of functional ATP synthase complexes. These observations form the basis for a model that describes the assembly pathway of the E. coli ATP synthase from pre-formed subcomplexes, thereby avoiding membrane proton permeability by a concomitant assembly of the open H+-translocating unit within a coupled FoF1 complex. PMID- 24059522 TI - GAPDH: the missing link between glycolysis and mitochondrial oxidative phosphorylation? AB - The main function of glycolysis and oxidative phosphorylation is to produce cellular energy in the form of ATP. In the present paper we propose a link between both of these energy-regulatory processes in the form of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and CytOx (cytochrome c oxidase). GAPDH is the sixth enzyme of glycolysis, whereas CytOx is the fourth complex of the mitochondrial oxidative phosphorylation system. In MS analysis, GAPDH was found to be associated with a BN-PAGE (blue native PAGE)-isolated complex of CytOx from bovine heart tissue homogenates. Both GAPDH and CytOx are highly regulated under normal energy metabolic conditions, but both of these enzymes are highly deregulated in the presence of oxidative stress. The interaction of GAPDH with CytOx could be the point of interest as it has already been shown that GAPDH protein damage results in a marked decrease in cellular ATP levels. On the other hand, decreasing the ATP/ADP ratio may ultimately result in switching off the allosteric ATP inhibition of CytOx leading to increased ROS (reactive oxygen species), cytochrome c release and apoptosis. Moreover, we have previously reported that allosteric ATP inhibition of CytOx is responsible for keeping the membrane potential at low healthy values, thus avoiding the production of ROS and this allosteric ATP inhibition is switched on at a high ATP/ADP ratio. So, in the present paper, we propose a scheme that could prove to be a link between these two enzymes and their role in the prevalence of diseases. PMID- 24059523 TI - Mitochondrial genome function and maternal inheritance. AB - The persistence of mtDNA to encode a small subset of mitochondrial proteins reflects the selective advantage of co-location of key respiratory chain subunit genes with their gene products. The disadvantage of this co-location is exposure of mtDNA to mutagenic ROS (reactive oxygen species), which are by-products of aerobic respiration. The resulting 'vicious circle' of mitochondrial mutation has been proposed to underlie aging and its associated degenerative diseases. Recent evidence is consistent with the hypothesis that oocyte mitochondria escape the aging process by acting as quiescent genetic templates, transcriptionally and bioenergetically repressed. Transmission of unexpressed mtDNA in the female germline is considered as a reason for the existence of separate sexes, i.e. male and female. Maternal inheritance then circumvents incremental accumulation of age related disease in each new generation. PMID- 24059524 TI - The alternative oxidases: simple oxidoreductase proteins with complex functions. AB - The alternative oxidases are membrane-bound monotopic terminal electron transport proteins found in all plants and in some agrochemically important fungi and parasites including Trypansoma brucei, which is the causative agent of trypanosomiasis. They are integral membrane proteins and reduce oxygen to water in a four electron process. The recent elucidation of the crystal structure of the trypanosomal alternative oxidase at 2.85 A (1 A=0.1 nm) has revealed salient structural features necessary for its function. In the present review we compare the primary and secondary ligation spheres of the alternative oxidases with other di-iron carboxylate proteins and propose a mechanism for the reduction of oxygen to water. PMID- 24059525 TI - Sulfide inhibition of and metabolism by cytochrome c oxidase. AB - Hydrogen sulfide (H2S), a classic cytochrome c oxidase inhibitor, is also an in vitro oxidase substrate and an in vivo candidate hormonal ('gasotransmitter') species affecting sleep and hibernation. H2S, nitric oxide (NO) and carbon monoxide (CO) share some common features. All are low-molecular-mass physiological effectors and also oxidase inhibitors, capable of binding more than one enzyme site, and each is an oxidizable 'substrate'. The oxidase oxidizes CO to CO2, NO to nitrite and sulfide to probable persulfide species. Mitochondrial cytochrome c oxidase in an aerobic steady state with ascorbate and cytochrome c is rapidly inhibited by sulfide in a biphasic manner. At least two successive inhibited species are involved, probably partially reduced. The oxidized enzyme, in the absence of turnover, occurs in at least two forms: the 'pulsed' and 'resting' states. The pulsed form reacts aerobically with sulfide to form two intermediates, 'P' and 'F', otherwise involved in the reaction of oxygen with reduced enzyme. Sulfide can directly reduce the oxygen-reactive a3CuB binuclear centre in the pulsed state. The resting enzyme does not undergo such a step, but only a very slow one-electron reduction of the electron-transferring haem a. In final reactivation phases, both the steady-state inhibition of catalysis and the accumulation of P and F states are reversed by slow sulfide oxidation. A model for this complex reaction pattern is presented. PMID- 24059526 TI - Microbial hydrogen splitting in the presence of oxygen. AB - The origin of the tolerance of a subclass of [NiFe]-hydrogenases to the presence of oxygen was unclear for a long time. Recent spectroscopic studies showed a conserved active site between oxygen-sensitive and oxygen-tolerant hydrogenases, and modifications in the vicinity of the active site in the large subunit could be excluded as the origin of catalytic activity even in the presence of molecular oxygen. A combination of bioinformatics and protein structural modelling revealed an unusual co-ordination motif in the vicinity of the proximal Fe-S cluster in the small subunit. Mutational experiments confirmed the relevance of two additional cysteine residues for the oxygen-tolerance. This new binding motif can be used to classify sequences from [NiFe]-hydrogenases according to their potential oxygen-tolerance. The X-ray structural analysis of the reduced form of the enzyme displayed a new type of [4Fe-3S] cluster co-ordinated by six surrounding cysteine residues in a distorted cubanoid geometry. The unusual electronic structure of the proximal Fe-S cluster can be analysed using the broken-symmetry approach and gave results in agreement with experimental Mobetabauer studies. An electronic effect of the proximal Fe-S cluster on the remote active site can be detected and quantified. In the oxygen-tolerant hydrogenases, the hydride occupies an asymmetric binding position in the Ni-C state. This may rationalize the more facile activation and catalytic turnover in this subclass of enzymes. PMID- 24059527 TI - Molecular mechanism and physiological role of active-deactive transition of mitochondrial complex I. AB - The unique feature of mitochondrial complex I is the so-called A/D transition (active-deactive transition). The A-form catalyses rapid oxidation of NADH by ubiquinone (k ~104 min-1) and spontaneously converts into the D-form if the enzyme is idle at physiological temperatures. Such deactivation occurs in vitro in the absence of substrates or in vivo during ischaemia, when the ubiquinone pool is reduced. The D-form can undergo reactivation given both NADH and ubiquinone availability during slow (k ~1-10 min-1) catalytic turnover(s). We examined known conformational differences between the two forms and suggested a mechanism exerting A/D transition of the enzyme. In addition, we discuss the physiological role of maintaining the enzyme in the D-form during the ischaemic period. Accumulation of the D-form of the enzyme would prevent reverse electron transfer from ubiquinol to FMN which could lead to superoxide anion generation. Deactivation would also decrease the initial burst of respiration after oxygen reintroduction. Therefore the A/D transition could be an intrinsic protective mechanism for lessening oxidative damage during the early phase of reoxygenation. Exposure of Cys39 of mitochondrially encoded subunit ND3 makes the D-form susceptible for modification by reactive oxygen species and nitric oxide metabolites which arrests the reactivation of the D-form and inhibits the enzyme. The nature of thiol modification defines deactivation reversibility, the reactivation timescale, the status of mitochondrial bioenergetics and therefore the degree of recovery of the ischaemic tissues after reoxygenation. PMID- 24059528 TI - Improvement of mitochondrial function and dynamics by the metabolic enhancer piracetam. AB - The metabolic enhancer piracetam is used in many countries to treat cognitive impairment in aging, brain injuries, as well as dementia such as AD (Alzheimer's disease). As a specific feature of piracetam, beneficial effects are usually associated with mitochondrial dysfunction. In previous studies we were able to show that piracetam enhanced ATP production, mitochondrial membrane potential as well as neurite outgrowth in cell and animal models for aging and AD. To investigate further the effects of piracetam on mitochondrial function, especially mitochondrial fission and fusion events, we decided to assess mitochondrial morphology. Human neuroblastoma cells were treated with the drug under normal conditions and under conditions imitating aging and the occurrence of ROS (reactive oxygen species) as well as in stably transfected cells with the human wild-type APP (amyloid precursor protein) gene. This AD model is characterized by expressing only 2-fold more human Abeta (amyloid beta-peptide) compared with control cells and therefore representing very early stages of AD when Abeta levels gradually increase over decades. Interestingly, these cells exhibit an impaired mitochondrial function and morphology under baseline conditions. Piracetam is able to restore this impairment and shifts mitochondrial morphology back to elongated forms, whereas there is no effect in control cells. After addition of a complex I inhibitor, mitochondrial morphology is distinctly shifted to punctate forms in both cell lines. Under these conditions piracetam is able to ameliorate morphology in cells suffering from the mild Abeta load, as well as mitochondrial dynamics in control cells. PMID- 24059529 TI - The superfamily of mitochondrial Complex1_LYR motif-containing (LYRM) proteins. AB - Mitochondrial LYRM (leucine/tyrosine/arginine motif) proteins are members of the Complex1_LYR-like superfamily. Individual LYRM proteins have been identified as accessory subunits or assembly factors of mitochondrial OXPHOS (oxidative phosphorylation) complexes I, II, III and V respectively, and they play particular roles in the essential Fe-S cluster biogenesis and in acetate metabolism. LYRM proteins have been implicated in mitochondrial dysfunction, e.g. in the context of insulin resistance. However, the functional significance of the common LYRM is still unknown. Analysis of protein-protein interaction screens suggests that LYRM proteins form protein complexes with phylogenetically ancient proteins of bacterial origin. Interestingly, the mitochondrial FAS (fatty acid synthesis) type II acyl-carrier protein ACPM associates with some of the LYRM protein-containing complexes. Eukaryotic LYRM proteins interfere with mitochondrial homoeostasis and might function as adaptor-like 'accessory factors'. PMID- 24059530 TI - Enhancing tissue engineering/regenerative medical product commercialization: the role of science in regulatory decision making for tissue engineering/regenerative medicine product development. PMID- 24059531 TI - Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. AB - BACKGROUND: Classical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications. METHODS: This study investigated the long term outcome of 80 patients with classical organic aciduria (38 with MMA, 24 with PA and 18 with IVA) by integrating clinical, radiological, biochemical and genetic data. RESULTS: Patients were followed-up for a mean of 14 years [age 3.3 46.3 years]. PA included a greater number of patients with abnormal neurological examination (37% in PA, 24% in MMA and 0% in IVA), lower psychometric scores (abnormal evaluation at age 3 years in 61% of patients with PA versus 26% in MMA and 18% in IVA) and more frequent basal ganglia lesions (56% of patients versus 36% in MMA and 17% in IVA). All patients with IVA presented a normal neurological examination and only 1/3 presented cognitive troubles. Prognosis for MMA was intermediate. Biochemical metabolite analysis excluding acute decompensations revealed significant progressive increases of glycine, alanine and glutamine particularly in PA and possibly in MMA but no correlation with neurological outcome. A significant increase of plasma methylmalonic acid was found in MMA patients with intellectual deficiency (mean level of 199 MUmol/L versus 70 MUmol/L, p < 0.05), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 167 MUmol/L. Urinary 3 hydroxypropionate (3-HP) levels were significantly higher in PA patients with intellectual deficiency (mean level of 68.9 MUmol/mmol of creatinine versus 34.6 MUmol/mmol of creatinine, p < 0.01), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 55 MUmol/mmol. As for molecular analysis, prognosis of MMA patients with mutations involving the MMAA gene was better compared to patients with mutations involving the MUT gene. CONCLUSION: Propionic aciduria had the most severe neurological prognosis. Our radiological and biochemical data are consistent with a mitochondrial toxicity mechanism. Follow-up plasma MMA and urinary 3-HP levels may have prognostic significance calling for greater efforts to optimize long term management in these patients. PMID- 24059532 TI - VEGF promotes cardiac stem cells differentiation into vascular endothelial cells via the PI3K/Akt signaling pathway. AB - Recent research suggested that cardiac stem cells (CSCs) may have the clinical application for cardiac repair. However, their characteristics and the regulatory mechanisms of their growth and differentiation have not been fully investigated. Vascular endothelial growth factor (VEGF, VEGF-A) is a major regulator of physiological and pathological angiogenesis. But the homing role of VEGF for CSCs is unclear. In this report, CSCs were isolated, purified, and expanded in vitro from rat heart. VEGF, SU5416 (VEGF receptor blocker), and Wortmannin (PI3K/Akt signaling pathway inhibitor) were used for differentiation into vascular endothelial cells (VECs). Real-time qPCR was selected to confirm the role of PI3K/Akt signaling pathway in VECs differentiation from rat CSCs. The result of real-time qPCR demonstrated that PI3K/Akt signaling pathway plays an important role in rat CSCs differentiated into VECs. So, our research provides a theoretical basis and experimental evidence for therapeutic application of rat CSCs to treat cardiac repair. PMID- 24059533 TI - Genetically encoded fluorescent probe for the selective detection of peroxynitrite. AB - Peroxynitrite is a highly reactive molecule involved in cell signaling and pathological processes. We hereby report a novel genetically encoded probe, pnGFP, which can selectively sense peroxynitrite. A boronic acid moiety was site specifically introduced into circularly permuted fluorescent proteins. By examining different protein templates followed with site-targeted random mutagenesis, we identified a selective peroxynitrite sensor, which is essentially unresponsive to other common cellular redox signaling molecules. The new probe has been genetically introduced into mammalian cells to image peroxynitrite at physiologically relevant concentrations. PMID- 24059534 TI - Thiamine and its phosphate esters in relation to cardiometabolic risk factors in Saudi Arabs. AB - BACKGROUND: Thiamine deficiency has suggested to be linked to several insulin resistance complications. In this study, we aim to associate circulating thiamine levels among cardiometabolic parameters in an Arab cohort using a simple, sensitive, rapid and selective high-performance liquid chromatography (HPLC) method that has recently been developed. METHODS: A total of 236 randomly selected, consenting Saudi adult participants (166 males and 70 females) were recruited and screened for the presence of the metabolic syndrome (MetS) using the modified National Cholesterol Education Program-Adult Treatment Panel III definition. Blood thiamine and its derivatives were quantified using HPLC. RESULTS: A total of 140 participants (53.9%) had MetS. The levels of thiamine and its derivatives of those with MetS were not significantly different from those without. However, hypertensive subjects had significantly higher urinary thiamine (P = 0.03) as well as significantly lower levels of thiamine diphosphate (TDP) (P = 0.01) and total thiamine (P = 0.02) than the normotensive subjects, even after adjusting for age and body mass index (BMI). Furthermore, age- and BMI-matched participants with elevated blood glucose levels had significantly lower levels of thiamine monophosphate (P = 0.020), TDP (P < 0.001) and total thiamine (P < 0.001) and significantly elevated levels of urinary thiamine (P = 0.005) compared to normoglycemic participants. CONCLUSIONS: Low thiamine levels are associated with elevated blood glucose and hypertension in Saudi adults. Determination of thiamine status may be considered and corrected among patients with, or at high risk for, MetS, but the question whether thiamine deficiency correction translates to improved cardiometabolic status needs further longitudinal investigation. PMID- 24059535 TI - The influence of a rocker sole adaptation on gait parameters in spinal cord injury patients ambulating with the advanced reciprocating gait orthosis - a pilot study. AB - OBJECTIVE: When walking with an advanced reciprocating gait orthosis (ARGO), ankle and knee joint motion is restricted which causes an un-cosmetic gait compared to normal walking. The purpose of this study was to develop and evaluate a rocker modification for use with the ARGO in order to improve hip joint kinematics, walking speed, step length and cadence. METHOD: Spinal cord injury patients (n = 4) with thoracic-level injury participated in this study, and walked with a standard ARGO and one which was also adapted with a rocker sole in a randomized order. RESULTS: Mean walking speed and step length were both significantly increased by volunteer SCI subjects when ambulating using the ARGO adapted with a rocker sole compared to the standard ARGO. Cadence was not significantly affected, but swing time was significantly reduced and mean hip flexion and extension were both significantly increased when walking with the adapted ARGO. CONCLUSION: The rocker sole modification produced an increase in walking speed and step length, and improved sagittal plane hip joint kinematics when ambulating using an ARGO. Using this type of shoe modification has the potential to improve gait parameters in SCI patients compared to the standard unmodified version. Implications for Rehabilitation The ARGO adapted with a rocker sole could be used by spinal cord injury patients. A major advantage of the walking with the ARGO adapted with a rocker sole was increased of walking speed and step length, and improvement of the sagittal plane hip joint kinematics. The findings of this study would appear to provide useful data for rehabilitation teams who utilize orthoses to walk and rehabilitate SCI subjects. Using this type of shoe modification has the potential to improve gait parameters in SCI patients compared to the standard un-modified version. PMID- 24059536 TI - A clinical screening protocol for the RSVP Keyboard brain-computer interface. AB - PURPOSE: To propose a screening protocol that identifies requisite sensory, motor, cognitive and communication skills for people with locked-in syndrome (PLIS) to use the RSVP KeyboardTM brain-computer interface (BCI). METHOD: A multidisciplinary clinical team of seven individuals representing five disciplines identified requisite skills for the BCI RSVP KeyboardTM. They chose questions and subtests from existing standardized instruments for auditory comprehension, reading and spelling, modified them to accommodate nonverbal response modalities, and developed novel tasks to screen visual perception, sustained visual attention and working memory. Questions were included about sensory skills, positioning, pain interference and medications. The result is a compilation of questions, adapted subtests and original tasks designed for this new BCI system. It was administered to 12 PLIS and 6 healthy controls. RESULTS: Administration required 1 h or less. Yes/no choices and eye gaze were adequate response modes for PLIS. Healthy controls and 9 PLIS were 100% accurate on all tasks; 3 PLIS missed single items. CONCLUSIONS: The RSVP BCI screening protocol is a brief, repeatable technique for patients with different levels of LIS to identify the presence/absence of skills for BCI use. Widespread adoption of screening methods should be a clinical goal and will help standardize BCI implementation for research and intervention. Implications for Rehabilitation People with locked-in syndrome must have certain sensory, motor, cognitive and communication skills to successfully use a brain-computer interface (BCI) for communication. A screening profile would be useful in identifying potentially suitable candidates for BCI. PMID- 24059538 TI - Folding paper-based lithium-ion batteries for higher areal energy densities. AB - Paper folding techniques are used in order to compact a Li-ion battery and increase its energy per footprint area. Full cells were prepared using Li4Ti5O12 and LiCoO2 powders deposited onto current collectors consisting of paper coated with carbon nanotubes. Folded cells showed higher areal capacities compared to the planar versions with a 5 * 5 cell folded using the Miura-ori pattern displaying a ~14* increase in areal energy density. PMID- 24059537 TI - Impact of oleic acid as co-substrate of glucose on "short" and "long-term" Crabtree effect in Saccharomyces cerevisiae. AB - BACKGROUND: Optimization of industrial biomass directed processes requires the highest biomass yield as possible. Yet, some useful yeasts like Saccharomyces cerevisiae are subject to the Crabtree effect under glucose excess. This phenomenon can occur in large scale tank where heterogeneities in glucose concentrations exist. Therefore yeasts encounter local environments with glucose excess leading to ethanol production to the detriment of biomass formation. We previously demonstrated that oleic acid as a co-substrate in glucose-limited chemostat allowed to delay and modulate the "short-term" Crabtree effect in Saccharomyces cerevisiae. Here we further investigated the effect of oleic acid as a modulator of the Crabtree effect. RESULTS: The impact of oleic acid as co substrate on the Crabtree effect was investigated in terms of i) strain specificity, ii) reversibility of the potential effect with aerobic glucose excess batches and iii) durability and maximal capacities under high ethanol stress with glucose-excess fed-batches. First, the addition of oleic acid resulted in an increase of the critical dilution rate by 8% and the specific carbon uptake rate by 18%. Furthermore, a delay was observed for the onset of ethanol production when a batch was inoculated with cells previously grown in glucose-oleate chemostat. Finally, the culture of adapted cells in a glucose oleate fed-batch led to a redirection of the carbon flux toward biomass production, with a 73% increase in the biomass yield. CONCLUSIONS: This work demonstrated clearly that the perturbation by oleic acid as co-substrate resulted in a decrease in the "short-term" and "long-term" Crabtree effects. This impact was not strain dependent and reversible. Thus, industrial applications of this biochemical strategy could be envisaged to tackle heterogeneities issues in large scale tanks or to prepare starter yeasts for various applications. PMID- 24059540 TI - Learned lessons, changing practice and cutting-edge research: how to reduce scientific uncertainty in neonatology pursuing the triple aim. PMID- 24059539 TI - Combining in silico prediction and ribosome profiling in a genome-wide search for novel putatively coding sORFs. AB - BACKGROUND: It was long assumed that proteins are at least 100 amino acids (AAs) long. Moreover, the detection of short translation products (e.g. coded from small Open Reading Frames, sORFs) is very difficult as the short length makes it hard to distinguish true coding ORFs from ORFs occurring by chance. Nevertheless, over the past few years many such non-canonical genes (with ORFs < 100 AAs) have been discovered in different organisms like Arabidopsis thaliana, Saccharomyces cerevisiae, and Drosophila melanogaster. Thanks to advances in sequencing, bioinformatics and computing power, it is now possible to scan the genome in unprecedented scrutiny, for example in a search of this type of small ORFs. RESULTS: Using bioinformatics methods, we performed a systematic search for putatively functional sORFs in the Mus musculus genome. A genome-wide scan detected all sORFs which were subsequently analyzed for their coding potential, based on evolutionary conservation at the AA level, and ranked using a Support Vector Machine (SVM) learning model. The ranked sORFs are finally overlapped with ribosome profiling data, hinting to sORF translation. All candidates are visually inspected using an in-house developed genome browser. In this way dozens of highly conserved sORFs, targeted by ribosomes were identified in the mouse genome, putatively encoding micropeptides. CONCLUSION: Our combined genome-wide approach leads to the prediction of a comprehensive but manageable set of putatively coding sORFs, a very important first step towards the identification of a new class of bioactive peptides, called micropeptides. PMID- 24059541 TI - UNICEF: immunization saves lives. PMID- 24059542 TI - Twins among history, myth and arts. PMID- 24059543 TI - Proteomics and metabolomics: can they solve some mysteries of the newborn? PMID- 24059544 TI - Twin, association and current "omics" studies. AB - This paper describes the estimation of heritability, the genetic analysis of comorbid traits based on twin designs and on indices based on measured genetic relatedness. Next, approaches to identify genes and to examine the modification of heritability are described. The paper concludes with a discussion on the continued value of twin studies. PMID- 24059545 TI - Omics in laboratory medicine. AB - In the last years, molecular diagnosis of human genetic diseases has greatly improved thanks to the knowledge of more than 7,000 disease genes (genomics). However, the study of such diseases revealed the very complex relationships between the phenotype of each disease and the molecular alterations responsible. The analysis of proteins (proteomics) revealed that most proteins are subjected to post-translational changes or to alternative splicing; the study of gene expression identified a series of mechanisms that modulate gene expression (epigenomics) which include microRNA regulation, histone acetylation and gene methylation. The alteration of all these mechanisms may contribute to the pathogenesis or to the phenotypic expression of most human genetic diseases. Molecular analysis became more and more complex, but "omics" studies revealed that each single individual is "unique". PMID- 24059546 TI - Metabolomics: a new tool for the investigation of metabolic changes induced by cytomegalovirus. AB - To date, cytomegalovirus (CMV) is one of the most studied and characterized virus, however the current knowledge on the effect of the human CMV (HCMV) infection on global metabolism is still poorly understood. Metabolomics is a new approach based on the systematic study of the complete set of low molecular weight compounds, both endogenous and exogenous, found within a cell, tissue, biofluid or organism. The purpose of this review is to provide insight into the use of the metabolomic approach on the study of the impact of HCMV on the human metabolome. The results described in this work suggest that metabolomics could be a new tool for HCMV investigation. PMID- 24059547 TI - Metabolomics in paediatric oncology: a potential still to be exploited. AB - Oncology is a branch of medicine in rapid evolution in the attempt to find innovative methods for early diagnosis and a better understanding of tumoral processes leading to the development of new therapies. Metabolomics is the emerging discipline among the "omics" sciences which makes it possible to further expand our knowledge concerning cancer biology. Different studies have revealed the potential role of metabolomics in gaining an understanding of pathophysiological processes in cancer, improving tumor staging, characterizing tumors and searching for biomarkers predictive of therapeutic responses. However, to date there are few works aimed at gaining deeper insights into infantile oncology through metabolomics. PMID- 24059548 TI - In search of biomarkers for diagnosing and managing neonatal sepsis: the role of angiopoietins. AB - Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are antagonistic ligands that bind to the extracellular domain of the Tie-2 receptor, which is almost exclusively expressed by endothelial cells. Angiopoietins can directly stimulate both endothelial cells and neutrophils for an overall proinflammatory and proangiogenic response. An increasing number of experimental and clinical studies gave evidence that in the course of sepsis the serum levels of Ang-1 and Ang-2 as well as their ratio significantly differ from those in healthy subjects, in non septic hospitalized patients, and in patients with non-infectious systemic inflammatory response syndrome (SIRS) or critical illness. Further evidences have demonstrated that the magnitude of Ang-2 dysregulation correlates with the severity of sepsis and the mortality rate. Since the onset of neonatal sepsis is often subtle and the diagnosis occurs later, Ang-1 and Ang-2 appear to be very promising biomarkers for improving the diagnosis and the management of septic newborns. PMID- 24059549 TI - Surfactant therapy for neonatal respiratory distress syndrome in 2013. AB - Surfactant whether given prophylactically in the delivery room or to babies with established respiratory distress syndrome (RDS) reduces the severity of RDS, incidence of air leaks and pneumothorax and, most importantly, neonatal death. Despite being the most intensively studied intervention in neonatal medicine, there is still debate among neonatologists regarding the best preparations, the optimal dose and mode of administration and when best to intervene with surfactant. European Consensus Guidelines on the management of RDS have been developed and updated twice since 2007 reflecting changes in practice as new evidence emerges and in this article we summarize current opinion regarding optimal surfactant use in the present era of non-invasive respiratory support. PMID- 24059550 TI - Microorganisms in human milk: lights and shadows. AB - Human milk has been traditionally considered germ free, however, recent studies have shown that it represents a continuous supply of commensal and potentially probiotic bacteria to the infant gut. Mammary microbioma may exercise anti infective, anti-inflammatory, immunomodulatory and metabolic properties. Moreover human milk may be a source of pathogenic microorganism during maternal infection, if contaminated during expression or in case of vaccination of the mother. The non-sterility of breast milk can, thus, be seen as a protective factor, or rarely, as a risk factor for the newborn. PMID- 24059551 TI - Factors influencing the development of a personal tailored microbiota in the neonate, with particular emphasis on antibiotic therapy. AB - In recent years, it has been clearly evidenced that most cells in a human being are not human: they are microbial, represented by more than 1000 microbial species. The vast majority of microbial species give rise to symbiotic host bacterial interactions that are fundamental for human health. The complex of these microbial communities has been defined as microbiota or microbiome. These bacterial communities, forged over millennia of co-evolution with humans, are at the basis of a partnership with the developing human newborn, which is based on reciprocal molecular exchanges and cross-talking. Recent data on the role of the human microbiota in newborns and children clearly indicate that microbes have a potential importance to pediatrics, contributing to host nutrition, developmental regulation of intestinal angiogenesis, protection from pathogens, and development of the immune system. This review is aimed at reporting the most recent data on the knowledge of microbiota origin and development in the human newborn, and on the multiple factors influencing development and maturation of our microbiota, including the use and abuse of antibiotic therapies. PMID- 24059552 TI - Next generation biomarkers for brain injury. AB - In perinatal medicine, there is an emerging interest on the potential usefulness of non-invasive brain biochemical monitoring in infants at risk for brain injury. To date, several biomarkers such as neuro-proteins, calcium binding proteins, oxidative stress markers, vasoactive agents, inflammatory mediators, have been investigated. Results showed that hypoxia insult, under different conditions, triggers a biochemical pathophysiological cascade of events leading to brain damage. In this setting, increased biomarkers concentrations in different biological fluids have been found to correlate with the occurrence of brain damage at short-long term both in preterm and term fetuses/newborns. However, before inclusion of any biomarker in guidelines, USA and European institutions have recently stated a panel of criteria that have to be fulfilled. Therefore, the present review offers an overview of the main biomarkers currently studied in perinatal medicine and their progresses according to institutions' criteria. PMID- 24059553 TI - Controversies in neonatal resuscitation. AB - Despite recent advances in perinatal medicine and in the art of neonatal resuscitation, resuscitation strategy and treatment methods in the delivery room should be individualized depending on the unique characteristics of the neonate. The constantly increasing evidence has resulted in significant treatment controversies, which need to be resolved with further clinical and experimental research. PMID- 24059554 TI - New perspectives in Respiratory Syncitial Virus infection. AB - Respiratory syncitial virus (RSV) is the most common cause of lower respiratory tract infections (LRTI) in children worldwide and it is associated with significant childhood morbidity. Acute infection may result in respiratory failure with varying degrees of severity, and increasing evidence supports a role of RSV infection as a key determinant for the development of subsequent chronic respiratory disease. Independent predictors of RSV severity include; prematurity, congenital heart disease, cystic fibrosis, immune defects and neuromuscular disorders. Passive immunization with palivizumab has proven to be safe and effective for preventing RSV hospitalization in infants at higher risk of acquiring severe RSV infection, but its expense and cumbersome monthly intravenous delivery schedule make it inaccessible to many. Furthermore, implementing prophylaxis in 32- to 35-week-gestational age infants and the mode of its administration still represent areas of uncertainty. In this review, we describe several aspects of RSV infection and analyze recent advances in the assessment of cost-effective palivizumab prophylaxis. PMID- 24059555 TI - Unique risks of red blood cell transfusions in very-low-birth-weight neonates: associations between early transfusion and intraventricular hemorrhage and between late transfusion and necrotizing enterocolitis. AB - Red blood cell transfusions can be life-saving for neonates with severe anemia or active hemorrhage. However, risks of transfusions exist and should always be weighed against potential benefits. At least two transfusion risks are unique to very low birth weight neonates. The first is an association between transfusions given in the first days after birth and the subsequent occurrence of a grade 3 or 4 intraventricular hemorrhage. The second is an association between "late" RBC transfusions and the subsequent occurrence of necrotizing enterocolitis. Much remains to be discovered about the pathogenesis of these two outcomes. Moreover, work is needed to clearly establish whether transfusions are causatively associated with these outcomes or are co-variables. This review will provide basic data establishing these associations and propose mechanistic explanations. PMID- 24059556 TI - SGA children: auxological and metabolic outcomes - the role of GH treatment. AB - The definition Small for Gestational Age (SGA) describes those newborns weighing and/or measuring in length <-2 SD than expected for their gestational age. These subjects are at higher risk of short stature, neonatal complications, alterations of glucose, lipid metabolism, body composition, bone metabolism and puberty, neurocognitive vulnerabilities and alterations of the GH-IGF-I axis. With regards to growth, in 85-90% of the cases children born SGA experience a period of catch up growth that allows them to achieve an adult stature within normal range. In a 10-15% of the cases, the catch up growth period does not take place and this entails short stature in adulthood. In the latter group, GH treatment may be considered to achieve adult height in the range of genetical target stature. With reference to glucose and lipid metabolism, young adults born SGA and particularly those with early catch up growth are at higher risk of developing insulin resistance, type 2 diabetes mellitus, arterial hypertension, dyslipidemia, overweight, obesity and metabolic syndrome. Subjects born SGA are in need of a correct diagnostic and eventually therapeutic approach. PMID- 24059557 TI - Prenatal screening and counseling for genetic disorders. AB - INTRODUCTION: The carriers of the same autosomal recessive disorder are usually unaware of onset of the genetic diseases in the children even if screenings are available for many of these disorders. In this paper, we report the experience of the Prenatal Diagnosis Center of AOU Federico II and we discuss the role of the screening for beta-thalassemia (BT), cystic fibrosis (CF) and for other rare genetic disorders. MATERIALS AND METHODS: We analyzed retrospectively the indication for Prenatal Diagnosis (PD) of all the couples referred to our center from January 1993 to May 2013. We divided our sample into three groups: couples at high risk for BT, for CF and for other rare genetic disorders. RESULTS: From January 1993 to May 2013, we performed 1269 PD for genetic disorders. There are still couples who discovered to be carriers of BT by screening after the birth of the affected child (n = 51 (11,3%)); the majority of the people were screened for CF carrier after the birth of an affected child (n = 155 (80,7%)) or through the cascade screening (n = 28 (14,6%)). Large-scale screenings for rare genetic conditions are not available and people were screened only if they have a positive familial history. CONCLUSION: Parental screening is available for many severe and rare diseases whose genetic origin is known. The proportion of patients referred for very high-risk indications increased over time with an higher demand for rare disease. An adequate counseling is fundamental to identify women at risk for having affected child. Screening, counseling and PD of genetic diseases is a complex matter and needs for a continuous update. PMID- 24059558 TI - S100B immunoreactivity: a new marker of hypoxia-related cardiac damage in newborn piglets. AB - OBJECTIVE: The evaluation of the expression of S100B protein, in the swine heart in an experimental model of hypoxia - reoxygenation. METHODS: Normocapnic hypoxia was induced in 40 male Landrace/Large White neonatal piglets by decreasing the inspired concentration of oxygen to 6-8%. When animals developed bradycardia or severe hypotension, reoxygenation was initiated. Piglets were allocated in four groups of 10, according to the oxygen concentration they were reoxygenated with: Group 1, 2, 3 and 4 resuscitated with 18%, 21%, 40% and 100% oxygen, respectively. The animals were further classified into 4 groups according with the time required for reoxygenation: group A (<15 min); group B (16-60 min); group C (>60 min); group D (deceased animals). RESULTS: Immunostaining for S100B protein was detected in 14 out of the 40 heart samples (35%), both inside the cytoplasm of cardiomyocytes and as globular deposits in the interstitial spaces. Significant differences were observed among groups 1-4 regarding S100B expression. Reactivity for S100B in cardiac cells was detected in 50%, 50%, 10% and 33% of animals in groups 1 and 2, 3 and 4, respectively. Marked differences were also observed among groups A-D: 75%, 33%, 12% and 22% of the animals in group 1, 2, 3 and 4, respectively, showed reactivity for S100B in the heart. CONCLUSIONS: Expression of S100B protein occurred in the heart of some of newborn piglets following severe hypoxia. S100B storage in cardiomyocytes correlates with the different oxygen concentration used during reoxygenation, being higher in piglets reoxygenated with 18% and 21%, and lower in animals reoxygenated with 40% oxygen. Intermediate levels of S100B expression were found in 100% O2-treated animals. The finding of a higher percentage of S100B-immunoreactive hearts in piglets with a fast recovery and the detection of a decreased reactivity in animals with a slow and a very slow recovery clearly indicates S100B protein as an early protective factor with a positive prognostic value in asphyxiated newborn piglets. PMID- 24059559 TI - Instituting a program to reduce the erythrocyte transfusion rate was accompanied by reductions in the incidence of bronchopulmonary dysplasia, retinopathy of prematurity and necrotizing enterocolitis. AB - Bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and necrotizing enterocolitis (NEC) all likely involve oxidative damage to immature tissues. It has been postulated that transfusions of adult erythrocytes contribute to the risk of developing these morbidities, as a consequence of adult hemoglobin releasing non-physiological quantities of O2 to developing tissues. In 2009, we instituted a concerted effort to diminish erythrocyte transfusions in our NICU, and in 2013 we performed a before vs. after practice change analysis of the incidence of BPD, ROP and NEC during the 8-year period spanning this change. The transfusion rate fell from a high of 14.8% of admissions in 2007 to a low of 6.3% in 2011 (p < 0.001). Concordant with this reduction patients had a lower incidence of; BPD (from 3.2% to 0.9%; OR, 3.722; CI 1.897-7.302), ROP (from 4.6% to 2.4%; OR 1.958, CI 1.247-3.073), and a trend toward less NEC (from 0.7% to 0.2%; OR 3.090, CI 0.835-11.443). PMID- 24059561 TI - Competition between polymers for adsorption on silica: a solvent relaxation NMR and small-angle neutron scattering study. AB - The competition between poly(vinylpyrrolidone) and poly(ethylene oxide) for adsorption at the silica surface was studied by solvent relaxation nuclear magnetic resonance and small-angle neutron scattering. The additive nature of the NMR relaxation rate enhancement was used to observe changes in the train layer when the two polymers were in direct competition for an increasing weight percentage of silica. PVP is shown to displace preadsorbed PEO from the particle surface, and this was observed for a range of PVP molecular weights. SANS measurements were found to give detailed information on the adsorption of the polymers in the separate systems; however, only qualitative information on the adsorption of the polymers could be obtained from the mixed samples. At a total polymer concentration of 0.4% w/v with 1.1% w/v silica, the SANS data were consistent with PVP adsorbing at the surface and dPEO remaining in solution, in agreement with the NMR data. PMID- 24059560 TI - Urinary NGAL and hematic ADMA levels: an early sign of cardio-renal syndrome in young adults born preterm? AB - BACKGROUND: Prematurity at birth is a known risk factor for the development of an early chronic renal disease. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a well established biomarker of kidney injury, while high blood levels of asymmetric dimethylarginine (ADMA) are associated with the future development of adverse cardiovascular events and cardiac death. AIMS: (1) to verify the presence of statistically significant differences between urinary NGAL and hematic ADMA levels in young adults born preterm at extremely low birth weight (<1000 g; ex-ELBW) and those of a control group of healthy adults born at term (C) (2) to seek correlations between NGAL and ADMA levels, which would indicate the presence of an early cardio-renal involvement in ex-ELBW. METHODS: Twelve ex ELBW subjects (six males and six female, mean age: 23.9 +/- 3.2 years) were compared with 12 C (six males and six female). Urinary NGAL and hematic ADMA levels were assessed. RESULTS: Urinary NGAL levels were higher in ex- ELBW subjects compared to C (p < 0.05), as well as hematic ADMA concentrations (p < 0.05). A statistically significant correlation was found between urinary NGAL and ADMA (r = -0.60, p < 0.04). CONCLUSIONS: Our preliminary findings support the hypothesis that in ex-ELBW subjects the development of an early chronic kidney disease contributes towards inducing an increase in the atherosclerotic process and in the risk of future adverse cardiovascular events. PMID- 24059562 TI - Reversible anuric acute kidney injury secondary to acute renal autoregulatory dysfunction. AB - Autoregulation of glomerular capillary pressure via regulation of the resistances at the afferent and efferent arterioles plays a critical role in maintaining the glomerular filtration rate over a wide range of mean arterial pressure. Angiotensin II and prostaglandins are among the agents which contribute to autoregulation and drugs which interfere with these agents may have a substantial impact on afferent and efferent arteriolar resistance. We describe a patient who suffered an episode of anuric acute kidney injury following exposure to a nonsteroidal anti-inflammatory agent while on two diuretics, an angiotensin converting enzyme inhibitor, and an angiotensin receptor blocker. The episode completely resolved and we review some of the mechanisms by which these events may have taken place and suggest the term "acute renal autoregulatory dysfunction" to describe this syndrome. PMID- 24059563 TI - Retrieval practice with short-answer, multiple-choice, and hybrid tests. AB - Retrieval practice improves meaningful learning, and the most frequent way of implementing retrieval practice in classrooms is to have students answer questions. In four experiments (N=372) we investigated the effects of different question formats on learning. Students read educational texts and practised retrieval by answering short-answer, multiple-choice, or hybrid questions. In hybrid conditions students first attempted to recall answers in short-answer format, then identified answers in multiple-choice format. We measured learning 1 week later using a final assessment with two types of questions: those that could be answered by recalling information verbatim from the texts and those that required inferences. Practising retrieval in all format conditions enhanced retention, relative to a study-only control condition, on both verbatim and inference questions. However, there were little or no advantages of answering short-answer or hybrid format questions over multiple-choice questions in three experiments. In Experiment 4, when retrieval success was improved under initial short-answer conditions, there was an advantage of answering short-answer or hybrid questions over multiple-choice questions. The results challenge the simple conclusion that short-answer questions always produce the best learning, due to increased retrieval effort or difficulty, and demonstrate the importance of retrieval success for retrieval-based learning activities. PMID- 24059564 TI - Ants' learning of nest entrance characteristics (Hymenoptera, Formicidae). AB - Young workers, experimentally removed from their nest and set in front of it, are not very good at finding the nest entrance and entering the nest. I examined how young ants learn their nest entrance characteristics, dealing only with the entrance sensu stricto, not with its vicinity. I observed that young ants have the innate behavior of trying to exit and re-enter their nest. I found that they are imprinted with the nest entrance odor while they are still living inside their nest and that they learn the visual aspect of their nest entrances, thanks to operant conditioning, when they exit their nest and succeed in re-entering in the course of their first short trips outside. PMID- 24059565 TI - Editorial. PMID- 24059566 TI - Editorial. PMID- 24059567 TI - MR Venographic Patterns in Chronic Intractable Headache. PMID- 24059568 TI - CSF Flow in Chiari I and Syringomyelia from the Perspective of Computational Fluid Dynamics. AB - Phase contrast MR in patients with the Chiari I malformation demonstrates abnormal CSF flow in the foramen magnum and upper cervical spinal canal, related to abnormal pressure gradients. The purpose of this study was to analyze the role of CSF pressure in the pathogenesis of syringomyelia, with computational models. The spinal cord was modeled as a cylindrical poro-elastic structure with homogenous and isotropic permeability. The permeability was then made heterogeneous and anisotropic to represent the different properties of the central canal, gray and white matter. Fluid with a defined pressure, varying both in time and space, was prescribed in the SAS. Simulations were performed to quantify deformations and fluid movement within the cord. In the simulations with uniform permeability fluid moved into the cord in regions of higher pressure and out of the cord in regions of lower pressure. With permeability differences simulating gray and white matter the pattern was more complex, but similar. Adding the central spinal canal, fluid moved into the cord as in the previous case. However, preferential flow along the central canal hindered fluid from flowing back into the SAS. Pressure gradients in the SAS produce movement of fluid in the spinal cord. Assuming different relative permeability in gray matter, white matter and the central spinal canal, abnormal CSF gradients lead to accumulation of fluid within and adjacent to the spinal cord central canal. PMID- 24059569 TI - Radiological Aspects of Genetic Disorders with Adult-onset CNS Symptoms. PMID- 24059570 TI - Clinical application of susceptibility weighted imaging: exploring from routine service. AB - To evaluate the usefulness of susceptibility weighted imaging (SWI) in clinical brain MRI. Retrospective study was performed after approval from institution Ethical Committee. The brain MRIs with SWI were selected from data base of the radiology department. Only cases with no abnormality in extra-axial location were included into the study. Two neuroradiologists revealed the images without knowledge of patients' history and diagnosis. The SWI was first interpreted. Then conventional MRI (cMRI) was interpreted after finishing data collection from SWI. Clinical data and final diagnosis were collected from information given on requested forms and followed up imaging studies. Descriptive analysis was performed. From January 2007 to December 2009, 82 cases were satisfied the inclusion criteria. There were 40 males and 42 females with age 7-79 years old (means = 47.45). The final diagnosis were normal brain imaging 4 cases (4.9%), dementia/atypical Parkinson disease 2 cases (2.4%), cerebrovascular disease 24 cases (29.3%), parenchymal brain tumors 35 cases (42.7%), infection 4 cases (4.9%), multiple sclerosis (MS) 6 cases (7.3%) and inconclusive diagnosis 7 cases (8.5%). The abnormalities found on SWI were related to cMRI in 67 cases (81.7%). Three cases (3.7%) had lesions on SWI not demonstrated on cMRI. The information got from SWI added on cMRI for interpretation and diagnosis in 43 cases (52.4%). SWI were shown more detectable microbleed and changing visualization of cortical and transmedullary veins. Microvascular structure inside the mass was demonstrated on SWI in brain tumor group. The increased transmedullary veins on SWI helped to confirm the non-neoplastic lesions. In selected cases with suspected or diagnosis of vascular disease and tumor, SWI added more information on cMRI especially microbleed and microvascular structure. PMID- 24059571 TI - Quantitative Evaluation of the Penumbra and Ischemic Core in Acute Cerebral Infarction Using Whole-Brain CT Perfusion. AB - The objectives of the study were to quantitatively assess whole-brain CT Perfusion (CTP) data using an automatic region of interest (ROI) analysis program in order to distinguish between the degree of ischemia in the ischemic core and that in the penumbra and to assess the relationship between expansion of the area of infarction. The subjects were 20 patients with acute cerebral infarction. Whole-brain CTP was performed for all subjects using a 320-row area detector CT scanner. The penumbra* is defined as the region in which the CBV value is 2 mL/100 g or more and the ischemic core* is defined as the region in which the CBV value is less than 2 mL/100 g. The quantitative values of CTP parameters were automatically measured using the automatic ROIs analysis program. The Mann Whitney U test was applied to differentiate between the ischemic core* and the penumbra*. The reduction in perfusion pressure in the penumbra* was smaller in the group with expansion of the area of infarction than in the group without expansion of the area of infarction. The difference in the median values between the penumbra* and the ischemic core* was larger in the group with expansion of the area of infarction than the group without expansion of the area of infarction. It is considered that the quantitative analysis method using whole brain CTP may be useful for more accurately distinguishing between the ischemic core and the penumbra and for evaluating the risk of expansion of the ischemic core into the penumbra. PMID- 24059572 TI - Developmental Venous Anomalies (DVA): What are they really? AB - PURPOSE: The aim of this paper is to analyse the pathophysiology of 3 DVA cases from our institution, review the literature and propose a classification of these lesions. MATERIALS & METHODS: The pathophysiology of DVAs were analysed with CT perfusion (CTP), 4 dimensional dynamic computed tomography angiography (4D CTA) and catheter digital subtraction angiography. RESULTS: Symptomatic DVAs may be caused by associated lesions and compression of neural structures by the DVAs. The imbalance between the inflow and outflow of these lesions, including venous ischaemia, has also been postulated as a cause. Our analysis showed that increased cerebral blood flow (CBF) and cerebral blood volume (CBV) and decreased mean transit time (MTT) and time to peak (TTP) were found in DVAs with micro arteriovenous shunting. DVAs without shunting had raised MTT and TTP instead. CONCLUSION: We postulate that the arteriovenous shunting resulted in arterial steal and chronic hypoxia which could be a pathophysiological mechanism for symptomatic DVAs. CTP and 4D CTA are effective non invasive tools to study DVAs. A classification is proposed. PMID- 24059573 TI - Change in regional cerebral function in l'aquila earthquake survivors with post traumatic stress disorder: preliminary findings. AB - Subjects with post-traumatic stress disorder (PTSD) present a diminished or blunted emotional response, sometimes called "emotional numbing" (EN), that constitutes one of the central symptoms in PTSD. Symptoms of EN include diminished interest in activities, feeling detached or estranged from others, and restricted range of affect (American Psychiatric Association, 2000). The present work studied the emotional components in individuals with PTSD with the principal aim of investigating subjects' functional alteration in the limbic regions, insula and frontal cortex during an emotional task compared with healthy subjects. Ten subjects with PTSD (survivors of the 6.3 magnitude earthquake of April 6, 2009 in L'Aquila) and ten healthy controls underwent fMRI. PTSD was diagnosed according to DSM-IV-R (APA 2000). All subjects underwent fMRI while viewing content-neutral and emotional stimuli. Data analysis revealed that PTSD subjects had significantly greater cerebral activation in particular in the right anterior insula and in bilateral inferior frontal gyrus. Our data suggest that there is a change in the activation of brain areas responsible for emotional processing in patients with PTSD and are consistent with previous findings demonstrating hyperactivation in frontolimbic structures during emotional tasks. Our study suggests that close personal experience may be critical in engaging the neural mechanisms underlying the emotional modulation of memory. Our findings provide evidence that significant alterations in brain function, similar in many ways to those observed in PTSD, can be seen shortly after major traumatic experiences, highlighting the need for early evaluation and intervention for trauma survivors. PMID- 24059574 TI - Challenges for non-invasive brain perfusion quantification using arterial spin labeling. AB - Arterial Spin Labeling (ASL) sequences for perfusion Magnetic Resonance Imaging (MRI) have recently become available to be used in the clinical practice, offering a completely non-invasive technique for the quantitative evaluation of brain perfusion. Despite its great potential, ASL perfusion imaging still presents important methodological challenges before its incorporation in routine protocols. Specifically, in some pathological conditions in which the cerebrovascular dynamics is altered, the standard application of ASL may lead to measurement errors. In these cases, it would be possible to estimate perfusion, as well as arterial transit times, by collecting images at multiple time points and then fitting a mathematical model to the data. This approach can be optimized by selecting a set of optimal imaging time points and incorporating knowledge about the physiological distributions of the parameters into the model estimation procedures. In this study, we address the challenges that arise in the measurement of brain perfusion using PASL, due to variations in the arterial transit times, by estimating the errors produced using different types of acquisitions and proposing methods for minimizing such errors. We show by simulation that multiple inversion time ASL acquisitions are expected to reduce measurement errors relative to standard approaches. In data collected from a group of subjects, we further observed reduced inter-subject variability in perfusion measurements when using a multiple versus single inversion time acquisitions. Both measurement errors and variability were further reduced if optimized acquisition and analysis techniques were employed. PMID- 24059575 TI - Quantification of Perfusion Changes during a Motor Task Using Arterial Spin Labeling. AB - Arterial spin labeling (ASL) is a non-invasive MRI technique that allows the quantitative measurement of perfusion, (regional cerebral blood flow (rCBF)). The ASL techniques use the labeling of the blood, by inverting or saturating the spins of water molecules of the blood supplying the imaged region. When reaching the capillary bed, these will be exchanged with tissue water giving rise to a perfusion-weighted signal. The subtraction of control (without label) from labeled images yields a signal difference that directly reflects the local perfusion. Being a non-invasive method, it can be repeated as many times as needed allowing the brain perfusion variation quantification associated with endogenous and exogenous stimuli. In this study, the authors have evaluated the CBF variation induced by the neural activity during a common motor task. The study was conducted on a Siemens Verio 3T system using a 12-channel head coil and a pulsed ASL Q2TIPS-PICORE sequence with a GE-EPI readout. The sequences were driven in 3D PACE mode for prospective motion correction. Fifteen healthy volunteers were studied using a simple motor task consisting in sequential thumb digit opposition. Two different functional ASL protocols were used: #1 one perfusion scan was obtained during rest and another one during an equal period of motor task (total scan time ~8 min) (TI1 = 700 ms, TI1s = 1600 ms, TI2 =1800 ms; 91 Interleaved tag and control volumes were acquired; TR/TE = 2500/25 ms and flip angle = 90 degrees ; nine contiguous axial slices of 8 mm thickness acquired in line with the AC-PC axis, positioned from the vertex of the brain to the top of cerebellum; FOV = 256 * 256 mm(2); matrix 64 * 64; gap between the labeling slab and the proximal 18.8 mm) and #2 a block design alternating five 25s periods of motor task with five 25s periods of rest (total scan time ~4 min) (TI1 = 700 ms, TI1s = 1600 ms, TI2 = 1800 ms; 101 interleaved tag and control volumes were acquired; TR/TE = 2500/11 ms and flip angle = 90 degrees ; nine contiguous axial slices of 6 mm thickness acquired in-line with the AC-PC axis, positioned from the vertex of the brain to the top of cerebellum; FOV = 256 * 256 mm(2) ; matrix 64 * 64; gap between the labeling slab and the proximal 18.8 mm). The post processing was performed using FSL (www.fmrib.ox.uk/fsl). The mean CBF values obtained for protocols #1 / #2 were: CBFrest = 61.0 / 69.4 ml/100g/min; CBFactivation = 104.8 / 109.9 ml/100g/min; and CBFvariation = CBFactivation - CBFrest = 43.7 / 40.5 ml/100g/min. The relative perfusion changes during activation [defined as CBFvariation / CBFrest (%)] were 73+/-6 % and 62+/-7 % (mean+/-SE) for protocols #1 and #2, respectively. These results show that both activation vs rest and block design functional protocols were capable to detect consistent variations in perfusion associated with a simple motor task. However, the block design has the advantages of requiring shorter acquisitions, directly comparing rest and activation conditions and allowing the acquisition of simultaneous Blood oxygenation level dependent (BOLD) contrast information, while still providing comparable results with the more conventional activation vs rest protocol. In conclusion, our results indicate that a block design ASL-BOLD protocol may be a preferable approach for the evaluation of perfusion changes to endogenous stimuli. PMID- 24059576 TI - MR Imaging in Multiple Sclerosis: The Accuracy of 3D Double Inversion Recovery at 3 Tesla and the Potential for Single Sequence Imaging. AB - To compare the accuracy of a three dimensional, T2-weighted double inversion recovery (DIR) sequence with two dimensional fluid attenuated inversion recovery (FLAIR) and dual echo T2 (DE T2) sequences at 3 Tesla in the detection of intracranial demyelinating lesions in patients with known or suspected multiple sclerosis (MS), and to consider the appropriateness of a stand-alone DIR sequence in MS imaging. The studies of 98 patients who underwent imaging with DE T2, FLAIR and DIR sequences for known or suspected multiple sclerosis were retrospectively reviewed. In 42 cases, a diagnosis of MS had been clinically suspected. In the remaining 56 cases, a diagnosis of MS had been previously established. All patients were imaged on a 3T MRI unit. Coronal and sagittal FLAIR, axial DE T2, and three dimensional T2-weighted DIR sequences were utilised. Of the 42 patients with suspected multiple sclerosis, 11 demonstrated lesions characteristic of the disease. Demyelinating plaques were seen in all of the 56 patients with known MS. In all cases, all lesions seen on DE T2-or FLAIR sequences were visible and more conspicuous on the DIR sequence. In 22 of the 67 patients (33%) with demyelinating lesions, the DIR sequence showed additional lesions not visible on any of the other sequences. Additional detected lesions predominantly involved grey matter. At 3 Tesla, a T2 weighted, three dimensional DIR sequence is as accurate at detecting the presence of intracranial demyelinating lesions as two dimensional FLAIR and DE T2 sequences combined. A greater number of lesions were detected with the DIR sequence, and all lesions were more conspicuous. A single, stand alone DIR sequence may be considered appropriate for monitoring MS. PMID- 24059577 TI - 3.0T MR Imaging of the Cranial Arterial Wall for the Strategy of Stroke Prevention. AB - 3.0T refined MRI reveals the anatomical structures clearly. Operative findings correspond well with MRI findings. The authors have used this equipment for prevention of stroke. Especially evaluation of the arterial wall is important for this purpose. Showing illustrative cases including operative ones, the authors discuss the MRI findings and strategy of treatment. The examinations of the Carotid artery (CA) and vertebro-basilar artery (VBA) were performed with 3.0T MRI (Philips Achiva 3.0T, Holland). Specialized sequences for each arterial wall were planned after TOF-MRA screening. The sequences include T1, T2 VISTA (3D Fatsaturation Volume ISotropic Turbospinecho Acquisition), mPROSET (Multiple Principle Selective Excitation Technique), B-FFE(Balanced Fast Field Echo) and T1 and T2 Black Blood. Intentionally directed pictures were acquired with reconstruction. Components of the plaque were estimated with the combination of the intensity of each picture. Distributions of carotid plaques were well demarcated and its components were diagnosed. Prognosis of each plaque was estimated and the surgical and/or non-surgical treatment plan was secured. Preoperative MRI plaque findings and the specimens from carotid endarterectomy (CEA) correlated well. The stability of the plaque could be evaluated, which afforded the decision of timing and method of operation. Lacerated walls of VBA dissection were well illustrated and strategies were planned. Intra-aneurysmal thrombus was revealed and its development was imaged. The wall of the unruptured aneurysm could be evaluated but not always. 3.0T MRI provides more anatomical and pathological information than conventional MRI. Prognosis of each lesion could be estimated. Routine examination of the cranial arterial wall contributes to the prevention of stroke. PMID- 24059578 TI - The effect of spatial resolution on wall shear stress measurements acquired using radial phase contrast magnetic resonance angiography in the middle cerebral arteries of healthy volunteers. Preliminary results. AB - We have recently implemented radial phase-contrast techniques that allow high resolution angiograms with velocity information to be acquired within clinically useful imaging times. 10 healthy volunteers were scanned using PC-VIPR and PC SOS, two high resolution phase-contrast techniques at spatial resolutions of 0.67*0.67*0.67 mm(3) and 0.4*0.4*1 mm(3) respectively. The velocity measurements from the two acquisitions were imported into a custom Matlab runtime environment that automatically calculated WSS values using Green's Theorem and B-spline interpolation. Time average axial WSS was 1.069 N/m(2) (95% confidence interval: 0.8628< x < 1.276) in the left and right middle cerebral arteries of the 10 healthy volunteers (n=20) when scanned by PC-VIPR, and 1.670 N/m(2) when scanned by PC-SOS (95% confidence interval: 1.395 < x < 1.946). This difference in means was statistically significant (p < 0.002). Previous investigators have found that higher spatial resolution results in higher WSS measurements because smaller voxel size results in fewer partial volume effects. This was true in our study as well. In this study, we found that PC-SOS has significantly higher spatial resolution than PC-VIPR and this followed in the WSS measurements. Higher in plane spatial resolution allows WSS calculations to be performed more accurately because of increased precision near the vessel boundary. PMID- 24059579 TI - Susceptibility weighted imaging and cerebrovascular disorders. AB - To investigate the correlation between the SWI findings and prognosis of the cerebrovascular disorders. From July 2008 to July 2010, 299 ischemic stroke patients were found in our hospital. The gender ratio is as male and female being 157 to 142. The mean age of all patients is 65.4, mean female age is 69.1, and mean male age is 62.6. There were 86 patients who had satisfactory pre-and post treatment of CT, MRI with SWI. 23 of these 86 patients had catheter cerebral angiography. 50 of these 86 patients had MR angiogram or CT angiogram. 13 of these 86 patients did not have angiogram. We have also collected 7 severe cardiac arrested and cessation of cerebral circulation and 2 patients with chronic venous hypertension. Among the 86 patients, 23 patients who had negative with deoxygenated vessel on SWI were with small infarction on DWI. Thirty-one patients had negative on initial CT head scan. CT finding did not accord with presence of hypointense vessel on SWI. Sixty-three patients had varied degree of abnormal hypointense vessels on SWI as deoxygenated vessels. The initial small foci on DWI may result with a larger infarction if there were with prominent hypointense vessels. PMID- 24059580 TI - Correlative ROI Calculation of MCAs: Another Promising Primary Sign of Acute Infarction? AB - The purpose of this project was to calculate the ROI of the middle cerebral artery (MCA) in patients with acute stroke to establish if this measurement could be used as another primary sign of infarction even if other established primary signs of infarction are absent. CT brain scans of 465 patients, who presented in the emergency room in the first six hours after the onset of symptoms, were studied retrospectively. Two polygonal ROIs were drawn on the M1 segments of both middle cerebral arteries and three parameters were calculated automatically: HU density, volume and surface of the corresponding artery segment. The age and gender of each patient were also recorded, as well as the CT findings (including the hyperdense appearance of MCA and the insular ribbon sign) and the neurological findings. The range of calculated ROIs was between 9 HU and 134 HU. A statistically significant difference was reported in ROI measurement between the right and left MCA in patients with left (or right) hemiparesis respectively. A significant difference was also reported between the ROIs of the right and left MCA in patients with acute ischemic stroke in the region of the brain supplied by the left (or right) MCA respectively. ROI measurement of MCA is easy to apply and interpret during the CT scan and might serve as an additional primary sign of infarction. PMID- 24059581 TI - Use of cervical spinal cord stimulation in treatment and prevention of arterial vasospasm after aneurysmal subarachnoid hemorrhage. Technical details. AB - Based on past laboratory and anecdotal clinical experience, we hypothesized that prolonged cervical spinal cord stimulation (SCS) in the acute settings of aneurysmal subarachnoid hemorrhage (aSAH) would be both safe and feasible, and that 2-week stimulation will reduce incidence of cerebral arterial vasospasm. The goal of our clinical study was to establish feasibility and safety of cervical SCS in a small group of selected aSAH patients. Single-arm non-randomized prospective study of cSCS in aSAH patients involved percutaneous implantation of 8-contact electrode in 12 consecutive aSAH patients that satisfied strict inclusion criteria. The electrode insertion was performed immediately upon surgical or endovascular securing of the ruptured aneurysm while the patient was still under general anesthesia. Patients were stimulated for 14 consecutive days or until discharge. There were no complications related to the electrode insertion or to SCS during the study and no long-term side effects of SCS during 1-year follow-up. There was 1 unrelated death and two electrode pullouts. This article summarizes technical details of SCS electrode insertion and the stimulation parameters used in the research study. Our study of SCS for prevention of vasospasm after aSAH conclusively shows both safety and feasibility of this promising treatment approach. Despite high level of acuity in aSAH patients, impaired level of consciousness, frequent patient re-positioning, need in multiple tests and variety of monitors, SCS electrodes may be safely implanted and maintained for the two-week period. Long-term follow up shows no adverse effects of cervical SCS in this patient category. PMID- 24059582 TI - Venous hypertension and cerebral aneurysm rupture. AB - To investigate the correlation between the sinus asymmetry and aneurysm rupture. We retrospectively reviewed all diagnostic and therapeutic conventional angiograms of patients with cerebral aneurysms in our hospital from January 2000 to April 2008. Cases were categorized according to gender, presence or absence of aneurysm rupture, and presence or absence of symmetric dural sinuses. Exclusion criteria included patients with underlying fibromuscular dysplasia, dissecting aneurysms, pseudoaneurysms, and the presence of arteriovenous malformations or fistulas. The venous pressure was measured by MR phase contrast with standard fluid dynamics notation as Poiseuille's Law. A total of 193 cases (131 females and 62 males) were included for Chi-squared analysis, which showed significant difference (p < 0.05) between aneurysm rupture and venous asymmetry in the entire group as well as in females, but not in males. There was an association between side of rupture and side of asymmetry as well as between the size of hemorrhage. Ruptured aneurysm is more frequent at the same side of dominant dural sinus than the side of hypoplasia venous sinus. MRA phase contrast is able to show the venous pressure gradient of asymmetrical dural sinuses. With our preliminary data, we propose that dural sinus asymmetry is associated with aneurysm rupture. PMID- 24059583 TI - Intravenous Glycoprotein IIb/IIIa inhibitor (Tirofiban) Followed by Low-dose Intra-arterial Urokinase and Mechanical Thrombolysis for the Treatment of Stroke. AB - We investigated the efficacy and safety of the combined use of IV tirofiban and IA urokinase and/or mechanical thrombolysis for treating acute stroke patients. Thirteen, consecutive patients who were treated with IV tirofiban and IA thrombolysis with mechanical and/or local IA urokinase infusion, were evaluated retrospectively. The amount of time before the beginning of treatment, urokinase dose, recanalization rates, and symptomatic hemorrhage were analyzed. Clinical outcome measures were assessed on admission, at discharge (National Institute of Health Stroke scale[NIHASS]), and three months after the end of their treatment (modified Rankin Scale scores[mRS]). There were 11 patients with internal carotid or middle cerebral artery occlusion treated within six hours of the onset of symptoms and two patients with basilar artery occlusion treated within 12 hours of their symptom onset. The median NIHSS score on admission was 18. The median amount of time from symptom onset to IV tirofiban infusion was 135 minutes, and the median time from symptom onset to IA therapy was 180 minutes. The median dose of urokinase was 200,000 U. Recanalization (thrombolysis in myocardial infarction grade 2 or 3) was achieved in 11 patients. No procedure-related complications were observed. There was one symptomatic hemorrhage. At discharge, the mean NIHSS score was 6.6 (range, 0- 15). Overall, at the time of the three-month follow-up the functional outcome was favorable (modified Rankin Scale score 0 -2) in eight of 13 (62%) patients. Death at 90 days occurred in two of the 13 (15%) patients. Combined IV tirofiban and IA thrombolysis with mechanical clot disruption seems to be a feasible treatment in acute stroke and may be successful in reestablishing vessel patency and result in a good functional outcome in patients with major cerebral arteries occlusions. PMID- 24059584 TI - Real-time prostate motion assessment: image-guidance and the temporal dependence of intra-fraction motion. AB - BACKGROUND: The rapid adoption of image-guidance in prostate intensity-modulated radiotherapy (IMRT) results in longer treatment times, which may result in larger intrafraction motion, thereby negating the advantage of image-guidance. This study aims to qualify and quantify the contribution of image-guidance to the temporal dependence of intrafraction motion during prostate IMRT. METHODS: One hundred and forty-three patients who underwent conventional IMRT (n=67) or intensity-modulated arc therapy (IMAT/RapidArc, n=76) for localized prostate cancer were evaluated. Intrafraction motion assessment was based on continuous RL (lateral), SI (longitudinal), and AP (vertical) positional detection of electromagnetic transponders at 10 Hz. Daily motion amplitudes were reported as session mean, median, and root-mean-square (RMS) displacements. Temporal effect was evaluated by categorizing treatment sessions into 4 different classes: IMRTc (transponder only localization), IMRTcc (transponder + CBCT localization), IMATc (transponder only localization), or IMATcc (transponder + CBCT localization). RESULTS: Mean/median session times were 4.15/3.99 min (IMATc), 12.74/12.19 min (IMATcc), 5.99/5.77 min (IMRTc), and 12.98/12.39 min (IMRTcc), with significant pair-wise difference (p<0.0001) between all category combinations except for IMRTcc vs. IMATcc (p>0.05). Median intrafraction motion difference between CBCT and non-CBCT categories strongly correlated with time for RMS (t-value=17.29; p<0.0001), SI (t-value=-4.25; p<0.0001), and AP (t-value=2.76; p<0.0066), with a weak correlation for RL (t-value=1.67; p=0.0971). Treatment time reduction with non-CBCT treatment categories showed reductions in the observed intrafraction motion: systematic error (Sigma)<0.6 mm and random error (sigma)<1.2 mm compared with <=0.8 mm and <1.6 mm, respectively, for CBCT-involved treatment categories. CONCLUSIONS: For treatment durations >4-6 minutes, and without any intrafraction motion mitigation protocol in place, patient repositioning is recommended, with at least the acquisition of the lateral component of an orthogonal image pair in the absence of volumetric imaging. PMID- 24059585 TI - Menstrual phase, depressive symptoms, and allopregnanolone during short-term smoking cessation. AB - Preclinical literature indicates that allopregnanolone (ALLO), a neuroactive steroid metabolized from progesterone, may protect against drug abuse behaviors. It is important to understand how ALLO varies during smoking changes in clinical samples with depressive symptoms (DS) given they are at high risk of smoking relapse. The purpose of this article is to characterize changes in ALLO by menstrual phase during short-term smoking cessation among women with and without DS. At screening, study participants (n = 84) were classified as either having past or current DS (n = 48) or not (n = 36). In a controlled crossover trial design, participants completed 2 testing weeks in the follicular (F; low ALLO) and luteal (L; high ALLO) menstrual phases. During each testing week, blood samples were collected during ad libitum smoking and on the fourth day of biochemically verified smoking abstinence. Participants were, on average, 30.1 +/ 6.7 years old, smoked 12.6 +/- 5.7 cigarettes per day, and most (73%) were White. The change in ALLO during short-term smoking cessation varied significantly by menstrual phase such that it decreased by 10% in the follicular phase and increased by 31% in the luteal phase. There were no significant differences in ALLO levels by DS group. In premenopausal women, ALLO levels varied by menstrual phase and smoking status, but not DS. Given that other research has indicated L phase is associated with improved smoking cessation outcomes, an increase in ALLO during short-term cessation in the L phase may protect against relapse whereas a decrease in ALLO, as observed in the F phase, may increase risk for relapse. PMID- 24059586 TI - Covalent binding and anchoring of cytochrome c to mitochondrial mimetic membranes promoted by cholesterol carboxyaldehyde. AB - Mitochondrial cholesterol has been reported to be increased under specific pathological conditions associated with enhanced oxidative stress parameters. In this scenario, cholesterol oxidation would be increased, leading to the production of reactive aldehydes, including cholesterol carboxyaldehyde (ChAld). By using SDS micelles as a mitochondrial mimetic model, we have demonstrated that ChAld covalently modifies cytochrome c (cytc), a protein known to participate in electron transport and apoptosis signaling. This mimetic model induces changes in cytc structure in the same way as mitochondrial membranes do. Tryptic digestion of the cytc-ChAld adduct followed by MALDI-TOF/TOF analyses revealed that modifications occur at Lys residues (K22) localized at cytc site L, a site involved in protein-protein and protein-membrane interactions. Interestingly, ChAld ligation prevented cytc detachment from liposomes even under high ionic strength conditions. Overall, it can be concluded that ChAld ligation to Lys residues at site L creates a hydrophobic tail at cytc, which promotes cytc anchoring to the membrane. Although not investigated in detail in this study, cytc adduction to cholesterol derived aldehydes could have implications in cytc release from mitochondria under apoptotic stimuli. PMID- 24059587 TI - microRNA in the development of diabetic complications. AB - Today's world population is currently faced with a new type of non-transmissible pandemic: obesity. This lifestyle-related condition is driving the emergence of the diabetes pandemic through the development of low-level chronic inflammation. In recent years, a novel class of non-coding RNA, microRNA (miRNA), have emerged as being important regulators of numerous biological functions. Among these functions are basic maintenance of cell signalling and tissue architecture. Disruption of miRNA levels can contribute not only to the development of the chronic inflammation observed in obese diabetics, but also the development of both pancreatic beta-cell dysfunction and loss, along with insulin resistance in metabolic tissues. These primary events set the scene for dysfunction of other tissues, including the retina, kidney, peripheral nerves, heart and the vasculature as a whole. Here, miRNAs again play a deterministic role in the development of a range of diseases collectively termed diabetic complications. Disturbances in miRNA levels appear to be reflected in the serum of patients and this may prove to be diagnostic in patients prior to clinical manifestation of disease, thus improving management of diabetes and its associated complications. Not only are miRNAs displaying promise as an early biomarker for disease, but a number of these miRNAs are displaying therapeutic potential with several in pre clinical development. The present review aims to highlight our current understanding of miRNAs and their interaction with inflammatory signalling in the development and progression of diabetes and its complications. Utilization of miRNAs as biomarkers and therapeutic targets will also be considered. PMID- 24059588 TI - New roles for old pathways? A circuitous relationship between reactive oxygen species and cyclo-oxygenase in hypertension. AB - Elevated production of prostanoids from the constitutive (COX-1) or inducible (COX-2) cyclo-oxygenases has been involved in the alterations in vascular function, structure and mechanical properties observed in cardiovascular diseases, including hypertension. In addition, it is well known that production of ROS (reactive oxygen species) plays an important role in the impaired contractile and vasodilator responses, vascular remodelling and altered vascular mechanics of hypertension. Of particular interest is the cross-talk between NADPH oxidase and mitochondria, the main ROS sources in hypertension, which may represent a vicious feed-forward cycle of ROS production. In recent years, there is experimental evidence showing a relationship between ROS and COX-derived products. Thus ROS can activate COX and the COX/PG (prostaglandin) synthase pathways can induce ROS production through effects on different ROS generating enzymes. Additionally, recent evidence suggests that the COX-ROS axis might constitute a vicious circle of self-perpetuating vasoactive products that have a pathophysiological role in altered vascular contractile and dilator responses and hypertension development. The present review discusses the current knowledge on the role of oxidative stress and COX-derived prostanoids in the vascular alterations observed in hypertension, highlighting new findings indicating that these two pathways act in concert to induce vascular dysfunction. PMID- 24059589 TI - Genetic, epigenetic and stem cell alterations in endometriosis: new insights and potential therapeutic perspectives. AB - Human endometrium is a highly dynamic tissue, undergoing periodic growth and regression at each menstrual cycle. Endometriosis is a frequent chronic pathological status characterized by endometrial tissue with an ectopic localization, causing pelvic pain and infertility and a variable clinical presentation. In addition, there is well-established evidence that, although endometriosis is considered benign, it is associated with an increased risk of malignant transformation in approximately 1.0% of affected women, with the involvement of multiple pathways of development. Increasing evidence supports a key contribution of different stem/progenitor cell populations not only in the cyclic regeneration of eutopic endometrium, but also in the pathogenesis of at least some types of endometriosis. Evidence has arisen from experiments in animal models of disease through different kinds of assays (including clonogenicity, the label-retaining cell approach, the analysis of undifferentiation markers), as well as from descriptive studies on ectopic and eutopic tissue samples harvested from affected women. Changes in stem cell populations in endometriotic lesions are associated with genetic and epigenetic alterations, including imbalance of miRNA expression, histone and DNA modifications and chromosomal aberrations. The present short review mainly summarizes the latest observations contributing to the current knowledge regarding the presence and the potential contribution of stem/progenitor cells in eutopic endometrium and the aetiology of endometriosis, together with a report of the most recently identified genetic and epigenetic alterations in endometriosis. We also describe the potential advantages of single cell molecular profiling in endometrium and in endometriotic lesions. All these data can have clinical implications and provide a basis for new potential therapeutic applications. PMID- 24059591 TI - Tautomers and UV-induced photoisomerization of a strongly intramolecularly H bonded aromatic azo-dye: 1-(cyclopropyl)diazo-2-naphthol. AB - Aromatic azo compounds have a wide range of industrial applications as dyes in optical and color-changing materials and can also be exploited in the design of new photodynamic molecular systems. The azo derivative 1-(cyclopropyl)diazo-2 naphthol was isolated in low-temperature cryogenic matrices, and its molecular structure, tautomeric equilibrium, and photochemical transformations were characterized by infrared spectroscopy and theoretical calculations. Only azo enol forms having the OH group involved in a strong intramolecular hydrogen bond, forming a six-membered ring with the azo group, were found experimentally. Irradiation with a narrowband source in the near-UV range generates different rotameric and tautomeric azo-enol and keto-hydrazone forms that can be interconverted at different irradiation wavelengths. PMID- 24059590 TI - The TCF7L2 rs7903146 (T) allele is associated with type 2 diabetes in urban Ghana: a hospital-based case-control study. AB - BACKGROUND: Type 2 diabetes mellitus is increasing dramatically in sub-Saharan Africa, and genetic predisposition is likely involved in that. Yet, genetic variants known to confer increased susceptibility among Caucasians are far from being established in African populations. In Ghanaian adults, we examined associations of several of these polymorphisms with type 2 diabetes. METHODS: A hospital-based case-control study on type 2 diabetes (and hypertension) was conducted in Kumasi, Ghana. TCF7L2 rs7903146, KCNJ11 rs5219, PPARgamma rs1801282 and CAPN10 rs3842570, rs3792267, and rs5030952 were typed and associations with type 2 diabetes and phenotypic traits examined. RESULTS: 675 patients with type 2 diabetes and 377 controls were compared. The minor allele frequency of the TCF7L2 (T) allele was 0.33. In the multivariate model, this allele increased the risk of type 2 diabetes by 39% (95% confidence interval (CI), 1.07-1.81; p = 0.014). The minor alleles KCNJ11 (G) and PPARgamma (G) were practically absent (each, 0.001). Minor allele frequencies of CAPN10 were for -43 (A) 0.11 and for -63 (C) 0.46. These variants showed no significant associations with type 2 diabetes. Two CAPN10 haplotypes tended to protect against type 2 diabetes: 211 (aOR, 0.32; 95% CI, 0.03-1.92; p = 0.31) and 221 (aOR, 0.73; 95% CI, 0.48-1.10; p = 0.13). CONCLUSIONS: In urban Ghana, the frequency of the TCF7L2 rs7903146 (T) allele is comparable to the one in Caucasians; the association with type 2 diabetes is slightly weaker. The risk allele KCNJ11 (G) and the protective allele PPARgamma (G) are virtually absent. The potential influence of comparatively rare CAPN10 haplotypes on type 2 diabetes risk in this population requires further evaluation. Large-scale genetic studies among native Africans aiming at fine mapping the candidate genes are needed to identify the actual factors involved in their increased susceptibility to type 2 diabetes. PMID- 24059592 TI - Al-Akhawayni, a contributor to medieval Persian knowledge on contraception. AB - Modern scientific achievements in the field of contraception are clearly indebted to past studies. Al-Akhawayni Bukhari was a Persian physician in the 10th century. He lived during the 'Golden Age of Islamic Medicine' (9th to 12th century AD). This scientist recorded his knowledge on various medical matters, including contraception, in the book 'Hidayat al-Muta'allemin Fi al-Tibb' (Learner's Guide to Medicine). These 10th century views on contraception are explored in this paper through a discussion of Al-Akhawayni Bukhari's surviving book, the 'Hidayat' (Guide). PMID- 24059594 TI - Pillar[5]arene as a co-factor in templating rotaxane formation. AB - After the manner in which coenzymes often participate in the binding of substrates in the active sites of enzymes, pillar[5]arene, a macrocycle containing five hydroquinone rings linked through their para positions by methylene bridges, modifies the binding properties of cucurbit[6]uril, such that the latter templates azide-alkyne cycloadditions that do not occur in the presence of only the cucurbit[6]uril, a macrocycle composed of six glycoluril residues doubly linked through their nitrogen atoms to each other by methylene groups. Here, we describe how a combination of pillar[5]arene and cucurbit[6]uril interacts cooperatively with bipyridinium dications substituted on their nitrogen atoms with 2-azidoethyl- to 5-azidopentyl moieties to afford, as a result of orthogonal templation, two [4]rotaxanes and one [5]rotaxane in >90% yields inside 2 h at 55 degrees C in acetonitrile. Since the hydroxyl groups on pillar[5]arene and the carbonyl groups on cucurbit[6]uril form hydrogen bonds readily, these two macrocycles work together in a cooperative fashion to the extent that the four conformational isomers of pillar[5]arene can be trapped on the dumbbell components of the [4]rotaxanes. In the case of the [5]rotaxane, it is possible to isolate a compound containing two pillar[5]arene rings with local C5 symmetries. In addition to fixing the stereochemistries of the pillar[5]arene rings, the regiochemistries associated with the 1,3-dipolar cycloadditions have been extended in their constitutional scope. Under mild conditions, orthogonal recognition motifs have been shown to lead to templation with positive cooperativity that is fast and all but quantitative, as well as being green and efficient. PMID- 24059593 TI - Characterization of structural stability of palm oil esters-based nanocosmeceuticals loaded with tocotrienol. AB - BACKGROUND: Palm oil esters (POEs) are esters derived from palm oil and oleyl alcohol have great potential in the cosmetic and pharmaceutical industries due to the excellent wetting behavior of the esters without the oily feel. The role of oil-in-water nanoemulsions loaded with tocotrienol sedimentation behavior was studied. LUMiFuge(r) 116 particle separation analyzer was used to investigate the sedimentation behavior of POEs/tocotrienol/xanthan gum nanoemulsion system during centrifugation. Analyzing the sedimentation kinetics of dispersions in a centrifugal field also yields information about the rheological behavior and structural stability. METHODS: Experiments were performed in an analytical centrifuge at 11 * g to 1140 * g (LUMiFuge(r) 116 particle separation analyzer). The samples in the LUMiFuge(r) 116 particle separation analyzer were centrifuged at 3000 rpm for 15 h at 32 degrees C. Sample volume of 2 cm3 was used. The rheological property of nanoemulsions was investigated using oscillatory measurements test. A rotational/oscillatory viscometer, Kinexus Rheometer (Malvern Instrument, UK) was used. All measurements were performed with a stainless steel cone-plate sensor at 25.0 +/- 0.1 degrees C with 4 degrees /40 mm. RESULTS: The stable nanoemulsions showed sedimentation rates at earth gravity of 5.2, 3.0 and 2.6 mm/month for 10%, 20% and 30% (w/w) oil phase, respectively. Rheological behavior is an important target during the design of palm oil esters based nanocosmeceuticals. The presence of a network structure was indicated by measurements which showed G' to be greater than G". This result implied the predominant elastic response and high storage stability of the nanoemulsion. It was also observed that the increase in oil phase concentration led to the profile which strongly indicated that the solid like elastic property; where the values of phase angle, delta of these nanoemulsions was lower than 45 degrees . CONCLUSIONS: The nanoemulsions with higher oil phase concentration (30% (w/w)) showed greater elasticity which implied strong dynamic rigidity of the nanoemulsion. It was the most stable with longest shelf-life. PMID- 24059595 TI - Design and implementation of frequency-following response recording system. AB - OBJECTIVE: The frequency-following response (FFR) is the compound phase-locked brainstem response to periodic components of sound stimuli, and is closely related to pitch perception. Its weak amplitude often prevents its measurement with a high signal-to-noise ratio (SNR). Recording of FFR using multichannel EEG is possible but expensive and it involves the manual screening of raw data. DESIGN: We describe a new method to extract FFR features by prescreening the raw data using automatic monitoring of sound pressure in the ear canal. Removal of stimulus artifacts, noise reduction, and data selection were systematically studied. STUDY SAMPLE: The reliability of our new method was tested by comparing FFRs tracking accuracy and pitch perception in fifteen individuals with normal hearing. RESULTS: The extracted FFRs tracking accuracy was significantly correlated with behavioral measures of pitch perception, indicating that FFR could be used to represent individual differences in pitch perception ability among a population with similar hearing characteristics. CONCLUSION: The designed system could extract FFR signals more accurately with high SNR after signal prescreen and noise reduction. PMID- 24059596 TI - Automated hearing screening for children: A pilot study in China. AB - OBJECTIVE: To establish the reliability and validity of an automated hearing screening test system for children. DESIGN: Cross-sectional within a comparative study of subjects. STUDY SAMPLE: Subjects were 325 first-grade and second-grade children (6-10 years old) from primary schools in Shenzhen, China. RESULTS: Using the conventional pure-tone screening test with the pass/refer criterion set as 25 dB HL, as the 'gold standard", the sensitivity and specificity of the automated hearing screening test was 0.63 and 0.82, respectively. No specific pattern in the failure rates was observed to relate to the students' grade. There was no statistically significant age effect or gender effect. CONCLUSIONS: The results suggest that with further improvement in terms of its sensitivity and specificity, it may be feasible to use the automated hearing screening test system to conduct routine school hearing screenings. PMID- 24059599 TI - Controlling subnanometer gaps in plasmonic dimers using graphene. AB - Graphene is used as the thinnest possible spacer between gold nanoparticles and a gold substrate. This creates a robust, repeatable, and stable subnanometer gap for massive plasmonic field enhancements. White light spectroscopy of single 80 nm gold nanoparticles reveals plasmonic coupling between the particle and its image within the gold substrate. While for a single graphene layer, spectral doublets from coupled dimer modes are observed shifted into the near-infrared, these disappear for increasing numbers of layers. These doublets arise from charger-transfer-sensitive gap plasmons, allowing optical measurement to access out-of-plane conductivity in such layered systems. Gating the graphene can thus directly produce plasmon tuning. PMID- 24059598 TI - Measuring the incidence and reporting of violence against women and girls in liberia using the 'neighborhood method'. AB - BACKGROUND: This paper reports on the use of a "neighborhood method" to measure the nature and incidence of violence against women and girls in post-conflict Liberia. METHODS: The study population comprised females in Montserrado and Nimba counties. Study participants were randomly selected for interviews using multi stage cluster sampling. 30 clusters of households were sampled in each county. Information on incidents of domestic violence and rape within the preceding 18 months was collected with regard to females of all ages in the respondent's household, and those of her four closest neighbors to make up the full sample. FINDINGS: Households in the sample contained 7015 females (1687 girls, 4586 women, 742 age missing) in Montserrado and 6632 (2070 girls, 4167 women, 95 age missing) in Nimba. In the previous 18 months 54.1% (CI 53.1-55.1) and 55.8% (CI 54.8-56.8) of females in Montserrado and Nimba respectively were indicated to have experienced non-sexual domestic abuse; 19.4% (CI 18.6-20.2) and 26.0% (CI 25.1-26.9) of females in Montserrado and Nimba respectively to have been raped outside of marriage; and 72.3% (CI 70.7-73.9) and 73.8% (CI 72.0-75.7) of married or separated women in Montserrado and Nimba respectively to have experienced marital rape. Husbands and boyfriends were reported as the perpetrators of the vast majority of reported violence. Strangers were reported to account for less than 2% of the perpetrators of rape in either county. Incidents were most commonly disclosed to other family members or to friends and neighbors, and less often to formal authorities such as the police, court or community leaders. Incidents were approaching fifty times more likely to be reported to police if perpetrated by strangers rather than intimate partners. CONCLUSIONS: Violence against women and girls is widespread in the areas studied. Programming needs to address the fact that this violence is primarily occurring in the household, where most incidents go unreported outside the immediate family or social circle. Police and hospital reports severely under-represent these known perpetrators. Inter-interviewer variance and differences in reports for self and neighbors for some outcomes caution the precision and validity of some estimates. However, the potential utility of the neighborhood method for estimating prevalence rates with an accuracy suitable for programmatic purposes in conflict-affected and post conflict settings is noted. PMID- 24059600 TI - Secondary cytoreduction surgery improves prognosis in platinum-sensitive recurrent ovarian cancer. AB - BACKGROUND: There is no consensus regarding the secondary cytoreduction surgery (CRS) in recurrent ovarian cancer patients. The present study aims to determine the value of secondary CRS and the eligible subgroup for this procedure. METHODS: 96 platinum-sensitive recurrent ovarian cancer patients were recruited from Jiangsu Institute of Cancer Research between 1992 and 2011. Follow-up was conducted based on the surveillance protocol of MD Anderson Cancer Center. Cox proportional hazards model and log-rank test were used to assess the associations between the survival durations and covariates. Logistic regression analysis was used to explore optimal secondary CRS related factors. RESULTS: Optimal secondary CRS was associated with time to progression (TTP) and overall survival (OS) in patients (p < 0.01 both). Optimal secondary CRS and asymptomatic recurrent were similarly associated with longer OS (median: 79.2 vs. 53.9 and 76.1 vs. 56.0 months with p = 0.02 and p = 0.04, respectively) and TTP (median: 13.9 vs. 10.5 and 19.3 vs. 9.0 months with p = 0.02 and p = 0.03, respectively) than counterparts. Optimal initial CRS (p = 0.01), asymptomatic recurrent (p = 0.02) and longer progression-free survival duration (p = 0.02) were the independent indicators of optimal secondary CRS. CONCLUSIONS: Optimal secondary CRS had survival benefit for platinum-sensitive epithelial ovarian cancer. Asymptomatic recurrent was one of the recruited factors for this procedure. PMID- 24059601 TI - Successful use of a military-grade haemostatic agent for a major head and neck bleed. AB - BACKGROUND: Major haemorrhage is a catastrophic complication occurring in 3-4 per cent of head and neck cancer patients. Massive haemorrhage also causes 50 per cent of preventable deaths in combat situations. There has been a surge of interest in the development of effective haemostatic products in the military, with chitosan being one such product. CASE REPORT: A 48-year-old lady presented with a life-threatening head and neck bleed. She was known to have a malignant peripheral nerve sheath sarcoma originating from the left parapharyngeal space. Bleeding was successfully controlled with the application of CeloxTM granules, a chitosan-based product currently used in the military. CONCLUSION: This paper describes the first known use of a military haemostatic agent to control a malignant head and neck bleed. Celox granules can be poured directly onto a wound to enhance haemorrhage control. The suggested mechanism of action and reports of current uses of haemostatic agents are described. PMID- 24059603 TI - Bench to business: a framework to assess technology readiness. PMID- 24059604 TI - The Anatomy of the Medial Lemniscus within the Brainstem Demonstrated at 3 Tesla with High Resolution Fat Suppressed T1-Weighted Images and Diffusion Tensor Imaging. AB - The medial lemniscus is part of the main somatosensory pathways ascending within the brainstem. It is formed by the heavily myelinated axons of the second order neurones of the dorsal column nuclei. This pathway ascends through the rostral medulla, pons and mesencephalon to finally terminate by synapsing with third order neurones in the ventral posterior nucleus of the thalamus. The medial lemniscus conveys proprioception and fine tactile discrimination as part of the somatosensory system. Conventional MRI studies of the brainstem have been relatively poor in demonstrating these fibre pathways. Diffusion tensor imaging and tractography may demostrated fibre pathways in the brainstem. These techniques do however suffer from relatively poor spatial resolution and some degree of image distortion - especially if based on echo planar imaging techniques. Knowledge of the anatomical relationships of the medial lemniscus is important for the understanding of clinical manifestations of disease processes affecting the somatosensory pathways and also to demonstrate important adjacent structures. Specifically, the pedunculopontine nucleus (PPN) lies in close anatomical relationship to the medial lemniscus and the decussation of the superior cerebellar peduncle. This nucleus is a promising target for deep brain stimulator placement for alleviation of non-dopamine responsive dystonias. Six healthy male volunteers (mean age 33 years) were imaged at 3 Tesla. Imaging protocols consisted of thin section, high resolution, fat suppressed T1-weighted sequences as well as thin section, high isotropic resolution diffusion tensor imaging (DTI), which was analysed to generate colour fractional anisotropy (FA) maps. These were correlated with the fat suppressed T1 weighted images. In all volunteers the medial lemniscus was seen as a pair of bands of low signal on axial, high resolution, fat suppressed T1-weighted images. They were indentified through the upper medulla, pons and mesencephalon. They correlated well with the head to foot orientated fibres on the colour FA maps generated from the DTI data. This study of normal volunteers has illustrated the value of high resolution, fat suppressed T1-weighted images in demonstrating the anatomy of the heavily myelinated medial lemniscus within the brainstem. These high resolution images with good spatial accuracy can potentially be used to aid the localisation of other nuclei, such as the PPN. PMID- 24059602 TI - Perineal Assessment and Repair Longitudinal Study (PEARLS): a matched-pair cluster randomized trial. AB - BACKGROUND: Perineal trauma during childbirth affects millions of women worldwide every year. The aim of the Perineal Assessment and Repair Longitudinal Study (PEARLS) was to improve maternal clinical outcomes following childbirth through an enhanced cascaded multiprofessional training program to support implementation of evidence-based perineal management. METHODS: This was a pragmatic matched-pair cluster randomized controlled trial (RCT) that enrolled women (n = 3681) sustaining a second-degree perineal tear in one of 22 UK maternity units (clusters), organized in 11 matched pairs. Units in each matched pair were randomized to receive the training intervention either early (group A) or late (group B). Outcomes within each cluster were assessed prior to any training intervention (phase 1), and then after the training intervention was given to group A (phase 2) and group B (phase 3). Focusing on phase 2, the primary outcome was the percentage of women who had pain on sitting or walking at 10 to 12 days post-natal. Secondary outcomes included use of pain relief at 10 to 12 days post natal, need for suture removal, uptake and duration of exclusive breastfeeding, and perineal wound infection. Practice-based measures included implementation of evidence into practice to promote effective clinical management of perineal trauma. Cluster-level paired t-tests were used to compare groups A and B. RESULTS: There was no significant difference between the clusters in phase 2 of the study in the average percentage of women reporting perineal pain on sitting and walking at 10 to 12 days (mean difference 0.7%; 95% CI -10.1% to 11.4%; P = 0.89). The intervention significantly improved overall use of evidence-based practice in the clinical management of perineal trauma. Following the training intervention, group A clusters had a significant reduction in mean percentages of women reporting perineal wound infections and of women needing sutures removed. CONCLUSION: PEARLS is the first RCT to assess the effects of a 'training package on implementation of evidence-based perineal trauma management. The intervention did not significantly improve the primary outcome but did significantly improve evidence-based practice and some of the relevant secondary clinical outcomes for women. TRIAL REGISTRATIONS: ISRCTN28960026 NIHR UKCRN portfolio no: 4785. PMID- 24059605 TI - Diffusion Tensor Imaging in Movement Disorders: Review of Major Patterns and Correlation with Normal Brainstem/cerebellar White Matter. AB - The authors reviewed the diffusion tensor imaging (DTI) and tractography (DTT) of the normal brainstem and cerebellar white matter in normal volunteers, correlating it with structural magnetic resonance (MR) imaging and DTI data obtained in patients evaluated in our institution with movement disorders, including multisystem atrophy (MSA), spinocerebellar ataxia (SCA), progressive supra-nuclear palsy (PSP) and idiopathic Parkinson's disease (PD). DTI and tractography data demonstrated major white-matter fibers within the brain stem and cerebellum, including cortico-spinal tracts, transverse pontine fibers, medial lemniscus and cerebellar peduncles. Visualization of selective degeneration of these individual fibre tracts with DTI, in our cases, added qualitative data to the differential diagnosis of movement disorders. PMID- 24059606 TI - Diffusion abnormality of corpus callosum in Alzheimer's disease. AB - This study investigated diffusion abnormalities in the parts of corpus callosum (CC) of patients with Alzheimer's disease (AD) using diffusion tensor magnetic resonance imaging (DT-MRI). Twenty-one patients with AD and 20 healthy volunteers participated in the study. MRI was performed with a 1.5 T system. Conventional MR images and diffusion tensor images were obtained for all participants. We divided the CC into three parts as rostrum, body and splenium. The apparent diffusion coefficiency (ADC) and fractional anisotropy (FA) were measured in all parts. FA values for the CC were lower in AD patients than the values of controls. In AD patients the lowest values were found in the rostrum of the CC and CC body FA values were also lower than the splenium, but the difference did not reach statistical significance. DT-MRI is a promising technique to investigate microstructural changes in white matter regions in AD. Early detection of the disease has been increasingly studied in AD. Further studies with larger populations are needed to confirm the role of diffusion tensor imaging in the evaluation of memory impairment. PMID- 24059607 TI - Stroke in young people: the increasing role of advanced imaging. AB - Ischemic stroke in young people is an unexpected event due to a wider variety of causes compared to the older population. This study highlights the increasing role of neuroimaging in the diagnosis, prognosis and treatment of young stroke patients. Thirty young adult patients (age range, 15-45 years) with acute ischemic stroke diagnosis were retrospectively included and studied at our institution during 2009. The mean age of patients was 35 years and 50% were men. The stroke etiology was established in 86% of cases (n=26), 7% (n=2) were due to atherosclerosis of the main vessels, 10% (n=3) were related to cardioembolism, 27% (n=8) were due to arterial dissection and 43% (n=13) responded to miscellaneous etiologies. The cause remained unexplained in 14% (n=4) of cases. The aims of neuroimaging in the challenging study of young stroke patients are to confirm the ischemic nature of the lesion, to determine its location, and to verify the patency of major neck and intracranial arteries. Both MRI and MSCT offer the best sensitivity and spatial resolution. PMID- 24059608 TI - Bilateral Polymicrogyria and MELAS/A3243G Mutation. A Very Uncommon Association. AB - A3243G mutation is associated with several mitochondrial disorders, MELAS syndrome being the most common. Polymicrogyrias constitute an extensive group of malformations of cortical development due to abnormal cortical organization. The association between MELAS/A3243G mutation and polymicrogyria is extremely rare; in 18 years of investigation regarding A3243G mutation and related disorders only one case has been reported. We describe a female patient with proven MELAS/A3243G mutation, developmental delay and mild left hemiparesis in whom MRI showed extensive bilateral polymicrogyria. The association of these two disorders and their possible relation are discussed. PMID- 24059609 TI - MRI Findings in Patients with Clinical Onset Consistent with Infantile Neuroaxonal Dystrophy (INAD), Literature Review, Clinical and MRI Follow-up. AB - Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder characterized by infantile onset and rapid progression of psychomotor regression and hypotonia evolving into spasticity. The neuroradiologic hallmark of the disease is represented by progressive cerebellar atrophy. Prior to the discovery of mutations in the PLA2G6 gene in family with INAD, the clinical diagnosis of the disease had been confirmed by the presence of spheroid bodies (SB) in a peripheral nerve biopsy. Various studies have found that some patients with mutations lacked SB and some without mutations had SB, indicating incomplete detection using either pathologic or molecular methods (7). This, together with the observation that the spectrum of clinical features associated with mutations in PLA2G6 is broader than previously described, has increased the usefulness of Magnetic Resonance (MR) in INAD diagnosis, particularly in the frequent occurrence of atypical cases, especially in the early stages of the disease. We retrospectively reviewed the MR studies of eight patients in whom clinical and imaging onset met the typical criteria for INAD. Their clinical and MR imaging (MRI) onset and follow-up were evaluated together with the neuroradiological findings reported in the literature in order to identify MRI features useful in differentiating INAD from other diseases with similar clinical onset and to discuss which of them are the most important, thus suggesting INAD diagnosis. Our contribution included the use of Proton Spectroscopy ((1)H-MR), diffusion weighted MR imaging (DWI) and diffusion tensor imaging (DTI) in the follow-up of seven of the eight patients. The literature reviewed included attempts to correlate clinical and MR data with the genotype in the group of patients carrying PLA2G6 mutations. From the limited and inhomogeneous cohort of patients included in our study, a correlation between the MR features, phenotype and genotype was not exhaustive. PMID- 24059610 TI - Neuroimaging in seizure patients associated with nonketotic hyperglycemia. AB - Nonketotic hyperglycemia (NKH) is a clinical syndrome consisting of hyperglycemia, hyperosmolality and intracellular dehydration but not ketoacidosis. This prospective study evaluated the clinical and magnetic resonance imaging abnormalities in six patients with NKH complicated with simple or complex partial seizures. Subcortical T2 hypointensity rather than hyperintensity together with contrast enhancement was a characteristic feature of seizures associated with NKH. Restricted diffusion on DWI and decreased NAA and/or Choline on MRS studies were also noted. PMID- 24059611 TI - Ultrasonography and MR Imaging in Progressive Supranuclear Palsy. AB - Progressive supranuclear palsy (PSP) also known as Steele, Richardson and Olszewski disorder (1-4) is a neurodegenerative brain disease that has no known cause, treatment or cure. PSP has no known geographical, occupational or racial preference and affects brain cells that control walking, balance, mobility, vision, speech and swallowing. Symptoms begin on average in the early 60s, but may start as early as in the 40s: a good history and physical examination support the clinical diagnosis and latency of each feature makes us suspect a probable PSP, an atypical Parkinsonism. The diagnosis of a large number of cases of PSP is missed or delayed: 75% of the patients are never clinically diagnosed by neurologist and in most cases the median interval between onset and diagnosis is three years. Notwithstanding such differences in clinical presentation, there remains an overlap in symptoms making the differential diagnosis between such neurodegenerative disorders challenging. A few imaging techniques developed to evaluate brain anatomy and function are used extensively to improve the diagnostic accuracy of different forms of Parkinsonism. Non-invasive and safe methods can now document brain structures. Transcranial sonography (TCS) is a very low cost tool to assess the basal ganglia and mesencephalic echogenicity (5,6). Conventional magnetic resonance imaging (MRI) is a valuable tool to exclude secondary Parkinsonism. Our purpose is to define characteristic objectively measured imaging markers that point out normal biological processes, and pathogenic processes in PSP. Such markers should be sufficiently sensitive and specific to show the underlying biological disease and the pharmacological responses to therapy. PMID- 24059612 TI - T2 FLAIR Increased Signal Intensity at the Posterior Limb of the Internal Capsule: Clinical Significance in ALS Patients. AB - Amyotrophic lateral sclerosis (ALS) is characterized by progressive upper and lower motor neuron degeneration. A hyperintense signal on T2-weighted images along the corticospinal tract has been reported in patients with confirmed ALS. However, the specificity of this finding is under consideration, since it is also identified in healthy controls. Moreover, the correlation of this finding with disease progression has not yet been established. The purpose of our study is to evaluate the frequency with which this high signal appears in the posterior limb of the internal capsule (PLIC), compare visual with quantitative measurements, and correlate these with the progression of the disease. Our prospective clinical study included 24 patients and 51 healthy volunteers. In the ALS patient group, the diagnosis was established according to the criteria of El Escorial in the revised form of Airlee House. All patients were neurologically examined and underwent diagnostic procedures to exclude other diseases resembling ALS. The initial MRI was performed six months to two years after the onset of symptomatology. All ALS patients were clinically examined regarding their symptoms from the upper and lower motor neurons. Follow-up MRIs were performed in nine out of 24 patients over a period of six months. Signal changes in the PLIC are visually evaluated on FLAIR images, and are classified as distinct, mild or no signal change. Fractional anisotropy (FA) measurements are performed by placing a region of interest (ROI) in the PLIC bilaterally. Both findings are being compared. Mild signal changes were visualized in the PLIC in ten volunteers and seven patients. Distinct T2 FLAIR signal changes were visualized in the PLIC in seven ALS patients. No distinct signal change was visualized in the controls. Moreover this increased T2 FLAIR signal change became more accentuated with disease progress. FA measurements in patients were lower than in age-matched healthy subjects, with a further decrease with disease progression. Our findings indicate that although mild hyperintensity of the PLIC is not pathognomonic for ALS, detection of a distinct PLIC hyperintensity that gradually accentuates might actually be a sign of progressive ALS. This finding is supported by the progressively decreasing FA measurements. Larger numbers of patients need to be included and re-evaluated to obtain statistically significant results. PMID- 24059613 TI - Striatal Distribution of Dopamine Transporters and Dopamine D2 Receptors at Different Stages of Parkinson's Disease. A CFT and RAC PET Study. AB - We investigated the alteration of dopaminergic system in striata of Parkinson's disease (PD) at different stages using positron emission tomography (PET), [(11)C]2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT) for dopamine transporter (DAT), and [(11)C]raclopride (RAC) for dopamine D2 receptor (D2R). We studied eight elderly healthy volunteers (Group A), 13 drug naive patients with PD (Group B), and seven advanced PD patients with mild dyskinesia (Group D). Six patients in Group B were re-examined after antiparkinsonian therapy (Group C). Regions of interest were drawn on the cerebellar hemisphere, head of the caudate nucleus (CN), and anterior (AP) and posterior putamen (PP) in the PET images. We calculated uptake ratio index (URI), asymmetry index (AI) and presynapse-to postsynapse ratio (PPR) to evaluate dopaminergic function. DAT was smaller in the three PD groups than the Group A. URI of RAC in the PP was significantly larger in Group B than in Groups A and C. AI of CFT in the putamen was larger in the PD groups than in normal subjects, and AI of RAC in the PP was the largest in the Group B. PPRs in the AP and PP were smaller in the three PD groups than in Group A. DAT decreased with disease progression in patients with PD. Binding of RAC was largest in the putamen of drug-naive PD patients, but the enhanced binding could not be detected in the therapeutic patients with PD because of weak D2R affinity of RAC. PMID- 24059614 TI - Extrapontine myelinolysis and cortical laminar necrosis caused by severe hypernatremia following peritoneal lavage for ruptured hydatid cyst of the liver. A case report and review of the literature. AB - Extrapontine myelinolysis (EPM) and cortical laminar necrosis (CLN) have rarely been reported in association with severe hypernatremia. We describe a patient with EPM associated with CLN following severe hypernatremia due to hypertonic peritoneal lavage after a ruptured hydatid cyst of the liver. Clinical and neuroimaging findings in acute stage and serial brain MRI at two and five month follow-up are discussed in detail. PMID- 24059615 TI - Superficial siderosis of the central nervous system. AB - Superficial siderosis of the central nervous system (CNS) is a rare entity characterized by the deposition of hemosiderin in the leptomeninges. In most cases it is caused by chronic and recurrent bleeding into the subarachnoid space as a subclinical form and for long periods of time. The cases described in the literature are associated with tumors, aneurysms, arteriovenous malformations, changes in post-surgical, traumatic cervical and brachial plexus injuries. However, the cause of bleeding is unclear in 40-50% of cases. This report describes the case of a 38-year-old man with a history of trauma with a complete lesion of the left brachial plexus. The patient presented progressively worsening gait imbalance, bilateral deafness, tinnitus and memory loss over two years. Neurological examination disclosed bilateral hearing loss, left upper limb plegia with atrophy of muscle mass, spastic paraparesis with pyramidal signs and gait ataxia. The analytical/genetic study was consistent with hereditary hemochromatosis. In addition to typical findings of siderosis, MR disclosed pseudomeningocele while CT angiography and angiography revealed an aneurysm of the internal carotid artery. Although rare, we should be aware of superficial siderosis especially in imaging studies in patients with deafness or ataxia and in those with lesions of the brachial plexus. The imaging signals are subtle and can easily go unrecognized. The radiological investigation must be extensive to find the primary cause. PMID- 24059616 TI - Cerebral amyloid angiopathy-related inflammation: an emerging disease. AB - Three elderly patients with, respectively: mild cognitive impairment, severe and progressive neurologic involvement, and focal neurologic deficit, were observed. MRI showed multiple areas of white matter edema, at times partially involving the cortex, in the first two patients, and a single area in the third. Treatment with steroids determined the disappearance of the lesions and clinical amelioration. The key to the diagnosis of cerebral amyloid angiopathy-related inflammation (CAA ri) was the demonstration, with appropriate MRI sequences, of microbleeds consistent with cerebral amyloid angiopathy (CAA). This diagnosis was supported by genetic analysis of APOE with demonstration of epsilon4/epsilon4 genotype, found in about 80% of CAA patients who develop inflammatory changes. In the appropriate clinical setting, MRI demonstration of microbleeds supported by results of genetic analysis of APOE may strongly support the diagnosis of CAA-ri thus avoiding cerebral biopsy. PMID- 24059617 TI - Posterior reversible encephalopathy syndrome with obstructive hydrocephalus. A case report. AB - We describe an unusual presentation of posterior reversible encephalopathy syndrome (PRES) with predominant posterior fossa edema, causing ascending transtentorial herniation, tonsillar herniation, and obstructive hydrocephalus. MR imaging with additional MR spectroscopy and MR perfusion helped discriminate PRES from infiltrative tumor, and supported the pathogenesis of hydrostatic edema. Infusion of an antihypertensive drug was promptly administered. Diversion of cerebrospinal fluid by ventriculostomy was subsequently performed. However, the patient developed thalamic hemorrhage and secondary intraventricular hemorrhage with contralateral hemiparesis. Awareness of this rare cause of obstructive hydrocephalus with aggressive treatment of high blood pressure may help obviate the need of ventriculostomy and may prevent the hemorrhagic complication. PMID- 24059618 TI - Neuronal basis of haedonic appraisal in early onset schizophrenia: FMRI investigation. AB - The most important symptoms associated with schizophrenia are affective flattening, decreased expression of emotions, anhedonia and social isolation. The purpose of the present study was to investigate the neural response to disgusting and pleasant visual stimuli in healthy subjects and in patients with first episode schizophrenia. Twelve subjects in the first episode of schizophrenia (DSM IV-R, APA, 2000) with a normal IQ and 12 healthy volunteers selected for age and education underwent functional magnetic resonance imaging (fMRI) during observation of pleasant and disgusting visual stimuli. Analysis showed that in healthy subjects, the prefrontal cortex and limbic areas are activated in response to pleasant and disgusting visual stimuli, whereas this does not occur in subjects with schizophrenia since the first episode of illness. PMID- 24059619 TI - Phase Contrast MR as Non-Invasive Tool in the Diagnosis of Benign Intracranial Hypertension. AB - Idiopathic intracranial hypertension (IIH) is characterized by an increased intracranial pressure in the absence of expansive lesions or cerebrospinal fluid (CSF) circulation obstructions. Its physiopathology is still not fully understood. The diagnosis is currently established on clinical grounds (Dandy criteria) along with an invasive measurement of CSF dynamic parameters through the infusion test. This study compares the invasive pressure measurements with the biomechanical CSF parameters derived from a phase-contrast MR protocol to evaluate the accuracy and reliability of the phase-contrast MR protocol. PMID- 24059620 TI - Intervention in stroke. The future ahead. AB - The treatment for acute stroke is evolving and we present the initial results of 18 patients presenting to our institution over a period of eight months with acute stoke where CTA confirmed the presence of a thrombus. These patients were resistant to IV rtPA and underwent partial to complete clot retrieval with IA thrombolysis or in conjunction with mechanical thrombectomy. 13 of the 18 patients underwent mechanical thrombectomy and Solitaire AB device was used in 12 of these patients. Efficacy was assessed radiologically by post-treatment thrombolysis in myocardial infarction (TIMI) scores and clinically by a 30-day Modified Rankin Scale (MRS) score A TIMI score of 3 was achieved in 91% of patients undergoing mechanical thrombectomy with Solitaire AB device. 61% of our patient group had a discharge MRS of <= 2. PMID- 24059621 TI - How to Distinguish between Venous and Arterial Strokes and Why? AB - Cerebral venous infarct is considered to be rare (0-5% of all strokes). In some cases venous infarcts with no specific signs on conventional CT or MR study are not diagnosed due to incomplete examination. A venous infarct more often (63%) than an arterial (15%) infarct is accompanied by hemorrhage (primary or secondary in the early period) and a high risk of hemorrhage should be a contraindication to intravenous thrombolysis. Consequently, the definition of the kind of a stroke should lead to different therapeutic tactics. Using MR and CT angiographic and perfusion techniques in the urgent examination of patients with an infarct, considering time necessary for the "time window", can lead to exact diagnosis and fewer complications. PMID- 24059622 TI - Fibromuscular dysplasia of the middle cerebral artery in an adolescent male. A case report. AB - To illustrate the imaging features of fibromuscular dysplasia (FMD) in this rare presumptive case of FMD in a sixteen year old male with intracranial features only and highlight it as an important cause of stroke in the young. FMD is a non atheroscelerotic, non-inflammatory vasculopathic arterial disease affecting large and medium size vessels of unknown aetiology. It is a rare cause of paediatric stroke and strokes in young adults. This is a pictorial presentation of an unusual presumptive case of fibromuscular dysplasia (FMD) affecting the middle cerebral artery in a sixteen year old male with classic Digital Subtraction Angiography (DSA) findings. The focal neurological findings and pattern seen on sequential brain scans clearly associates the presence of this vascular lesion to cerebral infarction. Classic imaging findings of the epidemiology, pathology and radiological appearance of FMD are discussed. Emphasis is placed on the patient's imaging presentations including DSA. FMD is a vascular dysplasia that typical affects the renal vasculature and commonly the extracranial internal carotid artery. When a young adult or child presents with stroke FMD should be considered and is more likely to have intracranial features. PMID- 24059623 TI - An early MRI change following reversible hypoxic brain injury. A case report. AB - We describe a patient who suffered reversible hypoxic brain injury. The initial MRI taken 3.5 hours after asphyxiation showed an abnormal lesion on DWI, but he recovered completely from coma. The presence of cytotoxic edema in the acute stage may not necessarily indicate a poor prognosis. PMID- 24059624 TI - Global Functional Disconnections in Post-anoxic Coma Patient. AB - Disorders of consciousness have been related to different disconnection patterns as assessed by neuroimaging tools such as PET or fMRI. In this report, we use resting-state functional MRI acquisition and a functional connectivity analysis by graph of brain networks, to investigate the global residual connection pattern in a patient with consciousness disorders following post-anoxic injury. We then compare this pattern with those of a group of twenty controls. We observed that the patient's graph presents multiple disconnections in primary areas and in high order associative areas. This pattern is consistent with a vegetative state, as reported by other groups. Further, the informations conveyed by this approach are consistent with those provided by PET, fMRI and EP. This new approach presents a very strong potential for diagnosis for consciousness disorder patients since it is applicable very early after the insult. PMID- 24059625 TI - Secondary corpus callosum abnormalities associated with antiepileptic drugs in temporal lobe epilepsy. A diffusion tensor imaging study. AB - Epilepsy is more than a grey-matter disorder affecting large white matter connections of the brain with seizure generation and propagation. The mechanism for such changes remains unclear. The purpose of this study was to investigate the microstructural changes in the corpus callosum in temporal lobe epilepsy (TLE) patients and whether these abnormalities are related to antiepileptic drug (AED) therapy. Ten TLE patients receiving AED therapy, ten TLE patients with no therapy and ten controls were included in the study. The regions of interest in the corpus callosum were outlined to each Witelson region (WR). Fractional anisotrophy (FA), apparent diffusion coefficient (ADC), three main diffusivity values (lambda1, lambda2, lambda3) and tractography were acquired from each WR. DTI indices of these tracts and each WR were compared between the three subject groups and correlates examined with clinical variables that included duration of epilepsy, gender, AED type and AED therapy exposure. In TLE subjects with receiving AED therapy significantly (p<0.05) decreased FA and increased ADC values of corpus callosum were obtained when compared to the other groups. There was no significant relationship between AED type and DTI indices. Analysis of eigen values in the splenium of corpus callosum (WR7) showed lambda1 values were significantly decreased in relation to AED medication duration (p<0.05). FA values of rostrum and corpus showed a reduction with duration of epilepsy. TLE is associated with abnormal integrity of corpus callosum white matter tracts. AED therapy may cause additional damage on secondary degeneration and medication time effects especially on the splenium of corpus callosum. PMID- 24059626 TI - Genome-wide copy number variations in Oryza sativa L. AB - BACKGROUND: Copy number variation (CNV) can lead to intra-specific genome variations. It is not only part of normal genetic variation, but also is the source of phenotypic differences. Rice (Oryza sativa L.) is a model organism with a well-annotated genome, but investigation of CNVs in rice lags behind its mammalian counterparts. RESULTS: We comprehensively assayed CNVs using high density array comparative genomic hybridization in a panel of 20 Asian cultivated rice comprising six indica, three aus, two rayada, two aromatic, three tropical japonica, and four temperate japonica varieties. We used a stringent criterion to identify a total of 2886 high-confidence copy number variable regions (CNVRs), which span 10.28 Mb (or 2.69%) of the rice genome, overlapping 1321 genes. These genes were significantly enriched for specific biological functions involved in cell death, protein phosphorylation, and defense response. Transposable elements (TEs) and other repetitive sequences were identified in the majority of CNVRs. Chromosome 11 showed the greatest enrichment for CNVs. Of subspecies-specific CNVRs, 55.75% and 61.96% were observed in only one cultivar of ssp. indica and ssp. japonica, respectively. Some CNVs with high frequency differences among groups resided in genes underlying rice adaptation. CONCLUSIONS: Higher recombination rates and the presence of homologous gene clusters are probably predispositions for generation of the higher number of CNVs on chromosome 11 by non-allelic homologous recombination events. The subspecies-specific variants are enriched for rare alleles, which suggests that CNVs are relatively recent events that have arisen within breeding populations. A number of the CNVs identified in this study are candidates for generation of group-specific phenotypes. PMID- 24059627 TI - Online capillary electrophoresis for monitoring carboxylic acid production by yeast during bioreactor cultivations. AB - Bioprocess monitoring can improve the understanding and control of biotechnological processes. When analyses are carried out as automated online measurements, manual steps of the analysis procedures are avoided, thus decreasing both the time required for analyses and systematic errors. In this study, an online capillary electrophoresis (CE) system with flow-through sample vial made in-house and action control programming was assembled to monitor carboxylic acid production by Kluyveromyces lactis and Saccharomyces cerevisiae during two different bioreactor cultivations. The relative standard deviations were less than 0.6% for intraday migration times and the total analysis time was less than 20 min. The system operated continuously and automatically up to 6 days and produced data concerning carboxylic acid production during the cultivations. The successful test runs demonstrated that this system has potential for the monitoring of biotechnological processes. PMID- 24059628 TI - The challenge of obesity. AB - This editorial discusses the problem of obesity in people with serious mental illnesses, as well as the role of those in the field of psychiatric/psychosocial rehabilitation (PSR) in addressing this issue. The term "obesogenic environment" has been coined to refer to environments that both promote weight gain and act as a barrier to weight loss. In an ecological model of obesity, people in obesogenic environments struggle against a culture that promotes consumption of high-fat, sugar-laden foods and encourages sedentary behaviors. Multiple influences affect an individual's response to obesogenic environments such as degree of exposure, access to resources, and biological predisposition to obesity. The ecological model of obesity has much to offer the field, given PSR's emphasis on community participation and social integration. By working together to propose, implement, and test changes at both organizational and professional levels, members can address overweight and obesity and alter the landscape of the obesogenic environments for those they serve and care about. PMID- 24059629 TI - Mental health system funding of cognitive enhancement interventions for schizophrenia: summary and update of the New York Office of Mental Health expert panel and stakeholder meeting. AB - TOPIC: A growing research literature indicates that cognitive enhancement (CE) interventions for people with schizophrenia can improve cognitive functioning and may benefit psychosocial functioning (e.g., competitive employment, quality of social relationships). Debate continues regarding the strength of evidence for CE and related policy implications, such as the appropriateness of funding CE services. PURPOSE: This paper summarizes and updates a meeting of experts and stakeholders convened in 2008 by the New York Office of Mental Health to review evidence on the impact of CE for people with schizophrenia and other serious mental illnesses, and addresses whether the evidence base for CE interventions is sufficient to warrant funding. SOURCES USED: Specific recommendations based on the extant literature are provided regarding the structure and components of CE programs that should be present in order to improve cognitive and psychosocial outcomes and therefore merit consideration of funding. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: These recommendations may serve as a starting point in developing standards for CE programs. Establishing evidence-based practice standards for implementing CE interventions for people with serious mental illnesses may facilitate dissemination of programs that have the greatest potential for improving individuals' functional outcomes while minimizing incremental costs associated with providing CE services. Important open questions include how the performance of CE programs should be monitored and which individuals might be expected to benefit from CE as evidenced by improved functioning in their everyday lives. PMID- 24059630 TI - Meaningful inclusion of consumers in research and service delivery. AB - OBJECTIVE: Although participatory methods have become increasingly popular, people with lived experience of mental illness and homelessness have been historically excluded from service planning and research. To better plan for meaningful inclusion of consumers, this study examines lessons learned from the People with Lived Experience Caucus in the Toronto Site of the At Home/Chez Soi Research Demonstration Project on Homelessness and Mental Health. METHOD: The inclusion of the People with Lived Experience Caucus was evaluated using qualitative methods and multiple data sources, including review of 42 documents, 11 individual interviews, and three focus groups. Caucus members were included in the study team. Transcripts were analyzed using grounded theory methodology. RESULTS: Findings revealed a complex story of Caucus engagement: Facing time constraints and given little direction, the Caucus developed through a tumultuous process related to both internal and external barriers to meaningful inclusion. Despite the challenges, the Caucus contributed meaningfully to various aspects of the research demonstration project. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: It is possible to successfully integrate psychiatric consumers with experience of homelessness in many aspects of research and service planning. Suggestions for future initiatives hoping to engage consumers include: early involvement, purposeful selection of members, clear communication of roles and responsibilities, a consumer coordinating group, and space for critical dialog throughout the process. Lessons learned can inform the inclusion of consumers in similar endeavors in other jurisdictions. PMID- 24059631 TI - Walking on the sunny side: what positive psychology can contribute to psychiatric rehabilitation concepts and practice. AB - TOPIC: This article suggests a positive psychology framework to strengthen and broaden psychiatric rehabilitation and recovery thought and practice. PURPOSE: We inform about positive psychology concepts and measures that can be used to further knowledge, enhance practice, and guide research. SOURCES USED: Foundational concepts are drawn from the published literature. Specific positive psychology concepts and measures are highlighted: complete mental health, well being, flourishing, positive emotions, flow, self-determination, posttraumatic growth, and resilience. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Employing a positive psychology framework can advance research on recovery phenomena and be used to assess rehabilitation outcomes. In addition we advocate positive psychology interventions in education and training of service providers that will enhance a positive focus and the culture of recovery. PMID- 24059632 TI - Benefits of working as a certified peer specialist: results from a statewide survey. AB - OBJECTIVE: Certified peer specialists (CPSs) are an emerging workforce across the United States and are a critical component of recovery-oriented mental health systems. This study examined possible benefits of working as a CPS. METHOD: A statewide survey of trained CPSs in Pennsylvania was conducted in Winter/Spring 2010. A total of 271 CPSs responded to the online survey. Data from 154 working CPSs were analyzed. RESULTS: Forty-one respondents (28.7%) were not working prior to their CPS employment and 60% of all respondents reported a decrease in Social Security entitlements. Statistically significant reductions were reported in case management, crisis services, and inpatient hospitalizations. Finally, respondents overwhelmingly reported personal, recovery-oriented benefits, and felt that they have a positive impact on their agencies. CONCLUSION AND IMPLICATIONS FOR PRACTICE: CPS initiatives appear to benefit the individual CPS worker and may result in societal cost savings. These results further expand the potential value of peer-support services. PMID- 24059633 TI - Illness insight and recovery: how important is illness insight in peoples' recovery process? AB - TOPIC: This account reflects on the topic of illness insight and recovery. PURPOSE: The purpose of the account is to clarify our understanding about the importance of illness insight in peoples' recovery process, especially when relating the question of illness insight to the question of identity. SOURCES USED: The writing is based on research literature related to illness insight and on personal recovery experiences. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: It is helpful to consider the integration of the issue of illness insight when addressing the questions and consequences of diagnosis, and to assist individuals to work through the false analogy between illness and identity while supporting the transformation from patient to person. It is also necessary for clinicians to develop a clear understanding of peoples' actual needs and gain more knowledge about peoples' own views and experiences in relation to the importance of illness insight in the recovery process. PMID- 24059634 TI - Crop dusting or composting? AB - In the education and training realm of psychiatric rehabilitation, this article uses a composting/crop-dusting metaphor to describe a competency-based framework of staff development. The crop-dusting, or "fly over," approach to training is likened to an aerial dump of information that may have some positive effect on growth if it's done at the right time and in the right place. The composting approach to training makes use of assessment, preparation, delivery, and follow up. These four phases are linked to the specific training content and individualized to both the organization and the learners. A thorough training assessment examines existing competencies, how the content will be applied on the job, and whether current job expectations and responsibilities will support the use of the new knowledge and skill. Preparation is important in designing the training activities that are so critical to meeting the needs of adult learners and to ensuring their ability to understand and apply the training content. Delivery of the training must include practice opportunities with feedback and opportunities for trainees to work with the new knowledge or skills in a way that will preview, enhance, and clarify using them on the job. Follow-up should be designed from the beginning and is determined by the purpose of the training. Finally, observation and evaluation bring the process full circle by beginning the assessment for the next round of training. PMID- 24059636 TI - Renal involvement in Waldenstrom's macroglobulinemia: case report and review of literature. AB - Waldenstrom's macroglobulinemia (WM) is a rare lymphoid neoplasia, accounting for 2% of all hematological malignancies. Renal complications occur rather rarely compared to multiple myeloma. The most common renal manifestations are mild proteinuria and microhematuria. We describe a case of MW presenting with acute renal failure and NS. A 67-year-old man was referred to our hospital for sudden onset nephrotic syndrome. Electrophoresis revealed a monoclonal component in the gamma region, which was classified as an IgM k. During hospitalization, acute kidney injury developed, with creatinine up to 5 mg/dL, despite adequate hydration and alkalinization. A kidney biopsy was performed, showing minimal change disease (MCD) with interstitial and capsular lymphoid infiltrates of B Lymphocytes CD20+. B-lymphocytes infiltration suggested the possibility of renal localization of lymphoproliferative disorder. So, bone marrow histology was performed, revealing lymphoplasmacytic lymphoma (WM). The patient was treated with bortezomib, desamethasone, and rituximab, with partial recovery of renal function (creatinine 1.5 mg/dL) and complete remission of proteinuria after 8 month follow-up. The remission of NS in our patient with rituximab seems to emphasize the pathogenetic role of B cells in MCD, although a coincident effect of immunosuppression on both the underlying renal disease and the hematologic disease cannot be excluded. PMID- 24059635 TI - In silico profiling of Escherichia coli and Saccharomyces cerevisiae as terpenoid factories. AB - BACKGROUND: Heterologous microbial production of rare plant terpenoids of medicinal or industrial interest is attracting more and more attention but terpenoid yields are still low. Escherichia coli and Saccharomyces cerevisiae are the most widely used heterologous hosts; a direct comparison of both hosts based on experimental data is difficult though. Hence, the terpenoid pathways of E. coli (via 1-deoxy-D-xylulose 5-phosphate, DXP) and S. cerevisiae (via mevalonate, MVA), the impact of the respective hosts metabolism as well as the impact of different carbon sources were compared in silico by means of elementary mode analysis. The focus was set on the yield of isopentenyl diphosphate (IPP), the general terpenoid precursor, to identify new metabolic engineering strategies for an enhanced terpenoid yield. RESULTS: Starting from the respective precursor metabolites of the terpenoid pathways (pyruvate and glyceraldehyde-3-phosphate for the DXP pathway and acetyl-CoA for the MVA pathway) and considering only carbon stoichiometry, the two terpenoid pathways are identical with respect to carbon yield. However, with glucose as substrate, the MVA pathway has a lower potential to supply terpenoids in high yields than the DXP pathway if the formation of the required precursors is taken into account, due to the carbon loss in the formation of acetyl-CoA. This maximum yield is further reduced in both hosts when the required energy and reduction equivalents are considered. Moreover, the choice of carbon source (glucose, xylose, ethanol or glycerol) has an effect on terpenoid yield with non-fermentable carbon sources being more promising. Both hosts have deficiencies in energy and redox equivalents for high yield terpenoid production leading to new overexpression strategies (heterologous enzymes/pathways) for an enhanced terpenoid yield. Finally, several knockout strategies are identified using constrained minimal cut sets enforcing a coupling of growth to a terpenoid yield which is higher than any yield published in scientific literature so far. CONCLUSIONS: This study provides for the first time a comprehensive and detailed in silico comparison of the most prominent heterologous hosts E. coli and S. cerevisiae as terpenoid factories giving an overview on several promising metabolic engineering strategies paving the way for an enhanced terpenoid yield. PMID- 24059637 TI - Ramadan fasting ameliorates arterial pulse pressure and lipid profile, and alleviates oxidative stress in hypertensive patients. AB - BACKGROUND AND AIM: Effects of Ramadan fasting on health are important. Its effects on arterial pulse pressure (PP), lipid profile and oxidative stress were characterized in hypertensives. METHODS: PP, indices of lipid profile and oxidative stress were measured pre-, during and post-fasting in equal (40 each), sex- and age-matched groups (age 55 +/- 5 years) of hypertensives (HT) and controls (C). RESULTS: Fasting reduced PP significantly by 17.2% and insignificantly by 9.3% in the HT and C groups, respectively. Total cholesterol (TC) was lowered insignificantly by 11.7% and 4.7% in the HT and C patients, respectively. Triglycerides (TG) and malondialdehyde (MDA) were significantly lowered by: TG: 24.5% and 22.8%; MDA: 45.6% and 54.3%; while glutathione (GSH) elevated by 56.8% and 52.6% in the HT and C groups, respectively. High-density lipoproteins (HDL) were raised significantly by 33.3% and insignificantly by 6.7%, whereas low-density lipoproteins (LDL) decreased significantly by 17.7% and insignificantly by 4.0% in the HT and C groups, respectively. At 6 weeks post fasting, MDA remained significantly lower than the pre-fasting level by 24.3% and 25.7%, and GSH higher by 30.2% and 26.3% in the HT and C groups, respectively, while PP and TC returned to pre-fasting values in both groups. The post-fasting, HDL was significantly higher by 20.3% and LDL lower by 12.0% than the fasting levels in the HT patients. CONCLUSION: Fasting improves PP and lipids profile and ameliorates oxidative stress in hypertensives. PMID- 24059639 TI - Internal jugular vein valve insufficiency is not increased in migraine: an ultrasound study in migraine patients and control participants. AB - BACKGROUND: Migraine is a common neurological disorder of unclear pathogenesis. Recently incompetence of internal jugular vein valve (IJVVI) was found to be associated with some neurological conditions of unknown etiology such as benign cough headache, primary exertional headache or transient global amnesia. Common vascular mechanism linking transiently increased cerebral venous pressure with the above mentioned conditions was then postulated. Therefore we decided to investigate whether IJVVI may be associated with migraine. AIM AND METHODS: The aim of our study was to evaluate the occurrence of IJVVI and retrograde flow duration in 70 (56 females) migraine patients by color Doppler ultrasound during Valsalva maneuver.We assessed internal jugular vein valve in 44 patients with migraine without aura (39 female); mean age 37 +/- 9 yrs. and in 26 patients with migraine with typical aura (17 female); mean age 34 +/- 9 yrs. Age- and sex matched control group consisted of 42 healthy persons (33 female); mean age 32 +/ 1 yrs. RESULTS: Frequency of the internal jugular vein valve insufficiency was similar in patients with migraine and in the healthy subjects (51% v. 40%, p = 0.26). Also mean values of retrograde flow duration were similar in both groups (2.4 +/- 0.8 sec in migraine group and 2.2 +/- 1.2 sec in controls, p = 0.14). CONCLUSION: The results of our study show no evidence for an increased prevalence of IJVVI in migraine patients. PMID- 24059638 TI - Peripheral blood mononuclear phagocytes from patients with chronic periodontitis are primed for osteoclast formation. AB - BACKGROUND: During inflammatory periodontal disease, peripheral blood mononuclear cells (PBMCs) are attracted to bone and differentiate into active bone-resorbing osteoclasts (OCs), thus providing evidence that the impact of chronic periodontitis (CP) on the activity of circulating mononuclear cells is of central importance. The authors test the hypothesis that peripheral blood mononuclear phagocytes (PBMPs) from patients with CP are activated and more susceptible to differentiation into OCs, which in turn would lead to more intense bone resorption. METHODS: In vitro cytokine production by both unstimulated and lipopolysaccharide-stimulated PBMCs from individuals with (n = 10) or without (n = 12) periodontitis was determined by cytokine array. OC differentiation from CD14(+) PBMCs was induced by receptor activator of nuclear factor-kappa B ligand (RANKL), either alone or in the presence of macrophage colony-stimulating factor (M-CSF). PBMC differentiation to OCs was confirmed by tartrate-resistant acid phosphatase staining; bone resorbing activity was assessed by using an osteologic plate assay (bone resorption pit formation). RESULTS: PBMCs from patients with CP produced tumor necrosis factor-alpha and higher amounts of interferon-gamma, interleukin (IL)-1alpha, IL-1beta, IL-1ralpha, CXC motif chemokine 10, macrophage migration inhibitory factor, macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta than the control cells. OC differentiation was induced by RANKL alone in PBMCs from patients with CP, but not in PBMCs from the healthy controls, which required the addition of M-CSF. In addition, PBMC-derived OCs from patients with CP showed significantly higher resorption activity than that observed in the healthy controls. Also, the circulating concentrations of M-CSF were significantly higher in patients with CP than in the control participants. CONCLUSIONS: These data indicate that in patients with CP, circulating PBMCs are primed for increased proinflammatory activity and that M-CSF plays a central role in this process by increasing OC formation and the consequent bone resorption activity. PMID- 24059640 TI - Chromium(VI) causes interstrand DNA cross-linking in vitro but shows no hypersensitivity in cross-link repair-deficient human cells. AB - Hexavalent chromium is a human carcinogen activated primarily by direct reduction with cellular ascorbate and to a lesser extent, by glutathione. Cr(III), the final product of Cr(VI) reduction, forms six bonds allowing intermolecular cross linking. In this work, we investigated the ability of Cr(VI) to cause interstrand DNA cross-links (ICLs) whose formation mechanisms and presence in human cells are currently uncertain. We found that in vitro reduction of Cr(VI) with glutathione showed a sublinear production of ICLs, the yield of which was less than 1% of total Cr-DNA adducts at the optimal conditions. Formation of ICLs in fast ascorbate-Cr(VI) reactions occurred during a short reduction interval and displayed a linear dose dependence with the average yield of 1.3% of total adducts. In vitro production of ICLs was strongly suppressed by increasing buffer molarity, indicating inhibitory effects of ligand-Cr(III) binding on the formation of cross-linking species. The presence of ICLs in human cells was assessed from the impact of ICL repair deficiencies on Cr(VI) responses. We found that ascorbate-restored FANCD2-null and isogenic FANCD2-complemented cells showed similar cell cycle inhibition and toxicity by Cr(VI). XPA-null cells are defective in the repair of Cr-DNA monoadducts, but stable knockdowns of ERCC1 or XPF in these cells with extended time for the completion of cross-linking reactions did not produce any sensitization to Cr(VI). Our results together with chemical and steric considerations of Cr(III) reactivity suggest that ICL generation by chromate is probably an in vitro phenomenon occurring at conditions permitting the formation of Cr(III) oligomers. PMID- 24059641 TI - Episodic itch in a case of spinal glioma. AB - BACKGROUND: Itch is a frequent complaint reported by patients and is usually ascribed to dermatological or metabolic causes. In neurological disorders, however, it is a very unusual symptom and thus its neurological aetiology is likely to be overlooked. There are only very few reports about permanent itch related to lesions of the central nervous system. To our knowledge we report the first case of episodic itch associated with a central nervous lesion. CASE PRESENTATION: A 74-year-old female suffered from long-standing episodes of itch of the dermatomes C2 to C6 on the right side that was refractory to any treatment. On occurrence it propagated in a proximal to distal fashion. Between the episodes the patient was asymptomatic. MRI of the cervical spine uncovered a spinal glioma that matched the location of the symptoms. Treatment with gabapentin led to a prompt reduction of the symptoms. CONCLUSION: Patients with intractable pruritus and dermatomal presentation ought to undergo neurological examination and spinal cord imaging. Thus, ongoing frustrating and sometimes even harmful treatment trials could be avoided. PMID- 24059642 TI - Malic acid supplementation increases urinary citrate excretion and urinary pH: implications for the potential treatment of calcium oxalate stone disease. AB - BACKGROUND AND PURPOSE: Raising urinary pH and citrate excretion with alkali citrate therapy has been a widely used treatment in calcium nephrolithiasis. Citrate lowers ionized Ca(+2) concentrations and inhibits calcium salt precipitation. Conservative alternatives containing citrate such as fruit juices have been investigated and recommended. Any compound that induces systemic alkalosis will increase citraturia. Malate, a polycarboxylic anion like citrate, is a potential candidate for chelating Ca(+2) and for inducing systemic alkalinization. We undertook to investigate these possibilities. MATERIALS AND METHODS: Theoretical modeling of malic acid's effects on urinary Ca(+2) concentration and supersaturation (SS) of calcium salts was achieved using the speciation program JESS. Malic acid (1200 mg/day) was ingested for 7 days by eight healthy subjects. Urines (24 hours) were collected at baseline and on day 7. They were analyzed for routine lithogenic components, including pH and citrate. Chemical speciation and SS were calculated in both urines. RESULTS: Modeling showed that complexation between calcium and malate at physiological concentrations of the latter would have no effect on SS. Administration of the supplement induced statistically significant increases in pH and citraturia. The calculated concentration of Ca(+2) and concomitant SS calcium oxalate (CaOx) decreased after supplementation, but these were not statistically significant. SS for the calcium phosphate salts hydroxyapatite and tricalcium phosphate increased significantly as a consequence of the elevation in pH, but values for brushite and octacalcium phosphate did not change significantly. CONCLUSIONS: We speculate that consumption of malic acid induced systemic alkalinization leading to reduced renal tubular reabsorption and metabolism of citrate, and an increase in excretion of the latter. The decrease in SS(CaOx) was caused by enhanced complexation of Ca(+2) by citrate. We conclude that malic acid supplementation may be useful for conservative treatment of calcium renal stone disease by virtue of its capacity to induce these effects. PMID- 24059643 TI - Tunable nucleation time of functional sphingomyelinase--lipid features studied by membrane array statistic tool. AB - Aggregation or assembly of lipids and proteins could significantly change the proteins' function. A peripheral membrane enzyme, sphingomyelinase (SMase), has been reported to be able to assemble to a functional feature with its lipid substrate, sphingomyelin (SM), and its lipid product, ceramide (Cer). SMase seems to processes its substrate more effectively in this feature. Here, we report that the functional feature has a tunable formation time. The peculiar behavior is that the feature formation has a time lag depending on the membrane composition. We hypothesized that the time lag is due to the significant nucleation energy barrier when the feature phase forms in its metastable parent phase in the 2-D lipid membrane. To study the stochastic nucleation of the feature, we built a corralled lipid membrane platform with numerous isolated membrane systems in parallel to capture the nucleation statistics. Using the high-throughput approach and the appropriate experimental design to circumvent the interplay of the complicated phase segregation in membranes induced by SMase, we found that the nucleation rate of the feature can be tuned by the supersaturation of the enzyme, the lipid substrate, and the lipid product, in the fluid phase of the membrane. The correlation between the supersaturation and the nucleation rate can be well described by the classical nucleation theory equation, suggesting that the feature formation follows the nucleation process with a certain component ratio specified in the equation. The certain relative component ratio suggests that the feature may have certain organization instead of being random aggregation. In addition, our finding suggests that nucleation could serve as a time lag control mechanism in this enzymatic system, and ways to reduce nucleation energy barrier could be used to shorten the aggregation time lag and vice versa. PMID- 24059644 TI - Dynamic and reversible fluorescence imaging of superoxide anion fluctuations in live cells and in vivo. AB - Overgeneration of reactive oxygen species (ROS) is closely associated with cellular damage and diseases. As superoxide anion (O2(*-)) is the precursor of other ROS, exploring O2(*-) fluctuations in cells and in vivo is of great significance. To address this critical need, we have developed a novel reversible fluorescent probe with one-photon and two-photon fluorescence properties, which is well suited for monitoring O2(*-) fluxes selectively and dynamically. Imaging results substantiate dynamic and reversible fluorescence responses of this probe to intracellular O2(*-) under apoptotic stimuli. Moreover, this probe can conveniently visualize changes in O2(*-) concentration during reperfusion injury in hepatocytes, zebrafish, and mice, by means of one-photon or two-photon imaging according to depths of various samples. The present study provides a powerful fluorescent imaging tool for dynamic tracking of O2(*-) in live cells and in vivo. PMID- 24059645 TI - Metastatic prostate cancer cell-specific phage-like particles as a targeted gene delivery system. AB - BACKGROUND: One of the cardinal requirements for effective therapeutic management of tumors is the selective delivery of cancer drugs to the right site by ligand decorated nanomedicines. Screening of 2 * 109 clone landscape phage library provides a reliable avenue for generating protein ligands specific for tumor cells. It was shown that selective phage proteins derived from landscape phage libraries against breast and prostate cancer cells are able to navigate drug or siRNA loaded liposomes to corresponding cancer cells with minimal toxicity to non neoplastic cells. In an alternative platform, glioma cell-specific phage proteins were used for assembling in vivo cancer-specific phage-like particles, named 'phagemid infective particles' as targeted gene-delivery vehicles. METHODS: To extend the panel of anticancer cell phages, we have screened a 2 * 109 clone landscape phage library f8/8 to select phage clones specific for metastatic prostate cancer cell PC-3M. The phage clones were characterized for their selective interaction with PC-3M cells using phage capture assay, immunofluorescence microscopy and electron microscopy. A prostate cancer selective phage was converted to phage-like particles harboring emerald green fluorescent protein. RESULTS: Phage clone EPTHSWAT (designated by the sequence of inserted peptide) was found to be most selective for PC-3M cells and was observed to internalize PC-3M cells as revealed by immunofluorescence microscopy and electron microscopy. Conversion of this phage to phage-like particles harboring emerald green fluorescent protein and the expression of emerald green fluorescent protein in the phage-like particles treated PC-3M cells showed potential of adoption of this phage-like particle in prostate cancer therapeutic gene delivery. CONCLUSION: Successful employment of phage-like particles expressing emerald green fluorescent protein genes targeted to prostate cancer cells PC-3M confirms a prospect of their use for targeted delivery of therapeutic genes to cancer cells. PMID- 24059646 TI - Gas-phase reactions of OH with methyl amines in the presence or absence of molecular oxygen. An experimental and theoretical study. AB - The rate coefficients for the reaction of OH with the alkyl amines: methylamine (MA), dimethylamine (DMA), trimethylamine (TMA), and ethylamine (EA) have been determined using the technique of pulsed laser photolysis with detection of OH by laser-induced fluorescence as a function of temperature from 298 K to ~600 K. The rate coefficients (10(11) * k/cm(3) molecule(-1) s(-1)) at 298 K in nitrogen bath gas (typically 5-25 Torr) are: k(OH+MA) = 1.97 +/- 0.11, k(OH+DMA) = 6.27 +/- 0.63, k(OH+TMA) = 5.78 +/- 0.48, k(OH+EA) = 2.50 +/- 0.13. The reactions all show a negative temperature dependence which can be characterized as: k(OH+MA) = (1.889 +/- 0.053) * 10(-11)(T/298 K)(-(0.56+/-0.10)), k(OH+DMA) = (6.39 +/- 0.35) * 10(-11)(T/298 K)(-(0.75+/-0.18)), k(OH+TMA) = (5.73 +/- 0.15) * 10(-11)(T/298 K)(-(0.71+/-0.10)), and k(OH+EA) = (2.54 +/- 0.08) * 10(-11)(T/298 K)(-(0.68+/ 0.10)). OH and OD reactions have very similar kinetics. Potential energy surfaces (PES) for the reactions have been characterized at the MP2/aug-cc-pVTZ level and improved single point energies of stationary points obtained in CCSD(T) and CCSD(T*)-F12a calculations. The PES for all reactions are characterized by the formation of pre- and post-reaction complexes and submerged barriers. The calculated rate coefficients are in good agreement with experiment; the overall rate coefficients are relatively insensitive to variations of the barrier heights within typical chemical accuracy, but the branching ratios vary significantly. The rate coefficients for the reactions of OH/OD with MA, DMA, and EA do not vary with added oxygen, but for TMA a significant reduction in the rate coefficient is observed consistent with OH recycling from a chemically activated peroxy radical. OH regeneration is pressure-dependent and is not significant at 298 K and atmospheric pressure, but the efficiency of recycling increases strongly with temperature. The PES for OH recycling have been calculated. There is evidence that the primary process in TMA photolysis at 248 nm is the loss of H atoms. PMID- 24059647 TI - Protection against radiation-induced hematopoietic damage in bone marrow by hepatocyte growth factor gene transfer. AB - PURPOSE: To investigate whether adenovirus-mediated delivery of the human hepatocyte growth factor (HGF) gene could prevent radiation-induced hematopoietic damage. MATERIALS AND METHODS: Thirty C57BL/6 mice were randomized into three groups, in which phosphate buffer saline (PBS), mock adenovirus vector (Ad-null) or adenovirus vector containing HGF (Ad-HGF) were injected into the tail vein of each group, respectively. After 48 hours, the mice received a single irradiation dose of 6.5 Gy (60)Co gamma rays. Blood samples were extracted via the tail vein at day 0, 4, 7, 10, 14, 21, 24 and 30 after irradiation, for red blood cell (RBC) and white blood cell (WBC) and cluster of differentiation4 (CD4)/cluster of differentiation8 (CD8) ratio assessment. At weekly intervals following irradiation, serum erythropoietin (EPO), Interleukin-6 (IL-6) and Interferon gamma (IFN-gamma) levels were measured using enzyme-linked immunosorbent assay (ELISA). On post-irradiation day 30, the mice were autopsied and erythroid burst forming units (BFU-E) were evaluated. RESULTS: Adenovirus-mediated HGF gene transfer could increase human HGF level in serum and have a significant elevation in RBC and WBC count. Ad-HGF increased EPO and IL-6 levels and prompted BFU-E formation. Ad-HGF decreased radiation- induced micronucleus frequency in the mouse bone marrow (BM). Most evidence of radiation-induced hematopoietic damage was observed morphologically in bone marrow specimen four weeks after irradiation. Ad-HGF protected against radiation-induced BM failure and increased survival. Finally, Ad-HGF increased the thymic index and enhanced immune function in the irradiated C57BL/6 mice. CONCLUSIONS: This is the first report to date that demonstrates the potential of HGF gene transfer to prevent radiation-induced hematopoietic damage. PMID- 24059648 TI - Spectroscopic evidence for a new type of bonding between a thioether radical cation and a phenyl group. AB - The oxidation potential of thioethers constrained to be near aromatic rings is lowered, due to an antibonding interaction between the p-type sulfur lone pair with the neighboring phenyl pi-system which on removal of an electron becomes a new kind of 3-electron S?pi bonding that reveals itself in the photoelectron spectrum and by an electronic transition involving the orbitals participating in the S?pi bond. PMID- 24059649 TI - Inulin controls inflammation and metabolic endotoxemia in women with type 2 diabetes mellitus: a randomized-controlled clinical trial. AB - There is limited evidence on the effects of prebiotics on inflammation. Therefore, the aim of this study was to evaluate the effects of inulin supplementation on inflammatory indices and metabolic endotoxemia in patients with type 2 diabetes mellitus. The participants included diabetic females (n = 49). They were divided into an intervention group (n = 24) as well as a control group (n = 25) and received 10 g/d inulin or maltodextrin for 8 weeks, respectively. Fasting blood sugar (FBS), HbA1c, insulin, high-sensitive C reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-alpha), interleukin 10 (IL-10), and plasma lipopolysaccharide (LPS) were measured pre and post intervention. Inulin-supplemented patients exhibited a significant decrease in FBS (8.5%), HbA1c (10.4%), fasting insulin (34.3%), homeostasis model assessment of insulin resistance (HOMA-IR) (39.5%), hs-CRP (35.6%), TNF-alpha (23.1%), and LPS (27.9%) compared with the maltodextrin group (p < 0.05). Increase in IL-10 was not significant in inulin compared with the maltodextrin group. It can be concluded that inulin supplementation seems to be able to modulate inflammation and metabolic endotoxemia in women with type 2 diabetes. PMID- 24059650 TI - Chondrogenic potential of articular chondrocytes depends on their original location. AB - OBJECTIVE: This study aimed to investigate the regenerative capacity of chondrocytes derived from debrided defect cartilage and healthy cartilage from different regions in the joint to determine the best cell source for regenerative cartilage therapies. METHODS: Articular cartilage was obtained from Outerbridge grade III and IV cartilage lesions and from macroscopically healthy weight bearing and nonweight-bearing (NWB) locations in the knee. Chondrocytes isolated from all locations were either pelleted directly (P0 pellets) or after expansion (P2 pellets) and analyzed for glycosaminoglycan (GAG), DNA, and cartilage specific gene expression. Harvested cartilage samples and cultured pellets were also analyzed by Safranin O histology and immunohistochemistry for collagen I, II, and X. Immunohistochemical stainings were quantified using a computerized pixel-intensity staining segmentation method. RESULTS: After 4 weeks of culture, the P0 pellets derived from grade III or healthy weight-bearing chondrocytes contained more (p<0.015) GAG and GAG normalized per DNA compared to those from grade IV and NWB locations. After expansion, these differences were lost. Cartilage-specific gene expression was higher (p<0.04) in P0 pellets from grade III chondrocytes compared to grade IV chondrocytes. Semiquantitative immunohistochemistry showed a more intense (p<0.033) collagen I and X staining for grade IV debrided cartilage compared to grade III and weight-bearing cartilage. Also, collagen type X staining intensity was higher (p<0.033) in NWB cartilage compared to grade III and weight-bearing regions. CONCLUSION: Chondrocytes derived from debrided cartilage perform better than cells from the NWB biopsy site, however, this difference is lost upon expansion. Based thereon, the debrided defect cartilage could be a viable donor site for regenerative cartilage surgery. PMID- 24059651 TI - The inaugural European emergency medical dispatch conference--a synopsis of proceedings. AB - The inaugural European Emergency Medical Dispatch conference was held in Stockholm, Sweden, in May 2013. We provide a synopsis of the conference proceedings, highlight key topic areas of emergency medical dispatch and suggest future research priorities. PMID- 24059652 TI - Isolation of anticancer constituents from flos genkwa (Daphne genkwa Sieb.et Zucc.) through bioassay-guided procedures. AB - BACKGROUND: Flos Genkwa (yuanhua in Chinese), the dried flower buds of Daphne genkwa Sieb.et Zucc. (Thymelaeaceae), is a traditional Chinese medicinal herb mainly used for diuretic, antitussive, expectorant, and anticancer effects. However, systematic and comprehensive studies on Flos Genkwa and its bioactivity are limited. RESULTS: After confirmation of the anti-tumor activity, the 95% ethanolic extract was subjected to successive solvent partitioning to petroleum ether, dichloromethane, n-butanol, and water soluble fractions. Each fraction was tested using the same biological activity model, and the dichloromethane fraction had the highest activity. The dichloromethane fraction was subjected to further chromatographic separation for the isolation of compounds 1-13. Among the 13 compounds, the diterpene esters (compounds 10-13) showed anticancer activity, whereas the flavonoids, lignanoids, and peptides showed moderate activity. Compound 13 was a new daphnane diterpenoid, which was named genkwanin VIII.The preliminary antitumor mechanism of yuanhuacine was studied by protein expression and cell cycle analysis in MCF-7 cancer cells. CONCLUSION: The present investigation tends to support the traditional use of Flos Genkwa for treating cancer. Through bioassay-guided fractionation and isolation techniques, the CH2Cl2 fraction was determined as the active fraction of the flower buds of D. genkwa, and the anti-tumor activity was ascribable to the compounds 10-13. PMID- 24059653 TI - Rare cause of weight loss in a kidney transplant recipient: iron overload. AB - Various reasons such as malignancies and chronic infections may cause weight loss in kidney transplant patients. In this report, iron overload as a rare cause of weight loss in a kidney transplant patient is presented. Forty-seven-year-old male patient who transplanted from a deceased donor 5 years ago was hospitalized because of 20 kg of weight loss. In medical history, he had history of hemodialysis for 89 months and received 100-300 mg of intravenous iron therapy per week before transplantation and transfused eight units of blood. In physical examination, weight and height were 45 kg and 185 cm, respectively. Respiratory and cardiac auscultation was normal. Laboratory results revealed as follow: glucose 76 mg/dL, urea 60 mg/dL, creatinine 1.35 mg/dL, aspartate aminotransferase 74 U/L, alanine aminotransferase 77 U/L, C-reactive protein 2.59 mg/dL, albumin 3.3 g/dL, globulin 3.4 g/dL, white blood cells 3200/mm(3), hemoglobin 13.1 g/dL and platelets 190,000/mm(3). Chest and abdominal tomography didn't reveal any pathology. Portal Doppler ultrasound showed signs of early cirrhosis. Viral and autoimmune hepatitis markers were negative. Ferritin was 5300 ng/mL and transferrin saturation was 82%. In liver biopsy, hemosiderosis was diagnosed and heterozygous H63D gene mutation was detected. Totally, 19 units of phlebotomy were performed. Liver function tests and serum ferritin decreased gradually. At outpatient follow-up in 6 months, he returned to former weight. In conclusion, there can be several causes of weight loss in kidney transplant patients. Iron overload can come across as a rare cause of weight loss. In these patients, ferritin levels should be checked and diagnosis should be clarified by liver biopsy and gene mutation analysis. PMID- 24059655 TI - TiO2-based solid phase extraction strategy for highly effective elimination of normal ribonucleosides before detection of 2'-deoxynucleosides/low-abundance 2'-O modified ribonucleosides. AB - A novel TiO2-based SPE strategy was developed for eliminating normal ribonucleosides before mass spectrometry (MS) analysis of 2'-deoxynucleosides and 2'-O-modified ribonucleosides. The chromatographic research for the retention behavior of ribonucleosides and 2'-deoxynucleosides on TiO2 materials was investigated using TiO2 separation column. The results indicated a specific affinity interaction mechanism between TiO2 and cis-diol-containing ribonucleosides, and the interaction was proved effective even under a wide range of pH conditions and salt concentrations. Benefiting from these features, a TiO2 based solid phase extraction (SPE) method was developed for highly efficient elimination of RNA contamination from genomic DNA. Compared with the widely used enzymatic digestion method, the proposed TiO2-based SPE method showed much more efficiency for the removal of RNA as well as provided high recoveries for the 2' deoxynucleosides. In addition, the sample processing time is dramatically shortened using the TiO2-based SPE method (~5 min) compared to the traditional enzymatic digestion method (~12 h). Finally, the purification of 2'-O-methylated ribonucleosides from RNA was successfully achieved in HeLa cells by the TiO2 based SPE method, which provided a proof-of-concept for the purification of relevant modified ribonucleosides from bulky normal ribonucleosides. Taken together, this strategy developed in the current study offers a promising option to purify 2'-deoxynucleosides/2'-O-modified ribonucleosides for their sensitive and accurate determination by eliminating normal ribonucleosides in biological samples. PMID- 24059654 TI - Inhibition of tumor promoting signals by activation of SSTR2 and opioid receptors in human breast cancer cells. AB - BACKGROUND: Somatostatin receptors (SSTRs) and opioid receptors (ORs) belong to the superfamily of G-protein coupled receptors and function as negative regulators of cell proliferation in breast cancer. In the present study, we determined the changes in SSTR subtype 2 (SSTR2) and MU, delta and kappa-ORs expression, signaling cascades and apoptosis in three different breast cancer cells namely MCF-7, MDA-MB231 and T47D. METHODS: Immunocytochemistry and western blot analysis were employed to study the colocalization and changes in MAPKs (ERK1/2 and p38), cell survival pathway (PI3K/AKT) and tumor suppressor proteins (PTEN and p53) in breast cancer cell lines. The nature of cell death upon activation of SSTR2 or OR was analysed using flow cytometry analysis. RESULTS: The activation of SSTR2 and ORs modulate MAPKs (ERK1/2 and p38) in cell dependent and possibly estrogen receptor (ER) dependent manner. The activation of tumor suppressor proteins phosphatase and tensin homolog (PTEN) and p53 antagonized the PI3K/AKT cell survival pathway. Flow cytometry analyses reveal increased necrosis as opposed to apoptosis in MCF-7 and T47D cells when compared to ER negative MDA MB231 cells. Furthermore, receptor and agonist dependent expression of ORs in SSTR2 immunoprecipitate suggest that SSTR2 and ORs might interact as heterodimers and inhibit epidermal growth factor receptor phosphorylation. CONCLUSION: Taken together, findings indicate a new role for SSTR2/ORs in modulation of signaling pathways involved in cancer progression and provide novel therapeutic approaches in breast cancer treatment. PMID- 24059656 TI - Intracranial Masses with Perilesional Edema: Differential Diagnosis with Perfusion CT. AB - Perilesional edema (PE) is commonly observed in association with an intracranial mass. PE is thought to be determined by vasogenic effects in the cerebral parenchyma surrounding the mass due to the loss or absence of the blood-brain barrier (BBB) inside the lesion. Alterations in capillary permeability induce extrusion of fluids into the extravascular space around the mass. On Computed Tomography (CT) PE corresponds to an area of low density for the increased water content, outside the margins of the lesion. It is difficult to differentiate PE from areas of parenchymal compressive ischemia and sometimes the two events could be associated. A solitary mass with PE is more commonly discovered on a non enhanced computed tomography (NECT) study performed for the onset of stable or rapidly progressive neurological symptoms. In such cases, a supplementary CT scan with contrast (CECT) is generally indicated to complete the baseline imaging before MRI. Contrast enhancement is generally present in a mass with PE and it is not specific for differential diagnosis. Perfusion computed tomography (PCT) requires a few minutes in addition to the time needed for CECT. PCT may give information on regional microvascular density, permeability and blood flow, thus it may play a role when tumoral neo-angiogenesis or non-neoplastic altered haemodynamics are suspected. We therefore investigated the utility of PCT in the differential diagnosis of the intracranial solitary masses with PE. PMID- 24059657 TI - Tuberculosis simulating brain tumour. AB - The purpose of the study is to highlight the varied presentation of tuberculosis (TB) simulating a brain tumour. Headache and seizures are becoming frequent presenting complaints without any history of tuberculosis. The study comprises 1200 patients of both sexes with ages ranging from ten to sixty years. CT scan and MRI brain control with and without contrast medium were the investigations performed in these cases. In some patients Electroencephalography (EEG), cerebral angiography (DSA) and spectroscopy were also performed. The final diagnosis of tuberculosis was made on the basis of craniotomy, stereotactic and burr hole biopsies with histopathology in most of the cases. Forty per cent of the patients were followed up for eight months. They were put on anti-tuberculosis treatment with symptomatic and anti-epileptic drugs. The incidence was 544 and 757 per 100,000 in Africa and Indo Pakistan respectively. The male to female ratio was 1:1. Tuberculosis, especially with CNS involvement, is not only common in immunosuppressed patients in our setting, but TB has been and remains an important public health problem. TB may involve the CNS either as meningitis or as parenchymal granulomas or abscesses. Patients with brain TB usually present with fever, multiple cranial nerve involvement and occasional behavioural changes. CSF findings remain non specific in most cases. The most common sites are the cerebral hemisphere and basal ganglion in adults and the cerebellum in children. Tuberculosis has unique findings on brain CT and MRI. Cortical and subcortical locations are typical whereas the brain stem is a less common site. Tuberculosis lesions are usually solitary but multiple in 10% to 35% of cases. In spite of all these facts some cases of brain TB still need aggressive neurointervention to reach the final diagnosis of brain TB. Tuberculosis in the CNS may manifest in many different ways. So one should always include tuberculosis in the differential diagnosis in the etiology of delayed onset epilepsy and acute on chronic headache. In case of a discrepancy between clinical manifestations and CT/MRI findings, one can always anticipate tuberculous lesion in the brain. PMID- 24059658 TI - Revisiting the CNS tuberculosis with emphasis on giant tuberculomas and introducing the "outer rim excrescence sign". AB - Central nervous system tuberculosis is a leading cause of morbidity and mortality in developing countries with Mycobacterium tuberculosis as the main etiological agent. Classical imaging findings pose no problem for diagnosis of CNS tuberculosis. Cases of giant or solitary ring enhancing lesions are increasing which mimic other infectious and noninfectious pathologies. This is a retrospective study of 40 patients (28 male and 12 female) of either surgically or clinically proven CNS tuberculosis. Solitary tuberculomas (ring or solid enhancing) were seen in 19 patients. Four patients showed presence of two to three lesions and the lesion more than one centimeter size was categorized as 'giant tuberculoma'. Multiple lesions with other associated findings were noted in 21 patients. Total 33 patients showed solitary or multiple ring enhancing lesions. Seven patients showed solid enhancing lesions (giant tuberculoma). The "Outer rim excrescence sign" was noted in a total of 16 patients. Both brain and spinal tuberculosis was noted in six patients. Seven patients presented with meningitis and hydrocephalous which is considered as the most common manifestation in the literature. Spinal leptomeningeal involvement was seen in five patients, whereas intramedullary cord tuberculomas were noted in four patients. Profound T2W hypointensity is a reliable predictor for giant tuberculomas with intense contrast enhancement, especially in deep locations. 'Outer rim excrescence' sign may contribute in cases of ring and solid enhancing lesions, however it requires further comprehensive study with MT Imaging and MR Spectroscopy to be recorded as a differentiating feature. PMID- 24059659 TI - CT and MRI Correlations in Patients with Suspected Cholesteatoma after Surgery. AB - The study of postoperative ear cavities in patients who underwent surgery for cholesteatoma is a difficult challenge for radiologists. In our study we make a correlation between CT and MRI findings, useful tools in patients with suspected residual or recurrent cholesteatoma. The use of different MRI sequences especially DWI can help radiologists to discriminate between cholesteatoma and other different processes. PMID- 24059660 TI - Dual-Acquisition Extracranial Computed Tomographic Angiography-Enhanced Neck Computed Tomography before Transoral Laser Microsurgery in Head and Neck Cancer Patients. Preliminary results. AB - Transoral laser microsurgery (TLM) is an alternative surgical technique for piecemeal endoscopic resection of mucosal-based aerodigestive tract tumors. Though uncommon, potentially catastrophic postoperative bleeding may occur with this technique secondary to vascular injury along invasive tumor inner margins. We describe our preliminary results using a preoperative dual-acquisition extracranial computed tomographic angiography (CTA)-enhanced neck computed tomographic (CT) imaging and postprocessing protocol developed to improve visualization of mucosal-based head and neck tumors and adjacent arterial branches with the objective of facilitating TLM surgery and reducing secondary bleeding complications. Twenty patients with known head and neck cancers anticipated for TLM resection were selected for a dual-acquisition CTA-CT scanning and postprocessing protocol. The mucosal-based pharyngeal tumors and peritumoral vessel enhancement were compared on matched CTA and enhanced neck CT axial images. Operative reports and clinical notes were retrospectively reviewed to identify patients in whom the TLM surgical approach was altered or changed to conventional open surgery as a result of presurgical CTA-CT findings. Enhancement of peritumoral vasculature was almost uniformly superior (19 of 20 patients) on extracranial CTA compared with enhanced neck CT images. In six candidates for TLM surgery (30%), CTA findings resulted in a change in surgical approach to improve intraoperative peritumoral vascular control. In this small pilot series, primary tumor-peritumoral vessel relationships delineated by the addition of extracranial CTA to preoperative enhanced neck CT frequently impacted the surgical approach and facilitated TLM planning. PMID- 24059661 TI - Characteristic Dynamic Enhancement Pattern of MR Imaging for Malignant Thyroid Tumor. Preliminary Report. AB - The purpose of this study was to determine the characteristic dynamic enhancement pattern of MR imaging for malignant thyroid tumor. Eight patients were collected, who had pathology confirmed malignant thyroid tumor preoperatively. There were five papillary carcinomas, one medullary carcinoma, one follicular carcinoma and one FNAB proven atypical cell. All images were obtained with a 3.0-T MR imaging system with and without iv contrast administration. Pathologic report and US imaging finding were collected retrospectively. Based on preoperative MR imaging, we compared dynamic MR enhancement pattern relating to pathologic type. All biopsy proven malignant thyroid tumors show hypoechogenicity on previous US imaging, except one follicular carcinoma (isoechogenicity). On T1-weighted images, one papillary carcinoma showed high SI and one medullary carcinoma showed low SI. The other cases were not differentiated with normal parenchyma. On T2 weighted images, three papillary carcinomas and one follicular carcinoma showed high SI and one papillary carcinoma showed low SI. The other case was not differentiated with normal parenchyma. On contrast agent-enhanced dynamic T1WI, five papillary carcinomas and one medullary carcinoma showed delayed enhancement compared to normal parenchyma. One follicular carcinoma showed stronger enhancement than normal parenchyma, one papillary carcinoma showed persistently decreased enhancement than normal parenchyma. Although this study is limited by the small patient population, the data suggest that delayed enhancement on enhanced dynamic T1WI may be a characteristic MR finding of malignant thyroid tumor. PMID- 24059662 TI - A Possible Role of BA8 in Pre-surgical fMRI. Homage to an Exceptional Neuroscientist. AB - More than 100 years ago Korbinian Brodmann published an article on the cytoarchitecture of the cortical areas of the human brain. This article is meant to honor this great neuroscientist and his incredible thorough analysis of the cortical layers, a work that still remains a valid reference to present day neuroscientists. This is illustrated by the fMRI observation of co-activation of Brodmann's area 8 with activation of Broca, confirming Broca's activation even when the Broca area is displaced by tumor. This connection helps to ascertain and even quantify uni - or bilateral presence of the executive language area's. Although DTI-fiber tracking allows visualization of the connection between Broca's and Wernicke's area by the arcuate fasciculus, no such "wiring" could be shown between Broca's area and Brodmann's area 8. PMID- 24059664 TI - Contrast Enhancement of Low Grade Gliomas (LGG) during Follow-Up. PMID- 24059663 TI - Five-Year Longitudinal MRI Follow-up and (1)H Single Voxel MRS in 14 patients with Gliomatosis Treated with Temodal, Radiotherapy and Antiangiogenic Therapy. AB - Gliomatosis cerebri (GC) is a challenging tumor, considered to have a poor prognosis and poor response to treatments. The purpose of this study is to better understand glial tumor metabolism and post chemotherapy, radiotherapy and antiangiogenic variations in a longitudinal study to determine cerebral variation in MRS area, amplitude, and ratios of metabolites and spectral profiles during a five year longitudinal follow-up in 14 patients with gliomatosis without initial hyperperfusion and treated with chemotherapy (Temozolomide (Temodal((r)))), radiotherapy and subsequent antiangiogenic therapy. The study also aimed to detect changes in infiltration, proliferation, lipids or glycolytic metabolism, as these changes could be monitored longitudinally in humans with glial brain tumors (low and high grade) after therapy, using conventional magnetic resonance imaging (MRI), spectroscopy (MRS) and MR perfusion. Most patients had first initial clinical and MRS improvement and stable MRI. After 12 to 24 chemotherapy treatment cycles MRS usually showed an increase in the Cho/Cr ratio (proliferation) and sometimes contrast enhancements. Later, the patients showed clinical deterioration and radiotherapy was started. There was an improvement with radiotherapy that lasted nine to 18 months. This was followed by a worsening that led to try antiangiogenic therapy. Later in the evolution for three patients with hyperperfusion this symptom disappeared, but proliferation, infiltration and glycolytic metabolism remained at a high level. Spectroscopic and metabolic changes often occur well before clinical deterioration and sometimes before improvement. Therefore, MRS could be more sensitive and could detect changes earlier than MRI and is sometimes predictive. Despite the difficulty, the variability and unknown factors, these repeated measurements give us a better insight into the nature of the different processes, tumor progression and could lead to better understanding of therapeutic response. PMID- 24059665 TI - Neurocysticercosis mimicking brain tumor. AB - Neurocysticercosis together with brain tumors is one of the leading causes of seizures in the developing world. In Western Europe NCC is rare and a high degree of physician awareness is necessary for diagnosis. PMID- 24059666 TI - Proton MR Spectroscopy in Patients with Leigh Syndrome. AB - The aim of the present study was to evaluate MRS findings in patients with Leigh syndrome. We report our results of HMR spectroscopic studies performed in six patients (aged four months to ten years) with clinically proved Leigh syndrome. All examinations were done with 1.5 T scanner using an eight-channel phased array head coil. HMRS data were obtained using 2D-chemical shift imaging (CSI) and SVS sequences with short (30 ms) and long (135 ms) echo time. The MR spectra were acquired in multiple voxel localized in deep gray matter and periventricular white matter. The results were compared to the control group data. In most of our patients we found bilateral lesions in the basal ganglia and brain stem. HMRS data revealed elevated lactate in the affected areas, significantly diminished NAA/Cr ratio. The relatively high Cho/Cr ratio in the gray and white matter was also noted. HMRS is an important tool for non-invasive brain tissue analysis in Leigh syndrome. PMID- 24059667 TI - Neurosarcoidosis: radiologic features in five patients. AB - This paper describes the radiological features in five biopsy-confirmed cases of neurosarcoidosis. The imaging appearance of neurosarcoidosis is highly variable, making the diagnosis difficult on the basis of intracranial images alone. However, if there is evidence of spread along the pia mater, and meningeal mass formation with a lower intensity in the central area and higher intensity in the peripheral area on T2-weighted and FLAIR images, neurosarcoidosis can be considered. PMID- 24059668 TI - Radiological appearances of oropharyngeal soft tissue reduction with bipolar radio-frequency ablation in sleep disordered breathing. A pilot study. AB - To demonstrate and track the changes of bipolar radiofrequency volumetric tissue reduction (BRFVTR) induced lesions of the tongue base and soft palate in the treatment of sleep disordered breathing (SDB) in a pilot study. PMID- 24059669 TI - MDCT Assessment of the Cochlear-Carotid Interval. AB - The close anatomic course between the cochlea and the carotid artery presents a possible surgical risk during increasingly popular cohlear implant surgery. The purpose of this study was to determine the normal range of the this region termed "cohlear- carotid interval" (CCI) by 64-slice multi-detector computed tomography (MDCT) in the population. The study investigated 1105 patients who had undergone temporal MDCT. The CCI measured by two observers from 0.5 mm thick coronal images with confirmation on axial and sagittal planes. Among 1105 patients and 2210 temporal sides CCI measured 0.0 mm unilaterally in eight (0.7%) and bilaterally in two patients (0.1%) with a score of ten in the total population (0.9%). Total scores ranged from 0.0 to 6 mm for right CCI and 0.0 to 5.9 mm for left CCI. The CCI showed no significant relationship with sex (P=.096) and there were no significant differences between readers (P=.457) and sides (P=.879). A positive correlation (r=0.741) was found between right and left CCI. The present study demonstrated that the CCI varies considerably between 0.0 mm and 6 mm independently of sex in the population. Understanding the importance of CCI and preoperative knowledge of thin or absent bone allows the radiologist to play a crucial role in alerting the surgeon to prevent penetration of the carotid canal during cochlear implant surgery. PMID- 24059670 TI - Magnetic resonance imaging of the oculomotor nerve. AB - Oculomotor/cranial nerve III palsy is caused by numerous etiologies involving the brainstem, subarachnoid space, cavernous sinus or superior orbital fissure or orbit. Magnetic resonance imaging (MRI) is the most suitable neuro-imaging technique in patients with this presentation to rule out a mass, aneurysm or ischemic vasculopathy. A pictorial review of various pathologies affecting the oculomotor nerve is presented along with their MRI morphology. PMID- 24059671 TI - Congenital cystic eye with corpus callosum hypoplasia: MRI findings. AB - Congenital cystic eye is an extremely rare congenital anomaly with fewer than 40 cases reported. Although its aetiology remains unknown, it results from partial to complete failure in invagination of the primary optic vesicle. It is usually unilateral and presents as a heterogeneous lesion with a cyst bulging the upper eyelid and a solid component consisting in neuroglial tissue. We describe a rare case of congenital cystic eye with corpus callosum hypoplasia with special focus on the magnetic resonance imaging (MRI) features and their role in the diagnosis. We conclude that MRI is not only useful in the diagnosis and management of this rare entity, but it can also be helpful in diagnosing associated brain abnormalities. PMID- 24059672 TI - Focal cortical dysplasia: a pictorial review. AB - Abnormalities of cortical development are frequent causes of refractory epilepsy. Among these pathologies, focal cortical dysplasia (FCD) is a heterogeneous group of disorders pathologically characterized by loss of normal cortical structure. Two distinct entities with different etiology have been described (FCD type I and FCD type II Taylor). This study presents relevant case studies, highlighting the pathological features in magnetic resonance imaging. PMID- 24059673 TI - Development of the hippocampal region demonstrated by fetal MRI. A preliminary report. AB - Coronal slices of three fetal MRIs performed post mortem and 37 performed in utero, all without intracranial pathology, was assessed. Progress of the hippocampal inversion was analyzed, the left and right sides were compared and occurrence of the collateral sulcus was revealed. The fetuses in the post mortem examinations were at gestation weeks (GW) 17-18 and in the in utero examinations at GW 19-35. The symmetric development of the hippocampal sulcus was revealed in 26 subjects and asymmetric in 14. The non-ovoid hippocampal formation could be evaluated at GW 24 at earliest and an ovoid hippocampus at GW 29. The collateral sulcus could be recognized at GW 17 in post mortem and at GW 22 in in utero examinations. From GW 29 onwards it was seen in all fetuses and it was symmetric in all but one case. Evaluation of the hippocampi is difficult on fetal MRI, especially in in utero examinations. The hippocampal development is not fulfilled at GW 21 as presumed. There is a wide temporal variation in the development of the hippocampal region, and the developmental process does not progress simultaneously in the right and left side of the same individual. PMID- 24059674 TI - Evaluation of the impact of three-dimensional vision on laparoscopic performance. AB - INTRODUCTION: Recent technological advancements have led to the introduction of new three-dimensional (3D) cameras in laparoscopic surgery. The 3D view has been touted as useful during robotic surgery, however, there has been limited investigation into the utility of 3D in laparoscopy. MATERIALS AND METHODS: We performed a prospective, randomized crossover trial comparing a 0 degrees 3D camera with a conventional 0 degrees two-dimensional (2D) camera using a high definition monitor (Karl Storz, Tuttlingen, Germany). All participants completed six standardized basic skills tasks. Quality testing scores were measured by the number of drops, grasping attempts, and precision of needle entry and exiting. Additionally, resolution, color distribution, depth of field and distortion were measured using optical test targets. RESULTS: In this pilot study, we evaluated 10 medical students, 7 residents, and 7 expert surgeons. There was a significant difference in the performance in all the six skill tasks, for the three levels of surgical expertise and training levels in 2D vs 3D except for the cut the line quality score and the peg transfer quality score. Adjusting for the training level, 3D camera image results were superior for the number of rings left (p=0.041), ring transfer quality score (p=0.046), thread the rings (no. of rings) (p=0.0004), and thread the rings quality score (p=0.0002). The 3D camera image was also superior for knot tying (quality score) (p=0.004), peg transfer (time in seconds) (p=0.047), peg transfer pegs left (p=0.012), and for peg transfer quality score (p=0.001). The 3D camera system showed significantly less distortion (p=0.0008), a higher depth of field (p=0.0004) compared with the 2D camera system. CONCLUSION: 3D laparoscopic camera equipment results in a significant improvement in depth perception, spatial location, and precision of surgical performance compared with the conventional 2D camera equipment. With this improved quality of vision, even expert laparoscopic surgeons may benefit from 3D imaging. PMID- 24059675 TI - Lancolides, antiplatelet aggregation nortriterpenoids with tricyclo[6.3.0.0(2,11)]undecane-bridged system from Schisandra lancifolia. AB - A new class of highly oxygenated Schisandra nortriterpenoids, lancolides A-D (1 4), from Schisandra lancifolia, represents the first example of natural products that possess a tricyclo[6.3.0.0(2,11)]undecane-bridged system. Their structures were elucidated by NMR spectra, X-ray diffraction, and quantum chemical calculations. Lancolides A (1) and D (4) had specific antiplatelet aggregation induced by platelet-activating factor (PAF). PMID- 24059676 TI - Non-apnea sleep disorder increases the risk of periodontal disease: a retrospective population-based cohort study. AB - BACKGROUND: The aim of this study is to determine whether patients with a non apnea sleep disorder (NA-SD) and comorbidity have an increased risk of periodontal disease. METHODS: Patients newly diagnosed with NA-SDs in 1997 to 2010 were identified as the study cohort from the Taiwan National Health Insurance database. For each patient with NA-SD, two matched controls without sleep disorders were randomly selected for comparison. RESULTS: The overall incidence rate ratio of severe periodontal diseases was 39% higher in the NA-SD cohort than in the comparison cohort (7.93 versus 5.69 per 1,000 person-years), with an adjusted hazard ratio (HR) of 1.36 (95% confidence interval [CI]: 1.30 to 1.43). The effect of NA-SD on the risk of severe periodontal diseases was higher in young and middle-aged patients compared with patients >65 years of age (<35 years of age, HR: 1.13, 95% CI: 1.04 to 1.24; 35 to 49 years of age, HR: 1.73, 95% CI: 1.61 to 1.86; 50 to 64 years of age, HR: 1.69, 95% CI: 1.58 to 1.81; >=65, HR: [reference] 1.0). CONCLUSION: NA-SD might increase the risk of periodontal disease. PMID- 24059677 TI - EGFR-inhibition enhances apoptosis in irradiated human head and neck xenograft tumors independent of effects on DNA repair. AB - Epidermal growth factor receptor (EGFR) inhibition using cetuximab improves the efficacy of radiotherapy in only a subgroup of head and neck squamous cell carcinoma (HNSCC) patients. Therefore, to improve patient selection a better understanding of tumor characteristics that affect treatment is necessary. Here, we investigated the effect of cetuximab on repair of radiation-induced DNA damage in a HNSCC xenograft model, which shows a synergistic effect to cetuximab and radiotherapy (SCCNij185) and a HNSCC model, which shows no additive effect of cetuximab to radiotherapy (SCCNij153). In both tumor models, clear increases were seen in the number of 53BP1 and Rad51 foci after irradiation. 53BP1 foci were present at comparable levels in hypoxic and normoxic tumor areas of the tumor xenografts, while the number of Rad51 foci was significantly higher in normoxic areas compared to hypoxic areas (P < 0.05). In both SCCNij185 and SCCNij153 xenografts an increased number of 53BP1 foci was observed in tumors treated with cetuximab and radiotherapy compared to radiotherapy alone. In SCCNij185 this increase was statistically significant in normoxic tumor areas (P = 0.04) and in SCCNij153 in both hypoxic and normoxic areas (P = 0.007 and P = 0.02, respectively). The number of Rad51 foci was not significantly different when cetuximab was added to radiotherapy compared to radiotherapy alone. Levels of pEGFR and pERK1/2 were decreased when cetuximab was added to radiotherapy in SCCNij185, but not in SCCNij153. Apoptosis was also only increased in SCCNij185 tumors at 4 days after cetuximab and radiotherapy treatment (P < 0.01). In conclusion, cetuximab inhibited DNA repair in both HNSCC models, but this effect was not predictive for the radiosensitizing effect of cetuximab in vivo. This lack of correlation may be related to differential effects of cetuximab and radiotherapy on ERK1/2 signaling and a decreased induction of apoptosis by cetuximab and radiotherapy in the resistant model. PMID- 24059678 TI - Radiation enhances the invasiveness of irradiated and nonirradiated bystander hepatoma cells through a VEGF-MMP2 pathway initiated by p53. AB - Recent evidence has shown that irradiation can promote the invasiveness of hepatocellular carcinoma cells and have an impact on the invasive behavior of nonirradiated surrounding cancer cells, which may enhance overall tumor aggressiveness. However, the role of the TP53 tumor suppressor gene in the invasion of irradiated hepatoma cells and their nonirradiated bystanders remain largely unknown. In the present study, we found that irradiation increased the invasiveness of human hepatoma HepG2 cells, and pretreatment of the cells with SU1498 (an inhibitor of vascular endothelial growth factor receptor 2, VEGFR2) and GM6001 (an inhibitor of matrix metalloproteinases 2, MMP2) demonstrated that radiation-enhanced invasiveness is associated with the interplay between MMP2 and VEGF signaling. In addition, while radiation-induced expression and phosphorylation of p53, inhibition of p53 function with pifithrin-alpha or transfection of cells with p53 siRNA significantly reduced the activation of both MMP2 and VEGF and resulted in a reduction of radiation-induced invasiveness. Interestingly, we also found that the invasiveness of the nonirradiated bystander cells was also elevated after co-culturing with irradiated cells and that bystander invasive potential was regulated paracrine in a manner by MMP2 and VEGF from the irradiated cells through a p53-dependent mechanism. Taken together, our data demonstrate that radiation-induced up-regulation of p53 is responsible for the promotion of VEGF-MMP2 pathway involved in the enhancement of invasiveness of both irradiated and bystander hepatoma cells. PMID- 24059679 TI - Glaucoma in atomic bomb survivors. AB - Radiation has been associated with increases in noncancerous diseases. An effect of low-dose radiation on the prevalence of clinically detected glaucoma has not been previously reported. We therefore investigated the prevalence of glaucoma in A-bomb survivors and its possible association with radiation dose. A total of 1,589 people who participated in the clinical examination program for A-bomb survivors at the Radiation Effects Research Foundation (RERF) between October 2006 and September 2008 and who had reconstructed radiation doses, were recruited into this cross-sectional screening study. The prevalence of glaucoma and its dose-response relationship to A-bomb radiation were measured. Each subject underwent an initial screening consisting of an interview and ophthalmological examination. Questionable cases with any indication of ocular disease, including glaucoma, were referred to local hospitals for more comprehensive evaluation. A diagnosis of glaucoma was made based on specific optic disc appearance, perimetric results and other ocular findings. Of 1,589 eligible people, we detected 284 (17.9%) cases of glaucoma overall, including 36 (2.3%) cases of primary open-angle glaucoma with intraocular pressure levels greater than 21 mmHg, 226 (14.2%) cases of normal-tension glaucoma and 25 (1.6%) cases of primary angle-closure glaucoma. Seven glaucoma risk factors were examined as potential confounders but only two needed to be included in the final model. Binary regression using a generalized estimating equation method, with adjustment for gender, age, city, cataract surgery or diabetes mellitus, revealed an odds ratio at 1 Gy of 1.31 (95% confidence interval 1.11-1.53, P = 0.001) in the case of normal-tension glaucoma, but no association for other types of glaucoma. The prevalence of normal-tension glaucoma may increase with A-bomb radiation dose, but uncertainties associated with nonparticipation (59% participation) suggest caution in the interpretation of these results until they are confirmed by other studies. PMID- 24059680 TI - The murine common deletion: mitochondrial DNA 3,860-bp deletion after irradiation. AB - This study demonstrates that mice, similar to humans, have a common mitochondrial DNA deletion (3,860 bp) that encodes 5 transfer RNA genes and 5 polypeptide genes that is related to aging, tissue type and radiotoxicity. Our research indicates that the deletion ratio in the liver was significantly higher than in the brain and gut tissues of 8-month-old mice, as compared to 8-week-old mice. Our results also demonstrate that tissue type, oxidative metabolic capacity and radiosensitivity influence the 3,860-bp deletion level. Therefore, this 3,860-bp deletion content may serve as a biomarker of aging and oxidative damage in mice. PMID- 24059681 TI - Thermal injury lowers the threshold for radiation-induced neuroinflammation and cognitive dysfunction. AB - The consequences of radiation exposure alone are relatively well understood, but in the wake of events such as the World War II nuclear detonations and accidents such as Chernobyl, other critical factors have emerged that can substantially affect patient outcome. For example, ~70% of radiation victims from Hiroshima and Nagasaki received some sort of additional traumatic injury, the most common being thermal burn. Animal data has shown that the addition of thermal insult to radiation results in increased morbidity and mortality. To explore possible synergism between thermal injury and radiation on brain, C57BL/6J female mice were exposed to either 0 or 5 Gy whole-body gamma irradiation. Irradiation was immediately followed by a 10% total-body surface area full thickness thermal burn. Mice were sacrificed 6 h, 1 week or 6 month post-injury and brains and plasma were harvested for histology, mRNA analysis and cytokine ELISA. Plasma analysis revealed that combined injury synergistically upregulates IL-6 at acute time points. Additionally, at 6 h, combined injury resulted in a greater upregulation of the vascular marker, ICAM-1 and TNF-alpha mRNA. Enhanced activation of glial cells was also observed by CD68 and Iba1 immunohistochemistry at all time points. Additionally, doublecortin staining at 6 months showed reduced neurogenesis in all injury conditions. Finally, using a novel object recognition test, we observed that only mice with combined injury had significant learning and memory deficits. These results demonstrate that thermal injury lowers the threshold for radiation-induced neuroinflammation and long-term cognitive dysfunction. PMID- 24059683 TI - Sensitivity and performance of azole-based energetic materials. AB - Imidazole, pyrazole, 1,2,3-triazole-, 1,2,4-triazole-, and tetrazole-based energetic materials are theoretically investigated by employing density functional theory (DFT). Heats of formation (DeltafH(0)'s) for the studied compounds (298 K) in the gas phase are determined at the B3P86/6-311G (d, p) theory level through isodesmic reactions. The bond dissociation energies (BDEs) corresponding to NO2, NH2, CH3, and Cl removal from carbon or nitrogen positions of the azole ring are also calculated at the B3P86/6-311G (d, p) theory level. The substituent effect of electron-withdrawing (NO2, Cl) and electron-donating (NH2, CH3) groups on the DeltafH(0)s and BDEs is discussed. Both electron withdrawing groups and electron-donating groups (except the CH3 group) dramatically increase the DeltafH(0)s of these energetic materials when the substituent is at an N position on the azole ring. For substitution at a C atom on the azole ring, electron-withdrawing and electron-donating groups have different effects on the DeltafH(0)s for different azole compounds. A correlation is developed for this series of energetics between impact sensitivity h50% and the defined sensitivity index (SI): based on this empirical relationship and its extrapolation, the impact sensitivities of compounds for which experiments are not available are provided. The promising energetic compounds in each groups, which have potentially good energetic performance and low sensitivity, are 1 amino-2,4,5-trinitroimidazole, 1-amino-3,4,5-trinitropyrazole, 1,4-dinitro-1,2,3 triazole, 1,3-dinitro-1,2,4-triazole, and 1-nitrotetrazole. PMID- 24059684 TI - Discovery of 6-deoxydapagliflozin as a highly potent sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. AB - Systematic mono-deoxylation of the four hydroxyl groups in the glucose moiety in dapagliflozin led to the discovery of 6-deoxydapagliflozin 1 as a more active sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (IC50 = 0.67 nM against human SGLT2 (hSGLT2) vs 1.16 nM for dapagliflozin). It exhibited more potent blood glucose inhibitory activity in rat oral glucose tolerance test and induced more urinary glucose in rat urinary glucose excretion test than its parent compound dapagliflozin. PMID- 24059682 TI - HIV-1 envelope glycoprotein signatures that correlate with the development of cross-reactive neutralizing activity. AB - BACKGROUND: Current HIV-1 envelope glycoprotein (Env) vaccines are unable to induce cross-reactive neutralizing antibodies. However, such antibodies are elicited in 10-30% of HIV-1 infected individuals, but it is unknown why these antibodies are induced in some individuals and not in others. We hypothesized that the Envs of early HIV-1 variants in individuals who develop cross-reactive neutralizing activity (CrNA) might have unique characteristics that support the induction of CrNA. RESULTS: We retrospectively generated and analyzed env sequences of early HIV-1 clonal variants from 31 individuals with diverse levels of CrNA 2-4 years post-seroconversion. These sequences revealed a number of Env signatures that coincided with CrNA development. These included a statistically shorter variable region 1 and a lower probability of glycosylation as implied by a high ratio of NXS versus NXT glycosylation motifs. Furthermore, lower probability of glycosylation at position 332, which is involved in the epitopes of many broadly reactive neutralizing antibodies, was associated with the induction of CrNA. Finally, Sequence Harmony identified a number of amino acid changes associated with the development of CrNA. These residues mapped to various Env subdomains, but in particular to the first and fourth variable region as well as the underlying alpha2 helix of the third constant region. CONCLUSIONS: These findings imply that the development of CrNA might depend on specific characteristics of early Env. Env signatures that correlate with the induction of CrNA might be relevant for the design of effective HIV-1 vaccines. PMID- 24059685 TI - The role of hepatocyte nuclear factor 4alpha in metastatic tumor formation of hepatocellular carcinoma and its close relationship with the mesenchymal epithelial transition markers. AB - BACKGROUND: Mesenchymal-epithelial transition (MET) is now suggested to participate in the process of metastatic tumor formation. However, in hepatocellular carcinoma (HCC) the process is still not well revealed. METHODS: Paraffin-embedded tissue samples were obtained from 13 patients with HCC in Shengjing Hospital of China Medical University. The expression of E-cadherin, Fibronectin, N-cadherin, Vimentin, Hepatocyte nuclear factor 4alpha (HNF4alpha), Snail and Slug was assessed in primary tumors and their corresponding metastases by immunohistochemical staining. Next, the expression of HNF4alpha and E-cadherin in four HCC cell lines was examined. Furthermore, SK-Hep-1 cells were transfected with human HNF4alpha expression vector, and the change of E-cadherin expression was assessed. RESULTS: 45.2% (14/31) of the lesions in the metastases showed increased E-cadherin expression compared with the primaries, suggesting the possible occurrence of MET in metastatic tumor formation of HCC, as re-expression of E-cadherin is proposed to be the important hallmark of MET. The occurrence of MET was also confirmed by the reduced expression of Fibronectin (54.8%, 17/31), N cadherin (38.7%, 12/31) and Vimentin (61.3%, 19/31) in the metastases. 45.2% (14/31) of the lesions in the metastases also showed increased HNF4alpha expression, and 67.7% (21/31) and 48.4% (15/31) of metastases showed decreased Snail and Slug expression respectively. Statistical results showed that the expression of HNF4alpha was positively related with that of E-cadherin, and negatively correlated with that of Snail, Slug and Fibronectin, suggesting that the expression change of the MET markers in the metastatic lesions might be associated with HNF4alpha. Among the four HCC cell lines, both HNF4alpha and E cadherin expressed high in Hep3B and Huh-7 cells, but low in SK-Hep-1 and Bel 7402 cells. Furthermore, the expression of E-cadherin increased accordingly when SK-Hep-1 cells were transfected with human HNF4alpha expression vector, further confirming the role of HNF4alpha in the regulation of E-cadherin expression. CONCLUSIONS: Our clinical observations and experimental data indicate that HNF4alpha might play a crucial role in the metastatic tumor formation of HCC, and the mechanism may be related with the process of phenotype transition. PMID- 24059686 TI - Growth of crystalline hydroxyapatite thin films at room temperature by tuning the energy of the RF-magnetron sputtering plasma. AB - Right angle radio frequency magnetron sputtering technique (RAMS) was redesigned to favor the production of high-quality hydroxyapatite (HA) thin coatings for biomedical applications. Stoichiometric HA films with controlled crystallinity, thickness varying from 254 to 540 nm, crystallite mean size of 73 nm, and RMS roughness of 1.7 +/- 0.9 nm, were obtained at room temperature by tuning the thermodynamic properties of the plasma sheath energy. The plasma energies were adjusted by using a suitable high magnetic field confinement of 143 mT (1430 G) and a substrate floating potential of 2 V at the substrate-to-magnetron distance of Z = 10 mm and by varying the sputtering geometry, substrate-to-magnetron distance from Z = 5 mm to Z = 18 mm, forwarded RF power and reactive gas pressure. Measurements that were taken with a Langmuir probe showed that the adjusted RAMS geometry generated a plasma with an adequate effective temperature of Teff ~ 11.8 eV and electron density of 2.0 * 10(15) m(-3) to nucleate nanoclusters and to further crystallize the nanodomains of stoichiometric HA. The deposition mechanism in the RAMS geometry was described by the formation of building units of amorphous calcium phosphate clusters (ACP), the conversion into HA nanodomains and the crystallization of the grain domains with a preferential orientation along the HA [002] direction. PMID- 24059687 TI - Weekend diagnosis of Escherichia coli urinary tract infection does not predict poor outcome. AB - It has been suggested that mortality is higher in patients admitted to hospitals during the weekend. The objective of this study was to compare outcomes in patients with E. coli urinary tract infection (UTI) depending on the hospital admission day. For this purpose, a secondary analysis of data from a prospective cohort of patients with E. coli UTI was conducted. Weekend diagnosis of UTI was not associated with higher mortality. However, mortality was associated with sepsis, sepsis-induced hypotension and intensive care unit (ICU) admission. Sepsis-induced hypotension and ICU admission were independent determinants of mortality. The results indicate that indicators of severity of illness are associated with higher mortality in patients with UTI rather than the time of diagnosis. PMID- 24059689 TI - Formation and tunable disassembly of polyelectrolyte-Cu2+ layer-by-layer complex film. AB - Layer-by-layer assembly of films containing metal ions was investigated. A complex between various metal ions and branched polyethyleneimine is formed in solution and then assembled into multilayer films with poly(acrylic acid). The metal-ligand complex formation results in brightly colored materials that deposit as thick layers. Cu(2+)-containing films were chosen as a model for studying the disassembly of these films in response to various stimuli, including pH, salt, and surfactants. The range of pH instability corresponds to the pH range over which pores are formed in the film. We demonstrate controllable disassembly of these materials, which could be used for antifungal or antibacterial applications. PMID- 24059688 TI - Ocular tissues and fluids oxidative stress in hares fed on verbascoside supplement. AB - The influence of a prolonged diet supplemented with the powerful antioxidant verbascoside on the oxidative state of 20 healthy hares eye fluids and tissues has been studied. Verbascoside was dosed at 2, 3, 4 mg/die and the impact on the oxidative state of ocular tissues and fluids was tested by TBARS (thio barbituric acid reactive substances) and TEAC (trolox equivalent antioxidant capacity) assays. The percentage of change in antioxidant activity increased largely in retina and lenses at a daily verbascoside dose of 3 mg, whereas for optic nerve and vitreous humor the higher antioxidant capacity was measured at 4 mg/die verbascoside dose. The present findings demonstrate that verbascoside supplementation is able to protect ocular tissue and fluids from naturally occurring oxidation and that its protective effect depends on the daily dose, being maximum up to 3 mg/die. PMID- 24059690 TI - Effects of nebivolol and atenolol on central aortic pressure in hypertensive patients: a multicenter, randomized, double-blind study. AB - INTRODUCTION: The main objective was to compare the mean change in augmentation index of hypertensive patients treated with nebivolol or atenolol. METHODS: Multicenter, double-blind randomized study conducted in six Spanish centers. We enrolled outpatients between the ages of 40 and 65 years with mild or moderate essential hypertension (systolic blood pressure, SBP >= 140 mmHg to <= 179 mmHg and diastolic blood pressure, DBP >= 90 mmHg to <= 109 mmHg after a 2-week run-in placebo period). Patients received nebivolol 5 mg or atenolol 50 mg once daily. At week 3, atenolol could be titrated up to 100 mg qd for non-responders. Additionally, patients not achieving normal blood pressure after 6 weeks could be treated with 25 mg hydrochlorothiazide. Follow-up visits were at 3, 6 and 10 weeks. RESULTS: The final study population of 138 patients (58% men; median age 52.6 years, range 40-67 years) was randomized into two groups of 69 patients each. Baseline characteristics of the two groups were similar. At the screening visit, 69% presented with mild hypertension. Nebivolol modified the mean augmentation index to a lesser extent than atenolol after 10 weeks (mean difference 3.1%, 95% CI 0.55-5.69; p = 0.027). A higher proportion of patients in the atenolol group required a diuretic. Reductions in central aortic pressure and peripheral arterial pressure were similar for both treatment groups. CONCLUSIONS: The study confirms that nebivolol produces a less pronounced impact on augmentation index than atenolol. PMID- 24059693 TI - Acquired Bartter-like syndrome association with netilmicin therapy in an extremely low birth weight infant. AB - Aminoglycosides are commonly used antibiotics with excellent renal parenchymal penetration. Their clinical effectiveness is counter balanced with the risk of renal toxicity, which develops in a dose-dependent fashion. Aminoglycoside induced renal tubular dysfunction could result in diffuse damage or manifest as a Fanconi-like syndrome, Bartter-like syndrome (BLS), or distal renal tubular acidosis.(1-4) Although tubulopathy associated with amikacin and gentamicin was reported in adults and rarely children, to the best of our knowledge, netilmicin associated BLS neither in adults nor in children has been reported in the literature. We here report a 30-week, 770 g male preterm infant who developed BLS just after netilmicin treatment for neonatal sepsis and recovered 6 weeks after the drug cessation. PMID- 24059692 TI - Age-dependent effects of microglial inhibition in vivo on Alzheimer's disease neuropathology using bioactive-conjugated iron oxide nanoparticles. AB - BACKGROUND: Tau dysfunction is believed to be the primary cause of neurodegenerative disorders referred to as tauopathies, including Alzheimer's disease, Pick's disease, frontotemporal dementia and Parkinsonism. The role of microglial cells in the pathogenesis of tauopathies is still unclear. The activation of microglial cells has been correlated with neuroprotective effects through the release of neurotrophic factors and through clearance of cell debris and phagocytosis of cells with intracellular inclusions. In contrast, microglial activation has also been linked with chronic neuroinflammation contributing to the development of neurodegenerative diseases such as tauopathies. Microglial activation has been recently reported to precede tangle formation and the attenuation of tau pathology occurs after immunosuppression of transgenic mice. METHODS: Here we report the specific inhibition of microglial cells in rTg4510 tau-mutant mice by using fibrin gamma377-395 peptide conjugated to iron oxide (gamma-Fe2O3) nanoparticles of 21 +/- 3.5 nm diameter. RESULTS: Stabilization of the peptide by its covalent conjugation to the gamma-Fe2O3 nanoparticles significantly decreased the number of the microglial cells compared to the same concentration of the free peptide. The specific microglial inhibition induces different effects on tau pathology in an age dependent manner. The reduction of activation of microglial cells at an early age increases the number of neurons with hyperphosphorylated tau in transgenic mice. In contrast, reduction of activation of microglial cells reduced the severity of the tau pathology in older mice. The number of neurons with hyperphosphorylated tau and the number of neurons with tangles are reduced than those in animals not receiving the fibrin gamma377-395 peptide-nanoparticle conjugate. CONCLUSIONS: These results demonstrate a differential effect of microglial activity on tau pathology using the fibrin gamma377-395 peptide-nanoparticle conjugate, depending on age and/or stage of the neuropathological accumulation and aggregation. PMID- 24059691 TI - Rapid genome wide mapping of phosphine resistance loci by a simple regional averaging analysis in the red flour beetle, Tribolium castaneum. AB - BACKGROUND: Next-generation sequencing technology is an important tool for the rapid, genome-wide identification of genetic variations. However, it is difficult to resolve the 'signal' of variations of interest and the 'noise' of stochastic sequencing and bioinformatic errors in the large datasets that are generated. We report a simple approach to identify regional linkage to a trait that requires only two pools of DNA to be sequenced from progeny of a defined genetic cross (i.e. bulk segregant analysis) at low coverage (<10*) and without parentage assignment of individual SNPs. The analysis relies on regional averaging of pooled SNP frequencies to rapidly scan polymorphisms across the genome for differential regional homozygosity, which is then displayed graphically. RESULTS: Progeny from defined genetic crosses of Tribolium castaneum (F4 and F19) segregating for the phosphine resistance trait were exposed to phosphine to select for the resistance trait while the remainders were left unexposed. Next generation sequencing was then carried out on the genomic DNA from each pool of selected and unselected insects from each generation. The reads were mapped against the annotated T. castaneum genome from NCBI (v3.0) and analysed for SNP variations. Since it is difficult to accurately call individual SNP frequencies when the depth of sequence coverage is low, variant frequencies were averaged across larger regions. Results from regional SNP frequency averaging identified two loci, tc_rph1 on chromosome 8 and tc_rph2 on chromosome 9, which together are responsible for high level resistance. Identification of the two loci was possible with only 5-7* average coverage of the genome per dataset. These loci were subsequently confirmed by direct SNP marker analysis and fine-scale mapping. Individually, homozygosity of tc_rph1 or tc_rph2 results in only weak resistance to phosphine (estimated at up to 1.5-2.5* and 3-5* respectively), whereas in combination they interact synergistically to provide a high-level resistance >200*. The tc_rph2 resistance allele resulted in a significant fitness cost relative to the wild type allele in unselected beetles over eighteen generations. CONCLUSION: We have validated the technique of linkage mapping by low-coverage sequencing of progeny from a simple genetic cross. The approach relied on regional averaging of SNP frequencies and was used to successfully identify candidate gene loci for phosphine resistance in T. castaneum. This is a relatively simple and rapid approach to identifying genomic regions associated with traits in defined genetic crosses that does not require any specialised statistical analysis. PMID- 24059695 TI - Migration of iron, lead, cadmium and tin from tinplate-coated cans into chickpeas. AB - Migration studies of trace metals were carried out on coated chickpea cans marketed in Lebanon. Four elements--(Fe), tin (Sn), lead (Pb) and cadmium (Cd)- were analysed by atomic absorption spectrometry (AAS) after microwave digestion. Over 3 months, three different storage temperatures (5 degrees C, room temperature and 40 degrees C) were tested. In all cases, the migration of Fe reached a plateau after around 50 days of storage, while the migration of Pb was slow till 50 days, then it increased rapidly. Cd and Sn levels did not increase. Moreover, no effect of temperature was observed in the case of Fe, whereas Pb levels showed slower migration in cans stored at 5 degrees C. Comparing cans from different chickpea brands (Lebanese and foreign) showed that the characteristics of the container have an effect on metal release. PMID- 24059694 TI - Benchmarking of protein descriptor sets in proteochemometric modeling (part 1): comparative study of 13 amino acid descriptor sets. AB - BACKGROUND: While a large body of work exists on comparing and benchmarking of descriptors of molecular structures, a similar comparison of protein descriptor sets is lacking. Hence, in the current work a total of 13 different protein descriptor sets have been compared with respect to their behavior in perceiving similarities between amino acids. The descriptor sets included in the study are Z scales (3 variants), VHSE, T-scales, ST-scales, MS-WHIM, FASGAI and BLOSUM, and a novel protein descriptor set termed ProtFP (4 variants). We investigate to which extent descriptor sets show collinear as well as orthogonal behavior via principal component analysis (PCA). RESULTS: In describing amino acid similarities, MSWHIM, T-scales and ST-scales show related behavior, as do the VHSE, FASGAI, and ProtFP (PCA3) descriptor sets. Conversely, the ProtFP (PCA5), ProtFP (PCA8), Z-Scales (Binned), and BLOSUM descriptor sets show behavior that is distinct from one another as well as both of the clusters above. Generally, the use of more principal components (>3 per amino acid, per descriptor) leads to a significant differences in the way amino acids are described, despite that the later principal components capture less variation per component of the original input data. CONCLUSION: In this work a comparison is provided of how similar (and differently) currently available amino acids descriptor sets behave when converting structure to property space. The results obtained enable molecular modelers to select suitable amino acid descriptor sets for structure-activity analyses, e.g. those showing complementary behavior. PMID- 24059697 TI - Reaction of a copper(II)-nitrosyl complex with hydrogen peroxide: phenol ring nitration through a putative peroxynitrite intermediate. AB - Copper(II) complex, 1, with the histidine-derived ligand L (L = methyl 2-(2 hydroxybenzylamino)-3-(1H-imidazol-5-yl)propanoate) has been synthesized and characterized. Single-crystal structure determination reveals a diphenolato bridged dicopper(II) core in 1. Addition of (*)NO to an acetonitrile solution of 1 affords the corresponding mononuclear copper(II)-nitrosyl complex, 2. In the presence of H2O2, 2 results in formation of the corresponding copper(I) peroxynitrite. Formation of peroxynitrite ((-)OONO) intermediate is evident from its characteristic phenol ring nitration reaction which resembles the tyrosine nitration in biological systems. Further, isolation of nitrate (NO3(-)) as the decomposition product from 2 at room temperature also supports the involvement of (-)OONO intermediate. PMID- 24059696 TI - Optimization of ultrasonic extraction of polysaccharides from Ziziphus jujuba Mill. by response surface methodology. AB - BACKGROUND: Ziziphus jujuba Mill. is nutritious and used as food and medicine for more than two thousand years. It has many pharmacological effects, such as elimination of fatigue, dilation of blood vessels, etc. The polysaccharide in it is one of the bioactive substances. In this paper, the ultrasonic extraction effects on the yield and activity of polysaccharide were studied. RESULTS: The optimum ultrasonic extraction conditions were investigated based on a Box-Behnken statistical experimental design. Response surface methodology (RSM) of three factors (ultrasonic power, extraction time and extraction temperature) and three levels was employed to optimize the yield and the antioxidant activity of the polysaccharides. The experimental data were fitted to quadratic response surface models using multiple regression analysis. The best extraction conditions were 120 W, 15 min. and 55 degrees C for highest yield, and 80 W, 15 min. and 40 degrees C for highest hydroxyl radical scavenging activity. CONCLUSION: The study showed that high ultrasonic power was good for obtaining high yield but bad for keeping the antioxidant activity of the polysaccharides. PMID- 24059698 TI - Chemically triggered C-ON bond homolysis of alkoxyamines. 8. Quaternization and steric effects. AB - The C-ON bond homolysis in alkoxyamine 2a was chemically triggered by quaternization of the 1-(pyridin-2-yl)ethyl fragment using protonation, acylation, and oxidation into the N-oxide. The solvent effect was also investigated, and DFT calculations were performed to explore this chemical activation. Alkoxyamines 2a-d were also compared to the 1-(pyridin-4-yl)ethyl analogues 3a-d. PMID- 24059700 TI - S-, N-, and Se-difluoromethylation using sodium chlorodifluoroacetate. AB - A simple protocol for the difluoromethylation of thiols is reported using chlorodifluoroacetate as the difluoromethylating agent. This cheap reagent undergoes smooth decarboxylation at 95 degrees C to afford difluorocarbene, which can be trapped with a variety of aromatic and heteroaromatic thiols. The reaction is also effective for the difluoromethylation of heterocyclic nitrogen compounds and phenylselenol. PMID- 24059699 TI - Tumor cell response to bevacizumab single agent therapy in vitro. AB - BACKGROUND: Angiogenesis represents a highly multi-factorial and multi-cellular complex (patho-) physiologic event involving endothelial cells, tumor cells in malignant conditions, as well as bone marrow derived cells and stromal cells. One main driver is vascular endothelial growth factor (VEGFA), which is known to interact with endothelial cells as a survival and mitogenic signal. The role of VEGFA on tumor cells and /or tumor stromal cell interaction is less clear. Condition specific (e.g. hypoxia) or tumor specific expression of VEGFA, VEGF receptors and co-receptors on tumor cells has been reported, in addition to the expression on the endothelium. This suggests a potential paracrine/autocrine loop that could affect changes specific to tumor cells. METHODS: We used the monoclonal antibody against VEGFA, bevacizumab, in various in vitro experiments using cell lines derived from different tumor entities (non small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer (BC) and renal cell carcinoma (RCC)) in order to determine if potential VEGFA signaling could be blocked in tumor cells. The experiments were done under hypoxia, a major inducer of VEGFA and angiogenesis, in an attempt to mimic the physiological tumor condition. Known VEGFA induced endothelial biological responses such as proliferation, migration, survival and gene expression changes were evaluated. RESULTS: Our study was able to demonstrate expression of VEGF receptors on tumor cells as well as hypoxia regulated angiogenic gene expression. In addition, there was a cell line specific effect in tumor cells by VEGFA blockade with bevacizumab in terms of proliferation; however overall, there was a limited measurable consequence of bevacizumab therapy detected by migration and survival. CONCLUSION: The present study showed in a variety of in vitro experiments with several tumor cell lines from different tumor origins, that by blocking VEGFA with bevacizumab, there was a limited autocrine or cell-autonomous function of VEGFA signaling in tumor cells, when evaluating VEGFA induced downstream outputs known in endothelial cells. PMID- 24059702 TI - Modulating biological events by biophysics: an innovative molecular methodology using ion cyclotron resonance--a pilot study. AB - The QUEC PHISIS(TM) technology, based on the theory of coherence domains of water, is the most advanced application of quantum electrodynamics coherence suitable for transferring highly targeted and personalized electromagnetic signals to the living cells. Several experimental studies in aged rats confirm its beneficial action on vital cellular parameters while also optimizing the bioavailability and absorption of fundamental elements in cellular metabolism. Clinical observations have followed and have strengthened its applicability in healthy volunteers and in patients with complex diseases such as cardiovascular, neuromuscular, and metabolic disorders. Our pilot study on severely compromised, frail subjects corroborates its relevance. The delivery of correct frequencies has the potential to become a safe, very affordable, and effective therapeutic modality that is amenable to being integrated with pharmacological drugs, thus representing a substantial innovation in medical practice. PMID- 24059703 TI - Ab initio chemical kinetics for SiH2 + Si2H6 and SiH3 + Si2H5 reactions and the related unimolecular decomposition of Si3H8 under a-Si/H CVD conditions. AB - The kinetics and mechanisms for SiH2 + Si2H6 and SiH3 + Si2H5 reactions and the related unimolecular decomposition of Si3H8 have been investigated by ab initio molecular orbital theory based on the QCISD(T)/CBS//QCISD/6-311++G(d,p) method in conjunction with quantum statistical variational Rice-Ramsperger-Kassel-Marcus (RRKM) calculations. For the barrierless radical association processes, their variational transition states have been characterized by the CASPT2//CASSCF method. The species involved in the study are known to coexist under CVD conditions. The results show that the association reaction of SiH2 and Si2H6 producing Si3H8 occurs by insertion via its lowest-energy path forming a loose hydrogen-bonding molecular complex with 8.3 kcal/mol binding energy; the reaction is exothermic by 55.0 kcal/mol. The chemically activated Si3H8 adduct can fragment by several paths, producing SiH4 + SiH3SiH (-0.7 kcal/mol), Si(SiH3)2 + H2 (-1.4 kcal/mol), and SiH3SiH2SiH + H2 (-1.4 kcal/mol). The predicted enthalpy changes as given agree well with available thermochemical data. Three other decomposition channels of Si3H8 occurring by Si-H or Si-Si breaking were found to be highly endothermic, and the reactions take place without a well-defined barrier. The heats of formation of Si3H8, SiH2SiH, Si2H4, i-Si3H7, n-Si3H7, Si(SiH3)2, and SiH3SiH2SiH have been predicted and found to be in close agreement with those available data in the literature. The product branching rate constants for SiH2 + Si2H6 and SiH3 + Si2H5 reactions and the thermal unimolecular decomposition of Si3H8 for all low-energy paths have been calculated with multichannel variational RRKM theory covering varying P,T conditions typically employed in PECVD and Cat-CVD processes for hydrogenated amorphous silicon (a Si/H) film growth. The results were also found to be in good agreement with available kinetic data. Our kinetic results may be employed to model and control very large-area a-Si/H film growth for a new generation of solar cell applications. PMID- 24059701 TI - Discovery of a series of hydroximic acid derivatives as potent histone deacetylase inhibitors. AB - To develop potent histone deacetylase inhibitors as antitumor agents, structural modification was performed. The synthesized molecules were tested by enzymatic inhibition assay and anti-proliferation assay. Several molecules show improved activities in the enzymatic inhibition assay. However, in the MTT assays, all these derived molecules have limited performance compared with SAHA. The IC50 values of molecule ((S)-N-(6-(hydroxyamino)-6-oxohexyl)-4-(3-(2-oxo-1-phenyl-2 ((3-(trifluoromethyl)phenyl)amino)ethyl)ureido)benzamide, L8) which has the best enzymatic inhibition activity (with an IC50 value of 11.7 nm and 967 nm against Hela nucleus extract and HDAC8, respectively) were calculated compared with SAHA. Molecular docking was performed to predict the binding mode of molecule L8 in the active site of HDAC2 and HDAC8. Hydrophobic interaction, chelate binding, electrostatic attraction and H-bond interaction in combination make contribution to the ligand-receptor interactions. PMID- 24059704 TI - Congenital CNS tumors diagnosed on prenatal MRI. AB - Congenital tumors form a unique group among pediatric neoplasms. They are different from other tumor groups in this population not only due to the onset time but also to their histopathology, anatomic location, biologic behavior and prognosis. The development of fetal MRI allowed early diagnosis of these tumors. Three fetuses with congenital central nervous system (CNS) tumors were diagnosed prenatally and confirmed with histopathology. Prenatal ultrasonography (US) and magnetic resonance imaging (MRI) were performed. After birth MRI or computed tomography (CT) were carried out. In one case a large intra-axial brain tumor was diagnosed with solid, cystic and hemorrhagic elements. After surgery the tumor turned out to be choroid plexus carcinoma. In the second case craniopharyngioma arising from the suprasellar region was diagnosed on the basis of prenatal MRI and confirmed. In the third case extra-axial meningioma-like tumor was visualized on fetal MRI. After surgery it turned out to be desmoplastic infantile astrocytoma. Intracranial teratoma, the most typical CNS congenital tumor, was not diagnosed in our material. Our cases were rarely encountered neoplasms: choroid plexus carcinoma, craniopharyngioma and desmoplastic infantile astrocytoma. The examinations were repeated after birth and did not add significant information. In utero diagnostics is easier and safer than postnatal imaging of the sick baby that may require life-support equipment, and provides information of equal value. PMID- 24059705 TI - The encephalopathic child. AB - Encephalopathy is a common paediatric emergency associated with a high risk of morbidity, mortality and long term neurodevelopmental delay in survivors. Prompt diagnosis of the cause of encephalopathy enables the paediatrician to deliver specific medical or surgical treatment that will facilitate a better short and long term outcome. Diagnostic imaging plays a pivotal role in diagnosis. Encephalopathy has many causes. The differential diagnosis includes non accidental injury, trauma, metabolic syndromes, meningo-encephalitis, toxins, hypoxia, demyelination, stroke, haemorrhage and tumours. We describe an approach that helps us formulate an imaging strategy using US, CT and MRI that facilitates patient care. PMID- 24059706 TI - Hippocampal MR Volumetric Studies in Paediatric Patients with Epilepsy and Normal Controls. AB - The aim of this study was to determine and compare the hippocampal volume in children with epilepsy and in children in a control group and to compare the mean of right and left hippocampal volume in control subjects. This study was carried out at University Sains Malaysia (USM) from January 2008 to June 2009. This is a cross sectional study of 40 children with epilepsy and 40 children in a control volunteer group. Serial MRI of brain and temporal lobe were performed using a Signa Horizon LX 1.0 Tesla system. Oblique coronal sections perpendicular to the axis of temporal lobe were done with 4 mm slice thickness and 1 mm gap. T1, T2, FLAIR and SPGR series were done. The whole hippocampal volume was measured. Volumetry was done manually by using Osirix workstation (v 3.5.1-64 bit). All slices were measured three times and the average volume was taken. Data were analyzed by paired t test and independent t test for univariate data. The mean hippocampal volume in the control group was 2.81 cm(3) (SD=0.38) and 2.65 cm(3) (SD=0.41) for right and left hippocampus respectively. The mean hippocampal volume in epilepsy patients was 2.47 cm(3) (SD=0.52) and 2.39 cm(3) (SD=0.44) for right and left respectively. The hippocampal volume in epileptic children was significantly smaller than normal control children in average volume (p=0.001) and both right (p=0.002) and left (p=0.007) individually. In the control group, the right hippocampus volume was much greater than the left (p<0.001). The data of this study provide a useful reference for the study of hippocampal volume in the Malay paediatric population. It is useful in doubtful cases to determine which side is affected and also serves as part of the study to establish the whole age-related hippocampal growth. PMID- 24059707 TI - Clinico-radiologic profile of spinal cord multiple sclerosis in adults. AB - MRI is extremely useful for the assessment of initial disease burden and to identify the dissemination of the multiple sclerosis (MS) in time and space. Though MRI of the spinal cord is not used to establish the diagnosis of MS, spinal cord is frequently involved in this disease and there has been increasing emphasis of the spinal imaging in making clinical decision in the management of MS. We undertook a retrospective study of patients with diagnosed MS: 1) to identify radiologic pattern of spinal cord involvement in MS and 2) to correlate radiologic findings with clinical presentation. We reviewed radiologic records from 2004 to 2009 of patients with abnormal T2 signal intensity of the spinal cord with radiologic concern of demyelinating disease. Patients in this cohort who met the Revised McDonald MS Diagnostic Criteria were included in this study. 166 patients were included in the study. There was preference for cervical spinal cord particularly posterior aspect of the spinal cord. Enhancement of the lesions was rare (4.1%). Mean lesion length was 18.2 mm. The average number of lesions per patient was 2.04. Sensory symptoms were predominating and most of the patients had relapsing-remitting course. Patients with sensory symptoms, bladder and bowel involvement and motor symptoms had almost equally distributed lesions among anterior, posterior and central spinal cord. However, all of the patients presented with posterior column signs and gait abnormality had involvement of the posterior spinal cord. Radiologic manifestation of spinal cord MS is extremely variable and can involve the entire length of the spinal cord. Clinical symptoms may or may not be associated with radiologic presentation of the lesions. PMID- 24059708 TI - Axial loaded imaging of the lumbar spine 18 years later. Is it still a valuable examination? AB - This paper reviews experience with 12100 Axial Loader (AL) studies of the lumbar spine both in CT and in MRI 18 years after the development of axial loaded CT and MRI. The Axial Loader device is described together with the CT and MR acquisitions. Disc, intersomatic and articular facet changes are described with a breakdown of the classification of abnormalities as elementary or complex dynamic modifications. PMID- 24059709 TI - Spinal arachnoid cyst as an infrequent cause of spinal cord compression. AB - Spinal arachnoid cysts are rare lesions that may produce symptoms by compressing the spinal cord or nerve roots. MRI is essential for diagnosing this entity. We retrospectively reviewed the medical charts, radiological examinations, and follow-up data of four adults with spinal arachnoid cysts diagnosed in our center over a two-year period (2007-2009). All cysts were located in the thoracic spine. Three were dorsolateral to the spinal cord and one was ventral. Most had multiple septa but one had a single septum. Cyst size varied greatly; one cyst extended through eight vertebral bodies. One patient treated expectantly died of cardiovascular problems one year after the cyst was diagnosed. The other three patients underwent laminectomy and cyst fenestration; two had clinical and imaging signs of relapse after surgery. One of the patients with a relapsed cyst worsened clinically, developing syringomyelia and requiring reintervention with shunting to the subarachnoid space. The outcome of the operation was good in the case of the single septum. Spinal arachnoid cyst is uncommon. Its diagnosis is complex because the symptoms are unspecific and the imaging findings are subtle. Spinal arachnoid cyst should be included in the differential diagnosis of chronic paraparesis. Imaging plays an essential role in the diagnosis, follow-up and management of spinal arachnoid cysts. PMID- 24059710 TI - Imaging artifacts in MRI simulators. AB - Artifactual images are created in the process of imaging. They are images that distort reality, i.e. they do not correspond to the image but they arise from them and are false. This paper describes image artifacts in MR that can lead to misdiagnosis, analyzes their causes and reviews the most common imaging artifacts. PMID- 24059711 TI - Diffusion-Weighted Imaging in the Early Diagnosis of EBV Meningoencephalitis. A Case Report. AB - We describe the case of a girl with EBV encephalitis diagnosed promptly with the help of diffusion-weighted imaging (DWI). DWI is a rapid pulse sequence that must be added to the routine MR imaging regimen in patients with suspected meningoencephalitis. It can improve the sensitivity of lesion detection and assist in lesion characterization. PMID- 24059712 TI - Examination portability. AB - Truly global radiology would exist if patients could visit any European physician without their CDs or films. It would be possible for patients to go to a hospital or a clinic in any European country and have their examinations done in a different country, analyzed and eventually compared with the examination done at that hospital. This paper analyzes two national projects that should be documented and analyzed: Scotland with a national archive with radiology images and Finland which is implementing a system that will create an online personal health record of the citizen with all health-related information. This possibility would improve quality in European radiology and create a true network of images and knowledge that can be the seed to improve efficiency by reducing costs and exposure to radiation and increasing knowledge sharing among Europeanradiologists/neuroradiologists. We present here the idea of a network between three centers in three different countries that can be the start for a global project. PMID- 24059713 TI - New imaging strategies in degenerative disease of the intervertebral disks: functional spine imaging. AB - As it does for the brain, functional imaging provides additional clinically valuable information on the spine, especially in the problem of back and neck pain. While conventional anatomic spine imaging demonstrates many abnormalities, such as herniation of the intervertebral disk, with nearly perfect accuracy, it does not effectively distinguish incidental degenerative changes in the disk from those that results in pain production. Functional imaging of the spine, still under development and evaluation, will facilitate the identification of painful disks and the selection of patients for innovative treatments that are presently under development. Functional imaging of the spine includes: MR spectroscopy, fMRI of the spinal cord, diffusion imaging, T2 relaxation time, T1 rho measurement and dynamic imaging. The purpose of this presentation is to review the status of these functional MR techniques. MRS: MR spectroscopy demonstrates tissue constituents that have characteristic resonant frequencies. For the disk, the substances that can be recognized in MR spectra and quantified include lactic acid and glycosaminoglycans. Lactic acid has been documented by direct sampling of the disk in painful degenerating disks. With MRS, the concentration of lactic acid is measured non-invasively. In pilot studies, lactic acid concentration effectively distinguishes symptomatic from asymptomatic degenerating disks. PMID- 24059714 TI - The "Dehydrated" Lumbar Intervertebral Disk on MR, its Anatomy, Biochemistry and Biomechanics. AB - MR imaging of the lumbar spine often is requested to identify the cause of back or radicular pain. Official reports of lumbar spine images tend to focus on changes in the disk margin that may cause nerve root compression. The potential role of the dark disk, in back pain has not been adequately emphasized. The purpose of this review is to discuss the dark disk that has not produced nerve root compression. On T2-weighted images, a disk that has diminished signal intensity is called a dark disk or a dehydrated disk. It corresponds to a stage III disk in the Pfirrmann or the Thompson scale. Such a disk has specific morphologic, chemical and biomechanical properties, which will be reviewed in this presentation. The goal is to suggest the clinical significance of finding a dark disk on an MR image. PMID- 24059715 TI - MR Myelography in Patients with Lumbosacral Radicular Pain: Diagnostic Value and Technique. AB - Lumbosacral radicular sciatic pain can frequently be the result of nerve root compression, for instance by a herniated lumbar disc. Spinal imaging may however reveal disc herniations which are not associated with sciatica, even present in individuals without any complaints. In addition, sciatic pain may be the result of spinal or even paraspinal pathology without any involvement of the nerve root: so-called "pseudo" radicular pain. It is important therefore in clinical diagnostic imaging to match the potential cause of sciatica (e.g. a disc herniation) as closely as possible with its effect (actual compression of the nerve root). Assessing nerve root compression is not always easy on standard MR images. MR myelography provides a high-resolution image of the normal or compressed nerve root in a very brief acquisition time which enables the MRM acquisition to be added on to the standard examination. The MRM images provide valuable supplementary information but cannot replace the standard T1- and T2 weighted sagittal and axial images. PMID- 24059716 TI - Abnormalities of the spinal dura mater: are multiple clinical syndromes with dural lesions associated with abnormal connective tissue? AB - We review several clinical and radiological entities that present with abnormalities of the spinal dura that may be related to each other. These include: the syndrome of spontaneous intracranial hypotension, neuroenteric cysts, spontaneous spinal cord herniation, degenerative disc disease associated with disc clefts or associated with intradural complications, and Hirayama disease. Our observations focus on common imaging findings of dural tears, abnormal peridural fluid and associated degenerative disc disease. We propose that T2 fat sat sequences should be routinely used in spinal imaging protocols to evaluate extradural fluid. PMID- 24059717 TI - Evaluating Marrow Signal Intensity: Comparison of T1 FLAIR and T1 FSE Images. AB - The purpose of the study was to determine whether there is a difference in the appearance of the marrow signal intensity on T1 FLAIR and T1 FSE images, and if so, whether the difference is related to age. T1 FLAIR and T1 FSE sequences, obtained prospectively in 93 patients, were compared after excluding patients older than 75 years, and patients with a history of prior lumbar surgery, or a predisposing medical condition, e.g. HIV disease, multiple myeloma, osteoporosis, metastatic disease, renal failure or severe degenerative disease. All studies were performed on a 1.5 T GE Signa/Excite. All case pairs were reviewed by three board certified radiologists, each with more than five years experience in MR imaging. Regardless of age, where a difference was perceived, the T1 FLAIR image was judged darker in 88% of patients. In order to avoid misdiagnoses and/or additional unnecessary exams, it is important to recognize that marrow signal intensity may appear artificially low in normal individuals. PMID- 24059718 TI - Assessment of the Correlation between Apparent Diffusion Coefficient and Intervertebral Disk Degeneration Using 3 Tesla MRI. AB - The objective is to use DW-MR imaging using 3 Tesla MRI to assess the correlation between the mean ADC with degenerative disk disease (DDD). We recruited 34 subjects and used DWI-MR to image lumbar intervertebral disks. We acquired a T2W scan and DWIs. The disks were graded for DDD. Assessment of correlation between mean ADC was made. 170 disks were evaluated. The observed sample correlation between mean ADC and disk degeneration was r = 0.65 [0.55-0.73]. The observed sample correlation between mid-sagittal ADC and disk degeneration was r = 0.61 [0.51-0.70]. The differences between mean ADC of each grade were significant, except between grades 4 and 5. There is a correlation of 0.65 between the mean ADC and disk degeneration. This correlation is not strong enough to use the ADC to determine DDD in clinical settings. There was no evident difference in ADC between the studied anatomic lumbar levels. PMID- 24059719 TI - MRI findings of dorsalgia. AB - We reviewed the thoracic vertebra MRI of patients whose chief complaint was dorsalgia (or + lower back dorsalgia). Thoracic vertebra MRI of 103 patients had dorsalgia as the chief complaint mainly or sometimes in 134 (man 61, woman 73) and had led them to consult an orthopaedic specialist. A difference was seen in the cavity diameter under the posterior arachnoid in 103 and 31 which led to MRI scan of the thoracic vertebra. The cavity diameter was equal to or more than 0.55 posterior space, equal to or less than 0.43 abdominal side space. We reviewed the thoracic vertebra MRI of the patients whose the chief complaint was dorsalgia (or lower back dorsalgia). On the thoracic vertebra sagittal T2w MR scans we obtained eccentricities from the center to the thoracic ventral aspect and to the dorsal aspect at the widest diameter of the spinal canal. The eccentricities were calculated as ratios of the diameter of the spinal canal at the maximal occipitofrontal diameter to the dorsal subarachnoid space diameter, and to the ventral subarachnoid space diameter. Spinal cord imaging was done by exclusion to the abdominal side because the cavity diameter under the posterior arachnoid was wide. The ventral root was towed and the dorsal root was assumed to be bent. PMID- 24059720 TI - Vertebral Body Stenting System for the Treatment of Osteoporotic Vertebral Compression Fracture: Follow-up at 12 Months in 20 Cases. AB - We describe our preliminary experience with the vertebral body stenting system (VBS) for the treatment of osteoporotic vertebral fracture or traumatic vertebral fracture showing our clinical results at 12 months follow-up. Twenty patients (16 women, four men, mean age 71 years): four with traumatic vertebral fracture (Magerl A1 fractures) and 16 with osteoporotic vertebral compression fracture (VCFs) resistant to conservative therapy, were treated by vertebral body stenting system (VBS) as follows: two at level T11, four at T12, one at L1, two at L2, five at L3 and six at L4. All patients were studied by MR (protocol: sagittal T1W, T2W and T2 STIR) and MDCT with MPR reconstructions. All procedures were performed under local anesthesia with fluoroscopy guidance and a bipeduncular approach. VBS, a new system of implantation of endovertebral stent used as an alternative to conventional vertebroplasty (VP), was implanted in all patients to restore the loss of height in the fractured vertebral body. A clinical and x-ray follow-up was performed at six and 12 months evaluating the result by VAS and ODS scale. New vertebral fractures at a distant level were observed in two cases and treated by VP. VBS was successful and led to an excellent outcome in all patients with clinical improvement stable at six months and one year follow-up. The height in the fractured vertebral body was increased in 12 of the 20 VCFs by an average of 1.5 mm. No vascular, extraforaminal or epidural leakage or other adverse events were observed. In the clinical 12 months follow-up we recorded a reduction of four scores in the VAS evaluation and a 40% reduction in the ODS score compared with the pre-treatment values. Endovertebral stents were stable at 12 months at x-ray control in 19/20 patients. No new vertebral fracture located in adjacent vertebrae were observed at 12 month follow-up. By using a stent, the VBS system reduces the collapsed vertebral body and offers good height restoration. The mechanical scaffold of the stent restores the height and at the same time offers a cavity for injection of highly viscous PMMA bone cement without increasing the rate of new vertebral fracture post-VP. A long-term follow-up is recommended. PMID- 24059721 TI - mild((r)) Lumbar Decompression for the Treatment of Lumbar Spinal Stenosis. AB - More than 1.2 million people are undergoing treatment for lumbar spinal stenosis (LSS) in the United States. Yet, therapeutic options for these patients are limited to either conservative treatments or highly invasive surgeries. A new image-guided interlaminar decompression procedure, mild((r)), offers significant relief for many of these patients by debulking dorsal element hypertrophy while preserving structural stability. mild can be performed without general anesthesia and offers a short recovery period. A meta-analysis of four clinical patient series from multiple institutions in the United States evaluated over 250 patients for safety and clinical efficacy of the mild procedure. Clinical efficacy was evaluated at baseline and at three-month follow-up using validated patient reported outcomes (PRO) instruments including the ten-point Visual Analog Scale (VAS) and the Oswestry Disability Index (ODI). Acute safety and patient outcomes was compared to the Spine Patient Outcomes Research Trial (SPORT). No device or procedure-related serious adverse events (SAEs) have been recorded with the mild procedure. Outcome metrics for patients treated with mild demonstrated statistically significant symptomatic improvement over baseline. When compared to open surgery, mild efficacy results compare favorably, and complication rates are much lower. mild is a safe and effective procedure that decompresses LSS in a minimally invasive manner while preserving the structural stability of the spine. PMID- 24059722 TI - Percutaneous treatment of lumbar intervertebral disc hernias with discogel. AB - A new percutaneous technique for the treatment of the backache and sciatica related to the lumbar disc herniation was applied in 34 patients at 40 levels. The technique is easy, safe, efficacious and without complications. In particular it is useful for the diagnosis and treatment of the underestimated "internal disc disruption" syndrome. PMID- 24059723 TI - Cauda equina cavernous angioma presenting as acute low back pain and sciatica. A report of two cases and literature review. AB - Spinal cavernous angiomas are rare vascular lesions occurring mainly in the vertebral bodies extending secondary into the extradural space. Only 3% of these lesions are intradural, usually localized within the spinal cord. Rarely, cavernous angioma has been reported to occur in the cauda equina. We describe clinical, diagnostic imaging, and surgical procedures of two cases of cavernous angioma of the cauda equina who presented with acute back pain and sciatica. The relevant literature is also reviewed. PMID- 24059724 TI - Advanced ossification of the posterior longitudinal ligament in a mildly symptomatic patient. A case report and literature review. AB - We describe the imaging findings of a man who developed neurologic symptoms due to ossification of the posterior longitudinal ligament with narrowing of the spinal canal and compression of the spinal cord. CT study allowed a detailed evaluation of the stenosis and the extension of the ossification while MRI gave an excellent visualization of the spinal lesions caused by spinal cord compression by the mass. The neurological status of patients with ossification of the posterior longitudinal ligament depends on many factors such as the degree of spinal canal stenosis, life style, accidental mechanical stress and trauma. PMID- 24059725 TI - Letters to the Editor. Comment to the paper "MRI Aspects of NeuroVascular Conflict of the VIII Nerve". PMID- 24059726 TI - Hepatic diseases related to triglyceride metabolism. AB - Triglycerides participate in key metabolic functions such as energy storage, thermal insulation and as deposit for essential and non-essential fatty acids that can be used as precursors for the synthesis of structural and functional phospholipids. The liver is a central organ in the regulation of triglyceride metabolism, and it participates in triglyceride synthesis, export, uptake and oxidation. The metabolic syndrome and associated diseases are among the main concerns of public health worldwide. One of the metabolic syndrome components is impaired triglyceride metabolism. Diseases associated with the metabolic syndrome promote the appearance of hepatic alterations e.g., non-alcoholic steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. In this article, we review the molecular actions involved in impaired triglyceride metabolism and its association with hepatic diseases. We discuss mechanisms that reconcile the chronic inflammation and insulin resistance, and new concepts on the role of intestinal micro-flora permeability and proliferation in fatty liver etiology. We also describe the participation of oxidative stress in the progression of events leading from steatosis to steatohepatitis and fibrosis. Finally, we provide information regarding the mechanisms that link fatty acid accumulation during steatosis with changes in growth factors and cytokines that lead to the development of neoplastic cells. One of the main medical concerns vis-a-vis hepatic diseases is the lack of symptoms at the onset of the illness and, as result, its late diagnosis. The understandings of the molecular mechanisms that underlie hepatic diseases could help design strategies towards establishing markers for their accurate and timely diagnosis. PMID- 24059727 TI - Review on in-vitro anti-malarial activity of natural beta-carboline alkaloids. AB - Malaria is one of the major health problems in developing countries. It kills 1-2 million people every year and also it affects financial status of many countries. Developed resistance to aminoquinoline (chloroquine), quinoline methanols (Quinine, Mefloquine) created troubles in malarial chemotherapy and signs of appearance of resistance to artemisinin based combination therapy (ACT) created emergency to develop novel antimalarial agents with high efficacy before spreading of resistance to ACT. From the ages natural products played an important role in antimalarial therapy, identification of natural products, semisynthetic and synthetic analogs with potent antiplasmodium activity is one of the best methods to develop novel antimalarial agents. In this review, we are presenting the antimalarial activity of natural beta-carboline alkaloids and special interest on manzamine alkaloids and their structure activity relationship. PMID- 24059728 TI - Three important clinical processes in individual and group interpersonal psychotherapy sessions. AB - I describe three clinical processes: (a) bringing the discussion into the here and-now; (b) making impact disclosures; and (c) creating a corrective emotional experience, derived from interpersonal theory, that occurs in most of my individual and group therapy sessions. For each of these clinical processes, I provide: (a) the theoretical principals that support the clinical process, (b) clinical descriptions and dialogue that demonstrate the process, and (c) a review of some of the research examining the clinical process. Finally, I propose a task model of interpersonal therapy, which illustrates how the three clinical processes come together in interpersonal therapy. PMID- 24059729 TI - Computers and psychotherapy: are we out of a job? AB - Over the past 15 years, technology has increasingly been incorporated into the provision of psychotherapy with studies emerging demonstrating the effectiveness of such models. However, randomized controlled trials remain scant and little is known about the impact of computer technology on the therapeutic alliance. The studies reported in this section are among the first randomized clinical trials of computer-assisted or internet-based therapies. The following commentary provides a brief overview of each paper and highlights the key issues involved. PMID- 24059730 TI - A randomized controlled trial of ecological momentary intervention plus brief group therapy for generalized anxiety disorder. AB - Momentary intervention has been proposed as a cost-effective, generalizable, and ecologically valid method to increase the efficiency of face-to-face cognitive behavioral therapy (CBT). The purpose of the current pilot study was to evaluate the efficacy of a six-session palmtop computer-assisted Group CBT for generalized anxiety disorder (GAD) (CAGT6) in comparison with a six-session Group CBT for GAD without the computer (CBGT6) and typical (12 session) Group CBT for GAD (CBGT12) in a randomized controlled trial. Thirty-four individuals with a primary diagnosis of GAD were randomized to one of the three conditions and completed measures of GAD and anxiety before therapy, after therapy, and at 6-, and 12 month follow-ups. Results indicated that CAGT6 was superior to CBGT6 at posttreatment, but not significantly different from CBGT12. At 6- and 12-month follow-ups, CAGT6 was neither significantly different from CBGT6, nor from CBGT12. Percentages of individuals achieving reliable change on two of the three GAD measures favored CAGT6 over CBGT6 at posttreatment, suggesting promise for the added value of the mobile technology. PMID- 24059731 TI - Negotiating therapeutic alliances with a family at impasse. AB - To bridge the science-practice gap, the APA Presidential Task Force endorsed the publication of evidence-based case studies, but to date, there have been few such investigations of conjoint family therapy. To fill this gap, we studied a successful case of treatment-as-usual in a community agency. Owing to the complexity of the working alliance in conjoint therapy, we examined how an experienced family therapist managed to develop and sustain multiple alliances over time with an estranged couple in crisis. The outcome data showed clinically meaningful changes as well as high satisfaction levels and notable declines in the target complaint discomfort levels of all family members. Alliance indicators showed that the therapist worked diligently over time to connect emotionally with each family member and to foster and maintain safety. Session impact scores showed consistently deep sessions but more variability in smoothness. By working toward the only shared treatment goal-to repair each parent's individual relationship with their very angry daughter-the therapist was able to reduce the effect of the marital estrangement on the child. At the end of the 10 contracted family sessions, the parents agreed to begin working on their relationship in couples therapy, which led shortly thereafter to a reconciliation. PMID- 24059732 TI - The use of empathy and transference as interventions in psychotherapy with attention deficit hyperactive disorder latency-aged boys. AB - Psychodynamic-oriented therapies are uniquely positioned to address the internal experiences of a child whose external presentation is consistent with an Attention Deficit Hyperactivity Disorder (ADHD) diagnosis, an area of treatment intervention that is conspicuously absent from common ADHD treatment modalities. This article presents two psychodynamic psychotherapy treatment interventions that demonstrate (1) the importance of empathy in the therapeutic relationship and (2) the use of transference in psychotherapy with ADHD children. Through the use of case examples, the use of empathy is demonstrated in developing the therapeutic alliance, facilitating the development of the child's reflective capacity on affective states, and organizing the child's affective experiences. The benefits of transference interventions with ADHD children are reviewed, and case examples are provided to demonstrate how the therapist worked with the idealized and mirroring transference. Interventions are presented in the context of Object Relations and Self-Psychology Theories. PMID- 24059733 TI - Fostering new relational experience: clinical process in couple psychotherapy. AB - One of the most critical goals for couple psychotherapy is to foster a new relational experience in the session where the couple feels safe enough to reveal more vulnerable emotions and to explore their defensive withdrawal, aggressive attacking, or blaming. The lived intimate experience in the session offers the couple an opportunity to gain integrative insight into their feelings, expectations, and behaviors that ultimately hinder intimacy. The clinical processes that are necessary include empathizing with the couple and facilitating safety within the session, looking for opportunities to explore emotions, ruptures, and unconscious motivations that maintain distance in the relationship, and creating a new relational experience in the session that has the potential to engender integrative insight. These clinical processes will be presented with empirical support. Experts from a session will be used to highlight how these processes influence the couple and promote increased intimacy. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 24059734 TI - Too close and too far: counseling emerging adults in a technological age. AB - Individuals increasingly connect with others via social media (e.g., blogs, social networking, chatrooms), a phenomenon that is likely to impact psychological well-being and development. As such, therapists play an important role in assisting their clients to identify how virtual and in-person relationships influence their sense of self, interpersonal communication, and how they engage in meaningful relationships. In this article, I describe 3 examples related to working with emerging adults that take into consideration how this population "does relationships" in this technological era. Specifically, 3 clinical exchanges illustrate ways to (a) enhance interpersonal skills, (b) develop self-awareness about emotions, and (c) gain a clearer understanding of the intersections of social identity. PMID- 24059735 TI - Computer-assisted cognitive-behavior therapy for depression. AB - This article reviews the use of computer technology in treating depression as a substitute or adjunct for standard therapy. It discusses advantages and disadvantages of introducing computer technology as a treatment option, problems and barriers to expanded use, the varieties of computer-assisted psychotherapy for major depression, and relevant research. Three specific Internet-based programs are described, assessed and compared: Good Days Ahead, Beating the Blues, and MoodGYM. The authors conclude that these and similar programs are promising. Preliminary outcome studies suggest that these programs produce outcome similar to standard therapy, although methodological shortcomings limit confidence in these findings. Suggestions are offered for practitioners considering the addition of computer assistance to their treatment of depression. PMID- 24059736 TI - Insight as a common and specific impact of psychotherapy: therapist-reported exploratory, directive, and common factor interventions. AB - The facilitation of insight-broadly defined as forming new connections about one's self, others, and emotions-is viewed as a key process in many forms of psychotherapy. However, relatively little empirical work has addressed what types of therapeutic techniques may facilitate or hinder insight, especially in applied settings. In this practice-research network study, 31 clients and 16 therapists completed questionnaires after 401 sessions of psychotherapy. Multilevel linear modeling was used to explore whether insights are associated with various types of treatments and therapist-reported interventions, while taking into account differences between clients, therapists, and sessions. The results indicate that the types of treatment, as defined by the theoretical orientation of therapists' supervision, were not related to client-rated insight, although this analysis requires more statistical power. However, sessions that included more therapist reported exploratory interventions than usual for a given client were found to be lower in insight than other sessions for the same client. Similarly, therapists who reported using more exploratory interventions than other therapists had clients who reported experiencing less insight after sessions than other clients. In contrast, therapists who reported using more directive interventions than other therapists, on average, had clients who reported more insight. However, interaction effects revealed that a more complex interpretation of the data was necessary. Specifically, therapists who reported using more directive interventions than their peers, on average, had clients who reported more insight only if the therapists did not also report using high levels of exploratory interventions. Furthermore, directive interventions were associated with insight only when they were used in sessions that also had high levels of common factors. Overall, this study shows that there are both treatment-specific interventions and common factors that are associated with insight, suggesting that understanding differences between types of psychotherapy may require more nuanced analyses within and between treatments. PMID- 24059737 TI - Empirical research on attachment in group psychotherapy: moving the field forward. AB - Despite a large literature applying attachment to individual, family, and couple psychotherapy, it has taken much longer for clinicians to apply attachment theory to group psychotherapy. The lack of research attention in this area makes these three studies in this special section even more important to the field. They contribute significant findings that have the potential to help group leaders facilitate more cohesive and effective treatments for patients as well as move the field forward. Not only do we see the long-term impact of group treatment for those with insecure attachments, but we also learn how attachment anxiety impacts the group process, and how the attachment to the therapy group itself relates to changes in group member's personal attachment styles. The greatest contribution is the drawing of our attention to the many future studies that are needed to fully understand how group therapy facilitates change and how attachment theory plays a critical role in this process. Clinical implications are presented. PMID- 24059738 TI - Group psychotherapy levels of interventions: a clinical process commentary. AB - Trainees may experience greater effectiveness as therapists by conceptualizing group therapy interactions as occurring at different levels of functioning. We teach group therapy trainees to be aware of and flexibly direct their interventions to three levels of the group: (a) the intraindividual level, (b) the interpersonal level, and (3) the group-as-a-whole level. Within this conceptualization, we also encourage trainees to reinforce the group structure especially related to safety and secure base and to help group members to self reflect about their interactions within the group. In this clinical process commentary, we describe a process of pregroup assessment and preparation that includes evaluating individual core relational patterns (CRPs) and how these patterns might express themselves in the three levels of group functioning. A running case presentation provides examples of a CRP formulation, levels of group functioning, and therapist interventions that are specific to each level. Making use of each group level within every session may allow the novice group therapist to sort the complex information they receive in a meaningful way. A therapist who can flexibly attend to and work within each group level will optimize the effectiveness of their interventions. PMID- 24059739 TI - Attachment-based family therapy interventions. AB - Attachment-Based Family Therapy is a treatment model designed specifically for depressed and suicidal adolescents. The primary goal of the treatment is to promote developmentally appropriate adolescent-parent attachment. Three core interventions are discussed: relational reframes; focusing on primary emotions and unmet attachment needs; and facilitating corrective attachment episodes. For each intervention, the theoretical/clinical rationale is presented followed by a brief illustration and relevant research findings. PMID- 24059740 TI - The importance of therapy motivation for patients with substance use disorders. AB - The present study aimed to examine whether patients' pretherapy motivation was related to other patient characteristics and whether it predicted retention in psychotherapy. Data were collected within a naturalistic outcome study of various forms of psychotherapy for patients (N = 172) with substance use disorders (SUD). Therapy motivation was measured using the Client Motivation for Therapy Scale (CMOTS), including the variables autonomous motivation, controlled motivation, and amotivation. Female patients had higher levels of autonomous motivation (d = .53), lower levels of controlled motivation (d = -.32), and lower levels of amotivation (d = -.62). Level of symptoms and impairment was significantly positively correlated with controlled motivation (r = .31). Autonomous motivation was positively correlated with four expectation subscales associated with constructive therapeutic work, whereas amotivation was negatively correlated with three of these subscales. Controlled motivation was positively correlated with the subscales external orientation, defensiveness, and support. In a logistic regression, amotivation stood out as a negative predictor of retention, in terms of starting in psychotherapy after assessment or not. Quite surprisingly, autonomous motivation was not a significant predictor of retention. The present study indicates that amotivation is a risk factor for early dropout among SUD patients. More efforts should be directed at preparing patients for psychotherapy through strengthening motivation. PMID- 24059741 TI - Feasibility of mentalization-based treatment for adolescents with borderline symptoms: a pilot study. AB - Mentalization-based treatment (MBT) is an evidence-based treatment for adults suffering from borderline personality disorder. Different adaptations of MBT for adolescents have been described, but almost none of these have been systematically evaluated so far. This article presents pilot data from a feasibility study of an adaptation of inpatient MBT for adolescents with borderline symptoms (MBT-A). Preliminary outcome results were examined in a pilot study including 11 female adolescents (aged 14-18 years) in a mental health care center in the Netherlands. Maximum treatment duration was 12 months and patients were assessed at start and at 12 months after start of treatment. Outcome measures included symptom severity (Brief Symptom Inventory), personality functioning (Severity Indices of Personality Problems), and quality of life (EuroQol). Results showed significant decreases in symptoms, and improvements in personality functioning and quality of life at 12 months after start of treatment. Effect sizes (d) ranged from .58 to 1.46, indicating medium to large effects. In total, 91% of the adolescents showed reliable change on the BSI, and 18% also moved to the functional range on the BSI. The results of this feasibility study are promising and encourage further research concerning the efficacy of MBT in adolescents with borderline symptoms, although some problems with implementation suggest that an outpatient variant of MBT for adolescents might be as effective while at the same time reducing potential iatrogenic effects of inpatient treatment for this age group. PMID- 24059742 TI - Vocal communication in a complex multi-level society: constrained acoustic structure and flexible call usage in Guinea baboons. AB - BACKGROUND: To understand the evolution of acoustic communication in animals, it is important to distinguish between the structure and the usage of vocal signals, since both aspects are subject to different constraints. In terrestrial mammals, the structure of calls is largely innate, while individuals have a greater ability to actively initiate or withhold calls. In closely related taxa, one would therefore predict a higher flexibility in call usage compared to call structure. In the present study, we investigated the vocal repertoire of free living Guinea baboons (Papio papio) and examined the structure and usage of the animals' vocal signals. Guinea baboons live in a complex multi-level social organization and exhibit a largely tolerant and affiliative social style, contrary to most other baboon taxa. To classify the vocal repertoire of male and female Guinea baboons, cluster analyses were used and focal observations were conducted to assess the usage of vocal signals in the particular contexts. RESULTS: In general, the vocal repertoire of Guinea baboons largely corresponded to the vocal repertoire other baboon taxa. The usage of calls, however, differed considerably from other baboon taxa and corresponded with the specific characteristics of the Guinea baboons' social behaviour. While Guinea baboons showed a diminished usage of contest and display vocalizations (a common pattern observed in chacma baboons), they frequently used vocal signals during affiliative and greeting interactions. CONCLUSIONS: Our study shows that the call structure of primates is largely unaffected by the species' social system (including grouping patterns and social interactions), while the usage of calls can be more flexibly adjusted, reflecting the quality of social interactions of the individuals. Our results support the view that the primary function of social signals is to regulate social interactions, and therefore the degree of competition and cooperation may be more important to explain variation in call usage than grouping patterns or group size. PMID- 24059743 TI - Benchmarking of protein descriptor sets in proteochemometric modeling (part 2): modeling performance of 13 amino acid descriptor sets. AB - BACKGROUND: While a large body of work exists on comparing and benchmarking descriptors of molecular structures, a similar comparison of protein descriptor sets is lacking. Hence, in the current work a total of 13 amino acid descriptor sets have been benchmarked with respect to their ability of establishing bioactivity models. The descriptor sets included in the study are Z-scales (3 variants), VHSE, T-scales, ST-scales, MS-WHIM, FASGAI, BLOSUM, a novel protein descriptor set (termed ProtFP (4 variants)), and in addition we created and benchmarked three pairs of descriptor combinations. Prediction performance was evaluated in seven structure-activity benchmarks which comprise Angiotensin Converting Enzyme (ACE) dipeptidic inhibitor data, and three proteochemometric data sets, namely (1) GPCR ligands modeled against a GPCR panel, (2) enzyme inhibitors (NNRTIs) with associated bioactivities against a set of HIV enzyme mutants, and (3) enzyme inhibitors (PIs) with associated bioactivities on a large set of HIV enzyme mutants. RESULTS: The amino acid descriptor sets compared here show similar performance (<0.1 log units RMSE difference and <0.1 difference in MCC), while errors for individual proteins were in some cases found to be larger than those resulting from descriptor set differences ( > 0.3 log units RMSE difference and >0.7 difference in MCC). Combining different descriptor sets generally leads to better modeling performance than utilizing individual sets. The best performers were Z-scales (3) combined with ProtFP (Feature), or Z-Scales (3) combined with an average Z-Scale value for each target, while ProtFP (PCA8), ST-Scales, and ProtFP (Feature) rank last. CONCLUSIONS: While amino acid descriptor sets capture different aspects of amino acids their ability to be used for bioactivity modeling is still - on average - surprisingly similar. Still, combining sets describing complementary information consistently leads to small but consistent improvement in modeling performance (average MCC 0.01 better, average RMSE 0.01 log units lower). Finally, performance differences exist between the targets compared thereby underlining that choosing an appropriate descriptor set is of fundamental for bioactivity modeling, both from the ligand- as well as the protein side. PMID- 24059744 TI - Enamel matrix derivative in propylene glycol alginate for treatment of infrabony defects with or without systemic doxycycline: 12- and 24-month results. AB - BACKGROUND: This aim of this study is to compare regenerative therapy of infrabony defects with and without administration of post-surgical systemic doxycycline (DOXY) 12 and 24 months after therapy. METHODS: In each of 57 patients, one infrabony defect (depth >= 4 mm) was treated regeneratively using enamel matrix derivative at two centers (Frankfurt am Main and Heidelberg). By random assignment, patients received either 200 mg DOXY per day or placebo (PLAC) for 7 days after surgery. Twelve and 24 months after surgery, clinical parameters (probing depths [PDs] and vertical clinical attachment level [CAL-V]) and standardized radiographs were obtained. Missing data were managed according to the last observation carried forward. RESULTS: Data of 57 patients (DOXY: 28; PLAC: 29) were analyzed (26 males and 31 females; mean age: 52 +/- 10.2 years; 13 smokers). In both groups, significant (P <0.01) PD reduction (DOXY: 3.7 +/- 2.2 mm; PLAC: 3.4 +/- 1.7 mm), CAL-V gain (DOXY: 2.7 +/- 1.9 mm; PLAC: 3.0 +/- 1.9 mm), and bone fill (DOXY: 1.6 +/- 2.7 mm; PLAC: 1.8 +/- 3.0 mm) were observed 24 months after surgery. However, the differences between both groups failed to be statistically significant (PD: P = 0.574; CAL-V: P = 0.696; bone fill: P = 0.318). CONCLUSIONS: Systemic DOXY, 200 mg/day for 7 days, after regenerative therapy of infrabony defects did not result in better PD reduction, CAL-V gain, or radiographic bone fill compared with PLAC 12 and 24 months after surgery, which may be attributable to low power and, thus, random chance. PMID- 24059745 TI - High-sensitivity cardiac troponin T levels in newly diagnosed hypertensive patients with different left ventricle geometry. AB - BACKGROUND: The high-sensitivity cardiac troponin T (hs-cTnT) assay provides important prognostic information on cardiovascular diseases. Although hs-cTnT is associated with left ventricle (LV) hypertrophy (LVH), it has not been investigated in different LV geometric patterns incorporating normal LV structure and concentric remodeling in addition to LVH. OBJECTIVES: We aimed to investigate the possible association between hs-cTnT and LV geometric patterns in newly diagnosed hypertensive patients. METHODS: We studied 306 patients with newly diagnosed hypertension (HT; mean age 51.7 +/- 5.6 years) and 44 healthy control subjects (mean age 51.3 +/- 4.7 years). Echocardiographic examination was performed in all subjects. Four different geometric patterns were determined in hypertensive patients according to LV mass index (LVMI) and relative wall thickness (RWth). hs-cTnT and other biochemical markers were measured in all participants. RESULTS: The highest hs-cTnT values were observed in the concentric hypertrophy group compared with the control, normal geometry, concentric remodeling and eccentric hypertrophy groups (p < 0.05, for all). Also, hs-cTnT values of the eccentric hypertrophy group were higher than the control, normal geometry and concentric remodeling groups (p < 0.05, for all). Multivariate regression analysis showed that hs-cTnT was independently associated with LV geometry (beta = 0.326, p = 0.001) as well as LVMI (beta = 0.228, p = 0.010) and creatinine level beta = 0.132, p = 0.012). CONCLUSION: hs-cTnT level is related not only to LVH but also to LV geometry in hypertensive patients. hs-cTnT levels may mediate poorer LV geometric patterns in hypertensive patients. PMID- 24059747 TI - Archetypal analysis of diverse Pseudomonas aeruginosa transcriptomes reveals adaptation in cystic fibrosis airways. AB - BACKGROUND: Analysis of global gene expression by DNA microarrays is widely used in experimental molecular biology. However, the complexity of such high dimensional data sets makes it difficult to fully understand the underlying biological features present in the data.The aim of this study is to introduce a method for DNA microarray analysis that provides an intuitive interpretation of data through dimension reduction and pattern recognition. We present the first "Archetypal Analysis" of global gene expression. The analysis is based on microarray data from five integrated studies of Pseudomonas aeruginosa isolated from the airways of cystic fibrosis patients. RESULTS: Our analysis clustered samples into distinct groups with comprehensible characteristics since the archetypes representing the individual groups are closely related to samples present in the data set. Significant changes in gene expression between different groups identified adaptive changes of the bacteria residing in the cystic fibrosis lung. The analysis suggests a similar gene expression pattern between isolates with a high mutation rate (hypermutators) despite accumulation of different mutations for these isolates. This suggests positive selection in the cystic fibrosis lung environment, and changes in gene expression for these isolates are therefore most likely related to adaptation of the bacteria. CONCLUSIONS: Archetypal analysis succeeded in identifying adaptive changes of P. aeruginosa. The combination of clustering and matrix factorization made it possible to reveal minor similarities among different groups of data, which other analytical methods failed to identify. We suggest that this analysis could be used to supplement current methods used to analyze DNA microarray data. PMID- 24059746 TI - Critical role of CCDC6 in the neoplastic growth of testicular germ cell tumors. AB - BACKGROUND: DNA damage response has been clearly described as an anti-cancer barrier in early human tumorigenesis. Moreover, interestingly, testicular germ cell tumors (TGCTs) have been reported to lack the DNA Damage Response (DDR) pathway activation. CCDC6 is a pro-apoptotic phosphoprotein substrate of the kinase ataxia telangectasia mutated (ATM) able to sustain DNA damage checkpoint in response to genotoxic stress and is commonly rearranged in malignancies upon fusion with different partners. In our study we sought to determine whether CCDC6 could have a role in the patho-genesis of testicular germ cell tumors. METHODS: To achieve this aim, analysis for CCDC6 expression has been evaluated on serial sections of the mouse testis by immunohistochemistry and on separate populations of murine testicular cells by western blot. Next, the resistance to DNA damage induced apoptosis and the production of reactive oxygen species has been investigated in GC1 cells, derived from immortalized type B murine germ cells, following CCDC6 silencing. Finally, the CCDC6 expression in normal human testicular cells, in Intratubular Germ Cell Neoplasia Unclassified (IGCNU), in a large series of male germ cell tumours and in the unique human seminoma TCam2 cell line has been evaluated by immunohistochemistry and by Western Blot analyses. RESULTS: The analysis of the CCDC6 expression revealed its presence in Sertoli cells and in spermatogonial cells. CCDC6 loss was the most consistent feature among the primary tumours and TCam2 cells. Interestingly, following treatment with low doses of H2O2, the silencing of CCDC6 in GC1 cells caused a decrease in the oxidized form of cytochrome c and low detection of Bad, PARP-1 and Caspase 3 proteins. Moreover, in the silenced cells, upon oxidative damage, the cell viability was protected, the gammaH2AX activation was impaired and the Reactive Oxygen Species (ROS) release was decreased. CONCLUSIONS: Therefore, our results suggest that the loss of CCDC6 could aid the spermatogonial cells to be part of a pro-survival pathway that helps to evade the toxic effects of endogenous oxidants and contributes to testicular neoplastic growth. PMID- 24059748 TI - Effects of extrusion conditions on physical and nutritional properties of extruded whole grain red sorghum (sorghum spp). AB - In order to analyze the effects of extrusion temperature (T: 164, 182, 200 degrees C) and grits moisture content (g/100 g sample) (%M: 14, 16.5, 19) on textural and physicochemical properties of red sorghum extrudates, whole grain flour was extruded according to a factorial experimental design. The higher values for specific mechanical energy consumption (1006.98 J/g) and expansion (3.36) were obtained at 164 degrees C-14%M and for sensorial hardness at 164 degrees C-19%M. While for specific volume, the highest value (10.41 cm3/g) was obtained at 200 degrees C-14%M. Water solubility and water absorption were directly related with T and inversely with M. Microscopic observation of the samples indicates that the greatest cooking degree was obtained at 200 degrees C 4%M and the lowest at 164 degrees C-19%M. Extrusion at 182 degrees C-14%M allows obtaining an expanded product with good properties. Proximal composition did not show statistically significant differences with raw sample. Extruded sample showed a 25.4% reduction of available lysine and a 31% increase in protein digestibility. PMID- 24059749 TI - Prolonged elevated postprandial sugar augments severity in kidney disease: a north Indian hospital-based study. AB - AIM: Diabetes plays a major role in progression of renal failure. The risk-factor profile changes during the progression of chronic kidney disease (CKD) from mild/moderate to end-stage renal disease. The relationship between glycemic indices, blood pressure, body mass index (BMI) and age at diagnosis in Indians has been less investigated. We assessed association of these risk factors with CKD stages in Indian population. METHODS: This study was carried out on patients (n = 162) who were diagnosed with CKD and normal control group (n = 155). For BMI, National Institutes for Health criteria were used to categorize the patients. RESULT: The mean age of CKD patients were significantly increased with the advancement of stage. BMI, systolic blood pressure (SBP), postprandial sugar level (PP), urea and creatinine were also significantly higher with elevated stages, whereas no differences were observed in diastolic blood pressure (DBP) and fasting blood sugar (FBS). The logistic regression study gave a significant result (p = 0.000) when we compared the group of CKD patients with established/prolonged postprandial blood sugar. It was independently associated with mild CKD [odds ratio (OR) = 5.213, 95% confidence interval (CI) = 2.06 13.21, p = 0.000], moderate CKD (OR = 7.724, 95% CI = 4.05-14.74, p = 0.000) and severe CKD (OR = 7.610, 95% CI = 4.03-14.36, p = 0.000). CONCLUSION: SBP and PP were the best predictors of prevalent nephropathy in this population, while DBP and FBS were found to be less effective. This may have implication for kidney disease risk stratification and protection. PMID- 24059750 TI - Polymorphisms in the oxytocin receptor gene are associated with the development of psychopathy. AB - The co-occurrence of child conduct problems (CPs) and callous-unemotional (CU) traits confers risk for psychopathy. The oxytocin (OXT) system is a likely candidate for involvement in the development of psychopathy. We tested variations in the OXT receptor gene (OXTR) in CP children and adolescents with varying levels of CU traits. Two samples of Caucasian children, aged 4-16 years, who met DSM criteria for disruptive behavior problems and had no features of autism spectrum disorder, were stratified into low versus high CU traits. Measures were the frequencies of nine candidate OXTR polymorphisms (single nucleotide polymorphisms). In Sample 1, high CU traits were associated with single nucleotide polymorphism rs1042778 in the 3' untranslated region of OXTR and the CGCT haplotype of rs2268490, rs2254298, rs237889, and rs13316193. The association of rs1042778 was replicated in the second rural sample and held across gender and child versus adolescent age groups. We conclude that polymorphic variation of the OXTR characterizes children with high levels of CU traits and CPs. The results are consistent with a hypothesized role of OXT in the developmental antecedents of psychopathy, particularly the differential amygdala activation model of psychopathic traits, and add genetic evidence that high CU traits specify a distinct subgroup within CP children. PMID- 24059751 TI - Core functional sequence of C-terminal GAG-binding domain directs cellular uptake of IGFBP-3-derived peptides. AB - The current study clarifies the role of the Glycosaminoglycan (GAG)-binding domain of insulin-like growth factor binding protein-3 (IGFBP-3) in cell penetration. The cell penetration function of IGFBP-3 has been mapped to an 18 residue GAG-binding domain in the C-terminal region that mobilizes cellular uptake and nuclear localization of unrelated proteins. Uptake of KW-22, a 22 residue peptide that encompasses the 18-residue GAG-binding domain, and another IGFBP-3 peptide carrying a streptavidin protein cargo was investigated in Chinese hamster ovary (CHO) cells defective at several steps of biosynthesis of cell surface GAGs. The severity of GAG truncation was highly correlated to the impairment of uptake ranging from complete abrogation to only a partial reduction, suggesting that GAG-binding is required for uptake. The 18-residue GAG binding domain consists of an 8-residue KK-8 basic sequence devoid of Arg and an adjacent 10-residue QR-10 sequence rich in Arg. Peptide mapping of uptake and GAG binding activities within the KW-22 peptide showed that the 8-residue KK-8 basic peptide retained 80% of GAG-binding activity with no uptake activity while the 10 residue QR-10 peptide retained 53% of uptake activity and 18% of GAG-binding activity. This suggests that KK-8 carries out the majority of GAG-binding function while QR-10 carries out the majority of the cell entry function. To our knowledge, this is the first report of physical separation of the uptake and GAG binding functions within a short cell penetrating peptide and may shed light on the general mechanism of uptake of Arg-rich CPPs and guide new design of Arg-rich CPP-assisted drug/gene delivery systems. PMID- 24059752 TI - Solubility and supersaturation-dependent protein misfolding revealed by ultrasonication. AB - Although alcohols are useful cosolvents for producing amyloid fibrils, the underlying mechanism of alcohol-dependent fibrillation is unclear. We studied the alcohol-induced fibrillation of hen egg-white lysozyme at various concentrations of ethanol, 2,2,2-trifluoroethanol (TFE), and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). Under the conditions where the alcohol-denatured lysozyme retained metastability, ultrasonication effectively triggered fibrillation. The optimal alcohol concentration depended on the alcohol species. HFIP showed a sharp maximum at 12-16%. For TFE, a broad maximum at 40-80% was observed. Ethanol exhibited only an increase in fibrillation above 60%. These profiles were opposite to the equilibrium solubility of lysozyme in water/alcohol mixtures. The results indicate that although fibrillation is determined by solubility, supersaturation prevents conformational transitions and ultrasonication is highly effective in minimizing an effect of supersaturation. We propose an alcohol dependent protein misfolding funnel useful for examining amyloidogenicity. This misfolding funnel will apply to fibrillation under physiological conditions where biological environments play important roles in decreasing the solubility. PMID- 24059753 TI - Treatment of a non-typical hepatic pseudolesion complicated by greatly elevated alpha fetoprotein: case report and literature review. AB - BACKGROUND: Hepatic pseudolesions detected by helical computed tomography (CT) are not rare, but it is difficult to make a final diagnosis when the hepatic lesion is complicated by the presence of greatly elevated alpha fetoprotein (AFP). Clinical treatment of non-typical hepatic pseudolesions complicated by greatly elevated AFP should confirm the diagnosis and minimize trauma. CASE PRESENTATION: Non-invasive procedures including ultrasonography, CT, and micro invasive digital subtraction angiography could not safely differentiate this lesion from a malignant focus when it was complicated by greatly elevated AFP. Laparoscopic hepatectomy was performed, and pathological analysis showed chronic hepatitis, nodular regenerative hyperplasia, focal nodular hyperplasia of the liver, and mild vascular malformation. The tissue was HbsAg(-), HbcAg(-), and AFP(+). CONCLUSION: Heightened awareness of hepatic pseudolesion complicated by primarily elevated AFP will help physicians avoid unnecessary invasive procedures. Hepatic biopsy is inevitable because of greatly elevated AFP. For suspected hepatic pseudolesion with elevated AFP, needle-core biopsy and follow up surveillance instead of hepatectomy are recommended to find the source of AFP and make a final diagnosis of pseudolesion. PMID- 24059755 TI - An evaluation of the 30-s chair stand test in older adults: frailty detection based on kinematic parameters from a single inertial unit. AB - BACKGROUND: A growing interest in frailty syndrome exists because it is regarded as a major predictor of co-morbidities and mortality in older populations. Nevertheless, frailty assessment has been controversial, particularly when identifying this syndrome in a community setting. Performance tests such as the 30-second chair stand test (30-s CST) are a cornerstone for detecting early declines in functional independence. Additionally, recent advances in body-fixed sensors have enhanced the sensors' ability to automatically and accurately evaluate kinematic parameters related to a specific movement performance. The purpose of this study is to use this new technology to obtain kinematic parameters that can identify frailty in an aged population through the performance the 30-s CST. METHODS: Eighteen adults with a mean age of 54 years, as well as sixteen pre-frail and thirteen frail patients with mean ages of 78 and 85 years, respectively, performed the 30-s CST while their trunk movements were measured by a sensor-unit at vertebra L3. Sit-stand-sit cycles were determined using both acceleration and orientation information to detect failed attempts. Movement-related phases (i.e. impulse, stand-up, and sit-down) were differentiated based on seat off and seat on events. Finally, the kinematic parameters of the impulse, stand-up and sit-down phases were obtained to identify potential differences across the three frailty groups. RESULTS: For the stand-up and sit-down phases, velocity peaks and "modified impulse" parameters clearly differentiated subjects with different frailty levels (p < 0.001). The trunk orientation range during the impulse phase was also able to classify a subject according to his frail syndrome (p < 0.001). Furthermore, these parameters derived from the inertial units (IUs) are sensitive enough to detect frailty differences not registered by the number of completed cycles which is the standard test outcome. CONCLUSIONS: This study shows that IUs can enhance the information gained from tests currently used in clinical practice, such as the 30 s CST. Parameters such as velocity peaks, impulse, and orientation range are able to differentiate between adults and older populations with different frailty levels. This study indicates that early frailty detection could be possible in clinical environments, and the subsequent interventions to correct these disabilities could be prescribed before further degradation occurs. PMID- 24059754 TI - Thrombin-mediated transcriptional regulation using DNA aptamers in DNA-based cell free protein synthesis. AB - Realizing the potential of cell-free systems will require development of ligand sensitive gene promoters that control gene expression in response to a ligand of interest. Here, we describe an approach to designing ligand-sensitive transcriptional control in cell-free systems that is based on the combination of a DNA aptamer that binds thrombin and the T7 bacteriophage promoter. Placement of the aptamer near the T7 promoter, and using a primarily single-stranded template, results in up to a 6-fold change in gene expression in a ligand concentration dependent manner. We further demonstrate that the sensitivity to thrombin concentration and the fold change in expression can be tuned by altering the position of the aptamer. The results described here pave the way for the use of DNA aptamers to achieve modular regulation of transcription in response to a wide variety of ligands in cell-free systems. PMID- 24059756 TI - Major nutrient compositions and functional properties of sorghum flour at 0-3 days of grain germination. AB - Germination is of importance to improving nutritional attributes of cereal grains for human consumption. The effect of germination time on major nutrient compositions and functional properties of sorghum flour was investigated in this study. Grains of Butanua, a new Sudanese sorghum cultivar, were germinated for 0, 1, 2, and 3 days to analyze their chemical and functional properties. The contents of starch, protein, oil, foaming stability, bulk density, and least gelation concentration of sorghum flour decreased, whereas oil absorption capacity, foaming capacity, and emulsion capacity and stability enhanced with an increase in germination time. Improved functional properties of sorghum flour by germination of the grains not only make it useful and suitable for various food processing formulations, but also improve the food product quality. This new finding will beneficially help develop innovative technologies, design new types of functional foods, and promote both sorghum production and relevant food processing industry in the future. PMID- 24059758 TI - Peak Finder Metaserver - a novel application for finding peaks in ChIP-seq data. AB - BACKGROUND: Finding peaks in ChIP-seq is an important process in biological inference. In some cases, such as positioning nucleosomes with specific histone modifications or finding transcription factor binding specificities, the precision of the detected peak plays a significant role. There are several applications for finding peaks (called peak finders) based on different algorithms (e.g. MACS, Erange and HPeak). Benchmark studies have shown that the existing peak finders identify different peaks for the same dataset and it is not known which one is the most accurate. We present the first meta-server called Peak Finder MetaServer (PFMS) that collects results from several peak finders and produces consensus peaks. Our application accepts three standard ChIP-seq data formats: BED, BAM, and SAM. RESULTS: Sensitivity and specificity of seven widely used peak finders were examined. For the experiments we used three previously studied Transcription Factors (TF) ChIP-seq datasets and identified three of the selected peak finders that returned results with high specificity and very good sensitivity compared to the remaining four. We also ran PFMS using the three selected peak finders on the same TF datasets and achieved higher specificity and sensitivity than the peak finders individually. CONCLUSIONS: We show that combining outputs from up to seven peak finders yields better results than individual peak finders. In addition, three of the seven peak finders outperform the remaining four, and running PFMS with these three returns even more accurate results. Another added value of PFMS is a separate report of the peaks returned by each of the included peak finders. PMID- 24059757 TI - Perceptions of intermittent preventive treatment of malaria in pregnancy (IPTp) and barriers to adherence in Nasarawa and Cross River States in Nigeria. AB - BACKGROUND: Malaria during pregnancy is dangerous to both mother and foetus. Intermittent preventive treatment of malaria in pregnancy (IPTp) is a strategy where pregnant women in malaria-endemic countries receive full doses of sulphadoxine-pyrimethamine (SP), whether or not they have malaria. The Nigerian government adopted IPTp as a national strategy in 2005; however, major gaps affecting perception, uptake, adherence, and scale-up remain. METHODS: A cross sectional study was conducted in peri-urban and rural communities in Nasarawa and Cross River States in Nigeria. Study instruments were based on the socio ecological model and its multiple levels of influences, taking into account individual, community, societal, and environmental contexts of behaviour and social change. Women of reproductive age, their front-line care providers, and (in Nasarawa only) their spouses participated in focus group discussions and in depth individual interviews. Facility sampling was purposive to include tertiary, secondary and primary health facilities. RESULTS: The study found that systems based challenges (stockouts; lack of provider knowledge of IPTp protocols) coupled with individual women's beliefs and lack of understanding of IPT contribute to low uptake and adherence. Many pregnant women are reluctant to seek care for an illness they do not have. Those with malaria often prefer to self medicate through drug shops or herbs, though those who seek clinic-based treatment trust their providers and willingly accept medicine prescribed. CONCLUSIONS: Failing to deliver complete IPTp to women attending antenatal care is a missed opportunity. While many obstacles are structural, programmes can target women, their communities and the health environment with specific interventions to increase IPTp uptake and adherence. PMID- 24059760 TI - Outcomes of Endovascular Coiling in Patients with Intracranial Aneurysms Presenting with Poor Clinical and SAH Grade. AB - Although the treatment of intracranial aneurysms has made significant advances, prediction of outcomes in poor grades has always been difficult. We present our findings of patients in poor clinical and SAH grade treated with endovascular coiling. We aimed to evaluate the clinical outcomes in patients presenting with poorer neurological and SAH grades treated by endovascular techniques. Of 190 patients who presented with SAH over a period of nine years, 34 were of poorer clinical grade (Hunt & Hess Grades 4 and 5), of whom 30 presented with H&H grade 4 and four with grade 5. 44.1% of the 34 patients belonged to Fischer grade 4. We assessed the technical success and final outcomes based on the Glasgow outcome scale. Of the 30 patients with grade 4, 81.4% had a good outcome. Two out of four patients with grade 5 had a poor outcome. 82.5% of the patients with Fischer grade 4 had a good outcome. None of the poor outcomes were procedure-related. Endovascular treatment with its higher rates of technical success, lower complication rates and better outcomes should be recommended as the treatment of choice in patients with intracranial aneurysms even in patients with poorer clinical and SAH grades. PMID- 24059759 TI - Cardiorespiratory effects of water ingestion during and after exercise. AB - BACKGROUND: In prolonged exercise, the state of hypohydration due to sweating raises physiological stress and induces a drop in sports performance. However, the impact of water intake in cardiorespiratory parameters when administered during and after physical activity has not been well studied. This study aimed to analyze the effects of water intake in heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), partial oxygen saturation (SpO2) and respiratory rate during and after prolonged exercise. METHODS: Thirty-one young males (21.55 +/- 1.89 yr) performed three different protocols (48 h interval between each stage): I) maximal exercise test to determine the load for the protocols; II) Control protocol (CP) and; III) Experimental protocol (EP). The protocols consisted of 10 min at rest with the subject in the supine position, 90 min of treadmill exercise (60% of VO2 peak) and 60 min of rest placed in the dorsal decubitus position. No rehydration beverage consumption was allowed during CP. During EP, however, the subjects were given water (Vittalev, Spaipa, Brazil). The parameters HR, SBP, DBP, SpO2 and respiratory rate were measured at the end of the rest, in 30, 60 and 90 minutes of the activity, except the respiratory rate parameter, and at 1, 3, 5, 7, 10, 20, 30, 40, 50 and 60 minute post- exercise. RESULTS: The hydration protocol provided minimal changes in SBP and DBP and a smaller increase in HR and did not significantly affect SpO2 during exercise and better HR recovery, faster return of SBP and DBP and a better performance for SpO2 and respiratory rate post-exercise. CONCLUSION: Hydration with water influenced the behavior of cardiorespiratory parameters in healthy young subjects. PMID- 24059761 TI - Endovascular treatment of ruptured and unruptured vertebral artery aneurysms. AB - This paper analyzes the success of endovascular management of ruptured and unruptured vertebral artery aneurysms. Sixty-three patients with 65 vertebral (both acute dissection and chronic larger aneurysms are included) treated at our hospital form the basis of the analysis. Clinical outcome was evaluated using the modified Rankin Scale. Angiographic follow-up data was obtained for 44 patients (69.8%) for periods ranging from three to 16 months (mean, eight months). Based on the Hunt and Hess grading scale, the patient population included 34 patients (54.0%) with unruptured aneurysms, 28 (44.4%) with Grade 1 aneurysms, one (1.6%) with Grade 2 aneurysms. The locations of the aneurysms included 25 (38.5%) at the distal to posterior inferior cerebellar artery (PICA), 22 (33.8%) at the proximal to PICA and 18 (27.7%) at the vertebral artery-posterior inferior cerebellar artery (VA-PICA). Of the 63 patients, 12 (19%) were women and 51 (81%) were men. The mean age at treatment was 41.7 years (range, six-77 yrs). Follow-up angiograms were obtained in 44 (69.8%) out of 63 patients. Complete or virtually complete thrombosis was confirmed on early posttreatment angiography in 39 (88.6%) out of 44 patients. A slight reduction in the size of the lesion was noted in three patients and there was a significant residual lesion in two (4.5%) patients. Clinical follow-up revealed 90.5% patients in the mRS 0-2 category, 4.8% patients in the mRS>2 category, and 4.8% patients had died (mRS 6). Three patients died of rebleeding (n=1) or progressive mass effect/brainstem ischemia (n=2). Ruptured and unruptured aneurysms of the vertebral artery can be well treated using endovascular techniques, overall long-term results were good in 90.5% of patients. PMID- 24059762 TI - Endovascular treatment of basilar trunk saccular aneurysms. AB - Basilar artery (BA) trunk aneurysms are rare and still remain a formidable surgical challenge. The purpose of this retrospective study was to report the clinical entities and results of endovascular surgery of BA trunk saccular aneurysms. Between 1995 and 2009, 14 patients with 14 BA trunk saccular aneurysms underwent endovascular surgery. Six patients presented subarachnoid hemorrhage (SAH), three patients had another associated aneurysm which developed SAH, one patient presented with mass effect to the brain stem, and four patients were incidentally discovered. Five ruptured and seven unruptured aneurysms were successfully treated by endovascular surgery. Another one incompletely embolized aneurysm had grown to huge size five years later and the patient underwent a Hunterian ligation with a radial artery graft between the extracranial vertebral artery and the posterior cerebral artery. In one ruptured case, we attempted neck clipping, but this was abandoned because of concern for neck tearing by clipping. The aneurysm was embolized using detachable coils later. BA trunk aneurysms showed characteristic features such as so-called lateral aneurysm (43%), multiple aneurysms (43%) and four BA fenestrations (36%). The unusual high incidence of associated various vascular anomalies suggests that focal wall weakness must be based on the mechanism of aneurysm initiation on the BA trunk. Most patients presented with SAH. Pre-treatment neurological state was predictive for clinical outcome. Endovascular surgery is an effective therapeutic alternative that is associated with low morbidity and mortality rates, and should be considered the first choice treatment. PMID- 24059763 TI - Endovascular management of pediatric aneurysms. AB - Although the general principles of endovascular aneurysm treatment in adults hold true in children, these young patients pose unique challenges: small anatomy, longer life expectancy, associated conditions and morphological characteristics of the aneurysms. Few publications in the literature address the role of endovascular treatment for pediatric aneurysms; including series by Agid et al. (2005) (1) revisiting the Toronto series, Lasjaunias et al. (2005) (2) updating the Bicetre series and Sanai et al (2006) (8) presenting the San Francisco series. In their conclusions, the authors of the former two publications favored endovascular treatment over microsurgery. On the other hand, the authors of the latter publication favored microsurgery over endovascular treatment. The authors reviewed Louisiana State University experience regarding endovascular treatment of pediatric aneurysms focusing on outcomes. A retrospective chart review was performed of children under 18, who underwent endovascular treatment for intracranial aneurysms between 2000 and 2009 in our institution. Twelve patients harboring seventeen aneurysms were identified. The patients ranged in age from seventeen months to seventeen years. Complete aneurysm obliteration following endovascular treatment was around 95%. Our results showed unique features for pediatric aneurysms when compared to adult aneurysms. No intra operative mortality was recorded. One aneurysm recurred (5% recurrence rate among total number of aneurysms). In this case, six months after treatment, a control angiogram showed that the coils were displaced toward the dome of the aneurysm. This recurrence occurred before the introduction of the hydro coils. One patient died during the post intervention period (8% occurrence rate among total number of patients). Outcomes were better in anterior circulation aneurysms than in posterior circulation lesions. We had no mortality, morbidity or disability in the anterior circulation aneurysm group. In the posterior circulation group, there was one death representing 14% of the nine patients with aneurysms in this group. One recurrence occurred in the posterior circulation group representing 11% of the nine aneurysms in this group. Follow-up of all patients ranged from two to eight years. Endovascular treatment of pediatric intracranial aneurysm is safe and efficacious. Endovascular treatment in many instances provides less morbidity and mortality for treatment of pediatric aneurysms in inaccessible or eloquent locations than microsurgical clipping. The result of endovascular treatment depends on the location of the aneurysms and the underlying pathology. We advocate a multidisciplinary approach when choosing the therapeutic modality for treatment of pediatric aneurysms. PMID- 24059764 TI - Treatment of spontaneous intradural vertebral artery dissections. AB - Spontaneous intradural vertebral artery dissections may cause subarachnoid hemorrhage and often result in devastating damage. Increased use of noninvasive imaging studies has allowed larger numbers of patients to be diagnosed. In addition, intracranial vertebral artery dissection tends to induce multiple lesions affecting both intracranial vertebral arteries recurrently. Although unruptured dissections in this area usually have a benign nature, some authors have reported on the incidence of rupture from this lesion. Once hemorrhage from a dissecting vessel wall has occurred, it needs to be treated in the acute phase because of the high risk of rebleeding resulting in high morbidity and mortality. From December 2004 to July 2010, we managed 47 patients with spontaneous vertebral artery dissection, 31 patients were ruptured and 16 were unruptured. All patients who suffered from subarachnoid hemorrhage were treated with endovascular procedures. Most of the patients with unruptured dissection received medical therapy, but if the aneurysmal dilatation persisted or grew, surgical interventions were performed. Stenting with or without coils was deployed for 13 patients with posterior inferior cerebellar artery involvement at the site of dissection and/or were affected on the dominant side. In some patients, stenting was performed even if they were in the acute phase. For other ruptured patients, internal coil trappings were performed. Six patients died due to severe initial subarachnoid hemorrhage and one patient, who underwent stent deployment with coils for the dominant vertebral artery, with bilateral dissection continuing to the basilar artery died due to rerupture while the next additional coiling was planning. There were two cases of complications related to the intervention. During the follow-up period no bleeding occurred in any of the patients except for the previously mentioned patient. In conclusion, internal coil trapping or stent placement with or without coils was effective in preventing rebleeding of ruptured vertebral artery dissection. If the dissection is unruptured, it is necessary to detect the risk of bleeding with careful watching and when progress appears to be made, patients should be treated promptly. Stent-assisted therapy for preserving the patency of the parent artery and major branches is a promising treatment for vertebral artery dissection, even in the acute stage of subarachnoid hemorrhage. However, the risk of acute rerupture and recurrence remains even with the porous stent placement with or without coils. PMID- 24059765 TI - Which factors increase procedural thromboembolic events in patients with unruptured paraclinoid internal carotid artery aneurysm treated by coil embolization? AB - We analyzed the factors which increase the frequency of procedural thromboembolic events during coil embolization of unruptured paraclinoid internal carotid artery aneurysms. Neurologically symptomatic complications did not occur in our series. Silent hyperintense lesions on postoperative DWI were frequently detected after the coiling procedure in which we needed to withdraw the unreleased coil. Patient's age, sex, aneurysm diameter, packing density, use of balloon-assisted technique, and exchanging maneuver of microcatheter during the procedure did not increase the frequency of silent thromboembolic events. PMID- 24059766 TI - Classification of Non-Aneurysmal Subarachnoid Haemorrhage: CT Correlation to the Clinical Outcome. AB - To propose a new computed tomography (CT)-based classification system for nonaneurysmal subarachnoid haemorrhage (SAH), which predicts patients' discharge clinical outcome and helps to prioritize appropriate patient management. A 5 year, retrospective, two-centre study was carried out involving 1486 patients presenting with SAH. One hundred and ninety patients with nonaneurysmal SAH were included in the study. Initial cranial CT findings at admission were correlated with the patients' discharge outcomes measured using the Modified Rankin Scale (MRS). A CT-based classification system (type 1 e 4) was devised based on the topography of the initial haemorrhage pattern. Seventy-five percent of the patients had type 1 haemorrhage and all these patients had a good clinical outcome with a discharge MRS of 1. Eight percent of the patients presented with type 2 haemorrhage, 62% of which were discharged with MRS of 1 and 12% of patients had MRS 3 or 4. Type 3 haemorrhage was found in 10%, of which 16% had good clinical outcome, but 53% had moderate to severe disability (MRS 3 and 4) and 5% were discharged with severe disability (MRS 5). Six percent of patients presented with type 4 haemorrhage of which 42% of the patients had moderate to severe disability (MRS 3 and 4), 42% had severe disability and one-sixth of the patients died. Highly significant differences were found between type 1 (1a and 1b) and type 2 (p1/4 0.003); type 2 and type 3 (p 1/4 0.002); type 3 and type 4 (p 1/4 0.001). Haemorrhages of the type 1 category are usually benign and do not warrant an extensive battery of clinical and radiological investigations. Type 2 haemorrhages have a varying prognosis and need to be investigated and managed along similar lines as that of an aneurysmal haemorrhage with emphasis towards radiological investigation. Type 3 and type 4 haemorrhages need to be extensively investigated to find an underlying cause. PMID- 24059767 TI - Endovascular treatment of distal cerebral aneurysms. AB - Distal cerebral aneurysms are difficult to treat. Endovascular treatment (EVT) although challenging, in many cases allows sparing of the parent artery. If a deconstructive approach is necessary, EVT enables hyperselective catheterization with sacrificing only the branch on which aneurysm is located. Consequently much of the surrounding arterial circulation is spared. We describe our series of endovascularly treated distal cerebral aneurysms in 2009. This is a retrospective review of seven consecutive patients (five women) with eight distal cerebral aneurysms (four ruptured) who underwent embolization in 2009. Patient ages ranged from 44 to 69 years. Aneurysm size distribution was: seven small (0-10 mm) and one large (11-24 mm). Two aneurysms required a deconstructive approach. Embolization was performed with coils in six cases, and with liquid embolic material Onyx in two cases. Endovascular treatment was successful in all cases. Immediate angiograms revealed complete occlusion in six aneurysms, none with neck remnants, and incomplete occlusion in two aneurysms. On first follow-up (3-6 month) obtained in six patients, five aneurysms showed stabile occlusion, and one recanalization due to coil impaction. None of the patients died. One patient had neurological deficit GOS (Glasgow Outcome Scale) score three caused by parent artery occlusion, which gradually improved to GOS score 4. EVT is safe and effective technique for distal cerebral aneurysms. PMID- 24059768 TI - Embolization of a wide neck giant basilar tip aneurysm using two coils. A case report. AB - Pictorial demonstration of aneurysm lumen thrombosis and diversion of flow hemodynamics with the use of a minimum number of coils in the treatment of hemorrhagic basilar tip aneurysm. We present a 62-year-old lady who underwent endovascular treatment for acute subarachnoid hemorrhage due to a giant basilar tip aneurysm and a left carotico-ophthalmic aneurysm. Following deployment of two of the longest available coils, the procedure was terminated due to a sudden change of jet flow within the aneurysm and unsustainable coil and microcatheter positions in spite of further attempts. Post-procedural follow-up angiogram on day 22, revealed an approximately 90% occlusion of the giant basilar tip aneurysm. Significant reduction in flow dynamic by minimum number of coils can achieve remarkable and near complete thrombosis and occlusion of a giant basilar tip aneurysm. PMID- 24059769 TI - Evaluation of Balloon Occlusion Test for Giant Brain Aneurysms under Local Anaesthesia. AB - We describe our experience in balloon test occlusion for giant carotid or basilar aneurysms under hypotension. Twenty-four patients underwent balloon test occlusion (BTO) during the year 2008. Only patients showed absence of any neurological deficits after 20 minutes under normal tension then another 20 minutes under hypotension were considered tolerable for occlusion of the parent artery. Of the 24 patients, four (16.67%) had deficits at normal tension and two (8.33%) had deficits at hypotensive phase. None of the 18 (75%) patients who clinically tolerated test occlusion and had parent artery sacrifice show any complication at follow-up period of two years. Two patients with clinical intolerability underwent carotid artery sacrifice after STA-MCA bypass without sequelae. Balloon test occlusion with hypotension is a useful, competent and simple technique in the evaluation of tolerance to parent artery occlusion in case of giant and complex intracranial aneurysms. PMID- 24059770 TI - Intracranial perianeurysmal cyst: still a dilemma. A case report with endovascular management. AB - Intracranial perianeurysmal cysts constitute an extremely rare entity with very few cases reported in the literature. These cysts present an unknown mechanism of formation and clinical significance. Several theories based on isolated cases have been proposed, without drawing a clear conclusion. It is also unknown if follow-up with imaging techniques is required or which is the most appropriate treatment. We describe an atypical case handled with a satisfactory outcome after endovascular treatment, suggesting the importance of hydrodynamic forces as the key factors in the mechanism of formation. We believe that this case can help in future analysis of this rare entity. PMID- 24059771 TI - Vertebral artery orifice stenosis: a report of 43 cases from northwest iran treated with angioplasty and stenting. AB - More than one quarter of all transient ischemic attacks (TIA's) and ischemic strokes involve tissue supplied by the vertebrobasilar (VB) circulation. Vertebral artery stenotic lesion, particularly at the origin of the vertebral artery, is not uncommon but it is a less studied area. Here we present our endovascular treatment experience in a group of patients with vertebral artery orifice stenosis. We enrolled a group of patients with vertebral artery orifice stenosis who presented with confirmed posterior circulation stroke. Vertebrobasilar insufficiency syndrome was confirmed by imaging studies and clinical findings. Vertebral artery stenosis diagnosed by CT or MR Angiography and confirmed by Conventional and digital subtraction angiography (DSA). Angiography was performed by using of femoral or radial artery approach. From October 2008 to January 2010, forty-three consecutive patients (69.8% men) underwent stent placement for symptomatic vertebral artery orifice stenosis. Mean degree of stenosis was 70.45 +/- 7.455 percent and mean age was 71.65 +/- 7.743 years . In the 22 patients (22/43, 51.16%) stenosis were in left side. In the thirty patients (30/43, 69.6%) there was evidence of atherosclerotic disease in the internal carotid artery and in the 23% contra lateral vertebral artery was involved. There were five different cases with left renal artery stenosis especially in the men with left vertebral artery stenosis. Initial technical success rate was 100%. No cerebrovascular complications or embolic events occurred. Six months control angiography follow-up revealed one patient with stent occlusion and moderate (40%) restenosis in the another patient. According to our finding angioplasty and stenting for vertebral artery orifice stenosis is safe and effective. Patients with vertebral artery orifice disease frequently have coexistent atherosclerotic stenosis in the other major extracranial arteries including carotid and renal arteries. PMID- 24059772 TI - Incidental finding of a proatlantal intersegmental artery. A case report. AB - We describe the case of a 70-year-old woman who had a left proatlantal intersegmental artery disclosed during carotid artery angiography with the findings of carotid-basilar anastomosis which originated from the petrous segment of the ICA and was filling the horizontal segment of the vertebral artery. Awareness of this vascular variation can prevent morbidity and mortality associated with carotid ligation or carotid endarterectomy, especially when an incomplete circle of Willis is present. PMID- 24059773 TI - CT Angiographic Diagnosis of a Ruptured Intraventricular Arteriovenous Malformation in a Teenager Playing a Video Game. AB - Intraventricular arteriovenous malformation (AVM) is a rare congenital vascular disorder that is often associated with primary intraventricular hemorrhage (IVH) and a rapid clinical course. Acute imaging diagnosis requires depiction of both the location of hemorrhage and vascular nidus for emergent management. In this report, a 17-year-old teenager developed primary IVH with presentation of consciousness change during a video game. Multidetector-row computed tomographic angiography (CTA) demonstrated an AVM in the right lateral ventricle and its angioarchitectural relationship to the surrounding intracranial structures. Although selective angiography is essential both in planning treatment for cerebral AVMs and in establishing the final diagnosis, CTA can be an important first-line imaging modality to quickly confirm the diagnosis and hence initiate prompt management. PMID- 24059774 TI - Eosinophilic granuloma presenting as post-traumatic scalp hematoma with epidural hemorrhage. A case report. AB - Langerhans cell histiocytosis (LCH) encompasses a range of clinical presentations. Pure osseous involvement is referred to as eosinophilic granuloma (EG), whereas systemic involvement can either be classified as Hand-Schuller Christian disease or Letterer-Siwe syndrome. It is estimated that of the total incidence of LCH (0.5 per 100,000 children per year in the United States), nearly 70% are categorized as EG (1). We describe a case of clinically occult calvarial eosinophilic granuloma brought to medical attention only after a traumatic event led to scalp and epidural hemorrhage at the site of the lesion. Osseous EG initially presents as a painful or tender mass, at times even mimicking osteomyelitis. Computed tomography (CT) reveals a lytic lesion with beveled edges. Magnetic resonance (MR) imaging is often non-specific, but usually demonstrates a marrow-replacing process that is T1 hypointense, T2 hyperintense, with homogenous enhancement. The complex MR imaging findings in our case provided a unique perspective regarding the presentation of EG. Once pathology established eosinophilic granuloma, skeletal survey confirmed the lesion was solitary, despite a compelling history of present illness. PMID- 24059775 TI - High-flow Neonatal Macrocerebral Arteriovenous Fistulas in Hereditary Hemorrhagic Telangiectasia. AB - Although some cases of vein of Galen aneurysmal malformation (VGAM) present initial clinical symptoms such as cardiopulmonary disturbance in the neonatal period, pial arteriovenous fistula is very seldom present as a clinical symptom immediately after birth. A neonatal patient, the first-born to his family, presented with tachypnea postpartum. This baby had a family history of hereditary hemorrhagic telangiectasia. A cerebral MR image revealed multiple macrocerebral arteriovenous fistulas (MCAVFs), resulting in a large partially thrombosed venous pouch within the cerebral cortex. Trans-arterial embolizations of the main two fistulas were performed using N-butyl cyanoacrylate (NBCA) with tantalum powder six months after birth. Post-embolization angiography confirmed the obliteration of the fistulas and magnetic resonance imaging (MRI) revealed thrombosis and reduction in size of the venous component. His tachypnea disappeared completely. There were no neurological complications due to the treatment. The prognosis of multiple MCAVFs mainly depends on the presence of medullar signs and symptoms and a delay before treatment. Pure glue endovascular intervention, as used in our case, is considered to be the first therapeutic choice to decrease the risk of neurological consequences. PMID- 24059776 TI - Remote cerebellar hemorrhage as an unusual complication of supratentorial surgery. A case report and literature review. AB - Remote cerebellar hemorrhage as a complication of supratentorial surgery is a rare entity in radiology literature, but not infrequently encountered in neurosurgical literature. Typical appearance and location in the posterior fossa, and remote site from the original surgical site, make the diagnosis easier if one aware of such a self-limiting condition. Diagnosis of this condition helps to differentiate it from other ominous causes of hemorrhage. In our institution, we came across such cases within a short period of time and present them as case reports along with review of the literature on this unusual complication. PMID- 24059777 TI - Evaluation of Spinal Vascular Malformations Using 64-Slice CT-Angiography. A Report of Three Cases. AB - Spinal vascular malformations are rare but they pose a great risk of disability for patients. Although spinal DSA is the gold standard in the diagnostic evaluation of these vascular anomalies, it is an invasive, technically complicated and time-consuming method. The purpose of this report is to add to the knowledge of CT angiography as a non-invasive method that may become an alternative diagnostic tool in the imaging of spinal vascular anomalies. PMID- 24059778 TI - Atypical presentation of coarctation of aorta mimicking a spinal vascular malformation. A case report. AB - Coarctation of the aorta accounts for about 8% of all congenital heart diseases. It usually presents in infancy or later in the third decade depending on its severity. It has a wide spectrum varying from an asymptomatic presentation to cardiac and extracardiac manifestations with neurological complications. Coarctation presenting as a spinal complication is extremely rare. We describe a case of coarctation detected on magnetic resonance imaging (MRI) in a 40-year-old man with an uncommon presentation mimicking a spinal arteriovenous malformation (AVM). To our knowledge, coarctation presenting with a spinal manifestation, resembling an AVM is rare, and has not been reported to date. PMID- 24059779 TI - Detached Coil Migration that Assisted Stent Migration, during Stent Assisted Coiling of a Recurrent Aneurysm. A Case Report. AB - This is a pictorial case report of previously unreported intra-procedural complication of an intra-procedural migrated stent-coil complex. It shows fluoroscopic detail of the migration of a stent with the help of a migrated coil with subsequent retrieval of coil and deployment of a second stent proximally. It also briefly covers postulated mechanisms for this in the discussion. In our clinical practice we experienced an unusual case during stent assisted coiling of a right Posterior Communicating Artery Aneurysm (PCOM) where a coil migrated through a deployed stent into the parent artery and become ensnared into a distal stent strut. This caused stent migration distally. Studies have shown that stent assisted coiling of cerebral aneurysms is an effective treatment that lowers the risk of recurrence. There are several complications associated with both coiling and stent deployment. Multiple cases of individual coil migration and stent misplacement have been described in the literature, such as coil protrusion through a stent with open cell designs and a single case of delayed coil migration through a deployed stent. Various aetiologies are described for these, which we cover, and we postulate on the factors relevant to our case and suggest the biggest contributing factor was an open side stent design. We believe this is a rare documented acute case of a migrated coil that has assisted stent migration. We suggest caution particularly when small coils need to be deployed alongside open cell and side design stents. PMID- 24059780 TI - Unusual acute complications of carotid cavernous fistula: therapeutic options. AB - We aimed to demonstrate the complications of carotid-cavernous fistula (CCF) and their correlation with venous hypertension. From August 2000 to April 2008 we performed more than 2400 catheter angiographic procedures. Among those, six unusual cases presented acute complications of CCF. The presented complications of CCF from our cases showed a possible correlation with venous hypertension. With the experiences from our cases, venous hypertension may complicate CCF with a poor prognosis. The condition should be carefully evaluated and if present prompt treatment is necessary. PMID- 24059781 TI - A case of primitive trigeminal artery-cavernous fistula: embolization, complications and strategy. AB - A 22-year-old man with primitive trigeminal artery-cavernous fistula was admitted to our hospital. Embolization with Guglielmi detachable coils and microcoils was attempted on the fistula from the internal carotid artery. The last microcoil was incorrectly released to the basilar artery through the primitive trigeminal artery. The misplaced microcoil was eventually retrieved by goose-neck snare. There was no related complication in the follow-up period. PMID- 24059782 TI - Radiation dose measurement with newly developed head phantom for interventional neuroradiology. AB - Although it is important to measure and record radiation dose to a patient's skin, no standardized measuring method is available to compare the performance of digital subtraction angiography (DSA) systems with those of other institutions. We developed a new bidirectional information exchange system using a web page and e-mail. Measurements are obtained using an original head phantom with skin dose monitors. This system was sent to institutions ordering it from the web page. The data obtained with this system by each institution were evaluated and displayed anonymously on a graph on the web page for comparison. This method for measuring radiation dose allows the comparison of DSA systems under identical conditions. This system can alert the user that the radiation dose delivered using ordinary parameters differs from that of other institutions or DSA systems. To promote the use of this system, we developed a web page with information about radiation dose measuring and initiated an online lending operation. This head phantom and standardized measuring method allows the accurate comparison of skin radiation dose and DSA performance under the same conditions. PMID- 24059783 TI - In and out of the rRNA genes: characterization of Pokey elements in the sequenced Daphnia genome. AB - BACKGROUND: Only a few transposable elements are known to exhibit site-specific insertion patterns, including the well-studied R-element retrotransposons that insert into specific sites within the multigene rDNA. The only known rDNA specific DNA transposon, Pokey (superfamily: piggyBac) is found in the freshwater microcrustacean, Daphnia pulex. Here, we present a genome-wide analysis of Pokey based on the recently completed whole genome sequencing project for D. pulex. RESULTS: Phylogenetic analysis of Pokey elements recovered from the genome sequence revealed the presence of four lineages corresponding to two divergent autonomous families and two related lineages of non-autonomous miniature inverted repeat transposable elements (MITEs). The MITEs are also found at the same 28S rRNA gene insertion site as the Pokey elements, and appear to have arisen as deletion derivatives of autonomous elements. Several copies of the full-length Pokey elements may be capable of producing an active transposase. Surprisingly, both families of Pokey possess a series of 200 bp repeats upstream of the transposase that is derived from the rDNA intergenic spacer (IGS). The IGS sequences within the Pokey elements appear to be evolving in concert with the rDNA units. Finally, analysis of the insertion sites of Pokey elements outside of rDNA showed a target preference for sites similar to the specific sequence that is targeted within rDNA. CONCLUSIONS: Based on the target site preference of Pokey elements and the concerted evolution of a segment of the element with the rDNA unit, we propose an evolutionary path by which the ancestors of Pokey elements have invaded the rDNA niche. We discuss how specificity for the rDNA unit may have evolved and how this specificity has played a role in the long-term survival of these elements in the subgenus Daphnia. PMID- 24059784 TI - The comparative effectiveness of Integrated treatment for Substance abuse and Partner violence (I-StoP) and substance abuse treatment alone: a randomized controlled trial. AB - BACKGROUND: Research has shown that treatments that solely addressed intimate partner violence (IPV) perpetration were not very effective in reducing IPV, possibly due to neglecting individual differences between IPV perpetrators. A large proportion of IPV perpetrators is diagnosed with co-occurring substance use disorders and it has been demonstrated that successful treatment of alcohol dependence among alcohol dependent IPV perpetrators also led to less IPV. The current study investigated the relative effectiveness of Integrated treatment for Substance abuse and Partner violence (I-StoP) to cognitive behavioral treatment addressing substance use disorders including only one session addressing partner violence (CBT-SUD+) among patients in substance abuse treatment who repeatedly committed IPV. Substance use and IPV perpetration were primary outcome measures. METHOD: Patients who entered substance abuse treatment were screened for IPV. Patients who disclosed at least 7 acts of physical IPV in the past year (N = 52) were randomly assigned to either I-StoP or CBT-SUD+. Patients in both conditions received 16 treatment sessions. Substance use and IPV perpetration were assessed at pretreatment, halfway treatment and posttreatment in blocks of 8 weeks. Both completers and intention-to-treat (ITT) analyses were performed. RESULTS: Patients (completers and ITT) in both conditions significantly improved regarding substance use and IPV perpetration at posttreatment compared with pretreatment. There were no differences in outcome between conditions. Completers in both conditions almost fully abstained from IPV in 8 weeks before the end of treatment. CONCLUSIONS: Both I-StoP and CBT-SUD+ were effective in reducing substance use and IPV perpetration among patients in substance abuse treatment who repeatedly committed IPV and self-disclosed IPV perpetration. Since it is more cost and time-effective to implement CBT-SUD+ than I-StoP, it is suggested to treat IPV perpetrators in substance abuse treatment with CBT-SUD+. PMID- 24059785 TI - Has the phase-out of PBDEs affected their atmospheric levels? Trends of PBDEs and their replacements in the Great Lakes atmosphere. AB - Air and precipitation samples were collected every 12 days at five sites near the North American Great Lakes from 2005 to 2011 (inclusive) by the Integrated Atmospheric Deposition Network (IADN). The concentrations of polybrominated diphenyl ethers (PBDEs) and selected alternative brominated flame retardants [pentabromoethyl benzene (PBEB), hexabromobenzene (HBB), 1,2-bis(2,4,6 tribromophenoxy)ethane (TBE or BTBPE), decabromodiphenylethane (DBDPE), 2 ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB), and bis(2-ethylhexyl)-tetrabromo phthalate (TBPH)] were measured in these samples. The concentrations of almost all of these flame retardants were related to the number of people within a 25 km radius of the sampling site, except for HBB, the concentrations of which were relatively high at Sturgeon Point, and PBEB, the concentrations of which were relatively high at Eagle Harbor. The temporal trends of all of these concentrations were variable. For example, BDE-47 vapor phase concentrations were increasing with doubling times of 5-10 years at Sturgeon Point, Sleeping Bear Dunes, and Eagle Harbor, but these concentrations were slowly decreasing in all phases at Chicago. The most consistent trend was for TBE, which showed concentrations that were unchanging or decreasing in all phases at all sites. TBPH concentrations in particles and HBB concentrations in precipitation were rapidly increasing at most sites with doubling times of ~2 years. The concentrations of DBDPE and BDE-209 were strongly and positively correlated, and the concentrations of TBB and TBPH were also strongly and positively correlated. The concentrations of TBB plus TBPH (representing Firemaster 550) and BDE-47, 85, 99, 100, 153, plus 154 (representing the withdrawn penta-BDE commercial mixture) were also strongly and positively correlated. These positive relationships indicate that the replacement of the deca-BDE commercial product by DBDPE and the penta-BDE product by Firemaster 550 have not yet become evident in the Great Lakes' atmospheric environment. PMID- 24059786 TI - Propofol infusion syndrome resuscitation with extracorporeal life support: a case report and review of the literature. AB - We report a case of propofol infusion syndrome (PRIS) in a young female treated for status epilepticus. In this case, PRIS rapidly evolved to full cardiovascular collapse despite aggressive supportive care in the intensive care unit, as well as prompt discontinuation of the offending agent. She progressed to refractory cardiac arrest requiring emergent initiation of venoarterial extracorporeal membrane oxygenation (ECMO) during cardiopulmonary resuscitation (CPR). She regained a perfusing rhythm after prolonged (>8 hours) asystole, was weaned off ECMO and eventually all life support, and was discharged to home. We also present a review of the available literature on the use of ECMO for PRIS. PMID- 24059787 TI - Blood pressure lowering effect of renal sympathetic denervation or placebo? - building expectations for Symplicity-HTN 3. PMID- 24059788 TI - Prevalence of resistant hypertension in 1810 patients followed up in a specialized outpatient clinic and its association with the metabolic syndrome. AB - We aimed to assess the prevalence of resistant hypertension (RH) in patients attending hypertension outpatient clinics and to identify risk factors for RH. We studied the medical records of the last visit of all patients (n = 1810; 40.4% males, age 56.5 +/- 13.5 years) who attended at least once our hypertension outpatient clinic during the last decade. RH was defined as blood pressure (BP) > 140/90 mmHg in patients without diabetes or chronic kidney disease (or BP > 130/80 mmHg in patients with the latter diseases) despite treatment with full doses of three antihypertensive agents from different classes or controlled BP on four or more different antihypertensive agents. The prevalence of RH was 12.3%, whereas 22.2% of the patients had well-controlled hypertension and 65.5% had uncontrolled hypertension but were on less than three antihypertensive agents. Independent predictors of RH were age (risk ratio, RR = 1.08, 95% confidence interval, CI 1.05-1.12, p < 0.001), body mass index (RR = 1.06, 95% CI 1.00-1.13, p < 0.05) and the presence of the metabolic syndrome (MetS) (RR = 2.01, 95% CI 1.03-3.91, p < 0.05). CONCLUSIONS: RH is frequent in patients followed up in hypertension outpatient clinics. In addition to age and obesity, MetS appears to be associated with increased risk for RH. Clarification of the mechanisms underpinning the association between MetS and hypertension might reduce the prevalence of RH. PMID- 24059789 TI - Comparison of host response mechanisms evoked by extended spectrum beta lactamase (ESBL)--and non-ESBL-producing uropathogenic E. coli. AB - BACKGROUND: Infections caused by extended spectrum beta-lactamases (ESBL) producing bacteria have been emerging worldwide and the majority of ESBL producing E. coli strains are isolated from patients with urinary tracts infections. The purpose of this study was to compare the host-response mechanisms in human polymorphonucleated leukocytes (PMN) and renal epithelial cells when stimulated by ESBL- or non-ESBL-producing uropathogenic E. coli (UPEC) isolates. The host-pathogen interaction of these ESBL-producing strains in the urinary tract is not well studied. RESULTS: The ability of ESBL strains to evoke ROS production from PMN cells was significantly higher than that of the non-ESBL strains. The growth of ESBL strains was slightly suppressed in the presence of PMN compared to non-ESBL strains after 30 min and 2h, but the opposite was observed after 5 and 6h. The number of migrating PMN was significantly higher in response to ESBL strains compared to non-ESBL strains. Stimulation of A498 cells with ESBL strains elicited lower production of IL-6 and IL-8 compared to non-ESBL strains. CONCLUSION: Significant differences in host-response mechanisms were identified when host cells were stimulated by ESBL- or non-ESBL producing strains. The obtained results on the early interactions of ESBL-producing strains with the host immune system may provide valuable information for management of these infections. PMID- 24059790 TI - Neurodevelopmental epigenetic etiologies: insights from studies on mouse models of fetal alcohol spectrum disorders. PMID- 24059791 TI - Menin/PRMT5/hedgehog signaling: a potential target for the treatment of multiple endocrine neoplasia type 1 tumors. PMID- 24059792 TI - Biomarker or pathophysiology? The role of DNA methylation in postpartum depression. PMID- 24059795 TI - Fighting disease from the chromosome end. PMID- 24059797 TI - Epigenetic targets in hepatocellular carcinoma cells: identification of chaperone protein complexes with histone deacetylases. AB - AIMS: The study was designed to find out the protein complex(s) associated with HDAC3 in liver cancer using a modified form of affinity purification coupled with a mass spectrometry technique in HepG2 cells. The organ-specific requirement for HDAC1 and HDAC3 during liver formation in zebrafish and their altered expression in liver cancer tissues indicates they are indispensible for hepato-organogenesis and hepatocarcinogenesis. However, how they exert their function is unknown. MATERIAL & METHODS: HepG2 cells were transfected with either mock or construct containing HDAC3 using a C-terminal strepIII-HA tag as bait. The bait proteins were purified by double affinity columns and were analyzed on a Thermo LTQ OrbitrapTM (Thermo Scientific, MA, USA) chromatography system. RESULTS: Affinity purification coupled with mass spectrometry resulted in the identification of 24 putative binders of HDAC3 in HepG2 cells. The majority (83%) of these are novel interactions are reported for the first time in this study. CONCLUSION: This is the first study reporting the affinity purification and identification of protein complexes with two closely related proteins in one cell line. The novel HDAC1 and HDAC3 complexes identified in HepG2 cells could serve as a platform for the design of future therapeutic medicine for the treatment of liver cancer. PMID- 24059798 TI - Establishing the clinical utility of epigenetic markers in cancer: many challenges ahead. AB - The use of epigenetic biomarkers in cancer management relies on the availability of robust assays and evidence that these markers are able to segregate clinically significant groups of patients. While many cancers are characterized by genetic and epigenetic modifications, it is far simpler to develop molecular tests that detect genetic rather than epigenetic changes. In this special report, we will describe the challenges associated with developing epigenetic assays and the practical issues that must be overcome before they can be used in the clinic. PMID- 24059796 TI - Early-life lead exposure results in dose- and sex-specific effects on weight and epigenetic gene regulation in weanling mice. AB - AIMS: Epidemiological and animal data suggest that the development of adult chronic conditions is influenced by early-life exposure-induced changes to the epigenome. This study investigates the effects of perinatal lead (Pb) exposure on DNA methylation and bodyweight in weanling mice. MATERIALS & METHODS: Viable yellow agouti (A(vy)) mouse dams were exposed to 0, 2.1, 16 and 32 ppm Pb acetate before conception through weaning. Epigenetic effects were evaluated by scoring coat color of A(vy)/a offspring and quantitative bisulfite sequencing of two retrotransposon-driven (A(vy) and CDK5 activator-binding protein intracisternal A particle element) and two imprinted (Igf2 and Igf2r) loci in tail DNA. RESULTS: Maternal blood Pb levels were below the limit of detection in controls, and 4.1, 25.1 and 32.1 ug/dl for each dose, respectively. Pb exposure was associated with a trend of increased wean bodyweight in males (p = 0.03) and altered coat color in A(vy)/a offspring. DNA methylation at A(vy) and the CDK5 activator-binding protein intracisternal A-particle element was significantly different from controls following a cubic trend (p = 0.04; p = 0.01), with male-specific effects at the A(vy) locus. Imprinted genes did not shift in methylation across exposures. CONCLUSION: Dose- and sex-specific responses in bodyweight and DNA methylation indicate that Pb acts on the epigenome in a locus-specific fashion, dependent on the genomic feature hosting the CpG site of interest, and that sex is a factor in epigenetic response. PMID- 24059799 TI - Epigenetic regulation of cell signaling pathways in acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is a heterogeneous cancer that is characterized by rapid and uncontrolled proliferation of immature B- or T lymphoid precursors. Although ALL has been regarded as a genetic disease for many years, the crucial importance of epigenetic alterations in leukemogenesis has become increasingly evident. Epigenetic mechanisms, which include DNA methylation and histone modifications, are critical for gene regulation during many key biological processes. Here, we review the cell signaling pathways that are regulated by DNA methylation or histone modifications in ALL. Recent studies have highlighted the fundamental role of these modifications in ALL development, and suggested that future investigation into the specific genes and pathways that are altered by epigenetic mechanisms can contribute to the development of novel drug based therapies for ALL. PMID- 24059800 TI - Epigenetic role of miRNAs in normal and leukemic hematopoiesis. AB - Hematopoiesis is a regulated multistep process, whereby transcriptional and epigenetic events contribute to progenitor fate determination. miRNAs have emerged as key players in hematopoietic cell development, differentiation and malignant transformation. From embryonic development through to adult life, miRNAs cooperate with, or are regulated, by epigenetic factors. Moreover, recent findings suggest that they contribute to chromatin structural modification, and the functional relevance of this 'epigenetic-miRNA axis' will be discussed in this article. Finally, emerging evidence has highlighted that miRNAs have functional control in human hematopoietic cells, involving targeted recruitment of epigenetic complexes to evolutionarily conserved complementary genomic loci. We propose the existence of epigenetic-miRNA loops that are able to organize the whole gene expression profile in hematopoietic cells. PMID- 24059802 TI - Genome-wide screening for understanding the role of DNA methylation in colorectal cancer. AB - DNA methylation analysis methods have undergone an impressive revolution over the past 15 years. Regarding colorectal cancer (CRC), the localization and distribution of several differently methylated genes have been determined by genome-wide DNA methylation assays. These genes do not just influence the pathogenesis of CRC, but can be used further as diagnostic or prognostic markers. Moreover, the identified four DNA methylation-based subgroups of CRC have important clinical and therapeutic merit. Since genome-wide DNA methylation analyzes result in a large amount of data, there is a need for complex bioinformatic and pathway analysis. Future challenges in epigenetic alterations of CRC include the demand for comprehensive identification and experimental validation of gene abnormalities. By introduction of genome-wide DNA methylation profiling into clinical practice not only the patients' risk stratification but development of targeted therapies will also be possible. PMID- 24059803 TI - Role of epigenetics in Rett syndrome. AB - Rett syndrome (RTT) is an X-linked neurodevelopmental disease caused by MECP2 mutations. The MeCP2 protein was originally thought to function as a transcription repressor by binding to methylated CpG dinucleotides, but is now also thought to be a transcription activator. Recent studies suggest that MeCP2 is not only being expressed in neurons, but also in glial cells, which suggests a new paradigm for understanding the pathogenesis of RTT. It has also been demonstrated that reintroduction of MeCP2 into behaviorally affected Mecp2-null mice after birth rescues neurological symptoms, which indicates that epigenetic failures in RTT are reversible. Therefore, RTT may well be seen as a model disease that can be potentially treated by taking advantage of the reversibility of epigenetic phenomena in various congenital neurodevelopmental diseases that were previously thought to be untreatable. PMID- 24059805 TI - In utero exposure to itraconazole during different gestational periods of rats. AB - The present study aimed to investigate the teratogenic and genotoxic effects of itraconazole administered orally to pregnant rats on gestation days 1-7 (implantation), 8-14 (organogenesis) and 14-20 (fetal developmental period) at doses 75, 100 or 150 mg/kg b.wt. The results indicated that itraconazole had embryolethal effect when administered at a dose of 150 mg/kg b.wt throughout implantation and organogenesis periods as well as at 100 mg/kg b.wt during implantation period. Itraconazole elevated the teratogenicity when administrated at a dose of 100 mg/kg b.wt during organogenesis period, the most prominent abnormalities were abdominal hernia, protruding tongue, exencephaly, incompletely ossified, unossified or missing skull bones (mostly frontal, parietal and interparietal), abnormal vertebrae and fused and supernumerary ribs. However, minimal adverse effects were observed at doses given during the fetal developmental period. Itraconazole increased DNA damage of fetal osteocytes via significant increase in the measured comet parameters in all the treated groups, indicating that itraconazole severely affects fetal genetic material. PMID- 24059801 TI - DNA methylation and differentiation: silencing, upregulation and modulation of gene expression. AB - Differentiation-related DNA methylation is receiving increasing attention, partly owing to new, whole-genome analyses. These revealed that cell type-specific differential methylation in gene bodies is more frequent than in promoters. We review new insights into the functionality of DNA methylation during differentiation, with emphasis on the methylomes of myoblasts, myotubes and skeletal muscle versus non-muscle samples. Biostatistical analyses of data from reduced representation bisulfite sequencing are discussed. Lastly, a model is presented for how promoter and intragenic DNA hypermethylation affect gene expression, including increasing the efficiency of polycomb silencing at some promoters, downmodulating other promoters rather than silencing them, counteracting enhancers with heterologous specificity, altering chromatin conformation by inhibiting the binding of CTCF, modulating mRNA transcript levels by inhibiting overlapping promoters of noncoding RNA genes or by regulating the use of alternative mRNA promoters, modulating transcription termination, regulating alternative splicing and acting as barriers to the spread of activating chromatin. PMID- 24059806 TI - Gut-targeted immunonutrition boosting natural killer cell activity using Saccharomyces boulardii lysates in immuno-compromised healthy elderly subjects. AB - The aim of this study was to assess the immunomodulatory effect of KC-1317 (a symbiotic mixture containing Saccharomyces boulardii lysate in a cranberry, colostrum-derived lactoferrin, fragaria, and lactose mixture) supplementation in immune-compromised but otherwise healthy elderly subjects. A liquid formulation of KC-1317 was administered in a randomized controlled trial (RCT) fashion to healthy volunteers (65-79 years) previously selected for low natural killer (NK) cell activity, and this parameter was checked at the completion of the study. A significant improvement in NK cell activity of KC-1317 consumers was observed as compared to placebo at the end of 2 months. Although preliminary, these beneficial immune-modulatory effects of KC-1317 in aged individuals might indicate its employment within a wider age-management strategy. PMID- 24059807 TI - Manganese-loaded dual-mesoporous silica spheres for efficient T1- and T2-weighted dual mode magnetic resonance imaging. AB - A novel class of manganese-based dual-mode contrast agents (DMCAs) based on the core-shell structured manganese-loaded dual-mesoporous silica spheres (Mn-DMSSs) for simultaneous T1- and T2-weighted magnetic resonance imaging (MRI) has been successfully reported. The in vitro MR tests demonstrate that the Mn-based DMCAs display an excellent simultaneous T1-weighted and T2-weighted MR imaging effect with a noticeably high T1 relaxivity (r1) of 10.1 mM(-1) s(-1) and a moderately high T2 relaxivity (r2) of 169.7 mM(-1) s(-1). The Mn-based DMCAs exhibit negligible cytotoxicity with >80% cell viability at a concentration of up to 200 MUg/mL in human liver carcinoma (HepG2) and mouse macrophage (RAW264.7) cells after 24 h. Confocal laser scanning microscopy (CLSM) results show that the Mn DMSSs were internalized via endocytosis and located in the cytoplasm but not in the nucleus. The in vivo experiment shows that the signals of rat liver increased by 29% under T1-weighted imaging mode and decreased by 28% under T2-weighted imaging mode in 5 min postinjection of Mn-DMSSs, which reveal that the novel Mn loaded DMSSs can be used as both positive (T1-weighted) and negative (T2 weighted) MR contrast agents in further biomedical applications. PMID- 24059808 TI - Three protocols for the formation of a [3]pseudorotaxane via orthogonal cryptand based host-guest recognition and coordination-driven self-assembly. AB - A novel bis(m-phenylene)-32-crown-10-based cryptand 1 with a pyridine nitrogen atom outside on the third arm was designed and synthesized. Subsequently, host guest complexation between cryptand 1 and a selection of bipyridinium guests has been studied. More interestingly, the [3]pseudorotaxane 2 is a superset of 5(2) was obtained in three methods by utilizing the noninterfering orthogonal nature of coordination-driven self-assembly and host-guest interactions. PMID- 24059809 TI - Hyperbilirubinemia and urinary tract infection: the effect of indirect hyperbilirubinemia on the in vitro growth of uropathogen Escherichia coli in newborn urine. AB - High serum bilirubin is antioxidant and cytoprotective. We evaluated if urine samples of hyperbilirubinemic newborns impede uropathogenic Escherichia coli growth. Bag-urine samples of hyperbilirubinemic newborns (study group) were cultured at presentation and during remission. Urine sample were obtained only once from healthy newborns (control group). Escherichia coli [2 * 104 colony forming unit (cfu)/mL] was inoculated into the sterile urine samples and colony counts were determined after 24 h. Bilirubin levels at presentation and remission were also recorded. Escherichia coli colony counts of the control versus study groups and of the presentation versus remission samples in the study group were compared. There were 13 study and 17 control cases. Escherichia coli colony counts were not different in the study group at presentation versus remission (5.4 +/- 0.7 vs. 5.5 +/- 0.8 log10, respectively; p = 0.659). Escherichia coli colony count of the control group (5.2 +/- 0.6 log10) was also not different from the study group. In conclusion, the urine of hyperbilirubinemic newborns did not affect the growth rate of uropathogenic E. coli. PMID- 24059810 TI - Unusual stability and carbon acidity of a dicationic carbon species. AB - 1,1'-Methylenebis(pyridinium) dication (MDP) is an unusual ion with two formal positively charged substituents attached to a central carbon, yet it is remarkably stable to hydrolysis at pH < 8. However, above this pH it undergoes a biphasic reaction liberating two equiv of pyridine sequentially. The rate of the first phase is second order in hydroxide ion, while that of the second is pH independent. The first phase is also accompanied by the generation of a chromophore at 366 nm, which has been identified as a pyridine-ring-opened unsaturated iminoaldehyde formed by an ANRORC-type mechanism. This intermediate then undergoes ring closure to give the second equiv of pyridine and formaldehyde. Below pD 8 there is a very slow alternative pathway for degradation that is first order in hydroxide ion, liberates only one equiv of pyridine, and forms N-(hydroxymethyl)pyridinium ion. Deuterium exchange of the central methylene in D2O is faster than the breakdown of MDP and is predominantly OD(-) catalyzed with a small amount of buffer catalysis. The estimated pKa of MDP dication in H2O, 21.2 at 25 degrees C and I = 1.0 M (KCl), is unexpectedly high but is about 9 units lower than that for the monocationic N-methylpyridinium ion. Deuterium exchange also occurs at the 2 and 6 positions of the pyridinium rings, but at a lower rate that is first order in deuteroxide ion and competitive with the breakdown of MDP only below pD 11. PMID- 24059811 TI - Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy. AB - Child conduct problems (CPs) are a robust predictor of adult mental health; the concurrence of callous-unemotional (CU) traits confers specific risk for psychopathy. Psychopathy may be related to disturbances in the oxytocin (OXT) system. Evidence suggests that epigenetic changes in the OXT receptor gene (OXTR) are associated with lower circulating OXT and social-cognitive difficulties. We tested methylation levels of OXTR in 4- to 16-year-old males who met DSM criteria for a diagnosis of oppositional-defiant or conduct disorder and were stratified by CU traits and age. Measures were DNA methylation levels of six CpG sites in the promoter region of the OXTR gene (where a CpG site is a cytosine nucleotide occurs next to a guanine nucleotide in the linear sequence of bases along its lenth, linked together by phosphate binding), and OXT blood levels. High CU traits were associated with greater methylation of the OXTR gene for two cytosine nucleotide and guanine nucleotide phosphate linked sites and lower circulating OXT in older males. Higher methylation correlated with lower OXT levels. We conclude that greater methylation of OXTR characterizes adolescent males with high levels of CU and CPs, and this methylation is associated with lower circulating OXT and functional impairment in interpersonal empathy. The results add genetic evidence that high CU traits specify a distinct subgroup within CP children, and they suggest models of psychopathy may be informed by further identification of these epigenetic processes and their functional significance. PMID- 24059812 TI - Initial validation of the prekindergarten Classroom Observation Tool and goal setting system for data-based coaching. AB - Although coaching is a popular approach for enhancing the quality of Tier 1 instruction, limited research has addressed observational measures specifically designed to focus coaching on evidence-based practices. This study explains the development of the prekindergarten (pre-k) Classroom Observation Tool (COT) designed for use in a data-based coaching model. We examined psychometric characteristics of the COT and explored how coaches and teachers used the COT goal-setting system. The study included 193 coaches working with 3,909 pre-k teachers in a statewide professional development program. Classrooms served 3 and 4 year olds (n = 56,390) enrolled mostly in Title I, Head Start, and other need based pre-k programs. Coaches used the COT during a 2-hr observation at the beginning of the academic year. Teachers collected progress-monitoring data on children's language, literacy, and math outcomes three times during the year. Results indicated a theoretically supported eight-factor structure of the COT across language, literacy, and math instructional domains. Overall interrater reliability among coaches was good (.75). Although correlations with an established teacher observation measure were small, significant positive relations between COT scores and children's literacy outcomes indicate promising predictive validity. Patterns of goal-setting behaviors indicate teachers and coaches set an average of 43.17 goals during the academic year, and coaches reported that 80.62% of goals were met. Both coaches and teachers reported the COT was a helpful measure for enhancing quality of Tier 1 instruction. Limitations of the current study and implications for research and data-based coaching efforts are discussed. PMID- 24059813 TI - Blood-brain barrier molecular trojan horse enables imaging of brain uptake of radioiodinated recombinant protein in the rhesus monkey. AB - Recombinant proteins are large molecule drugs that do not cross the blood-brain barrier (BBB). However, BBB-penetration of protein therapeutics is enabled by re engineering the recombinant protein as IgG fusion proteins. The IgG domain is a monoclonal antibody (mAb) against an endogenous BBB receptor-mediated transport system, such as the human insulin receptor (HIR), and acts as a molecular Trojan horse to ferry the fused protein across the BBB. In the present study, a recombinant lysosomal enzyme, iduronate 2-sulfatase (IDS), is fused to the HIRMAb, and BBB penetration of the IDS alone vs the HIRMAb-IDS fusion protein is compared in the Rhesus monkey. Recombinant IDS and the HIRMAb-IDS fusion protein were radiolabeled with indirect iodination with the [(125)I]-Bolton-Hunter reagent and with direct iodination with Iodogen/[(125)I]-idodine. IDS and the HIRMAb-IDS fusion protein have comparable plasma pharmacokinetics and uptake by peripheral organs. IDS does not cross the BBB. The HIRMAb-IDS fusion protein crosses the BBB and the brain uptake is 1% of injected dose/brain. Brain imaging shows HIRMAb-IDS penetration to all parts of brain, and immunoprecipitation of brain radioactivity shows intact fusion protein in brain. The use of BBB molecular Trojan horses enables brain imaging of recombinant proteins that are re engineered for BBB transport. PMID- 24059814 TI - Tannin structural elucidation and quantitative 31P NMR analysis. 1. Model compounds. AB - Tannins and flavonoids are secondary metabolites of plants that display a wide array of biological activities. This peculiarity is related to the inhibition of extracellular enzymes that occurs through the complexation of peptides by tannins. Not only the nature of these interactions, but more fundamentally also the structure of these heterogeneous polyphenolic molecules are not completely clear. This first paper describes the development of a new analytical method for the structural characterization of tannins on the basis of tannin model compounds employing an in situ labeling of all labile H groups (aliphatic OH, phenolic OH, and carboxylic acids) with a phosphorus reagent. The 31P NMR analysis of 31P labeled samples allowed the unprecedented quantitative and qualitative structural characterization of hydrolyzable tannins, proanthocyanidins, and catechin tannin model compounds, forming the foundations for the quantitative structural elucidation of a variety of actual tannin samples described in part 2 of this series. PMID- 24059815 TI - Morphological characterization of DMPC/CHAPSO bicellar mixtures: a combined SANS and NMR study. AB - Spontaneously forming structures of a system composed of dimyristoyl phosphatidylcholine (DMPC) and 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1 propanesulfonate (CHAPSO) were studied by small-angle neutron scattering (SANS), (31)P NMR, and stimulated echo (STE) pulsed field gradient (PFG) (1)H NMR diffusion measurements. Charged lipid dimyristoyl phosphatidylglycerol (DMPG) was used to induce different surface charge densities. The structures adopted were investigated as a function of temperature and lipid concentration for samples with a constant molar ratio of long-chain to short-chain lipids (= 3). In the absence of DMPG, zwitterionic bicellar mixtures exhibited a phase transition from discoidal bicelles, or ribbons, to multilamellar vesicles either upon dilution or with increased temperature. CHAPSO-containing mixtures showed a higher thermal stability in morphology than DHPC-containing mixtures at the corresponding lipid concentrations. In the presence of DMPG, discoidal bicelles (or ribbons) were also found at low temperature and lower lipid concentration mixtures. At high temperature, perforated lamellae were observed in high-concentration mixtures (>=7.5 wt %) whereas uniform unilamellar vesicles and bicelles formed in low concentration mixtures (<=2.5 wt %), respectively, when the mixtures were moderately and highly charged. From the results, spontaneous structural diagrams of the zwitterionic and charged systems were constructed. PMID- 24059816 TI - A traceless Staudinger reagent to deliver diazirines. AB - A triarylphosphine reagent that reacts with organic azides to install amide linked diazirines is reported. This traceless Staudinger reagent reacts with complex organic azides to yield amide-linked diazirines, thus expanding the scope of the utility of both azide and diazirine chemistry. PMID- 24059817 TI - Non-albuminuric renal disease among subjects with advanced stages of chronic kidney failure related to type 2 diabetes mellitus. AB - Urinary albumin excretion has been consistently found to be normal in a significant number of subjects with early stages of diabetic kidney disease. This study was aimed to estimate the prevalence and characteristics of non-albuminuric chronic kidney disease associated with type 2 diabetes mellitus among subjects who reach advanced stages of renal failure. Study population was composed of incident patients with advanced chronic kidney disease (glomerular filtration rate <30 mL/min) related to type 2 diabetes in a tertiary hospital from Gran Canaria (Spain) during a period of 2 years. Subjects were classified as normoalbuminuric (urinary albumin-to-creatine ratio [UACR] <30 mg/g), microalbuminuric (UACR >=30 and <300 mg/g), or proteinuric (UACR >=300 mg/g). Of 78 eligible patients, 21.8% had normoalbuminuria, 20.5% had microalbuminuria, and 57.7% had proteinuria. Individuals with normoalbuminuria were mostly women and had a lower prevalence of smoking and polyneuropathy than subjects with microalbuminuria or proteinuria. They also presented greater measures of body mass index and waist circumference, higher values of total and LDL cholesterol, and lower values of HbA1c and serum creatinine than subjects with microalbuminuria or proteinuria. Multivariate analysis demonstrated that female sex (positively) and HbA1c and polyneuropathy (negatively) were independently associated with absence of albuminuria. In conclusion, around 20% of subjects with diabetes-related advanced chronic kidney disease, characteristically women, have normal urinary albumin excretion. HbA1c and polyneuropathy are inversely related to this non-albuminuric form of nephropathy. PMID- 24059818 TI - Molecular "pincer" from a diimidazolium salt: a study of binding ability. AB - The anion recognition ability of the dicationic imidazolium salt 3,3'-di-n-octyl 1,1'-(1,3-phenylenedimethylene)diimidazolium 1,5-naphthalenedisulfonate ([m-Xyl (oim)2][1,5-NDS]) was investigated in acetonitrile solution by means of proton NMR titrations. A wide range of anions, comprising simple inorganic ions, halides, and mono- and dicarboxylates was taken into account. The study showed that this receptor binds carboxylate anions more strongly than halides. Moreover [m-Xyl-(oim)2][1,5-NDS] displays selectivity for di- over monocarboxylate anions. The complex stability was mainly affected by the anion basicity in the presence of monocarboxylates, whereas the flexibility of the alkyl chain linking the two carboxylate moieties appeared to play a major role in the presence of dicarboxylate anions. PMID- 24059820 TI - Negativity bias and task motivation: testing the effectiveness of positively versus negatively framed incentives. AB - People are frequently challenged by goals that demand effort and persistence. As a consequence, philosophers, psychologists, economists, and others have studied the factors that enhance task motivation. Using a sample of undergraduate students and a sample of working adults, we demonstrate that the manner in which an incentive is framed has implications for individuals' task motivation. In both samples we find that individuals are less motivated when an incentive is framed as a means to accrue a gain (positive framing) as compared with when the same incentive is framed as a means to avoid a loss (negative framing). Further, we provide evidence for the role of the negativity bias in this effect, and highlight specific populations for whom positive framing may be least motivating. Interestingly, we find that people's intuitions about when they will be more motivated show the opposite pattern, with people predicting that positively framed incentives will be more motivating than negatively framed incentives. We identify a lay belief in the positive correlation between enjoyment and task motivation as one possible factor contributing to the disparity between predicted and actual motivation as a result of the framing of the incentive. We conclude with a discussion of the managerial implications for these findings. PMID- 24059821 TI - Evaluating stress as a challenge is associated with superior attentional control and motor skill performance: testing the predictions of the biopsychosocial model of challenge and threat. AB - The biopsychosocial model of challenge and threat (Blascovich, 2008) suggests that individuals who evaluate a performance situation as a challenge will perform better than those who evaluate it as a threat. However, limited research has examined (a) the influence of challenge and threat evaluations on learned motor performance under pressure and (b) the attentional processes by which this effect occurs. In the present study 52 novices performed a motor task (laparoscopic surgery), for which optimal visual attentional control has been established. Participants performed a Baseline trial (when the task was novel) and were then trained to proficiency before performing under pressurized conditions designed to increase anxiety (Pressure). At Baseline, regression analyses were performed to examine the relationship between challenge/threat evaluations and the outcome variables (performance, cardiovascular response, and visual attention). At Pressure, hierarchical regression analyses (controlling for the degree of learning) were performed to examine the relationship between challenge/threat evaluations and the outcome variables. At both Baseline and Pressure tests evaluating the task as more of a challenge was associated with more effective attentional control and superior performance. In the Baseline test, evaluating the task as more of a challenge was associated with differential cardiovascular responses. Although there is some support for an attentional explanation of differential performance effects, additional analyses did not reveal mediators of the relationship between challenge/threat evaluations and motor performance. The findings have implications for the training and performance of motor skills in pressurized environments (e.g., surgery, sport, aviation). PMID- 24059822 TI - Making a task difficult: evidence that device-oriented steps are effortful and error-prone. AB - Errors in the execution of procedural tasks can have severe consequences. Attempts to ameliorate these slip errors through increased training and motivation have been shown to be ineffective. Instead, we identified the steps in a task procedure on which errors are most likely to occur, so that these might be designed out of the task procedure in the first place. Specifically, we considered whether device-oriented steps (i.e., steps in the task procedure that do not directly contribute to the achievement of the task goal) are more error prone than task-oriented steps (i.e., steps that do directly contribute to the task goal). Two experiments are reported in which participants were trained to perform a novel procedural task. Across conditions, we manipulated the extent to which each step in the task procedure appeared to contribute to the achievement of the task goal (i.e., alternating the assignment of a task step between device- and task-oriented), while keeping the interface and underlying task procedure the same. Results show that participants made more errors and took longer to complete a task step when it played a device-oriented role rather than a task-orientated role. These effects were exacerbated by the introduction of a secondary task designed to increase working memory load, suggesting that when a task step plays a device-oriented role it is more weakly represented in memory. We conclude that device-oriented task steps are inherently problematic and should be avoided where possible in the design of task procedures. PMID- 24059819 TI - Mother-infant attachment and the intergenerational transmission of posttraumatic stress disorder. AB - Evidence for the intergenerational transmission of posttraumatic stress disorder (PTSD) is documented in the literature, although the underlying mechanisms are poorly understood. Attachment theory provides a framework for elucidating the ways in which maternal PTSD may increase offspring PTSD vulnerability. The current study utilized two independent prospective data sets to test the hypotheses that (a) maternal PTSD increases the probability of developing an insecure mother-infant attachment relationship and (b) an insecure mother-infant attachment relationship increases the risk of developing PTSD following trauma exposure in later life. In the first study of urban, primarily low-income ethnic/racial minority mothers and infants (N = 45 dyads), elevated maternal PTSD symptoms at 6 months were associated with increased risk for an insecure, particularly disorganized, mother-infant attachment relationship at 13 months. In the second birth cohort of urban, low-income mothers and children (N = 96 dyads), insecure (avoidant or resistant) attachment in infancy was associated in a dose response manner with increased lifetime risk for a diagnosis of PTSD by adolescence. A history of disorganized attachment in infancy predicted severity of PTSD symptoms, including reexperiencing, avoidance, hyperarousal, and total symptoms, at 17.5 years. In both studies, associations between attachment and PTSD were not attributable to numerous co-occurring risk factors. The findings suggest that promoting positive mother-child relationships in early development, particularly in populations at high risk for trauma exposure, may reduce the incidence of PTSD. PMID- 24059823 TI - Detecting anomalous features in complex stimuli: the role of structured comparison. AB - The ability to detect anomalies in perceived stimuli is critical to a broad range of cognitive tasks, yet acquiring this ability often requires lengthy practice. In this research, we asked whether findings from research on analogical comparison can be used to aid in the acquisition of perceptual expertise. Building on findings that comparison can facilitate the detection of differences, the present research addressed two questions: (1) Does having an alignable comparison standard improve performance on a difficult detection task? (2) Can such comparison experience improve subsequent detection performance on single anomalous targets? Across 3 experiments, university undergraduates were asked to find an anomalous bone in drawings of animal skeletons. Target items including an anomaly were presented either alone or with a correct standard. Furthermore, to evaluate the impact of ease of alignment, the correct standard was presented either mirror-reversed (low alignable) or regular (high alignable). Results showed increased accuracy when a comparison standard was present and further gains when the standard was more easily alignable. In Experiment 3, we used a between-subjects design to reveal that advance comparison (as opposed to single item training) led to improved detection of anomalies in subsequent novel examples presented as isolated targets. We conclude that the availability of a standard and ease of alignment promote encoding and processing. Furthermore, comparison-based learning confers an ongoing advantage even without standards for comparison. Therefore, task performance in application areas requiring detection of nonobvious anomalies can be improved by providing alignable standards next to targets or in advance training. PMID- 24059824 TI - Tactile picture recognition by early blind children: the effect of illustration technique. AB - This study investigated factors that influenced haptic recognition of tactile pictures by early blind children. Such a research is motivated by the difficulty to identify tactile pictures, that is, two-dimensional representations of objects, while it is the most common way to depict the surrounding world to blind people. Thus, it is of great interest to better understand whether an appropriate representative technique can make objects' identification more effective and to what extent a technique is uniformly suitable for all blind individuals. Our objective was to examine the effects of three techniques used to illustrate pictures (raised lines, thermoforming, and textures), and to find out if their effect depended on participants' level of use of tactile pictures. Twenty-three early blind children (half with a regular or moderate level of use of tactile pictures, and half with either no use or infrequent use) were asked to identify 24 pictures of eight objects designed as the pictures currently used in the tactile books and illustrated using these three techniques. Results showed better recognition of textured pictures than of thermoformed and raised line pictures. Participants with regular or moderate use performed better than participants with no or infrequent use. Finally, the effect of illustration technique on picture recognition did not depend on prior use of tactile pictures. To conclude, early and frequent use of tactile material develops haptic proficiency and textures have a facilitating effect on picture recognition whatever the user level. Practical implications for the design of tactile pictures are discussed in the conclusion. PMID- 24059826 TI - Adaptive decision making in a dynamic environment: a test of a sequential sampling model of relative judgment. AB - Research has identified a wide range of factors that influence performance in relative judgment tasks. However, the findings from this research have been inconsistent. Studies have varied with respect to the identification of causal variables and the perceptual and decision-making mechanisms underlying performance. Drawing on the ecological rationality approach, we present a theory of the judgment and decision-making processes involved in a relative judgment task that explains how people judge a stimulus and adapt their decision process to accommodate their own uncertainty associated with those judgments. Undergraduate participants performed a simulated air traffic control conflict detection task. Across two experiments, we systematically manipulated variables known to affect performance. In the first experiment, we manipulated the relative distances of aircraft to a common destination while holding aircraft speeds constant. In a follow-up experiment, we introduced a direct manipulation of relative speed. We then fit a sequential sampling model to the data, and used the best fitting parameters to infer the decision-making processes responsible for performance. Findings were consistent with the theory that people adapt to their own uncertainty by adjusting their criterion and the amount of time they take to collect evidence in order to make a more accurate decision. From a practical perspective, the paper demonstrates that one can use a sequential sampling model to understand performance in a dynamic environment, allowing one to make sense of and interpret complex patterns of empirical findings that would otherwise be difficult to interpret using standard statistical analyses. PMID- 24059825 TI - Minimizing the disruptive effects of prospective memory in simulated air traffic control. AB - Prospective memory refers to remembering to perform an intended action in the future. Failures of prospective memory can occur in air traffic control. In two experiments, we examined the utility of external aids for facilitating air traffic management in a simulated air traffic control task with prospective memory requirements. Participants accepted and handed-off aircraft and detected aircraft conflicts. The prospective memory task involved remembering to deviate from a routine operating procedure when accepting target aircraft. External aids that contained details of the prospective memory task appeared and flashed when target aircraft needed acceptance. In Experiment 1, external aids presented either adjacent or nonadjacent to each of the 20 target aircraft presented over the 40-min test phase reduced prospective memory error by 11% compared with a condition without external aids. In Experiment 2, only a single target aircraft was presented a significant time (39-42 min) after presentation of the prospective memory instruction, and the external aids reduced prospective memory error by 34%. In both experiments, costs to the efficiency of nonprospective memory air traffic management (nontarget aircraft acceptance response time, conflict detection response time) were reduced by nonadjacent aids compared with no aids or adjacent aids. In contrast, in both experiments, the efficiency of the prospective memory air traffic management (target aircraft acceptance response time) was facilitated by adjacent aids compared with nonadjacent aids. Together, these findings have potential implications for the design of automated alerting systems to maximize multitask performance in work settings where operators monitor and control demanding perceptual displays. PMID- 24059827 TI - Photochemically prepared, two-component polymer-concentration gradients. AB - A versatile, photochemical surface-modification approach using nitrene-insertion reactions has been employed to develop an ultrathin, two-component, polymer gradient coating. Perfluorophenyl azide (PFPA) acted as the photosensitive moiety, forming a nitrene radical upon 254 nm UV exposure. Cationic poly(allyl amine) was grafted with PFPA and surface-anchored onto silicon wafers by means of electrostatic self-assembly. After spin-coating of polystyrene (PS), the substrate was illuminated from behind a moving shutter, thereby controlling the azide-to-nitrene conversion degree across the substrate, and leading to a gradually varying PS density after rinsing. Backfilling with poly(vinyl pyrrolidone) (PVP) and re-exposing to UV light formed a two-component polymer density gradient. The composition varied linearly following exposure to a linear UV exposure profile, as determined with spectroscopic ellipsometry (ELM) and X ray photoelectron spectroscopy (XPS). High-spatial-resolution, time-of-flight secondary ion mass spectrometry (ToF-SIMS) revealed a high degree of mixing between the two incompatible polymers on the micrometer scale. The dynamic water contact angle (dCA) was found to depend strongly on the sample history, suggesting adaptive properties of the coating, which was further confirmed by angle-resolved XPS (ARXPS). To confirm the applicability of the system for biological investigations, gradients were exposed to zoospores of the macrofouling alga Ulva linza , and a critical PS composition of 70% was identified, above which settlement started to increase. It has been shown that a two-component polymer-density gradient can provide a high-throughput platform for determining critical surface properties of polymer blend materials. PMID- 24059828 TI - Combining ultrasound-assisted extraction and a microliter colorimetric assay for the streamlined determination of urea in animal feedstuff. AB - This paper proposes a novel analytical strategy for the routine determination of urea in animal feedstuffs, combining an ultrasound-assisted miniaturized extraction protocol with a microplate colorimetric assay based on the reaction between 4-dimethylaminobenzaldehyde and urea. In order to accelerate the extraction, we introduced an ultrasound-assisted miniaturized protocol and compared it with both classic and miniaturized alternatives. The potential interference of amino acids was bypassed by shifting the detection wavelength from 435 to 450 nm. Urea could be quantified in the range 0.05-1.00% (w/w) with high precision (RSD < 5%). The results were in agreement with a commercial enzymatic method, demonstrating the accuracy and selectivity of the assay. The miniaturization led to a 50 times downscale when compared to the official method, resulting in a reduction of at least 90% in chemical consumption per determination, contributing to a more "green" and sustainable analytical methodology. PMID- 24059833 TI - Environmental context effects on alcohol-related outcome expectancies, efficacy, and norms: a field study. AB - The purpose of this study was to examine the effect of environmental contexts on alcohol norms, expectancies, and efficacy ratings. University students (n = 177) recruited via opportunity sampling completed questionnaires in either university lecture theaters or in a student bar. Positive social, fun, and tension reduction outcome expectancies were higher and social drink refusal self efficacy was lower in those participants questioned in a student bar relative to those questioned in a university lecture theater. These differences were found while controlling for between-groups variations in typical alcohol consumption quantities. Although hitherto largely unexamined by research, context appears to be a potentially important moderator of alcohol-related cognitions. Such findings require further exploration to inform more effective intervention approaches and have implications for the validity of existing literature. PMID- 24059834 TI - Stimulant medication use in college students: comparison of appropriate users, misusers, and nonusers. AB - While stimulant medication is commonly prescribed to treat Attention Deficit/Hyperactivity Disorder in children and adolescents (Merikangas, He, Rapoport, Vitiello, & Olfson, 2013; Zuvekas & Vitiello, 2012) and is considered an empirically supported intervention for those groups (Barkley, Murphy, & Fischer, 2008; Pelham & Fabiano, 2008; Safren et al., 2005) surprisingly little is known about the efficacy of stimulants in the slightly older emerging adult population. A focus has emerged, however, on illicit stimulant use among undergraduates, with studies suggesting such behavior is not uncommon (e.g., Arria et al., 2013). Unfortunately, details are lacking regarding outcomes and personal characteristics associated with different patterns of stimulant misuse. The current study compares the characteristics of four groups of college students, including those with stimulant prescriptions who use them appropriately (i.e., appropriate users), those who misuse their prescription stimulants (i.e., medical misusers), those who obtain and use stimulants without a prescription (i.e., nonmedical misusers), and those who do not use stimulant medications at all (i.e., nonusers). Undergraduates (N = 1,153) from the Southeastern, Midwest, and Rocky Mountain regions completed online measures evaluating patterns of use, associated motives, side effects, ADHD symptomatology, and other substance use. Both types of misusers (i.e., students who abused their prescriptions and those who obtained stimulants illegally) reported concerning patterns of other and combined substance use, as well as higher prevalence of debilitating side effects such as insomnia and restlessness. Research and practical implications are discussed. PMID- 24059835 TI - Perception of control over cocaine use and stages of change. AB - There is persistent disagreement over the degree of control that addicted patients are inferred to exercise over their drug use behavior. The study presented here proposes to investigate the perceptions and expectancies of controlled drug use in cocaine-addicted patients along the motivational stages that comprise their process of change. A total of 142 cocaine-addicted patients were evaluated with an original questionnaire--the Addictive Control Belief Inventory (ACBI)--and other validated inventories. The results were statistically analyzed. The precontemplative stage was characterized by the greatest perception of control over drug use, whereas maintenance showed the lowest perception of control. The results make it possible to infer a relation between awareness of the problematic aspects of drug use and a decrease in perceptions of controlled drug use. PMID- 24059836 TI - Using cross-game behavioral markers for early identification of high-risk internet gamblers. AB - Using actual gambling behavior provides the opportunity to develop behavioral markers that operators can use to predict the development of gambling-related problems among their subscribers. Participants were 4,056 Internet gamblers who subscribed to the Internet betting service provider bwin.party. Half of this sample included multiple platform gamblers who were identified by bwin.party's Responsible Gambling (RG) program; the other half were controls randomly selected from those who had the same first deposit date. Using the daily aggregated Internet betting transactions for gamblers' first 31 calendar days of online betting activities at bwin.party, we employed a 2-step analytic strategy: (a) applying an exploratory chi-squared automatic interaction detection (CHAID) decision tree method to identify characteristics that distinguished a subgroup of high-risk Internet gamblers from the rest of the sample, and (b) conducting a confirmatory analysis of those characteristics among an independent validation sample. This analysis identified two high-risk groups (i.e., groups in which 90% of the members were identified by bwin.party's RG program): Group 1 engaged in three or more gambling activities and evidenced high wager variability on casino type games; Group 2 engaged in two different gambling activities and evidenced high variability for live action wagers. This analysis advances an ongoing research program to identify potentially problematic Internet gamblers during the earliest stages of their Internet gambling. Gambling providers and public policymakers can use these results to inform early intervention programs that target high-risk Internet gamblers. PMID- 24059837 TI - I2-mediated oxidative C-O bond formation for the synthesis of 1,3,4-oxadiazoles from aldehydes and hydrazides. AB - A practical and transition-metal-free oxidative cyclization of acylhydrazones into 1,3,4-oxadiazoles has been developed by employing stoichiometric molecular iodine in the presence of potassium carbonate. The conditions of this cyclization reaction also work well with crude acylhydrazone substrates obtained from the condensation of aldehydes and hydrazides. A series of symmetrical and asymmetrical 2,5-disubstituted (aryl, alkyl, and/or vinyl) 1,3,4-oxadiazoles can be conveniently generated in an efficient and scalable fashion. PMID- 24059838 TI - Palliative care experience of US adult nephrology fellows: a national survey. AB - Palliative care (PC) training and experience of United States (US) adult nephrology fellows was not known. It was also not clear whether nephrology fellows in the US undergo formal training in PC medicine during fellowship. To gain a better understanding of the clinical training and experience of US adult nephrology fellows in PC medicine, we conducted a national survey in March 2012. An anonymous on-line survey was sent to US adult nephrology fellows via nephrology fellowship training program directors. Fellows were asked several PC medicine experience and training questions. A total of 105 US adult nephrology fellows responded to our survey (11% response rate). Majority of the respondents (94%) were from university-based fellowship programs. Over two-thirds (72%) of the fellows had no formal PC medicine rotation during their medical school. Half (53%) of the respondents had no formal PC elective experience during residency. Although nearly 90% of the fellows had a division or department of PC medicine at their institution, only 46.9% had formal didactic PC medicine experience. Over 80% of the respondent's program did not offer formal clinical training or rotation in PC medicine during fellowship. While 90% of the responding fellows felt most comfortable with either writing dialysis orders in the chronic outpatient unit, seeing an ICU consult or writing continuous dialysis orders in the ICU, only 35% of them felt most comfortable "not offering" dialysis to a patient in the ICU with multi-organ failure. Nearly one out of five fellows surveyed felt obligated to offer dialysis to every patient regardless of benefit. Over two-thirds (67%) of the respondents thought that a formal rotation in PC medicine during fellowship would be helpful to them. To enhance clinical competency and confidence in PC medicine, a formal PC rotation during fellowship should be highly considered by nephrology training community. PMID- 24059839 TI - Use of polyhydroxybutyrate and ethyl cellulose for coating of urea granules. AB - Fertilizers contain essential nutrients for agricultural growth and development. However, most nitrogen fertilizers are substances with high solubility of ions and are very susceptible to leaching and volatilization. To minimize these losses, an alternative is the creation of a physical barrier around granules. One way is to coat granules with polymers. In the present work urea granules were coated with polyhydroxybutyrate and ethyl cellulose in various conditions in the presence of emulsifiers. The original granules and the final products were characterized by scanning electron microscopy, Fourier transform infrared spectroscopy and thermogravimetry, to evaluate the surface morphology, the interaction between the granules and the coating, and the rates of mass change. The rates of urea release in distilled water were measured with a commercial enzyme kit. It is shown that those polymers are effective for coating of granules, leading to reduction of rates of urea dissolution in water. PMID- 24059840 TI - The course of neuropsychiatric symptoms in nursing-home patients with dementia over a 53-month follow-up period. AB - BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent in nursing-home (NH) patients with dementia, but little is known about the long-term course of these symptoms. METHODS: In this study, 931 NH patients with dementia took part in a prospective cohort study with four assessments over a 53-month follow-up period. NPS and level of dementia were assessed with the Neuropsychiatric Inventory scale and the Clinical Dementia Rating scale, respectively. RESULTS: Mild, moderate, and severe dementia was present in 25%, 33%, and 42%, respectively. There was an increase in the severity of the dementia from the first to the fourth assessment. Agitation, irritability, disinhibition, and apathy were the most prevalent and persistent symptoms during the study period. The affective subsyndrome (depression and anxiety) became less severe, whereas the agitation subsyndrome (agitation/aggression, disinhibition, and irritability) and apathy increased in severity during the follow-up period. More severe dementia was associated with more severe agitation, psychosis, and apathy, but not more severe affective symptoms. Mild dementia was associated with an increase in the severity of psychosis, whereas moderate or severe dementia was associated with decreasing severity of psychosis over the follow-up period. CONCLUSION: Nearly all the patients experienced clinically significant NPS, but individual symptoms fluctuated. Affective symptoms became less severe, while agitation and apathy increased in severity. An increase in dementia severity was associated with an increase in the severity of agitation, psychosis, and apathy, but not affective symptoms. The results may have implications when planning evaluation, treatment, and the prevention of NPS in NH patients. PMID- 24059841 TI - Synthesis, characterization, guest inclusion, and photophysical studies of gold nanoparticles stabilized with carboxylic acid groups of organic cavitands. AB - Water-soluble gold nanoparticles (AuNP) stabilized with cavitands having carboxylic acid groups have been synthesized and characterized by a variety of techniques. Apparently, the COOH groups similar to thiol are able to prevent aggregation of AuNP. These AuNP were stable either as solids or in aqueous solution. Most importantly, these cavitand functionalized AuNP were able to include organic guest molecules in their cavities in aqueous solution. Just like free cavitands (e.g., octa acid), cavitand functionalized AuNP includes guests such as 4,4'-dimethylbenzil and coumarin-1 through capsule formation. The exact structure of the capsular assembly is not known at this stage. Upon excitation there is communication between the excited guest present in the capsule and gold atoms and this results in quenching of phosphorescence from 4,4'-dimethylbenzil and fluorescence from coumarin-1. PMID- 24059842 TI - Longer storage duration of red blood cells is associated with an increased risk of acute lung injury in patients with sepsis. AB - BACKGROUND: The storage duration of red blood cells transfused to critically ill patients is associated with increased morbidity and mortality. Whether the association exists between storage duration of red blood cells transfused to patients with sepsis and the risk of developing ALI/ARDS is unknown. We aimed to determine the association of the storage duration of red blood cells transfused to patients with sepsis and risk of developing acute lung injury in the subsequent 96 hours, with comparator trauma and nonsepsis/nontrauma groups. METHODS: We conducted a retrospective observational study of 96 transfused, critically ill patients with sepsis, 176 transfused, critically ill patients with traumatic injury, and 125 transfused, critically ill nontrauma, nonsepsis patients. The primary outcome was the development of ALI/ARDS up to 96 hours after transfusion. RESULTS: In 96 patients with sepsis, 49 (51%) patients developed ALI/ARDS. The median storage duration of transfused blood in the ALI/ARDS group was greater (24.5 days, interquartile range (IQR) 20-31) compared with the patients who did not develop ALI/ARDS (21 days, IQR 15-27, p = 0.018). Longer median storage duration was independently associated with an increased risk of developing ALI/ARDS in the subsequent 4 days (odds ratio 1.8, p = 0.028). The same association was not seen in the trauma or nonsepsis, nontrauma patients. CONCLUSIONS: Transfusion of blood with longer median storage duration to patients with sepsis is associated with a higher risk of developing ALI up to 4 days after transfusion. This same association is not seen in other critically ill patient populations. PMID- 24059843 TI - Friends or foes: infants use shared evaluations to infer others' social relationships. AB - Predicting others' affiliative relationships is critical to social cognition, but there is little evidence of how this ability develops. We examined 9-month-old infants' inferences about 3rd-party affiliation based on shared and opposing evaluations. Infants expected 2 people who expressed shared evaluations to interact positively, whereas they expected 2 people who expressed opposing evaluations to interact negatively. A control condition revealed that infants' expectations could not be due to mere perceptual repetition. Thus, an abstract understanding that 3rd-party affiliation can be based on shared intentions has roots in the 1st year of life. These findings have implications for understanding humans' earliest representations of the social world. PMID- 24059844 TI - A functional basis for structure-seeking: exposure to structure promotes willingness to engage in motivated action. AB - A recurring observation of experimental psychologists is that people prefer, seek out, and even selectively "see" structure in their social and natural environments. Structure-seeking has been observed across a wide range of phenomena--from the detection of patterns in random arrays to affinities for order-providing political, religious, social, and scientific worldviews--and is exacerbated under psychological threat. Why are people motivated for structure? An intriguing, but untested, explanation holds that perceiving structure, even in domains unrelated to one's current behavioral context, can facilitate willingness to take goal-directed actions. Supporting this, in 5 studies, reminders of structure in nature or society increase willingness to engage in goal pursuit. PMID- 24059845 TI - Antioxidant and alpha-glucosidase inhibitory activities of cucurbit fruit vegetables and identification of active and major constituents from phenolic-rich extracts of Lagenaria siceraria and Sechium edule. AB - Antioxidant and alpha-glucosidase activities and total phenolic contents (TPC) in sequential extracts of dried pulps from seven cucurbit fruit vegetables were determined for the first time. The highest TPC and metal chelating activity were obtained from the chloroform extracts of Luffa acutangula (28.04 +/- 0.37 mg GAE/g extract) and Benincasa hispida (EC50 = 0.44 +/- 0.03 mg/mL), respectively. The ethyl acetate extract of Sechium edule showed the highest 1,1-diphenyl-2 picrylhydrazyl (DPPH) free radical scavenging activity (951.73 +/- 29.14 mM TE/g extract). The highest reducing and anti-alpha-glucosidase activities were shown by the methanol and ethyl acetate extracts of Momordica charantia (692.56 +/- 43.38 mM AscAE/g extract; 66.64 +/- 2.94%, respectively). The highest correlation (r = 0.99) was observed between the TPC and DPPH values of S. edule. Although caffeic acid was quantified as the major constituent in the methanol extract of Lagenaria siceraria , isoquercetin was found to be the main contributor to the activities. Gallic acid was identified as both the main and most active antioxidant constituent in the ethyl acetate extract of S. edule. PMID- 24059846 TI - Lexically guided phonetic retuning of foreign-accented speech and its generalization. AB - Listeners use lexical knowledge to retune phoneme categories. When hearing an ambiguous sound between /s/ and /f/ in lexically unambiguous contexts such as gira[s/f], listeners learn to interpret the sound as /f/ because gira[f] is a real word and gira[s] is not. Later, they apply this learning even in lexically ambiguous contexts (perceiving knife rather than nice). Although such retuning could help listeners adapt to foreign-accented speech, research has focused on single phonetic contrasts artificially manipulated to create ambiguous sounds; however, accented speech varies along many dimensions. It is therefore unclear whether analogies to adaptation to accented speech are warranted. In the present studies, the to-be-adapted ambiguous sound was embedded in a global foreign accent. In addition, conditions of cross-speaker generalization were tested with focus on the extent to which perceptual similarity between 2 speakers' fricatives is a condition for generalization to occur. Results showed that listeners retune phoneme categories manipulated within the context of a global foreign accent, and that they generalize this short-term learning to the perception of phonemes from previously unheard speakers. However, generalization was observed only when exposure and test speakers' fricatives were sampled across a similar perceptual space. PMID- 24059848 TI - Interleukin-6 polymorphisms and hematologic malignancy: a re-appraisal of evidence from genetic association studies. AB - CONTEXT: Interleukin-6 (IL-6) is implicated in the pathophysiology of hematologic neoplasia. OBJECTIVE: To review the role of IL-6 single nucleotide polymorphisms (SNPs) in hematologic neoplasia. METHODS: PubMed and EMBASE search of genetic association studies. Effects were summarized using the model-free generalized odds ratio (ORG), and the mode of inheritance was estimated for significant associations. RESULTS: Seventeen articles provided data on 20 distinct SNPs. The IL-6 receptor rs8192284 was associated with an increased risk of hematologic malignancy (combined ORG 1.42, 95%CI 1.03-1.96), including multiple myeloma (ORG 1.39, 95%CI 0.99-1.95). The IL-6 promoter rs1800795 conferred protection against young adult Hodgkin's disease (ORG 0.68, 95%CI 0.48-0.95). Significant single study effects for four other SNPs-disease associations were estimated. The IL-6 promoter rs1800795 and rs1800797 were not associated with overall susceptibility to non-Hodgkin's lymphomas. CONCLUSIONS: There is accumulating evidence that the IL-6 promoter, receptor and signal transducer SNPs can modify disease susceptibility. PMID- 24059849 TI - Borderline personality symptomatology and legal charges related to drugs. AB - OBJECTIVE: Borderline personality disorder (BPD) is associated with high lifetime prevalence rates of substance abuse as well as higher-than-expected rates of charges for various drug-related crimes and criminal behavior in general. However, whether criminal charges for assault and disorderly conduct are related specifically to drug misuse remains unknown - the focus of the present study. METHODS: Using a cross-sectional sample and a self-report survey methodology among a sample of 237 consecutive internal medicine outpatients, we examined: (1) BPD symptomatology using two self-report measures and (2) five charges for illegal behaviors defined as related to drugs. RESULTS: While there were no between-group differences with regard to drug-abuse violations (i.e., possession, sale, or use of illegal drugs), in participants with BPD symptomatology there was more probability to be charged with assault and disorderly conduct related to drug use as well as driving under the influence and drunkenness/public intoxication. CONCLUSIONS: The criminal behaviors of assault and disorderly conduct observed in BPD appear to be related, at least in part, to comorbid substance abuse. PMID- 24059847 TI - Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes. AB - BACKGROUND: Increased adipose thermogenesis is being considered as a strategy aimed at preventing or reversing obesity. Thus, regulation of the uncoupling protein 1 (UCP1) gene in human adipocytes is of significant interest. Retinoic acid (RA), the carboxylic acid form of vitamin A, displays agonist activity toward several nuclear hormone receptors, including RA receptors (RARs) and peroxisome proliferator-activated receptor delta (PPARdelta). Moreover, RA is a potent positive regulator of UCP1 expression in mouse adipocytes. RESULTS: The effects of all-trans RA (ATRA) on UCP1 gene expression in models of mouse and human adipocyte differentiation were investigated. ATRA induced UCP1 expression in all mouse white and brown adipocytes, but inhibited or had no effect on UCP1 expression in human adipocyte cell lines and primary human white adipocytes. Experiments with various RAR agonists and a RAR antagonist in mouse cells demonstrated that the stimulatory effect of ATRA on UCP1 gene expression was indeed mediated by RARs. Consistently, a PPARdelta agonist was without effect. Moreover, the ATRA-mediated induction of UCP1 expression in mouse adipocytes was independent of PPARgamma coactivator-1alpha. CONCLUSIONS: UCP1 expression is differently affected by ATRA in mouse and human adipocytes. ATRA induces UCP1 expression in mouse adipocytes through activation of RARs, whereas expression of UCP1 in human adipocytes is not increased by exposure to ATRA. PMID- 24059850 TI - Determination of chromium species in dietary supplements using speciated isotope dilution mass spectrometry with mass balance. AB - In order to determine the health impact of chromium in dietary supplements, the Cr(III) and Cr(VI) must be independently measured and verified with mass balance (sum of both species equaling independent measurements of total chromium), as both may be present in finished products. Because Cr(III) is stable in acidic conditions and Cr(VI) in alkaline conditions, interconversions between species may occur in complex matrices and during analytical extraction, increasing the difficulty of quantification. A study was conducted to determine Cr(VI) and Cr(III) in dietary supplements. EPA Method 3060A extraction protocol was performed to extract Cr(VI), and EPA Method 3052 was performed on the extracted residue to digest the remaining Cr(III). Speciated isotope dilution mass spectrometry (SIDMS), as described in the EPA Method 6800 (update V), was implemented with ion-exchange chromatography inductively coupled plasma mass spectrometry (IC-ICP-MS). Method 6800 uniquely enables tracking and correcting for the bidirectional chromium interspecies conversions that occur during extraction and sample handling prior to instrumental analysis. Mass balance results indicated that the off-the-shelf dietary supplements analyzed during this study contained hexavalent chromium ranging from
A (rs1800629). RESULTS: Demographic characteristics and procedural data revealed no significant differences between genotypes. No association between ApoE (E2,E3,E4) and TNF-alpha-308 G > A genotypes and the RIFLE criteria could be detected. Several multiple linear regression analyses for postoperative creatinine increase revealed highly significant associations for aortic cross clamp time (p < 0.001), CPB-time (p < 0.001), norepinephrine (p < 0.001), left ventricular function (p = 0.004) and blood transfusion (p < 0.001). No associations were found for ApoE (E2,E3,E4) and TNF-alpha-308 G > A genotypes or baseline creatinine. When the sample size is 1415, the multiple linear regression test of R(2 )= 0 for seven covariates assuming normal distribution will have at least 99% power with significance level 0.05 to detect an R(2) of 0.108 or 0.107 as observed in the data. CONCLUSIONS: ApoE (E2,E3,E4) polymorphism and the TNF-alpha-308 G > A polymorphism are not associated with renal injury after CPB. PMID- 24059883 TI - Dengue encephalitis associated with hydrocephalus. A case report. AB - We describe a case of dengue encephalitis with bilateral thalamus and cerebellum involvement. The cerebellar mass effect led to hydrocephalus requiring drainage. The patient recovered completely on follow-up. PMID- 24059884 TI - Intracranial Tumour Characterization: Whole Brain Evaluation with MR Perfusion Images and SPECT-CT. AB - A comparative study between perfusion magnetic resonance (MR) imaging and single photon emission tomography - computed tomography (SPECT-CT) was performed to disclose the indications and limits of the two techniques for brain tumour characterization. We compared these two techniques because they evaluate the entire brain and often a brain tumour can be too large to be studied entirely with MR spectroscopy. Forty-three patients with 56 lesions were studied with both techniques. The sensitivity in identifying neoplastic tissue was achieved. We did not evaluate the diagnostic sensitivity to differentiate high grade from low grade tumours because the features of grade II astrocytomas with SPECT methoxyisobutylisonitrile (SPECT-MIBI) are similar to those of normal brain tissue. Another question that advanced diagnostic techniques can solve is real glioma extension, but we did not consider also this aspect due to the low SPECT MIBI spatial resolution. In 29 (29/56) cases both techniques accurately identified the presence of neoplastic tissue. Only SPECT-CT was positive in eight cases, whereas perfusion MR was falsely negative. Only perfusion MR identified tumoral tissue in four cases and SPECT-CT not. Finally both perfusion MR and SPECT-CT failed to identify neoplastic tissue in 15 cases out of 56. In most cases the diagnostic gain of both techniques was the same. One technique was superior to the other in only in a few cases. We conclude that, if available, both techniques can be used to study suspected brain tumours to better characterize the lesion. PMID- 24059885 TI - (1)H MR Spectroscopy of Meningiomas at 3.0T: the Role of Glutamate-Glutamine Complex and Glutathione. AB - Proton magnetic resonance spectroscopy ((1)H MRS) has been used extensively for the characterization of the intracranial meningiomas. A major emphasis is placed on identification of an alanine (Ala) content within these tumors. Less attention is given to other metabolites such as glutamine and glutamate (Glx). Our objective was to assess the incidence and the relevance of the Glx content in meningiomas, to evaluate their usefulness versus Ala in the diagnosis of intracranial meningiomas and to indicate a potential role of other biochemical compounds such as glutathione (GSH). We performed a retrospective review of the (1)H MRS spectra at 3.0T of 16 intracranial meningiomas in 16 consecutive patients with newly diagnosed tumors. All meningiomas were evaluated with single- voxel (1)H MRS at short echo time using an automatic quantitation of the metabolites by linear combination model (LCModel) fitting. Detailed analysis of the spectra showed that the Glx content was a more common result (100%) than the Ala content (44%). The Glx content can be considered in high concentrations within these tumors resulting in overall levels comparable to normal brain values (P > 0.2). A glutathione (GSH) spectrum was added to the LCModel basis set in six meningiomas and in all of them a GSH peak was detected at 2.95 ppm (100%). Other metabolites such as guanidinoacetate (Gua) were detected in six meningiomas (38%) and this was not reported previously. Our data indicate that Glx and GSH are far more likely to be biochemical predictors than Ala in the (1)H MRS evaluation of intracranial meningiomas. The significance of Gua as another potential marker of the meningioma cell metabolism needs to be further investigated. PMID- 24059886 TI - Abnormal Cholesterol is Associated with Prefrontal White Matter Abnormalities among Obese Adults: a Diffusion Tensor Imaging Study. AB - The brain is the most cholesterol-rich organ in the body. Although most of the cholesterol in the brain is produced endogenously, some studies suggest that systemic cholesterol may be able to enter the brain. We investigated whether abnormal cholesterol profiles correlated with diffusion-tensor-imaging-based estimates of white matter microstructural integrity of lean and overweight/obese (o/o) adults. Twenty-two lean and 39 obese adults underwent magnetic resonance imaging, kept a three-day food diary, and had a standardized assessment of fasting blood lipids. The lean group ate less cholesterol-rich food than o/o although both groups ate equivalent servings of food per day. Voxelwise correlational analyses controlling for age, diabetes, and white matter hyperintensities, resulted in two significant clusters of negative associations between abnormal cholesterol profile and fractional anisotropy, located in the left and right prefrontal lobes. When the groups were split, the lean subjects showed no associations, whereas the o/o group expanded the association to three significant clusters, still in the frontal lobes. These findings suggest that cholesterol profile abnormalities may explain some of the reductions in white matter microstructural integrity that are reported in obesity. PMID- 24059887 TI - A case of ophthalmoplegic migraine: some observations. AB - We describe a 43-year-old man with a long-standing history of headache and ophthalmoplegia. Brain MRI showed a nodular enhancing lesion at the root exit zone of the left oculomotor nerve. Contrast enhancement on follow-up MRI and clinical symptoms showed a partial resolution on starting prophylactic anti migraine medications. This was confirmed to be a case of ophthalmoplegic migraine. Here we describe a rare case of OM in an adult patient with its characteristic imaging pattern and the differential diagnosis considered. PMID- 24059888 TI - Non-traumatic sphenoidal intradiploic arachnoid cyst as a cause of trigeminal neuralgia. A case report. AB - Non-traumatic intradiploic arachnoid cyst is a rare condition. We describe a young man with typical trigeminal neuralgia and intradiploic arachnoid cyst at the greater wing of the sphenoid. The patient was successfully treated with medical therapy. To our knowledge, this is the first case report of a possible correlation between trigeminal neuralgia and intraosseous arachnoid cyst. We describe the clinical case, the possible pathogenetic mechanism and briefly review the literature. PMID- 24059889 TI - High Resolution CT Angiography in Detection of an Aneurysm of the Vein of Galen as a Source of Intracranial Haemorrhage in a Newborn. AB - Cerebral haemorrhage is a rare condition in infants and carries a known poor prognosis. Common causes of spontaneous haemorrhage include various vascular venous lesions due to incomplete hydrovenous maturation, among them Galen vein aneurysm may be a very rare cause of cerebral haemorrhage. This report emphasizes the role of multidector CT with high resolution CT angiography in a newborn with cerebral hemorrhage caused by Galen vein aneurysm rupture. MDCT with high resolution CT angiography helps to differentiate the cause of haemorrhage, and to address the appropriate treatment. PMID- 24059890 TI - MR Study of Child Discloses Bilateral Papilledema and Optic Nerve Swelling. CSF Examination Positive for HSV-1 DNA. Could This Be a Rare Primary Manifestation of Herpes Infection? A Case Report. AB - We describe a rare case of bilateral papilledema and optic nerve swelling in a young patient with bilateral loss of visual acuity five days after onset of muscle contraction and pain involving the neck and right upper and lower limbs. This rare finding may be a possible first manifestation in a human patient of viral disease linked to HSV-1. MR study confirmed edema of the optic disc and evidence of optic nerve swelling. PCR for HSV-1 DNA was positive in the cerebrospinal fluid. PMID- 24059891 TI - Decision-making in the scheduling of endovascular treatment after brain arteriovenous malformation haemorrhage: a retrospective single centre study. AB - The appropriate timing for endovascular intervention after brain arteriovenous malformation (bAVM) rupture is not known. This paper aims to determine factors that lead to early endovascular intervention and to investigate whether early intervention has the same complication rate as late intervention in a single centre. All patients who underwent endovascular treatment for a ruptured bAVM at our institution in the period January 2007 and July 2010 were included in this retrospective observational study. Of 50 patients, 33 had early endovascular intervention, defined as within 30 days of haemorrhage and the remaining 17 patients had endovascular treatment at day 30 or beyond. A greater proportion of patients treated within the first 30 days were in neuro-intensive care preoperatively (51.5% vs. 23.5%, p=0.07). A 'high-risk' angioarchitectural feature was identified in more patients who had acute intervention (78.8% vs. 11.8%, p<0.0001) and targeted embolization was also more frequent in this group (48.5% vs. 5.9%, p=0.004). Nidal aneurysms, venous varices and impaired venous outflow (venous stenosis) were the principal 'high risk' features. Clinically apparent complications occurred in 10.8% of procedures with permanent neurological deficit in 3.6%. There was no directly procedure-related mortality. There was no statistically significant difference in the complication rate of early procedures compared with delayed interventions (12.5% vs. 7.4%, p=0.71). Greater initial injury severity and the presence of high-risk lesion characteristics are the factors that lead to early endovascular intervention. Early intervention is associated with a higher complication rate, but this difference is not statistically significant. PMID- 24059892 TI - Characteristics of Brain Arteriovenous Malformations Presenting with Seizures without Acute or Remote Hemorrhage. AB - We report on the predictors of seizure presention in unruptured brain arteriovenous malformations (AVMs). Between 1999 and 2008, 302 consecutive patients with AVMs were referred to our institution for endovascular treatment. Seventy-four patients (24.5%) experienced seizures without hemorrhage before treatment. We tested for statistical associations between angioarchitectural characteristics and seizure presentation. When we compared the 74 patients with seizures without hemorrhage with the 228 patients who did not experience seizures initially (total of 302 patients), male sex, cortical AVM location, AVM size of more than 3 cm, superficial venous drainage and presence of varices in the venous drainage were statistically associated with seizures (P=0.016, P=0.002, P=0.022, P=0.005, and P=0.022, respectively). Posterior fossa and deep locations and coexisting aneurysms were statistically associated with no seizures. The angioarchitectural characteristics of AVM associated with seizure presentation include male sex, cortical AVM location, AVM size of more than 3 cm, superficial venous drainage and presence of varices in the venous drainage. PMID- 24059893 TI - Intracranial Aneurysms and Vascular Malformations: Diagnosis for Therapy. A Long Term Study at a Central Hospital. A Neuroradiological Approach. Part II: 2000 2008. The Time of the Beginning with Newer Diagnostic Developments in CT, MR, DSA for Endovascular Intervention, Microneurosurgery, Radiotherapy. AB - In the second part of our overviewstudy the diagnosis for the treatment of our patients with intracranial vascular malformations (aneurysms / AVMF - arteriovenous malformations) is again shown in a region of about 500.000 inhabitants and just an overview of the outcome. This second part will be an overall comparison between the former diagnostic for the treatment and the here described diagnostic for the treatment (CTA, MRA, DSA rot / microsurgery, endovascular interventional techniques etc.), concerning also the topography and the demography. The future trends are also outlined. PMID- 24059894 TI - Endovascular treatment of ruptured intradural ophthalmic artery aneurysm. A case report and literature review. AB - We present a unique case of ruptured intradural ophthalmic artery aneurysm in a young man who presented with subarachnoid hemorrhage. By endovascular technique we successfully excluded the aneurysm from the circulation with preservation of antegrade flow in the ophthalmic artery. The presenting features and the technique of the treatment are described with a review of the literature. PMID- 24059895 TI - Spontaneous resolution in dissecting aneurysms of the distal middle cerebral artery. AB - Spontaneous resolution of intracranial aneurysms is a rare phenomenon. We describe two cases of ruptured distal middle cerebral artery branch aneurysms associated with initial neurological deficit. Follow-up angiography showed complete resolution of the aneurysms. PMID- 24059896 TI - Intravenous Glycoprotein IIb/IIIa Inhibitor (Tirofiban) Followed by Low-Dose Intra-Arterial Urokinase and Mechanical Thrombolysis for the Treatment of Acute Stroke. AB - We investigated the efficacy and safety of the combined use of IV tirofiban and IA urokinase and/or mechanical thrombolysis for treating acute stroke patients. Thirteen, consecutive patients treated with IV tirofiban and IA thrombolysis with mechanical and/or local IA urokinase infusion were evaluated retrospectively. The amount of time before the beginning of treatment, urokinase dose, recanalization rates, and symptomatic hemorrhage were analyzed. Clinical outcome measures were assessed on admission, at discharge (National Institute of Health Stroke scale [NIHSS]), and three months after the end of their treatment (modified Rankin Scale scores [mRS]). There were 11 patients with internal carotid or middle cerebral artery occlusion treated within six hours of the onset of symptoms and two patients with basilar artery occlusion treated within 12 hours of their symptom onset. The median NIHSS score on admission was 18. The median amount of time from symptom onset to IV tirofiban infusion was 135 minutes, and the median time from symptom onset to IA therapy was 180 minutes. The median dose of urokinase was 200,000 U. Recanalization (thrombolysis in myocardial infarction grade 2 or 3) was achieved in 11 patients. No procedure-related complications were observed. There was one symptomatic hemorrhage. At discharge, the mean NIHSS score was 6.6 (range, 0-15). Overall, at the time of the three-month follow-up the functional outcome was favorable (modified Rankin Scale score 0-2) in eight out of 13 (62%) patients. Death at 90 days occurred in two of the 13 (15%) patients. Combined IV tirofiban and IA thrombolysis with mechanical clot disruption seems to be a feasible treatment in acute stroke and may be successful in re-establishing vessel patency and result in a good functional outcome in patients with major cerebral arteries occlusions. PMID- 24059897 TI - Treatment of a Symptomatic Epidural Gas Cyst Using an Angiographic 5F Catheter in the Epidural Space of the Spinal Cord through the Sacral Hiatus. A Case Report. AB - An 85-year-old woman arrived at our institution because of left lumbar sciatica of about two years duration unrelieved by conventional oral pain therapy. A computed tomography scan obtained at the second visit showed an epidural gas cyst, with compression and dislocation of the left spinal nerve root L5. The common treatment of an epidural gas cyst is either a direct surgical approach or a CT-guided needle aspiration. We describe an alternative method to mechanical lysis of epidural gas cysts with the use of an 5F angiographic catheter inserted on a 0.035-inch guidewire. This procedure is less invasive than a surgical approach and safer than a CT-guided needle aspiration. Remission of symptoms was maintained at control visits at three and five months. PMID- 24059898 TI - CT-Guided Posterior Lumbar Interbody Fusion and Distraction. A Case Report. AB - We performed CT-guided posterior interbody fusion (PIF) with pedicle screw fixation and distraction to treat degenerative lumbar L4-L5 spondylolisthesis with severe left sciatica. The patient was suffering from L4 nerve root compression related to neural foramina stenosis. The dedicated tools to perform a CT-guided percutaneous PIF technique are described. The procedure was easy to apply with a total surgical time of 90 minutes. The neural foramina were investigated by CT scan reconstruction on sagittal plane demonstrating marked widening after PIF application. The left leg pain completely disappeared in two weeks and the patient remained painless at the three month follow-up control. To our knowledge, there are no other papers on CT-guided PIF procedure in the literature. PMID- 24059899 TI - Spontaneous internal carotid artery pseudoaneurysm in a patient with behcet disease. AB - We describe the uncommon case of a patient with Behcet disease who developed a giant spontaneous cervical internal carotid artery pseudoaneurysm confirmed at surgery. We also discuss the implications of this rare complication. PMID- 24059900 TI - MRI evaluation of the temporomandibular joints in juvenile rheumatoid arthritis: a retrospective review. AB - The purpose of this study was to evaluate the MRI findings of children with rheumatoid arthritis (JRA) affecting the temporomandibular joints (TMJ) and correlate these findings with symptoms. MRI studies of the TMJ in 26 children with a clinical diagnosis of JRA were retrospectively reviewed. All studies included oblique and sagittal T1, T2*, proton density/T2, and coronal T1-weighted images. T1 and proton density/T2-images were repeated with the mouth open. Post contrast sagittal and coronal T1-images were obtained in 19 patients. All studies were done on either 1.5 Tesla or 3.0 Tesla units with dedicated surface coils. By consensus, two radiologists evaluated the studies for abnormal condyles, bone erosions, presence or absence of discs, effusions, contrast enhancement and pannus. Open mouth views were assessed for incomplete or abnormal translation. Clinical records were reviewed to correlate symptoms with MRI findings. Abnormal condyles were seen in 49%. Discs were identifiable in 71%. Abnormal translation was seen in 71% and pannus in 49%. Erosions were seen in 37%, effusions in 24% and contrast enhancement in 50%. Correlation with clinical examination showed that of five asymptomatic patients, three had abnormal translation. Fifteen patients presented joint asymmetry on clinical examination and all showed abnormal translation on MRI. Our findings suggest that abnormal translation and joint enhancement may be the most common MRI findings in JRA patients with TMJ arthritis. Abnormalities may occur even in the absence of symptoms and the most common finding in symptomatic patients is abnormal translation. PMID- 24059901 TI - An orbital lymphoma involving the pterygopalatine and infratemporal fossae. A case report. AB - Lymphoma is the most common malignant orbital tumor. We describe the imaging features of diffuse orbital follicular lymphoma with extension into the pterygopalatine fossa and infratemporal fossa without bony infiltration. PMID- 24059902 TI - MRI localization of mildly symptomatic ectopic retropharyngeal parathyroid adenoma: the impact on surgical approach. A case report. AB - Ectopic parathyroid glands tend to be located in positions defined by their embryologic path during fetal development. We describe such a case of primary hyperparathyroidism due to ectopic retropharyngeal parathyroid adenoma (PTA) in a teenage girl with mild symptomatology. The initial workup with scintigraphy showed suspicious uptake above the level of thyroid gland, ultrasound, and computed tomography failed to localize an adenoma. Magnetic resonance imaging precisely localized an ectopic retropharyngeal PTA, which led to successful surgical removal. PMID- 24059903 TI - Rupture of a left internal jugular vein. A rare case. AB - A 60-year-old woman with neurofibromatosis type 1 presented with a nonpainful swelling in the left laterocervical region that had suddenly arisen after mild exertion the previous evening. Computed tomography with and without contrast enhancement revealed a rupture of the wall of the left internal jugular vein, with a diffuse subcutaneous hematoma. Postoperative histopathologic examination reported diffuse proliferation of plexiform neurofibromatous tissue within the vessel wall. PMID- 24059904 TI - MR Imaging Findings of Giant Trichilemmal Carcinoma on the Scalp. A Case Report. AB - We describe the magnetic resonance imaging findings of a huge trichilemmal carcinoma (TLC) on the parietal and occipital region of the scalp in one patient. Our aim is to discuss the clinical, radiologic, and pathologic features of scalp TLC and to review relevant literature regarding this tumor. One patient with recent rapid tumor growth in the parietal and occipital region of the scalp underwent MR studies and subtotal resection. The tumor was seen as a poorly marginated and lobulated soft-tissue mass with isointense signal on T1-weighted images and hyperintense signal on T2-weighted images. Necrosis and ulceration were also found on the tumor surface. The TLC has been massively invading the nearby skull, meninges, brain tissue, and superior sagittal sinus. After exhibiting contrast, the tumor showed significant enhancement, with small portions remaining unenhanced. Subtotal excision of the mass and reconstruction of the scalp were performed. Microscopically, the mass was composed of trabecular growth of tumor cells with clear cytoplasm, prominent nucleoli, frequent mitoses, and foci of trichilemmal keratinization. Tumor on the scalp with heterogeneous, mixed signals on T2-weighted images, significant enhancement of solid portion, and local infiltration accompanied by surface deep ulceration may indicate a TLC. Wide surgical excision with tumor-free margins remains the best choice for treatment. PMID- 24059905 TI - "Addressing the impact of stroke risk factors in a case control study in tertiary care hospitals": a case control study in Tertiary Care Hospitals of Peshawar, Khyber Phukhtoonkhwa (KPK) Pakistan. AB - BACKGROUND: Stroke was the second most common cause of death worldwide in 2004, resulting in 5.7 million deaths. This case controlled study was conducted in Tertiary care hospitals of Peshawar, KPK Pakistan about common risk factors of stroke and the impact of these risk factors. METHOD: Study was done at Government Tertiary Care Hospitals of Peshawar namely Khyber Teaching Hospital (KTH), Lady Reading Hospital (LRH) and Hayatabad Medical Complex (HMC).The hospital based case-control study included 50 cases (stroke patients) and 100 controls (non stroke patients). This study was accomplished from 24th April 2012 to October 2012 in tertiary care hospitals of Peshawar. A proper questionnaire was used to collect data from all the cases and controls, which was recorded in the form of tables and graphs. The risk factors studied were Hypertension, Smoking, diabetes, sedentary lifestyle, cardiac problems, B.M.I, diet, stress and family history of stroke. Anthropometric (weight, height, body mass index) measurements were done on all patients. For determination of association and impact of these risk factors, analyses were performed by calculation of Chi-Square test and confidence interval using SPSS version 16 program. RESULTS: Comparing the cases with controls, hypertension (p = 0.000), sedentary life style (p = 0.000), cardiac problems (p = 0.009), diabetes mellitus (p = 0.010), smoking (p = 0. 042) were significant risk factors whereas B.M.I (p = 0. 393), stress (p = 0.705), family history of stroke (p = 0.729), diet (p = 0.908), were not found to be statistically significant risk factors. The most significant risk factor was systemic hypertension (OR = 4.16) followed by sedentary life style (OR = 3.60), cardiac problems (OR = 2.74) diabetes (OR = 2.49) and smoking (OR = 2.05). CONCLUSION: Hypertension, Smoking, diabetes, sedentary lifestyle and cardiac problems have strong correlations and association with Stroke and are the major risk factors of stroke. Prevention of these risk factors can lead to decrease in the incidence of stroke. B.M.I, diet, stress and family history of stroke had no significant association. PMID- 24059907 TI - A powerful latent variable method for detecting and characterizing gene-based gene-gene interaction on multiple quantitative traits. AB - BACKGROUND: On thinking quantitatively of complex diseases, there are at least three statistical strategies for analyzing the gene-gene interaction: SNP by SNP interaction on single trait, gene-gene (each can involve multiple SNPs) interaction on single trait and gene-gene interaction on multiple traits. The third one is the most general in dissecting the genetic mechanism underlying complex diseases underpinning multiple quantitative traits. In this paper, we developed a novel statistic for this strategy through modifying the Partial Least Squares Path Modeling (PLSPM), called mPLSPM statistic. RESULTS: Simulation studies indicated that mPLSPM statistic was powerful and outperformed the principal component analysis (PCA) based linear regression method. Application to real data in the EPIC-Norfolk GWAS sub-cohort showed suggestive interaction (gamma) between TMEM18 gene and BDNF gene on two composite body shape scores (gamma = 0.047 and gamma = 0.058, with P = 0.021, P = 0.005), and BMI (gamma = 0.043, P = 0.034). This suggested these scores (synthetically latent traits) were more suitable to capture the obesity related genetic interaction effect between genes compared to single trait. CONCLUSIONS: The proposed novel mPLSPM statistic is a valid and powerful gene-based method for detecting gene-gene interaction on multiple quantitative phenotypes. PMID- 24059906 TI - Iron absorption from NaFeEDTA-fortified oat beverages with or without added vitamin C. AB - BACKGROUND: Food fortification is the best long-term approach for reducing the incidence of iron deficiency. OBJECTIVE: To determine iron absorption from NaFeEDTA-fortified oat beverages without and with vitamin C. MATERIALS AND METHODS: Iron absorption in 19 apparently healthy 6-year-old children was studied. Two oat beverages fortified with iron (labeled with stable isotopes of NaFeEDTA), zinc, and vitamin A, without and with vitamin C was consumed in two consecutive days in random order. Blood samples were taken 14 days later for stable isotope measurements. RESULTS: The mean fractional iron absorption from the fortified oat beverage without vitamin C (5.65 +/- 0.54%) was significantly lower than that from the beverage with vitamin C (7.14 +/- 0.90%; p < 0.05). CONCLUSION: Fortified oat beverages may offer a convenient and effective mechanism to improve the iron status of children. The addition of vitamin C improved iron absorption by an additional 1.5%. PMID- 24059908 TI - Nutrition and bone health: turning knowledge and beliefs into healthy behaviour. AB - Primary osteoporosis prevention requires healthy behaviours, such as regular physical exercise and adequate dietary intakes of calcium, vitamin D and protein. Calcium and vitamin D can decrease postmenopausal bone loss and prevent fracture risk. However, there is still a high prevalence of calcium and vitamin D insufficiency in women aged 50+ years. Dietary sources of these nutrients are the preferred choice, and dairy products represent a valuable dietary source of calcium due to the high content, high absorptive rate and relatively low cost. Furthermore, dairy products also contain other key nutrients including vitamin D, phosphorus and protein that contribute to bone health. Studies of women's beliefs and behaviours with respect to osteoporosis highlight poor knowledge of the importance of dietary nutrient intakes and low concern regarding bone health. Osteoporosis educational programmes exist to help women change behaviours relevant to bone health. Such programmes can have positive influences on women's knowledge, attitudes, perceived norms, motivation and behaviours. Increased awareness of the consequences of low calcium and vitamin D intakes may promote women's attitudes towards dietary sources, in particular dairy products, and lead to better adherence to health recommendations. Increasing dietary nutrient intakes through educational initiatives should be further developed to aid the prevention of osteoporosis and the efficacy of osteoporosis management. PMID- 24059909 TI - Cohort differences in dementia recognition and treatment indicators among assisted living residents in Maryland: did a change in the resident assessment tool make a difference? AB - BACKGROUND: There is a lack of empirical evidence about the impact of regulations on dementia care quality in assisted living (AL). We examined cohort differences in dementia recognition and treatment indicators between two cohorts of AL residents with dementia, evaluated prior to and following a dementia-related policy modification to more adequately assess memory and behavioral problems. METHODS: Cross-sectional comparison of two AL resident cohorts was done (Cohort 1 [evaluated 2001-2003] and Cohort 2 [evaluated 2004-2006]) from the Maryland Assisted Living studies. Initial in-person evaluations of residents with dementia (n = 248) were performed from a random sample of 28 AL facilities in Maryland (physician examination, clinical characteristics, and staff and family recognition of dementia included). Adequacy of dementia workup and treatment was rated by an expert consensus panel. RESULTS: Staff recognition of dementia was better in Cohort 1 than in Cohort 2 (77% vs. 63%, p = 0.011), with no significant differences in family recognition (86% vs. 85%, p = 0.680), or complete treatment ratings (52% vs. 64%, p = 0.060). In adjusted logistic regression, cognitive impairment and neuropsychiatric symptoms correlated with staff recognition; and cognitive impairment correlated with family recognition. Increased age and cognitive impairment reduced odds of having a complete dementia workup. Odds of having complete dementia treatment was reduced by age and having more depressive symptoms. Cohort was not predictive of dementia recognition or treatment indicators in adjusted models. CONCLUSIONS: We noted few cohort differences in dementia care indicators after accounting for covariates, and concluded that rates of dementia recognition and treatment did not appear to change much organically following the policy modifications. PMID- 24059910 TI - Seeming steady-state uphill diffusion of 22Na+ in compacted montmorillonite. AB - Whereas the transport of solutes in nonreactive porous media can mostly be described by diffusion driven by the concentration gradients in the external bulk water phase, the situation for dense clays and clay rocks has been less clear for a long time. The presence of fixed negative surface charges complicates the application of Fick's laws in the case of ionic species. Here we report the seeming uphill diffusion of a (22)Na(+) tracer in compacted sodium montmorillonite, that is, transport directed from a low to a high tracer concentration reservoir. In contrast to the classical through-diffusion technique the present experiments were carried out under the conditions of a gradient in the background electrolyte and using equal initial (22)Na(+) tracer concentrations on both sides of the clay sample. We conclude that the dominant driving force for diffusion is the concentration gradient of exchangeable cations in the nanopores. Commonly used diffusion models, based on concentration gradients in the external bulk water phase, may thus predict incorrect fluxes both in terms of magnitude and direction. PMID- 24059912 TI - Where are we heading with Salmonella molecular subtyping? PMID- 24059911 TI - Impact of retreatment with an artemisinin-based combination on malaria incidence and its potential selection of resistant strains: study protocol for a randomized controlled clinical trial. AB - BACKGROUND: Artemisinin-based combination therapy is currently recommended by the World Health Organization as first-line treatment of uncomplicated malaria. Recommendations were adapted in 2010 regarding rescue treatment in case of treatment failure. Instead of quinine monotherapy, it should be combined with an antibiotic with antimalarial properties; alternatively, another artemisinin-based combination therapy may be used. However, for informing these policy changes, no clear evidence is yet available. The need to provide the policy makers with hard data on the appropriate rescue therapy is obvious. We hypothesize that the efficacy of the same artemisinin-based combination therapy used as rescue treatment is as efficacious as quinine + clindamycin or an alternative artemisinin-based combination therapy, without the risk of selecting drug resistant strains. DESIGN: We embed a randomized, open label, three-arm clinical trial in a longitudinal cohort design following up children with uncomplicated malaria until they are malaria parasite free for 4 weeks. The study is conducted in both the Democratic Republic of Congo and Uganda and performed in three steps. In the first step, the pre-randomized controlled trial (RCT) phase, children aged 12 to 59 months with uncomplicated malaria are treated with the recommended first line drug and constitute a cohort that is passively followed up for 42 days. If the patients experience an uncomplicated malaria episode between days 14 and 42 of follow-up, they are randomized either to quinine + clindamycin, or an alternative artemisinin-based combination therapy, or the same first-line artemisinin-based combination therapy to be followed up for 28 additional days. If between days 14 and 28 the patients experience a recurrent parasitemia, they are retreated with the recommended first-line regimen and actively followed up for another 28 additional days (step three; post-RCT phase). The same methodology is followed for each subsequent failure. In any case, all patients without an infection at day 28 are classified as treatment successes and reach a study endpoint. The RCT phase allows the comparison of the safety and efficacy of three rescue treatments. The prolonged follow-up of all children until they are 28 days parasite-free allows us to assess epidemiological-, host- and parasite-related predictors for repeated malaria infection. TRIAL REGISTRATION: NCT01374581 and PACTR201203000351114. PMID- 24059913 TI - The potential of trans-translation inhibitors as antibiotics. PMID- 24059915 TI - Meeting the challenge of invasive fungal infections: part 2. AB - The 23rd European Congress of Clinical Microbiology and Infectious Diseases 2013 Berlin, Germany, 27-30 April 2013. This second and final installment of the report on the 23rd European Congress of Clinical Microbiology and Infectious Diseases follows on from Part 1, published in the September 2013 (volume 8, issue 9) issue of Future Microbiology. Invasive fungal infections (IFIs) are a well recognized complication in immunocompromised patients, with neutropenic patients with leukemia and hematopoietic stem cell transplant recipients at especially high risk. Early diagnosis of IFIs is essential, since delaying the initiation of adequate antifungal therapy increases the risk of death. The rapid diagnosis, and effective treatment and prophylaxis of IFIs were among the topics discussed during the 2013 conference of the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2013). PMID- 24059916 TI - Wolbachia and arbovirus inhibition in mosquitoes. AB - Wolbachia is a maternally inherited intracellular bacteria that can manipulate the reproduction of their insect hosts, and cytoplasmic incompatibility allows them to spread through mosquito populations. When particular strains of Wolbachia are transferred into certain Aedes mosquito species, the transmission capacity of important arthropod-borne viruses can be suppressed or abolished in laboratory challenges. Viral inhibition is associated with higher densities of transinfecting Wolbachia compared with wild-type strains of the bacterium. The upregulation of innate immune effectors can contribute to virus inhibition in Aedes aegypti, but does not seem to be required. Modulation of autophagy and lipid metabolism, and intracellular competition between viruses and bacteria for lipids, provide promising hypotheses for the mechanism of inhibition. Transinfecting virus-inhibiting strains can produce higher fitness costs than wild-type mosquito Wolbachia; however, this is not always the case, and the wMel strain has already been introduced to high frequency in wild Ae. aegypti populations. PMID- 24059917 TI - Bacterial killing in macrophages and amoeba: do they all use a brass dagger? AB - Macrophages are immune cells that are known to engulf pathogens and destroy them by employing several mechanisms, including oxidative burst, induction of Fe(II) and Mn(II) efflux, and through elevation of Cu(I) and Zn(II) concentrations in the phagosome ('brass dagger'). The importance of the latter mechanism is supported by the presence of multiple counteracting efflux systems in bacteria, responsible for the efflux of toxic metals. We hypothesize that similar bacteria killing mechanisms are found in predatory protozoa/amoeba species. Here, we present a brief summary of soft metal-related mechanisms used by macrophages, and perhaps amoeba, to inactivate and destroy bacteria. Based on this, we think it is likely that copper resistance is also selected for by protozoan grazing in the environment. PMID- 24059919 TI - Pathogenesis of adherent-invasive Escherichia coli. AB - The etiology of Crohn's disease (CD) is complex and involves both host susceptibility factors (i.e., the presence of particular genetic alleles) and environmental factors, including bacteria. In this regard, adherent-invasive Escherichia coli (AIEC), have recently emerged as an exciting potential etiological agent of CD. AIEC are distinguished from commensal strains of E. coli through their ability to adhere to and invade epithelial cells and replicate in macrophages. Recent molecular analyses have identified genes required for both invasion of epithelial cells and replication in the macrophage. However, these genetic studies, in combination with recent genome sequencing projects, have revealed that the pathogenesis of this group of bacteria cannot be explained by the presence of AIEC-specific genes. In this article, we review the role of AIEC as a pathobiont in the pathology of CD. We also describe the emerging link between AIEC and autophagy, and we propose a model for AIEC pathogenesis. PMID- 24059920 TI - Use of the plaque assay for testing the antibiotic susceptibility of intracellular bacteria. AB - The plaque assay was first described for titration of bacterial inoculums and clonal isolation, and was later adapted for testing antibiotics susceptibility and to study virulence factors and motility of bacteria. Over time, the sensitivity and reproducibility of the technique has been improved. Usually, the number of plaques is counted; however, the recent development of informatics tools has stimulated interest in the quantification of plaque size. Owing to this new approach, the plaque assay has been used to characterize the host cell response when infected cells are treated with antimicrobial agents. It was found that statins prevented cell lesions following rickettsial infection; in other studies, some antibiotics were found to cause apoptosis of host cells, suggesting a toxic activity. Here, we present an overview of the plaque assay as it has been used to investigate intracellular bacteria. PMID- 24059921 TI - Dietary protein metabolism by gut microbiota and its consequences for chronic kidney disease patients. AB - The breakdown of proteins and peptides by colonic microorganisms yields a great diversity of end products, including short-chain fatty acids, ammonia, amines, phenols, indoles, thiols, CO2, H2 and H2S, many of which have toxic properties. An increase of the dietary protein load in healthy individuals results in enhanced generation of these toxins, many of which are rapidly cleared by the kidneys. In this regard, the impact upon the colonic microbiota of controlled changes in the dietary protein has not been examined in chronic kidney disease patients. This review focuses on the impact of dietary proteins on the intestinal microbiota and its possible consequences for chronic kidney disease patients. PMID- 24059918 TI - Recent molecular insights into rickettsial pathogenesis and immunity. AB - Human infections with arthropod-borne Rickettsia species remain a major global health issue, causing significant morbidity and mortality. Epidemic typhus due to Rickettsia prowazekii has an established reputation as the 'scourge of armies', and as a major determinant of significant 'historical turning points'. No suitable vaccines for human use are currently available to prevent rickettsial diseases. The unique lifestyle features of rickettsiae include obligate intracellular parasitism, intracytoplasmic niche within the host cell, predilection for infection of microvascular endothelium in mammalian hosts, association with arthropods and the tendency for genomic reduction. The fundamental research in the field of Rickettsiology has witnessed significant recent progress in the areas of pathogen adhesion/invasion and host immune responses, as well as the genomics, proteomics, metabolomics, phylogenetics, motility and molecular manipulation of important rickettsial pathogens. The focus of this review article is to capture a snapshot of the latest developments pertaining to the mechanisms of rickettsial pathogenesis and immunity. PMID- 24059923 TI - An insight into pleiotropic regulators Agr and Sar: molecular probes paving the new way for antivirulent therapy. AB - Staphylococcus aureus pathogenesis is an intricate process involving a diverse array of extracellular proteins, biofilm and cell wall components that are coordinately expressed in different stages of infection. The expression of two divergent loci, agr and sar, is increasingly recognized as a key regulator of virulence in S. aureus, and there is mounting evidence for the role of these loci in staphylococcal infections. The functional agr regulon is critical for the production of virulence factors, including alpha, beta and delta hemolysins. The sar locus encodes SarA protein, which regulates the expression of cell wall associated and certain extracellular proteins in agr-dependent and agr independent pathways. Multidrug-resistant S. aureus is a leading cause of morbidity and mortality in the world and its management, especially in community acquired methicillin-resistant S. aureus infections, has evolved comparatively little. In particular, no novel targets have been incorporated into its treatment to date. Hence, these loci appear to be the most significant and are currently at the attention of intense investigation regarding their therapeutic prospects. PMID- 24059925 TI - Efficacy of work-based training for direct care workers in assisted living. AB - This article reports on the efficacy of a work-based learning program for direct care workers in assisted living. The program goal was to improve skills and facilitate career development. The training program had positive impacts at both individual and organizational levels. Survey data found that workers felt more competent and self-confident about their abilities to work with residents. Furthermore, increasing satisfaction with the training program over time led to greater job satisfaction and a desire for additional education. Organizations have better outcomes when workers are well trained, feel empowered, and are satisfied with their work. Policy implications for assisted living settings and meeting the growing demand for a competent direct care workforce are discussed. PMID- 24059926 TI - Work satisfaction and intention to leave among direct care workers in community and residential aged care in Australia. AB - Turnover in the Australian aged-care workforce is lower than in the United States but is still of concern. This research examined the effects of worker satisfaction, worker characteristics, work conditions, and workplace environment on intention to leave, using data from a 2007 national census of the aged-care workforce. A probit model was used to estimate the probability of care workers leaving their jobs in the next 12 months. While workers were satisfied, overall, with their work, improving some components of satisfaction and converting casual contracts to permanent work would reduce intention to leave. To these ends, a shift in focus is required away from worker characteristics and the nature of care work to job conditions and organizational matters amenable to management and policy action. PMID- 24059927 TI - The perspectives of older Greek-Australians toward changes in the nature of family support: implications for family care policies. AB - Internationally, public policies encourage "aging in place," and the majority of older Australians requiring care in the community receive informal care, supplemented by publicly subsidized formal services. The effect of contemporary social changes on informal care in aging migrant communities is poorly understood. This articles explores the perceptions of older Greek-Australians toward changes in the nature of family support. Bicultural and bilingual researchers carried out in-depth interviews (n = 27) and five focus groups (n = 63 total participants) with older Greek-Australians in modern Greek. While "cultures of care" remain among Greek-Australian families, the means for a family to assist have shifted, and these compromises are met with considerable powerlessness among older Greek-Australians. Implications for policy include the need to better involve older migrants and their families in decisions about their care needs, potentially involving consumer-directed care models. Service providers may also need to adopt the use of new technologies to communicate with increasingly time-pressured family members. PMID- 24059922 TI - Mechanisms of Candida biofilm drug resistance. AB - Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, beta glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases. PMID- 24059928 TI - US policies to enhance older driver safety: a systematic review of the literature. AB - The purpose of this study was to conduct a systematic review of the literature related to state policies concerning older drivers and to draw policy conclusions about which policies appear to work to reduce older driver crashes and to identify areas needed for further research. Specific policies examined in this paper concern medical reporting and medical review, license renewal processes, and driver testing. A study was included in the systematic review if it met the following criteria: published in English between 1991and January 2013; included data on human subjects aged 65 and older residing in the United States; included information on at least one policy related to older drivers; and had a transportation-related outcome variable (e.g., crash, fatality, renewal). A total of 29 studies met inclusion criteria. Twenty-two studies investigated license renewal and seven articles examined medical reporting. In-person license renewal requirements were associated with reduced risk for fatal crashes. Restricted licenses were associated with reduced number of miles driven per week. More intensive renewal requirements and being the subject of a medical report to the licensing authority was associated with delicensure. Given the importance of driving to mobility, quality of life, and public safety, more research is needed. PMID- 24059929 TI - A new genre of social protection policy for older people: a critical analysis of legislative development in Nepal. AB - This commentary critically discusses recent legislation promulgated in Nepal to safeguard older people's rights and promote their well-being. Using a human rights-based framework, the legislation is analyzed for its strengths and weaknesses. Emphasis has also been placed on discussing various aspects overlooked by the legislation, such as changing family structure, relations, and social values; the impact of employment structure and migration; and, importantly, maintaining a desired balance between the roles of the state and of the family in providing social security, support, and care to older people. Efforts have been made to reflect the promulgated law in light of the contemporary developments taking place globally, particularly in regions of Asia. Areas for future policy work are also identified in order to make legislation more inclusive and effective. PMID- 24059932 TI - Identification of an NF-kappaB p50/p65-responsive site in the human MIR155HG promoter. AB - BACKGROUND: MicroRNA-155 (miR-155) is the diced product of the MIR155HG gene. miR 155 regulates the expression of many immune-specific transcripts, is overexpressed in many human lymphomas, and has oncogenic activity in mouse transgenic models. MIR155HG has been proposed to be a target gene for transcription factor NF-kappaB largely due to the positive correlation between high nuclear NF-kappaB activity and increased miR-155 expression following treatment with NF-kappaB inducers or in subsets of hematopoietic cancers. Nevertheless, direct regulation of the human MIR155HG promoter by NF-kappaB has not been convincingly demonstrated previously. RESULTS: This report shows that induction of NF-kappaB activity rapidly leads to increased levels of both primary MIR155HG mRNA and mature miR-155 transcripts. We have mapped an NF-kappaB responsive element to a position approximately 178 nt upstream of the MIR155HG transcription start site. The -178 site is specifically bound by the NF-kappaB p50/p65 heterodimer and is required for p65-induced reporter gene activation. Moreover, the levels of miR-155 in nine human B-lymphoma cell lines generally correlate with increased nuclear NF-kappaB proteins. CONCLUSION: Overall, the identification of an NF-kappaB-responsive site in the MIR155HG proximal promoter suggests that MIR155HG is a direct NF-kappaB target gene in vivo. Understanding NF-kappaB-mediated regulation of miR-155 could lead to improved immune cell related diagnostic tools and targeted therapies. PMID- 24059933 TI - Examining the role of safe, stable, and nurturing relationships in the intergenerational continuity of child maltreatment--Introduction to the special issue. PMID- 24059934 TI - Disrupting intergenerational continuity in harsh and abusive parenting: the importance of a nurturing relationship with a romantic partner. AB - PURPOSE: Harsh, abusive, and rejecting behavior by parents toward their children is associated with increased risk for many developmental problems for youth. Earlier research also shows that children raised by harsh parents are more likely to treat their own children harshly. The present study evaluated nurturing and supportive behaviors of spouses or cohabiting romantic partners hypothesized to strengthen co-parent relationships and help break this intergenerational cycle of harsh parenting. METHODS: Data come from the Family Transitions Project, a 22 year, 3-generation study of a cohort of over 500 early adolescents (G2) grown to adulthood. During adolescence, observers rated G1 (parent of G2) harsh parenting to G2. Several years later, observers rated G2 harsh parenting toward their oldest child (G3). In addition, G2's romantic partner (spouse or cohabiting partner) was rated by observers on a range of behaviors expected to affect G2 harsh parenting. RESULTS: Romantic partner warmth and positive communication with G2 were associated with less G2 harsh parenting toward G3 (a compensatory or main effect) and when these partner behaviors were high, there was no evidence of intergenerational continuity from G1 to G2 harsh parenting (a moderating or protective effect). G1 harsh parenting slightly decreased the likelihood that G2 would select a supportive spouse or romantic partner (evidence of cumulative continuity). CONCLUSIONS: Romantic partner warmth and positive communication appear to disrupt continuity in harsh and abusive parenting. As appropriate, preventive interventions designed to reduce risk for child maltreatment should include a focus on spousal or partner behaviors in their educational or treatment programs. PMID- 24059935 TI - Tests of the mitigating effects of caring and supportive relationships in the study of abusive disciplining over two generations. AB - PURPOSE: To examine evidence of the continuity in abusive discipline across two generations (G1 and G2) and the role of safe, stable, and nurturing relationships (SSNRs) as protective factors. METHODS: Data are from the Lehigh Longitudinal Study, a prospective investigation of the causes and consequences child maltreatment that began in the 1970s with a sample of 457 children and their parents. Data were most recently collected in 2008-2010 from 80% of the original child sample (N = 357) when they were adults age 36 years on average. Of those assessed as adults, 268 participants (G2s) were parenting children and thus comprise the analysis sample. Analyses examined the association between harsh physical discipline practices by G1 parents and G2's reports of similarly severe discipline practices used in parenting their own children. Analyses also investigated the direct and interactive (protective) effects of SSNR variables that pertain to the care, warmth, and support children received from their mothers, fathers, and siblings over their lifetimes. A measure of an adult partner's warmth and support was also included. A case-level examination of G2 harsh discipliners was included to investigate other forms of past and more recent forms of abuse exposure. RESULTS: Results show a significant predictive association between physical discipline by G1 and G2 parents (beta = .30; p < .05; odds ratio, 1.14; confidence interval, 1.04-1.26), after accounting for childhood socioeconomic status and gender. Whereas being harshly disciplined as a child was inversely related to reports of having had a caring relationship with one's mother (r = -.25; p < .01), only care and support from one's father predicted a lower risk of harsh physical discipline by G2s (beta = -.24; p < .05; odds ratio, .74; confidence interval, .59-.92). None of the SSNR variables moderated the effect of G1 discipline on G2 discipline. A case-level examination of the abusive histories of G2 harsh discipliners found they had in some instances been exposed to physical and emotional abuse by multiple caregivers and by adult partners. CONCLUSIONS: There is continuity in physical disciplining over two generations. SSNRs measured in this study did not mediate or moderate the effect of G1 on G2 harsh physical discipline, although care and support from fathers was inversely related to the likelihood of G2 harsh physical discipline. This relationship is independent of abuse in childhood. Research is needed to identify factors that interrupt the intergenerational continuity of harsh physical (abusive) disciplining so that promising interventions can be developed and implemented. PMID- 24059937 TI - Safe, stable, nurturing relationships as a moderator of intergenerational continuity of child maltreatment: a meta-analysis. AB - PURPOSE: The present paper summarizes findings of the special issue papers on the intergenerational continuity of child maltreatment and through meta-analysis explores the potential moderating effects of safe, stable, nurturing relationships (SSNRs). METHODS: Studies were selected for inclusion in this meta analysis if they (1) were published in peer-reviewed journals; (2) tested for intergenerational continuity in any form of child maltreatment, using prospective, longitudinal data; and (3) tested for moderating effects of any variable of SSNRs on intergenerational continuity of child maltreatment. The search revealed only one additional study beyond the four reports written for this special issue that met inclusion criteria for the meta-analysis. RESULTS: Estimates of intergenerational stability of child maltreatment from the studies included in this special issue are consistent with several other studies, which find that child maltreatment in one generation is positively related to child maltreatment in the next generation. Furthermore, meta-analytic results from the five studies that met the inclusion criteria suggest a protective, moderating effect of SSNRs on intergenerational continuity of child maltreatment. The calculated fail-safe index indicated that 49 unpublished intergenerational studies with an average null effect would be required to render nonsignificant the overall moderation effect of SSNRs on child maltreatment. CONCLUSIONS: This special issue expanded the examination of SSNRs beyond the caregiver-child dyad. That is, these studies considered SSNRs in adult relationships as well as parent child relationships. Results suggest that certain types of SSNRs between parents and other adults (e.g., romantic partner, co-parent, or adult social support resource) may decrease maltreatment continuity. PMID- 24059938 TI - The complex etiology and lasting consequences of child maltreatment. PMID- 24059936 TI - Breaking the cycle of maltreatment: the role of safe, stable, and nurturing relationships. AB - PURPOSE: We examine two research questions. First, does a history of child maltreatment victimization significantly increase the likelihood of maltreatment perpetration during adulthood? Second, do safe, stable, and nurturing relationships (SSNRs) during early adulthood serve as direct protective factors, buffering protective factors, or both to interrupt intergenerational continuity in maltreating behaviors? METHODS: Data come from the Rochester Youth Development Study that followed a community sample from age 14 to 31 with 14 assessments. Maltreatment victimization records covering birth through age 17 were collected from Child Protective Services records as were maltreatment perpetration records from age 21 to 30. Data on five SSNRs were measured during three interviews from ages 21 to 23. RESULTS: There is a significant relationship between maltreatment victimization and maltreatment perpetration (odds ratio = 2.57; 95% confidence interval = 1.47-4.50). Three of the five SSNRs investigated-relationship satisfaction, parental satisfaction, and attachment to child-served as direct protective factors, significantly reducing risk for those who had been maltreated. However, none of the interaction terms--between maltreatment victimization and the SSNR--was statistically significant, indicating that the SSNRs did not serve as buffering protective factors CONCLUSIONS: Although a history of maltreatment significantly increases the risk of subsequent perpetration of maltreatment, enhancing SSNRs with intimate partners and with children during early adulthood can decrease the odds that a victim of maltreatment will become a perpetrator. Mandated reporters and service providers should be aware of the risk posed by earlier maltreatment and be prepared to ameliorate that risk, in part by strengthening supportive social relationships. PMID- 24059939 TI - Safe, stable, nurturing relationships break the intergenerational cycle of abuse: a prospective nationally representative cohort of children in the United Kingdom. AB - PURPOSE: To identify contextual and interpersonal factors that distinguish families in which the intergenerational transmission of maltreatment is maintained from families in which the cycle is broken. METHODS: The sample was composed of 1,116 families in the United Kingdom who participated in the Environmental Risk (E-Risk) Longitudinal Twin Study. We assessed mother's childhood history of maltreatment retrospectively with a validated and reliable interview. Prospective reports of children's physical maltreatment were collected repeatedly up to 12 years. We compared families in which mothers but not children had experienced maltreatment with families in which both mothers and children had experienced maltreatment, and with families without maltreatment, on a range of contextual and interpersonal factors known to affect child development. RESULTS: In multivariate analyses, supportive and trusting relationships with intimate partners, high levels of maternal warmth toward children, and low levels of partner violence between adults distinguished families in which mothers but not children experienced maltreatment from families in which mothers and children experienced maltreatment. Families in which only mothers experienced maltreatment were largely similar to families in which neither generation experienced maltreatment, except that mothers belonging to the former group were more likely to have a lifetime history of depression and low levels of social support. CONCLUSIONS: Safe, stable, nurturing relationships between intimate partners and between mothers and children are associated with breaking the cycle of abuse in families. Additional research is needed to determine whether these factors have a causal role in preventing the transmission of maltreatment from one generation to the next. PMID- 24059940 TI - Advances in understanding intergenerational transmission of parenting practices and the role of safe, stable, and nurturing relationships: comments on a promising approach, practical application, and some cautions. PMID- 24059941 TI - Photo-orientation of azobenzene-containing liquid-crystalline materials by means of domain structure rearrangement. AB - A novel mechanism of photo-orientation of azobenzene-containing liquid crystalline materials is proposed. This mechanism is based on the notion of photochemically induced domain rearrangement driven by destabilization of liquid crystalline phase in light absorbing domains due to photochemical formation of non-mesogenic cis-azobenzene moieties. The experimental evidence of photoinduced movement of a domain boundary is presented, and the velocity of this movement is measured. A mathematical model for photo-orientation of a polydomain azobenzene containing material is formulated. The values of model parameters for a liquid crystalline azopolymer have been measured in separate experiments. Theoretical predictions demonstrate quantitative agreement with the experimental observations. PMID- 24059943 TI - Adaptive backstepping sliding mode control with fuzzy monitoring strategy for a kind of mechanical system. AB - A novel adaptive backstepping sliding mode control (ABSMC) law with fuzzy monitoring strategy is proposed for the tracking-control of a kind of nonlinear mechanical system. The proposed ABSMC scheme combining the sliding mode control and backstepping technique ensure that the occurrence of the sliding motion in finite-time and the trajectory of tracking-error converge to equilibrium point. To obtain a better perturbation rejection property, an adaptive control law is employed to compensate the lumped perturbation. Furthermore, we introduce fuzzy monitoring strategy to improve adaptive capacity and soften the control signal. The convergence and stability of the proposed control scheme are proved by using Lyaponov's method. Finally, numerical simulations demonstrate the effectiveness of the proposed control scheme. PMID- 24059942 TI - The evolution of assessing bias in Cochrane systematic reviews of interventions: celebrating methodological contributions of the Cochrane Collaboration. PMID- 24059945 TI - [On the key point in improving the level of burn treatment from the five aspects of PRIDE]. AB - The "PRIDE"-five combined measures, including "protection of cell function and anti-shock treatment to reduce ischemic-hypoxic injury", "rehabilitation from early postburn stage", "inhalation injury treatment", "deep burn wound repair", and "enterogenous infection control", are key measures to improve the levels of burn treatment. The progressive advances in combined measures denoted as "PRIDE" have raised the burn treatment to a higher level and greatly elevated the survival rate. The degree of attention has also been raised from improvement in survival rate only to higher survival rate and better life quality with improvement in rehabilitation. Clinically however, many problems remain to be solved in the treatment of severe burn patients. Further basic and translational studies on "PRIDE" will be helpful to further improve the level of burn treatment. PMID- 24059944 TI - Comparative effectiveness of fingolimod versus interferons or glatiramer acetate for relapse rates in multiple sclerosis: a retrospective US claims database analysis. AB - OBJECTIVE: Disease-modifying therapies, such as fingolimod, interferon (IFN) and glatiramer acetate (GA), have differing effects on relapse rates in patients with multiple sclerosis (MS), but little is known about the real-world differences in relapse rates with these treatments. This retrospective study assessed relapse rates in patients with active MS initiating fingolimod, IFN or GA therapy in a real-world setting. METHODS: Using administrative claims data from the US PharMetrics Plus database, we identified previously treated and untreated patients with MS who initiated fingolimod, IFN or GA treatment between 1 October 2010 and 31 March 2011 and had experienced a relapse in the previous year. A claims-based algorithm was used to identify relapses over the persistence period in patients with 540 days of post-index continuous enrolment. A logistic regression model assessed the probability of having at least one relapse and a generalized linear model estimated differences in annualized relapse rates (ARRs). RESULTS: The study enrolled 525 patients (fingolimod, n = 128; combined IFN/GA cohort, n = 397) of the 31,041 initially identified. Similar findings for fingolimod and IFN/GA were observed for the unadjusted proportion of patients experiencing relapses (31.3% vs. 34.0%, respectively; p = 0.5653) and ARRs (0.50 vs. 0.55, respectively) while persistent to treatment. After adjusting for baseline differences, fingolimod was associated with a 52% reduction in the probability of having a relapse (odds ratio, 0.48; 95% confidence interval [CI], 0.28-0.84; p = 0.0097) and a 50% reduction in ARR (rate ratio, 0.50; 95% CI, 0.34 0.75; p = 0.0006) compared with IFN/GA. LIMITATIONS: Identification of relapses is based on the claims in the database rather than on a clinical assessment. CONCLUSIONS: In a real-world setting, fingolimod was shown to be associated with significantly lower relapse rates than IFN/GA in patients with MS who had a history of relapses. PMID- 24059946 TI - [Clinical study on hematocrit used as a predictor for evaluation of resuscitation effect in the early shock stage after burn]. AB - OBJECTIVE: To explore the clinical significance of hematocrit used as a predictor for diagnosis and evaluation of resuscitation effect in the early shock stage after burn. METHODS: Clinical data of 131 severely burned patients admitted to our burn unit from January 2000 to December 2011 were retrospectively analyzed. The burn patients were divided into group A (n = 80) and group B (n = 51) based on the hematocrit level at post burn hour (PBH) 24. The hematocrit levels in group A were less than or equal to 0.50, which in group B were higher than 0.50. There were no statistically significant differences between two groups in age, gender, body weight, admission time after burn, total burn area, full-thickness burn area, and degree of inhalation injury (P values all above 0.05). Hematocrit levels in the shock stage were recorded. Total urine output, base excess, and the volume of fluid infused per kg per %TBSA at PBH 24 were recorded. Rates of complication and mortality were recorded. Data were processed with t test, chi square test, and Wilcoxon rank sum test. RESULTS: Hematocrit level of group A at PBH 24 was decreased to about 0.45, while that of group B was decreased to about 0.55. The urine output in group A at PBH 24 [(61 +/- 22) mL/h] was higher than that in group B [(53 +/- 20) mL/h, t = 2.212, P < 0.05]. Base excess in group A at PBH 24 [(-6.1 +/- 2.9) mmol/L] was significantly higher than that in group B [(-9.0 +/- 3.8) mmol/L, t = 4.888, P < 0.01]. The volume infused per kg per %TBSA was higher in group A [(1.9 +/- 0.4) mL.kg(-1).%TBSA(-1)] than in group B [(1.7 +/- 0.4) mL.kg(-1).%TBSA(-1), t = 2.472, P < 0.05]. The rates of complication and mortality in group A [11.3%(9/80), 8.8%(7/80), respectively] were significantly lower than those in group B [27.5%(14/51), 21.6%(11/51), with chi(2) values respectively 5.648 and 4.318, P values all below 0.05]. CONCLUSIONS: Hematocrit can indirectly reflect resuscitation effect in the burn shock stage. Whether hematocrit level can be lowered to 0.45-0.50 during the first 24 hours after burn may be an important index for evaluation of fluid resuscitation effect in the early shock stage after severe burn. PMID- 24059947 TI - [Influence of haemoxygenase 1 (HO-1) gene expression on intestinal mucosa injury induced by intra-abdominal hypertension in rats]. AB - OBJECTIVE: To observe the effects of up- or down-regulation of haemoxygenase 1 (HO-1) gene expression on intestinal mucosa injury induced by intra-abdominal hypertension (IAH). METHODS: (1) Reproduction of rat model of up- or down regulation of HO-1 gene expression. Twenty-four healthy adult Wistar rats were divided into Co-PP (HO-1 specific revulsive) 2.5 mg, Co-PP 5.0 mg, Sn-PP (HO-1 specific inhibitor) 2.5 mg, and control groups according to the random number table, with six rats in each group. Rats in groups Co-PP 2.5 mg and Sn-PP 2.5 mg were respectively given Co-PP 2.5 mg/kg and Sn-PP 2.5 mg/kg by intraperitoneal injection, once every 12 hours for 3 days. The rats in group Co-PP 5.0 mg were intraperitoneally injected with Co-PP 5.0 mg/kg, once a day for 3 days. The rats in control group were treated with equal volume of normal saline by intraperitoneal injection. All rats were sacrificed on post injection day (PID) 4, and intestinal mucosa tissues were collected for determination of HO-1 mRNA expression. Optimal dose of Co-PP was chosen for the following experiment. (2) The influence of up- or down-regulation of HO-1 gene expression on intestinal mucosa injury under IAH condition. Another 24 healthy adult Wistar rats were divided into control, IAH, Co-PP+IAH, and Sn-PP+IAH groups according to the random number table, with six rats in each group. The rats in groups Co-PP+IAH and Sn-PP+IAH were intraperitoneally injected with 2.5 mg/kg Co-PP and 2.5 mg/kg Sn-PP, once every 12 hours for 3 days. Equal volume of normal saline was intraperitoneally injected into the rats in control group, once every 12 hours for 3 days. Then, nitrogen gas pneumoperitoneum was used to establish the model of IAH in rats of the latter three groups on PID 4, with IAP at 20 mm Hg (1 mm Hg = 0.133 kPa) , and it was maintained for 2 hours. Puncture and intubation were performed in rats of control group without inflating nitrogen gas. Jejunal segment in the length of 10-15 cm was harvested for collecting intestinal mucosa tissues to determine the HO-1 mRNA expression and diamine oxidase (DAO) content. Serum obtained from portal vein blood was collected to determine the D-lactate, TNF-alpha, and IL-6 contents. Another jejunal segment in the length of 1-2 cm was harvested for histopathological examination. Data were processed with one-way analysis of variance and t test. RESULTS: (1) The HO-1 mRNA expression in group Co-PP 2.5 mg was significantly higher than that in control and Co-PP 5.0 mg groups (with t values respectively 4.756, 3.175, P < 0.05 or P < 0.01). The HO-1 mRNA expression in group Sn-PP 2.5 mg was significantly lower than that in control group (t = 4.880, P < 0.01). The optimal dose of Co-PP for the following experiment was 2.5 mg/kg. (2) HO-1 mRNA expression in group Co-PP+IAH was 60 +/- 5, and it was obviously higher than that of group IAH (49 +/- 5, t = 3.811, P < 0.01) and control group (39 +/- 4, t = 8.034, P < .001) . HO-1 mRNA expression was higher in group IAH than in control group (t = 3.826, P < 0.01). HO-1 mRNA expression in group Sn-PP+IAH was 29 +/- 4, which was obviously lower than that of control group (t = 4.330, P < 0.01). The contents of DAO and D-lactate in group Co-PP+IAH were (0.52 +/- 0.05) U/mL and (1.9 +/- 0.6) mg/L, which were significantly lower than those in group IAH [(0.88 +/- 0.06) U/mL and (4.3 +/- 0.7) mg/L, with t values respectively 11.291, 6.376, P values all below 0.01], but still higher than those in control group [(0.34 +/- 0.04) U/mL, (1.2 +/- 0.5) mg/L, with t values respectively 6.886, 2.295, P < 0.05 or P < 0.01]. The contents of TNF-alpha and IL-6 were much lower in group Co-PP+IAH than in group IAH, but still higher than in control group (with t values from 3.781 to 18.557, P values all below 0.01). The contents of DAO, D-lactate, TNF-alpha, and IL-6 in group Sn-PP+IAH were all higher than those in the other 3 groups (with t values from 4.181 to 32.938, P values all below 0.01). Structure of epithelial cells from intestinal mucosa was intact and regularly arranged in rats of control group. Intestinal mucosal tissue was edematous, and the top of villi was anabrotic and necrotic in rats of group IAH. Compared with that of group IAH, the degree of intestinal mucosa injury was alleviated in rats of group Co-PP+IAH, while the pathology was aggravated in rats of group Sn-PP+IAH. CONCLUSIONS: Up regulation of HO-1 gene expression can ameliorate intestinal mucosa injury caused by IAH, thus protecting intestinal mucosa tissues. PMID- 24059948 TI - [Expression of aquaporin-1 in myocardium of rats in the early stage after scald and its relationship with myocardial edema]. AB - OBJECTIVE: To investigate the changes in aquaporin-1 (AQP-1) expression in myocardium of scalded rats in early stage of a burn injury, and to analyze its relationship with myocardial edema. METHODS: Thirty-six healthy Wistar rats were divided into normal control (n = 6, without scald) and scald (n = 30) groups according to the random number table. Rats in scald group were inflicted with 30%TBSA full-thickness scald on the back, and intraperitoneally injected with Ringer's solution for antishock treatment. Myocardium tissue from left ventricle and serum specimen in rats of scald group were collected at post scald hours (PSH) 2, 8, 12, 24, and 48 (with 6 rats at each time point). Myocardial water ratio was determined by dry-wet weight method. The distribution of AQP-1 protein in myocardium was observed with immunohistochemical staining. The expression of myocardial AQP-1 mRNA was assessed with quantitative real-time PCR. The serum content of cardiac troponin-I (cTnI) was determined with ELISA. The rats in normal control group were detected with above-mentioned method. Data were processed with one way analysis of variance and LSD test. Correlation analysis was performed between AQP-1 mRNA and myocardial water ratio, AQP-1 mRNA and the serum content of cTnI in scald group at each time point. RESULTS: Compared with that in normal control group, the myocardial water ratio in scald group was markedly increased during PSH 8-48 (P values all below 0.01), and it peaked at PSH 12 [(80.79 +/- 0.12)%]. In both groups, AQP-1 was mainly expressed in endothelial cells of capillaries and pericellular membrane of myocardial cells. The expression of AQP-1 in scald group was markedly increased from PSH 2 to PSH 48. The expression of myocardial AQP-1 mRNA in scald group was markedly higher from PSH 2 to PSH 48 than that in normal control group (P values all below 0.01), and it peaked at PSH 12 [(6.2 +/- 0.7)%]. The serum content of cTnI in scald group was obviously higher from PSH 2 to PSH 48 than that in normal control group (P values all below 0.01), and it peaked at PSH 12 [(5.83 +/- 0.51) ug/L]. There were statistically positive correlations between AQP-1 mRNA expression and myocardial water ratio (r = 0.849, P < 0.01), AQP-1 mRNA expression and the serum content of cTnI (r = 0.973, P < 0.01) in scald group. CONCLUSIONS: AQP-1 may play a key role in the development of myocardial edema in rats with scald. PMID- 24059949 TI - [Effects of adipose-derived stem cells on renal injury in burn mice with sepsis]. AB - OBJECTIVE: To investigate the effect of adipose-derived stem cells (ADSC) on renal injury in mice with burn injury and sepsis and its underlying mechanism. METHODS: (1) Adipose tissue was collected from both inguinal regions of 5 C57BL/6J mice to isolate, culture and purify ADSC through enzyme digestion, density gradient centrifugation, and adherence method. Cells of the third passage were used in the experiment. The morphologic change in cells was observed and the growth curve of cells was determined. The expression of cell surface antigen phenotype was analyzed by flow cytometry, and the cells were identified by adipogenic and osteogenic differentiation. (2) Another 37 C57BL/6J mice were divided into normal control group (n = 5), saline group (n = 16), and group ADSC (n = 16) according to the random number table. The mice in saline group and group ADSC were injected with Pseudomonas aeruginosa after being subjected to 15% TBSA full-thickness burn on the back to reproduce septic burn model. Then the mice were injected with saline and ADSC through tail vein respectively. At post burn hour (PBH) 12, 24, 48, and 72, the pathological change in kidney tissue was observed, the levels of blood urea nitrogen and serum creatinine were determined, and the levels of TNF-alpha, IL-12, IL-10, and cyclooxygenase-2 (COX2) mRNA were determined with real-time fluorescence quantitative PCR in both groups. Above mentioned indexes were also examined in the normal control group (without burn). Data were processed with multifactor analysis of variance and LSD- t test. RESULTS: (1) Cells in the third passage were orderly arranged with the shape similar to fibroblasts. The percentages of CD90(+), CD105(+), CD34(-), and CD45( ) cells were all above 90%. The cells could differentiate into osteoblasts and adipocytes. The cells were identified to be ADSC. (2) From PBH 12 to PBH 72, the neutrophil infiltration gradually increased, and the structure of kidney tubules and glomeruli were deranged in saline group. The pathological change in kidney tissue in group ADSC was less serious than that of normal control group at each time point. From PBH 12 to PBH 72, the levels of blood urea nitrogen and serum creatinine in saline group were significantly higher than those of normal control group and group ADSC (P values all below 0.01). Compared with those of the normal control group, the levels of TNF-alpha and IL-12 mRNA were higher in group ADSC and saline group at PBH 24 (P values all below 0.05). At PBH 24, the level of TNF alpha mRNA in group ADSC (1.58 +/- 0.19) was lower than that of saline group (3.36 +/- 0.30, P < 0.05). At PBH 24, the levels of IL-10 and COX2 mRNA in group ADSC (2.89 +/- 0.47, 4.90 +/- 0.59) were higher than those in normal control group (1.00 +/- 0.15, 1.00 +/- 0.27) and saline group (1.32 +/- 0.38, 1.57 +/- 0.38, P values all below 0.05). CONCLUSIONS: ADSC can decrease the levels of blood urea nitrogen and serum creatinine, promote the production of anti inflammatory cytokines IL-10 and COX2, and reduce the release of the pro inflammatory cytokines TNF-alpha and IL-12 to offer protective effects against renal injury in burn mice with sepsis. PMID- 24059950 TI - [Effects of high frequency oscillatory ventilation combined with incremental positive end-expiratory pressure on respiratory and circulatory functions of dogs with inhalation injury]. AB - OBJECTIVE: To study the effects of high frequency oscillatory ventilation (HFOV) combined with incremental positive end-expiratory pressure (IP) on respiratory and circulatory functions, and lung histopathology of dogs with smoke inhalation injury. METHODS: After being treated with conventional mechanical ventilation, 12 dogs were inflicted with severe smoke inhalation injury and divided into group HFOV and group HFOV+IP according to the random number table, with 6 dogs in each group. Then they received corresponding ventilation for 8 hours respectively. Blood gas analysis results (pH value, PaO2 and PaCO2 levels) and hemodynamic parameters [heart rate, mean arterial pressure (MAP), pulmonary arterial pressure (PAP), central venous pressure (CVP), cardiac output (CO)] were recorded before injury, immediately after injury, and at post ventilation hour (PVH) 2, 4, 6, and 8. The dogs of two groups were sacrificed at PVH 8. A healthy dog without any treatment and a dog with smoke inhalation injury but no subsequent treatment were sacrificed in addition. Lung tissues of all dogs were obtained for histopathological observation. Lung injury score examination was conducted in both groups. Data were processed with rank sum test, analysis of variance of repeated measurement, and LSD- t test. RESULTS: (1) The PaO2 levels in both groups were significantly decreased immediately after injury, compared with those before injury (with t values respectively 4.960, 5.310, P values all below 0.01). The PaO2 levels in both groups from PVH 2 to PVH 8 were significantly increased, compared with those observed immediately after injury (with t values from 4.930 to 6.050, P values all below 0.01). At PVH 2, 4, and 8, PaO2 levels in group HFOV+IP were significantly higher than those in group HFOV (with t values from 3.775 to 5.774, P values all below 0.01); no statistically significant differences were observed in pH value and PaCO2 level at each time point between two groups (with t values from 0.002 to 0.997, P values all above 0.05). (2) There were no statistically significant differences in MAP, PAP, and CVP within two groups at each time point (with F values from 1.316 to 4.959, P values all above 0.05). In group HFOV, heart rate from PVH 2 to PVH 8 was significantly lower than that observed immediately after injury (with t values from 3.780 to 8.970, P values all below 0.01). In group HFOV+IP, CO at PVH 4, 6, and 8 was significantly lower than that observed immediately after injury (with t values from 3.990 to 11.200, P values all below 0.01). There were no statistically significant differences in MAP, PAP, and CVP between two groups at the same time point (with t values from 0.089 to 2.123, P values all above 0.05). At PVH 4, 6, and 8, heart rate in group HFOV+IP was higher than that in group HFOV (with t values from 2.931 to 7.229, P < 0.05 or P < 0.01), while CO was lower (with t values from 4.297 to 11.206, P values all below 0.01). (3) Compared with those of the healthy dog, inflammatory cell infiltration and bleeding in the lung were observed in alveolar space in both group HFOV and group HFOV+IP, while the degree was less serious than that of the dog with smoke inhalation injury only. Compared with those of group HFOV, inflammatory cell infiltration in group HFOV+IP was less significant, the alveolar structure was relatively intact, and no thickening of alveolar walls was observed. The lung injury score in group HFOV [(3.27 +/- 0.24) points] was higher than that of group HFOV+IP [(2.79 +/- 0.31) points, t = 27, P < 0.05]. CONCLUSIONS: HFOV combined with IP can improve gas exchange and alleviate pulmonary injury without any adverse effect on blood gas analysis or hemodynamic parameters. Therefore, it may be considered as an appropriate mode of ventilation for the treatment of smoke inhalation injury. PMID- 24059951 TI - [Effects of phosphorylated mitogen-activated protein kinases on phosgene inhalation-induced lung injury in rats and its relationship with matrix metalloproteinase]. AB - OBJECTIVE: To investigate the effects of phosphorylated mitogen-activated protein kinases (MAPK), including the phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2), the phosphorylated protein p38 (p-p38), the phosphorylated c-Jun N-terminal kinase (p-JNK), on phosgene inhalation-induced lung injury and its relationship with matrix metalloproteinase 9 (MMP-9). METHODS: According to the random number table, 30 male Wistar rats were divided into air control group (C), phosgene inhalation group (P), PD98059 (specific inhibitor of ERK1/2) group, SB203580 (specific inhibitor of p38) group, and SP600125 (specific inhibitor of JNK) group, with 6 rats in each group. The number of neutrophils in the bronchoalveolar lavage fluid (BALF) was counted and the lung wet-dry ratio (W/D) was examined. The serum levels of inflammatory factors TNF-alpha, IL-1beta, IL-6, and IL-8 were determined with ELISA. The protein expressions of p-ERK1/2, p-p38, p-JNK, and MMP-9 in lung tissue were detected with Western blotting. The mRNA level of MMP-9 in lung tissue was detected with real-time fluorescence quantitative PCR. Data were processed with one-way analysis of variance (among groups) and SNK method (paired comparison). RESULTS: Compared with those of group C [respectively (2.0 +/- 0.7)*10(4) /mL and 3.7 +/- 0.6], the number of neutrophils and W/D of group P [respectively (10.7 +/- 1.4)*10(4) /mL and 7.6 +/- 0.4] were increased. The number of neutrophils in group SB203580 and group SP600125 was respectively (8.3 +/- 1.1)*10(4), (7.9 +/- 1.3)*10(4)/mL, with W/D respectively 6.1 +/- 1.4, 6.1 +/- 0.9, all of which decreased as compared with those of group P (with P values all below 0.01). Compared with those of group C, the levels of TNF-a, IL-1beta, IL-6, and IL-8 of group P were increased, but decreased in group SB203580 and group SP600125 compared with that of group P, though still higher than those of group C, and the differences were statistically significant (P < 0.05 or P<0.01). Protein quantities of p-p38 and p-JNK were higher in group P (respectively 1.19 +/- 0.22 and 1.43 +/- 0.14) than in group C (respectively 0.76 +/- 0.06 and 0.74 +/- 0.05). Compared with those of group P, the protein levels of p-ERK1/2 (0.47 +/- 0.05) in group PD98059, p-p38 (0.88 +/- 0.07) in group SB203580, and p-JNK (0.91 +/- 0.07) in group SP600125 were significantly reduced (P < 0.05 or P < 0.01). The protein and mRNA levels of MMP-9 were higher in group P (respectively 2.23 +/ 0.18 and 4.93 +/- 0.12) than in group C (respectively 1.26 +/- 0.14 and 1.80 +/- 0.03). The protein and mRNA levels of MMP-9 in group SB203580 (respectively 1.58 +/- 0.14 and 2.96 +/- 0.09) and group SP600125 (respectively 1.55 +/- 0.30 and 3.00 +/- 0.13) were lower than those in group P (P < 0.05 or P < 0.01). CONCLUSIONS: The phosgene inhalation can activate the MAPK signaling protein pathway by increasing expressions of p-p38 and p-JNK, which lead to an up regulation of MMP-9, and this may contribute to the phosgene inhalation-induced lung injury. PMID- 24059952 TI - [Effects of antisense p38 alpha mitogen-activated protein kinase on myocardial cells exposed to hypoxia and burn serum]. AB - OBJECTIVE: To study the effects of antisense p38alpha mitogen-activated protein kinase (hereinafter referred to as p38alpha) on myocardial cells exposed to hypoxia and burn serum. METHODS: Thirty adult SD rats were inflicted with 40% TBSA full-thickness burn on the back to obtain burn serum. The myocardial cells were isolated from 80 neonatal SD rats and cultured, then they were divided into 4 groups according to the random number table: normal control group (N, ordinary culture without any treatment), hypoxia+burn serum group (HB, exposed to hypoxia after being treated with 10% burn rat serum), hypoxia+burn serum+infection group (HBI, exposed to hypoxia and 10% burn rat serum after being infected with antisense p38alpha gene-carrying adenovirus), hypoxia+burn serum+empty vector infection group (exposed to hypoxia and 10% burn rat serum after being infected with adenovirus empty vector). At post hypoxia hour (PHH) 1, 3, 6, and 12, mRNA and protein expression levels of p38alpha in the latter 3 groups were determined by RT-PCR and Western blotting, cell viability was determined by methylthianolyldiphenyl-tetrazolium bromide assay, and lactate dehydrogenase (LDH) activity was assayed at the same time point. At PHH 1, 6, and 12, apoptosis rate of myocardial cells was assessed by annexin V staining method. The indexes of group N were determined with the methods mentioned-above. Three wells were set at each time point in each group. Data were processed with one-way analysis of variance and LSD- t test. RESULTS: (1) At PHH 1, 3, and 6, the p38alpha mRNA level was higher in group HB than in group N and group HBI (with t values from 2.725 to 4.375, P values all below 0.05). (2) At PHH 1, 3, and 6, the p38alpha protein level was higher in group HB than those in group N and group HBI (with t values from 5.351 to 7.981, P values all below 0.01). (3) At PHH 3, 6, and 12, the cell viability in group HB (0.115 +/- 0.007, 0.104 +/- 0.006, 0.094 +/- 0.005) was lower than that in group N (0.141 +/- 0.014) and group HBI (0.136 +/- 0.009, 0.124 +/- 0.010, 0.112 +/- 0.007, with t values from 2.357 to 6.812, P values all below 0.05). (4) The LDH activity was up-regulated in group HB as compared with that in group N and group HBI at each time point (with t values from 22.753 to 201.273, P values all below 0.01). (5) At PHH 1, 6, and 12, the apoptosis rate of myocardial cells in group HB [(5.4 +/- 0.7)%, (8.7 +/- 1.1)%, (13.6 +/- 1.7)%] was higher than that of group N [(3.1 +/- 0.3)%] and group HBI [(4.3 +/- 0.5)%, (5.1 +/- 0.7)%, (7.2 +/- 0.9)%, with t values from 2.345 to 9.700, P < 0.05 or P < 0.01]. CONCLUSIONS: Antisense p38alpha can protect the myocardial cells from the injury of hypoxia and burn serum. PMID- 24059953 TI - [Effects of resuscitation with different kinds of colloids on pulmonary edema in swine in shock stage of severe burn injury]. AB - OBJECTIVE: To observe and compare the effects of natural colloid and artificial colloid on pulmonary edema of swine during shock stage of severe burn injury. METHODS: Twelve Guangxi Bama miniature swine were inflicted with 40% TBSA full thickness burn on the back, and then they were divided into natural colloid group (N) and artificial colloid group (A) according to the random number table, with six swine in each group. At post injury hour (PIH) 2, fluid resuscitation was begun. The main part of electrolyte was lactic acid Ringer's solution. The colloids included swine plasma and hydroxyethyl starch 130/0.4. Before injury and at every hour within PIH 48, heart rate, blood pressure, urine volume, central venous pressure (CVP), and pulmonary arterial wedge pressure (PAWP) were recorded. The mean heart rate, blood pressure, urine volume per hour per kg of body weight, CVP, PAWP, resuscitation liquid volume, and the ratio of fluid intake to output during the first and second PIH 24 were calculated. At PIH 48, lung tissue was harvested for histopathological observation and calculation of lung water ratio. Data were processed with one-way analysis of variance, analysis of variance of repeated measurement, LSD test and independent sample t test. RESULTS: (1) There were no statistically significant differences between two groups in heart rate, blood pressure, and urine volume before injury and during the first and second PIH 24 (P values all above 0.05); during the first PIH 24, the CVP and PAWP of group A were significantly higher than those of group N (P values all below 0.05). Compared with those before injury, the heart rate, CVP and PAWP of two groups during the first and second PIH 24 were significantly higher (P < 0.05 or P < 0.01); the urine volume of group N was decreased during the first PIH 24 (P < 0.05), while there was no significant change in group A (P > 0.05); the urine volumes of two groups during the second PIH 24 were increased, while no statistically significant differences were observed (P values all above 0.05). There were no statistically significant differences in blood pressure of two groups between the first, second PIH 24 and before injury (P values all above 0.05). (2) There were no statistically significant differences in the resuscitation liquid volume and fluid intake to output ratio between two groups during the first and second PIH 24 (P values all above 0.05). (3) The alveolar septum was found widened in varying degrees, and there were edema fluid accumulating and inflammatory cell infiltrating within the pulmonary interstitial of lung tissue sections in both two groups. (4) The lung water ratio of group N [(71 +/- 10)%] was not statistically significant different from that of group A [(79 +/- 4)%, t = -1.753, P > 0.05]. CONCLUSIONS: The natural colloid or artificial colloid (hydroxyethyl starch 130/0.4) applied during shock stage had similar effects on pulmonary edema in swine with severe burn. PMID- 24059954 TI - [Reproduction of a mouse model of deep partial-thickness scald and determination of hypoxia in the wound]. AB - OBJECTIVE: To reproduce a stable mouse model of deep partial-thickness scald and to determine the hypoxia status in the wound. METHODS: (1) A homemade scald producing apparatus with constant steam (92 degrees C) emission was used to reproduce scald injury on the back (2 cm in diameter) in 80 male BALB/c mice for different duration (2, 4, 6, and 8 s), with 20 mice for each scald duration. The nozzle was aligned perpendicularly to the back of mice, 2 cm above the skin surface. The gross condition of wound was observed with naked eyes immediately after injury. Skin samples of 5 mice with different burn duration were harvested 0, 12, 24, and 48 h after scald for histopathological observation with hematoxylin and eosin staining, to screen the scalding time and time for biopsy of scalded skin to determine proper scalding time for the experiment. (2) Model of deep partial-thickness scald was reproduced with the desired scalding time as shown in the preliminary experiment in another 5 BALB/c mice. The hypoxia status in subcutaneous tissue was observed with immunohistochemical staining 72 h after scald. Another 20 BALB/c mice were divided into normal control group (n = 5, without scald) and deep partial-thickness scald group (n = 15, scalded for a suitable duration as determined in the preliminary experiment) according to the random number table. The subcutaneous oxygen content in wound center, the margin of the wound, and the normal skin adjacent to the wound was detected with laser Doppler transcutaneous oxygen tension 72 h after scald, with 5 mice in each region. Data were processed with one-way analysis of variance. RESULTS: (1) The wound of mice with different scald durations was pale, clean, and no exudate was observed right after injury. (2) The burn depth developed gradually along with the scalding time and sample harvesting time, and it became stable 24 h after scalding. A deep partial-thickness injury was observed in the dermis of mice scalded for 4 s and harvested 24 h after scald, and it was shown that the external hair sheath was still present, and it was determined to be a deep partial-thickness scald. (3) Dense staining of pimonidazole (hypoxia) was found in deep partial-thickness scald wound 72 h after scald, especially in the marginal zones of the wounds. The partial oxygen pressure in the wound center, wound margin, and normal skin around the wound was respectively (36.2 +/- 3.2), (37.0 +/- 1.4), (37.4 +/- 2.7) mm Hg (1 mm Hg = 0.133 kPa), showing no statistically significant difference among them (F = 74.705, P > 0.05), but they were significantly lower than that of the control group [(53.1 +/- 2.4) mm Hg, with F values respectively 82.377, 91.375, 100.531, P values all below 0.05]. CONCLUSIONS: Deep partial-thickness scald model can be reproduced in (20.0 +/- 1.0) g male BALB/c mice by scalding with 92 degrees C hot steam for 4 s, and the depth of wound becomes stable 24 h after scalding. Hypoxia can be found in the scalded wounds, especially in the marginal zones of the wounds. PMID- 24059955 TI - [Treatment of extensive acute radiation burn and its complications]. AB - This article reports the treatment of a patient suffered from acute radiation burn covering 41% TBSA, with deep partial-thickness and full-thickness injury, produced by exposure to a large-scale industrial electron accelerator. An open wound began to appear and enlarged gradually 10 weeks after the exposure. Serious wound infection with methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, pneumonia, respiratory failure, systemic inflammatory response syndrome, nephropathy and hypoproteinemia developed successively since 3 weeks after the wound formation. Skin grafts failed to survive, resulting in enlargement of the wound. After being treated with proper measures, including parenteral nutrition, respiratory support with a ventilator, appropriate antibiotics, steroid administration for nephropathy, deep debridement for wounds followed by skin grafting, the patient was cured and discharged after undergoing 15 operations in 500 days. The clinical condition of an extensive acute radiation burn is complicated. We should pay close attention to the changes in functions of organs, and strengthen the therapeutic strategies to support the function of organs to reduce the incidence of systemic complications. The control of the infection and the timely and effective repair of the wound are still the key points of the treatment of an extensive local radiation injury. PMID- 24059956 TI - [Advances in the research of fluid resuscitation for burn shock]. AB - The aim of fluid resuscitation is to restore tissue perfusion, ameliorate cellular injury, increase tissue perfusion and oxygenation, and improve end-organ functions. Many researches in the field of fluid resuscitation strategy have been made in the last decade, but vigorous debate on optimal method of resuscitation still exists. The hypotensive resuscitation strategy is particularly applicable in patients with uncontrollable hemorrhage, whereas, it is uncertain whether the theory could be used in burn shock management. Resuscitation using both colloid and crystalloid has a better outcome in treating extensive burns and septic shock. Caution should be exercised when using higher concentrations of artificial colloid and lactated Ringer's solution, of which some adverse effects have been observed. Along with the increasing use of novel hemodynamics monitoring in intensive care, parameters including stroke volume variation (SVV), intrathoracic blood volume index (ITBVI), and cardiac index (CI) have been examined as indexes of resuscitation endpoint. However, further studies should be made when applying SVV, ITBVI, and CI in guiding fluid resuscitation in burns. PMID- 24059957 TI - [Establishment and management of a burn ICU]. AB - This paper elaborates systemically the establishment and management of a burn ICU, and also the theory and technology related to shock resuscitation, respiratory support, infection, blood purification, nutritional support, cardiopulmonary resuscitation, sedation and analgesia, etc. from the perspective of critical care medicine. The relevant guidelines and recommendations are introduced in order to provide some guidance and help for the establishment of a burn ICU. PMID- 24059958 TI - [Effects of sodium tanshinone II A sulfonate on proliferation of fibroblasts in scar and the mRNA and protein expressions of transforming growth factor beta 1 and alpha smooth muscle actin]. AB - OBJECTIVE: To study the effects of sodium tanshinone II A sulfonate (STS) on proliferation of fibroblasts (Fbs) in human hypertrophic scar (HS), the mRNA and protein expressions of transforming growth factor beta 1 (TGF-beta1) and alpha smooth muscle actin (alpha-SMA), and to investigate the scar inhibition mechanism of STS. METHODS: Fbs were isolated from HS tissues that were removed from eight patients after burn injury, and they were cultured in vitro. Cells from the 3rd to the 6th passages were used in the experiment. Fbs were divided into control group and experimental group according to the random number table, and cells in the experimental group was divided into 0.050, 0.075, 0.100, 0.125, 0.150, 0.200 mg/mL STS subgroups. Cells in each subgroup were cultured with the corresponding concentration of STS, and cells in control group were cultured in equal volume of serum-free medium. After being cultured for 24 and 48 h, cell morphology was observed with inverted phase contrast microscope; cell proliferation was determined with MTT method and the proliferation inhibition rate (IR) was calculated. After being cultured for 48 h, the protein levels of TGF-beta1 and alpha-SMA were determined with Western blotting; the mRNA expressions of TGF beta1 and alpha-SMA were determined with RT-PCR (no 0.200 mg/mL STS subgroup was set for these two indicators). Data were processed with factorial analysis of variance; differences between groups were processed with LSD test or Games-Howell test for unequal variances. RESULTS: (1) Fbs grew well in control group, but reduction in adherence and disorderly arranged Fbs were observed in experimental group. The cells in experimental group became smaller and round, with increasing intracellular particles and necrosis. A large amount of necrotic debris of cells was observed in 0.200 mg/mL STS subgroup. (2) The absorbance value of Fbs in each experimental subgroup was significantly lower than that in control group (with P values all below 0.01). Along with the increase in the concentration of STS and extension of culture time, the IR value increased, showing a certain degree of time-concentration dependence. After being cultured with STS for 24 and 48 h, IR values of cells in the experimental subgroups were respectively 23.58%, 32.11%, 37.56%, 57.98%, 79.53%, 96.69% and 34.72%, 38.48%, 47.62%, 64.40%, 89.70%, 98.01%. (3) Except for the 0.050 mg/mL STS subgroup, the protein levels of TGF beta1 and alpha-SMA in the other subgroups were significantly lower than those in control group (with F values respectively 57.674, 47.795, P values all below 0.001). The protein levels of TGF-beta1 and alpha-SMA reached the nadir in 0.150 mg/mL STS subgroup, respectively 0.34 +/- 0.06, 0.33 +/- 0.07. The relative expression amounts of TGF-beta1 and alpha-SMA mRNA in the experimental subgroups were obviously decreased compared with those in control group (with F values respectively 68.548, 47.522, P values all below 0.001), which was most significant in 0.150 mg/mL STS subgroup, with TGF-beta1 mRNA and alpha-SMA mRNA respectively 0.39 +/- 0.07 and 0.42 +/- 0.08. CONCLUSIONS: STS can inhibit the proliferation of Fbs, reduce the protein and mRNA expressions of TGF-beta1 and alpha-SMA, which may be beneficial to ameliorate the formation and contracture of HS, and it is assumed as a potential drug for treating scars. PMID- 24059959 TI - [Expression of integrin-linked kinase in fibroblasts of scar induced by cobalt chloride and its effect on cell proliferation]. AB - OBJECTIVE: To explore the expression of integrin-linked kinase (ILK) in fibroblasts (Fbs) of scar induced by cobalt chloride (CoCl2) and its effect on cell proliferation. METHODS: The human hypertrophic scar Fbs of seven patients were isolated and cultured in vitro. Cells from the 5th to the 6th passages were used in the experiment. Six bottles of Fbs were obtained from each of the seven patients, and they were respectively cultured with DMEM nutrient solution containing CoCl2 in the concentration of 0, 50, 100, 150, 200, and 250 umol/L for 24 h. The expression of ILK mRNA was determined with real-time fluorescence quantitative PCR. Fbs were stimulated by CoCl2 in the most suitable concentration (100 umol/L) and the protein expression of ILK was determined 0, 1, 2, 4, 12, and 24 h after the stimulation. Then the Fbs were divided into control group (cultured with nutrient solution), negative control group (transfected with con siRNA), and ILK siRNA group (transfected with ILK siRNA). They were cultured with nutrient solution containing CoCl2 in different concentrations 24 h after transfection, with 4 wells for each concentration in each group. The cell proliferation was detected by XTT assay. Data were processed with one-way analysis of variance (ANOVA) and ANOVA for repeated measurement, and LSD method was used in multiple comparisons. RESULTS: The expression level of ILK mRNA was highest in Fbs cultured with 100 umol/L CoCl2 for 24 h, with significant difference compared with those of Fbs cultured with other concentrations of CoCl2 (F = 50.958, P < 0.001). The expression of ILK protein in Fbs cultured with 100 umol/L CoCl2 for 1 h (0.243 +/- 0.009) was lower than that cultured for 0 h (0.387 +/- 0.017), and it started to increase from 2 h (0.361 +/- 0.010), and exaggerated at 4 h (0.584 +/- 0.028), 12 h (0.730 +/- 0.029), and 24 h (0.785 +/- 0.031). The expression levels of ILK protein at 1, 4, 12, 24 h were statistically different from that at 0 h (P values all below 0.05). XTT showed that cell proliferation level was highest in control group when cultured with 100 umol/L CoCl2 (F = 488.026, P < 0.001), which decreased from 150 umol/L. The cell proliferation level in control group cultured with 250 umol/L CoCl2 was significantly lower than that with 0 umol/L (P values all below 0.05). There was no significant change in cell proliferation in ILK siRNA group among different concentrations of CoCl2 (F = 2.542, P = 0.056). The cell proliferation level in ILK siRNA group was significantly lower than that in control group and negative control group (F = 2519.542, P < 0.001). CONCLUSIONS: ILK may be a key protein in response of hypoxia in Fbs. The mild hypoxia can stimulate the expression of ILK and promote the proliferation of Fbs, while severe hypoxia can reduce the expression of ILK and inhibit cell proliferation. PMID- 24059960 TI - [Advances in the research of the relationship between calpains and post-burn skeletal muscle wasting]. AB - Calpains are intracellular nonlysosomal Ca(2+-) regulated cysteine proteases, widely located in the tissues of most mammals. Skeletal muscle tissue mainly expresses m-calpain, u-caplain, n-calpain, and their endogenous inhibitor calpastatin. They are closely related to the cell apoptosis, cytoskeleton formation, cell cycles, etc. Calpains are also considered to be participating in the protein degradation process. Severe burns are typically followed by hypermetabolic responses that are characterized by hyperdynamic circulatory responses with increased proteolysis and cell apoptosis. Recently, overloading of Ca(2+) in skeletal muscle cells, which activates the calpains is observed after a serious burn. This paper aims to review the current research of the relationship between calpains and post-burn skeletal muscle wasting from the perspectives of structure, function, and physiological activities. PMID- 24059961 TI - [Advances in the research of the biological activities of degradation products of extracellular matrix]. AB - ECM is a supporting structure for stabilizing the location of cells and preserving the structure of tissues. Recently, it has been discovered that ECM and its degradation products may exert profound influences on tissues and cells, such as activities of inflammatory cells and immune cells. Angiogenesis may be stimulated or inhibited by degradation products of ECM. Matrikines, liberated by partial proteolysis of ECM macromolecules, are found to regulate cell functional activities and play a significant role in wound healing or tumor invasion. Post burn denatured dermal matrix is being studied in burn healing now. The study of post-burn denatured or necrotic dermal matrix should be emphasized in future. PMID- 24059962 TI - Dissociable brain correlates for depression, anxiety, dissociation, and somatization in depersonalization-derealization disorder. AB - OBJECTIVE: The cerebral mechanisms of traits associated with depersonalization derealization disorder (DPRD) remain poorly understood. METHOD: Happy and sad emotion expressions were presented to DPRD and non-referred control (NC) subjects in an implicit event-related functional magnetic resonance imaging (fMRI) design, and correlated with self report scales reflecting typical co-morbidities of DPRD: depression, dissociation, anxiety, somatization. RESULTS: Significant differences between the slopes of the two groups were observed for somatization in the right temporal operculum (happy) and ventral striatum, bilaterally (sad). Discriminative regions for symptoms of depression were the right pulvinar (happy) and left amygdala (sad). For dissociation, discriminative regions were the left mesial inferior temporal gyrus (happy) and left supramarginal gyrus (sad). For state anxiety, discriminative regions were the left inferior frontal gyrus (happy) and parahippocampal gyrus (sad). For trait anxiety, discriminative regions were the right caudate head (happy) and left superior temporal gyrus (sad). Discussion The ascertained brain regions are in line with previous findings for the respective traits. The findings suggest separate brain systems for each trait. CONCLUSION: Our results do not justify any bias for a certain nosological category in DPRD. PMID- 24059963 TI - Are C-reps contextual representations? A reply to Brewin and Burgess. AB - Brewin and Burgess (2013) argue that our recent papers investigating the role of contextual representations in intrusive memories do not pose a challenge to dual representation theory as originally claimed (Pearson, 2012; Pearson, Ross, & Webster, 2012). Here I point out that their alternative explanation for our results can be rejected using data already published in both papers. I also argue that their definition of what constitutes a contextual representation renders their revised dual-representation theory incompatible with experimental results that have previously been argued in the literature to support it. Valuable though their contribution is, it does not impact on our main conclusion that abstract contextual representations serve to increase intrusive memories for traumatic material. PMID- 24059965 TI - The editor, the publisher, and his mother: the representation of lesbians and gays in the New York Times. AB - The attention and prominence given to issues in media outlets may affect the importance citizens attribute to them, so the actors who influence mass media coverage decisions may have political power in society generally. This article seeks to measure the relative influence of journalists, social trends, events, government officials, editors, and owners on the New York Times coverage of lesbians and gays from 1960 to 1995. Although many factors affected the nature and frequency of such coverage, the findings of this article show that the owners of the Times exerted decisive influence. Documentary evidence reveals that the Times' owners actively intervened to suppress coverage of lesbians and gays until 1987, even as reporters and editors recognized that increased social visibility made them newsworthy. Statistical analysis confirms that, although some actual events and statements of officials attracted attention from the newspaper throughout the period, they were more likely to generate prominent coverage after 1987 when the stories were consistent with the enthusiasms of the owners. PMID- 24059964 TI - Treatment of chronic hepatitis C with peginterferon alfa-2b, plus ribavirin in end stage renal disease patients treated by hemodialysis: single Saudi center experience. AB - INTRODUCTION: Hepatitis C virus (HCV) infection is a global health problem, common worldwide, leading to acute and chronic hepatitis and its consequences of hepatic cirrhosis and hepatocellular carcinoma. Antiviral therapy of HCV+ in dialysis patients with interferon-alpha (INF-alpha) gives slightly better results than in the general population, but is poorly tolerated and associated with side effects. Although, Ribavirin in not recommended for dialysis patients, the addition of small doses of this medication to pegylated INF is discussed. PURPOSE: The aim of this study is to assess the efficacy and safety of peginterferon alfa-2b (12 kDa) plus Ribavirin in hemodialysis chronic HCV patients. METHODS: Fourteen end-stage renal disease patients (ESRD) on regular hemodialysis (HD) in Prince Salman Center for Kidney Diseases (PSCKD), ten males (71.4%) and four females (28.6) were enrolled in a prospective study. All the patients have Hepatitis C Virus infection; were treated by pegylated interferon alpha-2b (peginterferon alfa-2b) 1 mcg/kg/week subcutaneously with Ribavirin 200 mg three times weekly; for 48 weeks. Two patients were non responsive to previous course of 24 weeks peginterferon alfa-2a. HCV -RNA PCR qualitative and quantitative were tested before, 12, 48 weeks of treatment and 24 weeks after for sustained virologic response (SVR) results. alpha-fetoprotein level was measured in all the 14 patients before starting treatment to exclude any evidence of hepatocellular carcinoma. RESULTS: One patient (7.1%) refused to complete the treatment because he could not tolerate the side effects and treatment was stopped after the third dose. After 12 weeks, three of 14 patients (21.4%) were still HCV-RNA PCR positive and there were not two log decrees in quantitative PCR, so treatment was stopped in this group of patients. One patient of the remaining had more than two log decrees in quantitative PCR, while nine were seroconverted to HCV-RNA PCR negative, so the treatment was completed for 48 weeks in 10 patients. After 48 weeks of treatment, qualitative and quantitative HCV-RNA PCR were done for 10 patients and the results were still negative (71.4%). Results of qualitative and quantitative HCV-RNA PCR done 24 weeks later showed that 10 patients still negative and SVR was (64%). Their mean ALT and AST dropped from 54.36 +/- 36.79 IU/dL and 31.52 +/- 17.02 IU/dL before starting therapy to 37.26 +/- 36.53 IU/dL and 25.37 +/- 23.72 IU/dL, respectively, after termination. Their mean hemoglobin (Hb) level dropped from 11.31 +/- 0.86 to 10.06 +/- 1.06 g/dL; (p < 0.001), and white blood cell count (WBC) dropped from 6.14 +/- 0.65 * 10(3)/mm(3) to 4.51 +/- 0.95 * 10(3)/mm(3); (p < 0.001). Platelet count fell from 130.11 +/- 48.06 * 10(3)/mm(3) to 63.03 +/- 23.19 * 10(3)/mm(3); (p < 0.001), also erythropoietin dose increased from 182.14 +/- 39.30 IU/kg/w to 253.93 +/- 83.07 IU/kg/w, (p = 0.776). CONCLUSION: Peginterferon alfa-2b (12 kDa) plus Ribavirin therapy in hemodialysis chronic HCV patients is safe, well tolerated and effective with accepted rates of sustained virological response up to 64%. PMID- 24059966 TI - To welcome or affirm: Black clergy views about homosexuality, inclusivity, and church leadership. AB - When the subject of the Black Church and homosexuality is broached, research often focuses on homophobia and correlates with HIV/AIDS. Fewer studies examine other problematic issues germane to gay and lesbian involvement in Black congregations. In this analysis, Black clergy dialogue during focus groups about inclusivity and church leadership by gays and lesbians. Informed by Cultural Theory, of equal interest is whether discourses are influenced by Black Church cultural tools, as well as cultural dynamics, from the broader Black community. As anticipated, findings suggest the tendency for clergy to promote welcoming church spaces, but to be reticent about affirming homosexuality as an acceptable lifestyle. Furthermore, although clergy are generally supportive of involvement by closeted gays and lesbians as lay leaders, most do not support their involvement in the clergy, particularly as pastors. However, views vary based on denomination and gender, and are informed by Black Church cultural components such as scripture and the call-and-response tradition. PMID- 24059967 TI - Lay theories of gender identity disorder. AB - This study examined lay theories regarding gender identity disorder (GID). Pilot interviews were completed with participants (n = 10) regarding their views on possible causes and treatments of GID. Participants (mainly young British people and students; n = 124) then completed a questionnaire that was based on the interviews and a review of the salient literature on lay theories. As hypothesized, participants believed most in biomedical causes and treatments of GID. Factor analysis (with varimax rotation) identified 4 factors in relation to causes of GID: upbringing and personal factors, pregnancy and brain abnormalities, environmental factors, and biomedical causes. Five factors that were identified in relation to the cure/treatment of GID were psychological assistance and personal factors, extreme medical and behavioral changes, alternative therapies, external factors, and medical treatments. The results indicated that participants neither agreed nor strongly disagreed about causes and cures regarding GID, but that these beliefs were logically related. Limitations, particularly of sampling, were considered. PMID- 24059968 TI - Hormones and silk. Gay men in the Spanish film comedies of the transition to democracy (1976-1981). AB - This article studies the representation of gay men in Spanish comedies of the 1970s. It analyzes how cinema used the stereotypical image of gay men projected by the dictatorship and how, once it ended, this image endured in the comedy genre. It introduces film theories on the construction of humor taken from relevant authors, such as Jordan, Charney, Voitylla, and Petri. Afterward, it focuses on the works of Ozores as a filmmaker who encapsulates the main characteristics of the so-called comedia de mariquitas (sissy comedy). It analyzes how the construction of humor was based on the Francoist conception of gay men, and questions why the figure of the gay man was so effective in the production of comedy. Finally, this article refers to Dyer's theories around stereotyping, and develops them to study the Spanish context. PMID- 24059969 TI - The workings of homonormativity: lesbian, gay, bisexual, and queer discourses on discrimination and public displays of affections in Portugal. AB - This article analyzes how heteronormative discourse may be (re)produced by the very same people it serves to oppress, binding heteronormativity to a specific form of homonormativity. Furthermore, this article also links Portuguese history and society by discussing the context and the recent legal changes that led to legislation providing for same-sex marriage. Using thematic analysis of 14 interviews, this article demonstrates how heteronorms are upheld in the discourses of the lesbian, gay, bisexual, and queer (LGBQ) participants. Themes linked to public displays of affection and discrimination emerged from the interviews. Participant discourses are analyzed in terms of their incorporation of heteronorms. Homonormativity is present in both the themes subject to analysis. Analysis of the interviews shows how transgressing the heteronorm implies costs and is ultimately perceived as a personal risk. This article concludes that the lack of discursive resistance denies the possibility of re signification and subversion even in LGBQ discourses. This clearly indicates the pervasiveness of discourses reiterating heteronorms, even those issued by those most oppressed by such norms. PMID- 24059970 TI - Status homophily, sexual identity, and lesbian social ties. AB - The literature on friendship and social networks finds that individuals form social ties with people who are like them--a much studied concept called homophily. However, few studies have explicitly examined sexual identity as a point of homophily. Scholars from multiple disciplines have long argued that sexuality influences the organization of our social worlds, yet most studies of friendship and social networks under-examine or overlook the influence of sexual identity. This study addresses that gap by looking at status homophily among lesbian social ties to examine the influence of sexual identity, as well as gender, race, class, and family, on their personal networks. Using survey data from 544 U.S. lesbian respondents, the findings make visible some of the factors and forces that shape social ties for lesbians. The results point to the importance of sexuality as an organizing element of social life, and suggest that studies that examine social networks or friendships more often make sexual identity, gender, and intersecting social locations a central focus. PMID- 24059971 TI - Frequency of sexual activity with most recent male partner among young, Internet using men who have sex with men in the United States. AB - Sex frequency, defined here as the number of oral or anal sex acts with the most recent partner in the past year, is a potential driver of risk for sexually transmitted infections. However, few data on sex frequency have been reported for men who have sex with men (MSM). Data from an Internet survey of MSM were used to describe sex frequency with most recent main and casual male partners and to estimate factors associated with higher sex frequency. Among 5,193 MSM, higher sex frequency was associated with younger age, shorter relationship duration, and reporting a main (vs. casual) partner; and lower sex frequency with male partners was associated with heterosexual or bisexual (vs. homosexual) identity or Black race (vs. non-Hispanic White). Secondary analyses of estimates of sex frequency from 2 publicly available nationally representative datasets comprised of primarily heterosexual survey respondents (the 2008 General Social Survey and the 1992 National Health and Social Life Survey) were performed. Sex frequency among MSM respondents was similar to that reported by heterosexuals. PMID- 24059972 TI - Impact of health claims in prebiotic-enriched breads on purchase intent, emotional response and product liking. AB - The impact of health claims on purchase intent, emotional response and liking has never been previously reported. In this study, prebiotic-enriched bread was used as a model functional food. Purchase intent, emotional response and liking were investigated in three phases: (1) focus groups were used to gauge consumer perception of health claims and functional foods, (2) the impact of health claims on purchase intent and emotional responses were measured using an online survey (n = 122) and (3) hedonic ratings on bread rolls presented with or without any associated claims were obtained (n = 100). A cluster analysis of the purchase intent data identified two clusters of consumers who were either receptive or non receptive to health claims. Receptive and non-receptive consumers significantly differed in the emotions they reported with respect to the claims. The hedonic ratings did not significantly differ between the breads tasted with or without health claims. PMID- 24059973 TI - The sodium channel gene family is specifically expressed in hen uterus and associated with eggshell quality traits. AB - BACKGROUND: Eggshell quality is important for the poultry industry. During eggshell formation a mass of inorganic minerals is deposited. The Sodium Channel (SCNN1) gene family plays an essential role in cation transportation. The objective of this study was to investigate the pattern of expression of members of the SCNN1 gene family, their variation and their effects on eggshell quality. RESULT: The highest expression of SCNN1a, SCNN1b, and SCNN1g genes were in the active uterus during eggshell mineralization, while SCNN1d showed its highest expression level in the quiescent uterus (no egg present). Nineteen candidate SNPs from the four genes were genotyped in a population of 338 White Leghorn layers. Association analysis between SNPs (haplotypes/diplotypes) and eggshell traits was performed. Among seven significant SNPs, five SNPs were associated with eggshell strength, eggshell thickness, eggshell percentage or/and egg weight, while the other two SNPs within SCNN1d were only associated with eggshell percentage. These SNPs had a 0.25-6.99% contribution to phenotypic variance, depending on the trait. In haplotype analysis, SCNN1b and SCNN1d were associated with egg weight. The SCNN1b and SCNN1g were significantly associated with eggshell weight while only SCNN1g explained 2.04% of phenotypic variance. All the alleles of the members of SCNN1 gene family were associated with eggshell percentage and eggshell thickness, and others members had an association with eggshell strength except for SCNN1a. The contribution of different haplotypes of the SCNN1 gene family to eggshell phenotypic variance ranged from 0.09% to 5.74%. CONCLUSIONS: Our study indicated that the SCNN1 gene family showed tissue expression specificity and was significantly associated with eggshell traits in chicken. This study provides evidence that genetic variation in members of the sodium channel can influence eggshell quality. PMID- 24059975 TI - Development and field validation of an indicator to assess the relative mobility and risk of pesticides in the Lourens River catchment, South Africa. AB - A GIS based pesticide risk indicator that integrates exposure variables (i.e. pesticide application, geographic, physicochemical and crop data) and toxicity endpoints (using species sensitivity distributions) was developed to estimate the Predicted Relative Exposure (PREX) and Predicted Relative Risk (PRRI) of applied pesticides to aquatic ecosystem health in the Lourens River catchment, Western Cape, South Africa. Samples were collected weekly at five sites from the beginning of the spraying season (October) till the beginning of the rainy season (April) and were semi quantitatively analysed for relevant pesticides applied according to the local farmers spraying programme. Monitoring data indicate that physicochemical data obtained from international databases are reliable indicators of pesticide behaviour in the Western Cape of South Africa. Sensitivity analysis identified KOC as the most important parameter influencing predictions of pesticide loading derived from runoff. A comparison to monitoring data showed that the PREX successfully identified hotspot sites, gave a reasonable estimation of the relative contamination potential of different pesticides at a site and identified important routes of exposure (i.e. runoff or spray drift) of different pesticides at different sites. All pesticides detected during a monitored runoff event, were indicated as being more associated with runoff than spray drift by the PREX. The PRRI identified azinphos-methyl and chlorpyrifos as high risk pesticides towards the aquatic ecosystem. These results contribute to providing increased confidence in the use of risk indicator applications and, in particular, could lead to improved utilisation of limited resources for monitoring and management in resource constrained countries. PMID- 24059974 TI - European starlings ( Sturnus vulgaris ) suggest that landfills are an important source of bioaccumulative flame retardants to Canadian terrestrial ecosystems. AB - Landfills are used as the primary means for the disposal of municipal solid waste in Canada. In the present study, polybrominated diphenyl ethers (PBDEs) and other flame retardants (FRs) were determined in fresh European starling ( Sturnus vulgaris ) eggs collected in 2009, 2010, and 2011 from nest boxes established within, adjacent to, and 10 and 40 km distant to five major urban centers across Canada, i.e., Vancouver, British Columbia (BC); Calgary, Alberta (AB); Hamilton, Ontario (ON); Montreal, Quebec (QC); and Halifax, Nova Scotia (NS). Nest boxes were located in several land use types: urban industrial areas (districts of industrial activity within city limits), landfill sites (adjacent to cities), and rural (agricultural) sites located 10 and 40 km distant from the major urban centers, as well as a national reference site. Of the 14 PBDE congeners and 16 non-PBDE FR substances determined in the starling eggs, BDE-17, -28, -47, -49, 66, -85, -99, -100, -138, -153, -154, -183, and -209, Dechlorane Plus isomers (anti and syn), and bis(2-ethylhexyl)-3,4,5,6-tetrabromophthalate (BEHTBP) were most frequently quantifiable. The data revealed orders of magnitude greater PBDE concentrations in eggs from starlings nesting in landfill sites (median: 28-280 ng/g wet weight) relative to those from urban industrial and rural environments. However, the percent fractional composition of the PBDE congener patterns did not vary significantly between the types of land uses or between years. Additionally, the median ?PBDE concentration in eggs from landfill sites and the human population density of the metropolitan region that the landfill serves were highly correlated (r(2) = 0.998, p < 0.001). As the first transcontinental effort in assessing FR contamination in Canadian terrestrial ecosystems, the present study strongly suggest that landfills are an important FR source to starlings nesting nearby and that other terrestrial organisms could also be similarly exposed. PMID- 24059976 TI - Desorption of biocides from renders modified with acrylate and silicone. AB - Biocides are used in the building industry to prevent algal, bacterial and fungal growth on polymericrenders and thus to protect buildings. However, these biocides are leached into the environment. To better understand this leaching, the sorption/desorption of biocides in polymeric renders was assessed. In this study the desorption constants of cybutryn, carbendazim, iodocarb, isoproturon, diuron, dichloro-N-octylisothiazolinone and tebuconazole towards acrylate and silicone based renders were assessed at different pH values. At pH 9.5 (porewater) the constants for an acrylate based render varied between 8 (isoproturon) and 9634 (iodocarb) and 3750 (dichloro-N-octylisothiazolinone), respectively. The values changed drastically with pH value. The results for the silicone based renders were in a similar range and usually the compounds with high sorption constants for one polymer also had high values for the other polymer. Comparison of the octanol water partitioning constants (Kow) with the render/water partitioning constants (Kd) revealed similarities, but no strong correlation. Adding higher amounts of polymer to the render material changed the equilibria for dichloro-N octylisothiazolinone, tebuconazole, cybutryn, carbendazim but not for isoproturon and diuron. PMID- 24059977 TI - Sedimentation of PCDD/Fs and PCBs in the Gulf of Finland and the Gulf of Bothnia, the Baltic Sea. AB - Sediment trap material was collected during May-December in the period 1996-2008 in three coastal areas and four open sea stations in the Finnish territory of the Baltic Sea. The highest sedimentation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) with a typical source-related congener profile from chlorophenol production dominated by highly chlorinated dibenzofurans was found close to a historical source in the Kymijoki estuary. This was an order of magnitude higher than in other river estuaries and two orders of magnitude higher than in the open sea stations. The sedimentation of polychlorinated biphenyls (PCBs) was also higher in river estuaries than in other areas. No significant decrease over a 12 year period of monitoring was found in concentration or in sedimentation in the Kymijoki estuary. In the western Gulf of Finland, the Archipelago Sea and the Gulf of Bothnia, the dominating congeners, calculated as toxic equivalent (TEQ) in sedimentation were 1, 2, 3, 7, 8-PeCDD and 2, 3, 4, 7, 8-PeCDF, often reported as the main congeners in deposition. PMID- 24059978 TI - Microalgae cultured by sewage and organic constituents. AB - The microalgae could be multiplied by supplying only sewage influent or effluent without any additional microalgal stock or nutrient salt. In a semicontinuous culture, the N:P weight ratios consumed were 14:1 and 18:1 for the sewage influent and effluent, respectively. The total cell number and green algae ratio of microalgae cultivated by semicontinuous culture exceeded those of batch culture. No cyanobacterial cells were observed in the semicontinuous culture using the sewage effluent. The organic components in the cultured microalgae using sewage effluent, eluted by n-hexane, were determined. The ratio of unsaturated fatty acid exceeded that of saturated fatty acid, which was possibly attributable to the fluidity of the cell membrane. The squalene was also obtained by the culture using sewage alone, free of any external stock or nutrient salt. The higher heating value of the microalgae of semicontinuous culture using the sewage influent was 25 MJ kg(-1), corresponding to the heating value of lignite and showing the potential of the sewage culture microalgae as a means of power generation and combustion aid. PMID- 24059979 TI - Cell-imprinted substrates direct the fate of stem cells. AB - Smart nanoenvironments were obtained by cell-imprinted substrates based on mature and dedifferentiated chondrocytes as templates. Rabbit adipose derived mesenchymal stem cells (ADSCs) seeded on these cell-imprinted substrates were driven to adopt the specific shape (as determined in terms of cell morphology) and molecular characteristics (as determined in terms of gene expression) of the cell types which had been used as template for the cell-imprinting. This method might pave the way for a reliable, efficient, and cheap way of controlling stem cell differentiation. Data also suggest that besides residual cellular fragments, which are presented on the template surface, the imprinted topography of the templates plays a role in the differentiation of the stem cells. PMID- 24059980 TI - Retinoblastoma in an adult. AB - BACKGROUND: Retinoblastoma is the most common pediatric ocular tumour. It may rarely present in adults. The present case adds to the number of 26 cases already published in literature since 1919 till 2013. Our aim is to highlight the rare occurrence of retinoblastoma in adults along with its features which differentiate it from paediatric retinoblastoma. CASE PRESENTATION: We describe a case of adult onset retinoblastoma (group E, according to the international classification of retinoblastoma) occurring in a 25 year old male. He presented with decreasing visual acuity in the right eye of 4 months duration. He had neo vascular glaucoma and pseudohypopyon. B scan ultrsonography of his right eye showed intraocular growth without any calcification. The CT scan of the orbits and brain showed intraocular growth in the right eye with no calcification. Enucleation of the right eye was carried out. Retinoblastoma was confirmed on histopathology of the enuleated globe. CONCLUSIONS: The present case adds to the number of adult Rb patients reported in literature. Early detection to salvage the life can be made possible if the clinician keeps a high index of suspicion when observing retinal mass of adult onset. Proper counselling of the patient in order to seek his full involvement in management may help in improving the prognosis of the disease. PMID- 24059982 TI - Interview with James Appleby. PMID- 24059981 TI - Estradiol prevents olfactory dysfunction induced by A-beta 25-35 injection in hippocampus. AB - BACKGROUND: Some neurodegenerative diseases, such as Alzheimer and Parkinson, present an olfactory impairment in early stages, and sometimes even before the clinical symptoms begin. In this study, we assess the role of CA1 hippocampus (structure highly affected in Alzheimer disease) subfield in the rats' olfactory behavior, and the neuroprotective effect of 17 beta estradiol (E2) against the oxidative stress produced by the injection of amyloid beta 25-35. RESULTS: 162 Wistar rats were ovariectomized and two weeks after injected with 2 MUl of amyloid beta 25-35 (A-beta25-35) in CA1 subfield. Olfactory behavior was evaluated with a social recognition test, odor discrimination, and search tests. Oxidative stress was evaluated with FOX assay and Western Blot against 4-HNE, Fluoro Jade staining was made to quantify degenerated neurons; all these evaluations were performed 24 h, 8 or 15 days after A-beta25-35 injection. Three additional groups treated with 17 beta estradiol (E2) were also evaluated. The injection of A-beta25-35 produced an olfactory impairment 24 h and 8 days after, whereas a partial recovery of the olfactory behavior was observed at 15 days. A complete prevention of the olfactory impairment was observed with the administration of E2 two weeks before the amyloid injection (A-beta25-35 24 h + E2) and one or two weeks after (groups 8 A-beta +E2 and 15 A-beta +E2 days, respectively); a decrease of the oxidative stress and neurodegeneration were also observed. CONCLUSIONS: Our finding shows that CA1 hippocampus subfield plays an important role in the olfactory behavior of the rat. The oxidative stress generated by the administration of A-beta25-35 is enough to produce an olfactory impairment. This can be prevented with the administration of E2 before and after amyloid injection. This suggests a possible therapeutic use of estradiol in Alzheimer's disease. PMID- 24059983 TI - FCET2EC (From controlled experimental trial to = 2 everyday communication): How effective is intensive integrative therapy for stroke-induced chronic aphasia under routine clinical conditions? A study protocol for a randomized controlled trial. AB - BACKGROUND: Therapy guidelines recommend speech and language therapy (SLT) as the "gold standard" for aphasia treatment. Treatment intensity (i.e., >=5 hours of SLT per week) is a key predictor of SLT outcome. The scientific evidence to support the efficacy of SLT is unsatisfactory to date given the lack of randomized controlled trials (RCT), particularly with respect to chronic aphasia (lasting for >6 months after initial stroke). This randomized waiting list controlled multi-centre trial examines whether intensive integrative language therapy provided in routine in- and outpatient clinical settings is effective in improving everyday communication in chronic post-stroke aphasia. METHODS/DESIGN: Participants are men and women aged 18 to 70 years, at least 6 months post an ischemic or haemorrhagic stroke resulting in persisting language impairment (i.e., chronic aphasia); 220 patients will be screened for participation, with the goal of including at least 126 patients during the 26-month recruitment period. Basic language production and comprehension abilities need to be preserved (as assessed by the Aachen Aphasia Test).Therapy consists of language systematic and communicative-pragmatic exercises for at least 2 hours/day and at least 10 hours/week, plus at least 1 hour self-administered training per day, for at least three weeks. Contents of therapy are adapted to patients' individual impairment profiles.Prior to and immediately following the therapy/waiting period, patients' individual language abilities are assessed via primary and secondary outcome measures. The primary (blinded) outcome measure is the A-scale (informational content, or 'understandability', of the message) of the Amsterdam Nijmegen Everyday Language Test (ANELT), a standardized measure of functional communication ability. Secondary (unblinded) outcome measures are language systematic and communicative-pragmatic language screenings and questionnaires assessing life quality as viewed by the patient as well as a relative.The primary analysis tests for differences between the therapy group and an untreated (waiting list) control group with respect to pre- versus post 3-week-therapy (or waiting period, respectively) scores on the ANELT A-scale. Statistical between group comparisons of primary and secondary outcome measures will be conducted in intention-to-treat analyses.Long-term stability of treatment effects will be assessed six months post intensive SLT (primary and secondary endpoints). TRIAL REGISTRATION: Registered in ClinicalTrials.gov with the Identifier NCT01540383. PMID- 24059984 TI - Labor induction outcomes in third-trimester stillbirths. AB - OBJECTIVE: To describe the management of third-trimester stillbirth at a single institution, stratifying induction intervals and adverse outcomes by method. METHODS: Women diagnosed with fetal demise at 28weeks or later and admitted to an academic hospital between January 2007 and September 2010 were identified. A chart review extracted demographics, history, induction method, delivery interval, and adverse outcomes. RESULTS: Seventy-four women were included, with a median gestational age of 35.5weeks (range, 28-40weeks). Ten women had undergone at least 1 prior cesarean. Induction methods included misoprostol alone or for cervical ripening; oxytocin and amniotomy; transcervical Foley catheter; and mifepristone. Overall, 88% of patients delivered within 24hours; median time to fetal delivery was 11hours 20minutes (range, 7minutes to 57hours 12minutes). Adverse outcomes included intrapartum fever and postpartum hemorrhage. In total, 98% of patients, including those with prior cesarean, had a successful vaginal delivery. CONCLUSION: Regardless of third-trimester induction method for management of stillbirth, the majority of women experience safe delivery within 24hours. The descriptive data imply that misoprostol-only inductions might confer the shortest induction intervals; however, further prospective trials are needed to identify the optimal misoprostol regimen for women with third-trimester stillbirth. PMID- 24059985 TI - Uterus-like mass of the broad ligament. PMID- 24059986 TI - [Emphasizing the management of anemia in patients with chronic kidney disease]. PMID- 24059987 TI - [Zero tolerance to ventilator-associated pneumonia: starting from guideline]. PMID- 24059988 TI - [Antithrombotic treatment in atrial fibrillation patients complicating coronary heart disease]. PMID- 24059989 TI - [Related factors and prognostic significance of intradialytic blood pressure variability in patients on maintenance hemodialysis]. AB - OBJECTIVE: To evaluate intradialytic blood pressure variability (BPV) in patients on maintenance hemodialysis (MHD), and to investigate the correlated factors of BPV in MHD process and its correlation with prognosis. METHODS: Patients with end stage renal disease on MHD before January 1, 2009 were enrolled and analyzed retrospectively. Blood pressure at the first hemodialysis every quarter during January, 2009 and December, 2010 were recorded. The systolic pressure, diastolic pressure were calculated, and dialysis systolic and diastolic BPV were expressed with discrete coefficients. As for patients with follow-up time less than 2 years, blood pressures in evenly distributed 6-8 courses were used for calculation.Cardiovascular events and death were recorded and the follow-up was lasted till December 31, 2011. RESULTS: A total of 280 patients were enrolled, with intradialytic systolic BPV of 0.119 +/- 0.029, and intradialytic diastolic BPV of 0.118 +/- 0.028. Intradialytic systolic BPV in the elderly group (n = 114) was significantly higher than that in the younger group (n = 166) (0.126 +/- 0.029 vs 0.114 +/- 0.028, P = 0.012), while no significant difference was found in diastolic BPV (0.117 +/- 0.031 vs 0.119 +/- 0.025, P = 0.498). Intradialytic systolic BPV was used as variates in multivariable regression analysis, and results showed that age, systolic blood pressure before dialysis, intradialytic weight gain (IDWG) rate during dialysis and hemoglobin level were independent influential factors for intradialytic systolic BPV. The intradialytic diastolic BPV was used as variates in multivariable regression analysis, and results showed that IDWG rate and average dehydration volume were independent influential factors for intradialytic diastolic BPV. During 3 years of follow-up, 64 patients died (22.9%). The survival analysis showed that the dialysis systolic BPV elevation was associated with the mortality rate (P < 0.01). CONCLUSIONS: Older age, high systolic pressure before hemodialysis, high IDWG rate, and low hemoglobin level were independent risk factors of high intradialytic systolic BPV increase. Intradialytic high IDWG is an independent risk factor of high intradialytic diastolic BPV increase in patients on MHD. Intradialytic systolic BPV increase is associated with all-cause mortality in patients on MHD. PMID- 24059990 TI - [The safety and efficacy of regional citrate anticoagulation in sustained low efficiency dialysis]. AB - OBJECTIVE: To evaluate the safety and efficacy of regional citrate anticoagulation in sustained low efficiency dialysis (SLED). METHODS: A total of 45 patients with acute kidney injury (AKI) or end stage renal disease (ESRD) admitted in our hospital from August 2011 to September 2012 were prospectively enrolled in this study. All the patients received SLED treatment by Fresenius 4008sARrTplus dialyzer through either femoral or internal jugular venous catheter, with each session of SLED treatment lasting for 8 hours. All the patients were pumped in 4% tri-sodium citrate solution through the arterial line at 130 ml/hour and 10% calcium gluconate through the venous line at 40 ml/hour. The blood flow was 150 ml/minute while the calcium-free dialysate was delivered at 200 ml/minute. Systemic citrate concentration, peripheral and post dialyzer ionized calcium levels at 0, 2 and 5 hour were recorded. RESULTS: All the 45 patients underwent 162 sessions of SLED with 2 were discontinued due to III degrees dialyzer coagulation, and other 160 SLED sessions (98.8%) were all successfully performed. The systemic citrate concentration at 0 hour was (0.14 +/ 0.06) mmol/L, the systemic citrate concentrations at 2 and 5 hour were slightly increased while no statistical difference was found[(1.08 +/- 0.12) mmol/L vs (1.11 +/- 0.17) mmol/L, P > 0.05]. The 0, 2, 5 hour peripheral blood ionized calcium levels were (1.04 +/- 0.13) mmol/L, (1.07 +/- 0.23) mmol/L and (1.04 +/- 0.24) mmol/L, respectively, with no significant difference (P > 0.05). The post dialyzer ionized calcium levels were (0.31 +/- 0.04) mmol/L at 2 hour and (0.29 +/- 0.03) mmol/L at 5 hour. The transmembrane pressure at 2 hour was (104.5 +/- 17.8) mm Hg(1 mm Hg = 0.133 kPa), and (109.3 +/- 20.1) mm Hg at 5 hour, however the increase was not of statistical significance (P > 0.05). At 5 hour, prothrombin time and activated partial thrombin time were identified to be similar to those before SLED. During the treatments, no bleeding complication, thrombocytopenia, cardiac arrhythmia, hypernatremia, metabolic alkalosis or hypotension was observed. CONCLUSION: SLED under regional citrate anticoagulation is safe and effective. Citrate achieves satisfying regional anticoagulation effect without interfering systemic clotting function, thus this study provides a new option of SLED anticoagulation for clinicians. PMID- 24059991 TI - [The effects of failure of low density lipoprotein receptor expression induced by inflammation on radial artery foam cell formation in patients with end-stage renal disease]. AB - OBJECTIVE: To investigate whether inflammation exacerbates lipid accumulation in the radial arteries of patients with end-stage renal disease (ESRD) and to explore its underlying mechanisms. METHODS: Thirty ESRD patients receiving arteriovenostomy were included. The patients were divided by the plasma level of C-reactive protein into control group (n = 16) and inflamed group (n = 14). Foam cell formation and lipid droplet accumulation were checked by HE staining and Oil red O staining. Tissue inflammation and intracellular cholesterol trafficking correlated proteins were examined by immunohistochemistry or immunofluorescent staining. RESULTS: There were no differences in primary diseases, age, body weight, hemoglobin, total protein, albumin, glucose, lipid profile between the two groups (all P values >0.05). The expressions of tumor necrosis factor alpha (TNFalpha) and monocyte chemotactic protein-1 (MCP-1) of the radial artery were increased in the inflamed group. There was significant lipid accumulation in the radial arteries of inflamed group compared to the control group, which was correlated with the increased protein expressions of low density lipoprotein receptor (LDLr), sterol regulatory element binding protein-2 (SREBP-2), and SREBP cleavage-activating protein (SCAP). Confocal microscopy observation showed that inflammation enhanced the translocation of SCAP escorting SREBP-2 from endoplasmic reticulum to Golgi, thereby activating LDLr gene transcription. Further analysis showed that dysregulation of LDLr pathway induced by inflammation was associated with increased protein expression of mTOR (r = 0.733, P < 0.05), especially with the enhanced co-expression of mTOR and SREBP-2(P < 0.05). CONCLUSION: Inflammation accelerates the progression of foam cell formation in ESRD patients via dysregulation of LDLr pathway, which might be partly through the activation of mTOR pathway. PMID- 24059992 TI - [The effects and mechanism of Tripterygium wilfordii Hook F combination with irbesartan on urinary podocyte excretion in diabetic nephropathy patients]. AB - OBJECTIVE: To investigate the effects of the combination of tripterygium wilfordii Hook F (TwHF) and irbesartan on urinary podocyte in diabetic kidney disease (DKD) patients, and to discuss the mechanism of protective effect of TwHF on DKD. METHODS: A total of 45 type 2 diabetic kidney disease patients were enrolled into this prospective study, and were randomly divided into 3 groups: TwHF treatment group (DT, n = 15), irbesartan treatment group (DI, n = 15), and TwHF combined with irbesartan treatment group (DTI, n = 15). After 6 weeks washout, the 3 groups were given TwHF (1-2 mg.kg-1.d-1), irbesartan (150-300 mg/d), and TwHF (1-2 mg.kg-1.d-1) combined with irbesartan (150-300 mg/d) for 12 weeks respectively. Fifteen healthy volunteers served as controls. Urinary podocytes were identified and quantitated by immunofluorescence staining of urinary sediments labeled by monoclonal antibody podocalyxin. In addition, we studied urinary connective tissue growth factor (CTGF), osteopontin (OPN) and transforming growth factor beta1 (TGFbeta1) concentrations in DKD patients by enzyme-linked immunosorbent assay. RESULTS: Urinary detached podocytes were obviously higher in the urine of DKD patients than in healthy controls (P < 0.01). Podocyte detection rate was 86.6% in the urine of DKD patients. The protein expressions of CTGF, OPN and TGFbeta1 in patients with urinary podocyte were significantly increased than those without urinary podocyte (P < 0.05 or 0.01).Correlation analysis showed that there was positive correlation between urinary protein excretion and urinary podocytes (r = 0.79, P < 0.01) and there were positive correlations between the number of urinary podocytes and urinary protein expressions of CTGF, OPN and TGFbeta1 (r = 0.56, 0.41, 0.44, respectively, all P values <0.01). Urinary albumin excretion and urinary podocytes were significantly decreased in all treatment groups (P < 0.01), simultaneously, urinary concentrations of CTGF, OPN and TGFbeta1 were reduced in all groups at week 12 after intervention of TwHF, irbesartan and TwHF combined with irbesartan(P < 0.01), and these changes were more distinguished in combined treatment group (P < 0.05). CONCLUSION: Urinary podocyte in the urine may be suggested to be an early effective marker of disease activity in DKD. TwHF may be effective to prevent podocyte injury in DKD, which may be mediated, at least partly, by down-regulating the expression of CTGF, OPN and TGFbeta1. There is a synergistic protective effect of TwHF combined with irbesartan on podocyte injury in DKD patients. PMID- 24059993 TI - [A study of in vitro activity of daptomycin against 2679 Gram-positive cocci]. AB - OBJECTIVE: To evaluate the in vitro activity of daptomycin against 2679 Gram positive cocci. METHODS: A total of 2679 non-duplicate Gram-positive cocci isolates were collected from 17 teaching hospitals during January, 2010 and December, 2011. The minimal inhibitory concentrations (MICs) of daptomycin and other anti-microbial agents against 4 Gram-positive cocci were determined by micro-broth dilution method and agar dilution respectively. The data of drug susceptibility were analyzed by WHONET5.6 software. RESULTS: Methicillin resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase negative Staphylococci (MRSCoN) detection rates were 45.8% and 84.2%, respectively. The susceptibility rates of sulfamethoxazole, chloramphenicol, erythromycin, tetracycline, clindamycin and rifampicin against MRSA were 93.1%, 85.5%, 13.8%, 26.6%, 63.2% and 50.0%, respectively. The susceptibility rates of daptomycin, vancomycin and linezolid against MRSA and MRSCoN were all 100.0%. The daptomycin MIC50 and MIC90 of MRSCoN and MRSA were 0.5 mg/L. The high level gentamicin resistance rate of 513 Enterococci isolates was 56.9%. The susceptibility rates of chloramphenicol and tetracycline were 76.0% and 44.1%, respectively. The susceptibility rates of tigecycline and daptomycin reached 100.0%. The MIC50 and MIC90 of daptomycin against 17 vancomycin-resistant Enterococci (VRE) were both 2 mg/L. The susceptibility rates of daptomycin against Streptococcus pneumoniae and beta-hemolytic Streptococcus were 100.0%. The prevalence of penicillin-nonsusceptible Streptococcus pneumoniae (PNSSP) was 63.1%. The MIC50 and MIC90 of daptomycin against PNSSP were 0.125 mg/L and 0.25 mg/L, respectively according to the breakpoint of oral penicillin. The MIC50 and MIC90 daptomycin against beta-hemolytic Streptococci were 0.008 mg/L and 0.032 mg/L. CONCLUSIONS: Daptomycin have excellent in vitro activity against common Gram-positive cocci, including multi-drug resistant bacteria. It may be a good choice for clinicians to treat drug-resistant Gram-positive cocci. PMID- 24059994 TI - [A cross-sectional survey of blood pressure control in overweight or obese type 2 diabetic patients in Guangdong province]. AB - OBJECTIVE: To investigate the current situation and influential factors of blood pressure (BP) control in type 2 diabetic patients with overweight or obesity in Guangdong province. METHODS: From August 2011 to March 2012, type 2 diabetic patients with overweight or obesity were recruited from 60 hospitals in 20 cities of Guangdong province, and received standard questionnaires. The conditions of demographic data, clinical examinations, the most recent laboratory assessment, history of disease and drug therapy were recorded. RESULTS: A total of 4029 patients were collected with age of (58.9 +/- 12.9) years, and body mass index (BMI) of (27.28 +/- 2.76) kg/m2. Among the participants, controlled BP was achieved in 23.8% patients. Multiple logistic regression analysis showed that older age, obesity, previous history of hypertension and inadequate glycemic control were the independent factors related to unsatisfactory blood pressure control rate. Among the patients with hypertension, 53.5% took 1 kind of antihypertensive drug, 32.5% took two, and 11.3% took three or more. CONCLUSIONS: Type 2 diabetic patients with overweight or obesity in Guangdong province have poor BP control. Thus, active lifestyle interventions and drug therapy as a comprehensive management way should be taken for the population so as to reduce their cardiovascular events. PMID- 24059995 TI - [Exercise echocardiography in the evaluation of obstructive types of hypertrophic cardiomyopathy]. AB - OBJECTIVE: To assess the condition of left ventricular outflow tract obstruction (LVOTO) under resting conditions and physiological exercise in hypertrophic cardiomyopathy (HCM) patients. METHODS: A total of 60 patients with HCM and left ventricular outflow tract gradient (LVOTG) <50 mm Hg (1 mm Hg = 0.133 kPa) at rest were enrolled consecutively, and LVOTG at rest and exercise were measured by echocardiography. Of 51 patients with gradients <30 mm Hg at rest, 26 were latent LVOTO with exercise peak value LVOTG >= 30 mm Hg, 25 were non LVOTO with exercise peak value LVOTG < 30 mm Hg, and 9 were resting obstruction with LVOTG 30-49 mm Hg. The morphological characteristics of different types of obstruction were analyzed. RESULTS: Patients with latent LVOTO were more likely to have SAM (73.1% vs 8.0%) , narrow of LVOT (46.2% vs 4.0%) , higher resting gradients [(16.9 +/- 7.2) mm Hg vs (7.1 +/- 4.3) mm Hg] and mitral regurgitation grade at rest than patients with non-obstructive (all P values <0.05). The distribution of septal hypertrophy were different in the two groups (P < 0.05). Multivariate logistic regression analysis showed independent predictors of latent LVOTO were SAM (OR 6.431, 95%CI 2.323-291.112, P = 0.002) at rest and distribution of septal hypertrophy(OR 0.011, 95% CI 0.001-0.179, P = 0.008). CONCLUSIONS: Approximately half of patients with non-obstructive HCM at rest have latent LVOTO. SAM and distribution of septal hypertrophy may be useful to identify patients with latent obstruction. PMID- 24059996 TI - [The correlation of helper T lymphocyte 1/helper T lymphocyte 2 with clinical and image features in patients with idiopathic pulmonary fibrosis]. AB - OBJECTIVE: To identify whether the helper T lymphocyte 1 (Th1)/helper T lymphocyte 2 (Th2) of patients' serum and bronchoalveolar lavage fluid (BALF) at admission could represent the severity of idiopathic pulmonary fibrosis (IPF) and whether its change at six months could predict the progression of the disease. METHODS: Eighty-three patients with IPF were subjected to pulmonary function tests (PFTs), dyspnea scores, arterial blood gas analysis, six-minute walk test (6MWT) and high-resolution computed tomography (HRCT). The serum and BALF specimen of these patients were obtained as well as 20 control serum and 10 control BALF specimen. A total of 55 patients were followed up, and their BALF and serum levels of interferon gamma(IFNgamma) and IL-4 were detected by enzyme linked immunoadsorbent assay (ELISA). The correlation between the IFNgamma/IL-4 levels (at admission and the change of that at six months follow-up) and the clinical, physiological and image features in the IPF patients were analyzed. RESULTS: The baseline serum and BALF level of IFNgamma/IL-4 (0.8 +/- 0.3) in the IPF patients was lower than that in the control group (1.4 +/- 0.2), which showed significant correlation with the course of disease, dyspnea scores, FEV1%, FVC%, TLC%, maximum desaturation, 6MWD and CT-fib (all P values<0.05). The serum level of IFNgamma/IL-4 showed positive correlation with CT-alv (r = 0.340, P<0.01). During follow-up, no statistic difference was found in the serum levels of IFNgamma, IL-4 and IFNgamma/IL-4 between the IPF patients with or without glucocorticoids treatment. There were significant aggravation in the dyspnea scores, FEV1%, FVC%, CT-alv, CT-fib, IFNgamma and IL-4 at six months follow-up. Significant correlation had been showed between the change of the serum IFNgamma/IL-4 level with the changes of the dyspnea scores, FVC%, TLC%, DLCO%, 6MWD and CT-fib in the IPF patients (P < 0.05). CONCLUSIONS: There are disequilibrium of the Th1/Th2 in the serum and the BALF of the IPF patients. The Th1/Th2 level could represent severity of the disease, and the serum level change of Th1/Th2 in the follow-up could predict the progression of the diseases in the IPF patients. PMID- 24059997 TI - [The prevalence of congenital heart disease in students of Liangshan prefecture in Sichuan province]. AB - OBJECTIVE: To investigate the congenital heart disease (CHD) prevalence of students in Liangshan prefecture in Sichuan province, and to explore the risk factors of CHD. METHODS: Stratified cluster sampling was conducted in collecting demographic data. Heart auscultation was used to screening the CHD, and colour Doppler flow imaging was used to diagnose the CHD. RESULTS: A total of 10,021 student were collected in this study. About 19.74% of total cases had cardiac murmur. Sixty-eight students were diagnosed as CHD through colour Doppler flow imaging, accounting for 0.68%. In addition, the top three ranks of CHD were atrial septal defect, patent ductus arteriosus, interventricular septal defect. Our study also found that per capita income of CHD families was lower than non CHD families, meanwhile, the CHD prevalence of Yi nationality was higher than other nationalities. There was no statistical significance in age, gender, height, weight, body mass index, head circumference, waist circumference between different types of CHD. CONCLUSIONS: The CHD prevalence of students in Liangshan prefecture has been in a high level in China; therefore we need pay more attention on screening for the CHD. PMID- 24059998 TI - [The difference in diagnosis rate of different diagnostic criteria of autoimmune pancreatitis and its major influential factors]. AB - OBJECTIVE: To discuss the difference in diagnostic criteria of autoimmune pancreatitis(AIP) and its major influential factors, so as to provide guidance for AIP diagnosis and treatment. METHODS: The clinical data of 561 cases of chronic pancreatitis admitted to PLA General Hospital from June, 2008 to January, 2013 were retrospectively reviewed and analyzed. Data were extracted and analyzed to summarize the reasons of the differences in AIP diagnosis rate diagnosed by different diagnostic criteria. RESULTS: A total of 34 cases were eligible for the 2006 American HISORt criteria of AIP of whom, 5, 10 and 26 met the criteria of histology, pancreatic imaging findings and increasing serum IgG4 levels, and response to steroids and increasing serum IgG4 levels, respectively. Seven AIP patients met the latter two criteria. Fifteen patients were eligible for the 2008 Asian diagnostic criteria for AIP, of which, 10 met the two necessary imaging findings and 5 met the criteria of pathology of lymphoplasmacytic sclerosing pancreatitis (LPSP) after surgical resection. CONCLUSIONS: AIP is characterized by autoimmune inflammatory process, and is easy to be misdiagnosed as pancreatic cancer or cholangiocarcinoma etc. As a few sets of criteria issued from different countries, the 2008 Asian diagnostic criterion is more suitable with Chinese population. We should pay full attention to the importance of imaging examination of the diagnosis of AIP on the base of the detection of immune parameters, pathological examination and response to steroids. PMID- 24059999 TI - [The impact of dietary methionine-restriction on tight junction expression and function in a rat colonitis model]. AB - OBJECTIVE: To study the impact of methionine restriction (MetR) on mucosal histopathology, permeability and tight junction composition in a dextran sulfate sodium (DSS)-induced colitis model, and to explore its underlying mechanism. METHODS: SD rats were randomly divided into 4 groups: normal rats fed by a complete amino acid (AA group) diet, normal rats fed by MetR diet (MetR group), DSS treated rats fed by a complete amino acid (DSS+AA group) and DSS treated rats fed by MetR diet (DSS+MetR group), each group had 15 rats.Abdominal aorta blood sampling was taken at day 21 after DSS model been established to analyze blood routine examination, liver and kidney function and level of electrolyte. Morphological changes in colonic mucosa were evaluated and scored by light microscopy. Myeloperoxidase (MPO) activity was measured. The effect of MetR on mucosal permeability of colon strips was detected by Ussing chamber. Claudin2, occludin, claudin3, ZO-1 expression were quantified by Western blot. RESULTS: The early clinical manifestation in the DSS treated rats were loose stool or diarrhea, hematochezia positive and bleeding, and weight losing. HE observation showed prominent colitis in distal colon with manifestations of crypt abscess and infiltration of inflammatory cells. Although MPO activity and WBC account between the DSS+MetR and DSS+AA group did not significantly changed, treatment with MetR diet significantly decreased the extent and severity of epithelial injury of DSS+MetR group (10.55 +/- 3.62 vs 15.00 +/- 4.89, P = 0.003). There were no significant difference in PCNA immunohistochemical result between the DSS+MetR group and DSS+AA group. Compared to the rats on AA diet, transepithelial electrical resistance (TEER) in DSS+AA group was obvious lower [(28.40 +/- 6.78) Omega.cm2 vs (46.53 +/- 4.03) Omega.cm2, P < 0.05], and TEER in MetR group were obviously higher [(60.64 +/- 8.40) Omega.cm2 vs (46.53 +/- 4.03) Omega.cm2, P < 0.05]. However, short-circuit current (Isc) in DSS+MetR group was obviously higher that of DSS+AA group [(35.01 +/- 2.19) uA/cm2 vs (29.61 +/- 1.19) uA/cm2, P < 0.05]. Western blot suggested that colon claudin2 expression was not found in colon epithelium of normal rats, and an obviously increase expression of claudin3 protein was found in the MetR group, compared to AA group; and an significantly increase in the abundance of claudin3 was found in the DSS+MetR group, but amount of claudin2 was decreased, compared with the DSS+MetR group. CONCLUSION: The MetR diet has obvious therapeutic effect on ulcerative colitis model rats induced by DSS, and its mechanism may not by regulating inflammatory cell infiltration and the way of promoting intestinal cell growth to alleviate inflammatory injury, but probably by changing the structure and function of tight junction protein and improve the intestinal mucosal barrier function, and promote the repair of damaged intestinal mucosa. PMID- 24060001 TI - Effects of gravity on the velopharyngeal structures in children using upright magnetic resonance imaging. AB - Objective : The influence of gravity on the velopharyngeal structures in children is unknown. The purpose of this study is to compare the velopharyngeal mechanism in the upright and supine positions while at rest and during sustained speech production in children between 4 and 8 years old. Methods : A 0.6 Tesla open type, multipositional magnetic resonance imaging scanner was used to image subjects in the upright and supine positions. The scanning protocol included a T2 fluid attenuation inversion recovery and an oblique coronal turbo spin echo scan with short scanning durations (7.9 seconds) to enable visualization of the velopharyngeal anatomy during rest and production of sustained /i/ and /s/. Results : The magnetic resonance imaging protocol used for this study enabled successful visualization of the velopharyngeal anatomy in the sagittal and oblique coronal planes at rest and during sustained phonation of /i/ and /s/. Positional differences demonstrated a small nonsignificant (P > .05) variation for velar measures (length, thickness, and height), retrovelar space, and levator veli palatini measures (length and angles of origin). Conclusions : Gravity had a negligible effect on velar length, velar thickness, velar height, retrovelar space, levator muscle length, and levator angles of origin. Supine imaging data can be translated to an upright activity such as speech. This is the first study to provide normative levator muscle lengths for children between 4 and 8 years old. Upright imaging may be a promising tool for difficult-to-test populations. PMID- 24060002 TI - Prevalence of transposed teeth as seen on panoramic radiographs in children with cleft lip and palate. AB - OBJECTIVE: To assess the prevalence of complete and incomplete transpositions of teeth in subjects with repaired cleft lip and/or palate. DESIGN: Retrospective review. Panoramic radiographs from 364 subjects with repaired cleft lip and/or palate and with or without syndromes were compared with 364 panoramic radiographs from noncleft controls. The percentages of completely or incompletely transposed teeth, missing teeth, and pegged teeth were recorded for each subject and control. SETTING: Primary care dental clinic in a university affiliated, not-for profit hospital. MAIN OUTCOME MEASURES: Presence of complete and incomplete transposed teeth, missing teeth, and pegged teeth detected on subjects' panoramic radiographs. RESULTS: This study revealed greater prevalence of tooth transposition in subjects with cleft lip and/or palate (52/364 = 14.3%) as compared with noncleft controls (1/364 = 0.3%; P < .001). CONCLUSIONS: There was a higher prevalence of tooth transpositions in subjects with repaired cleft lip and/or palate with/or without syndromes than in noncleft controls. There was a weak association between transpositions and missing teeth (P = .12) and between transpositions and pegged teeth (.23). PMID- 24060003 TI - p-Coumaric acid, a common dietary polyphenol, protects cadmium chloride-induced nephrotoxicity in rats. AB - The present study was conducted to elucidate the protective role of p-coumaric acid, a common dietary polyphenol against cadmium induced nephrotoxicity in rats. For the purpose of comparison, a standard reference drug silymarin (50 mg/kg b. wt) was used. In this experiment, the animals were divided into four groups, with each consisting of six animals. The animals in Group I animals received saline and served as a control group and those in Group II received cadmium chloride (3 mg/kg b. wt) subcutaneously once daily for 3 weeks, but Group III and IV animals received cadmium chloride followed by p-coumaric acid (100 mg/kg b. wt, oral) and silymarin (50 mg/kg b. wt, oral), respectively, daily for 3 weeks. At the end of the treatment, the animals were sacrificed, and the blood and kidney samples were collected. The results obtained in this study revealed the fact that the levels of lipid peroxidation, lysosomal enzymes, glycoprotein, cadmium and metallothionein were increased in the cadmium chloride alone treated rats and antioxidant status was found to be decreased, when compared to the control group. The levels of kidney functional markers (urea, uric acid and creatinine) were also found to be abnormal in serum and urine of cadmium chloride alone treated rats. On the other hand, the administration of p-coumaric acid along with cadmium chloride significantly protected the biochemical alterations as observed in the cadmium chloride alone treated rats as evidenced by histopathology. Thus, the oral administration of p-coumaric acid significantly protected the cadmium induced nephrotoxicity in rats. PMID- 24060004 TI - Calreticulin expression is reduced in high-grade ovarian serous carcinoma effusions compared with primary tumors and solid metastases. AB - The objective of this study was to analyze the expression and clinical role of calreticulin, a multifunctional Ca(2+)-binding chaperone of the endoplasmic reticulum, in advanced-stage high-grade serous ovarian carcinoma. Cellular calreticulin messenger RNA (mRNA) and protein expression was investigated in 102 and 56 tumors, respectively, using reverse transcriptase polymerase chain reaction and Western blotting. Secreted calreticulin level was further analyzed in 31 effusion supernatants. Results were analyzed for association with anatomical site and clinicopathologic parameters, including survival. Calreticulin mRNA and protein were detected in 101 of 102 and 55 of 56 tumors, respectively. Calreticulin mRNA was overexpressed in solid metastases (n = 15) compared with effusions (n = 55) and primary carcinomas (n = 32; P = .009), whereas protein expression was significantly higher in solid metastases and primary carcinomas compared with effusion specimens (P = .007). Secreted calreticulin levels were higher in peritoneal compared with pleural effusions (P = .02). Higher cellular calreticulin protein expression in effusions was associated with better response to chemotherapy at diagnosis (P = .037). Calreticulin mRNA and protein expression was unrelated to patient survival. In conclusion, calreticulin is frequently expressed in serous ovarian carcinoma cells at all anatomical sites, but expression is reduced in effusions. Calreticulin protein levels in effusions may be predictive of chemotherapy response at diagnosis. PMID- 24060005 TI - Phosphaturic mesenchymal tumors show positive staining for somatostatin receptor 2A (SSTR2A). AB - Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome associated with tumors that secrete phosphaturic hormones, most notably fibroblast growth factor 23 (FGF23). The majority of tumors associated with this syndrome show stereotypical histological features and are now known as phosphaturic mesenchymal tumors (PMTs). We postulated that immunohistochemistry for somatostatin receptor 2A (SSTR2A) could be used to definitively identify PMTs or other tumors that cause TIO. Immunohistochemistry for FGF23 and SSTR2A was performed on 15 tumors from 14 patients with a definite diagnosis of TIO. All showed positive staining for both markers. While FGF23 staining was quite focal in some tumors, SSTR2A showed diffuse strong expression. In 40 control tumors not known to be associated with the clinical or biochemical features of TIO, FGF23 expression was found in 2 cases (one aneurysmal bone cyst and one osteosarcoma). SSTR2A expression was found in 9 control tumors (4 synovial sarcomas, 2 hemangiomas, 2 aneurysmal bone cysts and one osteosarcoma). Only one tumor (an aneurysmal bone cyst) showed positive staining for both FGF23 and SSTR2A. SSTR2A also commonly stained neoplastic and non-neoplastic endothelial cells. We conclude that neither FGF23 nor SSTR2A expression are specific for the diagnosis of PMT. However both stains are highly sensitive. Because of its diffuse strong expression and widespread availability, immunohistochemistry for SSTR2A is useful to confirm the diagnosis of PMT in an appropriate setting particularly if material is limited. Negative staining can serve as an excellent rule out test for this diagnosis. PMID- 24060006 TI - Age differences in hippocampus-cortex connectivity during true and false memory retrieval. AB - The present functional magnetic resonance imaging (fMRI) study investigated developmental differences in functional connectivity associated with true and false memory retrieval. A sample of 8- to 9-year-olds and adults (N = 31) was assessed with the Deese/Roediger-McDermott (DRM) paradigm, known to induce high levels of false recognition of lures that are semantically associated with studied items. The strength of semantic association among list items was manipulated. Relative to children, adults correctly recognized more studied items and falsely recognized more critical lures. High-association lists resulted in higher recognition of both studied items and critical lures. Functional connectivity analysis revealed that, overall, true recognition was supported by coupling within two hippocampal-temporal and fronto-parietal set of regions; in contrast, coupling among more distributed hippocampal-temporal-parietal-frontal regions was observed during false recognition. Critically, adults, compared to children, exhibited stronger hippocampal/parietal coupling and stronger hippocampal/dorsolateral prefrontal cortex (PFC) coupling for veridical recognition of high-associative strength items. In contrast, children, compared to adults, exhibited stronger hippocampus/ventrolateral PFC coupling and stronger bilateral middle-temporal gyrus/ventrolateral PFC coupling for high-associative strength critical lures. Our results underscored a role for the anterior hippocampus in true and false recognition, showing different functional patterns as a function of age and association strength. PMID- 24060007 TI - Genomic distribution of AFLP markers relative to gene locations for different eukaryotic species. AB - BACKGROUND: Amplified fragment length polymorphism (AFLP) markers are frequently used for a wide range of studies, such as genome-wide mapping, population genetic diversity estimation, hybridization and introgression studies, phylogenetic analyses, and detection of signatures of selection. An important issue to be addressed for some of these fields is the distribution of the markers across the genome, particularly in relation to gene sequences. RESULTS: Using in-silico restriction fragment analysis of the genomes of nine eukaryotic species we characterise the distribution of AFLP fragments across the genome and, particularly, in relation to gene locations. First, we identify the physical position of markers across the chromosomes of all species. An observed accumulation of fragments around (peri) centromeric regions in some species is produced by repeated sequences, and this accumulation disappears when AFLP bands rather than fragments are considered. Second, we calculate the percentage of AFLP markers positioned within gene sequences. For the typical EcoRI/MseI enzyme pair, this ranges between 28 and 87% and is usually larger than that expected by chance because of the higher GC content of gene sequences relative to intergenic ones. In agreement with this, the use of enzyme pairs with GC-rich restriction sites substantially increases the above percentages. For example, using the enzyme system SacI/HpaII, 86% of AFLP markers are located within gene sequences in A. thaliana, and 100% of markers in Plasmodium falciparun. We further find that for a typical trait controlled by 50 genes of average size, if 1000 AFLPs are used in a study, the number of those within 1 kb distance from any of the genes would be only about 1-2, and only about 50% of the genes would have markers within that distance. CONCLUSIONS: The high coverage of AFLP markers across the genomes and the high proportion of markers within or close to gene sequences make them suitable for genome scans and detecting large islands of differentiation in the genome. However, for specific traits, the percentage of AFLP markers close to genes can be rather small. Therefore, genome scans directed towards the search of markers closely linked to selected loci can be a difficult task in many instances. PMID- 24060009 TI - The history of Croatian Trauma Society - a brief overview. AB - Croatian Trauma Society (CTS) has a 51 year of history and tradition. This article represents a brief overview from the times when it was founded, June 30, 1961, until the present time. It tells us about the idea how, where and when the "Section for Traumatology" was founded, its activities and influence not only to promote patient trauma care but initiation of other societies dealing with traumatized patients as well, including the evolution of the CTS itself. The authors thank to all the contributors that made this article possible. PMID- 24060008 TI - Dynamical treatment of charge transfer through duplex nucleic acids containing modified adenines. AB - We address the issue of whether chemical alterations of nucleobases are an effective tool to modulate charge transfer through DNA molecules. Our investigation uses a multilevel computational approach based on classical molecular dynamics and quantum chemistry. We find yet another piece of evidence that structural fluctuations are a key factor to determine the electronic structure of double-stranded DNA. We argue that the electronic structure and charge transfer ability of flexible polymers is the result of a complex intertwining of various structural, dynamical and chemical factors. Chemical intuition may be used to design molecular wires, but this is not the sole component in the complex charge transfer mechanism through DNA. PMID- 24060010 TI - Treatment outcomes of both-bone diaphyseal paediatric forearm fractures. AB - BACKGROUND: Elastic-stable intramedullary nailing (ESIN), is an accepted method for stabilization of unstable forearm shaft fractures in children. This study analyzed the radiographic and functional outcomes of intramedullary nailing of forearm diaphyseal fractures in children. MATERIALS AND METHODS: A retrospective analysis was performed of children with forearm shaft fractures and open epiphyseal plates, treated with ESIN between 2000 and 2012 in our institution. Evaluation of cases was conducted minimum 14 months after osteosynthesis. Clinical results were evaluated according to the criteria developed by Price et al. and Flynn et al. RESULTS: The study included 88 (42 boys) children. The average age of children at day injury was 10.5 +/- 2.59 years (range 4-16), and at the review clinic was 13.4 +/- 1.85 years (range 7-18). Forty six (52.3 %) had right forearm and 42 (47.7%) had left fracture respectively. Open reduction was required in 20 (22.7%) children. Primarily surgically were treated 62 (70.5%) children and 26 (29.5%) were operated as a second procedure after failed conservative management. There was one delayed union. Rotational forearm restriction with values between 11 and 20 degrees was present in nine children. Six children developed radial nerve hypoesthesia which eventually resolved with time. After removal of the implant one child sustained a re-fracture. The overall complication rate was 25%. Complete recovery to the original condition was noted in 76 (86.4%) children, eleven children (12.5%) had good and only one (1.1%) had poor outcome. CONCLUSION: Our study suggests that ESIN osteosynthesis for diaphyseal forearm fractures remains a valid technique with very good functional results. PMID- 24060011 TI - Intraoperative measurement of bone electrical potential: a piece in the puzzle of understanding fracture healing. AB - INTRODUCTION: Bone electrical potentials change with the force applied. Also, fracture alters the bone electrical potential, so it becomes more electronegative. These potentials have an important role in fracture healing, bone growth and remodelling. Literature data on the influence of fracture operative treatment on bone electrical potentials, and possible consequences of this influence, are sparse. The objective of this study was to establish a method of intraoperative bone potential measurement, and to try to find a correlation between electrical potential and fracture type, osteosynthesis method and prognosis. PATIENTS AND METHODS: 52 patients with a pertrochanteric fracture were included in the study. Bone electrical potentials were measured intraoperatively using a thin Kirschner wire introduced through bone cortex at the selected point and pointed to opposite cortex, not penetrating it. Kirschner wires were connected using clamps to multimeter (YF-78 Multimeter) device. Neutral electrode (inductive rubber) was placed behind ipsilateral gluteus. RESULTS: Near the fracture site potentials of -199 up to -267 mV were recorded. Mean measured potential of bone plate after fixation was -240 mV. Bone potentials correlated with the subtype of fracture and early mobilisation of patients. CONCLUSIONS: Bone potentials, caused by fracture, can be measured intraoperatively; the operative procedure appears to influence their generation. Measured potentials depend on the fracture type, and could be correlated with prognosis. PMID- 24060012 TI - Operative management of unstable ankle fractures in the elderly: our institutional experience. AB - Ankle fractures represent an exceptionally common injury within the elderly population. The total incidence of ankle fractures has been reported to be up to 184 fractures per 100,000 persons per year, of which 20 to 30 percent occur in the elderly. This study reports the results of operative management of ankle fractures in the elderly, with regard to functional outcome and complication rates. This was a retrospective, non-randomized observational study. Subjects were identified from a trauma registry kept in our Department and were tested for eligibility. Patients were then categorized into two groups according to their age: Group A included all patients less than 65 years of age and Group B included all patients over the age of 65. The outcome was measured using the AOFAS Ankle Hindfoot score and a Linear analog scale. A total of 120 consecutive patients fulfilled the eligibility criteria and were included in our study (60 patients in each group). We detected statistically significant difference between the LAS score of the two groups (p=0.02), the alignment between the two groups (p=0.04) and the AOFAS score versus LAS score in Group B (p=0.03). Two patients from Group B had wound dehiscence, but finally their wounds healed uneventfully. We didn't observe any serious complications such as skin necrosis, deep infection, osteomyelitis and failure of metalwork. Our study suggests that the operative management of Weber B2 and B3 injuries can result in a favorable outcome. It is however of great importance that there are no delays in treatment, that the reduction is anatomical, that the fracture fixation is satisfactory and that the rehabilitation is commenced early. PMID- 24060013 TI - Mathematical approximation of fibular malleolus curvature. AB - While there are several manuscripts describing the articular surfaces of the ankle joint and the fibula itself, there is no study describing the outer surface and the degree of curvature of the fibular malleolus. This paper aims to approximate the sagital curvature of the outer surface of the lateral malleolus mathematically. Such data would facilitate the design of the anatomic plate that can be used for the ostheosynthesis of the fibular malleolus fracture. 30 males who were examined in the emergency department due to ankle sprains, where they underwent a standard anteroposterior x-ray of the ankle in the neutral position were recruited. The radiographs which revealed no bony injury were digitized and statistically processed. A mathematical function for each separate fibula was obtained through the processing of the digitized x-rays. When all the functions were applied to one graph, common traits of all fibulas were noted. The mean value of all functions was obtained and it corresponds to the polynomial function of degree 6. Mathematical approximation of the curvature is a simple and reliable method that can be applied to other ellipsoid human bone structures besides the ankle, thus being a valuable method in anthropometric, radiological and virtual geometric calculations. PMID- 24060014 TI - Diagnostic value of US, MR and MR arthrography in shoulder instability. AB - INTRODUCTION: The aim of our study was to compare US, conventional MRI and MR arthrography findings in patients with anterior shoulder instability and with a clinical diagnosis of labral capsular ligamentous complex lesion. At the same time we evaluated the accuracy of MR arthrography in the diagnosis of this lesion. METHODS: After approval of the local Ethics Committee, our department's Trauma Registry from July 2008 up to February 2012 was retrospectively reviewed to identify all eligible patients. Eligibility criteria included: 1)history of acute or chronic shoulder instability (more than three dislocations over a period of more than two months); 2) diagnosis of labroligamentous lesion. All patients were investigated with plain radiographs, Ultrasound Scans (US), Magnetic Resonance Imaging (MRI) and MR arthrography. Finally, all patients underwent an arthroscopy that confirmed the diagnosis. RESULTS: A total of 200 consecutive patients who met the inclusion criteria were included in this study. The mean age was 39 years (range 15 to 83); 147 were male and 133 involved the right shoulder. Chronic instability was documented in 133 patients, whereas acute instability was documented in 67 patients. We detected a statistically significant difference between US and MR arthrography in SLAP (Superior Labrum Anterior to Posterior) lesions (TypeII, III and IV), in Bankart lesions, in glenohumeral ligament lesions (superior, middle, anterior-inferior and anterior inferior glenohumeral ligament) in Hill-Sachs lesions, in diagnosing internal subacromial impingement and in normal findings. MR arthrography was superior to the US. A statistically significant difference was evident between MRI and MR arthrography findings in SLAP lesions (III and IV Type lesions), in glenohumeral ligament lesions (anterior inferior and posterior inferior glenohumeral ligament), in partial rotator cuff ruptures and in normal findings. MR arthrography diagnosed this lesion better than MRI without contrast. We also found a statistically significant difference between US and MRI findings in SLAP Type II lesions, in partial rotator cuff ruptures, in Hill-Sachs lesions and in diagnosing internal subacromial impingement. CONCLUSION: The US scan is a valuable diagnostic technique for rotator cuff complete or incomplete ruptures. For evaluating Hill Sachs lesions or bony Bankart lesions, MRI is more accurate. In the case of labral capsular ligamentous complex lesions, MR arthrography is superior. PMID- 24060015 TI - A plea for Croatian trauma system. AB - This paper provides an insight into Croatian health system with special focus on trauma care. The current situation is explained from a domestic point of view, but an independent review by foreign observers is also included. Fragmented approach to the treatment of injured patients in Croatia should be replaced by networking of health care componenets into a unique chain of help. The concept and five methodological steps in the development of a succesfull trauma system are presented. A good start is definitely a reorganization of existing knowledge on the basis of internationally licesed courses and the adoption of trauma registry as a standard for future discussion. Individual components of the trauma system can not be separately "optimized" so clinical and financial decisions should be planned exclusively on the integral level. PMID- 24060016 TI - Influence of knee flexion and atraumatic mobilisation of infrapatellar fat pad on incidence and severity of anterior knee pain after tibial nailing. AB - We evaluated the incidence and aetiology of anterior knee pain (AKP) in a series of patients that underwent intramedullary nailing for stabilisation of tibial fractures. During the preparation of the entry site no excision of the infrapatellar fat was allowed and electrical haemostasis was kept at the lowest level. Medullary canal was reamed and the nails inserted in position of knee flexion over 100 degrees. All fractures were fixed using medial paratendinous approach. Functional outcome was measured using Lysholm knee score. The knee range of movement and return to previous level of activity were also documented and analysed. Mean follow up was 38.9 months (range 12-84 months). In total 60 patients with 62 tibial shaft fractures were analysed. The mean age at the time of final follow up was 49.4 years (range 20-87). In 22 (35.5%) a newly developed and persisting pain in the anterior region of the operated knee was reported. According to VAP scale, the pain was mild (VAS 1-3) in 12 cases (19.4%) and moderate (VAS 4-6) in 10 (16.1%). In 16 cases (73%) the pain was noticed 6-12 months after injury and subjectively related to return to full range of working and recreational activities. The mean Lysholm knee score in the group without AKP was 90.8. In the AKP group with mild pain it was 88.4 and in the group with moderate AKP it was 79.9. Complete return to previous professional and recreational activities occurred in 49/60 patients (81.7%). Content with the treatment regarding expectations in recovery dynamics and return to desired level of activity was present in 98.3% of patients; one patient was unsatisfied with the treatment. Our results indicate that respecting the physiological motion of Hoffa pad and menisci during knee flexion, accompanied with atraumatic mobilisation of retrotendinous fat, reduces incidence and severity of anterior knee pain following intramedullary fixation of tibial shaft fractures. PMID- 24060017 TI - Staged management of knee dislocation in polytrauma injured patients. AB - INTRODUCTION: Knee dislocation in the polytrauma setting is rare. The optimal method that this injury should be managed remains controversial. We therefore undertook a study to evaluate the incidence and outcomes of knee dislocation in polytrauma patients treated in our institution. PATIENTS AND METHODS: From January 2005 to February 2011, two hundred-seventy five polytrauma patients were managed in our institution. Knee dislocation was present in 14 patients (4%): 4 females, mean age 46 years (range 19-52), mean ISS 24 (range 18-34) and 10 males, mean age 45 years (18-48), mean ISS 28 (range 18-48). Knee dislocation was classified according to the Schenck classification. MRI was used routinely for accurate assessment of the knee lesions. Treatment protocol consisted of initially management with the ATLS guidelines, neurovascular assessment, emergency surgical care simultaneously with reanimation procedures and hospitalization at ICU. Upon full evaluation and stabilization of the patient's physiological status and acquisition of a knee MRI scan, one- to three-stage operative treatment was performed. Decision for one- or more-stage treatment was based on the evaluation of the systemic and local clinical status, injury classification, timing of surgery, and consequences that remained after associated injuries. Clinical outcome was evaluated by IKDC 2000 Subjective knee evaluation, IKDC Clinical Examination Scales and the Tegner-Lysholm scale. A specific accelerated rehabilitation program was completed according to the surgical treatment. The mean follow up was 2 years (range 19-48 months). RESULTS: Patients had a different type of knee dislocations: five KD II, six KD III, two KD V2 and one KD V3. Clinical results were low in patients that underwent the three-staged protocol, and good and high in one- or two-staged operative treatment respectively at the two year follow up. The difference between the results in three groups of treated patients was visible but not statistically significant. CONCLUSION: The physiological state of the patient along with the type of knee lesion dictates a timing and type of stage treatment. The best postoperative clinical results are fulfilled with the one-stage treatment and it should be the first choice of knee dislocation therapy. Two-stage treatment should be performed only if the general clinical status of polytrauma injured patient or local knee status does not allow a complete knee reconstructive surgery. Three-stage treatment results with the worst outcome and it should be avoided. PMID- 24060018 TI - Acute hyperextension/valgus trauma to the elbow in top-level adult male water polo goalkeepers: a cause of osteochondritis disecans of the capitellum? AB - We report on 2 cases of hyperextension/valgus elbow injuries in two adult male national team water polo goalkeepers. Both were healthy and had never sustained any major injuries of the elbow. Mechanism and type of injury in both of them was identical. Different medical treatment protocols of these injuries possibly have led to different outcomes, with one of them developing osteochondritis dissecans (OCD). Inadequate medical treatment of acute impact elbow injuries could lead to osteochondritis disecans of the elbow in top-level adult male water polo goalkeepers. PMID- 24060019 TI - Unilateral spinal anaesthesia in a patient with Osteogenesis Imperfecta with a lower leg fracture: a case report. AB - Osteogenesis Imperfecta is a rare, genetically determined disease with several possible complications in anaesthesia. Anaesthesiologists therefore pay special attention to the treatment of patients suffering from Osteogenesis Imperfecta since they commonly suffer from a difficult airway and intraoperative positioning difficulties. We report here the case of unilateral spinal anaesthesia in a patient suffering from Osteogenesis Imperfecta type I. A 28-year-old patient diagnosed with Osteogenesis Imperfecta type I was admitted to the hospital due to lower leg fracture requiring surgical treatment. The patient had blue sclerae, triangular-shaped face, macroglossia, scoliosis of thoracic and lumbar parts of the spine, pectus carinatum and thrombocytopenia. Upon the correction of thrombocytopenia, unilateral spinal anaesthesia with hyperbaric levobupivacain was chosen in order to avoid possible complications typical for general anaesthesia. Consequently, unilateral spinal anaesthesia with a customized local anesthetic could be consdered as a safe anesthetic method for such patients. PMID- 24060020 TI - Novel external fixation fracture method with circular locking mechanism compared with the application of dynamic axial external fixator on experimental tibial model ensures better stability in bending and favourable performance in dynamic loads. AB - OBJECTIVE: The aim of this study was to compare the biomechanical properties of a novel tibial external bone fracture fixator with a circular locking mechanism with standard dynamic axial external fixator. MATERIAL AND METHODS: In order to investigate the prototype usability in experimental conditions, a biomechanical study was performed in which 42 polyacetal tubes set in 14 experimental groups and subgroups represented the fractured tibia that were fixed by a standard dynamic axial external fixator and a novel fixator. Displacements under static and dynamic loads were measured, with static ones corresponding to three directions of fragment movement and dynamic simulating the human gait. Analysis was performed in SPSS v13, with significance set at P<0.05. RESULTS: The novel fixator showed biomechanical superiority in "fragments apart" study groups, while the standard dynamic axial external fixator outperformed the novel one in the situations of bending with "fragments in contact" study groups. There were no significant differences in dynamic load, despite better numerical result of the novel fixator. CONCLUSION: The novel fixator is expectedly faster applicable and offers greater extent of external fixation flexibility. Further developments of this model thus seems justified in both construction improvement and on clinical application. PMID- 24060021 TI - Comparative study of three models of extra-articular distal humerus fracture osteosynthesis using the finite element method on an osteoporotic computational model. AB - INTRODUCTION: The biomechanical properties of extra-articular fractures of the distal humerus have not been researched sufficiently. The aim of the study was to examine three different models of osteosynthesis for extra-articular distal humerus fractures. Osteosynthesis with two parallel or perpendicular plates is a common method of osteosynthesis for those fractures. We wanted to examine the biomechanical performance of a newly designed Y plate, and compare it to the previously used osteosynthesis methods. MATERIALS AND METHODS: On an osteoporotic computational model of the distal humerus, a 10 mm gap was made, 25 mm above the olecranon fossa, and osteosynthesis was performed with the newly designed Y shaped plate and with 3.5 reconstruction plates in parallel and perpendicular configuration. The numerical simulations in axial compression, bending and varus loading were conducted using the finite element method. RESULTS: On all models the largest displacements in the area of the fracture gap appear around the lower anterior edge. The parallel plate construct had the highest stiffness among the three plating techniques in axial compression. In bending and varus loading the construct with the newly designed plate had the highest stiffness, but in axial compression demonstrated the lowest. The parallel plate configurations had higher stiffness than the perpendicular ones in all three loading directions and the difference is most pronounced in axial compression. CONCLUSION: The displacements that appeared in all three plating systems are minimal and within the limits that meet the requirements of sufficient biomechanical stability in the usual time for the healing of fractures in that region. The newly designed Y-shaped plate for extra-articular fractures of the distal humerus is a possible alternative to the usual method of osteosynthesis with two plates in the case of an extra-articular fracture of the distal humerus. Further biomechanical studies are needed for a decisive conclusion. PMID- 24060022 TI - Periprosthetic bone loss following hemiarthroplasty: a comparison between cemented and cementless hip prosthesis. AB - The aim of this prospective randomized clinical study was to evaluate the magnitude of bone mineral changes as well as the clinical results after cemented and cementless haemiarthroplasty (HA) for femoral neck fracture. The study was comprised of 60 patients (mean age 85.2 years); 30 of them underwent cemented HA and 30 cementless HA. All patients underwent osteodensitometry for the purpose of Bone Mineral Density (BMD) evaluation. BMD was measured with dual-energy X-ray absorptiometry test (DEXA scans), which was scheduled at 1 month, 6 months and 1 year after surgery. BMD was evaluated at each of the seven Gruen zones. Harris Hip Score (HHS) at 3 months, 6 months and 12 months was used for evaluation of functional outcome. No difference was found between the two groups of patients in terms hospital stay, morbidity and mortality. The procedure took longer time in group A (cemented HA) compared to group B (cementless HA) (79.03 +/- 3.59 vs 68.02 +/- 5.97 minutes; p = 0.00). The Harris hip score averaged 76.97 +/- 7.49 one year after surgery. At each follow - up examination the HHS was significantly higher in patients with cemented HA. We noted a trend of less intensive BMD reduction in all Gruen zones in group A compared to group B. However, the difference in BMD reduction between these two groups was significant only in zones 2, 3 and 4. Our results support the view that cemented hemiarthroplasty should be used for the management of displaced femoral neck fractures providing better functional outcomes and lower periprosthetic bone loss. PMID- 24060023 TI - Isolated inferior peroneal retinculum tear in professional soccer players. AB - INTRODUCTION: Peroneal tendon dislocations are rare injuries that can easily be misdiagnosed. Up to date literature mostly describes proximal peroneal tendon dislocations due to superior peroneal retinaculum (SPR) tear. In this article, we present the assessment, diagnostic algorithm and a new therapeutic option for the distal dislocation of the long peroneal tendon due to isolated inferior peroneal retinaculum (IPR) tear. PATIENTS AND METHODS: Between 2001 and 2011 three patients with distal peroneal tendon dislocation were operated. All of them were competitive athletes in the national soccer league. They presented with an ankle sprain and prolonged problems on the lateral side of the foot with no improvement after conservative therapy measures. Coleman block test was performed; ultrasound and MRI showed a tendon dislocation under the IPR. The patients underwent surgical repair that consisted of peroneal tubercle excision, a new lateral calcanear groove formation for both peroneal tendons and IPR plasty. RESULTS: At the two year follow up the American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score showed a significant increase. The decrease of painful stimuli assessed by a Visual Analogue Scale (VAS) was significant as well. At an average of 12 weeks after the surgery, the patients returned to their level of sport activity before injury and didn't report similar problems later. CONCLUSION: Description of distal peroneal tendon dislocations is limited in the literature. This topic should be considered in differential diagnostics of an acute and chronic ankle sprain which leads to chronic ankle pain and instability. The authors recommend surgical treatment as a method of choice especially in professional athletes. PMID- 24060024 TI - High pressure injection injury of the foot: a role of negative pressure wound therapy. AB - High pressure injection injuries (HPII) of the foot are not common in every-day practice. We present a 50-year-old patient with a HPII of the left foot caused by water-gun in a self-inflicted accident working as a technical diver four meters under the sea surface. Surgical treatment included extensive debridement of necrotic tissue and fibrin deposits and removal of foreign material. A negative pressure wound therapy (NPWT) device was applied resulting in a good wound base for subsequent skin grafting leading to a good functional and cosmetic outcome. PMID- 24060025 TI - [The decipher, annotation and textual researches of 7 anti-dysentery prescriptions in the Tangut medical documents unearthed in Khara-Khoto]. AB - There were 7 anti-dysentery prescriptions in the Tangut medical documents unearthed in Khara-Khoto, preserved in Russia, which were deciphered, annotated and textually researched based on the Tangut tool books like Wenhai (Word Ocean), Tongyin (Homophones), and Fan han he shi zhang zhong zhu (A Tangut-Chinese Timely Gem Dictionary), combining with classical medical documents and application of knowledge of ancient Chinese language. It can be sure that these prescriptions came from the central plains of China during the Song Dynasty, which were made use of by the prescriptions as they were by the physicians of the Western Xia regime, either made modifications and adjustments or without any change. For example, local foods like local sugar and cheese were added. As for the administration and dosage, again, they were applied by following the original one or changing a little according to the local diet customs. PMID- 24060026 TI - [Textual research on the literature sources, its related names and medicinal part of Lonicera japonica Thunb]. AB - The "jin yin hua" (Lonicera japonica Thunb.) used in the clinic nowadays is the flower of honeysuckle, excluding its stem, leave, branch, vine or the whole plant. In the early time, the name of "ren dong" (honeysuckle) or "ren dong teng" (Caulis lonicerae) didn't refer exclusively to the flower of honeysuckle. A few early literature, such as Xin xiu ben cao (Newly Revised Materia Medica) recorded briefly the flower, yet only mentions its time of blossom and shape without mentioning the medicinal use of its flower, nor the title of "jin yin hua", as the identification for this plant. Therefore, it cannot be regarded as the primary source of "jin yin hua". This research points out that the first appearance of the name of "jin yin hua" should be in Su shen liang fang (Su Shen's Effective Prescriptions) of the Song Dynasty, and the first usage of the flower "jin yin hua" as a single drug was in Wai ke jing yao (Essence of External Diseases) of the Song Dynasty. Thus, the conclusion that "jin yin hua" is first seen in Xin xiu ben cao or lv chan yan ben cao (Mountainous Materia Medica) quoted in the ninth edition of teaching material of Traditional Chinese Pharmacology, and Chinese Materia Medica are all wrong and should be corrected accordingly. PMID- 24060027 TI - [The first General Nursing School in modern northern Henan]. AB - In 1888, the Canadian Presbyterian Church went to northern Henan as "medical missionary", and established the Boji Hospital in Weihui in 1903. The Hospital was expanded in size in another site with its name changed to Huimin Hospital in 1923. For satisfying the demand of increasing patients, and creating the Care and Management System for hospital and medical treatment, the General Nursing School of Huimin Hospital was established, emphasizing a new nursing system for a clean, comfortable, bright, quiet and orderly environment, paying more attention to practice-oriented teaching method. It opened a modern nursing culture with characteristics of northern Henan, and provided referential experience to medical education in northern Henan, which had a positive influence on localization of Western medicine. PMID- 24060028 TI - [Norman Bethune and field surgery of the Eighth Route Army]. AB - With long-term war experience abroad, combined with the actual situation of health work in China, Bethune put forward a series of strategy and theory used in battlefield conditions of rescuing the wounded in China, such as "fire rescue, early debridement", "emergency blood transfusion in battlefield" and "the crowd blood bank", which effectively improved the rate of saving the battlefield wounded rate in the actual war. Combining with his own practice, he invented a variety of surgical instruments and equipment, such as "lugou bridge" medicine cabinet, "Bipp ointment", which have been widely used in the battlefield. He paid more attention to the construction of battlefield hospital, proposed the establishment of "Model Hospital" and "Special Surgery Hospital" in the rear of Anti-Japanese War, founded the health school, and wrote many battlefield medical books and skills data. Bethune trained a large number of medical personnel for the war front, laid the foundation for the field surgery education of the Eighth Route Army. PMID- 24060029 TI - [Retrospect of the history of recognition on the mechanism of heart failure and its research in the 19(th) century]. AB - There were the records of heart failure in the 6(th) century B.C. At that time, clinical observation was the main approach. The combination of observation and anatomy in the 18(th) century rendered the application of pathological anatomy in the research of etiology and pathogenesis of heart failure possible. Up to the 19(th) century, with the upsurge of modern science, the laboratory became the center of medicine. The introduction of experiment into the clinic was used in the exploration of clinical significance of changes of the diseased heart's size and shape, and the difference between cardiac hypertrophy and cardiectasis was found. The pathogenesis of these two diseases was analyzed, and the significance of compensation in cardiac hypertrophy was revealed, then the relationship of cardiovalvular disease, cardiac hypertrophy and cardiac dilatation was demonstrated. PMID- 24060030 TI - [Textual research of Hou ke mi yao (Secret Key of Laryngology)]. AB - Hou ke mi yao (Secret Key of Laryngology) was one of the most popular books of throat department in the Qing Dynasty. Because of the inscription "Xiyuan Zheng of ancient She as the author, Xu Zuo-ting of Lequan revised and enlarged", this book was generally regarded as the important work of Xin'an Zheng's family of throat department. However, after the textual research, Hou ke mi yao, in fact, was edited on the basis of Zhang Zong-liang's Hou ke zhi zhang (Guide Book for Laryngology) of the Qing Dynasty: with the second volume, "method of processing" deleted, and Wu's "verse of 24 kinds of symptom of throat diseases" (his whole name unknown) and 12 pills added. Thus, the author of Hou ke mi yao was Zhang and Wu instead of Xiyuan Zheng, and the contents reflected the academic thought of Zhang Zong-liang and Wu. According to the record of General Catalogue of the Ancient Literature of Chinese Medicine in China, there were 14 editions of Hou ke mi yao available, however, only 12 editions are extant after the investigation. In addition, there are mistakes of its author, book title and editions included in the Textual Research on Chinese Medical Literature and General Catalogue of the Ancient Literature of Chinese Medicine in China which, therefore, should be corrected. PMID- 24060031 TI - [Textual research on the distribution and circulation of Yi lei yuan rong (Fighting Diseases in Medical Field)]. AB - Written by Wang Hao-gu (1200-1264) of the Yuan Dynasty, Yi lei yuan rong (Fighting Diseases in Medical Field) includes 12 volumes, with the twelve channels as its outline. It first describes the cold pathogenic diseases, and appended with the miscellaneous diseases. It is characterized by breaking the boundaries of cold pathogenic diseases and miscellaneous diseases, not only introducing the syndrome differentiation of six channels theory into the treatment of miscellaneous diseases, but also using the prescriptions of miscellaneous diseases for the treatment of six channels syndromes. The combination of treatment of these two kinds of diseases had a clinical significance. According to General Catalogue of the Ancient Literature of Chinese Medicine in China, there were many editions of the book, including 12-volume editions and 1-volume editions. The former was written by Wang Hao-gu and the later was the abstract of the book, compiled by Du Si-jing of the Yuan Dynasty. PMID- 24060032 TI - Preventing betrayal. PMID- 24060033 TI - Psychological responses after a major, fatal earthquake: the effect of peritraumatic dissociation and posttraumatic stress symptoms on anxiety and depression. AB - Following trauma, most people with initial symptoms of stress recover, but it is important to identify those at risk for continuing difficulties so resources are allocated appropriately. There has been limited investigation of predictors of posttraumatic stress disorder following natural disasters. This study assessed psychological difficulties experienced in 101 adult treatment seekers following exposure to a significant earthquake. Peritraumatic dissociation, posttraumatic stress symptoms, anxiety, depression, and emotional support were assessed. Path analysis was used to determine whether the experience of some psychological difficulties predicted the experience of other difficulties. As hypothesized, peritraumatic dissociation was found to predict posttraumatic stress symptoms and anxiety. Posttraumatic stress symptoms then predicted anxiety and depression. Depression and anxiety were highly correlated. Contrary to expectations, emotional support was not significantly related to other psychological variables. These findings justify the provision of psychological support following a natural disaster and suggest the benefit of assessing peritraumatic dissociation and posttraumatic stress symptoms soon after the event to identify people in need of monitoring and intervention. PMID- 24060034 TI - Can sudden, severe emotional loss be a traumatic stressor? AB - Aspects of the stressor criterion for posttraumatic stress disorder (PTSD) have been controversial since its inception, and the theoretical or empirical reasons for decisions about it have not been clear. To investigate whether sudden events involving severe emotional loss have the potential to precipitate PTSD, we assessed exposure to Criterion A stressors, sudden abandonment, sudden move or loss of home, and symptoms of PTSD and dissociation in a community sample of 427 adults. In regression analyses, models that included a severe emotional loss stressor accounted for a significant amount of additional variance in PTSD and dissociation symptoms beyond that accounted for by a model including only Criterion A stressors. The findings suggest that limiting Criterion A1 to events involving actual or threatened death or injury may be overly restrictive. Future research is needed to replicate these findings in a clinical sample and to prospectively examine the conditional probability of PTSD following these events. PMID- 24060035 TI - In an idealized world: can discrepancies across self-reported parental care and high betrayal trauma during childhood predict infant attachment avoidance in the next generation? AB - Adult caregivers' idealization of their parents as assessed by the Adult Attachment Interview is a risk factor for the intergenerational transmission of the insecure-avoidant attachment style. This study evaluated a briefer screening approach for identifying parental idealization, testing the utility of prenatal maternal self-report measures of recalled betrayal trauma and parental care in childhood to predict observationally assessed infant attachment avoidance with 58 mother-infant dyads 18 months postpartum. In a logistic regression that controlled for maternal demographics, prenatal psychopathology, and postnatal sensitivity, the interaction between women's self-reported childhood high betrayal trauma and the level of care provided to them by their parents was the only significant predictor of 18-month infant security versus avoidance. Results suggest that betrayal trauma and recalled parental care in childhood can provide a means of identifying caregivers whose infant children are at risk for avoidant attachment, potentially providing an efficient means for scientific studies and clinical intervention aimed at preventing the intergenerational transmission of attachment problems. PMID- 24060036 TI - Personality assessment inventory profile and predictors of elevations among dissociative disorder patients. AB - Assessing patients with dissociative disorders (DD) using personality tests is difficult. On the Minnesota Multiphasic Personality Inventory-2 ( J. N. Butcher, W. G. Dahlstrom, J. R. Graham, A. Tellegen, & B. Kaemmer, 1989 ), DD patients often obtain elevations on multiple clinical scales as well as on validity scales that were thought to indicate exaggeration yet have been shown to be elevated among traumatized individuals, including those with DD. No research has been conducted to determine how DD patients score on the Personality Assessment Inventory (PAI; L. C. Morey, 1991 ), which includes the symptom exaggeration scale Negative Impression (NIM) and the malingering scales Malingering Index (MAL) and Rogers Discriminant Function (RDF). The goals of this study were to document the PAI profile of dissociative identity disorder (DID) and dissociative disorder not otherwise specified (DDNOS) patients and to determine how the validity and Schizophrenia scales are related to other PAI scales as well as dissociation. A total of 42 inpatients with DID or DDNOS were assessed on the PAI as well as the Dissociative Experiences Scale-II. The DID/DDNOS patients were elevated on many PAI scales, including NIM and, to a lesser extent, MAL, but not RDF. Dissociation scores significantly and uniquely predicted NIM scores above and beyond Depression and Borderline Features. In addition, after we controlled for MAL and RDF, dissociation was positively associated with NIM. In contrast, after we controlled for the other 2 scales, dissociation was not related to MAL and was negatively related to RDF, indicating that RDF and, to a lesser extent, MAL are better correlates of feigning in DD patients than NIM. PMID- 24060037 TI - Do distress responses to a traumatic film predict susceptibility to the misinformation effect? AB - The misinformation effect is defined as an impairment in memory for past events due to exposure to misleading information (E. F. Loftus, 2005 ). Some people may be more susceptible to the misinformation effect than others, and this may also depend on their response to a distressing event. The purpose of the current study was to investigate several key factors that may contribute to misinformation susceptibility for distressing events, namely posttraumatic stress disorder symptoms such as avoidance, intrusions, and dissociation. Participants watched either a neutral or trauma film, rated their level of distress, and completed measures of trait and state dissociation. When participants returned a week later, misinformation was introduced via an eyewitness statement and free recall was assessed. Findings indicated that dissociation was related to higher distress ratings following the film but was not related to acceptance of misinformation. However, avoidance scores were related to increased recall of misinformation items, and reported experiences of intrusions were related to greater accuracy. These results are discussed in light of the paradoxical negative emotion hypothesis. PMID- 24060038 TI - Commentary on "Parent-child incest that extends into adulthood: a survey of international press reports, 2007-2011" and "Ongoing incestuous abuse during adulthood" (Middleton). PMID- 24060039 TI - Response to commentary by Adah Sachs on "Parent-child incest that extends into adulthood: a survey of international press reports, 2007-2011" and "Ongoing incestuous abuse during adulthood". PMID- 24060040 TI - Commentary: The rise and persistence of dissociative identity disorder. PMID- 24060047 TI - Development-associated microRNAs in grains of wheat (Triticum aestivum L.). AB - BACKGROUND: MicroRNAs (miRNAs) are a class of regulatory small RNAs (sRNAs) that down-regulate target genes by mRNA degradation or translational repression. Numerous plant miRNAs have been identified. Evidence is increasing for their crucial roles during plant development. In the globally important crop of wheat (Triticum aestivum L.), the process by which grains are formed determines yield and end-use quality. However, little is known about miRNA-mediated developmental regulation of grain production. Here, we applied high-throughput sRNA sequencing and genome-wide mining to identify miRNAs potentially involved in the developmental regulation of wheat grains. RESULTS: Four sRNA libraries were generated and sequenced from developing grains sampled at 5, 15, 25, and 30 days after pollination (DAP). Through integrative analysis, we identified 605 miRNAs (representing 540 families) and found that 86 are possibly involved in the control of grain-filling. Additionally, 268 novel miRNAs (182 families) were identified, with 18 of them also potentially related to that maturation process. Our target predictions indicated that the 104 grain filling-associated miRNAs might target a set of wheat genes involved in various biological processes, including the metabolism of carbohydrates and proteins, transcription, cellular transport, cell organization and biogenesis, stress responses, signal transduction, and phytohormone signaling. Together, these results demonstrate that the developmental steps by which wheat grains are filled is correlated with miRNA-mediated gene regulatory networks. CONCLUSIONS: We identified 605 conserved and 268 novel miRNAs from wheat grains. Of these, 104 are potentially involved in the regulation of grain-filling. Our dataset provides a useful resource for investigating miRNA-mediated regulatory mechanisms in cereal grains, and our results suggest that miRNAs contribute to this regulation during a crucial phase in determining grain yield and flour quality. PMID- 24060048 TI - Segmental motion of forefoot and hindfoot as a diagnostic tool. AB - Segmental motions derived from non-invasive motion analysis are being used to investigate the intrinsic functional behavior of the foot and ankle in health and disease. The goal of this research was to examine the ability of a generic segmented model of the foot to capture and differentiate changes in internal skeletal kinematics due to neuromuscular disease and/or trauma. A robotic apparatus that reproduces the kinematics and kinetics of gait in cadaver lower extremities was employed to produce motion under normal and aberrant neuromuscular activation patterns of tibialis posterior and/or tibialis anterior. Stance phase simulations were conducted on 10 donor limbs while recording three dimensional kinematic trajectories of (1) skin-mounted markers used clinically to construct segmented foot models, and (2) bone-mounted marker clusters to capture actual internal bone motion as the gold standard for comparison. The models constructed from external marker data were able to differentiate the kinematic behaviors elicited by different neuromuscular conditions in a manner similar to that using the bone-derived data. Measurable differences between internal and externally measured kinematics were small, variable and random across the three axes of rotation and neuromuscular conditions, with a tendency toward more differences noted during early and late stance. Albeit slightly different, three dimensional motion profiles of the hindfoot and forefoot segments correlated well with internal skeletal motion under all neuromuscular conditions, thereby confirming the utility of measuring segmental motions as a valid means of clinical assessment. PMID- 24060049 TI - Prevalence and characteristics of compulsive buying in college students. AB - Compulsive buying (CB) is a potentially devastating problem involving repetitive urges to shop and uncontrolled spending behaviors. Prevalence of CB in the general population has been estimated at 5.8%. This epidemiological study aims to better understand the prevalence and characteristics of college students who meet criteria for CB. During the spring of 2011, an online survey examining CB (using a clinically validated screening instrument, the Minnesota Impulse Disorders Interview), stress and mood states, psychiatric comorbidity, and psychosocial functioning was emailed to 2108 University students. Overall survey response rate was 35.1% (n=2108). Our data indicated that 3.6% (n=67) of college students surveyed met criteria for CB with significantly more women affected (4.4%, n=48) than men (2.5%, n=19). Relative to students not meeting criteria for CB, college students who met criteria for CB endorsed significantly greater psychiatric comorbidity, lower grade point averages, increased stress, and poorer physical health. Presence of CB is likely associated with a variety of problems in college students. These data may warrant increased screening of CB in college students to establish early interventions. PMID- 24060050 TI - Bioconcentration of aqueous film-forming foam (AFFF) in juvenile rainbow trout (Oncorhyncus mykiss). AB - This work investigated the bioconcentration of PFASs in juvenile rainbow trout by exposing the fish in separate tanks under flow-through conditions to water continuously spiked with either of the AFFFs FC-203CF light water AFFF 3% (3M) or Niagara 1-3 (Angus Fire); a nonspiked tank served as the control. Three fish in each tank were collected after 1, 3, 6, and 11 days of exposure, and 3, 7, 14, and 25 days of depuration. Liver and carcass homogenate samples were analyzed for 20 PFASs using LC-MS/MS. PFDS, PFOS, PFHxS, and EtFOSAA were detected in fish exposed to the 3M foam, while 6:2 and 8:2 FTSASs, 6:2 and 8:2 FTSAs, 5:3 and 7:3 FTCAs were measured in fish exposed to Angus Fire foam. Bioconcentration factors and rate constants for uptake and depuration were calculated. Total and extractable organofluorine were measured in the fish samples. After fish were exposed to AFFFs, not only known PFASs but also other unknown organofluorines were bioconcentrated. Compared to the control group, significantly greater amounts (at least 10-fold) and proportion of unidentified PFASs were found in both liver and carcass homogenate ranging from ~50% in 3M foam up to 95% in the Angus Fire foam at the end of exposure. PMID- 24060051 TI - Loss of genetic diversity and inbreeding in Kashmir red deer (Cervus elaphus hanglu) of Dachigam National Park, Jammu & Kashmir, India. AB - BACKGROUND: Hangul (Cervus elaphus hanglu), the eastern most subspecies of red deer, is now confined only to the mountains in the Kashmir region of Jammu & Kashmir State of India. It is of great conservation significance as this is the last and only hope for Asiatic survivor of the red deer species in India. Wild population of free ranging hangul deer inhabiting in and around Dachigam National Park was genetically assessed in order to account for constitutive genetic attributes of hangul population using microsatellite markers. RESULTS: In a pool of 36 multi-locus genotypes, 30 unique individuals were identified based on six microsatellite loci. The estimated cumulative probability of identity assuming all individuals were siblings (PID sibs) was 0.009 (9 in 1000). Altogether, 49 different alleles were observed with mean (+/- s.e.) allelic number of 8.17 +/- 1.05, ranging from 5 to 11 per locus. The observed heterozygosity ranged between 0.08 and 0.83, with mean 0.40 +/- 0.11 and the inbreeding coefficient ranged between -0.04 and 0.87 with mean 0.38 +/- 0.15. Majority of loci (5/6) were found to be informative (PIC value > 0.5). All loci deviated from Hardy-Weinberg equilibrium except Ca-38 (P > 0.05) and none of the pairs of loci showed significant linkage disequilibrium except the single pair of Ca-30 and Ca-43 (P < 0.05). CONCLUSIONS: The preliminary findings revealed that hangul population is significantly inbred and exhibited a low genetic diversity in comparison to other deer populations of the world. We suggest prioritizing the potential individuals retaining high heterozygosity for ex situ conservation and genetic monitoring of the hangul population should be initiated covering the entire distribution range to ensure the long term survival of hangul. We speculate further ignoring genetics attributes may lead to a detrimental effect which can negatively influence the reproductive fitness and survivorship of the hangul population in the wild. PMID- 24060052 TI - Comparison of the anti-tumor effects of denosumab and zoledronic acid on the neoplastic stromal cells of giant cell tumor of bone. AB - Denosumab and Zoledronic acid (ZOL) are two antiresorptive drugs currently in use for treating osteoporosis. They have different mechanisms of action but both have been shown to delay the onset of skeletal-related events in patients with giant cell tumor of bone (GCT). However, the anti-tumor mechanisms of denosumab on the neoplastic GCT stromal cells remain unknown. In this study, we focused on the direct effects of denosumab on the neoplastic GCT stromal cells and compared with ZOL. The microscopic view demonstrated a reduced cell growth in ZOL-treated but not in denosumab-treated GCT stromal cells. ZOL was found to exhibit a dose dependent inhibition in cell growth in all GCT stromal cell lines tested and cause apoptosis in two out of three cell lines. In contrast, denosumab only exerted a minimal inhibitory effect in one cell line and did not induce any apoptosis. ZOL significantly inhibited the mRNA expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) in two GCT stromal cell lines whereas their protein levels remained unchanged. On the contrary, denosumab did not regulate RANKL and OPG expression at both mRNA and protein levels. Moreover, the protein expression of Macrophage Colony-Stimulating Factor (M-CSF), Alkaline Phosphatase (ALP), and Collagen alpha1 Type I were not regulated by denosumab and ZOL either. Our findings provide new insights in the anti-tumor effect of denosumab on GCT stromal cells and raise a concern that tumor recurrence may occur after the withdrawal of the drug. PMID- 24060053 TI - Uphill running does not exacerbate collagenase-induced pathological changes in the Achilles tendon of rats selectively bred for high-capacity running. AB - The Achilles tendon is a frequent site for degeneration, and advanced understanding of this pathology requires an animal model that replicates the human condition. The aim of this study was to explore whether intratendinous collagenase injection combined with treadmill running created a pathology in the rat Achilles tendon consistent with human Achilles tendinosis. Collagenase was injected into one Achilles tendon of 88 high-capacity running (HCR) rats, which were randomized into treadmill running and cage control groups. Running animals ran at speeds up to 30 m/min on a treadmill at a 15 degrees incline for up to 1 h/d, 5 d/week for 4 or 10 weeks. Cage control animals maintained cage activity. Collagenase induced molecular, histopathological and mechanical changes within the Achilles tendon at 4 weeks. The mechanical changes persisted at 10 weeks; however, the histopathological and majority of the molecular changes were no longer present at 10 weeks. Treadmill running had minimal effect and did not exacerbate the collagenase-induced changes as there were no statistical interactions between the interventions. These data suggest combined intratendinous collagenase injection and treadmill running does not create pathology within the Achilles tendon of rats selectively bred for HCR that is consistent with human Achilles tendinosis. PMID- 24060054 TI - Human annulus cells regulate PAPP-A and IGFBP-4 expression, and thereby insulin like growth factor bioavailability, in response to proinflammatory cytokine exposure in vitro. AB - Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase which cleaves IGF binding protein (BP)-4 in the extracellular matrix, making IGF available to nearby cells. We have shown that PAPP-A is present in the human intervertebral disc, and is significantly upregulated in more degenerated discs where increased proinflammatory cytokine levels are present. We hypothesized that increased proinflammatory cytokines present in the degenerating disc might be related to PAPP-A expression. Experiments exposed human annulus cells to IL-1 beta or TNF-alpha to test this hypothesis. Treated cells showed significantly increased PAPP-A in conditioned media versus controls (p < 0.001). PAPP-A production following exposure to IL-1beta was significantly greater in cells derived from more degenerated versus healthier discs (p = 0.05). PAPP-A gene expression (microarray analysis) was significantly upregulated in IL-1beta- or TNF-alpha-exposed cells (p = 0.01-0.004). Quantitative RT-PCR confirmed significant upregulation of IGFBP-4 in IL-1beta- or TNF-alpha-exposed cells. Data have potential relevance to future cell-based biologic therapies for disc degeneration. PMID- 24060055 TI - Hypertrophy of the ligament flavum in degenerative lumbar stenosis associated with the increased expression of fractalkine (CX3CL1)/CX3CR1 chemokine. AB - Fractalkine (CX3CL1) and its receptor (CX3CR1) comprise a chemokine system involved in leukocyte recruitment and adhesion in chronic inflammatory disease, but its role in spinal diseases is unknown. The purpose of this study is to investigate the role of CX3CL1/CX3CR1 chemokine on hypertrophy of the ligamentum flavum (LF) in degenerative lumbar stenosis (DLS) compared with that of non degenerative spinal condition (NDS) of the lumbar spine and correlation between expression of CX3CL1/CX3CR1 chemokine and thickness of LF. The mRNA concentrations of CX3CL1/CX3CR1 chemokine were analyzed in the surgically obtained LF specimens from DLS (n = 10) and NDS (n = 11) by real-time PCR. The localization of CX3CL1/CX3CR1 chemokine within the LF was determined using immunohistochemical study. Plasma levels of soluble FKN (sFKN) were measured by enzyme-linked immunosorbent assay, respectively. The thickness of the LF was measured with axial T1-weighted MRI. The cells that express CX3CL1/CX3CR1 chemokine ratio in the LF observed in DLS group were substantially higher than in NDS group. In ELISA, the plasma levels of sFKN was significantly increased in DLS compared with patients in the other groups (p = 0.006). There was greater CX3CL1/CX3CR1 expression in DLS as quantified by RT-PCR (p = 0.004, 0.010). Thickness of LF in patients was significantly correlated with serum CX3CL1 level (R(2) = 0.824, p = 0.003) and with mRNA expression of CX3CL1/CX3CR1 (R(2) = 0.671, p = 0.000) (R(2) = 0.514, p = 0.001). This study identified for the first time that increases in CX3CL1 and CX3CR1-expressing cells are significantly related to LF hypertrophy. PMID- 24060057 TI - The hippocampus and episodic memory in children. PMID- 24060056 TI - Ameliorative effect of ferulic acid against renal injuries mediated by nuclear factor-kappaB during glycerol-induced nephrotoxicity in Wistar rats. AB - The pathogenesis of glycerol-induced myoglobinuric acute renal failure involves ischemia, vascular congestion and reactive oxygen metabolites. In this study, we have investigated for the first time, the role of ferulic acid in attenuating glycerol-induced nephrotoxicity. Male Wistar rats were injected intramuscularly with 8 mL/kg body weight of 50% glycerol, glycerol + ferulic acid at the dose of 5, 10, 15, 20 and 25 mg/kg body weight. After 24 h, the rats were sacrificed and the kidneys were removed for histological and immunohistochemical studies. Furthermore, determinations of lipid peroxidation (LPO) as well as antioxidant enzymes were also analyzed; blood, urine samples were collected in order to quantify renal function and nitric oxide generation, respectively. Glycerol induced rats showed a significant increase in the level of urinary markers assessed in serum as well as kidney and these were reversed upon ferulic acid treatment. A significant increase in urine nitric oxide, serum as well as kidney LPO, decrease in activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione were observed in glycerol-induced rats. Immunohistochemical study in glycerol-induced rats demonstrated an increase in the level of nuclear factor-kappaB (NF-kappaB). All these effects induced by glycerol were reduced upon treatment with ferulic acid in a dose-dependent manner. To conclude, ferulic acid enhances antioxidants and decreases NF-kappaB, thereby protecting the cells against stress induced by glycerol. PMID- 24060058 TI - Genome-wide transcriptional response of Trichoderma reesei to lignocellulose using RNA sequencing and comparison with Aspergillus niger. AB - BACKGROUND: A major part of second generation biofuel production is the enzymatic saccharification of lignocellulosic biomass into fermentable sugars. Many fungi produce enzymes that can saccarify lignocellulose and cocktails from several fungi, including well-studied species such as Trichoderma reesei and Aspergillus niger, are available commercially for this process. Such commercially-available enzyme cocktails are not necessarily representative of the array of enzymes used by the fungi themselves when faced with a complex lignocellulosic material. The global induction of genes in response to exposure of T. reesei to wheat straw was explored using RNA-seq and compared to published RNA-seq data and model of how A. niger senses and responds to wheat straw. RESULTS: In T. reesei, levels of transcript that encode known and predicted cell-wall degrading enzymes were very high after 24h exposure to straw (approximately 13% of the total mRNA) but were less than recorded in A. niger (approximately 19% of the total mRNA). Closer analysis revealed that enzymes from the same glycoside hydrolase families but different carbohydrate esterase and polysaccharide lyase families were up regulated in both organisms. Accessory proteins which have been hypothesised to possibly have a role in enhancing carbohydrate deconstruction in A. niger were also uncovered in T. reesei and categories of enzymes induced were in general similar to those in A. niger. Similarly to A. niger, antisense transcripts are present in T. reesei and their expression is regulated by the growth condition. CONCLUSIONS: T. reesei uses a similar array of enzymes, for the deconstruction of a solid lignocellulosic substrate, to A. niger. This suggests a conserved strategy towards lignocellulose degradation in both saprobic fungi. This study provides a basis for further analysis and characterisation of genes shown to be highly induced in the presence of a lignocellulosic substrate. The data will help to elucidate the mechanism of solid substrate recognition and subsequent degradation by T. reesei and provide information which could prove useful for efficient production of second generation biofuels. PMID- 24060059 TI - Do emotional support and classroom organization earlier in the year set the stage for higher quality instruction? AB - Many teachers believe that providing greater emotional and organizational supports in the beginning of the year strengthens their ability to teach effectively as the year progresses. Some interventions, such as the Responsive Classroom (RC) approach, explicitly embed this sequence into professional development efforts. We tested the hypothesis that earlier emotional and organizational supports set the stage for improved instruction later in the year in a sample of third- and fourth-grade teachers enrolled in a randomized controlled trial of the RC approach. Further, we examined the extent to which the model generalized for teachers using varying levels of RC practices as well as whether or not teachers were in the intervention or control groups. Teachers' emotional, organizational, and instructional interactions were observed using the Classroom Assessment Scoring System (Pianta, La Paro, & Hamre, 2008) on five occasions throughout the year. Results indicated a reciprocal relation between emotional and instructional supports. Specifically, higher levels of emotional support earlier in the year predicted higher instructional support later in the year. Also, higher levels of instructional support earlier in the year predicted higher emotional support later in the year. Classroom organization was not found to have longitudinal associations with the other domains across a year. This pattern was robust when controlling for the use of RC practices as well as across intervention and control groups. Further, teachers' use of RC practices predicted higher emotional support and classroom organization throughout the year, suggesting the malleability of this teacher characteristic. Discussion highlights the connection between teachers' emotional and instructional supports and how the use of RC practices improves teachers' emotionally supportive interactions with students. PMID- 24060060 TI - A randomized controlled trial of the impact of a teacher classroom management program on the classroom behavior of children with and without behavior problems. AB - This randomized controlled trial (RCT) evaluated the efficacy of the Incredible Years (IY) Teacher Classroom Management (TCM; Webster-Stratton & Reid, 2002) program to assess whether training teachers in IY-TCM principles improve teacher behavior, whether any observed improvements impact pupil behavior classroom-wide, and whether these effects can be demonstrated with children at risk of developing conduct problems. Six intervention and six control classrooms comprising 12 teachers and 107 children (aged 3 to 7years) were recruited. Children were screened for high or low behavior problems using the cut-off points of the teacher-rated Strengths and Difficulties Questionnaire (Goodman, 1997). The primary outcome measure was independent classroom observations using the Teacher Pupil Observation Tool (Martin et al., 2010). Multilevel modeling analyses were conducted to examine the effect of the intervention on teacher, classroom, and child behavior. Results showed a significant reduction in classroom off-task behavior (d=0.53), teacher negatives to target children (d=0.36), target child negatives towards the teacher (d=0.42), and target child off-task behavior (d=0.48). These preliminary results demonstrate the potential impact of IY-TCM on both teacher and child behavior. PMID- 24060061 TI - Mechanisms of change in adolescent life satisfaction: a longitudinal analysis. AB - This study explored the psychosocial mechanisms of change associated with differences in levels and linear change of adolescents' global life satisfaction across a 2-year time period. Based on a theoretical model proposed by Evans (1994), this study tested the relations between selected personality (i.e., extraversion and neuroticism) and environmental (stressful life events) variables and global life satisfaction when mediated by internalizing and externalizing problems. The results suggested support for internalizing problems as a mediator of the relationship of personality and environmental variables with life satisfaction. Pathways mediated by internalizing problems significantly predicted levels and linear change of life satisfaction across a 2-year time span. Furthermore, pathways mediated by externalizing problems significantly predicted the level but not the linear change of life satisfaction. Thus, behavior problems and their antecedents appear to relate significantly to adolescents' perceptions of their quality of life. Implications for adolescent mental health promotion were discussed. PMID- 24060062 TI - Examining classroom influences on student perceptions of school climate: the role of classroom management and exclusionary discipline strategies. AB - There is growing emphasis on the use of positive behavior supports rather than exclusionary discipline strategies to promote a positive classroom environment. Yet, there has been limited research examining the association between these two different approaches to classroom management and students' perceptions of school climate. Data from 1902 students within 93 classrooms that were nested within 37 elementary schools were examined using multilevel structural equation modeling procedures to investigate the association between two different classroom management strategies (i.e., exclusionary discipline strategies and the use of positive behavior supports) and student ratings of school climate (i.e., fairness, order and discipline, student-teacher relationship, and academic motivation). The analyses indicated that greater use of exclusionary discipline strategies was associated with lower order and discipline scores, whereas greater use of classroom-based positive behavior supports was associated with higher scores on order and discipline, fairness, and student-teacher relationship. These findings suggest that pre-service training and professional development activities should promote teachers' use of positive behavior support strategies and encourage reduced reliance on exclusionary discipline strategies in order to enhance the school climate and conditions for learning. PMID- 24060063 TI - Teacher-child relationships and academic achievement: a multilevel propensity score model approach. AB - A robust body of research finds positive cross-sectional and longitudinal associations between teacher-child relationships and children's academic achievement in elementary school. Estimating the causal effect of teacher-child relationships on children's academic achievement, however, is challenged by selection bias at the individual and school level. To address these issues, we used two multilevel propensity score matching approaches to estimate the effect of high-quality teacher-child relationships in kindergarten on math and reading achievement during children's transition to first grade. Multi-informant data were collected on 324 low-income, Black and Hispanic students, and 112 kindergarten and first-grade teachers. Results revealed significant effects of high-quality teacher-child relationships in kindergarten on math achievement in first grade. No significant effects of teacher-child relationships were detected for reading achievement. Implications for intervention development and public policy are discussed. PMID- 24060064 TI - In search of average growth: describing within-year oral reading fluency growth across Grades 1-8. AB - Measures of oral reading fluency (ORF) are perhaps the most often used assessment to monitor student progress as part of a response to intervention (RTI) model. Rates of growth in research and aim lines in practice are used to characterize student growth; in either case, growth is generally defined as linear, increasing at a constant rate. Recent research suggests ORF growth follows a nonlinear trajectory, but limitations related to the datasets used in such studies, composed of only three testing occasions, curtails their ability to examine the true functional form of ORF growth. The purpose of this study was to model within year ORF growth using up to eight testing occasions for 1448 students in Grades 1 to 8 to assess (a) the average growth trajectory for within-year ORF growth, (b) whether students vary significantly in within-year ORF growth, and (c) the extent to which findings are consistent across grades. Results demonstrated that for Grades 1 to 7, a quadratic growth model fit better than either linear or cubic growth models, and for Grade 8, there was no substantial, stable growth. Findings suggest that the expectation for linear growth currently used in practice may be unrealistic. PMID- 24060065 TI - The relation of parenting, child temperament, and attachment security in early childhood to social competence at school entry. AB - A wealth of research demonstrates the importance of early parent-child interactions on children's social functioning. However, less is known about the interrelations between child and parent characteristics and parent-child interactions in early childhood. Moreover, few studies have broadly examined the longitudinal relations between these constructs and social competence. This study is an examination of the relations between parent responsiveness, negativity, and emotional supportiveness, attachment security, and child temperament, and their impact on children's social competence from infancy to kindergarten entry. The sample was derived from the Early Childhood Longitudinal Study--Birth Cohort and included 6850 parent-child dyads. Observational and rating scale data were used. The proposed model was nearly fully supported by path analysis, and it provides insight into the complex relations between early parenting behaviors, child characteristics, and parent-child interactions in the development of social competence. PMID- 24060066 TI - [Focus on the conceptual change of pancreatic neoplasms]. PMID- 24060067 TI - [Introduction of WHO classification of tumours of soft tissue, the fourth edition]. PMID- 24060068 TI - [Clinicopathologic characteristics of fibrous mass-forming chronic pancreatitis]. AB - OBJECTIVE: To investigate clinicopathological features of fibrous mass-forming chronic pancreatitis (FMCP), to compare clinicopathological and immunohistochemical characteristics between autoimmune pancreatitis (AIP) and fibrous mass-forming non-autoimmune pancreatitis (nAIP) and to provide evidence for pathological diagnosis, differential diagnosis and clinical treatment strategy. METHODS: Clinicopathological features were analyzed in 81 cases of FMCP. Infiltrating IgG4(+) plasmacytes were counted by immunohistochemical staining. RESULTS: Among 81 cases of FMCP, 20 cases were diagnosed as AIP and 61 cases were interpreted as nAIP. AIP was more common in males over 50 years, whereas nAIP was seen in much younger patients (P = 0.001). The amount of inflammatory cells in the stroma of AIPs was remarkable higher than that in nAIPs (P = 0.002). The incidence of neuritis in AIPs (100%, 20/20) was also higher compared with that of nAIPs (75.4%, 46/61; P = 0.017). Storiformed-fibrosis was more common in AIPs (95.0%, 19/20) than in nAIPs (1.6%, 1/61;P = 0.000). Pancreatic intraepithelial neoplasia (PanIN) was observed in 50.0%(10/20) of AIPs and 32.8%(20/61) of nAIPs, with a greater severity observed in AIPs (P = 0.031). Tubular complex (TC) was more commonly observed in AIPs (65.0%, 13/20) than nAIPs (26.2%, 16/61;P = 0.002). Among 81 cases of FMCP, 61 cases had less than 11 IgG4(+) plasmacytes /HPF, 7 cases had 10-30/HPF and 13 cases had over 30/HPF. CONCLUSIONS: FMCPs include both AIP and nAIP. AIP has distinct pathological features and the presence of IgG4(+) plasmacyte is an important diagnostic parameter. FMCP appears to be an important precancerous lesion of pancreatic ductal adenocarcinoma. Surgery may be considered for patients with FMCP due to its mass-forming nature. In contrast, patients with AIP are treated medically due to its steroid-responsiveness. Therefore, accurate and timely diagnosis of AIP is of clinical relevance to avoid unnecessary surgical complications and to prevent progression of the disease. PMID- 24060069 TI - [Evaluation of the expression and significance of Claudin-5 and CD99 in solid pseudopapillary neoplasms and neuroendocrine tumors of pancreas]. AB - OBJECTIVE: To investigate the expression of endothelium tight junction protein Claudin-5 and intercellular adhesion molecule CD99 in solid-pseudopapillary neoplasms (SPN) and neuroendocrine tumors of pancreas (P-NET), and their significance in the differential diagnoses. METHODS: Immunohistochemical staining of Claudin-5 and CD99 was performed in 37 cases SPN and 21 cases of P-NET. RESULTS: Membranous Claudin-5 expression was observed in all cases of SPN but was absent in all cases of P-NET. The difference was significant (P < 0.01). In SPN, 91.9% (34/37) of the cases displayed paranuclear dot-like immunoreactivity for CD99; in contrast, 61.9% (13/21) of the cases of P-NET displayed membranous staining (P < 0.01). There was a positive association between the expression of Claudin-5 and CD99 in SPN (r = 0.421,P = 0.001). CONCLUSIONS: Although the macroscopic and microscopic features of SPN are quite characteristic, they may not allow confident differentiation from P-NET in all cases, especially when these characteristics are not classical. If necessary, immunostaining for Claudin 5 and CD99 can help to differentiate between these entities. PMID- 24060070 TI - [Primary hepatic angiosarcoma: a clinical and pathological analysis]. AB - OBJECTIVE: To investigate the clinicopathological characteristics, differential diagnosis, and prognosis of primary hepatic angiosarcoma, and to review the literature. METHODS: Twenty cases of primary hepatic angiosarcoma were analyzed by gross examination and light microscopy. Immunostaining was performed to detect the expression of CD34, CD31, FVIIIRAg, CK, GPC-3, Hepatocyte,vimentin, PTEN, desmin, and CD117. RESULTS: The age of the patients ranged from 7 to 86 years. Eleven cases were male, and 9 were female. All cases showed no specific clinical manifestations and imaging results. Macroscopically, the tumors showed diffuse multi-nodular or single nodular patterns with hemorrhage. Microscopically, there were various patterns such as cavernous vascular space and epithelioid hemangioendothelioma-like appearances; however, specific pathological diagnostic features of angiosarcoma still existed in all cases. All of the cases expressed at least one of the three immunohistochemical markers: CD31, CD34 and/or FVIIIRag. Ten cases had PTEN low expression. Ki-67 proliferative index was more than 10% in all cases. None of cases expressed desmin, CD117, GPC-3 or Hepatocyte. CONCLUSIONS: Primary hepatic angiosarcoma is a rare malignant tumor. Detailed morphological observation and using various vascular endothelial immunohistochemical markers can help to establish the diagnosis accurately. PMID- 24060071 TI - [Immunohistochemical study of perivascular epithelioid cell neoplasms]. AB - OBJECTIVE: To study the clinicopathologic features, immunophenotype and genetic changes of perivascular epithelioid cell neoplasms (PEComa). METHODS: A total of 25 cases of PEComa located in various anatomic sites were selected for immunohistochemical staining (SP or EnVision method). TFE3 fluorescence in-situ hybridization was also performed to determine the TFE3 gene status. RESULTS: The age of patient ranged from 21 to 61 years (mean = 43 years). The male-to-female ratio was 1: 1.3. Histologically, 22 cases represented conventional angiomyolipomas, composed of a mixture of adipose tissue, spindle element, epithelioid smooth muscle cells and abnormal thick-walled blood vessels in various proportions. Three cases involving lung, soft tissue and broad ligament had subtle but distinctive morphologic features. Nested or sheet-like architecture with epithelioid or spindle cells was observed. Immunohistochemical study showed that HMB 45, melan A, smooth muscle actin and cathepsin K were expressed in 80% (20/25), 88% (22/25), 88% (22/25) and 100% (25/25) of PEComa, respectively. Within positive cases, the average proportion of positive tumor cells was 36%, 41%, 35% and 90% respectively for HMB 45, melan A, smooth muscle actin and cathepsin K. TFE3 was negative in all of the 22 renal and hepatic PEComa studied, while it was positive in the 3 cases of extra-hepatorenal PEComa. None of the 25 cases exhibited evidence of TFE3 gene fusion or amplification. CONCLUSIONS: Extra-hepatorenal PEComa have distinctive morphologic features and are associated with TFE3 overexpression. Cathepsin K immunostaining demonstrates high sensitivity and specificity in PEComa, better than other commonly employed immunomarkers. This marker is thus useful in diagnosis of PEComa and distinction with other neoplasms. PMID- 24060072 TI - [Expression and significance of IgG4 in inflammatory disease of nasal cavity and paranasal sinuses]. AB - OBJECTIVE: To study the prevalence of IgG4-positive plasma cells in inflammatory disease of nasal cavity and paranasal sinuses and its association with IgG4 related sclerosing disease (IgG4-SD). METHODS: The expression of IgG4 and IgG in plasma cells of 103 cases diagnosed as inflammatory disease of nasal cavity and paranasal sinuses with dense lymphoplasmacytic infiltrate was studied by immunohistochemistry (EnVision) and quantitatively analyzed by medical image analysis system. RESULTS: Immunohistochemical study showed marked infiltration by IgG4-positive plasma cells (>50 per high-power field) in 28 cases, moderate infiltration (30 to 50 per high-power field) in 23 cases, mild (10 to 29 per high power field) in 30 cases and negative (<10 per high-power field) in 22 cases (P < 0.05). Twenty-two cases studied fulfilled the diagnostic criteria of IgG4-SD (>50 IgG4-positive plasma cells per high-power field and IgG4-to-IgG ratio > 40%), including 3 cases of chronic sinusitis (3/20), 3 cases of nasal polyps (3/18), 3 cases of inflammatory pseudotumor (3/17), 4 cases of fungal sinusitis (4/20), 1 case of rhinoscleroma (1/12), 7 cases of Wegener's granulomatosis (7/11) and 1 case of Rosai-Dorfman disease (1/2). CONCLUSION: Inflammatory disease of nasal cavity and paranasal sinuses fulfilling the diagnostic criteria IgG4-SD is not uncommon. Definitive diagnosis of IgG4-SD requires correlation with other clinical and laboratory findings. Some cases of unexplained inflammatory disease of nasal cavity and paranasal sinus may represent a member of the IgG4-SD spectrum. IgG4 carries diagnostic value in differential diagnosis of inflammatory disease occurring in nasal cavity and paranasal sinuses. PMID- 24060073 TI - [Target prediction and verification of miR-27a in pancreatic cancer]. AB - OBJECTIVE: To predict and verify the target gene of miR-27a in pancreatic cancer by combining the result of comparative proteome analysis. METHODS: The bioinformatics softwares of TargetScan,PicTar and miRanda were used to predict the possible target genes of miR-27a. Based on the results of comparative proteomics analysis, possible candidates of the target genes were selected. Expression vector of target gene 3'UTR was constructed, and then target gene was verified by dual-luciferase reporter assay system. The PANC-1 and BxPC-3 pancreatic cancer cells were treated with miR-27a mimics or negative control for 48 h. Western blot analysis was used to verify alterations of protein expression of the genes. RESULTS: PSMA1 was selected as the candidate target gene of miR-27a by bioinformatics prediction and comparative proteome analysis. Dual-luciferase reporter assay showed that miR-27a decreased luciferase activity in cells co transfected with pmirGLO-PSMA1-WT, compared to the negative control, although significant difference of luciferase activity was not observed in cells co transfected with pmirGLO-PSMA1-MUT between the two groups. The protein level of PSMA1 was down-regulated in pancreatic cancer cells transfected with miR-27a mimics in comparison with pancreatic cancer cells transfected with negative control. CONCLUSION: PSMA1 is the direct target gene of miR-27a in pancreatic cancer. PMID- 24060074 TI - [Expression of miR-191 and miR-221 in hepatocellular carcinoma and its clinical significance]. PMID- 24060075 TI - [Clinicopathologic study of adamantinoma]. PMID- 24060076 TI - [Relationship between HPVtype16/18 status and the development of cervical intraepithelial neoplasia]. PMID- 24060077 TI - [Consensus on dignosis for ALK positive non-small cell lung cancer in China, the 2013 version]. PMID- 24060078 TI - [Nemaline myopathy: report of a case]. PMID- 24060079 TI - [Malignant adenomyoepithelioma of breast with lymph node metastasis: report of a case]. PMID- 24060080 TI - [Nodular mucinosis of breast: report of a case and literature review]. PMID- 24060081 TI - [Update on hepatocellular nodular lesions]. PMID- 24060082 TI - [Molecular pathology, histopathologic features and differential diagnosis of sarcomatoid carcinoma of urinary bladder]. PMID- 24060083 TI - [Detection and assessment of Ki-67 in breast cancer]. PMID- 24060084 TI - [Introduction of 2010 WHO classification of pancreatic tumors]. PMID- 24060085 TI - [Diagnosis, histopathologic grading and prognostic moleculer marker analysis in patients with pancreatic neuroendocrine neoplasm]. PMID- 24060087 TI - Measurement, standards, and data needs for CO2 capture materials: a critical review. AB - The commercial deployment of cost-effective carbon capture technology is hindered partially by the lack of a proper suite of materials-related measurements, standards, and data, which would provide critical information for the systematic design, evaluation, and performance of CO2 separation materials. Based on a literature search and conversations with the carbon capture community, we review the current status of measurements, standards, and data for the three major carbon capture materials in use today: solvents, solid sorbents, and membranes. We highlight current measurement, standards and data activities aimed to advance the development and use of carbon capture materials and major research needs that are critical to meet if innovation in carbon capture materials is to be achieved. The review reveals that although adsorbents are considered to have great potential to reduce carbon capture cost, there is no consensus on the experimental parameters to be used for evaluating sorbent properties. Another important finding is the lack of in situ experimental tools for the structural characterization of solid porous materials during CO2 adsorption, and computational methods that would enable a materials-by-design approach for their development. PMID- 24060088 TI - Ropivacaine plus dexamethasone infiltration reduces postoperative pain after tonsillectomy and adenoidectomy. AB - OBJECTIVE: To compare the effect of ropivacaine plus dexamethasone and ropivacaine alone as infiltration anesthesia on postoperative pain, nausea and vomiting, and oral intake in children after tonsillectomy and adenoidectomy. METHODS: Two hundred pediatric patients scheduled for tonsillectomy and adenoidectomy were prospectively enrolled and randomly placed in a ropivacaine with dexamethasone group (RD) or a ropivacaine alone group (R). Treatment for both groups was administered by local infiltration, and pain scores were recorded at various intervals. Primary outcomes were pain scores recorded 4-24h postoperation. Secondary outcomes included time to the first administration of analgesic and total consumption of analgesics for all children, time to first water request, first oral intake, incidence of nausea or vomiting, and time to discharge. RESULTS: From postoperative hours 4-24, children in the RD group had lower pain scores than children in the R group (P < 0.05). Total fentanyl consumption was significantly decreased in the RD group compared to the R group (50.9 +/- 9.3 vs. 103.9 +/- 11.5 MUg, P < 0.001). The time to first water request and first oral intake were significantly shorter in the RD group [(40 min (27-64) vs. 64 min (43-89); P < 0.001) and (54 min (40-91) vs. 85 min (67-127); P < 0.001), respectively]. Oral intake was significantly improved, and the incidence of nausea and vomiting were reduced in the RD group (P < 0.05). The time to discharge was shorter in the RD group when compared with the R group (9.06 +/- 0.89 d vs. 7.05 +/- 0.71 d; P < 0.001). CONCLUSIONS: Ropivacaine plus dexamethasone infiltration effectively lowers pain, improves oral intake, lowers postoperative nausea and vomiting, and decreases the time to discharge. PMID- 24060089 TI - The otolaryngologic manifestations of Sotos syndrome. AB - OBJECTIVE: Soto's syndrome is a genetic disorder caused by mutations in the NSD1 gene. It is characterized by excessive growth in early life. It features craniofacial abnormalities, developmental delay, hypotonia and advanced bone age. A review of the current literature reveals only chronic otitis media and conductive hearing loss as otolaryngologic manifestations of Soto's syndrome. Our objective was to determine if there are additional manifestations relevant to the otolaryngologist. METHODS: We performed a retrospective case series in which the Department of Defense electronic medical record was searched for ICD 9 code 253.0 (acromegaly/gigantism). Records were reviewed for genetic testing indicative of Soto's syndrome. These records were further analyzed for evidence of otolaryngologic problems. RESULTS: Seventeen patients were identified with five having confirmed NSD1 mutations consistent with Soto's syndrome. Of these, 4/5 had otolaryngologic problems such as conductive hearing loss, aspiration, laryngomalacia, obstructive sleep apnea and sensorineural hearing loss. CONCLUSIONS: Currently there is no description in the literature of these additional manifestations of Soto's syndrome. We present this case series to support the idea that an otolaryngologist should be involved in the multidisciplinary care required for these patients. PMID- 24060090 TI - An unusual case of a large fibroepithelial stromal polyp presenting as a nipple mass. AB - BACKGROUND: Fibroepithelial stromal polyps (FESP) are benign lesions that typically occur in the genital area and are known to represent a diagnostic challenge for pathologists. Not only do they have a spectrum of morphological changes that ranges from bland morphology to rather atypical appearances, but they also share morphological features with a number of benign and malignant lesions.This is a report of a rare presentation of a FESP of the breast. CASE PRESENTATION: We describe an unusual case of a large polypoid mass arising from the nipple and connected to it by a long pedicle in a female of 45. The lesion comprised spindle and stellate shaped cells with bizarre stromal giant cells. The morphological and immunohistochemical diagnostic features are provided together with a discussion of possible mimics. CONCLUSION: FESPs may occur in the female breast. It is important to differentiate the lesion from other benign and malignant spindle cell lesions particularly metaplastic carcinoma. PMID- 24060091 TI - Construction of a high-density genetic map for sesame based on large scale marker development by specific length amplified fragment (SLAF) sequencing. AB - BACKGROUND: The genetics and molecular biology of sesame has only recently begun to be studied even though sesame is an important oil seed crop. A high-density genetic map for sesame has not been published yet due to a lack of sufficient molecular markers. Specific length amplified fragment sequencing (SLAF-seq) is a recently developed high-resolution strategy for large-scale de novo SNP discovery and genotyping. SLAF-seq was employed in this study to obtain sufficient markers to construct a high-density genetic map for sesame. RESULTS: In total, 28.21 Gb of data containing 201,488,285 pair-end reads was obtained after sequencing. The average coverage for each SLAF marker was 23.48-fold in the male parent, 23.38 fold in the female parent, and 14.46-fold average in each F2 individual. In total, 71,793 high-quality SLAFs were detected of which 3,673 SLAFs were polymorphic and 1,272 of the polymorphic markers met the requirements for use in the construction of a genetic map. The final map included 1,233 markers on the 15 linkage groups (LGs) and was 1,474.87 cM in length with an average distance of 1.20 cM between adjacent markers. To our knowledge, this map is the densest genetic linkage map to date for sesame. 'SNP_only' markers accounted for 87.51% of the markers on the map. A total of 205 markers on the map showed significant (P < 0.05) segregation distortion. CONCLUSIONS: We report here the first high density genetic map for sesame. The map was constructed using an F2 population and the SLAF-seq approach, which allowed the efficient development of a large number of polymorphic markers in a short time. Results of this study will not only provide a platform for gene/QTL fine mapping, map-based gene isolation, and molecular breeding for sesame, but will also serve as a reference for positioning sequence scaffolds on a physical map, to assist in the process of assembling the sesame genome sequence. PMID- 24060092 TI - Physical inactivity, insulin resistance, and the oxidative-inflammatory loop. AB - Epidemiological data indicate that physical inactivity, a main factor of global energetic imbalance, is involved in the worldwide epidemic of obesity and metabolic disorders such as insulin resistance. Although the complex pathogenesis of insulin resistance is not fully understood, literature data accumulated during the past decades clearly indicate that the activation of the oxidative inflammatory loop plays a major role. By activating the oxidative-inflammatory loop in insulin-sensitive tissues, fat gain and adipose tissue dysfunction likely contribute to induce insulin resistance during chronic and prolonged physical inactivity. However, in the past years, evidence has emerged showing that early insulin resistance also occurs after very short-term exposure to physical inactivity (1-7 days) without any fat gain or energetic imbalance. The possible role of liver disturbances or endothelial dysfunction is suggested, but further studies are necessary to really conclude. Inactive skeletal muscle probably constitutes the primary triggering tissue for the development of early insulin resistance. In the present review, we discuss on the current knowledge about the effect of physical inactivity on whole-body and peripheral insulin sensitivity, and how local inflammation and oxidative stress arising with physical inactivity could potentially induce insulin resistance. We assume that early muscle insulin resistance allows the excess nutrients to shift in the storage tissues to withstand starvation through energy storage. We also consider when chronic and prolonged, physical inactivity over an extended period of time is an underestimated contributor to pathological insulin resistance and hence indirectly to numerous chronic diseases. PMID- 24060093 TI - Properties of the retention time of ionizable analytes in reversed-phase liquid chromatography under organic modifier gradients in different eluent pHs. AB - This work provides a theoretical basis for an empirical model proposed in Fasoula et al. (2013) [2] for the retention of monoprotic acids/bases during linear organic modifier gradient runs performed with a fixed change of organic content but for different gradient durations and in different eluent pHs. Based on the analytical expressions derived in the above publication for the retention of monoprotic solutes under organic modifier gradients in different mobile phase pHs it was proved that the dependences of retention time of all monoprotic acids/bases upon each of two factors governed the gradient elution under consideration are always the following: practically linear upon gradient duration (for constant pH) and sigmoid upon pH (for constant gradient duration). PMID- 24060094 TI - A simple and automated method to determine macrocyclic musk fragrances in sewage sludge samples by headspace solid-phase microextraction and gas chromatography mass spectrometry. AB - For the first time, headspace solid-phase microextraction (HS-SPME) has shown to be a powerful technique to extract macrocyclic musk fragrances directly from sewage sludge. It avoids the need to use additional extraction/preconcentration techniques or clean-up procedure and facilitates the automation of the method. Thus, a simple and fully automated method based on HS-SPME and GC-MS has been developed which allows the determination of eight macrocyclic musk fragrances at ngg(-1) (d.w.) levels. The optimal HS-SPME conditions were achieved when a PDMS/DVB 65MUm fibre was exposed for 45min in the headspace of 0.25g sewage sludge samples mixed with 0.5mL of water stirred at 750rpm at 80 degrees C. Optimal desorption conditions were found to be 250 degrees C for 3min. Method detection limits were found in the low pgg(-1) range between 10pgg(-1) (d.w.) and 25pgg(-1) (d.w.) depending on the target analytes. In addition, under optimized conditions, the method gave good levels of intra-day and inter-day repeatabilities in sewage sludge with relative standard deviations varying between 1% to 9% and 6% to 15% respectively (n=5, 1000pgg(-1) d.w.). The applicability of the method was tested with sewage sludge from three urban sewage treatment plants (STPs). The analysis revealed the presence of the macrocyclic musks studied in several samples, with concentrations ranging between below MQL (method quantification limit) and 0.89ngg(-1) (d.w.). PMID- 24060095 TI - Exploring the basis for parents' negative reactions to being informed that their child is overweight. AB - OBJECTIVE: Increasing parental awareness of childhood obesity is an important part of tackling the issue. However, parents' negative reactions to being informed that their children are overweight or obese can hinder their engagement with relevant services. The present study aimed to develop a deeper understanding of why parents react negatively, to help commissioners and service providers design services that are more acceptable to them. DESIGN: Open, qualitative responses to a survey were collected using a postal questionnaire. Responses were analysed using content analysis. SETTING: One local authority in south-west England. SUBJECTS: The sample frame included all parents receiving letters informing them that their child was overweight (91st-98th centile) or very overweight (98th-100th centile) through the UK National Child Measurement Programme in 2012. RESULTS: Forty-five of 313 eligible parents (14 %) responded to the survey, of whom forty-three rejected either to the judgement that their child was overweight and/or being provided with this feedback. Primary reasons for objection included: lack of trust in the measures used, lack of belief that being overweight is important for children's health (relative to a healthy lifestyle), and fear that discussing weight with children will trigger eating disorders. In addition, parents' responses suggested that they considered receiving this feedback to be a criticism of their parenting skills. CONCLUSIONS: Overall, three areas for improving communication with parents were suggested: tailoring letters; providing information about the importance of weight independently of lifestyle; and addressing parents' concerns about the risks of talking to children about their weight. PMID- 24060096 TI - Rapid fetal fibronectin testing to predict preterm birth in women with symptoms of premature labour: a systematic review and cost analysis. AB - BACKGROUND: Premature birth is defined as birth of before 37 completed weeks' gestation. Not all pregnant women showing symptoms of preterm labour will go on to deliver before 37 weeks' gestation. Hence, addition of fetal fibronectin (fFN) testing to the diagnostic workup of women with suspected preterm labour may help to identify those women who do not require active management, and thus avoid unnecessary interventions, hospitalisations and associated costs. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of rapid fFN testing in predicting preterm birth (PTB) in symptomatic women. DATA SOURCES: Bibliographic databases (including EMBASE, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials) were searched from 2000 to September/November 2011. Trial registers were also searched. REVIEW METHODS: Systematic review methods followed published guidance; we assessed clinical effectiveness and updated a previous systematic review of test accuracy. Risk of bias was assessed using the Cochrane tool (randomised controlled trials; RCTs) and a modification of QUADAS-2 (diagnostic test accuracy studies; DTAs). Summary risk ratios or weighted mean difference were calculated using random-effects models. Summary sensitivity and specificity used a bivariate summary receiver operating characteristic model. Heterogeneity was investigated using subgroup and sensitivity analyses. Health economic analysis focused on cost consequences. The time horizon was hospital admission for observation. A main structural assumption was that, compared with usual care, fFN testing doesn't increase adverse events or negative pregnancy outcomes. RESULTS: Five RCTs and 15 new DTAs were identified. No RCT reported significant effects of fFN testing on maternal or neonatal outcomes. One study reported a subgroup analysis of women with negative fFN test observed > 6 hours, which showed a reduction in length of hospital stay where results were known to clinicians. Combining data from new studies and the previous systematic review, the pooled estimates of sensitivity and specificity were: 76.7% and 82.7% for delivery within 7-10 days of testing; 69.1% and 84.4% for delivery < 34 weeks' gestation; and 60.8% and 82.3% for delivery < 37 weeks' gestation. Estimates were similar across all subgroups sensitivity analyses. The base-case cost analysis resulted in a cost saving of L23.87 for fFN testing compared with usual care. The fFN testing was cost-neutral at an approximate cost of L45. Probabilistic sensitivity analysis gave an incremental cost (saving) of L25.59 (97.5% confidence interval -L304.96 to L240.06), indicating substantial uncertainty. Sensitivity analyses indicated that admission rate had the largest impact on results. CONCLUSIONS: Fetal fibronectin testing has moderate accuracy for predicting PTB. The main potential role is likely to be reducing health-care resource usage by identifying women not requiring intervention. Evidence from RCTs suggests that fFN does not increase adverse outcomes and may reduce resource use. The base-case analysis showed a modest cost difference in favour of fFN testing, which is largely dependent on whether or not fFN testing reduces hospital admission. Currently, there are no high-quality studies and the existing trials were generally underpowered. Hence, there is a need for high-quality adequately powered trials using appropriate study designs to confirm the findings presented. STUDY REGISTRATION: PROSPERO 2011:CRD42011001468. Available from www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42011001468. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 24060097 TI - The pill hustle: risky pain management for a gunshot victim. AB - How do gunshot victims manage pain without health care? This paper examines this question through ethnographic data of a single gunshot victim who self-medicated with Percocet. The observations for this paper were collected in Philadelphia between January of 2010 and October of 2011, and were part of a larger ethnographic study that included 40 gunshot victims recruited from an outpatient trauma clinic. Although this victim was able to manage his pain, he ultimately became addicted to Percocet and became entangled in the personal stress and conflicts of his pill hustlers. His story shows how health care insecurity can funnel victims of gun violence into increasingly risky ventures to find pain relief. The findings from this study show the pressing need to expand rehabilitative care to all gunshot victims. PMID- 24060098 TI - Molecular identification and antimicrobial susceptibility of Nocardia spp. isolated from bovine mastitis in Brazil. AB - Nocardia spp. infections can cause severe damage to the mammary gland due to suppurative pyogranulomatous lesions and lack of clinical cure in response to conventional antimicrobial therapy. Although Nocardia infections are considered relatively uncommon in cows, there has been an apparent worldwide increase in the incidence of bovine mastitis caused by Nocardia spp, perhaps due to environmental transmission of this ubiquitous pathogen. The objectives of present study were to determine: (i) species distribution of 80 Nocardia isolates involved in bovine mastitis (based on molecular methods); and (ii) antimicrobial susceptibility pattern of all isolates from three geographical areas in Brazil. In this study, Nocardia nova (80%) was the most frequently isolated species, followed by Nocardia farcinica (9%). Additionally, Nocardia puris, Nocardia cyriacigeorgica, Nocardia veterana, Nocardia africana, and Nocardia arthritidis were detected using 16S rRNA sequencing. This is apparently the first report of N. puris, N. veterana, N. cyriacigeorgica, N. arthritidis and N. africana in association with bovine mastitis. Based on the disk diffusion test, isolates were most frequently resistant to cloxacillin (75%), ampicillin (55%) and cefoperazone (47%), whereas few Nocardia spp. were resistant to amikacin, cefuroxime or gentamicin. PMID- 24060099 TI - Phylogeny and genetic diversity of foot and mouth disease virus serotype Asia1 in India during 1964-2012. AB - Foot and mouth disease virus (FMDV) serotype Asia1 was first identified in India in 1951 and since then causing significant proportion of FMD outbreaks in the country. In this paper genetic analysis of 219 isolates from India collected over a period of 48 years is described. Bayesian approach was used to estimate the date of divergence and evolutionary rate. Phylogenetic analysis indicated the circulation of three lineages (B, C and D) of which lineage B formed one genotype (I) which was prevalent during 1964-2000. Genotype II constituted by lineage C and D has been in circulation since 1979 till date. We observed dramatic form of clade turnover in serotype Asia1 in India. The time scale analysis indicated that the most recent common ancestors for Indian Asia1 strains existed around 77 years ago. The evolutionary rate of serotype Asia1 viruses (genotype II) from India was estimated at 5.871*10(-3) substitutions per site, per year. We observed several connections in our phylogeographic analysis indicating intense flow of virus among states. The antigenically critical sites were frequently substituted and positive selection was evident at many sites. Maximum likelihood analysis suggested that the strains circulating in the country since 2005 were different from the genetic groups (I-VII) identified earlier and designated here as Group VIII. PMID- 24060100 TI - Serological evidence of exposure to Coxiella burnetii in sheep and goats in central Portugal. AB - The recent outbreak of Q fever in The Netherlands warned European health authorities of the need of studying Coxiella burnetii. In Portugal, little is known about C. burnetii infection in animals. A cross-sectional study was designed to investigate the exposure to C. burnetii in sheep and goats in the Central region of Portugal, estimating the herd and individual prevalence. A serosurvey was conducted in a two levels random sampling of 89 herds and 460 animals. Individual blood samples were collected from animals older than 6 months, and specific antibodies anti-C. burnetii were detected by ELISA testing. Results showed a global herd prevalence of 32.6% (95% CI: 23.1-42.1%). Herd prevalence was higher in mixed herds (38.5%; 95% CI: 12-65%) and in sheep herds (37.5%; 95% CI: 21-54%) than in goat herds (28.8%; 95% CI: 17-41%). Global individual prevalence was estimated at 9.6% (95% CI: 6.9-12.2%), and it was higher in goats (10.4%; 95% CI: 7.8-13%) than in sheep (8.6%; 95% CI: 5.8-11.4%). Sample positive percentages (S/P) ranged from 41.5% to 185.9%. S/P percent higher than 100 was found in 18.2% (8/44) of sera from distinct herds. Positive results were significantly associated with goats, older animals and larger herds. These results revealed the presence of C. burnetii in small ruminants evidencing their potential role in the infection cycle. PMID- 24060101 TI - Hot bath for the treatment of chronic renal failure. AB - BACKGROUND: Dialysis and its complications were debated recently. There was lack of an adjuvant renal replacement method to reduce the complications of patients with chronic renal failure and dialysis itself. MATERIALS AND METHODS: In this article, we reviewed the role of thermal sweating in treating of the patients with chronic renal failure, and the role of traditional Chinese medicine in the therapy of chronic kidney diseases. RESULTS: Thermal sweating can reduce interdialytic weight gain and improve the patients' blood pressure; Chinese herbal medicine can promote the excretion of uremic toxicities and relieve the skin disorders of these patients. CONCLUSIONS: Traditional Chinese medicine mediated hot bath could be one of the adjuvant renal replacement methods. PMID- 24060102 TI - Comparative genomics of metabolic capacities of regulons controlled by cis regulatory RNA motifs in bacteria. AB - BACKGROUND: In silico comparative genomics approaches have been efficiently used for functional prediction and reconstruction of metabolic and regulatory networks. Riboswitches are metabolite-sensing structures often found in bacterial mRNA leaders controlling gene expression on transcriptional or translational levels.An increasing number of riboswitches and other cis-regulatory RNAs have been recently classified into numerous RNA families in the Rfam database. High conservation of these RNA motifs provides a unique advantage for their genomic identification and comparative analysis. RESULTS: A comparative genomics approach implemented in the RegPredict tool was used for reconstruction and functional annotation of regulons controlled by RNAs from 43 Rfam families in diverse taxonomic groups of Bacteria. The inferred regulons include ~5200 cis-regulatory RNAs and more than 12000 target genes in 255 microbial genomes. All predicted RNA regulated genes were classified into specific and overall functional categories. Analysis of taxonomic distribution of these categories allowed us to establish major functional preferences for each analyzed cis-regulatory RNA motif family. Overall, most RNA motif regulons showed predictable functional content in accordance with their experimentally established effector ligands. Our results suggest that some RNA motifs (including thiamin pyrophosphate and cobalamin riboswitches that control the cofactor metabolism) are widespread and likely originated from the last common ancestor of all bacteria. However, many more analyzed RNA motifs are restricted to a narrow taxonomic group of bacteria and likely represent more recent evolutionary innovations. CONCLUSIONS: The reconstructed regulatory networks for major known RNA motifs substantially expand the existing knowledge of transcriptional regulation in bacteria. The inferred regulons can be used for genetic experiments, functional annotations of genes, metabolic reconstruction and evolutionary analysis. The obtained genome-wide collection of reference RNA motif regulons is available in the RegPrecise database (http://regprecise.lbl.gov/). PMID- 24060103 TI - Building better drugs: developing and regulating engineered therapeutic proteins. AB - Most native proteins do not make optimal drugs and thus a second- and third generation of therapeutic proteins, which have been engineered to improve product attributes or to enhance process characteristics, are rapidly becoming the norm. There has been unprecedented progress, during the past decade, in the development of platform technologies that further these ends. Although the advantages of engineered therapeutic proteins are considerable, the alterations can affect the safety and efficacy of the drugs. We discuss both the key technological innovations with respect to engineered therapeutic proteins and advancements in the underlying basic science. The latter would permit the design of science-based criteria for the prediction and assessment of potential risks and the development of appropriate risk management plans. This in turn holds promise for more predictable criteria for the licensure of a class of products that are extremely challenging to develop but represent an increasingly important component of modern medical practice. PMID- 24060105 TI - Cognitive science in popular film: the Cognitive Science Movie Index. AB - HAL 9000. Morpheus. Skynet. These household names demonstrate the strong cultural impact of films depicting themes in cognitive science and the potential power of popular cinema for outreach and education. Considering their wide influence, there is value to aggregating these movies and reflecting on their renderings of our field. The Cognitive Science Movie Index (CSMI) serves these purposes, leveraging popular film for the advancement of the discipline. PMID- 24060104 TI - Stereoselective formation of mono- and dihydroxylated polychlorinated biphenyls by rat cytochrome P450 2B1. AB - Changes in atropisomer composition of chiral polychlorinated biphenyls (PCBs) and their mono- and dihydroxylated metabolites (OH- and diOH-PCBs) via rat cytochrome P450 2B1 (CYP2B1) mediated biotransformation were investigated in vitro. Rat CYP2B1 could stereoselectively biotransform chiral PCBs to generate meta-OH-PCBs as the major metabolites after 60 min incubations. Nonracemic enantiomer fractions (EFs: concentration ratios of the (+)-atropisomer or the first-eluting atropisomer over the total concentrations of two atropisomers) of 5-OH-PCBs, were 0.17, 0.20, 0.85, 0.77, and 0.41 for incubations with PCBs 91, 95, 132, 136, and 149, respectively. CYP-mediated stereoselective formation of diOH-PCBs from OH PCBs was observed for the first time. After 60 min stereoselective biotransformation, the EFs of both 4-OH-PCB 95 and 5-OH-PCB 95 changed from racemic (i.e., 0.50) to 0.62 and 0.46, respectively. These transformations generated statistically nonracemic 4,5-diOH-PCB 95, with EFs of 0.53 and 0.58 for 4-OH-PCB 95 and 5-OH-PCB 95 incubations, respectively. Biotransformation of PCBs 91 and 136 also generated 4,5-diOH-PCB 91 and 4,5-diOH-PCB 136, respectively. These in vitro results were consistent with that observed for stereoselective PCB biotransformation by rat liver microsomes and in vivo. Biotransformation interference between two atropisomers of PCB 136 was investigated for the first time in this study. The biotransformation process of (-)-PCB 136 was significantly disrupted by the presence of (+)-PCB 136 but not the other way around. Thus, stereoselective metabolism of chiral PCBs and OH-PCBs by CYPs is a major mechanism for atropisomer composition change of PCBs and their metabolites in the environment, with the degree of composition change dependent, at least in part, on stereoselective interference of atropisomers with each other at the enzyme level. PMID- 24060107 TI - Differential improvement in depressive symptoms for tDCS alone and combined with pharmacotherapy: an exploratory analysis from the Sertraline vs. Electrical Current Therapy for Treating Depression Clinical Study. AB - Transcranial direct current stimulation (tDCS) is a promising therapy for major depression treatment, although little is known of its effects in ameliorating distinct symptoms of depression. Thus, it is important, not only to increase knowledge of its antidepressant mechanisms, but also to guide its potential use in clinical practice. Using data from a recent factorial, double-blinded, placebo controlled trial applying tDCS-alone and combined with sertraline to treat 120 depressed outpatients over 6 wk (Brunoni et al., 2013), we investigated the pattern of improvement in symptoms of depression from the Montgomery-Asberg depression scale (MADRS). First, we performed one multivariate analysis of variance with the score improvement of the 10 MADRS items as dependent variables. Significant (p < 0.05) results were further explored with follow-up analyses of variance. TDCS (alone and combined with sertraline) improved concentration difficulties and pessimistic and suicidal thoughts. The combined treatment also improved apparent and reported sadness, lassitude and inability to feel. Indeed, tDCS/sertraline significantly ameliorated all but the 'vegetative' depression symptoms (inner tension, sleep and appetite items). We further discuss whether bifrontal tDCS over the dorsolateral prefrontal cortex could be associated with improvement in cognitive (concentration) and affective (pessimistic/suicidal thoughts) processing, while the combined treatment might have a more widespread antidepressant effect by simultaneously acting on different depression pathways. We also identified patterns of antidepressant improvement for tDCS that might aid in tailoring specific interventions for different subtypes of depressed patients, e.g. particularly those with suicidal ideation. PMID- 24060106 TI - A non-pharmacologic approach to address challenging behaviors of Veterans with dementia: description of the tailored activity program-VA randomized trial. AB - BACKGROUND: Behavioral symptoms accompanying dementia are associated with increased health care costs, reduced quality of life and daily functioning, heightened family caregiver burden, and nursing home placement. Standard care typically involves pharmacologic agents, but these are, at best, modestly effective, carry serious risks, including mortality, and do not address behavioral symptoms families consider most distressful and which may prompt nursing home placement. Given dementia's devastating effects and the absence of an imminent cure, the Veterans Administration has supported the development and testing of new approaches to manage challenging behaviors at home. METHODS/DESIGN: The Tailored Activity Program - Veterans Administration is a Phase III efficacy trial designed to reduce behavioral symptoms in Veterans with dementia living with their caregivers in the community. The study uses a randomized two-group parallel design with 160 diverse Veterans and caregivers. The experimental group receives a transformative patient-centric intervention designed to reduce the burden of behavioral symptoms in Veterans with dementia. An occupational therapist conducts an assessment to identify a Veteran's preserved capabilities, deficit areas, previous roles, habits, and interests to develop activities tailored to the Veteran. Family caregivers are then trained to incorporate activities into daily care. The attention-control group receives bi monthly telephone contact where education on topics relevant to dementia is provided to caregivers. Key outcomes include reduced frequency and severity of behavioral symptoms using the 12-item Neuropsychiatric Inventory (primary endpoint), reduced caregiver burden, enhanced skill acquisition, efficacy using activities, and time spent providing care at 4 months; and long-term effects (8 months) on the Veteran's quality of life and frequency and severity of behavioral symptoms, and caregiver use of activities. The programs' impact of Veterans Administration cost is also examined. Study precision will be increased through face-to-face research team trainings with procedural manuals and review of audio taped interviews and intervention sessions. DISCUSSION: The Tailored Activity Program - Veterans Administration is designed to improve the quality of life of Veterans with dementia and lessen the burden of care on caregivers. Activities are tailored to reflect the Veteran's preserved capabilities and interests to enhance active engagement, while not taxing areas of cognition that are most impaired. PMID- 24060108 TI - Melatonin suppresses nitric oxide production in glial cultures by pro inflammatory cytokines through p38 MAPK inhibition. AB - Melatonin has been shown to down-regulate inflammatory responses and provide neuroprotection. However, the mechanisms underlying the anti-inflammatory properties of melatonin are poorly understood. In the present work, we studied the modulatory effect of melatonin against pro-inflammatory cytokines in glial cell cultures. Treatment with pro-inflammatory cytokines mainly tumor necrosis factor-alpha, interleukin 1-beta, and interferon-gamma induces an increase in inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. Pre-treatment with melatonin produced an inhibitory effect on iNOS expression and NO production. The biochemical studies revealed that cytokine treatment favors the activation of several pathways, such as mitogen-activated protein kinases (MAPKs), STAT1, and STAT3; however, the anti-inflammatory effect of melatonin was accompanied only by a decrease in p38 MAPK activity. Likewise, SB203580 a p38 kinase inhibitor inhibits NO production. These data indicate that the anti-inflammatory action of melatonin in glial cells after stimulation with pro-inflammatory cytokines may be in part, attributable to p38 inhibition which down-regulates iNOS expression and NO production. PMID- 24060109 TI - Modulation in prototropism of the photosensitizer Harmane by host:guest interactions between beta-cyclodextrin and surfactants. AB - The present contribution demonstrates the photophysics of a prospective cancer cell photosensitizer Harmane (HM) belonging to the family of beta-carboline in mixed microheterogeneous environments of beta-cyclodextrin (beta-CD) and surfactants having varying surface charges using steady-state and time-resolved fluorescence spectroscopic techniques. The remarkable modulations in prototropic activities of the micelle-bound drug in the presence of beta-CD evinces for disruption of the micellar structural integrity by beta-CD. The results are meticulously discussed in relevance to the effect of a potential drug delivery vehicle (CD) on the membrane-mimetic micellar system. Further, application of an extrinsic fluorescence probe for monitoring such interactions is fraught by the possibilities of no less than three equilibria that can operate simultaneously viz., (i) surfactant-cyclodextrin, (ii) surfactant-fluorophore and (iii) cyclodextrin-fluorophore. This aspect highlights the enormous importance of the issue of suitability of the fluorescence probe to study such complicated systems and interaction phenomena. Also the varying interaction scenario of beta-CD with the nature of the surfactant highlights the importance of precise knowledge of the strength and locus of drug binding in delineating such complex interactions. The results of the present investigation advocate for the potential applicability of the drug (HM) itself as a fluorescence reporter in study of such complex microheterogeneous interactions. PMID- 24060110 TI - Myocarditis with fulminant type 1 diabetes mellitus diagnosed by cardiovascular magnetic resonance imaging: a case report. AB - BACKGROUND: Fulminant type 1 diabetes is a non-autoimmune disorder characterized by sudden onset. This complication is rarely associated with myocarditis, suggesting an involvement of viral infection. We report a patient with myocarditis who was admitted for fulminant type 1 diabetes and diagnosed using a combination of non-invasive techniques. CASE PRESENTATION: We describe the case of a 25-year-old Japanese man with fulminant type 1 diabetes complicated by myocarditis. The patient was admitted with flu-like symptoms and diabetic ketoacidosis, followed by chest pain the next day. Myocardial damage was suspected based on ST-segment elevation on electrocardiogram and elevation of cardiac enzymes. However, coronary angiography revealed no abnormality in the coronary arteries. We diagnosed myocarditis by a combination of echocardiography, cardiovascular magnetic resonance imaging (CMR), as well as Thallium-201 and Iodine-123 beta-methyl iodophenyl pentadecanoic acid (Tl-201 BMIPP and I-123 BMIPP) and myocardial imaging. More importantly, CMR revealed diffuse enhancement in the subepicardium of the left ventricle with late gadolinium enhancement, consistent with myocardial edema. The patient was successfully treated, received a two-week education program on diabetes and discharged without complication. CONCLUSIONS: The rapid onset and flu-like symptoms strongly suggest the involvement of viral infection in the pathogenesis of fulminant type 1 diabetes and myocarditis. While cardiac muscle biopsy is routinely performed, this case demonstrates that a combination of non-invasive techniques, especially CMR, may successfully diagnose myocarditis in patients with fulminant type 1 diabetes. PMID- 24060111 TI - Head-up tilt testing for diagnosing vasovagal syncope: a meta-analysis. PMID- 24060112 TI - Acupuncture for essential hypertension. AB - BACKGROUND: To systematically assess the current clinical evidence of acupuncture for hypertension. SEARCH STRATEGY: The PubMed, EMBASE, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wan-fang Data in the Cochrane Library were searched until January, 2013. All the randomized controlled trials (RCTs) based on acupuncture compared with western medicine, sham acupuncture or lifestyle intervention in patients with hypertension were included. RCTs were included as well as combined acupuncture with western medicine compared with western medicine. In addition, RCTs based on acupuncture compared with sham acupuncture combined with western medicine in patients with essential hypertension were included. No language restriction was used. Review Manager 5.1 software was used for data analysis. Study selection, data extraction, quality assessment, and data analyses were conducted according to the Cochrane standards. RESULTS: 35 randomized trials (involving 2539 patients) were included. The methodological quality of the included trials was evaluated as generally low. Two trials reported the effect of acupuncture compared with sham acupuncture in combinations of western medicine. Acupuncture significantly reduced SBP (-7.47 mmHg, 95% CI - 10.43 to -4.5, P<0.00001) and DBP (-4.22 mmHg, 95% CI - 6.26 to 2.18, P<0.0001) and no heterogeneity between studies was detected. However, other studies had substantial heterogeneity due to the quality of them was poor, and their sample sizes were not satisfactory as an equivalence study. Five trials described the adverse effects. CONCLUSIONS: While there are some evidences that suggest potential effectiveness of acupuncture for hypertension, the results were limited by the methodological flaws of the studies. Therefore, further thorough investigation, large-scale, proper study designed, randomized trials of acupuncture for hypertension will be required to justify the effects reported here. PMID- 24060113 TI - In-solution fluorescence in situ hybridization and fluorescence-activated cell sorting for single cell and population genome recovery. AB - Over the past decade, technological advances in whole genome amplification, microfluidics, flow sorting, and high-throughput sequencing have led to the development of single-cell genomics. Single-cell genomic approaches are typically applied to anonymous microbial cells with only morphology providing clues to their identity. However, targeted separation of microorganisms based on phylogenetic markers, such as the 16S rRNA gene, is beginning to emerge in the single-cell genomics field. Here, we describe an in-solution fluorescence in situ hybridization (FISH) protocol which can be combined with fluorescence-activated cell sorting (FACS) for separation of single cells or populations of interest from environmental samples. Sequencing of DNA obtained from sorted cells can be used for the recovery of draft quality genomes, and when performed in parallel with deep metagenomics, can be used to validate and further scaffold metagenomic assemblies. We illustrate in this chapter the feasibility of this FISH-FACS approach by describing the targeted recovery of a novel anaerobic methanotrophic archaeon. PMID- 24060114 TI - Whole cell immunomagnetic enrichment of environmental microbial consortia using rRNA-targeted Magneto-FISH. AB - Magneto-FISH, in combination with metagenomic techniques, explores the middle ground between single-cell analysis and complex community characterization in bulk samples to better understand microbial partnerships and their roles in ecosystems. The Magneto-FISH method combines the selectivity of catalyzed reporter deposition-fluorescence in situ hybridization (CARD-FISH) with immunomagnetic capture to provide targeted molecular and metagenomic analysis of co-associated microorganisms in the environment. This method was originally developed by Pernthaler et al. (Pernthaler et al., 2008; Pernthaler & Orphan, 2010). It led to the discovery of new bacterial groups associated with anaerobic methane-oxidizing (ANME-2) archaea in methane seeps, as well as provided insight into their physiological potential using metagenomics. Here, we demonstrate the utility of this method for capturing aggregated consortia using a series of nested oligonucleotide probes of differing specificity designed to target either the ANME archaea or their Deltaproteobacteria partner, combined with 16S rRNA and mcrA analysis. This chapter outlines a modified Magneto-FISH protocol for large- and small-volume samples and evaluates the strengths and limitations of this method predominantly focusing on (1) the relationship between FISH probe specificity and sample selectivity, (2) means of improving DNA yield from paraformaldehyde-fixed samples, and (3) suggestions for adapting the Magneto-FISH method for other microbial systems, including potential for single-cell recovery. PMID- 24060115 TI - Coupling FACS and genomic methods for the characterization of uncultivated symbionts. AB - Symbioses between microbes are likely widespread and functionally relevant in diverse biological systems; however, they are difficult to discover. Most microbes remain uncultivated, symbioses can be relatively rare or dynamic, and intercellular connections can be delicate. Thus, traditional methods such as microscopy are inadequate for efficient discovery and precise characterization of novel interactions, their metabolic basis, and the species involved. High throughput metagenomic sequencing of entire microbial communities has revolutionized the field of microbial ecology; however, genomic signals from symbionts can get buried in sequences from abundant organisms and evidence for direct links between microbial species cannot be gained from bulk samples. Thus, a specialized approach to the characterization of symbioses between naturally occurring microbes is required. This chapter presents methods for combining fluorescence-activated cell sorting to isolate and separate uncultivated symbionts with molecular biology techniques for DNA amplification in order to characterize uncultivated symbionts through genomic and metagenomic techniques. PMID- 24060117 TI - Quantifying and identifying the active and damaged subsets of indigenous microbial communities. AB - Flow cytometry and fluorescent dyes represent valuable experimental tools for studying complex microbial communities, enabling the quantification and sorting of cells with distinct levels of activity or damage, and providing information that can be difficult to infer from metagenomic sequencing alone. Despite this potential, these single-cell methods have seldom been applied to the study of host-associated microbial communities. Here, we present our recently developed protocols utilizing four distinct fluorescent dyes that label cells based on nucleic acid content, respiratory activity, and membrane damage. These methods have been successfully applied to study the trillions of microorganisms inhabiting the human gastrointestinal tract (the gut microbiota), in addition to a collection of isolates from five common gut-associated bacterial phyla. By merging these protocols with fluorescence-activated cell sorting and downstream multiplex 16S rRNA gene sequencing, it is possible to rapidly assess the taxonomic composition of each physiological category. These methods provide an initial step toward a robust toolkit allowing a rapid, culture-independent, and comprehensive assessment of the physiology and metabolic activity of host associated microbial communities. PMID- 24060118 TI - Preparation of BAC libraries from marine microbial populations. AB - A protocol is presented here for the construction of BAC (bacterial artificial chromosome) libraries from planktonic microbial communities collected in marine environments. The protocol describes the collection and preparation of the planktonic microbial cells, high molecular weight DNA purification from those cells, the preparation of the BAC vector, and the special ligation and electrotransformation procedures required for successful library preparation. With small modifications, this protocol can be applied to microbes collected from other environments. PMID- 24060116 TI - Optofluidic cell selection from complex microbial communities for single-genome analysis. AB - Genetic analysis of single cells is emerging as a powerful approach for studies of heterogeneous cell populations. Indeed, the notion of homogeneous cell populations is receding as approaches to resolve genetic and phenotypic variation between single cells are applied throughout the life sciences. A key step in single-cell genomic analysis today is the physical isolation of individual cells from heterogeneous populations, particularly microbial populations, which often exhibit high diversity. Here, we detail the construction and use of instrumentation for optical trapping inside microfluidic devices to select individual cells for analysis by methods including nucleic acid sequencing. This approach has unique advantages for analyses of rare community members, cells with irregular morphologies, small quantity samples, and studies that employ advanced optical microscopy. PMID- 24060119 TI - Preparation of fosmid libraries and functional metagenomic analysis of microbial community DNA. AB - One of the most important challenges in contemporary microbial ecology is to assign a functional role to the large number of novel genes discovered through large-scale sequencing of natural microbial communities that lack similarity to genes of known function. Functional screening of metagenomic libraries, that is, screening environmental DNA clones for the ability to confer an activity of interest to a heterologous bacterial host, is a promising approach for bridging the gap between metagenomic DNA sequencing and functional characterization. Here, we describe methods for isolating environmental DNA and constructing metagenomic fosmid libraries, as well as methods for designing and implementing successful functional screens of such libraries. PMID- 24060120 TI - Preparation of metagenomic libraries from naturally occurring marine viruses. AB - Microbes are now well recognized as major drivers of the biogeochemical cycling that fuels the Earth, and their viruses (phages) are known to be abundant and important in microbial mortality, horizontal gene transfer, and modulating microbial metabolic output. Investigation of environmental phages has been frustrated by an inability to culture the vast majority of naturally occurring diversity coupled with the lack of robust, quantitative, culture-independent methods for studying this uncultured majority. However, for double-stranded DNA phages, a quantitative viral metagenomic sample-to-sequence workflow now exists. Here, we review these advances with special emphasis on the technical details of preparing DNA sequencing libraries for metagenomic sequencing from environmentally relevant low-input DNA samples. Library preparation steps broadly involve manipulating the sample DNA by fragmentation, end repair and adaptor ligation, size fractionation, and amplification. One critical area of future research and development is parallel advances for alternate nucleic acid types such as single-stranded DNA and RNA viruses that are also abundant in nature. Combinations of recent advances in fragmentation (e.g., acoustic shearing and tagmentation), ligation reactions (adaptor-to-template ratio reference table availability), size fractionation (non-gel-sizing), and amplification (linear amplification for deep sequencing and linker amplification protocols) enhance our ability to generate quantitatively representative metagenomic datasets from low input DNA samples. Such datasets are already providing new insights into the role of viruses in marine systems and will continue to do so as new environments are explored and synergies and paradigms emerge from large-scale comparative analyses. PMID- 24060121 TI - Preparation and metatranscriptomic analyses of host-microbe systems. AB - Metatranscriptomics has increased our working knowledge of the functional significance and genetic variability of microbial communities, yet there is still limited information concerning how gene expression and regulation in a microbiome influences interactions with a host organism. During a pathogenic infection, eukaryotic organisms are subject to invasion by bacteria and other agents, or these "pathogens" can switch from a commensal to pathogenic trophic relationship with the host. Understanding how these trophic relationships initiate and persist in the host requires deciphering the functional response of the host and the microbiome, so-called Dual RNA-Seq. This technique is both fast and relatively cheap compared to proteomics and metabolomics and provides information on the potential functional interactions that occur between microbes, and with the host. These metatranscriptomic analyses can also be coupled with metagenomic analyses and statistical models to provide an in-depth approach to systems biology. In this chapter, we detail a standardized method to process and analyze host associated microbial metatranscriptomes independent of the associated host. PMID- 24060122 TI - Preparation of microbial community cDNA for metatranscriptomic analysis in marine plankton. AB - High-throughput sequencing and analysis of microbial community cDNA (metatranscriptomics) are providing valuable insight into in situ microbial activity and metabolism in the oceans. A critical first step in metatranscriptomic studies is the preparation of high-quality cDNA. At the minimum, preparing cDNA for sequencing involves steps of biomass collection, RNA preservation, total RNA extraction, and cDNA synthesis. Each of these steps may present unique challenges for marine microbial samples, particularly for deep-sea samples whose transcriptional profiles may change between water collection and RNA preservation. Because bacterioplankton community RNA yields may be relatively low (<500 ng), it is often necessary to amplify total RNA to obtain sufficient cDNA for downstream sequencing. Additionally, depending on the nature of the samples, budgetary considerations, and the choice of sequencing technology, steps may be required to deplete the amount of ribosomal RNA (rRNA) transcripts in a sample in order to maximize mRNA recovery. cDNA preparation may also involve the addition of internal RNA standards to biomass samples, thereby allowing for absolute quantification of transcript abundance following sequencing. This chapter describes a general protocol for cDNA preparation from planktonic microbial communities, from RNA preservation to final cDNA synthesis, with specific emphasis placed on topics of sampling bias and rRNA depletion. Consideration of these topics is critical for helping standardize metatranscriptomics methods as they become widespread in marine microbiology research. PMID- 24060123 TI - Sequential isolation of metabolites, RNA, DNA, and proteins from the same unique sample. AB - In microbial ecology, high-resolution molecular approaches are essential for characterizing the vast organismal and functional diversity and understanding the interaction of microbial communities with biotic and abiotic environmental factors. Integrated omics, comprising genomics, transcriptomics, proteomics, and metabolomics allows conclusive links to be drawn between genetic potential and function. However, this requires truly systematic measurements. In this chapter, we first assess the levels of heterogeneity within mixed microbial communities, thereby demonstrating the need for analyzing biomolecular fractions obtained from a single and undivided sample to facilitate multi-omic analysis and meaningful data integration. Further, we describe a methodological workflow for the reproducible isolation of concomitant metabolites, RNA (optionally split into large and small RNA fractions), DNA, and proteins. Depending on the nature of the sample, the methodology comprises different (pre)processing and preservation steps. If possible, extracellular polar and nonpolar metabolites may first be extracted from cell supernatants using organic solvents. Cells are homogenized by cryomilling before small molecules are extracted with organic solvents. After cell lysis, nucleic acids and protein fractions are sequentially isolated using chromatographic spin columns. To prove the broad applicability of the methodology, we applied it to microbial consortia of biotechnological (biological wastewater treatment biomass), environmental (freshwater planktonic communities), and biomedical (human fecal sample) research interest. The methodological framework should be applicable to other microbial communities as well as other biological samples with a minimum of tailoring and represents an important first step in standardization for the emerging field of Molecular Eco-Systems Biology. PMID- 24060124 TI - Use of internal standards for quantitative metatranscriptome and metagenome analysis. AB - Next generation sequencing-enabled metatranscriptomic and metagenomic datasets are providing unprecedented insights into the functional diversity of microbial communities, allowing detection of the genes present in a community as well as differentiation of those being actively transcribed. An emerging challenge of meta-omics approaches is how to quantitatively compare metagenomes and metatranscriptomes collected across spatial and temporal scales, or among treatments in experimental manipulations. Here, we describe the use of internal DNA and mRNA standards in meta-omics methodologies, and highlight how data collected in an absolute framework (per L or per cell) provides increased comparative power and insight into underlying causes of differences between samples. PMID- 24060125 TI - Sample processing and cDNA preparation for microbial metatranscriptomics in complex soil communities. AB - Soil presents one of the most complex environments for microbial communities as it provides many microhabitats that allow coexistence of thousands of species with important ecosystem functions. These include biomass and nutrient cycling, mineralization, and detoxification. Culture-independent DNA-based methods, such as metagenomics, have revealed operational taxonomic units that suggest a high diversity of microbial species and associated functions in soil. An emerging but technically challenging area to profile the functions of microorganisms and their activities is mRNA-based metatranscriptomics. Here, we describe issues and important considerations of soil sample processing and cDNA preparation for metatranscriptomics from bacteria and archaea and provide a set of methods that can be used in the required experimental steps. PMID- 24060126 TI - Sample preparation and processing for planktonic microbial community proteomics. AB - Advances in tandem mass spectrometry (tandem MS) and sequencing have enabled the field of community proteomics, which seeks to identify expressed proteins, their sequence variability, and the physiological responses of organisms to variable environmental conditions. Bottom-up tandem MS-based community proteomic approaches generate fragmentation spectra from peptides. Fragmentation spectra are then searched against genomic or metagenomic databases to deduce the amino acid sequences of peptides, providing positive identifications for proteins. Marine community proteomic studies have verified the importance of nutrient transport, energy generation, and carbon fixation functions in bacteria and archaea and revealed spatial and temporal shifts in the expressed functions of communities. Here, we discuss sample collection, preparation, and processing methods for planktonic tandem MS-based community proteomics. PMID- 24060127 TI - Sample handling and mass spectrometry for microbial metaproteomic analyses. AB - Metaproteomic studies of whole microbial communities from environmental samples (e.g., soil, sediments, freshwater, seawater, etc.) have rapidly increased in recent years due to many technological advances in mass spectrometry (MS). A single 24-h liquid chromatograph-tandem mass spectrometry (LC-MS/MS) measurement can potentially detect and quantify thousands of proteins from many dominant and subdominant naturally occurring microbial populations. Importantly, amino acid sequences and relative abundance information for detected peptides are determined, which allows for the characterization of expressed protein functions within communities and specific matches to be made to microbial lineages, with potential subspecies resolution. Continued optimization of protein extraction and fractionation protocols, development of quantification methods, and advances in mass spectrometry instrumentation are enabling more accurate and comprehensive peptide detection within samples, leading to wider research applicability, greater ease of use, and overall accessibility. This chapter provides a brief overview of metaproteomics experimental options, including a general protocol for sample handling and LC-MS/MS measurement. PMID- 24060128 TI - Molecular tools for investigating microbial community structure and function in oxygen-deficient marine waters. AB - Water column oxygen (O2)-deficiency shapes food-web structure by progressively directing nutrients and energy away from higher trophic levels into microbial community metabolism resulting in fixed nitrogen loss and greenhouse gas production. Although respiratory O2 consumption during organic matter degradation is a natural outcome of a productive surface ocean, global-warming-induced stratification intensifies this process leading to oxygen minimum zone (OMZ) expansion. Here, we describe useful tools for detection and quantification of potential key microbial players and processes in OMZ community metabolism including quantitative polymerase chain reaction primers targeting Marine Group I Thaumarchaeota, SUP05, Arctic96BD-19, and SAR324 small-subunit ribosomal RNA genes and protein extraction methods from OMZ waters compatible with high resolution mass spectrometry for profiling microbial community structure and functional dynamics. PMID- 24060129 TI - Assembling full-length rRNA genes from short-read metagenomic sequence datasets using EMIRGE. AB - Microbial ecologists have reaped enormous benefit from advances in high throughput DNA sequencing. However, the short read lengths of currently dominant technologies have made a seemingly simple question about shotgun metagenomic experiments difficult to answer: what small subunit ribosomal RNA (SSU rRNA) genes are present in a sequenced biological sample? Without these gene sequences, it is difficult to interpret a sample within the rich context of ribosomal rRNA databases accumulated over decades. This chapter presents specialized software, EMIRGE, for the assembly of SSU rRNA genes. EMIRGE is optimized to deal with strain similarity and the fluctuating levels of conservation within the SSU rRNA gene that make assembly difficult. It has been used to successfully assemble genes from shotgun metagenomes, long PCR amplicons, and total-RNA transcriptomes. A detailed discussion of how EMIRGE works and how it deals with the uncertainty inherent in the assembly problem is presented. Practical suggestions are given for understanding and optimizing parameter choice, data preprocessing and postprocessing, and creation of a candidate SSU rRNA gene database. When high throughput sequencing data are available, EMIRGE can serve as a valuable tool for interpreting microbial community structure. PMID- 24060130 TI - Computational methods for high-throughput comparative analyses of natural microbial communities. AB - One of the most widely employed methods in metagenomics is the amplification and sequencing of the highly conserved ribosomal RNA (rRNA) genes from organisms in complex microbial communities. rRNA surveys, typically using the 16S rRNA gene for prokaryotic identification, provide information about the total diversity and taxonomic affiliation of organisms present in a sample. Greatly enhanced by high throughput sequencing, these surveys have uncovered the remarkable diversity of uncultured organisms and revealed unappreciated ecological roles ranging from nutrient cycling to human health. This chapter outlines the best practices for comparative analyses of microbial community surveys. We explain how to transform raw data into meaningful units for further analysis and discuss how to calculate sample diversity and community distance metrics. Finally, we outline how to find associations of species with specific metadata and true correlations between species from compositional data. We focus on data generated by next-generation sequencing platforms, using the Illumina platform as a test case, because of its widespread use especially among researchers just entering the field. PMID- 24060132 TI - Disentangling associated genomes. AB - The recovery and assembly of genome sequences from samples containing communities of organisms pose several challenges. Because it is rarely possible to disassociate the resident organisms prior to sequencing, a major obstacle is the assignment of sequences to a single genome that can be fully assembled. This chapter delineates many of the decisions, methodologies, and approaches that can lead to the generation of complete or nearly complete microbial genome sequences from heterogeneous samples-that is, the procedures that allow us to turn metagenomes into genomes. PMID- 24060133 TI - Microbial community analysis using MEGAN. AB - Metagenomics, the study of microbes in the environment using DNA sequencing, depends upon dedicated software tools for processing and analyzing very large sequencing datasets. One such tool is MEGAN (MEtaGenome ANalyzer), which can be used to interactively analyze and compare metagenomic and metatranscriptomic data, both taxonomically and functionally. To perform a taxonomic analysis, the program places the reads onto the NCBI taxonomy, while functional analysis is performed by mapping reads to the SEED, COG, and KEGG classifications. Samples can be compared taxonomically and functionally, using a wide range of different charting and visualization techniques. PCoA analysis and clustering methods allow high-level comparison of large numbers of samples. Different attributes of the samples can be captured and used within analysis. The program supports various input formats for loading data and can export analysis results in different text based and graphical formats. The program is designed to work with very large samples containing many millions of reads. It is written in Java and installers for the three major computer operating systems are available from http://www ab.informatik.uni-tuebingen.de. PMID- 24060131 TI - Advancing our understanding of the human microbiome using QIIME. AB - High-throughput DNA sequencing technologies, coupled with advanced bioinformatics tools, have enabled rapid advances in microbial ecology and our understanding of the human microbiome. QIIME (Quantitative Insights Into Microbial Ecology) is an open-source bioinformatics software package designed for microbial community analysis based on DNA sequence data, which provides a single analysis framework for analysis of raw sequence data through publication-quality statistical analyses and interactive visualizations. In this chapter, we demonstrate the use of the QIIME pipeline to analyze microbial communities obtained from several sites on the bodies of transgenic and wild-type mice, as assessed using 16S rRNA gene sequences generated on the Illumina MiSeq platform. We present our recommended pipeline for performing microbial community analysis and provide guidelines for making critical choices in the process. We present examples of some of the types of analyses that are enabled by QIIME and discuss how other tools, such as phyloseq and R, can be applied to expand upon these analyses. PMID- 24060134 TI - A metagenomics portal for a democratized sequencing world. AB - The democratized world of sequencing is leading to numerous data analysis challenges; MG-RAST addresses many of these challenges for diverse datasets, including amplicon datasets, shotgun metagenomes, and metatranscriptomes. The changes from version 2 to version 3 include the addition of a dedicated gene calling stage using FragGenescan, clustering of predicted proteins at 90% identity, and the use of BLAT for the computation of similarities. Together with changes in the underlying software infrastructure, this has enabled the dramatic scaling up of pipeline throughput while remaining on a limited hardware budget. The Web-based service allows upload, fully automated analysis, and visualization of results. As a result of the plummeting cost of sequencing and the readily available analytical power of MG-RAST, over 78,000 metagenomic datasets have been analyzed, with over 12,000 of them publicly available in MG-RAST. PMID- 24060135 TI - A user's guide to quantitative and comparative analysis of metagenomic datasets. AB - Metagenomics has revolutionized microbiological studies during the past decade and provided new insights into the diversity, dynamics, and metabolic potential of natural microbial communities. However, metagenomics still represents a field in development, and standardized tools and approaches to handle and compare metagenomes have not been established yet. An important reason accounting for the latter is the continuous changes in the type of sequencing data available, for example, long versus short sequencing reads. Here, we provide a guide to bioinformatic pipelines developed to accomplish the following tasks, focusing primarily on those developed by our team: (i) assemble a metagenomic dataset; (ii) determine the level of sequence coverage obtained and the amount of sequencing required to obtain complete coverage; (iii) identify the taxonomic affiliation of a metagenomic read or assembled contig; and (iv) determine differentially abundant genes, pathways, and species between different datasets. Most of these pipelines do not depend on the type of sequences available or can be easily adjusted to fit different types of sequences, and are freely available (for instance, through our lab Web site: http://www.enve-omics.gatech.edu/). The limitations of current approaches, as well as the computational aspects that can be further improved, will also be briefly discussed. The work presented here provides practical guidelines on how to perform metagenomic analysis of microbial communities characterized by varied levels of diversity and establishes approaches to handle the resulting data, independent of the sequencing platform employed. PMID- 24060136 TI - Preface. Microbial metagenomics, metatranscriptomics, and metaproteomics. PMID- 24060138 TI - Reactions of Group 4 amide guanidinates with dioxygen or water. Studies of the formation of oxo products. AB - Reactions of the zirconium amide guanidinates (R2N)2M[(i)PrNC(NR2)N(i)Pr]2 (R = Me, M = Zr, 1; M = Hf, 2; R = Et, M = Zr, 3) with O2 or H2O give products that are consistent with the oxo dimers {M(MU-O)[(i)PrNC(NR2)N(i)Pr]2}2 (R = Me, M = Zr, 4; M = Hf, 5; R = Et, M = Zr, 6) and polymers {M(MU-O)[(i)PrNC(NR2)N(i)Pr]2}n (R = Me, M = Zr, 7; M = Hf, 8; R = Et, M = Zr, 9). Mass spectrometric (MS) analyses of the reactions of water in air with 1 and 2 show formation of the Zr monomer Zr(?O)[(i)PrNC(NMe2)N(i)Pr]2 (10), oxo dimers 4 and 5, and dihydroxyl complexes M(OH)2[(i)PrNC(NMe2)N(i)Pr]2 (M = Zr, 11; Hf, 12). Similar MS analyses of the reaction of diethylamide guanidinate 3 with water in air show the formation of Zr(?O)[(i)PrNC(NEt2)N(i)Pr]2 (13), Zr(OH)2[(i)PrNC(NEt2)N(i)Pr]2 (14), 6, and {(Et2N)Zr[(i)PrNC(NEt2)N(i)Pr]2}(+) (15). Kinetic studies of the reaction between 1 and a continuous flow of 1.0 atm of O2 at 80-105 degrees C indicate that it follows pseudo-first-order kinetics with DeltaH(?) = 8.7(1.1) kcal/mol, DeltaS(?) = -54(3) eu, DeltaG(?)(358 K) = 28(2) kcal/mol, and a half life of 213(1) min at 85 degrees C. PMID- 24060137 TI - Expression of the chicken GDNF family receptor alpha-1 as a marker of spermatogonial stem cells. AB - The identification, enrichment and subsequent isolation of spermatogonial stem cells (SSCs) are integral to the success of SCC transplants between fertile donor and sterilized recipient males. In birds generally and particularly in chicken, SSC-specific has yet to be identified. The receptor for glial cell-derived neurotrophic factor (GDNF), i.e. GDNF family receptor alpha-1 (GFRalpha1), has been identified as a potential marker for different mouse spermatogonial subtypes. In the present study, we characterized the chicken cGFRalpha1 receptor and compared its predicted amino-acid sequence with mouse, rat and human GFRalpha1 proteins. Using specific polyclonal mouse anti-cGFRalpha1 serum, a total of 2.8% cells were recognized as cGFRalpha1-positive among isolated testicular cells recovered from sexually mature cockerels. The percentages of cGFRalpha1-positive testicular cells with haploid, diploid, tetraploid and SP DNA content were 1.6%, 2.5%, 39.3% and 76.8%, respectively. The presence of cGFRalpha1 protein on the surfaces of all cells of the seminiferous epithelium was confirmed by immunocytochemical and immunohistochemical analyses. Tissue specificity of cGFRalpha1 mRNA expression was significantly higher in adult testes compared to brain tissue which itself was several times higher than tissues prepared from the spleen, liver and heart. No expression was observed in muscular tissue. At last, we demonstrated the successful repopulation of sterilized recipient's testes with transplanted cGFRalpha1-positive donor testicular cells. Recipient males subsequently produced functional heterologous spermatozoa capable of fertilizing an ovum and obtaining chicks with donor cell genotypes. PMID- 24060139 TI - Criteria to average out the chemical shift anisotropy in solid-state NMR when irradiated with BABA I, BABA II, and C7 radiofrequency pulse sequences. AB - Floquet-Magnus expansion is used to study the effect of chemical shift anisotropy in solid-state NMR of rotating solids. The chemical shift interaction is irradiated with two types of radiofrequency pulse sequences: BABA and C7. The criteria for the chemical shift anisotropy to be averaged out in each rotor period are obtained. PMID- 24060140 TI - Acute interstitial nephritis following kudzu root juice ingestion. AB - Recently, the use of herbal remedies and complementary and alternative medicine has increased globally. Kudzu root (Pueraria lobata) is a plant commonly used in traditional medicine to promote health. A middle-aged woman consumed kudzu root juice to promote health and well-being for 10 days. Subsequently, she developed anorexia, epigastric discomfort and azotemia. These symptoms improved rapidly within several days after discontinuation of the suspected offending agent and conservative treatment. Acute interstitial nephritis was diagnosed by renal biopsy. To our knowledge, this is the first case report describing acute interstitial nephritis following the ingestion of kudzu root juice. PMID- 24060141 TI - A practical thrice weekly Ertapenem dosage regime for chronic hemodialysis patients? PMID- 24060142 TI - Mitigation options to reduce phosphorus losses from the agricultural sector and improve surface water quality: a review. AB - The EU Water Framework Directive (WFD) obliges Member States to improve the quality of surface water and groundwater. The measures implemented to date have reduced the contribution of point sources of pollution, and hence diffuse pollution from agriculture has become more important. In many catchments the water quality remains poor. COST Action 869 was an EU initiative to improve surface water quality that ran from 2006 to 2011, in which 30 countries participated. Its main aim was a scientific evaluation of the suitability and cost-effectiveness of options for reducing nutrient loss from rural areas to surface waters at catchment scale, including the feasibility of the options under different climatic and geographical conditions. This paper gives an overview of various categories of mitigation options in relation to phosphorus (P). The individual measures are described in terms of their mode of action, applicability, effectiveness, time frame, environmental side-effects (N cycling) and cost. In total, 83 measures were evaluated in COST Action 869. PMID- 24060143 TI - Effect of povidone iodine on thyroid functions and urine iodine levels in caesarean operations. AB - OBJECTIVE: In the present study, the effects of povidone iodine (PI) used during Caesarean operations on maternal thyroid hormones and urine iodine levels in the infant and the mother were investigated. DESIGN: Twenty-seven patients were allocated to the PI group I (Gr I), and 28 to the non-PI group (Group II). Maternal preoperative and 24th-h postoperative free T3 (fT3), freeT4 (fT4), TSH, and urine iodine levels were determined, as well as infant urine iodine values. RESULTS: In both groups, fT3 levels before and after the operation were found to be reduced (p < 0.01, p = 0.01, respectively). However, the decrease in fT3 was approximately 1.5-fold higher in Gr I than in Gr II. TSH levels increased significantly in Gr I (p = 0.005). The urine iodine levels of the mothers increased 25% in Gr I, but only 2% in Gr II. CONCLUSIONS: The absorption of PI by the skin was found to lead to changes in fT3, TSH, and urine iodine excretion values in the mothers. The findings of this study of Caesarean operations, which have a short duration, might be a signal to be careful of thyroid hormone effects in operations lasting longer. PMID- 24060144 TI - Older adults with acquired brain injury: a population based study. AB - BACKGROUND: Acquired brain injury (ABI), which includes traumatic (TBI) and non traumatic brain injury (nTBI), is a leading cause of death and disability worldwide. The objective of this study was to examine the trends, characteristics, cause of brain injury, and discharge destination of hospitalized older adults aged 65 years and older with an ABI diagnosis in a population with universal access to hospital care. The profile of characteristics of patients with TBI and nTBI causes of injury was also compared. METHODS: A population based retrospective cohort study design with healthcare administrative databases was used. Data on acute care admissions were obtained from the Discharge Abstract Database and patients were identified using the International Classification of Diseases - Version 10 codes for Ontario, Canada from April 1, 2003 to March 31, 2010. Older adults were examined in three age groups - 65 to 74, 75 to 84, and 85+ years. RESULTS: From 2003/04 to 2009/10, there were 14,518 episodes of acute care associated with a TBI code and 51, 233 episodes with a nTBI code. Overall, the rate of hospitalized TBI and nTBI episodes increased with older age groups. From 2007/08 to 2009/10, the percentage of patients that stayed in acute care for 12 days or more and the percentage of patients with delayed discharge from acute care increased with age. The most common cause of TBI was falls while the most common type of nTBI was brain tumours. The percentage of patients discharged to long term care and complex continuing care increased with age and the percentage discharged home decreased with age. In-hospital mortality also increased with age. Older adults with TBI and nTBI differed significantly in demographic and clinical characteristics and discharge destination from acute care. CONCLUSIONS: This study showed an increased rate of acute care admissions for both TBI and nTBI with age. It also provided additional support for falls prevention strategies to prevent injury leading to cognitive disability with costly human and economic consequences. Implications for increased numbers of people with ABI are discussed. PMID- 24060145 TI - Review of cinacalcet hydrochloride in the management of secondary hyperparathyroidism. AB - Cinacalcet is the first Food and Drug Administration-approved calcimimetic for the treatment of secondary hyperparathyroidism in dialysis patients. It is effective in improving control of parathyroid hormone, serum calcium, phosphorus, and calcium-phosphorus product. The calcium-lowering effect of cinacalcet overcomes the limitations of standard therapy associated hypercalcemia. There is evidence to suggest that cinacalcet has important clinical implications, which extend beyond its relevance in the treatment of secondary hyperparathyroidism. This review summarizes the evidence regarding the role of cinacalcet in the treatment of secondary hyperparathyroidism, disrupted bone mineral metabolism, cardiovascular disease, and mortality. In addition, the cost implications of cinacalcet are briefly explored. PMID- 24060146 TI - New mechanisms and targets for IBD Therapy: translational gastroenterology comes of age. PMID- 24060147 TI - Osteoporosis and its association with non-gonadal hormones involved in hypertension, adiposity and hyperglycaemia. AB - Osteoporosis is a high-prevalence disease, particularly in developed countries, and results in high costs both to the individual and to society through associated fragility fractures. There is an urgent need for identification of novel drug targets and development of new anti-osteoporotic agents. Between 30 and 80% of osteoporotic fractures cannot be prevented despite current treatments achieving relative fracture risk reduction of up to 20%, 50%, and 70% for non vertebral, hip and spine fractures, respectively. Traditionally, the decline in gonadal hormones has been studied as the sole hormonal determinant for the loss of bone mineral density in osteoporosis. However, recent studies have identified receptors for numerous non-gonadal hormones such as PTH, angiotensin II, leptin, adiponectin, insulin and insulin-like growth factor-1 on the osteoblast lineage cells that directly regulate bone turnover. These hormones are also involved in the pathogenesis of metabolic syndrome risk factors, particularly hypertension, type-II diabetes and obesity. By activating their respective receptors on osteoblastic lineage cells, these hormones appear to act through a common mechanism by down-regulating receptors for activation of nuclear factor kappa B ligand (RANKL) and up-regulating osteoprotegerin (OPG) with inverse responses for adiponectin. Receptors for amylin, gastric inhibitory polypeptide and ghrelin and have also been identified on the osteoblast lineage cells although the roles of these receptors in bone turnover are controversial or poorly studied. Moreover, bone turnover may be independently regulated by modulation of osteoclast osteoblast function and bone marrow adiposity. Leptin appears to be the only hormone that is a known regulator of both bone mineralisation and bone adiposity. PMID- 24060148 TI - Sealing the broken barrier in IBD: intestinal permeability, epithelial cells and junctions. AB - Inflammatory bowel diseases (IBD) are considered barrier diseases. After misleading initial results, the pathogenic importance of a disturbed mucosa is now widely accepted, largely because a certain percentage of first-degree relatives of patients with IBD do have permeability alterations, as assessed by oral markers. In the presence of a normal appearing gut mucosa, functional alterations of the highly dynamic inter-enterocyte tight junctions have to be considered to be responsible for the observed alterations. Indeed, various alterations of the transmembrane and intracytoplasmic proteins have been reported in IBD. An important therapeutic goal is to maintain disease remission by preservation of the correct organization of these complexes. Of the potential therapeutic approaches, the various anti-TNF agents are the best-studied agents, but other treatments may tighten the gut through as yet unknown mechanisms. PMID- 24060149 TI - Electron absorbed dose measurements in LINACs by thermoluminescent dosimeters. AB - In this work, electron absorbed doses measurements in radiation therapy (RT) were obtained. Radiation measurements were made using thermoluminescent dosimeters of calcium sulfate doped with dysprosium (CaSO4:Dy) and zirconium oxide (ZrO2). TL response calibration was obtained by irradiating TLDs and a Farmer cylindrical ionization chamber PTW 30013 at the same time. Each TL material showed a typical glow curve according to each material. Both calcium sulfate doped with dysprosium and zirconium oxide exhibited better light intensity to high energy electron beam compared with lithium fluoride. TL response as a function of absorbed dose was analyzed. TL response as a function of high energy electron beam was also studied. PMID- 24060150 TI - mTOR: more targets of resveratrol? AB - Resveratrol (RSV) is a natural polyphenol produced by plants and is proposed to have multiple beneficial effects on health. In recent years, the interest in this molecule has increased nearly exponentially following the major findings that RSV (I) is chemo-preventive in some cancer models, (II) is cardio-protective and (III) has positive effects on metabolism in mammals and increases lifespan in lower organisms. Mechanistic target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism and angiogenesis. As a part of the mTORC1 and mTORC2 complexes, the mTOR kinase plays a key role in several pathways involved in cancer and metabolic diseases. Recent studies suggest that modulation of the mTOR signalling pathway could play an important role in mediating the beneficial effects of RSV. Therefore, this review summarises the current findings regarding RSV and its inhibition/activation of the proteins in the mTOR pathway, and thereby propose the proteins of the mTOR cascade to be primary targets for RSV. RSV affects many different targets related to mTOR, and it is not clear which is most relevant. However, most frequently, RSV is found to inhibit the activity of the mTOR pathway proteins, and to activate AMPK and LKB1, which can suppress mTOR signalling. Thus, it appears that RSV plays a role in modulation of proteins of the mTOR pathway although more research is still needed to fully understand the interaction. PMID- 24060151 TI - Molecular phenotype of primary mammary tumours and distant metastases in female dogs and cats. AB - Distant metastases represent a major step in the progression and fatal outcome of canine and feline mammary carcinomas. Recent studies have characterized the molecular phenotypes of mammary tumours and provided information on molecules that may allow targeted therapy in sites from which the tumours may not readily be surgically resected. Molecular phenotypes were determined immunohistochemically in three feline and two canine cases of mammary neoplasia, each presenting with multiple distant metastases. These tumours and their metastases often overexpressed the c-erbB-2 phenotype. A basal-like phenotype was found in the distant metastases from two cases. These findings suggest that canine and feline mammary tumours with distant metastases may be amenable to novel targeted therapies. PMID- 24060152 TI - Oxidative stress and redistribution of glutamine synthetase in California sea lions (Zalophus californianus) with domoic acid toxicosis. AB - The aim of this study was to test the hypothesis that oxidative stress and glutamine synthetase (GS) redistribution occur in domoic acid (DA) toxicosis in California sea lions (CSLs, Zalophus californianus). Sections of archived hippocampi from seven control and 13 CSLs diagnosed with DA toxicosis were labelled immunohistochemically for GS and for two markers of oxidative stress, malondialdehyde (MDA) and 3-nitrotyrosine (NT). The distribution and intensity of labelling were compared with the pathological changes seen in haematoxylin and eosin-stained sections. Increased expression of MDA and NT occurred in neurons of the hippocampal formation of CSLs with lesions consistent with DA toxicosis. The degree of oxidative stress was not affected significantly by the chronicity or severity of hippocampal damage. In six out of seven CSLs with chronic effects of DA toxicosis, in addition to the normal glial distribution of GS, GS expression was very strong in some neurons of the subiculum. However, neuronal GS labelling was also seen in one control CSL, an effect that may have been due to previous exposure to DA. GS expression in neurons was associated with decreases in GS labelling in neighbouring glial cell processes. DA toxicosis therefore induces increased expression of markers of oxidative stress in neurons consistent with oxidative stress contributing to the initial DA insult and also the epilepsy that often develops in chronic DA toxicosis. GS redistribution occurred primarily in chronic DA toxicosis, perhaps leading to alterations of the glutamine-glutamate GABA (gamma-aminobutyric acid) cycle and contributing to the excitotoxicity and seizures often seen in DA toxicosis. PMID- 24060153 TI - Proliferative lesions of intra-epidermal cytokeratin CAM5.2-positive cells in canine nipples. AB - Non-keratinocyte cells with clear or vacuolated cytoplasm are frequently observed in the epidermis of canine nipples. Most of these cells express cytokeratin (CK) CAM5.2, a marker of luminal epithelial cells. The morphological and immunohistochemical characteristics of these clear cells were investigated. Nipple tissue from 36 dogs of both sexes was collected and labelled immunohistochemically for CAM5.2, CK7, CK14, CK18, CK20, alpha-smooth muscle actin, p63, melan-A, E-cadherin, epidermal growth factor receptor and oestrogen receptor (OR). The intra-epidermal CAM5.2(+) clear cells were present singly or as small clusters, mostly within the basal layer, in 22 dogs (61%). These cells also expressed CK7, CK18, E-cadherin and OR. Electron microscopy revealed that some of these cells had surface microvilli. Multifocal proliferative lesions consisting of these cells were observed in the nipples of four dogs. In these lesions, proliferating cells formed bilayered tubules with CAM5.2(+) inner and CK14/p63(+) outer cells. This is the first report describing intra-epidermal CAM5.2(+) clear cells, distinct from melanocytes and Merkel cells in dog nipples. These cells might arise from the luminal epithelium of the papillary duct. PMID- 24060154 TI - Concurrent expression of cyclo-oxygenase-2 and epidermal growth factor receptor in canine malignant mammary tumours. AB - Canine mammary tumours (CMTs) are reported to express cyclo-oxygenase (COX)-2 and epidermal growth factor receptor (EGFR); however, no studies have evaluated concurrent expression of these proteins. In this study, 43 malignant CMTs were evaluated immunohistochemically for concurrent expression of COX-2 and EGFR and expression was correlated with malignancy. High COX-2 expression was associated with tumour size (P = 0.033), mitotic index (P = 0.040), nuclear grade (P = 0.021), histological grade of malignancy (P = 0.020) and lymph node metastasis (P = 0.029). High EGFR immunoreactivity was associated with tumour size (P = 0.001), necrosis (P = 0.001), mitotic index (P = 0.022), histological grade of malignancy (P = 0.041) and lymph node metastasis (P = 0.005). Simultaneous high-expression of COX-2 and EGFR was associated with high-nuclear grade (P = 0.049), high histological grade of malignancy (P = 0.031) and the presence of lymph node metastasis (P = 0.025). A positive correlation between COX-2 and EGFR expression (r = 0.474; P = 0.001) was also observed. These results suggest that combined use of selective inhibitors of COX-2 and EGFR may be a useful approach to the treatment of malignant CMTs. PMID- 24060155 TI - Thyroid follicular adenoma with accumulation of collagen type IV in a common marmoset (Callithrix jacchus). AB - A thyroid tumour was identified in a 10-year-old male common marmoset (Callithrix jacchus). The tumour was encapsulated by fibrous connective tissue and compressed the adjacent normal thyroid. The tumour was composed of variably sized and irregularly shaped thyroid follicles lined by a single layer of columnar epithelial cells. Eosinophilic material at the base of the neoplastic cells stained black with periodic acid-methenamine silver and red with periodic acid Schiff. Immunohistochemistry confirmed that this eosinophilic material was collagen type IV. Ultrastructurally, highly dense and amorphous material was observed at the base of the neoplastic cells. Small vesicles in the basolateral cytoplasm of the neoplastic cells contained similar material to that at the base of the cells. The tumour was diagnosed as a thyroid follicular adenoma with accumulation of collagen type IV. This is the first description of an endocrine tumour with accumulation of collagen type IV in animals. PMID- 24060156 TI - Association of serum arginase I with L-arginine, 3-nitrotyrosine, and exhaled nitric oxide in healthy Japanese workers. AB - The associations of serum arginase I with serum L-arginine, serum 3 nitrotyrosine, and fractional exhaled nitric oxide (FENO) were evaluated cross sectionally in healthy Japanese workers. The serum median (minimum-maximum) levels of arginase I, 3-nitrotyrosine, and FENO in healthy people (n = 130) were 14.6 (0.94-108.1) ng/mL, 81.0 (0.27-298.6) pmol/mg protein, and 14.0 (5.0-110.0) parts per billion, respectively. Significant correlations of arginase I with FENO, L-arginine, 3-nitrotyrosine, and percent predicted forced expiratory volume in 1 s (FEV1 (% predicted)) were observed, and correlations of FENO with immunoglobulin E (IgE), NOx, arginase I, and sex and allergy were also observed. By multiple regression analysis, arginase I showed positive associations with FENO and 3-nitrotyrosine, and a negative association with L-arginine; and FENO showed positive associations with IgE and NO2(-) + NO3(-) (NOx), and a negative association with L-arginine, as well as an association with sex. Moreover, logistic regression analysis showed linear inverse associations of arginase I and 3-nitrotyrosine with L-arginine, and showed linear positive associations of FENO with IgE and NOx. It was concluded that serum arginase I might regulate serum L arginine and 3-nitrotyrosine via L-arginine, and that IgE or NOx might regulate FENO in a healthy Japanese population. PMID- 24060157 TI - Formation of acene-based polymers: mechanistic computational study. AB - Understanding the mechanism of linear acene decomposition and its reactivity is a prerequisite for controlling the stability of acenes and their future applications. Previously, we suggested that long acenes may undergo polymerization since the polymerization product is thermodynamically more stable than the dimerization product. However, due to kinetic considerations, the most thermodynamically stable product, the polymer, might not necessarily be formed. To elucidate the situation, we investigated the mechanisms of acene polymerization computationally, using pentacene, hexacene, and heptacene as representative examples. Similarly to dimerization, acene polymerization follows a stepwise biradical pathway. Structural and steric hindrance of the polymer backbone forces acene polymerization to proceed via the less reactive noncentral benzene rings. Consequently, dimerization is always kinetically more favorable than polymerization, irrespective of acene length. Although, for long acenes starting from hexacene, both polymerization and dimerization are barrierless pathways relative to the reactants, polymerization is thermodynamically preferred for hexacene and heptacene and even more so for longer acenes (since polymerization forms four new C-C bonds while dimerization forms only two). Indeed, reinvestigation of available experimental data suggests that acene-based polymers were probably obtained experimentally previously. PMID- 24060158 TI - Exploring the effects of individual customer incivility encounters on employee incivility: the moderating roles of entity (in)civility and negative affectivity. AB - Incivility between customers and employees is common in many service organizations. These encounters can have negative outcomes for employees, customers, and the organization. To date, researchers have tended to study incivility as an aggregated and accumulated phenomenon (entity perspective). In the present study, we examined incivility as it occurs during a specific service encounter (event perspective) alongside the entity perspective. Using a mixed method multilevel field study of customer service interactions, we show that individual customer incivility encounters (i.e., events) trigger employee incivility as a function of the employee's overall accumulated impression of the (in)civility in his or her customer interactions, such that the effects are more pronounced among employees who generally perceive their customer interactions to be more versus less civil. We also find that these interactive effects occur only among employees who are lower (vs. higher) in negative affectivity. Our results show that, in order to expand the understanding of customer incivility, it is important to study the incivility encounter, the social context in which negative customer interactions occur, and individual differences. PMID- 24060159 TI - Leader-team congruence in power distance values and team effectiveness: the mediating role of procedural justice climate. AB - We examine the effect of (in)congruence between leaders' and teams' power distance values on team effectiveness. We hypothesize that the (in)congruence between these values would differentially predict team effectiveness, with procedural justice climate serving as a mediator. Using multisource data and polynomial regression, we found that similarities (and differences) between leaders' and their teams' power distance values can have consequential effects on teams' justice climate and, ultimately, their effectiveness (viz., team performance and team organizational citizenship behavior). We conclude that to fully understand the implications of power distance, one should consider the multiple perspectives of both leaders and team members. PMID- 24060160 TI - Show and tell: how supervisors facilitate leader development among transitioning leaders. AB - We argue that studying leaders experiencing a job transition offers a unique opportunity to explore initial changes in leaders' development in their cognition and action. Here, we examine 2 early indicators of leaders' development-their acquisition of knowledge regarding their new role (a cognitive outcome) and the time they allocate toward leading others (a behavioral outcome)-and how supervisors can facilitate these forms of development among transitioning leaders. With a sample of 110 first-line leaders who we tracked over approximately 10 months at 4 different points in time, we tested the efficacy of supervisors' support in the form of modeling effective leadership behavior (i.e., "show") and the provision of job information (i.e., "tell"). Results from random coefficient modeling revealed that the interactive effect of supervisors' "show" and "tell" accelerates the rate of transitioning leaders' self-perceived role knowledge acquisition over time. This upward trajectory is even more pronounced for transitioning leaders who have not been exposed to an exceptional leader during their careers. Further, with a lagged design, we found that leaders who report greater role knowledge allocate more time toward leading others, thus indicating initial changes in these leaders' behavior. We discuss these findings in light of their theoretical and practical importance to the field of leader development. PMID- 24060162 TI - [Omental torsion and infarction due to a left inguinal hernia]. PMID- 24060161 TI - [Effects of surgical simulation on the implementation of laparoscopic colorectal procedures]. AB - INTRODUCTION: Advanced laparoscopic surgery requires supplementary training outside the operating room. Clinical simulation with animal models or cadavers facilitates this learning. OBJECTIVE: We measured the impact on clinical practice of a laparoscopic colorectal resection training program based on surgical simulation. MATERIAL AND METHODS: Between March 2007 and March 2012, 163 surgeons participated in 30 courses that lasted 4 days, of 35 hours (18 h in the operating room, 12h in animal models, and 4h in seminars). In May 2012, participants were asked via an on-line survey about the degree of implementation of the techniques in their day-to-day work. RESULTS: Seventy surgeons (47%) from 60 different hospitals answered the survey. Average time elapsed after the course was 11.5 months (2-60 months). A total of 75% initiated or increased the number of surgeries performed after the training. The increase in practice was>10 cases/month in 19%, and<5 cases/month in 56% of surgeons. 38% of participants initiated this surgical approach. CONCLUSIONS: Seventy five percent of the surveyed surgeons increased the clinical implementation of a complicated surgical technique, such as laparoscopic colorectal surgery, after attending a training course based on clinical simulation. PMID- 24060163 TI - [Readability of surgical informed consent in Spain]. AB - INTRODUCTION: To assess the readability of informed consent documents (IC) of the different national surgical societies. METHODS: During January 2012 we collected 504 IC protocols of different specialties. To calculate readability parameters the following criteria were assessed: number of words, syllables and phrases, syllables/word and word/phrase averages, Word correlation index, Flesch-Szigriszt index, Huerta Fernandez index, Inflesz scale degree and the Gunning-Fog index. RESULTS: The mean Flesch-Szigriszt index was 50.65 +/- 6,72, so readability is considered normal. There are significant differences between specialties such as Urology (43.00 +/- 4.17) and Angiology and Vascular Surgery (63.00 +/- 3.26, P<.001). No IC would be appropriate for adult readability according to the Fernandez-Huerta index (total mean 55.77 +/- 6.57); the IC of Angiology and Vascular Surgery were the closest ones (67.85 +/- 3.20). Considering the Inflesz scale degree (total mean of 2.84 +/- 3,23), IC can be described as "somewhat difficult". There are significant differences between the IC of Angiology and Vascular Surgery (3.23 +/- 0.47) that could be qualified as normal, or Cardiovascular Surgery (2.79 +/- 0.43) as "nearly normal readability"; and others such as Urology (1, 70 +/- 0.46, P<.001) and Thoracic Surgery (1.90 +/- 0.30, P<.001), with a readability between "very" and "somewhat" difficult. The Gunning Fog indexes are far from the readability for a general audience (total mean of 26.29 +/- 10,89). CONCLUSIONS: IC developed by scientific societies of different surgical specialties do not have an adequate readability for patients. We recommend the use of readability indexes during the writing of these consent forms. PMID- 24060165 TI - Synthesis of 1,3-dichloro-cyclo-1,3-diphosphadiazanes from silylated amino(dichloro)phosphanes. AB - The synthesis of 1,3-dichloro-cyclo-1,3-diphosphadiazanes [ClP(MU-NR)]2 via elimination of Me3SiCl from silylated amino(dichloro)phosphanes, R-N(SiMe3)PCl2, was studied by different synthetic protocols starting from R-N(H)SiMe3 (R = Si(SiMe3)3 = Hyp, N(SiMe3)2, Mes* = 2,4,6-tri-tert-butylphenyl, Ter = 2,4 bis(2,4,6-trimethylphenyl)phenyl, Dipp = 2,6-diisopropylphenyl, Dmp =2,6 dimethylphenyl, Ad = Adamantyl, Trityl = Ph3C, Tos = tosyl = CH3C6H4SO2, n-Oct = n-octyl, and Me3Si). A new synthetic route using trimethylsilyl-substituted amino(dichloro)phosphanes, R-N(SiMe3)PCl2, was developed to form cyclo diphosph(III)-azanes simply by adding a mixture of R(f)OH/base (R(f)OH = hexafluoroisopropanole). By this method electron-rich/-poor aryl-, silyl-, and bissilylamino-substituted cyclo-diphosph(III)-azanes are accessible such as the unprecedented (Me3Si)2N-substituted species [ClP(MU-NN(SiMe3)2)]2 starting from tris(trimethylsilyl)hydrazine and PCl3. Additionally, the difficulties with the preparation of cyclo-diphosphadiazanes depending on the starting materials, solvents, and bases due to the competition of different reaction channels are studied. PMID- 24060164 TI - [Prospective randomized trial of long-term results of inguinal hernia repair using autoadhesive mesh compared to classic Lichtenstein technique with sutures and polypropylene mesh]. AB - INTRODUCTION: The use of autoadhesive meshes with hooks that allow fixation without sutures is a therapeutic alternative to decrease recurrence and chronic pain after inguinal hernia repair. The aim of this study was to evaluate if this kind of mesh has any advantage in long term results in comparison with the classic Lichtenstein technique with sutures and polypropylene mesh. MATERIAL AND METHODS: We report a prospective and randomized study of patients who have been operated on for inguinal hernia between march of 2009 to march 2010, divided into 2 groups of 45 patients. In AutoAdhesive (AA) group, we included patients operated on with an autoadhesive mesh and in Classic Lichtenstein (CL) group we included cases with an inguinal hernioplasty with sutured polypropylene mesh. We evaluated time of inactivity, complications, recurrences and grade of pain after one year. RESULTS: The mean age was 60 years in AA group and 49 in LC group. There were more men than women and there were no differences in co-morbilities between groups. The mean size of hernia orifice was 3cm in both groups and 60% of the hernias were indirect. After one year, 77 patients were evaluated; 39 in LC group and 38 in AA group. 86,8% and 87,2% of them were asymptomatic. The mean time of recovery of daily activities was 15 days in both groups. There were neither recurrences nor severe chronic pain in the AA group. The mean of grade of pain was 0 (range:0-4) in AA group and 0 (range: 0-5) in LC group. In this group, there was one recurrence and one patient was taking analgesics for intense pain. No mortality nor other long term complications were found. CONCLUSION: The use of autoadhesive and parcial reabsorbible meshes in inguinal hernia repair has no effect on recovery of daily activities, postoperative pain and long term complications compared with hernioplasty with polypropylene mesh fixed with monofilament suture. PMID- 24060166 TI - Gold nanoparticles as amyloid-like fibrillogenesis inhibitors. AB - Amyloid aggregates are one of the likely key factors leading to the development of Alzheimer's disease (AD) and other amyloidosis associated diseases. Several recent studies have shown that some anti-diabetic drugs have a positive therapeutic effect on AD patients by crossing the blood brain barrier (BBB) and preventing or reducing insulin resistance. Nanoparticles (NPs) or nanoscale objects (<600Da.), are able to cross the BBB at low concentrations, and can specifically target amyloidogenic structures. Thus, NPs are fast becoming indispensable tools for directed drug delivery, particularly when targeting structures or regions in the brain. Here, we have explored the inhibitory effect of gold nanoparticles (AuNPs) on the fibrillogenesis process of insulin fibrils. We found that when AuNPs were co-incubated with insulin, the structural transformation into amyloid-like fibrils was delayed by about a week. Further, the fibrils that formed, exhibited altered structure, shape, and dynamics, which further reduced fibril growth, and the stability of available amyloid-like fibrils with cross-beta structure for aggregation. Our results demonstrate that AuNPs disrupt insulin amyloid fibrillation resulting in fibrils that are shorter and more compact, and thus may serve a useful role in new therapeutic and diagnostic strategies for amyloid-related disorders. PMID- 24060168 TI - Paralysis following stereotactic spinal irradiation in pigs suggests a tolerance constraint for single-session irradiation of the spinal nerve. AB - BACKGROUND AND PURPOSE: Paralysis observed during a study of vertebral bone tolerance to single-session irradiation led to further study of the dose-related incidence of motor peripheral neuropathy. MATERIALS AND METHODS: During a bone tolerance study, cervical spinal nerves of 15 minipigs received bilateral irradiation to levels C5-C8 distributed into three dose groups with mean maximum spinal nerve doses of 16.9 +/- 0.3 Gy (n=5), 18.7 +/- 0.5 Gy (n=5), and 24.3 +/- 0.8 Gy (n=5). Changes developing in the gait of the group of pigs receiving a mean maximum dose of 24.3 Gy after 10-15 weeks led to the irradiation of two additional animals. They received mean maximum dose of 24.9 +/- 0.2 Gy (n=2), targeted to the left spinal nerves of C5-C8. The followup period was one year. Histologic sections from spinal cords and available spinal nerves were evaluated. MR imaging was performed on pigs in the 24.9 Gy group. RESULTS: No pig that received a maximum spinal nerve point dose <=19.0 Gy experienced a change in gait while all pigs that received >=24.1 Gy experienced paralysis. Extensive degeneration and fibrosis were observed in irradiated spinal nerves of the 24.9 Gy animals. All spinal cord sections were normal. Irradiated spinal nerve regions showed increased thickness and hypointensity on MR imaging. CONCLUSION: The single-session tolerance dose of the cervical spinal nerves lies between 19.0 and 24.1 Gy for this model. PMID- 24060167 TI - Development of a capillary electrophoresis platform for identifying inhibitors of protein-protein interactions. AB - Methods for identifying chemical inhibitors of protein-protein interactions (PPIs) are often prone to discovery of false positives, particularly those caused by molecules that induce protein aggregation. Thus, there is interest in developing new platforms that might allow earlier identification of these problematic compounds. Capillary electrophoresis (CE) has been evaluated as a method to screen for PPI inhibitors using the challenging system of Hsp70 interacting with its co-chaperone Bag3. In the method, Hsp70 is labeled with a fluorophore, mixed with Bag3, and the resulting bound and free Hsp70 are separated and detected by CE with laser-induced fluorescence detection. The method used a chemically modified CE capillary to prevent protein adsorption. Inhibitors of the Hsp70-Bag3 interaction were detected by observing a reduction in the bound-to-free ratio. The method was used to screen a library of 3443 compounds, and the results were compared to those from a flow cytometry protein interaction assay. CE was found to produce a lower hit rate with more compounds that were reconfirmed in subsequent testing, suggesting greater specificity. This finding was attributed to the use of electropherograms to detect artifacts such as aggregators and to differences in protein modifications required to perform the different assays. Increases in throughput are required to make the CE method suitable for primary screens, but at the current stage of development it is attractive as a secondary screen to test hits found by higher-throughput methods. PMID- 24060169 TI - The effect of progressive resistance training on lean body mass in post-treatment cancer patients - a systematic review. AB - Loss of lean body mass is a common problem in many post-treatment cancer patients and may negatively affect physical capacity in terms of maximal muscle strength and functional performance. The purpose of this study was to systematically review the scientific evidence on the effect of progressive resistance training on lean body mass in post-treatment cancer patients. A comprehensive literature search was conducted and ultimately 12 studies were included. Methodological quality of the included studies was evaluated using the PEDro scale and the effect of progressive resistance training was reported as the range of mean changes among RCTs and non-RCTs. Six RCTs and six non-RCTs were included in the study. In the RCTs the change in lean body mass in the progressive resistance training groups relative to control groups ranged from -0.4% to 3.9%, and in four of six trials the training effect was significantly larger than the change in the control groups. In the six non-RCTs, the mean change in lean body mass over time ranged from -0.01 to 11.8% which was significant in two of the trials. The included studies reported no or very limited adverse events following progressive resistance training. Based on 12 heterogenic studies there is moderate evidence supporting a positive effect of progressive resistance training on lean body mass in post-treatment cancer patients. PMID- 24060170 TI - Comment to the letter by SEOR, ALATRO and SPRO to the editor in response to ESTRO 2012 Strategy Meeting: vision for Radiation Oncology (published April 2012). PMID- 24060171 TI - Variation in background intensity affects PET-based gross tumor volume delineation in non-small-cell lung cancer: the need for individualized information. AB - PURPOSE: Efficient tumor volume delineation by the combined use of PET/CT scanning is necessary for the proper treatment of non-small cell lung cancer (NSCLC). To understand the effect of variation in background intensity on PET based gross tumor volume (GTV) delineation, we determined the background standard uptake values (SUVs) in normal lung, aorta (blood pool), and liver tissues and determined GTVs using different methods. METHODS: Thirty-seven previously untreated patients with pathologically confirmed NSCLC underwent PET/CT scanning with (18)F-fluorodeoxyglucose ((18)F-FDG). To obtain (18)F-FDG uptake values in normal tissues, regions of interest in the lung lobes (left upper, left lower, right upper, right middle, and right lower), aorta, and liver zones (left, intermediate, and right) were measured. The coefficient of variation (CV) of the SUV was measured for each normal structure. The CT-based GTV (GTV(CT)) was considered as the standard to which all PET-based GTVs were compared, and the correlation coefficient was analyzed to compare GTV obtained by the various delineation methods. Linear and logarithmic regression analyses were used to determine the relationship between GTV(CT) and GTV(PET). RESULTS: Normal lung tissue showed a significantly lower SUV and less stability than tissue of the aorta or liver. For the lung, aorta, and liver, the maximum SUV (SUV(max)) was 0.82 +/- 0.32, 2.35 +/- 0.37, and 3.24 +/- 0.50 (CV: 38.79%, 15.82%, and 15.30%) and average SUV (SUV(ave)) was 0.49 +/- 0.18, 1.68 +/- 0.32, and 2.34 +/- 0.36 (CV: 36.38%, 18.92%, and 15.44%), respectively. The SUVs of the lung varied from lobe to lobe. The GTV delineation method using the SUV(ave) of the lung lobe in which the tumor was found as background in the source-to-background ratio (SBR) method showed the best correlation with the volume of CT-based GTV (r=0.81). CONCLUSIONS: Our results show vast variation in the SUV among normal tissues, as well as in the different lung lobes. The tumor volume delineated using the SBR method correlated well with the CT-based tumor volume. We conclude that it is reasonable and precise to contour GTV in patients with NSCLC after taking into account the background intensity of the lung lobe in which the tumor is found. PMID- 24060172 TI - In response to ESTRO 2012 strategy meeting: vision for Radiation Oncology (published April 2012). PMID- 24060173 TI - Use of the LQ model with large fraction sizes results in underestimation of isoeffect doses. AB - PURPOSE: To test the appropriateness of the linear-quadratic (LQ) model to describe survival of jejunal crypt clonogens after split doses with variable (small 1-6 Gy, large 8-13 Gy) first dose, as a model of its appropriateness for both small and large fraction sizes. METHODS: C3Hf/KamLaw mice were exposed to whole body irradiation using 300 kVp X-rays at a dose rate of 1.84 Gy/min, and the number of viable jejunal crypts was determined using the microcolony assay. 14 Gy total dose was split into unequal first and second fractions separated by 4 h. Data were analyzed using the LQ model, the lethal potentially lethal (LPL) model, and a repair-saturation (RS) model. RESULTS: Cell kill was greater in the group receiving the larger fraction first, creating an asymmetry in the plot of survival vs size of first dose, as opposed to the prediction of the LQ model of a symmetric response. There was a significant difference in the estimated betas (higher beta after larger first doses), but no significant difference in the alphas, when large doses were given first vs small doses first. This difference results in underestimation (based on present data by approximately 8%) of isoeffect doses using LQ model parameters based on small fraction sizes. While the LPL model also predicted a symmetric response inconsistent with the data, the RS model results were consistent with the observed asymmetry. CONCLUSION: The LQ model underestimates doses for isoeffective crypt-cell survival with large fraction sizes (in the present setting, >9 Gy). PMID- 24060174 TI - Late radiologic changes after stereotactic ablative radiotherapy for early stage lung cancer: a comparison of fixed-beam versus arc delivery techniques. AB - BACKGROUND AND PURPOSE: To characterize the radiologic changes occurring following arc stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer relative to those following fixed-beam SABR. METHODS: Twenty nine patients treated with arc SABR without local recurrence and more than two years follow-up were retrospectively evaluated using a published scoring system. The late morphologic patterns, timing and severity of radiologic change were assessed and compared to 54 patients treated with fixed-beam SABR that we previously assessed using the same system. RESULTS: The baseline characteristics and follow-up of both cohorts were well matched and SABR technique was not associated with morphologic differences before 6 months (p=0.23). Thereafter the predicted probabilities of a modified-conventional pattern following arc and fixed-beam SABR were 96.3% vs. 68.9%, respectively (OR 11.7, 95% CI 3.38-40.8, p<0.001). In addition, at 1 year follow-up the predicted probabilities of arc and fixed-beam SABR patients having expected or pronounced radiologic changes were 64.9% and 22.1%, respectively (OR=6.56, 95% CI: 3.13-13,7, p<0.001). CONCLUSIONS: Post-SABR radiologic changes differ with delivery technique, which has important implications during follow-up. Confirmation in larger studies is required and etiologic factors remain to be determined. PMID- 24060175 TI - Stereotactic body radiotherapy for localized prostate cancer: pooled analysis from a multi-institutional consortium of prospective phase II trials. AB - PURPOSE: The effectiveness of stereotactic body radiotherapy (SBRT) for localized prostate cancer is tested. METHODS AND MATERIALS: A total of 1100 patients with clinically localized prostate cancer were enrolled in separate prospective phase 2 clinical trials of SBRT from 8 institutions during 2003-11 and pooled for analysis. SBRT using the CyberKnife delivered a median dose of 36.25Gy in 4-5 fractions. Patients were low-risk (58%), intermediate-risk (30%) and high-risk (11%). A short-course of androgen deprivation therapy (ADT) was given to 14%. PSA relapse defined as a rise >2ng/ml above nadir was analyzed with the Kaplan Meier method. RESULTS: With a median follow-up of 36months there were 49 patients with PSA failure (4.5%), 9 of whom were subsequently determined to be benign PSA bounces. The 5-year biochemical relapse free survival (bRFS) rate was 93% for all patients; 95%, 83% and 78% for GS ?6, 7 and ?8, respectively (p=0.001), and 95%, 84% and 81% for low-, intermediate- and high-risk patients, respectively (p<0.001). No differences were observed with ADT (p=0.71) or as a function of total dose (p=0.17). A PSA bounce of >0.2ng/ml was noted among 16% of patients. For 135 patients possessing a minimum of 5years follow-up, the 5-year bRFS rate for low- and intermediate-risk patients was 99% and 93%, respectively. CONCLUSION: PSA relapse-free survival rates after SBRT compare favorably with other definitive treatments for low and intermediate risk patients. The current evidence supports consideration of SBRT among the therapeutic options for these patients. PMID- 24060176 TI - Is there a relation between the radiation dose to the different sub-segments of the lower urinary tract and urinary morbidity after brachytherapy of the prostate with I-125 seeds? AB - BACKGROUND AND PURPOSE: To investigate possible relationships between the dose to the sub-segments of the lower urinary tract and lower urinary tract symptoms (LUTS) after brachytherapy of the prostate. MATERIALS AND METHODS: This study involved 225 patients treated for prostate cancer with I-125 seeds. Post-implant dose-volume histograms of the prostate, urethra, bladder wall, bladder neck and external sphincter were determined. Endpoints were the mean and the maximum International Prostate Symptom Score (IPSS) during the first 3months after the treatment. For binary analysis the patients were stratified in a group with enhanced LUTS and a group with non-enhanced LUTS. RESULTS: The dose to 0.5cm(3) of the bladder neck 'D0.5cc-blne' (p=0.002 and p=0.005), the prostate volume prior to treatment 'Vpr-0' (p=0.005 and p=0.024) and the pre-treatment IPSS (both p<0.001) were independently correlated with mean and maximum IPSS, respectively. Of the patients with a D0.5cc-blne?175Gy and a Vpr-0?42cm(3), 68% suffered from enhanced LUTS, against just 30% of the other patients (p<0.0001). CONCLUSIONS: Pre-treatment IPSS, prostate volume and dose to the bladder neck are correlated with post-implant IPSS. A combination of a large prostate and a high dose to the bladder neck is highly predictive for enhanced early LUTS. PMID- 24060177 TI - Time evolution of regional CT density changes in normal lung after IMRT for NSCLC. AB - PURPOSE: This study investigates the clinical radiobiology of radiation induced lung disease in terms of regional computed tomography (CT) density changes following intensity modulated radiotherapy (IMRT) for non-small-cell lung cancer (NSCLC). METHODS: A total of 387 follow-up CT scans in 131 NSCLC patients receiving IMRT to a prescribed dose of 60 or 66 Gy in 2 Gy fractions were analyzed. The dose-dependent temporal evolution of the density change was analyzed using a two-component model, a superposition of an early, transient component and a late, persistent component. RESULTS: The CT density of healthy lung tissue was observed to increase significantly (p<0.0001) for all dose levels after IMRT. The time evolution and the size of the density signal depend on the local delivered dose. The transient component of the density signal was found to peak in the range of 3-4 months, while the density tends to stabilize at times >12 months. CONCLUSIONS: The radiobiology of lung injury may be analyzed in terms of CT density change. The initial transient change in density is consistent with radiation pneumonitis, while the subsequent stabilization of the density is consistent with pulmonary fibrosis. PMID- 24060178 TI - The novel HDAC inhibitor NDACI054 sensitizes human cancer cells to radiotherapy. AB - BACKGROUND AND PURPOSE: Inhibition of histone deacetylases (HDACs) has preclinically and clinically shown promise to overcome radio- and chemoresistance of tumor cells. NDACI054 is a novel HDAC inhibitor, which has been evaluated here for its effects on cell survival and radiosensitization of human tumor cell lines from different origins cultured under more physiological three-dimensional (3D), extracellular matrix (ECM)-based conditions. MATERIAL AND METHODS: A549 lung, DLD 1 colorectal, MiaPaCa2 pancreatic and UT-SCC15 head and neck squamous cell carcinoma cells were treated with increasing NDACI054 concentrations (0-50 nM, 24 h) either alone or in combination with X-rays (single dose, 0-6 Gy). Subsequently, 3D clonogenic cell survival, HDAC activity, histone H3 acetylation, apoptosis, residual DNA damage (gammaH2AX/p53BP1 foci assay 24h post irradiation) and phosphorylation kinetics of Ataxia telangiectasia mutated (ATM), DNA dependent protein kinase (DNA-PK), Caspase-3 and Poly(ADP-ribose)-Polymerase 1 (PARP 1) cleavage were analyzed. RESULTS: NDACI054 potently decreased HDAC activity with concomitant increase in acetyl-histone H3 levels, mediated significant cytotoxicity and radiosensitization. These effects were accompanied by a significant increase of residual gammaH2AX/p53BP1-positive foci, slightly elevated levels of Caspase-3 and PARP 1 cleavage but no induction of apoptosis. CONCLUSIONS: Our data show potent antisurvival and radiosensitizing effects of the novel HDAC inhibitor NDACI054 encouraging further preclinical examinations on this compound for future clinical use. PMID- 24060179 TI - Expression of EGFR and HPV-associated p16 in oropharyngeal carcinoma: correlation and influence on prognosis after radiotherapy in the randomized DAHANCA 5 and 7 trials. AB - AIM: EGFR and HPV-associated p16 are among the most investigated biomarkers in head and neck cancer. The aim was to investigate the correlation and interaction between these two markers and to evaluate their potential prognostic significance when combined. MATERIALS AND METHODS: 336 Oropharyngeal carcinomas treated with primary radiotherapy (66-68 Gy, 2fx/day, 10-12 Gy/week) and with known EGFR/p16 status estimated semiquantitatively by immunohistochemistry were included in the study. Data were evaluated by EGFR-expression (high/low) and p16-status (positive/negative) consequently dividing tumours into four groups by combination of the biomarkers. Patient/tumour characteristics and complete 5-year follow-up were available. RESULTS: Low EGFR-expression was significantly more common in p16 positive tumours compared to p16-negative, p < 0.0001. p16 positivity showed a strong prognostic impact (p < 0.0001, HR = 0.22 [0.13-0.38]), whereas EGFR was a weak prognostic marker when local control was used as endpoint (p = 0.03, HR = 0.53 [0.29-0.94]). Combination of EGFR/p16 did not add significant information to p16 alone and by multivariable analysis only p16 showed significant prognostic information for all evaluated endpoints. CONCLUSIONS: Both EGFR and p16 bear prognostic information in oropharyngeal cancer, although p16 is, by far, the strongest prognostic factor. The markers seem to be correlated and this might have influence when evaluating the effect of EGFR inhibition in oropharyngeal tumours. PMID- 24060180 TI - What causes early mortality in patients with large tumors receiving radical chemo radiotherapy for non-small cell lung cancer? In response to Ball et al. PMID- 24060182 TI - Risk of preeclampsia: comparison between dichorionic and monochorionic twin pregnancies. PMID- 24060181 TI - Staphylococcus aureus colonization of healthy military service members in the United States and Afghanistan. AB - BACKGROUND: Staphylococcus aureus [methicillin-resistant and methicillin susceptible (MRSA/MSSA)] is a leading cause of infections in military personnel, but there are limited data regarding baseline colonization of individuals while deployed. We conducted a pilot study to screen non-deployed and deployed healthy military service members for MRSA/MSSA colonization at various anatomic sites and assessed isolates for molecular differences. METHODS: Colonization point prevalence of 101 military personnel in the US and 100 in Afghanistan was determined by swabbing 7 anatomic sites. US-based individuals had received no antibiotics within 30 days, and Afghanistan-deployed personnel were taking doxycycline for malaria prophylaxis. Isolates underwent identification and testing for antimicrobial resistance, virulence factors, and pulsed-field type (PFT). RESULTS: 4 individuals in the US (4 isolates- 3 oropharynx, 1 perirectal) and 4 in Afghanistan (6 isolates- 2 oropharynx, 2 nare, 1 hand, 1 foot) were colonized with MRSA. Among US-based personnel, 3 had USA300 (1 PVL+) and 1 USA700. Among Afghanistan-based personnel, 1 had USA300 (PVL+), 1 USA800 and 2 USA1000. MSSA was present in 40 (71 isolates-25 oropharynx, 15 nare) of the US based and 32 (65 isolates- 16 oropharynx, 24 nare) of the Afghanistan-based individuals. 56 (79%) US and 41(63%) Afghanistan-based individuals had MSSA isolates recovered from extra-nare sites. The most common MSSA PFTs were USA200 (9 isolates) in the US and USA800 (7 isolates) in Afghanistan. MRSA/MSSA isolates were susceptible to doxycycline in all but 3 personnel (1 US, 2 Afghanistan; all were MSSA isolates that carried tetM). CONCLUSION: MRSA and MSSA colonization of military personnel was not associated with deployment status or doxycycline exposure. Higher S. aureus oropharynx colonization rates were observed and may warrant changes in decolonization practices. PMID- 24060183 TI - A meta-analysis of the association of G915C, G800A, C509T gene polymorphism of transforming growth factor-beta1 with diabetic nephropathy risk. AB - This meta-analysis was conducted to evaluate the association of transforming growth factor-beta1 (TGF-beta1) G915C, G800A, C509T gene polymorphism with the risk of diabetic nephropathy (DN). The association literatures were identified from PubMed, Cochrane Library, and CBM-disc (China Biological Medicine Database) on March 1, 2013, and eligible reports were recruited and synthesized. Seven reports were recruited into this meta-analysis for the association of TGF-beta1 G800A, C509T, G915C gene polymorphism with DN risk. GG genotype, CC genotype, and C allele of TGF-beta1 G915C were not associated with the DN risk (GG: OR = 0.84, 95% CI: 0.62-1.14, p = 0.27; CC: OR = 1.05, 95% CI: 0.50-2.22, p = 0.90; C allele: OR = 1.16, 95% CI: 0.88-1.51, p = 0.29). Furthermore, TGF-beta1 G800A, C509T gene polymorphism was not associated with the DN risk. In conclusion, TGF beta1 G915C, G800A, and C509T gene polymorphism are not associated with the DN risk. However, more studies should be performed to confirm this relationship in the future. PMID- 24060184 TI - Synthesis and photocatalytic performance of ZnIn2S4 nanotubes and nanowires. AB - ZnIn2S4 nanotubes and nanowires have been selectively fabricated via a convenient one-step wet-chemical approach by using porous polycarbonate membrane as a hard template. The wall of nanotubes is as thin as 5 nm, and the diameter of them is 200 nm. Formation mechanism of ZnIn2S4 nanotubes and nanowires is also discussed according to the experimental results. The structure, morphology, and composition properties of the as-prepared samples were characterized using X-ray powder diffraction, UV-vis spectrophotometer, transmission electron microscopy, energy dispersive X-ray spectrometry, and scanning electron microscopy. PMID- 24060185 TI - Cassandra's prophecy: response on behalf of the Royal College of Obstetricians and Gynaecologists. PMID- 24060186 TI - Evidence-based medicine and the role of the National Health Service in assisted reproduction. AB - The wholesale introduction of any new procedure to medical practice requires an acceptance based on evidence-based medicine, which is primarily acquired using prospective randomized controlled trials. However, for self-funded treatments, as are the majority of IVF cycles, this has always been very difficult to achieve. Generally, new technologies are introduced and adopted by patients who have failed in previous attempts at IVF. Urging patients to enter into a prospective randomized controlled trial is problematic, especially when they are self funding; eagerness to conceive when time is against them, and/or having undergone previously failed treatment attempts, convince most patients to fund the new technology/opportunity rather than risk falling into the control arm and repeating their previous failure(s). The UK is uniquely placed to advance IVF medicine by helping practitioners and patients gain access to vital trials through the National Health Service. PMID- 24060187 TI - Cassandra's prophecy: communication, communication, communication. PMID- 24060188 TI - Palladium-catalyzed intermolecular aerobic oxidative cyclization of 2 ethynylanilines with isocyanides: regioselective synthesis of 4-halo-2 aminoquinolines. AB - A robust and regioselective palladium-catalyzed intermolecular aerobic oxidative cyclization of 2-ethynylanilines with isocyanides to the synthesis of 4-halo-2 aminoquinolines is reported herein. The procedure constructs various 4-halo-2 aminoquinolines with moderate to excellent yields (47-94%) and broad substrates scope. Furthermore, this process can be easily extended to synthesis of various 6H-indolo[2,3-b]quinolines via an intramolecular Buchwald-Hartwig cross-coupling reaction in two-step one-pot manner. PMID- 24060189 TI - A "strongly" self-catenated metal-organic framework with the highest topological density among 3,4-coordinated nets. AB - A new type of 3D "strongly" self-catenated metal-organic framework (SDU-9) has been constructed from [Cu2(COO)4] paddlewheel secondary building units and a tripodal carboxylate linker. SDU-9 ([Cu6(H2O)6L4].24H2O, where [H3L = 4,4',4" (hydroxysilanetriyl)tris(triphenyl-4-carboxylic acid), represents a rare example of a highly symmetrical coordination network and extremely tight self-catenation. To the best of our knowledge, SDU-9 has the highest topological density among all known 3,4-coordinated nets. PMID- 24060190 TI - The free scapular/parascapular flap as a reliable method of reconstruction in the head and neck region: a retrospective analysis of 130 reconstructions performed over a period of 5 years in a single department. AB - BACKGROUND: The scapular/parascapular free flap was described by Saijo in 1978 and has since then been widely used in reconstructive procedures. MATERIALS AND METHODS: This is a retrospective study, describing our experience with the use of free scapula/parascapular flap in 130 reconstructions over a period of 5 years in the Department of Oral and Maxillofacial Surgery of the University Hospital of Erlangen. Demographical data, data regarding the underlying pathology, flap raising details, microvascular anastomoses, early and late postoperative complications will be presented. RESULTS: The flap was raised without problems and the donor site was primarily closed in all cases. Sixteen flaps required revision. Five transplants were lost (failure rate of 3.85%). Loss of part of the flap was observed in 3 cases (2.3%). CONCLUSION: The free scapula/parascapular flap is a versatile and reliable flap that can find many applications in the reconstruction of complex head and neck defects. PMID- 24060191 TI - Plasma haemostatic potential of haemodialysis patients assessed by thrombin generation assay: hypercoagulability in patients with vascular access thrombosis. AB - INTRODUCTION: Patients with end-stage renal disease (ESRD) on maintenance haemodialysis are predisposed to bleeding and thrombotic events. Recently thrombin generation assay (TGA) has been introduced as a laboratory assessment of global haemostatic potential. We investigated the global haemostatic potential assessed by TGA in ESRD patients on haemodialysis and patients who developed vascular access thrombosis. MATERIALS AND METHODS: A total of 69 ESRD patients who underwent haemodialysis (58 stable patients and 11 vascular access thrombosis patients) were included and 33 healthy controls were included. TGA was performed on the calibrated automated thrombogram using tissue factor with/without addition of thrombomodulin or activated protein C, producing three parameters including lag time, endogenous thrombin potential (ETP) and peak thrombin. RESULTS: Haemodialysis patients showed low ETP values measured by thrombin generation assay compared with the healthy controls. Interestingly, patients with vascular access thrombosis exhibited short PT and aPTT and increased resistance of coagulation inhibition to APC anticoagulant protein, reflecting hyper coagulability. Haemodialysis patients who are taking anti-platelet agents showed decreased thrombin inhibition rate, representing antithrombotic effect of anti platelet agents. CONCLUSION: Whereas the haemodialysis patients showed hypo coagulability, the patients with vascular access thrombosis exhibited hyper coagulability. Further study is required to investigate how this haemostatic potential may be utilized to guide the physician to more effective management of haemostatic complication. PMID- 24060192 TI - Midregional proadrenomedullin (MR-proADM) in the risk stratification of patients with acute pulmonary embolism. AB - INTRODUCTION: According to current ESC guidelines not only hemodynamic parameters, but also indices of right ventricular dysfunction such as NT-proBNP have a significant prognostic value in acute pulmonary embolism (PE). MR-proADM is a significant predictor of short-term mortality in acute heart failure and adds prognostic value to NT-proBNP. We hypothesized that plasma MR-proADM is elevated in acute PE, correlates with the severity of PE and has prognostic value. We also compared prognostic values of MR-proADM and NT-proBNP for the prediction of early mortality in acute PE. MATERIAL & METHODS: We studied 98 patients (51F/47M, 59.6 +/- 18.4 yr) with acute PE. On admission blood samples were collected for MR-proADM and NT-proBNP. RESULTS: MR-proADM reflected the severity of acute PE: 0.734 nmol/L in low-risk acute PE (0.384-1.342), 0.995 nmol/L in intermediate-risk acute PE (0.394-7.499) and 2.062 nmol/L in high-risk acute PE (0.447-3.098), p<0.001. MR-proADM was higher in non-survivors than in survivors 2.123 nmol/L (1.543-4.220), vs. 0.910 nmol/L (0.384-7.449), p=0.0003. The AUC of MR-proADM and NT-proBNP ROC curves for predicting all-cause mortality were 0.935 (95% CI 0.861-0.977) and 0.844 (95% CI 0.749-0. 913), respectively. In univariable analysis NT-proBNP and MR-proADM were significant predictors of all cause mortality HR 1.00 (95% CI 1.000-1.0002, p=0.029) and 1.65 (95% CI 1.214 - 2.249, p=0.015). However, in multivariate analysis, MR-proADM but not NT-proBNP was a significant predictor of all-cause mortality. CONCLUSION: NT-proBNP and MR proADM are of similar predictive value in the assessment of outcome in acute PE, however MR-proADM seems to be superior in predicting all-cause mortality. PMID- 24060193 TI - Is skills training necessary for the primary prevention of marital distress and dissolution? A 3-year experimental study of three interventions. AB - OBJECTIVE: Evidence in support of skill-based programs for preventing marital discord and dissolution, while promising, comes mainly from studies using single treatment conditions, passive assessment-only control conditions, and short-term follow-up assessments of relationship outcomes. This study overcomes these limitations and further evaluates the efficacy of skill-based programs. METHOD: Engaged and newlywed couples (N = 174) were randomly assigned to a 4-session, 15 hr small-group intervention designed to teach them skills in managing conflict and problem resolution (PREP) or skills in acceptance, support, and empathy (CARE). These couples were compared to each other, to couples receiving a 1 session relationship awareness (RA) intervention with no skill training, and to couples receiving no treatment on 3-year rates of dissolution and 3-year trajectories of self-reported relationship functioning. RESULTS: Couples in the no-treatment condition dissolved their relationships at a higher rate (24%) than couples completing PREP, CARE, and RA, who did not differ on rates of dissolution (11%). PREP and CARE yielded unintended effects on 3-year changes in reported relationship behaviors. For example, wives receiving PREP showed slower declines in hostile conflict than wives receiving CARE, and husbands and wives receiving CARE showed faster declines in positive behaviors than husbands and wives receiving PREP. CONCLUSIONS: These findings highlight the potential value of cost effective interventions such as RA, cast doubt on the unique benefits of skill based interventions for primary prevention of relationship dysfunction, and raise the possibility that skill-based interventions may inadvertently sensitize couples to skill deficits in their relationships. PMID- 24060194 TI - Randomized controlled trial of parent-enhanced CBT compared with individual CBT for obsessive-compulsive disorder in young people. AB - OBJECTIVE: Obsessive-compulsive disorder (OCD) in young people can be effectively treated with Cognitive Behavior Therapy (CBT). Practice guidelines in the United Kingdom recommend that CBT be delivered with parental or family involvement; however, there is no evidence from randomized trials that this enhances effectiveness. The aim of this trial was to assess if CBT with high parental involvement was more effective than CBT with low parental involvement (individual CBT) in reducing symptoms of OCD. METHOD: Fifty young people ages 12-17 years with OCD were randomly allocated to individual CBT or parent-enhanced CBT. In parent-enhanced CBT parents attended all treatment sessions; in individual CBT, parents attended only Sessions 1, 7, and the final session. Participants received up to 14 sessions of CBT. Data were analyzed using intent-to-treat and per protocol methods. The primary outcome measure was the Children's Yale-Brown Obsessive Compulsion Scale (Scahill et al., 1997). RESULTS: Both forms of CBT significantly reduced symptoms of OCD and anxiety. Change in OCD symptoms was maintained at 6 months. Per-protocol analysis suggested that parent-enhanced CBT may be associated with significantly larger reductions in anxiety symptoms. CONCLUSIONS: High and low parental involvement in CBT for OCD in young people were both effective, and there was no evidence that 1 method of delivery was superior on the primary outcome measure. However, this study was small. Future trials should be adequately powered and examine interactions with the age of the young person and comorbid anxiety disorders. PMID- 24060195 TI - Therapist-aided exposure for women with lifelong vaginismus: a randomized waiting list control trial of efficacy. AB - OBJECTIVE: Vaginismus is commonly described as a persistent difficulty in allowing vaginal entry of a penis or other "objects" (e.g., tampons, fingers, speculum). Lifelong vaginismus is diagnosed when a woman has never been able to have intercourse. The aim of this study was to investigate the efficacy of therapist-aided exposure for lifelong vaginismus. METHOD: Seventy women and their partners were randomly allocated to exposure or a waiting-list control period of 3 months. The main outcome measure (intercourse ability) was assessed daily during 12 weeks. Secondary outcome measures were complaints about vaginismus, coital pain, coital fear, sexual distress, and sexual functioning. The exposure treatment consisted of a maximum of three 2-hr sessions during 1 week at a university hospital. Each participant performed vaginal penetration exercises herself, in the presence of her partner and a female therapist. Two follow-up sessions were scheduled over a 5-week period. RESULTS: Thirty-one out of 35 (89%; 95% CI [72%, 96%]) participants reported having had sexual intercourse at posttreatment compared with 4 out of 35 (11%; 95% CI [4%, 28%]) participants in the control condition. In most of the successfully treated women (90%), intercourse was possible within the first 2 weeks of treatment. Moreover, treatment resulted in clinical improvement regarding other symptoms related to vaginismus, coital fear, coital pain, and sexual distress. No treatment effects were found regarding other aspects of sexual functioning in women or their partners. CONCLUSIONS: This study provides evidence of the efficacy of therapist aided exposure therapy for women with lifelong vaginismus. PMID- 24060196 TI - Ensuring the sustainability of the Taiwan National Health Insurance. PMID- 24060197 TI - Second-line pemetrexed treatment in Taiwanese patients with advanced nonsmall cell lung cancer: an open-label single-arm study. AB - BACKGROUND/PURPOSE: Although global and Asian studies on second-line pemetrexed for the treatment of advanced nonsmall cell lung cancer have confirmed its efficacy and safety, a pivotal postcommitment study to consolidate the evidence regarding the Taiwanese population was warranted. This open-label single-arm study assessed the objective response rate to a tailored dose of single-agent pemetrexed in Taiwanese patients with advanced nonsmall cell lung cancer who had received prior chemotherapy. METHODS: Patients with stage IIIB/IV disease were treated with pemetrexed on day 1 of each 21-day cycle. A 500 mg/m(2) dose was administered in cycle 1. For cycle 2, the dose was increased to 1000 mg/m(2) (if there was no toxicity above predefined levels) or decreased to 375 mg/m(2). All patients received standard supplemental therapy. Patient follow-up continued until 18 months after the last patient was enrolled in this study or death. All patients were included in all analyses. RESULTS: Of the 33 patients who were enrolled, 25 (75.8%) received the 1000 mg/m(2) dose during cycle 2; 18 patients were dropped from the study, including 17 (51.5%) who had died by the time of analysis. The objective response and disease control rates were 18.2% (95% confidence limits [CI]: 7.0-35.5) and 54.5% (95% CI: 36.4-71.9), respectively. No patients exhibited a complete response. There were two serious drug-related adverse events (neutropenia and leukopenia) and two drug-related adverse events that resulted in removal from the study. Decreased neutrophil/granulocyte counts were the most frequently observed drug-related grade 3/4 events (9 patients, 24 treatment cycles). CONCLUSION: The objective response rate, disease control rate, and safety and tolerability profile in this population of Taiwanese patients were consistent with the published findings that were conducted using Asian and Western populations. These findings support the use of single-agent, second-line pemetrexed for the treatment of advanced nonsmall cell lung cancer in Taiwanese patients. PMID- 24060198 TI - Intrathoracic gastric volvulus as a severe, delayed surgical complication after left subphrenic peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced ovarian cancer. AB - Patients with extensive peritoneal spread from advanced ovarian cancer often undergo several upper abdominal surgical procedures including subphrenic peritonectomy to obtain optimal cytoreduction. The most common complications are pleural effusions, pancreatic leakage and endoabdominal collections. This case report describes an unusual complication, a diaphragmatic hernia with an intrathoracic gastric volvulus developing four months after the patient underwent left subphrenic peritonectomy during interval debulking surgery and hyperthermic intraperitoneal chemotherapy for advanced ovarian cancer. PMID- 24060200 TI - Chloramphenicol acetyltransferase as a selection marker for chlamydial transformation. AB - BACKGROUND: Chlamydia is a common bacterial pathogen responsible for many diseases. Methods for transforming this important organism using a beta-lactamase as a selection marker have been developed very recently. However, the National Institutes of Health Guidelines for Research Involving Recombinant DNA Molecules do not permit transformation experiments with beta-lactamase gene-containing vectors for certain human chlamydial pathogens. Therefore, a different selection marker is urgently needed for transformation of those chlamydiae. RESULTS: After transformation of plasmid-free Chlamydia trachomatis with pGFP:SW2, which carries a beta-lactamase and a chloramphenicol acetyltransferase gene fused to a green fluorescence protein gene, transformants were obtained by selection with either ampicillin or chloramphenicol. Stable chloramphenicol-resistant, but ampicillin sensitive, transformants were obtained using a pGFP:SW2 derivative without the beta-lactamase. All transformants expressed green fluorescence protein and had glycogen synthesis activity restored. CONCLUSIONS: Chloramphenicol resistance may be used as a selection marker for genetic experiments in Chlamydia. This eliminates the requirement for the use of beta-lactamase, of which dissemination to some C. trachomatis serovars may jeopardize clinical treatment of chlamydial infections in pregnant women. Chloramphenicol acetyltransferase may also serve as a useful secondary selection marker for genetic analyses in beta-lactamase transformed chlamydial strains. PMID- 24060201 TI - Copper-catalyzed activation of alpha-amino peroxy and hydroxy intermediates to iminium ion precursor: an access to C4-substituted 3,4-dihydroquinazolines via oxidative cross coupling strategy. AB - A simple and straightforward approach to access C4-substituted-3,4 dihydroquinazolines has been achieved, where copper-catalyzed activation of alpha amino peroxide and hydroxide intermediates to iminium ion precursors has been realized as an important step. Reactions of these intermediates with alkynes, indoles, pyrrole, and silylenol ether afforded the structurally diverse C4 substituted-3,4-dihydroquinazoline derivatives in good yields. PMID- 24060202 TI - Perinatal depression. PMID- 24060203 TI - Managing haematological disorders during pregnancy. AB - The management of patients with pre-existing haematological diseases during pregnancy can be particularly challenging. The potential maternal and foetal toxicities from treatment regimens including chemotherapy for malignant haematological disorders mean that joint management between obstetricians and haematologists is essential for achieving good outcomes for both mother and baby. Patients with inherited or acquired disorders of haemostasis including platelets (essential thrombocythaemia) and coagulation (antiphospholipid syndrome) resulting in a pro-thrombotic state also require special consideration as pregnancy is generally considered to be a pro-thrombotic condition which could exacerbate the pre-existing disorder. The choice, timing and duration of anticoagulation or anti-platelet therapy require careful coordination during the antenatal, perinatal as well as postnatal periods to ensure that both maternal and foetal risks are taken into consideration. Pregnancy in women with sickle cell disease has long been identified as high risk with medical and pregnancy related risks being more common compared to women without it. A range of foetal risks have also been reported but improvement in outcomes has been seen with better obstetric and haematological care and the emphasis on multidisciplinary teamwork. The meticulous management of iron overload and risks associated with repeated blood transfusions extends into the care of pregnant women with other haemoglobinopathies like thalassemias. PMID- 24060204 TI - Staff training makes a difference: improvements in neonatal illicit drug testing and intervention at a tertiary hospital. AB - OBJECTIVE: This project explored the impact of staff training on the rates of perinatal maternal and neonatal illicit drug testing. METHODS: Controlled, retrospective chart review on 1186 newborn and mother dyads from 2006 (pre training control group) and on 1861 dyads from 2009 (post-training study group) was completed. Differences between rates of infant and mother drug testing were compared. RESULTS: Increased drug testing rates for the mothers and infants led to increased case finding that tripled both for the mothers (13-3.7%, p < 0.001) and for the infants (0.9-2.9%, p < 0.001). Missed opportunities for newborn testing was reduced by 35 times (20.9-0.6%, p < 0.001). CONCLUSION: This retrospective study led to an increase in the number of documented drug-exposed newborns. This research emphasizes the importance of and encourages other hospitals to analyze the efficacy of their current protocol and staff training practices in place to ensure the best child protection services. PMID- 24060205 TI - Cubic and sponge phases in ether lipid-solvent-water ternary systems: phase behavior and NMR characterization. AB - The phase behavior of 1-glyceryl monoleyl ether (GME) in mixtures of water and the solvents 1,5-pentanediol (POL) or N-methyl-2-pyrrolidone (NMP) was investigated by ocular inspection, polarization microscopy, and small-angle X-ray diffraction (SAXD). Phase diagrams were constructed based on analyses of more than 200 samples prepared using the two different solvents at 20 degrees C. The inverse hexagonal phase formed by GME in excess of water was transformed into the cubic and sponge phase with the increasing amount of each solvent. Particularly POL allowed for the formation of an extended sponge phase area in the phase diagram, comprising up to 70% POL-water mixture. The phase behavior using NMP was found to be similar to the earlier investigated solvent propylene glycol. The extended sponge phase for the POL system was attributed to POLs strong surface/interfacial activity with the potential to stabilize the polar/apolar interface of the sponge phase. The cubic and sponge phases formed using POL were further studied by NMR in order to measure the partitioning of POL between the lipid and aqueous domains of the phases. The domain partition coefficient K (lipid domain/aqueous domain) for POL in cubic and sponge phases was found to be 0.78 +/- 0.14 and constant for the two phases. PMID- 24060199 TI - Dynamic logistic regression model and population attributable fraction to investigate the association between adherence, missed visits and mortality: a study of HIV-infected adults surviving the first year of ART. AB - BACKGROUND: Adherence is one of the most important determinants of viral suppression and drug resistance in HIV-infected people receiving antiretroviral therapy (ART). METHODS: We examined the association between long-term mortality and poor adherence to ART in DART trial participants in Uganda and Zimbabwe randomly assigned to receive laboratory and clinical monitoring (LCM), or clinically driven monitoring (CDM). Since over 50% of all deaths in the DART trial occurred during the first year on ART, we focussed on participants continuing ART for 12 months to investigate the implications of longer-term adherence to treatment on mortality. Participants' ART adherence was assessed by pill counts and structured questionnaires at 4-weekly clinic visits. We studied the effect of recent adherence history on the risk of death at the individual level (odds ratios from dynamic logistic regression model), and on mortality at the population level (population attributable fraction based on this model). Analyses were conducted separately for both randomization groups, adjusted for relevant confounding factors. Adherence behaviour was also confounded by a partial factorial randomization comparing structured treatment interruptions (STI) with continuous ART (CT). RESULTS: In the CDM arm a significant association was found between poor adherence to ART in the previous 3-9 months with increased mortality risk. In the LCM arm the association was not significant. The odds ratios for mortality in participants with poor adherence against those with optimal adherence was 1.30 (95% CI 0.78,2.10) in the LCM arm and 2.18 (1.47,3.22) in the CDM arm. The estimated proportions of deaths that could have been avoided with optimal adherence (population attributable fraction) in the LCM and CDM groups during the 5 years follow-up period were 16.0% (95% CI 0.7%,31.6%) and 33.1% (20.5%,44.8%), correspondingly. CONCLUSIONS: Recurrent poor adherence determined even through simple measures is associated with high mortality both at individual level as well as at the ART programme level. The number of lives saved through effective interventions to improve adherence could be considerable particularly for individuals monitored without using CD4 cell counts. The findings have important implications for clinical practice and for developing interventions to enhance adherence. PMID- 24060206 TI - Evaluation of underreporting of salmonellosis and shigellosis hospitalised cases in Greece, 2011: results of a capture-recapture study and a hospital registry review. AB - BACKGROUND: Salmonellosis and shigellosis are mandatorily notifiable diseases in Greece. Underreporting of both diseases has been postulated but there has not been any national study to quantify it. The objective of this study was to: a) estimate underreporting of hospitalised cases at public Greek hospitals in 2011 with a capture-recapture (C-RC) study, b) evaluate the accuracy of this estimation, c) investigate the possible impact of specific factors on notification rates, and d) estimate community incidence of both diseases. METHODS: The mandatory notification system database and the database of the National Reference Laboratory for Salmonella and Shigella (NRLSS) were used in the C-RC study. The estimated total number of cases was compared with the actual number found by using the hospital records of the microbiological laboratories. Underreporting was also estimated by patients' age-group, sex, type of hospital, region and month of notification. Assessment of the community incidence was based on the extrapolation of the hospitalisation rate of the diseases in Europe. RESULTS: The estimated underreporting of salmonellosis and shigellosis cases through the C-RC study was 47.7% and 52.0%, respectively. The reporting rate of salmonellosis significantly varied between the thirteen regions of the country from 8.3% to 95.6% (median: 28.4%). Age and sex were not related to the probability of reporting. The notification rate did not significantly differ between urban and rural areas, however, large university hospitals had a higher underreporting rate than district hospitals (p-value < 0.001). The actual underreporting, based on the hospital records review, was close to the estimated via the C-RC study; 52.8% for salmonellosis and 58.4% for shigellosis. The predicted community incidence of salmonellosis ranged from 312 to 936 and of shigellosis from 35 to 104 cases per 100,000 population. CONCLUSIONS: Underreporting was higher than that reported by other countries and factors associated with underreporting should be further explored. C-RC analysis seems to be a useful tool for the assessment of the underreporting of hospitalised cases. National data on underreporting and under-ascertainment rate are needed for assessing the accuracy of the estimation of the community burden of the diseases. PMID- 24060208 TI - Reactivity with electrophiles of imido groups supported on trinuclear titanium systems. AB - Several trinuclear titanium complexes bearing amido MU-NHR, imido MU-NR, and nitrido MUn-N ligands have been prepared by reaction of [{Ti(eta(5)-C5Me5)(MU NH)}3(MU3-N)] (1) with 1 equiv of electrophilic reagents ROTf (R = H, Me, SiMe3; OTf = OSO2CF3). Treatment of 1 with triflic acid or methyl triflate in toluene at room temperature affords the precipitation of compounds [Ti3(eta(5)-C5Me5)3(MU3 N)(MU-NH)2(MU-NH2)(OTf)] (2) or [Ti3(eta(5)-C5Me5)3(MU3-N)(MU-NH)(MU-NH2)(MU NMe)(OTf)] (3). Complexes 2 and 3 exhibit a fluxional behavior in solution consisting of proton exchange between MU-NH2 and MU-NH groups, assisted by the triflato ligand, as could be inferred from a dynamic NMR spectroscopy study. Monitoring by NMR spectroscopy the reaction course of 1 with MeOTf allows the characterization of the methylamido intermediate [Ti3(eta(5)-C5Me5)3(MU3-N)(MU NH)2(MU-NHMe)(OTf)] (4), which readily rearranges to give 3 by a proton migration from the NHMe amido group to the NH imido ligands. The treatment of 1 with 1 equiv of Me3SiOTf produces the stable ionic complex [Ti3(eta(5)-C5Me5)3(MU3-N)(MU NH)2(MU-NHSiMe3)][OTf] (5) with a disposition of the nitrogen ligands similar to that of 4. Complex 5 reacts with 1 equiv of [K{N(SiMe3)2}] at room temperature to give [Ti3(eta(5)-C5Me5)3(MU3-N)(MU-N)(MU-NH)(MU-NHSiMe3)] (6), which at 85 degrees C rearranges to the trimethylsilylimido derivative [Ti3(eta(5) C5Me5)3(MU3-N)(MU-NH)2(MU-NSiMe3)] (7). Treatment of 7 with [K{N(SiMe3)2}] affords the potassium derivative [K{(MU3-N)(MU3-NH)(MU3-NSiMe3)Ti3(eta(5) C5Me5)3(MU3-N)}] (8), which upon addition of 18-crown-6 leads to the ion pair [K(18-crown-6)][Ti3(eta(5)-C5Me5)3(MU3-N)(MU-N)(MU-NH)(MU-NSiMe3)] (9). The X-ray crystal structures of 2, 5, 6, and 8 have been determined. PMID- 24060207 TI - Therapeutic efficacy of fixed dose artesunate-mefloquine for the treatment of acute, uncomplicated Plasmodium falciparum malaria in Kampong Speu, Cambodia. AB - BACKGROUND: Cambodia stopped using co-blistered, non-fixed, artesunate-mefloquine (ASMQ) in 2008 when treatment failure rates approximated 20%. Fixed dose combination (FDC) ASMQ is efficacious against acute uncomplicated, drug resistant Plasmodium falciparum malaria in Southeast Asia but has not been tested in Cambodia. METHODS: A 42-day WHO therapeutic efficacy study (TES) was conducted in 2010 in Oral, Kampong Speu province, south-west Cambodia, in patients with acute uncomplicated P. falciparum. Daily administered FDC ASMQ for three days was dosed by age. Genotyping of isolates at day 0 and day of recrudescence by polymerase chain reaction (PCR) classified post-treatment recurrent falciparum parasitaemia. Ex vivo drug sensitivity testing ([3H] hypoxanthine method) was performed on baseline parasites and reported as the drug concentration inhibiting 50% parasite growth vs no drug (IC50). RESULTS: Recruited patients numbered 45; five aged <15 years. On day 3, five of 45 [11.1 (3.7-24.05)] % patients were still parasite positive; one of whom later failed treatment on day 21. There were 5/45 (11.1%) late treatment failures on day 21, 28 and 35; all were PCR diagnosed recrudescent infections. The day 0 MQ IC50s ranged from 11.5-238.9 (median 58.6) nM. CONCLUSIONS: This TES demonstrated reasonable efficacy in an area of possible reduced artemisinin sensitivity and high MQ IC50s. Efficacy testing of FDC ASMQ should continue in Cambodia and be considered for reintroduction if efficacy returns. PMID- 24060209 TI - Effect of carbon dioxide pneumoperitoneal pressure on the ultrastructure of implanted endometriotic lesions in a rat model. AB - OBJECTIVE: To evaluate the effect of carbon dioxide (CO2) pneumoperitonal pressure on the ultrastructure of implanted endometriotic lesions in a rat model. STUDY DESIGN: An endometriotic model was established in Sprague-Dawley rats with peritoneal implantation of their own endometrial tissue to form ectopic endometrial tissue. Thirty rats were divided at random into three groups: control group, 10 mmHg CO2 pneumoperitoneum group and 20 mmHg CO2 pneumoperitoneum group. CO2 inflation lasted for 1 h in both pneumoperitoneum groups. Selected endometriotic lesions were examined by electron microscopy 1 week after CO2 pneumoperitoneum to determine changes in the ultrastructure of cell organelles of glandular and stromal cells. RESULTS: In the control group, stromal cells had an orderly arrangement, and the structure of the microvilli was normal. The 10 mmHg and 20 mmHg CO2 pneumoperitoneum groups had increased chromatin margination of glandular epithelial cells, reduced or absent mitochondrial cristae and mitochondrial swelling. Further ultrastructural damage included reduced or absent microvilli, widened or collapsed cell junctions, and stromal cells with a disorderly arrangement. Ultrastructural damage of glandular epithelial cells was more severe in the 20 mmHg group compared with the 10 mmHg group. CONCLUSION: CO2 pneumoperitoneum leads to significant ultrastructural damage of endometriotic lesions. Higher CO2 pneumoperitoneal pressure resulted in more damage than lower CO2 pneumoperitoneal pressure. PMID- 24060211 TI - Human T-cell leukemia virus type 1: replication, proliferation and propagation by Tax and HTLV-1 bZIP factor. AB - Human T-cell leukemia virus type 1 (HTLV-1) spreads primarily by cell-to-cell transmission. Therefore, HTLV-1 promotes the proliferation of infected cells to facilitate transmission. In HTLV-1 infected individuals, the provirus is present mainly in effector/memory T cells and Foxp3+ T cells. Recent study suggests that this immunophenotype is acquired by infected cells through the function of HTLV-1 bZIP factor (HBZ). Tax, which is encoded by the plus strand, is crucial for viral replication and de novo infection, while HBZ, encoded by the minus strand, is important for proliferation of infected cells. Importantly, HBZ and Tax have opposing functions in most transcription pathways. HBZ and Tax cooperate in elaborate ways to permit viral replication, proliferation of infected cells and propagation of the virus. PMID- 24060210 TI - Assessing the reproducibility of the IOTA simple ultrasound rules for classifying adnexal masses as benign or malignant using stored 3D volumes. AB - OBJECTIVE: To analyze the reproducibility of the IOTA simple ultrasound rules for classifying adnexal masses as benign or malignant among examiners with different level of expertise using stored 3D volumes of adnexal masses. STUDY DESIGN: Five examiners, with different levels of experience and blinded to each other, evaluated 100 stored 3D volumes from adnexal masses and looked for the presence or absence of malignant or benign features according to the IOTA definitions. Multiplanar view and virtual navigation were used. All examiners had to assess the 3D volume of each adnexal mass and classify it as benign or malignant. To analyze intra-observer agreement each examiner performed the assessment twice with a two-week interval between the first and second assessments. To analyze the inter-observer agreement, the second assessment from each examiner was used. Reproducibility was assessed calculating the weighted Kappa index. RESULTS: Intra observer reproducibility was moderate or good for all observers (Kappa index ranging from 0.59 to 0.74). Inter-observer reproducibility was moderate to good (Kappa index range: 0.46-0.67). CONCLUSIONS: The simple rules are reasonably reproducible among observers with different level of expertise when assessed in stored 3D volumes. PMID- 24060212 TI - Upregulation of the proinflammatory cytokine-induced neutrophil chemoattractant-1 and monocyte chemoattractant protein-1 in rats' intestinal anastomotic wound healing--does it matter? AB - BACKGROUND: The proinflammatory cytokines and growth-promoting factor are essential components of the wound healing process. We hypothesized that under healthy conditions, faster healing of intestinal anastomotic wound is due to an early upregulation of proinflammatory cytokines, cytokine-induced neutrophil chemoattractant-1 (CINC-1) that is followed by a quicker upregulation of homeostatic chemokine, monocyte chemoattractant protein-1 (MCP-1) and late upregulation of transforming growth factor (TGF-beta). METHODS: We characterized the time course of CINC-1, MCP-1 and TGF-beta release at four wounds (skin, muscle, small bowel, and colonic anastomosis) after surgery on 38 juvenile male Sprague Dawley rats. The tissue samples of each site were harvested at 0 (control), 1, 3, 5, 7 and 14 days postoperatively (n = 6-8/group) and analyzed by ELISA kits for CINC-1, MCP-1 and TGF-beta. RESULTS: CINC-1 expression peaked earlier in muscle and colonic wounds when compared to skin and small bowel. MCP-1 levels were elevated early in skin and muscle wounds, but later expression of MCP 1 was shown in colonic wounds. TGF-beta levels were unchanged in all wound sites. CONCLUSION: An earlier peak in CINC-1 levels and later expression of MCP-1 were seen in colonic wounds, but no significant increase in TGF-beta levels was observed. These findings support the early healing process in intestinal anastomotic wounds. PMID- 24060213 TI - Response to: 'Comment on: Seizure-induced excitotoxicity: just considering it could be a fallacy'. PMID- 24060214 TI - Production of high titre antibody response against Russell's viper venom in mice immunized with ethanolic extract of fruits of Piper longum L. (Piperaceae) and piperine. AB - Piper longum L. fruits have been traditionally used against snakebites in north eastern and southern region of India. The aim of the study was to assess the production of antibody response against Russell's viper venom in mice after prophylactic immunization with ethanolic extract of fruits of Piper longum L. and piperine. The mice sera were tested for the presence of antibodies against Russell's viper venom by in vitro lethality neutralization assay and in vivo lethality neutralization assay. Polyvalent anti-snake venom serum (antivenom) manufactured by Haffkine Bio-Pharmaceutical Corporation Ltd. was used as standard. Further confirmation of presence of antibodies against the venom in sera of mice immunized with PLE and piperine was done using indirect enzyme linked immunosorbent assay (ELISA) and double immunodiffusion test. Treatment with PLE-treated mice serum and piperine-treated mice serum was found to inhibit the lethal action of venom both in the in vitro lethality neutralization assay and in vivo lethality neutralization assay. ELISA testing indicated that there were significantly high (p<0.01) levels of cross reactions between the PLE and piperine treated mice serum and the venom antigens. In double immunodiffusion test, a white band was observed between the two wells of antigen and antibodies for both the PLE-treated and piperine-treated mice serum. Thus it can be concluded that immunization with ethanolic extract of fruits of Piper longum and piperine produced a high titre antibody response against Russell's viper venom in mice. The antibodies against PLE and piperine could be useful in antivenom therapy of Russell's viper bites. PLE and piperine may also have a potential interest in view of the development of antivenom formulations used as antidote against snake bites. PMID- 24060215 TI - Effects of ophiopogonin D and spicatoside A derived from Liriope Tuber on secretion and production of mucin from airway epithelial cells. AB - In the present study, we investigated whether aqueous extract of Liriope Tuber, ophiopogonin D and spicatoside A derived from Liriope Tuber affect basal or phorbol ester (phorbol 12-myristate 13-acetate, PMA)-induced airway mucin production and secretion from airway epithelial cells. Confluent NCI-H292 cells were treated with each agent for 24 h (basal production) or pretreated with each agent for 30 min and then stimulated with PMA for 24 h (PMA-induced production and secretion), respectively. MUC5AC airway mucin production and secretion were measured by ELISA. The results were as follows: (1) aqueous extract of Liriope Tuber stimulated basal mucin production and did not inhibit but increased PMA induced mucin production; (2) ophiopogonin D and spicatoside A stimulated basal mucin production and did not inhibit but increased PMA-induced mucin production; (3) two compounds increased PMA-induced mucin secretion. These results suggest that ophiopogonin D and spicatoside A can increase mucin production and secretion, by directly acting on airway epithelial cells and, at least in part, explain the traditional use of aqueous extract of Liriope Tuber as expectorants in diverse inflammatory pulmonary diseases. PMID- 24060216 TI - Curcumin is a direct inhibitor of glucose transport in adipocytes. AB - Curcumin has been reported to inhibit insulin signaling and translocation of GLUT4 to the cell surface in 3T3-L1 adipocytes. We have investigated the effect of curcumin on insulin signaling in primary rat adipocytes. Curcumin (20 MUM) inhibited both basal and insulin-stimulated glucose transport (2-deoxyglucose uptake), but had no effect on insulin inhibition of lipolysis. Dose-response experiments demonstrated that curcumin (0-100 MUM) inhibited basal and insulin stimulated glucose transport, but even at the highest concentration tested did not affect lipolysis. Inhibition was equal in cells that had been pre-incubated with curcumin and in cells to which curcumin was added immediately before the glucose transport assay. Similarly, time-course experiments revealed that the inhibitory effect of curcumin was evident at the earliest time point tested (30 s). Thus it is unlikely that inhibition of insulin signaling or of translocation of GLUT4 to the cell surface is involved in the inhibitory effect of curcumin. Curcumin did not affect the stimulatory action of insulin on phosphorylation of Akt at serine 473. We conclude that curcumin is a direct inhibitor of glucose transporters in rat adipocytes. PMID- 24060217 TI - Effects of fermented rooibos (Aspalathus linearis) on adipocyte differentiation. AB - Rooibos (Aspalathus linearis) contains a rich complement of polyphenols, including flavonoids, considered to be largely responsible for its health promoting effects, including combatting obesity. The purpose of this study was to examine the effect of fermented rooibos hot water soluble solids on in vitro adipocyte differentiation by using differentiating 3T3-L1 adipocytes. Hot water soluble solids were obtained when preparing an infusion of fermented rooibos at "cup-of-tea" strength. The major phenolic compounds (>5 mg/g) were isoorientin, orientin, quercetin-3-O-robinobioside and enolic phenylpyruvic acid-2-O-beta-D glucoside. Treatment of 3T3-L1 adipocytes with 10 MUg/ml and 100 MUg/ml of the rooibos soluble solids inhibited intracellular lipid accumulation by 22% (p<0.01) and 15% (p<0.05), respectively. Inhibition of adipogenesis was accompanied by decreased messenger RNA (mRNA) expression of PPARgamma, PPARalpha, SREBF1 and FASN. Western blot analysis exhibited decreased PPARalpha, SREBF1 and AMPK protein expression. Impeded glycerol release into the culture medium was observed after rooibos treatment. None of the concentrations of rooibos hot water soluble solids was cytotoxic, in terms of ATP content. Interestingly, the higher concentration of hot water soluble solids increased ATP concentrations which were associated with increased basal glucose uptake. Decreased leptin secretion was observed after rooibos treatment. Our data show that hot water soluble solids from fermented rooibos inhibit adipogenesis and affect adipocyte metabolism, suggesting its potential in preventing obesity. PMID- 24060218 TI - A meta-analysis and systematic review: adjuvant interferon therapy for patients with viral hepatitis-related hepatocellular carcinoma. AB - OBJECTIVE: To evaluate the efficacy and safety of adjuvant IFN therapy for viral hepatitis-related hepatocellular carcinoma (HCC) after treatment with surgical resection or transarterial chemoembolization (TACE). METHODS: Controlled trials of adjuvant treatment with IFN for patients with HCC published between 2000 and 2012 were searched electronically in MEDLINE, PubMed, Cochrane Library, and EMBASE databases. According to the heterogeneity of the studies, two different models - the fixed-effect model and the random-effect model - were applied to analyze the results. RESULTS: Ten trials were screened according to inclusion and exclusion standards. Eight randomized, controlled trials and two non-randomized, controlled trials were included. These ten trials with a total of 1,029 subjects were eventually involved in the meta-analysis; 528 HCC patients were treated with adjuvant treatment with IFN and 501 patients with placebo. Compared to the control group, the recurrence rates of HCC in IFN group were significantly lower (odds ratio (OR) = 0.66; 95% confidence interval (CI) = 0.50 to 0.86; P = 0.02), especially after TACE treatment according to subgroup analysis (OR = 0.73; 95% CI = 0.52 to 1.01; P = 0.06 for surgical resection; and OR = 0.54; 95% CI = 0.33 to 0.86, P = 0.01 for TACE). The death rates in the IFN group also significantly decreased according to not only total events analysis (OR = 0.42; 95% CI = 0.32 to 0.56; P < 0.00001) but also subgroup analysis (OR = 0.51; 95% CI = 0.36 to 0.72; P = 0.0002 for surgical resection; and OR = 0.33; 95% CI = 0.21 to 0.50; P < 0.00001 for TACE). CONCLUSIONS: Adjuvant IFN therapy may significantly reduce the recurrence rates of patients with viral hepatitis-related HCC and improve the survival of patients after surgical resection or TACE. The ideal dose mostly selected is 3 MIU/ml, three times per week, which can make patients tolerate the adverse reactions of IFN better and maintain effective concentrations for a long time. PMID- 24060219 TI - Multi-dimensional coordination in cross-country skiing analyzed using self organizing maps. AB - This study sought to ascertain how multi-dimensional coordination patterns changed with five poling speeds for 12 National Standard cross-country skiers during roller skiing on a treadmill. Self-organizing maps (SOMs), a type of artificial neural network, were used to map the multi-dimensional time series data on to a two-dimensional output grid. The trajectories of the best-matching nodes of the output were then used as a collective variable to train a second SOM to produce attractor diagrams and attractor surfaces to study coordination stability. Although four skiers had uni-modal basins of attraction that evolved gradually with changing speed, the other eight had two or three basins of attraction as poling speed changed. Two skiers showed bi-modal basins of attraction at some speeds, an example of degeneracy. What was most clearly evident was that different skiers showed different coordination dynamics for this skill as poling speed changed: inter-skier variability was the rule rather than an exception. The SOM analysis showed that coordination was much more variable in response to changing speeds compared to outcome variables such as poling frequency and cycle length. PMID- 24060220 TI - Speed dependant influence of attentional focusing instructions on force production and muscular activity during isokinetic elbow flexions. AB - This experiment assessed the influence of internal (movement) or external (outcome) attentional focusing instructions on force production and muscular activity at different movement speeds. Twenty five participants completed 10 reps of single arm elbow flexions on an isokinetic dynamometer at speeds of 60 degrees , 180 degrees and 300 degrees s(-1) under three conditions (control trial, followed by counterbalanced internal and external focus trials). EMG activity of the biceps brachii and net joint elbow flexor torque were measured. An external focus was associated with significantly lower EMG at all speeds when compared to an internal focus. However, an external focus resulted in greater torque production only at 60 degrees s(-1) when compared to an internal focus. These findings suggest that movement speed may influence the efficacy of different attentional focusing instructions, with implications for the instruction of movements in sport, exercise and rehabilitation settings. PMID- 24060221 TI - Larger plantar flexion torque variability implies less stable balance in the young: an association affected by knee position. AB - The present study examined the association between plantar flexion torque variability during isolated isometric contractions and during quiet bipedal standing. For plantar flexion torque measurements in quiet stance (QS), subjects stood still over a force plate. The mean plantar flexion torque level exerted by each subject in QS (divided by 2 to give the torque due to a single leg) served as the target torque level for right leg force-matching tasks in extended knee (KE) and flexed knee (KF) conditions. Muscle activation levels (EMG amplitudes) of the triceps surae and mean, standard deviation and coefficient of variation of plantar flexion torque were computed from signals acquired during periods with and without visual feedback. No significant correlations were found between EMG amplitudes and torque variability, regardless of the condition and muscle being analyzed. A significant correlation was found between torque variability in QS and KE, whereas no significant correlation was found between torque variability in QS and KF, regardless of vision availability. Therefore, torque variability measured in a controlled extended knee plantar flexion contraction is a predictor of torque variability in the anterior-posterior direction when the subjects are in quiet standing. In other words, larger plantar flexion torque variability in KE (but not in KF) implies less stable balance. The mechanisms underlying the findings above are probably associated with the similar proprioceptive feedback from the triceps surae in QS and KE and poorer proprioceptive feedback from the triceps surae in KF due to the slackening of the gastrocnemii. An additional putative mechanism includes the different torque contributions of each component of the triceps surae in the two knee angles. From a clinical and research standpoint, it would be advantageous to be able to estimate changes in balance ability by means of simple measurements of torque variability in a force matching task. PMID- 24060222 TI - Retrieval practice in motor learning. AB - In this study we sought to determine whether testing promotes the generalization of motor skills during the process of encoding and/or consolidation. We used a dynamic arm movement task that required participants to reproduce a spatial temporal pattern of elbow extensions and flexions with their dominant right arm. Generalization of motor learning was tested by the ability to transfer the original pattern (extrinsic transformation) or the mirrored pattern (intrinsic transformation) to the unpractised left arm. To investigate the testing effects during both encoding and consolidation processing, participants were administered an initial testing session during early practice before being evaluated on a post practice testing session administered either 10min (Testing-Encoding group) or 24hr apart (Testing-Consolidation group), respectively. Control groups were required to perform a post-practice testing session administered after either a 10-min (Control-Encoding group) or 24-hr delay (Control-Consolidation group). The findings revealed that testing produced rapid, within-practice skill improvements, yielding better effector transfer at the 10-min testing for the Testing-Encoding group on both extrinsic and intrinsic transformation tests when compared with the Control-Encoding group. Furthermore, we found better performance for the Testing-Consolidation group at the 24-hr testing for extrinsic and intrinsic transformations of the movement pattern when compared with the Control-Consolidation group. However, our results did not indicate any significant testing advantage on the latent, between-session development of the motor skill representation (i.e., from the 10-min to the 24-hr testing). The testing benefits expressed at the 10-min testing were stabilised but did not extend during the period of consolidation. This indicates that testing contributes to the generalisation of motor skills during encoding but not consolidation. PMID- 24060223 TI - Do knee concentric and eccentric strength and sagittal-plane knee joint biomechanics differ between jumpers and non-jumpers in landing? AB - The purpose of this study was to investigate the differences of knee concentric and eccentric strength and impact related knee biomechanics between jumpers and non-jumpers during step-off landing tasks. Ten male college swimming athletes (non-jumpers) and 10 track and volleyball athletes (jumpers) were recruited to participate in two test sessions: a muscle strength testing session of concentric and eccentric extension for dominant knee joint at 60 degrees /s and 180 degrees /s and a landing testing session. The participants performed five trials of step off landing in each of four conditions: soft and stiff landing from 0.4m and 0.6m landing heights. The three-dimensional kinematics and ground reaction force were recorded simultaneously during step-off landing conditions. The results showed that the jumpers had significantly greater peak knee eccentric extension and concentric flexion torques compared to the non-jumpers. No significant group effects were found for peak vertical ground reaction force and knee range of motion during landing. The jumpers had significantly greater knee contact flexion angle, maximum knee flexion angle and initial knee extension moment compared to the non-jumpers. These results suggest that these athletes adopted a favorable impact attenuation strategy that is related to the greater knee eccentric muscle strength and training. PMID- 24060224 TI - Inter-individual variability of forces and modular muscle coordination in cycling: a study on untrained subjects. AB - The aim of this study was to investigate the muscle coordination underlying pedaling in untrained subjects by using the muscle synergies paradigm, and to connect it with the inter-individual variability of EMG patterns and applied forces. Nine subjects performed a pedaling exercise on a cycle-simulator. Applied forces were recorded by means of instrumented pedals able to measure two force components. EMG signals were recorded from eight muscles of the dominant leg, and Nonnegative Matrix Factorization was applied to extract muscle synergy vectors W and time-varying activation coefficients H. Inter-individual variability was assessed for EMG patterns, force profiles, and H. Four modules were sufficient to reconstruct the muscle activation repertoire for all the subjects (variance accounted for >90% for each muscle). These modules were found to be highly similar between subjects in terms of W (mean r=.89), while most of the variability in force profiles and EMG patterns was reflected, in the muscle synergy structure, in the variability of H. These four modules have a functional interpretation when related to force distribution along the pedaling cycle, and the structure of W is shared with that present in human walking, suggesting the existence of a modular motor control in humans. PMID- 24060225 TI - Effects of speed and accuracy strategy on choice step execution in response to the flanker interference task. AB - The purpose of this study is to examine the effects of a speed or accuracy strategy on response interference control during choice step execution. Eighteen healthy young participants were instructed to execute forward stepping on the side indicated by a central arrow (<-, left vs. ->, right) under task instructions that either emphasized speed or accuracy of response in the neutral condition. In the flanker condition, they were additionally required to ignore the 2 flanking arrows on each side (->->->->->, congruent or ->-><-->->, incongruent). Errors in the direction of the initial weight transfer (APA errors) and the step execution times were measured from the vertical force data. APA error was increased in response to the flanker task and step execution time was shortened with a speed strategy compared to an accuracy strategy. Furthermore, in response to the visual interference of the flanker task, speed instructions in particular increased APA errors more than other instructions. It may be important to manipulate the level of the speed-accuracy trade-off to improve efficiency and safety. Further research is needed to explore the effects of advancing age and disability on choice step reaction in a speed or accuracy strategy. PMID- 24060226 TI - Influence of wearing an unstable shoe construction on compensatory control of posture. AB - This study investigated the influence of wearing unstable shoe construction (WUS) on compensatory postural adjustments (CPA) associated with external perturbations. Thirty-two subjects stood on a force platform resisting an anterior-posterior horizontal force applied to a pelvic belt via a cable, which was suddenly released. They stood under two conditions: barefoot and WUS. The electromyographic (EMG) activity of gastrocnemius medialis, tibialis anterior, rectus femoris, biceps femoris, rectus abdominis, and erector spinae muscles and the center of pressure (CoP) displacement were acquired to study CPA. The EMG signal was used to assess individual muscle activity and latency, antagonist co activation and reciprocal activation at joint and muscle group levels. Compared to barefoot, WUS led to: (1) increased gastrocnemius medialis activity, (2) increased total agonist activity, (3) decreased antagonist co-activation at the ankle joint and muscle group levels, (4) increased reciprocal activation at the ankle joint and muscle group levels, and (5) decrease in all muscle latencies. No differences were observed in CoP displacement between conditions. These findings demonstrate that WUS led to a reorganization of the postural control system associated to improved performance of some components of postural control responses. PMID- 24060227 TI - Low motor performance scores among overweight children: poor coordination or morphological constraints? AB - This study examined whether lower motor performance scores can be full attributed to poor coordination, or whether weight related morphological constraints may also affect motor performance. Data for 666 children and adolescents from the longitudinal Western Australian Pregnancy Cohort (Raine) Study were grouped into normal weight, overweight and obese categories based on the International Obesity Task Force cut points. Participants completed the 10-item McCarron Assessment of Neuromuscular Development (MAND) at the 10 and 14 year follow-up. The prevalence of overweight and obese participants classified with mild or moderate motor difficulties was not different from the normal weight group at 10 years (chi2 = 5.8 p = .215), but higher at 14 years (chi2 = 11.3 p = .023). There were no significant differences in overall motor performance scores between weight status groups at 10 years, but at 14 years, the normal weight group achieved better scores than the obese group (p<.05). For specific items, the normal weight group consistently scored higher than the overweight and obese groups on the jump task at 10 (p<.001) and 14 (p<.01)years but lower on the hand strength task at both ages (p<.01). Our findings raise the question as to whether some test items commonly used for assessing motor competence are appropriate for an increasingly overweight and obese population. PMID- 24060228 TI - On the advantage of an external focus of attention: a benefit to learning or performance? AB - Although there is general agreement in the sport science community that the focus of attention (FOA) has significant effects on performance, there is some debate about whether or not the FOA adopted during training affects learning. A large number of studies on the focus of attention have shown that subjects who train with an external FOA perform better on subsequent retention and transfer tests. However, the FOA in these studies was not experimentally controlled during testing. Therefore, the current study used a dart-throwing paradigm in which the FOA was experimentally manipulated at both acquisition and testing over very short and long training times. Performance at test, in terms of accuracy and precision, was improved by adopting an external focus at test regardless of the focus instructed during acquisition, in both Experiment 1 and 2. Although an effect of acquisition focus during testing in Experiment 2 provides some evidence that FOA affects learning, the current data demonstrate a much stronger effect for performance than learning, and stronger effects of attention on precision than accuracy. Theoretical implications of these results are discussed, but in general these data provide a more nuanced understanding of how attentional focus instructions influence motor learning and performance. PMID- 24060229 TI - Side-docking technique for robot-assisted urologic pelvic surgery. AB - OBJECTIVE: To investigate the feasibility of side-docking techniques in robot assisted urologic pelvic surgery. MATERIALS AND METHODS: Six consecutive patients undergoing robot-assisted pelvic surgery participated in the study: 3 undergoing radical cystectomy for muscle-invasive bladder cancer, 1 patient undergoing ureteroneocystostomy for ureteric stricture, 1 patient undergoing partial cystectomy for urothelial cancer in a bladder diverticulum, and 1 undergoing transvesical simple prostatectomy. Each patient was placed in the lithotomy Trendelenburg position, with the robot docked over the patient's right side. RESULTS: All the procedures were completed without the need for redocking. Simultaneous cystourethroscopy was performed in 1 case to localize a bladder diverticular tumor during a partial cystectomy. Manipulation of the uterus and perineum was possible by the second assistant sitting between the patients' legs. No significant collision between the robotic arms occurred. There was no Clavien Dindo III-V complication in any case. CONCLUSION: Side docking for robot-assisted urologic pelvic surgery is a viable positioning alternative with the advantage of enhanced access to the perineum and urethra. This modified approach will be useful in robot-assisted radical cystectomy and other reconstructive urologic procedures. PMID- 24060230 TI - Spinal cord compression in pseudohypoparathyroidism. AB - BACKGROUND CONTEXT: Spinal cord compression associated with pseudohypoparathyroidism (PHP) is an increasingly reported sequelae of the underlying metabolic syndrome. The association of neurologic dysfunction with PHP is not well appreciated. We believe this to be secondary to a combination of underlying congenital stenosis, manifest by short pedicles secondary to premature physeal closure, and hypertrophic ossification of the vertebral bony and ligamentous complexes. PURPOSE: The purpose of this case report is to review the case of spinal stenosis in a child with PHP Type Ia. We are aware of only eight published reports of patients with PHP Type Ia and spinal stenosis-there are only two previously known cases of pediatric spinal stenosis secondary to PHP. STUDY DESIGN/SETTING: This is a case report detailing the symptoms, diagnosis, interventions, complications, and ultimate outcomes of a pediatric patient undergoing spinal decompression and fusion for symptomatic stenosis secondary to PHP Type Ia. Literature search was reviewed regarding the reports of spinal stenosis and PHP, and the results are culminated and discussed. PATIENT SAMPLE: We report on a 14-year-old obese male with PHP and progressive lower extremity weakness secondary to congenital spinal stenosis. Examination revealed functional upper extremities with spastic paraplegia of bilateral lower extremities. The patient's neurologic function was cautiously monitored, but he deteriorated to a bed-bound state, preoperatively. METHODS: The patient's chart was reviewed, summarized, and presented. Literature was searched using cross-reference of PHP and the terms "spinal stenosis," "myelopathy", "myelopathic," and "spinal cord compression." All relevant case reports were reviewed, and the results are discussed herein. RESULTS: The patient underwent decompression and instrumented fusion of T2-T11. He improved significantly with regard to lower extremity function, achieving unassisted ambulation function after extensive rehabilitation. Results from surgical decompression in previously reported cases are mixed, ranging from full recovery to iatrogenic paraplegia. CONCLUSIONS: The association of neurologic dysfunction with PHP is not well appreciated. It is important to highlight this rare association. Surgical decompression in patients with PHP yields mixed results but may be of greatest efficacy in younger patients who receive early intervention. PMID- 24060232 TI - Bacteria-polymeric membrane interactions: atomic force microscopy and XDLVO predictions. AB - Atomic force microscopy (AFM) in conjunction with a bioprobe developed using a polydopamine wet adhesive was used to directly measure the adhesive force between bacteria and different polymeric membrane surfaces. Bacterial cells of Pseudomonas putida and Bacillus subtilis were immobilized onto the tip of a standard AFM cantilever, and force measurements made using the modified cantilever on various membranes. Interaction forces measured with the bacterial probe were compared, qualitatively, to predictions by the extended Derjaguin Landau-Verwey-Overbeek (XDLVO) theory with steric interactions included. The XDLVO theory predicted attractive interactions between low energy hydrophobic membranes with high energy hydrophilic bacterium (P. putida). It also predicted a shallow primary maximum with the most hydrophilic bacterium, B. subtilis . Discrepancies between predictions using the XDLVO theory and theory require involvement of factors such as bridging effects. Differences in interaction between P. putida and B. subtilis are attributed to acid-base interactions and steric interactions. P. putida is Gram negative with lipopolysaccharides present in the outer cell membrane. A variation in forces of adhesion for bacteria on polymeric membranes studied was interpreted in terms of hydrophilicity and interfacial surface potential calculated from physicochemical properties. PMID- 24060231 TI - Prognostic factors for return to work in patients with sciatica. AB - BACKGROUND CONTEXT: Little is known about the prognostic factors for work-related outcomes of sciatica caused by disc herniation. PURPOSE: To identify the prognostic factors for return to work (RTW) during a 2-year follow-up among sciatica patients referred to secondary care. STUDY DESIGN/SETTING: Multicenter prospective cohort study including 466 patients. Administrative data from the National Sickness Benefit Register were accessed for 227 patients. PATIENT SAMPLE: Two samples were used. Sample A comprised patients who at the time of inclusion in the cohort reported being on partial sick leave or complete sick leave or were undergoing rehabilitation because of back pain/sciatica. Sample B comprised patients who, according to the sickness benefit register, at the time of inclusion received sickness benefits or rehabilitation allowances because of back pain/sciatica. OUTCOME MEASURES: In Sample A, the outcome was self-reported return to full-time work at the 2-year follow-up. In Sample B, the outcome was time to first sustained RTW, defined as the first period of more than 60 days without receiving benefits from the register. METHODS: Significant baseline predictors of self-reported RTW at 2 years (Analysis A) were identified by multivariate logistic regression. Significant predictors of time to sustained RTW (Analysis B) were identified by multivariate Cox proportional hazard modeling. Both analyses included adjustment for age and sex. To assess the effect of surgery on the probability of RTW, analyses similar to A and B were performed, including the variable surgery (yes/no). RESULTS: One-fourth of the patients were still out of work at the 2-year follow-up. In Sample A (n=237), younger age, better general health, lower baseline sciatica bothersomeness, less fear avoidance work, and a negative straight-leg-raising test result were significantly associated with a higher probability of RTW at the 2-year follow up. Surgery was not significantly associated with the outcome. In Sample B (n=125), history of sciatica, duration of the current sciatica episode more than 3 months, greater sciatica bothersomeness, fear-avoidance work, and back pain were significantly associated with a longer time to sustained RTW. Surgery was significantly negatively associated with time to sustained RTW both in univariate (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.39, 0.93; p=.02) and in multivariate (HR 0.49; 95% CI 0.31, 0.79; p=.003) analyses. CONCLUSIONS: The baseline factors associated with RTW identified in multivariate analysis were age, general health, history of sciatica, duration of the current episode, baseline sciatica bothersomeness, fear-avoidance work, back pain, and the straight-leg-raising test result. Surgical treatment was associated with slower RTW, but surgical patients were more severely affected than patients treated without surgery; so, this finding should be interpreted with caution. PMID- 24060233 TI - Impact of a health literacy assignment on student pharmacist learning. AB - BACKGROUND: The average American adult reads at the 8th grade level while most written health information materials, including medication guides, are written at the 12th grade level. To assist students with health literacy-sensitive communication, pharmacy schools should incorporate educational activities addressing health literacy competencies. OBJECTIVES: The objectives of this study were to evaluate the impact of a health literacy assignment on student pharmacists' perceptions of: 1) learning about health literacy; 2) ability to write health literacy level-appropriate patient education material; and 3) the use of these skills in future pharmacy practice. METHODS: Third professional year student pharmacists were asked to rewrite a patient medication information sheet at the 5th grade reading level, altering it from the 12th grade level. Following assignment completion, students responded to a 4-item open-ended questionnaire on what they learned from the activity, what information components were the most difficult to rewrite and reason for the difficulty, key strategies to accomplish the assignment, and their perception of the impact this assignment had on their future practice. Content analysis of the reflections was performed using QSR NVivo to identify themes grounded in the students' responses. RESULTS: Reflections were completed in 2009 (n = 159) and 2010 (n = 144), for a total of 303 completed reflections. Predominant themes included greater understanding about the challenges, importance, and methods of health literacy level appropriate communication and greater awareness of the role of pharmacists in presenting information clearly to patients. CONCLUSIONS: Students indicated the activity increased their understanding of the complexity of patient information, the educational needs of patients, and the importance of providing information that is understandable. Student pharmacists learned methods of effective communication with patients and should be better prepared to communicate in a health literacy-level appropriate manner. PMID- 24060234 TI - Importation of chloroquine-resistant Plasmodium falciparum by Guatemalan peacekeepers returning from the Democratic Republic of the Congo. AB - BACKGROUND: Malaria elimination is being pursued in five of seven Central American countries. Military personnel returning from peacekeeping missions in sub-Saharan Africa could import chloroquine-resistant Plasmodium falciparum, posing a threat to elimination and to the continued efficacy of first-line chloroquine (CQ) treatment in these countries. This report describes the importation of P. falciparum from among 150 Guatemalan army special forces and support staff who spent ten months on a United Nations' peacekeeping mission in the Democratic Republic of the Congo (DRC) in 2010. METHODS: Investigators reviewed patients' medical charts and interviewed members of the contingent to identify malaria cases and risk factors for malaria acquisition. Clinical specimens were tested for malaria; isolated parasites were characterized molecularly for CQ resistance. RESULTS: Investigators identified 12 cases (8%) of laboratory-confirmed P. falciparum infection within the contingent; one case was from a soldier infected with a CQ-resistant pfcrt genotype resulting in his death. None of the contingent used an insecticide-treated bed net (ITN) or completely adhered to malaria chemoprophylaxis while in the DRC. CONCLUSION: This report highlights the need to promote use of malaria prevention measures, in particular ITNs and chemoprophylaxis, among peacekeepers stationed in malaria endemic areas. Countries attempting to eliminate malaria should consider appropriate methods to screen peacekeepers returning from endemic areas for malaria infections. Cases of malaria in travellers, immigrants and soldiers returning to Central America from countries with CQ-resistant malaria should be assumed to be carry resistant parasites and receive appropriate anti-malarial therapy to prevent severe disease and death. PMID- 24060236 TI - Cesarean delivery and perinatal mortality rates in Japan, 2007-2011. AB - OBJECTIVE: Cesarean delivery (CD) rates are increasing dramatically in developed countries. In this study, we examined the relationship between CD rates and perinatal mortality (PM) rates in all 47 prefectures in Japan. METHODS: The CD rates were derived from a national obstetrics facility survey conducted by the Japan Association of Obstetricians and Gynecologists (JAOG), which included 94.1% of all childbirths in Japan during the 5-year period from 2007 to 2011. The PM rates were based on vital statistics during the same period. RESULTS: During the 5-year period from 2007 to 2011, the CD rates compiled for the 47 prefectures in Japan increased significantly in each successive year, whereas PM rates decreased significantly in each successive year. However, no statistically significant correlation between CD and PM rates was detected. CONCLUSION: There is a lack of evidence for a significant correlation between recently increasing CD rates and decreasing PM rates in Japan. PMID- 24060237 TI - Internalized Stigma of Mental Illness (ISMI) scale: a multinational review. AB - The Internalized Stigma of Mental Illness (ISMI) scale is a 29-item questionnaire measuring self-stigma among persons with psychiatric disorders. It was developed with substantial consumer input and has been widely used, but its psychometric qualities have not been comprehensively evaluated across multiple versions. Here we review the 55 known versions, and provide the 47 available versions, including: Arabic, Armenian, Bengali, Bulgarian, Chinese (Mainland, Taiwan, Hong Kong), Croatian, Dutch, English (USA, South Africa), Estonian, Farsi, Finnish, French, German, Greek, Hebrew, Hindi, Japanese, Khmer, Korean, Lithuanian, Lugandan, Maltese, Polish, Portuguese (Portugal, Brazil), Romanian, Russian, Samoan, Slovenian, Spanish (Spain), Swahili, Swedish, Tongan, Turkish, Urdu, and Yoruba, and qualitative English and Swahili versions, as well as versions for depression, schizophrenia, substance abuse, eating disorders, epilepsy, inflammatory bowel disease, leprosy, smoking, parents and caregivers of people with mental illness, and ethnicity. The various versions show reliability and validity across a wide range of languages, cultures, and writing systems. The most commonly reported findings of studies using the ISMI are that internalized stigma correlates with higher depression, lower self esteem, and higher symptom severity. Initial studies of ways to reduce internalized stigma are promising and warrant further investigation. PMID- 24060235 TI - Violence against women in sex work and HIV risk implications differ qualitatively by perpetrator. AB - BACKGROUND: Physical and sexual violence heighten STI/HIV risk for women in sex work. Against this backdrop, we describe the nature of abuse against women in sex work, and its STI/HIV implications, across perpetrators. METHODS: Adult women involved in sex work (n = 35) in Baltimore, MD participated in an in-depth interview and brief survey. RESULTS: Physical and sexual violence were prevalent, with 43% reporting past-month abuse. Clients were the primary perpetrators; their violence was severe, compromised women's condom and sexual negotiation, and included forced and coerced anal intercourse. Sex work was a factor in intimate partner violence. Police abuse was largely an exploitation of power imbalances for coerced sex. CONCLUSIONS: Findings affirm the need to address physical and sexual violence, particularly that perpetrated by clients, as a social determinant of health for women in sex work, as well as a threat to safety and wellbeing, and a contextual barrier to HIV risk reduction. PMID- 24060239 TI - Effect of rapid cessation of enzyme replacement therapy: a report of 5 more cases. PMID- 24060238 TI - Mosquitoes established in Lhasa city, Tibet, China. AB - BACKGROUND: In 2009, residents of Lhasa city, Tibet Autonomous Region (TAR), China reported large numbers of mosquitoes and bites from these insects. It is unclear whether this was a new phenomenon, which species were involved, and whether these mosquitoes had established themselves in the local circumstances. METHODS: The present study was undertaken in six urban sites of Chengguan district Lhasa city, Tibet. Adult mosquitoes were collected by bed net trap, labor hour method and light trap in August 2009 and August 2012. The trapped adult mosquitoes were initially counted and identified according to morphological criteria, and a proportion of mosquitoes were examined more closely using a multiplex PCR assay. RESULTS: 907 mosquitoes of the Culex pipiens complex were collected in this study. Among them, 595 were females and 312 were males. There was no significant difference in mosquito density monitored by bed net trap and labor hour method in 2009 and 2012. Of 105 mosquitoes identified by multiplex PCR, 36 were pure mosquitoes (34.29%) while 69 were hybrids (65.71%). The same subspecies of Culex pipiens complex were observed by bed net trap, labor hour method and light trap in 2009 and 2012. CONCLUSION: The local Culex pipiens complex comprises the subspecies Cx. pipiens pipiens, Cx. pipiens pallens, Cx. pipiens quinquefasciatus and its hybrids. Mosquitoes in the Cx. pipiens complex, known to be, potentially, vectors of periodic filariasis and encephalitis, are now present from one season to the next, and appear to be established in Lhasa City, TAR. PMID- 24060240 TI - Vitamin D3 derivatives increase soluble CD14 release through ERK1/2 activation and decrease IL-8 production in intestinal epithelial cells. AB - Dysfunction of the innate immune system has been reported to cause intestinal inflammation. Vitamin D3 is known to be an important immune system regulator and exerts anti-inflammatory effects. We investigated in vitro effects of vitamin D3 and its derivatives on the innate immune system in HT-29 cells, a line of human colon adenocarcinoma cells. Among the innate immune-related receptors such as Toll-like receptor (TLR) 1, 2, 4, 6, and CD14 examined by flow cytometry, only CD14 was up-regulated by vitamin D3 derivatives. Release of soluble form CD14 (sCD14) was also increased by vitamin D3 derivatives. The 1alpha,25-dihydroxy-22 oxavitamin D3 (Oxa-D3) induced-sCD14 release was inhibited by U0126 (a specific inhibitor of extracellular signal-regulated kinase; ERK1/2) but not by SB203580 (a specific inhibitor of p38 MAPK), and ERK1/2 phosphorylation was accelerated by Oxa-D3. These results indicate that Oxa-D3 facilitates the release of sCD14 through ERK1/2 activation. IL-8 production stimulated with LPS was diminished by vitamin D3 derivatives. Recombinant sCD14 also lowered the LPS-stimulated IL-8 production, suggesting neutralization of LPS by sCD14. The anti-inflammatory effect of vitamin D3 derivatives was thus associated with diminution of IL-8 production due to increased release of sCD14. PMID- 24060241 TI - Oncostatin M stimulates cell migration and proliferation by down-regulating E cadherin in HTR8/SVneo cell line through STAT3 activation. AB - BACKGROUND: During the first trimester of pregnancy, trophoblastic E-cadherin expression is down-regulated, thereby allowing extravillous trophoblasts (EVTs) to acquire the potential for migration and invasiveness. The aim of the present study was to investigate the role of OSM on the migration and proliferation of EVT cell line HTR8/SVneo with regard to its effects on the expression of E cadherin and STAT3 activation. METHODS: We investigated the effects of OSM on RNA and protein expression of E-cadherin by real time RT-PCR analyses, western blotting, and indirect immunofluorescence staining in HTR8/SVneo cells, as well as the effects on cell migration and proliferation. The selective signal transducer and activator of transcription (STAT)3 inhibitor, stattic, and STAT3 siRNA were used to investigate STAT3 activation by OSM. RESULTS: OSM significantly reduced RNA and protein expression of E-cadherin. Indirect immunofluorescence staining of HTR8/SVneo cells also revealed the down-regulation of E-cadherin, compared with the controls. OSM-stimulated cell migration was attenuated by anti-gp130 antibodies. OSM-induced STAT3 phosphorylation, and the down-regulation of E-cadherin by OSM treatment was restored by stattic and STAT3 siRNA. In addition, OSM-stimulated migration and proliferation were significantly suppressed by STAT3 inhibition. CONCLUSIONS: This study suggests that OSM stimulates the migration and proliferation of EVTs during the first trimester of pregnancy through the down-regulation of E-cadherin. In addition, this study suggests that the effects of OSM on migration and proliferation are related to STAT3 activation, which is important in trophoblast invasiveness. PMID- 24060242 TI - Perceptions of social and environmental changes in a Mediterranean forest during the last 100 years: the Gavarres Massif. AB - During the last century the landscape of the mid-Mediterranean mountains has undergone major transformations. The precipitous decline in the economic viability of forest products has engendered ever-thickening forests and agricultural lands have reverted to forest land cover. The related exodus of existing inhabitants since 1960 has led to new styles of occupancy: residential and touristic land uses have emerged while the primary and secondary sectors have largely disappeared. The object of the present study is to review how these transformations have developed in a specific area of north-eastern of Catalonia, known as the Gavarres Massif. The study applies a qualitative approach, based on interviews with stakeholders including active members of the local community and others who utilize or visit the area, all of whom are representatives of different social groups with a wide range of interests and points of view with regard to the massif. The information collected from the perspectives and opinions of the participants is coupled with objective data about the area. The result of this investigation is a rich variety of perceptions on landscape and social transformation and its current functional dynamics. Analyzing the information obtained allows us to understand the fact that the disappearance of the rural world is directly related to the collapse of an entire economic system that relied on the environment. In this study, two divergent points of view arise, one which supports recovering past landscapes and another which favours managing changes, conserving the existing landscape. Proposals for the current and future territorial management of Les Gavarres are presented. The diversity of opinions which emerges with regard to managing necessary changes in the massif emphasizes the importance of increased social dialogue. PMID- 24060243 TI - Spontaneous alternation and locomotor activity in three species of marine crabs: green crab (Carcinus maenas), blue crab (Callinectes sapidus), and fiddler crab (Uca pugnax). AB - Spontaneous alternation refers to the tendency of organisms to explore places that they have least recently visited. Our previous work showed that alternation performance of Carcinus maenas (invasive European green crab) was significantly higher than Callinectes sapidus (native blue crab), and chance level performance (Ramey, P. A., Teichman, E., Oleksiak, J., & Balci, F. [2009]. Spontaneous alternation in marine crabs: Invasive versus native species. Behavioural Processes, 82, 51-55.). In the current study, we first tested the robustness of these findings in the absence of visual cues, longer test durations, and wider maze dimensions. These manipulations enabled us to determine whether these two crab species relied on the visual cues provided during the spontaneous alternation task in our prior work, and allowed for better characterization of their exploratory activity in the maze. Our original findings were reproduced in the present study under these new task conditions, suggesting no role for visual cues during alternation, and emphasizing the robustness and generalizability of the corresponding interspecies differences in alternation performance. We also tested whether the lower alternation performance of C. sapidus also applied to another native crab species, Uca pugnax (fiddler crab). Spontaneous alternation performance of U. pugnax was significantly lower than C. maenas but indistinguishable from C. sapidus. Finally, we examined whether the potentially higher inherent risk-sensitivity of C. sapidus could have contributed to their lower alternation performance by testing C. maenas in the presence of a larger natural predator (stressor). Higher risk sensitivity presumably induced by the stressor led to locomotor activity patterns that better resembled those of C. sapidus, however the resultant reduction in alternation performance was not statistically significant. PMID- 24060245 TI - Endowment effects in gorillas (Gorilla gorilla). AB - Reports of endowment effects in nonhuman primates have received considerable attention in the comparative literature in recent years. However, little is known about the mechanisms underlying these effects. Continuing to explore endowment effects across different species of primate may reveal subtle differences in behavior that can help formulate specific hypotheses about the relevant mechanisms and the social and ecological factors that have shaped them. In this study, we use a paradigm that has previously been used to test chimpanzees (Pan troglodytes) and orangutans (Pongo spp.) to explore whether western lowland gorillas (Gorilla gorilla) exhibit comparable endowment effects. We find that gorillas exhibit endowment effects when in possession of food, but not nonfood, items, and that they show a statistically stronger effect than chimpanzees but not orangutans. These findings are consistent with the hypothesis that mechanisms for endowment effects in primates may be related to inhibitory control or risk aversion. PMID- 24060244 TI - Public information use in chimpanzees (Pan troglodytes) and children (Homo sapiens). AB - The discernment of resource quality is pertinent to many daily decisions faced by animals. Public information is a critical information source that promotes quality assessments, attained by monitoring others' performance. Here we provide the first evidence, to our knowledge, that chimpanzees (Pan troglodytes) use public information to guide resource selection. Thirty-two chimpanzees were presented with two simultaneous video demonstrations depicting a conspecific acquiring resources at a fast (resource-rich) or slow (resource-poor) rate. Subsequently, subjects selected the resource-rich site above chance expectation. As a comparison, we report evidence of public information use in young children. Investigation of public information use in primates is pertinent, as it can enhance foraging success and potentially facilitate payoff-biased social learning. PMID- 24060246 TI - Role of mental representations in quantity judgments by jackdaws (Corvus monedula). AB - The representation of quantity by the preverbal or nonverbal mind is a question of considerable interest in the study of cognition, as it should be generally adaptive to most animals to be able to distinguish quantity. We already know that some primate species and human infants represent and enumerate objects in similar ways. Considerable data also exist concerning such abilities in birds. Our aim in this study has been to find out whether jackdaws (Corvus monedula) are capable of performing relative quantity judgments based on mental representations, and if so, what are the limiting factors to their abilities. In our setting the birds were required to make a choice between two visibly and sequentially placed set of food items which, at the moment of choice were not visible to the subjects. We investigated all the number combinations between 1 and 5. Our results show that jackdaws are able to perform relative quantity judgments successfully, even when temporal cues are controlled for, whereas their performance declines in the direction of larger set size (numerical size effect), and when the difference between the two arrays decreases (numerical distance and ratio effect). These signatures are usually interpreted as evidence for the "accumulator" model of mental representation of quantity. Our control results suggest that jackdaws do not use temporal cues, but may well use total volume as basis for discrimination, perhaps among other attributes (choice may be based on multiple cues). PMID- 24060247 TI - Designing a handwashing station for infrastructure-restricted communities in Bangladesh using the integrated behavioural model for water, sanitation and hygiene interventions (IBM-WASH). AB - BACKGROUND: In Bangladesh diarrhoeal disease and respiratory infections contribute significantly to morbidity and mortality. Handwashing with soap reduces the risk of infection; however, handwashing rates in infrastructure restricted settings remain low. Handwashing stations--a dedicated, convenient location where both soap and water are available for handwashing--are associated with improved handwashing practices. Our aim was to identify a locally feasible and acceptable handwashing station that enabled frequent handwashing for two subsequent randomized trials testing the health effects of this behaviour. METHODS: We conducted formative research in the form of household trials of improved practices in urban and rural Bangladesh. Seven candidate handwashing technologies were tested by nine to ten households each during two iterative phases. We conducted interviews with participants during an introductory visit and two to five follow up visits over two to six weeks, depending on the phase. We used the Integrated Behavioural Model for Water, Sanitation and Hygiene (IBM WASH) to guide selection of candidate handwashing stations and data analysis. Factors presented in the IBM-WASH informed thematic coding of interview transcripts and contextualized feasibility and acceptability of specific handwashing station designs. RESULTS: Factors that influenced selection of candidate designs were market availability of low cost, durable materials that were easy to replace or replenish in an infrastructure-restricted and shared environment. Water storage capacity, ease of use and maintenance, and quality of materials determined the acceptability and feasibility of specific handwashing station designs. After examining technology, psychosocial and contextual factors, we selected a handwashing system with two different water storage capacities, each with a tap, stand, basin, soapy water bottle and detergent powder for pilot testing in preparation for the subsequent randomized trials. CONCLUSIONS: A number of contextual, psychosocial and technological factors influence use of handwashing stations at five aggregate levels, from habitual to societal. In interventions that require a handwashing station to facilitate frequent handwashing with soap, elements of the technology, such as capacity, durability and location(s) within the household are key to high feasibility and acceptability. More than one handwashing station per household may be required. IBM-WASH helped guide the research and research in-turn helped validate the framework. PMID- 24060248 TI - Review research to support the health of people with disabilities. PMID- 24060249 TI - Teaching health care students about disability within a cultural competency context. AB - The training of health care providers has been identified as key to resolving the health disparities experienced by persons with disabilities. We contend that: 1) cultural competency provides a useful conceptual framework for teaching disability-related content to health professions students; 2) educational experiences can be structured to reflect the socio-cultural complexity of the 'disability culture;' 3) desired competencies associated with culture can be defined with regard to professionals' approach to patients with disabilities; 4) exposure to persons who have disabilities in their homes allows the student to make connections between the nuances of daily life with a disability and one's health care needs; 5) the framework allows the disability culture to be integrated with other cultural contexts, including race and ethnicity; and 6) the framework acknowledges the potential impact of providers' conscious or unconscious recognition of their potential membership in the disability culture on their approach to patients with disabilities. PMID- 24060250 TI - Disparities in chronic conditions and health status by type of disability. AB - BACKGROUND: Prior research has established health disparities between people with and without disabilities. However, disparities within the disability population, such as those related to type of disability, have been much less studied. OBJECTIVE: To examine differences in chronic conditions and health status between subgroups of people with different types of disability. METHODS: We analyzed Medical Expenditure Panel Survey annual data files from 2002 to 2008. Logistic regression analyses considered disparity from three perspectives: 1) basic differences, unadjusted for other factors; 2) controlling for key demographic and health covariates; and 3) controlling for a larger set of demographic variables and socioeconomic status as well as health and access to healthcare. RESULTS: Individuals with vision, physical, cognitive, or multiple disability types fared worse than people with hearing impairment on most health outcomes. This was most consistently true for people with multiple disabilities. Even when all covariates were accounted for, people with multiple types of disability were significantly more likely (p < 0.05) than those with hearing impairment (reference group) to report every poor health outcome with the exception of BMI >= 25 and lung disease. CONCLUSIONS: While many of the differences between disability types were reduced when controlling for other factors, some differences remained significant. This argues for a more individualized approach to understanding and preventing chronic conditions and poor health in specific disability groups. PMID- 24060251 TI - Health care expenditures among working-age adults with physical disabilities: variations by disability spans. AB - BACKGROUND: Data on health care costs for working-age adults with physical disabilities are sparse and the dynamic nature of disability is not captured. OBJECTIVES: To assess the effect of 3 types of disability status (persistent disability, temporary disability, and no disability) on health care expenditures, out-of-pocket (OOP) spending, and financial burden. METHODS: Data from Medical Expenditure Panel Survey panel 12 (2007-2008) were used. Respondents were classified into 3 groups. Medians of average annual expenditures, OOP expenditures, and financial ratios were weighted. The package R was used for quantile regression analyses. RESULTS: Fifteen percent of the working-age population reported persistent disabilities and 7% had temporary disabilities. The persistent disability group had the greatest unadjusted annual medians for total expenditures ($4234), OOP expenses ($591), and financial burden ratios (1.59), followed by the temporary disability group ($1612, $388, 0.71 respectively). The persistent disability group paid approximately 15% of total health care expenditures out-of-pocket, while the temporary disability group and the no disability group each paid 22% out-of-pocket. After adjusting for other factors, quantile regression shows that the persistent disability group had significantly higher total expenditures, OOP expenses, and financial burden ratios (coefficients 1664, 156, 0.58 respectively) relative to the no disability group at the 50th percentile. Results for the temporary disability group show a similar trend except for OOP expenses. CONCLUSIONS: People who have disabling conditions for a longer period have better financial protection against OOP health care expenses but face greater financial burdens because of their higher out-of-pocket expenditures and their socioeconomic disadvantages. PMID- 24060252 TI - Hypertension medication use and adherence among adults with developmental disability. AB - BACKGROUND/OBJECTIVE: Adults with developmental disability (DD) have high prevalence of coronary artery disease risk factors, as well as impediments to optimal diagnosis and management. We analyzed antihypertensive medication (AM) use and adherence patterns in a Kansas Medicaid cohort. METHODS: We studied adults (18-64 years) with DD and claims for HT from 7/1/05 to 8/31/06, with review of prescription records of AM use and adherence from 9/1/06 to 8/31/07. Adherence was calculated as proportion of days covered (PDC). RESULTS: Of 3079 eligible people, 280 (9%) had claims for HT: 51% male, mean age 42 +/- 13, and 81% Caucasian. Of these, 280 (72%) had claims for at least 1 AM; 57% received >=2 AM. Angiotensin converting enzyme inhibitor/angiotensin receptor blockers were most commonly prescribed (65%) followed by diuretics (50%), beta blockers (34%), and calcium channel blockers (26%). Mean PDCs by class ranged from 0.622 to 0.693: 55% had a PDC >=0.80, a common goal for adherence. Younger individuals were more likely to be adherent (p <0.05), but adherence was not significantly associated with comorbid conditions, gender, or race. CONCLUSIONS: Of our cohort of adults with DD, 9% had HT of whom 72% submitted claims for AMs. A substantial proportion of subjects had inconsistent AM use suggesting suboptimal therapy. The association between younger ages and higher adherence may reflect better community-based support for younger adults. Further work is needed to identify barriers to optimal care for this vulnerable population. PMID- 24060254 TI - Personal care services provided to children with special health care needs (CSHCN) and their subsequent use of physician services. AB - BACKGROUND: Medicaid Personal Care Services (PCS) help families meet children's needs for assistance with functional tasks. However, PCS may have other effects on a child's well-being, but research has not yet established the existence of such effects. OBJECTIVES: To investigate the relationship between the number of PCS hours a child receives with subsequent visits to physicians for evaluation and management (E&M) services. METHODS: Assessment data for 2058 CSHCN receiving PCS were collected in 2008 and 2009. Assessment data were matched with Medicaid claims data for the period of 1 year after the assessment. Zero-inflated negative binomial and generalized linear multivariate regression models were used in the analyses. These models included patient demographics, health status, household resources, and use of other medical services. RESULTS: For every 10 additional PCS hours authorized for a child, the odds of having an E&M physician visit in the next year were reduced by 25%. However, the number of PCS hours did not have a significant effect on the number of visits by those children who did have a subsequent E&M visit. A variety of demographic and health status measures also affect physician use. CONCLUSIONS: Medicaid PCS for CSHCN may be associated with reduced physician usage because of benefits realized by continuity of care, the early identification of potential health threats, or family and patient education. PCS services may contribute to a child's well-being by providing continuous relationships with the care team that promote good chronic disease management, education, and support for the family. PMID- 24060255 TI - The effect of special health care needs and health status on school functioning. AB - BACKGROUND: Past studies have shown that specific child conditions are associated with poor school outcomes. A national health survey with noncategorical measures of health and indicators of school functioning offers the opportunity to examine this association. OBJECTIVES: To compare links between two health measures (children with special health care needs and general health status) and multiple school outcomes. METHODS: The analysis was based on 59,440 children aged 6-17 years from the 2007 National Survey of Children's Health. Child health was assessed using the Children with Special Health Care Needs (CSHCN) screener and a question on general health status. CSHCN were classified by the complexity of their health care needs. Indicators of school functioning included special education use, many problem reports, repeated a grade, lack of school engagement, and many missed school days. RESULTS: Overall 22% of children were identified as CSHCN: 13% with more complex needs (C-CSHCN) and 9% with medication use only (CSHCN-RX). Approximately 17% of children were in less than optimal health. After controlling for a child's sociodemographic characteristics C-CSHCN had an increased risk of all of the negative school outcomes compared to children without SHCN, while CSHCN-RX had an increased risk of only one school outcome (many missed school days). Children in less than optimal health were at an increased risk of all negative school outcomes compared to children in optimal health. CONCLUSIONS: The CSHCN screener and health status question identify related, but distinct, groups of children with worse outcomes on the indicators of school functioning. PMID- 24060253 TI - Breast cancer knowledge and practices among D/deaf women. AB - BACKGROUND: Limited scientific evidence is available regarding D/deaf women's breast cancer knowledge and early detection practices, as well as about how to increase D/deaf women's breast cancer control practices. OBJECTIVE/HYPOTHESIS: To assess baseline breast cancer knowledge and practices among a sample of D/deaf women recruited into a randomized controlled trial of a breast cancer education program developed for this population. METHODS: A written and signed (American Sign Language) survey was administered to a racially/ethnically diverse sample of 209 D/deaf women, 40+ years old, with lower levels of education, recruited in California between October 2008 and May 2009. RESULTS: There were misconceptions about breast cancer risk factors, screening, and treatment; only 64.2% of respondents correctly identified the purpose of mammography. Mammography in the prior 2 years was reported by 57.3% of the sample, by 69.8% of White women, and by 43.5% of women from other racial/ethnic groups. Rates also varied by education, having seen a physician in the prior year, and type of insurance. CONCLUSIONS: This study underscores significant gaps in breast cancer screening knowledge and practices, communication issues in health care settings, and unmet needs for tailored health information and materials in this population. Challenges faced in conducting the research needed to develop and test such programs are noted. PMID- 24060256 TI - Childhood vision impairment, hearing loss and co-occurring autism spectrum disorder. AB - BACKGROUND: Limited population-based data on prevalence of childhood vision impairment (VI) and hearing loss (HL), and their co-occurrence with autism spectrum disorder (ASD) exists. OBJECTIVE: To examine prevalence and characteristics of VI, HL and co-occurring ASD among 8-year-olds in metropolitan Atlanta 2000-2008. METHODS: We used data from the population-based Metropolitan Atlanta Developmental Disabilities Surveillance Program. Prevalence, birth and parental characteristics, presence and severity of other co-occurring developmental disabilities, and age of earliest identification of ASD, were examined for children with VI and HL, by co-occurring ASD. RESULTS: VI and HL prevalences were 1.2 and 1.3 per 1000 8-year-olds, respectively. Approximately 6 7% of children with VI or HL had co-occurring ASD. Children with VI or HL with co occurring ASD differed from those without co-occurring ASD by select birth characteristics and the presence of other co-occurring DDs. The median age of earliest known ASD diagnosis was significantly later among children with VI and ASD compared to children with ASD without VI (79 vs. 56 months). Children with HL and ASD were first evaluated by a community provider significantly earlier than those with ASD without HL (40 vs. 50 months). CONCLUSIONS: The frequency of co occurring ASD with VI and HL is higher than the population prevalence of ASD. The significant delays in diagnosis of ASD in children with VI and lack of earlier diagnosis of ASD among children with HL despite earlier evaluation highlight the importance of developing screening tools for early identification of ASD among children with VI and HL. PMID- 24060257 TI - Future plans and social/recreational activities of youth with special health care needs: the implications of parental help in completing surveys. AB - BACKGROUND: A major focus of the literature on youth with special health care needs (YSHCN) is the transition to adult health care. As perceptions of disability are a product of interactions between youth and their environment, it is important to understand youth's needs and experiences beyond health care. Few studies have addressed social/recreational activity participation and future plans and none have included parent/caregiver help in survey completion as a potential factor impacting responses. OBJECTIVES: We describe activity participation and identification of future plans among YSHCN and examine the impact of receiving parent/caregiver assistance to complete a survey on these responses. Implications for research, policy, and practice affecting programs serving and providing transition assistance for YSHCN are discussed. METHODS: Data are from a survey of YSHCN conducted during Alabama's 2010 Title V Maternal and Child Health Needs Assessment. Analyses included descriptive statistics, bivariate analysis, and multivariable logistic regression. RESULTS: Youth who received help completing the survey were less likely to report participating in certain social/recreational activities and key future plans, including hobbies, getting married, having children, and working for pay. CONCLUSIONS: For YSHCN, parent/caregiver assistance to complete a survey is a critical consideration in analyses and interpretation of results. Whether, how much, and what type of help received may represent a more objective proxy measure of perceptions of condition severity or impact on abilities than do self-reported ratings of these factors. Our results also raise questions about the distinctions between youth and parent/caregiver perceptions of independence, participation, and potential. PMID- 24060258 TI - Unemployment among Canadians with physical and a co-morbid mental disability: an examination of the 2006 Participation and Activity Limitation Survey (PALS). AB - BACKGROUND: Co-occurring disabilities are common and data indicate that those with both physical and mental disabilities face greater discrimination in the workforce. However, studies that consider disability type in determining labor market outcomes are needed; particularly in Canada. OBJECTIVE: The objective was to examine the association of disability type and unemployment among working-aged Canadians using data from the 2006 Participation and Activity Limitation Survey (PALS). METHODS: The 2006 PALS is a post-censal sample survey of individuals whose everyday activities are limited due to a physical/mental condition. The study design is cross-sectional. Two groups were compared: persons with one or more physical disabilities exclusively vs. those with one or more physical disabilities and a mental disability. We calculated the prevalence of unemployment and used multiple logistic regression to measure the association between disability type and unemployment, while considering relevant covariates. RESULTS: The prevalence of unemployment was 20% overall; 35.4% in those with a co morbid mental disability and 18.5% in those with exclusively physical disabilities. Those with a mental co-morbidity had approximately double the odds of being unemployed relative to those with exclusively physical disabilities and the effect remained significant (at p < 0.05) after adjustment for socio-economic indicators and disability severity. CONCLUSIONS: Compared to those with exclusively physical disabilities, individuals with co-morbid physical and mental disabilities were found to be at a significantly greater disadvantage when accessing employment. More research is needed to clarify whether these findings are indicative of discrimination and to proceed toward removing workplace barriers that persist in this population. PMID- 24060259 TI - Interactions between neighborhood characteristics and individual functional status in relation to disability among Quebec urbanites. AB - BACKGROUND: Disability is conceived as a person-context interaction. Neighborhoods are among the contexts potentially influencing disability. It is thus expected that neighborhood characteristics will be associated with disability prevalence and that such associations will be moderated by individual level functional status. Empirical research targeting the influences of features of urban environments is relatively rare. OBJECTIVES: To evaluate the presence of contextual differences in disability prevalence and to assess the moderating role of individual functional status on the association between neighborhood characteristics and disability prevalence. METHODS: Multi-level analyses of individual-level data obtained from the Canadian Community Health Survey and neighborhood-level data derived from the Canada census. RESULTS: A contextual component was observed in the variability of disability prevalence. Significant neighborhood-level differences in disability were found across levels of social deprivation. Evidence of person-place interaction was equivocal. CONCLUSIONS: The contextual component of the variability in disability prevalence offers potential for targeting interventions to neighborhoods. The pathway by which social structure is associated with disability prevalence requires further research. Analyses of particular functional limitations may enhance our understanding of the mechanisms by which socioenvironmental factors affect disability. Publicly available survey data on disability in the general Canadian population, while useful, has limitations with respect to estimating socioenvironmental correlates of disability and potential person-place interactions. PMID- 24060260 TI - Pain intensity is associated with self-reported disability for several domains of life in a sample of patients with musculoskeletal pain aged 50 or more. AB - BACKGROUND: Most studies that investigate the impact of pain on function have focused on a particular pain site and use unidimensional measures of disability, making it difficult to know how pain impacts on different areas of functioning and whether different pain characteristics impact differently on function. AIM: To investigate the relationship between pain characteristics and self-reported disability in patients with musculoskeletal pain aged >=50 years. METHODS: Two hundred and four consecutive patients with musculoskeletal pain aged >=50 years had their pain assessed (frequency, global pain intensity, pain intensity for the most painful site, location and number of pain sites) and were asked to fill in the World Health Organization Disability Assessment Schedule (WHODAS 2.0) that assesses disability in 6 domains of daily life. RESULTS: Most patients reported chronic (77.5%), multisite or widespread (55.4%) pain that was always present (90.2%) and of moderate to severe intensity (mean score for global pain intensity = 5.91; SD = 2.02). Mean WHODAS 2.0 total score was 28.06 and SD was 19.86, corresponding to moderate disability. When entering age, sex, level of education, depression, number of comorbid chronic conditions and pain characteristics in a stepwise regression analysis, global pain intensity was the most important predictor for the domains of getting around (adjusted R(2) = 0.21, p < 0.001), self-care (adjusted R(2) = 0.14, p < 0.001), household activities (adjusted R(2) = 0.20, p < 0.001) and work (adjusted R(2) = 0.34, p < 0.001) and total score (adjusted R(2) = 0.19, p < 0.001). CONCLUSIONS: Pain intensity seems to be an important predictor of disability for several domains of life, suggesting that pain-related disability should be assessed for these domains. PMID- 24060262 TI - Community use of a hospital pool by people with disabilities. AB - BACKGROUND: Individuals with disabling conditions are one of the most physically inactive groups within society. Hospital hydrotherapy pools are a potential resource for people with disability living in the community to access aquatic physical activity. OBJECTIVES: The aim of this qualitative study was to discover why community dwelling individuals with disability choose a hospital pool over other public pools in the area. METHODS: The study site was a hospital pool in New Zealand. Semi-structured interviews were held with 38 individuals from 17 community user groups to determine reasons for choosing the hospital pool. Interviews were audio-taped, transcribed and analyzed inductively for themes. RESULTS: The hospital hydrotherapy pool was perceived to be an invaluable facility, providing opportunity for people with disability to be physically active in a way that is pain free, enjoyable and beneficial for mind and body. In contrast public pool facilities within the metropolitan region are experienced and/or perceived as being inaccessible for people with disabilities due to physical, social and emotional barriers. CONCLUSIONS: This hospital pool provides a highly appreciated but oversubscribed resource for the people with disability in the local environs. If pools in the public domain were able to offer warmer water in a user-friendly environment, then this would promote health and well being to individuals with disabling conditions. PMID- 24060263 TI - How do municipality employees in Ankara approach persons with disabilities? AB - BACKGROUND: Municipalities have a crucial role in the adaptation of urban spaces, buildings, and public services for full use by persons with disabilities. OBJECTIVE: The aim of this study was to determine the attitudes toward persons with disabilities in municipal employees. METHODS: This descriptive study included 338 municipal employees of a major municipality in Ankara, Turkey. Data were collected via a questionnaire and the Attitude towards Persons with Disabilities Scale (ATPDS) (Dokmen, 2000). Descriptive statistics, the t test, ANOVA, and ordinal logistic regression were used to analyze the data. RESULTS: Among the participants, 5.1% had some type of disability, 15.0% had a family member with a disability, and 6.9% cared for a person with a disability. Pity was the most common feeling (30.6%) toward persons with disabilities. Mean ATPDS score was 115.6 +/- 15.1 out of 150. The attitudes of the employees with a family member or a friend with a disability, as well as those of the employees that had cared for a person with a disability were more favorable than their counterparts (p < 0.05). CONCLUSIONS: The present findings showed that close contact and interaction with persons with disabilities were associated with more positive attitudes. Therefore, promoting positive attitudes among municipal employees and the development of a supportive organizational culture with respect to the rights of persons with disabilities may be useful. Interventions aimed at increasing awareness of and interaction with persons with disabilities may improve the attitudes of municipal employees, and consequently improve the services municipalities provide to persons with disabilities. PMID- 24060261 TI - Factors associated with disability in a sample of adults with arthritis. AB - BACKGROUND: Arthritis is the most common cause of disability among US adults. Few studies have comprehensively examined factors associated with disability in this population. OBJECTIVE: To investigate the relationship between a number of disease and non-disease related factors and disability in sample of adults with self-reported doctor-diagnosed arthritis. METHODS: Participants (n = 396) taking part in a randomized controlled trial of arthritis self-management completed a comprehensive survey assessing a number of demographic, arthritis-specific, health-related, behavioral, and psychological variables at baseline. Disability, as measured by the Health Assessment Questionnaire (HAQ), was also measured. Hierarchical regression models examined the independent associations between blocks of variables and disability. RESULTS: Demographic variables (R(2) = 0.13), arthritis-specific demographics (i.e., type, medication use; DeltaR(2) = 0.16), physical health-related variables (DeltaR(2) = 0.06), arthritis-specific symptoms (DeltaR(2) = 0.12), health behaviors (DeltaR(2) = 0.00), and psychological variables (DeltaR(2) = 0.03) explained 50% of the variance in disability score (R(2) = 0.50). With the exception of health behaviors, the addition of each block of variables significantly improved the model, explaining additional variance in HAQ scores (p < 0.0001). In the final model, older age, less than a high school education, rheumatoid arthritis, greater arthritis duration, taking steroids, taking narcotics, greater pain, greater stiffness, greater depressive symptoms, and lower arthritis self-efficacy were associated with greater disability whereas male gender, fibromyalgia, and excellent/very good health were associated with less disability. CONCLUSIONS: A number of disease and non-disease related variables were associated with disability. These findings suggest that disability in adults with arthritis may be a complicated phenomenon; such complexity may make decreasing disability in this population challenging. PMID- 24060264 TI - Education and related support from medical specialists for Japanese patients with major skeletal dysplasias. AB - BACKGROUND: Skeletal dysplasias manifest various clinical symptoms. Age at onset, severity, and progression of symptoms differ even among individuals with the same diagnosis. Though necessary support in education is presumed to differ among patients with different disorders, few articles report on education in patients with skeletal dysplasias. OBJECTIVE: To clarify what types of schools children with major skeletal dysplasias attend, what kind of support they needed at schools, and how the advice on such support was conveyed from medical specialists to schools. METHODS: Questionnaire study on patients with achondroplasia or hypochondroplasia (A/HCH), and osteogenesis imperfecta (OI). RESULTS: In A/HCH childhood locomotion ability was high and most patients had received general education, irrespective of their generation. Children with OI showed a lower level of locomotion ability; only about half of them had received general education. In selecting schools, the patients received advice from pediatricians, physiatrists, and orthopedic surgeons. The degree of necessity and content of support at the schools differed between A/HCH and OI. Remodeling of the lavatory, washbasin, and chair and support during swimming lessons were common in A/HCH patients. Support in school for OI patients was more frequent and included propelling wheelchairs, assisting in the use of the bathroom, and remodeling the lavatory. Most children were restricted from participating in physical education classes. CONCLUSIONS: Locomotion ability and the necessary support at school differed between A/HCH and OI. Support and advice from medical specialists who recognize disability of patients with skeletal dysplasias may improve patients' participation and education in schools. PMID- 24060265 TI - Prevalence and incidence of workplace bullying among Spanish employees working with people with intellectual disability. AB - BACKGROUND: Although workplace bullying is a severe psychosocial risk with a high prevalence, there is a lack of studies addressing its incidence, particularly among staff working with people with intellectual disability. OBJECTIVES: We examined the prevalence and incidence of workplace bullying in a sample of Spanish employees working with people with intellectual disability. The socio demographic characteristics of victims and non-victims of workplace bullying were also analyzed. METHODS: Multicenter study with two phases (T1 and T2) carried out in Valencia (Spain). The sample consisted of 696 employees from 66 centers in T1. One year later (T2), 422 employees from 61 centers agreed to participate in the study again. Workplace bullying was assessed by means of the instrument "Mobbing UNIPSICO". RESULTS: The prevalence of workplace bullying was 18.9% and 20.4% in T1 and T2, respectively. Of the 335 employees who were not victims of workplace bullying at T1 who were followed up at T2, 36 reported that they suffered workplace bullying a year later, that is, the accumulated incidence was 11%. In contrast, 81 workers who had been victims of workplace bullying at T1 and who were followed up at T2, 32 reported that they did not suffered from workplace bullying a year later. The victims had more stable contracts and more seniority in the organization/job than the non-victims in T1, but this result was not replicated in T2. CONCLUSIONS: Workplace bullying is a phenomenon with substantial prevalence, but also with considerable incidence (11%) among staff working with people with an intellectual disability. PMID- 24060266 TI - Comorbid substance use disorders with other Axis I and II mental disorders among treatment-seeking Asian Americans, Native Hawaiians/Pacific Islanders, and mixed race people. AB - Little is known about behavioral healthcare needs of Asian Americans (AAs), Native Hawaiians/Pacific Islanders (NHs/PIs), and mixed-race people (MRs)-the fastest growing segments of the U.S. population. We examined substance use disorder (SUD) prevalences and comorbidities among AAs, NHs/PIs, and MRs (N = 4572) in a behavioral health electronic health record database. DSM-IV diagnoses among patients aged 1-90 years who accessed behavioral healthcare from 11 sites were systematically captured: SUD, anxiety, mood, personality, adjustment, childhood-onset, cognitive/dementia, dissociative, eating, factitious, impulse control, psychotic/schizophrenic, sleep, and somatoform diagnoses. Of all patients, 15.0% had a SUD. Mood (60%), anxiety (31.2%), adjustment (30.9%), and disruptive (attention deficit-hyperactivity, conduct, oppositional defiant, disruptive behavior diagnosis, 22.7%) diagnoses were more common than others (psychotic 14.2%, personality 13.3%, other childhood-onset 11.4%, impulse-control 6.6%, cognitive 2.8%, eating 2.2%, somatoform 2.1%). Less than 1% of children aged <12 years had SUD. Cannabis diagnosis was the primary SUD affecting adolescents aged 12-17. MRs aged 35-49 years had the highest prevalence of cocaine diagnosis. Controlling for age at first visit, sex, treatment setting, length of treatment, and number of comorbid diagnoses, NHs/PIs and MRs were about two times more likely than AAs to have >= 2 SUDs. Regardless of race/ethnicity, personality diagnosis was comorbid with SUD. NHs/PIs with a mood diagnosis had elevated odds of having SUD. Findings present the most comprehensive patterns of mental diagnoses available for treatment-seeking AAs, NHs/PIs, and MRs in the real-world medical setting. In-depth research is needed to elucidate intraracial and interracial differences in treatment needs. PMID- 24060268 TI - Characterization of the mobility and reactivity of water molecules on TiO2 nanoparticles by 1H solid-state nuclear magnetic resonance. AB - Understanding interfacial water behavior is essential to improving our understanding of the surface chemistry and interfacial properties of nanomaterials. Here using 1H solid-state nuclear magnetic resonance (1H SSNMR), we successfully monitored ligand exchange reaction between oleylamine (OLA) and adsorbed water on titanium dioxide nanoparticles (TiO2 NPs). Three different types of interfacial waters with different reactivities were distinguished. The mobility of the adsorbed water molecules was characterized by dipolar filtered 1H SSNMR. Our experimental results demonstrate that the adsorbed water can be categorized into three different layers: (i) rigid water species with restricted mobility closest to the surface of TiO2 NPs, (ii) less mobile water species weakly confined on TiO2 NPs, and (iii) water molecules with high mobility. Water in the third layer could be replaced by OLA, while water in the first and second layers remained intact. The finding that the interfacial water with the highest mobility has the strongest reactivity has guiding significance for tailoring the hydrophilic and hydrophobic properties of TiO2 NPs. PMID- 24060267 TI - Feeding probiotic Lactobacillus paracasei to Ossabaw pigs on a high-fat diet prevents cholesteryl-ester accumulation and LPS modulation of the Liver X receptor and inflammatory axis in alveolar macrophages. AB - Liver X receptors (LXR) play an integral role in cholesterol metabolism and the inflammatory response. High-fat (HF) diets and microbial infection can antagonize the LXR pathway leading to accumulation of cholesteryl-esters (CE) and increased expression of pro-inflammatory mediators in macrophages. The probiotic bacteria Lactobacillus paracasei possesses cholesterol lowering and immune modulating properties. Therefore, the present study sought to model whether daily feeding of L. paracasei to juvenile Ossabaw pigs fed a HF diet could modulate cholesterol metabolism and the LXR/inflammatory axis in lipopolysacharide (LPS)-stimulated alveolar macrophages (AM). The results showed that AM from pigs fed a HF diet had significantly higher concentrations of CE compared to AM from pigs fed a control (C) diet, but not in pigs fed a HF diet with L. paracasei (HFPB). Ex vivo LPS stimulation of AM opposed LXR agonist-mediated transcription of cholesterol metabolism related genes: ABCA1, CH25H and PPARgamma in pigs on the C diet, and LXRalpha, ABCA1, ABCG1, CH25H and PPARgamma in pigs on the HF diet. This effect was abrogated for all these genes except LXRalpha in AM from pigs given L. paracasei. Protein analysis of culture supernatants revealed that AM from HFPB fed pigs had significantly lower LPS-induced protein expression of IL-1beta than AM from HF-fed pigs. Moreover, AM from pigs fed the C diet and given L. paracasei, had significantly higher mRNA levels of IL-8, and IL-6, in response to LPS. These data demonstrated a role for L. paracasei in modulating AM cholesterol metabolism and the response to LPS. PMID- 24060269 TI - Effects of an acute bout of aerobic exercise on immediate and subsequent three day food intake and energy expenditure in active and inactive men. AB - This study examined the effects of an acute bout of low-intensity cycling on food intake and energy expenditure over four days. Thirty healthy, active (n=15) and inactive (n=15) men completed two conditions (exercise and control), in a randomised crossover fashion. The exercise experimental day involved cycling for one hour at an intensity equivalent to 50% of maximum oxygen uptake and two hours of rest. The control condition comprised three hours of rest. Participants arrived at the laboratory fasted overnight; breakfast was standardised and an ad libitum pasta lunch was consumed on each experimental day. Participants kept a food diary and wore an Actiheart to estimate energy intake and expenditure for the remainder of the experimental days and over the subsequent 3 days. Ad libitum lunch energy intake did not differ between conditions (p=0.32, d=0.18) or groups (p=0.43, d=0.27). Energy intake in the active group was greater on the exercise experimental day than on the control experimental day (mean difference=2070 kJ; 95% CI 397 to 3743 kJ, p=0.024, d=0.56) while in the inactive group it was increased on only the third day after exercise (mean difference=2225 kJ; 95% CI 414 to 4036 kJ, p=0.024, d=0.80). There was only a group effect (p=0.032, d=0.89) for free-living energy expenditure, indicating that active participants expended more energy than inactive over this period. Acute low-intensity exercise did not affect energy intake at the meal immediately after exercise, but induces an acute (within the experimental day) and delayed (third day after the experimental day) increase in energy intake in active and inactive participants, respectively with no compensatory changes to daily energy expenditure. These results suggest that active individuals compensate for an acute exercise-induced energy deficit quicker than inactive individuals. PMID- 24060270 TI - Emotionally focused group therapy and dietary counseling in binge eating disorder. Effect on eating disorder psychopathology and quality of life. AB - OBJECTIVE: To test the effect on psychopathology and quality of life of Emotionally Focused Therapy (EFT), Dietary Counseling (DC), and Combined Treatment (CT) in treatment-seeking patients with Binge Eating Disorder (BED) and obesity. METHODS: Utilizing an observational study design, 189 obese adult patients with BED were treated by manualized therapy protocols. An independent assessment of health-related quality of life (Obesity-Related Well-Being questionnaire - ORWELL-97), attitudes toward eating (Eating Inventory - EI), binge eating (Binge Eating Scale - BES) and body uneasiness (Body Uneasiness Test - BUT) was performed at baseline, end-of-treatment, and six-month follow-up. These data are the secondary outcomes of a previously published treatment study. RESULTS: A higher dropout rate was observed in the DC compared to the EFT and CT groups, while body weight decreased significantly in all three groups. Pre-post scores on the BES, BUT Global Severity Index, and EI Hunger subscale significantly decreased in the CT and EFT groups (but not the DC group). At six month follow-up, 71% of participants in CT and 46% of participants in EFT had a BES score below the threshold of attention for BED (<=16), whereas no participants in the DC group reached this target. Finally the ORWELL-97 score decreased significantly in all groups, but significantly more so in the CT and EFT groups. CONCLUSION: Results support the utility of combining EFT and DC in the treatment of patients with BED and obesity, emphasizing the usefulness of techniques focused on cognitive emotional processing for changing eating disorder psychopathology and quality of life. PMID- 24060271 TI - Cold pleasure. Why we like ice drinks, ice-lollies and ice cream. AB - This review discusses how the ingestion of cold foods and drinks may be perceived as pleasant because of the effects of cooling of the mouth. The case is made that man has originated from a tropical environment and that cold stimuli applied to the external skin may initiate thermal discomfort and reflexes such as shivering and vasoconstriction that defend body temperature, whereas cold stimuli applied to the mouth are perceived as pleasant because of pleasure associated with satiation of thirst and a refreshing effect. Cold water is preferred to warm water as a thirst quencher and cold products such as ice cream may also be perceived as pleasant because oral cooling satiates thirst. The case is made that cold stimuli may be perceived differently in the skin and oral mucosa, leading to different effects on temperature regulation, and perception of pleasure or displeasure, depending on the body temperature and the temperature of the external environment. PMID- 24060273 TI - A homozygous nonsense mutation in the gene for Tmem79, a component for the lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis. AB - BACKGROUND: Flaky tail (ma/ma Flg(ft/ft)) mice have a frameshift mutation in the filaggrin (Flg(ft)) gene and are widely used as a model of human atopic dermatitis associated with FLG mutations. These mice possess another recessive hair mutation, matted (ma), and develop spontaneous dermatitis under specific pathogen-free conditions, whereas genetically engineered Flg(-/-) mice do not. OBJECTIVE: We identified and characterized the gene responsible for the matted hair and dermatitis phenotype in flaky tail mice. METHODS: We narrowed down the responsible region by backcrossing ma/ma mice with wild-type mice and identified the mutation using next-generation DNA sequencing. We attempted to rescue the matted phenotype by introducing the wild-type matted transgene. We characterized the responsible gene product by using whole-mount immunostaining of epidermal sheets. RESULTS: We demonstrated that ma, but not Flg(ft), was responsible for the dermatitis phenotype and corresponded to a Tmem79 gene nonsense mutation (c.840C>G, p.Y280*), which encoded a 5-transmembrane protein. Exogenous Tmem79 expression rescued the matted hair and dermatitis phenotype of Tmem79(ma/ma) mice. Tmem79 was mainly expressed in the trans-Golgi network in stratum granulosum cells in the epidermis in both mice and humans. The Tmem79(ma/ma) mutation impaired the lamellar granule secretory system, which resulted in altered stratum corneum formation and a subsequent spontaneous dermatitis phenotype. CONCLUSIONS: The Tmem79(ma/ma) mutation is responsible for the spontaneous dermatitis phenotype in matted mice, probably as a result of impaired lamellar granule secretory system and altered stratum corneum barrier function. PMID- 24060272 TI - Diesel exhaust particle induction of IL-17A contributes to severe asthma. AB - BACKGROUND: IL-17A has been implicated in severe forms of asthma. However, the factors that promote IL-17A production during the pathogenesis of severe asthma remain undefined. Diesel exhaust particles (DEPs) are a major component of traffic-related air pollution and are implicated in asthma pathogenesis and exacerbation. OBJECTIVE: We sought to determine the mechanism by which DEP exposure affects asthma severity using human and mouse studies. METHODS: BALB/c mice were challenged with DEPs with or without house dust mite (HDM) extract. Airway inflammation and function, bronchoalveolar lavage fluid cytokine levels, and flow cytometry of lung T cells were assessed. The effect of DEP exposure on the frequency of asthma symptoms and serum cytokine levels was determined in children with allergic asthma. RESULTS: In mice exposure to DEPs alone did not induce asthma. DEP and HDM coexposure markedly enhanced airway hyperresponsiveness compared with HDM exposure alone and generated a mixed T(H)2 and T(H)17 response, including IL-13(+)IL-17A(+) double-producing T cells. IL-17A neutralization prevented DEP-induced exacerbation of airway hyperresponsiveness. Among 235 high DEP-exposed children with allergic asthma, 32.2% had more frequent asthma symptoms over a 12-month period compared with only 14.2% in the low DEP exposed group (P = .002). Additionally, high DEP-exposed children with allergic asthma had nearly 6 times higher serum IL-17A levels compared with low DEP exposed children. CONCLUSIONS: Expansion of T(H)17 cells contributes to DEP mediated exacerbation of allergic asthma. Neutralization of IL-17A might be a useful potential therapeutic strategy to counteract the asthma-promoting effects of traffic-related air pollution, especially in highly exposed patients with severe allergic asthma. PMID- 24060274 TI - Circadian regulation of allergic reactions by the mast cell clock in mice. AB - BACKGROUND: It remains elusive how allergic symptoms exhibit prominent 24-hour variations. In mammals the circadian clocks present in nearly all cells, including mast cells, drive the daily rhythms of physiology. Recently, we have shown that the circadian clocks drive the daily rhythms in IgE/mast cell-mediated allergic reactions. However, the precise mechanisms, particularly the specific roles of the mast cell-intrinsic clockwork in temporal regulation, remain unclear. OBJECTIVE: We determined whether the mast cell clockwork contributes to the temporal regulation of IgE/mast cell-mediated allergic reaction. METHODS: The kinetics of a time of day-dependent variation in passive cutaneous anaphylactic reactions were compared between mast cell-deficient mice reconstituted with bone marrow-derived cultured mast cells generated from mice with a wild-type allele and a dominant negative type mutation of the key clock gene Clock. We also examined the temporal responses of wild-type and Clock-mutated bone marrow derived cultured mast cells to IgE stimulation in vitro. Furthermore, factors influencing the mast cell clockwork were determined by using in vivo imaging. RESULTS: The Clock mutation in mast cells resulted in the absence of temporal variations in IgE-mediated degranulation in mast cells both in vivo and in vitro associated with the loss of temporal regulation of FcepsilonRI expression and signaling. Additionally, adrenalectomy abolished the mast cell clockwork in vivo. CONCLUSION: The mast cell-intrinsic clockwork, entrained by humoral factors from the adrenal gland, primarily contributes to the temporal regulation of IgE/mast cell-mediated allergic reactions. Our results reveal a novel regulatory mechanism for IgE-mediated mast cell responses that might underlie the circadian pathophysiology in patients with allergic diseases. PMID- 24060275 TI - Incidence rate of symptomatic venous thromboembolic disease in patients from a medical care program in Buenos Aires, Argentina: a prospective cohort. AB - BACKGROUND: The incidence of venous thromboembolic disease (VTED) is estimated to be, on average, 1-2 cases per 1,000 individuals per year worldwide. There are few data concerning the incidence rate (IR) of VTED in the Argentinean population at large.Our aim was to estimate the IR of VTED at the Italian Hospital Medical Care Program (IHMCP) in Buenos Aires, the most populous city in Argentina. METHODS: This prospective cohort study evaluated all consecutive incident cases of pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT) confirmed in patients over the age of 17 who were members of the IHMCP from June 2006 to May 2012. Any patient who had an initial confirmed VTED episode and was a member of the IHMCP at the time of diagnosis was considered an incident case. RESULTS: There were 1,138 cases of VTED for 687,871 person-years of follow-up. The crude IR of VTED was 1.65 (95% CI: 1.56 to 1.75) per 1,000 person-years. The highest IR was found in subjects >80 years old (5.92 per 1,000 person years; 95% CI: 5.41 to 6.49).The IRs adjusted to the population of the city of Buenos Aires were 0.90 (95% CI: 0.84 to 0.95) for VTED, 0.71 (95% CI: 0.66 to 0.76) for DVT, and 0.34 (95% CI: 0.31 to 0.37) for PTE. CONCLUSIONS: VTED is a common health problem with a high IR in members of the IHMCP, especially the elderly. This is the first paper to report prospectively the cumulative incidence of VTED in Latin America. PMID- 24060276 TI - Incidence of sport-related traumatic brain injury and risk factors of severity: a population-based epidemiologic study. AB - PURPOSE: Few studies of sport-related traumatic brain injury (TBI) are population based or rely on directly observed data on cause, demographic characteristics, and severity. This study addresses the epidemiology of sport-related TBI in a large population. METHODS: Data on all South Carolina hospital and emergency department encounters for TBI, 1998-2011, were analyzed. Annual incidence rate of sport-related TBI was calculated, and rates were compared across demographic groups. Sport-related TBI severity was modeled as a function of demographic and TBI characteristics using logistic regression. RESULTS: A total of 16,642 individuals with sport-related TBI yielded an average annual incidence rate of 31.5/100,000 population with a steady increase from 19.7 in 1998 to 45.6 in 2011. The most common mechanisms of sport-related TBI were kicked in football (38.1%), followed by fall injuries in sports (20.3%). Incidence rate was greatest in adolescents ages 12-18 (120.6/100,000/persons). Severe sport-related TBI was strongly associated with off-road vehicular sport (odds ratio [OR], 4.73; 95% confidence interval [95% CI], 2.92-7.67); repeated head trauma (OR, 4.36; 95% CI, 3.69-5.15); equestrian sport (OR, 2.73; 95% CI, 1.64-4.51); and falls during sport activities (OR, 2.72; 95% CI, 1.67-4.46). CONCLUSIONS: The high incidence of sport-related TBI in youth, potential for repetitive mild TBI, and its long term consequences on learning warrants coordinated surveillance activities and population-based outcome studies. PMID- 24060277 TI - Effects of legume kernel fibres and citrus fibre on putative risk factors for colorectal cancer: a randomised, double-blind, crossover human intervention trial. AB - BACKGROUND: In some studies, high intake of dietary fibre has been associated with a lower risk of colorectal cancer. The present study aimed to compare physiological effects of three legume kernel fibres and citrus fibre on blood lipids (primary outcome: LDL cholesterol) and colonic health. METHODS: Ninety-two subjects were recruited for the double-blind, controlled crossover trial. Seventy eight participants were randomly divided into three groups. Following run-in, half the volunteers from each group consumed 25 g/d of a legume fibre, comprising blue lupin fibre, white lupin fibre, and soya fibre for two weeks. The other half received the same amount of citrus fibre (active comparator). The intervention was crossed within each group after two weeks wash-out. At the end of run-in and intervention, a quantitative faeces collection took place and fasting blood samples were drawn. Repeated measures ANOVA with the general linear model were applied to evaluate changes following interventions. RESULTS: Seventy-six subjects completed the study. Dietary fibre intake during all interventions was approximately twice the fibre intake at run-in. The lupin fibre supplementations increased daily faecal dry matter and faecal weight compared to run-in, representing an increase of 1.76 g faeces/g additional dietary fibre contributed by blue lupin and of 1.64 g faeces/g by white lupin, respectively. Both lupin interventions led to a significantly enhanced formation of short-chain fatty acids, and blue lupin fibre to a decrease in faecal pH compared to run-in (0.27 units, P < 0.01). Further, blue lupin increased primary bile acids-excretion (P = 0.02). All legume fibres reduced faecal concentrations of total and secondary bile acids (blue lupin: 16% white lupin: 24% soya: 16%). Blood lipids were not influenced by any intervention. No serious adverse effects were observed. CONCLUSIONS: The tested fibre preparations do not affect lipid metabolism through bile acid-binding in normocholesterolaemic subjects. However, particularly blue lupin kernel fibre improve colonic function and have beneficial effects on putative risk factors for colorectal cancer such as faecal mass, transit time, SCFA, faecal pH, and secondary bile acid concentration. Therefore, enhancing dietary fibre intake through blue lupin up to about 50 g/d can be recommended. TRIAL REGISTRATION: NCT01036308. PMID- 24060278 TI - Reciprocal relation between GADD153 and Del-1 in regulation of salivary gland inflammation in Sjogren syndrome. AB - Endoplasmic reticulum (ER) stress response is a pivotal regulator of inflammation and cell death. An integral component of ER stress-induced apoptosis is expression of growth arrest- and DNA damage-inducible protein 153 (GADD153). Further, ER stress response is implicated in leukocyte adhesion and recent studies have discovered endogenous inhibitors of leukocyte adhesion including the developmental endothelial locus-1 (Del-1). Accordingly, we tested the hypothesis that Sjogren's syndrome (SS) is associated with increased salivary gland expression of GADD153 and increased leukocyte infiltration in association with decreased Del-1 thereby contributing to inflammation and cell death. We utilized the non-obese diabetic (NOD) mice, a model of SS-like disease, in association with immunostaining and flow cytometry-based studies. Salivary glands of 14-week old NOD mice displayed a) increased GADD153 expression, b) marked reduction in Del-1, c) inflammatory cell infiltrates including CD3+ T and CD19+ B lymphocytes as well as M1 and M2 macrophages and d) increased pro-inflammatory interleukin (IL)-17 but reduced anti-inflammatory cytokine, IL-10. These changes were accompanied with disruption of mitochondrial membrane potential and significant increase in apoptosis and necrosis of salivary gland cells of NOD than control mice. Our collective observations suggested that GADD153 directly and/or indirectly through downregulation of Del-1 contributes importantly to salivary gland inflammation and cell death. To establish the relevance of GADD153 and Del 1 for the human condition, lower lip biopsy samples of non-SS subjects and those with a diagnosis of SS were subjected to immunohistochemistry. The results show intense GADD153 immunostaining but marked reduction in Del-1 expression in biopsy samples of SS compared to non-SS subjects. Collectively, the results indicate that GADD153 regulates inflammation and cell death in salivary gland in SS. Further, Del-1 expression likely provides a mechanistic link between increased GADD153 and leukocyte infiltration and accompanying inflammation of salivary gland tissue in this condition. PMID- 24060279 TI - Adjuvanticity of compound astragalus polysaccharide and sulfated epimedium polysaccharide per os. AB - On the basis of previous researches, compound astragalus polysaccharide (APS) and sulfated epimedium polysaccharide (sEPS) oral liquid (AEO) was prepared. Three hundred and twenty 14-day-old chickens were randomly assigned into eight groups and vaccinated with ND vaccine except for blank control (BC) group, repeated vaccination at 28 days old. At the same time of each vaccination, the chickens in three experimental groups were taken orally with AEO, respectively, at three doses, in two component control groups with APS and sEPS, once a day for three successive days; in injection control group were injected with AEI once, and in vaccination control (VC) and BC groups were not administrated. On days 7, 14, 21, 28 and 35 after the first vaccination, peripheral lymphocyte proliferation, the serum antibody titer, IFN-gamma and IL-2 concentrations and on day 35 immune organ index were measured. The results showed that AEO at high and medium doses could significantly promote lymphocyte proliferation and development of immune organ, enhance antibody titer and IFN-gamma and IL-2 concentration, which was stronger than actions of AEI and two components. The results confirmed that AEO possessed reliable immunoenhancement and could be exploited into an oral immunopotentiator. PMID- 24060280 TI - Antioxidant activity of glycoprotein purified from Undaria pinnatifida measured by an in vitro digestion model. AB - The present study was performed to investigate the chemical composition and antioxidant activity of glycoprotein purified from Undaria pinnatifida Harvey (UPGP). On SDS-PAGE, UPGP migrated as a single band with a molecular weight of approximately 10 kDa and confirmed by staining with Schiff's reagent as glycoprotein. It consists of a carbohydrate component (42.53%) and protein component (57.47%). Amino acid profile, FT-IR spectrum and enzymatic glycosylation analysis suggested that protein is linked with carbohydrate by O glycosylation. UPGP showed dose-dependent antioxidant activities as detected by different assays before and after in vitro digestion. The IC50 values of undigested UPGP were 0.25 +/- 0.03, 0.08 +/- 0.005, 0.69 +/- 0.12, and 0.25 +/- 0.08 mg/mL for DPPH, ABTS, FRAP, and NO, respectively. Following in vitro digestion, the antioxidant activities of UPGP were decreased during the gastric phase compared to those of undigested UPGP, with an increase occurring during the duodenal phase in all assays. However, the reducing power was unchanged after in vitro digestion. Furthermore, UPGP showed protective activity against oxidative DNA damage both undigested, after saliva and duodenal phase of digestion. These results indicate that the antioxidant and DNA protection activities of UPGP may be pH-dependent and assay specific. PMID- 24060281 TI - Chitosan-hyaluronic acid/nano silver composite sponges for drug resistant bacteria infected diabetic wounds. AB - The aim of this work was to develop an antimicrobial sponge composed of chitosan, hyaluronic acid (HA) and nano silver (nAg) as a wound dressing for diabetic foot ulcers (DFU) infected with drug resistant bacteria. nAg (5-20 nm) was prepared and characterized. The nanocomposite sponges were prepared by homogenous mixing of chitosan, HA and nAg followed by freeze drying to obtain a flexible and porous structure. The prepared sponges were characterized using SEM and FT-IR. The porosity, swelling, biodegradation and haemostatic potential of the sponges were also studied. Antibacterial activity of the prepared sponges was analysed using Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa and Klebsiella pneumonia. Chitosan-HA/nAg composite sponges showed potent antimicrobial property against the tested organisms. Sponges containing higher nAg (0.005%, 0.01% and 0.02%) concentrations showed antibacterial activity against MRSA. Cytotoxicity and cell attachment studies were done using human dermal fibroblast cells. The nanocomposite sponges showed a nAg concentration dependent toxicity towards fibroblast cells. Our results suggest that this nanocomposite sponges could be used as a potential material for wound dressing for DFU infected with antibiotic resistant bacteria if the optimal concentration of nAg exhibiting antibacterial action with least toxicity towards mammalian cells is identified. PMID- 24060282 TI - Antitumor and immunomodulatory activity of Astragalus membranaceus polysaccharides in H22 tumor-bearing mice. AB - In the present study, we investigated the antitumor and immunomodulatory activity of Astragalus membranaceus polysaccharide (AMP) on liver cancer using murine H22 hepatocarcinoma model. The results showed that AMP (100 and 400 mg/kg) could effectively inhibit the solid tumor growth of H22 hepatocarcinoma transplanted in BALB/c mice. Besides, the body weight, spleen/thymus indexes and phagocytotic function of macrophage of H22 tumor bearing mice were also improved in two AMP treated groups. Furthermore, AMP treatment could promote the secretion of IL-2, IL-12 and TNF-alpha and decreased IL-10 level in serum. Taken together, these findings indicate that AMP has antitumor activity in vivo at least partly via improving immune responses of host organism, and seems to be safe and effective for the use of anti-tumor therapy. PMID- 24060283 TI - Hypolipidemic activity of the polysaccharides from Enteromorpha prolifera. AB - Enteromorpha prolifera is an edible alga that is used as a traditional herb to treat many diseases. This study prepared E. prolifera polysaccharides (EPPs) and determined their hypolipidaemic activity in rats. Forty-eight male Sprague-Dawley rats were divided into three groups and fed with diets containing either high fat (HF), EPPs or normal fat (NF) for 6 weeks. Compared with the HF group, the EPP group showed decreased body weight gain, plasma triacylglycerol (TG), total cholesterol (TC), plasma low-density lipoprotein cholesterol level, liver TG, liver TC and liver weight. The faecal fat, cholesterol and plasma high-density lipoprotein cholesterol of the EPP group were higher than those of the NF and HF groups. Results suggested that EPPs had a high hypolipidaemic activity and could be a suitable alternative hypolipidaemic source for humans. PMID- 24060284 TI - Investigation of thermal reversibility and stability of glycated human serum albumin. AB - Protein glycation, the process by which carbohydrates attach to proteins upon covalent binding, can alter protein thermal reversibility and stability. Protein stability and reversibility have important role in protein behavior and function. Also they are benefit properties for drug produce and protein industrial applications. In this research the thermal reversibility and stability changes in human serum albumin (HSA) were studied upon incubation with glucose (GHSA) under physiological conditions for 21 and 35 days. The thermal reversibility and stability changes in GHSA were evaluated using circular dichroism (CD), UV-vis spectroscopy, fluorescence spectroscopy and differential scanning calorimetry (DSC). Our results showed that the glycation of HSA increased its thermal reversibility and stability, but decreased its conformational entropy compared to fresh native HSA and untreated HSA. Free lysine content assay (TNBSA test) indicated glucose can bind to protein covalently. These alterations were mainly attributed to the formation of crosslink between the lysine residues of HSA upon incubation with glucose. PMID- 24060285 TI - Electronic and exchange coupling in a cross-conjugated D-B-A biradical: mechanistic implications for quantum interference effects. AB - A combination of variable-temperature EPR spectroscopy, electronic absorption spectroscopy, and magnetic susceptibility measurements have been performed on Tp(Cum,Me)Zn(SQ-m-Ph-NN) (1-meta) a donor-bridge-acceptor (D-B-A) biradical that possesses a cross-conjugated meta-phenylene (m-Ph) bridge and a spin singlet ground state. The experimental results have been interpreted in the context of detailed bonding and excited-state computations in order to understand the excited-state electronic structure of 1-meta. The results reveal important excited-state contributions to the ground-state singlet-triplet splitting in this cross-conjugated D-B-A biradical that contribute to our understanding of electronic coupling in cross-conjugated molecules and specifically to quantum interference effects. In contrast to the conjugated isomer, which is a D-B-A biradical possessing a para-phenylene bridge, admixture of a single low-lying singly excited D -> A type configuration into the cross-conjugated D-B-A biradical ground state makes a negligible contribution to the ground-state magnetic exchange interaction. Instead, an excited state formed by a Ph-NN (HOMO) -> Ph-NN (LUMO) one-electron promotion configurationally mixes into the ground state of the m-Ph bridged D-A biradical. This results in a double (dynamic) spin polarization mechanism as the dominant contributor to ground-state antiferromagnetic exchange coupling between the SQ and NN spins. Thus, the dominant exchange mechanism is one that activates the bridge moiety via the spin polarization of a doubly occupied orbital with phenylene bridge character. This mechanism is important, as it enhances the electronic and magnetic communication in cross-conjugated D-B-A molecules where, in the case of 1-meta, the magnetic exchange in the active electron approximation is expected to be J ~ 0 cm(-1). We hypothesize that similar superexchange mechanisms are common to all cross conjugated D-B-A triads. Our results are compared to quantum interference effects on electron transfer/transport when cross-conjugated molecules are employed as the bridge or molecular wire component and suggest a mechanism by which electronic coupling (and therefore electron transfer/transport) can be modulated. PMID- 24060286 TI - Intravascular large B-cell lymphoma--a diagnostic dilemma. PMID- 24060287 TI - Bendamustine and rituximab for indolent B-cell non-hodgkin lymphoma in patients with compensated hepatitis C cirrhosis: a case series. PMID- 24060288 TI - Detection of dormant chronic myeloid leukemia clones in the bone marrow of patients in complete molecular remission. AB - BACKGROUND: Several methods are available to detect MRD in patients with CML in complete molecular remission (CMR) and taking tyrosine kinase inhibitor (TKI) therapy. MATERIALS AND METHODS: We performed clonogenic assays on mononuclear bone marrow cells from 14 patients. Of the 10 assessable samples, 6 were from patients in CMR and 4 from patients in complete cytogenetic remission but had detectable MRD using polymerase chain reaction (PCR) analysis (positive controls). At least 10 colonies per sample were microaspirated and individual colonies were subjected to PCR analysis. RESULTS: Of the 6 patients in CMR, 5 harbored breakpoint cluster region abelson (BCR-ABL1) negative colonies but in 1 sample, 1 of the 10 colonies analyzed was positive for BCR-ABL1. Of the 4 patients with evidence of MRD in peripheral blood, 2 had negative and 2 had positive BCR-ABL1 colonies. CONCLUSION: MRD is still detectable using clonogenic assays in some patients with CML after achieving CMR using TKI therapy, which is likely responsible for relapse on TKI discontinuation. Because of the large number of single colonies that need to be analyzed, the use of clonogenic assays in clinical practice to determine the feasibility of TKI discontinuation is not recommended. PMID- 24060289 TI - Similar outcome of patients with chronic myeloid leukemia treated with imatinib in or out of clinical trials. AB - INTRODUCTION: Outcomes of CML-CP patients treated in clinical trials are frequently perceived to be not representative of those treated outside of clinical trials. PATIENTS AND METHODS: We investigated the outcomes of patients receiving imatinib outside of a clinical trial (off protocol) or in a clinical trial (on protocol) for CML-CP. RESULTS: We identified 65 patients treated with imatinib off protocol and 71 patients treated on protocol with standard-dose imatinib. The overall complete cytogenetic response (CCyR) rate was 83% for patients treated on and off protocol. CCyR rates 12 months after initiation of imatinib were not statistically different (61% vs. 66%, respectively; P = .15). Patients treated off protocol had similar rates of overall major molecular response (72% vs. 73%) compared with the patients treated on protocol. The 5-year event-free survival rates were 84% and 86% for off and on protocol patients, respectively. There was also no significant difference in 5-year transformation free survival (94% vs. 96%) and overall survival (96% vs. 90%). CONCLUSION: These results suggest that patients with CML treated outside of a clinical trial might have the same excellent outcome as those treated in a clinical trial provided they are followed with the same rigor. PMID- 24060290 TI - Environmental & economic life cycle assessment of current & future sewage sludge to energy technologies. AB - The UK Water Industry currently generates approximately 800GWh pa of electrical energy from sewage sludge. Traditionally energy recovery from sewage sludge features Anaerobic Digestion (AD) with biogas utilisation in combined heat and power (CHP) systems. However, the industry is evolving and a number of developments that extract more energy from sludge are either being implemented or are nearing full scale demonstration. This study compared five technology configurations: 1 - conventional AD with CHP, 2 - Thermal Hydrolysis Process (THP) AD with CHP, 3 - THP AD with bio-methane grid injection, 4 - THP AD with CHP followed by drying of digested sludge for solid fuel production, 5 - THP AD followed by drying, pyrolysis of the digested sludge and use of the both the biogas and the pyrolysis gas in a CHP. The economic and environmental Life Cycle Assessment (LCA) found that both the post AD drying options performed well but the option used to create a solid fuel to displace coal (configuration 4) was the most sustainable solution economically and environmentally, closely followed by the pyrolysis configuration (5). Application of THP improves the financial and environmental performance compared with conventional AD. Producing bio-methane for grid injection (configuration 3) is attractive financially but has the worst environmental impact of all the scenarios, suggesting that the current UK financial incentive policy for bio-methane is not driving best environmental practice. It is clear that new and improving processes and technologies are enabling significant opportunities for further energy recovery from sludge; LCA provides tools for determining the best overall options for particular situations and allows innovation resources and investment to be focused accordingly. PMID- 24060291 TI - Attitudes towards euthanasia in severely ill and dementia patients and cremation in Cyprus: a population-based survey. AB - BACKGROUND: Population studies on end-of-life decisions have not been conducted in Cyprus. Our study aim was to evaluate the beliefs and attitudes of Greek Cypriots towards end-of-life issues regarding euthanasia and cremation. METHODS: A population-based telephone survey was conducted in Cyprus. One thousand randomly selected individuals from the population of Cyprus age 20 years or older were invited to participate. Beliefs and attitudes on end-of-life decisions were collected using an anonymous and validated questionnaire. Statistical analyses included cross-tabulations, Pearson's chi-square tests and multivariable-adjusted logistic regression models. RESULTS: A total of 308 males and 689 females participated in the survey. About 70% of the respondents did not support euthanasia for people with incurable illness and/or elders with dementia when requested by them and 77% did not support euthanasia for people with incurable illness and/or elders with dementia when requested by relatives. Regarding cremation, 78% were against and only 14% reported being in favor. Further statistical analyses showed that male gender, being single and having reached higher educational level were factors positively associated with support for euthanasia in a statistically significant fashion. On the contrary, the more religiosity expressed by study participants, the less support they reported for euthanasia or cremation. CONCLUSIONS: The vast majority of Greek Cypriots does not support euthanasia for people with incurable illness and/or elders with dementia and also do not support cremation. Certain demographic characteristics such as age and education have a positive influence towards attitudes for euthanasia and cremation, while religiosity exerts a strong negative influence on the above. Family bonding as well as social and cultural traditions may also play a role although not comprehensively evaluated in the current study. PMID- 24060292 TI - Understanding the pathophysiology of essential tremor through advanced neuroimaging: a review. AB - Essential tremor (ET) is one of the most common neurological diseases; but aetio pathogenesis of ET is largely unknown. Major advances in neuroimaging may help us understand the mechanisms and networks involved in ET. Most commonly employed techniques include functional and structural neuroimaging. Functional imaging studies suggest that tremors in ET are of central origin with role of olivo cerebellar and cerebello-thalamo-cortical pathways in tremor generation. Apart from tremors, ET is also characterised by cognitive dysfunction. Functional magnetic resonance imaging (fMRI) studies suggest the role of cerebellum posterior lobules, dorsolateral prefrontal cortex and parietal lobules in cognitive impairment in ET. Positron emission tomography studies indicate the role of gamma-aminobutyric-acid dysfunction in tremor generation while most of the structural imaging studies (diffusion tensor imaging, voxel based morphometry, T2*-relaxometry on magnetic resonance imaging) along with magnetic resonance spectroscopic imaging point toward neurodegeneration. This review focuses on recent findings in the field of imaging in ET which may help understand the disease pathogenesis and mechanisms. PMID- 24060294 TI - National roadside survey of child restraint system use in Belgium. AB - In September 2011 the Belgian Road Safety Institute (BRSI) conducted its first roadside survey of child restraint system (CRS) use and misuse. The aim of this study was to obtain population-bases estimates of the prevalence of use and misuse of CRS and to identify predictors of misuse on the basis of observations in real traffic conditions. The survey was conducted on randomly selected sites across the country, stratified across various types of journeys. The principal parameters analysed were: the characteristics of the children and the car drivers, type of journey, types of CRS and types of misuse. The sample consisted of 1461 children (under 135cm) for whom the conditions of restraint were observed in detail and the driver was interviewed. At least 50% of the children were not correctly restrained and 10% were not restrained at all. The most significant factors associated with CRS use were the use of a seatbelt by the driver (31% of unrestrained children for unbelted drivers, compared to 7% for belted drivers - only 32% of correctly restrained children for unbelted drivers compared to 54% for belted drivers), whether the CRS was bought in a specialized shop (only 27% of misuse compared to 45% of misuse for CRS both in supermarkets) and the age of the children. The proportion of correctly restrained children (appropriate without misuse, the bottom category in the figure) has a roughly curvilinear relation with age; decreasing from 75% at age 0 to 24% at age 8 and going back up to 63% at age 10. Although the sample of ISOFIX users was small (n=76), it appears that the ISOFIX system reduced misuse significantly. Most of the drivers were ignorant of their own errors concerning the inappropriateness and/or misuse of the CRS or they were remiss and underestimated the risk. The three main reasons given by the drivers to explain or justify the misuse noticed were: low attention level to safety (inattention, time pressure, and short distance), the child's resistance to be restrained, children restraining themselves and problems with the CRS. The present results suggest little or no change in the level of correct CRS use over the last five years and clearly reveal the unacceptably high levels of incorrect and/or inappropriate CRS use. This calls for campaigns and other actions to inform and motivate the population. PMID- 24060295 TI - A R2R3-MYB transcription factor, GmMYB12B2, affects the expression levels of flavonoid biosynthesis genes encoding key enzymes in transgenic Arabidopsis plants. AB - Isoflavones play diverse roles in plant-microbe interactions and are potentially important for human nutrition and health. To study the regulation of isoflavonoid synthesis in soybean, the R2R3-MYB transcription factor GmMYB12B2 was isolated and characterized. Yeast expression experiments demonstrated that GmMYB12B2 showed transcriptional activity. GmMYB12B2 was localized in the nucleus when it was transiently expressed in onion epidermal cells. Real-time quantitative PCR analysis revealed that GmMYB12B2 transcription was increased in roots and mature seeds compared with other organs. The gene expression level in immature embryos was consistent with the accumulation of isoflavones. CHS8 is a key enzyme in plant flavonoid biosynthesis. Transient expression experiments in soybean calli demonstrated that CHS8 was regulated by GmMYB12B2 and produced more fluorescence. The expression levels of some key enzymes in flavonoid biosynthesis were examined in transgenic Arabidopsis lines. The results showed that the expression levels of PAL1, CHS and FLS in transgenic plants were significantly higher than those in wild type plants. However, the expression level of DFR was lower, and the expression levels of CHI, F3H and F3'H were the same in all lines. GmMYB12B2 expression caused a constitutive increase in the accumulation of flavonoids in transgenic Arabidopsis lines compared with wild type plants. PMID- 24060296 TI - Interleukin-1alpha -899 (+4845) C->T polymorphism increases the risk of chronic periodontitis: evidence from a meta-analysis of 23 case-control studies. AB - Many epidemiological studies have indicated that interleukin-1alpha (IL-1alpha) 899 (+4845) C->T polymorphism increases the risk of chronic periodontitis (CP), whereas some studies have reported opposite results. Accordingly, the aim of this meta-analysis is to investigate the association of the IL-1alpha -899 (+4845) C >T polymorphism with CP. We searched the PubMed database up to May 1, 2013 and finally obtained 23 case-control studies. After data extraction, we performed meta-analysis using Comprehensive Meta-Analysis v2.2 software. The overall result based on the fixed-effect model showed that IL-1alpha -899 (+4845) C->T polymorphism was significantly associated with increased risk of CP: [odds ratio (OR)=1.29, 95% confidence interval (CI)=1.15-1.44, p<0.001] for T vs. C; (OR=1.59, 95%CI=1.22-2.07, p=0.0005) for TT vs. CC; (OR=1.30, 95% CI=1.12-1.51, p=0.0004) for CT vs. CC; and (OR=1.40, 95% CI=1.21-1.61, p<0.001) for (CT+TT) vs. CC; (OR=1.47, 95% CI=1.16-1.87, p=0.002) for TT vs. (CT+CC). Stratified analyses revealed that there was a significantly increased risk for Caucasians and Asians. In conclusion, current evidence showed that IL-1alpha -899 (+4845) C->T polymorphism probably increased the risk of CP. PMID- 24060298 TI - Magnetoceramics from the bulk pyrolysis of polysilazane cross-linked by polyferrocenylcarbosilanes with hyperbranched topology. AB - In this contribution, we report a novel strategy for the synthesis of nanocrystal containing magnetoceramics with an ultralow hysteresis loss by the pyrolysis of commercial polysilazane cross-linked with a functional metallopolymer possessing hyperbranched topology. The usage of hyperbranched polyferrocenylcarbosilane offers either enhanced ceramic yield or magnetic functionality of pyrolyzed ceramics. The ceramic yield was enhanced accompanied by a decreased evolution of hydrocarbons and NH3 because of the cross-linking of precursors and the hyperbranched cross-linker. The nucleation of Fe5Si3 from the reaction of iron atoms with Si-C-N amorphous phase promoted the formation of alpha-Si3N4 and SiC crystals. After annealing at 1300 degrees C, stable Fe3Si crystals were generated from the transformation of the metastable Fe5Si3 phase. The nanocrystal containing ceramics showed good ferromagnetism with an ultralow (close to 0) hysteresis loss. This method is convenient for the generation of tunable functional ceramics using a commercial polymeric precursor cross-linked by a metallopolymer with a designed topology. PMID- 24060297 TI - Contraceptive adherence among HIV-infected women in Malawi: a randomized controlled trial of the copper intrauterine device and depot medroxyprogesterone acetate. AB - OBJECTIVE: To evaluate contraceptive adherence to the copper intrauterine device (Cu-IUD) and the injectable depot medroxyprogesterone acetate (DMPA) among women with HIV in Lilongwe, Malawi. METHODS: We randomized 200 HIV-infected women on highly active antiretroviral therapy (HAART) to either the Cu-IUD or DMPA and followed these women prospectively, evaluating adherence and factors associated with nonadherence. RESULTS: There was no difference in contraceptive adherence: 68% of Cu-IUD and 65% of DMPA users were adherent at 48 weeks. Receiving first choice contraceptive was not associated with adherence. Women commonly cited partner's disapproval as an indication for discontinuation. Women who experienced heavy menstruation and first-time contraceptive users were more likely to be nonadherent. Among ongoing users at study conclusion, 95% were happy with their method, and 98% would recommend their method to a friend. CONCLUSION: Contraceptive adherence between the Cu-IUD and DMPA was similar at 1 year. With similar adherence and similar high rates of satisfaction among users of both methods at 1 year, the Cu-IUD offers a hormone-free alternative to DMPA. IMPLICATIONS: Adherence to the Cu-IUD and DMPA is similar at 1 year among HIV infected women on HAART in a randomized controlled trial. Despite high method satisfaction, partner disapproval and heavy bleeding contribute to reduced adherence. Receiving a method that differs from participant's first-choice method did not influence adherence. PMID- 24060299 TI - [Pharmacogenetics and age-related macular degeneration, towards an individualized treatment of the disease]. PMID- 24060300 TI - [Intravitreal triamcinolone combined with grid laser photocoagulation for patients with cystoid macular edema and advanced diabetic retinopathy: pilot study]. AB - BACKGROUND: To determine if primary intravitreal injection of triamcinolone acetonide (TA) plus grid laser photocoagulation (GLP) is effective in treating cystoid diabetic macular edema (DME). METHODS: Prospective comparative non randomized clinical trial. Fourteen eyes (14 patients) diagnosed with cystoid DME were treated with GLP according to the Early Treatment Diabetic Retinopathy Study (ETDRS) guidelines, plus an intravitreal injection of 4 mg of TA. A matched control group (16 eyes [16 patients]) treated with GLP was selected retrospectively from our medical records. Best-corrected visual acuity (BCVA), and quantitative change in optical coherence tomography (OCT) macular thickness were assessed. RESULTS: Mean follow up was 14.9 months (12 to 19 months). In 3 (21.4%) eyes BCVA increased > 2 ETDRS lines, in 5 (35.7%) eyes BCVA remained the same, and BCVA decreased >2 ETDRS lines in 6 (42.8%) eyes. Central macular thickness, as measured by OCT, decreased a mean of 106.2 MUm (30.2%). The difference with the control group was not statistically significant (P = .2). Four (28.5%) eyes developed an increased in intraocular pressure in our study group. CONCLUSIONS: Although all of our patients showed an improvement of cystoid DME by means of OCT and fluorescein angiography, 42.8% (6 eyes) lost 2 or more lines in BCVA with primary intravitreal injection of TA plus GLP. Primary intravitreal injection of TA plus GLP may not be effective for cystoid DME at 12 months. PMID- 24060301 TI - [Responses to ranibizumab in wet age-related macular degeneration patients with vitreomacular traction]. AB - PURPOSE: The purpose of the present study is to compare the responses to ranibizumab between wet age-related macular degeneration patients, with and without accompanying vitreomacular traction syndrome. METHODS: Our database of optical coherence tomography files was searched for eyes of age-related macular degeneration patients that had been treated with ranibizumab, and that had evidence of vitreomacular traction. A control group was selected from the same database for comparison. The case history of each selected individual was reviewed for data regarding the evolution of visual acuity in that patient, and the number of intravitreal injections that had been required to date. RESULTS: From a database of 373 eyes, clear images of vitreomacular traction were obtained for a total of 18 eyes. The mean follow-up period was 20.6 months (SD=10.6, range=10.4-31.7). Patients in the vitreomacular traction group had been given an average of 5.1 injections versus an average of 4.2 injections in patients in the control group. The mean changes in visual acuity (which was measured using ETDRS charts) were -15 letters and -4 letters in the vitreomacular traction and control groups (P=.07), respectively. CONCLUSIONS: After ranibizumab treatment, age related macular degeneration patients with accompanying vitreomacular traction showed a tendency to have a poorer prognosis in terms of visual acuity than patients without this finding. In addition, higher numbers of intravitreal injections were required to obtain clinical responses in patients with vitreomacular traction. PMID- 24060302 TI - [Design and validation of a simulator for training in continuous circular capsulotomy for phacoemulsification]. AB - INTRODUCTION: To design and validate a simulator for learning and training in the capsulorhexis technique. METHODS: The system consists of a methacrylate support inclined 15 degrees for the surgeon's hand, an area of commercially available aluminum foil, and another one of similar characteristics, where the student performs the technique through some slots that are previously made in the support. In order to evaluate the feasibility of this simulator, data were collected from 65 ophthalmologists performing the technique during training activities. The ophthalmologists were randomly divided into one group of 30 specialists who start their learning on the eyes of an animal cadaver, and into another of 35 specialists who previously started with this simulator. RESULTS: A simulator is developed for training in the capsulorhexis technique. The students from the simulator group achieved a reduction in the use of cadaver eyes, and a higher efficiency in correct capsulorhexis, unlike the group who started directly on the cadaver eyes. CONCLUSIONS: This simulator is an innovation in training of the capsulorhexis technique as regards simplicity, cost, and reuse, as compared to other virtual simulators with more expensive computer equipment (CE) equipment that are more difficult to transport. It is an important step prior to the use of cadaver parts and experimental animals, decreasing the number of both, and therefore the teaching costs. PMID- 24060303 TI - [Variability and reproducibility of 3 methods for measuring the thickness of the nerve fiber layer]. AB - OBJECTIVE: To estimate the variability and reproducibility of confocal tomography (HRT), scanning laser polarimetry (GDx) and optical coherence tomography (OCT Cirrus) to determine the thickness of the layer of ganglion fibers. METHOD: A total of 75 normal eyes were examined twice. Inter-individual variability was analyzed after standardizing the results. The coefficient of variation was used to measure the variability between tests, and the Pearson coefficient was used to analyze the correlation between variables. RESULTS: The inter-individual variability was similar in GDx (8.9%) and OCT (11.1%), but very high in HRT (30.0%). No instrument detected significant changes with age. The coefficient of variation of the total thickness between the examinations of the same subject was significantly lower (P<.05) in GDx (1.4) than in OCT (2.0), but very high in HRT (6.4). The same was true when analyzing the upper fibers (GDx=1.8, OCT=2.9, HRT = 6.6), but not with the lower ones, where the only significant differences were observed with HRT (GDx = 2.2, OCT = 2.7, HRT = 7.0). Among the results of OCT and GDx, there was a significant correlation when comparing the first (r=0.46, P<.0001) and second examinations (r=0.52, P<.0001). However there was no significant relationship between the data provided by HRT for the two remaining instruments (P>.05). CONCLUSIONS: There is a wide variation in the inter individual and inter-test measurement of the thickness of the of nerve fibers layers using HRT. GDx has, in this respect, slight advantages over OCT. PMID- 24060304 TI - [Congenital mydriasis as an initial sign of septo-optic dysplasia]. AB - Septo-optic dysplasia (SOD)[MIM182230] consisting of a heterogeneous and uncommon condition characterised by the classictriad: optic nerve hypoplasia, abnormalities of pituitary hormone, and defects of thebrain midline (including agenesis of the septum pellucidum and/or the corpus callosum; ithas also been described associated cortical malformations, it was referred to as SOD plus syndrome).We report the first known case in which the initial diagnostic sign of SOD was a bilateralmydriasis as a manifestation ofhypoplasia of both optic nerves, pituitary hypoplasia andcerebral dysgenesis with neuronal migration disorder.We discuss thedifferential diagnosis of congenital mydriasis. PMID- 24060305 TI - [Papilledema secondary to tuberculous meningitis in a patient with type 1 diabetes mellitus]. AB - CASE REPORT: The case is presented of a 29-year-old woman who complained of headache over a period of several days, with loss of visual acuity and pain in her left eye. She had a 3-year history of type 1 diabetes mellitus, and was an immigrant from Ecuador. The funduscopic examination revealed a papilledema. The polymerase chain reaction (PCR) study of the cerebrospinal fluid was positive for Mycobacterium tuberculosis (MTB). She showed a marked improvement after treatment with anti-TB drugs. DISCUSSION: About a third of the world's population has a latent infection of MTB, comorbidity between diabetes mellitus and tuberculosis has been reported, particularly in undeveloped countries. PMID- 24060306 TI - [Ocular paraneoplastic syndrome: cancer-associated retinopathy]. AB - CASE REPORT: We review a patient with ocular manifestations of a paraneoplastic syndrome. It was a cancer-associated retinopathy (CAR) in a woman with visual loss, and attenuated and sheathed retinal arterioles. The electroretinography (ERG) showed severe abnormalities of the a and b-waves. The tumour process was not discovered until 6 months later, when a squamous neoplasia that invaded the uterus and vagina was observed. DISCUSSION: Paraneoplastic syndromes are a group of manifestations produced as a remote effect of cancer cells. CAR syndrome is caused by autoimmune reactions to retinal antigens induced by aberrant expression of recoverin in cancer tissues. Ophthalmologists must be aware of ocular paraneoplastic signs as they can be the first manifestations of a malignant tumour. PMID- 24060307 TI - [Sensimed Triggerfish((r)) as a new system for continuous recording of 24-hour intraocular pressure in glaucoma patients]. PMID- 24060308 TI - [Vodka eyeballing: Give me another drink ... in the eye, please!]. PMID- 24060309 TI - [Charles Bonnet and his theories]. PMID- 24060311 TI - [Eye pathology in the paintings by Jose de Ribera (I). The blind sculptor or Allegory of Touch]. PMID- 24060312 TI - Antibody-directed double suicide gene therapy targeting of MUC1- positive leukemia cells in vitro and in vivo. AB - Our aim was to specifically transfer the cytosine deaminase (CD) and thymidine kinase (TK) genes into mucin 1 (MUC1)-positive leukemia cells by anti-MUC1 antibody directed infection of replication-defective lentivirus and to evaluate the targeted cytotoxicity of double suicide genes to leukemia. The target gene vector (containing CD and TK) and envelope (containing GFP and anti-MUC1) and packaging plasmids were cotransfected into 293T cells to produce the recombinant lentivirus. Suicide genes in virus-infected leukemia cells (U937, Jurkat, and K562) were detected by western blot. The cytotoxicity and bystander effect in vitro and the therapeutic effect in vivo were detected after treatment with the prodrugs. The results revealed that combined treatment with prodrug 5 fluorocytosine (5-FC) and ganciclovir (GCV) inhibited leukemia cell growth and caused significant bystander effect than treatment with either prodrug alone. TK/GCV treatment alone induced degeneration and cell death while the effect of CD/5-FC alone mainly caused vacuolar degeneration and necrosis. The addictive effects of combinatorial use of GCV and 5-FC mainly induced swelling of the mitochondria followed by necrosis of the leukemia cells. In vivo experiments revealed that both single and combinatorial prodrug treatments could prolong the survival time of leukemic mice. In summary, anti-MUC1 antibody directed lentiviral vector successfully transduced dual suicide genes and exerted targeted cytotoxicity against MUC1 positive leukemia cells. This targeted lentiviral dual suicide gene delivering system provides a promising approach for clinical treatment of leukemia in future. PMID- 24060313 TI - Advances in recombinant adeno-associated viral vectors for gene delivery. AB - Recombinant adeno-associated viral vectors (rAAV) have now been used in several clinical trials to treat a variety of diseases, and are currently the preferred choice of many investigators in the field, due to both their low pathogenicity and immunogenicity compared with other viral vectors, as well as localized long term gene expression, despite their limitations of DNA size packaging and speed of expression. Recently, a number of advances have led to new generations of rAAV vectors, with improved features. This review addresses the various strategies employed to such effect, namely exploring distinct serotype tropisms, the production of mosaic and chimeric capsids, the selection of vectors through directed evolution, the development of self-complementary vectors, the use of pharmacological adjuvants and the induction of specific capsid mutations. Such approaches are expected to help the establishment of rAAV-based clinical gene therapy in the near future. PMID- 24060314 TI - Manganese superoxide dismutase gene therapy protects against irradiation- induced intestinal injury. AB - Radiation-induced intestinal injury is a common complication in radiotherapy for solid organ malignancies in abdomen or pelvis. However, currently there are no approved medical countermeasures for radiation-induced intestinal injury. Therefore, it is urgent to develop new treatments for radiation-induced intestinal injury. In the present study, we demonstrated that bone marrow derived mesenchymal stem cells (MSCs) and overexpression of human manganese superoxide dismutase (MnSOD) could ameliorate radiation-induced intestinal syndrome. NOD/SCID mice received abdominal irradiation at a selected dose of 5 Gy, and then infused intravenously with MnSOD-MSCs. Mice body weight, survival and diarrhea were monitored for 30-days. Colonization and differentiation of MnSOD-MSCs in the irradiated intestine were analyzed by histological and immunohistochemical methods. Consequently, our data demonstrated that intravenous administration of MnSOD-MSCs improved survival, decreased diarrhea occurrence and protected the small intestinal structural integrity of irradiated mice. Moreover, intravenously transplanted MnSOD-MSCs could colonize the irradiated intestine and repair injured sites. These findings suggested that MnSOD-MSCs may be an attractive and potential option for radiation-induced intestinal injury. PMID- 24060315 TI - Concentrations of preptin, salusins and hepcidins in plasma and milk of lactating women with or without gestational diabetes mellitus. AB - This study was undertaken to ascertain whether human milk contains preptin, salusin-alpha (salusin-alpha) and -beta (salusin-beta) and pro-hepcidin and hepcidin-25, and whether there are relationships between plasma and milk preptin, salusin-alpha and -beta and pro-hepcidin and hepcidin-25 concentrations in lactating mothers with and without gestational diabetes mellitus (GDM). Blood was obtained from non-lactating women (n = 12), non-diabetic lactating women (n = 12), and GDM lactating women (n = 12). Colostrum, transitional milk, and mature milk samples were collected just before suckling from healthy and GDM lactating women. Peptides concentrations were determined by ELISA and EIA. Mammary gland tissues were screened immunohistochemically for these peptides. Women with GDM had significantly higher plasma and colostum preptin concentrations than healthy lactating women during the colostral and transitional milk period. Salusin-alpha and -beta levels in milk and plasma were lower in women with GDM. Salusin-alpha and -beta were significantly lower in both plasma and colostrums of GDM than of healthy lactating women. Women with GDM had significantly higher colostum prohepcidin and hepcidin-25 concentrations than healthy lactating women during the colostral period. Plasma prohepcidin was also higher in women with GDM than in healthy lactating women during the colostral period, but plasma prohepcidin and hepcidin-25 levels decreased during mature milk period. Transitional milk pro hepcidin and hepcidin-25 levels in women with GDM were higher than in healthy lactating women. All these results revealed that the mammary gland produces those peptides, which were present in milk at levels correlating with plasma concentrations. PMID- 24060316 TI - A key region in the human parietal cortex for processing proprioceptive hand feedback during reaching movements. AB - Seemingly effortless, we adjust our movements to continuously changing environments. After initiation of a goal-directed movement, the motor command is under constant control of sensory feedback loops. The main sensory signals contributing to movement control are vision and proprioception. Recent neuroimaging studies have focused mainly on identifying the parts of the posterior parietal cortex (PPC) that contribute to visually guided movements. We used event-related TMS and force perturbations of the reaching hand to test whether the same sub-regions of the left PPC contribute to the processing of proprioceptive-only and of multi-sensory information about hand position when reaching for a visual target. TMS over two distinct stimulation sites elicited differential effects: TMS applied over the posterior part of the medial intraparietal sulcus (mIPS) compromised reaching accuracy when proprioception was the only sensory information available for correcting the reaching error. When visual feedback of the hand was available, TMS over the anterior intraparietal sulcus (aIPS) prolonged reaching time. Our results show for the first time the causal involvement of the posterior mIPS in processing proprioceptive feedback for online reaching control, and demonstrate that distinct cortical areas process proprioceptive-only and multi-sensory information for fast feedback corrections. PMID- 24060317 TI - Fiber-driven resolution enhancement of diffusion-weighted images. AB - Diffusion-weighted imaging (DWI), while giving rich information about brain circuitry, is often limited by insufficient spatial resolution and low signal-to noise ratio (SNR). This paper describes an algorithm that will increase the resolution of DW images beyond the scan resolution, allowing for a closer investigation of fiber structures and more accurate assessment of brain connectivity. The algorithm is capable of generating a dense vector-valued field, consisting of diffusion data associated with the full set of diffusion sensitizing gradients. The fundamental premise is that, to best preserve information, interpolation should always be performed along axonal fibers. To achieve this, at each spatial location, we probe neighboring voxels in various directions to gather diffusion information for data interpolation. Based on the fiber orientation distribution function (ODF), directions that are more likely to be traversed by fibers will be given greater weights during interpolation and vice versa. This ensures that data interpolation is only contributed by diffusion data coming from fibers that are aligned with a specific direction. This approach respects local fiber structures and prevents blurring resulting from averaging of data from significantly misaligned fibers. Evaluations suggest that this algorithm yields results with significantly less blocking artifacts, greater smoothness in anatomical structures, and markedly improved structural visibility. PMID- 24060320 TI - Clinical features of patients inappropriately undiagnosed of pulmonary embolism. AB - PURPOSES: The objective of this study was to identify clinical factors associated with delayed diagnosis of acute pulmonary embolism (PE) in the emergency department (ED). BASIC PROCEDURES: A retrospective observational study was performed at three University affiliated Hospitals; 436 consecutive patients who presented to the ED with an acute PE confirmed by chest computed tomography from 2008 to 2011 were included. Patients were divided into 3 groups: group 1, PE was diagnosed while the patient was still in the ED; group 2, PE was diagnosed during hospitalization; group 3, patients who were sent home with a wrong alternative diagnosis and returned to the ED and were diagnosed of PE. MAIN FINDINGS: One hundred forty-six patients (33.5%) had a delayed diagnosis of PE--21.5% belong to group 2 and 11.9% to Group 3. Chronic coexisting medical conditions like asthma or chronic obstructive pulmonary disease were independent predictors of a delayed diagnosis in patients who were admitted to hospital whereas non-specific and less severe symptoms like the presence of pleuro-mechanic thoracic pain, fever, hemoptysis, or the presence of a pulmonary infiltrate in chest x-ray were independent predictors of a delayed diagnosis in patients who were sent home. PRINCIPAL CONCLUSIONS: Delay in diagnosis of acute PE is frequent despite current diagnostic strategies. Patients are sent home or admitted to hospital with a wrong diagnosis depending on clinical presentation or coexisting medical conditions. PMID- 24060319 TI - Visualization of mouse barrel cortex using ex-vivo track density imaging. AB - We describe the visualization of the barrel cortex of the primary somatosensory area (S1) of ex vivo adult mouse brain with short-tracks track density imaging (stTDI). stTDI produced much higher definition of barrel structures than conventional fractional anisotropy (FA), directionally-encoded color FA maps, spin-echo T1- and T2-weighted imaging and gradient echo T1/T2*-weighted imaging. 3D high angular resolution diffusion imaging (HARDI) data were acquired at 48 micron isotropic resolution for a (3mm)(3) block of cortex containing the barrel field and reconstructed using stTDI at 10 micron isotropic resolution. HARDI data were also acquired at 100 micron isotropic resolution to image the whole brain and reconstructed using stTDI at 20 micron isotropic resolution. The 10 micron resolution stTDI maps showed exceptionally clear delineation of barrel structures. Individual barrels could also be distinguished in the 20 micron stTDI maps but the septa separating the individual barrels appeared thicker compared to the 10 micron maps, indicating that the ability of stTDI to produce high quality structural delineation is dependent upon acquisition resolution. Close homology was observed between the barrel structure delineated using stTDI and reconstructed histological data from the same samples. stTDI also detects barrel deletions in the posterior medial barrel sub-field in mice with infraorbital nerve cuts. The results demonstrate that stTDI is a novel imaging technique that enables three-dimensional characterization of complex structures such as the barrels in S1 and provides an important complementary non-invasive imaging tool for studying synaptic connectivity, development and plasticity of the sensory system. PMID- 24060321 TI - Bezold abscess: a rare complication of mastoiditis. AB - Bezold abscess is a rare complication of mastoiditis in which patients are often well appearing but require urgent intervention to prevent serious sequelae. We describe the case of a Bezold abscess in a 12-year-old girl. PMID- 24060318 TI - Characterization of a normal control group: are they healthy? AB - We examined the health of a control group (18-81years) in our aging study, which is similar to control groups used in other neuroimaging studies. The current study was motivated by our previous results showing that one third of the elder control group had moderate to severe white matter hyperintensities and/or cortical volume loss which correlated with poor performance on memory tasks. Therefore, we predicted that cardiovascular risk factors (e.g., hypertension, high cholesterol) within the control group would account for significant variance on working memory task performance. Fifty-five participants completed 4 verbal and spatial working memory tasks, neuropsychological exams, diffusion tensor imaging (DTI), and blood tests to assess vascular risk. In addition to using a repeated measures ANOVA design, a cluster analysis was applied to the vascular risk measures as a data reduction step to characterize relationships between conjoint risk factors. The cluster groupings were used to predict working memory performance. The results show that higher levels of systolic blood pressure were associated with: 1) poor spatial working memory accuracy; and 2) lower fractional anisotropy (FA) values in multiple brain regions. In contrast, higher levels of total cholesterol corresponded with increased accuracy in verbal working memory. An association between lower FA values and higher cholesterol levels were identified in different brain regions from those associated with systolic blood pressure. The conjoint risk analysis revealed that Risk Cluster Group 3 (the group with the greatest number of risk factors) displayed: 1) the poorest performance on the spatial working memory tasks; 2) the longest reaction times across both spatial and verbal memory tasks; and 3) the lowest FA values across widespread brain regions. Our results confirm that a considerable range of vascular risk factors are present in a typical control group, even in younger individuals, which have robust effects on brain anatomy and function. These results present a new challenge to neuroimaging studies both for defining a cohort from which to characterize 'normative' brain circuitry and for establishing a control group to compare with other clinical populations. PMID- 24060322 TI - Vertebral artery dissection mimicking status migrainosus. AB - Vertebral artery dissection (VAD) may uncommonly present as isolated headache. More rarely, it simulates classical headache syndromes, including migraine. We report a VAD mimicking status migrainosus. PMID- 24060323 TI - Pulmonary laceration secondary to a traumatic soccer injury: a case report and review of the literature. AB - Pulmonary lacerations are an uncommon injury typically associated with high impact trauma. Most cases occur as a result of high-speed road traffic collisions. Although chest wall and pleural injuries are commonly associated with sports-related thoracic trauma, pulmonary injuries are far less common. There are only a few reported cases of significant pulmonary trauma associated with sports injuries, the majority of which have described pulmonary contusions occurring as a result of thoracic injury sustained while playing high-impact contact sports such as American football. Pulmonary laceration occurring as result of soccer related thoracic trauma has never previously been reported. PMID- 24060324 TI - Community implementation of intravenous thrombolysis for acute ischemic stroke in the 3- to 4.5-hour window. AB - BACKGROUND: Intravenous (IV) tissue plasminogen activator (tPA) administration for ischemic stroke between 3 and 4.5 hours after onset was found to be safe and beneficial in the ECASS III trial. However, its use has remained controversial, and its benefit as applied in routine practice at community stroke centers is less well defined. METHODS: This retrospective database study compared safety and clinical outcomes in 500 patients given IV tPA either from 0 to 3 or 3 to 4.5 hours after onset at a high-volume community center from January 2008 to October 2012. Additional independent variables included for univariate and multivariate analysis were age, sex, hypertension, diabetes mellitus, National Institutes of Health stroke scale on arrival. RESULTS: There were no significant differences seen in rates of symptomatic intracranial hemorrhage (3.8% vs 5.8%, P > .05), in hospital mortality, or Barthel index at 3 months between groups. In addition, tPA administration despite ECASS III contraindications did not appear to be an independent predictor of hemorrhage in the first 24 hours. DISCUSSION: Our results show that the conclusions of the ECASS III trial can be applied to routine stroke treatment at a community center and that IV thrombolysis in the 3- to 4.5-hour window results in similar safety and efficacy functional outcome at 3 months compared with administration before 3 hours after onset. PMID- 24060325 TI - Hemodynamic rescue and ECG stability during chest compressions using adenosine and lidocaine after 8-minute asphyxial hypoxia in the rat. AB - INTRODUCTION: Sudden cardiac death generally arises from either ventricular fibrillation or asphyxial hypoxia. In an effort to translate the cardioprotective effects of adenosine and lidocaine (AL) from hemorrhagic shock to cardiopulmonary resuscitation, we examined the effect of AL on hemodynamics and electrocardiogram (ECG) stability in the rat model of asphyxial hypoxia. METHODS: Male Sprague Dawley rats were randomly assigned to 1 of 4 groups (n = 8): saline (SAL), adenosine (ADO), lidocaine (LIDO), and AL. Cardiac arrest (mean arterial pressure <10 mm Hg) was induced by clamping the ventilator line for 8 minutes. A 0.5-mL intravenous drug bolus was injected followed by chest compressions (300 min(-1)), which were repeated every 5 minutes for 1 hour. RESULTS: Return of spontaneous circulation was achieved in 5 SAL (62.6%), 4 ADO (50%), 7 LIDO (87.5%), and 8 AL rats (100%) within 5 minutes but could not be sustained. During chest compressions, mean arterial pressure was consistently higher in the AL-treated rats compared with all groups (P < .05; 35-45 and 55 minutes) followed by the LIDO group and was lowest in the ADO and SAL groups (P < .05). Systolic pressure followed a similar pattern. In addition, diastolic pressure in the AL-treated rats was significantly higher from 25 to 60 minutes than LIDO and ADO alone or SAL, and heart rate was 30% to 40% lower. Improved ECG rhythm and R-R variability were apparent in AL-treated rats during early compressions and hands-off intervals. CONCLUSIONS: We conclude that a small bolus of 0.9% NaCl AL improved hemodynamics with possible diastolic rescue and ECG stabilization during chest compressions compared with ADO, LIDO, or SAL controls. PMID- 24060326 TI - Aortic intramural hematoma and hepatic artery pseudoaneurysm: unusual complication following resuscitation. AB - We present a case of a 71-year-old woman with an unusual complication of aortic intramural hematoma and hepatic artery pseudoaneurysm following cardiopulmonary resuscitation and thrombolysis done for sudden cardiopulmonary arrest and pulmonary embolism. Patient was on Warfarin treatment for a prior history of pulmonary embolism and experienced recurrent cardiac arrests, which finally resolved after intravenous administration of thrombolytic agents. However, follow up computed tomographic angiography revealed descending aortic intramural hematoma with intramural blood pool and concomitant liver laceration with hepatic artery pseudoaneurysm. The patient received transcatheter embolization for the hepatic injury with careful follow-up for the aortic injury and was later discharged in a stable condition. Follow-up with subsequent computed tomographic angiography at a regular interval over 1 month shows near complete resolution of the intramural hematoma. The purpose of this report is to describe the rare complication of cardiopulmonary resuscitation and thrombolysis in the form of concomitant injuries of the aorta and liver. Although the use of thrombolytic agents in patients with pulmonary embolism and cardiac arrest is still a matter of debate, this case report supports the concept that thrombolysis has a role in restoring cardiopulmonary circulation, especially in recurrent cardiac arrests resulting from pulmonary embolism. On the other hand, this case also highlights the increased association of the bleeding-related complication as a result of vigorous efforts of cardiopulmonary resuscitation. Aggressive management with interventional radiology for hepatic pseudoaneurysm and conservative management of the aortic intramural hematoma resulted in favorable outcome for our patient. PMID- 24060328 TI - Eosinophilic meningitis: what's the "diff"? AB - We report a case of a 22-year-old man who presented to the emergency department (ED) with altered mental status and was diagnosed with eosinophilic meningitis due to Angiostrongylus cantonensis (AC) acquired in the United States after exposure to snails. PMID- 24060327 TI - Enhanced external counterpulsation improves cerebral blood flow following cardiopulmonary resuscitation. AB - BACKGROUND: To investigate the therapeutic value of enhanced external counterpulsation (EECP) on recovery of cerebral blood flow following cardiac arrest (CA) and successful resumption of spontaneous circulation (ROSC) by cardiopulmonary resuscitation. METHODS: CA models were conducted using beagle dogs induced by alternating current. After successful ROSC by cardiopulmonary resuscitation, 16 dogs were randomly divided into the EECP and control group (n = 8 per group). Dogs underwent dynamic contrast-enhanced and diffusion-weighted magnetic resonance imaging at baseline prior to CA and during the 3 days following ROSC. Mean blood pressure, right common carotid artery blood flow, intracranial microcirculation and blood lactate levels were measured. Neurological outcome was assessed by the neurologic deficit score. Hematoxylin eosin staining and transmission electron microscopy were performed for morphology and microconstruction of the cerebral cortex. RESULTS: The EECP group exhibited a significant elevation in right common carotid artery blood flow, intracranial microcirculation and a substantial decrease in blood lactate levels relative to the control group. Relative cerebral blood flow and volume were higher in the EECP group during the 3 days. Apparent diffusion coefficients were significantly higher in the EECP group on the first and third days. After ROSC, the neurologic deficit score was significantly higher in the control group compared to those in the EECP group during the three days of experiment. The cell swelling of neurons and increase of mitochondrial mass were more pronounced in the control group. CONCLUSION: EECP is beneficial for recovery of cerebral blood flow and attenuation of ischemic cerebral edema following CA and successful ROSC. PMID- 24060329 TI - Comparing diagnostic accuracy of bedside ultrasound and radiography for bone fracture screening in multiple trauma patients at the ED. AB - INTRODUCTION: Long bone fractures are currently diagnosed using radiography, but radiography has some disadvantages (radiation and being time consuming). The present study compared the diagnostic accuracy of bedside ultrasound and radiography in multiple trauma patients at the emergency department (ED). METHOD: The study assessed 80 injured patients with multiple trauma from February 2011 to July 2012. The patients were older than 18 years and triaged to the cardiopulmonary resuscitation ward of the ED. Bedside ultrasound and radiography were conducted for them. The findings were separately and blindly assessed by 2 radiologists. Sensitivity, specificity, the positive and negative predictive value, and kappa coefficient were measured to assess the accuracy and validity of ultrasound as compared with radiography. RESULTS: The sensitivity of ultrasound for diagnosis of limb bone fractures was not high enough and ranged between 55% and 75% depending on the fracture site. The specificity of this diagnostic method had an acceptable range of 62% to 84%. Ultrasound negative prediction value was higher than other indices under study and ranged between 73% and 83%, but its positive prediction value varied between 33.3% and 71%. The kappa coefficient for diagnosis of long bone fractures of upper limb (kappa = 0.58) and upper limb joints (kappa = 0.47) and long bones of lower limb (kappa = 0.52) was within the medium range. However, the value for diagnosing fractures of lower limb joints (kappa = 0.47) was relatively low. CONCLUSION: Bedside ultrasound is not a reliable method for diagnosing fractures of upper and lower limb bones compared with radiography. PMID- 24060330 TI - Spontaneous septic arthritis in a patient without trauma, coinfection, or immunosuppression. AB - Septic arthritis is a rare infection, most often affecting the knee and hip [1]. Infections are often secondary to joint repair or replacement surgery, systemic infection, or intravenous recreational drug use [1,2].Diabetes, rheumatoid arthritis, hepatic dysfunction, and immunosuppression are common risk factors [1,2]. Although septic arthritis can occur spontaneously, such occurrences are rare. We report a case of a previously healthy 54-year-old woman with no known risk factors presenting to a freestanding emergency department with 5 days of shoulder pain. PMID- 24060331 TI - 4000 clicks: a productivity analysis of electronic medical records in a community hospital ED. AB - OBJECTIVE: We evaluate physician productivity using electronic medical records in a community hospital emergency department. METHODS: Physician time usage per hour was observed and tabulated in the categories of direct patient contact, data and order entry, interaction with colleagues, and review of test results and old records. RESULTS: The mean percentage of time spent on data entry was 43% (95% confidence interval, 39%-47%). The mean percentage of time spent in direct contact with patients was 28%. The pooled weighted average time allocations were 44% on data entry, 28% in direct patient care, 12% reviewing test results and records, 13% in discussion with colleagues, and 3% on other activities. Tabulation was made of the number of mouse clicks necessary for several common emergency department charting functions and for selected patient encounters. Total mouse clicks approach 4000 during a busy 10-hour shift. CONCLUSION: Emergency department physicians spend significantly more time entering data into electronic medical records than on any other activity, including direct patient care. Improved efficiency in data entry would allow emergency physicians to devote more time to patient care, thus increasing hospital revenue. PMID- 24060332 TI - Middle latency auditory-evoked potential index for predicting the degree of consciousness of comatose patients in EDs. AB - INTRODUCTION: Digitized assessment of the degree of consciousness is a universal challenge in emergency departments (EDs) and intensive care units (ICUs). The middle latency auditory-evoked potential index (MLAEPi) monitor aepEX plus (Audiomex, Glasgow, Scotland, UK) is the first mobile middle latency auditory evoked potential monitor. We speculated that the initial MLAEPi determined on arrival at EDs could indicate cerebral function and predict the degree of consciousness of comatose patients. METHODS: We used MLAEPi-related data from 50 comatose patients with disturbance of consciousness (DOC), 50 patients with cardiopulmonary arrest (CPA), and 50 healthy volunteers (control). Comatose patients were defined as those with an initial Glasgow Coma Scale score of 8 or less. The CPA group consisted of patients who arrived at EDs without restoration of spontaneous circulation. Among the patients with DOC who underwent sedation at EDs, the change in the MLAEPi was evaluated between arrival at the ED and ICU admission. RESULTS: The initial MLAEPi was significantly lower in the DOC group than in the control group but significantly higher in the DOC group than in the CPA group. Among the comatose patients, the receiver operating characteristic curve for the initial MLAEPi showed an area under the curve of 0.93 (P < .01) for the DOC group. Thirty patients with DOC underwent sedation at EDs, and the initial MLAEPi was significantly higher than those at other periods during emergency care. CONCLUSION: The MLAEPi (simple numerical value) may be used to evaluate the degree of consciousness in comatose patients while performing emergency care in EDs. PMID- 24060333 TI - Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers. AB - INTRODUCTION: We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy. METHODS: Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX(r) were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years. RESULTS: In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results. CONCLUSIONS: Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy. PMID- 24060335 TI - Is Europe still heading to a common price level for on-patent medicines? An exploratory study among 15 Western European countries. AB - BACKGROUND: Previous studies have suggested that medicines prices in Europe converge over time as a result of policy measures such as external price referencing. OBJECTIVE: To explore whether ex-factory prices of on-patented medicines in Western European countries have converged over a recent period of time. METHODS: Prices of ten on-patent medicines in five years (2007, 2008, 2010, 2011, 2012) of 15 European countries were analyzed. The unit of analysis was the ex-factory price in Euro per defined daily dose (exchange rate indexed to 2007). A score (deviation from the average price) per country as well as the ranges were calculated for all medicines. RESULTS: The prices between countries and selected products varied to a great extent from as low as an average price of ? 1.3/DDD for sitagliptin in 2010-2012 to an average of ? 221.5/DDD for alemtuzumab in 2011. Between 2008 and 2012, a price divergence was seen which was fully driven by two countries, Germany (up to 27% more expensive than the average) and Greece (up to 32% cheaper than the average). All other countries had stable prices and centered around the country average. Prices of less expensive as well as expensive medicines remained relatively stable or decreased over time, while only the price of sirolimus relatively increased. CONCLUSIONS: Our study period included the time of the recession and several pricing policy measures may have affected the prices of medicines. Instead of the expected price convergence we observed a price divergence driven by price changes in only two of the 15 countries. All other European countries remained stable around the country average. Further research is needed to expand the study to a bigger sample size, and include prescribing data and Eastern European countries. PMID- 24060334 TI - Quality assessment of protein NMR structures. AB - Biomolecular NMR structures are now routinely used in biology, chemistry, and bioinformatics. Methods and metrics for assessing the accuracy and precision of protein NMR structures are beginning to be standardized across the biological NMR community. These include both knowledge-based assessment metrics, parameterized from the database of protein structures, and model versus data assessment metrics. On line servers are available that provide comprehensive protein structure quality assessment reports, and efforts are in progress by the world wide Protein Data Bank (wwPDB) to develop a biomolecular NMR structure quality assessment pipeline as part of the structure deposition process. These quality assessment metrics and standards will aid NMR spectroscopists in determining more accurate structures, and increase the value and utility of these structures for the broad scientific community. PMID- 24060336 TI - Factors that led to the implementation of the efficiency frontier approach to health economic evaluation in Germany: let's talk more about the elephant. PMID- 24060338 TI - Wide-gap semiconducting graphene from nitrogen-seeded SiC. AB - All carbon electronics based on graphene have been an elusive goal. For more than a decade, the inability to produce significant band-gaps in this material has prevented the development of graphene electronics. We demonstrate a new approach to produce semiconducting graphene that uses a submonolayer concentration of nitrogen on SiC sufficient to pin epitaxial graphene to the SiC interface as it grows. The resulting buckled graphene opens a band gap greater than 0.7 eV in the otherwise continuous metallic graphene sheet. PMID- 24060337 TI - Study protocol--Indigenous Australian social networks and the impact on smoking policy and programs in Australia: protocol for a mixed-method prospective study. AB - BACKGROUND: Tobacco use is the most preventable cause of morbidity and mortality in Australia. Comprehensive tobacco control has reduced smoking rates in Australia from approximately 34 per cent in 1980 to 15 per cent in 2010. However, 46 per cent of Aboriginal and Torres Strait Islander people (Indigenous Australians) smoke on a daily basis, more than double the rate of non-Indigenous Australians. The evidence of effective tobacco control strategies for Indigenous Australians is relatively scarce. The aim of this study is to (i) explore the influences of smoking in Indigenous Australian people and to (ii) help inform and evaluate a multi-component tobacco control strategy. The study aims to answer the following questions:--do individuals' social networks influence smoking behaviours;--is there an association between various social and cultural factors and being a smoker or non-smoker; and--does a multi-component tobacco control program impact positively on tobacco behaviours, attitudes and beliefs in Indigenous Australians. METHODS AND DESIGN: Our prospective study will use a mixed-method approach (qualitative and quantitative), including a pre- and post test evaluation of a tobacco control initiative. The study will explore the social and cultural context underlying Indigenous Australian tobacco use and associated factors which influence smoking behaviour. Primary data will be collected via a panel survey, interviews and focus groups. Secondary data will include de-identified PBS items related to smoking and also data collected from the Quitlines call service. Network analysis will be used to assess whether social networks influence smoking behaviours. For the survey, baseline differences will be tested using chi(2) statistics for the categorical and dichotomous variables and t-tests for the continuous variables, where appropriate. Grounded theory will be used to analyse the interviews and focus groups. Local Aboriginal community controlled organisations will partner in the study. DISCUSSION: Our study will explore the key factors, including the influence of social networks, that impact on tobacco use and the extent to which smoking behaviours transcend networks within the Indigenous Australian community in the ACT. This will add to the evidence-base, identifying influential factors to tobacco use and the effectiveness and influence of a multi-component tobacco control strategy. PMID- 24060339 TI - Knockdown of the C. elegans kinome identifies kinases required for normal protein homeostasis, mitochondrial network structure, and sarcomere structure in muscle. AB - BACKGROUND: Kinases are important signalling molecules for modulating cellular processes and major targets of drug discovery programs. However, functional information for roughly half the human kinome is lacking. We conducted three kinome wide, >90%, RNAi screens and epistasis testing of some identified kinases against known intramuscular signalling systems to increase the functional annotation of the C. elegans kinome and expand our understanding of kinome influence upon muscle protein degradation. RESULTS: 96 kinases were identified as required for normal protein homeostasis, 74 for normal mitochondrial networks and 50 for normal sarcomere structure. Knockdown of kinases required only for normal protein homeostasis and/or mitochondrial structure was significantly less likely to produce a developmental or behavioural phenotype than knockdown of kinases required for normal sarcomere structure and/or other sub-cellular processes. Lastly, assessment of kinases for which knockdown produced muscle protein degradation against the known regulatory pathways in C. elegans muscle revealed that close to half of kinase knockdowns activated autophagy in a MAPK dependent fashion. CONCLUSIONS: Roughly 40% of kinases studied, 159 of 397, are important in establishing or maintaining muscle cell health, with most required for both. For kinases where decreased expression triggers protein degradation, autophagy is most commonly activated. These results increase the annotation of the C. elegans kinome to roughly 75% and enable future kinome research. As 33% of kinases identified have orthologues expressed in human muscle, our results also enable testing of whether identified kinases function similarly in maintaining human muscle homeostasis. PMID- 24060340 TI - Formaldehyde exposure impairs the function and differentiation of NK cells. AB - We investigated the cytotoxic effects of formaldehyde (FA) on lymphocytes. FA exposed mice showed a profound reduction not only in the number of natural killer (NK) cells but also in the expression of NK cell-specific receptors, but these mice did not exhibit decreases in the numbers of T or B lymphocytes. FA exposure also induced decreases in NK cytolytic activity and in the expression of NK cell associated genes, such as IFN-gamma, perforin and CD122. To determine the effect of FA on tumorigenicity, C57BL/6 mice were subcutaneously injected with B16F10 melanoma cells after FA exposure. The mass of the B16F10 tumor and the concentration of extravascular polymorphonuclear leukocytes were greater than those in unexposed tumor-bearing control mice. The number and cytolytic activity of NK cells were also reduced in B16F10 tumor-bearing mice exposed to FA. To determine how FA reduces the NK cell number, NK precursor (pNK) cells were treated with FA, and the differentiation status of the NK cells was analyzed. NK cell differentiation was impaired by FA treatment in a concentration-dependent manner. These findings indicate that FA exposure may promote tumor progression by impairing NK cell function and differentiation. PMID- 24060341 TI - A binuclear complex constituted by diethyldithiocarbamate and copper(I) functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts. AB - It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF-Cu complex. DSF-Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC-Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticancer potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC-Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitinated proteins, and increased p27 as well as decreased NF-kappaB expression were detected in tumor tissues of DDTC-Cu(I)-treated group. Our data indicates that DDTC-Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer. PMID- 24060342 TI - Sudden hearing loss with simultaneous posterior semicircular canal BPPV: possible etiology and clinical implications. AB - OBJECTIVES: The objectives of this study were to describe the clinical course and outcome of patients with sudden sensorineural hearing loss (SSNHL) in conjunction with benign paroxysmal positional vertigo (BPPV), and hypothesize the possible pathophysiology of this entity. STUDY DESIGN: Retrospective study of all patients with evidence of SSNHL with any type of BPPV between 2008 and 2012. SETTINGS: Tertiary care university hospital. SUBJECTS AND METHODS: Five patients aged 56 to 71 were diagnosed with unilateral profound SSNHL and BPPV. Neurotologic examination revealed an ipsilateral torsional, up-beating nystagmus on Dix Hallpike exam. Severe or profound ipsilateral-sensorineural hearing loss was recognized on audiometry. The rest of the exam was normal; this was in keeping with the diagnosis of SSNHL with ipsilateral posterior semicircular canal BPPV. RESULTS: All patients were treated with a modified Epley maneuver; oral steroids were administered for two weeks. In all cases vertigo resolved and the Dix Hallpike exam became normal within several weeks. However, the hearing loss remained unchanged in two patients. Magnetic resonance imaging of the head was normal and ENG caloric test demonstrated mild ipsilateral canal paresis in two patients. CONCLUSIONS: 1. Patients with SSNHL and BPPV can have a variable clinical course and outcome. This entity may be quite common, but the diagnosis of BPPV can be missed if a complete neurological physical examination is not performed. 2. Arterial occlusions or selective multiple vascular or neural involvement may explain the pathophysiology of SSNHL with BPPV of the posterior semicircular canal. PMID- 24060343 TI - Voltage-gated sodium channels contribute to the b-wave of the rodent electroretinogram by mediating input to rod bipolar cell GABA(c) receptors. AB - Voltage-gated sodium (Nav) channels are known to augment cone bipolar cell light responses, increasing the electroretinogram (ERG) b-wave in response to stimulus strengths above the cone threshold. However previous in vivo studies on a number of animal models have not found a role for Nav channels in augmenting the b-wave in scotopic conditions below the cone threshold. We recorded ERGs from mice and rats using a series of TTX concentrations and tested retinal output to ensure complete Nav channel block. We found that TTX concentrations sufficient to completely suppress retinal output caused large (~40%) decrease in the scotopic electroretinogram (ERG) response to high stimulus strengths (1.0 log cd s/m(2)). In addition the b-wave was reduced by ~20% even at stimulus strengths that should predominately excite the rod pathway (-2.2 log cd s/m(2)). Modulating stimulus strength and background luminance showed that Nav channel contribution to the b wave is strongest in mesopic conditions with low strength stimuli. Blocking GABAc receptors indicted that Nav channels predominately contribute to the b-wave by supporting GABAc input to rod bipolar cells in addition to directly amplifying the light response of cone ON bipolar cells. We also determined that saturating levels of TTX reduced the rat b-wave below cone threshold. Nav channels increase the ERG b-wave in both rod and cone bipolar cell-dominated circuits. In circuits involving rod bipolar cells the effect is mediated indirectly via GABAergic inhibitory cells, while Nav channels directly located on cone bipolar cells amplify light responses in the cone pathways. PMID- 24060345 TI - The use of cultured human fetal retinal pigment epithelium in studies of the classical retinoid visual cycle and retinoid-based disease processes. AB - Human fetal retinal pigment epithelium (hfRPE), when harvested by mechanical dissection and cultured initially under low calcium conditions, will proliferate and tolerate cryopreservation for future use. Cryopreserved cells can be subsequently thawed and cultured in standard calcium and in the presence of appropriate nutrients to a high state of differentiation, allowing recapitulation of multiple in vivo functions. In this review we briefly discuss some of our previous studies of the classical retinoid visual cycle and introduce current studies in our laboratory that involve two new areas of investigation; the dynamic response of the receptor for retinol binding protein, STRA6 to the addition of holo-retinol binding protein to the culture medium and the protective complement-based response of hfRPE to the ingestion of toxic byproducts of the visual cycle. This response is studied in the context of genotyped hfRPE expressing either predisposing or protective variants of complement factor H. PMID- 24060346 TI - Role of nitric oxide in optic nerve head blood flow regulation during an experimental increase in intraocular pressure in healthy humans. AB - The present study set out to investigate whether nitric oxide, a potent vasodilator, is involved in the regulatory processes in optic nerve head blood flow during an experimental increase in intraocular pressure (IOP). The study was conducted in a randomized, double-masked, placebo-controlled, three way cross over design. 12 healthy subjects were scheduled to receive either L-NMMA (an unspecific nitric oxide synthase inhibitor), phenylephrine (an alpha-adrenoceptor agonist) or placebo on three different study days. Optic nerve head blood flow was measured using laser Doppler flowmetry and IOP was increased stepwise with a suction cup. Mean arterial pressure (MAP) and IOP were measured non-invasively and ocular perfusion pressure (OPP) was calculated as OPP = 2/3 MAP-IOP. Administration of L-NMMA and phenylephrine significantly increased MAP and therefore OPP at rest (p < 0.01). L-NMMA significantly reduced baseline blood flow in the optic nerve head (p < 0.01). Application of the suction cup induced a significant increase in IOP and a decrease in OPP (p < 0.01). During the stepwise increase in IOP, some autoregulatory potential was observed until OPP decreased approximately -30% below baseline. None of the administered substances had an effect on this autoregulatory behavior (p = 0.49). The results of the present study confirm that the human optic nerve head shows some regulatory capacity during a decrease in OPP. Nitric oxide is involved in the regulation of basal vascular tone in the optic nerve head but does not seem to be involved in the regulatory mechanisms during an acute increase in IOP in young healthy subjects. PMID- 24060344 TI - Retinal pigment epithelium development, plasticity, and tissue homeostasis. AB - The retinal pigment epithelium (RPE) is a simple epithelium interposed between the neural retina and the choroid. Although only 1 cell-layer in thickness, the RPE is a virtual workhorse, acting in several capacities that are essential for visual function and preserving the structural and physiological integrities of neighboring tissues. Defects in RPE function, whether through chronic dysfunction or age-related decline, are associated with retinal degenerative diseases including age-related macular degeneration. As such, investigations are focused on developing techniques to replace RPE through stem cell-based methods, motivated primarily because of the seemingly limited regeneration or self-repair properties of mature RPE. Despite this, RPE cells have an unusual capacity to transdifferentiate into various cell types, with the particular fate choices being highly context-dependent. In this review, we describe recent findings elucidating the mechanisms and steps of RPE development and propose a developmental framework for understanding the apparent contradiction in the capacity for low self-repair versus high transdifferentiation. PMID- 24060347 TI - Divergent evolution of ligand binding in the o-succinylbenzoate synthase family. AB - Thermobifida fusca o-succinylbenzoate synthase (OSBS), a member of the enolase superfamily that catalyzes a step in menaquinone biosynthesis, has an amino acid sequence that is 22 and 28% identical with those of two previously characterized OSBS enzymes from Escherichia coli and Amycolatopsis sp. T-1-60, respectively. These values are considerably lower than typical levels of sequence identity among homologous proteins that have the same function. To determine how such divergent enzymes catalyze the same reaction, we determined the structure of T. fusca OSBS and identified amino acids that are important for ligand binding. We discovered significant differences in structure and conformational flexibility between T. fusca OSBS and other members of the enolase superfamily. In particular, the 20s loop, a flexible loop in the active site that permits ligand binding and release in most enolase superfamily proteins, has a four-amino acid deletion and is well-ordered in T. fusca OSBS. Instead, the flexibility of a different region allows the substrate to enter from the other side of the active site. T. fusca OSBS was more tolerant of mutations at residues that were critical for activity in E. coli OSBS. Also, replacing active site amino acids found in one protein with the amino acids that occur at the same place in the other protein reduces the catalytic efficiency. Thus, the extraordinary divergence between these proteins does not appear to reflect a higher tolerance of mutations. Instead, large deletions outside the active site were accompanied by alteration of active site size and electrostatic interactions, resulting in small but significant differences in ligand binding. PMID- 24060348 TI - Weight management interventions in adults with intellectual disabilities and obesity: a systematic review of the evidence. AB - To evaluate the clinical effectiveness of weight management interventions in adults with intellectual disabilities (ID) and obesity using recommendations from current clinical guidelines for the first line management of obesity in adults. Full papers on lifestyle modification interventions published between 1982 to 2011 were sought by searching the Medline, Embase, PsycINFO and CINAHL databases. Studies were evaluated based on (1) intervention components, (2) methodology, (3) attrition rate (4) reported weight loss and (5) duration of follow up. Twenty two studies met the inclusion criteria. The interventions were classified according to inclusion of the following components: behaviour change alone, behaviour change plus physical activity, dietary advice or physical activity alone, dietary plus physical activity advice and multi-component (all three components). The majority of the studies had the same methodological limitations: no sample size justification, small heterogeneous samples, no information on randomisation methodologies. Eight studies were classified as multi-component interventions, of which one study used a 600 kilocalorie (2510 kilojoule) daily energy deficit diet. Study durations were mostly below the duration recommended in clinical guidelines and varied widely. No study included an exercise program promoting 225 300 minutes or more of moderate intensity physical activity per week but the majority of the studies used the same behaviour change techniques. Three studies reported clinically significant weight loss (>= 5%) at six months post intervention. Current data indicate weight management interventions in those with ID differ from recommended practice and further studies to examine the effectiveness of multi-component weight management interventions for adults with ID and obesity are justified. PMID- 24060349 TI - Time-dependent fracture probability of bilayer, lithium-disilicate-based, glass ceramic, molar crowns as a function of core/veneer thickness ratio and load orientation. AB - Recent reports on bilayer ceramic crown prostheses suggest that fractures of the veneering ceramic represent the most common reason for prosthesis failure. OBJECTIVE: The aims of this study were to test the hypotheses that: (1) an increase in core ceramic/veneer ceramic thickness ratio for a crown thickness of 1.6mm reduces the time-dependent fracture probability (Pf) of bilayer crowns with a lithium-disilicate-based glass-ceramic core, and (2) oblique loading, within the central fossa, increases Pf for 1.6-mm-thick crowns compared with vertical loading. MATERIALS AND METHODS: Time-dependent fracture probabilities were calculated for 1.6-mm-thick, veneered lithium-disilicate-based glass-ceramic molar crowns as a function of core/veneer thickness ratio and load orientation in the central fossa area. Time-dependent fracture probability analyses were computed by CARES/Life software and finite element analysis, using dynamic fatigue strength data for monolithic discs of a lithium-disilicate glass-ceramic core (Empress 2), and ceramic veneer (Empress 2 Veneer Ceramic). RESULTS: Predicted fracture probabilities (Pf) for centrally loaded 1.6-mm-thick bilayer crowns over periods of 1, 5, and 10 years are 1.2%, 2.7%, and 3.5%, respectively, for a core/veneer thickness ratio of 1.0 (0.8mm/0.8mm), and 2.5%, 5.1%, and 7.0%, respectively, for a core/veneer thickness ratio of 0.33 (0.4mm/1.2mm). CONCLUSION: CARES/Life results support the proposed crown design and load orientation hypotheses. SIGNIFICANCE: The application of dynamic fatigue data, finite element stress analysis, and CARES/Life analysis represent an optimal approach to optimize fixed dental prosthesis designs produced from dental ceramics and to predict time-dependent fracture probabilities of ceramic-based fixed dental prostheses that can minimize the risk for clinical failures. PMID- 24060350 TI - Web-based behavioral treatment for substance use disorders as a partial replacement of standard methadone maintenance treatment. AB - This study is the first experimental trial to evaluate the effectiveness of a Web based behavioral intervention when deployed in a model where it partially substituted for standard counseling in a community-based specialty addiction treatment program. New opioid-dependent intakes in methadone maintenance treatment (n=160) were randomly assigned for 12months to either: (1) standard treatment or (2) reduced standard treatment plus a Web-based psychosocial intervention, the Therapeutic Education System (TES). Results demonstrated that replacing a portion of standard treatment with TES resulted in significantly greater rates of objectively measured opioid abstinence (48% vs. 37% abstinence across all study weeks; F(1, 158)=5.90, p<.05 and 59% vs. 43% abstinence on weeks participants provided urine samples for testing; F(1, 158)=8.81, p<.01). This result was robust and was evident despite how opioid abstinence was operationally defined and evaluated. The potential implications for service delivery models within substance abuse treatment programs and other healthcare entities are discussed. PMID- 24060352 TI - Preparation of flexible organic solar cells with highly conductive and transparent metal-oxide multilayer electrodes based on silver oxide. AB - We report that significantly more transparent yet comparably conductive AgOx films, when compared to Ag films, are synthesized by the inclusion of a remarkably small amount of oxygen (i.e., 2 or 3 atom %) in thin Ag films. An 8 nm thick AgOx (O/Ag=2.4 atom %) film embedded between 30 nm thick ITO films (ITO/AgOx/ITO) achieves a transmittance improvement of 30% when compared to a conventional ITO/Ag/ITO electrode with the same configuration by retaining the sheet resistance in the range of 10-20 Omega sq(-1). The high transmittance provides an excellent opportunity to improve the power-conversion efficiency of organic solar cells (OSCs) by successfully matching the transmittance spectral range of the electrode to the optimal absorption region of low band gap photoactive polymers, which is highly limited in OSCs utilizing conventional ITO/Ag/ITO electrodes. An improvement of the power-conversion efficiency from 4.72 to 5.88% is achieved from highly flexible organic solar cells (OSCs) fabricated on poly(ethylene terephthalate) polymer substrates by replacing the conventional ITO/Ag/ITO electrode with the ITO/AgOx/ITO electrode. This novel transparent electrode can facilitate a cost-effective, high-throughput, room temperature fabrication solution for producing large-area flexible OSCs on heat sensitive polymer substrates with excellent power-conversion efficiencies. PMID- 24060351 TI - Identification of a Klf4-dependent upstream repressor region mediating transcriptional regulation of the myocardin gene in human smooth muscle cells. AB - Phenotypic switching of smooth muscle cells (SMCs) plays a central role in the development of vascular diseases such as atherosclerosis and restenosis. However, the factors regulating expression of the human myocardin (Myocd) gene, the master gene regulator of SMC differentiation, have yet to be identified. In this study, we sought to identify the critical factors regulating Myocd expression in human SMCs. Using deletion/genetic reporter analyses, an upstream repressor region (URR) was localised within the Myocd promoter, herein termed PrmM. Bioinformatic analysis revealed three evolutionary conserved Klf4 sites within the URR and disruption of those elements led to substantial increases in PrmM-directed gene expression. Furthermore, ectopic expression established that Klf4 significantly decreased Myocd mRNA levels and PrmM-directed gene expression while electrophoretic mobility shift assays and chromatin immunoprecipitation (ChIP) assays confirmed specific binding of endogenous Klf4, and not Klf5 or Klf2, to the URR of PrmM. Platelet-derived growth factor BB (PDGF-BB), a potent inhibitor of SMC differentiation, reduced Myocd mRNA levels and PrmM-directed gene expression in SMCs. A PDGF-BB-responsive region (PRR) was also identified within PrmM, overlapping with the previously identified URR, where either siRNA knockdown of Klf4 or the combined disruption of the Klf4 elements completely abolished PDGF-BB-mediated repression of PrmM-directed gene expression in SMCs. Moreover, ChIP analysis established that PDGF-BB-induced repression of Myocd gene expression is most likely regulated by enhanced binding of Klf4 and Klf5 to a lesser extent, to the PRR of PrmM. Taken together, these data provide critical insights into the transcriptional regulation of the Myocd gene in vascular SMCs, including during SMC differentiation. PMID- 24060353 TI - Invasive fungal infections in renal transplant recipients: about 11 cases. AB - Invasive fungal infections are a major complication and an important cause of morbidity and mortality among solid organ transplant recipients. Their diagnosis is difficult and their prognosis is often pejorative. OBJECTIVE: The aim of this study was to report the cases of invasive fungal infections in renal transplant recipients in Habib Bourguiba Sfax university hospital and to identify the main fungal agents. MATERIALS AND METHODS: It is a retrospective study of invasive fungal infections in renal transplant recipient reported in our hospital from January 1995 to February 2013. RESULTS: Invasive fungal infections were diagnosed in 11 cases (3.4%) among 321 renal transplant recipients. These infections included four cases of pneumocystosis, two cases of candidiasis, two cases of aspergillosis, two cases of cryptococcosis and one case of mucormycosis. There were six men and five women. The mean age was 37 years. The infection was late in 63% of cases (>3 months after transplantation). The prolonged corticosteroid and immunosuppressive therapy were the main risk factors (100%) followed by renal failure (45%), graft rejection (45%), broad spectrum antibiotics (45%), CMV infection (36%), neutropenia (36%) and dialysis (18%). The evolution under treatment was favourable only in two cases (18%). CONCLUSION: Invasive fungal infections are not common among kidney transplant recipients. However, they remain an important cause of morbidity and mortality in this group of patients. Prevention, early diagnosis and appropriate management are necessary to improve prognosis and reduce mortality rate. PMID- 24060354 TI - Pregnancy offers new insights into mechanisms of breast cancer risk and resistance. AB - Pregnancy induces long-lasting changes in gene expression that are associated with a reduction in breast cancer risk. Although several mechanisms have been proposed to mediate the reduction in breast cancer risk among parous women, recent studies focus attention on progenitor cells as major targets. The results suggest new biomarkers that may improve risk prediction and provide endpoints for assessment of clinical responses to prophylactic therapies. PMID- 24060355 TI - Spondyloarthritis-related and degenerative MRI changes in the axial skeleton--an inter- and intra-observer agreement study. AB - BACKGROUND: The Back Pain Cohort of Southern Denmark (BaPa Cohort) was initiated with the aim of evaluating the clinical relevance of magnetic resonance imaging (MRI) in the diagnosis of early spondyloarthritis (SpA). In order to facilitate the collection of MRI data for this study, an electronic evaluation form was developed including both SpA-related and degenerative axial changes. The objective of the current study was to assess the intra- and inter-observer agreement of the MRI changes assessed. METHODS: Three radiologists evaluated 48 MRI scans of the whole spine and the sacroiliac joints from a subsample of the BaPa Cohort, consisting of patients with non-specific low back pain and patients with different stages of SpA features. The spine was evaluated for SpA-related and degenerative MRI changes and the SIJ for SpA-related changes. Inter- and intra-observer agreements were calculated with kappa statistics. In the interpretation of the kappa coefficient, the standards for strength of agreement reported by Landis and Koch were followed. RESULTS: A total of 48 patients, 40% men and mean age of 31 years (range 18-40 years), were evaluated once by all three readers and re-evaluated by two of the readers after 4-12 weeks. For MRI changes in the spine, substantial to almost perfect observer agreement was found for the location and the size of vertebral signal changes and for disc degeneration and disc contour. For the sacroiliac joints, substantial or almost perfect observer agreement was found for the grading of bone marrow oedema and fatty marrow deposition, the depth of bone marrow oedema and for subchondral sclerosis. Global assessment of the SpA diagnosis had substantial to almost perfect observer agreements. CONCLUSION: The acceptable agreement for key MRI changes in the spine and sacroiliac joints makes it possible to use these MRI changes in the BaPa Cohort study and other studies investigating MRI changes in patients with non-specific low back pain and suspected SpA. PMID- 24060356 TI - Small tumour size is associated with new-onset chronic kidney disease after radical nephrectomy in patients with renal cell carcinoma. AB - BACKGROUND: To investigate the impact of tumour size on postoperative glomerular filtration rate (GFR) in patients undergoing radical nephrectomy (RN) for renal cell carcinoma (RCC). METHODS: We retrospectively identified 1371 patients who underwent RN between 1995 and 2010. Serum creatinine levels were measured preoperatively, within 7days of RN, at 3months, 1 and 3years. We divided patients into three groups based on tumour size: A: ?4cm, B: 4-7cm, C: >7cm. The changes in GFR were compared and multivariate logistic regression was used to analyse the predictive value of tumour size for new-onset chronic kidney disease (CKD, GFR<60mL/min/1.73m(2)). RESULTS: The preoperative GFR was significantly different among the three groups (A: 83.0, B: 82.0, C: 79.4ml/min/1.73m(2), P=0.040). The decrease in GFR from preoperative to within 7days was greater in group A than in groups B and C (28.2 versus 24.2 versus 18.5ml/min/1.73m(2), P<0.001). The GFR at 1year postoperative was lower in group A than in group C (58.4 versus 61.5ml/min/1.73m(2), P=0.009), in contrast to preoperative GFR. The incidence of GFR decrease >30% was higher in Group A than in Groups B and C at 1year (52.4% versus 41.5% versus 33.7%, P<0.001). On multivariate analysis Groups A and B had a 2.37-fold (95% confidence interval (CI) 1.56-3.60, P<0.001) and 2.24-fold (95% CI 1.49-3.38, P<0.001) higher risk of new-onset CKD compared with Group C. CONCLUSIONS: Small tumour size is associated with CKD after RN. Partial nephrectomy should be considered in patients with tumour size 7cm or less. PMID- 24060357 TI - Associations between cytokine receptor polymorphisms and variability in laboratory immune parameters in normal humans. AB - In every study involving human immune parameters, large inter-subject variability occurs which can make interpretation of results difficult. The aim of this study was to evaluate whether genetic variants in cytokine receptors could associate with variability in laboratory immune measures. A total of 207 normal volunteers were recruited in this study. Immunoregulatory profiles were measured by flow cytometry and genotyping assays were performed by allelic discrimination real time PCR. Immunoregulatory profiles were categorized according to various single nucleotide polymorphisms (SNPs) of cytokine receptors including T-56C and G-611A of IFN-gamma receptor 1 (IFNGR1); Q64R of IFNGR2; and Ile50Val, Q576R and S503P of IL4R. Results reveal that Th1 levels were significantly higher in the heterozygous of the IFNGR1 T-56C polymorphism (minor allele) compared to wild type (WT, major allele) (p = 0.006). For the Q576R of IL4R, Th1/Th2 ratio was significantly lower for the homozygous SNP (Arg/Arg) compared to the WT (Gln/Gln) (p = 0.035). In addition, the significant interaction effects of demographic characteristics on SNP-immune parameter associations were reported as well. We conclude that cytokine receptor polymorphisms might associate with variability in laboratory immune measures. Approach of SNP analysis of cytokine receptors can be useful in categorizing baseline immune responses to more accurately evaluate clinical immune data. PMID- 24060358 TI - Papillary endolymphatic sac tumor: Catastrophic presentation in a child. PMID- 24060359 TI - [Hurthle cell carcinoma with jugulo-subclavian venous thrombosis]. PMID- 24060360 TI - [Type III laryngeal cleft in an infant]. PMID- 24060361 TI - Pseudo-dextrocardia: an unusual case of giant biatrial enlargement. PMID- 24060362 TI - Sinus node dysfunction after partial anomalous pulmonary venous connection repair. AB - OBJECTIVE: Repair of partial anomalous pulmonary venous connection to superior vena cava using an internal patch has been described as a potential cause of obstruction at the systemic or pulmonary vein level and of sinus node dysfunction. Our experience with this operation was reviewed. METHODS: From 1991 to 2011, 59 patients with a diagnosis of partial anomalous pulmonary venous connection to superior vena cava underwent surgical repair with intracardiac patch rerouting alone (45 patients) or with associated superior vena cava patch enlargement (14 patients). Follow-up evaluation was performed, including electrocardiogram, echocardiogram, electrocardiogram Holter monitor recording, and exercise stress test. RESULTS: There were no early or late deaths and no reoperations at a mean follow-up of 46 +/- 45 months. All patients were asymptomatic in New York Heart Association class I. Echocardiographic evaluation excluded any obstruction at the pulmonary or systemic vein level. At follow-up, 55 patients (93%) presented sinus rhythm and were free from antiarrhythmic medications, 2 patients (3%) presented atrial fibrillation, 1 patient (2%) presented atrial fibrillation and asymptomatic sinus node dysfunction, and 1 patient (2%) presented ectopic atrial rhythm. Electrocardiogram Holter recording demonstrated sinus node dysfunction in 6 of 34 patients (18%). Exercise stress test showed chronotropic incompetence in 8 of 27 patients (30%): All except 1 patient presented sinus rhythm at basal electrocardiogram, and only 4 patients had some evidence of sinus node dysfunction on electrocardiogram Holter recording. CONCLUSIONS: Intracardiac repair of partial anomalous pulmonary venous connection can be performed with good results at medium-term follow-up. The rate of sinus node dysfunction or other arrhythmias and obstruction at pulmonary or systemic vein level is comparable to other techniques. Exercise stress test evaluation is the best way to detect asymptomatic sinus node dysfunction. PMID- 24060363 TI - Early postoperative systemic inflammatory response is an important determinant for adverse 2-year neurodevelopment-associated outcomes after the Norwood procedure. AB - OBJECTIVES: This study investigated the relationship between early postoperative serum C-reactive protein (CRP) levels, a marker of systemic inflammatory response, and 2-year neurodevelopment-associated outcomes among survivors after undergoing the Norwood procedure. METHODS: Among 53 neonates with hypoplastic left heart syndrome undergoing the Norwood procedure during 2003-2009, CRP was measured in 43 patients twice weekly within postoperative day 20. Two-year cognition, language, and motor scores were assessed with Bayley Scales of Infant and Toddler Development III in 26 patients (9 deaths, 2 lost, and 6 assessed with Bayley Scales of Infant Development II). Peak CRP levels of the 26 patients were recorded, with peak total and differential white blood cell counts (lowest lymphocytes) and glucose. Demographic data included age at surgery, socioeconomic status of the families, durations of cardiopulmonary bypass and aortic crossclamp, deep hypothermic circulatory arrest, and intensive care unit stay. RESULTS: The cognitive score was 91 +/- 13, language score was 86 +/- 13, and motor score was 85 +/- 17. The peak CRP level was 79 +/- 37 mg/L. Univariate regression showed that the cognitive score significantly and negatively correlated with peak CRP level (P = .004), and trended to a negative correlation with age at surgery (P = .097). The language score significantly and negatively correlated with peak CRP level (P < .0001) and age (P = .005). The motor score trended to a negative correlation with age (P = .08). Multivariate regression showed that both cognitive and language scores significantly and negatively correlated only with peak CRP level (P < .01 for both). CONCLUSIONS: The magnitude of systemic inflammatory response, among the perioperative factors examined, may be an important determinant for adverse 2-year cognition and language outcomes after the Norwood procedure. Confirmatory studies in larger populations, including those undergoing other types of cardiac surgeries, are warranted. PMID- 24060364 TI - Restrictive lung function in pediatric patients with structural congenital heart disease. AB - OBJECTIVES: We sought to describe the prevalence of restrictive lung function in structural congenital heart disease and to determine the effect of cardiothoracic surgical intervention. METHODS: The data from a retrospective review of the spirometry findings from pediatric patients with structural congenital heart disease were compared with the data from 220 matched controls. Restrictive lung function was defined as a forced vital capacity of <80%, with a preserved ratio of the forced expiratory volume in the first second to forced vital capacity of >80%. RESULTS: Of the children with congenital heart disease, 20% met the criteria for restrictive lung function compared with 13.2% of the controls (P = .03). The prevalence in those with congenital heart disease without a surgical history was similar to that of the controls (odds ratio, 0.62; 95% confidence interval, 0.34-1.13). Restrictive lung function was more likely if surgical intervention had occurred within the first year of life (odds ratio, 1.96; 95% confidence interval, 1.08-3.55; P < .0001). Those who had undergone both sternotomy and thoracotomy had a greater prevalence of restrictive lung function than those who had undergone sternotomy or thoracotomy alone (54.2% vs 25.6% and 23.5%, respectively; P < .0001). The prevalence of restrictive lung function increased significantly with each additional surgical intervention (odds ratio, 1.61; 95% confidence interval, 1.29-2.01; P < .0001). CONCLUSIONS: Restrictive lung function was more prevalent in those with congenital heart disease after cardiothoracic surgical intervention than in the controls or patients without surgical intervention. The prevalence was also greater with surgical intervention at an earlier age. The risk was equivalent when sternotomy alone was compared with thoracotomy alone but was significantly greater when both sternotomy and thoracotomy were performed. The risk increased with each additional surgery performed. PMID- 24060365 TI - The influence of preoperative weight loss on the postoperative course after esophageal cancer resection. AB - OBJECTIVE: Preoperative weight loss might increase the risk of postoperative morbidity and mortality after esophagectomy for cancer. We hypothesized that patients with esophageal cancer with >10% weight loss during the 3 months before their diagnosis would be at an increased risk of postoperative complications, have a longer length of stay, and have worse overall survival. METHODS: In the present hospital-based cohort study, all patients who had undergone surgery for esophageal cancer in 1990 to 2010 at the Erasmus University Medical Center Rotterdam were included. Weight loss was defined as "no, or limited" (<=10%) or "severe" (>10%). Logistic regression analysis was used to estimate the relative risk of complications, expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Hazard ratios were calculated to assess the length of hospital stay and survival. The risk estimates were adjusted for potential confounding factors. RESULTS: Of 922 included patients, 155 (17%) had experienced severe weight loss. These patients had no increased risk of early surgical, early nonsurgical, or late surgical complications (OR, 0.83 and 95% CI, 0.54-1.24; OR, 0.90 and 95% CI, 0.63-1.30; OR, 1.14 and 95% CI, 0.79-1.66, respectively) and had no increased length of stay (hazard ratio, 1.09; 95% CI, 0.89-1.35). Preoperative weight loss was followed by increased 5-year mortality (hazard ratio, 1.34; 95% CI, 1.02-1.74). CONCLUSIONS: A >10% preoperative weight loss was followed by decreased 5-year survival after esophageal cancer surgery but no increased risk of postoperative complications. PMID- 24060366 TI - Assessing species boundaries and the phylogenetic position of the rare Szechwan ratsnake, Euprepiophis perlaceus (Serpentes: Colubridae), using coalescent-based methods. AB - Delimiting species and clarifying phylogenetic relationships are the main goals of systematics. For species with questionable taxonomic status, species delimitation approaches using multi-species coalescent models with multiple loci are recommended if morphological data are unavailable or unhelpful. Moreover, these methods will also reduce subjectivity based on genetic distance or requirement of monophyletic genetic lineages. We determine the validity and phylogenetic position of a rare and long controversial species of Chinese reptile, the Szechwan ratsnake (Euprepiophis perlaceus), using multi-locus data from multiple individuals and coalescent-based approaches. Species were first delimited using Bayesian Phylogenetics & Phylogeography (BP&P), Brownie and Bayes Factor model comparison approaches, while relationships among species were estimated using species tree inference in (*)BEAST. Results indicate that Euprepiophis perlaceus is a distinct species sister to Euprepiophis mandarinus. Despite gene tree discrepancy, the coalescent model-based approaches used here demonstrate the taxonomic validity and the phylogenetic position of Euprepiophis perlaceus. These approaches objectively test the validity of questionable species diagnoses based on morphological characters and determine their phylogenetic position. PMID- 24060367 TI - How low can you go? The effects of mutation rate on the accuracy of species-tree estimation. AB - Although species-tree methods have been widely adopted for multi-locus data, little consideration has been given to the source and character of the loci used in these approaches. Decisions about which loci to target in empirical studies are typically constrained by availability, technology and funds - characteristics that are not typically considered in simulation studies. As a result, most real world datasets often combine one or two variable loci (such as mtDNA or chloroplast loci) with multiple lower-variation loci to estimate species trees. These locus selections impact the accuracy and the resolution of a phylogeny. Furthermore, the fact that using a larger sample of loci can result in lower posterior probabilities has been used as an excuse to drop loci from an analysis. Here we address these issues directly through a simulation approach designed to mimic situations arising in empirical datasets by combining loci with differing mutation rates. We show that low-variation loci can be utilized in species-tree analyses that account for gene-tree uncertainty (e.g., a Bayesian framework), whereas maximum likelihood approaches show no improvement in accuracy when low variation loci are added. We demonstrate that limited phylogenetic signal associated with low-variation loci constrains gains in species-tree estimation accuracy when adding loci. Lastly, we demonstrate that the inclusion of only a handful of loci with higher mutation rates, and hence greater phylogenetic information content, can make a tremendous difference in the accuracy of species tree estimates, suggesting that empiricists should consider the quality, and not just quantity, of loci in multi-locus phylogenetic analyses. PMID- 24060368 TI - Organic solvent desorption from two tegafur polymorphs. AB - Desorption behavior of 8 different solvents from alpha and beta tegafur (5-fluoro 1-(tetrahydro-2-furyl)uracil) has been studied in this work. Solvent desorption from samples stored at 95% and 50% relative solvent vapor pressure was studied in isothermal conditions at 30 degrees C. The results of this study demonstrated that: solvent desorption rate did not differ significantly for both phases; solvent desorption in all cases occurred faster from samples with the largest particle size; and solvent desorption in most cases occurred in two steps. Structure differences and their surface properties were not of great importance on the solvent desorption rates because the main factor affecting desorption rate was sample particle size and sample morphology. Inspection of the structure packing showed that solvent desorption rate and amount of solvent adsorbed were mainly affected by surface molecule arrangement and ability to form short contacts between solvent molecule electron donor groups and freely accessible tegafur tetrahydrofuran group hydrogens, as well as between solvents molecule proton donor groups and fluorouracil ring carbonyl and fluoro groups. Solvent desorption rates of acetone, acetonitrile, ethyl acetate and tetrahydrofuran multilayers from alpha and beta tegafur were approximately 30 times higher than those of solvent monolayers. Scanning electron micrographs showed that sample storage in solvent vapor atmosphere promotes small tegafur particles recrystallization to larger particles. PMID- 24060369 TI - A new hyaluronic acid pH sensitive derivative obtained by ATRP for potential oral administration of proteins. AB - Atom transfer radical polymerization (ATRP) has been successfully employed to obtain a new derivative of hyaluronic acid (HA) able to change its solubility as a function of external pH and then to be potentially useful for intestinal release of bioactive molecules, included enzymes and proteins. In particular, a macroinitiator has been prepared by linking 2-bromo-2-methypropionic acid (BMP) to the amino groups of ethylenediamino derivative of tetrabutyl ammonium salt of HA (HA-TBA-EDA). This macroinititor, named HA-TBA-EDA-BMP has been used for the ATRP of sodium methacrylate (MANa) using a complex of Cu(I) and 2,2'-bipyridyl (Byp) as a catalyst. The resulting copolymer, named HA-EDA-BMP-MANa, has been characterized by (1)H NMR and size exclusion chromatography (SEC) analyses. A turbidimetric analysis has showed its pH sensitive behavior, being insoluble in simulated gastric fluid but soluble when pH increases more than 2.5. To confirm the ability of HA-EDA-BMP-MANa in protecting peptides or proteins from denaturation in acidic medium, alpha-chymotrypsin has been chosen as a model of protein molecule and its activity has been evaluated after entrapment into HA-EDA BMP-MANa chains and treatment under simulated gastric conditions. Finally, cell compatibility has been evaluated by performing a MTS assay on murine dermal fibroblasts cultured with HA-EDA-BMP-MANa solutions. PMID- 24060370 TI - Alkyl glucopyranoside-based niosomes containing methotrexate for pharmaceutical applications: evaluation of physico-chemical and biological properties. AB - We designed novel niosomes based on alkyl glucopyranoside surfactants and containing methotrexate as anticancer drug, to be used in the pharmaceutical field. The effects of surfactants with chains of different length on niosome size and their distribution, drug entrapment efficiencies and in vitro drug release were determined. Systems made of alkyl glucopyranosides and cholesterol form vesicles whose average size scales with the alkyl chains length of such surfactants. Vesicles size ranges between 300 and 500 nm, with low polydispersity index. In addition, the hemolytic activity of alkyl glucopyranosides as surfactant solutions or vesicular formulations was studied and compared, to identify possible structure-activity relationships. High methotrexate entrapment efficiency was obtained, confirming significant interactions between the drug and the niosomal matrices. After 24h the amount of methotrexate released from niosomal formulations is effectively delayed, compared to the free drug in solution. Hemolytic tests show that sugar-based surfactants are more hemolytic the longer is their alkyl chain. When the surfactants are in vesicular form, the reverse behavior holds. It was also inferred that vesicle formation reduces the surfactant toxicity. These niosomal formulations can be used as methotrexate delivery systems in anticancer therapy. PMID- 24060371 TI - From rationally designed polymeric and peptidic systems to sophisticated gene delivery nano-vectors. AB - Lack of safe, efficient and controllable methods for delivering therapeutic genes appears to be the most important factor preventing human gene therapy. Safety issues encountered with viral vectors have prompted substantial attention to in vivo investigations with non-viral vectors throughout the past decade. However, developing non-viral vectors with effectiveness comparable to viral ones has been a challenge. The strategy of designing multifunctional synthetic carriers targeting several extracellular and intracellular barriers in the gene transfer pathway has emerged as a promising approach to improving the efficacy of gene delivery systems. This review will explain how sophisticated synthetic vectors can be created by combining conventional polycationic vectors such as polyethylenimine and basic amino acid peptides with additional polymers and peptides that are designed to overcome potential barriers to the gene delivery process. PMID- 24060373 TI - Increased long-term expression of pentraxin 3 in irradiated human arteries and veins compared to internal controls from free tissue transfers. AB - BACKGROUND: Clinical studies have shown that radiotherapy increases the risk of cardiovascular disease at irradiated sites years after exposure. However, there is a lack of biological explanations in humans. We therefore examined human blood vessels exposed to radiotherapy and studied C-reactive protein (CRP) and pentraxin 3 (PTX3), a new marker for adverse cardiovascular outcome dependent on TNF- alpha (TNFalpha) or interleukin-1beta (IL-1beta) expression. METHODS: Pairs of irradiated and non-irradiated human conduit arteries and veins were harvested from the same patient during autologous free tissue transfer for cancer reconstruction at a median time of 48 weeks after radiotherapy. Differential gene expression was studied using qRT-PCR, confirmed by immunohistochemistry and cellular origins determined by immunofluorescence. RESULTS: Gene expression in irradiated arteries compared to non-irradiated showed a consistent up-regulation of PTX3 in all patients and in a majority of veins (p < 0.001). Both TNFalpha and IL-1beta were increased in irradiated compared to non-irradiated arteries (p < 0.01) and IL-1beta correlated to the PTX3 expression (p = 0.017). Immunohistochemical and immunofluorescence staining confirmed an increased expression of PTX3 in endothelial cells, macrophages and smooth muscle cells. CONCLUSIONS: The sustained expression of PTX3 in arteries and veins tie biological evidence in humans to clinical studies and encourage further exploration of innate immunity in the pathogenesis of a radiation-induced vasculopathy. PMID- 24060374 TI - Acute toxicities of saxitoxin, neosaxitoxin, decarbamoyl saxitoxin and gonyautoxins 1&4 and 2&3 to mice by various routes of administration. AB - Saxitoxin and its derivatives, the paralytic shellfish toxins (PSTs), are known to be toxic to humans, and maximum permitted levels in seafood have been established by regulatory authorities in many countries. Until recently, the mouse bioassay was the reference method for determining the levels of these toxins in seafood, but this has now been superseded by chemical methods of analysis. The latter methods are able to determine the levels of many PSTs in shellfish, but for risk assessment an estimate of the relative toxicities of the individual components of the PST mixture is required. The relative toxicities are expressed as "Toxicity Equivalence Factors" (TEFs). At present, TEFs are based on relative specific activities in the mouse bioassay, rather than on acute toxicity determinations, as measured by median lethal doses (LD50s). In the present study, the median lethal doses of saxitoxin, neosaxitoxin, decarbamoyl saxitoxin and equilibrium mixtures of gonyautoxins 1&4 and gonyautoxins 2&3 have been determined by intraperitoneal injection, gavage and feeding. The results indicate that specific activities in the MBA do not consistently correlate with acute toxicities by any of the routes of administration, and TEFs, particularly for neosaxitoxin, require revision. PMID- 24060375 TI - Malnutrition alters the cardiovascular responses induced by central injection of tityustoxin in Fischer rats. AB - Scorpion envenoming and malnutrition are considered two important public health problems in Brazil, involving mainly children. Both these conditions are more common among the economically stratified lower income portion of the population, thus suggesting that these factors should be analyzed concomitantly. It is known that cardiorespiratory manifestations, as cardiac arrhythmias, arterial hypertension and hypotension, pulmonary edema and circulatory failure are the main "causa mortis" of scorpion envenomation. Additionally, there are evidences in the literature that deficiencies in dietary intake endanger the CNS and modify the cardiovascular homeostasis. Then, the objective of this work is to evaluate the protein malnourished effect on cardiovascular responses induced by tityustoxin (TsTX, an alpha-type toxin extracted from the Tityus serrulatus scorpion venom). Fischer rats (n = 20) were injected i.c.v. with TsTX and divided in control and malnorished groups, which were, respectively, submitted to a control and a low-protein diet. Arterial pressure recordings were done until death of the animals. Although both groups presented an increased mean arterial pressure after TsTX injection, this increase was smaller and delayed in malnourished rats, when compared to control rats. In addition, heart rate increased only in rats from the control group. Finally, malnourished rats had an increase in survival time (9:9/13.5 vs. 15.5:10.5/18 min; p = 0.0009). In summary, our results suggest that the protein restriction attenuates the cardiovascular manifestations resulting from TsTX action on CNS. PMID- 24060376 TI - Repeated oral co-exposure to yessotoxin and okadaic acid: a short term toxicity study in mice. AB - The polyethers yessotoxin (YTX) and okadaic acid (OA) are two marine algal toxins frequently associated as edible shellfish contaminants. Seafood contamination by these compounds, also at low concentrations and for a long period of time, can increase the possibility of their simultaneous and repeated ingestion, with possible synergistic toxic effects. Thus, in vivo toxicity by repeated oral exposure to a combination of fixed doses of YTX and OA (1 mg YTX/kg and 0.185 mg OA/kg, daily for 7 days) was investigated in mice, in comparison to that of each toxin alone. No mortality, signs of toxicity, diarrhea or hematological changes was induced by the toxins co-administration or by the single toxins. Light microscopy revealed changes at gastric level (multifocal subacute inflammation, erosions and epithelial hyperplasia) in 2/5 mice co-administered with the toxins. In animals dosed only with OA, epithelial hyperplasia of forestomach and slight focal subacute inflammation of its submucosa were noted. No changes were induced by the treatment with YTX. Ultrastructural analysis of the heart revealed some cardiomyocytes with "loose packing" of myofibrils and aggregated rounded mitochondria in mice co-administered with the toxins or with YTX; OA-treated mice showed only occasional mitochondrial assemblage and dilated sarcomeres. Thus, the combined oral doses of YTX (1 mg/kg/day) and OA (0.185 mg/kg/day) did not exert cumulative or additive toxic effects in mice, in comparison to the single toxins. PMID- 24060377 TI - Cell-free synthesis of functional thermostable direct hemolysins of Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus is a recognized enteropathogen causing diarrhea in humans and is one of the major causes of seafoodborne gastroenteritis. An important virulence factor is thermostable direct hemolysin (TDH), a pore-forming toxin, which is able to lyse eukaryotic cells. The active toxin is a tetramer of four identical protein subunits, which is secreted by the pathogen after cleavage of a signal peptide. To establish diagnostic detection systems for TDH we expressed the hemolysin with and without the signal peptide in a prokaryotic cell-free system to obtain pure toxin. In order to purify and to facilitate the isolation from cell lysates we synthesized TDH variants with different tags. Important regulatory sequences for cell-free protein synthesis as well as sequences for N terminal Strep-tag and C-terminal 6xHis-tag were added by a two-step PCR. For the expression in the cell-free system these linear tdh templates were subjected directly to prokaryotic cell extracts. Protein yields were in the range of 500 600 MUg/ml for the preproteins and approx. 300-400 MUg/ml for the mature proteins. The identities of expressed proteins were further confirmed by SDS PAGE, immunological and MALDI-TOF mass spectrometric analyses. The functionality of newly synthesized toxin variants was tested by performing qualitative and semiquantitative hemolysis assays. Cell-free produced mature TDH and its variants were active while the preprotein and its derivatives lacked hemolytic activity. A C-terminal 6xHis-tag showed less influence on functionality compared to the N terminal Strep-tag. PMID- 24060378 TI - Comparison of total protein and phospholipase A(2) levels in individual coralsnake venoms. AB - Studies of differences or changes in venom protein levels or enzymatic activities have significance only if contrasted to the normal variations between individual snakes. This study involves the analysis and comparison of venom from 13 individual Texas coralsnakes (Micrurus tener tener) in order to detect differences in the volume, total protein concentration, electrophoretic profile, and PLA2 enzyme activity. A significant inverse correlation between venom volume and total protein concentration was found. Although the 13 venoms were indistinguishable from their electrophoretic protein profiles, phospholipase A2 enzymatic activities varied considerably. PMID- 24060379 TI - [What is the impact of the dispositions of July 5, 2011 on care, 2 years after?]. PMID- 24060380 TI - Escherichia coli multiple [Ni-Fe]-hydrogenases are sensitive to osmotic stress during glycerol fermentation but at different pHs. AB - Escherichia coli evolves H2 via multiple [Ni-Fe]-hydrogenases (Hyd). This activity under hyper- and hypo-osmotic stress was investigated with mutants lacking different Hyd enzymes during glycerol fermentation. Inhibitory effects of hypo-stress on H2 production was stronger at pH 6.5 in wild type and mutants except fhlA, which encodes a transcriptional activator for Hyd-3, compared with the effects of N,N'-dicyclohexylcarbodiimide. These results indicate that Hyd-3 and Hyd-4 are osmosensitive at pH 7.5. Hyd-4 and FhlA are implicated in osmotic stress response at pH 6.5. Hyd-1 and FhlA might be osmosensitive at pH 5.5. Thus, osmosensitivity of Hyd enzymes is a novel property that depends on pH. This is significant for mechanisms of cell osmoregulation and H2 production biotechnology when glycerol is used as a fermentation substrate. PMID- 24060382 TI - Functionalization of single-wall carbon nanotubes with chromophores of opposite internal dipole orientation. AB - We report the functionalization of carbon nanotubes with two azobenzene-based chromophores with large internal dipole moments and opposite dipole orientations. The molecules are attached to the nanotubes noncovalently via a pyrene tether. A combination of characterization techniques shows uniform molecular coverage on the nanotubes, with minimal aggregation of excess chromophores on the substrate. The large on/off ratios and the subthreshold swings of the nanotube-based field effect transistors (FETs) are preserved after functionalization, and different shifts in threshold voltage are observed for each chromophore. Ab initio calculations verify the properties of the synthesized chromophores and indicate very small charge transfer, confirming a strong, noncovalent functionalization. PMID- 24060381 TI - Enhancing the quality of international orthopedic medical mission trips using the blue distinction criteria for knee and hip replacement centers. AB - BACKGROUND: Several organizations seek to address the growing burden of arthritis in developing countries by providing total joint replacements (TJR) to patients with advanced arthritis who otherwise would not have access to these procedures. Because these mission trips operate in resource poor environments, some of the features typically associated with high quality care may be difficult to implement. In the U.S., many hospitals that perform TJRs use the Blue Cross/Shield's Blue Distinction criteria as benchmarks of high quality care. Although these criteria were designed for use in the U.S., we applied them to Operation Walk (Op-Walk) Boston's medical mission trip to the Dominican Republic. Evaluating the program using these criteria illustrated that the program provides high quality care and, more importantly, helped the program to find areas of improvement. METHODS: We used the Blue Distinction criteria to determine if Op Walk Boston achieves Blue Distinction. Each criterion was grouped according to the four categories included in the Blue Distinction criteria--"general and administrative", "structure", "process", or "outcomes and volume". Full points were given for criteria that the program replicates entirely and zero points were given for criteria that are not replicated entirely. Of the non-replicated criteria, Op-Walk Boston's clinical and administrative teams were asked if they compensate for failure to meet the criterion, and they were also asked to identify barriers that prevent them from meeting the criterion. RESULTS: Out of 100 possible points, the program received 71, exceeding the 60-point threshold needed to qualify as a Blue Distinction center. The program met five out of eight "required" criteria and 11 out of 19 "informational" criteria. It scored 14/27 in the "general" category, 30/36 in the "structure" category, 17/20 in the "process" category, and 10/17 in the "outcomes and volume" category. CONCLUSION: Op-Walk Boston qualified for Blue Distinction. Our analysis highlights areas of programmatic improvement and identifies targets for future quality improvement initiatives. Additionally, we note that many criteria can only be met by hospitals operating in the U.S. Future work should therefore focus on creating criteria that are applicable to TJR mission trips in the context of developing countries. PMID- 24060383 TI - Encephalitozoon infections in Rodentia and Soricomorpha in Japan. AB - Encephalitozoon is an obligate intracellular microsporidian parasite that infects a wide range of mammalian hosts. In this study, we used nested PCR to investigate the presence of Encephalitozoon infection in Rodentia and Soricomorpha in Japan. We attempted to amplify and sequence Encephalitozoon-specific DNA from brain and viscera samples of 180 animals collected between 2008 and 2010. Forty-three samples (23.9%) from the orders Rodentia and Soricomorpha were positive for Encephalitozoon. This study is the first report of Encephalitozoon infection in Rodentia and Soricomorpha in Japan, and our findings suggest that these hosts may play a role in the spread of microsporidian spores in the environment. PMID- 24060384 TI - Embryotoxicity of TiO2 nanoparticles to Mytilus galloprovincialis (Lmk). AB - Few data exist on the ecotoxicological effects of nanosized titanium dioxide (nTiO2) towards marine species with specific reference to bivalve molluscs and their relative life stages. Mytilus galloprovincialis Lamarck was selected to assess the potential adverse effects of nTiO2 (0-64 mg/L) on its early larval development stages (pre-D shell stage, malformed D-shell stage and normal D-shell stage larvae) considering two exposure scenarios characterised by total darkness (ASTM protocol) and natural photoperiod (light/dark). This approach was considered to check the presence of potential effects associated to the photocatalytic properties of nTiO2. Parallel experiments were carried on with the bulk reference TiCl4. The toxicity of nTiO2 showed to be mainly related to its "nano" condition and to be influenced by the exposure to light that supported the increase in the number of pre-D shell stage (retarded) larvae compared to the malformed ones especially at the maximum effect concentrations (4 and 8 mg nTiO2/L). The non-linear regression toxicity data analysis showed the presence of two EC50 values per exposure scenario: a) EC(50)1 = 1.23 mg/L (0.00-4.15 mg/L) and EC(50)2 = 38.56 mg/L (35.64-41.47 mg/L) for the dark exposure conditions; b) EC(50)1 = 1.65 mg/L (0.00-4.74 mg/L) and EC(50)2 = 16.39 mg/L (13.31-19.48 mg/L) for the light/dark exposure conditions. The potential implication of agglomeration and sedimentation phenomena on ecotoxicological data was discussed. PMID- 24060385 TI - Halogenated phenolic contaminants in the blood of marine mammals from Japanese coastal waters. AB - Information on accumulation of halogenated phenolic contaminants in the blood of marine mammal is limited. The present study, we determined the residue levels and patterns of chlorinated and brominated phenolic contaminants (OH-PCBs, OH-PBDEs and bromophenols) in the blood collected from pinnipeds (northern fur seal, spotted seal, Steller sea lion and ribbon seal) and small cetaceans (harbor porpoise and Dall's porpoise) from Japanese coastal waters. Concentrations of PCBs and OH-PCBs found in pinnipeds were the same as in small cetaceans living in the same coastal area. However, significantly lower concentrations of brominated compounds (PBDEs, MeO-PBDEs, OH-PBDEs) were found in the blood of pinnipeds than the levels found in cetacean species which live same area (p < 0.05). This difference of accumulation pattern suggested pinnipeds have an enhanced capability to degrade organobromine compounds relative to cetaceans. PMID- 24060386 TI - Scavenger receptor class B type I regulates cellular cholesterol metabolism and cell signaling associated with breast cancer development. AB - INTRODUCTION: Previous studies have identified cholesterol as an important regulator of breast cancer development. High-density lipoprotein (HDL) and its cellular receptor, the scavenger receptor class B type I (SR-BI) have both been implicated in the regulation of cellular cholesterol homeostasis, but their functions in cancer remain to be established. METHODS: In the present study, we have examined the role of HDL and SR-BI in the regulation of cellular signaling pathways in breast cancer cell lines and in the development of tumor in a mouse xenograft model. RESULTS: Our data show that HDL is capable of stimulating migration and can activate signal transduction pathways in the two human breast cancer cell lines, MDA-MB-231 and MCF7. Furthermore, we also show that knockdown of the HDL receptor, SR-BI, attenuates HDL-induced activation of the phosphatidylinositol 3-kinase (PI3K)/protein Kinase B (Akt) pathway in both cell lines. Additional investigations show that inhibition of the PI3K pathway, but not that of the mitogen-activated protein kinase (MAPK) pathway, could lead to a reduction in cellular proliferation in the absence of SR-BI. Importantly, whereas the knockdown of SR-BI led to decreased proliferation and migration in vitro, it also led to a significant reduction in tumor growth in vivo. Most important, we also show that pharmacological inhibition of SR-BI can attenuate signaling and lead to decreased cellular proliferation in vitro. Taken together, our data indicate that both cholesteryl ester entry via HDL-SR-BI and Akt signaling play an essential role in the regulation of cellular proliferation and migration, and, eventually, tumor growth. CONCLUSIONS: These results identify SR-BI as a potential target for the treatment of breast cancer. PMID- 24060387 TI - Brain volume and fatigue in patients with postpoliomyelitis syndrome. AB - BACKGROUND: Acute paralytic poliomyelitis is associated with encephalitis. Early brain inflammation may produce permanent neuronal injury with brain atrophy, which may result in symptoms such as fatigue. Brain volume has not been assessed in postpoliomyelitis syndrome (PPS). OBJECTIVE: To determine whether brain volume is decreased compared with that in normal controls, and whether brain volume is associated with fatigue in patients with PPS. DESIGN: A cross-sectional study. SETTING: Tertiary university-affiliated hospital postpolio and multiple sclerosis (MS) clinics. PARTICIPANTS: Forty-nine ambulatory patients with PPS, 28 normal controls, and 53 ambulatory patients with MS. METHODS: We studied the brains of all study subjects with magnetic resonance imaging by using a 1.5 T Siemens Sonata machine. The subjects completed the Fatigue Severity Scale. Multivariable linear regression models were computed to evaluate the contribution of PPS and MS compared with controls to explain brain volume. MAIN OUTCOME MEASUREMENTS: Normalized brain volume (NBV) was assessed with the automated program Structured Image Evaluation, using Normalization, of Atrophy method from the acquired magnetic resonance images. This method may miss brainstem atrophy. RESULTS: Technically adequate NBV measurements were available for 42 patients with PPS, 27 controls, and 49 patients with MS. The mean (standard deviation) age was 60.9 +/- 7.6 years for patients with PPS, 47.0 +/- 14.6 years for controls, and 46.2 +/- 9.4 years for patients with MS. In a multivariable model adjusted for age and gender, NBV was not significantly different in patients with PPS compared with that in controls (P = .28). As expected, when using a similar model for patients with MS, NBV was significantly decreased compared with that in controls (P = .006). There was no significant association between NBV and fatigue in subjects with PPS (Spearman rho = 0.23; P = .19). CONCLUSIONS: No significant whole-brain atrophy was found, and no association of brain volume with fatigue in PPS. Brain atrophy was confirmed in MS. It is possible that brainstem atrophy was not recognized by this study. PMID- 24060388 TI - Functional differences between anatomical regions of the anconeus muscle in humans. AB - This study sought to resolve a longstanding debate of the function of anconeus. Intramuscular and surface electromyography electrodes recorded muscle activity from two regions of anconeus and from typical elbow flexion and extension muscles. Eleven participants performed pronation-supination around the medial and lateral axes of the forearm, elbow flexion-extension in pronation, supination and neutral positions of the forearm, and gripping. Maximal voluntary contractions (MVC) and submaximal (10% MVC) force-matching tasks were completed. Activity varied between longitudinal (AL) and transverse (AT) segments of anconeus. Although both muscle regions were active across multiple directions (including opposing directions), AL was more active during pronation than supination, whereas AT showed no such difference. During pronation, activity of AL and AT was greatest about the lateral forearm axis. AT was more active during elbow extension with the forearm in pronation, whereas AL did not differ between pronated and neutral forearm alignment. These findings are consistent with the proposal that AL makes a contribution to control of abduction of the ulna during forearm pronation. Different effects of forearm position on AL and AT activity during elbow extension may be explained by the anatomical differences between the regions. These data suggest anconeus performs multiple functions at the elbow and forearm and this varies between anatomically distinct regions of the muscle. PMID- 24060389 TI - Unweighted state as a sidestep preparation improve the initiation and reaching performance for basketball players. AB - The preparatory motion of a defensive motion in contact sport such as basketball should be small and involve landing on both feet for strict time and motion constraints. We thus proposed the movement creating a unweighted state. Ten basketball players performed a choice reaction sidestepping task with and without the voluntary, continuous vertical fluctuation movement. The results indicated that the preparatory movement shortened the time of their sidestep initiation (301 vs. 314 ms, p = 0.011) and reaching performance (883 vs. 910 ms, p = 0.018) but did not increase their peak ground reaction force or movement velocity. The mechanism of the improvement was estimated to be the following: in the preparation phase, the vertical body fluctuation created the force fluctuation; after the direction signal, the unweighted state can shorten the time required to initiate the sidestepping (unweighted: 279 ms; weighted: 322 ms, p = 0.002); around the initiation phase, the dropping down of the body and weighted state can contribute to the reaching performance. We conducted additional experiment investigating muscle-tendon-complex dynamics and muscle activity using ultrasound device and electromyography. The result suggests that the building up of active state of muscle might explain the improvement of sidestepping performance. PMID- 24060390 TI - The use of fine-wire EMG to investigate shoulder muscle recruitment patterns during cello bowing: the results of a pilot study. AB - The physical mechanics of music making is important both in the prevention of injuries and in guiding how music is performed and taught. Electromyography has potential as a resource in understanding the loads involved in instrumental playing; however, only a small number of projects have been undertaken, and little is understood on the muscle activity used during bowing on string instruments. This study aimed to measure the muscle activity at the bowing shoulder of a cellist during cello playing and to establish if fine-wire EMG is useful in understanding muscle recruitment in string players without interfering with normal playing ability. This project used a combination of fine-wire and surface EMG to evaluate the muscular load placed on the right shoulder of a professional cellist whilst playing a set of various bowing exercises. The results indicated that different bowing techniques produced statistically different muscle activity levels, with the supraspinatus muscle in particular maintaining higher mean contraction (20% MVC) during all bowing patterns tested. Fine-wire EMG was useful in measuring shoulder muscle load and did not interfere with normal playing technique of the subject. Overall, the study presents a working protocol from which future studies may be able conduct further research. PMID- 24060392 TI - The differences and similarities between intramural hematoma of the descending aorta and acute type B dissection. AB - INTRODUCTION: Aortic intramural hematoma type B (IMHB) is a variant of acute aortic syndrome, which presents with symptoms similar to classic type B aortic dissection (ABAD). However, the natural history of IMHB is not well understood. The purpose of this study was to better characterize IMHB, comparing its clinical characteristics, treatment, and in-hospital and long-term outcomes to those with classic ABAD. METHODS: A total of 107 IMHB and 790 ABAD patients enrolled in the International Registry of Acute Aortic Dissection (IRAD) between January 1996 and June 2012 were analyzed. Accordingly, differences in presentation, diagnostics, therapeutic management, and outcomes were assessed. RESULTS: As compared with the ABAD, IMHB presented predominantly in males (62% vs 33%; P < .001) at older age (69 +/- 12 vs 63 +/- 14; P < .001). IMHB patients more often had chest pain (80% vs 69%; P = .020) and periaortic hematoma (22% vs 13%; P = .020) and were more often treated medically (88% vs 62%; P < .001), with surgical/endovascular interventions being reserved for more complicated patients. Overall in-hospital mortality was 10% (IMHB, 7% vs ABAD, 11%; P = NS). Six out of seven IMHB deaths occurred during medical treatment, two due to aortic rupture. During follow-up in IMHB, patient mortality was 7%, and no adverse events, including progression to an aortic dissection or aortic rupture, were observed. Imaging showed significantly more aortic enlargement at the level of the descending aorta in ABAD patients (39% vs 61%; P = .034). CONCLUSIONS: Most IMHB patients can be treated medically, and aortic enlargement is less common during follow-up, which may suggest that IMHB may have a slightly more benign course compared with classic ABAD in the acute setting. PMID- 24060391 TI - Baseline impulsive choice predicts the effects of nicotine and nicotine withdrawal on impulsivity in rats. AB - Impulsive choice, a form of impulsivity, is associated with tobacco smoking in humans. Trait impulsivity may be a vulnerability factor for smoking, or smoking may lead to impulsive behaviors. We investigated the effects of 14-day nicotine exposure (6.32mg/kg/day base, subcutaneous minipumps) and spontaneous nicotine withdrawal on impulsive choice in low impulsive (LI) and high impulsive (HI) rats. Impulsive choice was measured in the delayed reward task in which rats choose between a small immediate reward and a large delayed reward. HI and LI rats were selected from the highest and lowest quartiles of the group before exposure to nicotine. In non-selected rats, nicotine or nicotine withdrawal had no effect on impulsive choice. In LI rats, chronic nicotine exposure decreased preference for the large reward with larger effects at longer delays, indicating increased impulsive choice. Impulsive choices for the smaller immediate rewards continued to increase during nicotine withdrawal in LI rats. In HI rats, nicotine exposure and nicotine withdrawal had no effect on impulsive choice, although there was a tendency for decreased preference for the large reward at short delays. These results indicate that nicotine- and nicotine withdrawal-induced increases in impulsive choice depend on trait impulsivity with more pronounced increases in impulsive choice in LI compared to HI subjects. Increased impulsivity during nicotine exposure may strengthen the addictive properties of nicotine and contribute to compulsive nicotine use. PMID- 24060393 TI - Human ex-vivo model of Stanford type B aortic dissection. AB - OBJECTIVE: To report a new human ex vivo model of type B aortic dissection (TBAD) and to assess if the locations of the primary entry tear determine the patterns of dissection propagation. METHODS: Twenty fresh human aortas were harvested. TBADs were surgically initiated 2 cm below the left subclavian artery at four different locations (lateral, n = 5; medial, n = 5; anterior, n = 5; posterior, n = 5). Aortas were thereafter connected to a bench-top pulsatile flow model to induce antegrade propagation of the dissection. RESULTS: Antegrade propagation of the dissection was achieved and reached at least the celiac trunk (CT) in all the cases. Dissection was propagated to the renal aorta in 16 (80%) and infrarenal aorta in seven cases (35%). Left renal artery with or without the CT originated more often from the false channel when primary entry tear was lateral. Right renal artery and the CT most often originated from the false channel when primary entry tear was medial. When the CT was the only one originating from the false channel, primary entry tear was more often anterior, whereas when it originated from the true channel, it was more often posterior. CONCLUSIONS: This human ex vivo model of TBAD is reproducible, since, in all the aortas, extended dissection was achieved and provides the first model of human aortic dissection with infrarenal aorta extension allowing future assessment of endovascular devices developed for human use. Furthermore, it allows clarification of the patterns of aortic dissection propagation and visceral and renal artery involvement according to the site of the primary entry tear. PMID- 24060394 TI - MRI evaluation of the effect of Kashin-Beck disease-affected feed and T-2 toxin on the rat knees. PMID- 24060395 TI - Reply to Marhadour et al. regarding their comment about our article entitled "Ivory vertebra and systemic mastocytosis". PMID- 24060396 TI - A charcoal-like synovial fluid. PMID- 24060397 TI - Sarcoidosis onset during TNFalpha-antagonist therapy: is infection the culprit? PMID- 24060398 TI - Chronic non-bacterial osteomyelitis in a patient with common variable immunodeficiency. PMID- 24060399 TI - Ultrasonography of shoulders in spondyloarthritis and rheumatoid arthritis: a case-control study. AB - INTRODUCTION: Shoulders are often involved in spondyloarthritis (SpA) and rheumatoid arthritis (RA). The diagnosis of peripheral SpA and its differential diagnosis with RA could be challenging. A recent ultrasound study showed that ultrasonography (US) of the hands might differentiate psoriatic arthritis to RA. The aim of the study was to compare different US features in SpA, RA and healthy controls. METHODS: A total of 38 SpA and 43 RA patients with clinical involvement of shoulders were included and compared to 33 controls. One blinded rheumatologist performed US examinations. The following items were assessed: gleno-humeral effusion, long-head biceps tendon tenosynovitis, subacromial and subdeltoid bursitis, acromio clavicular (AC) synovitis and humeral bone erosion. RESULTS: Thirty-eight SpA (mean age: 49.9 +/- 15.4 years, 58% of male), 43 RA patients (52.9 +/- 16.6 years, 26% of male) and 33 controls (55.2 +/- 16.9 years, 42% of male) were assessed. In comparison to RA, SpA patients had higher frequency of AC synovitis (66% vs 5%, P < 0.0001) but lower prevalence of subacromial and subdeltoid bursitis (39% vs 67%, P = 0.015), gleno-humeral effusion (5% vs 28%, P = 0.008) and humeral bone erosion (10% vs 56%, P < 0.0001). Unilateral abnormalities were found more frequently in SpA patients than in RA (64% vs 26%, P < 0.0001). CONCLUSION: Our results suggest that AC synovitis is highly evocative of SpA in patients with inflammatory painful shoulders. Thus, US might help to diagnose SpA and to differentiate with RA. PMID- 24060400 TI - Mesenchymal stem cells: uses in osteoarthritis. PMID- 24060401 TI - Salvage B-cell depletion therapy in rapidly progressive dermatomyositis associated interstitial lung disease. PMID- 24060402 TI - Linitis plastica presenting two years after elective Roux-en-Y gastric bypass for treatment of morbid obesity: a case report and review of the literature. PMID- 24060403 TI - Laparoscopic transgastric removal of an eroded adjustable gastric band. PMID- 24060405 TI - Different amounts of protein-bound citrulline and homocitrulline in foot joint tissues of a patient with anti-citrullinated protein antibody positive erosive rheumatoid arthritis. AB - BACKGROUND: Antibodies binding to citrullinated proteins are a frequent finding in rheumatoid arthritis patients and may precede the onset of clinical symptoms several years. The antibodies are a predisposing factor for bone erosions but their origin is unknown. In this study we analyze in detail the levels of protein bound citrulline and homocitrulline in several tissue samples of a single erosive arthritic surgery patient. METHODS: Serum antibodies binding to CCP, MCV and citrulline- or homocitrulline-containing type I and II collagen carboxytelopeptides were measured. Tissue samples of a single RA patient, taken in two separate operations performed with two-year time span were hydrolyzed and analyzed for citrulline and homocitrulline content by HPLC. RESULTS: Protein bound citrulline and homocitrulline were found in several joint tissues of a RA patient with ACPA-positive erosive disease. The amount of homocitrulline stayed relatively constant between the different tissues. The amount of citrulline in erosive tissue was 3-times higher than in non-erosive tissue in the first operation. In the samples of the second operation 3-4-times higher mean amounts of citrulline were found in two out of the six tissues investigated. CONCLUSIONS: Homocitrulline is present in rheumatoid nodule together with citrulline. There is more variation in the amount of citrulline than in the amount of homocitrulline between the tissues. The tissue sample containing the most citrulline was the most erosive. PMID- 24060406 TI - Kidney and bladder outcomes in children with hemorrhagic cystitis and BK virus infection after allogeneic hematopoietic stem cell transplantation. AB - BK virus (BKV) infection is associated with hemorrhagic cystitis (HC) in hematopoietic stem cell transplantation (HSCT) recipients and nephropathy after kidney transplantation. We assessed the association between BKV and kidney and bladder complications in children developing HC by retrospectively reviewing 221 consecutive pediatric allogeneic HSCT recipients at the Children's Hospital of Philadelphia from 2005 to 2011. We included all patients with BKV PCR testing performed for clinical indication from day 0 until 1 year post-HSCT (N = 68). We assessed the association of any BKV infection (urine and/or blood) or peak BK viremia >= 10,000 copies/mL (high viremia) with severe HC (defined as grade IV bladder catheterization or surgical intervention); the need for dialysis; serum creatinine-estimated glomerular filtration rate at the time of BKV testing, day 100, and day 365; and death. Children with high viremia more likely developed severe HC compared with those with peak viremia < 10,000 copies/mL (21% versus 2%; P = .02). BKV infection of the blood or urine was not associated with the need for dialysis, change in estimated glomerular filtration rate, or mortality. BKV infection is common after pediatric allogeneic HSCT, and plasma testing in those with HC may predict patients who will develop severe bladder injury. PMID- 24060407 TI - Comparison of unrelated cord blood transplantation and HLA-matched sibling hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in advanced stage. AB - This is the first report to present a clinical comparison of unrelated cord blood transplantation (CBT) and HLA-matched sibling allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in advanced stage (accelerated phase or blast crisis). A total of 32 consecutive patients with advanced CML received unrelated CBT (n= 16) or HLA-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo PBSCT/BMT) (n = 16) between 2002 and 2011. The median day to neutrophil engraftment and the median day to platelet engraftment were longer in the unrelated CBT group. The cumulative incidence of grades 1 to 2 acute graft-versus host disease (aGVHD), grades 3 to 4 aGVHD, and chronic graft-versus-host disease did not differ significantly between the 2 cohorts. The cumulative incidence of transplantation-related mortality (TRM) at day +180 was higher in CBT group (37.5% versus 12.5%, P = .013). The risk of relapse was lower in CBT patients compared with that of allo-PBSCT/BMT patients (14.2% versus 42.7%, P = .03). The long-term survival in CBT group patients was slightly better than that of allo PBSCT/BMT group, although the difference did not reach statistical significance: the 5-year overall survival for CBT patients and allo-PBSCT/BMT patients was 62.5% and 48.6%, respectively (P= .10), whereas the 5-year leukemia-free-survival rate was 50% and 40.5%, respectively (P = .12). Our comparisons suggest that patients with advanced CML receiving unrelated CBT had a lower relapse rate, a slightly better long-term survival, but a higher early TRM than those receiving HLA-matched related allo-PBSCT/BMT. PMID- 24060408 TI - Isolation and characterization of antimicrobial constituents of Searsia chirindensis L. (Anacardiaceae) leaf extracts. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Searsia chirindensis is used in South African traditional medicine for management of bacterial infections such as diarrhoea. Aim of the study was to examine the phytochemical composition from the leaves of Searsia chirindensis that is responsible for the ethnomedicinal use of this plant. MATERIALS AND METHODS: The crude extract (80% methanol) was extracted sequentially with dichloromethane (DCM), ethyl acetate (EtOAc) and n-butanol. The extracts and isolated compounds were tested for their antibacterial activity against Gram-negative (Campylobacter jejuni, Escherichia coli and Shigella flexneri) and Gram-positive (Staphylococcus aureus) bacterial strains using the microdilution method. Bioguided fractionation of EtOAc fraction afforded five phenolic compounds. Structural elucidation was carried out using NMR (1D and 2D) spectroscopic analyses. RESULTS: Of the three fractions obtained from the crude extract, EtOAc was the most active and its fractionation afforded methyl gallate (1), and four flavonol glycosides: myricetin-3-O-arabinopyranoside (2), myricetrin-3-O-rhamnoside (3), kaempferol-3-O-rhamnoside (4) and quercetin-3-O arabinofuranoside (5). These compounds are reported from Searsia chirindensis for the first time. All the compounds showed good antibacterial activity against all bacterial strains tested. Their minimum inhibitory concentrations ranged from 30 to 250 ug/mL. CONCLUSIONS: Antibacterial activity demonstrated by the extracts and isolated compounds provides credence to the ethnomedicinal use of Searsia chirindensis against diarrhoea. PMID- 24060409 TI - Dolichos falcata Klein attenuated the inflammation induced by monosodium urate crystals in vivo and in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dolichos falcata Klein (DF), a Chinese Dai ethnic medicine popularly known as "Tuoyeteng" in Yunnan province of China, has been widely used as a traditional herbal medicine for the treatment of fracture and beriberoid disease for a long time in China. The present study was carried out to investigate the anti-inflammatory activity and the bioactive chemical constituents of DF, and further to assess its possible mechanism on gouty arthritis in an animal model of the MSU crystals-induced gouty inflammation. MATERIALS AND METHODS: The ethanol extract (EE) of DF at the doses of 10, 20 and 40 mg/kg was administered to the rats treated with MSU crystals to evaluate the anti-gouty arthritis effect. Subsequently, the components of EE were isolated and identified using classical methods. Phyto-chemical analysis of EE was further carried out by HPLC-DAD. Finally, the anti-inflammatory effect of EE and two isolated components were assessed using the MSU crystals-treated monocyte/macrophage cell line RAW 264.7 in vitro. RESULTS: EE (10, 20 and 40 mg/kg) significantly attenuated the pain threshold value, the joint swelling degree, the inflammatory cell infiltration of articular tissue and the increased levels of pro-inflammatory cytokines in MSU crystals-treated rats. Moreover, doliroside A (DA) and medicagenic acid-3-O-beta-D-glucopyranoside (MG) were isolated and identified from EE. The major components of EE, including DA, MG and other triterpenoids, were well confirmed by HPLC. A further study revealed that EE, DA and MG (10, 20, 40MUg/mL) exhibited stronger inhibitory effects on the production of pro-inflammatory cytokines (including interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha) in MSU crystals-treated RAW 264.7 cells. CONCLUSION: These findings indicate that the major triterpenoids present in DF have a remarkable effect on improving symptoms of acute gouty arthritis induced by MSU crystals through inhibiting the production of pro-inflammatory cytokines. PMID- 24060410 TI - [Intervention by a geriatric interdisciplinary health and welfare unit (UFISS) in patients with hip fractures admitted to a Traumatology Department]. PMID- 24060411 TI - [Castleman's disease: a description of a case in octogenarian]. PMID- 24060412 TI - [Development of a risk-mortality index for elderly patients discharged from a geriatric acute care unit]. AB - OBJECTIVES: To identify predictive factors for 6 and 12-months mortality after discharge from a geriatric acute care unit, and from these, derive a mortality risk index. METHODS AND ANALYSIS: Prospective cohort study will be conducted on patients over 70 years-old admitted to a geriatric acute care unit and survived to hospital discharge. The main outcome measure will be mortality at 6 months and 12 months after discharge. Independent variables include sociodemographics, functional status, comorbidities, and clinical and laboratory characteristics. Risk factors associated with mortality will be constructed using multivariate logistic regression models. To build the mortality index, points will be assigned to each risk factor by dividing each beta coefficient in the logistic model by the lowest beta coefficient. A score will be assigned to each subject by adding up the points for each risk factor present in the model. The predictive accuracy of the model will be determined by comparing the predicted versus observed mortality in the study population and calculating the area under the ROC curves in both populations. CONCLUSIONS: The risk-mortality index developed would allow an easy estimate to be made of individual risk of death at 6 months and 12 months after discharge from a geriatric acute care unit, with the purpose of establishing care plans and individualising treatment, according to real objectives. PMID- 24060413 TI - Secretory cell expansion with aging: risk for pelvic serous carcinogenesis. AB - OBJECTIVE: Recent advances suggest that precancerous lesions of pelvic serous carcinoma (PSC) originate from tubal secretory cells. The purpose of our study was to determine if increased number of secretory cells shows difference in age and location and to examine their association with serous neoplasia. MATERIALS AND METHODS: Three groups (benign control, high-risk, and PSC) of patients with matched ages were studied. The age data was stratified into 10-year intervals ranging from age 20 to older than 80. The number of secretory and ciliated cells from both tubal fimbria and ampulla segments was counted by microscopy and immunohistochemical staining methods. The data was analyzed by standard contingency table and Poisson distribution methods after age justification. RESULTS: We found that the absolute number of tubal secretory cells increased significantly with age within each age group. Age remained a significant risk factor for serous neoplasia after age adjustment. In addition, a dramatic increase of secretory cells was observed in high-risk and PSC patients. Further, secretory cell expansion (SCE) was more prevalent than secretory cell outgrowth in both fimbria and ampulla tubal segments and was significantly associated with serous neoplasia (p<0.001). CONCLUSIONS: These findings suggest that SCE could potentially serve as a sensitive biomarker for early serous carcinogenesis within the fallopian tube. Findings support a relationship between serous neoplasia and increased secretory to ciliated cell ratios. Findings also support a relationship between frequency of SCE and increasing age, presence of high-risk factors and co existing serous cancers. PMID- 24060414 TI - Examination of the taste disorder associated with gynecological cancer chemotherapy. AB - OBJECTIVE: Taste disturbance is known to occur as one of the adverse events associated with chemotherapy for gynecological cancer, but few studies have attempted to assess it in practical terms. Therefore, a range of taste tests was performed in gynecological cancer patients. METHODS: The patients were 23 women with gynecological cancer being treated with anticancer agents. Subjective symptoms of altered taste were classified, and objective findings were obtained with the following four gustatory tests: serum trace element (zinc, copper, iron) levels, tongue cultures, electrogustometry, and the filter paper disc tests. RESULTS: Of the 23 subjects, 11 perceived taste disturbances. The serum zinc level was consistently below the lower limit of normal. On tongue cultures, indigenous bacteria were seen in all patients during the entire treatment period. Electrogustometry revealed a tendency for the development of hypogeusia in the chorda tympani nerve field. Conversely, hypergeusia tended to develop gradually in the greater petrosal nerve field. The filter paper disc test revealed a tendency for the development of hypergeusia for sweetness, saltiness, and sourness in the chorda tympani nerve field. Hypogeusia for bitterness tended to develop with increasing number of chemotherapy cycles. The glossopharyngeal nerve field exhibited the same tendencies as observed in the chorda tympani nerve field. In the greater petrosal nerve field, there was a tendency for the development of hypergeusia for sweetness, sourness, and bitterness. CONCLUSIONS: Abnormal test results were seen in half of patients after cancer chemotherapy. PMID- 24060415 TI - The role of surgery in the management of patients with platinum-sensitive recurrent ovarian cancer: survey among Dutch gynecologists and medical oncologists. AB - OBJECTIVE: Evidence of randomized comparative clinical trials on surgery in recurrent platinum-sensitive ovarian cancer is non-existing. Three randomized phase 3 trials are ongoing. The aim of this study is to evaluate the current opinion of Dutch gynecologists and medical oncologists awaiting the results of these three trials. METHODS: A 16-item questionnaire was sent to all gynecologists (N=124) and medical oncologists (N=195) with special interest in gynecologic oncology in the Netherlands. The data were collected and analyzed using descriptive statistics. RESULTS: In total, 80 (65.0%) gynecologists and 67 (34.0%) medical oncologists responded. Among the respondents, 11.3% and 26.9% were not convinced of the benefit of secondary cytoreductive surgery, respectively. For most gynecologists and medical oncologists completeness of primary surgery (74.6% and 75.5%, respectively) and performance status (100% and 98%, respectively) were important factors when considering surgery. For only about 17.5% of all respondents diagnostic laparoscopy before surgery is a prerequisite. Most respondents (81.7% and 87.8%, respectively) would use platinum based chemotherapy with paclitaxel as their agents of choice after surgery. In general medical oncologists settle for a smaller gain in both progression free as well as overall survival than gynecologists. CONCLUSIONS: Although most gynecologists and medical oncologists are already convinced of the usefulness of secondary cytoreductive surgery in certain patients, a better understanding of the real advantages and disadvantages and patient's selection criteria for secondary cytoreductive surgery will be achieved after the completion of three ongoing randomized controlled trials (DESKTOP III, GOG 213 and the SOCceR). PMID- 24060416 TI - Evaluation of the cost of CA-125 measurement, physical exam, and imaging in the diagnosis of recurrent ovarian cancer. AB - OBJECTIVE: Ovarian cancer accounts for 50% of deaths from gynecologic malignancies. We sought to determine the cost of common methods of surveillance of women with ovarian cancer in first clinical remission. The current standard for post treatment surveillance is the National Comprehensive Cancer Network (NCCN) guidelines. METHODS: We retrospectively determined how recurrence was initially detected at our institution and a cost model was created and applied to the United States population to calculate surveillance costs using the Surveillance Epidemiology & End Results (SEER) database. RESULTS: 57% (n=60) of first recurrences were identified by increasing CA 125 level. Routine office visit identified 27% (n=29) of recurrences, and 15% (n=16) were diagnosed initially with CT scan. In 5% (5/105), CT abnormality was the only finding. 95% (100/105) of patients had either elevated CA 125 or office visit findings at time of recurrence. Of the 22,000 women diagnosed with ovarian cancer yearly, 60% (n=13,266) will have advanced disease and are likely to recur. The surveillance cost for this population for 2 years using our model is $32,500,000 using NCCN guidelines and $58,000,000 if one CT scan is obtained. CONCLUSIONS: Our data suggests that following NCCN guidelines will detect 95% of recurrences. An additional $26 million will be needed to identify the 5% of women with recurrence seen on CT only. Post treatment surveillance of ovarian cancer patients contributes significantly to health care costs. Use of CT scan to follow these patients largely increases cost with only a small increase in recurrence detection. PMID- 24060417 TI - Inhibition of hepatocellular carcinoma growth using immunoliposomes for co delivery of adriamycin and ribonucleotide reductase M2 siRNA. AB - The chemotherapy combined with gene therapy has received great attention. We developed targeted LPD (liposome-polycation-DNA complex) conjugated with anti EGFR (epidermal growth factor receptor) Fab' co-delivering adriamycin (ADR) and ribonucleotide reductase M2 (RRM2) siRNA (ADR-RRM2-TLPD), to achieve combined therapeutic effects in human hepatocellular carcinoma (HCC) overexpressing EGFR. The antitumor activity and mechanisms of ADR-RRM2-TLPD were investigated. The results showed that RRM2 expression was higher in HCC than in non-HCC tissue, and RRM2 siRNA inhibited HCC cell proliferation, suggesting that RRM2 is a candidate target for HCC therapy. ADR-RRM2-TLPD delivered ADR and RRM2 siRNA to EGFR overexpressing HCC cells specifically and efficiently both in vitro and in vivo, resulting in enhanced therapeutic effects (cytotoxicity, apoptosis and senescence inducing activity) compared with single-drug loaded or non-targeted controls, including ADR-NC-TLPD (targeted LPD co-delivering ADR and negative control siRNA), RRM2-TLPD (targeted LPD delivering RRM2 siRNA) and ADR-RRM2-NTLPD (non targeted LPD co-delivering ADR and RRM2 siRNA). Mechanism studies showed that p21 is involved in the combined therapeutic effect of ADR-RRM2-TLPD. The average weight of the orthotopic HCC in mice treated with ADR-RRM2-TLPD was significantly lighter than that of mice treated with other controls. Thus, ADR-RRM2-TLPD represents a potential strategy for combined therapy of HCC overexpressing EGFR. PMID- 24060418 TI - Comparison of photopolymerizable thiol-ene PEG and acrylate-based PEG hydrogels for cartilage development. AB - When designing hydrogels for tissue regeneration, differences in polymerization mechanism and network structure have the potential to impact cellular behavior. Poly(ethylene glycol) hydrogels were formed by free-radical photopolymerization of acrylates (chain-growth) or thiol-norbornenes (step-growth) to investigate the impact of hydrogel system (polymerization mechanism and network structure) on the development of engineered tissue. Bovine chondrocytes were encapsulated in hydrogels and cultured under free swelling or dynamic compressive loading. In the acrylate system immediately after encapsulation chondrocytes exhibited high levels of intracellular ROS concomitant with a reduction in hydrogel compressive modulus and higher variability in cell deformation upon compressive strain; findings that were not observed in the thiol-norbornene system. Long-term the quantity of sulfated glycosaminoglycans and total collagen was greater in the acrylate system, but the quality resembled that of hypertrophic cartilage with positive staining for aggrecan, collagens I, II, and X and collagen catabolism. The thiol-norbornene system led to hyaline-like cartilage production especially under mechanical loading with positive staining for aggrecan and collagen II and minimal staining for collagens I and X and collagen catabolism. Findings from this study confirm that the polymerization mechanism and network structure have long-term effects on the quality of engineered cartilage, especially under mechanical loading. PMID- 24060419 TI - Relative impact of uniaxial alignment vs. form-induced stress on differentiation of human adipose derived stem cells. AB - ADSCs are a great cell source for tissue engineering and regenerative medicine. However, the development of methods to appropriately manipulate these cells in vitro remains a challenge. Here the proliferation and differentiation of ADSCs on microfabricated surfaces with varying geometries were investigated. To create the patterned substrates, a maskless biofabrication method was developed based on dynamic optical projection stereolithography. Proliferation and early differentiation of ADSCs were compared across three distinct multicellular patterns, namely stripes (ST), symmetric fork (SF), and asymmetric fork (AF). The ST pattern was designed for uniaxial cell alignment while the SF and AF pattern were designed with altered cell directionality to different extents. The SF and AF patterns generated similar levels of regional peak stress, which were both significantly higher than those within the ST pattern. No significant difference in ADSC proliferation was observed among the three patterns. In comparison to the ST pattern, higher peak stress levels of the SF and AF patterns were associated with up-regulation of the chondrogenic and osteogenic markers SOX9 and RUNX2. Interestingly, uniaxial cell alignment in the ST pattern seemed to increase the expression of SM22alpha and smooth muscle alpha-actin, suggesting an early smooth muscle lineage progression. These results indicate that geometric cues that promote uniaxial alignment might be more potent for myogenesis than those with increased peak stress. Overall, the use of these patterned geometric cues for modulating cell alignment and form-induced stress can serve as a powerful and versatile technique towards controlling differentiation in ADSCs. PMID- 24060420 TI - Carbon nanotube lipid drug approach for targeted delivery of a chemotherapy drug in a human breast cancer xenograft animal model. AB - Carbon nanotube (CNT) possesses excellent properties as a drug carrier. To overcome the challenge of drug functionalization with CNT, we have developed a lipid-drug approach for efficient drug loading onto CNT, in which a long chain lipid molecule is conjugated to the drug molecule so that the lipid-drug can be loaded directly onto CNT through binding of the lipid 'tail' in the drug molecule to CNT surfaces via hydrophobic interactions. In a proof-of-concept study, drug paclitaxel (PTX) was conjugated with a non-toxic lipid molecule docosanol for functionalization with CNT. Folic acid was also conjugated to CNT for targeted drug delivery. High level of drug loading onto SWNT could be achieved by lipid drug approach. Conjugation of FA to SWNT-lipid-PTX led to an increase in cell penetration capacity, and the targeted SWNT-lipid-PTX showed much improved drug efficacy in vitro in comparison to free drug Taxol and non-targeted SWNT-lipid PTX at 48 h (78.5% vs. 31.6% and 59.1% in cytotoxicity respectively, p < 0.01). In vivo analysis using a human breast cancer xenograft mice model also confirmed the improved drug efficacy. The targeted SWNT-lipid-PTX was found non-toxic as evaluated by biochemical analysis using blood samples, and by histological analysis of major organs. PMID- 24060421 TI - The modulation of attachment, growth and morphology of cancerous prostate cells by polyelectrolyte nanofilms. AB - The behaviour of cancerous epithelial prostatic cells (PC3) growing on polyelectrolytes (PE) coatings was compared to the behaviour of immortalized normal prostatic cells (PNT-2). The cell behaviour was evaluated and quantified in terms of initial cell attachment, growth, metabolic activity, morphometry, adhesion, apoptosis and stress related gene expression. Both the anionic PSS (poly(sodium 4-styrenesulphonate))-terminated surface and cationic PAH (poly(allylamine hydrochloride))-terminated surfaces were not cytotoxic. The initial attachment of cells was better on the PAH-terminated surface compared to fibronectin. However, the proliferation rate of PC3 cells was reduced on the PAH terminated surface and slightly increased on the PSS coatings. Only PAH prevented the clustering phenotype of PC3 and reduced the number of focal adhesion points as compared to fibronectin or PSS coatings. In contrast, none of the PE surfaces significantly affected the biological responses of PNT-2 cells. PAH-terminating films provide a tool to preferentially modulate the growth of some cancerous phenotypes, in this case as a micro-environment that reduces the growth of metastatic PC3 cells. PMID- 24060422 TI - Synthesis and orthogonal photopatterning of hyaluronic acid hydrogels with thiol norbornene chemistry. AB - The patterning of chemical and mechanical signals within hydrogels permits added complexity towards their use as cell microenvironments for biomedical applications. Specifically, photopatterning is emerging to introduce heterogeneity in hydrogel properties; however, currently employed systems are limited in the range of properties that can be obtained, as well as in decoupling mechanical properties from changes in chemical signals. Here, we present an orthogonal photopatterning system that utilizes thiol-norbornene chemistry and permits extensive hydrogel modification, including with multiple signals, due to the number of reactive handles accessible for secondary reaction. Hyaluronic acid was functionalized with norbornene groups (NorHA) and reacted with di-thiols to create non-toxic hydrogels with a wide range of mechanical properties. For example, for 4 wt% NorHA at 20% modification, hydrogel mechanics from ~ 1 kPa up to ~ 70 kPa could be obtained by simply changing the amount of crosslinker. By limiting the initial extent of crosslinking, NorHA gels were synthesized with remaining pendent norbornene groups that could be reacted with thiol containing molecules in the presence of light and an initiator, including with spatial control. Secondary reactions with a di-thiol crosslinker changed mechanical properties, whereas reaction with mono-thiol peptides had no influence on the gel elastic modulus. This orthogonal chemistry was used sequentially to pattern multiple peptides into a single hydrogel, demonstrating the robustness of this system for the formation of complex hydrogels. PMID- 24060423 TI - Human progenitor cell recruitment via SDF-1alpha coacervate-laden PGS vascular grafts. AB - Host cell recruitment is crucial for vascular graft remodeling and integration into the native blood vessel; it is especially important for cell-free strategies which rely on host remodeling. Controlled release of growth factors from vascular grafts may enhance host cell recruitment. Stromal cell-derived factor (SDF) 1alpha has been shown to induce host progenitor cell migration and recruitment; however, its potential in regenerative therapies is often limited due to its short half-life in vivo. This report describes a coacervate drug delivery system for enhancing progenitor cell recruitment into an elastomeric vascular graft by conferring protection of SDF-1alpha. Heparin and a synthetic polycation are used to form a coacervate, which is incorporated into poly(glycerol sebacate) (PGS) scaffolds. In addition to protecting SDF-1alpha, the coacervate facilitates uniform scaffold coating. Coacervate-laden scaffolds have high SDF-1alpha loading efficiency and provide sustained release under static and physiologically relevant flow conditions with minimal initial burst release. In vitro assays showed that coacervate-laden scaffolds enhance migration and infiltration of human endothelial and mesenchymal progenitor cells by maintaining a stable SDF 1alpha gradient. These results suggest that SDF-1alpha coacervate-laden scaffolds show great promise for in situ vascular regeneration. PMID- 24060424 TI - Modulation of the foreign body response to implanted sensor models through device based delivery of the tyrosine kinase inhibitor, masitinib. AB - The host foreign body response (FBR) adversely effects the performance of numerous implanted biomaterials especially biosensors, including clinically popular glucose-monitoring sensors. Reactive formation of a fibrous capsule around implanted sensors hinders the transport of essential analytes to the sensor from the surrounding tissue, resulting in loss of glucose response sensitivity and eventual sensor failure. Several strategies have sought to mitigate the foreign body response's effects on CGM sensors through the use of local delivery of pharmaceuticals and biomolecules with limited success. This study describes release of a tyrosine kinase inhibitor - masitinib - from the sensor implant to target tissue resident mast cells as key mediators of the FBR. Model implants are coated with a composite polymer hydrophilic matrix that rapidly dissolves upon tissue implantation to deposit slower-degrading polymer microparticles containing masitinib. Matrix dissolution limits coating interference with sensor function while establishing a local controlled-release delivery depot formulation to alter implant tissue pharmacology and addressing the FBR. Drug efficacy was evaluated in a murine subcutaneous pocket implant model. Drug release extends to more than 30 days in vitro. The resulting FBR in vivo, evaluated by implant capsule thickness and inflammatory cell densities at 14, 21, and 28 days, displays statistically significant reduction in capsule thickness around masitinib-releasing implant sites compared to control implant sites. PMID- 24060425 TI - In vivo stimulation of bone formation by aluminum and oxygen plasma surface modified magnesium implants. AB - A newly developed magnesium implant is used to stimulate bone formation in vivo. The magnesium implant after undergoing dual aluminum and oxygen plasma implantation is able to suppress rapid corrosion, leaching of magnesium ions, as well as hydrogen gas release from the biodegradable alloy in simulated body fluid (SBF). No released aluminum is detected from the SBF extract and enhanced corrosion resistance properties are confirmed by electrochemical tests. In vitro studies reveal enhanced growth of GFP mouse osteoblasts on the aluminum oxide coated sample, but not on the untreated sample. In addition to that a small amount (50 ppm) of magnesium ions can enhance osteogenic differentiation as reported previously, our present data show a low concentration of hydrogen can give rise to the same effect. To compare the bone volume change between the plasma-treated magnesium implant and untreated control, micro-computed tomography is performed and the plasma-treated implant is found to induce significant new bone formation adjacent to the implant from day 1 until the end of the animal study. On the contrary, bone loss is observed during the first week post operation from the untreated magnesium sample. Owing to the protection offered by the Al2O3 layer, the plasma-treated implant degrades more slowly and the small amount of released magnesium ions stimulate new bone formation locally as revealed by histological analyses. Scanning electron microscopy discloses that the Al2O3 layer at the bone-implant interface is still present two months after implantation. In addition, no inflammation or tissue necrosis is observed from both treated and untreated implants. These promising results suggest that the plasma-treated magnesium implant can stimulate bone formation in vivo in a minimal invasive way and without causing post-operative complications. PMID- 24060426 TI - Decontamination of chemical-warfare agent simulants by polymer surfaces doped with the singlet oxygen generator zinc octaphenoxyphthalocyanine. AB - Using reactive singlet oxygen (1O2), the oxidation of chemical-warfare agent (CWA) simulants has been demonstrated. The zinc octaphenoxyphthalocyanine (ZnOPPc) complex was demonstrated to be an efficient photosensitizer for converting molecular oxygen (O2) to 1O2 using broad-spectrum light (450-800 nm) from a 250 W halogen lamp. This photosensitization produces 1O2 in solution as well as within polymer matrices. The oxidation of 1-naphthol to naphthoquinone was used to monitor the rate of 1O2 generation in the commercially available polymer film Hydrothane that incorporates ZnOPPc. Using electrospinning, nanofibers of ZnOPPc in Hydrothane and polycarbonate were formed and analyzed for their ability to oxidize demeton-S, a CWA simulant, on the surface of the polymers and were found to have similar reactivity as their corresponding films. The Hydrothane films were then used to oxidize CWA simulants malathion, 2 chloroethyl phenyl sulfide (CEPS), and 2-chloroethyl ethyl sulfide (CEES). Through this oxidation process, the CWA simulants are converted into less toxic compounds, thus decontaminating the surface using only O2 from the air and light. PMID- 24060427 TI - Pleural ultrasonography versus chest radiography for the diagnosis of pneumothorax: review of the literature and meta-analysis. AB - INTRODUCTION: Ultrasonography is being increasingly utilized in acute care settings with expanding applications. Pneumothorax evaluation by ultrasonography is a fast, safe, easy and inexpensive alternative to chest radiographs. In this review, we provide a comprehensive analysis of the current literature comparing ultrasonography and chest radiography for the diagnosis of pneumothorax. METHODS: We searched English-language articles in MEDLINE, EMBASE and Cochrane Library dealing with both ultrasonography and chest radiography for diagnosis of pneumothorax. In eligible studies that met strict inclusion criteria, we conducted a meta-analysis to evaluate the diagnostic accuracy of pleural ultrasonography in comparison with chest radiography for the diagnosis of pneumothorax. RESULTS: We reviewed 601 articles and selected 25 original research articles for detailed review. Only 13 articles met all of our inclusion criteria and were included in the final analysis. One study used lung sliding sign alone, 12 studies used lung sliding and comet tail signs, and 6 studies searched for lung point in addition to the other two signs. Ultrasonography had a pooled sensitivity of 78.6% (95% CI, 68.1 to 98.1) and a specificity of 98.4% (95% CI, 97.3 to 99.5). Chest radiography had a pooled sensitivity of 39.8% (95% CI, 29.4 to 50.3) and a specificity of 99.3% (95% CI, 98.4 to 100). Our meta-regression and subgroup analyses indicate that consecutive sampling of patients compared to convenience sampling provided higher sensitivity results for both ultrasonography and chest radiography. Consecutive versus nonconsecutive sampling and trauma versus nontrauma settings were significant sources of heterogeneity. In addition, subgroup analysis showed significant variations related to operator and type of probe used. CONCLUSIONS: Our study indicates that ultrasonography is more accurate than chest radiography for detection of pneumothorax. The results support the previous investigations in this field, add new valuable information obtained from subgroup analysis, and provide accurate estimates for the performance parameters of both bedside ultrasonography and chest radiography for pneumothorax evaluation. PMID- 24060428 TI - The effect of platelet-rich plasma on clinical outcomes in lateral epicondylitis. AB - PURPOSE: To evaluate the evidence for application of platelet-rich plasma (PRP) in lateral epicondylitis. METHODS: We carried out a systematic review of the current evidence on the effects of PRP in lateral epicondylitis on clinical outcomes. We performed a comprehensive search of the PubMed, Medline, Cochrane, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Embase databases using various combinations of the commercial names of each PRP preparation and "lateral epicondylitis" (with its associated terms), looking specifically at human studies. Data validity was assessed and collected on clinical outcome. RESULTS: Nine studies met the inclusion criteria, of which 5 were randomized controlled trials. Two cohort studies showed that PRP improved clinical satisfaction scores. One case-control study showed that PRP yielded a significantly greater improvement in symptoms compared with bupivacaine. Two randomized controlled trials compared the effect of injections of PRP and blood. Only 1 of the studies noted a significant difference at the 6-week time point. Three randomized controlled trials compared corticosteroids with PRP. Two of the smaller trials, which had follow-up periods of 6 weeks and 3 months, showed no significant difference between treatment groups. The largest randomized controlled trial found that PRP had significant benefit compared with corticosteroids with regard to pain and Disabilities of the Arm, Shoulder and Hand scores at 1- and 2-year time points. CONCLUSIONS: This review highlights the limited but evolving evidence for the use of PRP in lateral epicondylitis; however, further research is required to understand the concentration and preparation that facilitate the best clinical outcome. Characterizing the timing of the intervention would optimize the health economics behind the decision to treat for the patient and health care provider. LEVEL OF EVIDENCE: Level III, systematic review of Level I to III studies. PMID- 24060429 TI - Neutrophil gelatinase associated lipocalin as an indicator of acute kidney injury and inflammation in burned children. AB - INTRODUCTION: Neutrophil gelatinase associated lipocalin (NGAL) is a novel predictor of acute kidney injury (AKI), which increases with inflammation. We aimed to assess whether serum NGAL (SNGAL) and urine NGAL (UNGAL) can predict AKI in burned children. METHODS: Patients were referred within the 12 h of burn to our center. Serum samples for SNGAL, C-reactive protein (CRP), procalcitonin (PCT) and urine for UNGAL, microalbumine (Umalb), creatinine (Ucr) were obtained at both admission and the 5th day after burn. Blood urea nitrogen (BUN) and serum creatinine (Scr) were examined daily. RESULTS: Twenty-two subjects were enrolled and six (27.2%) of them developed AKI within the 48 h of injury. Burn size and abbreviated burn severity index (ABSI) were significantly increased in patients with AKI. CRP, PCT, SNGAL and UNGAL levels at admission and day 5 were significantly higher in patients with AKI than in those without AKI and controls. Scr was not significant between AKI and non-AKI groups at hospital days 1 and 5. A SNGAL level of 315 ng/ml and a UNGAL level of 100 ng/ml were determined as predictive cut-off values of AKI at admission (sensitivity and specificity: 71.4%, 83.3% and 93.3%, 93.7%, respectively). SNGAL and UNGAL were positively correlated with CRP, PCT, ABSI and Umalb/Ucr. CONCLUSION: SNGAL and UNGAL are good early predictors of AKI in children with severe burn. NGAL might reflect the severity of burn insult and also could be used as an indicator of inflammation in burn children. PMID- 24060430 TI - Effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on parvalbumin- and calbindin-immunoreactive neurons in the limbic system and superior colliculus in rat offspring. AB - Previous studies have reported that maternal exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) induces socioemotional and cognitive disturbances in rat offspring. In the present study, the effects of maternal TCDD exposure on putative inhibitory interneurons were investigated in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), hippocampus (HP), and superior colliculus (SC) in rat offspring. Dams were given TCDD (1.0MUg/kg) on gestational day 15. When offspring rats reached adulthood (14 weeks old), parvalbumin (PV)- and calbindin (Calb)-immunoreactive neurons were immunohistochemically investigated. The histological investigations indicated that the mean area of the mPFC had increased, whereas the mean area of the SC decreased in the exposed male rats. In the exposed female rats, the mean SC area increased. Furthermore, the number and area of PV-immunoreactive neurons increased in the mPFC of the female exposed rats. In contrast, the number of PV immunoreactive neurons in the BLA, HP, and SC decreased in the male and female exposed rats. The number of Calb-immunoreactive neurons decreased in the HP of the male and female exposed rats and the SC of the female exposed rats. Because PV- and Calb-immunoreactive neurons, which are putatively GABAergic, have been implicated in various higher brain functions, the effects of TCDD on socioemotional and cognitive functions might be mediated partly through these alterations in PV- and Calb-immunoreactive neurons in these areas. PMID- 24060431 TI - Perinatal toxicity and carcinogenicity studies of styrene-acrylonitrile trimer, a ground water contaminant. AB - Styrene acrylonitrile (SAN) trimer is a by-product in the production of acrylonitrile styrene plastics. Following a report of a childhood cancer cluster in the Toms River section of Dover Township, New Jersey, SAN Trimer was identified as one of the groundwater contaminants at Reich Farm Superfund site in the township. The contaminants from the Reich Farm site's ground water plume impacted two wells at the Parkway well field. The National Toxicology Program (NTP) studied the toxicity and carcinogenicity of SAN Trimer in rats exposed during their perinatal developmental period and adulthood. The chronic toxicity and carcinogenicity studies in F344/N rats were preceded by 7- and 18-week perinatal toxicity studies to determine the exposure concentrations for the 2 year studies. Subsequently, Fisher 344 pregnant dams were exposed to SAN Trimer containing diet at 400, 800, or 1600ppm concentrations during gestation, nursing and weaning periods of offspring followed by two year of adult exposures to both male and female pups. There was no statistically significant evidence of carcinogenic activity following SAN-Trimer exposure; however, rare neoplasms in the brain and spinal cord were observed in males and to lesser extent in female rats. These incidences were considered within the range of historical background in the animal model used in the current studies. Therefore, the presence of a few rarely occurring CNS tumors in the treated groups were not judged to be associated with the SAN Trimer exposure. The major finding was a dose-related peripheral neuropathy associated with the sciatic nerves in females and spinal nerve roots in males and females thereby suggesting that SAN Trimer is potentially a nervous system toxicant. PMID- 24060432 TI - Evaluation of neurobehavioral and neuroinflammatory end-points in the post exposure period in rats sub-acutely exposed to manganese. AB - Manganese (Mn) can cause manganism, a neurological disorder similar to Parkinson' Disease (PD). The neurobehavioral and neuroinflammatory end-points in the Mn post exposure period have not been studied yet. Rats were injected on alternate days with 8 doses of MnCl2 (25mg/kg) or saline, then euthanized 1, 10, 30 or 70 days following the last dose. Whole-blood (WB) (p<0.05), urine (p<0.05) and brain cortical (p<0.0001) Mn levels were significantly increased 24h after the last dose. Decreases in the rats' ambulation were noted 1, 10 and 30 days after the last Mn dose (p<0.001; p<0.05; p<0.001, respectively) and also in the rearing activity at the four time-points (p<0.05). Cortical glial fibrillary acid protein immunoreactivity (GFAP-ir) was significantly increased at 1, 10, 30 (p<0.0001) and 70 (p<0.001) days after the last Mn dose, as well as tumor necrosis alpha (TNF-alpha) levels (p<0.05) but just on day 1. Taken together, the results show that, during the 70-day clearance phase of Mn, the recovery is not immediate as behavioral alterations and neuroinflammation persist long after Mn is cleared from the cortical brain compartment. PMID- 24060433 TI - What is the value of incorporating tear osmolarity measurement in assessing patient response to therapy in dry eye disease? AB - PURPOSE: To evaluate the correlation between changes in tear osmolarity, symptoms, and corneal fluorescein staining in patients with dry eye disease (DED). DESIGN: Retrospective, clinic-based cohort study. METHODS: In this single institution study, we reviewed the charts of 186 patients with DED from whom we had data on tear osmolarity, symptoms, and corneal fluorescein staining from 2 separate visits. Main outcomes included the correlation of the changes between the 2 visits for tear osmolarity (TearLab system), symptoms (Ocular Surface Disease Index), and corneal fluorescein staining (modified Oxford scheme). For tear osmolarity and corneal fluorescein staining the scores from the eye with highest readings were analyzed. The correlations were repeated on subgroups based on proposed cutoffs for DED severity and on patients' treatment. RESULTS: We found a modest, though statistically significant, correlation between changes in corneal fluorescein staining and symptoms of DED (R = 0.31; P < .001). However, there was no correlation between the recorded change in tear osmolarity and symptoms (R = -0.091; P = .38) or between changes in tear osmolarity and corneal fluorescein staining (R = -0.02; P = .80). This lack of correlation was consistent in all the subgroups studied. A multivariate analysis revealed that changes in corneal fluorescein staining had predictive value on symptom changes, whereas tear osmolarity changes did not. CONCLUSIONS: Changes in tear osmolarity do not correlate significantly with changes in patient symptoms or corneal fluorescein staining in dry eye disease. PMID- 24060434 TI - HCV, ribavirin, and anemia: a new dawn. PMID- 24060436 TI - Downstaging disease in patients with hepatocellular carcinoma outside of Milan criteria: strategies using drug-eluting bead chemoembolization. AB - PURPOSE: To assess downstaging rates in patients with United Network for Organ Sharing stage T3N0M0 hepatocellular carcinoma (HCC) treated with doxorubicin eluting bead transarterial chemoembolization to meet Milan criteria for transplantation. MATERIALS AND METHODS: A single-center retrospective review of 239 patients treated with doxorubicin-eluting bead (DEB) chemoembolization between September 2008 and December 2011 was undertaken. Baseline and follow-up computed tomography or magnetic resonance imaging was assessed for response based on the longest enhancing axial dimension of each tumor (ie, modified Response Evaluation Criteria In Solid Tumors measurements), and medical records were reviewed. Fisher exact tests and exact logistic regression were used to test the association of patient and disease characteristics with downstaging. RESULTS: After exclusions, 22 patients remained in the analysis, 17 of whom (77%) had their HCC downstaged to meet Milan criteria. Among those whose disease was downstaged, seven underwent transplantation, one remained listed for transplantation, six had disease progression beyond Milan criteria, two underwent conventional transarterial chemoembolization, and one underwent radiofrequency ablation. The seven patients who received transplants were still living, but recurrent HCC developed in two. Baseline age (P = .25), Model for End-stage Liver Disease score (P = .77), and alpha-fetoprotein (AFP) level (P = 1.00) were similar between patients with and without downstaged HCC. No associations were observed between the odds of downstaging and sex (P = .21), Child-Pugh class (P = .14), Child-Pugh class controlling for baseline tumor multiplicity (P = .15), Eastern Cooperative Oncology Group performance status (P = 1.00), tumor burden (P = .31), multiple tumors (P = .31), or hepatitis C virus infection (P = 1.00). Fifteen patients who did not receive transplants were alive at 1 year, with two progression-free. Baseline AFP levels differed between those who survived 1 year and those who did not (P = .02), but did not differ by progression-free survival status (P = .62). CONCLUSIONS: T3N0M0 HCC treatment with DEB chemoembolization has a high likelihood (77%) of downstaging the disease to meet Milan criteria. PMID- 24060438 TI - Transarterial embolization with sorafenib in animal livers: a pharmacokinetics study. AB - PURPOSE: To assess the safety and feasibility of the targeted delivery of the antiangiogenic drug sorafenib to the liver using transarterial chemoembolization methodology as a novel approach to hepatocellular carcinoma (HCC) therapy. MATERIALS AND METHODS: Seven healthy New Zealand white rabbits were used in the study. After placement of a catheter in the common hepatic artery, six rabbits were treated with chemoembolization of sorafenib in iodized oil (Lipiodol) (sorafenib dose 0.1 mg/kg), and one rabbit received Lipiodol only. Liquid chromatography tandem mass spectrometry was used to measure the concentration of sorafenib in the peripheral blood and liver tissue 24 hours and 72 hours after treatment. Histochemical staining of the liver sections and biochemical measurements were performed. RESULTS: The administration of sorafenib in Lipiodol emulsions by transarterial chemoembolization resulted in sorafenib concentrations of 794 ng/g +/- 240 and 64 ng/g +/- 15 in the liver tissue 24 hours and 72 hours after treatment. The average liver-to-serum ratios 24 hours and 72 hours after treatment were approximately 14 and 22. The histochemical staining of the liver tissue sections and aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase and total bilirubin concentrations indicated no significant liver damage. CONCLUSIONS: Transarterial chemoembolization with sorafenib in Lipiodol is an effective methodology for the localized delivery of this drug to the liver and has possible practical implications in therapeutic interventions for the treatment of hepatocellular carcinoma. PMID- 24060439 TI - Prediction of thoracic injury severity in frontal impacts by selected anatomical morphomic variables through model-averaged logistic regression approach. AB - This study resulted in a model-averaging methodology that predicts crash injury risk using vehicle, demographic, and morphomic variables and assesses the importance of individual predictors. The effectiveness of this methodology was illustrated through analysis of occupant chest injuries in frontal vehicle crashes. The crash data were obtained from the International Center for Automotive Medicine (ICAM) database for calendar year 1996 to 2012. The morphomic data are quantitative measurements of variations in human body 3-dimensional anatomy. Morphomics are obtained from imaging records. In this study, morphomics were obtained from chest, abdomen, and spine CT using novel patented algorithms. A NASS-trained crash investigator with over thirty years of experience collected the in-depth crash data. There were 226 cases available with occupants involved in frontal crashes and morphomic measurements. Only cases with complete recorded data were retained for statistical analysis. Logistic regression models were fitted using all possible configurations of vehicle, demographic, and morphomic variables. Different models were ranked by the Akaike Information Criteria (AIC). An averaged logistic regression model approach was used due to the limited sample size relative to the number of variables. This approach is helpful when addressing variable selection, building prediction models, and assessing the importance of individual variables. The final predictive results were developed using this approach, based on the top 100 models in the AIC ranking. Model averaging minimized model uncertainty, decreased the overall prediction variance, and provided an approach to evaluating the importance of individual variables. There were 17 variables investigated: four vehicle, four demographic, and nine morphomic. More than 130,000 logistic models were investigated in total. The models were characterized into four scenarios to assess individual variable contribution to injury risk. Scenario 1 used vehicle variables; Scenario 2, vehicle and demographic variables; Scenario 3, vehicle and morphomic variables; and Scenario 4 used all variables. AIC was used to rank the models and to address over-fitting. In each scenario, the results based on the top three models and the averages of the top 100 models were presented. The AIC and the area under the receiver operating characteristic curve (AUC) were reported in each model. The models were re-fitted after removing each variable one at a time. The increases of AIC and the decreases of AUC were then assessed to measure the contribution and importance of the individual variables in each model. The importance of the individual variables was also determined by their weighted frequencies of appearance in the top 100 selected models. Overall, the AUC was 0.58 in Scenario 1, 0.78 in Scenario 2, 0.76 in Scenario 3 and 0.82 in Scenario 4. The results showed that morphomic variables are as accurate at predicting injury risk as demographic variables. The results of this study emphasize the importance of including morphomic variables when assessing injury risk. The results also highlight the need for morphomic data in the development of human mathematical models when assessing restraint performance in frontal crashes, since morphomic variables are more "tangible" measurements compared to demographic variables such as age and gender. PMID- 24060437 TI - Soft-tissue cryoablation in diffuse locations: feasibility and intermediate term outcomes. AB - PURPOSE: To assess whether diverse tumor location(s) show differences in percutaneous cryoablation (PCA) outcomes of cancer control, morbidity, and ablation volume reduction for many soft-tissue tumor types. MATERIALS AND METHODS: A total of 220 computed tomography (CT)- and/or ultrasonography-guided percutaneous cryotherapy procedures were performed for 251 oligometastatic tumors from multiple primary cancers in 126 patients. Tumor location was grouped according to regional sites: retroperitoneal, superficial, intraperitoneal, bone, and head and neck. PCA complications were graded according to Common Terminology Criteria for Adverse Events (version 4.0). Local tumor recurrence and involution were calculated from ablation zone measurements, grouped into 1-, 3-, 6-, 12-, 18 , and 24-month (or later) statistical bins. RESULTS: Tumor and procedure numbers for each site were 75 and 69 retroperitoneal, 76 and 62 superficial, 39 and 32 intraperitoneal, 34 and 34 bone, and 27 and 26 head and neck. Average diameters of tumor and visible ice during ablation were 3.4 and 5.5 cm, respectively. Major complications (ie, grade >3) attributable to PCA occurred after five procedures (2.3%). At 11 months average follow-up (range, 0-82 mo), a 10% total recurrence rate (26 of 251) was noted; three occurred within the ablation zone, for a local progression rate of 1.2%. Average time to recurrence was 4.9 months, and, at 21 months, the initial ablation zone had reduced in volume by 93%. CONCLUSIONS: CT guided PCA is a broadly safe, effective local cancer control option for oligometastatic disease with soft-tissue tumors in most anatomic sites. Other than bowel and nerve proximity, PCA also shows good healing if proper visualization and precautions are followed. PMID- 24060440 TI - Random breath testing in Queensland and Western Australia: examination of how the random breath testing rate influences alcohol related traffic crash rates. AB - In this paper we explore the relationship between monthly random breath testing (RBT) rates (per 1000 licensed drivers) and alcohol-related traffic crash (ARTC) rates over time, across two Australian states: Queensland and Western Australia. We analyse the RBT, ARTC and licensed driver rates across 12 years; however, due to administrative restrictions, we model ARTC rates against RBT rates for the period July 2004 to June 2009. The Queensland data reveals that the monthly ARTC rate is almost flat over the five year period. Based on the results of the analysis, an average of 5.5 ARTCs per 100,000 licensed drivers are observed across the study period. For the same period, the monthly rate of RBTs per 1000 licensed drivers is observed to be decreasing across the study with the results of the analysis revealing no significant variations in the data. The comparison between Western Australia and Queensland shows that Queensland's ARTC monthly percent change (MPC) is 0.014 compared to the MPC of 0.47 for Western Australia. While Queensland maintains a relatively flat ARTC rate, the ARTC rate in Western Australia is increasing. Our analysis reveals an inverse relationship between ARTC RBT rates, that for every 10% increase in the percentage of RBTs to licensed driver there is a 0.15 decrease in the rate of ARTCs per 100,000 licenced drivers. Moreover, in Western Australia, if the 2011 ratio of 1:2 (RBTs to annual number of licensed drivers) were to double to a ratio of 1:1, we estimate the number of monthly ARTCs would reduce by approximately 15. Based on these findings we believe that as the number of RBTs conducted increases the number of drivers willing to risk being detected for drinking driving decreases, because the perceived risk of being detected is considered greater. This is turn results in the number of ARTCs diminishing. The results of this study provide an important evidence base for policy decisions for RBT operations. PMID- 24060441 TI - Endovascular treatment of acute limb ischemia and proximal deep vein thrombosis using rotational thrombectomy: A review of published literature. AB - Acute and subacute ischemia of the lower extremity is still a common reason for amputation. The treatment of this condition includes the well known procedure of local thrombolysis, surgical thrombectomy and, in recent times, percutaneous mechanical thrombectomy procedures such as rotational thrombectomy. However, in randomized studies Fogarty's procedure of surgical thrombectomy was associated with a high rate of perioperative complications and, in part, low technical success rates. On the other hand, local thrombolysis is associated with hemorrhage as well as high costs because of measures requiring substantial resources, such as intensive care monitoring or repeat angiographies. In several studies, the endovascular therapy options of Straub Rotarex(r) and Aspirex(r) systems, both products of technical advancements in the field, were shown to be successful in terms of amputation-free survival. Their use was also associated with low complication rates. The majority of studies were focused on arterial blood flow in the femur. However, in the meantime several registers and studies have shown that the systems can also be effectively used to treat proximal deep vein thrombosis. In the present report we review the current study-based value of rotational thrombectomy in the venous and arterial system. PMID- 24060442 TI - Adherence to osteoporosis regimens among men and analysis of risk factors of poor compliance: a 2-year analytical review. AB - BACKGROUND: To investigate adherence and patient-specific factors associated with poor compliance with osteoporosis regimens among men. METHODS: In this retrospective chart review study, we collected data on male patients with osteoporosis treated in accordance with therapeutic recommendations. Adherence was determined by the compliance and persistence of those patients who had been dispensed an osteoporosis regimen after an index prescription. All osteoporosis regimens were considered equivalent for the purpose of investigating adherence. RESULTS: The prescriptions of 333 males met the inclusion criteria for data collection. The mean age was 68.6 +/- 10.4 years. The median medication possession ratio (MPR, %) at years 1 and 2 was 90.1% (interquartile range (IQR) 19-100) and 53.7% (IQR 10.4-100), respectively; 52.3% of male patients at year 1 and 37.5% at year 2 had good compliance (defined as a MPR?80%). The 1- and 2-year persistence rates were 45.9% and 30.0%, respectively. Patient-specific factors associated with poor compliance (MPR < 80%) during year 1 were first prescriptions given by orthopedists (odds ratio (OR) = 2.67; 95% confidence interval (CI) = 1.58-4.53; adjusted OR = 2.30, 95% CI = 1.26-4.22, p = 0.007). Male patients with rheumatoid arthritis (RA) (OR = 0.22, 95% CI = 0.06-0.78, adjusted OR = 0.19, 95% CI = 0.04-0.81, p = 0.025) and baseline bone mineral density (BMD) measurements (OR = 0.52, 95% CI = 0.32-0.85; adjusted OR = 0.51; 95% CI = 0.28-0.93, p = 0.029) were less likely to have poor compliance. CONCLUSIONS: Adherence to osteoporosis regimens in males was suboptimal in our study. Poor compliance was more likely in prescription of the first anti osteoporotic regimen by an orthopedist. Men with RA and BMD measurements before therapy had a lower risk of non-adherence. Healthcare professionals need to target patients with specific factors to improve adherence to osteoporotic regimens. PMID- 24060443 TI - Maternal coffee consumption during pregnancy and risk of childhood acute leukemia: a metaanalysis. AB - OBJECTIVE: This study was undertaken to explore the association between maternal coffee consumption during pregnancy and childhood acute leukemia (AL). STUDY DESIGN: The PubMed database was used to search studies up to May 5, 2013, and the lists of references of retrieved articles were also screened to identify additional relevant studies. Studies were included if they reported the odds ratio and corresponding 95% confidence interval (CI) of childhood AL, including childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), with respect to maternal coffee consumption during pregnancy. RESULTS: Compared with non/lowest drinkers, the combined odds ratio regarding the relationship of maternal coffee consumption during pregnancy and childhood AL was 1.22 (95% CI, 1.04-1.43) for ever drinkers, 1.16 (95% CI, 1.00-1.34) for low to moderate-level drinkers, and 1.72 (95% CI, 1.37-2.16) for high-level drinkers. When analysis was conducted by subtypes of childhood AL, maternal coffee consumption (high-level drinkers vs non/lowest drinkers) was statistically significantly associated with childhood ALL (1.65; 95% CI, 1.28-2.12) and childhood AML (1.58; 95% CI, 1.20 2.08). We observed the linear dose-response relationship of coffee consumption and childhood AL (P for nonlinearity = .68), including childhood ALL and childhood AML; with increased coffee consumption, the risk of childhood AL increased. CONCLUSION: The findings of the metaanalysis suggest that maternal coffee consumption during pregnancy may increase the risk of childhood AL. Because of limited studies, further prospective studies are urgently needed to explore the adverse effect of coffee consumption on childhood AL. PMID- 24060444 TI - Hospital costs of total vaginal hysterectomy compared with other minimally invasive hysterectomy. AB - OBJECTIVE: The objective of the study was to determine total hospital costs and net hospital income for different types of minimally invasive hysterectomy and financial impact if a subset of patients underwent total vaginal hysterectomy (TVH) instead of their selected procedure. STUDY DESIGN: A retrospective chart review was performed of patients who underwent hysterectomy for benign disease by TVH, laparoscopic assisted vaginal hysterectomy (LAVH), total laparoscopic hysterectomy (TLH), and robotic hysterectomy (RH) between Jan. 1, 2007, and April 30, 2010, at Thomas Jefferson University Hospital. The hospital decision support database was used to calculate net hospital income. A subset of patients with at least 1 prior vaginal delivery, no more than 1 laparotomy, and a uterine size less than 14 weeks who had undergone RH, TLH, or LAVH was identified as potential TVH candidates. The financial impact of performing TVH over the selected hysterectomy was calculated. RESULTS: Three hundred thirty-four cases of minimally invasive hysterectomy were identified. Fifty-five percent were TVH, 33% LAVH, 3% TLH, and 9% RH. Mean total hospital costs for TVH were $7903, $10,069 for LAVH, $11,558 for TLH, and $13,429 for RH (P < .0001). Net hospital income was $1260 for TVH. The hospital incurred losses of $-1306 for LAVH, $-4049 for TLH, and $-4564 for RH (P = .03). Our criteria to determine the mode of hysterectomy increased TVH from 57% to 76% of all minimally invasive hysterectomy. CONCLUSION: Hospital costs were greater with LAVH, TLH, and RH than for TVH. The hospital incurred financial losses with LAVH, TLH, and RH. TVH was the only minimally invasive modality of hysterectomy that generated net hospital income. Our conservative criteria to determine the route of hysterectomy would increase the number of TVHs by more than 30%. PMID- 24060445 TI - Discussion: 'Expectant management of severe preeclampsia,' by Vigil-De Gracia et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Vigil-De Gracia P, Reyes Tejada O, Calle Minaca A, et al. Expectant management of severe preeclampsia remote from term. A randomized, multicenter clinical trial. The MEXPRE Latin Study. Am J Obstet Gynecol 2013;209:425.e1-8. PMID- 24060446 TI - Anthrax toxin receptor 2 promotes human uterine smooth muscle cell viability, migration and contractility. AB - OBJECTIVE: Previously we demonstrated anthrax toxin receptor 2 knockout (Antxr2( /-)) mice are fertile but fail to deliver their pups at term. This parturition defect is associated with overaccumulation of extracellular matrix proteins and decreased myometrial cell content in the uterus. Myometrial cell loss in Antxr2( /-) uterine tissue prompted us to evaluate if ANTXR2 is essential for human uterine smooth muscle cell viability and function. STUDY DESIGN: We subjected human uterine smooth muscle cell to lentiviral-mediated knock down or retroviral mediated overexpression of ANTXR2. Flow cytometry confirmed lentiviral-mediated knock down or retroviral-mediated overexpression in cell lines vs control. Cell behavior and function in control, lentiviral-mediated knock down and retroviral mediated overexpression cells were evaluated for apoptosis via TUNEL assay, migration via Boyden chamber assay and with oxytocin-mediated collagen contraction assays. Matrix metalloproteinase activity was evaluated using gelatin zymography. Cell lines and samples were run in duplicate. Student t test was used for statistical analysis. RESULTS: ANTXR2 is expressed by human uterine smooth muscle cell. Human uterine smooth muscle cell-lentiviral-mediated knock down cells exhibited increased apoptosis (P < .05) and decreased migration (P < .05), although human uterine smooth muscle cell-retroviral-mediated overexpression cells exhibited no change in apoptosis (P = .91) and increased migration (P = .05) vs control. Human uterine smooth muscle cell-lentiviral-mediated knock down cells contracted significantly less than control, although human uterine smooth muscle cell-retroviral-mediated overexpression cells showed no difference in contractility vs control. Matrix metalloproteinase activity 2 activity appeared slightly decreased in human uterine smooth muscle cell-lentiviral-mediated knock down cells and increased in human uterine smooth muscle cell-retroviral-mediated overexpression cells vs control. CONCLUSION: ANTXR2 is expressed by human uterine smooth muscle cell and appears important for normal human uterine smooth muscle cell viability, migration and contractility. Further studies are needed to delineate if ANTXR2 is important for normal and abnormal labor patterns. PMID- 24060447 TI - Expectant management of severe preeclampsia: Vigil-De Gracia et al. AB - The article below summarizes a roundtable discussion of a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Vigil-De Gracia P, Reyes Tejada O, Calle Minaca A, et al. Expectant management of severe preeclampsia remote from term. A randomized, multicenter clinical trial. The MEXPRE Latin Study. Am J Obstet Gynecol 2013;209:425.e1-8. PMID- 24060448 TI - End-stage renal disease after hypertensive disorders in pregnancy. AB - OBJECTIVE: The purpose of this study was to determine the long-term postpartum risk of end-stage renal disease in women with hypertensive disorders in pregnancy. Although most women with hypertensive disorders in pregnancy recover after delivery, some may experience acute renal failure. STUDY DESIGN: We searched Taiwan's National Health Insurance Research Database to identify women with hypertensive disorders in pregnancies and deliveries between 1998 and 2002. All cases were followed for a maximum of 11 years (median, 9 years; interquartile range, 7.79-10.02 years) to estimate the incidence of end-stage renal disease; Cox regression analysis that was adjusted for potential confounding was used to determine the relative risk. RESULTS: Of the 13,633 women with hypertensive disorders in pregnancy, 46 experienced end-stage renal disease. Women with hypertensive disorders in pregnancy had a risk of end-stage renal disease that was 10.64 times greater than did women without them (95% confidence interval [CI], 7.53-15.05). The risk was highest in women with a history of preeclampsia superimposed on chronic hypertension (hazard ratio, 44.72; 95% CI, 22.59-88.51). Women with gestational hypertension had a higher risk of end-stage renal disease than did women without hypertensive disorders in pregnancy (hazard ratio, 5.82; 95% CI, 2.15-15.77). CONCLUSION: Women with hypertensive disorders in pregnancy have a higher risk of postpartum end-stage renal disease, regardless of which type of hypertensive disorder they have. Women with a history of hypertensive disorders in pregnancy are encouraged to have regular postpartum checkups, especially of renal function. PMID- 24060449 TI - The Treatment of Obese Pregnant Women (TOP) study: a randomized controlled trial of the effect of physical activity intervention assessed by pedometer with or without dietary intervention in obese pregnant women. AB - OBJECTIVE: The objective of the study was to assess physical activity intervention assessed by a pedometer with or without dietary intervention on gestational weight gain (GWG) in obese pregnant women by comparing with a control group. STUDY DESIGN: This study was a randomized controlled trial of 425 obese pregnant women comparing 3 groups: (1) PA plus D, physical activity and dietary intervention (n = 142); (2) PA, physical activity intervention (n = 142); and (3) C, a control group receiving standard care (n = 141). All participants routinely in gestational weeks 11-14 had an initial dietary counseling session and were advised to limit GWG to less than 5 kg. Physical activity intervention included encouragement to increase physical activity, aiming at a daily step count of 11,000, monitored by pedometer assessment on 7 consecutive days every 4 weeks. Dietary intervention included follow-up on a hypocaloric Mediterranean-style diet. Instruction was given by a dietician every 2 weeks. The primary outcome measure was GWG, and the secondary outcome measures were complications of pregnancy and delivery and neonatal outcome. RESULTS: The study was completed by 389 patients (92%). Median values of GWG (ranges) were lower in each of the intervention groups (PA plus D, 8.6 [-9.6 to 34.1] kg, and group PA, 9.4 [-3.4 to 28.2] kg) compared with the control group (10.9 [-4.4 to 28.7] kg [PA+D vs C]; P = .01; PA vs C; P = .042). No significant difference was found between the 2 intervention groups. In a multivariate analysis, physical activity intervention decreased GWG by a mean of 1.38 kg (P = .040). The Institute of Medicine's recommendations for GWG were more frequently followed in the intervention groups. CONCLUSION: Physical activity intervention assessed by pedometer with or without dietary follow-up reduced GWG compared with controls in obese pregnant women. PMID- 24060450 TI - Could polymerase chain reaction tests on conjunctival swabs be useful to diagnose herpetic keratitis? AB - INTRODUCTION: Diagnosis of HSV-1 keratitis (HK) is frequently based on clinical findings. Invasive specimens (corneal scrapings, biopsies) are required for microbiological diagnosis. METHODS: Corneal scrapings and conjunctival swabs were collected on patients with/without clinical suspicion of HK from 2007 to 2012. RESULTS: The sensitivity, specificity, positive and negative predictive values for conjunctival swabs by PCR was 77.8, 92.1, 84.4 and 88.3, respectively. DISCUSSION: Conjunctival swabs by PCR may help in the diagnosis of HK, despite the limited sensitivity. PMID- 24060451 TI - A systematic review on robotic pancreaticoduodenectomy. AB - BACKGROUND: Robotic surgery might have several advantages in respect of the laparoscopic approach since might make more feasible the execution of a complex procedure such as pancreaticoduodenectomy (PD). The aim of the present systematic review is to evaluate the current state of the literature on robotic PD. METHODS: A systematic literature search was performed, from January 1st 2003 to July 31st 2012, for studies which reported PDs performed for neoplasm and in which at least one surgical reconstructive or resective step was robotically performed. RESULTS: Thirteen studies, representing 207 patients, met the inclusion criteria. The definition of the robotic approach was heterogeneous since the technique was defined as robotic, robotic-assisted, robot-assisted laparoscopic and robotic hybrid. Resection and reconstruction steps of robotic PD were also heterogeneous combining sequentially different approaches: totally robotic technique, laparoscopic-robotic resection and robotic reconstruction, laparoscopic resection and robotic reconstruction, hand port-assisted laparoscopic resection and robotic reconstruction, laparoscopic-robotic resection and reconstruction through mini laparotomy. As regard the type of PD 66% were classic Whipple operations and 34% pylorus-preserving pancreatoduodenectomies. The management of pancreatic stump was a pancreaticogastrostomy in 23%, end-to-side pancreaticojejunostomy in 67%, and fibrin glue occlusion of the main pancreatic duct in 10% of cases. The overall procedure failure (rates of conversion to open surgery) was 14%. The overall morbidity rate was 58% and the reoperation rate was 7.3%. CONCLUSIONS: There have been an increasing number of recent case series suggesting increased utilization of robotic PD over the past decade. The technical approach is heterogenous. For highly selected patient, robotic PD is feasible with similar morbidity and mortality compared to open or purely laparoscopic approaches. Data on cost analysis are lacking and further studies are needed to evaluate also the cost-effectiveness of the robotic approach for PD in comparison to open or laparoscopic techniques. The current state of the art analysis on robotic DP can be also useful in planning future trials. PMID- 24060452 TI - Asymmetric epoxidation with H2O2 by manipulating the electronic properties of non heme iron catalysts. AB - A non-heme iron complex that catalyzes highly enantioselective epoxidation of olefins with H2O2 is described. Improvement of enantiomeric excesses is attained by the use of catalytic amounts of carboxylic acid additives. Electronic effects imposed by the ligand on the iron center are shown to synergistically cooperate with catalytic amounts of carboxylic acids in promoting efficient O-O cleavage and creating highly chemo- and enantioselective epoxidizing species which provide a broad range of epoxides in synthetically valuable yields and short reaction times. PMID- 24060453 TI - Characterization of two geraniol synthases from Valeriana officinalis and Lippia dulcis: similar activity but difference in subcellular localization. AB - Two geraniol synthases (GES), from Valeriana officinalis (VoGES) and Lippia dulcis (LdGES), were isolated and were shown to have geraniol biosynthetic activity with Km values of 32 uM and 51 uM for GPP, respectively, upon expression in Escherichia coli. The in planta enzymatic activity and sub-cellular localization of VoGES and LdGES were characterized in stable transformed tobacco and using transient expression in Nicotiana benthamiana. Transgenic tobacco expressing VoGES or LdGES accumulate geraniol, oxidized geraniol compounds like geranial, geranic acid and hexose conjugates of these compounds to similar levels. Geraniol emission of leaves was lower than that of flowers, which could be related to higher levels of competing geraniol-conjugating activities in leaves. GFP-fusions of the two GES proteins show that VoGES resides (as expected) predominantly in the plastids, while LdGES import into to the plastid is clearly impaired compared to that of VoGES, resulting in both cytosolic and plastidic localization. Geraniol production by VoGES and LdGES in N. benthamiana was nonetheless very similar. Expression of a truncated version of VoGES or LdGES (cytosolic targeting) resulted in the accumulation of 30% less geraniol glycosides than with the plastid targeted VoGES and LdGES, suggesting that the substrate geranyl diphosphate is readily available, both in the plastids as well as in the cytosol. The potential role of GES in the engineering of the TIA pathway in heterologous hosts is discussed. PMID- 24060454 TI - Deoxysugar pathway interchange for erythromycin analogues heterologously produced through Escherichia coli. AB - The overall erythromycin biosynthetic pathway can be sub-divided into macrocyclic polyketide formation and polyketide tailoring to produce the final bioactive molecule. In this study, the native deoxysugar tailoring reactions were exchanged for the purpose of demonstrating the production of alternative final erythromycin compounds. Both the d-desosamine and l-mycarose deoxysugar pathways were replaced with the alternative d-mycaminose and d-olivose pathways to produce new erythromycin analogues through the Escherichia coli heterologous system. Both analogues exhibited bioactivity against multiple antibiotic-resistant Bacillus subtilis strains. Besides demonstrating an intrinsic flexibility for the biosynthetic system to accommodate alternative tailoring pathways, the results offer an initial attempt to leverage the E. coli platform for erythromycin analogue production. PMID- 24060455 TI - First-in-man randomized clinical trial of renal denervation for atrial arrhythmia raises concern. PMID- 24060456 TI - No support for renal denervation in a meta-analysis. PMID- 24060457 TI - Preparation, characterization and antioxidant activities of polymannuronic acid phosphate, H-phosphonate and sulfate. AB - Three derivatives of polymannuronic acid (PM) were prepared by chemically polyanionic modification. PM was substituted with phosphate (OPO3(2-)), H phosphonate (OPO2H(-)) and sulfate (OSO3(-)) groups with the degree of substitution (DS) of 0.41, 1.42 and 1.04, respectively. The structures of all PM derivatives were characterized by FT-IR, (31)P NMR and (13)C NMR spectroscopy. The weight average molecular weight (Mw) was determined by high performance gel permeation chromatography (HPGPC). The antioxidant activities of PM and its derivatives were evaluated in vitro. The results indicated that both phosphate and H-phosphonate groups improved the hydroxyl radical scavenging activity, while sulfate group enhanced the superoxide radical scavenging activity. However, all of the derivatives scavenged DPPH less effectively than PM. The mechanism for how the different anionic substituent groups influenced the antioxidant activities was discussed. PMID- 24060458 TI - Psychosocial stress induces hyperphagia and exacerbates diet-induced insulin resistance and the manifestations of the Metabolic Syndrome. AB - Stress and hypercaloric food are recognized risk factors for obesity, Metabolic Syndrome (MetS) and Type 2 Diabetes (T2D). Given the complexity of these metabolic processes and the unavailability of animal models, there is poor understanding of their underlying mechanisms. We established a model of chronic psychosocial stress in which subordinate mice are vulnerable to weight gain while dominant mice are resilient. Subordinate mice fed a standard diet showed marked hyperphagia, high leptin, low adiponectin, and dyslipidemia. Despite these molecular signatures of MetS and T2D, subordinate mice fed a standard diet were still euglycemic. We hypothesized that stress predisposes subordinate mice to develop T2D when synergizing with other risk factors. High fat diet aggravated dyslipidemia and the MetS thus causing a pre-diabetes-like state in subordinate mice. Contrary to subordinates, dominant mice were fully protected from stress induced metabolic disorders when fed both a standard- and a high fat-diet. Dominant mice showed a hyperphagic response that was similar to subordinate but, unlike subordinates, showed a significant increase in VO2, VCO2, and respiratory exchange ratio when compared to control mice. Overall, we demonstrated a robust stress- and social status-dependent effect on the development of MetS and T2D and provided insights on the physiological mechanisms. Our results are reminiscent of the effect of the individual socioeconomic status on human health and provide an animal model to study the underlying molecular mechanisms. PMID- 24060459 TI - Charge storage in polymer acid-doped polyaniline-based layer-by-layer electrodes. AB - Polymeric electrodes that can achieve high doping levels and store charge reversibly are desired for electrochemical energy storage because they can potentially achieve high specific capacities and energies. One such candidate is the polyaniline:poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (PANI:PAAMPSA) complex, a water-processable complex obtained via template polymerization that is known to reversibly achieve high doping levels at potentials of up to 4.5 V versus Li/Li+. Here, for the first time, PANI:PAAMPSA is successfully incorporated into layer-by-layer (LbL) electrodes. This processing technique is chosen for its ability to blend species on a molecular level and its ability to conformally coat a substrate. Three different polyaniline-based LbL electrodes comprised of PANI/PAAMPSA, PANI/PANI:PAAMPSA, and linear poly(ethylenimine)/PANI:PAAMPSA are compared in terms of film growth, charge storage, and reversibility. We found that the reversibility of PANI:PAAMPSA is retained within the LbL electrodes and that the PANI/PANI:PAAMPSA electrode exhibits the best performance in terms of capacity and cycle life. These results provide general guidelines for the assembly of PANI:PAAMPSA in LbL films and also demonstrate their potential as electrochemically active components in electrodes. PMID- 24060460 TI - Legal Medicine Information System using CDISC ODM. AB - We have developed a new database system for forensic autopsies, called the Legal Medicine Information System, using the Clinical Data Interchange Standards Consortium (CDISC) Operational Data Model (ODM). This system comprises two subsystems, namely the Institutional Database System (IDS) located in each institute and containing personal information, and the Central Anonymous Database System (CADS) located in the University Hospital Medical Information Network Center containing only anonymous information. CDISC ODM is used as the data transfer protocol between the two subsystems. Using the IDS, forensic pathologists and other staff can register and search for institutional autopsy information, print death certificates, and extract data for statistical analysis. They can also submit anonymous autopsy information to the CADS semi automatically. This reduces the burden of double data entry, the time-lag of central data collection, and anxiety regarding legal and ethical issues. Using the CADS, various studies on the causes of death can be conducted quickly and easily, and the results can be used to prevent similar accidents, diseases, and abuse. PMID- 24060461 TI - Postmortem ventilation in cases of penetrating gunshot and stab wounds to the chest. AB - We sought to determine the effect of postmortem ventilation in combination with a suction pump in cases showing penetrating trauma to the chest with haemo- and/or pneumothorax, for better evaluation of the lungs in postmortem computed tomography (PMCT). The study included 6 subjects (1 female, 5 male; age 32 67years) with a penetrating gunshot or stab wound to the chest and consecutive pneumo- and/or haemothorax. The pneumo- and haemothorax were evacuated by a suction pump, and postmortem ventilation was applied using a home care ventilator. PMCT images with and without postmortem ventilation were compared, as well as the autopsy results. In three cases haemo- and pneumothorax was clearly reduced. Postmortem ventilation led to distinct re-expansion of the lungs in two cases, and to re-expansion of single lung lobes in two cases with shotgun injuries. No visible effect was seen in the remaining two cases, because of extensive destruction of lung tissue and blood aspiration. In two cases the injuries sustained in the individual lung lobes were successfully located during postmortem ventilation. The bullet channel was apparent in one case; in another case, injury of the pericardium became visible by generating pneumopericardium. The present method is capable of improving evaluation of the postmortem lung in the presence of single stab or gunshot wounds and if there is no severe destruction of the respiratory system and aspiration. Forensic autopsy should still be considered as the gold standard, although in some cases the present method might be helpful, especially where no autopsy is required. PMID- 24060462 TI - Simulation in nursing education: an evaluation of students' outcomes at their first clinical practice combined with simulations. AB - BACKGROUND: Nursing students frequently report feeling anxiety prior to entering their first clinical setting. Education through simulations reduces the anxiety level of nursing students and contributes to various outcomes for students' learning processes. OBJECTIVES: The purpose of this study was twofold: to evaluate the effectiveness of simulations in reducing anxiety and promoting self confidence, caring ability, and satisfaction with simulation; and to investigate the predictors and mediators for caring efficacy among nursing students. The authors examined concepts that have been studied only minimally in the literature. DESIGN: A descriptive quantitative study. SETTING: Zefat Academic College, Nursing Department, Zefat, Israel. PARTICIPANTS: 61 second-year nursing students at their first clinical practice. METHOD: Data was collected before the first clinical and simulations practice (T1), and four months later (T2) after they had finished their first clinical practice in a hospital setting. Hierarchical linear regression was applied to examine the research hypotheses. RESULTS: The results revealed that anxiety scores decreased, while self confidence and caring ability scores increased after using simulations. Caring efficacy was negatively predicted by anxiety, and positively with self confidence, caring ability and satisfaction with simulation. CONCLUSIONS: The use of simulations before and during nursing students' first clinical practice is a useful and effective learning strategy. Nursing educators should be aware of the high level of anxiety among nursing students during their first clinical practice, and design a program to reduce the anxiety through simulations. PMID- 24060463 TI - Metabolic endocrine factors involved in spawning recovery and rematuration of iteroparous female rainbow trout (Oncorhynchus mykiss). AB - To determine how energy balance affects metabolic hormones hypothesized to play a role in the onset of a new reproductive cycle in iteroparous salmonids, food availability after spawning was restricted in female rainbow trout. These fish were compared with a control group that was fed a standard brood stock ration. Bodyweight, length, and muscle lipid content were determined, and blood was collected from fish at regular intervals; a subset of fish from each group was sacrificed at each sampling time for the collection of liver and ovary tissue, and to calculate hepatosomatic index (HSI) and gonadosomatic index (GSI). Plasma hormone levels were quantified by radioimmunoassay, and tissue gene expression levels were analyzed using q-RT-PCR. The experiment was conducted twice, using two-year-old and three-year-old post-spawned fish. Food-restriction arrested ovarian growth and development within 15-20 weeks, as evidenced by lower GSI in restricted-ration fish. Food restriction also reduced Fulton's condition factor, muscle lipid content, and specific growth rate from one month onward, and reduced HSI after 3 months. In the liver, insulin-like growth factor (igf1 and igf2) gene expression was reduced in three-year-old food-restricted fish within 2 months; however, no effect of ration on igf1 or igf2 expression was detected in two-year old fish. In both years, IGF binding protein-1 (igfbp1) gene expression decreased over time in both treatment groups. Liver leptin (slepA1) gene expression was lower in two-year-old food-restricted fish at 4 months. These results show that this feed restriction regime arrested reproductive development and affected factors associated with energy balance purported to play a role in initiating reproductive development within 2-4months after spawning. PMID- 24060464 TI - [Renal denervation for resistant hypertension without general anesthesia: advantage of a MEOPA morphine protocol. Preliminary experience]. AB - Renal denervation using the technique of radiofrequency is used only recently for the treatment of resistant hypertension. Normally, it is done under general anesthesia because the ablation point technique is painful. We suggest an alternative to general anesthesia comprising an association of morphin 0.1mg/kg IV to MEOPA (gas combining oxygen and azot protoxyd) delivered through an oxygen mask. Our series includes 12 consecutive patients treated between October 2011 and June 2013, the first five patients (group 1) have received only an hydroxizin and morphin sedation. Every five have felt the ablation painful, in two cases bearable pain (EVA<5), in three cases intense (EVA>5) pain leading to increasing doses of morphin, (total dose of 0.25mg/kg in two cases, 0.17mg in one case). For the seven following patients, a protocol including hydroxyzin, morphin and MEOPA given through a mask has been set up. Only one patient has felt a mild pain (EVA 5) leading to an increasing dose of morphin (total dose 0.17mg/kg). None of the six other patients has felt any pain during the procedure. The average dose of morphin is 0.17mg/kg in group 1, 0.11mg/kg in group 2. This is a preliminary study; if confirmed, it will allow a lot of hospitals without on-site possibilities of general anesthesia, to realize such procedures. CONCLUSION: regarding pain, the procedure of renal ablation was well tolerated for six among seven patients receiving the association MEOPA and IV morphin. In contrast, in the five patients treated only with IV morphin, we observed a less good tolerance to pain and the need to increase the doses of IV morphin. PMID- 24060465 TI - [Acute coronary syndrome in elderly patients: experience of Aix-en-Provence General Hospital]. AB - INTRODUCTION: Cardiovascular causes are the first causes of death in elderly patients. Nevertheless, elderly patients are underrepresented in randomized studies of acute coronary syndromes although treatment of ACS for elderly patients has specificities that need special attention. METHODS AND RESULTS: To discuss these specificities, we realized a retrospective study involving patients aged more than 75years old and admitted for ACS in the cardiology department of Aix-en-Provence General Hospital in the first six months of 2010 (Group A) and 2012 (Group B) which we compared. Initial presentation was chest pain in only 78.6% of Group A versus 81.6% in Group B (NS), renal insufficiency was found in 41.4% of the patients of Group A versus 50.5% of the patients in Group B (NS), anaemia was found in 34.3% of Group A patients versus 40.2% of Group B (NS), invasive strategy is less systematic with 74.2% of Group A patients having a revascularization versus 73.6% of Group B (NS), Drug Eluting Stents were less frequently used with 14.3% of Group A patients versus 14.7% of Group B (NS), radial access was used for angioplasty in 61.2% of Group A patients versus 80.2% of Group B (P=0.02), unfractioned heparin was used in 74.3% of the cases in Group A versus 68% in Group B (NS). DISCUSSION AND CONCLUSION: Acute coronary syndrome of the elderly patients has numerous specificities, first there are frequent unusual presentation making diagnosis more difficult, second they have frequent co morbidities making them frail patients with higher risk of hemorrhagic complications and lesser tendency to invasive evidence based treatment. In the absence of specific recommendations, their treatment should not differ from younger patients. This work allowed us also to evaluate our professional practices in order to improve them; we note a positive evolution with the significant raise in the use of radial access, invasive strategy though should be more systematic and use of low molecular weight heparin and Fondaparinux should be more frequent. PMID- 24060466 TI - [Platypnea-orthodeoxia syndrome: case report]. AB - We report the case of an 80-year-old woman with symptomatic postural hypoxaemia caused by a right-to-left shunt through a patent foramen ovale. The hypoxaemia was enhanced by the supine position and disappeared in upright position. Potential mechanisms underlying postural variations of the shunt seemed to be similar to those describe in platypnea-orthodeoxia syndrome. Patient became asymptomatic after shunt resolution. PMID- 24060467 TI - 7,8- and 5,8-Linoleate diol synthases support the heterolytic scission of oxygen oxygen bonds by different amide residues. AB - Linoleate diol synthases (LDS) are fungal dioxygenase-cytochrome P450 fusion enzymes. They oxidize 18:2n-6 sequentially to 8R-hydroperoxylinoleic acid (8R HPODE) and 7S,8S- or 5S,8R-dihydroxylinoleic acids (DiHODE) by intramolecular oxygen transfer. The P450 domains contain a conserved sequence, Ala-Asn-Gln-Xaa Gln, presumably located in the I-helices. The Asn938Leu replacement of 7,8-LDS of Gaeumannomyces graminis virtually abolished and the Asn938Asp and Asn938Gln replacements reduced the hydroperoxide isomerase activity. Gln941Leu and Gln941Glu substitutions had little effects. Replacements of the homologous Asn(887) and Gln(890) residues of 5,8-LDS of Aspergillus fumigatus yielded the opposite results. Asn887Leu and Asn887Gln of 5,8-LDS retained 5,8-DiHODE as the main metabolite with an increased formation of 6,8- and 8,11-DiHODE, whereas Gln890Leu almost abolished the 5,8-LDS activity. Replacement of Gln(890) with Glu also retained 5,8-DiHODE as the main product, but shifted oxygenation from C-5 to C-7 and C-11 and to formation of epoxyalcohols by homolytic scission of 8R-HPODE. P450 hydroxylases usually contain an "acid-alcohol" pair in the I-helices for the heterolytic scission of O2 and formation of compound I (Por(+) Fe(IV)=O) and water. The function of the acid-alcohol pair appears to be replaced by two different amide residues, Asn(938) of 7,8-LDS and Gln(890) of 5,8-LDS, for heterolysis of 8R-HPODE to generate compound I. PMID- 24060468 TI - Added value of cardiac magnetic resonance in etiological diagnosis of ventricular arrhythmias. AB - INTRODUCTION: Cardiac magnetic resonance (CMR) imaging is increasingly important in the diagnostic work-up of a wide range of heart diseases, including those with arrhythmogenic potential. OBJECTIVE: To assess the added value of CMR in etiological diagnosis of ventricular arrhythmias after an inconclusive conventional investigation. METHODS: Patients undergoing CMR between 2005 and 2011 for investigation of ventricular arrhythmias were included (n=113). All had documented arrhythmias. Those with a definite diagnosis from a previous investigation and those with evidence of coronary artery disease (acute coronary syndrome, typical angina symptoms, increase in biomarkers or positive stress test) were excluded. CMR results were considered relevant when they fulfilled diagnostic criteria. RESULTS: Of the 113 patients, 57.5% were male and mean age was 41.7 +/- 16.2 years. Regarding the initial arrhythmia, 38.1% had ventricular fibrillation/sustained ventricular tachycardia (VF/VT) and 61.9% had less complex ventricular ectopy. CMR imaging showed criteria of a specific diagnosis in 42.5% of patients, was totally normal in 36.3%, and showed non-specific alterations in the remainder. In VF/VT patients, specific criteria were found in 60.4%, and in 31.4% of those with less complex ectopy. The most frequent diagnoses were arrhythmogenic right ventricular dysplasia, ventricular non-compaction and myopericarditis. It is worth noting that, although there was no evidence of previous coronary artery disease, 6.2% of patients had a late gadolinium enhancement distribution pattern compatible with myocardial infarction. CONCLUSION: CMR gives additional and important information in the diagnostic work up of ventricular arrhythmias after an inconclusive initial investigation. The proportion of patients with diagnostic criteria was 42.5% (60.0% in those with VF/VT), and CMR was completely normal in 36.6%. PMID- 24060469 TI - Predicting fluid responsiveness during infrarenal aortic cross-clamping in pigs. AB - OBJECTIVE: Infrarenal aortic cross-clamping (ACC) induces hemodynamic disturbances that may affect respiratory-induced variations in stroke volume and, therefore, affect the ability of dynamic parameters such as pulse-pressure variation (PPV) to predict fluid responsiveness. Since this issue has not been investigated yet to authors' knowledge, the hypothesis was tested that ACC may change PPV and impair its ability to predict fluid responsiveness. DESIGN: Prospective laboratory experiment. SETTING: A university research laboratory. PARTICIPANTS: Nineteen anesthetized and mechanically ventilated pigs. INTERVENTIONS: Two courses of volume expansion were performed using 500 mL of saline before and during ACC. Animals were monitored using a systemic arterial catheter, and a pulmonary arterial catheter (stroke volume, central venous pressure, pulmonary arterial occlusion pressure). Animals were defined as responders to volume expansion if stroke volume increased >= 15%. RESULTS: Before ACC, 13 animals were responders. Fluid responsiveness was predicted by a PPV >= 14% with a sensitivity of 77% (95% CI = 46%-95%) and a specificity of 83% (95% CI = 36%-97%). The area under the receiver operating characteristic curve was 0.90(95% CI = 0.67-0.99) and was higher than those generated for central venous pressure and pulmonary arterial occlusion pressure. ACC induced an increase in PPV (p<0.0005). During ACC, 8 animals were responders. An 18% PPV threshold discriminated between responders and non-responders to volume expansion, with a sensitivity of 87% (95% CI = 47%-98%) and a specificity of 54% (95% CI = 23% 83%). The area under the receiver operating characteristic curve was 0.72 (95% CI = 0.47-0.90) and was not different from those generated for central venous pressure and pulmonary arterial occlusion pressure. CONCLUSIONS: ACC induced a significant increase in PPV and reduced its ability to predict fluid responsiveness. PMID- 24060470 TI - K-Map: connecting kinases with therapeutics for drug repurposing and development. AB - Protein kinases play important roles in regulating signal transduction in eukaryotic cells. Due to evolutionary conserved binding sites in the catalytic domain of the kinases, most inhibitors that target these sites promiscuously inhibit multiple kinases. Quantitative analysis can reveal complex and unexpected interactions between protein kinases and kinase inhibitors, providing opportunities for identifying multi-targeted inhibitors of specific diverse kinases for drug repurposing and development. We have developed K-Map-a novel and user-friendly web-based program that systematically connects a set of query kinases to kinase inhibitors based on quantitative profiles of the kinase inhibitor activities. Users can use K-Map to find kinase inhibitors for a set of query kinases (obtained from high-throughput 'omics' experiments) or to reveal new interactions between kinases and kinase inhibitors for rational drug combination studies. AVAILABILITY AND IMPLEMENTATION: K-Map has been implemented in python scripting language and the website is freely available at: http://tanlab.ucdenver.edu/kMap. PMID- 24060471 TI - Investigation of the kinetics of oil-suspended particulate matter aggregation. AB - The process of oil-suspended particulate matter aggregation (OSA) has been recognized by the oil spill remediation community to enhance the natural cleansing of oiled shorelines. A laboratory study was conducted to investigate the kinetics of OSA formation under various mixing intensities using the standard reference material 1941b and Arabian heavy crude oil. The results showed that formation of OSAs increased exponentially with mixing time and reached a maximum within 5h. The maximum oil trapping efficiency increased from 24% to 47%, and the required shaking time decreased from 4.5 to 1.2h as the sediment concentration and mixing energy increased. The maximum oil-to-sediment ratio reached 0.24-0.68 g oil/g sediment within 5h. Most of the formed OSAs were solid OSAs and single droplet OSAs with low mixing energies, and multi-droplet OSAs with high mixing energies. The sizes of the dispersed oil droplets and OSAs were also investigated. PMID- 24060472 TI - Is Jamaica a good model for understanding Caribbean coral reef dynamics? AB - Caribbean reefs have experienced unprecedented changes in the past 40 years. A major hypothesis to explain shifts in reef community composition relates to declining herbivory. This hypothesis was developed largely based on observations of Jamaican reefs from the 1980s onward, but it is widely held to be relevant regionally. We use a region-wide dataset on benthic composition to examine how well the pattern of ecological change on Jamaican reefs is mirrored by other Caribbean reefs. The extent to which macroalgal cover exceeds coral cover on Jamaican reefs is an order of magnitude more extreme than seen elsewhere. We suggest that Jamaican reefs are not representative of the degradation trajectory of Caribbean reefs and management based on the Jamaican experience may not be relevant elsewhere. However, the recovery of Jamaican reefs following the return of urchins gives us hope that Caribbean reefs are more resilient to catastrophic disturbances than previously thought. PMID- 24060473 TI - Heavy metals distribution and contamination in surface sediments of the coastal Shandong Peninsula (Yellow Sea). AB - Selected heavy metals (Cr, Cu, Ni, Pb and Zn) in surface sediments from the coastal Shandong Peninsula (Yellow Sea) have been determined to evaluate the spatial distribution and potential ecological risk. Results showed that heavy metal concentrations in the sediments generally met the criteria of China Marine Sediment Quality. However, both the enrichment factor (EF) and geoaccumulation index (Igeo) values suggested the elevation of Pb concentration in the region. Based on the effect-range classification (TEL-PEL SQGs), Cr, Cu and Ni were likely to pose environment risks. Spatial distribution of ecotoxicological index (mean-PEL-quotient) suggested that most of the surface sediments have a 21% probability of being toxic. Similar results were also obtained by pollution load index (PLI). The spatial distribution pattern of heavy metal in surface sediments is a basis for undertaking appropriate action to protect marine sediment quality. PMID- 24060475 TI - The cross-cultural bilingual brain: comment on "The bilingual brain: flexibility and control in the human cortex" by Buchweitz and Prat. PMID- 24060474 TI - Delinquency, depression, and substance use disorder among child welfare-involved adolescent females. AB - Although adolescents with delinquency are known to have higher-than-average rates of depression or substance use disorder (SUD), research on the topic is inconsistent. It remains unclear weather depression or SUD leads to delinquency, whether delinquency leads to depression or SUD, or whether there is bi directionality. Utilizing the National Survey of Child and Adolescent Well-Being (Wave I: 2008-2009; Wave II: 18 months later: N=5872), we used logistic regression to predict depression from delinquency (and vice versa), and SUD from delinquency (and vice versa). After inclusion of control variables, we found that females with minor theft in Wave I were more than 4 times as likely (adjusted odds ratio [aOR]=4.34; 95% CI: 1.10-17.16) as females without minor theft to be depressed in Wave II, and those with public disorder in Wave I were almost 3 times as likely (aOR=2.74; 95% CI: 1.03-7.30) as those without public disorder to have SUD in Wave II. Overall delinquency also predicted depression or SUD, and SUD predicted delinquency. Practitioners could address risk for depression or SUD among child welfare-involved adolescent females by focusing on overall delinquency or on specific types of delinquency (minor theft for depression and public disorder for SUD) and by offering interventions (e.g., cognitive behavioral psychotherapy) that have been shown to be effective in preventing depression or SUD. In addition, with respect to our finding that SUD predicts delinquency among adolescent females, practitioners can help prevent delinquency by offering interventions (e.g., intensive outpatient treatments) that have well documented effectiveness in addressing SUD. PMID- 24060476 TI - Cytocompatibility of pure metals and experimental binary titanium alloys for implant materials. AB - OBJECTIVE: This study was performed to evaluate the biocompatibility of nine types of pure metal ingots (Ag, Al, Cr, Cu, Mn, Mo, Nb, V, Zr) and 36 experimental titanium (Ti) alloys containing 5, 10, 15, and 20 wt% of each alloying element. METHODS: The cell viabilities for each test group were compared with that of CP-Ti using the WST-1 test and agar overlay test. RESULTS: The ranking of pure metal cytotoxicity from most potent to least potent was as follows: Cu>Al>Ag>V>Mn>Cr>Zr>Nb>Mo>CP-Ti. The mean cell viabilities for pure Cu, Al, Ag, V, and Mn were 21.6%, 25.3%, 31.7%, 31.7%, and 32.7%, respectively, which were significantly lower than that for the control group (p<0.05). The mean cell viabilities for pure Zr and Cr were 74.1% and 60.6%, respectively (p<0.05). Pure Mo and Nb demonstrated good biocompatibility with mean cell viabilities of 93.3% and 93.0%, respectively. The mean cell viabilities for all the Ti-based alloy groups were higher than 80% except for Ti-20 Nb (79.6%) and Ti-10 V (66.9%). The Ti-10 Nb alloy exhibited the highest cell viability (124.8%), which was higher than that of CP-Ti. Based on agar overlay test, pure Ag, Cr, Cu, Mn, and V were ranked as 'moderately cytotoxic', whereas the rest of the tested pure metals and all Ti alloys, except Ti-10 V (mild cytotoxicity), were ranked as 'noncytotoxic'. SIGNIFICANCE: The results obtained in this study can serve as a guide for the development of new Ti-based alloy implant systems. PMID- 24060477 TI - GPR119 agonists: a promising approach for T2DM treatment? A SWOT analysis of GPR119. AB - Ever since its advent as a promising therapeutic target for type 2 diabetes mellitus (T2DM), G-protein-coupled receptor 119 (GPR119) has received much interest from the pharmaceutical industry. This interest peaked in June 2010, when Sanofi-Aventis agreed to pay Metabolex (Cymabay Therapeutics) US$375 million for MBX-2982, which was a representative orally active GPR119 agonist. However, Sanofi-Aventis opted to terminate the deal in May 2011 and another leading GPR119 agonist, GSK1292263, had a loss of efficacy during its clinical trial. In this review, I discuss the pros and cons of GPR119 through a strengths, weaknesses, opportunities, and threats (SWOT) analysis and propose development strategies for the eventual success of a GPR119 agonist development program. PMID- 24060478 TI - Theoretical investigations on molecular structure, vibrational spectra, HOMO, LUMO, NBO analysis and hyperpolarizability calculations of thiophene-2 carbohydrazide. AB - The Fourier-Transform infrared and Fourier-Transform Raman spectra of thiophene-2 carbohydrazide (TCH) was recorded in the region 4000-400 cm(-1) and 3500-100 cm( 1). Quantum chemical calculations of energies, geometrical structure and vibrational wavenumbers of TCH were carried out by DFT (B3LYP) method with 6 311++G(d,p) as basis set. The difference between the observed and scaled wavenumber values of most of the fundamentals is very small. Stability of the molecule arising from hyper conjugative interaction and charge delocalization has been analyzed using natural bond orbital (NBO) analysis. UV spectrum was measured in different solvent. The energy and oscillator strength are calculated by Time Dependant Density Functional Theory (TD-DFT) results. The calculated HOMO and LUMO energies also confirm that charge transfer occurs within the molecule. The complete assignments were performed on the basis of the potential energy distribution (PED) of vibrational modes, calculated with scaled quantum mechanics (SQM) method. Finally the theoretical FT-IR, FT-Raman, and UV spectra of the title molecule have also been constructed. PMID- 24060479 TI - Synthesis, spectral characterization and catalytic activity of Co(II) complexes of drugs: crystal structure of Co(II)-trimethoprim complex. AB - New Co(II) complexes with drugs such as trimethoprim (TMP), cimetidine (CTD), niacinamide (NAM) and ofloxacin (OFL) as ligands were synthesized. The complexes were characterized by analytical analysis, various spectral techniques such as FT IR, UV-Vis, magnetic measurements and molar conductivity. The magnetic susceptibility results coupled with the electronic spectra suggested a tetrahedral geometry for the complexes. The coordination mode of trimethoprim ligand and geometry of the complex were confirmed by single crystal X-ray studies. In this complex the metal ion possesses a tetrahedral geometry with two nitrogen atom from two TMP ligands and two chloride ions coordinated to it. The catalytic activity of the complexes in aryl-aryl coupling reaction was screened and the results indicated that among the four complexes [Co(OFL)Cl(H2O)] exhibited excellent catalytic activity. PMID- 24060480 TI - Comprehensive evaluation of antioxidant activity: a chemometric approach using principal component analysis. AB - A novel chemometric approach is described for evaluating the radical scavenging activity of biogenic amine related compounds by using the 2,2-diphenyl-1 picrylhydrazyl (DPPH) procedure and principal component analysis (PCA) tool. By a comprehensive chemometric investigation of variations in the radical scavenging profiles provided by the full-range UV-Vis spectra for different test duration and different relative concentrations (different molar ratio - [AH]/[DPPH]) of the investigated compounds, new antioxidant activity evaluation parameters were proposed. The new proposed parameters (PC1, mPC1, maxPC1) are in good agreement with the reference DPPH results (% RSA and IC50 derived from the reference DPPH test), obtained for the investigated amines and reference antioxidants. Much more, the PCA profiles are better patterns for the comprehensive characterization of radical scavenging activity of compounds, allowing visualization of complex information by a simple graphical representation and underlying the (dis)similarity of compounds related both to the reaction kinetics and compounds concentration. PMID- 24060481 TI - An insight into the interaction of phenanthridine dyes with polyriboadenylic acid: spectroscopic and thermodynamic approach. AB - Interaction of two phenanthridine dyes, namely ethidium bromide (EB) and propidium iodide (PI) with polyriboadenylic acid was investigated using various spectroscopic techniques. They were found to bind only with the single stranded form of the polymer, while no affinity was observed for the double stranded form. Enhanced binding observed for PI compared to EB may be attributed to the presence of external alkyl chain in PI. Thermodynamic studies showed negative enthalpy and negative entropy changes for the binding of both the dyes. Salt dependent studies revealed a lesser electrolytic contribution compared to the nonelectrolytic contribution to the total Gibbs free energy change in each case. This indicated importance of hydrophobic and van der Waal's interaction for the binding process. Overall, the binding data and detail energetics of interaction presented here would be helpful in the design of phenanthridine based molecules that interact with specific RNA structure. PMID- 24060482 TI - Kinetics and its accompanying thermodynamics studies on simultaneous complexation of heterobimetallic neodymium (III) with zinc (II) and L-tryptophan in aquated DMF using 4f-4f absorption spectra. AB - The 4f-4f absorption spectra of the simultaneous heterobimetallic complexation of trivalent neodymium ion with l-tryptophan and divalent zinc ion in aquated DMF (50%, v/v) at pH 6.0 was recorded at the time interval of 1h. From the observed absorption spectra, the values of intensity parameters such as oscillator strength (P) and Judd-Ofelt intensity (Tlambda) parameters, kinetics and thermodynamics parameters were evaluated. The rate constant increases with an increase in the temperature along with the oscillator strengths and Judd-Ofelt intensity parameters. The positive values of the change in the standard enthalpy (DeltaH degrees ) and entropy (DeltaS degrees ) indicate that the complexation is endothermic. The negative values of the change in the standard free energy (DeltaG degrees ) in the range from 293.15 K to 308.15 K, indicate that the reaction occurs spontaneously and hence the formation of heterobimetallic complex in the solution is favored kinetically and thermodynamically. PMID- 24060483 TI - N2-, O2- and He-collision-induced broadening of sulfur dioxide ro-vibrational lines in the 9.2 MUm atmospheric window. AB - Sulfur dioxide (SO2) is a molecule of considerable interest for both atmospheric chemistry and astrophysics. In the Earth's atmosphere, it enters in the sulfur cycle and it is ubiquitous present in polluted atmospheres, where it is responsible for acid rains. It is also of astrophysical and planetological importance, being present on Venus and in interstellar clouds. In this work the collisional broadening of a number of nu1 ro-vibrational lines of SO2 perturbed by N2, O2 and He are investigated at room temperature in the 9 MUm atmospheric region by means of high resolution tunable diode laser (TDL) infrared spectroscopy. From N2- and O2-broadening coefficients, the broadening parameters of sulfur dioxide in air, useful for atmospheric applications, are derived as well. From the present measurements some conclusions on the quantum number dependence of the N2-, O2- and He-broadening coefficients are drawn. While the J dependence is weak for all the perturbers investigated, different trends with Ka are reported. N2-broadening coefficients show a slight decrease with increasing values of Ka, whereas O2 and He broadening cross sections first increase up to Ka(")~6 and then they keep a nearly constant value. A comparison and a brief discussion on the efficiency of self-, N2-, O2- and He-collisional dynamics are given. The data obtained represent a significant analysis on foreign broadening of SO2 useful for atmospheric remote sensing and astrophysical applications. PMID- 24060484 TI - A proposed mechanism for exercise attenuated methylglyoxal accumulation: activation of the ARE-Nrf pathway and increased glutathione biosynthesis. AB - The dicarbonyl methylglyoxal (MGO) is an endogenous metabolite and a known intracellular precursor of advanced glycation endproducts (AGEs). High serum levels of MGO have been correlated with MGO-derived AGEs in individuals with type 2 diabetes (T2DM). Furthermore, there is human and animal evidence to suggest that MGO is causal in copious pathologies related to AGE accumulation including heart disease, hypertension, nephropathy and insulin resistance. MGO is detoxified through the glutathione (GSH) dependent glyoxalase system and diminished glutathione status results in impaired MGO detoxification. Individuals with uncontrolled T2DM have diminished GSH status, suggesting the increase in serum MGO can be partially attributed to impaired MGO detoxification. GSH biosynthesis is heavily dependent upon the antioxidant response element-nuclear respiratory factor pathway (ARE-Nrf) and pharmacological and dietary intervention studies have demonstrated that activation of the ARE-Nrf pathway increases intracellular GSH and glyoxalase enzymes and reduces MGO levels. Acute and chronic exercise has also been shown to increase activation of the ARE-Nrf pathway and GSH biosynthesis, and to improve GSH status. Therefore, we propose that exercise improves MGO detoxification and attenuates MGO accumulation by increasing GSH biosynthesis and improving GSH status through activation of the ARE-Nrf pathway. PMID- 24060485 TI - Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis? AB - Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta blockers decrease the incidence and growth of hepatocellular carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta blockers are used for prevention of esophageal variceal bleeding. Recently, non hemodynamic effects of beta-blockers have received increasing attention. Blockage of beta-adrenoceptors in the intestinal mucosa and gut lymphatic tissue together with changes in type and virulence of the intestinal microbiota lead to reduced bacterial translocation and a subsequent decrease in the portal load of pathogen associated molecular patterns. This may reduce hepatic inflammation. Blockage of beta-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development and growth of hepatocellular carcinoma. Rodent and in vitro studies support the hypothesis, but clinical verification is needed. Different study designs may be considered. The feasibility of a randomized controlled trial is limited due to the necessary large number of patients and long follow-up. Observational studies carry a high risk of bias. The meta analytic approach may be used if the incidence and mortality of hepatocellular carcinoma can be extracted from trials on variceal bleeding and if the combined sample size and follow up is sufficient. PMID- 24060486 TI - Synthesis and biological evaluation of novel alkyl amide functionalized trifluoromethyl substituted pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents. AB - A series of novel alkyl amide functionalized trifluoromethyl substituted pyrazolo[3,4-b]pyridine derivatives 5, 6 and 7 were prepared starting from 6 phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine 3 via selective N alkylation, followed by reaction with different primary aliphatic amines, cyclic secondary amines or l-amino acids under different set of conditions. All the synthesized compounds 5, 6 and 7 were screened for anticancer activity against four cancer cell lines such as A549-Lung cancer (CCL-185), MCF7-Breast cancer (HTB-22), DU145-Prostate cancer (HTB-81) and HeLa-Cervical cancer (CCL-2). The compounds 5i and 6e are found to have promising bioactivity at micro molar concentration. PMID- 24060487 TI - Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib. AB - Lumiracoxib is a substrate-selective inhibitor of endocannabinoid oxygenation by cyclooxygenase-2 (COX-2). We assayed a series of lumiracoxib derivatives to identify the structural determinants of substrate-selective inhibition. The hydrogen-bonding potential of the substituents at the ortho positions of the aniline ring dictated the potency and substrate selectivity of the inhibitors. The presence of a 5'-methyl group on the phenylacetic acid ring increased the potency of molecules with a single ortho substituent. Des-fluorolumiracoxib (2) was the most potent and selective inhibitor of endocannabinoid oxygenation. The positioning of critical substituents in the binding site was identified from a 2.35A crystal structure of lumiracoxib bound to COX-2. PMID- 24060488 TI - Flavone-based analogues inspired by the natural product simocyclinone D8 as DNA gyrase inhibitors. AB - The increasing occurrence of drug-resistant bacterial infections in the clinic has created a need for new antibacterial agents. Natural products have historically been a rich source of both antibiotics and lead compounds for new antibacterial agents. The natural product simocyclinone D8 (SD8) has been reported to inhibit DNA gyrase, a validated antibacterial drug target, by a unique catalytic inhibition mechanism of action. In this work, we have prepared simplified flavone-based analogues inspired by the complex natural product and evaluated their inhibitory activity and mechanism of action. While two of these compounds do inhibit DNA gyrase, they do so by a different mechanism of action than SD8, namely DNA intercalation. PMID- 24060490 TI - Enhanced performance of semitransparent inverted organic photovoltaic devices via a high reflector structure. AB - Significantly enhanced performances of semitransparent inverted organic photovoltaic devices have been realized by simply introducing a high reflector structure, which comprises several pairs of MoO3/LiF with a thickness of 60 nm for MoO3 and 90 nm for LiF, respectively. After optimizing the reflector structure, the enhanced light harvesting is achieved, and thus the increased optical current is obtained. The short-circuit current density (JSC) and power conversion efficiency (PCE) are increased to 10.9 mA cm(-2) and 4.32%, compared to 8.09 mA cm(-2) and 3.36% in the control device. This leads to a 30% enhancement in PCE. According to the experimental and simulated results, the improved performance is attributed to the effective reflection of light at the wavelength from 450 to 600 nm, which corresponds to the absorption range of the active layer. The demonstrated light-trapping approach is expected to be an effective method to realize the high efficiency in semitransparent organic photovoltaic devices. PMID- 24060489 TI - Investigation of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7-diones as small molecule antagonists of beta-catenin/TCF transcription. AB - Nearly all colorectal cancers (CRCs) and varied subsets of other cancers have somatic mutations leading to beta-catenin stabilization and increased beta catenin/TCF transcriptional activity. Inhibition of stabilized beta-catenin in CRC cell lines arrests their growth and highlights the potential of this mechanism for novel cancer therapeutics. We have pursued efforts to develop small molecules that inhibit beta-catenin/TCF transcriptional activity. We used xanthothricin, a known beta-catenin/TCF antagonist of microbial origin, as a lead compound to synthesize related analogues with drug-like features such as low molecular weight and good metabolic stability. We studied a panel of six candidate Wnt/beta-catenin/Tcf-regulated genes and found that two of them (Axin2, Lgr5) were reproducibly activated (9-10 fold) in rat intestinal epithelial cells (IEC-6) following beta-catenin stabilization by Wnt-3a ligand treatment. Two previously reported beta-catenin/TCF antagonists (calphostin C, xanthothricin) and XAV939 (tankyrase antagonist) inhibited Wnt-activated genes in a dose dependent fashion. We found that four of our compounds also potently inhibited Wnt-mediated activation in the panel of target genes. We investigated the mechanism of action for one of these (8c) and demonstrated these novel small molecules inhibit beta-catenin transcriptional activity by degrading beta-catenin via a proteasome-dependent, but GSK3beta-, APC-, AXIN2- and betaTrCP-independent, pathway. The data indicate the compounds act at the level of beta-catenin to inhibit Wnt/beta-catenin/TCF function and highlight a robust strategy for assessing the activity of beta-catenin/TCF antagonists. PMID- 24060491 TI - Low-grade systemic inflammation and leptin levels were improved by arm cranking exercise in adults with chronic spinal cord injury. AB - OBJECTIVE: To ascertain the effect of arm cranking exercise on improving plasma levels of inflammatory cytokines and adipokines in untrained adults with chronic spinal cord injury (SCI). DESIGN: Longitudinal study. SETTING: Community-based supervised intervention. PARTICIPANTS: Men (N=17) with complete SCI at or below T5 volunteered for this study. Participants were randomly allocated to the intervention (n=9) or control group (n=8) using a concealed method. INTERVENTION: A 12-week arm cranking exercise program of 3 sessions per week consisted of warm up (10-15min), arm crank (20-30min; increasing 2min and 30s every 3wk) at a moderate work intensity of 50% to 65% of heart rate reserve (starting at 50% and increasing 5% every 3wk), and cool-down (5-10min). MAIN OUTCOME MEASURES: Plasma levels of leptin, adiponectin, plasminogen activator inhibitor-1, tumor necrosis factor-alpha, and interleukin-6 were determined. Furthermore, physical fitness (maximum oxygen consumption [VO2max]) and body composition (anthropometric index, waist circumference, and body mass index) were also assessed. RESULTS: Plasma levels of leptin, tumor necrosis factor-alpha, and interleukin-6 were significantly decreased after the completion of the training program. Similarly, the anthropometric index and waist circumference were diminished too. A moderate correlation was found between leptin and the anthropometric index. Finally, VO2max was significantly increased, suggesting an improvement of physical fitness in the intervention group. No changes were found in the control group. CONCLUSIONS: Arm cranking exercise improved low-grade systemic inflammation by decreasing plasma levels of inflammatory cytokines. Furthermore, it also reduced plasma leptin levels. Long-term, well-conducted studies are still required to determine whether these changes may improve clinical outcomes of adults with chronic SCI. PMID- 24060492 TI - Postanoxic myoclonus: two case presentations and review of medical management. AB - Postanoxic myoclonus is a rare manifestation after an anoxic event, with fewer than 150 cases reported in the literature. The condition is characterized by myoclonic jerks, which are worse on action than at rest, and postural lapses, ataxia, and dysarthria. The disability caused by postanoxic myoclonus can be profound, and treatment in the rehabilitation setting is exceptionally challenging. We present 2 patients who suffered from postanoxic myoclonus after an anoxic event, both of whom were successfully treated with a combination of levetiracetam, valproic acid, and clonazepam. These cases act as a framework for discussing the management of postanoxic myoclonus in the clinical setting. PMID- 24060494 TI - Fetal cerebral lobes development between 20 and 28 weeks gestational age: a postmortem MR study. AB - To investigate the fetal cerebral lobes development between 20 and 28 weeks gestational age, 36 fetus specimen without CNS abnormality, with 4 fetuses in each gestation week, were scanned with 3.0T MR. Lobular parameters were measured, including the parenchyma thickness of the frontoparietal and the temporal lobes, the margin length of frontoparietal, the insula and the temporal lobes, the Sylvian fissure and the perimeter of hippocampus, on the plane perpendicular to the longitudinal axis of hippocampus body across the base of cerebral peduncle. The relative value of parenchyma thickness and the lobes' length ratios to the same side hemisphere were calculated and their correlation with gestational weeks was analyzed. All measured parameters were positively correlated with gestational age. No significant tendency was found for relative value of the parenchyma thickness (P>0.05). The temporal lobe length ratio increased while the frontoparietal ratio decreased before 24 weeks GA and then the two reversed. The Sylvian fissure length ratio increased (P<0.001) and the hippocampus decreased (P<0.001) throughout this period. In conclusion, the early fetal cerebrum lobes developed asynchronously during this period, the 24 weeks GA could be a turning point for cerebrum development pattern changing from primitive to mature. PMID- 24060493 TI - Negative affect and sleep disturbance may be associated with response to epidural steroid injections for spine-related pain. AB - OBJECTIVE: To describe whether negative affect and sleep impairment are associated with the clinical effect of epidural steroid injections (ESIs) for low back pain. DESIGN: Observational study; patients were evaluated before ESI and 1 and 3 months after ESI. SETTING: Spine center and related treatment sites. PARTICIPANTS: Participants (N=158) seeking treatment for low back pain with or without radiculopathy. INTERVENTION: ESI for low back pain with or without radiculopathy. MAIN OUTCOME MEASURES: We assessed the dependent (global pain severity for back and leg pain, pain behavior, pain interference) and independent variables (depression, sleep disturbance, and covariates of back pain response) with the Patient-Reported Outcome Measurement Information System (PROMIS) and legacy measures. Outcome was assessed cross-sectionally using multiple regression and longitudinally with path analysis. RESULTS: After 1 month, sleep disturbance was the only predictor for the global ratings of improvement in back pain (R(2)=16.8%) and leg pain (R(2)=11.4%). The proportions of variance explained by sleep disturbance and negative affect for all dependent variables were greater at 3 months than 1 month. Mediation analysis was significant for negative affect for the 3-month outcomes on PROMIS pain behavior (beta=.87, P<.01) and pain interference (beta=.37, P<.01). There was no evidence of mediation by sleep disturbance for any outcome. CONCLUSIONS: Negative affect and sleep disturbance are associated with worse outcomes after ESI. Further research is needed to determine if treatment of negative affect and sleep disturbance prior to or concurrently with ESI will improve outcomes. PMID- 24060495 TI - The variability of the volume of os coxae and linear pelvic morphometry. Considerations for total hip arthroplasty. AB - This study investigated the variability of os coxae's volume and linear morphometry in 50 dry adult bones. There was a wide variability, with coefficients of variation exceeding 30%, of the bones' volumes (mean 142 ml, range 80 to 300 ml) and distances between the acetabular rim and the horizontal plane through the sciatic notch (mean 10.6 mm, range -7 to 19 mm). The smallest width of the ilium ranged between 3 and 9 mm at a level between 1.5 and 4 cm above the acetabulum. The volume of os coxae correlated with the acetabular diameter (r = 0.79), the height of os coxae (r = 0.88) and antero-posterior length of the ilium at mid-acetabular level (r = 0.70). Knowledge of the variability of os coxae may be useful during preoperative planning in primary and revision hip arthroplasty. PMID- 24060496 TI - Clinical impact of Gram-negative nonfermenters on adults with community-onset bacteremia in the emergency department. AB - BACKGROUND: To determine clinical predictors and impact of Gram-negative nonfermenters (GNNFs) infections among adults with community-onset bacteremia in the emergency department (ED). METHODS: Adults with bacteremia visiting the ED from January 2007 to June 2008 were identified retrospectively. Demographic characteristics, underlying illnesses, clinical conditions, bacteremic pathogens, antimicrobial agents, and outcome, were retrieved from chart records. RESULTS: After the exclusion of 261 patients with contamination of blood cultures and 24 patients referred from other hospitals, 518 adults with community-onset bacteremia were eligible; their mean age was 65.1 years, with slight predominance of female (262 patients, 50.6%). Of a total of 565 bacteremic isolates, Escherichia coli (228 isolates, 40.4%) and Klebsiella pneumoniae (100, 17.7%) were the major microorganisms. GNNFs caused bacteremia in 31 (6.0%) patients. A higher proportion of inappropriate antibiotic therapy in the ED (87.1% vs. 26.5%, p < 0.001) and higher 28-day crude mortality rate (19.4% vs. 8.4%, p = 0.05) were observed in bacteremic patients caused by GNNFs than those not caused by GNNFs. In further analysis of Kaplan-Meier survival curve, patients with GNNF bacteremia had a worse outcome than those due to other pathogens (p = 0.04). Multivariate analysis revealed that the independent predictors related to GNNF bacteremia included surgery during previous 4 weeks prior to ED arrival [odds ratio (OR), 10.79; 95% confidence interval (CI), 1.84-63.24; p = 0.01], residents in long term healthcare facilities (OR, 4.62; 95% CI, 2.08-10.29; p < 0.001), and malignancy (OR, 2.24; 95% CI, 1.10-5.40; p = 0.02). CONCLUSION: For adults with bacteremia visiting the ED, GNNF is associated with a higher mortality rate and more inappropriate empirical antibiotic therapy in the ED. To allow early administration of empirical antibiotics, several clinical predictors of GNNF infections were identified. PMID- 24060497 TI - Expression, purification and molecular analysis of the human ZNF706 protein. AB - BACKGROUND: The ZNF706 gene encodes a protein that belongs to the zinc finger family of proteins and was found to be highly expressed in laryngeal cancer, making the structure and function of ZNF706 worthy of investigation. In this study, we expressed and purified recombinant human ZNF706 that was suitable for structural analysis in Escherichia coli BL21(DH3). FINDINGS: ZNF706 mRNA was extracted from a larynx tissue sample, and cDNA was ligated into a cloning vector using the TOPO method. ZNF706 protein was expressed according to the E. coli expression system procedures and was purified using a nickel-affinity column. The structural qualities of recombinant ZNF706 and quantification alpha, beta sheet, and other structures were obtained by spectroscopy of circular dichroism. ZNF706's structural modeling showed that it is composed of alpha-helices (28.3%), beta-strands (19.4%), and turns (20.9%), in agreement with the spectral data from the dichroism analysis. CONCLUSIONS: We used circular dichroism and molecular modeling to examine the structure of ZNF706. The results suggest that human recombinant ZNF706 keeps its secondary structures and is appropriate for functional and structural studies. The method of expressing ZNF706 protein used in this study can be used to direct various functional and structural studies that will contribute to the understanding of its function as well as its relationship with other biological molecules and its putative role in carcinogenesis. PMID- 24060498 TI - Individual variation in testosterone and parental care in a female songbird; the dark-eyed junco (Junco hyemalis). AB - When competition for sex-specific resources overlaps in time with offspring production and care, trade-offs can occur. Steroid hormones, particularly testosterone (T), play a crucial role in mediating such trade-offs in males, often increasing competitive behaviors while decreasing paternal behavior. Recent research has shown that females also face such trade-offs; however, we know little about the role of T in mediating female phenotypes in general, and the role of T in mediating trade-offs in females in particular. Here we examine the relationship between individual variation in maternal effort and endogenous T in the dark-eyed junco, a common songbird. Specifically, we measure circulating T before and after a physiological challenge (injection of gonadotropin releasing hormone, GnRH), and determine whether either measure is related to provisioning, brooding, or the amount of T sequestered in egg yolk. We found that females producing more T in response to a challenge spent less time brooding nestlings, but provisioned nestlings more frequently, and deposited more T in their eggs. These findings suggest that, while T is likely important in mediating maternal phenotypes and female life history tradeoffs, the direction of the relationships between T and phenotype may differ from what is generally observed in males, and that high levels of endogenous T are not necessarily as costly as previous work might suggest. PMID- 24060499 TI - A longer waiting game: bridging children to heart transplant with the Berlin Heart EXCOR device--the United Kingdom experience. AB - BACKGROUND: Mechanical circulatory support (MCS) is used to support children with end-stage heart failure to heart transplant. METHODS: This was a retrospective cohort study of 7 years' experience with the Berlin Heart (BH) EXCOR (Berlin Heart AG, Berlin Germany) paracorporeal ventricular assist device (VAD) in 2 United Kingdom (UK) pediatric heart transplant centers and the effect of this program on the UK pediatric heart transplant service. RESULTS: Of 102 children who received BH support, 84% survived to transplant or BH explant and 81% survived to discharge. Neither age nor duration of support influenced outcome. Stroke, ongoing requirement for ventilation while on BH, and diagnosis other than dilated cardiomyopathy were the only independent mortality risk factors. Children who weighed < 20 kg had significantly (p = 0.03) longer support times than bigger children. The number of children treated with a BH increased over time (p = 0.01). Currently > 50% of pediatric heart transplants are bridged with a BH; however, pediatric transplants per year have not increased significantly (p = 0.07) CONCLUSIONS: BH use in the UK has allowed significant increases in the number of children with end-stage heart failure who can be successfully bridged to transplant and the length of time they can be supported. The total number of transplants has not increased. PMID- 24060500 TI - [Clinical practice guideline for the management of Hunter syndrome. Hunter Espana working group]. PMID- 24060501 TI - [The patient-reported outcomes in research: definition, impact, classification, measurement and assessment]. PMID- 24060502 TI - Antimicrobial peptides play a functional role in bumblebee anti-trypanosome defense. AB - Bumblebees, amongst the most important of pollinators, are under enormous population pressures. One of these is disease. The bumblebee and its gut trypanosome Crithidia bombi are one of the fundamental models of ecological immunology. Although there is previous evidence of increased immune gene expression upon Crithidia infection, recent work has focussed on the bumblebee's gut microbiota. Here, by knocking down gene expression using RNAi, we show for the first time that antimicrobial peptides (AMPs) have a functional role in anti Crithidia defense. PMID- 24060503 TI - Rainbow trout (Oncorhynchus mykiss) contain two calnexin genes which encode distinct proteins. AB - Calnexin (IP90/P88) is an integral membrane protein of the endoplasmic reticulum that binds newly synthesized N-linked glycoproteins during their folding in the ER including MHC class I molecule. This manuscript reports the identification of two unique cDNA clones of calnexin in rainbow trout. Both encode putative mature proteins of 579 and 592 aa respectively in addition to a 24 aa signal peptide. Sequence analysis revealed that only one of the two cDNA clones encodes a putative ER retention signal, K/QEDDL, followed by a serine phosphorylation site conserved with mammalian homologs. Amino acid sequence alignment illustrated conservation of the calnexin luminal domain, which consists of a globular and a P domain, in both copies. Southern blotting revealed that there are at least two copies of the calnexin gene in the trout genome and northern blotting showed a wide tissue distribution of an estimated 3 kbp calnexin transcript with an additional minor transcript of 2.3 kbp expressed only in head kidney, spleen PBLs and strongly in RTS11. Importantly, the smaller transcript was predominantly upregulated in RTS11 after a 24h treatment with the calcium ionophore A23187. In western blots, calnexin was detected primarily as a 120 kDa protein and upon A23187 treatment; a 100 kDa band was most prominently expressed. These results suggest that in salmonids there are two differentiated versions of the calnexin gene which encode proteins that may have diverged to perform unique biological functions. PMID- 24060504 TI - Nuclear factor 45 of tongue sole (Cynoglossus semilaevis): evidence for functional differentiation between two isoforms in immune defense against viral and bacterial pathogens. AB - Nuclear factor 45 (NF45) is known to play an important role in regulating interleukin-2 expression in mammals. The function of fish NF45 is largely unknown. In a previous study, we reported the identification of a NF45 (named CsNF45) from half smooth tongue sole (Cynoglossus semilaevis). In the present study, we identified an isoform of CsNF45 (named CsNF45i) from half smooth tongue sole and examined its biological properties in comparison with CsNF45. We found that CsNF45i is a truncated version of CsNF45 and lacks the N-terminal 38 residues of CsNF45. Genetic analysis showed that the CsNF45 gene consists of 14 exons and 13 introns, and that CsNF45 and CsNF45i are the products of alternative splicing. Constitutive expression of CsNF45 and CsNF45i occurred in multiple tissues but differed in patterns. Experimental infection with viral and bacterial pathogens upregulated the expression of both isoforms but to different degrees, with potent induction of CsNF45 being induced by bacterial pathogen, while dramatic induction of CsNF45i being induced by viral pathogen. Transient transfection analysis showed that both isoforms were localized in the nucleus and able to stimulate the activity of IL-2 promoter to comparable extents. To examine their in vivo effects, the two isoforms were overexpressed in tongue sole. Subsequent analysis showed that following viral and bacterial infection, the viral loads in CsNF45i-overexpressing fish were significantly lower than those in CsNF45-overexpressing fish, whereas the bacterial loads in CsNF45-overexpressing fish were significantly lower than those in CsNF45i-overexpressing fish. These results indicate that both CsNF45 and CsNF45i possess immunoregulatory properties, however, the two isoforms most likely participate in different aspects of host immune defense that target different pathogens. PMID- 24060505 TI - Nanoscale-phase-separated Pd-Rh boxes synthesized via metal migration: an archetype for studying lattice strain and composition effects in electrocatalysis. AB - Developing syntheses of more sophisticated nanostructures comprising late transition metals broadens the tools to rationally design suitable heterogeneous catalysts for chemical transformations. Herein, we report a synthesis of Pd-Rh nanoboxes by controlling the migration of metals in a core-shell nanoparticle. The Pd-Rh nanobox structure is a grid-like arrangement of two distinct metal phases, and the surfaces of these boxes are {100} dominant Pd and Rh. The catalytic behaviors of the particles were examined in electrochemistry to investigate strain effects arising from this structure. It was found that the trends in activity of model fuel cell reactions cannot be explained solely by the surface composition. The lattice strain emerging from the nanoscale separation of metal phases at the surface also plays an important role. PMID- 24060506 TI - Genotoxic effects of environmental endocrine disruptors on the aquatic insect Chironomus riparius evaluated using the comet assay. AB - Genotoxicity is one of the most important toxic endpoints in chemical toxicity testing and environmental risk assessment. The aim of this study was to evaluate the genotoxic potential of various environmental pollutants frequently found in aquatic environments and characterized by their endocrine disrupting activity. Monitoring of DNA damage was undertaken after in vivo exposures of the aquatic larvae of the midge Chironomus riparius, a model organism that represents an abundant and ecologically relevant macroinvertebrate, widely used in freshwater toxicology. DNA-induced damage, resulting in DNA fragmentation, was quantified by the comet assay after short (24 h) and long (96 h) exposures to different concentrations of the selected toxicants: bisphenol A (BPA), nonylphenol (NP), pentachlorophenol (PCP), tributyltin (TBT) and triclosan (TCS). All five compounds were found to have genotoxic activity as demonstrated by significant increases in all the comet parameters (%DNA in tail, tail length, tail moment and Olive tail moment) at all tested concentrations. Persistent exposure did not increase the extent of DNA damage, except for TCS at the highest concentration, but generally there was a reduction in DNA damage thought to be associated with the induction of the detoxification processes and repairing mechanisms. Comparative analysis showed differences in the genotoxic potential between the chemicals, as well as significant time and concentration-dependent variations, which most likely reflect differences in the ability to repair DNA damage under the different treatments. The present report demonstrates the sensitivity of the benthic larvae of C. riparius to these environmental genotoxins suggesting its potential as biomonitor organism in freshwater ecosystems. The results obtained about the DNA-damaging potential of these environmental pollutants reinforce the need for additional studies on the genotoxicity of endocrine active substances that, by linking genotoxic activity to other biological responses, could provide further understanding of adverse effects in aquatic environments. PMID- 24060507 TI - WITHDRAWN: Quercetin enhances the effect of hyperthermal intraperitoneal chemotherapy with cisplatin in mice. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1177/0960327113499048. The duplicate article has therefore been withdrawn. PMID- 24060508 TI - Effect of blueberries (BB) on micronuclei induced by N-methyl-N'-nitro-N nitrosoguanidine (MNNG) and 7,12-dimethylbenz(a)anthracene (DMBA) in mammalian cells, assessed in in vitro and in vivo assays. AB - The protective effect of blueberry (BB) on the clastogenic effects of MNNG and DMBA was evaluated with the induced micronucleus (MN) frequency as a biomarker, both in vitro and in vivo. Human hepatoma HepG2 cells, which contain most of the metabolic activating enzymes was used for the in vitro test. MN frequencies were determined in binucleated cells generated by blocking cytokinesis by use of cytochalasin-B. The MN frequency in vivo was determined in polychromatic erythrocytes (PCEs) from the bone marrow of treated mice. BB by itself was not toxic both in vivo and in vitro. There was no evidence of a potential physico chemical interaction between BB and the test carcinogens in vitro. Pre-treatment with BB reduced the MN frequency induced by MNNG. But, simultaneous treatment and post-treatment with BB did not affect the frequency of MNNG-induced MN. BB did not affect the frequency of DMBA-induced MN in vitro under any test condition. Under in vivo conditions, BB reduced the frequencies of MNNG- and DMBA-induced MN in PCEs, but in the case of the protective effect of BB against DMBA a dramatic reduction in the percentage of PCEs was observed, suggesting increased cytotoxicity. PMID- 24060509 TI - Evaluation of mutagenic and antimutagenic properties of new derivatives of pyrrolidine-2,5-dione with anti-epileptic activity, by use of the Vibrio harveyi mutagenicity test. AB - The Vibrio harveyi test was used to evaluate mutagenic and antimutagenic properties of nineteen new derivatives of pyrrolidine-2,5-dione (compounds 1-19) with antiepileptic activity. Four V. harveyi strains were used: BB7 (wild type) and the genetically modified strains BB7M, BB7X and BB7XM (i.e. strains with additional mucA and mucB genes, UV hypersensitivity, and UV hypersensitivity with plasmid pAB91273, respectively). None of the derivatives of 2-ethyl-2 methylsuccinic acid (compounds 1-7) had mutagenic activity against the tester strains of V. harveyi, but this set had strong or moderate antimutagenic activity against 4-nitroquinoline-N-oxide (NQNO) in the tester strains BB7, BB7X, and BB7M. This antimutagenic activity ranged from 51% to 67%, through 51-66% to 71 83% for V. harveyi BB7, BB7X and BB7M strains, respectively. Mutagenic activities in the group of 2,2-diphenyl-succinic acid derivatives (compounds 8-19) were variable and depended on the tester strain used. Compounds 8-19 were devoid of mutagenic properties against BB7 (wild-type strain). Among this group only compound 9, with the fluorine substituent in position 2 of the aromatic system, was devoid of mutagenic potential against all tester strains. The compounds in this group (8-19) demonstrated strong antimutagenic activity only against strain BB7 (inhibition ranging from 51% to 71%). We conclude that there are various mutagenic and antimutagenic activities of derivatives of pyrrolidine-2,5-dione. Moreover, our studies have proven that the V. harveyi test can be applied for primary mutagenicity and antimutagenicity assessment of these new compounds. PMID- 24060510 TI - A comparison of percutaneous needle fasciotomy and collagenase injection for dupuytren disease. AB - PURPOSE: To compare percutaneous needle fasciotomy (PNF) with collagenase injection in the treatment of Dupuytren contracture. METHODS: A retrospective review was performed for patients with Dupuytren disease treated with PNF or collagenase. Range of motion, patient satisfaction, and complications were recorded. RESULTS: There were 29 patients in the collagenase group with mean baseline contractures of 40 degrees for 22 affected metacarpophalangeal joints and 50 degrees for 12 affected proximal interphalangeal joints. The PNF group was composed of 30 patients with mean baseline contractures of 37 degrees for 32 affected metacarpophalangeal joints and 41 degrees for 18 affected proximal interphalangeal joints. All patients were observed for a minimum of 3 months. Clinical success (reduction of contracture within 0 degrees to 5 degrees of normal) was accomplished in 35 of 50 joints (67%) in the PNF group and in 19 of 34 joints (56%) in the collagenase group. Patient satisfaction was similar between groups. Only minor complications were observed, including skin tears, ecchymosis, edema, pruritus, and lymphadenopathy. CONCLUSIONS: In the short term, both PNF and collagenase have similar clinical outcomes and patient satisfaction. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 24060511 TI - Presentation and treatment of macrodactyly in children. AB - PURPOSE: To characterize the presentation, treatment, and early outcomes of children with isolated congenital macrodactyly of the hand. METHODS: We performed a retrospective chart review of isolated hand macrodactyly cases treated at our institution over a 15-year period. Data on clinical presentation, procedure details, and outcomes were collected. RESULTS: A total of 21 patients, 8 boys and 13 girls, were identified. Patients had a mean of 1.8 affected digits (median, 2; range, 1-3); most (n = 12; 57%) presented with multiple affected digits. The middle finger was most commonly affected (67%). Most patients had progressive overgrowth (n = 13; 67%). Twelve patients (57%) had nerve territory-oriented macrodactyly, whereas 9 (43%) presented with lipomatous type. There were no differences between the types of macrodactyly in sex, affected side, rate of growth, digits affected, or number of procedures. Patients underwent a mean of 3.2 staged corrective operations (median, 2; range, 1-12), including soft tissue debulking (n = 19 patients; 90%), ostectomy for volume reduction or partial amputation (n = 9; 43%), closing wedge osteotomy (n = 11; 52%), epiphysiodesis (n = 7; 33%), digit transfer (n = 3; 14%), toe transfer (n = 1; 5%), and ray amputation (n = 6; 29%). Patients with progressive growth underwent more procedures than patients with static growth. No major complications were reported. CONCLUSIONS: The diagnosis of macrodactyly should be reserved for patients with isolated congenital digit overgrowth affecting all tissue types, but clinical presentation and natural history of macrodactyly can vary greatly among patients. A variety of surgical techniques exist to reconstruct rather than amputate affected digits primarily. Although reconstruction will not result in a normal digit and requires multiple operations, our observations suggest that they are well tolerated and may offer some restored function and aesthetics. More long term outcomes and insight into the biological basis of this disorder are needed to make better-informed treatment decisions. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 24060512 TI - Brain peroxisomes. AB - Peroxisomes are essential organelles in higher eukaryotes as they play a major role in numerous metabolic pathways and redox homeostasis. Some peroxisomal abnormalities, which are often not compatible with life or normal development, were identified in severe demyelinating and neurodegenerative brain diseases. The metabolic roles of peroxisomes, especially in the brain, are described and human brain peroxisomal disorders resulting from a peroxisome biogenesis or a single peroxisomal enzyme defect are listed. The brain abnormalities encountered in these disorders (demyelination, oxidative stress, inflammation, cell death, neuronal migration, differentiation) are described and their pathogenesis are discussed. Finally, the contribution of peroxisomal dysfunctions to the alterations of brain functions during aging and to the development of Alzheimer's disease is considered. PMID- 24060518 TI - Timing of colonoscopy and outcomes in patients with lower GI bleeding: a nationwide population-based study. AB - BACKGROUND: The role of urgent colonoscopy in lower GI bleeding (LGIB) remains controversial. Population-based studies on LGIB outcomes are lacking. OBJECTIVE: To investigate the impact of the timing of colonoscopy on outcomes of patients with LGIB. DESIGN: Cross-sectional study. SETTING: Nationwide Inpatient Sample 2010. PATIENTS: International Classification of Diseases, Ninth Revision, Clinical Modification codes identified patients with LGIB who underwent colonoscopy. MAIN OUTCOME MEASUREMENTS: In-hospital mortality, length of stay, and hospitalization costs in patients who underwent early (<=24 hours) or delayed (>24 hours) colonoscopy. RESULTS: A total of 58,296 discharges with LGIB were identified; 22,720 had a colonoscopy performed during the hospitalization. A total of 9156 patients had colonoscopy performed within 24 hours (early colonoscopy), and 13,564 had colonoscopy performed after 24 hours (delayed colonoscopy). There was no difference in mortality in patients with LGIB who had early versus delayed colonoscopy (0.3% vs 0.4%, P = .24). However, patients who underwent early colonoscopy had a shorter length of hospital stay (2.9 vs 4.6 days, P < .001), decreased need for blood transfusion (44.6% vs 53.8%, P < .001), and lower hospitalization costs ($22,142 vs $28,749, P < .001). On multivariate analysis, timing of colonoscopy did not affect mortality (adjusted odds ratio 1.5; 95% confidence interval, 0.7-2.7). On multivariate analysis, delayed colonoscopy was associated with an increase in the length of hospital stay by 1.6 days and an increase in hospitalization costs of $7187. LIMITATIONS: Administrative dataset. CONCLUSIONS: Early colonoscopy within 24 hours is associated with decreased length of hospital stay and hospitalization costs in patients with LGIB. PMID- 24060519 TI - Comparison of endoscopic therapies and surgical resection in patients with early esophageal cancer: a population-based study. AB - BACKGROUND: Outcome data comparing endoscopic eradication therapy (EET) and esophagectomy are limited in patients with early esophageal cancer (EC). OBJECTIVE: To compare overall survival and EC-related mortality in patients with early EC treated with EET and esophagectomy. DESIGN AND SETTING: Population-based study. PATIENTS: Patients with early EC (stages T0 and T1) were identified from the Surveillance, Epidemiology, and End Results database (1998-2009). Demographics, tumor specific data, and survival were compared. Cox proportional hazards regression models were used to evaluate the association between treatment and EC-specific mortality. INTERVENTION: EET and esophagectomy. MAIN OUTCOME MEASUREMENTS: Mid- (2 years) and long- (5 years) term overall survival and EC specific mortality, outcomes based on histology and stage, treatment patterns, and predictors of cancer-specific mortality. RESULTS: A total of 430 (21%) and 1586 (79%) patients underwent EET and esophagectomy, respectively. There was no difference in the 2-year (EET: 10.5% vs esophagectomy: 12.7%, P = .27).and 5-year (EET: 36.7% vs esophagectomy: 42.8%, P = .16) EC-related mortality rates between the 2 groups. EET patients had higher mortality rates attributed to non-EC causes (5 years: 46.6% vs 20.6%, P < .001). Similar results were noted when comparisons were limited to patients with stage T0 and T1a disease and esophageal adenocarcinoma. There was no difference in EC-specific mortality in the EET compared with the surgery group (hazard ratio 1.4; 95% confidence interval, 0.9 2.03). Variables associated with mortality were older age, year of diagnosis, radiation therapy, higher stage, and esophageal squamous cell carcinoma. LIMITATIONS: Comorbidities and recurrence rates were not available. CONCLUSIONS: This population-based study demonstrates comparable mid- and long-term EC-related mortality in patients with early EC undergoing EET and surgical resection. PMID- 24060520 TI - ERCP in the management of pancreatic diseases in children. AB - BACKGROUND: ERCP experience in pancreatic disorders in children is limited. OBJECTIVE: This study evaluated the utility and efficacy of ERCP in children with pancreatic diseases at a tertiary care referral center. PATIENTS AND SETTINGS: Consecutive patients 18 years of age and younger who underwent ERCP for pancreatic diseases from January 2010 to June 2011 were identified. Indications, findings, interventions, adverse events, and outcomes were recorded. RESULTS: A total of 221 ERCPs were performed in 172 children (102 boys, mean +/- standard deviation age 13.8 +/- 3.2 years, 157 therapeutic). A total of 143 children (83.1%) had chronic pancreatitis (CP), 19 (11%) had recurrent acute pancreatitis (RAP), and 10 (5.8%) had acute pancreatitis (AP). Indications included pain (153, 89.4%), pancreatic fistula (11, 6.3%), symptomatic pseudocyst (4, 2.3%), and jaundice (3, 1.7%). In chronic pancreatitis patients, findings included a dilated and irregular main pancreatic duct (92, 64.3%), pancreatic duct (PD) calculi (76, 53%), dominant PD stricture (23, 16%), PD leak (7, 4.9%), pancreas divisum (35, 24.5%), and common bile duct (CBD) stricture (3, 2%). Therapeutic procedures included major papilla sphincterotomy (93, 65%), minor papilla sphincterotomy (32, 22.3%), PD stenting (77, 53.8%), and CBD stenting (3, 2.2%). PD stones larger than 5 mm were retrieved endoscopically after 57 extracorporeal shock wave lithotripsy sessions in 50 patients (34.9%). In patients with RAP, 6 (31.5%) had complete and 1 partial pancreas divisum. All underwent minor papillotomy. In patients with AP, 4 (40%) had stenting for PD leak, 2 (20%) underwent CBD clearance for biliary pancreatitis, and 4 (40%) had transpapillary pseudocyst drainage. During 13 +/- 4.7 months (range 6-22 months) of follow-up, improvement of symptoms was seen in 143 of 172 (83%) patients. Procedure-related adverse events were seen in 8 (4.7%) patients. LIMITATIONS: Retrospective study. CONCLUSION: ERCP is a safe therapeutic option for pancreatic disorders in children. PMID- 24060521 TI - Endoscopic submucosal dissection for gastric tube cancer after esophagectomy. AB - BACKGROUND: Recent improvements in the survival of patients after esophagectomy have led to an increasing occurrence of gastric tube cancer (GTC). Removal of the reconstructed gastric tube, however, can lead to high morbidity and mortality. OBJECTIVE: To assess the feasibility and effectiveness of endoscopic submucosal dissection (ESD) for GTC. DESIGN: Retrospective study. SETTING: National Cancer Center Hospital, Tokyo, Japan. PATIENTS: We investigated patients with GTC after esophagectomy undergoing ESD from 1998 to 2011. INTERVENTION ESD MAIN OUTCOME MEASUREMENTS: Patient characteristics, endoscopic findings, technical results, histopathology including curability and Helicobacter pylori gastritis, and long term outcomes. RESULTS: There were 51 consecutive patients with 79 lesions including 38 lesions (48%) meeting the absolute indication, 31 (39%) satisfying the expanded indications, and 10 (13%) falling outside such indications. The median procedure time was 90 minutes. There were 73 en bloc resections (92%), 59 en bloc resections with tumor-free margins (R0 resections, 75%), and 51 curative resections (65%) based on the Japanese Gastric Cancer Association criteria. Fifty patients (98%) were assessed as H pylori gastritis positive. Adverse events included 3 perforations (3.8%) during ESD and 2 delayed perforations (2.5%) without any emergency surgery and 3 delayed bleeding (3.8%). Local recurrence was detected in 4 patients (7.8%), and metachronous GTCs were identified in 18 patients (35%). Five patients (10%) died of GTC including 3 metachronous lesions. The 5-year overall survival rate was 68.4%, and the disease-specific survival rate was 86.7% with 100% for curative and 72.7% for non-curative patients during a median follow-up period of 3.8 years (range, 0-12.1 years). LIMITATION: Single center retrospective study. CONCLUSIONS: ESD for GTC was feasible and effective for curative patients; however, long-term outcomes for non-curative patients were less satisfactory. PMID- 24060522 TI - Colon capsule endoscopy is feasible to perform after incomplete colonoscopy and guides further workup in clinical practice. AB - BACKGROUND: Colon capsule endoscopy (CCE) could be an option to examine the colon after incomplete colonoscopy. OBJECTIVE: To investigate the extent that CCE complements incomplete colonoscopy and guides further workup. DESIGN: Prospective, follow-up study. SETTING: Three tertiary-care centers. PATIENTS: Consecutive outpatients after colonoscopy failure; 1-year study period. INTERVENTION: Patients underwent CCE either immediately after colonoscopy or were rescheduled. Further investigations were guided by the results of CCE. Patients were followed as long as 2 years. RESULTS: We studied 75 outpatients; 39 had a screening colonoscopy. One third of the patients underwent CCE immediately after colonoscopy. Overall, CCE reached or went beyond the colon segment at which colonoscopy stopped in 68 patients (91%). CCE technically complemented difficult colonoscopy independently of whether same-day CCE was performed (24 [96%]) or was not performed (44 [88%]). CCE detected additional significant findings in 36% of the same-day CCE cases and in 48% of the rescheduled ones. Two patients in the same-day group and 13 in the rescheduled CCE group underwent further colon examination that revealed additional significant findings in 3 of them. Ten percent of the patients reported mild adverse events (AE). If needed, 63 participants (84%) were willing to repeat CCE. Follow-up has not identified symptomatic missed colon cancers. LIMITATIONS: Selected patient population, first generation colon capsule, old preparation scheme. CONCLUSION: CCE performed immediately or at a scheduled date after colonoscopy failure is feasible and safe. CCE after incomplete colonoscopy appears to yield significant findings, guide further workup, and has high patient acceptance. PMID- 24060523 TI - Long-term effects of irbesartan on plasma aldosterone concentration and left atrial volume in hypertensive patients. AB - BACKGROUND: Plasma aldosterone concentration (PAC) is related to cardiac remodeling in patients with hypertension. However, we do not know the detailed relationship between changes in PAC and regression of left atrial (LA) volume following long-term treatment with angiotensin II receptor blocker (ARB) or calcium-channel blocker (CCB). OBJECTIVE: The aim of this study was to investigate the effects of anti-hypertensive monotherapy, an ARB irbesartan or a CCB amlodipine, on PAC and LA reverse remodeling in hypertensive patients. METHODS: A total of 48 patients with untreated hypertension were randomly assigned to irbesartan (ARB group, n=26) and amlodipine (CCB group, n=22). We examined the correlation between LA volume index (LAVI) and other echocardiographic parameters or PAC (n=40) at the baseline and after 12 months of treatment. RESULTS: After 12 months, blood pressure (BP) decreased similarly in both groups. LAVI and PAC significantly decreased in the ARB group, but not in the CCB group (-16+/-8% vs. 22+/-9%, p<0.01, -16+/-9% vs. 11+/-9%, p<0.05). Larger %-decrease in PAC was associated with larger %-reduction of LAVI in the ARB group (r=0.54, p<0.05), but not in the CCB group. CONCLUSIONS: While BP reduction was similar between the two groups, decrease in LA volume was larger in the ARB group than in the CCB group. Decrease in LA volume was larger in patients with a greater decrease in PAC than in those with smaller decrease in PAC. ARB may facilitate reverse remodeling of LA through decreases in PAC in hypertensive patients. PMID- 24060524 TI - Non-invasive and invasive evaluation of aortic valve area in 100 patients with severe aortic valve stenosis: comparison of cardiac computed tomography with ECHO (transesophageal/transthoracic) and catheter examination. AB - BACKGROUND: Current guidelines place emphasis on the determination of aortic valve area (AVA) for defining an appropriate treatment strategy. Invasive and non invasive modalities are used to perform planimetric [transesophageal echocardiography (TEE) and cardiac multidetector computed tomography (MDCT)] and calculated [catheter examination (CE), transthoracic echocardiography (TTE)] AVA measurements. PURPOSE AND METHODS: We investigated 100 patients admitted to evaluate the AVA using cardiac MDCT (CT), TEE/TTE as well as invasive CE. RESULTS: In all 100 patients we calculated a mean AVA of 0.79+/-0.29cm(2) (female 50/100, 0.70+/-0.19cm(2), male 0.9+/-0.21cm(2)) determined by all investigated examinations (mean+/-SEM). AVA measurements determined by CT were significantly greater (0.86+/-0.25cm(2)) than those determined by CE: 0.75+/-0.18cm(2), p=0.01. Echocardiographically determined AVA was comparable to CE (statistically not significant). Similar results were seen in all patients regardless of gender, presence of atrial fibrillation, and heart rate. We calculated a mean AVA for each patient and evaluated the variance of the AVA determined through investigated specific examinations as the bias. Overall, we found for CT 0.13+/ 0.1cm(2), CE 0.13+/-0.11cm(2), TEE 0.16+/-0.09cm(2), and for TTE 0.16+/-0.08cm(2) a specific statistical non-significant variance. On subgroups: sinus rhythm, atrial fibrillation, females, males or combination, we found no further significant relevance for the specific variance. CONCLUSION: Our data suggest the feasibility of cardiac MDCT to evaluate the correct AVA regardless of rhythm, heart rate, and sex. The planimetric concept to determine the AVA with CT displaces the "gold-standard" CE with respect to elucidating the potencies for complications, i.e. cerebral stroke. Regardless of CT's accessing of AVA measurement the TTE examination should remain the primary method of screening for aortic valve pathologies. PMID- 24060525 TI - The "obesity-mortality paradox" phenomenon among Asian patients following percutaneous coronary artery intervention. PMID- 24060526 TI - Aortic stiffness is increased in patients with premature coronary artery disease: a tissue Doppler imaging study. AB - BACKGROUND: Atherosclerosis and arterial stiffening may coexist and the correlation of these parameters in patients with premature coronary artery disease (CAD) has not been well elucidated. Tissue Doppler imaging of the ascending aorta may be used in the assessment of elastic properties of the great arteries. OBJECTIVE: To investigate the correlation between aortic stiffness and premature CAD using parameters derived from two-dimensional and tissue Doppler imaging (TDI) echocardiography of the ascending aorta. METHODS: Fifty consecutive subjects younger than 40 years old who were hospitalized with diagnosis of acute coronary syndrome and had undergone coronary angiography were recruited. The control group included 70 age-sex matched individuals without a diagnosis of CAD. Aortic stiffness index (SI), aortic distensibility (D), and pressure-strain elastic modulus (Ep) were calculated from the aortic diameters measured by two dimensional M-mode echocardiography and blood pressure obtained by sphygmomanometry. Aortic systolic velocity (SAo), and early (EAo) and late (AAo) diastolic velocities were determined by pulse-wave TDI from the anterior wall of ascending aorta 3cm above the aortic cusps in parasternal long-axis view. RESULTS: Stiffness index was higher [median 5.40, interquartile range (IQR) 5.98 vs. median 4.14 IQR 2.43; p=0.03] and distensibility was lower (median 2.86*10( 6)cm(2)/dyn, IQR 2.51*10(-6)cm(2)/dyn vs. median 3.46*10(-6)cm(2)/dyn, IQR 2.38*10(-6)cm(2)/dyn; p=0.04) in patients with CAD compared to the control group. EAo was significantly lower in the CAD group (7.2+/-1.8cm/s vs. 9.2+/-2.4cm/s, p<0.01). The difference in EAo remained significant when CAD patients with a left ventricular ejection fraction >55% was compared to the control group. SAo and AAo velocities of ascending aorta were similar in control and CAD groups. There was a significant correlation between EAo velocity and aortic stiffness index (r=-0.28, p=0.01), distensibility (r=0.19, p=0.04) and elastic modulus (r=-0.24, p=0.01). In multivariate regression analysis, decreased levels of high-density lipoprotein cholesterol [odds ratio (OR): 1.12 95% CI 1.06-1.19; p=0.01] and EAo (OR: 1.41 95% CI 1.12-1.79; p=0.01) measurements remained as the variables independently correlated with premature CAD in the study group. CONCLUSION: Arterial stiffness is increased in patients with premature CAD. EAo of the anterior wall of ascending aorta measured with pulse-wave TDI echocardiography is correlated with arterial stiffening and is decreased in patients with premature CAD. PMID- 24060527 TI - Proteorhodopsin. AB - Proteorhodopsins are the most abundant retinal based photoreceptors and their phototrophic function might be relevant in marine ecosystems. Here, we describe their remarkable molecular properties with a special focus on the green absorbing variant. Its distinct features include a high pKa value of the primary proton acceptor stabilized through an interaction with a conserved histidine, a long range interaction between the cytoplasmic EF loop and the chromophore entailing a particular mode of color tuning and a variable proton pumping vectoriality with complex voltage-dependence. The proteorhodopsin family represents a profound example for structure-function relationships. Especially the development of a biophysical understanding of green proteorhodopsin is an excellent example for the unique opportunities offered by a combined approach of advanced spectroscopic and electrophysiological methods. This article is part of a Special Issue entitled: Retinal Proteins-You can teach an old dog new tricks. PMID- 24060528 TI - Modification of the pheophytin redox potential in Thermosynechococcus elongatus Photosystem II with PsbA3 as D1. AB - In Photosystem II (PSII) of the cyanobacterium Thermosynechococcus elongatus, glutamate 130 in the high-light variant of the D1-subunit (PsbA3) was changed to glutamine in a strain lacking the two other genes for D1, psbA1 and psbA2. The resulting PSII (PsbA3/Glu130Gln) was compared with those from the "native" high light (PsbA3-PSII) and low-light (PsbA1-PSII) variants, which differ by 21 amino acid including Glu130Gln. H-bonding from D1-Glu130Gln to the primary electron acceptor, PheophytinD1 (PheoD1), is known to affect the Em of the PheoD1/PheoD1( ) couple. The Gln130 mutation here had little effect on water splitting, charge accumulation and photosensitivity but did slow down S2QA(-) charge recombination and up-shift the thermoluminescence while increasing its yield. These changes were consistent with a ~-30mV shift of the PheoD1/PheoD1(-)Em, similar to earlier single site-mutation results from other species and double the ~-17mV shift seen for PsbA1-PSII versus PsbA3-PSII. This is attributed to the influence of the other 20 amino-acids that differ in PsbA3. A computational model for simulating S2QA(-) recombination matched the experimental trend: the S2QA(-) recombination rate in PsbA1-PSII differed only slightly from that in PsbA3-PSII, while in Glu130-PsbA3-PSII there was a more pronounced slowdown of the radical pair decay. The simulation predicted a major effect of the PheoD1/PheoD1(-) potential on (1)O2 yield (~60% in PsbA1-PSII, ~20% in PsbA3-PSII and ~7% in Gln130-PsbA3 PSII), reflecting differential sensitivities to high light. PMID- 24060529 TI - Effect of tripterygium glycosides on pulmonary function in adjuvant arthritis rats. AB - BACKGROUND: Tripterygium is a Chinese herb with immunosuppressive effects and an established history of use in the treatment of rheumatoid arthritis. Previous studies demonstrated that tripterygium glycosides (TPG) alleviated Freund's complete adjuvant (FCA)-induced arthritis. Simultaneously, it has also been observed to impact the adjuvant arthritis (AA) associated with lung injury. In this study, we have investigated whether traditional Chinese medicine could attenuate lung injury induced by AA by observing the effects of TPG on the degree swelling, arthritis index (AI), lung index (LI), pulmonary function, cytokines, and the expression of regulatory T cells (Treg) and Foxp3 in AA rats. METHODS: A total of 48 rats were separated into four groups: normal control (NC), model control (MC), methotrexate (MTX), and TPG groups (12 in each). Except for the rats of NC group, those in the others groups were intracutaneously injected in the right hind limb with 0.1 ml of FCA. The NC and MC groups were treated with physiological saline, and the MTX and TPG groups were treated with MTX and TPG, respectively. Thirty days after administration, the changes in swelling degree, AI, LI, pulmonary function, Treg levels, the ultrastructure of the lung tissue, and the expression of Foxp3 in the lung tissue were observed. RESULTS: Compared with NC group, the level of swelling degree, AI, LI, 1 second average expiratory flow (FEV1/FVC %), the alveolar inflammation integration, tumor necrosis factor alpha (TNF-alpha), and endothelium-1 (ET-1) in the MC group had significantly increased (p < 0.01). However, the level of forced vital capacity (FVC), 25% vital capacity of the peak expiratory flow (FEF25), 50% vital capacity of the peak expiratory flow (FEF50), 75% vital capacity of the peak expiratory flow (FEF75), maximum mid-expiratory flow (MMF), peak expiratory flow (PEF), interleukin-10 (IL-10), CD4(+) CD25(+) Treg, and Foxp3 had significantly decreased (p < 0.01). LI, the alveolitis score, and ET-1 were found to decrease with TPG treatment. However, the levels of FVC, FEF25, FEF50, FEF75, MMF, PEF, IL 10 in serum, and CD4(+) CD25(+) Treg in peripheral blood had increased. The expressions of Foxp3 protein and mRNA in the lung tissue had also increased in the TPG group. Compared with the MTX group, the pulmonary function had enhanced, the structure of alveolar type II cells had improved, and the expression of the IL-10, Treg, and Foxp3 had elevated. However, the TNF-alpha and ET-1 levels had reduced as compared to the MTX group. CONCLUSION: The level of paw swelling and AI in the AA rats can be inhibited by TPG. The inflammatory response in lung tissue had also decreased, although there was significant improvement in the pulmonary function. The mechanism that would explain this observation is probably associated with the upregulation of the expression of IL-10, Treg, and Foxp3 and downregulation of the expression of TNF-alpha and ET-1. PMID- 24060530 TI - Readmission after stroke: recurrence or infection? PMID- 24060531 TI - Emerging from an unresponsive wakefulness syndrome: brain plasticity has to cross a threshold level. AB - Unresponsive wakefulness syndrome (UWS, previously known as vegetative state) occurs after patients survive a severe brain injury. Patients suffering from UWS have lost awareness of themselves and of the external environment and do not retain any trace of their subjective experience. Current data demonstrate that neuronal functions subtending consciousness are not completely reset in UWS; however, they are reduced below the threshold required to experience consciousness. The critical factor that determines whether patients will recover consciousness is the distance of their neuronal functions from this threshold level. Recovery of consciousness occurs through functional and/or structural changes in the brain, i.e., through neuronal plasticity. Although some of these changes may occur spontaneously, a growing body of evidence indicates that rehabilitative interventions can improve functional outcome by promoting adaptive functional and structural plasticity in the brain, especially if a comprehensive neurophysiological theory of consciousness is followed. In this review we will focus on the pathophysiological mechanisms involved in UWS and on the plastic changes operating on the recovery of consciousness. PMID- 24060532 TI - Deep brain stimulation in dementia-related disorders. AB - Memory loss is the key symptom of dementia-related disorders, including the prevalent Alzheimer's disease (AD). To date, pharmacological treatments for AD have limited and short-lasting effects. Therefore, researchers are investigating novel therapies such as deep brain stimulation (DBS) to treat memory impairment and to reduce or stop the progression of it. Clinical and preclinical studies have been performed and stimulations of the fornix, entorhinal cortex and nucleus basalis of Meynert have been carried out. The results of these studies suggest that DBS has the potential to enhance memory functions in patients and animal models. The mechanisms underlying memory enhancement may include the release of specific neurotransmitters and neuroplasticity. Some authors suggest that DBS might even be disease-modifying. Nevertheless, it is still premature to conclude that DBS can be used in the treatment of AD, and the field will wait for the results of ongoing clinical trials. PMID- 24060533 TI - Reply: endometrial TB-PCR positivity in women with unexplained infertility with no visible, microbiological or histopathological evidence of disease in a high TB burden area: whether to ignore or treat. PMID- 24060534 TI - Endometrial TB-PCR positivity in women with unexplained infertility with no visible, microbiological or histopathological evidence of disease in a high TB burden area: whether to ignore or treat. PMID- 24060535 TI - The development of meat tenderness is likely to be compartmentalised by ultimate pH. AB - Bull Musculus longissimus dorsi (n=63) were categorised into high (pH>=6.2), intermediate (pH 5.8-6.19) and low (<=5.79) ultimate pH (pHu) and aged up to 28 days post mortem at -1 degrees C. High pHu samples were acceptably tender at 1 day post mortem and significantly more tender than low pHu meat at all ageing timepoints (p<0.05). Rapid autolysis of MU-calpain in high pHu meat was linked with the more rapid degradation of titin, nebulin and filamin in this pHu group. Desmin degraded faster in low pHu meat and was concurrent with an increase of cathepsin B levels. The results from this study support the hypothesis that beef tenderisation is pHu compartmentalised with tenderness in high and low pHu meat characterised by variable rate of degradation of high and low molecular weight myofibrillar proteins during ageing, which are in turn regulated by MU-calpain and cathepsin B activities. PMID- 24060537 TI - Synthesis of divalent glycoamino acids with bis-triazole linkage. AB - Triazole-linked diversely functionalized divalent glycoconjugates were synthesized using Cu(I) catalyzed [3+2] cycloaddition reaction of the desired azides and alkynes. A series of per-O-acetylated glycopyranosyl azides and per-O acetylated glucopyranosyl azidoacetamide were reacted with nitro- and cyano functionalized dialkyne building blocks as precursors of alpha- and beta-amino acids, respectively. To introduce more conformational flexibility in the divalent molecules, peptoid-based triazole-linked divalent glycoconjugate was also synthesized. PMID- 24060536 TI - A real-time killing assay to follow viral epitope presentation to CD8 T cells. AB - The ability of cytotoxic T lymphocytes (CTL) to clear virus-infected cells requires the presentation of viral peptides intracellularly processed and displayed by major histocompatibility complex class I. Assays to measure CTL mediated killing often use peptides exogenously added onto target cells--which does not account for epitope processing--or follow killing of infected cells at a single time point. In this study we established a real-time fluorogenic cytotoxic assay that measures the release of the Glucose-6-phosphate-dehydrogenase by dying target cells every 5 min after addition of CTL. It has comparable sensitivity to (51)chromium-based killing assay with the additional advantage of incorporating the kinetics of epitope presentation. We showed that HIV infection of immortalized or primary CD4 T cells leads to asynchronous killing by two CTL clones specific for epitopes located in different proteins. Real-time monitoring of killing of virus-infected cells will enable identification of immune responses efficiently preventing virus dissemination. PMID- 24060538 TI - Efficient synthesis of pure monotosylated beta-cyclodextrin and its dimers. AB - 6-O-Monotosyl-beta-cyclodextrin (mono-Ts-betaCD) is one of the most important intermediates in the production of substituted betaCD. So far, performing the monotosylation reaction and, in particular, the purification steps was challenging, relied on toxic solvents, and resulted in long and expensive procedures at, importantly, low yields. Here, the reaction of cyclodextrin with p toluenesulfonyl chloride in aqueous environment is described to obtain a highly pure mono-Ts-betaCD, for which a single-step purification with a cation exchange resin was applied. With this synthetic route and purification, yields could be increased from typically <10-15% to 35%, and organic solvents could be avoided. As characterized by FTIR, mass spectrometry, elemental analysis, and NMR, mono-Ts betaCD was obtained with a molar purity of >98mol%. From mono-Ts-betaCD, beta cyclodextrin dimers linked by ethylenediamine (bis-Et-betaCD) were successfully prepared (yield 93%, purity 96mol%) in a one-step approach using an anion exchange resin to trap leaving groups that typically interfere in the reaction. This synthesis procedure with a direct collection of side-products may be a general strategy applicable for nucleophilic substitution of tosylated cyclodextrins. PMID- 24060539 TI - Rapid assessment procedures to detect hidden endemic foci in areas not subjected to mass drug administration in Sri Lanka. AB - For the declaration of elimination of lymphatic filariasis, reliable epidemiological data in all parts of a country are required. In Sri Lanka, due to social disturbance, there are 3 provinces whose endemicity has been declared unknown. Further, a recent report revealed an endemic pocket, which is on the border with the district that was not covered by the national elimination program. These facts indicate the necessity of more extensive studies to discover hidden endemic foci. To facilitate such studies, we evaluated 2 methods of Rapid Assessment Procedure (RAP) in Hambantota district, where the filariasis endemicity was low: (1) indirect questioning by mailing a questionnaire to each local leader (IndQ), asking about the presence of clinical cases, and (2) focus group discussion (FGD) by villagers. The information given by people was validated with clinical examination by doctors (CE) and IgG4 ELISA using urine samples. In the results: there was a strong positive correlation between CE and ELISA rates. The hydrocele rates obtained by FGD or IndQ were associated significantly with CE rates. The rates by FGD or Cluster-IndQ ('modified' IndQ) were also associated significantly with ELISA rates. The IndQ was most cost effective. Based on these findings, we have concluded that screening by IndQ and confirmation by the ELISA would be an effective and practical way in Sri Lanka to locate endemic foci in hitherto unsurveyed districts. PMID- 24060541 TI - Imaging mosquito transmission of Plasmodium sporozoites into the mammalian host: immunological implications. AB - The malaria infection is initiated in mammals by injection of the sporozoite stage of the parasite through the bite of Plasmodium-infected, female Anopheles mosquitoes. Sporozoites are injected into extravascular portions of the skin while the mosquito is probing for a blood source. Sporozoite gliding motility allows them to locate and penetrate blood vessels of the dermis or subcutaneous tissues; once in the blood, they reach the liver, within which they continue their development. Some of the injected parasites invade dermal lymph vessels and travel to the proximal draining lymphatic node, where they interact with host immunocytes. The host responds to viable or attenuated sporozoites with antibodies directed against the immunodominant circumsporozoite protein (CSP), as well as against other sporozoite proteins. These CSP antibodies can inhibit the numbers of sporozoites injected by mosquitoes and the motility of those injected into the skin. This first phase of the immune response is followed by cell mediated immunity involving CD8 T-cells directed against the developing liver stage of the parasite. This review discusses the early history of imaging studies, and focuses on the role that imaging has played in enabling a better understanding of both the induction and effector functions of the immune responses against sporozoites. PMID- 24060540 TI - Plasmodium falciparum: genetic diversity and complexity of infections in an isolated village in western Thailand. AB - Genetic diversity of Plasmodium falciparum is intimately associated with morbidity, mortality and malaria control strategies. It is therefore imperative to study genetic makeup and population structure of this parasite in endemic areas. In Kong Mong Tha, an isolated village in western Thailand, the majority of P. falciparum infections are asymptomatic. In this study we investigated complexity of infections and single nucleotide polymorphisms (SNPs) in the P. falciparum population of Kong Mong Tha, and compared results with those previously obtained from Mae Sod, in northwestern Thailand, where the majority of infections were symptomatic. Using PCR-based determination of the 5' merozoite surface protein 1 gene (msp1) recombinant types, we found that 39% of 59 P. falciparum isolates from Kong Mong Tha had multiple 5' recombinant types with a mean number of 1.54. These values were much lower than those obtained from Mae Sod: 96% for multiple infections and with a mean number of 3.61. Analysis of full length sequences of two housekeeping genes, the P-type Ca(2+)-transporting ATPase gene (n=33) plus adenylosuccinate lyase gene (n=33), and three vaccine candidate antigen genes, msp1 (n=26), the circumsporozoite protein gene, csp (n=30) and the apical membrane antigen 1 gene, ama 1 (n=32), revealed that in all of these genes within-population SNP diversity was at similar levels between Kong Mong Tha and Mae Sod, suggesting that the extent of MOI and clinical manifestations of malaria are not strongly associated with genetic diversity. Additionally, we did not detect significant genetic differentiation between the two parasite populations, as estimated by the Wright's fixation index of inter-population variance in allele frequencies, suggesting that gene flow prevented the formation of population structuring. Thus, this study highlights unique features of P. falciparum populations in Thailand. The implications of these finding are discussed. PMID- 24060542 TI - Insights into the development of Notocotylus attenuatus (Digenea: Notocotylidae) in Lymnaea stagnalis: from mother sporocyst to cercariae. AB - Notocotylus attenuatus (Digenea: Notocotylidae) is a monostome fluke parasitizing the intestinal caeca of waterfowl that uses an injection apparatus to infect its intermediate snail host. Morphology of the invading larva (a sporocyst), and the intramolluscan larval development of this fluke have not been characterized extensively. In this study, experimental infections of Lymnaea stagnalis using N. attenuatus eggs resulted in the development of sporocysts containing one germ ball or mother redia between 12 and 21 days post exposure (p.e.) within the hepatopancreas. Independent mother rediae and developing daughter rediae were present between day 25 and day 42 p.e. Cercariae, within the body of rediae, were detected 42 days p.e. The development of daughter rediae and cercariae started posteriorly in the body of parent redia and these larvae migrated anteriorly during development towards the birth pore. A cercaria was also observed emerging from the birth pore and released cercariae maturated further within the snail hepatopancreas prior to leaving the snail. The intramolluscan development was completed 45 days p.e. when the first fully formed cercariae were shed into the outer environment. These data detail the fascinating post-embryonic development of N. attenuatus and highlight the intricate nature of larval transitions within its snail host. PMID- 24060543 TI - Post-translational modification of the pyruvate phosphate dikinase from Trypanosoma cruzi. AB - In kinetoplastids such as Trypanosoma cruzi, glycolysis is compartmentalized in peroxisome-like organelles called glycosomes. Pyruvate phosphate dikinase (PPDK), an auxiliary enzyme of glycolysis, is also located in the glycosomes. We have detected that this protein is post-translationally modified by phosphorylation and proteolytic cleavage. On western blots of T. cruzi epimastigotes, two PPDK forms were found with apparent MW of 100 kDa and 75 kDa, the latter one being phosphorylated at Thr481, a residue present in a highly conserved region. In subcellular localization assays the 75 kDa PPDK was located peripherally at the glycosomal membrane. Both PPDK forms were found in all life-cycle stages of the parasite. When probing for both PPDK forms during a growth of epimastigotes in batch culture, an increase in the level of the 75 kDa form and a decrease of the 100 kDa one were observed by western blot analysis, signifying that glucose starvation and the concomitant switch of the metabolism to amino acid catabolism may play a role in the post-translational processing of the PPDK. Either one or both of the processes, phosphorylation and proteolytic cleavage of PPDK, result in inactivation of the enzyme. It remains to be established whether the phenomenon exerts a regulatory function. PMID- 24060544 TI - Zinc oxide nanoparticles inhibit Ca2+-ATPase expression in human lens epithelial cells under UVB irradiation. AB - Epidemiological and experimental studies have revealed that lens epithelial cells exposed to ultraviolet B (UVB) light could be induced apoptosis, and lens epithelial cell apoptosis can initiate cataractogenesis. Posterior capsular opacification (PCO), the most frequent complication after cataract surgery, is induced by the proliferation, differentiation, migration of lens epithelial cells. Thus, inhibiting the proliferation of lens epithelial cells could reduce the occurrence of PCO. It is reported that zinc oxide (ZnO) nanoparticles have great potential for the application of biomedical field including cancer treatment. In the present study, we investigated the cytotoxic effect of ZnO nanoparticles on human lens epithelial cell (HLEC) viability. In addition, changes in cell nuclei, apoptosis, reactive oxygen species and intracellular calcium ion levels were also investigated after cells treated with ZnO nanoparticles in the presence and absence of UVB irradiation. Meanwhile, the expression of plasma membrane calcium ATPase 1 (PMCA1) was also determined at gene and protein levels. The results indicate that ZnO nanoparticles and UVB irradiation have synergistic inhibitory effect on HLEC proliferation in a concentration-dependent manner. ZnO nanoparticles can increase the intracellular calcium ion level, disrupt the intracellular calcium homeostasis, and decrease the expression level of PMCA1. UVB irradiation can strengthen the effect of reduced expression of PMCA1, suggesting that both UVB irradiation and ZnO nanoparticles could exert inhibitory effect on HLECs via calcium-mediated signaling pathway. ZnO nanoparticles have great potential for the treatment of PCO under UVB irradiation. PMID- 24060545 TI - Establishment of an X-ray irradiation-induced glossitis model in rats: biphasic elevation of proinflammatory cytokines and chemokines. AB - Oral mucositis is a frequent and serious side effect in patients who receive radiotherapy for head and neck cancer. The purpose of this study was to develop a noninvasive and quantitative model of oral mucositis in rats, investigate the pathophysiology, and evaluate the efficacy of pharmacological interventions. Rats received a single dose of 15 Gy of X-rays to the snout after shielding of the remainder of the rat body with lead plates to protect the body from irradiation (day 0). After irradiation, the macroscopic area of tongue injury gradually increased. The total area of injury and the ulcer-like area reached a maximum on day 7 and then gradually decreased until disappearance on day 28. Expression of proinflammatory cytokines and chemokines occurred transiently within 1-4 hours after irradiation and returned to a normal level at 24 hours. This expression was again observed from days 3 to 5 and increased significantly on day 7, which approximately coincided with the histologic severity of tissue damage. Subcutaneous administration of palifermin at 3 mg/kg per day for 3 consecutive days before irradiation completely prevented ulcer formation in this model. In conclusion, we established a novel model of glossitis in rats, induced by X-ray irradiation, in which biphasic elevations of expression of proinflammatory cytokines and chemokines could be monitored. This model is considered useful to investigate the pathophysiology of oral mucositis and evaluate the preventive effect of pharmacological interventions on oral mucositis induced by X-ray irradiation. PMID- 24060546 TI - Human brains found in a fire-affected 4000-years old Bronze Age tumulus layer rich in soil alkalines and boron in Kutahya, Western Anatolia. AB - Undecomposed human bodies and organs always attracted interest in terms of understanding biological tissue stability and immortality. Amongst these, cases of natural mummification found in glaciers, bog sediments and deserts caused even more attention. In 2010, an archeological excavation of a Bronze Age layer in a tumulus near the Western Anatolia city Kutahya revealed fire affected regions with burnt human skeletons and charred wooden objects. Inside of the cracked skulls, undecomposed brains were discernible. To analyze the burial taphonomy of the rare phenomenon of brain preservation, we analyzed brains, bone, teeth and surrounding soils elements using Inductively Coupled Plasma-Mass Spectrometer (ICP-MS). Adipocere formation or saponification of postmortem tissue fat requires high levels of alkalinity and especially potassium. Indeed, ICP-MS analysis of the brain, teeth and bone and also of the surrounding soil revealed high levels of potassium, magnesium, aluminum and boron, which are compatible with the famous role of Kutahya in tile production with its soil containing high level of alkalines and tile-glazing boron. Fatty acid chromatography revealed simultaneous saturation of fats and protection of fragile unsaturated fatty acids consistent with soil-presence of both pro-oxidant and anti-oxidant trace metals. Computerized tomography revealed protection of diencephalic, metencephalic and occipital tissue in one of the best-preserved specimens. Boron was previously found as an intentional preservative of Tutankhamen and Deir el Bahari mummies. Here, in natural soil with its insect-repellant, anti-bacterial and fire resistance qualities it may be a factor to preserve heat-affected brains as almost bioporcellain specimens. PMID- 24060547 TI - [Maternal diabetic ketosic decompensation which occurred during corticotherapy for fetal lung maturation. A report of three cases]. AB - Three cases of ketosis decompensation occurring immediately in type I diabetic after corticotherapy for lung foetal maturation (LFM) are reported. Few of observations have been published. Increasing doses of insulin is mandatory under close monitoring of blood glucose levels, in particular according to the protocol proposed by Kaushal et al.: infusion of insulin adapted to the results of glucose levels, as a supplementation to the usual doses in each patient. Diabetes does not lead to hesitate prescribing a corticotherapy for LFM, but requires a strict control of needs in insulin to avoid a ketosis decompensation. PMID- 24060548 TI - Phasic boosting of auditory perception by visual emotion. AB - Emotionally negative stimuli boost perceptual processes. There is little known, however, about the timing of this modulation. The present study aims at elucidating the phasic effects of, emotional processing on auditory processing within subsequent time-windows of visual emotional, processing in humans. We recorded the electroencephalogram (EEG) while participants responded to a, discrimination task of faces with neutral or fearful expressions. A brief complex tone, which subjects, were instructed to ignore, was displayed concomitantly, but with different asynchronies respective to, the image onset. Analyses of the N1 auditory event-related potential (ERP) revealed enhanced brain, responses in presence of fearful faces. Importantly, this effect occurred at picture-tone asynchronies of, 100 and 150ms, but not when these were displayed simultaneously, or at 50ms or 200ms asynchrony. These results confirm the existence of a fast operating crossmodal effect of visual emotion on auditory, processing, suggesting a phasic variation according to the time-course of emotional processing. PMID- 24060549 TI - The syphilis epidemics in Hungary 1985-2004, before entering the European Union. AB - In the decade prior to the turn of the millennium, great interest was raised, and rightly so, by the STD (syphilis and HIV/AIDS) epidemic that developed in the Eastern-Central European Region. Its coincidence with the far-reaching political and economic changes that took place at that time suggested a link between the two events.Hungary, where these infections had had low incidence before the period investigated, also experienced an increase in STD incidence. The trend in syphilis infection during the 20 years between 1985-2004, that preceded the turn of the millennium and when finally Hungary joined the European Union, have been analyzed. Due to the nature of venereological epidemiological surveillance in Hungary, syphilis prevalence data are appropriate for further analysis from socio demographic aspects. Behavioural changes underlying the specific features of the epidemics in Hungary had developed several years earlier and cannot be linked to the political and economic changes that started in the early 90s. The only exception is the phenomenon of growing migration that appeared simultaneously with the political changes and had a decisive impact on the spread and level of infection in some areas in the country. As shown by our data, trends seen in specific demographic groups (females, rural population) preceded the suddenly occurring political changes by about 15 years. PMID- 24060550 TI - Syphilis and HIV coinfection - Hungarian Sexually Transmitted Infection Centre Experience between 2005 and 2013. AB - BACKGROUND: STIs like HIV and syphilis are acquired as comorbidities by high risk populations and may influence their original course and prognosis. METHODS: Between January of 2005 and 2013 data of syphilis and HIV patients were collected at the Department of Dermatology of Semmelweis University, Budapest. Diagnostic procedures included clinical analysis and screening of serum samples for Treponema pallidum and HIV antibodies. RESULTS: A total of 1,401 new syphilitic and 338 new HIV infections were diagnosed. In syphilis patients 86.58% had monoinfection,7.92% already had an HIV infection and 5.5% had acquired syphilis and HIV infection simultaneously, so 22.78% of the new HIV patients acquired the infection with syphilis together. Male gender, MSM (men who had sex with men) orientation and positive past venerological history were dominant in all groups. Most patients were diagnosed in a latent infectious stage based on the result of a serological check-up. Secondary stage and neurosyphilis were more common in coinfections. CONCLUSION: (i) male gender, MSM orientation, and positive venerological history are risk factors for acquiring new STIs, (ii) clinical course were different in HIV infected patients, (iii) but their timely and regular check-ups resulted in earlier diagnosis of syphilis, suggesting the necessity for frequent screening. PMID- 24060551 TI - Characterization of SCCmec types, antibiotic resistance, and toxin gene profiles of Staphylococcus aureus strains. AB - Methicillin-resistant Staphylococcus aureus (MRSA) causes serious nosocomial and community acquired infections. Resistance to methicillin is mediated by the mecA gene, which is inserted in a mobile genetic element called staphylococcal cassette chromosome mec (SCCmec). We determined the SCCmec types, the occurrence of genes encoding toxic shock syndrome toxin (tst), exfoliative toxin (eta, etb), Panton-Valentine leukocidin (pvl) as well as antibiotic susceptibility of these isolates. Among 65 hospital-acquired methicillin-resistant S. aureus (HA-MRSA) strains, SCCmec types II, III and IV were identified. Type III SCCmec was the most prevalent (62%), followed by mec types II (24%) and IV (14%). Four community acquired methicillin-resistant S. aureus (CA-MRSA) strains carried SCCmec type IV and were pvl-positive. The most prevalent gene among HA-MRSA was pvl. The toxic shock syndrome toxin and exfoliative toxin genes were found only in hospital acquired methicillin-resistant S. aureus. The results of this study demonstrate that the SCCmec type III is predominant among strains recovered from hospitalized patients with infections and that these strains were resistant to many antibiotics used in the treatment of staphylococcal infections. PMID- 24060552 TI - Strain differences in the humoral immune response to commensal bacterial antigens in rats. AB - We have investigated the immune response to commensal bacterial species in the two inbred rat strains: Dark Agouti (DA) and Albino Oxford (AO). The predominant Gram-negative aerobe in our rats' intestinal bacterial flora was Escherichia coli, while Proteus mirabilis was isolated only from DA rat strain. We report that sera from both DA and AO rat strains contain specific IgG against predominant intestinal flora. Intramuscular administration of commensal bacterial antigens provoked only Th1-type antibody response in AO rats while DA rats developed mixed Th1- and Th2-type antibody response to E. coli and Th1-type response to P. mirabilis antigens. Weaker antibody production to own E. coli and higher serum levels of natural IgG and IgA P. mirabilis-specific antibodies combined with higher CD3+ cells proliferation was found in AO rats. Strain difference in the pattern of antibody production and differential regulation of immune response to commensal bacteria may contribute to the marked differences in the immune reactivity of AO and DA rats. PMID- 24060553 TI - The effect of easily degradable substrate feeding on the community structure of laboratory-scale wastewater sludge digesters. AB - The effect of several easily degradable substrates, such as protein, starch and sunflower oil was investigated on the bacterial community of a laboratory-scale biogas model system. Besides measuring gas yield, Denaturing Gradient Gel Electrophoresis (DGGE), Phospholipids Fatty Acid Analysis (PLFA) for Bacteria and T-RFLP analysis of the mcrA gene for Archaea were used. The community of the examined biogas reactors adapted to the new substrates through a robust physiological reaction followed by moderate community abundance shifts. Gas yield data clearly demonstrated the physiological adaptation to substrate shifts. Statistical analysis of DNA and chemotaxonomic biomarkers revealed community abundance changes. Sequences gained from DGGE bands showed the dominance of the phyla Bacteroidetes and the presence of Firmicutes (Clostridia) and Thermotogae. This was supported by the detection of large amounts of branched 15-carbon non hydroxy fatty acids in PLFA profiles, as common PLFA markers of the Bacteroidetes group. Minor abundance ratios changes were observed in the case of Archaea in accordance with changes of the fed substrates. PMID- 24060554 TI - Use of a modified fluorescent in situ hybridization procedure to improve the identification of Streptococcus pneumoniae in blood cultures. AB - Streptococcus pneumoniae is an important causative agent for bacteremia. Fluorescent in situ hybridization (FISH) is a helpful molecular technique for the rapid identification of S. pneumoniae in positive blood cultures. There are many reports concerning the application of an enzymatic treatment with lysozyme in the FISH procedure for partial cell wall digestion of S. pneumoniae. However, this study was aimed to test the FISH procedure without enzymatic treatment for the identification of S. pneumoniae in blood culture specimens. Seventy-seven positive blood culture specimens containing Gram-positive cocci were examined by both the conventional laboratory methods and FISH. Detection of S. pneumoniae was performed by two FISH procedures: one procedure was performed with an enzymatic treatment step and the other one was done without enzymatic treatment. In addition, the specimens were tested by the FISH procedure with enzymatic treatment to detect Streptococcus pyogenes and Enterococcus. The specificity of FISH in comparison with conventional culture methods was 100%. The sensitivity of the FISH procedure with enzymatic treatment for the detection of S. pneumoniae was 90%, whereas, the sensitivity of the FISH procedure without enzymatic treatment was 100%. In fact, by omission of enzymatic treatment, detection of S. pneumoniae was improved in 6 specimens. The results of the FISH and culture methods for the detection of S. pyogenes and Enterococcus were compatible. Altogether, FISH procedure without enzymatic treatment step seems to improve the detection of S. pneumoniae in some cases. Thus, for successful detection of S. pneumoniae, we suggest the application of both FISH procedures (the procedure with enzymatic treatment and the procedure without enzymatic treatment) for each blood culture specimen. PMID- 24060555 TI - Twitching motility activity, biofilm formation, and genetic typing for clinical isolates of Pseudomonas aeruginosa by random amplified DNA PCR. AB - A total of 44 Pseudomonas aeruginosa clinical strains were studied by random amplified polymorphic DNA PCR. (RAPD)-PCR analysis determined the presence of 15 genotypes, with the most frequent genotype A detected in 27.3% of the strains. It was observed that clonally related strains were isolated from patients within the same ward and among different wards of two hospitals. The collection of P. aeruginosa was also screened in microtiter plates made of polystyrene to test for their ability to form a biofilm on an abiotic surface. Generally most of the strains (88.6%) showed a significant ability to form biofilm. We found a correlation between twitching motility activity and between biofilm production and source of isolation of strains. No correlation was observed between P. aeruginosa strain genotypes and biofilm formation, as well as source and place of isolation. PMID- 24060556 TI - Spatial and temporal changes of bacterial communities inhabiting the well waters of Harkany Spa. AB - In this study, changes in the bacterial community composition of the well waters of Harkany Spa were examined. Physical and chemical properties of mixing subsurface cold and thermal karst waters were correlated to shifts in bacterial community structures analyzed by denaturing gradient gel electrophoresis (DGGE) and principal component analysis (PCA). In addition, mineral components of the pellets were investigated by scanning electron microscopy. Samples from the effluent waters of Budostapolca I and II, Matty and Thermal VI wells were taken seasonally in 2007 and 2008. The comparison of the results of DGGE and PCA analyses showed that bacterial communities from the Budostapolca wells were distinct from those of Matty and Thermal VI, but seasonal changes were not detected. According to the phylogenetic analysis of the excised DGGE bands, presence of chemolithotrophic Proteobacteria (Thiobacillus, Thiothrix, and distant relatives of Sulfurospirillum) were typical in the Budostapolca wells, while members of Actinobacteria (Plantibacter, Actinobacterium, Microbacterium) and Firmicutes (Planococcus) were characteristic to the Matty and Thermal VI wells. In the pellets pyrite framboid crystals were observed by electron microscopy, which are minerals known to be biologically induced by dissimilatory iron- and sulfur (sulfate)-reducing bacteria. PMID- 24060557 TI - Application of special oligotrophic media for cultivation of bacterial communities originated from ultrapure water. AB - Because of the selectivity of the commonly used media it is very difficult to cultivate bacteria inhabiting ultrapure waters under laboratory conditions. In this study 5 new media (synthetic and complex) were developed to reveal bacterial community of the ultrapure water originated from the water purification system of a Hungarian power plant which was studied already with using traditional media. Composition of the new media tends to reproduce the nutrient deficient conditions of the investigated water, therefore media were highly oligotrophic. Altogether 122 bacterial strains were isolated from the 5 different media. Based on ARDRA grouping 27 strains were chosen for the partial 16S rRNA gene sequence analysis. The results showed that the applied media strongly influence the composition of the cultivable bacterial community. A larger scale of alpha-Proteobacteria (Mesorhizobium spp., Ancylobacter sp., Methylobacterium sp.) and many Actinobacteria (Leifsonia sp., Microbacterium spp., Mycobacterium spp.) could be isolated from the same ultrapure water system than with any other cultivation methods or media applied before. Moreover, two novel bacterial taxa could be isolated from the studied water purification system. PMID- 24060558 TI - Comparing the efficacy of hyper-pure chlorine-dioxide with other oral antiseptics on oral pathogen microorganisms and biofilm in vitro. AB - This study examines the antibacterial properties of sodium hypochlorite (NaOCl), chlorhexidine gluconate (CHX), Listerine(r), and high purity chlorine dioxide (Solumium, ClO2) on selected common oral pathogen microorganisms and on dental biofilm in vitro. Antimicrobial activity of oral antiseptics was compared to the gold standard phenol. We investigated Streptococcus mutans, Lactobacillus acidophilus, Enterococcus faecalis, Veillonella alcalescens, Eikenella corrodens, Actinobacillus actinomycetemcomitans and Candida albicans as some important representatives of the oral pathogens. Furthermore, we collected dental plaque from the upper first molars of healthy young students. Massive biofilm was formed in vitro and its reduction was measured after treating it with mouthrinses: CHX, Listerine(r) or hyper pure ClO2. Their biofilm disrupting effect was measured after dissolving the crystal violet stain from biofilm by photometer. The results have showed that hyper pure ClO2 solution is more effective than other currently used disinfectants in case of aerobic bacteria and Candida yeast. In case of anaerobes its efficiency is similar to CHX solution. The biofilm dissolving effect of hyper pure ClO2 is significantly stronger compared to CHX and Listerine(r) after 5 min treatment. In conclusion, hyper pure ClO2 has a potent disinfectant efficacy on oral pathogenic microorganisms and a powerful biofilm dissolving effect compared to the current antiseptics, therefore high purity ClO2 may be a new promising preventive and therapeutic adjuvant in home oral care and in dental or oral surgery practice. PMID- 24060560 TI - Making WAAVES in the vocalization community, but how big is the splash? PMID- 24060561 TI - Single-dose, randomized crossover comparisons of different-strength imatinib mesylate formulations in healthy Korean male subjects. AB - BACKGROUND: Imatinib mesylate is used to treat chronic myeloid leukemia and advanced gastrointestinal stromal tumors. OBJECTIVE: The purpose of this study was to compare the pharmacokinetics of 2 different strengths of the imatinib formulation containing 100 mg (reference) and 400 mg (test) to satisfy the regulatory requirement for marketing. METHODS: A single-center, randomized, single-dose, open-label, 2-period, 2-sequence, comparative crossover study with a 14-day washout period was conducted in 30 healthy male volunteers. Plasma samples for the drug analysis were collected up to 72 hours after drug treatment. Participants received either the reference (4 tablets of 100-mg imatinib) or the test (1 tablet of 400-mg imatinib) formulation during the first period and the alternative formulation during the second period. The safety profiles and tolerability of the 2 formulations were also assessed based on physical examinations, laboratory tests, a 12-lead ECG, and vital signs. RESULTS: Thirty participants were initially enrolled; their mean (SD) age, height, weight, and body mass index were 24.9 (2.0) years (range, 23-30 years), 174 (5) cm (range, 164-185 cm), 69.9 (2.0) kg (range, 54.1-87.4 kg), and 23.0 (2.0) kg/m(2) (range, 18.5-26.9 kg/m(2)); 28 healthy participants completed both treatment periods. Two subjects did not complete the study because they withdrew consent for personal reasons. The observed mean (SD) Cmax, AUC0-last, and AUC0-infinity values for the reference formulation were 1792 (357) ng/mL, 28,485 (6274) ng . h/mL, and 29,079 (6371) ng . h/mL, respectively. Corresponding values for the test formulation were 1710 (312) ng/mL, 27,222 (4624) ng . h/mL , and 27,872 (4751) ng . h/mL. The geometric mean ratios (90% CIs) between the 2 formulations at the 400-mg dose of imatinib were 0.9579 (0.9054-1.0136) for Cmax, 0.9652 (0.9174-1.0155) for AUC0 last, and 0.9679 (0.9203-1.0179) for AUC0-infinity, respectively. During the study period, 6 adverse events (3 for the reference and 3 for the test formulation) were reported; all were transient, mild, and resolved completely during the treatment period. There were 4 cases of nausea and 1 case each of dizziness and oropharyngeal pain. Four adverse events were considered related to the study drugs. CONCLUSIONS: The results showed that despite the different strengths of the 2 imatinib formations, the test and reference formulations both met the regulatory criteria for pharmacokinetic equivalence at a dose of imatinib 400 mg in these healthy Korean male subjects. Both imatinib formulations seemed to be generally well tolerated. ClinicalTrials.gov identifier: NCT01270984. PMID- 24060562 TI - Interaction of prenylated chalcones and flavanones from common hop with phosphatidylcholine model membranes. AB - Common hop (Humulus lupulus) constitutes a source of numerous prenylated chalcones such as xanthohumol (XH) and flavanones such as 8-prenylnaringenin (8 PN) and isoxanthohumol (IXH). Range of their biological activities includes estrogenic, anti-inflammatory, anti-infective, anti-cancer, and antioxidant activities. The aim of the present work was to characterize the influence of prenylated polyphenols on model 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) membranes by means of differential scanning calorimetry (DSC), fluorescence and attenuated total reflection Fourier transform infrared (ATR FTIR) spectroscopies. All studied compounds intercalated into DPPC bilayers and decreased its melting temperature as recorded by DSC, Laurdan and Prodan fluorescence, and ATR-FTIR. Polyphenols interacted mainly with glycerol backbone and acyl chain region of membrane. Magnitude of the induced effect correlated both with lipophilicity and molecular shape of the studied compounds. Elbow shaped 8-PN and IXH were locked at polar-apolar region with their prenyl chains penetrating into hydrophobic part of the bilayer, while relatively planar XH molecule adopted linear shape that resulted in its deeper insertion into hydrophobic region. Additionally, by means of DSC and Laurdan fluorescence IXH was demonstrated to induce lateral phase separation in DPPC bilayers in gel-like state. It was assumed that IXH-rich and IXH-poor microdomains appeared within membrane. Present work constitutes the first experimental report describing interactions of prenylated hop polyphenols with phospholipid model membranes. PMID- 24060563 TI - Description of a utrophin associated protein complex in lipid raft domains of human artery smooth muscle cells. AB - The dystrophin-associated protein complex (DAPC) is a multimeric complex that links the extracellular matrix to the actin cytoskeleton, and in some cases dystrophin can be substituted by its autosomal homologue utrophin to form the utrophin-associated protein complex (UAPC). Both complexes maintain the stability of plasma membrane during contraction process and play an important role in transmembrane signaling. Mutations in members of the DAPC are associated with muscular dystrophy and dilated cardiomyopathy. In a previous study with human umbilical cord vessels, we observed that utrophin colocalize with caveolin-1 (Cav 1) which proposed the presence of UAPC in the plasma membrane of vascular smooth muscle (VSM). In the current study, we demonstrated by immunofluorescence analysis, co-immunoprecipitation assays, and subcellular fractionation by sucrose gradients, the existence of an UAPC in lipid raft domains of human umbilical artery smooth muscle cells (HUASMC). This complex is constituted by utrophin, beta-DG, epsilon-SG, alpha-smooth muscle actin, Cav-1, endothelial nitric oxide synthase (eNOS) and cavin-1. It was also observed the presence of dystrophin, utrophin Dp71, beta-SG, delta-SG, delta-SG3 and sarcospan in non-lipid raft fractions. Furthermore, the knockdown of alpha/beta-DG was associated with the decrease in both the synthesis of nitric oxide (NO) and the presence of the phosphorylated (active) form of eNOS; and with a reduction in the downstream activation of some cGMP signaling transduction pathway components. Together these results show the presence of an UAPC complex in HUASMC that may participate in the activity regulation of eNOS and in the vascular function. PMID- 24060566 TI - Direct observation of antisite defects in LiCoPO4 cathode materials by annular dark- and bright-field electron microscopy. AB - LiCoPO4 cathode materials have been synthesized by a sol-gel route. X-ray diffraction analysis confirmed that LiCoPO4 was well-crystallized in an orthorhombic structure in the Pmna space group. From the high-resolution transmission electron microscopy (HR-TEM) image, the lattice fringes of {001} and {100} are well-resolved. The HR-TEM image and selected area electron diffraction pattern reveal the highly crystalline nature of LiCoPO4 having an ordered olivine structure. The atom-by-atom structure of LiCoPO4 olivine has been observed, for the first time, using high-angle annular dark-field (HAADF) and annual bright field scanning transmission electron microscopy. We observed the bright contrast in Li columns in the HAADF images and strong contrast in the ABF images, directly indicating the antisite exchange defects in which Co atoms partly occupy the Li sites. The LiCoPO4 cathode materials delivered an initial discharge capacity of 117 mAh/g at a C/10 rate with moderate cyclic performance. The discharge profile of LiCoPO4 shows a plateau at 4.75 V, revealing its importance as a potentially high-voltage cathode. The direct visualization of atom-by-atom structure in this work represents important information for the understanding of the structure of the active cathode materials for Li-ion batteries. PMID- 24060565 TI - Biomembrane disruption by silica-core nanoparticles: effect of surface functional group measured using a tethered bilayer lipid membrane. AB - Engineered nanomaterials (ENM) have desirable properties that make them well suited for many commercial applications. However, a limited understanding of how ENM's properties influence their molecular interactions with biomembranes hampers efforts to design ENM that are both safe and effective. This paper describes the use of a tethered bilayer lipid membrane (tBLM) to characterize biomembrane disruption by functionalized silica-core nanoparticles. Electrochemical impedance spectroscopy was used to measure the time trajectory of tBLM resistance following nanoparticle exposure. Statistical analysis of parameters from an exponential resistance decay model was then used to quantify and analyze differences between the impedance profiles of nanoparticles that were unfunctionalized, amine functionalized, or carboxyl-functionalized. All of the nanoparticles triggered a decrease in membrane resistance, indicating nanoparticle-induced disruption of the tBLM. Hierarchical clustering allowed the potency of nanoparticles for reducing tBLM resistance to be ranked in the order amine>carboxyl~bare silica. Dynamic light scattering analysis revealed that tBLM exposure triggered minor coalescence for bare and amine-functionalized silica nanoparticles but not for carboxyl-functionalized silica nanoparticles. These results indicate that the tBLM method can reproducibly characterize ENM-induced biomembrane disruption and can distinguish the BLM-disruption patterns of nanoparticles that are identical except for their surface functional groups. The method provides insight into mechanisms of molecular interaction involving biomembranes and is suitable for miniaturization and automation for high-throughput applications to help assess the health risk of nanomaterial exposure or identify ENM having a desired mode of interaction with biomembranes. PMID- 24060564 TI - PEGylated cationic liposome-DNA complexation in brine is pathway-dependent. AB - Cationic liposome-DNA (CL-DNA) complexes, are regarded as promising materials for safe and efficient delivery of genes for therapeutical applications. In order to be used in vivo, these complexes may be coated with a hydrophilic polymer (e.g. polyethylene-glycol, PEG) that provides steric stabilization towards adhesion of proteins and removal by the immune system. In this work we study the influence of the initial salt concentration (Cs) - which modulates the electrostatic interaction between oppositely charged vesicles and DNA - on the structure and stability of PEGylated CL-DNA particles. Previous small-angle X-ray scattering has shown that if non-PEGylated or PEGylated CL-DNA lamellar complexes are prepared in water, their structure is well defined with a high number of lipid membrane-DNA layers (larger than 20). Here we show that if these complexes are transferred to saline media (150mM NaCl or DMEM, both near physiological conditions), this structure remains nearly unchanged. Conversely, if PEGylated complexes are prepared in saline media, their lamellar structure is much looser, with fewer number of layers. This pathway dependent behavior of PEGylated complex formation in brine is modulated by the liposome membrane charge density and the mole fraction of PEG 2000 in the membranes, with the average number of layers decreasing with increasing Cs and in going from 5mol% to 10mol% PEG-lipid. Each of these structures (high and low number of layers) is stable with time, suggesting that despite complex formation being thermodynamically favored, the complexation process in PEGylated membranes, which determines the number of layers per particle, is kinetically controlled. In the extreme case (when polymer repulsions from 10mol% PEG-lipid are maximized and electrostatic attraction between PEGylated CLs and DNA are minimized at low membrane charge density) complex formation is suppressed at high Cs=150mM. PMID- 24060567 TI - Vaccines against diseases transmitted from animals to humans: a one health paradigm. AB - This review focuses on the immunization of animals as a means of preventing human diseases (zoonoses). Three frameworks for the use of vaccines in this context are described, and examples are provided of successes and failures. Framework I vaccines are used for protection of humans and economically valuable animals, where neither plays a role in the transmission cycle. The benefit of collaborations between animal health and human health industries and regulators in developing such products is discussed, and one example (West Nile vaccine) of a single product developed for use in animals and humans is described. Framework II vaccines are indicated for domesticated animals as a means of preventing disease in both animals and humans. The agents of concern are transmitted directly or indirectly (e.g. via arthropod vectors) from animals to humans. A number of examples of the use of Framework II vaccines are provided, e.g. against brucellosis, Escherichia coli O157, rabies, Rift Valley fever, Venezuelan equine encephalitis, and Hendra virus. Framework III vaccines are used to immunize wild animals as a means of preventing transmission of disease agents to humans and domesticated animals. Examples are reservoir-targeted, oral bait rabies, Mycobacterium bovis and Lyme disease vaccines. Given the speed and lost cost of veterinary vaccine development, some interventions based on the immunization of animals could lead to rapid and relatively inexpensive advances in public health. Opportunities for vaccine-based approaches to preventing zoonotic and emerging diseases that integrate veterinary and human medicine (the One Health paradigm) are emphasized. PMID- 24060568 TI - NIAID meeting report: improving malaria vaccine strategies through the application of immunological principles. AB - A highly efficacious vaccine to prevent malaria infection or clinical disease is still far from reality despite several decades of intensive effort and a growing global commitment in malaria vaccine development. Further understanding of the mechanisms required for induction of effective host immune responses and maintenance of long-term protective immunity is needed to facilitate rational approaches for vaccine design and evaluation. The National Institute of Allergy and Infectious Diseases (NIAID) conducted a workshop on June 18-19, 2012 with experts in the fields of malaria vaccine development, malaria immunology, and basic immunology to address issues associated with improving our current understanding of malaria vaccine immunity. This report summarizes the discussion and major recommendations generated by the workshop participants regarding the application of recent advances in basic immunology and state-of-the-art immunological tools to improve progress and help address current challenges and knowledge gaps in malaria vaccine development. PMID- 24060569 TI - Cost-effectiveness of rotavirus vaccination programs in Taiwan. AB - BACKGROUND: In Taiwan, two rotavirus vaccines are available on the private market, but are not included in the National Immunization Program (NIP). To help assess whether to include rotavirus vaccines in the NIP, we examined the potential impact and cost-effectiveness of vaccination, from the health care system perspective alone. METHODS: We used a Microsoft Excel-based model to assess rotavirus vaccination impact on rotavirus disease burden and the cost effectiveness of 2-dose and 3-dose vaccination programs among a birth cohort of Taiwanese children followed for 5 years. Principal model inputs included data on rotavirus disease burden and related healthcare costs, vaccination cost and coverage rates, and vaccine efficacy. Principal model outputs included the number of health-related events and costs averted and incremental cost per disability adjusted life year averted. RESULTS: A national rotavirus vaccination program, regardless of number of doses per course, would prevent 4 deaths, >10,500 hospitalizations, and >64,000 outpatient visits due to rotavirus infection among children <5 years annually, resulting in ~80%, 90%, and 70% declines in these outcomes, respectively, and a ~$7 million decline in annual medical costs. A national 2- or 3-dose vaccination program would be cost-saving up to $13.30/dose ($26.60/course) or $7.98/dose ($23.94/course), respectively; very cost-effective up to $24.08 per dose ($48.16/course) or $15.18/dose ($45.54/course), respectively; and cost-effective up to $45.65/dose ($91.30/course) or $29.59/dose ($88.77/course), respectively. CONCLUSIONS: A national rotavirus vaccination program could substantially reduce rotavirus disease burden among Taiwanese children and be potentially cost-effective, depending on the vaccine price. PMID- 24060570 TI - Prefrontal transcranial direct current stimulation (tDCS) changes negative symptoms and functional connectivity MRI (fcMRI) in a single case of treatment resistant schizophrenia. PMID- 24060572 TI - Factors affecting acceptance of routine human immunodeficiency virus screening by adolescents in pediatric emergency departments. AB - PURPOSE: Human immunodeficiency virus (HIV) screening in health care settings including emergency departments (EDs) is recommended for adolescents in the United States. This study aimed to evaluate the acceptance of and the factors affecting the HIV screening in pediatric EDs. METHODS: A prospective, cross sectional study of rapid opt-out oral HIV screening among adolescents >=13 years of age was conducted in two pediatric EDs during 2009-2011. Descriptive statistics and logistic regression models were used to identify factors associated with the acceptance of HIV screening. RESULTS: During 24 months, 8,519 adolescents were approached for HIV screening; 6,184 (72.6%) did not opt out, and of those 5,764 (93.2%) were tested for HIV. Most adolescents who accepted testing were black (80.5%), female (57.6%), aged 15-17 years (50.1%), and District of Columbia residents (67.7%), and were accompanied by a guardian (69.1%). Acceptance of HIV screening varied by age, race/ethnicity, and state of residence, with younger (<15 years) (adjusted odds ratio [aOR], 1.67; 95% confidence interval [CI], 1.33-2.09), non-black adolescents (aOR, .88; 95% CI, .77-.99) and non-District of Columbia residents (aOR, .86; 95% CI, .77-.96) being more likely to opt out of testing. Lower odds of opt-out of HIV testing were seen among adolescents with a guardian present (aOR, .42; 95% CI, .34-.53). The reasons for opt-out varied significantly by age and the presence of a guardian. CONCLUSIONS: The patient's age and the presence of a guardian were significantly associated with adolescents' decision and reasons to opt out of HIV screening in pediatric EDs. Further studies are necessary to evaluate the interventions needed to increase routine ED HIV screening in adolescents. PMID- 24060571 TI - Vitamin D deficiency in first episode psychosis: a case-control study. AB - BACKGROUND: Vitamin D deficiency is seen in a high proportion of people with established psychotic disorders, but it is not known if this is present at onset of the illness. We set out to examine vitamin D levels in people with their first episode of psychosis (FEP). METHOD: We conducted a matched case-control study to examine vitamin D levels and rates of vitamin D deficiency in sixty nine patients presenting with their FEP and sixty nine controls matched for age, sex and ethnicity. Differences between groups were tested using student's-t tests, paired t-tests and odds ratios for further analysis. RESULTS: Vitamin D levels were significantly lower in cases than in controls (p<0.001). The odds ratio of being vitamin D deficient was 2.99 in the FEP group relative to the control group. There was no correlation between vitamin D levels and length of hospitalisation in the patient group (r=-0.027, p=0.827). CONCLUSIONS: We found higher rates of vitamin D deficiency in people with FEP compared to matched controls. Given that vitamin D is neuroprotective; that developmental vitamin D deficiency may be a risk factor for psychosis, and that incipient psychosis may affect lifestyle factors and diet, future studies are required to examine this association further. In the meantime, there is a need for more widespread testing of vitamin D levels in FEP and for the development of appropriate management strategies. PMID- 24060573 TI - Predictors and patterns of cigarette and smokeless tobacco use among adolescents in 32 countries, 2007-2011. AB - PURPOSE: This study compared data from 32 countries to assess predictors and patterns of cigarette and smokeless tobacco (SLT) use among students aged 13-15 years old. METHODS: Data from the 2007-2008 Global Youth Tobacco Surveys were analyzed for students aged 13-15 years in 31 countries located in all six World Health Organization regions. In addition, the 2011 National Youth Tobacco Survey was analyzed for U.S. students aged 13-15 years. Country-specific prevalence of current smoking, current SLT use, and concurrent use patterns were assessed. RESULTS: The national prevalence of current cigarette smoking among students aged 13-15 years ranged from 1.8% (Rwanda) to 32.9% (Latvia), whereas current SLT use ranged from 1.1% (Montenegro) to 14.4% (Lesotho). In the U.S. and most European countries surveyed, current smoking prevalence was significantly higher than SLT prevalence, in contrast to patterns observed in low- and middle-income countries. Also, in most of the surveyed countries outside of Europe and the United States, SLT use among girls was as common as their use of cigarettes, and not significantly different from use by boys. When compared with U.S. adolescents, the odds of SLT use were highest among African adolescents (adjusted odds ratio = 3.98; 95% CI: 2.19-7.24) followed by those in the Southeast Asian region (adjusted odds ratio = 2.76; 95% CI: 1.38-5.53). CONCLUSIONS: Region-specific patterns of tobacco use were noticed. Furthermore, it is alarming that in several low- and middle-income countries, the prevalence of SLT use among females did not differ from that among males, suggesting the possibility of a future shared burden of disease between both males and females. PMID- 24060574 TI - The long-term effects of maternal depression: early childhood physical health as a pathway to offspring depression. AB - PURPOSE: Cross-sectional and retrospective studies have highlighted the long-term negative effects of maternal depression on offspring physical, social, and emotional development, but longitudinal research is needed to clarify the pathways by which maternal depression during pregnancy and early childhood affects offspring outcomes. The current study tested one developmental pathway by which maternal depression during pregnancy might negatively impact offspring mental health in young adulthood, via poor physical health in early childhood. METHODS: The sample consisted of 815 Australian youth and their mothers who were followed for 20 years. Mothers reported on their own depressive symptoms during pregnancy and offspring early childhood. Youth completed interviews about health related stress and social functioning at age 20 years, and completed a questionnaire about their own depressive symptoms 2 to 5 years later. RESULTS: Path analysis indicated that prenatal maternal depressive symptoms predicted worse physical health during early childhood for offspring, and this effect was partially explained by ongoing maternal depression in early childhood. Offspring poor physical health during childhood predicted increased health-related stress and poor social functioning at age 20. Finally, increased health-related stress and poor social functioning predicted increased levels of depressive symptoms later in young adulthood. Maternal depression had a significant total indirect effect on youth depression via early childhood health and its psychosocial consequences. CONCLUSIONS: Poor physical health in early childhood and its effects on young adults' social functioning and levels of health related stress is one important pathway by which maternal depression has long-term consequences for offspring mental health. PMID- 24060575 TI - Binge drinking trajectories across adolescence: for early maturing youth, extra curricular activities are protective. AB - PURPOSE: To describe adolescent binge drinking trajectories across grades 8-11 and examine their associations with pubertal timing, socioeconomic status (SES), and structured activity and sport involvement. METHODS: Longitudinal data were analyzed from the Youth Activity Participation Study (YAPS), an annual survey of youth in 39 schools across Western Australia (N = 1,342). RESULTS: Latent class growth analysis revealed four binge drinking trajectory groups: Accelerating (early onset, increased frequency), Steep Increase (delayed onset, rapid escalation), Slow Growth (delayed onset, gradual increase) and Stable Low (abstinence). Accelerating was characterized by early pubertal timing, low SES, and more sport involvement in grade 8, relative to Stable Low. The groups did not significantly differ in their grade 8 activity participation. However, for early maturers, greater grade 8 activity participation was associated with a decreased probability of belonging to Steep Increase relative to Stable Low. CONCLUSIONS: Early pubertal timing and sports participation increased the odds of belonging to a problematic binge drinking trajectory. For youth at-risk due to early pubertal timing, structured activities appear to be protective against a problematic developmental course of binge drinking. PMID- 24060576 TI - Worldwide never-smoking youth susceptibility to smoking. AB - PURPOSE: To estimate susceptibility to smoking among never-smoking youth globally and identify factors associated with such behavior. METHODS: Cross-sectional data for 168 countries were obtained from the Global Youth Tobacco Survey. Simple and multiple logistic regression analyses were conducted. Frequencies and proportions for descriptive statistics, and adjusted odds ratios with 95% confidence intervals for logistic regression models were reported. RESULTS: Approximately 12.5% of never-smoking youth worldwide were susceptible to smoking worldwide, of which 7.2% were males and 5.3% were females. Compared with youth in the Americas, those in other WHO regions were associated with decreased susceptibility to smoking. Regardless of gender, exposure to parental or peer smoking, secondhand smoke inside or outside home, and tobacco industry promotion was associated with increased smoking susceptibility. In contrast, support for smoke-free policies and school antismoking education was associated with decreased susceptibility to smoking among females. Moreover, exposure to antismoking media messages was associated with increased susceptibility to smoking among never-smoking youth. CONCLUSIONS: Approximately 1 in 8 never-smoking youth worldwide was found to be susceptible to smoking. A comprehensive approach involving parental and peer education, smoke-free policies, ban on tobacco advertising and promotions, and antismoking education in schools should be developed by policy makers and public health professionals to protect never-smoking youth from being susceptible to smoking and transforming into future regular smokers. PMID- 24060577 TI - Circulating tumor cells and response to neoadjuvant paclitaxel and HER2-targeted therapy: a sub-study from the NeoALTTO phase III trial. AB - BACKGROUND: The role of circulating tumor cells (CTCs) in HER2-positive breast cancer patients receiving neoadjuvant therapy is unclear. PATIENTS & METHODS: We describe the CTC detection rate, HER2 phenotyping and pathological complete response (pCR) in patients enrolled in the NeoALTTO phase III trial. Participation in the CTC sub-study was optional. CTC evaluation was performed centrally using CellSearch at baseline, week 2 and week 18 (prior to surgery) of neoadjuvant therapy. RESULTS: Samples for CTC analysis were available for 51/455 patients randomized. At baseline, week 2 and week 18, we detected >=1 CTC/22.5 ml in 5/46 (11%), 4/41 (10%), and 5/31 (16%) patients and >=1 HER2-positive CTC/22.5 ml in 2/46 (4%), 2/41 (5%), and 3/31 (10%) patients with evaluable samples, respectively. 11/51 patients (21%) had >=1 CTC/22.5 ml in at least one time point. pCR was observed in 3/11 (27.3%) versus 17/40 (42.5%) patients with detectable and no detectable CTCs, respectively (p = 0.36). No pCR was observed in the three patients with detectable HER2-positive CTCs prior to surgery. CONCLUSION: Numerically lower pCR rates were observed in patients with detectable CTCs, yet the study remains underpowered. A meta-analysis of CTC studies in this setting is warranted. PMID- 24060578 TI - Immunohistochemical prediction of brain metastases in patients with advanced breast cancer: the role of Rad51. AB - BACKGROUND: There are no clinically useful biomarkers predictive of brain metastases (BM) in breast cancer. In this study, we investigated the correlation between expression of selected proteins in the primary tumor and the risk of BM in patients with metastatic breast cancer (MBC). METHODS: The study included 198 MBC patients (96 with and 102 without BM). Using tissue microarrays derived from the primary tumor, we assessed by immunohistochemical expression of ER, PR, HER2, Ki-67, CK5/6, EGFR, HER3, CXCR4, Rad51, E-cadherin, and claudin 3 and 4. RESULTS: Ki-67 >=14% (hazard ratio [HR] 2.76; P < 0.001), cytoplasmic expression of Rad51 (HR 1.87; P = 0.014) and ER-negativity (HR 1.72; P = 0.029) were associated with increased risk of BM in the multivariate analysis. A three-biomarker profile including ER, Ki-67 and Rad51 vs. other subtypes combined yielded an HR of 4.43 (P < 0.001). CONCLUSIONS: ER-negativity, cytoplasmic expression of Rad51 and high Ki-67 are associated with increased risk of BM. PMID- 24060579 TI - Inhibitory effects of sanguinarine against the cyanobacterium Microcystis aeruginosa NIES-843 and possible mechanisms of action. AB - Sanguinarine showed strong inhibitory effect against Microcystis aeruginosa, a typical water bloom-forming and microcystins-producing cyanobacterium. The EC50 of sanguinarine against the growth of M. aeruginosa NIES-843 was 34.54+/-1.17 MUg/L. Results of chlorophyll fluorescence transient analysis indicated that all the electron donating side, accepting side, and the reaction center of the Photosystem II (PS II) were the targets of sanguinarine against M. aeruginosa NIES-843. The elevation of reactive oxygen species (ROS) level in the cells of M. aeruginosa NIES-843 upon exposure indicated that sanguinarine induced oxidative stress in the active growing cells of M. aeruginosa NIES-843. Further results of gene expression analysis indicated that DNA damage and cell division inhibition were also involved in the inhibitory action mechanism of sanguinarine against M. aeruginosa NIES-843. The inhibitory characteristics of sanguinarine against M. aeruginosa suggest that the ecological- and public health-risks need to be evaluated before its application in cyanobacterial bloom control to avoid devastating events irreversibly. PMID- 24060580 TI - Catabolism of volatile organic compounds influences plant survival. AB - Plants emit a diverse array of phytogenic volatile organic compounds (VOCs). The production and emission of VOCs has been an important area of research for decades. However, recent research has revealed the importance of VOC catabolism by plants and VOC degradation in the atmosphere for plant growth and survival. Specifically, VOC catabolism and degradation have implications for plant C balance, tolerance to environmental stress, plant signaling, and plant-atmosphere interactions. Here we review recent advances in our understanding of VOC catabolism and degradation, propose experiments for investigating VOC catabolism, and suggest ways to incorporate catabolism into VOC emission models. Improving our knowledge of VOC catabolism and degradation is crucial for understanding plant metabolism and predicting plant survival in polluted environments. PMID- 24060582 TI - The role of abnormalities in the distal pathway of cholesterol synthesis in the Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects (CHILD) syndrome. AB - CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects) is a rare X-linked dominant ichthyotic disorder. CHILD syndrome results from loss of function mutations in the NSDHL gene, which leads to inhibition of cholesterol synthesis and accumulation of toxic metabolic intermediates in affected tissues. The CHILD syndrome skin is characterized by plaques topped by waxy scales and a variety of developmental defects in extracutaneous tissues, particularly limb hypoplasia or aplasia. Strikingly, these alterations are commonly segregated to either the right or left side of the body midline with little to no manifestations on the ipsilateral side. By understanding the underlying disease mechanism of CHILD syndrome, a pathogenesis-based therapy has been developed that successfully reverses the CHILD syndrome skin phenotype and has potential applications to the treatment of other ichthyoses. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias. PMID- 24060581 TI - Sphingolipids in colon cancer. AB - Colorectal cancer is one of the major causes of death in the western world. Despite increasing knowledge of the molecular signaling pathways implicated in colon cancer, therapeutic outcomes are still only moderately successful. Sphingolipids, a family of N-acyl linked lipids, have not only structural functions but are also implicated in important biological functions. Ceramide, sphingosine and sphingosine-1-phosphate are the most important bioactive lipids, and they regulate several key cellular functions. Accumulating evidence suggests that many cancers present alterations in sphingolipids and their metabolizing enzymes. The aim of this review is to discuss the emerging roles of sphingolipids, both endogenous and dietary, in colon cancer and the interaction of sphingolipids with WNT/beta-catenin pathway, one of the most important signaling cascades that regulate development and homeostasis in intestine. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology. PMID- 24060583 TI - The Connexin40A96S mutation from a patient with atrial fibrillation causes decreased atrial conduction velocities and sustained episodes of induced atrial fibrillation in mice. AB - Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and a major cause of stroke. In the mammalian heart the gap junction proteins connexin40 (Cx40) and connexin43 (Cx43) are strongly expressed in the atrial myocardium mediating effective propagation of electrical impulses. Different heterozygous mutations in the coding region for Cx40 were identified in patients with AF. We have generated transgenic Cx40A96S mice harboring one of these mutations, the loss-of-function Cx40A96S mutation, as a model for atrial fibrillation. Cx40A96S mice were characterized by immunochemical and electrophysiological analyses. Significantly reduced atrial conduction velocities and strongly prolonged episodes of atrial fibrillation were found after induction in Cx40A96S mice. Analyses of the gating properties of Cx40A96S channels in cultured HeLa cells also revealed significantly lower junctional conductance and enhanced sensitivity voltage gating of Cx40A96S in comparison to Cx40 wild-type gap junctions. This is caused by reduced open probabilities of Cx40A96S gap junction channels, while single channel conductance remained the same. Similar to the corresponding patient, heterozygous Cx40A96S mice revealed normal expression levels and localization of the Cx40 protein. We conclude that heterozygous Cx40A96S mice exhibit prolonged episodes of induced atrial fibrillation and severely reduced atrial conduction velocities similar to the corresponding human patient. PMID- 24060584 TI - Early maternal deprivation immunologically primes hippocampal synapses by redistributing interleukin-1 receptor type I in a sex dependent manner. AB - Challenges experienced in early life cause an enduring phenotypical shift of immune cells towards a sensitised state that may lead to an exacerbated reaction later in life and contribute to increased vulnerability to neurological diseases. Peripheral and central inflammation may affect neuronal function through cytokines such as IL-1. The extent to which an early life challenge induces long term alteration of immune receptors organization in neurons has not been shown. We investigated whether a single episode of maternal deprivation (MD) on post natal day (PND) 9 affects: (i) the synapse distribution of IL-1RI together with subunits of NMDA and AMPA receptors; and (ii) the interactions between IL-1RI and the GluN2B subunit of the NMDAR in the long-term, at PND 45. MD increased IL-1RI levels and IL-1RI interactions with GluN2B at the synapse of male hippocampal neurons, without affecting the total number of IL-1RI or NMDAR subunits. Although GluN2B and GluN2A were slightly but not significantly changed at the synapse, their ratio was significantly decreased in the hippocampus of the male rats who had experienced MD; the levels of the GluA1 and GluA2 subunits of the AMPAR were also decreased. These changes were not observed immediately after the MD episode. None of the observed alterations occurred in the hippocampus of the females or in the prefrontal cortex of either sex. These data reveal a long-term, sex-dependent modification in receptor organisation at the hippocampal post-synapses following MD. We suggest that this effect might contribute to priming hippocampal synapses to the action of IL-1beta. PMID- 24060586 TI - A novel automated test battery reveals enduring behavioural alterations and cognitive impairments in survivors of murine pneumococcal meningitis. AB - Pneumococcal meningitis, caused by Streptococcus pneumoniae infection, is a major form of lethal bacterial meningitis. Survivors are predisposed to developing lifelong disabling sequelae, including cognitive impairment, psychological problems and motor deficits. In our experimental model, ventricular inoculation of 10(5) colony-forming units of S. pneumoniae type 3 caused 90% of mice to develop life-threatening meningitis within 48 h. Antibiotic treatment with ceftriaxone 20 h post infection reduced the incidence of severe meningitis to <10%. At the time of treatment, upregulation of pro-inflammatory cytokines was detected, including interleukin-1beta, interleukin-6 and tumour necrosis factor. We evaluated the long-term behavioural and cognitive sequelae in control mice and those surviving meningitis using an automated system (the IntelliCage) in which mice perform a range of behavioural and spatial tasks to obtain water rewards from conditioning units in their home cage. Surviving mice showed a number of altered behaviours relative to controls, including (i) hypoexploration when first exposed to the IntelliCage, (ii) altered activity patterns (fewer visits to conditioning stations during the light phase and more in the dark phase), (iii) avoidance of light (a constant or flashing LED stimulus), (iv) impaired spatial learning (a complex patrolling task), and (v) impaired discrimination reversal learning. Overall these results suggest photophobia and weakened learning ability in post-meningitic mice, particularly on tasks engaging hippocampal and prefrontal neural substrates. This study also demonstrates a standardised and comprehensive battery of tests that can be readily used to investigate neurological sequelae in undisturbed mice residing in a complex home cage environment. PMID- 24060585 TI - Poor sleep quality potentiates stress-induced cytokine reactivity in postmenopausal women with high visceral abdominal adiposity. AB - Sleep disturbance is a key behavioral risk factor for chronic medical conditions observed at high rates among overweight and obese individuals. Systemic inflammation, including that induced by stress, may serve as a common biological mechanism linking sleep, adiposity, and disease risk. To investigate these relationships, 48 postmenopausal women (mean age=61.8) completed a standardized laboratory stress task during which time blood was collected at baseline and 30, 50 and 90+ min after stressor onset to assess circulating levels of interleukin (IL)-6, IL-10, and IL-6/IL-10 ratio. Self-reported global sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) while adiposity was estimated by body mass index. Sagittal diameter was obtained in clinic to estimate visceral abdominal adiposity. Multi-level growth curve models revealed that poorer self-reported sleep quality was associated with greater stress induced increases in IL-6/IL-10 ratio. In terms of adiposity, higher sagittal diameter, but not BMI, was associated with greater IL-6 reactivity (p's<0.05). Further, associations between sleep quality and cytokine reactivity varied as a function of sagittal diameter. Among poor sleepers (1 SD above mean of PSQI score), stress-induced increases in IL-6 and IL-6/IL-10 ratio were significantly steeper in those with high visceral adiposity (1 SD above the mean of sagittal diameter) compared to those with low visceral adiposity (1 SD below the mean of sagittal diameter). In sum, poorer sleep quality and greater visceral adiposity, separately and especially in combination, are associated with greater stress related increases in systemic inflammation. This research may help elucidate the complex link between sleep, obesity and inflammatory disease risk. PMID- 24060587 TI - The nesfatin 1 level in male patients with manic episode and alterations of nesfatin 1 level after antipsychotic and electroconvulsive treatment. AB - BACKGROUND: Nesfatin 1 is a newly identified peptide structured satiety hormone that is claimed to be responsible for the provision of appetite and metabolic regulation in hypothalamus. The change in appetite and energy is a well-known clinical feature of affective disorders and within treatment. We aimed to investigate serum nesfatin 1 level in patients with bipolar disorder who were in manic episode and the influences of treatment modalities on nesfatin 1 level. METHODS: Sixty eight patients were elected and were divided into two groups as: antipsychotic treatment (haloperidol 10-30 mg/daily+quetiapine 100-900 mg/daily) arm and ECT+antipsychotic treatment arm. And 30 healthy controls were included in the study. RESULTS: There was no significant difference according to mean age between patients and controls. Initial nesfatin 1 levels in patients and in both subgroups of patients were statistically lower than in healthy control group. The initial level of nesfatin 1 between ECT+antipsychotic and pure antipsychotic patient groups was not statistically significant. We found a trend of increment in nesfatin 1 level after treatment in both patient groups. CONCLUSIONS: This study is the first that revealed significantly lower nesfatin 1 level in manic episode than healthy controls. ECT+antipsychotic and antipsychotic treatments have no significant effects on nesfatin 1 level after manic episode treatment. These findings should be interpreted cautiously because of small sample size and being drug free only for one week. PMID- 24060588 TI - Predicting response to cognitive therapy and interpersonal therapy, with or without antidepressant medication, for major depression: a pragmatic trial in routine practice. AB - BACKGROUND: Identifying patient characteristics that predict response within treatments (prognostic) or between treatments (prescriptive) can inform clinical decision-making. In this study, we sought to identify predictors of response to evidence-based treatments in a sample of depressed patients seeking help in routine practice. METHODS: Data come from a pragmatic trial of 174 patients with major depression who received an evidence-based treatment of their own choice: cognitive therapy (CT), interpersonal therapy (IPT), antidepressant medication (ADM) alone or in combination with either of the two psychotherapies. Patient characteristics measured at baseline were examined to see if they predicted subsequent response as measured with the Beck Depression Inventory (BDI) over the course of 26 weeks of treatment, using mixed regression modeling. RESULTS: Higher agoraphobia scores at baseline predicted more change in depression scores across treatments, irrespective of the treatment received. Physical functioning moderated the response to treatment: patients with high physical functioning fared better in combined treatment than patients with low physical functioning, whereas physical functioning did not predict a differential response in the psychotherapy group. Moreover, the lowest levels of physical functioning predicted an increase of depressive symptoms in combined treatment. LIMITATIONS: A relatively small sample size, and selection of several predictors that were less theory-driven, which hampers the translation to clinical practice. CONCLUSIONS: If replicated, the prognostic and prescriptive indices identified in this study could guide decision-making in routine practice. Development of more uniform requirements for the analysis and reporting of prediction studies is recommended. PMID- 24060589 TI - Risks associated with gender differences in bipolar I disorder. AB - BACKGROUND: Previous studies have demonstrated that bipolar patients may differ in several features according to gender, but a number of the differences found remain controversial. METHODS: The demographic, illness course, clinical, comorbidity and temperament characteristics of a total of 1090 consecutive DSM-IV bipolar I manic inpatients were compared according to gender. RESULTS: Bipolar illness in women was characterised by the predominance of depression, as indicated by a depressive polarity at onset, higher rates of mixed mania, more suicidal behaviour, and a greater number of temperaments with depressive propensities. In contrast, the manic component was found to predominate in men. Men also had an earlier onset of their illness. Women displayed more comorbidities with eating, anxiety, and endocrine/metabolic disorders, whereas men were more comorbid with alcoholism and other forms of substance abuse, neurological, and cancer disorders. The following independent variables were associated with male gender: being single (+), depressive temperament (-), excessive alcohol use (+), cyclothymic temperament (-), excessive other substance use (+), mood congruent psychotic features (+), and manic polarity at onset (+). LIMITATIONS: The retrospective design and the sample being potentially not representative of the bipolar disorder population are limitations. CONCLUSIONS: Findings from this study tend to confirm most of the differences previously observed among bipolar men and women. Furthermore, these results draw attention to the risks that may be specifically linked to gender differences in bipolar I patients. PMID- 24060590 TI - Differential expression and functional role of cannabinoid genes in alcohol users. AB - BACKGROUND: Genetic factors account for about fifty percent of the risk for alcoholism and alcohol dependence (AD) has been reported to be influenced by cannabinoid receptors (CBRs) and the endocannabinoid system (ECS). Previous studies have focused on cannabinoids and alcohol-related effects in the CNS; however, the role CBRs play on alcohol effects in the immune system has not been elucidated yet. Since alcohol can affect immune responses and have detrimental effects on immune cells such as dendritic cells (DCs), we hypothesize that alcohol can exert its effects on DCs by modulating changes in CBRs, which in turn can regulate important DC functions such as cytokine production. METHODS: Therefore, we studied the expression of CNR1 and CNR2, and the novel cannabinoid G protein-coupled receptor (GPCR) 55 (GPR55) in human monocyte-derived dendritic cells (MDDCs) from alcohol users. CNR1, CNR2, and GPR55 genes were measured by qRT-PCR and protein by flow cytometry. MDDCs from alcohol users show significantly higher levels of CNR2 and GPR55 compared to MDDCs from non-users. These findings were further confirmed using MDDCs treated with alcohol. Inflammatory cytokines were measured in EtOH-treated and non-treated cells by antibody array. RESULTS: Functional effects of CBRs on MDDCs were shown by CB2 and GPR55 siRNA transfection. Transfected EtOH-treated cells showed significantly higher levels of proinflammatory cytokine production as measured by IL-1beta expression. Our results provide insights into alcohol mechanisms of DC regulation and show, for the first time, that alcohol is inducing CNR2 and GPR55 in human DCs. PMID- 24060591 TI - Cyclin D1 (CCND1) messenger RNA expression as assessed by real-time PCR contributes to diagnosis and follow-up control in patients with mantle cell lymphoma. AB - Molecular diagnosis of mantle cell lymphoma (MCL) can be difficult because the t(11;14)/IGH@-CCND1 is extremely heterogeneous at the DNA level. Aiming to establish a reliable molecular tool that could be easily implemented in routine diagnostics, we developed a new real-time polymerase chain reaction (PCR) assay for CCND1 expression measurement and evaluated 451 cases: 142 MCL, 76 chronic lymphocytic leukemia, 20 hairy cell leukemia, 13 hairy cell leukemia-variant, 20 splenic marginal zone lymphoma, 91 other mature B-cell neoplasms, 29 other hematologic neoplasms, and 60 healthy individuals. Sensitivity of the real-time PCR assay was up to 10(-4). In t(11;14)/IGH@-CCND1 positive lymphoma samples (n = 150), median %CCND1/ABL1 expression level was 178.2 (range: 1.5-4, 152.0). Normalized by t(11;14)/IGH@-CCND1 positive cells as determined by fluorescence in situ hybridization IGH@-CCND1 positive samples showed a median %CCND1/ABL1 of 445.8 (range: 17.9-4,848.5). A normalized %CCND1/ABL1 expression of at least 17.0 was chosen as threshold for CCND1 positivity. For unnormalized samples, the positive detection rate of t(11;14)/IGH@-CCND1 by CCND1 expression was 87.3%. Healthy individuals had low %CCND1/ABL1 (median, 1.1; range, 0.0-7.8). The negative predictive value for exclusion of a t(11;14)/IGH@-CCND1 by CCND1 expression was 95.3% by the above threshold. %CCND1/ABL1 was higher in MCL than in the remaining B-cell lymphomas (mean +/- SD, 392.9 +/- 685.3 vs. 46.0 +/- 305.0; p < 0.001). In 66 follow-up samples, CCND1 showed 2.5-3.5 log reduction after chemotherapy and increase at relapse. CCND1 expression could serve as adjunct to other techniques in diagnosis and follow-up of B-cell lymphomas. PMID- 24060592 TI - The TGF-B1 and IL-10 gene polymorphisms are associated with risk of developing silent myocardial ischemia in the diabetic patients. AB - Silent myocardial ischemia (SMI) is a multifactorial and polygenic disorder that results from an excessive inflammatory response. Considering the prominent role of IL-10 and TGF-B1 as regulators of the inflammatory process and vascular physiology, the aim of the present study was to analyze whether IL-10 and TGF-B1 single nucleotide polymorphisms (SNPs) are associated with SMI. The IL-10-1082 A>G (rs1800896), IL-10-819 T>C (rs1800871), IL-10-592 A>C (rs1800872), TGF-beta1 509 T>C (rs1800469), and TGF-beta1 T29C (rs1800470) SNPs were analyzed by 5'exonuclease TaqMan genotyping assays in a group of 149 SMI patients and 248 healthy controls. The IL-10-1082 A>G (rs1800896) SNP was significantly associated with an increased risk of SMI as compared to controls under both dominant and heterozygous models (OR=1.77, Pdom=0.029 and OR=1.69, PHet=0.043). On the other hand, the TGF-beta1 509 T>C (rs1800469) SNP was significantly associated with increased risk of SMI as compared to controls under a dominant and additive models (OR=1.82, Pdom=0.035, OR=1.50, Padd=0.026). Finally, the TGF-beta1 T29C (rs1800470) SNP was significantly associated with increased risk of SMI as compared to controls under a co-dominant, dominant, recessive, and additive models (OR=3.63, PCod=0.004, OR=2.24, Pdom=0.002, OR=2.46, Prec=0.03 and OR=1.94, Padd=0.001). After adjusted for gender, age, and smoking, two haplotypes (CC and TT) were associated with decreased risk of SMI (OR=0.26, P<0.0001 and OR=0.15, P=0.017). In summary, our data suggest that the IL-10-1082 A>G (rs1800896), TGF beta1-509 T>C (rs1800469), and TGF-beta1 T29C (rs1800470) SNPs play an important role in the risk of developing SMI. In our study, it was possible to distinguish two protective haplotypes in TGF-beta1 for SMI development. PMID- 24060593 TI - Immunomodulatory properties of colonic mesenchymal stem cells. AB - AIM: To elucidate the immunomodulatory functions of colonic mesenchymal stem cells (MSCs) in the colonic mucosal immune system. METHODS: The colonic MSCs were isolated, enriched and expanded. The immunosuppressive role of colonic MSCs on activated T cells was evaluated. The cell cycle progression of T cells and the expression of FoxP3+ T cells were assessed by fluorescence-activated cell sorting (FACS). The levels of cytokines and PGE2 were measured by ELISA. RESULT: Mouse colonic MSCs can inhibit the proliferation of activated T cells by arresting cells in G0/G1 phase, induce the expression of CD4+CD25+Foxp3+ T cells (8.05%+/ 0.49% in transwell culture vs 8.45%+/-0.64% in direct contact culture vs 4.30%+/ 0.28% in control, p<0.05), downregulate the levels of the cytokines TNF-alpha and IFN-gamma, and increase the production of IL-10 (p<0.05). The data obtained from transwell culture and direct contact culture showed no difference (p>0.05). PGE2 level was increased when T cells were cultured with colonic MSCs (385.10+/-19.45 ng/l in transwell culture vs 387.91+/-19.85 ng/l in direct contact culture vs 276.21+/-25.49 ng/l in control, p<0.05). Blocking PGE2 partially reversed the immunosuppression of MSCs on activated T cells proliferation (p<0.05). CONCLUSION: Colonic MSCs have the same immunosuppressive property as other MSCs. They performed their functions partially through secreting soluble factor PGE2. The characterization of these colonic MSCs may be helpful for studying the involvement of stromal cell compartment in colon diseases. PMID- 24060594 TI - Genetic distribution on 20 STR loci from the Han population in Shanghai, China. PMID- 24060595 TI - Measurement of phenolic environmental estrogens in human urine samples by HPLC MS/MS and primary discussion the possible linkage with uterine leiomyoma. AB - A method was established for the determination of three phenolic environmental estrogens, namely bisphenol A (BPA), nonylphenol (NP) and octylphenol (OP), in urine from women of uterine leiomyoma group (n=49) and control group (n=29), by using solid-phase extraction (SPE) coupled with liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Urine samples were spiked with 2,4,6-tribromophenyl terminated tetrabromobisphenol-A carbonate oligomer (TBBPA) and nonylphenol D8 (NP-D8) as internal standard (I.S.) and de-conjugated by adding beta glucuronidase and sulfatase before the SPE. The extraction recoveries of BPA, NP and OP were more than 73.3%; the standard curve was linear over the validated concentrations in the range of 1.0-100.0ng/mL and the limits of detection (LOD) of BPA, NP and OP were 0.32ng/mL, 0.18ng/mL and 0.15ng/mL, respectively. Moreover, by analysing quality control urine samples in 5 days, the results showed that the method was precise and accurate, for the intra- and inter-day CV% within 15.2%. Except that OP was not found (3). NP levels were significantly higher in uterine leiomyoma patients than control group in low gravidity subgroup. Though BPA levels in experimental and control groups were not significantly different, the mean levels and concentration distribution were different. The study suggested that there is certain relationship between exposure concentrations of phenolic environmental estrogens and uterine leiomyoma disease. PMID- 24060596 TI - Protein addressing on patterned microchip by coupling chitosan electrodeposition and 'electro-click' chemistry. AB - Many applications in proteomics and lab-on-chip analysis require methods that guide proteins to assemble at surfaces with high spatial and temporal control. Electrical inputs are particularly convenient to control, and there has been considerable effort to discover simple and generic mechanisms that allow electrical inputs to trigger protein assembly on-demand. Here, we report the electroaddressing of a protein to a patterned surface by coupling two generic electroaddressing mechanisms. First, we electrodeposit the stimuli-responsive film-forming aminopolysaccharide chitosan to form a hydrogel matrix at the electrode surface. After deposition, the matrix is chemically functionalized with alkyne groups. Second, we ''electro-click' an azide-tagged protein to the functionalized matrix using electrical signals to trigger conjugation by Huisgen 1,3-dipolar cycloadditions. Specifically, a cathodic potential is applied to the matrix-coated electrode to reduce Cu(II) to Cu(I) which is required for the click reaction. Using fluorescently-labeled bovine serum albumin as our model, we demonstrate that protein conjugation can be controlled spatially and temporally. We anticipate that the coupling of polysaccharide electrodeposition and electro click chemistry will provide a simple and generic approach to electroaddress proteins within compatible hydrogel matrices. PMID- 24060598 TI - 30-day morbidity and mortality after elective shoulder arthroscopy: a review of 9410 cases. AB - BACKGROUND: Few studies have reported incidence of or risk factors for morbidity and mortality after elective shoulder arthroscopy. METHODS: We used Current Procedural Terminology (CPT) billing codes to query the National Surgical Quality Improvement Program database and identified 9410 cases of elective shoulder arthroscopy. Univariate and multivariate analyses were used to identify risk factors for complication. RESULTS: Among 9410 patients, 109 complications occurred in 93 (0.99%). Major morbidity was 0.54% (51 patients), which included 4 patients (0.04%) with a mortality, and minor morbidity was 0.44% (42 patients). The most common complication was a return to the operating room (29 cases, 0.31%). Superficial surgical site infections occurred in 15 cases (0.16%), deep infections in 1 (0.01%), deep venous thrombosis or thrombophlebitis in 8 (0.09%), peripheral nerve injury in 1 (0.01%), and pulmonary embolism in 6 (0.06%). The multivariate analysis showed smoking history (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.12-3.27), history of chronic obstructive pulmonary disease (OR, 3.25; 94% CI, 1.38-7.66), operative time of longer than 1.5 hours (OR, 2.1; 95% CI, 1.32-3.36), and American Society of Anesthesia class of 3 or 4 compared with 1 or 2 (OR, 1.82; 95% CI, 1.03-3.21) as risk factors for complication. CONCLUSIONS: Morbidity and mortality are rare events after elective shoulder arthroscopy, and the procedure should generally be considered safe. Surgeons should offer smoking cessation to active users of tobacco and should be efficient with operative time whenever possible. LEVEL OF EVIDENCE: Level II, prospective cohort design, treatment study. PMID- 24060599 TI - Interface effects on tunneling magnetoresistance in organic spintronics with flexible amine-Au links. AB - Organic spintronics is a promising emerging field, but the sign of the tunneling magnetoresistance (TMR) is highly sensitive to interface effects, a crucial hindrance to applications. A key breakthrough in molecular electronics was the discovery of amine-Au link groups that give a reproducible conductance. Using first-principles calculations, we predict that amine-Au links give improved reproducibility in organic spintronics junctions with Au-covered Fe leads. The Au layers allow only states with sp character to tunnel into the molecule, and the flexibility of amine-Au links results in a narrow range of TMR for a fixed number of Au layers. Even as the Au thickness changes, the TMR remains positive as long as the number of Au layers is the same on both sides of the junction. Since the number of Au layers on Fe surfaces or Fe nanoparticles can now be experimentally controlled, amine-Au links provide a route towards robust TMR in organic spintronics. PMID- 24060597 TI - Mitochondria: gatekeepers of response to chemotherapy. AB - Mitochondria are cellular organelles that regulate commitment to and execution of apoptosis. The intrinsic apoptotic pathway culminates in the permeabilization of the mitochondrial outer membrane and dismantling of the cell. Apoptosis of cancer cells is a favorable outcome when administering chemotherapeutic treatment, yet the basis for why some cancers are sensitive to chemotherapy whereas others are not has historically been poorly understood. In this review, we present recent work that has demonstrated the importance of mitochondrial apoptotic priming, or how close a cell is to the threshold of apoptosis, in determining whether a cell will undergo apoptosis after chemotherapy treatment. Differential levels of apoptotic priming in tumors create bona fide opportunities and challenges for effective use of targeted and cytotoxic chemotherapies. PMID- 24060600 TI - TEMPTING system: a hybrid method of rule and machine learning for temporal relation extraction in patient discharge summaries. AB - Patient discharge summaries provide detailed medical information about individuals who have been hospitalized. To make a precise and legitimate assessment of the abundant data, a proper time layout of the sequence of relevant events should be compiled and used to drive a patient-specific timeline, which could further assist medical personnel in making clinical decisions. The process of identifying the chronological order of entities is called temporal relation extraction. In this paper, we propose a hybrid method to identify appropriate temporal links between a pair of entities. The method combines two approaches: one is rule-based and the other is based on the maximum entropy model. We develop an integration algorithm to fuse the results of the two approaches. All rules and the integration algorithm are formally stated so that one can easily reproduce the system and results. To optimize the system's configuration, we used the 2012 i2b2 challenge TLINK track dataset and applied threefold cross validation to the training set. Then, we evaluated its performance on the training and test datasets. The experiment results show that the proposed TEMPTING (TEMPoral relaTion extractING) system (ranked seventh) achieved an F-score of 0.563, which was at least 30% better than that of the baseline system, which randomly selects TLINK candidates from all pairs and assigns the TLINK types. The TEMPTING system using the hybrid method also outperformed the stage-based TEMPTING system. Its F scores were 3.51% and 0.97% better than those of the stage-based system on the training set and test set, respectively. PMID- 24060601 TI - Curbing false discovery rates in interpretation of genome-wide expression profiles. AB - Fisher's exact test is widely used in biomedical research, particularly in genomic profile analysis. Since in most databases, the frequency distribution of genes is right skewed, we show here that its use can lead to excessive false positive discoveries. We propose to apply Zelen's exact test on a stratification of the gene set; this solves the false discovery problem, and should avoid misleading interpretations of lists of genes produced by various genome-wide analysis technologies. PMID- 24060602 TI - FALCON or how to compute measures time efficiently on dynamically evolving dense complex networks? AB - A large number of topics in biology, medicine, neuroscience, psychology and sociology can be generally described via complex networks in order to investigate fundamental questions of structure, connectivity, information exchange and causality. Especially, research on biological networks like functional spatiotemporal brain activations and changes, caused by neuropsychiatric pathologies, is promising. Analyzing those so-called complex networks, the calculation of meaningful measures can be very long-winded depending on their size and structure. Even worse, in many labs only standard desktop computers are accessible to perform those calculations. Numerous investigations on complex networks regard huge but sparsely connected network structures, where most network nodes are connected to only a few others. Currently, there are several libraries available to tackle this kind of networks. A problem arises when not only a few big and sparse networks have to be analyzed, but hundreds or thousands of smaller and conceivably dense networks (e.g. in measuring brain activation over time). Then every minute per network is crucial. For these cases there several possibilities to use standard hardware more efficiently. It is not sufficient to apply just standard algorithms for dense graph characteristics. This article introduces the new library FALCON developed especially for the exploration of dense complex networks. Currently, it offers 12 different measures (like clustering coefficients), each for undirected-unweighted, undirected weighted and directed-unweighted networks. It uses a multi-core approach in combination with comprehensive code and hardware optimizations. There is an alternative massively parallel GPU implementation for the most time-consuming measures, too. Finally, a comparing benchmark is integrated to support the choice of the most suitable library for a particular network issue. PMID- 24060603 TI - Omalizumab is an effective and rapidly acting therapy in difficult-to-treat chronic urticaria: a retrospective clinical analysis. AB - BACKGROUND: Omalizumab (anti-IgE) therapy is effective and safe in chronic urticaria (CU) in placebo-controlled clinical trials but real life clinical data are scarce. OBJECTIVE: To better understand the effects of omalizumab in CU patients treated outside of clinical trials. METHODS: In this retrospective clinical analysis, we assessed responder rates, optimal dosage, response to up /downdosing, time to relief of symptoms, rates of return and time of relapse after omalizumab administration, and safety in 51 CU patients, 20 with chronic spontaneous urticaria (CSU) alone, 21 with different forms of chronic inducible urticaria (CindU) and 10 with both. RESULTS: Omalizumab treatment led to complete remission in 83% of CSU and 70% of CindU patients. When starting with 150mg omalizumab 4 weekly, only 2/15 CSU and 7/17 CindU patients required updosing to achieve complete remission. In CSU, 57% of complete responses occurred within week one, all on the first day. Relapses were 2-8 weeks in all but six patients, where they were <4 months. Omalizumab was safe. Efficacy was not correlated to baseline IgE levels. CONCLUSION: Clinical experience from more than 1250 injections in 51 patients over four years indicates that omalizumab is a rapidly acting, highly effective and safe drug in CSU and CindU patients. Our observations in a real life clinical setting support the recommendation of current EAACI/GA(2)LEN/EDF/WAO guideline for the management of urticaria to use omalizumab to treat urticaria patients. PMID- 24060604 TI - Power to the will: how exerting physical effort boosts the sense of agency. AB - The sense of agency refers to the experience of being in control of one's actions and their consequences. The 19th century French philosopher Maine de Biran proposed that the sensation of effort might provide an internal cue for distinguishing self-caused from other changes in the environment. The present study is the first to empirically test the philosophical idea that effort promotes self-agency. We used intentional binding, which refers to the subjective temporal attraction between an action and its sensory consequences, as an implicit measure of the sense of agency. Effort was manipulated independent of the primary task by requiring participants to pull stretch bands of varying resistance levels. We found that intentional binding was enhanced under conditions of increased effort. This suggests not only that the experience of effort directly contributes to the sense of agency, but also that the integration of effort as an agency cue is non-specific to the effort requirement of the action itself. PMID- 24060605 TI - Temporal order perception of auditory stimuli is selectively modified by tonal and non-tonal language environments. AB - The close relationship between temporal perception and speech processing is well established. The present study focused on the specific question whether the speech environment could influence temporal order perception in subjects whose language backgrounds are distinctively different, i.e., Chinese (tonal language) vs. Polish (non-tonal language). Temporal order thresholds were measured for both monaurally presented clicks and binaurally presented tone pairs. Whereas the click experiment showed similar order thresholds for the two language groups, the experiment with tone pairs resulted in different observations: while Chinese demonstrated better performance in discriminating the temporal order of two "close frequency" tone pairs (600 Hz and 1200 Hz), Polish subjects showed a reversed pattern, i.e., better performance for "distant frequency" tone pairs (400 Hz and 3000 Hz). These results indicate on the one hand a common temporal mechanism for perceiving the order of two monaurally presented stimuli, and on the other hand neuronal plasticity for perceiving the order of frequency-related auditory stimuli. We conclude that the auditory brain is modified with respect to temporal processing by long-term exposure to a tonal or a non-tonal language. As a consequence of such an exposure different cognitive modes of operation (analytic vs. holistic) are selected: the analytic mode is adopted for "distant frequency" tone pairs in Chinese and for "close frequency" tone pairs in Polish subjects, whereas the holistic mode is selected for "close frequency" tone pairs in Chinese and for "distant frequency" tone pairs in Polish subjects, reflecting a double dissociation of function. PMID- 24060606 TI - Chemical analog-to-digital signal conversion based on robust threshold chemistry and its evaluation in the context of microfluidics-based quantitative assays. AB - In this article, we describe a nonlinear threshold chemistry based on enzymatic inhibition and demonstrate how it can be coupled with microfluidics to convert a chemical concentration (analog input) into patterns of ON or OFF reaction outcomes (chemical digital readout). Quantification of small changes in concentration is needed in a number of assays, such as that for cystatin C, where a 1.5-fold increase in concentration may indicate the presence of acute kidney injury or progression of chronic kidney disease. We developed an analog-to digital chemical signal conversion that gives visual readout and applied it to an assay for cystatin C as a model target. The threshold chemistry is based on enzymatic inhibition and gives sharper responses with tighter inhibition. The chemistry described here uses acetylcholinesterase (AChE) and produces an unambiguous color change when the input is above a predetermined threshold concentration. An input gives a pattern of ON/OFF responses when subjected to a monotonic sequence of threshold concentrations, revealing the input concentration at the point of transition from OFF to ON outcomes. We demonstrated that this threshold chemistry can detect a 1.30-fold increase in concentration at 22 degrees C and that it is robust to experimental fluctuations: it provided the same output despite changes in temperature (22-34 degrees C) and readout time (10-fold range). We applied this threshold chemistry to diagnostics by coupling it with a traditional sandwich immunoassay for serum cystatin C. Because one quantitative measurement comprises several assays, each with its own threshold concentration, we used a microfluidic SlipChip device to process 12 assays in parallel, detecting a 1.5-fold increase (from 0.64 (49 nM) to 0.96 mg/L (74 nM)) of cystatin C in serum. We also demonstrated applicability to analysis of patient serum samples and the ability to image results using a cell phone camera. This work indicates that combining developments in nonlinear chemistries with microfluidics may lead to development of user-friendly diagnostic assays with simple readouts. PMID- 24060608 TI - CRF system and mood disorders. AB - Since CRF discovery, there has been an impressive accumulation of data regarding the role of the CRF system in the regulation of the stress response. The link between stress and induction of a mood episode in the context of unipolar or bipolar disorder has been clearly demonstrated in several studies and is confirmed by clinical practice, particularly in bipolar disorder. Antidepressant like effects of CRFR1 antagonists in different animal models of depression have generated a strong interest in the clinical development of CRFR1 antagonist for the treatment of major depressive disorder. These efforts have so far not been rewarded by clinical efficacy. However, this therapeutic approach is still being explored. Finally, the accumulated genetic findings, mostly those related to variants within CRFR1, point to a role of the CRF system in the pathophysiology of depression and anxiety. PMID- 24060607 TI - Linkage of type 2 diabetes on chromosome 9p24 in Mexican Americans: additional evidence from the Veterans Administration Genetic Epidemiology Study (VAGES). AB - OBJECTIVE: Type 2 diabetes (T2DM) is a complex metabolic disease and is more prevalent in certain ethnic groups such as the Mexican Americans. The goal of our study was to perform a genome-wide linkage (GWL) analysis to localize T2DM susceptibility loci in Mexican Americans. METHODS: We used the phenotypic and genotypic data from 1,122 Mexican-American individuals (307 families) who participated in the Veterans Administration Genetic Epidemiology Study (VAGES). GWL analysis was performed using the variance components approach. Data from 2 additional Mexican-American family studies, the San Antonio Family Heart Study (SAFHS) and the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), were combined with the VAGES data to test for improved linkage evidence. RESULTS: After adjusting for covariate effects, T2DM was found to be under significant genetic influences (h2 = 0.62, p = 2.7 * 10(-6)). The strongest evidence for linkage of T2DM occurred between markers D9S1871 and D9S2169 on chromosome 9p24.2 p24.1 (LOD = 1.8). Given that we previously reported suggestive evidence for linkage of T2DM at this region also in SAFDGS, we found the significant and increased linkage evidence (LOD = 4.3, empirical p = 1.0 * 10(-5), genome-wide p = 1.6 * 10(-3)) for T2DM at the same chromosomal region, when we performed a GWL analysis of the VAGES data combined with the SAFHS and SAFDGS data. CONCLUSION: Significant T2DM linkage evidence was found on chromosome 9p24 in Mexican Americans. Importantly, the chromosomal region of interest in this study overlaps with several recent genome-wide association studies involving T2DM-related traits. Given its overlap with such findings and our own initial T2DM association findings in the 9p24 chromosomal region, high throughput sequencing of the linked chromosomal region could identify the potential causal T2DM genes. PMID- 24060609 TI - Embryonic and postnatal development of calcium-binding proteins immunoreactivity in the anterior thalamus of the guinea pig. AB - Our recent studies have shown that the distribution of calretinin (CR) in the anterior thalamic nuclei (ATN) changes significantly during the development of the guinea pig. The present study was designed to reveal the distribution pattern of calcium-binding proteins, i.e. calbindin (CB) and parvalbumin (PV), as well as the colocalization pattern of all three proteins, including CR, in the ATN of guinea pigs ranging from the 40th embryonic day (E40) to the 80th postnatal day (P80). According to these patterns, CB appears exclusively in the perikarya of the anteromedial nucleus (AM) not before P20 and always colocalizes with CR. Moreover, CB and CR colocalize in fibers of thin bundles traversing the anteroventral nucleus (AV) since E50. The ATN also display CB-positive neuropil in all studied stages, especially a strong one in the ventral part of the AV. PV was not observed in the perikarya of the ATN in all the stages, but was abundantly present in the neuropil of the anterodorsal nucleus (AD). No colocalizations exist between PV and the rest of the studied proteins. In conclusion, our study reveals that the distribution of the studied proteins differs greatly. Nevertheless, the postnatal coexistence of CB and CR in the AM perikarya may indicate the cooperation of both of the proteins in some functions of the nucleus. Parvalbumin is limited mostly to the neuropil of the AD, suggesting different functions in comparison to CB and CR. PMID- 24060610 TI - Chromosomal organization of repetitive DNA in Sorubim lima (Teleostei; Pimelodidae). AB - Interspaced repetitive DNA elements and segmental duplications have been extensively analyzed in fishes through physical chromosome mapping methods, providing a better comprehension of the structure and organization of the genome of this group. In order to contribute to this scenario, a sequence integration study of different classes of repetitive DNA with high resolution physical chromosome mapping was performed in Sorubim lima. Fluorescence in situ hybridization (FISH) and fiber-FISH with probes for 18S and 5S rRNA genes, TTAGGGn sequence and non-LTR retrotransposon family members Rex1, Rex3 and Rex6 showed that non-LTR elements may be dispersed in the chromosome set with relative concentration in heterochromatic regions, as shown by Rex1, or may even intercalate in 45S rDNA and the telomeric sequence, as found for Rex3 and Rex6. These results reinforce the presence of preferential regions of retroelement accumulation and contribute to a better understanding of the genomic organization of some repetitive DNA classes in fishes. PMID- 24060611 TI - Impact of vitamin D receptor VDR rs2228570 polymorphism in oldest old. AB - BACKGROUND: Calcitriol, a key player in the regulation of mineral metabolism, influences, directly or by increasing plasma Ca2+ and phosphate levels, a multitude of physiological functions, such as bone mineralization, cell proliferation, immune response, carbohydrate metabolism, blood pressure, platelet reactivity, gastric acid secretion, cognitive function and mood. Calcitriol is mainly effective by stimulation of the Vitamin D receptor VDR. The responsiveness of VDR may be affected by gene variants, such as the FokI polymorphism (rs2228570). The GG gene variant is expected to be more active than the GA or AA gene variant. The present study explored the impact of VDR rs2228570 on survival and health of oldest old individuals (> 90 years). METHODS: 101 individuals > 90 years were examined and genotyped. As a result, the prevalence of GG, GA & AA was 36 (10 ?, 26?), 52 (24 ?, 28?) and 13 (4 ?, 9?), respectively, a prevalence not significantly different from the frequency in public available dbSNP and a population (n = 208) of young volunteers (average age 49 years). RESULTS: As compared to carriers of GG, carriers of AA and/or GA displayed significantly (p<0.05) lower diastolic blood pressure (significant only in ?), higher instrumental activity of daily life (IADL) score and more frequent hospital visits (significant only in ?), significantly lower prevalence of depression (significant in ?+?), renal disease (significant only in ?), allergy, peptic ulcer and urolithiasis (significant only in ?), as well as significantly higher prevalence of transitoric ischemic attacks. In a younger population a German version of the NEO-FFI, allowing reliable and valid assessment of personality, revealed decreased neuroticism (significant only in ?) and increased extraversion in AA carriers. CONCLUSION: The Vitamin D receptor gene variant VDR rs2228570 has only little impact on life span but may affect a variety of pathophysiologically relevant functions including mood. PMID- 24060612 TI - Periodic coupling strength-dependent multiple coherence resonance by time delay in Newman-Watts neuronal networks. AB - Recently, multiple coherence resonance induced by time delay has been observed in neuronal networks with constant coupling strength. In this paper, by employing Newman-Watts Hodgkin-Huxley neuron networks with time-periodic coupling strength, we study how the temporal coherence of spiking behavior and coherence resonance by time delay change when the frequency of periodic coupling strength is varied. It is found that delay induced coherence resonance is dependent on periodic coupling strength and increases when the frequency of periodic coupling strength increases. Periodic coupling strength can also induce multiple coherence resonance, and the coherence resonance occurs when the frequency of periodic coupling strength is approximately multiple of the spiking frequency. These results show that for periodic coupling strength time delay can more frequently optimize the temporal coherence of spiking activity, and periodic coupling strength can repetitively optimize the temporal coherence of spiking activity as well. Frequency locking may be the mechanism for multiple coherence resonance induced by periodic coupling strength. These findings imply that periodic coupling strength is more efficient for enhancing the temporal coherence of spiking activity of neuronal networks, and thus it could play a more important role in improving the time precision of information processing and transmission in neural networks. PMID- 24060613 TI - Characterizations of Ohmic and Schottky-behaving contacts of a single ZnO nanowire. AB - Current-voltage and Kelvin probe force microscopy (KPFM) measurements were performed on single ZnO nanowires. Measurements are shown to be strongly correlated with the contact behavior, either Ohmic or diode-like. The ZnO nanowires were obtained by metallo-organic chemical vapor deposition (MOCVD) and contacted using electronic-beam lithography. Depending on the contact geometry, good quality Ohmic contacts (linear I-V behavior) or non-linear (diode-like) contacts were obtained. Current-voltage and KPFM measurements on both types of contacted ZnO nanowires were performed in order to investigate their behavior. A clear correlation could be established between the I-V curve, the electrical potential profile along the device and the nanowire geometry. Some arguments supporting this behavior are given based on technological issues and on depletion region extension. This work will help to better understand the electrical behavior of Ohmic contacts on single ZnO nanowires, for future applications in nanoscale field-effect transistors and nano-photodetectors. PMID- 24060614 TI - Quercitrin and taxifolin stimulate osteoblast differentiation in MC3T3-E1 cells and inhibit osteoclastogenesis in RAW 264.7 cells. AB - Flavonoids are natural antioxidants that positively influence bone metabolism. The present study screened among different flavonoids to identify biomolecules for potential use in bone regeneration. For this purpose, we used MC3T3-E1 and RAW264.7 cells to evaluate their effect on cell viability and cell differentiation. First, different doses of chrysin, diosmetin, galangin, quercitrin and taxifolin were analyzed to determine the optimum concentration to induce osteoblast differentiation. After 48h of treatment, doses >=100MUM of diosmetin and galangin and also 500MUM taxifolin revealed a toxic effect on cells. The same effect was observed in cells treated with doses >=100MUM of chrysin after 14 days of treatment. However, the safe doses of quercitrin (200 and 500MUM) and taxifolin (100 and 200MUM) induced bone sialoprotein and osteocalcin mRNA expression. Also higher osteocalcin secreted levels were determined in 100MUM taxifolin osteoblast treated samples when compared with the control ones. On the other hand, quercitrin and taxifolin decreased Rankl gene expression in osteoblasts, suggesting an inhibition of osteoclast formation. Indeed, osteoclastogenesis suppression by quercitrin and taxifolin treatment was observed in RAW264.7 cells. Based on these findings, the present study demonstrates that quercitrin and taxifolin promote osteoblast differentiation in MC3T3-E1 cells and also inhibit osteoclastogenesis in RAW264.7 cells, showing a positive effect of these flavonoids on bone metabolism. PMID- 24060617 TI - Enterotoxigenic Clostridium perfringens infection and pediatric patients with inflammatory bowel disease. AB - BACKGROUND AND AIMS: Clostridium difficile is the major cause of antibiotic associated diarrhea and is the most well known bacterial pathogen associated with inflammatory bowel disease (IBD). Enterotoxigenic Clostridium perfringens has also been detected in up to 15% of antibiotic-associated diarrhea cases, and it has not been found in healthy people. The aim of this study was to investigate the prevalence of C. perfringens infection in pediatric patients with IBD. METHODS: This was a prospective, controlled study evaluating pediatric IBD patients in the Department of Pediatric Gastroenterology and Nutrition in Warsaw, Poland. All of the patients were diagnosed according to the Porto criteria. There were two control groups: (1) non-IBD patients that were suspected for bacterial diarrhea and (2) healthy children. Stool samples were collected on the day of admission. C. perfringens infection diagnosis was based on a positive stool enzyme immunoassay (C. perfringens enterotoxin test kit TechLab). RESULTS: 91 fecal specimens from patients with IBD were collected. The average patient age was 11.7 years in IBD group, 7.4 years in non-IBD patients with diarrhea, and 7.4 years in healthy children. The prevalence of C. perfringens infection was 9% (8/91; CI 95% 4.6-16.4). There were more Crohn's patients (6/8) in the C. perfringens positive group. There was no C. perfringens infection in the two control groups. CONCLUSION: Our pilot data add evidence to the hypothesis that Clostridia other than C. difficile may play a significant role in the clinical course of IBD. However, further studies are needed to confirm this. PMID- 24060618 TI - Generalized hydromechanical model for stomatal responses to hydraulic perturbations. AB - Stomata respond in a common pattern to various hydraulic perturbations on any part of the 'soil-plant-air' system: initial transient 'wrong-way' responses and final stationary 'right-way' responses. In order to describe this pattern on the basis of statistical physics, we propose a simple model where turgor pressure of a cell is taken to be a power function of its volume, and obtain results in qualitative agreement with experimental data for responses to a variety of hydraulic perturbations: Firstly, stationary stomatal conductance as a function of the vapor pressure deficit divides into three regimes characterized by sensitivities of the stomatal conductance and the transpiration rate with respect to vapor pressure deficit; secondly, for every hydraulic perturbation, the initial transient 'wrong-way' responses always appear; thirdly, on condition that water is supplied insufficiently, stomatal oscillations are often observed; finally, stomatal responses following leaf excision exhibit, after the initial transient wrong-way responses, slow relaxation to stomatal closing. In particular, comparison of areoles having different numbers of stomata demonstrates that areoles with small numbers of stomata tend to provoke lack of water in the soil as well as in the plant. In addition, our model also describes well dependence of the stomatal conductance on temperature. It may be extended further to describe stomatal responses to other environmental factors such as carbon dioxide, light, and temperature. PMID- 24060619 TI - Parameter estimation for metabolic networks with two stage Bregman regularization homotopy inversion algorithm. AB - Metabolism is a very important cellular process and its malfunction contributes to human disease. Therefore, building dynamic models for metabolic networks with experimental data in order to analyze biological process rationally has attracted a lot of attention. Owing to the technical limitations, some unknown parameters contained in models need to be estimated effectively by means of the computational method. Generally, problems of parameter estimation of nonlinear biological network are known to be ill condition and multimodal. In particular, with the increasing amount and enlarging the scope of parameters, many optimization algorithms often fail to find a global solution. In this paper, two stage variable factor Bregman regularization homotopy method is proposed. Discrete homotopy is used to identify the possible extreme region and continuous homotopy is executed for the purpose of stability of path tracing in the special region. Meanwhile, Latin hypercube sampling is introduced to get the good initial guess value and a perturbation strategy is developed to jump out of the local optimum. Three metabolic network inverse problems are investigated to demonstrate the effectiveness of the proposed method. PMID- 24060620 TI - Neural field theory of synaptic metaplasticity with applications to theta burst stimulation. AB - Transcranial magnetic stimulation (TMS) is characterized by strong nonlinear plasticity effects. Experimental results that highlight such nonlinearity include continuous and intermittent theta-burst stimulations (cTBS and iTBS, respectively), where depression is induced in the continuous case, but insertion of an off period of around 8s for every 2s of stimulation changes the induced plasticity to potentiation in the intermittent case. Another nonlinearity is that cTBS and iTBS exhibit dosage dependency, where doubling of the stimulation duration changes the direction of induced plasticity. Guided by previous experimental results, this study postulates on the characteristics of metaplasticity and formulates a physiological system-level plasticity theory to predict TMS experiments. In this theory, plasticity signaling induces plasticity in NMDA receptors to modulate further plasticity signals, and is followed by a signal transduction delayed plasticity expression. Since this plasticity in NMDA receptor affects subsequent plasticity induction, it is a form of metaplasticity. Incorporating this metaplasticity into a recent neural field theory of calcium dependent plasticity gives a physiological basis for the theory of Bienenstock, Cooper, Munro (1982), where postsynaptic intracellular calcium level becomes the measure of temporal averaged postsynaptic activity, and converges to the plasticity threshold to give homeostatic effects. Simulations of TMS protocol responses show that intracellular calcium oscillations around the threshold predicts the aforementioned nonlinearities in TMS-induced plasticity, as well as the interpersonal TBS response polarity found experimentally, where the same protocol may induce opposite plasticity effect for different subjects. Thereby, recommendations for future experiments and TMS protocol optimizations are made. Input selectivity via spatially extended, mean field neural dynamics is also explored. PMID- 24060621 TI - Population-level consequences of heterospecific density-dependent movements in predator-prey systems. AB - In this paper we elucidate how small-scale movements, such as those associated with searching for food and avoiding predators, affect the stability of predator prey dynamics. We investigate an individual-based Lotka-Volterra model with density-dependent movement, in which the predator and prey populations live in a very large number of coupled patches. The rates at which individuals leave patches depend on the local densities of heterospecifics, giving rise to one reaction norm for each of the two species. Movement rates are assumed to be much faster than demographics rates. A spatial structure of predators and prey emerges which affects the global population dynamics. We derive a criterion which reveals how demographic stability depends on the relationships between the per capita covariance and densities of predators and prey. Specifically, we establish that a positive relationship with prey density and a negative relationship with predator density tend to be stabilizing. On a more mechanistic level we show how these relationships are linked to the movement reaction norms of predators and prey. Numerical results show that these findings hold both for local and global movements, i.e., both when migration is biased towards neighbouring patches and when all patches are reached with equal probability. PMID- 24060622 TI - Customized biomimetic scaffolds created by indirect three-dimensional printing for tissue engineering. AB - Three-dimensional printing (3DP) is a rapid prototyping technique that can create complex 3D structures by inkjet printing of a liquid binder onto powder biomaterials for tissue engineering scaffolds. Direct fabrication of scaffolds from 3DP, however, imposes a limitation on material choices by manufacturing processes. In this study, we report an indirect 3DP approach wherein a positive replica of desired shapes was printed using gelatin particles, and the final scaffold was directly produced from the printed mold. To create patient-specific scaffolds that match precisely to a patient's external contours, we integrated our indirect 3DP technique with imaging technologies and successfully created custom scaffolds mimicking human mandibular condyle using polycaprolactone and chitosan for potential osteochondral tissue engineering. To test the ability of the technique to precisely control the internal morphology of the scaffolds, we created orthogonal interconnected channels within the scaffolds using computer aided-design models. Because very few biomaterials are truly osteoinductive, we modified inert 3D printed materials with bioactive apatite coating. The feasibility of these scaffolds to support cell growth was investigated using bone marrow stromal cells (BMSC). The BMSCs showed good viability in the scaffolds, and the apatite coating further enhanced cellular spreading and proliferation. This technique may be valuable for complex scaffold fabrication. PMID- 24060623 TI - Endoscopic sphenoid sinus drainage in Lemierre syndrome. AB - Lemierre syndrome is a rare condition arising from an invasive oropharyngeal infection, which leads to septic thrombophlebitis of the internal jugular vein and multi-organ septic embolization. Intracranial complications are rare but serious, including subdural empyema, cavernous sinus thrombosis, and internal carotid artery aneurysms. We report a patient with Lemierre syndrome with multiple intracranial complications despite aggressive antimicrobial therapy. The patient eventually required transsphenoidal endoscopic drainage of the sphenoid sinus to help eradicate the infectious source. We postulate that in patients with Lemierre syndrome with evidence of infection in the paranasal sinuses, endoscopic sinus drainage can be an adjunct to antimicrobial therapy in achieving infection control. PMID- 24060624 TI - Evaluation of a screening questionnaire for Parkinson's disease in a Chinese population. AB - A questionnaire designed to detect Parkinson's disease (PD) was developed by Tanner et al. in 1990. It consists of nine symptom questions and has been tested in several languages. We investigated the validity of the questionnaire in a Chinese population. Because handwriting is not common for elderly Chinese people, item 2 about "smaller handwriting" may be of no use, thus we also computed the performance of the questionnaire without item 2. The questionnaire was administered face-to-face to all 59 PD patients registered in our hospital and 217 non-neurological outpatients from the same hospital. All 217 outpatients were offered a short interview and examination related to PD. Of the 59 PD patients, 47 participated the study. None of the 217 non-neurological outpatients was diagnosed with parkinsonism. A combination of any three questions yielded the best balance between sensitivity (93.6%) and specificity (88.9%). There was no difference in validity between the questionnaire with and without item 2. This symptom questionnaire is an appropriate instrument to identify PD in a Chinese population. The questionnaire without item 2 is also satisfactory as a screening instrument to detect PD and may be more suitable for areas with a high illiteracy rate. PMID- 24060625 TI - Parkin mutation and deep brain stimulation outcome. AB - Patients with parkin mutations are expected to be good candidates for deep brain stimulation (DBS) because of an excellent levodopa response and frequent occurrence of levodopa-induced dyskinesia. However, there are insufficient data on surgical outcome in patients with parkin mutations. This study aimed to compare the outcome of subthalamic nucleus DBS in patients with early-onset Parkinson's disease with and without parkin mutations. Fourteen patients with early-onset Parkinson's disease who underwent bilateral subthalamic nucleus DBS surgery were screened for parkin mutations and assessed for surgical outcomes at baseline and 2-5years after surgery. Three patients had homozygote/compound heterozygote mutations; two had single heterozygote mutations; and nine had no mutations. Patients with homozygote/compound heterozygote mutations were younger at disease onset and had longer disease duration than patients without a parkin mutation. Postoperatively, there were no significant differences in improvement on the Unified Parkinson's Disease Rating Scale part II, III, and IV, or the reduction of levodopa equivalent daily doses between patients with and without parkin mutations. The therapeutic effect of DBS did not differ between patients with and without parkin mutations. PMID- 24060626 TI - Utility of a rotation-suction microdebrider for tumor removal in endoscopic endonasal skull base surgery. AB - The microdebrider is a common tool used in endoscopic sinus surgery for removing polypoid and sinonasal tissue. It uses rotating blades and an integrated suction device for controlled removal of tissue under video-endoscopic visualization. To our knowledge, the application of the microdebrider for endoscopic removal of skull base tumors has not been reported. This study aimed to investigate the utility of the rotation-suction microdebrider as a tool for endoscopic endonasal removal of solid and fibrous skull base tumors. Thirty-two patients underwent endoscopic endonasal skull base surgery where the rotation-suction microdebrider was used as the primary tool for tumor removal and debulking. Pathologies included a variety of anterior skull base meningiomas, sinonasal skull base malignancies, juvenile nasopharyngeal angiofibromas, schwannomas, and other skull base lesions. Gross total and near total removal was achieved in 87.5% (28/32) of patients, and subtotal removal was performed in 12.5% (4/32) of patients. The microdebrider allowed efficient debulking and removal of solid and fibrous tumors, such as meningiomas, that were not responsive to standard ultrasonic aspiration. There were no complications of orbital or neurovascular injury, or thermal injury to the nostril. The rotation-suction microdebrider is a useful tool for endoscopic endonasal removal of skull base tumors. This is particularly useful for solid and fibrous tumors that are not responsive to standard ultrasonic aspiration. For intracranial tumors, it is critical to remain inside the tumor capsule during debulking so as to avoid injury to the surrounding neurovascular structures. PMID- 24060627 TI - Reinvestigation of growth of thiourea urea zinc sulfate crystal. AB - Reinvestigation of the growth of thiourea urea zinc sulfate crystal is reported. Aqueous reaction of thiourea, urea and zinc sulfate in 1:1:1 mol ratio results in the formation of the well known [Zn(tu)3(SO4)] (1) (tu=thiourea) crystal and not the 'so called' novel semiorganic nonlinear optical thiourea urea zinc sulfate (2) crystal, as claimed by Redrothu Hanumantha Rao, S. Kalainathan, Spectroscopic investigation, nucleation, growth, optical, thermal and second harmonic studies of novel semi-organic nonlinear optical crystal - Thiourea urea zinc sulfate, Spectrochim. Acta A97 (2012) 456-463. In this work, we demonstrate the usefulness of elemental analytical data, infrared and NMR spectra and X-ray powder pattern, for accurate product characterization. PMID- 24060628 TI - Inpatient cognitive behaviour therapy for anorexia nervosa: a randomized controlled trial. AB - BACKGROUND: The aim of this study was to compare the immediate and longer-term effects of two cognitive behaviour therapy programmes for hospitalized patients with anorexia nervosa, one focused exclusively on the patients' eating disorder features and the other focused also on mood intolerance, clinical perfectionism, core low self-esteem or interpersonal difficulties. Both programmes were derived from enhanced cognitive behaviour therapy (CBT-E) for eating disorders. METHODS: Eighty consecutive patients with severe anorexia nervosa were randomized to the two inpatient CBT-E programmes, both of which involved 20 weeks of treatment (13 weeks as an inpatient and 7 as a day patient). The patients were then followed up over 12 months. The assessments were made blind to treatment condition. RESULTS: Eighty-one percent of the eligible patients accepted inpatient CBT-E, of whom 90% completed the 20 weeks of treatment. The patients in both programmes showed significant improvements in weight, eating disorder and general psychopathology. Deterioration after discharge did occur but it was not marked and it was restricted to the first 6 months. There were no statistically significant differences between the effects of the two programmes. CONCLUSIONS: These findings suggest that both versions of inpatient CBT-E are well accepted by these severely ill patients and might be a viable and promising treatment for severe anorexia nervosa. There appears to be no benefit from using the more complex form of the treatment. PMID- 24060629 TI - Therapists' professional and personal characteristics as predictors of outcome in long-term psychodynamic psychotherapy and psychoanalysis. AB - BACKGROUND: Whether long-term psychodynamic therapy (LPP) and psychoanalysis (PA) differ from each other and require different therapist qualities has been debated extensively, but rarely investigated empirically. METHODS: In a quasi experimental design, LPP was provided for 128 and PA for 41 outpatients, aged 20 46 years and suffering from mood or anxiety disorder, with a 5-year follow-up from start of treatment. Therapies were provided by 58 experienced therapists. Therapist characteristics, measured pre-treatment, were assessed with the Development of Psychotherapists Common Core Questionnaire (DPCCQ). General psychiatric symptoms were assessed as the main outcome measure at baseline and yearly after start of treatment with the Symptom Check List, Global Severity Index (SCL-90-GSI). RESULTS: Professionally less affirming and personally more forceful and less aloof therapists predicted less symptoms in PA than in LPP at the end of the follow-up. A faster symptom reduction in LPP was predicted by a more moderate relational style and work experiences of both skillfulness and difficulties, indicating differences between PA and LPP in the therapy process. CONCLUSIONS: Results challenge the benefit of a classically "neutral" psychoanalyst in PA. They also indicate closer examinations of therapy processes within and between the two treatments, which may benefit training and supervision of therapists. PMID- 24060630 TI - The Riata lead recall--more data, but do we now know what we need to know? PMID- 24060631 TI - Development of neutralizing monoclonal antibodies against the pandemic H1N1 virus (2009) using plasmid DNA immunogen. AB - Reported here is the development and characterization of eighteen mouse monoclonal antibodies (MAbs) against the 2009 pandemic H1N1 influenza virus (A/Mexico/InDRE4487/2009). To our knowledge, this is the first report on pandemic (pH1) H1N1 MAbs developed using plasmid DNA encoding the viral surface glycoprotein, hemagglutinin (HA). All eighteen MAbs were specific for A/Mexico/InDRE4487/2009 HA. Ten MAbs were found to cross-react with A/Swine/Indiana/81 using a dot blot assay. However, there was no cross-reactivity detected against any other strains of influenza A viruses despite screening against all 16 hemagglutinin subtypes. Examination of these MAbs identified individual antibodies suitable for use in several practical applications including ELISA, immunoblot and immunofluorescence assays. Analysis of the kinetics of each MAb revealed significant binding affinities (K(D)<10(-8) M) confirming the antibodies are highly specific for A/Mexico/InDRE4487/2009 HA. Functional analysis demonstrated the panel of MAbs included antibodies with HA inhibition and virus neutralization activities. Not all MAbs inhibited hemagglutination or neutralized the virus. Furthermore, the panel of MAbs was not found to be cross-reactive against additional strains tested in hemagglutination inhibition assays. Finally, the MAbs were tested in competitive ELISA (cELISA) using reference serum antibodies developed against different clusters of H1 (pH1, alpha, beta, gamma, and delta). The developed MAbs outcompeted serum antibodies of pH1 in 16/18, 15/18 (gamma), 3/18 (alpha), 2/18 (delta1) and 1/18 (beta) samples. Overall, this panel of MAbs proved specific and highly sensitive for A/Mexico/InDRE4487/2009 HA and could potentially serve as immunodiagnostic tools for the rapid detection of this specific strain of influenza virus. PMID- 24060632 TI - Proteomic biomarkers for spontaneous preterm birth: a systematic review of the literature. AB - This review aimed to identify, synthesize, and analyze the findings of studies on proteomic biomarkers for spontaneous preterm birth (PTB). Three electronic databases (Medline, Embase, and Scopus) were searched for studies in any language reporting the use of proteomic biomarkers for PTB published between January 1994 and December 2012. Retrieved citations were screened, and relevant studies were selected for full-text reading, in triplicate. The search yielded 529 citations, 51 were selected for full-text reading and 8 studies were included in the review. A total of 64 dysregulated proteins were reported. Only 14-3-3 protein sigma, annexin A5, protein S100-A8, protein S100-A12, and inter-alpha-trypsin inhibitor heavy chain H4 were reported in more than 1 study, but results could not be combined due to heterogeneity in type of sample and analytical platform. In conclusion, according to the existing literature, there are no specific proteomic biomarkers capable of accurately predicting PTB. PMID- 24060633 TI - Levonorgestrel intrauterine system in adjuvant tamoxifen treatment: balance of breast risks and endometrial benefits--systematic review of literature. AB - Levonorgestrel intrauterine system (LNG-IUS) is used in patients with breast patients taking tamoxifen (TAM) to prevent endometrial proliferation. The benefits (on endometrium), the side effects (on breast), and the patients suitable for this treatment are not still clear. Aim of this systematic review is to define the breast risks and endometrial benefits in TAM-treated women using Mirena and to define which patients could benefit from LNG-IUS use. In all, 3 studies on LNG-IUS effects on endometrium in TAM-treated women and 4 studies on breast cancer recurrence were selected for the study. All studies described a reduction in benign endometrial pathologies among Mirena users, but controversial data showed malignant disease and breast cancer recurrence. So it is mandatory to define hormonal status before TAM treatment. In selected patients Mirena was proven to protect endometrium. Perspective clinical trials on Mirena pharmacological features are necessary to establish whether systemic levels of progesterone could increase breast cancer recurrence in such patients. PMID- 24060634 TI - KLF11 epigenetically regulates glycodelin-A, a marker of endometrial biology via histone-modifying chromatin mechanisms. AB - Endometrial biology is characterized by programmed proliferation and differentiation that is synchronous with ovarian folliculogenesis to maximize the chance of pregnancy. Glycodelin-A, an endometrial secretory protein, promotes pregnancy mostly through immunomodulatory mechanisms. Glycodelin-A is repressed during the proliferative and early secretory phase and activated thereafter. Progesterone activates glycodelin via the Sp1 (Specificity Protein 1) transactivator. We identify a novel role for Kruppel-like transcription factor 11 (KLF11) as a glycodelin-A repressor. Although KLF11 bound 2 distinct regulatory elements, it regulated glycodelin promoter activity differentially through each element. Whereas KLF11 weakly activated glycodelin promoter activity via a region that also bound Sp1, the dominant effect of KLF11 was repression of promoter activity, messenger RNA (mRNA), and protein expression via a novel, specific binding element. KLF11 mediated this repression by recruiting the SIN3/histone deacetylase (HDAC) corepressor complex to the glycodelin promoter. KLF11 may solely, or by competing with Sp1, repress glycodelin-A levels and thereby influence its role in the endometrium. PMID- 24060635 TI - Crosstalk between tyrosine kinase receptors, GSK3 and BMP2 signaling during osteoblastic differentiation of human mesenchymal stem cells. AB - Bone morphogenic proteins (BMPs) promote mesenchymal stem cell (MSC) osteogenic differentiation, whereas platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) activate their proliferation through receptors tyrosine kinase (RTK). The effects of PDGF or FGF receptor signaling pathway on BMP2 induced osteoblastic differentiation was investigated in human MSC (HMSC). Inhibition of PDGF or/and FGF receptors enhanced BMP2-induced alkaline phosphatase (ALP) activity, expression of Osterix, ALP and Bone sialoprotein, and matrix calcification. These effects were associated with increased Smad-1 activity, indicating that mitogenic factors interfere with Smad signaling in HMSC differentiation. RTK activate MAPK and inhibit GSK3 through the PI3K/Akt pathway. Biochemical analysis indicated that MAPK JNK and GSK3 especially are potential signaling molecules regulating BMP-induced osteoblastic HMSC differentiation. These observations highlight that the osteogenic effects of BMP2 are modulated by mitogenic factors acting through RTK. PMID- 24060636 TI - Reproductive actions of prolactin mediated through short and long receptor isoforms. AB - Prolactin (PRL) is a polypeptide hormone with a wide range of physiological functions, and is critical for female reproduction. PRL exerts its action by binding to membrane bound receptor isoforms broadly classified as the long form and the short form receptors. Both receptor isoforms are highly expressed in the ovary as well as in the uterus. Although signaling through the long form is believed to be more predominant, it remains unclear whether activation of this isoform alone is sufficient to support reproductive functions or whether both types of receptor are required. The generation of transgenic mice selectively expressing either the short or the long form of PRL receptor has provided insight into the differential signaling mechanisms and physiological functions of these receptors. This review describes the essential finding that both long and short receptor isoforms are crucial for ovarian functions and female fertility, and highlights novel mechanisms of action for these receptors. PMID- 24060638 TI - Nuclear receptors expression chart in peripheral blood mononuclear cells identifies patients with Metabolic Syndrome. AB - BACKGROUND: Nuclear receptors are a class of 48 ligand-activated transcription factors identified as key players of metabolic and developmental processes. Most of these receptors are potential targets for pharmacological strategies in the Metabolic Syndrome. In the present study, we analyzed changes in the mRNA expression of nuclear receptors in the peripheral blood mononuclear cells of patients with Metabolic Syndrome, in order to identify novel biomarkers of disease and candidate targets for putative therapeutical approaches. METHODS AND RESULTS: We enrolled thirty healthy controls (14 M:16 F) and thirty naive patients (16 M: 14 F; >3 criteria for Metabolic Syndrome upon Adult Treatment Panel III) without organ damage. Using quantitative real-time PCR, we assessed the expression patterns of nuclear receptors in peripheral blood mononuclear cells. 33/48 nuclear receptors were expressed in peripheral blood mononuclear cells. In patients with Metabolic Syndrome, we found a significant down regulation of the entire PPAR, NR4A and RAR families, together with a repression of RXRalpha, VDR, and Rev-Erbalpha. Furthermore, we performed a novel statistical analysis with classification trees, which allowed us to depict a predictive core of nuclear receptor expression patterns characterizing subjects with Metabolic Syndrome. Random Forest Analysis identified NOR1 and PPARdelta, which were both reduced in peripheral blood mononuclear cells and specifically in CD14(+) cells (mostly monocytes), as classifiers of Metabolic Syndrome, with high specificity and sensitivity. CONCLUSIONS: Our results point to the use of PPAR and NR4A mRNA levels in the overall peripheral blood mononuclear cells as biomarkers of Metabolic Syndrome and bona fide putative targets of pharmacological therapy. PMID- 24060639 TI - Risk of repeat anti-incontinence surgery following sling release: a review of 93 cases. AB - PURPOSE: Sling procedures are the most common surgery for stress urinary incontinence in women. Lower urinary tract symptoms are well documented complications of these procedures that develop in 5% to 20% of patients. A common treatment for postoperative urinary retention and bothersome obstructive voiding symptoms after anti-incontinence surgery is sling release. While previous studies indicated the risk of recurrent stress urinary incontinence after surgical release of slings, there is a paucity of data on how many patients require repeat anti-incontinence procedures. MATERIALS AND METHODS: After receiving institutional review board approval we retrospectively reviewed the records of 143 consecutive female sling release procedures performed by 2 subspecialized urologists at our clinic from January 2000 through August 2012. A total of 121 patients underwent documented followup at our clinic, of whom 93 were treated with sling release for obstruction or retention after sling placement. We identified the characteristics of this patient population, specifically the incidence of subsequent anti-incontinence procedures. RESULTS: Mean +/- SD patient age was 58 +/- 13.2 years and median patient followup after surgical sling release was 32 months (IQR 6, 67). Of the 93 patients 13 (14%) required a repeat anti-incontinence procedure after sling release at a median of 3 months. CONCLUSIONS: Sling release remains an important treatment option in patients with obstruction after anti-incontinence surgery. Only a small percent of patients require repeat anti-incontinence surgery for recurrent stress urinary incontinence. PMID- 24060640 TI - Simultaneous augmentation cystoplasty and cuff only artificial urinary sphincter in children and young adults with neurogenic urinary incontinence. AB - PURPOSE: We review our experience with artificial urinary sphincter and augmentation cystoplasty in patients with neurogenic bladder. This is the largest known series to specifically evaluate cuff only artificial urinary sphincter at augmentation cystoplasty. MATERIALS AND METHODS: A total of 18 males underwent simultaneous artificial urinary sphincter and augmentation cystoplasty at our institution between 1982 and 2012, of whom 13 (72%) underwent cuff only artificial urinary sphincter. Outcomes included urinary continence, emptying modality, artificial urinary sphincter status, complications and additional procedures. RESULTS: Of the patients undergoing augmentation cystoplasty and cuff only artificial urinary sphincter 10 (77%) were initially continent. Average time of continence was 52.9 months. Four patients (31%) required no additional procedures and remained continent. Urinary incontinence developed in 3 patients (23%) immediately postoperatively and in 6 (46%) subsequently. Ultimately 9 patients (69%) required conversion to complete artificial urinary sphincter at a mean of 36.9 months postoperatively. Overall 12 patients (92%) were continent at followup. There were no artificial sphincter specific complications in patients undergoing the cuff only procedure with conversion to complete artificial urinary sphincter. After conversion to complete artificial urinary sphincter 3 patients (23%) experienced artificial sphincter specific complications. Reoperation was performed in 10 patients (77%), for 13 total procedures (1.3 per patient). There were no complications with cuff only artificial urinary sphincter and 6 complications with complete artificial urinary sphincter (p = 0.025). Finally, patients undergoing cuff only artificial urinary sphincter requiring revision were younger than those not requiring revision (15.6 vs 30.8 years, p = 0.026). CONCLUSIONS: Simultaneous cuff only artificial urinary sphincter and augmentation cystoplasty appears safe and efficacious in patients with neurogenic bladder, with fewer complications than complete artificial urinary sphincter, and may provide definitive urinary continence in up to a third of patients. This procedure is technically easy, allows for outpatient revision, provides time for the child to mature and may be cost effective in avoiding placement of additional components in this select patient population. PMID- 24060637 TI - Mitochondria-targeted antioxidants for treatment of Parkinson's disease: preclinical and clinical outcomes. AB - Parkinson's disease is a progressive neurodegenerative disease in the elderly, and no cure or disease-modifying therapies exist. Several lines of evidence suggest that mitochondrial dysfunction and oxidative stress have a central role in the dopaminergic neurodegeneration of Parkinson's disease. In this context, mitochondria-targeted therapies that improve mitochondrial function may have great promise in the prevention and treatment of Parkinson's disease. In this review, we discuss the recent developments in mitochondria-targeted antioxidants and their potential beneficial effects as a therapy for ameliorating mitochondrial dysfunction in Parkinson's disease. PMID- 24060642 TI - Prospective comparison of molecular signatures in urothelial cancer of the bladder and the upper urinary tract--is there evidence for discordant biology? AB - PURPOSE: Upper tract urothelial carcinoma is rare and less well studied than bladder cancer. It remains questionable if findings in bladder cancer can safely be extrapolated to upper tract urothelial carcinoma. We prospectively evaluate molecular profiles of upper tract urothelial carcinoma and bladder cancer using a cell cycle biomarker panel. MATERIALS AND METHODS: Immunohistochemical staining for p21, p27, p53, cyclin E and Ki-67 was prospectively performed for 96 patients with upper tract urothelial carcinoma and 159 patients with bladder cancer with nonmetastatic high grade urothelial carcinoma treated with extirpative surgery. Data were compared between the groups according to pathological stage. Primary outcome was assessment of differences in marker expression. Secondary outcome was difference in survival according to marker status. RESULTS: During a median followup of 22.0 months 31.2% of patients with upper tract urothelial carcinoma and 28.3% of patients with bladder cancer had disease recurrence, and 20.8% and 27.7% died of upper tract urothelial carcinoma and bladder cancer, respectively. The number of altered markers was not significantly different between the study groups. Overall 34 patients (35.4%) with upper tract urothelial carcinoma and 62 (39.0%) with bladder cancer had an unfavorable marker score (more than 2 markers altered). There were no significant differences between upper tract urothelial carcinoma and bladder cancer in the alteration status of markers, the number of altered markers and biomarker score when substratified by pathological stage. There were no significant differences in survival outcomes between patients with upper tract urothelial carcinoma and those with bladder cancer according to the number of altered markers and biomarker score. CONCLUSIONS: Our results demonstrate the molecular similarity of upper tract urothelial carcinoma and bladder cancer in terms of cell cycle and proliferative tissue markers. These findings have important implications and support the further extrapolation of treatment paradigms established in bladder cancer to upper tract urothelial carcinoma. PMID- 24060641 TI - Prostate specific antigen velocity risk count predicts biopsy reclassification for men with very low risk prostate cancer. AB - PURPOSE: Prostate specific antigen velocity is an unreliable predictor of adverse pathology findings in patients on active surveillance for low risk prostate cancer. However, to our knowledge a new concept called prostate specific antigen velocity risk count, recently validated in a screening cohort, has not been investigated in an active surveillance cohort. MATERIALS AND METHODS: We evaluated a cohort of men from 1995 to 2012 with prostate cancer on active surveillance. They had stage T1c disease, prostate specific antigen density less than 0.15 ng/ml, Gleason score 6 or less, 2 or fewer biopsy cores and 50% or less involvement of any core with cancer. The men were observed by semiannual prostate specific antigen measurements, digital rectal examinations and an annual surveillance biopsy. Treatment was recommended for biopsy reclassification. Patients with 30 months or greater of followup and 3 serial prostate specific antigen velocity measurements were used in primary analysis by logistic regression, Cox proportional hazards, Kaplan-Meier analysis and performance parameters, including the AUC of the ROC curve. RESULTS: Primary analysis included 275 of 668 men who met very low risk inclusion criteria, of whom 83 (30.2%) were reclassified at a median of 57.1 months. Reclassification risk increased with risk count, that is a risk count of 3 (HR 4.63, 95% CI 1.54-13.87) and 2 (HR 3.73, 95% CI 1.75-7.97) compared to zero. Results were similar for Gleason score reclassification (HR 7.45, 95% CI 1.60-34.71 and 3.96, 95% CI 1.35 11.62, respectively). On secondary analysis the negative predictive value (risk count 1 or less) was 91.5% for reclassification in the next year. Adding the prostate specific antigen velocity risk count improved the AUC in a model including baseline prostate specific antigen density (0.7423 vs 0.6818, p = 0.025) and it outperformed the addition of overall prostate specific antigen velocity (0.7423 vs 0.6960, p = 0.037). CONCLUSIONS: Prostate specific antigen velocity risk count may be useful for monitoring patients on active surveillance and decreasing the frequency of biopsies needed in the long term. PMID- 24060643 TI - Expulsive therapy versus early endoscopic stone removal in patients with acute renal colic: a comparison of indirect costs. AB - PURPOSE: While medical expulsive therapy is associated with lower health care expenditures compared to early endoscopic stone removal in patients with renal colic, little is known about the effect of medical expulsive therapy on indirect costs. MATERIALS AND METHODS: Using a previously validated claims based algorithm we identified a cohort of patients with acute renal colic. After determining the up-front treatment type (ie an initial course of medical expulsive therapy vs early endoscopic stone removal) we compared differences in rates of short-term disability filing. We used propensity score matching to account for differences between treatment groups such that patients treated with medical expulsive therapy vs early endoscopic stone removal were similar with regard to measured characteristics. RESULTS: In total, 257 (35.8%) and 461 (64.2%) patients were treated with medical expulsive therapy or early endoscopic stone removal, respectively. There were no differences between treatment groups after propensity score matching. In the matched cohort the patients treated with medical expulsive therapy had a 6% predicted probability of filing a claim for short-term disability compared to 16.5% in the early endoscopic stone removal cohort (p <0.0001). Among the patients who filed for short-term disability those prescribed medical expulsive therapy had on average 1 fewer day of disability than those treated surgically (0.9 vs 1.8 days, p <0.001). CONCLUSIONS: An initial trial of medical expulsive therapy is associated with significantly lower indirect costs to the patient compared to early endoscopic stone removal. These findings have implications for providers when counseling patients with acute renal colic. PMID- 24060644 TI - The electrophysiological locus of the redundant target effect on visual discrimination in a dual singleton search task. AB - Task performance can be enhanced by the addition of extra information to a visual environment in which observers search for a target stimulus. One example of such information is the repetition of the searched-for stimulus; a form of target redundancy. In the present study, the electrophysiological correlates of such target redundancy were investigated in a visual discrimination task. Observers were asked to look for targets in displays that always contained two salient singletons (tilted lines; targets and/or nontargets) against a background of vertical distractor lines. Displays contained either two redundant targets, two nontargets, or a single target and nontarget, at opposite sides of the visual field. Search was most efficient when two targets were shown, and effects of target redundancy were observed on the event-related potential as well. Target redundancy modulated the anterior N2, and the P3 in both an early and a late window. The results are compatible with models of visual attention that support a relatively late (i.e., central or decisional) locus of redundancy processing. PMID- 24060646 TI - Aberrant N400 responses to phonological overlap during rhyme judgements in children at risk for dyslexia. AB - It is widely accepted that dyslexia is associated with difficulties in phonological awareness and that rhyme awareness in young children can predict later reading success. However, little is known regarding the underlying phonological mechanisms of rhyme awareness in dyslexia, as rhyme awareness is typically assessed using explicit behavioural measures that represent only the endpoint of processing and often lack phonological distracters. We examined event related potentials (ERPs) in response to auditory word pairs that differed in phonological overlap during a rhyme judgement task given to 6-year-old beginning readers who were at risk for dyslexia (n=30) and typical-reading age-matched controls (n=29). ERPs were recorded in response to word pairs with various types of phonological overlap, including rhyming (e.g., wall-ball), non-rhyming overlapping (e.g., bell-ball) and non-rhyming unrelated (e.g., sock-ball) word pairs. Both groups of participants exhibited N400 responses for basic rhyme judgements vs. unrelated targets. In the typical-reading controls, the neural responses also differed between the rhyming targets and the non-rhyming overlapping targets, whereas neural responses to these targets were similar in the group of children at risk for dyslexia, indicating difficulties in their ability to process similar-sounding, non-rhyming targets. These findings suggest that typical-reading children solve the rhyme judgement task using a more analytical approach, whereas children who are at risk for dyslexia base their judgments on a comparison of overall sound similarity. PMID- 24060645 TI - Effects of 5-HT1A receptor stimulation on striatal and cortical M1 pERK induction by L-DOPA and a D1 receptor agonist in a rat model of Parkinson's disease. AB - Motor symptoms of Parkinson's disease are commonly treated using l-DOPA although long-term treatment usually causes debilitating motor side effects including dyskinesias. A putative source of dyskinesia is abnormally high levels of phosphorylated extracellular-regulated kinase (pERK) within the striatum. In animal models, the serotonin 1A receptor agonist +/-8-OH-DPAT reduces dyskinesia, suggesting it may exhibit efficacy through the pERK pathway. The present study investigated the effects of +/-8-OH-DPAT on pERK density in rats treated with l DOPA or the D1 receptor agonist SKF81297. Rats were given a unilateral dopamine lesion with 6-hydroxydopamine and primed with a chronic regimen of l-DOPA, SKF81297 or their vehicles. On the final test day, rats were given two injections: first with +/-8-OH-DPAT, the D1 receptor antagonist SCH23390 or their vehicles, and second with l-DOPA, SKF81297 or their vehicles. Rats were then transcardially perfused for immunohistological analysis of pERK expression in the striatum and primary motor cortex. Rats showed greater dyskinesia in response to l-DOPA and SKF81297 after repeated injections. Although striatal pERK induction was similar between acute and chronic l-DOPA, SKF81297 caused the largest increase in striatal pERK after the first exposure. Neither compound alone affected motor cortex pERK. Surprisingly, in the ventromedial striatum, +/-8-OH DPAT potentiated l-DOPA-induced pERK; in the motor cortex, +/-8-OH-DPAT potentiated pERK with l-DOPA or SKF81297. Our results support previous work that the striatal pERK pathway is dysregulated after dopamine depletion, but call into question the utility of pERK as a biomarker of dyskinesia expression. PMID- 24060647 TI - Neurodegenerative diversity in human cortical contusion: histological analysis of tissue derived from decompressive craniectomy. AB - The principal aim in the management of patients with cerebral contusion (CC) following severe traumatic brain injury (TBI) is the prevention, amelioration, and treatment of secondary neuronal dysfunction and pathology. Distinguishing between irreversibly damaged and surviving tissue could have considerable therapeutic and prognostic implications for patients. To characterize structurally the neuronal compartment of the contused region in samples derived from patients who suffered severe TBI and were subjected to decompressive craniectomy, we used NeuN, a neuronal marker. We determined that NeuN "patches", sectors with loss of NeuN immunoreactivity (NeuN-IR), represented 25% of the area among the analyzed cases. We also found a 67% decrease in NeuN levels via Western blot. Tissue adjoining patches of NeuN-IR were considered "preserved" due to the apparent normal density of neurons and conservation of the six cortical layers. Nevertheless, these sectors retained only 39% of their neurons with the classical pattern described for normal NeuN-IR. Using Fluorojade we identified a 16-fold increase in density of moribund neurons in "preserved" sectors when compared to controls. Additionally these abnormalities were enhanced 5-fold in "patches" of NeuN-IR when compared to preserved regions. Therefore, NeuN/Fluorojade abnormalities are indicative of different cell fates characteristic of CC tissue. This analysis addressed exclusively the neuronal compartment and provides new insights into the degenerative state of neurons in the contused region that is likely to contribute to clinical outcome and differentiate TBI from ischemia. PMID- 24060648 TI - Altered somatosensory barrel cortex refinement in the developing brain of Mecp2 null mice. AB - Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MeCP2) gene. In previous studies, monoaminergic dysfunctions have been detected in patients with RTT and in a murine model of RTT, the Mecp2-null mouse. Therefore, the pathogenesis of RTT is thought to involve impairments in the monoaminergic systems. However, there have been limited data showing that the impairment of monoamines leads to early symptoms during development. We used histochemistry to study the somatosensory barrel cortex in the B6.129P2(C)-Mecp2(tm1.1Bird) mouse model of RTT. The barrel cortex is widely used to investigate neuronal development and its regulation by various neurotransmitters including 5-HT. 5-HT levels were measured by high performance liquid chromatography with electrochemical detection (HPLC/EC), and serotonin transporter (SERT) and 5-HT1B receptor mRNAs were measured in the somatosensory cortex, thalamus and striatum on postnatal days (P) 10, P20 and P40. Mecp2-null mice (Mecp2-/y) had significantly smaller barrel fields than age-matched wild type controls (Mecp2+/y) on P10 and P40, but the topographic map was accurately formed. Levels of 5-HT, and SERT and 5-HT1B receptor mRNA expression in the somatosensory cortex did not differ significantly between the Mecp2-null and wild type mice on P10. However, thalamic 5-HT was reduced in Mecp2-null mice. Our data indicate that a lack of MeCP2 may disturb the refinement of the barrel cortex in the early postnatal period. Our findings suggest that a decrease in thalamic 5-HT might be involved in this phenomenon. PMID- 24060649 TI - The medial based bi- or trilobed flap for repair of distal alar defects. AB - BACKGROUND: Reconstruction of defects of the lateral nasal ala might be challenging. Reconstruction with a bi- or trilobed flap is common. The laterally based bi- or trilobed flap for defects of the distal ala or lateral tip of the nose produces mostly tissue protrusion in the nasal groove which is aesthetically unpleasant. Why not use more the medially based bi- or trilobed flap? OBJECTIVE: To describe the utility of bilobed and trilobed flaps for alar defects insisting on the design of medially based flaps. METHODS: To show the technique and practical application for this kind of reconstruction. RESULTS: The bi- and trilobed flaps are useful for defect repair between the lateral nasal tip and the distal ala. We observed that in most cases the flap based medially respects anatomical subunits better than the laterally based flap for medium-sized defects of the distal ala of the nose. CONCLUSION: I suggest that the bi- and trilobed flaps for repair of the lateral tip/distal ala should more often be medially based. This flap has a specific indication and precise advantage compared to other reconstructions, especially to the laterally based multilobed flaps in this specific indication. PMID- 24060650 TI - Solid-liquid-vapor metal-catalyzed etching of lateral and vertical nanopores. AB - Etching is an essential tool for the creation of nanostructures, where patterned metal structures can be used as masks. Here, we investigate HCl gas etching of InP substrates decorated with Au nanoparticles, and find that the etch rate is strongly increased at the Au-InP interfaces. The {111}A facets of the InP are preferentially etched. The metal nanoparticles follow in the etch direction, thereby creating nanopores. The size and position of the pores is controlled by the Au nanoparticles, and we measure nanopores as thin as 20 nm with an aspect ratio of 25:1. The direction of the nanopores is influenced by the temperature and the substrate orientation, which we use to demonstrate lateral, vertical and inclined nanopores. We explain the process by a solid-liquid-vapor model, in which the liquid metal particle catalyzes the dissolution of the solid InP. PMID- 24060651 TI - Cloning and heterologous expression of serine protease SL41 related to biocontrol in Trichoderma harzianum. AB - Serine proteases are highly conserved among fungi and considered to play a key role in different aspects of fungal biology. These proteases are involved in fungal growth and have been related to biocontrol processes. To assess the functional role of serine proteases from Trichoderma harzianum T88, an effective biocontrol agent, on inhibition of phytopathogenic fungi, a gene (SL41) encoding a serine protease was isolated by 5' and 3' RACE (rapid amplification of cDNA ends). Northern blot analysis indicated that SL41 was induced in response to cell walls of different fungi. This protease gene was expressed in Saccharomyces cerevisiae under the control of the galactose-inducible GAL1 promoter. After induction, the enzyme activity was culminated (16.2 units ml(-1)) at 60 h of cultivation. The optimal enzyme reaction temperature was 40 degrees C and optimal pH was 10.5. Northern blot analysis indicated that the amount of the transcripts increased with the culture time in agreement with the measured enzyme activity. Antifungal activity of serine protease against five phytopathogens was investigated in vitro. It can inhibit the mycelial growth of phytopathogenic fungi and exerted broad spectrum antifungal activity against phytopathogenic fungi. This is the first time that the different regulation of serine protease in T. harzianum response to five phytopathogenic fungi was shown, the protease was functionally expressed in a heterologous host, and its antagonistic activity was evaluated in vitro. PMID- 24060652 TI - Removal of heavy metal cations by biogenic magnetite nanoparticles produced in Fe(III)-reducing microbial enrichment cultures. AB - The biogenic magnetite nanoparticles presented here had a high capacity of adsorbing metal cations, which was approximately 30- to 40-fold greater than commercially available magnetite. These results suggest the potential application of microbial magnetite formation in the removal of toxic metal cations from water. PMID- 24060653 TI - Combination of neonatal PolyI:C and adolescent phencyclidine treatments is required to induce behavioral abnormalities with overexpression of GLAST in adult mice. AB - Cumulative incidences of multiple risk factors are related to pathology of psychiatric disorders. The present study was designed to examine combinative effects of a neonatal immune challenge with adolescent abused substance treatment on the psychological behaviors and molecular expressions in the adult. C57BL/6J mice were neonatally treated, with polyriboinosinic-polyribocytidylic acid (PolyI:C: 5mg/kg) during postnatal days (PD) 2-6, then with phencyclidine (PCP: 10mg/kg) during adolescence (PD35-41). Locomotor activity was analyzed to evaluate sensitivity to PCP on PD35 and PD41. Emotional and cognitive tests were carried out on PD42-48. Neonatal PolyI:C treatment markedly enhanced sensitivity to PCP- and methamphetamine-induced hyperactivity in the adolescent. Mice treated with both neonatal PolyI:C and adolescent PCP (PolyI:C/PCP) showed social deficit and object recognition memory impairment. The expression of glutamate/aspartate transporter (GLAST) in the prefrontal cortex (PFC) was significantly increased in the (PolyI:C/PCP)-treated mice. Infusion of glutamate transporter inhibitor (DL TBOA: 1 nmol/bilaterally) into the PFC reversed the object recognition impairment in the (PolyI:C/PCP)-treated mice. These results indicate that the combined treatment of neonatal PolyI:C with adolescent PCP leads to behavioral abnormalities, which were associated with increase of GLAST expression in the adult PFC. PMID- 24060654 TI - Continuous central infusion of cannabinoid receptor agonist WIN 55,212-2 decreases maternal care in lactating rats: consequences for fear conditioning in adulthood males. AB - In lactating rats, maternal behavior consists of several integrated elements designed to promote care and nutrition of the offspring to ensure their survival. Given previous studies showing the role of the brain endocannabinoid system in maternal behavior, the objective of this work was to determine which changes in maternal care occur during continuous intracerebroventricular infusion of a cannabinoid receptor agonist (WIN 55,212-2). Maternal behavior was scored daily in 4 sessions of 72 min each (3 during the light phase and 1 during the dark phase). During drug infusion, the results indicated decreased time spent by the mother licking pups and an increase in feeding time. To determine the extent to which variations in maternal care during the neonatal period affect offspring later in life, we evaluated possible changes in the fear response of offspring once they reached adulthood. Offspring of mothers treated with a cannabinoid agonist presented a lower latency for freezing behavior and increased time spent freezing in a fear test. These results show that treatment with a cannabinoid agonist decreases maternal care, mainly licking, in lactating rats and is associated with increased fear responses in offspring later in life. PMID- 24060655 TI - The Tanner Model of Clinical Judgment to preceptorship. PMID- 24060656 TI - Time for realistic job previews in nursing as a recruitment and retention tool. AB - Realistic job previews are well-established, cost-effective, and evidence-based recruitment and retention tools that nurses in professional development have largely overlooked. A realistic job preview for experienced staff nurses pioneering the Clinical Nurse Leader(r) role is presented along with implications for nursing professional development practice. PMID- 24060657 TI - An exploration of the workplace bullying experience: coping strategies used by nurses. AB - This qualitative descriptive study explored nurses' experience of being bullied and examined their coping strategies. A purposive sample of 18 registered nurses who self-identified as being targets of bullying behavior was used. The authors found that nurses used a variety of coping strategies. An understanding of these strategies can assist staff development educators to develop interventions to eliminate this pervasive problem. PMID- 24060658 TI - Emergency nurse residency program evaluation. AB - The purpose of this mixed method descriptive study was to perform a program evaluation on an emergency nurse residency program. The study identified leaders' goals, objectives, and outcomes and the nurse residents' perceptions of the program, including whether they felt prepared to make the transition into their new role. The program evaluation revealed that the nurse residents felt confident, secure, and prepared to function as well-rounded emergency nurses after completing the emergency nurse residency program, in congruence with leaders' objectives. PMID- 24060659 TI - The nursing research idea fair: fostering research interest and activity among nurses. AB - Educators need creative means to enhance nurses' understanding of the research process. The Nursing Research Idea Fair provides a multifaceted educational experience to stimulate interest in research, educate nurses about research, and engage nurses in the research process in a fun, nonintimidating way. Nurse-driven research studies have increased fourfold since implementing the fair. PMID- 24060660 TI - Research utilization in baccalaureate-prepared registered nurses. AB - A focus group study was conducted to describe bachelor of science-prepared registered nurses' (n = 10) use of research in their everyday practice. Results indicate that participants feel prepared to use research upon entry into the workforce and do so to better patient care. However, research use is both positively and negatively affected by nursing leadership and the research culture of the workplace. The author includes implications for nursing professional development specialists and educators. PMID- 24060661 TI - Nursing education and research rounds: evaluation of a webinar-based education strategy to engage nurses and support practice. AB - Nursing Education and Research Rounds (NEARR), a webinar-based series of continuing education presentations focused on nursing research, was developed to engage nurses in discussion about evidence-based practice. Evaluation of NEARR indicated a large majority of participants considered the information provided useful in their practice and planned to attend future NEARR sessions. Nursing professional development specialists can use this approach to support evidence based practice. PMID- 24060662 TI - Hospital staff nurse perceptions of competency to care for patients with psychiatric or behavioral health concerns. AB - Disruptive behaviors are common among hospitalized patients with psychiatric and substance abuse behaviors. Nurses working on nonpsychiatric units, however, may lack competencies to care for patients with such behaviors. A survey was developed and administered to 844 nurses across three hospital settings that revealed a lack of nurse confidence to intervene in situations that require de escalation techniques and crisis communication. This study provides direction for further research and interventions in hospital settings with similar professional development needs. PMID- 24060663 TI - Integration of internationally educated nurses into the U.S. Workforce. AB - This study describes the integration experiences of internationally educated nurses, managers, and educators working in Northern California. The purpose of this qualitative pilot study was to explore the experiences of internationally educated nurses and the nurse managers and educators working with them, to understand the issues, and to highlight potential solutions for addressing integration challenges. Through interviews and qualitative analysis, successful strategies and persistent challenges were identified. Major themes identified included communication difficulties; financial challenges; the need for outside social support; and educational orientations focused on culture, nurse role, and communication techniques. PMID- 24060664 TI - Does academic dishonesty result in unethical professional practice? PMID- 24060666 TI - Nurse residency program leaders: who is at the helm? PMID- 24060665 TI - Tanner's Model of Clinical Judgment Applied to Preceptorship: part 1. PMID- 24060667 TI - Unannounced in situ simulations in the hospital setting: "to tell or not to tell". PMID- 24060670 TI - What changes in neural oscillations can reveal about developmental cognitive neuroscience: language development as a case in point. AB - EEG is a primary method for studying temporally precise neuronal processes across the lifespan. Most of this work focuses on event related potentials (ERPs); however, using time-locked time frequency analysis to decompose the EEG signal can identify and distinguish multiple changes in brain oscillations underlying cognition (Bastiaansen et al., 2010). Further this measure is thought to reflect changes in inter-neuronal communication more directly than ERPs (Nunez and Srinivasan, 2006). Although time frequency has elucidated cognitive processes in adults, applying it to cognitive development is still rare. Here, we review the basics of neuronal oscillations, some of what they reveal about adult cognitive function, and what little is known relating to children. We focus on language because it develops early and engages complex cortical networks. Additionally, because time frequency analysis of the EEG related to adult language comprehension has been incredibly informative, using similar methods with children will shed new light on current theories of language development and increase our understanding of how neural processes change over the lifespan. Our goal is to emphasize the power of this methodology and encourage its use throughout developmental cognitive neuroscience. PMID- 24060671 TI - Quantitative prediction of formulation-specific food effects and their population variability from in vitro data with the physiologically-based ADAM model: a case study using the BCS/BDDCS Class II drug nifedipine. AB - Quantitative prediction of food effects (FE) upon drug pharmacokinetics, including population variability, in advance of human trials may help with trial design by optimising the number of subjects and sampling times when a clinical study is warranted or by negating the need for conduct of clinical studies. Classification and rule-based systems such as the BCS and BDDCS and statistical QSARs are widely used to anticipate the nature of FE in early drug development. However, their qualitative rather than quantitative nature makes them less appropriate for assessing the magnitude of FE. Moreover, these approaches are based upon drug properties alone and are not appropriate for estimating potential formulation-specific FE on modified or controlled release products. In contrast, physiologically-based mechanistic models can consider the scope and interplay of a range of physiological changes after food intake and, in combination with appropriate in vitro drug- and formulation-specific data, can make quantitative predictions of formulation-specific FE including the inter-individual variability of such effects. Herein the Advanced Dissolution, Absorption and Metabolism (ADAM) model is applied to the prediction of formulation-specific FE for BCS/BDDCS Class II drug and CYP3A4 substrate nifedipine using as far as possible only in vitro data. Predicted plasma concentration profiles of all three studied formulations under fasted and fed states are within 2-fold of clinically observed profiles. The % prediction error (%PE) in fed-to-fasted ratio of Cmax and AUC were less than 5% for all formulations except for the Cmax of Nifedicron (%PE= 29.6%). This successful case study should help to improve confidence in the use of mechanistic physiologically-based models coupled with in vitro data for the anticipation of FE in advance of in vivo studies. However, it is acknowledged that further studies with drugs/formulations exhibiting a wide range of properties are required to further validate this methodology. PMID- 24060672 TI - PBPK models for the prediction of in vivo performance of oral dosage forms. AB - Drug absorption from the gastrointestinal (GI) tract is a highly complex process dependent upon numerous factors including the physicochemical properties of the drug, characteristics of the formulation and interplay with the underlying physiological properties of the GI tract. The ability to accurately predict oral drug absorption during drug product development is becoming more relevant given the current challenges facing the pharmaceutical industry. Physiologically-based pharmacokinetic (PBPK) modeling provides an approach that enables the plasma concentration-time profiles to be predicted from preclinical in vitro and in vivo data and can thus provide a valuable resource to support decisions at various stages of the drug development process. Whilst there have been quite a few successes with PBPK models identifying key issues in the development of new drugs in vivo, there are still many aspects that need to be addressed in order to maximize the utility of the PBPK models to predict drug absorption, including improving our understanding of conditions in the lower small intestine and colon, taking the influence of disease on GI physiology into account and further exploring the reasons behind population variability. Importantly, there is also a need to create more appropriate in vitro models for testing dosage form performance and to streamline data input from these into the PBPK models. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the current status of PBPK models available. The current challenges in PBPK set-ups for oral drug absorption including the composition of GI luminal contents, transit and hydrodynamics, permeability and intestinal wall metabolism are discussed in detail. Further, the challenges regarding the appropriate integration of results from in vitro models, such as consideration of appropriate integration/estimation of solubility and the complexity of the in vitro release and precipitation data, are also highlighted as important steps to advancing the application of PBPK models in drug development. It is expected that the "innovative" integration of in vitro data from more appropriate in vitro models and the enhancement of the GI physiology component of PBPK models, arising from the OrBiTo project, will lead to a significant enhancement in the ability of PBPK models to successfully predict oral drug absorption and advance their role in preclinical and clinical development, as well as for regulatory applications. PMID- 24060674 TI - Calcium-activated potassium channel SK1 is widely expressed in the peripheral nervous system and sensory organs of adult zebrafish. AB - Sensory cells contain ion channels involved in the organ-specific transduction mechanisms that convert different types of stimuli into electric energy. Here we focus on small-conductance calcium-activated potassium channel 1 (SK1) which plays an important role in all excitable cells acting as feedback regulators in after-hyperpolarization. This study was undertaken to analyze the pattern of expression of SK1 in the zebrafish peripheral nervous system and sensory organs using RT-PRC, Westernblot and immunohistochemistry. Expression of SK1 mRNA was observed at all developmental stages analyzed (from 10 to 100 days post fertilization, dpf), and the antibody used identified a protein with a molecular weight of 70kDa, at 100dpf (regarded to be adult). Cell expressing SK1 in adult animals were neurons of dorsal root and cranial nerve sensory ganglia, sympathetic neurons, sensory cells in neuromasts of the lateral line system and taste buds, crypt olfactory neurons and photoreceptors. Present results report for the first time the expression and the distribution of SK1 in the peripheral nervous system and sensory organs of adult zebrafish, and may contribute to set zebrafish as an interesting experimental model for calcium-activated potassium channels research. Moreover these findings are of potential interest because the potential role of SK as targets for the treatment of neurological diseases and sensory disorders. PMID- 24060673 TI - The South Asian Heart Lifestyle Intervention (SAHELI) study to improve cardiovascular risk factors in a community setting: design and methods. AB - Disseminating and implementing evidence-based, cardiovascular disease (CVD) prevention lifestyle interventions in community settings and in ethnic minority populations is a challenge. We describe the design and methods for the South Asian Heart Lifestyle Intervention (SAHELI) study, a pilot study designed to determine the feasibility and initial efficacy of a culturally-targeted, community-based lifestyle intervention to improve physical activity and diet behaviors among medically underserved South Asians (SAs). Participants with at least one CVD risk factor will be randomized to either a lifestyle intervention or a control group. Participants in both groups will be screened in a community setting and receive a primary care referral after randomization. Intervention participants will receive 6weeks of group classes, followed by 12weeks of individual telephone support where they will be encouraged to initiate and maintain a healthy lifestyle goal. Control participants will receive their screening results and monthly mailings on CVD prevention. Primary outcomes will be changes in moderate/vigorous physical activity and saturated fat intake between baseline, 3-, and 6-month follow-up. Secondary outcomes will be changes in weight, clinical risk factors, primary care visits, self-efficacy, and social support. This study will be one of the first to pilot-test a lifestyle intervention for SAs, one of the fastest growing racial/ethnic groups in the U.S. and one with disparate CVD risk. Results of this pilot study will provide preliminary data about the efficacy of a lifestyle intervention on CVD risk in SAs and inform community-engaged CVD prevention efforts in an increasingly diverse U.S. population. PMID- 24060675 TI - The early changes in behavior and the myelinated fibers of the white matter in the Tg2576 transgenic mouse model of Alzheimer's disease. AB - Recently, increasing evidences have indicated that abnormal behavior and white matter changes had appeared before senile plaques were formed in Alzheimer's disease (AD). However, the exact nature of these changes in behavior and white matter structure in early AD are unclear. This study used the Morris water maze, an ELISA assay, a transmission electron microscopic technique and new stereological methods to investigate the behavior, Abeta protein expression and white matter structure of Tg2576 transgenic mice at four ages. Only 10 months of age, the time latency in the Morris water maze tasks for Tg2576 transgenic mice were significantly longer than that of wild-type mice. The concentration of Abeta40 protein in the white matter of the Tg2576 transgenic mice was significantly increased in four ages mice, but the Abeta42 protein was significantly increased only in the 6-month-old mice. In 10-month-old mice, the axon volume in the white matter of the Tg2576 transgenic mice was significantly decreased when compared to the wild-type mice. These results suggest that the deposition of Abeta in the white matter of Tg2576 transgenic mice appeared before the spatial memory decline. The early detection of the Abeta content in the white matter of AD might help diagnose suspected AD. In addition, the axon changes in the white matter of AD might be one of the morphological causes of the behavioral deficits observed in 10-month-old transgenic mouse models of AD, and protecting the axons in the white matter might be an important method for delaying the progression of AD. PMID- 24060676 TI - Culture of mouse amniotic fluid-derived cells on irradiated STO feeders results in the generation of primitive endoderm cell lines capable of self-renewal in vitro. AB - The cells present in amniotic fluid (AF) are currently used for prenatal diagnosis of fetal anomalies but are also a potential source of cells for cell therapy. To better characterize putative progenitor cell populations present in AF, we used culture conditions that support self-renewal to determine if these promoted the generation of stable cell lines from AF-derived cells (AFC). Cells isolated from E11.5 mouse were cultured on irradiated STO fibroblast feeder layers in human embryonic germ cell derivation conditions. The cultures grew multicellular epithelial colonies that could be repropagated from single cells. Reverse transcription semiquantitative polymerase chain reaction of established cell lines revealed that they belonged to the extraembryonic endoderm (ExEn) expressing high levels of Gata6, Gata4, Sox17, Foxa2 and Sox7 mRNA. Hierarchical clustering based on the whole transcriptome expression profile of the AFC lines (AFCL) shows significant correlation between transcription profiles of AFCL and blastocyst-derived XEN, an ExEn cell line. In vitro differentiation of AFCL results in the generation of cells expressing albumin and alpha-fetoprotein (AFP), while intramuscular injection of AFCL into immunodeficient mice produced AFP-positive tumors with primitive endodermal appearance. Hence, E11.5 mouse AF contains cells that efficiently produce XEN lines. These AF-derived XEN lines do not spontaneously differentiate into embryonic-type cells but are phenotypically stable and have the capacity for extensive expansion. The lack of requirement for reprogramming factors to turn AF-derived progenitor cells into stable cell lines capable of massive expansion together with the known ability of ExEn to contribute to embryonic tissue suggests that this cell type may be a candidate for banking for cell therapies. PMID- 24060677 TI - Incarceration and unstable housing interact to predict sexual risk behaviours among African American STD clinic patients. AB - Given the dramatic racial disparities in the rates of HIV/sexually transmitted infections (STIs) among African Americans, understanding broader structural factors that increase the risk for HIV/STIs is crucial. This study investigated incarceration history and unstable housing as two structural predictors of HIV risk behaviour among 293 African Americans (159 men/134 women, mean age = 27). Participants were recruited from an urban sexually transmitted disease (STD) clinic in the southeastern U.S. Approximately half the sample had been incarcerated in their lifetime (54%), and 43% had been unstably housed in the past six months. Incarceration was independently associated with the number of sex partners and the frequency of unprotected sex. Unstable housing was independently associated with the frequency of unprotected sex. However, these main effects were qualified by significant interactions: individuals with a history of incarceration and more unstable housing had more sex partners and more unprotected sex in the past three months than individuals without these structural barriers. Implications for structural-level interventions are discussed. PMID- 24060678 TI - High-frequency oscillatory ventilation with low oscillatory frequency in pulmonary interstitial emphysema. AB - BACKGROUND: Pulmonary interstitial emphysema (PIE) is a common respiratory illness in preterm infants associated with significant morbidity and mortality for which the ventilatory management is imperfect. OBJECTIVES: To evaluate the impact of high-frequency oscillatory ventilation (HFOV) with a low oscillatory frequency and thus prolonged expiratory time in preterm infants with severe PIE. METHODS: In a retrospective cohort study, preterm infants <=30 weeks' gestation with radiological findings of severe PIE, and either high FiO2 or persistent respiratory acidosis were studied if managed on HFOV with a low frequency (5-6 Hz, inspiratory time 30%) for >24 h. Trends in physiological and ventilatory parameters were examined over the first 72 h, radiological changes noted, and in hospital outcomes ascertained. RESULTS: 19 cases were identified and analysed in two groups: 14 with bilateral and 5 with predominantly unilateral disease. After transition to low-frequency HFOV, physiological responses were seen in both groups, in particular a rapid and sustained improvement in oxygenation in the bilateral group (mean (SD) alveolar-arterial oxygen difference at baseline: 404 +/- 206 mm Hg; 4 h post-transition: 262 +/- 181 mm Hg; 72 h: 155 +/- 74 mm Hg; p = 0.0003). This occurred following a reduction in mean airway pressure (mean (SD) baseline: 14 +/- 3.9 cm H2O; 72 h: 12 +/- 2.9 cm H2O; p = 0.011). In the unilateral group, radiological resolution of PIE was observed on re-inflation following collapse of the affected lung. Overall, 15 infants survived, including 10 of the bilateral cases (71%), and all of the unilateral cases. CONCLUSION: HFOV with a low oscillatory frequency may afford benefit in preterm babies with severe PIE. PMID- 24060679 TI - Curcumin and resveratrol act by different ways on NADPH oxidase activity and reactive oxygen species produced by equine neutrophils. AB - In neutrophils (PMNs), superoxide anion (O2*-), the first reactive oxygen species (ROS) produced to kill pathogenic agents, is generated by NADPH oxidase, an enzymatic complex formed by the translocation of cytosolic subunits to the membrane flavocytochrome b558. In horses, excessive activation of PMNs is often associated with deadly pathologies and the modulation of their ROS production by acting on NADPH oxidase is a prime target to manage inflammation. We developed a cell-free assay to measure the activity of equine NADPH oxidase assembled in vitro, in order to test the effects of natural or synthetic compounds on the enzyme activity or assembly. The cell-free assay was validated with diphenyleneiodonium chloride and Gp91ds-tat, two inhibitors largely described for human NADPH oxidase. The anti-oxidant effects of curcumin and resveratrol at final concentration ranging from 10(-4) to 10(-6) M were studied on whole cells by chemiluminescence (CL) and by cell-free assay, in which the molecule was added before or after the enzyme assembly. The CL assay demonstrated that curcumin efficiently inhibited the O2(-) production and easily entered into PMNs or interacted with their membrane. Cell-free assay showed that curcumin acted on the reconstitution of NADPH oxidase even at 10(-5)M, while resveratrol appeared to be an O2*- scavenger rather than an inhibitor of NADPH oxidase activity, since it acted from outside the cell in CL and after the complex assembly in cell-free assay. By acting directly on NADPH oxidase, curcumin should be a good candidate for the treatment of acute or inflammatory diseases involving an excessive ROS production. PMID- 24060680 TI - Punarnavine, an alkaloid from Boerhaavia diffusa exhibits anti-angiogenic activity via downregulation of VEGF in vitro and in vivo. AB - Punarnavine, a quinolizidine alkaloid isolated from Boerhaavia diffusa is known to possess analgesic, anti-inflammatory, hepato-protective, immunomodulatory and anti-proliferative properties. However, its roles in tumor angiogenesis and the involved molecular mechanism are still unknown. Therefore, we examined its anti angiogenic effects and mechanisms in vitro and in vivo. We examined the effect of punarnavine on VEGF-A expression by RT-PCR, Western blotting and ELISA. In vivo antiangiogenic activity was determined using sponge implant angiogenesis assay and antitumor activity was evaluated against Ehrlich ascites carcinoma tumor. Punarnavine significantly inhibited endothelial cell migration and invasion and capillary structure formation of HUVECs. Punarnavine significantly at 50 MUM inhibited MMP-2 and MMP-9 expression in HUVECs in vitro. Punarnavine inhibited neovascularization in sponge implant assay. Punarnavine (15 mg/kg bw/d) treatment showed dose-dependent decrease in the ascitic fluid volume by 60.94% and tumor volume by 86.40% in Ehrlich ascites model. Reduction in peritoneal angiogenesis with punarnavine treatment suggests the anti-angiogenic activity of punarnavine. The present study sheds light on the potent anti-angiogenic of the punarnavine and can be extended further to develop therapeutic protocols for treatment of cancer. PMID- 24060681 TI - Activation of P27kip1-cyclin D1/E-CDK2 pathway by polysaccharide from Phellinus linteus leads to S-phase arrest in HT-29 cells. AB - Our previous study showed that polysaccharide (P1) from Phellinus linteus exhibits a significant inhibitive activity on human colorectal carcinoma cells (HT-29). However its novel molecular mechanism remains unknown. To obtain insights into P1's mechanism of action, we examined its effects on cell proliferation in vitro and in vivo, cell cycle distribution, apoptosis, autophagy, and expression of several cell cycle interrelated proteins in HT-29 cells. Interestingly, we found that volume and weight of the solid tumor significantly decreased in P1 (200mg/kg)-treated mice compared with the control. However, slightly increased the body weight of the P1 treated tumor-bearing mice, with no significant increased ALT, AST levels in serum and LPO concentration in liver and kidney indicated that P1 has no toxicity to mammals at a dose of 200mg/kg. Furthermore, P1 caused a significantly dose-dependent increase in the S phase cell cycle, but no apoptosis and autophagy in HT-29 cells. RT-PCR and Western blot results showed significantly down-regulated expressions of cyclin D1, cyclin E, and CDK2, as well as increased expressions of P27kip1 in P1 (100 MUg/mL)-treated HT-29 cells. These results suggested that the activation of P27kip1-cyclin D1/E-CDK2 pathway is involved in P1-induced S-phase cell cycle arrest in HT-29 cells. PMID- 24060682 TI - Differentiation between stoichiometric and anticatalytic antioxidant properties of benzoic acid analogues: a structure/redox potential relationship study. AB - We investigated the antioxidant activities of some phenolic acid derivatives on a cell free system and on cellular and enzymatic models involved in inflammation. The stoichiometric antioxidant activities of phenolic acid derivatives were studied by measuring their capacity to scavenge the radical cation 2,2'-azino bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS(+)) and reactive oxygen species (ROS) produced by stimulated neutrophils. The anticatalytic antioxidant capacity of the molecules was evaluated on the activity of myeloperoxidase (MPO), an oxidant enzyme present in and released by the primary granules of neutrophils. The ROS produced by PMA-stimulated neutrophils were measured by lucigenin enhanced chemiluminescence (CL) and the potential interaction of the molecules with MPO was investigated without interferences due to medium by Specific Immuno Extraction Followed by Enzyme Detection (SIEFED). The antioxidant activities of the phenolic compounds were correlated to their redox potentials measured by differential pulse voltammetry (DPV), and discussed in relation to their molecular structure. The ability of the phenolic molecules to scavenge ABTS radicals and ROS derived from neutrophils was inversely correlated to their increased redox potential. The number of hydroxyl groups (three) and their position (catechol) were essential for their efficacy as stoichiometric antioxidants or scavengers. On MPO activity, the inhibitory capacity of the molecules was not really correlated with their redox potential. Likewise, for the inhibition of MPO activity the number of OH groups and mainly the elongation of the carboxylic group were essential, probably by facilitating the interaction with the active site or the structure of the enzyme. The redox potential measurement, combined with ABTS and CL techniques, seems to be a good technique to select stoichiometric antioxidants but not anticatalytic ones, as seen for MPO, what rather involves a direct interaction with the enzyme. PMID- 24060683 TI - Anticarcinogenic effect of brucine in diethylnitrosamine initiated and phenobarbital-promoted hepatocarcinogenesis in rats. AB - We evaluated the effects of brucine on N-nitrosodiethylamine (DENA)-induced hepatocarcinogenesis in rats. Initiation of hepatocarcinogenesis was done by intraperitoneal injection of diethylnitrosamine (DENA) followed by promotion with phenobarbital. The rats were exposed to dietary brucine for 4 weeks prior to initiation, and the treatment was continued for 22 consecutive weeks. Brucine decreased the incidence, total number, multiplicity, size and volume of preneoplastic hepatic nodules in a dose-dependent manner. Administration of DENA induced hepatocellular carcinoma (HCC), as evidenced by changes in histopathological architecture, increased activity of cytochrome P450, decreased activity of glutathione Stransferase (GST) as well as decreased antioxidant status, enhanced lipid peroxidation, increased liver marker enzymes. Western blot analysis showed decreased expression of cyclin D1 and Bcl-2 with activation of caspase-3 and increased expression of Bax. Immunohistochemical demonstrated the decreased expression of the PCNA and VEGF. These results indicate that brucine prevents lipid peroxidation and hepatic cell damage and also protects the antioxidant system in DENA-induced hepatocarcinogenesis. PMID- 24060684 TI - Paraquat inhibits cell viability via enhanced oxidative stress and apoptosis in human neural progenitor cells. AB - Paraquat (PQ) is one of the most widely used herbicides in the world. Although available evidence indicates that people exposed to PQ have a higher risk of developing Parkinson's disease, adverse effects of PQ on neural progenitor cells have not been investigated yet. In this study, we investigated the in vitro effect of PQ on immortalized human embryonic neural progenitor cells (hNPCs) by treating them with various concentrations of PQ (0, 0.1, 1, 10 and 100 MUM) for 24h. We show that PQ treatment reduces the cell viability and proliferation and induces reactive oxygen species (ROS) production in a dose-dependent manner. In addition, apoptosis induced by PQ was significantly increased at a concentration of as low as 1 MUM. To illustrate the underlying molecular mechanisms, we examined the caspase-3 activity, intracellular calcium level, the NF-kappaB activity, as well as expression of p21, p53 and metallothionein-III mRNA. PQ significantly increased caspase-3 activity at the concentration of 100 MUM. Similarly, PQ triggered intracellular Ca(2+) releases and activation of NF-kappaB was observed after exposure of hNPCs at low concentrations of PQ (1 MUM). Meanwhile, p53 and p21 mRNA transcripts were significantly up-regulated at 10 MUM and 1 MUM of PQ, respectively. MT-III mRNA and protein expression was significantly up-regulated at 1 MUM of PQ and reached peak at 10 MUM. These results suggest that PQ could reduce viability of hNPCs by inducing oxidative stress and apoptosis. PMID- 24060685 TI - Structure and performance of dielectric films based on self-assembled nanocrystals with a high dielectric constant. AB - Self-assembled films built from nanoparticles with a high dielectric constant are attractive as a foundation for new dielectric media with increased efficiency and range of operation, due to the ability to exploit nanofabrication techniques and emergent electrical properties originating from the nanoscale. However, because the building block is a discrete one-dimensional unit, it becomes a challenge to capture potential enhancements in dielectric performance in two or three dimensions, frequently due to surface effects or the presence of discontinuities. This is a recurring theme in nanoparticle film technology when applied to the realm of thin film semiconductor and device electronics. We present the use of chemically synthesized (Ba,Sr)TiO3 nanocrystals, and a novel deposition polymerization technique, as a means to fabricate the dielectric layer. The effective dielectric constant of the film is tunable according to nanoparticle size, and effective film dielectric constants of up to 34 are enabled. Wide area and multilayer dielectrics of up to 8 cm(2) and 190 nF are reported, for which the building block is an 8 nm nanocrystal. We describe models for assessing dielectric performance, and distinct methods for improving the dielectric constant of a nanocrystal thin film. The approach relies on evaporatively driven assembly of perovskite nanocrystals with uniform size distributions in a tunable 7-30 nm size range, coupled with the use of low molecular weight monomer/polymer precursor chemistry that can infiltrate the porous nanocrystal thin film network post assembly. The intercrystal void space (low k dielectric volume fraction) is minimized, while simultaneously promoting intercrystal connectivity and maximizing volume fraction of the high k dielectric component. Furfuryl alcohol, which has good affinity to the surface of (Ba,Sr)TiO3 nanocrystals and miscibility with a range of solvents, is demonstrated to be ideal for the production of nanocomposites. The nanocrystal/furfuryl alcohol dispersions are suitable for the fabrication of thin films by chemical deposition techniques, including spin-coating, printing or a spraying process. To demonstrate the application of this technique to device fabrication, a multilayer capacitor with capacitance of 0.83 nF mm(-2) at 1 MHz is presented. PMID- 24060686 TI - Frequency of radiographic signs of slipped capital femoral epiphysiolysis sequelae in hip arthroplasty candidates for coxarthrosis. AB - INTRODUCTION: The rate of osteoarthritis of the hip secondary to slipped capital femoral epiphysis (SCFE) is a subject of debate, and its frequency is underestimated in particular because of subclinical forms that may not be diagnosed during childhood. HYPOTHESIS: The frequency of radiographic anomalies subsequent to SCFE in adults requiring hip arthroplasty is higher than that reported in recent studies (6% to 15%). MATERIALS AND METHODS: A prospective single-center epidemiological radiography study was performed by one observer. Hip X-rays of patients who were being treated by arthroplasty for advanced hip osteoarthritis between January 2010 and May 2012 were analyzed. The etiology of osteoarthritis was classified in each patient according to the data obtained (primary, SCFE, dysplasia, protrusio acetabuli, other). The lateral view head neck index (LVHNI) was used to quantify posterior translation of the femoral head, and identify SCFE sequelae. RESULTS: One hundred and eighty-six hips were included. Osteoarthritis was considered primary in 51 patients (27.4%), secondary to dysplasia in 42 (22.5%), protrusio acetabuli in 38 (20.5%) or another disease in nine (4.9%) while 46 hips (24.7%) presented a radiographic image suggesting SCFE past history. SCFE type deformities were the primary etiology of osteoarthritis in patients less than 60years old (30/84 or 35.7%). The mean age of patients in the SCFE group was 56.2years old (26-80) compared to 66 (54-91) for the primary osteoarthritis group (P<0.0001). The mean LVHNI was 13% (9-24%) in the SFCE group, the mean body mass index was 27.1kg/m(2) (+/-3.5; 18.2-35.4) in the SFCE group and the male to female ratio was 7.3/1. CONCLUSION: Our study identified a population with a morphological SCFE type anomaly of the coxofemoral joint (LVHNI>9%), which results in the development of earlier osteoarthritis than that found in the rest of the population. SCFE is more common than reported in the literature because it is the first etiology of osteoarthritis of the hip in subjects less than 60years old. LEVEL OF EVIDENCE: Level III. Diagnostic prospective study with a control group. PMID- 24060687 TI - Specificity of miR-378a-5p targeting rodent fibronectin. AB - One criterion for microRNA identification is based on their conservation across species, and prediction of miRNA targets by empirical approaches using computational analysis relies on the presence of conservative mRNA 3'UTR. Because most miRNA target sites identified are highly conserved across different species, it is not clear whether miRNA targeting is species-specific. To predict miRNA targeting, we aligned all available fibronectin 3'UTRs and observed significant conservation of all 20 species. Twelve miRNAs were predicted to target most fibronectin 3'UTRs, but rodent fibronectin showed potential binding sites specific for five different miRNAs. One of them, the miR-378a-5p, contained a complete matching seed-region for all rodent fibronectin, which could not be found in any other species. We designed experiments to test whether the species specific targeting possessed biological function and found that expression of miR 378a-5p decreased cancer cell proliferation, migration, and invasion, resulting in inhibition of tumor growth. Silencing fibronectin expression produced similar effects as miR-378a-5p, while transfection with a construct targeting miR-378-5p produced opposite results. Tumor formation assay showed that enhanced expression of fibronectin in the stromal tissues as a background environment suppressed tumor growth, while increased fibronectin expression inside the tumor cells promoted tumor growth. This was likely due to the different signaling direction, either inside-out or outside-in signal. Our results demonstrated that species specific targeting by miRNA could also exert functional effects. Thus, one layer of regulation has been added to the complex network of miRNA signaling. PMID- 24060688 TI - Role of serum vascular endothelial growth factor D in discrimination of patients with polycystic lung diseases. AB - INTRODUCTION: Polycystic lung diseases (PLDs) include numerous rare diseases including lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), and lymphocytic interstitial pneumonia. In these cases, diagnosis is based on a histological examination of open lung biopsy samples; however, it is not always possible to perform this procedure. Serum markers characteristic for a given entity are still being sought. OBJECTIVES: The aim of the study was to determine the usefulness of assessing serum vascular endothelial growth factor D (VEGF-D) concentration in the differential diagnosis of LAM and other PLDs (OPLDs). PATIENTS AND METHODS: Serum VEGF-D levels were measured by an enzyme linked immunosorbent assay in 75 patients with PLDs including 29 women with LAM and 46 patients with OPLDs (28 women and 18 men). RESULTS: Serum VEGF-D levels were significantly higher in patients with LAM (median, 1557 pg/ml; interquartile range [IQR], 636-2593 pg/ml) than in all patients with OPLDs (median, 292 pg/ml; IQR, 233-405 pg/ml, P <0.0001) or than in women with OPLDs (median, 344 pg/ml; IQR, 243-452 pg/ml, P <0.0001). The serum VEGF-D level exceeding 468 pg/ml identified LAM patients with the specificity of 90% and sensitivity of 87% (area under the curve of 0.908; 95% confidence interval, 0.820-0.996). In none of the patients with OPLDs serum VEGF-D concentrations exceeded 800 pg/ml. CONCLUSIONS: An increased serum VEGF-D level is a highly specific biomarker useful in a differential diagnosis of LAM and OPLDs. PMID- 24060689 TI - Huge pseudoaneurysm after mitral valve replacement. PMID- 24060690 TI - Favourable anatomy after end-to-side repair of interrupted aortic arch. AB - OBJECTIVE: To evaluate cardiovascular outcomes in patients with aortic arch repair and their possible correlation with arch geometry. METHODS: Ten patients who underwent end-to-side repair for aortic arch interruption (IAA), older than 10 years were compared to a cohort of 10 post coarctation (CoA) repair patients matched for age, sex and age at repair. Mean age at operation was 9.7+/-6.5 days. Patients underwent a resting and 24 h blood pressure measurements, exercise study, MRI, transthoracic echocardiography and vascular studies. RESULTS: Seven patients developed hypertension, two from IAA group and five from CoA group. Nine patients (45%) had gothic arch geometry, three from IAA group and six from CoA group. Despite differences in arch geometry, both groups had normal LV mass, LV function and vascular function. CONCLUSION: No differences in functional or morphologic outcomes could be demonstrated between the end-to-side repair of the arch by sternotomy and the conventional coarctation repair by thoracotomy. A favourable arch geometry can be achieved after the end-to-side repair of the aortic arch. In the present study, we could not correlate adverse arch geometry with any adverse cardio-vascular outcomes. After neonatal arch repair, the contributive role of aortic arch geometry to late hypertension remains uncertain. PMID- 24060691 TI - Artificial neural network based characterization of the volume of tissue activated during deep brain stimulation. AB - OBJECTIVE: Clinical deep brain stimulation (DBS) systems can be programmed with thousands of different stimulation parameter combinations (e.g. electrode contact(s), voltage, pulse width, frequency). Our goal was to develop novel computational tools to characterize the effects of stimulation parameter adjustment for DBS. APPROACH: The volume of tissue activated (VTA) represents a metric used to estimate the spatial extent of DBS for a given parameter setting. Traditional methods for calculating the VTA rely on activation function (AF) based approaches and tend to overestimate the neural response when stimulation is applied through multiple electrode contacts. Therefore, we created a new method for VTA calculation that relied on artificial neural networks (ANNs). MAIN RESULTS: The ANN-based predictor provides more accurate descriptions of the spatial spread of activation compared to AF-based approaches for monopolar stimulation. In addition, the ANN was able to accurately estimate the VTA in response to multi-contact electrode configurations. SIGNIFICANCE: The ANN-based approach may represent a useful method for fast computation of the VTA in situations with limited computational resources, such as a clinical DBS programming application on a tablet computer. PMID- 24060692 TI - A quick diagnosis unit as an alternative to conventional hospitalization in a tertiary public hospital: a descriptive study. AB - INTRODUCTION: Reports indicate that a significant number of patients admitted to internal medicine units could be studied on an outpatient basis. OBJECTIVES: This article assesses a quick diagnosis unit (QDU) as an alternative to acute hospitalization for the diagnostic study of patients with potentially serious diseases and suspected malignancy. PATIENTS AND METHODS: Between March 2008 and June 2012, 1226 patients were attended by the QDU. Patients were referred from the emergency department, primary health care centers, and outpatient clinics according to well-defined criteria. Clinical information was prospectively registered in a database. RESULTS: There were 634 men (51.7%), with a mean age of 60.5 +/-17.5 years. The mean time to the first visit was 3.5 +/-5.3 days. Most patients (65.7%) required only 2 visits. The mean interval to diagnosis was 12.2 +/-14.7 days. A total of 324 patients (26.4%) had cancer. The diagnosis was solid tumor in 81.5% of the cases, lymphoma in 19.8%, and various hematologic malignancies in 4.3%. The second most common diagnosis was anemia not associated with cancer (8.6% of the cases). Admission to the QDU allowed to avoid conventional hospitalization for diagnostic studies in 71.5% of the patients, representing a mean freeing-up rate of 7 internal medicine beds per day. In a satisfaction survey, 97% of the patients were completely or very satisfied and 96% preferred the QDU to conventional hospitalization. CONCLUSIONS: A QDU may be a feasible alternative to conventional hospitalization for the diagnosis of otherwise healthy patients with suspected severe disease. Appropriately managed and supported, QDUs can lighten the burden of emergency departments and reduce the need for hospitals beds. PMID- 24060693 TI - PCR detection of cytK gene in Bacillus cereus group strains isolated from food samples. AB - A method for detection of the cytotoxin K cytK structural gene and its active promoter preceded by the PlcR-binding box, controlling the expression level of this enterotoxin, was developed. The method was applied for the purpose of the analysis of 47 bacterial strains belonging to the Bacillus cereus group isolated from different food products. It was found that the majority of the analyzed strains carried the fully functional cytK gene with its PlcR regulated promoter. The cytK gene was not detected in four emetic strains of Bacillus cereus carrying the cesB gene and potentially producing an emetic toxin - cereulide. The cytotoxin K gene was detected in 4 isolates classified as Bacillus mycoides and one reference strain B. mycoides PCM 2024. The promoter region and the N-terminal part of the cytK gene from two strains of B. mycoides (5D and 19E) showed similarities to the corresponding sequences of Bacillus cereus W23 and Bacillus thuringiensis HD-789, respectively. It was shown for the first time that the cytK gene promoter region from strains 5D and 19E of Bacillus mycoides had a similar arrangement to the corresponding sequence of Bacillus cereus ATCC 14579. The presence of the cytK gene in Bacillus mycoides shows that this species, widely recognized as nonpathogenic, may pose potential biohazard to human beings. PMID- 24060694 TI - Evaluation of monoclonal antibody based immunochromatographic strip test for direct detection of Vibrio cholerae O1 contamination in seafood samples. AB - A strip test for the detection of Vibrio cholerae O1 was developed using two monoclonal antibodies (MAbs), VC-223 and VC-1226, specific to the lipopolysaccharides of Vibrio cholerae O1 Inaba and Ogawa serovars. The sensitivity of the test was 5 * 10(5)cfu/mL which was similar to that of dot blot test. The detection limit could be improved to 1cfu/mL of the original bacterial content after pre-incubation of the bacterium in alkaline peptone water (APW) for 12h. Detection of V. cholerae O1 in various fresh seafood samples such as shrimp, blood clam, mussel and oyster could be performed directly with sensitivities ranged from 5 * 10(5) to 10(6)cfu/mL. After pre-enrichment of the shrimp sample in APW, the detection sensitivities increased to 10(2) to 10CFU/mL of the original bacterial content after incubation for 12 and 24h. However, the detection sensitivities were also depending on the content of the other bacteria that might inhibit the growth of V. cholerae during pre-enrichment step. The V. cholerae O1 strip test has advantages in speed, and simplicity in not requiring sophisticated equipment or specialized skills and the sample could be directly examined without requirement for sample processing. PMID- 24060695 TI - In response. PMID- 24060696 TI - Iatrogenic syndesmosis malreduction via clamp and screw placement. PMID- 24060697 TI - In response. PMID- 24060698 TI - One-month subchronic toxicity study of cell-penetrating peptides for insulin nasal delivery in rats. AB - Recently, cell-penetrating peptides (CPPs) based vehicles have been developed for the delivery of different payloads in animals. Our studies have shown that nasal absorption of insulin and other therapeutic peptides and proteins can be improved significantly by co-administration of the CPP penetratin. Successful development of suitable CPP-based delivery systems, however, will depend not only on the efficiency of CPPs to transport therapeutic agents across the biological barriers of the nasal cavity, but also on the risk of adverse effects such as toxicity and undesired immunogenicity, especially in chronic therapy. In this study, we investigated the bioavailability (BA) of insulin and the adverse effects on the nasal mucosa in rats following a long-term dosing regimen of L-penetratin and the novel penetratin analogue "PenetraMax." Following nasal delivery, a significantly higher BA for insulin (almost 100% relative to subcutaneous (s.c.) injections) was observed for PenetraMax in comparison with the parent penetratin peptide after chronic administrations in rats. Importantly, there was negligible biomarker leakage in nasal lavage fluid and the integrity of the nasal epithelium remained unaffected when PenetraMax was used in long-term multiple administrations. In addition, no significant difference in the release of inflammatory and immunogenicity mediators in plasma was observed after nasal administration of PenetraMax with or without insulin solution. In conclusion, PenetraMax, a novel CPP candidate, can open a new avenue in clinical trials for noninvasive nasal insulin delivery. PMID- 24060699 TI - Gut hormones as therapeutic agents in treatment of diabetes and obesity. AB - Obesity and Type 2 Diabetes Mellitus (T2DM) present an ever-increasing threat to global health. Although bariatric surgery is an effective treatment, it cannot be applied to the vast majority of patients. The beneficial effects of bariatric surgery are related to complex alterations in the secretion of gut hormones. By recapitulation of the changes of gut hormone secretion after bariatric surgery, drugs based on gut hormones represent an exciting possibility for the treatment of T2DM and obesity. We review the rapidly emerging role of GLP-1 based treatments as well as the future for new drugs based on other gut hormones such as GIP, ghrelin, oxyntomodulin and peptide YY. PMID- 24060700 TI - OATP transporter-mediated drug absorption and interaction. AB - Although oral administration of drugs is the most favorable route, the precise mechanism of intestinal epithelial permeation is not well understood. Recently, compelling evidence has emerged to show that absorptive transporters such as OATPs contribute to intestinal drug absorption. Since changes in intestinal transporter activity may alter systemic exposure, a thorough understanding of the overall intestinal absorption mechanism is essential to predict possible toxicity and to achieve optimal therapeutic efficacy. The intestinal lumen is exposed continuously to ingested food and beverages, and interaction of their components with drugs during intestinal permeation might also be significant. OATP2B1 is expressed in human intestine and transports various drugs. In this review, we describe the importance of OATP2B1 in drug absorption and the possible influence beverage components have on OATP2B1 function and expression. PMID- 24060702 TI - Gut motility and enteroendocrine secretion. AB - The motility of the gastrointestinal (GI) tract is modulated by complex neural and hormonal networks; the latter include gut peptides released from enteroendocrine cells during both the interdigestive and postprandial periods. Conversely, it is increasingly recognised that GI motility is an important determinant of gut hormone secretion, in that the transit of luminal contents influences the degree of nutrient stimulation of enteroendocrine cells in different gut regions, as well as the overall length of gut exposed to nutrient. Of particular interest is the relationship between gallbladder emptying and enteroendocrine secretion. The inter-relationships between GI motility and enteroendocrine secretion are central to blood glucose homeostasis, where an understanding is fundamental to the development of novel strategies for the management of diabetes mellitus. PMID- 24060703 TI - Chicken or the leg: Sigmoid colon perforation by ingested poultry fibula proximal to an occult malignancy. AB - INTRODUCTION: Colonic perforation by ingested foreign bodies is exceedingly rare, with the diagnosis made more challenging by patients infrequently recalling any inadvertent ingestion and the poor sensitivity of plain radiography. PRESENTATION OF CASE: The presented case demonstrates that bony perforation of the large bowel might occur immediately proximal to an otherwise occult colonic malignancy. DISCUSSION: Ingestion of foreign bodies is common and rarely results in colonic perforation. However, bony ingestion is not usually remembered and can be missed even with cross-sectional imaging. If present, consideration should be given to the presence of an adjacent concealed colon cancer. CONCLUSION: The co-existence of separate pathology should be carefully assessed in these patients, since this has important implications for relevant investigations and appropriate surgical management. PMID- 24060704 TI - Pruritic acquired nevus of Ota. AB - Nevus of Ota is a unilateral, asymptomatic cutaneous and mucosal hyperpigmentation of the face that is congenital or may appear during childhood. We present a case of symptomatic acquired nevus of Ota in an adult, associated with intense pruritus, not described in the literature so far. A 32-year-old woman presented with brownish mottled macules which appeared on her face progressively over 8 days, following the distribution of the first and second divisions of the left trigeminal nerve and partially covering the iris and sclera of the left eye. She reported an intense pruritus in this area. We performed a biopsy on the left forehead, which confirmed the diagnosis of nevus of Ota. Specific stains and immunohistochemistry revealed increased numbers of mast cells. Ophthalmological tests showed acute acquired melanocytosis of the left iris and sclera. The origin of the nevus is still unclear. Several hypotheses suggest a reactivation of melanocytes during their migration from the neural crest. The pruritus reported in our patient may be explained by the increased quantity of mast cells observed in the lesion and/or neuronal stimulation of the ophthalmic and maxillary divisions of the fifth cranial nerve. PMID- 24060705 TI - Weighted relative entropy for phylogenetic tree based on 2-step Markov model. AB - The degree of similarity of DNA sequences can be concluded according to the comparison of DNA sequences, which helps to speculate their relationship in respect of the structure, function and evolution. In this paper, we introduce the fundamental of the weighted relative entropy based on 2-step Markov Model to compare DNA sequences. The DNA sequence, consisted of four characters A, T, C, G, can be considered as a Markov chain. By taking state space I={A, T, C, G} and describe the DNA sequences with 2-step transition probability matrix we can get the eigenvalue of the DNA sequence to define the similarity metric. Therefore, we find a new method to compare the DNA sequences, which is used to classify chromosomes DNA sequences obtained from 30 species. The phylogenetic tree built by the alignment-free method of the distance matrix resulted from the weighted relative entropy has clearer and more accurate division. PMID- 24060706 TI - Cell speed is independent of force in a mathematical model of amoeboidal cell motion with random switching terms. AB - In this paper the motion of a single cell is modeled as a nucleus and multiple integrin based adhesion sites. Numerical simulations and analysis of the model indicate that when the stochastic nature of the adhesion sites is a memoryless and force independent random process, the cell speed is independent of the force these adhesion sites exert on the cell. Furthermore, understanding the dynamics of the attachment and detachment of the adhesion sites is key to predicting cell speed. We introduce a differential equation describing the cell motion and then introduce a conjecture about the expected drift of the cell, the expected average velocity relation conjecture. Using Markov chain theory, we analyze our conjecture in the context of a related (but simpler) model of cell motion, and then numerically compare the results for the simpler model and the full differential equation model. We also heuristically describe the relationship between the simplified and full models as well as provide a discussion of the biological significance of these results. PMID- 24060701 TI - Light based anti-infectives: ultraviolet C irradiation, photodynamic therapy, blue light, and beyond. AB - Owing to the worldwide increase in antibiotic resistance, researchers are investigating alternative anti-infective strategies to which it is supposed microorganisms will be unable to develop resistance. Prominent among these strategies, is a group of approaches which rely on light to deliver the killing blow. As is well known, ultraviolet light, particularly UVC (200-280 nm), is germicidal, but it has not been much developed as an anti-infective approach until recently, when it was realized that the possible adverse effects to host tissue were relatively minor compared to its high activity in killing pathogens. Photodynamic therapy is the combination of non-toxic photosensitizing dyes with harmless visible light that together produce abundant destructive reactive oxygen species (ROS). Certain cationic dyes or photosensitizers have good specificity for binding to microbial cells while sparing host mammalian cells and can be used for treating many localized infections, both superficial and even deep-seated by using fiber optic delivered light. Many microbial cells are highly sensitive to killing by blue light (400-470 nm) due to accumulation of naturally occurring photosensitizers such as porphyrins and flavins. Near infrared light has also been shown to have antimicrobial effects against certain species. Clinical applications of these technologies include skin, dental, wound, stomach, nasal, toenail and other infections which are amenable to effective light delivery. PMID- 24060708 TI - Inpatient-based intensive interdisciplinary pain treatment for highly impaired children with severe chronic pain: randomized controlled trial of efficacy and economic effects. AB - Pediatric chronic pain, which can result in deleterious effects for the child, bears the risk of aggravation into adulthood. Intensive interdisciplinary pain treatment (IIPT) might be an effective treatment, given the advantage of consulting with multiple professionals on a daily basis. Evidence for the effectiveness of IIPT is scarce. We investigated the efficacy of an IIPT within a randomized controlled trial by comparing an intervention group (IG) (n=52) to a waiting-list control group (WCG) (n=52). We made assessments before treatment (PRE), immediately after treatment (POST), as well as at short-term (POST6MONTHS) and long-term (POST12MONTHS) follow-up. We determined a combined endpoint, improvement (pain intensity, disability, school absence), and investigated 3 additional outcome domains (anxiety, depression, catastrophizing). We also investigated changes in economic parameters (health care use, parental work absenteeism, subjective financial burden) and their relationship to the child's improvement. Results at POST showed that significantly more children in the IG than in the WCG were assigned to improvement (55% compared to 14%; Fisher P<.001; 95% confidence interval for incidence difference: 0.21% to 0.60%). Although immediate effects were achieved for disability, school absence, depression, and catastrophizing, pain intensity and anxiety did not change until short-term follow-up. More than 60% of the children in both groups were improved long-term. The parents reported significant reductions in all economic parameters. The results from the present study support the efficacy of the IIPT. Future research is warranted to investigate differences in treatment response and to understand the changes in economic parameters in nonimproved children. PMID- 24060707 TI - A pilot trial of intravenous pamidronate for chronic low back pain. AB - Intravenous (i.v.) bisphosphonates relieve pain in conditions such as Paget's disease of bone, metastatic bone disease, and multiple myeloma. Based on positive findings from a prior case series, we conducted a randomized placebo-controlled study to assess the analgesic effect of i.v. pamidronate in subjects with chronic low back pain (CLBP) and evidence of degenerative disease of the spine. Four groups of 11 subjects (7 active, 4 placebo) were enrolled at escalating dose levels of 30, 60, 90, and 180 mg pamidronate (the latter administered as two 90 mg infusions). Primary outcomes were safety and change from baseline in average daily pain scores, recorded at 1, 2, 3, and 6 months postinfusion using electronic diaries. Secondary outcomes included responder rate, daily worst pain, and pain-related interference with daily function. There were no pamidronate related serious adverse events or other significant safety findings. A statistically significant overall treatment difference in pain scores was observed, with clinically meaningful effects persisting for 6 months in the 180 mg pamidronate group. Least squares mean changes in daily average pain score were -1.39 (SE=0.43) for placebo, and -1.53 (0.71), -1.26 (0.81), -1.42 (0.65), and 4.13 (0.65) for pamidronate 30, 60, 90, and 180 mg, respectively (P=0.012 for pamidronate 180 mg vs placebo). The proportion of responders, changes in worst pain, and pain interference with daily function were also significantly improved for pamidronate 180 mg compared with placebo. In conclusion, i.v. pamidronate, administered as two 90 mg infusions, decreased pain intensity for 6 months in subjects with CLBP. PMID- 24060709 TI - Five-year outcome of concurrent radiotherapy and chemotherapy in Saudi women with locally advanced cervical cancer: single-institution experience. AB - BACKGROUND AND OBJECTIVES: We aimed to evaluate long-term treatment outcomes and toxicity profile of combined radiotherapy and chemotherapy in Saudi women with locally advanced cervical cancer. DESIGN AND SETTINGS: Retrospective study in a tertiary care cancer center in Riyadh, Saudi Arabia. METHODS AND MATERIALS: The medical records of patients with histopathologically proven, locally advanced cervical cancer were analyzed. These patients received three-dimensional conformal radiotherapy with concurrent chemotherapy followed by high dose rate brachytherapy in our center between July 2007 and April 2012. The data regarding the safety profile, response rates, occurrence of locoregional or distant failure, disease-free survival, and overall survival rates were recorded. RESULTS: The median follow-up period was 60 months (range, 8-66) for 74 patients. The median age of study population was 52.3 years (32-78), and the stage IIB was the predominant stage (49 patients [66.2%]). A total of 45 patients (60.9%) had radiologic-positive pelvic +/- para-aortic lymphadenopathy. The 5-year locoregional and distant control rates were 84.3% and 78.5%, respectively. The 5 year disease-free and overall survival rates were 75.7% and 64.5%, respectively. Stage, nodal status, and hemoglobin levels were found to be important prognostic factors for locoregional and distant control. Acute grade 3 hematological and nonhematological toxicities were seen in 4 (5.4%) and 4 (5.4%) patients. Late toxicities were mild, and only 1 (1.4%) patient presented with subacute intestinal obstruction. CONCLUSION: Concurrent chemoradiation in Saudi women with locally advanced cervical cancer showed better locoregional and distant control and survival rates with minimal toxicity. PMID- 24060710 TI - Clinical and radiological characteristics of Chinese patients with hepatic epithelioid hemangioendothelioma. AB - BACKGROUND AND OBJECTIVES: To study clinical features, imaging findings, and prognosis of hepatic epithelioid hemangioendothelioma (HEHE) in Eastern Hepatobiliary Surgical Hospital and to improve the level of recognition and preoperative diagnosis of HEHE. DESIGN AND SETTINGS: This is a retrospective study. The study was conducted at Eastern Hepatobiliary Surgical Hospital in Shanghai, China from 1999 to 2012. METHODS: Clinical data of 15 pathology confirmed HEHE patients admitted in our hospital from 1999-2010 were collected and analyzed retrospectively. RESULTS: Besides 7 cases of abdominal discomfort, this cohort of HEHE patients does not show common typical manifestations. Laboratory examinations found 8 low ALB/GLB cases, 3 mild anemia cases, and 1 high alanine aminotransferase case, but no abnormal a-fetoprotein, carcinoembryonic antigen, or CA19-9 cases. Plain computed tomography (CT) scanning found uneven multiple low-density lesions in most cases, dynamic enhanced CT scanning demonstrated peripheral enhancement in the hepatic arterial HA phase and more peripheral enhancement in the portal vein PV phase, and ring enhancement were detected in the delayed phase. Magnetic resonance imaging (MRI) demonstrated low signal intensity and even lower lesion centers in T1-weighted im.ages, but slightly high signal intensity lesions and higher lesion centers in T2-weighted images. Enhanced MRI scanning showed ring enhancements but no obvious enhanced centers. Lesions were further enhanced in delayed MRI scanning. Prognosis of this cohort: 10 of these 15 patients were alive, including 4 cases with a tumor. CONCLUSION: Comprehending the clinical and radiological characteristics of HEHE facilitates the level of recognition and preoperative diagnosis of this disease, and promotes surgeons to take active and appropriate surgeries. PMID- 24060711 TI - Gender inequality in the clinical outcomes of equally treated acute coronary syndrome patients in Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Gender associations with acute coronary syndrome (ACS), remain inconsistent. Gender-specific data in the Saudi Project for Assessment of Coronary Events registry, launched in December 2005 and currently with 17 participating hospitals, were explored. DESIGN AND SETTINGS: A prospective multicenter study of patient with ACS in secondary and tertiary care centers in Saudi Arabia were included in this analysis. PATIENTS AND METHODS: Patients enrolled from December 2005 until December 2007 included those presented to participating hospitals or transferred from non-registry hospitals. Summarized data were analyzed. RESULTS: Of 5061 patients, 1142 (23%) were women. Women were more frequently diagnosed with non ST-segment elevation myocardial infarction (NSTEMI [43%]) than unstable angina (UA [29%]) or ST-segment elevation myocardial infarction (STEMI [29%]). More men had STEMI (42%) than NSTEMI (37%) or UA (22%). Men were younger than women (57 vs 63 years) who had more diabetes, hypertension, and hyperlipidemia. More men had a history of coronary artery disease. More women received angiotensin receptor blockers (ARB) and fewer had percutaneous coronary intervention (PCI). Gender differences in the subset of STEMI patients were similar to those in the entire cohort. However, gender differences in the subset of STEMI showed fewer women given b-blockers, and an insignificant PCI difference between genders. Thrombolysis rates between genders were similar. Overall, in hospital mortality was significantly worse for women and, by ACS type, was significantly greater in women for STEMI and NSTEMI. However, after age adjustment there was no difference in mortality between men and women in patients with NSTEMI. The multivariate-adjusted (age, risk factors, treatments, door-to needle time) STEMI gender mortality difference was not significant (OR=2.0, CI: 0.7-5.5; P=.14). CONCLUSION: These data are similar to other reported data. However, differences exist, and their explanation should be pursued to provide a valuable insight into understanding ACS and improving its management. PMID- 24060712 TI - HIV-associated nephropathy in Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Human immunodeficiency virus-associated nephropathy (HIVAN) is the most common cause of chronic renal failure in HIV patients with African descent. It usually presents with proteinuria, enlarged kidneys, and rapidly progressive renal failure, often over several weeks to months. We conducted this study to determine the prevalence of HIVAN in our HIV population. DESIGN AND SETTINGS: Cross-sectional observational study in a referral center covering the period of 1990- 2010. METHODS: Proteinuria and estimated glomerular filtration rate (e-GFR) were used to identify renal disease and suspicious cases of HIVAN with abnormal proteinuria and e-GFR of < 60 mL/min/1.73 m2. RESULTS: Of 585 HIV-positive patients, 248 were eligible to inclusion criteria. Most of the patients were male, that is, 165 (67%) were male compared to 83 (33%) female with the mean age 39 years; 240 (96.7%) were on antiretroviral therapy. Thirty (12%) patients had abnormal proteinuria and 218 (88%) had normal urinary protein and e GFR. No significant differences were observed in demographic data, CD4+ T lymphocyte count, viral load, creatinine level, and e-GFR among both groups. Significant differences were observed in the prevalence of diabetes mellitus in the abnormal proteinuria group (10 patients [33.3%] compared to 30 patients [13.8%] in the normal group (P=.0139) and the prevalence of hypertension in the abnormal proteinuria group (11 patients [36.7%] compared to 22 patients [10%] in the normal group (P=.002). Sixteen patients (6.6% of the cohort) met the study definition of HIVAN. CONCLUSION: The prevalence of abnormal proteinuria and HIVAN among HIV-infected patients in Saudi Arabia is higher than that of non-African patients in developed countries. PMID- 24060713 TI - Causes and patterns of adult traumatic head injuries in Saudi Arabia: implications for injury prevention. AB - BACKGROUND AND OBJECTIVES: Data on the epidemiology of traumatic head injuries (THI) is essential for any organized prevention program. Such data are few in the developing world. Our primary goal was to study the causes, descriptive features, and outcomes of THI in adults in Saudi Arabia. DESIGN AND SETTINGS: The present study is a retrospective review. METHODS: This retrospective review included all consecutive cases of adults with THI ( > 18 years) who were admitted to a major trauma centre in Riyadh, Saudi Arabia, from May 2001 to July 2010. Patients were identified through a trauma database, which includes cases that required hospital admission or died in the emergency department. RESULTS: A total of 1870 patients met the inclusion criteria with a mean age of 32.6 years and a male predominance (91.2%). Most injuries were secondary to motor vehicle collisions (MVC; 69.4%). Pedestrian injuries were second (16.8%) and had 40% risk of mortality (odds ratio 0.62, 95% CI 0.48-0.8). Most patients (56.7%) had a severe THI (Glasgow coma score, GCS < 8). The overall mortality rate was 30%. Mortality was significantly associated with older age (P=.0001), lower GCS (P=.0001), and a higher injury severity score (ISS; P=.0001). CONCLUSION: The most common causes of hospital admission following injury were MVC and pedestrian injuries. Both were also the most common causes for injury-related deaths. Safety on the roads should be the primary target for any organized injury prevention programs to be successful. PMID- 24060714 TI - Obstetric factors for unsuccessful trial of labor in second-order birth following previous cesarean. AB - BACKGROUND AND OBJECTIVES: The trial of labor after previous cesarean (TOLAC) is an important strategy to limit repeat cesarean sections and their complications. An unsuccessful TOLAC leads to maternal and neonatal morbidities. The success or failure of TOLAC after the first cesarean is determinant for the subsequent vaginal birth. Limited studies are available from low-income countries, exclusively conducted in women in their sec.ond-order birth following the first cesarean section. This study aims at determining the frequency of unsuccessful attempts at vaginal delivery in the second-order term (37-41+6/7 weeks) birth among women with previous cesarean sections and to describe maternal and obstetric factors for unsuccessful laborTOLACs in the same group. DESIGN AND SETTINGS: A cross-sectional study conducted from April to December 2010 at Obstetrics & Gynaecology Unit II, Civil Hospital Karachi. PATIENTS AND METHODS: All eligible patients at term pregnancy in their second-order birth were included. The frequency of unsuccessful attempts at vaginal birth was determined, followed by secondary analysis by calculating odds ratio for maternal and obstetric factors, that is, body mass index (BMI), hight, gestation >=40 weeks, interdelivery interval, engagement of head in 5th, estimated fetal weight, ruptured membranes, duration of labor >=7 hours, augmentation of labor, cervical dilatation < 4 cm, and vertex station -2 or higher on admission. RESULTS: Out of 122 study subjects, the proportion of unsuccessful vaginal birth after cesarean (VBAC) was 27.9% (n=34). Among maternal and obstetric factors, BMI > 25 (AOR, 5.00), gestation >=40 weeks (AOR, 5.45), cervical dilatation < 4 cm (AOR, 5.90), and station of vertex -2 or higher (AOR, 3.83) had highly significant adjusted odds for failed TOLAC. CONCLUSION: With a well-defined protocol, the rates of unsuccessful attempts at VBAC are not high for the second-order birth. The risk of failure can be anticipated by factors such as BMI > 25, pregnancy duration >=40 weeks, cervical dilatation < 4 cm, and vertex station -2 or higher on admission. PMID- 24060715 TI - Imaging of disorder of sex development. AB - BACKGROUND AND OBJECTIVES: Disorders of sex development (DSDs), formerly termed ambiguous genitalia, are a group of conditions where the external genitalia appear abnormal. It represents a true medical and social emergency that needs a multidisciplinary team approach for elucidation. The pediatric radiologist plays an important role in defining the genital anatomy that remains one of the most important factors in sex determination, in addition to chromosomal analysis. DESIGN AND SETTINGS: A retrospective study, conducted between January 1995 and December 2010. MATERIALS AND METHODS: Imaging studies (ultrasound, genitogram, and/or magnetic resonance imaging) were performed in patients with ambiguous genitalia, confirmed by chromosomal analysis and appropriate hormonal investigations. RESULTS: The sensitivity of ultrasound is 89.5%, while its specificity reaches 100%. Retrograde genitogram is more invasive and less sensitive, as the yield of determining the presence of a uterus +/- vagina is 84.2%. However, magnetic resonance imaging (MRI) is more sensitive for gonadal tissue identification. Its specificity reaches up to 100% and can provide detailed internal structures (uterus, fallopian tubes, and gonads). CONCLUSION: Ultrasound examination is still the main modality of choice for screening patients with ambiguous genitalia. It is cheap and readily available everywhere. In addition to elucidating the uterus in 89.5%, it can also give more information on the adrenal glands. However, genitography is good--84.2% in elucidating genital anatomy--but it gives no information of the gonads and it is time consuming and invasive. MRI is helpful in cases with equivocal ultrasound, reaches 100% in elucidating internal extractor, and therefore could be reserved for that. PMID- 24060716 TI - Black hip: a rare case treated by total hip replacement. AB - BACKGROUND AND OBJECTIVE: Ochronic arthropathy of hip (Black Hip) is a rare clinical manifestation of congenital disorder of amino acid metabolism characterized by a classic triad: (1) degenerative arthritis, (2) ochronotic pigmentation, and (3) urine that turns black on long standing or alkalinization. We report a case of ochronic arthropathy of the left hip joint that was successfully treated by total hip arthroplasty. DESIGN AND SETTINGS: This is a case study conducted at PES Medical College, Andhra Pradesh, India. PATIENTS AND METHODS: A 60-year-old female patient came with a history of progressive pain in her left hip joint for the last 8 months. She was diagnosed to be suffering from ochronic arthritis of left hip. RESULTS: After tissue confirmation she was operated with total hip replacement. At the end of 2 years, the patient was symptom free without any implant loosening. CONCLUSION: Ochronotic arthropathy is a rare metabolic disorder that can be underdiagnosed many a times. Early management is only symptomatic, and advanced cases need surgical intervention. Vitamin preparations are given because of the influence of vitamin C on tyrosine and phenylalanine metabolism. In the cases of severe degenerative arthritis of hip, total hip replacement may be considered as a surgical option. PMID- 24060717 TI - UGT1A1 promoter polymorphism associated with serum bilirubin level in Saudi patients with sickle cell disease. AB - BACKGROUND AND OBJECTIVES: Polymorphism in (TA)n of the UGT1A1 promoter influences bilirubin level and risk of gallstones in patients with sickle cell disease (SCD) of African descent. Modifiers of bilirubin level and gallstones in Saudi patients with SCD are not known. DESIGN AND SETTINGS: Patients with SCD presenting to participating institutions between July 2009 and July 2012 were enrolled in our study. METHODS: A total of 223 SCD patients were enrolled. Laboratory workup at steady state included complete blood count, reticulocytes, serum bilirubin, lactate dehydrogenase (LDH), G6PD level, and hemoglobin (Hb) electrophoresis. The (TA)n UGT1A1 promoter polymorphism and presence of a thalassemia were also deter.mined. RESULTS: TA6/6 in the UGT1A1 promoter was identified in 189 patients (84.7%), TA7/7 in 26 (11.7%), TA5/5 in 6 (2.7%), and TA5/6 in 2 (0.9%). Increased (TA)n of the UGT1A1 promoter (P < .0001), male gender (P=.02), higher LDH (P=.001), and lower Hb level (P=.009) were associated with higher bilirubin level, while the co-inheritance of a-thalassemia (P=.003) was linked with lower bilirubin level. UGT1A1 (TA)n (P < .0001) and Hb level (P=.005) remained significant on multivariate analysis. Gallstones were more frequent in patients with TA7/7 (72%) compared to patients with TA6/6 (57%) and TA5/5 or 5/6 (37%); however, this difference was not statistically significance (P=.18). Older age (P=.0001) and absence of a-thalassemia (P=.03) were associated with higher risk of gallstones. CONCLUSION: (TA)n in the UGT1A1 promoter and intensity of hemolysis modify steady-state serum bilirubin level in SCD. Co inheritance of a-thalassemia reduces the risk of gallstones in Saudi patients with SCD. PMID- 24060719 TI - Mucolipidosis II: first report from Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Mucolipidosis II (MLII) is characterized by severe global developmental delay, coarse facial features, skeletal deformities, and other systemic involvement. It is caused by a deficiency in N-acetylglucosamine-1 phosphotransferase. DESIGN AND SETTINGS: This is a case series study conducted at King Abdulaziz Medical City in Riyadh, Saudi Arabia, between 2008-2012. PATIENTS AND METHODS: We described three unrelated Saudi children who presented with neonatal hyperparathyroidism, microcephaly, craniosynostosis, coarse facial features, cardiac involvement, and skeletal deformities. RESULTS: The MLII diagnosis was confirmed by assaying enzyme activities in fibroblasts, which showed a severe reduction in hydrolyzed substrates compared to controls, and by identifying a pathogenic homozygous GNPTAB gene mutation. One of the children died at 2 months of age due to severe pulmonary hypertension, and the other two children were still alive at 12 months and 18 months of age, respectively. Both surviving children had severe global developmental delay at 2 months of age. CONCLUSION: Clinicians should investigate any child presenting with neonatal hyperparathyroidism, craniosynostosis, skeletal deformities, and coarse facial features for MLII. PMID- 24060718 TI - Analysis of suicide deaths in a 15-year period in Eskisehir, western Anatolia, Turkey and the determination of risk factors. AB - BACKGROUND AND OBJECTIVES: It is estimated that every year 1 million people die all around the world due to suicide. The average rate of suicide in the world is reported as 16/100,000. In this study, we aimed to evaluate and discuss the suicide cases in our city Eskisehir that is located in western Anatolia. DESIGN AND SETTINGS: This is a retrospective study covering the period 1997-2011. METHODS: All deaths in Eskisehir caused due to the consumption of forensic medicines in a 15-year period between 1997 and 2011 were evaluated retrospectively. A total of 553 cases were determined to be suicidal following both forensic and criminal investigations, and were included in the study. Furthermore, death examination and autopsy reports were investigated, and judicial investigation records were also taken into account. RESULTS: In this period, the average rate of suicide in our city was determined as 5.1/100,000 of which 71.4% of the cases were male. It was determined that the suicides most commonly occurred between the ages of 19 and 29 (32.4%, n=179). The most commonly encountered suicide method was hanging (60.9%, n=337). CONCLUSION: It was ascertained that the suicide rate in our city was lower than the average rate in the world, but it was higher than the average rate in Turkey. Unemployment was determined as the most common risk factor in our study. A follow-up should be provided for people with a history of attempting to commit suicide or with a tendency to committing suicide due to a psychological disorder. PMID- 24060720 TI - Gender differences in the clinical characteristics of Saudi heart failure patients with subsequent stroke. AB - BACKGROUND AND OBJECTIVES: Studies about stroke in Saudi Arabia are limited. This retrospective study aims to determine the clinical characteristics of Saudi patients with heart failure (HF) with and without subsequent stroke, and also to find out whether gender differences exist in the presentation of HF patients who had stroke. DESIGN AND SETTINGS: Retrospective study done at King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia, from 2002-2008. PATIENTS AND METHODS: A total of 293 patient (151 males, 142 females) charts from 2002-2008 were re.viewed at KAMC. These charts were from Saudi patients who were diagnosed with HF, with and without subsequent stroke. Demographics, HF characteristics, stroke risk factors, and metabolic characteristics were noted and analyzed. RESULTS: No difference was observed in HF characteristics and stroke risk factors among HF patients with and without subsequent stroke. In terms of metabolic profile, those who had stroke had significantly higher low-density lipoprotein (LDL)- cholesterol levels as compared to those without (P=.03). Stratification to gender and adjusting for age and risk factors revealed that significantly higher LDL cholesterol and total cholesterol levels were observed in female stroke patients (P values .02, .028, respectively) and significantly higher blood urea nitrogen levels were observed in male stroke patients (P=.04) as compared to their counterparts who never had a stroke. CONCLUSION: The gender differences in the metabolic presentation of Saudi HF patients with stroke warrant further clinical investigation. Atherogenic dyslipidemia and renal insufficiency are suggested to be early predic.tors for stroke and should be closely monitored in Saudi HF patients. PMID- 24060721 TI - Brucella spp isolated from respiratory sample and grown in Mycobacterium growth indicator tube (MGIT). AB - Brucellosis remains endemic in many countries including Saudi Arabia. The disinfection of objects and surfaces contaminated with Brucella spp is not difficult, but we encountered a situation in which the organism survived the decontamination and liquefaction procedure adopted for AFB culture. A sputum specimen from a patient was sent for TB culture and the BACTEC MGIT 960 system isolated an organism identified as Brucella spp. The blood cultures and the serological testing had confirmed this case to be brucellosis. Isolation of Brucella spp from sputum samples is rare; this case appears to be the first of its kind. As the clinical presentation of TB may mimic brucellosis and vice versa, we recommend that handling specimens from all cases of undiagnosed PUO should be done with care because of the possibility that it may contain either of these organisms. PMID- 24060722 TI - Mimicry of sugar tumor and minute pulmonary meningothelial-like nodule to metastatic lung deposits in a patient with rectal adenocarcinoma. AB - Several reports have described different lung lesions mimicking primary or metastatic neoplasms. In this paper, we describe the different features of two uncommon and benign lung lesions mimicking metastasis from a primary large bowel adenocarcinoma. Our patient is a 75-year old female with a history of invasive rectal adenocarcinoma. One month after her surgery, she started complaining of coughing and shortness of breath. Clear cell sugar tumor and minute meningothelial-like nodules had been found incidentally and simultaneously during her chest x-ray. The diagnosis had been made based on morphology and was supported by a positive staining to a panel of immunohistochemical stains including CD34, vimentin, HMB45, melan A and S100. An ultra-structural examination was also performed and confirmed the presence of melanosomes in sugar tumor. The coexistence of lung sugar tumor and minute pulmonary meningothelial like nodules has never been reported in the literature and an awareness of these lesions is essential to correctly diagnose and stage patients. PMID- 24060723 TI - Lupus vulgaris in a young girl. AB - With the estimated global burden of TB being 8.8 million incident cases and 1.1 million deaths from TB in HIV-negative cases and additional 0.35 million deaths in HIV-associated cases,1 the total number of cutaneous TB cases ( < 1-2 % of total cases) becomes significant. With the WHO setting up public-private mix partnerships and a millenium development goal of a 50% reduction in the total number of incident cases, the case detection and reporting of unusual cutaneous TB cases becomes very important. We present a case of lupus vulgaris in a young girl with rapid progression of a large plaque with hypertrophic features in the periphery. The case is unusual due to its rapid progression, unusual site and extensive giant form which have never been reported previously. PMID- 24060724 TI - Collet-Sicard syndrome secondary to a large glomus jugulotympanicum. AB - Collet-Sicard syndrome is caused by various neoplastic and non-neoplastic lesions affecting the base of the skull with involvement of IX, X, XI and XII cranial nerves. Paraganglioma accounts for < 1% of all the neoplasms in the head and neck region. They are traditionally considered as benign, slow growing, locally invasive, encapsulated and highly vascular tumors. We report a case of Collet Sicard syndrome secondary to a large glomus jugulotympanicum in a 45-year-old woman who presented to the emergency department with complaints of recurrent episodes of a fresh bleeding from the left ear for the previous 5 days. She had pain and decreased hearing for the last 3 years and features of multiple cranial nerve palsies. A radiological diagnosis of glomus jugulotympanicum (paraganglioma) was made, which was confirmed by the biopsy tissue. At 6-month follow up, episodes of recurrent bleeding had stopped, but cranial nerve palsies persisted. PMID- 24060725 TI - Dental findings in the diagnosis of idiopathic hypoparathyroidism. AB - Idiopathic hypoparathyroidism (IHP) is a rare endocrinopathy, characterized by the disturbances in calcium and phosphorous metabolism, owing to deficiency in parathyroid hormone, which leads to tetanic manifestations. Onset of the clinical features occurs early in life, and the severity depends on the extent of chemical imbalance. This article describes a case of 22-year-old patient undiagnosed for 12 years with this endocrinopathy (IHP). Over retained deciduous teeth, delayed eruption, impacted tooth and short roots probably resulting from untreated hypocalcemia during the developmental phase of dentition enabled us to unearth this endocrinopathy through a series of investigations. Thus the article emphasizes the importance of dental findings of this endocrinopathy. PMID- 24060726 TI - Can arousing feedback rectify lapses in driving? Prediction from EEG power spectra. AB - OBJECTIVE: This study explores the neurophysiological changes, measured using an electroencephalogram (EEG), in response to an arousing warning signal delivered to drowsy drivers, and predicts the efficacy of the feedback based on changes in the EEG. APPROACH: Eleven healthy subjects participated in sustained-attention driving experiments. The driving task required participants to maintain their cruising position and compensate for randomly induced lane deviations using the steering wheel, while their EEG and driving performance were continuously monitored. The arousing warning signal was delivered to participants who experienced momentary behavioral lapses, failing to respond rapidly to lane departure events (specifically the reaction time exceeded three times the alert reaction time). MAIN RESULTS: The results of our previous studies revealed that arousing feedback immediately reversed deteriorating driving performance, which was accompanied by concurrent EEG theta- and alpha-power suppression in the bilateral occipital areas. This study further proposes a feedback efficacy assessment system to accurately estimate the efficacy of arousing warning signals delivered to drowsy participants by monitoring the changes in their EEG power spectra immediately thereafter. The classification accuracy was up 77.8% for determining the need for triggering additional warning signals. SIGNIFICANCE: The findings of this study, in conjunction with previous studies on EEG correlates of behavioral lapses, might lead to a practical closed-loop system to predict, monitor and rectify behavioral lapses of human operators in attention-critical settings. PMID- 24060727 TI - Perceived social support in adolescents with and without visual impairment. AB - The study assessed perceived availability of support from parents, peers, and teachers in adolescents with and without visual impairment. Adolescents with visual impairment perceived lower levels of parental support but higher levels of support from teachers than sighted adolescents, and these differences remained stable across a 2-year interval. There was considerable heterogeneity within the groups as adolescents with visual impairment were most often found in clusters with high levels as well as low levels of all assessed sources of support. High perceived support from all sources showed positive associations with life satisfaction of adolescents with and without visual impairment. As lower levels of perceived parental support of students with visual impairment were based on students from residential schools, we conclude that measures would be welcomed for improvement of parent-child contacts during the school days. PMID- 24060728 TI - Motor skills in Czech children with attention-deficit/hyperactivity disorder and their neurotypical counterparts. AB - Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioural disorder. Characterized by recurring problems with impulsiveness and inattention in combination with hyperactivity, motor impairments have also been well documented in the literature. The aim of this study was to compare the fine and gross motor skills of male and female children with ADHD and their neurotypical counterparts within seven skill assessments. This included three fine motor tasks: (1) spiral tracing, (2) dot filling, (3) tweezers and beads; and four gross motor tasks: (1) twistbox, (2) foot tapping, (3) small plate finger tapping, and (4) large plate finger tapping. It was hypothesized that children with ADHD would display poorer motor skills in comparison to neurotypical controls in both fine and gross motor assessments. However, statistically significant differences between the groups only emerged in four of the seven tasks (spiral tracing, dot filling, tweezers and beads and foot tapping). In line with previous findings, the complexity underlying upper limb tasks solidified the divide in performance between children with ADHD and their neurotypical counterparts. In light of similar research, impairments in lower limb motor skill were also observed. Future research is required to further delineate trends in motor difficulties in ADHD, while further investigating the underlying mechanisms of impairment. PMID- 24060729 TI - Altered red cell and platelet adhesion in hemolytic diseases: Hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria and sickle cell disease. AB - OBJECTIVES: Intravascular hemolysis may have important pathophysiological consequences, such as the induction of cellular adhesion and vasculopathy. We compared the adhesive properties of red cells (RBC) and platelets in hereditary spherocytosis (HS), paroxysmal nocturnal hemoglobinuria (PNH) and sickle cell disease (SCD) patients. DESIGN AND METHODS: The adhesion of RBC and platelets, from patients and healthy subjects, was determined using static adhesion assays. RBC surface markers were characterized by flow cytometry and lactate dehydrogenase (LDH), plasma hemoglobin (pHb) and TNF-alpha were assayed in serum/plasma samples. RESULTS: pHb levels were elevated in all three hemolytic diseases, indicating the incidence of intravascular hemolysis. RBC adhesion and TNF-alpha were augmented in HS and SCD, but not in PNH. Reticulocyte counts were raised in the three diseases, but were higher in HS and SCD than in PNH; high expressions of CD71, CD36 and CD49d were observed on SCD RBC, while CD71 alone was increased on HS and PNH RBC. Splenectomy was associated with reversals of increased pHb, RBC adhesion, reticulocytes, RBC marker expression and inflammation in HS. In contrast, platelet adhesion was elevated in SCD and PNH, but not HS. Platelet adhesion correlated significantly with serum LDH, but not pHb, in the hemolytic disease cohort; interestingly, LDH did not correlate with reticulocytes or pHb levels. CONCLUSIONS: Results indicate that extravascular, rather than intravascular, hemolysis (and ensuing RBC production) may contribute to elevations in RBC adhesive properties in HS and SCD, while mechanisms peculiar to each disease may augment platelet adhesion in SCD and PNH. PMID- 24060730 TI - Elevation of carbohydrate antigen 125 in chronic heart failure may be caused by mechanical extension of mesothelial cells from serous cavity effusion. AB - OBJECTIVES: The practical application of elevated carbohydrate antigen 125 (CA125) to predict clinical outcome in chronic heart failure (CHF) is under debate. The mechanism for this CA125 elevation remains unknown. We hypothesize that mechanical stress on mesothelial cells initiates CA125 synthesis. DESIGN AND METHODS: A total of 191 patients suffering from edema and/or dyspnea were enrolled. 109 patients were diagnosed as CHF, and 82 patients without CHF were assigned as control group. Echocardiography, CA125, N-terminal pro-brain natriuretic peptide (NT-proBNP), and other biochemical parameters were measured. All enrolled patients underwent heart function classification. RESULTS: Patients with serous cavity effusion (SCE) demonstrated higher serum CA125 than patients without SCE (82.91 (61.90-103.92) vs. 44.98 (29.66-60.30) U/mL, P<0.001). In the absence of SCE, CA125 levels in CHF patients were slightly higher than non-CHF patients (52.37 (34.85-69.90) vs. 35.15 (23.81-46.49) U/mL, P=0.017). Additionally, compared with non-CHF patients, CHF patients had higher levels of high-sensitivity C-reactive protein (hsCRP) and lower superoxide dismutase (SOD). In all enrolled patients, CA125 levels were negatively correlated with SOD concentrations (r=-0.567, P<0.001), and positively correlated with hsCRP levels (r=0.608, P<0.001). Receiver operating characteristic curve analysis showed that CA125 was better in predicting SCE than NT-proBNP, while NT-proBNP was more suitable for predicting CHF than CA125. The in vitro study demonstrated that MUC16, the CA125 coding gene, was up-regulated by mechanical stretch on human mesothelial cell line (MeT-5A). CONCLUSIONS: CA125 elevation in CHF was associated with SCE. Mechanical extension of mesothelial cells from SCE plays an important role in CA125 increase. PMID- 24060731 TI - Mycophenolic acid quantification in human peripheral blood mononuclear cells using liquid chromatography-tandem mass spectrometry. AB - BACKGROUND AND OBJECTIVES: Mycophenolic acid (MPA) is an immunosuppressant widely used to prevent organ rejection after organ transplantation. MPA therapeutic drug monitoring (TDM) is currently recommended by plasma C0 - or even better - by AUC determinations, but little is known about the potential interest of measuring the intra-lymphocyte MPA concentrations, representing the target site of action. The aim of this study is to develop and validate a selective and sensitive analytical method for quantification of MPA levels in human peripheral blood mononuclear cells (PBMCs). METHODS: PBMCs were extracted from heparin blood samples by Leucosep(r). Methanol and MPA-d3 were used as extraction solvent and internal standard, respectively. Chromatographic separation was obtained on a XBridge BEH C18 column (2.1mm*75mm, 2.5MUm) maintained at 50 degrees C on a Waters Alliance 2795 coupled to a QuattroMicro tandem mass-spectrometer. The multiple reaction monitoring transitions used for quantification were m/z 320.97->207.0 for MPA, and 324.2->210.1 for MPA-d3, in positive ESI mode. RESULTS: The total HPLC run time was 6min. The retention times for MPA-d3 and MPA were 2.55 for both compounds. The method was linear from 0.1 to 50ng/mL MPA. The coefficient r(2) ranged from 0.996 to 0.998. Intra-assay and inter-assay imprecisions were <10% in the whole range of concentrations, and <20% at the LLOQ, and accuracy level was >90%. The matrix and ion suppression effects were <6%. The MPA limit of quantification was 0.1ng/mL. No interference was identified in the assay. From the preliminary results, intra-cellular MPA concentrations in kidney transplant patients ranged from 0.69 to 3.39ng/10(7) cells. CONCLUSION: We described a robust, rapid and simple method suitable for the determination of MPA concentrations in PBMCs. This method is currently used in pharmacokinetics pharmacodynamics (PK-PD) clinical trials, in comparison to standard plasma TDM. PMID- 24060732 TI - Chitotriosidase variants in patients with Gaucher disease. Implications for diagnosis and therapeutic monitoring. AB - OBJECTIVES: Human plasma chitotriosidase (ChT) activity, a biomarker for evaluating and monitoring Gaucher disease (GD), varies in the general population owing to variants in the CHIT1 gene. Our aim is to determine the frequency of the c.1049_1072dup24 (dup24) and p.G102S polymorphisms, their influence on plasma ChT activity, and its change with enzyme replacement therapy (ERT). DESIGN AND METHODS: The study included 269 type1 GD patients. Genomic DNA was genotyped using PCR, restriction isotyping and agarose gel electrophoresis. ChT activity was measured with the 4-methylumbelliferyl-beta-D-N,N',N"triacetylchitotrioside substrate at non-saturating concentrations at diagnosis, before beginning therapy and after one year on ERT. RESULTS: Allele frequencies for dup24 and p.G102S were 0.22 and 0.27, respectively. Four percent of patients were homozygous and 37% heterozygous for dup24, and 9% homozygous and 37% heterozygous for p.G102S. The presence of dup24 and p.G102S polymorphisms in the CHIT1 gene significantly reduced plasma ChT activity in naive patients. By contrast, the percentage of ChT activity decrease after one year of ERT was independent of the presence of these genetic variants. CONCLUSIONS: This study indicates that genotyping for c.1049_1072dup24 and p.G102S polymorphisms will improve the interpretation of plasma chitotriosidase activity at diagnosis but, this is not mandatory for monitoring of enzyme replacement therapy. PMID- 24060733 TI - Intra-subspecies sequence variability of the MACPPE12 gene in Mycobacterium avium subsp. hominissuis. AB - The PE (Pro-Glu) and PPE (Pro-Pro-Glu) multigene families are unique to mycobacteria, and are highly expanded in the pathogenic members of this genus. We determined the intra-subspecies genetic variability of the MACPPE12 gene, which is a specific PPE gene in Mycobacterium avium subsp. hominissuis (MAH), using 334 MAH isolates obtained from different isolation sources (222 human isolates, 145 Japanese and 77 Korean; 37 bathroom isolates; and 75 pig isolates). In total, 31 single-nucleotide polymorphisms (SNPs), which consisted of 16 synonymous SNPs and 15 nonsynonymous SNPs, were determined through comparison with the MACPPE12 gene sequence of MAH strain 104 as a reference. As the result, the 334 MAH isolates were classified into 19 and 13 different sequevars at the nucleic acid level (NA types) and amino acid level (AA types), respectively. Among the 13 AA types, only one type, the AA02 type, presented various NA types (7 different types) with synonymous SNPs, whereas all other AA types had a one-to-one correspondence with the NA types. This finding suggests that AA02 is a longer discernible lineage than the other AA types. Therefore, AA02 was classified as an ancestral type of the MACPPE12 gene, whereas the other AA types were classified as modern types. The ubiquitous presence of AA02 in all of the isolation sources and all different sequevars classified by the hsp65 genotype further supports this classification. In contrast to the ancestral type, the modern types showed remarkable differences in distribution between human isolates and pig isolates, and between Japanese isolates and Korean isolates. Divergence of the MACPPE12 gene may thus be a good indicator to characterize MAH strains in certain areas and/or hosts. PMID- 24060734 TI - Perspective on emergence and re-emergence of amantadine resistant influenza A viruses in domestic animals in China. AB - In China, approximately 20% of the animal original influenza A viruses have molecular markers of amantadine resistance. Through phylogenetic data analyses and geospatial statistical analyses, this study suggests emergence of amantadine resistance in animal influenza could be due to selection pressures in China, for example, amantadine usage in some areas. PMID- 24060735 TI - Molecular epidemiology, phylogeny and evolution of dermatophytes. AB - Dermatophytes are fungi that invade and propagate in the keratinized skin of mammals, including humans, often causing contagious infections. The species of medical concern belong to the genera Microsporum, Trichophyton, Epidermophyton (in their anamorphic state) and Arthroderma (in their telomorphic state), which were traditionally identified based on their morphology and biochemical characters. Nonetheless, limitations linked to the differentiation of closely related agents at species and strains level have been recently overcome by molecular studies. Indeed, an accurate identification of dermatophytes is pivotal for the establishment of effective control and prevention programs as well as for determining the most appropriate and effective antifungal therapies to be applied. This article reviews the DNA techniques and the molecular markers used to identify and to characterize dermatophyte species, as well as aspects of their phylogeny and evolution. The applications of typing molecular strain to both basic and applied research (e.g., taxonomy, ecology, typing of infection, antifungal susceptibility) have also been discussed. PMID- 24060736 TI - Efficacy of the prothrombin complex concentrate prothromplex in patients requiring urgent reversal of vitamin K antagonists or presenting with uncontrolled bleeding: a retrospective, single center study. AB - The objective of the present study was to investigate the efficacy of a four factor prothrombin complex concentrate (Prothromplex, PTX) in shortening prolonged international normalized ratio or controlling life-threatening bleeding. The study was a retrospective single-centre study that included 142 patients treated with PTX and allocated in three groups: patients on vitamin K antagonists (VKA) (acenocumarol) and undergoing invasive procedure or presenting with severe bleeding (n = 76), patients treated with VKA presenting with intracranial haemorrhage (n = 22), and patients not on VKA and presenting with uncontrolled bleeding (n = 44). The primary outcome variable was international normalized ratio (INR) return to the norm after PTX infusion. Secondary outcome variables included bleeding control and reduction of transfusion rate. Overall, patients received a median of 1200 IU (~15 IU/kg) of PTX, and INR decreased from 4 +/- 3 to 1.7 +/- 1.2 (P < 0.01) in all groups, although it remained at least 1.4 in 38% of patients (29.3% among patients receiving 25 IU/kg vs. 42.6% among those receiving 15 IU/kg; P < 0.05). Patients with initial INR at least 4 benefited the most from treatment. After PTX administration, there was a significant reduction in both transfused blood components units (P < 0.01) and estimated blood loss volume (from 1500 +/- 1500 to 200 +/- 100 ml; P < 0.01), and only one episode of deep venous thrombosis was observed. Administration of fixed doses of PTX shortened prolonged international normalized ratio and improved life threatening bleeding in patients with or without VKA therapy. Higher dose attained a more adequate post-infusion INR. PMID- 24060737 TI - Perfusion index as a diagnostic tool for patent ductus arteriosus in preterm infants. AB - BACKGROUND: Perfusion index (PI) could reflect peripheral flow. Preterm infants with hemodynamically significant patent ductus arteriosus (hsPDA) will have left to-right shunt across PDA causing less blood flow to the lower legs. OBJECTIVE: To evaluate pre- and postductal PI differences (DeltaPI) in hsPDA. METHODS: Preterm infants with gestational age <34 weeks were assessed for DeltaPI on days 1, 3, and 7 of life with simultaneous echocardiography. Based on echocardiography, each infant was categorized into hsPDA, non-hsPDA, and no PDA. RESULTS: Thirty infants (16 males), median age 31 weeks (interquartile range, IQR, 29-32) and weight 1,490 g (IQR 1,100-1,670) were enrolled. On days 1 and 3 of life, the DeltaPI of infants with hsPDA (1.57%, IQR 0.28-2.32, n = 14, and 1.32%, IQR 0.28-1.83, n = 10) were significantly higher than those without hsPDA (0.14%, IQR -0.03 to 0.30, n = 16, and 0.08%, IQR -0.07 to 0.26, n = 20), p = 0.009 and 0.005, respectively. At all time points (days 1, 3, and 7 of life, n = 84), DeltaPI >1.05% had sensitivity, specificity, positive predictive value, and negative predictive value of 66.7, 100, 100, and 86.4%, respectively, to detect hsPDA. CONCLUSION: The pre- and postductal PI differences were significantly related to the hemodynamic changes of PDA and might be useful to detect hemodynamically significant PDA. PMID- 24060738 TI - Tetrabromobisphenol A and hexabromocyclododecane flame retardants in infant mother paired serum samples, and their relationships with thyroid hormones and environmental factors. AB - The concentrations of tetrabromobisphenol A (TBBPA) and hexabromocyclododecanes (HBCDs), and their correlations with thyroid hormones, were investigated in sera from 26 infants with congenital hypothyroidism, 12 healthy infants, and their mothers. The analyte concentrations were not significantly different in the two infant groups. Polybrominated diphenyl ethers (measured in a previous study) were the dominant brominated flame retardants, contributing 42-87% of the total, and HBCDs contributed 5-18%. TBBPA concentrations were 2-5 times higher in the infants than in the mothers. The TBBPA concentrations decreased dramatically with age for 2-3 months after birth, which might be caused by its relatively high maternal transfer rate, short half-life, and fast excretion. Significant correlations were found between mothers and infants in the TBBPA and HBCD concentrations, implying that maternal transfer was important. TBBPA correlated weakly with thyroid hormones, showing a positive relationship with FT4 but a negative relationship with T3. PMID- 24060739 TI - Environmental controls on ozone fluxes in a poplar plantation in Western Europe. AB - Tropospheric O3 is a strong oxidant that may affect vegetation and human health. Here we report on the O3 fluxes from a poplar plantation in Belgium during one year. Surprisingly, the winter and autumn O3 fluxes were of similar magnitude to ones observed during most of the peak vegetation development. Largest O3 uptakes were recorded at the beginning of the growing season in correspondence to a minimum stomatal uptake. Wind speed was the most important control and explained 44% of the variability in the nighttime O3 fluxes, suggesting that turbulent mixing and the mechanical destruction of O3 played a substantial role in the O3 fluxes. The stomatal O3 uptake accounted for a seasonal average of 59% of the total O3 uptake. Multiple regression and partial correlation analyses showed that net ecosystem exchange was not affected by the stomatal O3 uptake. PMID- 24060740 TI - Possible causes of the recent rapid increase in the radial increment of silver fir in the Western Carpathians. AB - Silver fir is one of the most productive and ecologically valuable native European tree species, however, it has been experiencing decline which has periodically occurred over its natural range. This paper aims to investigate the recent climate-growth relationships of silver fir (Abies alba Mill.) and its temporal change along the course of its life. Long-term tree-ring databases, as well as records on climate, atmospheric SO2, NO3 and acid concentrations from four different regions in the Western Carpathians were used. The results provide clear evidence of significant increase of silver fir's radial increment over the entire Western Carpathian area since 1970-1980. The results indicated that the most probable factors behind the rapid recovery of tree radial increment were reductions in emissions of NO3 and SO2, alongside a significant increase in mean June, July and April temperatures. PMID- 24060741 TI - Enriching for microbial reductive dechlorination of polychlorinated dibenzo-p dioxins and dibenzofurans. AB - Anaerobic enrichment cultures derived from contaminated Kymijoki River sediments dechlorinated 1,2,3,4-tetrachlorodibenzofuran (1,2,3,4-tetra-CDF), octachlorodibenzofuran (octa-CDF) and 1,2,3,4-tetrachlorodibenzo-p-dioxin (1,2,3,4-tetra-CDD). 1,2,3,4-tetra-CDF was dechlorinated via 1,2,3-, 2,3,4-, and 1,3,4/1,2,4-tri-CDFs to 1,3-, 2,3-, and 2,4-di-CDFs and finally to 4-mono-CDF. The dechlorination rate of 1,2,3,4-tetra-CDF was generally slower than that of 1,2,3,4-tetra-CDD. The rate and extent of 1,2,3,4-tetra-CDD dechlorination was enhanced by addition of pentachloronitrobenzene (PCNB) as a co-substrate. Dechlorination of spiked octa-CDF was observed with the production of hepta-, hexa-, penta- and tetra-CDFs over 6 months. Two major phylotypes of the Chloroflexi community showed an increase, one of which was identical to the Dehalococcoides mccartyi Pinellas subgroup. A set of twelve putative reductive dehalogenase (rdh) genes increased in abundance with addition of 1,2,3,4-tetra CDF, 1,2,3,4-tetra-CDD and/or PCNB. This information will aid in understanding how indigenous microbial communities impact the fate of PCDFs and in developing strategies for bioremediation of PCDD/F contaminated sediments. PMID- 24060742 TI - Management of large para-esophageal hiatal hernias. AB - Para-esophageal hernias are relatively rare and typically occur in elderly patients. The various presenting symptoms are non-specific and often occur in combination. These include symptoms of gastro-esophageal reflux (GERD) in 26 to 70% of cases, microcytic anemia in 17 to 47%, and respiratory symptoms in 9 to 59%. Respiratory symptoms are not completely resolved by surgical intervention. Acute complications such as gastric volvulus with incarceration or strangulation are rare (estimated incidence of 1.2% per patient per year) but gastric ischemia leading to perforation is the main cause of mortality. Only patients with symptomatic hernias should undergo surgery. Prophylactic repair to prevent acute incarceration should only be undertaken in patients younger than 75 in good condition; surgical indications must be discussed individually beyond this age. The laparoscopic approach is now generally accepted. Resection of the hernia sac is associated with a lower incidence of recurrence. Repair of the hiatus can be reinforced with prosthetic material (either synthetic or biologic), but the benefit of prosthetic repair has not been clearly shown. Results of prosthetic reinforcement vary in different studies; it has been variably associated with four times fewer recurrences or with no measurable difference. A Collis type gastroplasty may be useful to lengthen a foreshortened esophagus, but no objective criteria have been defined to support this approach. The anatomic recurrence rate can be as high as 60% at 12years. But most recurrences are asymptomatic and do not affect the quality of life index. It therefore seems more appropriate to evaluate functional results and quality of life measures rather than to gauge success by a strict evaluation of anatomic hernia reduction. PMID- 24060743 TI - Five-year results of sleeve gastrectomy. AB - OBJECTIVE: Our purpose was to evaluate the efficacy and safety of sleeve gastrectomy (SG) at 5 years after surgery. PATIENTS AND METHODS: From June 2005 to January 2007, 65 obese patients underwent SG. The percentage of excess weight loss (%EWL) and excess BMI loss (% EBL), obesity-related co-morbidities, and post SG complications were evaluated at 2 years after SG based on our database, and at 5 years after SG based on a questionnaire sent to the patients by one of the authors (IB) between May 2011 and February 2012. RESULTS: A complete data set was obtained for 53 of 65 patients (82%), including 45 patients who had SG as the only surgical treatment, and eight patients who had a second bariatric procedure at a later date because of insufficient weight loss (five gastric bypass (GBP), three SG revision). For these 53 patients, the mean %EWL was 54.4% at 2 years and 53.7% at 5 years, and the mean %EBL was 61% at 2 years and 60% at 5 years. Three patients (5.7%) had post-operative complications (two fistulas (3.8%), one hemorrhage (1.9%)). Three trocar-site hernias (5.7%) were observed between 10 months and 34 months post-SG. Sub-group analysis of the 45 patients who underwent SG alone showed a mean %EWL of 57.1% at 2 years and 50.7% at 5 years; the mean %EBL was 64% at 2 years and 56.8% at 5 years. Of these 45 patients, 13 (28.9%) required medication to treat diabetes (DM) before SG and only five (11.1%) at 5 years after SG (61.5% decrease); 18 (40%) had antihypertensive treatment before SG, and eight (17.8%) at 5 years after SG (55.5% decrease); 12 (26.7%) took lipid lowering medication before SG, and five (11.1%) at 5 years after SG (58.3% decrease); 24 (53.3%) had sleep apnea (SAS) before SG and six (17.8%) at 5 years after SG (75% decrease). However, while only five patients (11.1%) had GERD requiring PPI therapy before SG, 15 patients required PPI therapy (33.3%) at 5 years after SG (200% increase). CONCLUSION: Five years after performance of SG, weight loss was satisfactory, few complications were observed, the reduction of co-morbidities was significant, but there was an increase in the frequency of GERD. PMID- 24060744 TI - NiO-based nanostructures with efficient optical and electrochemical properties for high-performance nanofluids. AB - NiO nanostructures were synthesized via a simple wet chemical solution method with varying calcination temperatures. The synthesized nanostructures were characterized by XRD, TG/DSC, FT-IR and high-resolution electron microscopy techniques. The nanostructures revealed dependence of particle size, stoichiometry, optical band gap and luminescence intensity on calcination temperatures. The materials exhibited efficient electrochemical properties with decent capacitance values. Ethylene-glycol-based nanofluids of these nanoparticles registered excellent thermal conductivity enhancement of 59-69% in the room temperature region and 125% enhancement at higher temperatures (80 degrees C), establishing NiO to be a top-draw contender for high-performance heat transfer fluids. PMID- 24060745 TI - The identification and molecular characterization of the first archaeal bifunctional exo-beta-glucosidase/N-acetyl-beta-glucosaminidase demonstrate that family GH116 is made of three functionally distinct subfamilies. AB - BACKGROUND: beta-N-acetylhexosaminidases, which are involved in a variety of biological processes including energy metabolism, cell proliferation, signal transduction and in pathogen-related inflammation and autoimmune diseases, are widely distributed in Bacteria and Eukaryotes, but only few examples have been found in Archaea so far. However, N-acetylgluco- and galactosamine are commonly found in the extracellular storage polymers and in the glycans decorating abundantly expressed glycoproteins from different Crenarchaeota Sulfolobus sp., suggesting that beta-N-acetylglucosaminidase activities could be involved in the modification/recycling of these cellular components. METHODS: A thermophilic beta N-acetylglucosaminidase was purified from cellular extracts of S. solfataricus, strain P2, identified by mass spectrometry, and cloned and expressed in E. coli. Glycosidase assays on different strains of S. solfataricus, steady state kinetic constants, substrate specificity analysis, and the sensitivity to two inhibitors of the recombinant enzyme were also reported. RESULTS: A new beta-N acetylglucosaminidase from S. solfataricus was unequivocally identified as the product of gene sso3039. The detailed enzymatic characterization demonstrates that this enzyme is a bifunctional beta-glucosidase/beta-N-acetylglucosaminidase belonging to family GH116 of the carbohydrate active enzyme (CAZy) classification. CONCLUSIONS: This study allowed us to propose that family GH116 is composed of three subfamilies, which show distinct substrate specificities and inhibitor sensitivities. GENERAL SIGNIFICANCE: The characterization of SSO3039 allows, for the first time in Archaea, the identification of an enzyme involved in the metabolism beta-N-acetylhexosaminide, an essential component of glycoproteins in this domain of life, and substantially increases our knowledge on the functional role and phylogenetic relationships amongst the GH116 CAZy family members. PMID- 24060746 TI - Aquaporin-facilitated transmembrane diffusion of hydrogen peroxide. AB - BACKGROUND: Hydrogen peroxide (H2O2) is an important signaling compound that has recently been identified as a new substrate for several members of the aquaporin superfamily in various organisms. Evidence is emerging about the physiological significance of aquaporin-facilitated H2O2 diffusion. SCOPE OF REVIEW: This review summarizes current knowledge about aquaporin-facilitated H2O2 diffusion across cellular membranes. It focuses on physicochemical and experimental evidence demonstrating the involvement of aquaporins in the transport of this redox signaling compound and discusses the regulation and structural prerequisites of these channels to transmit this signal. It also provides perspectives about the potential importance of aquaporin-facilitated H2O2 diffusion processes and places this knowledge in the context of the current understanding of transmembrane redox signaling processes. MAJOR CONCLUSIONS: Specific aquaporin isoforms facilitate the passive diffusion of H2O2 across biological membranes and control H2O2 membrane permeability and signaling in living organisms. GENERAL SIGNIFICANCE: Redox signaling is a very important process regulating the physiology of cells and organisms in a similar way to the well-characterized hormonal and calcium signaling pathways. Efficient transmembrane diffusion of H2O2, a key molecule in the redox signaling network, requires aquaporins and makes these channels important players in this signaling process. Channel-mediated membrane transport allows the fine adjustment of H2O2 levels in the cytoplasm, intracellular organelles, the apoplast, and the extracellular space, which are essential for it to function as a signal molecule. This article is part of a Special Issue entitled Aquaporins. PMID- 24060747 TI - Current methods to study reactive oxygen species--pros and cons. Preface. PMID- 24060748 TI - The role of mitochondria in the aetiology of insulin resistance and type 2 diabetes. AB - BACKGROUND: The prevalence of type 2 diabetes is rapidly increasing world-wide and insulin resistance is central to the aetiology of this disease. The biology underpinning the development of insulin resistance is not completely understood and the role of impaired mitochondrial function in the development of insulin resistance is controversial. SCOPE OF REVIEW: This review will provide an overview of the major processes regulated by mitochondria, before examining the evidence that has investigated the relationship between mitochondrial function and insulin action. Further considerations aimed at clarifying some controversies surrounding this issue will also be proposed. MAJOR CONCLUSIONS: Controversy on this issue is fuelled by our lack of understanding of some of the basic biological interactions between mitochondria and insulin regulated processes in the context of insults thought to induce insulin resistance. Aspects that have not yet been considered are tissue/cell type specific responses, mitochondrial responses to site-specific impairments in mitochondrial function and as yet uncharacterised retrograde signalling from mitochondria. GENERAL SIGNIFICANCE: Further investigation of the relationship between mitochondria and insulin action could reveal novel mechanisms contributing to insulin resistance in specific patient subsets. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. PMID- 24060749 TI - Small molecule inhibitors of protein interaction with glycosaminoglycans (SMIGs), a novel class of bioactive agents with anti-inflammatory properties. AB - BACKGROUND: Small molecule inhibitors of biologically important protein glycosaminoglycan (GAG) interactions have yet to be identified. METHODS: Compound libraries were screened in an assay of L-selectin-IgG binding to heparin (a species of heparan sulfate [HS-GAG]). Hits were validated, IC-50s established and direct binding of hits to HS-GAGs was investigated by incubating compounds alone with heparin. Selectivity of inhibitors was assessed in 11 different protein-GAG binding assays. Anti-inflammatory activity of selected compounds was evaluated in animal models. RESULTS: Screening identified a number of structurally-diverse planar aromatic cationic amines. Scaffolds similar to known GAG binders, chloroquine and tilorone, were also identified. Inhibitors displayed activity also against bovine kidney heparan sulfate. Direct binding of compounds to GAGs was verified by incubating compounds with heparin alone. Selectivity of inhibitors was demonstrated in a panel of 11 heparin binding proteins, including selectins, chemokines (IL-8, IP-10), Beta Amyloid and cytokines (VEGF, IL-6). A number of selected lead compounds showed dose-dependent efficacy in peritonitis, paw edema and delayed type hypersensitivity. CONCLUSIONS: A new class of compounds, SMIGs, inhibits protein-GAG interaction by direct binding to GAGs. Although their IC-50s were in the low micro-molar range, SMIGs binding to HS-GAGs appeared to be stable in physiological conditions, indicating high avidity binding. SMIGs may interfere with major checkpoints for inflammatory and autoimmune events. GENERAL SIGNIFICANCE: SMIGs are a class of structurally diverse planar aromatic cationic amines that have an unusual mode of action - inhibiting protein-GAG interactions via direct and stable binding to GAGs. SMIGs may have therapeutic potential in inflammatory and autoimmune disorders. PMID- 24060750 TI - Tumor growth retardation and chemosensitizing action of fatty acid synthase inhibitor orlistat on T cell lymphoma: implication of reconstituted tumor microenvironment and multidrug resistance phenotype. AB - BACKGROUND: Orlistat, a fatty acid synthase (FASN) inhibitor, has been demonstrated to inhibit tumor cell survival. However, the mechanism(s) of its tumor growth retarding action against malignancies of hematological origin remains unclear. It is also not understood if the antitumor action of orlistat implicates modulated susceptibility of tumor cell to anticancer drugs. Therefore, the present investigation focuses to study the antitumor and chemosensitizing action of orlistat in a murine host bearing a progressively growing T cell lymphoma. METHODS: Tumor-bearing mice were administered with vehicle alone or containing orlistat followed by administration of PBS with or without cisplatin. Tumor progression and survival of tumor-bearing host were monitored along with analysis of tumor cell survival and apoptosis. Tumor ascitic fluid was examined for pH, NO and cytokines. Expression of genes and proteins was investigated by RT PCR and western blot respectively. ROS was analyzed by DCFDA staining and FASN activity by spectrophotometry. RESULTS: Orlistat administration to tumor-bearing mice resulted in tumor growth retardation, prolonged life span, declined tumor cell survival and chemosensitization to cisplatin. It was accompanied by increased osmotic fragility, modulated acidosis, expression of ROS, NO, cytokines, MCT-1 and VH(+) ATPase, Bcl2, Caspase-3, P53, inhibited FASN activity and declined expression of MDR and MRP-1 proteins. CONCLUSION: Orlistat manifests antitumor and chemosensitizing action implicating modulated regulation of cell survival, reconstituted-tumor microenvironment and altered MDR phenotype. GENERAL SIGNIFICANCE: These observations indicate that orlistat could be utilized as an adjunct regimen for improving antitumor efficacy of cisplatin. PMID- 24060751 TI - Dynamics of alpha-Hb chain binding to its chaperone AHSP depends on heme coordination and redox state. AB - BACKGROUND: AHSP is an erythroid molecular chaperone of the alpha-hemoglobin chains (alpha-Hb). Upon AHSP binding, native ferric alpha-Hb undergoes an unprecedented structural rearrangement at the heme site giving rise to a 6th coordination bond with His(E7). METHODS: Recombinant AHSP, WT alpha-Hb:AHSP and alpha-Hb(HE7Q):AHSP complexes were expressed in Escherichia coli. Thermal denaturation curves were measured by circular dichroism for the isolated alpha-Hb and bound to AHSP. Kinetics of ligand binding and redox reactions of alpha-Hb bound to AHSP as well as alpha-Hb release from the alpha-Hb:AHSP complex were measured by time-resolved absorption spectroscopy. RESULTS: AHSP binding to alpha Hb is kinetically controlled to prevail over direct binding with beta-chains and is also thermodynamically controlled by the alpha-Hb redox state and not the liganded state of the ferrous alpha-Hb. The dramatic instability of isolated ferric alpha-Hb is greatly decreased upon AHSP binding. Removing the bis-histidyl hexacoordination in alpha-HbH58(E7)Q:AHSP complex reduces the stabilizing effect of AHSP binding. Once the ferric alpha-Hb is bound to AHSP, the globin can be more easily reduced by several chemical and enzymatic systems compared to alpha Hb within the Hb-tetramer. CONCLUSION: alpha-Hb reduction could trigger its release from AHSP toward its final Hb beta-chain partner producing functional ferrous Hb-tetramers. This work indicates a preferred kinetic pathway for Hb synthesis. GENERAL SIGNIFICANCE: The cellular redox balance in Hb-synthesis should be considered as important as the relative proportional synthesis of both Hb-subunits and their heme cofactor. The in vivo role of AHSP is discussed in the context of the molecular disorders observed in thalassemia. PMID- 24060753 TI - Age- and diabetes-related nonenzymatic crosslinks in collagen fibrils: candidate amino acids involved in Advanced Glycation End-products. AB - Ageing and diabetes share a common deleterious phenomenon, the formation of Advanced Glycation Endproducts (AGEs), which accumulate predominantly in collagen due to its low turnover. Though the general picture of glycation has been identified, the detailed knowledge of which collagen amino acids are involved in AGEs is still missing. In this work we use an atomistic model of a collagen fibril to pinpoint, for the first time, the precise location of amino acids involved in the most relevant AGE, glucosepane. The results show that there are 14 specific lysine-arginine pairs that, due to their relative position and configuration, are likely to form glucosepane. We find that several residues involved in AGE crosslinks are within key collagen domains, such as binding sites for integrins, proteoglycans and collagenase, hence providing molecular-level explanations of previous experimental results showing decreased collagen affinity for key molecules. Altogether, these findings reveal the molecular mechanism by which glycation affects the biological properties of collagen tissues, which in turn contribute to age- and diabetes-related pathological states. PMID- 24060752 TI - Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol induced liver steatosis. AB - BACKGROUND: The mechanism(s) by which alcohol causes cell injury are still not clear but a major mechanism appears to be the role of lipid peroxidation and oxidative stress in alcohol toxicity. CYP2E1-generated ROS contributes to the ethanol-induced oxidant stress and inhibition of CYP2E1 activity decreases ethanol-induced fatty liver. The transcription factor Nrf2 regulates the expression of many cytoprotective enzymes which results in cellular protection against a variety of toxins. METHOD: The current study was designed to evaluate the ability of sulforaphane, an activator of Nrf2, to blunt CYP2E1-dependent, ethanol-induced steatosis in vivo and in vitro. RESULTS: The sulforaphane treatment activated Nrf2, increased levels of the Nrf2 target heme oxygenase-1 and subsequently lowered oxidant stress as shown by the decline in lipid peroxidation and 3-nitrotyrosine protein adducts and an increase in GSH levels after the acute ethanol treatment. It decreased ethanol-elevated liver levels of triglycerides and cholesterol and Oil Red O staining. Similar results were found in vitro as addition of sulforaphane to HepG2 E47 cells, which express CYP2E1, elevated Nrf2 levels and decreased the accumulation of lipid in cells cultured with ethanol. Sulforaphane treatment had no effect on levels of or activity of CYP2E1. CONCLUSIONS: Sulforaphane proved to be an effective in vivo inhibitor of acute ethanol-induced fatty liver in mice. GENERAL SIGNIFICANCE: The possible amelioration of liver injury which occurs under these conditions by chemical activators of Nrf2 is of clinical relevance and worthy of further study. PMID- 24060754 TI - Lumican affects tumor cell functions, tumor-ECM interactions, angiogenesis and inflammatory response. AB - The consecutive steps of tumor growth, local invasion, intravasation, extravasation and invasion of anatomically distant sites are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. Lumican, a class II small leucine-rich proteoglycans (SLRP) has been designated key roles both in extracellular matrix (ECM) organization and as an important modulator of biological functions. This review will critically discuss lumicans' roles in tumor development and progression. We will especially focus on correlating lumicans' expression and distribution in tumor tissues with: (1) the organization of the tumor matrices; (2) tumor cell signaling and functions; (3) tumor cell-matrix interface; (4) tumor angiogenesis; and (5) lumicans' potential roles in tumor-associated inflammatory response. Present knowledge of lumicans' biology provides a fundamental platform upon which to build and deepen our understanding of lumican function in tumorigenesis in order to be able to design credible anti-tumor approaches. PMID- 24060755 TI - Mobile EEG in epilepsy. AB - The sensitivity of routine EEG recordings for interictal epileptiform discharges in epilepsy is limited. In some patients, inpatient video-EEG may be performed to increase the likelihood of finding abnormalities. Although many agree that home EEG recordings may provide a cost-effective alternative to these recordings, their use is still not introduced everywhere. We surveyed Dutch neurologists and patients and evaluated a novel mobile EEG device (Mobita, TMSi). Key specifications were compared with three other current mobile EEG devices. We shortly discuss algorithms to assist in the review process. Thirty percent (33 out of 109) of Dutch neurologists reported that home EEG recordings are used in their hospital. The majority of neurologists think that mobile EEG can have additional value in investigation of unclear paroxysms, but not in the initial diagnosis after a first seizure. Poor electrode contacts and signal quality, limited recording time and absence of software for reliable and effective assistance in the interpretation of EEGs have been important constraints for usage, but in recent devices discussed here, many of these problems have been solved. The majority of our patients were satisfied with the home EEG procedure and did not think that our EEG device was uncomfortable to wear, but they did feel uneasy wearing it in public. PMID- 24060756 TI - Analysing the substrate multispecificity of a proton-coupled oligopeptide transporter using a dipeptide library. AB - Peptide uptake systems that involve members of the proton-coupled oligopeptide transporter (POT) family are conserved across all organisms. POT proteins have characteristic substrate multispecificity, with which one transporter can recognize as many as 8,400 types of di/tripeptides and certain peptide-like drugs. Here we characterize the substrate multispecificity of Ptr2p, a major peptide transporter of Saccharomyces cerevisiae, using a dipeptide library. The affinities (Ki) of di/tripeptides toward Ptr2p show a wide distribution range from 48 mM to 0.020 mM. This substrate multispecificity indicates that POT family members have an important role in the preferential uptake of vital amino acids. In addition, we successfully establish high performance ligand affinity prediction models (97% accuracy) using our comprehensive dipeptide screening data in conjunction with simple property indices for describing ligand molecules. Our results provide an important clue to the development of highly absorbable peptides and their derivatives including peptide-like drugs. PMID- 24060758 TI - Immunoregulatory pathways are active in the small intestinal mucosa of patients with potential celiac disease. AB - OBJECTIVES: Potential celiac disease (CD) relates to subjects with a normal small intestinal mucosa who are at increased risk of developing CD as indicated by positive CD-associated serology. The objective of this study was to investigate in the small intestinal mucosa of such patients the state of immunological activation with special emphasis on immunoregulatory circuits. METHODS: Duodenal biopsies from active CD (n=48), potential CD (n=58), and control patients (n=45) were studied. RNA expression for interferon gamma (IFNgamma) and interleukin-10 (IL-10) were quantified by real-time quantitative PCR. The percentage of CD4+CD25+Foxp3+ T regulatory cells (Foxp3+Tregs) was determinated by flow cytometry and the number of Foxp3+ and IL-15+ cells by immunohistochemistry. Furthermore, we analyzed the suppressive function of CD4+CD25+ T cells, isolated from potential CD biopsy samples, as well as the effect of IL-15, on autologous peripheral blood responder CD4+CD25- T cells. RESULTS: In potential CD patients with Marsh 1 lesion, IFNgamma-RNA expression was significantly less than in active, but enhanced if compared with potential CD patients with Marsh 0 lesion and with controls (P<0.001). The number of IL-15+ cells in subjects with potential CD was increased in comparison with controls (P<0.05), but lower than active CD (P<0.01). IL-10-RNA expression was upregulated in Marsh 0 potential CD patients if compared with those with Marsh 1 lesion (P<0.01) and controls (P<0.001), whereas there were no differences with active CD. The ratio IL 10/IFNgamma reached the highest value in Marsh 0 potential CD compared with the other groups (P<0.05). The percentage of Foxp3+Tregs was also higher in potential CD compared with controls (P<0.05), although it was lower than in active CD (P<0.01). In co-culture assay, intestinal CD4+CD25+ T cells from potential CD patients exerted suppressive effects on T responder cells, and their activity was not impaired by IL-15. CONCLUSIONS: Potential CD patients show a low grade of inflammation that likely could be due to active regulatory mechanisms preventing the progression toward a mucosal damage. PMID- 24060757 TI - Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome bowel habit subtypes. AB - OBJECTIVES: Alterations in 5-hydroxytryptamine (5-HT) signaling have been implicated as a factor contributing to the altered bowel habit of irritable bowel syndrome (IBS) patients. Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme in enterochromaffin cell 5-HT biosynthesis. We hypothesized that genetic variants affecting TPH1 gene expression might alter intestinal 5-HT bioavailability and subsequently the propensity for distinct bowel habit subtypes in IBS. In this study, we assessed the only common TPH1 proximal promoter variant (-347C/A; rs7130929) and its association with bowel habit predominance in IBS. METHODS: Electrophoretic mobility shift assays were performed to assess whether the -347C/A-allele variant affects the DNA binding of nuclear factors. Genotype distribution was determined for 422 IBS patients subtyped using the Rome III criteria and for 495 healthy controls recruited from two university medical centers. Association with bowel habit was tested using a multinomial logistic regression model controlling for race, anxiety, depression, and study site. RESULTS: Early growth response factor 1 (EGR-1) bound with higher affinity to a site comprising the minor A-allele of single-nucleotide polymorphism (SNP) 347C/A. TPH1 genotype frequencies did not differ between IBS patients and controls overall. The CC genotype was more prevalent in the IBS-D subtype (47%) than in the IBS-C (25%) and IBS-M (37%) subtypes (P=0.039) after adjusting for race and other covariates. Colonic biopsies from a small cohort of IBS patients from one center were tested for higher TPH1 mRNA expression in samples with CC compared with the CA genotype, but the results did not reach statistical significance. CONCLUSIONS: The TPH1 promoter SNP -347C/A differentially binds EGR 1 and correlates with IBS bowel habit subtypes and possibly colonic TPH1 expression consistent with its role in modulating intestinal 5-HT signaling. PMID- 24060759 TI - Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. AB - OBJECTIVES: Fecal microbiota transplantation (FMT) from healthy donors, which is an effective alternative for treatment of Clostridium difficile-associated disease, is being considered for several disorders such as inflammatory bowel disease, irritable bowel syndrome, and metabolic syndrome. Disease remission upon FMT is thought to be facilitated by an efficient colonization of healthy donor microbiota, but knowledge of the composition and temporal stability of patient microbiota after FMT is lacking. METHODS: Five patients with moderately to severely active ulcerative colitis (Mayo score >=6) and refractory to standard therapy received FMT via nasojejunal tube and enema. In addition to clinical activity and adverse events, the patients' fecal bacterial communities were monitored at multiple time points for up to 12 weeks using 16S rRNA gene-targeted pyrosequencing. RESULTS: FMT elicited fever and a temporary increase of C reactive protein. Abundant bacteria from donors established in recipients, but the efficiency and stability of donor microbiota colonization varied greatly. A positive clinical response was observed after 12 weeks in one patient whose microbiota had been effectively augmented by FMT. This augmentation was marked by successive colonization of donor-derived phylotypes including the anti inflammatory and/or short-chain fatty acid-producing Faecalibacterium prausnitzii, Rosebura faecis, and Bacteroides ovatus. Disease severity (as measured by the Mayo score) was associated with an overrepresentation of Enterobacteriaceae and an underrepresentation of Lachnospiraceae. CONCLUSIONS: This study highlights the value of characterizing temporally resolved microbiota dynamics for a better understanding of FMT efficacy and provides potentially useful diagnostic indicators for monitoring FMT success in the treatment of ulcerative colitis. PMID- 24060761 TI - Characterization and gene cloning of an acidic thaumatin-like protein (TLP 1), an allergen from sapodilla fruit (Manilkara zapota). AB - BACKGROUND: Allergy to sapodilla (Manilkara zapota) fruit ingestion is rare. An independent study from our group has identified a basic thaumatin-like protein (TLP 2) as the major allergen. The present study was aimed at identifying and characterizing additional allergens from sapodilla. METHODS: Allergic subjects were identified by case history, skin prick test (SPT) and allergen-specific IgE. Sapodilla extract was fractionated using SP-Sepharose into 3 components (SP1, SP2 and SP3) which were analyzed by native/SDS-PAGE, IgE-immunoblot, isoelectric focusing (IEF) and N-terminal sequencing. The conserved regions of plant TLPs and the N-terminal sequence were used to design primers for PCR. RESULTS: SPT and ELISA confirmed a subject with oral allergy syndrome (OAS) to sapodilla and custard apple. Two proteins (26.9 and 24.5kDa; reducing conditions) were detected as allergens, of which the latter in SP2 has already been identified as basic TLP (TLP 2). The 26.9kDa protein present in SP1 was identified as an acidic TLP based on native PAGE, IEF and N-terminal sequencing. Presence of a basic beta-1,3 glucanase in SP3 was inferred by zymography. Sequence analysis of the genomic clone of the acidic TLP gene revealed that it is intronless and non-glycosylated. Evolutionary relatedness to olive, grape and kiwi fruit allergenic TLPs were inferred by phylogenetic analysis. CONCLUSIONS: An acidic TLP (TLP 1) was identified as a new allergen in sapodilla. TLP 1 is a single polypeptide (207 residues) belonging to the thaumatin family of the GH64-TLP-SF superfamily. Clinically, sapodilla should be considered in the list of fruits causing OAS. PMID- 24060760 TI - Proton pump inhibitors and risk for recurrent Clostridium difficile infection among inpatients. AB - OBJECTIVES: Observational studies suggest that proton pump inhibitors (PPIs) are a risk factor for incident Clostridium difficile infection (CDI). Data also suggest an association between PPIs and recurrent CDI, although large-scale studies focusing solely on hospitalized patients are lacking. We therefore performed a retrospective cohort analysis of inpatients with incident CDI to assess receipt of PPIs as a risk factor for CDI recurrence in this population. METHODS: Using electronic medical records, we identified hospitalized adult patients between 1 December 2009 and 30 June 2012 with incident CDI, defined as a first positive stool test for C. difficile toxin B and who received appropriate treatment. Electronic records were parsed for clinical factors including receipt of PPIs, other acid suppression, non-CDI antibiotics, and comorbidities. The primary exposure was in-hospital PPIs given concurrently with C. difficile treatment. Recurrence was defined as a second positive stool test 15-90 days after the initial positive test. C. difficile recurrence rates in the PPI exposed and unexposed groups were compared with the log-rank test. Multivariable Cox proportional hazards modeling was performed to control for demographics, comorbidities, and other clinical factors. RESULTS: We identified 894 inpatients with incident CDI. The cumulative incidence of CDI recurrence in the cohort was 23%. Receipt of PPIs concurrent with CDI treatment was not associated with C. difficile recurrence (hazard ratio (HR)=0.82; 95% confidence interval (CI)=0.58 1.16). Black race (HR=1.66, 95% CI=1.05-2.63), increased age (HR=1.02, 95% CI=1.01-1.03), and increased comorbidities (HR=1.09, 95% CI=1.04-1.14) were associated with CDI recurrence. In light of a higher 90-day mortality seen among those who received PPIs (log-rank P=0.02), we also analyzed the subset of patients who survived to 90 days of follow-up. Again, there was no association between PPIs and CDI recurrence (HR=0.87; 95% CI=0.60-1.28). Finally, there was no association between recurrent CDI and increased duration or dose of PPIs. CONCLUSIONS: Among hospitalized adults with C. difficile, receipt of PPIs concurrent with C. difficile treatment was not associated with CDI recurrence. Black race, increased age, and increased comorbidities significantly predicted recurrence. Future studies should test interventions to prevent CDI recurrence among high-risk inpatients. PMID- 24060762 TI - Maculopapular-type drug eruption caused by Coughcode((r))-N combination tablets. PMID- 24060763 TI - Is bjerkandera allergy affected by the arrival of yellow sand dust? PMID- 24060764 TI - Decreased sudomotor function is involved in the formation of atopic eczema in the cubital fossa. AB - BACKGROUND: Eczema in the cubital fossa, which is susceptible to sweat, is frequently observed in atopic dermatitis (AD). However, there has been no direct evidence that sweating causes eczema in the cubital fossa. METHODS: To investigate this issue, axon reflex-mediated sweating volume (AXR) and skin barrier function in the cubital fossa were measured in subjects with AD and in healthy volunteers, and were applied to clinical feature of the cubital fossa. RESULTS: AXR in the cubital fossa decreased in AD subjects; it positively correlated only with water-holding capacity in healthy subjects but not in patients with in AD. Furthermore, AD subjects with lichenoid eczema and either prurigo or papules over the cubital fossa showed extremely decreased AXR. CONCLUSIONS: These results suggest that decreased sweating is a major source of water in the stratum corneum, and decreased sudomotor function may be involved in both the cause and aggravation of representative atopic eczema in the cubital fossa. PMID- 24060765 TI - Induction of thymic stromal lymphopoietin production by nonanoic acid and exacerbation of allergic inflammation in mice. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) plays critical roles in the induction and exacerbation of allergic diseases. We tested various chemicals in the environment and found that xylene and 1,2,4-trimethylbenzene induced the production of TSLP in vivo. These findings prompted us to search for additional chemicals that induce TSLP production. In this study, we examined whether fatty acids could induce the production of TSLP in vivo and exacerbate allergic inflammation. METHODS: Various fatty acids and related compounds were painted on the ear lobes of mice and the amount of TSLP in the homogenate of ear lobe tissue was determined. The effects of nonanoic acid on allergic inflammation were also examined. RESULTS: Octanoic acid, nonanoic acid, and decanoic acid markedly induced TSLP production, while a medium-chain aldehyde and alcohol showed only weak activity. Nonanoic acid induced the production of TSLP with a maximum at 24 h. TSLP production was even observed in nonanoic acid-treated C3H/HeJ mice that lacked functional toll-like receptor 4. The aryl hydrocarbon receptor agonist beta-naphthoflavone did not induce TSLP production. Nonanoic acid promoted sensitization to ovalbumin, resulting in an enhancement in the cutaneous anaphylactic response. In addition, painting of nonanoic acid after the sensitization augmented picryl chloride-induced thickening of the ear, which was reversed in TSLP receptor-deficient mice. CONCLUSIONS: Nonanoic acid and certain fatty acids induced TSLP production, resulting in the exacerbation of allergic inflammation. We propose that TSLP-inducing chemical compounds such as nonanoic acid be recognized as chemical allergo-accelerators. PMID- 24060766 TI - Arterial stiffness and endothelial function in obese children and adolescents and its relationship with cardiovascular risk factors. AB - BACKGROUND: Obesity is related to an increase in the rates of cardiovascular disease. OBJECTIVE: To establish the impact of obesity on vascular function (endothelial function and arterial stiffness) in children and adolescents and its relationship to cardiovascular risk factors. METHODS: In obese (OB) children and adolescents, endothelial function and arterial stiffness were evaluated by a pulse plethysmography method (reactive hyperemia and index of digital volume waveforms, respectively). Data were compared with the non-obese (non-OB) group (body mass index >10th to <97th percentile). Anthropometric parameters, body fat percentage, fasting glucose, lipid profile, insulinemia, HOMA-IR and hemodynamic parameters were determined in both groups. RESULTS: Body mass index, weight, waist circumference, body fat, insulinemia and HOMA-IR were significantly higher in the OB group. The OB group showed impaired endothelial function (15.8 +/- 0.2%, n = 37) compared to the non-OB group (41.4 +/- 5%, n = 20; p < 0.001) and increased arterial stiffness. Endothelial function was only negatively correlated with waist circumference and HOMA-IR in the OB group, whereas a positive correlation was found between insulinemia and HOMA-IR. CONCLUSIONS: This study shows that impaired vascular function is already present in OB children and adolescents. The fact that obesity is associated with some markers of cardiovascular risk suggests the importance of early lifestyle interventions in this population to prevent cardiovascular disease. PMID- 24060767 TI - Functional neuroimaging of breastfeeding analgesia by multichannel near-infrared spectroscopy. AB - BACKGROUND: Newborns perceive pain, and several non-pharmacologic analgesic methods have been used during painful procedures. Activation of the neonatal somatosensory cortex, in association with a painful procedure without analgesia, has been demonstrated by two-channel near-infrared spectroscopy (NIRS). OBJECTIVES: To evaluate both cortical and behavioural responses of healthy term newborns to a painful procedure during two non-pharmacologic analgesic interventions, i.e. glucose solution and breastfeeding. METHODS: The effects of glucose and breastfeeding on pain-associated neonatal cortical activity were studied in two groups (n = 30) by multichannel NIRS during a heel prick. Cortical activation was identified by variations in oxygenated haemoglobin. Neonatal pain expression was assessed by a validated scale. RESULTS: No significant variations in cortical activity emerged using glucose solution, whereas breastfed newborns showed widespread cortical activation. Breastfed neonates showed significantly less behavioural pain expression. CONCLUSIONS: Glucose is associated with no significant cortical activation and may interfere with pain-associated response at the cortical level. Conversely, breastfeeding analgesia is associated with generalized cortical activation and may act by multisensory stimulation, possibly overwhelming pain perception. PMID- 24060768 TI - Autonomic dysreflexia severity during urodynamics and cystoscopy in individuals with spinal cord injury. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVE: To compare autonomic dysreflexia (AD) severity during urodynamics and cystoscopy in individuals with spinal cord injury (SCI). SETTING: Outpatient urological clinic. METHODS: Demographic and clinical data were collected from charts of individuals with SCI who had blood pressure (BP) monitoring during urological procedures. Cardiovascular parameters were collected at baseline and during the various stages of two examinations. RESULTS: A total of 21 SCI individuals (mean age 49.4 years) who underwent both procedures developed episodes of AD. The majority of individuals had cervical SCI (85.7%). The median duration of injury was 183 months (ranging from 3 to 530 months). There was statistically more of an increase (P=0.039) in systolic BP during cystoscopy (67.1+/-33.8 mm Hg) in comparison with urodynamics (51.8+/-21.8 mm Hg). The BP response during episodes of AD was more pronounced in individuals with more than 2 years post SCI than with less than 2 years post SCI during both urodynamics and cystoscopy (P=0.047 and P=0.010, respectively). CONCLUSION: Even though cystoscopy filled the bladder to lesser volumes than did urodynamics (150 ml vs 500 ml), during cystoscopy the individuals developed greater changes in systolic BP, indicating that stimulation of the urethra/prostate/internal sphincter region probably is a more potent stimulus of AD than just the filling of the bladder. The severity of AD also increased with time post SCI during both procedures. Considering the high incidence of silent episodes of AD during the urological procedures, it is recommended that monitoring of cardiovascular parameters during these procedures be routinely performed. PMID- 24060769 TI - A multifaceted intervention to improve compliance with process measures for ICU clinician communication with ICU patients and families. AB - RATIONALE: Despite recommendations supporting the importance of clinician-family communication in the ICU, this communication is often rated as suboptimal in frequency and quality. We employed a multifaceted behavioral-change intervention to improve communication between families and clinicians in a statewide collaboration of ICUs. OBJECTIVES: Our primary objective was to examine whether the intervention resulted in increased compliance with process measures that targeted clinician-family communication. As secondary objectives, we examined the ICU-level characteristics that might be associated with increased compliance (open vs closed, teaching vs nonteaching, and medical vs medical-surgical vs surgical) and patient-specific outcomes (mortality, length of stay). METHODS: The intervention was a multifaceted quality improvement approach targeting process measures adapted from the Institute of Health Improvement and combined into two "bundles" to be completed either 24 or 72 hours after ICU admission. MEASUREMENTS AND MAIN RESULTS: Significant increases were seen in full compliance for both day 1 and day 3 process measures. Day 1 compliance improved from 10.7% to 83.8% after 21 months of intervention (p<0.001). Day 3 compliance improved from 1.6% to 28.8% (p<0.001). Improvements in compliance varied across ICU type with less improvement in open, nonteaching, and mixed medical-surgical ICUs. Patient specific outcome measures were unchanged, although there was a small increase in patients discharged from ICU to inpatient hospice (p=0.002). CONCLUSIONS: We found that a multifaceted intervention in a statewide ICU collaborative improved compliance with specific process measures targeting communication with family members. The effect of the intervention varied by ICU type. PMID- 24060770 TI - Differences in hospital mortality by ICU staffing models: you cannot always get what you want, but sometimes you get what you need. PMID- 24060771 TI - Why are they all so keen on communication? PMID- 24060772 TI - Rapid response teams--is reducing mortality the only goal or can being too fast be detrimental for patients? PMID- 24060773 TI - Ratio of PICU to ward cardiac arrest is increasing: so what? PMID- 24060774 TI - Body composition and parenteral nutrition: where is the beef? PMID- 24060775 TI - Prescribing patterns for corticosteroids in septic shock: translating guidelines to bedside practice. PMID- 24060776 TI - Penguins and palliative care: facilitating cultural change in the ICU. PMID- 24060777 TI - Test driving levosimendan as the new "kidney protector": first impressions... PMID- 24060778 TI - Chipping away at unnecessary antibiotic use in the ICU, one day and one study at a time. PMID- 24060779 TI - RBC transfusion practices: once again, we have met the enemy and they are us! PMID- 24060780 TI - Are the old really young at heart? PMID- 24060781 TI - Classifying infections in the ICU: seeking certainty in an uncertain environment. PMID- 24060782 TI - High level alert! Modeling temperature and phenytoin: appropriate risk management or virtual reality? PMID- 24060783 TI - Pediatric emergency department telemedicine: no answers and more questions. PMID- 24060784 TI - Prevention and treatment of ICU-acquired weakness: is there a stimulating answer? PMID- 24060785 TI - Deciphering the sepsis riddle: we can learn from Star Trek. PMID- 24060786 TI - Is time the missing component in protective ventilation strategies? PMID- 24060787 TI - Activated protein C: from excitement to disappointment? PMID- 24060788 TI - Eosinophilia: a diagnostic clue for nonbacterial diseases in patients with systemic inflammatory response syndrome. PMID- 24060789 TI - Eosinophils in severe sepsis in northern australia: do the usual rules apply in the tropics? AB - OBJECTIVES: Eosinophilia is rare in severe sepsis in temperate areas. We present a case of suspected severe sepsis with eosinophilia that proved fatal and was subsequently diagnosed as drug rash with eosinophilia and systemic symptoms. We aim to determine how common eosinophilia in severe sepsis is in the tropics, where there is a higher background rate of eosinophilia due to parasitic infection. DESIGN: Retrospective analysis of prospective cohort study. SETTING: Tertiary hospital in tropical northern Australia. PATIENTS: Prospectively recruited cohort including all patients at least 15 years old admitted to a 350 bed teaching hospital in northern Australia between May 6, 2007, and May 5, 2008, with community-onset severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Peripheral eosinophil counts on days 1 and 3 of admission and at the time of discharge were recorded for each patient. Eosinopenia was defined as less than 0.1*10 9/L and eosinophilia as greater than 0.6*10 9/L. The median eosinophil count on day 1 was 0.0 (interquartile range, 0.0-0.1; range, 0.0 0.7*10 9/L). Out of 245 patients, 243 patients (99.1%) had a normal or low eosinophil count at admission. Lower counts correlated with higher Acute Physiology and Chronic Health Evaluation II score and 28-day mortality (p=0.02 for both correlations). The median count rose during the course of admission to 0.2 (interquartile range, 0.1-0.4) at the time of discharge (p<0.001 compared with day 1 count). Patients with eosinophilia at discharge were more likely to be Indigneous or remote-dwelling than those without eosinophilia, suggesting an unmasking of preexisting eosinophilia as sepsis resolves. CONCLUSIONS: Eosinophilia is rare in severe sepsis, even in the tropics. Patients with suspected severe sepsis and eosinophilia should have diagnoses other than sepsis excluded. One such diagnosis is drug rash with eosinophilia and systemic symptoms. PMID- 24060790 TI - New recommendations for the use of serum albumin in patients with severe sepsis and septic shock. PMID- 24060791 TI - The authors reply. PMID- 24060792 TI - Sepsis-induced disseminated intravascular coagulation, symmetrical peripheral gangrene, and amputations. PMID- 24060793 TI - The authors reply. PMID- 24060794 TI - Surviving sepsis. PMID- 24060795 TI - The authors reply. PMID- 24060796 TI - Use of hydrocortisone for refractory shock in children. PMID- 24060797 TI - The authors reply. PMID- 24060798 TI - Benzodiazepines and delirium: the best option for the right patient. PMID- 24060799 TI - Continuous electroencephalographic monitoring and vasospasm. PMID- 24060800 TI - The authors reply. PMID- 24060801 TI - The association between early antibiotic discontinuation and superinfections. PMID- 24060802 TI - The authors reply. PMID- 24060803 TI - Education of minorities to increase organ donation consent rate. PMID- 24060805 TI - Pediatric ambulatory nurses at the intersection of healthcare reform and health information technology. PMID- 24060804 TI - The oxygen free radicals control MMP-9 and transcription factors expression in the spontaneously hypertensive rat. AB - Oxygen free radical and matrix metalloproteinases-9 (MMP-9) play an important pathophysiological role in the development of chronic hypertension. MMP-9 activities are regulated at different levels. We hypothesize that as mediators of the expression of MMP-9 the transcription factors like nuclear factor kappa B (NF kappaB), c-fos and retinoic acid receptors-alpha (RAR-alpha) with binding sites to the MMP-9 promoter are overexpressed in the spontaneously hypertensive rat (SHR) in a process that is regulated by oxygen free radicals. Transcription factor NF-kappaB, c-fos and RAR-alpha expression levels were determined by immunohistochemistry in renal, cardiac and mesentery microcirculation of the SHR and its normotensive control, the Wistar Kyoto (WKY) rat. The animals were treated with a superoxide scavenger (Tempol) for eight weeks. The elevated plasma levels of thiobarbituric acid reactive substances and MMP-9 levels in the SHR were significantly decreased by Tempol treatment (P<0.05). The NF-kappaB, c-fos and RAR-alpha expression levels in renal glomerular, heart and mesentery microvessels were enhanced in the SHR and could also be reduced by Tempol compared to untreated animals (P<0.05). The enhanced MMP-9 levels in SHR microvessels co-express with transcription factors. These results suggest that elevated NF-kappaB, c-fos and RAR-alpha expressions and MMP-9 activity in the SHR are superoxide-dependent. PMID- 24060806 TI - The effect of a cultural competence educational intervention for first-year nursing students in Israel. AB - PURPOSE: To evaluate the effectiveness of an educational intervention to increase general cultural competence of first-year nursing students. DESIGN: This was a quasi-experimental study that used a convenience sample with an experimental group and a control group and pre- and posttesting. The sample comprised 146 first-year nursing students enrolled in the Introduction to Nursing course divided into an intervention group (n = 58) of students from one school and a control group (n = 88) including students from two schools. The intervention group received a 2-hour faculty lecture on cultural competence, and students prepared and delivered a student group presentation about a cultural group in Israel, basing the presentation on Campinha-Bacote's five constructs. A demographic data instrument and Campinha-Bacote's Inventory for Assessing the Process of Cultural Competence Among Healthcare Professional-Revised(c) were used for pre- and posttesting. FINDINGS: Students who received the educational intervention increased scores significantly (68 +/- 6 to 73 +/- 6, p = .000), students who did not receive the educational intervention had no significant increase (67 +/- 6 to 66 +/- 6). DISCUSSION/CONCLUSIONS: Introducing the topic of cultural competence for nursing students in the first-year Introduction to Nursing course as an integrative learning strategy revealed significant increases in cultural competence scores. IMPLICATIONS FOR PRACTICE: Recommendations are to include evidence-based cultural competence teaching strategies into the nursing curriculum. PMID- 24060807 TI - Acceptability of the Fetzer/NIA Multidimensional Measure of Religiousness and Spirituality in a sample of community-dwelling Black adults. AB - PURPOSE: To examine the acceptability of the National Institute on Aging/Fetzer Multidimensional Measure of Religiousness and Spirituality in a sample of Black, community-dwelling, older adults using focus group inquiry (N =15). DESIGN AND METHOD: Focus group methodology was used for data collection and analysis. Three focus groups (N = 15) were conducted in two different urban settings in the northeastern part of the United States. FINDINGS: Key findings were that (a) self rating on religiousness was uncomfortable for many participants, (b) selfless was a word many participants confused with selfish, and (c) spirituality was an important concept. CONCLUSION: Overall, the Measure was found to be culturally acceptable and required little modification. IMPLICATIONS FOR PRACTICE: Religious health beliefs such as "rebuking" or "not claiming" medical diagnoses are important considerations to bear in mind in seeking to understand the impact of religiousness on health in this population. PMID- 24060808 TI - Incorporating prognostic imaging biomarkers into clinical practice. AB - A prognostic imaging biomarker can be defined as an imaging characteristic that is objectively measurable and provides information on the likely outcome of the cancer disease in an untreated individual and should be distinguished from predictive imaging biomarkers and imaging markers of response. A range of tumour characteristics of potential prognostic value can be measured using a variety imaging modalities. However, none has currently been adopted into routine clinical practice. This article considers key examples of emerging prognostic imaging biomarkers and proposes an evaluation framework that aims to demonstrate clinical efficacy and so support their introduction into the clinical arena. With appropriate validation within an established evaluation framework, prognostic imaging biomarkers have the potential to contribute to individualized cancer care, in some cases reducing the financial burden of expensive cancer treatments by facilitating their more rational use. PMID- 24060809 TI - Crystal structure of apo and copper bound HP0894 toxin from Helicobacter pylori 26695 and insight into mRNase activity. AB - The toxin-antitoxin (TA) systems widely spread among bacteria and archaea are important for antibiotic resistance and microorganism virulence. The bacterial kingdom uses TA systems to adjust the global level of gene expression and translation through RNA degradation. In Helicobacter pylori, only two TA systems are known thus far. Our previous studies showed that HP0894-HP0895 acts as a TA system and that HP0894 exhibits intrinsic RNase activity. However, the precise molecular basis for interaction with substrate or antitoxin and the mechanism of mRNA cleavage remain unclear. Therefore, in an attempt to shed some light on the mechanism behind the TA system of HP0894-HP0895, here we present the crystal structures of apo- and metal-bound H. pylori 0894 at 1.28A and 1.89A, respectively. Through the combined approach of structural analysis and structural homology search, the amino acids involved in mRNase active site were monitored and the reorientations of different residues were discussed in detail. In the mRNase active site of HP0894 toxin, His84 acts as a catalytic residue and reorients itself to exhibit this type of activity, acting as a general acid in an acid-base catalysis reaction, while His47 and His60 stabilize the transition state. Lys52, Glu58, Asp64 and Arg80 have phosphate binding and specific sequence recognition. Glu58 also acts as a general base, and substrate reorientation is caused by Phe88. Based on experimental findings, a model for antitoxin binding could be suggested. PMID- 24060810 TI - Catch and measure-mass spectrometry-based immunoassays in biomarker research. AB - Mass spectrometry-based (MS) methods are effective tools for discovering protein biomarker candidates that can differentiate between physiological and pathophysiological states. Promising candidates are validated in studies comprising large patient cohorts. Here, targeted protein analytics are used to increase sample throughput. Methods involving antibodies, such as sandwich immunoassays or Western blots, are commonly applied at this stage. Highly specific and sensitive mass spectrometry-based immunoassays that have been established in recent years offer a suitable alternative to sandwich immunoassays for quantifying proteins. Mass Spectrometric ImmunoAssays (MSIA) and Stable Isotope Standards and Capture by Anti-Peptide Antibodies (SISCAPA/iMALDI) are two prominent types of MS-based immunoassays in which the capture is done either at the protein or the peptide level. We present an overview of these emerging types of immunoassays and discuss their suitability for the discovery and validation of protein biomarkers. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. PMID- 24060811 TI - Activation of human biliverdin-IXalpha reductase by urea: generation of kinetically distinct forms during the unfolding pathway. AB - Activation of enzymes by low concentrations of denaturants has been reported for a limited number of enzymes including lipocalin-type prostaglandin D synthase (L PGDS) and adenylate kinase. During unfolding studies on human biliverdin-IXalpha reductase it was discovered that the enzyme is activated at low concentrations of urea. Under standard assay conditions the native enzyme displays pronounced substrate inhibition with biliverdin as variable substrate; however in the presence of 3M urea, the substrate inhibition is abolished and the enzyme exhibits Michaelian kinetics. When the initial rate kinetics with NADPH as variable substrate are conducted in 3M urea, the Vmax is increased 11-fold to 1.8MUmol/min/mg and the apparent Km for biliverdin increases from 1 to 3MUM. We report the existence of two kinetically distinct folded intermediates between the native and unfolded forms. When the period of incubation with urea was varied prior to measuring enzyme activity, the apparent Vmax was shown to decay to half that seen at zero time with a half life of 5.8minutes, while the apparent Km for NADPH remains constant at approximately 5MUM. With NADH as cofactor the half life of the activated (A) form was 2.9minutes, and this form decays in 3M urea to a less active (LA) form. The apparent Km for NADH increases from 0.33mM to 2mM for the A and LA forms. These kinetically distinct species are reminiscent of the activity-enhanced and inactive forms of L-PGDS observed in the presence of urea and guanidine hydrochloride. PMID- 24060812 TI - The effectiveness of evidence-based treatments for personality disorders when comparing treatment-as-usual and bona fide treatments. AB - OBJECTIVE: The purpose of Study 1 was to examine the relative efficacy of evidence-based treatments (EBTs) when compared to treatment-as-usual (TAU) for adults diagnosed with a personality disorder (PD). The purpose of Study 2 was to investigate the strength of the differences between bona fide psychotherapeutic treatments for PDs. METHOD: Two separate computerized searches were conducted of: (a) studies that directly compared an EBT with a TAU for treatment of PDs, or (b) studies that compared at least two bona fide treatments for PDs. Meta-analytic methods were used to estimate the effectiveness of the treatments when compared to one another and to model how various confounding variables impacted the results of this comparative research. RESULTS: A total of 30 studies (Study 1; N=1662) were included in the meta-analysis comparing EBTs to TAU. A total of 12 studies (Study 2; N=723) were included in the meta-analysis comparing bona fide treatments. Study 1 found that EBTs were superior to TAU, although the TAU conditions were not comparable in many respects (e.g., not psychotherapy, lacking supervision, lacking training, etc.) to the EBT and there was significant heterogeneity in the effects. Study 2 found that some bona fide treatments were superior to others. PMID- 24060813 TI - Significantly reduced thermal diffusivity of free-standing two-layer graphene in graphene foam. AB - We report on a thermal diffusivity study of suspended graphene foam (GF) using the transient electro-thermal technique. Our Raman study confirms the GF is composed of two-layer graphene. By measuring GF of different lengths, we are able to exclude the radiation effect. Using Schuetz's model, the intrinsic thermal diffusivity of the free-standing two-layer graphene is determined with a high accuracy without using knowledge of the porosity of the GF. The intrinsic thermal diffusivity of the two-layer graphene is determined at 1.16-2.22 * 10(-4) m(2) s( 1). The corresponding intrinsic thermal conductivity is 182-349 W m(-1) K(-1), about one order of magnitude lower than those reported for single-layer graphene. Extensive surface impurity defects, wrinkles and rough edges are observed under a scanning electron microscope for the studied GF. These structural defects induce substantial phonon scattering and explain the observed significant thermal conductivity reduction. Our thermal diffusivity characterization of GF provides an advanced way to look into the thermal transport capacity of free-standing graphene with high accuracy and ease of experimental implementation. PMID- 24060814 TI - The use of contrast-enhanced ultrasound in blunt abdominal trauma: advantages and limitations. AB - Computed tomography (CT) is the imaging method of choice in the assessment of multiple trauma patients. However, in patients who suffered from low-energy abdominal trauma, the use of CT is controversial, since the probability of injury is low and therefore most of the studies are normal. Thus, conventional US imaging has increasingly been employed as the initial imaging modality in the work-up of minor traumatic emergency condition. More recently, the introduction of a new contrast-enhanced ultrasound (CEUS) technique, using second-generation ultrasound contrast agents, has led to a notable increase in the diagnostic accuracy of US in many organs. Therefore, in trauma patients, following assessment with conventional US imaging, a CEUS exam can be performed, to provide a more reliable assessment of solid organ injuries. CEUS has the potential to detect active bleeding from a variety of traumatic origins. Similar to CT, active extravasation is considered when there is evidence of contrast agent collection with echogenicity similar to that of an adjacent vessel. On the other hand, at least some drawbacks have to be addressed, including operator competence and reduced panoramic view. Moreover, CEUS, like conventional US imaging, cannot depict some lesions, such as diaphragmatic ruptures, bowel, and mesenteric traumatic injuries. This technique represents a non-invasive and repeatable method that can be performed at patient's bedside and is therefore extremely helpful for the follow-up of solid organs traumas managed conservatively, especially in pediatric patients and women of fertile age. Moreover, it may reduce the number of CT scans and expedite patient discharge. PMID- 24060815 TI - Ultrasound assessment of the elbow joint in infants and toddlers and its clinical significance. AB - BACKGROUND: Ultrasound can be used for the diagnosis of elbow injuries in infants and toddlers. However, ultrasound is highly operator-dependent and accurate ultrasound examinations require a complete understanding of the complex anatomy of the elbow joint. PURPOSE: To report the normal ultrasound anatomy of the elbow, particularly of the humeroulnar joint, in infants and toddlers. MATERIAL AND METHOD: Thirty subjects aged <3 years with no history of elbow injuries underwent ultrasound examinations of the elbow joint from six directions: (i) lateral to the humeroradial joint; (ii) anterior to the humeroradial joint; (iii) posterior to the humeroradial joint; (iv) medial to the humeroulnar joint; (v) anterior to the humeroulnar joint; and (vi) posterior to the humeroulnar joint. RESULTS: The appearance of the humeroradial joint observed from three directions was similar and resembled a pair of double fists ("double-breast sign"). The appearance of the humeroulnar joint observed from three directions was different, which is related to the irregular morphology of the medial sides of the humerus and ulna. Anteroposteriorly, the coronoid and olecranon epiphyses and coronoid fossa appear anteriorly and the olecranon and trochlear epiphyses and olecranon fossa appear posteriorly, resembling a "check-mark sign". The medial epicondyle, cubital tunnel and distal humerus appear together ("double-hump sign"). The "anterior hump" is the medial epicondyle and is always higher than the "posterior hump", which is the bony protrusion on the articular surface of the distal humerus. The ultrasound signal of cortical bone in the metaphysis of the distal humerus is continuous with that of the epiphysis of the medial epicondyle. CONCLUSION: Ultrasound is useful for the diagnosis of elbow injuries in infants and toddlers. PMID- 24060816 TI - Emergency room decision-making for urgent cranial computed tomography: selection criteria for subsets of non-trauma patients. AB - BACKGROUND: Computed tomography (CT) of the brain is used extensively in the urgent work-up of patients with a suspicion of intracranial pathology, but is often normal. Previously proposed selection criteria aim at limiting the ordering of urgent cranial CT in the non-trauma population, while maintaining high sensitivity for diagnoses demanding immediate attention. PURPOSE: To retrospectively evaluate these selection criteria in a general non-trauma population from a Swedish tertiary hospital, as well as in a nested subgroup that lacks guidelines at present, namely where the chief complaint was not headache, symptoms clearly indicating stroke, seizures, or vertigo. MATERIAL AND METHODS: Medical records of 346 patients (114 in the nested group) who had undergone urgent cranial CT were reviewed. Selection criteria as proposed by Rothrock (patient age >=60 years, presence of new onset focal neurologic deficit, headache with vomiting, or altered mental status) were used. Acute cerebral infarction, intracranial hemorrhage, malignancy, infection, cerebral edema, or hydrocephalus were considered significant findings. RESULTS: The prevalence of significant findings was 10.1%. The Rothrock criteria had a sensitivity of 97.1% (identifying 34 of 35 significant findings) among all 346 patients and 100% (10/10) among the 114 patients in the subgroup and resulted in a potential scan reduction rate of 22.8% and 11.4%, respectively. In the patient with significant pathology, that was not selected for CT, focal neurological symptoms were not described as newly onset. CONCLUSION: Although 100% sensitivity was not achieved, our results may contribute to the evidence that in the absence of focal neurologic deficit, headache with vomiting or altered mental status in patients aged <60 years cranial tomography can be refrained from, in the general population as well as in the subgroup defined above. Further research might validate patient history as a parameter. PMID- 24060817 TI - Comparison of patient comfort between iodixanol and iopamidol in contrast enhanced computed tomography of the abdomen and pelvis: a randomized trial. AB - BACKGROUND: Previous clinical studies have shown that iso-osmolar iodixanol (Visipaque(r)) causes less patient discomfort than low-osmolar contrast media (LOCM) when administered via intra-arterial injection. No data are available comparing these agents for patient discomfort when administered intravenously (i.v.) using power injectors. PURPOSE: To compare the frequency and intensity of patient discomfort between iodixanol and iopamidol (Isovue(r)) administered i.v. using a power injector in contrast-enhanced computed tomography (CECT) of the abdomen and pelvis. MATERIAL AND METHODS: This was a prospective, randomized, double-blind, multicenter study of iodixanol 320 mg I/mL or iopamidol 370 mg I/mL on patient discomfort. The presence of discomfort (heat, pain, coldness) and intensity was verbally rated by patients on a 0-10 scale and converted into four categories (0, none; 1-3, mild; 4-7, moderate; 8-10, severe). Image quality was evaluated. RESULTS: Of the 299 evaluable patients enrolled at nine centers, 151 received iodixanol and 148 received iopamidol. The average age was 58 years. Iodixanol patients experienced significantly less moderate/severe discomfort (35.1% vs. 67.3%; P < 0.0001) or heat (29.8% vs. 63.9%; P < 0.0001), and severe discomfort (2.6% vs. 16.3%; P = 0.0004) or heat (2.6% vs. 15%; P = 0.0008), but three times more no discomfort (21.2% vs. 7.5%; P = 0.0008) than iopamidol patients. Excellent image quality was in 95.4% of iodixanol vs. 89.9% of iopamidol patients (P = 0.0508). Overall, adverse event (AE) rate excluding patient discomfort was 19.9% in the iodixanol group and 14.9% in the iopamidol group (P = 0.2870), but contrast-related AEs were comparable: 11.3% vs. 10.1% (P = 0.8522). Delayed skin reactions occurred in 2.6% of patients in the iodixanol group and in no patient in the iopamidol group (P = 0.1226). CONCLUSION: Patients receiving iodixanol had significantly lower moderate-to-severe or severe discomfort than patients receiving iopamidol, with heat being the major contributor. Iodixanol use trended towards better image quality but the difference was not statistically significant. No significant differences in incidences of overall or contrast-related AEs or delayed skin reactions were seen between the two groups. These data support that CM osmolality may be a key determinant of patient discomfort. PMID- 24060818 TI - DJ-1 ameliorates ischemic cell death in vitro possibly via mitochondrial pathway. AB - DJ-1 is an important redox-reactive neuroprotective protein implicated in regulation of oxidative stress after ischemia. However the molecular mechanism, especially the mitochondrial function, by which DJ-1 protects neuronal cells in stroke remains to be elucidated. The aim of this study was to reveal whether DJ-1 translocates into the mitochondria in exerting neuroprotection against an in vitro model of stroke. Human neural progenitor cells (hNPCs) were initially exposed to oxygen-glucose deprivation and reperfusion injury, and thereafter, DJ 1 translocation was measured by immunocytochemistry and its secretion by hNPCs was detected by enzyme-linked immunosorbant assay (ELISA). Exposure of hNPCs to experimental stroke injury resulted in DJ-1 translocation into the mitochondria. Moreover, significant levels of DJ-1 protein were secreted by the injured hNPCs. Our findings revealed that DJ-1 principally participates in the early phase of stroke involving the mitochondrial pathway. DJ-1 was detected immediately after stroke and efficiently translocated into the mitochondria offering a new venue for developing treatment strategies against ischemic stroke. PMID- 24060819 TI - A proposal for integrated efficacy-to-effectiveness (E2E) clinical trials. AB - We propose an "efficacy-to-effectiveness" (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial. Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses. An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and foster incorporation of effectiveness information into regulatory processes. PMID- 24060821 TI - Optical nonlinearities of hybrid pairs of organic molecules. AB - The excited electronic states of nearby molecules are in general coupled via Coulomb interaction even in the absence of wavefunction overlap. When two different organic molecules having a nearly resonant excited state are close enough, the dipole-dipole interaction can significantly affect their optical response. Even though they do not chemically interact, concerning their coupling to light, such molecules do not act independently, but rather as a 'virtual heterodimer' the response of which stems from, but is different from that of each molecule alone. We discuss here a simple and general model to estimate their resonant nonlinear susceptibilities. PMID- 24060822 TI - Liquid diets reduce cell proliferation but not neurogenesis in the adult rat hippocampus. AB - Neurogenesis continues to occur in restricted regions of the brain throughout adulthood and can be modulated by dietary factors. Liquid or "soft" diets are commonly used for the administration of drugs in experimental models of disease, making it critical to determine whether dietary composition itself can affect neurogenesis. In this study Sprague-Dawley rats were fed either a liquid or a solid diet of identical composition from weaning until young adulthood. No differences in neuronal differentiation and survival of newly born cells were observed between rats that were fed a liquid diet and those that received a solid diet. However, a significant reduction in hippocampal cell proliferation was observed in the liquid diet-fed group, as assessed by the expression of two endogenous proliferation markers, Ki67 and proliferating cell nuclear antigen (PCNA). The method of feeding did not alter the basal function of the hypothalamic-pituitary-adrenal (HPA) axis in these animals, as no changes in circulating levels of corticosterone (CORT) were detected between liquid and solid diet-fed groups. There was also a significant reduction in cellular proliferation in the hypothalamus of liquid diet-fed rats, a brain region known to be involved in feeding-related behaviors. These findings indicate that liquid diets themselves can directly impact rates of cellular proliferation, but this does not seem to impact levels of overall neurogenesis in the adult brain. PMID- 24060823 TI - Lesion of the commissural nucleus of the solitary tract/A2 noradrenergic neurons facilitates the activation of angiotensinergic mechanisms in response to hemorrhage. AB - In the present study, we investigated the effects of lesions of A2 neurons of the commissural nucleus of the solitary tract (cNTS) alone or combined with the blockade of angiotensinergic mechanisms on the recovery of arterial pressure (AP) to hemorrhage in conscious rats. Male Holtzman rats (280-320g) received an injection of anti-dopamine-beta-hydroxylase-saporin (12.6ng/60nl; cNTS/A2-lesion, n=28) or immunoglobulin G (IgG)-saporin (12.6ng/60nl, sham, n=24) into the cNTS and 15-21days later had a stainless steel cannula implanted in the lateral ventricle. After 6days, rats were submitted to hemorrhage (four blood withdrawals, 2ml/300g of body weight every 10min). Both cNTS/A2-lesioned and sham rats had similar hypotension to hemorrhage (-62+/-7 and -73+/-7mmHg, respectively), however cNTS/A2-lesioned rats rapidly recovered from hypotension ( 5+/-3mmHg at 30min), whereas sham rats did not completely recover until the end of the recording (-20+/-3mmHg at 60min). Losartan (angiotensin type 1 receptor antagonist) injected intracerebroventricularly (100MUg/1MUl) or intravenously (i.v.) (10mg/kg of body weight) impaired the recovery of AP in cNTS/A2-lesioned rats (-24+/-6 and -35+/-7mmHg at 30min, respectively). In sham rats, only i.v. losartan affected the recovery of AP (-39+/-6mmHg at 60min). The results suggest that lesion of the A2 neurons in the cNTS facilitates the activation of the angiotensinergic pressor mechanisms in response to hemorrhage. PMID- 24060824 TI - Dose-dependent effects of D-methionine for rescuing noise-induced permanent threshold shift in guinea-pigs. AB - The purpose of this study was to examine the dose-response effectiveness of d methionine (d-met) in rescuing a noise-induced permanent threshold shift (PTS) and cochlear biochemistry following noise exposure. One hour after being exposed to continuous broadband white noise at 105dB sound pressure level (SPL) for 6h, guinea-pigs were treated five times at 12-h intervals with 200, 400, or 600mg/kg d-met or sterile 0.9% saline (each group, N=6) by intraperitoneal injection. Six guinea-pigs with normal hearing that were not exposed to noise served as control animals. Although administration of d-met 200mg/kg did not significantly reduce the mean PTS, treatment with d-met 600mg/kg achieved a complete rescue response. The level of rescue from noise-induced PTS following treatment with 200, 400, or 600mg/kg d-met was dose dependent. The attenuation of the noise-induced decreases in the activities of the Na(+), K(+)-ATPase and Ca(2+)-ATPase following treatment with 200, 400, or 600mg/kg d-met was also dose dependent. Likewise, d-met-dose dependent decreases in mean lipid peroxidation and nitric oxide levels were observed in the d-met treated groups. Significant attenuation of increased oxidative stress and decreased ATPase activities was concurrent with the d-met mediated improvements in noise-induced auditory dysfunction. PMID- 24060825 TI - Sexual well-being of cervical cancer survivors under 50 years old and the factors affecting their libido. AB - OBJECTIVES: This paper aims to study the relationship between the sexual well being and quality of life (QOL) of cervical cancer patients and analyze the factors influencing their libidos. MATERIALS AND METHODS: The subjects in this study were Chinese cervical cancer survivors under 50 years old. The information on their disease and treatments was obtained through their medical records. The subjects were surveyed in their homes regarding their sexual well-being, age, educational level, and QOL. MAIN RESULTS: 59% of the subjects did not want to have a sex life, and 65.09% were unsatisfied with their sex life. Among the women who did not want to have a sex life, the following reasons were given: 52.38% due to the side effects of treatments, 23.81% feared that sex would damage their surgical sites, 9.52% lacked libido, 9.52% feared that sex would make their conditions worse, and 4.76% feared that having sex would transmit the disease to their spouses. After adjusting the age and survival time, the women's sexual well being was able to explain 61.80% of the variations in QOL. In addition, libido and sexual satisfaction affected the women's social/family well-being (both p < 0.01). CONCLUSIONS: The sexual well-being of Chinese women with cervical cancer is poor. The main reasons for not wanting to have a sex life are treatment induced vaginal conditions and lack of disease- and treatment-related knowledge. Improvement of women's sexual well-being plays an important role in the improvement of their QOL. Healthcare nurses should be concerned about women's needs for sex-related knowledge after cervical cancer treatment and provide them with psychological help. PMID- 24060826 TI - Feeding regimens and necrotizing enterocolitis. Concerning the letter by S. Meyer and M. Butte: Feeding regimens and necrotising enterocolitis [Neonatology 2013;103:233-234]. PMID- 24060827 TI - Biotransformation of glycerol to 3-hydroxypropionaldehyde: improved production by in situ complexation with bisulfite in a fed-batch mode and separation on anion exchanger. AB - 3-Hydroxypropionaldehyde (3HPA) is an important C3 chemical that can be produced from renewable glycerol by resting whole cells of Lactobacillus reuteri. However the process efficiency is limited due to substrate inhibition, product-mediated loss of enzyme activity and cell viability, and also formation of by-products. Complex formation of 3HPA with sodium bisulfite and subsequent binding to Amberlite IRA-400 was investigated as a means of in situ product recovery and for overcoming inhibition. The adsorption capacity and -isotherm of the resin were evaluated using the Langmuir model. The resin exhibited maximum capacity of 2.92 mmol complex/g when equilibrated with 45 mL solution containing an equilibrium mixture of 2.74 mmol 3HPA-bisulfite complex and 2.01 mmol free 3HPA. The dynamic binding capacity based on the breakthrough curve of 3HPA and its complex on passing a solution with 2.49 mmol complex and 1.65 mmol free 3HPA was 2.01 mmol/g resin. The bound 3HPA was desorbed from the resin using 0.20 M NaCl with a high purity as a mixture of complexed- and free 3HPA at a ratio of 0.77 mol/mol. Fed batch biotransformation of glycerol (818.85 mmol) with in situ 3HPA complexation and separation on the bisulfite-functionalized resin resulted in an improved process with consumption of 481.36 mmol glycerol yielding 325.54 mmol 3HPA at a rate of 17.13 mmol/h and a yield of 68 mol%. Also, the cell activity was maintained for at least 28 h. PMID- 24060828 TI - Genome-wide transcriptome analysis of Clavibacter michiganensis subsp. michiganensis grown in xylem mimicking medium. AB - The interaction between Clavibacter michiganensis subsp. michiganensis with its host, the tomato plant (Solanum lycopersicum), is poorly understood and only few virulence factors are known. While studying of the bacteria in planta is time consuming and difficult, the analysis in vitro would facilitate research. Therefore, a xylem mimicking medium (XMM) for C. michiganensis subsp. michiganensis was established in this study based on an apoplast medium for Xanthomonas campestris pv. vesicatoria. In contrast to the apoplast medium, XMM contains no sugars, but amino acids which serve as nitrogen and carbon source. As a result, growth in XMM induced transcriptional changes of genes encoding putative sugar, amino acid and iron uptake systems. In summary, mRNA levels of about 8% of all C. michiganensis subsp. michiganensis genes were changed when XMM grown bacteria were compared to M9 minimal medium-grown cells. Almost no transcriptional changes of genes encoding hydrolytic enzymes were detected, leading to the idea that XMM reflects the situation in the beginning of infection and therefore allows the characterization of virulence factors in this early stage of infection. The addition of the plant wound substance acetosyringone to the XMM medium led to a change in transcript amount, including genes coding for proteins involved in protein transport, iron uptake and regulation processes. PMID- 24060820 TI - CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. AB - The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy. PMID- 24060829 TI - Sustainability of industrial yeast serial repitching practice studied by gene expression and correlation analysis. AB - Bottom-fermenting Saccharomyces pastorianus strains driving brewing fermentation processes are usually reused several times. It is still unclear, whether the number of successions may have an impact on cell physiology prompting consequences for brewing quality. In this study, fermentation performance of up to twenty consecutive runs in a brewery was investigated. For each run mRNA expression levels of cellular marker molecules, which are known to correlate with metabolism, hexose transport, aging processes, stress response mechanisms and flocculation capability was estimated to obtain information on changes in cell physiology over the successive runs. Low-density microarrays were used for this purpose and the resulting gene expression profiles were finally correlated with changes in the abiotic micro-environments. A surprising stability of the marker molecule expression profiles within each specific serial repitching was stated. Loss of flocculation or an advanced aging could not be detected during serial repitching in the analyzed brewery. However, certain runs of the serial repitchings showed high variation in stress response which was found to be caused by perturbations of the abiotic conditions. Regardless, the study showed that S. pastorianus can be used repeatedly in serial repitching processes without loss of prominent physiological characteristics. PMID- 24060831 TI - Cavity Optical Pulse Extraction: ultra-short pulse generation as seeded Hawking radiation. AB - We show that light trapped in an optical cavity can be extracted from that cavity in an ultrashort burst by means of a trigger pulse. We find a simple analytic description of this process and show that while the extracted pulse inherits its pulse length from that of the trigger pulse, its wavelength can be completely different. Cavity Optical Pulse Extraction is thus well suited for the development of ultrashort laser sources in new wavelength ranges. We discuss similarities between this process and the generation of Hawking radiation at the optical analogue of an event horizon with extremely high Hawking temperature. Our analytic predictions are confirmed by thorough numerical simulations. PMID- 24060830 TI - Development of an intra-molecularly shuffled efficient chimeric plant promoter from plant infecting Mirabilis mosaic virus promoter sequence. AB - We developed an efficient chimeric promoter, MUASMSCP, with enhanced activity and salicylic acid (SA)/abscisic acid (ABA) inducibility, incorporating the upstream activation sequence (UAS) of Mirabilis mosaic virus full-length transcript (MUAS, -297 to -38) to the 5' end of Mirabilis mosaic virus sub-genomic transcript (MSCP, -306 to -125) promoter-fragment containing the TATA element. We compared the transient activity of the MUASMSCP promoter in tobacco/Arabidopsis protoplasts and in whole plant (Petunia hybrida) with the same that obtained from CaMV35S and MUAS35SCP promoters individually. The MUASMSCP promoter showed 1.1 and 1.5 times stronger GUS-activities over that obtained from MUAS35SCP and CaMV35S promoters respectively, in tobacco (Xanthi Brad) protoplasts. In transgenic tobacco (Nicotiana tabacum, var. Samsun NN), the MUASMSCP promoter showed 1.1 and 2.2 times stronger activities than MUAS35SCP and CaMV35S(2) promoters respectively. We observed a fair correlation between MUASMSCP-, MUAS35SCP- and CaMV35S(2)-driven GUS activities with the corresponding uidA-mRNA level in transgenic plants. X-gluc staining of transgenic germinating seed sections and whole seedlings also support above findings. Protein-extracts made from tobacco protoplasts expressing GFP and human-IL-24 genes driven individually by the MUASMSCP promoter showed enhanced expression of the reporters compared to that obtained from the CaMV35S promoter. Furthermore, MUASMSCP-driven protoplast derived human IL-24 showed enhanced cell inhibitory activity in DU-145 prostate cancer cells compared to that obtained from the CaMV35S promoter. We propose chimeric MUASMSCP promoter developed in the study could be useful for strong constitutive expression of transgenes in both plant/animal cells and it may become an efficient substitute for CaMV35S/CaMV35S(2) promoter. PMID- 24060833 TI - Mimics of pancreatic ductal adenocarcinoma. AB - Several uncommon primary pancreatic tumors, inflammatory conditions, metastasis to the pancreas and peripancreatic masses can mimic the appearance of pancreatic ductal adenocarcinoma (PDA). Differentiation between these lesions and PDA can be challenging, due to the overlap in imaging features; however, familiarity with their typical imaging features and clinical presentation may be helpful in their differentiation, as in some cases, invasive diagnostic tests or unnecessary surgery can be avoided. The different pathologies that can mimic PDA include inflammatory conditions such as the various forms of pancreatitis (chronic-focal mass-forming, autoimmune and groove pancreatitis), pancreatic neuroendocrine tumors, solid pseudopapillary tumors, metastasis (solid non-lymphomatous and hematologic), congenital variants (annular pancreas), as well as peripancreatic lesions (accessory spleen, adrenal masses, duodenal masses, lymph nodes and vascular lesions), and certain rare pancreatic tumors (e.g., acinar cell tumors, solid serous tumors, hamartoma and solitary fibrous tumors). The clinical presentation and imaging features of the most commonly encountered mimics of PDA are discussed in this presentation with representative illustrations. PMID- 24060832 TI - Neural correlates of alcohol-approach bias in alcohol addiction: the spirit is willing but the flesh is weak for spirits. AB - Behavioral studies have shown an alcohol-approach bias in alcohol-dependent patients: the automatic tendency to faster approach than avoid alcohol compared with neutral cues, which has been associated with craving and relapse. Although this is a well-studied psychological phenomenon, little is known about the brain processes underlying automatic action tendencies in addiction. We examined 20 alcohol-dependent patients and 17 healthy controls with functional magnetic resonance imaging (fMRI), while performing an implicit approach-avoidance task. Participants pushed and pulled pictorial cues of alcohol and soft-drink beverages, according to a content-irrelevant feature of the cue (landscape/portrait). The critical fMRI contrast regarding the alcohol-approach bias was defined as (approach alcohol>avoid alcohol)>(approach soft drink>avoid soft drink). This was reversed for the avoid-alcohol contrast: (avoid alcohol>approach alcohol)>(avoid soft drink>approach soft drink). In comparison with healthy controls, alcohol-dependent patients had stronger behavioral approach tendencies for alcohol cues than for soft-drink cues. In the approach, alcohol fMRI contrast patients showed larger blood-oxygen-level-dependent responses in the nucleus accumbens and medial prefrontal cortex, regions involved in reward and motivational processing. In alcohol-dependent patients, alcohol craving scores were positively correlated with activity in the amygdala for the approach-alcohol contrast. The dorsolateral prefrontal cortex was not activated in the avoid-alcohol contrast in patients vs controls. Our data suggest that brain regions that have a key role in reward and motivation are associated with the automatic alcohol-approach bias in alcohol-dependent patients. PMID- 24060835 TI - The prediction of lean body mass and fat mass from arm anthropometry at diagnosis in children with cancer. AB - Maintenance of adequate nutrition is important in the care of children with cancer. In clinical practice, determination of nutritional status can be accomplished with measurement of body composition by dual-energy x-ray absorptiometry (DXA). However, DXA is seldom available in low-income countries where most children with cancer live. This study sought to provide predictive equations for lean body mass and fat mass, measured by DXA, on the basis of simple arm anthropometry providing measures of mid-upper arm circumference and triceps skin-fold thickness in a population (N=99) of children diagnosed with cancer. Such equations were derived successfully with the inclusion of absolute body weight, the body weight Z-score, and the predicted whole-body bone mineral content on the basis of age and sex. Attempted validation in a small sample (N=7) of children who completed therapy for acute lymphoblastic leukemia revealed disparities reflective of the prevalence of obesity in such survivors. Further validation must be undertaken in large samples of children with a variety of malignant diseases to assess the robustness of the equations predictive of body composition. PMID- 24060834 TI - Emotional distress in 652 Dutch very long-term survivors of childhood cancer, using the hospital anxiety and depression scale (HADS). AB - BACKGROUND: After a more successful treatment of pediatric cancer, the number of childhood cancer survivors is progressively increasing. Consequently, awareness of psychological late sequelae is important. PROCEDURE: The Hospital Anxiety and Depression Scale (HADS) was used as a screening tool for emotional distress in a single center cohort of 652 childhood cancer survivors (median age 23 y [range, 15 to 46 y], median follow-up time 15 y [range, 5 to 42 y]). Results were compared with a control group of 440 Dutch subjects. A higher HADS score linearly reflect a higher level of emotional distress, and a score >=15 is indicative of clinically significant emotional distress. RESULTS: Mean HADS score of the childhood cancer survivors was not different from the control group (P=0.38). Survivors exposed to global central nervous system (CNS) irradiation had a significantly higher HADS score than the control group (8.3+/-6.6; P=0.05) as well as other survivors (P=0.01). Forty-three survivors (7%) had a HADS score >=15. Survivors with a HADS score >=15 were variously spread over the diagnostic related and treatment-related subgroups. Linear regression analysis showed that high educational achievement (beta=-1.28; P<0.01) and age at the time of the study (beta=0.08; P=0.03) were both significantly associated with the HADS score. CONCLUSIONS: Emotional distress does not occur more often in childhood cancer survivors than in the normal population. No disease-related or treatment-related variable was independently associated with emotional distress. PMID- 24060836 TI - The use of complementary and alternative medicine by irish pediatric cancer patients. AB - INTRODUCTION: The use of complementary and alternative medicine (CAM) in the Irish pediatric cancer setting has not previously been established. METHODS: To investigate the prevalence and predictors of CAM use in this group of patients, an anonymous cross-sectional survey was offered to all carers of patients either on or off treatment for malignancy at a single pediatric cancer center over an 8 week period. RESULTS: Of a total of 220 questionnaires distributed, 98 (43%) were returned. Six were excluded because of inadequate data. A total of 58% of children were male and the mean age was 9 years. The most common cancer diagnosis was leukemia (45%). Fifty-two respondents (57%) said their child had used or was using CAM, and 55% of whom had started since their cancer diagnosis. The most common types of CAM used were vitamins and minerals (18%), reflexology (11%), dietary supplements (11%), faith healers (9%), and energy therapies (9%). The most common reason for CAM use was to improve physical well-being (31%). A total of 65% of CAM users had not told their doctor that they were doing so. Of the 52 CAM users, 30 (58%) were using oral CAM medication. A total of 86% of CAM users reported benefit from the treatment, and no respondent reported side effects.There was no significant relationship between sex, tumor type, age, income, previous treatment, and CAM use. Where parents had a higher level of education, children were more likely to use CAM (P=0.035.) There was a statistically significant relationship between respondents rating of conventional therapy and CAM use (P=0.007). Interestingly, parents who were satisfied with conventional therapy were more likely to use CAM. CONCLUSION: The high prevalence of CAM use demonstrated in this study and particularly the high use of CAM medication therapies underlines the importance of physicians asking routinely about CAM use in this population. PMID- 24060837 TI - In response. PMID- 24060838 TI - A case of mannitol hypersensitivity. AB - Mannitol is used for increased intracranial pressure and prevention of nephrotoxicity. We present a case report of a patient who experienced an anaphylactic response to mannitol and review the literature. PMID- 24060841 TI - Local crystallography analysis for atomically resolved scanning tunneling microscopy images. AB - Scanning probe microscopy has emerged as a powerful and flexible tool for atomically resolved imaging of surface structures. However, due to the amount of information extracted, in many cases the interpretation of such data is limited to being qualitative and semi-quantitative in nature. At the same time, much can be learned from local atom parameters, such as distances and angles, that can be analyzed and interpreted as variations of local chemical bonding, or order parameter fields. Here, we demonstrate an iterative algorithm for indexing and determining atomic positions that allows the analysis of inhomogeneous surfaces. This approach is further illustrated by local crystallographic analysis of several real surfaces, including highly ordered pyrolytic graphite and an Fe based superconductor FeTe0.55Se0.45. This study provides a new pathway to extract and quantify local properties for scanning probe microscopy images. PMID- 24060840 TI - Clinical therapy using iPSCs: hopes and challenges. AB - Induced pluripotent stem cells (iPSCs) are generated by ectopic expression of defined transcription factors in somatic cells. They can undergo unlimited self renewal and maintain the embryonic stem cells (ESCs)-like ability to differentiate into all three germ layers. iPSCs can potentially provide unlimited autologous cells for therapy and therefore hold great promise for regenerative medicine. Here we reviewed the recent advances in iPSC studies on disease modeling and clinical treatment as well as challenges correlated with clinical development of iPSCs, like tumorigenicity, immunogenicity and genomic instability. PMID- 24060842 TI - Prenatal developmental toxicity study of n-heneicosane in Wistar rats. AB - n-Heneicosane (C21) is one of the vital pheromone for attracting mosquitoes of Aedes spp to lay their eggs in areas of stagnant fresh water, for their subsequent destruction, thus controlling spread of dangerous disease transmission by the vectors. As part of a safety evaluation, we have investigated embryo toxic and teratogenic potential, if any, of C21 following OECD Test Guideline 414. C21 was offered at a dose of 1 g/kg body weight mixed in the standard rat pellet diet to treated rats, whereas the control group received only standard rat pellet diet. There were no mortalities and animals did not show any clinical signs of toxicity. A similar pattern of body weight gain, feed and water intake was observed in treated and control groups. Analysis of maternal toxic response, maternal end points of development of the foetus and developmental end points for litters did not show any gross structural abnormality in dams or foetus of treated group compared to that of the control group. Thus, it was concluded that C21 at a dose of 1 g/kg was neither embryo toxic nor teratogenic in Wister rats. Furthermore, the no observed adverse effect level for teratogenicity for C21 in rats may be considered as 1 g/kg body weight under the present experimental conditions. PMID- 24060839 TI - Cellular reprogramming of human peripheral blood cells. AB - Breakthroughs in cell fate conversion have made it possible to generate large quantities of patient-specific cells for regenerative medicine. Due to multiple advantages of peripheral blood cells over fibroblasts from skin biopsy, the use of blood mononuclear cells (MNCs) instead of skin fibroblasts will expedite reprogramming research and broaden the application of reprogramming technology. This review discusses current progress and challenges of generating induced pluripotent stem cells (iPSCs) from peripheral blood MNCs and of in vitro and in vivo conversion of blood cells into cells of therapeutic value, such as mesenchymal stem cells, neural cells and hepatocytes. An optimized design of lentiviral vectors is necessary to achieve high reprogramming efficiency of peripheral blood cells. More recently, non-integrating vectors such as Sendai virus and episomal vectors have been successfully employed in generating integration-free iPSCs and somatic stem cells. PMID- 24060843 TI - Efficient gate-tunable light-emitting device made of defective boron nitride nanotubes: from ultraviolet to the visible. AB - Boron nitride is a promising material for nanotechnology applications due to its two-dimensional graphene-like, insulating, and highly-resistant structure. Recently it has received a lot of attention as a substrate to grow and isolate graphene as well as for its intrinsic UV lasing response. Similar to carbon, one dimensional boron nitride nanotubes (BNNTs) have been theoretically predicted and later synthesised. Here we use first principles simulations to unambiguously demonstrate that i) BN nanotubes inherit the highly efficient UV luminescence of hexagonal BN; ii) the application of an external perpendicular field closes the electronic gap keeping the UV lasing with lower yield; iii) defects in BNNTS are responsible for tunable light emission from the UV to the visible controlled by a transverse electric field (TEF). Our present findings pave the road towards optoelectronic applications of BN-nanotube-based devices that are simple to implement because they do not require any special doping or complex growth. PMID- 24060844 TI - Humor processing in children: influence of temperament, age and IQ. AB - Emerging evidence from fMRI studies suggests that humor processing is a specific social cognitive-affective human function that comprises two stages. The first stage (cognitive humor component) involves the detection and resolution of incongruity, and is associated with activity in temporo-occipito-parietal brain areas. The second stage (emotional humor component) comprises positive feelings related to mirth/reward, and is linked with reward-related activity in mesocorticolimbic circuits. In healthy adults, humor processing was shown to be moderated by temperament traits like intro-/extraversion, neuroticism, or social anxiety, representing risk factors for psychopathology. However, comparable data from early developmental stages is crucially lacking. Here, we report for the first time data from 22 children (ages 6 to 13) revealing an influence of temperament on humor processing. Specifically, we assessed the effects of Emotionality, Shyness, and Sociability, which are analogous to neuroticism, behavioral inhibition/fear and extraversion in adults. We found Emotionality to be positively, but Shyness negatively associated with brain activity linked with both cognitive and emotional humor components. In addition, Shyness and Sociability were positively related to activity in the periaqueductal gray region during humor processing. These findings are of potential clinical relevance regarding the early detection of childhood psychopathology. Previous data on humor processing in both adults and children furthermore suggest that intelligence (IQ) supports incongruity detection and resolution, whereas mirth and associated brain activity diminishes with increasing age. Here, we found that increasing age and IQ were linked with stronger activity to humor in brain areas implicated in the cognitive component of humor. Such data suggest that humor processing undergoes developmental changes and is moderated by higher IQ scores, both factors likely improving incongruity detection and resolution. PMID- 24060845 TI - The role of beat gesture and pitch accent in semantic processing: an ERP study. AB - The present study investigated whether and how beat gesture (small baton-like hand movements used to emphasize information in speech) influences semantic processing as well as its interaction with pitch accent during speech comprehension. Event-related potentials were recorded as participants watched videos of a person gesturing and speaking simultaneously. The critical words in the spoken sentences were accompanied by a beat gesture, a control hand movement, or no hand movement, and were expressed either with or without pitch accent. We found that both beat gesture and control hand movement induced smaller negativities in the N400 time window than when no hand movement was presented. The reduced N400s indicate that both beat gesture and control movement facilitated the semantic integration of the critical word into the sentence context. In addition, the words accompanied by beat gesture elicited smaller negativities in the N400 time window than those accompanied by control hand movement over right posterior electrodes, suggesting that beat gesture has a unique role for enhancing semantic processing during speech comprehension. Finally, no interaction was observed between beat gesture and pitch accent, indicating that they affect semantic processing independently. PMID- 24060846 TI - Determination of the geometry change of 5-cyanoindole upon electronic excitation from a combined Franck-Condon/rotational constants fit. AB - The geometry change of 5-cyanoindole upon electronic excitation from the ground to the lowest excited singlet state has been determined from a combined fit of the rotational constant changes upon excitation and the vibronic intensities in various fluorescence emission spectra using the Franck-Condon principle. The so determined geometry change is compared to the results of ab initio calculations and points to an excited state geometry, which is La-like in the nomenclature of Platt. A mode selective coupling of vibronic bands to higher-lying excited states is discussed on the basis of Herzberg-Teller contributions to the Frank-Condon intensities. PMID- 24060847 TI - Molecular pathways and functional analysis of miRNA expression associated with paclitaxel-induced apoptosis in hepatocellular carcinoma cells. AB - BACKGROUND: We postulated that microRNAs (miRNAs) might be involved in hepatocellular carcinoma (HCC) targeted chemotherapy with paclitaxel. This study sought to generate a list of potential miRNA-based biomarkers and their potential targets to better understand the response to paclitaxel treatment in HCC. METHODS: Cell viability proliferation assays were conducted to test the sensitivity of the HepG2 cells to paclitaxel. The morphological changes of apoptosis were assessed with 4',6-diamidino-2-phenylindole staining. Differential expression patterns of miRNA in the HepG2 cells either treated or not treated were analyzed using miRNA microarrays. RESULTS: The array experiments have identified 54 miRNAs whose basal expression levels differed by >2-fold and p < 0.05 between the two phenotypic groups. The data were validated by a quantitative real-time PCR of 8 selected miRNAs (miR-21, miR-1274a, miR-1260, miR-1290, miR 508-5p, miR-877, miR-1246, miR-183*). The PI3K/Akt, mitogen-activated protein kinase (MAPK), TGF-beta, ErbB, p53, cell cycle, mammalian target of rapamycin, and Jak-STAT signaling pathways were involved in paclitaxel-induced apoptosis. CONCLUSIONS: The manipulation of one or more of these miRNAs could be an important approach for the improved management of paclitaxel therapy. PMID- 24060848 TI - Potent and direct presynaptic modulation of glycinergic transmission in rat spinal neurons by atrial natriuretic peptide. AB - Atrial and brain natriuretic peptides (ANP and BNP) exist in the central nervous system and modulate neuronal function, although the locus of actions and physiological mechanisms are still unclear. In the present study we used rat spinal sacral dorsal commissural nucleus (SDCN) and hippocampal 'synaptic bouton' preparations, to record both spontaneous and evoked glycinergic inhibitory postsynaptic currents (sIPSCs and eIPSCs) in SDCN neurons, and the evoked excitatory postsynaptic currents (eEPSCs) in hippocampal CA3 neurons. ANP potently and significantly reduced the sIPSC frequency without affecting the amplitude. ANP also potently reduced the eIPSCs amplitude concurrently increasing the failure rate and the paired pulse ratio response. These ANP actions were blocked by anantin, a specific type A natriuretic peptide receptor (NPR-A) antagonist. The results clearly indicate that ANP acts directly on glycinergic presynaptic nerve terminals to inhibit glycine release via presynaptic NPR-A. The ANP effects were not blocked by the membrane permeable cGMP analog (8Br-cGMP) suggesting a transduction mechanisms not simply related to increasing cGMP levels in nerve terminals. BNP did not affect on glycinergic sIPSCs and eIPSCs. Moreover, both ANP and BNP had no effect on glutamatergic EPSCs in hippocampal CA3 neurons. The results indicate a potent and selective presynaptic inhibitory action of ANP on glycinergic transmission in spinal cord sensory circuits. PMID- 24060849 TI - Chinese alligator genome illustrates molecular adaptations. AB - In the September issue of Cell Research, Wan et al. analyze the Chinese Alligator genome and identify multiple instances of positively-selected changes in protein coding genes and expansions of multi-gene families that appear to explain suites of phenotypes central to the unique habits and physiology of crocodilian reptiles. They demonstrate the effectiveness of comparative systems genomics in integrating information from comparative genomics, molecular evolution, and systems biology to understand the evolutionary dynamics of complex systems. PMID- 24060850 TI - Hepatitis C: a mouse at the end of the tunnel. AB - Since its discovery in 1989, researchers strive after a small animal model for Hepatitis C virus infection, so far with very limited success. A study recently published in Nature now for the first time reports the recapitulation of the complete life cycle of this virus in inbred mice with a functional adaptive immune system. PMID- 24060852 TI - Regioselective Heck reaction of aliphatic olefins and aryl halides. AB - A regioselective Heck reaction of aliphatic olefins and aryl bromides is realized at internal carbons of olefins. Methanol solvent promoted halide ionization from neutral arylpalladium halide complexes via hydrogen bonding, so as to create cationic aryl-Pd species for regioselective olefin insertion. PMID- 24060851 TI - The ubiquitin conjugating enzyme UBE2L3 regulates TNFalpha-induced linear ubiquitination. PMID- 24060853 TI - Electronic properties of a quantum wire interacting with a surface: the role of periodically placed impurities. AB - The transmittance and density of states (DOS) of a quantum wire which is tunnel coupled to the underlying substrate are investigated theoretically using the retarded Green's function method. The wire is composed of periodically placed impurities with Coulomb interactions and is modeled by a tight-binding Hamiltonian within the mean-field approximation. For a given periodicity of impurities along the wire we observe energy gaps in the structure of DOS. These gaps disappear for a wire coupled with the substrate electrode with localized electrons which leads to a metal-insulator transition in the system. Our numerical studies reveal that the transmittance through the system strongly depends on whether or not the substrate electrons are localized. PMID- 24060856 TI - Towards a bioengineered liver. PMID- 24060855 TI - Effect of bariatric surgery on liver glucose metabolism in morbidly obese diabetic and non-diabetic patients. AB - BACKGROUND & AIMS: Bariatric surgery reduces weight and improves glucose metabolism in obese patients. We investigated the effects of bariatric surgery on hepatic insulin sensitivity. METHODS: Twenty-three morbidly obese (nine diabetic and fourteen non-diabetic) patients and ten healthy, lean control subjects were studied using positron emission tomography to assess hepatic glucose uptake in the fasting state and during euglycemic hyperinsulinemia. Magnetic resonance spectroscopy was performed to measure liver fat content and magnetic resonance imaging to obtain liver volume. Obese patients were studied before bariatric surgery (either sleeve gastrectomy or Roux-en-Y gastric bypass) and six months after surgery. RESULTS: Insulin-induced hepatic glucose uptake was increased by 33% in non-diabetic and by 36% in diabetic patients at follow-up compared with baseline, but not totally normalized. The liver fat content was reduced by 76%, liver volume by 26% and endogenous glucose production by 19% in non-diabetic patients. The respective changes in diabetic patients were 73%, 24%, and 25%. Postoperatively, liver fat content and endogenous glucose production were almost normalized to lean controls, but liver volume remained greater than in control subjects. CONCLUSIONS: This study shows that bariatric surgery leads to a significant improvement in hepatic insulin sensitivity: insulin-stimulated hepatic glucose uptake was improved and endogenous glucose production reduced when measured, six-months, after surgery. These metabolic effects were accompanied by a marked reduction in hepatic volume and fat content. Overall, the gain in hepatic insulin sensitivity in diabetic patients was quite similar to non diabetic patients for the same weight reduction. PMID- 24060854 TI - A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury. AB - BACKGROUND & AIMS: Hepatic stellate cells (HSCs) that express glial fibrillary acidic protein (GFAP) are located between the sinusoidal endothelial cells and hepatocytes. HSCs are activated during liver injury and cause hepatic fibrosis by producing excessive extracellular matrix. HSCs also produce many growth factors, chemokines and cytokines, and thus may play an important role in acute liver injury. However, this function has not been clarified due to unavailability of a model, in which HSCs are depleted from the normal liver. METHODS: We treated mice expressing HSV-thymidine kinase under the GFAP promoter (GFAP-Tg) with 3 consecutive (3 days apart) CCl4 (0.16 MUl/g; ip) injections to stimulate HSCs to enter the cell cycle and proliferate. This was followed by 10-day ganciclovir (40 MUg/g/day; ip) treatment, which is expected to eliminate actively proliferating HSCs. Mice were then subjected to hepatic ischemia/reperfusion (I/R) or endotoxin treatment. RESULTS: CCl4/ganciclovir treatment caused depletion of the majority of HSCs (about 64-72%), while the liver recovered from the initial CCl4-induced injury (confirmed by histology, serum ALT and neutrophil infiltration). The magnitude of hepatic injury due to I/R or endotoxemia (determined by histopathology and serum ALT) was lower in HSC-depleted mice. Their hepatic expression of TNF-alpha, neutrophil chemoattractant CXCL1 and endothelin-A receptor also was significantly lower than the control mice. CONCLUSIONS: HSCs play an important role both in I/R- and endotoxin-induced acute hepatocyte injury, with TNF-alpha and endothelin-1 as important mediators of these effects. PMID- 24060857 TI - Ilizarov in relapsed clubfoot: a necessary evil? AB - This study aims to retrospectively evaluate the results of soft tissue distraction using Ilizarov in relapsed clubfeet following a previous posteromedial soft tissue release. This study, as compared with previous studies, has a cohort of patients with relapsed clubfeet only following posteromedial soft tissue release. Fifteen patients (16 feet) were assessed using the International Clubfoot Study Group score and plantigrade foot was achieved in all except one patient who had equinus deformity. Fourteen feet were graded as showing excellent or good result on the basis of the International Clubfoot Study Group (ICFSG) score. Although no patient had an ICFSG score of 0, parental satisfaction was good. This report supports the use of Ilizarov as the benefits offered outweigh the risk of associated complications, making this potentially cumbersome apparatus a useful tool in the armamentarium to treat relapsed clubfeet following soft tissue release. PMID- 24060858 TI - DNA damage: Running in parallel. PMID- 24060860 TI - Genomics: Mutator catalogues. PMID- 24060861 TI - Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. AB - The burgeoning field of anaplastic lymphoma kinase (ALK) in cancer encompasses many cancer types, from very rare cancers to the more prevalent non-small-cell lung cancer (NSCLC). The common activation of ALK has led to the use of the ALK tyrosine kinase inhibitor (TKI) crizotinib in a range of patient populations and to the rapid development of second-generation drugs targeting ALK. In this Review, we discuss our current understanding of ALK function in human cancer and the implications for tumour treatment. PMID- 24060862 TI - Kruppel-like factors in cancer. AB - Kruppel-like factors (KLFs) are a family of DNA-binding transcriptional regulators with diverse and essential functions in a multitude of cellular processes, including proliferation, differentiation, migration, inflammation and pluripotency. In this Review, we discuss the roles and regulation of the 17 known KLFs in various cancer-relevant processes. Importantly, the functions of KLFs are context dependent, with some KLFs having different roles in normal cells and cancer, during cancer development and progression and in different cancer types. We also identify key questions for the field that are likely to lead to important new translational research and discoveries in cancer biology. PMID- 24060863 TI - Cancer drug resistance: an evolving paradigm. AB - Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification. PMID- 24060866 TI - Activity of ceftaroline against Enterococcus faecium PBP5. AB - The opportunistic human pathogen Enterococcus faecium overproduces the low affinity PBP5. In clinical strains, mutations in PBP5 further reduce its acylation rate by beta-lactams. Previous studies have reported that ceftaroline had poor inhibitory activity against beta-lactam-resistant E. faecium strains. In this study, we show that ceftaroline exhibits killing activity against our laboratory-derived ampicillin-resistant E. faecium mutant that overproduces a wild-type PBP5 and that ceftaroline inactivates PBP5 much faster than benzylpenicillin and faster than ceftobiprole. PMID- 24060864 TI - Unravelling cancer stem cell potential. AB - The maintenance and repair of many adult tissues are ensured by stem cells (SCs), which reside at the top of the cellular hierarchy of these tissues. Functional assays, such as in vitro clonogenic assays, transplantation and in vivo lineage tracing, have been used to assess the renewing and differentiation potential of normal SCs. Similar strategies have suggested that solid tumours may also be hierarchically organized and contain cancer SCs (CSCs) that sustain tumour growth and relapse after therapy. In this Opinion article, we discuss the different parallels that can be drawn between adult SCs and CSCs in solid tumours. PMID- 24060865 TI - History of myeloid-derived suppressor cells. AB - Tumour-induced granulocytic hyperplasia is associated with tumour vasculogenesis and escape from immunity via T cell suppression. Initially, these myeloid cells were identified as granulocytes or monocytes; however, recent studies have revealed that this hyperplasia is associated with populations of multipotent progenitor cells that have been identified as myeloid-derived suppressor cells (MDSCs). The study of MDSCs has provided a wealth of information regarding tumour pathobiology, has extended our understanding of neoplastic progression and has modified our approaches to immune adjuvant therapy. In this Timeline article, we discuss the history of MDSCs, their influence on tumour progression and metastasis, and the crosstalk between tumour cells, MDSCs and the host macroenvironment. PMID- 24060867 TI - Fluconazole assists berberine to kill fluconazole-resistant Candida albicans. AB - It was found in our previous study that berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. The aim of the present study was to clarify how BBR and FLC worked synergistically and the underlying mechanism. Antifungal time-kill curves indicated that the synergistic effect of the two drugs was BBR dose dependent rather than FLC dose dependent. In addition, we found that BBR accumulated in C. albicans cells, especially in the nucleus, and resulted in cell cycle arrest and significant change in the transcription of cell cycle-related genes. Besides BBR, other DNA intercalators, including methylene blue, sanguinarine, and acridine orange, were all found to synergize with FLC against FLC-resistant C. albicans. Detection of intracellular BBR accumulation by fluorescence measurement showed that FLC played a role in increasing intracellular BBR concentration, probably due to its effect in disrupting the fungal cell membrane. Similar to the case with FLC, other antifungal agents acting on the cell membrane were able to synergize with BBR. Interestingly, we found that the efflux of intracellular BBR was FLC independent but strongly glucose dependent and associated with the drug efflux pump Cdr2p. These results suggest that BBR plays a major antifungal role in the synergism of FLC and BBR, while FLC plays a role in increasing the intracellular BBR concentration. PMID- 24060868 TI - Adapted J6/JFH1-based Hepatitis C virus recombinants with genotype-specific NS4A show similar efficacies against lead protease inhibitors, alpha interferon, and a putative NS4A inhibitor. AB - To facilitate studies of hepatitis C virus (HCV) NS4A, we aimed at developing J6/JFH1-based recombinants with genotype 1- to 7-specific NS4A proteins. We developed efficient culture systems expressing NS4A proteins of genotypes (isolates) 1a (H77 and TN), 1b (J4), 2a (J6), 4a (ED43), 5a (SA13), 6a (HK6a), and 7a (QC69), with peak infectivity titers of ~3.5 to 4.5 log10 focus-forming units per ml. Except for genotype 2a (J6), growth depended on adaptive mutations identified in long-term culture. Genotype 1a, 1b, and 4a recombinants were adapted by amino acid substitutions F772S (p7) and V1663A (NS4A), while 5a, 6a, and 7a recombinants required additional substitutions in the NS3 protease and/or NS4A. We demonstrated applicability of the developed recombinants for study of antivirals. Genotype 1 to 7 NS4A recombinants showed similar responses to the protease inhibitors telaprevir (VX-950), boceprevir (Sch503034), simeprevir (TMC435350), danoprevir (ITMN-191), and vaniprevir (MK-7009), to alpha interferon 2b, and to the putative NS4A inhibitor ACH-806. The efficacy of ACH-806 was lower than that of protease inhibitors and was not influenced by changes at amino acids 1042 and 1065 (in the NS3 protease), which have been suggested to mediate resistance to ACH-806 in replicons. Genotype 1a, 1b, and 2a recombinants showed viral spread under long-term treatment with ACH-806, without acquisition of resistance mutations in the NS3-NS4A region. Relatively high concentrations of ACH-806 inhibited viral assembly, but not replication, in a single-cycle production assay. The developed HCV culture systems will facilitate studies benefitting from expression of genotype-specific NS4A in a constant backbone in the context of the complete viral replication cycle, including functional studies and evaluations of the efficacy of antivirals. PMID- 24060869 TI - A cysteine protease inhibitor rescues mice from a lethal Cryptosporidium parvum infection. AB - Cryptosporidiosis, caused by the protozoan parasite Cryptosporidium parvum, can stunt infant growth and can be lethal in immunocompromised individuals. The most widely used drugs for treating cryptosporidiosis are nitazoxanide and paromomycin, although both exhibit limited efficacy. To investigate an alternative approach to therapy, we demonstrate that the clan CA cysteine protease inhibitor N-methyl piperazine-Phe-homoPhe-vinylsulfone phenyl (K11777) inhibits C. parvum growth in mammalian cell lines in a concentration-dependent manner. Further, using the C57BL/6 gamma interferon receptor knockout (IFN-gammaR KO) mouse model, which is highly susceptible to C. parvum, oral or intraperitoneal treatment with K11777 for 10 days rescued mice from otherwise lethal infections. Histologic examination of untreated mice showed intestinal inflammation, villous blunting, and abundant intracellular parasite stages. In contrast, K11777-treated mice (210 mg/kg of body weight/day) showed only minimal inflammation and no epithelial changes. Three putative protease targets (termed cryptopains 1 to 3, or CpaCATL-1, -2, and -3) were identified in the C. parvum genome, but only two are transcribed in infected mammals. A homology model predicted that K11777 would bind to cryptopain 1. Recombinant enzymatically active cryptopain 1 was successfully targeted by K11777 in a competition assay with a labeled active-site-directed probe. K11777 exhibited no toxicity in vitro and in vivo, and surviving animals remained free of parasites 3 weeks after treatment. The discovery that a cysteine protease inhibitor provides potent anticryptosporidial activity in an animal model of infection encourages the investigation and development of this biocide class as a new, and urgently needed, chemotherapy for cryptosporidiosis. PMID- 24060870 TI - Gallium nitrate is efficacious in murine models of tuberculosis and inhibits key bacterial Fe-dependent enzymes. AB - Acquiring iron (Fe) is critical to the metabolism and growth of Mycobacterium tuberculosis. Disruption of Fe metabolism is a potential approach for novel antituberculous therapy. Gallium (Ga) has many similarities to Fe. Biological systems are often unable to distinguish Ga(3+) from Fe(3+). Unlike Fe(3+), Ga(3+) cannot be physiologically reduced to Ga(2+). Thus, substituting Ga for Fe in the active site of enzymes may render them nonfunctional. We previously showed that Ga inhibits growth of M. tuberculosis in broth and within cultured human macrophages. We now report that Ga(NO3)3 shows efficacy in murine tuberculosis models. BALB/c SCID mice were infected intratracheally with M. tuberculosis, following which they received daily intraperitoneal saline, Ga(NO3)3, or NaNO3. All mice receiving saline or NaNO3 died. All Ga(NO3)3-treated mice survived. M. tuberculosis CFU in the lungs, liver, and spleen of the NaNO3-treated or saline treated mice were significantly higher than those in Ga-treated mice. When BALB/c mice were substituted for BALB/c SCID mice as a chronic (nonlethal) infection model, Ga(NO3)3 treatment significantly decreased lung CFU. To assess the mechanism(s) whereby Ga inhibits bacterial growth, the effect of Ga on M. tuberculosis ribonucleotide reductase (RR) (a key enzyme in DNA replication) and aconitase activities was assessed. Ga decreased M. tuberculosis RR activity by 50 to 60%, but no additional decrease in RR activity was seen at Ga concentrations that completely inhibited mycobacterial growth. Ga decreased aconitase activity by 90%. Ga(NO3)3 shows efficacy in murine M. tuberculosis infection and leads to a decrease in activity of Fe-dependent enzymes. Additional work is warranted to further define Ga's mechanism of action and to optimize delivery forms for possible therapeutic uses in humans. PMID- 24060871 TI - Identification of MMV malaria box inhibitors of plasmodium falciparum early-stage gametocytes using a luciferase-based high-throughput assay. AB - The design of new antimalarial combinations to treat Plasmodium falciparum infections requires drugs that, in addition to resolving disease symptoms caused by asexual blood stage parasites, can also interrupt transmission to the mosquito vector. Gametocytes, which are essential for transmission, develop as sexual blood stage parasites in the human host over 8 to 12 days and are the most accessible developmental stage for transmission-blocking drugs. Considerable effort is currently being devoted to identifying compounds active against mature gametocytes. However, investigations on the drug sensitivity of developing gametocytes, as well as screening methods for identifying inhibitors of early gametocytogenesis, remain scarce. We have developed a luciferase-based high throughput screening (HTS) assay using tightly synchronous stage I to III gametocytes from a recombinant P. falciparum line expressing green fluorescent protein (GFP)-luciferase. The assay has been used to evaluate the early-stage gametocytocidal activity of the MMV Malaria Box, a collection of 400 compounds with known antimalarial (asexual blood stage) activity. Screening this collection against early-stage (I to III) gametocytes yielded 64 gametocytocidal compounds with 50% inhibitory concentrations (IC50s) below 2.5 MUM. This assay is reproducible and suitable for the screening of large compound libraries, with an average percent coefficient of variance (%CV) of <=5%, an average signal-to-noise ratio (S:N) of >30, and a Z' of ~0.8. Our findings highlight the need for screening efforts directed specifically against early gametocytogenesis and indicate the importance of experimental verification of early-stage gametocytocidal activity in the development of new antimalarial candidates for combination therapy. PMID- 24060872 TI - Antifungal prophylaxis with posaconazole in patients with acute myeloid leukemia: dose intensification coupled with avoidance of proton pump inhibitors is beneficial in shortening time to effective concentrations. AB - This study aimed to assess the influence of dose frequency and the presence or absence of cotreatment with proton pump inhibitors (PPIs) on the time to a target trough concentration (Cmin) of >700 ng/ml with posaconazole in the first 8 days of antifungal prophylaxis in hematological patients. This was a retrospective, observational study performed with 42 adult patients with acute myeloid leukemia who underwent posaconazole prophylaxis with 200 mg every 8 h (q8h) or 200 mg q6h after receiving induction chemotherapy and who had at least three subsequent therapeutic drug monitoring assessments during the first 8 days of treatment. The cohort was split into four groups (group 1, 200 mg q8h without PPI; group 2, 200 mg q8h with PPI; group 3, 200 mg q6h without PPI; group 4, 200 mg q6h with PPI). Rapid attainment of the target Cmin was obtained only in group 3 (P < 0.01) (median Cmin on day 4 of 935.5 ng/ml [interquartile range, 760.0 to 1,270.0 ng/ml] in group 3, versus 567.0 ng/ml [346 to 906 ng/ml] in group 1, 420.0 ng/ml [326.2 to 527.2 ng/ml] in group 2, and 514.0 ng/ml [403.7 to 564.7 ng/ml] in group 4). A linear accumulation of posaconazole over time was observed among patients in groups 1 and 3, regardless of the total daily dosage, differently from what occurred among those receiving PPI cotreatment (groups 2 and 4). Dose intensification (200 mg q6h) coupled with avoidance of PPI coadministration may represent a very powerful strategy to rapidly achieve effective concentrations with posaconazole in neutropenic hematological patients. PMID- 24060873 TI - Anidulafungin and micafungin MIC breakpoints are superior to that of caspofungin for identifying FKS mutant Candida glabrata strains and Echinocandin resistance. AB - By CLSI interpretive criteria, anidulafungin and micafungin MICs determined by various methods were sensitive (60 to 70%) and highly specific (94 to 100%) for identifying FKS mutations among 120 Candida glabrata isolates. Anidulafungin and micafungin breakpoints were more specific than CLSI's caspofungin breakpoint in identifying FKS mutant strains and patients with invasive candidiasis who were likely to fail echinocandin treatment (P <= 0.0001 for both). Echinocandin MICs were most useful clinically when interpreted in the context of prior echinocandin exposure. PMID- 24060874 TI - Activity of Tigecycline in combination with Colistin, Meropenem, Rifampin, or Gentamicin against KPC-producing Enterobacteriaceae in a murine thigh infection model. AB - Limited antimicrobials remain active for treating severe infections due to KPC producing pathogens, and optimal regimens have not been established. In murine thigh infections caused by nine KPC-producing clinical strains of Enterobacteriaceae (meropenem MICs, 1 to 4 MUg/ml), we evaluated the activities of tigecycline, colistin, meropenem, rifampin, and gentamicin in single and combination regimens lasting for 24 h and 48 h. Rifampin, tigecycline, and gentamicin were the most effective monotherapies, reducing significantly the CFU counts yielded from thighs infected by 88.9 to 100%, 77.8 to 88.9%, and 66.7 to 88.9% of strains, respectively; meropenem and colistin alone exhibited considerably lower performance (significant CFU reduction in 33.3% and 22.2 to 33.3% of the strains, respectively). The addition of rifampin or gentamicin to tigecycline produced synergistic effect in most strains, while antagonism was observed in 33.3 to 44.4% of the strains when colistin was added to tigecycline and in 44.4 to 55.5% of the strains for meropenem combination with tigecycline. Tigecycline combinations with gentamicin or with rifampin caused higher CFU reductions than did tigecycline plus colistin or plus meropenem with almost all strains. Furthermore, tigecycline plus gentamicin was significantly more effective than tigecycline plus colistin or tigecycline plus meropenem in 33.3 to 44.4% and 55.5 to 66.7% of the strains, respectively, while tigecycline plus rifampin significantly outperformed tigecycline plus colistin and tigecycline plus meropenem in 33.3% and 66.7 to 77.8% of the strains, respectively. Overall, our in vivo study showed that tigecycline plus rifampin or plus gentamicin is a robust regimen against soft tissue infections caused by KPC-producing strains. The combinations of tigecycline with colistin or meropenem should be considered with caution in clinical practice. PMID- 24060875 TI - Induction of influx and efflux transporters and cytochrome P450 3A4 in primary human hepatocytes by rifampin, rifabutin, and rifapentine. AB - Rifampin is a potent inducer of cytochrome P450 (CYP) enzymes and transporters. Drug-drug interactions during tuberculosis treatment are common. Induction by rifapentine and rifabutin is understudied. Rifampin and rifabutin significantly induced CYP3A4 (80-fold and 20-fold, respectively) in primary human hepatocytes. The induction was concentration dependent. Rifapentine induced CYP3A4 in hepatocytes from 3 of 6 donors. Data were also generated for ABCB1, ABCC1, ABCC2, organic anion-transporting polypeptide 1B1 (OATP1B1), and OATP1B3. This work serves as a basis for further study of the extent to which rifamycins induce key metabolism and transporter genes. PMID- 24060877 TI - In vitro susceptibility of Mycobacterium tuberculosis to trimethoprim and sulfonamides in France. AB - Five type strains and 55 Mycobacterium tuberculosis complex clinical isolates were found resistant to trimethoprim with a MIC of >200 mg/liter and susceptible to both sulfadiazine and cotrimoxazole with a MIC90 of 10 mg/liter. Two M. canettii isolates uniquely yielded silent mutations C156 -> T and G238 -> C in the folP1 gene. Combined with scarce published data, these data indicate that sulfamides could be considered alternative antituberculous antibiotics. PMID- 24060876 TI - Can inhibitor-resistant substitutions in the Mycobacterium tuberculosis beta Lactamase BlaC lead to clavulanate resistance?: a biochemical rationale for the use of beta-lactam-beta-lactamase inhibitor combinations. AB - The current emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis calls for novel treatment strategies. Recently, BlaC, the principal beta-lactamase of Mycobacterium tuberculosis, was recognized as a potential therapeutic target. The combination of meropenem and clavulanic acid, which inhibits BlaC, was found to be effective against even extensively drug resistant M. tuberculosis strains when tested in vitro. Yet there is significant concern that drug resistance against this combination will also emerge. To investigate the potential of BlaC to evolve variants resistant to clavulanic acid, we introduced substitutions at important amino acid residues of M. tuberculosis BlaC (R220, A244, S130, and T237). Whereas the substitutions clearly led to in vitro clavulanic acid resistance in enzymatic assays but at the expense of catalytic activity, transformation of variant BlaCs into an M. tuberculosis H37Rv background revealed that impaired inhibition of BlaC did not affect inhibition of growth in the presence of ampicillin and clavulanate. From these data we propose that resistance to beta-lactam-beta-lactamase inhibitor combinations will likely not arise from structural alteration of BlaC, therefore establishing confidence that this therapeutic modality can be part of a successful treatment regimen against M. tuberculosis. PMID- 24060878 TI - Whole-cell screening-based identification of inhibitors against the intraphagosomal survival of Mycobacterium tuberculosis. AB - We describe here an efficient strategy that employs whole-cell-based screening and further short listing of the compounds by cytotoxicity- and fluorescence based intracellular assays, resulting in potential bactericidal hits against the growth of Mycobacterium tuberculosis in broth culture as well as in phagosomes. These compounds also inhibited multidrug-resistant strains of M. tuberculosis but showed no or poor inhibition of nonpathogenic mycobacteria or other bacterial species such as Escherichia coli. PMID- 24060879 TI - Characterization of a novel composite staphylococcal cassette chromosome mec (SCCmec-SCCcad/ars/cop) in the neonatal sepsis-associated Staphylococcus capitis pulsotype NRCS-A. AB - Multiresistant Staphylococcus capitis pulsotype NRCS-A has been reported to be a major pathogen causing nosocomial bacteremia in preterm infants. We report that the NRCS-A strain CR01 harbors a novel 60.9-kb composite staphylococcal cassette chromosome mec (SCCmec) element, composed of an SCCmec with strong homologies to Staphylococcus aureus ST398 SCCmec and of an SCCcad/ars/cop harboring resistance genes for cadmium, arsenic, and copper. Whole-genome-based comparisons of published S. capitis strains suggest that strain CR01 acquired the two elements independently. PMID- 24060880 TI - Effect of peptide secondary structure on adsorption and adsorbed film properties on end-grafted polyethylene oxide layers. AB - Poly-l-lysine (PLL), in alpha-helix or beta-sheet configuration, was used as a model peptide for investigating the effect of secondary structures on adsorption events to poly(ethylene oxide) (PEO) modified surfaces formed using theta solvents. Circular dichroism results showed that the secondary structure of PLL persisted upon adsorption to Au and PEO modified Au surfaces. Quartz crystal microbalance with dissipation (QCM-D) was used to characterize the chemisorbed PEO layer in different solvents (theta and good solvents), as well as the sequential adsorption of PLL in different secondary structures (alpha-helix or beta-sheet). QCM-D results suggest that chemisorption of PEO 750 and 2000 from theta solutions led to brushes 3.8 +/- 0.1 and 4.5 +/- 0.1 nm thick with layer viscosities of 9.2 +/- 0.8 and 4.8 +/- 0.5 cP, respectively. The average number of H2O per ethylene oxides, while in theta solvent, was determined as ~0.9 and ~1.2 for the PEO 750 and 2000 layers, respectively. Upon immersion in good solvent (as used for PLL adsorption experiments), the number of H2O per ethylene oxides increased to ~1.5 and ~2.0 for PEO 750 and 2000 films, respectively. PLL adsorbed masses for alpha-helix and beta-sheet on Au sensors was 231 +/- 5 and 1087 +/- 14 ng cm(-2), with layer viscosities of 2.3 +/- 0.1 and 1.2 +/- 0.1 cP, respectively; suggesting that the alpha-helix layer was more rigid, despite a smaller adsorbed mass, than that of beta-sheet layers. The PEO 750 layer reduced PLL adsorbed amounts to ~10 and 12% of that on Au for alpha-helices and beta sheets respectively. The PLL adsorbed mass to PEO 2000 layers dropped to ~12% and 4% of that on Au, for alpha-helix and beta-sheet respectively. No significant differences existed for the viscosities of adsorbed alpha-helix and beta-sheet PLL on PEO surfaces. These results provide new insights into the fundamental understanding of the effects of secondary structures of peptides and proteins on their surface adsorption. PMID- 24060881 TI - A mussel-derived one component adhesive coacervate. AB - Marine organisms process and deliver many of their underwater coatings and adhesives as complex fluids. In marine mussels one such fluid, secreted during the formation of adhesive plaques, consists of a concentrated colloidal suspension of a mussel foot protein (mfp) known as Mfp-3S. The results of this study suggest that Mfp-3S becomes a complex fluid by a liquid-liquid phase separation from equilibrium solution at a pH and ionic strength reminiscent of the conditions created by the mussel foot during plaque formation. The pH dependence of phase separation and its sensitivity indicate that inter-/intra molecular electrostatic interactions are partially responsible for driving the phase separation. Hydrophobic interactions between the non- polar Mfp-3S proteins provide another important driving force for coacervation. As complex coacervation typically results from charge-charge interactions between polyanions and polycations, Mfp-3S is thus unique in being the only known protein that coacervates with itself. The Mfp-3S coacervate was shown to have an effective interfacial energy of ?1mJm(-2), which explains its tendency to spread over or engulf most surfaces. Of particular interest to biomedical applications is the extremely high adsorption capacity of coacervated Mfp-3S on hydroxyapatite. PMID- 24060885 TI - Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome. AB - Failure to transform uteroplacental spiral arteries is thought to underpin disorders of pregnancy, including preeclampsia and fetal growth restriction (FGR). In this study, spiral artery remodeling and extravillous-cytotrophoblast were examined in placental bed biopsies from normal pregnancy (n = 25), preeclampsia (n = 22), and severe FGR (n = 10) and then compared with clinical parameters. Biopsies were immunostained to determine vessel wall integrity, extravillous-cytotrophoblast location/density, periarterial fibrinoid, and endothelium. Muscle disruption was reduced in myometrial spiral arteries in preeclampsia (P = 0.0001) and FGR (P = 0.0001) compared with controls. Myometrial vessels from cases with birth weight <5th percentile (P<0.001), abnormal uterine Doppler (P<0.01), abnormal umbilical artery Doppler (P<0.001), and preterm delivery (P<0.001) had less muscle destruction compared with >5th percentile. Fewer extravillous-cytotrophoblast surrounded both decidual and myometrial vessels in the normal group and preeclampsia group compared with the FGR group (P = 0.001). For myometrial vessels, the normal group contained more intramural extravillous-cytotrophoblast than in preeclampsia (P = 0.015). Decidual vessels in the FGR group had less fibrinoid deposition compared with controls (P = 0.013). For myometrial vessels, less fibrinoid was deposited in both the preeclampsia group (P = 0.0001) and the FGR group (P = 0.01) when compared with controls, and less fibrinoid was deposited in the preeclampsia group when compared with FGR group (P<0.001). Myometrial vessels obtained from birth weights <5th percentile had less periarterial fibrinoid than those with >5th percentile (P<0.02). A major defect in myometrial spiral artery remodeling occurs in preeclampsia and FGR that is linked to clinical parameters. Interstitial extravillous-cytotrophoblast is not reduced in preeclampsia but is increased in FGR. PMID- 24060886 TI - Urinary excretion of C5b-9 in severe preeclampsia: tipping the balance of complement activation in pregnancy. AB - The complement cascade is activated in normal pregnancy, and excessive complement activation propagates the systemic inflammatory response in severe preeclampsia. Consequently, biomarkers of complement dysregulation may be useful for prediction or treatment of disease. Because renal damage with proteinuria is a characteristic pathological feature of preeclampsia, we hypothesized that complement markers in urine, rather than plasma, could better reflect complement dysregulation in disease. To investigate this, we performed a case-control study of pregnant women, enrolling 25 cases with severe preeclampsia, 25 controls with chronic hypertension, and 25 healthy controls without hypertension matched by gestational age and parity. Subjects were recruited from the Brigham and Women's Hospital from March 2012 to March 2013. Urine and blood samples were collected on the day of enrollment, with complement activation (C3a, C5a, and C5b-9) measured by ELISA. Severe preeclampsia was associated with marked elevations in urinary C5b-9 (median [interquartile range], 4.3 [1.2-15.1] ng/mL) relative to subjects with chronic hypertension (0 [0-0]) and healthy controls (0 [0-0]; P<0.0001). Urinary excretion of C5b-9 was detected in 96% of cases with severe preeclampsia, 12% of controls with chronic hypertension, and 8% of healthy controls. Cases were also notable for significantly greater urinary excretion of C3a and C5a. Plasma levels of C5a and C5b-9, but not C3a, were increased in the cases with severe preeclampsia compared with healthy controls; however, they did not distinguish preeclampsia from chronic hypertension, supporting our hypothesis that complement markers in urine, rather than plasma, better reflect complement dysregulation. Complement inhibition is an intriguing treatment option for patients with severe preeclampsia. PMID- 24060887 TI - Central aortic blood pressure and management of hypertension: confirmation of a paradigm shift? PMID- 24060888 TI - Does atrial fibrillation affect the automated oscillometric blood pressure measurement? PMID- 24060889 TI - CXCL16: a chemokine-causing chronic kidney disease. PMID- 24060890 TI - Chronic angiotensin II infusion drives extensive aldosterone-independent epithelial Na+ channel activation. AB - The inability of mineralocorticoid receptor (MR) blockade to reduce hypertension associated with high angiotensin (Ang) II suggests direct actions of Ang II to regulate tubular sodium reabsorption via the epithelial Na(+) channel (ENaC) in the aldosterone-sensitive distal nephron. We used freshly isolated aldosterone sensitive distal nephron from mice to delineate the synergism and primacy between aldosterone and Ang II in controlling functional ENaC activity. Inhibition of MR specifically prevented the increased number of functionally active ENaC, but not ENaC open probability elicited by a low sodium diet. In contrast, we found no functional role of glucocorticoid receptors in the regulation of ENaC activity by dietary salt intake. Simultaneous inhibition of MR and Ang II type 1 receptors ameliorated the enhanced ENaC activity caused by low dietary salt intake and produced significantly greater natriuresis than either inhibitor alone. Chronic systemic Ang II infusion induced more than 2 times greater increase in ENaC activity than observed during dietary sodium restriction. Importantly, ENaC activity remained greatly above control levels during maximal MR inhibition. We conclude that during variations in dietary salt intake both aldosterone and Ang II contribute complementarily to the regulation of ENaC activity in the aldosterone-sensitive distal nephron. In contrast, in the setting of Ang II dependent hypertension, ENaC activity is upregulated well above the physiological range and is not effectively suppressed by inhibition of the aldosterone-MR axis. This provides a mechanistic explanation for the resistance to MR inhibition that occurs in hypertensive subjects having elevated intrarenal Ang II levels. PMID- 24060891 TI - Randomized trial of guiding hypertension management using central aortic blood pressure compared with best-practice care: principal findings of the BP GUIDE study. AB - Arm cuff blood pressure (BP) may overestimate cardiovascular risk. Central aortic BP predicts mortality and could be a better method for patient management. We sought to determine the usefulness of central BP to guide hypertension management. This was a prospective, open-label, blinded-end point study in 286 patients with hypertension randomized to treatment decisions guided by best practice usual care (n=142; using office, home, and 24-hour ambulatory BP) or, in addition, by central BP intervention (n=144; using SphygmoCor). Therapy was reviewed every 3 months for 12 months, and recommendations were provided to each patient and his/her doctor on antihypertensive medication titration. Outcome measures were as follows: medication quantity (daily defined dose), quality of life, and left ventricular mass (3-dimensional echocardiography). There was 92% compliance with recommendations on medication titration, and quality of life improved in both groups (post hoc P<0.05). For usual care, there was no change in daily defined dose (all P>0.10), but with intervention there was a significant stepwise decrease in daily defined dose from baseline to 3 months (P=0.008) and each subsequent visit (all P<0.001). Intervention was associated with cessation of medication in 23 (16%) patients versus 3 (2%) in usual care (P<0.001). Despite this, there were no differences between groups in left ventricular mass index, 24 hour ambulatory BP, home systolic BP, or aortic stiffness (all P>0.05). We conclude that guidance of hypertension management with central BP results in a significantly different therapeutic pathway than conventional cuff BP, with less use of medication to achieve BP control and no adverse effects on left ventricular mass, aortic stiffness, or quality of life. PMID- 24060892 TI - cGMP-dependent protein kinase 1 polymorphisms underlie renal sodium handling impairment. AB - Defective pressure-natriuresis related to abnormalities in the natriuretic response has been associated with hypertension development. A major signaling pathway mediating pressure natriuresis involves the cGMP-dependent protein kinase 1 (PRKG1) that, once activated by Src kinase, inhibits renal Na(+) reabsorption via a direct action on basolateral Na-K ATPase and luminal Na-H exchanger type 3, as shown in renal tubuli of animals. Because a clear implication of PRKG1 in humans is still lacking, here we addressed whether PRKG1 polymorphisms affect pressure-natriuresis in patients. Naive hypertensive patients (n = 574), genotyped for PRKG1 rs1904694, rs7897633, and rs7905063 single nucleotide polymorphisms (SNPs), underwent an acute Na(+) loading, and the slope of the pressure-natriuresis relationship between blood pressure and Na(+) excretion was calculated. The underlying molecular mechanism was investigated by immunoblotting protein quantifications in human kidneys. The results demonstrate that the PRKG1 risk haplotype GAT (rs1904694, rs7897633, rs7905063, respectively) associates with a rightward shift of the pressure-natriuresis curve (0.017 +/- 0.004 MUEq/mm Hg per minute) compared with the ACC (0.0013 +/- 0.003 MUEq/mm Hg per minute; P = 0.001). In human kidneys, a positive correlation of protein expression levels between PRKG1 and Src (r = 0.83; P<0.001) or alpha1 Na-K ATPase (r = 0.557; P<0.01) and between alpha1 Na-K ATPase and Na-H exchanger type 3 (r = 0.584; P<0.01) or Src (r = 0.691; P<0.001) was observed in patients carrying PRKG1 risk GAT (n = 23) but not ACC (n = 14) variants. A functional signaling complex among PRKG1, alpha1 Na-K ATPase, and Src was shown by immunoprecipitation from human renal caveolae. These findings indicate that PRKG1 risk alleles associate with salt-sensitivity related to a loss of the inhibitory control of renal Na(+) reabsorption, suggestive of a blunt pressure-natriuresis response. PMID- 24060893 TI - Cellular and molecular mechanisms of arterial stiffness associated with obesity. PMID- 24060895 TI - Ambulatory blood pressure measurement: what is the international consensus? PMID- 24060894 TI - Arterial stiffening precedes systolic hypertension in diet-induced obesity. AB - Stiffening of conduit arteries is a risk factor for cardiovascular morbidity. Aortic wall stiffening increases pulsatile hemodynamic forces that are detrimental to the microcirculation in highly perfused organs, such as the heart, brain, and kidney. Arterial stiffness is associated with hypertension but presumed to be due to an adaptive response to increased hemodynamic load. In contrast, a recent clinical study found that stiffness precedes and may contribute to the development of hypertension although the mechanisms underlying hypertension are unknown. Here, we report that in a diet-induced model of obesity, arterial stiffness, measured in vivo, develops within 1 month of the initiation of the diet and precedes the development of hypertension by 5 months. Diet-induced obese mice recapitulate the metabolic syndrome and are characterized by inflammation in visceral fat and aorta. Normalization of the metabolic state by weight loss resulted in return of arterial stiffness and blood pressure to normal. Our findings support the hypothesis that arterial stiffness is a cause rather than a consequence of hypertension. PMID- 24060896 TI - Prostaglandin E2 mediates connecting tubule glomerular feedback. AB - Connecting tubule glomerular feedback (CTGF) is a mechanism in which Na reabsorption in the connecting tubule (CNT) causes afferent arteriole (Af-Art) dilation. CTGF is mediated by eicosanoids, including prostaglandins and epoxyeicosatrienoic acids; however, their exact nature and source remain unknown. We hypothesized that during CTGF, the CNT releases prostaglandin E2, which binds its type 4 receptor (EP4) and dilates the Af-Art. Rabbit Af-Arts with the adherent CNT intact were microdissected, perfused, and preconstricted with norepinephrine. CTGF was elicited by increasing luminal NaCl in the CNT from 10 to 80 mmol/L. We induced CTGF with or without the EP4 receptor blocker ONO-AE3 208 added to the bath in the presence of the epoxyeicosatrienoic acid synthesis inhibitor MS-PPOH. ONO-AE3-208 abolished CTGF (control, 9.4 +/- 0.5; MS-PPOH+ONO AE3-208, -0.6 +/- 0.2 MUm; P<0.001; n=6). To confirm these results, we used a different, specific EP4 blocker, L161982 (10(-5) mol/L), that also abolished CTGF (control, 8.5 +/- 0.9; MS-PPOH+L161982, 0.8 +/- 0.4 MUm; P<0.001; n=6). To confirm that the eicosanoids that mediate CTGF are released from the CNT rather than the Af-Art, we first disrupted the Af-Art endothelium with an antibody and complement. Endothelial disruption did not affect CTGF (7.9 +/- 0.9 versus 8.6 +/ 0.6 MUm; P=NS; n=7). We then added arachidonic acid to the lumen of the CNT while maintaining zero NaCl in the perfusate. Arachidonic acid caused dose dependent dilation of the attached Af-Art (from 8.6 +/- 1.2 to 15.3 +/- 0.7 MUm; P<0.001; n=6), and this effect was blocked by ONO-AE3-208 (10(-7) mol/L). We conclude that during CTGF, the CNT releases prostaglandin E2, which acts on EP4 on the Af-Art inducing endothelium-independent dilation. PMID- 24060897 TI - Critical role of CXCL16 in hypertensive kidney injury and fibrosis. AB - Recent evidence indicates that inflammation plays a critical role in the initiation and progression of hypertensive kidney disease. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We found that chemokine (C-X-C motif) ligand 16 (CXCL16) was induced in renal tubular epithelial cells in response to angiotensin II in a nuclear factor-kappaB dependent manner. To determine whether CXCL16 plays a role in angiotensin II induced renal inflammation and fibrosis, wild-type and CXCL16 knockout mice were infused with angiotensin II at 1500 ng/kg per minute for up to 4 weeks. Wild-type and CXCL16 knockout mice had comparable blood pressure at baseline. Angiotensin II treatment led to an increase in blood pressure that was similar between wild type and CXCL16 knockout mice. CXCL16 knockout mice were protected from angiotensin II-induced renal dysfunction, proteinuria, and fibrosis. CXCL16 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the kidneys of angiotensin II-treated mice, which was associated with less expression of extracellular matrix proteins. Furthermore, CXCL16 deficiency inhibited infiltration of F4/80(+) macrophages and CD3(+) T cells in the kidneys of angiotensin II-treated mice compared with wild-type mice. Finally, CXCL16 deficiency reduced angiotensin II-induced proinflammatory cytokine expressions in the kidneys. Taken together, our results indicate that CXCL16 plays a pivotal role in the pathogenesis of angiotensin II-induced renal injury and fibrosis through regulation of macrophage and T cell infiltration and bone marrow-derived fibroblast accumulation. PMID- 24060898 TI - Left ventricular radial function associated with genetic variation in the cGMP dependent protein kinase. AB - cGMP-dependent protein kinase type I is a major mediator of cGMP signaling in the cardiovascular system. Recent studies on cardiac-specific PRKG1 knockout mice demonstrated that cGMP-dependent protein kinase type I mediates the negative inotropic effect of cGMP in the myocardium. We therefore investigated the association between left ventricular (LV) function and common polymorphisms in the PRKG1 gene in a general population. In 609 randomly selected participants (51.2% women; mean age, 48.8 years; 36.6% hypertensive) who were free from overt cardiac disease, we performed echocardiography and genotyped intronic tag single nucleotide polymorphisms (SNPs) rs1904694, rs7897633, and rs7905063 in PRKG1. On the basis of color Doppler myocardial motion data, we calculated end-systolic longitudinal and radial deformation (strain) of the LV inferolateral wall. In multivariable-adjusted analyses accounting for confounders and relatedness, systolic radial strain was significantly (P <= 0.005) higher in homozygotes for rs1904694 (GG), rs7897633 (AA), and rs7905063 (TT) compared with heterozygotes or noncarriers. Haplotype analysis confirmed that LV radial strain was significantly higher in GAT homozygotes than in noncarriers (62.3% versus 56.0%; P = 0.0005). Transmission of the PRKG1 GAT haplotype to informative offspring was associated with higher LV radial strain (effect size, 6.11%; P = 0.017). For other LV phenotypes, none of the phenotype-genotype associations reached statistical significance. In conclusion, LV systolic radial function was associated with common polymorphisms in PRKG1. If experimental studies and longitudinal follow-up of LV function confirm the causality of this association, interference with cGMP dependent protein kinase type I function might be a target for pharmacological intervention. PMID- 24060899 TI - Administration of interleukin-17 soluble receptor C suppresses TH17 cells, oxidative stress, and hypertension in response to placental ischemia during pregnancy. AB - Preeclampsia, new onset hypertension with proteinuria during pregnancy, is associated with chronic inflammation and placental oxidative stress (ROS). Chronic interleukin-17 (IL-17) increases blood pressure, autoantibodies (angiotensin II type I receptor [AT1-AA]), and ROS during pregnancy. The objective of this study was to determine whether T-helper 17 (TH17) suppression via IL-17 recombinant receptor C (IL-17RC) decreases pathophysiology associated with placental ischemia (reduced uterine perfusion pressure [RUPP]). On gestation day 14, miniosmotic pumps infusing 100 pg of IL-17RC per day were implanted into pregnant rats undergoing RUPP. On gestation day 18, carotid catheters were inserted. On gestation day 19, mean arterial pressure was recorded and TH17 cells, oxidative stress, and AT1-AA were measured and analyzed via 1-way ANOVA. Mean arterial pressure increased from 101 +/- 2 mm Hg in normal pregnant rats (n = 19) to 120 +/- 1 mm Hg in RUPP rats (n = 17) but decreased to 110 +/- 2 mm Hg in RUPP+IL-17RC rats (n = 22). Pup weight decreased from 2.28 +/- 0.2 g in normal pregnant rats to 1.96 +/- 0.3 g in RUPP rats but was significantly increased to 2.01 +/- 0.1 in RUPP+IL-17RC rats. TH17 cells were 1.77% in RUPP rats but decreased to 0.65% in RUPP+IL-17RC rats. Urinary isoprostanes were normalized in RUPP+IL-17RC rats (52 pg/ug) compared with 89 pg/ug in RUPP controls. Placental ROS was 652 relative light units in RUPP rats but decreased to 337 relative light units in RUPP+IL-17RC rats. AT1-AA was 17.27 +/- 0.7 bpm in RUPP rats but decreased to 5.00 +/- 0.5 bpm in RUPP+IL-17RC rats. With this study, we show that infusion of IL-17RC blunts TH17s, oxidative stress, AT1-AA, and hypertension in the RUPP model of preeclampsia, indicating that TH17 cells may play an important role in disease pathophysiology. PMID- 24060901 TI - Use of contrast agents in oncological imaging: magnetic resonance imaging. AB - Magnetic resonance plays a leading role in the management of oncology patients, providing superior contrast resolution and greater sensitivity compared with other techniques, which enables more accurate tumor identification, characterization and staging. Contrast agents are widely used in clinical magnetic resonance imaging; approximately 40-50% of clinical scans are contrast enhanced. Most contrast agents are based on the paramagnetic gadolinium ion Gd3+, which is chelated to avoid the toxic effects of free gadolinium. Multiple factors such as molecule structure, molecule concentration, dose, field strength and temperature determine the longitudinal and transverse relaxation rates (R1 and R2, respectively) and thus the T1- and T2-relaxivities of these chelates. These T1- and T2-relaxivities, together with their pharmacokinetic properties (i.e. distribution and concentration in the area of interest), determine the radiologic efficacy of the gadolinium-based contrast agents. PMID- 24060904 TI - Effective management of passive layers using composite cathodes in solid state magnesium batteries. AB - A simple and effective method for the management of the passive layer in solid state batteries is reported. The success is achieved using a composite cathode with embedded channels of polyaniline allowing smooth charge transfer across the passive layer. The composite cathode manifested better performance in terms of the cell characteristics and shelf life. PMID- 24060903 TI - Effect of aromatic ring fluorination on CH...pi interactions: rotational spectrum and structure of the fluorobenzene...acetylene weakly bound dimer. AB - The rotational spectra for the normal isotopic species and for six (13)C singly substituted isotopologues (in natural abundance) of the fluorobenzene...acetylene (C6H5F...HCCH) weakly bound dimer have been measured in the 6.5-18.5 GHz region using chirped-pulse Fourier-transform microwave spectroscopy. The HCCH molecule interacts with the fluorobenzene via a CH...pi contact and is determined to lie almost over the center of, and approximately perpendicular to, the aromatic ring, with an H...pi distance (perpendicular distance from the H atom to the ring plane) of around 2.492(47) A; a slight tilt of HCCH towards the para carbon atom of the fluorobenzene is evident. Binding energies of this complex and related benzene and fluorobenzene dimers obtained from the pseudodiatomic approximation are compared and indicate that fluorobenzene...acetylene lies among the more weakly bound of the complexes exhibiting some type of CH...pi interaction. PMID- 24060902 TI - Foxo-mediated Bim transcription is dispensable for the apoptosis of hematopoietic cells that is mediated by this BH3-only protein. AB - The BH3-only protein Bim is a critical initiator of apoptosis in hematopoietic cells. Bim is upregulated in response to growth factor withdrawal and in vitro studies have implicated the transcription factor Foxo3a as a critical inducer. To test the importance of this regulation in vivo, we generated mice with mutated Foxo-binding sites within the Bim promoters (Bim(DeltaFoxo/DeltaFoxo)). Contrary to Bim-deficient mice, Bim(DeltaFoxo/DeltaFoxo) mice had a normal hematopoietic system. Moreover, cytokine-dependent haematopoietic cells from Bim(DeltaFoxo/DeltaFoxo) and wt mice died at similar rates. These results indicate that regulation of Bim by Foxo transcription factors is not critical for the killing of hematopoietic cells. PMID- 24060900 TI - B-cell receptor signaling as a driver of lymphoma development and evolution. AB - The B-cell receptor (BCR) is essential for normal B-cell development and maturation. In an increasing number of B-cell malignancies, BCR signaling is implicated as a pivotal pathway in tumorigenesis. Mechanisms of BCR activation are quite diverse and range from chronic antigenic drive by microbial or viral antigens to autostimulation of B-cells by self-antigens to activating mutations in intracellular components of the BCR pathway. Hepatitis C virus infection can lead to the development of splenic marginal zone lymphoma, while Helicobacter pylori infection is associated with the development of mucosa-associated lymphoid tissue lymphomas. In some of these cases, successful treatment of the infection removes the inciting antigen and results in resolution of the lymphoma. Chronic lymphocytic leukemia has been recognized for decades as a malignancy of auto reactive B-cells and its clinical course is in part determined by the differential response of the malignant cells to BCR activation. In a number of B cell malignancies, activating mutations in signal transduction components of the BCR pathway have been identified; prominent examples are activated B-cell-like (ABC) diffuse large B-cell lymphomas (DLBCL) that carry mutations in CD79B and CARD11 and display chronic active BCR signaling resulting in constitutive activation of the NF-kappaB pathway. Despite considerable heterogeneity in biology and clinical course, many mature B-cell malignancies are highly sensitive to kinase inhibitors that disrupt BCR signaling. Thus, targeted therapy through inhibition of BCR signaling is emerging as a new treatment paradigm for many B cell malignancies. Here, we review the role of the BCR in the pathogenesis of B cell malignancies and summarize clinical results of the emerging class of kinase inhibitors that target this pathway. PMID- 24060905 TI - Effects of the thioredoxin-1 inhibitor PX-12 on blood-brain barrier permeability in the early stage of focal cerebral ischemia. AB - BACKGROUND/AIMS: Since a thioredoxin-1 (Trx-1) inhibitor, 1-methylpropyl-2 imidazolyl disulfide (PX-12) which is an antitumor agent, significantly decreased vascular permeability in tumor xenografts within a few hours of treatment, we tested whether PX-12 would attenuate blood-brain barrier (BBB) disruption in the early stage of focal cerebral ischemia and whether its action could be affected by vascular endothelial growth factor (VEGF) which interacts with the Trx-1 system. METHODS: In rats, 40 min after intravenous infusion of either 25 mg/kg of PX-12 (PX-12 group) or normal saline (control group), a middle cerebral artery (MCA) was occluded. In half of each group, VEGF (10(-10) mol/l) was applied topically in the ischemic cortex (IC). Ninety minutes after MCA occlusion, the transfer coefficient (Ki) of (14)C-alpha-aminoisobutyric acid and the volume of (3)H-dextran distribution were determined to measure the degree of BBB disruption. VEGF protein levels were determined using Western blot analysis. RESULTS: MCA occlusion increased the Ki in the control (+196%) as well as in the PX-12-treated rats (+90%), but the Ki of the IC of the PX-12 group was lower ( 42%) than that of the control rats. VEGF protein levels were decreased in both the IC (-9.5%) and the contralateral cortex (CC; -10.2%) with PX-12 treatment. In the VEGF-treated rats, PX-12 also attenuated (-41%) the Ki of the IC. The difference in the volume of dextran distribution between the IC and the CC became insignificant with PX-12 treatment with or without VEGF application. CONCLUSION: Our data demonstrated that PX-12 was effective in decreasing BBB disruption in the early stage of focal cerebral ischemia and that VEGF is not an important factor involved in the action of PX-12 on BBB permeability. PMID- 24060906 TI - Terpenoids and their anti-HIV-1 activities from Excoecaria acerifolia. AB - Five new diterpenoids named excocarinols A-E (1-5) including three pimaranes, one cleistanthane, and one nor-beyerane, together with nine known compounds, were isolated from the EtOAc extract of the Chinese ethnodrug Gua-jing-ban (Excoecaria acerifolia Didr.). Their structures were elucidated by the analysis of spectroscopic data including 1D, 2D NMR and HR-MS. The anti-HIV-1 bioassay on the diterpenoids showed that excocarinol A (1) exhibited moderate anti-HIV-1 activity with EC50 5.58 MUM and SI (Selection Index) over 112.71. PMID- 24060907 TI - Apigenin protects ovalbumin-induced asthma through the regulation of Th17 cells. AB - The aim of the study was to investigate the anti-asthmatic effects of apigenin and the possible mechanisms. Asthma model was established by ovalbumin-induced asthma. A total of 50 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2 mg/kg) and apigenin (5 mg/kg, 10 mg/kg). Airway resistance (Raw) was measured, histological studies were evaluated by hematoxylin and eosin (HE) staining, OVA-specific serum and BALF IgE levels and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA), Th17 cells were evaluated by flow cytometry (FCM), and protein level of RORgammat was measured by western blotting. Our study demonstrated that apigenin inhibited OVA induced increases in Raw and eosinophil count; interleukin (IL)-6, TNF- and IL 17A levels were recovered. Histological studies demonstrated that apigenin substantially inhibited OVA-induced eosinophilia in lung tissue and airway tissue. Flow cytometry studies demonstrated that apigenin substantially inhibited Th17 cells. Western blotting studies demonstrated that apigenin substantially inhibited RORgammat protein level. These findings suggest that apigenin may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma. PMID- 24060908 TI - Two new stereoisomeric antioxidant triterpenes from Potentilla fulgens. AB - The roots of Potentilla fulgens have been used for a long time as a folk remedy for many ailments without having information on its pharmacological action. Of the various extracts prepared by partitioning of the methanol extract, the ethyl acetate fraction was found to possess better antioxidant and cytotoxic activities. The degree of reduction in cloning efficiencies of MCF-7 cell lines was more with ethyl acetate than with hexane fraction of the root-extract. Hence, this fraction was further purified and nine compounds, including two new ursane type triterpenoids Fulgic acid A (4) and Fulgic acid B (5), were identified and characterized. Other compounds were identified as ursolic acid, euscaphic acid, corosolic acid, epicatechin, catechin, p-hydroxybenzaldehyde and gallic acid. Chemical structures were elucidated by spectroscopic methods, especially ESIHRMS and 2D NMR techniques. The new compounds showed good antioxidant activity and therefore this plant can be a source of natural antioxidants. PMID- 24060909 TI - Psoralen inhibits bone metastasis of breast cancer in mice. AB - Breast cancer is the most common female malignancy and it frequently metastasizes to bone. Metastatic breast cancer continues to be the primary cause of death for women in East and Southeast Asia. Psoralen is a furocoumarin that can be isolated from the seeds of Psoralea corylifolia L. Psoralen exhibits a wide range of biological properties and has been demonstrated as an antioxidant, antidepressant, anticancer, antibacterial, and antiviral agent. Additionally, it is involved in the formation and regulation of bone. This study investigated whether psoralen can inhibit metastasis of breast cancer to bone in vivo. Histological, molecular biological, and imaging analyses revealed that psoralen inhibits bone metastases in mice. Psoralen may function to inhibit breast cancer cell growth in the bone microenvironment and regulate the function of osteoblasts and osteoclasts in tumor-bearing mice. The results of this study suggest that psoralen is a bone-modifying agent and a potential therapeutic to treat patients with bone metastases. PMID- 24060910 TI - Cytotoxic and antioxidant dihydrobenzofuran neolignans from the seeds of Crataegus pinnatifida. AB - Eight new dihydrobenzofuran neolignans, pinnatifidanin C I-VIII (1-8), together with two known analogs (9-10) were isolated from the seeds of Crataegus pinnatifida. Their structures were elucidated by spectroscopic analyses, especially 1D, 2D NMR and CD spectra. The cytotoxic activities of all isolates against human cancer cell lines were assayed, and most interestingly, compound 10 revealed preferred cytotoxicity on the HT-1080 cell line and displayed much stronger inhibitory activity (IC50=8.86 MUM) compared with positive control 5 fluorouracil (IC50=35.62 MUM). Meanwhile, antioxidant activities of all the isolates were evaluated using 2,2-diphenyl-1-pikrylhydrazyl (DPPH) and 2,2'-azino bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assays, and the results showed that most of the isolates exhibited potent antioxidant activity. PMID- 24060911 TI - Simultaneous determination of 19 flavonoids in commercial trollflowers by using high-performance liquid chromatography and classification of samples by hierarchical clustering analysis. AB - The flowers of Trollius species, named Jin Lianhua in Chinese, are widely used traditional Chinese herbs with vital biological activity that has been used for several decades in China to treat upper respiratory infections, pharyngitis, tonsillitis, and bronchitis. We developed a rapid and reliable method for simultaneous quantitative analysis of 19 flavonoids in trollflowers by using high performance liquid chromatography (HPLC). Chromatography was performed on Inertsil ODS-3 C18 column, with gradient elution methanol-acetonitrile-water with 0.02% (v/v) formic acid. Content determination was used to evaluate the quality of commercial trollflowers from different regions in China, while three Trollius species (Trollius chinensis Bunge, Trollius ledebouri Reichb, Trollius buddae Schipcz) were explicitly distinguished by using hierarchical clustering analysis. The linearity, precision, accuracy, limit of detection, and limit of quantification were validated for the quantification method, which proved sensitive, accurate and reproducible indicating that the proposed approach was applicable for the routine analysis and quality control of trollflowers. PMID- 24060912 TI - Delayed sleep phase disorder in youth. AB - PURPOSE OF REVIEW: For over 30 years, delayed sleep phase disorder (DSPD) has been defined as a debilitating sleep condition. Recently, there is more awareness of DSPD in young people, yet considerable information is needed to understand its cause and treatment. This review describes the latest research findings describing the clinical features, cause, and treatment of DSPD. RECENT FINDINGS: The prevalence of DSPD in adolescents and young adults ranges from 1 to 16%. The impact on the individuals is significant, particularly in the domains of school/work performance and mental health. We describe various contributing factors including reduced homeostatic sleep pressure, a lengthened and delayed circadian rhythm, insensitivity to clock-resetting morning light, and heightened cognitive activity. Evening melatonin administration as a sole treatment appears promising, as is a combination of cognitive-behavior therapy and morning bright light. SUMMARY: Recent findings suggest clinicians to be aware of the clinical features (i.e., significant daytime sleepiness, anxiety and depression symptoms, potential for school dropout) of DSPD, as several biological features underpinning this disorder are unseen in clinical settings. We advise clinicians to become familiar with exogenous evening melatonin administration, and cognitive and behavioral techniques to simultaneously treat the delayed circadian rhythm and associated sleep-onset insomnia. PMID- 24060913 TI - Philosophical issues in the paraphilias. AB - PURPOSE OF REVIEW: Controversies surrounded the development of paraphilias in the Diagnostic and Statistical Manual of Mental Disorders (DSM) 5. This review examines the philosophical issues that emerge from an analysis of those debates and current literature. RECENT FINDINGS: The resolution of controversies in the publication of the DSM 5 drew upon the available evidence, theories of mental disorder, and normative assumptions. The rise of the Internet presents difficult challenges in this field. SUMMARY: Numerous philosophical assumptions underlie the psychiatric understandings of paraphilias. The focus here is on the nosological issues such as boundary justification for the determinations of normative and nonnormative human sexuality; the importance of not collapsing the distinction between mental disorder and crime, and the relationship between fantasy and action; epistemological questions of perspectivity, reasons-giving, and relationship of communication to truth claims; and sex differences not only in the paraphilias but also in the social context in which sex is formed and given expression. PMID- 24060914 TI - Epidemiology, course, and outcome of eating disorders. AB - PURPOSE OF REVIEW: To review the recent literature about the epidemiology, course, and outcome of eating disorders in accordance with the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). RECENT FINDINGS: The residual category 'eating disorder not otherwise specified' (EDNOS) was the most common DSM-IV eating disorder diagnosis in both clinical and community samples. Several studies have confirmed that the DSM-5 criteria for eating disorders effectively reduce the proportion of EDNOS diagnoses. The lifetime prevalence of DSM-5 anorexia nervosa among women might be up to 4%, and of bulimia nervosa 2%. In a cross-national survey, the average lifetime prevalence of binge eating disorder (BED) was 2%. Both anorexia nervosa and bulimia nervosa are associated with increased mortality. Data on long-term outcome, including mortality, are limited for BED. Follow-up studies of BED are scarce; remission rates in randomized controlled trials ranged from 19 to 65% across studies. On a community level, 5-year recovery rates for DSM-5 anorexia nervosa and bulimia nervosa are 69 and 55%, respectively; little is known about the course and outcome of BED in the community. SUMMARY: Applying the DSM-5 criteria effectively reduces the frequency of the residual diagnosis EDNOS, by lowering the threshold for anorexia nervosa and bulimia nervosa, and adding BED as a specified eating disorder. Course and outcome studies of both anorexia nervosa and bulimia nervosa show that no significant differences exist between DSM-5 and DSM-IV definitions. PMID- 24060915 TI - Advances in the neurobiology of eating disorders. AB - PURPOSE OF REVIEW: To systematize new neurobiological findings on the cause and treatment of eating disorders. RECENT FINDINGS: The conceptual framework of the cause of eating disorders has undergone great changes in the past decades. Recently, the National Institute of Mental Health proposed a new set of criteria for research purposes--the Research Domain Criteria (RDoC). We aim to structure this study as much as possible using these constructs across biological units of analysis, summarizing new findings. Brain imaging techniques have become sophisticated in identifying brain circuits related to illness behaviour and to fundamental traits such as reward and social processing. Genetic studies have moved from candidate gene studies onto genome-wide association studies; however, the field needs to cooperate to collect larger samples in order to benefit from this approach. Hormonal changes as the results of starvation or as underlying factors for behavioural changes still receive attention in both animal and human studies. Advances made in neuropsychology show problems in cognition (set shifting and central coherence) and in other RDoC domains. Some of these findings have been translated into treatment. SUMMARY: New biological models are being developed which explain causal and maintaining factors. The RDoC construct may be used to systematize these findings. PMID- 24060916 TI - Circadian rhythms and psychiatric illness. AB - PURPOSE OF REVIEW: The present review provides a conceptual introduction to sleep and circadian research in psychiatric illness, and discusses recent experimental and intervention findings in this area. RECENT FINDINGS: In this review, studies published since January 2011 on circadian disturbance and psychiatric illness have been summarized. SUMMARY: Exciting new results have increasingly utilized objective and validated instruments to measure the circadian system in experimental studies. Since 2011, treatment research has still predominantly utilized self-report measures as outcome variables. However, research in the treatment domain for sleep/circadian disturbances comorbid with psychiatric illness has advanced the field in its work to broaden the validation of existing sleep treatments to additional patient populations with comorbid sleep/circadian disruptions and address how to increase access to and affordability of treatment for sleep and circadian dysfunction for patients with psychiatric disorders, and how to combine psychosocial treatments with psychopharmacology to optimize treatment outcomes. PMID- 24060918 TI - Developmental changes in sleep and their relationships to psychiatric illnesses. AB - PURPOSE OF REVIEW: Sleep undergoes major changes during development. Its relationship to the complex process of maturation in health and disease has recently received increased attention. This review aims to highlight the recent literature examining the interplay of altered sleep, brain development and emerging psychiatric illnesses in children and adolescents. RECENT FINDINGS: In addition to a temporal relationship of sleep disturbances preceding the onset of psychiatric illnesses, a bi-directional interaction of altered sleep and symptom severity has increasingly been shown. Sleep architecture shows drastic age dependent alterations on a structural level during the first 2 decades of life. However, findings regarding disease-specific patterns have remained inconsistent. On a functional level, recent evidence about sleep electroencephalographic characteristics points to a close relationship between slow waves, reflecting the depth of sleep, and cortical plasticity. SUMMARY: Sleep provides a rich source of information to gain insight into both the healthy and disturbed processes of brain function and maturation. Emerging data suggest that the investigation of slow wave activity is a novel and promising tool for monitoring both of these processes. It is important to understand when and how deviations from typical developmental sleep alterations occur in order to improve prevention and early treatment of disorders affecting a substantial number of children and adolescents. PMID- 24060917 TI - Psychological treatments for eating disorders. AB - PURPOSE OF REVIEW: This review summarizes recent evidence on psychological treatments for eating disorders. RECENT FINDINGS: Eating disorders are serious psychiatric conditions requiring evidence-based intervention. Treatments have been evaluated within each eating disorder diagnosis and across diagnoses. For adults with anorexia nervosa, no one specialist treatment has been shown to be superior. Cognitive behavioral therapy and interpersonal psychotherapy remain the most established treatments for bulimia nervosa and binge eating disorder, with stepped-care approaches showing promise and new behavioral treatments under study. Enhanced cognitive behavioral therapy has improved symptoms in adults and youth. Maudsley family-based therapy is the most established treatment for youth with anorexia nervosa and may be efficacious for youth with bulimia nervosa. Interpersonal psychotherapy for the prevention of excess weight gain may be efficacious for reducing loss of control eating and weight gain in overweight youth. SUMMARY: Significant advances in treatments have been made, including evaluation of long-term outcomes, novel approaches, and tailored extension for specific patient profiles. However, widespread access to effective eating disorder treatments remains limited. Increasing the potency and expanding the implementation of psychological treatments beyond research settings into clinical practice has strong potential to increase access to care, thereby reducing the burden of eating disorders. PMID- 24060919 TI - Feeding and eating disorders in children. AB - PURPOSE OF REVIEW: The past few years have seen a steep increase in journal articles relating to feeding and eating disorders in children, making a succinct overview timely. The relevance of this review is enhanced by the recent publication of revised feeding and eating disorder diagnostic criteria in DSM-5. These have significant implications for younger patients, in particular through the inclusion of the new diagnostic category Avoidant/Restrictive Food Intake Disorder (ARFID). It is likely that this will encourage increased research interest in this field. RECENT FINDINGS: Recent publications included in this article cover a broad range of topics relevant to childhood feeding and eating disorders, to include: presentation, diagnosis and classification; epidemiology; risk factors; assessment measures; treatment, prognosis and outcome. SUMMARY: The area of feeding and eating disorders in children remains relatively under researched, with significant gaps in knowledge about epidemiology, course and prognosis as well as a limited evidence base for treatment. However, important and promising avenues are increasingly being explored. In relation to clinical practice, there is now a much better recognition of these disorders and a greater awareness of their complexity, severity and potential impact in both the short and the longer term if not appropriately managed. PMID- 24060920 TI - Ethical and conceptual issues in eating disorders. AB - PURPOSE OF REVIEW: This review considers the literature on ethical and conceptual issues in eating disorders from the last 18 months. Some reference to earlier work is necessary in order to provide context for the recent findings from research that is ongoing. RECENT FINDINGS: Empirical ethics research on anorexia nervosa includes novel ethical and conceptual findings on the role of authenticity and personal identity in individuals' reports of their experience, as well as new evidence on the role of affective states and values in decision making at later stages of the illness. Evidence points to the hypothesis that anorexia nervosa may be a distinct affective syndrome that organizes feelings and emotions in accordance with a fixed idea. SUMMARY: There has been impressive progress in empirical ethics research on anorexia nervosa, with important implications for ethical and conceptual issues that surround decision-making capacity and our understanding of the illness. PMID- 24060921 TI - Classification, epidemiology and treatment of DSM-5 feeding and eating disorders. PMID- 24060922 TI - Stimuli-responsive cross-linked micelles for on-demand drug delivery against cancers. AB - Stimuli-responsive cross-linked micelles (SCMs) represent an ideal nanocarrier system for drug delivery against cancers. SCMs exhibit superior structural stability compared to their non-cross-linked counterpart. Therefore, these nanocarriers are able to minimize the premature drug release during blood circulation. The introduction of environmentally sensitive cross-linkers or assembly units makes SCMs responsive to single or multiple stimuli present in tumor local microenvironment or exogenously applied stimuli. In these instances, the payload drug is released almost exclusively in cancerous tissue or cancer cells upon accumulation via enhanced permeability and retention effect or receptor mediated endocytosis. In this review, we highlight recent advances in the development of SCMs for cancer therapy. We also introduce the latest biophysical techniques, such as electron paramagnetic resonance (EPR) spectroscopy and fluorescence resonance energy transfer (FRET), for the characterization of the interactions between SCMs and blood proteins. PMID- 24060924 TI - Encapsulating magnetic and fluorescent mesoporous silica into thermosensitive chitosan microspheres for cell imaging and controlled drug release in vitro. AB - In this study, for the first time, multifunctional inorganic/organic core/shell hybrid microspheres consisted of Fe3O4 nanoparticles/CdTe quantum dots dual embedded mesoporous silica nanocomposites (MQ-MSN) as cores and P(N isopropylacrylamide)-graft-Chitosan microgels (PNIPAM-g-CS) as shells were prepared by copolymerization of NIPAM and CS in the presence of MQ-MSN. The preparation of microspheres (i.e., MQ-MSN/PNIPAM-g-CS) included three stages. First, Fe3O4/CdTe nanocomposites (MQ NCs) were prepared by self-assembly of electrostatic adsorption. Second, MQ NCs were encapsulated into silica spheres by modified Stober method to obtain MQ-MSN. Third, NIPAM monomers were initiated to fabricate PNIPAM networks with MQ-MSN distributed below the lower critical solution temperature (LCST) of PNIPAM, and then PNIPAM reacted with CS to form PNIPAM-g-CS copolymers above the LCST, meanwhile the PNIPAM networks collapsed to form microspheres, resulting in the MQ-MSN encapsulated into microspheres. The microspheres were systematically characterized, displaying perfect magnetic/fluorescent properties and thermo-sensitivity. HepG2 cancer cells treated with the microspheres revealed bright fluorescence imaging. Both the efficiency and capacity of Adriamycin (ADM) loaded into the microspheres were gradually increased with ADM concentration increasing. The ADM cumulative release in vitro from ADM-loaded microspheres was significant at a higher temperature (or a lower pH). The released ADM still maintained high anticancer activity, and the blank microsphere carriers hardly produced toxicity to HepG2 cells. Hence, the multifunctional microspheres exhibited a promising application especially as thermo/pH-sensitive drug carriers for in vivo therapy. PMID- 24060925 TI - Effect of solvent type on retardation properties of diltiazem HCl form liquisolid tablets. AB - Liquisolid technique is a new approach to formulate sustained release dosage forms. It seems that the solubility of an active ingredient in solvent plays an important role in drug release profile. The aim of present study was to investigate the effect of solvent type on diltiazem hydrochloride release profile from liquisolid compacts. To examine aforementioned idea, the drug solubility was studied in several conventional nonvolatile solvents. Liquisolid formulations of diltiazem HCl in the different solvents were prepared and their release profiles were also obtained. Effect of aging on the hardness and drug release profile was studied as well. X-ray crystallography and differential scanning calorimetry (DSC) were used to investigate the formation of any complex between drug and carrier or any crystallinity changes during the manufacturing process. The results showed that diltiazem HCl had lowest solubility in polysorbate 20. Highest amount was devoted to polysorbate 80 and propylene glycol. Type of nonvolatile solvent and its physicochemical properties as well as solubility of the drug in the applied solvent found to have important role on release profile of the drug from liquisolid compacts. Hardness and dissolution profile of the drug were not affected by aging. Amorphous form was obtained during the process of liquisolid formulation. It follows that the optimized new technique can be used to prepare sustained release formulations of water-soluble drugs. PMID- 24060926 TI - Quercetin-nanostructured lipid carriers: characteristics and anti-breast cancer activities in vitro. AB - Quercetin (Q), a common dietary flavonoid, has gained research attention in cancer chemo-prevention, but its low level of aqueous solubility, stability, cellular bioavailability has limited its application. We have synthesized biocompatible and biodegradable Q-nanostructured lipid carriers (Q-NLC) using a novel phase inversion-based process method. The average size of Q-NLC was 32 nm in diameter. Q-NLC had good chemical and physical stability, and showed a sustained release pattern. The encapsulation efficiency and loading capacity of Q NLC were 95% and 11%, respectively. The aqueous solubility of Q was dramatically improved by at least 1000 folds. The results from Raman spectroscopy, powder X ray diffraction (XRD) and differential scanning calorimetry (DSC) demonstrated that Q presented in NLC as an encapsulated molecule form. As compared to native Q, Q-NLC dramatically increased cytotoxicity in a dose-dependent manner (1-50 MUM) and induced apoptosis at 20 MUM in MCF-7 and MDA-MB-231 breast cancer cells. The enhanced cytotoxicity and apoptosis were parallel to increased Q uptake by those cancer cells. Void NLC did not change the viability and apoptosis of those cancer cells as compared to phosphate buffered saline. In conclusion, Q-NLC dramatically enhanced the anti-cancer activities of Q, which were associated with enhanced Q solubility and stability, and increased Q content in those cancer cells. Q-NLC have a potential for chemo-preventive use in breast cancer. PMID- 24060927 TI - Surface modification of polyurethane films by plasma and ultraviolet light to improve haemocompatibility for artificial heart valves. AB - Prosthetic cardiac valves implantation is a common procedure used to treat heart valve diseases. Although there are different prostheses already available in the market (either mechanical or bioprosthetic), their use presents several problems, specifically concerning thrombogenicity and structural failure. Recently, some progresses have been achieved in developing heart valves based on synthetic materials with special emphasis in polymers. Among them, polyurethanes are one of the most commonly used for the production of these devices. Herein, Elastollan((r))1180A50, a thermoplastic polyurethane (TPU), was used to formulate films whose surfaces were modified by grafting 2-hydroxyethylmethacrylate (HEMA) either by ultra-violet (UV) or by plasma treatment. All films were analyzed before and after grafting. X-ray photoelectron spectroscopy (XPS) measurements were used to evaluate TPU surfaces functionalization. HEMA grafting was confirmed by the increase of the hydroxyl (OH) groups' concentration at the surface of the films. Atomic force microscopy (AFM) analysis was done to evaluate the surface topography of the biomaterials. Results showed that the roughness of the surface decreased when HEMA was grafted, especially for plasma treated samples. After grafting the films' hydrophilicity was improved, as well as the polar component of the surface energy, by 15-30%. Hydrophobic recovery studies using milli Q water or PBS were also performed to characterize the stability of the modified surface, showing that the films maintained their surface properties along time. Furthermore, blood-contact tests were performed to evaluate haemolytic and thrombogenic potential. The results obtained for HEMA grafted surfaces, using plasma treatment, confirmed biomaterials biocompatibility and low thrombogenicity. Finally, the cytotoxicity and antibacterial activity of the materials was assessed through in vitro assays for both modified films. The obtained results showed enhanced bactericidal activity, especially for the films modified with plasma. PMID- 24060928 TI - The effect of anti-TGF-beta2 antibody functionalized intraocular lens on lens epithelial cell migration and epithelial-mesenchymal transition. AB - Migration and epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) are main causes of central posterior capsule opacification after cataract extraction combined with intraocular lens (IOL) implantation. In this study, commercially available hydrophobic acrylic IOLs were first pretreated with atmospheric pressure glow discharge plasma to produce plenty of negatively charged chemical groups onto IOL surface, then polyethylenimine was deposited onto IOL surfaces as a precursor monolayer, and then anti-TGF-beta2 (anti-T) antibody and poly-l-lysine were sequentially deposited onto IOL surface for four cycles followed by another upmost monolayer of anti-T antibody via layer-by-layer self-assembly technique. After the fabrication of anti-T antibody multilayers on IOL surface, the surface characteristics of the anti-T antibody functionalized IOL, as well as its effect on LECs adhesion, proliferation, migration and EMT were then tested in this study. Our results revealed that anti-T antibody multilayers could be successfully immobilized onto IOL surfaces by plasma pretreatment and layer-by-layer self-assembly technique, and could keep stable for at least 3 months on IOL surface. The anti-T antibody immobilized in the multilayers on IOL surfaces showed good immunological activity by its specific antigen-antibody interaction with exogenous TGF-beta2. Anti-T antibody functionalized IOL surface was as smooth and flat as the untreated IOL surface. No difference in optical or physical properties was found between the anti-T antibody functionalized IOLs and the untreated IOLs. Compared with the untreated IOLs, the anti-T antibody functionalized IOL greatly inhibited LECs from migration and EMT, yet showed only transient inhibition to LECs adhesion and no inhibition to LECs proliferation. With these data, we demonstrate a simple, inexpensive, and feasible method to fabricate surface functionalized IOL for in situ capture and neutralization of TGF-beta2 in the capsular bag, which might be a possible solution to preventing posterior capsule opacification after cataract surgery. PMID- 24060923 TI - Multifunctional nanoparticles for brain tumor imaging and therapy. AB - Brain tumors are a diverse group of neoplasms that often carry a poor prognosis for patients. Despite tremendous efforts to develop diagnostic tools and therapeutic avenues, the treatment of brain tumors remains a formidable challenge in the field of neuro-oncology. Physiological barriers including the blood-brain barrier result in insufficient accumulation of therapeutic agents at the site of a tumor, preventing adequate destruction of malignant cells. Furthermore, there is a need for improvements in brain tumor imaging to allow for better characterization and delineation of tumors, visualization of malignant tissue during surgery, and tracking of response to chemotherapy and radiotherapy. Multifunctional nanoparticles offer the potential to improve upon many of these issues and may lead to breakthroughs in brain tumor management. In this review, we discuss the diagnostic and therapeutic applications of nanoparticles for brain tumors with an emphasis on innovative approaches in tumor targeting, tumor imaging, and therapeutic agent delivery. Clinically feasible nanoparticle administration strategies for brain tumor patients are also examined. Furthermore, we address the barriers towards clinical implementation of multifunctional nanoparticles in the context of brain tumor management. PMID- 24060929 TI - Paclitaxel-loaded PCL-TPGS nanoparticles: in vitro and in vivo performance compared with Abraxane(r). AB - The purpose of this work was to develop Cremophor((r)) EL-free nanoparticles (NPs) loaded with Paclitaxel (PTX) in order to improve the drug i.v. pharmacokinetic profile and to evaluate its activity against commercially available formulations such as Taxol((r)) and Abraxane((r)). PTX-loaded poly(epsilon-caprolactone)-alpha tocopheryl polyethylene glycol 1000 succinate (PCL-TPGS) NPs were prepared using three different techniques: (i) by nanoprecipitation (NPr-method), (ii) by emulsion-solvent evaporation homogenized with an Ultra-Turrax((r)) (UT-method) and (iii) by emulsion-solvent evaporation homogenized with an ultrasonicator (US-method). The NPs prepared by US-method showed the smallest size and the highest drug content. The NPs exhibited a slow and continuous release of PTX. The in vitro anti-tumoral activity was assessed using two human breast cancer cell lines (MCF-7 and MDA-MB-231) with the WTS assay. Cytotoxicity studies with both cell lines showed that PTX-loaded PCL-TPGS NPs exhibited better anti-cancer activity compared to PTX solution and the commercial formulation Abraxane((r)) at different concentrations. Importantly, in the case of triple negative MDA-MB-231 breast cancer cells, the IC50 value for PTX-loaded PCL-TPGS NPs was 7.8 times lower than Abraxane((r)). Finally, in vivo studies demonstrated that PTX-loaded PCL-TPGS NPs exhibited longer systemic circulation time and slower plasma elimination rate than Taxol((r)) and Abraxane((r)). Therefore, the novel NPs investigated might be an alternative nanotechnological platform for PTX delivery system in cancer chemotherapy. PMID- 24060930 TI - Adsorption and release of ofloxacin from acid- and heat-treated halloysite. AB - Halloysite nanotube is an ideal vehicle of the controlled release of drugs. In this study, we systematically investigated the effects of acid- and heat treatments on the physicochemical properties, structure and morphology of halloysite by XRD, FTIR, SEM and TEM. Afterwards, the adsorption and in vitro release properties of halloysite for cationic ofloxacin (OFL) were evaluated. The results indicate that HCl treatment has no influence on the crystal structure of halloysite, whereas it becomes amorphous after calcined at temperature higher than 500 degrees C. Both acid- and heat-treatments have no evident influence on the tubular structure of halloysite. OFL was adsorbed onto halloysite via electrostatic interaction between protonated OFL and negative halloysite surface, cation exchange as well as electrostatic interaction between the OFL-Al(3+) complexes and the negative halloysite surface. Acid-treatment facilitates the release of the adsorbed OFL compared with the natural halloysite in spite of a slight decrease of adsorption capacity. However, heat-treatment results in a sharp decrease of adsorption capacity for OFL owning to the OFL-promoted dissolution of aluminum and the disappearance of the porous structure. Although heat-treatment also facilitates release of the adsorbed OFL, the amount of OFL released is in fact less than the natural halloysite owing to the very low adsorption capacity. Thus, acid-activation is an effective protocol to improve the adsorption and release of halloysite for cationic drug molecules. PMID- 24060931 TI - Disinfection action of electrostatic versus steric-stabilized silver nanoparticles on E. coli under different water chemistries. AB - The capping layer stabilizing silver nanoparticles (AgNPs) affects its aggregation, dissolution, and net disinfection action, especially under conditions of varying water composition, such as, pH, ionic strength and organic matter content. Herein, we correlate the silver ion (Ag(+)) release and reactive oxygen species (ROS) generation rates for AgNPs of varying functionalization to their net disinfection coefficient on Escherichia coli, under conditions of differing water chemistries. For electrostatically stabilized citrate-capped AgNPs, the rate of ROS generation, as measured using a fluorescent dye, is found to dominate over that of Ag(+) release, especially for smaller sized AgNP suspensions (~10nm) at low pH (~6.2). For these AgNPs, the ROS disinfection mechanism is confirmed to dominate net disinfection action, as measured by the live/dead assay, especially at low levels of organic matter. Steric stabilization of AgNPs by protein or starch-capped layers enables disinfection through reducing AgNP aggregation and promoting silver dissolution over ROS generation. We suggest the involvement of protons and dissolved oxygen in causing the independent formation of Ag(+) and ROS, regardless of the AgNP capping layer. While protein capping layers effectively stabilize AgNPs, the generated ROS is likely dissipated by interference with the bulky capping layer, whereas the interference is lower with citrate-capping layers. Steric stabilization of AgNPs enables disinfection within a wide range of water chemistries, whereas effective disinfection can occur under electrostatic stabilization, only at low NaCl (<1 mmol/L) and organic matter (<5 mg/L) levels. PMID- 24060932 TI - Detection of real sample DNA at a cadmium sulfide--chitosan/gelatin modified electrode. AB - Cadmium sulfide (CdS) was combined with chitosan (Chi) and gelatin (Gel) to prepare a CdS-Chi/Gel modified electrode. Chi exhibits a large positive charge density and was to provide a uniform of CdS surface. Gel exhibits high mechanical strength and low toxicity toward mammalian cells, and is non-antigenic biopolymer. CdS-Chi exhibits a lower contact angle than that of bare CdS, indicating that the hydrophilicity of the sample surface had increased. Electrochemical impedance spectroscopy (EIS) was used to determine diffusion coefficients and to characterize the electron transfer kinetics during the redox reactions. The surface morphologies of CdS-Chi and Gel were characterized using scanning electron microscopy (SEM) and atomic force microscopy (AFM). Differential pulse voltammetry (DPV) was used to detect the analytes. DPV not only increased the linear range of the electrocatalytic current, but also lowered the overpotential for oxidation interference in the measurements. The CdS electrode exhibited a enhanced electrocatalytic activity toward the analytes evaluated in this study. The presence of Gel enhanced the loading and stability of the electrode. The fabricated electrode was successfully used for the simultaneous electrochemical oxidation of guanine (G) and adenine (A). PMID- 24060933 TI - Improved oral bioavailability of core-shell structured beads by redispersion of the shell-forming nanoparticles: preparation, characterization and in vivo studies. AB - In order to increase the dissolution rate and oral bioavailability of bifendate, coated beads with core-shell structure were prepared via a combination use of wet media milling method and bead layering process. Hydroxypropyl cellulose (HPC-SL) and sodium lauryl sulfate (SLS) were found to be the best pair to stabilize the nanosuspension during milling process. A 10:1 ratio of mixture of mannitol and SLS was chosen as most suitable coating matrix to maintain the redispersability of dried nanoparticles in the shell of beads. The mean particle size of the nanosuspension was 139 nm and the zeta potential was -20.2 mV. Nanoscale bifendate particles with a mean diameter of 360 nm could be generated when redispersing the prepared beads in water. The differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) analysis indicated that the crystalline state of the drug was not changed. The stability test confirmed that coated beads showed no distinct difference in particle size and dissolution velocity during 6 month storage while liquid nanosuspension was stable no more than 3 weeks. Dissolution rate of coated beads was increased significantly compared with commercially available pills. Likewise, the Cmax and AUC (0->24) of nanosuspension based beads in beagle dogs were 2.40-fold and 1.66-fold greater than that of commercially available pills, respectively. The present work is a reliable approach to stabilize nanosuspension based product, and improve dissolution velocity and bioavailability of poor soluble drugs. PMID- 24060934 TI - Effects of plasma treatment to nanofibers on initial cell adhesion and cell morphology. AB - Poly-L-lactic acid (PLLA) nanofibers were fabricated by electrospinning and treated with O2 plasma. The surface properties of PLLA nanofibers before and after plasma treatment were characterized by water contact angle measurement and X-ray photoelectron spectroscopy (XPS). It was found that the hydrophilicity of PLLA nanofibers was improved and the amount of oxygen-containing groups increased after plasma treatment. Initial cell adhesion was evaluated by cell capture efficiency based on the cell count method. The results showed that initial porcine mesenchymal stem cells (pMSCs) adhesion to plasma-treated nanofibers was significantly enhanced. Moreover, the morphology of pMSCs on PLLA nanofibers (PLLA NFS) and plasma-treated PLLA nanofibers (P-PLLA NFS) were observed by scanning electron microscope (SEM) after 10 min, 20 min, 30 min and 60 min cell adhesion. It was found that plasma treatment to electrospun nanofibers had a great effect on pMSCs morphology at earlier time points. Therefore, plasma treatment is an efficient surface modification strategy to improve cell adhesion in earlier culture time intervals. It may be a promising method in the design of novel tissue-engineered scaffolds. PMID- 24060935 TI - Stabilization of water in oil in water (W/O/W) emulsion using whey protein isolate-conjugated durian seed gum: enhancement of interfacial activity through conjugation process. AB - The present work was conducted to investigate the effect of purification and conjugation processes on functional properties of durian seed gum (DSG) used for stabilization of water in oil in water (W/O/W) emulsion. Whey protein isolate (WPI) was conjugated to durian seed gum through the covalent linkage. In order to prepare WPI-DSG conjugate, covalent linkage of whey protein isolate to durian seed gum was obtained by Maillard reaction induced by heating at 60 degrees C and 80% (+/-1%) relative humidity. SDS-polyacrylamide gel electrophoresis was used to test the formation of the covalent linkage between whey protein isolate and durian seed gum after conjugation process. In this study, W/O/W stabilized by WPI-conjugated DSG A showed the highest interface activity and lowest creaming layer among all prepared emulsions. This indicated that the partial conjugation of WPI to DSG significantly improved its functional characteristics in W/O/W emulsion. The addition of WPI-conjugated DSG to W/O/W emulsion increased the viscosity more than non-conjugated durian seed gum (or control). This might be due to possible increment of the molecular weight after linking the protein fraction to the structure of durian seed gum through the conjugation process. PMID- 24060936 TI - Anti-adhesion and antibacterial activity of silver nanoparticles supported on graphene oxide sheets. AB - This work reports on the preparation, characterization and antibacterial activity of a nanocomposite formed from graphene oxide (GO) sheets decorated with silver nanoparticles (GO-Ag). The GO-Ag nanocomposite was prepared in the presence of AgNO3 and sodium citrate. The physicochemical characterization was performed by UV-vis spectroscopy, X-ray diffraction (XRD), thermogravimetric analysis (TGA), Raman spectroscopy and transmission electron microscopy (TEM). The average size of the silver nanoparticles anchored on the GO surface was 7.5 nm. Oxidation debris fragments (a byproduct adsorbed on the GO surface) were found to be crucial for the nucleation and growth of the silver nanoparticles. The antibacterial activity of the GO and GO-Ag nanocomposite against the microorganism Pseudomonas aeruginosa was investigated using the standard counting plate methodology. The GO dispersion showed no antibacterial activity against P. aeruginosa over the concentration range investigated. On the other hand, the GO Ag nanocomposite displayed high biocidal activity with a minimum inhibitory concentration ranging from 2.5 to 5.0 MUg/mL. The anti-biofilm activity toward P. aeruginosa adhered on stainless steel surfaces was also investigated. The results showed a 100% inhibition rate of the adhered cells after exposure to the GO-Ag nanocomposite for one hour. To the best of our knowledge, this work provides the first direct evidence that GO-Ag nanocomposites can inhibit the growth of microbial adhered cells, thus preventing the process of biofilm formation. These promising results support the idea that GO-Ag nanocomposites may be applied as antibacterial coatings material to prevent the development of biofilms in food packaging and medical devices. PMID- 24060937 TI - An impedance-based integrated biosensor for suspended DNA characterization. AB - Herein, we describe a novel integrated biosensor for performing dielectric spectroscopy to analyze biological samples. We analyzed biomolecule samples with different concentrations and demonstrated that the solution's impedance is highly correlated with the concentration, indicating that it may be possible to use this sensor as a concentration sensor. In contrast with standard spectrophotometers, this sensor offers a low-cost and purely electrical solution for the quantitative analysis of biomolecule solutions. In addition to determining concentrations, we found that the sample solution impedance is highly correlated with the length of the DNA fragments, indicating that the sizes of PCR products could be validated with an integrated chip-based, sample-friendly system within a few minutes. The system could be the basis of a rapid, low-cost platform for DNA characterization with broad applications in cancer and genetic disease research. PMID- 24060938 TI - Anodic bonded 2D semiconductors: from synthesis to device fabrication. AB - Two-dimensional semiconductors are increasingly relevant for emergent applications and devices, notably for hybrid heterostructures with graphene. We fabricate few-layer, large-area (a few tens of microns across) samples of the III VI semiconductors GaS, GaSe and InSe using the anodic bonding method and characterize them by simultaneous use of optical microscopy, atomic force microscopy and Raman spectroscopy. Two-terminal devices with a gate are constructed to show the feasibility of applications based on these. PMID- 24060939 TI - High diversity in CMA3/DAPI-banding patterns in Heteropterans. AB - Heteroptera is the most numerous and diverse suborder of Hemiptera, with about 38,000 species. This diversity also involves cytogenetic features, including chromosome number and a sex determining system. Information about heterochromatin occurrence and distribution is scarce in heteropterans, but still, there is some evidence of variability. We determined the chromosome number and CMA3/DAPI banding pattern of 179 individuals of 25 heteropteran species from Brazil. Eight species of Pentatomidae exhibited a constant chromosome number (2n = 12 + XY), but in Coreidae (12 species), Largidae (1 species), Rhopalidae (1 species), and Pyrrhocoridae (3 species), the numbers ranged from 2n = 10 + 2m + X0 to 2n = 24 + 2m + X0. Although there were no large differences in the chromosome size between species, the CMA3/DAPI-banding patterns differed markedly. Among the genera, species of Edessa, Spartocera, Hypselonotus, Phtia,Holhymenia and Euryophthalmus showed a large accumulation of heterochromatin, while the other species exhibited few or no heterochromatic bands. In general, when heterochromatin was more accumulated, this occurred preferentially at terminal positions, except in Holhymenia histrio, which exhibited intercalary bands. This study made it possible to identify some chromosome rearrangements and to enhance our knowledge of the evolutionary mechanisms that determine karyotype differentiation in Heteroptera. PMID- 24060940 TI - Perovskite transparent conducting oxides: an ab initio study. AB - We present an ab initio study of the electronic structure and of the formation energies of various point defects in BaSnO3 and SrGeO3. We show that La and Y impurities substituting Ba or Sr are shallow donors with a preferred 1 + charge state. These defects have a low formation energy within all the suitable equilibrium growth conditions considered. Oxygen vacancies behave as shallow donors as well, preferring the 2 + charge state. Their formation energies, however, are higher in most growth conditions, indicating a limited contribution to conductivity. The calculated electron effective mass in BaSnO3, with a value of 0.21 m(e), and the very high mobility reported recently in La-doped BaSnO3 single-crystals, suggest that remarkably low scattering rates can be achieved in the latter. In the case of SrGeO3, our results point to carrier density and mobility values in the low range for typical polycrystalline TCOs, in line with experiment. PMID- 24060941 TI - Endocarditis in congenital heart disease: who is at highest risk? PMID- 24060942 TI - Infective endocarditis in children with congenital heart disease: cumulative incidence and predictors. AB - BACKGROUND: The American Heart Association guidelines for prevention of infective endocarditis (IE) in 2007 reduced the groups of congenital heart disease (CHD) patients for whom antibiotic prophylaxis was indicated. The evidence base in CHD patients is limited. We sought to determine the risk of IE in children with CHD. METHODS AND RESULTS: We performed a population-based analysis to determine the cumulative incidence and predictors of IE in children (0-18 years) with CHD by the use of the Quebec CHD Database from 1988 to 2010. In 47 518 children with CHD followed for 458 109 patient-years, 185 cases of IE were observed. Cumulative incidence of IE was estimated in the subset of 34 279 children with CHD followed since birth, in whom the risk of IE up to 18 years of age was 6.1/1000 children (95% confidence interval, 5.0-7.5). In a nested case-control analysis, the following CHD lesions were at highest risk of IE in comparison with atrial septal defects (adjusted rate ratio, 95% confidence interval): cyanotic CHD (6.44, 3.95 10.50), endocardial cushion defects (5.47, 2.89-10.36), and left-sided lesions (1.88, 1.01-3.49). Cardiac surgery within 6 months (5.34, 2.49-11.43) and an age of <3 years (3.53, 2.51-4.96; reference, ages 6-18) also conferred an elevated risk of IE. CONCLUSIONS: In a large population-based cohort of children with CHD, we documented the cumulative incidence of IE and associated factors. These findings help identify groups of patients who are at the highest risk of developing IE. PMID- 24060943 TI - Pulmonary vascular hemodynamic response to exercise in cardiopulmonary diseases. PMID- 24060945 TI - Recurrent Ebstein-Barr virus-associated diffuse large B-cell lymphoma in an ascending aorta graft. PMID- 24060946 TI - Inversion of the left atrial appendage: an unusual finding after pediatric heart transplantation. PMID- 24060948 TI - Letter by Opolski et al regarding article, "Computed tomography coronary angiography in patients with acute myocardial infarction without significant coronary stenosis". PMID- 24060949 TI - Response to the letter by Opolski et al regarding article, "Computed tomography coronary angiography in patients with acute myocardial infarction without significant coronary stenosis". PMID- 24060951 TI - Impact of probiotics on colonic microflora in patients with colitis: a prospective double blind randomised crossover study. AB - BACKGROUND & AIMS: The aim of this study was to investigate the spectrum of colonic microflora in patients with colitis and if this could be altered with one month's treatment with synbiotics. METHODS: This was a pilot study in which patients were randomised to either receive a synbiotics preparation for a month and then "crossed over" to receive a placebo, or alternatively to receive the placebo first followed in the second month by synbiotic. Stool samples were collected on entry into the study and then at the end of first and second months respectively. Colonic microflora was measured by terminal restriction fragment length polymorphism technique. Quantitative PCR was used to determine the concentration of individual species. RESULTS: Sixteen patients completed the study of whom 8 had Crohn's colitis and 8 had ulcerative colitis. Their median age was 62 (IQR 50-65) years. An average of 22 terminal restriction fragments (T RF's) was identified in each patient. Dice cluster analysis showed that each patient had a unique microbial composition which did not change significantly at different time points in the study, irrespective of whether they had probiotics or the placebo. Probiotic organisms were identified in stool samples but did not alter overall spectrum of microflora. In this pilot study we were unable to identify any specific characteristics related to nature of colitis. CONCLUSIONS: This study suggests that there is no difference in colonic microflora between patients with Crohn's or Ulcerative colitis and that the spectrum of bacteria was not altered by synbiotic administration. PMID- 24060952 TI - Synthesis and antiproliferative activity of novel steroidal dendrimer conjugates. AB - We describe the synthesis of steroidal dendrimer conjugates of first and second generation with tetramethylene core and 5-hydroxy-isophtalic acid dimethyl ester as branching unit modified to incorporate ethynylestradiol or 17alpha-estradiol as terminal units. The steroidal dendrimer conjugates, the free drug (steroids) and dendrimer were tested against a panel of cancer cell lines (CEM, MCF7, HeLa) and normal human fibroblast (BJ). The steroidal dendrimer conjugates of first generation exhibited cytotoxic activity and induced apoptosis in chronic leukemia (CEM) as resultant activation of caspase cascade which is mainly provoked in G2/M arrested cells. PMID- 24060953 TI - The diagnosis of contrast-induced neurotoxicity. PMID- 24060954 TI - Steal phenomena in TEVAR, a reality after all. PMID- 24060955 TI - Reasons to recommend lifestyle changes in type 2 diabetes mellitus and obesity. PMID- 24060956 TI - Interventional cardiology: Streamlining reperfusion for STEMI. PMID- 24060957 TI - Surgery: Remote ischaemic conditioning--approaching prime time? PMID- 24060960 TI - The donor/acceptor edge-modification: an effective strategy to modulate the electronic and magnetic behaviors of zigzag silicon carbon nanoribbons. AB - Based on first principles computations, we systematically investigated electronic and magnetic properties of zSiCNRs with unilateral/bilateral modification by employing electron donor/acceptor groups, where five chemical functional groups are sampled, namely, CH3, OH, NH2, CN and NO2. Our computed results reveal that the edge modification with donor/acceptor groups can break the magnetic degeneracy of pristine zSiCNRs, and intriguing antiferromagnetic (AFM) half metallicity, AFM metallicity and ferromagnetic (FM) metallicity can be achieved. This overcomes the bottleneck that FM metallicity and AFM half-metallicity in pristine zSiCNRs are vulnerable under even small disturbances, due to the energy degeneracy between the FM and AFM states. Obviously, edge modification with donor/acceptor groups can be an effective strategy to modulate the electronic and magnetic behaviors of zSiCNRs, which will be advantageous for promoting SiC-based nanomaterials in the application of spintronics and multifunctional nanodevices in the near future. PMID- 24060959 TI - Medial and intimal calcification in chronic kidney disease: stressing the contributions. PMID- 24060958 TI - Demystifying the management of hypertriglyceridaemia. AB - Hypertriglyceridaemia (typical triglyceride level 1.7-5.0 mmol/l) is caused by interactions between many genetic and nongenetic factors, and is a common risk factor for atherosclerotic cardiovascular disease (CVD). Patients with hypertriglyceridaemia usually present with obesity, insulin resistance, hepatic steatosis, ectopic fat deposition, and diabetes mellitus. Hypertriglyceridaemia reflects the accumulation in plasma of proatherogenic lipoproteins, triglyceride rich lipoprotein (TRL) remnants, and small, dense LDL particles. Mendelian randomization studies and research on inherited dyslipidaemias, such as type III dysbetalipoproteinaemia, testify that TRLs are causally related to atherosclerotic CVD. Extreme hypertriglyceridaemia (a triglyceride level >20 mmol/l) is rare, often monogenic in aetiology, and frequently causes pancreatitis. Treatment of hypertriglyceridaemia relies on correcting secondary factors and unhealthy lifestyle habits, particularly poor diet and lack of exercise. Pharmacotherapy is indicated for patients with established CVD or individuals at moderate-to-high risk of CVD, primarily those with metabolic syndrome or diabetes. Statins are the cornerstone of treatment, followed by fibrates and n-3 fatty acids, to achieve recommended therapeutic levels of plasma LDL cholesterol, non-HDL cholesterol, and apolipoprotein (apo) B-100. The case for using niacin has been weakened by the results of clinical trials, but needs further investigation. Extreme hypertriglyceridaemia requires strict dietary measures, and patients with a diagnosis of genetic lipoprotein lipase deficiency might benefit from LPL gene replacement therapy. Several therapies for regulating TRL metabolism, including inhibitors of diacylglycerol O-acyltransferase and microsomal triglyceride transfer protein, and apoC-III antisense oligonucleotides, merit further investigation in patients with hypertriglyceridaemia. PMID- 24060962 TI - Dispersive micro-solid phase extraction based on self-assembling, ionic liquid coated magnetic particles for the determination of clofentezine and chlorfenapyr in environmental water samples. AB - Two ionic liquid-coated-Fe3O4 magnetic particles (IL-Fe3O4 MPs) were developed for use in two types of dispersive micro-solid phase extraction (D-MU-SPE) for the high-performance liquid chromatographic analysis of clofentezine and chlorfenapyr in environmental water samples. Self-assembling IL-Fe3O4 MPs were used in D-MU-SPE as adsorbents. Two D-MU-SPE extraction methods, namely, direct dispersive micro-solid phase extraction (d-D-MU-SPE) and in situ solvent formation-based dispersive micro-solid phase extraction (ISF-D-MU-SPE), were proposed, using [C8MIM][PF6] to extract analytes through two pathways. Lower IL doses were required in the extraction process compared with those in other IL based methods. Fe3O4 MPs can also be recycled and reused after extraction and are thus environmentally friendly. These newly developed methods were demonstrated to be feasible for use in the quantitation of clofentezine and chlorfenapyr at trace levels, with lower limit of detection values ranging from 0.4 to 0.5 ng mL(-1) for d-D-MU-SPE and 0.4 ng mL(-1) for ISF-D-MU-SPE. Finally, relative standard deviations of less than 6.0% were obtained. PMID- 24060961 TI - Hype or hypervirulence: a reflection on problematic C. difficile strains. AB - Clostridium difficile infections (CDI) have emerged as a major cause of healthcare associated disease, and recent epidemiological evidence also suggests an important role in community-acquired diarrhea. This increase is associated with specific types, especially PCR ribotypes 027 and 078, which are sometimes referred to as "hypervirulent". Over the past years major advances have been made in our understanding of C. difficile pathogenicity, with the identification and characterization of the major clostridial toxins TcdA and TcdB. However, the relation between the toxins, their regulation, and "hypervirulence" remain unclear. Here I review our current understanding of C. difficile pathogenicity and argue that "hypervirulent" is an inadequate term to describe PCR ribotypes 027 and 078, that the ability of C. difficile to cause problematic infections is a consequence of a multifactorial process that extends beyond toxins, sporulation, and antimicrobial resistance, and that vigilance is in order toward types that are closely related to ribotypes 027 and 078, but are currently not considered problematic. PMID- 24060964 TI - Honor thy Go(na)ds. PMID- 24060963 TI - C5a, but not C5a-des Arg, induces upregulation of heteromer formation between complement C5a receptors C5aR and C5L2. AB - Receptors for C5a have an important role in innate immunity and inflammation where their expression and activation is tightly regulated. There are two known receptors for C5a: the C5a receptor (C5aR) and the C5a receptor like-2 (C5L2) receptor. Here we hypothesized that activation of C5aR might lead to heteromer formation with C5L2, as a downregulatory mechanism for C5aR signaling. To investigate this experimentally, bioluminescent resonance energy transfer (BRET) was implemented and supported by wide-field microscopy to analyze receptor localization in transfected HEK293 cells and human monocyte-derived macrophages (HMDM). BRET experiments indicated the presence of constitutive C5aR-C5L2 heteromers, where C5a, but not C5a-des Arg, was able to induce further heteromer formation, which was inhibited by a C5aR-specific antagonist. The data obtained suggest that C5aR-C5L2 can form heteromers in a process enhanced by C5a, but not by C5a-des Arg. There was also a significant difference in the levels of the anti inflammatory cytokine IL-10 detected in HMDM following exposure to C5a compared with that seen for C5a-des Arg but no differences in the pro-inflammatory cytokines TNFalpha and IL-6. These subtle differences in C5a and C5a-des Arg induced receptor function may be of benefit in understanding the regulation of C5a in acute inflammation. PMID- 24060965 TI - Microtubule-stabilizing agents delay the onset of EAE through inhibition of migration. AB - We have shown previously that microtubule-stabilizing agents (MSA), a class of anti-proliferative compounds, can delay disease onset and reduce cumulative disease in an experimental model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). To explore how MSA could alter EAE disease processes, we compared the effect of administering MSA before or after peak antigen-specific proliferation and found that treatment before proliferation completely inhibited antigen-specific responses in the spleen; whereas administration of an MSA such as paclitaxel or docetaxel after peak proliferation did not. Despite the presence of antigen-specific responses in mice treated at the later time point, both treatment periods resulted in similar protection against EAE, suggesting that the protective effect of MSA in EAE could not be solely attributed to anti proliferative activity. Instead, using in vivo migration assays, it was shown that MSA inhibit immune cell infiltration into the central nervous system (CNS). Furthermore, we found that the efficacy of an MSA could be enhanced by administering low doses of two different MSA together, such as peloruside A and ixabepilone, indicating that these MSA synergize in vivo to suppress disease. Taken together, these data suggest that MSA can suppress EAE by at least two distinct mechanisms of action--prevention of proliferation and inhibition of migration into the CNS. Finally, we have shown that a combination treatment with synergizing MSA may provide enhanced protection at lower therapeutic doses. PMID- 24060966 TI - Harsh voice quality and its association with blackness in popular American media. AB - Performers use various laryngeal settings to create voices for characters and personas they portray. Although some research demonstrates the sociophonetic associations of laryngeal voice quality, few studies have documented or examined the role of harsh voice quality, particularly with vibration of the epilaryngeal structures (growling). This article qualitatively examines phonetic properties of vocal performances in a corpus of popular American media and evaluates the association of voice qualities in these performances with representations of social identity and stereotype. In several cases, contrasting laryngeal states create sociophonetic contrast, and harsh voice quality is paired with the portrayal of racial stereotypes of black people. These cases indicate exaggerated emotional states and are associated with yelling/shouting modes of expression. Overall, however, the functioning of harsh voice quality as it occurs in the data is broader and may involve aggressive posturing, comedic inversion of aggressiveness, vocal pathology, and vocal homage. PMID- 24060967 TI - On how accent distribution can signal speaker adaptation. AB - Some dialogues are perceived as running more smoothly than others. To some extent that impression could be related to how well speakers adapt their prosody to each other. Adaptation in prosody can be signaled by the use of pitch accents that indicate how utterances are structurally related to those of the interlocutor (prosodic function) or by copying the interlocutor's prosodic features (prosodic form). The same acoustic features, such as pitch, are involved in both ways of adaptation. Further, function and form may require a different prosody for successful adaptation in certain discourse contexts. In this study we investigate to what extent interlocutors are perceived as good adapters, depending on whether the prosody of both speakers is functionally coherent or similar in form. This is done in two perception tests using prosodically manipulated dialogues. Results show that coherent functional prosody can be a cue for speaker adaptation and that this cue is more powerful than similarity in prosodic form. PMID- 24060968 TI - Prosodic variation for topic shift and other functions in local contrasts in conversation. AB - Speakers and listeners have been shown to use phonetic cues to help them in tracking the ongoing structure of conversational interaction, but fragmentation between qualitative and quantitative research means that the forms and functions of these cues have been given varying characterizations. The current study explores prosodic variation in contrastive structures in conversational data, using a combined methodology adopting aspects from both qualitative (conversation analysis) and quantitative (experimental phonetics/phonology) approaches. Statistical and conversation-analytical methods used together reveal relationships between prosodic variation and interactional function, such as variations in pitch range across adjacent turns being linked to the presence of 'stepwise' topic changes. PMID- 24060969 TI - From phonetics to phonology and back again. Ladd, D.R.: phonetics in phonology; in Goldsmith, Riggle, Yu, the handbook of phonological theory; 2nd ed., pp. 348 373 (Wiley-Blackwell, Chichester 2011). PMID- 24060971 TI - Investigation of film formation properties during electrochemical oxidation of serotonin (5-HT) at polycrystalline boron doped diamond. AB - The change in surface morphology of oxygen-terminated polycrystalline boron doped diamond (pBDD) during electrochemical oxidation of the neurotransmitter serotonin (5-HT), resulting in a corresponding deterioration of the current signal, is investigated for the first time using both high resolution ex situ and in situ microscopy under a range of different electrochemical conditions. In situ electrochemical-atomic force microscopy (EC-AFM) reveals the formation of a granular film over the surface, which grows faster at higher-doped regions of the electrode surface and increases in thickness with repetitive potential cycles. The film properties were investigated using both cyclic voltammetry, with a range of redox species varying in charge, and conducting-AFM. These studies reveal the film to be positively charged and electrically insulating. The extent to which the film forms during 5-HT oxidation could be significantly minimised using different electrochemical procedures, as verified by voltammetry and in situ EC AFM. Finally, even after extensive film formation, the original current signal could be recovered simply by leaving the electrode at open circuit potential for a short period of time, highlighting the suitability of BDD electrodes for neurotransmitter detection. PMID- 24060972 TI - Highly sensitive covalently functionalised integrated silicon nanowire biosensor devices for detection of cancer risk biomarker. AB - In this article we present ultra-sensitive, silicon nanowire (SiNW)-based biosensor devices for the detection of disease biomarkers. An electrochemically induced functionalisation method has been employed to graft antibodies targeted against the prostate cancer risk biomarker 8-hydroxydeoxyguanosine (8-OHdG) to SiNW surfaces. The antibody-functionalised SiNW sensor has been used to detect binding of the 8-OHdG biomarker to the SiNW surface within seconds of exposure. Detection of 8-OHdG concentrations as low as 1 ng/ml (3.5 nM) has been demonstrated. The active device has been bonded to a disposable printed circuit which can be inserted into an electronic readout system as part of an integrated Point of Care (POC) diagnostic. The speed, sensitivity and ease of detection of biomarkers using SiNW sensors render them ideal for eventual POC diagnostics. PMID- 24060973 TI - Selection of peptide ligands for piezoelectric peptide based gas sensors arrays using a virtual screening approach. AB - Virtual and experimental affinity binding properties of 5 different peptides (cysteinylglycine, glutathione, Cys-Ile-His-Asn-Pro, Cys-Ile-Gln-Pro-Val, Cys-Arg Gln-Val-Phe) vs. 14 volatile compounds belonging to relevant chemical classes were evaluated. The peptides were selected in order to have a large variability in physicochemical characteristics (including length). In virtual screening a rapid and cost-effective computational methodology for predicting binding scores of small peptide receptors vs. volatile compounds is proposed. Flexibility was considered for both ligands and peptides and each peptide conformer was treated as a possible receptor, generating a dedicated box and then running a docking process vs. all possible conformers of the 14 volatile compounds. The 5 peptides were covalently bound to gold nanoparticles and deposited onto 20 MHz quartz crystal microbalances to realize gas sensors. Gas sensing confirmed that each of the peptide conferred to the gold nanoparticles a particular selectivity pattern able to discriminate the 14 volatile compounds. The largest response was obtained for the pentapeptides Cys-Ile-His-Asn-Pro and Cys-Ile-Gln-Pro-Val while low response was achieved for the dipeptide. The comparative study, carried using a two-tailed T test, demonstrated that virtual screening was able to predict reliably the sensing ability of the pentapeptides. The dipeptide receptor exhibited 29% of virtual-experimental matching vs. 71% of glutathione and up to 93% for the pentapeptides. This virtual screening approach was proved to be a promising tool in predicting the behaviour of sensors array for gas detection. PMID- 24060974 TI - Disposable amperometric magnetoimmunosensors using nanobodies as biorecognition element. Determination of fibrinogen in plasma. AB - Two different fibrinogen (Fib) amperometric immunosensing designs based on the use of magnetic beads (MBs) and a novel specific nanobody (Nb) expressed in Escherichia coli are described for the first time. The immunological reaction for Fib detection was performed on COOH-MBs or His-Tag-Isolation-MBs as solid support for the immobilization of the antigen or the captured Nb. Direct and indirect competitive magnetoimmunosensing configurations have been tested and compared. In the former one, Fib and biotinylated Fib competed for the immobilized Nb binding sites while the latter configuration involved competition of free Fib in solution and immobilized Fib for binding to a fixed amount of the specific biotinylated Nb. Labeling of the captured biotinylated Nb or antigen was made with streptavidin-HRP. The modified magnetic beads were captured by a neodymium magnet on the surface of screen-printed carbon electrodes (SPCEs). Amperometric detection was accomplished at -0.20 V (vs. Ag pseudo-reference electrode) by measuring the catalytic current arising upon addition of H2O2 and using hydroquinone (HQ) as redox mediator in solution. A better analytical performance was achieved with the indirect competitive immunoassay with a detection limit of 0.044 MUg mL(-1) Fib. The usefulness of both approaches was successfully demonstrated by analyzing an international standard for Fib plasma. The assays could be carried out in diluted plasma samples in a total analysis time of 90 min. PMID- 24060975 TI - Amplified colorimetric detection of mercuric ions through autonomous assembly of G-quadruplex DNAzyme nanowires. AB - An amplified colorimetric detection of Hg(2+) is proposed by combining T-Hg(2+)-T base pairs and hybridization chain reaction (HCR). Two hairpins consisting of three-fourths and one-fourth of the horseradish peroxidase (HRP)-mimicking DNAzyme in inactive configuration are used as functional elements. In the presence of Hg(2+), one of the hairpins is opened by an assistant probe with the help of T-Hg(2+)-T base pairs and this triggers an autonomous cross-opening of the two hairpins using the strand displacement principle, resulting in the formation of DNA nanowires consisting of numerous reunited Q-quadruplex DNAzyme units. The resulting catalytically active hemin/G-quadruplex HRP-mimicking DNAzymes catalyze the oxidation of ABTS(2-) by H2O2 into a green-colored cationic radical ABTS(*+) for the colorimetric readout. This "turn-on" sensing system enables the high sensitive and selective detection of aqueous Hg(2+) with a detection limit of 9.7 pM. PMID- 24060976 TI - Characterization of a novel fusion protein from IpaB and IpaD of Shigella spp. and its potential as a pan-Shigella vaccine. AB - Shigellosis is an important disease in the developing world, where about 90 million people become infected with Shigella spp. each year. We previously demonstrated that the type three secretion apparatus (T3SA) proteins IpaB and IpaD are protective antigens in the mouse lethal pulmonary model. In order to simplify vaccine formulation and process development, we have evaluated a vaccine design that incorporates both of these previously tested Shigella antigens into a single polypeptide chain. To determine if this fusion protein (DB fusion) retains the antigenic and protective capacities of IpaB and IpaD, we immunized mice with the DB fusion and compared the immune response to that elicited by the IpaB/IpaD combination vaccine. Purification of the DB fusion required coexpression with IpgC, the IpaB chaperone, and after purification it maintained the highly alpha helical characteristics of IpaB and IpaD. The DB fusion also induced comparable immune responses and retained the ability to protect mice against Shigella flexneri and S. sonnei in the lethal pulmonary challenge. It also offered limited protection against S. dysenteriae challenge. Our results show the feasibility of generating a protective Shigella vaccine comprised of the DB fusion. PMID- 24060977 TI - Pancreatic ductal adenocarcinoma staging. AB - In addition to clinical history and evaluations, the results of laboratory tests and imaging studies help clinicians in determining treatment strategies. Imaging plays a central role in the management of oncology patients including the initial diagnosis, staging, and follow-up to assess treatment response. Historically, radiologists have relied on free-style dictations to convey the results of imaging findings in radiology reports to referring clinicians. These unstructured free-style dictations can potentially be a source of frustration as the pertinent information needed to guide treatment may be omitted or difficult to extract from the report, thereby limiting its completeness and usefulness. These limitations can be overcome by adopting a structured and reproducible form of reporting imaging studies to help clinicians in deciding the best treatment strategy for each patient. There is a growing need to establish standardized radiology reporting templates for specific disease processes. One such example involves patients with pancreatic ductal adenocarcinoma, as imaging findings determine the treatment arm to which the patient is assigned. In this presentation, we outline a list of essential features that need to be included in a structured report and highlight this with illustrative case examples. PMID- 24060978 TI - The economic impact of obstructive sleep apnea. AB - PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) has a substantial economic impact on healthcare systems. We reviewed parameters affecting healthcare costs (race, low education, and socioeconomic status) on OSA comorbidity, and costs and the effect of OSA treatment on medical costs. RECENT FINDINGS: OSA is associated with increased cardiovascular disease (CVD) morbidity and substantially increased medical costs. Risk for OSA and resulting CVD are associated with obesity, tobacco smoking, black race, and low socioeconomic status; all these are associated with poor continuous positive airway pressure (CPAP) adherence. Healthcare costs are not normally distributed, that is, the costliest and the sickest upper third of patients consume 65-82% of all medical costs. Only a limited number of studies have explored the effect of CPAP on medical costs. SUMMARY: Costs of untreated OSA may double the medical expenses mainly because of CVD. Identifying the costliest, sickest upper third of OSA patients will reduce expenses to healthcare systems. Studies exploring the effect of CPAP on medical costs are essential. In addition, tailoring intervention programs to reduce barriers to adherence have the potential to improve CPAP treatment, specially in at-risk populations that are sicker and consume more healthcare costs. PMID- 24060979 TI - Cystic fibrosis-related bone disease. AB - PURPOSE OF REVIEW: This review highlights recently published data on the pathophysiology, guidelines and treatment of cystic fibrosis (CF)-related bone disease. RECENT FINDINGS: The exact role of the cystic fibrosis transmembrane conductance regulator (CFTR), specifically the DeltaF508 allele, has been investigated in F508del-CFTR homozygous mice and the F508del-CFTR mutation may contribute to CF-related bone disease by slowing new bone formation. The European Cystic Fibrosis Society has issued guidelines for bone mineral density assessment, management of low-trauma fractures and bisphosphonate therapy. A systematic review based on meta-analyses reports that oral and intravenous bisphosphonates both improve bone mineral density in CF patients, but no data are available concerning the reduction of low-trauma fractures. SUMMARY: European Cystic Fibrosis Society guidelines may help physicians to improve the management of CF-related bone disease. PMID- 24060980 TI - Current opinions on non-invasive ventilation as a treatment for chronic obstructive pulmonary disease. AB - PURPOSE OF REVIEW: This review examines the current reports, the evidence and the issues surrounding the use of non-invasive ventilation (NIV) for the treatment of chronic obstructive pulmonary disease (COPD) in both the acute and domiciliary setting. RECENT FINDINGS: With the increasing use of NIV, more recent studies have focused on investigating the outcomes of our current practice. Although overall morbidity and mortality outcomes in the acute setting have improved, patients who initially stabilize but then deteriorate during an acute exacerbation of COPD have a poor prognosis. The focus must be on phenotyping this high-risk group to investigate other potential rescue treatments, including extracorporeal carbon dioxide removal. Indeed, phenotyping appears to favour the obese COPD patient, which may have a protective role in reducing the risk of NIV failure and recurrent hospital admissions. Randomized controlled trial evidence to support the use of NIV in a domiciliary setting as a treatment for COPD is awaited, and until the data from a number of ongoing clinical trials are available, the wide variation in global practice will continue. Increased understanding of patient ventilator asynchrony has improved domiciliary NIV set up, which is expected to enhance the tolerability of NIV, promoting patient adherence. SUMMARY: NIV is the established standard of care to treat acute hypercapnic exacerbations of COPD postoptimal medical management. NIV as a long term treatment for COPD remains controversial based on the evidence from the published randomized controlled trials. With increasing experience of NIV therapy, patient outcomes are improving; however, further work is still required to better characterize and target the patients who will most benefit from NIV. PMID- 24060981 TI - Intestinal complications of cystic fibrosis. AB - PURPOSE OF REVIEW: The article reviews advances in gastrointestinal aspects of cystic fibrosis (CF) published in the literature over the past year, and highlights new and interesting research. RECENT FINDINGS: Animal models can be used to understand the pathophysiology of gastrointestinal complications in CF. The CF mouse is useful for studying distal intestinal obstruction, dysmotility and dysbiosis, and the CF pig model has helped us better understand meconium ileus and pancreatic and hepatobiliary secretory problems. Studies in humans help elucidate the evolution of pancreatic insufficiency, how reflux may lead to lung disease, problems with intestinal dysmotility, mechanisms leading to pancreatitis and the increased prevalence of gastrointestinal cancer. Biomarkers are shedding light on CF-related liver disease. Rectal biopsies can help in diagnosis and in studying new drugs for CF. SUMMARY: Gastrointestinal complications of CF are likely to be seen with increasing frequency as patients with CF lead longer lives. CF animal models and modern research techniques are providing new insights into extrapulmonary complications. CF clinicians should be familiar with diagnosis and management of common gastrointestinal complications and should build bridges with specialists so that referrals can be made when needed. PMID- 24060982 TI - The impact of medication adherence on lung health outcomes in cystic fibrosis. AB - PURPOSE OF REVIEW: As new medications continue to come to market to improve health in individuals with cystic fibrosis (CF), patient adherence is increasingly more important to address. Currently, adherence for pulmonary medications is approximately 50% for people with CF. There has been recent research that has demonstrated that poor adherence is linked to worse health outcomes. This review summarizes recent research on the impact of adherence on lung health and highlights future areas of research and clinical practice to address this growing need. RECENT FINDINGS: Recent research has indicated that nonadherence is associated with increased hospitalizations and pulmonary exacerbations, lower baseline lung function, and longer length of stays. However, most of the research has been done using pharmacy refill records as an objective measure of adherence. Electronic monitoring of medications provides more detailed information about patterns of use, which can directly inform clinical care. Furthermore, there have been few published clinical trials evaluating behavioral interventions to promote adherence. SUMMARY: Given the recent research linking adherence to lung health outcomes, there is a growing need to measure and evaluate adherence in clinical care. As new medications are approved for CF, methods to monitor adherence also need to be developed and approved. Clinicians need to continue to assess barriers to adherence to be able to individually tailor interventions to a patient's needs. PMID- 24060983 TI - On treatment but still sleepy: cause and management of residual sleepiness in obstructive sleep apnea. AB - PURPOSE OF REVIEW: Although continuous positive airway pressure (CPAP) treatment effectively reduces sleepiness in obstructive sleep apnea (OSA) patients, some patients remain sleepy in spite of proper treatment. After exclusion or treatment of known causes of sleepiness, residual sleepiness may be diagnosed. Recent changes in approval for currently available wakefulness stimulants in Europe, development of new stimulants and questions about the reality of residual sleepiness prompted this review. RECENT FINDINGS: Prevalence of residual sleepiness is approximately 10% and clearly decreases with increased nightly use of CPAP. Before treatment, patients with residual sleepiness are younger, suffer from less severe OSA and have worse health perception and mood than patients who respond to CPAP. Residual sleepiness is accompanied by other residual symptoms (e.g. fatigue, poor quality of life), suggesting the existence of a 'CPAP resistant syndrome'. Pathophysiological mechanisms remain unclear. Stimulant medication may be beneficial in some patients and is well tolerated. SUMMARY: In spite of a substantial prevalence, residual sleepiness remains still poorly understood and may be difficult to treat. There remains a need for large prospective studies to better define predictive baseline characteristics and further research on causal mechanisms and pharmacological treatments, including large, long-term clinical trials of wakefulness stimulants, is needed. PMID- 24060984 TI - Fungal infections and treatment in cystic fibrosis. AB - PURPOSE OF REVIEW: This review summarizes some of the important recent findings concerning fungal airway infections in patients with cystic fibrosis (CF). For many years, both researchers and clinicians have focused on the problems in CF caused by chronic bacterial airway infection with organisms such as Haemophilus, Staphylococcus and Pseudomonas. However, until recently, the lack of sensitive culture techniques to isolate fungi in sputum, bronchoalveolar lavage fluid and other respiratory tract samples has limited the recognition of fungal species and their possible role in CF airway infections. RECENT FINDINGS: Recent studies using fungal-selective culture media and molecular techniques have shown a plethora of different fungal species in the sputum expectorated from CF patients. Cross-sectional studies have shown associations between Aspergillus and Candida in the sputum and worse lung function. The presence of allergic bronchopulmonary aspergillosis is likely to be a negative prognostic factor, but whether simple fungal colonization itself indicates future problems is not clear. Current research is now examining these epidemiological associations to try to determine the clinical implications. This will help determine whether fungal colonization/infection is associated with worse outcome in CF patients. SUMMARY: At present, there is no conclusive evidence that fungal organisms cause respiratory decline. Recent studies of antifungal therapy in CF patients have reported differing results, so further investigations in this area are needed. PMID- 24060985 TI - Synthesis of graphene-supported noble metal hybrid nanostructures and their applications as advanced electrocatalysts for fuel cells. AB - Graphene (GN) is an emerging carbon material that may soon find practical applications. With its unusual properties, GN is an ideal platform for constructing a series of GN-based functional nanomaterials. Among them, GN/noble metal hybrids become one of the families of composite materials with extraordinary properties by combining the advantages of noble metal nanostructures and GN. The recent progress in the synthesis of GN/noble metal hybrids is presented first, such as in situ solution based methods, electrochemical deposition methods, self-assembly and other methods. Then, the applications of these novel GN/noble metal hybrids in fuel cells are summarized and discussed. Future research trends and challenges of design and synthesis of GN/noble metal hybrids are proposed. PMID- 24060986 TI - I2-PPh3 mediated spiroannulation of unsaturated beta-dicarbonyl compounds. The first synthesis of (+/-)-negundoin A. AB - An efficient and stereoselective spiroannulation of unsaturated enols is reported. Unsaturated beta-dicarbonyl compounds undergo cyclization by reaction with catalytic I2-PPh3, affording the corresponding spiro enol ether derivatives, with complete regio- and stereoselectivity, under mild conditions. Utilizing this new methodology, the first total synthesis of the anti-inflammatory diterpene negundoin A and a naturally occurring trypanocidal aldehyde is reported. PMID- 24060987 TI - Citrus flavanones enhance carotenoid uptake by intestinal Caco-2 cells. AB - The health benefit of a diet rich in fruits and vegetables could be attributed to the presence of a large diversity of phytochemicals, including carotenoids. Bioactivities of carotenoids greatly depend on their bioavailability that could be modulated by the presence of other dietary constituents. Because citrus juices contain diverse antioxidant phytochemicals, the effects of flavonoids and ascorbic acid on intestinal carotenoid uptake were investigated. Experiments were conducted by using a Caco-2 cell monolayer exposed to micelles enriched in beta cryptoxanthin (b-CX, 5 MUM) and beta-carotene (b-C, 5 MUM) in the presence of hesperetin (HES, 250 MUM), hesperidin (HES-G, 250 MUM), naringenin (NGN, 250 MUM), acid ascorbic (AA, 50 MUM) and iron. At 5 h or 24 h incubation, HES-G and HES significantly increased b-CX and b-C uptake by 1.7- and 1.6-fold, respectively (p < 0.05). Interestingly, AA was shown to eliminate the enhancing effect of HES-G by decreasing significantly the cellular uptake of carotenoids from 48.2 to 39.8% after 5 h incubation (p < 0.05). Iron decreased the carotenoid uptake, while HES-G in the presence of iron restored it, suggesting that the enhancing effect of HES-G on carotenoid uptake could be attributed to its iron chelating activity. PMID- 24060988 TI - Metal-mediated crystallization of the xylose transporter XylE from Escherichia coli in three different crystal forms. AB - XylE is a major facilitator (MFS) xylose transporter, which is homologous to the mammalian glucose transporters (GLUT family). We have previously reported the structure of XylE in fully inward open and partially occluded inward open conformations in space groups P61 and C2, respectively. Here we present the crystallization of a third crystal form, P212121 (~4 A resolution), also representing an inward facing conformation, and analyze all three forms in terms of crystallization conditions and packing. The crystallization conditions were generally very similar with only slight changes needed to favor one form over another, e.g. the presence of lanthanide ions greatly favors C2 over P212121 under otherwise identical conditions. Cadmium was essential for crystallization of all three forms, which indeed all contain a Cd(2+) ion in a crystal packing interface, though surprisingly in different positions. Cadmium was also found to bind to XylE in solution. The diffraction data were highly anisotropic for all forms, reflecting a lack of ordered crystal contacts along one or two of the cell axes. The best diffracting directions thus consistently correlate with the presence of ordered contacts, most of which are metal-mediated. The data presented here highlight the utility of metal ions in membrane protein crystallization and suggest that metal site engineering may be a productive path towards obtaining additional crystal forms of XylE and other membrane proteins. PMID- 24060989 TI - gEMfitter: a highly parallel FFT-based 3D density fitting tool with GPU texture memory acceleration. AB - Fitting high resolution protein structures into low resolution cryo-electron microscopy (cryo-EM) density maps is an important technique for modeling the atomic structures of very large macromolecular assemblies. This article presents "gEMfitter", a highly parallel fast Fourier transform (FFT) EM density fitting program which can exploit the special hardware properties of modern graphics processor units (GPUs) to accelerate both the translational and rotational parts of the correlation search. In particular, by using the GPU's special texture memory hardware to rotate 3D voxel grids, the cost of rotating large 3D density maps is almost completely eliminated. Compared to performing 3D correlations on one core of a contemporary central processor unit (CPU), running gEMfitter on a modern GPU gives up to 26-fold speed-up. Furthermore, using our parallel processing framework, this speed-up increases linearly with the number of CPUs or GPUs used. Thus, it is now possible to use routinely more robust but more expensive 3D correlation techniques. When tested on low resolution experimental cryo-EM data for the GroEL-GroES complex, we demonstrate the satisfactory fitting results that may be achieved by using a locally normalised cross-correlation with a Laplacian pre-filter, while still being up to three orders of magnitude faster than the well-known COLORES program. PMID- 24060990 TI - The spinal reflex cannot be perceptually separated from voluntary movements. AB - Both voluntary and involuntary movements activate sensors in the muscles, skin, tendon and joints. As limb movement can result from a mixture of spinal reflexes and voluntary motor commands, the cortical centres underlying conscious proprioception might either aggregate or separate the sensory inputs generated by voluntary movements from those generated by involuntary movements such as spinal reflexes. We addressed whether healthy volunteers could perceive the contribution of a spinal reflex during movements that combined both reflexive and voluntary contributions. Volunteers reported the reflexive contribution in leg movements that were partly driven by the knee-jerk reflex induced by a patellar tendon tap and partly by voluntary motor control. In one condition, participants were instructed to kick back in response to a tendon tap. The results were compared to reflexes in a resting baseline condition without voluntary movement. In a further condition, participants were instructed to kick forwards after a tap. Volunteers reported the perceived reflex contribution by repositioning the leg to the perceived maximum displacement to which the reflex moved the leg after each tendon tap. In the resting baseline condition, the reflex was accurately perceived. We found a near-unity slope of linear regressions of perceived on actual reflexive displacement. Both the slope value and the quality of regression fit in individual volunteers were significantly reduced when volunteers were instructed to generate voluntary backward kicks as soon as they detected the tap. In the kick forward condition, kinematic analysis showed continuity of reflex and voluntary movements, but the reflex contribution could be estimated from electromyography (EMG) recording on each trial. Again, participants' judgements of reflexes showed a poor relation to reflex EMG, in contrast to the baseline condition. In sum, we show that reflexes can be accurately perceived from afferent information. However, the presence of voluntary movement significantly impairs reflex perception. We suggest that perceptual separation between voluntary and reflex movement is poor at best. Our results imply that the brain has no clear marker for perceptually separating voluntary and involuntary movement. Attribution of body movement to voluntary or involuntary motor commands is surprisingly poor when both are present. PMID- 24060991 TI - Is this my finger? Proprioceptive illusions of body ownership and representation. AB - Body 'ownership' defines which things belong to us and can be manipulated by signals from cutaneous or muscle receptors. Whether signals from muscle proprioceptors on their own influence perceived ownership is unknown. We used finger-joint movement to induce illusory ownership of an artificial finger without vision. We coupled the subject's index finger to an artificial finger 12 cm above it. The experimenter held the subject's other index finger and thumb on the artificial finger and passively moved them congruently or incongruently for 3 min with the index finger and the grasping index finger and thumb intact or anaesthetised. When intact, congruent movement (19 subjects) reduced perceived vertical distance between index fingers to 1.0 (0.0, 2.0) cm [median (IQR)] from 3.0 (3.0, 4.0) cm with incongruent movement (P < 0.01). Simply grasping the artificial finger reduced perceived spacing between the grasping and test index fingers from 6.0 (5.0, 9.0) cm to 3.0 (3.0, 6.0) cm (P < 0.01), a new grasp illusion. Digital anaesthesia eliminated this grasp effect, after which congruent movement still reduced the perceived spacing between the index fingers to 1.0 (0.0, 2.75) cm compared to 4.0 (3.25, 6.0) cm with incongruent movement (P < 0.001). Subjects more strongly agreed that they were holding their own finger after congruent but not incongruent movement (P < 0.01). We propose that the brain generates possible scenarios and tests them against available sensory information. This process can function without vision or motor commands, and with only one channel of somatic information. PMID- 24060992 TI - Glucose utilization rates regulate intake levels of artificial sweeteners. AB - It is well established that animals including humans attribute greater reinforcing value to glucose-containing sugars compared to their non-caloric counterparts, generally termed 'artificial sweeteners'. However, much remains to be determined regarding the physiological signals and brain systems mediating the attribution of greater reinforcing value to sweet solutions that contain glucose. Here we show that disruption of glucose utilization in mice produces an enduring inhibitory effect on artificial sweetener intake, an effect that did not depend on sweetness perception or aversion. Indeed, such an effect was not observed in mice presented with a less palatable, yet caloric, glucose solution. Consistently, hungry mice shifted their preferences away from artificial sweeteners and in favour of glucose after experiencing glucose in a hungry state. Glucose intake was found to produce significantly greater levels of dopamine efflux compared to artificial sweetener in dorsal striatum, whereas disrupting glucose oxidation suppressed dorsal striatum dopamine efflux. Conversely, inhibiting striatal dopamine receptor signalling during glucose intake in sweet naive animals resulted in reduced, artificial sweetener-like intake of glucose during subsequent gluco-deprivation. Our results demonstrate that glucose oxidation controls intake levels of sweet tastants by modulating extracellular dopamine levels in dorsal striatum, and suggest that glucose utilization is one critical physiological signal involved in the control of goal-directed sweetener intake. PMID- 24060993 TI - Chronic renin inhibition lowers blood pressure and reduces upright muscle sympathetic nerve activity in hypertensive seniors. AB - Cardiovascular risk remains high in patients with hypertension even with adequate blood pressure (BP) control. One possible mechanism may be sympathetic activation via the baroreflex. We tested the hypothesis that chronic inhibition of renin reduces BP without sympathetic activation, but diuresis augments sympathetic activity in elderly hypertensives. Fourteen patients with stage-I hypertension (66 +/- 5 (SD) years) were treated with a direct renin inhibitor, aliskiren (n = 7), or a diuretic, hydrochlorothiazide (n = 7), for 6 months. Muscle sympathetic nerve activity (MSNA), BP, direct renin and aldosterone were measured during supine and a graded head-up tilt (HUT; 5 min 30 degrees and 20 min 60 degrees ), before and after treatment. Sympathetic baroreflex sensitivity (BRS) was assessed. Both groups had similar BP reductions after treatment (all P < 0.01), while MSNA responses were different between hydrochlorothiazide and aliskiren (P = 0.006 pre/post * drug). Both supine and upright MSNA became greater after hydrochlorothiazide treatment (supine, 72 +/- 18 post vs. 64 +/- 15 bursts (100 beats)(-1) pre; 60 degrees HUT, 83 +/- 10 vs. 78 +/- 13 bursts (100 beats)(-1); P = 0.002). After aliskiren treatment, supine MSNA remained unchanged (69 +/- 13 vs. 64 +/- 8 bursts (100 beats)(-1)), but upright MSNA was lower (74 +/- 15 vs. 85 +/- 10 bursts (100 beats)(-1); P = 0.012 for pre/post * posture). Direct renin was greater after both treatments (both P < 0.05), while upright aldosterone was greater after hydrochlorothiazide only (P = 0.002). The change in upright MSNA by the treatment was correlated with the change of aldosterone (r = 0.74, P = 0.002). Upright sympathetic BRS remained unchanged after either treatment. Thus, chronic renin inhibition may reduce upright MSNA through suppressed renin activity, while diuresis may evoke sympathetic activation via the upregulated renin-angiotensin-aldosterone system, without changing intrinsic sympathetic baroreflex function in elderly hypertensive patients. PMID- 24060995 TI - Ab initio-aided CALPHAD thermodynamic modeling of the Sn-Pb binary system under current stressing. AB - Soldering is an ancient process, having been developed 5000 years ago. It remains a crucial process with many modern applications. In electronic devices, electric currents pass through solder joints. A new physical phenomenon--the supersaturation of solders under high electric currents--has recently been observed. It involves (1) un-expected supersaturation of the solder matrix phase, and (2) the formation of unusual "ring-shaped" grains. However, the origin of these phenomena is not yet understood. Here we provide a plausible explanation of these phenomena based on the changes in the phase stability of Pb-Sn solders. Ab initio-aided CALPHAD modeling is utilized to translate the electric current induced effect into the excess Gibbs free energies of the phases. Hence, the phase equilibrium can be shifted by current stressing. The Pb-Sn phase diagrams with and without current stressing clearly demonstrate the change in the phase stabilities of Pb-Sn solders under current stressing. PMID- 24060994 TI - Quantification of human urinary exosomes by nanoparticle tracking analysis. AB - Exosomes are vesicles that are released from the kidney into urine. They contain protein and RNA from the glomerulus and all sections of the nephron and represent a reservoir for biomarker discovery. Current methods for the identification and quantification of urinary exosomes are time consuming and only semi-quantitative. Nanoparticle tracking analysis (NTA) counts and sizes particles by measuring their Brownian motion in solution. In this study, we applied NTA to human urine and identified particles with a range of sizes. Using antibodies against the exosomal proteins CD24 and aquaporin 2 (AQP2), conjugated to a fluorophore, we could identify a subpopulation of CD24- and AQP2-positive particles of characteristic exosomal size. Extensive pre-NTA processing of urine was not necessary. However, the intra-assay variability in the measurement of exosome concentration was significantly reduced when an ultracentrifugation step preceded NTA. Without any sample processing, NTA tracked exosomal AQP2 upregulation induced by desmopressin stimulation of kidney collecting duct cells. Nanoparticle tracking analysis was also able to track changes in exosomal AQP2 concentration that followed desmopressin treatment of mice and a patient with central diabetes insipidus. When urine was stored at room temperature, 4 degrees C or frozen, nanoparticle concentration was reduced; freezing at -80 degrees C with the addition of protease inhibitors produced the least reduction. In conclusion, with appropriate sample storage, NTA has potential as a tool for the characterization and quantification of extracellular vesicles in human urine. PMID- 24060996 TI - Absolute proteomic quantification of the activity state of proteases and proteolytic cleavages using proteolytic signature peptides and isobaric tags. AB - Proteolytic processing alters the structure and function of a wide range of proteins in the proteome. We describe a method for the absolute quantification of proteolysis that is compatible with existing quantitative proteomic applications and could be applied on a protein-family wide scale. A tryptic peptide spanning a cleavage site differentiates this intact form of the protein from the corresponding semi-tryptic peptides of a protease cleaved protein. We term such proteomic signatures of specific proteolytic events "proteolytic signature peptides" (PSPs). By quantifying both the tryptic and semi-tryptic PSPs simultaneously with proteotypic peptides common to all forms of the protein both the relative and the absolute amounts of the intact and cleaved protein can be determined. Using synthetic PSP standards of cleavage sites in intact and cleaved proteins the absolute amounts of each form of the protein can be determined. The technique was demonstrated by the simultaneous identification and quantification of matrix metalloproteinase zymogens and their proteolytically activated forms in parallel with conventional absolute quantification of their TIMP inhibitors. For quantification we synthesized a pair of isobaric mass tags, we term CLIP-TRAQ, using C(13) labeled reagents that when fragmented during CID generate signature ions at 113.1 or 114.1 respectively. As an expandable platform this allows for the simultaneous identification of multiple proteins and their proteolytic state in complex proteomes on a family-wide scale in parallel with conventional proteomic analysis. This article is part of a Special Issue entitled: CNPN 2013. BIOLOGICAL SIGNIFICANCE: Proteolysis is key to various biological processes and the activity and function of many proteins are dictated by their proteolytic state. The development of methods to quantify protein abundance in conjunction to determining their proteolytic state and hence activity is essential for the complete understanding of the processes for which proteolysis is involved. This article is part of a Special Issue: Can Proteomics Fill the Gap Between Genomics and Phenotypes? PMID- 24060997 TI - Identification of proteins interacting with HSP70 mRNAs in Leishmania braziliensis. AB - HSP70 protein is involved in Leishmania differentiation, apoptosis, antimony resistance and host-immune response. Therefore, this protein and the regulatory mechanisms of HSP70 gene expression are promising targets for therapeutic intervention against leishmaniasis. The regulation of mRNA expression in trypanosomatids operates mostly through the interaction of trans-acting proteins, and elements located in the untranslated regions of mRNAs. The aim of this work was to identify protein factors interacting specifically with the Leishmania braziliensis HSP70 mRNAs. Thus, the 5' UTR and the two types of 3' UTRs (UTR-I and UTR-II) from L. braziliensis HSP70 genes were used as baits in pull down assays using total protein extracts from parasites cultured at 26 or 35 degrees C. The captured proteins were resolved by two-dimensional gel electrophoresis (2 DE) and identified by mass spectrometry (MS) analysis. As a result, 52 different proteins were identified based on their binding to the L. braziliensis HSP70 mRNAs. As expected, several of the identified proteins were related to RNA metabolism (27%) and translation process (7%). In addition, five hypothetical conserved proteins having motifs related with RNA interaction were also identified (9.6%). Nevertheless, unexpected proteins, apparently unrelated to the mRNA expression, were also identified. The biological significance of these and others L. braziliensis detected proteins, including the HSP70 itself, is discussed. BIOLOGICAL SIGNIFICANCE: For the first time, a riboproteomic analysis of the proteins interacting with the untranslated regions of the heat shock protein 70 (HSP70) mRNA from Leishmania braziliensis was carried out. This work provides new insights related to protein factors putatively involved in the regulation of HSP70 gene expression in L. braziliensis, and thereby, contributes to a better understanding of the parasite biology, and ultimately to the development of novel therapeutic interventions for controlling the important diseases caused by this parasite. PMID- 24060998 TI - Mass spectrometry-based identification of proteins interacting with nucleic acids. AB - The identification of the regulatory proteins that control DNA transcription as well as RNA stability and translation represents a key step in the comprehension of gene expression regulation. Those proteins can be purified by DNA- or RNA affinity chromatography, followed by identification by mass spectrometry. Although very simple in the concept, this represents a real technological challenge due to the low abundance of regulatory proteins compared to the highly abundant proteins binding to nucleic acids in a nonsequence-specific manner. Here we review the different strategies that have been set up to reach this purpose, discussing the key parameters that should be considered to increase the chances of success. Typically, two categories of biological questions can be distinguished: the identification of proteins that specifically interact with a precisely defined binding site, mostly addressed by quantitative mass spectrometry, and the identification in a non-comparative manner of the protein complexes recruited by a poorly characterized long regulatory region of nucleic acids. Finally, beside the numerous studies devoted to in vitro-assembled nucleic acid-protein complexes, the scarce data reported on proteomic analyses of in vivo assembled complexes are described, with a special emphasis on the associated challenges. PMID- 24060999 TI - A proteomic approach of pediatric astrocytomas: MiRNAs and network insight. AB - Pediatric astrocytomas, a leading cause of death associated with cancer, are the most common primary central nervous system tumors found in children. Most studies of these tumors focus on adults, not on children. We examined the global protein and microRNA expression pattern by 2D SDS-PAGE, mass spectrometry (MALDI-TOF), and RT(2) miRNA PCR Array System. Proteomic studies revealed 49 proteins with changes on the expression. Interactome showed that vimentin, calreticulin, and 14 3-3 epsilon protein are hub proteins in these neoplasms. MicroRNA analyses demonstrated for the first time novel microRNAs involved in the astrocytoma biology. In conclusion, our results show that novel proteins and microRNAs with expression changes on pediatric astrocytoma could serve as biomarkers of tumor progression. BIOLOGICAL SIGNIFICANCE: Astrocytomas are tumors that progress rapidly and that invade surrounding tissues. Although some drugs have been developed to treat these neoplasms, the mortality of patients is still very high. In this study, we describe for the first time, to our knowledge, some proteins and miRNAs associated with the biology of astrocytic tumors that could be postulated as possible diagnostic or prognostic biomarkers. Altogether, our results indicate that large-scale analyses allow making a fairly accurate prediction of different cellular processes altered in astrocytic tumors. PMID- 24061000 TI - From brain to blood: New biomarkers for ischemic stroke prognosis. AB - Despite being ischemic stroke a leading cause of death and functional disability, there are no other accurate tools to predict outcome of patients beyond clinical variables such as age and stroke severity. In this scenario, defining protein changes associated with acute ischemic brain damage might help to identify new biomarker candidates for stroke prognosis. By means of mass spectrometry-based proteomics, we identified 51 proteins which levels were altered in the infarcted area of the human brain after stroke. Among 8 selected protein candidates, circulating levels of gelsolin, dihydropyrimidinase-related protein 2 and cystatin A were independent predictors of poor outcome. Logistic regression models including these innovative biomarkers significantly improved the predictive value with respect to the only use of clinical variables in both discrimination and reclassification analyses. Our results indicate that early blood determination of these three biomarkers might predict outcome of patients and might help in decision-making processes related to ischemic stroke management. BIOLOGICAL SIGNIFICANCE: Circulating levels of gelsolin, dihydopyrimidinase-related protein 2 and cystatin A, proteins found altered in human brain after cerebral ischemia, demonstrate potential usefulness as biomarkers for long-term stroke prognosis. PMID- 24061001 TI - Mono-dimensional blue native-PAGE and bi-dimensional blue native/urea-PAGE or/SDS PAGE combined with nLC-ESI-LIT-MS/MS unveil membrane protein heteromeric and homomeric complexes in Streptococcus thermophilus. AB - Protein interactions are essential elements for the biological machineries underlying biochemical and physiological mechanisms indispensable for microorganism life. By using mono-dimensional blue native polyacrylamide gel electrophoresis (1D-BN-PAGE), two-dimensional blue native/urea-PAGE (2D-BN/urea PAGE) and two-dimensional blue native/SDS-PAGE (2D-BN/SDS-PAGE), membrane protein complexes of Streptococcus thermophilus were resolved and visualized. Protein complex and oligomer constituents were then identified by nLC-ESI-LIT-MS/MS. In total, 65 heteromeric and 30 homomeric complexes were observed, which were then associated with 110 non-redundant bacterial proteins. Protein machineries involved in polysaccharide biosynthesis, molecular uptake, energy metabolism, cell division, protein secretion, folding and chaperone activities were highly represented in electrophoretic profiles; a number of homomeric moonlighting proteins were also identified. Information on hypothetical proteins was also derived. Parallel genome sequencing unveiled that the genes coding for the enzymes involved in exopolysaccharide biosynthesis derive from two separate clusters, generally showing high variability between bacterial strains, which contribute to a unique, synchronized and active synthetic module. The approach reported here paves the way for a further functional characterization of these protein complexes and will facilitate future studies on their assembly and composition during various growth conditions and in different mutant backgrounds, with important consequences for biotechnological applications of this bacterium in dairy productions. BIOLOGICAL SIGNIFICANCE: Combined proteomic procedures have been applied to the characterization of heteromultimeric and homomeric protein complexes from the membrane fraction of S. thermophilus. Protein machineries involved in polysaccharide biosynthesis, molecular uptake, energy metabolism, cell division, protein secretion, folding and chaperone activities were identified; information on hypothetical and moonlighting proteins were also derived. This study is original in the lactic bacteria context and may be considered as preliminary to a deeper functional characterization of the corresponding protein complexes. Due to the large use of S. thermophilus as a starter for dairy productions, the data reported here may facilitate future investigations on protein complex assembly and composition under different experimental conditions or for bacterial strains having specific biotechnological applications. PMID- 24061002 TI - A proteomics approach to the identification of biomarkers for psoriasis utilising keratome biopsy. AB - The discovery of plasma biomarkers for psoriasis vulgaris may aid clinicians in disease grading and monitoring of treatment response. We have therefore developed a proteomics/mass spectrometry based workflow which enables biomarker discovery from psoriasis patient samples. We have utilised keratome skin biopsy, which results in reduced cellular complexity compared to punch biopsy. Furthermore, we applied short term ex vivo culture in order to enrich for a "secretome" sub proteome reflective of the disease and enriched in potential biomarkers. Using these sample preparation techniques we performed a quantitative proteomics screen of four patients with psoriasis using stable isotope dimethyl labelling and identified over 50 proteins consistently altered in abundance in psoriasis lesional versus non-lesional skin. This includes several canonical psoriasis related proteins (e.g. S100A7 [Psoriasin] and FABP5 [Epidermal Fatty Acid Binding Protein]) and more than 30 novel alterations. From this disease localised dataset we further assessed several proteins as potential biomarkers in the plasma of patients with psoriasis versus healthy controls utilising selected reaction monitoring mass spectrometry (SRM-MS/MS). BIOLOGICAL SIGNIFICANCE: The significance of this study for proteome research in psoriasis and dermal disease is threefold. 1) A novel sample preparation method for isolation of dermal proteomes enriched in extracellular proteins is described, which may be of interest to other researchers in the field. 2) Novel psoriasis associated alterations in protein abundance are described at the disease site, bolstering knowledge in an area dominated by transcript level studies and 3) Profilin 1 is described as a candidate plasma biomarker of psoriasis, this is of value in itself and it proves that our workflow can yield results in terms of biomarker discovery. PMID- 24061003 TI - Analysis of protein composition and protein expression in the tear fluid of patients with congenital aniridia. AB - Aniridia is a rare congenital genetic disorder caused by haploinsuffiency of the PAX6 gene, the master gene for development of the eye. The expression of tear proteins in aniridia is unknown. To screen for proteins involved in the aniridia pathophysiology, the tear fluid of patients with diagnosed congenital aniridia was examined using two-dimensional electrophoresis (2-DE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two-dimensional map of tear proteins in aniridia has been established and 7 proteins were differentially expressed with P<0.01 between aniridia patients and control subjects. Five of them were more abundant in healthy subjects, particularly alpha-enolase, peroxiredoxin 6, cystatin S, gelsolin, apolipoprotein A-1 and two other proteins, zinc-alpha2-glycoprotein and lactoferrin were more expressed in the tears of aniridia patients. Moreover, immunoblot analysis revealed elevated levels of vascular endothelial growth factor (VEGF) in aniridia tears which is in concordance with clinical finding of pathological blood and lymph vessels in the central and peripheral cornea of aniridia patients. The proteins with different expression in patients' tears may be new candidate molecules involved in the pathophysiology of aniridia and thus may be helpful for development of novel treatment strategies for the symptomatic therapy of this vision threatening condition. BIOLOGICAL SIGNIFICANCE: This study is first to demonstrate protein composition and protein expression in aniridic tears and identifies proteins with different abundance in tear fluid from patients with congenital aniridia vs. healthy tears. PMID- 24061004 TI - [Policies and practices in mental health: the evidence in question]. AB - The paper analyzes some current questions related to the choice of evidence in order to provide guidelines for public policy and practices in mental health care. It starts with a critical reflection on the categories of evidence proposed by Evidence-Based Medicine, and also the concept of qualitative evidence. The issue is analyzed specifically in relation to mental health care users and their demands to have services organized in a way that incorporates their perceptions and values, and to the Psychiatric Reform field proper firmly grounded in ethical and political precepts. PMID- 24061005 TI - [The search for truth in the field of health science]. PMID- 24061006 TI - [The Human Being between the measurable and immeasurable. What is the "proof"?]. PMID- 24061007 TI - [The authors reply]. PMID- 24061008 TI - [The use of interviews in participative intervention and research: the GAM tool as a collective interview]. AB - This paper seeks to assess a way of conducting interviews in line with the ideology of Brazilian Psychiatric Reform. In the methodology of participative intervention and research in mental health, the interview is less a data collection than a data harvesting procedure. It is designed to apply the principles of psychosocial care, autonomy as the basis for treatment, the predominance of the users and of their social networks and civic participation. Inspired by the Explicitation Interview technique, the contention is that the handling of the interview presupposes an open attitude able to promote and embrace different viewpoints. This attitude makes the interview a collective experience of sharing and belonging, allowing participants to reposition themselves subjectively in treatment with the emergence of groupality. As an example of using the interview as a methodological tool in mental health research, we examine research into adaptation of the tool of Autonomous Medication Management (GAM). It is an interventionist approach guided by principles that foster autonomy and the protagonist status of users of psychotropic medication, their quality of life, their rights and recognition of the multiple significances of medication, understood here as a collective interview technique. PMID- 24061009 TI - [Empowerment of users and family members in mental health care and in evaluative/interventional research: a brief comparison between the Anglo-Saxon tradition and the Brazilian experience]. AB - The scope of this article is to assess the main characteristics of the traditions and experiences of empowerment of users and family members in mental health treatment and services in Anglo-Saxon countries and in Brazil and the repercussions and strategies thereof in the field of evaluative and interventional research in mental health. Based on a brief bibliographical review of the literature, the aim is to compare how the empowerment tradition has developed in the two realities, based on the characteristics of the economic, political, social - and especially cultural - context. The review revealed how these contexts induce different perspectives on how to foster the autonomy and empowerment of users and family members in social policies and mental health, as well as their appropriation in the field of evaluative and interventional research. In Anglo-Saxon countries, this tradition has been vigorously promoted over the past four decades, and in Brazil the participative strategies emphasize mixed mechanisms - professionals, users and family members together - with the dominant presence of the professionals. The strategies in Brazil more directly designed for users and family members are recent and have been implemented from 2005 onwards. PMID- 24061010 TI - [Brazilian experiences in the participation of users and family members in mental health research]. AB - In this paper the authors describe and contextualize the participation of users and family members in mental health research in Brazil, addressing the recent tradition of the experiences of recovery and empowerment to define the analysis of some Brazilian experiences of evaluative research and intervention projects, which count on these social actors to act as researchers. The experiences of Self Help Groups and the Guide to Autonomous Medication Management are described briefly, in order to analyze the limits and possibilities of participation of users and their family members in research, which is still incipient and sporadic in the Brazilian reality. The authors also recommend the creation of an agenda in public health policy that encourages this participation. PMID- 24061011 TI - [Narratives in the study of mental health care practices: contributions of the perspectives of Paul Ricoeur, Walter Benjamin and of medical anthropology]. AB - Narratives are ever more frequent in qualitative studies seeking to interpret experiences and the different viewpoints of individuals in a given context. Starting from this concept, the tradition that addresses narrative is reexamined, including the philosophy of Paul Ricoeur, the historical perspective of Walter Benjamin and the field of medical anthropology grounded in phenomenology. In Ricoeur, with hermeneutics as a variation derived from phenomenology, narrative is linked to temporality. In Benjamin, narrative comprised of bits and pieces, always inconclusive, emerges in spite of the official stories. If Ricoeur retrieves tradition from Gadamer as a fundamental component for the construction of the world of a text that makes imitation of life possible, Benjamin, faced with the collapse of tradition, suggests the invention of narrative forms outside the traditional canons, making it possible to hark to the past in order to change the present. Assumptions of medical anthropology are also presented, as they consider narrative a dimension of life and not its abstraction, namely an embodied and situated narrative. Lastly, three distinct research projects in mental health that use narrative linked to the theoretical concepts cited with their differences and similarities are presented. PMID- 24061012 TI - [Ethnographic approaches to research and intervention in mental health]. AB - The specifics of ethnographic approaches to mental health research are examined, highlighting the motives why the type of knowledge produced by ethnography is relevant to the context of Psychiatric Reform and the biomedicalization of existence. The discussion is focused on interpretation-based ethnography in the field of mental health, stressing the theoretical and methodological foundations of a comprehensive form of apprehending the scope of mental health as an object akin to a clinic of the individual. The centrality of social and cultural aspects in the ethnographic approach and the inflexions mediated by the type of ethnographic methodological undertaking is stressed. Lastly, the ethnography of madness is seen as a fitting example that substantiates some of these characteristics. The contention is that accessing psychotic persons (and others who may speak about these experiences) from varied areas of their daily life, situated in their various social inscriptions, while confronting these interpretations with other interpretative dimensions of their social reality and within the logic linked to local psychologies, is a pertinent procedure, from whence certain aspects of an understanding of madness (or causes of its incomprehension) can emerge. PMID- 24061013 TI - [Participation of users in exercises regarding mental health services planning and organization in Quebec]. PMID- 24061014 TI - Gaining Autonomy & [corrected] Medication Management (GAM): new perspectives on well-being, quality of life and psychiatric medication. AB - Autonomous Medication Management (GAM) is an innovative approach developed in partnership with medication users. It takes their subjective experience into account and strives to place the individual at the center of pharmacological treatment in psychiatry with a view to improving well-being and quality of life. It creates spaces of open dialogue on the issue of medication amongst users, physicians and their family and friends. This article is derived from a research study and presents the principles, practices and main impacts of GAM on how people relate to their medications and the physicians who prescribe them. The major positive effects were the users' clearer understanding of their experience of taking psychiatric medication and their rights, the reduction or elimination of sudden and unsupervised treatment interruptions and the users' sense of having more control over their treatment. It includes inner experience and life, an improved relationship with professionals and space for negotiation with the physician and, lastly, changes to prescriptions that significantly improved well being and recovery. The distinguishing features of GAM are described and compared with other approaches, giving a voice to people who take medication. PMID- 24061016 TI - [Relations between research and clinical care in co-management studies with mental health care users]. AB - This paper is derived from the experience of conducting research with mental health users (not about them, nor for them), analyzing aspects of a study in which different ways of structuring the relationship between clinical practice and research were put into play, thereby questioning the boundaries and ethical issues involved. The clinical practice and research fields that are dealt with are studied with the input of authors who, on the basis of institutional analysis, propose the idea of interventional research, and in the context of public health, revert to the concept of broadened clinical care. The relationship between these two terms - interventional research and broadened clinical care - is based on the notion of subjectivity that operates within the scope of public health and which culminates in the concept of autonomy. Lastly, co-management is proposed as a strategy based on which the different actors involved in conducting research and exercising clinical care can collectively build working principles that are both therapeutic and ethical. PMID- 24061015 TI - [Autonomous Medication Management: an analytical intervention in mental health care services]. AB - In a context of high rates of medicalization of the population and in light of the scantly critical use of psychiatric medications in mental health services, this paper reports aspects of a qualitative study that had the opportunity to intervene in care practices in three major Brazilian cities. Following the principle of Brazilian Psychiatric Reform championing users' rights to participate in decisions about their treatment, the research intervened in psychosocial care centers (CAPS) seeking the empowerment of the users regarding the use of drugs in their therapeutic projects. Interviews were conducted and focus groups set up. From this recorded material, the paper analyzed some situations that, among other things, attested to the difficulty of avoiding the exercise of power over users via the administration of psychotropic drugs. Little dialogue about drugs, and the existence of stigmatization spaces where user rights are inhibited or "accepted with caution," was also detected in the services surveyed. PMID- 24061017 TI - [The ritual of crack consumption: socio-anthropological aspects and impacts on the health of users]. AB - The use of crack cocaine has given rise to an intense discussion in society. Research has contributed to the characterization of users and the negative consequences of its use. However, few studies have conducted in-depth study of the social and cultural contexts in which crack cocaine is used. Thus, this study seeks to discuss the ritual of crack cocaine use and its social and health consequences for the user. It is a qualitative study developed in the Psychosocial Care Centers for Alcohol and Drugs (Portuguese acronym: Caps-ad). The individuals were selected in two groups of key-informants: crack cocaine users undergoing treatment and health professionals. Data was obtained by means of semi-structured interviews. The results revealed that the use of crack cocaine is not dissociated with the current organizational structure of society. There is a link between the use of this substance and the social organization for its use. By using crack cocaine, the individuals try to be part of a consumer market, actively participating in what society perceives as new. The forms and locations of use are directly related to users' health, making it necessary for healthcare services to detect, approach and make health interventions in these locations of use. PMID- 24061018 TI - [The Citizen Committee as a co-management strategy in participatory research in the field of mental health in Quebec]. AB - The theme of users' rights has become a central issue in contemporary debate on mental health. Drawing from the experiences of "Comite Cidadao" (Citizen Committee), consisting of users and family members in an international research alliance between Brazil and Canada, an attempt is made to discuss the effects of the experience of co-management of the so-called Autonomous Medication Administration (GAM - Gestao Autonoma da Medicacao) participatory research project on these individuals. By means of a detailed description of the background of the Committee and interviews and analysis of the voice transcriptions of its members, the problems raised by the relation of dialogue between scientific knowledge and users' knowledge are examined in a methodological approach of participatory research. As a result of the research, it was established that the experience of the Citizens Committee in co-management of health research can be propitious to the increase in the degree of autonomy, greater empowerment and the exercise of leadership and citizenship, with the consequent emergence of subjects with rights. PMID- 24061019 TI - [Contribution of day hospitals to psychiatry in the contemporary field of mental health in Quebec]. PMID- 24061020 TI - [Access to first-person experience in research into mental health]. AB - This article presents and discusses the epistemological and methodological challenges related to the empirical study of first-person experience in mental health research. Considering the field of qualitative research, the methodological principles of phenomenology and medical anthropology are examined from a historical and conceptual perspective. The main operational concepts of the phenomenological method applied to empirical research, as well as their two main lines of approach, namely descriptive and psychological/transcendental phenomenology and hermeneutical or interpretative phenomenology, are described. The contributions of medical anthropology are studied especially with respect to the experience of illness and its forms of narrative. Lastly, considering the distinction between experience and narrative based on the theoretical benchmarks of phenomenology and medical anthropology, a more in-depth debate on access to first-person experience is conducted. PMID- 24061021 TI - [A perspective overview of dementia in Brazil: a demographic approach]. AB - It is only to be expected that the elderly population manifests a high prevalence of chronic diseases that jeopardize their autonomy. One example is syndromes of dementia. The scope of this paper is to make projections of the number of elderly individuals with dementia. An estimate of the current number is made by applying age-related prevalence data to the population of 65 and over, by age-group, with the figures from the Brazilian Demographic Census of 2010. The data were obtained from assessments found in the literature. For a national measure, a weighted average of the estimated prevalence was used. Prevalence rates by age and gender were calculated for the elderly Brazilian population. Current investigations show a steep increase of dementia with age. Women and illiterate individuals have a higher prevalence. The mean prevalence in Brazil is higher than that found in the rest of the world. Projections for the Brazilian population point to a small increase in the prevalence of dementia in the 65+ age-group, from 7.6% to 7.9% between 2010 and 2020, which means 55,000 new cases a year. Dementia is a public health issue, and elicits a strong bioethical concern with aging, due to the loss of autonomy of the affected individuals and the responsibility of the health system to provide adequate care. PMID- 24061022 TI - The prevalence of medical/clinical technology over psychosocial care actions in outpatient mental health services. AB - The scope of this study was to evaluate how aspects of mental health policy in Brazil have been conceived and implemented in outpatient services, such as the Regional Outpatient Mental Health Clinic and the Psychosocial Care Center II, both in Ribeirao Preto, Sao Paulo. Semi-direct interviews and focus groups were conducted with 22 health professionals. The theoretical method and data analysis were supported by the dialectical hermeneutic framework of Jurgen Habermas. The following aspects were detected: considerable technological advancement in health actions and centrality of clinical-medical technology in relation to other nonmedical therapeutic actions; the prioritization of treatment options emphasizing pathology and drug therapy, and a process of mounting precariousness in labor relations. With respect to psychosocial rehabilitation, analysis revealed that instrumental and technically-oriented treatment is imposed upon the practical and dialogical rationale proposed by Brazilian Psychiatric Reform. As an alternative, participatory evaluative research is required in order to unify clinical and psychosocial rehabilitation actions in therapeutic projects, while establishing mechanisms to promote the improvement of care based on the psychosocial care model. PMID- 24061023 TI - [The influence of organizational ties in the consolidation of psychosocial care centers]. AB - This article seeks to investigate the influence of organizational ties in the consolidation of Psychosocial Care Centers (CAPS - II and AD [Alcohol and Drugs]) in the city of Petrolina, State of Pernambuco, Brazil. Based on qualitative research, semi-structured interviews were conducted with a multi-professional team from both CAPS, with the sample consisting of one representative from each professional category. A critical review of the data was based on content analysis prepared from categorization of the discourses. The results showed that, in general, the teams do not possess sufficient theoretical knowledge about the system of which they are part. Moreover, although there is a high level of satisfaction, precarious working conditions and a lack of professional recognition and labor input can negatively affect the institutional dynamics. Lastly, a quantitative equivalence was also detected regarding affective and calculative aspects of organizational commitment and a close relationship between length of service and involvement with the work. PMID- 24061024 TI - [Psychomotor development and its disorders: between normal and pathological development]. AB - This article discusses some aspects of psychomotor development and its disorders, with special emphasis on psychomotor retardation. Diagnostic classifications of psychomotor problems, such as DSM-IV and CIE-10, are referred to and their advantages and disadvantages are analyzed. The concept of normality as a synonym for the statistical mean in the context of psychomotor disorders is also analyzed in order to consider its dynamic and variability, thereby avoiding the normality/pathology opposition, while some issues, such as the social and cultural aspects, are highlighted, making it possible to rethink the universality and relativity of psychomotor development. PMID- 24061025 TI - [Different aspects of depression in suicide among the elderly]. AB - This article analyzes different aspects of depression association with suicide among the elderly based on psychological autopsies. The retrospective method was used to study indeterminate deaths, based on interviews and reports, which analyze psychosocial circumstances related to suicide. The paper reveals the predominance of gender, social class and race - women, middle and upper class, white - and, in an unprecedented manner, contextualizes depression in a poorly studied population in Brazil and in the world with high risk of suicide. The physical and mental health, social circumstances and predominant biographical characteristics of the suicide victim were reconstructed in order to assess the impact of depression on suicide. Depression was presented in almost all cases, in primary or secondary diagnosis, as the symptom associated with other co morbidities or as a reaction to social stressors, demanding different therapeutic approaches and procedures. The association between depression and multiple co morbidity accentuates the case prognosis and cumulatively increases the risk of suicide. Depression followed by suicidal tendencies is a risk factor which justifies immediate preventive measures. Increasing assertive ways to diagnose and treat depression in old age is recommended. PMID- 24061027 TI - [The prevalence and factors associated with diabetic foot amputations]. AB - The scope of this investigation was to establish the prevalence of diabetic foot amputations and analyze associations with factors related to the individual and to primary health care. It is a cross-sectional epidemiological study and the sample included 214 inpatients with diabetic feet in one of the four hospitals specialized in vascular surgery in the state of Pernambuco. Data were collected using semi-structured questionnaires. In the data analysis, chi-square association, Poisson regression (p < 0.05) and descriptive statistics procedures were applied. The prevalence of amputation ascertained was 50%. The following factors related to the individual were associated with its occurrence: low education (p = 0.027); two or more people living in the household (p = 0.046); and patient income below the minimum wage (p = 0.004). The following factors related to primary health care were associated with amputation: not having feet examined (PR = 1.17); not receiving guidance on foot care (PR = 2.24) in consultations in the past year; not using the drug for DM control as prescribed (PR = 1.60); and inadequate glycemic control (PR = 1.83). Understanding these factors helps to identify aspects of preventive care that require improvement. PMID- 24061026 TI - [Psychological violence and the family context of adolescent users of outpatient services in a public tertiary pediatric hospital]. AB - The scope of this research was to investigate the association of psychological violence (PV) during adolescence with social and demographic factors, family structure/relationships and with other forms of maltreatment. A questionnaire was applied to 229 adolescents (11-18 years) in outpatient services in a state-run tertiary pediatric hospital. It was found that 26.4% of respondents suffered severe PV in the family context, and only 5 of the respondents reported they did not suffer any PV in the family context, illustrating how this kind of violence is seen as commonplace in the family relationship. The most common forms of PV behavior were: being criticized for what one does or says; not being encouraged when trying to act autonomously; being called nasty names, and having an adult saying one is wrong when one tries to act. Dissatisfaction of parents with the adolescent, the nuclear family structure, the position of the child among siblings sharing the same parents were associated with PV occurring within the family context. In order to enable it to detect signs of PV, the health sector can promote the right to comprehensive health of adolescents, confirming itself as one of the main social sectors capable of acting preventively on the forms of violence suffered and practiced by the family group. PMID- 24061028 TI - Analysis of treatment of comorbidities and the profile of medical consultations for diabetes mellitus. AB - The scope of this paper was to analyze the profile of medical consultations and drugs used for the treatment of comorbidities in patients with diabetes attended in the Brazilian Unified Health System. This was a pharmaco-epidemiological cross sectional study conducted between March 2006 and February 2007 All patients with diabetes attended in the western sanitary district of Ribeirao Preto in the state of Sao Paulo were included in the study. The types of medical attendance (primary, secondary and emergency care) and the drugs prescribed for the treatment of comorbidities were analyzed. The drugs were classified according to the Anatomical Therapeutic Chemical Classification System and 3,198 patients were identified. The mean age was 60.4 years and more than 55% of the patients were 60 years or older. The cardiovascular drugs most used were captopril or enalapril (60%). About 40.6% of the patients used acetylsalicylic acid in platelet antiaggregant doses. The patients had an average of 5.1 medical consultations per year (primary care, secondary care and emergency care). The utilization of statins and acetylsalicylic acid was less than that reported in the literature and the data indicate a high prevalence of admission to emergency care. PMID- 24061029 TI - [Functional skills of children with deficiencies in school inclusion: barriers to effective inclusion]. AB - The scope of this article is to describe the disabilities of students in the process of inclusion by means of the PEDI - Pediatric Evaluation of Disability Inventory. A cross-sectional analysis was conducted. The population studied included 181 students (7-10 years old) from 31 public schools in Sao Paulo. Using a questionnaire applied to the caregiver, 197 activities were evaluated in the areas of self-care, mobility and social function. In accordance with the PEDI, differences (p < 0.05) in student performance were observed between grades in the scales of self-care (average of 77.8% in the 1st grade and 95.2% in the 4th grade) and mobility (average of 90% in the 1st grade and 99.8% in the 4th grade); social function had the lowest averages, except for those with physical disabilities, in which the most affected area was mobility (average of 62.7%). The PEDI enabled the identification of disabilities per group and individual disability, which may constitute an important tool for targeted intervention and follow-up at school. PMID- 24061030 TI - [Ethics and values in professional training in health: a case study]. AB - The scope of this research was to analyze the ethical dimension of the training of health professionals, specifically in Dentistry. Interviews were conducted with teachers, in addition to observation of academic activities and focus groups with students of two undergraduate courses. Data analysis revealed some elements of the hidden curriculum that influences the ethical dimension of training. The results discussed here suggest different ethical concepts in the academic environment with the predominance of an implicit code of ethics, the consequences of which require attention in the management of daily ethical conflicts. Based on common sense and a lack of intentionality of the academic staff with respect to the ethical training of students, it is imperative to know the values + they cherish in order to understand their moral development and identify a bioethical benchmark upon which the pedagogical-ethical issue is grounded. By way of conclusion, it is essential to assume individual and collective teaching responsibility for the ethical dimension of training in order that the professional training also has the potential for the integrated training of the human being as a whole. PMID- 24061031 TI - [Information from the invoicing sector as support for decision-making: a case study at the University Hospital of the Federal University of Grande Dourados (UFGD)]. AB - The public sector is the main financing agent of hospital admissions and the information generated constitutes the input for the hospital information network of the Unified Health System (SUS). This paper seeks to design a report template to be used for decision-making in both public and university hospitals. The theoretical approach sought inspiration in discussions about the SUS, hospital institutions, hospital information systems and decision-making. The methodological procedures used are characterized as qualitative-descriptive methods and were conducted in a single case study and action research. The primary data analysis was carried out in two stages from January through December 2007 and from January through December 2008. Based on these periods, the findings were described and the elaboration of new reports was presented, with the importance and need for each being duly emphasized. Lastly, a structured report template was created for the case study that includes information discussed in the article. The conclusion reached is that the hospital information system can become a potential support tool, as the necessary adjustments are made and the report is structured to furnish the institution with an objective communication tool for decision-making. PMID- 24061032 TI - [The use of antimicrobial drugs by the population in the city of Jatai, State of Goias, Brazil]. AB - One factor that contributes to the emergence of multidrug-resistant microorganisms is the inappropriate use of antimicrobials. In this study 192 homes were visited to apply a questionnaire regarding the consumption habits of antimicrobials of all residents. The data revealed that 6.8% of participants had used antimicrobial agents in recent months. Users were predominantly female, aged between 20 and 59, with an income of 1 to 3 minimum salaries. Of the total, 9.1% made use of antimicrobials without prescription and 4.6% did not complete the treatment cycle, citing either improvement in symptoms or side effects. The most reported reason for treatment was oropharyngeal infection. Inappropriate use of antibiotics was also detected, such as for the treatment of fever, influenza and allergy. Among the respondents, 20.5% traditionally recommend the use of antimicrobials to family and friends. This study was conducted before the prohibition of the sale of antibiotics without a prescription. The majority of respondents are unaware of the risks of inappropriate use and a considerable percentage of individuals recommend these drugs to others. With the implementation of the law prohibiting sale without prescription, it is hoped that this problem will be minimized. PMID- 24061033 TI - [The profile of hospitalizations and associated factors among elderly users of the Brazilian Unified Health System (SUS)]. AB - This article seeks to establish the causes of hospitalizations among the elderly and identify the prevalence and associated factors. It is a cross-sectional study with 418 elderly users of SUS selected by multistage proportional sampling in the nine Sanitary Districts of Goiania. Hospitalization was defined as a positive response to the question: "Were you hospitalized in the past year?" The independent variables were collected on a standardized questionnaire. Associations were explored through the prevalence ratio and the respective 95% CI. Multivariate analysis was conducted using hierarchical Poisson regression. The prevalence of hospitalizations was 24.4% and the major causes were circulatory (28.4%), respiratory (9.8%) and infectious and parasitic diseases (9.8%). In multivariate analysis, the following variables continued to be associated with hospitalizations: A/B economic class, reports of five or more diseases and weight loss. The results revealed a high prevalence of hospitalizations and that factors involved are mainly related to socioeconomic issues and health status, which demonstrates that it is necessary to monitor these cases in primary health care to prevent unnecessary hospitalization. PMID- 24061035 TI - [Information on health: production, consumption and biopower]. AB - This article seeks to elicit misgivings regarding the value attributed to medical truth found in the biomedical literature. The issue of the protection of sexual practices was taken by way of example and the works of thinkers like Nietzsche, Baudrillard, Bourdieu, and especially Michel Foucault, were consulted. This was done in order to consider that the elaboration and use of health information can be interpreted as a practice constituting a policy that dynamically inspires both experts and non-experts on medical truth, constituting a morality that is based on the production and consumption of this truth. It is a policy that Foucault called biopolitics, able to establish ways of living where the exercise of thought does not seem to be so "rewarding," where practices of command and obedience are mediated by health information. In this perspective, physicians and non-physicians have been seduced by the desire to attain the truth, such that the commitment of everyone is seen to concentrate on the production and use of statements that they believe can prolong life and save from getting sick. These are discourses cultivated in the market of a media-dominated society in which individuals controlled by information produce subjectivities that are anchored in the medical-capital truth binomial. PMID- 24061034 TI - [An approach regarding the use of medication in biology textbooks as a strategy for health promotion]. AB - The inappropriate use of medication represents a major threat to public health and drugs rank first among the agents causing intoxication in Brazil, ahead of poisons for rodents and insects, illegal drugs, pesticides, cleaning products and spoiled food. The National Curriculum of Secondary Education Parameters (PCN+) give major emphasis to health, since the reference to Drugs is mentioned repeatedly in the text. The scope of this research was to study the approaches to drug use in textbooks. For this purpose, eleven biology textbooks were analyzed, namely six single volumes and five with three volumes each, i.e. a total of twenty-one volumes. The rational use of medication should be considered an important topic for the promotion of health which affects all sectors of society and should be emphasized in basic education. In line with this idea and based on the results obtained, it is suggested that the textbooks analyzed should be adapted to the new legislation and content that addresses Rational Drug Use, thus meeting the recommendations of PCN+. In this context, the books should concisely address the following topics: self-medication, adherence to drug treatment, advertisements and reports on drugs, among others. PMID- 24061036 TI - [Daily difficulties associated with full conventional dentures]. AB - The effectiveness of health services can be evaluated from the quality of life (QOL) standpoint. Thus, this study evaluated rehabilitation services using full conventional dentures (FCD) of Specialized Dental Care Centers (SDCC) in Rio Grande do Norte (RN) regarding daily difficulties associated with these dentures made between 2007 and 2009. A cross-sectional study was conducted with 138 users of these FCD, collecting data by clinical examination and a questionnaire based on the Oral Impacts on Daily Performances index. The Fisher and chi-square tests were used to test the association between the variables. The result was that 42% of users reported difficulties in executing oral activities due to FCDs. These difficulties were more frequent and intense in the activities of eating, speaking and smiling. In general, 58.7% of users did not have functional teeth. In relation to the clinical evaluation of FCDs, 57.2% of upper and 9.2% of lower FCDs were satisfactory. There was an association between difficulty and the absence of functional teeth, but not with inadequate FCDs. Thus, the SDCCs were effective in upper FCD rehabilitation, since the difficulties encountered are within the standard limitations of this type of rehabilitation. On the other hand, the cost-benefit of rehabilitation of lower FCDs must be evaluated. PMID- 24061041 TI - Targeted therapies: another option for metastatic RCC. PMID- 24061042 TI - Gastrointestinal cancer: is now the time to extend biomarker stratification to other RAS-family genes? PMID- 24061043 TI - Epitaxial assembly dynamics of mutant amyloid beta25-35_N27C fibrils explored with time-resolved scanning force microscopy. AB - Amyloid beta25-35 (Abeta25-35) is a toxic fragment of Alzheimer's beta peptide. We have previously shown that Abeta25-35 fibrils form a trigonally oriented network on mica by epitaxial growth mechanisms. Chemical reactivity can be furnished to the fibril by introducing a cysteine residue (Abeta25-35_N27C) while maintaining oriented assembly properties. Previously we have shown that fibril binding to mica is strongly influenced by KCl concentration. In the present work we explored the kinetics of epitaxial assembly of the mutant fibrils at different peptide and KCl concentrations by using in situ time-resolved AFM. We measured the length of Abeta25-35_N27C fibrils as a function of time. Increasing free peptide concentration enhanced fibril growth rate, and the critical peptide concentration of fibril assembly was 3.92MUM. Increasing KCl concentration decreased the number of fibrils bound to the mica surface, and above 20mM KCl fibril formation was completely abolished even at high peptide concentrations. By modulating peptide and KCl concentrations in the optimal ranges established here the complexity of the Abeta25-35_N27C network can be finely tuned. PMID- 24061044 TI - Spin crossover complexes [Fe(NH2trz)3](X)2.nH2O investigated by means of polarized Raman scattering and DFT calculations. AB - Vibrational spectra of the spin crossover (SCO) polymers [Fe(NH2trz)3](X)2.nH2O where NH2trz = 4-NH2-1,2,4-triazole and X = Cl, Br, BF4, and NO3 have been analyzed. Our results show that the anions and water molecules have no significant influence on the vibrational properties of the Fe(NH2-trz)3 polymer chains. A detailed study of the nitrate derivative, based on the DFT analysis of the polarized spectra of single crystals, has been undertaken to propose the normal mode assignment of the Raman peaks in the low spin state of the compound. Changes in the Raman spectra in the high spin state could therefore be analyzed and interpreted by several Raman bands identified as molecular probes of the SCO phenomenon. Various factors (laser power, humidity, pressure) that influence the transition temperatures and the hysteresis loops have been identified and adjusted for obtaining reliable measurements. We demonstrate in particular that all the techniques used to probe the phase transition process give comparable results providing that the sample environment is well controlled. PMID- 24061039 TI - Gastric cancer-molecular and clinical dimensions. AB - Gastric cancer imposes a considerable health burden around the globe despite its declining incidence. The disease is often diagnosed in advanced stages and is associated with a poor prognosis for patients. An in-depth understanding of the molecular underpinnings of gastric cancer has lagged behind many other cancers of similar incidence and morbidity, owing to our limited knowledge of germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets). A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1 and MET) alterations are emerging and some are being pursued clinically. Novel somatic gene targets (ARID1A, FAT4, MLL and KMT2C) have also been identified and are of interest. Variations in the therapeutic approaches dependent on geographical region are evident for localized gastric cancer-differences that are driven by preferences for the adjuvant strategies and the extent of surgery coupled with philosophical divides. However, greater uniformity in approach has been noted in the metastatic cancer setting, an incurable condition. Having realized only modest successes, momentum is building for carrying out more phase III comparative trials, with some using biomarker-based patient selection strategies. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer. PMID- 24061045 TI - Theory of amplitude modulated electrostatic force microscopy for dielectric measurements in liquids at MHz frequencies. AB - A theoretical analysis of amplitude modulated electrostatic force microscopy (AM EFM) in liquid media at MHz frequencies, based on a simple tip-sample parallel plate model, is presented. The model qualitatively explains the main features of AM-EFM in liquid media and provides a simple explanation of how the measured electric forces are affected by: the frequency of the applied voltage, the tip sample distance, the ionic concentration, the relative dielectric constant of the solution, and the relative dielectric constant and thickness of the sample. These results provide a simple framework for the design of AM-EFM measurements for localized dielectric characterization in liquid media. PMID- 24061046 TI - Life cycle assessment of sewage sludge management: a review. AB - In this article, 35 published studies on life cycle assessment (LCA) of sewage sludge were reviewed for their methodological and technological assumptions. Overall, LCA has been providing a flexible framework to quantify environmental impacts of wastewater and sewage sludge treatment and disposal processes for multiple scales, ranging from process selection to policy evaluation. The results of LCA are, in principle, unique to the goal and scope of each study, reflecting its local conditions and comparison between different LCAs is not intended. Furthermore, the assessments are limited by the methodological development of the life cycle impact assessment (LCIA) and the advancement of research in quantifying environmental emissions associated with wastewater and sewage sludge treatment processes. Thus, large discrepancies were found in the selection of the environmental emissions to be included and how they were estimated in the analysis. In order to reduce these choice uncertainties, consolidation of the modelling approach in the following area are recommended: quantification of fugitive gas emissions and modelling of disposal practices. Besides harmonization of the key technical assumptions, clear documentation of the modelling approach and the uncertainties associating with each assumption is encouraged so as to improve the integrity and robustness of assessment. PMID- 24061047 TI - Structures and chiroptical properties of the BINAS-monosubstituted Au38(SCH3)24 cluster. AB - The structure and optical properties of a set of R-1,1'-binaphthyl-2,2'-dithiol (R-BINAS) monosubstituted A-Au38(SCH3)24 clusters are studied by means of time dependent density functional theory (TD-DFT). While it was proposed earlier that BINAS selectively binds to monomer motifs (SR-Au-SR) covering the Au23 core, our calculations suggest a binding mode that bridges two dimer (SR-Au-SR-Au-RS) motifs. The more stable isomers show a negligible distortion induced by BINAS adsorption on the Au38(SCH3)24 cluster which is reflected by similar optical and Circular Dichroism (CD) spectra to those found for the parent cluster. The results furthermore show that BINAS adsorption does not enhance the CD signals of the Au38(SCH3)24 cluster. PMID- 24061048 TI - Urinary incontinence: the role of menopause. AB - OBJECTIVE: This study aims to explore the effects of menopause and hormone therapy on the symptoms and signs of stress urinary incontinence and urge urinary incontinence. METHODS: Records of women who attended a tertiary urogynecological unit were reviewed retrospectively. A standardized interview included evaluations of symptoms, menopause age (ie, time since last menstrual period or onset of menopausal symptoms), current or previous hormone use, and visual analogue scales for bother. Multichannel urodynamics, including urethral pressure profilometry and determination of abdominal leak point pressure, was performed. RESULTS: Of 382 women seen during the inclusion period, 62% were postmenopausal. Current systemic or local hormone use was reported by 7% and 6%, respectively. Two hundred eighty-eight women (76%) reported symptoms of stress urinary incontinence, with a mean bother of 5.7, and 273 women (72%) reported symptoms of urge urinary incontinence, with a mean bother of 6.4. On univariate analysis, symptoms and bother of urge incontinence were significantly related to menopause age, whereas this relationship was not found for stress incontinence. After calendar age was controlled for, length of menopause showed no significant relationship with any symptom or sign of urinary incontinence. CONCLUSIONS: Hormone deficiency after menopause is unlikely to play a major role in urinary incontinence. PMID- 24061049 TI - Risk of glaucoma after early bilateral oophorectomy. AB - OBJECTIVE: Because early estrogen deficiency may increase the susceptibility of the optic nerve to glaucoma, we studied the association of early bilateral oophorectomy with glaucoma. METHODS: In the Mayo Clinic Cohort Study of Oophorectomy and Aging, we studied the risk of glaucoma by comparing women who underwent bilateral oophorectomy from 1950 to 1987 with age-matched referent women who did not undergo unilateral or bilateral oophorectomy. Glaucoma diagnostic codes were identified in the records linkage system of the Rochester Epidemiology Project. Hazard ratios (HRs) were calculated during a median follow up of 25.5 years. Analyses were stratified by age at the time of bilateral oophorectomy (in tertiles). RESULTS: Of 1,044 women who underwent bilateral oophorectomy before menopause, 147 developed glaucoma. Of 1,070 referent women, 133 developed glaucoma. Women who underwent bilateral oophorectomy showed no increased risk of glaucoma in the overall group (HR, 1.12; 95% CI, 0.89-1.42). However, women who underwent oophorectomy before the age of 43 years (n = 344; first tertile) had a significantly increased risk of glaucoma (HR, 1.60; 95% CI, 1.15-2.23). The results did not change after adjustment for hypertension, obesity, diabetes, or disorders of lipid metabolism at baseline. Approximately 11% of women who had undergone bilateral oophorectomy before the age of 43 years were treated with estrogen up to the age of 50 years; however, treatment did not reduce the association (HR, 1.59; 95% CI, 0.81-3.13). CONCLUSIONS: Bilateral oophorectomy before the age of 43 years may increase the risk of glaucoma, and estrogen treatment does not seem to attenuate the risk. PMID- 24061050 TI - Effects of testosterone on visuospatial function and verbal fluency in postmenopausal women: results from a functional magnetic resonance imaging pilot study. AB - OBJECTIVE: This study aims to investigate the effects of testosterone on cognitive performance during functional magnetic resonance imaging (fMRI) in healthy estrogen-treated postmenopausal women. METHODS: This was an open-label study in which postmenopausal women on nonoral estrogen therapy were treated with transdermal testosterone for 26 weeks. Women performed tests of verbal fluency (number of words) and mental rotation (reaction time and accuracy) during pretreatment and posttreatment fMRI. Blood oxygen level-dependent (BOLD) signal intensity was measured during fMRI tasks. RESULTS: Nine women with a mean (SD) age of 55.4 (3.8) years completed the study. Twenty-six weeks of testosterone therapy was associated with significant decreases in BOLD intensity during the mental rotation task in the right superior parietal, left inferior parietal, and left precuneus regions, and during the verbal fluency task in the left inferior frontal gyrus, left lingual gyrus, and medial frontal gyrus (all P < 0.05), with no change in task performance, accuracy, or speed. CONCLUSIONS: Testosterone therapy is associated with reduced BOLD signal activation in key anatomical areas during fMRI verbal fluency and visuospatial tasks in healthy estrogen-treated postmenopausal women. Our interpretation is that testosterone therapy facilitates preservation of cognitive function with less neuronal recruitment. PMID- 24061051 TI - Effective Hamiltonian parameters for ab initio energy-level calculations of SrCl2:Yb2+ and CsCaBr3:Yb2+. AB - Calculated energy levels from recent ab initio studies of the electronic structure of SrCl2:Yb(2+) and CsCaBr3:Yb(2+) are fitted with a semi-empirical 'crystal-field' Hamiltonian, which acts within the model space 4f(14) + 4f(13)5d + 4f(13)6s. Parameters are obtained for the minima of the potential energy curves for each energy level and also for a range of anion-cation separations. The parameters are compared with published parameters fitted to experimental data and to atomic calculations. The states with significant 4f(13)6s character give a good approximation to the impurity-trapped exciton states that appear in the ab initio calculations. PMID- 24061052 TI - Greenhouse gas fluxes from agricultural soils under organic and non-organic management--a global meta-analysis. AB - It is anticipated that organic farming systems provide benefits concerning soil conservation and climate protection. A literature search on measured soil-derived greenhouse gas (GHG) (nitrous oxide and methane) fluxes under organic and non organic management from farming system comparisons was conducted and followed by a meta-analysis. Up to date only 19 studies based on field measurements could be retrieved. Based on 12 studies that cover annual measurements, it appeared with a high significance that area-scaled nitrous oxide emissions from organically managed soils are 492 +/- 160 kg CO2 eq. ha(-1) a(-1) lower than from non organically managed soils. For arable soils the difference amounts to 497 +/- 162 kg CO2 eq. ha(-1) a(-1). However, yield-scaled nitrous oxide emissions are higher by 41 +/- 34 kg CO2 eq. t(-1) DM under organic management (arable and use). To equalize this mean difference in yield-scaled nitrous oxide emissions between both farming systems, the yield gap has to be less than 17%. Emissions from conventionally managed soils seemed to be influenced mainly by total N inputs, whereas for organically managed soils other variables such as soil characteristics seemed to be more important. This can be explained by the higher bioavailability of the synthetic N fertilisers in non-organic farming systems while the necessary mineralisation of the N sources under organic management leads to lower and retarded availability. Furthermore, a higher methane uptake of 3.2 +/- 2.5 kg CO2 eq. ha(-1) a(-1) for arable soils under organic management can be observed. Only one comparative study on rice paddies has been published up to date. All 19 retrieved studies were conducted in the Northern hemisphere under temperate climate. Further GHG flux measurements in farming system comparisons are required to confirm the results and close the existing knowledge gaps. PMID- 24061053 TI - Hexabromocyclododecane concentrations in Canadian human fetal liver and placental tissues. AB - Detectable concentrations of the flame retardant hexabromocyclododecane (HBCD) have been reported in human tissues worldwide, but investigations to determine fetal exposure to this brominated flame retardant are lacking. This study was undertaken to determine the concentrations of alpha-, beta- and gamma-HBCD in human tissues (fetal liver and placenta) from Canada. Tissue samples were collected over a thirteen year period following elective pregnancy terminations in Montreal, Quebec, Canada. Samples were extracted using homogenisation with solvent, cleaned up using adsorption chromatography and analysis was performed with liquid chromatography-tandem mass spectrometry. Total HBCD concentrations ranged from below the limit of detection (10%); group 2, night SBP <120 mm Hg and nondipping (<=10%); group 3, nocturnal hypertension (SBP >=120 mm Hg) and normal dipping; and group 4, nocturnal hypertension and nondipping. RESULTS: The smallest proportion of patients with additional cardiovascular risk factors, organ damage, and history of previous events was observed in the group with both normal night SBP and dipping, whereas those with both nocturnal hypertension and nondipping showed the largest proportion of cardiovascular risk factors and diseases. When groups showing only 1 abnormality were compared, nondipping was associated with female sex, reduced renal function, and previous cardiovascular events, whereas nocturnal hypertension was associated with male sex, smoking, and increased urinary albumin excretion. In treated patients, it was also associated with the presence of diabetes. CONCLUSION: Nondipping is related to more advanced disease (reduced renal function and clinical evidence of cardiovascular disease), whereas nocturnal hypertension is associated with albuminuria. The worst cardiovascular risk profile is present in patients exhibiting both nocturnal hypertension and nondipping. PMID- 24061071 TI - Favorable effects of concord grape juice on endothelial function and arterial stiffness in healthy smokers. AB - BACKGROUND: Smoking is associated with impaired vascular function. Concord grape juice (CGJ), a rich source of flavonoids, can modify cardiovascular risk factors. Endothelial function and arterial stiffness are surrogate markers of arterial health. We examined the impact of CGJ on arterial wall properties in healthy smokers. METHODS: We studied the effect of a 2-week oral treatment with CGJ in 26 healthy smokers on 3 occasions (day 0 (baseline), day 7, and day 14) in a randomized, placebo-controlled, double-blind, crossover study. Measurements were taken before (pSm), immediately after (Sm0), and 20 minutes after (Sm20) cigarette smoking. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness. RESULTS: Compared with placebo, treatment with CGJ resulted in a significant improvement in pSm values of FMD (P = 0.02) and PWV (P = 0.04). At baseline, smoking decreased FMD in both the CGJ group (P < 0.001) and the placebo group (P < 0.001). Compared with placebo, CGJ treatment prevented the acute smoking-induced decrease in FMD on day 7 (P = 0.02) and day 14 (P < 0.001). Moreover, at baseline, smoking induced a significant elevation in PWV in both the CGJ group (P = 0.02) and the placebo group (P = 0.04). Treatment with CGJ prevented the smoking-induced elevation in PWV on day 7 (P = 0.003) and day 14 (P < 0.001). CONCLUSIONS: CGJ consumption improved endothelial function and vascular elastic properties of the arterial tree in healthy smokers and attenuated acute smoking-induced impairment of arterial wall properties. PMID- 24061072 TI - Orthostatic hypotension does not increase cardiovascular risk in the elderly at a population level. AB - BACKGROUND: The general belief that orthostatic hypotension (OH) predisposes to cardiovascular events is based on sparse and contradictory data, rarely derived from population studies. METHODS: A total of 1,016 men and women aged >=65 years was studied in a 12-year epidemiological population-based study. Cardiovascular events were detected in subjects with and without OH (blood pressure (BP) decrease >=20mm Hg for systolic or >=10mm Hg for diastolic), and Cox analysis was performed including OH as an independent variable. RESULTS: In univariate analysis, coronary (20.2% vs. 13.1%, P = 0.05), cerebrovascular (13.1% vs. 8.4%, P = 0.05), and heart failure (HF) events (20.2% vs. 13.8%, P = 0.03) were apparently more incidental in subjects with OH than in those without OH. Nevertheless, after adjusting for age, gender, and systolic BP as confounders, OH did not act as a cardiovascular predictor (relative risk for cerebrovascular events 1.33, 95% confidence interval (CI), 0.78-2.2, for coronary events 1.25, CI 0.82-1.88, for HF 1.07, CI 0.71-1.62, for arrhythmias 0.82, CI 0.40-1.37, and for syncope 0.58, CI 0.13-2.71). CONCLUSIONS: Although OH seems to be a predictor of coronary, cerebrovascular, and HF events, no predictive role was found in models that include biological confounders. Independent of the cause of OH, age and systolic BP, which are positively associated with OH, fully explain the greater incidence of cardiovascular events and the greater cardiovascular risk observed in subjects with OH. PMID- 24061074 TI - The differential diagnosis of systemic sclerosis. AB - PURPOSE OF REVIEW: The new American College of Rheumatology/European League Against Rheumatism classification criteria will enable earlier diagnosis and, therefore, the use of newer treatment modalities for systemic sclerosis (SSc). It is therefore critical to exclude non-SSc causes for diffuse skin thickening as early as possible. RECENT FINDINGS: The recently described gadolinium-induced nephrogenic systemic fibrosis may mimic SSc as may other conditions which require a different treatment strategy. Recently, treatment with immunoablation and autologous stem cell transplantation has been shown to significantly benefit some patients with conditions such as scleromyxoedema and SSc. The more accurate measurement of SSc-specific autoantibodies such as topoisomerase 1, centromere and RNA polymerase has recently allowed a more precise subclassification of SSc with implications for treatment and prognosis. SUMMARY: Skin thickening is a nonspecific manifestation of many different processes including (rarely) early scleroderma, which is mostly symmetrical and associated with Raynaud's phenomenon, nailfold capillaroscopic changes and antinuclear antibodies. If the latter three factors are absent, then other conditions must be excluded, the commonest being eosinophilic fasciitis. Skin biopsy (looking for eosinophil infiltration, increased mucin or amyloid deposition), SSc-specific autoantibodies or paraproteins in blood and a careful medical history and system screening will exclude nonscleroderma conditions. PMID- 24061073 TI - The role of p38 MAPK in neutrophil functions: single cell chemotaxis and surface marker expression. AB - Neutrophils act as the first line of defence in the human immune system by migrating to the site of abnormal events and performing their designated roles. One major signalling pathway that drives neutrophil action in vivo is the p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Herein, a microfluidic platform is employed to explore the mechanistic role of p38 MAPK in neutrophil chemotaxis. Neutrophils, with and without p38 MAPK inhibition, were exposed to pairwise competing gradients of chemotaxis-inducing molecules. Overall, p38 MAPK inhibitor-treated neutrophils were still capable of moving toward a chemoattractant signal; however, the hierarchy of neutrophil response to various chemoattractants changed and there was more deviation from direct movement toward a chemoattractant signal in p38 MAPK-blocked cells. In a parallel fluorescence imaging study, neutrophil expression of surface receptors (CXCR1, FPR2, BLTR, CD11b and CD66b) changed when comparing untreated and p38 MAPK-blocked cells. All results demonstrate that the p38 MAPK-dependent pathway plays a critical role in neutrophil chemotaxis and this role is, in part, through the regulation of surface receptor expression. These data regarding how receptor expression and chemotaxis are influenced by the p38 MAPK pathways lend insight into neutrophil behaviour in physiological environments and the potential manipulation of p38 MAPK for therapeutic purposes. PMID- 24061075 TI - Lung transplantation in patients with scleroderma. AB - PURPOSE OF REVIEW: Systemic sclerosis (SSc) is an autoimmune disorder that involves skin and internal organs. Pulmonary diseases, comprising interstitial lung disease and pulmonary arterial hypertension, are the leading causes of morbidity and mortality in patients with SSc. Lung transplantation in patients with SSc remains controversial owing to a presumed heightened risk in the postoperative period from SSc-related gastroesophageal reflux, renal impairment, and skin fibrosis. In this article, we review the indications and patient selection criteria for lung transplantation in patients with SSc, discuss the implications and recommendations related to single versus bilateral lung transplantation, and review postlung transplantation survival data. RECENT FINDINGS: Early aggressive surgical treatment of gastroesophageal reflux disease decreases the rate of bronchiolitis and improves survival in lung transplant patients. Heart transplantations remain rare owing to frequent involvement of other organ systems in SSc patients with cardiac manifestations. The procedure of choice in patients with SSc has not been determined, but given the dearth of donor lungs, single lung transplantation has become commonplace for most SSc patients without severe pulmonary hypertension. Carefully selected patients without extrapulmonary systemic disease experience similar survival after lung transplantation compared to those with other end-stage pulmonary diseases. Patients with SSc undergoing lung transplantation have similar rates of chronic rejection as patients transplanted for nonconnective tissue disease-related interstitial lung disease. SUMMARY: Lung transplantation represents a viable therapeutic option to consider for patients with end-stage lung disease due to SSc who have limited extrapulmonary manifestations. PMID- 24061076 TI - What does global gene expression profiling tell us about the pathogenesis of systemic sclerosis? AB - PURPOSE OF REVIEW: The purpose of this study is to review recent hypothesis driven studies that utilize global gene expression data for elucidating the molecular basis of systemic sclerosis (SSc) and its various clinical manifestations. RECENT FINDINGS: The longitudinal skin gene expression studies indicate that the previously identified molecular subsets are stable over time and might identify inherent subgroups of SSc patients. Skin transcript follow-up studies indicate that the Wnt/beta-catenin pathway plays an important role in promotion of fibrogenesis in fibroblasts and preadipocytes. Furthermore, the transcript profile of sclerodermatous graft-versus-host disease (sclGVHD) mice resembles the skin transcriptomes of a subgroup of SSc patientswith IL13/IL4 inducible skin signature wherein the profibrotic chemokine CCL2 plays a key role. The comparison of skin biopsies from SSc patients to skin lesions of patients with cutaneous lupus and dermatomyositis has provided valuable information about the interferon (IFN) signature in these autoimmune diseases. Furthermore, plasma IFN-inducible chemokines correlate with the IFN gene expression score in SSc patients, enabling researchers to examine this molecular signature in large SSc cohorts with serum or plasma collection. SUMMARY: Global gene expression profiling in skin and peripheral blood can contribute to a better understanding of SSc pathogenesis and identify novel biomarkers and therapeutic targets. PMID- 24061077 TI - The spectrum of statin myopathy. AB - PURPOSE OF REVIEW: This review discusses the spectrum of myopathies associated with statin use, with special attention given to a recently identified statin associated autoimmune-necrotizing myopathy. The clinical characteristics of these patients, pathologic findings, associated autoantibody and immunogenetic risk factors are discussed. RECENT FINDINGS: In the past several years, a novel form of autoimmunemyopathy associated with statin use has been described. Patients with this form of myositis have unique clinical, pathologic and pathophysiologic features when compared with those with self-limited statin toxic myopathy. An autoantibody directed against HMG-CoA reductase (HMGCR), the pharmacologic target of statins, characterizes the disease and can be used in clinical practice to identify these patients and direct therapy. Still, many questions remain to be answered regarding the pathogenic mechanisms at play, risk factors for developing the disease, long-term prognosis and effects of rechallenge with statins or other cholesterol-lowering drugs. SUMMARY: Statins can cause a spectrum of muscle diseases, most of which are self-limited and improve with discontinuation of the offending agent. In a subgroup, an autoimmune necrotizing myopathy develops that persists after discontinuation of statins. Specific autoantibody testing can help identify these patients in clinical practice and determine the need for immunosuppressive therapy. PMID- 24061078 TI - Update in juvenile myositis. AB - PURPOSE OF REVIEW: This update on childhood idiopathic inflammatory myopathies (IIMs) reviews recent progress in the field of translational science and clinical research over the past 12-18 months. RECENT FINDINGS: Several new studies, including results from the international genome-wide association study, point to abnormalities of the adaptive immune system in childhood IIMs. Circulating T follicular helper cells promote plasma cell differentiation and have been found in high levels in juvenile dermatomyositis (JDM), which may account the frequency of autoantibodies seen in this disease. One of the latest to be identified in JDM targets the protein NXP-2 and is associated with an increased risk of calcinosis in young patients. The first randomized controlled clinical trial in refractory adult and childhood IIMs was reported this year. B-cell depletion with the anti CD20 antibody, rituximab, failed to achieve its primary end point, but patients with JDM did show good improvement in disease activity. A new international definition of disease remission in JDM has been agreed, which will aid disease assessment in future therapeutic trials. SUMMARY: The challenges of studying a rare disease such as JDM have been overcome by several collaborative studies and have led to significant progress in understanding the cause, treatment and prognosis of childhood IIMs. PMID- 24061079 TI - Editorial: collaborative international research leads to new biomarkers for diagnosis and prediction of outcome in the idiopathic inflammatory myopathy spectrum. PMID- 24061080 TI - Obesity: Metabolic effects of fructose. PMID- 24061081 TI - Pharmacotherapy: Cardiovascular safety of antihyperglycaemic drugs in patients with type 2 diabetes mellitus. PMID- 24061082 TI - The value of sharing treatment decision making with patients: expecting too much? PMID- 24061083 TI - Inhalation as a source of iron in secondary iron overload. PMID- 24061084 TI - Assessing the extent of "conflict of use" in multipurpose tropical forest trees: a regional view. AB - In the context of multiple forest management, multipurpose tree species which provide both timber and non-timber forest products (NTFP), present particular challenges as the potential of conflicting use for either product may be high. One key aspect is that the magnitude of conflict of use can be location specific, thus adding complexity to policy development. This paper focuses on the extent to which the potential for conflict of use in multipurpose tree species varies across the Amazonian lowland forests shared by Peru, Bolivia, Colombia, Ecuador and Venezuela, emphasizing the economic dimension of conflict. Based on a review of the current normative and regulatory aspects of timber and NTFP extraction in the five countries, the paper also briefly discusses the opportunities and constraints for harmonization of timber and NTFP management of multipurpose species across the region. It was found that about half of the 336 timber species reviewed across the five countries also have non-timber uses. Eleven timber species are multipurpose in all five countries: Calophyllum brasiliense, Cedrela odorata, Ceiba pentandra, Clarisia racemosa, Ficus insipida, Jacaranda copaia, Schefflera morototoni, Simarouba amara and Terminalia amazonia. Seven other multipurpose species occurred only in either Venezuela (Tabebuia impetiginosa, Spondias mombin, Pentaclethra macroloba, Copaifera officinalis, Chlorophora tinctoria, Carapa guianensis) or Ecuador (Tabebuia chrysantha). Four multipurpose tree species presented the highest potential of conflict of use across the region: Dipteryx odorata, Tabebuia serratifolia, Hymenaea courbaril and Myroxylon balsamum yet these were not evenly distributed across all five countries. None of the five studied countries have specific legislation to promote sustainable use of any of the multipurpose species reported here and thus mitigate potential conflict of use; nor documented management options for integration or else segregation of both their timber and NTFP values. PMID- 24061085 TI - The impact of a shade coffee certification program on forest conservation: a case study from a wild coffee forest in Ethiopia. AB - In recent years, shade coffee certification programs have attracted increasing attention from conservation and development organizations. Certification programs offer an opportunity to link environmental and economic goals by providing a premium price to producers and thereby contributing to forest conservation. However, the significance of the conservation efforts of certification programs remains unclear because of a lack of empirical evidence. The purpose of this study was to examine the impact of a shade coffee certification program on forest conservation. The study was conducted in the Belete-Gera Regional Forest Priority Area in Ethiopia, and remote sensing data of 2005 and 2010 were used to gauge the change of forest area. Using propensity score matching estimation, we found that forests under the coffee certification program were less likely to be deforested than forests without forest coffee. By contrast, the difference in the degree of deforestation between forests with forest coffee but not under the certification program and forests with no forest coffee is statistically insignificant. These results suggest that the certification program has had a large effect on forest protection, decreasing the probability of deforestation by 1.7 percentage points. PMID- 24061086 TI - Breaking news! When it comes to complications of catheter ablation of atrial fibrillation, experience matters. PMID- 24061087 TI - In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: analysis of 93 801 procedures. AB - BACKGROUND: Atrial fibrillation ablation has made tremendous progress with respect to innovation, efficacy, and safety. However, limited data exist regarding the burden and trends in adverse outcomes arising from this procedure. The aim of our study was to examine the frequency of adverse events attributable to atrial fibrillation (AF) ablation and the influence of operator and hospital volume on outcomes. METHODS AND RESULTS: With the use of the Nationwide Inpatient Sample, we identified AF patients treated with catheter ablation. We investigated common complications including cardiac perforation and tamponade, pneumothorax, stroke, transient ischemic attack, vascular access complications (hemorrhage/hematoma, vascular complications requiring surgical repair, and accidental arterial puncture), and in-hospital death described with AF ablation, and we defined these complications by using validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. An estimated 93,801 AF ablations were performed from 2000 to 2010. The overall frequency of complications was 6.29% with combined cardiac complications (2.54%) being the most frequent. Cardiac complications were followed by vascular complications (1.53%), respiratory complications (1.3%), and neurological complications (1.02%). The in-hospital mortality was 0.46%. Annual operator (<25 procedures) and hospital volume (<50 procedures) were significantly associated with adverse outcomes. There was a small (nonsignificant) rise in overall complication rates. CONCLUSIONS: The overall complication rate was 6.29% in patients undergoing AF ablation. There was a significant association between operator and hospital volume and adverse outcomes. This suggests a need for future research into identifying the safety measures in AF ablations and instituting appropriate interventions to improve overall AF ablation outcomes. PMID- 24061089 TI - High ionicity ionic liquids (HIILs): comparing the effect of ethylsulfonate and ethylsulfate anions. AB - The subject of ionicity has been extensively discussed in the last decade, due to the importance of understanding the thermodynamic and thermophysical behaviour of ionic liquids. In our previous work, we established that ionic liquids' ionicity could be improved by the dissolution of simple inorganic salts in their milieu. In this work, a comparison between the thermophysical properties of two binary systems of ionic liquid + inorganic salt is presented. The effect of the ammonium thiocyanate salt on the ionicity of two similar ionic liquids, 1-ethyl-3 methylimidazolium ethylsulfonate and ethylsulfate, is investigated in terms of the related thermophysical properties, such as density, viscosity and ionic conductivity in the temperature range 298.15-323.15 K. In addition, spectroscopic (NMR and Raman) and molecular dynamic studies were conducted in order to better understand the interactions that occur at a molecular level. The obtained results reveal that although the two anions of the ionic liquid exhibit similar chemical structures, the presence of one additional oxygen in the ethylsulfate anion has a major impact on the thermophysical properties of the studied systems. PMID- 24061088 TI - Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction. AB - BACKGROUND: Magnetic resonance imaging (MRI) in the CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial revealed that cardiosphere-derived cells (CDCs) decrease scar size and increase viable myocardium after myocardial infarction (MI), but MRI has not been validated as an index of regeneration after cell therapy. We tested the validity of contrast-enhanced MRI in quantifying scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. METHODS AND RESULTS: Yucatan minipigs underwent induction of MI and 2-3 weeks later were randomized to receive intracoronary infusion of 12.5*10(6) mismatched allogeneic CDCs or vehicle. Allogeneic CDCs induced mild local mononuclear infiltration but no systemic immunogenicity. MRI revealed that allogeneic CDCs attenuated remodeling, improved global and regional function, decreased scar size, and increased viable myocardium compared with placebo 2 months post-treatment. Extensive histological analysis validated quantitatively the MRI measurements of scar size, scar mass, and viable mass. CDCs neither altered gadolinium contrast myocardial kinetics nor induced changes in vascular density or architecture in viable and scarred myocardium. Histology demonstrated that CDCs lead to cardiomyocyte hyperplasia in the border zone, consistent with the observed stimulation of endogenous regenerative mechanisms (cardiomyocyte cycling, upregulation of endogenous progenitors, angiogenesis). CONCLUSIONS: Contrast-enhanced MRI accurately measures scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. MRI represents a useful tool for assessing dynamic changes in the infarct and monitoring regenerative efficacy. PMID- 24061091 TI - A comparative study of space radiation organ doses and associated cancer risks using PHITS and HZETRN. AB - NASA currently uses one-dimensional deterministic transport to generate values of the organ dose equivalent needed to calculate stochastic radiation risk following crew space exposures. In this study, organ absorbed doses and dose equivalents are calculated for 50th percentile male and female astronaut phantoms using both the NASA High Charge and Energy Transport Code to perform one-dimensional deterministic transport and the Particle and Heavy Ion Transport Code System to perform three-dimensional Monte Carlo transport. Two measures of radiation risk, effective dose and risk of exposure-induced death (REID) are calculated using the organ dose equivalents resulting from the two methods of radiation transport. For the space radiation environments and simplified shielding configurations considered, small differences (<8%) in the effective dose and REID are found. However, for the galactic cosmic ray (GCR) boundary condition, compensating errors are observed, indicating that comparisons between the integral measurements of complex radiation environments and code calculations can be misleading. Code-to-code benchmarks allow for the comparison of differential quantities, such as secondary particle differential fluence, to provide insight into differences observed in integral quantities for particular components of the GCR spectrum. PMID- 24061092 TI - Should benzodiazepines be replaced by antidepressants in the treatment of anxiety disorders? Fact or fiction? PMID- 24061093 TI - Cohesive band structure of carbon nanotubes for applications in quantum transport. AB - An integrated cohesive band structure of carbon nanotubes (CNTs) applicable to all chirality directions (n, m), starting from the Dirac cone of a graphene nanolayer in k-space, is demarcated, in direct contrast to dissimilar chiral and achiral versions in the published literature. The electron wave state of a CNT is quantized into one-dimensional (1-D) nanostructure with a wrapping mode, satisfying the boundary conditions from one Dirac K-point to an equivalent neighboring one with an identical phase and returning to the same K point. The repetitive rotation for an identical configuration with added band index (n m)mod3, yields one metallic (M) with zero bandgap corresponding to (n-m)mod3 = 0, semiconducting state SC1 with (n-m)mod3 = 1 and SC2 with (n-m)mod3 = 2. The band gap and effective mass of SC2 state are twice as large as those of SC1 state. A broad-spectrum expression signifying the linear dependence of the effective mass on the bandgap is obtained. Both the Fermi energy and the intrinsic velocity limiting the current to the saturation level is calculated as a function of the carrier concentration. Limitations of the parabolic approximation are pointed out. Several new features of the band structure are acquired in a seamlessly unified mode for all CNTs, making it suitable for all-encompassing applications. Applications of the theory to high-field transport are advocated with an example of a metallic CNT, in agreement with experimental observations. The mechanism behind the breakdown of the linear current-voltage relation of Ohm's law and the associated surge in resistance are explained on the basis of the nonequilibrium Arora's distribution function (NEADF). These results are important for the performance evaluation and characterization of a variety of applications on CNT in modern nanoscale circuits and devices. PMID- 24061094 TI - Don't come up short. PMID- 24061095 TI - Core measures: getting to the top decile. PMID- 24061096 TI - Practice models: a concept analysis. PMID- 24061097 TI - Nursing's role in ACOs. PMID- 24061098 TI - Salary survey 2013: a staff report. PMID- 24061100 TI - Stop the revolving door: implement retention initiatives that work. PMID- 24061101 TI - The international Magnet(r) journey. PMID- 24061102 TI - Bull's eye! Hitting the financial knowledge target. PMID- 24061103 TI - Leadership q&a. PMID- 24061104 TI - Dissociations and associations of performance in syntactic comprehension in aphasia and their implications for the nature of aphasic deficits. AB - Sixty-one pwa were tested on syntactic comprehension in three tasks: sentence picture matching, sentence-picture matching with auditory moving window presentation, and object manipulation. There were significant correlations of performances on sentences across tasks. First factors on which all sentence types loaded in unrotated factor analyses accounted for most of the variance in each task. Dissociations in performance between sentence types that differed minimally in their syntactic structures were not consistent across tasks. These results replicate previous results with smaller samples and provide important validation of basic aspects of aphasic performance in this area of language processing. They point to the role of a reduction in processing resources and of the interaction of task demands and parsing and interpretive abilities in the genesis of patient performance. PMID- 24061105 TI - Fricke dosimeter gel measurements of the profiles of shielded fields. AB - In radiation therapy, the shielding of normal tissue can be made using Cerrobend(r) blocks or a multileaf collimator. In this work, profiles of shielded fields collimated by Cerrobend blocks were obtained through the Fricke Xylenol Gel (FXG) dosimeter irradiated with 6 MV photon beams. The results show that the FXG system can be used in profile measurements of small fields in radiotherapy. PMID- 24061106 TI - Metastatic renal cell cancer. AB - Targeted therapy is the treatment of choice in patients with metastatic renal cell cancer (mRCC) at most institutions although a combination of cytokine therapy and targeted therapy still is being investigated. Morphological size based criteria (RECIST) has failed in monitoring the effect of targeted therapy in patients with mRCC, as successful therapy often does not result in a decrease in tumour size. Modifications of size-based criteria and criteria based on computed tomography (CT) contrast enhancement has been introduced. Different imaging modalities that rely on characteristics other than size such as dynamic contrast-enhanced (DCE) ultrasonography, DCE CT, DCE magnetic resonance imaging (MRI), diffusion-weighted MRI, positron emission tomography and texture analysis seem to contribute with prognostic information, even at baseline scans, and can predict tumour response early after initiating therapy. No new standard for the imaging follow-up of targeted therapy in mRCC has been established. PMID- 24061107 TI - Hierarchical structure formation in layered superconducting systems with multi scale inter-vortex interactions. AB - We demonstrate the formation of hierarchical structures in two-dimensional systems with multiple length scales in the inter-particle interaction. These include states such as clusters of clusters, concentric rings, clusters inside a ring, and stripes in a cluster. We propose to realize such systems in vortex matter (where a vortex is mapped onto a particle with multi-scale interactions) in layered superconducting systems with varying inter-layer thicknesses and different layer materials. PMID- 24061108 TI - A route to phase controllable Cu2ZnSn(S(1-x)Se(x))4 nanocrystals with tunable energy bands. AB - Cu2ZnSn(S(1-x)Se(x))4 nanocrystals are an emerging family of functional materials with huge potential of industrial applications, however, it is an extremely challenging task to synthesize Cu2ZnSn(S(1-x)Se(x))4 nanocrystals with both tunable energy band and phase purity. Here we show that a green and economic route could be designed for the synthesis of Cu2ZnSn(S(1-x)Se(x))4 nanocrystals with bandgap tunable in the range of 1.5-1.12 eV. Consequently, conduction band edge shifted from -3.9 eV to -4.61 eV (relative to vacuum energy) is realized. The phase purity of Cu2ZnSn(S(1-x)Se(x))4 nanocrystals is substantiated with in depth combined optical and structural characterizations. Electrocatalytic and thermoelectric performances of Cu2ZnSn(S(1-x)Se(x))4 nanocrystals verify their superior activity to replace noble metal Pt and materials containing heavy metals. This green and economic route will promote large-scale application of Cu2ZnSn(S(1-x)Se(x))4 nanocrystals as solar cell materials, electrocatalysts, and thermoelectric materials. PMID- 24061109 TI - Towards efficient solar hydrogen production by intercalated carbon nitride photocatalyst. AB - The development of efficient photocatalytic material for converting solar energy to hydrogen energy as viable alternatives to fossil-fuel technologies is expected to revolutionize energy shortage and environment issues. However, to date, the low quantum yield for solar hydrogen production over photocatalysts has hindered advances in the practical applications of photocatalysis. Here, we show that a carbon nitride intercalation compound (CNIC) synthesized by a simple molten salt route is an efficient polymer photocatalyst with a high quantum yield. We found that coordinating the alkali metals into the C-N plane of carbon nitride will induce the un-uniform spatial charge distribution. The electrons are confined in the intercalated region while the holes are in the far intercalated region, which promoted efficient separation of photogenerated carriers. The donor-type alkali metal ions coordinating into the nitrogen pots of carbon nitrides increase the free carrier concentration and lead to the formation of novel nonradiative paths. This should favor improved transport of the photogenerated electron and hole and decrease the electron-hole recombination rate. As a result, the CNIC exhibits a quantum yield as high as 21.2% under 420 nm light irradiation for solar hydrogen production. Such high quantum yield opens up new opportunities for using cheap semiconducting polymers as energy transducers. PMID- 24061110 TI - Proteomics in Venom Research: a Focus on PLA2 Molecules. AB - This paper focuses on the application of proteomic tools to study the composition and natural history of snake venoms, and their crossreactivity with current homologous and heterologous antivenoms. Proteomic analyses on Bothrops indicated the suitability of using PLA2 molecules as taxonomic and population-specific markers. The lack of phylogenetic clustering among Neotropical and Neartic rattlesnakes with neurotoxic PLA2 molecules in their venoms suggests that phylogeny may not be an important consideration in venom evolution. Proteomic guided identification of evolutionary and immunological trends among venoms may aid replacing the traditional geographic- and phylogenetic-driven hypotheses for antivenom production strategies by a more rationale approach based on venom proteome phenotyping and immunological profile similarities. Recent proteomic and antivenomic surveys on Bothrops, Crotalus, and Bothriechis illustrate the feasibility of this view. PMID- 24061111 TI - Evolution of phospholipase A2 toxins in venomous animals. AB - Franc Gubensek devoted much of his research career to the phospholipases A2 (PLA2), which are the major pharmacologically active components of snake venoms. Our long collaboration started with an analysis of Vipera ammodytes ammodytoxin and ammodytin cDNAs and genes. These PLA2 genes provided us with an entry into the exciting area of molecular evolution. We studied the structures of the PLA2 genes, the evolution of multigene families encoding PLA2 toxins, and the horizontal transfer of unusual retroelements that we found in these genes. In the last decade a number of novel features have emerged concerning the evolution of PLA2s in venomous animals. The large amount of recently accumulated data has provided a timely opportunity to review current understanding of the evolution of PLA2 toxins in venomous animals. PMID- 24061112 TI - Phospholipases A2 from viperidae snake venoms: how do they induce skeletal muscle damage? AB - Phospholipases A2 (PLA2s) are abundant components in snake venoms, which play important toxic roles. This review focuses on group II PLA2s endowed with myotoxic effects, present in Viperidae venoms. These PLA2s are subdivided into catalytically-active (Asp49) PLA2s, and catalytically-inactive PLA2 homologues, the latter most frequently presenting the Lys49 substitution. Both protein subgroups induce skeletal muscle necrosis, although by different mechanisms. Current evidence indicates that phospholipid hydrolysis plays a central role in the necrotizing action of Asp49 myotoxins, whereas PLA2 homologues rely on the direct membrane-destabilizing actions of their cationic C-terminal region to achieve such effect, in the absence of catalysis. Both mechanisms converge in sarcolemmal permeabilization, triggering a series of intracellular events that lead to necrosis. Most viperid PLA2 myotoxins act only locally, but those forming heterodimeric complexes such as crotoxin spread to distant muscles and induce rhabdomyolysis. This divergence between local and systemic myotoxicity might be related to differences in binding specificity to cell targets. Nevertheless, the identity of molecular targets recognized by viperid PLA2 myotoxins remains elusive. Identification of their membrane target(s), and a deeper understanding of the catalytic-dependent and -independent mechanisms that result in membrane destabilization, are two crucial, but still unclarified aspects of their myotoxic action. PMID- 24061113 TI - Structure-function relationship studies of ammodytoxins and ammodytins by protein engineering. AB - Ammodytoxins (Atxs) and ammodytins (Atns) are group IIA phospholipases A2 (sPLA2s) and their homologues, secreted by venom glands of the nose-horned viper (Vipera a. ammodytes). The molecular mechanisms underlying their various pharmacological effects, including neurotoxicity, myotoxicity and anticoagulant activity, are still not completely understood. The structure-function relationships of Atxs and Atns have been studied by site-directed and cassette mutagenesis. We cloned their complementary DNA reversely transcribed from the mRNA isolated from the venom glands, and expressed the mature protein regions in Escherichia coli. The recombinant proteins were isolated in their inactive forms and renatured in vitro to the properly folded and biologically active forms. More than fifty site-directed mutants and chimeric sPLA2 proteins of Atxs and Atns were produced and their properties analysed. In the course of these studies, the three-dimensional crystal structure was determined of the most neurotoxic venom sPLA2, AtxA, that induces complete failure of vertebrate neuromuscular transmission, using the recombinant protein. The results have contributed significantly to a better understanding of the molecular mechanism of presynaptic toxicity of sPLA2 neurotoxins. In addition, the activity of enzymatically inactive sPLA2 homologues and their evolution are now better understood. PMID- 24061114 TI - Structural and Functional Characterization of Anticoagulant, FXa-binding Viperidae Snake Venom Phospholipases A2. AB - Certain snake venom phospholipases A2 (PLA2) have been identified as specific, non-competitive blood coagulation inhibitors that bind with high affinity to human activated blood coagulation factor X (hFXa). Recent determination of the three-dimensional structures of PLA2 isoforms which differ in anticoagulant activity contributes to a better understanding of their mode of binding to human FXa. Detailed analysis of the crystal structures of natural PLA2 isoforms from Viperidae snake venom which differ in binding affinity to hFXa allows us to detect local conformational changes and precisely delineate the role of critical residues in the anticoagulant function of these PLA2. We find conformational changes at conserved position Lys127 and mutated position Lys128 > Glu in the C terminal regions of less potent anticoagulant PLA2 (AtxC and CBa2), which contribute to the observed decrease in affinity for hFXa. The mutation His1 > Ser in less potent CBa2 is associated with a significant displacement of the side chain of Lys69 and Trp70 in the loop 65-72 and could also explain the reduced anticoagulant activity of the CBa2-FXa complex. Knowledge of the spatial arrangement of the sites of interaction of PLA2 with hFXa is important for understanding of the hemostatic process at the molecular level and could provide new anticoagulant drug leads. PMID- 24061115 TI - Secreted Phospholipases A2 - not just Enzymes. AB - Secreted phospholipases A2 (sPLA2s) constitute, physiologically and pathologically, a very important family of enzymes. Most actions of sPLA2s have been explained by their phosphatidylglycerol sn-2 hydrolytic activity. However, since pharmacologically active sPLA2 molecules without enzymatic activity have been discovered, first in snake venom and then also in human, it has become increasingly evident that, on many occasions, the action of these proteins has to be considered as arising from the interplay of their receptor-binding and enzymatic functions. The number of known sPLA2-interacting molecules is growing and, with the development of more sensitive biochemical techniques, further discoveries are expected. In this paper we are reviewing all the currently known sPLA2-binding proteins. The structural versatility of these molecules establishes sPLA2s as ligands with a broad interaction spectrum, in agreement with the already recognized multifunctional nature of these proteins. Mechanistic descriptions of the multitude of actions of sPLA2s is today one of the most exciting and promising research areas, and the description of the sPLA2 interactome is for sure one of its vital parts. PMID- 24061116 TI - Snake toxins from mamba venoms: unique tools for the physiologist. AB - Snake venoms are complex mixtures of small molecules, peptides and proteins. Most of the biologically active toxins are peptides or enzymes. The peptides belong to several structural classes, and they have many different biological actions. The best characterised are the so-called three-finger toxins that have three peptide loops stabilised by four disulphide bridges. Despite their common 3D shape, these peptides can interfere selectively with different biological targets, including nicotinic and muscarinic acetylcholine receptors, acetylcholinesterase, ion channels, and cell membranes. Other small peptides can block K+ or Ca2+ channels and are based on Kunitz serine proteinase inhibitors. This article summarises the proteins and peptides isolated from venoms of mamba snakes (Dendroaspis genus) that have been useful as experimental tools for physiologists and pharmacologists. PMID- 24061117 TI - Evolution of three-finger toxins - a versatile mini protein scaffold. AB - Among snake venom toxins, three-finger toxins - a superfamily of nonenzymatic proteins - are found in the venoms of all families of snakes. They share a common structure of three beta-stranded loops extending from a central core containing all four conserved disulfide bonds. Despite the similar structural fold, they exhibit a wide variety of biological effects. This review describes briefly the structure-function relationships and evolution of this group of toxins. The functional sites in these ssibling' toxins are located on various segments of the molecular surface. This group of mini proteins appears to evolve through a combination of accelerated rate of exchange of segments as well as point mutations in exons. PMID- 24061118 TI - An update on the mechanism of action of tetanus and botulinum neurotoxins. AB - Tetanus and botulinum neurotoxins, produced by anaerobic bacteria of the genus Clostridium, are the most toxic proteins known and are the sole responsible for the pathogenesis of tetanus and botulism. They enter peripheral cholinergic nerve terminals and cleave proteins of the neuroexocytosis apparatus causing a persistent, but reversible, inhibition of neurotransmitter release. Botulinum neurotoxins are used in the therapy of many human syndromes caused by hyperactive cholinergic nerve terminals. Here we focus on the many advances that were recently made on the understanding of their molecular mechanism of action and on their use in human therapy. PMID- 24061119 TI - Effects of microcystins, cyanobacterial toxins, on Mammalian cells and organs. AB - Microcystins are hepatotoxic cyclic heptapeptides characterized by the presence of non proteinogenic b-amino acid ADDA. They are produced by numerous bloom forming cyanobacterial genera. Acute lethal intoxications of humans are rare, but especially chronic exposure to these toxins presents a serious threat to the health of human population. Microcystins enter cells mostly via bile acid transporters; therefore liver is the main target organ in acute intoxication. It has been shown that microcystins are potent inhibitors of intracellular protein phosphatases 1 and 2A. This leads to hyper-phosphorylation of a number of intracellular structural and signal proteins, activation of caspases, and apoptosis of the affected cells. Tumour promoting effects of microcystins have also been described. Considering reports by several authors showing harmful effects of long term exposure to microcystins in several highly populated regions of the planet it must be emphasized that high safety measures should be taken in monitoring the quality of water and food used in human nutrition and medical care. PMID- 24061120 TI - Novel active principles from spider venom. AB - Spiders are one of the most intriguing groups of venomous animals. Substances found in their venom vary from simple inorganic compounds to large multi-domain proteins. In this article, we review some of the latest work presenting active principles that add to the known spider toxin universe. Two aspects of novelty are addressed in particular, structural (novel types of molecules in terms of structure) and functional (novel types of biological targets hit by substances from spider venom and novel mechanisms of action). PMID- 24061121 TI - Cytolytic proteins from cnidarians - an overview. AB - Cnidarians, mostly soft-bodied water organisms, produce several classes of toxins deployed in biological warfare or signalling. Cytolytic toxins, that form pores in cell membranes, form a significant part of their "weaponry". Here, we describe the physiological relevance of membrane permeabilization, and present basic data on those proteinaceous cnidarian cytolysins proven or presumed to damage cell membranes by pore formation. We describe cytolysins that have been at least partially characterized, both functionally and structurally. PMID- 24061122 TI - The Evolution of alphaD-Conopeptides Targeting Neuronal Nicotinic Acetylcholine Receptors. AB - Venoms of the marine cone snails (Conus spp.) consist of numerous proteins and peptides showing a wide variety of biological activities such as on ion-channels and receptors. Peptides acting on neuronal nicotinic acetylcholine receptors belong to several peptide superfamilies including the recently described alphaD conopeptides which are homodimers of identical peptides with 47-49 amino acids. Among the venom glands of 27 Conus species analyzed by cDNA cloning, precursors of alphaD-conopeptides were identified in four species only: C. betulinus, C. capitaneus, C. mustelinus, and C. vexillum. Phylogenetic analysis of the relationships among the alphaD-conopeptides revealed that they belong to clades, which are characterized by an AVV- and EMM-motif in the signal peptide sequence. PMID- 24061123 TI - TRPV1 Channel as New Target for Marine Toxins: Example of Gigantoxin I, a Sea Anemone Toxin Acting Via Modulation of the PLA2 Pathway. AB - Gigantoxin I, isolated from sea anemone Stichodactyla gigantea, was previously described as the first epidermal growth factor (EGF)-like toxin from natural origin. In this study, we discovered the interaction between the transient receptor potential vanilloid subtype I (TRPV1) channels and gigantoxin I. The TRPV1 channel is a non-selective cation channel involved in pain sensation and is described as pharmacological target of cnidaria venom. Our results highlight the involvement of the epidermal growth factor receptor/phospholipaseA2/arachidonic acid/lipoxygenase (EGFR/PLA2/AA/ LOX) pathway in the indirect activation of TRPV1 channels by gigantoxin I. This is the first time that this pathway is described in the indirect activation of TRPV1 channels by toxins. This knowledge not only gives insights into the possible induced effects by this new group of toxins, but also leads to a better understanding of the regulatory mechanism of TRPV1 channels themselves. PMID- 24061124 TI - Using phage display in autoimmunity research. AB - Autoimmune diseases affect approximately 3% of the population and are a significant cause of morbidity and mortality. Therefore, they are the focus of vivid research aimed at the delineation of pathology, more efficient diagnosis and therapy. Phage display is a simple methodology markedly useful in studying protein-protein interactions which are the driving forces of (patho)physiological processes, including autoimmunity. The commercially available phage display peptide libraries allow the characterization and identification of antibody antigen and receptor-ligand binding sites, thus providing basic insight into the pathological network. Through the phage display of antibody's, receptor's or ligand's protein domains it is possible to produce various self-specificities that have already been proven useful in the therapy of autoimmune diseases. Phage antibody display libraries are able to reprint the in vivo autoimmune response which significantly facilitates structural and functional analyses of auto reactive antibodies and assessing their role in disease pathology. The aim of this review was an overview of the versatile applications of phage display technology to determine their potential advantages in studying autoimmune diseases and to critically categorize and analyze the usefulness of phage displays towards understanding pathology and towards development of improved diagnostic tools. Above all its focus was on targeted therapy. PMID- 24061125 TI - A Convenient Methods for Synthetic Isomeric Structures of Pyrimido-1,2,4-triazine Derivatives as Biocidal Agents. AB - Some new isomeric structures of pyrimido[2,1-c][1,2,4]triazines 4-8 and 10-14 have been synthesized via the ring closure reactions of 2-hydrazinyl-1 methylpyrimidine 3 and/or 2-hydrazinopyrimidine 9 with acyclic and cyclic oxygen compounds under various conditions. Structures of the targets have been established from their elemental analyses and spectral data (UV, IR, 1H/13C NMR and mass spectrometry). Most of the obtained compounds were evaluated as antimicrobial agents and compared with pipericillin and mycostatine as standard antibiotics. Only compound 7 had highly biocidal effects. PMID- 24061126 TI - Determination of estrogens in water samples using dispersive liquid liquid microextraction and high performance liquid chromatography. AB - A new method for the analysis of estrogens including estrone (E1), 17b- estradiol (E2) and diethylstilbestrol (DES) in aqueous samples was performed using dispersive liquid liquid microextraction (DLLME) and high- performance liquid chromatography (HPLC). In order to optimize DLLME some important parameters such as type and volume of extraction and disperser solvent, extraction time, ionic strength and pH of sample were studied and optimum condition was obtained. Under optimum condition (extraction solvent: 80 uL CCl4; dispersive solvent: 1.25 mL acetone; NaCl: 12% (w/w) and pH of sample = 10.0), the enrichment factors and extraction recoveries were 71.0-78.5 and 85.2-94.2 respectively. Linearity was observed in the range of 0.02-500.0 ug L-1 for DES and 0.03-500.0 ug L-1 for E1 and E2. Limits of detection were 0.008 ug L-1 for DES and 0.010 ug L-1 for E1 and E2. The relative standard deviations (RSDs) for determination of estrogens in water were in the range of 2.4-3.2% (n = 5). PMID- 24061127 TI - Synthesis and Crystal Structure of Copper(I) Nitrate pi-complex with 1 allylbenzotriazole of Equimolar Composition. AB - The CuNO3 * C6H4N3(C3H5) compound (I) was obtained by alternating current electrochemical synthesis, starting from an ethanol solution containing Cu(NO3)2 * 3H2O and a mixture of 1- and 2-allylbenzotriazole titrated by HNO3 to pH = 4. The C=C bond of one 1-allylbenzotriazole molecule, the nitrogen atom from another ligand moiety, and two oxygen atoms from two nitrate-anions form a trigonal pyramidal environment of the metal atom. The bridging function of the ligand moiety results in infinite metal-organic chains, interconnected by weak CH...O hydrogen bonds, pi-pi and pi-sigma stacking and van der Waals interactions. PMID- 24061128 TI - Voltammetric determination of folic Acid using liquid mercury free silver amalgam electrode. AB - The electrochemical behavior of folic acid (FA) on a polished silver solid amalgam electrode (p-AgSAE), as a liquid mercury free electrode, has been studied in this paper. Differential pulse voltammetry (DPV) was found as a suitable method for voltammetric determination of folic acid. A limit of detection as 5.88 * 10-10 M (after 60 s of accumulation) was calculated for FA determination in an acetate buffer (pH 5). P-AgSAE in connection with DPV with optimized parameters was successfully applied for the determined folic acid compound in two types of vitamin preparations and two kinds of fruit juices. It was found that p-AgSAE is an appropriate tool for voltammetric determination of this vitamin in these real samples and it can replace mercury electrodes in voltammetric analysis of folic acid. PMID- 24061129 TI - Fluoxetine decreases glutathione reductase in erythrocytes of chronically isolated wistar rats. AB - Alterations in the antioxidative defense parameters upon chronic stress are considered critical for pathophysiology of stress related psychiatric disorders, and their status in blood serves as biomarker for effects of pharmacological treatments. The present study was designed to investigate the modulation of erythrocyte antioxidant enzymes (AOEs): CuZn superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR) activities and their protein expression in Wistar male rats subjected to chronic psychosocial isolation and/or to pharmacological treatment with fluoxetine. Chronically isolated animals exhibited decreased levels of serum corticosterone, as opposed to other chronic stress paradigms. In addition to that, SOD, CAT and GPx status was not altered either by chronic psychosocial isolation or by fluoxetine treatment. In contrast, GLR activity and its protein level were both markedly reduced by fluoxetine. Since, GLR is crucial for overall oxido-reductive balance through maintaining optimal ratio of reduced/oxidized glutathione level (GSH/GSSG) in erythrocytes, these results could indicate that in spite of numerous beneficial effects of fluoxetine, it may compromise both haemoglobin function and oxygen transport. PMID- 24061130 TI - Physico-Chemical Studies of Some Bio-active Solutes in Pure Methanoic Acid. AB - The apparent molar volume (PhiV), viscosity B-coefficient, adiabatic compressibility (PhiK) and molar refraction (R) of L-Glycine, L-Alanine, L-Valine and L-Leucine have been determined in methanoic acid at 298.15 K from density (rho), viscosity (eta), speed of sound (u) and refractive index (nD) respectively. The apparent molar volumes have been extrapolated to zero concentration to obtain the limiting values at infinite dilution using Masson equation. The limiting apparent molar volume (PhiV0) and experimental slopes (S*V) obtained from the Masson equation have been interpreted in terms of solute solvent and solute-solute interactions, respectively. The viscosity data were analyzed using the Jones-Dole equation, and the derived parameters A and B have also been interpreted in terms of solute-solute and solute-solvent interactions, respectively in the solutions. Molar refraction (R) have been calculated using the Lorentz-Lorenz equation. Limiting apparent molar adiabatic compressibilities (PhiK0) of these amino acids at infinite dilution were evaluated. PMID- 24061131 TI - Estimation of the mean distance of closest approach of actinides and lanthanides ions in aqueous solutions: some experimental and theoretical calculations. AB - The estimation of numerical values of the mean distance of closest approach of ions, a, of lanthanides and actinides ion salts in aqueous solutions, determined from activity coefficients, as well as from different theoretical approaches, is presented and discussed. PMID- 24061132 TI - Synthesis and Antimycobacterial Activity of Various 1-(8-Quinolinyloxy)-3 piperazinyl(piperidinyl)-5-(4-cyano-3-trifluoromethylphenylamino)-s-triazines. AB - This study presents the synthesis of novel 1-(8-quinolinyloxy)-3 piperazinyl(piperidinyl)-5-(4-cyano-3-trifluoromethylphenyl amino)-s-triazines. The synthetic route to final piperazinyl s-triazines consists of two nucleophilic substitution reactions of 4-amino-2-trifluoromethylbenzonitrile and 8 hydroxyquinoline with 2,4,6-trichloro-1,3,5-triazine resulting in 2,4 disubstituted-6-chloro-1,3,5-triazine derivatives to introduce the piperazinyl or piperidinyl functionality. The structures of the compounds were elucidated with the aid of IR, 1H NMR, 19F NMR, mass spectroscopy and elemental analysis. The title compounds were then investigated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain by using BACTEC MGIT and Lowenstein-Jensen MIC method. Compound 4-[4-(3,5-dimethylpiperidin-1-yl)-6 (quinolin-8-yloxy)-1,3,5-triazin-2-ylamino]-2-trifluoromethylbenzonitrile (5n) was the most potent one among the tested compounds. It was as potent as ethambutol to inhibit M. tuberculosis H37Rv completely (99%) at the minimum inhibitory concentration (MIC) of 3.12 ug/mL. Compounds 5p, 5s and 5u have shown equal potency to that of pyrazinamide at the minimum inhibitory concentration (MIC) of 6.25 mg/mL to inhibit (99%) M. tuberculosis H37Rv. PMID- 24061133 TI - DNA-Binding Studies of Some Potential Antitumor 2,2'-bipyridine Pt(II)/Pd(II) Complexes of piperidinedithiocarbamate. Their Synthesis, Spectroscopy and Cytotoxicity. AB - In this study two platinum(II) and palladium(II) complexes of the type [M(bpy)(pip-dtc)]NO3 (where M=Pt(II) or Pd(II), bpy=2,2'-bipyridine, pip dtc=piperidinedithiocarbamate) were synthesized by reaction between diaquo-2,2' bipyridine Pt(II)/Pd(II) nitrate and sodium salt of dithiocarbamate. These cationic water soluble complexes were characterized by elemental analysis, molar conductance, IR, electronic and 1H NMR spectroscopic studies. The cyclic dithiocarbamate was found to coordinate as bidentate fasion with Pt(II) or Pd(II) center. Their biological activities were tested against chronic myelogenous leukemia cell line, K562, at micromolar concentration. The obtained cytotoxic concentration (IC50) values were much lower than cisplatin. The interaction of these complexes with highly polymerized calf thymus DNA (ct-DNA) was extensively studied by means of electronic absorption, fluorescence, circular dichroism and other measurements. The experimental results, thermodynamic and binding parameters, suggested that these complexes cooperatively bind to DNA presumably via intercalation. Moreover, the tendency of the Pt(II) complex to interact with DNA was more than that of Pd(II) complex. PMID- 24061134 TI - Two Ketimine Polymorphs of 2-{1-[(2-Aminophenyl)imino]ethyl}phenol. AB - Two polymorphic structures of the Schiff base 2-1-[(2 aminophenyl)imino]ethylphenol, compound (1), C14H14N2O are reported. Depending on the solvent used for recrystallization it crystallizes as either a monoclinic or an orthorhombic polymorph. The monoclinic form, polymorph [1] contains three, while the orthorhombic polymorph [2] contains only one molecule in the asymmetric unit. In both polymorphs, a strong intramolecular O-H***N hydrogen bond is present from the stereochemical reason due to the rigidity of the chelate ring. Weak intermolecular N-H***O interactions appearing in both structures combine the molecules in the form of infinite columns by the graph-set motif C22(7). PMID- 24061135 TI - A new voltammetric method for the determination of lercanidipine in biological samples. AB - Electrochemical behavior and adsorption-diffusion properties of lercanidipine (LCN) on a glassy carbon electrode (GCE) were investigated in a mixture of ethanol-Britton Robinson buffer (BR) using voltammetric methods. From experimental results LCN was found to be reduced irreversibly via a single four electron process controlled mainly by diffusion with some adsorption contribution at about -0.65 V (vs. Ag/AgCl reference electrode). Therefore, a new, accurate, rapid, selective and simple square-wave cathodic adsorptive stripping voltammetric (SWCAdSV) method could be developed for direct determination of LCN in pharmaceutical preparations, spiked human urine and spiked human serum samples without time-consuming steps prior to drug assay. The peak current of the reduction wave linearly changed with the concentration of LCN in the concentration range between 4.0 * 10-8 molL-1 and 7.6 * 10-6 molL-1 in two different regions where optimum preconcentration potential and optimum preconcentration time were applied as -0.20 V and 90 s, respectively. The limit of detection (LOD) and the limit of quantitation (LOQ) values were found to be 2 * 10-8 molL-1 (0.01 mgL-1) and 6 * 10-8 molL-1 (0.04 mgL-1), respectively. The method was applied to determine the content of LCN in commercial pharmaceutical preparation, spiked human serum and spiked human urine. The method was found to be highly accurate and precise, having a relative standard deviation of less than 10% in all applications. PMID- 24061136 TI - Three-component Synthesis of Novel Highly Functionalized 2,6-dihydropyrimido[2,1 a]isoindole Derivatives. AB - Three-component reaction of dialkyl acetylenedicarboxylates, isocyanides and 1,3- diimino isoindoline affords highly functionalized 2,6-dihydropyrimido[2,1 a]isoindole derivatives in good yields under catalyst free and mild reaction conditions. PMID- 24061137 TI - DFT Study on the Complexation of Bambus[6]uril with the Perchlorate and Tetrafluoroborate Anions. AB - By using quantum mechanical DFT calculations, the most probable structures of the bambus[6]uril.ClO4- and bambus[6]uril.BF4- anionic complex species were derived. In these two complexes having C3 symmetry, each of the considered anions, included in the macrocyclic cavity, is bound by 12 weak hydrogen bonds between methine hydrogen atoms on the convex face of glycoluril units and the respective anion. PMID- 24061138 TI - Individual extraction constants of some univalent anions in the two-phase water phenyltrifluoromethyl sulfone system. AB - From extraction experiments and g-activity measurements, the extraction constants corresponding to the general equilibrium Cs+(aq) + A- (aq) <-> Cs+(org) + A- (org) taking place in the two-phase water-phenyltrifluoromethyl sulfone (FS 13) system (A-= I-, ClO4-, MnO4-, Br-3, I-3, picrate, tetraphenylborate (BPh-4); aq = aqueous phase, org = FS 13 phase) were evaluated. Furthermore, the individual extraction constants of these 7 anions in the mentioned two-phase system were calculated; they were found to increase in the series of I-< ClO4- < Br-3 < MnO4 , picrate < I-3 < BPh-4. PMID- 24061139 TI - Impact of Elastane Addition on UV Protective Properties of Viscose and Polyacrylonitrile Knits. AB - Textiles can provide effective protection against UV radiation because they reflect, absorb and scatter solar wavelengths. Properly designed, they significantly increase the area of covered skin. The optimal combination of thickness, fabric density, mass per unit area, knitted structure, yarn type and yarn linear density, facilitate the production of textiles with high UV protection properties. The objective of this research was to evaluate the impact of elastane on UV protection properties of viscose and polyacrylonitrile knitted structures. The investigation illustrated that wet relaxed elasticized knits show good UV radiation protection with UPF 20-40. In contrast, non-elasticized viscose and polyacrylonitrile knits are inappropriate for UV radiation protection. Comparing viscose samples, UPF is higher for dry relaxed elasticized structures, whilst for polyacrylonitrile samples, UPF is higher for wet relaxed elasticized structures. For non-elasticized structures, the UPF of polyacrylonitrile samples is greater than that of viscose samples. Generally, polyacrylonitrile knits investigated ensure better UV protection than viscose knits. PMID- 24061140 TI - Solvent extraction of calcium and strontium into nitrobenzene by using a synergistic mixture of hydrogen dicarbollylcobaltate and 2,6 (diphenylphosphino)pyridine dioxide. AB - Solvent extraction of microamounts of calcium and strontium by a nitrobenzene solution of hydrogen dicarbollylcobaltate (H+B-) in the presence of 2,6 (diphenylphosphino)pyridine dioxide (DPPPDO, L) has been investigated. The equilibrium data have been explained assuming that the species HL+, HL+2, CaL2+2, CaL2+3, SrL2+2, SrL2+3 and SrL2+4 are extracted into the organic phase. The values of extraction and stability constants of the species in nitrobenzene saturated with water have been determined. PMID- 24061141 TI - Students' Hands-on Experimental Work vs Lecture Demonstration in Teaching Elementary School Chemistry. AB - Science educators have suggested many benefits that accrue from engaging students in experimental activities, therefore, experimental work has a long and distinctive role in chemistry curriculum since. The presented empirical study focuses on the valuation of effectiveness of different forms of experimental work - students' hands-on experimental work vs teacher's lecture demonstration - from the viewpoint of the quality of content knowledge acquisition and knowledge retention in teaching primary school chemistry. 106 primary school students (age 14-15 years) participated in the study. The data was collected via pre- and post- test protocol and two delayed post tests. Additionally 16 students selected from the sample were interviewed. The results indicate that students' content knowledge gained through teacher's demonstration of experiment is better and better knowledge retention takes place in comparison to students' knowledge gained through students' hands-on experimental work. However, most of the inteviewed students stated that they prefered conducting of experiments by themselves in comparison to observation of teacher's demonstration. PMID- 24061142 TI - Why has the bohr-sommerfeld model of the atom been ignoredby general chemistry textbooks? AB - Bohr's model of the atom is considered to be important by general chemistry textbooks. A major shortcoming of this model was that it could not explain the spectra of atoms containing more than one electron. In order to increase the explanatory power of the model, Sommerfeld hypothesized the existence of elliptical orbits. This study has the following objectives: 1) Formulation of criteria based on a history and philosophy of science framework; and 2) Evaluation of university-level general chemistry textbooks based on the criteria, published in Italy and U.S.A. Presentation of a textbook was considered to be "satisfactory" if it included a description of the Bohr-Sommerfeld model along with diagrams of the elliptical orbits. Of the 28 textbooks published in Italy that were analyzed, only five were classified as "satisfactory". Of the 46 textbooks published in U.S.A., only three were classified as "satisfactory". This study has the following educational implications: a) Sommerfeld's innovation (auxiliary hypothesis) by introducing elliptical orbits, helped to restore the viability of Bohr's model; b) Bohr-Sommerfeld's model went no further than the alkali metals, which led scientists to look for other models; c) This clearly shows that scientific models are tentative in nature; d) Textbook authors and chemistry teachers do not consider the tentative nature of scientific knowledge to be important; e) Inclusion of the Bohr-Sommerfeld model in textbooks can help our students to understand how science progresses. PMID- 24061143 TI - From ambivalent to divalent: Has the "zinc age" finally arrived? PMID- 24061144 TI - Going after the money: curbing the rapid growth in medicare expenditures for medical services more than 30 days after hospital admission. PMID- 24061145 TI - Are thiazide diuretics safe and effective antihypertensive therapy in kidney transplant recipients? AB - BACKGROUND/AIMS: There are no published studies assessing the safety and efficacy of thiazides as antihypertensives in kidney transplantation (KTX). METHODS: This was a longitudinal retrospective cohort study conducted in adult KTX recipients. Patients were grouped based on receiving thiazides following KTX. Safety and efficacy comparisons were made between thiazide recipients and unexposed patients, as well as change in blood pressure (BP) within thiazide patients. RESULTS: 1,093 patients were included (thiazide group: 108, unexposed group: 985). Mean follow-up was 7.3 +/- 4.5 years. Thiazide recipients were older (53 +/ 11 vs. 48 +/- 13 years, p < 0.001) and more likely to be female (52 vs. 41%, p = 0.023) and have pre-KTX hypertension (97 vs. 88%, p = 0.004) or diabetes (36 vs. 27%, p = 0.035). After controlling for baseline differences, safety analysis revealed thiazide recipients were not more likely to be readmitted to the hospital, but were at higher risk to develop hyperkalemia (56 vs. 38%, p < 0.001) or hypokalemia (28 vs. 18%, p = 0.010), with similar rates of hypotension, decreased estimated glomerular filtration rate, graft loss and death. Efficacy analysis demonstrated systolic (147 +/- 17 to 139 +/- 18 mm Hg, p < 0.001) and diastolic (79 +/- 9 to 77 +/- 11 mm Hg, p < 0.001) BPs were significantly reduced after thiazide initiation. Compared to unexposed patients, thiazide recipients had higher mean BPs during the entire follow-up (142/78 vs. 136/77, p < 0.001), with similar BPs while on thiazides and comparable rates of goal BPs (<130/80 mm Hg, 32 vs. 36%, p = 0.219). CONCLUSIONS: In KTX, based on long-term outcomes, thiazides appear to be safe and effective antihypertensives; in the short-term, thiazides may increase the risk of developing potassium disturbances. PMID- 24061147 TI - Gene regulation: Chromatin editing reveals enhancer targets. PMID- 24061146 TI - Host cell-induced signaling causes Clostridium perfringens to upregulate production of toxins important for intestinal infections. AB - Clostridium perfringens causes enteritis and enterotoxemia in humans and livestock due to prolific toxin production. In broth culture, C. perfringens uses the Agr-like quorum sensing (QS) system to regulate production of toxins important for enteritis/enterotoxemia, including beta toxin (CPB), enterotoxin, and epsilon toxin (ETX). The VirS/VirR two-component regulatory system (TCRS) also controls CPB production in broth cultures. Both the Agr-like QS and VirS/VirR systems are important when C. perfringens senses enterocyte-like Caco-2 cells and responds by upregulating CPB production; however, only the Agr-like QS system is needed for host cell-induced ETX production. These in vitro observations have pathophysiologic relevance since both the VirS/VirR and Agr like QS signaling systems are required for C. perfringens strain CN3685 to produce CPB in vivo and to cause enteritis or enterotoxemia. Thus, apparently upon sensing its presence in the intestines, C. perfringens utilizes QS and TCRS signaling to produce toxins necessary for intestinal virulence. PMID- 24061148 TI - Radical cascades in electron transfer dissociation (ETD) - implications for characterizing peptide disulfide regio-isomers. AB - Direct characterization of peptides with multiple disulfide bonds by mass spectrometry is highly desirable. In this study, electron transfer dissociation (ETD) of peptide disulfide regio-isomers was studied using model peptides containing two intrachain disulfide bonds. ETD provided rich sequence information (c/z ions) even for the backbone region under the coverage of two disulfide bonds. This behavior presented an analytical advantage over low energy collision induced dissociation (CID) of protonated intact peptide ions, which produced very limited sequence (b/y) ions. Mechanistic studies suggested that the formation of c/z ions under the two disulfide bond covered region resulted from an initial N Calpha bond cleavage, followed by radical cascades to cleave multiple disulfide bonds. The ETD spectra of the disulfide regio-isomers produced similar product ions due to radical cascades; while the relative intensities of the product ions varied, to a certain degree, which could be helpful in distinguishing isomers with overlapping disulfide bonds. PMID- 24061149 TI - Fucosylated chondroitin sulfate from Acaudina molpadioides improves hyperglycemia via activation of PKB/GLUT4 signaling in skeletal muscle of insulin resistant mice. AB - In this study, we investigated the improvement of fucosylated chondroitin sulfate (CHS) from the cucumber Acaudina molpadioides on hyperglycemia in skeletal muscle of insulin resistant mice. CHS, rosiglitazone (RSG), and their combinations were supplemented to high-fat high-sucrose diet (HFSD)-fed C57BL/6J mice for 19 weeks. The results showed that CHS treatment remarkably decreased blood glucose level and insulin resistance. The glucose metabolism-related genes expressions at the transcriptional level were apparently increased in skeletal muscle. Although the total protein expressions of IR-beta, IRS-1, PI3K, PKB and GLUT4 in skeletal muscle were not affected, insulin-stimulated GLUT4 translocation and phosphorylation of Tyr-IR-beta, Tyr612-IRS-1, p85-PI3K, Ser473-PKB, and Thr308 PKB were significantly increased by CHS supplement. Additionally, combination of CHS and RSG produced synergistic effects on anti-hyperglycemia. These results indicate that CHS can alleviate hyperglycemia via activation of the PKB/GLUT4 signaling pathway in skeletal muscle of insulin resistant mice. PMID- 24061151 TI - Association of Lumican gene polymorphism with high myopia: a meta-analysis. AB - PURPOSE: Numerous studies have evaluated the association between the single nucleotide polymorphism (SNP) (rs3759223, C->T) in Lumican gene and high myopia risk in the Chinese population. However, the results have been inconsistent. We therefore here examined whether the rs3759223 polymorphism confers high myopia risk by conducting a meta-analysis. METHODS: PubMed, EMBASE, Science Citation Index, and Chinese National Knowledge Infrastructure (up to November 30, 2012) were searched by two investigators independently. Pooled relative ratios (RRs) and 95% confidence interval (CI) were used to assess the strength of the associations between SNP rs3759223 and myopia. Statistical analysis was undertaken using the program STATA 11.0 software (Stata Corporation, College Station, TX). RESULTS: Five case-control studies involving 923 patients with high myopia and 622 controls were included in this meta-analysis. A significant relationship between SNP rs3759223 and high myopia in the Chinese population was found under the homozygote (RR = 1.47, 95% CI 1.01-2.12, p = 0.04) and recessive (RR = 1.69, 95% CI 1.09-2.62, p = 0.02) genetic models. However, no significant association was found under the heterozygote (RR = 1.01, 95% CI 0.76-1.35, p = 0.93) and dominant (RR = 1.06, 95%CI 0.90-1.26, p = 0.48) genetic models. CONCLUSIONS: This meta-analysis showed the evidence that SNP rs3759223 may affect individual susceptibility to high myopia in the Chinese population. Given the limited sample size, further investigations are needed to validate the association. PMID- 24061150 TI - Direct approach for flexoelectricity from first-principles calculations: cases for SrTiO3 and BaTiO3. AB - Understanding the nature of flexoelectricity, which is the linear response of electric polarization to a strain gradient, has recently become crucial for nanostructured dielectrics and ferroelectrics because of their complicated strain distribution. This paper presents a direct and full approach at the atomic level to predict flexoelectricity for dielectrics based on first-principles calculations. The flexoelectric coefficients of BaTiO3 and SrTiO3 are directly calculated as the representatives of ferroelectric and paraelectric materials, respectively. For SrTiO3, the flexoelectric coefficients predicted from our approach are in good agreement with the experimental measurements. For BaTiO3, our predictions have a large discrepancy from the experimental measurements. In a practical situation, defect and surface effects are inevitable, and have a significant influence on the flexoelectricity. Direct methods have the advantage of including the extrinsic contributions from surface and defect effects. PMID- 24061152 TI - Multifocal contact lens myopia control. AB - PURPOSE: Previous studies on soft multifocal contact lens myopia control published in the peer-reviewed literature reported findings of noncommercial contact lenses worn for 1 year or less. This study sought to determine the progression of myopia and axial elongation of children fitted with commercially available distance center soft multifocal contact lenses for 2 years. METHODS: Eight- to eleven-year-old children with -1.00 D to -6.00 D spherical component and less than 1.00 D astigmatism were fitted with soft multifocal contact lenses with a +2.00 D add (Proclear Multifocal "D"; CooperVision, Fairport, NY). They were age- and gender-matched to participants from a previous study who were fitted with single-vision contact lenses (1 Day Acuvue; Vistakon, Jacksonville, FL). A-scan ultrasound and cycloplegic autorefraction were performed at baseline, after 1 year, and after 2 years. Multilevel modeling was used to compare the rate of change of myopia and axial length between single-vision and soft multifocal contact lens wearers. RESULTS: Forty participants were fitted with soft multifocal contact lenses, and 13 did not contribute complete data (5 contributed 1 year of data). The adjusted mean +/- standard error spherical equivalent progression of myopia at 2 years was -1.03 +/- 0.06 D for the single-vision contact lens wearers and -0.51 +/- 0.06 for the soft multifocal contact lens wearers (p < 0.0001). The adjusted mean axial elongation was 0.41 +/- 0.03 and 0.29 +/- 0.03 for the single-vision and soft multifocal contact lens wearers, respectively (p < 0.0016). CONCLUSIONS: Soft multifocal contact lens wear resulted in a 50% reduction in the progression of myopia and a 29% reduction in axial elongation during the 2-year treatment period compared to a historical control group. Results from this and other investigations indicate a need for a long-term randomized clinical trial to investigate the potential for soft multifocal contact lens myopia control. PMID- 24061153 TI - Hyperopic defocus and diurnal changes in human choroid and axial length. AB - PURPOSE: To investigate the influence of monocular hyperopic defocus on the normal diurnal rhythms in axial length and choroidal thickness of young adults. METHODS: A series of axial length and choroidal thickness measurements (collected at ~3 hourly intervals, with the first measurement at ~9 am and the final measurement at ~9 pm) were obtained for 15 emmetropic young adults over three consecutive days. The natural diurnal rhythms (day 1, no defocus), diurnal rhythms with monocular hyperopic defocus (day 2, -2.00 DS spectacle lens over the right eye), and the recovery from any defocus induced changes (day 3, no defocus) in diurnal rhythms were examined. RESULTS: Both axial length and choroidal thickness underwent significant diurnal changes on each of the three measurement days (p < 0.0001). The introduction of monocular hyperopic defocus resulted in significant changes in the diurnal variations observed in both parameters (p < 0.05). A significant (p < 0.001) increase in the mean amplitude (peak to trough) of change in axial length (mean increase, 0.016 +/- 0.005 mm) and choroidal thickness (mean increase, 0.011 +/- 0.003 mm) was observed on day 2 with hyperopic defocus compared to the two "no defocus" days (days 1 and 3). At the second measurement (mean time 12:10 pm) on the day with hyperopic defocus, the eye was significantly longer by 0.012 +/- 0.002 mm compared to the other two days (p < 0.05). No significant difference was observed in the average timing of the daily peaks in axial length (mean peak time 12:12 pm) and choroidal thickness (21:02 pm) over the three days. CONCLUSIONS: The introduction of monocular hyperopic defocus resulted in a significant increase in the amplitude of the diurnal change in axial length and choroidal thickness that returned to normal the following day after removal of the blur stimulus. PMID- 24061154 TI - Effects of local myopic defocus on refractive development in monkeys. AB - PURPOSE: Visual signals that produce myopia are mediated by local, regionally selective mechanisms. However, little is known about spatial integration for signals that slow eye growth. The purpose of this study was to determine whether the effects of myopic defocus are integrated in a local manner in primates. METHODS: Beginning at 24 +/- 2 days of age, seven rhesus monkeys were reared with monocular spectacles that produced 3 diopters (D) of relative myopic defocus in the nasal visual field of the treated eye but allowed unrestricted vision in the temporal field (NF monkeys). Seven monkeys were reared with monocular +3 D lenses that produced relative myopic defocus across the entire field of view (FF monkeys). Comparison data from previous studies were available for 11 control monkeys, 8 monkeys that experienced 3 D of hyperopic defocus in the nasal field, and 6 monkeys exposed to 3 D of hyperopic defocus across the entire field. Refractive development, corneal power, and axial dimensions were assessed at 2- to 4-week intervals using retinoscopy, keratometry, and ultrasonography, respectively. Eye shape was assessed using magnetic resonance imaging. RESULTS: In response to full-field myopic defocus, the FF monkeys developed compensating hyperopic anisometropia, the degree of which was relatively constant across the horizontal meridian. In contrast, the NF monkeys exhibited compensating hyperopic changes in refractive error that were greatest in the nasal visual field. The changes in the pattern of peripheral refractions in the NF monkeys reflected interocular differences in vitreous chamber shape. CONCLUSIONS: As with form deprivation and hyperopic defocus, the effects of myopic defocus are mediated by mechanisms that integrate visual signals in a local, regionally selective manner in primates. These results are in agreement with the hypothesis that peripheral vision can influence eye shape and potentially central refractive error in a manner that is independent of central visual experience. PMID- 24061156 TI - Optimal control of molecular fragmentation with homologous families of photonic reagents and chemical substrates. AB - This work investigates laser optimally controlled fragmentation in a series of chemically related halomethane compounds in order to determine the extent to which regular trends in objective yields are observed upon variation of both the laser pulse shape and the chemical substrate. Three control objectives defined by ratios of fragment ions were considered, where families of shaped pulses were found that produced optimal objective yields. For the objective defined by the ratio of a halogen ion to a methyl halide ion, a systematic correlation between the optimal objective yield and chemical composition was revealed. Furthermore, some of the optimal shaped pulses were found to successfully control the same objective in closely related molecular substrates. These results provide a basis to expect systematic chemical responses from optimally shaped laser pulses acting as "photonic reagents" in analogy with the action of traditional chemical reagents. PMID- 24061157 TI - Fabrication and characterization of Ag film with sub-nanometer surface roughness as a flexible cathode for inverted top-emitting organic light-emitting devices. AB - An ultra-smooth Ag film with sub-nanometer surface roughness on a flexible substrate has been fabricated by a template-stripping process and its effect on the carrier injection and transport in organic light-emitting devices (OLEDs) has been investigated. The use of the ultra-smooth Ag film as an electrode results in both enhanced carried injection due to the improved contact between the electrode and the organic layer and enhanced carrier transport due to the larger grain size of the deposited organic layer on it. The ultra-smooth Ag film on the flexible substrate has been applied in inverted top-emitting OLEDs (ITOLEDs) as cathode, which exhibit improved efficiency due to the enhanced electron injection and transport. The maximum current efficiency of the ITOLEDs on the flexible substrate is 9.72 cd A(-1), whereas it is 6.03 cd A(-1) for the devices on the conventional Si substrate, which corresponds to about a 62% enhancement. Moreover, the flexible ITOLEDs keep their good performance under a small bending radius and after repeated bending. PMID- 24061155 TI - Nitric oxide synthase inhibitors prevent the growth-inhibiting effects of quinpirole. AB - PURPOSE: Both dopamine and nitric oxide (NO) have been implicated in the signal cascade mediating ocular growth inhibition. If both are part of the same pathway, which precedes the other? We tested the hypothesis that dopamine acts upstream of NO, by using two NOS inhibitors in combination with the dopamine agonist quinpirole, and measured the effects on ocular growth rate. METHODS: Chicks wore 10 D lenses or diffusers (FD) for 4 days starting at age 13 days. Experimental eyes received daily 20 MUL injections of the following: quinpirole-lens: n = 12, FD: n = 20; n-omega-propyl-L-arginine (NPA)-lens: n = 6, FD: n = 4; quinpirole + NPA-lens: n = 17, FD: n = 19; and quinpirole + L-NIO-lens: n = 12, FD: n = 12. Saline injections were done as controls. High-frequency ultrasonography was done at the start, and on day 5, prior to injections and 3 hours later. Refractions were measured on day 5. RESULTS: As expected, quinpirole prevented the development of axial myopia in both paradigms. When quinpirole was combined with either NOS inhibitor, however, eyes became myopic compared to quinpirole (FD: NPA: -5.9 D vs. -3.4 D; L-NIO: -5.8 D vs. -3.4 D; lens: NPA: -3.5 D vs. -0.4 D; p < 0.05 for all; L-NIO was not significant). This was the result of a disinhibition of vitreous chamber growth versus quinpirole (FD: NPA: 401 vs. 275 MUm/4 d; L-NIO: 440 vs. 275 MUm/4 d; LENS: NPA: 407 vs. 253um/4 d; L-NIO: 403 vs. 253 MUm/4 d; p < 0.05). Only NPA prevented the quinpirole-induced choroidal thickening in lens-wearing eyes (0 vs. 31 MUm/3 h; p < 0.05). Choroidal thickening was not inhibited by either drug in FD eyes. CONCLUSIONS: Dopamine acts upstream of NO and the choroidal response in the signal cascade mediating ocular growth inhibition in both form deprivation and negative lens wear. That neither NOS inhibitor inhibits choroidal thickening in FD eyes suggests that the choroidal mechanisms differ in the two paradigms. PMID- 24061158 TI - Benzodiazepines revisited. PMID- 24061159 TI - Sensing of hydrophobic cavity of serum albumin by an adenosine analogue: fluorescence correlation and ensemble spectroscopic studies. AB - Adenosine is a naturally occurring purine nucleoside that plays important role in various biochemical processes. We have studied the binding of TNP-Ado (trinitrophenylated-adenosine), a fluorescent analogue of adenosine (which itself is a weak fluorophore), with a model transport protein, bovine serum albumin (BSA). The binding affinity was determined using Fluorescence correlation spectroscopy (FCS) and compared with its value obtained from macroscopic fluorescence spectroscopic studies. Fluorescence and circular dichroism (CD) spectroscopies were employed together with molecular docking study to locate the probable binding site of TNP-Ado on BSA and its effect on the conformation and stability of BSA. Fluorescence studies showed that TNP-Ado binds to BSA in 1:1 stoichiometry via an entropically favoured process. Induced CD spectra revealed that a chiro-optical switching of TNP-Ado occurs upon binding to BSA. Results on urea-induced denaturation of BSA and docking study suggested that the binding site for the ligand is in the hydrophobic subdomain IIA of BSA, consistent with the results of other measurements. This study establishes TNP-Ado as a sensor of hydrophobic regions in proteins like serum albumin, having the capability of detecting a minimum concentration of 140ng/ml protein. FCS measurement of binding interaction of rhodamine-labeled TNP-Ado (RTNP-Ado) with BSA yielded an association constant of KFCS=(1.03+/-0.06) * 10(4)M(-1). The association constants (Ka) obtained for binding of BSA with rhodamine-free (i.e. TNP-Ado) and rhodamine-labeled (RTNP-Ado) ligands, obtained using the ensemble spectroscopic technique, were (2.3+/-0.06) * 10(5)M(-1) and (3.4+/-0.03) * 10(4)M(-1), respectively. The difference between the values of Ka for the free and labeled ligands suggests that fluorescent labeling of small molecules perceptibly interferes with the binding process. On the other hand, the difference in Ka obtained by FCS and ensemble techniques is due to the fact that while the former measures the change in the diffusion constant (i.e. size) of RTNP-Ado upon binding to BSA, the latter focuses on the change of tryptophan emission properties of BSA due to the presence of bound RTNP-Ado. PMID- 24061160 TI - Bioimaging, antibacterial and antifungal properties of imidazole-pyridine fluorophores: synthesis, characterization and solvatochromism. AB - A series of imidazole derivatives connected with pyridine moiety through phenyl groups were synthesized by using Suzuki coupling followed by multicomponent cyclization reaction. Results obtained from spectroscopic ((1)H NMR, (13)C NMR, Mass) and single crystal X-ray diffraction analysis of synthesized compound was in very good agreement with its chemical structure. UV-Vis and fluorescence studies in various solvents with different polarity demonstrated that these compounds were sensitive to the polarity of the microenvironment. In addition, multi linear regression analysis based on Kamlet-Taft and Catalan new four parameter solvent scale results in solvatochromism and was mainly influenced by solvent polarisability and dipolarity of the environment. The electrochemical stability of the compounds was also studied by cyclic voltammetry. An excellent fluorescent nature with high quantum efficiency of the compounds was successfully utilized to probe the bacteria by using fluorescence microscopy. In addition, the antibacterial and antifungal activity of these compounds were also studied in vitro by the disk diffusion assay against one Gram-positive, three Gram-negative bacteria and Candida albicans. MPBI showed relatively good inhibitory action against Gram-negative bacteria and TPBI against Gram-positive bacteria and 3PBI against C. albicans. PMID- 24061161 TI - Predicting tumour response. AB - Response prediction is an important emerging concept in oncologic imaging, with tailored, individualized treatment regimens increasingly becoming the standard of care. This review aims to define tumour response and illustrate the ways in which imaging techniques can demonstrate tumour biological characteristics that provide information on the likely benefit to be received by treatment. Two imaging approaches are described: identification of therapeutic targets and depiction of the treatment-resistant phenotype. The former approach is exemplified by the use of radionuclide imaging to confirm target expression before radionuclide therapy but with angiogenesis imaging and imaging correlates for genetic response predictors also demonstrating potential utility. Techniques to assess the treatment-resistant phenotype include demonstration of hypoperfusion with dynamic contrast-enhanced computed tomography and magnetic resonance imaging (MRI), depiction of necrosis with diffusion-weighted MRI, imaging of hypoxia and tumour adaption to hypoxia, and 99mTc-MIBI imaging of P-glycoprotein mediated drug resistance. To date, introduction of these techniques into clinical practice has often been constrained by inadequate cross-validation of predictive criteria and lack of verification against appropriate response end points such as survival. With further refinement, imaging predictors of response could play an important role in oncology, contributing to individualization of therapy based on the specific tumour phenotype. This ability to predict tumour response will have implications for improving efficacy of treatment, cost-effectiveness and omission of futile therapy. PMID- 24061162 TI - Design and performance evaluation of a 20-aperture multipinhole collimator for myocardial perfusion imaging applications. AB - Single photon emission computed tomography (SPECT) myocardial perfusion imaging remains a critical tool in the diagnosis of coronary artery disease. However, after more than three decades of use, photon detection efficiency remains poor and unchanged. This is due to the continued reliance on parallel-hole collimators first introduced in 1964. These collimators possess poor geometric efficiency. Here we present the performance evaluation results of a newly designed multipinhole collimator with 20 pinhole apertures (PH20) for commercial SPECT systems. Computer simulations and numerical observer studies were used to assess the noise, bias and diagnostic imaging performance of a PH20 collimator in comparison with those of a low energy high resolution (LEHR) parallel-hole collimator. Ray-driven projector/backprojector pairs were used to model SPECT imaging acquisitions, including simulation of noiseless projection data and performing MLEM/OSEM image reconstructions. Poisson noise was added to noiseless projections for realistic projection data. Noise and bias performance were investigated for five mathematical cardiac and torso (MCAT) phantom anatomies imaged at two gantry orbit positions (19.5 and 25.0 cm). PH20 and LEHR images were reconstructed with 300 MLEM iterations and 30 OSEM iterations (ten subsets), respectively. Diagnostic imaging performance was assessed by a receiver operating characteristic (ROC) analysis performed on a single MCAT phantom; however, in this case PH20 images were reconstructed with 75 pixel-based OSEM iterations (four subsets). Four PH20 projection views from two positions of a dual-head camera acquisition and 60 LEHR projections were simulated for all studies. At uniformly-imposed resolution of 12.5 mm, significant improvements in SNR and diagnostic sensitivity (represented by the area under the ROC curve, or AUC) were realized when PH20 collimators are substituted for LEHR parallel-hole collimators. SNR improves by factors of 1.94-2.34 for the five patient anatomies and two orbital positions studied. For the ROC analysis the PH20 AUC is larger than the LEHR AUC with a p-value of 0.0067. Bias performance, however, decreases with the use of PH20 collimators. Systematic analyses showed PH20 collimators present improved diagnostic imaging performance over LEHR collimators, requiring only collimator exchange on existing SPECT cameras for their use. PMID- 24061164 TI - Coupling of a dipolar emitter into one-dimensional surface plasmon. AB - Quantum plasmonics relies on a new paradigm for light-matter interaction. It benefits from strong confinement of surface plasmon polaritons (SPP) that ensures efficient coupling at a deep subwavelength scale, instead of working with a long lifetime cavity polariton that increases the duration of interaction. The large bandwidth and the strong confinement of one dimensional SPP enable controlled manipulation of a nearby quantum emitter. This paves the way to ultrafast nanooptical devices. However, the large SPP bandwidth originates from strong losses so that a clear understanding of the coupling process is needed. In this report, we investigate in details the coupling between a single emitter and a plasmonic nanowire, but also SPP mediated coupling between two emitters. We notably clarify the role of losses in the Purcell factor, unavoidable to achieve nanoscale confinement down to 10(-4)(lambda/n)(3). Both the retarded and band edge quasi-static regimes are discussed. PMID- 24061163 TI - Emergency department-reported injuries associated with mechanical home exercise equipment in the USA. AB - The goal of this study was to generate national estimates of injuries associated with mechanical home exercise equipment, and to describe these injuries across all ages. Emergency department (ED)-treated injuries associated with mechanical home exercise equipment were identified from 2007 to 2011 from the National Electronic Injury Surveillance System. Text narratives provided exercise equipment type (treadmill, elliptical, stationary bicycle, unspecified/other exercise machine). Approximately 70 302 (95% CI 59 086 to 81 519) mechanical exercise equipment-related injuries presented to US EDs nationally during 2007 2011, of which 66% were attributed to treadmills. Most injuries among children (<=4 years) were lacerations (34%) or soft tissue injuries (48%); among adults (>=25 years) injuries were often sprains/strains (30%). Injured older adults (>=65 years) had greater odds of being admitted, held for observation, or transferred to another hospital, compared with younger ages (OR: 2.58; 95% CI 1.45 to 4.60). Mechanical exercise equipment is a common cause of injury across ages. Injury awareness and prevention are important complements to active lifestyles. PMID- 24061167 TI - Nitroderivatives of catechol: from synthesis to application. AB - Nitroderivatives of catechol (NDCs) are reviewed with special emphasis on their complexes and applications. Binary, ternary and quaternary NDC complexes with more than 40 elements (aluminum, arsenic, boron, beryllium, calcium, cobalt, copper, iron, gallium, germanium, magnesium, manganese, molybdenum, niobium, rare earth elements, silicon, tin, strontium, technetium, thallium, titanium, uranium, vanadium, tungsten, zinc and zirconium) are discussed and the key characteristics of the developed analytical procedures - tabulated. The bibliography includes 206 references. PMID- 24061165 TI - CD8 T cells regulate allergic contact dermatitis by modulating CCR2-dependent TNF/iNOS-expressing Ly6C+ CD11b+ monocytic cells. AB - Monocytes and their derived cells have critical roles in inflammation and immune defense. However, their function in skin diseases such as allergic contact dermatitis remains poorly defined. Using a model of contact hypersensitivity (CHS) toward 2,4-dinitrochlorobenzene, we show that Ly6C+ CD11b+ monocytic cells participate in the pathophysiology of CHS and their accumulation is regulated by effector CD8 T cells. These Ly6C+ CD11b+ monocytic cells are the primary contributors of tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) and derive from Ly6C(hi)CCR2+ monocytes, as they were absent in non-inflamed skin and accumulate as a consequence of inflammation in a C-C chemokine receptor type 2 (CCR2)-dependent manner. Importantly, CCR2(-/-) mice, or wild-type mice depleted of monocytes via clodronate liposomes, display a marked decrease in TNF-alpha and iNOS expression accompanied by attenuated skin inflammation. Using transgenic mice and antibody depletion, we show that effector CD8 T cells regulate the accumulation of Ly6C+ CD11b+ monocytic cells through IL 17 and activate them for TNF-alpha and iNOS through IFN-gamma. CD8 T cell-derived IFN-gamma was also critical for the accumulation of the major histocompatibility complex II-expressing Ly6C+ CD11b+ subset, which expressed intermediate levels of CD11c and costimulatory molecules. Taken together, our findings provide further insight into the pathophysiology of allergic contact dermatitis by showing that CD8 T cells regulate the inflammatory cascade through TNF/iNOS-expressing Ly6C+ CD11b+ monocytic cells. PMID- 24061168 TI - Complexation of Amlodipine Besylate with beta-Cyclodextrin. AB - In this paper the procedure for the preparation of inclusion compounds of bioactive substance 2-[(2-aminoetoxy)-methyl]-4-(2-chlorophenyl)-1,4-dihydro-6 methyl-3,5-pyridine dicarboxylic acid 3-ethyl-5-methyl esterbenzene sulfonate, called amlodipine besylate with beta-cyclodextrin (beta-CD) and their structural characterization was described. Molecular inclusion compound of amlodipine besylate is obtained by different preparation method: kneading, co-precipitation and freeze-drying. The so obtained compounds were investigated by FTIR spectroscopy, X-ray diffraction method and differential scanning calorimetric measurements (DSC) to evidence their formation. Molecular modeling (using DFT theoretical computations) shows the spatial architecture of the inclusion compound in good agreement with FTIR experimental data: the drug is included with dihydropyridine dicarboxylate part inside beta-cyclodextrin cavity. The inclusion of amlodipine besylate in beta-cyclodextrin increases the stability and bioavailability of the drug. PMID- 24061166 TI - Filaggrin deficiency leads to impaired lipid profile and altered acidification pathways in a 3D skin construct. AB - Mutations in the filaggrin (FLG) gene are strongly associated with common dermatological disorders such as atopic dermatitis. However, the exact underlying pathomechanism is still ambiguous. Here, we investigated the impact of FLG on skin lipid composition, organization, and skin acidification using a FLG knockdown (FLG-) skin construct. Initially, sodium/hydrogen antiporter (NHE-1) activity was sufficient to maintain the acidic pH (5.5) of the reconstructed skin. At day 7, the FLG degradation products urocanic (UCA) and pyrrolidone-5 carboxylic acid (PCA) were significantly decreased in FLG- constructs, but the skin surface pH was still physiological owing to an upregulation of NHE-1. At day 14, secretory phospholipase A2 (sPLA2) IIA, which converts phospholipids to fatty acids, was significantly more activated in FLG- than in FLG+. Although NHE-1 and sPLA2 were able to compensate the FLG deficiency, maintain the skin surface pH, and ensured ceramide processing (no differences detected), an accumulation of free fatty acids (2-fold increase) led to less ordered intercellular lipid lamellae and higher permeability of the FLG- constructs. The interplay of the UCA/PCA and the sPLA2/NHE-1 acidification pathways of the skin and the impact of FLG insufficiency on skin lipid composition and organization in reconstructed skin are described. PMID- 24061170 TI - One-pot Synthesis, Molecular Modeling and In Vitro Antibacterial Activity of Novel 3-(1,3,4-Oxadiazol-2-yl) Quinoxaline 1,4-Dioxide and Pyrazolyl Analogs. AB - The new 1,3,4-oxadiazolylquinoxaline ring system was synthesized by the condensation of the quinoxaline 1,4-dioxide acid hydrazide 6 with acetyl chloride in one-pot synthesis. In which the hydrazide was refluxed in excess of acetyl chloride, acetic anhydride or acetic acid in the presence of phosphorus oxychloride forming the 1,3,4-oxadiazolylquinoxaline ring system. Molecular modeling studies have been performed to evaluate their recognition at the hDHFR binding-pocket as potential hDHFR inhibitors. The antibacterial properties of these compounds showed reasonable activities towards gram negative bacteria, Escherichia coli. Compound 20 performed appropriate complementarity study rather well; the conserved amino acids of hDHFR enzyme imitating the MTX docking pattern. Besides, compound 20 showed highest antibacterial activity against E. coli in comparison with the well known bacteriostatic chloramphenicol; the pyrazolyl analogues also have moderate affinity toward the applied bacteria. PMID- 24061169 TI - Biosorption of methylene blue by chaetophora elegans algae: kinetics, equilibrium and thermodynamic studies. AB - Adsorptive removal capacities of renewable and highly available Chaetophora elegans algae have been investigated in this study. To assess the use of this soft water algae to remove organic pollutants from aqueous solution, Methylene blue (MB) dye was used as a model molecule. The effect of dye concentrations, pH, adsorbent mass, temperature, and particle size have been evaluated. The algal biomass showed quite interesting adsorption capacity under optimized operating conditions (333 mg of dye per gram of biomass at 30 degrees C). Pseudo-first and pseudo-second order kinetic models were applied to the adsorption dynamic data. Pseudo second order model was well in line with the experimental data, therefore suggesting a probable chemically-based adsorption process. Several isotherm models were investigated to monitor the adsorption behavior. The Langmuir Freundlich isotherm model fitted the experimental data best. The adsorption thermodynamic parameters DeltaG degrees , DeltaH degrees and DeltaS degrees were calculated. The maximum uptake is independent of temperature. From the values of the thermodynamic parameters, we concluded that the adsorption is exothermic, more ordered and spontaneous. PMID- 24061171 TI - Influence of sunflower oil qualities and antioxidants on oxidative stability on whey-based salad dressings. AB - The antioxidant effect of ascorbic acid and EDTA (ethylenediaminetetraacetic acid) in food emulsions, based on whey and sunflower oils with enhanced oleic acid, alpha- and beta- tocopherol content, was not described up to now. Salad dressings based on cold-pressed high-oleic/alpha-, beta- tocopherol sunflower oil were oxidatively stable after 3 months of storage at 25 degrees C regarding primary (peroxide value, PV) and secondary (hexanal) lipid oxidation products (PV = 0.34 mmol O2 kg-1, hexanal value = 1.54 mg kg-1). Slight enhancement of PV and hexanal values was recorded in salad dressings prepared with cold-pressed medium oleic/alpha-, beta- tocopherol oil, after 3 months of storage at 25 degrees C, and was inhibited by ascorbic acid or EDTA. Ascorbic acid (0.50 g kg-1) reduced PV by 80% and hexanal value by 32%. EDTA (0.075 g kg-1) reduced PV by 60% and hexanal value by 27%. In salad dressings, containing linoleic/a- tocopherol sunflower oil, the antioxidant effects of ascorbic acid and EDTA were as following: ascorbic acid (0.25-4.00 g kg-1) reduced PV by 83-100% and hexanal value by 82-73%; EDTA (0.075 g kg-1) reduced PV by 75% and hexanal value by 76%, after 12 months of storage at 4 degrees C. PMID- 24061172 TI - Determination of Oxygen by Means of a Biogas and Gas - Interference Study Using an Optical Tris (4,7-Diphenyl-1,10-Phenanthroline) Ruthenium(II) Dichloride Complex Sensor. AB - Biogas is a mixture of gases produced by anaerobic fermentation where biomass or animal waste is decomposed and methane and carbon dioxide are mainly released. Biogas also has a very high moisture content (up to 80%), temperatures of around 60 degrees C, high pressure, and can contain other gases (N2, H2S, NH3 and H2). We searched for an appropriate measuring system for the determining of oxygen in biogas, since the production process of biogas must be run under anaerobic conditions; as the presence of oxygen decreases the quality of the biogas. Ruthenium (II) complexes are by far the most widely-used oxygen dyes within optical oxygen sensors. In general, they have efficient luminescences, relatively long-life metal-ligand charge-transfer excited states, fast response times, strong visible absorptions, large Stokes shifts, and high-photochemical stability. The purpose of this work was to characterise and optimize an optical oxygen sensor using tris (4,7-diphenyl-1,10-phenanthroline) ruthenium(II) dichloride complex for measuring oxygen. Different sensor properties were additionally studied, focusing on the interference of external light, temperature, and various gases. A special gas-mixing chamber was developed for gas interference study, and on-line experiments are presented for oxygen determination within the pilot biogas reactor. PMID- 24061173 TI - Gene Expression Profiling of Recombinant Protein Producing E. coli at Suboptimal Growth Temperature. AB - Recent studies have revealed that at lower cultivation temperatures (25 degrees C) much higher percentage of correctly folded recombinant hG-CSF protein can be extracted from inclusion bodies. Hence, the goal of our research was to investigate mechanisms determining characteristics of non-classical inclusion bodies production using gene expression profiling, focusing on proteases and chaperones gene expression. Statistical analysis of microarray data showed prominent changes in energy metabolism, in metabolism of amino acids and nucleotides, as well as in biosynthesis of cofactors and secondary metabolites if the culture was grown below its optimal temperature. Moreover, 24 differentially expressed up to now known genes classified among proteases, chaperones and other heat or stress related genes. Among chaperones UspE and among proteases YaeL and YeaZ might play an important role in accumulation of correctly folded recombinant proteins. Membrane localized protease yaeL gene was found to have higher activity at 25 degrees C and is thus potentially functionally related to the more efficient recombinant protein production at lower temperatures. The results of this study represent advance in the understanding of recombinant protein production in E. coli. Genes potentially influencing production of recombinant protein at lower growth temperature represent basis for further research towards improvement of E. coli production strains as well as fermentation process. PMID- 24061174 TI - Synthesis and Structural Characterization of Nano-sized Copper Tungstate Particles. AB - The nano-sized copper tungstate (CuWO4) was prepared by precipitation method in the presence of non-ionic copolymer surfactant (polyoxyethylene-polyoxypropylene block copolymer) and consequent annealing at low temperature (400 degrees C). The scanning electron microscopy (SEM) indicated formation of spherical CuWO4 particles in the size range from 10 to 90 nm. The thermogravimetric analysis was used to study dehydration processes. The X-ray diffraction analysis undoubtedly confirmed formation of triclinic CuWO4 and the refinement of the diffraction data showed that CuWO4 powder belongs to the distorted tungstate type of structure with space group P1-. The structure of the CuWO4 can be described as infinite zigzag chains formed by edge-sharing alternating [W-O6] and [Cu-O6] octahedra. Indirect and direct band-gap energies of CuWO4 (2.3 and 3.5 eV, respectively) were determined using optical measurements. PMID- 24061175 TI - Photoinduced tautomerism of 2-thiobarbituric Acid studied by theoretical and experimental methods. AB - Combined, theoretical and experimental, investigation was performed to study the mechanism of the photoinduced tautomerism of 2-thiobarbituric acid (TBA). The irradiation of the solution of TBA in polar aprotic solvent with UV light (maximum at 366 nm) showed oxo-hydroxy photoisomerization of the triketo form of TBA to the hydroxy-imino tautomer. The studied mechanisms (TD DFT) of the photoinduced NH and OH dissociations in the keto and enol tautomer revealed that the proton detachment in the triketo tautomer occurs in the bright 1nSsigma* excited state. In the hydroxy-imino tautomer this mechanism is driven by the repulsive 1pisigma* excited state. The excited-state relaxation mechanisms occur by low-lying So-S1 conical intersections. PMID- 24061176 TI - Membrane Changes Associated with Exposure of Pseudomonas putida to Selected Environmental Pollutants and their Possible Roles in Toxicity. AB - A bacterial model system (Pseudomonas putida DSM 50026) was used in this research to assess potential effect of five selected chemically diverse environmental pollutants on cell membranes. Long chain fatty acid profiles of cultures exposed to environmentally relevant concentrations of atrazine (ATR), metolachlor (MET), pentachlorobiphenyl (PCB), hexachlorobenzene (HCB) and fluoranthene (FL), were analyzed and compared to non-exposed cultures. To assess sensitivity of membrane based responses, the impact of each toxicant on culture growth was also followed spectrophotometrically. Results revealed changes in fatty acid profiles when cells were exposed to PCB, HCB and FL in concentrations below the inhibitory levels. Moreover, the observed membrane responses were similar to the ones previously associated with adaptation to some membrane-active compounds. On the other hand, exposure of cells to any of the two herbicides, ATR or MET, did not induce any significant changes in fatty acid profiles. However, when combined with a commonly used fertilizer compound, NH4NO3 growth impairment was observed. Synergistic effect of the two herbicides with NH4NO3 might be a consequence of changes in fatty acid profile increasing membrane fluidity, likely induced by NH4+ ions. PMID- 24061177 TI - Labeled Undecahydro-closo-dodecaborates Based on Azo Dyes for Boron Neutron Capture Therapy: Synthesis, Characterization, and Visualization in Cells. AB - A general approach to the synthesis of novel boronated azo dyes derived from undecahydro-closo-dodecaborates as a convenient preparation of dye labeled for boron neutron capture therapy (BNCT) is described. The method focused on the synthesis of two classes of dye-labeled dodecaborate anions. One is the reaction of (CH3)4NB12H11NH3- with NaNO2 in acetonitrile/water to give its diazonium salt which consequently reacted with substituted phenols to produce boronated azo-dyes (B12H11-N=N-Ar-, Ar = 4-HOC6H5, 1-naphthol, 2-naphthol, 2,3-(HO)2C6H4, 3-MeO-4 HOC6H4, 2-HO-5-MeOC6H4, and 4-Me2N-C6H4). The second is the reaction of aryldiazonium salt as couplers with disodium salt of dodecaborates (B12H11X2-, X = SH or OH) to yield substituted dodecaborate azo-dyes (HXB12H10-N=N-Ar-, Ar = para-bromo, para-nitro, para-carboxy, meta-carboxy, para-sulfonamide, and para sulfonic acid). The results show the expected effect of the various substituents on the efficiency of the coupling reactions. Extension of similar strategies to tyrosine and 5-(para-aminophenyl)-10,15,20-triphenylporphyrin diazonium salt, we succeeded to get dodecaborate anion containing amino acid or porphyrin as candidates for BNCT, respectively. Dye-labeled dodecaborates were obtained in acceptable yields. The proposed methodology provides not only a convenient way to synthesize libraries of boron cluster modified azo dyes for various applications but also for the visualization of boron clusters in cells. PMID- 24061178 TI - Analytical application of nano-sized titanium dioxide for the determination of trace inorganic antimony in natural waters. AB - In this work, solid phase extraction (SPE) using nano-sized TiO2 as a solid sorbent was used for separation/preconcentration of total inorganic antimony (iSb) before its determination by electrothermal atomic absorption spectrometry (ETAAS). After adsorption of iSb onto nano-sized TiO2, direct TiO2-slurry sampling was used for sample injection into a graphite tube. The conditions for the reliable slurry sampling together with careful control of the temperature program for the slurry solutions were worked out. Extraction conditions for both inorganic antimony species (Sb(III) and Sb(V)) and interference studies of coexisting ions were studied in detail. The accuracy of the optimized method was checked by the certified reference material (CRM) for trace elements in lake water TMDA-61. Finally, the optimized method was used for the determination of trace inorganic antimony in synthetic and natural waters. PMID- 24061179 TI - DFT investigation of the mecahanism and stereochemistry of electrophilic transannular addition reaction of bromine to tricyclo[4.2.2.02,5]deca-3,7-diene. AB - Full geometric optimization of tricyclo[4.2.2.02,5]deca-3,7-diene (TDD) has been done by DFT/B3LYP methods and the structure of the molecule was investigated. Cyclobuten double bond (I) of molecule is syn pyramidalized, and bicyclookten double bond (II) is also exo pyramidalized. The double bond (I) is more pyramidalized than the double bond (II) and it has higher reactivity. The TDD-Br2 system has been investigated by B3LYP/6-311++G(d,p) method and their stable configurations have been determined. The cationic intermediates and products obtained as a result of the addition reaction has been studied using B3LYP/6 311G(d,p) and B3LYP/6-311++G(d,p) methods. Bridged bromonium cation is more stable than U-type cation. Considering that the bridged cation does not isomerize to the less stable U-type cation, it is not possible for the U-type product to be obtained in the reaction. The bridged bromonium cation transformed into the more stable N-type cation and the N-type product was obtained via this cation. The thermodynamic stability of the anti, exo and anti, endo isomers of N-type dibromide molecule were almost identical. N-type product is 11.759 kcal mol more stable than U-type product. PMID- 24061180 TI - Polymorphism of LaTaTiO6. AB - Two polymorphs of LaTaTiO6, i.e. monoclinic and orthorhombic, were synthesized by solid-state reaction technique. Both were found to be isostructural with analogous niobium compounds which were used as structural models. Structural characterization was performed on X-ray powder data by Rietveld refinement procedure which resulted in final Rwp values of 7.01 and 7.52% for orthorhombic and monoclinic form, respectively. Comparisons between both title compounds are given and their plausibility is proved by bond valence sums and global instability index calculations. For the monoclinic polymorph, dielectric properties measured at 1 MHz are also given. PMID- 24061181 TI - Optimization of determination of platinum group elements in airborne particulate matter by inductively coupled plasma mass spectrometry. AB - Determination of automotive traffic-emitted platinum group metals (PGM) by inductively coupled plasma quadrupole mass spectrometry (ICP-MS) was optimized. The interferences from Sr, Cu, Pb, Y, Cd, Zr and Hf were evaluated using model solutions. Plasma radiofrequency (RF) power and nebulizer gas flow were optimized for 103Rh, 105Pd, 108Pd and 195Pt. Two standard reference materials were analyzed: SARM-7 Platinum ore and BCR-723 Road dust. The optimized procedure was used to analyze samples of airborne particulate matter collected in the urban site with heavy automotive traffic in the centre of Bratislava, Slovakia. PMID- 24061182 TI - Voltammetric detection of adenosine-5'-diphosphate with a carbon paste electrode modified by a hydroxyl functionalized imidazolium-based ionic liquid. AB - A hydroxyl functionalized ionic liquid (IL) 1-(3-chloro-2-hydroxy-propyl)-3 methylimidazolium tetrafluoroborate (PMIMBF4) was used for the preparation of bulky-modified carbon paste electrode (IL-CPE), which was applied to the sensitive detection of adenosine-5'-diphosphate (ADP) in a pH 5.0 Britton Robinson (B-R) buffer solution. IL-CPE is demonstrated to promote the oxidation of ADP with strong electrocatalytic ability. An irreversible oxidation peak appeared with adsorption-controlled process and enhanced electrochemical response on the IL-CPE. The electrode reaction parameters such as electron transfer coefficient (alpha) and electron transfer number (n) of ADP were calculated respectively. By using differential pulse votammetry the oxidation peak current was linearly dependent on the ADP concentration in the range from 10.0 to 1000.0 umol/L with the detection limit as 3.23 umol/L (3sigma). The proposed method showed good selectivity to the ADP detection without the interferences of coexisting substances, which could be further used for the synthetic sample detection. PMID- 24061183 TI - Second-Order Derivative UV Spectrophotometric Method for the Determination of Fesoterodine and Comparison with LC, CE and LC-MS/MS in Commercial Extended Release Tablets. AB - The present work describes a second-order derivative UV spectrophotometric method for determination of a potent antimuscarinic drug, fesoterodine, in extended release tablets. The method was developed and satisfactory validated according to ICH guideline with respect to specificity, linearity, precision, accuracy, and robustness. The response was linear in the concentration range of 2-24 ug mL-1 (r2 = 0.9999, n = 7) at wavelength 228 nm, which was the zero crossing point of excipient solutions. The detection and quantitation limits were 0.38 and 1.27 ug mL-1, respectively. Precision and accuracy data evaluated by relative standard deviation were lower than 2%. The method proved to be robust by a Plackett-Burman design evaluation. It is simple, it has low cost, and it has low use of polluting reagents. Therefore, the proposed method was successfully applied for the quantitative analysis of fesoterodine in commercial tablets, and the results were compared to validated methods by liquid chromatography, capillary electrophoresis and liquid chromatography-tandem mass spectrometry showing non-significant difference (P > 0.05). PMID- 24061184 TI - The Effect of pH Value of a Simulated Physiological Solution on the Corrosion Resistance of Orthopaedic Alloys. AB - Metals and alloys used in orthopaedics and dentistry are exposed in vivo to various agents and environmental conditions. One of the important factors that determine the corrosion behaviour of metallic biomaterials is the pH of the environment. The corrosion resistance of stainless steel 316L (Fe/Cr18/Ni10/Mo3), titanium and titanium alloy Ti-6Al-4V (Ti90/Al6/V4) was studied in terms of their electrochemical properties and biodegradation in simulated physiological solutions of different pH values (4.5, 6.5, 7.5 and 8). The electrochemical characteristics of individual metal components were also investigated using cyclic voltammetry, linear polarization and potentiodynamic polarization methods. The concentration of dissolved metal ions released during 32 days immersion under simulated physiological conditions was determined by inductively coupled plasma mass spectroscopy. The corrosion behaviour of stainless steel 316L is strongly affected by the pH of the physiological solution in the range from 4.5 to 8.0. The corrosion resistance was enhanced at higher pH and the concentrations of released metal ions lower. The behaviour of titanium and its alloy however is almost independent of the pH. PMID- 24061185 TI - Use of factorial design for evaluation of factors affecting the chemical stability of sirolimus (rapamycin) in solid dosage form. AB - Effects of four process and formulation parameters (spraying rate of ethanol solution, drying and tablet hardness and hydroxypropyl methyl cellulose (HPMC) content) were evaluated in terms of initial quality of tablets using factorial design approach. For determination of stability of final drug product, the tablets were exposed to stress testing conditions and the three most significant factors were investigated (spraying rate of ethanol solution, drying and HPMC content). Considering the chemical stability of Sirolimus, the following responses were found to be most important: total sum of degradation products, levels of impurity I and assay of isomer C. Investigated factors and their interactions most significantly affected the assay of isomer C in initial and in stressed stability testing samples. The factorial design approach is a very economic way of obtaining the maximum amount of information in a short period of time, which is especially important in studies that include a variety of different factors and their interactions. PMID- 24061186 TI - Synthesis and fluorescent properties of chromium-doped aluminate nanopowders. AB - Nanocrystalline chromium-doped Al2O3 and MgAl2O4 products were synthesised by combustion method in the presence of urea. The powders were characterised by X ray diffraction analysis (XRD), scanning electron microscopy (SEM), BET surface area analysis, induction coupled plasma analysis (ICP) and mapping energy dispersive X-ray analysis (EDX). Fluorescence properties of the products were investigated in order to find the applications in fluorescent sensor and in the production of transparent polycrystalline ceramic materials for laser and optical application. PMID- 24061187 TI - A Dynamic Electrode for the Estimation of Praseodymium(III) using 1,5-Bis-(o aminophenol)-3-thiapentane as an Ionophore. AB - This study is related with the development of Pr3+ selective membrane sensor using 1,5-Bis-(o-aminophenol)-3-thiapentane as a neutral carrier. The sensor with membrane composition of 33% PVC, 54%, o-NPOE, 8% NaTPB and 5% ionophore, exhibits a Nernstian response for Pr3+ ion, with a wide concentration range of 3.0 * 10-9 1.0 * 10-2 mol/L, low detection limit (1.0 * 10-9 mol/L) and slope of 23.50.3mV decade-1 of activity with in pH range of 2.0-8.8 and fast response time of 7s. The sensor was also found to work satisfactorily in partially non-aqueous media up to 25% (v/v) content of methanol, ethanol or acetone and could be used for a period of 8 months without any change in response characteristics. The proposed membrane electrode was successfully applied as an indicator electrode for the titration of Pr3+ ion (1.0 * 10-3 M) with a standard EDTA solution (1.0 * 10-3 M). PMID- 24061188 TI - Sumanene Units in P-type Surface Networks. AB - Sumanene is a synthesized circulene molecule, with formula: 6:(5,6)3. We propose here units for periodic P-type surface networks, based on their stability, evaluated at the Hartree-Fock HF level of theory. Design of the yet hypothetical lattices was performed by using operations on maps, as provided by CVNET and Nano Studio software. The topology of the network was characterized by Omega polynomial. PMID- 24061189 TI - A Rapid Synthesis of Some 1,4-aryldiazines by the Use of Lithium Chloride as an Effective Catalyst. AB - The synthesis of some 1,4-aryldiazines (novel and known dibenzo[a,c]phenazines and quinoxalines) based on the condensation of 1,2-aryldiamines with aromatic 1,2 dicarbonyl compounds in the presence of lithium chloride as a heterogeneous catalyst is presented as convenient and efficient strategy. This method has advantages such as excellent yields, short reaction times, and simple work-up procedure. PMID- 24061190 TI - Synergistic Extraction of Strontium into Nitrobenzene by Using Hydrogen Dicarbollylcobaltate and N,N,N',N'-Tetracyclohexyl-oxybis(o-phenyleneoxy) diacetamide. AB - Extraction of microamounts of strontium by a nitrobenzene solution of hydrogen dicarbollylcobaltate (H+B-) in the presence of N,N,N',N'-tetracyclohexyl-oxybis(o phenyleneoxy)diacetamide (abbrev. barium ionophore I, L) has been investigated. The equilibrium date have been explained assuming that the species HL+, SrL2+ and SrL2+2 are extracted into the organic phase. The values of extraction and stability constants of the cationic complexes in nitrobenzene saturated with water have been determined. PMID- 24061191 TI - Estimation of Stability of Cadmium(II) Mono-Complexes with Monodentate and Bidentate Ligands by Models Based on 3chiv Connectivity Index. AB - Based on the quadratic function used previously for the estimation of copper(II) amino acid mono-complexes, we developed the model for the estimation of the stability constant K1 of cadmium(II) complexes with five amino acids (glycine, alanine, 2-aminobutanoic, 2-aminopentanoic, and 2-aminohexanoic acid). The model gave R2 = 0.960 and S.E. = 0.03. Also, for the first time we proposed (univariate linear) model for the estimation of K1 of complexes with monodentate ligands, namely the Cd(II) complexes with methanoic, ethanoic, propanoic, 2 methylpropanoic, butanoic, 2-methylbutanoic, 2-hydroxyethanoic, 2 hydroxypropanoic and 2-hydroxybutanoic acid. The model is capable to discriminate monodentate from bidentate ligands; much better statistic was obtained (R2 = 0.966 and S.E. = 0.05) if 2-hydroxybutanoic acid was assumed to be bidentate. PMID- 24061192 TI - Experimental and Theoretical Study on the Complexation of the Thallium Cation with Dibenzo-18-crown-6. AB - From extraction experiments and gamma-activity measurements, the extraction constant corresponding to the equilibrium Tl+(aq) + 1.Na+(nb) <-> 1.Tl+(nb) + Na+(aq) taking place in the two-phase water-nitrobenzene system (1 = dibenzo-18 crown-6; aq = aqueous phase, nb = nitrobenzene phase) was evaluated as log Kex(Tl+, 1.Na+) = 2.1. Further, the stability constant of the complex 1.Tl+ in nitrobenzene saturated with water was calculated for a temperature of 25 degrees C: log betanb (1.Tl+) = 6.6. Finally, by using quantum mechanical DFT calculations, the most probable structure of the resulting complex 1.Tl+ was solved. PMID- 24061193 TI - Synthesis of Organotitanium(IV) Fluoride Phosphates and the Crystal Structure of [(C5Me4Et)TiF(u-F){u-O2P(OSiMe3)2}]2. AB - The complexes [(C5Me4R)TiF(u-F)u-O2P(OSiMe3)2]2 [R = Me (1), Et (2)] were prepared from [(C5Me4R)TiF3]2, (R = Me, Et) and OP(OSiMe3)3. The molecular structure of 2 has been determined by single-crystal X-ray diffraction analysis. An eight-membered Ti2O4P2 metallacycle bridged by two fluorine ligands between two titanium centers is observed. PMID- 24061194 TI - Estimation of kinetic parameters for enzyme-inhibition reaction models using direct time-dependent equations for reactant concentrations. AB - To facilitate the determination of a reaction type and its kinetics constants for reversible inhibitors of Michaelis-Menten-type enzymes using progress-curve analysis, I present here an explicit equation for direct curve fitting to full time-course data of inhibited enzyme-catalyzed reactions. This algebraic expression involves certain elementary functions where their values are readily available using any standard nonlinear regression program. Hence this allows easy analysis of experimentally observed kinetics without any data conversion prior to fitting. Its implementation gives correct parameter estimates that are in very good agreement with results obtained using both the numerically integrated Michaelis-Menten rate equation or its exact closed-form solution which is expressed in terms of the Lambert W function. PMID- 24061195 TI - Preparation of Atomically Flat Gold Substrates for AFM Measurements. AB - Sample preparation is the most important part of a successful measurement with an atomic force microscope (AFM). While various kinds of substrates are used for that purpose, atomically flat gold proved to possess some advantages, namely chemical inertness against oxygen, stability against radicals and suitability for formation of self-assembled monolayers (SAMs) of organic alkanethiols. Fast and simple preparation procedures to achieve quality atomically flat gold substrates are necessary to achieve reproducible results in high resolution imaging. Here we report an improved technique to produce atomically flat gold in a reliable way. We demonstrate its use on the example of high resolution imaging of single walled carbon nanotubes as test molecules. PMID- 24061196 TI - Recent advances in enzymatic and chemical deracemisation of racemic compounds. AB - Deracemisation of racemic compounds is still the most important strategy to produce optically pure compounds despite many recent advances in asymmetric synthesis. Especially deracemisation approaches that give rise to single enantiomers are preferred, which can be achieved either by invoking organocatalysts, metal complexes or enzymes - leading to dynamic kinetic resolution - or by applying other deracemisation techniques based on stereoinversion or enantioconvergence. In this tutorial review, we will provide an overview of new, recently developed approaches that lead to the important goal of creating organic compounds of single chirality. PMID- 24061197 TI - Ultrastructural findings in noncompaction prevail with neuromuscular disorders. AB - OBJECTIVES: Little is known about the ultrastructural abnormalities of left ventricular hypertrabeculation/noncompaction (LVHT). This literature review aimed to summarize and discuss ultrastructural abnormalities described in LVHT so far. METHODS: The literature search was conducted via MEDLINE using the search terms 'non-compaction', 'noncompaction', 'left ventricular hypertrabeculation', 'spongy myocardium' in combination with the terms 'ultra-structural', or 'electron microscopy'. RESULTS: Altogether, 11 studies reporting ultrastructural investigations of LVHT were retrieved. In these 11 studies, data on 13 patients with LVHT were presented. Ultrastructural abnormalities found in these study patients were generally nonspecific and included an increase in the number of mitochondria (n = 3), abnormally shaped mitochondria (n = 2), distorted cristae (n = 3), sarcomeric derangement (n = 3), immature cardiomyocytes (n = 1), lipid like inclusions (n = 1), enlarged interstitial spaces (n = 1), increased interstitial collagen (n = 1), or increased glycogen (n = 1). The morphological abnormalities were most prominent in patients with a neuromuscular disorder like Barth syndrome or mitochondrial myopathy. CONCLUSIONS: Only in few patients with LVHT, ultrastructural investigations have been performed so far. Ultrastructural abnormalities in LVHT are nonspecific and most prominent in patients with a neuromuscular disorder. There is a strong need to carry out thorough ultrastructural investigations of LVHT to contribute to the understanding of this still unexplained myocardial abnormality. PMID- 24061198 TI - Hypokalemic periodic paralysis induced by thymic hyperplasia and relieved by thymectomy. AB - IMPORTANCE: Hypokalemic periodic paralysis is a muscle channelopathy based on mutations or predisposing variants or secondary to potassium wasting. In contrast to myasthenia gravis, an association with thymic hyperplasia has not yet been reported, to our knowledge. OBSERVATIONS: We report a male patient in his mid-20s with progressive episodes of flaccid muscle weakness, associated low serum potassium levels, and a pathologic decrement in the long exercise test. Because the familial inheritance in the family was initially unknown, thorough diagnostic tests were performed including contrast-enhanced computed tomography scan, which displayed a mass in the anterior mediastinum. The test results for autoantibodies against myasthenia gravis (acetylcholine receptor, muscle-specific tyrosine kinase, and low-density lipoprotein receptor-related protein 4) and other end plate channelopathies were negative, and test results for hypokalemia-inducing hormones (thyroid, corticotropin, and cortisol) were negative. Surgery identified a thymus of 13 * 8 * 3 cm(3). Histologic analysis was consistent with thymic hyperplasia of the follicular subtype and immunohistologic analysis showed cytokeratin 5/6 in hyperplastic epithelial cells. A 2-year follow-up revealed the postoperative absence of weakness episodes. As in 30% of familial cases, molecular genetics testing failed to identify a mutation in periodic paralysis genes. CONCLUSIONS AND RELEVANCE: Thymic hyperplasia can clinically manifest susceptibility to hypokalemic periodic paralysis. For patients with late onset or increasing weakness episodes, we recommend imaging to assess for thymic enlargement and thymectomy at thymic hyperplasia. PMID- 24061199 TI - The right care in the right place. PMID- 24061200 TI - GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures. AB - OBJECTIVE: Several antiepileptic drugs (AEDs) are known to target the GABA(A) receptor through positive allosteric modulation of the receptors, thereby enhancing GABA(A) receptor-mediated inhibition. The large diversity of GABA(A) receptors has been reported in the central nervous system; some of these have been implicated in epilepsy susceptibility and AED resistance, which we aimed to examine. MATERIALS AND METHODS: We investigated the association of single nucleotide polymorphisms in GABA(A) receptor subunit subtype genes namely; rs2279020 (GABRA1), rs3219151 (GABRA6), rs2229944 (GABRB2), and rs211037 (GABRG2) with predisposition to epilepsy and AED resistance. This was assessed in three cohorts of ethnically matched South Indian ancestry: mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype of AED-resistant epilepsy syndrome), juvenile myoclonic epilepsy (prototype of AED-responsive epilepsy syndrome), and nonepilepsy controls. RESULTS: A significant allelic (P=0.0006, odds ratio=1.6, 95% confidence interval=1.22-2.08) and genotypic (P=0.001) association of a synonymous variant in GABRG2, rs211037 (Asn196Asn) was observed with epilepsy irrespective of its phenotype, that is, MTLE-HS or juvenile myoclonic epilepsy. However, this association was not retained in epilepsy patients with a history of febrile seizures. The GABA(A) receptor subunit subtype genes were not found to have any association with AED resistance. In-silico analysis indicated that rs211037 plays a significant role in the transcriptional regulation and splicing regulation. CONCLUSION: We could substantiate that among the GABA(A) receptor subunit gene cluster polymorphisms, the GABRG2, rs211037 predisposes susceptibility to epilepsy, irrespective of its phenotype, but not to AED resistance. PMID- 24061201 TI - A novel specific pyrosequencing method for genotyping FCGR3A rs396991 without coamplification of homologous gene FCGR3B. AB - Monoclonal antibodies, such as rituximab, trastuzumab, and cetuximab, mediate immune response by binding to Fcgamma receptors. The frequently occurring Phe158Val variant of the FCGR3A gene has increased binding affinity and consequently may affect immune response. Several pharmacogenetic association studies have genotyped this variant (FCGR3A rs396991), but with disconcordant results. In addition, in some of these studies genotype distribution was not in Hardy-Weinberg equilibrium, and samples were excluded from analysis because of genotype inconsistency. Genotyping problems of FCGR3A rs396991 are most likely due to sequence homology with the FCGR3B gene. For that reason, we developed a novel pyrosequencing method specifically for genotyping FCGR3A rs396991 and confirmed that the FCGR3B gene is not coamplified. PMID- 24061202 TI - Predictors of consent to pharmacogenomics testing in the IDEAL study. AB - INTRODUCTION: Pharmacogenomic testing is important in developing individualized therapeutic approaches. In the phase 3 IDEAL (Individualized Dosing to Assess Optimal Pegylated Interferon Therapy) clinical trial, a subset of patients receiving peginterferon and ribavirin for treatment of chronic hepatitis C agreed to provide blood samples for genetic testing. Genome-wide association studies subsequently identified associations between IL28B polymorphism and sustained virologic response, and ITPA polymorphism and ribavirin-associated anemia. OBJECTIVE: To characterize the groups of patients who accepted or declined pharmacogenomic testing in the IDEAL study. METHODS: Clinical and demographic factors and treatment outcomes were compared at all sites that had approved pharmacogenomic testing. Differences between patients who consented to and declined pharmacogenomic testing were analyzed using Student's t-test and chi2 test. RESULTS: In total, 109 of 118 sites participated in the pharmacogenomic substudy, and 1674 of 2949 (57%) patients enrolled at these sites consented to pharmacogenomic testing. More patients treated in academic medical centers than in community centers (60 vs. 52%, P<0.001) provided consent. More men than women (58 vs. 54%, P=0.04) consented to pharmacogenomic testing. There was no significant difference in pharmacogenomic participation between patients from different racial groups, including whites and African Americans (58 vs. 54%, P=0.07). Treatment outcomes were also similar according to pharmacogenomic participation. CONCLUSION: In the IDEAL study, patient consent to pharmacogenomic testing did not introduce selection bias. Treatment at an academic center and male sex were associated with higher rates of pharmacogenomic testing consent. Efficacy and safety outcomes were similar in patients who accepted and declined pharmacogenomic testing. PMID- 24061203 TI - Noninvasive evaluation of NAFLD. AB - A common clinical concern in patients with NAFLD is whether they have NASH or simple steatosis and, more importantly, what the stage of fibrosis is and whether the level of fibrosis has increased over time. Such concern is based on the fact that patients with NAFLD with advanced fibrosis are at greatest risk of developing complications of end-stage liver disease. Although it lacks sensitivity, ultrasonography is an accepted tool for steatosis screening. The controlled attenuation parameter or CAP seems a promising screening technique, but requires further validation. Cytokeratin-18 has been extensively validated, but it is an imperfect serum marker of NASH. Ultrasonography-based transient elastography can exclude advanced fibrosis and cirrhosis, but its main limitation is its reduced applicability in patients with NAFLD, which is not completely solved by use of the XL probe. Of the noninvasive serum markers, the NAFLD fibrosis score is the most validated and has appropriate accuracy in distinguishing patients with and without advanced fibrosis. Although noninvasive methods require further validation, they could be useful for selecting those patients with NAFLD who require a liver biopsy. This Review discusses the advantages and limitations of noninvasive methods for the management of adults with NAFLD, including diagnosis and quantification of steatosis, diagnosis of NASH and staging of hepatic fibrosis. PMID- 24061206 TI - Large magnetovolume effects due to transition from the ferromagnetic to antiferromagnetic state in Hf0.825Ta0.175Fe2 intermetallic compound. AB - Intrinsic magnetic properties and magnetovolume effects have been investigated for the Hf0.825Ta0.175Fe2 itinerant-electron system, which exhibits a temperature induced first-order transition from the ferromagnetic (FM) to the antiferromagnetic (AFM) state. The spontaneous volume magnetostriction contraction due to this transition from the high-volume FM state to the low volume AFM state is about 0.66%. Applying a magnetic field increases significantly the FM-AFM transition temperature T(FM-AFM), with a rate of 7.2 K T(-1). At temperatures T > T(FM-AFM) a first-order metamagnetic transition between the AFM and FM states has been observed from isothermal magnetization curves, a result attributed to the itinerant-electron character of the Fe magnetism. This AFM-FM transition is accompanied by a huge field-induced volume magnetostriction. The change in DeltaV/V due to the AFM-FM transition is about 0.75%. PMID- 24061204 TI - The gut as a sensory organ. AB - The gastrointestinal tract presents the largest and most vulnerable surface to the outside world. Simultaneously, it must be accessible and permeable to nutrients and must defend against pathogens and potentially injurious chemicals. Integrated responses to these challenges require the gut to sense its environment, which it does through a range of detection systems for specific chemical entities, pathogenic organisms and their products (including toxins), as well as physicochemical properties of its contents. Sensory information is then communicated to four major effector systems: the enteroendocrine hormonal signalling system; the innervation of the gut, both intrinsic and extrinsic; the gut immune system; and the local tissue defence system. Extensive endocrine-neuro immune-organ-defence interactions are demonstrable, but under-investigated. A major challenge is to develop a comprehensive understanding of the integrated responses of the gut to the sensory information it receives. A major therapeutic opportunity exists to develop agents that target the receptors facing the gut lumen. PMID- 24061207 TI - Mechanisms of the ammonia oxidation by hydrogen peroxide over the perfect and defective Ti species of TS-1 zeolite. AB - The catalytic performances of titanium species in TS-1 zeolite for the hydroxylamine formation have been investigated using the density functional theory with the ONIOM scheme. The reaction process for making hydroxylamine is divided into two steps: (i) the H2O2 decomposition over the Ti species to produce the peroxo titanium species and (ii) the NH3 oxidation over the generated oxidizing species. Our results indicated that defective Ti species in the TS-1 zeolite are the dominant catalytic sites for H2O2 decomposition rather than perfect Ti species, leading to the formation of =Ti-OOH species as oxygen donating intermediates for NH3 oxidation reaction. The energetic profiles for the ammonia oxidation over the =TiOOH species and the catalytic effect from water were fully investigated, consisting of three proposed mechanisms. The most favored pathway was found to be: the adsorption of ammonia (NH3/eta(1)=TiOOH) -> ammonia oxide complex (NH3O/=TiOH) -> hydrated-titanium-oxyamine species (H2O/=TiONH2) -> hydroxylamine product (NH2OH/=TiOH), in which the highest energy barrier is 16.3 kcal mol(-1). Besides the hydrolysis of titanium-oxyamine species, the hydroxylamine was also generated through the second H2O2 decomposition over the titanium-oxyamine species whereas the activation energy for this step was slightly decreased to be 15.7 kcal mol(-1). PMID- 24061205 TI - The genetics of NAFLD. AB - NAFLD is a disease spectrum ranging from simple steatosis, through steatohepatitis to fibrosis and, ultimately, cirrhosis. This condition is characterized by considerable interpatient variability in terms of severity and rate of progression: although a substantial proportion of the population is at risk of progressive disease, only a minority experience associated morbidity. As such, NAFLD is best considered a complex disease trait resulting from environmental exposures acting on a susceptible polygenic background and comprising multiple independent modifiers. Much ongoing research is focused on identifying the genetic factors that contribute to NAFLD pathogenesis. This Review describes the current status of the field, discussing specific genetic and epigenetic modifiers, including the mechanisms through which genes identified by genome-wide association studies, including PNPLA3, influence disease progression. PMID- 24061209 TI - The ammonium-promoted formylation of indoles by DMSO and H2O. AB - DMSO and H2O is an efficient combination in the NH4OAc-promoted formylation of indole, where DMSO serves as a C1 carbon source. The mechanism study reveals that the procedure involves a usual and unusual Pummerer reaction. PMID- 24061208 TI - A co-culture device with a tunable stiffness to understand combinatorial cell cell and cell-matrix interactions. AB - Cell behavior on 2-D in vitro cultures is continually being improved to better mimic in vivo physiological conditions by combining niche cues including multiple cell types and substrate stiffness, which are well known to impact cell phenotype. However, no system exists in which a user can systematically examine cell behavior on a substrate with a specific stiffness (elastic modulus) in culture with a different cell type, while maintaining distinct cell populations. We demonstrate the modification of a silicon reconfigurable co-culture system with a covalently linked hydrogel of user-defined stiffness. This device allows the user to control whether two separate cell populations are in contact with each other or only experience paracrine interactions on substrates of controllable stiffness. To illustrate the utility of this device, we examined the role of substrate stiffness combined with myoblast co-culture on adipose derived stem cell (ASC) differentiation and found that the presence of myoblasts and a 10 kPa substrate stiffness increased ASC myogenesis versus co-culture on stiff substrates. As this example highlights, this technology better controls the in vitro microenvironment, allowing the user to develop a more thorough understanding of the combined effects of cell-cell and cell-matrix interactions. PMID- 24061210 TI - A practical approach to radiological evaluation of CT lung cancer screening examinations. AB - Lung cancer is the most common cause of cancer-related death in the world. The Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON) was launched to investigate whether screening for lung cancer by low-dose multidetector computed tomography (CT) in high-risk patients will lead to a decrease in lung cancer mortality. The NELSON lung nodule management is based on nodule volumetry and volume doubling time assessment. Evaluation of CT examinations in lung cancer screening can also include assessment of coronary calcification, emphysema and airway wall thickness, biomarkers for major diseases that share risk factors with lung cancer. In this review, a practical approach to the radiological evaluation of CT lung cancer screening examinations is described. PMID- 24061211 TI - Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. AB - BACKGROUND: Placebo-controlled trials showed that both benzodiazepines (BDZ) and antidepressant drugs (AD) are effective in treating anxiety disorders. However, in the last years a progressive shift in the prescribing pattern from BDZ to newer AD has taken place. The aim of this systematic review and meta-analysis is to analyze whether controlled comparisons support such a shift. METHODS: CINHAL, the Cochrane Library, MEDLINE, PubMed and Web of Science were searched from inception up to December 2012. A total of 22 studies met the criteria for inclusion. They were mostly concerned with tricyclic antidepressants (TCA; 18/22) and involved different anxiety disorders. In order to reduce clinical heterogeneity, only the 10 investigations that dealt with the comparison between TCA and BDZ in panic disorder were submitted to meta-analysis, whereas the remaining papers were individually summarized and critically examined. RESULTS: According to the systematic review, no consistent evidence emerged supporting the advantage of using TCA over BDZ in treating generalized anxiety disorder (GAD), complex phobias and mixed anxiety-depressive disorders. Indeed, BDZ showed fewer treatment withdrawals and adverse events than AD. In panic disorder with and without agoraphobia our meta-analysis found BDZ treatments more effective in reducing the number of panic attacks than TCA (risk ratio, RR = 1.13; 95% CI = 1.01-1.27). Furthermore, BDZ medications were significantly better tolerated than TCA drugs, causing less discontinuation (RR = 0.40; 95% CI = 0.20-0.57) and side effects (RR = 0.41; 95% CI = 0.34-0.50). As to newer AD, BDZ trials resulted in comparable or greater improvements and fewer adverse events in patients suffering from GAD or panic disorder. CONCLUSIONS: The change in the prescribing pattern favoring newer AD over BDZ in the treatment of anxiety disorders has occurred without supporting evidence. Indeed, the role and usefulness of BDZ need to be reappraised. PMID- 24061212 TI - Why compete when you can share? Competitive reactivity of germanium and phosphorus with selenium. AB - Addition of one equivalent of selenium to a germanium-phosphanide complex results in insertion of selenium into the Ge-P bond, not oxidation at germanium or phosphorus. Addition of excess selenium results in oxidation at phosphorus, although of germanium oxidation is still observed. PMID- 24061213 TI - Environmental and genetic variation in leaf anatomy among populations of Andropogon gerardii (Poaceae) along a precipitation gradient. AB - PREMISE OF THE STUDY: Phenotypes of two Andropogon gerardii subspecies, big bluestem and sand bluestem, vary throughout the prairie ecosystem of North America. This study sought to determine the role of genetics and environment in driving adaptive variation of leaf structure in big bluestem and sand bluestem. * METHODS: Four populations of big bluestem and one population of sand bluestem were planted in common gardens at four sites across a precipitation gradient from western Kansas to southern Illinois. Internal leaf structure and trichome density of A. gerardii were examined by light microscopy to separate genetic and environmentally controlled traits. Leaf thickness, midrib thickness, bulliform cells, interveinal distance, vein size, and trichome density were quantified. * KEY RESULTS: At all planting sites, sand bluestem and the xeric population of A. gerardii had thicker leaves and fewer bulliform cells compared with mesic populations. Environment and genetic source population were both influential for leaf anatomy. Leaves from plants grown in mesic sites (Carbondale, Illinois and Manhattan, Kansas) had thicker midribs, larger veins, fewer trichomes, and a greater proportion of bulliform cells compared to plants grown in drier sites (Colby and Hays, Kansas). * CONCLUSIONS: Water availability has driven adaptive variation in leaf structure in populations of A. gerardii, particularly between sand bluestem and big bluestem. Genetically based differences in leaves of A. gerardii indicate adaptive variation and evolutionary forces differentiating sand bluestem from big bluestem. Environmental responses of A. gerardii leaves suggest an ability to adjust to drought, even in populations adapted to mesic home environments. PMID- 24061214 TI - Branch architecture in Ginkgo biloba: wood anatomy and long shoot-short shoot interactions. AB - PREMISE: Ginkgo, centrally placed in seed plant phylogeny, is considered important in many phylogenetic and evolutionary studies. Shoot dimorphism of Ginkgo has been long noted, but no work has yet been done to evaluate the relationships between overall branch architecture and wood ring characters, shoot growth, and environmental conditions. * METHODS: Branches, sampled from similar canopy heights, were mapped with the age of each long shoot segment determined by counting annual leaf-scar series on its short shoots. Transverse sections were made for each long shoot segment and an adjacent short shoot; wood ring thickness, number of rings, and number of tracheids/ring were determined. Using branch maps, we identified wood rings for each long shoot segment to year and developmental context of each year (distal short shoot growth only vs. at least one distal long shoot). Climate data were also analyzed in conjunction with developmental context. * KEY RESULTS: Significantly thicker wood rings occur in years with distal long shoot development. The likelihood that a branch produced long shoots in a given year was lower with higher maximum annual temperature. Annual maximum temperature was negatively correlated with ring thickness in microsporangiate trees only. Annual minimum temperatures were correlated differently with ring thickness of megasporangiate and microsporangiate trees, depending on the developmental context. There were no significant effects associated with precipitation. * CONCLUSIONS: Overall, developmental context alone predicts wood ring thickness about as well as models that include temperature. This suggests that although climatic factors may be strongly correlated with wood ring data among many gymnosperm taxa, at least for Ginkgo, correlations with climate data are primarily due to changes in proportions of shoot developmental types (LS vs. SS) across branches. PMID- 24061215 TI - Evaluation of the potential of volatile organic compound (di-methyl benzene) removal using adsorption on natural minerals compared to commercial oxides. AB - This study is dedicated to the investigation of the potential of volatile organic compounds (VOC) adsorption over low cost natural minerals (bentonite and diatomite). The performances of these solids, in terms of adsorption/desorption properties, were compared to commercial adsorbents, such as silica, alumina and titanium dioxide. The solids were first characterized by different physico chemical methods and di-methyl benzene (dMB) was selected as model VOC pollutant for the investigation of adsorptive characteristics. The experiments were carried out with a fixed bed reactor under dynamic conditions using Fourier Transform InfraRed spectrometer to measure the evolution of dMB concentrations in the gaseous stream at the outlet of the reactor. The measured breakthrough curves yields to adsorbed amounts at saturation that has been used to obtain adsorption isotherms. The latters were used for determination of the heat involved in the adsorption process and estimation of its values using the isosteric method. Furthermore, the performances of the studied materials were compared considering the adsorption efficiency/cost ratio. PMID- 24061216 TI - Effects of electrode geometry on the performance of dielectric barrier/packed-bed discharge plasmas in benzene degradation. AB - In this study, the effects of electrode geometry on benzene degradation in a dielectric barrier/packed-bed discharge plasma reactor with different electrodes were systematically investigated. Three electrodes were employed in the experiments, these were coil, bolt, and rod geometries. The reactor using the coil electrode showed better performance in reducing the dielectric loss in the barrier compared to that using the bolt or rod electrodes. In the case of the coil electrode, both the benzene degradation efficiency and energy yield were higher than those for the other electrodes, which can be attributed to the increased role of surface mediated reactions. Irrespective of the electrode geometry, the packed-bed discharge plasma was superior to the dielectric barrier discharge plasma in benzene degradation at any specific applied voltage. The main gaseous products of benzene degradation were CO, CO2, H2O, and formic acid. Discharge products such as O3, N2O, N2O5, and HNO3 were also detected in the outlet gas. Moreover, the presence of benzene inhibited the formation of ozone because of the competing reaction of oxygen atoms with benzene. This study is expected to offer an optimized approach combining dielectric barrier discharge and packed-bed discharge to improve the degradation of gaseous pollutants. PMID- 24061217 TI - Chromium accumulation and changes in plant growth, selected phenolics and sugars of wild type and genetically modified Nicotiana langsdorffii. AB - Chromium accumulation, dry weight (DW) biomass yield, water content and concentrations of some selected phenolic compounds and carbohydrates were determined in root and shoot of Nicotiana langsdorffii, either wild type (WT) or genetically modified by the insertion of GR and rolC genes, in response to the presence of Cr(VI) in the growth medium. A biomass decrease was observed for WT plants, but not for GR and rolC transformations, in response to Cr(VI) in the growth medium, highlighting a stress situation only in WT line. Shoot chromium concentrations were in all cases about 300 mg kg(-1) DW. In root higher concentrations were found in rolC than in GR and WT (3843, 2600 and 2751 mg kg( 1) DW, respectively). Based on the DW biomass, GR and WT accumulated higher chromium quantities than rolC, both in root (330 and 424 versus 85 MUg Cr per plant) and shoot (282 and 275 versus 121 MUg Cr per plant). Therefore, GR should be preferred to WT as a promising candidate for chromium phytoremediation. Metabolic shifts of sugars and phenolics were generally observed in response to either gene insertions or exposure to Cr(VI), being the latter more related to the resistance to Cr(VI) than the former. PMID- 24061218 TI - Readout strategy of an electro-optical coupled PET detector for time-of-flight PET/MRI. AB - Combining PET with MRI in a single system provides clinicians with complementary molecular and anatomical information. However, existing integrated PET/MRI systems do not have time-of-flight (ToF) PET capabilities. This work describes an MRI-compatible front-end electronic system with ToF capabilities. The approach employs a fast arrival-time pickoff comparator to digitize the timing information, and a laser diode to drive a 10 m fiber-optic cable to optically transmit asynchronous timing information to a photodiode receiver readout system. The FWHM jitter of the comparator and this electo-optical link is 11.5 ps in response to a fast digital pulse. When configured with LYSO scintillation crystals and Hamamatsu MPPC silicon photo-multipliers the comparator and electro optical link achieved a 511 keV coincidence time resolution of 254.7 ps +/- 8.0 ps FWHM with 3 * 3 * 20 mm(3) crystals and 166.5 +/- 2.5 ps FWHM with 3 * 3 * 5 mm(3) crystals. PMID- 24061219 TI - A Mossbauer effect study of single crystals of the non-superconducting parent compound Fe1.09Te and the superconductor FeSe0.4Te0.6. AB - The results of a (57)Fe Mossbauer spectroscopy study between 2.0 and 297 K of the parent compound Fe1.09Te and the superconductor FeSe0.4Te0.6 are reported. It is shown that in both compounds the magnitude of the quadrupole splitting increases with decreasing temperature and is well described by a T(3/2) power-law relation. The presence of incommensurate spin-density-wave antiferromagnetism in Fe1.09Te is demonstrated, with the Neel temperature T(N) = 71.1(6) K. A theoretical prediction (Zhang et al 2009 Phys. Rev. B 79 012506) of the Fe magnetic moment at the 2c sites being significantly larger than that at the 2a sites in the parent compound is confirmed experimentally by showing that these moments at 4.4 K are, respectively, 3.20(4) and 1.78(3) MU(B). The absence of magnetic order in FeSe0.4Te0.6 down to 2.0 K is confirmed. The Debye temperatures of Fe1.09Te and FeSe0.4Te0.6 are found to be 290(1) and 233(1) K, respectively. PMID- 24061221 TI - Protein folding: Misfolded proteins join the Q. PMID- 24061220 TI - Profiling the impact of medium formulation on morphology and functionality of primary hepatocytes in vitro. AB - The characterization of fully-defined in vitro hepatic culture systems requires testing of functional and morphological variables to obtain the optimal trophic support, particularly for cell therapeutics including bioartificial liver systems (BALs). Using serum-free fully-defined culture medium formulations, we measured synthetic, detoxification and metabolic variables of primary porcine hepatocytes (PPHs)--integrated these datasets using a defined scoring system and correlated this hepatocyte biological activity index (HBAI) with morphological parameters. Hepatic-specific functions exceeded those of both primary human hepatocytes (PHHs) and HepaRG cells, whilst retaining biotransformation potential and in vivo like ultrastructural morphology, suggesting PPHs as a potential surrogate for PHHs in various biotech applications. The HBAI permits assessment of global functional capacity allowing the rational choice of optimal trophic support for a defined operational task (including BALs, hepatocellular transplantation, and cytochrome P450 (CYP450) drug metabolism studies), mitigates risk associated with sub-optimal culture systems, and reduces time and cost of research and therapeutic applications. PMID- 24061222 TI - Cell signalling: Responding to intracellular pH. PMID- 24061223 TI - Mechanotransduction: Lamin A for tension relief. PMID- 24061224 TI - Stem cells: No limits to iPS cells? PMID- 24061225 TI - The many sides of CIN. PMID- 24061226 TI - The first chaperonin. PMID- 24061229 TI - Effects of buffering properties and undissociated acid concentration on dissolution of dental enamel in relation to pH and acid type. AB - To quantify the relationships between buffering properties and acid erosion and hence improve models of erosive potential of acidic drinks, a pH-stat was used to measure the rate of enamel dissolution in solutions of citric, malic and lactic acids, with pH 2.4-3.6 and with acid concentrations adjusted to give buffer capacities (beta) of 2-40 (mmol.l(-1)).pH(-1) for each pH. The corresponding undissociated acid concentrations, [HA], and titratable acidity to pH 5.5 (TA5.5) were calculated. In relation to beta, the dissolution rate and the strength of response to beta varied with acid type (lactic > malic >= citric) and decreased as pH increased. The patterns of variation of the dissolution rate with TA5.5 were qualitatively similar to those for beta, except that increasing pH above 2.8 had less effect on dissolution in citric and malic acids and none on dissolution in lactic acid. Variations of the dissolution rate with [HA] showed no systematic dependence on acid type but some dependence on pH. The results suggest that [HA], rather than buffering per se, is a major rate-controlling factor, probably owing to the importance of undissociated acid as a readily diffusible source of H(+) ions in maintaining near-surface dissolution within the softened layer of enamel. TA5.5 was more closely correlated with [HA] than was beta, and seems to be the preferred practical measure of buffering. The relationship between [HA] and TA5.5 differs between mono- and polybasic acids, so a separate analysis of products according to predominant acid type could improve multivariate models of erosive potential. PMID- 24061230 TI - Catalytic and regiospecific extradiol cleavage of catechol by a biomimetic iron complex. AB - An iron(III)-catecholate complex of a facial tridentate ligand reacts with dioxygen in the presence of ammonium acetate-acetic acid buffer to cleave the aromatic C-C bond of 3,5-di-tert-butylcatechol regiospecifically resulting in the formation of an extradiol product with multiple turnovers. PMID- 24061231 TI - What molecular assembly can learn from catalytic chemistry. AB - One important objective of molecular assembly research is to create highly complex functional chemical systems capable of responding, adapting, and evolving. Compared with living systems, the synthetic systems are still rather primitive and are far from realizing those features. Nature is by far the most important source of inspiration for designing and creating such systems. In this critical review, we summarize an alternative approach, inspired by catalysis, to examine and describe some molecular assembly processes. A new term, "catassembly," is suggested to refer to the increase in the rate and control of a molecular assembly process. This term combines the words "catalysis" and "assembly," and identifiably retains the Greek root "cat-" of catalysis. The corresponding verb is "catassemble" and the noun is "catassembler", referring to the "helper" species. Catassembly in molecular assembly is a concept that is analogous to catalysis in chemical synthesis. After using several examples to illustrate the characteristics of catassembly, we discuss future methodological and theoretical developments. We also emphasize the significance of the synergy between chemical synthesis and molecular assembly, especially for hierarchical assembly systems. Because most efforts in the field of molecular assembly have been devoted to the design and synthesis of molecular building blocks, we wish to stress the apparently missing yet critical link to complex chemical systems, i.e., the design and utilization of molecular catassemblers to facilitate the formation of functional molecular assemblies from building blocks with high efficiency and selectivity. This rational control and accelerated method will promote the systems chemistry approach, and may expand the spectrum of molecular assembly from basic science to applications. PMID- 24061232 TI - The effect of chemical substituents on the functionality of a molecular switch system: a theoretical study of several quinoline compounds. AB - This study investigates the effect of chemical substituents on the functional properties of a molecular photoswitch (Phys. Chem. Chem. Phys., 2008, 10, 1243) by means of theoretical tools. Molecular switches are known to consist of so called frame and crane components. Several functional groups are substituted to the 7-hydroxyquinoline molecular frame at position 8 as crane fragments. The impact of pi-electron donating NH2 groups attached to the frame is also investigated. Excited state intramolecular hydrogen transfer mediated by the frame-crane torsion has been considered as a possible reaction mechanism. For all the investigated systems, we present the resulting potential energy profiles of the ground and first excited states. Vertical excitation energies and oscillator strengths of the 5 lowest-lying excited electronic states calculated at the two terminal points of the reaction path are also presented. Single point calculations were carried out at the CC2 level, while the presence of conical intersections between the ground and first excited states near perpendicular twisted geometries was demonstrated using the CASSCF method. Our results undoubtedly reveal the fulfillment of several molecular switch properties of the studied quinoline compounds. Comparisons between the different substituted systems have also been made. PMID- 24061228 TI - Protein rescue from aggregates by powerful molecular chaperone machines. AB - Protein quality control within the cell requires the interplay of many molecular chaperones and proteases. When this quality control system is disrupted, polypeptides follow pathways leading to misfolding, inactivity and aggregation. Among the repertoire of molecular chaperones are remarkable proteins that forcibly untangle protein aggregates, called disaggregases. Structural and biochemical studies have led to new insights into how these proteins collaborate with co-chaperones and utilize ATP to power protein disaggregation. Understanding how energy-dependent protein disaggregating machines function is universally important and clinically relevant, as protein aggregation is linked to medical conditions such as Alzheimer's disease, Parkinson's disease, amyloidosis and prion diseases. PMID- 24061233 TI - Breastfeeding in women with epilepsy. PMID- 24061234 TI - Review of the catalytic voltammetric determination of titanium traces. AB - Catalytic and catalytic adsorptive stripping voltammetry are some of the most sensitive analytical methods. A review of various catalytic and catalytic adsorptive systems of titanium and their use in voltammetric analysis is presented. The mechanisms of catalytic reactions are discussed in detail. In addition to a survey of literature (91 references), catalytic polarographic, voltammetric and catalytic adsorptive stripping voltammetric determination of titanium traces at liquid mercury and metallic films electrodes are discussed briefly. Moreover, the application of the redox systems Ti(IV)/Ti(III) for the indirect determination of voltammetrically inactive oxidizers participating in catalytic reactions (e.g. chlorates) and voltammetrically inactive ligands (e.g. organic acids and thiocyanates) is also presented. PMID- 24061235 TI - Tertiary Structure Prediction of a-Glucosidase and Inhibition Properties of N (Phenoxydecyl) Phthalimide Derivatives. AB - Due to increasing of population of diabetic patients, identifying factors for disease control has received much attention. alpha-glucosidase (EC 3.2.1.20) is an essential enzyme that helps to digestion of carbohydrates such as starch and sugar. Carbohydrates are normally converted into simple sugars, which can be absorbed through the intestine. Therefore, alpha-glucosidase inhibitors can be used to decrease the blood sugar level. We have studied the effect of inhibition of N-(phenoxydecyl) phthalimide derivatives by a computer drug-design protocol involving homology modeling, docking simulation and Quantitative Structure Activity Relationship. The homology modeling of alpha-glucosidase showed a structure very similar to the crystal structure of oligo-1,6-glucosidase from Saccharomyces cerevisiae. Docking results showed the position of inhibitors binding site is close to active site and the carboxyl oxygen in phthalimide is an effective functional group for binding inhibitors to protein. The equation obtained by QSAR showed that, logIC50 decreases and so inhibition property increases when the size, polarity, geometry and number of halogen factors increase. PMID- 24061236 TI - Improved HPLC method with the aid of chemometric strategy: determination of loxoprofen in pharmaceutical formulation. AB - Loxoprofen belongs to a class of Nonsteroidal anti-inflammatory drug acts by inhibiting isoforms of cyclo-oxygenase 1 and 2. In this study an improved RP-HPLC method was developed for the quantification of loxoprofen in pharmaceutical dosage form. For that purpose an experimental design approach was employed. Factors-independent variables (organic modifier, pH of the mobile phase and flow rate) were extracted from the preliminary study and as dependent variables three responses (loxoprofen retention factor, resolution between loxoprofen probenecid and retention time of probenecid) were selected. For the improvement of method development and optimization step, Derringer's desirability function was applied to simultaneously optimize the chosen three responses. The procedure allowed deduction of optimal conditions and the predicted optimum was acetonitrile: water (53:47, v/v), pH of the mobile phase adjusted at to 2.9 with ortho phosphoric acid. The separation was achieved in less than 4minutes. The method was applied in the quality control of commercial tablets. The method showed good agreement between the experimental data and predictive value throughout the studied parameter space. The optimized assay condition was validated according to International conference on harmonisation guidelines to confirm specificity, linearity, accuracy and precision. PMID- 24061237 TI - Development of Artificial Neural Network Model for Diesel Fuel Properties Prediction using Vibrational Spectroscopy. AB - This paper describes development of artificial neural network models which can be used to correlate and predict diesel fuel properties from several FTIR-ATR absorbances and Raman intensities as input variables. Multilayer feed forward and radial basis function neural networks have been used to rapid and simultaneous prediction of cetane number, cetane index, density, viscosity, distillation temperatures at 10% (T10), 50% (T50) and 90% (T90) recovery, contents of total aromatics and polycyclic aromatic hydrocarbons of commercial diesel fuels. In this study two-phase training procedures for multilayer feed forward networks were applied. While first phase training algorithm was constantly the back propagation one, two second phase training algorithms were varied and compared, namely: conjugate gradient and quasi Newton. In case of radial basis function network, radial layer was trained using K-means radial assignment algorithm and three different radial spread algorithms: explicit, isotropic and K-nearest neighbour. The number of hidden layer neurons and experimental data points used for the training set have been optimized for both neural networks in order to insure good predictive ability by reducing unnecessary experimental work. This work shows that developed artificial neural network models can determine main properties of diesel fuels simultaneously based on a single and fast IR or Raman measurement. PMID- 24061238 TI - Refractive index, molar refraction and comparative refractive index study of propylene carbonate binary liquid mixtures. AB - Refractive indices (n) have been experimentally determined for the binary liquid liquid mixtures of Propylene carbonate (PC) (1) with benzene, ethylbenzene, o xylene and p-xylene (2) at 298.15, 303.15 and 308.15 K over the entire mole fraction range. The experimental values of n are utilised to calculate deviation in refractive index (Deltan), molar refraction (R) and deviation in molar refraction (DeltaR). A comparative study of Arago-Biot (A-B), Newton (NW), Eyring and John (E-J) equations for determining refractive index of a liquid has been carried out to test their validity for all the binary mixtures over the entire composition range at 298.15 K. Comparison of various mixing relations is represented in terms of average deviation (AVD). The Deltan and DeltaR values have been fitted to Redlich-Kister equation at 298.15 K and standard deviations have been calculated. The results are discussed in terms of intermolecular interactions present amongst the components. PMID- 24061239 TI - Antibacterial and Photodegradative Properties of Metal Doped TiO2 thin Films Under Visible Light. AB - Doped (Au, Ag) and undoped TiO2 thin films were prepared on soda-lime glass via the sol-gel method by dip-coating from TiCl4 precursor, followed by 30 minutes calcination at 500 degrees C to obtain transparent thin films with good adhesion to the substrate. XRD analysis showed that the particle size of samples heat treated at 500 degrees C was ~10 nm for all of the samples prepared, both doped and undoped ones. SEM images revealed that the thin film surface was homogeneous and nano-porous. The hydrophilicity of the thin films was estimated by contact angle measurements. The photodegradation rate of an aqueous solution of the azo dye Plasmocorinth B on the thin films was tested by in-situ UV-Vis spectroscopic measurements of the dye solution. The best photocatalytic activity under visible and UVA light was exhibited by undoped TiO2 thin films, whereas Au doped thin films were slightly less active. On the other hand, the best antimicrobial activity toward the E. coli strain DH5a under visible light was displayed by the Au/TiO2 thin films. PMID- 24061240 TI - Gas-phase Acidity and Liquid Phase pKa Calculations of Some Cyclic Oxocarbon Acids (CnOnH2 (n = 3, 4, 5, 6)): A Theoretical Investigation. AB - The gas-phase acidity and the pKa values of the organic acids have been attracting a lot of attention from organic and analytical chemists. The gas-phase acidity and pKa calculations for some oxocarbon acids were investigated under B3LYP/6-311+G(d,p) level of theory. In this study, four oxocarbon acids, CnOnH2 were selected, namely deltic acid (n = 3), squaric acid (n = 4), croconic acid (n = 5) and rhodizonic acids (n = 6). The calculations in gas phase show that the gas-phase acidity of the acids increases as the ring size increases due to the formation of resonance-stabilized monoanions and dianions. Solvation free energy is required in pKa calculation. However, there is significant uncertainty in calculating the solvation free energy using theoretical methods. Therefore, three methods to calculate the free energy of solvation were adopted for comparison, which are the (i) solvent reaction field (SCRF) method using the Simple United Atom Topological Model (UA0); (ii) SCRF using the United Atom Topological Model (UAHF) optimized for HF/6-31G(d) level of theory; and (iii) Langevin dipoles (LD) method. From the results obtained, it was shown that SCRF method with UAHF atomic radii has the potential of reproducing the experimental values. The calculated pKa values were in good agreement with experimental results and have shown that the croconic acid, C5O5H2 is found to be the most acidic in aqueous phase. PMID- 24061241 TI - Exploration of the chemical space of novel naphthalene-sulfonamide and anthranilic Acid-based inhibitors of penicillin-binding proteins. AB - Penicillin-binding proteins are a well established, validated and still a very promising target for the design and development of new antibacterial agents. Based on our previous discovery of several noncovalent small-molecule inhibitor hits for resistant PBPs we decided to additionally explore the chemical space around these compounds. In order to clarify their structure-activity relationships for PBP inhibition two new series of compounds were synthesized, characterized and evaluated biochemically: the derivatives of anthranilic acid and naphthalene-sulfonamide derivatives. The target compounds were tested for their inhibitory activities on three different transpeptidases: PBP2a from methicillin-resistant Staphylococcus aureus (MRSA) strains, PBP5fm from Enterococcus faecium strains, and PBP1b from Streptococcus pneumoniae strains. The most promising results for both of these series of compounds were obtained against the PBP2a enzyme with the IC50 values in the micromolar range. Although these results do not represent a significant breakthrough in the field of noncovalent PBP inhibitors, they do provide useful structure-activity relationship data, and thus a more solid basis for the design of potent and noncovalent inhibitors of resistant PBPs. PMID- 24061242 TI - Organic-inorganic Hybrid Gels of Diol-TEOS Type. Synthesis and Study on the Chemical Interaction. AB - Hybrid inorganic-organic materials, silica - diol, were prepared by the sol-gel process from mixtures of tetraethyl orthosilicate (TEOS) and two diols (1,2 propanediol and 1,4-butanediol), using different molar ratios TEOS: diol, in acidic catalysis. The resulted materials were studied by thermal analysis, FT-IR spectroscopy, 29Si-NMR and nitrogen adsorption measurements. The thermal analysis of the gels, in air and nitrogen, has clearly evidenced the chemical bonding of the studied diols with the Si-OH groups resulting from the hydrolysis of TEOS, forming hybrid gels. The mass loss registered on TG in the range 250-300 degrees C, corresponding to the burning of the organic chains from the hybrid network allowed us to calculate the fraction of the bonded diol. This fraction depends on the initial molar ratio TEOS:diol and on the diol's nature. By annealing the hybrid gels at 600 degrees C we have obtained silica matrices with different textural parameters. PMID- 24061243 TI - Synthesis and Crystal Structure of a Five-Coordinate Complex of Copper(II) with 4 Nitrobenzenesulfonate and 2, 2'-Bipyridine. AB - [Cu(bipy)2Cl](nbs) (1) (bipy = 2,2'-bipyridine, nbs = 4-nitrobenzenesulfonate) was obtained from the reaction of 4-nitrobenzenesulfonyl chloride and 2-amine-4 methylopyridine with CuCl2 in the presence of 2,2'-bipyridine and characterized by elemental analysis, IR spectra and X-ray single-crystal diffraction. The asymmetric unit of (1) contains the cationic complex [Cu(bipy)2Cl]+ and, in the outer coordination sphere, an (nbs)- counter ion. PMID- 24061244 TI - The Synthesis of Novel S-, S,S-, S,S,S-, S,O-, N,S-Substituted Halogenobuta-1,3 dienes. AB - In this work, thiosubstituted nitrodiene compounds (3, 4a, 5a,b, 6c, 7a, 7c, 9) were obtained from the reactions of some thiols with 2-nitropentachloro-1,3 butadiene. N,S-Substituted nitrodiene compounds (11a-g, 13, 15) were obtained from 2-nitropentachloro-1,3-butadiene and some amines (morpholine and piperazine derivatives). The compound 4a was crystallized in the triclinic crystal system (space group P-1) with the unit cell parameters a = 6.6525(7) A, b = 10.7906(5) A, c = 10.8339(4) A, alpha = 72.57(3) degrees , beta = 84.23(4) degrees , gamma = 75.81(3) degrees , V = 719.03(9) A3, Z = 2. The novel compounds were characterized by elemental analysis, UV-VIS, FT-IR, 1H-NMR, NMR (13C or APT) and mass spectroscopy. PMID- 24061245 TI - Immobilization of Glucose Oxidase in GLYMO/MTEOS Sol-Gel Film for Glucose Biosensor Application. AB - An electrochemical biosensor was developed by using the sol-gel coating solution. The modified platinum electrode used in the study was constructed by immobilization of glucose oxidase under a layer of sol-gel film. The coating solution was prepared by using GLYMO, and MTEOS. Electrochemical measurements were carried out amperometrically by determining hydrogen peroxide produced by the enzymatic reaction between glucose and glucose oxidase. It was observed that the amperometric response of the enzyme electrode was linear for glucose concentrations in the range from 2 to10 mM. The response time of the biosensor to reach a steady-state current value was approximately 80 s. The glucose selectivity of the biosensor was determined in the presence of some interfering substances, such as lactose, sucrose, urea, uric acid, oxalic acid, and ascorbic acid.It was observed that the interfering molecules did not cause any observable signal. The stability of the sensor was investigated, and it was found hat the initial sensor response decreased approximately 44% over a period of 30 days of storage in dry state at 4 degrees C. PMID- 24061246 TI - An experimental design approach to optimization of the liquid chromatographic separation conditions for the determination of metformin and glibenclamide in pharmaceutical formulation. AB - An optimization methodology is introduced for investigating the retention behavior and the separation factor of metformin, gliclazide (I.S.) and glibenclamide. This investigation has been focused on studying the influence of pH value of the mobile phase, concentration of acetonitrile and column temperature, which affect a complete separation of the chromatographic peaks of these compounds. The significant factors were optimized using full factorial design. Retention factor and separation factor were chosen as dependent variable. Optimum RP-LC chromatographic conditions for the separation of metformin, glibenclamide and gliclazide were obtained using X Terra column (150 mm * 4.6 mm I.D., 5 um). The results show that the percentage of acetonitrile are the most important to investigate and sspH of the mobile phase and column temperature do not significantly affect the experimental results. The procedure was validated for linearity, accuracy, precision and recovery. Quantitation was accomplished using internal standard method. PMID- 24061247 TI - Quantification of Isoxicam in the Presence of Related Compounds by TLC Densitometry. AB - A simple, sensitive, selective and precise TLC-densitometric determination of isoxicam as a drug was developed and validated. The method employed TLC aluminium plates precoated with silica gel 60 F254 as a stationary phase. The mobile phase consisted of ethyl acetate : toluene : butylamine (2:2:1, v/v/v). The system was found to give good resolution for isoxicam (RF value of 0.56). Densitometric detection was carried out at lambda = 350 nm. The calibration plots showed good linear relationship in the working concentration range of 0.7 to 2.2 ug per band. The method was validated for precision (RSD < 1%), specificity, limit of detection and quantitation (0.22 and 0.67 ug per band, respectively). The drug was subjected to acidic and basic hydrolysis at different temperatures. All the peaks of the degradation products were well-resolved from the isoxicam with significantly different RF values. The products formed were identified by their TLC retention times (RF values), absorption spectra and HPLC-MS/MS analysis. The developed TLC-densitometric method can be applied for identification and quantitation of isoxicam in drugs, and it can be using as a screening method in pharmaceutical research. As the TLC method can effectively separate the drug from its degradation products it can be employed as a stability-indicating one and can be utilized to investigate the kinetics of degradation process. PMID- 24061248 TI - Synthesis, Crystal Structure and Electrochemical Behavior of Two New Ni-based Complexes: [Ni2(ttpy)2(SCN)4] and [Ni(ttpy)2](CH3OH)2 (2I). AB - A simple synthetic procedure has been used to prepare two new nickel(II) complexes [Ni2(ttpy)2(SCN)4], (1) and [Ni(ttpy)2](CH3OH)2 (2I), (2) from 4'-p tolyl-2,2':6',2"-terpyridine (ttpy) ligand, potassium thiocyanate, and potassium iodide in good yields. The single crystal X-ray analyses reveal that the metals in these complexes are sixfold coordinated with M:L ratio of 1:1 and 1:2 for (1) and (2), respectively. In both complexes, the Ni(II) has distorted octahedral geometry including N5S and N6 environments. Versatile interactions in supramolecular level containing coordinative bonding, I***H, and N***H hydrogen bonding, pi-pi stacking play considerable roles in forming crystal packing of (1) and (2). From obtained data it is concluded that differences in coordination abilities, of used counterions, cause the formation of complexes with 1:1 or 1:2 ratio of metal and ligand. Electrochemical behaviors of the both complexes were investigated. PMID- 24061249 TI - Modified silica sol coatings for surface enhancement of leather. AB - The presented study reports on differently modified silica sols for coating applications on leather. Silica sols are prepared by acidic hydrolysis of tetraethoxysilane and modified by silane compounds with fluorinated and non fluorinated alkylgroups. In contrast to many earlier investigations regarding sol gel applications on leather, no acrylic resin is used together with the silica sols when applying on leather. The modified silica particles are supposed to aggregate after application, forming thus a modified silica coating on the leather substrate. Scanning electron microscopy investigation shows that the applied silica coatings do not fill up or close the pores of the leather substrate. However, even if the pores of the leather are not sealed by this sol gel coating, an improvement of the water repellent and oil repellent properties of the leather substrates are observed. These improved properties of leather by application of modified silica sols can provide the opportunity to develop sol gel products for leather materials present in daily life. PMID- 24061250 TI - Deposition of DLC Film on Stainless Steel Substrates Coated by Nickel Using PECVD Method. AB - Research on diamond-like carbon (DLC) films has been devoted to find both optimized conditions and characteristics of the deposited films on various substrates. In the present work, we investigate the quality of the DLC films grown on stainless steel substrates using different thickness of the nickel nanoparticle layers on the surface. Nickel nanoparticles were sputtered on the stainless steel substrates at 200 degrees C by a DC-sputtering system to make a good adherence between DLC coating and steel substrates. Atomic Force Microscopy was used to characterize the surface roughness and distribution function of the nickel nanoparticles on the substrate surface. Diamond like carbon films were deposited on stainless steel substrates coated by nickel using pure acetylene and C2H2/H2 with 15% flow ratio by DC-Plasma Enhanced Chemical Vapor Deposition (PECVD) systems. Microstructural analysis by Raman spectroscopy showed a low intensity ratio ID/IG for DLC films by increasing the Ni layer thickness on the stainless steel substrates. Fourier Transforms Infrared spectroscopy (FTIR) evidenced the peaks attributed to C-H bending and stretching vibration modes in the range of 1300-1700 cm-1 and 2700-3100 cm-1, respectively, in good agreement with the Raman spectroscopy and confirmed the DLC growth in all samples. PMID- 24061251 TI - Miniaturized membrane sensors for potentiometric determination of metoprolol tartrate and hydrochlorothiazide. AB - Four microsized graphite and platinum wire poly(vinyl chloride) matrix membrane electrodes responsive to some drugs affecting cardiovascular system, Metoprolol tartrate (MT) and Hydrochlorothiazide (HZ) were developed, described and characterized. These sensors were constructed by using (2-Hydroxypropyl)-beta cyclodextrin (2HP beta-CD) as an ionophore which has a significant influence on increasing both membrane sensitivity and selectivity. The four sensors were fabricated in a polymeric matrix of carboxylated polyvinyl chloride (PVC-COOH) and dioctylphthalate (DOP) as a plasticizer, based on the interaction between the drugs and the dissociated COOH groups in the PVC-COOH. Fast and stable Nernstian responses of 1.0 * 10-6-1.0 * 10-2 M for MT (sensors 1 and 2) and of 1.0 * 10-7 1.0 * 10-3 M for HZ (sensors 3 and 4) over pH range 3.0-9.0 and 3.0-7.0 for the MT and HZ sensors respectively were obtained. Nernstian slopes of 56.2, 54.6, 19.0 and 20.8 mV/decade for electrodes 1-4 respectively were observed. The proposed method displayed useful analytical characteristics for the determination of MT and HZ in their pure powder forms with average recoveries of 99.11 +/- 0.357, 99.21 +/- 0.389, 100.08 +/- 0.459 and 100.28 +/- 0.438% for sensors 1-4 respectively. The lower limit of detection (LOD) were 5.5 * 10-6, 4.5 * 10-6, 4.8 * 10-8 and 5.0 * 10-8 M for sensors 1-4 respectively indicated high sensitivity. The four sensors displayed a good stability over a period of 6 weeks. The selectivity coefficients of the developed sensors indicated excellent selectivity. Results obtained by the four electrodes revealed the performance characteristics of these electrodes which evaluated according to IUPAC recommendations. The method was successively applied for the determination of MT and HZ in presence of each other, in presence of Salamide (SA), the main degradation product of HZ, in their pharmaceutical formulations and in human plasma samples. Statistical comparison between the results obtained by this method and those obtained by the official methods of the drugs was done and no significant difference was found. PMID- 24061252 TI - Calculations of Diffusion Coefficients of Iron Salts in Aqueous Solutions at 298.15 K: A Useful Tool for the Knowledge of the Structure of these Systems. AB - Diffusion coefficients, thermodynamic and mobility factors of iron salts in aqueous solutions are estimated from Onsager-Fuoss model. The influence of the ion size parameter a, "mean distance of closest approach of ions", determined from different approaches, on the variation of diffusion coefficients with concentration, is also discussed. The aim of this work is to have a better understanding of the structure of these systems and of the thermodynamic behaviour of iron salts in aqueous media. PMID- 24061253 TI - Ionization of elements in medium power capacitively coupled argon plasma torch with single and double ring electrodes. AB - A medium power, low Ar consumption capacitively coupled plasma torch (275 W, 0.4 L min-1) with molybdenum tubular electrode and single or two ring electrodes in non-local thermodynamic equilibrium (LTE) was characterized with respect to its ability to achieve element ionization. Ionization degrees of Ca, Mg, Mn and Cd were determined from ionic-to-atomic emission ratio and ionization equilibrium according to Saha's equation. The ionization degrees resulted from the Saha equation were higher by 9-32% than those obtained from spectral lines intensity in LTE regime and closer to reality. A linear decrease of ionization with increase of ionization energy of elements was observed. Plasma torch with two ring electrodes provided higher ionization degrees (85 +/- 7% Ca, 79 +/- 7% Mn, 80 +/- 7% Mg and 73 +/- 8% Cd) than those in single ring arrangement (70 +/- 6% Ca, 57 +/- 7% Mn, 57 +/- 8% Mg and 42 +/- 9% Cd). The Ca ionization decreased linearly by up to 79 +/- 4% and 53 +/- 6% in plasma with two ring electrodes and single ring respectively in the presence of up to 400 ug mL-1 Na as interferent. The studied plasma was effective in element ionization and could be a potential ion source in mass spectrometry. PMID- 24061254 TI - A facile route to the synthesis of coated maghemite nanocomposites for hyperthermia applications. AB - CM-dextran-covered maghemite particles for applications in magnetic hyperthermia treatments were synthesized and their physical, magnetic and morphological properties were examined. Magnetic fluids were prepared and their heating properties in an alternating magnetic field were studied. The results reveal that the particle size and the thickness of the carboxy-methyl-dextran (CM-dextran) coatings have a decisive influence on the heating properties: specific absorption rate (SAR). The majority of the magnetic dissipation comes from the Neel relaxation, while the Brown contribution is small. A thermal steady state at the selected temperature (42 degrees C) can be achieved using synthesized maghemite particles with proper particle morphology and by controlling the magnetic field intensity or the frequency. PMID- 24061255 TI - Preparation and Characterization of a New Example of a Double Salt of Nickel(II) Complexes. AB - A new double salt of nickel(II) complexes, formulated as, [Ni(bipy)(H2O)4][Ni(H2O)6][Ni(pydc)2]2 * 6H2O, (1), (pydc = pyridine-2,6 dicarboxylate anion, bipy = 2,2'-bipyridine) has been hydrothermally synthesized. Complex was characterized by FT-IR spectroscopy, elemental analysis and X-ray diffraction studies. The compound 1 consists of [Ni(H2O)6]2+, [Ni(bipy)(H2O)4]2+, two symmetry-independent anionic complexes [Ni(pydc)2]2- and six co-crystallized water molecules. In the crystal structure of compound 1, the formation of extensive O-H...O hydrogen bonds between uncoordinated water molecules and cationic or anionic complexes play important roles in stabilizing the corresponding lattice and formation of 3-dimensional networks. PMID- 24061256 TI - Conversion and Estrogenicity of 17beta-estradiol During Photolytic/Photocatalytic Oxidation and Catalytic Wet-air Oxidation. AB - Estrogen 17beta-estradiol (E2), produced by human body and excreted into municipal wastewaters, belongs to the group of endocrine disrupting compounds that are resistant to biological degradation. The aim of this study was to assess the efficiency of E2 removal from aqueous solutions by means of catalytic wet-air oxidation (CWAO) and photolytic/photocatalytic oxidation. CWAO experiments were conducted in a trickle-bed reactor at temperatures up to 230 degrees C and oxygen partial pressure of 10 bar over TiO2 and Ru/TiO2 solids. Photolytic/photocatalytic oxidation was carried out in a batch slurry reactor employing a TiO2 P-25 (Degussa) catalyst under visible or UV light. HPLC analysis and yeast estrogen screen assay were used to evaluate the removal of E2 and estrogenicity of treated samples. The latter was completely removed during photolytic/photocatalytic oxidation under UV (365 nm) light and photocatalytic oxidation under visible light. In CWAO experiments, complete removal of both E2 and estrogenicity from the feed solution were noticed in the presence of TiO2 and Ru/TiO2 catalysts. PMID- 24061257 TI - Comparison of GC and OxiTop Analysis of Biogas Composition Produced by Anaerobic Digestion of Glucose in Cyanide Inhibited Systems. AB - The purpose of this study was to compare the composition of the biogas produced by the anaerobic degradation of glucose with or without the addition of cyanide (32.0 mg L-1) during the digestion process using the qualitative OxiTop method and the quantitative gas chromatography (GC). For the non-inhibited systems the biogas composition obtained from OxiTop was in good correlation with the results obtained using gas chromatography analysis. On the other hand, a great difference was observed for the biogas composition of the inhibited system. We have shown that the necessary assumption, when using the OxiTop method, that the residual gas after carbon dioxide elimination was only methane, was not accurate for the inhibited reaction system. PMID- 24061258 TI - Synthesis of New Series of Pyrazole and Imidazole Derivatives and their Antimicrobial Activity. AB - New series of pyrazole derivatives 3-(furan-2-yl)-4-(5-hydroxy-4H-pyrazol-3-yl)-N phenylbutanamide 1-5 and imidazole derivatives 3-(furan-2-yl)-3-(1H-imidazol-1 yl)-N-phenylpropanamide 6-10 were synthesized by the Mannich base method. Synthesized compounds 1-10 were confirmed by IR, 1H NMR, 13C NMR, Mass and elemental analysis and further screened for antimicrobial activity. PMID- 24061259 TI - Synthesis and Characterization of BINOL Based Axially Chiral Nitronyl Nitroxide Radicals. AB - Four novel axially chiral nitronyl nitroxides derived from S- or R-1,l'-bi-2 naphthol were synthesized and their crystal structures discussed. Circular dichroism spectra of these compounds showed significant Cotton effects between 200 and 400 nm, and also confirmed the optical activity of these enantiomers. The magnetic properties of the two pairs of nitronyl nitroxide radicals were characterized by magnetic susceptibility measurements. The results showed that in these four radicals exist antiferromagnetic interactions in all cases at low temperatures. PMID- 24061260 TI - Synergistic Extraction of Some Univalent Cations into Nitrobenzene by Using Sodium Dicarbollylcobaltate and Dibenzo-21-crown-7. AB - From extraction experiments and gamma-activity measurements, the exchange extraction constants corresponding to the general equilibrium M+ (aq) + 1*Na+ (nb) <-> 1*M+ (nb) + Na+ (aq) taking place in the two-phase water-nitrobenzene system (M+ = Li+, H+, NH+4, Ag+, K+, Rb+, Tl+, Cs+; 1 = dibenzo-21-crown-7; aq = aqueous phase, nb = nitrobenzene phase) were evaluated. Furthermore, the stability constants of the 1*M+ complexes in water - saturated nitrobenzene were calculated; they were found to increase in the series of H+ < Ag+ < Li+ < Cs+ < K+, Rb+ < NH+4 < Tl+. PMID- 24061261 TI - Experimental and theoretical study on the complexation of beauvericin with the ammonium cation. AB - From extraction experiments and gamma-activity measurements, the extraction constant corresponding to the equilibrium NH4+(aq) + NaL+ (nb) <-> NH4L+(nb) + Na+ (aq) taking place in the two-phase water-nitrobenzene system (L = beauvericin; aq = aqueous phase, nb = nitrobenzene phase) was evaluated as log Kex (NH4+, NaL+) = 1.5 +/- 0.1. Further, the stability constant of the NH4L+ complex in water-saturated nitrobenzene was calculated for a temperature of 25 degrees C as log betanb (NH4L+) = 4.6 +/- 0.2. Finally, by using quantum mechanical DFT calculations, the most probable structure of the NH4L+ cationic complex species was derived. In this complex having C3 symmetry, the ammonium cation NH4+ is bound by three strong linear hydrogen bonds to the three corresponding oxygen atoms of the parent beauvericin ligand L. The interaction energy of the resulting complex NH4L+ was found to be -828.8 kJ/mol, confirming the formation of the considered complex NH4L+. PMID- 24061262 TI - Solvent Extraction of Calcium into Nitrobenzene by Using an Anionic Ligand Based on Cobalt Bis(Dicarbollide) Anion with Covalently Bonded CMPO Function. AB - From extraction experiments and gamma-activity measurements, the exchange extraction constantcorresponding to the general equilibrium Ca2+(aq) + 2HL(nb) < > CaL2(nb) + 2H+(aq) taking place in the two-phase water-nitrobenzene (L- = anionic ligand based on cobalt bis(dicarbollide) anion with covalently bonded CMPO function; aq = aqueous phase, nb = nitrobenzene phase) was evaluated as log Kex (Ca2+, 2HL) = 0.0 +/- 0.1. Further, the stability constant of the electroneutral complex species CaL2 in water-saturated nitrobenzene was calculated for a temperature of 25 degrees C : log betanb (CaL2) = 11.0 +/- 0.2. PMID- 24061263 TI - Procedures for Preparation and Radiolabeling of a 3-Fluoropyrrolidine-Containing FDDNP Analog. AB - A novel FDDNP analog, namely 1-[6-(3-fluoropyrrolidin-1-yl)-2 naphthyl]ethylidenemalononitrile, was synthesized to probe the influence of the applied structural changes at the donor-side of the molecule on tau protein aggregate binding. Reported is also a synthetic procedure, which can be directly applied to the preparation of the [18F]-radiolabeled compound. PMID- 24061264 TI - Direct spectrophotometric determination of hesperidin in pharmaceutical preparations. AB - A simple, rapid and reliable direct spectrophotometric method for the determination of hesperidin is proposed and validated. The influence of wavelength, solvent, the ionic strength, pH and temperature on hesperidin determination were investigated. Under the optimum conditions, lambda = 283 nm, 60% methanol as the solvent, ionic strength, I = 2.5 * 10-5 mol L-1, pH = 6.4 and T = 37.0 degrees C, the Beer's law is obeyed in the concentration range 1.83 24.5 ug mL-1. The molar absorptivity and Sandells sensitivity were found to be 1.8 * 104 L mol-1 cm-1 and 0.03 ug cm-2, respectively. The sensitivity of the proposed method was 0.9 ug mL-1 (as limit of detection) and 3.2 ug mL-1 (as limit of quantification). Applicability of the proposed method to the direct determination of total flavonoids as hesperidin equivalents in pharmaceutical formulation (Vitamin C with citrus bioflavonoids & Rose Hips) was demonstrated. Although the presence of ascorbic acid may cause problem in identification and measurements, hesperidin has been determined successfully. PMID- 24061265 TI - Health insurance status and the care of nursing home residents with advanced dementia. AB - IMPORTANCE: Nursing home residents with advanced dementia commonly experience burdensome and costly hospitalizations that may not extend survival or improve the quality of life. Fragmentation in health care has contributed to poor coordination of care for acutely ill nursing home residents. OBJECTIVE: To compare patterns of care and quality outcomes for nursing home residents with advanced dementia covered by managed care with those covered by traditional fee for-service Medicare. DESIGN, SETTING, AND PARTICIPANTS: Choices, Attitudes, and Strategies for Care of Advanced Dementia at the End-of-Life (CASCADE) was a prospective cohort study including 22 nursing homes in the Boston, Massachusetts, area that monitored 323 nursing home residents for 18 months to better understand the course of advanced dementia at or near the end of life. Data from CASCADE and Medicare were linked to determine the health insurance status of study participants. EXPOSURES: The health insurance status of the resident, either managed care or traditional fee for service. MAIN OUTCOMES AND MEASURES: The outcomes included survival, symptoms related to comfort, treatment of pain and dyspnea, presence of pressure ulcers, presence of a do-not-hospitalize order, treatment of pneumonia, hospital transfer (admission or emergency department visit) for an acute illness, hospice referral, primary care visits, and family satisfaction with care. RESULTS: Residents enrolled in managed care (n = 133) were more likely to have do-not-hospitalize orders compared with those in traditional Medicare fee for service (n = 158) (63.7% vs 50.9%; adjusted odds ratio, 1.9; 95% CI, 1.1-3.4), were less likely to be transferred to the hospital for acute illness (3.8% vs 15.7%; adjusted odds ratio, 0.2; 95% CI, 0.1-0.5), had more primary care visits per 90 days (mean [SD], 4.8 [2.6] vs 4.2 [5.0]; adjusted rate ratio, 1.3; 95% CI, 1.1-1.6), and had more nurse practitioner visits (3.0 [2.1] vs 0.8 [2.6]; adjusted rate ratio, 3.0; 95% CI, 2.2-4.1). Survival, comfort, and other treatment outcomes did not differ significantly across groups. CONCLUSIONS AND RELEVANCE Medicare managed-care programs may offer a promising approach to ensure that nursing homes are able to provide appropriate, less burdensome, and affordable care, especially at the end of life. PMID- 24061266 TI - CT texture analysis using the filtration-histogram method: what do the measurements mean? AB - Analysis of texture within tumours on computed tomography (CT) is emerging as a potentially useful tool in assessing prognosis and treatment response for patients with cancer. This article illustrates the image and histological features that correlate with CT texture parameters obtained from tumours using the filtration-histogram approach, which comprises image filtration to highlight image features of a specified size followed by histogram analysis for quantification. Computer modelling can be used to generate texture parameters for a range of simple hypothetical images with specified image features. The model results are useful in explaining relationships between image features and texture parameters. The main image features that can be related to texture parameters are the number of objects highlighted by the filter, the brightness and/or contrast of highlighted objects relative to background attenuation, and the variability of brightness/contrast of highlighted objects. These relationships are also demonstrable by texture analysis of clinical CT images. The results of computer modelling may facilitate the interpretation of the reported associations between CT texture and histopathology in human tumours. The histogram parameters derived during the filtration-histogram method of CT texture analysis have specific relationships with a range of image features. Knowledge of these relationships can assist the understanding of results obtained from clinical CT texture analysis studies in oncology. PMID- 24061267 TI - A variant (rs932335) in the HSD11B1 gene is associated with colorectal cancer in a Chinese population. AB - Glucocorticoid hormones have been reported to contribute to the regulation of cellular proliferation and differentiation and to inhibit the growth of cells in several colon tumors and adenocarcinoma cell lines. As a regulator of glucocorticoid levels, type I isoform HSD11B1 is a bidirectional enzyme but acts predominantly as an oxidoreductase to yield active glucocorticoids, cortisol or corticosterone. To date, studies investigating the associations between the polymorphisms of HSD11B1 and the risk for cancer have shown inconclusive results. In our study, we aimed to investigate whether the polymorphisms of HSD11B1 may influence the genetic susceptibility to colorectal cancer (CRC) in a Chinese population. Four single-nucleotide polymorphisms of HSD11B1 (rs846910 G/A, rs11807619 G/T, rs932335 C/G, and rs13306421 G/A) were detected using a PCR ligase detection reaction in a case-control study comprising 110 CRC patients and 118 controls. Logistic regression was used to evaluate genetic associations with the occurrence of CRC. Real-time PCR was used to test the mRNA expression of HSD11B1 in 18 CRC tissues. The frequencies of the rs932335 GC genotype were significantly higher among the patients compared with controls (P=0.019). Compared with individuals carrying the GG genotype, individuals with the GC/CC genotype had a significantly increased susceptibility to CRC occurrence (odds ratio=2.23, 95% confidence interval=1.27-3.94, P=0.008). In cancer tissues, patients carrying the GG genotype also displayed an increased mRNA level of HSD11B1 (P=0.019). These results suggested that the HSD11B1 rs932335 G/C polymorphism had an effect on CRC occurrence. These findings also suggest that the functional polymorphism rs932335 in intron4 of HSD11B1 may influence the susceptibility to and progression of CRC in a Chinese population. Large population-based prospective studies are required to validate our findings. PMID- 24061268 TI - Age-period-cohort effect on lung cancer mortality in southern Spain. AB - The aim of this study was to evaluate the age-period-cohort effects on lung cancer mortality in Andalusia (southern Spain) as a whole as well as in each of its eight provinces during the period between 1981 and 2008. A population-based ecological study was conducted. In all, 74 255 deaths from lung cancer were analysed for individuals aged between 40 and 84 years who died in Andalusia during the period of study. A nonlinear regression model was estimated for both sexes and each geographical area. The effects of age, year of death and birth cohort were parameterized using B-spline smoothing functions. There is an upward trend in mortality by age until around the age of 75 years, from which point the trend turns downwards for men and remains stable for women. The analysis of the cohort effect revealed a steady fall in the lung cancer mortality risk for male generations born after 1950. The mortality risk for women is increasing for the generations born after 1932. The death rates for men declined from 1995 until the end of the study period. For women, the death rates increased from the end of the 1990s. There is a similar age-period-cohort effect on lung cancer mortality in all the provinces of Andalusia and for Andalusia as a whole. If the current trends continue, it can be expected that these effects will continue to reduce male mortality and increase female mortality. PMID- 24061269 TI - Hepatitis B and pancreatic cancer. PMID- 24061271 TI - Temporal changes in pneumococcal colonization in a rural African community with high HIV prevalence following routine infant pneumococcal immunization. AB - BACKGROUND: Pneumococcal conjugate vaccine (PCV) immunization of children decreases their risk of nasopharyngeal acquisition of vaccine serotypes. We studied the impact of routine infant PCV immunization alone on the epidemiology of nasopharyngeal pneumococcal colonization among a rural African community with high prevalence of HIV positivity. METHODS: Two cross-sectional surveys were undertaken in a rural South African community from May to October 2009 (period 1) and 2011 (period 2). Seven-valent PCV was introduced into the public immunization program for infants in April 2009, without catch-up campaign for older children. Randomly selected households with at least 1 child<2 years of age were recruited. Nasopharyngeal swabs from all consenting household members were obtained for Streptococcus pneumoniae culture and serotyping by Quellung method. RESULTS: The median ages (SD) of children enrolled were 4.32 (SD, 3.4) and 3.80 (SD, 3.4) years in periods 1 and 2, respectively. Overall, the prevalence of vaccine serotype colonization declined from 18.3% (368/2010) in period 1 to 11.4% (418/3659) by period 2 (P<0.0001). This included reductions (adjusted risk ratio) of 50% [95% confidence interval (95% CI): 0.42-0.59], 34% (95% CI: 0.48-0.92) and 64% (95% CI: 0.18-0.74) in age groups<2 years, 6-12 years and adults. The prevalence of vaccine serotype colonization among primary caregivers decreased from 10.2% to 5.4% (P<=0.001) by period 2. The prevalence of nonvaccine serotype colonization increased by 35% (95% CI: 1.17-1.56) among <2-year-old children by period 2, while it declined by 45-54% among adolescents and adults. CONCLUSIONS: An indirect effect of PCV7 was realized in a high HIV prevalence setting within 2 years of PCV introduction. The unexpected decline in nonvaccine serotypes colonization among adolescents/adults may indicate lag in replacement colonization by nonvaccine serotypes in this group. PMID- 24061274 TI - Characteristics of vaccine failures in a randomized placebo-controlled trial of inactivated influenza vaccine in children. AB - BACKGROUND: Infections occurring among vaccinated persons (vaccine failures) are known to occur in vaccines with imperfect efficacy. Failures among vaccinated children who were infected with vaccine-matched influenza B virus strain have not been adequately characterized. METHODS: Taking advantage of a randomized controlled trial of trivalent seasonal influenza vaccine (TIV), the viral shedding and clinical symptoms associated with reverse transcriptase polymerase chain reaction-confirmed influenza B infection and serum hemaggluttination inhibiting antibody response to vaccine were compared between children 6 and 17 years receiving TIV and placebo. RESULTS: Vaccine failures were observed to show lower antibody response to TIV compared with other vaccine recipients. We did not find any evidence that vaccination reduced the severity or duration of clinical symptoms of reverse transcriptase polymerase chain reaction-confirmed vaccine matched influenza B infections. Vaccination was not observed to alter viral load or shedding duration. CONCLUSIONS: TIV was not observed to ameliorate clinical symptoms or viral shedding among vaccine failures compared with infected placebo recipients. Lower antibody response might have explained vaccine failure and also lack of effect in reducing clinical symptoms and viral shedding upon infection. Our results are based on a randomized controlled trial of split virus inactivated vaccine and may not be applicable to other vaccine types. Further studies in vaccine failure among children will be important in future vaccine development. PMID- 24061276 TI - Tissue Doppler septal Tei index indicates severity of illness in pediatric patients with congestive heart failure. AB - The Doppler Tei index is an independent predictor of outcomes in adult heart failure. Tissue Doppler imaging (TDI) may be a superior method to measure the Tei index in children because it is less affected by heart rate variability. We hypothesized that the TDI Tei index reflects severity of illness in pediatric heart failure. Twenty-five pediatric heart failure patients were prospectively enrolled. Listing for heart transplantation or death were the outcomes used to define severity of illness. Baseline demographics, brain natriuretic peptide (BNP), and standard echocardiographic and TDI-derived parameters were analyzed to determine outcome indicators. Ten of the 25 patients (40%) were listed for transplantation. There were no deaths. Multivariate analysis combining age, heart rate, standard echocardiographic parameters, and BNP resulted in shortening fraction (p = 0.002) as the best indicator of listing for transplantation (R(2) = 0.32). A second multivariate analysis combining age, heart rate, TDI parameters, and BNP resulted in age (p = 0.03) and septal Tei index (p = 0.03) as the best predictive model (R(2) = 0.36). The area under the receiver operating characteristic (ROC) curve for septal Tei index was 0.84 (95% confidence interval = 0.64-0.96,), and it was comparable with the ROC curve for shortening fraction, p = 0.76. Optimal values of sensitivity (100%) and specificity (60%) were obtained with septal Tei index values >0.51. The TDI septal Tei index is an indicator of disease severity in pediatric heart failure patients and offers potential advantages compared with standard echocardiographic measures of left ventricular ejection. PMID- 24061277 TI - Growth in medicare expenditures for patients with acute myocardial infarction: a comparison of 1998 through 1999 and 2008. AB - IMPORTANCE: Medicare expenditures continue to grow rapidly, but the reasons are uncertain. OBJECTIVE: To compare expenditures from 1998 through 1999 and 2008 for Medicare beneficiaries hospitalized for acute myocardial infarction (AMI). DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of a random 20% sample of fee-for-service Medicare beneficiaries admitted with AMI from 1998 through 1999 (n = 105,074) and a 100% sample for 2008 (n = 212,329). MAIN OUTCOMES AND MEASURES: Per-beneficiary expenditures, standardized for price and adjusted for risk and inflation. Expenditures were measured across 4 periods: overall (index admission to 1 year), index (within the index admission), early (postindex admission to 30 days), and late (31-365 days). RESULTS Compared with the subjects from 1998 through 1999, those in 2008 were older and had more comorbidities but slightly less ischemic heart disease and cerebrovascular disease. Although there was a 19.2% decline in the rate of hospitalizations for AMI, overall expenditures per patient increased by 16.5% (absolute difference, $6094). Of the total risk-adjusted increase in expenditures, 25.6% occurred within 30 days (22.0% attributed to the index admission), and 74.4% happened 31 to 365 days after the index admission. Spending per beneficiary within 30 days increased by $1560 (7.5%), and spending between 31 and 365 days increased by $4535 (28.0%). Expenditures for skilled nursing facilities, hospice, home health agency, durable medical equipment, and outpatient care nearly doubled 31 to 365 days after admission. Mortality within 1 year declined from 36.0% in 1998 through 1999 to 31.7% in 2008; of the decline, 3.3% was in the 30 days following admission, and 1.0% was in days 31 to 365. CONCLUSIONS AND RELEVANCE: Between 1998 and 2008, Medicare expenditures per patient with an AMI substantially increased, with about three-fourths of the increase in expenditures occurring 31 to 365 days after the date of hospital admission. Although current bundled payment models may contain expenditures within 30 days of an AMI, they do not contain spending beyond 30 days. PMID- 24061278 TI - Modern methods to interrogate microtubule dynamics. AB - Microtubules are essential protein filaments required to organize and rearrange the interior of the cell. They must be stiff with mechanical integrity to support the structure of the cell. Yet, they must also be dynamic to enable rearrangements of the cell during cell division and development. This dynamic nature is inherent to microtubules and comes about through the hydrolysis of chemical energy stored in guanosine triphosphate (GTP). Dynamic instability has been studied with a number of microscopy techniques both in cells and in reconstituted systems. In this article, we review the techniques used to examine microtubule dynamic instability and highlight future avenues and still open questions about this vital and fascinating activity. PMID- 24061280 TI - Complex regional pain syndrome involving the face following snowball injury. AB - Complex regional pain syndrome (CRPS) is a condition of unknown etiology characterized by autonomic, sensory, and motor disturbance. CRPS usually follows an injury in the affected limb, which is often trivial in nature. CRPS involving the facial region is rare, and there have been no previous descriptions in children. We describe a 13-year-old girl with CRPS involving the face, which developed after being struck by a snowball. The clinical characteristics were similar to those of CRPS elsewhere in the body involving burning pain, hyperalgesia, and hyperesthesia. This was later accompanied by skin edema, fluctuating color, and temperature changes, as well as loss of eyebrow hair. Following detailed but inconclusive investigations, a clinical diagnosis of CRPS was made in line with Budapest diagnostic criteria. Over the next year, her condition gradually improved with ongoing comprehensive multidisciplinary input. We present this patient to alert clinicians to consider CRPS in the differential diagnosis of similar cases who present with chronic facial pain and skin changes. PMID- 24061279 TI - ActiTrainer-determined segmented moderate-to-vigorous physical activity patterns among normal-weight and overweight-to-obese Czech schoolchildren. AB - This study uncovered the patterns of moderate-to-vigorous physical activity (MVPA) in normal-weight and overweight/obese children before, during, and after school lessons. ActiTrainer-based MVPA was assessed over 2 school days (with and without a physical education lesson [PEL] in a sample of three hundred thirty eight 9- to 11-year-old children (50.3 % female; 29.6 % overweight/obese), in the Czech Republic, during spring 2012. MVPA was quantified based on the step count (number), MVPA duration, and MVPA heart-rate response (minutes). No differences in the MVPA based on the time during the school day were confirmed in normal weight versus overweight/obese girls, whereas normal-weight boys significantly exceed their overweight/obese peers in step count and after-school and daylong MVPA. Active participation in PEL contributes to a significantly higher step count, exercise duration, and MVPA heart-rate response in normal-weight and overweight/obese boys (p < 0.001) and normal-weight (p < 0.001) and overweight/obese (p < 0.04) girls during school time. Moreover, active participation in PEL significantly (p < 0.04) increases the overall daily step count, duration, and MVPA heart-rate response in normal-weight boys and overweight/obese girls. Active exercise during PEL accounted for 16.7 % of the total number of steps, 25.1 % of overall MVPA duration, and 24.1 % of the MVPA heart-rate response in 9- to 11-year-old children. During days with a PEL, a significantly (p < 0.02) higher number of overweight/obese girls and a higher number of normal-weight boys achieved the duration of 60 min/day of MVPA compared with days without a PEL. CONCLUSION: Adding one PEL or an equivalent amount of MVPA to the daily school routine appears to be a promising strategy to effectively increase daily MVPA, particularly among overweight/obese girls. PMID- 24061281 TI - Deep peroneal nerve palsy during growth spurt: a case report. AB - Peripheral nerve injuries may have a number of causes, most commonly mechanical. We describe a case of a deep peroneal nerve palsy in an adolescent boy which coincided with a large growth spurt. Spontaneous recovery of full function was seen without intervention. CONCLUSION: In the absence of any other causative factors, we believe that this growth spurt resulted in temporary compression of the deep peroneal nerve at the level of the knee producing transient neurapraxia. PMID- 24061283 TI - Effect of different substituents on the water-solubility and stability properties of 1 : 2 [60]fullerene derivative.gamma-cyclodextrin complexes. AB - We have demonstrated that C60 derivatives bearing a pyrrolidine moiety as well as a variety of other substituents can form 1 : 2 complexes with gamma-cyclodextrin (gamma-CDx) using a mechanochemical high-speed vibration milling apparatus. When the influence of the steric hindrance of the substituents on the formation of the complexes was negligible, the water-solubilities of the complexes were shown experimentally to be completely dependent on the hydrophobic properties of the substituent. Furthermore, the stabilities of the gamma-CDx-complexes of several different C60 derivatives were found to be similar to or slightly higher than that of the C60.gamma-CDx complex, with the solubilities of the complexes showing no correlation to the stabilities. Based on the results of a series of theoretical investigations, we have shown that the stabilities of the gamma-CDx complexes can be affected not only by steric effects but also by the polarities of the substituent groups, which exist in the vicinity of the upper rim of gamma CDx, because the water bound to the polar group can assist in the stabilisation of the complexes. PMID- 24061282 TI - Efficacy and limitations of a STEMI network: 3 years of experience within the myocardial infarction network of the region of Augsburg - HERA. AB - AIMS: The HERA Registry investigates logistics, adherence to standards, time intervals, and mortality in a regional network for primary percutaneous coronary intervention (PPCI) in ST-elevation myocardial infarction (STEMI) in a mixed urban and rural area. METHODS AND RESULTS: We included 826 consecutive patients (pts) within the HERA network with its dedicated PPCI strategy (female n = 243, mean age 64 years, range 25-98 years) with acute STEMI (May 2007 until January 2010). 680 pts (82 %) received PPCI and 45 (5.4 %) acute bypass surgery. Of 512 pts seen by an emergency physician (EP) as first medical contact (FMC) 87 % received on-scene 12-lead ECG. ECG transmission rate to the PPCI center was 29 %. Median FMC-to-balloon time (CBT) was 135 min and door-to-balloon time (DBT) 70 min. With EP FMC DBT was 38 min with direct transfer to cath lab (n = 70), 69 min via ICU (n = 240), and 132 min via ER (n = 91, p < 0.01). Out of 826 pts, 143(17.3 %) presented in cardiogenic shock. In-hospital mortality was 8.8 % (n = 73), 35.7 % for shock pts versus 3.2 % for non-shock pts (p < 0.01). For pts receiving PPCI, in-hospital mortality was 6.2 %, for shock pts (n = 107) 28.0 %, and for non-shock pts (n = 573) 2.1 % (p < 0.01). CONCLUSION: Prehospital management, CBT and DBT compare favourably to data from studies and registries, but do not yet fulfill strict guideline requirements. Real world mortality in non shock pts is very low. Direct transfer to cath lab reduces DBTs by 49 %. For this crucial improvement, transmission of a 12-lead ECG to the PPCI center is mandatory. PMID- 24061285 TI - A pilot study of a modified radiographic technique for detecting early proximal cavities. AB - Diagnosing the necessity of cavity preparation in demineralized proximal areas has been considered as a challenge in restorative treatment planning. The purpose of this study was to investigate the clinical performance of a modified radiographic technique for the detection of proximal cavities. The sample consisted of 44 proximal surfaces in 38 dental students. The patients had radiolucent proximal lesions restricted to the inner half of enamel or the outer third of dentine in bitewing radiographs, and there was doubt regarding the presence or absence of cavities in the approximal areas. The suspected surfaces were then examined by secondary bitewing radiographs which were taken after pressing radiopaque material into the proximal areas. Finally, orthodontic elastic separators were placed in the contact areas to provide enough space for direct visual and tactile examination, thus detecting any proximal cavity (reference standard). The sensitivity, specificity and accuracy of the modified bitewing radiography were calculated against the reference standard. Overall, 7 surfaces presented caries cavities according to the reference standard. All proximal radiolucencies observed in the inner half of enamel and 46% of those extended to the outer third of dentine were not cavitated when evaluated by direct visual and tactile examination. The sensitivity, specificity and accuracy of bitewing radiography with opaque material for detecting proximal cavities (n = 7) were 86, 100 and 98%, respectively. The tested radiographic technique displayed good validity in this pilot study for detecting proximal cavities in posterior teeth and should be further investigated. PMID- 24061286 TI - Auto-antibodies to vascular endothelial cadherin in humans: association with autoimmune diseases. AB - To identify patients with autoimmune diseases who are at high risk of developing vascular cell dysfunction, early biomarkers must be identified. This study was designed to detect and characterize circulating autoantibodies to VE-cadherin (AAVEs) in patients with early-stage autoimmune diseases. An enzyme-linked immunosorbent assay (ELISA) was developed to capture autoantibodies, using a recombinant human VE-cadherin fragment covering the extracellular domains as a target antigen. AAVEs specificity for the target antigen was confirmed by western blotting. Basal AAVEs levels were determined for healthy donors (n=75). Sera from patients (n=100) with various autoimmune diseases, including rheumatoid arthritis (n=23), systemic lupus erythematosus (SLE, n=31), systemic sclerosis (n=30), and Behcet's disease (BD, n=16) were also tested. Levels of AAVEs were significantly higher in rheumatoid arthritis (P<0.0001), SLE (P<0.05), and BD (P<0.05) populations than in healthy subjects. Purified immunoglobulin G (IgG) from a BD patient with exceptionally high AAVEs levels recognized the EC1-4 fragment in western blots. Further characterization of the epitopes recognized by AAVEs showed that BD patients had antibodies specific for the EC3 and EC4 domains, whereas SLE patients preferentially recognized the EC1 fragment. This suggests that distinct epitopes of human VE-cadherin might be recognized in different immune diseases. Purified IgG from BD patients was found to induce endothelial cell retraction, redistribution of VE-cadherin, and cause the formation of numerous intercellular gaps. Altogether, these data demonstrate a potential pathogenic effect of AAVEs isolated from patients with dysimmune disease. This is the first description of AAVEs in humans. Because regions EC1 and EC3-4 have been shown to be involved in homophilic VE-cadherin interactions, AAVEs produced in the course of dysimmune diseases might be specific biomarkers for endothelial injury, which is part of the early pathogenicity of these diseases. PMID- 24061287 TI - Role of cysteinyl-leukotrienes for portal pressure regulation and liver damage in cholestatic rat livers. AB - Kupffer cells (KCs) have a major role in liver injury, and cysteinyl-leukotrienes (Cys-LTs) are known to be involved as well. The KC-mediated pathways for the production and secretion of Cys-LT in cholestatic liver injury have not yet been elucidated. Here, we hypothesized that KC activation by Toll-like receptor ligands results in Cys-LT-mediated microcirculatory alterations and liver injury in acute cholestasis. We hypothesized further that this situation is associated with changes in the secretion and production of Cys-LT. One week after bile duct ligation (BDL), livers showed typical histological signs of cholestatic liver injury. Associated microcirculatory disturbances caused increased basal and maximal portal pressure following KC activation. These differences were determined in BDL livers compared with sham-operated livers in vivo (KC activation by LPS 4 mg/kg b.w.) and in isolated perfused organs (KC activation by Zymosan A, 150 MUg/ml). Treatment with the 5-lipoxygenase inhibitor MK-886 alone did not alter portal perfusion pressure, lactate dehydrogenase (LDH) efflux, or bile duct proliferation in BDL animals. Following KC activation, portal perfusion pressure increased. The degree of cell injury was attenuated by MK-886 (3 MUM) treatment as estimated by LDH efflux. In normal rats, a large amount of Cys-LT efflux was found in the bile. Only a minor amount was found in the effluent perfusate. In BDL livers, the KC-mediated Cys-LT efflux into the sinusoidal system increased, although the absolute Cys-LT level was still grossly lower than the biliary excretion in sham-operated livers. In conclusion, our results indicate that treatment with Cys-LT inhibitors might be a relevant target for attenuating cholestatic liver damage. PMID- 24061288 TI - Pathophysiologic mechanisms in septic shock. AB - The systemic inflammatory response that occurs in the septic patient as a result of an infectious insult affects multiple organs and systems, causing numerous physiological derangements. Alterations in phagocytic, lymphocytic and endothelial cell function and immune regulation are evident, leading to heterogeneity in a host's response to a septic challenge. In addition, the normal hemostatic balance shifts toward a procoagulant state through alterations in tissue factor, antithrombin, protein C and the inhibition of fibinolysis, which can result in thrombus formation and paradoxical hemostatic failure. In an effort to diagnose sepsis and predict outcomes, biomarkers such as C-reactive protein, pro-calcitonin, pro- and anti-inflammatory cytokines have been investigated with varying results. Targeted therapies for sepsis, most notably Xigris (recombinant human activated protein C), have proven unsuccessful and treatment continues to remain reliant on source control, antibiotics and supportive interventions, specifically early goal-directed therapy. This brief review gives an overview of the immunopathologic and coagulopathic alterations that occur in sepsis, soluble inflammatory mediators as potential diagnostic and prognostic biomarkers, and the clinical management of the septic patient. PMID- 24061290 TI - Acute kidney injury: renal hazards of anticoagulant therapy. PMID- 24061289 TI - Evaluation of the effect of respiratory and anatomical variables on a Fourier technique for markerless, self-sorted 4D-CBCT. AB - A novel technique based on Fourier transform theory has been developed that directly extracts respiratory information from projections without the use of external surrogates. While the feasibility has been demonstrated with three patients, a more extensive validation is necessary. Therefore, the purpose of this work is to investigate the effects of a variety of respiratory and anatomical scenarios on the performance of the technique with the 4D digital extended cardiac torso phantom. FT-phase and FT-magnitude methods were each applied to identify peak-inspiration projections and quantitatively compared to the gold standard of visual identification. Both methods proved to be robust across the studied scenarios with average differences in respiratory phase <10% and percentage of projections assigned within 10% of the gold standard >90%, when incorporating minor modifications to region-of-interest (ROI) selection and/or low-frequency location for select cases of DA and lung percentage in the field of view of the projection. Nevertheless, in the instance where one method initially faltered, the other method prevailed and successfully identified peak-inspiration projections. This is promising because it suggests that the two methods provide complementary information to each other. To ensure appropriate clinical adaptation of markerless, self-sorted four-dimensional cone-beam CT (4D-CBCT), perhaps an optimal integration of the two methods can be developed. PMID- 24061296 TI - Probing the Temperature Unfolding of a Variety of DNA Secondary Structures Using the Fluorescence Properties of 2-aminopurine. AB - The fluorescence probe 2-aminopurine (2AP) is widely used to monitor the molecular environment, including the local solvent environment, and overall dynamics of nucleic acids and nucleic acid-ligand complexes. This work reports on the temperature-induced conformational flexibility of a variety of secondary structures of nucleic acids using optical and calorimetric melting techniques, and evaluates the usefulness of fluorescence melting curves obtained from monitoring the fluorescence changes of 2AP as a function of temperature. Furthermore, the base stacking properties of 2AP are examined in these structures for a first time. Specifically, we incorporated single A -> 2AP substitutions into a variety of DNA structures, such as a single strand (SS), a dodecamer duplex (Duplex), a hairpin loop (Hairpin), a G-quadruplex (G2), and an intramolecular triplex (Triplex). A combination of fluorescence, UV, and circular dichroism spectroscopies, and differential scanning calorimetric (DSC) techniques is used to investigate their temperature-induced unfolding. The melting curves of each molecule show monophasic transitions with similar TMs and van't Hoff enthalpies indicating that all transitions are two-state and that the fluorescence changes for the unstacking of 2AP follow the unfolding of the whole molecule. The DSC thermodynamic profiles of each 2AP modified molecule, relative to their unmodified control molecules, yielded folding DeltaDeltaG degrees s of 1.6 kcal/mol (Duplex), 3.1 kcal/mol (Hairpin), 1.6 kcal/mol (Triplex), and -1.7 kcal/mol (G2). These DeltaDeltaG degrees s are driven by unfavorable differential enthalpies (Duplex and Hairpin), favorable differential enthalpy (G2), and by a favorable differential entropy term for Triplex. These enthalpy effects are explained in terms of stacking and hydration contributions, that are associated with the local environment that 2AP is experiencing. For example, the lower DeltaDeltaHcal value of 8.7 kcal/mol (Hairpin), relative to Duplex, is due to weaker base-pair stacks and higher hydration state of the stem of Hairpin. We conclude that the incorporation of 2AP in nucleic acids is a useful tool to monitor their temperature-induced unfolding; especially, when these sensitive fluorescent moieties are placed in the proper molecular environment of the nucleic acid. PMID- 24061295 TI - Early child development and exposure to antiepileptic drugs prenatally and through breastfeeding: a prospective cohort study on children of women with epilepsy. AB - IMPORTANCE: Exposure to antiepileptic drugs during pregnancy is associated with adverse effects on psychomotor development. OBJECTIVES: To determine whether signs of impaired development appear already during the first months of life in children exposed prenatally to antiepileptic drugs, and to explore potential adverse effects of antiepileptic drug exposure through breastfeeding. DESIGN, SETTING, AND PARTICIPANTS: Mothers at 13 to 17 weeks of pregnancy were recruited in the population-based, prospective Norwegian Mother and Child Cohort Study from 1999 to 2009. The mothers reported on their child's motor and social skills, language, and behavior using items from standardized screening tools at 6 months (n = 78,744), 18 months (n = 61,351), and 36 months (n = 44,147) of age. The mothers also provided detailed information on breastfeeding during the first year. MAIN OUTCOMES AND MEASURES The risk of adverse development in children according to maternal or paternal epilepsy was estimated as the odds ratio with corresponding 95% confidence interval, adjusted for maternal age, parity, education, smoking, breastfeeding, depression/anxiety, folate supplementation, and congenital malformation in the child. RESULTS: At age 6 months, infants of mothers using antiepileptic drugs (n = 223) had a higher risk of impaired fine motor skills compared with the reference group (11.5% vs 4.8%, respectively; odds ratio = 2.1; 95% CI, 1.3-3.2). Use of multiple antiepileptic drugs compared with the reference group was associated with adverse outcome for both fine motor skills (25.0% vs 4.8%, respectively; odds ratio = 4.3; 95% CI, 2.0-9.1) and social skills (22.5% vs 10.2%, respectively; odds ratio = 2.6; 95% CI, 1.2-5.5). Continuous breastfeeding in children of women using antiepileptic drugs was associated with less impaired development at ages 6 and 18 months compared with those with no breastfeeding or breastfeeding for less than 6 months. At 36 months, prenatal antiepileptic drug exposure was associated with adverse development regardless of breastfeeding status during the first year. Children of women with epilepsy who did not use antiepileptic drugs and children of fathers with epilepsy had normal development at 6 months. CONCLUSIONS AND RELEVANCE: Prenatal exposure to antiepileptic drugs was associated with impaired fine motor skills already at age 6 months, especially when the child was exposed to multiple drugs. There were no harmful effects of breastfeeding. Women with epilepsy should be encouraged to breastfeed their children irrespective of antiepileptic drug treatment. PMID- 24061297 TI - Chromatographic Enantiomer Separation Using 9-Amino-9-(deoxy)-epiquinine-derived Chiral Selectors: Control of Chiral Recognition via Introduction of Additional Stereogenic Centers. AB - Three new cinchona-type chiral selectors have been prepared by attaching N pivaloyl-glycine, N-pivaloyl-(S)-valine and N-pivaloyl-(R)-valine segments to the C9-amino function of 9-amino-9-(deoxy)-epiquinine (eAQN), and immobilized to silica to provide the corresponding chiral stationary phases (CSPs). Evaluation of the chromatographic enantioseparation characteristics of these CSPs with a broad assortment of N-carbamoyl protected amino acids under polar organic mobile phase conditions revealed modest chiral recognition capabilities for N-Fmoc-, N Cbz- and N-Boc-derivatives. It was found that the enantioselective analyte binding to these CSPs is strictly controlled by the absolute stereo-chemistry of the amino acid functionalities attached to the C9-amino group of the eAQN framework. Specifically, the CSP derived from (S)-valine-based selector exhibits preferential binding of N-carbamoyl-(S)-amino acids, while the CSPs featuring (R) valine- and the glycine-derived selectors show opposite enantioselective binding preference. The observed impact of analyte structure on enantioselectivity and the specific preferences in enantioselective binding point to chiral recognition mechanisms capitalizing on intermolecular ion pairing, hydrogen bonding and subtle steric interactions, with the latter making the crucial contributions to stereodiscrimination. The finding that the chiral recognition characteristics of epiquinine can be readily controlled via incorporation of additional stereogenic centers remote from the cinchona scaffold might be useful information for the design of new enantioselective receptors and organocatalysts. PMID- 24061298 TI - Synthesis of the Peptide-Based Phenanthridine-Nucleobase Conjugates and Study of Their Interactions With ds-DNA. AB - Series of novel peptide-bridged phenanthridine-nucleobase conjugates were prepared by solid phase peptide synthesis, which allowed easy and fast tuning of structure properties. Compounds were fully characterized in aqueous medium, pointing out to intramolecularly stacked structures. The stacked phenanthridine thymine-phenanthridine system revealed characteristic excimeric fluorescence band and very specific CD spectrum. Studied compounds interact with double stranded DNA by intercalation, whereby binding is to minor extent influenced by attached thymine and amino-acid sequence of the peptide backbone. PMID- 24061299 TI - Is There Any Proton Exchange Between Ammonium Ions localized Within the d(G3T4G4)2 Quadruplex? AB - It is generally appreciated that stability, dynamics and function of nucleic acids are affected by nature of cations that are involved in interaction with specific functionalities. DNA G-quadruplexes are unique among nucleic acid structures in their metal ion requirements. Cations inside G-quadruplex structures have been shown to exchange between binding sites and bulk solution. However, in d(G3T4G4)2 G-quadruplex ammonium ions do not exchange through the central G-quartet plane. Passage of larger cations through a G-quartet such as potassium or ammonium ions requires partial opening of G-quartets. The use of HzExHSQC experiment demonstrates that smaller protons move through the central G quartet plane. PMID- 24061300 TI - Two concomitant polymorphs of monomeric nickel acetate with 2-pyridineethanol. AB - A new mononuclear nickel(II) acetate with 2-pyridineethanol, Ni(ac)2(2-PyEtOH)2 has been prepared. The reaction product is a mixture of two polymorphic forms that crystallize concomitantly: triclinic (PI) and monoclinic (P21/c). Their structures have been determined at 150 K. The molecular structure of the mononuclear complex shows similar geometry in both polymorphic structures but they differ notably in the arrangement of mononuclear entities in space. The crystal densities are significantly different, nevertheless they behave as concomitant polymorphs. PMID- 24061301 TI - Products of the Reactions Between Pyridine and 1,2- or 1,3-phenylenediacetic Acid: Salts or Co-crystals? AB - Reaction of pyridine with 1,2- or 1,3-phenylenediacetic acids, denoted as 1,2 phdaH2 or 1,3-phdaH2, afforded two crystalline products, [PyH+ ][1,2-dphaH-] * 1,2-dphaH2 (1) and [PyH + ][1,3-dphaH-] (2) (PyH+ = C5H5NH+ , pyridinium cation). Compound 1 contains apart from protonated pyridine molecule also two 1,2 phenylenediacetic acid species, a semi-1,2-phenylenediacetate ion and a neutral acid molecule, one of each per formula unit. As such, it can be classified among co-crystals. The 1,2-phenylenediacetic acid species are assembled into double chains via O-H***O hydrogen bonds. Pyridinium cations are attached to these chains via N+ -H***O-(carboxylate) interactions. The X-ray structure analysis of compound 2 revealed a hydrogen bond of moderate strength occurring between the pyridine nitrogen and oxygen atom of one COOH function, N***H***O = 2.539(2) A. The position of hydrogen is almost half way between the two atoms. Compound 2 can neither be considered as a pure salt nor as a pure co-crystal. As in 1, the O H***O interactions link the 1,3-phenylenediacetic acid residues into chains. PMID- 24061302 TI - Thermodynamics of Asymmetric Primitive Model Electrolytes via the Hypernetted Chain Approximation. AB - The accuracy of the activity coefficient expression (Hansen-Vieillefosse-Belloni (HVB) equation), valid within the hypernetted-chain (HNC) approximation, was tested in a wide concentration range against newly obtained grand canonical Monte Carlo data for the size and charge asymmetric primitive model electrolytes. In some cases, uncharged hard sphere component was also present. The HVB expression enables a direct calculation of the excess chemical potential, without invoking the time consuming calculation via the Gibbs-Duhem relation. We found the Ornstein-Zernike (OZ)/HNC results for the mean activity coefficient, as well as for the reduced excess internal energy and osmotic coefficient, to be in good agreement with the machine calculations performed for the same model. The accuracy of the results was found to be dependent on the packing fraction of the solutions. The mean spherical approximation calculations were also used to describe the thermodynamics of these systems and compared with the OZ/HNC and simulation results. PMID- 24061303 TI - The role of specific interaction in phase behavior of polyelectrolyte-surfactant water mixtures. AB - Aqueous phase behavior and structures of phases were studied in systems containing sodium poly(styrenesulfonate), NaPSS, and complex salt CTAPSS, formed between cetyltrimethylammonium cations, CTA+, and PSS- anions. It was shown that hydrophobic interaction of the polyion styrene groups with surfactant aggregates, which supports the strong electrostatic attraction between CTA+ and PSS-, has a significant effect on phase behavior and structures. Only the disordered micellar (L1) and the ordered hexagonal (H1) phase were found that are connected over a broad two-phase region of L1-H1 coexistence. At water contents above 60 wt%, CTAPSS is easily dissolved in proportion to the amount of added NaPSS, whereas at lower water contents a large excess of NaPSS is needed to dissolve CTAPSS. Phase separation in the two-phase region is controlled by two tendencies: (i) to maximize the contact between the hydrophobic groups and micelles (assisted by hydrophobic interaction) and (ii) to form as dense phase as possible (assisted by both, electrostatic and hydrophobic interactions). Structural characteristics of soluble non-stoichiometric complexes from the L1 phase show that hydrophobic interaction contributes also to a relatively small size of PSS-induced micelles and leads to a network-like association between PSS chains in which micelles serve as cross-links. PMID- 24061304 TI - Electrochemical impedance spectroscopy as a tool in the plate making process optimization. AB - The structure of the porous aluminium-oxide layer, which builds non-image areas, has the most significant influence on the quality of final graphical product. This paper presents the results of the application of EIS in the characterisation and detection of changes on the aluminium-oxide layer caused by chemical processing in highly alkaline solution. The Al2O3 layer was characterised using SEM, fractal dimension and surface free energy calculation and EIS analysis. The results of the investigation showed that chemical processing has a significant influence on the structure of aluminium-oxide which could lead to a decrease in the quality of the printing plate. EIS enables the detection of changes on the aluminium-oxide layer. The two equivalent circuits are proposed. Based on modelling with the obtained EIS spectra, precise evaluation of developing time in which complete removal of the photoactive layer is achieved. This makes EIS a powerful tool in optimizing chemical processing of lithographic printing plates. PMID- 24061305 TI - Structural study of simple organic acids by small-angle x-ray scattering and monte carlo simulations. AB - This study represents an extension of our previous research on the structural properties of simple organic liquids to the systems of organic acids. A set of simple acids from ethanoic to octanoic was modelled with the TraPPE-UA force field and configurational bias Monte Carlo (CBMC) simulations were used to obtain a number of configurations of each system. These data were subsequently used as a basis for the calculation of X-ray scattering intensities, partial radial distribution functions and statistical analysis of molecular aggregation in liquid organic acids. The comparison of simulated X-ray scattering curves with the results of SAXS measurements has shown the agreement to be overall somewhat poorer than in our previous studies on alcohols and aldehydes, although it did improve with increasing molecular length. Hydrogen bonds between the hydroxylhydrogen atom and the carbonyl oxygen have been found to have a profound effect on the structure of the liquid acids. However, the model-based results showed that the formation of intermolecular hydrogen bonds involving the hydroxyl oxygen was disproportionately scarce in these systems. Statistical evaluation of the model configurations has shown that only about 4% of acid molecules form such a type of hydrogen bonds, in contrast to 68% of molecules that form the hydrogen bond with the carbonyl oxygen. This suggests that the force field might be underestimating the hydrogen bonding via hydroxyl oxygen. The statistical analysis has also shown that the simulated molecules preferred to assemble into small molecular aggregates, particularly into double-bonded molecule pairs. PMID- 24061306 TI - The application of the replica ornstein-zernike methodology for studying ionic membrane equilibria. AB - The applicability of the replica Ornstein-Zernike (ROZ) method, often used to explore the partly quenched systems, for studying ionic equilibria in membrane like systems was investigated. A simple +1:-1 electrolyte solution was modelled as a primitive model electrolyte on the McMillan-Mayer level of approximation. The particles mimicking membrane were modelled as permeable hard spheres frozen in space in their positions. The ion-membrane potential was chosen to conform as closely as possible to the experimental data. The density profiles of ions near the membrane, as well as adsorption isotherms, were calculated using the ROZ equations complemented by the hypernetted chain (HNC) approximation. The method provides reasonable results in qualitative agreement with experimental observations. PMID- 24061307 TI - Global thermodynamic analysis of conductivity data. AB - Conductivity can serve as a tool to study ion properties in different solvents. In the current study, principles of the global modelling of the conductivity data measured at different concentrations and temperatures are demonstrated. Global model was developed on the basis of two modern conductivity theories; the low concentration chemical model and the Quint-Viallard model. It was tested on three different systems; NaCl in water, NaCl in water-1,4 dioxane mixture and MgSO4 in water. It turned out, that such approach successfully describes all the measured experimental data simultaneously. The applied global analysis of the experimental data allows determination of the thermodynamic profile of ion pairing process and the transport properties of ions at the same time. PMID- 24061308 TI - Quantum chemical tests of water-water potential for interaction site water models. AB - Accuracy of different simple interaction site water models was tested. Instead of assessing their quality through the calculations of various water physical properties (dipole moment, dielectric constant, phase-equilibria diagrams, etc.) and comparison with experimental values, we calculated water-water potential and compared it with the potential from quantum chemical calculations. Using density functional theory (DFT) water-water potential was calculated for different positions of two water molecules, which was compared with the interaction used in water models. Different simple interaction site water models were then evaluated and assessed. Special emphasis is placed on angle and distance dependence of water-water potential around minima in the potential. Among three-, four-and five site electrostatic water models, TIP3P, TIP4P/2005 and TIP5P were found to be the most accurate. PMID- 24061309 TI - Differences in Unfolding Energetics of CcdB Toxins From V. fischeri and E. coli. AB - Ccd system is a toxin-antitoxin module (operon) located on plasmids and chromosomes of bacteria. CcdBF encoded by ccd operon located on Escherichia coli plasmid F and CcdBVfi encoded by ccd operon located on Vibrio fischeri chromosome are members of the CcdB family of toxins. Native CcdBs are dimers that bind to gyrase-DNA complexes and inhibit DNA transcription and replication. While thermodynamic stability and unfolding characteristics of the plasmidic CcdBF in denaturant solutions are reported in detail, the corresponding information on the chromosomal CcdBVfi is rather scarce. Therefore, we studied urea-induced unfolding of CcdBVfi at various temperatures and protein concentrations by circular dichroism spectroscopy. Global model analysis of spectroscopic data suggests that CcdBVfi dimer unfolds to the corresponding monomeric components in a reversible two-state manner. Results reveal that at physiological temperatures CcdBVfi exhibits lower thermodynamic stability compared to CcdBF. At high urea concentrations CcdBVfi, similarly to CcdBF, retains a significant amount of secondary structure. Differences in thermodynamic parameters of CcdBVfi and CcdBF unfolding can reasonably be explained by the differences in their structural features. PMID- 24061310 TI - A microscopic theory of solvation of monoions. AB - The solvation free energies of ions are often computed using continuum theories, like the Born model. The Born model has the disadvantages that to fit experimental data, ionic radii are taken as adjustable parameters and you need to know the dielectric constant. We present here a more microscopic treatment for computing the free energies of ion solvation in water. Like the Born model, it gives an expression that is simple and can be computed quickly, but unlike the Born model, it uses true ionic radii and does not require inputting a dielectric constant. We show that the present model gives predictions for the free energies of transfer of alkali and halide ions into water that are in excellent agreement with recent experimentally derived estimates. PMID- 24061311 TI - The Mean Activity Coefficients of Fullerenehexamalonates Th-C66(COO-M+)12 in Aqueous Solutions. AB - The Poisson-Boltzmann equation has been solved for the spherical cell model of a fullerenehexamalonate solution to obtain the contributions of the macroion and its counterions to the total electrostatic free energies. The contribution of the macroion is large and positive, whereas the contribution of the counterions is small and negative. From these data the concentration dependence of the activity coefficients of the macroion and counterions have been calculated, as well as the mean activity coefficient of the fullerenehexamalonate electrolyte. Calculated values for the mean activity coefficient have been compared with the existing experimental data and a good agreement has been observed. PMID- 24061312 TI - What affects the degree of micelle ionization: conductivity study of alkyltrimethylammonium chlorides. AB - The critical micelle concentration, cmc, and the degree of micelle ionization, beta, of decyltrimethylammonium chloride (DeTAC), dodecyltrimethylammonium chloride (DTAC) and tetradecyltrimethylammonium chloride (TTAC) in water, 0.01 M, and 0.1 M NaCl solution were determined from the electrical conductivity data in the temperature range from 278.15 to 328.15 K. It has been found that cmc is decreasing with increasing surfactant chain length and increasing concentration of added NaCl, whereas the temperature dependence of cmc shows the typical U shaped form with a minimum around (306 +/- 3) K. Further, beta is decreasing with lengthening the alkyl chain of surfactant and increasing with increasing temperature, but no distinct influence of added salt has been found actually. It can be concluded that the effect of electrolyte on micelle ionization is quite complex. PMID- 24061313 TI - UV/Vis Study of the Alkali Salts of Poly(thiophen-3-ylacetic acid) in Water. AB - UV/Vis spectroscopic investigation of aqueous solutions of regio-irregular poly(thiophen-3-ylacetic acid) (PTAA) with and without methyl-ester groups in the presence of sodium and lithium ions as counterions is presented. The samples were carefully purified and characterized with respect to molar mass and the amount of -COOH groups present. We examined how the UV/Vis spectra of solution change with aging of PTAA solution, polymer concentration, addition of low molecular weight salt, temperature, and some other parameters. We show that results crucially depend on whether the spectra are taken for freshly prepared or mature solutions. We demonstrate the validity of the Beer-Lambert law for PTANa, PTAA/Na, and PTAA/Li (aged solution), and violation of this law for PTANa/Me (fresh) solutions in water; the latter system is instead found to exhibit an isosbetic point at 402 nm. We prove that UV/Vis spectra of polythiophene derivatives in water depend on the "age" (time after dissolution) of the solution. The inconsistencies among the spectroscopic data found in literature, as also the discrepancies with our own measurements on PTAA-based systems are discussed. PMID- 24061314 TI - Potentiometric and Conductometric Study of Aqueous Solutions of Lithium and Sodium Salts of Poly(thiophen-3-ylacetic acid). AB - The title polymer, PTAA, practically free of ester groups was obtained by oxidative polymerization of methyl thiophen-3-ylacetate and subsequent basic hydrolysis of primary polymer. Poly(thiophen-3-ylacetic acid) has been thoroughly characterized by NMR, IR, Raman, and UV/Vis spectroscopy. The polyacid behavior during neutralization titrations with lithium and sodium hydroxides, carried out under nitrogen atmosphere, has been studied by conductometry and potentiometry. Henderson-Hasselbach plots of potentiometric titration curves show a break point at pH around 6, where the curve slope drops from 1.8 (at lower pH) to a value from 1.05 to 1.3 (at higher pH values). The UV/Vis spectra monitored during back titration show: (i) monotonous decrease of both lambdamax and epsilonmax as pH decreases, (ii) the presence of the isosbestic point at 401 nm that can be ascribed to conformational transition of PTAA chains, and (iii) absence of the isosbestic point at 392 nm reported previously by other authors. PMID- 24061315 TI - Kinetically Governed Formation of d(G4T2G4) Assemblies. AB - The most frequently appearing form of DNA is a double helical structure in which two single strands are held together by Watson-Crick base pairs. In addition, guanine rich DNA sequences are known to adopt several unusual structures with G quartet as a basic repeating motif. Recently large self-assembling nanostructures, called G-wires have become of great interest because of their potential use in molecular electronics. To better understand the forces driving structural transitions of G-wires formed from d(G4T2G4) oligonucleotide in Na+ solutions, we employed a number of techniques such as UV and CD spectroscopy, differential scanning calorimetry (DSC), gel electrophoresis, small angle X-ray scattering (SAXS) and dynamic light scattering (DLS). All the experimental techniques showed that thermally induced folding transitions depend on the cooling rate. In addition, DSC shows that thermally induced unfolding transition depends on heating rate, thus leading to the conclusion that structural transitions of d(G4T2G4) are kinetically governed processes. PMID- 24061316 TI - Attraction between like-charged surfaces: effect of counterion dimerization. AB - A force between two equally charged surfaces depends on the composition of intervening solution. While the force is always repulsive for monovalent counterions, multivalent counterions turn the interaction into the attractive one. An example of the attraction between like charged surfaces is the aggregation of colloidal particles mediated by multivalent counterions with spatially separated charges. A model system represents the colloids by equally charged planar surfaces. In our consideration the intervening salt-free solution is composed of rod-like dimmers. Some of dimmers can be disconnected to monovalent ions. This model system was solved using the Monte Carlo (MC) simulations and the Poisson-Boltzmann (PB) theory, which was extended to deal with rigid complex ions. The study was made by varying a range of parameters including the surface charge density and the ratio of the number of monovalent counterions to the number of all counterions. The calculated pressure shows that with increasing surface charge density the lower fraction of dimeric counterions is needed to induce attractive force between surfaces. A good agreement between the MC simulations and the theoretical results was obtained. PMID- 24061317 TI - Method and apparatus for determination of relative permittivity of solvents. AB - In this work a modification of an existing coaxial cylindrical capacitor cell is described, that is compatible with a system built recently for precise measuring of temperature dependent data in electrolyte solutions. The method and apparatus, presented in detail in this technical paper, turned out to be a reliable and easy procedure for determination of the relative permittivity of diverse solvents. It will be used further in our laboratory for collecting these data which are indispensable for conductivity studies. PMID- 24061318 TI - Potential Solutions for CO2-capturing Technologies in the Slovenian Context. AB - Human activities have caused an enormous rise of the CO2 concentration in the Earth's atmosphere over the past 200 years. In order to alleviate this problem, the threats to and the concerns of the international community need to be converted into economic opportunities for national economies, which shall develop and utilize technological opportunities rather than simply accepting international obligations to reduce CO2 emissions. In the article we analyze technological possibilities in the Slovenian context as possible opportunities for promoting sustainable development based on regional, renewable resources. Beginning with an analysis of the amine process for CO2 concentration and its possibilities, we continue with CO2 chemistry examples, like the precipitation of calcium carbonate from Ca++ sources like lime or fly ash. Through the concept of product engineering we emphasize the need for a stepwise realization from the laboratory to a pilot plant and then to the industrial scale. The growth of biomass through forestry or algae production can provide an additional CO2 sink. However, for an efficient technical solution and implementation a close working relationship between biologists and engineers is required. PMID- 24061319 TI - Synthesis, characterization and biological activities of ciprofloxacin drug based metal complexes. AB - The interaction of small molecules with DNA has attracted a great deal of attention. Mixed ligand copper(II) complexes of type [Cu(cpf)(Ln)Cl] [cpf = ciprofloxacin, Ln = phenanthroline derivatives] were synthesized and characterized by elemental analysis, reflectance, IR and mass spectra. Viscosity measurements, absorption titration and DNA melting temperature studies were employed to determine the mode of binding of complexes with DNA. DNA cleavage study showed better cleaving ability of the complexes compare to metal salts and standard drug. The SOD mimic study showed IC50 value of complexes in the range of 0.95 to 1.75 uM. Antibacterial activity was assayed against selective Gram(-ve) and Gram(+ve) microorganisms. PMID- 24061320 TI - Construction of some new bioactive building block of thiazolidines. AB - An efficient route for the synthesis of new series of N-[3-(1H-1,2,3-benzotriazol 1-yl)-propyl]-2-(substituted phenyl)-4-oxo-5-(substituted benzylidene)-1,3 thiazolidine-carboxamide has been devised; compounds 5a-j have been synthesized and characterized by IR, 1H NMR, 13C NMR, FAB-MS and chemical elemental analysis. All final compounds were screened for their antimicrobial activity against some selected bacteria and fungi and antituberculosis study against Mycobacterium tuberculosis and antiinflammatory activity on albino rats. PMID- 24061321 TI - Spectrophotometric determination of trace levels of nickel in water samples after dispersive liquid liquid microextraction using 2,2'-furildioxime as the complexing agent. AB - A new method of dispersive liquid-liquid microextraction (DLLME) combined with UV Vis spectrophotometry was proposed for the determination of trace nickel using 2,2'-Furildioxime as chelating and spectrophotometric reagent. In the proposed approach chloroform and ethanol were used as extraction and dispersive solvents, respectively. Some factors influencing the extraction efficiency of nickel and its subsequent determination were studied and optimized, such as the extraction and dispersive solvent type and volume, pH of the sample solution, extraction time and ionic strength. Under the optimal conditions, the calibration curve was linear within the range of 5-180 ug L-1 of nickel with R2 = 0.9960. Limit of detection (3Sb/m) was 0.6 ug L-1 in the original solution and the relative standard deviation for ten replicate determination of 100 ug L-1 nickel was 2.9%. The proposed method has been applied for the determination of nickel in various water samples with satisfactory results. PMID- 24061322 TI - New Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones Fluoroderivatives as Human A1 Adenosine Receptor Ligands. AB - In this paper we report the synthesis and biological evaluation of a new series of pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as human A1 adenosine receptor ligands. The tricyclic scaffold was modified at position 6 and 9 by introducing small alkyl chains and substituted phenyls. The most interesting compounds showed Ki for A1 in the submicromolar range (0.105-0.244 uM) and the most interesting term (compound 4c) combined an appreciable affinity for A1 (Ki = 0.132 uM) with a good selectivity toward A2A (43% inhibition at 10 uM) and A3 (46% inhibition at 10 uM). PMID- 24061323 TI - Synthesis and Spectroscopic Studies of Novel Rhodanine Azo Dyes: An Excellent Selective Chemosensor for Naked-eye Detecting of Cu2+ Ion. AB - This study is first report on the synthesis of novel rhodanine based azo dyes and their fluorogenic and chromogenic sensing behaviors with metal ions (Li+, Na+, K+, Rb+, Pb2+, Ni2+, Zn2+, Cu2+) by using UV-vis and fluorescence spectroscopy techniques. The results of spectroscopic experiments for rhodanine based azo dye 1a exhibited excellent selectivity for Cu2+ over the other metal ions. Furthermore, anti-bacterial studies of rhodanine azo dyes were performed towards some selected bacteria via microbroth dilution method. Obtained results showed that rhodanine ionophore 1a showed strong antibacterial activity against S.aureus. PMID- 24061324 TI - Ultrasound-promoted One-pot Synthesis of 8-Aryl-7,8-dihydro-[1,3]-dioxolo[4,5 g]quinolin-6(5H)-one Derivatives under Catalyst-free and Solvent-free Conditions. AB - An ultrasound-accelerated one-pot procedure has been explored for the synthesis of 8-aryl-7,8-dihydro-[1,3]-dioxolo[4,5-g]quinolin-6(5H)-one derivatives using the reaction between 3,4-methylendioxyaniline 1, aldehyde 2 and isopropylidene malonate 3 under catalyst-free and solvent-free conditions. High yields of the products, mild reaction condition, environmentally friendly procedure, catalyst- and solvent-free conditions are the main advantages of this protocol. PMID- 24061325 TI - Solvent-free Mechanosynthesis of Two Thermochromic Schiff Bases. AB - Two thermochromic Schiff bases mostly in keto-amine tautomeric form were obtained by means of mechanochemical synthesis. Both Schiff bases Compound 1 and Compound 2, respectively are derived from the same primary amine 2-amino-5-methylphenol. Salicylaldehyde was used as aldehyde component in preparation of 1, and o vanillin as substituted salicylaldehyde component in synthesis of 2. Powder products of the neat grinding and liquid-assisted grinding syntheses of 1 and 2 were compared with the crystalline products, obtained by recrystallization from a small amount of solvent. Both raw powder and recrystallized products were characterized and compared by means of PXRD, DSC and IR. PMID- 24061326 TI - Two methods for spirothiohydantoin synthesis. AB - Two methods for spirothiohydantoin synthesis are presented. The title compounds were prepared with reaction of the corresponding 1-aminocycloalkanecarboxylic acids and thiourea. These compounds were also prepared by a hydrolysis of the relevant spirodithiohydantoins with barium hydroxide. The structures of the compounds obtained were verified by comparison of 1H, and 13C NMR, IR and MS spectral data. PMID- 24061327 TI - Synergistic extraction of calcium and strontium into nitrobenzene by using hydrogen dicarbollylcobaltate and n,n'-dimethyl-n,n'-diphenyl-2,6-dipicolinamide. AB - Extraction of microamounts of calcium and strontium by a nitrobenzene solution of hydrogen dicarbollylcobaltate (H+B-) in the presence of N,N'-dimethyl-N,N' diphenyl-2,6-dipicolinamide (MePhDPA, L) has been investigated. The equilibrium data have been explained assuming that the species HL+, HL+2, ML2+2 and ML2+3 (M2+ = Ca2+, Sr2+) are extracted into the organic phase. The values of extraction and stability constants of the cationic complex species in nitrobenzene saturated with water have been determined. PMID- 24061328 TI - One-pot, Three-component Synthesis of Dialkyl 4-(alkylamino)-7-alkoxy-5-oxo-1 pyridine-2-yl-1,5-dihydrofuro[3,4-b]pyridine-2,3-dicarboxylate. AB - A one-pot isocyanide-based three-component reaction of 2-aminopyridine and acetylenic esters with alkyl isocyanides afforded tetraalkyl 4-(alkylamino)-2H 1,2'-bipyridine-2,3,5,6-tetracarboxylate and dialkyl 4-(alkylamino)-7-alkoxy-5 oxo-1-pyridin-2-yl-1,5-dihydrofuro[3,4-b]pyridine 2,3-dicarboxylate in good to high yields under mild reaction conditions. PMID- 24061329 TI - ZnO Nanoparticles as New and Efficient Catalyst for the One-pot Synthesis of Polyfunctionalized Pyridines. AB - In this research, an efficient one-pot synthesis of 2-amino-3,5-dicyano-4-phenyl 6-(phenylthio)pyridines has been developed via multi-component reaction of aldehydes, thiols and malononitrile in the presence of ZnO nanoparticles. Poly substituted pyridines as heterocyclic privileged medicinal scaffolds are prepared via carbon-carbon and carbon-heteroatom bond formation. The present methodology provides a novel and efficient method for the synthesis of pyridine derivatives with some advantages such as short reaction times, excellent yields, recoverability and low catalyst loading. PMID- 24061330 TI - Complexation of the Silver Cation with Dibenzo-30-crown-10: Extraction and DFT Study. AB - From extraction experiments and gamma-activity measurements, the exchange extraction constant corresponding to the equilibrium Ag+(aq) + 1.Cs+(nb) <-> 1.Ag+ (nb) + Cs+(aq) taking place in the two-phase water-nitrobenzene system (1 = dibenzo-30-crown-10; aq = aqueous phase, nb = nitrobenzene phase) was determined as log Kex (Ag+, 1.Cs+) = -1.7 +/- 0.1. Further, the stability constant of the complex 1.Ag+ in nitrobenzene saturated with water was calculated for a temperature of 25 degrees C: log betanb (1.Ag+) = 6.0 +/- 0.2. Finally, by using quantum mechanical DFT calculations, the most probable structure of the resulting complex 1.Ag+ was solved. PMID- 24061331 TI - Remission of generalized anxiety disorder after 6 months of open-label treatment with venlafaxine XR. AB - BACKGROUND: Remission has become one of the leading outcome criteria in clinical trials. Data collected by this research group assessed the rate of remission after 6 months of treatment of generalized anxiety disorder (GAD) with venlafaxine XR, to search for predictors of remission and to define how early on in treatment later remission can be predicted. METHOD: Two hundred sixty-eight patients with a GAD diagnosis enrolled into an open-label 6-month-treatment trial with venlafaxine XR (75-225 mg/day). Remission was defined by a Hamilton anxiety scale total score <=7. Logistic regression approaches were used to find out how early on in treatment later remission could be predicted, as well as to determine predictors of remission. In addition, adverse events were also followed over time. RESULTS: While the total enrolled patient sample (n = 268) had a remission rate of 53%, 6-month completers (n = 159) had a remission rate of 79%. The only statistically significant predictor of remission, independent of baseline anxiety and depression levels, was a low Eysenck neuroticism score. The remission status outcome could best be predicted after 8 weeks of treatment when a CGI-I score of 1 or 2 predicted later remission with 78% accuracy and later nonremission with 91% accuracy. The incidence of adverse events decreased over the 6-month period, with sexual adverse events decreasing the least. CONCLUSION: The only significant predictor of remission was a low score on the Eysenck neuroticism scale. The earliest reliable prediction of later remission, based on improvement, could be made after 8 weeks of treatment with 91% accuracy. PMID- 24061332 TI - Realising Haldane's vision for a Chern insulator in buckled lattices. AB - The Chern insulator displays a quantum Hall effect with no net magnetic field. Proposed by Haldane over 20 years ago, it laid the foundation for the fields of topological order, unconventional quantum Hall effects, and topological insulators. Despite enormous impact over two decades, Haldane's original vision of a staggered magnetic field within a crystal lattice has been prohibitively difficult to realise. In fact, in the original paper Haldane stresses his idea is probably merely a toy model. I show that buckled lattices with only simple hopping terms, within in-plane magnetic fields, can realise these models, requiring no exotic interactions or experimental parameters. As a concrete example of this very broad, and remarkably simple principle, I consider silicene, a honeycomb lattice with out-of-plane sublattice anisotropy, in an in-plane magnetic field, and show that it is a Chern insulator, even at negligibly small magnetic fields, which is analogous to Haldane's original model. PMID- 24061333 TI - Electron transport through 5-substituted pyrimidines in DNA: electron affinities of uracil and cytosine derivatives differently affect the apparent efficiencies. AB - We investigated excess electron transport (EET) in DNA containing cytosine derivatives. By arranging the derivatives according to their electron affinities, the apparent EET efficiency was successfully regulated. Unexpectedly, however, providing gradients of electron affinity by inserting 5-fluorocytosine did not always enhance EET. PMID- 24061334 TI - A computational study of acid catalyzed aerosol reactions of atmospherically relevant epoxides. AB - Epoxides are important intermediates of atmospheric isoprene oxidation. Their subsequent reactions in the particle phase lead to the production of organic compounds detected in ambient aerosols. We apply density functional theory to determine the important kinetic factors that drive epoxide reactions in the particle phase. Specifically, the importance of acid catalysis and solvent polarity are investigated using a variety of epoxides and nucleophiles. The condensed phase is modeled using molecular clusters immersed in a dielectric continuum and a majority of the calculations are performed with the M062x density functional and the 6-311++G** basis set. Calculations of acid catalyzed epoxide hydrolysis transition states for simple primary, secondary and tertiary epoxides are consistent with an A-2 mechanism where the nucleophile (water) interacts with an epoxide carbon in the transition state. By applying transition state theory to this mechanism, the overall rate constants of epoxide reactions such as hydrolysis, organosulfate formation, organonitrate formation and oligomerization are determined. The calculations indicate that the acid catalyzed hydrolysis rate constant of 2-methyl-2,3-epoxybutane-1,4-diol (beta-IEPOX--an isoprene epoxide produced under low NOx conditions) is approximately 30 times greater than 2 methyl-2,3-epoxypropanoic acid (MAE--methacrylic acid epoxide derived from isoprene and produced at high NOx concentrations). Furthermore, acid catalyzed organosulfate formation and epoxide oligomerization reactions are competitive and appear to be kinetically favorable over the hydrolysis of IEPOX. PMID- 24061335 TI - Central venous catheter dress rehearsals: translating simulation training to patient care and outcomes. AB - INTRODUCTION: Central line-associated blood stream infection (CLABSI) is a preventable burden to our current health care system. Inconsistencies in knowledge and practice of central venous catheters (CVC) dressing change procedures are associated with CLABSI. We hypothesized that participation in a "just-in-time" and "just-in-place" CVC dressing change program would improve nurses' knowledge, confidence, and psychomotor performance on mannequins (eg, T1 outcomes). Moreover, this simulation program would be associated with improved procedural competence on real patients (T2 outcomes) and hospital CLABSI rate (T3 outcomes). METHODS: We conducted a prospective before and after timed series study at a large urban children's hospital. This program provided an opportunity to practice a CVC dressing change using a simulated patient chest/arm. Cognitive and psychomotor skills were evaluated using a pre-self-assessment/post-self assessment, written knowledge test and direct observation using a standardized checklist. Central line-associated blood stream infection rates were monitored monthly by the Office of Quality and Patient Safety. RESULTS: Five hundred twenty four inpatient nurses participated in this program between November 2008 and May 2010. Knowledge and self-confidence improved significantly (knowledge, 4.1 [0.7] vs. 4.6 [0.5], P < 0.001; self-confidence, 4.1 [0.8] vs. 4.6 [0.6], P < 0.001). Of 2469 real-patient CVC dressing changes observed, dress rehearsal trainees required fewer corrective prompts (9% vs. 21%, P < 0.001), and CLABSI rates decreased from 5.3/1000 to 2.9/1000 line days (P < 0.001) during the study. DISCUSSION: This program improved nurse's knowledge, self-confidence, and psychomotor skill performance on mannequins (eg, T1 outcomes). These improvements were associated with improved procedural competence on real patients (T2 outcomes) and a temporal association with decreased hospital CLABSI rates (T3 outcomes). PMID- 24061336 TI - The effectiveness of simulation-based blood pressure training in preregistration nursing students. AB - INTRODUCTION: Mastery of auscultatory blood pressure is challenging for preregistration nursing students. This phenomenon has been attributed to the psychomotor skills required, knowledge about blood pressure measurement, and the teaching modality type. Most studies focus on developing blood pressure proficiency without determining the measurement accuracy. We sought to determine the efficacy of simulation-based learning on blood pressure measurement accuracy in first-year preregistration nursing students. METHODS: First-year preregistration nursing students from a clinical subject were randomly assigned to laboratory groups, which formed the control and intervention groups. Each group received identical blood pressure measurement education, with the intervention group undertaking 2 additional hours of tuition, using human patient simulators programmed with a wide range of blood pressure measurements to replicate patient's blood pressures observed in clinical settings. At the end of the semester and after 40 hours of hospital clinical practice, participants were assessed for blood pressure accuracy on live subjects and completed a questionnaire on self-ratings of confidence and technical ability. RESULTS: Blood pressure accuracy was not significantly different between participants and assessors or between the control and intervention groups (all P > 0.05). The intervention group reported greater levels of confidence (P = 0.02) and self rated technical ability (P = 0.01) in blood pressure measurement at week 14 of the semester; however, these difference were not observed at the end of 40 hours of clinical practice (P < 0.05). CONCLUSIONS: Accuracy in taking blood pressure was not enhanced by the use of a patient simulator, despite improvements in self reported confidence and technical competency. Further research is required to evaluate the inclusion of simulation-based learning for blood pressure training in nursing students. PMID- 24061337 TI - Femto- to micro-second photobehavior of photosensitizer drug trapped within a cyclodextrin dimer. AB - The interactions of 5,10,15,20-tetrakis(4-sulfonatophenyl)-porphyrin (TSPP, a singlet oxygen photosensitiser molecule) with a hexa-2,4-diynediyl bridged beta cyclodextrin dimer (CD-CD) in aqueous solutions of pH 7 were studied using steady state UV-visible absorption/emission and femto- to millisecond time-resolved spectroscopy. TSPP forms 1 : 1 complexes with CD-CD (K(e) = 1.9 * 10(8) M(-1) at 293 K). The value of K(e) indicates a high affinity of TSPP to form complexes with CD-CD. The chemical nano-cavity has a notable effect on the fluorescence lifetimes of the Q(x) state (9.3 ns in water and 10.8 ns in CD-CD). The rotational times (410 ps for TSPP in water and 0.03 ns (12%) and 1.1 ns (88%) for the TSPP:CD-CD complexes) indicate the robustness of the formed entities, and fast depolarization of emission, most probably involving the porphyrin skeleton and phenyl ring motions. The ultrafast femtosecond component (60-100 fs) of TSPP is moderately affected by the confining environment, which instead strongly influences the ps component (1-2 ps in water and 5 ps within CD-CD) assigned to the vibrational relaxation of the Q(x) state. Moreover, a 50 ps component emerges in the emission transients in the 640-720 nm range, and which is assigned to a thermalization of the hot Q(x) state. The effect of O2 on the triplet state of the encapsulated TSPP was also studied and discussed in light of the shielding effect of the CD-CD cavity. We observed comparable quantum yield (0.62 and 0.69) of the generated singlet molecular oxygen of TSPP without and with CD-CD. We believe that our results on the molecular interaction between TSPP and CD-CD from femtosecond to millisecond regime at both ground and electronically first excited states give relevant information for improving our understanding of this kind of caged drugs, and thus for a better design of drug:nanocarrier complexes. A particular implication for the use of CD-CD as a drug carrier is the high affinity of this host for complex formation with TSPP, while the yield of singlet oxygen generation is still high. PMID- 24061338 TI - Triple-stranded ferric helices: a pi-pi interaction-driven structural hierarchy of Fe5, Fe7, and Fe17 clusters. AB - Three polypyridine ligand-supported multinuclear iron complexes, [Fe5], [Fe7] and [Fe17], were synthesized and their physical properties were investigated. The complexes had triple-stranded helical structures with pseudo threefold symmetry, and were stabilized by varying degrees of intramolecular pi-pi stacking. The pentanuclear iron complex consisted of two Fe(II) and three Fe(III) ions, supported by three ligands, while the heptanuclear complex comprised four Fe(II) centres, three Fe(III) ions, and six ligands, and the heptadecanuclear complex contained seventeen Fe(III) ions and nine ligands. Electrochemical studies revealed that the pentanuclear and heptanuclear iron complexes showed pseudo reversible three- and five-step redox behaviours, respectively. Magnetic measurements conducted on the pentanuclear and heptanuclear complexes revealed that antiferromagnetic interactions were operative between neighbouring iron ions through the oxo- and pyrazole-bridges. PMID- 24061339 TI - MU-eLCR: a microfabricated device for electrochemical detection of DNA base changes in breast cancer cell lines. AB - Microfabricated devices for the electrochemical detection of single DNA base changes in cancer cell lines are highly desirable due to the inherent advantages such as portability, simplicity, and the rapid and inexpensive nature of electrochemical readout methods. Moreover, molecular sensors that use microscale footprint working electrodes have shown high signal-to-noise ratio. Herein we report a microdevice-based electrochemical assay (MU-eLCR) measuring ligase chain reaction (LCR)-amplified long and short "knife" motifs which reflect the presence or absence of a DNA base change of interest in a target sequence. This MU-eLCR approach has higher sensitivity (4.4 to 10 fold improvement over macrodisk electrodes) and good reproducibility (%RSD 6.5%, n = 12) for the detection of LCR amplified DNA bases. The devices also exhibited excellent sensitivity for the detection of DNA methylation (C to T base change in a locus associated with cancer metastasis) in two cell lines and serum derived DNA samples. We believe that the MU-eLCR device may be a useful diagnostic tool for inexpensive and rapid detection of single DNA base change applications such as DNA methylation and single nucleotide polymorphism (SNP) detection. PMID- 24061340 TI - Comparison of laparoscopy and laparotomy for management of endometrial carcinoma: a prospective randomized study with 11-year experience. AB - PURPOSE: We compared laparoscopic approach with the conventional laparotomy approach for the treatment of patients with endometrial carcinoma in developing country. METHODS: Two hundred and seventy-two patients with endometrial carcinoma were enrolled in a prospective randomized trial and treated with laparoscopic or laparotomy approach. RESULTS: One hundred and fifty-one patients were treated by laparoscopy, while one hundred and twenty-one patients were treated by laparotomy. The median operative time was 211 min in the laparoscopy group and 231 min in the laparotomy group (P > 0.05). The median blood loss was 86 ml in the laparoscopy group and 419 ml in the laparotomy group (P < 0.05). The median length of hospital stay was 3 days in the laparoscopy group and 6 days in the laparotomy group (P < 0.05). Pelvic lymphadenectomy was performed in all the patients. Para-aortic lymphadenectomy was performed in 15 % of the laparoscopy and 31.4 % of laparotomy group (P < 0.05). The overall survival and 5-year survival rate for the TLH were 94 and 96 % compared with 90.1 and 91 % in the TAH, respectively (P > 0.05). CONCLUSIONS: Laparoscopic surgery is a safe and reliable alternative to laparotomy in the management of endometrial carcinoma patients, with significantly reduced hospital stay and postoperative complications; however, it does not seem to improve the overall survival and 5 year survival rate, although multicenter randomized trials are required to evaluate the overall oncologic outcomes of this procedure. PMID- 24061341 TI - Loss of chromosome 4 correlates with better long-term survival and lower relapse rate after R0-resection of colorectal liver metastases. AB - PURPOSE: Liver metastases are the major cause of cancer-related death in colorectal cancer patients with a tendency to recur in over 50 % of the cases even after curatively intended surgery. Prognosis after liver resection, however, can neither be based on macroscopic or light microscopic evaluation of the metastases nor on clinical data alone. This is a pilot study in order to determine a potential influence of chromosomal aberrations on overall survival and relapse rate after curative liver resection. METHODS: Twenty randomly selected cases (10 patients with a survival of more and 10 patients with a survival of less than 5 years after resection) were studied by array comparative genomic hybridization. RESULTS: The distributions concerning age, gender, stage and grading of primary tumor, percentage of patients with chemotherapy, number and distribution of the liver metastases, Nordlinger and Fong scores showed no differences between long- and short-term survivors and no correlation to any chromosomal aberration. However, the relapse rate of patients with (partial) monosomy 4 was lower and the long-time survival better than in the other patients. CONCLUSIONS: Loss of chromosome 4 in colorectal liver metastases seems not only to be associated with the progression of the primary tumor as reported in the literature, but also with the long-term survival and the cumulative relapse rate after complete resection of colorectal liver metastases. PMID- 24061343 TI - Environmental controls on the activity of aquifer microbial communities in the 300 area of the Hanford site. AB - Aquifer microbes in the 300 Area of the Hanford Site in southeastern Washington State, USA, are located in an oligotrophic environment and are periodically exposed to U(VI) concentrations that can range up to 10 MUM in small sediment fractures. Assays of (3)H-leucine incorporation indicated that both sediment associated and planktonic microbes were metabolically active, and that organic C was growth-limiting in the sediments. Although bacteria suspended in native groundwater retained high activity when exposed to 100 MUM U(VI), they were inhibited by U(VI) <1 MUM in synthetic groundwater that lacked added bicarbonate. Chemical speciation modeling suggested that positively charged species and particularly (UO2)3(OH)5 (+) rose in concentration as more U(VI) was added to synthetic groundwater, but that carbonate complexes dominated U(VI) speciation in natural groundwater. U toxicity was relieved when increasing amounts of bicarbonate were added to synthetic groundwater containing 4.5 MUM U(VI). Pertechnetate, an oxyanion that is another contaminant of concern at the Hanford Site, was not toxic to groundwater microbes at concentrations up to 125 MUM. PMID- 24061342 TI - Differences in the methanogen population exist in sika deer (Cervus nippon) fed different diets in China. AB - Understanding the methanogen structure from sika deer (Cervus nippon) in China may be beneficial to methane mitigation. In the present preliminary study, we investigated the methanogen community in the rumen of domesticated sika deer fed either tannin-rich plants (oak leaf, OL group) or corn stalk (CS group) using 16S rRNA gene clone libraries. Overall, we obtained 197 clone sequences, revealing 146 unique phylotypes, which were assigned to 36 operational taxonomic units at the species level (98 % identity). Methanogens related to the genus Methanobrevibacter were the predominant phylotypes representing 83.9 % (OL library) and 85.9 % (CS library) of the clones. Methanobrevibacter millerae was the most abundant species in both libraries, but the proportion of M. millerae related clones in the CS library was higher than in the OL library (69.5 and 51.4 %, respectively). Moreover, Methanobrevibacter wolinii-related clones (32.5 %) were predominant in the OL library. Methanobrevibacter smithii-related clones and Methanobrevibacter ruminantium-related clones accounted for 6.5 and 6.6 % in the CS library, respectively. However, these clones were absent from the OL library. The concentrations of butyrate and total short-chain fatty acids (SCFAs) were significantly higher in the OL group, but the concentrations of acetate, propionate, and valerate and the acetate to propionate ratio in the OL group were not significantly different between the two groups. Tannin-rich plants may have affected the distribution of genus Methanobrevibacter phylotypes at the species level and the concentration and composition of SCFAs. PMID- 24061344 TI - Variable viral and grazer control of prokaryotic growth efficiency in temperate freshwater lakes (French Massif Central). AB - The effects of viral lysis and heterotrophic nanoflagellate grazing (top down forces) on prokaryotic mortality and their subsequent impact on their metabolism were estimated in the upper euphotic and deeper aphotic depth of 11 freshwater lakes located in the French Massif Central. The standing stocks of viruses (VA) and heterotrophic nanoflagellate (HNF) varied significantly (p < 0.05) with sampled depth. VA was substantially (twofold on an average) and significantly higher (p < 0.03) at the aphotic compared to euphotic depth, whereas the reverse was true (p < 0.02) for HNF. Among the prokaryote subgroup, high nucleic acid content prokaryotes explained for significant variability in the total VA and served as principle host target for viral proliferation. Like standing stocks, flagellate grazing and viral infection rates also followed similar patterns. In the investigated lakes, the mechanism for regulating prokaryotic production varied with sampled depth from grazing control in the euphotic to control due to viral lysis in the aphotic. We also tested the hypothesis of top down control on prokaryotic growth efficiency (PGE, which we used as an index of prokaryotic physiological and energetic status at the community level) at both depths. Overall, among the studied lakes, PGE varied widely (4-51 %) with significantly (p < 0.05) lower values in the aphotic (mean = 18 +/- 4 %) than euphotic depth (mean = 32 +/- 9 %). Contrasting observations on the top down control of PGE between sampled depths were observed. The presence of grazers was found to stimulate PGE at the euphotic, whereas viruses through their lytic infection had a strong negative impact on PGE at the aphotic depth. Such observed differences in PGE and the mechanism controlling prokaryotic production with depth could eventually have strong implication on carbon and nutrient flux patterns in the studied lakes. PMID- 24061345 TI - Management of obstructive sleep apnea in adults: A clinical practice guideline from the American College of Physicians. AB - DESCRIPTION: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the management of obstructive sleep apnea (OSA) in adults. METHODS: This guideline is based on published literature from 1966 to September 2010 that was identified by using MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews. A supplemental MEDLINE search identified additional articles through October 2012. Searches were limited to English language publications. The clinical outcomes evaluated for this guideline included cardiovascular disease (such as heart failure, hypertension, stroke, and myocardial infarction), type 2 diabetes, death, sleep study measures (such as the Apnea-Hypopnea Index), measures of cardiovascular status (such as blood pressure), measures of diabetes status (such as hemoglobin A1c levels), and quality of life. This guideline grades the evidence and recommendations using ACP's clinical practice guidelines grading system. RECOMMENDATION 1: ACP recommends that all overweight and obese patients diagnosed with OSA should be encouraged to lose weight. (Grade: strong recommendation; low-quality evidence) RECOMMENDATION 2: ACP recommends continuous positive airway pressure treatment as initial therapy for patients diagnosed with OSA. (Grade: strong recommendation; moderate-quality evidence) RECOMMENDATION 3: ACP recommends mandibular advancement devices as an alternative therapy to continuous positive airway pressure treatment for patients diagnosed with OSA who prefer mandibular advancement devices or for those with adverse effects associated with continuous positive airway pressure treatment. (Grade: weak recommendation; low-quality evidence). PMID- 24061346 TI - Is laparoscopy-assisted total gastrectomy feasible for the treatment of gastric cancer? A case-matched study. AB - BACKGROUND: The aim of this study was to clarify the short- and long-term outcomes of laparoscopy-assisted total gastrectomy (LATG) for gastric cancer compared to conventional open total gastrectomy (COTG) with a case-control study. METHODS: Between January 2002 and December 2010, a series of 264 patients with gastric cancer underwent R0 total gastrectomy (61 LATG patients and 203 COTG patients). Age, gender, and pathological stage were matched by propensity scoring, and 120 patients (60 LATG and 60 COTG) were selected for analysis. RESULTS: There were no significant differences in the clinicopathological features between the two groups. Regarding postoperative outcomes, first flatus time was significantly shorter in the LATG group than in the COTG group (p < 0.001), while operation time was significantly longer in the LATG group than in the COTG group (p < 0.001). Postoperative complications occurred in 5 cases (8.3%) of the LATG group and in 11 cases (18.3%) of the COTG group (p = 0.178). There were two recurrences in the LATG group and three recurrences in the COTG group. There was no significant difference in the 5-year survival rate between the two groups (p = 0.667). CONCLUSIONS: LATG for gastric cancer may be both feasible and efficient compared to COTG for experienced laparoscopic surgeons. This study is valuable for a prospective randomized controlled trial of LATG for gastric cancer in a larger number of patients. PMID- 24061347 TI - Associations between energy intake, daily food intake and energy density of foods and BMI z-score in 2-9-year-old European children. AB - PURPOSE: The aim of this study was to investigate the associations between proxy reported energy intake, daily food intake and energy density of foods and body mass index (BMI) z-score in 2-9-year-old European children. METHODS: From 16,225 children who participated in the identification and prevention of dietary- and lifestyle-induced health effects in children and infants (IDEFICS) baseline examination, 9,782 children with 24-h proxy dietary information and complete covariate information were included in the analysis. Participating children were classified according to adapted Goldberg cutoffs: underreports, plausible energy reports and overreports. Energy intake, daily food intake and energy density of foods excluding noncaloric beverages were calculated for all eating occasions. Effect of energy intake, daily food intake and energy density of foods on BMI z score was investigated using multilevel regression models in the full sample and subsample of plausible energy reports. Exposure variables were included separately; daily food intake and energy intake were addressed in a combined model to check for interactions. RESULTS: In the group of plausible energy reports (N = 8,544), energy intake and daily food intake were significantly positively associated with BMI z-score. Energy density of foods was not associated with BMI z-score. In the model including energy intake, food intake and an interaction term, only energy intake showed a significantly positive effect on BMI z-score. In the full sample (N = 9,782), only energy intake was significantly but negatively associated with BMI z-score. CONCLUSION: Proxy reporters are subject to misreporting, especially for children in the higher BMI levels. Energy intake is a more important predictor of unhealthy weight development in children than daily food intake. PMID- 24061348 TI - Low dietary calcium and obesity: a comparative study in genetically obese and normal rats during early growth. AB - PURPOSE: A low calcium intake (LCaI) may predispose to obesity, and excessive fat mass may be detrimental to bone. The impact of Ca inadequacy would be greater in subjects predisposed to obesity. LCaI effect on obesity development during the rapid growth period was compared in two strains of rats: spontaneously obese IIMb/beta (O) and Wistar (W). Pregnant rats were fed 0.5% (N) or 0.2% (L) of Ca (OLCa, ONCa, WLCa and WNCa). Male pups were fed the maternal diet until day 60. METHODS: Body composition, lipid profile, glucose homeostasis, 25 hydroxyvitamin D, Ca-phosphorus, and bone metabolism were evaluated. RESULTS: BW and body fat were higher, whereas body protein was lower in OLCa versus ONCa (p < 0.05). OLCa presented the highest body fat, glucose, non-HDL and total cholesterol, TGL, insulin levels, and HOMA-IR, liver weight, and adipose perigonadal plus retroperitoneal pads (p < 0.05). WLCa did not exhibit an increase BW and only showed a slight change in body composition with minor biochemical alterations compared to WNCa (p < 0.05). Osteocalcin, CTX, and proximal tibia and lumbar spine BMDs were lower in O than in W rats fed the same Ca diet (p < 0.05). Body ash and Ca content, and total skeleton BMC/BW were lower in OLCa and WLCa versus their corresponding NCa groups (p < 0.05). CONCLUSION: The negative effect of a low Ca diet on fat mass accumulation and lipid profile may be more evident in rats predisposed to obesity. Nevertheless, low CaI interferes with the normal glucose homeostasis leading to an increase in insulin resistance. Low CaI during early growth may be an obesogenic factor that may persist into adult life and may account for the development of obesity and some of its co-morbidities. PMID- 24061350 TI - Structure-immunogenicity relationship of kresoxim-methyl regioisomeric haptens. AB - Kresoxim-methyl was one of the two first strobilurins to be discovered, and nowadays it is widely used as an antifungal agent in crop protection. Because of its low molecular weight and negligible structural complexity, the generation of antibodies to kresoxim-methyl noticeably requires the preparation of functionalized haptens. In this study, the introduction of a hydrocarbon spacer arm at the aromatic moieties of the target molecule was carried out by a convergent strategy based on the Sonogashira cross-coupling reaction, and functionalized linkers of the same length were also tethered to the aliphatic toxophore group by the O-alkylation reaction. Evaluation of the immune response, in terms of antibody affinity, showed a differential behavior among five synthesized haptens whose sole dissimilarity was the derivatization site. The characteristic (methoxyimino)acetate moiety of strobilurins was revealed as the optimum linker position for high-affinity polyclonal and monoclonal antibody production. However, good monoclonal antibodies were isolated from mice immunized with a hapten carrying the linker at an opposite site, which otherwise generated a poor polyclonal response in rabbits. Site-heterology was confirmed as a feasible approach for the improvement of the apparent affinity, particularly with polyclonal antibodies. Several of the monoclonal antibodies generated in the context of this project could be proper binders for kresoxim-methyl immunosensing over different analytical platforms. PMID- 24061349 TI - Fucoxanthin in association with vitamin C acts as modulators of human neutrophil function. AB - INTRODUCTION: Neutrophils provide the first line of defense of the innate immune system by phagocytosing, killing and digesting bacteria and fungi. During this process, neutrophils produce reactive oxygen species (ROS), which in excess, can damage the cells themselves and surrounding tissues. The carotenoid fucoxanthin (Fc) has been studied concerning its antioxidant and anti-inflammatory actions. Vitamin c (Vc) also demonstrates potent antioxidant action. This study aimed to evaluate the effect of Fc (2 MUM) in association with Vc (100 MUM) on functional parameters of human neutrophils in vitro. MATERIALS AND METHODS: We evaluated the migration and phagocytic capacity, intracellular calcium mobilization, ROS production (O2(.)-, H2O2, HOCl), myeloperoxidase activity, profile of antioxidant enzymes, phosphorylation of p38 MAPK and p65 NFkappaB subunit, GSH/GSSG ratio and release of pro-inflammatory cytokines (TNF-alpha and IL-6) in neutrophils under different stimuli. RESULTS: We verified an increase in phagocytic capacity for all treatments, together with an increase in intracellular calcium only in cells treated with Fc and Fc + Vc. ROS production was reduced by all treatments, although Vc was a better antioxidant than Fc. Phosphorylation of the p-65 subunit of NFkappaB was reduced in cells treated with Fc + Vc and release of TNF-alpha and IL-6 was reduced by all treatments. These findings indicate that the regulation of inflammatory cytokines by neutrophils is not exclusively under the control of the NFkappaB pathway. Fc reduced the activity of some antioxidant enzymes, whereas Vc increased GR activity and the GSH/GSSG ratio. CONCLUSION: In conclusion, the results presented in this study clearly show an immunomodulatory effect of the carotenoid fc alone or in combination with Vc on the function of human neutrophils. PMID- 24061351 TI - On the importance of prompt oxygen changes for hypofractionated radiation treatments. AB - This discussion is motivated by observations of prompt oxygen changes occurring prior to a significant number of cancer cells dying (permanently stopping their metabolic activity) from therapeutic agents like large doses of ionizing radiation. Such changes must be from changes in the vasculature that supplies the tissue or from the metabolic changes in the tissue itself. An adapted linear quadratic treatment is used to estimate the cell survival variation magnitudes from repair and reoxygenation from a two-fraction treatment in which the second fraction would happen prior to significant cell death from the first fraction, in the large fraction limit. It is clear the effects of oxygen changes are likely to be the most significant factor for hypofractionation because of large radiation doses. It is a larger effect than repair. Optimal dose timing should be determined by the peak oxygen timing. A call is made to prioritize near real time measurements of oxygen dynamics in tumors undergoing hypofractionated treatments in order to make these treatments adaptable and patient-specific. PMID- 24061352 TI - Mixing times in a stirred vessel with a modified turbine. AB - We present a mixing-time analysis for a double-disk turbine (DDT, SI Pat.No. 22243) and the well-known Rushton turbine (RuT) based on liquid stirring in a baffled vessel. The mixing time was measured locally based on the pulse/response technique. A small quantity of hot water, poured into the liquid bulk, just above the measurement location, was used as the pulse, while the change in the liquid temperature represented the system response. The results were obtained in two ways: (i) from measurements on the set-up and (ii) based on a CFD analysis. The pouring of the hot water was numerically simulated through the initialization of the scalar field. The duration of the temperature-pulse initialization around the measuring location corresponded to the pouring time in the experiment. All the energy introduced was freely swept away by the flow. The CFD-analyzed mixing times were consistently higher than the measured ones across the whole testing range, from 150 to 460 min-1. When comparing our mixing-time results with those from the literature based on a dimensionless mixing time we found them to be in good agreement. PMID- 24061353 TI - Organic synthetic environmental endocrine disruptors: structural classes and metabolic fate. AB - Endocrine disruption is the modification of the endocrine system causing harmful effects in healthy subjects or their offspring. Physiological endocrine hormones act at very low plasma concentrations, and certain chemicals known as endocrine disrupting compounds (EDCs) are suspected of modifying endocrine function at similarly low concentrations. In our review we focus mainly on the structural classes of organic synthetic environmental endocrine disruptors and their common structural elements that enable them to interact with estrogen signalling. EDCs can affect estrogenic signalling directly through interaction with estrogen receptors (ERs) or indirectly through transcription factors such as the aryl hydrocarbon receptor (AhR) or by modulation of critical metabolic enzymes engaged in estrogen biosynthesis and metabolism. However, some structural elements can also pose a great risk of cytotoxicity and genotoxicity, especially after biotransformation to reactive metabolites. PMID- 24061355 TI - Desensitization of TNAZ via Molecular Structure Modification and Explosive Properties - A DFT Study. AB - TNAZ (1,3,3-trinitroazetidine) is a highly nitrated four membered nitrogen heterocyclic ring with greater performance when compared to melt castable explosive, TNT (trinitrotoluene). Desensitization of explosives is a significant area in military use. One current method is to use additives and coatings for explosives, as in the case of RDX. Another tactic would be to attempt small molecular level chemical changes in the explosive that bring the expected decrease in sensitivity without noteworthy loss in performance. TNAZ has three nitro groups. We thought that conversion of the nitro groups to nitroso and amine groups may decrease the sensitivity. We have correlated the bond dissociation energies with sensitivity and h50 values obtained from Keshavarz relations. We have also investigated chemical hardness and Mulliken electronegativities employing the frontier molecular orbitals. Furthermore, the explosive properties, i.e. detonation velocity (D), and detonation pressure (P) have been questioned by using both Kamlet-Jacobs equations and Keshavarz relations. Detonation products and power index values have also been calculated. We have proved that molecular modification is an operative method in desensitization of TNAZ. PMID- 24061354 TI - Synthesis and Biological Evaluation of Some Novel 3,5-Disubstituted-1,2,4 triazole Incorporated 2-Mercaptobenzothiazoles. AB - Several 2-mercaptobenzothiazole derivatives 5a-i containing 1,2,4-triazole moiety incorporating two additional substituents were synthesized. All the newly synthesized compounds were tested for in vitro activity against certain strains of bacteria such as Enterococcus faecalis, Bacillus coagulans, Pseudomonas aeruginosa, Escherichia coli and Candida albicans. Compound 5a showed significant activity against the Gram-negative bacteria Escherichia coli. Compounds 5a-i were also screened for their antifungal activity against Candida albicans and compounds 5a, 5b, 5d and 5g displayed significant activity against this fungus. Some of these compounds were evaluated for their in vivo anti-inflammatory activity, acute toxicity and ulcerogenic actions. Tested compounds 5g and 5h showed significant anti-inflammatory activity and significant gastrointestinal protection compared to the standard drug diclofenac sodium. Molecular modeling studies of the synthesized compounds are presented. PMID- 24061356 TI - Influence of Nafion in Titania Sol-gel Matrix on Analytical Characteristic of Amperometric Phenol Biosensor Based on Tyrosinase. AB - For detection of phenolic compounds a simple amperometric biosensor based on tyrosinase immobilized in titania sol-gel/Nafion composite was employed. Titania sol-gel was mixed with Nafion (v/v) in ratios 1:1 (TiO2/NF-1/1) and 2:1 (TiO2/NF 2/1), v/v. Morphology of immobilization composites was characterized by scanning electron microscopy. Analytical performance of biosensors with Nafion and based only on titania sol-gel (TiO2) was compared. Apart from sensitivity, linear range and detection limit also repeatability, reproducibility and storage stability were evaluated. The biosensor based on titania sol mixed with Nafion in ratio 1:1 (v/v) exhibited the best analytical parameters in terms of sensitivity: 2.84 uA L umol-1, corresponding LOD, 0.056 umol L-1, and the long-term stability within 20 days: it retained 80% of initial activity. PMID- 24061357 TI - Synthesis and Characterization of Ca and Ba Doped LAMOX Materials and Surface Study by X-ray Photoelectron Spectroscopy. AB - (La1-xCax)2Mo2O9-d and (La1-xBax)2Mo2O9-d (x = 0.05, 0.1, 0.15, 0.2) materials were prepared at 800 degrees C by co-precipitation method and characterized by X ray diffraction and scanning electron microscope. The XRD diagrams showed the presence of CaMoO4 and BaMoO4 secondary phases only at high contents of the dopants. X-ray photoelectron spectroscopy was used to study the surface chemical structure of doped and undoped materials (La2Mo2O9). It was found that the La and Mo atoms had 3+ and 6+ valence states, respectively. The absence of carbides and carbonates at surface suggests that, the unavoidable carbon contamination did not interact with the metal atoms, which allows applications using carbonaceous fuels, and, that the formation of secondary phases did not influence the surface state. XPS spectra show that the covalent character of the La-O bond was enhanced with calcium doping as compared to barium, predicting interesting conductive and catalytic properties of the materials. PMID- 24061358 TI - Some connectivity indices and zagreb index of polyhex nanotubes. AB - Several topological indices are investigated in polyhex nanotubes: Randic connectivity index, sum-connectivity index, atom-bond connectivity index, geometric-arithmetic index, First and Second Zagreb indices and Zagreb polynomials. Formulas for calculating the above topological descriptors in polyhex zigzag TUZC6[m,n] and armchair TUAC6[m,n] nanotube families are given. PMID- 24061359 TI - Stabilization of ZnS Nanoparticles in Micellar Dispersion of Cetyltrimethylammonium Bromide. AB - ZnS nanoparticles were precipitated in micellar dispersions of cetyltrimethylammonium bromide (CTAB). ZnS nanoparticles and cetyltrimethylammonium (CTA+) ions formed positively charged ZnS-CTA micelles with the mode zeta potential of 35 mV. The ZnS-CTA micelles were simulated by molecular modelling that confirmed the formation of positive CTA+ bilayers on the ZnS surface. The large agglomerates of the ZnS-CTA micelles were observed by the dynamic light scattering (DLS) method and electron transmission microscopy (TEM). The size of the ZnS nanoparticles of about 5 nm was estimated from their band-gap energy obtained from UV spectra and electron transmission micrographs. The relationship between zeta potentials (xi) and hydrodynamic sizes (d) was found as xi = 641/d - 5.9. PMID- 24061360 TI - Synthesis, Crystal Structure and Magnetic Properties of a new Hydroxylammonium Fluoroferrate. AB - This paper reports on the synthesis of a new hydroxylammonium fluoroferrate, with the formula (NH3OH)3FeF6, obtained after dissolving iron powder in hydrofluoric acid and adding solid NH3OHF. This new compound has been characterized by chemical and thermal analysis, single-crystal X-ray diffraction, and magnetic measurements. The title compound crystallizes trigonal, R3c, with cell parameters a = 11.4154(2) A, c = 11.5720(2) A, Z = 6. The structure consists of NH3OH+ cations and isolated FeF63- octahedra in which the central ion lies on a threefold axis. The oxygen and nitrogen atoms of the hydroxylammonium cations are donors of hydrogen bonds to fluoride anions, resulting in a network of hydrogen bonds between counterions. The effective magnetic moment ueff = 5.8 BM was calculated and perfectly matches the expected value of high-spin Fe(III) ions. The thermal decomposition of the compound was studied by TG, DSC, and X-ray powder diffraction. PMID- 24061361 TI - Polybenzene revisited. AB - Polybenzene was described by O'Keeffe et al., as an embedding of a 6.82 net in the infinite periodic minimal D-surface, with a single type of carbon atoms and was predicted to have a substantially lower energy per atom in comparison to C60, the reference structure in Nanoscience. They also described a 6.82 net embedded in the periodic minimal P-surface. We give here a rational structure construction for three benzene-based units (a third one described here for the first time in literature) and the corresponding networks. Their stability, relative to C60 but also to diamonds (the classical diamond D6 and the pentagon-based diamond D5), was calculated at the Hartree-Fock level of theory. The results confirmed the previous stability evaluation and support these structures for laboratory preparation. A Graph-theoretical description, in terms of Omega polynomial, of the three infinite networks is also presented. PMID- 24061362 TI - Comparison of Different Extraction Methods for the Determination of Essential oils and Related Compounds from Coriander (Coriandrum sativum L.). AB - The volatile oil of coriander (Coriandrum sativum L.) obtained from the fruits by soxhlet-dynamic headspace (S-DHS), solvent extraction (SE), steam distillation (SD), hydrodistillation (HYD) and supercritical CO2 extraction (SC-CO2) were analyzed by GC-FID and GC-MS. The SC-CO2 offered a higher yield (4.5%, w/w) than the other used techniques. Among the identified constituents, linalool was the main compound whatever the employed extraction procedure in contrast to the remaining components which varied according to the isolation technique showing a strong effect of the method used on the composition of these minor compounds. SC CO2 as compared to the other extraction techniques revealed its high efficiency in addition to the integrity saving of coriander fruit volatiles. Statistical analysis showed that all the detected and identified compounds were highly (P > 0.001) affected by the extraction technique used except the a-terpineol which appear stable. On the other hand, principal component analysis (PCA) revealed on the determination of one group represented by SC-CO2, S-DHS and HYD suggesting a similar essential oil composition. Obtained results show that, in Tunisian coriander essential oil, linalool was the main compound. PMID- 24061363 TI - A novel, heterogeneous and recyclable polymeric catalyst for the one-pot synthesis of polyhydroquinoline and 1,8-dioxohexahydroacridine derivatives under solvent-free conditions. AB - An efficient, recyclable and environmental-friendly synthetic route to polyhdroquinoline and 1,8-dioxohexahydroacridine derivatives have been developed via multi-component one-pot Hantzsch reaction of various aldehydes and ammonium acetate with (a) cyclic 1,3-dicarbonyl compounds and ethyl acetoacetate, and (b) 2 equivalents of cyclic 1,3-dicarbonyl compounds in the presence of novel polymeric catalyst [poly(AMPS-co-AA)] under solvent-free conditions. The present approach offers several advantages such as short reaction times, easy isolation and purification of product, and safe, non-toxic, recyclable and economic use of catalyst. PMID- 24061364 TI - Amperometric enzyme electrodes for xanthine determination with different mediators. AB - Two new amperometric carbon paste enzyme electrodes were developed for xanthine determination. 1,4-benzoquinone and poly(vinylferrocene) (PVF) were investigated as mediators. The parameters affecting the analytical performance of the enzyme electrode have been investigated in detail and optimized for modified enzyme electrodes. 1,4-benzoquinone modified enzyme electrode (BQ-CPEE) exhibited linear response from 1.9 * 10-7 M to 5.5 * 10-6 M and from 5.2 * 10-5 M to 8.2 * 10-4 M with a good detection limit of 1.0 * 10-7 M. The linear working range of the PVF modified enzyme electrode was between 1.9 * 10-7-2.1 * 10-6 M, 1.9 * 10-6-1.0 * 10-5 M and 1.1 * 10-4-8.8 * 10-4 M with a detection limit of 1.0 * 10-7 M. Hypoxanthine response of the electrodes was also determined. Modified enzyme electrodes were used for xanthine determination in real samples and good recoveries were obtained. PMID- 24061365 TI - Study of the Crystallization Fields of Vanadyl(IV) Selenites in the System VOSeO3 - SeO2 - H2O. AB - The solubility of VOSeO3-SeO2-H2O system was studied within the temperature interval 50-300 degrees C. The phase diagram of vanadyl(IV) selenites was plotted and the crystallization fields were determined for the different phases. Depending on the conditions for hydrothermal synthesis, several types of selenites were obtained - [VO(SeO3)(H2O)2] * 0.5 H2O, VOSeO3 * H2O, VOSeO3 and VOSe2O5. The different phases were established and characterized by chemical, thermal and powder X-ray diffraction analyses, as well as by IR spectroscopy. PMID- 24061366 TI - Photodegradation of Adsorbed Bovine Serum Albumin on TiO2 Anatase Investigated by In-Situ ATR-IR Spectroscopy. AB - A Fourier transform infrared-attenuated total reflection (FTIR-ATR) spectroscopy study of the photodegradation of adsorbed bovine Serum Albumin (BSA) on porous TiO2 films was carried out. The experiments were performed in a flow-through cell in water at concentrations of 10-6 mol/L at room temperature. The curve fitting method of the second derivative spectra allowed us to explore details of the secondary structure of pure BSA in water and conformation changes during adsorption and illumination processes. The results clearly demonstrate that the amount of adsorbed BSA decreased under UV illumination although adsorption without illumination is considered as irreversible. The influence of irradiation on the adsorption is not yet well understood. Also, during illumination of adsorbed BSA dissolved CO2 at 2341 cm-1 was observed, which indicates that part of the BSA is mineralized. The analysis of second derivative of infrared spectra was used to obtain direct quantitative information on the secondary structure components of BSA which show that the percentage of a-helix decreases from around 63% to 54% during UV light illumination whereas the percentage of b-turn increases. PMID- 24061367 TI - Determination of Equilibrium Constants of Some Novel Antioxidant Compounds and Study on their Complexes with Some Divalent Metal ions in Ethanol-water Mixed. AB - This study aims to investigate the nature and type of complexes formed in solution, between novel antioxidant compounds [P1(4-(1-(3-hydroxy-4 methoxyphenyl)propyl)benzene-1,2-diol) and P2(4-(1-(3-hydroxy-4 methoxyphenyl)propyl)benzene-1,3-diol)] and the ions Cu2+, Ni2+, Zn2+ and Co2+. Potentiometric titration technique was used to follow the formation of complexes during the course of coordination. The stability of the complexes formed was controlled through the determination of stability constants in aqueous ethanol solution at 25 +/- 0.1 C degrees and ionic strength of 0.1 M NaCl. Basicity of the ligand was also assessed by the determination of the dissociation constants of the ligand. All the constants were computed by computer refinement of pH volume data using the SUPERQUAD program. The species distribution diagram of each type of complex has been obtained after computer calculation process. PMID- 24061368 TI - Comparison of Micelle-Mediated Extraction and Diazotized 2,4-Dimethoxyaniline Methods for the Simultaneous Determination of Carbamate Insecticides by HPLC-UV. AB - The feasibilities of two strategies for the simultaneous analysis of five carbamate insecticides (i.e. propoxur, carbofuran, carbaryl, isoprocarb, and promecarb) by high performance liquid chromatography (HPLC) have been investigated. The first method is the preconcentration strategy based on micelle mediated extraction (MME) using sodium dodecyl sulfate. The second strategy uses chemical derivatization with 2,4-dimethoxyaniline (DMA) reagent before subjecting to HPLC. The parameters affecting the analysis were optimized. For MME, the optimum conditions were 4.0% (w/v) SDS in the presence of 5.0 mol L-1 HCl. Meanwhile, the DMA derivatization condition was 1.5 mmol L-1 DMA, 7 mmol L-1 NaNO2, and 50 mmol L-1 HCl, and 250 mmol L-1 NaOH for the hydrolysis of carbamates before their derivatization. The target carbamates and their derivatives were monitored at wavelengths of 270 and 380 nm for the MME and DMA derivatization methods, respectively. The capability of each developed method was compared in terms of separation time and limits of detection (LODs). The results show that the five studied insecticides were successfully separated within 8 min (DMA) and 27 min (MME), respectively. LODs of the insecticides obtained from DMA (0.01-0.04 mg L-1) were lower than those obtained from MME (0.1-0.7 mg L-1). The proposed DMA method is versaltile and superior to MME for the analysis of carbamate insecticides in tap water samples. PMID- 24061369 TI - Synthesis of zinc hydroxide nanocrystals and application as a new electrochemical sensor for determination of selected sympathomimetic drugs. AB - Zinc hydroxide (Zn(OH)2) nanoparticles with nanocrystal morphology and grain size ~48 nm have been successfully synthesized by using a two-step, template- and surfactant-free method. The synthesized product was characterized by FTIR, powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and energy-dispersive spectroscopy (EDX). The XRD pattern of zinc oxide confirms formation of the wurtzite structure of Zn(OH)2. For the first time zinc oxide nanostructures have been used for electrocatalytic oxidation and determination of sympathomimetic drugs in aqueous solution. The electrochemical parameters of sympathomimetic drugs were investigated by means of cyclic voltammetry and differential pulse voltammetry as well as flow injection analysis. PMID- 24061370 TI - Ion-Selective Electrodes for the Potentiometric Determination of Pramoxine HCl Using Different Ionophores. AB - Four novel pramoxine HCl (PAM) selective electrodes were investigated with 2 nitrophenyl octylether as a plasticiser in a polymeric matrix of polyvinyl chloride (PVC). Sensor 1 was fabricated using sodium-tetraphenylborate (TPB) as an anionic exchanger without incorporation of an ionophore. Sensor 2 used 2 hydroxy propyl -cyclodextrin as an ionophore, while sensors 3 and 4 were constructed using 4-sulfocalix-6-arene and 4-sulfocalix-8-arene respectively as ionophores. Linear responses of PAM within the concentration ranges of 1.0 * 10-4 to 1.0 * 10-2 mol L-1 and 1.0 * 10-5 to 1.0 * 10-2 mol L-1 were obtained using sensors 1 and 2, respectively and 1.0 * 10-6 to 1.0 * 10-2 mol L-1 were obtained using sensors 3 and 4. Nernstian slopes of 50.4 +/- 0.6, 54.3 +/- 0.8, 56.3 +/- 0.3 and 59.1 +/- 0.5 mV/decade over the pH range of 3.0-6.0 were observed. The selectivity coefficients of the developed sensors indicated excellent selectivity for PAM. The utility of 2-hydroxy- propylcyclodextrin (2HP-beta-CD) and 4 sulfocalix [6,8] arene (SC 6, 8) as ionophores had a significant influence on increasing the membrane sensitivity and selectivity of sensors 2, 3 and 4 compared to sensor 1. The proposed sensors displayed useful analytical characteristics for the determination of PAM in bulk powder, pharmaceutical formulation, and in biological fluid. Validation of the method showed the suitability of the proposed electrodes for the use in the quality control assessment of the drug. Furthermore, statistical comparison between the results obtained by the proposed method and the official method of the drug was performed and no significant difference was found. PMID- 24061371 TI - Influence of process parameters on the extraction of flavanones from mandarin peel. AB - Flavanones are an important group of flavonoids that are characteristic for citrus. In the present work isolation of flavanones from mandarin peel was performed by conventional extraction using water, ethanol, acetone and aqueous solutions of acetone and ethanol. The extracts were analysed on the content and composition of flavanones. Furthermore the DPPH radical scavenging activity of extracts was determined. Finally, the influence of extraction parameters (particle size, extraction temperature, extraction time, material to solvent ratio, number of extraction stages and type of solvent) on the yield and the efficiency of extraction were determined by Plackett-Burman experimental design. The results showed that 70% aqueous solution of acetone was the most efficient solvent for isolation of flavanones from mandarin peel. The main flavanones present in the obtained extracts were hesperidin (HES) and narirutin (NRT). The number of extraction stages influenced the yield of extraction, type of solvent influenced the hesperidin extraction efficiency and particle size of material influenced the narirutin extraction efficiency. PMID- 24061372 TI - Separation of Biogas Components with Single Wall Carbon Nanotubes: a GCMC Simulation. AB - Biogas is a green energy source that mainly contains CH4, CO2 ,traces of H2S and fractions of H2O vapor. One of the effective methods in biogas treatment from its pollutants is adsorptive separation. Here, enrichment of methane using (10, 10) and (6, 6) carbon nanotubes (CNTs) in modelled biogas consisting CH4, CO2 and H2S is studied. Simulations were carried out using Grand Canonical Monte Carlo (GCMC) method. Adsorption isotherms obtained at various temperatures and pressures for two single wall carbon nanotubes (SWCNTs). To quantify the separation ability of the nanotubes the adsorptive separation factors for H2S/CH4 and CO2/CH4 were calculated. For studding temperature effect, simulations at two (0.1 and 1 MPa) pressures and four temperatures: 288, 298, 318 and 338 K have been performed. In all studied conditions, CO2 is preferentially adsorbed by CNTs. Results have shown that the two separation factors are considerable, particularly for (10, 10) CNT. Additionally, the adsorption and selectivity behaviour of studied gases were considered in (6,6), (8,8) and (10,10) CNT hexagonal bundles for comparison. The results for single nanotubes were confirmed with the bundles. Hence, despite lower concentration of CO2 than CH4 and trace amount of H2S in biogas, they can be separated from methane effectively by CNTs as adsorbents. Our results showed that the CNTs can be remarkable tools in methane separation from biogas. PMID- 24061373 TI - Synthesis, Characterization and Crystal Structure Studies of Nickel(II) Complexes With NO Donor Schiff Base Ligands. AB - Four complexes of the type [Ni(N-substituted-salicydenaminato)2], with bidentate Schiff base ligands (L1-L4), have been synthesized. The complexes were characterized by IR and elemental analysis methods. The solid state structures of three complexes (1-3) were determined by X-ray crystallography. The complexes show mononuclear, four-coordinate, slightly distorted square-planar trans Ni(N2O2) geometry. The angles around the Ni center deviate slightly from 90 degrees indicating a rectangular distortion. The chelating N-Ni-O angles are larger than 90 degrees whereas the non-chelating N-Ni-O angles are smaller than 90 degrees . The crystallograpic studies indicate that any steric/electronic effects due to CH3 and Br moieties have had no significant impact on the coordination sphere. PMID- 24061374 TI - 2-(Naphthalen-2-yl)-1,2,3,4-tetrahydroquinazoline-2-carbaldehyde Oxime and Co(III) and Ni(II) Complexes of Tridentate Ligand Containing Oxime, Imine and Amine Donor Groups: Syntheses, Characterisation and Thermal Properties. AB - A novel 1,2,3,4-tetrahydroquinazoline oxime was synthesised from a condensation reaction of 2-(naphthalen-2-yl)-2-oxoacetaldehyde oxime with 2-aminobenzylamine. Subsequently, a-imine oxime complexes of this compound that formed with Co(III) and Ni(II) metal ions were obtained. All structures were characterised by spectral methods (FT-IR, nmr, AAS, mass), elemental analysis, thermal analyses, magnetic susceptibility and molar conductivity. The analyses confirmed the following molecular formulae: [Co(L)2]Cl * C2H5OH * 0,5H2O and [Ni(HL)2]Cl2. The Co(III) complex is diamagnetic. Magnetic susceptibility measurements revealed octahedral geometry for the Co(III) and Ni(II) complexes. In the complexes, the chloride ion was found to be noncoordinated to the metal ions as confirmed by conductivity measurements. The NMR spectra of the Co(III) complex confirmed the presence ofethanol in the Co(III) complex. The experimental results of TG-DTA showed that the Co(III) complex contained ethanol and crystal water in the first two stages. The end of the thermal decomposition of the complexes yielded a final product of a metal oxide. PMID- 24061375 TI - Structural and Luminescent Properties of Eu2+-doped Aluminates Prepared by the Sol-gel Method. AB - Alkaline earth aluminates with the overall nominal compositions Mg0.5Sr0.5Al2O4 (MSA), Ca0.5Sr0.5Al2O4 (CSA) and Ca0.5Mg0.5Al2O4 (CMA) doped with 0.5 or 1 mol% of Eu2+ ions were obtained by a modified aqueous sol-gel method and annealed in a reductive atmosphere at 900, 1000, 1100 and 1300 degrees C. The sample compositions and their structures were studied by XRD employing the Rietveld method. Solid solubility was confirmed in CSA only, due to the similar ionic radii of Ca2+ and Sr2+. UV excited luminescence was observed in the blue region (lambda = 440 nm) in samples of CSA and CMA containing the monoclinic phase of CaAl2O4 and in the green region (lambda = 512 nm) in samples of MSA containing hexagonal or monoclinic phases of SrAl2O4. PMID- 24061376 TI - Ion-Association Reaction of Rb+ and Br- in 2-Methylpropan-2-ol + Water Mixtures. AB - The molar conductivity of RbBr solutions in 2-methylpropan-2-ol (tert-butanol) + water mixtures at alcohol mass fractions of 0.70, 0.80 and 0.90 was measured at temperatures from 288.15 to 308.15 K at 5 K intervals. The limiting molar conductivity (Deltao) and the ion-pair formation constant (KoA) were determined by the Lee-Wheaton conductivity equation. Thermodynamic quantities, Gibbs energy (DeltaGo), enthalpy (DeltaHo) and entropy (DeltaSo), for the ion-association reaction were derived from the temperature dependence of KoA; the activation energy of the ionic movement (DeltaH*) was derived from the temperature dependence of Lambdao. These values were compared with those obtained earlier for HBr and NaBr in the same mixtures. PMID- 24061377 TI - Structural, Morphological and Electrical Properties of La1-xSrxAlO3-delta (x = 0, 0.1, 0.15) Synthesized by the Pechini Method. AB - La1-xSrxAlO3-delta (x = 0, 0.1, 0.15) fine particles were prepared by the Pechini process using citric acid and ethylene glycol at low temperature 900 degrees C. The powders were studied by several physical characterization techniques. The FTIR spectrum of the resin treated at 200 degrees C revealed the formation of a metalorganic complex and a polymerized form of ethylene glycol. XRD spectra of the samples, calcined at 900 degrees C, illustrated a single phase LaAlO3. However, La0.9Sr0.1AlO3-delta and La0.85Sr0.15AlO3-delta powders mainly consist of a deficient hexagonal perovskite phase with a small amount of a second phase (LaSrAl3O7). Ionic conductivities of these materials were studied by impedance spectroscopy in the range of 100-700 degrees C in air. PMID- 24061378 TI - Solvent Extraction of Some Divalent Metal Cations into Nitrobenzene by Using a Synergistic Mixture of Strontium Dicarbollylcobaltate and p-tert Butylcalix[4]arene-tetrakis (N,N-Diethylacetamide). AB - From extraction experiments and g-activity measurements, the exchange extraction constants corresponding to the general equilibrium M2+(aq) + 1*Sr2+(nb) <-> 1*M2+(nb) + Sr2+(aq) taking place in the two-phase water-nitrobenzene system (M2+ = Ca2+, Ba2+, Cu2+, Zn2+, Cd2+, Pb2+, UO22+, Mn2+, Co2+, Ni2+; 1 = p-tert butylcalix[4]arene-tetrakis(N,N-diethylacetamide); aq = aqueous phase, nb = nitrobenzene phase) were determined. Further, the stability constants of the 1*M2+ complexes in water-saturated nitrobenzene were calculated; they were found to increase in the series of Cu2+ < Ba2+ < Zn2+ < Ni2+ < UO22+ < Co2+ < Mn2+ < Cd2+ < Ca2+ < Pb2+. PMID- 24061379 TI - In Vitro Antioxidant Activity of Two 6-(propan-2-yl)-4-methyl-morpholine-2,5 diones. AB - In vitro antioxidant activity of two cyclodidepsipeptides, 3-(2-methylpropyl)-6 (propan-2-yl)-4-methyl-morpholine-2,5-dione and 3,6-di(propan-2-yl)-4-methyl morpholine-2,5-dione, was investigated. Our data indicate moderate antioxidant potentials of the two studied cyclodepsipeptides. A high correlation between 2,2 diphenyl-1-picrylhydrazyl (DPPH)-radical scavenging capacity and total reducing power were found. According to the density functional theory (DFT) calculations, the most probable mechanism of antioxidant action is hydrogen atom abstraction from the activated C-H group at 3-position in the morpholinedione ring. To the best of our knowledge this is the first report about the antioxidant properties of morpholine-2,5-diones derivatives. PMID- 24061380 TI - Extraction and DFT Study on the Complexation of the TRIS+ Cation with a Hexaarylbenzene-Based Receptor. AB - From extraction experiments and ?-activity measurements, the exchange extraction constant corresponding to the equilibrium TRIS+(aq) + 1.Cs+(nb) <-> 1.TRIS+(nb) + Cs+(aq) taking place in the two-phase water-nitrobenzene system (TRIS+ = (HOCH2)3C-NH3+, 1 = hexaarylbenzene - based receptor; aq = aqueous phase, nb = nitrobenzene phase) was evaluated as log Kex (TRIS+, 1.Cs+) = -2.0 +/- 0.1. Further, the stability constant of the hexaarylbenzene - based receptor .TRIS+ complex (abbrev. 1.TRIS+) in nitrobenzene saturated with water was calculated for a temperature of 25 degrees C : log betanb (1.TRIS+) = 6.0 +/- 0.2. By using quantum mechanical calculations, the most probable structure of the 1.TRIS+ complex species was solved. In this complex having C3 symmetry, the cation TRIS+ synergistically interacts with the polar ethereal oxygen fence and with the central hydrophobic benzene bottom via cation - pi interaction. PMID- 24061381 TI - Synthesis, crystal structure and fluorescence of an unusual terbium carboxylate. AB - A novel terbium-containing fluorescent material, [Tb(CH3COO)2(H2O)3]Cl (1), has been prepared by a facile approach, i.e. an ultrasonic synthesis. Compound 1 has been structurally characterized via single-crystal X-ray diffraction and it crystallizes in the space group P21/n of the monoclinic system with four formula units in a cell. Compound 1 features a novel one-dimensional (1-D) chain-like structure. The 1-D chains are interconnected by hydrogen bonds to yield a 3-D supramolecular framework. Photoluminescent investigation reveals that compound 1 displays strong emission bands identified as the characteristic emissions of 5D4 > 7FJ (J = 3, 4, 5, 6) of Tb3+. PMID- 24061382 TI - Synthesis and Crystal Structure of a New Hetro-nuclear Cu2Sr Complex of Salen Type Ligand. AB - A new hetero-trinuclear complex [Cu2(u-L)2Sr(NO3)2] has been synthesized and characterized by elemental analysis, IR, UV-Vis and X-ray crystallography, where L is a dianionic tetradentate Schiff base ligand with N2O2 donor atoms. The X-ray structure indicates that the trinuclear complex adopts a bent structure for the three metal atoms, with a Cu1-Sr-Cu2 intramolecular angle of approximately 99.1 degrees . In the complex, the two terminal Cu ions are situated in a distorted square planar geometry coordinated by two imine nitrogen atoms and two phenolato oxygen atoms from the Schiff base ligand. The two neutral CuL complexes are bonded to a Sr(II) ion. The geometry of central strontium atom is a distorted square antiprism formed by eight oxygen atoms, four oxygen atoms belonging to the two Schiff base ligands from two units of CuL and four oxygen atoms belonging to the two bidentate nitrate ions. The two bidentate nitrates are cis to each other. PMID- 24061383 TI - Synergistic extraction of calcium and strontium into nitrobenzene by using hydrogen dicarbollylcobaltate and 1,2-bis(diphenylphosphino)ethane dioxide. AB - Extraction of microamounts of calcium and strontium by a nitrobenzene solution of hydrogen dicarbollylcobaltate (H+B-) in the presence of 1,2 bis(diphenylphosphino)ethane dioxide (DPPEtDO, L) has been investigated. The equilibrium data have been explained assuming that the species HL+, HL+2, ML2+2 and ML2+3 (M2+ = Ca2+, Sr2+) are extracted into the organic phase. The values of extraction and stability constants of the cationic complexes in nitrobenzene saturated with water have been determined. In the considered nitrobenzene medium, it was found that the stability constants of the complexes CaL2+2 and CaL2+3 , where L is DPPEtDO, are somewhat higher than those of the corresponding complex species SrL2+2 and SrL2+3 with the same ligand L. PMID- 24061384 TI - Computing Theta(G,x) and Pi(G,x) Polynomials of an Infinite Family of Benzenoid. AB - The topological index of a graph G is a numeric quantity related to G which is invariant under automorphisms of G. The Omega polynomial Omega(G,x) for counting qoc strips in G is defined as Omega(G,x) = Sigmac m(G,c)xc with m(G,c) being the number of strips of length c. Other three related polynomials can be calculated on ops as Theta(G,x) = Sigmacm(G,c)cxc, Sd(G,x) = Sigmacm(G,c)x|E(G,x)|-c and Pi(G,x) = Sigmacm(G,c)cx|E(G)|-c. The above polynomials count codistant and non codistant edges, respectively. In this paper we compute the Theta Theta(G,x), Pi Pi(G,x) polynomials and the corresponding indices in the circumcoronene series of benzenoids. PMID- 24061385 TI - A Conventional Method for Valid "Actual Soil pH" Measurement. AB - After recognition of the Suspension Effect problem in potentiometric measurements in aqueous suspensions, no scientific consensus about its cause and nature was obtained. Numerous conventional methods of soil pH measurement were therefore introduced for practical soil pH determination. Most of the results of these methods are not valid with regard to the international pH scale. The method proposed in the present work rejects improper procedures and introduces correct soil sampling and a suitable pH measuring technique, as follows: the indicator glass electrode, substituting for roots in the soil, is inserted in a partly diluted sample suspension of the original soil and the modified reference electrode contacts the sample in a manner that eliminates the abnormal liquid junction potential. "Actual soil pH values" measured in this way are valid but the method used is a conventional one. Namely, the irreversible potential of the glass electrode includes the suspension effect of the first kind (SE1) and is a mixed steady-state potential. It is considered by convention as a substitute for and equivalent to the equilibrium potential which as a rule does not exist in a suspension. The soil pH values measured by the proposed conventional method are reproducible and valid with regard to the international hpH scale. They could be considered as the pH values, with uncertainty of +/- 0.1 pH unit, to which the roots are exposed. PMID- 24061386 TI - Single-base DNA discrimination via transverse ionic transport. AB - We suggest the discrimination of single DNA bases via transverse ionic transport, namely by detecting the ionic current that flows in a channel while a single stranded DNA is driven through an intersecting nanochannel. Our all-atom molecular dynamics simulations indeed show that the ionic currents of the four bases are statistically distinct, thus offering another possible approach to sequencing DNA. PMID- 24061387 TI - Brief Internet-based intervention reduces posttraumatic stress and prolonged grief in parents after the loss of a child during pregnancy: a randomized controlled trial. AB - BACKGROUND: The loss of a child during pregnancy causes significant psychological distress for many women and their partners, and may lead to long-lasting psychiatric disorders. Internet-based interventions using exposure techniques and cognitive restructuring have proved effective for posttraumatic stress disorder (PTSD) and prolonged grief. This study compared the effects of an Internet-based intervention for parents after prenatal loss with a waiting list condition (WLC). METHODS: The Impact of Event Scale - Revised assessed symptoms of PTSD; the Inventory of Complicated Grief and the Brief Symptom Inventory assessed depression, anxiety, and general mental health. The 228 participants (92% female) were randomly allocated to a treatment group (TG; n = 115) or a WLC group (n = 113). The TG received a 5-week cognitive behavioral intervention including (1) self-confrontation, (2) cognitive restructuring, and (3) social sharing. RESULTS: The TG showed significantly reduced symptoms of posttraumatic stress, prolonged grief, depression, and anxiety relative to the WLC control group. Intention-to treat analysis revealed treatment effects of between d = 0.84 and d = 1.02 for posttraumatic stress and prolonged grief from pre- to posttreatment time points. Further significant improvement in all symptoms of PTSD and prolonged grief was found from the posttreatment evaluation to the 12-month follow-up. The attrition rate of 14% was relatively low. CONCLUSIONS: The Internet-based intervention proved to be a feasible and cost-effective treatment, reducing symptoms of posttraumatic stress, grief, depression, anxiety, and general mental health after pregnancy loss. Low-threshold e-health interventions should be further evaluated and implemented routinely to improve psychological support after pregnancy loss. PMID- 24061388 TI - Artificial semiconductor/insulator superlattice channel structure for high performance oxide thin-film transistors. AB - High-performance thin-film transistors (TFTs) are the fundamental building blocks in realizing the potential applications of the next-generation displays. Atomically controlled superlattice structures are expected to induce advanced electric and optical performance due to two-dimensional electron gas system, resulting in high-electron mobility transistors. Here, we have utilized a semiconductor/insulator superlattice channel structure comprising of ZnO/Al2O3 layers to realize high-performance TFTs. The TFT with ZnO (5 nm)/Al2O3 (3.6 nm) superlattice channel structure exhibited high field effect mobility of 27.8 cm(2)/Vs, and threshold voltage shift of only < 0.5 V under positive/negative gate bias stress test during 2 hours. These properties showed extremely improved TFT performance, compared to ZnO TFTs. The enhanced field effect mobility and stability obtained for the superlattice TFT devices were explained on the basis of layer-by-layer growth mode, improved crystalline nature of the channel layers, and passivation effect of Al2O3 layers. PMID- 24061391 TI - If less is more, which outcomes should be presented in facilitating prostate cancer screening decision making? PMID- 24061392 TI - General health checks in adults. PMID- 24061393 TI - If less is more, which outcomes should be presented in facilitating prostate cancer screening decision making? - reply. PMID- 24061394 TI - Pacemaker indication must meet Medicare coverage determination. PMID- 24061395 TI - General health checks in adults - reply. PMID- 24061396 TI - Testing patient comprehension of medication labeling is important. PMID- 24061397 TI - Cardiac arrests during endoscopy with anesthesia assistance. PMID- 24061398 TI - Cardiac arrests during endoscopy with anesthesia assistance - reply. PMID- 24061400 TI - Blastoid mantle cell lymphoma with cutaneous involvement and aberrant immunophenotype. PMID- 24061399 TI - Benign subclinical syringomatous proliferations adjacent to a microcystic adnexal carcinoma: a tumor mimic with significant patient implications. AB - Microcystic adnexal carcinoma (MAC) is an uncommon, locally aggressive, malignant cutaneous tumor with pilar and eccrine differentiation. Mohs micrographic surgery is the treatment of choice for this condition, but specific histological findings can complicate MAC removal and leave doubt as to whether the tumor has been completely removed. Here we describe the clinical and pathological characteristics of a case in which a patient with an MAC underwent multiple reexcisions because of the presence of benign subclinical syringomatous proliferations adjacent to the primary lesion. Our case raises awareness of syringomatous proliferation, a benign process histologically similar but behaviorally distinct from a primary MAC. This experience highlights the importance of continued communication between dermatopathologists and dermatologic surgeons in providing quality patient care. PMID- 24061401 TI - Immunohistochemical evaluation of COX-1 and COX-2 expression in keloid and hypertrophic scar. AB - Both keloids (KLs) and hypertrophic scars (HSs) are considered as dermal fibroproliferative diseases that differ clinically and histopathologically. Although several factors have been postulated in the etiopathogenesis of these conditions, there has been growing evidence to suggest the role of COXs in the pathogenesis of abnormal wound healing because of the reduction of formation of KL and HS in patients using nonsteroidal anti-inflammatory drugs and a COX-2 inhibitor. The aim of the present work is to evaluate the pattern and localization of COX-1 and COX-2 expression in KL and HS compared with surgical scars. COX-1 and COX-2 were analyzed on skin biopsies of 30 patients who presented with KL (15) and HS (15) and 10 normal surgical scars (controls). Both COX-1 and COX-2 were expressed not only in dermal components (fibroblasts, inflammatory cells, and endothelial cells) but also in keratinocytes of the overlying epidermis in the different studied scar lesions. The percentage of COX 1 expression increased progressively from surgical scar (40%) to HS (53.3%) to KL (100%) with a statistically significant difference (P = 0.002). COX-2 was expressed in 100% of surgical scars, 73.3% of HS and 86.7% of KL with the absence of significant differences (P > 0.05). The significant difference in COX-1 expression between HS and KL may refer to the presence of different pathways for the emergence of these diseases. The expression of COX-2 in all scars (normal or abnormal) indicates its active role as an inflammatory mediator. Keratinocytes play an active role in induction of scarring by up-regulation of inflammatory mediators, such as COX-1 and COX-2. PMID- 24061403 TI - Painful plaques on extremities of a woman: challenge, answer. Diagnosis: Lupus erythematosus profundus with extensive calcification. PMID- 24061402 TI - The utility of C4d immunohistochemistry on formalin-fixed paraffin-embedded tissue in the distinction of polymorphic eruption of pregnancy from pemphigoid gestationis. AB - Polymorphic eruption of pregnancy (PEP), formerly known as pruritic urticarial papules and plaques of pregnancy, is a dermatosis of pregnancy that must be distinguished from pemphigoid gestationis (PG). Although this differential diagnosis may be possible on routine histology, an additional biopsy for direct immunofluorescence (DIF) is often needed. Recent studies have demonstrated the utility of anti-C4d or anti-C3d antibodies in the diagnosis of bullous pemphigoid (BP) in formalin-fixed paraffin-embedded tissue (FFPE). We investigated the utility of routine immunohistochemistry (IHC) for anti-C4d in FFPE tissue in the specific differential diagnosis of PEP versus PG in known, DIF-proven cases. We performed C4d IHC on PEP (n = 11), PG (n = 8), DIF-proven BP (n = 12), and other common dermatoses (n = 12) that are typically DIF negative. None of the PEP cases (0/11) or the other common dermatoses (0/12) demonstrated C4d positivity at the basement membrane zone. In comparison, 100% of PG cases (8/8) and 83.3% of BP cases (10/12) showed linear C4d immunoreactant deposition along the basement membrane zone. The results demonstrate the potential utility of C4d IHC in FFPE tissue for distinguishing PEP from PG, thus potentially obviating the need of a repeat biopsy for DIF, particularly in C4d-negative cases where there is a low suspicion of PG on both clinical and histological grounds. Also, patients with positive C4d-positive immunoreactivity may also potentially proceed directly to less invasive serological confirmatory testing, such as BP180 NC16a enzyme-linked immunoabsorbent assay. PMID- 24061404 TI - Atypical fibrous histiocytoma arising in the perianal area: a case report and review of the literature. AB - Atypical fibrous histiocytoma (AFH) is an uncommon variant of cutaneous fibrous histiocytoma that can display histologic features associated with malignancy. Fewer than 150 cases have been reported in the literature. The majority of these lesions present on the trunk and extremities of middle-aged women. Genital lesions are rare, with one documented case of vulvar AFH and another case of scrotal AFH in the literature. We report an additional case of a 68-year-old woman who was diagnosed with an AFH in an unusual location, the perianal area. Histologically, the lesion was characterized by a nodular fairly well circumscribed proliferation of large epithelioid macrophages with scattered lymphocytes and mast cells in the background. The atypical macrophages contained enlarged markedly pleomorphic nuclei with prominent nucleoli. Scattered multinucleated "monster cells" and atypical mitoses were observed throughout the lesion. Immunologically, the lesional cells were focally positive when stained with antibodies against CD163 and Factor XIIIa. They were negative for CD34, CD31, desmin, smooth muscle actin, CAM 5.2, keratin 5/6, S100, CD3, CD20, and CD30. The constellation of histologic and immunologic features was most consistent with an AFH. To our knowledge, this case is the first perianal presentation of AFH to date. PMID- 24061406 TI - Efficient SO2 capture by amine functionalized PEG. AB - Polyethylene glycols (PEGs) are a class of non-toxic, non-volatile, biocompatible, and widely available polymers. In this work, we synthesized N ethyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-aminoethanol (EE3AE) that combines the properties of PEG and amines, and N-decyl-N-ethyl-2-aminoethanol (DEAE). Their performances to capture SO2 were studied at different temperatures, pressures, and absorption times. The interaction between the absorbents and SO2 were characterized by NMR and FTIR techniques. It was demonstrated that both EE3AE and DEAE could absorb SO2 efficiently, and there existed chemical and physical interactions between the absorbents and SO2. In particular, the absorption capacity of EE3AE could be as high as 1.09 g SO2 per g EE3AE at 1 atm. The absorption capacity of EE3AE was much larger than that of DEAE because the ether group in the EE3AE interacted with SO2 more strongly than the alkyl group in the DEAE. The SO2 absorbed by EE3AE could be stripped out by bubbling N2 or by applying a vacuum and the EE3AE could be reused. Moreover, both absorbents exhibited a high SO2-CO2 selectivity. PMID- 24061407 TI - Important components to create personal working alliances with clients in the mental health sector to support the recovery process. AB - Personligt ombud (PO) is a Swedish version of case management that aims to support individuals with psychiatric disabilities. Guidelines to the PO service emphasize the different role that the PO plays with respect to the relationship with clients. The aim of this study was to investigate the components that POs found to be important in the relationship with clients. Telephone interviews with 22 POs across Sweden were carried out. The interviews were recorded, transcribed, and analyzed using qualitative content analysis. The relationship with each client was described as the foundation of the POs' work; it was the only 'tool' they had. The findings were reflected in a main theme, which showed the importance of creating personal working alliances with each client where POs put the client at the center of the work and adjusted their support according to the client's needs at the time. Important components were that the PO and the client trusted each other, that the power between the PO and the client was balanced, and to be a personal support. Many of the components that POs found to be important are shown as essential in recovery-oriented services. POs followed the client in the process and remained as long as necessary and this is one way of bringing hope to the client's recovery process. However, the personal tone can be fraught with difficulties and to maintain professionalism, it is necessary to reflect, through discussions with colleagues, with the leader and in supervision. PMID- 24061408 TI - UV induced visual cues in grasses. AB - Grasses are traditionally considered as wind pollinated, however, field observations confirmed frequent insect visits to grass flowers, suggesting insect pollination. Fruit and seed predators inflict heavy losses to cereals and millets during their growth, maturation and storage. The actual factors guiding insects and predators to grass flowers, fruits and seeds are not clear. Here, we report attractive blue fluorescence emissions on grass floral parts such as glumes, lemma, palea, lodicules, staminal filaments, pollens and fruits in ultraviolet (UV) 366 nm, whereas the stigmatic portions were not blue, but red fluorescent. We characterized the blue fluorescent constituent in grass reproductive structures as ferulic acid (FA). Fluorescence spectra of blue-emitting grass floral, seed extracts and isolated FA on excitation at 366 nm showed their emissions at 420-460 nm. We propose these FA-based blue fluorescence emissions in grass reproductive structures as visual cues that attract pollinators, predators and even pests towards them. PMID- 24061409 TI - Bottom-up assembly of ultrathin sub-micron size metal-organic framework sheets. AB - A solution-based two-dimensional interfacial reaction between 5,10,15,20-tetra(4 pyridyl)-porphinato zinc(II) (ZnTPyP, 1) and Cu(NO3)2.3H2O, 2, results in the assembly of uniform preferentially oriented highly crystalline metal-organic framework nanosheets, NAFS-21 that have sub-micron planar size and mono-molecular thickness. PMID- 24061410 TI - Lipid drug conjugate nanoparticle as a novel lipid nanocarrier for the oral delivery of decitabine: ex vivo gut permeation studies. AB - The purpose of this study was to develop lipid drug conjugate (LDC) nanoparticles of decitabine (DCB) using stearic acid as a lipid to increase the permeability of the drug along with its protection from chemical degradation. The LDC was prepared by salt formation of DCB with stearic acid and followed by cold homogenization technique to produce the LDC nanoparticles. The role of key independent variables influencing on dependent variables were determined by using a Box-Behnken design. The optimized batch revealed spherical morphology under TEM analysis with particle size of 202.6 +/- 1.65 nm and 0.334 +/- 0.987 PDI. The zeta potential and %EE were found to be -33.6 +/- 0.845 mV and 68.89% +/- 0.59 respectively. Lyophilized powder showed the crystalline structure under DSC analysis. In vitro release studies showed the initial burst release followed by a sustained release up to 24 h in PBS pH 7.4 and the data were further studied using release kinetic models which revealed the first-order model as a best fitting model. Ex vivo gut permeation studies proved that the formulation containing lipid and surfactants has a higher permeability than the plain drug solution with nearly fourfold increase in the apparent permeability coefficients. Finally, LDC nanoparticles prepared by using stearic acid as a lipid and surfactants as Tween 80, Poloxamer 188, and Labrasol in equal ratio possess high potential for the oral delivery of hydrophilic drugs. PMID- 24061411 TI - Size-selective collection of circulating tumor cells using Vortex technology. AB - A blood-based, low cost alternative to radiation intensive CT and PET imaging is critically needed for cancer prognosis and management of its treatment. "Liquid biopsies" of circulating tumor cells (CTCs) from a relatively non-invasive blood draw are particularly ideal, as they can be repeated regularly to provide up to date molecular information about the cancer, which would also open up key opportunities for personalized therapies. Beyond solely diagnostic applications, CTCs are also a subject of interest for drug development and cancer research. In this paper, we adapt a technology previously introduced, combining the use of micro-scale vortices and inertial focusing, specifically for the high-purity extraction of CTCs from blood samples. First, we systematically varied parameters including channel dimensions and flow rates to arrive at an optimal device for maximum trapping efficiency and purity. Second, we validated the final device for capture of cancer cell lines in blood, considering several factors, including the effect of blood dilution, red blood cell lysis and cell deformability, while demonstrating cell viability and independence on EpCAM expression. Finally, as a proof-of-concept, CTCs were successfully extracted and enumerated from the blood of patients with breast (N = 4, 25-51 CTCs per 7.5 mL) and lung cancer (N = 8, 23 317 CTCs per 7.5 mL). Importantly, samples were highly pure with limited leukocyte contamination (purity 57-94%). This Vortex approach offers significant advantages over existing technologies, especially in terms of processing time (20 min for 7.5 mL of whole blood), sample concentration (collecting cells in a small volume down to 300 MUL), applicability to various cancer types, cell integrity and purity. We anticipate that its simplicity will aid widespread adoption by clinicians and biologists who desire to not only enumerate CTCs, but also uncover new CTC biology, such as unique gene mutations, vesicle secretion and roles in metastatic processes. PMID- 24061412 TI - Medications to decrease the risk for breast cancer in women: recommendations from the U.S. Preventive Services Task Force recommendation statement. AB - DESCRIPTION: Update of the 2002 U.S. Preventive Services Task Force (USPSTF) recommendation on the use of medications for breast cancer risk reduction. METHODS: The USPSTF reviewed evidence on the effectiveness,adverse effects, and subgroup variations of medications to reduce the risk for breast cancer specifically, the selective estrogen receptor modulators tamoxifen and raloxifene. The USPSTF also reviewed a meta-analysis of placebo-controlled trials to understand the relative benefits and harms of tamoxifen and raloxifene. POPULATION: This recommendation applies to asymptomatic women aged 35 years or older without a prior diagnosis of breast cancer,ductal carcinoma in situ, or lobular carcinoma in situ. RECOMMENDATION: The USPSTF recommends that clinicians engage in shared, informed decision making with women who are at increased risk for breast cancer about medications to reduce their risk.For women who are at increased risk for breast cancer and at low risk for adverse medication effects, clinicians should offer to prescribe risk-reducing medications, such as tamoxifen or raloxifene. (B recommendation)The USPSTF recommends against the routine use of medications,such as tamoxifen or raloxifene, for risk reduction of primary breast cancer in women who are not at increased risk for breast cancer. (D recommendation). PMID- 24061413 TI - An L-glucitol oxidizing dehydrogenase from Bradyrhizobium japonicum USDA 110 for production of D-sorbose with enzymatic or electrochemical cofactor regeneration. AB - A gene in Bradyrhizobium japonicum USDA 110, annotated as a ribitol dehydrogenase (RDH), had 87 % sequence identity (97 % positives) to the N-terminal 31 amino acids of an L-glucitol dehydrogenase from Stenotrophomonas maltophilia DSMZ 14322. The 729-bp long RDH gene coded for a protein consisting of 242 amino acids with a molecular mass of 26.1 kDa. The heterologously expressed protein not only exhibited the main enantio selective activity with D-glucitol oxidation to D fructose but also converted L-glucitol to D-sorbose with enzymatic cofactor regeneration and a yield of 90 %. The temperature stability and the apparent K m value for L-glucitol oxidation let the enzyme appear as a promising subject for further improvement by enzyme evolution. We propose to rename the enzyme from the annotated RDH gene (locus tag bll6662) from B. japonicum USDA as a D-sorbitol dehydrogenase (EC 1.1.1.14). PMID- 24061414 TI - Scale-up from shake flasks to pilot-scale production of the plant growth promoting bacterium Azospirillum brasilense for preparing a liquid inoculant formulation. AB - Azospirillum brasilense has industrial significance as a growth promoter in plants of commercial interest. However, there is no report in the literature disclosing a liquid product produced in pilot-scale bioreactors and is able to be stored at room temperature for more than 2 years. The aim of this work was to scale up a process from a shake flask to a 10-L lab-scale and 1,000-L pilot-scale bioreactor for the production of plant growth-promoting bacterium A. brasilense for a liquid inoculant formulation. Furthermore, this work aimed to determine the shelf life of the liquid formulation stored at room temperature and to increase maize crops yield in greenhouses. Under a constant oxygen mass transfer coefficient (K L a), a fermentation process was successfully scaled up from shake flasks to 10- and 1,000-L bioreactors. A concentration ranging from 3.5 to 7.5 * 10(8) CFU/mL was obtained in shake flasks and bioreactors, and after 2 years stored at room temperature, the liquid formulation showed one order of magnitude decrease. Applications of the cultured bacteria in maize yields resulted in increases of up to 95 % in corncobs and 70 % in aboveground biomass. PMID- 24061415 TI - Toxin-antitoxin-stabilized reporter plasmids for biophotonic imaging of Group A streptococcus. AB - Bioluminescence is a rapid and cost-efficient optical imaging technology that allows the detection of bacteria in real-time during disease development. Here, we report a novel strategy to generate a wide range of bioluminescent group A streptococcus (GAS) strains by using a toxin-antitoxin-stabilized plasmid. The bacterial luciferin-luciferase operon (lux) or the firefly luciferase gene (ffluc) was introduced into GAS via a stabilized plasmid. The FFluc reporter gave significantly stronger bioluminescent signals than the Lux reporter, and was generally more stable. Plasmid-based luciferase reporters could easily be introduced into a variety of GAS strains and the signals correlated linearly with viable cell counts. Co-expression of the streptococcal omega-epsilon-zeta toxin antitoxin operon provided segregational stability in the absence of antibiotics for at least 17 passages in vitro and up to 7 days in a mouse infection model. In addition, genome-integrated reporter constructs were also generated by site specific recombination, but were found to be technically more challenging. The quick and efficient generation of various M-type GAS strains expressing plasmid based luciferase reporters with comparable and quantifiable bioluminescence signals allows for comparative analysis of different GAS strains in vitro and in vivo. PMID- 24061416 TI - Enhanced production of a novel cytotoxic chromone oxalicumone A by marine-derived mutant Penicillium oxalicum SCSIO 24-2. AB - Many marine natural products hold great potential for the development of new and much needed drugs. However, the production of active metabolites by marine derived microorganisms is usually very low, and large-scale culture has to be involved to meet the need of chemical structural modification and deep pharmacy study. In order to enhance the production of a novel cytotoxic sulfur-containing chromone oxalicumone A (OA), germinating spores of a marine-derived wild strain Penicillium oxalicum SCSGAF 0023 were mutated by microwave and ultraviolet light irradiation, which led to the obtainment of a mutant P. oxalicum SCSIO 24-2 that could produce fivefold increase in OA production (3.42 +/- 0.21 mg/l) as compared to the wild strain. This is the first report that germinating spores are applied in marine-derived Penicillium sp. mutating to enhance the production of OA. Further, Plackett-Burman design and central composite design were adopted to optimize the basic medium components for increasing OA production by the mutant SCSIO 24-2 in shake flasks. The results indicated that three medium components including mannitol, maltose, and L-cysteine had significant effects on OA production, and their concentrations were optimized as 36, 27.9, and 0.99 g/l, respectively. In the optimized medium, the OA production (18.31 +/- 0.27 mg/l) by mutant SCSIO 24-2 was 4.4-fold higher than that in the basic medium. These results of this work promise to improve the present production of OA and may be adopted to enhance other objective products' production by marine-derived fungi. PMID- 24061417 TI - Two new beta-glucosidases from ethanol-fermenting fungus Mucor circinelloides NBRC 4572: enzyme purification, functional characterization, and molecular cloning of the gene. AB - Two beta-glucosidases (BGLs 1 and 2) were purified to homogeneity from the extracellular enzyme preparations of the ethanol-fermenting Mucor circinelloides NBRC 4572 statically grown on rice straw. BGLs 1 and 2 are monomeric glycoproteins whose apparent molecular masses (Ms) are around 78 kDa, which decreased by approximately 10 kDa upon enzymatic deglycosylation. Both BGLs showed similar enzyme characteristics in optimal temperature and pH, stability, and inhibitors. They were active against a wide range of aryl-beta-glucosides and beta-linked glucose oligosaccharides. Their amino acid sequences shared 81% identity and exhibited less than 60% identity with the known family-3 BGLs. Considering properties such as reduced inhibition by ethanol, glucose, and cellobiose, low transglucosylation activity, wider substrate range, less binding affinity to lignocellulosic materials, and abundant expression, BGL1 is likely to be more suitable for bioethanol production than BGL2 via simultaneous saccharification and fermentation of rice straw with M. circinelloides. PMID- 24061418 TI - Antrodia camphorata-fermented product cultured in deep ocean water has more liver protection against thioacetamide-induced fibrosis. AB - Antrodia camphorata is a unique fungus in Taiwan; the submerged fermentation product is used as the functional food for liver protection. Deep ocean water (DOW) containing rich metals and trace elements is proven to stimulate the production of functional metabolites and health function of functional fungus product in our previous study. Therefore, A. camphorata-fermented product cultured in DOW (DOW-AC) or reverse osmosis water (ROW-AC) as culture water was daily fed thioacetamide (TAA)-induced fibrosis rat for 8 weeks in order to investigate whether DOW promoted the effect of A. camphorata-fermented product on the prevention against TAA-induced liver damage and fibrosis. In the results, feeding one dose of DOW-AC prevented from TAA-induced weight loss and had more effect on inhibiting lipid peroxidation, reactive oxygen species, iNOS, and TNF alpha expression than one dose of ROW-AC. Furthermore, DOW-AC also had more potent effect on protection against TAA-induced liver damage and fibrosis according to the results of H&E stain and collagen stain. However, higher liver protection of DOW-AC should be due to the fact that DOW not only increased the production of A. camphorata-fermented functional metabolites including triterpenoids, polysaccharides, flavonoids, and polyphenols but also contributed to protection against TAA-induced damage and fibrosis. PMID- 24061432 TI - Study of ligand effects in aurophilic interactions using local correlation methods. AB - In this study, we present a series of calculations on Au(I) dimer complexes, investigating the interactions in play through the use of local correlation methods. The focus is placed on the impact of ligand effects in the interaction energy. Aurophilicity (the interaction between the closed shell Au(I) cationic centers) is commonly considered to be the major driving force for dimer formation. However, our calculations show that weak interactions between ligands can dominate even in relatively small complexes. This, in turn, can lead to an ambiguous ordering of the metallophilicity of Group 11 elements. We propose an unbiased separation of the metal-metal interaction through the use of local correlation and orbital population analysis. The latter reveals a constant energy profile for a variety of complexes which could in turn be used for the analysis of d(10)-d(10) interactions in more complex systems. PMID- 24061433 TI - CD40L contributes to angiotensin II-induced pro-thrombotic state, vascular inflammation, oxidative stress and endothelial dysfunction. AB - CD40 ligand (CD40L) is involved in the vascular infiltration of immune cells and pathogenesis of atherosclerosis. Additionally, T cell CD40L release causes platelet, dendritic cell and monocyte activation in thrombosis. However, the role of CD40L in angiotensin II (ATII)-driven vascular dysfunction and hypertension remains incompletely understood. We tested the hypothesis that CD40L contributes to ATII-driven vascular inflammation by promoting platelet-leukocyte activation, vascular infiltration of immune cells and by amplifying oxidative stress. C57BL/6 and CD40L-/- mice were infused with ATII (1 mg/kg/day for 7 days) using osmotic minipumps. Vascular function was recorded by isometric tension studies, and reactive oxygen species (ROS) were monitored in blood and heart by optical methods. Western blot, immunohistochemistry, FACS analysis and real-time RT-PCR were used to analyze immune cell distribution, pro-inflammatory cytokines, NAPDH oxidase subunits, T cell transcription factors and other genes of interest. ATII treated CD40L-/- mice showed improved endothelial function, suppression of blood platelet-monocyte interaction (FACS), platelet thrombin generation (calibrated automated thrombography) and coagulation (bleeding time), as well as decreased oxidative stress in the aorta, heart and blood compared to wild-type mice. Moreover, ATII-treated CD40L-/- mice displayed decreased levels of TH1 cytokines released by splenic CD4+ T cells (ELISA) and lower expression levels of NOX-2, T bet and P-selectin as well as diminished immune cell infiltration in aortic tissue compared to controls. Our results demonstrate that many ATII-induced effects on vascular dysfunction, such as vascular inflammation, oxidative stress and a pro-thrombotic state, are mediated at least in part via CD40L. PMID- 24061434 TI - Sleepwalking, REM sleep behaviour disorder and overlap parasomnia in patients with Parkinson's disease. AB - BACKGROUND/AIMS: In a questionnaire survey, we identified 36 (9%) of 417 Parkinson's disease (PD) patients with sleepwalking (SW); 72% of them also had a history of REM sleep behaviour disorder (RBD). We aimed to assess the clinical and polysomnographic characteristics of SW in PD and to compare them to patients with PD with and without a history of RBD. METHODS: We performed video polysomnography and detailed clinical examination in 30 PD patients from the above-mentioned survey: 10 patients with a history of SW, 10 patients with a history of RBD, and 10 patients with no history of either SW or RBD. RESULTS: PD patients with SW had higher depression, anxiety and Hoehn & Yahr scores and lower activities of daily living scores than patients without a history of RBD but did not differ from patients with RBD. Patients with SW and RBD also had more often dyskinesia and hallucinations. By polysomnography, RBD was observed in 8 patients with SW and in all patients with a history of RBD. A total of 5 patients without a history of either SW or RBD had REM sleep without atonia without behavioural peculiarities. CONCLUSION: SW in PD is associated with depression, higher disease severity and functional disability. The simultaneous occurrence of SW and RBD (overlap parasomnia) in most patients suggests a common underlying disturbance of motor control during sleep in PD, with variable manifestations in different sleep stages. PMID- 24061435 TI - Neuro-oncology: The long and winding road--gene therapy for glioma. PMID- 24061440 TI - Epilepsy: Repeat MRI in patients with chronic epilepsy. AB - In patients with chronic epilepsy, MRI-based detection of an underlying brain lesion can offer the potential for surgical treatment, but a substantial proportion of patients have normal MRI scans. A recent study has shown that repeat neuroimaging with improved MRI technology can enable detection of previously unidentified epileptogenic lesions. PMID- 24061441 TI - Regulation of the expression of the liver cancer susceptibility gene MICA by microRNAs. AB - Hepatocellular carcinoma (HCC) is a threat to public health worldwide. We previously identified the association of a single nucleotide polymorphism (SNP) at the promoter region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of hepatitis-virus-related HCC. Because this SNP affects MICA expression levels, regulating MICA expression levels may be important in the prevention of HCC. We herein show that the microRNA (miR) 25-93-106b cluster can modulate MICA levels in HCC cells. Overexpression of the miR 25-93-106b cluster significantly suppressed MICA expression. Conversely, silencing of this miR cluster enhanced MICA expression in cells that express substantial amounts of MICA. The changes in MICA expression levels by the miR25-93-106b cluster were biologically significant in an NKG2D-binding assay and an in vivo cell-killing model. These data suggest that the modulation of MICA expression levels by miRNAs may be a useful method to regulate HCCs during hepatitis viral infection. PMID- 24061442 TI - Simultaneous quantification of linezolid, tinidazole, norfloxacin, moxifloxacin, levofloxacin, and gatifloxacin in human plasma for therapeutic drug monitoring and pharmacokinetic studies in human volunteers. AB - BACKGROUND: Linezolid may be administered in combination with norfloxacin, gatifloxacin, levofloxacin, moxifloxacin, and tinidazole for the treatment of various infections, such as urinary and respiratory tract infections, to improve the efficacy of the treatment or to reduce the duration of therapy. Knowledge of the antibiotic plasma concentrations combined with bacterial susceptibility evaluated in terms of minimum inhibitory concentration would optimize treatment efficacy while limiting the risk of dose-related adverse effects and avoiding suboptimal concentrations. METHODS: A new high-performance liquid chromatography assay method was developed and validated for determination of the above-mentioned drugs in small samples of human plasma. After protein precipitation with acetonitrile:methanol (1:1, vol/vol), satisfactory separation was achieved on a Hypersil BDS C18 column (250 * 4.6 mm, 5 MUm) using a mobile phase comprising 20 mM sodium dihydrogen phosphate-2 hydrate (pH = 3.2) and acetonitrile at a ratio of 75:25, vol/vol; the elution was isocratic at ambient temperature with a flow rate of 1.5 mL/min. The ultraviolet detector was set at 260 nm. The validated method was applied to assay real plasma samples used for pharmacokinetic studies and therapeutic drug monitoring of the selected drugs. RESULTS: The assay method described was found to be rapid, sensitive, reproducible, precise, and accurate. Linearity was demonstrated over the concentration ranges as follows: 0.1-30 MUg/mL for linezolid and tinidazole; 0.05-5 MUg/mL for norfloxacin; and 0.1-10 MUg/mL for moxifloxacin, levofloxacin, and gatifloxacin (mean r = 0.9999, n = 12). The observed within- and between-day assay precisions were within 12.5%, whereas accuracy ranged between 92.0% and 112% for all the analytes. The lower limit of quantification was 0.1 MUg/mL for all the analytes except norfloxacin which was 0.05 MUg/mL. CONCLUSIONS: This assay method was valid within a wide range of plasma concentrations and may be proposed as a suitable method for pharmacokinetic studies, therapeutic drug monitoring implementation, and routine clinical applications, especially for some populations of patients who receive a combination of these drugs. PMID- 24061443 TI - Racial comparisons of everolimus pharmacokinetics and pharmacodynamics in adult kidney transplant recipients. AB - BACKGROUND: There is limited data analyzing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of everolimus (EVR) between African Americans and Caucasians. The purpose of this study was to determine and compare the EVR PKs and concentration-associated efficacy and toxicity in African American and Caucasian adult kidney transplant recipients. METHODS: This was a retrospective PK and PD analysis of all patients who received EVR at the Medical University of South Carolina Transplant Center between 2006 and 2012. RESULTS: Forty-three patients received EVR (22 African Americans, 21 Caucasians). Baseline demographics, immunosuppression, and immunologic risk were similar between races, except for preexisting hypertension, deceased donor type, and cold ischemic time, which were higher in African American patients. PK analysis revealed that African American patients received higher initial EVR doses (2.1 +/- 0.8 versus 1.6 +/- 0.6 mg/d, P = 0.036), leading to higher early EVR concentrations (EVR >6 ng/mL during the first 60 days: 36% versus 10%, P = 0.037). Efficacy analysis demonstrated similar EVR effects on acute rejection rates (9% versus 10%, P = 0.961), chronic allograft changes (18% versus 14%, P = 0.729), and renal function, with both groups having improved creatinine clearance with EVR therapy (DeltaeGFR: 27 versus 12 mL.min.1.73 m). Toxicity analysis demonstrated that African American patients had a trend toward higher rates of EVR discontinuation (46% versus 19%, P = 0.065) and significantly more diarrhea/gastrointestinal intolerance (73% versus 38%, P = 0.022). CONCLUSIONS: These results demonstrate EVR therapy is effective at preventing rejection and improving graft function in both African American and Caucasian adult renal transplant patients. Conflicting with previous mammalian target of rapamycin PK/PD analyses in African American patients, this study cohort demonstrated higher early EVR levels in the African American patients. PMID- 24061444 TI - Interindividual and intra-individual variabilities of darunavir and ritonavir plasma trough concentrations in multidrug experienced HIV patients receiving salvage regimens. AB - BACKGROUND: There is no consensus on darunavir (DRV) target levels in plasma for clinical use, and information about variability in plasma concentrations is limited. AIM: : To investigate the variability in DRV plasma trough concentrations in the clinical setting, evaluating interindividual and intraindividual variabilities of plasma drug levels among HIV-infected patients receiving ritonavir (RTV)-boosted DRV (DRV/r) within salvage regimens, and evaluate the potential correlation between variability and virological response. METHODS: Sixty-two patients taking DRV/r (600/100 mg twice a day) were evaluated for trough plasma concentrations and immunovirological parameters after 6 months from the start of the regimen. A subgroup of patients (n = 21) was also evaluated for intraindividual variability (expressed as coefficient of variation) on 2 samples taken at different time points. Drug concentrations were assayed by high performance liquid chromatography with ultraviolet detection, and the values were expressed as medians with interquartile range (IQR). Genotypic sensitivity score and genotypic inhibitory quotient were calculated. RESULTS: DRV/r was used with a median of 3 other antiretroviral drugs (raltegravir use 88.7%). Median plasma concentrations were 3.22 mcg/mL (IQR, 2.04-5.69) for DRV and 0.44 mcg/mL (IQR, 0.21-0.70) for RTV. Both drugs showed a high interindividual variability in plasma concentrations (61% and 99.3%, respectively). Only 3 patients (4.8%) had undetectable DRV plasma levels. DRV plasma concentrations showed a significant positive correlation with age (r = 0.298, P = 0.019), but no significant correlation between DRV genotypic inhibitory quotient and HIV-RNA plasma levels (P = 0.614) was found. Intraindividual coefficients of variation were 58.4% for DRV and 47.1% for RTV. Patients with undetectable HIV-RNA showed a trend for lower intraindividual coefficients of variation compared with patients with detectable HIV-RNA (55.9% versus 83.8%, P = 0.156). No major interaction effects with other antiretroviral drugs were found. CONCLUSIONS: In a context of salvage therapy, both DRV and RTV plasma levels showed high interindividual and intraindividual variabilities. Lower intraindividual variability could be beneficial in maintaining viral suppression. PMID- 24061445 TI - Impact of POR*28 on the pharmacokinetics of tacrolimus and cyclosporine A in renal transplant patients. AB - BACKGROUND: The P450 oxidoreductase (POR)*28 variant allele has been associated with altered cytochrome P450 3A enzyme activities. Both CYP3A5 and CYP3A4 are involved in the metabolism of calcineurin inhibitors and recent data show that POR*28 may explain part of the variability observed in tacrolimus (Tac) pharmacokinetics. The aim of this study was to investigate the impact of the POR*28 allele on Tac and cyclosporine A (CsA) immunosuppressive therapies. METHODS: Kidney transplant recipients receiving either Tac (n = 184) or CsA (n = 174), participating in a prospective multicenter trial, were genotyped for POR*28, CYP3A4*22, and CYP3A5*3. RESULTS: CYP3A5 expressers that were carriers of at least 1 POR*28 allele had a 16.9% decrease in dose-adjusted predose concentrations when compared CYP3A5 expressers that carried the POR*1/*1 genotype (P = 0.03), indicating an increased CYP3A5 activity for POR*28 carriers. In CYP3A5, nonexpressers carrying 2 POR*28 alleles, a 24.1% (confidence interval95% = -39.4% to -4.9%; P = 0.02) decrease in dose-adjusted predose concentrations was observed for Tac, suggesting higher CYP3A4 activity. For CsA, POR*28/*28 patients not expressing CYP3A5 and not carrying the CYP3A4*22 decrease-of-function allele showed 15% lower CsA dose-adjusted predose concentrations (P = 0.01), indicating also increased CYP3A4 activity. In both cohorts (ie, Tac and CsA), the POR*28 allele was neither associated with the incidence of delayed graft function nor with biopsy-proven acute rejection. These results were further confirmed in 2 independent cohorts. CONCLUSIONS: Our results show that the POR*28 allele is associated with increased in vivo CYP3A5 activity for Tac in CYP3A5 expressers, whereas POR*28 homozygosity was associated with a significant higher CYP3A4 activity in CYP3A5 nonexpressers for both Tac and CsA. PMID- 24061447 TI - Detection of neonatal drug exposure using umbilical cord tissue and liquid chromatography time-of-flight mass spectrometry. AB - BACKGROUND: A method for qualitative detection of 57 drugs and metabolites in umbilical cord tissue using liquid chromatography time-of-flight (TOF) mass spectrometry is described. METHODS: Results from 32 deidentified positive specimens analyzed by an outside laboratory using "screen with reflex to confirmation" testing were compared with TOF results. In addition, 57 umbilical cord tissue specimens paired with corresponding chart review data and 37 with meconium test results were analyzed by TOF. Urine drug test results from mother (n = 18) and neonate (n = 30) were included if available. Cutoff concentrations, recovery, and matrix effects were determined by analyzing fortified drug-free cord tissue and negative specimens. Cutoffs (in nanograms per gram) ranged from 1 to 10 for opioids and opioid antagonists, 5-10 for benzodiazepines and nonbenzodiazepine hypnotics, 20-40 for barbiturates, 8 for stimulants, and 4 for phencyclidine. Adequate sensitivity for the detection of cannabis exposure could not be realized with this method. CONCLUSIONS: Liquid chromatography time-of flight mass spectrometry can provide accurate and sensitive detection of in utero drug exposure using umbilical cord tissue. PMID- 24061446 TI - Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematopoietic stem cell transplantation. AB - BACKGROUND AND OBJECTIVE: Intravenous (IV) busulfan (Bu) combined with therapeutic drug monitoring-guided dosing is associated with better event-free survival (EFS), lower transplant-related mortality. But optimal target steady state concentration (Css) of Bu in children undergoing hematopoietic stem cell transplantation (HSCT) remains unclear. This study aimed to evaluate the relation between Css of Bu and clinical outcomes in children receiving Bu before HSCT. METHODS: This study includes 75 children receiving IV Bu in 16 doses, with first dose assigned based on age. Bu first-dose pharmacokinetic parameters were estimated from Bu plasma concentrations measured at 6 time points by high performance liquid chromatography. Doses were adjusted at the fifth dose to a target Css of 600-900 ng/mL. Cumulative incidence of overall survival (OS), EFS, transplant-related mortality, acute graft-versus host disease (aGVHD), and other toxicities in relation to Css of Bu were analyzed using Kaplan-Meier curves in univariate and Cox's proportional hazards model in multivariate analysis. RESULTS: After the first dose, median Css was 578 (325-1227) ng/mL. Forty-one patients had Bu IV dose increased by > 10%. Neutrophil and platelet recoveries, grade 2-4 aGVHD, and nonrelapse mortality (NRM) incidences were 90%, 91%, 12%, and 13%, respectively. Relapse incidence was 33%. Incidence of veno-occlusive disease, hemorrhagic cystitis, and lung toxicities were 13%, 24%, and 7%, respectively. OS and EFS were 70% and 58%. First-dose Bu Css >600 ng/mL was associated with a higher NRM (P < 0.001) and grade 2-4 aGVHD (P = 0.04), a lower EFS (P < 0.001), and OS (P = 0.001). CONCLUSIONS: This study demonstrated a significant association between the first-dose pharmacokinetics of Bu and NRM, OS, and EFS. Bu therapeutic drug monitoring provides information that potentially influences outcomes of HSCT in pediatric patients. PMID- 24061448 TI - Simultaneous quantification of IMPDH activity and purine bases in lymphocytes using LC-MS/MS: assessment of biomarker responses to mycophenolic acid. AB - BACKGROUND: The development of biomarkers describing the individual responses to the immunosuppressant mycophenolic acid (MPA) has focused on the target enzyme activity [inosine 5'-monophosphate dehydrogenase (IMPDH)]. An extended strategy is to quantify the metabolic consequences of IMPDH inhibition. The aim of this study was to develop an assay for quantification of IMPDH activity and related purine bases and to provide preliminary data on the behavior of these biomarkers during clinical exposure to MPA. METHODS: Liquid chromatography-mass spectrometry was used to determine xanthine (IMPDH activity in incubated cell lysate), hypoxanthine, guanine, and adenine derived from free nucleotides in lymphocytes. Analytical performance was assessed, and the biomarkers were examined in CD4+ cells from 2 groups: Healthy individuals in a single-dose MPA study (n = 5) and liver transplant recipients on MPA therapy (n = 15). RESULTS: Coefficients of variation between series were below 10% and 15% for measurement of the purines and IMPDH activity, respectively. Although IMPDH was inhibited, the purine levels increased in response to MPA in 3 of the 5 healthy individuals, and this positive response seemed to be associated with IMPDH1 c.579 + 119 G/G and c.580 - 106 G/G. In the liver transplant study, guanine was not reduced in response to the transient drop in IMPDH activity after MPA dosing. However, there were trends toward decrease in guanine and elevation of hypoxanthine during prolonged MPA therapy. The guanine/hypoxanthine ratio (median) was 37% lower and the adenine level was 21% lower at day 17 compared with day 4 after transplantation. CONCLUSIONS: The assay allows precise quantification of IMPDH activity, hypoxanthine, guanine, and adenine in lymphocytes. Some individuals may possess a counteracting purine response to the MPA-mediated inhibition of IMPDH. Reduction of the guanine/hypoxanthine ratio may be related to prolonged inhibition of IMPDH and seems as an intriguing pharmacodynamic biomarker for MPA. PMID- 24061449 TI - Detection of 4 benzodiazepines in oral fluid as biomarker for presence in blood. AB - BACKGROUND: Analysis of samples of oral fluid (mixed saliva) is increasingly being used to detect recent drug use. The aim of this investigation was to assess the suitability of testing oral fluid as a biomarker for the presence of 4 benzodiazepines in blood and its possible application in clinical settings and in research on drug use. METHODS: Paired samples of oral fluid and blood from 4080 individuals in 4 European countries were collected and analyzed for benzodiazepines using gas or liquid chromatography with mass spectroscopic detection. RESULTS: Concentration data for the 4 most commonly detected benzodiazepines were studied: alprazolam, clonazepam, diazepam, and nordiazepam. Large variations in oral fluid to blood concentration ratios were observed for the studied benzodiazepines. The interquartile ranges for the oral fluid to blood concentrations ratios corresponded to 88%-197% of the median values. Selecting cutoff concentrations in oral fluid that gave the best accuracy in identifying individuals with benzodiazepine concentrations in blood above chosen thresholds produced accuracies of 74%-85% and the fraction of false negatives was 9%-23%. CONCLUSIONS: The concentration of the 4 studied benzodiazepines in oral fluid can neither be used to accurately estimate the concentrations in blood nor to correctly identify patients with blood drug concentrations below or above recommended therapeutic levels. When using analytical methods with limits of quantitation corresponding to concentrations less than 0.5 ng/mL in undiluted oral fluid, it may be used to confirm a recent intake of benzodiazepines. However, it is likely that some false negatives may occur. PMID- 24061450 TI - Abstracts of the 5th International Whiplash Trauma Congress - August 24-28, 2011, Lund, Sweden. PMID- 24061451 TI - Transapical valve-in-valve-in-ring for stenotic mitral valve repair. AB - A 53-year-old woman, previously treated with irradiation and chemotherapy for Hodgkin lymphoma, was referred for redo valve surgery. She had had a pacemaker implantation and undergone coronary bypass surgery, mitral valve repair with a Carpentier-Edwards 28-mm Physio-annuloplasty ring, as well as a mechanical tricuspid valve replacement and a transfemoral CoreValve 26-mm implantation. She had cardiac cachexia, pleura effusion, and a failed mitral valve repair with stenosis. She was judged inoperable for open surgery but suitable for a transapical valve-in-valve implantation on partial femorofemoral bypass. A 26-mm Edwards SAPIEN XT aortic valve inversely mounted on the Ascendra + delivery catheter was balloon expanded into the Physio ring. During expansion, the introducer sheath remained too deep into the left ventricle and rotated the SAPIEN valve upward to the left atrium, creating the onset of a new mitral regurgitation and retaining the stenosis. Another Edwards SAPIEN XT 26-mm valve was then positioned into the first valve in a "valve-in-valve-in-ring" tandem configuration. Both valves were supported by the Physio ring. The stenosis and the regurgitation were thereafter eliminated. PMID- 24061452 TI - Prostate cancer disease characteristics for foreign-born South Asian men living in the United States. AB - INTRODUCTION: We report the largest known cohort of South Asian (SA) men treated by radical prostatectomy living in the United States. Our objective was to characterize this sub-population and compare them to our wider cohort of prostate cancer patients treated with radical prostatectomy in the United States. MATERIALS AND METHODS: All patients who underwent radical prostatectomy at two high-volume United States academic institutions at separate geographic locations between 1990 and 2011 were identified. Demographic data, pre-operative Prostate Specific Antigen (PSA), biopsy Gleason score, pathology Gleason score, pathology Stage, margin status, and node status were collected. In addition to SA men, African American (AA) men were identified and used for comparative analysis as a high-risk cohort. RESULTS: A total of 69 SA men were identified in Cohort 1 and 24 men were identified in Cohort 2. When comparing SA men against the entire cohort, no significant difference was found for age, year of surgery, biopsy Gleason score, or path Gleason score for either cohort. However, significant differences were found in pre-operative PSA (P = 0.01), pathologic stage (P<0.01), and positive node status (P = 0.04) for SA men in Cohort 1. Whereas in Cohort 2, SA men had a significantly higher proportion of positive surgical margins (P = 0.04). In all significant comparisons, characteristics were worse in SA men and similar to that of AA men. CONCLUSIONS: SA men have worse pathologic disease profiles when compared to the general population of men undergoing radical prostatectomy. SA men living in the United States have pathologic disease profiles that are comparable to AA men. PMID- 24061453 TI - Immunohistochemical detection of p53 and MDM2 expressions in liposarcoma with World health organization classification. AB - BACKGROUND: Liposarcomas are among the most common soft tissue sarcomas in adulthood. AIM: The purpose of the study is to perform a histopathologic typing according to World Health Organization (WHO) classification of cases diagnosed with liposarcoma and to examine the difference of p53 and MDM2 expressions. MATERIALS AND METHODS: The haematoxylin-eosin stained sections of 48 subjects enrolled in the study have been evaluated on the basis of the WHO classification for liposarcoma and sections stained using p53 and MDM2. STATISTICAL ANALYSIS USED: Chi-Square test was applied. RESULTS: 20 subjects were diagnosed with well differentiated liposarcoma (WLS), 16 myxoid liposarcoma (ML), 7 pleomorphic liposarcoma (PL), and 5 de-differentiated liposarcoma (DLS). The number of cases stained positive with MDM2 and p53 were positive correlated in all subjects (P = 0.02). p53 and MDM2 positivity increased in high grade tumors (P = 0.01). CONCLUSION: p53 and MDM2 immuno-reactivity was found to be potentially useful in liposarcoma diagnosis but a definitive implication would be rather unhealthy due to the small number of cases in our study. PMID- 24061454 TI - Diagnostic dilemma in histopathology report following robot assisted laparoscopic prostatectomy: tumour 'hide and seek'. AB - INTRODUCTION: Widespread PSA (prostate specific antigen) screening has resulted in stage migration of prostate cancer. Smaller tumor volumes are being detected in radical prostatectomy specimens. This has coincided with increasing reports about the 'vanishing cancer phenomenon.' AIMS: To analyse the cases of robot assisted laparoscopic prostatectomy (RALP) at our institute in which the pre operative prostate biopsy was positive for adenocarcinoma but no tumor could be identified in the final histopathology, and to review the literature for possible reasons for such a phenomenon. MATERIALS AND METHODS: Nine patients were identified out of a total of 184 cases of RALP in which the final histopathology did not correlate with the initial biopsy report. The initial biopsy slides as well as the final histopathology slides were reviewed by a second pathologist. The specimens were processed in entirety and additional sections were taken until no tissue was left. RESULTS: Two patients had cancer diagnosed on TURP (transurethral resection of prostate) chips, while the remaining patients had undergone TRUS biopsy for elevated PSA. The final histopathological diagnosis was benign prostatic hyperplasia in two patients, chronic prostatitis in four patients, and acute florid prostatitis in one patient, granulomatous prostatitis with glandulostromal hyperplasia in one patient and TCC (transitional cell carcinoma) of prostate in one patient. CONCLUSION: Most cases of pT0 are due to inability of routine histopathological analysis to identify minute tumor focus. Urologists need to be aware of this in view of the potential medico legal implications. PMID- 24061455 TI - Cell-free DNA concentration and integrity as a screening tool for cancer. AB - AIM OF THE STUDY: This study aims to evaluate cell-free DNA (CFDNA) concentration and integrity in patients with malignant and nonmalignant diseases and in controls to investigate their value as a screening test for cancer, and to correlate them with clinicopathological parameters of cancer patients. MATERIALS AND METHODS: The study included three groups; group I: 120 cancer patients, group II: 120 patients with benign diseases and group III: 120 normal healthy volunteers as control. One plasma sample was collected from each subject. CFDNA was purified from the plasma then its concentration was measured and integrity was assessed by PCR amplification of 100, 200, 400, and 800 bp bands. RESULTS: There was a highly significant difference in CFDNA levels between cancer group and each of benign and control groups. AUC of ROC curve for cancer group versus normal and benign groups were 0.962 and 0.895, which indicated the efficiency of CFDNA as a marker of cancer. As for integrity, normal and benign subjects showed only two bands at 100 and 200 bp, while all cancer patients demonstrated the 400 bp band and 78% of them had the 800 bp whose presence correlated with vascular invasion. CONCLUSION: The combined use of CFDNA concentration and integrity is a candidate for a universal screening test of cancer. Upon setting suitable boundaries for the test it might be applied to identify cancer patients, particularly among subjects with predisposing factors. Being less expensive, CFDNA concentration could be applied for mass screening and for patients with values overlapping those of normal and benign subjects, the use of the more expensive, yet more specific, integrity test is suggested. PMID- 24061456 TI - Adjuvant chemoradiation for resected gallbladder cancer: Treatment strategies for one of the leading causes of cancer death in Chilean women. AB - BACKGROUND: Gallbladder cancer (GBC) is the second leading cause of cancer death in women in Chile. Even after curative surgery, prognosis is grim. To evaluate acute and late toxicity and efficacy of adjuvant chemoradiation (CRT) after curatively resected GBC. MATERIALS AND METHODS: We retrospectively analyzed the cohort of patients diagnosed between January 1999 and December 2009, treated with adjuvant CRT at our institution. Treatment protocol considered external beam radiation (RT) (45-54 Gy) to tumor bed and regional lymph nodes with or without concurrent 5-fluorouracil (5-FU) (500 mg/m2/day by 120-hours continuous infusion on days 1-5 and 29-33). Data was obtained from medical records, mortality from death certificates. Survival was estimated by Kaplan- Meier curves. RESULTS: 46 patients with curatively resected GBC received adjuvant CRT. Median age was 57 years (range 33-76); 39 patients were female. After diagnosis, a second surgery was performed in 42 patients. Cholecystectomy with hepatic segmentectomy and lymphadenectomy was the curative surgery in 41 patients. All patients received RT with a planned dose of 45 Gy in 25 fractions, 11 patients received a boost to the tumor bed up to 54 Gy and 34 patients had concurrent 5-FU. Therapy was well tolerated. Five patients experienced grade 3 toxicities. No grade 4 or 5 toxicity was observed. No grade >2 late toxicity was observed. Three- and 5-year overall survival (OS) were 57% and 51%, respectively. CONCLUSIONS: Adjuvant chemoradiation is well tolerated and might impact favorably on survival in patients with curatively resected GBC. PMID- 24061457 TI - Expression of vimentin in breast carcinoma, its correlation with Ki67 and other histopathological parameters. AB - CONTEXT: Vimentin is a mesenchymal marker, known to express in some epithelial carcinomas. AIMS: 1. To find out the expression of vimentin in infiltrating ductal carcinoma of breast (not otherwise specified), 2. To find out the correlation between expression of vimentin and prognostic markers such as tumor size, tumor grade, lymph node status, proliferation index (measured by Ki 67), and Nottingham prognostic index (NPI). MATERIALS AND METHODS: Study was done at Department of Pathology; 50 cases of infiltrating ductal carcinoma (NOS) were studied for tumor grade; immunohistochemistry was done using antibodies against vimentin and Ki 67. Percentages of positive cells were documented. An immunoscore was also calculated for vimentin. Vimentin expression was correlated with tumor size, lymph node status, Nottingham prognostic index, and Ki 67. STATISTICAL ANALYSIS USED: statistical correlation was done using Pearson's chi-square test. A P value less than 0.01 was considered significant. RESULTS: Vimentin expression was seen in 18% of cases. Its expression correlated with high tumor grade and high growth fraction (P value < 0.01). It did not correlate with lymph node status, tumor size, and NPI. CONCLUSIONS: Increased vimentin expression is associated with bad prognostic factors. Immunohistochemistry with vimentin may be helpful in knowing the prognosis in cases of infiltrating ductal carcinoma of breast (NOS). PMID- 24061458 TI - P-glycoprotein expression as a predictor of response to neoadjuvant chemotherapy in breast cancer. AB - BACKGROUND: Chemoresistance is an important factor determining the response of tumor to neoadjuvant chemotherapy (NACT). P-glycoprotein (P-gp) expression mediated drug efflux is one of the mechanisms responsible for multi-drug resistance. Our study was aimed to determine the role of P-gp expression as a predictor of response to NACT in locally advanced breast cancer (LABC) patients. MATERIALS AND METHODS: P-gp expression was performed by real-time quantitative polymerase chain reaction [qRT-PCR] in 76 patients with LABC. Response to adriamycin-based regimen was assessed both clinically and with contrast enhanced computed tomography (CECT) scan before and after NACT. The significance of correlation between tumor and P-gp levels was determined with Chi-square test. RESULTS: Twenty-one had high and 55 had low P-gp expression. On analyzing P-gp expression with response by World Health Organization (WHO) criteria, statistical significance was obtained (P = 0.038). Similarly, assessment of P-gp expression with response by Response Evaluation in Solid Tumors (RECIST) criteria in 48 patients showed statistical significance (P = 0.0005). CONCLUSION: This study proves that P-gp expression is a determinant factor in predicting response to NACT. Finally, detection of P-gp expression status before initiation of chemotherapy can be used as a predictive marker for NACT response and will also aid in avoiding the toxic side effects of NACT in non-responders. PMID- 24061459 TI - Immunohistochemical expression of MIB-1 and PCNA in precancerous and cancerous lesions of uterine cervix. AB - BACKGROUND AND OBJECTIVE: The present study was done to analyze the immunoexpression of diagnostic markers (MIB-1: molecular immunology borstel and PCNA: proliferating cell nuclear antigen) in grading cervical intraepithelial lesion (CIN) and squamous cell carcinoma (SCC) in cervix. SETTING AND DESIGN: Total 150 cervical biopsies were divided into four groups respectively; Group I Normal (n = 32), Group II- CIN (n = 60), Group III- SCC (n = 44), Group IV- CA cervix (n = 14) respectively. MATERIALS AND METHODS: These biopsies were stained with monoclonal antibodies by streptavidin--biotin method. Mean labeling index was calculated and grading was performed using the I--III scoring system. STATISTICAL ANALYSIS: Findings were correlated with age and menopausal status. Statistical analysis was done by using student sample't' test and analysis of variance (ANOVA) by SPSS 10 package. RESULTS: MIB-1 immunostaining was positive in 112/150 (74.6%) cases and PCNA in 118 /150 (78.6%) cases. Labeling indices showed linear progression from normal to CIN to SCC to cancer lesion. Few cases of low-grade CIN lesion had high proliferative index. A significant positive correlation was found between age and PCNA and MIB-1 values (P < 0.05) when comparison was made for all the cases. CONCLUSION: These markers may be useful in identifying low-grade CIN lesion with high proliferative index. These cases should be kept for follow up studies so that proper intervention can be taken at an early stage. This method is simple and cost effective and can easily be done in formaline-fixed paraffin embedded tissues in a clinical laboratory for grading CIN and SCC lesions in cervix. PMID- 24061460 TI - Mitochondria and tumors: a new perspective. AB - BACKGROUND: Mitochondrial DNA (Mt DNA) defects have been identified in a variety of Tumors, but the exact role of these defects in the pathogenicity and tumor progression is poorly understood. This study aims at identifying the status of mitochondrial OXPHOS genes in neoplastic transformation and attempts to establish a cause and effect relationship between mitochondrial OXPHOS defects and tumor progression. MATERIALS AND METHODS: Mutational, expression and functional analysis of l2 of the 13 mitochondrial OXPHOS genes has been carried out using PCR, Real-Time PCR and protein modeling in 180 sporadic samples of a heterogeneous group of benign and malignant tumors like that of benign, malignant, matched blood and adjacent normal tissue of breast and benign hemangioma. RESULTS: Mutations were identified in the ND4L, ND6 and COX-II regions of the mitochondrial OXPHOS genes. All the mutations were limited only to the malignant breast tissues. On relative quantification, a compromised expression of OXPHOS genes was identified in all the malignant tissues irrespective of their mutational states. Protein modeling revealed loss of function mutations of ND6 and COX-II proteins. CONCLUSION: This is the first study worldwide wherein a comparative study using different benign and malignant tumors has been carried out to assess the role of Mt DNA defects. Our data reveals mitochondrial dysfunction only in malignant cells and not in their benign counterparts, indicating that the dysfunction may arise after the pro proliferative pathway has set in. We hypothesize that compromised OXPHOS may be a responsive mechanism of the cell to counter cancers, rather than a mechanism of initiating tumorigenesis. PMID- 24061461 TI - The stem cell self-renewal gene, Musashi 1, is highly expressed in tumor and non tumor samples of human bladder. AB - CONTEXT: The stem cell model for cancer assumes that a key event in tumorigenesis is the deregulation of genes involved in the regulation of stem cell self renewal. The Musashi family is an evolutionarily conserved group of neural RNA binding proteins. In mammals, the family consists of two individual genes, Musashi 1 (MSI1) and MSI2, encoding the Musashi 1 and Musashi 2 proteins. Musashi 1 is involved in the regulation of self-renewal of stem cells. Recently, its over expression has also been reported in a variety of human tumors. AIMS: To investigate a potential expression of the stem cell self-renewal gene, Musashi 1, in human bladder cancer, we examined its gene expression in a series of tumor and non-tumor tissue samples of bladder. MATERIALS AND METHODS: Relative expression of MSI1 was determined by the real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 70 surgical samples of bladder. RESULTS: Using specific primers for MSI1 and TBP (as an internal control) for qRT-PCR technique, we found a relatively high expression level of MSI1 in all examined tumor and non-tumor bladder tissue specimens. However, our data did not show any correlation between the level of gene expression and tumor/non-tumor states of the samples (P>0.05). CONCLUSIONS: All together, our data demonstrated that Musashi 1 is highly and un-differentially expressed in both examined tumoral and apparently normal bladder tissues. PMID- 24061462 TI - Assesment of the reactions of caregivers of a cancer patients: validity and reliability of the scale of "Your reactions helping your family member" in Turkish society. AB - BACKGROUND: This study has been descriptively designed in order to evaluate the validity and reliability of the scale of "Your Reactions to Helping Your Family Member" for Turkish society. The scale that was developed by Archbold and Steward in 1983 being applied at caregivers is included within Family Care Inventory. MATERIALS AND METHODS: The scale which is adapted for Turkey was applied to 132 caregivers of cancer patients, who are family members, twice by face-to-face interview method. Sample of the study consists of 132 caregivers of cancer patients who had outpatient treatment in chemotherapy unit of a university hospital in Izmir. Quantitative and percentage Ugur and Fadiloglu tests were used in the analysis of descriptive data regarding caregivers, Kendall W analysis was used to assess content validity of the scale, Pearson's Product Moment Correlation was used for test-retest reliability of the scale and Cronbach Alpha Analysis was used for internal consistency. RESULTS: Validity of the scale was determined by using Kendall's Coefficient of Concordance (W: 0.62, p > 0.05) and it was evaluated as there's no difference ofopinion among the experts. Test retest reliability coefficient between the first and the second application of the scale was found - as. 88. CONCLUSIONS: The scale which is ascertained to be valid and reliable as a result of our study can be used to assess the reactions of caregivers of cancer patients during the care giving period in Turkish society. PMID- 24061463 TI - Stereotactic body radiotherapy in early stage non-small cell lung cancer: first experience from an Indian Centre. AB - BACKGROUND: Surgery is the standard of care for early stage (T1-2, N0, M0) non small cell lung cancer. A considerable number of these patients are ineligible for surgery due to age and comorbidities. Hypo fractionated high-dose stereotactic body radiotherapy (SBRT) is being performed for these group of patients. There is paucity of literature regarding this novel technique from the Indian subcontinent. AIMS AND OBJECTIVES: We hereby report the dosimetry, response and outcome of our small cohort of early stage non-small cell lung cancer patients treated with SBRT. MATERIALS AND METHODS: Between December 2007 and December 2010, 8 patients of early stage (T1-2N0M0) underwent SBRT at our centre. All the patients had undergone whole body PET-CT scan, MRI brain and pulmonary function test (PFT with DLCO). The SBRT schedules included 48 Gy in 6 fractions for peripherally located and 48 Gy in 8 fractions for centrally located tumors. Response and toxicity were assessed in 3 monthly follow up visits. RESULTS: The median duration of follow up was 18 months (range 8-44 months). The median age of the patients was 70 years (range 63-82 years) and the median tumor diameter was 4 cm (range 2.8-5.0 cm). The mean PTV volume was 165 cc(range 127.3- 193.9 cc). The mean dose to the PTV was 99.5% (range 97.7- 102.1%). After 3 months, 7 patients had complete metabolic response and 1 patient had partial metabolic response. Overall survival at 1.5 years was 87.5%. One patient had grade 2 pneumonitis. No toxicities of grade 3 or higher were identified. CONCLUSION: SBRT for early stage NSCLC resulted in excellent local control with minimal toxicity and can be considered as a treatment option in properly selected patients. PMID- 24061464 TI - Evaluation of changes in the attitudes and behaviors of relatives of lung cancer patients toward cancer prevention and screening. AB - BACKGROUND: Cancer diagnosis affects all the relatives living with the patient; however, whether the behavior of family members changes or not is unknown. To end this we evaluated the relatives of lung cancer patients. MATERIALS AND METHODS: Forty-one questions were used to collect data from the relatives of lung cancer patients who had been living with them for at least one year, to evaluate changes in their attitudes and behaviors related to cancer prevention. RESULTS: The study included 246 lung cancer patients' relatives, of them 172 (69.9%) were women and 74 (30.1%) were men. The median age was 46 years (range: 20-83 years). Patients and their relatives had been living together for an average of 28 years (range: 1 68 years), and 88 (35.7%) of the patients' relatives were their children. We found changes in the attitudes and behaviors toward prevention and screening for cancer in 92 (37.4%) of the relatives. Fifty-two (21.1%) of them changed their smoking habits, 34 (13.8%) altered their eating habits, 25 (10.2%) changed their exercise habits, 13 (5.3%) visited a doctor due to a suspicion of having cancer, 12 (4.9%) changed their lifestyles, seven (2.8%) underwent cancer screening tests, three (1.2%) started using alternative medicines, and three (1.2%) started using vitamins for cancer prevention. CONCLUSIONS: Important changes occur in the attitudes and behaviors of patients' relatives toward cancer prevention and screening after the patients are diagnosed with lung cancer. Being aware of how patients' relatives react to a family member's cancer diagnosis may provide healthcare professionals with more incentive to address the relatives' special needs. PMID- 24061465 TI - Presence of CD3+ tumor infiltrating lymphocytes is significantly associated with good prognosis in infiltrating ductal carcinoma of breast. AB - BACKGROUND: Aim of this study was to investigate the prognostic significance of CD3+ TILs in infiltrating ductal carcinoma (IDC) of the breast. MATERIALS AND METHODS: Immuno-histochemistry was done with CD3 antibodies in tissue sections of 127 breast cancer patients, and CD3+ intra-tumoral and stromal TILs were counted in relation to clinico-pathological variables. RESULTS: Intra-tumoral and stromal CD3+ TILs were significantly associated with positive lymph node status (P = 0.006, P = 0.043, respectively) without significant association with age, menopausal status, family history, and hormonal status. The higher CD3 intra tumoral and stromal counts both showed significant association with good prognosis (P = 0.039, P = 0.044, respectively). The intra-tumoral count was higher than stromal count and was independently associated with disease-free survival in stage I and II cancer (P = 0.021). CONCLUSIONS: CD3+ TILs may serve as independent marker of good prognosis in IDC breast. The findings of this study need further validation on a larger sample size. PMID- 24061466 TI - Tobacco industry tactics with advertisements at the point of sale in Mumbai. AB - INTRODUCTION: The Cigarettes and Other Tobacco Products (Prohibition of Advertising and Regulations of Trade and Commerce, Production, Supply and Distribution) Act 2003 (COTPA) set out a number of stringent regulations to address tobacco promotion, some of which were revised in 2004. The aim of the study was to monitor the industry tactics at the point of sale with advertising and promotion of tobacco product in Mumbai. MATERIALS AND METHODS: The study was carried out by Cancer Patients Aid Association in Mumbai with the help of volunteers. The surveys consisted of two parts, observational information and an interviewer administered questionnaire. Observations like size of board, display of advertisement, backlighting, and use of any promotion were noted. A questionnaire captured information about any incentives from tobacco companies for advertisement and promotion was administered to the vendors who agreed to participate. Study was approved by the Scientific and independent Ethics committee. RESULTS: Total 125 establishments (58 shops, 55 kiosks, 12 other sites) with display boards were surveyed across 5 wards in Mumbai. It was noted that the most common violation was the placements of boards, mainly placed above the shop. The display boards were oversized and few of the advertisements were highlighted with backlights. Out of 125 tobacco vendors surveyed, 107 (85.5%) vendors agreed to answer the questionnaire. We noted that a majority of 67% (84 vendors) stated that they had been approached by tobacco companies to place the signages during the past 5 years post COTPA came into effect. 79 vendors (65 %) admitted to being paid by the tobacco companies. DISCUSSION: Although the civil society and various non-governmental organizations has casted voice against the industry tactics but ineffective enforcement of the law is a major hurdle. It is likely that cigarette companies will be further able to overcome advertising restrictions by finding loopholes in tobacco legislation unless the decision makers ban it comprehensively as evident in other countries. PMID- 24061467 TI - Preliminary evaluation of children treated with metronomic chemotherapy and valproic acid in a low-income country: Metro-Mali-02. AB - BACKGROUND: Metronomics is defined by the combination of metronomic chemotherapy and drug repositioning. Since off-patent chemotherapeutic drugs can be used and given the low toxicity profile of this approach, metronomics appears to be an invaluable alternative to bring affordable targeted therapies in low-income countries. OBJECTIVE: The aim of this study was to report on the preliminary efficacy and safety of a metronomic vincristine/cyclophosphamide/methotrexate/valproic acid regimen given to children with refractory cancer of various tumor types or with a very advanced disease. MATERIALS AND METHODS: This prospective, single-center study evaluated the use of a metronomics protocol, consisting of a first cycle of weekly vincristine 1.5 mg/m2 (days: 1, 8, 15 and 22), daily cyclophosphamide 25 mg/m2 (days: 1-21), twice weekly methotrexate 15 mg/m2 (days: 21-42) and daily valproic acid (30 mg/kg/d) followed by a 1-week break. For the following cycles, vincristine was administrated only at week 1 and 5 of the cycle. This treatment was proposed to children with refractory disease and patients who were not eligible for the protocols available in the hospital. Adverse events were determined through laboratory analyses and investigator observations. RESULTS: From January 2010 to January 2011, 7 children (mean age: 5.4 +/- 3 years old) were treated. Most frequent diagnosis was retinoblastoma. Two partial responses were observed in patients with neuroblastoma and retinoblastoma. These two patients are alive with stable disease at last follow-up (6 and 26 months, respectively) after stopping treatment. CONCLUSION: Metronomics allows treating patients with advanced or refractory or relapsing disease and the introduction of targeted treatments in low-income countries. The potential of metronomics in children and young adults living in middle- and low-income countries warrants further larger studies. PMID- 24061468 TI - Presentation, complications, and impact of concurrent malaria infection on anticancer therapy. AB - BACKGROUND: There is very limited data on the effects of malaria on on-going anticancer therapy. MATERIALS AND METHODS: We performed a retrospective analysis of adult solid tumor patients who contracted malaria while on active anticancer therapy. We noted their demographic profile, clinical course and the effects of malaria infection on their on-going anticancer therapy. Analysis was done with simple percentages. RESULTS: We analyzed 33 malarial episodes in 30 patients over 3 months. Plasmodium vivax was the most common type of infection (75%). Presenting symptoms included the typical triad of fever with chills and rigors. Malaria caused multiple complications, necessitating hospitalization in half of the patients and intensive care unit care in 1 of 8 patients. Common complications included thrombocytopenia (73%), anemia (67%), hyponatremia (66%), hepatic dysfunction (27%), and hypotension (12%). There were no deaths as a result of malaria. Malaria caused treatment delays with an average of 2.42 days per event. Plasmodium vivax caused more complications and therapy delays, average: 3.7 days per event, while non-vivax malaria caused an average of 0.5 days delay per event. There was a high level of resistance to chloroquine. CONCLUSION: Malaria is a significant problem in adult solid tumor patients, leading to multiple complications and therapy delays. PMID- 24061469 TI - Clinico-pathological impact of cytogenetic subgroups in B-cell chronic lymphocytic leukemia: experience from India. AB - BACKGROUND: The present study of 238 B-cell Chronic Lymphocytic Leukemia (B-CLL) patients were undertaken to seek the prevalence and to evaluate clinico pathological significance of recurrent genetic abnormalities such as del(13q14.3), trisomy 12, del(11q22.3) (ATM), TP53 deletion, del(6q21) and IgH translocation/deletion. MATERIALS AND METHODS: We applied interphase - fluorescence in situ hybridization (FISH) on total 238 cases of B-CLL. RESULTS: Our study disclosed 69% of patients with genetic aberrations such as 13q deletion (63%), trisomy 12 (28%), 11q deletion (18%), 6q21 deletion (11%) with comparatively higher frequency of TP53 deletion (22%). Deletion 13q displayed as a most frequent sole abnormality. In group with coexistence of >=2 aberrations, 13q deletion was a major clone indicating del(13q) as a primary event followed by 11q deletion, TP53 deletion, trisomy 12, 6q deletion as secondary progressive events. In comparison with del(13q), trisomy 12, group with coexistence of >=2 aberrations associated with poor risk factors such as hyperleukocytosis, advanced stage, and multiple nodes involvement. In a separate study of 116 patients, analysis of IgH abnormalities revealed either partial deletion (24%) or translocation (5%) and were associated with del(13q), trisomy 12, TP53 and ATM deletion. Two of 7 cases had t(14;18), one case had t(8;14), and four cases had other variant IgH translocation t(?;14). CONCLUSION: Detail characterization and clinical impact are necessary to ensure that IgH translocation positive CLL is a distinct pathological entity. Our data suggests that CLL with various cytogenetic subsets, group with coexistence of >=2 aberrations seems to be a complex cytogenetic subset, needs more attention to understand biological significance and to seek clinical impact for better management of disease. PMID- 24061470 TI - Sunitinib in metastatic renal cell carcimoma: a single-center experience. AB - INTRODUCTION: Historically, metastatic renal cell carcinoma (RCC) has had poor prognosis; the outcomes have improved with the introduction of tyrosine-kinase inhibitors, such as sunitinib. There is no reported literature from India on the use of sunitinib in metastatic RCC. We present an analysis of sunitinib at our institute over 4 years. MATERIALS AND METHODS: An unselected population of patients with metastatic or relapsed metastatic RCC receiving sunitinib was analyzed with respect to patient characteristics, response, toxicity, and outcomes. RESULTS: Fifty-nine patients (51 males, 8 females) with a median age of 55 years were included in the study. Lungs and bones were the most common site of metastases. The patients received a median number of 4 cycles, with 23 patients requiring dose-modification and 12 discontinuing therapy due to toxicity. Overall, 38 patients (65%) had CR, PR, or standard deviation while 14 had progression or death at initial evaluation. The median progression-free survival (PFS) was 11.4 months and overall survival was 22.6 months. Hand-foot syndrome, fatigue, mucositis, skin rash, and vomiting were seen more often among our patients, whereas hypertension was not as common compared with previously published reports. CONCLUSION: Sunitinib is a viable option for the treatment of metastatic RCC and shows a comparable PFS in Indian patients. Although toxicity remains a concern, most of the adverse effects can be managed conservatively. Careful patient selection, tailoring the dose of therapy, adequate counseling, and careful follow-up is essential for optimum therapy. PMID- 24061471 TI - Various methods available for detection of apoptotic cells--a review. AB - Apoptosis is a process of programmed cell death occurring in multicellular organisms in whom development, maintenance and sculpturing organs and tissues. Taken together, apoptotic processes are of widespread biological significance; being involved in e.g. development, differentiation, proliferation/homoeostasis, regulation and function of the immune system and in the removal of defected harmful cells. Dys regulation of apoptosis can play a primary or secondary role leading to cancer whereas excessive apoptosis contributes to neuro degeneration, autoimmunity, AIDS, and ischemia. Gaining insight into the techniques for detecting apoptotic cells will allow the development of more effective, higher specific and therefore better-tolerable therapeutic approaches. The goal of this review article is to provide a general overview of current knowledge, on the various technical approaches for detecting apoptotic cells. PMID- 24061473 TI - Coordination environment evolution of Eu3+ during the dehydration and re crystallization processes of Sm(1-x)Eu(x)[B9O13(OH)4].H2O by photoluminescent characteristics. AB - There are limited photoluminescence (PL) studies for rare earth borates with crystalline water molecules, which are usually supposed to have low PL efficiency because the vibrations of H2O or -OH may lead to emission quenching. We investigated the PL properties of Sm(1-x)Eu(x)[B9O13(OH)4].H2O (x = 0-1.00) and their dehydrated products alpha-Sm(1-x)Eu(x)B5O9. There is no quenching effect in those studied polyborates because the large borate ionic groups isolate the Eu(3+) activators very well. Sm(3+) and Eu(3+) are basically separated luminescent activators. Comparatively, Sm(3+) shows a very small emission intensity, which can be almost ignored, therefore our interest is focused on the Eu(3+) luminescence. By TG-DSC and powder XRD experiments, we defined three weight-loss steps for Eu[B9O13(OH)4].H2O and a re-crystallization process to alpha-EuB5O9, during which luminescent spectra of Eu(3+) are recorded. It shows an interesting variety and therefore is a good medium to understand the coordination environment evolution of Eu(3+), even for the intermediate amorphous phase. In fact, the coordination symmetry of Eu(3+) in the amorphous state is the lowest. The high efficiency of the f-f transitions and large R/O value (3.8) imply this amorphous phase is potentially a good red-emitting UV-LED phosphor. Anhydrous alpha-EuB5O9 shows the highest luminescent efficiency excited by Eu(3+) CT transition. In addition, alpha-Sm(1-x)Eu(x)B5O9 was synthesized by a sol-gel method directly for the first time, and alpha-EuB5O9 shows superior PL properties due to its better crystallinity. A lot of hydrated polyborates with crystalline water molecules remain unexplored and our study shows their potential as good phosphors. PMID- 24061474 TI - Protein inhibitor of activated STAT 1 (PIAS1) is identified as the SUMO E3 ligase of CCAAT/enhancer-binding protein beta (C/EBPbeta) during adipogenesis. AB - It is well recognized that PIAS1, a SUMO (small ubiquitin-like modifier) E3 ligase, modulates such cellular processes as cell proliferation, DNA damage responses, and inflammation responses. Recent studies have shown that PIAS1 also plays a part in cell differentiation. However, the role of PIAS1 in adipocyte differentiation remains unknown. CCAAT/enhancer-binding protein beta (C/EBPbeta), a major regulator of adipogenesis, is a target of SUMOylation, but the E3 ligase responsible for the SUMOylation of C/EBPbeta has not been identified. The present study showed that PIAS1 functions as a SUMO E3 ligase of C/EBPbeta to regulate adipogenesis. PIAS1 expression was significantly and transiently induced on day 4 of 3T3-L1 adipocyte differentiation, when C/EBPbeta began to decline. PIAS1 was found to interact with C/EBPbeta through the SAP (scaffold attachment factor A/B/acinus/PIAS) domain and SUMOylate it, leading to increased ubiquitination and degradation of C/EBPbeta. C/EBPbeta became more stable when PIAS1 was silenced by RNA interference (RNAi). Moreover, adipogenesis was inhibited by overexpression of wild-type PIAS1 and promoted by knockdown of PIAS1. The mutational study indicated that the catalytic activity of SUMO E3 ligase was required for PIAS1 to restrain adipogenesis. Importantly, the inhibitory effect of PIAS1 overexpression on adipogenesis was rescued by overexpressed C/EBPbeta. Thus, PIAS1 could play a dynamic role in adipogenesis by promoting the SUMOylation of C/EBPbeta. PMID- 24061475 TI - Downregulation of PHLPP expression contributes to hypoxia-induced resistance to chemotherapy in colon cancer cells. AB - Hypoxia is a feature of solid tumors. Most tumors are at least partially hypoxic. This hypoxic environment plays a critical role in promoting resistance to anticancer drugs. PHLPP, a novel family of Ser/Thr protein phosphatases, functions as a tumor suppressor in colon cancers. Here, we show that the expression of both PHLPP isoforms is negatively regulated by hypoxia/anoxia in colon cancer cells. Interestingly, a hypoxia-induced decrease of PHLPP expression is attenuated by knocking down HIF1alpha but not HIF2alpha. Whereas the mRNA levels of PHLPP are not significantly altered by oxygen deprivation, the reduction of PHLPP expression is caused by decreased protein translation downstream of mTOR and increased degradation. Specifically, hypoxia-induced downregulation of PHLPP is partially rescued in TSC2 or 4E-BP1 knockdown cells as the result of elevated mTOR activity and protein synthesis. Moreover, oxygen deprivation destabilizes PHLPP protein by decreasing the expression of USP46, a deubiquitinase of PHLPP. Functionally, downregulation of PHLPP contributes to hypoxia-induced chemoresistance in colon cancer cells. Taken together, we have identified hypoxia as a novel mechanism by which PHLPP is downregulated in colon cancer, and the expression of PHLPP may serve as a biomarker for better understanding of chemoresistance in cancer treatment. PMID- 24061476 TI - A C-terminal acidic domain regulates degradation of the transcriptional coactivator Bob1. AB - Bob1 (Obf-1 or OCA-B) is a 34-kDa transcriptional coactivator encoded by the Pou2af1 gene that is essential for normal B-cell development and immune responses in mice. During lymphocyte activation, Bob1 protein levels dramatically increase independently of mRNA levels, suggesting that the stability of Bob1 is regulated. We used a fluorescent protein-based reporter system to analyze protein stability in response to genetic and physiological perturbations and show that, while Bob1 degradation is proteasome mediated, it does not require ubiquitination of Bob1. Furthermore, degradation of Bob1 in B cells appears to be largely independent of the E3 ubiquitin ligase Siah. We propose a novel mechanism of Bob1 turnover in B cells, whereby an acidic region in the C terminus of Bob1 regulates the activity of degron signals elsewhere in the protein. Changes that make the C terminus more acidic, including tyrosine phosphorylation-mimetic mutations, stabilize the instable murine Bob1 protein, indicating that B cells may regulate Bob1 stability and activity via signaling pathways. Finally, we show that expressing a stable Bob1 mutant in B cells suppresses cell proliferation and induces changes in surface marker expression commonly seen during B-cell differentiation. PMID- 24061477 TI - Molecular insights revealing interaction of Tim23 and channel subunits of presequence translocase. AB - Tim23 is an essential channel-forming subunit of the presequence translocase recruiting multiple components for assembly of the core complex, thereby regulating the protein translocation process. However, understanding of the precise interaction of subunits associating with Tim23 remains largely elusive. Our findings highlight that transmembrane helix 1 (TM1) is required for homodimerization of Tim23, while, together with TM2, it is involved in preprotein binding within the channel. Based on our evidence, we predict that the TM1 and TM2 from each dimer are involved in the formation of the central translocation pore, aided by Tim17. Furthermore, TM2 is also involved in the recruitment of Tim21 and the presequence-associated motor (PAM) subcomplex to the Tim23 channel, while the matrix-exposed loop L1 generates specificity in their association with the core complex. Strikingly, our findings indicate that the C-terminal sequence of Tim23 is dispensable for growth and functions as an inhibitor for binding of Tim21. Our model conceptually explains the cooperative function between Tam41 and Pam17 subunits, while the antagonistic activity of Tim21 predominantly determines the bound and free forms of the PAM subcomplex during import. PMID- 24061478 TI - Cloning expeditions: risky but rewarding. AB - In the 1980s, a good part of my laboratory was using the then-new recombinant DNA techniques to clone and characterize many important cell surface membrane proteins: GLUT1 (the red cell glucose transporter) and then GLUT2 and GLUT4, the red cell anion exchange protein (Band 3), asialoglycoprotein receptor subunits, sucrase-isomaltase, the erythropoietin receptor, and two of the subunits of the transforming growth factor beta (TGF-beta) receptor. These cloned genes opened many new fields of basic research, including membrane insertion and trafficking of transmembrane proteins, signal transduction by many members of the cytokine and TGF-beta families of receptors, and the cellular physiology of glucose and anion transport. They also led to many insights into the molecular biology of several cancers, hematopoietic disorders, and diabetes. This work was done by an exceptional group of postdocs and students who took exceptionally large risks in developing and using novel cloning technologies. Unsurprisingly, all have gone on to become leaders in the fields of molecular cell biology and molecular medicine. PMID- 24061479 TI - Loss of tumor suppressor RPL5/RPL11 does not induce cell cycle arrest but impedes proliferation due to reduced ribosome content and translation capacity. AB - Humans have evolved elaborate mechanisms to activate p53 in response to insults that lead to cancer, including the binding and inhibition of Hdm2 by the 60S ribosomal proteins (RPs) RPL5 and RPL11. This same mechanism appears to be activated upon impaired ribosome biogenesis, a risk factor for cancer initiation. As loss of RPL5/RPL11 abrogates ribosome biogenesis and protein synthesis to the same extent as loss of other essential 60S RPs, we reasoned the loss of RPL5 and RPL11 would induce a p53-independent cell cycle checkpoint. Unexpectedly, we found that their depletion in primary human lung fibroblasts failed to induce cell cycle arrest but strongly suppressed cell cycle progression. We show that the effects on cell cycle progression stemmed from reduced ribosome content and translational capacity, which suppressed the accumulation of cyclins at the translational level. Thus, unlike other tumor suppressors, RPL5/RPL11 play an essential role in normal cell proliferation, a function cells have evolved to rely on in lieu of a cell cycle checkpoint. PMID- 24061480 TI - Rac1 activation in podocytes induces rapid foot process effacement and proteinuria. AB - The kidney's vital filtration function depends on the structural integrity of the glomerulus, the proximal portion of the nephron. Within the glomerulus, the architecturally complex podocyte forms the final cellular barrier to filtration. Injury to the podocyte results in a morphological change called foot process effacement, which is a ubiquitous feature of proteinuric diseases. The exact mechanism underlying foot process effacement is not known, but recently it has been proposed that this change might reflect activation of the Rac1 GTPase. To test this hypothesis, we generated a podocyte-specific, inducible transgenic mouse line that expressed constitutively active Rac1. When the Rac1 transgene was induced, we observed a rapid onset of proteinuria with focal foot process effacement. Using superresolution imaging, we verified that the induced transgene was expressed in damaged podocytes with altered foot process morphology. This work sheds new light on the complex balance of Rho GTPase signaling that is required for proper regulation of the podocyte cytoskeleton. PMID- 24061481 TI - Dietary manipulation of serotonergic and dopaminergic function in C57BL/6J mice with amino acid depletion mixtures. AB - Amino acid (AA) depletion techniques have been used to decrease serotonin (5-HT) and/or dopamine (DA) synthesis after administration of a tryptophan (acute tryptophan depletion, ATD) or phenylalanine/tyrosine-free (phenylalanine-tyrosine depletion, PTD) AA formula and are useful as neurochemical challenge procedures to study the impact of DA and 5-HT in patients with neuropsychiatric disorders. We recently demonstrated that the refined Moja-De ATD paradigm decreases brain 5 HT synthesis in humans and mice and lowers brain 5-HT turnover. In the present study we validated the neurochemical effects of three developed AA formulas on brain 5-HT and DA function in mice. To distinguish the direct and indirect effects of such mixtures on 5-HT and DA and to determine whether additive depletion of both could be obtained simultaneously, we compared the effects of ATD for 5-HT, PTD for DA, and a combined monoamine depletion mixture (CMD) compared to a control condition consisting of a balanced amino acid mixture. Food deprived male C57BL/6J mice were gavaged with AA mixtures. Serum and brain samples were collected and analyzed for determination of tryptophan (Trp), tyrosine (Tyr), 5-HT, 5-HIAA, DA, DOPAC and HVA levels. ATD was the most effective at decreasing Trp, 5-HT and 5-HIAA. In contrast, PTD reduced Tyr globally but HVA only in certain brain regions. Although CMD affected both 5-HT and DA synthesis, it was less effective when compared with ATD or PTD alone. The present results demonstrate that two newly developed PTD and CMD formulas differentially impact brain 5-HT and DA synthesis relative to 5-HT-specific ATD Moja-De. Different effects on 5-HT and DA function by these mixtures suggest that the exact composition may be a critical determinant for effectiveness with respect to the administered challenge procedure. PMID- 24061482 TI - Short-term ethanol exposure causes imbalanced neurotrophic factor allocation in the basal forebrain cholinergic system: a novel insight into understanding the initial processes of alcohol addiction. AB - Alcohol ingestion affects both motor and cognitive functions. One brain system that is influenced by ethanol is the basal forebrain (BF) cholinergic projection system, which projects to diverse neocortical and limbic areas. The BF is associated with memory and cognitive function. Our primary interest is the examination of how regions that receive BF cholinergic projections are influenced by short-term ethanol exposure through alterations in the mRNA levels of neurotrophic factors [nerve growth factor/TrkA, brain-derived neurotrophic factor/TrkB, and glial-derived neurotrophic factor (GDNF)/GDNF family receptor alpha1]. Male BALB/C mice were fed a liquid diet containing 5 % (v/v) ethanol. Pair-fed control mice were maintained on an identical liquid diet, except that the ethanol was isocalorically substituted with sucrose. Mice exhibiting signs of ethanol intoxication (stages 1-2) were used for real-time reverse transcription polymerase chain reaction analyses. Among the BF cholinergic projection regions, decreased levels of GDNF mRNA and increased levels of TrkB mRNA were observed in the basal nucleus, and increased levels of TrkB mRNA were observed in the cerebral cortex. There were no significant alterations in the levels of expression of relevant neurotrophic factors in the septal nucleus and hippocampus. Given that neurotrophic factors function in retrograde/anterograde or autocrine/paracrine mechanisms and that BF cholinergic projection regions are neuroanatomically connected, these findings suggested that an imbalanced allocation of neurotrophic factor ligands and receptors is an initial phenomenon in alcohol addiction. The exact mechanisms underlying this phenomenon in the BF cholinergic system are unknown. However, our results provide a novel notion for the understanding of the initial processes in alcohol addiction. PMID- 24061484 TI - Neurosubstrates of remission following prolonged exposure therapy in veterans with posttraumatic stress disorder. AB - BACKGROUND: Prolonged exposure (PE) therapy is the first-line treatment for posttraumatic stress disorder (PTSD) in combat veterans. The underlying brain changes of treatment effect in PTSD are currently unknown. METHODS: A total of 31 veterans with PTSD completed an fMRI scan performing an affective anticipation task at baseline and were enrolled in PE therapy. Of these, 7 prematurely terminated therapy, while 24 individuals completed PE therapy and an identical follow-up fMRI scan. At follow-up, 15 of the 24 completers still had diagnosable PTSD (NR-PTSD) and 9 of the 24 completers showed complete remission from PTSD (R PTSD), i.e. they did not meet diagnostic criteria for PTSD. RESULTS: The left anterior insula showed a significant group by scan session interaction. Specifically, the R-PTSD group showed decreased activation during anticipation of negative images from pre- to posttreatment scans, while the NR-PTSD group showed increased activation during anticipation of positive images in this region. Furthermore, the change in functional activation in the insula co-occurred with increased connectivity between this insular region and the right cingulate and right mid-posterior insular region in R-PTSD. CONCLUSIONS: These findings suggest that the capacity to effectively remit from PTSD symptoms after PE treatment requires the ability to connect with physiological signals and moderate the discomfort of anticipatory anxiety of exposure therapy. These processes appear to be controlled by a network where the anterior insula is connected with the cingulate and the mid-posterior insula. PMID- 24061483 TI - NRG3 gene is associated with the risk and age at onset of Alzheimer disease. AB - The Neuregulin 3 (NRG3) gene at 10q22-q24 has been implicated in multiple psychiatric traits such as cognitive impairment. We therefore hypothesized that NRG3 gene polymorphisms may play a role in Alzheimer disease (AD). This present study explored the association of NRG3 with the age at onset (AAO) of AD and the risk of developing AD. Secondary data analysis of 257 single-nucleotide polymorphisms (SNPs) in NRG3 gene was performed in 806 Alzheimer's disease patients and 782 controls using logistic regression and linear regression analyses. Eight SNPs were associated with the risk of AD (p < 0.05), while linear regression analysis showed 33 SNPs associated with the AAO of AD (p < 0.05). Two SNP haplotype analyses based on UNPHASED revealed that the G-C haplotype from rs17685233 and rs17101017 was significantly associated with AD (p = 0.0031) and the A-G haplotype from rs504522 and rs474018 as well as the A-G haplotype from rs504522 and rs2483295 were more significantly associated with the AAO of AD (p = 6.72 * 10(-5)). Using an independent family-based sample, we found one SNP rs11192423 associated with AAO both in the case-control sample (p = 0.0155) and in the family sample (p = 0.0166). In addition, we observed nominally significant associations with AD and AAO for several flanking SNPs (p < 0.05). This is the first study demonstrating that genetic variants in the NRG3 gene play a role in AD. Our results also revealed that SNPs in the NRG3 genes were more strongly associated with AAO of AD. PMID- 24061486 TI - The multifaceted dissociation chemistry of anionic aggregates containing functionalised amines and CO2. AB - Specific products and their relative abundances observed in gas-phase collision induced dissociation experiments for [amine-H + CO2 + H2O](-) reflect the behaviour of the bulk aqueous amines in the presence of CO2. PMID- 24061485 TI - Genetic analysis and detection of the gene MlLX99 on chromosome 2BL conferring resistance to powdery mildew in the wheat cultivar Liangxing 99. AB - KEY MESSAGE: The effectiveness of wheat cultivar Liangxing 99 against powdery mildew was shown to be controlled by a single dominant gene located on a new locus of chromosome 2BL in the bin 2BL2-0.35-0.50. Liangxing 99, one of the most widely grown commercial cultivars in the winter wheat (Triticum aestivum) producing regions in northern China, was shown to provide a broad spectrum of resistance to Blumeria graminis f. sp. tritici (Bgt) isolates originating from that region. Using an F2 population and F2:3 lines derived from a cross of Liangxing 99 * Zhongzuo 9504, genetic analysis demonstrated that a single dominant gene, designated MlLX99, was responsible for the resistance of Liangxing 99 to Bgt isolate E09. The results of molecular analysis indicated that this gene is located on chromosome 2BL and flanked by the SSR marker Xgwm120 and EST-STS marker BE604758 at genetic distances of 2.9 and 5.5 cM, respectively. Since the flanking markers of MlLX99 were previously mapped to the bin 2BL2-0.36-0.50, MlLX99 must be located in this chromosomal region. MlLX99 showed a different resistance reaction pattern to 60 Bgt isolates from Pm6, Pm33, and PmJM22, which were all previously mapped on chromosome 2BL, but differed in their positions from MlLX99. Due to its unique position on chromosome 2BL, MlLX99 appears to be a new locus for resistance to powdery mildew. Liangxing 99 has shown superior yield performance and wide adaptation to different agricultural conditions, which has resulted in its extensive use as a wheat cultivar in China. The identification of resistance gene MlLX99 facilitates the use of this cultivar in the protection of wheat from damage caused by powdery mildew. PMID- 24061487 TI - Measurement of small molecule diffusion with an optofluidic silicon chip. AB - In this work we explore the micro-ring resonator platform to study the diffusion driven mass transport of small molecules within microfluidic channels. The micro ring resonators are integrated on a silicon-on-insulator photonic chip and combined with microfluidics in poly(dimethylsiloxane) (PDMS). We apply a strong initial gradient in the solute concentration and use the micro-ring resonators to observe how this concentration evolves over time and space. This can be achieved by tracking the optical resonances of multiple micro-rings as they shift with changing solute concentration. Experiments are performed for both glucose and NaCl and at different temperatures. The measured concentration profiles are used to calculate the diffusion coefficient of both glucose and NaCl in water. The good agreement between measurement and theoretical prediction demonstrates the relevance of this method. PMID- 24061488 TI - Ricinosomes provide an early indicator of suspensor and endosperm cells destined to die during late seed development in quinoa (Chenopodium quinoa). AB - BACKGROUND AND AIMS: In mature quinoa (Chenopodium quinoa) seeds, the lasting endosperm forms a micropylar cone covering the radicle. The suspensor cells lie within the centre of the cone. During the final stage of seed development, the cells of the lasting endosperm accumulate protein and lipids while the rest are crushed and disintegrated. Both the suspensor and endosperm die progressively from the innermost layers surrounding the embryo and extending towards the nucellar tissue. Ricinosomes are endoplasmic reticulum-derived organelles that accumulate both the pro-form and the mature form of cysteine endopeptidase (Cys EP), first identified in castor bean (Ricinus communis) endosperm during germination. This study sought to identify associations between the presence of ricinosomes and programmed cell death (PCD) hallmarks in suspensor and endosperm cells predestined to die during quinoa seed development. METHODS: A structural study using light microscopy and transmission electron microscopy was performed. To detect the presence of Cys-EP, both western blot and in situ immunolocalization assays were carried out using anti-R. communis Cys-EP antibody. A TUNEL assay was used to determine DNA fragmentation. RESULTS AND CONCLUSIONS: Except for the one or two cell layers that constitute the lasting endosperm in the mature seed, ricinosomes were found in suspensor and endosperm cells. These cells were also the site of morphological abnormalities, including misshapen and fragmented nuclei, vesiculation of the cytosol, vacuole collapse and cell wall disorganization. It is proposed that, in suspensor and endosperm cells, the early detection of Cys-EP in ricinosomes predicts the occurrence of PCD during late seed development. PMID- 24061490 TI - Among-species differences in pollen quality and quantity limitation: implications for endemics in biodiverse hotspots. AB - BACKGROUND AND AIMS: Insufficient pollination is a function of quantity and quality of pollen receipt, and the relative contribution of each to pollen limitation may vary with intrinsic plant traits and extrinsic ecological properties. Community-level studies are essential to evaluate variation across species in quality limitation under common ecological conditions. This study examined whether endemic species are more limited by pollen quantity or quality than non-endemic co-flowering species in three endemic-rich plant communities located in biodiversity hotspots of different continents (Andalusia, California and Yucatan). METHODS: Natural variations in pollen receipt and pollen tube formation were analysed for 20 insect-pollinated plants. Endemic and non-endemic species that co-flowered were paired in order to estimate and compare the quantity and quality components of pre-zygotic pollination success, obtained through piecewise regression analysis of the relationship between pollen grains and pollen tubes of naturally pollinated wilted flowers. KEY RESULTS: Pollen tubes did not frequently exceed the number of ovules per flower. Only the combination of abundant and good quality pollen and a low number of ovules per flower conferred relief from pre-zygotic pollen limitation in the three stochastic pollination environments studied. Quality of pollen receipt was found to be as variable as quantity among study species. The relative pollination success of endemic and non-endemic species, and its quantity and quality components, was community dependent. CONCLUSIONS: Assessing both quality and quantity of pollen receipt is key to determining the ovule fertilization potential of both endemic and widespread plants in biodiverse hotspot regions. Large natural variation among flowers of the same species in the two components and pollen tube formation deserves further analysis in order to estimate the environmental, phenotypic and intraindividual sources of variation that may affect how plants evolve to overcome this limitation in different communities worldwide. PMID- 24061489 TI - Auxin and cytokinin control formation of the quiescent centre in the adventitious root apex of Arabidopsis. AB - BACKGROUND AND AIMS: Adventitious roots (ARs) are part of the root system in numerous plants, and are required for successful micropropagation. In the Arabidopsis thaliana primary root (PR) and lateral roots (LRs), the quiescent centre (QC) in the stem cell niche of the meristem controls apical growth with the involvement of auxin and cytokinin. In arabidopsis, ARs emerge in planta from the hypocotyl pericycle, and from different tissues in in vitro cultured explants, e.g. from the stem endodermis in thin cell layer (TCL) explants. The aim of this study was to investigate the establishment and maintenance of the QC in arabidopsis ARs, in planta and in TCL explants, because information about this process is still lacking, and it has potential use for biotechnological applications. METHODS: Expression of PR/LR QC markers and auxin influx (LAX3)/efflux (PIN1) genes was investigated in the presence/absence of exogenous auxin and cytokinin. Auxin was monitored by the DR5::GUS system and cytokinin by immunolocalization. The expression of the auxin-biosynthetic YUCCA6 gene was also investigated by in situ hybridization in planta and in AR-forming TCLs from the indole acetic acid (IAA)-overproducing superroot2-1 mutant and its wild type. KEY RESULTS: The accumulation of auxin and the expression of the QC marker WOX5 characterized the early derivatives of the AR founder cells, in planta and in in vitro cultured TCLs. By determination of PIN1 auxin efflux carrier and LAX3 auxin influx carrier activities, an auxin maximum was determined to occur at the AR tip, to which WOX5 expression was restricted, establishing the positioning of the QC. Cytokinin caused a restriction of LAX3 and PIN1 expression domains, and concomitantly the auxin biosynthesis YUCCA6 gene was expressed in the apex. CONCLUSIONS: In ARs formed in planta and TCLs, the QC is established in a similar way, and auxin transport and biosynthesis are involved through cytokinin tuning. PMID- 24061491 TI - Cluster-root formation and carboxylate release in three Lupinus species as dependent on phosphorus supply, internal phosphorus concentration and relative growth rate. AB - BACKGROUND AND AIMS: Some Lupinus species produce cluster roots in response to low plant phosphorus (P) status. The cause of variation in cluster-root formation among cluster-root-forming Lupinus species is unknown. The aim of this study was to investigate if cluster-root formation is, in part, dependent on different relative growth rates (RGRs) among Lupinus species when they show similar shoot P status. METHODS: Three cluster-root-forming Lupinus species, L. albus, L. pilosus and L. atlanticus, were grown in washed river sand at 0, 7.5, 15 or 40 mg P kg( 1) dry sand. Plants were harvested at 34, 42 or 62 d after sowing, and fresh and dry weight of leaves, stems, cluster roots and non-cluster roots of different ages were measured. The percentage of cluster roots, tissue P concentrations, root exudates and plant RGR were determined. KEY RESULTS: Phosphorus treatments had major effects on cluster-root allocation, with a significant but incomplete suppression in L. albus and L. pilosus when P supply exceeded 15 mg P kg(-1) sand. Complete suppression was found in L. atlanticus at the highest P supply; this species never invested more than 20 % of its root weight in cluster roots. For L. pilosus and L. atlanticus, cluster-root formation was decreased at high internal P concentration, irrespective of RGR. For L. albus, there was a trend in the same direction, but this was not significant. CONCLUSIONS: Cluster-root formation in all three Lupinus species was suppressed at high leaf P concentration, irrespective of RGR. Variation in cluster-root formation among the three species cannot be explained by species-specific variation in RGR or leaf P concentration. PMID- 24061492 TI - Bilateral cerebellar and brain stem infarction resulting from vertebral artery injury following cervical trauma without radiographic damage of the spinal column: a case report. AB - Vertebral artery injury can be a complication of cervical spine injury. Although most cases are asymptomatic, the rare case progresses to severe neurological impairment and fatal outcomes. We experienced a case of bilateral cerebellar and brain stem infarction with fatal outcome resulting from vertebral artery injury associated with cervical spine trauma. A 69-year-old male was admitted to our hospital because of tetraplegia after falling down the stairs and hitting his head on the floor. Marked bony damage of the cervical spine was not apparent on radiographs and CT scans, so the injury was initially considered to be a cervical cord injury without bony damage. However, an intensity change in the intervertebral disc at C5/C6, and a ventral epidural hematoma were observed on MRI. A CT angiogram of the neck showed the right vertebral artery was completely occluded at the C4 level of the spine. Forty-eight hours after injury, the patient lapsed into drowsy consciousness. The cranial CT scan showed a massive low-density area in the bilateral cerebellar hemispheres and brain stem. Anticoagulation was initiated after a diagnosis of the right vertebral artery injury, but the patient developed bilateral cerebellar and brain stem infarction. The patient's brain herniation progressed and the patient died 52 h after injury. We considered that not only anticoagulation but also treatment for thrombosis would have been needed to prevent cranial embolism. We fully realize that early and appropriate treatment are essential to improve the treatment results, and constructing a medical system with a team of orthopedists, radiologists, and neurosurgeons is also very important. PMID- 24061493 TI - Synovial hemangioma of the hip joint in a pediatric patient. AB - Hemangiomas of the articular synovium are rare and commonly associated with recurrent joint swelling and painful limitation of motion. The knee joint is the most commonly involved site, with most patients diagnosed in the second to third decade of life. Although over 200 cases have been reported in the English language medical literature, only three have originated within the hip joint, all of which were in adult patients reported in the surgical literature. We describe a histologically proven synovial hemangioma of the hip joint in a pediatric patient that invaded the femur, acetabulum, and adjacent soft tissues, with a detailed discussion of the differential diagnosis based on the radiographic and magnetic resonance imaging (MRI) findings. PMID- 24061494 TI - Intraneural perineurioma of the sciatic nerve: an under-recognized nerve neoplasm with characteristic MRI findings. AB - Intraneural perineurioma is a benign peripheral nerve neoplasm that typically affects teenagers and young adults and tends to result in a motor-predominant neuropathy. The lesion is rare, but has likely been underdiagnosed due to a lack of familiarity among both clinicians and radiologists. There have been few reports in the radiology literature despite the lesion having a fairly characteristic imaging appearance. We report a case of a 26-year-old woman with an intraneural perineurioma of the left sciatic nerve confirmed with excisional biopsy and pathologic analysis. PMID- 24061495 TI - Antidepressant-like and anxiolytic-like effects following activation of the MU delta opioid receptor heteromer in the nucleus accumbens. AB - Treatment-resistant major depressive disorder remains inadequately treated with currently available antidepressants. Opioid receptors (ORs) are involved in the pathophysiology of depression yet remain an untapped therapeutic intervention. The MU-delta OR heteromer represents a unique signaling complex with distinct properties compared with MU- and delta-OR homomers; however, its role in depression has not been characterized. As there are no ligands exclusively targeting the MU-delta heteromer, we devised a strategy to selectively antagonize the function of the MU-deltaOR complex using a specific interfering peptide derived from the deltaOR distal carboxyl tail, a sequence implicated in MU deltaOR heteromerization. In vitro studies using a minigene expressing this peptide demonstrated a loss of the unique pharmacological and trafficking properties of delta-agonists at the MU-delta heteromer, with no effect on MU- or delta-OR homomers, and a dissociation of the MU-deltaOR complex. Intra-accumbens administration of the TAT-conjugated interfering peptide abolished the antidepressant-like and anxiolytic-like actions of the delta-agonist UFP-512 (H Dmt-Tic-NH-CH(CH2-COOH)-Bid) measured in the forced swim test, novelty-induced hypophagia and elevated plus maze paradigms in rats. UFP-512's antidepressant like and anxiolytic-like actions were abolished by pretreatment with either MUOR or deltaOR antagonists. Overall, these findings demonstrate that the MU-delta heteromer may be a potential suitable therapeutic target for treatment-resistant depression and anxiety disorders. PMID- 24061496 TI - Functional effects of dopamine transporter gene genotypes on in vivo dopamine transporter functioning: a meta-analysis. AB - Much psychiatric genetic research has focused on a 40-base pair variable number of tandem repeats (VNTR) polymorphism located in the 3'-untranslated region (3'UTR) of the dopamine active transporter (DAT) gene (SLC6A3). This variant produces two common alleles with 9- and 10-repeats (9R and 10R). Studies associating this variant with in vivo DAT activity in humans have had mixed results. We searched for studies using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) to evaluate this association. Random effects meta-analyses assessed the association of the 3'UTR variant with DAT activity. We also evaluated heterogeneity among studies and evidence for publication bias. We found twelve studies comprising 511 subjects, 125 from PET studies and 386 from SPECT studies. The PET studies provided highly significant evidence that the 9R allele was associated with increased DAT activity in human adults. The SPECT studies were highly heterogeneous. As a group, they suggested no association between the 3'UTR polymorphism and DAT activity. When the analysis was limited to the most commonly used ligand, [123I]beta-CIT, stratification by affection status dramatically reduced heterogeneity and revealed a significant association of the 9R allele with increased DAT activity for healthy subjects. In humans, the 9R allele of the 3'UTR polymorphism of SLC6A3 regulates dopamine activity in the striatal brain regions independent of the presence of neuropsychiatric illness. Differences in study methodology account for the heterogeneous results across individual studies. PMID- 24061498 TI - Photolysis of cycloxydim, a cyclohexanedione oxime herbicide. Detection, characterization and reactivity of the iminyl radical. AB - Cyclohexanedione oxime herbicides have been reported to be readily photodegraded in the environment but the reaction mechanism has never been studied in detail. Here we investigated the photolysis of cycloxydim (CD) in acetonitrile and water, solvents in which CD is present as two distinct tautomeric forms: keto form in water and enol form with an intramolecular hydrogen bond between the enolic proton and the nitrogen atom of the oxime in acetonitrile O-H...N. CD (E isomer) undergoes photoisomerization in water but not in acetonitrile. This difference is attributed to the inhibiting effect of the intramolecular hydrogen bond existing in acetonitrile. In both solvents, irradiation of CD leads to the cleavage of the N-O bond as evidenced by the imine formation. The iminyl radical could be detected in acetonitrile by nanosecond laser-flash photolysis (lambda(max) = 280, 320 and 480 nm, tau ~ 100 MUs). This radical is unreactive toward oxygen but readily abstracts an H atom from methanol (k = 1.8 * 10(5) M(-1) s(-1)). Quantum calculations confirm the assignment of the transient species to the iminyl radical by showing that (i) the most stable structure of the iminyl carries a large spin density on the ring carbon and on the nitrogen atoms, (ii) the enolic H atom is transferred to the nitrogen atom and (iii) the intramolecular hydrogen bond OH-N is responsible for both the iminyl long wavelength absorption and its high hydrogen abstraction reactivity. PMID- 24061497 TI - Chronic gamma-secretase inhibition reduces amyloid plaque-associated instability of pre- and postsynaptic structures. AB - The loss of synapses is a strong histological correlate of the cognitive decline in Alzheimer's disease (AD). Amyloid beta-peptide (Abeta), a cleavage product of the amyloid precursor protein (APP), exerts detrimental effects on synapses, a process thought to be causally related to the cognitive deficits in AD. Here, we used in vivo two-photon microscopy to characterize the dynamics of axonal boutons and dendritic spines in APP/Presenilin 1 (APP(swe)/PS1(L166P))-green fluorescent protein (GFP) transgenic mice. Time-lapse imaging over 4 weeks revealed a pronounced, concerted instability of pre- and postsynaptic structures within the vicinity of amyloid plaques. Treatment with a novel sulfonamide-type gamma secretase inhibitor (GSI) attenuated the formation and growth of new plaques and, most importantly, led to a normalization of the enhanced dynamics of synaptic structures close to plaques. GSI treatment did neither affect spines and boutons distant from plaques in amyloid precursor protein/presenilin 1-GFP (APPPS1-GFP) nor those in GFP-control mice, suggesting no obvious neuropathological side effects of the drug. PMID- 24061499 TI - Peritoneal carcinomatosis of colorectal origin: is it really an end-stage disease? PMID- 24061500 TI - Surgical site infection rates: open versus hand-assisted colorectal resections. AB - PURPOSE: This study was performed to determine impact of open and hand-assisted colorectal resection on surgical site infection (SSI) rates. METHODS: National Surgical Quality Improvement Project data from 2006 to 2008 were supplemented with an institutional review board-approved chart review. Primary endpoint was SSI rates defined by the Centers for Disease Control National Nosocomial Infections Surveillance system and classified as superficial, deep incisional, and organ space. Inclusion criteria were elective or emergency open or hand assisted colorectal resections. Wounds were classified as clean-contaminated, contaminated, or dirty-infected. Patients were not included if they underwent laparoscopic colorectal resection, small bowel resection, or stoma creation. RESULTS: Two hundred and forty-five consecutive patients were included over a 29 month period. One hundred and ninety-five open and 50 hand-assisted patients were comparable for gender, body mass index, ethnicity, tobacco addiction, steroid use, type of colorectal resection, operating time, and method of wound closure. Differences in ASA class, wound classification, and preexisting comorbidities resolved when 80 open and 5 hand-assisted patients who underwent emergency resections were excluded from analysis. Rate of stoma creation remained higher in open patients even after excluding emergency cases (p < 0.01). Overall SSI rates following open and hand-assisted resections were 28 and 44 %, respectively (p = 0.015). Superficial SSI rates were higher in hand-assisted patients (20 vs. 40 %, p = 0.006). Deep (2.1 vs. 4 %, p = 0.605) and organ space SSI rates (5.1 vs. 0 %, p = 0.221) did not differ. These results did not change when emergency resections were excluded: overall 28 and 44 % (p = 0.015), superficial (23 vs. 44 %, p = 0.009), deep (3.5 vs. 4.4 %, p = 0.541), and organ space (7 vs. 0 %, p = 0.066). CONCLUSION: This study seems to suggest possibly higher rates of incisional SSI in patients who underwent hand-assisted colorectal resection as compared to open. This retrospective study had, however, insufficient power to stratify by surgeon and control for risk factors by logistic regression. PMID- 24061503 TI - A multiphase strategy for realizing green cathodoluminescence in 12CaO.7Al2O3 CaCeAl3O7:Ce3+,Tb3+ conductive phosphor. AB - A multiphase strategy is proposed and successfully applied to make the insulating green phosphor CaCeAl3O7:Tb(3+) conductive in the form of 12CaO.7Al2O3 CaCeAl3O7:Ce(3+),Tb(3+). The phosphor shows bright green-light emission with a short lifetime (2.51 ms) under low-voltage electron beam excitation (3 kV). The green photo- and cathodoluminescence from (5)D4-(7)F(J) (J = 6, 5, 4, 3) transitions of Tb(3+) are significantly enhanced in comparison with pure C12A7:Tb(3+). It was confirmed that this enhancement is the consequence of the joint effects of energy transfer from Ce(3+) to Tb(3+) and broadening of the absorption spectrum of Ce(3+) due to the existence of multiple phases. In particular, under 800 V electron beam excitation, cathodoluminescence is improved by the modified electrical conductivity of the phosphor. When compared to the commercial Zn2SiO4:Mn(2+) with a long luminescence lifetime of 11.9 ms, this conductive green phosphor has greater advantage for fast displays. PMID- 24061502 TI - The landscape of comparative effectiveness research in rheumatology. AB - Comparative effectiveness research (CER) is a growing area of investigation aimed at determining the most beneficial treatments for patients in view of their clinical characteristics. CER provides personalized treatment information that cannot be obtained from traditional clinical trials. However, many analytical challenges to performing CER remain, particularly in nonexperimental settings. The main obstacles to CER include bias from variation in use of treatments, and heterogeneity in types and quality of data across registries. Increasing standardization of care and consensus among stakeholders regarding CER methodology will strengthen the validity of CER from observational data. Innovations in outcomes measurement, and the ability to repurpose electronic health record data for research will increase the capability to assess treatment effects by CER in clinical practice. Investment in infrastructure, informatics, and data management to sustain high-quality registries, along with engagement of stakeholders to maintain a co-ordinated research agenda, are essential for successful CER in rheumatology. PMID- 24061501 TI - Serum amyloid A, phospholipase A2-IIA and C-reactive protein as inflammatory biomarkers for prostate diseases. AB - INTRODUCTION: Serum amyloid A (SAA), secreted group IIA phospholipase A2 (sPLA2 IIA), and C-reactive protein (CRP) are acute-phase proteins whose serum concentrations increase not only during inflammatory disorders, but also in the course of malignant diseases. MATERIALS AND METHODS: In this study we analyzed serum levels of these inflammatory markers along with prostate-specific antigens (PSA) in patients with benign prostatic hyperplasia (BPH, n = 55), localized prostate cancers (PCa, n = 55), and metastatic prostate cancers (mPCa, n = 27) using immunological assays. RESULTS: We found that in comparison to healthy individuals (n = 55), patients with BPH, PCa and mPCa have elevated serum levels of SAA, sPLA2-IIA, and CRP, in addition to elevated levels of PSA. Significant differences with respect to inflammatory biomarkers were found between localized and metastatic PCa (p < 0.001), suggesting a prognostic value of these parameters. In addition, serum concentrations of SAA and sPLA2-IIA positively correlate with CRP in BPH patients (p < 0.05) and in patients with PCa and mPCa (p < 0.001), but not with PSA levels, Gleason score, or tumor stage, emphasizing a role of SAA and sPLA2-IIA as circulating biomarkers of inflammation rather than of neoplastic transformation. In contrast to PSA, which differed significantly between BPH and localized PCa patients (p < 0.01), such a difference was not found for SAA, sPLA2-IIA, and CRP. In order to elucidate whether the elevated levels of SAA and sPLA2-IIA can be caused by cancer cell-associated synthesis, in vitro studies were performed. These analyses demonstrated the expression of SAA and sPLA2-IIA in LNCaP and PC-3 prostate cell lines, which can be further upregulated by pro-inflammatory cytokines in a cell type-dependent manner. This might suggest that, in addition to the hepatic origin, SAA and sPLA2-IIA can also be synthesized and secreted by prostatic cancer tissue itself. CONCLUSION: The results of the present study emphasize the utility of SAA, sPLA2-IIA, and CRP as circulating biomarkers of inflammation during BPH development and PCa progression. PMID- 24061504 TI - Forging new frontiers: the 17th Annual Conference of the Injury Free Coalition for Kids. Editor's foreword. PMID- 24061505 TI - An evaluation of a dog bite prevention intervention in the pediatric emergency department. AB - BACKGROUND: This study aimed to determine the efficacy of a video-based dog bite prevention intervention at increasing child knowledge and describe any associated factors and to assess the acceptability of providing this intervention in a pediatric emergency department (PED). METHODS: This cross-sectional, quasi experimental study enrolled a convenience sample of 5-year-old to 9-year-old patients and their parents, presenting to a PED with nonurgent complaints or dog bites. Children completed a 14-point simulated scenario test used to measure knowledge about safe dog interactions before and after a video intervention. Based on previous research, a passing score (>= 11/14) was defined a priori. Parents completed surveys regarding sociodemographics, dog-related experiential history, and the intervention. RESULTS: There were 120 child-parent pairs. Mean (SD) child age was 7 (1) years, and 55% were male. Of the parents, 70% were white, two thirds had higher than high school education, and half had incomes less than $40,000. Current dog ownership was 77%; only 6% of children had received previous dog bite prevention education. Test pass rate was 58% before the intervention and 90% after the intervention. Knowledge score increased in 83% of children; greatest increases were in questions involving stray dogs or dogs that were fenced or eating. Younger child age was the only predictor of failing the posttest (p < 0.001). Nearly all parents found the intervention informative; 93% supported providing the intervention in the PED. CONCLUSION: Child knowledge of dog bite prevention is poor. The video-based intervention we tested seems efficacious at increasing short-term knowledge in 5-year-old to 9-year-old children and is acceptable to parents. Parents strongly supported providing this education. PMID- 24061506 TI - Prevalence of male adolescent dating violence in the pediatric emergency department. AB - BACKGROUND: Adolescent dating violence (DV) is a growing problem in the United States. Identifying the most optimal venue for screening and determining risk factors for DV is important for treatment and prevention programs. The purposes of this study were to determine the prevalence of DV among male teens presenting to a Midwestern pediatric emergency department (PED) and to determine risk factors, types of injuries sustained, and interest in social service assistance. METHODS: Males (13-21 year old) presenting to a PED were prospectively enrolled. Exclusions included never dated, non-English speaking, critically ill, active psychosis, or caregiver nonwillingness to leave during study participation. The computerized survey consisted of demographics, a validated DV screen, risk factor assessment, and injuries from DV. At completion, all participants received DV educational materials and were offered social service referral. RESULTS: Of the 262 eligible approached participants, 198 (75.6%) were enrolled. The mean +/- SE age of participants was 16.2 +/- 0.13 years, with 106 white (53%) and 77 African American (39%). A total of 99 (50%) had DV education in the past; 39 (19.7%) screened positive for DV. Risk factors for those who screened positive include the following: 9 (29%) endorse riding in a car with a dating partner who was driving intoxicated, 27 (87%) admitted to drinking alcohol, and 11 (35%) have been treated for an sexually transmitted infection. Almost all injuries sustained as a result of DV (83%) were minor (scratches or scrapes). Only 2 (5%) accepted social service intervention and none for their DV exposure. CONCLUSION: One in five teen males who present to a PED in our population screened positive for DV. Using specific risk factors could aid practitioners in identifying those children more likely to screen positive. Injuries sustained were mild, and most did not accept social services consultation. PMID- 24061507 TI - Can nurse education in the postpartum period reduce car seat misuse among newborns? AB - BACKGROUND: Despite national, state, and hospital policies that require newborns to be transported in correctly used child safety seats (CSSs), significant CSS misuse frequently occurs among newborn infants. The objective of this study was to evaluate a comprehensive educational CSS training program for nurses and parents in a maternal/newborn unit. METHODS: In the preintervention phase, we conducted a survey among maternal/newborn unit nurses in a large urban teaching hospital to measure CSS knowledge, attitude, and practice. We then enrolled 60 maternal-newborn dyads at discharge to survey maternal CSS knowledge and observe the CSS misuse rate. Our intervention phase included a 1-hour "mandatory" nurse CSS education classroom session, a nurse hands-on CSS demonstration and practice in a mother's room. During the postintervention phase, we enrolled 70 maternal newborn dyads at discharge to survey maternal CSS knowledge and observe change in CSS misuse rate. RESULTS: In the preintervention phase, 43 (73%) of 59 eligible nurses completed the survey, and 47 (80%) of 59 completed the CSS education and training program. In the preintervention CSS survey, 23% of the nurses reported that education is part of their routine, 44% have CSS educational materials, 32% feel comfortable providing CSS education to parents, 12% feel CSS trained, 25% have time, 84% identify that CSS misuse is a problem, and 16% received CSS training.Enrolled mothers reflect maternal/newborn unit demographics as follows: maternal mean age of 29 years (range, 16-48 years), white (54%), black (11%), Hispanic origin (28%), English as primary language (83%), high school degree (31%), college degree (30%), Medicaid (23%), and private insurance (65%).Of 70 postintervention mothers, 44% reported receiving no nurse education, 21% reported receiving a brochure only, and 31% reported receiving nurse education. CSS misuse among mothers who received registered nurse education was not reduced compared with mother's who received a brochure only and those who did not receive CSS education.Comparison of CSS misuse before (n = 60) and after (n = 70) observations revealed an increase in average misuse (1.8 vs. 3.0, p < 0.05) and a decreases or no significant change in appropriate use as follows: harness in lowest slot (95% vs. 87%), retainer clip at axilla level (63% vs. 33%, p < 0.01), harness snug (50% vs. 27%, p < 0.01), attached to the vehicle (80% vs. 80%), 45 degree angle (60% vs. 19%, p < 0.01), and CSS moves (32% vs. 27%). CONCLUSION: Car safety seat misuse did not improve following implementation of a comprehensive nursing education and training program. CSS misuse in our study population was frequent and may increase injury risk in the event of a motor vehicle crash. Future work is needed to develop novel approaches and identify appropriate settings to reduce newborn CSS misuse. PMID- 24061508 TI - Coronary heart disease differences across Europe: a contribution from the Seven Countries Study. AB - In the Seven Countries Study of Cardiovascular Diseases, 16 cohorts of middle aged men were enrolled in eight nations of seven countries in three continents in the late 1950s and early 1960s for a total of 12 763 individuals. Thirteen cohorts were located in Europe, two in Finland, one in the Netherlands, three in Italy, two in Croatia - former Yugoslavia, three in Serbia - former Yugoslavia, and two in Greece. Another cohort was enrolled in the USA and two cohorts in Japan. Baseline prevalence of coronary heart disease (CHD) was largely different across areas, as well as 10-year incidence of major CHD events and CHD mortality for periods ranging from 25 to 40 years of follow-up. Higher rates were found in Northern Europe, lower rates in Southern Europe and intermediate rates in Eastern Europe, represented by Serbia. Differences across countries were partly explained by different entry mean levels of serum cholesterol, blood pressure, consumption of saturated fatty acids and adherence to traditional dietary patterns. Forty year trends of CHD mortality were largely explained by early changes in serum cholesterol and blood pressure levels, with large risk increases in Serbia and Greece, and the tendency to declines in Finland and the Netherlands. These trends in Seven Countries' experience are in line with those manifests in official mortality data. An attempt of interpretation is presented pointing to socio economic evolution in the involved countries, which heavily modifies health and dietary habits and contributes to explaining these differences at population level. PMID- 24061509 TI - High-spin states and level structure in stable nucleus strontium-84. AB - High-spin states of (84)Sr are populated through the reaction (70)Zn ((18)O, 4n) (84)Sr at the beam energy of 75 MeV. The measurements of excitation functions, gamma-gamma coincidences, directional correlations of oriented states (DCO) ratios and gamma-transition intensities are performed using eight anticompton HPGe detectors and one planar HPGe detector. Based on the experimental results, we establish a new level scheme of (84)Sr, in which 12 new states and nearly 30 new gamma-transitions are identified in the present work. The positive-parity yrast band is extended to spin I(pi) = 24(+), while one negative-parity band is extended to spin I(pi) = 19(-) and it is found that the even-spin and odd-spin members in high-spin states show the nature of signature staggering. The deformation of (84)Sr is studied by calculating the total-Routhian-surfaces (TRS) of positive-parity yrast states in the cranked shell model formalism. PMID- 24061510 TI - Ultrafast imaging of electronic relaxation in o-xylene: a new competing intersystem crossing channel. AB - The ultrafast dynamics of the second singlet electronically excited state (S2) in o-xylene was investigated by femtosecond time-resolved photoelectron imaging. A new competing relaxation channel of the S2 state was observed and assigned to the T3 <- S2 intersystem crossing. Interestingly, it is found that the relaxation via this channel occurs on a comparable femtosecond timescale as the S1 <- S2 internal conversion. A lifetime of ~60 fs for the initially excited S2 state, of 540 (+/-17) fs for the secondary populated S1 state, and of 7.23 (+/-0.21) ps for the T3 state could be inferred. PMID- 24061511 TI - Association between exposure to low to moderate arsenic levels and incident cardiovascular disease. A prospective cohort study. AB - BACKGROUND: Long-term exposure to high levels of arsenic is associated with increased risk for cardiovascular disease, whereas risk from long-term exposure to low to moderate arsenic levels (< 100MUg/L in drinking water) is unclear. OBJECTIVE: To evaluate the association between long-term exposure to low to moderate arsenic levels and incident cardiovascular disease. DESIGN: Prospective cohort study. SETTING: The Strong Heart Study baseline visit between 1989 and 1991, with follow-up through 2008. PATIENTS: 3575 American Indian men and women aged 45 to 74 years living in Arizona, Oklahoma, and North and South Dakota. MEASUREMENTS: The sum of inorganic and methylated arsenic species in urine at baseline was used as a biomarker of long-term arsenic exposure. Outcomes were incident fatal and nonfatal cardiovascular disease. RESULTS: A total of 1184 participants developed fatal and nonfatal cardiovascular disease. When the highest and lowest quartiles of arsenic concentrations (> 15.7 vs. < 5.8 MUg/g creatinine) were compared,the hazard ratios for cardiovascular disease, coronary heart disease, and stroke mortality after adjustment for sociodemographic factors, smoking, body mass index, and lipid levels were 1.65 (95%CI, 1.20 to 2.27; P for trend < 0.001), 1.71 (CI, 1.19 to 2.44; P for trend < 0.001), and 3.03 (CI, 1.08 to 8.50; P for trend = 0.061),respectively. The corresponding hazard ratios for incident cardiovascular disease, coronary heart disease, and stroke were 1.32 (CI,1.09 to 1.59; P for trend = 0.002), 1.30 (CI, 1.04 to 1.62; P for trend = 0.006), and 1.47 (CI, 0.97 to 2.21; P for trend = 0.032).These associations varied by study region and were attenuated after further adjustment for diabetes, hypertension, and kidney disease measures. LIMITATION: Direct measurement of individual arsenic levels in drinking water was unavailable. CONCLUSION: Long-term exposure to low to moderate arsenic levels was associated with cardiovascular disease incidence and mortality. PMID- 24061512 TI - Gastrointestinal stromal tumors with KIT exon 9 mutations: Update on genotype phenotype correlation and validation of a high-resolution melting assay for mutational testing. AB - KIT exon 9 mutations in gastrointestinal stromal tumors (GISTs) are highly relevant and have direct therapeutic implications. In this context, we established and validated a fast and sensitive high-resolution melting assay. Analyzing 126 primary and 18 metastatic KIT exon 9-mutated cases from our registry, we demonstrate that the mutational spectrum of exon 9 is broader than previously thought and describe 3 novel mutations. Including these cases and the common p.A502_Y503dup mutation, we provide a comprehensive list of all known KIT exon 9 mutations according to the Human Genome Variation Society nomenclature. Two of the newly described mutations were associated with an aggressive phenotype and tumor progression while being treated with 400 mg imatinib, indicating that also GIST with rare exon 9 mutations could be treated with increased imatinib dosage. On the basis of >1500 GISTs from our registry, we have determined the frequency of KIT exon 9 mutations to be 9.2% among all GISTs and 22.5% among small-bowel cases. We describe for the first time that nearly 20% of exon 9 mutated GIST occur in the stomach or rectum. Furthermore, we provide first evidence that exon 9-mutated GISTs metastasize significantly more often to the peritoneum than to the liver. Performing extensive statistical analyses on data from our registry and from the literature, we demonstrate that KIT exon 9 mutations are neither associated with intermediate-risk/high-risk status nor overrepresented among metastatic lesions. Thus, we conclude that exon 9 mutations per se do not have prognostic relevance. PMID- 24061513 TI - GNAS Is frequently mutated in a specific subgroup of intraductal papillary neoplasms of the bile duct. AB - Intraductal papillary neoplasms of the bile duct (IPN-Bs) share clinicopathologic features with intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Approximately two thirds of IPMNs have activating point mutations of GNAS at codon 201. The role of GNAS mutation is unclear in IPN-B. In this study, we evaluated 41 patients diagnosed with IPN-B for clinicopathologic characteristics and follow-up information. Mutation analyses of GNAS and KRAS were performed. Twenty-three cases (56.1%) of IPN-B were categorized as the intestinal subtype, and 18 (43.9%) were considered the gastric/pancreatobiliary subtype. IPN-Bs showing intestinal differentiation demonstrated high immunohistochemical expressions of CK20, CDX2, and MUC2, as well as a significant association with macroscopic and microscopic mucin hypersecretions and villous architecture. GNAS and KRAS mutations were detected in 29% and 32% of IPN-Bs, respectively. All IPN Bs with GNAS mutation showed intestinal differentiation. GNAS-mutated IPN-B was highly significantly associated with certain pathologic characteristics, including macroscopic and microscopic mucin hypersecretion and villous architecture. IPN-B with GNAS mutation tended to more frequently harbor KRAS mutation than those without GNAS mutation. IPN-Bs with intestinal differentiation, villous architecture, and mucin hypersecretion constitute a distinct subgroup of IPN-B, which frequently has GNAS mutation. This subtype shares common genetic alterations with IPMN of the pancreas. PMID- 24061514 TI - Sevelamer crystals in the gastrointestinal tract (GIT): a new entity associated with mucosal injury. AB - We report the first description of sevelamer crystals (Renagel and Renvela, Genzyme; phosphate-lowering agents) in the gastrointestinal tract. We prospectively collected cases with novel, histologically identical crystals from 4 major academic centers over a 1-year period and studied pertinent clinicopathologic features. Sevelamer usage in the setting of chronic kidney disease was demonstrated in all cases (n=15 total cases, 7 patients). Sites of involvement included the esophagus (n=2), small bowel (n=2), and colon (n=11). The background mucosa was normal in only 1 case. Notable mucosal abnormality included chronic mucosal damage (n=5), acute inflammation (n=4), inflammatory polyp (n=2), extensive ulceration (n=2), ischemia (n=1), and necrosis (n=1). In general, sevelamer crystals displayed broad, curved, and irregularly spaced "fish scales" with a variably eosinophilic to rusty brown color on hematoxylin and eosin (H&E) staining and violet color on periodic acid-Schiff-alcian special staining with diastase (PAS/D). To validate these findings, sevelamer tablets (Renvela) were crushed and submitted for histologic processing; the findings were identical to those in the patient specimens. The possibility of Kayexalate (sodium polystyrene sulfonate) and cholestyramine had been raised in error. However, Kayexalate has narrow, rectangular "fish scales" and is violet on H&E and magenta on PAS/D; cholestyramine lacks internal "fish scales," is bright orange on H&E, variably gray or hot pink on PAS/D, and is unassociated with mucosal injury. Further study is required to determine whether sevelamer plays a causal role in these injuries; however, its crystal is an important mimic of both Kayexalate and choleystyramine. As the history of sevelamer administration was not documented in any pathology requisition, awareness of sevelamer's characteristic morphology is crucial to avoid the diagnostic pitfalls of its mimics. PMID- 24061516 TI - Florid mesothelial hyperplasia of the tunica vaginalis mimicking malignant mesothelioma: a clinicopathologic study of 12 cases. AB - The tunica vaginalis is an embryologically derived mesothelium-lined outpouching of the peritoneal cavity, which may develop neoplastic mesothelial proliferations similar to, although much less commonly than, pleural or peritoneal surfaces. We herein report our experience with 12 cases of florid paratesticular mesothelial hyperplasia, highlighting the spectrum of morphologic changes seen and the utility of fluorescence in situ hybridization analysis of homozygous deletion of 9p21 as an adjunct diagnostic tool. All cases were referred because of concern regarding the nature of the mesothelial proliferation. The median age of patients at presentation was 44.5 years (range, 16 to 71 y). Ten of 12 patients clinically presented with hydroceles (2 of which were complicated by infection or hemorrhage), 1 with "paraepididymal cyst" and 1 patient with an epididymal cyst. In contrast to the normal tunica consisting of a thin fibrous wall lined by a monolayer of flattened bland mesothelium and no significant inflammation, all of our cases were characterized by background changes of fibroblastic organization and stromal chronic inflammation. In all cases, the mesothelial proliferation within the fibrous and inflamed stroma was sparse and consisted of linear arrays of widely spaced horizontally orientated simple nonbranching elongated tubules and small solid nests and cords that were well spaced apart. There was an abrupt linear demarcation of tubules at the deep aspect of the fibrous tissue, with no evidence of definite invasion into the submesothelial tissue. Fluorescence in situ hybridization for 9p21 was negative in all 5 cases in which tissue was available for analysis. Nine patients with extended follow-up were alive (median 8 y; range, 1 to 13 y). In summary, the proliferative changes seen in reactive mesothelial hyperplasia associated with hydroceles may be florid and mimic malignant mesothelioma. In particular, the entrapment of isolated mesothelial clusters within deep fibrous tissue may be the cause of significant diagnostic difficulty. There are, however, morphologic clues such as linear arraying of widely spaced architecturally simple cell clusters that may aid in the correct identification of the benignity of these proliferations. PMID- 24061515 TI - The pattern of myometrial invasion as a predictor of lymph node metastasis or extrauterine disease in low-grade endometrial carcinoma. AB - The purpose of this study was to examine predictors of lymph node (LN) metastases or extrauterine disease (ED) in low-grade (FIGO grade 1 or 2) endometrioid carcinoma (LGEC) in a multi-institutional setting. For LGEC with and without LN metastasis or ED, each of the 9 participating institutions evaluated patients' age, tumor size, myometrial invasion (MI), FIGO grade, % solid component, the presence or absence of papillary architecture, microcystic, elongated, and fragmented glands (MELF), single-cell/cell-cluster invasion (SCI), lymphovascular invasion (LVI), lower uterine segment (LUS) and cervical stromal (CX) involvement, and numbers of pelvic and para-aortic LNs sampled. A total of 304 cases were reviewed: LN(+) or ED(+), 96; LN(-)/ED(-), 208. Patients' ages ranged from 23 to 91 years (median 61 y). Table 1 summarizes the histopathologic variables that were noted for the LN(+) or ED(+) group: tumor size >=2 cm, 93/96 (97%); MI>50%, 54/96 (56%); MELF, 67/96 (70%); SCI, 33/96 (34%); LVI, 79/96 (82%); >20% solid, 65/96 (68%); papillary architecture present, 68/96 (72%); LUS involved, 64/96 (67%); and CX involved, 41/96 (43%). For the LN(-)/ED(-) group, the results were as follows: tumor size >=2 cm, 152/208 (73%); MI>50%, 56/208 (27%); MELF, 79/208 (38%); SCI, 19/208 (9%); LVI, 56/208 (27%); >20% solid, 160/208 (77%); papillary architecture present, 122/208 (59%); LUS involved, 77/208 (37%); CX involved, 24/208 (12%). There was no evidence of a difference in the number of pelvic or para-aortic LNs sampled between groups (P=0.9 and 0.1, respectively). After multivariate analysis, the depth of MI, CX involvement, LVI, and SCI emerged as significant predictors of advanced-stage disease. Although univariate analysis pointed to LUS involvement, MELF pattern of invasion, and papillary architecture as possible predictors of advanced-stage disease, these were not shown to be significant by multivariate analysis. This study validates MI, CX involvement, and LVI as significant predictors of LN(+) or ED(+). The association of SCI pattern with advanced-stage LGEC is a novel finding. PMID- 24061517 TI - Synovial sarcoma of the kidney: a clinicopathologic, immunohistochemical, and molecular genetic study of 16 cases. AB - We report the clinicopathologic and immunohistochemical features of 16 cases of genetically confirmed primary synovial sarcoma of the kidney. The cases occurred in 9 men and 7 women ranging in age from 17 to 78 years (mean, 46 y). The tumors were grossly large, solid, and variably cystic (2.2 to 19.0 cm; mean 8.6 cm). Microscopically, all tumors were of the monophasic type and diffusely immunoreactive for TLE1 and BCL-2. Focal pankeratin positivity was found in just under half. Ten cases carried an SS18-SSX2 fusion transcript, and 5 cases showed an SS18-SSX1 transcript by reverse transcription polymerase chain reaction. The remaining case demonstrated SS18 rearrangement by fluorescence in situ hybridization. Clinical follow-up information was available for 12 patients (range, 1 to 77 mo; mean, 32.5 mo). Fourteen patients underwent radical nephrectomy, and 3 patients had lung metastases at presentation. Six patients died of disease within 1 to 58 months (mean, 31 mo) of their diagnosis. Five patients were alive without evidence of disease 12 to 77 months (mean, 39 mos) after surgery. A single patient was alive with metastases to the spine 11 months after surgery. We conclude that renal synovial sarcoma is an aggressive tumor, with adverse patient outcome in >50% of cases. Synovial sarcoma must be distinguished from morphologically similar lesions of the kidney. PMID- 24061518 TI - Histopathologic distinction between fibrosing cholestatic hepatitis C and biliary obstruction. AB - The histopathologic distinction between posttransplantation fibrosing cholestatic hepatitis C (FCH-C) and biliary obstruction (BO) is challenging. We sought to identify histopathologic features that could be useful in the differential diagnosis between these 2 entities. A total of 38 cases of hepatitis C virus (HCV)-negative, cholangiography-proven BO (including 16 posttransplant and 22 nontransplant patients) and 13 patients with posttransplantation FCH-C were included. FCH-C patients were characterized by cholestatic disease, high HCV viral load, no evidence of biliary tract obstruction on imaging, and typical histopathologic findings (>=3 of the following: 1, prominent ductular reaction; 2, hepatocyte swelling with lobular disarray; 3, periportal sinusoidal fibrosis, and 4, cholestasis). Biopsies were evaluated with hematoxylin and eosin, Masson trichrome, Victoria blue, and rhodanine stains. Cytokeratin 7 (CK7) immunohistochemistry was used to assess for the presence of CK7+ intermediate hepatobiliary cells. We found that portal edema (63.1% vs. 7.6%; P<0.0001), bile duct dilatation (26.3% vs. 0%; P=0.0003), acute cholangitis (15.7% vs. 0%; P=0.008), bile infarcts (10.5% vs. 0%; P=0.03), periductal fibrosis (23.6% vs. 0%; P=0.0007), and periportal copper deposition (60.5% vs. 15.3%; P=0.0006) are significantly more common in BO, whereas hepatocellular swelling with lobular disarray (84.6% vs. 5.2%; P<0.0001) and periportal sinusoidal fibrosis (34.2% vs. 100%; P<0.0001) are seen more frequently in FCH-C. Furthermore, marked ductular reaction with rare or absent CK7+ intermediate cells is highly suggestive of FCH C in this context (73.6% vs. 7.6%; P<0.0001). In summary, this study offers a comprehensive characterization of the histologic features discriminating FCH-C from BO. PMID- 24061519 TI - Testicular hemorrhage, necrosis, and vasculopathy: likely manifestations of intermittent torsion that clinically mimic a neoplasm. AB - We report 30 cases of testicular hemorrhage and/or necrosis with associated vascular damage that caused clinical concern for a neoplasm and that raised the question of a vasculitis syndrome on pathologic examination. The patients were 12 to 66 years old (median, 33 y) and presented with pain (n=15), mass (n=12), or both (n=2); 1 case had no available clinical information. Ultrasonographic interpretations included a neoplasm in the differential diagnoses in 14 of 18 cases in which this information was available, and most (n=24) had orchiectomy because of this possibility. Only 4 were clinically suspected to represent testicular infarction. Circumscribed, hemorrhagic lesions occurred in 10 cases, less demarcated hemorrhagic foci in 5, and discrete nodules or ill-defined foci of varying color and consistency in the remainder. No clear testicular lesion was described in 2, with 1 of these having a "dusky" appearance. On microscopic examination all but 1 case showed damaged blood vessels (vasculopathy), with either associated hemorrhage/hematoma (n=24) and/or areas of parenchymal necrosis (n=21). One case showed only segmental tubular atrophy with interstitial inflammation and vasculopathy; no infarct or hemorrhage was identified. A variety of vascular changes was identified, including prominent intimal thickening in arteries (n=22) and fibrinoid change in both arteries (n=5) and vessels of indeterminate type (n=8). Medial fibrosis was present in veins (n=12) and vessels of indeterminate type (n=4), whereas thrombi (remote, recanalized, and/or recent) occurred in arteries (n =7), veins (n=9), and vessels of indeterminate type (n=11). Dilated, blood-filled vessels were present in the testis and/or paratestis in 15 cases. In addition, 7 cases showed arteriolar hyalinization, and 19 had inflammation of blood vessels. The latter was lymphohistiocytic and mostly light but occasionally prominent (n=5). Interstitial inflammation was seen adjacent to damaged testicular parenchyma in all 30 cases. Clinical follow-up in 20 patients (4 to 131 mo, mean 38 mo) showed no evidence of recurrence in the contralateral testis or later development of systemic vasculitis. The histologic findings were compared with those in 11 orchiectomies resected for clinical acute torsion. All clinical acute torsion cases showed both parenchymal and fibrinoid vascular necrosis, and 10 had hemorrhage/hematoma; they lacked vasculitis, interstitial inflammation, and chronic vascular changes. Testicular vasculopathy, characterized by acute and chronic vascular injury, commonly occurs in testes with parenchymal hemorrhage and necrosis that clinically mimic a tumor. It shares the acute features of recent torsion but also has findings indicative of chronic injury. Testicular vasculopathy is most likely a result of chronic intermittent torsion that leads to localized hemorrhage/necrosis and should be distinguished from cases of systemic vasculitis given the significantly different clinical implications. PMID- 24061520 TI - PEComa of the gastrointestinal tract: clinicopathologic study of 35 cases with evaluation of prognostic parameters. AB - Perivascular epithelioid cell tumors (PEComas) are distinctive mesenchymal neoplasms that most often arise in the retroperitoneum, visceral organs, and abdominopelvic sites and usually show reactivity for melanocytic and smooth muscle markers. Fewer than 20 PEComas of the gastrointestinal (GI) tract have been reported, and behavior and criteria for malignancy are incompletely defined. The purpose of this study was to examine the clinicopathologic features of a series of GI PEComas and to evaluate prognostic parameters. A total of 35 PEComas of the GI tract were retrieved from consult and surgical files. Clinical and pathologic features were evaluated, and immunohistochemical analysis was performed. Clinical follow-up information was obtained from medical records and referring physicians. Nineteen patients were female and 16 male (median age 45 y; range, 7 to 70 y). One patient had tuberous sclerosis. Nineteen tumors arose in the colon, 12 in the small bowel, 2 in the stomach, and 1 each in gallbladder and omentum. Median tumor size was 6.2 cm (range, 0.8 to 22 cm). Three tumors were limited to the mucosa and submucosa, 8 extended to the muscularis propria, 15 to the subserosa/serosa, and 8 into the mesentery. The tumors were composed of nests and sheets of usually epithelioid cells with abundant granular eosinophilic to clear cytoplasm, surrounded by a delicate capillary vasculature. Thirteen tumors had mixed epithelioid and spindle cell components, and 2 were purely spindled. Sixteen tumors showed marked nuclear atypia. Seventeen tumors contained occasional pleomorphic cells, and 12 showed diffuse cellular pleomorphism. The median mitotic rate was 2/10 HPF (range, 0 to 36). Vascular invasion was present in 5 cases, and 16 tumors showed necrosis. By immunohistochemistry, 23/35 were positive for HMB45, 23/34 for melan-A, 15/25 for MiTF, 20/35 for smooth muscle actin, 26/35 for desmin, and 3/20 for TFE3. Focal cytoplasmic S100 protein was present in 5/27 cases, 2/25 cases were positive for KIT, and 1 case each was positive for EMA and keratin. Follow-up information was available for 31 patients (median 36 mo; range, 2 to 176 mo). Thirteen patients have developed metastases (10 liver, 3 peritoneum, 4 lymph node, 3 lung, 1 bone, 1 brain, and 1 adrenal). Thus far, 5 patients have died of disease. Metastases were significantly associated with marked atypia, diffuse pleomorphism, and mitoses >=2/10 HPF. In summary, PEComas of the GI tract occur at similar frequency in female and male patients, most commonly involve the colon, and exhibit variable clinical behavior, ranging from benign lesions to aggressive, high-grade sarcomas. The presence of marked nuclear atypia, diffuse pleomorphism, and mitotic activity are the strongest predictors of malignant behavior. PMID- 24061521 TI - GATA-3 immunohistochemistry in the differential diagnosis of adenocarcinoma of the urinary bladder. AB - GATA-3 is a newly described marker that labels urothelial and breast carcinoma. However, no prior study has evaluated the expression of GATA-3 in primary bladder adenocarcinoma. Tissue microarrays (TMAs) containing 46 primary bladder adenocarcinomas were constructed. They contained 19 signet ring cell (SRC) and 27 conventional adenocarcinomas. Three additional cases of SRC using routine sections were included resulting in a total of 22 SRCs. In addition, TMAs containing 32 primary gastric signet ring adenocarcinomas and 36 primary lobular breast carcinomas were evaluated. The TMAs were subjected to immunohistochemical analysis for GATA-3, with nuclear labeling scored by intensity and percentage labeling. Breast and urothelial TMAs were also labeled for estrogen receptor, progesterone receptor, and gross cystic duct fluid protein. Diffuse nuclear GATA 3 labeling was seen in 9/22 (41.0%) SRCs and in 2/27 (7.0%) conventional adenocarcinomas (P=0.01). Extracellular mucin production was seen in 12 SRCs. One of 12 (8.0%) SRCs with extracellular mucin was GATA-3 positive, and 8/10 SRCs without extracellular mucin was GATA-3 positive (P=0.005). No nuclear GATA-3 labeling was seen in any gastric signet ring carcinoma. Diffuse, moderate to strong nuclear GATA-3 labeling was seen in 36/36 (100%) primary lobular breast carcinomas. Nuclear GATA-3 labeling is a useful marker for primary adenocarcinomas of the urinary bladder with signet ring features and can be helpful in distinguishing primary signet ring carcinomas of the urinary bladder from gastric signet ring carcinomas. GATA-3 is rarely positive in bladder adenocarcinomas that lack signet ring features and in SRCs displaying extracellular mucin production. PMID- 24061522 TI - Frequent mutation and nuclear localization of beta-catenin in sertoli cell tumors of the testis. AB - The Sertoli cell tumor (SCT) of the testis is a sex cord stromal tumor, usually sporadic, rarely associated with genetic syndromes. Much remains unclear about the molecular genetic changes involved in SCT and its histogenesis. Recently, nuclear beta-catenin immunostaining has been reported in a case of bilateral SCT, but the molecular basis of the aberrant nuclear beta-catenin expression remains uncertain. In the present study, beta-catenin immunohistochemical assay and mutational analysis of exon 3 of the CTNNB1 gene by direct sequencing were performed in 14 SCTs, 2 of which had an unfavorable clinical course. Immunohistochemical study showed that beta-catenin was located in the cytoplasm of tumor cells in 4 cases (28.6%) and in both the nuclei and the cytoplasm in the remaining 10 cases (71.4%). beta-Catenin mutations were detected in 10 of the 14 patients (71.4%) under evaluation. Ten of 10 mutation-carrying cases showed strong nuclear and diffuse cytoplasmic beta-catenin immunoreactivity. Seven of the 8 CTNNB1-mutated tumors tested for cyclin D1 displayed diffuse immunoreactivity in the nuclei of tumor cells. We conclude that CTNNB1 exon 3 mutations are likely to be involved in the pathogenesis of male SCT with nuclear accumulation of beta-catenin and affect the expression of cyclin D1. PMID- 24061523 TI - Ambiguous melanocytic tumors in a tertiary referral center: the contribution of fluorescence in situ hybridization (FISH) to conventional histopathologic and immunophenotypic analyses. AB - The diagnosis of benign versus malignant melanocytic proliferations remains an important challenge. The current diagnostic algorithm typically involves an assessment of histopathologic and immunohistochemical parameters by light microscopy. Recently, fluorescence in situ hybridization (FISH) was reported as a useful ancillary diagnostic tool in melanocytic lesions, but the utility of FISH in melanocytic tumors that are difficult to diagnose with standard morphologic analysis remains controversial. To address this issue, we collected 34 ambiguous melanocytic tumors for FISH testing (NeoGenomics). Before FISH testing, cases were designated as "favor benign" (n=24) or "favor malignant" (n=10) by a consensus group (up to 7 dermatopathologists) on the basis of clinical, histopathologic, and immunophenotypic parameters. FISH was positive in 3/24 "favor benign" lesions and in 5/10 "favor malignant" lesions. The histopathologic, immunophenotypic, and FISH parameters informing our diagnostic impression were correlated with the final consensus diagnosis and clinical follow up; in all cases, the initial diagnosis remained unchanged. In this series, the sensitivity of FISH for the histopathologic diagnosis of melanoma was 50%, the specificity was 87.5%, the positive predictive value was 62.5%, and the negative predictive value was 80.7%. Follow-up information was available for 25 patients (17 benign and 8 malignant diagnoses). Among benign lesions, the mean follow-up was 16.8 months (range, 8 to 25 mo); no metastases have been reported to date. Among the malignant lesions, the mean follow-up was 14.6 months (range, 7 to 23 mo); a single lymph node metastasis was identified in a 4-year-old girl with a histopathologic diagnosis of melanoma, which was negative on FISH. In our experience, in the setting of a lesion with predominantly benign findings, a negative FISH test-given its high specificity-is a reassuring finding that supports a benign diagnosis. In contrast, a positive FISH test should be carefully interrogated in the context of the complete histopathologic findings. PMID- 24061525 TI - Lichenoid esophagitis: clinicopathologic overlap with established esophageal lichen planus. AB - Lichen planus (LP) affects mucocutaneous surfaces and is characterized by intraepithelial and lamina propria lymphocytosis and squamous cell apoptosis (Civatte bodies). Lichen planus esophagitis (LPE) is underrecognized; concurrent cutaneous disease is present in some patients, but LPE alone is more common. We diagnose patients with characteristic pathologic findings of LPE and known correlation with skin disease or immunofluorescence (IF) results as LPE but use descriptive terminology ("lichenoid esophagitis pattern" [LEP]) when confirmation is unavailable. We reviewed clinicopathologic features of patients diagnosed at our institution with LPE or LEP. There were 88 specimens with LPE or LEP from 65 patients. Most patients were female. Seventeen patients had LPE confirmed by IF. Five patients had both esophageal (1 with IF) and skin LP. Strictures were a prominent presenting feature in LPE patients, with disease distribution more frequent in the upper and lower esophagus. Dysphagia was a common reason for endoscopy in LEP patients. Rheumatologic diseases are more common in patients with LPE compared with LEP. Viral hepatitides and human immunodeficiency virus (HIV) infections are associated with LEP. We defined polypharmacy as patients taking >3 medications; this finding was present in both LPE and LEP cohorts; however, this is a prominent feature in those with established LPE. Progression to dysplasia was noted in both cohorts. About 5% of LPE patients have tandem skin manifestations. LPE is more likely than LEP to arise in women, result in stricture formation, and be associated with rheumatologic disorders and polypharmacy, whereas LEP is associated with viral hepatitis and HIV. Both can progress to neoplasia. As the risk of stricture formation is high in patients with LPE, it is worth performing pertinent IF studies to confirm LPE, although knowledge of the clinical association of LEP with viral hepatitis, HIV, and use of multiple medications is of value in daily practice. PMID- 24061526 TI - Involvement of the testis and related structures by Rosai-Dorfman disease: report of 2 new cases and review of the literature. AB - This report describes 2 new cases of testicular involvement by Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy, and reviews the clinical and pathologic features of the other cases documented in the literature (4 cases) or included in the sinus histiocytosis with massive lymphadenopathy registry (7 cases). Our patients were 42 and 68 years of age, respectively, reflecting the usual middle-age of all the previously reported cases in this location, except for 1, which occurred in a child. Five cases were bilateral, and other sites, such as lymph nodes, kidney, skin, and adrenal gland, were involved in 8 cases. The histories were noteworthy in 2 of the cases, inasmuch as 1 patient had chronic lymphocytic leukemia, and another had a B-cell lymphoma. On gross examination, the testicular masses did not exhibit specific diagnostic features, whereas microscopic examination revealed the typical population of histiocytes, with abundant eosinophilic cytoplasm often exhibiting so-called emperipolesis. The differential diagnosis includes non-neoplastic conditions such as granulomatous orchitis, hematolymphoid disorders, a variety of metastatic tumors, and germ cell tumors. PMID- 24061524 TI - Data set for pathology reporting of cutaneous invasive melanoma: recommendations from the international collaboration on cancer reporting (ICCR). AB - An accurate and complete pathology report is critical for the optimal management of cutaneous melanoma patients. Protocols for the pathologic reporting of melanoma have been independently developed by the Royal College of Pathologists of Australasia (RCPA), Royal College of Pathologists (United Kingdom) (RCPath), and College of American Pathologists (CAP). In this study, data sets, checklists, and structured reporting protocols for pathologic examination and reporting of cutaneous melanoma were analyzed by an international panel of melanoma pathologists and clinicians with the aim of developing a common, internationally agreed upon, evidence-based data set. The International Collaboration on Cancer Reporting cutaneous melanoma expert review panel analyzed the existing RCPA, RCPath, and CAP data sets to develop a protocol containing "required" (mandatory/core) and "recommended" (nonmandatory/noncore) elements. Required elements were defined as those that had agreed evidentiary support at National Health and Medical Research Council level III-2 level of evidence or above and that were unanimously agreed upon by the review panel to be essential for the clinical management, staging, or assessment of the prognosis of melanoma or fundamental for pathologic diagnosis. Recommended elements were those considered to be clinically important and recommended for good practice but with lesser degrees of supportive evidence. Sixteen core/required data elements for cutaneous melanoma pathology reports were defined (with an additional 4 core/required elements for specimens received with lymph nodes). Eighteen additional data elements with a lesser level of evidentiary support were included in the recommended data set. Consensus response values (permitted responses) were formulated for each data item. Development and agreement of this evidence-based protocol at an international level was accomplished in a timely and efficient manner, and the processes described herein may facilitate the development of protocols for other tumor types. Widespread utilization of an internationally agreed upon, structured pathology data set for melanoma will lead not only to improved patient management but is a prerequisite for research and for international benchmarking in health care. PMID- 24061527 TI - [Annual report 2011 of the German pacemaker and defibrillator register: Section pacemakers and AQUA-Institute for Applied Quality Improvement and Research in Health Care]. PMID- 24061528 TI - Validation of reference transcripts in strawberry (Fragaria spp.). AB - Contemporary methods to assay gene expression depend on a stable set of reference transcripts for accurate quantitation. A lack of well-tested reference genes slows progress in characterizing gene expression in high-value specialty crops. In this study, a set of strawberry (Fragaria spp.) constitutively expressed reference genes has been identified by merging digital gene expression data with expression profiling. Constitutive reference candidates were validated using quantitative PCR and hybridization. Several transcripts have been identified that show improved stability across tissues relative to traditional reference transcripts. Results are similar between commercial octoploid strawberry and the diploid model. Our findings also show that while some never-before-used references are appropriate for most applications, even the most stable reference transcripts require careful assessment across the diverse tissues and fruit developmental states before being adopted as controls. PMID- 24061529 TI - Oncologic outcome after laparoscopic radical cystectomy without neoadjuvant or adjuvant therapy with a median follow-up of 32 months. AB - INTRODUCTION: We report the oncological outcome after laparoscopic radical cystectomy (LRC) and standard laparoscopic pelvic lymph node dissection (PLND) without neoadjuvant or adjuvant therapy in the treatment of bladder cancer with a median follow-up of 32 months. MATERIALS AND METHODS: From September 2006 to January 2011, 40 consecutive patients underwent an LRC and standard laparoscopic PLND, and were included in this prospective observational cohort study. No patient received neoadjuvant or adjuvant therapy. Demographic, perioperative, complication, histopathologic and survival data were collected and analyzed. RESULTS: The 2002 TNM staging for the tumors were: pT0, 4 cases; pTis, 5 cases; pT1, 4 cases; pT2, 7 cases; pT3, 13 cases; pT4, 7 cases. Positive surgical margins were reported in 3 patients (7.5%) and lymph node involvement in 9 patients (23.7%). No patient was lost to follow-up. The overall, cancer-specific and recurrence-free survival rates were 53, 73 and 70% with a median follow-up of 32 months. Eleven patients (27.5%) died of metastatic disease or local recurrence. Nonorgan-confined disease (>=pT3) and primary lymph node involvement (pN+) were significantly associated with worse overall, cancer-specific and recurrence-free survival rates. CONCLUSION: We report acceptable mid-term and promising long-term oncological outcome after LRC and standard laparoscopic PLND without neoadjuvant or adjuvant therapy. PMID- 24061530 TI - Photolysis of endoperoxides in the presence of nitroxides: a laser flash photolysis study with optical and ESR detection. AB - Time-resolved electron paramagnetic resonance spectroscopy, transient absorption, and phosphorescence spectroscopy were used to investigate the spin polarization of a nitroxide free radical induced by interaction with singlet oxygen ((1)O2). The latter was generated by photolysis of endoperoxides of two anthracene derivatives. Although both anthracene endoperoxides are structurally similar, opposite spin polarization of the nitroxide was observed. Photolysis of one endoperoxide leads to absorptive nitroxide spin polarization due to interaction with the generated (1)O2. Photolysis of the other endoperoxide generated emissive nitroxide spin polarization, probably due to interaction of the endoperoxide triplet states with nitroxides. PMID- 24061531 TI - Transperineal biopsy of the prostate--is this the future? AB - Transperineal prostate biopsy is re-emerging after decades of being an underused alternative to transrectal biopsy guided by transrectal ultrasonography (TRUS). Factors driving this change include possible improved cancer detection rates, improved sampling of the anteroapical regions of the prostate, a reduced risk of false negative results and a reduced risk of underestimating disease volume and grade. The increasing incidence of antimicrobial resistance and patients with diabetes mellitus who are at high risk of sepsis also favours transperineal biopsy as a sterile alternative to standard TRUS-guided biopsy. Factors limiting its use include increased time, training and financial constraints as well as the need for high-grade anaesthesia. Furthermore, the necessary equipment for transperineal biopsy is not widely available. However, the expansion of transperineal biopsy has been propagated by the increase in multiparametric MRI guided biopsies, which often use the transperineal approach. Used with MRI imaging, transperineal biopsy has led to improvements in cancer detection rates, more-accurate grading of cancer severity and reduced risk of diagnosing clinically insignificant disease. Targeted biopsy under MRI guidance can reduce the number of cores required, reducing the risk of complications from needle biopsy. PMID- 24061533 TI - Prostate cancer: Oncological vs functional outcomes for RARP--finding a balance. PMID- 24061532 TI - MRI-targeted prostate biopsy: a review of technique and results. AB - Multiparametric magnetic resonance imaging (mpMRI) is of interest for the diagnosis of clinically significant prostate cancer and mpMRI-targeted biopsies are being used increasingly in clinical practice. Target acquisition is performed using a range of magnet strengths and varying combinations of anatomical and functional sequences. Target identification at the time of biopsy can be carried out in the MRI scanner (in-bore biopsy) or, more commonly, the MRI-target is biopsied under ultrasonographic guidance. Many groups use cognitive or visual registration, whereby the biopsy target is identified on MRI and ultrasonography is subsequently used to direct the needle to the same location. Other groups use registration software to show prebiopsy MRI data on real-time ultrasonography. The reporting of histological results in MRI-targeted biopsy studies varies greatly. The most useful reports compare the detection of clinically significant disease in standard cores versus mpMRI-targeted cores in the same cohort of men, as recommended by the STAndards of Reporting for MRI-Targeted biopsy studies (START) consensus panel. Further evidence is needed before an mpMRI-targeted strategy can be recommended as the standard intervention for men at risk of prostate cancer. PMID- 24061534 TI - Prostate cancer: New nomogram predicts risk of Gleason upgrading. PMID- 24061535 TI - Chemical modification of single walled carbon nanotubes with tetrazine-tethered gold nanoparticles via a Diels-Alder reaction. AB - A versatile methodology for the modification of single walled carbon nanotubes (SWCNTs) through an inverse electron demand Diels-Alder reaction with tetrazine AuNPs (-AuNPs) under ambient conditions is described. A robust covalently bonded hybrid nanocomposite is formed. PMID- 24061536 TI - Proteasome inhibition induces DNA damage and reorganizes nuclear architecture and protein synthesis machinery in sensory ganglion neurons. AB - Bortezomib is a reversible proteasome inhibitor used as an anticancer drug. However, its clinical use is limited since it causes peripheral neurotoxicity. We have used Sprague-Dawley rats as an animal model to investigate the cellular mechanisms affected by both short-term and chronic bortezomib treatments in sensory ganglia neurons. Proteasome inhibition induces dose-dependent alterations in the architecture, positioning, shape and polarity of the neuronal nucleus. It also produces DNA damage without affecting neuronal survival, and severe disruption of the protein synthesis machinery at the central cytoplasm accompanied by decreased expression of the brain-derived neurotrophic factor. As a compensatory or adaptive survival response against proteotoxic stress caused by bortezomib treatment, sensory neurons preserve basal levels of transcriptional activity, up-regulate the expression of proteasome subunit genes, and generate a new cytoplasmic perinuclear domain for protein synthesis. We propose that proteasome activity is crucial for controlling nuclear architecture, DNA repair and the organization of the protein synthesis machinery in sensory neurons. These neurons are primary targets of bortezomib neurotoxicity, for which reason their dysfunction may contribute to the pathogenesis of the bortezomib-induced peripheral neuropathy in treated patients. PMID- 24061537 TI - Combinatorial activity of Six1-2-4 genes in cephalic neural crest cells controls craniofacial and brain development. AB - The combinatorial expression of Hox genes is an evolutionarily ancient program underlying body axis patterning in all Bilateria. In the head, the neural crest (NC)--a vertebrate innovation that contributes to evolutionarily novel skeletal and neural features--develops as a structure free of Hox-gene expression. The activation of Hoxa2 in the Hox-free facial NC (FNC) leads to severe craniofacial and brain defects. Here, we show that this condition unveils the requirement of three Six genes, Six1, Six2, and Six4, for brain development and morphogenesis of the maxillo-mandibular and nasofrontal skeleton. Inactivation of each of these Six genes in FNC generates diverse brain defects, ranging from plexus agenesis to mild or severe holoprosencephaly, and entails facial hypoplasia or truncation of the craniofacial skeleton. The triple silencing of these genes reveals their complementary role in face and brain morphogenesis. Furthermore, we show that the perturbation of the intrinsic genetic FNC program, by either Hoxa2 expression or Six gene inactivation, affects Bmp signaling through the downregulation of Bmp antagonists in the FNC cells. When upregulated in the FNC, Bmp antagonists suppress the adverse skeletal and cerebral effects of Hoxa2 expression. These results demonstrate that the combinatorial expression of Six1, Six2, and Six4 is required for the molecular programs governing craniofacial and cerebral development. These genes are crucial for the signaling system of FNC origin, which regulates normal growth and patterning of the cephalic neuroepithelium. Our results strongly suggest that several congenital craniofacial and cerebral malformations could be attributed to Six genes' misregulation. PMID- 24061538 TI - Dissection of a Krox20 positive feedback loop driving cell fate choices in hindbrain patterning. AB - Although feedback loops are essential in development, their molecular implementation and precise functions remain elusive. Using enhancer knockout in mice, we demonstrate that a direct, positive autoregulatory loop amplifies and maintains the expression of Krox20, a transcription factor governing vertebrate hindbrain segmentation. By combining quantitative data collected in the zebrafish with biophysical modelling that accounts for the intrinsic stochastic molecular dynamics, we dissect the loop at the molecular level. We find that it underpins a bistable switch that turns a transient input signal into cell fate commitment, as we observe in single cell analyses. The stochasticity of the activation process leads to a graded input-output response until saturation is reached. Consequently, the duration and strength of the input signal controls the size of the hindbrain segments by modulating the distribution between the two cell fates. Moreover, segment formation is buffered from severe variations in input level. Finally, the progressive extinction of Krox20 expression involves a destabilization of the loop by repressor molecules. These mechanisms are of general significance for cell type specification and tissue patterning. PMID- 24061539 TI - Biomedically relevant circuit-design strategies in mammalian synthetic biology. AB - The development and progress in synthetic biology has been remarkable. Although still in its infancy, synthetic biology has achieved much during the past decade. Improvements in genetic circuit design have increased the potential for clinical applicability of synthetic biology research. What began as simple transcriptional gene switches has rapidly developed into a variety of complex regulatory circuits based on the transcriptional, translational and post-translational regulation. Instead of compounds with potential pharmacologic side effects, the inducer molecules now used are metabolites of the human body and even members of native cell signaling pathways. In this review, we address recent progress in mammalian synthetic biology circuit design and focus on how novel designs push synthetic biology toward clinical implementation. Groundbreaking research on the implementation of optogenetics and intercellular communications is addressed, as particularly optogenetics provides unprecedented opportunities for clinical application. Along with an increase in synthetic network complexity, multicellular systems are now being used to provide a platform for next generation circuit design. PMID- 24061540 TI - Salt-inducible kinases 1 and 3 negatively regulate Toll-like receptor 4-mediated signal. AB - Salt-inducible kinases (SIKs) are a family of related serine-threonine kinases and are involved in controlling various metabolisms such as liver glucose homeostasis, hepatic lipogenesis, steroidogenesis, and adipogenesis. Here we investigated the regulatory role of SIK proteins in Toll-like receptor 4 (TLR4) mediated signaling. Overexpression of SIK1 and SIK3, but not SIK2, significantly inhibited nuclear factor-kappaB activity in response to lipopolysaccharide stimulation and affected the expression of proinflammatory cytokines. In contrast, both SIK1(KD) and SIK3(KD) Raw 264.7 cells exhibit dramatic elevations of nuclear factor-kappaB activation and activations of downstream signaling molecules, such as TGF-beta-activated kinase 1, p38, and c-Jun N-terminal kinase, in response to TLR4 stimulation, indicating that SIK1 and SIK3 are negatively involved in the TLR4-mediated signaling. Through biochemical studies, we found that SIK1 and SIK3 interact with TGF-beta-activated kinase 1-binding protein 2 (TAB2), and interrupt the functional complex of TAB2-TNF receptor-associated factor 6 (TRAF6). Interestingly, the molecular interruption is induced to suppress the ubiquitination of TRAF6 in response to TLR4 stimulation. These result suggest that SIK1 and SIK3 negatively regulate TLR4-mediated signaling through the interruption of TAB2-TRAF6 complex and thereby the inhibition of ubiquitination of TRAF6. The present findings can be useful for a better understanding of multilevel interactions between the metabolic and immune systems. PMID- 24061541 TI - Serum 25-hydroxyvitamin D below 25 ng/mL is a risk factor for long bone fracture comparable to bone mineral density in Japanese postmenopausal women. AB - There is emergent evidence for divergent associations between 25(OH)D levels and fractures by race and ethnicity, but data on Asian populations are sparse. We investigated this association in a primary care cohort of 1470 postmenopausal Japanese women followed for a mean period of 7.2 years and explored a potential threshold of 25(OH)D. Endpoints were incident vertebral, proximal femur, and long bone fractures. Rate ratios were estimated using multivariate Poisson regression adjusted for lumbar or femur bone mineral density (BMD) less than -2.5 SD of the young adult mean (YAM), age, weight, presence of diabetes mellitus, parathyroid hormone, estimated glomerular filtration rate, prior fracture, back pain, present medications and past medical history. Mean age was 63.7 +/- 10.7 years and osteoporosis patients were 41.3 %. The background data of the present participants were almost identical to the subjects participating in the National Health and Nutrition Survey of 2003. Overall, 49.6 % of the subjects had a 25(OH)D value <20 ng/mL and 27.8 % had a 25(OH)D value from 20 to 24 ng/mL. The propensity score for exposure to 25(OH)D < 25 ng/mL in the present and independent community dwelling populations, namely the Miyama and Taiji cohorts, were not significantly different, suggesting no evidence for selection bias. The generalized additive models showed clear decreasing trends in incidence rates of proximal femur and long bone fractures at higher levels of 25(OH)D, and the annual incidence rate of proximal femur fracture was around 0.0005 in women with 25(OH)D > 25 ng/mL, probably leading to the decreasing trend in long bone fracture. Multivariate-adjusted rate ratios of 25(OH)D < 25 ng/mL were 1.01 (95 % confidence interval [CI], 0.84-1.22, p = 0.88) for vertebral fracture, 2.71 (95 % CI 0.94-7.83, p = 0.07) for proximal femur fracture, and 2.20 (95 % CI 1.37-3.53, p < 0.01) for long bone fracture. The respective rate ratios of a BMD level lower than -2.5 SD of the YAM were 1.61 (95 % CI 1.33-1.94, p < 0.01), 1.52 (95 % CI 0.67-3.45, p = 0.32), and 1.54 (95 % CI 1.02-2.33, p = 0.04). In conclusion, 25(OH)D is a leading risk factor for long bone fracture comparable to BMD in Japanese postmenopausal women. The contribution of 25(OH)D to fracture risks is substantial even below 25 ng/mL and is possibly site-specific. We recommend measuring the serum 25(OH)D level in primary care settings. PMID- 24061542 TI - A functionalized heterobimetallic (99m)Tc/Re complex as a potential dual-modality imaging probe: synthesis, photophysical properties, cytotoxicity and cellular imaging investigations. AB - A novel bimodal fluorescent/radiolabelled probe based on a pyridyltriazole scaffold (known as pyta) is reported here. The final dual imaging agent combines carboxylate functionalization, for biomolecule conjugation, with two distinct metal chelating sites: a pyta-based tricarbonylrhenium moiety as a fluorescent probe and a (99m)Tc(CO3)(+) core through the tridentate chelating iminodiacetic acid (IDA) clamp as a SPECT reporter. The heterodinuclear (99m)Tc/Re complex , as well as its non-radioactive dirhenium analog , was prepared in six steps. The (99m)Tc/Re agent is water-soluble and stable against histidine challenge. Its structural characterization was achieved by HPLC comparison with the non radioactive complex . Upon excitation in the MLCT band at 321 nm, the compound exhibits a bright green luminescence centered at 496 nm, with a quantum yield of 0.86% in Tris buffer, pH 7.4. Additionally, the influence of this compound on cell viability was tested on malignant cell lines (A549, HT29 and MCF-7 human lung, colon and breast carcinomas, respectively). Cell viability after 72 h incubation at 37 degrees C with 300 MUmol of complex was >60% for all cell lines. Finally, cellular uptake studies of compound were performed by fluorescent microscopy, showing that the complex was clearly detected at the cellular level in A549 cells and to a lesser extent in HT29 cells. Taking into consideration the luminescent properties, the good radiochemical purity and the promising biological data (in vitro stability, non-toxicity, and cell tracking in two cell lines), the functionalized (99m)Tc/Re dinuclear compound can be considered a potential pre- and intraoperative diagnostic probe. PMID- 24061544 TI - An efficient buffer-mediated control between free radical substitution and proton coupled electron transfer: dehalogenation of iodoethane by the alpha-hydroxyethyl radical in aqueous solution. AB - A remarkable buffer-mediated control between free-radical substitution (FRS) and proton-coupled electron transfer (PCET) is demonstrated for the reaction between iodoethane and the alpha-hydroxyethyl radical in neutral aqueous solution in the presence of bicarbonate or phosphate buffer. The reaction is initiated by the gamma-radiolysis of the water solvent, and the products, either the iodine atom (FRS) or anion (PCET), are analysed using ion chromatographic and spectrophotometric techniques. A detailed insight into the mechanism is gained by employing density functional theory (M06-2X), Moller-Plesset perturbation treatment to the second order (MP2), and multireference methods (CASSCF/CASPT2). Addition of a basic buffer anion is indispensable for the reaction to occur and the competition between the two channels depends subtly on its proton accepting affinity, with FRS being the dominant channel in the phosphate and PCET in the bicarbonate containing solutions. Unlike the former, the latter channel sustains a chain-like process which significantly enhances the dehalogenation. The present systems furnish an example of the novel PCET/FRS dichotomy, as well as insights into possibilities of its efficient control. PMID- 24061543 TI - Role of natural killer and Gamma-delta T cells in West Nile virus infection. AB - Natural Killer (NK) cells and Gamma-delta T cells are both innate lymphocytes that respond rapidly and non-specifically to viral infection and other pathogens. They are also known to form a unique link between innate and adaptive immunity. Although they have similar immune features and effector functions, accumulating evidence in mice and humans suggest these two cell types have distinct roles in the control of infection by West Nile virus (WNV), a re-emerging pathogen that has caused fatal encephalitis in North America over the past decade. This review will discuss recent studies on these two cell types in protective immunity and viral pathogenesis during WNV infection. PMID- 24061545 TI - Arterial stiffness/central hemodynamics, renal function, and development of hypertension over the short term. AB - OBJECTIVES: We examined the following: whether the estimated glomerular filtration rate calculated from the serum cystatin C levels (eGFRcys) and the brachial-ankle pulse wave velocity (baPWV) might be independent predictors of the development of hypertension over the short term, without any interaction; whether the baPWV may be directly associated with the development of hypertension without the mediation of the arterial stiffness-related acceleration of renal functional decline; whether the second peak of the radial pressure waveform (SP2) might also be a significant independent predictor of the development of hypertension. METHODS: In 1229 middle-aged normotensive Japanese men with preserved renal function, the baPWV, SP2 and eGFRcys were measured at the baseline and at the end of the 3-year study period. RESULTS: Hypertension was detected at the end of the 3-year study period in 127 men. The logistic regression analysis with adjustments demonstrated significant independent odds ratios of the baPWV and eGFRcys for the presence of hypertension at the end of the 3-year study period, without any interaction. When entered simultaneously in this model, the SP2 also showed a significant odds ratio. General linear model analysis revealed that none of the baPWV or SP2 measured at the baseline was related to the renal function assessed at the end of the 3-year study period. CONCLUSIONS: The mechanisms underlying the association between arterial stiffness/central hemodynamics and the short-term development of hypertension appear to differ from those underlying the association between kidney function and the short-term development of hypertension. PMID- 24061547 TI - Facets of hypertension research. PMID- 24061546 TI - Systolic and diastolic component of orthostatic hypotension and cardiovascular events in hypertensive patients: the Captopril Prevention Project. AB - OBJECTIVE: Impact of SBP vs. DBP decrement during orthostasis on cardiovascular events in hypertension is not clear. METHODS: We assessed prospective association of orthostatic hypotension with mortality and major cardiovascular events [myocardial infarction (MI) and stroke] among 8788 treated hypertensive patients (52.2% men; mean age 52 years, mean BP 161/99 mmHg) without history of MI or stroke at baseline. Orthostatic hypotension was defined according to combined international consensus criteria, and as either systolic (decrease >=20 mmHg) or diastolic orthostatic hypotension (decrease >=10 mmHg). Final Cox regression model was adjusted for age, sex, supine SBP and DBP, diabetes, smoking, and total cholesterol. RESULTS: A total of 1060 (12.1%) study participants fulfilled combined orthostatic hypotension criteria, of these 886 (10.1%) met systolic and 290 (3.3%) diastolic criterion. In the crude analysis, combined orthostatic hypotension criteria were predictive of the composite endpoint, major cardiovascular event, total mortality, and stroke but not MI. After full adjustment, combined orthostatic hypotension criteria and systolic orthostatic hypotension were independently associated with stroke only (hazard ratio: 1.48, 1.07-2.05, P = 0.019, and 1.53, 1.08-2.15, P = 0.015, respectively), whereas the composite endpoint tended in the same direction (hazard ratio: 1.21, 0.98-1.51, P = 0.075, and 1.24, 0.99-1.55, P = 0.066, respectively). In contrast, diastolic orthostatic hypotension was associated with increased risk of MI (hazard ratio: 2.04, 1.20-3.46, P = 0.008). CONCLUSION: Orthostatic hypotension has a dual role in cardiovascular events among hypertensive patients: SBP fall indicates higher risk of stroke, whereas DBP fall confers higher risk of MI. PMID- 24061548 TI - Flow enhanced non-linear magnetophoretic separation of beads based on magnetic susceptibility. AB - Magnetic separation provides a rapid and efficient means of isolating biomaterials from complex mixtures based on their adsorption on superparamagnetic (SPM) beads. Flow enhanced non-linear magnetophoresis (FNLM) is a high-resolution mode of separation in which hydrodynamic and magnetic fields are controlled with micron resolution to isolate SPM beads with specific physical properties. In this article we demonstrate that a change in the critical frequency of FNLM can be used to identify beads with magnetic susceptibilities between 0.01 and 1.0 with a sensitivity of 0.01 Hz(-1). We derived an analytical expression for the critical frequency that explicitly incorporates the magnetic and non-magnetic composition of a complex to be separated. This expression was then applied to two cases involving the detection and separation of biological targets. This study defines the operating principles of FNLM and highlights the potential for using this technique for multiplexing diagnostic assays and isolating rare cell types. PMID- 24061549 TI - Frequent triple-hit expression of MYC, BCL2, and BCL6 in primary lymphoma of the central nervous system and absence of a favorable MYC(low)BCL2 (low) subgroup may underlie the inferior prognosis as compared to systemic diffuse large B cell lymphomas. PMID- 24061550 TI - Heteroannulation of arynes with N-aryl-alpha-aminoketones for the synthesis of unsymmetrical N-aryl-2,3-disubstituted indoles: an aryne twist of Bischler-Mohlau indole synthesis. AB - Reaction of 2-(trimethylsilyl)aryl triflates 1 with N-aryl-alpha-amino ketones 2 afforded N-aryl-2,3-disubstituted indoles in good to excellent yields with complete control of the substitution patterns. This methodology allowed for the first time a one-step synthesis of unsymmetrical 2,3-dialkyl substituted indoles in a regiospecific manner. PMID- 24061551 TI - Does the invasive Lupinus polyphyllus increase pollinator visitation to a native herb through effects on pollinator population sizes? AB - Invasive plants may compete with native species for abiotic factors as light, space and nutrients, and have also been shown to affect native pollination interactions. Studies have mainly focused on how invasive plants affect pollinator behaviour, i.e. attraction of pollinators to or away from native flowers. However, when an invasive plant provides resources utilized by native pollinators this could increase pollinator population sizes and thereby pollination success in natives. Effects mediated through changes in pollinator population sizes have been largely ignored in previous studies, and the dominance of negative interactions suggested by meta-analyses may therefore be biased. We investigated the impact of the invasive Lupinus polyphyllus on pollination in the native Lotus corniculatus using a study design comparing invaded and uninvaded sites before and after the flowering period of the invasive. We monitored wild bee abundance in transects, and visit rate and seed production of potted Lotus plants. Bumblebee abundance increased 3.9 times in invaded sites during the study period, whereas it was unaltered in uninvaded sites. Total visit rate per Lotus plant increased 2.1 times in invaded sites and decreased 4.4 times in uninvaded sites. No corresponding change in seed production of Lotus was found. The increase in visit rate to Lotus was driven by an increase in solitary bee visitation, whereas mainly bumblebees were observed to visit the invasive Lupinus. The mechanism by which the invasive increases pollinator visit rates to Lotus could be increased availability of other flower resources for solitary bees when bumblebees forage on Lupinus. PMID- 24061552 TI - Direct observation of multiferroic vortex domains in YMnO3. AB - Topological vortices with swirling ferroelectric, magnetic and structural anti phase relationship in hexagonal RMnO3 (R = Ho to Lu, Y, and Sc) have attracted much attention because of their intriguing behaviors. Herein, we report the structure of multiferroic vortex domains in YMnO3 at atomic scale using state-of the-art aberration-corrected scanning transmission electron microscopy (STEM). Two types of displacements were identified among six domain walls (DWs); six translation-ferroelectric domains denoted by alpha+, gamma-, beta+, alpha-, gamma+ and beta-, respectively, were recognized, demonstrating the interlocking nature of the anti-vortex domain. We found that the anti-vortex core is about four unit cells wide. In addition, we reconstructed the vortex model with three swirling pairs of DWs along the [001] direction. These results are very critical for the understanding of topological behaviors and unusual properties of the multiferroic vortex. PMID- 24061553 TI - Rice bran extract affects differentiation of mesenchymal stem cells potency into osteogenic cells. AB - As rice bran contains various nutrients and other proteins of which a part has biological effects on animal cells, we tested the effect of rice bran extract on rat mesenchymal stem cells (rMSCs) obtained from bone marrow. These rMSCs are pluripotent and can be readily induced to differentiate into a number of cell types, including bone and cartilage. rMSC was aggregated by culturing in serum free condition with rice bran extract, but was not aggregated by culturing in serum-free condition or in serum-containing medium. Moreover, the longer aggregates of rMSCs were cultured in serum-free condition with rice bran extract, the more the aggregates grew. After two passages in serum-free conditions, rMSCs lost their potency for differentiation into osteogenic cells; however, the addition of rice bran extract to serum-free medium successfully prevented the loss of this ability for differentiation. In addition, MSC makers CD105 and CD166 gene expression in serum-free condition with rice barn extract corresponded to these expressions in serum-containing medium. This result suggests that certain factors in rice bran could be bioactive and contribute toward retaining the ability of MSCs to differentiate into osteogenic cells after passaging. PMID- 24061555 TI - Arsenic and cardiovascular disease: new evidence from the United States. PMID- 24061554 TI - Anti-apoptotic mechanism of Bacoside rich extract against reactive nitrogen species induced activation of iNOS/Bax/caspase 3 mediated apoptosis in L132 cell line. AB - Nitric oxide is a highly reactive free radical gas that reacts with a wide range of bio-molecules to produce reactive nitrogen species and exerts nitrative stress. Bacopa monniera is a traditional folk and ayurvedic medicine known to alleviate a variety of disorders. Aim of the present study is to evaluate the protective propensity of Bacopa monniera extract (BME) through its oxido nitrosative and anti-apoptotic mechanism to attenuate sodium nitroprusside (SNP) induced apoptosis in a human embryonic lung epithelial cell line (L132). Our results elucidate that pre-treatment of L132 cells with BME ameliorates the mitochondrial and plasma membrane damage induced by SNP as evidenced by MTT and LDH leakage assays. BME pre-treatment inhibited NO generation by down-regulating inducible nitric oxide synthase expression. BME exhibited potent antioxidant activity by up-regulating the antioxidant enzymes. SNP-induced damage to cellular, nuclear and mitochondrial integrity was also restored by BME, which was confirmed by ROS estimation, comet assay and mitochondrial membrane potential assays respectively. BME pre-treatment efficiently attenuated the SNP-induced apoptotic biomarkers such as Bax, cytochrome-c and caspase-3, which orchestrate the proteolytic damage of the cell. By considering all these findings, we report that BME protects L132 cells against SNP-induced toxicity via its free radical scavenging and anti-apoptotic mechanism. PMID- 24061556 TI - Assessment of left atrial mechanical functions in thyroid dysfunction. AB - INTRODUCTION: Thyroid hormone deficiency can lead to the impairment of cardiac function. OBJECTIVES: The aim of the study was to determine the left atrial (LA) mechanical function in patients with subclinical hypothyroidism (SHT) and overt hypothyroidism (OHT) and investigate associations of LA mechanical function with diastolic function. PATIENTS AND METHODS: Twenty-six patients with newly diagnosed SHT (mean age, 42.2 +/-12.5 years), 21 patients with OHT (40.2 +/-8.5 years) and 28 healthy volunteers (42.4 +/-11.2 years) were enrolled in this study. Patients were evaluated by standard M-mode echocardiographic measurements, mitral Doppler flow analysis, and tissue Doppler parameters at the lateral, septal, and right ventricular annuli. LA volumes were measured using the disc method, and the parameters of LA mechanical function were calculated. RESULTS: The active emptying volume (AEV) and active emptying fraction (AEF) were significantly higher in the OHT and SHT groups compared with controls. The passive emptying volume and passive emptying fraction were lower in the OHT and SHT groups compared with controls, but the differences were not significant. The conduit volume and the E/A ratio were significantly lower in the OHT and SHT groups compared with controls. The lateral and septal E/Em were significantly higher in the OHT and SHT groups than in the control group, but the septal Em/Am was significantly lower. Diastolic function parameters showed significant associations with AEV and AEF. CONCLUSIONS: LA mechanical function is impaired in patients with thyroid dysfunction. Our findings suggest that this impairment is secondary to that of the left ventricular diastolic function. PMID- 24061557 TI - Similar effects on cognitive performance during high- and low-carbohydrate obesity treatment. AB - OBJECTIVE: Low-carbohydrate (L-CHO) diets are often used for weight loss but their effects on cognitive function are not well understood. The present study compared the effects of a L-CHO and high-carbohydrate (H-CHO) weight-loss diet on cognitive function adults. DESIGN: PARTICIPANTS were randomized to either a L-CHO (n=22) or H-CHO (n=25) weight-loss diet. Cognitive function was evaluated by four computerized cognitive tasks (Stroop Task, Continuous Performance Task, Word Recall and Wisconsin Card Sorting Task) presented in random order before and at 1, 4, 12 and 24 weeks after the initiation of the L-CHO or H-CHO diet. PARTICIPANTS: Forty-seven adults (25 males) with a mean+/-s.d. age of 47.4+/-8.7 years and body mass index of 35.3+/-3.4 kg m(-2). RESULTS: There were no significant differences in weight loss between groups at any time point. There were significant improvements on color Stroop task accuracy over time in both diet groups (P<0.05), but there were no differences in performance between groups on this or any other cognitive task at any time period. CONCLUSION: These findings suggest that weight loss has neither a positive nor a negative effect on cognitive function and that L-CHO and H-CHO weight-loss diets have similar effects on cognitive performance. PMID- 24061558 TI - Incidence of venous thromboembolism in the setting of hematopoietic cell transplantation. AB - The underlying risk of venous thromboembolism (VTE) is unclear in patients undergoing hematopoietic cell transplantation (HCT). As such, these patients should still be considered at risk for development of VTE due to factors such as their underlying malignancy and the marked inflammatory state that develops from treatment. The purpose of this study was to characterize the incidence of VTE in patients undergoing HCT. Retrospective chart review of patients from the Indiana University Stem Cell Transplant Unit treated between January 1, 2008, and May 24, 2011. Patients were older than 18 years and had undergone HCT. The primary objective was to analyze the incidence of VTE in patients undergoing autologous HCT versus allogeneic HCT. Secondary objectives included documentation of VTE treatment strategies and time to occurrence of VTE. Of the 567 patients who underwent autologous HCT, 14 developed VTE (2.5%), whereas 5 of the 180 patients who underwent allogeneic HCT developed VTE (2.8%; P = 1.000). The median time to development of VTE from admission for HCT was 12 days in the autologous HCT arm versus 19 days in the allogeneic HCT arm (P = 0.610). The most commonly used VTE treatment strategy was enoxaparin (12 out of 19 VTEs). This study illustrates that VTE does occur rarely in patients who have undergone HCT. The optimal treatment regimen in this population requires further evaluation. Until a reliable protocol for treatment and evidence for risk factors are established, providers should be vigilant for occurrence of VTE in these patients. PMID- 24061559 TI - The mechanism of copper uptake by tyrosinase from Bacillus megaterium. AB - Tyrosinase belongs to the type 3 copper enzyme family, containing a dinuclear copper center, CuA and CuB. It is mainly responsible for melanin production in a wide range of organisms. Although copper ions are essential for the activity of tyrosinase, the mechanism of copper uptake is still unclear. We have recently determined the crystal structure of tyrosinase from Bacillus megaterium (TyrBm) and revealed that this enzyme has tighter binding of CuA in comparison with CuB. Investigating copper accumulation in TyrBm, we found that the presence of copper has a more significant effect on the diphenolase activity. By decreasing the concentration of copper, we increased the diphenolase to monophenolase activity ratio twofold. Using a rational design approach, we identified five variants having an impact on copper uptake. We have found that a major role of the highly conserved Asn205 residue is to stabilize the orientation of the His204 imidazole ring in the binding site, thereby promoting the correct coordination of CuB. Further investigation of these variants revealed that Phe197, Met61, and Met184, which are located at the entrance to the binding site, not only play a role in copper uptake, but are also important for enhancing the diphenolase activity. We propose a mechanism of copper accumulation by the enzyme as well as an approach to changing the selectivity of TyrBm towards L-dopa production. PMID- 24061561 TI - A 3d-4f heterometallic 3D POMOF based on lacunary Dawson polyoxometalates. AB - A novel compound, Na2[Ce4(H2O)22(dpdo)5](Mn2HP2W15O56)2.8H2O (1) (dpdo = 4,4' bipyridine-N,N'-dioxide) with 3d-4f heterometallic 3D POMOF that can be described as a self-penetrating (4,4,6)-connected net topology, has been isolated via a stepwise method, and its magnetic and electrocatalytic properties have been investigated. PMID- 24061560 TI - Yeast copper-zinc superoxide dismutase can be activated in the absence of its copper chaperone. AB - Copper-zinc superoxide dismutase (Sod1) is an abundant intracellular enzyme that catalyzes the disproportionation of superoxide to give hydrogen peroxide and dioxygen. In most organisms, Sod1 acquires copper by a combination of two pathways, one dependent on the copper chaperone for Sod1 (CCS), and the other independent of CCS. Examples have been reported of two exceptions: Saccharomyces cerevisiae, in which Sod1 appeared to be fully dependent on CCS, and Caenorhabditis elegans, in which Sod1 was completely independent of CCS. Here, however, using overexpressed Sod1, we show there is also a significant amount of CCS-independent activation of S. cerevisiae Sod1, even in low-copper medium. In addition, we show CCS-independent oxidation of the disulfide bond in S. cerevisiae Sod1. There appears to be a continuum between CCS-dependent and CCS independent activation of Sod1, with yeast falling near but not at the CCS dependent end. PMID- 24061562 TI - Development of a sampler to estimate regional deposition of aerosol in the human respiratory tract. AB - A multistage sampler was developed and tested to estimate regional deposition of aerosol in the human respiratory system. The motivation for this research is to improve our ability to estimate inhaled aerosol dose. Current methods for aerosol measurement and exposure/risk assessment are based on particle aspiration (e.g. inhalable PM) or on penetration to various regions of the respiratory system (e.g. PM10). The sampler developed here operates at 1 m(3) h(-1) (16.7 l min(-1)) of flow and utilizes several substrates, connected in series, to mimic regional particle deposition. Two sets of polyurethane foam substrates are used to mimic particle deposition in the head airways and tracheobronchial regions, respectively. Particle deposition in the alveolar region is mimicked using diffusion screens. These substrates are amenable to trace chemical analyses but not gravimetric analyses, due to water vapor uptake with small changes in relative humidity. PMID- 24061563 TI - Optimization, production and characterization of glycolipid biosurfactant from the marine actinobacterium, Streptomyces sp. MAB36. AB - A potential glycolipid biosurfactant producer Streptomyces sp. MAB36 was isolated from marine sediment samples. Medium composition and culture conditions for the glycolipid biosurfactant production by Streptomyces sp. MAB36 were optimized, using two statistical methods: Plackett-Burman design was applied to find out the key ingredients and conditions for the best yield of glycolipid biosurfactant production and central composite design was used to optimize the concentration of the four significant variables, starch, casein, crude oil and incubation time. Fructose and yeast extract were the best carbon and nitrogen sources for the production of the glycolipid biosurfactant. Biochemical characterizations including FTIR and MS studies suggested the glycolipid nature of the biosurfactant. The isolated glycolipid biosurfactant reduced the surface tension of water from 73.2 to 32.4 mN/m. The purified glycolipid biosurfactant showed critical micelle concentrations of 36 mg/l. The glycolipid biosurfactant was effective at very low concentrations over a wide range of temperature, pH, and NaCl concentration. The purified glycolipid biosurfactant showed strong antimicrobial activity. Thus, the strain Streptomyces sp. MAB36 has proved to be a potential source of glycolipid biosurfactant that could be used for the bioremediation processes in the marine environment. PMID- 24061564 TI - Soybean hull peroxidase immobilization on macroporous glycidyl methacrylates with different surface characteristics. AB - Soybean hull peroxidase (SHP, E.C. 1.11.1.7) was immobilized by a glutaraldehyde and periodate method onto series of macroporous copolymers of glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EGDMA), poly(GMA-co-EGDMA) with various surface characteristics and pore size diameters ranging from 44 to 200 nm. Glutaraldehyde immobilization method and poly(GMA-co-EGDMA) named SGE 20/12 with pore sizes of 120 nm gave immobilized enzyme with highest specific activity of 25 U/g. Deactivation studies showed that immobilization increased stability of SHP and that surface characteristics of the used copolymer had a major influence on a stability of immobilized enzyme at high temperatures and in an organic solvent. The highest thermostability was obtained using the copolymer SGE 20/12 with pore size of 120 nm, while the highest stability in dioxane had SHP immobilized onto copolymer SGE 10/4 with pore size of 44 nm. Immobilized SHP showed a wider pH optimum as compared to the native enzyme especially at alkaline pH values and 3.2 times increased K m value for pyrogallol. After 6 cycles of repeated use in batch reactor, immobilized SHP retained 25 % of its original activity. Macroporous copolymers with different surface characteristics can be used for fine tuning of activity and stability of immobilized SHP to obtain a biocatalyst suitable for phenol oxidation or polymer synthesis in organic solvents. PMID- 24061565 TI - Development of the ciliary body: morphological changes in the distal portion of the optic cup in the human. AB - This study seeks to determine the main events that occur in the development of the ciliary body (CB) in the 5-14th week of development. The CB develops from the distal portion of the optic cup (OC) and the neighboring mesenchyme. During the 5th week of development, 4 zones were observed in the distal portion of the OC: in zone 1, the epithelia of the outer and inner layers of the OC came into contact. This contact coincided with the appearance of mainly apical granule pigments. This zone corresponded to the anlage of the epithelial layers of the CB. In zone 2, the cells surrounded the marginal sinus and contained scarce pigment granules and nuclei in the basal position. This zone corresponded to the anlage of the iris. Zone 3 was triangular in shape and its vertex ran towards the marginal sinus and corresponded to common cell progenitors. Zone 4 corresponded to the retinal pigment epithelium anlage and the neural retina anlage. We determined the onset of the stroma and the ciliary muscle anlage at the end of the 7th week. In the 13-14th week, we observed the anlage of the orbicularis ciliaris (pars plana of the CB) and corona ciliaris (pars plicata of the CB), in addition to the anlage of the ciliary muscle. Our study, therefore, establishes a precise timetable of the development of the CB. PMID- 24061566 TI - Optimized invertase expression and secretion cassette for improving Yarrowia lipolytica growth on sucrose for industrial applications. AB - Yarrowia lipolytica requires the expression of a heterologous invertase to grow on a sucrose-based substrate. This work reports the construction of an optimized invertase expression cassette composed of Saccharomyces cerevisiae Suc2p secretion signal sequence followed by the SUC2 sequence and under the control of the strong Y. lipolytica pTEF promoter. This new construction allows a fast and optimal cleavage of sucrose into glucose and fructose and allows cells to reach the maximum growth rate. Contrary to pre-existing constructions, the expression of SUC2 is not sensitive to medium composition in this context. The strain JMY2593, expressing this new cassette with an optimized secretion signal sequence and a strong promoter, produces 4,519 U/l of extracellular invertase in bioreactor experiments compared to 597 U/l in a strain expressing the former invertase construction. The expression of this cassette strongly improved production of invertase and is suitable for simultaneously high production level of citric acid from sucrose-based media. PMID- 24061567 TI - Evolutionary concepts in natural products discovery: what actinomycetes have taught us. AB - Actinomycetes are a very important source of natural products for the pharmaceutical industry and other applications. Most of the strains belong to Streptomyces or related genera, partly because they are particularly amenable to growth in the laboratory and industrial fermenters. It is unlikely that chemical synthesis can fulfil the needs of the pharmaceutical industry for novel compounds so there is a continuing need to find novel natural products. An evolutionary perspective can help this process in several ways. Genome mining attempts to identify secondary metabolite biosynthetic clusters in DNA sequences, which are likely to produce interesting chemical entities. There are often technical problems in assembling the DNA sequences of large modular clusters in genome and metagenome projects, which can be overcome partially using information about the evolution of the domain sequences. Understanding the evolutionary mechanisms of modular clusters should allow simulation of evolutionary pathways in the laboratory to generate novel compounds. PMID- 24061568 TI - Quality of life after microsurgery for vestibular schwannoma via the middle cranial fossa approach. AB - The aim of this study was to analyse the quality of life (QOL) of patients who had undergone microsurgery for vestibular schwannomas (VS). A questionnaire was sent to 117 consecutive patients who had been operated on using the middle cranial fossa (MCF) approach between October 2005 and June 2011. The response rate was 91/117 (78%) of which 86 were suitable for analysis. The questionnaire consisted of the Short Form-36 (SF-36) Health Survey including a self-designed, disease-specific section. Demographic data, tumour size, hearing status and facial nerve function were extracted from our VS database. Patients scored significantly lower in seven of the eight subscales of the SF-36 compared to German normative QOL data. But when compared to a normative group of patients with hearing loss, only two subscales were affected. The alteration of the subscales was correlated with objective and subjective parameters. Vertigo and postoperative hearing status could be identified as the parameters with the strongest influence on QOL. PMID- 24061569 TI - Radiofrequency ablation in advanced head and neck cancer. PMID- 24061570 TI - Assessment of effectiveness of acoustic analysis of voice for monitoring the evolution of vocal nodules after vocal treatment. AB - In the present study, we report the results of acoustic analysis of voice in 97 patients diagnosed with vocal nodules before and after the vocal logopedic treatment, to evaluate its effectiveness in monitoring the evolution. We analyzed five parameters: the mean fundamental frequency (F0) and its standard deviation, jitter, shimmer, and normalized noise energy (NNE). Our results indicate that most patients showed a reduction of fundamental frequency, an increase of perturbation (jitter and shimmer), and an increase of NNE before the treatment. We did not find any statistically significant relationship between previous values of the five parameters analyzed and the clinical course. We did not find significant differences between the two groups (with and without clinical improvement) in the evolution of any of the five parameters, although these differences were greater in the case of jitter. We conclude that the acoustic analysis of voice can be useful as a complementary tool in the diagnosis of vocal nodules, but the parameter values analyzed before treatment did not correlate with the clinical course and we believe that its usefulness in the evaluation of results after the vocal treatment is limited. PMID- 24061571 TI - Degree of myelination (g-ratio) of the human recurrent laryngeal nerve. AB - The g-ratio (estimated by dividing the axon diameter by the myelinated fiber diameter) can be useful to the evaluation of the relationship between nerve conduction velocity and fiber morphology during peripheral nerve regeneration. However, there is little detailed information about the g-ratio of the human recurrent laryngeal nerve (RLN), especially between men and women. The objective of this study was to investigate the g-ratio of the RLN by quantifying histomorphometric data (axon diameter and myelinated fiber diameter) in the RLN of men and women. The RLN was bilaterally studied in human specimens obtained from necropsies (seven men and seven women). The nerves were analyzed using histology, and the morphometric parameters were measured using Image Pro-Plus Software (Image Pro-Plus 6.0; Media Cybernetics, Silver Spring, MD, USA). When compared with the RLN of the women, the parameters of the RLN of the men are significantly larger, as shown by the axon diameter (19.0%) (P = 0.0001), myelinated fiber diameter (7.1%) (P = 0.0497), and g-ratio (12.5%) (P = 0.0005). Our findings demonstrated that there are morphological asymmetries between the g ratio (degree of the myelination) of the masculine and feminine RLN. These morphological findings are probably related to physiological differences. PMID- 24061572 TI - Extended vertical hemilaryngectomy and reconstruction with a neovascularised tracheal autograft for advanced unilateral laryngeal tumours: a learning curve. AB - Extended vertical hemilaryngectomy and reconstruction with a neovascularised tracheal autograft is a two-stage procedure for advanced unilateral tumours of the larynx. The purpose of this study was to review our early experience of this technique by reporting our clinical outcomes and highlighting some key learning points. Patients were identified from the Liverpool Head and Neck Cancer electronic database. Case notes were reviewed for demographic data, tumour stage, treatment, complications and outcomes. Eleven patients (all males) were identified. The mean age of the cohort was 58.2 years (range 37-78 years). The overall average follow-up period was 41.5 months (range 14 days-75 months). Of the 11 cases, 3 had completed stage 1 only. The most common complications following stage 1 procedure are related to the surgical neck wound (36% of cases). Of the remaining eight patients who completed the first two surgical stages, closure of tracheostomy stoma was possible in seven; all seven subsequently resumed a normal oral diet. All these patients have subsequently remained free of disease at latest follow-up. There were two cases of post operative pneumonia and one case of radial forearm free-flap failure. In contrast, only one case of post-operative pneumonia was recorded following the stage 2 procedure. In total, three patients in this cohort were dead at follow up. This technique has a role in the management of a select group of fit patients presenting with unilateral tumours of the glottis and who are otherwise destined for a total laryngectomy. Whilst the technique is complex, we have shown that its introduction is possible in a suitably specialised and motivated surgical unit. PMID- 24061574 TI - Spectroscopic signatures of the carbon buckyonions C60@C180 and C60@C240: a dispersion-corrected DFT study. AB - We have investigated, using dispersion corrected DFT methods, the structure and the spectroscopic properties of carbon buckyonions C60@C180 and C60@C240. C60, C180 and C240 showed a noticeable variation of their geometries in C60@C180 and C60@C240, upon encapsulation. Inclusion of the dispersion correction term in the calculations has a significant effect on the geometry. C60@C180 has a large positive interaction energy, while for C60@C240 a negative value is found indicating that only C240 can easily accommodate C60. In both cases dispersion interactions strongly contribute to the stabilization of the complexes. Vibrational frequencies, electronic transitions and NMR properties have been computed. The results show that encapsulation leads to appreciable variation in the characteristic resonances thus offering a useful tool for a spectroscopic identification of these species. PMID- 24061573 TI - Inner ear deficits after chronic otitis media. AB - Investigation of the causes of vestibular symptoms in patients with chronic otitis media (COM) faces frustration, mainly because the bithermal caloric test using tap water is generally contraindicated in perforated ears. This study utilized audiometry, ocular vestibular-evoked myogenic potential (oVEMP) test, and cervical VEMP (cVEMP) test to evaluate inner ear deficits after COM. A total of 85 COM patients (117 ears) underwent otoscopy, image study, audiometry, oVEMP test, and cVEMP test. Mean bone-conducted (BC) hearing threshold <=25 dB was observed in 74 ears, 26-40 dB in 30 ears, and >40 dB in 13 ears. Restated, abnormal BC hearing threshold was identified in 43 ears (37 %). Percentages of abnormal cVEMP test, oVEMP test, and BC hearing threshold in 117 COM ears were 65, 62, and 37 %, respectively, exhibiting a significantly declining sequence in inner ear function. Furthermore, cVEMP/oVEMP test results were significantly correlated with BC hearing threshold, whereas no correlation existed between the cVEMP and oVEMP test results. In conclusion, the sequence of inner ear deficits after COM runs from the saccule/utricle to the cochlea and semicircular canals. Restated, in addition to BC hearing test, the cVEMP/oVEMP test may serve as a supplementary tool for early detection of inner ear involvement in COM patients. PMID- 24061575 TI - Estrogen receptor beta activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo. AB - Estrogen receptor (ER)-beta has been shown to possess a tumor suppressive effect, and is a potential target for cancer therapy. Using gene-expression meta-analysis of human malignant pleural mesothelioma, we identified an ESR2 (ERbeta coding gene) signature. High ESR2 expression was strongly associated with low succinate dehydrogenase B (SDHB) (which encodes a mitochondrial respiratory chain complex II subunit) expression. We demonstrate that SDHB loss induced ESR2 expression, and that activated ERbeta, by over-expression or by selective agonist stimulation, negatively affected oxidative phosphorylation compromising mitochondrial complex II and IV activity. This resulted in reduced mitochondrial ATP production, increased glycolysis dependence and impaired cell proliferation. The observed in vitro effects were phenocopied in vivo using a selective ERbeta agonist in a mesothelioma mouse model. On the whole, our data highlight an unforeseen interaction between ERbeta-mediated tumor suppression and energy metabolism that may be exploited to improve on the therapy for clinical management of malignant mesothelioma. PMID- 24061576 TI - Suppression of SCARA5 by Snail1 is essential for EMT-associated cell migration of A549 cells. AB - Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT) might be a key event for cancer progression. The upregulation of Snail1, one of the most extensively studied EMT regulators, has been implicated in cancer metastasis, but the underlying mechanisms remain unclear. This study aims to identify that Snail1 targets regulating EMT-associated cancer cell migration. Human lung carcinoma A549 cells were treated with transforming growth factor beta 1 (TGF-beta1), and EMT-associated phenotypic and functional alterations were monitored. TGF-beta1 induced typical EMT-like morphological changes, 'cadherin switching' and cell migration in A549 cells. TGF-beta1 stimulation induced rapid and persistent upregulation of Snail1. Moreover, Snail1 upregulation was required for EMT-associated cell migration. Several metastasis suppressors with putative Snail1-binding sites in their promoters were dramatically repressed in A549 cells during TGF-beta1-induced EMT. Gain- and loss-of Snail1 function experiments demonstrated that scavenger receptor class A member 5 (SCARA5) was negatively regulated by Snail1. Importantly, SCARA5 downregulation was essential for EMT induced migration in A549 cells. The chromatin immunoprecipitation assay revealed that Snail1 could bind to the E-box elements in SCARA5 promoter, implying that SCARA5 is a direct Snail1 target modulating cancer cell mobility during EMT. In addition, we showed that DNA methyltransferase 1 was physically associated with Snail1 to silence SCARA5 expression with an unidentified DNA methylation independent mechanism, suggesting the complexity of Snail1-mediated epigenetic regulation. Collectively, our data demonstrated that EMT-regulator Snail1 suppresses the expression of SCARA5 to promote cancer progression, highlighting the possibility to target Snail1 and SCARA5 for cancer treatment. PMID- 24061578 TI - Change is good: introducing the 2014 Magnet(r) Application Manual. AB - This month's Magnet Perspectives column discusses the changes to the Magnet Recognition Program's(r) Application Manual. PMID- 24061577 TI - New non-covalent strategies for stable surface treatment of thermoplastic chips. AB - In order to be more extensively used outside of research laboratories, lab-on chip technologies must be mass-produced using low-cost materials such as thermoplastics. Thermoplastics, however, are generally hydrophobic in their native state, which makes them unsuitable for direct use with biological samples in aqueous solution, and thus require surface coating. This coating should be robust, inexpensive and simple to implement, in order not to hinder the industrial advantage of thermoplastic chips. Cyclic Olefin Copolymer (COC) is a particularly appealing polymer, but it is also difficult to functionalize due to its chemical inertness. Here we introduce and compare the performance of two new approaches for COC coating. One relies on the use of a commercial triblock copolymer, Pluronic(r) F127. The second approach uses new copolymers synthesized by radical polymerization, and consisting of a dimethylacrylamide (DMA) backbone carrying aliphatic side chains (C22). Two DMA-C22 copolymers were synthesized with various C22/DMA ratios: DMA-S at 0.175% and DMA-M at 0.35%. Different physicochemical properties of the polymers such as critical micellar concentration (CMC), water contact angle, electroosmosis were investigated. Coated COC chips were then tested for their ability to reduce the adsorption of proteins, microparticles, and for protein electrophoresis. For each application we found an optimal treatment protocol to considerably improve the performance of the thermoplastic chip. These treatments use physisorption in situ which requires no photografting or chemical reaction and can be performed by a simple incubation either after chip production, or just prior to use. PMID- 24061579 TI - Influencing the nursing commitment to workforce satisfaction and the origins of magnet: an interview with Dr Michael Evans by Jeffrey M. Adams. AB - This department highlights nursing leaders who have demonstrated a commitment to patient care leadership. This interview profiles Michael Evans, PhD, RN, FAAN, dean of the Texas Tech University School of Nursing and president of the American Nurses Credentialing Center. PMID- 24061580 TI - Designing tomorrow: creative and effective succession planning. AB - This department column is devoted to posing thought-provoking insights about transitions through, to, and from administrative roles in nursing. In this article, I explore an effective approach to succession planning for the role of director of surgical services, implemented in my role as chief nursing officer for a tertiary, acute care hospital. The plan provided a creative solution to the succession challenge and important lessons learned. PMID- 24061581 TI - Alternative strategies to constant patient observation and sitters: a proactive approach. AB - The evidence is inconclusive as to whether better patient outcomes for behavioral issues in acute care are achieved using constant patient observation. Nurse leaders at a northern California hospital designed and implemented proactive strategies to identify patients at risk for behavioral issues, developed evidence based interventions to reduce the use of sitters and constant observation, and maintained or improved patient safety. PMID- 24061582 TI - Patient satisfaction with nursing care in an urban and suburban emergency department. AB - REVIEW OF LITERATURE: Patient satisfaction is an important outcome measurement in the emergency department (ED). When unavoidable, the negative effect of patient wait time may be lessened by communicating expected wait time, affective support, health information, decisional control, and competent providers. METHODS: This controlled quasi-experimental design used a convenience sample. The patient questionnaire included demographics, expected and perceived wait time, receiving of comfort items, information and engaging activities and their perceived helpfulness for coping with waiting, and the Consumer Emergency Care Satisfaction Scale measure of patient satisfaction with nursing. Systematic offering of comfort items, clinical information, and engaging activities were statistically analyzed for impact on perceived wait times, helpfulness in waiting, and satisfaction with nursing care. RESULTS: Interventions were supported by the data as helpful for coping with waiting and were significantly related to nursing care satisfaction. Interventions were less helpful for suburban patients who were also less satisfied. CONCLUSION: Nurses can influence patient satisfaction in the ED through communication and caring behaviors. PMID- 24061583 TI - Using a shared governance structure to evaluate the implementation of a new model of care: the shared experience of a performance improvement committee. AB - Sustaining change in the behaviors and habits of experienced practicing nurses can be frustrating and daunting, even when changes are based on evidence. Partnering with an active shared governance structure to communicate change and elicit feedback is an established method to foster partnership, equity, accountability, and ownership. Few recent exemplars in the literature link shared governance, change management, and evidence-based practice to transitions in care models. This article describes an innovative staff-driven approach used by nurses in a shared governance performance improvement committee to use evidence-based practice in determining the best methods to evaluate the implementation of a new model of care. PMID- 24061584 TI - Ensuring specialty nurse competence to care for older adults: reflections on a decade of collaboration between specialty nursing associations and the Hartford Institute for Geriatric Nursing. AB - Geriatric preparation of specialty nurses is critical because their direct care and administrative responsibilities profoundly impact the care of countless older patients in all settings. For a decade, the Hartford Institute for Geriatric Nursing, NYU College of Nursing, has worked with 54 national specialty nursing associations, and intensely with 14, to develop strategies for new standards for quality care for older patients. A successful blueprint for specialty associations to sustain and enhance these outcomes will be presented. PMID- 24061585 TI - Registered nurse perceptions after implementation of a nurse residency program. AB - Nurse residency programs (NRPs) are an effective mechanism for transitioning newly licensed registered nurses (NLRNs) to practice. No studies have investigated how experienced nurses view NLRN performance after NRPs. The purpose of this quality initiative was to identify experienced nurses' satisfaction with NLRN proficiency before and after implementation of an NRP using the Nursing Practice Readiness Tool. Findings indicate that experienced nurses are more satisfied with the performance of NLRNs after the new nurse participated in an NRP. PMID- 24061586 TI - Barcode medication administration work-arounds: a systematic review and implications for nurse executives. AB - Safe medication administration is necessary to ensure quality healthcare. Barcode medication administration systems were developed to reduce drug administration errors and the related costs and improve patient safety. Work-arounds created by nurses in the execution of the required processes can lead to unintended consequences, including errors. This article provides a systematic review of the literature associated with barcoded medication administration and work-arounds and suggests interventions that should be adopted by nurse executives to ensure medication safety. PMID- 24061587 TI - Relationship of workplace incivility, stress, and burnout on nurses' turnover intentions and psychological empowerment. AB - This study explored the relationships among perceived workplace incivility, stress, burnout, perceived turnover intentions, and perceived level of psychological empowerment among acute care nurses (medical-surgical and critical care) in community and tertiary hospitals through the lens of complexity science. An exploratory study was conducted, and findings demonstrate significant relationships among workplace incivility, stress, burnout, turnover intentions, total years of nursing experience, and RN education levels. Creating targeted retention strategies and policies that will be sensitive to the needs and interests of nurses at high risk for leaving their organizations is imperative for nurse executives. PMID- 24061588 TI - Right person, right skills, right job: the contribution of objective structured clinical examinations in advancing staff nurse experts. AB - Recruitment processes need to discriminate among candidates to ensure that the right person with the right skills is selected for advancement opportunities. An innovative recruitment process using an objective structured clinical examination grounded in best practice guidelines resulted in improved recruitment practices for senior nursing clinical expert roles. Candidates' skills, knowledge, and attitudes in the areas of patient focus, clinical expertise, teamwork, and leadership were assessed using a clinical simulation. Candidates achieving advancement were assessed at 6 months to validate the efficacy of the process. PMID- 24061589 TI - California's nurse-to-patient ratios, part 2: 8 years later, what do we know about hospital level outcomes? AB - OBJECTIVE: The aim of the study was to identify and describe the impact of California's nurse-to-patient ratios on hospital level outcomes from a comprehensive literature review. BACKGROUND: While implemented in 2004, questions remain about the effects ratios have had on hospitals' financial status and access to care. METHODS: A comprehensive literature review was conducted. RESULTS: Findings suggest labor costs increased, and some reductions in services were made after the implementation of staffing ratios. CONCLUSIONS: Implementing staffing ratios had a negative financial impact on selected outcomes of California hospitals. PMID- 24061590 TI - Endoscopic treatment of benign biliary strictures using covered self-expandable metal stents (CSEMS). AB - BACKGROUND AND AIMS: Traditional endoscopic management of benign biliary strictures (BBS) consists of placement of one or more plastic stents. Emerging data support the use of covered self-expandable metal stents (CSEMS). We sought to assess outcome of endoscopic temporary placement of CSEMS in patients with BBS. METHODS: This was a retrospective study of CSEMS placement for BBS between May 2005 and July 2012 from two tertiary care centers. A total of 145 patients (81 males, median age 59 years) with BBS were identified; 73 of which were classified as extrinsic and were caused by chronic pancreatitis, and 70 were intrinsic. Main outcome measures were resolution of stricture and adverse events (AEs) due to self-expandable metal stents (SEMS)-related therapy. RESULTS: Fully covered and partially covered 8-10 mm diameter SEMS were placed and subsequently removed in 121/125 (97 %) attempts in BBS (failure to remove four partially covered stents). Stricture resolution occurred in 83/125 (66 %) patients after a median stent duration of 26 weeks (median follow-up 90 weeks). Resolution of extrinsic strictures was significantly lower compared to intrinsic strictures (31/65, 48 % vs. 52/60, 87 %, p = 0.004) despite longer median stent duration (30 vs. 20 weeks). Thirty-seven AEs occurred in 25 patients (17 %), with 12 developing multiple AEs including cholangitis (n = 17), pancreatitis (n = 5), proximal stent migration (n = 3), cholecystitis (n = 2), pain requiring SEMS removal and/or hospitalization (n = 3), inability to remove (n = 4), and new stricture formation (n = 3). CONCLUSIONS: Benign biliary strictures can be effectively treated with CSEMS. Successful resolution of biliary strictures due to extrinsic disease is seen significantly less often than those due to intrinsic disease. Removal is successful in all patients with fully covered SEMS. PMID- 24061592 TI - Screening colonoscopy: still the best choice, but for how long? PMID- 24061591 TI - Lysophosphatidic acid stimulates activation of focal adhesion kinase and paxillin and promotes cell motility, via LPA1-3, in human pancreatic cancer. AB - BACKGROUND: Pancreatic cancer is highly metastatic and with poor prognosis. In previous studies, lysophosphatidic acid (LPA) was shown to be a critical component of ascites which promoted the invasion and metastasis of pancreatic cancer. Two focal adhesion proteins, focal adhesion kinase (FAK) and paxillin, were crucially involved in cell migration, cytoskeleton reorganization, and the dynamics of focal adhesion. OBJECTIVES: This study examined the involvement of LPA1-3 in LPA-induced activation of FAK and paxillin, and in cell motility, in pancreatic cancer PANC-1 cells. METHODS: Reverse transcriptase polymerase chain reaction analysis was used to examine mRNA expression of LPA receptors in PANC-1. Cellular protein expression of FAK and paxillin was analyzed by western blotting. The subcellular location of FAK and paxillin was visualized by immunofluorescence. Cell migration was measured by use of a transwell migration chamber. RESULTS: Three LPA receptors (LPA1, LPA2, and LPA3) were significantly expressed in PANC-1 cells. Treatment with LPA induced both time and dose dependent tyrosine phosphorylation of FAK and paxillin. LPA also affected translocation of FAK and paxillin from cytoplasm to focal adhesions at the cell periphery and enhanced cell motility of PANC-1. Pretreatment with 3-(4-(4-((1-(2 chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5 isoxazolyl)benzylsulfanyl)propanoic acid (Ki16425), an antagonist of LPA1 and LPA3, before LPA attenuated the LPA-induced tyrosine phosphorylation and redistribution of FAK and paxillin and abrogated LPA-induced cellular migration activity. CONCLUSIONS: These results suggest LPA induces activation of FAK and paxillin via LPA1-3, which may contribute to the increased cell motility in human pancreatic cancer PANC-1 cells. Thus, an understanding of the regulation by LPA of cell motility in pancreatic cancer could identify novel targets for therapy. PMID- 24061593 TI - Changing patterns of mortality in 25 European countries and their economic and political correlates, 1955-1989. AB - OBJECTIVES: We investigated trends in mortality in European countries by cause of death in the period 1955-1989, and studied the role of economic and political conditions. METHODS: We extracted data on age-standardised mortality by country (n = 25), sex, cause of death (n = 17) and calendar year from an internationally harmonised dataset. We analysed changes in dispersion of mortality as well as changes in the association of mortality with average income and levels of democracy. RESULTS: After 1960, dispersion in all-cause mortality in Europe as a whole increased due to diverging trends for many specific causes of death, particularly for cerebrovascular disease. This coincided with widening disparities in average income, and strengthening of the association between levels of democracy and mortality. Divergence in Central and Eastern Europe could largely be explained from stagnating trends in average income and an increasing mortality disadvantage related to its democratic deficit. CONCLUSIONS: Although this was a politically stable period, mortality patterns were highly dynamic, and prefigured the more dramatic mortality trends after 1990. Economic and political stagnation probably explains the diverging trends in Central and Eastern Europe. PMID- 24061595 TI - Accessing 4f-states in single-molecule spintronics. AB - Magnetic molecules are potential functional units for molecular and supramolecular spintronic devices. However, their magnetic and electronic properties depend critically on their interaction with metallic electrodes. Charge transfer and hybridization modify the electronic structure and thereby influence or even quench the molecular magnetic moment. Yet, detection and manipulation of the molecular spin state by means of charge transport, that is, spintronic functionality, mandates a certain level of hybridization of the magnetic orbitals with electrode states. Here we show how a judicious choice of the molecular spin centres determines these critical molecule-electrode contact characteristics. In contrast to late lanthanide analogues, the 4f-orbitals of single bis(phthalocyaninato)-neodymium(III) molecules adsorbed on Cu(100) can be directly accessed by scanning tunnelling microscopy. Hence, they contribute to charge transport, whereas their magnetic moment is sustained as evident from comparing spectroscopic data with ab initio calculations. Our results showcase how tailoring molecular orbitals can yield all-electrically controlled spintronic device concepts. PMID- 24061594 TI - Cannabis and traffic collision risk: findings from a case-crossover study of injured drivers presenting to emergency departments. AB - OBJECTIVES: This study examined whether acute cannabis use leads to an increased collision risk. METHODS: Participants were 860 drivers presenting to emergency departments in Toronto and Halifax, Canada, with an injury from a traffic collision, between April 2009 and July 2011. Cannabis and other drug use were identified either through blood sample or self-report. A case-crossover design was employed with two control conditions: a fixed condition measuring substance use during last time driving, and whether the driver typically uses cannabis prior to driving. Collision risk was assessed through conditional fixed-effects logistic regression models. RESULTS: Results revealed that 98 (11 %; 95 % CI: 9.0 13.1) drivers reported using cannabis prior to the collision. Regression results measuring exposure with blood and self-report data indicated that cannabis use alone was associated with a fourfold increased (OR 4.11; 95 % CI: 1.98-8.52) odds of a collision; a regression relying on self-report measures only found no significant association. CONCLUSIONS: Main findings confirmed that cannabis use increases collision risk and reinforces existing policy and educational efforts, in many high-income countries, aimed at reducing driving under the influence of cannabis. PMID- 24061596 TI - Placebo response and the company it keeps. PMID- 24061597 TI - Neonatal exposure to sevoflurane in mice causes deficits in maternal behavior later in adulthood. AB - BACKGROUND: In animal models, exposure to general anesthetics induces widespread increases in neuronal apoptosis in the developing brain. Subsequently, abnormalities in brain functioning are found in adulthood, long after the anesthetic exposure. These abnormalities include not only reduced learning abilities but also impaired social behaviors, suggesting pervasive deficits in brain functioning. But the underlying features of these deficits are still largely unknown. METHODS: Six-day-old C57BL/6 female mice were exposed to 3% sevoflurane for 6 h with or without hydrogen (1.3%) as part of the carrier gas mixture. At 7-9 weeks of age, they were mated with healthy males. The first day after parturition, the maternal behaviors of dams were evaluated. The survival rate of newborn pups was recorded for 6 days after birth. RESULTS: Female mice that received neonatal exposure to sevoflurane could mate normally and deliver healthy pups similar to controls. But these dams often left the pups scattered in the cage and nurtured them very little, so that about half of the pups died within a couple of days. Yet, these dams did not show any deficits in olfactory or exploratory behaviors. Notably, pups born to sevoflurane-treated dams were successfully fostered when nursed by control dams. Mice coadministered of hydrogen gas with sevoflurane did not exhibit the deficits of maternal behaviors. CONCLUSION: In an animal model, sevoflurane exposure in the developing brain caused serious impairment of maternal behaviors when fostering their pups, suggesting pervasive impairment of brain functions including innate behavior essential to species survival. PMID- 24061598 TI - Systemic thrombus formation in cardiac arrest: manifestation of cardiac arrest related hypercoagulability visualized by transesophageal echocardiography. PMID- 24061599 TI - Altered states: psychedelics and anesthetics. AB - The psychedelic experience has been reported since antiquity, but there is relatively little known about the underlying neural mechanisms. A recent neuroimaging study on psilocybin revealed a pattern of decreased cerebral blood flow and functional disconnections that is surprisingly similar to that caused by various anesthetics. In this article, the authors review historical examples of psychedelic experiences induced by general anesthetics and then contrast the mechanisms by which these two drug classes generate altered states of consciousness. PMID- 24061600 TI - A donor-acceptor cyclopropene as a dipole source for a silver(I) catalyzed asymmetric catalytic [3+3]-cycloaddition with nitrones. AB - Silver(I)-catalyzed asymmetric formal [3+3]-cycloaddition of nitrones with a donor-acceptor cyclopropene, formed in situ from dirhodium acetate-catalyzed dinitrogen extrusion/intramolecular cyclization of enoldiazoacetates, effectively generates 3,6-dihydro-1,2-oxazine derivatives in high yield and with exceptional stereocontrol. PMID- 24061601 TI - Vascular endothelial growth factor polymorphisms and clinical outcome in patients with metastatic breast cancer treated with weekly docetaxel. AB - The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a phase II trial. This study evaluated weekly docetaxel, as first-line treatment for metastatic breast cancer. Existing data from in vitro and animal model experiments suggest that docetaxel at low doses has anti-angiogenic activity. DNA was extracted from blood samples of 86 patients participating in the trial. Genotyping was performed for selected single-nucleotide polymorphisms (SNPs; VEGF-2578, -1498, -1154, and +936). Moreover, due to the highly polymorphic nature of the studied areas, we were able to analyze additional registered SNPs. All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (42.9% vs 0.0%, P=0.048). Moreover, the VEGF-2578 AA genotype was associated with longer PFS compared with CC (hazard ratio (HR)=0.40; 95% confidence interval (CI) 0.17-0.98; pairwise P=0.0457). Patients with the VEGF-1190 GG genotype demonstrated shorter PFS compared with those with the alternative genotypes (GA and AA) combined (HR=3.85; 95% CI: 1.20-12.50; P=0.0224). In addition, the VEGF-2551/-2534 homozygous del18bp and VEGF-2430/-2425 homozygous ins1bp genotypes were associated with worse PFS compared with no deletion and no insertion, respectively (HR=2.49; 95% CI: 1.02-6.07; pairwise P=0.0442 and HR=2.57; 95% CI: 1.05-6.27; pairwise P=0.0385, respectively). Furthermore, patients with the VEGF-1498 CC genotype exhibited longer median OS compared with those with the alternatives genotypes (CT and TT) combined (HR=0.27; 95% CI: 0.08-0.89; P=0.0311). In multivariate analysis, the VEGF-2578 AA genotype retained its significance (P=0.0220) for PFS. Our results support the association of specific VEGF genotypes with clinical outcome in patients with metastatic breast cancer treated with a potentially anti angiogenic regimen, such as weekly docetaxel. However, current results should be validated prospectively in larger cohorts. PMID- 24061602 TI - Flexure-based device for cyclic strain-mediated osteogenic differentiation. AB - Application of low-magnitude strains to cells on small-thickness scaffolds, such as those for rodent calvarial defect models, is problematic, because general translation systems have limitations in terms of generating low-magnitude smooth signals. To overcome this limitation, we developed a cyclic strain generator using a customized, flexure-based, translational nanoactuator that enabled generation of low-magnitude smooth strains at the subnano- to micrometer scale to cells on small-thickness scaffolds. The cyclic strain generator we developed showed predictable operational characteristics by generating a sinusoidal signal of a few micrometers (4.5 MUm) without any distortion. Three-dimensional scaffolds fitting the critical-size rat calvarial defect model were fabricated using poly(caprolactone), poly(lactic-co-glycolic acid), and tricalcium phosphate. Stimulation of human adipose-derived stem cells (ASCs) on these fabricated scaffolds using the cyclic strain generator we developed resulted in upregulated osteogenic marker expression compared to the nonstimulated group. These preliminary in vitro results suggest that the cyclic strain generator successfully provided mechanical stimulation to cells on small-thickness scaffolds, which influenced the osteogenic differentiation of ASCs. PMID- 24061603 TI - Computational modeling of non-Newtonian blood flow through stenosed arteries in the presence of magnetic field. AB - Steady flow simulations of blood flow in an axisymmetric stenosed artery, subjected to a static magnetic field, are performed to investigate the influence of artery size, magnetic field strength, and non-Newtonian behavior on artery wall shear stress and pressure drop in the stenosed section. It is found that wall shear stress and pressure drop increase by decreasing artery size, assuming non-Newtonian fluid, and increasing magnetic field strength. In the computations, the shear thinning behavior of blood is accounted for by the Carreau-Yasuda model. Computational results are compared and found to be inline with available experimental data. PMID- 24061604 TI - Effect of fluoride gels supplemented with sodium trimetaphosphate in reducing demineralization. AB - OBJECTIVES: The objective of this study was to evaluate the in vitro effect of low-fluoride (F) gels supplemented with sodium trimetaphosphate (TMP) on enamel demineralization. MATERIALS AND METHODS: Bovine enamel blocks (n = 160) were selected based on surface hardness (SH) and divided into eight treatment groups (n = 20 per group): no F or TMP (placebo), 3 % TMP (3 %TMP), 5 % TMP (5 %TMP), 4,500 MUg F/g (4,500), 4,500 MUg F/g + 3 % TMP (4,500 3 %TMP), 4,500 MUg F/g + 5 % TMP (4,500 5 %TMP), 9,000 MUg F/g (9,000), and 12,300 MUg F/g (acid gel). Blocks were subjected to demineralization/remineralization cycling for 5 days. Subsequently, surface hardness (SH1) and integrated loss of subsurface hardness (DeltaKHN) were assessed, and the concentrations of loosely bound (CaF2-like) and firmly bound (FA-like) formed and retained F were determined. RESULTS: The 4,500 5 %TMP and acid gel groups showed similar results and had the lowest mineral loss (SH1 and ?KHN). The acid gel group had the highest concentration of CaF2-like F, but the formation and retention of FA-like F was greater in the 4,500 5 %TMP group than in the acid gel group (p < 0.05). CONCLUSION: It is possible to inhibit enamel demineralization with low-F gels supplementing these gels with 5 % TMP. CLINICAL RELEVANCE: The low-F gel containing TMP can be regarded as a safer alternative for clinical use from a toxicological point of view since it contains half of the amount of a conventional formulation while promoting similar anticaries effect. PMID- 24061605 TI - Effect of a sugar-free pediatric antibiotic on primary tooth enamel hardness when exposed to different sucrose exposure conditions in situ. AB - OBJECTIVES: This in situ study aimed to investigate the effect of a sugar-free antibiotic suspension containing amoxicillin and clavulanic acid on enamel hardness of human primary teeth simulating different conditions of cariogenic challenge. MATERIALS AND METHODS: A crossover, partially double-blind study was conducted in three phases of 14 days each, during which 11 volunteers wore palatal devices containing six dental enamel blocks covered with plastic meshes to allow biofilm formation. Dental blocks were extraorally submitted to treatment with a 20 % sucrose solution at three different daily frequencies of exposure (0, 3, and 8 times/day), and to the antibiotic suspension or its excipients at an 8-h time interval application regimen. On the 14th day of each phase, the blocks were removed for enamel analysis (surface and cross-sectional microhardness--SMH and CSMH). RESULTS: The antibiotic suspension showed significant higher SMH and CSMH values than the excipients (p < 0.05; Wilcoxon), regardless of the frequency of sucrose exposure. Sucrose exposure did not account for further enamel demineralization both for antibiotic and excipients (p > 0.05; Friedman). CONCLUSIONS: A protective effect of the antibiotic suspension on enamel demineralization was verified because its excipients alone promoted more pronounced surface and subsurface enamel demineralization, even in the absence of sucrose exposure. CLINICAL RELEVANCE: The use of a sugar-free amoxicillin/clavulanic acid suspension may promote a protective effect on primary enamel demineralization probably due to its topical effect on dental biofilm. PMID- 24061606 TI - Oral health behaviors and metabolic syndrome: the 2008-2010 Korean National Health and Nutrition Examination Survey. AB - OBJECTIVES: This study examined whether oral health behaviors are associated with metabolic syndrome (MetS) in Korean adults involved in the 2008-2010 Korea National Health and Nutrition Examination Survey (KNHANES). MATERIALS AND METHODS: A total of 18,742 subjects (8,034 men and 10,708 women) were included. MetS was defined according to the criteria of the American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement for Asians. Oral health behavior was assessed using a questionnaire included in the KNHANES. RESULTS: Subjects with MetS brushed their teeth less frequently and used fewer secondary oral products than subjects without MetS (p < 0.01). As frequency of toothbrushing and number of secondary oral products increased, body mass index, waist circumference, diastolic blood pressure, fasting plasma glucose, triglyceride, and white blood cell count decreased, but high-density lipoprotein cholesterol increased (all p for trend <0.01). In the multivariable logistic regression models, as frequency of toothbrushing increased, the odds ratios (ORs) for MetS, abdominal obesity, and hyperglycemia are more than one after adjusting for age, gender, education, income, alcohol and tobacco use, physical activity, and the components of MetS. The ORs for MetS, abdominal obesity, and high blood pressure were more than one in subjects who do not use dental floss after adjusting for all covariates. CONCLUSION: MetS is associated with infrequent daily toothbrushing and disuse of dental floss in South Korean. CLINICAL RELEVANCE: Dentists may recommend evaluation for MetS in the patients with infrequent daily toothbrushing and disuse of dental floss. PMID- 24061607 TI - Common and disease-specific dysfunctions of brain systems underlying attentional and executive control in schizophrenia and bipolar disorder. AB - Schizophrenia and bipolar disorder broadly overlap in multiple areas involving clinical phenomenology, genetics, and neurobiology. Still, the investigation into specific elementary (sub-)processes of executive functioning may help to define clear points of distinction between these categorical diagnoses to validate the nosological dichotomy and, indirectly, to further elucidate their pathophysiological underpinnings. In the present behavioral study, we sought to separate common from diagnosis-specific deficits in a series of specific elementary sub-functions of executive processing in patients with schizophrenia and bipolar disorder. For our purpose, we administered a modern and multi-purpose neuropsychological task paradigm to equal-sized and matched groups of schizophrenia patients, patients with bipolar disorder, and healthy control subjects. First, schizophrenia patients compared to the bipolar group exhibited a more pronounced deficit in general measures of task performance comprising both response speed and accuracy. Additionally, bipolar patients showed increased advance task preparation, i.e., were better able to compensate for response speed deficits when longer preparation intervals were provided. Set-shifting, on the other hand, was impaired to a similar degree in both patient groups. Finally, schizophrenia patients exhibited a specific deficit in conflict processing (inhibitory control) and the shielding of task-relevant processing from distraction (i.e., attentional maintenance). The present investigation suggests that specific neuropsychological measures of elementary executive functions may represent important points of dissociation between schizophrenia and bipolar disorder, which may help to differentiate the pathophysiological underpinnings of these major psychiatric disorders. In this context, the present findings highlight the measures of inhibitory control and attentional maintenance as promising candidates. PMID- 24061608 TI - Modulating neural plasticity with non-invasive brain stimulation in schizophrenia. AB - Schizophrenia is a severe mental disorder characterised by a complex phenotype including positive, negative, affective and cognitive symptoms. Various theories have been developed to integrate the clinical phenotype into a strong neurobiological framework. One theory describes schizophrenia as a disorder of impaired neural plasticity. Recently, non-invasive brain stimulation techniques have garnered much attention to their ability to modulate plasticity and treat schizophrenia. The aim of this review is to introduce the basic physiological principles of conventional non-invasive brain stimulation techniques and to review the available evidence for schizophrenia. Despite promising evidence for efficacy in a large number of clinical trials, we continue to have a rudimentary understanding of the underlying neurobiology. Additional investigation is required to improve the response rates to non-invasive brain stimulation, to reduce the interindividual variability and to improve the understanding of non invasive brain stimulation in schizophrenia. PMID- 24061609 TI - Cylinders or walls? A new computational model to estimate the MR transverse relaxation rate dependence on trabecular bone architecture. AB - OBJECTIVE: Bone density is distributed in a complex network of interconnecting trabecular plates and rods that are interspersed with bone marrow. A computational model to assess the dependence of the relaxation rate on the geometry of bone can consider the distribution of bone material in the form of two components: cylinders and open walls (walls with gaps). We investigate whether the experimentally known dependence of the transverse relaxation rate on the trabecular bone structure can be usefully interpreted in terms of these two components. MATERIALS AND METHODS: We established a computer model based on an elementary computational cell. The model includes a variable number of open walls and infinitely long cylinders as well as multiple geometric parameters. The transverse relaxation rate is computed as a function of these parameters. Within the model, increasing the trabecular spacing with a fixed trabecular radius is equivalent to thinning the trabeculae while maintaining constant spacing. RESULTS: Increasing the number of cylinder and wall gap elements beyond their nearest neighbors does not change the transverse relaxation rate. Although the absolute contribution to the relaxation due to open walls is on average more important than that due to cylinders, the latter drops off rapidly. The change on transverse relaxation rate is larger for changing cylinder geometry than for changing wall geometry, as it can be seen from the effect on the relaxation rate when trabecular spacing is varied, compared to varying the size of wall gaps. CONCLUSION: Our results provide strong evidence that trabecular thinning, which is associated with increasing age, decreases the relaxation rates. The effect of thinning plates and rods on the transverse relaxation can be understood in terms of simple cylinders and open walls. A reduction in the relaxation rate can be seen as an indication of thinning cylinders, corresponding to reduced bone stability and ultimately, osteoporosis. PMID- 24061613 TI - Rotational motion of a single water molecule in a buckyball. AB - Encapsulation of a single water molecule in a buckyball (C60) can provide fundamental insights into the properties of water. Investigation of a single water molecule is feasible through its solitary confinement in C60. In this paper, we performed a detailed study of the properties and dynamics of a single water molecule in a buckyball using DFT and MD simulations. We report on the enhancement of rotational diffusion and entropy of a water molecule in C60, compared to a bulk water molecule. H2O@C60 has zero translational diffusion and terahertz revolution frequency. The harmonic, high amplitude rotation of a single water molecule in C60 is compared to stochastic behavior of bulk water molecules. The combination of large rotational and negligible translational motion of water in C60 creates new opportunities in nanotechnology applications. PMID- 24061611 TI - Acoustic noise reduction in pseudo-continuous arterial spin labeling (pCASL). AB - OBJECT: While pseudo-continuous arterial spin labeling (pCASL) is a promising imaging technique to visualize cerebral blood flow, it is also (acoustically) very loud during labeling. In this paper, we reduced the labeling loudness on our scanner by increasing the interval between the RF pulses from the literature standard of 1.0 ms. We also propose recommendations to reduce the loudness on scanners of the same type at other sites. MATERIALS AND METHODS: First, the sound pressure level (SPL) was both simulated and measured as a function of the labeling interval (1.0-1.8 ms) and longitudinal position in the scanner (-10 to +10 cm, relative to isocenter). Subsequently, we selected the labeling interval with the lowest overall SPL for the "SPL-optimized" pCASL sequence. Nine volunteers were scanned to compare raw signal intensity, temporal signal-to-noise ratio (tSNR) and labeling efficiency between the SPL-optimized and the standard PCASL sequence. RESULTS: Sound pressure level measurements on our scanner showed that loudness was reduced by 6.5 dB at the approximate location of the ear by adjusting the labeling interval to 1.4 ms. Furthermore, image quality was not affected, since no significant differences in signal intensity, tSNR and labeling efficiency were observed. CONCLUSION: By increasing the pCASL labeling interval, acoustic noise in the pCASL sequence was reduced with 6.5 dB, while image quality was preserved. PMID- 24061612 TI - Purely phase-encoded MRI of turbulent flow through a dysfunctional bileaflet mechanical heart valve. AB - OBJECT: We have used a purely phase-encoded magnetic resonance imaging (MRI) technique, single-point ramped imaging with T1 enhancement (SPRITE), to investigate the steady, turbulent flow dynamics through a bileaflet mechanical heart valve (BMHV). MATERIALS AND METHODS: We have measured in vitro the turbulent diffusivity and velocity downstream of the valve in two configurations (fully opened and partially opened), which mimic normal and dysfunctional operation. Our constant-time implementation of the MRI measurement is unusually robust to fast turbulent flows, and to artefacts caused by the pyrolytic carbon construction of the valve. RESULTS: Turbulent diffusivity downstream of the normally functioning valve peaks at 1.05 * 10(-6)m(2)/s, while the turbulent diffusivity is higher downstream of the dysfunctional valve (peaking at 3.15 * 10(-6) m(2)/s) and is accompanied by a high-velocity fluid jet and re-circulating flow. The fluid jet is not along the centreline of the valve, as might be anticipated in conventional Doppler echocardiography measurements. CONCLUSION: The nature of motion-sensitized SPRITE makes it unusually capable in turbulent flows and near to boundaries between different magnetic susceptibilities. These qualities have allowed us to compare the three-dimensional flow fields through normal and dysfunctional BMHVs. PMID- 24061614 TI - Diagnosis of gestational diabetes mellitus: it is time for international consensus. PMID- 24061616 TI - Addition of a phosphine ligand switches an N-heterocyclic carbene-zirconium catalyst from oligomerization to polymerization of 1-hexene. AB - A catalyst for the oligomerization of 1-hexene, generated by the activation of a benzimidazolylidene zirconium dibenzyl complex, switches to a polymerization catalyst on addition of a trialkylphosphine. PMID- 24061615 TI - Digital droplet PCR for rapid quantification of donor DNA in the circulation of transplant recipients as a potential universal biomarker of graft injury. AB - BACKGROUND: Cell-free DNA (cfDNA) from grafts in the circulation of transplant recipients is a potential biomarker of rejection. Its usefulness was investigated after heart transplantation during the maintenance phase by use of microarrays and massive parallel sequencing of donor and recipient DNA. Disadvantages of these methods are high costs, long turnaround times, and need for donor DNA. Therefore, we sought to develop a rapid and cost-effective method using digital droplet PCR (ddPCR). METHODS: Plasma samples were collected from stable recipients after liver (LTx, n = 10), kidney (KTx, n = 9), and heart (HTx, n = 8) transplantation as well as from 7 additional patients directly after LTx. Known single-nucleotide polymorphisms were selected for high minor allelic frequencies, of which 41 hydrolysis probe assays were established. Plasma cfDNA was preamplified, followed by conventional real-time PCR to define informative (heterologous) SNPs, which were then used for quantification (percentage) of graft-derived cfDNA (GcfDNA) using ddPCR. RESULTS: Mean recovery was 94% (SD, 13%) with an imprecision of 4%-14% with the use of controls with 2% minor allele. GcfDNA in stable patients was <6.8% (LTx), <2.5% (KTx), and <3.4% (HTx). On the day of LTx, GcfDNA was approximately 90% and by day 10 it was <15% in complication-free LTx recipients. In 2 patients with biopsy-proven rejection, GcfDNA increased to >60%, whereas in 1 patient with cholestasis no increase was found. CONCLUSIONS: A novel, cost-effective, rapid technique was developed to quantify GcfDNA in transplant recipients. This technique embodies a promising, potentially universal biomarker for early detection of rejection, which could enable more effective therapeutic interventions. PMID- 24061618 TI - Preface to guidelines: laparoscopic treatment of ventral and incisional hernias by the International Endohernia Society (IEHS). PMID- 24061617 TI - Decreased expression of interleukin-36alpha correlates with poor prognosis in hepatocellular carcinoma. AB - Interleukin-36alpha (IL-36alpha) has been found to have a prominent role in the pathogenesis of inflammatory disorders; however, little is known about the role of IL-36alpha in cancer. In this study, we investigated the expression, prognostic value, and the underlying antitumor mechanism of IL-36alpha in hepatocellular carcinoma (HCC). From immunohistochemistry analysis, IL-36alpha expression was lower in poorly differentiated HCC cells. In clinicopathological analysis, low IL-36alpha expression significantly correlated with tumor size, histological differentiation, tumor stage, and vascular invasion, and low intratumoral IL-36alpha expression had significantly worse overall survival rates and shorter disease-free survival rates. Moreover, intratumoral IL-36alpha expression was an independent risk factor for overall survival. Consecutive sections were used to detect CD3+, CD8+, and CD4+ tumor-infiltrating lymphocytes (TILs), and we found that high-IL-36alpha-expressing tumor tissues exhibited a significantly higher proportion of intratumoral CD3+ and CD8+ TILs, but not CD4+ TILs. Our in vitro model confirmed that supernatant from IL-36alpha overexpressing human HCC cells had an increased capacity to recruit CD3+ and CD8+ T cells. Consistently, mouse HCC cells engineered to overexpress IL-36alpha demonstrated markedly delayed growth in vivo, as well as higher levels of intratumoral CD3+ and CD8+ TILs, compared with control mice. In vitro chemotaxis analysis also showed that mouse HCC cells overexpressing IL-36alpha could recruit more number of CD3+ and CD8+ T cells. These results show that IL-36alpha expression may play a pivotal role in determining the prognosis of patients with HCC, which we attribute to the activation of adaptive T cell immunity, especially CD8+ T cell immune response. PMID- 24061619 TI - Location and number of sutures placed for hiatal hernia repair during laparoscopic adjustable gastric banding: does it matter? AB - BACKGROUND: It has been demonstrated that hiatal hernia repair (HHR) during laparoscopic adjustable gastric banding (LAGB) decreases the rate of reoperation. However, the technical aspects (location and number of sutures) are not standardized. It is unknown whether such technical details are associated with differing rates of reoperation for band-related problems. METHODS: A retrospective analysis was performed from a single institution, including 2,301 patients undergoing LAGB with HHR from July 1, 2007 to December 31, 2011. Independent variables were number and location of sutures. Data collected included demographics, operating room (OR) time, length of stay (LOS), follow-up time, postoperative BMI/%EWL, and rates of readmission/reoperation. Statistical analyses included ANOVA and Chi squared tests. Kaplan-Meier, log-rank, and Cox regression tests were used for follow-up data and reoperation rates, in order to account for differential length of follow-up and confounding variables. RESULTS: There was no difference in length of follow-up among all groups. The majority of patients had one suture (range 1-6; 55 %). Patients with fewer sutures had shorter OR time (1 suture 45 min vs. 4+ sutures 56 min, p < 0.0001). LOS, 30-day readmission, band-related reoperation, and postop BMI/%EWL were not statistically significant. Anterior suture placement (vs. posterior vs. both) was most common (61 %). OR time was shorter in those with anterior suture (41 min vs. posterior 56 min vs. both 59 min, p < 0.0001). Patients with posterior suture had a longer LOS (84 % 1 day vs. anterior 74 % 1 day vs. both 74 % 1 day, p < 0.0001). There was no difference in 30-day readmission, band-related reoperation, and postoperative BMI/%EWL. CONCLUSIONS: Patients with fewer or anterior sutures have shorter OR times. However, 30-day readmission, band-related reoperation, and postoperative weight loss were unaffected by number or location of suture. The technical aspects of HHR did not appear to be associated with readmission or reoperation, and therefore a standardized approach may not be necessary. PMID- 24061620 TI - A novel liver retractor for reduced or single-port laparoscopic surgery. AB - BACKGROUND: Retraction of either lobe of liver is required for surgical access to the respective organ. A novel liver retractor device and technique is described, which applies a vacuum between the liver and diaphragm to lift the liver, and which does not require additional incisions. METHODS: A novel liver retractor was tested in two anesthetized sheep at incrementally higher levels of suction from 100 to -700 mmHg (-13 to -93 kPa), and any signs of trauma were recorded. The animals recovered for 5 days, then were humanely killed and postmortem examination of the liver and diaphragms performed. RESULTS: Successful liver retraction was achieved from -200 to -600 mmHg (-27 to -80 kPa) suction. An imprint of the retractor was observed on the liver surface, but there was no breach of the liver serosa. Negligible ecchymoses were observed on the corresponding surface of the diaphragms. Both sheep recovered well after surgery. There was no macroscopic evidence of injury to the liver and diaphragm 5 days postoperatively. Histological examination revealed normal liver parenchyma deep to the site where the devices had been placed, and hemorrhagic changes within the serosa only varied between a few microns to a maximum of 1.4-mm depth. CONCLUSIONS: The novel liver retractor described achieved an effective liver retraction without trauma. It has potential application in reduced or single-port laparoscopic upper abdominal surgery. PMID- 24061621 TI - Single-port laparoscopy and extraperitoneal para-aortic lymphadenectomy for locally advanced cervical cancer: assessment after 52 consecutive patients. AB - BACKGROUND: To report the feasibility and reproducibility of single-port extraperitoneal para-aortic (PA) lymphadenectomy exclusively using conventional instruments in locally advanced cervical cancer (LACC) and to evaluate the learning curve. METHODS: From January 2011 to January 2013, 52 a total of consecutive patients with LACC were candidates for extraperitoneal PA lymphadenectomy via an original single-port approach that we developed. All patients underwent positron emission tomography-computed tomography that indicated no PA uptake. RESULTS: Fifty consecutive patients underwent single-port staging surgery. Two patients had peritoneal carcinomatosis and were not submitted to PA lymphadenectomy. Median age and body mass index were, respectively 47 (range 27-68) years and 23 (range 16-37) kg/m(2). In one case, lymphadenectomy was unfeasible because of renal vessel anomalies (a bifurcated left renal vein crossed the aorta at the level of the inferior mesenteric artery), and two nodes were removed. Conventional instruments were used in all cases. The median operative time was 180 (range 110-270) min. The median and mean number of nodes removed were, respectively, 18 (range 2-47) and 19.4. Six (12 %) patients had metastatic PA disease. No conversion to laparotomy or conventional multiport laparoscopy was required. The median postoperative hospital stay and the interval between staging surgery and the beginning of chemoradiation were, respectively, 2 (range 1-26) days and 16.5 (range 1-60) days. The learning curve was evaluated at seven procedures with a decreased median operative time at 160 (range 110-240) min. CONCLUSIONS: Extraperitoneal staging via a single-port left iliac approach is feasible with conventional tools, is reproducible and safe, and offers a high degree of cosmetic satisfaction. PMID- 24061622 TI - Safety and efficacy of a new procedure for treating traumatic iliopsoas hematoma: a retroperitoneoscopic approach. AB - BACKGROUND: Surgical treatment is often recommended for traumatic iliopsoas hematoma. Open surgeries lead to severe surgical trauma, and minimally invasive surgeries cannot completely remove the hematoma. A new treatment protocol for traumatic iliopsoas hematoma by retroperitoneoscopic approach has been introduced. The goal of this study was to determine the safety and efficacy of retroperitoneoscopic approach used to remove iliopsoas hematoma. METHODS: Between January 2009 and July 2012, 13 patients were diagnosed of traumatic iliopsoas hematoma. Retroperitoneoscopic surgeries were performed on all patients to remove the hematomas after admission. The size of hematoma, VASA score and neurologic status were dynamic evaluated before and after surgery. Soft tissue damage and complications caused by retroperitoneoscopic approach also were recorded and evaluated. RESULTS: We performed retroperitoneoscopic surgery to remove traumatic iliopsoas hematoma successfully on 13 patients without complications. The mean procedure time was 52.5 +/- 13.4 min, and mean blood loss was 30.7 +/- 9.2 ml. Hematoma was completely removed confirmed by ultrasound after surgery. Pain in the affected lower abdominal and thigh immediately was relieved totally for ten patients and partly for three patients after surgery. Quadriceps strength was restored to grade 5 and pain completely disappeared 2 months postoperatively on all patients. Numbness along the femoral nerve distribution disappeared for 11 patients and improved for 2 patients until the last follow-up. None of 13 patients suffered from infection or a new hematoma during follow-up. CONCLUSIONS: Retroperitoneoscopic approach is a safe and effective procedure alternative to conventional surgical approach for treating traumatic iliopsoas hematoma in terms of complete removal of hematoma, minimal invasiveness, absence of radiation, and rapid recovery. PMID- 24061623 TI - Transanal single-port microsurgery for rectal tumors: minimal invasive surgery under spinal anesthesia. AB - BACKGROUND: Transanal minimally invasive surgery (TAMIS) for rectal tumors has been introduced as an alternative approach to transanal endoscopic microsurgery (TEM). TEM has some limitations, such as the need for special equipment, expensive cost, and steep learning curve. In this study, we address the technical feasibility of TAMIS under spinal anesthesia and its short-term postoperative outcomes. METHODS: From July 2011 to September 2012, 25 consecutive patients with middle or upper third rectal masses underwent TAMIS. Tumors were located 6-17 cm from the anal verge. After spinal anesthesia, a single-incision laparoscopic surgery port was inserted into the anal canal. With this access, conventional laparoscopic instruments, including a grasper and monopolar electrocautery and suction device, were used to perform the transanal excision. A hook-type monopolar electrocautery or harmonic scalpel was used for dissection. The defect of the rectum was closed by interrupted sutures. Data concerning demographics, details of operative procedure, postoperative pain, and pathologic results were collected prospectively. To evaluate anal sphincter injury, an endoanal ultrasonography and fecal incontinence severity index survey were performed at 3 6 months after the operation. RESULTS: Of the 25 patients, nine had adenocarcinomas, nine had neuroendocrine tumors, three had tubular adenomas with high-grade dysplasia, three had tubular adenomas, one had a tubulovillous adenoma, and one had a gastrointestinal stromal tumor. The median distance from the tumor mass to the anal verge was 9.0 (range 6-17) cm. The median operative time was 45.0 (range 20-120) min. All patients received TAMIS without conversion to laparoscopic resection. There were no intraoperative complications or postoperative morbidity. The median postoperative hospital stay was 3.0 (range 2 7) days. No sphincter injury was detected by endoanal ultrasonography. CONCLUSIONS: TAMIS under spinal anesthesia is a safe and feasible technique for resection of middle and upper rectal masses. Spinal anesthesia is adequate for this procedure. PMID- 24061624 TI - Risk-reducing laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for low-grade appendiceal mucinous neoplasm: early outcomes and technique. AB - BACKGROUND: Low-grade appendiceal mucinous neoplasm (LAMN) is a precursor lesion of pseudomyxoma peritonei, which, if treated suboptimally, may later disseminate throughout the abdominal cavity. We previously demonstrated the role of cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) to reduce the dissemination risk. Here we describe the feasibility and safety of minimal access cytoreductive surgery (MACRS) and HIPEC as an alternative to the open approach. METHODS: We evaluated patients with LAMNs at risk of dissemination (known as LAMN II) who were referred to a national treatment centre between 2010 and 2012 and comparison is made between this group and patients undergoing open CRS and HIPEC for the same pathology over the same time period. RESULTS: Of the 39 patients with LAMN II, 10 patients were treated by MACRS and HIPEC and 7 were treated by an open approach. Among the MACRS procedures, there were no conversions to open surgery; median procedure length, median length of stay, and complication rates were similar between groups and there were no 30-day deaths. After 3- and 11-months median follow-up respectively, no patients have evidence of disease progression. CONCLUSIONS: The present series demonstrates that MACRS and HIPEC is a feasible and safe alternative to the open procedure with the advantage of smaller abdominal wounds and comparable morbidity and inpatient stay. Longer follow-up is needed to assess the impact on disease progression. PMID- 24061625 TI - Health-related quality of life after TAPP repair for the sportsmen's groin. AB - BACKGROUND: Sportsmen's groin (SG) is a clinical diagnosis of chronic, painful musculotendinous injury to the medial inguinal floor in the absence of a groin hernia. Long-term results for laparoscopic inguinal hernia repair, especially data on health-related quality of life (HRQOL), are scant and there are no available data whatsoever on HRQOL after SG. The main goal of this study was to compare postoperative QOL data in the long term after transabdominal preperitoneal hernioplasty (TAPP) in groin hernia and SG patients with QOL data of a normal population. METHODS: This study included all patients (n = 559) who underwent TAPP repair between 2000 and 2005. Forty seven patients (8.4 %) were operated on for SG. We sent out the Short Form 36 Health Survey (SF-36) questionnaire for QOL evaluation. QOL data were compared with data from an age- and sex-matched normal population. RESULTS: Ultimately, 383 completed questionnaires were available for evaluation (69 % response rate). The mean follow-up time was 94 +/- 20 months. In the SG group there were statistically significant differences in three subscales of the SF-36 and the mental component summary measure, showing better results for the SG group compared to the sex- and age-matched normal group data. There were no statistically significant differences between groin hernia patients and the sex- and age-matched normal population. CONCLUSION: TAPP repair for SG as well as groin hernia results in good HRQOL in the long term. Results for SG patients are comparable with QOL data of a normal population or even better. PMID- 24061626 TI - Preoperative opioid use and the outcome of thoracoscopic splanchnicectomy in chronic pancreatitis: a systematic review. AB - BACKGROUND: Thoracoscopic splanchnicectomy (TS) is a minimally invasive intervention to relieve pain in patients with chronic pancreatitis (CP) with equivocal results. Preoperative opioid use seems to impair TS outcome but this has not been investigated in a systematic matter. METHODS: We searched PubMed, EMBASE, and The Cochrane Library for studies on the outcome of TS in CP patients. Studies with >=5 patients and a follow-up of >=12 months were included. Success was defined as the proportion of patients free of opioids or who had a reduction of >=4 points on a pain scale. The effect of opioid use on the success rate of TS was analyzed by uni- and multivariate regression. RESULTS: Sixteen studies with 484 patients were included in our review. The mean (+/-SD) age of the patients was 44 +/- 4.3 years and 66 % were male. Median follow-up period was 21 months (IQR 14-35). Median preoperative opioid use was 85 % (IQR 54-100 %). After TS, a median of 49 % (IQR 22-75 %) of patients were free of opioids at end of follow up. The median success rate was 62 % (IQR 48-86 %). Mean success rate in studies in which <=50 % of the patients used opioids preoperatively was 81 % (SD +/- 21) compared to 60 % (SD +/- 15) for other studies (p = 0.049). Higher age, male gender, and lower rates of preoperative opioid use were associated with a higher success rate (p = 0.003, 0.047, and 0.017, respectively). Multivariate regression, including age, gender, preoperative opioid use, and duration of follow-up, identified age and preoperative opioid use as independent predictors of success after TS (both p = 0.002). CONCLUSION: Preoperative opioid use is associated with a worse outcome after TS in CP patients. To optimize outcome, use of TS may be considered at an earlier stage in the treatment of patients with CP before prolonged opioid therapy. PMID- 24061627 TI - Construct and concurrent validity of a Nintendo Wii video game made for training basic laparoscopic skills. AB - BACKGROUND: Virtual reality (VR) laparoscopic simulators have been around for more than 10 years and have proven to be cost- and time-effective in laparoscopic skills training. However, most simulators are, in our experience, considered less interesting by residents and are often poorly accessible. Consequently, these devices are rarely used in actual training. In an effort to make a low-cost and more attractive simulator, a custom-made Nintendo Wii game was developed. This game could ultimately be used to train the same basic skills as VR laparoscopic simulators ought to. Before such a video game can be implemented into a surgical training program, it has to be validated according to international standards. METHODS: The main goal of this study was to test construct and concurrent validity of the controls of a prototype of the game. In this study, the basic laparoscopic skills of experts (surgeons, urologists, and gynecologists, n = 15) were compared to those of complete novices (internists, n = 15) using the Wii Laparoscopy (construct validity). Scores were also compared to the Fundamentals of Laparoscopy (FLS) Peg Transfer test, an already established assessment method for measuring basic laparoscopic skills (concurrent validity). RESULTS: Results showed that experts were 111 % faster (P = 0.001) on the Wii Laparoscopy task than novices. Also, scores of the FLS Peg Transfer test and the Wii Laparoscopy showed a significant, high correlation (r = 0.812, P < 0.001). CONCLUSIONS: The prototype setup of the Wii Laparoscopy possesses solid construct and concurrent validity. PMID- 24061628 TI - Development of a geriatric vulnerability score in elderly patients with advanced ovarian cancer treated with first-line carboplatin: a GINECO prospective trial. AB - BACKGROUND: Two previous GINECO elderly specific studies in advanced ovarian cancer (AOC) patients highlighted the prognostic value of geriatric covariates for overall survival (OS). PATIENTS AND METHODS: This open-label prospective trial was designed to identify the impact of geriatric covariates on OS in AOC patients >=70 years treated with first-line carboplatin. RESULTS: Geriatric covariates of the 111 patients included median age 79 years (>=80 years: 41%); performance status (PS) >=2: 47%; >=3 major comorbidities: 24%; >=4 comedications: 68%; activities of daily living (ADL) score <6: 55%; instrumental activities of daily living (IADL) score <25: 69%; Hospital Anxiety and Depression Scale (HADS) >14: 37%. The median OS was 17.4 months. Overall, 74% of patients completed the six planned chemotherapy cycles. Grade 3-4 haematological toxic effects were frequent (50%) but manageable. Grade 3-4 non-haematological toxicities included fatigue (15%), anorexia (12%), infections (9%) and thrombosis (2%). A survival score = exp(0.327*GVS) was developed, where the geriatric vulnerability score (GVS) is the sum of the following (each assigned a value of one): albuminaemia <35 g/l; ADL score <6; IADL score <25; lymphopaenia <1 G/l; and HADS >14. With a cut-off >=3, GVS discriminated two groups with significantly different OS, treatment completion, severe adverse events and unplanned hospital admissions rates. CONCLUSIONS: The GVS is a valuable tool for identifying vulnerable patients when treating an elderly AOC population. PMID- 24061630 TI - Identification of biomarkers for unstable angina by plasma metabolomic profiling. AB - Unstable angina (UA) is one of the most dangerous types of coronary heart disease and has high mortality and morbidity rates worldwide. However, the diagnostic accuracy for UA is unsatisfactory in clinical practice. In this study, we investigated the application of plasma metabolomics in discovering potential biomarkers for the diagnosis of UA. Plasma samples from 45 UA and 43 atherosclerosis (AS) in-patients were collected and analyzed using rapid resolution liquid chromatography quadrupole time-of-flight mass spectrometry (RRLC-QTOF/MS) in both positive and negative ion modes. Good separations were observed between the UA patients and AS controls. Tandem mass spectrometry experiments were carried out to identify biomarker candidates that contributed most to the discrimination (VIP > 1.2 and p < 0.05). Sixteen potential endogenous biomarkers for UA were identified, and those could perform a satisfactory diagnostic accuracy for discrimination between UA and AS patients (AUC = 0.9143). In the UA patients compared to the AS controls, the plasma concentrations of 12 metabolites were higher while the concentrations of four metabolites were lower. In conclusion, our study demonstrated that plasma metabolomics analyzed by RRLC QTOF/MS had great potential in biomarker discovery for UA. These biomarkers could not only be helpful for the diagnosis of patients with UA, but also provide more information for further understanding of the metabolic processes of UA. PMID- 24061631 TI - Fluid challenge: tracking changes in cardiac output with blood pressure monitoring (invasive or non-invasive). AB - PURPOSE: To assess whether invasive and non-invasive blood pressure (BP) monitoring allows the identification of patients who have responded to a fluid challenge, i.e., who have increased their cardiac output (CO). METHODS: Patients with signs of circulatory failure were prospectively included. Before and after a fluid challenge, CO and the mean of four intra-arterial and oscillometric brachial cuff BP measurements were collected. Fluid responsiveness was defined by an increase in CO >=10 or >=15% in case of regular rhythm or arrhythmia, respectively. RESULTS: In 130 patients, the correlation between a fluid-induced increase in pulse pressure (Delta500mlPP) and fluid-induced increase in CO was weak and was similar for invasive and non-invasive measurements of BP: r2 = 0.31 and r2 = 0.29, respectively (both p < 0.001). For the identification of responders, invasive Delta500mlPP was associated with an area under the receiver operating curve (AUC) of 0.82 (0.74-0.88), similar (p = 0.80) to that of non invasive Delta500mlPP [AUC of 0.81 (0.73-0.87)]. Outside large gray zones of inconclusive values (5-23% for invasive Delta500mlPP and 4-35% for non-invasive Delta500mlPP, involving 35 and 48% of patients, respectively), the detection of responsiveness or unresponsiveness to fluid was reliable. Cardiac arrhythmia did not impair the performance of invasive or non-invasive Delta500mlPP. Other BP derived indices did not outperform Delta500mlPP. CONCLUSIONS: As evidenced by large gray zones, BP-derived indices poorly reflected fluid responsiveness. However, in our deeply sedated population, a high increase in invasive pulse pressure (>23%) or even in non-invasive pulse pressure (>35%) reliably detected a response to fluid. In the absence of a marked increase in pulse pressure (<4-5%), a response to fluid was unlikely. PMID- 24061632 TI - Sedation level and prevalence of delirium: response to Brummel and Ely. PMID- 24061633 TI - Statin use and incident prostate cancer risk: does the statin brand matter? A population-based cohort study. AB - BACKGROUND: Statins have known anticarcinogenic effects; evidence for long-term statin use as effective chemoprevention for prostate cancer is inconsistent. METHODS: We conducted a population-based cohort study to examine the association between statin use and risk of prostate cancer using the Database of Clalit Health Services. A total of 66,741 eligible participants were identified at 1 January 2001 and followed through to 31 December 2009. Cox proportional hazard models were used to compute hazard ratios (HRs) of incident prostate cancer associated with statin therapy controling for patients' clinical and sociodemographic characteristics. RESULTS: A total of 1813 cases of prostate cancer were diagnosed. Statin use was associated with a decreased incidence of prostate cancer, the association was stronger with increasing total dose, hydrophobic statins use and longer periods of treatment. When comparing statin use of over 6 months, this association was strongest for simvastatin (HR 0.51, 95% confidence interval (CI) 0.47-0.56), atorvostatin (HR 0.48, 95% CI 0.33-0.68) and rosuvastatin (HR 0.22, 95% CI 0.08-0.75). CONCLUSIONS: Our findings suggest that prolonged statin use is associated with a reduced risk of prostate cancer; however, this was not true for all types of statin. PMID- 24061635 TI - Imaging of spatial many-body wave functions via linear momentum measurements. AB - The equivalence of a complete characterization of linear momenta of fragments from a many-body fragmentation process and the spatial wave function of the many body system is discussed. Our experiment on three-body dissociation of state selected H3 and D3 molecules into ground-state hydrogen atoms strongly suggests the existence of such a close relationship as it is also predicted by theory in the form of the imaging theorem. We conclude that prudent imaging of many-body fragmentation provides a laboratory view of the squared many-body wave function at a spatial scale of molecular dimensions at which fragments exit into the realm of independent free particles. PMID- 24061634 TI - Genetic variation in IL-16 miRNA target site and time to prostate cancer diagnosis in African-American men. AB - BACKGROUND: Men with a family history of prostate cancer and African-American men are at high risk for prostate cancer and in need of personalized risk estimates to inform screening decisions. This study evaluated genetic variants in genes encoding microRNA (miRNA) binding sites for informing of time to prostate cancer diagnosis among ethnically diverse, high-risk men undergoing prostate cancer screening. METHODS: The Prostate Cancer Risk Assessment Program (PRAP) is a longitudinal screening program for high-risk men. The eligibility includes men aged between 35 and 69 years with a family history of prostate cancer or African descent. Participants with ?1 follow-up visit were included in the analyses (n=477). Genetic variants in genes encoding miRNA binding sites (ALOX15 (arachidonate 15-lipooxygenase), IL-16, IL-18 and RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1)) previously implicated in prostate cancer development were evaluated. Genotyping methods included Taqman SNP Genotyping Assay or pyrosequencing. Cox models were used to assess time to prostate cancer diagnosis by risk genotype. RESULTS: Among 256 African Americans with ?one follow-up visit, the TT genotype at rs1131445 in IL-16 was significantly associated with earlier time to prostate cancer diagnosis vs the CC/CT genotypes (P=0.013), with a suggestive association after correction for false discovery (P=0.065). Hazard ratio after controlling for age and PSA for TT vs CC/CT among African Americans was 3.0 (95% confidence interval: 1.26-7.12). No association with time to diagnosis was detected among Caucasians by IL-16 genotype. No association with time to prostate cancer diagnosis was found for the other miRNA target genotypes. CONCLUSIONS: Genetic variation in IL-16 encoding miRNA target site may be informative of time to prostate cancer diagnosis among African-American men enrolled in prostate cancer risk assessment, which may inform individualized prostate cancer screening strategies in the future. PMID- 24061636 TI - Murine double minute 2 rs2279744 polymorphism and hepatocellular carcinoma risk in East Asians: a meta-analysis. AB - Murine double minute 2 (MDM2) is a crucial negative regulator of p53 function through several mechanisms. There are many studies performed to assess the association between MDM2 rs2279744 polymorphism and hepatocellular carcinoma risk, but the impact of MDM2 rs2279744 polymorphism on hepatocellular carcinoma in East Asians is unclear owing to the inconsistent findings from previous studies. We conducted a comprehensive meta-analysis of epidemiological studies to shed some light on these contradicting results. We used pooled odds ratio (OR) with its 95 % confidence intervals (95 % CI) to assess the association. Overall, seven studies with a total of 4,993 subjects were finally included. The meta analysis suggested that MDM2 rs2279744 polymorphism was significantly associated with increased risk of hepatocellular carcinoma in East Asians (G versus T: OR = 1.27, 95 % CI 1.06-1.52, P = 0.01; GG versus TT: OR = 1.59, 95 % CI 1.11-2.27, P = 0.01; GG/GT versus TT: OR = 1.41, 95 % CI 1.07-1.87, P = 0.02; GG versus TT/GT: OR = 1.32, 95 % CI 1.08-1.62, P = 0.008). Sensitivity analysis by excluding low quality study still suggested that the association above was still significant. Thus, the findings from the meta-analysis support that MDM2 rs2279744 polymorphism is significantly associated with increased risk of hepatocellular carcinoma in East Asians. PMID- 24061637 TI - Heat shock protein 27: a potential biomarker of peritoneal metastasis in epithelial ovarian cancer? AB - Ovarian cancer is the major gynaecologic malignancy and the leading cause of death in gynaecological cancer. Heat shock proteins (HSPs) are highly expressed in many malignant cancers and involved in metastasis including ovarian cancer. The early detection of peritoneal metastases in epithelial ovarian cancer may be more important in clinical care. HSP27, a small heat shock protein, is correlated with peritoneal metastases in epithelial ovarian cancer tissues. In this study, we investigated whether the levels of total HSP27 were detectable in serum and whether it could be a predictive biomarker for peritoneal metastases in epithelial ovarian cancer. Serum samples from 48 patients with epithelial ovarian cancer, 35 patients with benign ovarian tumours and 24 healthy women were included in this study. The serum levels of total HSP27 were measured by enzyme linked immunosorbent assay (ELISA). There was no difference in the serum levels of total HSP27 between women with benign ovarian tumours and healthy women. However, the serum levels of total HSP27 were significantly increased in patients with epithelial ovarian cancer. The increased serum levels of total HSP27 were only seen in patients with peritoneal metastases. Furthermore, increased serum levels of total HSP27 were significantly reduced after the combination chemotherapies in patients with peritoneal metastases. These data suggest that circulating HSP27 levels were increased in epithelial ovarian cancer and correlated with peritoneal metastases. The measurement of serum HSP27 levels may be used as a potential additional indicator for peritoneal metastases in epithelial ovarian cancer and response to treatment. PMID- 24061638 TI - Antiapoptotic gene BAG-1 vector structure of RNA interference and endogenous targeted screening in colon cancer cell lines. AB - The purposes of the present work were to construct the shRNA plasmids for BAG-1 gene of human and test the expression of mRNA and protein of BAG-1. Recombinant plasmids containing green fluorescent protein reporter genes are constructed using gene cloning methods. The shRNA plasmids for the BAG-1 gene are constructed by RNA interference technology. We applied fluorescent plasmid-transfected target cells in the cell transfection experiments and monitored the transfection rate of plasmids by observing the fluorescence amount. We transfected three synthesized shRNA in target screening cell and adopted RT-PCR and Western test to identify the difference of target gene transfection and translation level in cells. The specific shRNA plasmid for the BAG-1 gene was successfully recombined, and stably transfected colon cancer Lo Vo cell lines were obtained. The results present that the constructed shRNA plasmids significantly inhibited the expression of mRNA and protein of Lo Vo cell BAG-1, and can maintain the effect for a long term. pGPH1/GFP/Neo-BAG-1-homo-825 was screened as the optimum sequence of interference so as to lay a solid foundation to explore into the research on the BAG-1 gene and the biological behavior of colon cancer cells. It showed the remarkable advantage of RNAi in the generation of posttranscriptional gene silencing. PMID- 24061639 TI - Association between XRCC3 Thr241Met polymorphism and risk of brain tumors: a meta analysis. AB - X-ray repair cross-complementing group 3 (XRCC3) plays an important role in the process of homologous recombination repair for DNA double-strand breaks which further maintains the stability of the genome. XRCC3 Thr241Met polymorphism has been indicated in the development of cancers, but the association of the XRCC3 Thr241Met polymorphism with risk of brain tumors is still unclear owing to the conflicting findings from previous studies. We performed a meta-analysis to provide a better understanding on the association between the XRCC3 Thr241Met polymorphism and risk of brain tumors. The pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was used to assess the association. Thirteen case-control studies involving a total of 4,984 cases and 7,472 controls were included. Overall, there was no statistically significant association between the XRCC3 Thr241Met polymorphism and risk of brain tumors under all contrast models. Subgroup analysis by race suggested that the XRCC3 Thr241Met polymorphism was associated with increased risk of brain tumors in Asians under all four contrast models (Met vs. Thr: OR = 1.22, 95 % CI 1.09-1.36, P < 0.01; MetMet vs. ThrThr: OR = 1.89, 95 % CI 1.38-2.57, P < 0.01; MetMet vs. ThrThr/ThrMet: OR = 1.78, 95 % CI 1.31-2.40, P < 0.01; and MetMet vs. ThrThr/ThrMet: OR = 1.19, 95 % CI 1.04-1.36, P = 0.01). However, there was no significant association between the XRCC3 Thr241Met polymorphism and risk of brain tumors in Caucasians. Therefore, the XRCC3 Thr241Met polymorphism is associated with increased risk of brain tumors, especially in Asians. PMID- 24061640 TI - Quantitative assessment of the association between XPG Asp1104His polymorphism and bladder cancer risk. AB - Published data regarding the association between XPG Asp1104His polymorphism and bladder cancer risk remained controversial. This meta-analysis of literatures was performed to draw a more precise estimation of the relationship. We systematically searched PubMed, Embase, and Web of Science with a time limit of June 22, 2013. Summary odds ratios (ORs) with 95 % CIs were used to assess the strength of the association between XPG Asp1104His polymorphism and bladder cancer risk using random effects model. A total of eight case-control studies including 2,613 cases and 2,934 controls were included for analysis. Overall, no significant association was found between XPG Asp1104His polymorphism and bladder cancer susceptibility for CC vs. GG (OR = 1.12, 95 % CI = 0.74-1.69), GC vs. GG (OR = 1.12, 95 % CI = 0.86-1.46), the dominant model CC + GC vs. GG (OR = 1.08, 95 % CI = 0.85-1.38), and the recessive model CC vs. GC + GG (OR = 0.92, 95 % CI = 0.66-1.29). In the subgroup analysis, no significant associations were found in either Asian or non-Asian population. This meta-analysis suggested that XPG Asp1104His polymorphism was not associated with bladder cancer risk. PMID- 24061641 TI - Prognostic value of EpCAM/MUC1 mRNA-positive cells in non-small cell lung cancer patients. AB - The aim of this study was to assess the prognostic value of EpCAM/MUC1 mRNA positive circulating tumor cells (CTCs) in patients with non-small cell lung cancer (NSCLC). The presence of EpCAM/MUC1 mRNA-positive CTCs was evaluated in 74 NSCLC patients before the initiation of any therapy, from which 61 patients with surgical resection of tumor were also evaluable for EpCAM/MUC1 mRNA-positive CTC analysis after surgery, by quantitative real-time PCR assay. Sixty patients with benign lung disease (BLD) entered this study as controls. The results showed that blood levels of EpCAM and MUC1 mRNA in NSCLC patients before and after surgery were significantly higher than those in BLD patients (P = 0.001 and P = 0.015, respectively, for EpCAM; P = 0.003 and P = 0.026, respectively, for MUC1), and the levels of the two gene mRNA in NSCLC patients significantly decreased after surgery (P = 0.025 and P = 0.033, respectively). Disease recurrence significantly increased in NSCLC patients with EpCAM/MUC1 mRNA-positive CTC preoperation and postoperation (P = 0.004 and P = 0.001, respectively). Disease-free survival and overall survival significantly reduced in patients with EpCAM/MUC1 mRNA-positive CTC preoperation and postoperation (P = 0.012 and P = 0.002, respectively, for preoperation; both P < 0.001 for postoperation). Multivariate analysis demonstrated that the presence of EpCAM/MUC1 mRNA-positive CTCs before and after surgery was an independent factor associated with disease recurrence. In conclusion, the detection of EpCAM/MUC1 mRNA-positive CTCs in the blood before and after surgery is useful for predicting a poor prognosis in NSCLC patients who undergo curative surgery. PMID- 24061643 TI - Renin-angiotensin system in ureteric bud branching morphogenesis: implications for kidney disease. AB - Failure of normal branching morphogenesis of the ureteric bud (UB), a key ontogenic process that controls organogenesis of the metanephric kidney, leads to congenital anomalies of the kidney and urinary tract (CAKUT), the leading cause of end-stage kidney disease in children. Recent studies have revealed a central role of the renin-angiotensin system (RAS), the cardinal regulator of blood pressure and fluid/electrolyte homeostasis, in the control of normal kidney development. Mice or humans with mutations in the RAS genes exhibit a spectrum of CAKUT which includes renal medullary hypoplasia, hydronephrosis, renal hypodysplasia, duplicated renal collecting system and renal tubular dysgenesis. Emerging evidence indicates that severe hypoplasia of the inner medulla and papilla observed in angiotensinogen (Agt)- or angiotensin (Ang) II AT 1 receptor (AT 1 R)-deficient mice is due to aberrant UB branching morphogenesis resulting from disrupted RAS signaling. Lack of the prorenin receptor (PRR) in the UB in mice causes reduced UB branching, resulting in decreased nephron endowment, marked kidney hypoplasia, urinary concentrating and acidification defects. This review provides a mechanistic rational supporting the hypothesis that aberrant signaling of the intrarenal RAS during distinct stages of metanephric kidney development contributes to the pathogenesis of the broad phenotypic spectrum of CAKUT. As aberrant RAS signaling impairs normal renal development, these findings advocate caution for the use of RAS inhibitors in early infancy and further underscore a need to avoid their use during pregnancy and to identify the types of molecular processes that can be targeted for clinical intervention. PMID- 24061644 TI - Ureteral or vesical involvement in Henoch-Schonlein syndrome: a systematic review of the literature. AB - BACKGROUND: Little information is available on ureteral or vesical involvement in Henoch-Schonlein syndrome. To determine the features of this condition we performed a formal analysis of peer-reviewed scientific literature on this topic. METHODS: The US National Library of Medicine database was used as the data source. All articles published as full-length articles or letters were collected. Reports published in languages other than English, French, German, Italian or Spanish were not considered. RESULTS: We analyzed 32 reports describing 35 cases (24 male and 11 female subjects aged between 3.5 and 63, median 7.0 years) with ureteral (n = 30), vesical (n = 4), or both ureteral and vesical involvement (n = 1). The presentation included colicky abdominal pain, macroscopic hematuria (sometimes containing blood clots), urinary tract infection or urinary retention. The diagnosis of ureteral involvement was often fortuitous. Patients with vesical involvement were managed conservatively. However, the majority of those with ureteral involvement were managed surgically. CONCLUSIONS: Ureteral or vesical involvement is unusual and likely underappreciated in Henoch-Schonlein syndrome. Improved recognition and wider appreciation of this involvement can help to avoid associated morbidity. Management must be individualized for each patient. A multidisciplinary approach may be of value in planning medical treatment, surgical intervention, and follow-up. PMID- 24061645 TI - Malignancies after pediatric kidney transplantation: more than PTLD? AB - Post-transplant lymphoproliferative disease (PTLD) is the most frequent malignant complication of transplantation in childhood. Even with modern post-transplant immunosuppressive strategies, 1-2% of all kidney transplant recipients will develop PTLD within the first 5 years after transplantation, and the risk remains high even thereafter as long as immunosuppression is required. In addition to PTLD, adult kidney transplant recipients have an increased incidence of other immunosuppression-related malignancies, such as non-melanoma skin cancer or Kaposi's sarcoma. It is foreseeable that pediatric transplant recipients will face similar complications during their adult life. Not only immunosuppression but also other risk factors have been identified for some of these malignancies. Strategies addressing these risk factors during childhood may contribute to life long cancer prevention. Furthermore, early recognition and regular screening may facilitate early diagnosis and treatment, thereby reducing transplant-related morbidity. In this review we focus on malignant complications after renal transplantation and discuss known risk factors. We also review current screening strategies for malignancies during post-transplant follow-up. PMID- 24061646 TI - Dimethyl fumarate for treatment of multiple sclerosis: mechanism of action, effectiveness, and side effects. AB - Dimethyl fumarate is an orally available treatment option for relapsing-remitting multiple sclerosis (MS) in a new formulation with improved gastroenteric coating. The mode of action comprises immunomodulatory effects and an activation of nuclear (erythroid-derived 2) related factor mediated antioxidative response pathways leading to additional cytoprotective effects. In two pivotal phase III trials, dimethyl fumarate, 240 mg twice daily, reduced relapse rates by about 50 % as compared with placebo. In the DEFINE trial, progression of disability was also significantly reduced. Both trials demonstrated a significant reduction of gadolinium-enhanced lesions as well as T2 lesions on cranial MRI. The studies revealed a beneficial safety profile of dimethyl fumarate. The most prevalent side effects were transient flushing and gastrointestinal tract irritation. Dimethyl fumarate has recently been approved in the USA for the treatment of relapsing-remitting MS. The compound is a welcome addition to the immunomodulatory treatment armamentarium for MS patients and physicians alike. PMID- 24061647 TI - The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants. AB - The receptor tyrosine kinase MET is a prime target in clinical oncology due to its aberrant activation and involvement in the pathogenesis of a broad spectrum of malignancies. Similar to other targeted kinases, primary and secondary mutations seem to represent an important resistance mechanism to MET inhibitors. Here, we report the biologic activity of a novel MET inhibitor, EMD1214063, on cells that ectopically express the mutated MET variants M1268T, Y1248H, H1112Y, L1213V, H1112L, V1110I, V1206L, and V1238I. Our results show a dose-dependent decrease in MET autophosphorylation in response to EMD1214063 in five of the eight cell lines (IC50 2-43 nmol/L). Blockade of MET by EMD1214063 was accompanied by a reduced activation of downstream effectors in cells expressing EMD1214063-sensitive mutants. In all sensitive mutant-expressing lines, EMD1214063 altered cell-cycle distribution, primarily with an increase in G1 phase. EMD1214063 strongly influenced MET-driven biologic functions, such as cellular morphology, MET-dependent cell motility, and anchorage-independent growth. To assess the in vivo efficacy of EMD1214063, we used a xenograft tumor model in immunocompromised mice bearing NIH3T3 cells expressing sensitive and resistant MET-mutated variants. Animals were randomized for the treatment with EMD1214063 (50 mg/kg/d) or vehicle only. Remarkably, five days of EMD1214063 treatment resulted in a complete regression of the sensitive H1112L-derived tumors, whereas tumor growth remained unaffected in mice with L1213V tumors and in vehicle-treated animals. Collectively, the current data identifies EMD1214063 as a potent MET small-molecule inhibitor with selective activity towards mutated MET variants. PMID- 24061649 TI - Large volume monolithic stationary phases: preparation, properties, and applications. AB - Monoliths represents the 4th generation of chromatographic supports. They consist of a single piece of highly porous material with interconnected flow through pores. Because of that transport is based on convection what results in a flow unaffected separation and dynamic binding capacity. This is especially important when large molecular weight molecules such as proteins, DNA or viruses have to be purified. For this purpose large volume monolithic columns are needed. In this article preparation of such columns is described together with their main applications. The article is dedicated to Prof. Tine Koloini who substantially contributed to this topic. PMID- 24061648 TI - Urokinase plasminogen activator system-targeted delivery of nanobins as a novel ovarian cancer therapy. AB - The urokinase system is overexpressed in epithelial ovarian cancer cells and is expressed at low levels in normal cells. To develop a platform for intracellular and targeted delivery of therapeutics in ovarian cancer, we conjugated urokinase plasminogen activator (uPA) antibodies to liposomal nanobins. The arsenic trioxide-loaded nanobins had favorable physicochemical properties and the ability to bind specifically to uPA. Confocal microscopy showed that the uPA-targeted nanobins were internalized by ovarian cancer cells, whereas both inductively coupled plasma optical mass spectrometry (ICP-MS) and fluorescence-activated cell sorting (FACS) analyses confirmed more than four-fold higher uptake of targeted nanobins when compared with untargeted nanobins. In a coculture assay, the targeted nanobins showed efficient uptake in ovarian cancer cells but not in the normal primary omental mesothelial cells. Moreover, this uptake could be blocked by either downregulating uPA receptor expression in the ovarian cancer cells using short-hairpin RNA (shRNA) or by competition with free uPA or uPA antibody. In proof-of-concept experiments, mice bearing orthotopic ovarian tumors showed a greater reduction in tumor burden when treated with targeted nanobins than with untargeted nanobins (47% vs. 27%; P < 0.001). The targeted nanobins more effectively inhibited tumor cell growth both in vitro and in vivo compared with untargeted nanobins, inducing caspase-mediated apoptosis and impairing stem cell marker, aldehyde dehydrogenase-1A1 (ALDH1A1), expression. Ex vivo fluorescence imaging of tumors and organs corroborated these results, showing preferential localization of the targeted nanobins to the tumor. These findings suggest that uPA-targeted nanobins capable of specifically and efficiently delivering payloads to cancer cells could serve as the foundation for a new targeted cancer therapy using protease receptors. PMID- 24061650 TI - Effect of Complexation Cyclodextrins with Phenolic Acids and Coenzyme Q10 on their Physico-Chemical Properties and Bioavailability. AB - This article deals with the oxidation problems of food caused by atmospheric oxygen. Two approaches to overcome these problems are involved: (i) by reducing the double bonds in unsaturated fatty acids in lipids, the so-called hydrogenation; and (ii) by introduction of some antioxidants, modified by cyclodextrins, in order to protect food against the oxidation processes. In the area of hydrogenation, an alternative method of hydrogenation was presented, catalytic transfer hydrogenation of edible oils, using sodium formate as a hydrogen donor. This method is fast, simple, safe, economical and offers good selectivity and therefore good oxidative stability of the product. In the area of inclusion between phenolic acids and coenzyme Q10 with cyclodextrins, increased stability, solubility and antioxidative activities of included compounds were achieved. Complex of coenzyme Q10 with beta-cyclodextrin shows superior bioavailability over formulations based on lipid soluble coenzyme Q10. PMID- 24061651 TI - The Seveso II Directive in New European Member States: the Case of Slovenia. AB - New member states have adopted European legislation in the field of environmental protection and after its adoption they put this legislation into power. The article deals with the problems with implementation of the Seveso II Directive, which have been discovered by the reviewing safety reports, submitted to the competent authority. At first glance the legislation does not seem to be very problematic, but after a closer look a number of problems can be unveiled which we think could be of interest to a wider community. Operators of the upper tier facilities should according to legislation prepare safety reports which should demonstrate that they identified the hazards and that they know how to deal with them. This can be done only by knowledgeable people who can also make the use of the results for improving safety. PMID- 24061652 TI - Synthesis of aryl alkyl ethers by alkylation of phenols with quaternary ammonium salts. AB - Phenolic compounds can be efficiently O-methylated with tetramethylammonium chloride in diglyme or polyethyleneglycol (PEG) at temperatures of 150-160 degrees C and in the presence of either K2CO3 or NaOH. When applying benzyltrimethylammonium chloride as a reagent, the benzylation and methylation of phenols occurs, with the benzylation product always predominating. With allyl substituted phenols as substrates and using NaOH as a base it was possible to achieve both the alkylation and the double-bond isomerization of the allyl group to obtain (E/Z)-propenyl-substituted methyl and benzyl aryl ethers in a single preparative step. PMID- 24061653 TI - Determination of nickel in active pharmaceutical ingredients by electrothermal atomic absorption spectrometry. AB - An electrothermal atomic absorption spectrometric procedure for the determination of nickel in active pharmaceutical ingredients was developed. Since the recoveries of nickel by the direct dissolution of samples in diluted nitric acid were low and caused errors in the determination of Ni in pharmaceutical samples, different approaches for sample pre-treatment were examined. It was found that the microwave digestion was the most suitable way for sample preparation. Various combinations of digestion agents and different microwave conditions were tested. The combination of nitric acid and hydrogen peroxide was found to be the most appropriate. The validity of the method was evaluated by recovery studies of spiked samples and by the comparison of the results obtained by inductively coupled plasma mass spectrometry (ICP-MS). The recovery ranged from 87.5 to 104.0% and a good agreement was achieved between both methods. The detection limit and the limit of quantification were 0.6 and 2.1 ug g-1 respectively. The precision of the method was confirmed by the determination of Ni in the spiked samples and was below 4%, expressed in terms of a relative standard deviation. The method was applied to the determination of nickel in production samples of active pharmaceutical ingredients and intermediates. PMID- 24061654 TI - Estimation of the specific surface area for a porous carrier. AB - In biofilm systems, treatment performance is primarily dependent upon the available biofilm growth surface area in the reactor. Specific surface area is thus a parameter that allows for making comparisons between different carrier technologies used for wastewater treatment. In this study, we estimated the effective surface area for a spherical, porous polyvinyl alcohol (PVA) gel carrier (Kuraray) that has previously demonstrated effectiveness for retention of autotrophic and heterotrophic biomass. This was accomplished by applying the GPS X modeling tool (Hydromantis) to a comparative analysis of two moving-bed biofilm reactor (MBBR) systems. One system consisted of a lab-scale reactor that was fed synthetic wastewater under autotrophic conditions where only the nitrification process was studied. The other was a pre-denitrification pilot-scale plant that was fed real, primary-settled wastewater. Calibration of an MBBR process model for both systems indicated an effective specific surface area for PVA gel of 2500 m2/m3, versus a specific surface area of 1000 m2/m3 when only the outer surface of the gel beads is considered. In addition, the maximum specific growth rates for autotrophs and heterotrophs were estimated to be 1.2/day and 6.0/day, respectively. PMID- 24061655 TI - Lin-log Model of E. coli Central Metabolism. AB - Mathematical models of dynamics of metabolic pathways are used for analysis of complex regulations of biochemical reactions as an intrinsic property of a metabolism. The models are derived under assumptions of kinetic rate functions and usually result in simplification in view of the model theoretical scope and/or its practical application. The main obstacle in kinetic modeling is the dimensionality of the parametric space, its nonlinearity and ill-conditioned relations for kinetic parameter estimation. In this work these problems are effectively resolved by use of an approximate linear-logarithmic (Lin-log) applied in analysis of regulation of Escherichia coli central metabolism. Complex multiplicative Michaelis-Menten kinetic rate expressions are transformed into simple in parameter linear functions and non-linear logarithmic dependencies on concentrations of substrates, and cofactors. The Lin-log kinetic rates enable direct estimation of rate elasticities which are the key parameters in metabolic control analysis (MCA). Due to in the parameter linearity, the estimation problem is solved in a non-iterative least square algorithm. Applied is singular value decomposition (SVD) algorithm for system matrix pseudoinversion with the eigenvalue cut-off threshold at 0.01. The results are presented as parameters of enzyme activities and reaction elasticities. Evaluated activities and elasticities provided insight into the fluxes regulation. Comparison of the simulation results by Lin-log and Michaelis-Menten model reveals that errors are of the same order of magnitude. PMID- 24061656 TI - Extraction of Lutein Diesters from Tagetes Erecta using Supercritical CO2 and Liquid Propane. AB - The efficiency of high pressure extraction of lutein diesters from marigold (Tagetes erecta) flower petals has been investigated. The solvents used for extraction were supercritical carbon dioxide and liquid propane. Operating parameters were 300 bar and 40, 60 and 80 degrees C for CO2 and 100, 150, 200 bar and 40 and 60 degrees C for propane, respectively. The influence of process parameters on the total yield of extraction and content of lutein diesters in the extracts was investigated. The results show, that solvent power of propane for lutein diesters is approximately 3.5 times higher than of CO2. The calculation procedure based on the Fick's second law was applied to determine the diffusivities of lutein diesters during extraction from marigold flower petals for both extraction stages: a constant rate stage followed by a stage of decreasing rate. The mathematical model based on the Fick's second law well described the experimental extraction results. PMID- 24061657 TI - Calorimetric Insight into Coupling between Functionalized Primary Alkyl Halide and Vinylic Organocuprate Reagent: Experimental Determination of Reaction Enthalpies in the Synthesis of (R)-Ethyl 3-(tert-butyldimethylsilyloxy)hex-5 enoate - a Key Lactonized Statin Side Chain Precursor. AB - The first calorimetric study of coupling between organocuprate, derived from Grignard reagent (vinyl magnesium chloride), and primary alkyl halide (e.g. (S) ethyl 3-(tert-butyldimethylsilyloxy)-4-iodobutanoate) has been conducted. This transformation is paramountly important for efficient preparation of (R)-ethyl 3 (tert-butyldimethylsilyloxy)hex-5-enoate - a key lactonized statin side chain precursor. The results obtained give thorough calorimetric insight into this complex low-temperature synthesis as well as a new understanding of the suggested reductive elimination of the final intermediates in the coupling reaction. Namely, the surprising unexpected spontaneous three-step exothermal event has been observed during controlled progressive heating of the mixture of the final intermediates to the room temperature. This phenomenon confirms that coupling between functionalized primary alkyl halide and vinylic organocuprate reagent is not a simple SN2 substitution reaction. The presented study provides among others the first reported values of reaction enthalpies and corresponding adiabatic temperature rises of reaction mixture for all exothermic events that occurred in the (R)-ethyl 3-(tert-butyldimethylsilyloxy)hex-5-enoate synthesis. The obtained results ensure consequential thermal process safety knowledge which can be incorporated into safe process scale-up as well as design of reactor system with sufficient cooling capacity for industrial production of (R)-ethyl 3-(tert butyldimethylsilyloxy)hex-5-enoate. Moreover, the results provide a basic guidance for other organocuprate coupling reaction systems. PMID- 24061658 TI - Synthesis and redox properties of azino-chalcogenoazafulvalenes: an entry to electroactive azino macrocyclic compounds. AB - The synthesis of a series of dimers containing two redox active moieties, such as azino-chalcogenoazafulvalenes, connected through one or two non conjugated spacer group is reported. Various heterocycles have been used to build these donor molecules incorporating an azino spacer group between two thiazole moieties or a thiazole core and a selenazole one or two selenazole cores or a thiazole and a dithiole moiety. Cyclic voltammetry experiments have evidenced the influence of the nature of the heterocycle on the donating ability of these dimers. Moreover, sizable intramolecular interactions between the two electroactive moieties are observed depending on the length and the number of the non conjugated spacer group. PMID- 24061659 TI - Feasibility of Fenton's Oxidation for Removal of Estrogens from Aqueous Solutions. AB - Presented research has been focused on the effectiveness of degradation of natural (17?-estradiol - E2) and synthetic (17alpha-ethinylestradiol - EE2) hormones with Fenton's oxidation. Numerous studies have demonstrated, that the impact of hormones on organisms was shown already at environmental concentrations close to 1 pg L-1, so their effective removal from wastewaters is important. Fenton's oxidation is very efficient in terms of oxidation of organics, while its main withdrawal is the formation of waste sludge, leading to adsorption of organics, which sometimes makes it impossible to reliably value the extent of actual degradation. The ratio among degradation and adsorption of estrogens on sludge during oxidative treatment was determined as a part of our study. It depends upon the molar ratio of reagents Fe2+ and H2O2 (1:0.5, 1:10; 1:20; 1:33), reaction time and initial concentrations of the investigated estrogens E2 (0.279/27.9 mg L-1) and EE2 (0.296/29.6 mg L-1). The most efficient removal of E2 was achieved at 1:33 molar ratio of reagents (100%, 26-50% adsorption) while EE2 removed efficiently at 1:10 and 1:33 ratios (99-100%, 20-76% adsorption). It was confirmed, that adsorption plays an important role in Fenton's oxidative treatment of estrogens. It is prevailing process at higher pHs, while at lower ones (pH = 3.0-5.0) oxidation is dominant, because it is not limited by mass transport. PMID- 24061660 TI - Modeling and finite difference numerical analysis of reaction-diffusion dynamics in a microreactor. AB - A theoretical description with numerical experiments and analysis of the reaction diffusion processes of homogeneous and non-homogeneous reactions in a microreactor is presented considering the velocity profile for laminar flows of miscible and immiscible fluids in a microchannel at steady-state conditions. A Mathematical model in dimensionless form, containing convection, diffusion, and reaction terms are developed to analyze and to forecast the reactor performance. To examine the performance of different types of reactors, the outlet concentrations for the plug-flow reactor (PFR), and the continuous stirred-tank reactor (CSTR) are also calculated for the case of an irreversible homogeneous reaction of two components. The comparison of efficiency between ideal conventional macroscale reactors and the microreactor is presented for a wide range of operating conditions, expressed as different Pe numbers (0.01 < Pe < 10). The numerical procedure of complex non-linear systems based on an implicit finite-difference method improved by non-equidistant differences is proposed. PMID- 24061661 TI - Oxidation of Coniferyl Alcohol Catalyzed by Laccases from Trametes versicolor. AB - Oxidation of coniferyl alcohol catalyzed by commercial laccase and crude laccase produced during the submerged cultivation of Trametes versicolor MZKI G-99 in a medium containing the waste from paper industry was investigated. pH of 6.6 and temperature of 35 degrees C was found to be optimal for coniferyl alcohol oxidation catalyzed by commercial laccase. Based on the initial reaction rate measurements, apparent Michaelis-Menten kinetic parameters for commercial laccase were determined in an aqueous media (Vm = 4.387 U mg-1, Km = 0.025 mmol dm-3), as well as in 1:1 (v/v) methanol: phosphate buffer mixture (Vm = 0.979 U mg-1, Km = 0.019 mmol dm-3). Inhibition of substrate was found for crude laccase and the following apparent kinetic parameters Vm = 9.272 U mg-1, Km = 0.045 mmol dm-3 and Ki = 0.002 mmol dm-3 were estimated. Mathematical model of batch process, which includes double-substrate Michaelis-Menten kinetics with oxygen as the second substrate and mass balances, has been developed and validated in experiments with or without additional aeration. 100 % conversions of up to 0.8 mmol dm-3 of coniferyl alcohol in batch experiment due to the high operational stability of enzymes was realized with both laccases. PMID- 24061662 TI - Impact of the buildings areas on the fire incidence. AB - A survey of statistical studies shows that probability of fires is expressed by the equation P(A) = KAalpha, where A = total floor area of the building and K and ? are constants for an individual group, or risk category. This equation, which is based on the statistical data on fires in Great Britain, does not include the impact factors such as the number of employees and the activities carried out in these buildings. In order to find out possible correlations between the activities carried out in buildings, the characteristics of buildings and number of fires, we used a random sample which included 134 buildings as industrial objects, hotels, restaurants, warehouses and shopping malls. Our study shows that the floor area of buildings has low impact on the incidence of fires. After analysing the sample of buildings by using multivariate analysis we proved a correlation between the number of fires, floor area of objects, work operation period (per day) and the number of employees in objects. PMID- 24061663 TI - Oxygen transfer in a laboratory stirred tank bioreactor during Mammalian cell culture cultivation. AB - The influence of power consumption on the volumetric mass transfer coefficient was studied in a 5 liter stirred tank bioreactor during cultivation of a recombinant Chinese Hamster Ovary (CHO) cell line, which requires low aeration and mixing intensity. Under these conditions and at high cell concentrations, oxygen mass transfer coefficient and consequently volumetric oxygen mass transfer rate was not sufficient for the oxygen requirements. This problem was successfully solved by introducing pure oxygen into the bioreactor and the oxygen mass balance was studied. For that purpose, respiration rate as a function of cell concentration, as well as volumetric oxygen mass transfer rate at different operating conditions were measured. Graphical presentation of the results show the process control possibilities and the role of mixing intensity necessary to ensure that there is sufficient oxygen supply for a given cell concentration and respiration rate. PMID- 24061664 TI - Evaluation of Burning Test Rate Method for Flammable Solids to Increase air-Cargo Safety. AB - This paper deals with a standard classification procedure for readily combustible solids and their assignment to the relevant packing groups according to international air-cargo legislation and regulations. The current International Air Transport Association and United Nations Orange Book regulations were used on chemically similar substances: hexamethylenetetramine and Dancook ignition briquettes, which are both assigned into the same Packing Group III. To critically evaluate the degree of hazard both chemicals present, a standard burning test rate as well as thermogravimetry, differential scanning calorimetry and evolved gas analysis measurements were performed. It was shown that relatively small changes in the chemical composition of the material may have essential influence on the package group determination. Taking into account all the facts collected in the experimental work, it was concluded that ignition briquettes will undergo spontaneous combustion if exposed to elevated temperatures and, from this point of view, represent higher risk than hexamethylenetetramine during air transportation. Therefore, ignition briquettes should be classified into Packing Group II. PMID- 24061665 TI - Designing an underground car park fire scenarios on a probabilistic basis. AB - Designing a fire safety measures can be usually achieved in a two ways. One or we should say more conservative way is the use of prescriptive based codes, where all design prerequisites are mainly written in codes. Other or second option is the use of performance based design, where the group of designers, building owners and authorities having jurisdiction are setting up a milestone and design requirements. Simulation of fire and its consequences constitutes a cornerstone of modern fire safety engineering: the simulations enable to examine computationally the adequacy of the design with respect to a wide range of fire safety objectives including safety of life, directly exposed or neighboring property and infrastructure as well as the environment. Each simulation must be based on a realistic fire scenario, which technically formulates social expectation of safety. Designing realistic fire scenarios is even more important when underground car park is chosen as the subject of analysis. Setting the realistic goals and outcomes is a real technical problem that requires realistic and reliable inputs. It is found that fire scenario inputs can be statistical weighted and analyzed. PMID- 24061666 TI - Immobilization of yeast cells within microchannels of different materials. AB - Saccharomyces cerevisiae was successfully immobilized on the inner wall surface of channels of submillimeter diameter, which can be further used for the development of a highly productive continuous biotransformation process within a microfluidic device. Covalent bonding by means of 3-aminopropyltriethoxysilane (APTES) and glutaraldehyde was used for immobilization of cells to microchannels made of glass, polystyrene (PS), polytetrafluoroethylene (PTFE), perfluoroalkoxy (PFA) and fluorinated ethylene propylene (FEP). All tested materials were successfully functionalized with H2SO4 to promote silanization. The effect of reaction time with acid on immobilization efficiency was studied for polymer materials. This is the first report on cell immobilization onto PTFE, FEP and PFA surface, which enables to develop a microfluidic device with surface bound biocatalyst from low cost and disposable materials. PMID- 24061667 TI - Heat transfer in citric Acid production with axial and radial flow impellers. AB - In order to produce fermentation broth for downstream recovery, a total of 15 fermentations were done in a 15 m3 and two 7.5 m3 vessels. Apart from the evaluation of fermentation yield and productivity, information on the heat and mass transfer coefficients were required for design purposes. The focus of the fermentation study was therefore directed to obtain information on broth rheology, heat transfer aspects and considerations. Broth rheology was found to deviate from Newtonian behavior with increasing biomass concentration. Using axial flow impellers, rather than radial flow producing Rushton turbines, significantly improved heat transfer in this study. PMID- 24061668 TI - Electrocatalytic Oxidation of Isoproterenol and its Voltammetric Determination in Pharmaceuticals and Urine Samples Using a Poly(1-methylpyrrole)-DNA Modified Electrode. AB - Determination of isoproterenol (ISP) was carried out using a DNA incorporated poly(1-methylpyrrole) modified glassy carbon electrode (GCE). The poly(1 methylpyrrole)-DNA/GCE showed an excellent electrocatalytic effect on the oxidation of ISP. The poly(1-methypyrrole)-DNA/GCE also accelerated the rate of electron transfer reaction of ISP. Compared with a bare GCE, the poly(1 methylpyrrole)-DNA/GCE exhibits a distinct shift of the oxidation potential of ISP in the cathodic direction and a marked enhancement of the current response. A linear calibration plot was obtained covering the concentration range from 2.0 * 10-6 to 6.0 * 10-5 M with a detection limit of 1.60 * 10-7 M by cyclic voltammetry. The electrode system has also successfully resolved the overlapping anodic peak of ISP and uric acid (UA) into two well-defined voltammetric peaks in cyclic voltammetry at 0.416 V and 0.552 V for ISP and UA, respectively. The poly(1-methypyrrole)-DNA/GCE has successfully been utilised for the determination of ISP in pharmaceutical preparations. The validity of the proposed method was also assured by the recovery of ISP and UA in urine samples. PMID- 24061669 TI - Biosorption of Cadmium, Cobalt and Zinc by Moss Rhytidiadelphus squarrosus in the Single and Binary Component Systems. AB - Biomass of moss Rhytidiadelphus squarrosus was studied as a potential biosorbent for cadmium, cobalt and zinc removal from single and binary solutions. It was shown that solution pH significantly influenced Cd, Co and Zn biosorption. Maximum uptake was reached at pH 5.0-6.0 and negligible biosorption was observed at pH 2.0. Experimental equilibrium biosorption data for cadmium, cobalt and zinc were analysed by the Langmuir and Freundlich isotherm models. The Langmuir isotherm was found to well represent the measured sorption data in single metal systems. The maximum sorption capacities Qmax onto moss biomass were 186 umol/g for Zn, 173 umol/g for Cd and 123 umol/g for Co. Results revealed that the presence of Cd more significantly decreased the sorption of Co in binary Cd-Co mixtures than vice versa. In Cd-Zn binary system, both cadmium and zinc were sorbed with equal efficiency. The competitive Langmuir equations were used to fit the experimental data from the Zn-Cd and Cd-Co binary systems and simple two dimensional isotherm curves were replaced by three-dimensional sorption isotherm surfaces. PMID- 24061670 TI - Discharge characteristics and non-spectral interferences on the emission of ca species in a medium power radiofrequency capacitively coupled plasma source. AB - Non-spectral interference of easily ionized elements (EIEs) as chlorides and Al as AlCl3 and Al(NO3)3 on the emission of Ca II 393.367 nm, Ca I 422.673 nm, CaOH 554 nm and 622 nm were studied in a medium power radiofrequency capacitively coupled Ar plasma (275 W, 27.12 MHz) with single (SRTrfCCP) and double ring electrode (DRTrfCCP). The mechanisms of interferences were explained based on the matrix energy demand (MED) supposing the local thermal equilibrium (LTE) in plasma, emphasizing also processes contrasting with this model. Matrix effects were found to be dependent on the coupling geometry of the rf power to the torch, observation height, emitting Ca species and EIEs matrix nature but independent from Al as regards its salt origin. The magnitude of the matrix effects was correlated with the electron number density and the discharge temperature. The optimization of the observation height and use of the DRT geometry allowed the reduction of EIEs and Al matrix effects on the emission of Ca species compared to SRT. The best Ca detection limits in SRTrfCCP were at CaOH 622 nm (106-450 ng ml 1), while in DRTrfCCP at Ca I 422.673 nm (92-145 ng ml-1). PMID- 24061671 TI - Genetic polymorphisms in base excision repair in healthy slovenian population and their influence on DNA damage. AB - Genetic polymorphisms in DNA repair genes may result in altered DNA damage. The aim of our study was to determine the frequencies of common functional single nucleotide polymorphisms (SNPs) in specific base-excision DNA repair (BER) genes in healthy Slovenian population and evaluate their influence on DNA damage established by comet assay. In total 141 unrelated healthy subjects were genotyped for hOGG1 Ser326Cys, XRCC1 Arg194Trp and Arg399Gln polymorphisms by real-time TaqMan assay. The frequencies of the hOGG1 326Ser/Ser, 326Ser/Cys and 326Cys/Cys genotypes were 63.8, 29.8, and 6.4%, respectively. The frequency distribution of XRCC1 polymorphism was 88.7% for 194Arg/Arg, 9.2% for 194Arg/Trp, 2.1% for 194Trp/Trp and 46.8% for 399Arg/Arg 40.4% for 399Arg/Gln, 12.8% for 399Gln/Gln. The influence of selected BER polymorphisms on the percentage of comet tail DNA (% TD) was determined in a subgroup of 26 subjects. We found that% TD was significantly increased among individuals with hOGG1 326Ser/Cys heterozygous variant genotype as compared to 326Ser/Ser wild-type genotype (% TD = 8.9 +/- 4.2 vs. % TD = 6.9 +/- 1.4, P = 0.017). No significant associations between XRCC1 Arg194Trp and Arg399Gln polymorphisms and% TD were found. Our results confirmed that DNA damage is modulated by hOGG1 Ser326Cys polymorphism. PMID- 24061672 TI - Electrochemical and Spectroscopic Behaviors of 1-(o-, m-, p- Cl, or Br) Substituted Phenyl-3, 5-diphenylformazans in Dimethyl Sulfoxide. AB - 1-(o-, m-, p-Cl, -Br) substituted phenyl-3, 5-diphenylformazans were synthesized. Their structures were elucidated and spectral behaviours were investigated by elemental analysis, FT-IR, UV-vis spectral data. The electrochemical properties such as number of electrons transferred (n), diffusion coefficient (D) and heterogeneous rate constant (ks) were determined and possible mechanisms were proposed using platinum and ultramicro platinum electrodes, cyclic voltammetry, linear sweep voltammetry and chronoamperometry. The oxidations were carried out at different electrochemical steps that were dependent upon the structure of formazans. The relation between their absorption properties with electrochemical properties was investigated. A suitable correlation was obtained between the absorption lambdamax with electrochemical properties, and between the oxidation peak potentials Eox1 with ks values of formazans. PMID- 24061673 TI - pH Metric, Spectroscopic and Thermodynamic Study of Complexation Behavior of 2 aminobenzothiazole with Ni (II) in Presence of Amino Acids. AB - The complexation of 2-aminobenzothiazole (2abt) [A] with Ni(II) in presence of amino acids viz., glycine (gly), L-alanine (ala), L-valine (val) and L phenylalanine (pal) [B] in 50% (v/v) water-ethanol mixture containing NaClO4 (0.15 M) has been studied by pH metrically at various temperatures (300, 310, 320 and 330 +/- 0.1 K). Mixed ligand complexes of types NiAB and NiAB2 were observed and their stability constants were determined. The stabilization of mixed ligand complexes over binary analogues has been derived from Delta log K, log X' and log X values. The thermodynamic parameters DeltaG, DeltaH and DeltaS were derived from the temperature dependence of the equilibrium constants. The complexation behavior has also been studied by means of electronic spectra. On the basis of stability constants and electronic spectra, it is revealed that the mixed ligand complexes have six-coordinated octahedral structure. The binary and mixed ligand complexes were screened for their microbial activities in vitro on common bacteria, fungi and yeast. The DNA cleaving activities were studied by electrophoresis method. PMID- 24061674 TI - A study of midazolam plasma concentrations in patients undergoing conscious sedation. AB - We studied midazolam plasma concentrations in patients undergoing middle ear surgery (MES) in local anesthesia and sedation. This study was based on the clinical measurement of the level of sedation and determination of the sedation dose of midazolam. For optimal level of sedation for this type of surgery we suggest the midazolam plasma concentrations with median of 0.03 mg L-1 and range from 0.01-0.10 mg L-1. This can be contrasted to the other studies where considerably higher plasma concentrations of midazolam (0.2 mg L-1) were proposed (S. Michalk et al., Intens. Care Med. 1988, 15, 37-41). Despite low midazolam concentrations the level of sedation was adequate. PMID- 24061675 TI - Synthesis, Spectral, Thermal Analysis, Biological Activity and Kinetic Studies of Copper(II)-Pyridine-2,5-dicarboxylate Complexes with 2-Aminomethylpyridine and 8 Hydroxyquinoline. AB - In this work we report the synthesis of two novel square-planar copper(II) complexes, namely, (2-aminomethylpyridinium-pyridinedicarboxylato)copper(II) dihydrate, [Cu(pydc)(2-amp)] * 2H2O (1) and (8-hydroxyquinolinum pyridinedicarboxylato)copper(II) hydrate, [Cu(pydc)(8-HQ)] * H2O (2) (2-amp = 2 aminomethylpyridine, 8-HQ = 8-hydroxyquinoline, H2pydc = pyridine-2,5 dicarboxylic acid or isocinchomeronic acid) and present the first preliminary study on kinetics and biological activities of copper complexes. The synthesized complexes have been characterized by elemental, spectroscopic (FT-IR, UV and mass spectra), thermal analysis, magnetic and conductivity measurements techniques. Kinetic parameters were obtained for each stage of thermal degradation of the complexes using Coats-Redfern and Horowitz-Metzger methods. Antimicrobial activities of two complexes and two ligands were evaluated using agar diffusion method. Antimicrobial activity of complex 2 was determined with the agar dilution methods. The results were compared with two well known antibiotics, namely, tetracycline and nystatin. PMID- 24061676 TI - Amberlite XAD-4 Impregnated With a New Pentadentate Schiff base: a Chelating Collector for Separation and Preconcentration of Trace Amounts of Gallium (III) and Indium (III). AB - A new solid-phase extraction method for separation and preconcentration of trace amounts of Ga(III) and In(III) in biological and water samples is proposed. The procedure is based on the adsorption of Ga(III) and In(III) ions on a column of Amberlite XAD-4 resin loaded with newly-synthesized pentadentate naphthol derivative Schiff base 1-[(6-[(E)-1-(2-hydroxy-1-naphthyl)methylidene]amino-2 pyridyl)imino]methyl-2-naphthol (HMPN) prior to their determination by flame atomic absorption spectrometry (FAAS). The optimum pH values for quantitative sorption of Ga(III) and In(III) are 4.5-6.0 and 4.5-8.0, respectively, and their desorptions can be achieved by using 5 mL of 0.5 M HNO3. The sorption capacities of the resin for Ga(III) and In(III) were 1.27 and 1.45 mg g-1, respectively. The enrichment factor for preconcentration of Ga(III) and In(III) was found to be 200. The precision of the method, evaluated as the relative standard deviation obtained by analyzing a series of ten replicates, was below 3% for both elements. The proposed procedure was applied to the analysis of synthetic seawater, natural waters, wastewater and human blood serum using flame AAS. PMID- 24061677 TI - New fused pyrimidines of potential biosignificant interest. Syntheses and molecular modelling studies. AB - New derivatives of thieno[3,2-d]pyrimidine and thieno[2,3-b]pyrrole 5a,b and 6a,b, respectively, were obtained from the corresponding thiophene-2-carboxamides 4a,b. On the basis of compounds 5b, 6a and 6b, two novel series of tricyclic- and tetracyclic-condensed pyrimidines 8-15 and 16-19, respectively, were synthesized by the application of the cyclization reactions of 5b and 6a,b with a variety of commercially available reactants. Geometry optimization of selected structures, using the AM1 semiemperical method, revealed a smaller ionization potential and a lower degree of conformational freedom for the tetracyclic pyrimidine derivatives relative to their tricyclic counterparts. Interestingly, computation of the solvation free energies of the lowest energy conformers at physiological conditions indicated that the series is highly soluble under these conditions. The trend in solubility as implied by the relative magnitudes of the solvation free energies is suggestive of a greater contribution of higher moments of charge distribution in modulating the interaction of the structures with the biological environment which could be detrimental for the binding modes of these structures to their putative receptor sites. PMID- 24061678 TI - Enzymatic Esterification of Glycerol and Stearic Acid in Non-conventional Media. AB - Ionic liquids as trihexyl-tetradecyl-phophonium-dicyanamide (Cyphos 105) and cocosalkyl-pentaethoxi-methyl-ammonium-methosulfate (Ammoeng 100) were applied for the esterification of stearic acid and glycerol using Candida antarctica lipase (Novozyme 435). When only ILs were applied as solvents at 1:15 initial substrate molar ratio the conversion was 76 and 78 % in the case of two kinds of ILs, respectively. Mixed the ILs and supercritical CO2 the conversion reached 79 and 86 %. The conversion was found highest in supercritical CO2, reached 90 %. Moreover formation of glycerol-di-stearate is much lower in the case of ILs comparing with SCCO2. PMID- 24061679 TI - Ionic conductance of Lithium Exchanged Phases in Amorphous and Crystalline Zirconium Titanium Phosphate. AB - Lithium exchanged phases of amorphous and crystalline zirconium titanium phosphate have been synthesized by an ion exchange technique. These materials have been characterized by elemental analysis (ICP-AES and AAS), spectral analysis (FTIR), thermal analysis (TGA) and X-ray diffraction studies. The conductance properties of these materials have been explored by measuring specific conductance at different temperatures in the range of 30-250 degrees C at 10 degrees C intervals, using impedance analyzer over a frequency range 1 Hz 32 MHz at a signal level below 1 V. Lithium exchanged phases of amorphous and crystalline zirconium phosphate and titanium phosphate have also been synthesized under identical conditions, characterized and their conductance properties investigated for comparative studies. It is observed that, in all cases, conductivity decreases with increasing temperature. Conductance performance is discussed based on conductivity data and activation energy. PMID- 24061680 TI - Synthesis and Characterization of Two Diimine Schiff Bases Derived from 2,4 Dimethoxybenzaldehyde: The Crystal Structure of N,N'-Bis(2,4-dimethoxy benzylidene)-1,2-diaminoethane. AB - Two diimine Schiff bases derived from 2,4-dimethoxybenzaldehyde; N,N'-bis(2,4 dimethoxybenzylidene)-1,2-diaminoethane (1) and N,N'-bis(2,4 dimethoxybenzylidene)-1,4-diaminobutane (2), were prepared and characterized by elemental analyses, FT-IR and 1H NMR spectroscopy. The crystal structure of 1 has been determined by single crystal X-ray diffraction. Its molecule adopts an E configuration with respect to the C=N bond and is located on a center of inversion with one half-molecule in the asymmetric unit. PMID- 24061681 TI - The relationship between parent attitudes about childhood vaccines survey scores and future child immunization status: a validation study. AB - IMPORTANCE: Acceptance of childhood vaccinations is waning, amplifying interest in developing and testing interventions that address parental barriers to immunization acceptance. OBJECTIVE: To determine the predictive validity and test retest reliability of the Parent Attitudes About Childhood Vaccines survey (PACV), a recently developed measure of vaccine hesitancy. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort of English-speaking parents of children aged 2 months and born from July 10 through December 10, 2010, who belonged to an integrated health care delivery system based in Seattle and who returned a completed baseline PACV. Parents who completed a follow-up survey 8 weeks later were included in the reliability analysis. Parents who remained continuous members in the delivery system until their child was 19 months old were included in the validity analysis. EXPOSURE: The PACV, scored on a scale of 0 to 100 (100 indicates high vaccine hesitancy). MAIN OUTCOMES AND MEASURES: Child's immunization status as measured by the percentage of days underimmunized from birth to 19 months of age. RESULTS: Four hundred thirty-seven parents completed the baseline PACV (response rate, 50.5%), and 220 (66.5%) completed the follow-up survey. Of the 437 parents who completed a baseline survey, 310 (70.9%) maintained continuous enrollment. Compared with parents who scored less than 50, parents who scored 50 to 69 on the survey had children who were underimmunized for 8.3% (95% CI, 3.6%-12.8%) more days from birth to 19 months of age; those who scored 70 to 100, 46.8% (40.3%-53.3%) more days. Baseline and 8-week follow-up PACV scores were highly concordant (rho = 0.844). CONCLUSIONS AND RELEVANCE: Scores on the PACV predict childhood immunization status and have high reliability. Our results should be validated in different geographic and demographic samples of parents. PMID- 24061682 TI - Microbial community analysis of Deepwater Horizon oil-spill impacted sites along the Gulf coast using functional and phylogenetic markers. AB - We investigated the impact of the Deepwater Horizon oil spill on microbial communities in wetland sediment and seawater samples collected from sites along the Gulf shore. Based on GC/MS analysis, the sediment from Bay Jimmy, LA had detectable signs of hydrocarbon contamination, identified as n-alkanes in the GC/MS spectrum similar to that of the Deepwater Horizon source oil (MC-252). To identify changes in microbial assemblage structure and functional diversity in response to hydrocarbon contamination, five genes (bacterial 16S rRNA, Pseudomonas-specific 16S rRNA, alkB, P450, and PAH-RHDalpha) were selected based on the specific enzymes encoded by bacteria to degrade alkanes or polycyclic aromatic hydrocarbons. A quantitative PCR analysis revealed the presence of alkane and PAH-degrading genes in both contaminated and non-contaminated samples with no significant difference in gene content between contaminated and non contaminated samples. However, the ribotype analysis based on pyrosequencing identified 17 bacteria genera known for their capacity to degrade hydrocarbons, including Mycobacterium, Novosphingobium, Parvibaculum, Pseudomonas, and Sphingomonas, in the contaminated sediment sample. Furthermore, the contaminated sample had a very high relative abundance of 16S rRNA gene sequences affiliated with the genus Parvibaculum, members of which have been characterized for their degradative abilities. These data suggest that specific bacterial taxa within the genus Parvibaculum have the capacity for hydrocarbon degradation and could use the hydrocarbons as a carbon and energy source, resulting in a dominant population in a hydrocarbon-contaminated soil. In summary, when exposed to the spilled oil, the distinct wetland microbial communities responded with decreased diversity and increased abundance of selective degradative species. PMID- 24061683 TI - Left ventricular synchrony and function in pediatric patients with definitive pacemakers. AB - BACKGROUND: Chronic right ventricular pacing (RVP) induces a dyssynchronous contraction pattern,producing interventricular and intraventricular asynchrony. Many studies have shown the relationship of RVP with impaired left ventricular (LV) form and function. OBJECTIVE: The aim of this study was to evaluate LV synchrony and function in pediatric patients receiving RVP in comparison with those receiving LV pacing (LVP). METHODS: LV systolic and diastolic function and synchrony were evaluated in 80 pediatric patients with either nonsurgical or postsurgical complete atrioventricular block, with pacing from either the RV endocardium (n = 40) or the LV epicardium (n = 40). Echocardiographic data obtained before pacemaker implantation, immediately after it, and at the end of a mean follow-up of 6.8 years were analyzed. RESULTS: LV diastolic function did not change in any patient during follow-up. LV systolic function was preserved in patients with LVP. However, in children with RVP the shortening fraction and ejection fraction decreased from medians of 41% +/- 2.6% and 70% +/- 6.9% before implantation to 32% +/- 4.2% and 64% +/- 2.5% (p < 0.0001 and p < 0.0001), respectively, at final follow-up. Interventricular mechanical delay was significantly larger with RVP (66 +/- 13 ms) than with LVP (20 +/- 8 ms). Similarly, the following parameters were significantly different in the two groups: LV mechanical delay (RVP: 69 +/- 6 ms, LVP: 30 +/- 11 ms, p < 0.0001); septal to lateral wall motion delay (RVP: 75 +/- 19 ms, LVP: 42 +/- 10 ms, p < 0.0001); and, septal to posterior wall motion delay (RVP: 127 +/- 33 ms, LVP: 58 +/- 17 ms, p < 0.0001). CONCLUSION: Compared with RV endocardium, LV epicardium is an optimal site for pacing to preserve cardiac synchrony and function. PMID- 24061684 TI - Mechanical dyssynchrony is similar in different patterns of left bundle-branch block. AB - BACKGROUND: Left bundle-branch block (LBBB) and the presence of systolic dysfunction are the major indications for cardiac resynchronization therapy (CRT). Mechanical ventricular dyssynchrony on echocardiography can help identify patients responsive to CRT. Left bundle-branch block can have different morphologic patterns. OBJECTIVE: To compare the prevalence of mechanical dyssynchrony in different patterns of LBBB in patients with left systolic dysfunction. METHODS: This study assessed 48 patients with ejection fraction (EF) < 40% and LBBB consecutively referred for dyssynchrony analysis. Conventional echocardiography and mechanical dyssynchrony analysis were performed, interventricular and intraventricular, with ten known methods, using M mode, Doppler and tissue Doppler imaging, isolated or combined. The LBBB morphology was categorized according to left electrical axis deviation in the frontal plane and QRS duration > 150 ms. RESULTS: The patients' mean age was 60 +/- 11 years, 24 were males, and mean EF was 29% +/- 7%. Thirty-two had QRS > 150 ms, and22, an electrical axis between -30o and +90o. Interventricular dyssynchrony was identified in 73% of the patients, while intraventricular dyssynchrony, in 37% 98%. Patients with QRS > 150 ms had larger left atrium and ventricle, and lower EF (p < 0.05). Left electrical axis deviation associated with worse diastolic function and greater atrial diameter. Interventricular and intraventricular mechanical dyssynchrony (ten methods) was similar in the different LBBB patterns (p = ns). CONCLUSION: In the two different electrocardiographic patterns of LBBB analyzed, no difference regarding the presence of mechanical dyssynchrony was observed. PMID- 24061685 TI - Analysis of the sensitivity and specificity of noninvasive imaging tests for the diagnosis of renal artery stenosis. AB - BACKGROUND: Aging and atherosclerosis are related to renovascular hypertension in elderly individuals. Regardless of comorbidities, renal artery stenosis is itself an important cause of cardiovascular morbidity and mortality. OBJECTIVE: To define the sensitivity, specificity, positive predictive value, and negative predictive value of noninvasive imaging tests used in the diagnosis of renal artery stenosis. METHODS: In a group of 61 patients recruited, 122 arteries were analized, thus permitting the definition of sensitivity, specificity, and the relative contribution of each imaging study performed (Doppler, scintigraphy and computed tomographic angiography in comparison to renal arteriography). RESULTS: The mean age was 65.43 years (standard deviation: 8.7). Of the variables related to the study population that were compared to arteriography, two correlated with renal artery stenosis, renal dysfunction and triglycerides. The median glomerular filtration rate was 52.8 mL/min/m2. Doppler showed sensitivity of 82.90%, specificity of 70%, a positive predictive value of 85% and negative predictive value of 66.70%. For tomography, sensitivity was 66.70%, specificity 80%, positive predictive value 87.50% and negative predictive value 55.20%. With these findings, we could identify the imaging tests that best detected stenosis. CONCLUSION: Tomography and Doppler showed good quality and efficacy in the diagnosis of renal artery stenosis, with Doppler having the advantage of not requiring the use of contrast medium for the assessment of a disease that is common in diabetics and is associated with renal dysfunction and severe left ventricular dysfunction. PMID- 24061686 TI - Risk of ionizing radiation in women of childbearing age undergoing radiofrequency ablation. AB - BACKGROUND: The International Commission of Radiology recommends a pregnancy screening test to all female patients of childbearing age who will undergo a radiological study. Radiation is known to be teratogenic and its effect is cumulative. The teratogenic potential starts at doses close to those used during these procedures. The prevalence of positive pregnancy tests in patients undergoing electrophysiological studies and/or catheter ablation in our midst is unknown. OBJECTIVE: To evaluate the prevalence of positive pregnancy tests in female patients referred for electrophysiological study and/or radiofrequency ablation. METHODS: Cross-sectional study analyzing 2966 patients undergoing electrophysiological study and/or catheter ablation, from June 1997 to February 2013, in the Institute of Cardiology of Rio Grande do Sul. A total of 1490 procedures were performed in women, of whom 769 were of childbearing age. All patients were screened with a pregnancy test on the day before the procedure. RESULTS: Three patients tested positive, and were therefore unable to undergo the procedure. The prevalence observed was 3.9 cases per 1000 women of childbearing age. CONCLUSION: Because of their safety and low cost, pregnancy screening tests are indicated for all women of childbearing age undergoing radiological studies, since the degree of ionizing radiation needed for these procedures is very close to the threshold for teratogenicity, especially in the first trimester, when the signs of pregnancy are not evident. PMID- 24061687 TI - Production of biosurfactant on crude date syrup under saline conditions by entrapped cells of Natrialba sp. strain E21, an extremely halophilic bacterium isolated from a solar saltern (Ain Salah, Algeria). AB - A bacterial strain E21 was isolated from a sample of water collected in the salt lake located close to Ain Salah, Algeria. The analysis of 16S rRNA gene sequence had indicated that the strain had 93 % sequence similarity with the genus Natrialba sp. strain E21 (GenBank, FR750525.1) and was considered extremely halophilic. Production of biosurfactant by the strain E21 with free and entrapped cells was investigated using soluble starch in the saline conditions. Biosurfactant synthesis was followed by measuring the surface tension and emulsifying index 9 days under optimal conditions (40 degrees C, pH 7). Some diffusional limitations in alginate and agar beads affected the kinetics of biosurfactant production when compared to that obtained with free cells culture. The minimum values of surface tension were 27 and 30 mN m(-1) achieved after 9 days with free and immobilized cells, respectively, while the corresponding maximum E24 values were 65.3 and 62.3 %, respectively. The re-use of bacterial cells along with the limited cell losses provided by the immobilized system might lead to significant reduction of the biosurfactant production cost. PMID- 24061688 TI - Molecular epidemiology of Newcastle disease viruses in Vietnam. AB - Newcastle disease virus (NDV) causes significant economic losses to the poultry industry in Southeast Asia. In the present study, 12 field isolates of NDV were recovered from dead village chickens in Vietnam between 2007 and 2012, and were characterized. All the field isolates were classified as velogenic. Based on the sequence analysis of the F variable region, two distinct genetic groups (Vietnam genetic groups G1 and G2) were recognized. Phylogenetic analysis revealed that all the 12 field isolates fell into the class II genotype VII cluster. Ten of the field isolates, classified as Vietnam genetic group G1, were closely related to VIIh viruses that had been isolated from Indonesia, Malaysia, and Cambodia since the mid-2000s, while the other two field isolates, of Vietnam genetic group G2, clustered with VIId viruses, which were predominantly circulating in China and Far East Asia. Our results indicate that genotype VII viruses, especially VIIh viruses, are predominantly responsible for the recent epizootic of the disease in Vietnam. PMID- 24061689 TI - Persistent organic pollutants in solid waste management. PMID- 24061690 TI - The role of transcription in heterologous expression of polyketides in bacterial hosts. AB - Heterologous expression of biosynthetic pathways is an indispensable tool in the discovery, production, engineering, and characterization of bacterial polyketides and the complex enzymology involved in their biosynthesis. Ensuring transcription of polyketide biosynthetic gene clusters in heterologous hosts is a pressing problem. This review evaluates the two strategies used to ensure transcription. The first is a promoter replacement approach where promoters known to function in the heterologous host are inserted into the biosynthetic gene cluster. The second is an approach that relies on the heterologous host recognizing and utilizing promoters native to the gene cluster. Both have been successful methodologies and have different strengths and weaknesses, which are highlighted and discussed. PMID- 24061691 TI - Prediction of outcomes in MCI with (123)I-IMP-CBF SPECT: a multicenter prospective cohort study. AB - OBJECTIVE: The multicenter prospective cohort study (Japan Cooperative SPECT Study on Assessment of Mild Impairment of Cognitive Function: J-COSMIC) aimed to examine the value of (123)I-N-isopropyl-4-iodoamphetamine cerebral blood flow (IMP-CBF) SPECT in regards to early diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). METHODS: Three hundred and nineteen patients with amnestic MCI at 41 participating institutions each underwent clinical and neuropsychological examinations and (123)I-IMP-CBF SPECT at baseline. Subjects were followed up periodically for 3 years, and progression to dementia was evaluated. SPECT images were classified as AD/DLB (dementia with Lewy bodies) pattern and non-AD/DLB pattern by central image interpretation and automated region of interest (ROI) analysis, respectively. Logistic regression analyses were used to assess whether baseline (123)I-IMP-CBF SPECT was predictive of longitudinal clinical outcome. RESULTS: Ninety-nine of 216 amnestic MCI patients (excluding 3 cases with epilepsy (n = 2) or hydrocephalus (n = 1) and 100 cases with incomplete follow-up) converted to AD within the observation period. Central image interpretation and automated ROI analysis predicted conversion to AD with 56 and 58 % overall diagnostic accuracy (sensitivity, 76 and 81 %; specificity, 39 and 37 %), respectively. Multivariate logistic regression analysis identified SPECT as a predictor, which distinguished AD converters from non-converters. The odds ratio for a positive SPECT to predict conversion to AD with automated ROI analysis was 2.5 and combining SPECT data with gender and mini-mental state examination (MMSE) further improved classification (joint odds ratio 20.08). CONCLUSIONS: (123)I-IMP-CBF SPECT with both automated ROI analysis and central image interpretation was sensitive but relatively nonspecific for prediction of clinical outcome during the 3-year follow-up in individual amnestic MCI patients. A combination of statistically significant predictors, both SPECT with automated ROI analysis and neuropsychological evaluation, may increase predictive utility. PMID- 24061692 TI - Solid dispersion tablets of breviscapine with polyvinylpyrrolidone K30 for improved dissolution and bioavailability to commercial breviscapine tablets in beagle dogs. AB - Breviscapine, one of cardiovascular drugs extracted from a Chinese herb Erigeron breviscapinus, has been frequently used to treat cardiovascular diseases such as hypertension, angina pectoris, coronary heart disease and stroke. However, its poor water solubility and low bioavailability in vivo severely restrict the clinical application. To overcome these drawbacks, breviscapine solid dispersion tablets consisting of breviscapine, polyvinylpyrrolidone K30 (PVP K30), microcrystalline cellulose and crospovidone were appropriately prepared. In vitro dissolution profiles showed that breviscapine released percentage of solid dispersion tablets reached 90 %, whereas it was only 40 % for commercial breviscapine tablets. Comparative pharmacokinetic study between solid dispersion tablets and commercial products was investigated on the normal beagle dogs after oral administration. Results showed that the bioavailability of breviscapine was greatly increased by 3.45-fold for solid dispersion tablets. The greatly improved dissolution rate and bioavailability might be attributed to intermolecular hydrogen bonding reactions between PVP K30 and scutellarin. These findings suggest that our solid dispersion tablets can greatly improve the bioavailability as well as the dissolution rate of breviscapine. PMID- 24061693 TI - Intermediate to long-term follow-up results of INH chemoprophylaxis prior to anti TNF-alpha therapy in a high-risk area for tuberculosis. AB - BACKGROUND: The use of anti-TNF drugs for rheumatic diseases has increased in recent years. Several studies have reported an increased risk of reactivation of tuberculosis (TB) with anti-TNF agents. OBJECTIVES: The aim of this study was to present the follow-up results of a single center from Turkey, a country with a high rate of active and latent tuberculosis infection (LTBI), for INH chemoprophylaxis in patients receiving anti-TNF-alpha therapy for rheumatic diseases infection. METHODS: In this prospective observational study, consenting patients who were to be administered an anti-TNF agent for a rheumatic disease were evaluated for the presence of active infection or LTBI by a chest X-ray and a tuberculin skin test. Patients with LTBI were given chemoprophylaxis 1 month prior to commencement of anti-TNF treatment. All patients were followed-up bimonthly for any signs of pulmonary or extrapulmonary TB. RESULTS: A total of 73 patients, 23 female (31.5 %) and 50 male (68.5 %), with a mean age of 41.0 +/- 13.1 years (18-78) were enrolled in the study. Overall, 44 patients (60.3 %) had ankylosing spondylitis, 18 (24.7 %) had rheumatoid arthritis, 7 (9.6 %) had juvenile rheumatoid arthritis, and 3 (4.1 %) had psoriatic arthritis. LTBI was identified in 58 patients all of whom received chemoprophylaxis for 9 months. None of the patients in the study developed any signs of tuberculosis reactivation during follow-up. CONCLUSIONS: TST is a reliable and cost-effective method for the diagnosis of LTBI in patients prior to anti-TNF therapy. Moreover, chemoprophylaxis with INH seems to be effective for the prevention of TB reactivation in individuals with LTBI. PMID- 24061695 TI - Epidemiology of patients hospitalised for pneumonia in 2011: a prospective multicentre cohort study. AB - This study was conducted to investigate the age dependent epidemiology of pneumonia and risk factors for mortality.The data were derived from the Austrian Pneumonia Network (APNET), comprising nine Departments for Internal Medicine with a total of 1,011 hospital beds. All inpatients diagnosed with pneumonia during 2011 were followed until discharge. Identification of microorganisms was performed according to local standard methods. Data of patients < 65 years and >= 65 years were compared by Mann-Whitney and the Chi-square tests. Risk factors for hospital mortality were evaluated by univariate and multivariate analyses.Overall, 1,956 patients were included. The hospital mortality was 10.4 %, and was higher in patients >= 65 (12.7 %) than in patients < 65 years of age (5.0 %; p < 0.001). Streptococcus (S.) pneumoniae was the most important pathogen. Enterobacteriacaeae were revealed significantly more often in patients >= 65 years. Age >= 65 years, chronic heart failure (CHF) and neurological disease increased the risk of hospital mortality 1.96 (95 % CI 1.19-3.20), 1.59 (95 % CI 1.10-2.29), and 1.7 (95 % CI 1.19-2.41)-fold, respectively.In conclusion, pneumonia patients with CHF, neurological disease and age >= 65 years could benefit from intensified care due to increased risk of in-hospital death. PMID- 24061696 TI - Transperineal template-guided biopsy for diagnosis of prostate cancer in patients with at least two prior negative biopsies. AB - OBJECTIVE: To evaluate the prostate cancer (PCa) detection rate, PCa location, PCa significance and complications of a standardized 24-core template-guided transperineal biopsy (TPB) approach in patients with at least two negative transrectal biopsies. METHODS: We prospectively recruited 50 men who had at least two negative transrectal ultrasound-guided extended biopsies in the past 24 months, a prostate-specific antigen (PSA) < 20 ng/mL, a prostate volume < 100 mL, and life expectancy of at least 90 % at 10 years. All patients underwent a standardized 24-core template-guided TPB biopsy. The PCa detection rate, PCa location, PCa significance, and complications were recorded. RESULTS: Median age was 57.5 years and the median PSA level was 7.3 ng/ml. PCa was detected in 24 patients (48 %). The anterior zone was involved in 16 (32 %) PCa. Six PCa (25 %) were insignificant. Biopsy related complications occurred in 2 patients (4 %). CONCLUSIONS: A 24-core TPB is a safe procedure with a high PCa detection rate. Few of the detected PCa are clinically insignificant. Men with at least two negative transrectal biopsies may be counseled to undergo TPB. PMID- 24061694 TI - Review on novel concepts of columnar lined esophagus. AB - BACKGROUND: Columnar lined esophagus (CLE) is a marker for gastroesophageal reflux and associates with an increased cancer risk among those with Barrett's esophagus. Recent studies fostered the development of integrated CLE concepts. METHODS: Using PubMed, we conducted a review of studies on novel histopathological concepts of nondysplastic CLE. RESULTS: Two histopathological concepts-the squamo-oxyntic gap (SOG) and the dilated distal esophagus (DDE), currently model our novel understanding of CLE. As a consequence of reflux, SOG interposes between the squamous lined esophagus and the oxyntic mucosa of the proximal stomach. Thus the SOG describes the histopathology of CLE within the tubular esophagus and the DDE, which is known to develop at the cost of a shortened lower esophageal sphincter and foster increased acid gastric reflux. Histopathological studies of the lower end of the esophagus indicate, that the DDE is reflux damaged, dilated, gastric type folds forming esophagus and cannot be differentiated from proximal stomach by endoscopy. While the endoscopically visible squamocolumnar junction (SCJ) defines the proximal limit of the SOG, the assessment of the distal limit requires the histopathology of measured multilevel biopsies. Within the SOG, CLE types distribute along a distinct zonation with intestinal metaplasia (IM; Barrett's esophagus) and/or cardiac mucosa (CM) at the SCJ and oxyntocardiac mucosa (OCM) within the distal portion of the SOG. The zonation follows the pH-gradient across the distal esophagus. Diagnosis of SOG and DDE includes endoscopy, histopathology of measured multi-level biopsies from the distal esophagus, function, and radiologic tests. CM and OCM do not require treatment and are surveilled in 5 year intervals, unless they associate with life quality impairing symptoms, which demand medical or surgical therapy. In the presence of an increased cancer risk profile, it is justified to consider radiofrequency ablation (RFA) of IM within clinical studies in order to prevent the progression to dysplasia and cancer. Dysplasia justifies RFA +/- endoscopic resection. CONCLUSIONS: SOG and DDE represent novel concepts fusing the morphological and functional aspects of CLE. Future studies should examine the impact of SOG and DDE for monitoring and management of gastroesophageal reflux disease (GERD). PMID- 24061697 TI - Estimated glomerular filtration rate and albuminuria: true predictors of cardiovascular events in obese patients with type 2 diabetes? AB - BACKGROUND: The widely used MDRD formula underestimates kidney function in obese patients with diabetes mellitus. Therefore we aimed to evaluate the predictive value of estimated glomerular filtration rate (eGFR) for cardiovascular events in a typical cohort of patients with diabetes mellitus. METHODS: A total of 988 patients were analyzed. Cox regression models including the variables HbA1c, age, duration of diabetes, eGFR and urinary albumin to creatinine ratio (UACR) were run. First the whole collective was analyzed, in a second step the cohort was split into four different groups according to body mass index (BMI) and eGFR (Group 1, 475 Pts: eGFR > 60 ml/min; BMI < 30 kg/m(2), Group 2, 274 Pts: eGFR > 60 ml/min;BMI > 30 kg/m(2), Group 3, 110 Pts,: eGFR < 60 ml/min; BMI > 30 kg/m(2) and Group 4, 129 Pts.: eGFR < 60 ml/min;BMI < 30 kg/m(2)). eGFR was calculated using MDRD, Cockroft-Gault, and CKD-EPI formula. The endpoint was defined as unplanned cardiovascular hospitalization. RESULTS: Patients (571 male, 417 female) were 61 +/- 22 years of age, mean duration of diabetes was 14.3 +/- 12.3 years. After a median follow-up of 29 months 95 (9.6 %) patients reached the defined endpoint. The first model, including all patients showed that UACR (HR 1.001, p < 0.001) and eGFR (HR 0.957, p < 0.001) were significant predictors of the composite endpoint. In obese patients eGFR completely lost its predictive value for cardiovascular events. The prevalence of normoalbuminuria in patients with an eGFR below 60 ml/min was 59.4 %. CONCLUSION: In obese patients eGFR is not predictive for cardiovascular events. PMID- 24061699 TI - Estimation of sex from sternal dimensions derived from chest plate radiographs in contemporary Spaniards. AB - A number of previous studies have demonstrated that osteometric analysis of the sternum provides a highly accurate method for discriminating adult sex in diverse population groups. In this study, sternal measurements were recorded from posteroanterior digital radiographs of the chest plate of 116 Spanish individuals (65 males and 51 females). Results demonstrated that all linear dimensions of the manubrium and mesosternum, sternal area, and sternal index were significantly sexually dimorphic in this population group. Discriminant function analyses incorporating several of these variables, individually or in combination, provided sex classification accuracy rates greater than 80.0%, with associated sex biases below 5.0%. A stepwise procedure, which can be used when a complete sternum is present, yielded the highest correct sex classification rate at 89.7%. Only slightly lower allocation accuracy rates were obtained for multivariate equations which incorporated either dimensions of the manubrium or mesosternum (87.1% for both formulae). Thus, the derived discriminant function equations should prove useful in forensic investigations, particularly those in which the pelvis or bones of the extremities are not available for analysis. PMID- 24061700 TI - Allergic reactions following contrast material administration: nomenclature, classification, and mechanisms. AB - In forensic pathology routine, fatal cases of contrast agent exposure can be occasionally encountered. In such situations, beyond the difficulties inherent in establishing the cause of death due to nonspecific or absent autopsy and histology findings as well as limited laboratory investigations, pathologists may face other problems in formulating exhaustive, complete reports, and conclusions that are scientifically accurate. Indeed, terminology concerning adverse drug reactions and allergy nomenclature is confusing. Some terms, still utilized in forensic and radiological reports, are outdated and should be avoided. Additionally, not all forensic pathologists master contrast material classification and pathogenesis of contrast agent reactions. We present a review of the literature covering allergic reactions to contrast material exposure in order to update used terminology, explain the pathophysiology, and list currently available laboratory investigations for diagnosis in the forensic setting. PMID- 24061702 TI - Variations of the cerebellar arteries at CT angiography. AB - PURPOSE: There are few studies that investigated variations of the cerebellar arteries, and the prevalence of some variations has not been reported. We aim to identify and evaluate variations of the cerebellar arteries using CTA. METHODS: The findings in 341 patients who underwent 64-slice CTA were reviewed for anatomical variations of the cerebellar arteries. We assessed variations and classified our findings to describe the results of our analysis. We attempted to create an anatomical model for CTA that is somewhat different from previous studies and described our findings according to vascular anatomy. RESULTS: Only 11.7% of the 341 patients had all the cerebellar arteries without anatomical variations. Vertebral artery continuation as posterior inferior cerebellar artery (PICA) was found in 4.4% of the patients. Absence of the anterior inferior cerebellar artery (AICA) was observed in 36.1%, and absence of the PICA was observed in 6.7% of the patients. The origin of the PICA was extradural in 71 (20.8%) patients. Double origin of the PICA, PICA duplication, and fenestration were rarely found. Duplication of the AICA (7.9%), and superior cerebellar artery (SCA) (20.5%), and early bifurcation of SCA (9.4%) were frequently observed. Superior cerebellar artery and posterior cerebral artery (PCA) common trunk and SCA originating from PCA were found 9.4 and 8.2%, respectively. CONCLUSION: Variations of the cerebral arteries can be easily evaluated by CTA. Recognizing and reporting them at cerebral CT angiography may be clinically important. PMID- 24061701 TI - The future of osteoarthritis therapeutics: targeted pharmacological therapy. AB - Osteoarthritis (OA) is one of the most common forms of degenerative joint disease and a major cause of pain and disability affecting the aging population. It is estimated that more than 20 million Americans and 35 to 40 million Europeans suffer from OA. Analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) are the only therapeutic treatment options for OA. Effective pharmacotherapy for OA, capable of restoring the original structure and function of damaged cartilage and other synovial tissue, is urgently needed, and research into such disease modifying osteoarthritis drugs (DMOADs) is in progress. This is the first of three reviews focusing on OA therapeutics. This paper provides an overview of current research into potential structure-modifying drugs and more appropriately targeted pharmacological therapy. The challenges and opportunities in this area of research and development are reviewed, covering the most up-to-date initiatives, trends, and topics. PMID- 24061703 TI - [Operative management of clavicular non-union : Iliac crest bone graft and anatomic locking compression plate]. AB - OBJECTIVE: The objective in treating clavicular non-union is an anatomic reconstruction of the clavicle with an iliac crest bone graft and anatomic locking compression plates. INDICATIONS: Non-union or bony defects of the clavicle larger than 1.5 cm. CONTRAINDICATIONS: Any suspicion of infection, elevated risk of transplant necrosis or recurrent non-union due to concomitant disease, medication, cigarette smoking (>10 cig./d), poor therapeutic compliance regarding specific postoperative management and poor physical status. SURGICAL TECHNIQUE: Patient in beach chair position with a flexible affected arm. An longitudinal skin incision is made below the clavicle with subsequent incision through the clavipectoral fascia and the periosteum, complex multidimensional osteotomy of the clavicle with medial and lateral axial correction of the pseudarthrosis up to vital bone, harvesting of a tricortical iliac crest bone graft with the size measured in preoperative computed tomography (CT) according to the length of the healthy contralateral clavicle. Final shaping of the iliac crest bone graft regarding the future clavicular position, positioning of the anatomic plate (LCP superior anterior clavicle plate with or without lateral extension, Depuy Synthes, Umkirch, Germany) and drilling and screw insertion under radiological guidance. If necessary additional attachment of the iliac crest bone graft with suture cerclage (FiberWire, Arthrex, Karlsfeld, Germany) or screw should be carried out. A final radiological examination and hemostasis of the iliac crest with a Lyostypt collagen hemostatic fleece and the clavicle. Drains might be needed and wound closure layer by layer with sutures. POSTOPERATIVE MANAGEMENT: Arm sling protection for 6 weeks with physiotherapeutic exercises and increased range of motion every 2 weeks and unrestricted range of motion from week 7 onwards. Full weight bearing is not allowed before week 12 and X-ray examinations to confirm bone healing should be done 3, 6, 12 and 24 weeks postoperatively. Implant removal at an earliest time point of 2 years can be performed when full osseous integration of the graft is radiologically confirmed. RESULTS: At our department 10 consecutive patients suffering from clavicular non union have been treated with this technique with a minimum follow-up of 1 year. All patients showed anatomic restoration of the radiologically confirmed healed clavicle with very good patient satisfaction. PMID- 24061704 TI - A secure RFID-based WBAN for healthcare applications. AB - A Wireless Body Area Network (WBAN) allows the seamless integration of small and intelligent invasive or non-invasive sensor nodes in, on or around a human body for continuous health monitoring. These nodes are expected to use different power efficient protocols in order to extend the WBAN lifetime. This paper highlights the power consumption and security issues of WBAN for healthcare applications. Numerous power saving mechanisms are discussed and a secure RFID-based protocol for WBAN is proposed. The performance of the proposed protocol is analyzed and compared with that of IEEE 802.15.6-based CSMA/CA and preamble-based TDMA protocols using extensive simulations. It is shown that the proposed protocol is power-efficient and protects patients' data from adversaries. It is less vulnerable to different attacks compared to that of IEEE 802.15.6-based CSMA/CA and preamble-based TDMA protocols. For a low traffic load and a single alkaline battery of capacity 2.6 Ah, the proposed protocol could extend the WBAN lifetime, when deployed on patients in hospitals or at homes, to approximately five years. PMID- 24061705 TI - An improved and effective secure password-based authentication and key agreement scheme using smart cards for the telecare medicine information system. AB - Recently Lee and Liu proposed an efficient password based authentication and key agreement scheme using smart card for the telecare medicine information system [J. Med. Syst. (2013) 37:9933]. In this paper, we show that though their scheme is efficient, their scheme still has two security weaknesses such as (1) it has design flaws in authentication phase and (2) it has design flaws in password change phase. In order to withstand these flaws found in Lee-Liu's scheme, we propose an improvement of their scheme. Our improved scheme keeps also the original merits of Lee-Liu's scheme. We show that our scheme is efficient as compared to Lee-Liu's scheme. Further, through the security analysis, we show that our scheme is secure against possible known attacks. In addition, we simulate our scheme for the formal security verification using the widely accepted AVISPA (Automated Validation of Internet Security Protocols and Applications) tool to show that our scheme is secure against passive and active attacks. PMID- 24061706 TI - The secure authorization model for healthcare information system. AB - Exploring healthcare system for assisting medical services or transmitting patients' personal health information in web application has been widely investigated. Information and communication technologies have been applied to the medical services and healthcare area for a number of years to resolve problems in medical management. In the healthcare system, not all users are allowed to access all the information. Several authorization models for restricting users to access specific information at specific permissions have been proposed. However, as the number of users and the amount of information grows, the difficulties for administrating user authorization will increase. The critical problem limits the widespread usage of the healthcare system. This paper proposes an approach for role-based and extends it to deal with the information for authorizations in the healthcare system. We propose the role-based authorization model which supports authorizations for different kinds of objects, and a new authorization domain. Based on this model, we discuss the issues and requirements of security in the healthcare systems. The security issues for services shared between different healthcare industries will also be discussed. PMID- 24061707 TI - Hydrogen-bonding interactions between [BMIM][BF4] and acetonitrile. AB - In this work, the interactions between a representative imidazolium-based ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]) and acetonitrile (CH3CN) were investigated in detail using attenuated total reflection infrared spectroscopy (ATR-IR), hydrogen nuclear magnetic resonance ((1)H NMR), and density functional theory calculations. The main conclusions are: (1) a number of species in the [BMIM][BF4]-CH3CN mixtures were identified with the help of excess infrared spectroscopy and quantum chemical calculations. The dilution process of the ionic liquid by acetonitrile was found to be the transformation from ion clusters to ion pairs. (2) The solvent molecules cannot break apart the strong Coulombic interaction between [BMIM](+) and [BF4](-) but can break apart the ion cluster into an ion pair within the concentration range investigated. The strength of hydrogen bonds between the C-Hs of [BMIM](+) and the N of acetonitrile is enhanced during the dilution process. (3) The methyl group of CH3CN locates above/below the imidazolium ring in the solution. These in depth studies on the properties of the ionic liquid-acetonitrile mixed solvents may shed light on exploring their applications as reaction media in electrochemistry and chemical synthesis. PMID- 24061709 TI - Non-renal adverse reactions to contrast media: separating fact from myth. PMID- 24061708 TI - Influence of bedsharing activity on breastfeeding duration among US mothers. AB - IMPORTANCE: Some professional associations advocate bedsharing to facilitate breastfeeding, while others recommend against it to reduce the risk of sudden infant death syndrome and suffocation deaths. A better understanding of the quantitative influence of bedsharing on breastfeeding duration is needed to guide policy. OBJECTIVE: To quantify the influence of bedsharing on breastfeeding duration. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal data were from the Infant Feeding Practices Study II, which enrolled mothers while pregnant and followed them through the first year of infant life. Questionnaires were sent at infant ages 1 to 7, 9, 10, and 12 months, and 1846 mothers answered at least 1 question regarding bedsharing and were breastfeeding at infant age 2 weeks. EXPOSURES: Bedsharing, defined as the mother lying down and sleeping with her infant on the same bed or other sleeping surfaces for nighttime sleep or during the major sleep period. MAIN OUTCOMES AND MEASURES: Survival analysis to investigate the effect of bedsharing on duration of any and exclusive breastfeeding. RESULTS: Longer duration of bedsharing, indicated by a larger cumulative bedsharing score, was associated with a longer duration of any breastfeeding but not exclusive breastfeeding, after adjusting for covariates. Breastfeeding duration was longer among women who were better educated, were white, had previously breastfed, had planned to breastfeed, and had not returned to work in the first year postpartum. CONCLUSIONS AND RELEVANCE: Multiple factors were associated with breastfeeding, including bedsharing. Given the risk of sudden infant death syndrome related to bedsharing, multipronged strategies to promote breastfeeding should be developed and tested. PMID- 24061710 TI - Right statistical methods should be driven to get the right answers from research studies. PMID- 24061711 TI - Reply to 'Right statistical methods should be driven to get the right answers from research studies'. PMID- 24061712 TI - Effect of test duration and feeding on relative sensitivity of genetically distinct clades of Hyalella azteca. AB - The amphipod Hyalella azteca is widely used in ecotoxicology laboratories for the assessment of chemical risks to aquatic environments, and it is a cryptic species complex with a number of genetically distinct strains found in wild populations. While it would be valuable to note differences in contaminant sensitivity among different strains collected from various field sites, those findings would be influenced by acclimation of the populations to local conditions. In addition, potential differences in metabolism or lipid storage among different strains may confound assessment of sensitivity in unfed acute toxicity tests. In the present study, our aim was to assess whether there are genetic differences in contaminant sensitivity among three cryptic provisional species of H. azteca. Therefore, we used organisms cultured under the same conditions, assessed their ability to survive for extended periods without food, and conducted fed and unfed acute toxicity tests with two anions (nitrate and chloride) whose toxicities are not expected to be altered by the addition of food. We found that the three genetically distinct clades of H. azteca had substantially different responses to starvation, and the presence/absence of food during acute toxicity tests had a strong role in determining the relative sensitivity of the three clades. In fed tests, where starvation was no longer a potential stressor, significant differences in sensitivity were still observed among the three clades. In light of these differences in sensitivity, we suggest that ecotoxicology laboratories consider using a provisional species in toxicity tests that is a regionally appropriate surrogate. PMID- 24061713 TI - Efficacy of common surgical compounds in preventing articular chondrocyte death from desiccation. AB - PURPOSE: Purpose of this study was to identify potential substances that prevent desiccation of chondrocytes. METHODS: Macroscopically normal bovine cartilage explants (n = 80) were exposed to room air, or covered with surgical lubricant, Lactated ringer (LR) or Seprafilm (Genzyme Biosurgery, Cambridge, MA) for 0, 30, 60 or 120 min. The viability of superficial chondrocytes was measured after 48 h of incubation in tissue culture media at 37 degrees C by Live/Dead staining. Chondrotoxicity was measured as the extent of cell death below the articular surface. Statistical analysis was performed with a two-way analysis of variance on the data set and a subsequent Tukey's post hoc test. RESULTS: Chondrocyte death correlated positively with the length of exposure, regardless of the treatment (p < 0.0001). The extent of superficial chondrocyte death was minimally lower in the LR (89.1 +/- 2.6 %, 80.8 +/- 1.2 %) and surgical lube (84.3 +/- 1.8 %, 75.9 +/- 2.7 %) groups than the control (82 +/- 5.7 %, 65.6 +/- 13.3 %) and Seprafilm group (77.6 +/- 3.9 %, 63.3 +/- 6.9 %) (p < 0.001) at the first two time points, with no significant difference between the latter groups. After 60 and 120 min, surgical lube resulted in less chondrocyte death than all other groups (70.4 +/- 6.8 % and 60.9 +/- 5.9 %, all p < 0.0001). CONCLUSION: The data suggest that depending on the expected length of exposure of the articular cartilage surface, different compounds appear to be protective. For exposures exceeding 60 min, surgical lubricant demonstrated the highest protective potential. Results from this study indicate that protecting exposed articular surfaces with surgical lubricant for orthopaedic procedures lasting more than 1 h lead to decreased chondrocyte death and suggest improved cartilage functional outcomes postoperatively. PMID- 24061714 TI - Long-term clinical and radiographic outcome of patello-femoral realignment procedures: a minimum of 15-year follow-up. AB - PURPOSE: A retrospective single-centre study was focused on the long-term outcome after different patello-femoral (PF) realignment procedures. METHODS: Thirty-nine patients treated for recurrent PF instability were examined after a mean post operative time of 22.5 years. Their 78 knees were divided into: non-operated knees (NON-OPERATED)-N = 24, isolated proximal procedures (PROXIMAL)-N = 22, isolated distal procedures (DISTAL)-N = 10, and combined procedures (COMBINED)-N = 22. PF-related medical history together with clinical, subjective (KOOS and Kujala scores), and radiographic (Caton-Deschamps PF height index, Kellgren Lawrence scale for tibio-femoral OA, and Iwano classification for PF OA) evaluation was conducted. RESULTS: PF re-dislocation rate was comparable between PROXIMAL (36%), DISTAL (20%), and COMBINED (32%). Isolated proximal procedures revealed less central patella positions (PROXIMAL 64%; DISTAL 90%; COMBINED 95%) and more frequent PF apprehension test (PROXIMAL 82%; DISTAL 40%, COMBINED 50%). KOOS and Kujala scores were similar in all three surgical subgroups, but significantly lower than in NON-OPERATED. Patellas were positioned lower after DISTAL, 0.8 (0.5-1.0) or COMBINED, 0.9 (0.4-1.3). Kellgren-Lawrence scores >=2 were found in 42% NON-OPERATED, 37% PROXIMAL, 70% DISTAL, and 59% COMBINED, whereas Iwano classification >=2 was confirmed in 46% NON-OPERATED, 64% PROXIMAL, 80% DISTAL, and 86% COMBINED. CONCLUSIONS: High PF re-dislocation rates together with a very high incidence of PF OA indicate that PF realignment strategies used traditionally had failed to reach their long-term expectations. The transfer of tibial tuberosity resulted in more constrained PF joints than isolated proximal procedures which allowed for more residual PF instability. Distal procedures additionally increased the likelihood for tibio-femoral OA. LEVEL OF EVIDENCE: III. PMID- 24061715 TI - Navigated total knee arthroplasty: is it error-free? AB - PURPOSE: The aim of this study was to determine whether errors do occur in navigated total knee arthroplasty (TKAs) and to study whether errors in bone resection or implantation contribute to these errors. METHODS: A series of 20 TKAs was studied using computer navigation. The coronal and sagittal alignments of the femoral and tibial cutting guides, the coronal and sagittal alignments of the final tibial implant and the coronal alignment of the final femoral implant were compared with that of the respective bone resections. To determine the post implantation mechanical alignment of the limb, the coronal alignment of the femoral and tibial implants was combined. RESULTS: The median deviation between the femoral cutting guide and bone resection was 0 degrees (range -0.5 degrees to +0.5 degrees ) in the coronal plane and 1.0 degrees (range -2.0 degrees to +1.0 degrees ) in the sagittal plane. The median deviation between the tibial cutting guide and bone resection was 0.5 degrees (range -1.0 degrees to +1.5 degrees ) in the coronal plane and 1.0 degrees (range -1.0 degrees to +3.5 degrees ) in the sagittal plane. The median deviation between the femoral bone resection and the final implant was 0.25 degrees (range -2.0 degrees to 3.0 degrees ) in the coronal plane. The median deviation between the tibial bone resection and the final implant was 0.75 degrees (range -3.0 degrees to +1.5 degrees ) in the coronal plane and 1.75 degrees (range -4.0 degrees to +2.0 degrees ) in the sagittal plane. The median post-implantation mechanical alignment of the limb was 0.25 degrees (range -3.0 degrees to +2.0 degrees ). CONCLUSIONS: When navigation is used only to guide the positioning of the cutting jig, errors may arise in the manual, non-navigated steps of the procedure. Our study showed increased cutting errors in the sagittal plane for both the femur and the tibia, and following implantation, the greatest error was seen in the sagittal alignment of the tibial component. Computer navigation should be used not only to guide the positioning of the cutting jig, but also to check the bone resection and implant position during TKA. LEVEL OF EVIDENCE: IV. PMID- 24061716 TI - Recommendations for the management of septic arthritis after ACL reconstruction. AB - PURPOSE: To evaluate the current evidence for the management of septic arthritis after anterior cruciate ligament (ACL) reconstruction, the factors that affect the outcome after treatment and the retention of graft and implants. METHODS: A systematic literature search of the PubMed database was performed on septic arthritis after ACL reconstruction. A total of 301 publications were initially identified, and 17 papers were found to fulfil the criteria to be included in the review. RESULTS: There were 196 cases of septic arthritis after ACL reconstruction in over 30,000 ACL reconstructions, making the proportion of infection 0.6%. Most patients (114/123, 92.6%) had an acute or subacute infection at an average of 16.8 +/- 10.5 days after ACL reconstruction. Coagulase-negative Staphylococci (CNS) was the most common organism (67/147, 45.6%) followed by Staphylococcus aureus (SA) (35/147, 23.8%); 86.9% underwent surgical treatment of which 92.8% had an average of 1.54 (up to 4) arthroscopic debridements. The group with SA infection had a higher graft removal rate (33.3%, p = 0.019), a longer antibiotic duration (35.4 days, p = 0.047) and a worse range of flexion (111.5 degrees , p = 0.036) than the CNS group. CONCLUSIONS: CNS was the most common organism in septic arthritis after ACL reconstruction followed by SA. For most authors, arthroscopic debridement combined with intravenous antibiotic therapy was the initial treatment of choice. Antibiotic therapy with or without multiple irrigations of the joint is not recommended based on the high failure rates. Delayed diagnosis of more than 7 days or SA infection required a longer duration of antibiotic therapy and increased the likelihood for graft removal and restricted range of motion. Fungal infection and tubercular infection had a high prevalence of late diagnosis and open debridement. LEVEL OF EVIDENCE: Systematic review, Level IV. PMID- 24061717 TI - Influence of response shift on early patient-reported outcomes following autologous chondrocyte implantation. AB - PURPOSE: Response shift is the phenomenon by which an individual's standards for evaluation change over time. The purpose of this study was to determine whether patients undergoing autologous chondrocyte implantation (ACI) experience response shift. METHODS: Forty-eight patients undergoing ACI participated. The "then-test" method was used to evaluate response shift in commonly used patient-reported outcome measures (PROMs)-the SF-36 Physical Component Scale (SF-36 PCS), WOMAC, IKDC, and Lysholm. Each PROM was completed pre- and 6 and 12 months post-surgery. At 6 and 12 months, an additional "then" version of each form was also completed. The "then" version was identical to the original except that patients were instructed to assess how they were prior to ACI. Traditional change, response shift adjusted change, and response shift magnitude were calculated at 6 and 12 months. T tests (p < 0.05) were used to compare traditional change to response shift-adjusted change, and response shift magnitude values to previously established minimal detectable change. RESULTS: There were no differences between traditional change and response-shift-adjusted change for any of the PROMs. The mean response shift magnitude value of the WOMAC at 6 months (15 +/- 14, p = 0.047) was greater than the previously established minimal detectable change (10.9). The mean response shift magnitude value for the SF-36 PCS at 12 months (9.4 +/- 6.8, p = 0.017) also exceeded the previously established minimal detectable change (6.6). CONCLUSIONS: There was no evidence of a group-level effect for response shift. These results support the validity of pre-test/post test research designs in evaluating treatment effects. However, there is evidence that response shifts may occur on a patient-by-patient basis, and scores on the WOMAC and SF-36 in particular may be influenced by response shift. LEVEL OF EVIDENCE: II. PMID- 24061718 TI - Utility of multimodal analgesia with fascia iliaca blockade for acute pain management following hip arthroscopy. AB - PURPOSE: The purpose of this study was to evaluate the utility of multimodal analgesia with fascia iliaca blockade and for acute pain control in patients undergoing hip arthroscopy. METHODS: Thirty consecutive patients undergoing primary hip arthroscopy were prospectively studied. All patients were treated preoperatively with ultrasound-guided single injection fascia iliaca blockade and multimodal analgesia. Data collected included post-operative nausea, numeric rating scale (NRS) pain scores during rest and activity, opioid consumption during the first five days (recorded as tablets of 5 mg hydrocodone/500 mg acetaminophen) and overall patient satisfaction with analgesia. RESULTS: This study included 23 female and 7 male patients with a median age of 35 years (range 14-58). No patient required medication for post-operative nausea. The overall NRS scores were an average of 3.9 on day 0, 3.6 on day 1, 3.4 on day 2, 2.9 on day 3, 3.0 on day 4 and 2.7 on day 5. The average tablets of opioid taken were 1.5 on day 0, 1.2 on day 1, 1.3 on day 2, 1.0 on day 3, 1.1 on day 4 and 0.9 on day 5. Overall, 20 patients rated their post-operative pain control as very satisfied (67 %), and 10 patients as satisfied (33 %). There were no complications or side effects from the fascia iliaca blockade. CONCLUSION: In this prospective study, multimodal analgesia with fascia iliaca blockade following hip arthroscopy was safe and effective. The quality of early post-operative analgesia provided by the fascia iliaca blockade was excellent and resulted in low opioid consumption, high quality of pain relief and high overall patient satisfaction. PMID- 24061719 TI - Intra- and post-operative accuracy assessments of two different patient-specific instrumentation systems for total knee replacement. AB - PURPOSE: The aim of this study is to assess and compare the accuracy of two different patient-specific instrumentation (PSI) systems for total knee replacement, both intra-operatively for bone preparation and post-operatively for final component alignment. METHODS: Twenty-five patients were treated according to a computer tomography (CT)-based PSI system (group A) and 25 to a magnetic resonance imaging (MRI)/X-ray-based system (group B). Alignments on the three anatomical planes and resection thickness at the cutting blocks and at the resulting bone cuts were recorded intra-operatively by a standard surgical navigation system. Alignments of the prosthetic components and mechanical axis were also measured post-operatively on radiographs. These measurements at both the femur and tibia were compared with those of the corresponding pre-operative planning, considering discrepancies larger than 3 degrees as outliers. RESULTS: In both groups, the mean absolute differences between pre-operatively planned alignments and corresponding intra- and post-operative measurements ranged from a minimum of 1.2 degrees to a maximum of 2.9 degrees in all three anatomical planes. In both groups and in both femur and tibia, the plane with the smallest percentage of outliers was the coronal, maximum 17%. The comparison between two groups was statistically significant (p = 0.02) in the femoral sagittal plane, where group B showed smaller alignment discrepancies at the cutting blocks. CONCLUSIONS: Both PSI systems showed good alignments in the coronal plane in all stages. For a few measurements, a better performance was observed in the MRI/X ray-based system than in the CT-based system. LEVEL OF EVIDENCE: I. PMID- 24061721 TI - Potential of phenolic antioxidants. AB - In vitro studies have shown a link between the consumption of food rich in (poly)phenols, especially flavonoids, and reduced risk of coronary heart diseases. Several flavonoids have been reported to prevent low density lipoprotein cholesterol oxidation in vitro. The aim of our work was to determine antioxidant and radical scavenging activity of flavonoids myricetin, quercetin, rutin, luteolin, apigenin, kaempferol, catechin, epicatechin and epigallocatechin gallate and to study the influence of chemical structure and flavonoid interactions on the ability to inhibit oxidation and scavenge free radicals. Two in vitro methods, i.e. oxidation of b-carotene in an emulsion system and DPPH (1,1-Diphenyl-2-picrylhydrazyl) radical scavenging assay, were applied. In addition, a review of in vivo studies that investigate the effectiveness of food flavonoids in reducing oxidative damage in human body was done and their results were analyzed and compared to in vitro results obtained in our laboratory. Although all tested flavonoids except apigenin showed strong antioxidant and antiradical properties in vitro, these findings can not be completely confirmed from the reviewed in vivo human studies since those results are sometimes contradictory and inconsistent. PMID- 24061720 TI - Effect of femoral tunnel position on graft tension curves and knee stability in anatomic double-bundle anterior cruciate ligament reconstruction. AB - PURPOSE: To evaluate the effect of the femoral tunnel position of the anteromedial bundle (AMB) and the posterolateral bundle (PLB) on the graft tension curves and knee stability in anatomic double-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: Forty-five patients who underwent anatomic double-bundle ACL reconstruction were included. AMB and PLB were provisionally fixed to a graft tensioning system in the following settings during surgery: (1) AMB at 20 degrees and PLB at 0 degrees (A20P0), (2) AMB at 20 degrees and PLB at 20 degrees (A20P20), and (3) AMB at 20 degrees and PLB at 45 degrees (A20P45). Bundle tension was recorded during knee flexion-extension. A pivot shift test was also evaluated. Femoral tunnel positions of the AMB and PLB were then assessed by three-dimensional computed tomography, and the correlation between femoral tunnel position and tension change pattern or residual pivot shift was evaluated. RESULTS: The depth of the PLB tunnel position was correlated with the extent of tension reduction in the PLB between 0 degrees and 30 degrees irrespective of graft fixation settings, while neither the AMB tunnel position nor the height of the PLB tunnel position affected the tension change pattern. Ten cases showed grade 1 pivot shift only in the A20P0 setting. The PLB tunnel position in the pivot shift-positive cases was significantly deeper than that in the pivot shift-negative cases (27.5 +/- 6.2 and 34.1 +/- 5.5%, respectively, P = 0.002). CONCLUSIONS: In anatomic double-bundle reconstruction, deeper PLB tunnel position was correlated with the larger tension reduction in the PLB between 0 degrees and 30 degrees . Fixation of the AMB at 20 degrees and the PLB at 0 degrees resulted in residual pivot shift phenomenon in 10/45 cases, and the PLB tunnel position in the pivot shift-positive cases was significantly deeper than that in the pivot shift-negative cases. In anatomic double-bundle reconstruction, the placement of PLB femoral tunnel must not be too deep, as it might lead to significant tension reduction in the PLB near extension and thus insufficient tension in the PLB, resulting in residual pivot shift phenomenon. LEVEL OF EVIDENCE: IV. PMID- 24061722 TI - Metallic fluoride complexes as phosphate analogues for structural and mechanistic studies of phosphoryl group transfer enzymes. AB - There have been intensive efforts to try to understand the details of phosphoryl transfer reactions extending from nonenzymatic (or enzyme model) systems to the mechanisms of the enzyme catalysed reactions. As phosphate analogues, few metallic fluorides AlFx, BeFx and MgFx affect the activity of a variety of phosphoryl transfer enzymes, and it is accepted that these small inorganic complexes are useful chemical probes for structural and mechanistic studies in enzymology because they are able to mimic phosphoryl group in ground state (BeFx) as well as in transition state (AlFx,MgFx). Al3+ and Be2+ tend to form stable complexes with different fluoride anions (x = 1 to 4) spontaneously in aqueous solution but Mg2+ does not. BeFx geometry is strictly tetrahedral resembling the phosphate ground state when bound to an acyl group of protein active site (phosphorylated acyl groups are unstable otherwise), or the Michaelis complex when BeFx concominantly with nucleoside diphosphate replaces g-phosphate group in nucleoside triphosphate sites. AlFx and MgFx are identified as enzymatic analogues of phosphoryl transition state where both are able to form different coordination geometries within the enzyme active sites: trigonal bipyramidal (AlF3 and MgF3-) or octahedral (AlF4- or MgF42-). The geometry and charge of MgF3 are the best suited to mimicking the trigonal planar PO3- moiety of phosphoryl transfer transition state but MgF3- does not, unlike aluminum and beryllium fluoride complexes, exists in solution and can be assembled and stabilized in suitable active site only. Therefore it is particularly interesting to characterize as a potentially highly accurate transition state analogue and may be the best reagent of choice for studying phosphoryl transfer reactions in future. PMID- 24061723 TI - Velocity of detonation-a mathematical model. AB - Based on the principles of conservation of energy and momentum, a mathematical formula has been derived for the squares of detonation velocities of a large set of explosives. The equation is a function of the total energy and molecular weight of an explosive compound considered. A regressed equation has been obtained for a pool of explosives of various types including nitramines, aliphatic and aromatic nitro compounds. Also another regressed equation for nitramines only is given. For the regression, the total energies are obtained using DFT (UB3LYP/6-31G(d)). The regression statistics are given and discussed. PMID- 24061724 TI - A new pyrrole derivative from the extracts of the fungus monascus pilosus fermented rice. AB - A chemical study on the n-BuOH-soluble fraction of the 95% EtOH extract of red yeast rice fermented with the fungus Monascus pilosus BCRC 38093 (Eurotiaceae) has resulted in the isolation of one new natural pyrrole derivative, designated as monascuspyrrole (1) together with nine known compounds, 3beta-hydroxystigmast 5-en-7-one (2), beta-sitostenone (3), monascin (4), ankaflavin (5), N-trans feruloyltyramine (6), N-cis-feruloyltyramine (7), vanillic acid (8), methyl paraben (9), and syringaldehyde (10). The structure of the new compound 1 was identified by 1D and 2D NMR spectroscopy, as well as by high-resolution mass spectrometry. Other known compounds were identified by comparison of their spectral data with the literature data of authentic samples. Compounds 1 and 4 displayed mild inhibitory effect of nitric oxide production. Among the nine known isolates, compounds 2, 3, 6, and 7 were found for the first time in this species. PMID- 24061725 TI - Kinetics of the Ligand Exchange Reaction Between Tetradentate Schiff Base N,N' ethylen-bis (salicylaldimine) and Cu(N,N'-propylen-bis(salicylaldimine)). AB - Visible spectrophotometry is used to study the kinetic of ligand exchange in the system Cu(salpn)/H2salen with or without triethylamine (NEt3) and H2O in acetonitrile solvent at 25 +/- 0.1 degrees C and 0.01 M NaNO3 (H2salen and H2salpn are N,N'-ethylen-bis(salicylaldimine) and N,N'-propylen bis(salicylaldimine), respectively). It is found that the reaction rate is first order with respect to Cu(salpn). In addition, the ligand exchange rate increases when NEt3 is added to the reaction mixture, as shown by a break in the kobs vs. [NEt3] plot. The effects of NEt3 and H2O on the ligand exchange rate are discussed, and reaction mechanism is proposed. PMID- 24061726 TI - Improving the Response of Copper(II) Selective PVC Membrane Electrode by Modification of N2S2 Donor Ligand. AB - S,S'-bis(2-aminophenyl)ethanebis(thioate), (APhET), is reported as N2S2 ligand which form chelate with copper of high stability as compared to the other metals. Two modification of APhET, simpler 1,2-di-(o-aminophenylthio)ethane (DAPhTE), and the complex one 1,2-di-(o-salicylaldiminophenylthio)ethane (SAPhTE), were examined as the active material for copper(II) ion selective PVC membrane electrodes, and observed results are correlated. The obtained results with DAPhTE based electrodes show that only coordination abilities of ligand are insufficient for preparing the efficient membrane material. On the other hand, the results that are achieved with electrodes based on SAPhTE actuate interaction of ligand with polymer membrane matrix and necessity of ionophore immobilization in membrane. Optimized SAPhTE based membrane electrode has a linear range down to 10 6 mol L-1, with slope of 27.0 mV per decade, very rapid response time (under 5 seconds) and detection limit of 5.1 * 10-7 mol L-1. Such electrode is suitable for determination of copper(II) in analytical measurements by direct potentiometry and in potentiometric titrations, within pH between 2 and 7. The electrode is selective for copper(II) ions over a large number of metal ions, with the exception on Hg2+ ion when is present in concentrations above 2 * 10-5 mol L-1. PMID- 24061727 TI - Solvent effects on protonation equilibria of some amino acids and peptides in different aqueous solutions of ethanol. AB - The protonation constants of glycine, L-alanine, glycyl-glycine, glycyl-glycyl glycine and glycyl-L-alanine have been determined in 10-80% (v/v) ethanol-water mixtures at 25 degrees C and constant ionic strength (0.1 mol L-1 sodium perchlorate), by potentiometric technique and calculated using a suitable computer program, which employs a nonlinear least-squares method. The effect of solvent composition on the protonation constants in the mixed solvents were correlated with the Kamlet-Taft solvatochromic parameters (alpha, beta and pi*). It was shown that logK1 and logK2 values of glycine, L-alanine and peptides increasing with increase ethanol content up to 50% and then tend to decrease. Further, an overview of the effect of preferential solvation and solvent structure of electrolytes in ethanol-water mixtures on the values of the protonation constants in these media were also discussed. PMID- 24061728 TI - Quantification of the Vasoactive Agent Buflomedil HCl in Pharmaceutical Formulation and Human Serum by Stripping Voltammetry and Liquid Chromatography. AB - Buflomedil HCl, was reduced at the mercury electrode in buffered solutions of various pH values (2-11) via a single 2-electron irreversible step corresponding to reduction of its C=O double bond. Buflomedil HCl has interfacial adsorptive behavior onto the mercury electrode surface and a monolayer surface coverage of 2.37 * 10-10 mol cm-2 was estimated. Each adsorbed buflomedil HCl molecule was found to occupy an area of 0.69 nm2 onto the HMDE surface. Differential-pulse (DP), liner-sweep (LS) and square-wave (SW) adsorptive cathodic stripping voltammetry (AdCSV) methods were described for its determination in the bulk form. The sensitivity of the described electro-analytical methods increases in the direction: DP-AdCSV < LS-AdCSV < SW-AdCSV since their achieved limits of detection were: 2.4 * 10-8, 1.5 * 10-8 and 1.2 * 10-9 M bulk buflomedil HCl, respectively. Besides, a simple high-performance liquid chromatographic method was also developed for determination of bulk buflomedil HCl with a detection limit of 3.0 * 10-8 M. The described voltammetric and chromatographic methods were successfully applied for determination of buflomedil HCl in its formulations. Besides these methods were applied for determination of buflomedil HCl in spiked human serum (limit of detection varying from 1.5 * 10-9 to 4.5 * 10 8 M buflomedil HCl) without the necessity for pretreatment and/or time-consuming extraction steps prior to the analysis. No significant interferences from excipients or from endogenous human serum substances were obtained. The described SW-AdCS voltammetry method is much more sensitive than the described chromatographic one. However the described chromatographic method is substantially simpler, faster and more sensitive than the previously reported HPLC methods. PMID- 24061729 TI - Isopolyniobotungstate HxNb2W4O19(4-x)- Ions: Analysis of the State of the Ions in Aqueous Solutions, Formation Constants Calculation and Thallium Salts Synthesis. AB - By means of pH-potentiometric titration, the processes of the complexes formation in the system Nb6O198-WO42-H+-H2O with CNb : CW = 2: 4 was studied at different Nb + W concentrations. Exerimental data, being processed by mathematical modeling, allowed to obtain the distribution diagrams of individual niobium and tungsten isopoly anions, and mixed isopolyniobotungstates in the range of Z = C0H+/C0Nb+W = 0 - 2.0 (background electrolyte is NaCl). Concentrational and thermodynamic formation constants were calculated using quasi-Neuton method (CLINP 2.1 software) and it was shown, that the formation of isopolyniobotungstates (HxNb2W4O19(4-x)-, x = 0 - 2) of the 6th row of Periodic table proceeds through intermediate Nb3W3O195- ion formation. Thallium salts Tl3HNb2W4O19 * 10H2O and Tl2H2Nb2W4O19 * 10H2O were isolated and characterized by elemental and EDX spectral analysis, electron microscopy and FTIR-spectroscopy. PMID- 24061730 TI - Preparation, Characterization and Crystal Structure of [Cu2(O2CH)4(nicotinamide)2]. AB - The novel copper(II) coordination compound, [Cu2(O2CH)4(nia)2] (nia = nicotinamide), was isolated from the reaction mixture containing Cu2(OH)2CO3, nicotinamide, methanoic acid and ethanol. The new complex was characterized by X ray single crystal diffraction and other standard physico-chemical methods. The structure contains binuclear centrosymmetric molecules in which two central atoms are bridged by four methanoate bridges forming a paddle-wheel structure type. The fifth coordination site completing the distorted square pyramid around copper is occupied by aromatic nitrogen of nicotinamide. The molecules pack together via hydrogen bonds resulting in a formation of extended supramolecular sheets. The results of other physical measurements are also in a complete agreement with the obtained structure. PMID- 24061731 TI - Synthesis and Biological Evaluation of some new Imidazo[1,2-a]pyridines. AB - A series of new 1-[(2,8-dimethylimidazo[1,2-a]pyridine-3-yl)carbonyl]-4 alkyl/arylthiosemicarbazides, 2-[(2,8-dimethylimidazo[1,2-a]pyridine-3 yl)carbonyl]hydrazono-3-alkyl thiazolidin-4-ones, 2-(2,8-dimethylimidazo[1,2 a]pyridine-3-yl)-5-arylamino-1,3,4-oxadiazoles and 4-alkyl/aryl-2,4-dihydro-5 (2,8-dimethylimidazo[1,2-a]pyridine-3-yl)-3H-1,2,4-triazole-3-thiones were synthesized. The structures of the compounds have been elucidated by IR, 1H NMR, EI mass spectra and elemental analysis. Antibacterial, antifungal and antimycobacterial activities of compounds were evaluated against various microorganisms and some of them were found to be active in varying degrees against Staphylococcus aureus, Staphylococcus epidermidis or Mycobacterium tuberculosis H37Rv. PMID- 24061732 TI - Synthesis, structural studies and biological activity of a dioxovanadium(v) complex with pyridoxal semicarbazone. AB - Reaction between the NH4VO3 and pyridoxal semicarbazone (PLSC) in a methanol/ammonia solution forms an orange, diamagnetic, mononuclear NH4[VO2(PLSC 2H)] complex in which vanadium is in the oxidation state +5, and pyridoxal semicarbazone is coordinated in its dianionic form. The complex cocrystallizes with a neutral molecule of PLSC and two water molecules. The coordination environment around vanadium can be described as an almost ideal square-pyramid. The complex was characterized by elemental analysis, conductometric and magnetochemical measurements, IR spectra, X-ray diffraction, and in vitro cytotoxicity analysis. PMID- 24061733 TI - Low Temperature Heat Capacities and Standard Molar Enthalpy of Formation of 2 Pyrazinecarboxylic Acid (C5H4N2O2)(s). AB - Low-temperature heat capacities of 2-pyrazinecarboxylic acid (C5H4N2O2)(s) were measured by a precision automated adiabatic calorimeter over the temperature range from 78 to 400 K. A polynomial equation of heat capacities as a function of temperature was fitted by least squares method. Based on the fitted polynomial, the smoothed heat capacities and thermodynamic functions of the compound relative to the standard reference temperature 298.15 K were calculated and tabulated at 10 K intervals. The constant-volume energy of combustion of the compound at T = 298.15 K was measured by a precision rotating-bomb combustion calorimeter to be DeltacU = -(17839.40 +/- 7.40) J g-1. The standard molar enthalpy of combustion of the compound was determined to be DeltacH0m = -(2211.39 +/- 0.92) KJ mol-1, according to the definition of combustion enthalpy. Finally, the standard molar enthalpy of formation of the compound was calculated to be DeltafH0m = -(327.82 +/- 1.13) kJ mol-1 in accordance with Hess law. PMID- 24061734 TI - Preformulation investigation of some clopidogrel addition salts. AB - Physico-chemical properties of active substances such as solubility, dissolution rate, chemical stability, pharmaceutical processibility, etc. can be improved by salt formation of active substances. Characterization of physical properties of such salts is important for selection of an optimal salt having required biopharmaceutical properties, stability and manufacturability. The present study deals with the preformulation study of selected clopidogrel acid addition salts, i.e. hydrogen sulfate, hydrochloride (HCl), hydrobromide (HBr), besylate and (-) camphor-10-sulfonate salt (CSA) and two commercially available polymorphic forms of hydrogen sulphate salt, i.e. form 1 (HS F1) and form 2 (HS F2). Clopidogrel salts were characterized by means of thermal analysis (TG, DSC), X-ray powder diffraction (XRPD), infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), dynamic vapor sorption (DVS), true density, scanning electron microscopy (SEM) and solubility. Distinct differences in tested parameters were found among acid addition salts and crystalline forms of clopidogrel. Higher melting point of both hydrogen sulphate salt was attributed to presence of hydrogen bonds among HS anions, connecting them into a chain. All salts included in the present study were anhydrous, except HBr which was in the form of monohydrate. The two tested polymorphic forms of clopidogrel HS salt are enantiotropically related to each other and showed the highest hygroscopicity among the tested salts. This is important for development of solid dosage form containing both polymorphic forms and for selection of primary packaging. Solubility studies in different aqueous media showed comparable solubility for clopidogrel hydrogen sulfate (polymorphic forms 1 and 2), hydrochloride (form 1) and hydrobromide hydrate (form 1) whereas clopidogrel camphorsulfonate (CSA) and besylate salt showed slightly lower solubility. PMID- 24061735 TI - Study of Solution Equilibria Between Gadolinium(III) Ion and Moxifloxacin. AB - The complex formation equilibria between gadolinium(III) ion and moxifloxacin (MOXI) were studied in aqueous solutions. The investigations were performed by glass electrode potentiometric (ionic medium: 0.1mol dm-3 LiCl, 298 K) and UV spectrophotometric measurements. In the concentration range 0.5<= [Gd3+] <= 1.0; 1.0 <= [MOXI] L 2.0 mmol dm-3 ([MOXI]/[Gd] = 1: 1to 5: 1) and pH between 2.5and 9.0, gadolinium(III) and moxifloxacin form the complexes of the composition: Gd(HMOXI)3+, Gd(HMOXI)23+, Gd(HMOXI)33+, Gd(HMOXI)2MOXI2+, Gd(HMOXI)(MOXI)2+, Gd(MOXI)3. The stability constants of the complexes were calculated with the aid of Hyperquad2006 suite of programs, taking into account the hydrolysis of Gd3+ ion and protonation of moxifloxacin anion. The possible structure of the complexes, in solution, and their formation mechanism is suggested. The effect of moxifloxacin, and for comparison purpose, DTPA on gadolinium(III) plasma speciation was evaluated by computer simulation. PMID- 24061736 TI - Effect of dielectric constant on protonation equlibria of L-dopa and 1, 10 phenanthroline in dioxan-water mixtures. AB - Solute-solvent interactions of L-dopa and 1, 10-phenanthroline have been studied in 0-60% v/v dioxan-water media using pH-metric method. The protonation constants have been calculated with the computer program MINIQUAD75. Selection of the best fit chemical model of the protonation equilibria is based on standard deviation in protonation constants and residual analysis using crystallographic R-factor and sum of squares of residuals in all mass balance equations. Linear variation of protonation constants with inverse of dielectric constants of the solvent mixture has been attributed to the dominance of the electrostatic forces. Distribution of species, protonation equilibria and effect of influential parameters on the protonation constants have also been presented. PMID- 24061737 TI - One Step Preparation of TiO2 Layer for High Efficiency Dye-sensitized Solar Cell. AB - A novel titanium dioxide paste based on Pechini sol-gel method and nanocrystalline TiO2 powder has been successfully developed and tested. The paste enables the formation of sponge like structure of the TiO2 layer i.e. highly porous and at the same time well connected TiO2 network. The layers have been used to assemble dye sensitized solar cells (DSSC) with two ruthenium complex based dyes, N719 and black dye, respectively. Overall conversion efficiencies of ionic liquid electrolyte based DSSC sensitized with N719 and black dye was 6.1% and 2.0%, respectively, when determined under standard test conditions (100 mW/cm2, AM1.5, 25 degrees C). PMID- 24061738 TI - Diffusion coefficients of sodium fluoride in aqueous solutions at 298.15 k and 310.15 k. AB - Mutual diffusion coefficients (interdiffusion coefficients) have been measured for sodium fluoride in water at 298.15 K and 310.15 K at concentrations between 0.003 mol dm-3 and 0.05 mol dm-3. The diffusion coefficients were measured using a conductimetric cell. The experimental mutual diffusion coefficients are discussed on the basis of the Onsager-Fuoss model. The limiting molar conductivity of the fluoride ion in these solutions at 310.15 K has been estimated using these results. PMID- 24061739 TI - Bleaching Kinetic and Mechanism Study of Congo Red Catalyzed by ZrO2 Nanoparticles Prepared by Using a Simple Precipitation Method. AB - Bleaching of Congo red catalyzed by ZrO2 nanoparticles was study under UV and sunlight irradiations. The nanoparticles of ZrO2 have been synthesized by controlled precipitation method. The concentration of ZrOCl2 and ammonia reactants and the calcinations temperature of ZrO2 were optimized for the control of nanoparticles size. Characterization of the prepared nanoparticles was studied by using XRD patterns, TEM images and FT-IR spectra. The tetragonal phase of zirconium oxide was obtained at 550 degrees C and show the most catalytic effect in dye degradation. The various parameters such as the irradiation time, amount of nanophotocatalyst, pH of samples, and initial concentration of Congo red were studied to find desired conditions of photodegradation process. The degradation 98% was achieved at pH 7 catalyzed by 0.7 g/L if ZrO2 nanoparticles in duration time of 125 min. The effect of iso-PrOH, hydrogen peroxide and inorganic anions was studied on the degradation efficiency of dye. The degradation 98% was obtained in the presence of prepared nanosized zirconia in comparison with degradation 65% catalyzed by commercially zirconia. PMID- 24061740 TI - The Effect of Temperature and Fe3+ Concentration on the Formation of gamma-Fe2O3 Nanoparticles Embedded in Silica Matrix. AB - The paper presents a study on the formation and thermal stability of gamma-Fe2O3 nanoparticles within the silica matrix depending on the Fe(III) carboxylate-type precursors, their annealing temperature and the concentration of Fe3+. Obtaining of the precursors, within the pores of the gel, bases on the redox reaction between Fe(NO3)3 and diols: ethylene glycol (EG) and 1,4 buthane diol (1,4 BG), respectively. Thus, we have prepared gels with different Fe2O3/SiO2 ratios (20, 30, 50, 70 wt% Fe2O3) which were annealed in the temperature range 573-1273 K. The formation and stability of the single gamma-Fe2O3 phase within the pores is strongly influenced by the reducing atmosphere generated upon thermal decomposition of the Fe(III) carboxylates. The XRD analysis evidenced a much stronger crystallization of gamma-Fe2O3 in case of the nanocomposites synthesized with 1,4 BG than with EG. The magnetic measurements confirm the crystallinity of gamma-Fe2O3 within the silica matrix. PMID- 24061742 TI - Water sorption characteristics of a new type of gelatine powder, produced by a new high-pressure micronisation process. AB - A new high-pressure micronisation process for Gelatine has been developed. By applying this process to gelatine, a new type of Gelatine was produced: Dry and pure Gelatine powder of high molecular mass. This powder was investigated, regarding its sorption behaviour and compared to its feedstock material. The feedstock Gelatine was of type B 200 Bloom, 6 mesh, having a molecular mass of 150,000 g mol-1. The produced Gelatine powder's molecular mass was around 130,000 g mol-1, while its mean particle size was 300 um. Their sorption isotherms were investigated at 30 degrees C, 40 degrees C and 60 degrees C and water activities in the range from 0.055 to 0.836. At given water activities the Equilibrium Moisture Contents (EMC) decreases with increasing temperature. The measured sorption isotherms were fit with the Brunauer- Emmet- Teller (BET)- model and the Guggenheim- Anderson- deBoer (GAB)- model. Both models described the adsorption behaviour well in their range of validity, while only the GAB model was adequate for describing the desorption behaviour. Hysteresis effect occurred in each adsorption-desorption pair. The isosteric heat of sorption of both substances was determined for adsorption, desorption respectively. Slight differences in the sorption behaviour occurred due to processing, while quality of the gelatine was not affected. PMID- 24061741 TI - Self-assembled Polyelectrolyte Nanocomplexes of Alginate, Chitosan and Ovalbumin. AB - Polyelectrolyte complex (PEC) nanoparticles for delivering model protein drug ovalbumin were prepared from two polysaccharide polymers, alginate and chitosan. The parameters influencing the complex formation were characterised using colloid titration in combination with dynamic light scattering. The polyelectrolyte interactions and morphology of the formed complexes were verified by differential scanning calorimetry and scanning electron microscopy, respectively. The PEC formation was predominantly pH- and concentration-dependent. The complexation of ovalbumin with a negatively charged alginate occurred only at a pH below the isoelectric point of the ovalbumin. After the complexation, negatively charged complexes of alginate and ovalbumin were further coated with chitosan. The optimal composition of the PEC, yielding 280 nm sized particles having a zeta potential -40 mV, was determined for alginate:ovalbumin:chitosan in a mass ratio 1: 1: 0.1, respectively, giving their final concentration 0.5: 0.5: 0.05mg/ml. The loading of ovalbumin in the PEC depended on the initial amount of ovalbumin used to produce the PEC, and ranged from 7-38% for different formulations, however, the association efficiency remained pretty similar for all formulations, i.e. 80-85%. Mild formulation conditions, nanometre-sized particles, and a high protein association efficiency are promising factors towards the development of a delivery system for proteins. PMID- 24061743 TI - Silver Nanoparticles in SiO2 Microspheres - Preparation by Spray Drying and Use as Antimicrobial Agent. AB - Silver nanoparticles embedded in SiO2 particles of micrometer size are prepared using spray drying. The spray drying is performed with a SiO2 sol (solvent water:ethanol 4: 1) containing SiO2 and silver particles of nanometer size. During spray drying the SiO2 nanoparticles aggregate to SiO2 microspheres whereas the silver particles exhibit only a small tendency of aggregation and keep their nanometer size. However under special conditions also the formation of crystalline silver rods is observed. The antibacterial activity of the resulting Ag/SiO2 powders is determined against the bacteria Escherichia coli and Bacillus subtilis. Because of this antibacterial acitivity and the fact that the powder of SiO2 microspheres exhibits a good dispersibility, such materials have an immense potential to be used as antimicrobial additive in processes like master batch or fiber production. PMID- 24061744 TI - Low-temperature Heat Capacities and Thermodynamic Properties of Crystalline 2 Aminopyridinium Benzoate (C12H12N2O2) (s). AB - 2-Aminopyridinium benzoate was synthesized. Chemical analysis, elemental analysis, and X-ray crystallography were applied to characterize the composition and crystal structure of the compound. The lattice potential energy of the title compound was calculated to be UPOT = 284.297 kJ mol-1. Low-temperature heat capacities of the compound were measured by a precision automatic adiabatic calorimeter over the temperature range from 78 K to 365 K. A polynomial equation of heat capacities against the temperature in the region of 78 K to 365 K was fitted by a least square method. Based on the fitted polynomial equation, the smoothed heat capacities and thermodynamic functions of the compound relative to the standard reference temperature 298.15 K were calculated at intervals of 5 K. According to the synthesis reaction, the standard molar enthalpies of dissolution for the reactants and product in the selected solvent were measured by an isoperibol solution-reaction calorimeter, respectively. Accordingly, the enthalpy change of the synthesis reaction was calculated to be DeltarHom = -(20.016 +/- 0.182) kJ mol-1. Finally, the standard molar enthalpy of formation of 2 aminopyridinium benzoate was determined to be DeltafHom = - (365.416 +/- 0.961) kJ mol-1 in accordance with Hess law. PMID- 24061745 TI - H-beta? Zeolite: an Efficient, Reusable Catalyst for One-Pot Synthesis of Isatins from Anilines. AB - We describe a simple and highly efficient procedure for the single-step preparation of isatins from the commercially available anilines using H-beta zeolite as a truly heterogeneous catalyst. H-beta zeolite is readily separated from reaction mixture by simple filtration and reused several times without considerable loss of activity. PMID- 24061746 TI - Distribution of Microamounts of Cesium in the Two-Phase Water-HCl-Nitrobenzene 2,3-Naphtho-15-crown-5-Hydrogen Dicarbollylcobaltate Extraction System. AB - Extraction of microamounts of cesium by a nitrobenzene solution of hydrogen dicarbollylcobaltate (H+B-) in the presence of 2,3-naphtho-15-crown-5 (N15C5, L) has been investigated. The equilibrium data have been explained assuming that the complexes HL+, HL+2, CsL+ and CsL+2 are extracted into the organic phase. The values of extraction and stability constants of the species in nitrobenzene saturated with water have been determined. PMID- 24061747 TI - Synthesis and Characterization of Co(II) Complexes of N-Thiophosphorylated Thioureas RC(S)NHP(S)(OiPr)2 (R = Me2N, 2-MeC6H4NH, 2,6-Me2C6H3NH, 2,4,6 Me3C6H2NH). AB - Reaction of the potassium salts of N-thiophosphorylthioureas RC(S)NHP(S)(OiPr)2 (R = Me2N, HLI; 2-MeC6H4NH, HLII; 2,6-Me2C6H3NH, HLIII; 2,4,6-Me3C6H2NH, HLIV) with Co(II) cations in aqueous EtOH leads to the complexes [Co(LI-IV-S,S')2] ([CoLI-IV2]). The structures of the complexes were studied by IR, UV-Vis spectroscopy and microanalysis. The crystal and molecular structure of [CoLI2] was elucidated by single crystal X-ray diffraction. The metal center is found in a tetrahedral S4 environment formed by the C=S and P=S sulfur atoms of two deprotonated ligands LI. Magnetic properties of [CoLI2] were also investigated. PMID- 24061748 TI - The Combinatorial Isomer Enumeration of 1, 3, 5-trimethylbenzene by Fujita's Topological Index. AB - The unmatured full non-rigid group of 1,3,5-trimethylbenzene is isomorphic to the wreath product of the cyclic group of order three and the symmetric group of order six on three letters (see Int. J. Quantum Chem. 2007, 107, 340 and Bull. Chem. Soc. Jpn. 2008, 81, 279). In this paper the unit subduced cycle index table introduced by S. Fujita of the full non-rigid group 1,3,5-trimethylbenzene of order 162 are successfully derived for the first time. PMID- 24061749 TI - Extraction of Calcium and Strontium into Phenyltrifluoromethyl Sulfone by Using Synergistic Mixture of Hydrogen Dicarbollylcobaltate and "Classical" CMPO. AB - Solvent extraction of microamounts of calcium and strontium by a phenyltrifluoromethyl sulfone (FS 13) solution of hydrogen dicarbollylcobaltate (H+B-) in the presence of octyl-phenyl-N,N-diisobutylcarbamoylmethyl phosphine oxide ("classical" CMPO, L) has been investigated. The equilibrium data have been explained assuming that the species HL+, HL2+, ML2+, ML2+2 and ML2+3 (M2+ = Ca2+, Sr2+) are extracted into the organic phase. The values of extraction and stability constants of the cationic complex species in FS 13 saturated with water have been determined. In the considered FS 13 medium, it was found that the stability constants of the complex species CaL2+n, where n = 1, 2, 3 and L is "classical" CMPO, are higher than those of the corresponding complexes SrL2+n. PMID- 24061750 TI - A new method for indirect determination of iodide and thiosulfate in table salt and milk based on a combination of solid-phase extraction and flame atomic absorption spectrometry. AB - A new indirect method for the determination of iodide and thiosulfate ions in table salt and milk by flame atomic absorption spectrometry was described. This method is based on the reduction of chromium (VI) to chromium(III) with the reducing action of iodide and/or thiosulfate, separation of unreacted Cr(VI) as its 1,5-diphenilcarbazide complex on a column filled with Amberlite XAD-16, elution of the complex by 10 mL of 0.05 mol L-1 H2SO4 in methanol and determination by flame atomic absorption spectrometry. Amount of the analytes were calculated from the amount of Cr(VI) reacted with the analytes. The optimum conditions for the determination of iodide and thiosulfate ions, including pH and volume of sample solution were examined. The effect of interfering species on the recovery of the iodide and thiosulfate ions was also investigated. The precision of the proposed method is good as it provides relative standard deviation value of 3.5% for thiosulfate and 4.5% for iodide during five replicate determinations of 10 ug mL-1 of thiosulfate and 15 ug mL-1 of iodide, respectively. The accuracy of the procedure was tested by analyzing spiked real samples and certified reference sample (BCR 150 Milk powder). The procedure described was successfully applied for the determination of iodide in table salt and milk and, thiosulfate in table salt. Iodide and thiosulfate ions have been determined in real samples with relative error below 15%. PMID- 24061751 TI - The Inhibition of Mild Steel Corrosion in 1 N HCl by Imidazole Derivatives. AB - The inhibition effect of imidazole derivatives 4-methyl-2-propyl-1H-benzimidazole 6-carboxylic acid (MPBI) and 1,4'-Dimethyl-2'-propyl-1H,3'H-2,5'-dibenzimidazole (DPBI) against mild steel corrosion in 1 N HCl solutions were evaluated using conventional weight loss, potentiodynamic polarization, linear polarization and electrochemical impedance spectroscopy. The weight loss results showed that both are excellent corrosion inhibitors, electrochemical polarizations data revealed the mixed mode of inhibition and the results of electrochemical impedance spectroscopy have shown that the change in the impedance parameters, charge transfer resistance and double layer capacitance, with the change in concentration of the inhibitor is due to the adsorption of the molecule leading to the formation of a protective layer on the surface of mild steel. The inhibition action of these compounds was, assumed to occur via adsorption on the steel surface through the active centres contained of the molecule. PMID- 24061752 TI - High Resolution Melting Curve Analysis for High-Throughput SNP Genotyping in IL23R Gene and Association of IL23R with Slovenian Inflammatory Bowel Diseases Patients. AB - Single nucleotide polymorphism (SNP) analysis is important tool in the studies of genetic factors associated with complex diseases and with genetically influenced response to drug therapy (pharmacogenetics). Recently, a new generation of generic dsDNA binding dyes (LCGreenTM) contributed to the development of fast and low-cost method for SNP detection and/or genotyping based on high resolution melting (HRM) analysis. The aim of our study was to develop HRM assay for IL23R gene (rs7517847) and to perform association study in Slovenian inflammatory bowel diseases (IBD) patients. We genotyped 345 Slovenian healthy controls and 295 IBD patients including 159 with Crohn's disease (CD) and 136 with ulcerative colitis (UC) for rs7517847 polymorphism in IL23R gene using standard RFLP and optimized HRM methods. In this study, we showed, that HRM is a simple, fast and reliable method for genotyping of clinical samples where homozygotes (GG and TT) were determined by "Tm calling method" and difference between homozygotes and heterozygotes was determined by different melting curve shape using "gene scanning method". With combination of results from "Tm calling" and "gene scanning" methods, we achieved 98,6% concordance between PCR-RFLP and PCR-HRM results, based on the analysis of 640 samples. We found statistically significant association of IL23R polymorphism with Slovenian Crohn's disease patients when comparing genotype and allele frequencies between CD patients and controls. Allele frequency of minor allele G was 0,46 in controls and was reduced to 0,33 in CD patients (p < 0,001, OR = 0,588). The frequency of T/T genotype carriers was higher in CD patients (50,3%) than in controls (26,7%, p = 0,002, OR = 2,558). We found weak association between IL23R polymorphism and Slovenian UC patients. Carriers of T/T genotype have higher risk for UC (p = 0,035, OR = 1,599). These results suggest IL23R plays important role in CD and UC development in Slovenian patients. PMID- 24061753 TI - New DH-BSC recommendations on optimal management of hypertension in diabetics. PMID- 24061754 TI - Prevalence of dyslipidemia in children with congenital heart disease. AB - Dyslipidemia is one of the main risk factors associated with cardiovascular diseases. Few data on the impacts of congenital heart diseases are available with regard to the prevalence of dyslipidemia in children. Our study evaluated the lipid profile in children with congenital heart disease at a referral center. From January 2011 to July 2012, 52 pediatric patients had their lipid, metabolic and clinical profiles traced. The mean age was 10.4 +/- 2.8 years and male/female rate of 1.38:1. Our population had 53.8% patients with high levels of total cholesterol and 13.4% (CI 95 %, from 6.6 to 25.2%) of them also presenting LDL levels >= 130 mg/dL, which characterizes dyslipidemia. The group of dyslipidemic patients presented only two obese individuals. Our data show that the presence of congenital heart disease does not lead to higher risk associated with the prevalence of dyslipidemia. Therefore, the screening of this specific population should follow the regular pediatric guidelines, which are also independent of the nutritional status of the children tested. PMID- 24061755 TI - Feminization of medicine. PMID- 24061756 TI - Mean platelet volume may be associated with extent of coronary artery disease. PMID- 24061757 TI - Case 4: 84-year old female with precordial pain and cardiac arrest with pulseless electrical activity. PMID- 24061758 TI - Percutaneous management of coronary artery fistula in an adult and clinical outcome. PMID- 24061759 TI - Percutaneous treatment of refractory angina secondary to left subclavian artery stenosis in patients after coronary artery bypass grafting. PMID- 24061760 TI - On the gravity of the acute rheumatic fever in children from Pernambuco, Brazil. PMID- 24061761 TI - Hypertension control in brazilian publications. AB - Hypertension is a major public health problem due to its high prevalence and cardiovascular complications. Its treatment is aimed at reducing cardiovascular morbidity and mortality, its goal being to maintain blood pressure levels below 140/90 mm Hg. Hypertension control in Brazil is low, and nationwide rates are unknown. The objective of this review was to provide an overview on hypertension control in Brazil from publications in a database. We identified 45 publications. In population-based studies, the highest control rate (57.6%) was reported in a multicenter study in 100 municipalities and the city of Sao Jose do Rio Preto, Sao Paulo state (52.4%), while the lowest rates (around 10%) were identified in microregions of the Rio Grande do Sul state and in the city of Tubarao, Santa Catarina state. In conclusion, the studies assessed showed a wide variation in hypertension control rates. It is worth noting that the comparison between studies was a major limiting factor, because of the different methods used. PMID- 24061763 TI - Facile synthesis of yolk-shell magnetic mesoporous carbon microspheres for efficient enrichment of low abundance peptides. AB - Magnetic mesoporous carbon microspheres with a yolk-shell structure (YSMMCS) have been prepared via a new in situ carbon source strategy. The material was fabricated by two shells coated onto the Fe3O4 particles; the inner dense and thick silica shell could protect the magnetic core from harsh acidic solvents as well as induce the void between the core and the outer shell for the yolk-shell structure, while the outer organosilica shell was used as the template and carbon source for in situ preparation of a carbon shell with mesoporous structure. A C18 alkyl chain was incorporated in situ as the carbon precursor efficiently, avoiding the conventional infiltration step, which was very difficult to manipulate and time-consuming with the possibility of losing the carbon precursor. The resulting yolk-shell magnetic mesoporous carbon microspheres exhibited a high surface area (273.15 m(2) g(-1)), a large pore volume (0.31 cm(3) g(-1)), and a strong magnetic response (a saturation magnetization value of 34.57 emu g(-1)). As a result of the void between the core and the outer shell and the pi-pi stacking effect, adsorption capacity reached 191.64 mg g(-1) by using Rhodamine B as a standard analyte, indicating the great potential application of the material as drug carriers. Owing to the inherent hydrophobicity and high surface area, the composite material showed better performance in the enrichment of peptides than a magnetic mesoporous silica material (Fe2O3@nSiO2@mSiO2). According to the LC-MS/MS results, about 51 and 29 nonredundant peptides were identified from tryptic digests of 5 nM BSA. Additionally, taking advantage of the mesoporous structure and strong magnetic response, the material was utilized to selectively extract low abundance endogenous peptides from human serum in the presence of high abundance proteins. Based on the LC-MS/MS results, 962 endogenous peptides were obtained by 2.5 mg YSMMCS relative to 539 endogenous peptides by 5 mg Fe2O3@nSiO2@mSiO2, confirming the outstanding performance of YSMMCS in peptidome analysis. PMID- 24061764 TI - A comparative study on the use of tamsulosin versus alfuzosin in spontaneous micturition recovery after transurethral catheter removal in patients with benign prostatic growth. AB - PURPOSE: To compare the efficacy and safety of tamsulosin and alfuzosin in patients with acute urinary retention (AUR) secondary to benign prostatic hyperplasia (BPH). METHODS: Ninety men with AUR due to BPH underwent urinary catheterization and were randomly assigned to treatment groups with tamsulosin 0.4 mg (37 patients), alfuzosin 10 mg (34 patients), and placebo (19 patients). After 4 days of the drug treatment, the catheters were removed, and the patients underwent trial without catheter (TWOC). A TWOC was considered successful if the patient had a voided volume >100 ml and post-void residual urine <200 ml. RESULTS: TWOC was successful in 16 patients (43.2 %) in the tamsulosin group, 12 patients (35.2 %) in the alfuzosin group, and 5 patients (26.3 %) in the placebo group. Logistic regression analysis showed that both drugs were equally effective and that the type of alpha-blocker was not a predictive factor for TWOC success (OR 1.137, 95 % CI 0.639-2.022) (p = 0.662). CONCLUSION: Even though there were no statistically significant differences when comparing the three groups, tamsulosin showed a tendency to be more effective in a successful catheter removal. The lack of objective criteria in the definition of successful micturition leads us to believe that the effectiveness of both drugs reported in the literature is overestimated. PMID- 24061765 TI - Pedicled rectus abdominis muscle and fascia flap sling the bulbar urethra for treatment for male-acquired urinary incontinence: report of ten cases. AB - PURPOSE: Male urinary incontinence is relatively common complication of radical prostatectomy and of posterior urethroplasty following traumatic pelvic fracture. Here, we investigate the use of pedicled rectus abdominis muscle and fascia flap sling of the bulbar urethra for treatment for male-acquired urinary incontinence. MATERIALS AND METHODS: Ten patients with acquired urinary incontinence were included in the study. Urinary incontinence was secondary to TURP in three patients and was secondary to posterior urethroplasty performed following traumatic pelvic fracture in seven patients. Pedicled rectus abdominalis muscle and fascial flaps, approximately 2.5 cm wide and 15 cm long, were isolated. The flaps were inserted into a perineal incision through a subcutaneous tunnel. The free end of the flap was sectioned to form two muscle strips, each 3 cm in length, and inserted into the space between bulbar urethra and corpus cavernosa. After adequate sling tension had been achieved, the two strips of muscle were anastomosed around the bulbar urethra using a 2-zero polyglactin suture. RESULTS: The patients were followed up for between 12 and 82 months (mean 42.8 months). Complete continence was achieved with good voiding in seven of the 10 patients. In other three patients achieved good voiding following catheter removal, but incontinence was only moderately improved. CONCLUSIONS: A pedicled rectus muscle fascial sling of the bulbar urethra is an effective and safe treatment for male patients with mild to moderate acquired urinary incontinence, but it may not be suitable for severe incontinence or for patients with weak rectus abdominalis muscles. PMID- 24061766 TI - Comparative outcomes of the tubularized incised plate and transverse island flap onlay techniques for the repair of proximal hypospadias. AB - PURPOSE: The optimal management of proximal hypospadias remains uncertain. In this study, the surgical outcomes of tubularized incised plate repair (TIP) and transverse island flap (TVIF) onlay urethroplasty in boys with hypospadias were compared. METHODS: A total of 176 patients with proximal hypospadias underwent TIP (n = 83) or TVIF onlay repairs (n = 93) by a single surgeon and were evaluated retrospectively. No patient received a testosterone injection prior to surgery. A retrospective review of their medical records collected data regarding age at surgery, chordee, dorsal plication, hypospadias site, penoscrotal transposition, bifid scrotum, congenital hernia, undescended testis and any postoperative complications, including fistula, recurrent curvature, dehiscence, diverticulum, meatal stenosis and urethral stricture. The pediatric penile perception score (PPPS) was completed by parents to evaluate their perception of cosmetic outcomes. RESULTS: There was no statistical difference in age or any of the anatomical and clinical features of hypospadias. The median follow-up duration was 22 months (range 12-48 months) and 25 months (14-51 months) for the TIP and TVIF onlay groups, respectively. The overall complication rate in the TVIF onlay group was 21.5% (20/93), which was higher than 18.1% (15/83) in the TIP group, but the difference was not statistically significant (P = 0.569). The most common complication was urethrocutaneous fistula, occurring in 9.6% (8/83) of the TIP group and 10.8% (10/93) of the TVIF onlay group. There were no significant differences in the rate of any complication and the overall PPPS between the two groups. CONCLUSION: TIP and TVIF onlay are clinically equivalent for the repair of proximal hypospadias. PMID- 24061767 TI - Ocular flutter in essential tremor: clinical course and response to primidone. PMID- 24061768 TI - Inherited neuropathies: an update. AB - In this review, progress in hereditary neuropathy research published in the Journal of Neurology over the last 18 months is summarised. PMID- 24061769 TI - Vestibular rehabilitation outcomes in patients with and without vestibular migraine. AB - Vestibular rehabilitation programs do appear to play a beneficial role in the treatment of dizziness in patients with vestibular migraine. Anecdotally, however, patients with vestibular migraine may report persistent significant symptoms at the end of a standard treatment period where other non-migrainous patients are accomplishing their treatment goals. Therefore, the objective of this study was to assess the efficacy of vestibular rehabilitation in patients with vestibular migraine compared to patients with vestibular symptoms without migraine. Thirty-six patients (vestibular migraine = 20, vestibular impairment = 16) with significant daily vestibular symptoms received a nine week customized vestibular rehabilitation program. Each subject attended five therapy appointments occurring at initial, two, five, nine and six months. A range of subjective and physical performance outcome measures were taken at baseline, nine weeks and six months. The vestibular migraine group showed poorer subjective performance at the onset of therapy, which was not reflected in the difference in physical performance between the groups. Both groups benefitted equally from rehabilitation. The same degree of improvement was observed in the migraine group regardless of medication regime. This study has validated vestibular rehabilitation as an effective treatment in dizzy patients both with and without vestibular migraine where the use of medication did not preclude benefit from therapy. However, further research is required to clarify the role of specific vestibular suppressant medications and the scheduling of their use in relation to physical therapy. PMID- 24061770 TI - Wilhelm Heinrich Erb (1840-1921). PMID- 24061771 TI - Introgression of A- and B-genome of tetraploid triticale chromatin into tetraploid rye. AB - An improvement of rye is one of the mainstream goals of current breeding. Our study is concerned with the introduction of the tetraploid triticale (ABRR) into the 4x rye (RRRR) using classical methods of distant crossing. One hundred fifty BC1F9 hybrid plants [(4x rye * 4x triticales) * 4x rye] obtained from a backcrossing program were studied. The major aim of this work was to verify the presence of an introgressed A- and B- genome chromatin of triticale in a collection of the 4x rye-tiritcale hybrids and to determine their chromosome compositions. In the present study, karyotypes of the previously reported BC1F2s and BC1F3s were compared with that of the BC1F9 generation as obtained after several subsequent open pollinations. The genomic in situ hybridisation (GISH) allowed us to identify 133 introgression forms in which chromosome numbers ranged between 26 and 32. Using four DNA probes (5S rDNA, 25S rDNA, pSc119.2 and pAs1), the fluorescence in situ hybridisation (FISH) was carried out to facilitate an exact chromosome identification in the hybrid plants. The combination of the multi-colour GISH with the repetitive DNA FISH singled out five types of translocated chromosomes: 2A.2R, 4A.4R, 5A.5R, 5B.5R and 7A.7R among the examined BC1F9s. The reported translocation lines could serve as valuable sources of wheat chromatin suitable for further improvements of rye. PMID- 24061772 TI - Paternal bone marrow infusion as salvage therapy for severe GVHD following maternal haploidentical transplantation resulting in biparental chimerism. AB - We describe a case of severe GVHD in a 3-year-old child who had received a maternal haploidentical allograft for thalassemia major, which was refractory to several lines of therapy, including weekly infusion of mesenchymal cells. The child was infused paternal marrow graft from which T cells were depleted using Campath 'in the bag' without conditioning. There was significant improvement in gut and liver GVHD over the next few weeks along with persistent mixed biparental chimerism before the child succumbed to CMV pneumonitis. This approach hints at the possibility of using parental TCD marrow to salvage GVHD caused by a graft from the other parent, and raises the possibility of biparental grafting along the same lines as double cord transplantation. PMID- 24061773 TI - Acute myeloid leukemia and colon carcinoma during the course of acromegaly. AB - We describe the case of a 70-year-old male with acromegaly who developed colon carcinoma and myelodysplastic syndrome (MDS) during the course of acromegaly. MDS progressed to acute myeloid leukemia, but was refractory to chemotherapy. Acromegaly is a rare disorder caused by excessive amounts of growth hormone (GH) primarily secreted by pituitary adenomas. Patients with acromegaly are more prone to develop various malignancies, but there are few reports of hematological malignancies in such patients. In the present case, excessive endogenous GH and insulin-like growth factor-I levels may have altered cell proliferation and thereby affected the oncogenesis and chemosensitivity of both malignancies. PMID- 24061774 TI - Multiparameter flow cytometry is necessary for detection, characterization and diagnostics of composite mature B-cell lymphoproliferative neoplasms. AB - Composite mature B-cell lymphoproliferative neoplasms are rare entities characterized by the simultaneous presence of two or more distinctive B-cell derived monoclonal malignancies. This retrospective study used multiparametric flow cytometric analysis aimed at immunophenotypic profiling of composite mature B-cell lymphoproliferative neoplasms in a cohort of 413 subsequent patients with de novo leukemic B-cell chronic lymphoproliferative disorders diagnosed in our institution during a 30-month period. Biclonality was found in 16 (3.9 %) patients. The vast majority (88 %) of the cases had one of the clones phenotypically corresponding to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Only when composite cases were categorized by phenotype of the non-CLL/SLL malignant population did we find a statistically significant (P = 0.001) higher frequency of biclonality among cases with hairy cell leukemia (22 %). Biclonal cases had the overall B-cell membrane kappa to lambda ratio within the normal range (median, 1.9; reference interval 0.5-4.0), making recognition of malignancy somewhat challenging. Our analysis strategy was therefore based on the detection of aberrant B-cell phenotypes, with subsequent confirmation of the monoclonal nature of neoplastic clones with regards to light chain restriction analysis. Discrimination of the coexisting clones in biclonal cases was possible on the basis of the expression of other antigen(s) (63 %), light scatter properties (44 %), different surface light chain restriction (69 %) and/or pattern of expression (44 %). The most informative cell surface antigens proved to be CD22, CD20, surface IgM, and CD23. In conclusion, historic kappa/lambda ratio is not a reliable approach and is a poor measurement for the detection of composite lymphomas. More creative analysis techniques should be utilized for this purpose. PMID- 24061775 TI - Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B. AB - Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography. The pharmacokinetics was evaluated after a single intravenous bolus injection in mice, rats, and macaques. Toxicity was assessed in rats and macaques, safety pharmacology in rabbits and macaques, and immunogenicity in mice. BAX326 was shown to be efficacious in all three primary pharmacodynamic studies (P <= 0.0076). Hemostatic efficacy was dose related and similar for the three lots tested. Pharmacokinetic results showed that rFIX activity and rFIX antigen concentrations declined in a bi-phasic manner, similar to a previously licensed rFIX product. BAX326 was well tolerated in rabbits and macaques at all dose levels; no thrombogenic events and no adverse clinical, respiratory, or cardiovascular effects occurred. BAX326 was also shown to have a similar immunogenicity profile to the comparator rFIX product in mice. These results demonstrate that BAX326 has a favorable preclinical safety and efficacy profile, predictive of a comparable effect to that of the previously licensed rFIX in humans. PMID- 24061776 TI - Examining the role of carbon capture and storage through an ethical lens. AB - The risk posed by anthropogenic climate change is generally accepted, and the challenge we face to reduce greenhouse gas (GHG) emissions to a tolerable limit cannot be underestimated. Reducing GHG emissions can be achieved either by producing less GHG to begin with or by emitting less GHG into the atmosphere. One carbon mitigation technology with large potential for capturing carbon dioxide at the point source of emissions is carbon capture and storage (CCS). However, the merits of CCS have been questioned, both on practical and ethical grounds. While the practical concerns have already received substantial attention, the ethical concerns still demand further consideration. This article aims to respond to this deficit by reviewing the critical ethical challenges raised by CCS as a possible tool in a climate mitigation strategy and argues that the urgency stemming from climate change underpins many of the concerns raised by CCS. PMID- 24061778 TI - Trainee outcomes after the Mersey and north-west 'pre-ST4' neonatal simulation course. PMID- 24061777 TI - Sleep patterns in children with autistic spectrum disorders: a prospective cohort study. AB - OBJECTIVE: To investigate longitudinal sleep patterns in children with autistic spectrum disorders (ASDs). STUDY DESIGN: Prospective longitudinal study using Avon Longitudinal Study of Parents and Children, an English cohort born in 1991 1992. Parental reports of sleep duration were collected by questionnaires at 8 time points from 6 months to 11 years. Children with an ASD diagnosis at age 11 years (n=73) were identified from health and education records. RESULTS: From aged 30 months to 11 years old, children with ASD slept for 17-43 min less each day than contemporary controls. No significant difference in total sleep duration was found in infancy, but from 30 months of age children with ASD slept less than their peers, a difference that remained significant after adjusting for sex, ethnicity, high parity and epilepsy. The reduction in total sleep was wholly due to changes in night rather than daytime sleep duration. Night-time sleep duration was shortened by later bedtimes and earlier waking times. Frequent waking (3 or more times a night) was also evident among the children with ASD from 30 months of age. Age-specific decreases of >1SD within individuals in sleep duration across adjacent time points was a predictor of ASD between 18 months and 30 months of age (p=0.04) and from 30 months to 42 months (p=0.02). CONCLUSIONS: Sleep duration in children with ASD is reduced from 30 months of age and persists until adolescence. PMID- 24061779 TI - Malaria vaccines: past, present and future. AB - The currently available malaria control tools have allowed malaria elimination in many regions but there remain many regions where malaria control has made little progress. A safe and protective malaria vaccine would be a huge asset for malaria control. Despite the many challenges, efforts continue to design and evaluate malaria vaccine candidates. These candidates target different stages in the life cycle of Plasmodia. The most advanced vaccine candidates target the pre erythrocytic stages in the life cycle of the parasite and include RTS,S/AS01, which has progressed through clinical development to the stage that it may be licensed in 2015. Attenuated whole-parasite vaccine candidates are highly protective, but there are challenges to manufacture and to administration. Cellular immunity is targeted by the prime-boost approach. Priming vectors trigger only modest responses but these are focused on the recombinant antigen. Boosting vectors trigger strong but broad non-specific responses. The heterologous sequence produces strong immunological responses to the recombinant antigen. Candidates that target the blood stages of the parasite have to result in an immune response that is more effective than the response to an infection to abort or control the infection of merozoites and hence disease. Finally, the sexual stages of the parasite offer another target for vaccine development, which would prevent the transmission of malaria. Today it seems unlikely that any candidate targeting a single antigen will provide complete protection against an organism of the complexity of Plasmodium. A systematic search for vaccine targets and combinations of antigens may be a more promising approach. PMID- 24061780 TI - Imaging in craniosynostosis. PMID- 24061781 TI - Effects of telemonitoring in cancer patients. PMID- 24061782 TI - Femoral placement of totally implantable venous power ports as an alternative implantation site for patients with central vein occlusions. AB - PURPOSE: To evaluate the indication, technical success, clinical outcome and safety of percutaneously placed totally implantable venous power ports (TIVPPs) in a femoral position in patients with contraindications to implantation in a standard position. METHODS: Retrospectively, we screened our interventional radiology department database between 12/2,009 and 3/2,013 to identify 1,729 patients with a port implantation. In 8/1,729 (0.47 %) patients (1 male, 7 female, mean age 55.5 +/- 9.6 years) the TIVPP was implanted via the common femoral vein with the port placed in the anterior thigh. All devices were high pressure injectable, implanted under local anaesthesia with sonographic as well as fluoroscopic guidance, and were tunnelled subcutaneously. Indication, technical success and complications were retrospectively analysed according to the Society of Interventional Radiology (SIR) criteria. RESULTS: Indications were planned chemotherapy for breast (n = 6) and oesophagus cancer (n = 1) as well as need for long-term central venous access for intravenous therapy (n = 1) with a contraindication to or failed implantation in a standard position owing to central vein occlusions. Technical success was 100 %. A number of five devices were placed in the right, three in the left thigh. Altogether 1,979 catheter days were analysed. One device was explanted owing to infection after 84 days (late complication, 0.05/100 catheter days). No early complication was observed. CONCLUSIONS: Our data suggest that if implantation of a TIVPP is not favourable in a standard chest, upper arm or forearm position, femoral placement of the device may alternatively be used safely and with high technical success. PMID- 24061783 TI - Pilot-scale in situ bioremediation of HMX and RDX in soil pore water in Hawaii. AB - A nine-month in situ bioremediation study was conducted in Makua Military Reservation (MMR) in Oahu, Hawaii (USA) to evaluate the potential of molasses to enhance biodegradation of royal demolition explosive (RDX) and high-melting explosive (HMX) contaminated soil below the root zone. MMR has been in operation since the 1940's resulting in subsurface contamination that in some locations exceeds USEPA preliminary remediation goals for these chemicals. A molasses-water mixture (1 : 40 dilution) was applied to a treatment plot and clean water was applied to a control plot via seven flood irrigation events. Pore water samples were collected from 12 lysimeters installed at different depths in 3 boreholes in each test plot. The difference in mean concentrations of RDX in pore water samples from the two test plots was very highly significant (p < 0.001). The concentrations differences with depth were also very highly significant (p < 0.001) and degradation was greatly enhanced at depths from 5 to 13.5 ft. biodegradation was modeled as first order and the rate constant was 0.063 per day at 5 ft and decreased to 0.023 per day at 11 ft to 13.5 ft depth. Enhanced biodegradation of HMX was also observed in molasses treated plot samples but only at a depth of 5 ft. The difference in mean TOC concentration (surrogate for molasses) was highly significant with depth (p = 0.003) and very highly significant with treatment (p < 0.001). Mean total nitrogen concentrations also differed significantly with treatment (p < 0.001) and depth (p = 0.059). The molasses water mixture had a similar infiltration rate to that of plain water (average 4.12 ft per day) and reached the deepest sensor (31 ft) within 5 days of application. Most of the molasses was consumed by soil microorganisms by about 13.5 feet below ground surface and treatment of deeper depths may require greater molasses concentrations and/or more frequent flood irrigation. Use of the bioremediation method described herein could allow the sustainable use of live fire training ranges by enhancing biodegradation of explosives in situ and preventing them from migrating to through the vadose zone to underlying ground water and off-site. PMID- 24061785 TI - You can't drink a word: lexical and individual emotionality affect subjective familiarity judgments. AB - For almost 30 years, subjective familiarity has been used in psycholinguistics as an explanatory variable, allegedly able to explain many phenomena that have no other obvious explanation (Gernsbacher in J Exp Psychol General 113:256-281, 1984). In this paper, the hypothesis tested is that the subjective familiarity of words is reflecting personal familiarity with or importance of the referents of words. Using an empirically-grounded model of affective force derived from Wundt (Grundriss der Psychologie [Outlines of Psychology]. Engelmann, Leibzig, 1896) and based in a co-occurrence model of semantics (which involves no human judgment), it is shown that affective force can account for the same variance in a large set of human subjective familiarity judgments as other human subjective familiarity judgments, can predict whether people will rate new words of the same objective frequency as more or less familiar, can predict lexical access as well as human subjective familiarity judgments do, and has a predicted relationship to age of acquisition norms. Individuals who have highly affective reactivity [as measured by Carver and White's (J Pers Soc Psychol 67(2):319-333, 1994) Behavioral Inhibition Scale and Behavioral Activation Scales] rate words as significantly more familiar than individuals who have low affective reactivity. PMID- 24061784 TI - Baseline factors predicting placebo response to treatment in children and adolescents with autism spectrum disorders: a multisite randomized clinical trial. AB - IMPORTANCE: The finding of factors that differentially predict the likelihood of response to placebo over that of an active drug could have a significant impact on study design in this population. OBJECTIVE: To identify possible nonspecific, baseline predictors of response to intervention in a large randomized clinical trial of children and adolescents with autism spectrum disorders. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of citalopram hydrobromide for children and adolescents with autism spectrum disorders and prominent repetitive behavior. Baseline data at study entry were examined with respect to final outcome to determine if response predictors could be identified. A total of 149 children and adolescents 5 to 17 years of age (mean [SD] age, 9.4 [3.1] years) from 6 academic centers were randomly assigned to citalopram (n = 73) or placebo (n = 76). Participants had autistic disorder, Asperger syndrome, or pervasive developmental disorder, not otherwise specified; had illness severity ratings that were moderate or more than moderate on the Clinical Global Impression-Severity scale; and scored moderate or more than moderate on compulsive behaviors measured with the modified Children's Yale-Brown Obsessive Compulsive Scale. INTERVENTIONS: Twelve weeks of treatment with citalopram (10 mg/5 mL) or placebo. The mean (SD) maximum dose of citalopram was 16.5 (6.5) mg by mouth daily (maximum dose, 20 mg/d). MAIN OUTCOMES AND MEASURES: A positive response was defined as having a score of at least much improved on the Clinical Global Impression-Improvement scale at week 12. Baseline measures included demographic (sex, age, weight, and pubertal status), clinical, and family measures. Clinical variables included baseline illness severity ratings (the Aberrant Behavior Checklist, the Child and Adolescent Symptom Inventory, the Vineland Adaptive Behavior Scales, the Repetitive Behavior Scale-Revised, and the Children's Yale-Brown Obsessive-Compulsive Scale). Family measures included the Caregiver Strain Questionnaire. RESULTS: Several baseline predictors of response were identified, and a principal component analysis yielded 3 composite measures (disruptive behavior, autism/mood, and caregiver strain) that significantly predicted response at week 12. Specifically, participants in the placebo group were significantly less likely than participants in the citalopram group to respond at week 12 if they entered the study more symptomatic on each of the 3 composite measures, and they were at least 2 times less likely to be responders. CONCLUSIONS AND RELEVANCE: This analysis suggests strategies that may be useful in anticipating and potentially mitigating the nonspecific response in randomized clinical trials of children and adolescents with autism spectrum disorders. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00086645. PMID- 24061786 TI - Reversible cerebral vasoconstriction syndrome resulted in cerebral infarction after allogeneic stem cell transplantation: a case report. PMID- 24061787 TI - Visceral leishmaniasis clinically mimicking lymphoma. PMID- 24061788 TI - Clinical implication of F-18 FDG PET/CT in patients with secondary hemophagocytic lymphohistiocytosis. AB - The contribution that F-18 fluoro-2-deoxyglucose positron emission tomography/computed tomography (F-18 FDG) PET/CT makes to the diagnosis of malignancy in patients with hemophagocytic lymphohistiocytosis (HLH) is still uncertain. The aim of this study was to evaluate the diagnostic performance of F 18 FDG PET/CT for the detection of underlying malignancy, to investigate the correlation between PET and laboratory parameters, and to identify prognosis related factors in patients with secondary HLH. We enrolled 14 patients who were diagnosed with HLH and referred for F-18 FDG PET/CT to exclude malignancy. The diagnostic performance of F-18 FDG PET/CT for malignancy detection was assessed. The correlations between PET and laboratory parameters were determined. The prognostic significance of the following factors was evaluated: PET and laboratory parameters, age in years, presence of underlying malignancy, and fever and splenomegaly. Six of the 14 patients had malignancies (four with lymphoma, one with multiple myeloma, and one with colonic malignancy). Sensitivity, specificity, and diagnostic accuracy of F-18 FDG PET/CT for malignancy detection were 83, 62.5, and 71.4 %, respectively. F-18 FDG uptake in the bone marrow and spleen was positively correlated with neutrophil count and C-reactive protein. All of the PET parameters, but none of the clinical or laboratory parameters, were significantly associated with patient outcome, as determined by univariate analysis. Given the small sample size, F-18 FDG PET/CT was useful for detecting underlying malignancy, and PET parameters correlated with laboratory parameters that reflected inflammatory status. F-18 FDG PET/CT might provide prognostic information for the management of patients with secondary HLH. PMID- 24061789 TI - The impact of an anti-idling campaign on outdoor air quality at four urban schools. AB - Idling school buses may increase concentrations of air pollutants including fine particulate matter (PM2.5) and elemental carbon (EC) near schools. Efforts to reduce vehicle idling near schools have rarely included air sampling to objectively assess changes in concentrations of air pollutants. The objective was to determine the impact of an anti-idling campaign on outdoor air quality at four schools with varying exposure to bus and automobile traffic. Outdoor air sampling for PM2.5, EC and particle number concentration (PNC) was conducted at four schools for five days before and after an anti-idling campaign. Sampling began before the morning arrival of buses and concluded after their afternoon departure. Sampling was simultaneously conducted at four corresponding community sites. Differences in PM2.5, EC, and PNC measured at school and community sites for each sampling day were calculated before and after the campaign. Before the campaign, the average outdoor concentration of PM2.5 during the school day at three of the four schools exceeded community background levels and the difference was greatest (4.11 MUg m(-3), p < 0.01) at the school with the most buses (n = 39). The largest difference in EC between school and community sites was also observed at the school with the greatest number of buses (0.40 MUg m(-3), p < 0.01). Following the anti-idling campaign, the average difference in PM2.5 at the school with the most buses decreased from 4.11 MUg m(-3) to 0.99 MUg m(-3) (p < 0.05). Similarly, at this school, the difference in the EC level decreased from 0.40 MUg m(-3) to 0.15 MUg m(-3) and PNC decreased from 11,560 to 1690 particles per cm(3) (p < 0.05). The outdoor concentrations of pollutants at schools with fewer buses (n = 5-11) were not significantly reduced. The concentration of air pollutants near schools may significantly exceed community background levels, particularly in the presence of idling school buses. Anti-idling campaigns are effective in reducing PM2.5, EC and PNC at schools with significant amounts of buses and passenger cars. PMID- 24061790 TI - Vegetation dynamics during different abandoned year spans in the land of the Loess Plateau of China. AB - In this semi-arid area, many studies focused on the two-phase vegetation pattern were carried out to explore a changing vegetation trajectory on degraded land. However, this study conducted an analysis of a two-phase vegetation pattern and explored the successional vegetation trajectories in a positive succession without disturbance. In this work, 60 randomly distributed plots (1 * 1 m) were invested on four abandoned land areas (4-, 12-, 22-, and 50-year abandoned land) to determine attributes of vegetation, and soil physical and nutritional properties. It was found that vegetation distribution development went from homogeneous on 4-year abandoned land to heterogeneous on 50-year abandoned land, with a positive succession. Meanwhile, there was a significant difference in soil physical and nutritional properties for the inside and outside of vegetation patches. Vegetation patches can supply better soil physical and nutritional properties for vegetation than bare patches along the abandoned time. Vegetation diversity changes without a regular trend which may be due to the effect of environment and interspecies competition. This work picked up the slack for vegetation patterns succession research and provided a quantitative analysis approach. PMID- 24061792 TI - How to build a multiscale model in biology. AB - Biological processes span several scales in space, from the single molecules to organisms and ecosystems. Multiscale modelling approaches in biology are useful to take into account the complex interactions between different organisation levels in those systems. We review several single- and multiscale models, from the most simple to the complex ones, and discuss their properties from a multiscale point of view. Approaches based on master equations for stochastic processes, individual-based models, hybrid continuous-discrete models and structured PDE models are presented. PMID- 24061791 TI - Trends in nutrient and sediment retention in Great Plains reservoirs (USA). AB - Reservoirs are artificial ecosystems with physical, chemical, and biological transitional characteristics between rivers and lakes. Greater water retention time in reservoirs provides conditions for cycling materials inputs from upstream waters through sedimentation, biological assimilation and other biogeochemical processes. We investigated the effects of reservoirs on the water quantity and quality in the Great Plains (Kansas, USA), an area where little is known about these dominant hydrologic features. We analyzed a 30-year time-series of discharge, total phosphorus (TP), nitrate (NO3(-)), and total suspended solids (TSS) from six reservoirs and estimated overall removal efficiencies from upstream to downstream, testing correlations among retention, discharge, and time. In general, mean removal of TP (42-74%), TSS (0-93%), and NO3(-) (11-56%) from upstream to downstream did not change over 30 years. TP retention was associated with TSS removal, suggesting that nutrient substantial portion of P was adsorbed to solids. Our results indicated that reservoirs had the effect of lowering variance in the water quality parameters and that these reservoirs are not getting more or less nutrient-rich over time. We found no evidence of temporal changes in the yearly mean upstream and downstream discharges. The ratio upstream/downstream discharge was analyzed because it allowed us to assess how much contribution of additional unsampled tributaries may have biased our ability to calculate retention. Nutrient and sediment removal was less affected by hydraulic residence time than expected. Our study demonstrates that reservoirs can play a role in the removal and processing of nutrient and sediments, which has repercussions when valuing their ecological services and designing watershed management plans. PMID- 24061793 TI - Patterns of ring current in coronene isomers. AB - The ipsocentric pseudo-p model is used to predict maps of induced current density for isomeric variations of coronene in which the central hexagonal ring is surrounded by 5, 6, and 7-membered rings. All isomers in the set are predicted to support strong diatropic perimeter ring currents, thereby conforming to the magnetic criterion of aromaticity. PMID- 24061794 TI - HOMO-LUMO Maps for Fullerenes. AB - The HOMO-LUMO map is found to be a useful tool for classifying p-electron configurations of fullerenes and identifying research questions about their adjacency spectra. PMID- 24061795 TI - On sum-connectivity matrix and sum-connectivity energy of (molecular) graphs. AB - If G is a (molecular) graph with n vertices, and di is the degree of its i-th vertex, then the sum-connectivity matrix of G is the n * n matrix whose (i, j) entry is equal to 1/?di + dj if the i-th and the j-th vertices are adjacent and 0 otherwise. The sum-connectivity energy of a graph G is defined as the sum of the absolute values of the eigenvalues of the sum-connectivity matrix. Some properties including upper and lower bounds for the eigenvalues of the sum connectivity matrix and the sum-connectivity energy are established, and the extremal cases are characterized. PMID- 24061796 TI - Note on the comparison of the first and second normalized zagreb eccentricity indices. AB - The conjecture Sigmauv V(G) dG(u)2 / n(G) <= Sigmauvv E(G) dG(u)dG(v) / m(G) that compares normalized Zagreb indices attracted recently a lot of attention1-9. In this paper we analyze analogous statement in which degree dG(u) of vertex u is replaced by its eccentricity deltaG(u) in which way we define novel first and second Zagreb eccentricity indices. We show that Sigmauv V(G) epsilonG(u)2 / n(G) >= Sigmauvv E(G) epsilonG(u)epsilonG(v) / m(G) holds for all acyclic and unicyclic graphs and that neither this nor the opposite inequality holds for all bicyclic graphs. PMID- 24061797 TI - Chemometrical Exploration of Combinatorially Generated Drug-like Space of 6 fluoroquinolone Analogs: A QSAR Study. AB - A classical virtual combinatorial chemistry approach (CombiChem) was applied for combinatorial generation of 5590 novel structurally-similar 6-fluoroquinolone analogs by using a virtual synthetic pathway with selected primary (43) and secondary amines (130). The obtained virtual combinatorial library was filtered using an in-house developed set of cheminformatics drug-likeness filters with pre integrated Boolean options (TRUE/FALSE) for compounds reduction/selection. The retained number (304) of fluoroquinolone analogs (with TRUE outcome) defines the drug-like chemical space (CombiData). Quantitative structure-activity relationships (QSAR) study on these 304 virtually generated 6-fluoroquinolone analogs with unknown activity values was performed using a pre-built five parameter multiple linear regression (MLR) model developed on a set of compounds with experimentally determined activity values (Rtr = 0.8417, Rtr-cv = 0.7884). The obtained activity values for the unknown compounds together with the model results were used to define the applicability domain (AD). The obtained AD offers a good graphical representation and establishment of structure-activity relationships (SAR) which could be used for design of new 6-fluoroquinolones with possible better activity. PMID- 24061798 TI - Prediction of Anticancer Activity of 2-phenylindoles: Comparative Molecular Field Analysis Versus Ridge Regression using Mathematical Molecular Descriptors. AB - Topological indices (TIs) and atom pairs (APs) were used to develop quantitative structure-activity relationships (QSARs) for anticancer activity for a set of 43 derivatives of 2-phenylindole. Results show that QSARs formulated using TI+AP outperform those using either TI or AP alone. The q2 of the ridge regression model using TI+AP was 0.867 as compared to 0.705 reported in the literature using the comparative molecular field analysis (CoMFA) method. PMID- 24061799 TI - Counting Polynomials in Tori T(4,4)S[c,n]. AB - A counting polynomial P(x) is a description of a graph property P(G) in terms of a sequence of numbers so that the exponents express the extent of its partitions while the coefficients are related to the number of partitions of a given extent. Basic definitions and some properties are given for two classes of polynomials, called here polynomials of vertex proximity and edge proximity, respectively. Formulas to calculate these polynomials in T(4,4)[c,n] tori are derived by a cutting procedure. PMID- 24061800 TI - Shell-polynomials and cluj-tehran index in tori t(4,4)s[5,n]. AB - Weighted Hosoya polynomials have been developed by Diudea, in ref. Studia Univ. "Babes-Bolyai", 2002, 47, 131-139. Among various weighting schemes, those polynomials obtained by using Diudea's Shell matrix operator are far more interesting. We present here the Shell-Distance and Shell-Degree-Distance polynomials and close formulas to calculate them and derived Cluj-Tehran CT index in the family of square tiled tori T(4,4)S[5,n]. Applications of the proposed descriptors are also presented. PMID- 24061801 TI - Omega polynomial revisited. AB - Omega polynomial was proposed by Diudea (Omega Polynomial, Carpath. J. Math., 2006, 22, 43-47) to count the opposite topologically parallel edges in graphs, particularly to describe the polyhedral nanostructures. In this paper, the main definitions are re-analyzed and clear relations with other three related polynomials are established. These relations are supported by close formulas and appropriate examples. PMID- 24061802 TI - Multivariate data analysis of erythrocyte membrane phospholipid Fatty Acid profiles in the discrimination between normal blood tissue and various disease States. AB - The investigation presented here aims to compare the fatty acid composition of red blood cells of patients with different disease states and to test the hypothesis that the changes in fatty acid profiles derived from erythrocyte phospholipids might be relevant to various diseases. The study sample consisted of 342 blood donors, among them 135 with inflammatory bowel disease, 53 with uterine leiomyoma, 14 with verified absence of uterine leiomyoma, 52 with asthma, 18 with colon adenomas, and 70 blood samples without any of mentioned diseases that was used as a control group. After the isolation of erythrocytes from blood samples, total extracted lipids were separated by solid-phase extraction (SPE) into non polar lipids and polar phospholipids. After the saponification of phospholipid fraction, the esterification process followed with boron trifluoride methanol reagent. The fatty acid methyl ester (FAME) composition of the total red blood cell phospholipid fraction was analyzed by gas chromatography (GC) with flame ionization detector (FID). Additionally two fatty aldehyde dimethyl acetals (hexadecanal and octadecanal dimethyl acetals; 16:0 DMA and 18:0 DMA) derived from erythrocyte membrane plasmalogen phospholipids were also determined. The resulting fatty acid and plasmalogen linked fatty acid composition was evaluated by the principal component analysis (PCA). We demonstrated decreased levels of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in red blood cell membrane of patients with colon adenomas. Also, a large negative correlation was observed among all samples between the quantity of saturated acids and arachidonic (20:4n6) acid as well as saturated acids and adrenic (22:4n6) acid. In PCA score plot a group of female donors is distinguished mainly by the content of linoleic (18:2n6) acid; a small subgroup shows its concentration highly above the average value. At the same time, the same subgroup has both dimethyl acetals below the average concentrations. The study demonstrates feasibility of multivariate data analysis in discrimination of patients with different diseases according to fatty acid profile and suggests considerable differences in membrane fatty acid profiles in patients with various disease states. PMID- 24061803 TI - Modeling of the Mass Spectrometric Response Factors in Non-target Analysis. AB - Experimental MS response factors were measured for 36 different saturated and unsaturated volatile organic compounds (VOC) containing carbon, hydrogen and halogen atoms. Chemical structure was encoded using various molecular descriptors. A quantitative structure-property relationship model was established using the multiple linear regression models. The cross-validation ability of the created model was estimated by leave-one-out cross-validation procedure. Error in the cross-validation of response factors was calculated by cross-validation procedure and was 15%, which is sufficient for the determination of VOCs in the air. The proposed procedure can be used for simultaneous qualitative and quantitative determination of volatile organic compounds in the atmosphere. PMID- 24061805 TI - Vector representations of kekule structures of benzenoids. AB - Milan Randic's contributions to resonance in benzenoids is recalled, with particular focus on his recent identification and exploration of his "algebraic Kekule structures" (in terms of a suitable sequence of digits). In particular, further such vectorial representations of Kekule structures are noted, are characterized a bit, and are compared to one another. PMID- 24061804 TI - Ranking of QSAR Models to Predict Minimal Inhibitory Concentrations Toward Mycobacterium tuberculosis for a Set of Fluoroquinolones. AB - CP-ANN technique was used to build 54 different QSAR models. The models were built for three sets (assays) of fluoroquinolones considering their antituberculosis activity and using different technical parameters (dimension of network and number of learning epochs). The models served as a reliable basis for ranking by a new powerful method based on sum of ranking differences (SRD). With the applied SRD procedure we can find the optimal ones. The best model can be selected easily for the first assay. Two models can be recommended for the second assay, and no recommended model was found for the assay3. PMID- 24061806 TI - Randic index, irregularity and complex biomolecular networks. AB - A new formulation of Randic index is carried out as a minimization of a quadratic form which involves the Laplacian matrix of a graph. Using this formulation it is easy to realize that Randic index is useful in defining a new index of irregularity, which is then formulated here. A new context for the study of irregularity of graphs is advanced as a necessity for studying complex (biological) networks. We analyze both Randic and irregularity indices for random networks with Poisson and power-law degree distributions. Then, we analyze the irregularity of 10 protein-protein interaction networks in different organisms ranging from 50 to 3000 nodes. Finally, some sruminations' about the elegance and applicability of Randic index are remarked. PMID- 24061807 TI - Extended connectivity in directed graphs. AB - An algorithm for the evaluation of the extended connectivity in directed graphs is described and discussed. The algorithm is a general purpose one for finding the number of all paths from any given node Vi in a directed graph toward all leaves that can be reached from that particular node Vi in the graph. PMID- 24061808 TI - A new version of atom-bond connectivity index. AB - The atom-bond connectivity index is a recently introduced topological index defined as [Formula: see text], where du denotes degree of vertex u. Here we define a new version of the ABC index as [Formula: see text], where nu denotes the number of vertices of G whose distances to vertex u are smaller than those to other vertex v of the edge e = uv, and nv is defined analogously. The goal of this paper is to study the ABC2 index. PMID- 24061809 TI - Art and science: geodesy in materials science. AB - A 3-dimensional model based on a molecular structural recipe having some unique and unexpected shape characteristics is demonstrated. The project was originally initiated to satisfy the aesthetic creative impulse to build a 3-dimensional model or sculpture. Further scientific investigation explained some important nanoscale structural observations that had been seen many years beforehand and mistakenly explained. This is a rare example of artistic creativity resulting in a key scientific advance. PMID- 24061810 TI - Cytokinins and their function in developing seeds. AB - Cytokinins are a major group of plant hormones that control various processes in plant growth and development. Chemically they are N6-substituated adenine derivatives, including their respective ribotides, ribosides and glucosides. The inter-conversion between different cytokinins metabolites represents the transition between active, inactive, storage and transport forms. This process is in vivo rather dynamic and rapid. We have finally begun to understand the role of cytokinins in plant development through the identification of genes for the first plant enzyme in the biosynthetic pathway, isopentenyl transferases, less than 10 years ago, in addition to research of other enzymes and their corresponding genes that are involved in cytokinin metabolism and signal transduction. This review focuses on the recent findings on cytokinins with an emphasis on their role during the development of seedsfrom which the first natural cytokinin was isolated more that half a century ago. PMID- 24061811 TI - An overview of conventional and alternative strategies for developing new antibacterial agents. AB - Although there is an increased need for novel antibacterial compounds, a regress in developing new antibiotic drugs has been registered in the past decades, as a result of economic, medical, social and political factors. The present paper aims to bring together and to discuss the wealth of information in the subject by presenting both traditional and new approaches for antibiotic drug discovery. The route starting from analogues derived from well-known antibiotics seems that will be the one to offer the great part of new antibiotics having the potential to enter the marketplace. The target-based approach, well-validated biomolecular targets and new potential targets emerging from complex resistance mechanisms of bacteria and bacterial virulence, are disscused. Moreover, strategies based on the multiplicity of targets to be addressed by an antibacterial agent in order to limit the problem of antibiotic resistance are highlighted in the present paper. Challenging sources for developing new antibacterial agents, e.g. bacteriophages, non-multiplying and non-culturable bacteria are also considered. PMID- 24061812 TI - Synthesis, Spectroscopic, Spectrophotometric and Crystallographic Investigations of 4-{[(1E)-(3,4-dimethoxyphenyl)methylene]amino}-1,5-dimethyl-2-phenyl-1,2 dihydro-3H-pyrazol-3-one and 4-{[(1E)-(2-hydroxy-5-methoxyphenyl)methylene]amino} 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one. AB - Two new Schiff base ligands 4-[(1E)-(3,4-dimethoxyphenyl)methylene]amino-1,5 dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (1) and 4-[(1E)-(2-hydroxy-5 methoxyphenyl)methylene]amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (2) have been prepared and characterized using elemental analysis, UV-vis, FT-IR, 1H and 13C NMR spectroscopy, and X-ray crystallographic technique. Tautomeric equilibria (phenol-imine, O-H...N and keto-amine, O...H-N forms) have been studied by using UV-vis absorption spectra for the compound 2 in some solutions. Crystal structure analyses showed that the title molecules 1 and 2 crystallize in the monoclinic space group P21/c and P21 with the unit cell parameters: a = 12.5665(3) A and 5.6666(2) A; b = 10.4791(2) A and 12.2444(5) A; c = 14.6240(3) A and 12.1556(4) A; V =1820.65(7) A3 and 826.84(5) A3; Dx = 1.282 g.cm-3 and 1.355 g.cm-3; and Z = 4 and 2, respectively. PMID- 24061813 TI - Apparent molar volumes and viscosity B-coefficients of glycine in aqueous silver sulphate solutions at T = (298.15, 308.15, 318.15) k. AB - Apparent molar volumes (phiV) and viscosity B-coefficients for glycine in 0.005, 0.010, 0.015, and 0.020 mol dm-3 aqueous silver sulphate (Ag2SO4) solutions have been determined from solution density and viscosity measurements at (298.15, 308.15, and 318.15) K as a function of glycine concentration. The standard partial molar volume (phiV0) and experimental slopes (SV*) obtained from the Masson equation have been interpreted in terms of solute-solvent and solute solute interactions, respectively. The viscosity data were analyzed using the Jones-Dole equation, and the derived parameters A and B were interpreted in terms of solute-solute and solute-solvent interactions, respectively. The standard volumes of transfer (DeltaphiV0) and viscosity B-coefficients of transfer (DeltaB) of glycine from water to aqueous Ag2SO4 solutions were derived to study various interactions in the ternary solutions. The structure making or breaking ability of glycine has been discussed in terms of the sign of (delta2phiV0/deltaT2)P. The activation parameters of viscous flow for the ternary solutions were also calculated and explained in terms of transition state theory. PMID- 24061814 TI - Synthesis, Characterization and Antimicrobial Study of Novel 4-{[(8 Hydroxyquinolin-5-yl)methyl]amino}benzenesulfonamide and Its Oxinates. AB - A novel 4-[(8-hydroxyquinolin-5-yl)methyl]aminobenzenesulfonamide (HQMABS) was synthesized by optimized reaction of 4-aminobenzenesulfonamide with 5 chloromethyl-8-hydroxyquinoline hydrochloride (CMHQ). Various oxinates of HQMABS were also prepared using Mn(II), Fe(II), Co(II), Ni(II), Cu(II), and Zn(II) metal salts. All compounds were analyzed by physicochemical, thermogravimetric and spectroscopic techniques. Antimicrobial activity was carried out using agar-plate method against various strains of bacteria (Staphylococcus aureus, Bacillus subtillis, Pseudomonas aerugionsa, and Escherichia coli) and spores of fungi (Aspergillus niger and Aspergillus flavous). The results showed significantly higher antimicrobial activity of HQMABS compared to the parent 8-hydroxyquinoline and sulfonamide, while oxinates of HQMABS showed milder activity. PMID- 24061815 TI - How Safe are Antioxidant Food Supplements Containing Selenium? AB - Three antioxidant food supplements were analysed for selenium (Se) and its species. Sample A main constituents were coenzyme Q10, selenium (as medical yeast), vitamin C and natural vitamin E. The product is used for maintaining health and strengthening physical and mental abilities, stimulating the immune system, inhibiting the development of atherosclerosis, strengthening a weakened heart. Sample B main constituents were coenzyme Q10, selenium, vitamin E and beta carotene. The product is advertised as high dosage natural coenzyme Q10, which provides supply of energy to all cells of human body. Sample C main ingredients were coenzyme Q10, selenium (as sodium selenite), beta-carotene and vitamin E with the same positive effects described as for the samples A and B. The samples were digested and analysed for Se content by hydride generation atomic fluorescence spectrometry (HG-AFS). For Se speciation, enzymatic hydrolysis with the enzyme protease was performed and soluble Se species was determined by ion exchange chromatography coupled with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). The results showed that the value of Se obtained for one of the products (C) far exceeded the declared value; instead of 10 ug Se per capsule, 69 ug of Se per capsule was found. The declared Se species in the same product was sodium selenite, but only SeCys2 was detected (55% of the total Se). In product B that did not have a declared Se form added, we detected 60% of total Se as selenite. In product A 75% of total Se was present as SeMet. It is worrying that the Se species determined and declared were different in two selected antioxidant food supplements. PMID- 24061816 TI - Hydrogenation of Unsaturated Carbonyl Compounds on non-Calcined LDHs. I. Synthesis and Characterization of ZnNiCuAl Hydrotalcite-like Materials. AB - Several Zn/Ni/Cu/Al layered double hydroxides (LDH) with variable Ni/Cu ratios but constant Zn/Al, as well as M2+/M3+ ratios, were synthesized by coprecipitation method with CO32- as compensating anion. The main goal of the study was to investigate the influence of the catalysts composition, especially Ni/Cu ratio, on the physical and catalytic properties of these materials. The XRD results show that all the LDHs samples are well crystallized and contain only pure phases. Moreover, the spectral techniques (FT-IR and DR-UV-VIS) indicated that both Ni and Cu species are present in the brucite-like layers of LDHs. The shape of the nitrogen physisorption isotherms obtained at -196 degrees C indicates a predominantly mesoporous materials; the surface areas and pore volumes are in the specific ranges between 37-86 m2.g-1 and 0.31-0.75 cm3.g-1, respectively. Three characteristic weight losses between 30 and 400 degrees C are identified by TG analysis for the hydrotalcite-like materials synthesized in this study. Moreover, an influence of the Ni/Cu ratios on the amount of the physisorbed water was noticed. The preliminary catalytic test revealed unusual catalytic properties of the non-calcined samples in the liquid phase hydrogenation of trans-cinnamaldehyde. PMID- 24061817 TI - The possibility of simultaneous voltammetric determination of desloratadine and 3 hydroxydesloratadine. AB - The electrochemical behaviour of desloratadine (DLOR) and its derivative 3 hydroxydesloratadine (3OH-DLOR) was investigated by direct current (DCP) polarography, cyclic (CV), differential pulse (DPV) and square-wave (SWV) voltammetry in Britton-Robinson (BR) buffer solutions (pH 4-11). Both compounds are reduced at mercury electrode in irreversible two electron reduction of the C=N bond of the pyridine ring in their molecules. The difference in their electrochemical behaviour was investigated, and the most pronounced distinction is observed at pH > 9, as a consequence of the deprotonation of the phenolic moiety in 3OH-DLOR molecule, yielding significant change in their reduction potentials (Ep DLOR = -1.48 V, and Ep 3OH-DLOR = -1.6 V). The observed results correlate with calculated LUMO energy levels and Hammet substituent constants (sigma). Based on the difference in the reduction potential for DLOR and 3OH DLOR, conditions for simultaneous determination these two molecules in alkaline medium were established. The best selectivity was achieved using SWV method at pH 10. The linearity of the calibration graphs were achieved in the concentration range from 1.5 * 10-6 M - 1 * 10-5 M for DLOR and 7.5 * 10-6 M - 5 * 10-5 M for 3OH-DLOR with detection limits of 2.29 * 10-7 M and 2.08 * 10-6 M, and determination limits of 7.64 * 10-7 M and 6.94 * 10-6 M, for DLOR and 3OH-DLOR, respectively. The method was checked in human plasma sample. Good response was obtained with LOD and LOQ values of 4.63 * 10-7 M and 1.54 * 10-6 M, for DLOR and 2.39 * 10-6 M and 7.97 * 10-6 M, 3OH-DLOR, respectively. PMID- 24061818 TI - Utilisation of Agriculture Weed for the Removal of Cr(VI) from Aqueous Solution. AB - The present study investigates the potential use of activated carbon prepared from Cassia tora by sulphuric acid treatment for the removal of Chromium(VI) from aqueous solution. The effects of pH, initial concentration, contact time, and carbon concentration were studied for the sorption of Cr(VI) in batch mode. The optimum pH value for Cr(VI) adsorption was determined as 2.0. The experimental results were fitted with the Freundlich, Langmuir and Redlich Peterson equations to describe the equilibrium isotherms. The Langmuir and Redlich - Peterson isotherm models were found better to describe the experimental data. The maximum adsorption capacity obtained from Langmuir equation was 72.4 mg/g. The kinetic data were then fitted with the Lagergren-first-order, pseudo-second-order and intraparticle models. Further, adsorption kinetics of Cr(VI) was studied and the rate of adsorption was found to confirm pseudo-second-order kinetics with a good correlation and intraparticle diffusion as one of the rate determining steps. Activated carbon developed from Cassia tora can be a potential alternative for Cr(VI) removal from aqueous solution. PMID- 24061819 TI - Zeta potential determination of polymeric materials using two differently designed measuring cells of an electrokinetic analyzer. AB - The so-called zeta potential can be determined through electrokinetic measurements and indicates the status regarding surface charges along the interface between solids and liquids. Surface charge gives us information about the condition, quality, and characteristics of a macroscopic surface in the polar medium. In our study the zeta potential was determined using a "SurPASS" electrokinetic analyzer based on the streaming current and streaming potential measurements. The aim of the research was to compare the results of two differently designed measuring cells ("Adjustable Gap Cell" and "Clamping Cell") but operating on the same principle. In order to investigate this problem, the zeta potential was determined for the three polymeric materials: poly(ethylene terephthalate) foil, thin-film polyamide composite membranes for nanofiltration and reverse osmosis. The results obtained with "Clamping Cell" versus "Adjustable Gap Cell" showed differences in zeta potential, where the "Adjustable Gap Cell" gave more reproducible results. One reason for this behaviour could be the different geometries of the streaming channels. A more likely reason is the design of the "Clamping Cell", that requires a sample size larger than necessary for zeta potential determination. PMID- 24061820 TI - Densities and Viscosities of Alkylethanoates +Cyclohexane, +Benzene, +1,4 dimethylbenzene, and +1,3.5-trimethylbenzene at 308.15 K. AB - Densities (rho12) and viscosities (eta12) of binary mixtures of alkylethanoates, + cyclohexane, benzene, 1,4-dimethylbenzene and 1,3,5-trimethylbenzene have been measured over the whole mole fractions range at atmospheric pressure and temperature 308.15 K. Deviations of experimental viscosities from the linear mixing rule (Deltaeta) for binary mixtures of the esters and cyclohexane are large and negative. Deltaeta values are less and negative for binary mixtures of esters and aromatic hydrocarbons except binary mixtures of n-propylethanoate and benzene which show less positive Deltaeta values. Deltaeta values for binary mixtures of ethylethanoate + 1,4-dimethylbenzene, +1,3,5-trimethylbenzene and n propylethanoate +1,4-dimethylbenzene are both less negative and less positive. Deltaeta values are fitted into Redlich-Kister polynomial equation and standard deviations, sigma of Deltaeta for all the binary mixtures are reported. Several viscosity equations are critically analysed. The strengths of molecular interactions are discussed on the basis of Grunberg-Nissan interaction parameters. PMID- 24061821 TI - Zinc(II) Thiosemicarbazone Complex As a Ligand Towards Some Transition Metal Ions: Synthesis, Spectroscopic and Antimicrobial Studies. AB - Heterobinuclear complexes have been synthesized by stepwise reactions using the mononuclear complex, [Zn(Tsc)2] * H2O, as a complex ligand towards the metal ions, vanadyl(IV), manganese(II), iron(III), cobalt(II), nickel(II) and copper(II). The complex ligand was synthesized by the reaction of zinc acetate dihydrate with salicylaldehyde followed by the condensation with thiosemicarbazide. The structures of the complex ligand and the prepared complexes were elucidated by elemental analyses, IR, electronic, mass, 1H and 13C NMR spectra as well as molar conductivity and magnetic susceptibility measurements. All the complexes exhibited octahedral geometrical arrangements formulated as [Zn(Tsc)2VO(SO4)(H2O)], [Zn(Tsc)2MCl2(H2O)2] (M = Mn, Fe and Co) and [Zn(Tsc)2Fe(ox)Cl2] except the nickel(II) and copper(II) complexes, [Zn(Tsc)2CuCl(H2O)], [Zn(Tsc)2NiCl2], which have square planar geometries. The complex ligand and some of its heterobinuclear complexes showed antibacterial activity against the sensitive organisms Staphylococcus aureus as Gram-positive bacteria, Escherichia coli as Gram-negative bacteria and antifungal activity against the fungi Candida albicans and Aspergillus flavus. PMID- 24061822 TI - Synthesis and Evaluation of Novel Bis[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles as Potent Antimicrobial Agents. AB - A series of novel bis[4-methoxy-3-(6-aryl[1,2,4]triazolo[3,4 b][1,3,4]thiadiazol)phenyl]methanes 5a-l has been synthesized and characterized via IR, 1H NMR, 13C NMR, MS and elemental analyses. All the newly synthesized compounds were screened for their antibacterial activity against Bacillus subtilis, Bacillus sphaericu, Staphylococcus aureus, Pseudomonas aeruginosa, Klobsinella aerogenes and Chromobacterium violaceum and antifungal activity against Candida albicans, Aspergillus fumigatus, Trichophyton rubrum and Trichophyton mentagrophytes. Compounds 5e, 5f, 5h, 5i, 5k and 5l exhibited potent activity against the test bacteria and fungi, and emerged as potential molecules for further development. PMID- 24061823 TI - Motivational profiles of slovenian high school students and their academic performance outcomes. AB - Self-determination theory defines motivation as a multidimensional concept, with autonomous and controlled motivation as central factors of broader distinctions. Previous research has proven that academic achievements are positively correlated with autonomous motivation. Students from 10 Slovenian grammar schools were involved in empirical study, in which a cluster analysis revealed two motivational profiles: a low quantity motivation group (low controlled and autonomous motivation) and a good quality motivation group (high autonomous and low or average controlled motivation). Statistically significant differences between the two identified motivational profiles were found for students' general as well as chemistry performance in three grades of schooling. Furthermore, a good quality motivation group is also more in favour of autonomy-supportive teaching methods used in chemistry classes. Examination of students' opinions about important chemistry topics, and on the other hand, unimportant ones, and not connected with life, reveals that the basic reason for distinction might lie in the chemistry teacher's approach used while presenting these topics. Some chemistry teachers are not using an autonomy-supportive way of teaching which would contribute to better teaching outcomes; therefore a need for further research on Slovenian chemistry teachers' motivation and their teaching approaches was recognized. PMID- 24061824 TI - Room-Temperature Synthesis of 2-Arylbenzothiazoles using Sulfuric Acid Immobilized on Silica as a Reusable Catalyst under Heterogeneous Condition. AB - Application of sulfuric acid immobilized on silica gel as an efficient and benign catalyst has been explored in the synthesis of 2-arylbenzothiazoles via condensation reaction of aldehydes with 2-aminothiophenol. The reactions proceed under heterogeneous and mild conditions in ethanol at room temperature to provide 2-arylbenzothiazoles in high yields. PMID- 24061825 TI - Kinetics and mechanism of the metal exchange reaction between N,N'-bis(? carbamoylethyl) ethylendiamine nickel(II) and copper(II). AB - The kinetics of the [Ni N,N'-bis(beta-carbamoylethyl) ethylendiamine)]2+/Cu2+, Ni(bcen)2+/Cu2+ metal exchange reaction in aqueous solution has been studied using spectrophotometry to follow Cu(bcen)2+ formation at 640 nm (bcen is N,N' bis(beta-carbamoylethyl) ethylendiamine). The reaction was studied at pH 6.9, ionic strength 0.5 M and in the temperature range 15 to 35 degrees C. The kinetics was studied under pseudo-order conditions with [Ni(bcen)2+] >> [Cu2+]. The reaction this under the condition has been found to be a two-step process mechanism is proposed involving: (1) partially dissociation of the Ni(bcen)2+ complex, following with formation of a dinuclear intermediate and (2) metal exchange. Step 1 is rapid and depends on [Ni(bcen)2+] while step 2 is rate determining and independent of [Ni(bcen)2+]. The rate constants k1 (step 1) and k2 (step 2) are 4.40 + 0.14 M-1s-1 and (11.25 + 0.94) * 10-2 s-1 respectively at 25 degrees C. Activation parameters are also reported. PMID- 24061826 TI - Sorptive removal of crystal violet from aqueous solution using spent tea leaves: part I optimization of sorption conditions and kinetic studies. AB - The low cost adsorbent, spent tea leaves (STL) has been tested for the effectiveness in decolorization of wastewater containing crystal violet dye in batch experiments. Effect of various parameters such as agitation time, pH, temperature and adsorbent dose has been investigated. The dye uptake has been found to increase with pH and temperature. The kinetic uptake data, obtained at different sorbate concentrations, is best interpreted by pseudo second order model and rate constants for adsorption are found to be 8.5 * 10-3, 22.2 * 10-3 and 42.0 * 10-3 g mg-1 min-1 for initial dye concentrations of 10, 20 and 30 mg L 1 respectively. The dye uptake was found to increase with temperature and the activation energy for adsorption process was found to be 10.45 +/- 0.89 kJ mol-1. PMID- 24061827 TI - Analysis and Modeling of Boundary Layer Separation Method (BLSM). AB - Nowadays rules of environmental protection strictly regulate pollution material emission into environment. To keep the environmental protection laws recycling is one of the useful methods of waste material treatment. We have developed a new method for the treatment of industrial waste water and named it boundary layer separation method (BLSM). We apply the phenomena that ions can be enriched in the boundary layer of the electrically charged electrode surface compared to the bulk liquid phase. The main point of the method is that the boundary layer at correctly chosen movement velocity can be taken out of the waste water without being damaged, and the ion-enriched boundary layer can be recycled. Electrosorption is a surface phenomenon. It can be used with high efficiency in case of large electrochemically active surface of electrodes. During our research work two high surface area nickel electrodes have been prepared. The value of electrochemically active surface area of electrodes has been estimated. The existence of diffusion part of the double layer has been experimentally approved. The electrical double layer capacity has been determined. Ion transport by boundary layer separation has been introduced. Finally we have tried to estimate the relative significance of physical adsorption and electrosorption. PMID- 24061828 TI - One year results of anti-VEGF treatment in pigment epithelial detachment secondary to macular degeneration. AB - PURPOSE: Pigment epithelial detachment (PED) may be seen in all stages of age related macular degeneration (ARMD) and may lead to poor prognosis. In this study, we retrospectively examined the effect of anti-VEGF treatments in ARMD patients with vascularized PED. METHODS: Medical records of 15 patients with PED secondary to ARMD were reviewed retrospectively. The diagnosis of PED was made with fundoscopy, fundus fluorescein angiography and optical coherence tomography. Patients were treated with intravitreal ranibizumab or/and bevacizumab and followed up for a minimum of one year. PED height and best corrected visual acuity (BCVA) was obtained before the first intravitreal anti-VEGF injection and again at the 1st, 3rd, 6th and 12th month after the injection. RESULTS: The mean baseline BCVA was 0.71 +/- 0.48 logarithm of the minimal angle of resolution (logMAR) unit and the mean baseline PED height was 361 +/- 153 u. The mean injection count per eye was 3.9 +/- 2.9. There was a significant reduce in mean PED height (247 +/- 177 u) also in 2 eyes PED completely resolved at the end of the follow up period. The mean BCVA at 12th month (0,69 +/- 0,37) were not different from the baseline record. CONCLUSIONS: This retrospective case series showed that intravitreal anti-VEGF therapy preserved vision and reduced PED height in PED patients in a one-year follow-up period. PMID- 24061829 TI - The surgical management of massive intraoperative and postoperative suprachoroidal hemorrhage: anatomic and functional outcomes. AB - PURPOSE: To describe the clinical characteristics, management and treatment outcomes of patients with post-surgical suprachoroidal hemorrhage (SCH). METHODS: A retrospective cross-sectional study was conducted, in which the medical records of 9 consecutive patients with SCH admitted to the Goldschleger Eye Institute were reviewed. RESULTS: The mean age was 74 years (range 61-84) and the mean follow-up time was 38.3 +/- 0.1 months (range 4-87 months). Four cases were associated with glaucoma surgeries (2 trabeculectomies and 2 Ahmed valve implantations), 3 cases with cataract surgery and 2 cases with pars plana vitrectomy. The diagnosis of SCH was ranging from intra-operative to 8 days following the primary procedure. Most patients underwent posterior sclerotomies and drainage alone or combined with pars plana vitrectomy in a mean timing of intervention of 11 +/- 4 days. At one month of follow-up the visual acuity improved in 7 eyes and remained stable in 2, compared to the VA prior to the drainage operation. The mean VA improved from 2.03 to 1.285 logMAR units at 1 month following the drainage procedure (p=0.003). CONCLUSIONS: SCH still remains a challenging complication of many ophthalmological procedures. The current surgical management may improve visual acuity though the general prognosis is still poor. PMID- 24061830 TI - Contact lenses fitting after intracorneal ring segments implantation in keratoconus. AB - PURPOSE: Evaluate contact lenses fitting after intracorneal ring implantation for keratoconus, its visual acuity and comfort. METHODS: Retrospective study of patients undergoing contact lenses fitting, after intracorneal ring for keratoconus. The criterion for contact lens fitting was unsatisfactory visual acuity with spectacle correction as referred by the patients. All patients were intolerants to contact lenses prior to intracorneal implantation. Visual acuity analysis was done by conversion of Snellen to logMAR scales. The comfort was evaluated according subjective questioning of good, medium or poor comfort. RESULTS: Nineteen patients were included in the study. Two patients (10.5%) did not achieved good comfort with contact lenses and underwent penetrating keratoplasties. All the others 17 patients showed good or medium comfort. Four rigid gas-permeable contact lenses were fitted, one piggyback approach, 3 toric soft contact lenses, 2 soft lenses specially design for keratoconus and 7 disposable soft lenses. The average visual acuity improved from 0.77 +/- 0.37 to 0.19 +/- 0.13 logMAR units after contact lenses fitting. CONCLUSION: Contact lens fitting after intracorneal ring is possible, provides good comfort, improves visual acuity, and therefore, may postpone the need for penetrating keratoplasty. PMID- 24061831 TI - An evaluation of estimation methods for determining addition in presbyopes. AB - PURPOSE: The optical correction of presbyopia must be handled individually. Our aim was to compare the methods used in addition to the refractive near vision, with the final addition used in presbyopic patients. METHODS: Eighty healthy subjects with a mean age of 49.7 years (range 40 to 60 years) were studied. Tentative near additions were determined using four different techniques: one half amplitude accommodation with minus lenses (AAL); one-third accommodative demand with positive lens (ADL); balanced range of accommodation with minus and positive lenses (BRA) and crossed cylinder test with initial myopisation (CCT). The power of the addition was then refined to arrive at the final addition. RESULTS: The mean tentative near additions were lower than the final addition for ADL and BRA addition methods. The mean differences between tentative and final additions were low for all the tests examined (less than 0.25 D). The intervals between the 95% limits of agreement differed substantially and were always higher than +/-0.50 D. CONCLUSION: All the methods used displayed similar behavior and provided a tentative addition close to the final addition. The coefficient of agreements (COA) detected suggests that every tentative addition should be adjusted according to the particular needs of the patient. PMID- 24061832 TI - The prevalence of ocular surface complaints in Brazilian patients with glaucoma or ocular hypertension. AB - PURPOSE: To examine the prevalence of ocular surface complaints in Brazilian patients with glaucoma or ocular hypertension who used topical intraocular pressure (IOP)-lowering regimens. METHODS: In this multicenter, noninterventional, single-visit study, adults with glaucoma or ocular hypertension treated with an IOP-lowering regimen were administered the 12-item ocular surface disease index (OSDI) questionnaire. Each response was scored on a 5-point scale, with 0 indicating symptom present none of the time and 4 indicating symptom present all of the time. The average of the 12 item responses for each patient was transformed to a scale from 0 to 100, with higher scores representing worse disabilities. OSDI results then were categorized as absence of OSD (scores of 0-12), mild OSD (scores of 13-22), moderate OSD (scores of 23-32), or severe OSD (scores of 33100). RESULTS: The 173 enrolled patients had a mean age of 61.2 years, were women in 65.3% of cases, and had glaucoma in 89.0% of cases and ocular hypertension in 11.0% of cases. OSDI scores for 158 patients using 1 IOP-lowering therapy indicated no OSD in 37.3% of patients (59/158), mild OSD in 20.9% (33/158), moderate OSD in 17.1% (27/158), and severe OSD in 24.7% (39/158). For the 120 patients using 1 IOP-lowering medication and having a known duration of diagnosis of glaucoma or ocular hypertension, mean OSDI scores were numerically higher (worse) for the 39 patients with a diagnosis >=6 years long (score 25 [+/- 20], indicating moderate OSD) than for the 81 patients with a diagnosis lasting <6 years (score 22 [+/- 20], indicating mild OSD); however, no significant differences in OSDI scores by duration of diagnosis were evident in means (P=0.49), distributions (P>=0.26), or correlation (P=0.77). CONCLUSIONS: A large proportion of Brazilian patients treated with 1 IOP-lowering therapy had some ocular surface complaints. PMID- 24061833 TI - Intracapsular dexamethasone implant in patients undergoing phacoemulsification and intraocular lens implantation. AB - PURPOSE: To relate the outcomes of 7 eyes of 7 patients in which a dexamethasone 0.7 mg implant (Ozurdex((r))) was placed inside the capsule bag after phacoemulsification and intraocular lens (IOL) implantation and compare with the fellow eyes, that were operated by the same technique and received dexamethasone eyedrops in the post-operatory. METHODS: Report review of 7 eyes of 7 patients who received dexamethasone 0.7 mg implant after phacoemulsification and IOL, comparing them to the fellow eyes. All the patients underwent bilateral cataract surgery, with one month interval, by the same technique and by experienced surgeons, without complications. Post operatory medication consisted of moxifloxacin eye drops for all the 14 eyes and topic dexamethasone for the 7 eyes that did not received the implant. RESULTS: Nuclear cataract classification (according to LOCS III) was 3.28 +/- 0.69 in the implant eye group and 3.14 +/- 0.83 in the fellow eye group. Postoperative best spectacle correct visual acuity (BSCVA) was 0.85 +/- 0.12 and 0.87 +/- 0.13, respectively in the implant and fellow eye groups. The intraocular pressure remained stable and similar to the pre-operative measurements. Anterior chamber reaction and cornea edema were similar in both groups in the follow-up. Two of the four no sutured pellet migrated to the anterior chamber during the first post-operative week and had to be repositioned. Another no sutured pellet dislocated and remained partially inside the capsule bag. The 3 patients with IOL haptic-sutured pellet had no complications. CONCLUSIONS: In the present study, dexamethasone 0.7 mg implant were effective in controlling the inflammation after phacoemulsification and IOL implantation, with no significant side effects. PMID- 24061834 TI - Effects of age on corneal deformation by non-contact tonometry integrated with an ultra-high-speed (UHS) Scheimpflug camera. AB - PURPOSE: To correlate parameters derived from corneal deformation resulting from non-contact tonometry integrated with an ultra-high-speed (UHS) Scheimpflug camera (Oculus Corvis ST, Scheimpflug Technology; Wetzlar, Germany) with age in normal eyes from young patients. METHODS: Observational, retrospective study involving one eye randomly selected from study participants, totaling 89 healthy eyes. The Scheimpflug images were taken with an ultra-high-speed camera during each measurement by the corvis ST. The deformation amplitude (DA) and other parameters (e.g., pachy apex, intraocular pressure, 1(st) A time, highest concavity-time, 2(nd) A time, 1(st) A Length, 2(nd) A Length, Wing-Dist, curvature radius highest concavity, curvature radius normal, Vin, Vout) measured by the corvis ST were correlated with age. The Kolmogorov-Smirnov test was applied, and Spearman's correlation test was utilized to evaluate the parameters measured by the Corvis ST and age. RESULTS: Mean patient age was 27.50 +/- 6.30 years. The highest concavity-time was the only studied parameter statistically significantly correlated to age (i.e., p=0.04, rs=0.18). All other corvis parameters were not correlated to age. This included DA (p=0.319), intraocular pressure (p=0.854), pachy apex (p=0.066), 1(st) A time (p=0.959), 2(nd) A time (p=0.561), 1(st) Length (0.552), 2nd Length (p=0.697), Wing-Dist (p=0.769), curvature radius HC (p=0.145), curvature radius normal (p=0.513), Vin (p=0.980) and Vout (p=0.592). CONCLUSIONS: In healthy eyes, age and pressure or biomechanics as derived from the Corvis ST parameters were not associated with exception to highest concavity-time, i.e., the time from starting until the highest concavity is reached. PMID- 24061835 TI - [Patients with astigmatism who underwent cataract surgery by phacoemulsification: toric IOL x asferic IOL?]. AB - PURPOSES: Compare the visual acuity of patients who underwent cataract surgery by phacoemulsification with IOL AcrySof((r)) toric implantation versus AcrySof((r)) IQ and evaluate the reduction of cylindrical diopters (CD) in the postoperative period. METHODS: Analytical and retrospective study of 149 eyes with 1 or more diopters of regular symmetrical keratometric astigmatism, which underwent cataract surgery by phacoemulsification. The eyes were divided into two groups: the toric group with 85 eyes and the non-toric group with 64 eyes. In the pre operative phase, topographic data and refraction of each eye to be operated were assessed. In the postoperative phase, refraction and visual acuity with and without correction were measured. RESULTS: The preoperative topographic astigmatism ranged from 1.00 to 5.6 DC in both groups. Average reduction of 1.37 CD (p<0.001) and 0.16 CD (p=0.057) was obtained for the toric and non-toric group when compared to the refractive astigmatism, respectively. Considering visual acuity without correction (NCVA), the toric group presented 44 eyes (51.7%) with NCVA of 0 logMAR (20/20) or 0.1 logMAR (20/25) and the toric group presented 7 eyes (10.93%) with these same NCVA values. DISCUSSION: The results show that patients with a significant keratometric astigmatism presented visual benefits with the toric IOL implantation. The reduction of the use of optical aids may be obtained provided aberrations of the human eye are corrected more accurately. Currently, phacoemulsification surgery has been used not only for functional improvement, but also as a refraction procedure. PMID- 24061836 TI - Prevalence of refractive errors in Mobius sequence. AB - PURPOSE: To assess the prevalence of refractive errors in Mobius sequence. METHODS: This study was carried out during the Annual Meeting of the Brazilian Mobius Society in November 2008. Forty-four patients diagnosed with the Mobius sequence were submitted to a comprehensive assessment, on the following specialties: ophthalmology, neurology, genetics, psychiatry, psychology and dentistry. Forty-three patients were cooperative and able to undertake the ophthalmological examination. Twenty-two (51.2 %) were male and 21 (48.8%) were female. The average age was 8.3 years (from 2 to 17 years). The visual acuity was evaluated using a retro-illuminated logMAR chart in cooperative patients. All children were submitted to exams on ocular motility, cyclopegic refraction, and fundus examination. RESULTS: From the total of 85 eyes, using the spherical equivalent, the major of the eyes (57.6%) were emmetropics (>-0.50 D and <+2.00 D). The prevalence of astigmatism greater than or equal to 0.75 D was 40%. CONCLUSION: The prevalence of refractive errors, by the spherical equivalent, was 42.4% in this studied group. PMID- 24061837 TI - Congenital cataract surgery with intraocular lens implantation in microphthalmic eyes: visual outcomes and complications. AB - PURPOSE: To report the visual outcomes and complications of congenital cataract surgery with primary intraocular lens implantation in microphthalmic eyes of children younger than 4 years of age. METHODS: This retrospective interventional case series included 14 microphthalmic eyes from 10 children who underwent congenital cataract surgery with primary intraocular lens implantation younger than 4 years of age. Seven patients had bilateral cataracts (11 eyes met the study's inclusion criteria) and 3 patients had unilateral cataract. Patients' medical charts were reviewed to obtain information regarding the preoperative and postoperative ophthalmological examination. Main outcome measures were intraocular pressure (IOP), best-corrected visual acuity, and intraoperative and postoperative complications. RESULTS: Mean age at the time of surgery was 21.7 +/ 2.9 months. Mean ocular axial length was 19.2 +/- 0.9 mm. Mean preoperative IOP was 9.7 +/- 1.7 mmHg and 10.3 +/- 3.1 mmHg on final follow-up (P=0.18). There were no intraoperative complications. Two (15.4%) eyes developed secondary visual axis opacification, of which only one needed to be reoperated due to significantly decreased vision (0.5 logMAR). Preoperative and postoperative best corrected visual acuity was 2.09 +/- 0.97 logMAR and 0.38 +/- 0.08 logMAR in bilateral cases and 1.83 +/- 1.04 logMAR and 0.42 +/- 0.13 logMAR in unilateral cases, respectively. CONCLUSION: Primary intraocular lens implantation in congenital cataract surgery in microphthalmic eyes resulted in a significant best corrected visual acuity improvement with no intraoperative complications and minimal postoperative complications. PMID- 24061838 TI - [Periorbital liposarcoma in pediatric patient: a case report]. AB - The purpose of this study is report a child with periorbital liposarcoma describing the clinical, epidemiological and therapeutic aspects. Six-months-old female baby with increasing tumor in the right fronto-zigomatic region wich was submitted to excision and the patologic and immunohistochemistry analisys observed typical findings of lipoblastoma. After that, there were three tumors relapse with the same diagnosis. One year after the last surgery there was a recurrence of the tumor but at this time the diagnosis was lipossarcoma and the patient was referred for additional treatment wilth radiotherapy and chemotherapy no new injuries so far Due to its rarity, liposarcoma usually does not enter the differencial diagnosis in the patients with orbital masses, however because of its local aggressiveess, it's vital the early identification and treatment to provide better therapeutic results and quality of life. PMID- 24061839 TI - Orbital retinoblastoma: case report. AB - We describe the case of a 9-month old boy with unilateral retinoblastoma and bulftalmo. Primary enucleation was the treatment of choice due to the lack of visual prognosis. The histology of the enucleated eye showed massive choroidal invasion by the tumor and the optic nerve free of neoplastic tissue. Therefore, no adjuvant chemotherapy or radiotherapy was indicated. Three months after the enucleation, the patient returned with massive orbital retinoblastoma with exposure of the conjunctiva. Treated with chemotherapy, the patient has been in remission for 12 months. The risk factors for orbital recurrence are discussed. PMID- 24061840 TI - Choroidal metastasis as the first sign of bronchioloalveolar lung cancer: case report. AB - Metastatic tumors are the most common intraocular malignances and choroid is by far the most common site. Breast and lung cancer are the first cause in women and men respectively. We report the case of a 71-year old woman who had choroidal tumor in her left eye. Further image body scans demonstrated several lesions in both sides of the lungs with dissemination to other organs. Diagnosis of a brochioloalveolar carcinoma established after a biopsy carried out. The patient died before initiating a proper treatment. PMID- 24061841 TI - Torpedo maculopathy with an anisometropic amblyopia in a 5-year-old Caucasian girl: case report. AB - The aim of this study is to report a clinical case of asymptomatic female Caucasian children with torpedo maculopathy. A 5-year-old girl was referred to our clinic for routine evaluation. The ophthalmic examination revealed best corrected visual acuity of 20/20 in both eyes, without any changes in the biomicroscopy. Fundus examination showed normal findings in one eye, whereas in the contralateral eye it disclosed, in the temporal sector of the macular region, a whitish, atrophic, oval chorioretinal lesion with clearly defined margins. Posterior evaluations documented the stability of the lesion. Torpedo maculopathy diagnosis is based on its characteristic shape and peculiar location. The differential diagnosis has to be established versus choroidal lesions (melanoma and nevus), congenital or iatrogenic hyperplasia of the retinal pigment epithelium (RPE) and particularly versus the congenital pigmented lesions associated with Gardner's syndrome. PMID- 24061842 TI - [Diffuse unilateral subacute neuroretinitis (DUSN): current update]. AB - Diffuse unilateral subacute neuroretinitis (DUSN) is a form of uveitis that can potentially lead to blindness. In Brazil and other parts of South America, diffuse unilateral subacute neuroretinitis is an important cause of posterior uveitis in children and healthy young adults. If diagnosed and treated in early stage, allows a resolution of symptoms with improvement of visual acuity. If the disease progresses to the late stage, can result in significant visual loss. In this study, through a literature review, we describe the main characteristics of this disease, including the following aspects: history, etiology, physiopathology, clinical features, diagnosis, differential diagnosis and treatment. PMID- 24061843 TI - Current treatment of amblyopia: where are we? PMID- 24061844 TI - Civilian gunshot injuries: editorial comment. PMID- 24061845 TI - High level of residual symptoms in young patients after total knee arthroplasty. AB - BACKGROUND: TKA is among the fastest growing interventions in medicine, with procedure incidence increasing the most in younger patients. Global knee scores have a ceiling effect and do not capture the presence of difficulty or dissatisfaction with specific activities important to patients. QUESTIONS/PURPOSES: We quantified the degree of residual symptoms and specific functional deficits in young patients who had undergone TKA. METHODS: In a national multicenter study, we quantified the degree of residual symptoms and specific functional deficits in 661 young patients (mean age, 54 years; range, 19 60 years; 61% female) at 1 to 4 years after primary TKA. To eliminate observer bias, satisfaction and function data were collected by an independent, third party survey center with expertise in administering medical outcomes questionnaires for federal agencies. RESULTS: Overall, 89% of patients were satisfied with their ability to perform normal daily living activities, and 91% were satisfied with their pain relief. After TKA, 66% of patients indicated their knees felt normal, 33% reported some degree of pain, 41% reported stiffness, 33% reported grinding/other noises, 33% reported swelling/tightness, 38% reported difficulty getting in and out of a car, 31% reported difficulty getting in and out of a chair, and 54% reported difficulty with stairs. After recovery, 47% reported complete absence of a limp and 50% had participated in their most preferred sport or recreational activity in the past 30 days. CONCLUSIONS: When interviewed by an independent third party, about 1/3 of young patients reported residual symptoms and limitations after modern TKA. We recommend informing patients considering surgery about the high likelihood of residual symptoms and limitations after contemporary TKA, even when performed by experienced surgeons in high-volume centers, and taking specific steps to set patients' expectations to a level that is likely to be met by the procedure as it now is performed. PMID- 24061846 TI - CORR Insights (r): Causes, risk factors, and trends in failures after TKA in Korea over the past 5 years: a multicenter study. PMID- 24061847 TI - Is tibialis anterior tendon transfer effective for recurrent clubfoot? AB - BACKGROUND: Tibialis anterior tendon transfer surgery forms a part of Ponseti management for children with congenital talipes equinovarus who, after initial correction, present with residual dynamic supination. Although retrospective studies support good outcomes, prospective longitudinal studies in this population are lacking. QUESTIONS/PURPOSES: We assessed strength, plantar loading, ROM, foot alignment, function, satisfaction, and quality of life in patients with clubfoot that recurred after Ponseti casting who met indications for tibialis anterior tendon transfer surgery, and compared them with a group of patients with clubfoot treated with casting but whose deformity did not recur (therefore who were not indicated for tibialis anterior tendon transfer surgery). METHODS: Twenty children with idiopathic congenital talipes equinovarus indicated for tibialis anterior tendon transfer surgery were recruited. Assessment at baseline (before surgery), and 3, 6, and 12 months (after surgery) included strength (hand-held dynamometry), plantar loading (capacitance transducer matrix platform), ROM (Dimeglio scale), foot alignment (Foot Posture Index((c))), function and satisfaction (disease-specific instrument for clubfoot), and quality of life (Infant Toddler Quality of Life QuestionnaireTM). Outcomes were compared with those of 12 age-matched children with congenital talipes equinovarus not indicated for tibialis anterior tendon transfer surgery. Followup was 100% in the control group and 95% (19 of 20) in the tibialis anterior transfer group. RESULTS: At baseline, the tibialis anterior tendon transfer group had a significantly worse eversion-to-inversion strength ratio, plantar loading, ROM, foot alignment, and function and satisfaction. At 3 months after surgery, eversion-to-inversion strength, plantar loading, and function and satisfaction were no longer different between groups. Improvements were maintained at 12 months after surgery (eversion-to-inversion strength mean difference, 8% body weight; 95% CI, -26% to 11%; p = 0.412; plantar loading, p > 0.251; function and satisfaction, p = 0.076). ROM remained less and foot alignment more supinated in the tibialis anterior tendon transfer group between baseline and followup (p < 0.001, p < 0.001). CONCLUSIONS: Tibialis anterior tendon transfer surgery was an effective procedure, which at 12-month followup restored the balance of eversion to-inversion strength and resulted in plantar loading and function and satisfaction outcomes similar to those of age-matched children with congenital talipes equinovarus who after Ponseti casting were not indicated for tibialis anterior tendon transfer. PMID- 24061848 TI - Low molecular weight pentastarch is more effective than crystalloid solution in goal-directed fluid management in patients undergoing major gastrointestinal surgery. AB - BACKGROUND: This prospective observational study compared the volume effect between hydroxyethyl starch (HES) and crystalloid solution and its context dependency in intraoperative goal-directed fluid management. METHODS: With institutional review board (IRB) approval, 35 patients undergoing major gastrointestinal surgery were enrolled. Fluid challenge consisting of 250 ml of either bicarbonate Ringer solution (BRS) or low molecular weight pentastarch (HES 70/0.5) was given to maintain stroke volume index >35 ml/m2. The context of fluid challenge was classified as related to either epidural block (EB) or blood loss (BL) or as nonspecific. The primary end point was the interval between index fluid challenge and the next fluid challenge, and the secondary end point was the hemodynamic parameter at the end of fluid challenge. Differences in these parameters in each clinical context were compared between BRS and HES 70/0.5. A p value <0.05 was considered statistically significant. RESULTS: Eighty-eight, 77, and 127 fluid challenges were classified as related to EB and BL and as nonspecific, respectively. In the nonspecific condition, the median (range) interval after fluid challenge with HES 70/0.5 and BRS was 45 (11-162) min and 18 (8-44) min, respectively, and the difference was statistically significant. Also, mean arterial pressure and stroke volume index significantly increased, whereas stroke volume variation significantly decreased after fluid challenge with HES 70/0.5 compared with BRS. Such differences were not observed in the other situations. CONCLUSIONS: HES 70/0.5 exerted larger volume effects than did crystalloid under nonspecific conditions. However, similar volume effects were observed during volume loss and extensive sympathetic blockade. PMID- 24061849 TI - Influence of apneic oxygenation on cardiorespiratory system homeostasis. AB - PURPOSE: The aim of this study was to elucidate the magnitude of variations in oxygenation indices and the pattern of hemodynamic changes in response to the net effect of tracheal apneic oxygenation (AO) with a view to define the safe time limit of its application. METHODS: After obtaining Animal Research Ethics Committee approval, AO was applied in 12 piglets for 40 min. Arterial (a) and mixed venous (v) blood samples for oxygen (O2) and carbon dioxide (CO2) tension (PaO2/PvO2, PaCO2/PvCO2), O2 saturation (SaO2/SvO2), pHa, base excess (BEa), and bicarbonate (HCO3a) determination and for alveolar O2 tension (PAO2), PaO2/FiO2 and PaO2/PAO2 ratio, arterial-mixed venous O2 content (AVDO2), and O2 extraction ratio (O2ER) estimation were collected on anesthesia induction, 10, 20, 30, and 40 min during AO and 10 and 20 min after reconnection to the ventilator. Concomitant hemodynamic data were obtained. RESULTS: Besides PvO2 and PAO2, AO adversely influenced PaO2 (248-113 mmHg), PaCO2 (35-145 mmHg), PvCO2, PaO2/FiO2, and PaO2/PAO2 in a time-depended fashion, whereas SvO2, AVDO2, and O2ER were minimally affected. P(a - v)CO2 was reversed throughout AO. Acid-base status derangement, consisting of HCO3a elevation, BEa widening, and acidemia (pH 6.9) maximized 40 min after AO. During AO, heart rate, systemic and pulmonary circulation pressures, and cardiac output were progressively elevated, whereas systemic vascular resistance was reduced. All the studied parameters reverted almost to baseline within the 20-min period of ventilator reconnection. CONCLUSION: Tracheal AO for 40 min ensures acceptable blood oxygenation, promotes notable hypercapnic acidosis, and consequent transient hemodynamic alterations, which are almost completely reversible after reconnection to the ventilator. PMID- 24061850 TI - Quantification of cellular protein expression and molecular features of group 3 LEA proteins from embryos of Artemia franciscana. AB - Late embryogenesis abundant (LEA) proteins are highly hydrophilic, low complexity proteins whose expression has been correlated with desiccation tolerance in anhydrobiotic organisms. Here, we report the identification of three new mitochondrial LEA proteins in anhydrobiotic embryos of Artemia franciscana, AfrLEA3m_47, AfrLEA3m_43, and AfrLEA3m_29. These new isoforms are recognized by antibody raised against recombinant AfrLEA3m, the original mitochondrial-targeted LEA protein previously reported from these embryos; mass spectrometry confirms all four proteins share sequence similarity. The corresponding messenger RNA (mRNA) species for the four proteins are readily amplified from total complementary DNA (cDNA) prepared from embryos. cDNA sequences of the four mRNAs are quite similar, but each has a stretch of sequence that is absent in at least one of the others, plus multiple single base pair differences. We conclude that all four mitochondrial LEA proteins are products of independent genes. Each possesses a mitochondrial targeting sequence, and indeed Western blots performed on extracts of isolated mitochondria clearly detect all four isoforms. Based on mass spectrometry and sodium dodecyl sulfate polyacrylamide gel electrophoresis migration, the cytoplasmic-localized AfrLEA2 exists primarily as a homodimer in A. franciscana. Quantification of protein expression for AfrLEA2, AfrLEA3m, AfrLEA3m_43, and AfrLEA3m_29 as a function of development shows that cellular concentrations are highest in diapause embryos and decrease during development to low levels in desiccation-intolerant nauplius larvae. When adjustment is made for mitochondria matrix volume, the effective concentrations of cytoplasmic versus mitochondrial group 3 LEA proteins are similar in vivo, and the values provide guidance for the design of in vitro functional studies with these proteins. PMID- 24061851 TI - Stress-induced localization of HSPA6 (HSP70B') and HSPA1A (HSP70-1) proteins to centrioles in human neuronal cells. AB - The localization of yellow fluorescent protein (YFP)-tagged HSP70 proteins was employed to identify stress-sensitive sites in human neurons following temperature elevation. Stable lines of human SH-SY5Y neuronal cells were established that expressed YFP-tagged protein products of the human inducible HSP70 genes HSPA6 (HSP70B') and HSPA1A (HSP70-1). Following a brief period of thermal stress, YFP-tagged HSPA6 and HSPA1A rapidly appeared at centrioles in the cytoplasm of human neuronal cells, with HSPA6 demonstrating a more prolonged signal compared to HSPA1A. Each centriole is composed of a distal end and a proximal end, the latter linking the centriole doublet. The YFP-tagged HSP70 proteins targeted the proximal end of centrioles (identified by gamma-tubulin marker) rather than the distal end (centrin marker). Centrioles play key roles in cellular polarity and migration during neuronal differentiation. The proximal end of the centriole, which is involved in centriole stabilization, may be stress sensitive in post-mitotic, differentiating human neurons. PMID- 24061852 TI - Skeletal alterations in women affected by obesity. AB - Obesity has always been considered a protective factor for the skeleton and for osteoporosis. However, new epidemiologic and clinical data have shown that high level of fat mass might be a risk factor for osteoporosis and fragility fractures. Further, increasing evidences seem to indicate that the different components of metabolic syndrome (i.e. hypertension, increased triglycerides, and reduced high-density lipoprotein cholesterol) are also potential risk factors for the development of low bone mineral density and osteoporosis. PMID- 24061853 TI - Molecular basis of lateral force spectroscopy nano-diagnostics: computational unbinding of autism related chemokine MCP-1 from IgG antibody. AB - Monocyte-chemoattractant protein-1 (MCP-1), also known as CCL2, is a potent chemoattractant of T cells and monocytes, involved in inflammatory and angio proliferative brain and retinal diseases. Higher expression of MCP-1 is observed in metastatic tumors. Unusual levels of MCP-1 in the brain may be correlated with autism. Immunochemistry where atomic force microscope (AFM) tips functionalized with appropriate antibodies against MCP-1 are used could in principle support medical diagnostics. Useful signals from single molecule experiments may be generated if interaction forces are large enough. The chemokine-antibody unbinding force depends on a relative motion of the interacting fragments of the complex. In this paper the stability of the medically important MCP-1- immunoglobulin G antibody Fab fragment complex has been studied using steered molecular dynamics (SMD) computer simulations with the aim to model possible arrangements of nano-diagnostics experiments. Using SMD we confirm that molecular recognition in MCP1-IgG is based mainly on six pairs of residues: Glu39A - Arg98H, Lys56A - Asp52H, Asp65A - Arg32L, Asp68A - Arg32L, Thr32A - Glu55L, Gln61A - Tyr33H. The minimum external force required for mechanical dissociation of the complex depends on a direction of the force. The pulling of the MCP-1 antigen in the directions parallel to the antigen-antibody contact plane requires forces about 20 %-40 % lower than in the perpendicular one. Fortunately, these values are large enough that the fast lateral force spectroscopy may be used for effective nano-diagnostics purposes. We show that molecular modeling is a useful tool in planning AFM force spectroscopy experiments. PMID- 24061854 TI - Destabilization of the MutSalpha's protein-protein interface due to binding to the DNA adduct induced by anticancer agent carboplatin via molecular dynamics simulations. AB - DNA mismatch repair (MMR) proteins maintain genetic integrity in all organisms by recognizing and repairing DNA errors. Such alteration of hereditary information can lead to various diseases, including cancer. Besides their role in DNA repair, MMR proteins detect and initiate cellular responses to certain type of DNA damage. Its response to the damaged DNA has made the human MMR pathway a useful target for anticancer agents such as carboplatin. This study indicates that strong, specific interactions at the interface of MutSalpha in response to the mismatched DNA recognition are replaced by weak, non-specific interactions in response to the damaged DNA recognition. Data suggest a severe impairment of the dimerization of MutSalpha in response to the damaged DNA recognition. While the core of MutSalpha is preserved in response to the damaged DNA recognition, the loss of contact surface and the rearrangement of contacts at the protein interface suggest a different packing in response to the damaged DNA recognition. Coupled in response to the mismatched DNA recognition, interaction energies, hydrogen bonds, salt bridges, and solvent accessible surface areas at the interface of MutSalpha and within the subunits are uncoupled or asynchronously coupled in response to the damaged DNA recognition. These pieces of evidence suggest that the loss of a synchronous mode of response in the MutSalpha's surveillance for DNA errors would possibly be one of the mechanism(s) of signaling the MMR-dependent programed cell death much wanted in anticancer therapies. The analysis was drawn from dynamics simulations. PMID- 24061855 TI - A single glycine in extracellular loop 1 is the critical determinant for pharmacological specificity of dopamine D2 and D3 receptors. AB - Subtype-selective agents for the dopamine D3 receptor (D3R) have been considered as potential medications for drug addiction and other neuropsychiatric disorders. Medicinal chemistry efforts have led to the discovery of 4-phenylpiperazine derivatives that are >100-fold selective for the dopamine D3 receptor over dopamine D2 receptor (D2R), despite high sequence identity (78% in the transmembrane domain). Based on the recent crystal structure of D3R, we demonstrated that the 4-phenylpiperazine moiety in this class of D3R-selective compounds binds to the conserved orthosteric binding site, whereas the extended aryl amide moiety is oriented toward a divergent secondary binding pocket (SBP). In an effort to further characterize molecular determinants of the selectivity of these compounds, we modeled their binding modes in D3R and D2R by comparative ligand docking and molecular dynamics simulations. We found that the aryl amide moiety in the SBP differentially induces conformational changes in transmembrane segment 2 and extracellular loop 1 (EL1), which amplify the divergence of the SBP in D3R and D2R. Receptor chimera and site-directed mutagenesis studies were used to validate these binding modes and to identify a divergent glycine in EL1 as critical to D3R over D2R subtype selectivity. A better understanding of drug dependent receptor conformations such as these is key to the rational design of compounds targeting a specific receptor among closely related homologs, and may also lead to discovery of novel chemotypes that exploit subtle differences in protein conformations. PMID- 24061857 TI - Dietary supplementation in children and adolescents: supplementing with the "correct" amount. PMID- 24061856 TI - A novel noncanonical signaling pathway for the MU-opioid receptor. AB - The u-opioid receptor (OPRM1) signals as a classic G protein-coupled receptor by activating heterotrimeric Gi/Go proteins resulting in adenylyl cyclase (AC) inhibition. Such AC inhibition is desensitized after prolonged agonist treatment. However, after receptor desensitization, the intracellular cAMP level remains regulated by OPRM1, as demonstrated by the intracellular cAMP level increase or AC superactivation upon removal of an agonist or addition of an antagonist. We now demonstrate that such intracellular cAMP regulation is mediated by a novel noncanonical signaling pathway resulting from OPRM1 being converted to a receptor tyrosine kinase (RTK)-like entity. This noncanonical OPRM1 signaling is initiated by the receptor recruiting and activating Src kinase within the receptor complex, leading to phosphorylation of the OPRM1 Tyr(336) residue. Phospho-Tyr(336) serves as the docking site for growth factor receptor-bound protein/son of sevenless, leading to the recruitment and activation of the Ras/Raf-1 and subsequent phosphorylation and activation of AC5/6 by Raf-1. Such sequence of events was established by the absence of Ras/Raf1 recruitment and activation by the OPRM1 Y336F mutant, by the presence of Src kinase inhibitor 4-amino-5-(4-chlorophenyl) 7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) or the absence of Src activity, by the presence of specific Raf-1 inhibitor GW5074 (5-iodo-3-[(3,5-dibromo-4 hydroxyphenyl) methylene]-2-indolinone) or the absence of Raf-1, or by the dominant negative RasN17 mutant. Src together with Ras activates Raf1 which was established by the inability of the Raf1-Tyr(340/341) mutant to activate AC. Hence, the phosphorylation of OPRM1 at Tyr(336) by Src serves as the trigger for the conversion of a classic Gi/Go-coupled receptor into an RTK-like entity, resulting in a noncanonical pathway even after the original Gi/Go signals are blunted. PMID- 24061858 TI - Cognitive vulnerabilities amplify the effect of early pubertal timing on interpersonal stress generation during adolescence. AB - Early pubertal timing has been found to confer risk for the occurrence of interpersonal stressful events during adolescence. However, pre-existing vulnerabilities may exacerbate the effects of early pubertal timing on the occurrence of stressors. Thus, the current study prospectively examined whether cognitive vulnerabilities amplified the effects of early pubertal timing on interpersonal stress generation. In a diverse sample of 310 adolescents (M age = 12.83 years, 55 % female; 53 % African American), early pubertal timing predicted higher levels of interpersonal dependent events among adolescents with more negative cognitive style and rumination, but not among adolescents with lower levels of these cognitive vulnerabilities. These findings suggest that cognitive vulnerabilities may heighten the risk of generating interpersonal stress for adolescents who undergo early pubertal maturation, which may subsequently place adolescents at greater risk for the development of psychopathology. PMID- 24061859 TI - The Native American adolescent: social network structure and perceptions of alcohol induced social problems. AB - Race/ethnicity and the structure of an adolescent's social network are both important factors in the etiology of delinquent behavior. Yet, much of the minority-group delinquency literature overlooks the Native American youth population that traditionally exhibits high rates of alcohol use and abuse. Utilizing data from the National Longitudinal Study of Adolescent Health, we compare the structural characteristics of school-based friendship networks of American Indian youth and other racial/ethnic groups. Our core sample for the descriptive analysis consists of 70,841 youth (Caucasian = 42,096; Black = 13,554; Asian = 4,758; Hispanic = 4,464; American Indian = 3,426; Other = 2,543; Female = 50%). We find that Native American youth generally occupy similar social positions within school hierarchies compared to other minority groups. However, American Indian youth have fewer ties at the school level than Caucasian youth, including reports of fewer reciprocated friendships, a smaller number of in school friends, and membership in less cohesive personal networks. We also focus on the detrimental social and physical consequences of alcohol use during adolescence and offer an extended consequences model (n = 5,841) that includes the interactive effects of race/ethnicity, age, and drinking influences on relationships with friends (Caucasian = 59%; Black = 19%; Asian = 7%; Hispanic = 7%; American Indian = 5%; Other = 3%; Female = 54%). American Indian youth are no more likely than other youth to report personal drinking as being detrimental to social relationships with parents, peers, and romantic partners. We address ties between our findings and criminal justice policies and practices, as well as the implications for similar network analyses involving other racial/ethnic groups. PMID- 24061861 TI - Cancer risk and overall survival in mismatch repair proficient hereditary non polyposis colorectal cancer, Lynch syndrome and sporadic colorectal cancer. AB - Mismatch repair proficient hereditary non-polyposis colorectal cancer (MSS-HNPCC) encloses a heterogeneous group of families consisting of different unknown genetic syndromes and/or aggregations cases. The lack of information about the hereditability of cancer risk in these families makes it difficult to carry out an individualized Genetic Counseling. Therefore, deep description of such families becomes important for a better classification and search for underlying susceptibility causes. The aim of this study is to describe and compare the clinical, morphological features, tumor KRAS status and overall survival in MSS HNPCC, Lynch and sporadic colorectal cancer. A total of 37 MSS-HNPCC families, 50 Lynch families and 612 sporadic CRC were included. Clinical and morphological data were evaluated by reviewing medical and pathology reports of 55, 69 and 102 tumors respectively. KRAS/BRAF status were detected by allele specific real-time PCR. Standardized incidence ratios (SIR) were calculated among 602 MSS-HNPCC relatives and 668 Lynch relatives. Main features distinguishing MSS-HNPCC were diagnosis age (55.1 +/- 12.6), preferential distal location (76%), polyp detection (45%) and familial colorectal cancer incidence (SIR = 6.6). In addition, we found increased incidences rates for kidney, stomach and uterus tumors. KRAS mutation rates were similar in the study populations (48.8 +/- 5.8) but higher than those described before by Sanger sequencing. MSS-HNPCC overall survival was similar to Lynch in B Dukes' stage tumors and between Lynch and sporadic in C stage tumors. Anatomical and morphological data of MSS-HNPCC are consistent with other described populations. Our studies disclose an increased HNPCC-extracolonic tumors incidence and improved overall survival in MSS-HNPCC families. PMID- 24061862 TI - Prevalence of PALB2 mutation c.509_510delGA in unselected breast cancer patients from Central and Eastern Europe. AB - Inherited mutations in PALB2 are known to be associated with increased breast cancer risk. We aimed to investigate the prevalence and risk association of a recurrent PALB2 mutation, c.509_510delGA, among 3,924 unselected breast cancer patients from Belarus, Russia or Germany. High-resolution melting analyses and direct sequencing identified the c.509_510delGA allele in 3/1,008 (0.3 %) German breast cancer patients, 2/994 (0.2 %) Russian breast cancer patients and 5/1,922 (0.3 %) Byelorussian breast cancer patients. Breast tumours were mainly estrogen receptor positive and included both ductal and lobular histology. Only one of the ten patients had a first-degree family history of breast cancer. The mutation was not detected in 2,827 healthy females from the same populations, confirming the association of PALB2*c.509_510delGA with breast cancer risk (p = 0.007). These data indicate that the PALB2*c.509_510delGA mutation is prevalent in about 1 in 400 breast cancer patients from Central and Eastern Europe, and the low occurrence of familial clustering is consistent with a moderate penetrance of this mutation. PMID- 24061863 TI - Physiologically based pharmacokinetic modelling of Busulfan: a new approach to describe and predict the pharmacokinetics in adults. AB - PURPOSE: A physiologically based pharmacokinetic (PBPK) model was established and evaluated describing the pharmacokinetics (PK) of the DNA-alkylating agent Busulfan in adults in order to predict the systemic Busulfan drug exposure in both plasma and toxicity-related organs. METHODS: A generic PBPK model was tailored to describe Busulfan PK by implementing compound-specific physicochemical and metabolism data. With regard to possible influences of glutathione S transferase (GST) variations on Busulfan PK, two different PBPK model parameterizations were investigated: a first parameterization with individual GST activity (expressed as different estimated V(max) values) for each patient, and a resulting second model parameterization with a mean GST activity for all patients. Simulations were computed and compared to concentration-time data after intravenous Busulfan administration to 108 adults serving as development dataset. Subsequently, appropriateness of the PBPK model was evaluated with an external dataset not used for model development, consisting of 95 adults. RESULTS: Both PBPK model parameterizations of Busulfan successfully described the observed plasma concentrations. For the validation dataset, calculated PK parameters were as follows: clearance 0.16 +/- 0.03 L/h/kg and volume of distribution 0.65 +/- 0.06 L/kg (mean +/- standard deviation). Mean absolute percentage error was less than 30 % for each PK parameter. Mass balances for distribution and excretion were in good agreement with the literature data. CONCLUSIONS: Both PBPK model parameterizations sufficiently described the observed concentration-time data while showing an adequate predictive performance. The model should be further evaluated for its ability to explain the between-subject variability in intravenous Busulfan PK parameters. PMID- 24061864 TI - Circadian variability of pharmacokinetics of cisplatin in patients with non-small cell lung carcinoma: analysis with the NONMEM program. AB - PURPOSE: The aim of this study was to describe the nonlinear pharmacokinetics of total and unbound plasma cisplatin under different administered time in patients with non-small-cell lung carcinoma. METHODS: Patients receiving chemotherapy with cisplatin were included in this analysis. Patients were divided into two groups depending on the administrated time of cisplatin: 6:00 (Group A) and 18:00 (Group B). The population pharmacokinetics of cisplatin was calculated using nonlinear mixed-effects modeling (NONMEM) method, and the possible influence of covariates on the population pharmacokinetics of cisplatin was also explored. RESULTS: The pharmacokinetics of total and unbound cisplatin could be described well by a linear two-compartment model. The mean population estimates for total and unbound drug were, respectively, 0.463 (17.0 %) and 25.4 (14.0 %) l h-1 for clearance (CL), 24.2 (19.9 %) and 20.5 (27.1 %) l for central distribution volume (V1), 10.2 (18.2 %) and 9.82 (28.1) l h-1 for intercompartmental clearance (Q) and 32.0 (24.1 %) and 6.77 (25.4 %) l for peripheral compartment volume (V2). The CL for total and unbound cisplatin was dependent on body surface area (BSA). When cisplatin was administered at 18:00, the CL was 1.38- and 1.22-fold higher than those administered at 6:00 for total and unbound cisplatin, respectively (P < 0.05). The mean parameter estimates from a nonparametric bootstrap procedure were comparable and within 5 % of the estimates from NONMEM. CONCLUSIONS: The results showed that circadian could influence the metabolism of cisplatin and suggested the conventional dose adjustment of cisplatin based on BSA. PMID- 24061865 TI - Effects of the aldehyde dehydrogenase inhibitor disulfiram on the plasma pharmacokinetics, metabolism, and toxicity of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice. AB - PURPOSE: Benzaldehyde dimethane sulfonate (DMS612, NSC281612, BEN) is an alkylator with activity against renal cell carcinoma, currently in phase I trials. In blood, BEN is rapidly metabolized into its highly reactive carboxylic acid (BA), presumably the predominant alkylating species. We hypothesized that BEN is metabolized to BA by aldehyde dehydrogenase (ALDH) and aimed to increase BEN exposure in blood and tissues by inhibiting ALDH with disulfiram, thereby shifting BA production from blood to tissues. METHODS: Female CD2F1 mice were dosed with 20 mg/kg BEN iv alone or 24 h after 300 mg/kg disulfiram ip. BEN, BA, and metabolites were quantitated in plasma and urine, and toxicities were assessed. RESULTS: BEN had a plasma t1/2 <5 min and produced at least 12 products. The metabolite half-lives were <136 min. Disulfiram increased BEN plasma exposure 368-fold (AUC0-inf from 0.11 to 40.5 mg/L min), while plasma levels of BA remained similar. Urinary BEN excretion increased (1.0-1.5 % of dose), while BA excretion was unchanged. Hematocrit, white blood cell counts, and percentage lymphocytes decreased after BEN administration. Coadministration of disulfiram appeared to enhance these effects. Profound liver pathology was observed in mice treated with disulfiram and BEN. CONCLUSIONS: BEN plasma concentrations increased after administration of disulfiram, suggesting that ALDH mediates the rapid metabolism of BEN in vivo, which may explain the increased toxicity seen with BEN after administration of disulfiram. Our results suggest that the coadministration of BEN with drugs that inhibit ALDH to patients that are ALDH deficient may cause liver damage. PMID- 24061866 TI - Differential regulation of sunitinib targets predicts its tumor-type-specific effect on endothelial and/or tumor cell apoptosis. AB - PURPOSE: Sunitinib is an inhibitor of tyrosine-kinase receptors, and no biomarker predictive of sunitinib response is available. The purpose of this preclinical study was to show whether sunitinib molecular targets could be used as biomarkers to assess tumor response to sunitinib in human cancer cell line xenografts of three different tumor types. METHODS: Using mice xenografted with liver, breast and renal carcinoma cell lines, we sequentially analyzed the effect of 7-day sunitinib treatment on tumor and vascular compartments. RESULTS: In all xenografts, microvessel damage occurred from Day 1. Tumor damage also occurred in liver, breast, but not in renal xenografts. Using specific human and mouse probes for genes encoding sunitinib targets, we showed a significant relation between apoptotic tumor cell numbers and human PDGFRBeta and RET mRNA expression in liver cancer and to human VEGFR2 expression in breast cancer xenografts. In contrast, in renal cancer xenografts, vascular effect evaluated by measuring endothelial cell apoptosis was related to mouse Vegfr1, Vegfr2 and Vegfa-164 expression. CONCLUSION: This study identifies sunitinib vascular and tumor effects according to different tumor types and shows that sunitinib molecular targets used as biomarkers enable assessment of therapeutic response. PMID- 24061867 TI - An evaluation of ventilator-associated pneumonia process measure sampling strategies in a surgical ICU. AB - Ventilator-associated pneumonia (VAP) is common, lethal, and expensive. Little is known about optimal strategies to evaluate process measures for VAP prevention. The authors conducted a prospective study of different sampling strategies for evaluating head of bed (HOB) elevation and oral care. There was no significant difference between morning and evening shift HOB elevation compliance rates (P = .47). If oral care was performed at least once during a 12-hour shift, there was an 87% probability that it also was performed at least twice. If oral care was performed at least twice during a 12-hour shift, then there was a 93% probability that chlorhexidine oral care was performed at least once. The results of this study suggest that sampling HOB elevation twice as compared with once daily is unlikely to change the estimate of performance, oral care need not be frequently sampled, and high oral care compliance may predict chlorhexidine oral care compliance. PMID- 24061868 TI - A multifaceted initiative to improve clinician awareness of pain management disparities. AB - Patients belonging to some racial, ethnic, and socioeconomic groups are at risk of receiving suboptimal pain management. This study identifies health care provider attitudes, knowledge, and practices regarding the treatment of chronic pain in vulnerable patient populations and assesses whether a certified continuing medical education (CME) intervention can improve knowledge in this area. Survey responses revealed several knowledge gaps, including a lack of knowledge that the undertreatment of pain is more common in minority patients than others. Respondents identified language barriers, miscommunication, fear of medication diversion, and financial barriers as major obstacles to optimal pain management for this patient population. Participants who completed a CME certified activity on pain management disparities demonstrated increased confidence in caring for disadvantaged patients, but only 1 of 3 knowledge items improved. Understanding clinician factors that underlie suboptimal pain management is necessary to develop effective strategies to overcome disparities and improve quality of care for patients with chronic pain. PMID- 24061869 TI - Isolation and quantification of major chlorogenic acids in three major instant coffee brands and their potential effects on H2O2-induced mitochondrial membrane depolarization and apoptosis in PC-12 cells. AB - Coffee is a most consumed drink worldwide, with potential health effects on several chronic diseases including neuronal degenerative diseases. Chlorogenic acids (CHAs) are phenolic compounds found in coffee and they are reported to have strong antioxidant and anti-inflammatory activities. However, the amounts of CHAs often vary in coffee drinks and their potential effects on ROS-induced neuronal cell death still require more investigation. Therefore, in this paper, major CHAs were isolated from three major instant coffee brands, confirmed and quantified using HPLC and NMR spectroscopic methods. Then, their antioxidant activities and protective effects on H2O2-induced apoptosis in PC-12 cells were investigated using radical scavenging, mitochondrial membrane potential and caspase assays. In the coffee samples, three major CHAs (3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid, 5-O-caffeoylquinic acid) and some minor CHAs (3-O-feruloylquinic acid, 4-O feruloylquinic acid, 5-O-feruloylquinic acid, 3,5-O-dicaffeoylquinic acid, 3,4-O dicaffeoylquinic acid, and 4,5-O-dicaffeoylquinic acid) were detected. The three major CHAs were further isolated and their chemical structures were confirmed using NMR spectroscopic techniques. Also, the amounts of the three major CHAs were individually quantified using a HPLC method. At the concentration of 10 MUM, all three major CHAs quenched DPPH and/or xanthine oxidase-generated radical species by 21-51% (P < 0.014). They also inhibited H2O2-induced mitochondrial membrane depolarization and caspase-9 activation by 27% (P < 0.034) and 50% (P < 0.05), respectively. This study suggests that the major CHAs found in coffee are likely to be potent antioxidant compounds able to quench radical species as well as inhibit H2O2-induced apoptosis via suppressing mitochondrial membrane depolarization and caspase-9 activation in the cells. PMID- 24061871 TI - [Alice in intensiveland : Essay on nonsense and common sense in intensive care unit after the manner of Lewis Carroll]. PMID- 24061870 TI - [Pediatric postoperative quality analysis : Pain and postoperative nausea and vomiting]. AB - BACKGROUND: For the evaluation of postoperative pain therapy, nausea and vomiting (PONV), the Children's Hospital in Lucerne acts as a member of the postoperative quality improvement project QUIPSi for children. Initial results and the potential for evaluation of the postoperative pain therapy and PONV are presented here. The central questions are whether the postoperative therapy concept is sufficient and if QUIPSi serves as an ideal tool for postoperative quality improvement? METHODS: Over a period of 1.5 years a total of 460 children aged between 4 to 17 years evaluated their postoperative pain, requirements for more analgesic medicine and the incidence of PONV according to a standardized questionnaire on the first postoperative day. The administration of analgesic medicine was recorded until finishing the questionnaire. RESULTS: In this study 5 pediatric outpatient operation groups (hernia repair n = 36, bone surgery n = 23, metal removal surgery n = 31, circumcision n = 65 and soft tissue surgery n = 49) and 9 pediatric inpatient operation groups (appendectomy n = 21, bone surgery n = 78, metal removal surgery n = 24, orchidopexy n = 31, combined operation (orchidopexy + hernia repair or circumcision) n = 14, otoplasty n = 9, tonsillectomy n = 41 and pectus excavatum surgery n = 6 and soft tissue surgery n=28) could be classified. All operation groups except the inpatient and outpatient soft tissue surgery groups received regional or infiltration anesthesia. Analgesic medicine was prescribed with the maximum permitted daily dose per kg body weight (paracetamol 100 mg/kgBW, metamizole 80 mg/kgBW, diclofenac 3 mg/kgBW and ibuprofen 40 mg/kgBW; in reserve tramadol 8 mg/kgBW and nalbuphine 2.4 mg/kgBW). The following operation groups complained of persistent pain (scale according to Hicks 0-10) and/or required more pain medicine (%): pediatric outpatients circumcision 5.1/19 %, pediatric inpatients appendectomy 6.5/43 %, tonsillectomy 6.4/32 %, pectus excavatum surgery 7.7/33 %, orchidopexy 4.2/19.4 %, otoplasty 3.1/22.2 %. The reason for the elevated postoperative pain was mainly insufficient administered pain medicine despite the prescription of the maximum daily dose per kg body weight or maybe due to a late administration. Circumcision/appendectomy/tonsillectomy/pectus excavatum surgery/orchidopexy/otoplasty (% of max. daily dose): paracetamol 5/58/99/36/57/37 %, metamizole 0,4/18/8/54/4/4 %, diclofenac 44/45/3/97/51/68 % or ibuprofen 42/1/0/0/0/0 %, tramadol 0,4/0/0/0/0/0 %, nalbuphine 0,4/1/16/0/2/0 %). As the standard inhalative general anesthesia and PONV prophylaxis with tropisetron (body weight: < 20 kg 1 mg, > 20 kg: 2 mg intravenous bolus) was performed. Dexamethasone (0.15-0.5 mg/kgBW, maximum allowed dose 8 mg intravenous bolus) was administered as a back-up drug for PONV. The nausea incidence was higher in the inpatient group (14-50 %) than in the outpatient group (10-29 %). The incidence of vomiting was higher in the inpatient (0-37 %) than in the outpatient group (3-17 %). CONCLUSIONS: The quality analysis showed that especially children with the requirement for more pain medicine and a high PONV incidence (inpatient group) need further improvement in postoperative care. Because of small numbers in some operation groups this qualitative evaluation of the postoperative pain and PONV management only gives an approximate overview. The results of QUIPSi uncovered gaps in the postoperative pain management which will help improve the quality in the postoperative setting. The QUIPSi approach should be integrated as a daily tool into all pediatric surgical departments. PMID- 24061872 TI - [Increased intracranial pressure and brain edema]. AB - In primary and secondary brain diseases, increasing volumes of the three compartments of brain tissue, cerebrospinal fluid, or blood lead to a critical increase in intracranial pressure (ICP). A rising ICP is associated with typical clinical symptoms; however, during analgosedation it can only be detected by invasive ICP monitoring. Other neuromonitoring procedures are not as effective as ICP monitoring; they reflect the ICP changes and their complications by other metabolic and oxygenation parameters. The most relevant parameter for brain perfusion is cerebral perfusion pressure (CPP), which is calculated as the difference between the middle arterial pressure (MAP) and the ICP. A mixed body of evidence exists for the different ICP-reducing treatment measures, such as hyperventilation, hyperosmolar substances, hypothermia, glucocorticosteroids, CSF drainage, and decompressive surgery. PMID- 24061873 TI - Biomass composition, lipid characterization, and metabolic profile analysis of the fed-batch fermentation process of two different docosahexanoic acid producing Schizochytrium sp. strains. AB - Growth and fermentation characteristics, biomass composition, lipid characterization and metabolic profiling analysis of two different Schizochytrium sp. strains, the original strain and the industrial adaptive strain, were investigated in the fed-batch fermentation process. The final cell biomass, total lipids content, docosahexanoic acid (DHA) content and DHA productivity of the adaptive strain were much higher than those of the original strain. The metabolic distinctions which extensively existed between these two strains were revealed by the score plot of principal component analysis. In addition, potential biomarkers responsible for discriminating different strains were identified as myo-inositol, histidine, alanine, asparagine, cysteine, and oxalic acid. These findings provided new insights into the industrial strain screening and further improvement of DHA production by Schizochytrium sp. PMID- 24061874 TI - Sodium chloride-induced modulation of the activity and thermal stability of short chain oxidoreductase from the archaeon Thermococcus sibiricus. AB - Recently, we have studied properties and structural features of the thermostable halotolerant alcohol dehydrogenase from archaeon Thermococcus sibiricus (TsAdh319). In the present work, the effect of sodium chloride on activity and thermostability was explored using circular dichroism, fluorescent spectroscopy, and differential scanning calorimetry. The activity of TsAdh319 increased in the presence of NaCl and remained at the elevated level up to 4 M of NaCl. Sodium chloride at molar concentrations reduced the optimal reaction temperature, increased both Michaelis constant (K m) and k cat values for the substrates tested, decreased affinity for the coenzyme, and stoichiometry of coenzyme binding. No changes were revealed in a secondary or quaternary structure of the protein in the presence of NaCl up to 90 degrees C. According to differential scanning calorimetry, the irreversible unfolding started around 90 degrees C, the addition of NaCl decreased T m from 104.2 to 102.2 degrees C, and reduced DeltaH from 438 to 348 kJ/mol. Kinetic studies revealed positive effect of NaCl on the TsAdh319 thermostability. The results are interpreted in regard to TsAdh319 structural data. PMID- 24061875 TI - Simultaneous identification of pork and poultry origins in pet foods by a quick multiplex real-time PCR assay using EvaGreen florescence dye. AB - EvaGreen multiplex real-time polymerase chain reaction (EMRT-PCR) was designed for an assay that can join the advantages of multiplex PCR and real-time PCR to recognize animal genes more quickly in pet foods. EMRT-PCR based on melting temperatures discrimination by using EvaGreen fluorescence dye was developed for the analysis of pork and poultry in pet food. The method combines the use of poultry- and pork-specific primers that amplify small fragments of 12S rRNA and mitochondrial DNA genes. Appropriate mixtures of poultry and pork meat in reference samples were used to develop the assay. Gene yields of poultry and pork were represented in two melting peaks generated simultaneously at temperatures of 80.5 and 87.2 degrees C, respectively. Based upon the assay results, it has been concluded that EMRT-PCR assay might be an efficient tool for the verification of species origin in pet foods. PMID- 24061876 TI - Cellulosomes - promising supramolecular machines of anaerobic cellulolytic microorganisms. AB - Cellulose is the main structural component of plant cell wall and thus the most abundant carbohydrate in nature. However, extracting the energy from this abundant source is limited by its recalcitrant nature. The hydrolysis of plant cell wall requires synergystic action of different enzymes, including multiple cellulases, hemicellulases, pectinases, etc. Meanwhile aerobic cellulolytic microorganisms release large quantities of synergistically acting free enzymes in their environment, most anaerobic microorganisms evolved more efficient strategies to optimize the process of plant cell wall degradation, for example production of extracellular multi-enzyme complexes (cellulosomes). Cellulosomes consist of at least one core structural protein, named scaffoldin, which firmly binds numerous enzymatic subunits, and usually also plays a major role in substrate binding. Although the general structure of cellulosomes seems universal, differences in number and identity of complex components do exist among microorganisms. The article surveys the current knowledge about cellulosomes, focusing on three best investigated cellulolytic clostridia, one representative of ruminal bacteria and novel findings concerning anaerobic fungi. Efforts in construction of artificially engineered cellulosomal systems (designer cellulosomes) as well as their biotechnological potential are also discussed. PMID- 24061877 TI - Metal Ion Prompted Macrocyclic Complexes Derived from Indole-2,3-dione (isatin) and O-phenylenediamine With their Spectroscopic and Antibacterial Studies. AB - A novel series of the complexes of the type:[M(TML)X]X2; where TML is a tetradentate macrocyclic ligand; M=Cr(III), Fe(III); X=Cl-, NO3-, OAc- has been synthesized by condensation of indole-2,3-dione (isatin) and o-phenylenediamine in the methanolic medium. The complexes have been characterized with the help of various physicochemical techniques like elemental analyses, conductance measurements, magnetic measurements, infrared and electronic spectral studies. Molar conductance values indicate they are 1:2 electrolytes. Electronic spectra along with magnetic moments suggest the five coordinate square-pyramidal geometry for these complexes. The complexes were also tested for their in vitro antibacterial activities. Some of the complexes showed remarkable antibacterial activities against some of the selected bacterial strains. PMID- 24061878 TI - Spectrophotometric estimation of total carotenoids in cereal grain products. AB - Total carotenoids (TC) were determined as a measure of total xanthophylls in grain flours and grits, by new validated spectrophotometric method based on A1cm1%-approach. The general analytical procedure is easily adjustable to different samples, the number of extraction steps depending on TC concentration in the sample. Basically, two methods have been suggested: the rapid one for low TC samples (white corn, wheat, soybean, sorghum) including one to two extractions, and the one for high-TC samples (yellow corn) needing three to four extractions. Method's accuracy was proven against the reference standard material (102.1+/-3.9%) and the reference method. Good precision (repeatability and intermediate precision of upto 9% for yellow corn products) and sensitivity with LOD (limit of detection) and LLOQ (lower limit of quantitation) of 0.2 and 0.6 mg kg-1 TC, resp., were estimated. The method was applied to the control of nutritional value of cereal grain products. TC concentration (in mg kg-1) in the samples ranged from 11-23 in yellow corn flours, 0.7-0.9 in white corn flours, 17 22 in yellow corn grits, 1.1-1.3 in wheat flours, 1.6 in wheat grits and 1.5 in sorghum flour, to 0.9-9.9 in soybean flours. PMID- 24061879 TI - Use of Genetic Algorithm for Fitting Sovova's Mass Transfer Model. AB - A genetic algorithm with resizable population has been applied to the estimation of parameters for Sovova's mass transfer model. The comparison of results between a genetic algorithm and a global optimizer from the literature shows that a genetic algorithm performs as good as or better than a global optimizer on a given set of problems. Other benefits of the genetic algorithm, for mass transfer modeling, are simplicity, robustness and efficiency. PMID- 24061880 TI - Synthesis and in vitro Study of Some New Bis(thiadiazolyl-2H-pyrazolo[3,4 d][1,3]thiazole)-methanes as Potential Nematicides. AB - A new series of bis(pyrazolo[3,4-d][1,3]thiazoles) 7a-j has been synthesized and characterized via IR, 1H NMR, 13C NMR, MS and elemental analyses. All the newly synthesized compounds 7a-j have been assayed for their nematicidal activity against Ditylenchus myceliophagus and Caenorhabditis elegans by aqueous in vitro screening technique. The screened data reveal that the compound 7e is most effective against D. myceliophagus and C. elegans with LD50 of 160 and 180 ppm respectively and is almost equal to the activity of the standard levamisole. The compounds 7h and 7j are also most active against C. elegans with LD50 of 190 ppm and D. myceliophagus with LD50 of 180 ppm, respectively. Further, 7a-j were screened for their antibacterial activity. Most of these new compounds showed potent activity against the test bacteria and emerged as potential molecules for further development. PMID- 24061881 TI - A novel green chemical route for synthesis of silver nanoparticles using camellia sinensis. AB - The thrust to develop environmental friendly procedures for production of Nanoparticles arises from the very fact that current nanotechnology research uses a lot of chemicals, which are potential threat to both environment and public health. Tea (Camellia Sinensis) with its rich source of polyphenolic compounds has been exploited for the reduction and capping of silver nanoparticles (Ag NPs), making it a complete green chemical route. The reduction of Ag+ to Ag0 was observed by the color change from pale yellow to dark yellow. The reaction was followed with the help of UV-Visible spectrometer. Crystal structure was obtained by carrying out X-ray diffraction studies and it showed face centered cubic (fcc) structure. The particle size and morphology were obtained from transmission electron microscopy (TEM) and small angle X-ray scattering (SAXS) studies. An average particle size of 25 nm silver particles could be obtained using this method and the TEM and SAXS data corroborate with each other. PMID- 24061882 TI - Tungsten - Tungsten Trioxide Electrodes for the Long-term Monitoring of Corrosion Processes in Highly Alkaline Media and Concrete-based Materials. AB - The determination of pH in highly alkaline solutions and concrete materials is extremely important for monitoring or predicting the corrosion processes of reinforced concrete structures and to follow the hydration process of Portland cement, fly-ash, micro silica and other materials used in concrete manufacturing. The corrosion of reinforced concrete structures and the hydration of pozzolanic materials are long-term processes, which means, that appropriate durable, and resilient pH electrodes are needed, for direct implantation regarding solid concrete bodies. The purpose of this work was to characterise the potentiometric and surface properties of tungsten electrodes after exposure to extreme alkaline solutions. The tungsten wire surface was activated at 800 degrees C for 30 min within an oxygen flow. The formation of homogenous and compact multiple layers of WO3 crystals was observed using X-ray diffraction and scanning electron microscopy. X-ray diffraction of those tungsten electrodes exposed to saturated calcium hydroxide solution or the pore-water of cement-based materials during 10 months, indicated partly dissolved WO3. Two new compounds appeared on the electrodes surfaces; pure tungsten and CaWO4. The presence of tungsten was affecting any potentiometric response in acidic pH region (2-5) but in pH 5-12 region the response still remained linear with a slope of 42 +/- 2 mV/pH unit. The W/WO3 electrode was suitable for the long-term monitoring of corrosion processes in concrete-based materials according to the pH changes as it has stable and repeatable responses to alkaline solutions (pH > 12). All the tested interferring ions had no significant influence on electrode potential. The W/WO3 electrode is simple, robust, inexpensive, and temperature resistant and can be applied in potentiometric titrations as well as in batch and flow-injection analysis. The prepared electrode is a highly promising pH sensor for the monitoring of pH changes in highly alkaline capillary water of concrete. PMID- 24061883 TI - Application of 4,4,4-Trifluoro-1-(Biphenyl-4-yl)Butane-1,3-Dione as a Chelating Extractant in the Solvent Extraction and Separation of Light Lanthanoids in Combination with Phosphine Oxides. AB - The 4,4,4-trifluoro-1-(biphenyl-4-yl)butane-1,3-dione(HL) has been synthesized and its complexation properties in solution was examined. Mixed ligand chelate extraction of light trivalent lanthanoids (La/Gd) from chloride medium at constant ionic strength u = 0.1 into C6H6 with HL in combination with one of the three phosphine oxide compounds trioctylphosphine oxide(TOPO), tributylphosphine oxide(TBPO) or triphenyphosphine oxide(TPPO) was studied. The composition of the extracted species was established as LnL3 with HL alone and as LnL3 2S in the presence of TOPO and TBPO or LnL3 S with the mixture of HL-TPPO. The 28 values of the overall equilibrium constants were calculated. A synergic effect up to 103 104 was observed for the extraction of the above-mentioned lanthanoid ions with binary mixtures of extractants. The change of the synergistic agent causes a significant increase of the KL,S values in the order TBPO < TPPO < TOPO. The parameters of the extraction process were determined and the separation factors between two adjacent Ln(III) were calculated. PMID- 24061884 TI - Hydrophobicity and retention coefficient of selected bile Acid oxo derivatives. AB - Retention coefficients (k) of cholic acid and its keto derivatives are determined by means of Reversed Phase High Pressure Liquid Chromatography at different temperatures (303K, 309K, and 313K). At each studied temperature, retention factor decreases if the hydroxyl group in the cholic acid molecule replaces oxo group. In addition, the change of retention coefficient in a function of temperature (Deltak/DeltaT) is dominant for the cholic acid while by increasing the number of oxo groups it decreases. Introduction of an oxo group in a bile acid molecule leads to the lower hydrophobicity of the beta side of the steroid nucleus. Because of that, less interaction happens between beta side of the steroid nucleus and stationary phase. For dehydrocholic acid (three- oxo derivative), the value for Deltak/DeltaT shows an exception of this explanation. This suggests that in this molecule the planar polarity is disturbed. Partition coefficient K of nitrazepam (probe molecule) in micelles of bile acid salts at the examined temperatures shows a high linear correlation with retention factors of the selected bile acids. This indicates the importance of hydrophobic interactions in mixed micelles between the examined drug and bile acid salts. Haemolytic potential (erythrocyte haemolysis, log (Lys50)) represents measure of membranotoxicity of bile acids. In addition, it is shown that haemolytic potential correlates highly with the retention coefficient. All experiments that we conducted to obtain the values of K and log (Lys50) as well as their correlations with k, contribute to significance of retention coefficient as a measure of hydrophobicity in biopharmaceutical experiments. PMID- 24061885 TI - Synthesis and Reactions of 2-Carboxyvinyl-4-chloro-6,8-dibromoquinazoline and Some New Fused Triazolo-Quinazoline Derivatives. AB - Synthesis of 2-carboxyvinyl-4-chloro-6,8-dibromoquinazoline (2) has been achieved via chlorination of the corresponding 6,8-dibromoquinazoline analog. The simple replacement of the chlorine atom at the position 4 of quinazoline nucleus with different amines has produced derivatives of the 4-heteroarylquinazoline and the fused quinazolino[4,3-c]quinazoline. The reaction of the chloroquinazoline derivative 2 with hydrazine hydrate and subsequent condensation with different aromatic aldehydes furnished a series of fused 5-substituted [1,2,4]triazoloquinazoline derivatives. Finally, its reaction with acyl hydrazide (acetyl hydrazide) furnished the heterocyclic system 7,9-dibromo-3-methyl [1,2,4]triazolo[4,3-c]Quinazolin-5-yl-2-propenoic acid. PMID- 24061886 TI - DFT Investigation of the Mechanism and Stereochemistry of Electrophilic Transannular Addition Reaction of Chlorine to Bisbenzotetracyclo[6.2.2.23,6 .02,7]tetradeca-4,9,11,13-tetraene. AB - The mechanism and stereochemistry of electrophilic addition of chlorine to bisbenzotetracyclo[6.2.2.23,6.02,7]tetradeca-4,9,11,13-tetraene (BBTT) molecule were investigated by DFT methods. The geometry and the electronic structure of BBTT molecule was studied by DFT/B3LYP method using the 6-311G(d) and 6 311++G(d,p) basis sets. The double bonds of BBTT molecule are endo-pyramidalized. The structure and stability of the cationic intermediates and products of the addition reaction were investigated by B3LYP/6-311G(d) and B3LYP/6-311+G(2d,p) methods. The solvent effect was evaluated using SCI-PCM method. The bridged chloronium cation is isomerized into the more stable nonclassical delocalized N- and U-type cations, and the difference between the stability of these cations is small. For the determination of the direction of addition reaction and the stereochemistry of the products, the stability of nonclassical delocalized N- and U-type ions and the structure of their cationic centres play a vital role for the determination of the direction of addition reaction and the stereochemistry of the products. Since the cationic centre of the N-type ion is in interaction with the benzene ring from the exo face, the nucleophilic attack of the chloride anion to this centre occurs from the endo face, and the exo,endo-isomer of the N-type product is obtained. The attack of chloride anion towards the cationic centre of U-type ion from the endo face is sterically hindered by the hydrogen atom, therefore the attack occurs from the exo face, which interacts with the benzene ring and the more stable exo,exo-isomer of U-type product is formed. Although, the U-type cation was 3.485 kcal mol-1 more stable than the N-type cation, the U type product was 1.886 kcal mol-1 [SCI-PCM-B3LYP/6-311++G(2d,p)// B3LYP/6 311G(d)] less stable than the N-type product. PMID- 24061887 TI - Osmotic coefficient of aqueous solutions of cyclohexylsulfamic Acid at the freezing point of solutions. AB - The osmotic coefficient of aqueous solutions of cyclohexylsulfamic acid was determined by freezing point measurements up to the molality 0.65 mol kg-1. The osmotic coefficients were fitted to the Pitzer equation, and ion interaction parameters alpha1, beta(0) and beta(1) were evaluated. The mean ion activity coefficient of the solute was calculated, and the non-ideal behaviour of the system investigated was characterized by calculation of the excess Gibbs energy of solution, as well as the respective partial molar functions of solute and solvent. The partial molar excess Gibbs energy of the solute is negative, like the excess Gibbs energy of its solution, while the partial molar excess Gibbs energy of the solvent is positive and increases with increasing concentration of the solute. The solvation ability of water was calculated from the difference between the Gibbs energy of solution of water in solution and that of pure water, and found to be positive and small for the solute investigated, throughout the concentration range studied. PMID- 24061888 TI - Infrared spectroscopic and conductivity studies of ureasil-based proton conducting membranes for medium temperature fuel cell applications. AB - Proton conducting membranes for fuel cells were prepared by the sol-gel process from two different ureasil organic-inorganic hybrid precursors: bis[(N-(3 triethoxysilylpropyl)ureido]-terminated poly(propylene glycol) 4000 (PPGU) and bis[3-(N-(3-triethoxysilylpropyl)ureido)propyl]-terminated poly(dimethylsiloxane) 1000 (PDMSU). Heteropoly silicotungstic acid was added to actuate the reactions of hydrolysis and condensation and to introduce proton conductivity. XRD measurements of membranes revealed the presence of a diffraction peak at 6.3 degrees , which could be ascribed to gradual formation of R-(SiO3/2) silsesquioxane clusters, i.e. arrangement of the Si-O-Si skeleton on the nano scale. TG and DSC measurements showed thermal stability of the membranes above 120 degrees C. Proton conductivities at room temperature were of the order of 10 4 to 10-3 S/cm, classifying the membranes in the group of super ionic conductors. At elevated temperatures up to 160 degrees C and at conditions of autogenous pressure, conductivities increased up to values acceptable for fuel cells of 10-1 S/cm, which could be the result of the presence of H3O+ ions. The protonation of the urea groups and the formation of amidonium ions [C(OH)=NH+] were followed using IR ATR spectroscopy. PMID- 24061889 TI - Estimation of Stability Constants of Cadmium(II) bis-Complexes with Amino Acids by Model Based on 3chiv Connectivity Index. AB - Linear model for estimation of the second, K2, and overall, beta2, stability constant of cadmium(II) binary and ternary bis-complexes with five aliphatic chi amino acids based on valence connectivity index of the 3rd order (3chiv) was developed. Set of amino acids included glycine, alanine, 2-aminobutanoic, 2 aminopentanoic (norvaline) and 2-aminohexanoic acid (norleucine), which by bonding to the cadmium(II) gave 25 K2 and 15 beta2 values. For estimation of log beta2, the model gave r = 0.940, and the S.E.cv = 0.10, and for the two subsets of log K2 constants the model yielded r = 0.936 and 0.842, and S.E.cv = 0.09. The complex CdGG was excluded from all regressions. PMID- 24061890 TI - Conversion of Methanol on CuO/H-MOR and CuO/H-ZSM-5 Catalysts. AB - This paper deals with maximizing dimethyl ether (DME) production from methanol due to its industrial importance as a future diesel fuel. The high acidity and the micro-porous structure of the catalysts encouraged this reaction. Catalysts containg 6% CuO supported on H-ZSM-5 and H-MOR zeolites give high activities for DME production. The 6% CuO/HMOR is more selective for DME production, while the 6% CuO/HZSM-5 is more selective for olefins (ethylene and propylene) formation. The higher acid site strength of CuO/HMOR is the principal factor for DME formation whereas olefins production is more activated on CuO/HZSM-5 due to its narrower pore volume. PMID- 24061891 TI - Wide-bore P-methylstyrene-co-dimethylbis(p-vinylbenzyl) silane Based-monoliths Columns for Separation of Peptides and Proteins. AB - Wide-bore monolithic columns of p-methylstyrene-co-dimethylbis(p vinylbenzyl)silane were prepared within glass columns (100 * 3 mm I.D.). Monolithic columns differing in the amount of initiator were fabricated. The pressure drop vs. flow-rate measurements and the relatively low swelling propensity factor indicated the good cross-linking homogeneity and good mechanically stability. The chromatographic performance of monoliths prepared was assessed by analysis of protein and peptide mixtures. Five proteins were separated in less than 2 minutes. Moreover, a mixture of 9 peptides was separated in less than 11 minutes, aside from the co-elution of vasopressin [arg8] and methionine enkephalin. PMID- 24061892 TI - Bacterial expression and simple purification of human group x secretory phospholipase A2. AB - Secreted group X phospholipase A2 (sPLA2-X) is one of the most effective mammalian PLA2 enzymes at hydrolyzing plasma lipoproteins and phospholipids in the membranes of intact cells, due in particular to its relatively high binding affinity to zwitterionic phospholipid substrates, such as phosphatidylcholine. The products of its enzymatic activity, lysophospholipids and free fatty acids, especially arachidonic acid, are involved in various physiological and pathological processes and currently being studied intensively. In spite of numerous studies, the biological roles of sPLA2-X have not been completely elucidated. With the aims of studying various cellular functions and designing effective enzyme inhibitors, we prepared a high amount of recombinant human sPLA2 X. Here we describe an effective Escherichia coli expression system, together with an in vitro refolding and simple purification procedure, that yields up to 10 mg of mature human sPLA2-X from a litre of culture. In contrast to the natural protein, the recombinant enzyme was produced in bacterial cells without the N terminal propeptide, i.e. as a mature protein, and was not N-glycosylated. It however retained all the enzymatic properties for hydrolysis of vesicular substrates composed of either phosphatidylglycerol or phosphatidylcholine. PMID- 24061893 TI - Using different experimental designs in drug-excipient compatibility studies during the preformulation development of a stable solid dosage formulation. AB - Different types of factorial experimental designs can be used in compatibility studies of drug development, where many different factors and their interactions should be evaluated to predict their effects on the degradation of the drug substance under study. All possible main and interaction effects of different potential excipients that can constitute the drug product should be evaluated in order to select the best combination of excipients that give the lowest possible degradation, i.e., the most stable drug product. Statistical experimental designs enable the user to obtain the maximum amount of information, i.e., the degradation effects of excipients and their interactions on the stability of the drug substance, on the basis of the smallest possible number of experiments. The use of full and two different fractional factorial designs is described using a real example where the excipients that stabilize the drug substance or cause as little degradation as possible are selected for a solid dosage formulation. It was shown that the type and the sequence of design used during the studies are also important to get reliable and valuable results. A thorough explanation of the statistical evaluation of data and different presentations of final solutions are given. PMID- 24061894 TI - The Influence of Different Models on 15-years-old Students' Understanding of the Solid State of Matter. AB - Different models are an indispensable part of teaching and learning chemistry for students to develop adequate mental models of solid states of matter. The aim of this study was to establish the importance of using physical models (teachers' demonstrations and students' modelling) and virtual models of solid states in the educational process for students' to acquire a better understanding of the crystal structures of substances. First year grammar school students (average age 15.4 years) participated in the study. All students were divided into three groups, depending on what sort of activity involving models was used in the chemistry teaching and learning process. The solid state of matter was taught in the first group by students' constructing physical models. In the second group virtual models were used, while the third group was taught by teachers' demonstration of physical models. Students' understanding of the solid state structures was assessed with a knowledge test after the educational strategy, whereas the knowledge retention was evaluated one month following the applications of the teaching strategies with the delayed test. The students who modelled physical models scored better on the test than did the students who used virtual models and also those who were taught the solid state of matter by the teachers' demonstration of physical models. Those students who used virtual models or modelling during chemistry learning achieved statistically the same results on the delayed test, whereas the students who were exposed to the teachers' model demonstration achieved the lowest test score. It can be concluded that students who are engaged in active learning strategies that include modelling or computer interaction using virtual models develop more adequate mental models of solid state substance structures. PMID- 24061895 TI - Quantification of the Rubidium in Beverage Products Micro Samples by Platinum wire Loop in Flame Atomization Atomic Emission Spectrometry. AB - The rubidium content in 3 uL of some beverage products (beer, wine, vegetable and fruit juices) atomized from a Ptwire in the methaneair flame has been determined by atomic emission spectrometry. The flame atomization conditions of rubidium were optimized, they are: lambda = 780.0 nm, the height of 8 mm over the burner head, gas flow rates of 300 L h-1 air and 34 L h-1 methane. The effect of Na, K, Cs, Sr and acetone on the emission of rubidium was studied too. The limit of quantification (6sigma) obtained is of 4.3+/-1.8 pg in the presence of 50 mg L-1 K and 5% v/v acetone (P = 0.05). The rubidium content of the samples has been determined with continuous nebulization and by atomization from the Ptwire, using the standard calibration curve and the standard addition method. The results of the two procedures agree within the determination errors. PMID- 24061896 TI - Chemical speciation of binary complexes of embelin with some biologically important metal ions. AB - Protonation and complexation equilibria of embelin were investigated in 86% v/v dimethyl sulphoxide - water mixture electrometrically at an ionic strength of 0.17 mol dm-3 and at a temperature of 303K. The best fit chemical models were arrived at based on statistical grounds employing crystallographic R factor, chi2, skewness and kurtosis. The existence of binary complex species with Co(II), Ni(II), Cu(II) and Zn(II) were established from modeling studies using the computer program MINIQUAD75. Distribution diagrams of various species of the complex in relation to pH are presented. PMID- 24061897 TI - Solvent extraction of barium into nitrobenzene by using hydrogen dicarbollylcobaltate in the presence of slovafol 909. AB - Extraction of microamounts of barium by a nitrobenzene solution of hydrogen dicarbollylcobaltate (H+B-) in the presence of Slovafol 909 (L) has been investigated. The equilibrium data have been explained assuming that the species HL+, HL+2, BaL2+ and BaL2+2 are extracted into the organic phase. The values of extraction and stability constants of the complex species in nitrobenzene saturated with water have been determined. PMID- 24061898 TI - PEG1000-DAIL / Toluene Temperature-dependent Biphasic System that Regulate Homogeneously Catalyzed Oxidation of Primary Alcohols to Carboxylic Acids. AB - An efficient and convenient procedure for the hydrogen peroxide oxidation of primary alcohols to the carboxylic acids in aqueous media in regulated temperature-dependant; recyclable phase-separation catalytic system comprised of the PEG1000-based dicationic acidic ionic liquid and toluene under homogeneous conditions in good to excellent yield is reported. PMID- 24061899 TI - Tetrabutylammonium Bromide in Water as a Green Media for the Synthesis of Pyrano[2,3-d]pyrimidinone and Tetrahydrobenzo[b]pyran Derivatives. AB - Tetrabutylammonium bromide (TBAB) was used as a green catalyst for the synthesis of tetrahydrobenzo[b]pyran and pyrano[2,3-d]pyrimidinone derivatives in water as a solvent. Use of nontoxic reaction components, short reaction times, easy work up and high yields are some important advantages of this method. PMID- 24061900 TI - Structural similarity between native proteins and chimera constructs obtained by inverting the amino Acid sequence. AB - The analysis of the symmetry of protein three-dimensional structures can be extremely useful in order to understand and classify the protein structural universe. The structures of proteins with back-traced amino acid sequence were modeled and compared to the structures of their native counterparts. Only in a very limited set of cases, the two objects showed a significant level of similarity. These extremely symmetric examples can be of any structural class and of any dimension. The lack of biunique "N to C" and "C to N" symmetry at the structural level mirrors that at the sequence level and we propose to design as a dlof symmetry the cases in which a protein structure is similar to its back traced variant. PMID- 24061901 TI - Reactions of 1,3-Diphenyl-2-pyrazolin-5-one and 4-Amino-1,5-dimethyl-2-phenyl-1H pyrazol-3(2H)-one. Synthesis of Some New Pyrazoles and Pyrazolones. AB - 1,3-Diphenyl-2-pyrazolin-5-one 1 was converted to 5-azido-4-formylpyrazolone 3 which is used as the key starting compounds of some new pyrazole derivatives 4-9. Also, 4-amino-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one 10 is coupled with some diazonium salts to give coloured products 11, and reacted with isocyanates and isothiocyanates to give pyrazolylurea and thiourea derivatives which are then reacted with organohalogen compounds under PTC conditions to give 13,14 while with some active methylene compounds yielded 15 via Michael 1,4-addition reaction. PMID- 24061902 TI - Extraction and DFT study on the complexation of k+ with a hexaarylbenzene - based polyaromatic receptor. AB - From extraction experiments and gamma-activity measurements, the exchange extraction constant corresponding to the equilibrium K+ (aq) + 1*Cs+(nb)sipky ⇄ 1*K+ (nb) + Cs+(aq) taking part in the two-phase water-nitrobenzene system (1 = hexaarylbenzene - based polyaromatic receptor; aq = aqueous phase, nb = nitrobenzene phase) was evaluated as log Kex (K+, 1*Cs+) = -1.0 +/- 0.1. Further, the stability constant of the hexaarylbenzene - based polyaromatic receptor * K+ complex (abbrev. 1*K+) in nitrobenzene saturated with water was calculated for a temperature of 25 degrees C: log betanb (1*K+) = 5.1 +/- 0.2. By using quantum mechanical DFT calculations, the most probable structure of the 1*K+ complex species was solved. In this complex having C3 symmetry, the cation K+ synergistically interacts with the polar ethereal oxygen fence and with the central hydrophobic benzene bottom via cation - pi interaction. Finally, the calculated binding energy of the resulting complex 1*K+ is -282.8 kJ mol-1, confirming the relatively high stability of the considered cationic complex species. PMID- 24061903 TI - A Facile One-Pot Synthesis of Functionalized 4,8-Dihydropyrano[3,2-b]-pyran-4 ones. AB - The reactive intermediates generated by the addition of alkyl isocyanides and dialkyl acetylenedicarboxylates were trapped by 5-hydroxy-2-hydroxymethyl-4H pyran-4-one (kojic acid) to yield functionalized 4,8-dihydropyrano[3,2-b]-pyran-4 ones at ambient temperature in good yields. PMID- 24061904 TI - Elastane addition impact on structural and transfer properties of viscose and polyacrylonitrile knits. AB - The objective of the research was to compare the porosity/compactness of the knitted structures made from viscose and polyacrylonitrile yarns with incorporated elastane and without elastane, respectively, and to evaluate the elastane addition impact to their moisture management and air permeability properties. The addition of elastane considerably reduces the wettability of the wet relaxed viscose knits, while it moderately increases the wettability of the wet relaxed polyacrylonitrile knits. The polyacrylonitrile knits exhibit distinctively better wickability than comparable viscose knits. When no elastane is added, air permeability is better for viscose knits while with the elastane addition, air permeability is better for polyacrylonitrile knits. PMID- 24061905 TI - Extraction of colour inkjet printing inks from printouts for forensic purpose. AB - The ability to differentiate between inkjet printing inks is of great interest in document examination. The aim of this work was to develop a procedure for effective ink extraction so that the ink could be reliably analyzed by capillary electrophoresis. Conditions such as type and composition of extracting mixtures, as well as duration of extraction and sonication procedures were taken into consideration. A set of different agents was used to extract inks of inkjet printers produced by Hewlett-Packard, Canon, Brother, Epson and Lexmark. Extraction efficiency was examined visually and then by means of UV/Vis spectrometry. It was ascertained that the most promising extracting agents are mixtures of borate buffer with SDS and with acetonitrile, or alternatively with methanol, which are both suitable background electrolytes for further CE analysis. However, in some exceptional cases, highly efficient extraction was achieved by a mixture of DMF, DMSO, EtOH and MEE with water. PMID- 24061906 TI - Pesticide residues in cauliflower, eggplant, endive, lettuce, pepper, potato and wheat of the slovene origin found in 2009. AB - In the year 2009, 170 cauliflower, eggplant, endive, lettuce, pepper, potato and wheat samples from Slovene producers were analysed for pesticide residues. The samples were analysed for the presence of 214 different active compounds using three analytical methods. MRL exceedances have not been observed, which is better than the results obtained from the monitoring of pesticide residues in the products of plant origin in the European Union, Norway, Iceland and Liechtenstein for the years 2004 to 2006. We have observed that MRL exceedances in Slovenia have been reduced in recent times. We assume that the farmers have learned how to use PPP safely in accordance with good agricultural practice. PMID- 24061907 TI - Spectrophotometric determination of acidity constants of some macrolides in acetonitrile-water binary mixtures. AB - The acidity constants of eight macrolides (erythromycin, roxithromycin, oleandomycin, azithromycin, josamycin, tylosin tartrate, tilmicosin and spiramycin) have been determined in acetonitrile-water binary mixtures (30%, 40% and 50% (v/v)) by spectrophotometric method. The pKa's available in literature determined by various methods are compiled in comparison with the value of this work. These results are expected to essentially facilitate the research on occurrence, fate and effects, analysis method development, and control of antibiotics in various treatment occurrences. PMID- 24061908 TI - Modeling potential time to event data with competing risks. AB - Patients receiving radical prostatectomy are at risk of metastasis or prostate cancer related death, and often need repeated clinical evaluations to determine whether additional adjuvant or salvage therapies are needed. Since the prostate cancer is a slowly progressing disease, and these additional therapies come with significant side effects, it is important for clinical decision making purposes to estimate a patient's risk of cancer metastasis, in the presence of a competing risk by death, under the hypothetical condition that the patient does not receive any additional therapy. In observational studies, patients may receive additional therapy by choice; the time to metastasis without any therapy is often a potential outcome and not always observed. We study the competing risks model of Fine and Gray (J Am Stat Assoc, 94:496-509, 1999) with adjustment for treatment choice by inverse probability censoring weighting (IPCW). The model can be fit using standard software for partial likelihood with double IPCW weights. The proposed methodology is used in a prostate cancer study to predict the post prostatectomy cumulative incidence probability of cancer metastasis without additional adjuvant or salvage therapies. PMID- 24061909 TI - An omnibus CUSUM chart for monitoring time to event data. AB - A non-parametric method is proposed for monitoring time-to-event data. A cumulative sum chart is constructed that is able to detect an unknown out-of control state. This method exploits the absolute differences between the Kaplan Meier estimator and the in-control distribution over specific time intervals. The efficiency of the algorithm is studied via a simulation and a real data study. The new method is also tested via the simulation study against existing methods. PMID- 24061910 TI - Tocilizumab for retinal vasoproliferative tumor secondary to juvenile idiopathic arthritis-associated uveitis: a case report. PMID- 24061911 TI - Endoglin and activin receptor-like kinase 1 heterozygous mice have a distinct pulmonary and hepatic angiogenic profile and response to anti-VEGF treatment. AB - Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia associated with dysregulated angiogenesis and arteriovascular malformations. The disease is caused by mutations in endoglin (ENG; HHT1) or activin receptor-like kinase 1 (ALK1; HHT2) genes, coding for transforming growth factor beta (TGF-beta) superfamily receptors. Vascular endothelial growth factor (VEGF) has been implicated in HHT and beneficial effects of anti-VEGF treatment were recently reported in HHT patients. To investigate the systemic angiogenic phenotype of Endoglin and Alk1 mutant mice and their response to anti-VEGF therapy, we assessed microvessel density (MVD) in multiple organs after treatment with an antibody to mouse VEGF or vehicle. Lungs were the only organ showing an angiogenic defect, with reduced peripheral MVD and secondary right ventricular hypertrophy (RVH), yet distinctly associated with a fourfold increase in thrombospondin-1 (TSP-1) in Eng (+/-) versus a rise in angiopoietin-2 (Ang-2) in Alk1 (+/-) mice. Anti-VEGF treatment did reduce lung VEGF levels but interestingly, led to an increase in peripheral pulmonary MVD and attenuation of RVH; it also normalized TSP-1 and Ang-2 expression. Hepatic MVD, unaffected in mutant mice, was reduced by anti-VEGF therapy in heterozygous and wild type mice, indicating a liver-specific effect of treatment. Contrast-enhanced micro ultrasound demonstrated a reduction in hepatic microvascular perfusion after anti VEGF treatment only in Eng (+/-) mice. Our findings indicate that the mechanisms responsible for the angiogenic imbalance and the response to anti-VEGF therapy differ between Eng and Alk1 heterozygous mice and raise the need for systemic monitoring of anti-angiogenic therapy effects in HHT patients. PMID- 24061913 TI - Monitoring side-chain dynamics of proteins using (2)H relaxation. AB - Nuclear magnetic resonance (NMR) is a powerful technique capable of monitoring a wide range of motions in proteins on a per residue basis. A variety of (2)H relaxation experiments have been developed for monitoring side-chain methyl group motions on the picosecond-nanosecond timescale. These experiments enable determination of the order parameter, S (2) axis, which reports on the rigidity of the C-CH3 bond for side-chain methyl groups. The application of a commonly used subset of these experiments is described in this chapter. It is intended to serve as a practical guide to investigators interested in monitoring side-chain motions. PMID- 24061912 TI - The first isolation of a cyanophage-Synechococcus system from the East China Sea. AB - A cyanophage strain and its host Synechococcus were isolated from the East China Sea. The host Synechococcus sp. SJ01 was characterized by its 16S rRNA, ITS, and psbA gene sequences as well as by its morphological appearance and pigmentation. The cyanophage, strain S-SJ2, was able to cause a lytic infection of the coastal Synechococcus. TEM of negative-stained specimens showed that the phage isolate has an isometric head with a diameter of 68 nm and a long tail with a length of 280 nm. The cyanophage-Synechococcus system from the East China Sea shares many properties with other marine cyanophage-Synechococcus systems worldwide. PMID- 24061914 TI - CPMG relaxation dispersion. AB - NMR relaxation is sensitive to molecular and internal motion of proteins. (15)N longitudinal relaxation rate (R 1), transverse relaxation rate (R 2), and {(1)H} (15)N Nuclear Overhauser Effect (NOE) experiments are often performed to globally elucidate protein dynamics, primarily on the sub-nanosecond timescale. In contrast, constant relaxation time R 2 dispersion experiments are applied to characterize protein equilibrium conformations that interconvert on the millisecond timescale. Information on local conformational equilibria of proteins provides important insights about protein energy landscapes and is useful to interpret molecular recognition mechanisms as well. Here, we describe a protocol for performing (15)N Carr-Purcell-Meiboom-Gill (CPMG) R 2 dispersion measurements in solution, including protein preparation, step-by-step experimental parameter settings, and the first step of data analysis. PMID- 24061915 TI - Confocal single-molecule FRET for protein conformational dynamics. AB - Single-molecule Forster-type resonance energy transfer (smFRET) is a unique technique capable of following conformational motions of individual protein molecules. The direct observation of individual proteins provides rich information that would be washed away in ensemble measurements, hence opening up new avenues for establishing the protein structure-function relationships through dynamics. Retrieving dynamics information of biomolecular motions via smFRET, though, requires careful experiment design and rigorous treatment of single molecule statistics. Here, we describe the rudimentary steps for an smFRET experiment, including sample preparation for the microscope, building of critical parts for single-molecule FRET detection, and a robust methodology for photon-by photon data analysis. PMID- 24061916 TI - Protein structural dynamics revealed by site-directed spin labeling and multifrequency EPR. AB - Multifrequency electron paramagnetic resonance (EPR) of spin-labeled protein is a powerful spectroscopic technique to study protein dynamics on the rotational correlation time scale from 100 ps to 100 ns. Nitroxide spin probe, attached to cysteine residue, reports on local topology within the labeling site, dynamics of protein domains reorientation, and protein global tumbling in solution. Due to spin probe's magnetic tensors anisotropy, its mobility is directly reflected by the EPR lineshape. The multifrequency approach significantly decreases ambiguity of EPR spectra interpretation. The approach, described in this chapter, provides a practical guideline that can be followed to carry out the experiments and data analysis. PMID- 24061917 TI - Probing backbone dynamics with hydrogen/deuterium exchange mass spectrometry. AB - Protein dynamics can be probed by the solution technique amide hydrogen/deuterium exchange. The exchange rate of hydrogen for deuterium along a peptide backbone is dependent on the extent of hydrogen bonding from secondary structure, accessibility by D2O, and protein motions. Both global and local conformational changes that alter bonding or structure will lead to changes in the amount of deuterium incorporated. The deuterium can be localized via pepsin digestion of the protein and quantified by electrospray ionization mass spectrometry through the mass shifts of the resulting peptides. The technique is emerging as an essential tool to study protein structure in solution due to the exceptional capability of examining both dynamic and structural changes related to protein function. PMID- 24061918 TI - Carbon-deuterium bonds as non-perturbative infrared probes of protein dynamics, electrostatics, heterogeneity, and folding. AB - Vibrational spectroscopy is uniquely able to characterize protein dynamics and microenvironmental heterogeneity because it possesses an inherently high temporal resolution and employs probes of ultimately high structural resolution-the bonds themselves. The use of carbon-deuterium (C-D) bonds as vibrational labels circumvents the spectral congestion that otherwise precludes the use of vibrational spectroscopy to proteins and makes the observation of single vibrations within a protein possible while being wholly non-perturbative. Thus, C D probes can be used to site-specifically characterize conformational heterogeneity and thermodynamic stability. C-D probes are also uniquely useful in characterizing the electrostatic microenvironment experienced by a specific residue side chain or backbone due to its effect on the C-D absorption frequency. In this chapter we describe the experimental procedures required to use C-D bonds and FT IR spectroscopy to characterize protein dynamics, structural and electrostatic heterogeneity, ligand binding, and folding. PMID- 24061919 TI - Balancing bond, nonbond, and go-like terms in coarse grain simulations of conformational dynamics. AB - Characterization of the protein conformational landscape remains a challenging problem, whether it concerns elucidating folding mechanisms, predicting native structures or modeling functional transitions. Coarse-grained molecular dynamics simulation methods enable exhaustive sampling of the energetic landscape at resolutions of biological interest. The general utility of structure-based models is reviewed along with their differing levels of approximation. Simple Go models incorporate attractive native interactions and repulsive nonnative contacts, resulting in an ideal smooth landscape. Non-Go coarse-grained models reduce the parameter set as needed but do not include bias to any desired native structure. While non-Go models have achieved limited success in protein coarse-graining, they can be combined with native structured-based potentials to create a balanced and powerful force field. Recent applications of such Go-like models have yielded insight into complex folding mechanisms and conformational transitions in large macromolecules. The accuracy and usefulness of reduced representations are also revealed to be a function of the mathematical treatment of the intrinsic bonded topology. PMID- 24061920 TI - A tutorial on building markov state models with MSMBuilder and coarse-graining them with BACE. AB - Markov state models (MSMs) are a powerful means of (1) making sense of molecular simulations, (2) making a quantitative connection between simulation and experiment, and (3) driving efficient simulations. A Markov model can be thought of as a map of the conformational space a molecule explores. Instead of having towns and cities connected with roads labeled with speed limits, a Markov model has conformational states and probabilities of transitioning between pairs of these states. This tutorial describes how to build Markov models and a few of the basic analyses that can be performed with the MSMBuilder software package. PMID- 24061921 TI - Analysis of protein conformational transitions using elastic network model. AB - In this chapter, we demonstrate the usage of a coarse-grained elastic network model to analyze protein conformational transitions in the NS3 helicase (NS3hel) of Hepatitis C virus (HCV). This analysis allows us to identify and visualize collective domain motions involved in the conformational transitions and predict the order of structural events during the transitions. It is highly efficient and applicable to many multi-domain protein structures which undergo large conformational changes to fulfill their functions. This method is made available through a Web server ( http://enm.lobos.nih.gov ). PMID- 24061922 TI - Geometric simulation of flexible motion in proteins. AB - This chapter describes the use of physically simplified analysis and simulation methods-pebble-game rigidity analysis, coarse-grained elastic network modeling, and template-based geometric simulation-to explore flexible motion in protein structures. Substantial amplitudes of flexible motion can be explored rapidly in an all-atom model, retaining realistic covalent bonding, steric exclusion, and a user-defined network of noncovalent polar and hydrophobic interactions, using desktop computing resources. Detailed instructions are given for simulations using FIRST/FRODA software installed on a UNIX/Linux workstation. Other implementations of similar methods exist, particularly NMSim and FRODAN, and are available online. Topics covered include rigidity analysis and constraints, geometric simulation of flexible motion, targeting between known structures, and exploration of motion along normal mode eigenvectors. PMID- 24061923 TI - Principal component analysis: a method for determining the essential dynamics of proteins. AB - It has become commonplace to employ principal component analysis to reveal the most important motions in proteins. This method is more commonly known by its acronym, PCA. While most popular molecular dynamics packages inevitably provide PCA tools to analyze protein trajectories, researchers often make inferences of their results without having insight into how to make interpretations, and they are often unaware of limitations and generalizations of such analysis. Here we review best practices for applying standard PCA, describe useful variants, discuss why one may wish to make comparison studies, and describe a set of metrics that make comparisons possible. In practice, one will be forced to make inferences about the essential dynamics of a protein without having the desired amount of samples. Therefore, considerable time is spent on describing how to judge the significance of results, highlighting pitfalls. The topic of PCA is reviewed from the perspective of many practical considerations, and useful recipes are provided. PMID- 24061924 TI - A case study comparing quantitative stability-flexibility relationships across five metallo-beta-lactamases highlighting differences within NDM-1. AB - The Distance Constraint Model (DCM) is an ensemble-based biophysical model that integrates thermodynamic and mechanical viewpoints of protein structure. The DCM outputs a large number of structural characterizations that collectively allow for Quantified Stability-Flexibility Relationships (QSFR) to be identified and compared across protein families. Using five metallo-beta-lactamases (MBLs) as a representative set, we demonstrate how QSFR properties are both conserved and varied across protein families. Similar to our characterizations on other protein families, the backbone flexibility of the five MBLs are overall visually conserved, yet there are interesting specific quantitative differences. For example, the plasmid-encoded NDM-1 enzyme, which leads to a fast spreading drug resistant version of Klebsiella pneumoniae, has several regions of significantly increased rigidity relative to the other four. In addition, the set of intramolecular couplings within NDM-1 are also atypical. While long-range couplings frequently vary significantly across protein families, NDM-1 is distinct because it has limited correlated flexibility, which is isolated within the active site S3/S4 and S11/H6 loops. These loops are flexibly correlated in the other members, suggesting it is important to function, but the others also have significant amounts of correlated flexibility throughout the rest of their structures. PMID- 24061925 TI - Towards comprehensive analysis of protein family quantitative stability flexibility relationships using homology models. AB - The Distance Constraint Model (DCM) is a computational modeling scheme that uniquely integrates thermodynamic and mechanical descriptions of protein structure. As such, quantitative stability-flexibility relationships (QSFR) that describe the interrelationships of thermodynamics and mechanics can be quickly computed. Using comparative QSFR analyses, we have previously investigated these relationships across a small number of protein orthologs, ranging from two to a dozen [1, 2]. However, our ultimate goal is provide a comprehensive analysis of whole protein families, which requires consideration of many more structures. To that end, we have developed homology modeling and assessment protocols so that we can robustly calculate QSFR properties for proteins without experimentally derived structures. The approach, which is presented here, starts from a large ensemble of potential homology models and uses a clustering algorithm to identify the best models, thus paving the way for a comprehensive QSFR analysis across hundreds of proteins in a protein family. PMID- 24061926 TI - Using the COREX/BEST server to model the native-state ensemble. AB - Protein structures under normal conditions exist as ensembles of interconverting, transient microstates. A computer algorithm known as COREX/BEST (Biology using Ensemble-based Structural Thermodynamics) was developed to model microstate structures and describe the native ensembles of proteins in statistical thermodynamic terms. This algorithm has been tested extensively and validated through experimental comparisons examining a range of biophysical and functional phenomena, such as structural cooperativity, pH-dependent stability, and cold denaturation. Here, we describe a Web-based implementation of the COREX/BEST algorithm, called the COREX/BEST Server, and demonstrate how to use this online resource to characterize the structural and thermodynamic properties of the native protein ensemble. PMID- 24061927 TI - Morphing methods to visualize coarse-grained protein dynamics. AB - Morphing was initially developed as a cinematic effect, where one image is seamlessly transformed into another image. The technique was widely adopted by biologists to visualize the transition between protein conformational states, generating an interpolated pathway from an initial to a final protein structure. Geometric morphing seeks to create visually suggestive movies that illustrate structural changes between conformations but do not necessarily represent a biologically relevant pathway, while minimum energy path (MEP) interpolations aim at describing the true transition state between the crystal structure minima in the energy landscape. PMID- 24061928 TI - Contrasting preferences of arbuscular mycorrhizal and dark septate fungi colonizing boreal and subarctic Avenella flexuosa. AB - Arbuscular mycorrhizal (AM) and dark septate endophytic (DSE) fungi are ubiquitous in grass roots, but their colonizations may vary according to latitudinal gradient and site conditions. We investigated how vegetation zone (boreal vs. subarctic), humus thickness, and site openness affect root fungal colonizations of the grass Avenella flexuosa. More precisely, we hypothesized that AM and DSE fungal colonizations would have different responses to environmental conditions such that AM fungi could be more common in boreal zone, whereas we expected DSE fungi to be more affected by the amount of humus. We found site openness to affect AM and DSE fungi in a contrasting manner, in interaction with the vegetation zone. AM colonization was high at open coastal dunes, whereas DSE fungi were more common at forested sites, in the boreal zone. Humus thickness affected AM fungi negatively and DSE fungi positively. To conclude, the observed AM and DSE fungal colonization patterns were largely contrasting. AM fungi were favored in seashore conditions characterized by thin humus layer, whereas DSE fungi were favored in conditions of higher humus availability. PMID- 24061930 TI - Build your own social network laboratory with Social Lab: a tool for research in social media. AB - Social networking has surpassed e-mail and instant messaging as the dominant form of online communication (Meeker, Devitt, & Wu, 2010). Currently, all large social networks are proprietary, making it difficult to impossible for researchers to make changes to such networks for the purpose of study design and access to user generated data from the networks. To address this issue, the authors have developed and present Social Lab, an Internet-based free and open-source social network software system available from http://www.sociallab.es . Having full availability of navigation and communication data in Social Lab allows researchers to investigate behavior in social media on an individual and group level. Automated artificial users ("bots") are available to the researcher to simulate and stimulate social networking situations. These bots respond dynamically to situations as they unfold. The bots can easily be configured with scripts and can be used to experimentally manipulate social networking situations in Social Lab. Examples for setting up, configuring, and using Social Lab as a tool for research in social media are provided. PMID- 24061929 TI - A highly oriented hybrid microarray modified electrode fabricated by a template free method for ultrasensitive electrochemical DNA recognition. AB - Highly oriented growth of a hybrid microarray was realized by a facile template free method on gold substrates for the first time. The proposed formation mechanism involves an interfacial structure-directing force arising from self assembled monolayers (SAMs) between gold substrates and hybrid crystals. Different SAMs and variable surface coverage of the assembled molecules play a critical role in the interfacial directing forces and influence the morphologies of hybrid films. A highly oriented hybrid microarray was formed on the highly aligned and vertical SAMs of 1,4-benzenedithiol molecules with rigid backbones, which afforded an intense structure-directing power for the oriented growth of hybrid crystals. Additionally, the density of the microarray could be adjusted by controlling the surface coverage of assembled molecules. Based on the hybrid microarray modified electrode with a large specific area (ca. 10 times its geometrical area), a label-free electrochemical DNA biosensor was constructed for the detection of an oligonucleotide fragment of the avian flu virus H5N1. The DNA biosensor displayed a significantly low detection limit of 5 pM (S/N = 3), a wide linear response from 10 pM to 10 nM, as well as excellent selectivity, good regeneration and high stability. We expect that the proposed template-free method can provide a new reference for the fabrication of a highly oriented hybrid array and the as-prepared microarray modified electrode will be a promising paradigm in constructing highly sensitive and selective biosensors. PMID- 24061931 TI - Global self-esteem and method effects: competing factor structures, longitudinal invariance, and response styles in adolescents. AB - The Rosenberg Self-Esteem Scale (RSES) is a widely used measure for assessing self-esteem, but its factor structure is debated. Our goals were to compare 10 alternative models for the RSES and to quantify and predict the method effects. This sample involves two waves (N =2,513 9th-grade and 2,370 10th-grade students) from five waves of a school-based longitudinal study. The RSES was administered in each wave. The global self-esteem factor with two latent method factors yielded the best fit to the data. The global factor explained a large amount of the common variance (61% and 46%); however, a relatively large proportion of the common variance was attributed to the negative method factor (34 % and 41%), and a small proportion of the common variance was explained by the positive method factor (5% and 13%). We conceptualized the method effect as a response style and found that being a girl and having a higher number of depressive symptoms were associated with both low self-esteem and negative response style, as measured by the negative method factor. Our study supported the one global self-esteem construct and quantified the method effects in adolescents. PMID- 24061932 TI - Health policy basics: health insurance marketplaces. AB - Starting on 1 October 2013, most individuals and small businesses will be able to shop for and enroll in health insurance coverage through their state's health insurance marketplace, also known as an exchange. The health insurance marketplaces will serve as a one-stop resource to help the uninsured and the underinsured find comprehensive health coverage that fits their needs and budget and determine whether they qualify for health insurance tax credits provided by the Patient Protection and Affordable Care Act. Physicians may benefit because insured patients are more likely to have a regular source of care, adhere to medical regimens, and access preventive care. However, implementation of the marketplaces may prove challenging if enrollment numbers are insufficient, technical problems arise, and patients are unable to access providers. Despite these potential issues, physicians are encouraged to educate themselves about how the marketplaces work so they can direct their patients to find the coverage that best meets their medical needs. PMID- 24061933 TI - Comparison of the 1987 American College of Rheumatology and the 2010 American College of Rheumatology/European League against Rheumatism criteria for classification of rheumatoid arthritis in the Nurses' Health Study cohorts. AB - Performance of rheumatoid arthritis (RA) classification by the 2010 American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) criteria, compared to the 1987 ACR criteria, has not been assessed in population based cohorts in which disease identification is by mailed questionnaire. Women followed in the Nurses' Health Study and Nurses' Health Study II cohorts self reported new doctor-diagnosed RA on biennial questionnaires. Two RA experts reviewed medical records of 128 new RA self-reports to obtain individual 1987 and 2010 criteria and arrived at a consensus opinion. We compared agreement in classification by the two criteria sets (kappa), and calculated sensitivity and specificity, with reviewers' opinion as gold standard. Ninety-eight (77%) participants were classified as RA by reviewers' consensus opinion; 98 (77%) fulfilled 1987 criteria, while 79 (63%) fulfilled 2010 criteria. Seventy-two (56%) were classified as RA by both sets, 21 (16%) by neither, 26 (20%) by only 1987 criteria, and 9 (7%) by only 2010 criteria. Kappa for concordance was 0.36 (95% CI 0.20-0.53). Compared to reviewer's opinion, sensitivity and specificity were 0.93 and 0.77 for 1987 criteria, and 0.79 and 0.87 for 2010 criteria. Participants fulfilling 1987 criteria only were more likely to be seronegative. In these prospective population-based cohorts, significant discordance between 1987 ACR and 2010 ACR/EULAR criteria for classifying RA exists. Using the 2010 ACR/EULAR criteria alone had decreased sensitivity, and seronegative RA cases would be excluded in particular. Combined use of both will be necessary to maximize inclusion and allow sensitivity analyses. PMID- 24061934 TI - Effect of temperature on swimming performance of juvenile Schizothorax prenanti. AB - The migration of Schizothorax prenanti, an ecologically important and commercially valuable species, is impeded by dams. Effective fishways would contribute to conservation of wild populations, and swimming performance data are necessary for fishway design. The swimming performance of S. prenanti was investigated at four temperatures (15, 19, 23, 27 degrees C), and numerical models were used to characterize the effect of temperature on swimming performance. As temperature increases, critical swimming speed (U crit) increases from 15 to 23 degrees C and then decreases significantly. The highest U crit (7.71 BL/s) occurs at 24 degrees C, as estimated by interpolation. Swimming efficiency was similar from 19 to 23 degrees C, but decreases significantly at 27 degrees C. The temperature range 15-23 degrees C is suitable for S. prenanti. However, the excess post-exercise oxygen consumption values of Q 10 for the four temperature increments indicate that 19-23 degrees C is the optimal range for swimming performance. Maximum tail beat amplitude increased >25 % (0.35 0.45 BL) over the temperature range considered, but variation of tail beat frequency was erratic. White muscle fiber begins to contribute to swimming at swimming speeds ~40 % U crit at the lower three temperatures, but increases to almost 60 % at 27 degrees C, and the contribution is relatively small. The results of this investigation advance the knowledge of fish metabolism while swimming provides data critical for fishway design. PMID- 24061936 TI - The Characterization and Potential use of G-CSF Dimers and their Pegylated Conjugates. AB - G-CSF successfully prevents chemotherapy-induced neutropenia. Two second generation drugs with improved therapeutic properties are already available and the development of new forms is still ongoing. For an efficient receptor dimerization two G-CSF molecules have to bind. Development of G-CSF dimers acting as receptor dimerizers was explored and their potential use evaluated. The in vitro biological activities of the prepared dimers were lower than G-CSF monomer activity, presumably due to non-optimal spatial orientation of the molecules. Most likely two dimers had to bind to trigger receptor dimerization instead of one dimer acting as a dimerizer. Although significantly lower in the residual in vitro biological activity, the diPEG-Fdim conjugate exhibited pharmacokinetical (PK) and pharmacodynamical (PD) properties comparable to pegfilgrastim or even better. An interesting PD profile with the second maximum in absolute neutrophil count (ANC) and a balanced elevated ANC profile over the longer time interval was namely observed. PMID- 24061935 TI - Morphologic study of the liver of lambari (Astyanax altiparanae) with emphasis on the distribution of cytokeratin. AB - Studies on the morphology of the liver of teleosts reflect some controversy in the interpretation of the data, but also provide confirmation of variations in the structure of the organ in several species. Thus, we intend to understand the specific structural organization of the liver of Astyanax altiparanae. Specimens were collected in the city of Andira, Parana, Brazil. The livers were processed according to histological routine for inclusion in Paraplast, and the sections were stained with HE and Mallory's trichrome or followed the protocol for fluorescence immunohistochemistry, anti-cytokeratin. The liver of A. altiparanae was covered by a capsule of connective tissue, without delimiting lobes. The hepatocytes had an arrangement in cords around sinusoids. Melanomacrophage centers were observed. The vascular components and intrahepatic pancreatic acini were distributed between hepatocytes. Presence of cytokeratin was detected in tissues that lined the liver and endothelial cells of sinusoids. The comparison of the liver of A. altiparanae to other characids corroborates with the fact that there is variation in the morphology of the liver even between closely related species. Moreover, it appears that in this species, endothelial cells of sinusoids can synthesize the cytokeratin filaments required for the regulation of blood flow in capillaries in adults. PMID- 24061937 TI - Tele-substitutions in Heterocyclic Chemistry. AB - Particular and rare examples of aromatic nucleophilic substitution are described as tele-substitution. Usually strong nucleophiles are involved and the entering group is introduced at a position distant from the expected leaving group. Examples of tele-substitution in various heteroaromatic systems are presented. PMID- 24061938 TI - Production of Melamine-Formaldehyde PCM Microcapsules with Ammonia Scavenger used for Residual Formaldehyde Reduction. AB - Paraffinic phase change materials (PCM) were microencapsulated by in situ polymerization of melamine-formaldehyde prepolymers. Partly methylated trimethylolmelamine was used as an aminoaldehyde prepolymer for the microcapsule wall, a styrene-maleic acid anhydride copolymer as an emulsifier and modifying agent, and ammonia as a scavenger for reducing residual formaldehyde. For the determination of residual formaldehyde in a ppm concentration range, EDANA and malachite green analytical methods were studied, and the EDANA 210.1-99 was applied for the determination of residual formaldehyde in 25 samples of microcapsules, produced in a 200-L reactor. A linear correlation was observed between the added ammonia scavenger concentration and the reduction of residual formaldehyde concentration. Compared with 0.45% (4500 ppm) formaldehyde in a non treated microcapsule suspension, with ammonia scavenger concentrations 0.80, 0.90 and 1.35%, the concentration of residual formaldehyde dropped to 0.27, 0.20 and 0.09% (i.e. 2700, 2000 and 900 ppm), respectively. Morphological characterisation of microcapsules by SEM and microcapsule wall permeability measurements by gravimetry / mass loss at an elevated temperature (135 degrees C) suggested that ammonia positively contributed to the wall elasticity / durability, while microcapsules with no ammonia scavenger added tended to have more brittle walls, and were more prone to cracking. PMID- 24061939 TI - The Adsorption of Tetramethylthiourea at the Interface Electrode - NaClO4 in the Presence of Sodium 1-decanesulfonate. AB - Mixed adsorption layers properties made by two organic substances in which 1 decanesulfonic acid sodium salt undergoes physical adsorption and tetramethylthoiurea (TMTU) chemical adsorption in 1M NaClO4 on the mercury electrode are described. Based on differential capacity data - potential curves obtained at mercury electrode the double layers TMTU adsorption parameters were calculated whereas the adsorption constants were derived from pressure data as a function of electrode charge density and TMTU's bulk concentration. The interaction parameters point to weak repulsive interaction between the adsorbed TMTU molecules. The free adsorption energy was clearly smaller than in the detergent's absence. The potential drop rectilinear segments across the inner layer dependence on the relative surface excess were analyzed in order to calculate the electrostatic parameters of the inner layer. Zn2+ ions reduction in kinetic studies provided information concerning adsorption equilibrium at potentials distant from adsorption maximum. PMID- 24061940 TI - Dermatophyte Trichophyton mentagrophytes Produces Cysteine Protease Inhibitor. AB - The protein inhibitor of cysteine proteases was isolated from an important zoophilic dermatophyte species Trichophyton mentagrophytes (T. mentagrophytes) and partially characterized. The isolation process involved affinity chromatography, followed by ion-exchange chromatography and reverse phase high performance liquid chromatography. The fungal inhibitor appears to exist in a high (24 kDa) and low (12 kDa) molecular mass form. It inhibits proteolytic activity of papain, cathepsins B and L but not of cathepsin H or trypsin. Results of immunoblotting procedures indicate that sera of T. mentagrophytes infected rabbits contain antibodies against higher molecular mass forms of the inhibitor. Since no sequence homology has been found between partial protein sequences of T. mentagrophytes inhibitor and other known cysteine protease inhibitors so far, we can speculate that this inhibitor has some structurally unique characteristics. The T. mentagrophytes inhibitor shares some biochemical similarities (molecular mass, high and low molecular mass forms, inhibitory profiles) with clitocypin from Clitocybe nebularis and macrocypins from Macrolepiota procera. PMID- 24061941 TI - Unexpected Course of [2+3] Cycloaddition of 2-nitropropene to (Z)-C,N diphenylnitrone. AB - The [2+3] cycloaddition of 2-nitropropene to (Z)-C,N-diphenylnitrone leads to 3,4 trans-2,3-diphenyl-4-nitro-4-methyl- and 3,5-trans-2,3-diphenyl-5-nitro-5 methylisoxazolidines as primary reaction products. This, however, is not the only pathway of 2-nitropropene conversion. In the reaction conditions, the nitroalkene also undergoes isomerisation and the resulting trans- and cis-1-nitropropenes yield respective stereoisomeric 2,3-diphenyl-4-nitro-5-methylisoxazolidines in the reaction with (Z)-C,N-diphenylnitrone. PMID- 24061942 TI - A Fast Response Membrane Sensor based on Ethyl 1, 2, 3, 4-tetrahydro-6-methyl-4 phenyl-2-thioxopyrimidine-5-carboxylate for Detection of Lanthanum (III) Ions at Wide Concentration Range. AB - A PVC membrane La (III) ion-selective electrode has been constructed using ethyl1,2,3,4-tetrahydro-6-methyl-4-phenyl-2-thioxopyrimidine-5-carboxylate (ETMPTC) as a neutral ionophore. This electrode responds to La (III) ion with a sensitivity of 19.9 +/- 0.3 mV/decade over the range 9.3 * 10-8 to 1.0 * 10-1 M at pH 3.0-10.0. The limit of detection was 1.7 * 10-8 M. It has a response time of < 11s and can be used for at least 3 months without any divergence in potentials. The proposed electrode shows fairly good discrimination of La (III) ion from several cations. The effect of organic solvents on electrode response was examined. The results show that this electrode can be used in ethanol media until 20% (v/v) concentration without interference. The isothermal temperature coefficient of this electrode amounted to 0.00013 V/ degrees C. This sensor not only was used as an indicator electrode in potentiometric titration of lanthanum ion against EDTA but also was used to determination of La3+ concentration in the presence of certain interfering ions. PMID- 24061943 TI - Synthesis and antimicrobial activity of some new 1,3,4-thiadiazoles and 1,3,4 thiadiazines containing 1,2,4-Triazolo nucleus. AB - The desired fused ring system 3-(3-chlorophenyl)-6-aryl-5,6 dihydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 5a-j were synthesized by the reaction of 4-amino-5-(3-chlorophenyl)-4H-1,2,4-triazole-3-thiol and different aryl aldehydes in the presence of catalytic amount of p-TsOH in dry DMF, while 3 (3-chlorophenyl)-6-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 7a-j were synthesized by using 4-amino-5-(3-chlorophenyl)-4H-1,2,4-triazole-3-thiol and different phenacyl bromides in dry methanol. Their IR, 1H NMR, mass spectral data and elemental analyses were in accord with assigned structures. All the newly synthesized compounds were screened for their antimicrobial activity. Some of the compounds exhibited significant inhibition on bacterial and fungal growth as compared to standard drugs. PMID- 24061944 TI - Preparation and chromatographic evaluation of columns for reversed-phase liquid chromatography. AB - Column selection in reversed-phase liquid chromatography is still not a straightforward process. In this study, we have evaluated and compared the performance of several traditional C18 phases with polar-modified phases and found distinct differences in the chromatographic behavior between two groups, as well as a high degree of variability within each group. The polar-endcapped phases exhibit similar hydrophobic selectivity, higher hydrogen bonding capacities and silanol activity with reference to the conventional C18 columns. The polar-embedded phases displayed a greatly reduced hydrophobic nature and a significantly reduced silanol activity compared to the conventional C18 phases. It appears that ionic and/or dipole interactions play a significant role in the overall retention behavior of the polar-modified phases towards basic and acidic analytes. PMID- 24061945 TI - Electrochemical determination of acetaminophen in different pharmaceutical forms with gold nanoparticles carbon paste electrode. AB - The electrochemical behavior of acetaminophen on a gold nanoparticles (nAu) carbon paste electrode (CPE) was investigated. Cyclic voltammograms of acetaminophen with nAu-CPE exhibited two well defined redox waves for anodic and cathodic peak, respectively. The oxidation reaction of acetaminophen was studied with differential pulse voltammetry (DPV) and square wave voltammetry (SWV). The oxidation of acetaminophen occurs at 405 and 440 mV by DPV and SWV, respectively. Under the optimum pH of 4.7 in 0.1 mol l-1 Britton-Robinson (B-R) buffer solution, the DPV anodic peak current showed a linear relation versus acetaminophen concentration in the range of 5.0 * 10-8 -1.0 * 10-4 mol l-1 with a detection limit of 2.6 * 10-8 for DPV, and from 9.0 * 10-7 - 1.0 * 10-4 mol l-1 for SWV with a detection limit of 1.0 * 10-7. The performance of this modified electrode was verified by the determination of acetaminophen in dosage form tablet. The result obtained in the recovery study was comparable to its labeled. PMID- 24061946 TI - Cathodic adsorptive stripping voltammetric determination of prednisolone in pharmaceutical preparation and human urine. AB - Differential pulse cathodic adsorptive stripping voltammetric method was developed for the determination of prednisolone based on electrochemical reduction of the drug at a hanging mercury drop electrode (HMDE) in 0.04 M Britton-Robinson buffer pH 3.5. The peak current varied linearly over the concentration range 7.21-144.2 ng/ml prednisolone with limit of detection and limit of quantification of 3.95 and 13.17 ng/ml prednisolone, respectively. The proposed method was successfully applied for the determination of the drug in commercial tablets and spiked human urine samples. PMID- 24061947 TI - A New Ceramide Isolated from Ficus lutea Vahl (Moraceae). AB - In addition to benjaminamide (2), beta-amyrin, beta-amyrin acetate, lupeol, betulinic acid, beta-sitosterol glucoside, a new ceramide glycoside was isolated from the woods of Ficus lutea Vahl (Moraceae). Using mass fragmentation pattern, 1 and 2D NMR spectra and by comparison with published data, the new compound was characterized as 1-O-beta-D-glucopyranosyl-(2S,3R,5E,12E)-2N-[(2'R) hydroxyhexadecanoyl]-octadecasphinga-5,12-dienine (1a) for which the trivial name lutaoside was proposed. Some isolated compounds were evaluated for their antimicrobial activities. Compounds 1a and 2 showed some antimicrobial activity. PMID- 24061948 TI - A Facile One-pot Synthesis and Antimicrobial Activity of Pyrido [2,3 d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones. AB - A series of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones (8) has been synthesised via reaction of 5-substituted-2-thioxo-2,3-dihydro-1H-pyrido[2,3 d]pyrimidin-4-one (3) or its methylthio derivative 4 with hydrazonoyl chlorides 5. Alternative syntheses of products 8 were carried out either by reaction of enaminone 1 with 7-amino-1,3-disubstituted[1,2,4]triazolo[4,3-a]pyrimidin-5-one (10) or via the Japp-Klingemann reaction of compound 13. Both conventional thermal and microwave irradiation techniques were used for synthesis of the target products 8 and a comparative study of these techniques using triethylamine or chitosan, as basic catalysts, was carried out. The mechanisms of the reactions under investigation are discussed. In addition, the antimicrobial activity of the newly synthesized products was evaluated. PMID- 24061949 TI - Design and Synthesis of New Peptidomimetics as Potential Inhibitors of MurE. AB - With the continuing emergence and spread of multidrug-resistant bacteria, there is an urgent need for the development of new antimicrobial agents. One possible source of new antibacterial targets is the biosynthesis of the bacterial cell wall peptidoglycan. The assembly of the peptide stem is carried out by four essential enzymes, known as the Mur ligases (MurC, D, E and F). We have designed and synthesised a focused library of compounds as potential inhibitors of UDP-N acetylmuramoyl-L-alanyl-D-glutamate:L-lysine ligase (MurE) from Staphylococcus aureus. This was achieved using two approaches: (i) synthesis of transition-state analogues based on the methyleneamino core; and (ii) synthesis of MurE reaction product analogues. Two methyleneamino-based compounds are identified as initial hits for inhibitors of MurE. PMID- 24061950 TI - Synthesis and Biological Activity of New Series of N-[3-(1H-1,2,3-Benzotriazol-1 yl)propyl]-2-(substituted Phenyl)-3-Chloro-4-Oxo-1-Azetidinecarboxamide. AB - The synthesis of a new series of N-[3-(1H-1,2,3-benzotriazol-1-yl)propyl]-2-(4 substituted phenyl)-3-chloro-4-oxo-1-azetidinecarboxamides 4a-s has been executed from 1,2,3-benzotriazole as a starting material by conventional method. Compounds 4a-s were screened for their antibacterial, antifungal and antitubercular activities. Structures of all the synthesized compounds were confirmed by chemical and spectroscopic analyses such as IR, 1H NMR, 13C NMR and FAB mass spectroscopy. PMID- 24061951 TI - Development of an ion chromatographic method for determination of inorganic anions in surface water by using computer-assisted gradient optimization methodology. AB - This work focuses on computer-assisted gradient elution method development in inorganic anion analysis of surface water using ion chromatography. An integral elution model was applied to model gradient retention behavior based on isocratic experimental information. Applied optimization strategy incorporates in-house developed elimination criteria for optimal condition search routine with gradient retention modeling resulting in baseline separation within satisfactory run time. The reliability of developed method was extensively tested by carrying out a performance characteristics evaluation process. Based on the evaluation results it can be stated that the method developed shows more than satisfactory performance characteristics, proving that the applied computer-assisted method development process is a very useful alternative when surface waters differing in composition significantly have to be analyzed in a limited time frame. PMID- 24061952 TI - Presence of nonylphenols in plastic films and their migration into food simulants. AB - Nonylphenols (NP) possess estrogenic activities and may cause increased risk of cancerous and reproductive abnormalities in several living organisms. Despite their harmful nature, NPs are used as additives in food packaging material, especially plastic, which is the main food contact material in today's packaging landscape. According to the fact that food packaging is one of the major potential food contaminant sources regarding NPs, there is a need for more information on identifying and quantifying of these chemicals when migrating into food. Seventeen plastic films for food packaging were analyzed for the presence of NPs; nine of them were plastic films for deep freeze food packaging. We determined and quantified NPs by Gas Chromatography-Mass Spectrometry (GC-MS) using the internal standard method. All plastic films for deep freeze food packaging contained NPs within a concentration range from 11.9 to 43.7 mg/kg. We also studied the migration of NPs from three of the plastic films for deep freeze food packaging into food simulants. The migration of NPs from these plastic films into 95% ethanol and 10% ethanol was higher than the amount migrating into distilled water or 3% acetic acid. PMID- 24061953 TI - First Silver(I) - Complexes with Tetrazole Allyl Derivatives. Synthesis and Crystal Structure of [Ag2(C10H10N4S)2(H2O)2](BF4)2 and [Ag(C10H9ClN4S)(NO3)] pi Compounds (C10H10N4S and C10H9ClN4S - 5-(Allylthio)-1-phenyl- and 5-(Allylthio)-1 (4-chlorophenyl)-1H-tetrazole). AB - Crystalline silver(I) pi complexes [Ag2(atpt)2(H2O)2](BF4)2 (1) (atpt - 5 (allylthio)-1-phenyl-1H-tetrazole (C10H10N4S)) and [Ag(atcpt)(NO3)] (2) (atcpt - 5-(allylthio)-1-(4-chlorophenyl)-1H-tetrazole (C10H9ClN4S)) complexes have been obtained using silver salt and the organic ligands. Compounds were characterized by X-ray single crystal diffraction: for 1 space group P21/n, a = 10.4560(5), b = 11.4008(5), c = 12.7550(7) A, beta = 98.128(3) degrees , V = 1505.21(13) A3 at 200 K, Z = 2; for 2: space group P21/a, a = 8.6790(8), b = 13.7324(10), c = 12.4597(13) A, beta = 102.288(5) degrees , V = 1451.0(2) A3 at 200 K, Z = 4. In both structures silver(I) atoms possess a trigonal pyramidal coordination environment with essentially different coordination modes of organic ligands. The Ag(I) arrangement in 1 involves the N3 and N4 atoms of two adjacent atpt molecules, an olefin C=C bond and a water molecule at the apical position. In crystal structure of 2 two O atoms from NO3- anions occupy two equatorial position of silver(I) coordination polyhedron, and atcpt is attached to the metal centre through the N4 atom of tetrazole core only. The weakly bound C=C bond is located at the apical position of Ag(I) environment. PMID- 24061954 TI - Report on isoelectric focusing trial of erythropoietin profiling in two cancer patients during chemotherapy and darbepoetin treatment. AB - The level of erythropoietin, main regulator of erythropoiesis, is affected by hypoxia, anaemia, application of recombinant erythropoietin, chemotherapy and others. Isoelectric focusing (IEF) combined with double immunobloting is a method that enables distinct analysis of endogenous and recombinant erythropoietin isoforms. Aim of our study was to set up analysis of treatment effects on the pattern of endogenous erythropoietin in anaemic breast cancer patient. Urine and blood samples were collected during and after termination of the treatment and analysed by isoelectric focusing. Endogenous erythropoietin was found lower, but still detectable during darbepoetin treatment. Normal shift of erythropoietin isoforms between serum vs. urine, ordinary seen in healthy volunteers, was not observed indicating kidney damage. The patient was suffering from heavy proteinuria and had low Glomerular filtration rate indicating acute renal failure, probably caused by clinical status or cisplatin chemotherapy. IEF has not yet been used for follow up of erythropoietin profile in cancer patients. It enables to monitor the effects of treatment on the level of endogenous erythropoietin and indirectly indicates kidney function. PMID- 24061955 TI - Two nd-zn and sm-zn isonicotinic/nicotinic Acid complexes. AB - The 4f-3d heterometallic complexes [Nd(L)3(H2O)2]2(ZnCl4)3n * 4nH2O (1) (L = isonicotinic acid) and [Sm(L')3(H2O)2]2(ZnCl4)n * 2nH2O (2) (L' = nicotinic acid) have been obtained by hydrothermal reactions and structurally characterized by X ray single-crystal diffractions. Both complexes feature an infinite 1-D polycationic chain-like structure. Photoluminescent investigations reveal that both complexes display totally different emissions. The emission of complex 1 is attributed to the pi -> pi* charge-transfer interaction of the isonicotinic acid. Complex 2 exhibits emissions in a wide range, and the emissions are ascribed to the characteristic emissions of 4G5/2 -> 6HJ (J = 5/2, 7/2, 9/2, 11/2) of Sm3+ ions. PMID- 24061956 TI - Preparation and Reactivity of 5-benzylidenebarbituric and 5-benzylidene-2 thiobarbituric Acids. AB - The reaction between barbituric acid or 2-thiobarbituric acid and different benzaldehydes, dependent upon the applied reaction conditions, selectively yields three different product types, i.e. 5-benzylidene(thio)barbituric acids II, symetric Michael adducts III or 5-phenyl-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H) diones and 5-phenyl-2-thioxo-2,3-dihydro-1H-pyrano[2,3-d]pyrimidin-4(5H)-ones IV. The reaction mechanisms and reactivity of different benzaldehydes are discussed. PMID- 24061957 TI - Anaerobic digestion of brewery spent grain in a semi-continuous bioreactor: inhibition by phenolic degradation products. AB - In this study anaerobic digestion of selected lignocellulosic substrate, namely brewery spent grain (BSG), was studied. In order to facilitate anaerobic digestion several types of pretreatment methods were tested such as: mechanical, chemical (alkali and acid) and thermo-chemical. The anaerobic digestion experiments were carried out in a semi-continuous stirred bioreactors with the organic loading rates between 2.9 and 3.9 kgCOD m-3 d-1 (1.9 and 2.5 kgVSS m-3 d 1 respectively) and corresponding hydraulic retention times of 33-39 days. Biogas production and composition, pH, COD, TSS and VSS, short chain fatty acids and phenolic compounds were measured. A significant inhibition of biogas production occurred, depending on the type of substrate pretreatment. There are indications that p-cresol is responsible for process inhibition when its concentration in the reaction mixture exceeds critical value between 115 and 240 mg L-1. Anaerobic digestion of chemically pretreated BSG (acid and alkali) and untreated-raw BSG was inhibited between the days 56 and 63 of the experiment, followed by thermo chemically pretreated BSG on day 112 and mechanically pretreated BSG on day 126. Analyses of the substrates showed no phenolic compounds either in raw-untreated BSG or pretreated substrates, therefore the recorded p-cresol is an intermediate degradation product, responsible for process inhibition. PMID- 24061958 TI - In Situ Synthesis, Crystal Structure and Fluorescence of Zn(C5H4NCO2H)2(H2O)2 * 2Cl. AB - Zn(C5H4NCO2H)2(H2O)2 * 2Cl (1) has been synthesized in situ via hydrothermal reaction and characterized by single crystal X-ray diffraction. The crystal belongs to monoclinic, space group P21/c with a = 6.342(2), b = 10.164(3), c = 13.717(4) A, beta = 113.62(1) degrees , C12H14Cl2N2O6Zn, Mr = 418.54, V = 810.1(4) A3, Z = 2, Dc = 1.716 g/cm3, S = 1.063, u(MoKalpha) = 1.875 mm-1, F(000) = 424, R = 0.0276 and wR = 0.0780. The crystal structure analysis of 1 reveals that the title compound features a structure consisting of isolated units, based on discrete chloride ions and octahedral zinc cations six-coordinated by four oxygen and two nitrogen atoms. The chloride ions and [Zn(C5H4NCO2H)2(H2O)2]2+ moieties are interconnected by hydrogen bonding interactions to yield a 3-D supramolecular framework. Luminescent investigation reveals an emission in blue region, which may be originating from pi->pi* charge-transfer interaction of the pyridine-2-carboxylic acid. PMID- 24061959 TI - General Microbial Community Flexibility in Biochemical Methane Potential Assay is Highly Correlated to Initial Biogas Production Rates. AB - Degradation of brewery spent grain as a novel test substrate was explored in routine biochemical methane potential assays (BMP) using three different inocula. Significant differences in the initial biogas production rates from spent grain, methane yield coefficients and final spent grain degradation were observed between inocula. Initial and developed communities degrading novel substrate showed significant differences in archaeal community fingerprints. Differences were observed irrespective of substrate identity (no substrate, glucose, spent grain) providing evidence of a significant general influence of BMP incubation on the microbial phylotypes. A linear relationship between microbial community flexibility in BMP assay and corresponding initial biogas production rates was identified as a novel parameter to diagnose anaerobic processes, particularly under dynamic conditions like start-up. PMID- 24061960 TI - Solvent Extraction of Strontium into Nitrobenzene by Using a Synergistic Mixture of Hydrogen Dicarbollylcobaltate and Dibenzo-30-crown-10. AB - Extraction of microamounts of strontium by a nitrobenzene solution of hydrogen dicarbollylcobaltate (H+B-) in the presence of dibenzo-30-crown-10 (DB30C10, L) has been investigated. The equilibrium data have been explained assuming that the species HL+, SrL2+, SrHL3+ and SrHL3+2 are extracted into the organic phase. The values of extraction and stability constants of the cationic complexes in nitrobenzene saturated with water have been determined. PMID- 24061961 TI - A DNA origami of slovenia in nano dimensions. AB - The principle of the rapidly evolving DNA nanotechnology is the design of nanostructures based only on the Watson-Crick base pairing and the oligonucleotide sequence. DNA origami technique is able to produce a variety of different shapes by constraining a long single stranded DNA molecule with a large number of short oligonucleotides. We designed 227 short oligonucleotides in order to scaffold the long strand of M13 bacteriophage single-stranded DNA into the shape of Slovenia. After annealing DNA origamis of Slovenia were observed by atomic force microscopy showing that most of the structures followed the design. Our results demonstrate that DNA origami technique can be used for construction of irregular asymmetric shapes with curvy edges and prove the feasibility of this technique. PMID- 24061962 TI - Rapid and sensitive analytical method for monitoring of 12 organotin compounds in natural waters. AB - A rapid analytical method for the simultaneous determination of 12 different organotin compounds (OTC): methyl-, butyl-, phenyl- and octyl-tins in natural water samples was developed. It comprises of in situ derivatisation (by using NaBEt4) of OTC in salty or fresh water sample matrix adjusted to pH 6 with Tris citrate buffer, extraction of ethylated OTC into hexane, separation of OTC in organic phase on 15 m GC column and subsequent quantitative determination of separated OTC by ICP-MS. To optimise the pH of ethylation, phosphate, carbonate and Tris-citrate buffer were investigated alternatively to commonly applied sodium acetate - acetic acid buffer. The ethylation yields in Tris-citrate buffer were found to be better for TBT, MOcT and DOcT in comparison to commonly used acetate buffer. Iso-octane and hexane were examined as organic phase for extraction of ethylated OTC. The advantage of hexane was in its ability for quantitative determination of TMeT. GC column of 15 m in length was used for separation of studied OTC under the optimised separation conditions and its performances compared to 30 m column. The analytical method developed enables sensitive simultaneous determination of 12 different OTC and appreciably shortened analysis time in larger series of water samples. LOD's obtained for the newly developed method ranged from 0.05-0.06 ng Sn L-1 for methyl-, 0.11-0.45 ng Sn L-1 for butyl-, 0.11-0.16 ng Sn L-1 for phenyl-, and 0.07-0.10 ng Sn L-1 for octyl-tins. By applying the developed analytical method, marine water samples from the Northern Adriatic Sea containing mainly butyl- and methyl-tin species were analysed to confirm the proposed method's applicability. PMID- 24061963 TI - Role of zinc in the regulation of autophagy during ethanol exposure in human hepatoma cells. AB - Faulty autophagy has been linked to various diseases including neurodegenerative disorders, diabetes, and cancer. Increasing evidence support the notion that activation of autophagy protects against ethanol-induced steatosis and liver injury. Herein, we investigated the role of zinc in autophagy in human hepatoma cells VL-17A exposed or not to ethanol. LC3II/LC3I ratio, p62, and Beclin-1 expression and autophagosomes number were determined in cells incubated in medium containing various concentrations of zinc with or without ethanol. In addition, labile zinc and mRNA expression of metallothionein and the zinc transporters SLC39A8, SLC39A14, and SLC30A10 were evaluated in cells exposed to ethanol and the autophagy inhibitor 3-methyladenine. Zinc depletion caused a significant suppression of autophagy in cells. Conversely, zinc addition to medium stimulated autophagy in cells. Moreover, cotreatment with ethanol and excess zinc (40 MUM) had an additive effect on the induction of autophagy. 3-methyadenine treatment decreased labile zinc, but this effect was more pronounced in cells exposed to ethanol. Lastly, ethanol and 3-methyladenine caused significant changes in the expression of metallothionein and zinc transporters. The results from this study support the hypothesis that zinc is critical for autophagy under basal conditions and during ethanol exposure. PMID- 24061964 TI - Arsenic trioxide co-exposure potentiates benzo(a)pyrene genotoxicity by enhancing the oxidative stress in human lung adenocarcinoma cell. AB - Although both arsenic trioxide (As2O3) and benzo(a)pyrene (BaP) are well established human carcinogens, the interaction between As2O3 and BaP is synergistic or antagonistic remains controversial in terms of the existing studies. In addition, the mechanisms responsible for the combined effects are still unclear. In this study, we examined the potential interactive effects between As2O3 (1, 5, and 10 MUM) and BaP (5, 10, and 20 MUM) in cultured A549 cells by treating with BaP and As2O3 alone or in combination at various concentrations for 24 h. The single and combined effects of As2O3 and BaP on the cytotoxicity, DNA/chromosomal damage, and oxidative stress were examined by using tetrazolium (3-(4,5-dimethyithiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) dye colorimetric assay, colony formation assay, fluorescence probe, chemical colorimetry, comet assay as well as micronucleus test. Our results showed that As2O3 synergistically enhanced the cytotoxicity, genotoxicity, and level of oxidative stress induced by BaP at various tested concentrations. Also, our experimental results showed that intracellular glutathione (GSH) contents were increased by various doses of BaP, but single or cotreatment with As2O3 significantly decreased the GSH level in the cells at all tested concentrations. Taken together, our results suggest that As2O3 may exert its synergistic cyto- and genotoxic effects with BaP mainly via elevated intracellular reactive oxygen species and reduced GSH contents and superoxide dismutase activities, thus promoting high level of oxidative stress, which may be a pivotal mechanism underlying As2O3 cocarcinogenic action. PMID- 24061965 TI - Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([(18)F]AV-133). AB - The 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP)-induced parkinsonism model, particularly in non-human primates, remains the gold-standard for studying the pathogenesis and assessing novel therapies for Parkinson's disease. However, whether the loss of dopaminergic neurons in this model is progressive remains controversial, mostly due to the lack of objective in vivo assessment of changes in the integrity of these neurons. In the present study, parkinsonism was induced in cynomolgus monkeys by intravenous administration of MPTP (0.2 mg/kg) for 15 days; stable parkinsonism developed over 90 days, when the symptoms were stable. Noninvasive positron emission tomographic neuroimaging of vesicular monoamine transporter 2 with 9-[(18)F] fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV 133) was used before, and 15 and 90 days after the beginning of acute MPTP treatment. The imaging showed evident progressive loss of striatal uptake of [(18)F]AV-133. The dopaminergic denervation severity had a significant linear correlation with the clinical rating scores and the bradykinesia subscores. These findings demonstrated that [(18)F]AV-133 PET imaging is a useful tool to noninvasively evaluate the evolution of monoaminergic terminal loss in a monkey model of MPTP-induced parkinsonism. PMID- 24061966 TI - Magnetic resonance imaging evaluation after implantation of a titanium cervical disc prosthesis: a comparison of 1.5 and 3 Tesla magnet strength. AB - PURPOSE: Cervical disc prostheses induce significant amount of artifact in magnetic resonance imaging which may complicate radiologic follow-up after surgery. The purpose of this study was to investigate as to what extent the artifact, induced by the frequently used Discover((r)) cervical disc prosthesis, impedes interpretation of the MR images at operated and adjacent levels in 1.5 and 3 Tesla MR. METHODS: Ten subsequent patients were investigated in both 1.5 and 3 Tesla MR with standard image sequences one year following anterior cervical discectomy with arthroplasty. OUTCOME MEASURES: Two neuroradiologists evaluated the images by consensus. Emphasis was made on signal changes in medulla at all levels and visualization of root canals at operated and adjacent levels. A "blur artifact ratio" was calculated and defined as the height of the artifact on T1 sagittal images related to the operated level. RESULTS: The artifacts induced in 1.5 and 3 Tesla MR were of entirely different character and evaluation of the spinal cord at operated level was impossible in both magnets. Artifacts also made the root canals difficult to assess at operated level and more pronounced in the 3 Tesla MR. At the adjacent levels however, the spinal cord and root canals were completely visualized in all patients. The "blur artifact" induced at operated level was also more pronounced in the 3 Tesla MR. CONCLUSIONS: The artifact induced by the Discover((r)) titanium disc prosthesis in both 1.5 and 3 Tesla MR, makes interpretation of the spinal cord impossible and visualization of the root canals difficult at operated level. Adjusting the MR sequences to produce the least amount of artifact is important. PMID- 24061967 TI - Answer to the letter to the editor of F. M. Kovacs et al. entitled "overviews should meet the methodological standards of systematic reviews" concerning "the evidence on surgical interventions for low back disorders, an overview of systematic reviews" by Wilco C.H. Jacobs et al.; Eur Spine J, doi:10.1007/s00586 013-2823-4. PMID- 24061968 TI - Zero-P: a new zero-profile cage-plate device for single and multilevel ACDF. A single institution series with four years maximum follow-up and review of the literature on zero-profile devices. AB - PURPOSE: To analyze the prospectively collected data in a series of patients treated with single- or multilevel ACDF with a stand-alone, zero-profile device, focusing on clinico-radiological outcome, complications and technical hints, and to review the literature on such new devices. METHODS: Eighty-five patients harboring symptomatic DDD underwent ACDF with the Zero-P cage-plate: 29 at 1 level and 56 at 2-4 levels (total 162 devices). In the multilevel group, 9 patients received a combination of Zero-P and stand-alone cages (hybrid implants). This study focuses on 32 patients with follow-up ranging from 20 to 48 months. NDI, SF-36 and arm pain VAS scores were registered preoperatively and at follow-up visits. Dysphagia was assessed using the Bazaz score. Imaging included X-rays, CT and MRI, also to assess the presence of vertebral body fractures in multilevel cases. Paired Student t test was used for statistical analysis. RESULTS: SF-36 and NDI showed a statistically significant improvement (p < 0.01) and mean arm pain VAS score decreased from 79 to 41. X-rays and CT demonstrated, respectively, a 94.5 % and a 92 % fusion rate. Three patients complained of moderate and two of mild transient dysphagia (15.5 %). No device-related complications occurred and no fractures, secondary to four screws insertion in one vertebral body (i.e., swiss cheese effect), were detected in multilevel cases. In patients with extensive anterior osteophytes only a "focal spondylectomy" was required. CONCLUSION: The Zero-P device is safe and efficient, even in multilevel cases. Dysphagia is minimal, extensive anterior osteophytectomy is unnecessary and technical hints may ease the surgical workflow. This is the largest series, with the longest follow-up, reported. PMID- 24061969 TI - Importance of spinal deformity index in risk evaluation of VCF (vertebral compression fractures) in obese subjects: prospective study. AB - INTRODUCTION: Obesity and osteoporosis share many features and recent studies have identified many similarities suggesting common pathophysiological mechanisms. Obesity is associated with a higher risk of non-traumatic fractures despite bone mineral density (BMD) being normal or even increased. MATERIALS AND METHODS: 54 obese subjects were analyzed (51 +/- 16 years, 10 males, 44 females). Spinal deformity index (SDI) is a semi-quantitative method that may be a surrogate index of bone microarchitecture. SDI index was higher in patients than in controls. In 87.5 % of patients and 10 % of controls we found morphometric vertebral fractures, despite a DEXA Tscore not diagnostic of osteoporosis. CONCLUSION: The objective of this study was to assess in obese patients levels of 25OH vitamin D, parathyroid hormone, serum and urinary calcium (Ca) and phosphorus (P), BMD, and SDI. 87.5 % of the obese subjects present nontraumatic vertebral fractures and reduced bone quality as measured by SDI. PMID- 24061970 TI - Surgical treatment of adult degenerative scoliosis. AB - INTRODUCTION: The surgical treatment of adult scoliosis still presents many points of discussion. Decision-making on the type of treatment is mandatory to evaluate all the possible alternatives to surgery. MATERIALS AND METHODS: From January 2000 to December 2008, 49 cases of adult degenerative scoliosis and kyphoscoliosis were surgically treated. Thirty-six patients were monitored for a mean of 8 years (5-10). There were 10 males and 26 females, with a mean age of 66 years (55-80). Arthrodesis was carried out using pedicle screws at all levels extending to the sacrum in 30 cases and to the ileum in 4. Laminectomy was performed in 20 cases, radicular liberation in 15, PLIF in 10. RESULTS: After an average term of 8 years (5-10) we record 8 (23 %) excellent cases, 10 (29 %) good, 12 (34 %) satisfactory, 5 (14 %) bad. The VAS in the pre-operative period had a value of 7 (5-9) passed in the post-operative period of 3 (0-6). 13 reoperations were performed (36 %). PMID- 24061971 TI - Sagittal balance in adolescent idiopathic scoliosis: radiographic study of spino pelvic compensation after surgery. AB - STUDY DESIGN: Radiographic retrospective study of a consecutive series of 76 patients with adolescent idiopathic scoliosis (AIS) undergoing posterior only surgical correction and fusion. OBJECTIVE: To evaluate the sagittal profile changes in a population of adolescent idiopathic scoliosis after posterior only surgical correction. Although the relationship between pelvic indexes and sagittal profile is well known, little has been published about the sagittal profile changes after posterior surgery in adolescent idiopathic scoliosis. METHODS: Radiological data of 76 AIS patients were analyzed by an independent observer to compare pelvic indexes and spino-pelvic parameters before and at the last follow-up after surgical posterior correction. All patients underwent a posterior only surgical correction by using different anchor techniques (all screws or hybrid construct), but the same derotation correction maneuver (C-D technique). The collected data were analyzed, on AP and LL radiographic views of the entire spine in the upright position, from the same independent observer and using the same Impax software analysis. We collected for each patient on latero lateral X-rays the following data: pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL), thoracic kyphosis (TK), C7 plumb line (C7PL) and spino-sacral angle (SSA). All data were analyzed using a D'Agostino Pearson normality test and the comparison between the groups was performed with a student's t test. RESULTS: The mean pelvic incidence (PI) of the cohort was 48.89 degrees (+/- 11.24), with a mean Cobb angle for the main curve of 60.13 degrees (+/- 13.6). The mean value of residual scoliosis after surgery was 28.18 degrees (+/- 13.22) with an average improvement of the curve in the frontal plane of 53.2 %. The amount of curve correction of the primary scoliosis curve was statistically significant (p < 0.0001). In the evaluation of the whole group after surgery, we observed an increasing amount of PT (average delta value 2.38 degrees ) with a statistical significance (p = 0.0034). If we compare the mean ideal PT value (11.09 degrees ) with the pre- and post-operative mean true PT values, we found statistical significance only for the post-operative difference (p = 0.0014). In the general assessment, C7PL seems to remain stable after surgery, and in particular it remains negative. In Lenke 1 group, there was a mean PI value of 50.54 degrees (+/- 11.45) which is higher than the one reported in the global assessment. Also in this subgroup, we observed a reduction in the mean SS values, with consequent increase in the PT values, as in the general assessment. The C7PL tends to move posteriorly after surgery and this difference is statistically significant. In Lenke 1 group we found a strong statistical significance between pre- and post-surgery data for the Cobb primary curve and for the C7PL, which continues to remain negative. The C7PL remains relatively stable only in the normokyphotic group, while it tends to move behind in the other three groups (Lenke 3, hyperkyphosis and hypokyphosis). CONCLUSIONS: In our series of 76 adolescent affected by AIS, we reported mean PI values of 48.9 degrees with a mean pre-operative PT of 11.51 degrees . After surgery we observed an increase in the PT mean value, about three degrees higher than the ideal value, meaning that there was some compensatory mechanism. Patients affected by AIS showed a slight posterior imbalance and the intervention of scoliosis correction seems to cause a slight further posterior imbalance, especially in Lenke 1 type curves and in patients with hypokyphosis. The clinical significance of this slight imbalance must be carefully evaluated. Further studies are necessary to better establish which could be the best surgical strategy to obtain an optimal spinal sagittal balance. PMID- 24061972 TI - Failures and revisions in surgery for sagittal imbalance: analysis of factors influencing failure. AB - INTRODUCTION: Sagittal imbalance is an important risk factor for spinal disability, pain and loss of health related quality of life. Its correction has a positive impact on these outcomes. Still, it is a very aggressive surgery, with a high revision rate. The aim of this study is to analyze the most important causes of failure of surgery for correction of sagittal imbalance. DESIGN AND METHODS: In this retrospective observational cohort study twelve patients who previously underwent surgery for sagittal imbalance correction were revised in the period 2009-10. We analyzed angular parameters of sagittal balance before and after primary surgery, type of instrumentation, modality of fusion, implant density, instrumented levels, modality of failure, time from first surgery and angular parameters after revision. RESULTS AND CONCLUSION: Causes of failure were insufficient correction, junctional kyphosis, screw loosening and pseudoarthrosis with rod breakage. In every case, patients presented a new onset or a worsening of sagittal imbalance and pain. PMID- 24061973 TI - Preoperative calculation of the necessary correction in sagittal imbalance surgery: validation of three predictive methods. AB - INTRODUCTION: Surgery for correction of sagittal imbalance has frequent adverse events and complications. The most frequent cause of failure is inadequate correction of imbalance. The aim of this study is to verify the accuracy of three published methods (exact method by Ondra, FBI method by Le Huec and spinofemoral angle method by Lamartina) to preoperatively calculate the needed correction. DESIGN: This is a retrospective cohort study. METHODS: Fifteen patients treated for correction of sagittal imbalance, with preoperative and postoperative lateral standing whole spine radiographs, were identified. Preoperative calculation of the amount of needed correction has been done using these methods. In postoperative X-rays, the amount of correction obtained with and the degree of correction of sagittal imbalance have been measured. RESULTS AND DISCUSSION: The FBI and SFA methods obtain equivalent calculations of the amount of needed correction. The estimated correction angle with both methods is higher than that calculated with the exact trigonometric method. The difference between the latter and the former methods is equivalent to the observed excess of pelvic tilt. PMID- 24061974 TI - Treatment of severe scoliosis with posterior-only approach arthrodesis and all pedicle screw instrumentation. AB - PURPOSE: Posterior-only approach arthrodesis by all-pedicle screw instrumentation has a correction rate similar to correction obtained by traditional combined anterior/posterior approach surgery and avoids the complications associated with the thoracic approach. METHODS: We treated 25 patients, with a mean age 16.5 years, with severe adolescent idiopathic scoliosis by posterior-only approach using all-screw instrumentation arthrodesis. Mean scoliosis curve in Cobb degrees was 95 degrees Cobb. All cases were treated by the same senior surgeon, by free hand technique, without intraoperative neurophysiologic monitoring and spine navigation aids. RESULTS: Mean scoliosis curve after surgery was 37 degrees Cobb. Mean follow-up was 4 years. No perioperative complications, curve progression or arthrodesis malunion were reported at the follow-up. CONCLUSIONS: Posterior spinal fusion with pedicle screw-only instrumentation obtains a good and stable correction of severe scoliosis; compared to hybrid instrumentation, it allows a greater coronal correction of the deformity and less correction loss at the follow-up. PMID- 24061975 TI - Mesenchymal stem cells derived from vertebrae (vMSCs) show best biological properties. AB - PURPOSE: Due to their properties and characteristics human mesenchymal stem cells (MSCs) appear to have great therapeutic potential. Many different populations of MSCs have been described and to understand whether they have equivalent biological properties is a critical issue for their therapeutic application. METHODS: We proposed to analyze the in vitro growth kinetics of MSCs derived from different body sites (iliac crest bone marrow, vertebrae bone marrow, colon mucosa, dental pulp). RESULTS: Mesenchymal stem cells derived from vertebrae can be maintained in culture for a greater number of steps and they also generate mature cells of all mesenchymal lineages with greater efficiency, when induced into osteogenic, adipogenic and chondrogenic differentiation. CONCLUSIONS: The ability of vertebrae-derived MSCs in terms of expansion and differentiation is very interesting at the light of a clinical application for bone fusion in spine surgery. PMID- 24061976 TI - Anterior spinal pseudomeningocele after C0-C2 traumatic injuries: role of the "dural transitional zone" in the etiopathogenesis. AB - PURPOSE: Spinal pseudomeningoceles (SPM) are extradural collections of CSF (cerebrospinal fluid); a frequent association with upper cervical injuries (UCI) has been observed. We propose a possible etiopathogenetic mechanism supporting the formation of cervical SPM based on some considerations. METHODS: We present four cases of SPM. All patients sustained a severe UCI. Three patients were symptomatic with delayed and progressive clinical signs. RESULTS: One patient was misinterpreted as epidural hematoma and operated on due to progressive signs with postoperative clinical improvement. The rest of patients were treated conservatively; spontaneous reduction of CSF collection occurred. From a radiological standpoint: (1) a line of demarcation separated the intradural cervical compartment from the anterior epidural space, (2) CSF epidural collection was never evident at C0-C2 level and extended from C2 downwards, and (3) shape of collection was similar to epidural hematomas suggesting a ball-valve mechanism. CONCLUSIONS: The dural layer at C0-C2 level is adherent to the thick ligamentous apparatus, as opposed to the segments below where it is solely covered by the posterior longitudinal ligament. A "transitional zone" of dura exists between the C0-C2 region and subaxial segment of the cervical spine. This watershed area constitutes a point of minor resistance. Lacerations of the meningeal layers, caused by severe UCI at the "transitional zone", drain CSF into the anterior epidural space and form SPM. PMID- 24061977 TI - Do benefits overcome the risks related to surgery for adult scoliosis? A detailed analysis of a consecutive case series. AB - PURPOSE: The surgical approach to adult spine deformities is complex and presents a high incidence of complications. METHODS: We report here a prospective consecutive case series analysis of 20 patients submitted to posterior correction and instrumented fusion for adult degenerative scoliosis. Clinical outcomes were assessed by self-reported measures. Pre-operative and post-operative complications were analysed during a mean 30-month follow-up period. RESULTS: Eleven patients (55 %) presented pre-operative or post-operative complications. Fifteen different complications occurred, six in the early pre-operative period and nine during follow-up period: ten of these complications occurred in patients who underwent a previous surgery for spine disease. CONCLUSIONS: The clinical improvement at the final follow-up resulted as statistically significant only for the group of patients exposed to posterior fusion without interbody fusion. The observations reported here have to be considered for a shared decision-making in the management of adult scoliosis. PMID- 24061978 TI - Navigation-assisted surgery for tumors of the spine. AB - PURPOSE: Computer-assisted navigation systems are largely used for pedicle screws positioning in degenerative and traumatic spine surgery. In oncologic spine surgery its use is still developing and could be extended for tumor identification and excision. Aim of this paper is to present our experience. METHODS: Seven selected patients (5 females, 2 males), mean age 44 years (min 17 max 62) affected by primary benign or malignant tumors of the spine or spine metastases were surgically treated with the use of computer-assisted navigation system from March to October 2011. RESULTS: At 18 months mean F.U. (min 15-max 23), no LR were observed. Revision surgery was necessary only in one case for C1 pedicle screw malpositioning. CONCLUSIONS: Navigation system can improve surgical accuracy in screws placement and tumor localization and excision. Learning curve and technical aspects must be considered to avoid potential serious mistakes. PMID- 24061979 TI - Spine surgery and clinical research in Italy. PMID- 24061980 TI - [Nationwide speaking tour of standardized diagnosis and treatment for esophageal cancer]. AB - For a long time, the diagnosis and treatment protocol for esophageal cancer has been made either entirely based on the experience of Western countries or on our own experience alone. A suitable standardized guideline for diagnosis and treatment of esophageal cancer in our country has not been established until 2010. Due to lack of opportunities for mutual exchange and learning, the overall level of standardized diagnosis and treatment was relatively low in China. In addition, less advanced technologies were applied and varying treatment protocols were implemented in different districts, the treatment results has been unsatisfactory, and the overall 5-year survival rate after surgical treatment has been maintained from 30% to 40%. Therefore, it is imperative that China needs to conduct its own clinical studies and establish its own suitable standardized treatment and diagnosis guideline for esophageal cancer. This article reviews and also made comments on the process of academic speaking tour and development of standardized diagnosis and treatment guidelines as well as the problems resolved by these activities for esophageal cancer since the beginning of this century. PMID- 24061981 TI - [Biomarkers of predicting response to neoadjuvant chemoradiotherapy in esophageal cancer]. AB - The prognosis of patients with locally advanced esophageal cancer treated by surgery alone is poor. The neoadjuvant chemoradiotherapy is considered to improve the long-term survival of patients with locally advanced esophageal cancer. The combination of neoadjuvant chemoradiotherapy and surgery has been recommended to be the standard treatment for the locally advanced esophageal cancer in China even in Europe and America countries. However, available evidence suggests that only those who had histopathologic response seemed to benefit the most from neoadjuvant chemotherapy while non-responders even had rather worse outcome compared to patients with surgery alone. Therefore, predictive markers of response to neoadjuvant chemoradiotherapy in locally advanced esophageal cancer are highly significant and needed. These markers would allow a tailored treatment to guide non-responders to alternative preoperative therapies and ultimately avoid ineffective, costly and seriously cytotoxic treatments. Results of most studies on biomarkers for predicting response to neoadjuvant chemoradiotherapy in esophageal cancer are promising. The potential utilization of biomarkers in clinical practice is urgently expected and needed, which plays an important role in guiding and improving the individualization of multimodality therapy in locally advanced esophageal cancer. PMID- 24061982 TI - [Strengthen perioperative multimodality treatment in order to improve long-term outcomes of esophageal cancer]. AB - Esophageal squamous cell carcinoma (ESCC) is one of the commonest malignancies in China. Surgery is the main treatment for ESCC. However, the long-term survival is very poor by surgery alone. Perioperative multimodality treatment, including locally and systemically administrated, preoperatively and postoperatively, has been and will be the standard treatment in terms of improving long-term survival. Base on decades of practice and clinical trials, it is believed that preoperative treatment is better than postoperative treatment, and that chemotherapy plus radiotherapy preoperatively is better than either chemotherapy or radiotherapy alone. Therefore, preoperative radiochemotherapy followed by surgery is the standard treatment and future direction for locally advanced ESCC. PMID- 24061983 TI - [Multimodality management of squamous cell carcinoma of thoracic esophagus]. AB - Most patients with esophageal cancer have advanced disease at presentation. The efficacy of surgical resection alone is often unsatisfactory in patients with stage III or more advanced cancer according to the seventh edition of UICC staging system for esophageal cancer. The systematic multidisciplinary treatment is important. Mounting evidence indicates that preoperative concurrent chemoradiotherapy is the most effective induction therapy to down-stage tumor and increase radical resection rate. For the esophageal squamous cell carcinoma patients with multi-stations and multi-fields lymph node metastasis, preoperative induction chemotherapy would be a viable option. For locally advanced cancers which have been surgically resected, postoperative adjuvant radiotherapy maybe helpful to improve local control for the insufficient surgical dissection. The role of adjuvant chemotherapy also needs further studies. Thoracic esophageal squamous cell carcinoma and lower esophageal adenocarcinoma which is common in western countries are different. We need more prospective clinical studies to establish our treatment modalities for esophageal cancer. PMID- 24061984 TI - [Application of sentinel lymph node biopsy in esophageal cancer]. AB - The sentinel lymph node (SLN) is defined as the lymph node(s) first receiving lymphatic drainage from the site of primary tumor. The application of SLN navigation surgery has been widely confirmed in both melanoma and breast cancer. In recent years, the concept of SLN has gained high attention in gastrointestinal tumors. However, the validity and feasibility of the SLN concept remains controversial for esophageal cancer due to its special anatomical sites and lymphatic drainage pathways. Lymph node micrometastasis is an important prognostic factor in esophageal cancer patients without lymph node metastasis. Detection of micrometastases in SLN of esophageal cancer plays an important role in determining the treatment options. In this article, we make a brief discussion on the application of SLN biopsy in esophageal surgery and explain its clinical significance. PMID- 24061985 TI - [Prognostic value of metastatic lymph node ratio in adenocarcinoma of the gastroesophageal junction]. AB - OBJECTIVE: To compare the prognostic value of AJCC/UICC pN stage with metastatic lymph node ratio (MLR) and the prognostic difference between the tumor-node metastasis (TNM) stage and tumor-ratio-metastasis (TRM) stage in patients with adenocarcinoma of the gastroesophageal junction. METHODS: Clinical data of 414 patients with adenocarcinoma of the gastroesophageal junction undergoing curative resection at the Tianjin Medical University Cancer Institute and Hospital from January 2000 to June 2007 were retrospectively reviewed. Spearman correlation analysis was performed to examine the correlations between pN, MLR and retrieved nodes. Univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis were performed to analyze the effects of pN, MLR, TNM and TRM stage on the prognosis of these patients. The area under the ROC curve (AUC) was plotted to compare the value of these stages and to predict the 5 year survival rate. RESULTS: The median number of retrieved nodes was 17 (4-71) per patient, and the median number of positive nodes was 4 (0-67) per patient. The number of metastatic lymph node was positively correlated with that of retrieved nodes (P<0.01), but MLR was not correlated with the number of retrieved nodes (P>0.05). Univariate and multivariate survival analysis showed that either pN or MLR could be used as an independent risk factor for survival (P<0.01) and the hazard ratio of MLR stage was larger than that of pN stage (1.573 vs 1.382). While pN and MLR were entered into the Cox hazard ratio model as covariates at the same time, MLR remained as the independent prognostic factor (P<0.01), but pN lost significance (P>0.05). The AUC of MLR and pN staging was 0.726 and 0.714, and of TRM and TNM staging was 0.747 and 0.736, respectively, however the differences were not statistically significant (all P>0.05). CONCLUSIONS: MLR is an independent prognostic factor for patients with adenocarcinoma of the gastroesophageal junction. The value of MLR and TRM staging systems may be superior to pN and TNM staging systems in evaluating the prognosis of these patients. PMID- 24061986 TI - [Influence of preoperative chemoradiotherapy on pulmonary function and postoperative pulmonary complication in esophageal cancer patients]. AB - OBJECTIVE: To study the influence of preoperative chemoradiotherapy (CRT) on pulmonary function and postoperative pulmonary complications in esophageal cancer patients. METHODS: Pulmonary function and postoperative pulmonary complications of 63 esophageal cancer patients undergoing preoperative CRT and operation in Cancer Center of Sun Yat-sen University between 2002 and 2013 were collected retrospectively. The influence of preoperative CRT on pulmonary functional indexes and postoperative pulmonary complications were analyzed. RESULTS: After preoperative CRT, DLco% decreased significantly (83.7+/-17.7 vs. 96.4+/-17.8, P<0.01), while no obvious changes in other indexes were found. Postoperative pulmonary complication rate was 34.9% (22/63), including 19 cases of pneumonia and 3 cases of acute pulmonary injury/acute respiratory distress syndrome. Differences in postoperative pulmonary complication rates were not statistically significant between patients with DLco% <80 and those with DLco% >=80 patients (29.7% vs. 41.7%, P>0.05), and between patients with DLco% decline >=15% and those with DLco% decline <15% patients (31.6% vs. 37.8%, P>0.05). CONCLUSION: Preoperative CRT can damage the diffusion function but not ventilation function of esophageal cancer patients, and does not increase the postoperative pulmonary complication rate. PMID- 24061987 TI - [Risk factors of recurrence and metastasis in pN1 stage squamous cell carcinoma of the thoracic esophagus after radical esophagectomy with lymphadenectomy]. AB - OBJECTIVE: To analyze the clinical and pathologic risk factors of early recurrence in patients with pathological N1 (pN1) stage esophageal squamous cell carcinoma after radical esophagectomy. METHODS: A retrospective study was carried out on 95 consecutive pN1 stage esophageal squamous cell carcinoma patients undergoing esophagectomy with lymphadenectomy by the same surgical team from January 2004 to December 2010 was performed. The Cox proportional hazards model was used to determine the independent risk factors for recurrence and metastasis within 3 years after the operation. RESULTS: Recurrence was identified in 52 patients (54.7%) within 3 years after operation. Local recurrence was found in 42 patients (44.2%), and distant metastasis in 10 patients (10.5%). The Cox multivariate analysis showed that pT3-4a stage (RR=3.604, P=0.027), positive lymph node metastasis in two stations (RR=4.834, P=0.009) or two fields (RR=5.689, P=0.003), and postoperative adjuvant chemotherapy (RR=1.594, P=0.048) were independent risk factors for postoperative recurrence. CONCLUSIONS: Postoperative adjuvant chemotherapy can decrease the probability of postoperative recurrence and metastasis of pN1 esophageal squamous cell carcinoma. As for patients who are identified as multi-station or multi-field lymph node metastasis, preoperative induced therapy maybe further improve treatment outcomes. PMID- 24061988 TI - [Clinical study of the characteristics of lymph node metastasis in thoracic esophageal cancer]. AB - OBJECTIVE: To explore the characteristics of lymph node metastasis in thoracic esophageal cancer in order to provide evidence for the extent of lymph node dissection and the operation access. METHODS: A retrospective study was performed on the specimens of 72 patients who underwent radical operation of right transthoracic approach and the features of lymph node metastasis were explored. RESULTS: Lymph node metastases were found in 48 of 72 patients (66.7%). In 1495 lymph nodes dissected, metastases was identified in 181 lymph nodes (12.1%). The rate of lymph node metastasis in the right and left recurrent laryngeal nerve was 30.6% and 12.5% respectively. Lymph node metastasis was associated with tumor size and tumor invasion depth (both P<0.05), while tumor location and differentiation of tumor cells were not significant (both P>0.05). CONCLUSIONS: The lymph node metastasis in thoracic esophageal carcinoma can be easily found in the right recurrent laryngeal nerve. The best surgical approach of thoracic esophageal carcinoma is the right transthoracic approach. PMID- 24061989 TI - [Clinical significance of serum high-mobility group box 1 detection in esophageal squamous cell carcinoma]. AB - OBJECTIVE: To explore the level of serum high-mobility group box 1 (HMGB1) in patients with esophageal squamous cell carcinoma (ESCC) and the feasibility of HMGB1 as a tumor marker. METHODS: Serum HMGB1, carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen (Cyfra21-1) and squamous cell carcinoma antigen (SCC) were measured by enzyme-linked immunosorbent assay (ELISA), electrochemiluminescence immunoassay (ECLIA) and microparticle enzyme immunoassay (MEIA) respectively in 78 patients with ESCC preoperatively as well as a month after esophagectomy. At the same time, serum HMGB1, CEA, Cyfra21-1 and SCC of 60 healthy adult volunteers were detected with the same method. The unilateral P95 value of serum HMGB1 (>96 MUg/L) was defined as positive. According to the Roche kit diagnostic criteria, CEA>5.0 MUg/L, Cyfra21-1>3.3 MUg/L and SCC>1.5 MUg/L were defined as positive. RESULTS: The preoperative positive ratio of serum HMGB1 in 78 patients with ESCC was 84.6%, and the level of serum HMGB1 was associated with the tumor size, infiltration depth, lymph node metastasis and tumor stage (P<0.01 or P<0.05). One month after esophagectomy, the level of serum HMGB1 in ESCC declined significantly compared with the preoperative level (P<0.01), and the level of serum HMGB1 in T4, N1, stage III was higher compared to corresponding T, N and tumor stage (P<0.01 or P<0.05). The positive ratio of CEA, Cyfra21-1 and SCC was 10.3%, 25.6% and 42.3% respectively in 78 ESCC patients preoperatively, so the sensitivity of these tumor markers was lower. One month after esophagectomy, serum Cyfra21-1 and serum SCC were significantly decreased compared to the preoperative level (P<0.01). However, there was no significant difference of preoperative serum CEA compared to a month after esophagectomy in ESCC (P>0.05). The specificity of HMGB1, CEA, Cyfra21-1 and SCC were 93.3%, 88.3%, 90.0% and 93.3% respectively. CONCLUSION: Compared to CEA, Cyfra21-1 and SCC, serum HMGB1 in ESCC patients is easier for detection and its sensitivity and specificity are higher, which may be used as a marker in diagnosis, prediction of prognosis and monitor of postoperative recurrence of ESCC. PMID- 24061990 TI - [A randomized controlled trial of intensity-modulated radiation therapy plus docetaxel and cisplatin versus simple intensity-modulated radiation therapy in II III stage esophageal carcinoma]. AB - OBJECTIVE: To compare the efficacy and toxicity of intensity- modulated radiation therapy plus chemotherapy (IMRT-TP) with simple intensity-modulated radiation therapy (IMRT) in the treatment of locally advanced esophageal carcinoma. METHODS: A total of 170 eligible patients with locally advanced esophageal carcinoma were recruited prospectively from September 2004 to April 2008 and randomly divided into IMRT-TP group and IMRT group. Two groups were treated with IMRT of 6MV-X. The radiation dose was 60 Gy in 30 fractions in IMRT-TP group and 66 Gy in 30 fractions in IMRT group. The regimen of chemotherapy consisted of docetaxel and cisplatin in IMRT-TP group for 2 cycles. RESULTS: Of 170 patients, 160 completed the trial, including 75 patients of IMRT-TP group and 85 of IMRT group. As compared to IMRT group, total recurrence rate [69.3% (52/75) vs. 84.7% (72/85), P=0.020] and local recurrence rate [50.7% (38/75) vs. 67.1% (57/85), P=0.035] decreased in IMRT-TP group, the 5-year overall survival (29.3% vs. 15.3%, P=0.031) and 5-year recurrence free survival (24.0% vs. 10.6%, P=0.015) increased in IMRT-TP group. While severe side effect ratio increased obviously in IMRT-TP group [54.7% (41/75) vs. 4.7% (4/85), P=0.000]. CONCLUSION: As compare to simple IMRT, IMRT plus docetaxel and cisplatin can decrease the local recurrence rate, prolong the overall survival and regression-free survival, but bring more side effects. PMID- 24061991 TI - [Meta-analysis on reconstructions of posterior mediastinal route and anterior mediastinal route after esophagectomy]. AB - OBJECTIVE: To evaluate the efficacy and safety of posterior mediastinal route (PR) as compared with anterior mediastinal route (AR) after esophagectomy. METHODS: A systematic literature retrieval was carried out to obtain studies of randomized controlled trials (RCT) comparing PR with AR after esophagectomy before June 2012. Study selection, data collections and methodological quality assessments of retrieved studies were independently performed by two individual reviewers and meta-analysis was conducted using the RevMan 5.0 software. RESULTS: Six RCTs involving 376 patients (PR:197 cases, AR:179 cases) met the selection criteria. Meta-analysis showed that operative mortality (RR=0.49, 95%CI:0.18 1.36), anastomotic leaks (RR=0.95, 95%CI:0.44-2.07), cardiac morbidity (RR=0.51, 95%CI:0.25-1.04), pulmonary morbidity (RR=0.69, 95%CI:0.41-1.15), anastomotic strictures (RR=0.88, 95%CI:0.62-1.25), dysphagia (RR=1.26, 95%CI:0.75-2.11), 6 month body weight after esophagectomy were not significantly different between these two routes of reconstruction (all P>0.05). CONCLUSION: AR should be the choice of reconstruction in view of its potential advantages in the prevention of tumor recurrence within the gastric conduit and avoidance of conduit irradiation when undergoing postoperative radiotherapy. However, further studies are needed to confirm the difference of long-term efficacy between the two routes. PMID- 24061992 TI - [Anatomy of mesoesophagus in esophagectomy with minimally invasive three-fields lymphadenectomy]. AB - OBJECTIVE: To explore the anatomic features of mesoesophagus in combined thoracoscopic and laparoscopic esophagectomy with three-fields lymphadenectomy. METHODS: Clinical data of 67 patients undergoing thoracoscopic and laparoscopic esophagectomy with three-fields lymphadenectomy from July 2011 to September 2012 were analyzed retrospectively. All the patients underwent three-fields lymphadenectomy. Proper surgical planes were selected according to anatomy of mesoesophagus. Thoracoscopic surgical space was bounded on azygotic vein and divided into upper and low esophageal triangle. Pancreas was the key anatomical mark for laparoscopic gastric dissection, and peripancreatic space was the natural laparoscopic surgical plane. Prevertebral fascia was bottom surface of neck dissection and carotid sheath was the boundary of two sides. RESULTS: The median operative time was 251.6 min (range, 220 to 320 min). The median operative blood loss was 105.6 ml (range, 40 to 320 ml). The median number of lymph nodes dissected was 29.1 (range, 13 to 46, totally 1949). There was no perioperative death. Sixty-six patients were followed up with a mean follow-up time of 8.2 months (range, 2 to 14 months). Postoperative complications included reflux esophagitis in 10 and anastomotic stenosis in 3 cases. CONCLUSION: It is safe and more radical for minimally invasive esophagectomy that overall concept of minimally invasive anatomy of mesoesophagus is applied to identify the anatomic plane and landmark during operation. PMID- 24061993 TI - [Clinical analysis of 83 cases undergoing esophageal leiomyoma enucleation by video-assisted thoracoscopy]. AB - OBJECTIVE: To investigate the feasibility of video-assisted thoracoscopic surgery in the treatment of esophageal leiomyoma. METHODS: Clinical data of 83 patients with esophageal leiomyoma from December 2002 to August 2012 treated by video assisted thoracoscopic surgery were retrospectively analyzed. RESULTS: Video assisted thoracoscopic leiomyoma enucleations were performed in 82 patients. One patient was converted to thoracotomy to repair the esophageal mucosa and two patients required intraoperative mucosal repair by video-assisted thoracoscopic surgery for esophageal mucosa rupture. The mean operative time was 83.0 min (range, 40-300 min), and the mean blood loss was 52.4 ml (range, 20-150 ml). The mean length of postoperative hospital stay was 5.8 d (range, 3-50 d). The mean tumor diameter was 3.3 cm (range, 0.8-12.0 cm). One case with postoperative esophageal fistula was cured by conservative treatment. Eighty patients were followed up for 2-117 months, and all the patients were free of dysphagia without recurrence or other related complications. CONCLUSIONS: Thoracoscopic enucleation of esophageal leiomyoma can be performed effectively and safely. Thoracoscopic techniques for the removal of larger esophageal leiomyoma may be recommended as the treatment of choice in centers experienced with minimally invasive surgery. PMID- 24061994 TI - [Treatment strategy and prognosis analysis in children with type I esophageal atresia]. AB - OBJECTIVE: To analyze the postoperative short-term and long-term outcomes in the management of type I esophageal atresia, and to explore the ideal operative strategy. METHODS: Clinical data of 22 patients with type I esophageal atresia treated from January 2005 to September 2012 were retrospectively reviewed. Of 22 patients, 6 patients gave up the treatment. Two underwent primary repair after birth. Of 14 patients undergoing cervical esophagostomy and gastrostomy, 8 patients received esophageal replacement. Postoperative short-term and long-term complications, nutritional state and neurodevelopment were studied on above 10 children with radical operations. RESULTS: Of 10 patients with radical operation, the short-term complications were hydrothorax in 1 case, anastomotic leakage in 4, dumping syndrome in 1, anastomotic stricture in 1. The long-term complications were esophageal stricture in 2 cases, and repeated respiratory infection in 3. These complications could be managed successfully. The postoperative follow-up duration ranged from 2 to 62 months. Two cases were lost during follow-up after 2 years. Weight-for-age was normal in 2 patients, mild malnutrition in 5 patients, and moderate malnutrition in 1 patients. Neurodevelopment is significantly delayed as compared to normal children. CONCLUSIONS: Operative strategy should be chosen according to the distance between proximal and distal esophagus in the treatment of type I esophageal atresia. The efficacy of radical operation is relative satisfactory in terms of short-term and long-term complications and the quality of life. PMID- 24061995 TI - [Perioperative nutrition support for esophageal cancer complicated with diabetes mellitus]. AB - OBJECTIVE: To compare the efficacy between perioperative enteral and parenteral nutrition support for esophageal cancer patients complicated with diabetes mellitus. METHODS: Thirty esophageal cancer patients complicated with diabetes mellitus between September and November 2012 were prospectively enrolled in this trial. According to random number table, 30 cases were randomly divided into enteral group (n=15) and parenteral group (n=15). During the period between 3 days before operation and 8 days after operation, patients received enteral nutrition (AnSure) and parenteral nutrition support respectively. The daily dynamic monitoring of blood glucose was performed. Nutritional indexes (albumin and prealbumin) were evaluated 1-day before operation and 8-day after operation. Postoperative recovery time of gastrointestinal function and complications associated with nutritional support were observed. The cost of nutritional support was calculated. RESULTS: Patients in the two groups achieved satisfactory perioperative blood glucose control. Finger tip blood glucose was 5.0-9.0 mmol/L before meal, 7.0-10.0 mmol/L 2-hour after meal, and 4.0-8.0 mmol/L at 10 PM and 3 AM. No hypoglycemia (<3.5 mmol/L) was found in all the patients. The time to first flatus after surgery was (62.4+/-15.7) in the enteral group, significantly earlier than (90.8+/-22.4) h in the parenteral group (P<0.01). Postoperative nutritional indices and associated complications were not significantly different between two groups (all P>0.05). Cost in the enteral group was significantly lower than that in the parenteral group [(650.8+/-45.8) RMB vs. (3016.5+/-152.6) RMB, P<0.01]. CONCLUSION: Perioperative nutrition support can effectively control blood glucose and improve perioperative nutritional status simultaneously for esophageal cancer patients with diabetes mellitus. Compared with parenteral nutrition, enteral nutrition can accelerate the recovery of gastric bowel function and reduce the cost of nutritional support. PMID- 24061996 TI - [Clinicopathological characteristics and prognosis of young esophageal cancer patients]. AB - OBJECTIVE: To compare the clinicopathological features and prognosis of esophageal cancer between young and elderly patients. METHODS: Clinical data of 716 patients with esophageal squamous cell carcinoma undergoing curative operation from January 1990 to December 1998 at the Cancer Center of Sun Yat-sen University were analyzed retrospectively. Clinicopathological features and prognosis of 117 patients aged <=45 years (young group) at diagnosis were compared with 599 patients aged >45 years (elderly group). RESULTS: Except for tumor stage, there were no significant differences of clinicopathology between the young group and the elderly group (all P>0.05). There were more pathologic stage III cancer in the young group than the elderly group (47.9% vs. 33.6%, P=0.010). The 5-year survival rate (36.0% vs 33.8%) and 10-year survival rate (29.2% vs 25.0%) were not significantly different between the two groups (P=0.418). Multivariate analysis showed that the age was not the independent prognostic factors of esophageal squamous cell carcinoma (P=0.160, RR=1.187, 95%CI:0.935-1.506). CONCLUSION: Young esophageal cancer patients have more advanced tumors than elderly patients. However, the survival is comparable to the elderly. PMID- 24061997 TI - [Clinical features and management of pyothorax due to postoperative cervical anastomotic leakage in esophageal cancer surgery]. AB - OBJECTIVE: To investigate the clinical characteristics and managements of pyothorax due to postoperative cervical anastomotic leakage after esophageal cancer surgery. METHODS: From January 2006 to January 2013, 3342 patients with esophageal carcinoma underwent esophagectomy and cervical esophagogastric anastomosis. Of them, 19 patients developed pyothorax following cervical anastomotic leakage and their clinicopathological data were analyzed retrospectively. RESULTS: All the patients underwent a cervical anastomosis via a three-incisional approach (right cervicothoracic mid-abdominal incision, RT group, n=1094) or a two-incisional approach (left cervicothoracic incision, LT group, n=2248). The total number of cervical anastomotic leakage cases was 237, of which 152 cases were in LT group (6.8%), and 85 cases in RT group (7.8%), respectively (P=0.287). The incidence of pyothorax was 2.0% (n=3) in LT group, and 18.8% (n=16) in RT group, respectively (P<0.01). Fourteen cases develop pyothorax within 3 days after operation. The main symptoms were high fever, dyspnea and chest pain. All the pyothorax patients received conservative treatments, including thoracic closed drainage, nasogastric tube placement, jejunal stoma, nutritional support, antibiotics and symptomatic treatment. Sixteen cases were cured, while 3 cases were dead. CONCLUSIONS: The right thoracotomy approach predisposes the cervical anastomotic leakage-associated pyothorax. Sufficient drainage and sufficient nutritional support are critical to the treatment. PMID- 24061999 TI - [Effect of erythromycin on electrical activity and gastric emptying of the intrathoracic stomach after esophagectomy for esophageal cancer]. AB - OBJECTIVE: To investigate the effect of erythromycin on electrical activity and emptying of the intrathoracic stomach after esophagectomy for esophageal cancer. METHODS: Thirty patients undergoing esophagectomy for cancer and esophagogastrostomy above the aortic arch were divided into the study group (n=15) and the control group (n=15). Electrogastrography and radionuclide gastric emptying were examined for these patients before and 1, 3, 6, 12 months after surgery. Patients in the study group received erythromycin (0.25 g tid po) for 1 week before examination. RESULTS: The wave amplitude (Uv), dominant frequency (CPM) and percentage of normal slow wave (%) of electrogastrogram decreased after surgery and returned to normal at the first postoperative month in the study group and the 12th postoperative month in the control group (P>0.05). Gastric emptying was significantly delayed after esophagectomy, and returned to normal one year after operation in the study group (P>0.05). However, gastric emptying remained abnormal in the control group (P<0.01). CONCLUSIONS: Erythromycin improves electrical activity and emptying of the stomach after esophagectomy for cancer. Gastric emptying recovery later than the recovery of electrical activity, which may be related to gastric ischemia and edema. PMID- 24061998 TI - [Effect of PC cell-derived growth factor RNA interference on biological behavior of esophageal squamous carcinoma cells]. AB - OBJECTIVE: To investigate the effect of PC cell-derived growth factor (PCDGF) RNA interference on esophageal squamous carcinoma cells Eca-109 in vitro. METHODS: The PCDGF-shRNA expression vector was transfected into the Eca-109 cells by liposome. After transfection, the mRNA and protein expressions of PCDGF were detected by RT-PCR and Western-blot respectively. Cell Counting Kit-8 (CCK-8) assay and Boyden chamber method were performed to measure the cell proliferation and invasion ability respectively. RESULTS: The expression levels of PCDGF mRNA and protein were both decreased in Eca-109 cells transfected with PCDGF-shRNA expression vector (transfection group). Twenty-four, 48 and 72 h after transfection, the cells proliferation in the transfection group was inhibited, and the inhibition rate was 20.4%, 21.1% and 20.9% respectively. The cell proliferation activity in the transfection group was significantly lower than that in the non-transfection group, liposome group and negative vector group (all P<0.05). The number of cell migration in the non-transfection group,negative vector group, liposome group and transfection group was 118.8+/-12.0, 100.8+/ 9.0, 114.3+/-4.7, and 53.5+/-16.3 respectively. The differences were statistically significant between the transfection group and the other 3 groups (all P<0.05). CONCLUSIONS: PCDGF RNA interference can inhibit the proliferation and invasion abilities of esophageal squamous carcinoma cells in vitro. PCDGF gene may be the new target of gene therapy. PMID- 24062000 TI - [Application of totally laparoscopic anastomosis in laparoscopic gastrectomy]. AB - OBJECTIVE: To explore the safety and feasibility of the total laparoscopic anastomosis in laparoscopic gastrectomy. METHODS: Clinical data of 36 patients who received totally laparoscopic anastomosis and another 47 patients who received anastomosis through small incision in our department from July 2012 to July 2013 were retrospectively analyzed. Clinical outcomes were compared between the two groups. RESULTS: The operation was successfully carried out in all the 83 patients. The mean incision length was (7.1+/-0.9) cm in small incision group and (2.6+/-0.4) cm in totally laparoscopic group, while the mean time of anastomosis was (70.9+/-9.0) min and (29.1+/-4.9) min respectively. Six patients felt moderate pain and 41 felt severe pain in small incision group, while 29 patients felt moderate pain and 7 felt severe pain in totally laparoscopic group. Anastomotic leakage occurred in 1 case after operation in small incision group and there was no related anastomosis complication in totally laparoscopic group. CONCLUSIONS: Total laparoscopic anastomosis is safe and feasible in laparoscopic gastrectomy for gastric cancer. Compared with small incision-assisted anastomosis, totally laparoscopic anastomosis is associated with shorter time and less pain. PMID- 24062001 TI - [Multimordality of cluster treatment strategy for early postoperative inflammatory small bowel obstruction]. AB - OBJECTIVE: To explore the application of multimordality of cluster treatment strategy in early postoperative inflammatory small bowel obstruction. METHODS: Clinical data of 31 cases of early postoperative inflammatory small bowel obstruction in our department from July 2007 to July 2011 were analyzed retrospectively. Multimordality of cluster treatment strategy was used in 13 cases (treatment group), and other non-surgical treatment was applied in 18 cases (control group). Efficacy and prognosis were compared between the two groups. RESULTS: Four-day improvement rate was 76.9% (10/13) and 44.4% (8/18), and 7-day cure rate was 92.3% (12/13) and 77.8% (14/18) in the treatment group and the control group, respectively. The differences were statistically significant (both P<0.05). The recovery time of bowel sounds and flatus, defecation time, bloating free time, oral intake time, abdominal CT intestine improvement time, and hospital stay were all significantly shorter in the treatment group as compared to the control group (all P<0.05). CONCLUSION: Multimordality of cluster treatment strategy can effectively shorten the healing time of early postoperative inflammatory small bowel obstruction, which possesses a good clinical application prospect. PMID- 24062002 TI - [Effect of RNA interference inhibition to expression of CD133 on tumor cell biological characteristics in KATO-III CD133(+) cells of human gastric cancer]. AB - OBJECTIVE: To investigate the changes in proliferation, invasiveness, clone sphere formation and chemosensitivity of human gastric cancer cell lines of KATO III CD133(+) cells transfected with small interfering RNA (siRNA) against CD133 gene. METHODS: CD133(+) cells of KATO-III cell lines were isolated by magnetic activated cell sorting (MACS). CD133 siRNA was designed and synthesized, and then transfected into KATO-III CD133(+) cells. Cell fluorescence counting under confocal laser scanning microscope was used to determine the transfection efficiency after transfection with the CD133 FITC-siRNA. The knock-down effect of the CD133 gene and expression of epithelial-mesenchymal transition (EMT)-related factors were detected by RT-PCR and Western blotting. Cell counting kit-8 assay (CCK-8), transwell chamber and colony sphere forming assay were performed to measure the variation of cell proliferative, invasive, colony formation viability and chemosensitivity to 5-FU after the above-mentioned treatment. RESULTS: The transfection efficiency was (87.7+/-8.1)%. The CD133 mRNA and protein expression levels in the interference group were lower than those in negative control group. Twenty-four, 48 and 72 hours after transfection, cells proliferation activity was significantly inhibited in the interference group compared with negative control group, (all P<0.01). Seventy-two hours after transfection, compared with negative control group, cells proliferation activity was reduced by (52.1+/-8.0)%. The invasive cell number reduced (41.7+/-6.0 vs. 130.3+/-11.0, P<0.05) and clone formation rate decreased significantly [(24.3+/-4.3)% vs. (45.1+/-6.4)%, P<0.01] in the interference group. EMT-related gene E-cadherin protein expression increased, while the Snail and N-cadherin protein expression reduced in the interference group (all P<0.01). The cells sensitivity to 5-FU was significantly enhanced in the interference group, and the cell inhibition rate of 5-Fu was (62.4+/-3.3)%, higher than that in negative control group [(21.5+/-2.2)%, P<0.01]. CONCLUSIONS: The expression of CD133 gene plays an important role in cell proliferation, invasiveness, colony formation and resistance to chemotherapy of KATO-III CD133(+) gastric cancer cells. It suggests that CD133 can be used as one of surface markers for detection of gastric cancer stem cells. Inhibition of CD133 expression may be a promising way for gastric cancer biotherapy. PMID- 24062003 TI - [Association of 5-lipoxygenase expression and clinicopathological factors in colorectal carcinoma]. AB - OBJECTIVE: To examine the association of 5-lipoxygenase (5-LOX) expression with clinicopathological factors in colorectal cancer. METHODS: Immunohistochemical stain was used to detect the 5-LOX expression in 52 resected specimens of colorectal cancer. The association between 5-LOX expression and clinicopathological factors was examined. RESULTS: The positive rate of 5-LOX expression in 52 specimens of colorectal carcinoma was 73.1% (38/52). In 41 colorectal cancer specimens with lymph node metastasis, the positive rate of 5 LOX expression was higher than that in the specimens without metastasis (87.8% vs. 18.2%, P<0.05). The positive rate of 5-LOX expression in the specimens with deep infiltration (T3 and T4) was higher than that in the specimens with superficial infiltration (T1 and T2) (81.1% vs. 53.3%, P<0.05). The positive rate of 5-LOX expression in TNM stage III and IIII cancer was higher than that in stage I and II (79.5% vs. 53.8%, P<0.05). The positive rate of 5-LOX expression in cancers of poor differentiation and non-differentiation adenocarcinoma was higher than that of well and moderately differentiated cancer (100% vs. 50.0%, P<0.05). There were no significant differences of 5-LOX expression with tumor size,vascular invasion and peritoneal dissemination. CONCLUSION: 5-LOX expression in colorectal carcinoma is closely associated with lymph node metastasis, infiltration depth, differentiation degree and TNM stage. PMID- 24062004 TI - [Analysis of the protein expression and gene amplification of HER2 in gastric cancer]. AB - OBJECTIVE: To explore the clinical significance of protein expression and gene amplification of HER2 in gastric cancer. METHODS: Immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) method were used to detect protein expression and gene amplification of HER2 in 80 specimens of gastric cancer patients. RESULTS: Protein expression of HER2 was negative in 51 cases, (+) in 12 cases, (++) in 12 cases, (+++) in 5 cases, and the positive expression rate was 21.3% (17/80). Seven (8.8%) cases had gene amplification of HER2, including gene critical amplification in 3 (3.8%) cases. The result of IHC was positively correlated with CISH (P<0.05), and the coincidence rate was 85.0% (68/80). HER2 positive expression rate was higher in the gastroesophageal junction carcinoma, poorly differentiated and stage III-IIII gastric cancer (all P<0.05). CONCLUSION: The gastric cancer tissue has high positive rate of protein expression and gene amplification of HER2, which is closely correlated to the development of gastric cancer. PMID- 24062005 TI - [The role of glucagon-like peptide-1 and its receptor in the mechanism of metabolic surgery]. AB - At present, surgery has become one of the treatments for type 2 diabetes, but it is still unclear about the therapeutic mechanism. Many experiments has proved that the anatomical and physiological structure has been altered leading to significant changes related to the secretion of gastrointestinal hormones and neuropeptides. These molecular are related to the metabolism of glucose, functions of islet cells and sensitivity of insulin. Intensive studies of glucagon-like peptide-1 (GLP-1) play an important role in the surgical treatment of diabetes and now it has gained increasing recognition. However, GLP-1 must be combined with GLP-1 receptor (GLP-1R) to execute its function. In this paper we reviewed the role of GLP-1 and its receptor in the mechanism of metabolic surgery. PMID- 24062006 TI - Vertical nanowire arrays as a versatile platform for protein detection and analysis. AB - Protein microarrays are valuable tools for protein assays. Reducing spot sizes from micro- to nano-scale facilitates miniaturization of platforms and consequently decreased material consumption, but faces inherent challenges in the reduction of fluorescent signals and compatibility with complex solutions. Here we show that vertical arrays of nanowires (NWs) can overcome several bottlenecks of using nanoarrays for extraction and analysis of proteins. The high aspect ratio of the NWs results in a large surface area available for protein immobilization and renders passivation of the surface between the NWs unnecessary. Fluorescence detection of proteins allows quantitative measurements and spatial resolution, enabling us to track individual NWs through several analytical steps, thereby allowing multiplexed detection of different proteins immobilized on different regions of the NW array. We use NW arrays for on-chip extraction, detection and functional analysis of proteins on a nano-scale platform that holds great promise for performing protein analysis on minute amounts of material. The demonstration made here on highly ordered arrays of indium arsenide (InAs) NWs is generic and can be extended to many high aspect ratio nanostructures. PMID- 24062007 TI - Comparison of patterns and knowledge of benefits and warnings of fish consumption between parents and children. AB - We examined generational differences in fish consumption and knowledge of benefits/warnings of fish consumption among parents and children. This cross sectional study gathered self-administered questionnaire data, including demographics, fish consumption behavior (including specific fish species) and knowledge of fish consumption warnings and benefits. Fish were later grouped into four categories by potential mercury contamination. Descriptive statistics were conducted for all variables comparing all adults and children. Benefit/risk knowledge variables were also descriptively analyzed among parent-child pairs only. Multivariate Poisson regression was conducted on pairs to assess risk factors for children eating higher mercury fish. 421 adults and 207 children (171 adult-child pairs) participated (family response rate: 71%). Slightly more adults (97.6%) ate fish in the last year than children (92.3%); however, there was no difference between consumption of fish by category of potential mercury contamination. Both adults (44%) and children (45%) ate high-mercury fish. In 71% of parent-child pairs, both the parent and the child knew of benefits of consuming fish; only 31% knew of warnings. Parental consumption of high or moderately-high-mercury fish was related to the child's consumption of fish in the same category. Parents and children need additional education to make better choices about fish consumption. Education should target the family and include specifics about benefits and risks. PMID- 24062008 TI - The intravenous perfluorocarbon emulsion Oxycyte does not increase hyperbaric oxygen-related seizures in a non-sedated swine model. AB - PURPOSE: Standard treatment for decompression sickness (DCS) is recompression therapy with hyperbaric oxygen (HBO). Non-recompressive therapies are needed to address mass casualty scenarios such as a disabled submarine rescue or DCS therapy in remote environments. Intravenously delivered perfluorocarbon (PFC) emulsions improve blood oxygen content and decrease mortality in several animal models of DCS. However, the enhanced oxygen delivery of PFC emulsions may increase CNS oxygen toxicity (seizures) risk when used in conjunction with HBO. We studied seizure latency and duration in swine randomized to receive PFC or normal saline with 6 ATA of oxygen. METHODS: Yorkshire swine (n = 31) were fitted with EEG electrodes and randomized to receive 5 ml/kg of the PFC Oxycyte (Oxygen Biotherapeutics Inc., Morrisville, NC) or saline intravenously 1 h before HBO. Unsedated animals were fitted with a snout mask for inhaled gas delivery, positioned inside the hyperbaric chamber, and compressed to 165 ft of sea water (6 ATA). After 2.5 min at 6 ATA, breathing gas was switched to 100 % O2 until signs of seizure were observed and EEG activity was evident. At seizure onset gas was switched back to air for 3 min, then the chamber was decompressed. After 24 h, the dive profile/oxygen exposure was repeated to ensure no secondary effects of PFC drug redistribution or emulsion metabolism. RESULTS/CONCLUSION: Intravenous PFC emulsion did not decrease seizure latency or increase duration on initial HBO exposure or after 24 h. This finding demonstrates the safety of PFC use in conjunction with recompression therapy to treat DCS. PMID- 24062009 TI - Telomere length and adrenergic-induced left ventricular dilatation and systolic chamber dysfunction in rats. AB - PURPOSE: The mechanisms responsible for telomere shortening in heart failure are uncertain. We evaluated whether left ventricular (LV) dilatation and systolic chamber dysfunction produced by chronic beta-adrenergic receptor (beta-AR) activation is associated with leukocyte or cardiac telomere shortening. METHODS: Following 6 months of daily injections of the beta-AR agonist, isoproterenol (0.02 mg/kg/day) or the saline vehicle to rats, the extent of LV dilatation and LV systolic chamber dysfunction were determined using echocardiography and isolated perfused heart procedures, and relative telomere length of leukocyte (LTL) and cardiac (CTL) deoxyribonucleic acid were determined using a quantitative real-time polymerase chain reaction assay. RESULTS: beta-AR activation resulted in LV dilatation as indexed by increased LV diastolic diameters (9.2 +/- 0.6 vs. 8.4 +/- 0.9 mm, P = 0.01) and increased diastolic volume intercepts at zero pressure of the LV diastolic pressure-volume relationship (isolated, perfused heart preparation) (0.40 +/- 0.06 vs. 0.37 +/- 0.08 ml, P = 0.03). Moreover, beta-AR activation resulted in LV systolic chamber dysfunction as indexed by reductions in LV endocardial fractional shortening (0.40 +/- 0.05 vs. 0.45 +/- 0.06, P = 0.01) and the slope of the LV systolic pressure-volume relation (609 +/- 176 vs. 901 +/- 230, P = 0.01). Although LTL decreased with age in rats receiving either the beta-AR agonist or the saline vehicle (P < 0.05), neither CTL (-0.10 +/- 0.14 vs. -0.15 +/- 0.12, P = 0.3) nor LTL (-0.11 +/- 0.19 vs. -0.15 +/- 0.18, P = 0.5) were modified by beta-AR activation. CONCLUSION: In conclusion, chronic beta-AR activation sufficient to produce LV dilatation and systolic chamber dysfunction is not associated with alterations in leukocyte or cardiac telomere length. Telomere shortening in chronic heart failure is unlikely to be attributed to chronic beta-AR activation. PMID- 24062010 TI - Gender differences in offaxis neuromuscular control during stepping under a slippery condition. AB - PURPOSE: Females are at greater risks of musculoskeletal injuries than are males, which may be related to decreased neuromuscular control in axial and/or frontal planes, offaxis neuromuscular control. The objective of this study was to investigate gender differences in offaxis neuromuscular control during stepping under a slippery condition. METHODS: Forty-three healthy subjects (21 males and 22 females) performed different stepping tasks under a slippery condition, namely, free pivoting task (FPT) to control axial plane pivoting, free sliding task (FST) to control frontal plane sliding, and free pivoting and sliding task (FPST) to control axial pivoting, and frontal sliding on a custom-made offaxis elliptical trainer. RESULTS: Compared to males, females showed significantly higher pivoting instability, higher max internal and external pivoting angles, higher mean max medial and lateral sliding distance, and higher entropy of time to peak EMG in the medial and lateral gastrocnemius muscles during the FPST and higher entropy of time to peak EMG in the lateral gastrocnemius muscle during the FPT and FST. CONCLUSIONS: The findings may help us understand potential injury risk factors associated with gender differences, and provide a basis for developing targeted neuromuscular training to improve offaxis neuromuscular control, and reduce musculoskeletal injuries associated with excessive offaxis loadings. PMID- 24062011 TI - Positive airway pressure therapy in patients with opioid-related central sleep apnea. AB - PURPOSE: This study aims to compare treatment response and adherence rate to positive airway pressure (PAP) in patients with opioid-related central sleep apnea (O-CSA) and idiopathic central sleep apnea (I-CSA). METHODS: We performed a retrospective chart over a 5-year period performed at a VA sleep center. Continuous PAP (CPAP) was prescribed initially for all participants. For those nonresponders (apnea hypopnea index (AHI) of >10/h), bi-level PAP (BiPAP) or adaptive servoventilation (ASV) was instituted upon provider's discretion. Adherence to therapy was checked with the built-in meter. RESULTS: Thirty-four patients with O-CSA and 61 with I-CSA were included in the analysis. The two groups were comparable with respect to age, body mass index (BMI), Epworth Sleepiness Scale, and burden of comorbidities. The mean daily equivalent dose of morphine in the O-CSA was 168 mg (range 30-1,217 mg). In the O-CSA group, 24% of PAP-naive patients responded to CPAP compared to 38% in the I-CSA group. BiPAP and ASV were comparable in eliminating central events in both O-CSA (66 versus 60 %) and I-CSA (93 versus 90%), respectively. Eight patients (24%) with O-CSA and six patients (10%) with I-CSA were considered nonresponders. The adherence rate was 48 and 24% in the I-CSA group compared to 23 and 18% in the O-CSA group at 3 and 12 months following initiation of effective treatment (p = 0.04 and p = 0.6). CONCLUSIONS: The presence of O-CSA does not preclude an adequate response to CPAP. Adherence rate to PAP was poor in both the O-CSA and I-CSA groups. Further studies are needed to define optimal adherence rate and long-term benefits of PAP in CSA. PMID- 24062012 TI - Validation of blood pressure monitoring using pulse transit time in heart failure patients with Cheyne-Stokes respiration undergoing adaptive servoventilation therapy. AB - PURPOSE: Using pulse transit time (PTT) and an ECG appears to be a promising alternative for invasive or noninvasive monitoring of blood pressure (BP). This study assessed the validity of PTT for BP monitoring in clinical practice. METHODS: Twenty-nine patients with chronic heart failure (HF; 27 male, 70.5 +/- 9.9 years) and nocturnal Cheyne-Stokes respiration were noninvasively ventilated for one hour using adaptive servoventilation (ASV) therapy (PaceWave, ResMed). BP was measured using two devices (oscillometrically via Task Force Monitor, CNSystems and PTT via SOMNOscreen, Somnomedics) at least every 7 min for 30 min before, during, and after ASV. RESULTS: Mean systolic BP was 118.1 +/- 14.4 mmHg vs. 115.9 +/- 14.1 mmHg for oscillometric method vs PTT, respectively. Corresponding values for diastolic BP were 72.3 +/- 10.3 mmHg and 69.4 +/- 11.1 mmHg. While clinically comparable, differences between the two methods were statistically significant (p < 0.05). The difference between the two methods showed an increasing trend over time. A total of 18.5 % of PTT-based measurements could not be analyzed. The direction of a change in BP was opposite for PTT vs oscillometry for 17.0 % and 32.8 % of systolic and diastolic BP measurements, respectively. CONCLUSIONS: When monitoring BP in HF patients, overall BP monitoring using PTT is comparable to oscillometry for a period of 2 h (including a 1-h ASV phase). However, PTT shows a tendency to underestimate BP over time and during ASV. PMID- 24062013 TI - Comprehensive hormone profiling of the developing seeds of four grain legumes. AB - KEY MESSAGE: Developmental context and species-specific hormone requirements are of key importance in the advancement of in vitro protocols and manipulation of seed development. Improvement of in vitro tissue and cell culture protocols in grain legumes such as embryo rescue, interspecific hybridization, and androgenesis requires an understanding of the types, activity, and balance of hormones within developing seeds. Towards this goal, the concentration of auxin, cytokinin, gibberellin, and abscisic acid (ABA) and their precursors and derivatives were measured in the developing seeds of field pea (Pisum sativum L.), chickpea (Cicer arietinum L.), lentil (Lens culinaris Medik.), and faba bean (Vicia faba L.) from 4 days after anthesis until 8 days after reaching maximum fresh weight. The importance of developmental context (developmental time and space) is demonstrated in both the differences and similarities between species for hormone profiles, especially with regard to cytokinin and ABA biosynthesis during the embryo formation. Auxin and its conjugates are significant during the pattern formation stage of all legumes; however, IAA-Asparagine appears important in the Vicieae species and its concentrations are greater than IAA from the globular stage of embryo development on in multi-seed fruits. Finally, the significance of non-polar gibberellins during lentil seed development is highlighted. PMID- 24062014 TI - Biomechanical strength analysis of mini anchors for the temporomandibular joint. AB - INTRODUCTION: The usage of mini anchors for the treatment of internal derangements of the temporomandibular joint (TMJ) is considered an innovative treatment, and it has presented excellent clinical results in the stabilization of the articular disc. This study aimed to evaluate, through mechanical tensile testing, the resistance of mini anchors for TMJ articular disc repositioning. MATERIALS AND METHODS: Ten thermoplastic polymer poly-ether-ether-ketone (PEEK) mini anchors were tested in artificial polyurethane blocks with a pullout test in a mechanical InstronTM machine, model 4411. The mini anchors were pulled out until failure and the force and displacement were recorded for each specimen. A small standard deviation was noted, which indicated reproducibility. RESULTS: The findings indicate that CillenTM mini anchors presented a mean force at failure up to 46.1 N with similar values in the scientific literature. Nevertheless, further studies should be conducted for a comparison of PEEK mini anchors with other commercially available anchors, in addition to studies related to PEEK, a scarcely known material in the dentistry field. PMID- 24062015 TI - Social media technologies for HIV prevention study retention among minority men who have sex with men (MSM). AB - This brief report describes results on study retention among minority men who have sex with men (MSM) from a 12-week, social networking-based, HIV prevention trial with 1-year follow-up. Participants, primarily minority MSM, were recruited using online and offline methods and randomly assigned to a Facebook (intervention or control) group. Participants completed a baseline survey and were asked to complete two follow-up surveys (12-week follow-up and 1-year post intervention). 94 % of participants completed the first two surveys and over 82 % completed the baseline and both post-intervention surveys. Participants who spent a greater frequency of time online had almost twice the odds of completing all surveys. HIV negative participants, compared to those who were HIV positive, had over 25 times the odds of completing all surveys. HIV prevention studies on social networking sites can yield high participant retention rates. PMID- 24062016 TI - Induction of mitochondrial permeability transition (MPT) pore opening and ROS formation as a mechanism for methamphetamine-induced mitochondrial toxicity. AB - During the past 10 years, the use of methamphetamine (METH) has significantly increased in Iran and around the world. The widespread use of 3,4 methylenedioxymethamphetamine as a recreational drug has been responsible for the incidence of several cases of liver failure in young people. This issue made researchers focus on METH toxicity due to the lack of effective treatment and human health risk assessment. There are several reports showing that its long term use increases the risk for dopamine depletion, but the toxicity mechanisms of METH in liver are not well understood. Therefore, we aimed to investigate the mitochondrial toxicity mechanisms of METH on isolated mitochondria. Rat liver mitochondria were obtained by differential ultracentrifugation, and the isolated mitochondria were then incubated with different concentrations of METH (2.5-20 MUM). Our results showed that this agent could induce oxidative stress via rising in mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential collapse, and mitochondrial swelling. In addition, collapse of mitochondrial membrane potential, mitochondrial swelling, and release of cytochrome c following METH treatment were well inhibited by pretreatment of mitochondria with cyclosporin A and butylated hydroxytoluene. Finally, it is suggested that METH could interact with respiratory complexes (II and III) and METH-induced liver toxicity may be the result of its disruptive effect on mitochondrial respiratory chain that is the obvious cause of ROS formation, mitochondrial membrane potential decline, and cytochrome c expulsion which start cell death signaling. PMID- 24062017 TI - Integrating in vitro sensitivity and dose-response slope is predictive of clinical response to ABL kinase inhibitors in chronic myeloid leukemia. AB - BCR-ABL mutations result in clinical resistance to ABL tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Although in vitro 50% inhibitory concentration (IC(50)) values for specific mutations have been suggested to guide TKI choice in the clinic, the quantitative relationship between IC(50) and clinical response has never been demonstrated. We used Hill's equation for in vitro response of Ba/F3 cells transduced with various BCR-ABL mutants to determine IC(50) and the slope of the dose-response curve. We found that slope variability between mutants tracked with in vitro TKI resistance, provides particular additional interpretive value in cases where in vitro IC(50) and clinical response are disparate. Moreover, unlike IC(50) alone, higher inhibitory potential at peak concentration (IPP), which integrates IC(50), slope, and peak concentration (Cmax), correlated with improved complete cytogenetic response (CCyR) rates in CML patients treated with dasatinib. Our findings suggest a metric integrating in vitro and clinical data may provide an improved tool for BCR-ABL mutation-guided TKI selection. PMID- 24062018 TI - Comprehensive analysis of PTEN status in Sezary syndrome. AB - Sezary syndrome (SS) is an incurable leukemic variant of cutaneous T-cell lymphoma characterized by recurrent chromosomal alterations, among which, chromosome 10q deletion is very frequent. In this study, we investigated the PTEN status, on locus 10q23, in 44 SS patients; our findings show that PTEN is deleted in 36% of SS cases, whereas PTEN downregulation is observed in almost all of the samples evaluated by quantitative reverse-transcriptase polymerase chain reaction and Western blotting analysis. Neither DNA sequence mutation nor promoter hypermethylation were found at the PTEN locus, but we demonstrate that PTEN level can be also reduced by a group of miRs previously found upregulated and of prognostic relevance in SS; particularly, miR-21, miR-106b, and miR-486 were able to control PTEN abundance either in vitro or in vivo. Finally, because reduced PTEN activates the PI3/AKT-mediated pathway of cell growth and survival, we demonstrate that PTEN deficiency is associated with activated AKT in skin resident but not circulating SS cells, suggesting that the cutaneous milieu may strongly contribute to the SS cell growth. To our knowledge, this is the first study fully exploring the PTEN status in a large cohort of SS patients, unveiling potential elements of clinical utility in this malignancy. PMID- 24062019 TI - Antimicrobial activity and cytotoxicity of some 2-amino-5-alkylidene-thiazol-4 ones. AB - We report a small, focused library of 30 diverse 2-amino-5-alkylidene-thiazol-4 ones that was assayed in a whole-cell antibacterial screen against a panel of several bacterial strains and a yeast. Most of the compounds exhibited modest to significant antibacterial activity against Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus, and no activity against Salmonella typhimurium and Escherichia coli. The antibacterial activity depends markedly upon substituents on the thiazol-4-one core, and the most potent compound assayed ([Formula: see text]-4-((2-(4-methylpiperidin-1-yl)-4-oxothiazol-5(4H) ylidene)methyl)benzonitrile) reached a minimal inhibitory concentration (MIC) value of [Formula: see text] on P. aeruginosa strain. An important feature of the tested compounds is their low influence on cell viability, as determined in a HEK 293 metabolic activity assay. In light of the encouraging in vitro antimicrobial assay results against several bacterial strains, we have generated a pharmacophore model using the Discovery studio 3.0 package (Accelrys Inc., San Diego, USA), which exposed the spatial arrangement of key molecular properties responsible for our observed MIC results. Considering the absence of a defined target and the limitation of the described approach to pool different scaffolds, the calculated pharmacophore model could be used for library enrichment to identify compounds with a thiazolidinone scaffold with improved antimicrobial potency and physico-chemical properties. PMID- 24062020 TI - [Disease management programs: data for the waste bin?]. PMID- 24062021 TI - [Disease management programs in Germany: Validity of the medical documentation]. AB - BACKGROUND AND AIM: The specific documentation for disease management programs (DMP) in Germany with respect to S 137 Social Code Book V is the basis for evaluating the DMP. DMP run up costs of the order of a billion euro without assessing evidence-based benefit so far. Aim of this study was to question if and to which extent this documentation may be suitable for reliable quality assurance in its present form. METHODS: Data of nearly 300000 insured persons of a German Statutory Health Insurance (Techniker Krankenkasse, TK) which were continuously registered from July 1st 2009 until December 31st 2010 in a DMP were analyzed. We analyzed how items which were components of claims data and of DMP documentation were matched. RESULTS: With regard to prescriptions there were some considerable differences. Prescription of glibenclamid was documented twice as frequently in the DMP documentation compared to prescriptions filled in pharmacies. Only a fraction of emergency hospitalizations documented in the claims data were found in the DMP documentation. Investigations of the fundus oculi for diabetics are mentioned three times more frequently in the DMP documentation than they are accounted by ophthalmologists. CONCLUSION: There are considerable differences between claims data and DMP specific documentation. The latter shows a plainly reduced validity for investigated fields in the documentation forms. Reasons for this are manifold. Former evaluations of DM Ps carried out just on the basis of DMP documentation are thus highly questionable. Therefore, the DMPs themselves and their documentation have to be reformed. PMID- 24062022 TI - Inhibitory effect of gallic acid on advanced glycation end products induced up regulation of inflammatory cytokines and matrix proteins in H9C2 (2-1) cells. AB - Accumulating evidences have demonstrated that increased production of advanced glycation end products (AGEs) contributes to etiology of cardiac complications in diabetes. However, the underlying mechanism of AGE-induced effects is not well understood. Recent studies evince the beneficial role of phytochemicals in reducing the risk of cardiovascular morbidity and mortality in patients with cardiovascular diseases and diabetes mellitus. Hence, in the present study, the cardioprotective role of gallic acid (GA) against in vitro synthesized AGE in H9C2 (2-1) cells was elucidated. H9C2 (2-1) cells exposed to AGE (100 MUg/ml) with/without GA pre-treatment (10 MUM) and the release of reactive oxygen species (ROS), expression of oxidative stress markers, matrix proteins, and cytokines were analyzed. Cells exposed to AGE demonstrate a significant increase in ROS release with augmented expression (P < 0.01) of receptor for AGE (RAGE) and NOX p47 phox (P < 0.001) proteins compared to untreated control cells. Moreover, an increased expression of matrix proteins and cytokines such as TNF-alpha (P < 0.01), TGF-beta (P < 0.001), and iNOS (P < 0.001) was also found in AGE-treated cells, whereas, cells pre-treated with N-acetyl cysteine or RAGE neutralizing antibody notably (P < 0.01) impede the ROS release. Further, cells pre-treated with GA significantly attenuated the expression of NOX, RAGE, and other cytokines. In addition, the abnormal expressions of matrix proteins were also decreased especially in GA-treated cells. Thus, the results of the present study demonstrated the deleterious effect of AGEs that directly induce oxidative stress and matrix derangement and, on the other way, the "pleiotropic" activity of GA in reducing the risk of AGE-mediated cellular complications. PMID- 24062023 TI - Silibinin potentially attenuates arsenic-induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats. AB - Cardiac dysfunction is one of the major causes of mortality and morbidity throughout the world. Chronic exposure of arsenic (As) mainly leads to cardiotoxic effect. Cardiotoxicity was induced by the sodium arsenite as the source of As (5 mg/kg BW, PO) for 4 weeks. As intoxication significantly (p < 0.05) increased the serum cardiac markers, viz. creatine kinase-MB, lactate dehydrogenase, aspartate transaminase, alanine transaminase and alkaline phosphatase, oxidative stress markers in heart, plasma total cholesterol (TC), triglycerides (TG), phospholipids (PL), free fatty acids (FFA), low density lipoprotein cholesterol, very low density lipoprotein cholesterol as well as cardiac lipid profile (TC, TG and FFA) and significantly (p < 0.05) decreased the level of serum high density lipoprotein cholesterol, cardiac PL, mitochondrial enzymes such as ICDH, SDH, MDH, alpha-KDH and NADH dehydrogenase, levels of enzymatic antioxidant, nonenzymatic antioxidants and membrane-bound ATPases in heart. In addition, As-intoxicated rats showed a significant (p < 0.05) up regulation of myocardial NADPH (NOX) oxidase sub units such as NOX2 and NOX4 as well as Keap-1 and down-regulation of Nrf2 and HO-1 protein expressions. Pre administration of silibinin (SB) (75 mg/kg BW) remarkably recovered all these altered parameters to near normalcy in As-induced cardiotoxic rat. Moreover, the light microscopic and transmission electron microscopic study further supports the protective efficacy of SB on the heart mitochondria. In conclusion, our data demonstrate that SB has a potential to extenuate the arsenic-induced cardiotoxicity and dyslipidemia in rat. PMID- 24062024 TI - Multiscale tomographic analysis of polymer-nanoparticle hybrid materials for solar cells. AB - The present work focuses on the study of the three-dimensional (3D) morphology of polymer and nanoparticle hybrid nanocomposites used as active layers in solution processed solar cells. The hybrid consists of blends of regioregular poly(3 alkylthiophene) and CdSe nanorods. Electron tomography (ET) analysis performed in high-angle annular dark-field scanning transmission electron microscopy (HAADF STEM) allows resolving single nanorods in the hybrid blend. These results are compared with those obtained using focused ion beam coupled with scanning electron microscopy (FIB-SEM), operated in a so-called 3D "slice-and-view" mode. This technique allows 3D information to be obtained on a whole device stack (hybrid active layers plus electrodes and the substrate) for significantly larger surface areas than with ET (~10 vs. ~0.1 MUm(2)). The combination of ET and 3D FIB "slice-and-view" reconstructions provides complementary and coherent information on the 3D morphology of the hybrid systems at different length scales. Phase separation between the nanoparticles and the polymer is investigated by a quantitative analysis of the reconstructed volumes and is related to the performances of the hybrid devices. PMID- 24062025 TI - [Delayed effects of oncological therapy]. AB - Due to therapy-associated improvements in survival rates, delayed effects of cancer are a rapidly increasing but as yet only poorly recognized problem. These delayed sequelae, which by definition occur years after the primary disease, include secondary tumors and many non-oncological internal medical problems. Little attention has so far been paid to the cardiovascular, gastrointestinal, renal and endocrinal delayed side effects and must be specifically addressed due to the often slowly progressing symptoms. PMID- 24062027 TI - Structure, Function and Regulation of Group IV Phospholipase A2 Family. AB - The Group IV phospholipase A2 family is consisted of six intracellular enzymes. They catalyze hydrolysis of the sn-2 ester bond of glycerophospholipids, releasing fatty acid metabolites and lysophospholipids. Agonist-induced release of arachidonic acid for the production of eicosanoids by PLA2IValpha enzyme is important in regulating normal and pathological processes in a variety of target tissues. Here, we compare PLA2IValpha, and its paralogs beta, gamma, delta, epsilon and zeta in term of of their structure, function and regulation. PMID- 24062026 TI - Depressive symptoms and inflammatory biomarkers in patients with heart failure. AB - BACKGROUND: Inflammation may be a link between depressive symptoms and outcomes in patients with heart failure. It is not clear whether inflammatory markers are independently related to depressive symptoms in this population. AIM: To determine which inflammatory biomarkers are independently associated with depressive symptoms in heart failure. METHODS AND RESULTS: We analyzed data from 428 outpatients enrolled in a heart failure registry (32% female, 61 +/- 12 years, 48% New York Heart Association Class III/IV). Depressive symptoms were measured with the Beck Depression Inventory-II. Serum C-reactive protein (CRP), cytokines (interleukin 1 receptor antagonist, 2, 4, 6, 8, 10), tumor necrosis alpha, and soluble receptors sTNFR1 and sTNFR2 were measured with enzyme immunoassay. Multiple regressions were used to determine which biomarkers were associated with depressive symptoms controlling for demographics, heart failure severity, and clinical variables. Twenty-seven percent (n = 119) had depressive symptoms. CRP was related to depressive symptoms after controlling for age and gender, but no inflammatory biomarkers were associated with depressive symptoms after controlling for all variables in the model. CONCLUSIONS: There was no relationship between inflammatory biomarkers and depressive symptoms. Our findings, in combination with prior researchers', suggest there is not a robust relationship between depressive symptoms and individual biomarkers of inflammation in heart failure. PMID- 24062028 TI - Overview of the development and application of the hyphenated techniques in nutritional analysis. AB - The development of some sensitive assays for quantitative nutritional analysis with an emphasis on selected hyphenated analytical techniques is reviewed in the present paper. The majority of work is dedicated to reviewing the development of analytical tools for routine analysis of carbohydrates and lipids in biological samples, many of them introduced in our laboratory. Handling biological matrices, where endogenous compounds can mask the analyte of interest or where the occurrence of the coelution effect of several compounds present in different amounts hinders the analyte's peak integration, is a major challenge. To overcome this challenge, hyphenated techniques have become widespread in laboratory practice. Some of these techniques are reviewed, with special attention given to an effective on-line interface for thin-layer chromatography-mass spectrometry and on-line coupling thin-layer chromatography-gas chromatography. Recently introduced an on-line coupling of ion chromatograph and hybrid RF/DC quadrupole linear ion trap mass spectrometer represent an analytical tool for the solution of bioanalytical problems. Developed methods using ion chromatography-pulsed amperometric detection and ion chromatography-mass spectrometry techniques for the quantitative evaluation of sugars are presented. This paper represents basic contributions of our research work connected with some of modern hyphenated techniques. However, this review is restricted to the published papers to be significant developments or improvements during the last three decades. PMID- 24062029 TI - Optical behaviour of copper phthalocyanine preparations for inkjet inks. AB - The present study investigates the preparation of the copper phthalocyanine pigment for inkjet printing inks. The pigment particle size distribution was measured with laser diffraction at different times of wet milling. Simultaneously, the absorbance spectra in a visible-near infrared spectral region of the corresponding diluted pigment dispersions were measured. At the beginning of the milling process, the particle size distribution is bimodal, showing the presence of aggregates and agglomerates. During the second hour of milling, the particle size distribution changes to unimodal due to the breaking of agglomerates, and the corresponding absorbance spectra change accordingly. Further milling diminishes the size of pigment aggregates up to the steady state value of around 130 nm, where also the absorbance in the corresponding spectra does not increase. A detailed analysis of intensity and position of the absorbance peak at 340 nm in dependence on the milling time and pigment concentration confirms the idea that an optical spectroscopy could be used for the assessment of optimal milling time required for the preparation of pigments with the maximum absorption ability. PMID- 24062030 TI - Relative Stability and Spectroscopic Regularity of C80O Based on C80(D5d). AB - The relative stabilities of the nine possible isomers for C80O based on C80(D5d) were investigated via density function theory (DFT) at B3LYP/6-31G(d) level. The most stable geometry of C80O is predicted to be 23,24-C80O, where an annulene like structure is formed. The stretching vibration frequencies of the C=C bonds in the IR spectrum of C80O compared with those of the C=C bonds in the IR spectrum of C80(D5d) are basically blue-shifted. The signals of the bridged carbon atoms in the NMR spectrum of C80O, computed at B3LYP/6-31G level, are changed upfield compared with those of the correspoding carbon atoms in the NMR spectrum of C80(D5d). The anti-aromaticity of rings in C80O relative to that of the corresponding rings in C80(D5d) is decreased according to the NICS values at the dummy centers of these rings calculated at B3LYP/6-31G level. A hexagon in 21,22-C80O even shows a tendency of aromaticity. PMID- 24062031 TI - Kinetics of Crystal Violet Fading in the Presence of TX-100, DTAB and SDS. AB - The rate constant of alkaline fading of crystal violet (CV+) was measured in the presence of non ionic (TX-100), cationic (DTAB) and anionic (SDS) surfactants. This reaction was studied at 283-303 K. The rate of reaction showed remarkable dependence on the electrical charge of the used surfactants. It was observed that the reaction rate constant increased in the presence of TX-100 and DTAB and decreased in the presence of SDS. Binding constants of CV+ with TX-100 and DTAB and the related thermodynamic parameters were obtained by classical (or stoichiometric) model. The results show that binding of CV+ to TX-100 is endothermic and binding of CV+ to DTAB and SDS is exothermic in the used concentration range of surfactants. PMID- 24062032 TI - Ab Initio Intermolecular Potential Energy Surface of CO2-C2H2 Complex. AB - A new four-dimensional potential energy surface for CO2-C2H2 complex has been calculated by the ab initio methods at MP2/cc-pVXZ and MP2/aug-cc-pVXZ theory. For calculating the PES of the CO2-C2H2 complex, we have chosen to follow the supermolecule approach. The complete basis set limit of potential energy surface has been taken by extrapolation. Our MP2 results showed the most stable form of CO2-C2H2 complex is a parallel configuration. The complete basis set limit of ab initio potential energy surfaces have fitted to an analytic function and performance of fitting assessed. The electrostatic contribution to the PES has calculated and shows that it is anisotropic. PMID- 24062033 TI - Freeze-drying and release characteristics of polyelectrolyte nanocarriers for the mucosal delivery of ovalbumin. AB - Polyelectrolyte complexes (PEC) consisting of an alginate core entrapping the protein ovalbumin and the chitosan coating were prepared by the self-assembly of oppositely charged polyelectrolytes. The PEC were prepared at pH 4.0 and consisted of alginate, ovalbumin and chitosan in a concentration of 0.5, 0.5 and 0.05 mg/ml, respectively, having a particle size of around 300nm, a zeta potential of -44 mV and a protein association efficiency of 80%. The release of ovalbumin from PEC was mostly dependant on the pH of release medium and the presence of strong electrolytes contributed to higher release. Approximately 90% of the ovalbumin was released in a phosphate buffer media, pH 7.4. The release was lower in media with pH 4.0, reaching the value of app. 40% and 60% of ovalbumin released in water (pH 4.0) and NaCl solution (0.9% w/v, pH 4.0), respectively. In an acidic saline solution, pH 3.0, there was only 5% of ovalbumin release, however, increasing the pH to 6.8, approximately 70% of ovalbumin immediately released from the PEC. The PEC were freeze-dried aided by various excipients. Their efficiency on the redispersibility of the freeze-dried product was evaluated according to the mean particle diameter, polydispersity, average scattering intensity (particle concentration) and visual appearance of the PEC (Tyndal effect). In the presence of trehalose and mannitol, the aggregation and integrity of the PEC were prevented, yielding properties similar to the PEC dispersion before lyophilisation. The surface hydrophobicity of the ovalbumin either free or formulated in the nanocomplexes was determined by the bis-ANS fluorescence intensity, indicating a higher surface hydrophobicity for the PEC. The mild formulation conditions, nanometre-sized particles, high protein association efficiency, pH-dependant release, and modified surface properties are promising factors towards the development of an oral delivery system for protein made by the self-assembly of oppositely charged polyelectrolytes. PMID- 24062034 TI - Concentration and Temperature Effects on the Electronic Absorption Spectra of 1 pyridinyl-2-methylene-benzenecarbohydrazonic Acid Following Solvatochromic Studies. AB - In this work, UV-Vis. electronic spectra of 1-pyridinyl-2-methylene-benzene carbohydrazonic acid (L) have been studied. The different bands observed have been assigned to the proper electronic transitions. The solvatochromic behavior of this compound is investigated by studying their electronic spectra in organic solvents with different polarities. The longer wavelength band is assigned to an intermolecular charge transfer (CT) transition. The solvated H-bonding complexes formed between dimethylformamide and L is also investigated. DeltaG, and Kf values of this complex have been determined. Effects of temperature increase and concentration changes on the longer spectroscopic wavelength band of 1-pyridinyl 2-methylene-benzenecarbohydrazonic acid were studied too. PMID- 24062035 TI - 1,3-dipolar cycloaddition reactions of N-methyl-substituted tricyclic imides. AB - The [3+2] cycloadditions of N-methyl derivatives of unsaturated imides with various nitrile oxides to yield new bridged isoxazoline derivatives with potential biological activity is described. PMID- 24062036 TI - Analysis of Nefopam by TLC-densitometry. A Study of Degradation Mechanism in Solutions Under Stress Conditions. AB - A new, simple, selective, precise and accurate thin-layer chromatographic method for quantification of nefopam hydrochloride in formulations has been established and validated. TLC F254 silica gel plates in combination with a mixture of chloroform : methanol : glacial acetic acid (9 : 2: 0.1, v/v/v) as mobile phase were used. UV detection was performed densitometrically at a wavelength of 222nm. The method was validated for linearity, precision, accuracy, selectivity and specificity in accordance with ICH guidelines. Nefopam hydrochloride was subjected to acid and alkaline hydrolysis at different temperatures. The degradation products were well resolved from the pure drug with substantially different RF values and absorption spectra. LC-MS/MS analysis was used to characterize the chemical properties of degradation products. The likely chemical structures of the major degradation products are 2-[(2 benzylbenzyl)(methyl)amino]ethanol, 2-[2-[hydroxyl(phenyl)methyl]-benzyl(methyl) amino] ethanol and diphenylmethanone. PMID- 24062037 TI - Electrochemical studies of adsorption and inhibitive performance of basic yellow 28 dye on mild steel corrosion in Acid solutions. AB - Organic corrosion inhibitors are widely used to control the corrosion of different metals in various corrosive solutions. The inhibition performance of Basic yellow 28 (BY28) dye for mild steel corrosion was investigated in 0.1 M HCl solution and in a solution of 0.1 M HCl and 1% NaCl. Two electrochemical methods including Tafel polarization and electrochemical impedance spectroscopy (EIS) measurements were used. The corrosion parameters as well as inhibition efficiencies were obtained for different concentrations of inhibitor. The inhibition efficiencies showed that the BY28 dye acts as a good corrosion inhibitor for mild steel in both solutions. The studies on adsorption isotherm of the dye on mild steel proved that the adsorption of BY28 obeys the Langmuir adsorption isotherm. The average value of -DeltaGads in both solutions was more than 20 and a little less than 40 kJ mol-1. Therefore, both chemisorption and physisorption phenomena were involved in the adsorption of the studied dye on mild steel surface. PMID- 24062038 TI - First and second derivative synchronous fluorescence and spectrophotometric spectroscopy for the simultaneous determination of fexofenadine hydrochloride in presence of its degradation products. Application to stability studies. AB - Two rapid, simple, sensitive, selective and economic derivative spectrophotometric (first [D1] and second [D2]) and synchronous spectrofluorimetric (FDSFS and SDSFS) methods have been developed for the analysis of fexofenadine hydrochloride (FXD) in the presence of its different degradation products. Derivative spectrophotometry (D1) was used to measure FXD at 223 nm in the presence of its alkaline or acidic degradation products, and at 211 nm in the presence of its oxidative degradation product. Derivative spectrophotometry (D2) was used to determine FXD at 217 nm in the presence of its alkaline or acidic degradation products, and at 215 nm in the presence of its oxidative degradation product; the UV degradation product was measured at 211 nm. Synchronous spectrofluorimetry (FDSFS) was used to measure FXD in the presence of its alkaline or acidic degradation products at 406 nm, and at 367 nm in the presence of its oxidative or UV degradation products. Synchronous spectrofluorimetry (SDSFS) was applied to determine the drug at 225 nm in the presence of its alkaline, acidic, oxidative or UV degradation products. The proposed methods were successfully applied for the determination of the studied compound in its commercial tablets. The results obtained were in good agreement with those obtained by the comparison method. PMID- 24062039 TI - Spectrophotometric Determination of Fe3+ and Pb2+ in Real Samples after Micelle mediated Extraction. AB - A cloud-point extraction process using micelle of the cationic surfactant CTAB to extract Fe3+and Pb2+ from aqueous solutions was investigated. The method is based on the color reaction of Fe3+and Pb2+ with bromopyrogallol red at pH 5.0 and micelle-mediated extraction of the complex. The optimal extraction and reaction conditions (e.g., surfactant concentration, reagent concentration and effect of time) were studied and the analytical characteristics of the method (e.g., limit of detection, linear range, preconcentration and improvement factors) were obtained. Linearity was obeyed in the range of 0.05-43.00 ng mL-1 of Fe3+ ion and 0.10-40.00 ng mL-1 of Pb2+ ion and the detection limit of the method was 0.020 and 0.040 ng mL-1 for Fe3+ and Pb2+, respectively. The interference effect of some anions and cations was also tested. The method was applied to the determination of Fe3+ and Pb2+ in vegetable (lettuce, spinach, cabbage, parsley, and dill), tea, rice, human hair, liver, and chicken and water samples. PMID- 24062040 TI - Design, Synthesis and in vitro Biochemical Activity of Novel Amino Acid Sulfonohydrazide Inhibitors of MurC. AB - Mur ligases are essential enzymes involved in the cytoplasmic steps of peptidoglycan synthesis which remain attractive, yet unexploited targets. In order to develop new antibacterial agents, we have designed a series of new MurC and MurD inhibitors bearing amino acid sulfonohydrazide moiety. The L-Leu series of this class displayed the highest enzyme inhibition with IC50 in the concentration range between 100 and 500 uM, with L-Thr, L-Pro and L-Ala derivatives being inactive. The most promising compound of the series also expressed weak antibacterial activity against S. aureus with MIC = 128 ug/mL. PMID- 24062041 TI - Dispersive liquid-liquid microextraction of copper ions as neocuproine complex in environmental aqueous samples. AB - In the present study, a simple and efficient extraction method based on dispersive liquid-liquid microextraction prior to UV-Vis spectrophotometry was developed for the preconcentration and determination of copper ions in environmental samples. Briefly, cupric ions (Cu II) were reduced to cuprous (Cu I) with addition of hydroxyl amine hydrochloride and formed hydrophobic chelates with neocuproine. Then, a proper mixture of acetonitrile (as dispersive solvent) and choloroform (as extraction solvent) was rapidly injected into the solution and a cloudy solution was formed. After centrifuging, choloroform was sedimented at the bottom of a conical tube and diluted with 100 uL of methanol for further UV-Vis spectrophotometry measurement. An orthogonal array design (OAD) was employed to study the effects of different parameters on the extraction efficiency. Under the optimum experimental conditions, a preconcentration factor up to 63.6 was achieved for extraction from 5.0 mL of sample solution. The limit of detection (LOD) based on S/N = 3 was 0.33 ug L-1 and the calibration curve was linear in the range of 1-200 ug L-1 with reasonable linearity (r2 > 0.997). Finally, the accuracy of the proposed method was successfully evaluated by determination of trace amounts of copper ions in different water samples and satisfactory results were obtained. PMID- 24062042 TI - Study of Immediate Release Spherical Microparticles Containing Clarithromycin using a Hot-melt Fluid Bed Technique. AB - The aim of the study was to evaluate a hot-melt technique for preparation of immediate release spherical microparticles containing clarithromycin with acceptable characteristics and process yield. A modified fluid bed apparatus with rotor insert was used to prepare spherical microparticles in the size range of 125-355 um. Poloxamer 188, PEG-32 glyceryl laurate (Gelucire 44/14) and a mixture of polyethylene glycol (PEG) 4000 with PEG 400 were used as meltable binders. Key process parameters were identified and optimized and their influence on process yield and microparticles characteristics was determined. Microparticles with poloxamer 188 and PEG exhibited relatively good mechanical properties. Process yield was around 70% and 60% in the case of PEG and poloxamer 188 respectively. Microparticles prepared with PEG-32 glyceryl laurate exhibited poor mechanical properties and process yield compared to other microparticles. The process was shown to be limited by the bed temperature, exhibiting the best process stability with poloxamer 188 followed by PEG and PEG-32 glyceryl laurate. Dissolution rate and equilibrium concentration of clarithromycin released from prepared microparticles was improved compared to similar particles prepared by wet granulation. PMID- 24062043 TI - Stability of pesticides' residues under ultraviolet germicidal irradiation. AB - Legislation for food safety is limited mostly to pesticides monitoring and no attention is paid to the presence and toxicity of by-products formed after pesticide application. Stability studies of three selected transformation products: IMP - 2-isopropyl-6-methyl-4-pyrimidinol (diazinon hydrolysis product), TCP - 3,5,6-trichloro-2-pyridinol (chlorpyrifos transformation product), and 6CNA - 6-chloronicotinic acid (imidacloprid and acetamiprid transformation product) were performed under exposure to sunlight at room temperature (22 degrees C) and in the dark at 4 degrees C over 90 days. The results showed slight change in concentration with samples under refrigeration in darkness.Alternatively, an aqueous solution of TCP exposed to sunlight resulted in a high decrease of initial concentration within time. The toxicity assessment was performed using luminescent bacteria Vibrio fischeri and the results expressed low toxicity in the case of IMP and 6CNA. However, for TCP the calculated EC50 value after 30 minutes of exposure equated to roughly 15.1 mg L-1. Stability of the selected transformation products upon 245 nm irradiation indicated little decrease in concentration for IMP and 6CNA in deoxygenated and oxygenated aqueous solutions. In the case of TCP, the photochemical behaviour appeared to depend on oxygen concentration in the medium. For more detailed comparison, the degradation quantum yields were calculated. PMID- 24062044 TI - Optimal process mode selection for clone screening. AB - A significant amount of data is generated during clone screening procedures because several cultivation systems are used such as well-plates, shake-flasks, laboratory-scale bioreactors among others. The amount of data can often be staggering and thus requires the use of statistical and data mining procedures in order to extract hidden information. In regard to a biosimilar monoclonal antibody project, data from the shake-flask scale was observed when comparing batch and fed-batch processes for several individual clones derived from two different cell lines. The aim of the research presented in this paper was to determine if clone selection based on batch data during the initial screening phase was equivalent to the results from fed-batch selection. It was determined that fed-batch processes should be implemented early during the screening procedure, if a choice is made that the final manufacturing process should also be operated in a fed-batch mode, as clone selection based on both batch and fed batch analytical data was divergent. PMID- 24062045 TI - Influence of dielectric constant on protonation equilibria of L-aspartic Acid in acetonitrile- and ethylene glycol-water mixtures. AB - The protonation constants of L-Aspartic acid have been studied pH-metrically in various concentrations (0-60% v/v) of acetonitrile- and ethylene glycol-water mixtures maintaining an ionic strength of 0.16 mol L-1 at 303K. The protonation constants have been calculated with the computer program MINIQUAD75 and are selected based on statistical parameters. Linear variation of step-wise protonation constants (log K) with the reciprocal of the dielectric constant of the solvent mixture has been attributed to the dominance of the electrostatic forces. PMID- 24062046 TI - Imatinib Quantification in Human Serum for Clinical Purposes using High performance Liquid Chromatography with a Diode Array Detector. AB - The popularity of imatinib in modern medicine has underscored the need for a fast and effective quantification method without the use of expensive instruments. The aim of this study was to develop and validate a relatively fast, cheap and effective HPLC method for the quantification of imatinib in human serum. This method uses a simple preparation step with an Extrelut(r) NT 3 extraction tube and commercial available solvents. A Marcherey-Nagel Lichrospher 100-5 RP8 250 * 4 mm column held at 30 degrees C, a mobile phase of 0.05 M H3PO4/KH2PO4 acetonitrile (7:3, v/v) at a flow rate of 1 mL/min and a diode array detector operated at a wavelength of 265 nm were used for the analysis of 50 uL prepared sample injected into the HPLC. A single run was completed in 15 min. The method presented here has a limit of quantification of 30 ng/mL and is linear between 0.1 and 10 ug/mL. PMID- 24062047 TI - Contribution to the thermodynamics of sc3+, y3+, la3+ and trivalent lanthanide cations in the two-phase water-nitrobenzene extraction system. AB - From the exchange extraction constants corresponding to the general equilibrium M3+(aq) + 3H+(nb) <-> M3+(nb) + 3H+(aq) occurring in the two-phase water nitrobenzene system (M3+ = Sc3+, Y3+, La3+, Ce3+, Pr3+, Nd3+, Sm3+, Eu3+, Gd3+, Tb3+, Dy3+, Ho3+, Er3+, Tm3+, Yb3+, Lu3+; aq = aqueous phase, nb = nitrobenzene phase), the individual extraction constants of 16 trivalent metal cations were calculated. It was found that these individual extraction constants in the mentioned two-phase system increase in the following cation order: Sc3+ < Yb3+< Ho3+ < Er3+ < Tm3+, Lu3+ < Y3+, Dy3+ < Tb3+ < Gd3+ < Eu3+ < Sm3+ < Nd3+ < Pr3+ < La3+, Ce3+. PMID- 24062048 TI - Extraction and DFT Study on the Complexation of the Sodium Cation with Dibenzo-18 crown-6. AB - From extraction experiments and gamma-activity measurements, the extraction constant corresponding to the equilibrium Na+(aq) + A-(aq) + 1(nb) left arrow over right arrow 1*Na+(nb) + A-(nb) taking place in the two-phase water nitrobenzene system (A- = picrate, 1 = dibenzo-18-crown-6; aq = aqueous phase, nb = nitrobenzene phase) was evaluated as was log Kex (1*Na+, A-) = 1.7 +/- 0.1. Further, the stability constant of the complex 1*Na+ in nitrobenzene saturated with water calculated for a temperature of 25 degrees C: log betanb (1*Na+) = 6.9 +/- 0.1. Finally, by using quantum mechanical DFT calculations, the most probable structures of the resulting complex were solved. PMID- 24062049 TI - Thieno[2,3-b]thiophenes: Part 7. Some Heterocyclization Reactions with Ethyl 3,4 diamino-5-cyanothieno[2,3-b]thiophene-2-carboxylate. AB - Ethyl 3,4-diamino-5-cyanothieno[2,3-b]thiophene-2-carboxylate (1) was treated with a mixture of carbon disulfide and halo compounds to give the corresponding bisthiazole and bisthiolane derivatives 2-4. Treatment of compound 1 with 2,5 dimethoxytetrahydrofuran gave the corresponding 3,4-dipyrrol-1-ylthienothiophene (5). Condensation of compound 5 with hydrazine afforded the carbohydrazide derivative 6, which was treated with CS2 or PhNCS to afford oxadiazole or triazole derivatives 7a,b. The cycloaddition reaction of compound 5 with CS2 or PhNCS under phase transfer conditions gave 1,4-thiazepino- or 1,4 diazepinothieno[2,3-b]thiophenes 8 and 9, respectively. Basic hydrolysis of compound 1 yielded 3,4-diaminothieno[2,3-b]thiophene (10), which was subjected to react with different reagents to give the corresponding bispyrido- and bispyrrolothieno[2,3-b]thiophenes, and bisarylideneaminothieno[2,3-b]thiophenes 11-15, respectively. PMID- 24062050 TI - A cobalt nitrate/hydrogen peroxide system as an efficient reagent for the synthesis of 2-aryl benzimidazoles and benzothiazoles. AB - Benzimidazoles and benzothiazoles show significant and promising activities against various viruses such as HIV and HCMV-1. Their synthesis using cobalt nitrate and hydrogen peroxide in N,N-dimethylformamide has been presented in the following study. The cobalt nitrate/H2O2 appears to be a smooth and efficient reagent system for the synthesis of 2-aryl substituted benzimidazoles and benzothiazoles. Simple and convenient reaction procedures and shorter reaction times are the salient features of the presented route. PMID- 24062051 TI - Removal Efficiency of COD, Total P and Total N Components from Municipal Wastewater using Hollow-fibre MBR. AB - The membrane bioreactor (MBR) integrates well within the conventionally activated sludge system regarding advanced membrane separation for wastewater treatment. Over the last decade, a number of MBR systems have been constructed worldwide and this system is now accepted as a technology of choice for wastewater treatment especially for municipal wastewater. The aim of this work was to investigate and compare submerged MBR with conventionally-activated sludge system for the treatment of municipal wastewater in Maribor, Slovenia. It can be concluded from the results, that the efficiencies being determined by the parameters were satisfied, such as, chemical oxygen demand, total phosphorous, and total nitrogen, which were 97%, 75%, and 90%, respectively. The efficiencies of ultrafiltration membrane for the same parameters were also determined, and compared with biological treatment. The results of this analysis show an additional effect regarding an improvement in the quality of the permeate but primary treatment is also very important. For successfully application of MBR system smaller grid for primary treatment is needed. PMID- 24062052 TI - Connexin 43 is not essential for the control of renin synthesis and secretion. AB - The juxtaglomerular areas of mammalian kidneys express the gap junction proteins connexin 37, 40, 43, and 45. Among these, Cx40 plays a major role for the function of juxtaglomerular renin-expressing cells, while Cx37 and Cx45 appear to be less relevant in this context. Since the role of the remaining Cx43 for the function of renin expression is not well understood, this study aimed to systematically characterize the direct role of Cx43 for renin expression and secretion. For this aim, we generated mice with endothelium and with renin cell specific deletions of Cx43, and we characterized the regulation of renin expression and renin secretion in the kidneys of these mice on normal salt diet and during chronic challenge of the renin system by pretreatment of mice with a low-salt diet in combination with an angiotensin I-converting enzyme inhibitor. We found that renal renin mRNA abundance, plasma renin concentration, and systolic blood pressure did not differ between wild-type, Cx43(fl/fl) Ren1d(+/Cre) mice as well as Cx43(fl/fl) Tie-2(+/Cre) mice under basal conditions nor under chronic stimulation by salt depletion. The localization of renin expressing cells was also regular in kidneys of all genotypes, and moreover, regulation of renin secretion by beta-adrenergic stimulation and renal perfusion pressure measured in isolated perfused kidneys of Cx43(fl/fl) Ren1d(+/Cre) and Cx43(fl/fl) Tie-2(+/Cre) mice was not different from control. We infer from these results that Cx43 plays if at all only a minor role for the functional control of renin-producing cells in the kidney. PMID- 24062053 TI - Social deprivation influences the epidemiology and outcome of proximal humeral fractures in adults for a defined urban population of Scotland. AB - We present the epidemiology and incidence of proximal humeral fractures over a 17 year period for a defined urban population that represents approximately 13% of the population in Scotland, and functional outcome in relation to the socio economic status of the patient. The incidence of proximal humeral fractures significantly increased during the study period from 47.9/10(5)/year to 98.7/10(5)/year in 2008 (p < 0.0001), which was greatest for the most socially deprived patients reaching 274.2/10(5)/year in 2008 (p < 0.0001). The most deprived patients sustained their fracture 4 years earlier than the most affluent patients (p = 0.026). Social deprivation was an independent predictor, after adjusting for other confounding variables using multivariable regression analysis, of a significantly worse functional outcome according to the Constant score at 1 year (p = 0.046). Preventative measures, especially for the most socially deprived patients within society, need to be instigated urgently to address the increasing incidence of proximal humeral fractures and alleviate the burden of these morbid fractures in the future. Whether the observed increased incidence is generalisable to a national population would need to be confirmed in future studies. PMID- 24062054 TI - Custom-fit total knee arthroplasty: our initial experience with 30 knees. AB - We report our initial experience of total knee arthroplasty (TKA) using customized cutting block technology in 30 TKAs from December 2010 to September 2012. Customized blocks were generated for each of the knees using preoperative magnetic resonance imaging of knee and long-leg weight-bearing radiographs. At 30 days, long-leg radiographs were obtained to evaluate the coronal alignment. Twenty-six of the 30 knees had a mechanical axis restored to within 3 degrees of neutral. We conclude that this technology can be safely used in most of the cases of osteoarthritis. PMID- 24062055 TI - Palliative embolization for osteosarcoma. AB - BACKGROUND: The prognosis of patients with metastatic, recurrent, and/or unresectable osteosarcoma is poor. Aggressive local and medical treatments are available for palliation. Palliative treatments include isolated limb perfusion, radiation therapy, embolization, chemoembolization, thermal ablation, and cryoablation. Their aim is pain relief and tumor size reduction with minimum complications. MATERIALS AND METHODS: We present 19 patients with metastatic, recurrent, and/or unresectable osteosarcoma of the pelvis and lower lumbar spine treated with palliative selective embolization using N-2-butyl cyanoacrylate. All patients had chemotherapy. At the time of embolization, they experienced severe pain refractory to analgesics. Diagnostic angiography was performed pre embolization to determine the vascular mapping and hemodynamic status of the tumor. Post-embolization angiography was done to evaluate for complete occlusion of the pathological vessels. Mean follow-up was 18 months. Local pain, tumor necrosis and size, and complications were recorded. RESULTS: In all patients, pre embolization angiography showed hypervascularity of the tumor from extensive neovascularization. Five patients had repeat embolization. All patients experienced pain relief at a mean of 3 days post-embolization. No patient had recurrent pain with the intensity of that before embolization. Variable tumor necrosis was observed in follow-up imaging, and reduction in tumor size was minimum. All patients experienced pain at the site of embolization, which resolved completely 1-5 days after embolization. Four patients with pelvic osteosarcomas experienced paraesthesias at the distribution of the sciatic nerve. CONCLUSION: Selective arterial embolization is a useful local palliative treatment for patients with advanced osteosarcoma for pain relief. PMID- 24062056 TI - Extent of linkage disequilibrium in large-breed dogs: chromosomal and breed variation. AB - The aim of this study was to better define the extent of linkage disequilibrium (LD) in populations of large-breed dogs and its variation by breed and chromosomal region. Understanding the extent of LD is a crucial component for successful utilization of genome-wide association studies and allows researchers to better define regions of interest and target candidate genes. Twenty-four Golden Retriever dogs, 28 Rottweiler dogs, and 24 Newfoundland dogs were genotyped for single-nucleotide polymorphism (SNP) data using a high-density SNP array. LD was calculated for all autosomes using Haploview. Decay of the squared correlation coefficient (r (2)) was plotted on a per-breed and per-chromosome basis as well as in a genome-wide fashion. The point of 50 % decay of r (2) was used to estimate the difference in extent of LD between breeds. Extent of LD was significantly shorter for Newfoundland dogs based upon 50 % decay of r (2) data at a mean of 344 kb compared to Golden Retriever and Rottweiler dogs at 715 and 834 kb, respectively (P < 0.0001). Notable differences in LD by chromosome were present within each breed and not strictly related to the length of the corresponding chromosome. Extent of LD is breed and chromosome dependent. To our knowledge, this is the first report of SNP-based LD for Newfoundland dogs, the first report based on genome-wide SNPs for Rottweilers, and an almost tenfold improvement in marker density over previous genome-wide studies of LD in Golden Retrievers. PMID- 24062057 TI - Expression of programmed death-1 (PD-1) on CD4+ and CD8+ T cells in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is characterized by chronic inflammatory process that targets the synovial lining of diarthrodial joints. Programmed death 1 (PD-1) plays a key role in the negative regulation of the immune response. In the current study, we investigated the expression of PD-1 on peripheral CD4+ and CD8+ T cells in RA patients. Percentage of PD-1+ cells was measured by flow cytometry in 82 RA cases and 90 healthy controls. Results showed that PD-1 expression was significantly decreased in both peripheral CD4+ and CD8+ T cells in RA (p = 0.002 and p < 0.001, respectively). Similarly, serum levels of soluble PD-1 were also downregulated in RA cases. When comparing PD-1 level in RA patients with different clinical parameters, patients with positive C-reactive protein (CRP) revealed lower proportion of PD-1 on CD4+ and CD8+ T cells than those with negative CRP. Also, disease activity score of RA patients was inversely correlated with PD-1 expression on peripheral CD4+ and CD8+ T cells. These data suggested that PD-1 may act as a negative regulator in the pathogenesis and progression of RA. PMID- 24062058 TI - Inhibition of P2X4 suppresses joint inflammation and damage in collagen-induced arthritis. AB - Recent data have shown that the purinergic receptor P2X4 plays key roles in inflammatory responses. We evaluated whether P2X4 inhibition could affect the development of arthritis and autoimmunity in collagen-induced arthritis (CIA) model. P2X4 antisense oligonucleotide (asODN) was injected intravenously via tail vein into the CIA mice to selectively inhibit P2X4 expression daily for 14 days. P2X4 asODN treatment reduced the clinical score of CIA in mice. P2X4 asODN also decreased the levels of serum IL-1beta, TNF-alpha, IL-6, and IL-17. P2X4 asODN treatment significantly inhibited synovial inflammation and joint destruction. P2X4 asODN treatment also suppressed the NLR family, pyrin domain containing 1 (NLRP1) inflammasome activation in CIA mice and synovial cells of human rheumatoid arthritis. These data show that P2X4 asODN confers a therapeutic benefit on CIA. Inhibition of the NLRP1 inflammasome signaling pathway is the underlying mechanism of action. PMID- 24062059 TI - Identification of microRNAs dysregulated in CD14 gene silencing RAW264.7 macrophage cells. AB - A cluster of differentiation antigen 14 (CD14) is involved in lipopolysaccharide (LPS)-induced proinflammatory cytokine release and LPS-induced septic shock. MicroRNAs (miRNAs) are short non-coding RNAs that are involved in the epigenetic regulation of cellular process and bacterial infection. Our previous study indicated that siRNA against CD14 effectively inhibited LPS-induced tumor necrosis factor alpha, chemokine (C-X-C motif) ligand 2, interleukin-6 release, and NO production. To identify miRNAs which are affected by CD14 gene silencing and dissect the mechanisms of the attenuating of LPS-induced damaging immune activation more clearly, based on the CD14 knockdown RAW264.7 macrophage cell line established in our previous study, miRNAs expression profiling of CD14 knockdown RAW264.7 cells were analyzed with miRNA microarray and validated by qRT PCR, the potential targets were predicted and subjected to gene ontology (GO) pathway and biological processes analysis. We demonstrated for the first time that CD14 knockdown significantly changed the expression of 199a-3p, miR-199a-5p, and miR-21-5p in RAW264.7 cells, and significantly enriched GO terms in the predicted target genes of these miRNAs were apoptosis process, immune response, inflammatory response, innate immune response, anti-apoptosis, cytokine production, and cytokine-mediated signaling pathway. These findings may improve our understanding about functional mechanism of miRNAs in the attenuating of LPS induced damaging immune activation more clearly. PMID- 24062061 TI - Observations of mercury wet deposition in Mexico. AB - We provide a longer-term record of Hg wet deposition at two tropical latitude monitoring sites in Mexico, selected to provide regionally representative data. Weekly wet deposition samples were collected over 2 years, from September 2003 to November 2005. Based on this data set, we discuss the magnitude and seasonal variation of Hg in wet deposition and compare the results to other measurement sites and to several model estimates. With precipitation-weighted mean (PWM) concentrations of 8.2 and 7.9 ng L(-1), respectively, during the sampling period from Sep 30 2003 to Oct 11 2005, and median weekly concentrations of 9.4 +/- 1 ng L(-1) for both sites, the wet Hg concentrations and deposition at HD01 were much lower than those observed at the US Gulf Coast MDN sites while the wet Hg deposition at OA02 was much lower than most MDN sites, but somewhat similar to US MDN sites along the Pacific Coast. Based on the limited available data, we conclude that the approximately 30 % higher average precipitation at HD01 and roughly equal PWM concentrations lead to the higher deposition at HD01 versus OA02. We believe that these observations may offer scientists and modelers additional understanding of the depositional fluxes in the lower latitudes of North America. PMID- 24062060 TI - Cepharanthine attenuates lipopolysaccharide-induced mice mastitis by suppressing the NF-kappaB signaling pathway. AB - Cepharanthine (CEP), a biscoclaurine alkaloid isolated from Stephania cepharantha Hayata, has been reported to have potent anti-inflammatory properties. However, the anti-inflammatory effects of CEP on a mouse model of lipopolysaccharide (LPS) induced mastitis and its underlying molecular mechanisms remain to be elucidated. The purpose of the present study was to investigate the effects of CEP on LPS induced mouse mastitis. The mouse model of mastitis was induced by inoculation of LPS through the canals of the mammary gland. CEP was administered intraperitoneally at 1 h before and 12 h after induction of LPS. The results show that CEP significantly attenuates the infiltration of neutrophils, suppresses myeloperoxidase activity, and reduces the levels of TNF-alpha, IL-1beta, and IL-6 in LPS-induced mouse mastitis. Furthermore, CEP inhibited the phosphorylation of NF-kappaB p65 subunit and the degradation of its inhibitor IkappaBalpha. All the results suggest that CEP exerts potent anti-inflammatory effects on LPS-induced mouse mastitis. Accordingly, CEP might be a potential therapeutic agent for mastitis. PMID- 24062062 TI - Degradation of deicing chemicals affects the natural redox system in airfield soils. AB - During winter operations at airports, large amounts of organic deicing chemicals (DIC) accumulate beside the runways and infiltrate into the soil during spring. To study the transport and degradation of DIC in the unsaturated zone, eight undisturbed soil cores were retrieved at Oslo airport, Norway, and installed as lysimeters at a nearby field site. Before snowmelt in 2010 and 2011, snow amended with a mix of the DICs propylene glycol (PG) and formate as well as bromide as conservative tracer was applied. Water samples were collected and analyzed until summer 2012. Water flow and solute transport varied considerably among the lysimeters but also temporally between 2010 and 2011. High infiltration rates during snowmelt resulted in the discharge of up to 51 and 82% PG in 2010 and 2011, respectively. The discharge of formate remained comparatively low, indicating its favored degradation even at freezing temperatures compared with PG. Manganese (Mn) and iron (Fe) were observed in the drainage in autumn owing to the anaerobic degradation of residual PG during summer. Our findings suggest that upper boundary conditions, i.e., snow cover and infiltration rate, and the extent of preferential flowpaths, control water flow and solute transport of bromide and PG during snowmelt. PG may therefore locally reach deeper soil regions where it may pose a risk for groundwater. In the long term, the use of DIC furthermore causes the depletion of potential electron acceptors and the transport of considerable amounts of Fe and Mn. To avoid an overload of the unsaturated zone with DIC and to maintain the natural redox system, the development of suitable remediation techniques is required. PMID- 24062063 TI - Metal contamination in urban street sediment in Pisa (Italy) can affect the production of antioxidant metabolites in Taraxacum officinale Weber. AB - Taraxacum officinale Weber (dandelion) is a very ubiquitous species, and it can grow in urban environments on metal-polluted sediments deposited in the gutters. This study represents a preliminary step to verify the presence of metals in sediments collected in urban streets in Pisa and to assess the alteration in dandelion metabolites in order to understand its adaptation to polluted environments. The soil and sediments were collected at three urban streets and analyzed for total and extractable Cr, Pb, Cu, Ni, and Zn. The total values of Pb and Zn in street sediments exceeded the limits for residential areas of soils. Zn was the most mobile of the metals analyzed. Floating cultivations trials were set up with dandelion seedlings and street sediments. The metals were analyzed in roots and leaves. Antioxidant power, anthocyanins, polyphenols, non-protein thiols (NP-TH) and chlorophylls were measured in dandelion leaves. The first two parameters (anthocyanins and antioxidant power) were higher in the polluted samples compared to the control; chlorophyll content was lower in the treated samples, whereas NP-TH showed no differences. NP-TH groups determined in roots were associated with the root content of Zn and Pb. These results indicate that dandelion can tolerate plant stress by altering its metabolite content. PMID- 24062064 TI - Biodegradation of atrazine by Rhodococcus sp. BCH2 to N-isopropylammelide with subsequent assessment of toxicity of biodegraded metabolites. AB - Atrazine is a persistent organic pollutant in the environment which affects not only terrestrial and aquatic biota but also human health. Since its removal from the environment is needed, atrazine biodegradation is achieved in the present study using the bacterium Rhodococcus sp. BCH2 isolated from soil, long-term treated with atrazine. The bacterium was capable of degrading about 75 % atrazine in liquid medium having pH 7 under aerobic and dark condition within 7 days. The degradation ability of the bacterium at various temperatures (20-60 degrees C), pH (range 3-11), carbon (glucose, fructose, sucrose, starch, lactose, and maltose), and nitrogen (ammonium molybdate, sodium nitrate, potassium nitrate, and urea) sources were studied for triumph optimum atrazine degradation. The results indicate that atrazine degradation at higher concentrations (100 ppm) was pH and temperature dependent. However, glucose and potassium nitrate were optimum carbon and nitrogen source, respectively. Atrazine biodegradation analysis was carried out by using high-performance thin-layer chromatography (HPTLC), Fourier transform infrared spectroscopy (FTIR), and liquid chromatography quadrupole time of-flight (LC/Q-TOF-MS) techniques. LC/Q-TOF-MS analysis revealed formation of various intermediate metabolites including hydroxyatrazine, N-isopropylammelide, deisopropylhydroxyatrazine, deethylatrazine, deisopropylatrazine, and deisopropyldeethylatrazine which was helpful to propose biochemical degradation pathway of atrazine. Furthermore, the toxicological studies of atrazine and its biodegraded metabolites were executed on earthworm Eisenia foetida as a model organism with respect to enzymatic (SOD and Catalase) antioxidant defense mechanism and lipid peroxidation studies. These results suggest innocuous degradation of atrazine by Rhodococcus sp. BCH2 in nontoxic form. Therefore the Rhodococcus sp.BCH2 could prove a valuable source for the eco-friendly biodegradation of atrazine pesticide. PMID- 24062065 TI - Comparison of lignin peroxidase and horseradish peroxidase for catalyzing the removal of nonylphenol from water. AB - Concentrations of aqueous-phase nonylphenol (NP), a well-known endocrine disrupting chemical, are shown to be reduced effectively via reaction with lignin peroxidase (LiP) or horseradish peroxidase (HRP) and hydrogen peroxide. We systematically assessed their reaction efficiencies at varying conditions, and the results have confirmed that the catalytic performance of LiP toward NP was more efficient than that of HRP under experimental conditions. Mass spectrum analysis demonstrated that polymerization through radical-radical coupling mechanism was the pathway leading to NP transformation. Our molecular modeling with the assistance of ab initio suggested the coupling of NP likely proceeded via covalent bonding between two NP radicals at their unsubstituted carbons in phenolic rings. Data from acute immobilization tests with Daphnia confirm that NP toxicity is effectively eliminated by LiP/HRP-catalyzed NP removal. The findings in this study provide useful information for understanding LiP/HRP-mediated NP reactions, and comparison of enzymatic performance can present their advantages for up-scale applications in water/wastewater treatment. PMID- 24062067 TI - The recovery of oyster (Saccostrea glomerata) populations in Sydney estuary (Australia). AB - The current work documented a significant and widespread increase in the abundance of the Sydney rock oyster Saccostrea glomerata, in Sydney estuary (Australia) by undertaking surveys of oyster density in the estuary in 1989 and annually from 1994 to 2006. Oyster density at six control sites located in nearby National Parks unaffected by boating and stormwater discharges were compared to 17 study sites widely distributed within Sydney estuary. No oyster populations were evident in Sydney estuary in 1989; however, by 1994 oysters had colonised areas of the lower and central estuary and by 2002 densities were statistically similar to control sites. The timing of estuary-wide increases in oyster abundance suggests that the partial banning of tributyltin in 1989 for vessels under 25 m long may have played a major role in the increase of S. glomerata in this estuary. PMID- 24062066 TI - Characterization of Cd-, Pb-, Zn-resistant endophytic Lasiodiplodia sp. MXSF31 from metal accumulating Portulaca oleracea and its potential in promoting the growth of rape in metal-contaminated soils. AB - The aim of this study was to characterize the features of a Cd-, Pb-, and Zn resistant endophytic fungus Lasiodiplodia sp. MXSF31 and to investigate the potential of MXSF31 to remove metals from contaminated water and soils. The endophytic fungus was isolated from the stem of Portulaca oleracea growing in metal-contaminated soils. The maximum biosorption capacities of MXSF31 were 3.0 * 10(3), 1.1 * 10(4), and 1.3 * 10(4) mg kg(-1) for Cd, Pb, and Zn, respectively. The biosorption processes of Cd, Pb, and Zn by MXSF31 were well characterized with the pseudo-second-order kinetic model. The biosorption isotherm processes of Pb and Zn by the fungus were fitted better with the Langmuir model, while the biosorption processes of Cd was better fitted with the Freundlich model. The biosorption process of MXSF31 was attributed to the functional groups of hydroxyl, amino, carbonyl, and benzene ring on the cell wall. The active biomass of the strain removed more Cd, Pb, and Zn (4.6 * 10(4), 5.6 * 10(5), and 7.0 * 10(4) mg kg(-1), respectively) than the dead biomass. The inoculation of MXSF31 increased the biomass of rape (Brassica napus L.), the translocation factor of Cd, and the extraction amount of Cd by rape in the Cd+Pb-contaminated soils. The results indicated that the endophytic fungus strain had the potential to remove heavy metals from water and soils contaminated by multiple heavy metals, and plants accumulating multiple metals might harbor diverse fungi suitable for bioremediation of contaminated media. PMID- 24062068 TI - Stress tolerance and growth physiology of yeast strains from the Brazilian fuel ethanol industry. AB - Improved biofuels production requires a better understanding of industrial microorganisms. Some wild Saccharomyces cerevisiae strains, isolated from the fuel ethanol industry in Brazil, present exceptional fermentation performance, persistence and prevalence in the harsh industrial environment. Nevertheless, their physiology has not yet been systematically investigated. Here we present a first systematic evaluation of the widely used industrial strains PE-2, CAT-1, BG 1 and JP1, in terms of their tolerance towards process-related stressors. We also analyzed their growth physiology under heat stress. These strains were evaluated in parallel to laboratory and baker's strains. Whereas the industrial strains performed in general better than the laboratory strains under ethanol or acetic acid stresses and on industrial media, high sugar stress was tolerated equally by all strains. Heat and low pH stresses clearly distinguished fuel ethanol strains from the others, indicating that these conditions might be the ones that mostly exert selective pressure on cells in the industrial environment. During shake flask cultivations using a synthetic medium at 37 degrees C, industrial strains presented higher ethanol yields on glucose than the laboratory strains, indicating that they could have been selected for this trait-a response to energy demanding fermentation conditions. These results might be useful to guide future improvements of large-scale fuel ethanol production via engineering of stress tolerance traits in other strains, and eventually also for promoting the use of these fuel ethanol strains in different industrial bioprocesses. PMID- 24062069 TI - Geomicrobium sediminis sp. nov., a novel bacterium isolated from a sediment sample collected from the South China Sea, and emended description of the genus Geomicrobium. AB - A novel bacterium, designated YIM M13075(T), was isolated from a sediment sample collected from the South China Sea. Growth occurred from 4 to 45 degrees C (optimum 28 degrees C), pH 6.0-11.0 (optimum pH 8.0). The strain formed yellow cream colonies after 5 days incubation on TSA modified with 5 % NaCl medium at 28 degrees C. Cells were Gram-positive, short rods and motile. Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain YIM M13075(T) was affiliated with the genus Geomicrobium (93.5 %). The strain YIM M13075(T) contained meso-diaminopimelic acid in the cell wall. The major polar lipids were diphosphatidylglycerol and phosphatidylglycerol. The major fatty acids were iso C15:0 and anteiso-C15:0. The predominant menaquinones were MK-7 and MK-6. The genomic DNA G+C content was 42.7 mol%. On the basis of the morphological and chemotaxonomic characteristics as well as genotypic data, strain YIM M13075(T) represents a novel species in the genus Geomicrobium, for which the name Geomicrobium sediminis sp. nov. is proposed. The type strain is YIM M13075(T) (=DSM 25540(T) =JCM 18144(T) =CCTCC AB 2013245(T)). An emended description of the genus Geomicrobium is also proposed in the light of the new data. PMID- 24062071 TI - Comparison of enzymatic activity of two linoleic acid isomerases expressed in E. coli. AB - Conjugated linoleic acid (CLA) refers to a group of positional and geometric isomers of octadecadienoic fatty acid with conjugated double bonds. CLA possesses many important physiological functions and it can be produced from linoleic acid (LA) by LA isomerases. In this report, we first cloned the genes encoding LA isomerases: C12 isomerases and C9 isomerase, then transformed the recombinant plasmids into Escherichia coli TOP10 and induced E. coli with IPTG (isopropylthio beta-D-galactoside) to express the recombinant proteins. Next, we purified the isomerases using a HisTrapTM HP column, followed with the analysis by SDS-PAGE or Western blot. Finally, we compared their enzymatic activity by biotransformation of LA into CLA. Plasmids containing LA isomerase genes were successfully constructed. LA isomerases were found expressed in E. coli, and the molecular weight was 64 KD for C12 LA isomerase and 55 KD for C9 LA isomerase. The enzyme activity (9.93 +/- 0.01 U/ml for C12 LA isomerase and 8.12 +/- 0.02 U/ml for C9 LA isomerase) of both LA isomerases reached the highest when IPTG concentration is 0.2 mM and the induction time is 18 h. After purification, C9 LA isomerase was enriched in peak 4 and C12 LA isomerase was enriched in peak 3. Optimum pH for C9 LA and C12 LA isomerases were 7.5 and 7.0 separately, and optimum temperatures was 37 degrees C for highest concentration of CLA. The work may provide theoretical significance for an effective production process of CLA for the medical and nutritional purposes. PMID- 24062073 TI - PPARgamma mediates the effects of WIN55,212-2, an synthetic cannabinoid, on the proliferation and apoptosis of the BEL-7402 hepatocarcinoma cells. AB - Cannabis sativa has long been used as a traditional medicine in China. Among its effective compounds are cannabinoids. This study determined the effect of WIN55,212-2 (WIN), a synthetic cannabinoid, on the BEL-7402 human hepatocellular carcinoma (HCC) cell line. The results showed that WIN could decrease the proliferation of BEL-7402 cells. Moreover, WIN could cause apoptosis of the cells via up-regulation of Bax expression, down-regulation of Bcl-2 expression, induction of the mitochondrial membrane potential, increase of caspase-3, -8 and 9 activities, and induction of the cleavage of caspase-3 and poly-ADP-ribose polymerase (PARP). The WIN-induced apoptosis was accompanied by the up-regulation of PPARgamma expression, the activation of PPARgamma DNA binding activity, and a down-regulation of PPARgamma target oncogene c-myc. Conversely, the effects of WIN could be attenuated by PPARgamma antagonist GW9662, and the WIN induced PPARgamma expression was partially attenuated by AM630, a cannabinoid receptor-2 antagonist, whereas the WIN-induced reduction of c-myc expression was partially restored by GW9662. Collectively, our results suggest that WIN can decrease the proliferation and cause apoptosis of the BEL-7402 cells via a mitochondrial caspase pathway and mediated by PPARgamma. These results may provide a basis for the application of WIN in HCC treatment. PMID- 24062074 TI - Losartan reverses glomerular podocytes injury induced by AngII via stabilizing the expression of GLUT1. AB - Podocyte impairment is a key pathogenic even in the initiation and development of glomerular diseases associated with proteinuria. The type 2 diabetic patients is characterized by progressive increases in albuminuria which are associated with the development of characteristic histopathological features. Losartan had a benefit in decreasing albuminuria in type 2 diabetic patients,suggesting that losartan may have another effect other than blockade of the traditional renin angiotensin system (RAS). However, the mechanism has remained undetermined. Glucose transporter 1 (GLUT1) is the predominant basal glucose transporter. In the kidney, GLUT1 was overexpressed predominantly in glomerular mesangial cells and in small vessels, rather than in podocytes. The increased glomerular GLUT1 mimicked diabetes-induced glomerular GLUT1 expression. In this study, we hypothesized that increased GLUT1 expression induced by angiotensinII (AngII) contributes to the progression of podocytes injury, losartan can block the effect of AngII and protect podocytes via stabilizing the expression of GLUT1, our results strongly suggest that losartan has a direct and protective effect on podocytes. This represents a novel mechanism by which losartan may protect podocyte from apoptotic death and improve podocyte function via stabilizing the expression of GLUT1. This finding underlines the crucial role of GLUT1 in the pathogenesis of podocyte injury and proteinuria. PMID- 24062075 TI - Expression of cell cycle regulatory factors hus1, gadd45a, rb1, cdkn2a and mre11a correlates with expression of clock gene per2 in human colorectal carcinoma tissue. AB - Deregulated expression of clock gene per2 has previously been associated with progression of cancer. The aim of the present study was to identify genes related to per2 expression and involved in cell cycle control. Patients surgically treated for colorectal carcinoma with up-regulated and down-regulated per2 expression in cancer versus adjacent tissue were studied. Total RNA from cancer tissue of these patients was used to specify genes associated with altered per2 expression using the Human Cell Cycle RT(2) profiler PCR array system. We identified seven genes positively correlated (hus1, gadd45alpha, rb1, cdkn2a, cdk5rp1, mre11a, sumo1) and two genes negatively correlated (cdc20, birc5) with per2 expression. Expression of these seven genes was subsequently measured by real time PCR in all patients of the cohort. Patients were divided into three groups according to TNM classification. We observed an increase in gene expression in cancer tissue compared to adjacent tissue in the first group of patients in all genes measured. Expression of genes positively associated with per2 gene expression was dependent on tumor staging and changes were observed preferentially in cancer tissue. For genes negatively associated with per2 expression we also detected changes in expression dependent on tumor staging. Expression of cdc20 and birc5 was increasing in the proximal tissue and decreasing in the cancer tissue. These results implicate functional involvement of per2 in the process of carcinogenesis via newly uncovered genes. The relevancy of gene expression for determination of diagnosis and prognosis should be considered in relation to tumor staging. PMID- 24062072 TI - Regulation of paracellular permeability: factors and mechanisms. AB - Epithelial permeability is composed of transcellular permeability and paracellular permeability. Paracellular permeability is controlled by tight junctions (TJs). Claudins and occludin are two major transmembrane proteins in TJs, which directly determine the paracellular permeability to different ions or large molecules. Intracellular signaling pathways including Rho/Rho-associated protein kinase, protein kinase Cs, and mitogen-activated protein kinase, modulate the TJ proteins to affect paracellular permeability in response for diverse stimuli. Cytokines, growth factors and hormones in organism can regulate the paracellular permeability via signaling pathway. The transcellular transporters such as Na-K-ATPase, Na(+)-coupled transporters and chloride channels, can interact with paracellular transport and regulate the TJs. In this review, we summarized the factors affecting paracellular permeability and new progressions of the related mechanism in recent studies, and pointed out further research areas. PMID- 24062076 TI - Mitochondrial DNA diversity of mud crab Scylla olivacea (Portunidae) in Peninsular Malaysia: a preliminary assessment. AB - A primary factor in population management and wildlife conservation is the delineation of population units derived from descriptions of population genetic structure. Yet, predicting factors that influence the patterns of gene flow in a population particularly at landscape scales remains a major challenge in evolutionary biology. Here we report a population genetic study of the mud crab Scylla olivacea examined based on a 542 bp segment of the mitochondrial DNA cytochrome c oxidase I gene among 91 individuals from six localities in the west and east coast of Peninsular Malaysia. In total 55 unique haplotypes were distinguished with 45 private haplotypes and a single common haplotype shared among all populations studied. The other ten haplotypes were shared among various populations. The sharing of this haplotype reflects the connection of the mangrove areas between east and west coast of Peninsular Malaysia. High haplotype diversity (h = 0.968 +/- 0.021; mean +/- SD) and low nucleotide diversity (pi = 0.120 +/- 0.015; mean +/- SD) were displayed, which may be indicative of genetic bottleneck events. No significant phylogenetic lineages were recognized using neighbour-joining and maximum parsimony methods. Hierarchical AMOVA analysis indicated that 99.33 % of the genetic variation was contained within populations and 0.67 % occurred among populations, suggesting no geographical patterning among populations studied, supported by F st test. Mismatch distribution analysis showed that the observed distribution of the pairwise mutation differences among haplotypes was multimodal, which is not concordant with a sudden range expansion scenario. However, neutrality tests showed non-significant negative values suggesting that the populations studied may have experienced past population growth, but the expansion may have been restricted to separate local areas that resulted in the non-significant negative Fu's Fs and Tajima's D value. Overall, this present preliminary study was able to be a reference on the phylogenetic relationships and assessment of genetic structure of Scylla sp. in Malaysia. PMID- 24062077 TI - Self-compatibility in 'Zaohong' Japanese apricot is associated with the loss of function of pollen S genes. AB - While most Japanese apricot (Prunus mume Sieb. et Zucc.) cultivars display typical S-RNase-based gametophytic self-incompatibility, some self-compatible (SC) cultivars have also been identified. In this study, we confirmed SC of 'Zaohong' through replicated self-pollination tests. Cross-pollination tests showed that SC of 'Zaohong' was caused by a loss of pollen function, so we determined that the S-genotype of 'Zaohong' was S 2 S 15 . Sequence analysis of the S-haplotypes of 'Zaohong' showed no mutations which were likely to alter gene function. Furthermore, expression analysis based on RT-PCR of S-locus genes revealed no differences at the transcript level when compared with 'Xiyeqing', a self-incompatible cultivar with the same S haplotypes. In addition, except for S locus genes, a new type of F-box gene encoding a previously uncharacterised protein with high sequence similarity (61.03-64.65 %) to Prunus SFB genes was identified. Putative structural regions of PmF-box genes have been described, corresponding to regions in PmSFB alleles, but with some sequence variations. These results suggest that SC in 'Zaohong' occurs in pollen, and that other factors outside the S-locus, including PmF-box genes, might be associated with the loss of function of pollen S genes. PMID- 24062078 TI - The use of alternative polyadenylation in the tissue-specific regulation of human SMS1 gene expression. AB - Sphingomyelin synthase 1 (SMS1) is an essential enzyme that catalyses the synthesis of sphingomyelin and diacylglycerol from phosphatidylcholine and ceramide in eukaryotic cells. We previously studied the structure of the human SMS1 gene in detail, and identified its numerous transcripts. We revealed mRNA isoforms that varied in the 5'-untranslated region (UTR) and encoded the full length protein as well as transcripts resulting from alternative combinations of the exons in the gene's coding region and the 3'-UTR. In the present work, we used real-time PCR data to determine the expression patterns of SMS1 transcripts encoding the full-length protein and the alternative transcripts whose coding region had been interrupted by their alternative exons, which are the conserved portions of intron VII. Our results indicate that the amount of SMS1 transcripts varies considerably between different human tissues. The mechanisms controlling the level of SMS1 transcripts might include tissue-specific intron polyadenylation causing the appearance of truncated transcripts not involved in the synthesis of the full-length protein SMS1. PMID- 24062079 TI - Downregulation of PAK5 inhibits glioma cell migration and invasion potentially through the PAK5-Egr1-MMP2 signaling pathway. AB - PAK5 (p21 activated kinase 5) is upregulated in human colorectal carcinoma cells and is a known tumor promoter in carcinogenesis of the colon. Little is known regarding the mechanisms underlying the downstream targets of PAK5, and information concerning its biological significance in glioma is lacking. In this study, we investigated the effects of PAK5 on proliferation, migration, invasion, and apoptosis in human U87 and U251 glioma cells and examined the underlying molecular mechanism. We performed cell growth assays and cell cycle analysis to observe the cell proliferation. Flow cytometry analysis was performed to evaluate apoptosis, and in vitro scratch assays, cell migration assays, and gelatin zymography were performed to examine cell migration. Western blot analysis was performed to examine signal transduction in the cells. We demonstrated that suppression of PAK5 in glioma cells significantly inhibited cell migration and invasion. We also observed that suppression of PAK5 in human glioma cell lines inhibited cell growth because of G1 phase arrest. Additionally, flow cytometry and Western blot analysis indicated that PAK5 could inhibit cell apoptosis. These results suggest that the PAK5-Egr1-MMP2 signaling pathway is involved in tumor progression and may have a potential role in cancer prevention and treatment. PMID- 24062080 TI - A new flavonol glycoside from the aerial part of Rudbeckia laciniata. AB - The phytochemical investigation of Rudbeckia laciniata L. obtained a new flavonol glycoside (1), together with four flavonol glycosides (2-5) and eight quinic acid derivatives (6-13). The structure was elucidation by means of spectroscopic methods and chemical evidence. The isolated compounds were tested for cytotoxicity against four human tumor cell lines in vitro using the sulforhodamine B bioassay. PMID- 24062081 TI - Synthesis, antimycobacterial and anticancer activity of novel indole-based thiosemicarbazones. AB - Based on the structural elements of bioactive indole-based compounds, a series of novel 1-substituted indole-3-carboxaldehyde thiosemicarbazones were synthesized as potential antimycobacterial and anticancer agents. The derivatives were prepared via a two-step methodology including N-alkylation(benzylation) of indole 3-carboxaldehyde and conversion of the intermediate aldehydes to corresponding thiosemicarbazones. The derivatives were evaluated for their antimycobacterial activity and compounds 3d (R = propyl) and 3q (R = 4-nitrobenzyl) were among the most potent and selective derivatives with IC50 values of 0.9 and 1.9 MUg/mL respectively. The anticancer activity of the derivatives was also assessed against a panel of tumor cell lines. Compounds 3t, 3u, 3v and 3w efficiently inhibited the majority of the cancer cell lines with considerable selectivity. PMID- 24062082 TI - Secondary metabolites isolated from Castilleja rubra exert anti-inflammatory effects through NF-kappaB inactivation on lipopolysaccharide-induced RAW264.7 macrophages. AB - 8-Epiloganin (1), mussaenoside (2), and 5-O-caffeoylshikimic acid (3) have been isolated from Castilleja rubra, and the anti-inflammatory properties of these metabolites in a cell culture system were investigated. Compounds 1-3 suppressed not only the production of nitric oxide (NO) and prostaglandin E2, but also the expression of inducible NO synthase and cyclooxygenase-2 induced by lipopolysaccharide (LPS) in the RAW264.7 murine macrophage cell line. Compounds 1 3 also inhibited the release of pro-inflammatory cytokines induced by LPS, namely, tumor necrosis factor-alpha and interleukin-1beta. The underlying mechanism of the anti-inflammatory action of compounds 1-3 was associated with downregulation of nuclear factor-kappaB. PMID- 24062083 TI - Wound dressings: selecting the most appropriate type. AB - Appropriate wound dressing selection is guided by an understanding of wound dressing properties and an ability to match the level of drainage and depth of a wound. Wounds should be assessed for necrosis and infection, which need to be addressed prior to selecting an ideal dressing. Moisture-retentive dressings include films, hydrogels, hydrocolloids, foams, alginates, and hydrofibers and are useful in a variety of clinical settings. Antimicrobial-impregnated dressings can be useful in wounds that are superficially infected or are at higher risk for infection. For refractory wounds that need more growth stimulation, tissue engineered dressings have become a viable option in the past few decades, especially those that have been approved for burns, venous ulcers, and diabetic ulcers. As wounds heal, the ideal dressing type may change, depending on the amount of exudate and depth of the wound; thus success in wound dressing selection hinges on recognition of the changing healing environment. PMID- 24062084 TI - Noradrenergic alpha2A-receptor stimulation in the ventral hippocampus reduces impulsive decision-making. AB - RATIONALE: Guanfacine, an alpha2A-adrenergic receptor agonist, is currently in use for treatment of a variety of psychiatric disorders that are associated with impulsive decision-making (e.g., attention-deficit hyperactivity disorder; ADHD). In animals and humans, the behavioral effects of adrenergic agents are presumed to involve neuromodulation of the prefrontal cortex, consistent with the demonstrated actions of dopaminergic agents. However, recent experimental work has shown that the ventral hippocampus (vHC) contributes to decision-making and impulse control, raising the possibility that the hippocampus may be an important site of action for these drugs. OBJECTIVE: The purpose of this study was to examine the effect of local vHC infusions of guanfacine and other neuropharmacological agents on behavioral decisions that involve a trade-off between reward size and delay. METHODS: Different cohorts of rats were implanted with bilateral guide cannulae targeting the vHC. We examined the animals' behavior in a touchscreen version of a delay discounting task following intra-vHC infusions of: (a) guanfacine (alpha2A-adrenergic receptor agonist), (b) SCH 23390 (dopamine D1 receptor antagonist), and (c) muscimol/baclofen (GABAA/B agonists). RESULTS: Guanfacine led to a dose-dependent reduction in impulsive decision making, increasing the animals' tolerance for delay in exchange for a larger reward. By contrast, infusion of SCH 23390 had no behavioral effects. Consistent with previous lesion studies, reversible pharmacological inactivation with muscimol/baclofen increased impulsive decision-making. CONCLUSIONS: These data provide the first evidence that guanfacine, a commonly used treatment for ADHD, may derive its clinical benefits through hippocampal stimulation, via alpha2A adrenergic receptors. PMID- 24062085 TI - Comparative functional analysis of six drought-responsive promoters in transgenic rice. AB - Rice production is greatly affected by environmental stresses such as drought and high salinity. Transgenic rice plants tolerant to such stresses are expected to be produced. Stress-responsive promoters with low expression under normal growth conditions are needed to minimize the adverse effects of stress-tolerance genes on rice growth. We performed expression analyses of drought-responsive genes in rice plants using a microarray, and selected LIP9, OsNAC6, OsLEA14a, OsRAB16D, OsLEA3-1, and Oshox24 for promoter analysis. Transient assays using the promoters indicated that AREB/ABF (abscisic acid (ABA)-responsive element-binding protein/ABA-binding factor) transcription factors enhanced expressions of these genes. We generated transgenic rice plants containing each promoter and the beta glucuronidase (GUS) reporter gene. GUS assays revealed that the LIP9 and OsNAC6 promoters were induced by drought, high salinity, and ABA treatment, and both promoters showed strong activity under normal growth conditions in the root. The other promoters were strongly induced by stresses and ABA, but showed low activity under normal growth conditions. In seeds, GUS staining showed that Oshox24 expression was low and expressions of the other genes were high. Transgenic rice plants overexpressing OsNAC6 under the control of the Oshox24 promoter showed increased tolerance to drought and high salinity, and no growth defects. These data suggest that the Oshox24 promoter is useful to overexpress stress-tolerance genes without adversely affecting growth. PMID- 24062087 TI - Middle-preserving pancreatectomy with reversed pancreaticogastrostomy: report of a case. AB - Parenchyma-sparing pancreatic resections have been reported increasingly in recent years; however, for multifocal diseases involving the head and the tail of the pancreas, total pancreatectomy is still the preferred procedure. The possible consequence of this procedure is loss of normal pancreatic parenchyma, resulting in insufficiency of pancreatic exocrine and endocrine functions. Various types of limited resection have been introduced for isolated or multiple pancreatic lesions, depending on the location of the tumor. Even for multifocal diseases, if the pancreatic body is spared, a middle-preserving pancreatectomy (MPP) can be performed to assure maximal pancreatic function and uncompromised quality of life. Yet, few papers have introduced the feasibility of MPP for a better outcome. This report describes a new surgical technique for MPP using an alternative approach for the remnant pancreas anastomosis. We used this technique successfully to remove a bifocal neoplasm: adenocarcinoma of the distal bile duct and mucinous cyst adenoma in the tail of the pancreas. PMID- 24062088 TI - A transient elevated irisin blood concentration in response to prolonged, moderate aerobic exercise in young men and women. AB - Irisin, a newly discovered, PGC-1alpha dependent myokine, has recently been shown to increase in circulation in response to sprint exercise. This study examined the effect of prolonged exercise on irisin concentrations in young men (n=7) as well as in young women (n=5) during different stages of the menstrual cycle. Seven young men completed 90 min of treadmill exercise at 60% of VO2max and a resting control trial. Five women completed the same exercise protocol in two different trials: during the early follicular phase and mid-luteal phase of the menstrual cycle. Blood samples were collected and analyzed for irisin concentrations immediately before exercise, at 54 and 90 min of exercise, and at 20 min of recovery (R20). Findings revealed that by 54 min of a 90 min treadmill exercise protocol at 60% of VO2max, irisin concentrations significantly increased 20.4% in young men and 20.3% as well as 24.6% in young women during the early follicular and mid-luteal phases of the menstrual cycle, respectively. However, by 90 min of exercise as well as R20, irisin concentrations were no longer elevated. Stage of the menstrual cycle did not affect responses in young women. Findings indicate that prolonged aerobic exercise produces a transient increase in irisin concentrations during the first hour of exercise for both genders and suggest that this form of moderate exercise may be helpful in improving fat metabolism. PMID- 24062086 TI - Applications and challenges of next-generation sequencing in Brassica species. AB - Next-generation sequencing (NGS) produces numerous (often millions) short DNA sequence reads, typically varying between 25 and 400 bp in length, at a relatively low cost and in a short time. This revolutionary technology is being increasingly applied in whole-genome, transcriptome, epigenome and small RNA sequencing, molecular marker and gene discovery, comparative and evolutionary genomics, and association studies. The Brassica genus comprises some of the most agro-economically important crops, providing abundant vegetables, condiments, fodder, oil and medicinal products. Many Brassica species have undergone the process of polyploidization, which makes their genomes exceptionally complex and can create difficulties in genomics research. NGS injects new vigor into Brassica research, yet also faces specific challenges in the analysis of complex crop genomes and traits. In this article, we review the advantages and limitations of different NGS technologies and their applications and challenges, using Brassica as an advanced model system for agronomically important, polyploid crops. Specifically, we focus on the use of NGS for genome resequencing, transcriptome sequencing, development of single-nucleotide polymorphism markers, and identification of novel microRNAs and their targets. We present trends and advances in NGS technology in relation to Brassica crop improvement, with wide application for sophisticated genomics research into agronomically important polyploid crops. PMID- 24062089 TI - Changes in renal glucose transporters in an animal model of metabolic syndrome. AB - Considering the similarity between structural, hemodynamic, and functional changes of obesity-related renal disease and diabetic nephropathy, we hypothesized that renal glucose transporter changes occur in obesity as in diabetes. The aim of the work was to evaluate GLUT1 and GLUT2 in kidneys of an animal model of metabolic syndrome. Neonate spontaneously hypertensive rats (SHR), n=15/group, were treated with monosodium glutamate (5 mg/g) (MetS) for 9 days and compared with saline-treated Wistar-Kyoto (C) and SHR (H) rats. Lee index, systolic arterial pressure (SAP), glycemia, insulin resistance, triglycerides, and HDL cholesterol were evaluated at 3 and 6 months. Medullar GLUT1 and cortical GLUT2 were analyzed by Western blot. MetS vs. C and H rats had the highest Lee index (p<0.001) and insulin resistance (3-months C: 4.3+/-0.7, H: 3.9+/-0.9, MetS: 2.7+/-0.6; 6-months C: 4.2+/-0.6, H: 3.8+/-0.5, MetS: 2.4+/-0.6% . min-1, p<0.001), similar glycemia, and the lowest HDL-cholesterol at 6-months (p<0.001). In the MetS and H rats, SAP was higher vs. C at 3-months (p<0.001) and 6-months (C: 151+/-15, H: 190+/-11, MetS: 185+/-13 mm Hg, p<0.001) of age. GLUT1 was 13* lower (p<0.001) at 3-months, reestablishing its content at 6-months in MetS group, while GLUT2 was 2* higher (p<0.001) in this group at 6-months of age. Renal GLUT1 and GLUT2 are modulated in kidney of rats with metabolic syndrome, where obesity, insulin resistance and hypertension coexist, despite normoglycemia. Like in diabetes, cortical GLUT2 overexpression may contribute to the development of kidney disease. PMID- 24062090 TI - Testosterone therapy improves the heart rate turbulence without effect on NT proBNP level in men with metabolic syndrome. AB - It is now known that BNP and NT-proBNP levels are decreasing with increased BMI, regardless of other metabolic syndrome (MS) constituents. Additionally, testosterone deficiency may intensify frequency of ventricular rhythm disorders in obese individuals by inhibition of the parasympathetic system. Determination of heart rhythm turbulence (HRT) is a useful, noninvasive method used for evaluation of equilibrium of the vegetative system. The aim of the study was to evaluate effect of testosterone therapy on HRT and NT-proBNP levels in MS patients. Eighty males were qualified for the study. They were divided into 3 groups: I (n=30), males with testosterone deficiency syndrome and metabolic syndrome (MS+TDS+); II (n=25), males with MS+TDS-; III (n=25), healthy males. The patients with MS+TDS+ received Omnadrem 250 in the form of intramuscular injections for 9 weeks. Laboratory tests and 24-h Holter ECG were taken twice before the therapy and directly after completion of the therapy. Males with MS+TDS+ more often presented irregular HRT parameters and were characterised by lower NT-proBNP levels compared to the healthy individuals. Testosterone replacement therapy caused improvement of HRT and had no significant effect on the NT-proBNP level. Testosterone replacement therapy and body weight reduction may significantly decrease negative consequences of MS and TDS. PMID- 24062091 TI - Hypothalamic glucose-sensing: role of Glia-to-neuron signaling. AB - The hypothalamus senses hormones and nutrients in order to regulate energy balance. In particular, detection of hypothalamic glucose levels has been shown to regulate both feeding behavior and peripheral glucose homeostasis, and impairment of this regulatory system is believed to be involved in the development of obesity and diabetes. Several data clearly demonstrate that glial cells are key elements in the perception of glucose, constituting with neurons a "glucose-sensing unit". Characterization of this interplay between glia and neurons represents an exciting challenge, and will undoubtedly contribute to identify new candidates for therapeutic intervention. The purpose of this review is to summarize the current data that stress the importance of glia in central glucose-sensing. The nature of the glia-to-neuron signaling is discussed, with a special focus on the endozepine ODN, a potent anorexigenic peptide that is highly expressed in hypothalamic glia. PMID- 24062094 TI - Influence of proton transfer degree on the potential energy surface for two very short hydrogen bonds. AB - The influence of temperature on the proton location in hydrogen bonds has been systematically studied by neutron diffraction in only a few crystal structures. Two of these are the 1:1 complex of urea - phosphoric acid with an OHO hydrogen bond and 4-methylpyridine -pentachlorophenol with an OHN hydrogen bond. Based on these earlier determined crystal structures the potential energy surface (PES) at different temperatures has now been determined by DFT calculations at the B3LYP/6 31++G** level of theory using the Gaussian03 system. In general PES is practically unchanged as the proton moves from the donor to the acceptor. This is not surprising as the crystal structure does not undergo significant changes as the proton successively moves along the hydrogen bond. For both complexes PES is characterized by only one minimum, which is not located at the centre where the distances of the proton to the bridge atoms are the same. The experimental proton positions are located close to the calculated energy minima; the slight deviations are probably an effect of the crystalline environment which has not been taken into account in the calculations. PMID- 24062092 TI - Comparison of oncological outcomes between retropubic radical prostatectomy and robot-assisted radical prostatectomy: an analysis stratified by surgical experience. AB - OBJECTIVES: To compare oncological outcomes of a consecutive retropubic radical prostatectomy (RRP) and robot-assisted radical prostatectomy (RARP) series performed by a single surgeon who had performed >750 prior RRPs and was starting to perform RARPs. MATERIALS AND METHODS: Prospectively collected longitudinal data of 277 RRP and 730 RARP cases over a 5-year period were retrospectively analyzed. The RARP series were divided into 3 subgroups (1st, <250 cases; 2nd, 250-500; and 3rd, >500) according to the surgical period. The positive surgical margin (PSM) and biochemical recurrence-free survival (BCRFS) rates were compared at each pathological stage. RESULTS: The pT2 PSM rates showed no significant difference between the RRP (7.8%) and RARP series (1st, 9.5%; 2nd, 14.1%; and 3rd, 9.8%) throughout the study period (P = 0.689, 0.079, and 0.688, respectively). Although the pT3 PSM rates of the 1st (50.6%) and 2nd RARP series (50.0%) were higher than that of the RRP series (36.0%; P = 0.044 and P = 0.069, respectively), the 3rd RARP series had a comparable pT3 PSM rate (32.4%, P = 0.641). The 3-year BCRFS rates of the RRP and RARP series were similar at each pathological stage (pT2, 92.1 vs. 96.8%, P = 0.517; pT3, 60.0 vs. 67.3%, P = 0.265, respectively). CONCLUSIONS: The pT2 PSM and short-term BCRFS rates were similar between RRP and RARP, and RARP showed comparable pT3 PSM rate with RRP after >500 cases of surgical experience. Our data suggest that an experienced robotic surgeon at a high-volume center may achieve comparable oncological outcomes with open prostatectomy even in locally advanced disease. PMID- 24062095 TI - Structure Elucidation of Transmembrane Proteins using Public-Available Databases and Experimental Data on Competitive Inhibition. AB - We present an approach towards structure elucidation of bilitranslocase, the membrane protein which transports bilirubin from blood to liver cells. The sequence and secondary structure information of transmembrane segments of proteins with known 3D structure is exploited to predict the transmembrane domains of structurally unresolved target protein. With the help of known structures the transmembrane domains are encoded in such a way that it is possible to group and classify them with respect to their specific sub-structural characteristics and to build a model for prediction of transmembrane segments. We have shown that the model for prediction of transmembrane segments proposed four transmembrane alpha helices, each containing around 20 amino acids. This result is partially confirmed with experimental studies using particular antibodies corresponding to parts of amino acid sequences of bilitranslocase. In order to shed light on the bilitranslocase transport mechanism, we also tested a set of non-congeneric compounds for their competitive inhibition constants in the investigated protein-substrate system. The information about chemical structure of small molecules that either pass or block the transmembrane path enabled by bilitranslocase helps us to build a hypothesis about the transport mechanism of the studied biological system. PMID- 24062093 TI - Association of diabetes mellitus and metformin use with biochemical recurrence in patients treated with radical prostatectomy for prostate cancer. AB - PURPOSE: The impact of diabetes mellitus (DM) and metformin use on biochemical recurrence (BCR) in patients treated with radical prostatectomy (RP) remains controversial. METHODS: We retrospectively evaluated 6,863 patients who underwent RP for clinically localized PC between 2000 and 2011. Univariable and multivariable Cox regression models addressed the association of DM and metformin use with BCR. RESULTS: Overall, 664 patients had a diagnosis of DM from which 287 (43 %) were on metformin and 377 (57 %) were on anti-diabetics other than metformin. DM and metformin were not associated with any clinicopathologic features (p values >0.05). Within a median follow-up of 25 months (interquartile range 35 months), 774 (11.3 %) patients experienced BCR. Actuarial 5-year biochemical-free survival was 83 % for non-diabetic, 79 % for diabetic patients without metformin use, and 85 % for diabetic patients with metformin use (log rank p = 0.17). In uni- and multivariable Cox regression analyses with the non diabetic group as referent, DM without metformin use (HR = 0.99; 95 % CI 0.75 1.30, p = 0.65) and DM with metformin use (HR = 0.84, 95 % CI 0.58-1.22, p = 0.36) were not associated with BCR after RP. A subgroup analysis stratified by nodal status, surgical margins, tumor stage, and Gleason sum did not reveal any significant association between DM, use of metformin and risk of BCR. CONCLUSIONS: We found no association between DM or metformin use and cancer specific features or BCR in patients treated with RP. The effect of DM and metformin on complications, wound healing and overall survival needs to be assessed in similar cohorts. PMID- 24062096 TI - The Muon F-u+-F Hydrogen Bond-like Complex. AB - Muon spin rotation (uSR) and relaxation has been used to study the local magnetic structure of K3Fe5F15. A collinear F-u+-F "hydrogen bond-like" symmetric double minimum type complex with a F...F distance of 2.8 A and a separation between the two minima of 0.8 A has been found in the paramagnetic phase. The apparent central position of the muon seems to be the result of fast muon tunneling between two equivalent minima in the F-u+-F bond. PMID- 24062097 TI - Binding-sites Prediction Assisting Protein-protein Docking. AB - Most biological actions of proteins, including their ability to interact with one another, involve some specific parts of their three-dimensional structure, called binding sites. These have evolved for their ability to bind other molecules effectively and are often conserved in different proteins. Identifying protein protein binding sites in a protein that is known to interact with other proteins can provide important clues to the function of the protein and can also be used in protein-protein docking studies to reduce the search space explored by docking algorithms. We have developed an algorithm for structural similarity search in a database of non-redundant protein structures to find conserved binding regions on proteins involved in protein-protein interactions. We have used this algorithm to find conserved regions on a protein surface. The structurally conserved residues found were labeled as a protein-protein binding site, which allowed us to tune the AutoDock docking algorithm to predict the native protein complex structure from unbound protein structures. The conservation of protein structures that correctly predicted protein-protein binding site was used in AutoDock program to improve protein-protein docking. A web application based on our method is available at http://probis.cmm.ki.si. PMID- 24062099 TI - Laser control of single and double proton transfer reactions. AB - Theory and simulation of laser control of single and double proton transfer reactions in hydrogen-bonded molecular systems are reviewed. Different approaches to the construction of potential energy surfaces are introduced as a means to design simple models for unraveling basic mechanistic principles of laser control. Obtaining the control laser field is the central task and various methods such as optimal control theory are outlined. Applications are presented for the infrared laser-driven single proton transfer in models of thioacetylacetone and acetylacetone as well as for the double proton transfer in porphycene derivatives. PMID- 24062098 TI - Spectroscopic Signatures of [H9O4]+ and [H13O6]+ Ions in a Polar Aprotic Environment Revealed Under DFT-PCM Approximation. AB - The structures, relative stability, infrared (IR) and Raman spectra of the most stable forms of [H9O4]+ and [H13O6]+ ions in acetonitrile are computed using the B3LYP functional combined with the Polarizable Continuum Model approximation. These forms are hydrated [H3O]+ and [H5O2]+ cores. Of interest are two main environmental effects on the spectroscopic features of protonated water hydrates: (i) polarization of the solvent by the hydrate dipole moment; (ii) formation of H bonds with bulky counterions (ClO4- and BF4-). The effect of the polarization on the structure of the [H3O]+ core strongly depends on the symmetry of the hydration shell. A distortion of a hydrated [H3O]+ easily changes its structure to the [H7O3]+ one that causes a change in the nature of the most IR-intensive bands. Thus, the specificity of this core can be easily lost that prevents identification of the corresponding species. By contrast, the [H5O2]+ core is more stable against distortion. It is characterized by the short O...O distance (< 2.45 A), IR-intensive band near 1720 cm-1 and Raman-intensive line around 500 cm-1. The [H5O2]+ core remains identifiable even when protonated hydrate is involved in specific interactions with a bulky counterion. Geometrical criteria for identification of the [H3O]+, [H5O2]+ and [H7O3]+ cores are discussed. PMID- 24062101 TI - Filming atomic motions in liquids. AB - Basic techniques in ultrafast time-resolved optical spectroscopy and x-ray diffraction are described for a broad scientific community. Basic experimental setups are presented, and theories for the interpretation of experimental data are briefly described. The power of these ultrafast techniques is shown with a few selected examples. It is shown in particular how they permit to film atomic motions during a chemical reaction. The strong and weak points of the two complementary techniques are discussed in some detail. A number of basic references are included to help interested readers. Future developments of ultrafast techniques are conjectured at the end of the paper. PMID- 24062100 TI - Solid-state NMR spectroscopy and first-principles calculations: a powerful combination of tools for the investigation of polymorphism of indomethacin. AB - Two polymorphs of indomethacin were investigated by 1H MAS and CRAMPS, and 1H-13C CPMAS and HETCOR NMR techniques. The obtained spectra clearly elucidated the structural differences between the polymorphs, especially the different numbers of indomethacin molecules within the crystallographic asymmetric units and the different schemes of hydrogen bonding among the molecules. Known structure of indomethacin gamma was used in first-principles DFT/GIPAW calculations of 1H and 13C isotropic chemical shifts. Two packages, freely available Quantum Espresso and commercially available CASTEP, were employed. They both provided values that excellently agreed with the measured values, and thus allowed unambiguous assignment of 1H and 13C spectral lines. PMID- 24062102 TI - Low-frequency Vibrations of DNA and Base Pair Opening. AB - DNA melts at temperatures around 70 degrees C (~340 K) depending on the base pair composition, level of hydration, type of counterions and excess salt concentration. Vibrational modes, which increase the separation between base molecules, i.e. perform the base pair opening, are thought to play an important role in DNA-bubble formation but these are typically assigned frequencies around 90 cm-1 (120 K). Understanding DNA melting and related biological processes requires this apparent energy gap of more than 200 K to be understood. We have performed atomistic molecular simulations which enable us to reconcile this energy difference between cause and effect. Using quasi-harmonic analysis we have analyzed the way in which vibrational modes of DNA change with the temperature. PMID- 24062103 TI - Algebraic clar formulas - numerical representation of clar structural formula. AB - We outline the construction of an algebraic (numerical) representation for Clar's valence formulas which in their geometrical form are illustrated with pi-aromatic sextets as inscribed circles in benzenoid rings. PMID- 24062104 TI - 1H, 13C NMR and DFT Study of Hydrogen Bonding in Imidazolium-based Ionic Liquids. AB - The ionic liquid 1-decyl-3-methyl-imidazolium bromide [C10mim][Br], the neat material, and also dissolved (~0.01 mole fraction) in various dielectric media (acetonitrile, benzene, chloroform, dichloromethane, methanol, 2-butanol and H2O) was studied using 1H and 13C NMR spectroscopy. The most important interaction in this compound is considered to be the Br-...H-C2+ hydrogen bond, which is formed between the anions and cations. The obtained results show that dielectric medium influence mostly the behavior of the Br-...H-C2+ bridge proton. The changes observed in 1H and 13C NMR spectra of [C10mim][Br] with increasing solvents polarity and temperature can be explained applying the model of the lengthening of the H2...Br- bond with the accompanying thickening of the solvation shell of bromine anion and C2-H bond contraction. The short-range order effects related to the configuration of neighboring dipoles of solvent molecules are more important for the solvation ability of small anions than the bulk solvent field effect. However, the solvents, molecules of which tend to associate via hydrogen bonding, can significantly affect the dynamics of anions. PMID- 24062105 TI - Crystal Structures of CaLa8Ti9O31 and Ca2La4Ti6O20 Determined from Powder Diffraction Data. AB - The ceramic materials of CaLa8Ti9O31 and Ca2La4Ti6O20 were synthesized using the solid-state reaction method. The crystal structures were determined from powder diffraction data using direct space methods. Like in similar compounds of the general formula AnBnO3n+2, the title compounds are composed of perovskite-like slabs, separated by oxygen-rich layers, where Ca or La occupy the A site. PMID- 24062106 TI - Nuclear quadrupole resonance study of hydrogen bonded solid materials. AB - Nuclear quadrupole resonance is presented as a method for the study of solid hydrogen bonded materials. NQR study of hydrogen bonds in ferroelectric and paraelectric KH2PO4, antiferroelectric and paraelectric squaric acid, ferroelectric croconic acid and antiferroelectric and paraelectric cocrystal 5' dimethyl-2, 2'-bipyridine - chloranilic acid (1:1) are discussed in more details. A 14N NQR study of the strong short O-HKN hydrogen bond in two polymorphic forms of cocrystal isonicotinamide-oxalic acid (2:1) is presented as well. Various correlations between the NQR parameters and between the NQR and structural parameters have been observed. These correlations may be used to determine the proton position in a hydrogen bond and some other structural parameters from the NQR data. PMID- 24062107 TI - Infrared and Raman Spectra of Magnesium Ammonium Phosphate Hexahydrate (Struvite) and its Isomorphous Analogues. VIII. Spectra of Protiated and Partially Deuterated Magnesium Rubidium Phosphate Hexahydrate and Magnesium Thallium Phosphate Hexahydrate. AB - The infrared and Raman spectra of magnesium rubidium phosphate hexahydrate MgRbPO4 * 6H2O and magnesium thallium phosphate hexahydrate, MgTlPO4 * 6H2O were recorded at room temperature (RT) and the boiling temperature of liquid nitrogen (LNT). To facilitate their analysis, also recorded were the spectra of partially deuterated analogues with varying content of deuterium. The effects of deuteration and those of lowering the temperature were the basis of the conclusions drawn regarding the origin of the observed bands which were assigned to vibrations which are predominantly localized in the water molecules (four crystallographically different types of such molecules exist in the structures) and those with PO43- character. It was concluded that in some cases coupling of phosphate and water vibrations is likely to take place. The appearance of the infrared spectra in the O-H stretching regions of the infrared spectra is explained as being the result of an extensive overlap of bands due to components of the fundamental stretching modes of the H2O units with a possible participation of bands due to second-order transitions. A broad band reminiscent of the B band of the well-known ABC trio characteristic of spectra of substances containing strong hydrogen bonds in their structure was found around 2400 cm-1 in the infrared spectra of the two studied compounds. PMID- 24062108 TI - Linear vs. Non-linear Modelling. Case study: modelling of binding affinity of inhibitors to Trypsin. AB - On the set of 53 trypsin inhibitors the affinity to the covalent bound ligands is modeled using linear (MLR) and non-linear (ANN) methods. Each compound is represented by 343 chemical descriptors. The hypothesis was that linear models are not sufficiently flexible to yield the best model, because in MLR (multiple regression analysis) the number of variables (descriptors) is limited by the number of objects in the training set. On the other hand the CP-ANN (counter propagation-artificial neural network) is not limited by this restriction and can thus involve larger number of variables than there are compounds in the training set. Both methods are applied on the same division of 53 compounds on the training, test, and validation sets. In a systematic GA (genetic algorithm) search the MLR models containing all possible forms of linear polynomials, i.e., from 3 to 25 variables were scanned and no better model that one obtained by the CP-ANN model was found. PMID- 24062109 TI - A novel crystal form of cabergoline, form L. AB - A new crystal form of cabergoline, form L, was discovered and characterized by thermal analyses, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, dynamic vapor sorption (DVS), and comparative dissolution behavior. The morphology of rod-shaped crystals was investigated by scanning electron microscopy (SEM). Form L was compared to other non-solvated forms of cabergoline such as form I, II, VII and to the amorphous form. The thermodynamic stability of form L is supported by its long-term stability. Form L is a pharmaceutically applicable crystal form. PMID- 24062110 TI - A highly accurate, analytic potential energy surface of the hydrogendifluoride anion in the gas phase. AB - We calculated the full three-dimensional potential energy surface (PES) of an isolated hydrogendifluoride anion (FHF-) in the electronic ground state at a very accurate Coupled Cluster approach and large correlation-consistent valence triple zeta basis set [CCSD(T)/aug-cc-pVTZ]. The PES was evaluated at more than 30.000 points corresponding to different geometries of the system. Analytical form of the PES was expressed in an internal coordinate set which included the F...F separation (internal coordinate R) and the longitudinal and transversal projection (internal coordinates x and y) of the proton position on the F...F line. For each constant value of x a two-dimensional fit along y and R was performed by using displaced Gaussian functions. The fitted parameters of Gaussians were then spline-interpolated along x to get the final analytical form of the three-dimensional PES. The maximum fitting error was less than 0.01 kcal/mol in the lowest 20 kcal/mol region of the PES, yielding an accurate and conveniently formulated surface which can be readily used for advanced calculations, including fully coupled anharmonic vibrational analysis and quantum dynamics simulation. PMID- 24062111 TI - Protonation of azines and purines as a model for the electrophilic aromatic substitution - rationalization by triadic formula. AB - First gas-phase carbon proton affinities of eleven azines and purines (pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, bicyclic purine, pyridine-N-oxide, 2-aminopyrimidine and uracil) were calculated by a composite G3B3 methodology and used to probe their susceptibility to undergo electrophilic aromatic substitution (EAS), taking benzene as a reference molecule. The results revealed excellent agreement with the available experimental data and were interpreted using the triadic approach. We found out that pyrroles, which are more reactive towards EAS reaction than benzene, are stronger carbon bases than the latter compound, whereas pyridines exhibit lower carbon basicity, being at the same time less reactive toward substitution by electrophiles than benzene. In all of the investigated molecules the frontier orbital describing the corresponding p-electron density at the carbon atom to be protonated is HOMO as calculated by the HF/G3large//B3LYP/6-31G(d) level of theory. Our results are in a disagreement with the work by D'Auria (M. D'Auria, Tetrahedron Lett. 2005, 46, 6333-6336; Lett. Org. Chem. 2005, 2, 659-661), who at B3LYP/6-311+G(d, p) level found out that in some of systems investigated here the HOMO orbital is not of ? symmetry, which was used to rationalize the lower reactivity of these systems towards EAS. It turned out that energies of HOMO orbitals alone correlate very poorly with carbon proton affinities, unlike the difference in proton affinities between the most basic carbon atom and thermodynamically the most favourable site of protonation, which performs much better. Triadic analysis demonstrated the importance of considering a complete picture of the protonation process and all three terms appearing in the triadic scheme individually when discussing trends in basicity/nucleophilicity of closely related molecules. PMID- 24062112 TI - The very short hydrogen bond in the pyridine N-oxide - trichloroacetic Acid complex: an inelastic neutron scattering and computational study. AB - We have investigated the dynamics of the very short hydrogen bond (RO...O = 2.430 A) of the pyridine N-oxide trichloroacetic acid complex in the solid state by combining vibrational spectroscopy using inelastic neutron scattering with extensive computational studies and analysis of the vibrational spectra. The Density Functional Theory (DFT) computational models used ranged from the isolated gas phase cluster to three approaches with periodic boundary conditions, namely CRYSTAL, CPMD and VASP, all of which, however calculate frequencies in the harmonic approximation. While all but the gas phase calculation yield structural parameters for the hydrogen bond in reasonable agreement with experiment, only the periodic VASP and CPMD approaches resulted in INS spectra (calculated with the program a-climax) that adequately reproduced some of the key features of the experimental spectrum related to the in-plane and out-of-plane bending modes of the H-bond. No clear indication was found either in experiment or computational studies for OH stretching. More sophisticated and time-consuming calculations are therefore indicated to elaborate on the hydrogen bond dynamics including molecular dynamics simulations or the use of quantum dynamics on multidimensional potential energy surfaces. PMID- 24062113 TI - Dispersion analysis of polarized bulk reflectance spectra of potassium hydrogen succinate monocrystal. AB - Reflectance spectra may show very different and interesting shapes. The most interesting may be connected to Evans holes. Model calculations to reproduce this effect were done applying model dielectric function functions. When a weak oscillator appears within the frequency region of a strong one (i.e. between its TO and LO frequencies), its LO-mode frequency shifts towards higher wavenumbers. As a consequence, the oscillator strength of the corresponding weak mode becomes negative which produces a dip (Evans hole) in the reflectance spectrum. This model was successfully applied to analyze polarized reflectance spectra of potassium hydrogen succinate monocrystal in the ac crystal plane. The crystal symmetry was described by phenomenological model and by full symmetry consideration. The phenomenological approach applies the four-parametric model for dielectric function which allows good evaluation of asymmetric reflectance bands. A cosine dependence of oscillator strength on polarization angle was obtained for some bands, most likely due to small deviation of the crystal symmetry from orthorhombic. This is why the phenomenological approach provides good parameters for almost all phonon modes. The full symmetry consideration applies real description of dielectric tensor in the ac plane and the three parameter model for dielectric function. This model could give very accurate directions of transition dipole moments, but cannot fit asymmetric bands well to measured reflectance. Both approaches describe all basic spectral features, the wide reflectance of ?asOH and the two Evans holes appearing on its shoulder. PMID- 24062114 TI - Synthesis, Spectroscopic Characterization and Antibacterial Activity of some Chloro Dimethylsulphoxide/ Tetramethylenesulphoxide Ruthenium (II)/(III) Complexes with 1, 2, 3-Benzotriazole. AB - Synthesis and characterization of seven ruthenium (II) and ruthenium (III) chloro sulphoxide complexes with 1, 2, 3-benzotriazole are reported. Three different formulations exist: [cis, fac-RuCl2(so)3(btz)]; [trans-RuCl2(so)3(btz)] and [trans-RuCl4(so)(btz)]-[X]+; where so=dimethylsulphoxide/ tetramethylenesulphoxide; btz = 1, 2, 3-benzotriazole and [X]+ = [(btz)H]+ or Na+. These complexes were characterized by elemental analysis, conductivity measurements, magnetic susceptibility, FT-IR, 1H-NMR, 13C1H-NMR and electronic spectroscopy. Complexes were screened for their antibacterial activity and found more potent than 1, 2, 3-benzotriazole ligand and precursor ruthenium compounds against gram-negative bacteria Escherichia coli. All the samples were compared with antibiotic Chloramphenicol for reference. PMID- 24062115 TI - Photopyroelectric Investigation of Thermal Effusivity of Binary Liquid Mixtures by FPPE-TWRC Method. AB - An alternative front photopyroelectric configuration (FPPE) that uses the thermal wave resonator cavity method (TWRC) is proposed for measuring the thermal effusivity of a liquid, inserted as backing in the detection cell. A theory for a 5 layers (air, sensor, coupling fluid, solid separator layer, and liquid backing) detection cell is developed. The method seems to be particularly suitable when measuring the thermal effusivity of binary liquid mixtures. If the coupling fluid is one component of the binary mixture, the technique acts a "quasi-differential" method and low concentration of the second component of the mixture can be detected. In the paper the method was applied to binary liquid mixtures of water with ethanol, ethylene glycol and DMSO. PMID- 24062116 TI - Flow Injection Potentiometric Determination of Cd2+ Ions Using a Coated Graphite Plasticized PVC-Membrane Electrode Based on 1, 3-Bis(2-cyanobenzene)triazene. AB - 1, 3-Bis(2-cyanobenzene)triazene, L, was used as a suitable ionophore for the fabrication of a new PVC-based polymeric membrane coated graphite electrode for selective sensing of Cd2+ ion. The electrode exhibited a selective linear Nernstian response to Cd2+ ion at an optimal pH range of 6-9 with a limit of detection of 8.0 * 10-6 M and a fast response time of about 2 s. The electrode was used as a proper detection system in flow-injection potentiometry of cadmium ion and resulted in well defined peaks for cadmium ions with stable baseline, excellent reproducibility and high sampling rates of over 100 injections per hour. It showed good stability, reproducibility and fast response time. The practical utility of the proposed system has also been reported. PMID- 24062117 TI - Simple chemiluminescence determination of pilocarpine in pharmaceuticals and human serum. AB - A new method using flow injection analysis (FIA) and chemiluminescence (CL) detection has been developed for the rapid, simple and precise determination of pilocarpine hydrochloride (PH). The method is based on the CL reaction of PH with tris(1, 10 phenanthroline)ruthenium(II), [Ru(phen)32+], and Ce(IV) in sulfuric acid medium. Effects of chemical variables were investigated using a central composite design (CCD) and the response surface methodology (RSM). Under optimum conditions, the CL intensity was proportional to the concentration of the drug in solution over the range 0.12-40.00 ug mL-1. The limit of detection (S/N = 3) was 34 ng mL-1. The method was applied successfully to the determination of PH in pharmaceutical formulations and spiked human serum. The relative standard deviation for determination of 7 replicates at a level of 1.5 ug mL-1 of PH was 0.6%. The minimum sampling rate was 70 samples per hour. PMID- 24062118 TI - Determination of Nitrite and Nitrate in Freshwaters using Flow Injection Luminol Chemiluminescence Detection. AB - A flow injection method for determination of nitrite and nitrate in freshwaters is described based on luminol-hypochlorite chemiluminescence (CL) system. Nitrate is reduced on-line with a cadmium reduction column to nitrite and its inhibition effect on luminol CL emission was measured. The effects of chemical and physical parameters such as buffer pH and concentration, luminol, sodium hypochlorite and sulfuric acid concentrations, flow rate, and sample volume were investigated. The calibration graphs were linear over the range 0.1-50 uM (R2 = 0.9989 and 0.9984) for nitrite and nitrate respectively with a limit of detection (S/N = 3) of 4.0 * 10-8 M and a sample throughput of 120 samples per hour. The effect of foreign ions was studied and the method was successfully applied to the determination of nitrite and nitrate in water samples. The results obtained were in good agreement with those achieved by a spectrophotometric reference method at the 95% confidence level. Standard addition method was also applied to the freshwater samples and the recovery values were found in the range of 92-109% and 94-105% for nitrite and nitrate respectively. PMID- 24062119 TI - Synthesis of Novel Linked Pyrazolyl-thiazolidinone Heterocycles as Potent Antibacterial Agents. AB - A novel series of 2-(3, 5-dimethyl-1-phenyl-1H-4-pyrazolyl)-3-(aryl/heteroaryl) 1, 3-thiazolidin-4-one derivatives 4a-h has been synthesized readily in one-pot from 3, 5-dimethyl-1-phenyl-1H-4-pyrazolecarbaldehyde (3), and characterized via IR, NMR, MS and elemental analyses. Further, these compounds were screened for antibacterial (MIC) activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Staphylococcus pyogenes. Amongst them, compounds containing pyridyl 4g and pyrimidinyl 4h moiety exerted superior antibacterial activity against S. aureus and E. coli at the concentration of 6.25 ug/mL, which is less than the concentration of the standards neomycin and streptomycin, and emerged as potential molecules for further development. PMID- 24062120 TI - Synthesis of Some Novel Bis[1, 2, 4]triazolo[3, 4-b][1, 3, 4]thiadiazine Derivatives for Antimicrobial Evaluation. AB - A new series of novel bis[1, 2, 4]triazolo[3, 4-b][1, 3, 4]thiadiazines 7a-j has been synthesized by the reaction of [5, 5'-methylenebis(3-methylbenzofuran-7, 5 diyl)]bis[(4-amino-5-thioxo-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl)methanone] (6) with a variety of phenacyl bromides in ethanol under reflux for 6 h. All the newly synthesized compounds were tested for in vitro activity against certain strains of bacteria such as Escherichia coli, Klebsiella pneumoniae, Shigella dysenteriae and Shigella flexneri. Compounds 7a, 7c and 7g were highly active against the entire organism employed. Compound 7c showed the activity higher than the standard drug neomycin, and almost equal to the streptomycin. Compounds 7a-j were also screened for their antifungal activity against Aspergillus niger, Candida albicans, Aspergillus flavus and Rhizopus oryzae. Compounds with methoxyphenyl moiety 7d and dichlorophenyl moiety 7f showed significant activity against the tested fungal strains. PMID- 24062121 TI - Potentiometric Study of a Benzene-based Tripodal Triamine as Chelator for Zn(II) Ion. AB - The complexation of a C3-symmetrical tripodal triamine ligand, N1, N3, N5-tris(2 aminoethyl)benzene-1, 3, 5-tricarboxamide (TAT, L) with Zn(II) ion was investigated at an ionic strength of 0.1 M NaClO4 and 25 +/- 1 degrees C in aqueous medium. Formation of complex species [ZnL(H2O)]2+ and [ZnL(OH)]+ were depicted in solution, where the ligand is tri-coordinated through three amine N atoms and their stability constants were calculated with the HYPERQUAD 2000 computer program. The pKa of the zinc-bound water molecule is 7.84, making the Zn(TAT) complex a viable model of carbonic anhydrase. PMID- 24062122 TI - Single-pot conversion of an Acid to the corresponding 4-chlorobutyl ester. AB - A single pot conversion of carboxylic acids into the corresponding 4-chlorobutyl esters has been achieved by a novel procedure. The intermediate acid chlorides are not isolated. The double bond and aromatic methoxy group survive the mild reaction conditions. In almost all the examples studied the products are purified by simple flash chromatography. PMID- 24062123 TI - Synergistic extraction of europium into nitrobenzene by using hydrogen dicarbollylcobaltate and 2, 6 - (diphenylphosphino)pyridine dioxide. AB - Solvent extraction of microamounts of europium by a nitrobenzene solution of hydrogen dicarbollylcobaltate (H+B-) in the presence of 2, 6 - (diphenylphosphino)pyridine dioxide (DPPPDO, L) has been investigated. The equilibrium data have been explained assuming that the species HL+, HL+2, EuL3+3 and EuL3+4 are extracted into the organic phase. The values of extraction and stability constants of the species in nitrobenzene saturated with water have been determined. PMID- 24062124 TI - Diels-alder reactions of styrylcyclohexenones: an efficient procedure for the synthesis of substituted dehydrodecaline derivatives. AB - The Diels-Alder reaction of styrylcyclohex-2-enone derivatives 1 with N phenylmaleimide was shown to be an efficient pathway for the synthesis of substituted dehydrodecaline derivatives. At elevated temperatures, mixtures of endo/exo adducts were formed, while in the presence of TiCl4 exclusive formation of the endo stereoisomer was observed. Spectroscopic analysis and X-ray crystallography confirmed the formation of the endo adducts. PMID- 24062125 TI - A combined experimental and DFT study on the complexation of the hydrazinium cation with a hexaarylbenzene - based receptor. AB - From extraction experiments and gamma-activity measurements, the exchange extraction constant corresponding to the equilibrium N2H+5 (aq) + 1.Cs+(nb) <-> 1.N2H+5 (nb) + Cs+(aq) taking place in the two-phase water-nitrobenzene system (1 = hexaarylbenzene - based receptor; aq = aqueous phase, nb = nitrobenzene phase) was evaluated as log Kex (N2H+5, 1.Cs+) = -1.2 +/- 0.1. Further, the stability constant of the hexaarylbenzene - based receptor .N2H+5 complex (abbrev. 1.N2H+5) in nitrobenzene saturated with water was calculated for a temperature of 25 degrees C: log betanb (1.N2H+5) = 5.6 +/- 0.2. By using quantum mechanical DFT calculations, the most probable structure of the 1.N2H+5 complex species was solved. In this complex, the cation N2H+5 synergistically interacts with the polar ethereal oxygen fence and with the central hydrophobic benzene bottom via cation - pi interaction. Finally, the calculated binding energy of the resulting complex 1.N2H+5 is -270.5 kJ/mol, confirming the relatively high stability of the considered cationic complex species. PMID- 24062126 TI - Synthesis, crystal structure and photoluminescence of a novel zinc-isonicotinic Acid complex. AB - A novel zinc-isonicotinic acid complex [Zn(Hini)(Ini)Cl]n (1) (Hini = isonicotinic acid; Ini = deprotoned isonicotinic acid) has been synthesized via a hydrothermal reaction and structurally characterized by a single-crystal X-ray diffraction. Complex 1 crystallizes in the space group P21/c of the monoclinic system with four formula units in a cell: a = 7.654(4), b = 13.540(7), c = 14.213(3) A, beta = 122.21(1), V = 1246.2(10) A3, C12H9ClN2O4Zn, Mr = 346.05, Dc = 1.844 g/cm3, S = 1.017, u(MoKalpha) = 2.199 mm-1, F(000) = 696, R = 0.0206 and wR = 0.0500. Complex 1 is characteristic of a novel one-dimensional (1-D) chain like structure. Photoluminescence investigation reveals a strong emission, which may originate from pi -> pi* charge-transfer interaction of the isonicotinic acid ligand. PMID- 24062127 TI - Volumetric and spectrophotometric determination of oxcarbazepine in tablets. AB - Two cerimetric procedures are described for the assay of oxcarbazepine (OXC) in bulk drug and in tablets. Titrimetry (method A) is based on the reaction of OXC by a measured excess cerium(IV) sulphate in sulphuric acid medium and the determination of the unreacted oxidant by titration with iron(II) solution using ferroin as indicator. Spectrophotometry (method B) is based on oxidation of OXC by cerium(IV) in perchloric acid (HClO4) medium and the determination of the unreacted oxidant using a colour reaction with p-dimethylaminobenzaldehyde (p DMAB) having an absorption maximum of 460 nm. The titrimetric method is applicable in the range of 2.0-20.0 mg OXC with a 1:2 reaction stoichiometry [OXC:Ce(IV)]. In the spectrophotometric method a rectilinear relationship is obtained over the concentration range of 0.3-6.0 ug mL-1 OXC. The linear regression equation of the calibration graph is A = 0.9820-0.1477 C with a regression coefficient (r) of -0.9967 (n = 6). The molar absorptivity is calculated to be 3.76 * 104 L mol-1 cm-1 and the Sandell sensitivity is 0.0067 ug cm-2. The limits of detection (LOD) and quantification (LOQ) values are calculated according to ICH guidelines. The methods are successfully applied to the determination of OXC in tablets. PMID- 24062128 TI - Molecular dynamic simulation: a powerful method for prediction of apoptotic pore formation. PMID- 24062129 TI - mir-143 and it's emerging role as a modulator of systemic carcinogenesis. PMID- 24062130 TI - An observational study of autologous bone marrow-derived stem cells transplantation in seven patients with nervous system diseases: a 2-year follow up. AB - Currently, autologous bone marrow-derived stem cell is one of the most innovative areas of stem cells research. Previous studies on animal models of nervous system diseases have shown that these cells have a good effect on nervous system disorders. The alternative treatment with stem cells for the nervous system diseases has also gradually reached to clinical application stage. The prospect is captivating, but the safety and efficacy of this procedure need further research. To observe the clinical efficacy and side effects of the treatment for autologous mesenchymal stem cells and neural stem/progenitor cells which are in differentiated form by inducing with cerebrospinal fluid in the patients with nervous system diseases, thirty patients were selected from our hospital (2009-10 to 2012-07) and were followed at 1 month, 3 months, 6 months, 1 year and 2 years after the treatment with autologous mesenchymal stem cells and neural stem/progenitor cells in differentiated form was introduced. In this paper, we will introduce the process to make cells accessible for the clinical application by the description of the changes observed in 7 cases were followed for 2 years. The time for bone marrow mesenchymal stem cells could be available for clinical needs is as early as 5 days, not later than 10 days, and the median time is 8 days, while neural stem/progenitor cells in differentiated form can be available for clinical needs in as early as 12 days, not later than 15 days, and the median time is 13.5 days (statistical explanation: Case 5 only uses autologous mesenchymal stem cells, and Case 7 has two times bone marrow punctures). The neurological function of the patients was improved in 1-month follow-up, and the patients have a better discontinuous trend (statistical explanation: sometimes the neurological function of the patients between two adjacent follow-ups does not change significantly). After transplantation, four patients appeared to have transient fever, but it was easily controlled by symptomatic treatment. Seven patients did not appear to show secondary tumor induced by transplantation of stem cells in 2-year follow-up. Thus, it suggests that the use of autologous bone marrow-derived stem cells transplantation in patients with nervous system diseases is a feasible, convenient, safe, and effective method. PMID- 24062132 TI - Lycopene production in recombinant strains of Escherichia coli is improved by knockout of the central carbon metabolism gene coding for glucose-6-phosphate dehydrogenase. AB - Genetic manipulation was undertaken in order to understand the mechanism involved in the heterologous synthesis of lycopene in Escherichia coli. Knockout of the central carbon metabolic gene zwf (glucose-6-phosphate dehydrogenase) resulted in the enhancement of lycopene production (above 130 % relative to control). The amplification and overexpression of rate-limiting steps encoded by idi (isopentenyl diphosphate isomerase), dxs (1-deoxyxylulose-5-phosphate synthase) and ispDF (4-diphosphocytidyl-2C-methyl-D-erythritol synthase and 2C-methyl-D erythritol 2,4-cyclodiphosphate synthase) genes improved lycopene synthesis from 0.89 to 5.39 mg g(-1) DCW. The combination of central metabolic genes knockout with the amplification of MEP pathway genes yielded best amounts of lycopene (6.85-7.55 mg g(-1) DCW). Transcript profiling revealed that idi and dxs were up regulated in the zwf knock-out strain, providing a plausible explanation for the increase in lycopene yield observed in this strain. An increase in precursor availability might also have contributed to the improved lycopene production. PMID- 24062131 TI - Treating colon cancer with injectable PLGA-PEG-PLGA as a carrier for iodine-125. AB - PURPOSE OF WORK: Provide a safer way for treating various cancers with PLGA-PEG PLGA (PPP)-embedded iodine-125. To improve the safety of iodine treatment for colon cancer, iodine-125 solution was embedded into PLGA-PEG-PLGA (PPP) (synthesized by bulk co-polymerization of DL-polylactide glycolide and PEG). Xenograft-carrying nude mice were then treated with iodine-125-PPP. Proliferating cell nuclear antigen and Terminal Transferase dUTP Nick-End Labeling were used to measure proliferation and apoptosis in the tumors, respectively. Simultaneously, immunohistochemistry SP was used to detect the expression levels of p53. In addition, the microvessel density (MVD) of the tumors was recorded. PPP-embedded iodine-125 induced apoptosis by increasing the expression of p53, and by decreasing the levels of VEGF and MVD in the colon cancer tumors (P < 0.01). Significant inhibition of tumor growth is seen with iodine-125 from 0.4 to 0.8 mCi. PPP-embedded iodine-125 has a similar inhibitory efficiency to using the iodine-125 seeds for the treatment of colon tumors (P > 0.05). The findings therefore provide a potentially safer method for treating various tumors with radioactive iodine. PMID- 24062133 TI - Biodiesel production in a magnetically-stabilized, fluidized bed reactor with an immobilized lipase in magnetic chitosan microspheres. AB - Biodiesel production by immobilized Rhizopus oryzae lipase in magnetic chitosan microspheres (MCMs) was carried out using soybean oil and methanol in a magnetically-stabilized, fluidized bed reactor (MSFBR). The maximum content of methyl ester in the reaction mixture reached 91.3 (w/v) at a fluid flow rate of 25 ml/min and a magnetic field intensity of 150 Oe. In addition, the MCMs immobilized lipase in the reactor showed excellent reusability, retaining 82 % productivity even after six batches, which was much better than that in a conventional fluidized bed reactor. These results suggested that a MSFRB using MCMs-immobilized lipase is a promising method for biodiesel production. PMID- 24062134 TI - Elevated 3-hydroxypropionaldehyde production from glycerol using a Citrobacter freundii mutant. AB - A mutant strain of Citrobacter freundii capable of elevated 3 hydroxypropionaldehyde production from glycerol was isolated using chemical mutagenesis and a screening protocol. The protocol involved screening mutagenized bacterial cells on solid minimal medium containing 5 % (v/v) glycerol. Colonies were picked onto duplicate solid minimal medium plates and one plate was stained with 1 % (w/v) phloroglucinol. Those colonies staining red were further screened and a mutant, HPAO-1, was identified. The mutant strain produced a several-fold higher 3-hydroxypropionaldehyde concentration than did the parent strain when grown on 5 % (v/v) glycerol. The ratio of culture volume to flask volume influenced 3-hydroxypropionaldehyde production by the mutant cells compared to the parent cells. Aldehyde production was highest when the mutant strain was grown on 5 % (v/v) glycerol at a ratio of culture volume to flask volume of 1:3 or 1:12.5. PMID- 24062135 TI - Oxidative stress and production of bioactive monoterpene indole alkaloids: biotechnological implications. AB - Monoterpene indole alkaloids (MIAs) encompass plant natural products with important pharmacological relevance. They include the anti-tumoral MIAs found in Catharanthus roseus and Camptotheca acuminata. The often low yields of bioactive alkaloids in plants has prompted research to identify the factors regulating MIA production. Oxidative stress is a general response associated with biotic and abiotic stresses leading to several secondary responses, including elicitation of MIA production. These changes in secondary metabolism may take place directly or via second messengers, such as Ca(2+) and reactive oxygen species (ROS). H2O2 is the main ROS that participates in MIA biosynthesis. This review analyzes the links between oxidative stress, elicitation of bioactive MIA production and their potential roles in antioxidant defense, as well as exploring the implications to developing biotechnological strategies relevant for alkaloid supply. PMID- 24062136 TI - Low temperature cell pausing: an alternative short-term preservation method for use in cell therapies including stem cell applications. AB - Encouraging advances in cell therapies have produced a requirement for an effective short-term cell preservation method, enabling time for quality assurance testing and transport to their clinical destination. Low temperature pausing of cells offers many advantages over cryopreservation, including the ability to store cells at scale, reduced cost and a simplified procedure with increased reliability. This review will focus on the importance of developing a short-term cell preservation platform as well highlighting the major successes of cell pausing and the key challenges which need addressing, to enable application of the process to therapeutically relevant cells. PMID- 24062137 TI - HCN production and hydroxynitrile lyase: a natural activity in plants and a renewed biotechnological interest. AB - Over 3,000 plant species are cyanogenic. Cyanogenesis is defined as the hydroxynitrile lyase catalysed release of a cyanide group in the form of HCN and the corresponding aldehyde or ketone. When a plant is attacked, HCN released is a self defence mechanism. A special characteristic of enzymatic reactions is that all enzymatic reactions are reversible-hydroxynitrile lyases can also be used for the synthesis of enantiomerically pure cyanohydrins which are of great importance in industry. This article presents a comprehensive review of the role of hydroxynitrile lyases, both in nature and industry, and an insightful. Areas covered include: history, discovery and natural sources of the hydroxynitrile lyase. Molecular cloning for mass production of this enzyme, including detailed information about several successful recombinant hydroxynitrile lyases is also included. PMID- 24062138 TI - MicroRNA-650 expression in glioma is associated with prognosis of patients. AB - MicroRNAs are known as non-coding RNAs that regulate the expression of target mRNA. Accumulating evidence has indicated that microRNA expression in human malignancies can be utilized as a prognostic marker for patients. However, the prognostic value of miR-650 in human glioma has not been investigated yet. In the present investigation, we have recruited 168 cases glioma specimens and 21 normal control brain specimens. Quantitative real-time PCR was carried out to investigate the expression of miR-650. Kaplan-Meier analysis and Cox's proportional hazards model was used to evaluate the association of miR-650 with prognosis of glioma patients. Results showed that miR-650 expression was increased in glioma compared with normal control specimens (P < 0.001). It was also found that miR-650 expression was related to World Health Organization grade and Karnofsky performance score (KPS) for high expression was more frequently detected in glioma of high grade or low KPS score (P < 0.001). The prognosis of glioma with high miR-650 expression was significantly worse compared with that of glioma with low miR-650 expression. These results proved that miR-650 expression was a significant prognostic indicator in glioma, which may suggest new management of human glioma. PMID- 24062139 TI - Surgical outcomes in spinal cord subependymomas: an institutional experience. AB - Spinal cord subependymomas are very rare. Most studies on spinal cord subependymomas have been case reports with literature reviews. This study presented a surgical series of 13 patients with histologically proven spinal cord subependymomas. Their clinical data, radiological findings, operative records, and follow-up outcomes were reviewed. There were 5 male and 8 female patients with a mean age of 39.5 years. The mean follow-up period was 67.8 months. Four tumors were located in the cervical spine, 5 in the cervicothoracic spine, and 4 in the thoracic spine. Gross total resection (GTR) of the tumor with a well demarcated dissection plane was achieved in 9 cases, and subtotal resection was achieved in 4 cases. The symptoms present before the surgery were improved in 11 cases at last follow-up and the current status of 2 patients had no change compared to the preoperative presentation at last follow-up. The postoperative follow-up magnetic resonance imaging showed no recurrence in the 9 GTR cases during the mean follow-up period of 70.3 months. No recurrence/regrowth of the residual tumors was observed in the 4 STR cases during the mean follow-up period of 62.0 months. Spinal cord subependymomas are amenable to surgical resection. It is possible to achieve GTR of intramedullary subependymomas that have a well demarcated dissection plane. When GTR cannot be achieved, STR of the lesion for decompression is advised, and follow-up imaging is needed. A good clinical outcome after GTR or STR can be expected. PMID- 24062140 TI - Cytotoxic human peripheral blood-derived gammadeltaT cells kill glioblastoma cell lines: implications for cell-based immunotherapy for patients with glioblastoma. AB - Glioblastoma (GBM) is a highly aggressive brain tumor for which novel therapeutic approaches, such as immunotherapy, are urgently needed. Zoledronate (ZOL), an inhibitor of osteoclastic activity, is known to stimulate peripheral blood derived gammadeltaT cells and sensitize tumors to gammadeltaT cell-mediated killing. To investigate the feasibility of gammadeltaT cell-based immunotherapy for patients with GBM, we focused on the killing of GBM cell lines by gammadeltaT cells and the molecular mechanisms involved in these cell-cell interactions. Peripheral blood mononuclear cells were expanded in ZOL and interleukin (IL)-2 for 14 days, and gammadeltaT cells were enriched in the expanded cells by the immunomagnetic depletion of alphabetaT cells. Gliomas are resistant to NK cells but susceptible to lymphokine-activated killer cells and some cytotoxic T lymphocytes. When the gammadeltaT cell-mediated killing of three GBM cell lines (U87MG, U138MG and A172 cells) and an NK-sensitive leukemia cell line (K562 cells) were tested, 32% U87MG, 15% U138MG, 1% A172, and 50% K562 cells were killed at an effector:target ratio of 5:1. The gammadeltaT cell-mediated killing of all three GBM cell lines was significantly enhanced by ZOL and this ZOL enhanced killing was blocked by an anti-T cell receptor (TcR) antibody. These results indicated that TcR gammadelta is crucial for the recognition of ZOL treated GBM cells by gammadeltaT cells. Since the low level killing of GBM cells by the gammadeltaT cells was enhanced by ZOL, gammadeltaT cell-targeting therapy in combination with ZOL treatment could be effective for patients with GBM. PMID- 24062141 TI - A high selective and sensitive liquid chromatography-tandem mass spectrometry method for quantization of BPA urinary levels in children. AB - A selective and highly sensitive liquid chromatography-tandem mass spectrometry method has been developed and validated for determination of Bisphenol A (BPA) in human urine using labeled d6-BPA as internal standard. BPA was purified from human urine by affinity chromatography on solid extraction AFFINIMIP(r) Bisphenol A cartridges, based on molecularly imprinted polymers. After purification, the samples were analyzed on a Phenomenex Kinetex 100 * 4.6 mm, 2.6 MUm particle PFP reversed-phase HPLC column, coupled to a triple quadrupole mass spectrometer by an electrospray ion source. Analyses were performed in the multiple reaction monitoring mode and negative ionization; the product ions at 133.2 and 212.1 m/z for BPA and at 138.2 and 215.0 m/z for d6-BPA were monitored to assess unambiguous identification. The linearity of the detector response was verified in human urine over the concentration range 0.100-200 ng/mL. The detection limit was calculated as 0.03 ng/mL and the limit of quantification of the method is 0.10 ng/mL. This LC/ESI-MS/MS method was in-house validated evaluating specificity, trueness, within-day and between-days precision. The mean recoveries of BPA from spiked urine samples were higher than 94% and good reproducibility (relative standard deviations <= 8.1%) was observed. The developed method was applied to a pilot study involving 105 children, aged from 6 to 14 years (16 normal weight and 89 obese children), from the Regione Campania (Southern Italy). The aim of this study was to determine the concentrations of BPA in urine of children and possible correlations with childhood obesity. PMID- 24062142 TI - Long-term outcomes after obturator hernia repair: retrospective analysis of 80 operations at a single institution. AB - PURPOSE: Long-term outcomes after obturator hernia surgery remain unclear. METHODS: Between 1979 and 2012, 80 consecutive operations for obturator hernia were performed for 70 patients at our hospital. Their charts were retrospectively reviewed, and the patients were contacted by telephone to check for the presence of an episode of recurrence. Including bilateral cases, a total of 104 obturator hernia repairs were divided by type into either mesh repair (n = 29) or non-mesh repair (n = 75). Recurrence rate was then calculated and compared between groups. RESULTS: Median age at the time of initial surgery was 84 years. Postoperative complications occurred in 31 operations (39 %), including four in-hospital deaths (5 %). After the initial obturator hernia surgery, the 2- and 5-year survival rates were 74 and 55 %, respectively. Seventeen recurrences were detected, all after non-mesh repairs. Recurrence rates at 3 years after obturator hernia repair were 0 % for mesh repair and 22 % for non-mesh repair (P = 0.048). CONCLUSIONS: Once patients recover from an incarcerated obturator hernia, they may still enjoy their super-aged lives. To prevent the recurrence, mesh repair is preferable if no contraindications are present. PMID- 24062143 TI - Biomechanical evaluation of fixation properties of fibrin glue for ventral incisional hernia repair. AB - INTRODUCTION: Use of adhesives for mesh fixation in hernia is increasing. There has been minimal study of mesh incorporation and interface strength with adhesive fixation for ventral hernia repair. The purpose of this study was to evaluate the fixation properties of fibrin glue as it compared to suture fixation of mesh in an onlay position. METHODS: Twenty-four mongrel pigs were divided into three study arms based on time points for biomechanical evaluation: 24 h (n = 8), 7 days (n = 8), and 14 days (n = 8). Initial procedures included placement of two 4 * 6 cm pieces of wide-pore polypropylene mesh in an onlay position. One was fixated with 4 ml of fibrin glue and the other with four interrupted 2-0 polypropylene sutures. The shear strength of fixation was evaluated using a uniaxial testing device along with histological evaluation. Maximum force was normalized by the width of the mesh. RESULTS: Mesh-tissue interface of glued and sutured specimens at 7 and 14 days did not fail in our testing configuration. Only at the 24-h time point the mesh detached from the tissue, and the sutured interface (10.4 N/cm) was significantly stronger than glued interface (4.9 N/cm, p = 0.004). Histopathologic and gross evaluations of the specimens revealed similar histologic features at all time points for both glued and sutured specimens. CONCLUSIONS: With mesh in the onlay position, fixation to the abdominal wall occurs quickly. Though sutures were stronger at 24 h, as early as 1 week, the strength of the fixation exceeded the tissue or the mesh strength in our testing configuration for both glue and suture groups. Fixation strength is independent of technique at the latter time points. There are potential clinical advantages to the exclusive use of fibrin glue for fixation including acute post operative pain, chronic post-operative pain, and recurrence for ventral incisional hernia repair. PMID- 24062144 TI - Evolutions in both co-payment and generic market share for common medication in the Belgian reference pricing system. AB - BACKGROUND: In Belgium, a co-insurance system is applied in which patients pay a portion of the cost for medicines, called co-payment. Co-payment is intended to make pharmaceutical consumers more responsible, increase solidarity, and avoid or reduce moral hazards. OBJECTIVE: Our objective was to study the possible influence of co-payment on sales volume and generic market share in two commonly used medicine groups: cholesterol-lowering medication [statins (HMG-CoA reductase inhibitors) and fibrates] and acid-blocking agents (proton pump inhibitors and histamine H2 receptor antagonists). METHODS AND DATA: The data were extracted from the Pharmanet database, which covers pharmaceutical consumption in all Belgian ambulatory pharmacies. First, the proportion of sales volume and costs of generic products were modelled over time for the two medicine groups. Second, we investigated the relation between co-payment and contribution by the national insurance agency using change-point linear mixed models. RESULTS: The change point analysis suggested several influential events. First, the generic market share in total sales volume was negatively influenced by the abolishment of the distinction in the maximum co-payment level for name brands and generics in 2001. Second, relaxation of the reimbursement conditions for generic omeprazole stimulated generic sales volume in 2004. Finally, an increase in co-payment for generic omeprazole was associated with a significant decrease in omeprazole sales volume in 2005. The observational analysis demonstrated several changes over time. First, the co-payment amounts for name-brand and generic drugs converged in the observed time period for both medicine groups under study. Second, the proportion of co-payment for the total cost of simvastatin and omeprazole increased over time for small packages, and more so for generic than for name brand products. For omeprazole, both the proportion and the amount of co-payment increased over time. Third, over time the prescription of small packages shifted to an emphasis on larger packages. CONCLUSIONS: As maximum co-payment levels decreased over time, they overruled the reference pricing system in Belgium. The changes in co-payment share over time also significantly affected sales volume, but whether physicians or patients are the decisive actors on the demand side of pharmaceutical consumption remains unclear. PMID- 24062146 TI - Developmental trajectories of anxiety symptoms in early adolescence: the influence of anxiety sensitivity. AB - Children and adolescents seem to suffer from anxiety disorders at rates similar to adults. Interestingly, anxiety symptoms appear to generally decline over time within children as evidenced by lower rates in early and middle adolescence. There is some evidence that there may be heterogeneous subpopulations of adolescent children with different trajectories of anxiety symptoms, including a class of adolescents with elevated levels of anxiety that do not dissipate over time. Anxiety sensitivity has been identified as an important risk factor in the development of anxiety psychopathology. This study prospectively examined the development of anxiety symptoms in a sample of 277 adolescents (M age = 11.52; 44 % female, 56 % male) over a 3 year period including the influence of anxiety sensitivity on this development. Further, this study investigated whether there were distinct classes of adolescents based on their anxiety symptom trajectories and including anxiety sensitivity as a predictor. Consistent with other reports, findings indicated an overall decline in anxiety symptoms over time in the sample. However, three classes of adolescents were found with distinct anxiety symptom trajectories and anxiety sensitivity was an important predictor of class membership. Adolescents with elevated anxiety sensitivity scores were more likely to be classified as having high and increasing anxiety symptoms over time versus having moderate to low and decreasing anxiety symptoms over time. There are important implications for identification of adolescents and children who are at risk for the development of an anxiety disorder. PMID- 24062147 TI - Dose-finding study of landiolol hydrochloride: a short-acting beta1-blocker for controlling heart rate during coronary computed-tomography angiography in Japan. AB - INTRODUCTION: Coronary computed-tomography angiography (CCTA) has high diagnostic performance, but it sometimes does not allow evaluation because of artifacts. Currently, the use of a beta-blocker is recommended to prevent motion artifacts, but the beta-blocker (metoprolol, propranolol, etc.) commonly used has a slow onset and long duration of action. Landiolol hydrochloride is an intravenous beta1-blocker with a very short half-life. We investigated the efficacy and optimal dose of this drug for reduction of heart rate in patients undergoing CCTA. METHODS: Eighty-seven subjects with ischemic heart disease were divided into three groups to receive landiolol hydrochloride at a dose of 0.125 (Group L), 0.25 (Group M), or 0.5 mg/kg (Group H). CCTA was performed at 3-7 min after administration, and heart rate, blood pressure, and image quality were assessed. RESULTS: Heart rate decreased rapidly after completion of landiolol hydrochloride administration in all groups, with a heart rate reduction of 15.55 +/- 6.56% in Group L, 16.48 +/- 7.80% in Group M, and 21.49 +/- 6.13% in Group H (Group L vs Group H, P = 0.0008; Group M vs Group H, P = 0.0109). Since there was no significant difference in heart rate during imaging among the three groups, although there was a significant difference between groups L and H and groups M and H in terms of percent change in heart rate, coronary stenosis was diagnosable in all groups with no significant difference. CONCLUSION: Landiolol hydrochloride showed a rapid onset and short beta-blocking effect, and was most effective at a dose of 0.5 mg/kg. However, the diagnosable proportion had no significant differences among the three groups in CCTA. Therefore, the clinically recommended dose was 0.125 mg/kg or less, considering the heart rate of patients with suspected coronary stenosis during CCTA. PMID- 24062148 TI - [Pigment dispersion syndrome and pigmentary glaucoma. Morphometric analysis of the anterior chamber segment with SL-OCT]. AB - BACKGROUND: The purpose of this study was to analyze if anterior chamber parameters are risk factors for the development of pigment dispersion syndrome (PDS) and/or for the conversion to pigmentary glaucoma (PG). PATIENTS AND METHODS: This study included a total of 63 eyes from 35 patients with PDS and PG and 65 eyes from 49 unaffected volunteers as the control group. The following parameters were measured by slit lamp optical coherence tomography (SL-OCT): anterior chamber volume (ACV) and depth (ACD), angle opening distance (AOD) and the trabecular iris space area (TISA) at 500 um and 750 MUm from the scleral spur. Comparisons between the following groups were performed: between the PDS/PG and the control group, between PDS and PG and between male and female patients. RESULTS: The results of ACV, ACD, AOD and TISA were significantly higher in PDS/PG patients when compared to the control group. There were no significant differences between PDS and PG. The gender-specific comparison also showed no significant differences. CONCLUSIONS: Significantly higher anterior chamber parameters are a possible risk factor for development of PDS; however, a higher risk of conversion to PG does not seem to correlate with increased anterior chamber parameters. The parameters of the anterior chamber are apparently not associated with the male predominance of PDS and PG. PMID- 24062149 TI - [Retinal vasculitis as manifestation of multiple sclerosis]. AB - Multiple sclerosis (MS) is the most common chronic disease of the central nervous system in Germany. In 80 % of patients early stages of the disease are characterized by a clinically isolated episodic course. Ocular manifestations are common and mostly affect the optic nerve or the uvea and in some cases the retinal vessels. Here we report on a bilateral retinal vasculitis as the first manifestation of MS in a 27-year-old patient. All symptoms resolved after high dose steroid treatment; however, intensive follow-up is crucial due to potential occlusive, ischemic complications. PMID- 24062150 TI - [Young woman with loss of vision and metamorphopsia]. PMID- 24062151 TI - [Tear in the retinal pigment epithelium by intravitreal injection of aflibercept]. AB - Development of tears in the retinal pigment epithelium (RIP) has been described as a possible complication following anti-vascular endothelial growth factor (VEGF) antibody therapy with substances which have been available for years when treating pigment epithelium detachment (PED) in eyes affected by age-related macular degeneration (AMD). Aflibercept has become available for the treatment of exsudative AMD since December 2012. This case report describes a further patient in addition to the only other case published so far who developed RIP after aflibercept treatment for PED. Patients have to be thoroughly informed about this potential side effect before initiation of intravitreal aflibercept injection therapy. PMID- 24062152 TI - [Differences between patients in consultation psychiatry and psychiatric inpatients]. AB - OBJECTIVE: To optimize psychiatric consultation service epidemiological information is needed. METHODS: We compared data on gender, age and diagnoses of patients in the consultation service to psychiatric inpatients. RESULTS: In psychiatric consultation service patients are older (56.6 vs. 44.9 years, p < 0.05) and males are older than females (58.8 vs. 54.4 years, p < 0.05). For male patients, the psychiatric consultation service is contacted more often in cases of organic disorders, for females in adjustment disorders (p < 0.05). CONCLUSION: The diagnostic spectrum in psychiatric consultation service is different for males and females with relevance for diagnostic and therapeutic procedures. PMID- 24062153 TI - [Diagnosing and diagnosis coding of dementias in claims data from German statutory health insurance]. AB - OBJECTIVE: On the basis of data from one German Sickness Fund we analyzed which medical discipline coded the incident diagnosis of dementia in ambulatory medical care in Germany, which type of dementia was coded and how the initial code eventually changed during the year of incidence. METHODS: Claims data of 1,848 insured people aged >= 65 years in 2004 with incident dementia were analyzed by means of descriptive statistics. RESULTS: The diagnosis within the first quarter of the incidence year was coded by the GP in 71%, by a psychiatrist or neurologist in 14%, by both in 6% and by other disciplines in 9% of the cases. The percentage of unspecified diagnoses was 62% among GPs and 46% among psychiatrists or neurologists, a number differing largely from epidemiological studies. In 27% of the cases patients received two or more different dementia diagnoses during the incidence year. CONCLUSION: Studies and care concepts regarding dementia on the basis of diagnosis codes in ambulatory claims data should be interpreted with great caution. PMID- 24062154 TI - [The Hamburg-model of integrated care for patients with psychosis: Part 2. Results of the clinical course over 2- and 4-years of treatment]. AB - OBJECTIVE: Since the beginning of the integrated care model for severely ill patients with psychotic disorders ("Hamburg model") in 2007 different clinical parameters have been consecutively assessed within a naturalistic, observational, prospective study. METHODS: Clinical outcome of the 2-year and 4-year follow-ups of n = 158 patients. RESULTS: A significant and ongoing improvement of psychopathology, severity of illness, functional outcome, quality of life and satisfaction with care in this sample of severely ill and merely chronic patients with psychosis was shown. Moreover, medication adherence improved and quality and quantity of outpatient treatment increased. CONCLUSION: The ongoing psychosocial stabilisation of the patients most likely result from a combination of various factors: continuity of care, multimodal and individualized care, therapeutic specialisation and the multidisciplinary ACT team. RESULTS provide clinical and scientific evidence for future implementations of the integrated care model "Hamburg Model" for the treatment of psychosis. PMID- 24062155 TI - [The Hamburg-model of integrated care for patients with psychosis: Part 1. Rationale, treatment concept and results of the pre-study]. AB - OBJECTIVE: The "Hamburg model" designates an integrated care model for severely ill patients with psychotic disorders financed by the health insurance system in accordance with S 140 SGB V. METHODS: It comprises comprehensive and long-term treatment within a regional network of the psychosis center of the University Medical Center Hamburg-Eppendorf (UKE) and private psychiatrists. The treatment model consists of therapeutic assertive community treatment (ACT) provided by a highly specialized treatment team and need-adapted in- and outpatient care. RESULTS AND CONCLUSIONS: The present article summarizes the disease- and treatment-specific rationales for the model development as well as the model structure and treatment contents. The article further summarizes the effectiveness and efficiency results of a study comparing the Hamburg model and treatment as usual (without ACT) within a 12-month follow-up study (ACCESS trial). PMID- 24062156 TI - [Hyperkinetic disorders in children and adolescents in Germany: administrative prevalence and regional differences regarding the frequency of diagnosis assignment]. AB - OBJECTIVE: To analyse the administrative prevalence and regional differences in hyperkinetic disorder (HK) diagnoses in Germany. METHODS: The administrative prevalence of HK (ICD-10 F90) was analysed for 3,6 million children, up to 18 years old and in the whole year 2009 insured by the AOK, using health insurance data. Additionally, administrative prevalence changes between 2006 and 2008 were investigated. The prevalence analyses were differenciated according to postal code areas and regions of the associations of statutory health insurance physicians (SHIP-regions). RESULTS: The analyses revealed a continous increase of the administrative HK-prevalence between 2006 (2,8 %) and 2009 (3,8 %). The administrative prevalence was notably lower in the city states Bremen, Hamburg and Berlin, but rather high in four of five SHIP-regions in the New Laender. 14 % of children with HK were diagnosed with HK and ICD-10 F98.8. In 47 % these different diagnoses had been coded by different physicians. CONCLUSIONS: Regional differences in administrative prevalence rates and discrepancies in diagnosis coding by different physicians may indicate uncertainties regarding HK-diagnosis in routine health care. Future studies should analyse these associations more detailed. PMID- 24062158 TI - Identifying subgroup markers in heterogeneous populations. AB - Traditional methods that aim to identify biomarkers that distinguish between two groups, like Significance Analysis of Microarrays or the t-test, perform optimally when such biomarkers show homogeneous behavior within each group and differential behavior between the groups. However, in many applications, this is not the case. Instead, a subgroup of samples in one group shows differential behavior with respect to all other samples. To successfully detect markers showing such imbalanced patterns of differential signal, a different approach is required. We propose a novel method, specifically designed for the Detection of Imbalanced Differential Signal (DIDS). We use an artificial dataset and a human breast cancer dataset to measure its performance and compare it with three traditional methods and four approaches that take imbalanced signal into account. Supported by extensive experimental results, we show that DIDS outperforms all other approaches in terms of power and positive predictive value. In a mouse breast cancer dataset, DIDS is the only approach that detects a functionally validated marker of chemotherapy resistance. DIDS can be applied to any continuous value data, including gene expression data, and in any context where imbalanced differential signal is manifested. PMID- 24062157 TI - A DNA break inducer activates the anticodon nuclease RloC and the adaptive immunity in Acinetobacter baylyi ADP1. AB - Double-stranded DNA breaks (DSB) cause bacteria to augment expression of DNA repair and various stress response proteins. A puzzling exception educes the anticodon nuclease (ACNase) RloC, which resembles the DSB responder Rad50 and the antiviral, translation-disabling ACNase PrrC. While PrrC's ACNase is regulated by a DNA restriction-modification (R-M) protein and a phage anti-DNA restriction peptide, RloC has an internal ACNase switch comprising a putative DSB sensor and coupled ATPase. Further exploration of RloC's controls revealed, first, that its ACNase is stabilized by the activating DNA and hydrolysed nucleotide. Second, DSB inducers activated RloC's ACNase in heterologous contexts as well as in a natural host, even when R-M deficient. Third, the DSB-induced activation of the indigenous RloC led to partial and temporary disruption of tRNA(Glu) and tRNA(Gln). Lastly, accumulation of CRISPR-derived RNA that occurred in parallel raises the possibility that the adaptive immunity and RloC provide the genotoxicated host with complementary protection from impending infections. PMID- 24062159 TI - Condensin aids sister chromatid decatenation by topoisomerase II. AB - The condensin complex is a key determinant of mitotic chromosome architecture. In addition, condensin promotes resolution of sister chromatids during anaphase, a function that is conserved from prokaryotes to human. Anaphase bridges observed in cells lacking condensin are reminiscent of chromosome segregation failure after inactivation of topoisomerase II (topo II), the enzyme that removes catenanes persisting between sister chromatids following DNA replication. Circumstantial evidence has linked condensin to sister chromatid decatenation but, because of the difficulty of observing chromosome catenation, this link has remained indirect. Alternative models for how condensin facilitates chromosome resolution have been put forward. Here, we follow the catenation status of circular minichromosomes of three sizes during the Saccharomyeces cerevisiae cell cycle. Catenanes are produced during DNA replication and are for the most part swiftly resolved during and following S-phase, aided by sister chromatid separation. Complete resolution, however, requires the condensin complex, a dependency that becomes more pronounced with increasing chromosome size. Our results provide evidence that condensin prevents deleterious anaphase bridges during chromosome segregation by promoting sister chromatid decatenation. PMID- 24062160 TI - Independent parallel functions of p19 plant viral suppressor of RNA silencing required for effective suppressor activity. AB - Plant viruses ubiquitously mediate the induction of miR168 trough the activities of viral suppressors of RNA silencing (VSRs) controlling the accumulation of ARGONAUTE1 (AGO1), one of the main components of RNA silencing based host defence system. Here we used a mutant Tombusvirus p19 VSR (p19-3M) disabled in its main suppressor function, small interfering RNA (siRNA) binding, to investigate the biological role of VSR-mediated miR168 induction. Infection with the mutant virus carrying p19-3M VSR resulted in suppressed recovery phenotype despite the presence of free virus specific siRNAs. Analysis of the infected plants revealed that the mutant p19-3M VSR is able to induce miR168 level controlling the accumulation of the antiviral AGO1, and this activity is associated with the enhanced accumulation of viral RNAs. Moreover, saturation of the siRNA-binding capacity of p19 VSR mediated by defective interfering RNAs did not influence the miR168-inducing activity. Our data indicate that p19 VSR possesses two independent silencing suppressor functions, viral siRNA binding and the miR168 mediated AGO1 control, both of which are required to efficiently cope with the RNA-silencing based host defence. This finding suggests that p19 VSR protein evolved independent parallel capacities to block the host defence at multiple levels. PMID- 24062162 TI - Novel mitochondrial C15620A variant may modulate the phenotype of mitochondrial G11778A mutation in a Chinese family with Leigh syndrome. AB - We report a case of 3-year-old boy who presented with Leigh syndrome but carried a mitochondrial G11778A mutation in the fourth subunit of the NADH dehydrogenase gene (MTND4). Additional to G11778A mutation, a novel C15620A variant was detected, which resulted in the conversion from leucine to isoleucine in the mitochondrial cytochrome b gene. As G11778A mutation is the most common mutation associated with Leber's hereditary optic neuropathy (LHON), given the unusual phenotype, the C15620A mutation was postulated to influence the pathogenicity of the G11778A mutation. This case further expands the clinical spectrum associated with the primary G11778A LHON mutation. PMID- 24062163 TI - The relationship between insulin sensitivity and maximal oxygen uptake is confounded by method of adjustment for body composition. AB - BACKGROUND: The use of ratios for analyzing physiologic variables often creates spurious associations. METHODS: Results of a euglycaemic clamp, a graded exercise test to measure maximal oxygen uptake (VO2max) and underwater weighing in 358 nondiabetic adults (166 women and 192 men) were used to compare the effects of weight standardization by division or by partial Spearman correlations on the association between VO2max and insulin sensitivity. RESULTS: VO2max and insulin sensitivity were negatively correlated when VO2max was divided by weight. When partial Spearman correlations were used to adjust VO2max for body composition, the correlation between VO2max and insulin sensitivity was greatly diminished. CONCLUSIONS: Division of VO2max by weight does not adjust for weight, but it creates spurious associations between VO2max and insulin sensitivity. PMID- 24062164 TI - Pre-transplant signal induction for vascularisation in human islets. AB - Human islet transplant success is partially impaired by slow revascularisation. Our study investigated the potential for rotational cell culture (RC) of human islets combined with thiazolidinedione (TZD) stimulation of peroxisome proliferator-activated receptor gamma (PPARgamma) to upregulate vascular endothelial growth factor (VEGF) expression in the islets. Four groups of human islets were studied: static culture (SC) with and without 25 mmol/L TZD and RC with and without 25 mmol/L TZD. These were assessed for insulin secretion and soluble VEGF-A release. Both proteins were quantified by enzyme-linked immunosorbent assay (ELISA), supported with qualitative immunofluorescence staining. RC + TZD increased insulin secretion by >20% (p < 0.05-0.001) in response to 16.7 mmol/L glucose and 16.7 mmol/L glucose + 10 mmol/L theophylline (G + T). This effect was seen at all time intervals compared with SC and without addition of TZD. Soluble VEGF-A release was significantly augmented by RC and TZD exposure with an increased effect of >30% (p < 0.001) at 72 h under both SC and RC conditions. RC supplemented with a TZD enhances and prolongs the release of insulin and soluble VEGF-A by isolated human islets. PMID- 24062161 TI - Sumoylation of critical proteins in amyotrophic lateral sclerosis: emerging pathways of pathogenesis. AB - Emerging lines of evidence suggest a relationship between amyotrophic lateral sclerosis (ALS) and protein sumoylation. Multiple studies have demonstrated that several of the proteins involved in the pathogenesis of ALS, including superoxide dismutase 1, fused in liposarcoma, and TAR DNA-binding protein 43 (TDP-43), are substrates for sumoylation. Additionally, recent studies in cellular and animal models of ALS revealed that sumoylation of these proteins impact their localization, longevity, and how they functionally perform in disease, providing novel areas for mechanistic investigations and therapeutics. In this article, we summarize the current literature examining the impact of sumoylation of critical proteins involved in ALS and discuss the potential impact for the pathogenesis of the disease. In addition, we report and discuss the implications of new evidence demonstrating that sumoylation of a fragment derived from the proteolytic cleavage of the astroglial glutamate transporter, EAAT2, plays a direct role in downregulating the expression levels of full-length EAAT2 by binding to a regulatory region of its promoter. PMID- 24062165 TI - Intrinsic potential for immediate biodegradation of toluene in a pristine, energy limited aquifer. AB - Pristine and energy-limited aquifers are considered to have a low resistance and resilience towards organic pollution. An experiment in an indoor aquifer system revealed an unexpected high intrinsic potential for the attenuation of a short term toluene contamination. A 30 h pulse of 486 mg of toluene, used as a model contaminant, and deuterated water (D2O) through an initially pristine, oxic, and organic carbon poor sandy aquifer revealed an immediate aerobic toluene degradation potential. Based on contaminant and tracer break-through curves, as well as mass balance analyses and reactive transport modelling, a contaminant removal of 40 % over a transport distance of only 4.2 m in less than one week of travel time was obtained. The mean first-order degradation rate constant was lambda = 0.178 day(-1), corresponding to a half-life time constant T1/2 of 3.87 days. Toluene-specific stable carbon isotope analysis independently proved that the contaminant mass removal can be attributed to microbial biodegradation. Since average doubling times of indigenous bacterial communities were in the range of months to years, the aerobic biodegradation potential observed is assumed to be present and active in the pristine, energy-limited groundwater ecosystems at any time. Follow-up experiments and field studies will help to quantify the immediate natural attenuation potential of aquifers for selected priority contaminants and will try to identify the key-degraders within the autochthonous microbial communities. PMID- 24062167 TI - Dental care too expensive for many middle-income Canadians. PMID- 24062166 TI - Standard and intensive lipid-lowering therapy with statins for the primary prevention of vascular diseases: a population-based study. AB - PURPOSE: To describe the clinical profile of the patients that initiate statin therapy for the primary prevention of vascular diseases and to investigate the extent to which clinicians use intensive vs. standard regimens. METHODS: A cross sectional analysis of nationwide individual data regarding individuals >= 11 years with a first prescription of statin, recorded between 1 January 2007 and 31 December 2011. Subjects were defined as intensive therapy initiators if a statin dose superior to simvastatin 40 mg (or equivalent dose if different statin) was first prescribed. Multivariable logistic regression models were built for dependent summary variables to evaluate the strength of the association between them and the use of intensive therapy. RESULTS: Overall, 69,737 patients receiving a first prescription of statin for the primary prevention of vascular diseases were identified. Predictors for intensive therapy initiation were male gender (adjusted OR: 1.28; 95%CI: 1.10-1.48), history of hypothyroidism (1.47; 1.17-1.85), current treatment of diabetes (1.18; 1.00-1.41), proteinuria (1.87; 1.12-3.12), age, and year of statin prescription. Modifiable risk factors associated with intensive therapy were elevated tryglicerides (1.63; 1.39-1.91), elevated LDL-C (1.96; 1.69-2.28), obesity (1.25; 1.07-1.47), smoking (1.32; 1.14 1.55), comedication with ezetimibe (3.76; 1.87-7.55), fibrates (1.96; 1.43-2.70) and calcium antagonists in women (1.42; 1.02-1.98). CONCLUSIONS: The use of intensive therapy with statins in primary prevention was not very high in absolute terms, but is increasing considerably. The association between intensive therapy and previous hypothyroidism or its combination with fibrates may raise additional safety and tolerability concerns. PMID- 24062168 TI - Scientists, supporters rally in Canadian cities to support basic research. PMID- 24062169 TI - A 68-year-old woman with sleep-onset insomnia. PMID- 24062170 TI - Management of insomnia and long-term use of sedative-hypnotic drugs in older patients. PMID- 24062171 TI - Enhancing the quality of end-of-life care in Canada. PMID- 24062172 TI - Alberta launches physician assistant pilot project. PMID- 24062173 TI - Morning handover. PMID- 24062174 TI - Electronic cigarettes. PMID- 24062175 TI - UK Health Check contradicts best evidence. PMID- 24062176 TI - Insurer denies coverage for fertility doctor facing lawsuit. PMID- 24062177 TI - People with dementia need better pain management. PMID- 24062178 TI - Persistence of bactericidal antibodies following early infant vaccination with a serogroup B meningococcal vaccine and immunogenicity of a preschool booster dose. AB - BACKGROUND: The multicomponent serogroup B meningococcal (4CMenB) vaccine was recently licensed for use in Europe. There are currently no data on the persistence of bactericidal antibodies induced by use of this vaccine in infants. Our objective was to evaluate serogroup B-specific bactericidal antibodies in children aged 40-44 months previously vaccinated at 2, 4, 6 and 12 months of age. METHODS: Participants given 4 doses of 4CMenB as infants received a fifth dose of the vaccine at 40-44 months of age. Age-matched participants who were MenB vaccine-naive received 4CMenB and formed the control group. We evaluated human complement serum bactericidal activity (hSBA) titres at baseline and 1 month after each dose of 4CMenB. RESULTS: Before a booster dose at enrolment, 41%-76% of 17 participants previously vaccinated with 4CMenB in infancy had hSBA titres of 4 or greater against 4 reference strains. Before vaccination in the control group (n = 40) these proportions were similar for strains 44/76-SL (63%) and M10713 (68%) but low for strains NZ98/254 (0%) and 5/99 (3%). A booster dose in the 4CMenB-primed participants generated greater increases in hSBA titres than in controls. INTERPRETATION: As has been observed with other meningococcal vaccines, bactericidal antibodies waned after vaccination with 4CMenB administered according to an approved infant vaccination schedule of 2, 4, 6 and 12 months of age, but there was an anamnestic response to a booster dose at 40-44 months of age. If 4CMenB were introduced into routine vaccination schedules, assessment of the need for a booster dose would require data on the impact of these declining titres on vaccine effectiveness. ClinicalTrials.gov, no. NCT01027351. PMID- 24062179 TI - GABAA-R alpha4 subunits are required for the low dose locomotor stimulatory effect of alphaxalone, but not for several other behavioral responses to alphaxalone, etomidate or propofol. AB - gamma-Aminobutyric acid type A receptors (GABAA-Rs) are considered to be the primary molecular targets of injectable anesthetics such as propofol, etomidate and the neurosteriod, alphaxalone. A number of studies have sought to understand the specific GABAA-R subtypes involved in the mechanism of action of these three drugs. Here, we investigated the role of alpha4-subunit containing GABAA-Rs in the neurobehavioral responses to these drugs. Drug responses in alpha4 subunit knockout (KO) mice were compared to wild type (WT) littermate controls. While etomidate and propofol are currently used as injectable anesthetics, alphaxalone belongs to the class of neurosteroid drugs having anesthetic effects. Low dose effects of etomidate and alphaxalone were studied using an open field assay. The moderate and high dose effects of all three anesthetics were measured using the rotarod and loss of righting reflex assays, respectively. The locomotor stimulatory effect of alphaxalone was reduced significantly in alpha4 KO mice compared to WT controls. Neither the low dose sedating effect of etomidate, nor the moderate/high dose effect of any of the drugs differed between genotypes. These results suggest that alpha4 subunit-containing GABAA-Rs are required for the low dose, locomotor stimulatory effect of alphaxalone but are not required for the sedating effect of etomidate or the moderate/high dose effects of etomidate, propofol or alphaxalone on motor ataxia and loss of righting reflex. PMID- 24062180 TI - Pharmacokinetics, safety, and tolerability of saroglitazar (ZYH1), a predominantly PPARalpha agonist with moderate PPARgamma agonist activity in healthy human subjects. AB - BACKGROUND AND OBJECTIVES: Dyslipidaemia is a major cardiovascular risk factor associated with type 2 diabetes mellitus. Saroglitazar (ZYH1) is a novel peroxisome proliferator-activated receptor (PPAR) agonist with predominant PPARalpha and moderate PPARgamma activity. It has been developed for the treatment of dyslipidaemia and has favourable effects on glycaemic parameters in type 2 diabetes mellitus. The objective of this phase 1 study was to evaluate the pharmacokinetics, safety and tolerability of saroglitazar in healthy human subjects. METHODS: This was a randomized, double-blind, placebo-controlled, single-centre, phase I study in healthy human volunteers, and was performed in two parts; part I evaluated single ascending oral doses of saroglitazar (0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64 and 128 mg) in healthy subjects, and part II measured the effects of food and sex on the pharmacokinetics of 1 mg saroglitazar, the human equivalent efficacy dose derived from pre-clinical studies. A total of 96 subjects were enrolled in the study, which included 88 healthy male subjects in part I and 16 healthy subjects (8 males from part I of the study and 8 females) in part II. RESULTS: Saroglitazar was rapidly and well absorbed across all doses in the single-dose pharmacokinetic study, with a median time to the peak plasma concentration (t(max)) of less than 1 h (range 0.63-1 h) under fasting conditions across the doses studied. The maximum plasma concentration ranged from 3.98 to 7,461 ng/mL across the dose range. The area under the plasma concentration-time curve increased in a dose-related manner. The average terminal half-life of saroglitazar was 5.6 h. Saroglitazar was not eliminated via the renal route. There was no effect of sex on the pharmacokinetics of saroglitazar, except for the terminal half-life, which was significantly shorter in females than in males. Food had a small effect on the pharmacokinetics; however, it was not consistent in males and females. Single oral doses of saroglitazar up to 128 mg were well tolerated. No serious adverse events were reported. Adverse events were generally mild and moderate in nature. Saroglitazar did not show any clinically relevant findings in clinical laboratory investigations, physical examinations, vital signs and electrocardiograms. CONCLUSION: The highest dose of saroglitazar evaluated in this study was 128 mg, several times the estimated therapeutic doses (1-4 mg). The pharmacokinetics of saroglitazar support a once daily dosage schedule. Saroglitazar was found to be safe and well tolerated in this study. PMID- 24062181 TI - Self-regulation strategies support children with ADHD to overcome symptom-related behavior in the classroom. AB - Children with attention deficit hyperactivity disorder (ADHD) suffer from self regulation deficits that cause inattention, impulsivity, and hyperactivity. Self regulation interventions may address these deficits, but to date, only few empirical studies have examined their benefits for children with ADHD in everyday life. The present study investigated three classroom interventions to promote self-regulation and tested their benefit on self-regulatory competencies (assessed with an ADHD questionnaire) in children with ADHD. Students of a special education school for children with ADHD participated in the intervention study that included three sessions (Session 1: Goal Intention or Goal Intention + If-Then Plan; Session 2: Goal Intention + If-Then Plan; Session 3: Goal Intention + If-Then Plan + Self-Monitoring). Teacher-rated self-regulatory competencies were assessed both before and after the intervention sessions. Children with ADHD had better self-regulatory competencies after their first Goal Intention + If Then Plan Session, but lasting intervention effects were found only when children started with a mere goal intention session. PMID- 24062182 TI - Influenza virosomes supplemented with GPI-0100 adjuvant: a potent vaccine formulation for antigen dose sparing. AB - Adjuvants can stimulate vaccine-induced immune responses and can contribute decisively to antigen dose sparing when vaccine antigen production is limited, as for example during a pandemic influenza outbreak. We earlier showed that GPI 0100, a semi-synthetic saponin derivative with amphiphilic structure, significantly stimulates the immunogenicity and protective efficacy of influenza subunit vaccine administered via a systemic route. Here, we evaluated the adjuvant effect of GPI-0100 on a virosomal influenza vaccine formulation. In contrast to influenza subunit vaccine adjuvanted with GPI-0100, virosomal vaccine supplemented with the same dose of GPI-0100 provided full protection of mice against infection at the extremely low antigen dose of 2 * 8 ng hemagglutinin. Overall, adjuvanted virosomes elicited higher antibody and T-cell responses than did adjuvanted subunit vaccine. The enhanced immunogenicity of the GPI-0100 adjuvanted virosomes, particularly at low antigen doses, is possibly due to a physical association of the amphiphilic adjuvant with the virosomal membrane. These results show that a combination of GPI-0100 and a virosomal influenza vaccine formulation is highly immunogenic and allows the use of very low antigen doses without compromising the protective potential of the vaccine. PMID- 24062183 TI - Exploring the relationship of autonomic and endocrine activity with social functioning in adults with autism spectrum disorders. AB - Several studies indicate that autonomic and endocrine activity may be related to social functioning in individuals with autism spectrum disorder (ASD), although the number of studies in adults is limited. The present study explored the relationship of autonomic and endocrine activity with social functioning in young adult males with ASD compared to young adult males without ASD. Autonomic and endocrine activity (i.e. heart rate, heart rate variability and salivary cortisol) were measured during rest and social interaction. No differences in heart rate, heart rate variability and cortisol between both groups were found during rest and social interaction. Repeated measures ANOVA's indicate a main effect of time for heart rate and cortisol, indicating an increase in these measures for both groups. An interaction effect between time and group was found for heart rate, with the ASD group showing a blunted increase in heart rate from rest to social interaction as compared to those without ASD. Future research should focus on replicating the present findings with larger sample sizes which also enables assessing inter-individual variability in autonomic and endocrine activity in relation to social functioning. PMID- 24062184 TI - Pseudo-postpacing interval of diastolic potential after entrainment pacing of remote bystander pathway in reentrant ventricular tachycardia. AB - After entrainment pacing, the postpacing interval of a diastolic potential may be misinterpreted if the distal tip of the ablation catheter captures a remote bystander pathway adjacent to the critical isthmus of a complex reentrant circuit in a structurally diseased heart. We discuss this possible pitfall of entrainment mapping of reentrant ventricular tachycardia, observed after a healed myocardial infarction. PMID- 24062186 TI - Picture quiz. Traumatic knee injury. PMID- 24062185 TI - Nanosecond electric pulses affect a plant-specific kinesin at the plasma membrane. AB - Electric pulses with high field strength and durations in the nanosecond range (nsPEFs) are of considerable interest for biotechnological and medical applications. However, their actual cellular site of action is still under debate -due to their extremely short rise times, nsPEFs are thought to act mainly in the cell interior rather than at the plasma membrane. On the other hand, nsPEFs can induce membrane permeability. We have revisited this issue using plant cells as a model. By mapping the cellular responses to nsPEFs of different field strength and duration in the tobacco BY-2 cell line, we could define a treatment that does not impinge on short-term viability, such that the physiological responses to the treatment can be followed. We observe, for these conditions, a mild disintegration of the cytoskeleton, impaired membrane localization of the PIN1 auxin-efflux transporter and a delayed premitotic nuclear positioning followed by a transient mitotic arrest. To address the target site of nsPEFs, we made use of the plant-specific KCH kinesin, which can assume two different states with different localization (either near the nucleus or at the cell membrane) driving different cellular functions. We show that nsPEFs reduce cell expansion in nontransformed cells but promote expansion in a line overexpressing KCH. Since cell elongation and cell widening are linked to the KCH localized at the cell membrane, the inverted response in the KCH overexpressor provides evidence for a direct action of nsPEFs, also at the cell membrane. PMID- 24062187 TI - Picture quiz. A 70 year old woman with chest pain after a stressful event. PMID- 24062188 TI - Lifestyle advice by text messages helps prevent type 2 diabetes in high risk men. PMID- 24062189 TI - Better sex education for children is needed to combat dangers of pornography. PMID- 24062190 TI - Bowel screening has long term benefits, research shows. PMID- 24062191 TI - Detection and correct handling of prescribing errors in Dutch hospital pharmacies using test patients. AB - BACKGROUND: Hospital pharmacists and pharmacy technicians play a major role in detecting prescribing errors by medication surveillance. At present the frequency of detected and correctly handled prescribing errors is unclear, as are factors associated with correct handling. OBJECTIVE: To examine the frequency of detection of prescribing errors and the frequency of correct handling, as well as factors associated with correct handling of prescribing errors by hospital pharmacists and pharmacy technicians. SETTING: This study was conducted in 57 Dutch hospital pharmacies. METHOD: Prospective observational study with test patients, using a case-control design to identify factors associated with correct handling. A questionnaire was used to collect the potential factors. Test patients containing prescribing errors were developed by an expert panel of hospital pharmacists (a total of 40 errors in nine medication records divided among three test patients; each test patient was used in 3 rounds; on average 4.5 prescribing error per patient per round). Prescribing errors were defined as dosing errors or therapeutic errors (contra-indication, drug-drug interaction, (pseudo)duplicate medication). The errors were selected on relevance and unequivocalness. The panel also defined how the errors should be handled in practice using national guidelines and this was defined as 'correct handling'. The test patients had to be treated as real patients while conducting medication surveillance. The pharmacists and technicians were asked to report detected errors to the investigator. MAIN OUTCOME MEASURE: The percentages of detected and correctly handled prescribing errors were the main outcome measures. Factors associated with correct handling were determined, using multivariate logistic regression analysis. RESULTS: Fifty-nine percent of the total number of intentionally added prescribing errors were detected and 57 % were handled correctly by the hospital pharmacists and technicians. The use of a computer system for medication surveillance compared to no computer system was independently associated with correct handling [odds ratio (OR) 15.39 (95 % confidence interval (CI) 3.62-65.50] for computerized physician order entry system; OR 15.40 (95 % CI 3.61-65.70) for order entry by pharmacy technicians), but because the reference category contained only one hospital these results can't be interpreted. Furthermore, manual screening of dosages in children with or without computerized surveillance compared to no dosage checks for children [OR 2.02 (95 % CI 1.06-3.84)], qualified pharmacy technicians compared to no qualified pharmacy technicians [OR 1.32 (95 % CI 1.03-1.67)] and pharmacy technicians using protocols compared to ones not using protocols [OR 1.30 (95 % CI 1.04-1.61)] were independently associated with correct handling. CONCLUSION: This study showed that the quality of medication surveillance in Dutch hospital pharmacies can be subject to improvement and the identified factors may give direction to such improvements. PMID- 24062193 TI - A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. AB - Evidence-based medicine (EBM) is a broad concept, but the key elements include the incorporation of clinical judgment (which requires clinical experience) together with relevant scientific evidence while remaining mindful of the individual patient's values and preferences. Using the framework and philosophy of EBM, this systematic review summarizes the pharmacology, efficacy, and tolerability of newly approved oral antipsychotics, including iloperidone, asenapine, and lurasidone, and outlines what is known about agents that are in late-stage clinical development, such as cariprazine, brexpiprazole, zicronapine, bitopertin, and EVP-6124. Potential advantages and disadvantages of these agents over existing antipsychotics are outlined, centered on clinically relevant issues such as the potential for weight gain and metabolic abnormalities, potential association with somnolence/sedation, extra-pyramidal side effects, akathisia, and prolongation of the electrocardiogram (ECG) QT interval, as well as practical issues regarding dosing instructions, titration requirements, and drug-drug interactions. Lurasidone appears to be best in class in terms of minimizing untoward alterations in body weight and metabolic variables. However, iloperidone, asenapine, lurasidone, and cariprazine differ among themselves in terms of on-label dosing frequency (once daily for lurasidone and, presumably, cariprazine versus twice daily for iloperidone and asenapine), the need for initial titration to a therapeutic dose for iloperidone and possibly cariprazine, requirement to be taken sublingually for asenapine, requirement for administration with food for lurasidone, lengthening of the ECG QT interval (greater for iloperidone than for asenapine and no effect observed with lurasidone), and adverse effects such as akathisia (seen with cariprazine, lurasidone, and asenapine but not with iloperidone) and sedation (most notable with asenapine). PMID- 24062194 TI - VEGF and bFGF increase survival of xenografted human ovarian tissue in an experimental rabbit model. AB - PURPOSE: The aim of this study is to determine whether vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) could increase the survival of xenografted human ovarian tissue in an experimental rabbit model. METHODS: Fresh human ovarian tissue was xenotransplanted into the back muscle of 25 castrated female New Zealand rabbits for 6 weeks with the immunosuppression of FTY720 (2 mg/kg/d). Rabbits were randomly divided into five experimental groups: (A) graft and host treatment with VEGF (50 ng/ml); (B) graft and host treatment with bFGF (100 ng/ml); (C) graft and host treatment with VEGF(50 ng/ml) + bFGF (100 ng/ml); (D) graft and host treatment with normal saline; (E) control group, no treatment. 4 weeks after transplantation, human menopausal gonadotropin (HMG) 10 IU was administered every second day in group A, group B, group C and group D for 2 weeks. Graft survival was assessed by graft recovery rate, histological analysis, immunohistochemical staining for CD31 and Ki-67expression, TUNEL assay. RESULTS: After 6 weeks of grafting, the number of CD31-positive stained cells increased significantly in group A, group B and group C compared to the control group. All groups showed strong Ki-67 immunostaining in ovarian stroma. Only one rabbit in group C retained the grafts' follicles. Grafting resulted in relative lower fibrosis in group A and group C compared to the control group. Apoptosis was significantly lower in group C compared to the control group. CONCLUSIONS: Fresh human ovarian cortex grafted into the back muscle of rabbit can sustain part of ovarian tissue function with the immunosuppression of FTY720, although follicle number diminishes significantly after grafting. The administration of VEGF and bFGF, especially the combination of them, may trigger angiogenesis, reduce apoptosis and fibrosis, increase survival in transplanted human ovarian tissue. PMID- 24062195 TI - Live birth following serial vitrification of embryos and PGD for fragile X syndrome in a patient with the premutation and decreased ovarian reserve. AB - PURPOSE: To present a live birth resulting from serial vitrification of embryos and pre-implantation genetic diagnosis (PGD). METHODS: A 31-year-old with primary infertility, fragile-X premutation, and decreased ovarian reserve (DOR) (baseline FSH level 33 IU/L), presented after failing to stimulate to follicle diameters >10 mm with three cycles of invitro fertilization (IVF). After counseling, the couple opted for serial in-vitro maturation (IVM), embryo vitrification, and genetic testing using array comparative genomic hybridization (aCGH) and PGD. Embryos were vitrified 2 days after intra-cytoplasmic sperm injection (ICSI). Thawed embryos were biopsied on day-three and transferred on day-five. RESULTS: The couple underwent 20 cycles of assisted reproductive technology. A total of 23 in-vivo mature and five immature oocytes were retrieved, of which one matured in vitro. Of 24 embryos, 17/24 (71 %) developed to day two and 11/24 (46 %) survived to blastocyst stage with a biopsy result available. Four blastocysts had normal PGD and aCGH results. Both single embryo transfers resulted in a successful implantation, one a blighted ovum and the other in a live birth. CONCLUSIONS: Young patients with DOR have potential for live birth as long as oocytes can be obtained and embryos created. Serial vitrification may be the mechanism of choice in these patients when PGD is needed. PMID- 24062196 TI - MicroRNAs responsive to Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis LPS modulate expression of genes regulating innate immunity in human macrophages. AB - MicroRNAs (miRNAs) are a class of small, noncoding RNAs that regulate post transcriptional expression of their respective target genes and are responsive to various stimuli, including LPS. Here we examined the early (4 h) miRNA responses of THP1-differentiated macrophages challenged with LPS derived from the periodontal pathogens, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis or environmentally-modified LPS obtained from P. gingivalis grown in cigarette smoke extract. Predicted miRNA-gene target interactions for LPS responsive miR-29b and let-7f were confirmed using dual-luciferase assays and by transfection experiments using miRNA mimics and inhibitors. Convergent and divergent miRNA profiles were observed in treated samples where differences in miRNA levels related to the type, concentration and incubation times of LPS challenge. Dual-luciferase experiments revealed miR-29b targeting of interleukin 6 receptoralpha (IL-6Ralpha) and IFN-gamma inducible protein 30 and let-7f targeting of suppressor of cytokine signaling 4 and thrombospondin-1. Transfection experiments confirmed miR-29b and let-7f modulation of IL-6Ralpha and SOCS4 protein expression levels, respectively. Thus, we have demonstrated convergent/divergent miRNA responses to wild type LPS and its environmentally modified LPS, and demonstrate miRNA targeting of key genes linked to inflammation and immunity. Our data indicate that these LPS-responsive miRNAs may play a key role in fine-tuning the host response to periodontal pathogens. PMID- 24062197 TI - Modulation of virus-induced innate immunity and type 1 diabetes by IL-1 blockade. AB - We used the LEW1.WR1 model of Kilham rat virus (KRV)-induced type 1 diabetes (T1D) to test the hypothesis that blocking IL-1 pathways early in the course of the disease can modulate virus-induced innate immunity and prevent disease progression. Administering KRV plus IL-1 receptor antagonist (Anakinra) for 14 d prevented insulitis and T1D. Anakinra reversed the KRV-induced systemic inflammation evidenced by the accumulation of T cells in the spleen and pancreatic lymph nodes on d 5 post-infection. Blocking IL-1 modulated the level of IRF-7 and IL-6 gene expression in the spleen and the p40 subunit of IL-12 and IL-23 in the serum. Anakinra did not interfere with the ability of LEW1.WR1 rats to clear the virus from the spleen, pancreatic lymph nodes or serum. Consistent with these data, normal levels of KRV-specific adaptive immune responses were detected in in the spleen and peripheral blood of the treated animals. Finally, blocking IL-1 pathways reversed the KRV-induced modulation of gut bacterial communities. The data may imply that IL-1 pathways are directly linked with early mechanisms whereby KRV infection leads to islet destruction, raising the hypothesis that blocking IL-1 pathways early in the course of the disease could be a useful therapeutic approach for disease prevention. PMID- 24062198 TI - Mucopolysaccharidosis VI: cardiac involvement and the impact of enzyme replacement therapy. AB - OBJECTIVE: To describe cardiac abnormalities in patients with mucopolysaccharidosis (MPS) VI and to evaluate the impact of enzyme replacement therapy (ERT) on cardiac structure and function. METHODS: Data from electrocardiographic and echocardiographic evaluations were retrospectively collected from patients with MPS VI who are followed up at the Children's Hospital of Mainz. RESULTS: The study included 44 (16 male and 28 female) patients. At baseline, valvular regurgitation (mainly aortic and mitral) and left ventricular (LV) volume overload were present in over half of patients. Other common cardiac manifestations were sinus tachycardia, LV hypertrophy, concentric LV remodelling, and pulmonary hypertension. One patient had left atrial dilation and one had congestive heart failure. Interventricular septal wall thickness and LV posterior wall thickness were above normal in most patients. Twenty five patients had a pre-ERT and at least one follow-up visit after ERT start. Mean follow-up after ERT start was 5.6 (SD 2.3) years. Despite the late onset (mean age 14.6 years) of treatment, ERT appeared to improve or arrest the progression of LV remodelling and LV hypertrophy and suspend the progression of cardiac valve disease. CONCLUSIONS: MPS VI is associated with an array of cardiac manifestations. ERT appears to have some impact on cardiac structure and function when started late in life, but may have better long-term results when started during early infancy. PMID- 24062199 TI - Transurethral removal of a "neglected" Foley catheter with severe encrustation: a case report. PMID- 24062200 TI - Capsaicin 8% patch for treprostinil subcutaneous infusion site pain in pulmonary hypertension patients. AB - BACKGROUND: Treprostinil sodium improves haemodynamics and symptoms in pulmonary arterial hypertension (PAH) patients, but its subcutaneous (s.c.) administration can produce severe local site pain, and lead to discontinuation of vital treatment. Treprostinil is a prostacyclin analogue which stimulates prostacyclin receptors in skin nociceptor terminals, resulting in pain and cutaneous hypersensitivity, for which current pain remedies have limited effect. Capsaicin 8% patch relieves neuropathic pain for 3 months after a single 60 min cutaneous application; we investigated whether its pre-application can reduce s.c. trepostinil-induced pain. METHODS: A single-centre, double-blind, randomized, placebo-controlled, crossover study was conducted to assess the safety and efficacy of a single capsaicin 8% patch pre-application for s.c. treprostinil pain in 11 PAH patients, relative to control patch with low-dose capsaicin 0.075% cream. RESULTS: The primary efficacy endpoint, mean difference between the two treatment arms in an 11-point numerical pain rating scale from baseline to 2 weeks after patch applications, was significantly lower on the capsaicin 8% patch treatment arm [P=0.01, mean difference=-1.47 units, 95% credible interval (CI): 2. 59 to -0.38] in the patients who completed the study per protocol, although intention-to-treat analysis did not show significant difference (P=0.28). Heat pain thresholds were decreased (P=0.027, mean difference=5.43 degrees C, 95% CI: 0.71-10.21) and laser Doppler flux increased (P=0.016, mean difference=370 units, 95% CI: 612 to 127.9) at the application site immediately after capsaicin 8% patch, confirming activity. CONCLUSIONS: Further investigation of the efficacy of capsaicin 8% patch in this indication is warranted. PMID- 24062201 TI - Low doses of etanercept can be effective to maintain remission in ankylosing spondylitis patients. AB - We wanted to do a prospective open-label study to evaluate if ankylosing spondylitis (AS) patients in clinical remission with twice weekly etanercept (ETN) 25 mg therapy could be changed to weekly regimen or even to every other week regimen without increased dose for injection. Thirty-eight AS patients self administered 25 mg of ETN (Wyett) subcutaneously. According to the protocol, patients who were in clinical partial remission with twice weekly ETN 25 mg at week 12 and 16 changed to a weekly regimen without a change of the dose. If clinical remission, despite the reduction of the dose, persists at week 24 and 28, patients changed to an every-other-week regimen, continuing with this administration schedule for the entire duration of the study if at week 36 and 46 clinical remission was maintained. At the end of the study, 18 patients (47 %) were still in remission, 4 (10 %) with a weekly regimen, and 14 (37 %) with an every-other-weekly regimen. Our study indicates that a consistent percentage of subjects with AS, treated with ETN 25 mg twice weekly, achieved clinical remission within the first 3 months of therapy, and also, a substantial percentage of these patients maintains the partial remission with an every other week regimen. PMID- 24062202 TI - Increased reliance upon photosystem II repair following acclimation to high-light by coral-dinoflagellate symbioses. AB - Changing light environments force photoautotroph cells, including coral symbionts, to acclimate to maintain photosynthesis. Photosystem II (PSII) is subjected to photoinactivation at a rate proportional to the incident light, and cells must adjust their rates of protein repair to counter this photoinactivation. We examined PSII function in the coral symbiont Symbiodinium to determine the effect of photoacclimation on their capacity for PSII repair. Colonies of the coral Stylophora pistillata were collected from moderate light environments on the Lizard Island reef (Queensland, Australia) and transported to a local field station, where they were assigned to lower or higher light regimes and allowed to acclimate for 2 weeks. Following this photoacclimation period, the low-light acclimated corals showed greater symbiont density, higher chlorophyll per symbiont cell, and higher photosystem II protein than high-light acclimated corals did. Subsequently, we treated the corals with lincomycin, an inhibitor of chloroplastic protein synthesis, and exposed them to a high-light treatment to separate the effect of de novo protein synthesis in PSII repair from intrinsic susceptibility to photoinactivation. Low-light acclimated corals showed a sharp initial drop in PSII function but inhibition of PSII repair provoked only a modest additional drop in PSII function, compared to uninhibited corals. In high light acclimated corals inhibition of PSII repair provoked a larger drop in PSII function, compared to uninhibited high-light corals. The greater lincomycin effects in the corals pre-acclimated to high-light show that high-light leads to an increased reliance on the PSII repair cycle. PMID- 24062203 TI - The ultrastructural effects of long-term use of henna on the albino rat skin. AB - Tattooing with henna is a routine practice in the Arab world. To the best of our knowledge, no previous studies have evaluated the adverse histological effects following henna tattooing on the ultrastructure of the skin. The objectives of this study were to diagnose the cytopathological alterations induced by commercial henna and to investigate the adverse role of henna when combined with sun ray on the skin. The skin of albino rats was tattooed with natural and black henna for three months, skin samples were examined by transmission electron microscope. In addition, the concentration of lead in henna samples was estimated by using atomic absorption spectrophotometry. The results expanded the understanding of the pathogenesis of henna-induced phytophotodermatitis. We hypothesized that henna-associated additives penetrated the epidermal barrier to gain access to the vascular dermis where the harmful ingredients became concentrated, leading to skin pathology through a dual mechanism. First, these ingredients became re-transported into the epidermis through vesicular trafficking leading to dermo-epidermal blistering and cytoplasmic vacuolization of the stratum basal cells. Following this, cytoplasmic vacuoles poured their content into the nuclei through continuities with the perinuclear cisterna, possibly leading to genetic mutation. The progression of keratinocytes into the next layers became associated with nuclear and cytoplasmic signs of apoptosis with subsequent phagocytosis in other epidermal cells, most probably keratinocytes. The second mechanism of injury was mediated through accumulation of inflammatory cells around capillaries in the dermis with the release of angiogenic and mitogenic mediators resulting in vasculopathy. PMID- 24062204 TI - Ocriplasmin: a review of its use in patients with symptomatic vitreomacular adhesion. AB - Ocriplasmin (JETREA((r))) is a recombinant human serine protease plasmin with proteolytic activity against the protein components (e.g. laminin, fibronectin and collagen) of the vitreous and vitreoretinal interface, thereby facilitating vitreous liquefaction and separation of vitreous from the retina. Intravitreal ocriplasmin is indicated for the treatment of symptomatic vitreomacular adhesion (USA) and vitreomacular traction including when associated with a macular hole of diameter <=400 MUm in adult patients (EU). The efficacy of ocriplasmin at the recommended dose of a single 125 MUg intravitreal injection was demonstrated in two well-designed pivotal phase III trials of virtually identical design (TG-MV 006 and TG-MV-007) in patients with symptomatic vitreomacular adhesion. A significantly greater proportion of patients treated with ocriplasmin than those treated with placebo achieved nonsurgical resolution of vitreomacular adhesion at day 28 (primary endpoint), with the significant between-group difference sustained until study end (month 6). At day 28, the proportion of eyes achieving total posterior vitreous detachment or nonsurgical closure of macular holes was also significantly greater with ocriplasmin than with placebo. Ocriplasmin was generally well tolerated in these trials, with most ocular adverse events being mild in severity and transient in nature. Current evidence suggests that ocriplasmin is a useful treatment option for patients with symptomatic vitreomacular adhesion. PMID- 24062205 TI - Folliculitis decalvans: a rare scarring alopecia misinterpreted as a laceration of the scalp at the scene. PMID- 24062207 TI - Analysis of phyllodes tumor recurrence according to the histologic grade. AB - Local recurrence of phyllodes tumor (PT) of the breast is an adverse outcome that can result in sarcomatous degeneration. The aim of this study was to investigate the histologic and surgical factors associated with local recurrence. A total of 193 PT cases were studied: 145 (75.1 %) benign cases, 33 (17.1 %) borderline cases, and 15 (7.8 %) malignant cases. Stratifying our analysis according to histologic grade, we investigated the relationship between disease-free survival (DFS) and both histologic and surgical factors, including histologic grade, stromal cellularity, stromal atypia, stromal mitosis, stromal overgrowth, tumor margin, type of surgical procedure (local excision, wide excision, and mastectomy), surgical margin status, and radiation therapy. In the case of benign PT, all patients with local recurrences (3.4 %) had been treated with local excision, and all recurrent tumors were also benign. The local recurrence rate for locally excised benign PTs was not associated with surgical margin status or radiation therapy. In the case of borderline PT, local excision was associated with an increased local recurrence rate (P = 0.046). In malignant PT, small tumor size (<=4.0 cm) was associated with an increased local recurrence rate (P = 0.041). Univariate analyses indicated that surgical procedure (mastectomy < local excision < wide excision; P < 0.001) was significantly associated with shorter DFS in borderline PT. A positive surgical resection margin (P < 0.001) was associated with DFS in malignant PT. The factors associated with local recurrence differed with the histologic grade of PT, as did the features of local recurrence itself. In particular, benign PT had very low rate of local recurrence regardless of surgical margin status or radiation therapy, even when treated with local excision. In the case of benign PT, no recurrent tumors had worse histologic grades than the initial tumors. PMID- 24062206 TI - Hierarchical control of two-dimensional gaze saccades. AB - Coordinating the movements of different body parts is a challenging process for the central nervous system because of several problems. Four of these main difficulties are: first, moving one part can move others; second, the parts can have different dynamics; third, some parts can have different motor goals; and fourth, some parts may be perturbed by outside forces. Here, we propose a novel approach for the control of linked systems with feedback loops for each part. The proximal parts have separate goals, but critically the most distal part has only the common goal. We apply this new control policy to eye-head coordination in two dimensions, specifically head-unrestrained gaze saccades. Paradoxically, the hierarchical structure has controllers for the gaze and the head, but not for the eye (the most distal part). Our simulations demonstrate that the proposed control structure reproduces much of the published empirical data about gaze movements, e.g., it compensates for perturbations, accurately reaches goals for gaze and head from arbitrary initial positions, simulates the nine relationships of the head-unrestrained main sequence, and reproduces observations from lesion and single-unit recording experiments. We conclude by showing how our model can be easily extended to control structures with more linked segments, such as the control of coordinated eye on head on trunk movements. PMID- 24062208 TI - Racial disparities in treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer. AB - Data characterizing demographics, treatment patterns, and clinical outcomes in black patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) are limited. registHER is a large, observational cohort study of patients (n = 1,001) with HER2-positive MBC diagnosed <=6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up of 27 months). Demographics, treatment patterns, and clinical outcomes were described for black (n = 126) and white patients (n = 793). Progression-free survival (PFS) following first-line therapy and overall survival (OS) were examined. Multivariate analyses adjusted for baseline and treatment factors. Black patients were more likely than white patients to be obese (body mass index >=30), to have diabetes, and to have a history of cardiovascular disease; they were also less likely to have estrogen receptor or progesterone receptor positive disease. In patients treated with trastuzumab, the incidence of cardiac safety events (grade >=3) was higher in black patients (10.9 %) than in white patients (7.9 %). Unadjusted median OS and PFS (months) were significantly lower in black patients than in white patients (OS: black: 27.1, 95 % confidence interval [CI] 21.3-32.1; white: 37.3, 95 % CI 34.6-41.1; PFS: black: 7.0, 95 % CI 5.7-8.2; white: 10.2, 95 % CI 9.3-11.2). The adjusted OS hazard ratio (HR) for black patients compared with white patients was 1.29 (95 % CI 1.00-1.65); adjusted PFS HR was 1.29 (95 % CI 1.05-1.59). This real-world evaluation of a large cohort of patients with HER2-positive MBC shows poorer prognostic factors and independently worse clinical outcomes in black versus white patients. Further research is needed to identify potential biologic differences that could have predictive impact for black patients or that could explain these differences. PMID- 24062209 TI - Genetic variants in microRNAs and breast cancer risk in African American and European American women. AB - MicroRNAs (miRNAs) are an integral part of the post-transcriptional machinery of gene expression and have been implicated in the carcinogenic cascade. Single nucleotide polymorphisms (SNPs) in miRNAs and risk of breast cancer have been evaluated in populations of European or Asian ancestry, but not among women of African ancestry. Here we examined 145 SNPs in six miRNA processing genes and in 78 miRNAs which target genes known to be important in breast cancer among 906 African American (AA) and 653 European American (EA) cases and controls enrolled in the Women's Circle of Health Study. Allele frequencies of most SNPs (87 %) differed significantly by race. We found a number of SNPs in miRNAs and processing genes in association with breast cancer overall or stratified by estrogen receptor (ER) status. Several associations were significantly different by race, with none of the associations being significant in both races. Using a polygenic risk score to combine the effects of multiple SNPs, we found significant associations with the score in each subgroup analysis. For ER positive cancer, each unit increment of the risk score was associated with a 51 % increased risk in AAs (OR = 1.51, 95 % CI = 1.30-1.74, p = 3.3 * 10(-8)) and a 73 % increased risk in EAs (OR = 1.73, 95 % CI = 1.45-2.06, p = 1.4 * 10(-9)). These data show, for the first time, that miRNA-related genetic variations may underlie the etiology of breast cancer in both populations of African and European ancestries. Future studies are needed to validate our findings and to explore the underlying mechanisms. PMID- 24062210 TI - Personalized medicine in breast cancer: tamoxifen, endoxifen, and CYP2D6 in clinical practice. AB - Tamoxifen is metabolized into endoxifen, a potent antagonist of the estrogen receptor, in part through cytochrome p450 (CYP) 2D6. Genotypic variation in CYP2D6 affects endoxifen levels, and some have argued that patients who do not efficiently metabolize tamoxifen might wish to consider alternative hormonal treatments. This study evaluated an algorithm in which endoxifen levels and CYP2D6 genotypes were used to make hormonal therapy recommendations for patients on adjuvant tamoxifen for breast cancer. Patients with stage I-III breast cancer who had been taking adjuvant tamoxifen for 8-56 weeks were eligible. At enrollment, baseline whole blood and serum were sent for genotyping by Amplichip and endoxifen measurement, respectively, and endoxifen levels were also measured 3 weeks later. Results were returned to oncologists along with an algorithm generated treatment recommendation. The algorithm recommended that participants with poor metabolizer genotype and/or baseline endoxifen level <6 ng/mL consider alternative endocrine therapy. A medical record review evaluated actual treatment decisions. Of 99 patients on study, 18 (18 %) had findings that triggered algorithm-based recommendations to consider a change in endocrine therapy due to endoxifen <6 ng/mL (all 18 patients) and/or poor metabolizer CYP2D6 genotype (2 of the 18). Endoxifen levels were >=6 ng/mL in four of them 3 weeks later. Seven (39 % of 18) switched to a different treatment (one based on toxicity, not the algorithm). Hot flash burden was not found to be significantly associated with endoxifen <6 ng/mL or genotype. Prospective testing of tamoxifen metabolism as gauged by CYP2D6 genotype and serum endoxifen levels is feasible. Future studies of tamoxifen metabolism and efficacy should consider including measurement of serial endoxifen levels. Although clinical evidence at present is insufficient to warrant routine CYP2D6 or endoxifen testing, some clinicians and patients did utilize this predefined algorithm to inform clinical decisions regarding optimal adjuvant endocrine therapy. PMID- 24062212 TI - Neurosyphilis manifesting with rapidly progressive dementia: report of three cases. AB - Neurosyphilis is rather an unusual cause of dementia characterized by a rapidly progressive course and psychiatric symptoms. Diagnosis of neurosyphilis should be suspected in the presence of a global cognitive impairment consisting in disorientation, amnesia and severe impairment of speech and judgement and psychiatric symptoms such as depression, mania and psychosis, with a subacute onset. More commonly, clinical manifestations of neurosyphilis include general PARESIS (involvement of Personality, Affect, Reflexes, Eye, Sensorium, Intellect and Speech). Upon clinical suspicion, diagnosis of neurosyphilis is confirmed by a reactive cerebrospinal fluid (CSF)-Venereal Disease Research Laboratory. Here we report three Human Immunodeficiency Virus (HIV)-negative male patients presenting with psychiatric symptoms and a rapidly evolving dementia. Although magnetic resonance imaging did not address to diagnosis, CSF examination was mandatory in neurosyphilis diagnosis. Other diagnostic tools such as neuropsychology and single-photon emission computed tomography resulted supportive in the diagnosis. We showed that a prompt antibiotic treatment might stop disease progression. Therefore, neurosyphilis should be always considered even in HIV-negative patients in the presence of unexpected psychiatric symptoms accompanied by a rapidly evolving cognitive decline. PMID- 24062211 TI - DHA is a more potent inhibitor of breast cancer metastasis to bone and related osteolysis than EPA. AB - Breast cancer patients often develop bone metastasis evidenced by osteolytic lesions, leading to severe pain and bone fracture. Attenuation of breast cancer metastasis to bone and associated osteolysis by fish oil, rich in EPA and DHA, has been demonstrated previously. However, it was not known whether EPA and DHA differentially or similarly affect breast cancer bone metastasis and associated osteolysis. In vitro culture of parental and luciferase gene encoded MDA-MB-231 human breast cancer cell lines treated with EPA and DHA revealed that DHA inhibits proliferation and invasion of breast cancer cells more potently than EPA. Intra-cardiac injection of parental and luciferase gene encoded MDA-MB-231 cells to athymic NCr nu/nu mice demonstrated that DHA-treated mice had significantly less breast cancer cell burden in bone, and also significantly less osteolytic lesions than EPA-treated mice. In vivo cell migration assay as measured by luciferase intensity revealed that DHA attenuated cell migration specifically to the bone. Moreover, the DHA-treated group showed reduced levels of CD44 and TRAP positive area in bone compared to EPA-treated group. Breast cancer cell burden and osteolytic lesions were also examined in intra-tibially breast cancer cell injected mice and found less breast cancer cell growth and associated osteolysis in DHA-treated mice as compared to EPA-treated mice. Finally, doxorubicin-resistant MCF-7 (MCF-7dox) human breast cancer cell line was used to examine if DHA can improve sensitization of MCF-7dox cells to doxorubicin. DHA improved the inhibitory effect of doxorubicin on proliferation and invasion of MCF-7dox cells. Interestingly, drug resistance gene P-gp was also down-regulated in DHA plus doxorubicin-treated cells. In conclusion, DHA attenuates breast cancer bone metastasis and associated osteolysis more potently than EPA, possibly by inhibiting migration of breast cancer cell to the bone as well as by inhibiting osteoclastic bone resorption. PMID- 24062213 TI - Clinical and neuropathological findings in Hashimoto's encephalopathy: a case report. PMID- 24062214 TI - A slowly proliferating subpopulation in human umbilical cord mesenchymal stem cells in culture. AB - In this report, a slow-growing subpopulation of human umbilical cord mesenchymal stromal cells (MSCs) was identified. These cells were around 5 MUm in diameter and their relative gravity was between 1.031 and 1.043 g/ml. In sharp contrast to the parent MSCs, they expressed highly CD271 and poorly the receptor for platelet derived growth factor. Quantitative PCR with the identification of the products by DNA sequencing proved that these cells expressed Nanog at a higher level than cells from the other subpopulation (approximately 30-fold), which was further confirmed by western blotting. Furthermore, they did not grow at clonal density and depletion of these cells from the population had little effect on the colony formation of the parent MSCs. The results here indicate that a subpopulation of cells with special biological features exist in human cord MSCs in culture. PMID- 24062215 TI - The medication appropriateness index at 20: where it started, where it has been, and where it may be going. AB - Potentially inappropriate prescribing for older adults is a major public health concern. While there are multiple measures of potentially inappropriate prescribing, the medication appropriateness index (MAI) is one of the most common implicit approaches published in the scientific literature. The objective of this narrative review is to describe findings regarding the MAI's reliability, comparison of the MAI with other quality measures of potentially inappropriate prescribing, its predictive validity with important health outcomes, and its responsiveness to change within the framework of randomized controlled trials. A search restricted to English-language literature involving humans aged 65+ years from January 1992 to June 2013 was conducted using MEDLINE and EMBASE databases using the search term 'medication appropriateness index'. A manual search of the reference lists from identified articles and the authors' article files, book chapters, and recent reviews was conducted to identify additional articles. A total of 26 articles were identified for inclusion in this narrative review. The main findings were that the MAI has acceptable inter- and intra-rater reliability, it more frequently detects potentially inappropriate prescribing than a commonly used set of explicit criteria, it predicts adverse health outcomes, and it is able to demonstrate the positive impact of interventions to improve this public health problem. We conclude that the MAI may serve as a valuable tool for measuring potentially inappropriate prescribing in older adults. PMID- 24062216 TI - Management of inflammatory bowel disease in the elderly: do biologicals offer a better alternative? AB - The management of inflammatory bowel disease (IBD) in elderly patients provides added complexity for healthcare providers who need to take into account the high likelihood of co-morbid disease, the need for polypharmacy and, in many instances, greater patient fragility. While biologics are often considered first line corticosteroid-sparing strategies for moderate to severe disease, the additional variables unique to an elderly patient warrant consideration when discussing IBD therapeutics. As chronic corticosteroid use, although relatively common among older IBD patients, is suboptimal, the efficacy and safety of biologics compared with immunomodulators among older IBD patients needs additional investigation. PMID- 24062217 TI - Effect of flavonoids and saponins extracted from black bean (Phaseolus vulgaris L.) seed coats as cholesterol micelle disruptors. AB - Strategies for reducing plasma cholesterol have been focused on reducing the absorption or synthesis of cholesterol. The aim of this study was to correlate the content of flavonoids and saponins in black bean (Phaseolus vulgaris L.) seed coats extracts with a potential effect in lowering cholesterol absorption by the inhibition of cholesterol micellar solubility. Extracts with different flavonoids and saponins concentration were obtained from a Box-Behnken design used to optimize extraction temperature, stirring time and solvent composition. Major flavonoids and saponins were quantified by HPLC-PDA-ELSD and confirmed through mass spectrometry. Contrary to the flavonoid content, saponins were correlated to the inhibitory effect of cholesterol micelle solubility as an approach to a potential reduction of cholesterol absorption. Extracts with the highest saponin content strongly inhibited cholesterol micellization with values of 55.4 +/- 1.9 %, while stigmasterol used as control, only reached 12 +/- 2.3 % at the same concentration (5 mg/ml). The optimal extracting conditions for saponins were 25 degrees C, during 3 h in 85 % aqueous-methanol. Correlations of inhibitory effect of cholesterol micellar solubility with the content of each identified saponin suggested that the reduction of cholesterol micellization depends on the C-22 substitution of saponins. PMID- 24062218 TI - The lesser trochanter as a cause of hip impingement: pathophysiology and treatment options. AB - Impingement of the lesser trochanter on the ischium or the posterior acetabular rim is not a frequent pathology, but has recently received increased recognition. We have seen 14 cases over a period of 14 years, but concentrate on eight hips showing complex deformities revealing similar characteristics. All eight hips had a residual Perthes or a Perthes-like disease with an elliptically deformed femoral head, but a congurent joint a short or absent femoral neck, a high riding greater trochanter, and a reduced vertical distance between the head and the lesser trochanter. Impingement took place between the lesser trochanter and the ischium or the posteroinferior acetabular border, but was hardly recognisable due to the predominant intraarticular impingement of the nonspherical femoral head and the extraarticular impingement of the greater trochanter. In three cases the impingement showed reproducible subluxation of the hip. While in our hips, excision was the preferred treatment for impingement due to an oversized lesser trochanter, distal advancement was used in the hips with the Perthes morphology; the surgical time was not longer. The overall clinical results in this group however were dominated by a substantial increase in the range of motion (ROM), dependent mainly on the achieved contour of the femoral head and the relative lengthening of the neck. Strength of active hip flexion was normal. Recurrent subluxation disappeared and no complications were recorded. PMID- 24062219 TI - MRI evaluation of hip containment and congruency after closed reduction in congenital hip dislocation. AB - BACKGROUND: Developmental dysplasia of the hip is the most common congenital skeletal disease. In its most severe form--dislocation--the treatment is directed at reducing the hip and establishing normal congruency between the femoral head and the acetabulum. Closed reduction with casting is a common primary treatment, where reduction is confirmed by magnetic resonance imaging (MRI). OBJECTIVE: This study analyses anatomical aspects depicted on MRI after closed reduction to identify disparities in the growth behaviour of dislocated hips. MATERIALS AND METHODS: In 38 patients MRI after closed reduction was available for analysis. After exclusion of children with underlying diseases or syndromes, MRIs of 28 children were evaluated with respect to head coverage index, acetabular head index and sphericity. The results were compared to the stable opposite sides. RESULTS: Twenty-two stable and 27 initially unstable hips were available for further analysis. The head coverage index as well as the acetabular head index of the unstable hips was significantly smaller than that of the stable hips. The sphericity score of the dislocated femoral heads was significantly lower than that of the stable ones. CONCLUSION: Dislocated hips showed significantly lower values for all of the evaluated parameters concerning congruency and containment. MRI is not only useful to confirm successful reduction but may also help to predict outcome by evaluating following dislocation. PMID- 24062220 TI - The usage of image trigonometry in bone measurements. AB - The entire musculo-skeletal system responds dynamically to stresses and strains applied to it. Restoring normal biomechanics contributes to the normal function that ensures that physiological stresses and strains are preserved. Appropriate preoperative planning is mandatory to restore normal biomechanics at reconstructive surgery. Effective preoperative planning depends on the ability to reproducibly make accurate measurements of lengths and angles from plain radiographs. Measurement has become an integral part of orthopaedics to define morphological abnormality, to plan for reconstruction and for comparative research. The most prevalent method of measurement is usually based on lines drawn on radiographs with no accurate reference to the actual geometry of the structures. This two-dimensional projection of an asymmetrical three-dimensional structure leads to inaccuracy and consequently to a compromise in the overall precision of many procedures. In addition it is also difficult to monitor the progression of disease as the exact relationship of the bones and joints to each other, and to prosthetics, cannot be accurately recorded. This paper presents a method of digitally measuring relevant bone parameters in a geometric manner in order to achieve accurate, repeatable measurements. PMID- 24062221 TI - Early results of the Bernese periacetabular osteotomy for symptomatic dysplasia in Charcot-Marie-Tooth disease. AB - INTRODUCTION: Charcot-Marie-Tooth disease (CMTD) is one of the most common inherited neurologic disorders and can be associated with hip dysplasia. Little is known regarding outcomes of the PAO for patients with CMTD. Our purpose is to document the early results and complications of the PAO for hip dysplasia associated with CMTD. METHODS: A two centre, retrospective clinical and radiographic review was performed. Demographic and surgical data were recorded. Pre- and postoperative lateral centre edge angle (LCEA), acetabular index (AI), ventral centre edge angle (VCEA), and Tonnis osteoarthritis grade were compared. Hips were classified according to Severin. The Harris Hip Score (HHS) and the Western Ontario and McMasters University (WOMAC) index documented self-reported function. RESULTS: Nineteen hips in 14 patients underwent PAO, mean age 16.2 (range 11.2-21 years). Thirteen concomitant procedures were performed, including seven proximal femoral osteotomies. Average follow-up was 3.4 years (range 0.9 8.5). Postoperative radiographic measurements significantly improved. Complications included femoral head AVN, transient complete bilateral peroneal nerve palsy, inferior rami fractures, and heterotopic ossification (Brooker stage 3). The HHS significantly improved from a mean 49.6 preoperatively to 82.2 at final follow-up of four patients. Seven subjects reported a mean postoperative WOMAC score of 94 (range 58.3-100). CONCLUSIONS: Most patients presented with severe dysplasia in the second decade of life. The PAO successfully corrected the radiographic abnormalities. Complications were common. The majority of patients reported improved outcomes, although seven showed signs of radiographic progression of osteoarthritis. PMID- 24062222 TI - Discrimination of abnormal gait parameters due to increased femoral anteversion from other effects in cerebral palsy. AB - The effects of increased femoral anteversion (IFA) on gait pattern have a complex relationship with other orthopaedic and neurological abnormalities of cerebral palsy (CP). The aim of this study was to differentiate the effects of IFA from other factors in CP. The four groups in this study included: 15 typically developing children (Group: TDC) (age: 9.7 +/- 0.5); 14 TDC with IFA (7.5 +/- 1.7) (Group: TDC-IFA); 8 CP participants with IFA (age: 6.3 +/- 1.7) (Group: CP IFA); and 10 CP participants with nearly normal femoral anteversion (age: 10.3 +/ 4.7) (Group: CP-NFA). Altered peak knee-extension angle and stance-time, increased internal hip-rotation, internal foot-progression (p<=0.05) were influenced by IFA in both groups of CP-NFA and TDC-IFA. For the TDC groups; pelvic-rotation increased and peak knee and hip-extension, knee flexion-moment, peak knee-power generation in late-stance decreased among children with IFA (p<=0.05). For CP children; anterior pelvic-tilt, hip-flexion and peak knee extension, hip power-absorbsion and generation, and peak knee power-absorsion (K3) increased and peak knee-flexion was delayed by IFA (p<=0.05). Therefore, IFA effects are different in CP and TDC. Peak knee-extension angle increased in TDC and decreased in CP with IFA. Besides the well known gait parameters related to IFA which are increased internal hip-rotation and foot-progression angle, it is recognised that peak knee-extension and stance-time are also influenced. Therefore, before muscle lengthening, femoral derotational osteotomy should be considered in the early stages of growth in CP to improve pelvic stability and the knee extensor mechanism. PMID- 24062223 TI - Comparison of Refobacin bone cement and palacos with gentamicin in total hip arthroplasty: an RSA study with two years follow-up. AB - Previous experience has demonstrated the importance of testing new bone cement in vivo before widespread clinical use. We performed a consecutive, radiostereometric (RSA) study comparing Refobacin Bone Cement (RBC) to the well proven Palacos with Gentamicin (PWG). According to the manufacturer of RBC it has the equivalent characteristics as PWG, and in vitro tests show good results. The purpose of this study was to evaluate whether RBC is safe to use in clinical practice for total hip arthroplasty (THA). Two consecutive series of patients with primary osteoarthritis received a THA using a highly polished, collarless, tapered stem with a hollow centralizer. The study comprises 21 hips with RBC and 30 with PWG. The patients were followed up for two years with repeated RSA examinations and clinical outcome questionnaires SF-12 and WOMAC. There were no statistically significant migratory differences between the groups. The mean subsidence after two years was 1.28 mm and 1.40 mm, and the mean retroversion was 1.03 degrees and 0.99 degrees , for the RBC and the PWG groups respectively. Almost all migration occurred in the interface between the stem and the cement. The WOMAC and SF12 clinical scores did not reveal any clinical differences between the groups. We conclude that, as previous in vitro tests indicate, RBC performs as well as PWG and seems to be safe to use in clinical practice for THA. PMID- 24062224 TI - Treatment of avascular necrosis of the femoral head utilising free vascularised fibular graft: a systematic review. AB - We conducted a systematic review to determine whether the literature supports the use of free vascularised fibular graft (FVFG) over other salvage procedures for the treatment of avascular necrosis (AVN) of the femoral head, and if there are patient-specific and defect-specific factors that may predict better outcomes after FVFG. Fifteen total studies were identified for inclusion. Three comparative studies showed an overall statistically significant superiority of FVFG over NVFG; two comparative studies demonstrated FVFG better than core decompression. One study show a better but not statistically significant superiority of FVFG comparing with vascularised iliac pedicle bone graft procedures, likely due to small sample size. This review suggests that vascularised fibular grafting is a better treatment option than core decompression and nonvascularised fibular grafting. PMID- 24062225 TI - Periacetabular osteotomy: sporting, social and sexual activity 9-12 years post surgery. AB - Hip joint survivorship and functional outcome are traditional outcome measures applied after periacetabular osteotomy (PAO). Younger adults however have greater demands and expectations on the function of their hip joints and these demands are not expressed using traditional outcome assessment tools. The main purpose of this study was to explore alternative functional and quality of life measure after PAO.A cross sectional survey of preserved hip joints following PAO was performed. Fifty-two patients (68 hips), mean age 41 years (range 24-67), returned a questionnaire examining satisfaction, willingness to repeat surgery, quality of life, abilities in social activities, sports and sex-life, pain, limp, and stability of the hip.Median satisfaction was 5 (range 1-5) and 44 of 49 patients were willing to repeat surgery. Significant improvements were seen in quality of life, ability to do sports, participate in social activities and sex life (p values <0.001) (although sex-life for males (p = 0.102)). Traditional outcomes (pain, stability and limp) showed significant improvements (p<0.001). Lasting improvements in patients' sex life, social life and ability to do sports nine to 12 years following PAO were reported. Such factors are important measures of outcome in a younger adult cohort. PMID- 24062226 TI - Total acetabular retroversion following pelvic osteotomy: presentation, management, and outcome. AB - Acetabular retroversion following acetabular osteotomy in hips with dysplasia can negatively effect the outcome. Total retroversion, where the entire anterior rim is lateral to the posterior rim, is rare and can easily be missed on pelvic radiographs due to the lack of a crossover sign. We evaluated the clinical and radiographic presentation, the surgical management, and the outcome of hips with total acetabular retroversion. We retrospectively reviewed 26 patients (26 hips) with total retroversion following 15 periacetabular osteotomies (PAO), 10 triple type, and one Salter osteotomy. We obtained range of motion (ROM), anterior impingement test, Drehmann's sign, Merle d'Aubigne-Postel score, and Tonnis score for osteoarthrosis. Corrective surgery included 19 revision PAOs and seven total hip arthroplasties (THA). The mean follow-up was 4.7 +/- 4.2 (range 0.5-13.8) years. Patients presented with a restricted ROM (flexion and internal rotation), a positive anterior impingement test, a positive Drehmann's sign, and a decreased Merle d'Aubigne-Postel score due to pain. Corrective surgery was performed after mean of 7 +/- 5 (1-15) years. Complications for revision PAO and THA occurred in 37% and 29%, respectively. At follow-up, the Merle d'Aubigne-Postel score improved for both revision PAOs and THAs. The prevalence of a positive anterior impingement test and Drehmann's sign decreased for revision PAOs. There was a tendency for progression of OA in hips with revision PAO. Iatrogenic total acetabular retroversion following reorientation is a disabling condition for the patients. Corrective surgery including revision PAO and THA results in improved clinical outcome. However, these procedures are technically challenging and associated with high complication rates. PMID- 24062227 TI - Single tranexamic acid dose to reduce perioperative morbidity in primary total hip replacement: a randomised clinical trial. AB - INTRODUCTION: Although prophylactic tranexamic acid (TXA) is a safe, low-cost option to reduce bleeding in patients undergoing total hip replacement (THR), its optimal dose and duration is unknown. We compared the safety and effectiveness of TXA given as either a single injection or continuous infusion in THR patients, hypothesising that a second TXA dose would not offer any clinical advantages over the single injection. MATERIALS AND METHODS: One hundred and sixty-four patients undergoing unilateral THR were randomised. Exclusion criteria were history of thromboembolic events (TE), epilepsy, thrombophilia, and severe chronic renal failure. Patients received either a single dose of 30 mg/kg TXA on induction of surgery (one shot [OS] group), or a loading dose of 10 mg/kg TXA followed two hours later by a continuous infusion of 2 mg/kg per hour for 20 hours (one day [OD] group). The primary outcome was blood loss (BL) calculated from haematocrit levels. Secondary outcomes were mortality and TE events within 90 days postoperatively. RESULTS: All patients completed treatment, with none lost to follow-up. Mean BL was 1107 +/- 508 ml in Group OS and 1047 +/- 442 ml in Group OD (p = 0.43). No patients were transfused prior to Day 10 postoperatively. At final follow-up, no patients had died, and there were no occurrences of major TE. CONCLUSION: The 30 mg/kg TXA single shot was as safe as continuous infusion. As it is also less cumbersome, we recommend it as part of routine care in THR patients. PMID- 24062228 TI - Expanded carrier screening panels-does bigger mean better? PMID- 24062229 TI - Beta blockers for acute traumatic brain injury: a systematic review and meta analysis. AB - BACKGROUND: Traumatic brain injury (TBI) is associated with a systemic hyperadrenergic state. Through activation of beta adrenoreceptors, catecholamines may induce hypermetabolism and increase both cardiac and cerebral oxygen demands. We conducted a systematic review to appraise the available evidence examining the safety and efficacy of beta blockers in patients with acute TBI. METHODS: We systematically searched CENTRAL, MEDLINE, EMBASE and the reference lists of relevant articles from database inception until March 19, 2013. The outcomes assessed were in-hospital mortality, functional outcome and quality of life. Common adverse effects of beta blockers were examined including clinically significant hypotension, bradycardia, bronchospasm and congestive heart failure. Data on study outcomes and quality were abstracted in duplicate. The results were summarized descriptively and quantitatively. RESULTS: One randomized controlled trial was found with a high risk of bias. Eight retrospective cohort studies were found with a moderate risk of bias; however, only four of these studies were identified as unique after excluding overlapping cases. The cohort studies reported mortality outcomes; however, none of these included studies assessed functional outcomes or quality of life. Meta-analysis on the cohort studies (n = 4,782 patients) demonstrated that exposure to beta blockers after TBI was associated with a reduction in the adjusted odds of in-hospital mortality by 65 % (pooled adjusted odds ratio 0.35; 95 % CI 0.27-0.45). CONCLUSIONS: The current body of evidence is suggestive of a benefit of beta blockers following TBI. However, methodologically sound randomized controlled trials are indicated to confirm the efficacy of beta blockers in patients with TBI. PMID- 24062230 TI - Biodegradable amphiphilic block-graft copolymers based on methoxy poly(ethylene glycol)-b-(polycarbonates-g-polycarbonates) for controlled release of doxorubicin. AB - In this paper, novel biodegradable amphiphilic block-graft copolymers based on methoxy poly(ethylene glycol)-b-(polycarbonates-g-polycarbonates) (mPEG-b-(PATMC g-PATMC)) were synthesized successfully for controlled release of doxorubicin (DOX). Backbone block copolymer, methoxy poly(ethylene glycol)-b-poly(5-allyloxy 1,3-dioxan-2-one) (mPEG-b-PATMC) was synthesized in bulk catalyzed by immobilized porcine pancreas lipase (IPPL). Then, mPEG-b-PATMC-O, the allyl epoxidation product of mPEG-b-PATMC, was further grafted by PATMC itself also using IPPL as the catalyst. The copolymers were characterized by (1)N HMR and gel permeation chromatography results showed narrow molecular weight distributions. Stable micelle solutions could be prepared by dialysis method, while a monomodal and narrow size distribution could be obtained. Transmission electron microscopy (TEM) observation showed the micelles dispersed in spherical shape with nano-size before and after DOX loading. Compared with the block copolymers, the grafted structure could enhance the interaction of polymer chains with drug molecules and improve the drug-loading capacity and entrapment efficiency. Furthermore, the amphiphilic block-graft copolymers mPEG-b-(PATMC-g-PATMC) had low cytotoxicity and more sustained drug release behavior. PMID- 24062233 TI - The interrelationships between moral attitudes, posttraumatic stress disorder symptoms and mixed lateral preference in Israeli reserve combat troops. AB - BACKGROUND: Combat soldiers often encounter moral dilemmas during operational deployment, especially when an armed engagement is situated within a civilian setting. The study of moral dilemmas and posttraumatic stress disorder (PTSD) has mostly focused on the impact of war atrocities and moral injury. However, the relationship between moral attitudes and different combat-related pathologies has not been thoroughly addressed by quantitative studies. AIMS: We aimed to assess the relationship between combatant's moral attitudes, severity of PTSD symptoms and mixed lateral preference. METHODS: Data on moral objection, PTSD severity and lateral preference were collected in a right-handed non-pathologic sample (n = 147) of reserve combat troops in the Israel Defense Forces (IDF). RESULTS: Nearly one-fifth (19.7%) of the reserve personnel who served in the occupied territories have reported high moral objection to the commands they were expected to act upon. This group of participants exhibited more PTSD symptoms and higher levels of mixed lateral preference. Multiple linear regression analyses revealed a mediating role of moral objection in the relationship between PTSD symptoms severity and lateral preference. CONCLUSIONS: Our findings suggest that moral objection has significant implications on combatant's psychological and organic well-being. The findings highlight the need to include moral attitudes in research and clinical practice among combat personnel and veterans. PMID- 24062232 TI - Mental health consumer and caregiver perceptions of stigma in Australian community pharmacies. AB - BACKGROUND: The stigma of mental illness can be a barrier to effective medication management in the community pharmacy setting. This article explored mental health consumers' or caregivers' experiences of stigma in Australian community pharmacies. MATERIALS: Semi-structured interviews and focus groups were conducted with a purposive sample of consumers or caregivers (n = 74). Interview transcripts were analysed using a general inductive approach. DISCUSSION: Stigma presented a barrier to effective mental health management. Self-stigma impeded consumers' community pharmacy engagement. Positive relationships with knowledgeable staff are fundamental to reducing stigma. CONCLUSIONS: Findings provide insight into the stigma of mental illness in community pharmacies. PMID- 24062231 TI - DNA double-strand break repair genotype and phenotype and breast cancer risk within sisters from the New York site of the Breast Cancer Family Registry (BCFR). AB - PURPOSE: We previously observed that poor DNA repair phenotype is associated with increased breast cancer (BC) risk within families. Here, we examined whether genetic variation in double-strand break repair (DSBR) genes is associated with BC risk and if genotypes are related to phenotype in unaffected women. METHODS: Using data from the New York site of the Breast Cancer Family Registry, we investigated 25 single-nucleotide polymorphism (SNPs) involved in DSBR using biospecimens from 337 BC cases and 410 unaffected sister controls. RESULTS: Genotypes in XRCC4 were associated with BC risk, with ORs of 1.67 (95 % CI 1.01 2.76) for the combined GA/AA of rs1805377 and 1.69 (95 % CI 1.03-2.77) for rs1056503 TG/GG; these associations were no longer statistically significant in multivariable conditional logistic regression models. When examining the association of SNPs with phenotype, we found that genotypes of XRCC5 rs3834 and rs1051685, which were highly correlated with each other, were associated with end joining (EJ) capacity; women with the XRCC5 rs3834 GA genotype had better DNA repair as measured by higher levels of EJ capacity (37.8 +/- 14.1 % for GA vs. 27.9 +/- 11.8 % for GG carriers p = 0.0006). Women with the AA genotype of BRCA1 rs799917 also had higher EJ capacity (35.1 +/- 9.2 %) than those with GG (26.4 +/ 10.1 %, p = 0.02). CONCLUSIONS: Overall, we found that selected DSBR genotypes were associated with phenotype, although they were not associated with BC risk itself, suggesting that phenotypic measures are influenced by endogenous and exogenous factors across the life course and may be better markers than genotypic measures for ascertaining BC risk. PMID- 24062234 TI - Development of a questionnaire to assess the impact of chronic low back pain for use in regulated clinical trials. AB - BACKGROUND: Chronic low back pain (CLBP) is the most common chronic pain condition and is associated with clinical, economic, social, and public health impacts. The effect of CLBP on patients' health-related quality of life (HRQoL) is significant. The symptoms and impacts most often associated with CLBP include pain and disability; patients most affected are often crippled by the condition. CLBP also affects patients' mental, physical, and psychosocial well-being. A variety of self-report measures have been developed for the assessment of CLBP, such as the Roland Morris Disability Questionnaire (RMDQ); however, existing measures may not meet current regulatory expectation for the development, documentation, and use of patient-reported outcomes (PRO) questionnaires (U.S. Department of Health and Human Services, Food and Drug Administration, 2009). OBJECTIVES: This report describes the qualitative development of the Chronic Low Back Pain Impact Questionnaire (CLBP-IQ), created for use in clinical trials. METHODS: A total of 22 CLBP patients recruited by clinicians participated in concept elicitation interviews to identify target measurement concepts. An instrument development team generated the instructions, items, and response options guided by patient input. Cognitive debriefing interviews were conducted with 21 patients recruited by the same clinicians who recruited for concept elicitation interviews. During cognitive interviews, a draft instrument composed of 28 items was presented to individuals with CLBP to evaluate its readability and comprehensiveness. All research activities were conducted in the US. RESULTS: During concept elicitation interviews, participants reported a variety of physical, emotional, and social impacts associated with CLBP. Participants also reported CLBP impacts on sleep, energy, daily activities, work, household activities, leisure activities, cognition, self-care, and sex life. Impacts deemed simple, important, and relevant to CLBP patients became targets of measurement for the CLBP-IQ. During cognitive debriefing, seventeen items were interpreted as intended by at least 90 % of participants, and no items were interpreted incorrectly by more than five patients (24 %). Additionally, seventeen items were experienced by at least 90 % of participants, and no single item was experienced by less than 67 % of participants (n = 14). CONCLUSIONS: The CLBP-IQ was developed in accordance with current US Food and Drug Administration guidance on instrument development. Results from both concept elicitation and cognitive debriefing interviews support the content validity of the CLBP-IQ in patients with CLBP. Future development should proceed with psychometric evaluation. PMID- 24062236 TI - Accumulation of carbapenem resistance mechanisms in VIM-2-producing Pseudomonas aeruginosa under selective pressure. AB - Pseudomonas aeruginosa has the potential to achieve resistance to carbapenems via the acquisition of carbapenemase-encoding genes, the downregulation of the OprD porin, the overexpression of efflux systems and the overproduction of cephalosporinases. One hundred and fifty carbapenem-non-susceptible isolates from 2008 to 2010 were screened for carbapenemase production, OprD porin loss, efflux pumps overexpression and inducible AmpC beta-lactamase production. For comparison reasons, the presence of the same mechanisms was also assessed in a previous collection of 30 carbapenem-non-susceptible P. aeruginosa isolated between 2003 and 2005. Results showed the accumulation of various resistance mechanisms among VIM-2 producers isolated between 2008 and 2010 with a parallel considerable increase in imipenem MIC90 and the geometric mean of the MIC values of imipenem and meropenem between the two study groups. The accumulation of carbapenem resistance mechanisms highlights the potential of this formidable pathogen for evolutionary success under antibiotic selective pressure. PMID- 24062235 TI - Risk factors for levofloxacin-nonsusceptible Streptococcus pneumoniae in community-acquired pneumococcal pneumonia: a nested case-control study. AB - This study was performed to evaluate the clinical features of community-onset levofloxacin-nonsusceptible pneumococcal pneumonia and to identify risk factors for levofloxacin resistance. Using the database of a surveillance study of community-acquired pneumococcal infections in Asian countries, we conducted a nested case-control study to identify risk factors for levofloxacin nonsusceptible S. pneumoniae in community-acquired pneumonia in adults. Of 981 patients with pneumococcal pneumonia, 46 (4.7 %) had levofloxacin-nonsusceptible S. pneumoniae, of whom 39 evaluable cases were included in the analysis. All cases were from Korea, Taiwan, and Hong Kong. Among patients with levofloxacin susceptible S. pneumoniae, 490 controls were selected based on patient country. Of the 39 cases of levofloxacin-nonsusceptible pneumococcal pneumonia, 23 (59.0 %) were classified as healthcare-associated, while 164 (33.5 %) of the 490 controls of levofloxacin-susceptible S. pneumoniae (P = 0.001) were classified as healthcare-associated. Multivariate analysis showed that previous treatment with fluoroquinolones, cerebrovascular disease, and healthcare-associated infection were significantly associated with levofloxacin-nonsusceptible pneumococcal pneumonia (all P < 0.05). Levofloxacin-nonsusceptible pneumococci pose an important new public health threat in our region, and more information on the emergence and spread of these resistant strains will be necessary to prevent spread throughout the population. PMID- 24062237 TI - Development of a measure of asthma-specific quality of life among adults. AB - PURPOSE: A key goal in asthma treatment is improvement in quality of life (QoL), but existing measures often confound QoL with symptoms and functional impairment. The current study addresses these limitations and the need for valid patient reported outcome measures by using state-of-the-art methods to develop an item bank assessing QoL in adults with asthma. This article describes the process for developing an initial item pool for field testing. METHODS: Five focus group interviews were conducted with a total of 50 asthmatic adults. We used "pile sorting/binning" and "winnowing" methods to identify key QoL dimensions and develop a pool of items based on statements made in the focus group interviews. We then conducted a literature review and consulted with an expert panel to ensure that no key concepts were omitted. Finally, we conducted individual cognitive interviews to ensure that items were well understood and inform final item refinement. RESULTS: Six hundred and sixty-one QoL statements were identified from focus group interview transcripts and subsequently used to generate a pool of 112 items in 16 different content areas. CONCLUSIONS: Items covering a broad range of content were developed that can serve as a valid gauge of individuals' perceptions of the effects of asthma and its treatment on their lives. These items do not directly measure symptoms or functional impairment, yet they include a broader range of content than most existent measures of asthma specific QoL. PMID- 24062238 TI - Quality of life of glaucoma patients in China: sociodemographic, clinical, and psychological correlates-a cross-sectional study. AB - PURPOSE: To assess vision-related quality of life (VRQoL) in Chinese glaucoma patients and explore its sociodemographic, clinical and psychological correlates, and determine which of them explain the largest variation. METHODS: This cross sectional study included 508 Chinese glaucoma patients. Chinese-version Glaucoma Quality of Life-15 questionnaire (CHI-GQL-15) and Hospital Anxiety and Depression Scales were administered to all participants to evaluate their VRQoL and psychological distresses. Visual functions (habitual-corrected visual acuity (HCVA), intraocular pressure, and mean defect (MD) of visual field) were assessed through clinical examinations by professionals. Sociodemographic information and other treatment histories were collected via interviews and chart review. Stepwise multiple linear regression analyses were performed to identify sociodemographic, clinical, and psychological predictors of VRQoL. RESULTS: The mean summary score for CHI-GQL-15 was 28.79 +/- 12.74. Patients exhibited the greatest difficulty in activities involving glare and dark adaptation (28.19 +/- 22.86), followed by central and near vision (26.18 +/- 26.56), peripheral vision (18.03 +/- 21.37), and the least difficulty for outdoor mobility (15.06 +/- 24.57). Moderate and heavy economic burden, HCVA and MD of both the better and the worse eyes, number of glaucoma surgeries in the treatment history and the presence of depression were independent predictors for VRQoL of glaucoma patients. Clinical factors explained the largest variation. CONCLUSION: VRQoL of glaucoma patients is multifactorial and was primarily determined by clinical indices. VRQoL assessment could be informative when adopted as a complement to objective visual measures in clinical practice. PMID- 24062239 TI - Development and validation of the functional assessment of chronic illness therapy treatment satisfaction (FACIT TS) measures. AB - PURPOSE: To develop and validate a new functional assessment of chronic illness therapy (FACIT) measure of satisfaction with treatment for chronic illnesses such as cancer and HIV/AIDS. METHODS: To define domains and generate items, a literature review informed creation of semi-structured interview guides for patients and an international expert panel of clinicians and researchers. Patients and experts also rated 15 areas of satisfaction for relevance. The final list of items underwent further refinement by the original expert panel and a new group of clinical experts. Items were tested in four studies (primarily lung cancer) and data were pooled for analysis. Exploratory and confirmatory factor analyses (CFA), and item response theory modeling were conducted to evaluate dimensionality. Internal consistency reliability and test-retest reliability were both evaluated. Validity was evaluated by correlating the FACIT subscale scores and measures of comparable concepts and by testing the scales' ability to distinguish people according to their overall treatment satisfaction. RESULTS: Two instruments were created: the FACIT TS-general (G), an overall evaluation of current treatment, and the FACIT TS-patient satisfaction (PS), a measure of patient satisfaction. CFA results were not optimal for a five-factor solution for PS. Internal consistency reliability met psychometric standards (>=0.70) for all PS subscales. Construct validity was established for the PS subscales: Physician Communication, Treatment Staff Communication, Technical Competence, Confidence and Trust, and Nurse Communication. CONCLUSIONS: The two instruments generated here offer a new way to assess several key dimensions of patient satisfaction with treatment, especially for people with lung cancer. PMID- 24062240 TI - Health-risk behaviors and quality of life among young men. AB - PURPOSE: To examine the associations between substance use and other health-risk behaviors and quality of life (QOL) among young men. METHODS: The analytical sample consisted of 5,306 young Swiss men who participated in the Cohort Study on Substance Use Risk Factors. Associations between seven distinct self-reported health-risk behaviors (risky single-occasion drinking; volume drinking; cigarette smoking; cannabis use; use of any other illicit drugs; sexual intercourse without a condom; low physical activity) were assessed via chi-square analysis. Logistic regression analyses were conducted to study the associations between each particular health-risk behavior and either physical or mental QOL (assessed with the SF-12v2) while adjusting for socio-demographic variables and the presence of all other health-risk behaviors. RESULTS: Most health-risk behaviors co-occurred. However, low physical activity was not or negatively related to other health-risk behaviors. Almost all health-risk behaviors were associated with a greater likelihood of compromised QOL. However, sexual intercourse without a condom (not associated with both physical and mental QOL) and frequent risky single-occasion drinking (not related to mental QOL after adjusting for the presence of other health-risk behaviors; positively associated with physical QOL) differed from this pattern. CONCLUSIONS: Health-risk behaviors are mostly associated with compromised QOL. However, sexual intercourse without a condom and frequent risky single-occasion drinking differ from this pattern and are therefore possibly particularly difficult to change relative to other health-risk behaviors. PMID- 24062241 TI - Qualitative development of the 'Questionnaire on Pain caused by Spasticity (QPS),' a pediatric patient-reported outcome for spasticity-related pain in cerebral palsy. AB - PURPOSE: To develop a patient-reported outcome measure for spasticity-related pain in children/adolescents (age 2-17 years) with cerebral palsy (CP), the 'Questionnaire on Pain caused by Spasticity (QPS).' METHODS: Using a semi structured interview guide, concept elicitation interviews on spasticity-related pain in upper and lower limbs were conducted in 21 children and caregiver pairs. Data were used to modify initial QPS modules and develop six draft modules, which were subsequently refined and finalized in four consecutive cognitive interview waves (12 children and caregiver pairs). RESULTS: To accommodate the broad range in the children's communication skills, QPS child/adolescent modules were developed in both interviewer-administered and self-administered formats. With the additional parent modules, three QPS modules were developed for each of the upper and lower limb applications. Information gained from the parent/caregiver modules complements the child/adolescent assessment. Parents report observed signs and frequency of pain in the same situations used to capture the child/adolescent reports of pain severity (e.g., rest, usual daily activities, active mobilization, and physically difficult activities). Participating children/adolescents and parents/caregivers reported that the final QPS instruments were comprehensive, relevant to the child's spasticity-related experience, and easy to understand and complete. CONCLUSIONS: The QPS is a novel instrument for the assessment of spasticity-related pain in children/adolescents with CP that was developed with direct patient input. Its modules allow the use of this instrument in children/adolescents with varied levels of impairment and communication skills. PMID- 24062242 TI - Validity and reliability of the Chinese version of the Short Form of Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF). AB - PURPOSE: The Short Form version of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) was designed to measure patients' subjective experience of enjoyment and satisfaction. However, it had not yet been validated for Chinese societies. This paper reports on the validation of the Chinese version of the Q-LES-Q-SF among primary care patients in Taiwan. METHODS: The study included adult patients in primary care clinics. The participants completed the Q-LES-Q-SF, the Patient Health Questionnaire, and the Short Form Health Survey. After that, the trained researchers interviewed the patients using the mood module of the Schedules for Clinical Assessment in Neuropsychiatry and the 17-item Hamilton Rating Scale for Depression. A subsample of participants was reassessed with Q-LES-Q-SF within a 2-week interval. RESULTS: A total of 1,482 patients completed the Q-LES-Q-SF. The content validity was good, with no significant floor/ceiling effect. The internal consistency of the Q-LES-Q-SF proved to be substantial as well as the test-retest reliability. The factor structure was examined by exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). The EFA yielded a 2-factor structure, which was confirmed by a CFA with acceptable fit indices. Known-group validity of the Q-LES-Q-SF was satisfactory in distinguishing patients with and without depression, according to hierarchical regression analyses. Evidence of concurrent validity was provided for the Q-LES-Q-SF, and its two subscales identified significant correlations with other measures. CONCLUSION: The Chinese Q-LES-Q-SF was shown to have adequate validity and reliability. It may be a useful tool to measure patients' quality of life in Chinese societies. PMID- 24062243 TI - Understanding social forces involved in diabetes outcomes: a systems science approach to quality-of-life research. AB - PURPOSE: The field of quality-of-life (QOL) research would benefit from learning about and integrating systems science approaches that model how social forces interact dynamically with health and affect the course of chronic illnesses. Our purpose is to describe the systems science mindset and to illustrate the utility of a system dynamics approach to promoting QOL research in chronic disease, using diabetes as an example. METHODS: We build a series of causal loop diagrams incrementally, introducing new variables and their dynamic relationships at each stage. RESULTS: These causal loop diagrams demonstrate how a common set of relationships among these variables can generate different disease and QOL trajectories for people with diabetes and also lead to a consideration of non clinical (psychosocial and behavioral) factors that can have implications for program design and policy formulation. CONCLUSIONS: The policy implications of the causal loop diagrams are discussed, and empirical next steps to validate the diagrams and quantify the relationships are described. PMID- 24062244 TI - Carboxyl-ester lipase maturity-onset diabetes of the young is associated with development of pancreatic cysts and upregulated MAPK signaling in secretin stimulated duodenal fluid. AB - Carboxyl-ester lipase (CEL) maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes and pancreatic exocrine dysfunction due to mutations in the CEL gene encoding CEL. The pathogenic mechanism for diabetes development is unknown. Since CEL is expressed mainly in pancreatic acinar cells, we asked whether we could find structural pancreatic changes in CEL-MODY subjects during the course of diabetes development. Furthermore, we hypothesized that the diseased pancreas releases proteins that are detectable in pancreatic fluid and potentially reflect activation or inactivation of disease-specific pathways. We therefore investigated nondiabetic and diabetic CEL-mutation carriers by pancreatic imaging studies and secretin-stimulated duodenal juice sampling. The secretin-stimulated duodenal juice was studied using cytokine assays, mass spectrometry (MS) proteomics, and multiplexed MS-based measurement of kinase activities. We identified multiple pancreatic cysts in all eight diabetic mutation carriers but not in any of the four nondiabetic mutation carriers or the six healthy controls. Furthermore, we identified upregulated mitogen-activated protein kinase (MAPK) target proteins and MAPK-driven cytokines and increased MAPK activity in the secretin-stimulated duodenal juice. These findings show that subjects with CEL-MODY develop multiple pancreatic cysts by the time they develop diabetes and that upregulated MAPK signaling in the pancreatic secretome may reflect the pathophysiological development of pancreatic cysts and diabetes. PMID- 24062245 TI - Growth differentiation factor-5 promotes brown adipogenesis in systemic energy expenditure. AB - Although growth differentiation factor-5 (GDF5) has been implicated in skeletal development and joint morphogenesis in mammals, little is known about its functionality in adipogenesis and energy homeostasis. Here, we show a critical role of GDF5 in regulating brown adipogenesis for systemic energy expenditure in mice. GDF5 expression was preferentially upregulated in brown adipose tissues from inborn and acquired obesity mice. Transgenic overexpression of GDF5 in adipose tissues led to a lean phenotype and reduced susceptibility to diet induced obesity through increased systemic energy expenditure. Overexpression of GDF5 facilitated the development of brown fat-like cells, called brite or beige cells, along with the expression of uncoupling protein-1 in inguinal subcutaneous white adipose tissue. In mutant mice harboring the dominant-negative GDF5, marked impairment in energy expenditure and thermogenesis was seen under obesogenic conditions. Recombinant GDF5 promoted brown adipogenesis through the mothers against decapentaplegic homolog (Smad) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) pathways after activation of bone morphogenetic protein receptor (BMPR). These results suggest that brown adipogenesis and energy homeostasis are both positively regulated by the GDF5/BMPR/Smad/PGC-1alpha signaling pathway in adipose tissues. Modulation of these pathways might be an effective therapeutic strategy for obesity and type 2 diabetes. PMID- 24062246 TI - Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice. AB - Differences in susceptibility to diabetic nephropathy (DN) between mouse strains with identical levels of hyperglycemia correlate with renal levels of oxidative stress, shown previously to play a central role in the pathogenesis of DN. Susceptibility to DN appears to be genetically determined, but the critical genes have not yet been identified. Overexpression of the enzyme glyoxalase 1 (Glo1), which prevents posttranslational modification of proteins by the glycolysis derived alpha-oxoaldehyde, methylglyoxal (MG), prevents hyperglycemia-induced oxidative stress in cultured cells and model organisms. In this study, we show that in nondiabetic mice, knockdown of Glo1 increases to diabetic levels both MG modification of glomerular proteins and oxidative stress, causing alterations in kidney morphology indistinguishable from those caused by diabetes. We also show that in diabetic mice, Glo1 overexpression completely prevents diabetes-induced increases in MG modification of glomerular proteins, increased oxidative stress, and the development of diabetic kidney pathology, despite unchanged levels of diabetic hyperglycemia. Together, these data indicate that Glo1 activity regulates the sensitivity of the kidney to hyperglycemic-induced renal pathology and that alterations in the rate of MG detoxification are sufficient to determine the glycemic set point at which DN occurs. PMID- 24062247 TI - Glutathionylated lipid aldehydes are products of adipocyte oxidative stress and activators of macrophage inflammation. AB - Obesity-induced insulin resistance has been linked to adipose tissue lipid aldehyde production and protein carbonylation. Trans-4-hydroxy-2-nonenal (4-HNE) is the most abundant lipid aldehyde in murine adipose tissue and is metabolized by glutathione S-transferase A4 (GSTA4), producing glutathionyl-HNE (GS-HNE) and its metabolite glutathionyl-1,4-dihydroxynonene (GS-DHN). The objective of this study was to evaluate adipocyte production of GS-HNE and GS-DHN and their effect on macrophage inflammation. Compared with lean controls, GS-HNE and GS-DHN were more abundant in visceral adipose tissue of ob/ob mice and diet-induced obese, insulin-resistant mice. High glucose and oxidative stress induced production of GS-HNE and GS-DHN by 3T3-L1 adipocytes in a GSTA4-dependent manner, and both glutathionylated metabolites induced secretion of tumor necrosis factor-alpha from RAW 264.7 and primary peritoneal macrophages. Targeted microarray analysis revealed GS-HNE and GS-DHN induced expression of inflammatory genes, including C3, C4b, c-Fos, igtb2, Nfkb1, and Nos2. Transgenic overexpression of GSTA4 in mouse adipose tissue led to increased production of GS-HNE associated with higher fasting glucose levels and moderately impaired glucose tolerance. These results indicated adipocyte oxidative stress results in GSTA4-dependent production of proinflammatory glutathione metabolites, GS-HNE and GS-DHN, which may represent a novel mechanism by which adipocyte dysfunction results in tissue inflammation and insulin resistance. PMID- 24062248 TI - Impaired leptin gene expression and release in cultured preadipocytes isolated from individuals born with low birth weight. AB - Low birth weight (LBW) is associated with increased risk of the development of type 2 diabetes (T2D). The appetite-regulating hormone leptin is released from mature adipocytes, and its production may be decreased in immature preadipocytes from LBW individuals. We recruited 14 men born with LBW and 13 controls born with normal birth weight (NBW). Biopsy samples were obtained from subcutaneous abdominal fat depots, and preadipocytes were isolated and cultured. Gene expression of leptin and selected differentiation markers were analyzed during preadipocyte differentiation, and cell culture media were collected to analyze leptin secretion. DNA methylation of CpG sites in the leptin promoter was measured using pyrosequencing. We found that differentiating preadipocytes from LBW individuals showed reduced leptin gene expression and a corresponding reduced leptin release compared with NBW individuals. Mean DNA methylation of the proximal LEP promoter was increased in LBW compared with NBW individuals. The notion of impaired adipocyte maturation in LBW individuals was supported by a lower mRNA expression of the differentiation markers; fatty acid binding protein 4, peroxisome proliferator-activated receptor gamma, and GLUT4. Our findings are consistent with impaired preadipocyte maturation, contributing to an increased risk of the development of T2D in LBW subjects. PMID- 24062250 TI - Fibroblast growth factor 21 (FGF21) and glucagon-like peptide 1 contribute to diabetes resistance in glucagon receptor-deficient mice. AB - Mice genetically deficient in the glucagon receptor (Gcgr(-/-)) show improved glucose tolerance, insulin sensitivity, and alpha-cell hyperplasia. In addition, Gcgr(-/-) mice do not develop diabetes after chemical destruction of beta-cells. Since fibroblast growth factor 21 (FGF21) has insulin-independent glucose lowering properties, we investigated whether FGF21 was contributing to diabetes resistance in insulin-deficient Gcgr(-/-) mice. Plasma FGF21 was 25-fold higher in Gcgr(-/-) mice than in wild-type mice. FGF21 was found to be expressed in pancreatic beta- and alpha-cells, with high expression in the hyperplastic alpha cells of Gcgr(-/-) mice. FGF21 expression was also significantly increased in liver and adipose tissue of Gcgr(-/-) mice. To investigate the potential antidiabetic actions of FGF21 in insulin-deficient Gcgr(-/-) mice, an FGF21 neutralizing antibody was administered prior to oral glucose tolerance tests (OGTTs). FGF21 neutralization caused a decline in glucose tolerance in insulin deficient Gcgr(-/-) mice during the OGTT. Despite this decline, insulin-deficient Gcgr(-/-) mice did not develop hyperglycemia. Glucagon-like peptide 1 (GLP-1) also has insulin-independent glucose-lowering properties, and an elevated circulating level of GLP-1 is a known characteristic of Gcgr(-/-) mice. Neutralization of FGF21, while concurrently blocking the GLP-1 receptor with the antagonist Exendin 9-39 (Ex9-39), resulted in significant hyperglycemia in insulin-deficient Gcgr(-/-) mice, while blocking with Ex9-39 alone did not. In conclusion, FGF21 acts additively with GLP-1 to prevent insulinopenic diabetes in mice lacking glucagon action. PMID- 24062249 TI - Both acyl and des-acyl ghrelin regulate adiposity and glucose metabolism via central nervous system ghrelin receptors. AB - Growth hormone secretagogue receptors (GHSRs) in the central nervous system (CNS) mediate hyperphagia and adiposity induced by acyl ghrelin (AG). Evidence suggests that des-AG (dAG) has biological activity through GHSR-independent mechanisms. We combined in vitro and in vivo approaches to test possible GHSR-mediated biological activity of dAG. Both AG (100 nmol/L) and dAG (100 nmol/L) significantly increased inositol triphosphate formation in human embryonic kidney 293 cells transfected with human GHSR. As expected, intracerebroventricular infusion of AG in mice increased fat mass (FM), in comparison with the saline infused controls. Intracerebroventricular dAG also increased FM at the highest dose tested (5 nmol/day). Chronic intracerebroventricular infusion of AG or dAG increased glucose-stimulated insulin secretion (GSIS). Subcutaneously infused AG regulated FM and GSIS in comparison with saline-infused control mice, whereas dAG failed to regulate these parameters even with doses that were efficacious when delivered intracerebroventricularly. Furthermore, intracerebroventricular dAG failed to regulate FM and induce hyperinsulinemia in GHSR-deficient (Ghsr(-/-)) mice. In addition, a hyperinsulinemic-euglycemic clamp suggests that intracerebroventricular dAG impairs glucose clearance without affecting endogenous glucose production. Together, these data demonstrate that dAG is an agonist of GHSR and regulates body adiposity and peripheral glucose metabolism through a CNS GHSR-dependent mechanism. PMID- 24062251 TI - Treatment of 14 intracranial aneurysms with the FRED system. AB - BACKGROUND: Endovascular treatment of intracranial aneurysms via flow diversion has become increasingly popular over the past several years. The flow redirection endoluminal device (FRED; Microvention, Tustin, California, USA) system is a next generation closed cell paired stent flow diversion device. OBJECTIVE: Our initial clinical experience with the FRED system is described. We believe this series to be the first use of the FRED system in the western hemisphere. METHODS: 14 aneurysms were treated utilizing the FRED system in 13 patients. Post-deployment angiography and fluoro CTs were obtained in all cases. RESULTS: Immediate post treatment angiography demonstrated reduced flow into all aneurysms although no long term angiographic data are yet available. The device proved technically easy to deploy and recapture after partial deployment if needed. No complications, technical or otherwise, were encountered. Radiographic visibility and ability to maintain its internal cylindrical shape in tortuous arteries, as demonstrated by fluoro CT, was at least as good as the pipeline embolization device. CONCLUSIONS: The FRED system was technically easy to deploy with no procedural complications occurring in this first reported series of 14 aneurysms. The ability of the FRED system to be recaptured after partial deployment and to maintain its internal shape in tortuous vessels was demonstrated well. Long term clinical and angiographic follow-up along with prospective studies are now needed to ascertain the role of the FRED in intracranial aneurysm treatment. PMID- 24062253 TI - Mid and long term outcomes of dural arteriovenous fistula endovascular management with Onyx. Experience of a single tertiary center. AB - INTRODUCTION: The natural history of intracranial dural arteriovenous fistulas (DAVFs) with cortical venous drainage is unfavorable, and treatment is recommended in most cases. Early reports have documented excellent initial clinical and radiographic outcomes after Onyx embolization of DAVFs but little evidence is available regarding the long term durability of this technique. METHODS: We retrospectively reviewed a database of 63 DAVFs in 53 consecutive patients who underwent Onyx embolization of a DAVF between 2001 and 2012 at our institution. Cognard types I and III were seen most commonly. RESULTS: A total of 72 Onyx embolization procedures were successfully completed during the study period, resulting in complete or near complete occlusion by the end of the study period in 58 (92.1%) DAVFs. For DAVFs in which complete or near complete obliteration was attained, stability of obliteration at 6, 12, 24, and 46 months was 100%, 95.4%, 93.8%, and 92.3%, respectively. DAVF recanalization/regrowth was discovered on delayed follow-up angiography in only five instances in which immediate post-embolization angiography revealed complete obliteration. Complications were seen in seven embolization procedures and included cranial nerve palsies (n=3), embolic infarcts (n=2), intraparenchymal hemorrhage (n=1), and unintentional stent deployment (n=1). CONCLUSIONS: Early evidence has indicated that endovascular Onyx embolization is safe and effective at achieving an initial angiographic cure. Results of our series suggest that angiographic and clinical outcomes of Onyx embolization remain relatively stable at mid and long term follow-up. PMID- 24062252 TI - North American Solitaire Stent Retriever Acute Stroke registry: post-marketing revascularization and clinical outcome results. AB - BACKGROUND: Limited post-marketing data exist on the use of the Solitaire FR device in clinical practice. The North American Solitaire Stent Retriever Acute Stroke (NASA) registry aimed to assess the real world performance of the Solitaire FR device in contrast with the results from the SWIFT (Solitaire with the Intention for Thrombectomy) and TREVO 2 (Trevo versus Merci retrievers for thrombectomy revascularization of large vessel occlusions in acute ischemic stroke) trials. METHODS: The investigator initiated NASA registry recruited North American sites to submit retrospective angiographic and clinical outcome data on consecutive acute ischemic stroke (AIS) patients treated with the Solitaire FR between March 2012 and February 2013. The primary outcome was a Thrombolysis in Myocardial Ischemia (TIMI) score of >=2 or a Treatment in Cerebral Infarction (TICI) score of >=2a. Secondary outcomes were 90 day modified Rankin Scale (mRS) score, mortality, and symptomatic intracranial hemorrhage. RESULTS: 354 patients underwent treatment for AIS using the Solitaire FR device in 24 centers. Mean time from onset to groin puncture was 363.4+/-239 min, mean fluoroscopy time was 32.9+/-25.7 min, and mean procedure time was 100.9+/-57.8 min. Recanalization outcome: TIMI >=2 rate of 83.3% (315/354) and TICI >=2a rate of 87.5% (310/354) compared with the operator reported TIMI >=2 rate of 83% in SWIFT and TICI >=2a rate of 85% in TREVO 2. CLINICAL OUTCOME: 42% (132/315) of NASA patients demonstrated a 90 day mRS <=2 compared with 37% (SWIFT) and 40% (TREVO 2). 90 day mortality was 30.2% (95/315) versus 17.2% (SWIFT) and 29% (TREVO 2). CONCLUSIONS: The NASA registry demonstrated that the Solitaire FR device performance in clinical practice is comparable with the SWIFT and TREVO 2 trial results. PMID- 24062254 TI - Role of argatroban during neurointerventional procedures in patients with heparin induced thrombocytopenia. AB - BACKGROUND: Currently, heparin is used routinely for anticoagulation during cerebral angiography and neurointerventional procedures. In patients with heparin sensitivity, however, heparin cannot be used. Therefore, an alternative method of anticoagulation is necessary to prevent clot formation during such procedures. METHODS: Argatroban, a direct thrombin inhibitor, is used as an alternate to heparin for anticoagulation. It is indicated for treatment of heparin induced thrombocytopenia as well as for prophylaxis during percutaneous coronary intervention. There are no reports describing the protocols for its use during neurointerventional procedures. We report on a series of three patients where argatroban was used in a series of three patients who underwent endovascular interventional procedures. RESULTS: Argatroban was given in a loading dosage of 4 MUg/kg/min for 10 min followed by an infusion of 1.0 MUg/kg/min. During the procedure, no procedural complications were reported. Activated thrombin time was used to monitor anticoagulation. CONCLUSIONS: We describe here the use of argatroban as an alternate anticoagulant during such procedures, as well as outline our protocol for its administration. PMID- 24062255 TI - Systemization of advanced stroke care: the dollars and sense of comprehensive stroke centers. PMID- 24062256 TI - Neuroangiography simulation using a silicone model in the angiography suite improves trainee skills. AB - PURPOSE: Simulation techniques in neurosurgical training are becoming more important. The purpose of this study was to determine whether silicone vascular models used in the angiography suite can render improvement in trainee performance and safety in neuroendovascular procedures. METHODS: 10 residents from neurosurgery and radiology training programs were asked to perform a diagnostic angiogram on a silicone based vascular model (United Biologics, Tustin, USA). This was done in the angiography suite with the full biplane fluoroscopy machine (Siemens, Munich, Germany). On their first attempt, they were coached by a faculty member trained in endovascular neurosurgery; on their second attempt, they received coaching only if the procedure had stalled. Technique was scored on multiple criteria by the faculty, and total time and fluoroscopy time were recorded on both attempts. RESULTS: In this group of 10 residents, overall procedure time significantly decreased from 51 to 42 min (p=0.01), and total fluoro time significantly decreased from 12 to 9 min (p=0.002) between the first attempt and the second attempt. Technical skill increased significantly in navigation, vessel selection, projection setup, and road map usage. CONCLUSIONS: Silicone vascular models used in the angiography suite, with the clinical working tools and biplane fluoroscopy, provide a valuable experience for training residents in diagnostic angiography, and improved performance and safety. PMID- 24062257 TI - Cranial radiation exposure during cerebral catheter angiography. AB - BACKGROUND: Radiation exposure to patients and personnel remains a major concern in the practice of interventional radiology, with minimal literature available on exposure to the forehead and cranium. OBJECTIVE: In this study, we measured cranial radiation exposure to the patient, operating interventional neuroradiologist, and circulating nurse during neuroangiographic procedures. We also report the effectiveness of wearing a 0.5 mm lead equivalent cap as protection against radiation scatter. DESIGN: 24 consecutive adult interventional neuroradiology procedures (six interventional, 18 diagnostic) were prospectively studied for cranial radiation exposures in the patient and personnel. Data were collected using electronic detectors and thermoluminescent dosimeters. RESULTS: Mean fluoroscopy time for diagnostic and interventional procedures was 8.48 (SD 2.79) min and 26.80 (SD 6.57) min, respectively. Mean radiation exposure to the operator's head was 0.08 mSv, as measured on the outside of the 0.5 mm lead equivalent protective headgear. This amounts to around 150 mSv/year, far exceeding the current deterministic threshold for the lens of the eye (ie, 20 mSv/year) in high volume centers performing up to five procedures a day. When compared with doses measured on the inside of the protective skullcap, there was a statistically significant reduction in the amount of radiation received by the operator's skull. CONCLUSIONS: Our study suggests that a modern neurointerventional suite is safe when equipped with proper protective shields and personal gear. However, cranial exposure is not completely eliminated with existing protective devices and the addition of a protective skullcap eliminates this exposure to both the operator and support staff. PMID- 24062258 TI - Histo-biological comparative analysis of bilateral breast cancer. AB - Bilateral breast cancer occurs in approximately 7% of surviving breast cancer patients. However, a dilemma exists concerning the notion of whether this represents a de novo second primary tumor versus a breast metastasis. We analyzed 81 patients with bilateral breast cancer, 47 (58%) synchronous tumors and 34 (42%) metachronous tumors. Additionally, charts were reviewed for age, family history, full histology data and biological receptors. We found there were no significant differences in concordance between the first and second primary tumors (in both synchronous and metachronous bilateral breast cancer) with respect to histology; grade; T-category; N-category; ER, PR and HER-2 status. In addition, there was no significant difference in the strength of correlation between ER and PR in the first and secondary primary tumors. Our findings suggest that the differentiation of the origin of contralateral breast cancer based on routine histological and biological concordance is inconclusive. Furthermore, the dilemma will continue to exist until additional molecular approaches are applied routinely for research purposes to resolve the debate. PMID- 24062259 TI - Retrospective study of modified SMILE chemotherapy for advanced-stage, relapsed, or refractory extranodal natural killer (NK)/T cell lymphoma, nasal type. AB - Extranodal natural killer/T cell lymphomas, nasal type (ENKLs), which are a group of non-Hodgkin lymphomas with poor prognoses, are much more common in China than in Western countries. Here, we retrospectively assessed the impact of two treatment regimens on clinical response and survival among 42 ENKL patients. All patients were diagnosed with stage IV, relapsed, or refractory ENKL. Twenty patients received modified SMILE (consisting of L-asparaginase, methotrexate, ifosphamide, etoposide, and dexamethasone) chemotherapy, and 22 control patients received CHOP (consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone) treatment. Higher complete response (CR) and overall response rates (ORR) (CR 45.0 vs. 13%, ORR 70 vs. 36%) were observed among the patients treated with the modified SMILE regimen (Fisher's exact = 0.040, Pearson chi(2) P = 0.030). Similarly, a higher ORR rate was observed among Epstein-Barr virus positive patients (ORR 50.0 vs. 18.0%, Fisher's exact = 0.049). The treatment group was also significantly associated with longer overall survival (OS) and progression-free survival (PFS) (Log-rank, P = 0.0341, P = 0.0142, respectively), but OS did not seem to be longer. Treatment-related toxicity was monitored in all patients throughout the protocol. There were no significant differences in the incidence of hematological and non-hematological toxicities between the two groups (P < 0.05), with the exception of peripheral neuropathy (treatment = 0 control = 5, Fisher's exact = 0.049). PMID- 24062261 TI - Comparison of human nasal epithelial cells grown as explant outgrowth cultures or dissociated tissue cultures in vitro. AB - The purpose of this study was to compare cell growth characteristics, ciliated cell differentiation, and function of human nasal epithelial cells established as explant outgrowth cultures or dissociated tissue cultures. Human nasal mucosa of the uncinate process was obtained by endoscopy and epithelial cell cultures were established by explant outgrowth or dissociated tissue culture methods. Epithelial cell growth characteristics were observed by inverted phase contrast microscopy. Ciliated cell differentiation was detected by beta-tubulin IVand ZO-1 immunocytochemistry. Basal and ATP-stimulated ciliary beat frequency (CBF) was measured using a highspeed digital microscopic imaging system. Both the explant and dissociated tissue cultures established as monolayers with tight junctions and differentiated cell composition, with both types of cultures comprising ciliated and non-ciliated epithelial cells. Fibroblasts were also frequently found in explant cultures but rarely seen in dissociated tissue cultures. In both culture systems, the highest ciliated cell density appeared at 7th-10th culture day and declined with time, with the lifespan of ciliated cells ranging from 14 to 21 days. Overall, 10% of the cells in explant cultures and 20% of the cells in the dissociated tissue cultures were ciliated. These two cultures demonstrated similar ciliary beat frequency values at baseline (7.78 +/- 1.99 Hz and 7.91 +/- 2.52 Hz, respectively) and reacted equivalently following stimulation with 100 MUM ATP. The results of this study indicate that both the explant outgrowth and dissociated tissue culture techniques are suitable for growing well differentiated nasal ciliated and non-ciliated cells, which have growth characteristics and ciliary activity similar to those of nasal epithelial cells in vivo. PMID- 24062260 TI - Emerin and histone deacetylase 3 (HDAC3) cooperatively regulate expression and nuclear positions of MyoD, Myf5, and Pax7 genes during myogenesis. AB - The spatial organization of chromatin is critical in establishing cell-type dependent gene expression programs. The inner nuclear membrane protein emerin has been implicated in regulating global chromatin architecture. We show emerin associates with genomic loci of muscle differentiation promoting factors in murine myogenic progenitors, including Myf5 and MyoD. Prior to their transcriptional activation Myf5 and MyoD loci localized to the nuclear lamina in proliferating progenitors and moved to the nucleoplasm upon transcriptional activation during differentiation. The Pax7 locus, which is transcribed in proliferating progenitors, localized to the nucleoplasm and Pax7 moved to the nuclear lamina upon repression during differentiation. Localization of Myf5, MyoD, and Pax7 to the nuclear lamina and proper temporal expression of these genes required emerin and HDAC3. Interestingly, activation of HDAC3 catalytic activity rescued both Myf5 localization to the nuclear lamina and its expression. Collectively, these data support a model whereby emerin facilitates repressive chromatin formation at the nuclear lamina by activating the catalytic activity of HDAC3 to regulate the coordinated spatiotemporal expression of myogenic differentiation genes. PMID- 24062262 TI - Surveillance of gastric intestinal metaplasia for the prevention of gastric cancer. AB - BACKGROUND: Adenocarcinoma of the stomach is the second leading cause of cancer related death in the world. Gastric intestinal metaplasia (GIM) is a recognised premalignant condition of the stomach. It has been described as occurring in up to one in five patients in western countries. Although there is a definite risk of progression from GIM to cancer, published guidelines and statements differ as to the utility and structure of surveillance programs for this condition. OBJECTIVES: To see whether or not endoscopic or biochemical surveillance of patients with gastric intestinal metaplasia (GIM) could result in increased detection of dysplasia and early gastric cancer to decrease gastric cancer mortality. SEARCH METHODS: We performed a search of the following electronic databases from inception to October 2012: CENTRAL, EMBASE, MEDLINE and LILACS. We handsearched for abstracts from relevant conferences. SELECTION CRITERIA: Randomised controlled trials only were included. DATA COLLECTION AND ANALYSIS: No studies met the inclusion criteria. MAIN RESULTS: No studies met the inclusion criteria. AUTHORS' CONCLUSIONS: There is a lack of randomised data on the utility of surveillance of GIM. The observational data from non-randomised studies are discussed and would suggest that although a randomised trial would be a desirable undertaking to attain the highest grade of clinical evidence, given the ethical and acceptability issues involved, further non-randomised clinical studies focussing on surveillance protocols and the role of Helicobacter pylori eradication may be a more pragmatic means of addressing the core clinical question. PMID- 24062263 TI - Influence of small RNAs on biofilm formation process in bacteria. AB - Small non-coding RNAs (sRNAs) play a significant role in regulation of bacterial physiological behaviors. After sensing any environmental cue such as fluctuation of nutrient concentration, temperature, pH, and osmolarity, these sRNAs interfere to transmit these signals to target regulators and genes. sRNAs have key role in biofilm formation process by base pairing with target mRNAs or interaction with modulating proteins to both positive and negative regulation mechanisms. There are various regulatory systems to characterize the initiation and formation of special bacterial biofilms that are mostly described as two component systems based on sRNAs functions. In this study, regulatory pathways that are important for biofilm formation and genetic responses to environmental stimuli in mature biofilms were evaluated. Some of the regulatory systems that produce common types of biofilms such as curli, PGA, cellulose and polysaccharides such as alginate, colonic acid, Psl and their involved sRNAs functions were also discussed. PMID- 24062265 TI - ADad 9: Suicidal behavior in Anxiety Disorders among adolescents in a rural community population in India. AB - OBJECTIVE: The risk of suicidal behavior associated with Anxiety Disorders (AD) among adolescents is known. However, concurrent mood disorders complicate these findings, and no data is available from India as well as from the community. This study aimed to address the suicidal risk associated with AD from different perspectives. METHODS: The authors prospectively collected data for 500 adolescents in a community with independent, trained raters. Risk for suicidal behavior was measured with SADPERSONS scale, socio-economic status with Modified Kuppuswamy Scale, depression and anxiety disorders with Beck Depression Inventory and Screen for Child Anxiety Related Emotional Disorders respectively. The relationship between predictors and need for preventive action was analyzed with univariate and multivariate regression analyses and a predictive model was built. RESULTS: Suicidal behavior was increased by the presence of AD (adjusted OR = 6.28), the number of co-morbid AD (adjusted OR = 2.04), severity of the AD (adjusted OR = 4.98). Being a boy increased the risk of suicidal behavior associated with AD (adjusted OR = 9.37), Generalized Anxiety Disorder (adjusted OR = 5.65), Separation Anxiety Disorder (unadjusted OR = 3.28), Social Anxiety Disorder (unadjusted OR = 5.91) while controlling for the confounding effect of Depressive Disorder. Gender did not have an influence on Panic Disorder. Presence of AD and co-morbid Depressive Disorder significantly contributed to a risk model for suicidal behavior. CONCLUSIONS: Anxiety Disorder is associated with the risk for potential suicidal behavior. Adolescent boys with AD and Depressive Disorder need to be identified as the high risk group for suicide prevention in the community. PMID- 24062264 TI - Covalent immobilization of alcohol dehydrogenase (ADH2) from Haloferax volcanii: how to maximize activity and optimize performance of halophilic enzymes. AB - Alcohol dehydrogenase from halophilic archaeon Haloferax volcanii (HvADH2) was successfully covalently immobilized on metal-derivatized epoxy Sepabeads. The immobilization conditions were optimized by investigating several parameters that affect the halophilic enzyme-support interaction. The highest immobilization efficiency (100 %) and retention activity (60 %) were achieved after 48 h of incubation of the enzyme with Ni-epoxy Sepabeads support in 100 mM Tris-HCl buffer, pH 8, containing 3 M KCl at 5 degrees C. No significant stabilization was observed after blocking the unreacted epoxy groups with commonly used hydrophilic agents. A significant increase in the stability of the immobilized enzyme was achieved by blocking the unreacted epoxy groups with ethylamine. The immobilization process increased the enzyme stability, thermal activity, and organic solvents tolerance when compared to its soluble counterpart, indicating that the immobilization enhances the structural and conformational stability. One step purification-immobilization of this enzyme has been carried out on metal chelate-epoxy Sepabeads, as an efficient method to obtain immobilized biocatalyst directly from bacterial extracts. PMID- 24062266 TI - Fat-soluble antioxidant vitamins, iron overload and chronic malnutrition in beta thalassemia major. AB - OBJECTIVE: To assess the antioxidant vitamins A (retinol) and E (alpha tocopherol) levels, iron status and growth retardation in children with beta thalassemia major in Odisha, an eastern state of India. METHODS: Forty three children aged 1-15 y diagnosed with beta-thalassemia major (28 males and 15 females) and 42 age-matched healthy controls (22 males and 20 females) were studied. beta-thalassemia was detected by using Bio-rad variant assay. Measurement of blood hemoglobin (Hb), hematocrit, serum vitamins (A and E) and ferritin was carried out by standard methods. RESULTS: Mean hemoglobin (6.60 +/- 1.84 vs. 11.8 +/- 2.29 g/dL, p < 0.01), serum retinol (28.0 +/- 17.67 vs. 54.4 +/ 36.56 MUg/dL, p < 0.001) and alpha-tocopherol (0.2 +/- 0.34 vs. 1.1 +/- 0.82 mg/dL, p < 0.001) were significantly lower in children with thalassemia compared with control group, however, serum ferritin (storage iron) was elevated in thalassemia patients (553.7 +/- 176.80 vs. 57.3 +/- 40.73 ng/mL, p < 0.001). Vitamin E had significantly correlated with hemoglobin and hematocrit values in the patients. Growth retardation in terms of stunting (79 % vs. 24 %, p < 0.0001) and thinness (32.6 % vs. 9.5 %, p < 0.05) was significantly higher in thalassemic children compared with normal children. CONCLUSIONS: This study shows that children with beta-thalas-semia major are in a state of oxidative stress of hyperfer-ritinemia with deprived antioxidant vitamins (A and E) and poor growth status suggesting a possible need for reduction in iron overload and additional antioxidant supplementation. PMID- 24062267 TI - The importance of recognizing protracted bacterial bronchitis in children. PMID- 24062268 TI - Cushing syndrome. AB - Cushing syndrome is the constellation of signs and symptoms caused by protracted exposure to glucocorticoids. The most common cause of Cushing syndrome in children and adolescents is exogenous administration of glucocorticoids. Presenting features commonly include weight gain, growth retardation, hirsutism, obesity, striae, acne and hypertension. Almost invariably, linear growth is severely diminished, a factor which may be useful in differentiating between childhood obesity and Cushing syndrome. Diagnostic approaches are based on distinguishing between adrenocorticotropic hormone (ACTH)-dependent and ACTH independent etiologies, and consideration of the most likely diagnosis by age. Treatment modality is dependent upon etiology. After cure, important components of care include attention to linear growth, pubertal progression and body composition. PMID- 24062269 TI - ADad 5: the co-morbidity in Anxiety Disorders among adolescents in a rural community population in India. AB - OBJECTIVE: Anxiety Disorders (AD) have been known to have high prevalence of intra-AD and extra-AD co-morbidities. This study documents the prevalence and profile of intra and extra-AD co-morbidities, the effect of the presence and number of co-morbidities on the severity of anxiety symptoms and the influence of age as well as gender on the co-morbidity. METHODS: In a prospective community survey of 500 adolescents, independent raters administered the Screen for Child Anxiety Related Emotional Disorders (SCARED) and Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Version (K-SADS PL) to collect the required data. Descriptive statistics, independent t tests, one-way ANOVA and Chi-square tests were done to evaluate the prevalence and profile of co-morbidity presentation, compare the effect of co-morbidity on severity of anxiety symptoms as well as analyse the influence of age groups and gender on intra-AD co-morbidities. RESULTS: Among those with AD, 14.2% had a DSM IV-TR intra-AD co-morbidity and 70% had SCARED based intra-AD co-morbidity. Adolescents with Separation Anxiety Disorder and Generalised Anxiety Disorder had the highest SCARED and DSM-IV-TR prevalence of intra-AD co-morbidity respectively. Also, 23.7% had overlapping extra-AD co-morbidity. Presence and number of intra-AD co-morbidity was significantly associated with severity of total anxiety score and subscale scores (all with P = 0.001). Age and gender of adolescents were not related to the co-morbidity. CONCLUSIONS: Intra and extra-AD co-morbidities are quite prevalent among adolescents with Anxiety Disorders in India. As such, co-morbidities increase the severity of anxiety symptoms, they should be identified and appropriate management should be established. PMID- 24062270 TI - ADad 11: Needs and service provisions for Anxiety Disorders among adolescents in a rural community population in India. AB - OBJECTIVE: Despite the need to have adolescent-centric policies and mental health services, India is yet far from having one. The authors aimed at generating opinions on the need to have adolescent focused policies and clinical services using the data on Anxiety Disorders they collected from the community. METHODS: This qualitative study used Focus Group Discussions (FGD) to generate opinions on the various needs to enhance better mental health services and policies for adolescents in India. A Modified Delphi technique was used with experts in mental health to prioritize these needs. Experts gave their plans on how to approach the needs during the in-depth interviews. RESULTS: The mental health professionals viewed scaled-up mental health services to include adolescent mental health services; improve the consumer opinion about public sector health providers; strengthening the government hospitals; capacity building among the health sector and non-health sector; research in service delivery models and policy changes as the needs. The parents felt the need to address the stigma associated with their children's mental illness, minimize the barriers in approaching mental health services and involve non-medical agencies in mental health care. These needs were prioritized and solutions to these problems were discussed. CONCLUSIONS: India centric and adolescent specific mental health policies and services need to be developed as well as integrated into the existing health system in India. PMID- 24062271 TI - ADad 7: Relationship between depression and Anxiety Disorders among adolescents in a rural community population in India. AB - OBJECTIVES: Anxiety Disorders (AD) often co-exist with the heterotypic co morbidity of Major Depressive Disorder (MDD) and Dysthymia (DysD). This study documents the prevalence of concurrent Depressive Disorder and its subtypes among AD, relationship between specific AD and Depressive Disorders, influence of severity of Depressive Disorders (DD) on AD and vice-versa, as well as the effect of age and gender on this co-morbidity. METHODS: In a prospective community survey of 500 adolescents, independent raters administered the Screen for Child Anxiety Related Emotional Disorders, Beck Depression Inventory and Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Version to collect the required data. Descriptive statistics, Independent t tests and Chi-square tests were done to evaluate the prevalence of concurrent Depressive Disorders among AD, relationship between specific AD and Depressive Disorders, severity of DD, and effect of age and gender on this co morbidity. RESULTS: Depressive Disorders were concurrently present in 23.7% of adolescents with AD, while 13.9% had concurrently only MDD, 8.3% had only DysD and 1.5% had both. More adolescents with AD had multiple mood disorders than otherwise. Twenty percent of adolescents with Panic Disorder, 12.1% with Generalised anxiety Disorder, 5.3% with Separation Anxiety Disorder and 12% with Social Anxiety Disorder had Depressive Disorders. Dysthymic disorder was statistically significantly more among those with PD (P = 0.009). Depressive Disorders were more severe among those with AD (P = 0.001) and the AD was more severe in those with DD (P = 0.01). As the severity of AD increased the severity of the DD also increased (P = 0.001). While DD were more prevalent among the late adolescence (P = 0.001), gender did not have any influence. CONCLUSIONS: The two way overlap between AD and DD is prevalent. Adolescents with Anxiety Disorders should be screened for Depressive Disorders, and when present should be treated. PMID- 24062272 TI - ADad 4: the symptomatology and clinical presentation of Anxiety Disorders among adolescents in a rural community population in India. AB - OBJECTIVES: Anxiety Disorders (AD) in children and adolescents present with unique clinical features and exhibit phenotypic diversity. The symptom presentation varies with regard to age of onset, developmental factors and gender. This study documents the clinical presentation of AD among adolescents in India, and explores the symptom clusters among the different age groups as well as gender. METHODS: Five hundred adolescents aged between 11 and 19 y from Pattanakad ICDS block, of Allapuzha district in Kerala were recruited and assessed using the self-rated Screen for Child Anxiety Related Emotional Disorders (SCARED) questionnaire to identify symptom clusters of anxiety and this was followed by confirmation of the diagnosis using DSM-IV TR within a week. Anxiety symptom clusters and severity (obtained from continuous SCARED scores) were compared between early, middle and late adolescence subgroups as well as between sexes. RESULTS: The most predominant anxiety symptoms across the subtypes were the anxious mood, which was noted in 12.60% followed by cognitive symptoms in 9.94% of the cases and finally physical symptoms in 9.22% of the study sample. The symptom clusters varied among the subtypes with anxious mood being commoner in Panic Disorder (PD), cognitive symptoms in Generalised Anxiety Disorder (GAD) and physical symptoms were prominent among Separation Anxiety (SeAD) and Social Anxiety Disorders (SoAD). The severity of anxiety disorder in general and its various subtypes were mostly of mild intensity although significant proportion had a severe form of the disease(s). The severity of the AD among girls was statistically significantly higher than boys (P = 0.02). There was no significant difference on symptom frequency or anxiety severity with regard to age. CONCLUSIONS: Understanding of age appropriate presentation of anxiety symptoms may help in streamlining the treatment guidelines and yield a better estimate of the disease process. PMID- 24062273 TI - Clinical characteristics and lung function in chronic obstructive pulmonary disease complicated with impaired peripheral oxygenation. AB - During exercise testing, patients with chronic obstructive pulmonary disease (COPD) often present with ventilatory limitations and various combinations of impaired peripheral oxygenation (IPO) to the exercising muscles. The entities of IPO include anemia, circulation impairment and deconditioning. COPD-IPO is not widely accepted as being a subgroup of COPD. Therefore, the aim of this study was to evaluate the clinical features of COPD-IPO patients. Forty-seven COPD patients underwent cardiopulmonary exercise testing. COPD-IPO was identified when all IPO variables had abnormal values. The patients who did not meet the COPD-IPO criteria were defined as the NIPO group. The variables with abnormal values included peak oxygen uptake (VO2) <85% predicated, anaerobic threshold <40% VO2max pred, VO2-work rate slope <8.6 ml/watt, oxygen pulse <80%pred, and ventilatory equivalents for O2 and CO2 at nadir (>31 and >34, respectively). Anthropometrics, biochemistry, and lung function were compared between the groups. Forty-six COPD patients were enrolled after excluding one patient who had technical difficulties in performing the exercise tests. Despite FEV1 and FVC being similarly reduced (p = NS) between the groups, the COPD-IPO (n = 13, 28%) patients had lower body mass index and were taller, and had impaired diffusing capacity and larger total lung capacity and air-trapping (all p < 0.05). We concluded that COPD patients with all six variables having abnormal values are a unique subgroup and that identification of these patients is worthwhile for further investigations and management such as exercise training and nutritional supplements. PMID- 24062274 TI - Feedback techniques to target functional deficits following anterior cruciate ligament reconstruction: implications for motor control and reduction of second injury risk. AB - Primary anterior cruciate ligament (ACL) injury prevention training has been shown to reduce the risk of injury. Less is known about the effect of prevention on second injury after ACL reconstruction (ACLR). Given recent findings that second injury rates exceed 20 % in only the first year following the return to sport, it is imperative that rehabilitation after ACLR is scrutinized so that second injury preventative strategies can be optimized. A potential limitation of current rehabilitative processes following ACLR could be a deficiency in the transition from conscious awareness achieved during rehabilitation sessions to unexpected and automatic movements required for athletic activities on the field. Learning strategies with an internally directed focus have traditionally been utilized but may be less suitable for acquisition of control of complex motor skills required for sport reintegration. Conversely, an externally focused rehabilitation strategy may enhance skill acquisition more efficiently and increase the potential to transfer to competitive sport. This article presents new insights gained from the motor learning domain that may improve neuromuscular training programmes via increased retention from improved techniques and may ultimately reduce the incidence of second ACL injuries. PMID- 24062276 TI - Daily Symptom Profiles of Children With ADHD Treated With Modified-Release Methylphenidate. AB - OBJECTIVE: The aim was to identify subgroups of patients with ADHD with different daily symptom profiles and to characterize their response to modified-release methylphenidate (MR MPH) treatment, using data from the observational trial OBSEER. METHOD: OBSEER included patients aged 6 to 17 years receiving MR MPH under routine care. To detect subgroups, a latent class cluster analysis was applied. Sex, age, MR MPH dose, and emotional symptoms were considered predictors of response. RESULTS: The analysis included 637 patients (81.3% male), with a mean age (standard deviation) of 10.1 (2.5) years. A two-class solution best fit the data, identifying a high-severity group (49.8%) with pronounced symptom reduction, and a low-severity group (50.2%) with minor changes throughout the day. Younger age, male sex, and higher MPH doses were predictive of the high severity class. CONCLUSION: Children with ADHD treated with MR MPH are heterogeneous, and subgroups with differential treatment response can be identified. PMID- 24062275 TI - Conceptual framework for strengthening exercises to prevent hamstring strains. AB - High-speed running accounts for the majority of hamstring strains in many sports. The terminal swing phase is believed to be the most hazardous as the hamstrings are undergoing an active lengthening contraction in a long muscle length position. Prevention-based strength training mainly focuses on eccentric exercises. However, it appears crucial to integrate other parameters than the contraction type. Therefore, the aim of this study is to present a conceptual framework based on six key parameters (contraction type, load, range of motion, angular velocity, uni-/bilateral exercises, kinetic chain) for the hamstring's strength exercise for strain prevention. Based on the biomechanical parameters of sprinting, it is proposed to use high-load eccentric contractions. The movement should be performed at a slow to moderate angular velocity and focused at the knee joint, while the hip is kept in a large flexion position in order to reach a greater elongation stress of the hamstrings than in the terminal swing phase. In this way, we believe that, during sprinting, athletes would be better trained to brake the knee extension effectively in the whole range of motion without overstretch of the hamstrings. Finally, based on its functional application, unilateral open kinetic chain should be preferred. PMID- 24062277 TI - A Review of Peer Relationships and Friendships in Youth With ADHD. AB - OBJECTIVE: The purpose of this essay is to examine peer relationships in youth with ADHD and to review current peer functioning interventions. METHOD: The studies included in this review were identified using the following search terms: "attention-deficit/hyperactivity disorder," "ADHD," "peer relationships," "friendships," "social skills," "intervention," and "treatment." Other than a few seminal studies published prior to 2000, studies included were published between 2000 and 2012. RESULTS/DISCUSSION: Background information regarding peer relationship difficulties and specific social skills deficits of youth with ADHD is reviewed and current social skills and friendship intervention programs are examined. Future directions also are provided. PMID- 24062279 TI - Association Between Insecure Attachment and ADHD: Environmental Mediating Factors. AB - OBJECTIVE: Psychological theories have postulated an association between insecure attachment and ADHD. The objective of this study is to investigate possible association between insecure attachment and ADHD in children and adults. METHOD: Review of literature was performed using the PsycINFO, Medline, and EMBASE databases. RESULTS: Twenty-nine studies were included in the review. Overall, the studies showed that parental attachment problems and environmental mediating factors were significantly associated with childhood ADHD. Adults with ADHD had a much higher incidence of insecure attachment styles than reported in the general population. CONCLUSION: There seems to be a clear association between ADHD and insecure attachment. It is likely that early intervention in the form of parent training and pharmacological treatment may prevent development of attachment problems. But such studies have not been carried out. Furthermore, adults with ADHD might need treatment for their lack of attachment competences as well. More research on this topic is much needed. PMID- 24062278 TI - Canine-assisted therapy for children with ADHD: preliminary findings from the positive assertive cooperative kids study. AB - OBJECTIVE: The objective of this study was to provide preliminary findings from an ongoing randomized clinical trial using a canine-assisted intervention (CAI) for 24 children with ADHD. METHOD: Project Positive Assertive Cooperative Kids (P.A.C.K.) was designed to study a 12-week cognitive-behavioral intervention delivered with or without CAI. Children were randomly assigned to group therapy with or without CAI. Parents of children in both groups simultaneously participated in weekly parent group therapy sessions. RESULTS: Across both treatment groups, parents reported improvements in children's social skills, prosocial behaviors, and problematic behaviors. In both groups, the severity of ADHD symptoms declined during the course of treatment; however, children who received the CAI model exhibited greater reductions in the severity of ADHD symptoms than did children who received cognitive-behavioral therapy without CAI. CONCLUSION: Results suggest that CAI offers a novel therapeutic strategy that may enhance cognitive-behavioral interventions for children with ADHD. PMID- 24062281 TI - Two Koreas, war and health. PMID- 24062280 TI - Dietary CLA-induced lipolysis is delayed in soy oil-fed mice compared to coconut oil-fed mice. AB - Conjugated linoleic acid (CLA) has been shown to cause a reduction in obesity in several species. CLA-induced body fat loss is enhanced when mice are fed coconut oil (CO) and involves increased lipolysis. The objective of this paper was to determine if the CLA-induced lipolysis in mice fed with different oil sources was time-dependent. Mice were fed 7 % soybean oil (SO) or CO diets for 6 week and then supplemented with 0 or 0.5 % CLA for 3, 7, 10 or 14 days. Body fat and ex vivo lipolysis was determined. Body fat was reduced by CO on day 7 (P < 0.01) and in both CO and SO-fed mice (P < 0.05) in response to CLA on d14. Lipolysis was increased by CLA in CO-fed mice (P < 0.01) but not in SO-fed mice on day 7 and 10, but on day 14 CLA increased lipolysis in both CO- and SO-fed mice (P < 0.001). Expression and activation level of proteins involved in lipolysis and lipogenesis was determined by western blotting and real-time PCR, respectively. No significant differences were detected in protein expression. CO-fed mice had greater fatty acid synthase and stearyl CoA desaturase 1 mRNA expression and less acetyl CoA carboxylase mRNA expression (P < 0.01). Sterol regulatory binding protein 1c was decreased by CLA in CO-fed mice and increased in SO-fed mice (P < 0.05). Malic enzyme expression was increased by CLA (P < 0.001) and CO (P < 0.01). Therefore, CLA-induced lipolysis occurs more rapidly in CO vs SO-fed mice and lipogenesis is decreased in CO-fed mice with CLA supplementation. PMID- 24062282 TI - One hundred years of Medical Research--the UK Medical Research Council Centenary. PMID- 24062283 TI - The inheritance of complex growth forms, such as stature, on Mendel's theory. PMID- 24062284 TI - Commentary: Dr John Brownlee MA, MD, DSc, DPH (Cantab), FRFPS, FSS, FRMetS (1868 1927), public health officer, geneticist, epidemiologist and medical statistician. AB - In July 1914 Dr John Brownlee was appointed head of the Statistical Department of the newly established Medical Research Committee. He had qualified in mathematics, natural philosophy and medicine at the University of Glasgow, and by 1914 had established a reputation as a public health officer, an expert in infectious diseases, and as a proponent of the Pearsonian school of the application of statistics and mathematics to medicine: an ideal background for his new position. In celebration of the centenary anniversary of the Medical Research Council and as a tribute to John Brownlee's involvement at the start, the International Journal of Epidemiology is reprinting in this issue one of his early papers on genetics. We comment on this paper, as well as Brownlee's background, achievements, research and his somewhat enigmatic though likeable character. PMID- 24062285 TI - Commentary: Height and Mendel's theory: the long and the short of it. PMID- 24062286 TI - Profile: the Niakhar Health and Demographic Surveillance System. AB - The Health and Demographic Surveillance System (HDSS) in Niakhar, a rural area of Senegal, is located 135 km east of Dakar. The HDSS was established in 1962 by the Institut de Recherche pour le Developpement (IRD) of Senegal to face the shortcomings of the civil registration system and provide demographic indicators. Some 65 villages in the Niakhar area were followed annually by the HDSS from 1962 1969. The study zone was reduced to 8 villages from 1969-1983, and from then on the HDSS was extended to include 22 other villages, covering a total of 30 villages for a population estimated at 43 000 in January 2012. Thus, 8 villages in the Niakhar area have been under demographic surveillance for almost 50 years and 30 villages for 30 years. Vital events, migrations, marital changes, pregnancies, and immunizations are routinely recorded every 4 months. The HDSS data base also includes epidemiological, economic, and environmental information obtained from specific surveys. Data were collected through annual rounds from 1962 to 1987. The rounds became weekly from 1987-1997, followed by routine visits conducted every 3 months between 1997 and 2007 and every 4 months since then. The data collected in the HDSS are not open to access, but can be fairly shared under conditions of collaboration and endowment. PMID- 24062287 TI - Why representativeness should be avoided. PMID- 24062288 TI - Commentary: On representativeness. PMID- 24062289 TI - Commentary: Epidemiologists have debated representativeness for more than 40 years--has the time come to move on? PMID- 24062290 TI - Commentary: Representativeness is usually not necessary and often should be avoided. PMID- 24062291 TI - Commentary: Should we always deliberately be non-representative? PMID- 24062292 TI - Rebuttal: When it comes to scientific inference, sometimes a cigar is just a cigar. PMID- 24062293 TI - Association between various sedentary behaviours and all-cause, cardiovascular disease and cancer mortality: the Multiethnic Cohort Study. AB - BACKGROUND: It has been proposed that time spent sitting increases all-cause mortality, but evidence to support this hypothesis, especially the relative effects of various sitting activities alone or in combination, is very limited. METHODS: The association between various sedentary behaviours (time spent: sitting watching television (TV); in other leisure activities; in a car/bus; at work; and at meals) and mortality (all-cause and cause-specific) was examined in the Multiethnic Cohort Study, which included 61 395 men and 73 201 women aged 45 75 years among five racial/ethnic groups (African American, Latino, Japanese American, Native Hawaiian and White) from Hawaii and Los Angeles, USA. RESULTS: Median follow-up was 13.7 years and 19 143 deaths were recorded. Total daily sitting was not associated with mortality in men, whereas in women the longest sitting duration (>= 10 h/day vs <5 h/day) was associated with increased all cause (11%) and cardiovascular (19%) mortality. Multivariate hazard ratios (HR) for >= 5 h/day vs <1 h/day of sitting watching TV were 1.19 in men (95% confidence interval (CI) 1.10-1.29) and 1.32 in women (95% CI 1.21-1.44) for all cause mortality. This association was consistent across four racial/ethnic groups, but was not seen in Japanese Americans. Sitting watching TV was associated with an increased risk for cardiovascular mortality, but not for cancer mortality. Time spent sitting in a car/bus and at work was not related to mortality. CONCLUSIONS: Leisure time spent sitting, particularly watching television, may increase overall and cardiovascular mortality. Sitting at work or during transportation was not related to mortality. PMID- 24062295 TI - Commentary: Identification, neighbourhoods and families. PMID- 24062294 TI - The impact of neighbourhood deprivation on adolescent violent criminality and substance misuse: a longitudinal, quasi-experimental study of the total Swedish population. AB - BACKGROUND: A number of studies suggest associations between neighbourhood characteristics and criminality during adolescence and young adulthood. However, the causality of such neighbourhood effects remains uncertain. METHODS: We followed all children born in Sweden from 1975-1989 who lived in its three largest cities by the age of 15 years and for whom complete information was available about individual and contextual factors (N = 303 465). All biological siblings were identified in the sample (N = 179 099). Generalized linear mixed effects models were used to assess the effect of neighbourhood deprivation on violent criminality and substance misuse between the ages of 15 and 20 years, while taking into account the cross-classified data structure (i.e. siblings in the same families attending different schools and living in different neighbourhoods at age 15). RESULTS: In the crude model, an increase of 1 SD in neighbourhood deprivation was associated with a 57% increase in the odds of being convicted of a violent crime (95% CI 52%-63%). The effect was greatly attenuated when adjustment was made for a number of observed confounders (OR 1.09, 95% CI 1.06-1.11). When we additionally adjusted for unobserved familial confounders, the effect was no longer present (OR 0.96, 95% CI 0.84-1.10). Similar results were observed for substance misuse. The results were not due to poor variability either between neighbourhoods or within families. CONCLUSIONS: We found that the adverse effect of neighbourhood deprivation on adolescent violent criminality and substance misuse in Sweden was not consistent with a causal inference. Instead, our findings highlight the need to control for familial confounding in multilevel studies of criminality and substance misuse. PMID- 24062296 TI - Parvovirus B19 infection in pregnancy and subsequent morbidity and mortality in offspring. AB - BACKGROUND: Because parvovirus B19 infection in pregnancy has been associated with infant morbidity and mortality in case reports and after intrauterine transfusion, we tested the population-based association using serum and hospital data of high quality. METHODS: We established a cohort of 113 228 children born to women tested for parvovirus B19 infection during pregnancy in a major diagnostic laboratory in Denmark, from 1994 to 2009. Information on 20 selected morbidity diagnoses and on mortality was obtained from the Danish National Patient Register, the Danish Cancer Register and the Danish Civil Registration System. Incidence rate ratios (IRR) were estimated by log-linear Poisson regression with adjustment for age and sex of the child, maternal age and year of maternal parvovirus B19 test. RESULTS: A total of 1095 (1.0%) children were born to mothers who were infected with parvovirus B19 during pregnancy. During 1 million person-years of follow-up, 10 856 children experienced morbidity and 590 children died. Overall, maternal infection status was neither associated with morbidity during infancy (IRR 0.64; 95% CI: 0.40 to 1.02) or childhood (IRR 0.93; 95% CI: 0.77 to 1.14), nor with infant mortality (IRR 0.98; 95% CI: 0.44 to 2.20). Specifically, there was no association with 19 of 20 morbidities. An excess risk of cancer in the central nervous system was observed (IRR 5.88; 95% CI: 1.41 to 24.6); however, the number of exposed cases was very small (n = 2). CONCLUSIONS: Parvovirus B19 infection during pregnancy was not associated with overall morbidity or mortality in infancy and childhood. PMID- 24062297 TI - Chronic respiratory symptoms in children following in utero and early life exposure to arsenic in drinking water in Bangladesh. AB - BACKGROUND: Arsenic exposure via drinking water increases the risk of chronic respiratory disease in adults. However, information on pulmonary health effects in children after early life exposure is limited. METHODS: This population-based cohort study set in rural Matlab, Bangladesh, assessed lung function and respiratory symptoms of 650 children aged 7-17 years. Children with in utero and early life arsenic exposure were compared with children exposed to less than 10 ug/l in utero and throughout childhood. Because most children drank the same water as their mother had drunk during pregnancy, we could not assess only in utero or only childhood exposure. RESULTS: Children exposed in utero to more than 500 ug/l of arsenic were more than eight times more likely to report wheezing when not having a cold [odds ratio (OR) = 8.41, 95% confidence interval (CI): 1.66-42.6, P < 0.01] and more than three times more likely to report shortness of breath when walking on level ground (OR = 3.86, 95% CI: 1.09-13.7, P = 0.02) and when walking fast or climbing (OR = 3.19, 95% CI: 1.22-8.32, P < 0.01]. However, there was little evidence of reduced lung function in either exposure category. CONCLUSIONS: Children with high in utero and early life arsenic exposure had marked increases in several chronic respiratory symptoms, which could be due to in utero exposure or to early life exposure, or to both. Our findings suggest that arsenic in water has early pulmonary effects and that respiratory symptoms are a better marker of early life arsenic toxicity than changes in lung function measured by spirometry. PMID- 24062298 TI - Acetaminophen and/or antibiotic use in early life and the development of childhood allergic diseases. AB - BACKGROUND: Our understanding of whether the use of acetaminophen and/or antibiotics in early life can cause allergic diseases in later childhood remains inconclusive. The objective of this study was to investigate the temporal relationship between exposure to acetaminophen and/or antibiotics in early life and the development of allergic diseases in later childhood, using two independent birth cohorts derived from the National Health Insurance Research Database (NHIRD) in Taiwan. METHODS: The authors conducted a prospective birth cohort study of 263 620 children born in 1998 and 9910 children born in 2003, separately, from the NHIRD. Exposure status of acetaminophen and/or antibiotics and potential confounding factors were included in the analyses. Cox proportional hazards models were applied to determine the temporal relationship between acetaminophen and/or antibiotic exposure and the development of allergic diseases. RESULTS: We observed a positive relationship between acetaminophen and/or antibiotic exposure during the 1st year of life and the subsequent development of the three examined allergic diseases (atopic dermatitis, asthma and allergic rhinitis) in the 1998 birth cohort, but the observed relationship of drug exposure in the 2003 cohort, especially for atopic dermatitis and asthma, was lower than for those in the 1998 cohort and was not statistically significant. CONCLUSIONS: Our findings provide suggestive evidence that the temporal effect of exposure to acetaminophen and/or antibiotics influences the development of common allergic diseases in later childhood. Further functional studies and/or animal studies are needed to better understand the underlying regulatory mechanisms driving this important clinical and public health issue. PMID- 24062299 TI - Use of allele scores as instrumental variables for Mendelian randomization. AB - BACKGROUND: An allele score is a single variable summarizing multiple genetic variants associated with a risk factor. It is calculated as the total number of risk factor-increasing alleles for an individual (unweighted score), or the sum of weights for each allele corresponding to estimated genetic effect sizes (weighted score). An allele score can be used in a Mendelian randomization analysis to estimate the causal effect of the risk factor on an outcome. METHODS: Data were simulated to investigate the use of allele scores in Mendelian randomization where conventional instrumental variable techniques using multiple genetic variants demonstrate 'weak instrument' bias. The robustness of estimates using the allele score to misspecification (for example non-linearity, effect modification) and to violations of the instrumental variable assumptions was assessed. RESULTS: Causal estimates using a correctly specified allele score were unbiased with appropriate coverage levels. The estimates were generally robust to misspecification of the allele score, but not to instrumental variable violations, even if the majority of variants in the allele score were valid instruments. Using a weighted rather than an unweighted allele score increased power, but the increase was small when genetic variants had similar effect sizes. Naive use of the data under analysis to choose which variants to include in an allele score, or for deriving weights, resulted in substantial biases. CONCLUSIONS: Allele scores enable valid causal estimates with large numbers of genetic variants. The stringency of criteria for genetic variants in Mendelian randomization should be maintained for all variants in an allele score. PMID- 24062300 TI - Visualizing Europe's demographic scars with coplots and contour plots. AB - We present two enhancements to existing methods for visualizing vital statistics data. Data from the Human Mortality Database were used and vital statistics from England and Wales are used for illustration. The simpler of these methods involves coplotting mean age of death with its variance, and the more complex of these methods is to present data as a contour plot. The coplot method shows the effect of the 20th century's epidemiological transitions. The contour plot method allows more complex and subtle age, period and cohort effects to be seen. The contour plot shows the effects of broad improvements in public health over the 20th century, including vast reductions in rates of childhood mortality, reduced baseline mortality risks during adulthood and the postponement of higher mortality risks to older ages. They also show the effects of the two world wars and the 1918 influenza pandemic on men of fighting age, women and children. The contour plots also show a cohort effect for people born around 1918, suggesting a possible epigenetic effect of parental exposure to the pandemic which shortened the cohort's lifespan and which has so far received little attention. Although this article focuses on data from England and Wales, the associated online appendices contain equivalent visualizations for almost 50 series of data available on the Human Mortality Database. We expect that further analyses of these visualizations will reveal further insights into global public health. PMID- 24062301 TI - Mortality estimates for South East Asia, and INDEPTH mortality surveillance: necessary but not sufficient? PMID- 24062302 TI - Comment on Mortality estimates for South East Asia, and INDEPTH mortality surveillance: necessary, but not sufficient. PMID- 24062303 TI - Authors' response to: Mortality estimates for South East Asia, and INDEPTH mortality surveillance: necessary, but not sufficient. PMID- 24062304 TI - P-glycoprotein mediates drug resistance via a novel mechanism involving lysosomal sequestration. AB - Localization of the drug transporter P-glycoprotein (Pgp) to the plasma membrane is thought to be the only contributor of Pgp-mediated multidrug resistance (MDR). However, very little work has focused on the contribution of Pgp expressed in intracellular organelles to drug resistance. This investigation describes an additional mechanism for understanding how lysosomal Pgp contributes to MDR. These studies were performed using Pgp-expressing MDR cells and their non resistant counterparts. Using confocal microscopy and lysosomal fractionation, we demonstrated that intracellular Pgp was localized to LAMP2-stained lysosomes. In Pgp-expressing cells, the Pgp substrate doxorubicin (DOX) became sequestered in LAMP2-stained lysosomes, but this was not observed in non-Pgp-expressing cells. Moreover, lysosomal Pgp was demonstrated to be functional because DOX accumulation in this organelle was prevented upon incubation with the established Pgp inhibitors valspodar or elacridar or by silencing Pgp expression with siRNA. Importantly, to elicit drug resistance via lysosomes, the cytotoxic chemotherapeutics (e.g. DOX, daunorubicin, or vinblastine) were required to be Pgp substrates and also ionized at lysosomal pH (pH 5), resulting in them being sequestered and trapped in lysosomes. This property was demonstrated using lysosomotropic weak bases (NH4Cl, chloroquine, or methylamine) that increased lysosomal pH and sensitized only Pgp-expressing cells to such cytotoxic drugs. Consequently, a lysosomal Pgp-mediated mechanism of MDR was not found for non ionizable Pgp substrates (e.g. colchicine or paclitaxel) or ionizable non-Pgp substrates (e.g. cisplatin or carboplatin). Together, these studies reveal a new mechanism where Pgp-mediated lysosomal sequestration of chemotherapeutics leads to MDR that is amenable to therapeutic exploitation. PMID- 24062305 TI - Thioredoxin 1 is inactivated due to oxidation induced by peroxiredoxin under oxidative stress and reactivated by the glutaredoxin system. AB - The mammalian cytosolic thioredoxin system, comprising thioredoxin (Trx), Trx reductase, and NADPH, is the major protein-disulfide reductase of the cell and has numerous functions. Besides the active site thiols, human Trx1 contains three non-active site cysteine residues at positions 62, 69, and 73. A two-disulfide form of Trx1, containing an active site disulfide between Cys-32 and Cys-35 and a non-active site disulfide between Cys-62 and Cys-69, is inactive either as a disulfide reductase or as a substrate for Trx reductase. This could possibly provide a structural switch affecting Trx1 function during oxidative stress and redox signaling. We found that two-disulfide Trx1 was generated in A549 cells under oxidative stress. In vitro data showed that two-disulfide Trx1 was generated from oxidation of Trx1 catalyzed by peroxiredoxin 1 in the presence of H2O2. The redox Western blot data indicated that the glutaredoxin system protected Trx1 in HeLa cells from oxidation caused by ebselen, a superfast oxidant for Trx1. Our results also showed that physiological concentrations of glutathione, NADPH, and glutathione reductase reduced the non-active site disulfide in vitro. This reaction was stimulated by glutaredoxin 1 via the so called monothiol mechanism. In conclusion, reversible oxidation of the non-active site disulfide of Trx1 is suggested to play an important role in redox regulation and cell signaling via temporal inhibition of its protein-disulfide reductase activity for the transmission of oxidative signals under oxidative stress. PMID- 24062306 TI - The N-terminal flanking region of the A1 domain regulates the force-dependent binding of von Willebrand factor to platelet glycoprotein Ibalpha. AB - Binding of platelet glycoprotein Ibalpha (GPIbalpha) to von Willebrand factor (VWF) initiates platelet adhesion to disrupted vascular surface under arterial blood flow. Flow exerts forces on the platelet that are transmitted to VWF GPIbalpha bonds, which regulate their dissociation. Mutations in VWF and/or GPIbalpha may alter the mechanical regulation of platelet adhesion to cause hemostatic defects as found in patients with von Willebrand disease (VWD). Using a biomembrane force probe, we observed biphasic force-decelerated (catch) and force-accelerated (slip) dissociation of GPIbalpha from VWF. The VWF A1 domain that contains the N-terminal flanking sequence Gln(1238)-Glu(1260) (1238-A1) formed triphasic slip-catch-slip bonds with GPIbalpha. By comparison, using a short form of A1 that deletes this sequence (1261-A1) abolished the catch bond, destabilizing its binding to GPIbalpha at high forces. Importantly, shear dependent platelet rolling velocities on these VWF ligands in a flow chamber system mirrored the force-dependent single-bond lifetimes. Adding the Gln(1238) Glu(1260) peptide, which interacted with GPIbalpha and 1261-A1 but not 1238-A1, to whole blood decreased platelet attachment under shear stress. Soluble Gln(1238)-Glu(1260) reduced the lifetimes of GPIbalpha bonds with VWF and 1238-A1 but rescued the catch bond of GPIbalpha with 1261-A1. A type 2B VWD 1238-A1 mutation eliminated the catch bond by prolonging lifetimes at low forces, a type 2M VWD 1238-A1 mutation shifted the respective slip-catch and catch-slip transition points to higher forces, whereas a platelet type VWD GPIbalpha mutation enhanced the bond lifetime in the entire force regime. These data reveal the structural determinants of VWF activation by hemodynamic force of the circulation. PMID- 24062307 TI - Diversity of Delta12 fatty acid desaturases in santalaceae and their role in production of seed oil acetylenic fatty acids. AB - Plants in the Santalaceae family, including the native cherry Exocarpos cupressiformis and sweet quandong Santalum acuminatum, accumulate ximenynic acid (trans-11-octadecen-9-ynoic acid) in their seed oil and conjugated polyacetylenic fatty acids in root tissue. Twelve full-length genes coding for microsomal Delta12 fatty acid desaturases (FADs) from the two Santalaceae species were identified by degenerate PCR. Phylogenetic analysis of the predicted amino acid sequences placed five Santalaceae FADs with Delta12 FADs, which include Arabidopsis thaliana FAD2. When expressed in yeast, the major activity of these genes was Delta12 desaturation of oleic acid, but unusual activities were also observed: i.e. Delta15 desaturation of linoleic acid as well as trans-Delta12 and trans-Delta11 desaturations of stearolic acid (9-octadecynoic acid). The trans-12 octadecen-9-ynoic acid product was also detected in quandong seed oil. The two other FAD groups (FADX and FADY) were present in both species; in a phylogenetic tree of microsomal FAD enzymes, FADX and FADY formed a unique clade, suggesting that are highly divergent. The FADX group enzymes had no detectable Delta12 FAD activity but instead catalyzed cis-Delta13 desaturation of stearolic acid when expressed in yeast. No products were detected for the FADY group when expressed recombinantly. Quantitative PCR analysis showed that the FADY genes were expressed in leaf rather than developing seed of the native cherry. FADs with promiscuous and unique activities have been identified in Santalaceae and explain the origin of some of the unusual lipids found in this plant family. PMID- 24062308 TI - Identification of conformationally sensitive residues essential for inhibition of vesicular monoamine transport by the noncompetitive inhibitor tetrabenazine. AB - Vesicular monoamine transporter 2 (VMAT2) transports monoamines into storage vesicles in a process that involves exchange of the charged monoamine with two protons. VMAT2 is a member of the DHA12 family of multidrug transporters that belongs to the major facilitator superfamily of secondary transporters. Tetrabenazine (TBZ) is a non-competitive inhibitor of VMAT2 that is used in the treatment of hyperkinetic disorders associated with Huntington disease and Tourette syndrome. Previous biochemical studies suggested that the recognition site for TBZ and monoamines is different. However, the precise mechanism of TBZ interaction with VMAT2 remains unknown. Here we used a random mutagenesis approach and selected TBZ-resistant mutants. The mutations clustered around the lumenal opening of the transporter and mapped to either conserved proline or glycine, or to residues immediately adjacent to conserved proline and glycine. Directed mutagenesis provides further support for the essential role of the latter residues. Our data strongly suggest that the conserved alpha-helix breaking residues identified in this work play an important role in conformational rearrangements required for TBZ binding and substrate transport. Our results provide a novel insight into the mechanism of transport and TBZ binding by VMAT2. PMID- 24062309 TI - Redox control of the senescence regulator interleukin-1alpha and the secretory phenotype. AB - Senescent cells accumulate in aged tissue and are causally linked to age associated tissue degeneration. These non-dividing, metabolically active cells are highly secretory and alter tissue homeostasis, creating an environment conducive to metastatic disease progression. IL-1alpha is a key senescence associated (SA) proinflammatory cytokine that acts as a critical upstream regulator of the SA secretory phenotype (SASP). We established that SA shifts in steady-state H2O2 and intracellular Ca(2+) levels caused an increase in IL-1alpha expression and processing. The increase in intracellular Ca(2+) promoted calpain activation and increased the proteolytic cleavage of IL-1alpha. Antioxidants and low oxygen tension prevented SA IL-1alpha expression and restricted expression of SASP components IL-6 and IL-8. Ca(2+) chelation or calpain inhibition prevented SA processing of IL-1alpha and its ability to induce downstream cytokine expression. Conditioned medium from senescent cells treated with antioxidants or Ca(2+) chelators or cultured in low oxygen markedly reduced the invasive capacity of proximal metastatic cancer cells. In this paracrine fashion, senescent cells promoted invasion by inducing an epithelial-mesenchymal transition, actin reorganization, and cellular polarization of neighboring cancer cells. Collectively, these findings demonstrate how SA alterations in the redox state and Ca(2+) homeostasis modulate the inflammatory phenotype through the regulation of the SASP initiator IL-1alpha, creating a microenvironment permissive to tumor invasion. PMID- 24062310 TI - Eukaryotic oligosaccharyltransferase generates free oligosaccharides during N glycosylation. AB - Asparagine (N)-linked glycosylation regulates numerous cellular activities, such as glycoprotein quality control, intracellular trafficking, and cell-cell communications. In eukaryotes, the glycosylation reaction is catalyzed by oligosaccharyltransferase (OST), a multimembrane protein complex that is localized in the endoplasmic reticulum (ER). During N-glycosylation in the ER, the protein-unbound form of oligosaccharides (free oligosaccharides; fOSs), which is structurally related to N-glycan, is released into the ER lumen. However, the enzyme responsible for this process remains unidentified. Here, we demonstrate that eukaryotic OST generates fOSs. Biochemical and genetic analyses using mutant strains of Saccharomyces cerevisiae revealed that the generation of fOSs is tightly correlated with the N-glycosylation activity of OST. Furthermore, we present evidence that the purified OST complex can generate fOSs by hydrolyzing dolichol-linked oligosaccharide, the glycan donor substrate for N-glycosylation. The heterologous expression of a single subunit of OST from the protozoan Leishmania major in S. cerevisiae demonstrated that this enzyme functions both in N-glycosylation and generation of fOSs. This study provides insight into the mechanism of PNGase-independent formation of fOSs. PMID- 24062311 TI - Loss of TBK1 induces epithelial-mesenchymal transition in the breast cancer cells by ERalpha downregulation. AB - Estrogen receptor alpha (ERalpha) is the pivotal regulator of proliferation and differentiation in mammary epithelia, where it serves as a crucial prognostic marker and therapeutic target in breast cancer. In this study, we show that the loss of the kinase TANK-binding kinase 1 (TBK1) induces epithelial-mesenchymal transition in ERalpha-positive breast cancer cells by downregulating ERalpha expression. TBK1 was overexpressed in ERalpha-positive breast cancers, where it was associated with distant metastasis-free survival in patients, whereas it was underexpressed in ERalpha-negative breast cancers. TBK1 silencing decreased expression of epithelial markers and increased expression of mesenchymal markers in ERalpha-positive breast cancer cells, enhancing tumor growth and lung metastasis in vivo in a manner associated with downregulation of ERalpha expression. Mechanistically, TBK1 silencing reduced FOXO3A binding to the ERalpha promoter by inducing the translocation of phosphorylated FOXO3A from the nucleus to the cytoplasm. Thus, our results indicate that the loss of TBK1 expression parallels the loss of ERalpha expression, in turn helping drive an aggressive breast cancer phenotype. PMID- 24062312 TI - The emerging role of immunosurveillance in dictating metastatic spread in breast cancer. AB - It is now well known that the immune system can recognize transformed cells and control the initiation and growth of some cancers, a process termed tumor immunosurveillance. Key regulators of this process have been described in the primary tumor setting, where the balance of protumor and antitumor responses dictates tumor initiation and progression. Accumulating evidence suggests that immunosurveillance may also be critical for regulating metastatic spread, the most fatal aspect of cancer, and that mechanisms of overcoming immune control may be quite different from those at the primary site. Our recent findings support loss of type I interferon (IFN) signaling as a tumor-cell intrinsic mechanism of evading metastasis-specific immune responses in breast cancer. We revealed that type I IFN-induced innate (natural killer) and adaptive (CD8(+) T cell) responses suppressed bone metastatic growth and this was associated with decreased accumulation of immune suppressor cells (myeloid-derived suppressor cells). This review summarizes recent findings that are in support of tumor-induced immunosurveillance in regulating metastatic spread, including evidence that immune regulation of primary tumors may be distinct from those dictating metastasis. PMID- 24062313 TI - Why your preferred targeted drugs may become unaffordable. AB - Trastuzumab, a monoclonal antibody directed at the HER2 receptor, is one of the most impressive targeted drugs developed in the last two decades. Indeed, when given in conjunction with chemotherapy, it improves the survival of women with HER2 positive breast cancer, both in advanced and in early disease. Its optimal duration, however, is poorly defined in both settings with a significant economic impact in the adjuvant setting where the drug is arbitrarily given for 1 year. This article reviews current attempts at shortening this treatment duration, emphasizing the likelihood of inconclusive results and, therefore, the need to investigate this important variable as part of the initial pivotal trials and with the support of public health systems. Failure to do so has major consequences on treatment affordability. Ongoing adjuvant trials of dual HER2 blockade, using trastuzumab in combination with a second anti-HER2 agent, and trials of the antibody-drug conjugate T-DM1 (trastuzumab-emtansine) have to all be designed with 12 months of targeted therapy. PMID- 24062316 TI - Unraveling the anxious mind: anxiety, worry, and frontal engagement in sustained attention versus off-task processing. AB - Much remains unknown regarding the relationship between anxiety, worry, sustained attention, and frontal function. Here, we addressed this using a sustained attention task adapted for functional magnetic resonance imaging. Participants responded to presentation of simple stimuli, withholding responses to an infrequent "No Go" stimulus. Dorsolateral prefrontal cortex (DLPFC) activity to "Go" trials, and dorsal anterior cingulate (dACC) activity to "No Go" trials were associated with faster error-free performance; consistent with DLPFC and dACC facilitating proactive and reactive control, respectively. Trait anxiety was linked to reduced recruitment of these regions, slower error-free performance, and decreased frontal-thalamo-striatal connectivity. This indicates an association between trait anxiety and impoverished frontal control of attention, even when external distractors are absent. In task blocks where commission errors were made, greater DLPFC-precuneus and DLPFC-posterior cingulate connectivity were associated with both trait anxiety and worry, indicative of increased off task thought. Notably, unlike trait anxiety, worry was not linked to reduced frontal-striatal-thalamo connectivity, impoverished frontal recruitment, or slowed responding during blocks without commission errors, contrary to accounts proposing a direct causal link between worry and impoverished attentional control. This leads us to propose a new model of the relationship between anxiety, worry and frontal engagement in attentional control versus off-task thought. PMID- 24062317 TI - Multisensory self-motion compensation during object trajectory judgments. AB - Judging object trajectory during self-motion is a fundamental ability for mobile organisms interacting with their environment. This fundamental ability requires the nervous system to compensate for the visual consequences of self-motion in order to make accurate judgments, but the mechanisms of this compensation are poorly understood. We comprehensively examined both the accuracy and precision of observers' ability to judge object trajectory in the world when self-motion was defined by vestibular, visual, or combined visual-vestibular cues. Without decision feedback, subjects demonstrated no compensation for self-motion that was defined solely by vestibular cues, partial compensation (47%) for visually defined self-motion, and significantly greater compensation (58%) during combined visual-vestibular self-motion. With decision feedback, subjects learned to accurately judge object trajectory in the world, and this generalized to novel self-motion speeds. Across conditions, greater compensation for self-motion was associated with decreased precision of object trajectory judgments, indicating that self-motion compensation comes at the cost of reduced discriminability. Our findings suggest that the brain can flexibly represent object trajectory relative to either the observer or the world, but a world-centered representation comes at the cost of decreased precision due to the inclusion of noisy self-motion signals. PMID- 24062318 TI - Coding of object location in the vibrissal thalamocortical system. AB - In whisking rodents, object location is encoded at the receptor level by a combination of motor and sensory related signals. Recoding of the encoded signals can result in various forms of internal representations. Here, we examined the coding schemes occurring at the first forebrain level that receives inputs necessary for generating such internal representations--the thalamocortical network. Single units were recorded in 8 thalamic and cortical stations in artificially whisking anesthetized rats. Neuronal representations of object location generated across these stations and expressed in response latency and magnitude were classified based on graded and binary coding schemes. Both graded and binary coding schemes occurred across the entire thalamocortical network, with a general tendency of graded-to-binary transformation from thalamus to cortex. Overall, 63% of the neurons of the thalamocortical network coded object position in their firing. Thalamocortical responses exhibited a slow dynamics during which the amount of coded information increased across 4-5 whisking cycles and then stabilized. Taken together, the results indicate that the thalamocortical network contains dynamic mechanisms that can converge over time on multiple coding schemes of object location, schemes which essentially transform temporal coding to rate coding and gradual to labeled-line coding. PMID- 24062319 TI - Impact of sex and age at onset of diabetes on mortality from ischemic heart disease in patients with type 1 diabetes. AB - OBJECTIVE To study whether ischemic heart disease (IHD) mortality among patients with type 1 diabetes (T1D) depends on the age at onset of diabetes and whether this effect is sex specific. RESEARCH DESIGN AND METHODS The study examined long term IHD-specific mortality in a Finnish population-based cohort of patients with early-onset (0-14 years) and late-onset (15-29 years) T1D (n = 17,306). RESULTS During 433,782 person-years of follow-up, 478 deaths from IHD were observed. Within the early-onset cohort, the average crude mortality rate in women was 33.3% lower than in men, whereas in the late-onset cohort, mortality was only one half that in men. In contrast, the standardized mortality ratio (SMR) was higher in women than in men (21.6 [95% CI 17.2-27.0] vs. 5.8 [5.1-6.6]). The difference in SMR between sexes was more striking in the early-onset cohort (women 52.8 [36.3-74.5], men 12.1 [9.2-15.8]). The SMR was also greater in women in the late onset cohort (15.8 [11.8-20.7]) compared with men (5.0 [4.3-5.8]). The relative risk of dying from IHD was greatest in women aged <40 years and 40-60 years in the early- and late-onset cohorts, respectively. CONCLUSIONS The risk of mortality from IHD is exceptionally high in women with early-onset T1D compared with women in the background population. These observations underscore the importance of identifying risk factors early in women and delivering more aggressive treatment after diagnosis. PMID- 24062320 TI - Obstructive sleep apnea and diabetic nephropathy: a cohort study. AB - OBJECTIVE: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Obstructive sleep apnea (OSA) is common in type 2 diabetes and increases oxidative stress. Hence, OSA could promote the development and progression of DN. RESEARCH DESIGN AND METHODS: This was a cohort study in adults with type 2 diabetes. Patients with known OSA or ESRD were excluded. DN was defined as the presence of albuminuria or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. DN progression was based on eGFR measurements. OSA was defined as apnea hypopnea index (AHI) >=5 events/h. Serum nitrotyrosine abundance (a marker of nitrosative stress) was measured by ELISA. RESULTS: A total of 224 patients were included. OSA and DN prevalence was 64.3 and 40.2, respectively. DN prevalence was higher in patients with OSA (OSA+) compared with those without OSA (OSA-) (49.3% vs. 23.8%, P < 0.001). After adjustment, OSA (odds ratio 2.64 [95% CI 1.13-6.16], P = 0.02) remained independently associated with DN. After an average follow-up of 2.5 (0.7) years, eGFR decline was greater in OSA+ compared with OSA- patients (median -6.8% [interquartile range -16.1 to 2.2] vs. -1.6% [ 7.7 to 5.3%], P = 0.002). After adjusting, both baseline OSA (B = -3.8, P = 0.044) and AHI (B = -4.6, P = 0.02) remained independent predictors of study-end eGFR. Baseline serum nitrotyrosine abundance (B = -0.24, P = 0.015) was an independent predictor of study-end eGFR after adjustment. CONCLUSIONS: OSA is independently associated with DN in type 2 diabetes. eGFR declined faster in patients with OSA. Nitrosative stress may provide a pathogenetic link between OSA and DN. Interventional studies assessing the impact of OSA treatment on DN are needed. PMID- 24062321 TI - Impact of glucose tolerance status, sex, and body size on glucose absorption patterns during OGTTs. AB - OBJECTIVE: We studied whether patterns of glucose absorption during oral glucose tolerance tests (OGTTs) were abnormal in individuals with impaired glucose regulation and whether they were related to sex and body size (height and fat free mass). We also examined how well differences in insulin sensitivity and beta cell function measured by gold-standard tests were reflected in the corresponding OGTT-derived estimates. RESEARCH DESIGN AND METHODS: With validated methods, various aspects of glucose absorption were estimated from 12-point, 3-h, 75-g OGTTs in 66 individuals with normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), or isolated impaired glucose tolerance (i-IGT). Insulin sensitivity and beta-cell function were measured with the euglycemic hyperinsulinemic clamp and intravenous glucose tolerance tests, respectively. Surrogate markers of both conditions were calculated from OGTTs. RESULTS: More rapid glucose absorption (P <= 0.036) and reduced late glucose absorption (P <= 0.039) were observed in the i-IFG group relative to NGT and i-IGT groups. Women with i-IGT had a lower early glucose absorption than did men with i-IGT (P = 0.041); however, this difference did not persist when differences in body size were taken into account (P > 0.28). Faster glucose absorption was related to higher fasting (P = 0.001) and lower 2-h (P = 0.001) glucose levels and to greater height and fat-free mass (P < 0.001). All OGTT-derived measures of insulin sensitivity, but only one of three measures of beta-cell function, reflected the differences for these parameters between those with normal and impaired glucose regulation as measured by gold-standard tests. CONCLUSIONS: Glucose absorption patterns during an OGTT are significantly related to plasma glucose levels and body size, which should be taken into account when estimating beta-cell function from OGTTs in epidemiological studies. PMID- 24062322 TI - HbA1c and lower-extremity amputation risk in low-income patients with diabetes. AB - OBJECTIVE: Diabetes confers a very high risk of lower-extremity amputation (LEA); however, few studies have assessed whether blood glucose control can reduce LEA risk among patients with diabetes, especially in practice settings where low income patients predominate. RESEARCH DESIGN AND METHODS: We performed a prospective cohort study (2000-2009) on patients with diabetes that included 19,808 African Americans and 15,560 whites. The cohort was followed though 31 May 2012. Cox proportional hazards regression models were used to estimate the association of HbA1c with LEA risk. RESULTS: During a mean follow-up of 6.83 years, 578 LEA incident cases were identified. The multivariable-adjusted hazard ratios of LEA associated with different levels of HbA1c at baseline (<6.0% [reference group], 6.0-6.9, 7.0-7.9, 8.0-8.9, 9.0-9.9, and >=10.0%) were 1.00, 1.73 (95% CI 1.07-2.80), 1.65 (0.99-2.77), 1.96 (1.14-3.36), 3.02 (1.81-5.04), and 3.30 (2.10-5.20) (P trend <0.001) for African American patients with diabetes and 1.00, 1.16 (0.66-2.02), 2.28 (1.35-3.85), 2.38 (1.36-4.18), 2.99 (1.71-5.22), and 3.25 (1.98-5.33) (P trend <0.001) for white patients with diabetes, respectively. The graded positive association of HbA1c during follow-up with LEA risk was observed among both African American and white patients with diabetes (all P trend <0.001). With stratification by sex, age, smoking status, blood pressure, LDL cholesterol, BMI, use of glucose-lowering agents, and income, this graded association of HbA1c with LEA was still present. CONCLUSIONS: The current study conducted in a low-income population suggests a graded association between HbA1c and the risk of LEA among both African American and white patients with type 2 diabetes. PMID- 24062323 TI - Co-occurrence of risk alleles in or near genes modulating insulin secretion predisposes obese youth to prediabetes. AB - OBJECTIVE: Paralleling the rise of pediatric obesity, the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) is increasing among youth. In this study, we asked whether the co-occurrence of risk alleles in or near five genes modulating insulin secretion (TCF7L2 rs7903146, IGF2BP2 rs4402960, CDKAL1 rs7754840, HHEX rs1111875, and HNF1A rs1169288) is associated with a higher risk of IGT/T2D in obese children and adolescents. RESEARCH DESIGN AND METHODS: We studied 714 obese subjects (290 boys and 424 girls; mean age 13.6 +/- 3.1 years; mean z score BMI 2.2 +/- 0.4) and evaluated the insulin secretion by using the oral minimal model and, in a subgroup of 37 subjects, the hyperglycemic clamp. Also, 203 subjects were followed up for a mean of 2.1 years. RESULTS: We observed that the increase of risk alleles was associated with a progressive worsening of insulin secretion (P < 0.001) mainly due to an impairment of the dynamic phase of insulin secretion (P = 0.004); the higher the number of the risk alleles, the higher the chance of progression from normal glucose tolerance (NGT) to IGT/T2D (P = 0.022). Also, for those who were IGT at baseline, a higher risk score was associated with a lower odds to revert to NGT (P = 0.026). CONCLUSIONS: Obese children and adolescents developing IGT/T2D have a higher genetic predisposition than those who do not show these diseases, and this predisposition is mainly related to gene variants modulating the early phase of insulin secretion. Although these data are very interesting, they need to be replicated in other cohorts. PMID- 24062324 TI - SIRS is valid in discriminating between severe and moderate diabetic foot infections. AB - OBJECTIVE: This retrospective, single-center study was designed to distinguish severe diabetic foot infection (DFI) from moderate DFI based on the presence or absence of systemic inflammatory response syndrome (SIRS). RESEARCH DESIGN AND METHODS: The database of a single academic foot and ankle program was reviewed and 119 patients were identified. Severe DFI was defined as local infection associated with manifestation of two or more objective findings of systemic toxicity using SIRS criteria. RESULTS: Patients with severe DFI experienced a 2.55-fold higher risk of any amputation (95% CI 1.21-5.36) and a 7.12-fold higher risk of major amputation (1.83-41.05) than patients with moderate DFI. The risk of minor amputations was not significantly different between the two groups (odds ratio 1.02 [95% CI 0.51-2.28]). The odds of having a severe DFI was 7.82 times higher in patients who presented with gangrene (2.03-44.81) and five times higher in patients who reported symptoms of anorexia, chills, nausea, or vomiting (2.22 11.25). The mean hospital length of stay for patients with severe DFI was ~4 days longer than for patients with moderate DFI, and this difference was statistically significant. CONCLUSIONS: SIRS is valid in distinguishing severe from moderate DFI in hospitalized patients. Patients with severe DFI, as by manifesting two or more signs of systemic inflammation or toxicity, had higher rates of major amputation and longer hospital stays and required more surgery and more subsequent admissions than patients who did not manifest SIRS. PMID- 24062325 TI - Reversal of early abnormalities in glucose metabolism in obese youth: results of an intensive lifestyle randomized controlled trial. AB - OBJECTIVE: The childhood obesity epidemic has been accompanied by an increasing prevalence of type 2 diabetes (T2D), particularly in minority children. Twenty to thirty percent of obese youth have "prediabetes," a precursor to diabetes marked by insulin resistance, beta-cell dysfunction, and impaired glucose tolerance. The Diabetes Prevention Program demonstrated that T2D could be prevented/delayed by intensive lifestyle modification in adults with prediabetes, but efficacy of similar interventions in youth has not been established. Therefore, we evaluated the effects of the Bright Bodies (BB) Healthy Lifestyle Program on 2-h oral glucose tolerance test (OGTT) glucose in comparison with adolescents receiving standard of care. RESEARCH DESIGN AND METHODS: A parallel-group randomized controlled trial comparing BB with standard clinical care (CC) in obese adolescents (10-16 years old, Tanner stage >2) with elevated OGTT 2-h blood glucose (130-199 mg/dL) from a racially/ethnically diverse population. OGTTs, including cardiovascular and anthropometric assessments, were conducted at baseline and 6 months. Children attended BB twice per week for exercise and nutrition/behavior modification, and the CC group received CC from their pediatrician. Primary outcome was change in 2-h OGTT glucose and percentage conversion from elevated 2-h blood glucose to nonelevated (<130 mg/dL) 2-h blood glucose. Changes in outcomes were compared between groups using an ANCOVA, with adjustment for baseline outcome and multiple imputation for missing data. RESULTS: Reductions in 2-h glucose were more favorable in BB compared with CC ( 27.2 vs. -10.1 mg/dL; difference = -17.1, 95% CI; P = 0.005). Moreover, greater conversion to <130 mg/dL 2-h glucose occurred in BB than CC (P = 0.003), and other insulin sensitivity indices were significantly improved. CONCLUSIONS: Compared with standard of care, the Yale BB Program is a more effective means of reducing the risk of T2D in obese adolescents with elevated 2-h glucose levels. PMID- 24062326 TI - Prandial insulin dosing using the carbohydrate counting technique in hospitalized patients with type 2 diabetes. AB - OBJECTIVE: To compare a modified fixed meal dosing strategy to flexible meal dosing in hospitalized patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients (N = 126) with refractory hyperglycemia or requiring at least 20 units of insulin per day were randomly assigned to fixed meal dosing (including withholding the dose if less than half of the meal tray was consumed) or flexible meal dosing based upon carbohydrate intake. The inpatient diabetes management team made all treatment adjustments. Outcomes included day 3 mean glucose, 72-h glucose trend analysis, hypoglycemia (<3.9 mmol/L), and inpatient diabetes treatment satisfaction. RESULTS: The mean glucose on day 3 was 9.5 and 8.8 mmol/L in the fixed and flexible meal groups, respectively (P = 0.26). The frequency of hypoglycemia was 23 and 39% overall in the fixed and flexible meal groups (P = 0.08), with half of events occurring in the morning. There was a wide range of carbohydrate intake (median 51 g/meal, 10-90% range 26-72 g on day 3). The fixed dose group required significantly more prandial insulin overall and more correction insulin over time. There was no difference in composite treatment satisfaction or dosing miscalculations between groups. CONCLUSIONS: A fixed meal dosing strategy provided similar glucose control as flexible meal dosing, when managed by an inpatient diabetes treatment team. However, a larger sample size would be needed to definitively evaluate a treatment effect of flexible meal dosing in the hospital. Further study is needed to improve the delivery of bolus insulin in hospitalized patients. PMID- 24062327 TI - Effects of adding linagliptin to basal insulin regimen for inadequately controlled type 2 diabetes: a >=52-week randomized, double-blind study. AB - OBJECTIVE: To evaluate the efficacy and long-term safety of linagliptin added to basal insulins in type 2 diabetes inadequately controlled on basal insulin with or without oral agents. RESEARCH DESIGN AND METHODS: A total of 1,261 patients (HbA1c >=7.0% [53 mmol/mol] to <=10.0% [86 mmol/mol]) on basal insulin alone or combined with metformin and/or pioglitazone were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo for >=52 weeks. The basal insulin dose was kept unchanged for 24 weeks but could thereafter be titrated according to fasting plasma glucose levels at the investigators' discretion. The primary end point was the mean change in HbA1c from baseline to week 24. The safety analysis incorporated data up to a maximum of 110 weeks. RESULTS: At week 24, HbA1c changed from a baseline of 8.3% (67 mmol/mol) by -0.6% (-6.6 mmol/mol) and by 0.1% (1.1 mmol/mol) with linagliptin and placebo, respectively (treatment difference -0.65% [95% CI -0.74 to -0.55] [-7.1 mmol/mol]; P < 0.0001). Despite the option to uptitrate basal insulin, it was adjusted only slightly upward (week 52, linagliptin 2.6 IU/day, placebo 4.2 IU/day; P < 0.003), resulting in no further HbA1c improvements. Frequencies of hypoglycemia (week 24, linagliptin 22.0%, placebo 23.2%; treatment end, linagliptin 31.4%, placebo 32.9%) and adverse events (linagliptin 78.4%, placebo 81.4%) were similar between groups. Mean body weight remained unchanged (week 52, linagliptin -0.30 kg, placebo -0.04 kg). CONCLUSIONS: Linagliptin added to basal insulin therapy significantly improved glycemic control relative to placebo without increasing hypoglycemia or body weight. PMID- 24062328 TI - Intima-media thickness in severe obesity: links with BMI and metabolic status but not with systemic or adipose tissue inflammation. AB - OBJECTIVE: Obesity is associated with cardiovascular risk and a low-grade inflammatory state in both blood and adipose tissue (AT). Whether inflammation contributes to vascular alteration remains an open question. To test this hypothesis, we measured arterial intima-media thickness (IMT), which reflects subclinical atherosclerosis, in severely obese subjects and explored associations with systemic inflammation and AT inflammation. RESEARCH DESIGN AND METHODS: IMT of the carotid artery (C-IMT) and IMT of the femoral artery (F-IMT) were measured in 132 nonobese (control) subjects (BMI 22.3 kg/m2; mean age 44.8 years) and 232 subjects who were severely obese without diabetes (OB/ND; n = 146; BMI 48.3 kg/m2; age 38.2 years) or severely obese with type 2 diabetes (OB/D; n = 86; BMI 47.0; age 49.4 years). In 57 OB/ND subjects, circulating soluble E-selectin, matrix metalloproteinase 9, myeloperoxidase, soluble intracellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, tissue plasminogen activator inhibitor 1, cystatin C, cathepsin S, and soluble CD14 were measured in serum. AT macrophages were quantified by CD68 immunochemistry. RESULTS: Both C IMT and F-IMT increased in OB/ND and OB/D patients. In OB/ND patients, age was the sole independent determinant of IMT. No significant association was found with circulating inflammation-related molecules, number of CD68+ cells, or the presence of crown-like structures in visceral or subcutaneous AT of OB/ND patients. CONCLUSIONS: IMT increased with severe obesity but was not influenced by the degree of systemic inflammation or AT macrophage accumulation. PMID- 24062329 TI - Expression of mesenchymal and alpha-cell phenotypic markers in islet beta-cells in recently diagnosed diabetes. AB - OBJECTIVE: Relative contributions of reversible beta-cell dysfunction and true decrease in beta-cell mass in type 2 diabetes remain unclear. Definitive rodent lineage-tracing studies have identified beta-cell dedifferentiation and subsequent reprogramming to alpha-cell fate as a novel mechanism underlying beta cell failure. The aim was to determine whether phenotypes of beta-cell dedifferentiation and plasticity are present in human diabetes. RESEARCH DESIGN AND METHODS: Immunofluorescence colocalization studies using classical endocrine and mesenchymal phenotypic markers were undertaken using pancreatic sections and isolated islets from three individuals with diabetes and five nondiabetic control subjects. RESULTS: Intraislet cytoplasmic coexpression of insulin and vimentin, insulin and glucagon, and vimentin and glucagon were demonstrated in all cases. These phenotypes were not present in nondiabetic control subjects. CONCLUSIONS: Coexpression of mesenchymal and alpha-cell phenotypic markers in human diabetic islet beta-cells has been confirmed, providing circumstantial evidence for beta cell dedifferentiation and possible reprogramming to alpha-cells in clinical diabetes. PMID- 24062331 TI - Effect of a cooked meat meal on serum creatinine and estimated glomerular filtration rate in diabetes-related kidney disease. AB - OBJECTIVE: Fasting is not routinely recommended for renal function tests, despite the known effects of cooked meat on creatinine. We therefore studied variation in creatinine and estimated glomerular filtration rate (eGFR) after a standardized cooked meat meal in 80 subjects: healthy volunteers and diabetic patients with chronic kidney disease (CKD) stages 1 and 2, 3a, 3b, and 4 (n = 16/group). RESEARCH DESIGN AND METHODS: The interventions were a standardized cooked meat and a nonmeat meal, each providing ~54 g protein, together with 250 mL water, on separate days. Fasting and postprandial blood samples at 1, 2, and 4 h were drawn for creatinine measurement using a kinetic alkaline picrate assay on an Olympus AU640 analyzer. The modified four-variable Modification of Diet in Renal Disease equation traceable to isotope dilution mass spectrometry creatinine was used to calculate eGFR. RESULTS: Consumption of a standardized cooked meat meal significantly increased serum creatinine and resulted in significant fall in eGFR in all stages of CKD studied; 6 of 16 CKD 3a patients were misclassified as CKD 3b. This effect of cooked meat on serum creatinine disappears after 12 h of fasting in all study participants. CONCLUSIONS: Creatine in meat is converted to creatinine on cooking, which is absorbed, causing significant increases in serum creatinine. This could impact management, as threshold for commencing and withdrawing certain medications and expensive investigations is defined by eGFR. eGFR calculated using fasting serum creatinine would be a better reflection of kidney function in these patients. PMID- 24062332 TI - Blood viscosity in subjects with normoglycemia and prediabetes. AB - OBJECTIVE: Blood viscosity (BV) is higher in diabetic patients and might represent a risk factor for the development of insulin resistance and type 2 diabetes. However, data in subjects with normal glucose or prediabetes are missing. In the current study, we evaluated the relationship between BV and blood glucose in subjects with normal glucose or prediabetes. RESEARCH DESIGN AND METHODS: Enrolled subjects were divided into three groups according to blood glucose: group A (n = 74), blood glucose <90 mg/dL; group B (n = 96), blood glucose ranging from 90 to 99 mg/dL; and group C (n = 94), blood glucose ranging from 100 to 125 mg/dL. BV was measured at 37 degrees C with a cone-plate viscometer at shear rates ranging from 225 to 22.5 s(-1). RESULTS: Blood pressure, blood lipids, fibrinogen, and plasma viscosity were similar in the three groups. BMI and waist circumference were significantly increased in group C. Hematocrit (P < 0.05) and BV (P between 0.01 and 0.001) were significantly higher in groups B and C compared with group A. Blood glucose was significantly and inversely correlated with HDL cholesterol and directly with BMI, waist, hematocrit (r = 0.134), and BV (from 225 s(-1) to 22.5 s(-1); r ranging from 0.162 to 0.131). BV at shear rate 225 s(-1) was independently associated with blood glucose. CONCLUSIONS: The current study shows a direct relationship between BV and blood glucose in nondiabetic subjects. It also suggests that, even within glucose values considered completely normal, individuals with higher blood glucose levels have increased BV comparable with that observed in subjects with prediabetes. PMID- 24062330 TI - Prediction of diabetes based on baseline metabolic characteristics in individuals at high risk. AB - OBJECTIVE: Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance. RESEARCH DESIGN AND METHODS: We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years. RESULTS: In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, G0-120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln I0-120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [I0-120/G0-120]) during the OGTT was associated with decreased risk of diabetes. Higher beta-cell function (insulin secretion/insulin resistance or disposition index; ln [I0-120/G0-120 * Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes. CONCLUSIONS: In a stepwise multiple-variable analysis, only HbA1c and beta-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001). PMID- 24062333 TI - Fitness, fatness, and survival in adults with prediabetes. AB - OBJECTIVE: The purpose of this study was to examine independent and joint associations of cardiorespiratory fitness (CRF) and different adiposity measures with mortality risk in individuals with prediabetes (or impaired fasting glucose). RESEARCH DESIGN AND METHODS: We examined associations of CRF and fatness with cardiovascular disease (CVD) and all-cause mortality in a cohort of 17,044 participants (89% men) with prediabetes (defined as 100 mg/dL <= fasting plasma glucose < 126 mg/dL), who did not have a history of diabetes, CVD, or cancer. RESULTS: We identified 832 deaths (246 from CVD) during 13.9 +/- 7.0 years (mean +/- SD) follow-up. Normal-weight individuals who were unfit (lowest one-third) had a higher risk of all-cause (hazard ratio 1.70 [95% CI 1.32-2.18]) and CVD (1.88 [1.13-3.10]) mortality compared with the normal-weight and fit (upper two-thirds) reference group in a model adjusted for age, sex, examination year, and multiple risk factors. The mortality risk for fit individuals who were overweight or obese did not differ significantly from the reference group. Similar patterns were observed for sex-specific thirds of waist circumference and % body fat. CONCLUSIONS: CRF markedly modifies the relationship between adiposity and mortality in persons with prediabetes. Unfit individuals have a higher and fit individuals have a lower mortality risk irrespective of adiposity level in this high-risk group. PMID- 24062334 TI - Quarterly visits with glycated hemoglobin monitoring: the sweet spot for glycemic control in youth with type 1 diabetes. AB - OBJECTIVE: To evaluate the association between the frequency of visits and glycated hemoglobin (GHb) measurements on glycemic control in youth with type 1 diabetes. RESEARCH DESIGN AND METHODS: A retrospective longitudinal cohort study of 1,449 youth with type 1 diabetes (mean age 11.4 years, 50% female, 74% Caucasian, 24% with Medicaid) followed at five pediatric endocrinology clinics from the years 2008-2011 was conducted. By hierarchical cluster analysis, three homogeneous groups of patients were generated: those with a relative increase in GHb (worsened [n = 237]), no change in GHb (stable [n = 842]), and a decrease in GHb (improved [n = 370]) over the study period. The number of visits and GHb measurements per year were compared among the three groups by multinomial logistic regression analysis using one visit or GHb test per year as a reference and controlling for patient demographic and baseline characteristics. RESULTS: Patients with quarterly visits were least likely to have worsened glycemic control (odds ratio 0.33, P < 0.05) and were most likely to have improved glycemic control (3.48, P < 0.01). Patients with four GHb tests a year (0.53, P < 0.05) were least likely to have worsened glycemic control. CONCLUSIONS: Quarterly visits and GHb testing are associated with glycemic control in youth with type 1 diabetes. PMID- 24062335 TI - Cyclophilin D modulates mitochondrial acetylome. AB - RATIONALE: Mice lacking cyclophilin D (CypD(-/-)), a mitochondrial chaperone protein, have altered cardiac metabolism. As acetylation has been shown to regulate metabolism, we tested whether changes in protein acetylation might play a role in these metabolic changes in CypD(-/-) hearts. OBJECTIVE: Our aim was to test the hypothesis that loss of CypD alters the cardiac mitochondrial acetylome. METHODS AND RESULTS: To identify changes in lysine-acetylated proteins and to map acetylation sites after ablation of CypD, we subjected tryptic digests of isolated cardiac mitochondria from wild-type and CypD(-/-) mice to immunoprecipitation using agarose beads coupled to antiacetyl lysine antibodies followed by mass spectrometry. We used label-free analysis for the relative quantification of the 875 common peptides that were acetylated in wild-type and CypD(-/-) samples and found 11 peptides (10 proteins) decreased and 96 peptides (48 proteins) increased in CypD(-/-) samples. We found increased acetylation of proteins in fatty acid oxidation and branched-chain amino acid metabolism. To evaluate whether this increase in acetylation might play a role in the inhibition of fatty acid oxidation that was previously reported in CypD(-/-) hearts, we measured the activity of l-3-hydroxyacyl-CoA dehydrogenase, which was acetylated in the CypD(-/-) hearts. Consistent with the hypothesis, l-3-hydroxyacyl-CoA dehydrogenase activity was inhibited by ~50% compared with the wild-type mitochondria. CONCLUSIONS: These results implicate a role for CypD in modulating protein acetylation. Taken together, these results suggest that ablation of CypD leads to changes in the mitochondrial acetylome, which may contribute to altered mitochondrial metabolism in CypD(-/-) mice. PMID- 24062336 TI - Jekyll and Hyde of HDL: a lipoprotein with a split personality. PMID- 24062337 TI - Cyclin B1 mRNA translation is temporally controlled through formation and disassembly of RNA granules. AB - Temporal control of messenger RNA (mRNA) translation is an important mechanism for regulating cellular, neuronal, and developmental processes. However, mechanisms that coordinate timing of translational activation remain largely unresolved. Full-grown oocytes arrest meiosis at prophase I and deposit dormant mRNAs. Of these, translational control of cyclin B1 mRNA in response to maturation-inducing hormone is important for normal progression of oocyte maturation, through which oocytes acquire fertility. In this study, we found that dormant cyclin B1 mRNA forms granules in the cytoplasm of zebrafish and mouse oocytes. Real-time imaging of translation revealed that the granules disassemble at the time of translational activation during maturation. Formation of cyclin B1 RNA granules requires binding of the mRNA to Pumilio1 protein and depends on actin filaments. Disruption of cyclin B1 RNA granules accelerated the timing of their translational activation after induction of maturation, whereas stabilization hindered translational activation. Thus, our results suggest that RNA granule formation is critical for the regulation of timing of translational activation. PMID- 24062338 TI - Stochastic association of neighboring replicons creates replication factories in budding yeast. AB - Inside the nucleus, DNA replication is organized at discrete sites called replication factories, consisting of DNA polymerases and other replication proteins. Replication factories play important roles in coordinating replication and in responding to replication stress. However, it remains unknown how replicons are organized for processing at each replication factory. Here we address this question using budding yeast. We analyze how individual replicons dynamically organized a replication factory using live-cell imaging and investigate how replication factories were structured using super-resolution microscopy. Surprisingly, we show that the grouping of replicons within factories is highly variable from cell to cell. Once associated, however, replicons stay together relatively stably to maintain replication factories. We derive a coherent genome-wide mathematical model showing how neighboring replicons became associated stochastically to form replication factories, which was validated by independent microscopy-based analyses. This study not only reveals the fundamental principles promoting replication factory organization in budding yeast, but also provides insight into general mechanisms by which chromosomes organize sub-nuclear structures. PMID- 24062339 TI - The formin FHOD1 and the small GTPase Rac1 promote vaccinia virus actin-based motility. AB - Vaccinia virus dissemination relies on the N-WASP-ARP2/3 pathway, which mediates actin tail formation underneath cell-associated extracellular viruses (CEVs). Here, we uncover a previously unappreciated role for the formin FHOD1 and the small GTPase Rac1 in vaccinia actin tail formation. FHOD1 depletion decreased the number of CEVs forming actin tails and impaired the elongation rate of the formed actin tails. Recruitment of FHOD1 to actin tails relied on its GTPase binding domain in addition to its FH2 domain. In agreement with previous studies showing that FHOD1 is activated by the small GTPase Rac1, Rac1 was enriched and activated at the membrane surrounding actin tails. Rac1 depletion or expression of dominant negative Rac1 phenocopied the effects of FHOD1 depletion and impaired the recruitment of FHOD1 to actin tails. FHOD1 overexpression rescued the actin tail formation defects observed in cells overexpressing dominant-negative Rac1. Altogether, our results indicate that, to display robust actin-based motility, vaccinia virus integrates the activity of the N-WASP-ARP2/3 and Rac1-FHOD1 pathways. PMID- 24062340 TI - Independence of symmetry breaking on Bem1-mediated autocatalytic activation of Cdc42. AB - The ability to break symmetry and polarize through self-organization is a fundamental feature of cellular systems. A prevailing theory in yeast posits that symmetry breaking occurs via a positive feedback loop, wherein the adaptor protein Bem1 promotes local activation and accumulation of Cdc42 by directly tethering Cdc42(GTP) with its guanine nucleotide exchange factor (GEF) Cdc24. In this paper, we find that neither Bem1 nor the ability of Bem1 to bind Cdc42(GTP) is required for cell polarization. Instead, Bem1 functions primarily by boosting GEF activity, a role critical for polarization without actin filaments. In the absence of actin-based transport, polarization of Cdc42 is accomplished through Rdi1, the Cdc42 guanine nucleotide dissociation inhibitor. A mathematical model is constructed describing cell polarization as a product of distinct pathways controlling Cdc42 activation and protein localization. The model predicts a nonmonotonic dependence of cell polarization on the concentration of Rdi1 relative to that of Cdc42. PMID- 24062342 TI - Lemierre syndrome: more than "the forgotten disease". AB - A 54-year-old woman presented with fever, spasmodic torticollis, ptosis, and chemosis in her left eye. CT venous angiography revealed cavernous sinus thrombosis (CST) and left internal jugular vein thrombosis (IJVT) (figure, A), cervical MRI detected a retropharyngeal abscess and epidural empyema (figure, B and C), and chest X-ray showed multiple pulmonary opacities (figure, D). The clinical/radiologic picture, due to anaerobic septicemia, was consistent with Lemierre syndrome (LS), the so-called "forgotten disease."(1) Extensive neuroimaging studies are mandatory to detect an abscess in the neck of patients with CST and IJVT for early diagnosis and treatment. LS is still relevant today. PMID- 24062341 TI - A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton. AB - Chromosome pairing is an essential meiotic event that ensures faithful haploidization and recombination of the genome. Pairing of homologous chromosomes is facilitated by telomere-led chromosome movements and formation of a meiotic bouquet, where telomeres cluster to one pole of the nucleus. In metazoans, telomere clustering is dynein and microtubule dependent and requires Sun1, an inner nuclear membrane protein. Here we provide a functional analysis of KASH5, a mammalian dynein-binding protein of the outer nuclear membrane that forms a meiotic complex with Sun1. This protein is related to zebrafish futile cycle (Fue), a nuclear envelope (NE) constituent required for pronuclear migration. Mice deficient in this Fue homologue are infertile. Males display meiotic arrest in which pairing of homologous chromosomes fails. These findings demonstrate that telomere attachment to the NE is insufficient to promote pairing and that telomere attachment sites must be coupled to cytoplasmic dynein and the microtubule system to ensure meiotic progression. PMID- 24062343 TI - Hemichorea-hemiballism associated with hyperglycemia and a developmental venous anomaly. PMID- 24062344 TI - Decreased iron levels in the temporal cortex in postmortem human brains with Parkinson disease. AB - Yu et al.(1) reported that iron levels in the temporal cortex were reduced in patients with Parkinson disease (PD) compared with age-matched controls. They also determined that patients with Alzheimer disease (AD) had no change in iron levels in the temporal cortex. We would like to know whether Yu et al.(1) included any patients with memory disturbance in this study. PMID- 24062345 TI - Teaching video neuroimages: reading epilepsy: a seizure in a thousand words (or less). AB - A 14-year-old right-handed boy developed spells of lip twitching only while reading. With prolonged reading, he occasionally experienced loss of awareness and limb jerking (figure and video on the Neurology(r) Web site at www.neurology.org). Reading epilepsy is a rare form of reflex seizure in which reading (silently or aloud) may trigger orofacial myoclonus, stammering, aphasia, or generalized convulsions. Onset is typically in early adulthood, with 2:1 male predominance. It occurs in isolation or autosomal dominant fashion.(1) Previous reports suggest efficacy of clonazepam, valproate, or levetiracetam.(2) Our patient did not tolerate levetiracetam but remains seizure-free on oxcarbazepine. Reading epilepsy should be recognized and promptly treated to avoid unnecessary academic struggles. PMID- 24062346 TI - Teaching Neuroimages: a pediatric patient with headache and neck stiffness. AB - A 14-year-old right-handed boy presented with sudden onset of severe headache and neck stiffness. Physical examination showed arm asymmetry with smaller size and muscle bulk (present since childhood) and increased deep tendon reflexes on the right, but normal strength. Brain CT and lumbar puncture ruled out subarachnoid hemorrhage or infection. MRI and angiography (figure) identified an unruptured type III spinal arteriovenous malformation at the C3-C4 level, supplied by the right vertebral artery.(1) Subtle physical examination findings can indicate underlying pathology and should not be overlooked in the proper context. Vascular studies should be considered for severe headache with negative initial workup.(2.) PMID- 24062347 TI - Stroke, tPA, and physician decision-making. PMID- 24062348 TI - Mystery case: Cowden syndrome presenting with partial epilepsy related to focal cortical dysplasia. AB - A 55-year-old man presented with seizures characterized by "tightening" of the right side and variable loss of awareness. EEG showed focal epileptogenic abnormalities over left and midline central regions. MRI showed left frontal focal cortical dysplasia (figure 1). He had multiple skin lesions (figure 2) and colonoscopy revealed gastrointestinal mucosal ganglioneuromas. Genetic testing of PTEN gene confirmed a diagnosis of Cowden syndrome (CS). PMID- 24062349 TI - Re: Double arterial perfusion strategy for extensive thoracic aortic surgery to avoid lower body hypothermic circulatory arrest. PMID- 24062350 TI - Pleural ultrasound as an adjunct to physical examination in the preoperative evaluation of lung cancer patients. AB - OBJECTIVES: Preoperative evaluation of patients with suspected or confirmed lung cancer consists of clinical and radiological staging. Malignant pleural effusion is a poor prognosticator in non-small-cell lung cancer. Pleural ultrasound (PU) allows for the assessment of pleural effusion, providing real-time guidance for its aspiration and cytological analysis. Pleural Ultrasonography in Lung Cancer (PULC) as an adjunct to physical examination has the potential to improve preoperative staging of non-small-cell lung cancer during first surgical encounter by allowing the evaluation of previously unassessed pleural effusion. METHODS: This study consisted of a prospective trial of surgeon-performed PU in the preoperative evaluation of lung cancer patients. All patients evaluated in the thoracic surgery clinic with the new or presumed diagnosis of lung cancer were eligible. A portable ultrasound machine was used to evaluate pleural fluid in the bilateral costophrenic sulci with pleural fluid aspiration for cytological analysis. RESULTS: Forty-five patients were prospectively enrolled over a 3-month period. Thirteen patients had ultrasound evidence of a pleural effusion, of which 3 were significant enough for aspiration. Cytological analysis of these effusions yielded malignant cells in 1 patient. Positive PULC evaluation led to a change in clinical staging (M0 to M1a) in 10 patients and a change in pathological staging (pleural fluid cytology positive) in 1 patient. The time required for PULC examination was 15 +/- 7 min. There were no complications related to the procedures. CONCLUSIONS: Preoperative pleural ultrasonography is a rapid and effective way to improve precision of staging in patients with lung cancer. More precise staging may allow for more appropriate testing, patient prognostication and operative planning. PMID- 24062351 TI - National perioperative outcomes of pulmonary lobectomy for cancer: the influence of nutritional status. AB - OBJECTIVES: Nutritional assessment is not included yet as a major recommendation in lung cancer guidelines. The purpose of this study was thus to assess the influence on surgical outcome of the nutritional status of patients with primary lung cancer undergoing lobectomy. METHODS: We queried Epithor, the national clinical database of the French Society of Thoracic and Cardiovascular Surgery, and identified a retrospective cohort of 19 635 patients having undergone lobectomy for a primary lung cancer in the years 2005-11. Their nutritional status was categorized according to the WHO definition: underweight (BMI < 18.5): 857 patients (4.4%), normal (18.5 <= BMI < 25): 9391 patients (47.8%), overweight (25 <= BMI < 30): 6721 patients (34.2%), obese (BMI >= 30): 2666 patients (13.6%). Operative mortality, pulmonary, cardiovascular, infectious and surgical complications rates were collected and analysed for these various BMI groups. RESULTS: In the normal-weight category, operative mortality, pulmonary, surgical, cardiovascular and infectious complications rates were 2.7, 14.6, 13.8, 5.5 and 4.1%, respectively. When compared with that of normal BMI patients, adjusted operative mortality was significantly lower in overweight (2.3%; odd ratio (OR): 0.72 [95% confidence interval (CI): 0.59-0.89]; P = 0.002) and obese patients (1.9%, OR: 0.54 [95% CI: 0.40-0.74]; P < 0.001), and significantly higher in underweight patients (4.1%, OR: 1.89 [95% CI: 1.30-2.75]; P = 0.001). Underweight patients experienced significantly more pulmonary (21.1%; P < 0.001), surgical (23.2%; P < 0.001) and infectious (5.1%; P = 0.05) complications (P < 0.0001). Among surgical complications, prolonged air leaks (17.6%; P < 0.001) and bronchial stump dehiscence (1.5%; P = 0.001) were significantly more frequent in underweight patients than in normal BMI patients. Obesity was not associated with increased incidence of postoperative complications, except for arrhythmia (5.6%; P < 0.05), deep venous thrombosis and pulmonary embolism (1.5%; P = 0.005). Moreover, a statistical protective effect of obesity was observed regarding surgical complications (7.1%; P < 0.001). CONCLUSIONS: Despite having an increased risk of some postoperative cardiovascular complications, obese patients should undergo surgical standard of care therapy for appropriately stage-specific lung cancer. In underweight patients, in addition to preoperative rehabilitation including a nutritional program, attention should be given to aggressive prophylactic respiratory therapy in the perioperative period, and specific intraoperative actions to prevent prolonged air leaks and bronchial stump dehiscence. PMID- 24062352 TI - Development of novel, 384-well high-throughput assay panels for human drug transporters: drug interaction and safety assessment in support of discovery research. AB - Transporter proteins are known to play a critical role in affecting the overall absorption, distribution, metabolism, and excretion characteristics of drug candidates. In addition to efflux transporters (P-gp, BCRP, MRP2, etc.) that limit absorption, there has been a renewed interest in influx transporters at the renal (OATs, OCTs) and hepatic (OATPs, BSEP, NTCP, etc.) organ level that can cause significant clinical drug-drug interactions (DDIs). Several of these transporters are also critical for hepatobiliary disposition of bilirubin and bile acid/salts, and their inhibition is directly implicated in hepatic toxicities. Regulatory agencies took action to address transporter-mediated DDI with the goal of ensuring drug safety in the clinic and on the market. To meet regulatory requirements, advanced bioassay technology and automation solutions were implemented for high-throughput transporter screening to provide structure activity relationship within lead optimization. To enhance capacity, several functional assay formats were miniaturized to 384-well throughput including novel fluorescence-based uptake and efflux inhibition assays using high-content image analysis as well as cell-based radioactive uptake and vesicle-based efflux inhibition assays. This high-throughput capability enabled a paradigm shift from studying transporter-related issues in the development space to identifying and dialing out these concerns early on in discovery for enhanced mechanism-based efficacy while circumventing DDIs and transporter toxicities. PMID- 24062355 TI - Chemical pathology at the Royal College of Pathologists: heading for extinction? PMID- 24062354 TI - Irisin mRNA and circulating levels in relation to other myokines in healthy and morbidly obese humans. AB - OBJECTIVE: Skeletal muscle is considered to be an endocrine organ that secretes a number of myokines including follistatin (FST), myostatin (MSTN), activin A, and the newly identified irisin. Irisin's biology and function exhibit similarities with the functions of the FST-MSTN-activin A axis. It remains unknown whether there is any interplay among these molecules. The aim of this study is to examine potential associations of irisin with the FST, MSTN, and activin A axis. METHODS: Two observational studies were performed to evaluate the associations of irisin with the other three peptides. Study A included 150 healthy males aged 18.48+/ 0.16 years with BMI 23.18+/-3.75 kg/m(2). Fasting serum samples were used to measure the levels of the molecules of interest. Study B included 14 morbidly obese individuals, candidates for bariatric surgery, aged 53.14+/-8.93 years with BMI 50.18+/-10.63 kg/m(2). Blood samples were obtained after an overnight fast. Eight out of the 14 participants consented to an optional thigh biopsy during their bariatric surgery. Using the above blood and tissue samples, we measured circulating levels and muscle mRNA of irisin, FST, MSTN, and activin A. RESULTS: We report that FNDC5 mRNA in muscle is positively correlated with FST mRNA expression in morbidly obese subjects (rho=0.93, P<0.001). We also found that circulating irisin is positively correlated with FST circulating levels among lean subjects (rho=0.17, P=0.05) while this association was suggestive among the obese (rho=0.56, P=0.07). CONCLUSION: The newly identified myokine irisin may be positively associated with FST at both the mRNA and circulating protein level. PMID- 24062356 TI - S100A4 expression is a prognostic indicator in small intestine adenocarcinoma. AB - AIMS: Due to the rarity of small intestine adenocarcinoma (SIAC), estimating the prognosis for patients with surgically resected SIAC is difficult. Overexpression of S100A4 has been linked to worse patient survival in several malignant neoplasms, but its significance in SIAC has not been determined. METHODS: S100A4 protein expression was assessed in 197 surgically resected SIAC cases and compared with clinicopathological factors, including patient survival. RESULTS: A progressive increase in S100A4 labelling was observed in normal intestinal epithelium, adenoma and adenocarcinoma (p<0.001), and 50 SIAC cases (26.2%) showed strong S100A4 expression. Patients with SIAC with strong S100A4 expression had a higher pT classification (p=0.05), as well as increased lymph node metastasis (p=0.009) and perineural invasion (p=0.002). Patients with SIAC with strong S100A4 expression had significantly worse survival (median survival, 21 months) than those with weak/no S100A4 expression (42.5 months) by univariable (p=0.04) and multivariable (p=0.01) analyses. CONCLUSIONS: S100A4 overexpression is observed in a subset of SIACs, is associated with advanced disease and can be used as a prognostic indicator of poor prognosis in patients with SIAC. PMID- 24062357 TI - Broad fibrovascular cores may not be an exclusively benign feature in papillary lesions of the breast: a cautionary note. AB - AIMS: A prominent fibrovascular stromal core is one of the widely accepted histological features of breast papillomas, but some papillary carcinomas also show such broad fibrovascular cores, leading to confusion in diagnosis, particularly in needle biopsy specimens. We investigated the histological characteristics of papillary lesions, focusing on broad fibrovascular cores and their relationship with the architectural patterns. METHODS: Among 185 cases of needle biopsies of papillomas and papillary carcinomas, the number of cases with broad fibrovascular cores in each group was compared. The broad fibrovascular core density in the subsequently resected specimens was evaluated and compared between papillary predominant pattern (papillary structures >80% of tumours) and mixed pattern (papillary, solid, cribriform and others) within the lesions. RESULTS: Significantly more papillary carcinomas than papillomas and B3 atypical papillary lesions had broad fibrovascular cores (p=0.0091 and p=0.0164, respectively). The papillary predominant pattern was more prominent in carcinomas than in papillomas in the needle biopsies (p=0.048) and showed the same tendency in the resections (p=0.058). The broad fibrovascular core density was significantly lower in the 18 papillomas than in the 37 papillary carcinomas (p=0.0079) and was not significantly different between the papillary predominant and mixed patterns in carcinomas and papillomas. CONCLUSIONS: Broad fibrovascular cores in mammary papillary lesions are not specific for papillomas, as they are also present focally in papillary carcinomas. As the frequency of papillary carcinoma with broad fibrovascular cores is relatively high, caution in diagnosis has to be exercised, especially in needle biopsy specimens. PMID- 24062358 TI - CD133 expression in colorectal adenomas. PMID- 24062359 TI - Mind the gap: are NHS trusts falling short of recommended standards for consent to autopsy? AB - The decline of the hospital autopsy is a well-known phenomenon that shows no sign of ending. Debate continues for the reasons behind this, but inadequate consent practices are thought to play a role. The furore resulting from organ retention scandals at Bristol Royal Infirmary and The Royal Liverpool Children's Hospital led to widespread soul searching in the medical profession, and a fundamental change in how we treat the dead body. In response, the 2004 Human Tissue Act was created, and consent is now centrally placed to permit all activities dealing with the cadaver, including autopsy. This article reflects on consent practices for hospital autopsy in England and Wales. Relevant policies from 26 National Health Service trusts were examined against the recommended standards set by the Human Tissue Authority. We found numerous failures of multiple trusts to follow these standards. Several trust policies failed to outline basic information to guide staff in conducting the consent process, such as the training requirements of the consent taker, and the desired approach to take consent. Many trusts failed to outline vital recommendations of the Human tissue Authority, such as the requirement of the consent taker to be experienced, trained in dealing with the bereaved and well informed on autopsy practice, as well as the requirement to have witnessed an autopsy. We recommend trusts reassess their practices in order meet the established standards with an emphasis on educating staff and developing a team-based approach to consent taking. PMID- 24062360 TI - HER2 testing for breast carcinoma: recommendations for rapid diagnostic pathways in clinical practice. AB - Human epidermal growth factor receptor 2 (HER2) testing is required for newly diagnosed breast cancer and advised for recurrent and metastatic breast cancer, to determine treatment planning using HER2-directed therapy in the neoadjuvant, adjuvant and advanced disease settings. Wide variation, nationally, in the turnaround time for HER2 testing may hinder equity of access for patients to both clinical trials and the timely implementation of HER2-directed therapy particularly in the neo-adjuvant setting. Process mapping from three recognised laboratories in the UK was applied to the logistics of HER2 testing in different geographic hub and spoke models. Consequently, recommendations for HER2 testing likely to facilitate access to clinical trials and timely patient care are presented. PMID- 24062361 TI - Epithelial-mesenchymal transition phenotypes are associated with patient survival in intrahepatic cholangiocarcinoma. AB - BACKGROUND: The aim of this study was to evaluate the epithelial-mesenchymal transition (EMT) and to assess its prognostic significance in intrahepatic cholangiocarcinoma. METHODS: We performed immunohistochemical stainings for E cadherin, beta-catenin, vimentin and fibronectin in a total of 85 cases. RESULTS: Expression of vimentin and reduced expression of E-cadherin were found to show correlation with poor differentiation (p=0.017, p=0.010). Reduced expression of beta-catenin showed significant association with poor differentiation (p=0.023), tumour size (p=0.028) and lymph node metastasis (p=0.011). According to the expression pattern of E-cadherin, beta-catenin, vimentin and fibronectin we categorised four phenotypes: complete type, hybrid type, null type and wild type. The complete type of beta-catenin with vimentin or fibronectin was found to show an association with lymph node metastasis (p=0.048, p=0.012). Significantly worse overall survival (OS) and disease-free survival (DFS) was observed for the complete type, and the best OS and DFS were observed for the wild type. CONCLUSIONS: EMT phenotypes can be useful markers for prediction of patient outcomes. PMID- 24062362 TI - An open-source data storage and visualization back end for experimental data. AB - In this article, a flexible free and open-source software system for data logging and presentation will be described. The system is highly modular and adaptable and can be used in any laboratory in which continuous and/or ad hoc measurements require centralized storage. A presentation component for the data back end has furthermore been written that enables live visualization of data on any device capable of displaying Web pages. The system consists of three parts: data-logging clients, a data server, and a data presentation Web site. The logging of data from independent clients leads to high resilience to equipment failure, whereas the central storage of data dramatically eases backup and data exchange. The visualization front end allows direct monitoring of acquired data to see live progress of long-duration experiments. This enables the user to alter experimental conditions based on these data and to interfere with the experiment if needed. The data stored consist both of specific measurements and of continuously logged system parameters. The latter is crucial to a variety of automation and surveillance features, and three cases of such features are described: monitoring system health, getting status of long-duration experiments, and implementation of instant alarms in the event of failure. PMID- 24062363 TI - Engineered micromechanical cues affecting human pluripotent stem cell regulations and fate. AB - The survival, growth, self-renewal, and differentiation of human pluripotent stem cells (hPSCs) are influenced by their microenvironment, or so-called "niche," consisting of particular chemical and physical cues. Previous studies on mesenchymal stem cells and other stem cells have collectively uncovered the importance of physical cues and have begun to shed light on how stem cells sense and process such cues. In an attempt to support similar progress in mechanobiology of hPSCs, we review mechanosensory machinery, which plays an important role in cell-extracellular matrix interactions, cell-cell interactions, and subsequent intracellular responses. In addition, we review recent studies on the mechanobiology of hPSCs, in which engineered micromechanical environments were used to investigate effects of specific physical cues. Identifying key physical cues and understanding their mechanism will ultimately help in harnessing the full potential of hPSCs for clinical applications. PMID- 24062364 TI - Recognition and treatment of anaphylaxis in the school setting: the essential role of the school nurse. AB - Since anaphylaxis is unpredictable, rapid in onset, and potentially life threatening, it is critical for school staff to recognize and respond to its symptoms quickly. The symptoms of anaphylaxis can be challenging to differentiate, particularly in school-age children who may have trouble explaining what they are experiencing. School staff must understand the distinctive ways in which children describe and manifest anaphylactic symptoms, and the school nurse has a key leadership role in providing this training. The school nurse should create and coordinate individualized emergency care/action plans for students with known allergies, as well as a comprehensive care plan for all students, to ensure a safe environment and a rapid response to any life threatening allergic reaction. This should include having epinephrine stocked and readily accessible so that it can be given promptly in the case of an anaphylactic emergency. PMID- 24062366 TI - Children's participation in medicaid: a matter of time. PMID- 24062365 TI - Prediction of neonatal outcomes in extremely preterm neonates. AB - OBJECTIVE: To develop and validate a statistical prediction model spanning the severity range of neonatal outcomes in infants born at <= 30 weeks' gestation. METHODS: A national cohort of infants, born at 23 to 30 weeks' gestation and admitted to level III NICUs in Canada in 2010-2011, was identified from the Canadian Neonatal Network database. A multinomial logistic regression model was developed to predict survival without morbidities, mild morbidities, severe morbidities, or mortality, using maternal, obstetric, and infant characteristics available within the first day of NICU admission. Discrimination and calibration were assessed using a concordance C-statistic and the Cg goodness-of-fit test, respectively. Internal validation was performed using a bootstrap approach. RESULTS: Of 6106 eligible infants, 2280 (37%) survived without morbidities, 1964 (32%) and 1251 (21%) survived with mild and severe morbidities, respectively, and 611 (10%) died. Predictors in the model were gestational age, small (<10th percentile) for gestational age, gender, Score for Neonatal Acute Physiology version II >20, outborn status, use of antenatal corticosteroids, and receipt of surfactant and mechanical ventilation on the first day of admission. High model discrimination was confirmed by internal bootstrap validation (bias-corrected C statistic = 0.899, 95% confidence interval = 0.894-0.903). Predicted probabilities were consistent with the observed outcomes (Cg P value = .96). CONCLUSIONS: Neonatal outcomes ranging from mortality to survival without morbidity in extremely preterm infants can be predicted on their first day in the NICU by using a multinomial model with good discrimination and calibration. The prediction model requires additional external validation. PMID- 24062367 TI - A longitudinal view of child enrollment in Medicaid. AB - BACKGROUND: Although national cross-sectional estimates of the percentage of children enrolled in Medicaid are available, the percentage of children enrolled in Medicaid over longer periods of time is unknown. Also, the percentage and characteristics of children who rely on Medicaid throughout childhood, rather than transiently, are unknown. METHODS: We performed a longitudinal examination of Medicaid coverage among children across a 5-year period. Children 0 to 13 years of age in the 2004 National Health Interview Survey file were linked to Medicaid Analytic eXtract files from 2004 to 2008. The percentage of children enrolled in Medicaid at any time during the 5-year observation period and the number of years during which children were enrolled in Medicaid were calculated. Duration of Medicaid enrollment was compared across sociodemographic characteristics by using chi(2) tests. RESULTS: Forty-one percent of all US children were enrolled in Medicaid at least some time during the 5-year period, compared with a single-year estimate of 32.8% in 2004 alone. Of enrolled children, 51.5% were enrolled during all 5 years. Children with lower parental education, with lower household income, of minority race or ethnicity, and in suboptimal health were more likely to be enrolled in Medicaid during all 5 years. CONCLUSIONS: Longitudinal data reveal higher percentages of children with Medicaid insurance than shown by cross-sectional data. Half of children enrolled in Medicaid are enrolled during at least 5 consecutive years, and these children have higher risk sociodemographic profiles. PMID- 24062368 TI - Bariatric surgery for severe obesity in two adolescents with type 1 diabetes. AB - Bariatric surgery has been effective in treating type 2 diabetes mellitus (T2DM); it has not been used frequently in obese patients with type 1 diabetes mellitus (T1DM). This is the first case series reporting on the effect of bariatric surgery on diabetes control in adolescents with T1DM. Patient A is a 19-year-old obese man with T1DM who underwent vertical sleeve gastrectomy. At 12 months after surgery he demonstrated 28% reduction in BMI. His daily total insulin requirement had decreased; however, hemoglobin A1c remained primarily unchanged at 8.8%. Patient B is a 13-year-old obese girl with an initial clinical diagnosis of T2DM controlled on only metformin. She underwent Roux-en-Y gastric bypass; at 1 month after surgery she presented in diabetic ketoacidosis and was found to have positive islet cell antibodies, which were also present before surgery. Her diagnosis was revised to T1DM, and she was started on insulin. By 28 months after surgery her BMI had decreased by 42%. Since initiation of insulin, her daily total insulin requirement had decreased, but hemoglobin A1c had significantly worsened from 6.3% to 10%. We found that despite significant weight loss, improvements in cardiovascular risk factors (dyslipidemia and obstructive sleep apnea), and quality of life in our patients, bariatric surgery does not necessarily lead to improved glycemic control of T1DM. Patients with T1DM have ongoing dependency on exogenous insulin, and optimal glycemic control still depends on patient compliance with diabetes care. PMID- 24062369 TI - Trends in child protection and out-of-home care. AB - BACKGROUND: Over the past decades, increased knowledge about childhood abuse and trauma have prompted changes in child welfare policy, and practice that may have affected the out-of-home (OOH) care population. However, little is known about recent national trends in child maltreatment, OOH placement, or characteristics of children in OOH care. The objective of this study was to examine trends in child maltreatment and characteristics of children in OOH care. METHODS: We analyzed 2 federal administrative databases to identify and characterize US children who were maltreated (National Child Abuse and Neglect Data System) or in OOH care (Adoption and Foster Care Analysis and Reporting System). We assessed trends between 2000 and 2010. RESULTS: The number of suspected maltreatment cases increased 17% from 2000 to 2010, yet the number of substantiated cases decreased 7% and the number of children in OOH care decreased 25%. Despite the decrease in OOH placements, we found a 19% increase in the number of children who entered OOH care because of maltreatment (vs other causes), a 36% increase in the number of children with multiple (vs single) types of maltreatment, and a 60% increase in the number of children in OOH care identified as emotionally disturbed. CONCLUSIONS: From 2000 to 2010, fewer suspected cases of maltreatment were substantiated, despite increased investigations, and fewer maltreated children were placed in OOH care. These changes may have led to a smaller but more complex OOH care population with substantial previous trauma and emotional problems. PMID- 24062370 TI - Association of race and ethnicity with management of abdominal pain in the emergency department. AB - OBJECTIVE: To determine if race/ethnicity-based differences exist in the management of pediatric abdominal pain in emergency departments (EDs). METHODS: Secondary analysis of data from the 2006-2009 National Hospital Ambulatory Medical Care Survey regarding 2298 visits by patients <= 21 years old who presented to EDs with abdominal pain. Main outcomes were documentation of pain score and receipt of any analgesics, analgesics for severe pain (defined as >= 7 on a 10-point scale), and narcotic analgesics. Secondary outcomes included diagnostic tests obtained, length of stay (LOS), 72-hour return visits, and admission. RESULTS: Of patient visits, 70.1% were female, 52.6% were from non Hispanic white, 23.5% were from non-Hispanic black, 20.6% were from Hispanic, and 3.3% were from "other" racial/ethnic groups; patients' mean age was 14.5 years. Multivariate logistic regression models adjusting for confounders revealed that non-Hispanic black patients were less likely to receive any analgesic (odds ratio [OR]: 0.61; 95% confidence interval [CI]: 0.43-0.87) or a narcotic analgesic (OR: 0.38; 95% CI: 0.18-0.81) than non-Hispanic white patients (referent group). This finding was also true for non-Hispanic black and "other" race/ethnicity patients with severe pain (ORs [95% CI]: 0.43 [0.22-0.87] and 0.02 [0.00-0.19], respectively). Non-Hispanic black and Hispanic patients were more likely to have a prolonged LOS than non-Hispanic white patients (ORs [95% CI]: 1.68 [1.13-2.51] and 1.64 [1.09-2.47], respectively). No significant race/ethnicity-based disparities were identified in documentation of pain score, use of diagnostic procedures, 72-hour return visits, or hospital admissions. CONCLUSIONS: Race/ethnicity-based disparities exist in ED analgesic use and LOS for pediatric abdominal pain. Recognizing these disparities may help investigators eliminate inequalities in care. PMID- 24062371 TI - Evaluation of an early risk screener for PTSD in preschool children after accidental injury. AB - OBJECTIVES: To evaluate the effectiveness and most powerful selection of predictors of an early screening tool for posttraumatic stress disorder (PTSD) in a sample of 87 children ages 2 to 6 years after unintentional injury. METHODS: The examined screener was administered within 6 to 13 days post accident and consisted of an adapted version of the Pediatric Emotional Distress Scale (PEDS), the PEDS-ES (PEDS Early Screener), and questions on 5 additional risk factors (preexisting child behavioral problems, parental preexisting chronic mental or physical illness, pretraumatic life events in the family, parental feelings of guilt, parental posttraumatic stress). The PTSD Semi-structured Interview and Observational Record for Infants and Young Children served as criterion measure 6 months after the accident. A case was deemed positive when meeting criteria for full or partial PTSD. RESULTS: Use of the PEDS-ES without the additional risk factors performed best, with good sensitivity (85%) and moderate specificity (63%) for full or partial PTSD. CONCLUSIONS: The PEDS-ES allows for successful early screening of preschool-aged children after single accidental trauma. It may be used within a stepped-care model for early identification of individuals designated for possible secondary preventative interventions. PMID- 24062372 TI - Late preterm infants: near term but still in a critical developmental time period. AB - Late preterm (LP) infants are defined as those born at 34-0/7 to 36-6/7 weeks' gestational age. LP infants were previously referred to as near term infants. The change in terminology resulted from the understanding that these infants are not fully mature and that the last 6 weeks of gestation represent a critical period of growth and development of the fetal brain and lungs, and of other systems. There is accumulating evidence of higher risks for health complications in these infants, including serious morbidity and a threefold higher infant mortality rate compared with term infants. This information is of critical importance because of its scientific merits and practical implications. However, it warrants a critical and balanced review, given the apparent overall uncomplicated outcome for the majority of LP infants. Others reviewed the characteristics of LP infants that predispose them to a higher risk of morbidity at the neonatal period. This review focuses on the long-term neurodevelopmental and respiratory outcomes, with the main aim to suggest putative prenatal, neonatal, developmental, and environmental causes for these increased morbidities. It demonstrates parallelism in the trajectories of pulmonary and neurologic development and evolution as a model for fetal and neonatal maturation. These may suggest the critical developmental time period as the common pathway that leads to the outcomes. Disruption in this pathway with potential long-term consequences in both systems may occur if the intrauterine milieu is disturbed. Finally, the review addresses the practical implications on perinatal and neonatal care during infancy and childhood. PMID- 24062373 TI - Trends in invasive methicillin-resistant Staphylococcus aureus infections. AB - OBJECTIVE: To describe trends in the incidence of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections in children during 2005-2010. METHODS: We evaluated reports of invasive MRSA infections in pediatric patients identified from population-based surveillance during 2005-2010. Cases were defined as isolation of MRSA from a normally sterile site and classified on the basis of the setting of the positive culture and presence or absence of health care exposures. Estimated annual changes in incidence were determined by using regression models. National age- and race-specific incidences for 2010 were estimated by using US census data. RESULTS: A total of 876 pediatric cases were reported; 340 (39%) were among infants. Overall, 35% of cases were hospital-onset, 23% were health care-associated community-onset, and 42% were community-associated (CA). The incidence of invasive CA-MRSA infection per 100000 children increased from 1.1 in 2005 to 1.7 in 2010 (modeled yearly increase: 10.2%; 95% confidence interval: 2.7%-18.2%). No significant trends were observed for health care-associated community-onset and hospital-onset cases. Nationally, estimated invasive MRSA incidence in 2010 was higher among infants aged <90 days compared with older infants and children (43.9 vs 2.0 per 100000) and among black children compared with other races (6.7 vs 1.6 per 100000). CONCLUSIONS: Invasive MRSA infection in children disproportionately affects young infants and black children. In contrast to reports of declining incidence among adults, there were no significant reductions in health care-associated MRSA infections in children. Concurrently, the incidence of CA-MRSA infections has increased, underscoring the need for defining optimal strategies to prevent MRSA infections among children with and without health care exposures. PMID- 24062374 TI - Quality indicators for high acuity pediatric conditions. AB - OBJECTIVE: Identifying gaps in care and improving outcomes for severely ill children requires the development of evidence-based performance measures. We used a systematic process involving multiple stakeholders to identify and develop evidence-based quality indicators for high acuity pediatric conditions relevant to any emergency department (ED) setting where children are seen. METHODS: A prioritized list of clinical conditions was selected by an advisory panel. A systematic review of the literature was conducted to identify existing indicators, as well as guidelines and evidence that could be used to inform the creation of new indicators. A multiphase, Rand-modified Delphi method consisting of anonymous questionnaires and a face-to-face meeting of an expert panel was used for indicator selection. Measure specifications and evidence grading were created for each indicator, and the feasibility and reliability of measurement was assessed in a tertiary care pediatric ED. RESULTS: The conditions selected for indicator development were diabetic ketoacidosis, status asthmaticus, anaphylaxis, status epilepticus, severe head injury, and sepsis. The majority of the 62 selected indicators reflect ED processes (84%) with few indicators reflecting structures (11%) or outcomes (5%). Thirty-seven percent (n = 23) of the selected indicators are based on moderate or high quality evidence. Data were available and interrater reliability acceptable for the majority of indicators. CONCLUSIONS: A systematic process involving multiple stakeholders was used to develop evidence-based quality indicators for high acuity pediatric conditions. Future work will test the reliability and feasibility of data collection on these indicators across the spectrum of ED settings that provide care for children. PMID- 24062376 TI - Interprofessional practice and school nursing. PMID- 24062375 TI - Breastfeeding concerns at 3 and 7 days postpartum and feeding status at 2 months. AB - OBJECTIVE: We characterized breastfeeding concerns from open-text maternal responses and determined their association with stopping breastfeeding by 60 days (stopping breastfeeding) and feeding any formula between 30 and 60 days (formula use). METHODS: We assessed breastfeeding support, intentions, and concerns in 532 expectant primiparas and conducted follow-up interviews at 0, 3, 7, 14, 30, and 60 days postpartum. We calculated adjusted relative risk (ARR) and adjusted population attributable risk (PAR) for feeding outcomes by concern category and day, adjusted for feeding intentions and education. RESULTS: In 2946 interviews, 4179 breastfeeding concerns were reported, comprising 49 subcategories and 9 main categories. Ninety-two percent of participants reported >= 1 concern at day 3, with the most predominant being difficulty with infant feeding at breast (52%), breastfeeding pain (44%), and milk quantity (40%). Concerns at any postpartum interview were significantly associated with increased risk of stopping breastfeeding and formula use, with peak ARR at day 3 (eg, stopping breastfeeding ARR [95% confidence interval] = 9.2 [3.0-infinity]). The concerns yielding the largest adjusted PAR for stopping breastfeeding were day 7 "infant feeding difficulty" (adjusted PAR = 32%) and day 14 "milk quantity" (adjusted PAR = 23%). CONCLUSIONS: Breastfeeding concerns are highly prevalent and associated with stopping breastfeeding. Priority should be given to developing strategies for lowering the overall occurrence of breastfeeding concerns and resolving, in particular, infant feeding and milk quantity concerns occurring within the first 14 days postpartum. PMID- 24062377 TI - Peri-interventional echo assessment for the MitraClip procedure. AB - Worldwide, there have been more than 6500 MitraClip procedures performed to treat either functional or degenerative mitral regurgitation (MR). The MitraClip procedure is the only available percutaneous device available to reduce MR by creating a double mitral valve (MV) orifice and decreasing MV annular diameter. As the mitral leaflets cannot be assessed by fluoroscopy, procedural success is dependent upon echocardiographic guidance. In this review, we describe the assessment necessary to determine eligibility for the MitraClip procedure. This includes accurate assessment of MR and detailed analysis of MV morphology by 2D and 3D echocardiography. In addition, each of the intraprocedural steps involved in the deployment of this device and the guidance of these steps by 2D and 3D echo are described in detail, along with the use of echo to detect procedural complications. Thus the focus of this review is on the peri-interventional echocardiographic assessment before, during, and after the MitraClip procedure. PMID- 24062378 TI - Clinical effects of pre-adjusted edgewise orthodontic brackets: a systematic review and meta-analysis. AB - BACKGROUND: Fixed-appliance treatment is a major part of orthodontic treatment, but clinical evidence remains scarce. OBJECTIVES: Objective of this systematic review was to investigate how the therapeutic effects and side-effects of brackets used during the fixed-appliance orthodontic treatment are affected by their characteristics. SEARCH METHODS AND SELECTION CRITERIA: We searched MEDLINE and 18 other databases through April 2012 without restrictions for randomized controlled trials and quasi-randomized controlled trials investigating any bracket characteristic. DATA COLLECTION AND ANALYSIS: After duplicate selection and extraction procedures, risk of bias was assessed also in duplicate according to Cochrane guidelines and quality of evidence according to the Grades of Recommendation. Assessment, Development and Evaluation approach. Random-effects meta-analyses, subgroup analyses, and sensitivity analyses were performed with the corresponding 95 per cent confidence intervals (CI) and 95 per cent prediction intervals (PI). RESULTS: We included 25 trials on 1321 patients, with most comparing self-ligated (SL) and conventional brackets. Based on the meta analyses, the duration of orthodontic treatment was on average 2.01 months longer among patients with SL brackets (95 per cent CI: 0.45 to 3.57). The 95 per cent PIs for a future trial indicated that the difference could be considerable (-1.46 to 5.47 months). Treatment characteristics, outcomes, and side-effects were clinically similar between SL and conventional brackets. For most bracket characteristics, evidence is insufficient. Some meta-analyses included trials with high risk of bias, but sensitivity analyses indicated robustness. CONCLUSIONS: Based on existing evidence, no clinical recommendation can be made regarding the bracket material or different ligation modules. For SL brackets, no conclusive benefits could be proven, while their use was associated with longer treatment durations. PMID- 24062379 TI - A preliminary study of the effects of low-intensity pulsed ultrasound exposure on the stability of orthodontic miniscrews in growing rats. AB - BACKGROUND: Orthodontic miniscrews placed in growing subjects often loosen during orthodontic treatment. The ability to place miniscrews, regardless of age, would be clinically beneficial. OBJECTIVES: To assess the effects of low-intensity pulsed ultrasound (LIPUS) on the stability of orthodontic miniscrews in growing rats. MATERIALS/METHODS: The mobility of miniscrews after placement was recorded and the miniscrew-bone interface was examined histomorphometrically using tibiae of seven male Sprague-Dawley rats (aged 6 weeks). Field-emission scanning electron microscopic images were used to evaluate the bone-miniscrew interface, and a mobility test device was used to assess the stiffness of miniscrew placement. Fourteen custom-made miniscrews with 1.4mm diameters and 4.0mm lengths were placed in the right and left tibiae. LIPUS was used to stimulate right tibiae at the sites of miniscrew placement, and left tibiae were left untreated as controls. RESULTS: Significantly lower mobility was observed in the LIPUS treated group compared with the control group (P < 0.05). Histomorphometric evaluation indicated that bone-miniscrew adhesion was significantly better in the LIPUS-treated group than in the control group (P < 0.05). LIMITATIONS: This in vivo study used tibiae rather than jaw bones because the jaw bones of 6-week-old rats were too small to allow miniscrew placement. CONCLUSIONS: LIPUS was able to increase the bone-miniscrew contact and reduce the mobility of miniscrews in growing subjects. IMPLICATIONS: LIPUS may accelerate the bone healing process after miniscrew placement in growing subjects and can reduce the latent period. PMID- 24062380 TI - Three-dimensional assessment of facial asymmetry among pre-pubertal class III subjects: a controlled study. AB - BACKGROUND/OBJECTIVE: Facial asymmetry is very common in adult class III patients; however, the degree of facial asymmetry in growing class III subjects has been poorly investigated. Therefore, the aim was to assess the degree of facial asymmetry of growing class III subjects and to compare it with a sample of growing subjects without malocclusion, recorded using a three-dimensional laser scanning method and classified according to the dentition phase. SUBJECTS/METHODS: A group of 156 Caucasian subjects, 52 with class III malocclusion (28 females and 24 males) and 104 without malocclusion (control, 51 females and 53 males), with an overall mean age 6.7+/-1.4 years (range 4.3-10.3 years), were included. The subjects were further subdivided according to the presence of either primary or early/intermediate mixed dentitions. Facial asymmetry was assessed on three-dimensional surface facial images obtained using a laser scanning device in terms of mirrored face distances and percentages of asymmetry. Multivariate analyses were used to assess the differences among class III and control groups. RESULTS: Complete facial symmetry was not seen in any subject. No significant differences of facial asymmetry were observed between the class III and control groups, neither in the primary nor in the early/intermediate mixed dentition phases. LIMITATIONS: No conclusions about longitudinal changes in the degree of facial asymmetry among class III subjects could be drawn from the present cross-sectional study. CONCLUSIONS: Based on three-dimensional facial asymmetry analysis, class III subjects do not show clinically relevant facial asymmetry, at least during the pre-pubertal growth period. PMID- 24062381 TI - Bonding orthodontics brackets to enamel using experimental composites with an iodonium salt. AB - OBJECTIVES: This study investigated whether the addition of diphenyliodonium chloride (DPC) to experimental resin bonding agents would allow fixation of brackets to enamel using shorter light exposure times. METHODS: Photoactivated dimethacrylate-based composites were prepared containing DPC molar concentrations of 0 (control), 0.5 (R05), or 1 per cent (R1). Metallic brackets were bonded to bovine incisors and the bond strengths were evaluated using a shear test. In total, 18 groups were tested (n = 15 per group) defined by three bonding materials (control, R05, or R1), three light-activation time (8, 20, or 40 seconds), and two storage periods (10 minutes or 24 hours). The adhesive remnant index (ARI) was scored under magnification. Data were statistically analysed at a 5 per cent significance level. RESULTS: At 10 minutes, the control composite showed lower bond strengths than the DPC-modified bonding agents for all light activation times. Differences in bond strengths between both DPC-modified agents were not significant. Lower bond strengths at 10 minutes were generally observed for groups light activated for 8 seconds compared with groups light activated for 20 and 40 seconds. At 24 hours, no significant differences were observed among the light-activation times. The bond strengths at 24 hours were higher than the bond strengths at 10 minutes for all groups. A predominance of ARI scores 2 and 3 was generally observed. CONCLUSION: The use of a ternary photoactivation system containing an iodonium salt in bonding composites may allow bonding brackets to enamel using reduced light exposure times. PMID- 24062389 TI - Defining patient-specific risk in acute myeloid leukemia. PMID- 24062388 TI - Frequency of allogeneic hematopoietic cell transplantation among patients with high- or intermediate-risk acute myeloid leukemia in first complete remission. AB - PURPOSE: To determine the frequency of allogeneic hematopoietic cell transplantation (HCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). PATIENTS AND METHODS: Between January 1, 2008, and March 1, 2011, 212 newly diagnosed patients with AML received treatment at our center. Ninety-five patients age less than 75 years with intermediate- or high risk AML achieved a complete remission, and 21 patients achieved a morphologic remission with incomplete blood count recovery. RESULTS: Seventy-eight (67%; 95% CI, 58% to 76%) of 116 patients received HCT at a median of 2.8 months (range, 0.5 to 19 months) from their CR1 date. The median age was 57 years in both the HCT patient group (range, 18 to 75 years) and the non-HCT patient group (range, 24 to 70 years; P = .514). Between the HCT patients and the non-HCT patients, the mean Eastern Cooperative Oncology Group performance status was 1.1 compared with 1.5, respectively (P = .005), and the average HCT comorbidity score within 60 days of CR1 was 1.7 and 2.1, respectively (P = .68). Twenty-nine (76%) of 38 non HCT patients were HLA typed, and matched donors were found for 13 of these 29 patients (34% of all non-HCT patients). The most common causes for patients not receiving transplantation in CR1 were early relapse (within 6 months) in 12 patients (32%), poor performance status in eight patients (21%), and physician decision in five patients (13%). CONCLUSION: HCT can be performed in CR1 in the majority of patients with AML for whom it is currently recommended. The main barriers to HCT were early relapse and poor performance status, highlighting the need for improved therapies for patients with AML of all ages. PMID- 24062390 TI - Rituximab maintenance or retreatment after autologous transplantation for relapsed follicular lymphoma? PMID- 24062391 TI - Impact of rituximab and radiotherapy on outcome of patients with aggressive B cell lymphoma and skeletal involvement. AB - PURPOSE: To study clinical presentation, outcome, and the role of radiotherapy in patients with aggressive B-cell lymphoma and skeletal involvement treated with and without rituximab. PATIENTS AND METHODS: Outcome of patients with skeletal involvement was analyzed in a retrospective study of nine consecutive prospective trials of the German High-Grade Non-Hodgkin lymphoma Study Group. RESULTS: Of 3,840 patients, 292 (7.6%) had skeletal involvement. In the MabThera International Trial (MInT) for young good-prognosis patients and the Rituximab With CHOP Over 60 Years (RICOVER-60) study for elderly patients, the randomized addition of rituximab improved event-free survival (EFS; hazard ratio for MInT [HRMInT] = 0.4, P > 001; hazard ratio for RICOVER-60 [HRRICOVER-60] = 0.6, P > .001) and overall survival (OS; HRMInT = 0.4, P < .001; HRRICOVER-60 = 0.7, P = .002) in patients without skeletal involvement, but failed to improve the outcome of patients with skeletal involvement (EFS: HRMInT = 1.4, P = .444; HRRICOVER-60 = 0.8, P = .449; OS: HRMInT = 0.6, P = .449; HRRICOVER-60 = 1.0, P = .935). Skeletal involvement was associated with a worse outcome after cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (HREFS = 1.5, P = .048; HROS = 1.1; P = .828), but not after CHOP without rituximab (HREFS = 0.8, P = .181; HROS = 0.7, P = .083). In contrast to rituximab, additive radiotherapy to sites of skeletal involvement was associated with a decreased risk (HREFS = 0.3, P = .001; HROS = 0.5; P = .111). CONCLUSION: Rituximab failed to improve the outcome of patients with diffuse large B-cell lymphoma with skeletal involvement, although our data suggest a beneficial effect of radiotherapy to sites of skeletal involvement. Whether radiotherapy to sites of skeletal involvement can be spared in cases with a negative positron emission tomography after immunochemotherapy should be addressed in appropriately designed prospective trials. PMID- 24062392 TI - Combination of BRAF Inhibitors and Brain Radiotherapy in Patients With Metastatic Melanoma Shows Minimal Acute Toxicity. PMID- 24062393 TI - Clonal heterogeneity as detected by metaphase karyotyping is an indicator of poor prognosis in acute myeloid leukemia. AB - PURPOSE: In acute myeloid leukemia (AML), studies based on whole-genome sequencing have shown genomic diversity within leukemic clones. The aim of this study was to address clonal heterogeneity in AML based on metaphase cytogenetics. PATIENTS AND METHODS: This analysis included all patients enrolled onto two consecutive, prospective, randomized multicenter trials of the Study Alliance Leukemia. Patients were newly diagnosed with non-M3 AML and were fit for intensive chemotherapy. RESULTS: Cytogenetic subclones were detected in 418 (15.8%) of 2,639 patients from the whole study population and in 418 (32.8%) of 1,274 patients with aberrant karyotypes. Among those, 252 karyotypes (60.3%) displayed a defined number of distinct subclones, and 166 (39.7%) were classified as composite karyotypes. Subclone formation was particularly frequent in the cytogenetically adverse group, with subclone formation in 69.0%, 67.1%, and 64.8% of patients with complex aberrant, monosomal, and abnl(17p) karyotypes (P < .001 each). Two-subclone patterns typically followed a mother-daughter evolution, whereas for >= three subclones, a branched pattern prevailed. In non-core binding factor AML, subclone formation was associated with inferior event-free and overall survival and was confirmed as an independent predictor of poor prognosis in multivariate analysis. Subgroup analysis showed that subclone formation adds prognostic information particularly in the cytogenetic adverse-risk group. Allogeneic stem-cell transplantation improved the prognosis of patients with subclone karyotypes as shown in landmark analyses. CONCLUSION: Cytogenetic subclones are frequent in AML and permit tracing of clonal evolution and architecture. They bear prognostic significance with clonal heterogeneity as an independent adverse prognostic marker in cytogenetically adverse-risk AML. PMID- 24062394 TI - Phase II trial of palliative radiotherapy for hepatocellular carcinoma and liver metastases. AB - PURPOSE: To evaluate the feasibility and response of liver radiotherapy (RT) in improving symptoms and quality of life in patients with hepatocellular carcinoma (HCC) or liver metastases (LM). PATIENTS AND METHODS: Eligible patients had HCC or LM, unsuitable for or refractory to standard therapies, with an index symptom of pain, abdominal discomfort, nausea, or fatigue. The Brief Pain Inventory (BPI), Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep), and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) were completed by patients at baseline and each follow-up. The primary outcome was the percentage of patients with a clinically significant change at 1 month in the BPI subscale of symptom on average in the past 24 hours. Secondary outcomes were improvement in other BPI subscales and at other time points, FACT-Hep and EORTC QLQ-C30 at each follow-up, and toxicity at 1 week. RESULTS: Forty-one patients (30 men and 11 women) with HCC (n = 21) or LM (n = 20) were accrued. At 1 month, 48% had an improvement in symptom on average in the past 24 hours. Fifty-two percent of patients had improvement in symptom at its worst, 37% at its least, and 33% now. Improvements in the FACT-G and hepatobiliary subscale were seen in 23% and 29% of patients, respectively, at 1 month. There were also improvements in EORTC QLQ-C30 functional (range, 11% to 21%) and symptom (range, 11% to 50%) domains. One patient developed grade 3 nausea at 1 week. CONCLUSION: Improvements in symptoms were observed at 1 month in a substantial proportion of patients. A phase III study of palliative liver RT is planned. [Corrected] PMID- 24062395 TI - Endothelial damage in long-term survivors of childhood cancer. AB - PURPOSE: To evaluate the presence of vascular damage in long-term childhood cancer survivors (CCS) and sibling controls, and to evaluate the association between vascular damage parameters and cancer treatment and influence of cardiovascular risk factors. PATIENTS AND METHODS: Vascular assessment was performed in 277 adult CCSs (median age at diagnosis, 9 years; range, 0 to 20 years; median current age, 28 years; range, 18 to 48 years) treated with potentially cardiovascular toxic anticancer treatment (ie, anthracyclines, platinum, and/or radiotherapy [RT]). Measurements included carotid- and femoral wall intima-media thickness (IMT), flow-mediated vasodilatation of the brachial artery by ultrasound, assessment of endothelial and inflammatory marker proteins (including tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor type 1 [PAI-I]), and cardiovascular risk factors. CCS assessments were compared with those of 130 sibling controls (median age, 26 years; range, 18 to 51 years). RESULTS: At a median of 18 years (range, 5 to 31 years) after treatment, carotid and femoral IMTs in CCSs were not different from those of controls. However, CCSs who received RT as part of their treatment regimen had increased carotid and femoral IMTs and higher t-PA and PAI-I levels, indicating vascular damage and persistent endothelial activation. Patients treated with RT to the neck or chest also had greater femoral IMT. Greater IMT was associated with presence of cardiovascular risk factors (eg, hypertension and overweight). CONCLUSION: After potentially cardiovascular toxic anticancer treatment, CCSs who received RT showed signs of endothelial damage and an unfavorable cardiovascular risk profile compared with controls. CCSs treated with localized RT had increased IMT outside the primary irradiation field. These abnormalities are probably involved in the pathogenesis of cardiovascular morbidity in CCSs. PMID- 24062396 TI - Marriage is as protective as chemotherapy in cancer care. PMID- 24062397 TI - Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti inflammatory drug therapy in colorectal cancer. AB - PURPOSE: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) and are associated with reduced disease recurrence and improved outcome after primary treatment. However, toxicities of NSAIDs have limited their use as antineoplastic therapy. Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers. We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin. METHODS: We performed molecular analysis of tumors from 896 participants in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial, a large randomized trial comparing rofecoxib with placebo after primary CRC resection. We compared relapse-free survival and overall survival between rofecoxib therapy and placebo and between the use and nonuse of low-dose aspirin, according to tumor PIK3CA mutation status. RESULTS: We found no evidence of a greater benefit from rofecoxib treatment compared with placebo in patients whose tumors had PIK3CA mutations (multivariate adjusted hazard ratio [HR], 1.2; 95% CI, 0.53 to 2.72; P = .66; (P)INTERACTION = .47) compared with patients with PIK3CA wild-type cancers (HR, 0.87; 95% CI, 0.64 to 1.16; P = .34). In contrast, regular aspirin use after CRC diagnosis was associated with a reduced rate of CRC recurrence in patients with PIK3CA-mutant cancers (HR, 0.11; 95% CI, 0.001 to 0.832; P = .027; (P)INTERACTION = .024) but not in patients lacking tumor PIK3CA mutation (HR, 0.92; 95% CI, 0.60 to 1.42; P = .71). CONCLUSION: Although tumor PIK3CA mutation does not predict benefit from rofecoxib treatment, it merits further evaluation as a predictive biomarker for aspirin therapy. Our findings are concordant with recent data and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant CRC. PMID- 24062398 TI - Reply to N. Rompoti et al. PMID- 24062399 TI - Functional decline in older patients with cancer receiving first-line chemotherapy. AB - PURPOSE: To determine factors associated with early functional decline during first-line chemotherapy in older patients. PATIENTS AND METHODS: Patients age >= 70 years receiving first-line chemotherapy for cancer were prospectively considered for inclusion across 12 centers in France. Functional decline was defined as a decrease of >= 0.5 points on the Activities of Daily Living (ADL) scale between the beginning of chemotherapy and the second cycle. Factors associated with functional decline were sought from pretreatment abbreviated comprehensive geriatric assessment, including ADL, Instrumental ADL (IADL), Mini Nutritional Assessment (MNA), Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS15), and Timed Get Up and Go (GUG) test, and from comorbidities (Cumulative Illness Rating Scale-Geriatrics), MAX2 index, and baseline biologic and clinical information. RESULTS: Of 364 included patients, 50 experienced functional decline (16.7%; median, 0.5 points). Abnormal preadmission performance status, IADL, GDS15, MMSE, GUG, and MNA were associated with increased likelihood of functional decline (univariate analysis). In the multivariate model adjusted for baseline ADL and MAX2 index, high baseline GDS (odds ratio [OR], 2.16; 95% CI, 1.09 to 4.30; P = .03) and low IADL scores (OR, 2.87; 95% CI, 1.06 to 7.79; P = .04) were independently associated with increased risk of functional decline. CONCLUSION: Our results outline associations between baseline depression, instrumental dependencies, and early functional decline during chemotherapy for older patients. ADL should be sequentially evaluated early during treatment. Baseline evaluation of GDS15 and IADL may be proposed to anticipate this event. PMID- 24062400 TI - High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. AB - PURPOSE: Half the patients with acute myeloid leukemia (AML) who achieve complete remission (CR), ultimately relapse. Residual treatment-surviving leukemia is considered responsible for the outgrowth of AML. In many retrospective studies, detection of minimal residual disease (MRD) has been shown to enable identification of these poor-outcome patients by showing its independent prognostic impact. Most studies focus on molecular markers or analyze data in retrospect. This study establishes the value of immunophenotypically assessed MRD in the context of a multicenter clinical trial in adult AML with sample collection and analysis performed in a few specialized centers. PATIENTS AND METHODS: In adults (younger than age 60 years) with AML enrolled onto the Dutch Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research Acute Myeloid Leukemia 42A study, MRD was evaluated in bone marrow samples in CR (164 after induction cycle 1, 183 after cycle 2, 124 after consolidation therapy). RESULTS: After all courses of therapy, low MRD values distinguished patients with relatively favorable outcome from those with high relapse rate and adverse relapse-free and overall survival. In the whole patient group and in the subgroup with intermediate-risk cytogenetics, MRD was an independent prognostic factor. Multivariate analysis after cycle 2, when decisions about consolidation treatment have to be made, confirmed that high MRD values (> 0.1% of WBC) were associated with a higher risk of relapse after adjustment for consolidation treatment time-dependent covariate risk score and early or later CR. CONCLUSION: In future treatment studies, risk stratification should be based not only on risk estimation assessed at diagnosis but also on MRD as a therapy-dependent prognostic factor. PMID- 24062401 TI - Sitting with grandma. PMID- 24062402 TI - Intermittent versus continuous androgen deprivation treatment of prostate cancer. PMID- 24062403 TI - Prognostic relevance of treatment response measured by flow cytometric residual disease detection in older patients with acute myeloid leukemia. AB - PURPOSE: Older patients with acute myeloid leukemia (AML) have a high relapse rate after standard chemotherapy. We investigated whether measuring chemotherapy sensitivity by multiparameter flow cytometric minimal residual disease (MFC-MRD) detection has prognostic value in patients older than age 60 years or is simply a surrogate for known age-related risk factors. PATIENT AND METHODS: Eight hundred ninety-two unselected patients treated intensively in the United Kingdom National Cancer Research Institute AML16 Trial were assessed prospectively for MFC-MRD during treatment. Eight hundred thirty-three patients had leukemia-associated immunophenotypes (LAIPs) identified by pretreatment screening. Four hundred twenty-seven patients entered complete remission (CR) after one or two courses (designated C1 and C2, respectively) and were MFC-MRD assessable by LAIP detection in CR bone marrow for at least one of these time points. MRD positivity was defined as residual disease detectable by LAIP. RESULTS: MFC-MRD negativity, which was achieved in 51% of patients after C1 (n = 286) and 64% of patients after C2 (n = 279), conferred significantly better 3-year survival from CR (C1: 42% v 26% in MRD-positive patients, P < .001; C2: 38% v 18%, respectively; P < .001) and reduced relapse (C1: 71% v 83% in MRD-positive patients, P < .001; C2: 79% v 91%, respectively; P < .001), with higher risk of early relapse in MRD positive patients (median time to relapse, 8.5 v 17.1 months, respectively). In multivariable analysis, MRD status at the post-C1 time point independently predicted survival, identifying a subgroup of intermediate-risk patients with particularly poor outcome. However, survival benefit from gemtuzumab ozogamicin was not associated with MFC-MRD chemotherapy sensitivity. CONCLUSION: Early assessment of treatment response using flow cytometry provides powerful independent prognostic information in older adults with AML, lending support to the incorporation of MRD detection to refine risk stratification and inform clinical trial design in this challenging group of patients. PMID- 24062404 TI - Improving survival in acute myeloid leukemia: pick the best subjects? PMID- 24062405 TI - Marital status and survival in patients with cancer. AB - PURPOSE: To examine the impact of marital status on stage at diagnosis, use of definitive therapy, and cancer-specific mortality among each of the 10 leading causes of cancer-related death in the United States. METHODS: We used the Surveillance, Epidemiology and End Results program to identify 1,260,898 patients diagnosed in 2004 through 2008 with lung, colorectal, breast, pancreatic, prostate, liver/intrahepatic bile duct, non-Hodgkin lymphoma, head/neck, ovarian, or esophageal cancer. We used multivariable logistic and Cox regression to analyze the 734,889 patients who had clinical and follow-up information available. RESULTS: Married patients were less likely to present with metastatic disease (adjusted odds ratio [OR], 0.83; 95% CI, 0.82 to 0.84; P < .001), more likely to receive definitive therapy (adjusted OR, 1.53; 95% CI, 1.51 to 1.56; P < .001), and less likely to die as a result of their cancer after adjusting for demographics, stage, and treatment (adjusted hazard ratio, 0.80; 95% CI, 0.79 to 0.81; P < .001) than unmarried patients. These associations remained significant when each individual cancer was analyzed (P < .05 for all end points for each malignancy). The benefit associated with marriage was greater in males than females for all outcome measures analyzed (P < .001 in all cases). For prostate, breast, colorectal, esophageal, and head/neck cancers, the survival benefit associated with marriage was larger than the published survival benefit of chemotherapy. CONCLUSION: Even after adjusting for known confounders, unmarried patients are at significantly higher risk of presentation with metastatic cancer, undertreatment, and death resulting from their cancer. This study highlights the potentially significant impact that social support can have on cancer detection, treatment, and survival. PMID- 24062406 TI - Adherence to CONSORT adverse event reporting guidelines in randomized clinical trials evaluating systemic cancer therapy: a systematic review. AB - PURPOSE: The Consolidated Standards of Reporting Trials (CONSORT) guidance was extended in 2004 to provide a set of 10 specific and comprehensive guidelines regarding adverse event (AE) reporting in randomized clinical trials (RCTs). Limited data exist regarding adherence to these guidelines in publications of oncology RCTs. METHODS: All phase III RCTs published between 2007 and 2011 were reviewed using a 16-point AE reporting quality score (AERQS) based on the 2004 CONSORT extension. Multivariable linear regression was used to identify features associated with improved reporting quality. RESULTS: A total of 325 RCTs were reviewed. The mean AERQS was 10.1 on a 16-point scale. The most common items that were poorly reported were the methodology of AE collection (adequately reported in only 10% of studies), the description of AE characteristics leading to withdrawals (15%), and whether AEs are attributed to trial interventions (38%). Even when reported, the methods of AE collection and analysis were highly heterogeneous. The multivariable regression model revealed that industry funding, intercontinental trials, and trials in the metastatic setting were predictors of higher AERQS. The quality of AE reporting did not improve significantly over time and was not better among articles published in journals with a high impact factor. CONCLUSION: Our findings show that some methodologic aspects of AE collection and analysis were poorly reported. Given the importance of AEs in evaluating new treatments, authors should be encouraged to adhere to the 2004 CONSORT guidelines regarding AE reporting. PMID- 24062407 TI - Reply to C. Fozza. PMID- 24062409 TI - Reply to J. Zhu et al. PMID- 24062408 TI - Patient-physician communication about health-related quality-of-life problems: are non-Hodgkin lymphoma survivors willing to talk? AB - PURPOSE: To investigate non-Hodgkin lymphoma (NHL) survivors' willingness to discuss health-related quality-of-life (HRQOL) problems with their follow-up care physician. PATIENTS AND METHODS: Willingness to discuss HRQOL problems (physical, daily, emotional, social, and sexual functioning) was examined among 374 NHL survivors, 2 to 5 years postdiagnosis. Survivors were asked if they would bring up HRQOL problems with their physician and indicate reasons why not. Logistic regression models examined the association of patient sociodemographics, clinical characteristics, follow-up care variables, and current HRQOL scores with willingness to discuss HRQOL problems. RESULTS: Overall, 94%, 82%, 76%, 43%, and 49% of survivors would initiate discussions of physical, daily, emotional, social, and sexual functioning, respectively. Survivors who indicated their physician "always" spent enough time with them or rated their care as "excellent" were more willing to discuss HRQOL problems (P < .05). Survivors reporting poorer physical health were less willing to discuss their daily functioning problems (P < .001). Men were more willing to discuss sexual problems than women (P < .001). One in three survivors cited "nothing can be done" as a reason for not discussing daily functioning problems, and at least one in four cited "this was not their doctor's job" and a preference to "talk to another clinician" as reasons for not discussing emotional, social, and sexual functioning. CONCLUSION: NHL survivors' willingness to raise HRQOL problems with their physician varied by HRQOL domain. For some domains, even when survivors were experiencing problems, they may not discuss them. To deliver cancer care for the whole patient, interventions that facilitate survivor-clinician communication about survivors' HRQOL are needed. PMID- 24062410 TI - Intelligence in early adulthood and mortality from natural and unnatural causes in middle-aged Danish men. AB - BACKGROUND: High intelligence early in life has consistently been associated with decreased mortality, but the mechanisms are still not fully understood. In this cohort study, we examined the association between intelligence in early adulthood and later mortality from natural and unnatural causes taking birth weight, parental socioeconomic position, participants' own education and body mass index into account. METHODS: 13 536 Danish men born in 1953 and 1959-1961 with data from birth certificates and intelligence test scores from conscription were followed until 2009. Information on vital status was obtained from the Civil Registration System. Mortality risks were analysed by the multiple Cox proportional hazards model. RESULTS: The risk of mortality from natural as well as unnatural causes was more than twice as high among men in the lowest scoring intelligence tertile (HRnatural deaths=2.24; 1.90-2.65 and HRunnatural deaths=2.67; 2.03-3.53). Adjusting for all covariates attenuated the estimates, but the association remained (HRnatural deaths=1.82; 1.48-2.25 and HRunnatural deaths=2.30; 1.63-3.25). CONCLUSIONS: In men, intelligence in early adulthood was inversely associated with midlife mortality from natural and unnatural causes. The associations remained after adjustments for a range of covariates. PMID- 24062411 TI - Is participation contagious? Evidence from a household vector control campaign in urban Peru. AB - OBJECTIVES: High rates of household participation are critical to the success of door-to-door vector control campaigns. We used the Health Belief Model to assess determinants of participation, including neighbour participation as a cue to action, in a Chagas disease vector control campaign in Peru. METHODS: We evaluated clustering of participation among neighbours; estimated participation as a function of household infestation status, neighbourhood type and number of participating neighbours; and described the reported reasons for refusal to participate in a district of 2911 households. RESULTS: We observed significant clustering of participation along city blocks (p<0.0001). Participation was significantly higher for households in new versus established neighbourhoods, for infested households, and for households with more participating neighbours. The effect of neighbour participation was greater in new neighbourhoods. CONCLUSIONS: Results support a 'contagion' model of participation, highlighting the possibility that one or two participating households can tip a block towards full participation. Future campaigns can leverage these findings by making participation more visible, by addressing stigma associated with spraying, and by employing group incentives to spray. PMID- 24062412 TI - Notchless-dependent ribosome synthesis is required for the maintenance of adult hematopoietic stem cells. AB - Blood cell production relies on the coordinated activities of hematopoietic stem cells (HSCs) and multipotent and lineage-restricted progenitors. Here, we identify Notchless (Nle) as a critical factor for HSC maintenance under both homeostatic and cytopenic conditions. Nle deficiency leads to a rapid and drastic exhaustion of HSCs and immature progenitors and failure to maintain quiescence in HSCs. In contrast, Nle is dispensable for cycling-restricted progenitors and differentiated cells. In yeast, Nle/Rsa4 is essential for ribosome biogenesis, and we show that its role in pre-60S subunit maturation has been conserved in the mouse. Despite its implication in this basal cellular process, Nle deletion affects ribosome biogenesis only in HSCs and immature progenitors. Ribosome biogenesis defects are accompanied by p53 activation, which causes their rapid exhaustion. Collectively, our findings establish an essential role for Nle in HSC and immature progenitor functions and uncover previously unsuspected differences in ribosome biogenesis that distinguish stem cells from restricted progenitor populations. PMID- 24062414 TI - Goodbye to all that: a short history of CCSVI. PMID- 24062413 TI - Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. AB - NOD2 functions as an intracellular sensor for microbial pathogen and plays an important role in epithelial defense. The loss-of-function mutation of NOD2 is strongly associated with human Crohn's disease (CD). However, the mechanisms of how NOD2 maintains the intestinal homeostasis and regulates the susceptibility of CD are still unclear. Here we found that the numbers of intestinal intraepithelial lymphocytes (IELs) were reduced significantly in Nod2(-/-) mice and the residual IELs displayed reduced proliferation and increased apoptosis. Further study showed that NOD2 signaling maintained IELs via recognition of gut microbiota and IL-15 production. Notably, recovery of IELs by adoptive transfer could reduce the susceptibility of Nod2(-/-) mice to the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Our results demonstrate that recognition of gut microbiota by NOD2 is important to maintain the homeostasis of IELs and provide a clue that may link NOD2 variation to the impaired innate immunity and higher susceptibility in CD. PMID- 24062415 TI - Disease-modifying treatments for progressive multiple sclerosis. AB - The last 20 years have seen major progress in the treatment of relapsing remitting multiple sclerosis (RRMS) using a variety of drugs targeting immune dysfunction. In contrast, all clinical trials of such agents in primary progressive multiple sclerosis (PPMS) have failed and there is limited evidence of their efficacy in secondary progressive disease. Evolving concepts of the complex interplay between inflammatory and neurodegenerative processes across the course of multiple sclerosis (MS) may explain this discrepancy. This paper will provide an up-to-date overview of the rationale and results of the published clinical trials that have sought to alter the trajectory of both primary and secondary MS, considering studies involving drugs with a primary immune target and also those aiming for neuroprotection. Future areas of study will be discussed, building on these results combined with the experience of treating RRMS and new concepts emerging from laboratory science and animal models. PMID- 24062416 TI - Evolution of tumefactive lesions in multiple sclerosis: a 12-year study with serial imaging in a single patient. AB - We describe the acute presentation and the long-term evolution of recurrent tumefactive lesions (TLs) in a patient with relapsing-remitting multiple sclerosis. Five TLs occurred on three different occasions over a period of 12 years and these were followed by 73 serial magnetic resonance images (MRI). TL evolution was described by means of magnetization transfer imaging (MTI) and cerebrospinal fluid tissue specific imaging (TSI) over the follow-up period. During the study period, the patient had three clinical relapses with only minimal disability progression. MTI demonstrated that only the peripheral portion of each TL reverted to pre-lesional MT ratios within six months' post enhancement. Recurring TLs may present a similar pattern of evolution that may be associated with a long-term favourable clinical outcome. PMID- 24062417 TI - Recognizing and overcoming challenges of couple interview research. AB - In this article we discuss some methodological and ethical challenges we faced when conducting a couple-based study on men's role in contraceptive switching, and how we overcame them. The challenges we discuss include recruiting couples with a range of experiences, ensuring informed consent of participants, maintaining confidentiality within interviews, and participants discussing interview content between interviews. As appropriate, we have drawn on study participants' views of these challenges. We conclude that although couple research poses challenges, they can be overcome or minimized, and that for certain research questions this methodology is well worth using. PMID- 24062418 TI - Processes of change in an asthma self-care intervention. AB - In this article, we present a qualitative exploration of the psychological and communication processes that occur within an intervention to improve self-care for people with asthma. In the context of a primary-care-based trial of the intervention, we collected data at three time points for 21 patients, comprising 2 audiotaped consultations (nurse and patient together) and individual semistructured interviews 3 months after the second consultation. Using framework analysis, we identified both psychological processes (illness understanding, affective response to asthma, and reasoned motivation) and patient-provider interactions (active patient involvement and individual tailoring). We use these findings to extend and refine the pre-existing theoretical model of behavior change underpinning the intervention, in particular with relation to patient provider interaction processes. We conclude that it is important for developers and providers of asthma self-care interventions to attend to the style of delivery as well as the behavior change techniques involved. PMID- 24062419 TI - Parental advocacy styles for special education students during the transition to adulthood. AB - In an ethnographic study of planning for the transition to adulthood, we explored parental advocacy styles in special education settings for youth and young adults with chronic health conditions and developmental disabilities. Of 61 parents, 43 were satisfied with outcomes in negotiations for school services for their children. We identified three parental advocacy styles for these parents: (a) high-profile parents, who insisted on specific, wide-ranging services for their children that often resulted in conflict with educators; (b) strategic parents, who negotiated for selected goals and were willing to compromise, and (c) grateful-gratifier parents, who formed close relationships with educators and trusted them to make appropriate decisions. Eighteen parents were overwhelmed, burned out, or unfocused, and generally dissatisfied with outcomes of educational planning meetings. Professional efforts to enhance parental advocacy can target development of skills and strategies that have worked for successful negotiators. PMID- 24062420 TI - Working in partnership with interpreters: studies on individuals affected by HIV/AIDS in Vietnam. AB - This article brings together two American qualitative researchers and two Vietnamese interpreters who investigated the social impacts of HIV/AIDS in Vietnam from the standpoint of the local community. As cultural outsiders with limited Vietnamese language skills, the researchers relied on the insights and expertise of the interpreters to the extent that interpreter roles expanded to become co-researchers. We explain the guidelines we used to work in partnership in the field. We then describe how the relationship between researcher and interpreter developed into co-researching, and how we utilized this relationship to respond to challenges in the work. Despite an increasing number of international qualitative studies, little research has focused on the nuances of a working partnership between researcher and interpreter, and few studies include interpreters as co-researchers. This article contributes to an understanding of how the researcher-interpreter relationship impacts the voice of the participant and, ultimately, the final outcomes of the project. PMID- 24062421 TI - Promoting an equal and healthy environment: Swedish students' views of daily life at school. AB - Education is an important factor in health equity, but many students still do not complete high school. A focus on the school context rather than on individual problems might help to create a supportive environment for health and learning. In this study we explored factors that promote health and learning from the perspective of vocational and low-achieving high school students in Sweden. We used grounded theory with a constructivist orientation, informed and sensitized by the concept of salutogenesis. Students from a school in a mid-sized municipality in Sweden participated, and we collected data using the photovoice method and interviews. Students identified general factors as significant to their well-being and success in school. The main theme, "promoting driving forces for health and learning," emerged from the categories "longing to be seen by teachers," "longing for support," and "longing for recuperation." PMID- 24062422 TI - Calorie or carbohydrate restriction? The ketogenic diet as another option for supportive cancer treatment. PMID- 24062423 TI - In reply. PMID- 24062424 TI - "Double reflection": a practical approach to teach patient-doctor communication in oncology. PMID- 24062425 TI - In reply. PMID- 24062427 TI - Predicted relative prevalence estimates for obstructive sleep apnoea and the associated healthcare provision across the UK. AB - We surveyed the UK distribution of five factors commonly associated with obstructive sleep apnoea (OSA) to produce an overall risk map that could be used to predict relative prevalence estimates. The weighting and mapping of selected risk factors associated with OSA highlighted significant regional variation in predicted prevalence estimates. These data provide the first attempt to systematically map the UK for OSA and identify areas where the condition is likely to be more prevalent. The data show a significant mismatch between areas identified as having a high predicted prevalence estimate and the distribution of existing sleep centres. PMID- 24062428 TI - Feynman's clock, a new variational principle, and parallel-in-time quantum dynamics. AB - We introduce a discrete-time variational principle inspired by the quantum clock originally proposed by Feynman and use it to write down quantum evolution as a ground-state eigenvalue problem. The construction allows one to apply ground state quantum many-body theory to quantum dynamics, extending the reach of many highly developed tools from this fertile research area. Moreover, this formalism naturally leads to an algorithm to parallelize quantum simulation over time. We draw an explicit connection between previously known time-dependent variational principles and the time-embedded variational principle presented. Sample calculations are presented, applying the idea to a hydrogen molecule and the spin degrees of freedom of a model inorganic compound, demonstrating the parallel speedup of our method as well as its flexibility in applying ground-state methodologies. Finally, we take advantage of the unique perspective of this variational principle to examine the error of basis approximations in quantum dynamics. PMID- 24062429 TI - Sleep spindles in midday naps enhance learning in preschool children. AB - Despite the fact that midday naps are characteristic of early childhood, very little is understood about the structure and function of these sleep bouts. Given that sleep benefits memory in young adults, it is possible that naps serve a similar function for young children. However, children transition from biphasic to monophasic sleep patterns in early childhood, eliminating the nap from their daily sleep schedule. As such, naps may contain mostly light sleep stages and serve little function for learning and memory during this transitional age. Lacking scientific understanding of the function of naps in early childhood, policy makers may eliminate preschool classroom nap opportunities due to increasing curriculum demands. Here we show evidence that classroom naps support learning in preschool children by enhancing memories acquired earlier in the day compared with equivalent intervals spent awake. This nap benefit is greatest for children who nap habitually, regardless of age. Performance losses when nap deprived are not recovered during subsequent overnight sleep. Physiological recordings of naps support a role of sleep spindles in memory performance. These results suggest that distributed sleep is critical in early learning; when short term memory stores are limited, memory consolidation must take place frequently. PMID- 24062430 TI - Single-molecule FRET and linear dichroism studies of DNA breathing and helicase binding at replication fork junctions. AB - DNA "breathing" is a thermally driven process in which base-paired DNA sequences transiently adopt local conformations that depart from their most stable structures. Polymerases and other proteins of genome expression require access to single-stranded DNA coding templates located in the double-stranded DNA "interior," and it is likely that fluctuations of the sugar-phosphate backbones of dsDNA that result in mechanistically useful local base pair opening reactions can be exploited by such DNA regulatory proteins. Such motions are difficult to observe in bulk measurements, both because they are infrequent and because they often occur on microsecond time scales that are not easy to access experimentally. We report single-molecule fluorescence experiments with polarized light, in which tens-of-microseconds rotational motions of internally labeled iCy3/iCy5 donor-acceptor Forster resonance energy transfer fluorophore pairs that have been rigidly inserted into the backbones of replication fork constructs are simultaneously detected using single-molecule Forster resonance energy transfer and single-molecule fluorescence-detected linear dichroism signals. Our results reveal significant local motions in the ~100-MUs range, a reasonable time scale for DNA breathing fluctuations of potential relevance for DNA-protein interactions. Moreover, we show that both the magnitudes and the relaxation times of these backbone breathing fluctuations are significantly perturbed by interactions of the fork construct with a nonprocessive, weakly binding bacteriophage T4-coded helicase hexamer initiation complex, suggesting that these motions may play a fundamental role in the initial binding, assembly, and function of the processive helicase-primase (primosome) component of the bacteriophage T4-coded DNA replication complex. PMID- 24062431 TI - Existence of an information unit as a postulate of quantum theory. AB - Does information play a significant role in the foundations of physics? Information is the abstraction that allows us to refer to the states of systems when we choose to ignore the systems themselves. This is only possible in very particular frameworks, like in classical or quantum theory, or more generally, whenever there exists an information unit such that the state of any system can be reversibly encoded in a sufficient number of such units. In this work, we show how the abstract formalism of quantum theory can be deduced solely from the existence of an information unit with suitable properties, together with two further natural assumptions: the continuity and reversibility of dynamics, and the possibility of characterizing the state of a composite system by local measurements. This constitutes a set of postulates for quantum theory with a simple and direct physical meaning, like the ones of special relativity or thermodynamics, and it articulates a strong connection between physics and information. PMID- 24062433 TI - War, space, and the evolution of Old World complex societies. AB - How did human societies evolve from small groups, integrated by face-to-face cooperation, to huge anonymous societies of today, typically organized as states? Why is there so much variation in the ability of different human populations to construct viable states? Existing theories are usually formulated as verbal models and, as a result, do not yield sharply defined, quantitative predictions that could be unambiguously tested with data. Here we develop a cultural evolutionary model that predicts where and when the largest-scale complex societies arose in human history. The central premise of the model, which we test, is that costly institutions that enabled large human groups to function without splitting up evolved as a result of intense competition between societies primarily warfare. Warfare intensity, in turn, depended on the spread of historically attested military technologies (e.g., chariots and cavalry) and on geographic factors (e.g., rugged landscape). The model was simulated within a realistic landscape of the Afroeurasian landmass and its predictions were tested against a large dataset documenting the spatiotemporal distribution of historical large-scale societies in Afroeurasia between 1,500 BCE and 1,500 CE. The model predicted pattern of spread of large-scale societies was very similar to the observed one. Overall, the model explained 65% of variance in the data. An alternative model, omitting the effect of diffusing military technologies, explained only 16% of variance. Our results support theories that emphasize the role of institutions in state-building and suggest a possible explanation why a long history of statehood is positively correlated with political stability, institutional quality, and income per capita. PMID- 24062432 TI - Childhood abuse, parental warmth, and adult multisystem biological risk in the Coronary Artery Risk Development in Young Adults study. AB - Childhood abuse increases adult risk for morbidity and mortality. Less clear is how this "toxic" stress becomes embedded to influence health decades later, and whether protective factors guard against these effects. Early biological embedding is hypothesized to occur through programming of the neural circuitry that influences physiological response patterns to subsequent stress, causing wear and tear across multiple regulatory systems. To examine this hypothesis, we related reports of childhood abuse to a comprehensive 18-biomarker measure of multisystem risk and also examined whether presence of a loving parental figure buffers against the impact of childhood abuse on adult risk. A total of 756 subjects (45.8% white, 42.7% male) participated in this ancillary substudy of the Coronary Artery Risk Development in Young Adults Study. Childhood stress was determined by using the Risky Families Questionnaire, a well-validated retrospective self-report scale. Linear regression models adjusting for age, sex, race, parental education, and oral contraceptive use found a significant positive relationship between reports of childhood abuse and multisystem health risks [B (SE) = 0.68 (0.16); P < 0.001]. Inversely, higher amounts of reported parental warmth and affection during childhood was associated with lower multisystem health risks [B (SE) = -0.40 (0.14); P < 0.005]. A significant interaction of abuse and warmth (P < 0.05) was found, such that individuals reporting low levels of love and affection and high levels of abuse in childhood had the highest multisystem risk in adulthood. PMID- 24062434 TI - Indirection and symbol-like processing in the prefrontal cortex and basal ganglia. AB - The ability to flexibly, rapidly, and accurately perform novel tasks is a hallmark of human behavior. In our everyday lives we are often faced with arbitrary instructions that we must understand and follow, and we are able to do so with remarkable ease. It has frequently been argued that this ability relies on symbol processing, which depends critically on the ability to represent variables and bind them to arbitrary values. Whereas symbol processing is a fundamental feature of all computer systems, it remains a mystery whether and how this ability is carried out by the brain. Here, we provide an example of how the structure and functioning of the prefrontal cortex/basal ganglia working memory system can support variable binding, through a form of indirection (akin to a pointer in computer science). We show how indirection enables the system to flexibly generalize its behavior substantially beyond its direct experience (i.e., systematicity). We argue that this provides a biologically plausible mechanism that approximates a key component of symbol processing, exhibiting both the flexibility, but also some of the limitations, that are associated with this ability in humans. PMID- 24062435 TI - Structure and nucleic acid binding activity of the nucleoporin Nup157. AB - At the center of the nuclear pore complex (NPC) is a uniquely versatile central transport channel. Structural analyses of distinct segments ("protomers") of the three "channel" nucleoporins yielded a model for how this channel is constructed. Its principal feature is a midplane ring that can undergo regulated diameter changes of as much as an estimated 30 nm. To better understand how a family of "adaptor" nucleoporins--concentrically surrounding this channel--might cushion these huge structural changes, we determined the crystal structure of one adaptor nucleoporin, Nup157. Here, we show that a recombinant Saccharomyces cerevisiae Nup157 protomer, representing two-thirds of Nup157 (residues 70-893), folds into a seven-bladed beta-propeller followed by an alpha-helical domain, which together form a C-shaped architecture. Notably, the structure contains a large patch of positively charged residues, most of which are evolutionarily conserved. Consistent with this surface feature, we found that Nup157(70-893) binds to nucleic acids, although in a sequence-independent manner. Nevertheless, this interaction supports a previously reported role of Nup157, and its paralogue Nup170, in chromatin organization. Based on its nucleic acid binding capacity, we propose a dual location and function of Nup157. Finally, modeling the remaining C terminal portion of Nup157 shows that it projects as a superhelical stack from the compact C-shaped portion of the molecule. The predicted four hinge regions indicate an intrinsic flexibility of Nup157, which could contribute to structural plasticity within the NPC. PMID- 24062436 TI - Activity of striatal neurons reflects social action and own reward. AB - Social interactions provide agents with the opportunity to earn higher benefits than when acting alone and contribute to evolutionary stable strategies. A basic requirement for engaging in beneficial social interactions is to recognize the actor whose movement results in reward. Despite the recent interest in the neural basis of social interactions, the neurophysiological mechanisms identifying the actor in social reward situations are unknown. A brain structure well suited for exploring this issue is the striatum, which plays a role in movement, reward, and goal-directed behavior. In humans, the striatum is involved in social processes related to reward inequity, donations to charity, and observational learning. We studied the neurophysiology of social action for reward in rhesus monkeys performing a reward-giving task. The behavioral data showed that the animals distinguished between their own and the conspecific's reward and knew which individual acted. Striatal neurons coded primarily own reward but rarely other's reward. Importantly, the activations occurred preferentially, and in approximately similar fractions, when either the own or the conspecific's action was followed by own reward. Other striatal neurons showed social action coding without reward. Some of the social action coding disappeared when the conspecific's role was simulated by a computer, confirming a social rather than observational relationship. These findings demonstrate a role of striatal neurons in identifying the social actor and own reward in a social setting. These processes may provide basic building blocks underlying the brain's function in social interactions. PMID- 24062437 TI - Iceberg discharges of the last glacial period driven by oceanic circulation changes. AB - Proxy data reveal the existence of episodes of increased deposition of ice-rafted detritus in the North Atlantic Ocean during the last glacial period interpreted as massive iceberg discharges from the Laurentide Ice Sheet. Although these have long been attributed to self-sustained ice sheet oscillations, growing evidence of the crucial role that the ocean plays both for past and future behavior of the cryosphere suggests a climatic control of these ice surges. Here, we present simulations of the last glacial period carried out with a hybrid ice sheet-ice shelf model forced by an oceanic warming index derived from proxy data that accounts for the impact of past ocean circulation changes on ocean temperatures. The model generates a time series of iceberg discharge that closely agrees with ice-rafted debris records over the past 80 ka, indicating that oceanic circulation variations were responsible for the enigmatic ice purges of the last ice age. PMID- 24062438 TI - Expressomal approach for comprehensive analysis and visualization of ligand sensitivities of xenoestrogen responsive genes. AB - Although biological effects of endocrine disrupting chemicals (EDCs) are often observed at unexpectedly low doses with occasional nonmonotonic dose-response characteristics, transcriptome-wide profiles of sensitivities or dose-dependent behaviors of the EDC responsive genes have remained unexplored. Here, we describe expressome analysis for the comprehensive examination of dose-dependent gene responses and its applications to characterize estrogen responsive genes in MCF-7 cells. Transcriptomes of MCF-7 cells exposed to varying concentrations of representative natural and xenobiotic estrogens for 48 h were determined by microarray and used for computational calculation of interpolated approximations of estimated transcriptomes for 300 doses uniformly distributed in log space for each chemical. The entire collection of these estimated transcriptomes, designated as the expressome, has provided unique opportunities to profile chemical-specific distributions of ligand sensitivities for large numbers of estrogen responsive genes, revealing that at low concentrations estrogens generally tended to suppress rather than to activate transcription. Gene ontology analysis demonstrated distinct functional enrichment between high- and low sensitivity estrogen responsive genes, supporting the notion that a single EDC chemical can cause qualitatively distinct biological responses at different doses. Expressomal heatmap visualization of dose-dependent induction of Bisphenol A inducible genes showed a weak gene activation peak at a very low concentration range (ca. 0.1 nM) in addition to the main, strong gene activation peak at and above 100 nM. Thus, expressome analysis is a powerful approach to understanding the EDC dose-dependent dynamic changes in gene expression at the transcriptomal level, providing important information on the overall profiles of ligand sensitivities and nonmonotonic responses. PMID- 24062439 TI - Robust increases in severe thunderstorm environments in response to greenhouse forcing. AB - Although severe thunderstorms are one of the primary causes of catastrophic loss in the United States, their response to elevated greenhouse forcing has remained a prominent source of uncertainty for climate change impacts assessment. We find that the Coupled Model Intercomparison Project, Phase 5, global climate model ensemble indicates robust increases in the occurrence of severe thunderstorm environments over the eastern United States in response to further global warming. For spring and autumn, these robust increases emerge before mean global warming of 2 degrees C above the preindustrial baseline. We also find that days with high convective available potential energy (CAPE) and strong low-level wind shear increase in occurrence, suggesting an increasing likelihood of atmospheric conditions that contribute to the most severe events, including tornadoes. In contrast, whereas expected decreases in mean wind shear have been used to argue for a negative influence of global warming on severe thunderstorms, we find that decreases in shear are in fact concentrated in days with low CAPE and therefore do not decrease the total occurrence of severe environments. Further, we find that the shift toward high CAPE is most concentrated in days with low convective inhibition, increasing the occurrence of high-CAPE/low-convective inhibition days. The fact that the projected increases in severe environments are robust across a suite of climate models, emerge in response to relatively moderate global warming, and result from robust physical changes suggests that continued increases in greenhouse forcing are likely to increase severe thunderstorm occurrence, thereby increasing the risk of thunderstorm-related damage. PMID- 24062440 TI - Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG drug conjugate and cell-penetrating moiety. AB - In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting, insufficient tumor cell internalization/bioavailability, and side effects, we developed a unique tumor targeted micellar drug-delivery platform. Using paclitaxel as a model therapeutic, a nanopreparation composed of a matrix metalloproteinase 2 (MMP2) sensitive self-assembly PEG 2000-paclitaxel conjugate (as a prodrug and MMP 2 sensitive moiety), transactivating transcriptional activator peptide-PEG1000 phosphoethanolamine (PE) (a cell-penetrating enhancer), and PEG1000-PE (a nanocarrier building block) was prepared. Several major drug delivery strategies, including self-assembly, PEGylation, the enhanced permeability and retention effect, stimulus sensitivity, a cell-penetrating moiety, and the concept of prodrug, were used in design of this nanoparticle in a collaborative manner. The nanopreparation allowed superior cell internalization, cytotoxicity, tumor targeting, and antitumor efficacy in vitro and in vivo over its nonsensitive counterpart, free paclitaxel and conventional micelles. This uniquely engineered nanoparticle has potential for effective intracellular delivery of drug into cancer cells. PMID- 24062441 TI - Basal variability in CREB phosphorylation predicts trait-like differences in amygdala-dependent memory. AB - Much of what is known about the neurobiology of learning and memory comes from studies of the average behavior. In contrast, intersubject differences that emerge within groups are difficult to study systematically and are often excluded from scientific discussion. Nevertheless, population-wide variability is a virtually universal feature of both complex traits, such as intelligence, and hardwired responses, such as defensive behaviors. Here, we use outbred rats to investigate if cAMP response element-binding protein (CREB), a transcription factor that has long been known in experimental settings to be crucial for associative plasticity, participates in natural memory phenotypes. Using a combination of behavioral, biochemical, and viral techniques, we show that a subset of rats with trait-like deficits in aversive memory have basally reduced CREB activity in the lateral amygdala but can be induced to perform at average levels by directly or indirectly enhancing pretraining CREB phosphorylation. These data suggest that endogenous CREB activity in the amygdala may set a critical threshold for plasticity during memory formation. PMID- 24062442 TI - A transformation for the mechanical fingerprints of complex biomolecular interactions. AB - Biological processes are carried out through molecular conformational transitions, ranging from the structural changes within biomolecules to the formation of macromolecular complexes and the associations between the complexes themselves. These transitions cover a vast range of timescales and are governed by a tangled network of molecular interactions. The resulting hierarchy of interactions, in turn, becomes encoded in the experimentally measurable "mechanical fingerprints" of the biomolecules, their force-extension curves. However, how can we decode these fingerprints so that they reveal the kinetic barriers and the associated timescales of a biological process? Here, we show that this can be accomplished with a simple, model-free transformation that is general enough to be applicable to molecular interactions involving an arbitrarily large number of kinetic barriers. Specifically, the transformation converts the mechanical fingerprints of the system directly into a map of force dependent rate constants. This map reveals the kinetics of the multitude of rate processes in the system beyond what is typically accessible to direct measurements. With the contributions from individual barriers to the interaction network now "untangled", the map is straightforward to analyze in terms of the prominent barriers and timescales. Practical implementation of the transformation is illustrated with simulated biomolecular interactions that comprise different patterns of complexity--from a cascade of activation barriers to competing dissociation pathways. PMID- 24062444 TI - Asexual Daphnia genomes expose something old, new, borrowed, and blue. PMID- 24062443 TI - Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. AB - In 2012, a novel betacoronavirus, designated Middle East respiratory syndrome coronavirus or MERS-CoV and associated with severe respiratory disease in humans, emerged in the Arabian Peninsula. To date, 108 human cases have been reported, including cases of human-to-human transmission. The availability of an animal disease model is essential for understanding pathogenesis and developing effective countermeasures. Upon a combination of intratracheal, ocular, oral, and intranasal inoculation with 7 * 10(6) 50% tissue culture infectious dose of the MERS-CoV isolate HCoV-EMC/2012, rhesus macaques developed a transient lower respiratory tract infection. Clinical signs, virus shedding, virus replication in respiratory tissues, gene expression, and cytokine and chemokine profiles peaked early in infection and decreased over time. MERS-CoV caused a multifocal, mild to marked interstitial pneumonia, with virus replication occurring mainly in alveolar pneumocytes. This tropism of MERS-CoV for the lower respiratory tract may explain the severity of the disease observed in humans and the, up to now, limited human-to-human transmission. PMID- 24062445 TI - Precocious cerebellum development and improved motor functions in mice lacking the astrocyte cilium-, patched 1-associated Gpr37l1 receptor. AB - In the developing cerebellum, the proliferation and differentiation of glial and neuronal cell types depend on the modulation of the sonic hedgehog (Shh) signaling pathway. The vertebrate G-protein-coupled receptor 37-like 1 (GPR37L1) gene encodes a putative G-protein-coupled receptor that is expressed in newborn and adult cerebellar Bergmann glia astrocytes. This study shows that the ablation of the murine Gpr37l1 gene results in premature down-regulation of proliferation of granule neuron precursors and precocious maturation of Bergmann glia and Purkinje neurons. These alterations are accompanied by improved adult motor learning and coordination. Gpr37l1(-/-) mice also exhibit specific modifications of the Shh signaling cascade. Specific assays show that in Bergmann glia cells Gpr37l1 is associated with primary cilium membranes and it specifically interacts and colocalizes with the Shh primary receptor, patched 1. These findings indicate that the patched 1-associated Gpr37l1 receptor participates in the regulation of postnatal cerebellum development by modulating the Shh pathway. PMID- 24062446 TI - Preverbal infants expect members of social groups to act alike. AB - The short ontogenetic time courses of conformity and stereotyping, both evident in the preschool years, point to the possibility that a central component of human social cognition is an early developing expectation that social group members will engage in common behaviors. Across a series of experiments, we show that by 7 months of age preverbal infants differentiate between actions by individuals that are and are not consistent with the actions of their social group members. Infants responded to group-inconsistent actions only in a social context: they failed to distinguish the same behavioral differences when presented with collections of nonsocial agents or inanimate objects. These results suggest that infants expect social group membership and behavior to covary, before extensive intergroup experience or linguistic input. This expectation is consistent with the socially motivated imitation and stereotyping evident in toddlers and preschoolers, and may play a role in the early emergence of one or both of these aspects of social behavior and cognition. PMID- 24062447 TI - Epigenetic control of natural killer cell maturation by histone H2A deubiquitinase, MYSM1. AB - Histone modifications play critical roles in regulating immunity; however, little is known about the epigenetic control of natural killer (NK) cell development. Here, we found that NK cell development is severely impaired in mice deficient in the histone H2A deubiquitinase MYSM1. We demonstrated that MYSM1 is required for NK cell maturation but not for NK lineage specification and commitment. We also found that MYSM1 intrinsically controls this NK cell maturation. Mechanistic studies revealed that the expression of transcription factor, inhibitor of DNA binding protein (ID2), a critical factor for NK cell development, is impaired in Mysm1(-/-) NK cells. MYSM1 interacts with nuclear factor IL-3 (NFIL3, also known as E4BP4), a critical factor for mouse NK cell development, and the recruitment of nuclear factor Il-3 to the ID2 locus is dependent on MYSM1. Further, we observed that MYSM1 is involved in maintaining an active chromatin at the ID2 locus to promote NK cell development. Hence this study demonstrates the critical epigenetic regulation of NK cell development by the histone H2A deubiquitinase MYSM1 through the transcriptional control of transcription factors important for NK cell development. PMID- 24062448 TI - Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via beta-adrenergic induction of myelopoiesis. AB - Across a variety of adverse life circumstances, such as social isolation and low socioeconomic status, mammalian immune cells have been found to show a conserved transcriptional response to adversity (CTRA) involving increased expression of proinflammatory genes. The present study examines whether such effects might stem in part from the selective up-regulation of a subpopulation of immature proinflammatory monocytes (Ly-6c(high) in mice, CD16(-) in humans) within the circulating leukocyte pool. Transcriptome representation analyses showed relative expansion of the immature proinflammatory monocyte transcriptome in peripheral blood mononuclear cells from people subject to chronic social stress (low socioeconomic status) and mice subject to repeated social defeat. Cellular dissection of the mouse peripheral blood mononuclear cell transcriptome confirmed these results, and promoter-based bioinformatic analyses indicated increased activity of transcription factors involved in early myeloid lineage differentiation and proinflammatory effector function (PU.1, NF-kappaB, EGR1, MZF1, NRF2). Analysis of bone marrow hematopoiesis confirmed increased myelopoietic output of Ly-6c(high) monocytes and Ly-6c(intermediate) granulocytes in mice subject to repeated social defeat, and these effects were blocked by pharmacologic antagonists of beta-adrenoreceptors and the myelopoietic growth factor GM-CSF. These results suggest that sympathetic nervous system-induced up regulation of myelopoiesis mediates the proinflammatory component of the leukocyte CTRA dynamic and may contribute to the increased risk of inflammation related disease associated with adverse social conditions. PMID- 24062450 TI - Phosphate release coupled to rotary motion of F1-ATPase. AB - F1-ATPase, the catalytic domain of ATP synthase, synthesizes most of the ATP in living organisms. Running in reverse powered by ATP hydrolysis, this hexameric ring-shaped molecular motor formed by three alphabeta-dimers creates torque on its central gamma-subunit. This reverse operation enables detailed explorations of the mechanochemical coupling mechanisms in experiment and simulation. Here, we use molecular dynamics simulations to construct a first atomistic conformation of the intermediate state following the 40 degrees substep of rotary motion, and to study the timing and molecular mechanism of inorganic phosphate (Pi) release coupled to the rotation. In response to torque-driven rotation of the gamma subunit in the hydrolysis direction, the nucleotide-free alphabetaE interface forming the "empty" E site loosens and singly charged Pi readily escapes to the P loop. By contrast, the interface stays closed with doubly charged Pi. The gamma rotation tightens the ATP-bound alphabetaTP interface, as required for hydrolysis. The calculated rate for the outward release of doubly charged Pi from the alphabetaE interface 120 degrees after ATP hydrolysis closely matches the ~1 ms functional timescale. Conversely, Pi release from the ADP-bound alphabetaDP interface postulated in earlier models would occur through a kinetically infeasible inward-directed pathway. Our simulations help reconcile conflicting interpretations of single-molecule experiments and crystallographic studies by clarifying the timing of Pi exit, its pathway and kinetics, associated changes in Pi protonation, and changes of the F1-ATPase structure in the 40 degrees substep. Important elements of the molecular mechanism of Pi release emerging from our simulations appear to be conserved in myosin despite the different functional motions. PMID- 24062452 TI - Historical warming reduced due to enhanced land carbon uptake. AB - Previous studies have demonstrated the importance of enhanced vegetation growth under future elevated atmospheric CO2 for 21st century climate warming. Surprisingly no study has completed an analogous assessment for the historical period, during which emissions of greenhouse gases increased rapidly and land-use changes (LUC) dramatically altered terrestrial carbon sources and sinks. Using the Geophysical Fluid Dynamics Laboratory comprehensive Earth System Model ESM2G and a reconstruction of the LUC, we estimate that enhanced vegetation growth has lowered the historical atmospheric CO2 concentration by 85 ppm, avoiding an additional 0.31 +/- 0.06 degrees C warming. We demonstrate that without enhanced vegetation growth the total residual terrestrial carbon flux (i.e., the net land flux minus LUC flux) would be a source of 65-82 Gt of carbon (GtC) to atmosphere instead of the historical residual carbon sink of 186-192 GtC, a carbon saving of 251-274 GtC. PMID- 24062451 TI - Broad domain generality in focal regions of frontal and parietal cortex. AB - Unlike brain regions that respond selectively to specific kinds of information content, a number of frontal and parietal regions are thought to be domain- and process-general: that is, active during a wide variety of demanding cognitive tasks. However, most previous evidence for this functional generality in humans comes from methods that overestimate activation overlap across tasks. Here we present functional MRI evidence from single-subject analyses for broad functional generality of a specific set of brain regions: the same sets of voxels are engaged across tasks ranging from arithmetic to storing information in working memory, to inhibiting irrelevant information. These regions have a specific topography, often lying directly adjacent to domain-specific regions. Thus, in addition to domain-specific brain regions tailored to solve particular problems of longstanding importance to our species, the human brain also contains a set of functionally general regions that plausibly endow us with the cognitive flexibility necessary to solve novel problems. PMID- 24062453 TI - Postsynaptic neural activity regulates neuronal addition in the adult avian song control system. AB - A striking feature of the nervous system is that it shows extensive plasticity of structure and function that allows animals to adjust to changes in their environment. Neural activity plays a key role in mediating experience-dependent neural plasticity and, thus, creates a link between the external environment, the nervous system, and behavior. One dramatic example of neural plasticity is ongoing neurogenesis in the adult brain. The role of neural activity in modulating neuronal addition, however, has not been well studied at the level of neural circuits. The avian song control system allows us to investigate how activity influences neuronal addition to a neural circuit that regulates song, a learned sensorimotor social behavior. In adult white-crowned sparrows, new neurons are added continually to the song nucleus HVC (proper name) and project their axons to its target nucleus, the robust nucleus of the arcopallium (RA). We report here that electrical activity in RA regulates neuronal addition to HVC. Decreasing neural activity in RA by intracerebral infusion of the GABAA receptor agonist muscimol decreased the number of new HVC neurons by 56%. Our results suggest that postsynaptic electrical activity influences the addition of new neurons into a functional neural circuit in adult birds. PMID- 24062454 TI - On reversible H2 loss upon N2 binding to FeMo-cofactor of nitrogenase. AB - Nitrogenase is activated for N2 reduction by the accumulation of four electrons/protons on its active site FeMo-cofactor, yielding a state, designated as E4, which contains two iron-bridging hydrides [Fe-H-Fe]. A central puzzle of nitrogenase function is an apparently obligatory formation of one H2 per N2 reduced, which would "waste" two reducing equivalents and four ATP. We recently presented a draft mechanism for nitrogenase that provides an explanation for obligatory H2 production. In this model, H2 is produced by reductive elimination of the two bridging hydrides of E4 during N2 binding. This process releases H2, yielding N2 bound to FeMo-cofactor that is doubly reduced relative to the resting redox level, and thereby is activated to promptly generate bound diazene (HN=NH). This mechanism predicts that during turnover under D2/N2, the reverse reaction of D2 with the N2-bound product of reductive elimination would generate dideutero-E4 [E4(2D)], which can relax with loss of HD to the state designated E2, with a single deuteride bridge [E2(D)]. Neither of these deuterated intermediate states could otherwise form in H2O buffer. The predicted E2(D) and E4(2D) states are here established by intercepting them with the nonphysiological substrate acetylene (C2H2) to generate deuterated ethylenes (C2H3D and C2H2D2). The demonstration that gaseous H2/D2 can reduce a substrate other than H(+) with N2 as a cocatalyst confirms the essential mechanistic role for H2 formation, and hence a limiting stoichiometry for biological nitrogen fixation of eight electrons/protons, and provides direct experimental support for the reductive elimination mechanism. PMID- 24062455 TI - Genetically dictated change in host mucus carbohydrate landscape exerts a diet dependent effect on the gut microbiota. AB - We investigate how host mucus glycan composition interacts with dietary carbohydrate content to influence the composition and expressed functions of a human gut community. The humanized gnotobiotic mice mimic humans with a nonsecretor phenotype due to knockout of their alpha1-2 fucosyltransferase (Fut2) gene. The fecal microbiota of Fut2(-) mice that lack fucosylated host glycans show decreased alpha diversity relative to Fut2(+) mice and exhibit significant differences in community composition. A glucose-rich plant polysaccharide deficient (PD) diet exerted a strong effect on the microbiota membership but eliminated the effect of Fut2 genotype. Additionally fecal metabolites predicted host genotype in mice on a polysaccharide-rich standard diet but not on a PD diet. A more detailed mechanistic analysis of these interactions involved colonization of gnotobiotic Fut2(+) and Fut2(-) mice with Bacteroides thetaiotaomicron, a prominent member of the human gut microbiota known to adaptively forage host mucosal glycans when dietary polysaccharides are absent. Within Fut2(-) mice, the B. thetaiotaomicron fucose catabolic pathway was markedly down-regulated, whereas BT4241-4247, an operon responsive to terminal beta-galactose, the precursor that accumulates in the Fut2(-) mice, was significantly up-regulated. These changes in B. thetaiotaomicron gene expression were only evident in mice fed a PD diet, wherein B. thetaiotaomicron relies on host mucus consumption. Furthermore, up-regulation of the BT4241-4247 operon was also seen in humanized Fut2(-) mice. Together, these data demonstrate that differences in host genotype that affect the carbohydrate landscape of the distal gut interact with diet to alter the composition and function of resident microbes in a diet-dependent manner. PMID- 24062456 TI - Differential effect of aneuploidy on the X chromosome and genes with sex-biased expression in Drosophila. AB - Global analysis of gene expression via RNA sequencing was conducted for trisomics for the left arm of chromosome 2 (2L) and compared with the normal genotype. The predominant response of genes on 2L was dosage compensation in that similar expression occurred in the trisomic compared with the diploid control. However, the male and female trisomic/normal expression ratio distributions for 2L genes differed in that females also showed a strong peak of genes with increased expression and males showed a peak of reduced expression relative to the opposite sex. For genes in other autosomal regions, the predominant response to trisomy was reduced expression to the inverse of the altered chromosomal dosage (2/3), but a minor peak of increased expression in females and further reduced expression in males were also found, illustrating a sexual dimorphism for the response to aneuploidy. Moreover, genes with sex-biased expression as revealed by comparing amounts in normal males and females showed responses of greater magnitude to trisomy 2L, suggesting that the genes involved in dosage-sensitive aneuploid effects also influence sex-biased expression. Each autosomal chromosome arm responded to 2L trisomy similarly, but the ratio distributions for X-linked genes were distinct in both sexes, illustrating an X chromosome-specific response to aneuploidy. PMID- 24062459 TI - Chain conformations dictate multiscale charge transport phenomena in disordered semiconducting polymers. AB - Existing models for the electronic properties of conjugated polymers do not capture the spatial arrangement of the disordered macromolecular chains over which charge transport occurs. Here, we present an analytical and computational description in which the morphology of individual polymer chains is dictated by well-known statistical models and the electronic coupling between units is determined using Marcus theory. The multiscale transport of charges in these materials (high mobility at short length scales, low mobility at long length scales) is naturally described with our framework. Additionally, the dependence of mobility with electric field and temperature is explained in terms of conformational variability and spatial correlation. Our model offers a predictive approach to connecting processing conditions with transport behavior. PMID- 24062461 TI - NF-kappaB inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF-kappaB in immune-mediated diseases. AB - Activation of the nuclear transcription factor kappaB (NF-kappaB) regulates the expression of inflammatory genes crucially involved in the pathogenesis of inflammatory diseases. NF-kappaB governs the expression of adhesion molecules that play a pivotal role in leukocyte-endothelium interactions. We uncovered the crucial role of NF-kappaB activation within endothelial cells in models of immune mediated diseases using a "sneaking ligand construct" (SLC) selectively inhibiting NF-kappaB in the activated endothelium. The recombinant SLC1 consists of three modules: (i) an E-selectin targeting domain, (ii) a Pseudomonas exotoxin A translocation domain, and (iii) a NF-kappaB Essential Modifier-binding effector domain interfering with NF-kappaB activation. The E-selectin-specific SLC1 inhibited NF-kappaB by interfering with endothelial IkappaB kinase 2 activity in vitro and in vivo. In murine experimental peritonitis, the application of SLC1 drastically reduced the extravasation of inflammatory cells. Furthermore, SLC1 treatment significantly ameliorated the disease course in murine models of rheumatoid arthritis. Our data establish that endothelial NF-kappaB activation is critically involved in the pathogenesis of arthritis and can be selectively inhibited in a cell type- and activation stage-dependent manner by the SLC approach. Moreover, our strategy is applicable to delineating other pathogenic signaling pathways in a cell type-specific manner and enables selective targeting of distinct cell populations to improve effectiveness and risk-benefit ratios of therapeutic interventions. PMID- 24062462 TI - Electron transfer precedes ATP hydrolysis during nitrogenase catalysis. AB - The biological reduction of N2 to NH3 catalyzed by Mo-dependent nitrogenase requires at least eight rounds of a complex cycle of events associated with ATP driven electron transfer (ET) from the Fe protein to the catalytic MoFe protein, with each ET coupled to the hydrolysis of two ATP molecules. Although steps within this cycle have been studied for decades, the nature of the coupling between ATP hydrolysis and ET, in particular the order of ET and ATP hydrolysis, has been elusive. Here, we have measured first-order rate constants for each key step in the reaction sequence, including direct measurement of the ATP hydrolysis rate constant: kATP = 70 s(-1), 25 degrees C. Comparison of the rate constants establishes that the reaction sequence involves four sequential steps: (i) conformationally gated ET (kET = 140 s(-1), 25 degrees C), (ii) ATP hydrolysis (kATP = 70 s(-1), 25 degrees C), (iii) Phosphate release (kPi = 16 s(-1), 25 degrees C), and (iv) Fe protein dissociation from the MoFe protein (kdiss = 6 s( 1), 25 degrees C). These findings allow completion of the thermodynamic cycle undergone by the Fe protein, showing that the energy of ATP binding and protein protein association drive ET, with subsequent ATP hydrolysis and Pi release causing dissociation of the complex between the Fe(ox)(ADP)2 protein and the reduced MoFe protein. PMID- 24062463 TI - Strong cross-system interactions drive the activation of the QseB response regulator in the absence of its cognate sensor. AB - Bacterial two-component systems (TCSs) mediate specific responses to distinct conditions and/or stresses. TCS interactions are highly specific between cognate partners to avoid unintended cross-talk. Although cross-talk between a sensor kinase and a noncognate response regulator has been previously demonstrated, the majority of reported interactions have not been robust. Here, we report that in the case of the quorum-sensing Escherichia coli (Qse)BC TCS, absence of the cognate sensor QseC leads to robust, constitutive activation of the QseB response regulator by the noncognate polymyxin resistance (Pmr) sensor kinase PmrB. Remarkably, the noncognate PmrB exhibits a kinetic preference for QseB that is similar to QseC. However, although PmrB readily phosphorylates QseB in vitro, it is significantly less efficient at dephosphorylating QseB, compared with QseC, thereby explaining the increased levels of active QseB in the qseC mutant. In addition to PmrB activating QseB on the protein level, we found that the PmrA response regulator contributes to qseB transcription in the absence of QseC and PmrA specifically binds the qseBC promoter, indicative of a direct regulation of qseBC gene transcription by PmrAB under physiological conditions. Addition of ferric iron in the growth medium of wild-type uropathogenic E. coli induced the expression of qseBC in a PmrB-dependent manner. Taken together, our findings suggest that (i) robust cross-talk between noncognate partners is possible and (ii) this interaction can be manipulated for the development of antivirulence strategies aimed at targeting uropathogenic Escherichia coli and potentially other QseBC-PmrAB-bearing pathogens. PMID- 24062464 TI - Short-term synaptic plasticity in the deterministic Tsodyks-Markram model leads to unpredictable network dynamics. AB - Short-term synaptic plasticity strongly affects the neural dynamics of cortical networks. The Tsodyks and Markram (TM) model for short-term synaptic plasticity accurately accounts for a wide range of physiological responses at different types of cortical synapses. Here, we report a route to chaotic behavior via a Shilnikov homoclinic bifurcation that dynamically organizes some of the responses in the TM model. In particular, the presence of such a homoclinic bifurcation strongly affects the shape of the trajectories in the phase space and induces highly irregular transient dynamics; indeed, in the vicinity of the Shilnikov homoclinic bifurcation, the number of population spikes and their precise timing are unpredictable and highly sensitive to the initial conditions. Such an irregular deterministic dynamics has its counterpart in stochastic/network versions of the TM model: The existence of the Shilnikov homoclinic bifurcation generates complex and irregular spiking patterns and--acting as a sort of springboard--facilitates transitions between the down-state and unstable periodic orbits. The interplay between the (deterministic) homoclinic bifurcation and stochastic effects may give rise to some of the complex dynamics observed in neural systems. PMID- 24062465 TI - X-ray absorption spectroscopic investigation of the electronic structure differences in solution and crystalline oxyhemoglobin. AB - Hemoglobin (Hb) is the heme-containing O2 transport protein essential for life in all vertebrates. The resting high-spin (S = 2) ferrous form, deoxy-Hb, combines with triplet O2, forming diamagnetic (S = 0) oxy-Hb. Understanding this electronic structure is the key first step in understanding transition metal-O2 interaction. However, despite intense spectroscopic and theoretical studies, the electronic structure description of oxy-Hb remains elusive, with at least three different descriptions proposed by Pauling, Weiss, and McClure-Goddard, based on theory, spectroscopy, and crystallography. Here, a combination of X-ray absorption spectroscopy and extended X-ray absorption fine structure, supported by density functional theory calculations, help resolve this debate. X-ray absorption spectroscopy data on solution and crystalline oxy-Hb indicate both geometric and electronic structure differences suggesting that two of the previous descriptions are correct for the Fe-O2 center in oxy-Hb. These results support the multiconfigurational nature of the ground state developed by theoretical results. Additionally, it is shown here that small differences in hydrogen bonding and solvation effects can tune the ground state, tipping it into one of the two probable configurations. These data underscore the importance of solution spectroscopy and show that the electronic structure in the crystalline form may not always reflect the true ground-state description in solution. PMID- 24062466 TI - Nrf2 acts cell-autonomously in endothelium to regulate tip cell formation and vascular branching. AB - Angiogenesis, in which new blood vessels form via endothelial cell (EC) sprouting from existing vessels, is a critical event in embryonic development and multiple disease processes. Many insights have been made into key EC receptors and ligands/growth factors that govern sprouting angiogenesis, but intracellular molecular mechanisms of this process are not well understood. NF-E2-related factor 2 (Nrf2) is a transcription factor well-known for regulating the stress response in multiple pathologic settings, but its role in development is less appreciated. Here, we show that Nrf2 is increased and activated during vascular development. Global deletion of Nrf2 resulted in reduction of vascular density as well as EC sprouting. This was also observed with specific deletion of Nrf2 in ECs, but not with deletion of Nrf2 in the surrounding nonvascular tissue. Nrf2 deletion resulted in increased delta-like ligand 4 (Dll4) expression and Notch activity in ECs. Blockade of Dll4 or Notch signaling restored the vascular phenotype in Nrf2 KOs. Constitutive activation of endothelial Nrf2 enhanced EC sprouting and vascularization by suppression of Dll4/Notch signaling in vivo and in vitro. Nrf2 activation in ECs suppressed Dll4 expression under normoxia and hypoxia and inhibited Dll4-induced Notch signaling. Activation of Nrf2 blocked VEGF induction of VEGFR2-PI3K/Akt and downregulated HIF-2alpha in ECs, which may serve as important mechanisms for Nrf2 inhibition of Dll4 and Notch signaling. Our data reveal a function for Nrf2 in promoting the angiogenic sprouting phenotype in vascular ECs. PMID- 24062467 TI - Structural insights into proteoglycan-shaped Hedgehog signaling. AB - Hedgehog (Hh) morphogens play fundamental roles during embryogenesis and adulthood, in health and disease. Multiple cell surface receptors regulate the Hh signaling pathway. Among these, the glycosaminoglycan (GAG) chains of proteoglycans shape Hh gradients and signal transduction. We have determined crystal structures of Sonic Hh complexes with two GAGs, heparin and chondroitin sulfate. The interaction determinants, confirmed by site-directed mutagenesis and binding studies, reveal a previously not identified Hh site for GAG binding, common to all Hh proteins. The majority of Hh residues forming this GAG-binding site have been previously implicated in developmental diseases. Crystal packing analysis, combined with analytical ultracentrifugation of Sonic Hh-GAG complexes, suggests a potential mechanism for GAG-dependent Hh multimerization. Taken together, these results provide a direct mechanistic explanation of the observed correlation between disease and impaired Hh gradient formation. Moreover, GAG binding partially overlaps with the site of Hh interactions with an array of protein partners including Patched, hedgehog interacting protein, and the interference hedgehog protein family, suggesting a unique mechanism of Hh signaling modulation. PMID- 24062469 TI - Perturbation of the left inferior frontal gyrus triggers adaptive plasticity in the right homologous area during speech production. AB - The role of the right hemisphere in aphasia recovery after left hemisphere damage remains unclear. Increased activation of the right hemisphere has been observed after left hemisphere damage. This may simply reflect a release from transcallosal inhibition that does not contribute to language functions. Alternatively, the right hemisphere may actively contribute to language functions by supporting disrupted processing in the left hemisphere via interhemispheric connections. To test this hypothesis, we applied off-line continuous theta burst stimulation (cTBS) over the left inferior frontal gyrus (IFG) in healthy volunteers, then used functional MRI to investigate acute changes in effective connectivity between the left and right hemispheres during repetition of auditory and visual words and pseudowords. In separate sessions, we applied cTBS over the left anterior IFG (aIFG) or posterior IFG (pIFG) to test the anatomic specificity of the effects of cTBS on speech processing. Compared with cTBS over the aIFG, cTBS over the pIFG suppressed activity in the left pIFG and increased activity in the right pIFG during pseudoword vs. word repetition in both modalities. This effect was associated with a stronger facilitatory drive from the right pIFG to the left pIFG during pseudoword repetition. Critically, response became faster as the influence of the right pIFG on left pIFG increased, indicating that homologous areas in the right hemisphere actively contribute to language function after a focal left hemisphere lesion. Our findings lend further support to the notion that increased activation of homologous right hemisphere areas supports aphasia recovery after left hemisphere damage. PMID- 24062471 TI - African hominin stable isotopic data do not necessarily indicate grass consumption. PMID- 24062472 TI - Episodic-like memory and divergent brain systems in mammals and birds. PMID- 24062473 TI - A qualitative study examining the influences on situation awareness and the identification, mitigation and escalation of recognised patient risk. AB - BACKGROUND: Situation awareness (SA)-the perception of data elements, comprehension of their meaning and projection of their status in the near future has been associated with human performance in high-risk environments, including aviation and the operating room. The influences on SA in inpatient medicine are unknown. METHODS: We conducted seven focus groups with nurses, respiratory therapists and resident physicians using a standardised semistructured focus group guide to promote discussion. Recordings of the focus groups were transcribed verbatim, and transcripts were qualitatively analysed by two independent reviewers to identify convergent and divergent themes. RESULTS: Three themes emerged: (1) team-based care, (2) availability of standardised data and (3) standardised processes and procedures. We categorised these into social, technological and organisational influences on SA. Subthemes that emerged from each focus group were shared language to describe at-risk patients, provider experience in critical care/deterioration and interdisciplinary huddles to identify and plan for at-risk patients. An objective early warning score, proactive assessment and planning, adequate clinician staffing and tools for entering, displaying and monitoring data trends were identified by six of seven groups. Our data better reflected the concepts of team SA and shared SA than individual SA. CONCLUSIONS: Team-based care and standardisation support SA and the identification and treatment of patient risk in the complex environment of inpatient care. These findings can be used to guide the development and implementation of targeted interventions such as huddles to proactively scan for risk and electronic health record displays of data trends. PMID- 24062474 TI - Prevalence of melioidosis in patients with suspected pulmonary tuberculosis and sputum smear negative for acid-fast bacilli in northeast Thailand. AB - The clinical and radiological features of pulmonary melioidosis can mimic tuberculosis. We prospectively evaluated 118 patients with suspected pulmonary tuberculosis who were acid-fast bacilli (AFB) smear negative at Udon Thani Hospital, northeast Thailand. Culture of residual sputum from AFB testing was positive for Burkholderia pseudomallei in three patients (2.5%; 95% confidence interval [CI] 0.5-7.3%). We propose that in melioidosis-endemic areas, residual sputum from AFB testing should be routinely cultured for B. pseudomallei. PMID- 24062475 TI - Serotype-specific host responses in rhesus macaques after primary dengue challenge. AB - Dengue virus (DENV) is considered to be the most important arthropod-borne viral disease and causes more than 100 million human infections annually. To further characterize primary DENV infection in vivo, rhesus macaques were infected with DENV-1, DENV-2, DENV-3, or DENV-4 and clinical parameters, as well as specificity and longevity of serologic responses, were assessed. Overt clinical symptoms were not present after infection. However, abnormalities in blood biochemical parameters consistent with heart, kidney, and liver damage were observed, and changes in plasma fibrinogen, D-dimers, and protein C indicated systemic activation of the blood coagulation pathway. Significant homotypic and heterotypic serum immunoglobulins were present in all animals, and IgG persisted for at least 390 days. Serum neutralizing antibody responses were highly serotype specific by day 120. However, some heterotypic neutralizing activity was noted in infected animals. Identification of serotype-specific host responses may help elucidate mechanisms that mediate severe DENV disease after reinfection. PMID- 24062476 TI - Norovirus genogroup II gastroenteritis in hospitalized children in South India. AB - The distribution of norovirus (NoV) genogroup II in children < 5 years of age admitted to a south Indian hospital with diarrhea was investigated. Viral RNA extracted from 282 stool samples were screened for NoV GII and positive amplicons sequenced. Twenty-eight (9.9%) had NoV GII infection with a median age of 6 months, with more severe episodes of diarrhea among infected (median Vesikari score 13, interquartile range [IQR] 10-15) than children without infection (median score 10, IQR 8-13, P = 0.002). The study documents NoV GII infections as an important cause of gastroenteritis and the genetic diversity of circulating strains. PMID- 24062477 TI - Mapping malaria transmission intensity in Malawi, 2000-2010. AB - Substantial development assistance has been directed towards reducing the high malaria burden in Malawi over the past decade. We assessed changes in transmission over this period of malaria control scale-up by compiling community Plasmodium falciparum rate (PfPR) data during 2000-2011 and used model-based geostatistical methods to predict mean PfPR2-10 in 2000, 2005, and 2010. In addition, we calculated population-adjusted prevalences and populations at risk by district to inform malaria control program priority setting. The national population-adjusted PfPR2-10 was 37% in 2010, and we found no evidence of change over this period of scale-up. The entire population of Malawi is under meso endemic transmission risk, with those in districts along the shore of Lake Malawi and Shire River Valley under highest risk. The lack of change in prevalence confirms modeling predictions that when compared with lower transmission, prevalence reductions in high transmission settings require greater investment and longer time scales. PMID- 24062478 TI - Animal husbandry practices in rural Bangladesh: potential risk factors for antimicrobial drug resistance and emerging diseases. AB - Antimicrobial drug administration to household livestock may put humans and animals at risk for acquisition of antimicrobial drug-resistant pathogens. To describe animal husbandry practices, including animal healthcare-seeking and antimicrobial drug use in rural Bangladesh, we conducted semi-structured in-depth interviews with key informants, including female household members (n = 79), village doctors (n = 10), and pharmaceutical representatives, veterinarians, and government officials (n = 27), and performed observations at animal health clinics (n = 3). Prevalent animal husbandry practices that may put persons at risk for acquisition of pathogens included shared housing and water for animals and humans, antimicrobial drug use for humans and animals, and crowding. Household members reported seeking human and animal healthcare from unlicensed village doctors rather than formal-sector healthcare providers and cited cost and convenience as reasons. Five times more per household was spent on animal than on human healthcare. Strengthening animal and human disease surveillance systems should be continued. Interventions are recommended to provide vulnerable populations with a means of protecting their livelihood and health. PMID- 24062479 TI - Leishmaniases in Greece. AB - Abstract. During the last 35 years, visceral leishmaniasis has spread in Greece with autochthonous human cases appearing in 41 of the 54 prefectures. The occurrence of the disease was mapped and related to dog seropositivity, environmental and geospatial risk factors. Average dog seropositivity was 22.1% and positive animals were found in 43 of 54 prefectures. Factors like: altitude, presence of water bodies, land use, wind speed, mean land surface temperature, mean relative humidity, and mean annual rainfall were found to affect dog seropositivity. Cases of cutaneous leishmaniasis, caused by Leishmania tropica are also increasing. Phlebotomus similis believed to be the potential vector of L. tropica in Greece, was found in areas where the disease is widespread but also where cases have never been reported implying a danger of introduction of this anthroponotic parasite to new regions. PMID- 24062480 TI - Bartonella and Toxoplasma infections in stray cats from Iraq. AB - Because of overpopulation, stray/feral cats were captured on military bases in Iraq as part of the US Army Zoonotic Disease Surveillance Program. Blood samples were collected from 207 cats, mainly in Baghdad but also in North and West Iraq, to determine the prevalence of Bartonella and Toxoplasma infections. Nine (4.3%) cats, all from Baghdad, were bacteremic with B. henselae type I. Seroprevalence was 30.4% for T. gondii, 15% for B. henselae, and 12.6% for B. clarridgeiae. Differences in Bartonella prevalence by location were statistically significant, because most of the seropositive cats were from Baghdad. There was no association between T. gondii seropositivity and either of the two Bartonella species surveyed. This report is the first report on the prevalence of Bartonella and T. gondii among stray cats in Iraq, which allows for better evaluation of the zoonotic risk potential to the Iraqi people and deployed military personnel by feral cat colonies. PMID- 24062481 TI - Persistence of detectable immunoglobulin M antibodies up to 8 years after infection with West Nile virus. AB - In Houston, we have been monitoring the immune response to West Nile virus (WNV) infection in a large cohort of study participants since 2002. Using enzyme-linked immunosorbent assay techniques, serum from 163 participants was tested for the presence of anti-WNV immunoglobulin M (IgM) and IgG antibodies. We found that 42%, 34%, and 23% of study participants had either positive or equivocal results when tested for anti-WNV IgM antibodies approximately 1, 6, and 8 years post infection, respectively. Conversely, almost one-half of study participants (46%) had undetectable anti-WNV IgG antibodies by 8 years post-infection. This study is the first study to calculate the slope of the rate of decay of antibodies over time as well as show persistence of detectable anti-WNV IgM antibodies up to 8 years post-infection. These findings warrant additional investigation, particularly the determination of whether persistence of IgM is related to persistent infection with WNV. PMID- 24062482 TI - The impact of a short depression and anxiety screening tool in epilepsy care in primary health care settings in Zambia. AB - Up to 60% of the 50 million persons with epilepsy (PWE) worldwide have depression and anxiety and 80% of PWE live in low-income regions. Common psychiatric comorbidities are often unrecognized and undertreated. We developed and validated a 10-item screening tool for the detection of depression and anxiety at primary healthcare clinics in Zambia in which the baseline detection rate among PWE was 1%. We trained primary care clinic workers in selected clinics to use this screening tool. A retrospective chart review was conducted for 120 consecutive PWE who received care one month after training. Detection improved from 1% to 49%, and treatment was frequently initiated. Of the 120 screened, 59 (49.2%) scored above cutoff point of 18. Of these persons, 43 (73.0%) were positive for depression, 16 (23.0%) were positive for anxiety, 38 (64.4%) received counseling, 18 (30.5%) received antidepressants, and 3 (5.1%) were referred to a psychiatrist. Use of this screening tool resulted in improved mental health care for PWE. PMID- 24062483 TI - An improved selective culture medium enhances the isolation of Burkholderia pseudomallei from contaminated specimens. AB - Burkholderia pseudomallei is a Gram-negative environmental bacterium found in tropical climates that causes melioidosis. Culture remains the diagnostic gold standard, but isolation of B. pseudomallei from heavily contaminated sites, such as fecal specimens, can be difficult. We recently reported that B. pseudomallei is capable of infecting the gastrointestinal tract of mice and suggested that the same may be true in humans. Thus, there is a strong need for new culture techniques to allow for efficient detection of B. pseudomallei in fecal and other specimens. We found that the addition of norfloxacin, ampicillin, and polymyxin B to Ashdown's medium (NAP-A) resulted in increased specificity without affecting the growth of 25 B. pseudomallei strains. Furthermore, recovery of B. pseudomallei from human clinical specimens was not affected by the three additional antibiotics. Therefore, we conclude that NAP-A medium provides a new tool for more sensitive isolation of B. pseudomallei from heavily contaminated sites. PMID- 24062484 TI - Malaria diagnostics in clinical trials. AB - Malaria diagnostics are widely used in epidemiologic studies to investigate natural history of disease and in drug and vaccine clinical trials to exclude participants or evaluate efficacy. The Malaria Laboratory Network (MLN), managed by the Office of HIV/AIDS Network Coordination, is an international working group with mutual interests in malaria disease and diagnosis and in human immunodeficiency virus/acquired immunodeficiency syndrome clinical trials. The MLN considered and studied the wide array of available malaria diagnostic tests for their suitability for screening trial participants and/or obtaining study endpoints for malaria clinical trials, including studies of HIV/malaria co infection and other malaria natural history studies. The MLN provides recommendations on microscopy, rapid diagnostic tests, serologic tests, and molecular assays to guide selection of the most appropriate test(s) for specific research objectives. In addition, this report provides recommendations regarding quality management to ensure reproducibility across sites in clinical trials. Performance evaluation, quality control, and external quality assessment are critical processes that must be implemented in all clinical trials using malaria tests. PMID- 24062485 TI - Detection of Leishmania siamensis DNA in saliva by polymerase chain reaction. AB - Polymerase chain reaction was used to detect Leishmania siamensis DNA from clinical samples collected from six leishmaniasis patients during 2011-2012. The samples used in this study came from bone marrow, blood, buffy coat, saliva, urine, and tissue biopsy specimens. Saliva was a good source for L. siamensis DNA by polymerase chain reaction. L. siamensis DNA was also found in saliva of an asymptomatic case-patient. Levels of L. siamensis DNA in saliva decreased until being undetectable after treatment. These levels could be used as a marker to evaluate efficacy of the treatment. A larger study is needed to evaluate this method as a screening and survey tool to study the silent background of Leishmania infection among the at-risk population. PMID- 24062486 TI - Chimeric anti-CD14 IGG2/4 Hybrid antibodies for therapeutic intervention in pig and human models of inflammation. AB - CD14 is a key recognition molecule of innate immune responses, interacting with several TLRs. TLR signaling cross-talks extensively with the complement system, and combined CD14 and complement inhibition has been proved effective in attenuating inflammatory responses. Pig models of human diseases have emerged as valuable tools to study therapeutic intervention, but suitable neutralizing Abs are rare. Undesired Fc-mediated functions, such as platelet activation and IL-8 release induced by the porcine CD14-specific clone Mil2, limit further studies. Therefore, an inert human IgG2/IgG4 hybrid C region was chosen for an rMil2. As revealed in ex vivo and in vivo pig experiments, rMil2 inhibited the CD14 mediated proinflammatory cytokine response similar to the original clone, but lacked the undesired Fc-effects, and inflammation was attenuated further by simultaneous complement inhibition. Moreover, rMil2 bound porcine FcRn, a regulator of t1/2 and biodistribution. Thus, rMil2, particularly combined with complement inhibitors, should be well suited for in vivo studies using porcine models of diseases, such as sepsis and ischemia-reperfusion injury. Similarly, the recombinant anti-human CD14 IgG2/4 Ab, r18D11, was generated with greatly reduced Fc-mediated effects and preserved inhibitory function ex vivo. Such Abs might be drug candidates for the treatment of innate immunity-mediated human diseases. PMID- 24062488 TI - Neutrophils amplify autoimmune central nervous system infiltrates by maturing local APCs. AB - Multiple sclerosis is considered to be initiated by a deregulated, myelin specific T cell response. However, the formation of inflammatory CNS lesions and the contribution of different leukocyte subsets in setting up these lesions are still incompletely understood. In this study, we show that, in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, neutrophil granulocytes are important contributors in preparing CNS inflammation. Preclinical single-dose Ab-mediated depletion of neutrophils delayed the onset and continuous depletion attenuated the development of experimental autoimmune encephalomyelitis, whereas the generation of a myelin-specific T cell response remained unaffected. Neutrophil-related enzymes such as myeloperoxidase and neutrophil elastase did not contribute in mounting CNS inflammation, as analyzed by using respective knockout mice and inhibitors. CNS-infiltrating neutrophils secreted proinflammatory molecules and matured bone marrow-derived dendritic cells in vitro, which in turn enhanced their ability to restimulate myelin specific T cells. This was mirrored in vivo, in which depletion of neutrophils specifically impaired maturation of microglia and macrophages into professional APCs, resulting in a diminished amplification of early CNS inflammation. Therefore, inside the CNS neutrophils provide local cofactors that are required for the maturation of myeloid cells into professional APCs representing an essential step for the local restimulation of myelin-specific T cells and the development of autoimmune disease. PMID- 24062487 TI - Suprachiasmatic astrocytes modulate the circadian clock in response to TNF-alpha. AB - The immune and the circadian systems interact in a bidirectional fashion. The master circadian oscillator, located in the suprachiasmatic nuclei (SCN) of the hypothalamus, responds to peripheral and local immune stimuli, such as proinflammatory cytokines and bacterial endotoxin. Astrocytes exert several immune functions in the CNS, and there is growing evidence that points toward a role of these cells in the regulation of circadian rhythms. The aim of this work was to assess the response of SCN astrocytes to immune stimuli, particularly to the proinflammatory cytokine TNF-alpha. TNF-alpha applied to cultures of SCN astrocytes from Per2(luc) knockin mice altered both the phase and amplitude of PER2 expression rhythms, in a phase-dependent manner. Furthermore, conditioned media from SCN astrocyte cultures transiently challenged with TNF-alpha induced an increase in Per1 expression in NIH 3T3 cells, which was blocked by TNF-alpha antagonism. In addition, these conditioned media could induce phase shifts in SCN PER2 rhythms and, when administered intracerebroventricularly, induced phase delays in behavioral circadian rhythms and SCN activation in control mice, but not in TNFR-1 mutants. In summary, our results show that TNF-alpha modulates the molecular clock of SCN astrocytes in vitro, and also that, in response to this molecule, SCN astrocytes can modulate clock gene expression in other cells and tissues, and induce phase shifts in a circadian behavioral output in vivo. These findings suggest a role for astroglial cells in the alteration of circadian timing by immune activation. PMID- 24062489 TI - Estrogen signaling through the G protein-coupled estrogen receptor regulates granulocyte activation in fish. AB - Neutrophils are major participants in innate host responses. It is well known that estrogens have an immune-modulatory role, and some evidence exists that neutrophil physiology can be altered by these molecules. Traditionally, estrogens act via classical nuclear estrogen receptors, but the identification of a G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor that binds estradiol and other estrogens, has opened up the possibility of exploring additional estrogen-mediated effects. However, information on the importance of GPER for immunity, especially, in neutrophils is scant. In this study, we report that gilthead seabream (Sparus aurata L.) acidophilic granulocytes, which are the functional equivalent of mammalian neutrophils, express GPER at both mRNA and protein levels. By using a GPER selective agonist, G1, it was found that GPER activation in vitro slightly reduced the respiratory burst of acidophilic granulocytes and drastically altered the expression profile of several genes encoding major pro- and anti-inflammatory mediators. In addition, GPER signaling in vivo modulated adaptive immunity. Finally, a cAMP analog mimicked the effects of G1 in the induction of the gene coding for PG-endoperoxide synthase 2 and in the induction of CREB phosphorylation, whereas pharmacological inhibition of protein kinase A superinduced PG-endoperoxide synthase 2. Taken together, our results demonstrate for the first time, to our knowledge, that estrogens are able to modulate vertebrate granulocyte functions through a GPER/cAMP/protein kinase A/CREB signaling pathway and could establish therapeutic targets for several immune disorders in which estrogens play a prominent role. PMID- 24062490 TI - Preclinical in vivo modeling of cytokine release syndrome induced by ErbB retargeted human T cells: identifying a window of therapeutic opportunity? AB - The ErbB network is dysregulated in many solid tumors. To exploit this, we have developed a chimeric Ag receptor (CAR) named T1E28z that targets several pathogenetically relevant ErbB dimers. T1E28z is coexpressed with a chimeric cytokine receptor named 4alphabeta (combination termed T4), enabling the selective expansion of engineered T cells using IL-4. Human T4(+) T cells exhibit antitumor activity against several ErbB(+) cancer types. However, ErbB receptors are also expressed in several healthy tissues, raising concerns about toxic potential. In this study, we have evaluated safety of T4 immunotherapy in vivo using a SCID beige mouse model. We show that the human T1E28z CAR efficiently recognizes mouse ErbB(+) cells, rendering this species suitable to evaluate preclinical toxicity. Administration of T4(+) T cells using the i.v. or intratumoral routes achieves partial tumor regression without clinical or histopathologic toxicity. In contrast, when delivered i.p., tumor reduction is accompanied by dose-dependent side effects. Toxicity mediated by T4(+) T cells results from target recognition in both tumor and healthy tissues, leading to release of both human (IL-2/IFN-gamma) and murine (IL-6) cytokines. In extreme cases, outcome is lethal. Both toxicity and IL-6 release can be ameliorated by prior macrophage depletion, consistent with clinical data that implicate IL-6 in this pathogenic event. These data demonstrate that CAR-induced cytokine release syndrome can be modeled in mice that express target Ag in an appropriate distribution. Furthermore, our findings argue that ErbB-retargeted T cells can achieve therapeutic benefit in the absence of unacceptable toxicity, providing that route of administration and dose are carefully optimized. PMID- 24062493 TI - Tailoring oral contraceptive pills to meet the needs of women. PMID- 24062494 TI - NICE CG156: fertility update. What it means for general practitioners. PMID- 24062495 TI - Embracing post-fertilisation methods of family planning: a call to action. AB - Family planning methods that act when administered after fertilisation would have substantial benefits: they could be used longer after sex than current emergency contraceptives, and potentially a woman could use them only on relatively rare occasions when her menstrual period is delayed. Although such methods would displease abortion opponents, they would likely be welcomed by many women. Research to develop post-fertilisation fertility control agents should be pursued. PMID- 24062496 TI - Henry Morgentaler: model for the UK? PMID- 24062499 TI - Testing association with Fisher's Exact test. PMID- 24062500 TI - Contraceptive and sexual health care issues in women with schizophrenia. PMID- 24062501 TI - Welcome Prince George, but if only... PMID- 24062502 TI - Sexual health: the Cinderella of reproductive health services. PMID- 24062503 TI - The erotic imagery of the geisha. PMID- 24062504 TI - Stonewall. PMID- 24062505 TI - Comment on 'Statement on combined hormonal contraceptives containing third- or fourth-generation progestogens or cyproterone acetate, and the associated risk of thromboembolism'. PMID- 24062506 TI - Comment on 'Statement on combined hormonal contraceptives containing third- or fourth-generation progestogens or cyproterone acetate, and the associated risk of thromboembolism': author's response. PMID- 24062507 TI - Comment on 'An emergency contraception algorithm based on risk assessment: changes in clinicians' practice and patients' choices'. PMID- 24062508 TI - Comment on journal review of 'Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture'. PMID- 24062509 TI - Comment on 'An emergency contraception algorithm based on risk assessment: changes in clinicians' practice and patients' choices': authors' response. PMID- 24062510 TI - Comment on 'The policing of abortion services in England'. PMID- 24062511 TI - Comment on 'Adverse reaction to Nexplanon(r)'. PMID- 24062512 TI - Comment on 'Adverse reaction to Nexplanon(r)': author's response. PMID- 24062513 TI - Comment on 'The policing of abortion services in England': author's response. PMID- 24062514 TI - Infections post-Nexplanon(r) insertion. PMID- 24062515 TI - Cases of blunt needle in Nexplanon(r) insertion device. PMID- 24062516 TI - Do UK Faculty registered trainers teach the insertion and removal of subdermal contraceptive implants in a similar fashion? PMID- 24062517 TI - IUD insertions and analgesia. PMID- 24062518 TI - Comment on 'Unusual shaped IUS'. PMID- 24062519 TI - Sufficient production of geranylgeraniol is required to maintain endotoxin tolerance in macrophages. AB - Endotoxin tolerance allows macrophages to produce large quantities of proinflammatory cytokines immediately after their contact with lipopolysaccharides (LPSs), but prevents their further production after repeated exposure to LPSs. While this response is known to prevent overproduction of proinflammatory cytokines, the mechanism through which endotoxin tolerance is established has not been identified. In the current study, we demonstrate that sufficient production of geranylgeraniol (GGOH) in macrophages is required to maintain endotoxin tolerance. We show that increased synthesis of 3-hydroxy-3 methyl-glutaryl-CoA reductase (HMGCR) protein following LPS treatment is required to produce enough GGOH to inhibit expression of Malt1, a protein known to stimulate expression of proinflammatory cytokines, in macrophages repeatedly exposed to LPSs. Depletion of GGOH caused by inhibition of HMGCR led to increased Malt1 expression in macrophages subjected to repeated exposure to LPSs. Consequently, endotoxin tolerance was impaired, and production of interleukin 1 beta and other proinflammatory cytokines was markedly elevated in these cells. These results suggest that insufficient production of GGOH in macrophages may cause autoinflammatory diseases. PMID- 24062520 TI - Colonic milk curd obstruction in an extremely low birthweight infant. PMID- 24062521 TI - Genetic variants in CHI3L1 influencing YKL-40 levels: resequencing 900 individuals and genotyping 9000 individuals from the general population. AB - BACKGROUND: Despite its important role in many serious diseases, the genetic background for plasma YKL-40 has still not been systematically catalogued. Therefore, we aimed at identifying genetic variants in CHI3L1 influencing plasma YKL-40 levels in the general population. METHODS: We resequenced the promoter, all 10 exons and exon-flanking intron segments of CHI3L1 in 904 individuals from the Danish general population (n=8899) with extreme plasma YKL-40 levels, adjusted for age. To potentially identify clinically important genetic variants with elevated plasma YKL-40 levels, we included twice as many individuals with the highest plasma YKL-40 levels (n=603) compared with the lowest plasma YKL-40 levels (n=301). Next, we mapped linkage disequilibrium for all variants with a minor allele frequency (MAF)>0.005. Finally, all participants were genotyped for eight variants that had divergent MAFs in the two extreme plasma YKL-40 groups. RESULTS: We identified 59 genetic variants in CHI3L1. Fifteen of the genetic variants were associated with plasma YKL-40 levels. Three promoter SNPs, 1 non synonymous SNP, and four intronic SNPs in CHI3L1 were associated with plasma YKL 40 levels at or below genome-wide association significance levels (unadjusted p for trend: from 4 * 10(-8) to 6 * 10(-243); age adjusted percentiles p for trend: from 3 * 10(-12) to 2 * 10(-304)). CONCLUSIONS: In a systematic search to identify genetic variants influencing plasma YKL-40 levels, we identified eight SNPs associated with plasma YKL-40 levels in the general population. PMID- 24062522 TI - Measurement of dengue epidemic spreading pattern using density analysis method: retrospective spatial statistical study of dengue in Subang Jaya, Malaysia, 2006 2010. AB - BACKGROUND: Dengue has emerged as one of the major public health problems in Malaysia. The Ministry of Health, Malaysia, is committed in monitoring and controlling this disease for many years. The objective of this study is to analyze the dengue outbreak pattern on a monthly basis in Subang Jaya in terms of their spatial dissemination and hotspot identification. METHODS: Collated dengue cases data covering a 5-year period (2006-2010) retrieved from a municipal surveillance system of Subang Jaya were georeferenced and then converted into Geographical Information System format. Average nearest neighbor (ANN) analysis and kernel density (KD) estimation were used to assess the spatial dissemination of dengue cases and detect dengue hotspots, respectively. RESULTS: The spatial patterns of dengue fever cases during the 5-year period were spatially clustered (with R values < 1) based on the monthly frequency data. The hotspot map produced by the KD techniques showed a spatially diffused pattern. CONCLUSION: The methodology used in the study and the result obtained could be useful not only for documentation by epidemiologists but also for active surveillance of dengue outbreak in a locality. PMID- 24062523 TI - Assessing full immunisation coverage using lot quality assurance sampling in urban and rural districts of southwest Nigeria. AB - BACKGROUND: This study was conducted to identify administrative wards (lots) with unacceptable levels of full child immunisation coverage, and to identify factors associated with achievement of a complete child immunisation schedule in Ibadan North East (IBNE) and Ido local government areas (LGAs) of Oyo State, Nigeria. METHODS: A cross-sectional survey involving 1178 mothers, 588 from IBNE LGAs and 590 from Ido LGAs, with children 12-23 months of age was conducted. Children were considered 'fully-immunised' if they received all the vaccines included in the immunisation schedule. Lot quality assurance sampling was used to determine lots with acceptable and non-acceptable coverage. Samples were weighted based on the population by lot to estimate overall coverage in the two LGAs and a logistic regression model was used to identify factors associated with the fully immunised child. RESULTS: Mean age of the mothers was 28.5 +/- 5.6 and 28.1+/- 6.0 years in IBNE and Ido LGAs, respectively. Eleven of 12 wards in IBNE and all the wards in Ido had unacceptable coverage. The proportion of fully immunised children was 40.2% in IBNE and 41.3% in Ido. Maternal age >=30 years, retention of an immunisation card, completion of tertiary education, or secondary education, hospital birth and first-order birth were significant predictors of complete childhood immunisation. CONCLUSION: The level of full immunisation coverage was unacceptable in almost all the wards. Educational intervention on the importance of completion of immunisation schedule should target young, uneducated mothers, mothers who delivered their babies at home and those with a high birth order. PMID- 24062524 TI - Prevalence and predictors of hypoxaemia in respiratory and non-respiratory primary diagnoses among emergently ill children at a tertiary hospital in south western Nigeria. AB - BACKGROUND: Hypoxaemia is a potentially harmful complication of both acute lower respiratory tract infections (ALRI) and non-ALRI in children but its contribution to burden and outcomes of hospital admissions in Africa is unclear. We investigated prevalence and predictors of hypoxaemia in ALRI and non-ALRI according to age and primary diagnoses in emergently ill children in south western Nigeria. METHODS: In 1726 emergently ill children admitted to a tertiary hospital in Ibadan, south western Nigeria, oxygen saturation was measured shortly after admission. Hypoxaemia was defined as oxygen saturation <90%. Clinical features and the primary admission diagnoses were recorded. Prevalence of hypoxaemia according to age and diagnoses was calculated. Symptoms and signs associated with hypoxaemia were compared between children with ALRI and those with non-ALRI. RESULTS: Hypoxaemia was detected in 28.6% (494/1726) of admissions. Prevalence of hypoxaemia varied in different conditions: it was 49.2% (154/313) in ALRI, 41.1% (188/454) in neonates, 27.2% (6/22) in post-neonatal tetanus, 23.3% (14/60) in sickle cell anaemia, 22.6% (38/168) in septicaemia and 14.4% (76/527) of malaria cases. Nasal flaring (OR 3.86; 95% CI 1.70 to 8.74) and chest retraction (OR 4.77; 95% CI 1.91 to 11.92) predicted hypoxaemia in ALRI but not in non-ALRI. CONCLUSIONS: Hypoxaemia is common among Nigerian children admitted to an emergency unit and is associated with a poor outcome irrespective of primary admission diagnosis. Provision of equipment to measure oxygen saturation and facilities for effective oxygen delivery might substantially reduce mortality. PMID- 24062526 TI - Novel facts about FAK: new connections to drug resistance? PMID- 24062525 TI - Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer. AB - BACKGROUND: We previously found focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to taxanes; however, the mechanisms are not well understood. METHODS: We characterized the biologic response of taxane-resistant and taxane sensitive ovarian cancer models to a novel FAK inhibitor (VS-6063). We used reverse-phase protein arrays (RPPA) to identify novel downstream targets in taxane-resistant cell lines. Furthermore, we correlated clinical and pathological data with nuclear and cytoplasmic expression of FAK and YB-1 in 105 ovarian cancer samples. Statistical tests were two-sided, and P values were calculated with Student t test or Fisher exact test. RESULTS: We found that VS-6063 inhibited FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner. The combination of VS-6063 and paclitaxel markedly decreased proliferation and increased apoptosis, which resulted in 92.7% to 97.9% reductions in tumor weight. RPPA data showed that VS-6063 reduced levels of AKT and YB-1 in taxane-resistant cell lines. FAK inhibition enhanced chemosensitivity in taxane-resistant cells by decreasing YB-1 phosphorylation and subsequently CD44 in an AKT-dependent manner. In human ovarian cancer samples, nuclear FAK expression was associated with increased nuclear YB-1 expression (chi2) = 37.7; P < .001). Coexpression of nuclear FAK and YB-1 was associated with statistically significantly worse median overall survival (24.9 vs 67.3 months; hazard ratio = 2.64; 95% confidence interval = 1.38 to 5.05; P = .006). CONCLUSIONS: We have identified a novel pathway whereby FAK inhibition with VS-6063 overcomes YB-1 mediated paclitaxel resistance by an AKT-dependent pathway. These findings have implications for clinical trials aimed at targeting FAK. PMID- 24062527 TI - Construction of reference chromosome-scale pseudomolecules for potato: integrating the potato genome with genetic and physical maps. AB - The genome of potato, a major global food crop, was recently sequenced. The work presented here details the integration of the potato reference genome (DM) with a new sequence-tagged site marker-based linkage map and other physical and genetic maps of potato and the closely related species tomato. Primary anchoring of the DM genome assembly was accomplished by the use of a diploid segregating population, which was genotyped with several types of molecular genetic markers to construct a new ~936 cM linkage map comprising 2469 marker loci. In silico anchoring approaches used genetic and physical maps from the diploid potato genotype RH89-039-16 (RH) and tomato. This combined approach has allowed 951 superscaffolds to be ordered into pseudomolecules corresponding to the 12 potato chromosomes. These pseudomolecules represent 674 Mb (~93%) of the 723 Mb genome assembly and 37,482 (~96%) of the 39,031 predicted genes. The superscaffold order and orientation within the pseudomolecules are closely collinear with independently constructed high density linkage maps. Comparisons between marker distribution and physical location reveal regions of greater and lesser recombination, as well as regions exhibiting significant segregation distortion. The work presented here has led to a greatly improved ordering of the potato reference genome superscaffolds into chromosomal "pseudomolecules". PMID- 24062528 TI - A mutation in the FHA domain of Coprinus cinereus Nbs1 Leads to Spo11-independent meiotic recombination and chromosome segregation. AB - Nbs1, a core component of the Mre11-Rad50-Nbs1 complex, plays an essential role in the cellular response to DNA double-strand breaks (DSBs) and poorly understood roles in meiosis. We used the basidiomycete Coprinus cinereus to examine the meiotic roles of Nbs1. We identified the C. cinereus nbs1 gene and demonstrated that it corresponds to a complementation group previously known as rad3. One allele, nbs1-2, harbors a point mutation in the Nbs1 FHA domain and has a mild spore viability defect, increased frequency of meiosis I nondisjunction, and an altered crossover distribution. The nbs1-2 strain enters meiosis with increased levels of phosphorylated H2AX, which we hypothesize represent unrepaired DSBs formed during premeiotic replication. In nbs1-2, there is no apparent induction of Spo11-dependent DSBs during prophase. We propose that replication-dependent DSBs, resulting from defective replication fork protection and processing by the Mre11-Rad50-Nbs1 complex, are competent to form meiotic crossovers in C. cinereus, and that these crossovers lead to high levels of faithful chromosome segregation. In addition, although crossover distribution is altered in nbs1-2, the majority of crossovers were found in subtelomeric regions, as in wild-type. Therefore, the location of crossovers in C. cinereus is maintained when DSBs are induced via a Spo11-independent mechanism. PMID- 24062529 TI - Mapping condition-dependent regulation of lipid metabolism in Saccharomyces cerevisiae. AB - Lipids play a central role in cellular function as constituents of membranes, as signaling molecules, and as storage materials. Although much is known about the role of lipids in regulating specific steps of metabolism, comprehensive studies integrating genome-wide expression data, metabolite levels, and lipid levels are currently lacking. Here, we map condition-dependent regulation controlling lipid metabolism in Saccharomyces cerevisiae by measuring 5636 mRNAs, 50 metabolites, 97 lipids, and 57 (13)C-reaction fluxes in yeast using a three-factor full factorial design. Correlation analysis across eight environmental conditions revealed 2279 gene expression level-metabolite/lipid relationships that characterize the extent of transcriptional regulation in lipid metabolism relative to major metabolic hubs within the cell. To query this network, we developed integrative methods for correlation of multi-omics datasets that elucidate global regulatory signatures. Our data highlight many characterized regulators of lipid metabolism and reveal that sterols are regulated more at the transcriptional level than are amino acids. Beyond providing insights into the systems-level organization of lipid metabolism, we anticipate that our dataset and approach can join an emerging number of studies to be widely used for interrogating cellular systems through the combination of mathematical modeling and experimental biology. PMID- 24062531 TI - Microtubule depolymerization activates the Epstein-Barr virus lytic cycle through protein kinase C pathways in nasopharyngeal carcinoma cells. AB - Elevated levels of antibodies against Epstein-Barr virus (EBV) and the presence of viral DNA in plasma are reliable biomarkers for the diagnosis of nasopharyngeal carcinoma (NPC) in high-prevalence areas, such as South-East Asia. The presence of these viral markers in the circulation suggests that a minimal level of virus reactivation may have occurred in an infected individual, although the underlying mechanism of reactivation remains to be elucidated. Here, we showed that treatment with nocodazole, which provokes the depolymerization of microtubules, induces the expression of two EBV lytic cycle proteins, Zta and EA D, in EBV-positive NPC cells. This effect was independent of mitotic arrest, as viral reactivation was not abolished in cells synchronized at interphase. Notably, the induction of Zta by nocodazole was mediated by transcriptional upregulation via protein kinase C (PKC). Pre-treatment with inhibitors for PKC or its downstream signalling partners p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) abolished the nocodazole-mediated induction of Zta and EA-D. Interestingly, the effect of nocodazole, as well as colchicine and vinblastine, on lytic gene expression occurred only in NPC epithelial cells but not in cells derived from lymphocytes. These results establish a novel role of microtubule integrity in controlling the EBV life cycle through PKC and its downstream pathways, which represents a tissue-specific mechanism for controlling the life-cycle switch of EBV. PMID- 24062533 TI - An insulin-like growth factor homologue of Singapore grouper iridovirus modulates cell proliferation, apoptosis and enhances viral replication. AB - Insulin-like growth factors (IGFs) play crucial roles in regulating cell differentiation, proliferation and apoptosis. In this study, a novel IGF homologue gene (IGF-like) encoded by Singapore grouper iridovirus (SGIV) ORF062R (termed SGIV-IGF), was cloned and characterized. The coding region of SGIV-IGF is 771 bp in length, with a variable number of tandem repeats (VNTR) locus at the 3' end. We cloned one isoform of this novel gene, 582 bp in length, containing the predicted IGF domain and 3.6 copy numbers of the 27 bp repeat unit. SGIV-IGF was an early transcribed gene during viral infection, and SGIV-IGF was distributed predominantly in the cytoplasm with a diffused granular appearance. Intriguingly, overexpression of SGIV-IGF was able to promote the growth of grouper embryonic cells (GP cells) by promoting G1/S phase transition, which was at least partially dependent on its 3'-end VNTR locus. Furthermore, viral titre assay and real-time quantitative PCR (RT-qPCR) analysis proved that SGIV-IGF could promote SGIV replication in grouper cells. In addition, overexpression of SGIV-IGF mildly facilitated apoptosis in SGIV-infected non-host fathead minnow (FHM) cells. Together, our study demonstrated a novel functional gene of SGIV which may regulate viral replication and cellular processes through multiple mechanisms that appear to be cell type-dependent. PMID- 24062530 TI - Cell-type-specific transcriptional profiles of the dimorphic pathogen Penicillium marneffei reflect distinct reproductive, morphological, and environmental demands. AB - Penicillium marneffei is an opportunistic human pathogen endemic to Southeast Asia. At 25 degrees P. marneffei grows in a filamentous hyphal form and can undergo asexual development (conidiation) to produce spores (conidia), the infectious agent. At 37 degrees P. marneffei grows in the pathogenic yeast cell form that replicates by fission. Switching between these growth forms, known as dimorphic switching, is dependent on temperature. To understand the process of dimorphic switching and the physiological capacity of the different cell types, two microarray-based profiling experiments covering approximately 42% of the genome were performed. The first experiment compared cells from the hyphal, yeast, and conidiation phases to identify "phase or cell-state-specific" gene expression. The second experiment examined gene expression during the dimorphic switch from one morphological state to another. The data identified a variety of differentially expressed genes that have been organized into metabolic clusters based on predicted function and expression patterns. In particular, C-14 sterol reductase-encoding gene ergM of the ergosterol biosynthesis pathway showed high level expression throughout yeast morphogenesis compared to hyphal. Deletion of ergM resulted in severe growth defects with increased sensitivity to azole-type antifungal agents but not amphotericin B. The data defined gene classes based on spatio-temporal expression such as those expressed early in the dimorphic switch but not in the terminal cell types and those expressed late. Such classifications have been helpful in linking a given gene of interest to its expression pattern throughout the P. marneffei dimorphic life cycle and its likely role in pathogenicity. PMID- 24062532 TI - Kolente virus, a rhabdovirus species isolated from ticks and bats in the Republic of Guinea. AB - Kolente virus (KOLEV) is a rhabdovirus originally isolated from ticks and a bat in Guinea, West Africa, in 1985. Although tests at the time of isolation suggested that KOLEV is a novel rhabdovirus, it has remained largely uncharacterized. We assembled the complete genome sequence of the prototype strain DakAr K7292, which was found to encode the five canonical rhabdovirus structural proteins (N, P, M, G and L) with alternative ORFs (>180 nt) in the P and L genes. Serologically, KOLEV exhibited a weak antigenic relationship with Barur and Fukuoka viruses in the Kern Canyon group. Phylogenetic analysis revealed that KOLEV represents a distinct and divergent lineage that shows no clear relationship to any rhabdovirus except Oita virus, although with limited phylogenetic resolution. In summary, KOLEV represents a novel species in the family Rhabdoviridae. PMID- 24062534 TI - Multiple introductions of salmonid alphavirus from a wild reservoir have caused independent and self-sustainable epizootics in aquaculture. AB - Salmonid alphavirus (SAV) causes infections in farmed Atlantic salmon and rainbow trout in Europe. Genetic diversity exists among SAV strains from farmed fish and six subtypes have been proposed based on genetic distance. Here, we used six full genome sequences and 71 partial sequences of the structural ORF to estimate the evolutionary rate of SAV. The rate, 2.13*10(-4) nt substitutions per site per year, was further used to date evolutionary events in a Bayesian phylogenetic framework. The comparison of these dates with known historical events suggested that all six subtypes diverged prior to the twentieth century, earlier than the first attempts to introduce and farm rainbow trout in Europe. The subtypes must therefore have existed in a wild reservoir, as yet unidentified. The strains of each subtype, with the exception of subtype 2, have a common ancestor that existed after the 1970s - the start of modern farming of Atlantic salmon. These ancestors are likely to represent the independent introductions to farmed fish populations from the wild reservoir. The subtypes have developed subsequently into self-sustainable epizootics. The most parsimonious phylogeographic reconstruction suggested that the location of the wild reservoir is in or around the North Sea. After the initial introductions to aquaculture, further transmission of SAV was likely related to the industry infrastructure. This was exemplified by the finding of genetically identical subtype 2 and 3 strains separated by large geographical distances, as well as genetically distinct co circulating lineages within the same geographical area. PMID- 24062540 TI - Fast computation of minimal cut sets in metabolic networks with a Berge algorithm that utilizes binary bit pattern trees. AB - Minimal cut sets are a valuable tool for analyzing metabolic networks and for identifying optimal gene intervention strategies by eliminating unwanted metabolic functions and keeping desired functionality. Minimal cut sets rely on the concept of elementary flux modes, which are sets of indivisible metabolic pathways under steady-state condition. However, the computation of minimal cut sets is nontrivial, as even medium-sized metabolic networks with just 100 reactions easily have several hundred million elementary flux modes. We developed a minimal cut set tool that implements the well-known Berge algorithm and utilizes a novel approach to significantly reduce the program run time by using binary bit pattern trees. By using the introduced tree approach, the size of metabolic models that can be analyzed and optimized by minimal cut sets is pushed to new and considerably higher limits. PMID- 24062545 TI - The impact of perinatal death on obstetrics nurses: a longitudinal and cross sectional examination. AB - Mental health and well-being among obstetrics nurses after perinatal death are understudied. Beyond the normal strain imposed on obstetric nurses, exposure to perinatal death may add significant stress. Two studies were conducted on obstetrics nurses. In study 1, obstetrics nurses were measured longitudinally, at baseline (with no recent history of exposure to perinatal death in the past 3 months), and 3 months after (2 months after two consecutive events of perinatal death have occurred 1 month after baseline). In study 2, a cross-sectional study was conducted comparing obstetrics nurses with a history of perinatal death (nurses from study 1) to obstetrics nurses with no history of exposure to perinatal death in the past 6 months. The results of study 1 showed that obstetrics nurses showed a higher level of psychiatric symptoms [posttraumatic stress disorder (PTSD), depressive, and psychosomatic symptoms] at time 2 (after exposure to perinatal death) in comparison to time 1. The results of study 2 showed a higher level of psychiatric symptoms (PTSD, depressive, and psychosomatic symptoms) in the exposed group in comparison to the non-exposed group. The effect of exposure to perinatal death is severe and needs to be addressed by developing intervention and preparation programs to help obstetric nurses cope with this critical incident. PMID- 24062546 TI - Influence of antenatal magnesium sulfate application on cord blood levels of brain-derived neurotrophic factor in premature infants. AB - AIM: To investigate the influence of antenatal magnesium sulfate (MgSO4) application on cord blood brain-derived neurotrophic factor (BDNF) levels - the first-line neuroprotection for preventing cerebral palsy in prematurely born infants. SUBJECTS AND METHODS: A randomized controlled trial was conducted by observing 72 pregnant women who were divided into three groups: group I (preterm pregnancy with MgSO4), group II (preterm pregnancy without MgSO4), and group III (full-term pregnancy as control group). Groups I and II were selected by block permutation randomization on subjects. Inclusion criteria consisted of preterm pregnancy at 34 weeks of gestation or less who were in labor or having planned terminations and receiving antenatal corticosteroids. Exclusion criteria consisted of previous complications caused by MgSO4, previous history of antenatal MgSO4 application in the current pregnancy infant was born before 4 h administration of MgSO4 or unborn more than 72 h after maximum course of antenatal MgSO4 of 24 h, prolonged antenatal MgSO4 treatment (>24 h), refusal to participate, and emergent adverse events during the study. Group I was given intravenous MgSO4; initial dose was 4 g, which was maintained at 1 g/h up to maximum of 24 h. Meanwhile, groups II and III were not given any special treatment. BDNF was examined by ELISA by taking 5 mL cord blood sample shortly after birth. The result was statistically measured by ANOVA. RESULTS: The cord blood BDNF levels in premature infants with antenatal MgSO4 was significantly higher than in premature infants without antenatal MgSO4 (11,568 vs. 5027 pg/mL, P=0.000). Moreover, the result was statistically comparable to full-term infants (11,568 vs. 13,300 pg/mL, P=0.085). CONCLUSION: The application of antenatal MgSO4 in preterm delivery increased cord blood BDNF levels, which could have a potential role on fetal neuroprotection. Further investigation is needed. PMID- 24062547 TI - Novel, closely related, white spot syndrome virus (WSSV) genotypes from Madagascar, Mozambique and the Kingdom of Saudi Arabia. AB - White spot syndrome virus (WSSV) is highly pathogenic to penaeid shrimp and has caused significant economic losses in the aquaculture industry around the world. During 2010 to 2012, WSSV caused severe mortalities in cultured penaeid shrimp in Saudi Arabia, Mozambique and Madagascar. To investigate the origins of these WSSV, we performed genotyping analyses at 5 loci: the 3 open reading frames (ORFs) 125, 94 and 75, each containing a variable number of tandem repeats (VNTR), and deletions in the 2 variable regions, VR14/15 and VR23/24. We categorized the WSSV genotype as {N125, N94, N75, DeltaX14/15, DeltaX23/24} where N is the number of repeat units in a specific ORF and DeltaX is the length (base pair) of deletion within the variable region. We detected 4 WSSV genotypes, which were characterized by a full-length deletion in ORF94/95, a relatively small ORF75 and one specific deletion length in each variable region. There are 2 closely related genotypes in these 3 countries: {6125, del94, 375, Delta595014/15, Delta1097123/24} and {7125, del94, 375, Delta595014/15, Delta1097123/24}, where del is the full-length ORF deletion. In Saudi Arabia, 2 other related types of WSSV were also found: {6125, 794, 375, Delta595014/15, Delta1097123/24} and {8125, 1394, 375, Delta595014/15, Delta1097123/24}. The identical patterns of 3 loci in these 4 types indicate that they have a common lineage, and this suggests that the WSSV epidemics in these 3 countries were from a common source, possibly the environment. PMID- 24062548 TI - Within-farm spread of infectious salmon anemia virus (ISAV) in Atlantic salmon Salmo salar farms in Chile. AB - Spread of infectious salmon anemia virus (ISAV) at the cage level was quantified using a subset of data from 23 Atlantic salmon Salmo salar farms located in southern Chile. Data collected from official surveillance activities were systematically organized to obtain detailed information on infectious salmon anemia (ISA) outbreaks. Descriptive statistics for outbreak duration, proportion of infected fish, and time to secondary infection were calculated to quantify the magnitude of ISAV incursions. Linear and multiple failure time (MFT) regression models were used to determine factors associated with the cage-level reproduction number (Rc) and hazard rate (HR) for recurrent events, respectively. In addition, the Knox test was used to assess if cage-to-cage transmissions were clustered in space and time. Findings suggest that within farms, ISA outbreaks, on average, lasted 30 wk (median = 26 wk, 95% CI = 24 to 37 wk) and affected 57.3% (95% CI = 47.7 to 67.0%) of susceptible cages. The median time to secondarily diagnosed cages was 23 d. Occurrence of clinical ISAV outbreaks was significantly associated with increased Rc, whereas increased HR was significantly associated with clinical outbreaks and with a large number of fish. Spatio-temporal analysis failed to identify clustering of cage cases, suggesting that within-farm ISAV spread is independent of the spatial location of the cages. Results presented here will help to better understand ISAV transmission, to improve the design of surveillance programs in Chile and other regions in which salmon are intensively farmed, and to examine the economic impact of ISAV and related management strategies on various cost and demand shifting factors. PMID- 24062549 TI - Comparison of Vietnamese and US isolates of Edwardsiella ictaluri. AB - We compared Edwardsiella ictaluri from striped catfish in Vietnam with US channel catfish isolates. Biochemical analyses and sequencing of the 16S rRNA gene confirmed that the Vietnamese isolates were E. ictaluri. Comparison using rep-PCR fingerprinting demonstrated no significant differences between the isolates, but plasmid analysis indicated that the Vietnamese isolates grouped into 4 plasmid profiles, each different from the typical pEI1 and pEI2 plasmid profile found in the US isolates. Sequencing plasmids representative of the 4 profiles indicated that all contained derivatives of the E. ictaluri plasmid pEI1, whereas only 1 contained a plasmid derivative of the E. ictaluri plasmid pEI2. The pEI2 encoded type III secretion effector, EseI, and its chaperone, EscD, were found to be present on the chromosome in isolates lacking a pEI2 derivative. In addition, 1 isolate carried a 5023 bp plasmid that does not have homology to either pEI1 or pEI2. Furthermore, Vietnamese isolates were PCR positive for the type III and type VI secretion system genes esrC and evpC, respectively, and the urease enzyme, but were PCR-negative for the putative type IV secretion system gene virD4. A monoclonal antibody against the lipopolysaccharide of E. ictaluri ATCC 33202 did not react with the Asian isolates or with the more recent US isolates. Antibiotic resistance patterns were variable and did not correlate to the presence of any particular plasmid profile. Finally, the Vietnamese isolates were avirulent and had a significantly reduced capacity for intracellular replication within head-kidney-derived channel catfish macrophages. PMID- 24062550 TI - A novel agent (Endozoicomonas elysicola) responsible for epitheliocystis in cobia Rachycentrum canadum larvae. AB - Aquaculture of cobia has gained popularity in the last decade, and this species is now farmed in several countries in Latin America and Asia. Despite recent improvement in production techniques that allowed the expansion of the industry, little is known about the diseases that affect cobia during the larviculture stage. In this article we investigated the cause of mass mortalities occurring 13 20 d post-hatching in 3 cycles of cobia larviculture. Wet mounts from diseased larvae gills revealed the presence of cyst-like basophilic inclusions. DNA from the cysts was extracted and PCR amplified using the 16S rRNA gene universal primers for prokaryotes. The amplified products were sequenced and analyzed using BLAST, finding a similarity of 99% with Endozoicomonas elysicola, a Gram-negative bacterium. Confirmation of E. elysicola was conducted by designing a specific probe for in situ hybridization. Specific primers were also designed for diagnostic purposes. This is the first report of epitheliocystis in cobia larvae and also the first report of E. elysicola as an epitheliocystis-causing agent. PMID- 24062551 TI - Protection against Vibrio alginolyticus in crimson snapper Lutjanus erythropterus immunized with a DNA vaccine containing the ompW gene. AB - The outer membrane proteins of Vibrio alginolyticus play an important role in the virulence of the bacterium and are potential candidates for vaccine development. In the present study, the ompW gene was cloned, expressed and purified. A DNA vaccine was constructed by inserting the ompW gene into a pcDNA plasmid. Crimson snapper Lutjanus erythropterus (Bloch) were injected intramuscularly with the recombinant plasmid pcDNA-ompW. The expression of the DNA vaccine was detected in gill, head kidney, heart, liver, spleen and injection site muscle of crimson snapper by RT-PCR 7 and 28 d post-vaccination. The ELISA results demonstrated that the DNA vaccine produced an observable antibody response in all sera of the vaccinated fish. In addition, crimson snapper immunized with the DNA vaccine showed a relative percentage survival (RPS) of 92.53%, indicating effective protection against V. alginolyticus infection. PMID- 24062552 TI - Ovarian alterations in wild northern pike Esox lucius females. AB - The aim of the present study was to analyse the occurrence of macroscopically visible ovary alterations in 2 populations of northern pike Esox lucius L. originating from lakes in the Mazurian Lake District (NE Poland). The alterations were characterised by ovary tissue that was morphologically malformed, in part or in whole, and contained immature oocytes, i.e. trophoplastic or previtellogenic oocytes instead of vitellogenic oocytes. These alterations were found only in the ovaries, and no morphological alterations of the testes were noted. Macroscopic and histological analyses were carried out in order to classify the observed alterations in the ovaries. Three types of alterations were identified in which morphological malformations as well as histological investigation of the ovaries were considered. An analysis of the size and age of the fish in relation to the occurrence of alterations as well as of the macroscopic and histological nature of the alteration types was made. The data obtained revealed no lake or age dependency of the observed alterations. Based on the results obtained, we suggest that the presence of endocrine disruptors in the environment or/and genetic factors could be responsible for these kinds of gonad anomalies. However, our results did not allow us to determine the aetiology of the alterations. PMID- 24062553 TI - Small leucine-rich proteoglycans in the vertebrae of Atlantic salmon Salmo salar. AB - We analysed the distribution and expression of the small leucine-rich proteoglycans (SLRPs) decorin, biglycan and lumican in vertebral columns of Atlantic salmon Salmo salar L. with and without radiographically detectable deformities. Vertebral deformities are a reoccurring problem in salmon and other intensively farmed species, and an understanding of the components involved in the pathologic development of the vertebrae is important in order to find adequate solutions to this problem. Using immunohistology and light microscopy, we found that in non-deformed vertebrae biglycan, lumican and decorin were all expressed in osteoblasts at the vertebral growth zones and at the ossification front of the chondrocytic arches. Hence, the SLRPs are expressed in regions where intramembranous and endochondral ossification take place. In addition, mRNA expression of biglycan, decorin and lumican was demonstrated in a primary osteoblast culture established from Atlantic salmon, supporting the in vivo findings. Transcription of the SLRPs increased during differentiation of the osteoblasts in vitro and where lumican mRNA expression increased later in the differentiation compared with decorin and biglycan. Intriguingly, in vertebral fusions, biglycan, decorin and lumican protein expression was extended to trans differentiating cells at the border between arch centra and osteoblast growth zones. In addition, mRNA expression of biglycan, decorin and lumican differed between non-deformed and fused vertebrae, as shown by quantitative PCR (qPCR). Western blotting revealed an additional band of biglycan in fused vertebrae which had a higher molecular weight than in non-deformed vertebrae. Fourier-transform infrared (FTIR) spectroscopy revealed more spectral focality in the endplates of vertebral fusions and significantly more non-reducible collagen crosslinks compared with non-deformed vertebrae, thus identifying differences in bone structure. PMID- 24062554 TI - Coral diseases are major contributors to coral mortality in Shingle Island, Gulf of Mannar, southeastern India. AB - The present study reports coral mortality, driven primarily by coral diseases, around Shingle Island, Gulf of Mannar (GOM), Indian Ocean. In total, 2910 colonies were permanently monitored to assess the incidence of coral diseases and consequent mortality for 2 yr. Four types of lesions consistent with white band disease (WBD), black disease (BD), white plaque disease (WPD), and pink spot disease (PSD) were recorded from 4 coral genera: Montipora, Pocillopora, Acropora, and Porites. Porites were affected by 2 disease types, while the other 3 genera were affected by only 1 disease type. Overall disease prevalence increased from 8% (n = 233 colonies) to 41.9% (n = 1219) over the 2 yr study period. BD caused an unprecedented 100% mortality in Pocillopora, followed by 20.4 and 13.1% mortality from WBD in Montipora and Acropora, respectively. Mean disease progression rates of 0.8 +/- 1.0 and 0.6 +/- 0.5 cm mo-1 over live coral colonies were observed for BD and WBD. Significant correlations between temperature and disease progression were observed for BD (r = 0.86, R2 = 0.75, p < 0.001) and WBD (R2 = 0.76, p < 0.001). This study revealed the increasing trend of disease prevalence and progression of disease over live coral in a relatively limited study area; further study should investigate the status of the entire coral reef in the GOM and the role of diseases in reef dynamics. PMID- 24062555 TI - Biliary cirrhosis caused by Campula spp. in a dolphin and four porpoises. AB - Biliary cirrhosis produced by Campula spp. is described in 1 striped dolphin Stenella coeruleoalba and 4 harbour porpoises Phocoena phocoena. The hepatic lesions consisted of severe proliferation of fibrous connective tissue with loss of the lobular pattern, nodular regeneration of the hepatic tissue, bile duct hyperplasia and severe inflammatory infiltrate composed of eosinophils, macrophages, lymphocytes and plasma cells. These lesions were associated with severe infestation by Campula spp. Although inflammatory and degenerative hepatic lesions are frequently found in stranded dolphins, biliary cirrhosis has not been previously reported in cetaceans. Massive infestation by these parasites should be included as a cause of hepatic failure resulting in stranding of marine mammals. PMID- 24062556 TI - Detection and characterization of Bonamia ostreae in Ostrea edulis imported to China. AB - The protozoan parasite Bonamia ostreae is a destructive pathogen of flat oysters and has been reported to be widespread in Europe and North America. The biological characteristics of this unicellular parasite are still not fully understood. In this study, 104 Ostrea edulis imported from the USA to the Guangdong province of China for consumption were examined for Bonamia infection. PCR assay, combined with restriction fragment length polymorphism, sequencing and BLAST analysis, showed that B. ostreae DNA could be detected in 1 of the 104 oyster samples. Light microscopy revealed Bonamia-like organisms in the oyster. PCR assay and fluorescent in situ hybridization showed that B. ostreae organisms were present and retained their integrity after 4 wk in culture. Acridine orange ethidium bromide staining indicated that the B. ostreae were still alive. In conclusion, B. ostreae was present in oysters imported to China. More importantly, the parasite was able to survive for at least 4 wk of in vitro culture at 4 degrees C, which further implied a long-term transmission risk of B. ostreae. Considering the wide culture beds of Crassostrea ariakensis and C. gigas in China, and that C. ariakensis and C. gigas are susceptible hosts or reservoirs of B. ostreae, our study highlights the potential risk of introducing B. ostreae by importing O. edulis from a Bonamia endemic area. PMID- 24062557 TI - Science to practice: can stem cells be labeled inside the body instead of outside? AB - Instead of conventional labeling ex vivo in cell culture, mesenchymal stem cells (MSCs) were labeled in vivo with intravenous injection of ferumoxytol (Feraheme; AMAG Pharmaceuticals, Lexington, Mass), a Food and Drug Administration (FDA) approved intravenous iron supplement. After their isolation and processing from bone marrow, the same MSCs were injected in rats with an osteochondral defect, allowing MR monitoring of their engraftment for at least 4 weeks. This straightforward labeling approach, avoiding several regulatory issues, may accelerate clinical translation of magnetic resonance (MR) imaging for stem cell tracking. PMID- 24062558 TI - Revascularization grading: the devil is in the details. PMID- 24062560 TI - Imaging review of the temporal bone: part I. Anatomy and inflammatory and neoplastic processes. AB - From a clinical-radiologic standpoint, there are a limited number of structures and disease entities in the temporal bone with which one must be familiar in order to proficiently interpret a computed tomographic or magnetic resonance imaging study of the temporal bone. It is helpful to examine the region in an organized and systematic fashion, going through the same checklist of key structures each time. This is the first of a two-part review that provides a practical approach to understanding temporal bone anatomy, localizing a pathologic process with a focus on inflammatory and neoplastic processes, identifying pertinent positives and negatives, and formulating a differential diagnosis. PMID- 24062559 TI - Quantitative imaging in cancer evolution and ecology. AB - Cancer therapy, even when highly targeted, typically fails because of the remarkable capacity of malignant cells to evolve effective adaptations. These evolutionary dynamics are both a cause and a consequence of cancer system heterogeneity at many scales, ranging from genetic properties of individual cells to large-scale imaging features. Tumors of the same organ and cell type can have remarkably diverse appearances in different patients. Furthermore, even within a single tumor, marked variations in imaging features, such as necrosis or contrast enhancement, are common. Similar spatial variations recently have been reported in genetic profiles. Radiologic heterogeneity within tumors is usually governed by variations in blood flow, whereas genetic heterogeneity is typically ascribed to random mutations. However, evolution within tumors, as in all living systems, is subject to Darwinian principles; thus, it is governed by predictable and reproducible interactions between environmental selection forces and cell phenotype (not genotype). This link between regional variations in environmental properties and cellular adaptive strategies may permit clinical imaging to be used to assess and monitor intratumoral evolution in individual patients. This approach is enabled by new methods that extract, report, and analyze quantitative, reproducible, and mineable clinical imaging data. However, most current quantitative metrics lack spatialness, expressing quantitative radiologic features as a single value for a region of interest encompassing the whole tumor. In contrast, spatially explicit image analysis recognizes that tumors are heterogeneous but not well mixed and defines regionally distinct habitats, some of which appear to harbor tumor populations that are more aggressive and less treatable than others. By identifying regional variations in key environmental selection forces and evidence of cellular adaptation, clinical imaging can enable us to define intratumoral Darwinian dynamics before and during therapy. Advances in image analysis will place clinical imaging in an increasingly central role in the development of evolution-based patient-specific cancer therapy. PMID- 24062561 TI - MR imaging of the arterial vessel wall: molecular imaging from bench to bedside. AB - Cardiovascular diseases remain the leading cause of morbidity and mortality in the Western world and developing countries. In clinical practice, in vivo characterization of atherosclerotic lesions causing myocardial infarction, ischemic stroke, and other complications remains challenging. Imaging methods, limited to the assessment luminal stenosis, are the current reference standard for the assessment of clinically significant coronary and carotid artery disease and the guidance of treatment. These techniques do not allow distinction between stable and potentially vulnerable atherosclerotic plaque. Magnetic resonance (MR) imaging is a modality well suited for visualization and characterization of the relatively thin arterial vessel wall, because it allows imaging with high spatial resolution and excellent soft-tissue contrast. In clinical practice, atherosclerotic plaque components of the carotid artery and aorta may be differentiated and characterized by using unenhanced vessel wall MR imaging. Additional information can be gained by using clinically approved nonspecific contrast agents. With the advent of targeted MR contrast agents, which enhance specific molecules or cells, pathologic processes can be visualized at a molecular level with high spatial resolution. In this article, the pathophysiologic changes of the arterial vessel wall underlying the development of atherosclerosis will be first reviewed. Then basic principles and properties of molecular MR imaging contrast agents will be introduced. Additionally, recent advances in preclinical molecular vessel wall imaging will be reviewed. Finally, the clinical feasibility of arterial vessel wall imaging at unenhanced and contrast material-enhanced MR imaging of the aortic, carotid, and coronary vessel wall will be discussed. PMID- 24062563 TI - Case 198: solitary fibrous tumor of the liver. PMID- 24062564 TI - Long-term outcomes of breast cancer ablation. PMID- 24062565 TI - Anterior segment and medial segment of the left lower lobe: a new and unknown nomenclature. PMID- 24062566 TI - Dietary alpha-linolenic acid from flaxseed oil improved folliculogenesis and IVF performance in dairy cows, similar to eicosapentaenoic and docosahexaenoic acids from fish oil. AB - The objectives of this study were to determine the differential incorporation of various omega-3 (n-3) fatty acids (FAs) supplemented to dairy cows into ovarian compartments and assess the effects on IVF. Forty-two 256-day pregnant cows were supplemented with encapsulated fats, in treatments designated as i) SFA - saturated fat at 240 and 560 g/day per cow, prepartum and post partum (PP) respectively; ii) FLX - flaxseed oil at 300 and 700 g/day per cow prepartum and PP respectively; and iii) FO - fish oil at 300 and 700 g/day per cow prepartum and PP respectively. Commencing at 60 days in lactation, ovum pickup (OPU) was performed twice weekly (20 sessions; five cows per group) and in vitro maturation and IVF were conducted. The proportion of alpha-linolenic acid (ALA) was greater in follicular fluid (FF), granulosa cells, and cumulus-oocyte complexes (COCs) of FLX cows than in other groups (P<0.001). The proportion of docosahexaenoic acid (DHA) was 6.7 times as great in FF of FO as in other groups (P<0.001); docosapentaenoic acid n-3 and DHA were detected in COCs of FO but not in others. The follicle number during OPU was higher in FLX and FO than in SFA (P<0.05), and the oocyte cleavage rate was higher in FLX and FO than in SFA (P<0.01). Also, the percentage of oocytes that developed to blastocysts tended to be higher in both n 3 groups than in SFA (P<0.1). In conclusion, both dietary n-3 FAs similarly improved folliculogenesis and IVF performance; therefore, ALA-rich botanical n-3 seems to be a satisfactory approach to improve oocyte quality. PMID- 24062567 TI - Semen analysis: update on clinical value, current needs and future perspectives. AB - At present, evaluation of male reproductive function consists primarily of routine semen analysis, a collection of conventional microscopic assessments ideally performed following the guidelines set by the World Health Organization. While providing some insight into testicular function, these long-performed tests are limited in the information that they impart; more specifically, they are unable to predict true fertility potential. As a consequence, there is a need for the appraisal and consideration of newer semen parameters that may be more indicative of reproductive success. Although various novel assays have been introduced that broaden the scope of information available to both researcher and clinician, the utility of these tests remains limited due to the lack of standardisation of protocols and the absence of clinically established, dependable reference ranges. As such, it is not surprising that most of these parameters and their associated methods remain recommended for 'research purposes only'. With the burgeoning 'omics' revolution, nanotechnology and the development of new analytical instruments, there is now an opportunity for the identification and measurement of previously unknown features that may prove to be more indicative of each sperm's true functional status and capability. Once optimised, simplified, clinically validated and made more readily accessible, these new approaches hold the promise of forming the fulcrum upon which andrological investigations can enter a new era. PMID- 24062568 TI - Roles of poly (ADP-ribose) polymerase (PARP1) cleavage in the ovaries of fetal, neonatal, and adult pigs. AB - Poly(ADP-ribosylation), which occurs rapidly in cells following DNA damage and is regulated by poly (ADP-ribose) polymerase 1 (PARP1), is a post-translational modification of proteins playing a crucial role in many processes, including DNA repair and cell death. Although PARP1 has recently been implicated in a variety of physiological and pathological processes, its role in the process of follicular development and atresia is not yet completely defined. This study was designed to investigate the cellular expression pattern and immunolocalization of PARP1, cleaved PARP1, caspase 3, and cleaved caspase 3 in fetal, neonatal, and adult porcine ovaries. Our results showed that in fetal and neonatal pigs, PARP1 cleavage is involved in the process of oocyte nest breakdown, primordial follicle formation, and transition to primary follicles. The results of immunohistochemistry indicated that PARP1 cleavage was involved in the process of follicular development and atresia, which was in accordance with our previous study; however, it was noted that cleaved caspase 3 was mainly localized in and around the nucleus of apoptotic granulosa cells (GCs), whereas cleaved PARP1 was mainly localized in the nucleus of the apoptotic GCs. RIA data showed increased serum progesterone and estradiol concentrations with age after birth. Collectively, our findings suggest that the PARP1 signaling pathway is involved in oocyte nest breakdown and primordial follicle formation in fetal and neonatal porcine ovaries, but is different from follicular atresia in adult porcine ovaries that involves cellular apoptosis. PMID- 24062569 TI - KCNH1 potassium channels are expressed in cervical cytologies from pregnant patients and are regulated by progesterone. AB - Potassium voltage-gated channel, subfamily H (eag-related), member 1 (KCNH1) potassium channels are potential tumour markers and cancer therapeutic targets and are up-regulated by oestrogens and human papilloma virus (HPV) oncogenes. However, the role of KCNH1 in normal tissues is poorly understood, and its expression in pregnancy is unknown. We wondered whether KCNH1 channels are expressed in cervical cells from pregnant patients and whether progesterone (P4) regulates KCNH1. The association with HPV was also investigated. KCNH1 protein expression was studied by immunocytochemistry in liquid-based cervical cytologies; 93 samples were obtained from pregnant patients at different trimesters, and 15 samples were obtained from non-pregnant women (controls). The presence of HPV was studied by PCR with direct sequencing and nested multiplex PCR. HeLa cervical cancer cells were transfected with human progesterone receptor B (PR-B) and treated with P4. KCNH1 mRNA expression in these cultures was studied by real-time PCR. KCNH1 protein was detected in 100% of the pregnancy samples and in 26% of the controls. We found 18 pregnant patients infected with HPV and detected 14 types of HPV. There was no association between the percentage of cells expressing KCNH1 and either the presence or type of HPV. P4 induced KCNH1 mRNA and protein expression in cells transfected with human PR-B. No regulation of KCNH1 by P4 was observed in non-transfected cells. We show for the first time the expression of an ion channel during human pregnancy at different trimesters and KCNH1 regulation by P4 in human cells. These data raise a new research field for KCNH1 channels in human tissues. PMID- 24062570 TI - EP3 receptor isoforms are differentially expressed in subpopulations of primate granulosa cells and couple to unique G-proteins. AB - Prostaglandin E2 (PGE2) produced within the ovarian follicle is necessary for ovulation. PGE2 is recognized by four distinct G-protein-coupled receptors. Among them, PTGER3 (also known as EP3) is unique in that mRNA splicing generates multiple isoforms. Each isoform has a distinct amino acid composition in the C terminal region, which is involved in G-protein coupling. To determine whether monkey EP3 isoforms couple to different G-proteins, each EP3 isoform was expressed in Chinese hamster ovary cells, and intracellular signals were examined after stimulation with the EP3 agonist sulprostone. Stimulation of EP3 isoform 5 (EP3-5) reduced cAMP in a pertussis toxin (PTX)-sensitive manner, indicating involvement of Galphai. Stimulation of EP3-9 increased cAMP, which was reduced by the general G-protein inhibitor GDP-beta-S, and also increased intracellular calcium, which was reduced by PTX and GDP-beta-S. So, EP3-9 likely couples to both Galphas and a PTX-sensitive G-protein to regulate intracellular signals. Stimulation of EP3-14 increased cAMP, which was further increased by PTX, so EP3 14 likely regulates cAMP via multiple G-proteins. Granulosa cell expression of all EP3 isoforms increased in response to an ovulatory dose of human chorionic gonadotropin. Two EP3 isoforms were differentially expressed in functional subpopulations of granulosa cells. EP3-5 was low in granulosa cells at the follicle apex while EP3-9 was high in cumulus granulosa cells. Differential expression of EP3 isoforms may yield different intracellular responses to PGE2 in granulosa cell subpopulations, contributing to the different roles played by granulosa cell subpopulations in the process of ovulation. PMID- 24062571 TI - FMRP regulates actin filament organization via the armadillo protein p0071. AB - Loss of fragile X mental retardation protein (FMRP) causes synaptic dysfunction and intellectual disability. FMRP is an RNA-binding protein that controls the translation or turnover of a subset of mRNAs. Identifying these target transcripts is an important step toward understanding the pathology of the disease. Here, we show that FMRP regulates actin organization and neurite outgrowth via the armadillo protein p0071. In mouse embryonic fibroblasts (MEFs) lacking FMRP (Fmr1-), the actin cytoskeleton was markedly reorganized with reduced stress fibers and F-actin/G-actin ratios compared to fibroblasts re expressing the protein. FMRP interfered with the translation of the p0071 mRNA in a 3'-UTR-dependent manner. Accordingly, FMRP-depleted cells revealed elevated levels of p0071 protein. The knockdown of p0071 in Fmr1- fibroblasts restored stress fibers and an elongated cell shape, thus rescuing the Fmr1- phenotype, whereas overexpression of p0071 in Fmr1+ cells mimicked the Fmr1- phenotype. Moreover, p0071 and FMRP regulated neurite outgrowth and branching in a diametrically opposed way in agreement with the negative regulation of p0071 by FMRP. These results identify p0071 as an important and novel FMRP target and strongly suggest that impaired actin cytoskeletal functions mediated by an excess of p0071 are key aspects underlying the fragile X syndrome. PMID- 24062572 TI - Bicaudal-C spatially controls translation of vertebrate maternal mRNAs. AB - The Xenopus Cripto-1 protein is confined to the cells of the animal hemisphere during early embryogenesis where it regulates the formation of anterior structures. Cripto-1 protein accumulates only in animal cells because cripto-1 mRNA in cells of the vegetal hemisphere is translationally repressed. Here, we show that the RNA binding protein, Bicaudal-C (Bic-C), functioned directly in this vegetal cell-specific repression. While Bic-C protein is normally confined to vegetal cells, ectopic expression of Bic-C in animal cells repressed a cripto 1 mRNA reporter and associated with endogenous cripto-1 mRNA. Repression by Bic-C required its N-terminal domain, comprised of multiple KH motifs, for specific binding to relevant control elements within the cripto-1 mRNA and a functionally separable C-terminal translation repression domain. Bic-C-mediated repression required the 5' CAP and translation initiation factors, but not a poly(A) tail or the conserved SAM domain within Bic-C. Bic-C-directed immunoprecipitation followed by deep sequencing of associated mRNAs identified multiple Bic-C regulated mRNA targets, including cripto-1 mRNA, providing new insights and tools for understanding the role of Bic-C in vertebrate development. PMID- 24062573 TI - Thermodynamic contribution and nearest-neighbor parameters of pseudouridine adenosine base pairs in oligoribonucleotides. AB - Pseudouridine (Psi) is the most common noncanonical nucleotide present in naturally occurring RNA and serves a variety of roles in the cell, typically appearing where structural stability is crucial to function. Psi residues are isomerized from native uridine residues by a class of highly conserved enzymes known as pseudouridine synthases. In order to quantify the thermodynamic impact of pseudouridylation on U-A base pairs, 24 oligoribonucleotides, 16 internal and eight terminal Psi-A oligoribonucleotides, were thermodynamically characterized via optical melting experiments. The thermodynamic parameters derived from two state fits were used to generate linearly independent parameters for use in secondary structure prediction algorithms using the nearest-neighbor model. On average, internally pseudouridylated duplexes were 1.7 kcal/mol more stable than their U-A counterparts, and terminally pseudouridylated duplexes were 1.0 kcal/mol more stable than their U-A equivalents. Due to the fact that Psi-A pairs maintain the same Watson-Crick hydrogen bonding capabilities as the parent U-A pair in A-form RNA, the difference in stability due to pseudouridylation was attributed to two possible sources: the novel hydrogen bonding capabilities of the newly relocated imino group as well as the novel stacking interactions afforded by the electronic configuration of the Psi residue. The newly derived nearest-neighbor parameters for Psi-A base pairs may be used in conjunction with other nearest-neighbor parameters for accurately predicting the most likely secondary structure of A-form RNA containing Psi-A base pairs. PMID- 24062575 TI - Projecting cell polarity into the next decade. PMID- 24062574 TI - MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases. AB - MicroRNAs (miRNAs) play a key role in regulating mRNA expression, and individual miRNAs have been proposed as diagnostic and therapeutic candidates. The identification of such candidates is complicated by the involvement of multiple miRNAs and mRNAs as well as unknown disease topology of the miRNAs. Here, we investigated if disease-associated miRNAs regulate modules of disease-associated mRNAs, if those miRNAs act complementarily or synergistically, and if single or combinations of miRNAs can be targeted to alter module functions. We first analyzed publicly available miRNA and mRNA expression data for five different diseases. Integrated target prediction and network-based analysis showed that the miRNAs regulated modules of disease-relevant genes. Most of the miRNAs acted complementarily to regulate multiple mRNAs. To functionally test these findings, we repeated the analysis using our own miRNA and mRNA expression data from CD4+ T cells from patients with seasonal allergic rhinitis. This is a good model of complex diseases because of its well-defined phenotype and pathogenesis. Combined computational and functional studies confirmed that miRNAs mainly acted complementarily and that a combination of two complementary miRNAs, miR-223 and miR-139-3p, could be targeted to alter disease-relevant module functions, namely, the release of type 2 helper T-cell (Th2) cytokines. Taken together, our findings indicate that miRNAs act complementarily to regulate modules of disease-related mRNAs and can be targeted to alter disease-relevant functions. PMID- 24062576 TI - Symmetry breaking and polarity establishment during mouse oocyte maturation. AB - Mammalian oocyte meiosis encompasses two rounds of asymmetric divisions to generate a totipotent haploid egg and, as by-products, two small polar bodies. Two intracellular events, asymmetric spindle positioning and cortical polarization, are critical to such asymmetric divisions. Actin but not microtubule cytoskeleton has been known to be directly involved in both events. Recent work has revealed a positive feedback loop between chromosome-mediated cortical activation and the Arp2/3-orchestrated cytoplasmic streaming that moves chromosomes. This feedback loop not only maintains meiotic II spindle position during metaphase II arrest, but also brings about symmetry breaking during meiosis I. Prior to an Arp2/3-dependent phase of fast movement, meiotic I spindle experiences a slow and non-directional first phase of migration driven by a pushing force from Fmn2-mediated actin polymerization. In addition to illustrating these molecular mechanisms, mathematical simulations are presented to elucidate mechanical properties of actin-dependent force generation in this system. PMID- 24062577 TI - From simple to detailed models for cell polarization. AB - Many mathematical models have been proposed for the process of cell polarization. Some of these are 'functional models' that capture a class of dynamical behaviour, whereas others are derived from features of signalling molecules. Some mechanistic models are detailed, and therefore complex, whereas others are simplified. Each type contributes to our understanding of cell polarization. However, the huge variety at different levels of detail makes comparisons challenging. Here, we provide examples of both elementary and more detailed models for polarization. We also display how a recent mathematical method, local perturbation analysis, can provide an appropriate tool for such comparisons. This technique simplifies and speeds up the model development process by revealing the effect of model extensions, parameter variations and in silico manipulations such as knock-out or over-expression of key molecules. Finally, simulations in both one dimension and two dimensions, and particularly in deforming two-dimensional 'cells', can highlight behaviour not captured by traditional simulation methods. PMID- 24062578 TI - Actin polymerization or myosin contraction: two ways to build up cortical tension for symmetry breaking. AB - Cells use complex biochemical pathways to drive shape changes for polarization and movement. One of these pathways is the self-assembly of actin filaments and myosin motors that together produce the forces and tensions that drive cell shape changes. Whereas the role of actin and myosin motors in cell polarization is clear, the exact mechanism of how the cortex, a thin shell of actin that is underneath the plasma membrane, can drive cell shape changes is still an open question. Here, we address this issue using biomimetic systems: the actin cortex is reconstituted on liposome membranes, in an 'outside geometry'. The actin shell is either grown from an activator of actin polymerization immobilized at the membrane by a biotin-streptavidin link, or built by simple adsorption of biotinylated actin filaments to the membrane, in the presence or absence of myosin motors. We show that tension in the actin network can be induced either by active actin polymerization on the membrane via the Arp2/3 complex or by myosin II filament pulling activity. Symmetry breaking and spontaneous polarization occur above a critical tension that opens up a crack in the actin shell. We show that this critical tension is reached by growing branched networks, nucleated by the Arp2/3 complex, in a concentration window of capping protein that limits actin filament growth and by a sufficient number of motors that pull on actin filaments. Our study provides the groundwork to understanding the physical mechanisms at work during polarization prior to cell shape modifications. PMID- 24062579 TI - Interaction between bud-site selection and polarity-establishment machineries in budding yeast. AB - Saccharomyces cerevisiae yeast cells polarize in order to form a single bud in each cell cycle. Distinct patterns of bud-site selection are observed in haploid and diploid cells. Genetic approaches have identified the molecular machinery responsible for positioning the bud site: during bud formation, specific locations are marked with immobile landmark proteins. In the next cell cycle, landmarks act through the Ras-family GTPase Rsr1 to promote local activation of the conserved Rho-family GTPase, Cdc42. Additional Cdc42 accumulates by positive feedback, creating a concentrated patch of GTP-Cdc42, which polarizes the cytoskeleton to promote bud emergence. Using time-lapse imaging and mathematical modelling, we examined the process of bud-site establishment. Imaging reveals unexpected effects of the bud-site-selection system on the dynamics of polarity establishment, raising new questions about how that system may operate. We found that polarity factors sometimes accumulate at more than one site among the landmark-specified locations, and we suggest that competition between clusters of polarity factors determines the final location of the Cdc42 cluster. Modelling indicated that temporally constant landmark-localized Rsr1 would weaken or block competition, yielding more than one polarity site. Instead, we suggest that polarity factors recruit Rsr1, effectively sequestering it from other locations and thereby terminating landmark activity. PMID- 24062580 TI - Actin dynamics rapidly reset chemoattractant receptor sensitivity following adaptation in neutrophils. AB - Neutrophils are cells of the innate immune system that hunt and kill pathogens using directed migration. This process, known as chemotaxis, requires the regulation of actin polymerization downstream of chemoattractant receptors. Reciprocal interactions between actin and intracellular signals are thought to underlie many of the sophisticated signal processing capabilities of the chemotactic cascade including adaptation, amplification and long-range inhibition. However, with existing tools, it has been difficult to discern actin's role in these processes. Most studies investigating the role of the actin cytoskeleton have primarily relied on actin-depolymerizing agents, which not only block new actin polymerization but also destroy the existing cytoskeleton. We recently developed a combination of pharmacological inhibitors that stabilizes the existing actin cytoskeleton by inhibiting actin polymerization, depolymerization and myosin-based rearrangements; we refer to these processes collectively as actin dynamics. Here, we investigated how actin dynamics influence multiple signalling responses (PI3K lipid products, calcium and Pak phosphorylation) following acute agonist addition or during desensitization. We find that stabilized actin polymer extends the period of receptor desensitization following agonist binding and that actin dynamics rapidly reset receptors from this desensitized state. Spatial differences in actin dynamics may underlie front/back differences in agonist sensitivity in neutrophils. PMID- 24062581 TI - The PAR network: redundancy and robustness in a symmetry-breaking system. AB - To become polarized, cells must first 'break symmetry'. Symmetry breaking is the process by which an unpolarized, symmetric cell develops a singularity, often at the cell periphery, that is used to develop a polarity axis. The Caenorhabditis elegans zygote breaks symmetry under the influence of the sperm-donated centrosome, which causes the PAR polarity regulators to sort into distinct anterior and posterior cortical domains. Modelling analyses have shown that cortical flows induced by the centrosome combined with antagonism between anterior and posterior PARs (mutual exclusion) are sufficient, in principle, to break symmetry, provided that anterior and posterior PAR activities are precisely balanced. Experimental evidence indicates, however, that the system is surprisingly robust to changes in cortical flows, mutual exclusion and PAR balance. We suggest that this robustness derives from redundant symmetry-breaking inputs that engage two positive feedback loops mediated by the anterior and posterior PAR proteins. In particular, the PAR-2 feedback loop stabilizes the polarized state by creating a domain where posterior PARs are immune to exclusion by anterior PARs. The two feedback loops in the PAR network share characteristics with the two feedback loops in the Cdc42 polarization network of Saccharomyces cerevisiae. PMID- 24062582 TI - Cell polarity in morphogenesis and metastasis. AB - Most human cancers arise either from epithelial cells or their progenitors. Epithelial cells possess a distinctive apical-basal polarity and loss of polarity is frequently assumed to be a common feature of cancer progression. In particular, cancer cell dissemination to ectopic sites, and metastatic growth at those sites, is often considered to require a mesenchymal transition in which the transformed epithelial cells lose their apical-basal polarity. However, many cancers retain epithelial characteristics, and until recently there has been little conclusive evidence for an involvement of the cell polarity machinery in tumour growth and metastasis. In this article, we discuss evidence that polarity proteins can be potent invasion suppressors but that loss of epithelial character is not essential either for tumour growth and invasion, or metastatic colonization. PMID- 24062583 TI - Roles of Rho GTPases in leucocyte and leukaemia cell transendothelial migration. AB - Leucocytes migrate into and out of blood vessels at multiple points during their development and maturation, and during immune surveillance. In response to tissue damage and infection, they are rapidly recruited through the endothelium lining blood vessels into the tissues. Leukaemia cells also move in and out of the bloodstream during leukaemia progression. Rho GTPases are intracellular signalling proteins that regulate cytoskeletal dynamics and are key coordinators of cell migration. Here, we describe how different members of the Rho GTPase family act in leucocytes and leukaemia cells to regulate steps of transendothelial migration. We discuss how inhibitors of Rho signalling could be used to reduce leucocyte or leukaemia cell entry into tissues. PMID- 24062584 TI - Cell and tissue polarity in the intestinal tract during tumourigenesis: cells still know the right way up, but tissue organization is lost. AB - Cell and tissue polarity are tightly coupled and are vital for normal tissue homeostasis. Changes in cellular and tissue organization are common to even early stages of disease, particularly cancer. The digestive tract is the site of the second most common cause of cancer deaths in the developed world. Tumours in this tissue arise in an epithelium that has a number of axes of cell and tissue polarity. Changes in cell and tissue polarity in response to genetic changes that are known to underpin disease progression provide clues about the link between molecular-, cellular- and tissue-based mechanisms that accompany cancer. Mutations in adenomatous polyposis coli (APC) are common to most colorectal cancers in humans and are sufficient to cause tumours in mouse intestine. Tissue organoids mimic many features of whole tissue and permit identifying changes at different times after inactivation of APC. Using gut organoids, we show that tissue polarity is lost very early during cancer progression, whereas cell polarity, at least apical-basal polarity, is maintained and changes only at later stages. These observations reflect the situation in tumours and validate tissue organoids as a useful system to investigate the relationship between cell polarity and tissue organization. PMID- 24062586 TI - Spindle orientation and epidermal morphogenesis. AB - Asymmetric cell divisions (ACDs) result in two unequal daughter cells and are a hallmark of stem cells. ACDs can be achieved either by asymmetric partitioning of proteins and organelles or by asymmetric cell fate acquisition due to the microenvironment in which the daughters are placed. Increasing evidence suggests that in the mammalian epidermis, both of these processes occur. During embryonic epidermal development, changes occur in the orientation of the mitotic spindle in relation to the underlying basement membrane. These changes are guided by conserved molecular machinery that is operative in lower eukaryotes and dictates asymmetric partitioning of proteins during cell divisions. That said, the shift in spindle alignment also determines whether a division will be parallel or perpendicular to the basement membrane, and this in turn provides a differential microenvironment for the resulting daughter cells. Here, we review how oriented divisions of progenitors contribute to the development and stratification of the epidermis. PMID- 24062585 TI - p120catenin alteration in cancer and its role in tumour invasion. AB - Since its discovery in 1989 as a substrate of the Src oncogene, p120catenin has been revealed as an important player in cancer initiation and tumour dissemination. p120catenin regulates a wide range of cellular processes such as cell-cell adhesion, cell polarity and cell proliferation and plays a pivotal role in morphogenesis, inflammation and innate immunity. The pleiotropic effects of p120catenin rely on its interactions with numerous partners such as classical cadherins at the plasma membrane, Rho-GTPases and microtubules in the cytosol and transcriptional modulators in the nucleus. Alterations of p120catenin in cancer not only concern its expression level but also its intracellular localization and can lead to both pro-invasive and anti-invasive effects. This review focuses on the p120catenin-mediated pathways involved in cell migration and invasion and discusses the potential consequences of major cancer-related p120catenin alterations with respect to tumour spread. PMID- 24062587 TI - Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR 4. AB - The PAR clan of polarity regulating genes was initially discovered in a genetic screen searching for genes involved in asymmetric cell divisions in the Caenorhabditis elegans embryo. Today, investigations in worms, flies and mammals have established PAR proteins as conserved and fundamental regulators of animal cell polarization in a broad range of biological phenomena requiring cellular asymmetries. The human homologue of invertebrate PAR-4, a serine-threonine kinase LKB1/STK11, has caught attention as a gene behind Peutz-Jeghers polyposis syndrome and as a bona fide tumour suppressor gene commonly mutated in sporadic cancer. LKB1 functions as a master regulator of AMP-activated protein kinase (AMPK) and 12 other kinases referred to as the AMPK-related kinases, including four human homologues of PAR-1. The role of LKB1 as part of the energy sensing LKB1-AMPK module has been intensively studied, whereas the polarity function of LKB1, in the context of homoeostasis or cancer, has gained less attention. Here, we focus on the PAR-4 identity of LKB1, discussing the weight of evidence indicating a role for LKB1 in regulation of cell polarity and epithelial integrity across species and highlight recent investigations providing new insight into the old question: does the PAR-4 identity of LKB1 matter in cancer? PMID- 24062588 TI - Adaptive molecular networks controlling chemotactic migration: dynamic inputs and selection of the network architecture. AB - Eukaryotic signalling networks underlying the cell's ability to sense the gradient of chemotactic cues frequently have the dual property of perfect adaptation to spatially homogeneous inputs, and persistent activation by inputs that are spatially graded. This property is also shared by bacterial chemotaxis networks, raising the question of whether these two types of chemotactic processes also have similar organization of the underlying biomolecular processes. Interestingly, perfect adaptation can only be achieved robustly by a handful of mechanisms, and while eukaryotic chemotactic networks appear to rely on one of these-the incoherent feed-forward loop, bacterial chemotaxis depends on another-the negative feedback loop. In this review, we discuss how this conclusion can be reached even if the details of the molecular networks are incompletely understood. Furthermore, we argue that the use of distinct network architectures is not accidental and may be a consequence of the nature of the signalling inputs and the limitations of the sensory properties of different cell types. PMID- 24062591 TI - Cell polarity. PMID- 24062589 TI - Functional genomics in the study of yeast cell polarity: moving in the right direction. AB - The budding yeast Saccharomyces cerevisiae has been used extensively for the study of cell polarity, owing to both its experimental tractability and the high conservation of cell polarity and other basic biological processes among eukaryotes. The budding yeast has also served as a pioneer model organism for virtually all genome-scale approaches, including functional genomics, which aims to define gene function and biological pathways systematically through the analysis of high-throughput experimental data. Here, we outline the contributions of functional genomics and high-throughput methodologies to the study of cell polarity in the budding yeast. We integrate data from published genetic screens that use a variety of functional genomics approaches to query different aspects of polarity. Our integrated dataset is enriched for polarity processes, as well as some processes that are not intrinsically linked to cell polarity, and may provide new areas for future study. PMID- 24062590 TI - Epithelial polarity and spindle orientation: intersecting pathways. AB - During asymmetric stem cell divisions, the mitotic spindle must be correctly oriented and positioned with respect to the axis of cell polarity to ensure that cell fate determinants are appropriately segregated into only one daughter cell. By contrast, epithelial cells divide symmetrically and orient their mitotic spindles perpendicular to the main apical-basal polarity axis, so that both daughter cells remain within the epithelium. Work in the past 20 years has defined a core ternary complex consisting of Pins, Mud and Galphai that participates in spindle orientation in both asymmetric and symmetric divisions. As additional factors that interact with this complex continue to be identified, a theme has emerged: there is substantial overlap between the mechanisms that orient the spindle and those that establish and maintain apical-basal polarity in epithelial cells. In this review, we examine several factors implicated in both processes, namely Canoe, Bazooka, aPKC and Discs large, and consider the implications of this work on how the spindle is oriented during epithelial cell divisions. PMID- 24062592 TI - The social defeat hypothesis of schizophrenia: an update. AB - According to the social defeat (SD) hypothesis, published in 2005, long-term exposure to the experience of SD may lead to sensitization of the mesolimbic dopamine (DA) system and thereby increase the risk for schizophrenia. The hypothesis posits that SD (ie, the negative experience of being excluded from the majority group) is the common denominator of 5 major schizophrenia risk factors: urban upbringing, migration, childhood trauma, low intelligence, and drug abuse. The purpose of this update of the literature since 2005 is to answer 2 questions: (1) What is the evidence that SD explains the association between schizophrenia and these risk factors? (2) What is the evidence that SD leads to sensitization of the mesolimbic DA system? The evidence for SD as the mechanism underlying the increased risk was found to be strongest for migration and childhood trauma, while the evidence for urban upbringing, low intelligence, and drug abuse is suggestive, but insufficient. Some other findings that may support the hypothesis are the association between risk for schizophrenia and African American ethnicity, unemployment, single status, hearing impairment, autism, illiteracy, short stature, Klinefelter syndrome, and, possibly, sexual minority status. While the evidence that SD in humans leads to sensitization of the mesolimbic DA system is not sufficient, due to lack of studies, the evidence for this in animals is strong. The authors argue that the SD hypothesis provides a parsimonious and plausible explanation for a number of epidemiological findings that cannot be explained solely by genetic confounding. PMID- 24062593 TI - Characterization of psychotic experiences in adolescence using the specific psychotic experiences questionnaire: findings from a study of 5000 16-year-old twins. AB - We aimed to characterize multiple psychotic experiences, each assessed on a spectrum of severity (ie, quantitatively), in a general population sample of adolescents. Over five thousand 16-year-old twins and their parents completed the newly devised Specific Psychotic Experiences Questionnaire (SPEQ); a subsample repeated it approximately 9 months later. SPEQ was investigated in terms of factor structure, intersubscale correlations, frequency of endorsement and reported distress, reliability and validity, associations with traits of anxiety, depression and personality, and sex differences. Principal component analysis revealed a 6-component solution: paranoia, hallucinations, cognitive disorganization, grandiosity, anhedonia, and parent-rated negative symptoms. These components formed the basis of 6 subscales. Correlations between different experiences were low to moderate. All SPEQ subscales, except Grandiosity, correlated significantly with traits of anxiety, depression, and neuroticism. Scales showed good internal consistency, test-retest reliability, and convergent validity. Girls endorsed more paranoia, hallucinations, and cognitive disorganization; boys reported more grandiosity and anhedonia and had more parent rated negative symptoms. As in adults at high risk for psychosis and with psychotic disorders, psychotic experiences in adolescents are characterized by multiple components. The study of psychotic experiences as distinct dimensional quantitative traits is likely to prove an important strategy for future research, and the SPEQ is a self- and parent-report questionnaire battery that embodies this approach. PMID- 24062595 TI - Managed Care's Dual Impact on Outpatient Substance Abuse Treatment: Methadone Maintenance vs. Drug Free. AB - The number and type of services offered at substance abuse treatment (SAT) facilities are important aspects of the quality of care. Managed care (MC) is a growing presence in SAT and has been shown to affect the provision of treatment. We expand on earlier work and examine the impact of managed care on the number and type of services offered by methadone maintenance (MM) and drug-free (DF) outpatient treatment facilities. We use the econometric technique of instrumental variables to address the issue of endogeneity of MC and service offerings, thereby allowing a causal interpretation of results. Using data from the 2000 National Survey of Substance Abuse Treatment Services, we find that MC significantly increases the total number of services offered in MM outpatient facilities by four, yet decreases the number by two in DF outpatient facilities. We also show how the impact on specific services differs by modality and provide explanations for our findings. PMID- 24062594 TI - Clinical features of schizophrenia with enhanced carbonyl stress. AB - Accumulating evidence suggests that advanced glycation end products, generated as a consequence of facilitated carbonyl stress, are implicated in the development of a variety of diseases. These diseases include neurodegenerative illnesses, such as Alzheimer disease. Pyridoxamine is one of the 3 forms of vitamin B6, and it acts by combating carbonyl stress and inhibiting the formation of AGEs. Depletion of pyridoxamine due to enhanced carbonyl stress eventually leads to a decrease in the other forms of vitamin B6, namely pyridoxal and pyridoxine. We previously reported that higher levels of plasma pentosidine, a well-known biomarker for advanced glycation end products, and decreased serum pyridoxal levels were found in a subpopulation of schizophrenic patients. However, there is as yet no clinical characterization of this subset of schizophrenia. In this study, we found that these patients shared many clinical features with treatment resistant schizophrenia. These include a higher proportion of inpatients, low educational status, longer durations of hospitalization, and higher doses of antipsychotic medication, compared with patients without carbonyl stress. Interestingly, psychopathological symptoms showed a tendency towards negative association with serum vitamin B6 levels. Our results support the idea that treatment regimes reducing carbonyl stress, such as supplementation of pyridoxamine, could provide novel therapeutic benefits for this subgroup of patients. PMID- 24062596 TI - A Month of Breastfeeding Associated with Greater Adherence to Pediatric Nutrition Guidelines. AB - BACKGROUND: Research has shown that both breastfeeding and delaying the introduction of solids or liquids other than breast milk protect against obesity later in early childhood. OBJECTIVES: To compare whether breastfeeding mothers adhere to more of the American Academy of Pediatrics (AAP) feeding recommendations for infants. METHOD: This longitudinal study compared the breastfeeding knowledge, intentions, and practices as well as complementary feeding choices of 163 ethnically diverse, primiparous women over the first 18 months of motherhood. RESULTS: Although almost all women knew about the health benefits of (98%) breastfeeding and intended to (98%) breastfeed, only 85% initiated and 51% continued beyond 4 weeks. Breastfeeding for longer durations was associated with better feeding choices. Mothers who breastfed for more weeks were more likely to adhere to AAP guidelines on liquids other than breast milk at 4, 6, and 12 months, and introduce solids, liquids other than breast milk, and other complimentary foods at later ages. Furthermore, mothers who breastfed for less than 1 month were more likely to introduce solids by 2 months in comparison to mothers who breastfed for 1 month or more (OR=3.22). CONCLUSION: Knowledge and intentions do not explain breastfeeding initiation or continuation. However, when women committed to more weeks of breastfeeding, especially more than 4 weeks, they made better nutrition choices for their infants. PMID- 24062597 TI - A new, simple, green, and one-pot four-component synthesis of bare and poly(alpha,gamma, L-glutamic acid)-capped silver nanoparticles. AB - A simple and green chemical method has been developed to synthesize stable bare and capped silver nanoparticles based on the reduction of silver ions by glucose and capping by poly(alpha,gamma,L-glutamic acid) (PGA). The use of ammonia during synthesis was avoided. PGA has had a dual role in the synthesis and was used as a capping agent to make the silver nanoparticle more biocompatible and to protect the nanoparticles from agglomerating in the liquid medium. The synthesized PGA capped silver nanoparticles in the size range 5-45 nm were stable over long periods of time, without signs of precipitation. Morphological examination has shown that the silver nanoparticles had a nearly spherical, multiply twinned structure. The effects of the reaction temperature and the reaction time during the synthesis were investigated too. The biocompatibility of the PGA-capped silver nano-particles is discussed in terms of in vitro toxicity with human intestinal Caco-2 cells. The samples were characterized by UV-Visible spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, and zeta potential measurements. PMID- 24062598 TI - Kernel Estimation of Rate Function for Recurrent Event Data. AB - Recurrent event data are largely characterized by the rate function but smoothing techniques for estimating the rate function have never been rigorously developed or studied in statistical literature. This paper considers the moment and least squares methods for estimating the rate function from recurrent event data. With an independent censoring assumption on the recurrent event process, we study statistical properties of the proposed estimators and propose bootstrap procedures for the bandwidth selection and for the approximation of confidence intervals in the estimation of the occurrence rate function. It is identified that the moment method without resmoothing via a smaller bandwidth will produce a curve with nicks occurring at the censoring times, whereas there is no such problem with the least squares method. Furthermore, the asymptotic variance of the least squares estimator is shown to be smaller under regularity conditions. However, in the implementation of the bootstrap procedures, the moment method is computationally more efficient than the least squares method because the former approach uses condensed bootstrap data. The performance of the proposed procedures is studied through Monte Carlo simulations and an epidemiological example on intravenous drug users. PMID- 24062599 TI - Measuring Physical Activity in Older Adults with and without Early Stage Alzheimer's Disease. AB - We compared subjective reports of physical activity with objective measures of physical fitness including cardiorespiratory capacity, body composition, and physical performance in 146 older adults with and without early stage Alzheimer's disease (ESAD). Respondents reported primarily unstructured and low-intensity activities, including walking and housework. Individuals with ESAD participated in fewer and lower intensity physical activities than those without ESAD. In those without ESAD, housework was related to lower body mass index, leisure walking was related to faster speed on a timed walking test, and participation in sports was related to higher peak oxygen intake. In individuals with ESAD, reported physical activities did not predict any of the physical fitness, body composition, or physical performance measures. We conclude that measures of physical activity require expansion of unstructured and low intensity activities to improve sensitivity in sedentary populations, especially in older adults with ESAD. PMID- 24062600 TI - Language, literacy, attentional behaviors, and instructional quality predictors of written composition for first graders. AB - We had two primary purposes in the present study: (1) to examine unique child level predictors of written composition which included language skills, literacy skills (e.g., reading and spelling), and attentiveness and (2) to examine whether instructional quality (quality in responsiveness and individualization, and quality in spelling and writing instruction) is uniquely related to written composition for first-grade children (N = 527). Children's written composition was evaluated on substantive quality (ideas, organization, word choice, and sentence flow) and writing conventions (spelling, mechanics, and handwriting). Results revealed that for the substantive quality of writing, children's grammatical knowledge, reading comprehension, letter writing automaticity, and attentiveness were uniquely related. Teachers' responsiveness was also uniquely related to the substantive quality of written composition after accounting for child predictors and other instructional quality variables. For the writing conventions outcome, children's spelling and attentiveness were uniquely related, but instructional quality was not. These results suggest the importance of paying attention to multiple component skills such as language, literacy, and behavioral factors as well as teachers' responsiveness for writing development. PMID- 24062601 TI - The Preoperative Assessment of Hepatic Tumours: Evaluation of UK Regional Multidisciplinary Team Performance. AB - Introduction. In the UK, patients where liver resection is contemplated are discussed at hepatobiliary multidisciplinary team (MDT) meetings. The aim was to assess MDT performance by identification of patients where radiological and pathological diagnoses differed. Materials and Methods. A retrospective review of a prospectively maintained database of all cases undergoing liver resection from March 2006 to January 2012 was performed. The presumed diagnosis as a result of radiological investigation and MDT discussion is recorded at the time of surgery. Imaging was reviewed by specialist gastrointestinal radiologists, and resultswereagreedonby consensus. Results. Four hundred and thirty-eight patients were studied. There was a significant increase in the use of preoperative imaging modalities (P <= 0.01) but no change in the rate of discrepant diagnosis over time. Forty-two individuals were identified whose final histological diagnosis was different to that following MDT discussion (9.6%). These included 30% of patients diagnosed preoperatively with hepatocellular carcinoma and 25% with cholangiocarcinoma of a major duct. Discussion. MDT assessment of patients preoperatively is accurate in terms of diagnosis. The highest rate of discrepancies occurred in patients with focal lesions without chronic liver disease or primary cancer, where hepatocellular carcinoma was overdiagnosed and peripheral cholangiocarcinoma underdiagnosed, where particular care should be taken. Additional care should be taken in these groups and preoperative multimodality imaging considered. PMID- 24062602 TI - Heterostructuring Nanocrystal Quantum Dots Toward Intentional Suppression of Blinking and Auger Recombination. AB - At the level of a single particle, nanocrystal quantum dots (NQDs) are observed to fluoresce intermittently or "blink." They are also characterized by an efficient non-radiative recombination process known as Auger Recombination (AR). Recently, new approaches to NQD heterostructuring have been developed that directly impact both blinking and AR, resulting in dramatic suppression of these unwanted processes. The three successful hetero-NQD motifs are reviewed here: (1) interfacial alloying, (2) thick or "giant" shells, and (3) specific type-II electronic structures. These approaches, which rely on modifying or tuning internal NQD core/shell structures, are compared with alternative strategies for blinking suppression that rely, instead, on surface modifications or surface mediated interactions. Finally, in each case, the unique synthetic approaches or challenges addressed that have driven the realization of novel and important functionality are discussed, along with the implications for development of a comprehensive 'materials design' strategy for blinking and AR-suppressed heterostructured NQDs. PMID- 24062603 TI - Alcohol is an oxidative stressor for gastric epithelial cells: detection of superoxide in living cells. AB - Alcohol/ethanol has been reported to derived necrosis and apoptosis with an oxidative stress in gastric mucosal cells. However the clear evidence for reactive oxygen species (ROS) generation by alcohol in gastric cells in vitro is none. In this study, we elucidated ethanol is an oxidative stress inducer on rat gastric epithelial cells by electron paramagnetic resonance measurement in living cells. We also confirmed whether ethanol-induced cellular ROS was derived from mitochondria or not. The results of cellular ROS determination showed that an increment of cellular ROS was shown for 15 min from exposing 1% (v/v) ethanol. Lipid peroxidation in cellular membrane also induced by 1% ethanol and the tendency is same in the results of cellular ROS determination. JC-1 stained showed the decrement of mitochondrial membrane potential. Additionally the localization of cellular ROS coincided with mitochondria. These results indicated that ethanol is not merely a necrotizing factor for gastric epithelial cells, but also an oxidative stress inducer via injured mitochondria. PMID- 24062604 TI - Extension of lifespan and protection against oxidative stress by an antioxidant herb mixture complex (KPG-7) in Caenorhabditis elegans. AB - Excessive generation of reactive oxygen species within cells results in oxidative stress. Furthermore, accumulation of reactive oxygen species has been shown to reduce cell longevity. Many dietary supplements are believed to have anti-aging effects. The herb mixture KPG-7 contains several components with antioxidant activity. We aim to clarify the mechanisms responsible for the antioxidant activity of KPG-7 and to establish whether KPG-7 has an anti-aging effect. We examined whether dietary supplementation with KPG-7 could provide protection against oxidative stress, extend lifespan, and delay aging in Caenorhabditis elegans (C. elegans). We found that KPG-7 extended lifespan and delayed aging in adult C. elegans. The expression of oxidation resistance 1 protein was induced by juglone and this effect was significantly suppressed in KPG-7-treated. In addition, the amount of oxidized protein was significantly lower in KPG-7-treated worms than untreated worms. Furthermore, locomotive activity was increased in C. elegans at 3 days of age following the treatment with KPG-7. On the other hand, the level of cellular ATP was lower at 3 days of age in worms treated with KPG-7 than in untreated worms. KPG-7 increases lifespan and delays aging in C. elegans, well corresponding to its activity to protect against oxidative stress. PMID- 24062605 TI - Mithramycin A induces apoptosis by regulating the mTOR/Mcl-1/tBid pathway in androgen-independent prostate cancer cells. AB - Mithramycin A (Mith) is an aureolic acid-type polyketide produced by various soil bacteria of the genus Streptomyces. Mith inhibits myeloid cell leukemia-1 (Mcl-1) to induce apoptosis in prostate cancer, but the molecular mechanism underlying this process has not been fully elucidated. The aim of this study was therefore to investigate the detailed molecular mechanism related to Mith-induced apoptosis in prostate cancer cells. Mith decreased the phosphorylation of mammalian target of rapamycin (mTOR) in both cell lines overexpressing phospho-mTOR compared to RWPE-1 human normal prostate epithelial cells. Mith significantly induced truncated Bid (tBid) and siRNA-mediated knock-down of Mcl-1 increased tBid protein levels. Moreover, Mith also inhibited the phosphorylation of mTOR on serine 2448 and Mcl-1, and increased tBid protein in prostate tumors in athymic nude mice bearing DU145 cells as xenografts. Thus, Mith acts as an effective tumor growth inhibitor in prostate cancer cells through the mTOR/Mcl-1/tBid signaling pathway. PMID- 24062606 TI - S-Allyl cysteine improves nonalcoholic fatty liver disease in type 2 diabetes Otsuka Long-Evans Tokushima Fatty rats via regulation of hepatic lipogenesis and glucose metabolism. AB - It is important to prevent and improve diabetes mellitus and its complications in a safe and low-cost manner. S-Allyl cysteine, an aged garlic extract with antioxidant activity, was investigated to determine whether S-allyl cysteine can improve type 2 diabetes in Otsuka Long-Evans Tokushima Fatty rats with nonalcoholic fatty liver disease. Male Otsuka Long-Evans Tokushima Fatty rats and age-matched Long-Evans Tokushima Otsuka rats were used and were divided into two groups at 29 weeks of age. S-Allyl cysteine (0.45% diet) was administered to rats for 13 weeks. Rats were killed at 43 weeks of age, and detailed analyses were performed. S-Allyl cysteine improved hemoglobinA1c, blood glucose, triglyceride, and low-density lipoprotein cholesterol levels. Furthermore, S-allyl cysteine normalized plasma insulin levels. S-Allyl cysteine activated the mRNA and protein expression of both peroxisome proliferator-activated receptor alpha and gamma, as well as inhibiting pyruvate dehydrogenase kinase 4 in Otsuka Long-Evans Tokushima Fatty rat liver. Sterol regulatory element-binding protein 1c and forkhead box O1 proteins were normalized by S-allyl cysteine in Otsuka Long-Evans Tokushima Fatty rat liver. In conclusions, these findings support the hypothesis that S-allyl cysteine has diabetic and nonalcoholic fatty liver disease therapeutic potential as a potent regulating agent against lipogenesis and glucose metabolism. PMID- 24062607 TI - The effects of soy isoflavone on bone density in north region of climacteric Chinese women. AB - Only a few investigations were based on limb bone density. This study evaluated the efficacy of soy isoflavone in the treatment of the principal menopausal disorders, limb bone density and the role of pathway. The research protocol involved the random subdivision of the enrolled sample into two groups of 40 women, who were to receive treatment for 6 months with isoflavone (90 mg/day) and with placebo. All of the patients were asked to fill in a questionnaire concerning their complaints. BMD of the radius and tibia were measured using quantitative ultrasound. Bone metabolism indexes calcium, phosphorus and alkaline phosphatase (ALP) were examined regularly. Serum cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) examined by ELISA. The results of the score of Kupperman table showed that the isoflavone can lead to a significant reduction in some of the disorders. Compared with placebo, the tibia bone density in isoflavone group increased obviously against the base value before trail. Isoflavone led to a stronger descent of the concentration of ALP and a decrease of IL-6 and TNF-alpha level than placebo. For climacteric women, soy isoflavone in the dose of 90 mg/day could improve some menopausal syndromes and was effective on increasing limb bone density, which maybe had the relationship with the levels of IL-6, TNF-alpha and ALP in serum. PMID- 24062608 TI - Vitamin K1 (phylloquinone) and K2 (menaquinone-4) supplementation improves bone formation in a high-fat diet-induced obese mice. AB - Several reports suggest that obesity is a risk factor for osteoporosis. Vitamin K plays an important role in improving bone metabolism. This study examined the effects of vitamin K1 and vitamin K2 supplementation on the biochemical markers of bone turnover and morphological microstructure of the bones by using an obese mouse model. Four-week-old C57BL/6J male mice were fed a 10% fat normal diet group or a 45% kcal high-fat diet group, with or without 200 mg/1000 g vitamin K1 (Normal diet + K1, high-fat diet + K1) and 200 mg/1000 g vitamin K2 (Normal diet + K2, high-fat diet + K2) for 12 weeks. Serum levels of osteocalcin were higher in the high-fat diet + K2 group than in the high-fat diet group. Serum OPG level of the high-fat diet group, high-fat diet + K1 group, and high-fat diet + K2 group was 2.31 +/- 0.31 ng/ml, 2.35 +/- 0.12 ng/ml, and 2.90 +/- 0.11 ng/ml, respectively. Serum level of RANKL in the high-fat diet group was significantly higher than that in the high-fat diet + K1 group and high-fat diet + K2 group (p<0.05). Vitamin K supplementation seems to tend to prevent bone loss in high fat diet induced obese state. These findings suggest that vitamin K supplementation reversed the high fat diet induced bone deterioration by modulating osteoblast and osteoclast activities and prevent bone loss in a high fat diet-induced obese mice. PMID- 24062609 TI - Upregulation of fatty acid synthesis and the suppression of hepatic triglyceride lipase as a direct cause of hereditary postprandial hypertriglyceridemia in rabbits. AB - Rabbits with hereditary postprandial hypertriglyceridemia exhibit central obesity and are regarded as a reliable model for metabolic syndrome. This study was performed to gain insight into the affected process of lipid metabolism and into the causative genes of the postprandial hypertriglyceridemia rabbits. Eleven genes that play key roles in lipid metabolism were selected, their mRNA levels were assessed by quantitative PCR, and their expressions were compared among postprandial hypertriglyceridemia rabbits using Japanese white rabbits as the control. Two genes appeared to be in causal connection with postprandial hypertriglyceridemia, and these were regarded as likely candidates for the pathogenesis. One was the fatty acid synthase gene, which had an expression constitutively higher in postprandial hypertriglyceridemia rabbits than in Japanese white rabbits during the fasting state and reached quite high levels after feeding. The other was the gene for hepatic triglyceride lipase with an expression that was approximately one order lower than that found in the Japanese white rabbits. The low plasma hepatic triglyceride lipase activities were consistent with the low levels of the transcript in the livers of the postprandial hypertriglyceridemia rabbits. Thus, elevated fatty acid synthesis and defected lipid hydrolysis together would cause the postprandial hypertriglyceridemia in postprandial hypertriglyceridemia rabbits. PMID- 24062610 TI - Changes of energy metabolism, nutritional status and serum cytokine levels in patients with Crohn's disease after anti-tumor necrosis factor-alpha therapy. AB - We investigated the effects of treatment with antibodies against tumor necrosis factor (TNF)-alpha on energy metabolism, nutritional status, serum cytokine levels in patients with Crohn's disease (CD). Twelve patients were enrolled. Resting energy expenditure (REE) levels were measured by indirect calorimetry. Crohn's disease activity index (CDAI) significantly decreased after treatment with anti-TNF-alpha therapy. Anti-TNF-alpha therapy did not affect REE, but respiratory quotient (RQ) significantly increased after treatment. Serum interleukin-6 levels were significantly decreased and RQ were significantly increased in high REE (>=25 kcal/kg/day) group as compared to low REE (<25 kcal/kg/day) group. In conclusion, high REE value on admission is a predictive factor for good response to treatment with anti-TNF-alpha antibodies in active CD patients. PMID- 24062612 TI - Oxidized LDL induces alternative macrophage phenotype through activation of CD36 and PAFR. AB - OxLDL is recognized by macrophage scavenger receptors, including CD36; we have recently found that Platelet-Activating Factor Receptor (PAFR) is also involved. Since PAFR in macrophages is associated with suppressor function, we examined the effect of oxLDL on macrophage phenotype. It was found that the presence of oxLDL during macrophage differentiation induced high mRNA levels to IL-10, mannose receptor, PPAR gamma and arginase-1 and low levels of IL-12 and iNOS. When human THP-1 macrophages were pre-treated with oxLDL then stimulated with LPS, the production of IL-10 and TGF- beta significantly increased, whereas that of IL-6 and IL-8 decreased. In murine TG-elicited macrophages, this protocol significantly reduced NO, iNOS and COX2 expression. Thus, oxLDL induced macrophage differentiation and activation towards the alternatively activated M2 phenotype. In murine macrophages, oxLDL induced TGF- beta , arginase-1 and IL-10 mRNA expression, which were significantly reduced by pre-treatment with PAFR antagonists (WEB and CV) or with antibodies to CD36. The mRNA expression of IL 12, RANTES and CXCL2 were not affected. We showed that this profile of macrophage activation is dependent on the engagement of both CD36 and PAFR. We conclude that oxLDL induces alternative macrophage activation by mechanisms involving CD36 and PAFR. PMID- 24062611 TI - Electronegative LDL: a circulating modified LDL with a role in inflammation. AB - Electronegative low density lipoprotein (LDL(-)) is a minor modified fraction of LDL found in blood. It comprises a heterogeneous population of LDL particles modified by various mechanisms sharing as a common feature increased electronegativity. Modification by oxidation is one of these mechanisms. LDL(-) has inflammatory properties similar to those of oxidized LDL (oxLDL), such as inflammatory cytokine release in leukocytes and endothelial cells. However, in contrast with oxLDL, LDL(-) also has some anti-inflammatory effects on cultured cells. The inflammatory and anti-inflammatory properties ascribed to LDL(-) suggest that it could have a dual biological effect. PMID- 24062613 TI - Transforming growth factor beta1 genotypes in relation to TGFbeta1, interleukin 8, and tumor necrosis factor alpha in induced sputum and blood in cystic fibrosis. AB - BACKGROUND: High-producer TGFbeta1 genotypes are associated with severe lung disease in cystic fibrosis (CF), but studies combining IL-8, TNFalpha-, and TGFbeta1(+genotype) levels and their impact on CF lung disease are scarce. AIM: Assessing the relationship between TGF beta 1, IL-8, and TNF- alpha and lung disease in CF in an exacerbation-free interval. METHODS: Twenty four patients delta F508 homozygous (median age 20.5 y, Shwachman score 75, FEV1(%) 83) and 8 controls (median age 27.5 y) were examined. TGF beta 1 was assessed in serum and induced sputum (IS) by ELISA, for IL-8 and TNF- alpha by chemiluminescence in IS and whole blood. Genotyping was performed for TGF beta 1 C-509T and T+869C utilizing RFLP. RESULTS: TGF beta 1 in IS (CF/controls median 76.5/59.1 pg/mL, P < 0.074) was higher in CF. There was a negative correlation between TGF beta 1 in serum and lung function (LF) (FEV1 (r = -0.488, P = 0.025), MEF 25 (r = -0.425, P = 0.055), and VC (r = -0.572, P = 0.007)). Genotypes had no impact on TGF beta 1 in IS, serum, and LF. In IS TGF beta 1 correlated with IL-8 (r = 0.593, P < 0.007) and TNF- alpha (r = 0.536, P < 0.018) in patients colonized by bacteria with flagellin. CONCLUSION: TGF beta 1 in serum not in IS correlates with LF. In patients colonized by bacteria with flagellin, TGF beta 1 correlates with IL-8 and TNF- alpha in IS. PMID- 24062614 TI - Estrogen modulates the influence of cardiac inflammatory cells on function of cardiac fibroblasts. AB - BACKGROUND: Inflammatory cells play a major role in the pathology of heart failure by stimulating cardiac fibroblasts to regulate the extracellular matrix in an adverse way. In view of the fact that inflammatory cells have estrogen receptors, we hypothesized that estrogen provides cardioprotection by decreasing the ability of cardiac inflammatory cells to influence fibroblast function. METHODS: Male rats were assigned to either an untreated or estrogen-treated group. In the treated group, estrogen was delivered for 2 weeks via a subcutaneous implanted pellet containing 17beta-estradiol. A mixed population of cardiac inflammatory cells, including T-lymphocytes (about 70%), macrophages (about 12%), and mast cells (about 12%), was isolated from each rat and cultured in a Boyden chamber with cardiac fibroblasts from untreated adult male rats for 24 hours. To examine if tumor necrosis factor-alpha (TNF-alpha) produced by inflammatory cells represents a mechanism contributing to the stimulatory effects of inflammatory cells on cardiac fibroblasts, inflammatory cells from the untreated group were incubated with cardiac fibroblasts in a Boyden chamber system for 24 hours in the presence of a TNF-alpha-neutralizing antibody. Cardiac fibroblasts were also incubated with 5 ng/mL of TNF-alpha for 24 hours. Fibro blast proliferation, collagen synthesis, matrix metalloproteinase activity, beta1 integrin protein levels, and the ability of fibroblasts to contract collagen gels were determined in all groups and statistically compared via one-way analysis of variance. RESULTS: INFLAMMATORY CELLS FROM THE UNTREATED GROUP RESULTED IN: 1) an increased fibroblast proliferation, collagen production and matrix metalloproteinase activity; and 2) a loss of beta1 integrin protein and a reduced ability to contract collagen gels. In contrast, inflammatory cells from the treated group resulted in: 1) an attenuated fibroblast proliferation; 2) a nonsignificant reduction in collagen production; 3) the prevention of matrix metalloproteinase activation and the loss of beta1 integrin by fibroblasts and 4) a preservation of the fibroblasts' ability to contract collagen gels. The TNF alpha neutralizing antibody attenuated or prevented the untreated inflammatory cell-induced fibroblast proliferation, collagen production, matrix metalloproteinase activation and loss of beta1 integrin protein as well as preserved fibroblast contractile ability. Incubation with TNF-alpha yielded changes in the cardiac fibroblast parameters that were directionally similar to the results obtained with untreated inflammatory cells. CONCLUSION: These results and those of our previous in vivo studies suggest that a major mechanism by which estrogen provides cardioprotection is its ability to modulate synthesis of TNF alpha by inflammatory cells, thereby preventing inflammatory cell induction of cardiac fibroblast events that contribute to adverse extracellular matrix remodeling. PMID- 24062615 TI - Anti-inflammatory effects of budesonide in human lung fibroblast are independent of histone deacetylase 2. AB - OBJECTIVE AND DESIGN: Reduced expression of histone deacetylase 2 (HDAC2) in alveolar macrophages and epithelial cells may account for reduced response of chronic obstructive pulmonary disease (COPD) patients to glucocorticoids. HDAC2 expression and its role in mediating glucocorticoid effects on fibroblast functions, however, has not been fully studied. This study was designed to investigate whether HDAC2 mediates glucocorticoid effects on release of inflammatory cytokines and matrix metalloproteinases (MMPs) from human lung fibroblasts. METHODS: Human lung fibroblasts (HFL-1 cells) were stimulated with interleukin (IL)-1 beta plus tumor necrosis factor (TNF)-alpha in the presence or absence of the glucocorticoid budesonide. Cytokines (IL-6 and IL-8) were quantified by enzyme linked immunosorbent assay (ELISA) and MMPs (MMP-1 and MMP 3) by immunoblotting in culture medium. The role of HDAC2 was investigated using a pharmacologic inhibitor as well as a small interfering ribonucleic acid (siRNA) targeting HDAC2. RESULTS: We have demonstrated that budesonide concentration dependently (10(-10)-10(-7) M) inhibited IL-6, IL-8, MMP-1, and MMP-3 release by HFL-1 cells in response to IL-1beta plus TNF-alpha. While an HDAC inhibitor significantly blocked the inhibitory effect of budesonide on human bronchial epithelial cells (HBECs) and monocytes (THP-1 cells), it did not block the inhibitory effect of budesonide on release of cytokines and MMPs from HFL-1 cells. Similarly, an HDAC2-siRNA blocked budesonide inhibition of cytokine release in HBECs, but it did not block the inhibitory effect of budesonide on HFL 1 cytokine and MMP release. Furthermore, budesonide significantly blocked release of cytokines and MMPs to a similar degree in normal and COPD lung fibroblasts as well as in HFL-1 cells exposed or not exposed to cigarette smoke extract. CONCLUSION: These findings suggest that, in contrast to airway epithelial cells and monocytes/macrophages, HDAC2 is not required for budesonide to inhibit MMP and cytokine release by lung fibroblasts and this inhibitory pathway appears to be intact in cultured fibroblasts from COPD patients. These results also suggest that budesonide has the potential to modulate fibroblast-mediated tissue remodeling following airway inflammation in COPD, which is mediated via an HDAC2 independent pathway. PMID- 24062616 TI - The role of inflammation and interleukin-1 in acute cerebrovascular disease. AB - Acute cerebrovascular disease can affect people at all stages of life, from neonates to the elderly, with devastating consequences. It is responsible for up to 10% of deaths worldwide, is a major cause of disability, and represents an area of real unmet clinical need. Acute cerebrovascular disease is multifactorial with many mechanisms contributing to a complex pathophysiology. One of the major processes worsening disease severity and outcome is inflammation. Pro inflammatory cytokines of the interleukin (IL)-1 family are now known to drive damaging inflammatory processes in the brain. The aim of this review is to discuss the recent literature describing the role of IL-1 in acute cerebrovascular disease and to provide an update on our current understanding of the mechanisms of IL-1 production. We also discuss the recent literature where the effects of IL-1 have been targeted in animal models, thus reviewing potential future strategies that may limit the devastating effects of acute cerebrovascular disease. PMID- 24062617 TI - Predicting early epidurals: association of maternal, labor, and neonatal characteristics with epidural analgesia initiation at a cervical dilation of 3 cm or less. AB - BACKGROUND: Retrospective studies have associated early epidural analgesia with cesarean delivery, but prospective studies do not demonstrate a causal relationship. This suggests that there are other variables associated with early epidural analgesia that increase the risk of cesarean delivery. This study was undertaken to determine the characteristics associated with early epidural analgesia initiation. METHODS: Information about women delivering at 37 weeks or greater gestation with epidural analgesia, who were not scheduled for cesarean delivery, was extracted from the McGill Obstetric and Neonatal Database. Patients were grouped into those who received epidural analgesia at a cervical dilation of <=3 cm and >3 cm. Univariable and multivariable logistic regression was used to determine the maternal, neonatal, and labor characteristics that increased the risk of inclusion in the early epidural group. RESULTS: Of the 13,119 patients analyzed, multivariable regression demonstrated odds ratios (OR) of 2.568, 5.915 and 10.410 for oxytocin augmentation, induction, and dinoprostone induction of labor (P < 0.001). Increasing parity decreased the odds of early epidural analgesia (OR 0.780, P < 0.001), while spontaneous rupture of membranes (OR 1.490) and rupture of membranes before labor commenced (OR 1.288) were also associated with early epidural analgesia (P < 0.001). Increasing maternal weight (OR 1.049, P = 0.002) and decreasing neonatal weight (OR 0.943, P < 0.001) were associated with increasing risk of early epidural analgesia. CONCLUSION: Labor augmentation and induction, nulliparity, rupture of membranes spontaneously and before labor starts, increasing maternal weight, and decreasing neonatal weight are associated with early epidural analgesia. Many of these variables are also associated with cesarean delivery. PMID- 24062618 TI - Polysomnographic Sleep and Circadian Temperature Rhythms as a Function of Prior Shift Work Exposure in Retired Seniors. AB - In an earlier published telephone interview study (n > 1,000) we have shown that retired shift workers subjectively report worse sleep than retired day workers. This laboratory study sought to determine whether these findings held up when objective polysomnograhic (PSG) measures of sleep were taken and whether retirees' circadian temperature rhythms differed as a function of shift work exposure. All completers of the telephone interview were invited to attend a 36 hour laboratory study for which participants were paid. This involved continuous core body temperature measurement (using an ingestible pill-based system) and 2 nights of PSG. Shift work exposure (plus other measures) was collected by taking a detailed work history. The second laboratory night was scored into sleep stages. Post hoc, we divided participants into 4 shift work exposure groups: 0 years (ie, no exposure to shift work), 1 to 7 years, 7 to 20 years, and >20 years. Sample sizes were 11, 16, 15, and 15, respectively, with approximate equality in mean age (71.7 years of age, 69.1 years of age, 70.0 years of age, and 70.4 years of age, respectively) and percent male (63%, 50%, 67%, and 73%, respectively). Shift work exposure was associated with worse PSG sleep in a dose related fashion. The percentages of participants with sleep efficiency, 80% for the 0 years, 1 to 7 years, 7 to 20 years, and >20 years groups were 36%, 63%, 67%, and 73%, respectively (P < 0.01), and the percentages with total sleep time (TST), 6 hours were 36%, 56%, 53%, and 73%, respectively (P < 0.01). From the circadian rhythm record, shift work exposure appeared to result (P = 0.06) in an increased spread of phase angles (difference between habitual bedtime and time of temperature trough). In conclusion, it appears likely that shift work may be related to a scarring of sleep and circadian rhythms. This may be associated with a change in the relationship between habitual sleep timing and the phase of the circadian pacemaker. PMID- 24062620 TI - Emergency medicine residents' attitudes and opinions of in-training exam preparation. AB - PURPOSE: Emergency Medicine (EM) residents take the American Board of Emergency Medicine (ABEM) in-training exam, and performance on this exam has been shown to correlate to performance on the ABEM qualifying exam. Though many residencies have in-training exam preparation activities, there is little data on the effectiveness of these efforts. This study aimed to elicit resident perspectives about the exam and exam preparation in order to generate hypotheses and better inform future preparation efforts. METHODS: Second- and third-year EM residents at a single institution were interviewed using a semi-structured format. Qualitative methodology was used to analyze the data. RESULTS: Thirteen EM residents participated in the study. Eight major themes and 18 sub-themes were identified. These were further characterized as relating to the exam itself or to exam preparation. Residents generally value the in-training exam. Sixty-nine percent noted that it provided an assessment of their current knowledge and deficiencies. Thirty-eight percent noted that it improved familiarity with the qualifying exam. Regarding exam preparation, residents stated that a question format was preferred, especially when accompanying explanations were of high quality. Additionally, practical considerations, such as portability, impacted resident selection of study tools. CONCLUSION: Residents value the in-training exam as a marker of their academic progress and for their ability to gain familiarity with the qualifying exam. They prefer question-based preparation over text-based learning, as long as there is a detailed explanation of each answer. Educators creating structured in-training review may want to focus on question based material with detailed explanations. PMID- 24062619 TI - Rates of mood and anxiety disorders and contributors to continued heroin use in methadone maintenance patients: A comparison by HIV status. AB - The frequency of mood and anxiety disorders is elevated among individuals with a history of intravenous drug abuse and among those with human immunodeficiency virus (HIV), and these disorders are associated with continued substance use despite treatment. The present study examined rates of mood and anxiety disorders, and recent heroin use, among HIV-infected and HIV-noninfected patients receiving methadone maintenance therapy. Participants were 160 (80 HIV-infected, 80 HIV-noninfected) methadone patients. Clinician-administered, semistructured interviews were used to identify unipolar and bipolar depression, and four major anxiety disorders (panic disorder with agoraphobia [PDA], generalized anxiety disorder [GAD], post-traumatic stress disorder [PTSD], and social anxiety disorder [SAD]). Toxicology screens and self-reporting were used to assess heroin, cocaine, marijuana, and alcohol use over the past month. The entire sample met criteria for at least one psychiatric disorder other than substance dependence. Substantial proportions of participants met criteria for major depressive disorder (55.6%), bipolar I, bipolar II, or cyclothymia (6.4%), PDA (34.4%), GAD (22.5%), SAD (16.9%), and PTSD (34.4%). A greater proportion of HIV infected participants met criteria for SAD (chi2 = 5.03), and a greater proportion of HIV-noninfected participants met criteria for GAD (chi2 = 5.39, P < 0.01). About 14% of participants continued to use heroin over the past month, a significantly greater proportion of whom were HIV-infected. In adjusted analyses, none of the mood or anxiety disorders emerged as significant predictors of recent heroin use, but being HIV-infected did. This study highlights the high rate of psychopathology and continued heroin use despite substance abuse treatment, and underscores the need for interventions that help mitigate these problems among methadone patients. PMID- 24062621 TI - Writing about an experience of illness in medical students. AB - Pathography is defined as "historical biography from a medical, psychological, and psychiatric viewpoint." We thought that writing about an experience of illness might help students understand patients' experience and in turn grow in terms of self-understanding. Participants included 151 medical students. Students wrote about their own experience of illness and were asked to answer questions from the Likert scale. Most students wrote about themselves (79.2%); however, some students (20.8%) wrote about the illness of others. Among the 149 pathographies, ecopathography was most frequent (30.9%), followed by testimonial pathography (25.5%); angry pathography (13.4%) and alternative pathography (12.1%) were relatively less frequent. Eighty-eight pathographies (59.1%) showed 120 expressions of family relationship. Among the 120 cases, worrying about family members was most frequent (47.5%), followed by reliance on a family member (32.5%). All students wrote about the enlightenment experienced on returning to daily life. The sense of belonging together was most frequent (38.3%), followed by gratitude for living (20.8%), resolution to be a good doctor (18.1%), and a will to live and be healthy (12.1%). Answers on the Likert scale (total 5) for pathography beneficence were very high in understanding desirable doctor image (4.46), attaining morals and personality as a health care professional (4.49), and understanding basic communication skills (4.46). Writing about an experience of illness allows students to better understand patients' experience and to grow in self-understanding. PMID- 24062622 TI - The availability of teaching-pedagogical resources used for promotion of learning in teaching human anatomy. AB - Five hundred students attending higher education institutions in northeastern Brazil responded to questionnaires about their anatomy classes; students represented a variety of different health sciences disciplines. Analysis of the responses revealed the participation of teaching assistants in a large percentage of classes and the use of teaching resources, particularly images, from conventional radiographs to magnetic resonance images. The number of classes for cadaver dissection and the number of students with access to that type of class were small. In most cases, dissection was performed according to anatomic regions or systems. Medicine and nursing students had the highest number of practical dissection classes. Most students were assessed using practical and theoretical tests. Findings revealed conditions similar to those found elsewhere. Resources should be renewed and used to improve teaching for students whose courses demand the study of human anatomy. PMID- 24062623 TI - The interaction of representation and reasoning. AB - Automated reasoning is an enabling technology for many applications of informatics. These applications include verifying that a computer program meets its specification; enabling a robot to form a plan to achieve a task and answering questions by combining information from diverse sources, e.g. on the Internet, etc. How is automated reasoning possible? Firstly, knowledge of a domain must be stored in a computer, usually in the form of logical formulae. This knowledge might, for instance, have been entered manually, retrieved from the Internet or perceived in the environment via sensors, such as cameras. Secondly, rules of inference are applied to old knowledge to derive new knowledge. Automated reasoning techniques have been adapted from logic, a branch of mathematics that was originally designed to formalize the reasoning of humans, especially mathematicians. My special interest is in the way that representation and reasoning interact. Successful reasoning is dependent on appropriate representation of both knowledge and successful methods of reasoning. Failures of reasoning can suggest changes of representation. This process of representational change can also be automated. We will illustrate the automation of representational change by drawing on recent work in my research group. PMID- 24062624 TI - Stokes flow singularities in a two-dimensional channel: a novel transform approach with application to microswimming. AB - A transform method for determining the flow generated by the singularities of Stokes flow in a two-dimensional channel is presented. The analysis is based on a general approach to biharmonic boundary value problems in a simply connected polygon formulated by Crowdy & Fokas in this journal. The method differs from a traditional Fourier transform approach in entailing a simultaneous spectral analysis in the independent variables both along and across the channel. As an example application, we find the evolution equations for a circular treadmilling microswimmer in the channel correct to third order in the swimmer radius. Significantly, the new transform method is extendible to the analysis of Stokes flows in more complicated polygonal microchannel geometries. PMID- 24062625 TI - Making waves round a structured cloak: lattices, negative refraction and fringes. AB - Using the framework of transformation optics, this paper presents a detailed analysis of a non-singular square cloak for acoustic, out-of-plane shear elastic and electromagnetic waves. Analysis of wave propagation through the cloak is presented and accompanied by numerical illustrations. The efficacy of the regularized cloak is demonstrated and an objective numerical measure of the quality of the cloaking effect is provided. It is demonstrated that the cloaking effect persists over a wide range of frequencies. As a demonstration of the effectiveness of the regularized cloak, a Young's double slit experiment is presented. The stability of the interference pattern is examined when a cloaked and uncloaked obstacle are successively placed in front of one of the apertures. This novel link with a well-known quantum mechanical experiment provides an additional method through which the quality of cloaks may be examined. In the second half of the paper, it is shown that an approximate cloak may be constructed using a discrete lattice structure. The efficiency of the approximate lattice cloak is analysed and a series of illustrative simulations presented. It is demonstrated that effective cloaking may be obtained by using a relatively simple lattice structure, particularly, in the low-frequency regime. PMID- 24062626 TI - The Oxford Questions on the foundations of quantum physics. AB - The twentieth century saw two fundamental revolutions in physics-relativity and quantum. Daily use of these theories can numb the sense of wonder at their immense empirical success. Does their instrumental effectiveness stand on the rock of secure concepts or the sand of unresolved fundamentals? Does measuring a quantum system probe, or even create, reality or merely change belief? Must relativity and quantum theory just coexist or might we find a new theory which unifies the two? To bring such questions into sharper focus, we convened a conference on Quantum Physics and the Nature of Reality. Some issues remain as controversial as ever, but some are being nudged by theory's secret weapon of experiment. PMID- 24062627 TI - Erratum: Thermal analysis of injectable, cellular-scale optoelectronics with pulsed power. AB - [This corrects the article DOI: 10.1098/rspa.2013.0142.]. PMID- 24062628 TI - Does the Orphan Disadvantage "Spill Over?" An analysis of whether living in an area with a higher concentration of orphans is associated with children's school enrollment in sub-Saharan Africa. AB - BACKGROUND: Despite considerable concern regarding the social consequences of sub Saharan Africa's high orphan prevalence, no research investigates how living in a community densely populated with orphans is more broadly associated with children's-including nonorphans'-acquisition of human capital. OBJECTIVE: We provide a new look at the implications of widespread orphanhood in sub-Saharan Africa by examining whether living in an area with a high concentration of orphans is associated with children's likelihood of school enrollment. METHODS: We use data from the Demographic and Health Survey (DHS) and the Multiple Indicators Cluster Survey (MICS) to estimate multilevel logistic regression models to assess whether living in a setting with a higher concentration of orphans is associated with school enrollment among 383,010 children in 336 provinces in 34 sub-Saharan African countries. RESULTS: Orphan concentration has a curvilinear association with children's school enrollment in western and eastern Africa: the initially positive association becomes negative at higher levels. In central and southern Africa, orphan concentration has a positive linear association with children's school enrollment. CONCLUSION: In western and eastern Africa, the negative association between living in a setting more densely populated with orphans and children's school enrollment provides suggestive evidence that the orphan disadvantage "spills over" in the communities most heavily affected. Conversely, in central and southern Africa, the positive association between living in a setting more densely populated with orphans and children's school enrollment highlights the resiliency of these relatively wealthier communities with high levels of orphans. Although longitudinal research is needed to confirm these findings and clarify the underlying mechanisms, this study lays the groundwork for a new body of research aimed at understanding the broader social implications of widespread orphanhood in sub-Saharan Africa. PMID- 24062629 TI - Fixed point results of locally contractive mappings in ordered quasi-partial metric spaces. AB - Fixed point results for a self-map satisfying locally contractive conditions on a closed ball in an ordered 0-complete quasi-partial metric space have been established. Instead of monotone mapping, the notion of dominated mappings is applied. We have used weaker metric, weaker contractive conditions, and weaker restrictions to obtain unique fixed points. An example is given which shows that how this result can be used when the corresponding results cannot. Our results generalize, extend, and improve several well-known conventional results. PMID- 24062630 TI - The effect of anabolic steroid administration on passive stretching-induced expression of mechano-growth factor in skeletal muscle. AB - BACKGROUND: Stretching of skeletal muscle induces expression of the genes which encode myogenic transcription factors or muscle contractile proteins and results in muscle growth. Anabolic steroids are reported to strengthen muscles. We have previously studied the effects of muscle stretching on gene expression. Here, we studied the effect of a combination of passive stretching and the administration of an anabolic steroid on mRNA expression of a muscle growth factor, insulin-like growth factor-I autocrine variant, or mechano-growth factor (MGF). METHODS: Twelve 8-week-old male Wistar rats were used. Metenolone was administered and passive repetitive dorsiflexion and plantar flexion of the ankle joint performed under deep anesthesia. After 24 h, the gastrocnemius muscles were removed and the mRNA expression of insulin-like growth factor-I autocrine variant was measured using quantitative real-time polymerase chain reaction. RESULTS: Repetitive stretching in combination with metenolone, but not stretching alone, significantly increased MGF mRNA expression. CONCLUSION: Anabolic steroids enhance the effect of passive stretching on MGF expression in skeletal muscle. PMID- 24062631 TI - The effect of reduction mammaplasty on the vertebral column: a radiologic study. AB - Some studies emphasized that anatomic mechanisms of vertebral aberrations could be associated with large breasts. The effect of mammaplasty operation on the vertebral column and body posture seems to be beneficial; in this trial, it was planned to investigate the objective radiologic effect of reduction mammaplasty on the posture of the vertebral column in a group of patients operated due to the large breasts. Thirty-four white women with large breasts were enrolled in this study. The patients were divided into three groups according to their breast cup sizes. Anteroposterior and lateral radiographs of the lumbosacral and thoracic spine were taken at baseline preoperatively, and the same radiographic images were taken in an average of 12 months later than the reduction mammaplasty operation. All were evaluated and compared for thoracic kyphosis angle and lumbar lordosis angle both preoperatively and postoperatively. The mean thoracic kyphosis angle was 40,53 preoperatively and 39,38 postoperatively. However, there was no statistically significant difference between the preoperative and postoperative measurements in all groups (P > 0,05). The mean lumbar lordosis angle was 54,71 preoperatively and 53,18 postoperatively. Regarding the preoperative and postoperative measurements of lumbar lordosis angles, no statistically significant difference was found between the groups (P > 0,05). Although breast size may be an important factor that affects body posture, reduction mammaplasty operations have little or no radiologic effect on the vertebral column. PMID- 24062632 TI - Gap analysis and conservation network for freshwater wetlands in Central Yangtze Ecoregion. AB - The Central Yangtze Ecoregion contains a large area of internationally important freshwater wetlands and supports a huge number of endangered waterbirds; however, these unique wetlands and the biodiversity they support are under the constant threats of human development pressures, and the prevailing conservation strategies generated based on the local scale cannot adequately be used as guidelines for ecoregion-based conservation initiatives for Central Yangtze at the broad scale. This paper aims at establishing and optimizing an ecological network for freshwater wetland conservation in the Central Yangtze Ecoregion based on large-scale gap analysis. A group of focal species and GIS-based extrapolation technique were employed to identify the potential habitats and conservation gaps, and the optimized conservation network was then established by combining existing protective system and identified conservation gaps. Our results show that only 23.49% of the potential habitats of the focal species have been included in the existing nature reserves in the Central Yangtze Ecoregion. To effectively conserve over 80% of the potential habitats for the focal species by optimizing the existing conservation network for the freshwater wetlands in Central Yangtze Ecoregion, it is necessary to establish new wetland nature reserves in 22 county units across Hubei, Anhui, and Jiangxi provinces. PMID- 24062634 TI - Selective impairment of emotion recognition through music in Parkinson's disease: does it suggest the existence of different networks for music and speech prosody processing? PMID- 24062633 TI - Inflammatory macrophage phenotype in BTBR T+tf/J mice. AB - Although autism is a behaviorally defined disorder, many studies report an association with increased pro-inflammatory cytokine production. Recent characterization of the BTBR T+tf/J (BTBR) inbred mouse strain has revealed several behavioral characteristics including social deficits, repetitive behavior, and atypical vocalizations which may be relevant to autism. We therefore hypothesized that, asocial BTBR mice, which exhibit autism-like behaviors, may have an inflammatory immune profile similar to that observed in children with autism. The objectives of this study were to characterize the myeloid immune profile of BTBR mice and to explore their associations with autism relevant behaviors. C57BL/6J (C57) mice and BTBR mice were tested for social interest and repetitive self-grooming behavior. Cytokine production was measured in bone-marrow derived macrophages incubated for 24 h in either growth media alone, LPS, IL-4/LPS, or IFNgamma/LPS to ascertain any M1/M2 skewing. After LPS stimulation, BTBR macrophages produced higher levels of IL-6, MCP-1, and MIP 1alpha and lower IL-10 (p < 0.01) than C57 mice, suggesting an exaggerated inflammatory profile. After exposure to IL-4/LPS BTBR macrophages produced less IL-10 (p < 0.01) than C57 macrophages and more IL-12p40 (p < 0.01) suggesting poor M2 polarization. Levels of IL-12(p70) (p < 0.05) were higher in BTBR macrophages after IFNgamma/LPS stimulation, suggesting enhanced M1 polarization. We further observed a positive correlation between grooming frequency, and production of IL-12(p40), IL-12p70, IL-6, and TNFalpha (p < 0.05) after treatment with IFNgamma/LPS across both strains. Collectively, these data suggest that the asocial BTBR mouse strain exhibits a more inflammatory, or M1, macrophage profile in comparison to the social C57 strain. We have further demonstrated a relationship between this relative increase in inflammation and repetitive grooming behavior, which may have relevance to repetitive and stereotyped behavior of autism. PMID- 24062635 TI - Individual differences in social information gathering revealed through Bayesian hierarchical models. AB - As studies of the neural circuits underlying choice expand to include more complicated behaviors, analysis of behaviors elicited in laboratory paradigms has grown increasingly difficult. Social behaviors present a particular challenge, since inter- and intra-individual variation are expected to play key roles. However, due to limitations on data collection, studies must often choose between pooling data across all subjects or using individual subjects' data in isolation. Hierarchical models mediate between these two extremes by modeling individual subjects as drawn from a population distribution, allowing the population at large to serve as prior information about individuals' behavior. Here, we apply this method to data collected across multiple experimental sessions from a set of rhesus macaques performing a social information valuation task. We show that, while the values of social images vary markedly between individuals and between experimental sessions for the same individual, individuals also differentially value particular categories of social images. Furthermore, we demonstrate covariance between values for image categories within individuals and find evidence suggesting that magnitudes of stimulus values tend to diminish over time. PMID- 24062636 TI - Teneurin C-terminal associated peptides (TCAP): modulators of corticotropin releasing factor (CRF) physiology and behavior. AB - The existence of the teneurin C-terminal associated peptides (TCAP) was reported in 2004 after screening a rainbow trout hypothalamic cDNA for corticotropin releasing factor (CRF)-related homologs. In vertebrates, there are four TCAP paralogs, where each peptide is associated with a teneurin transmembrane protein. The TCAPs are 40 or 41 amino acids in length and possess less than 20% residue identity with the CRF family of paralogs. Orthologs of TCAP are found in all metazoans with the possible exception of poriferans and cnidarians. Recent evidence indicates that TCAP and the teneurins may have been introduced into the Metazoa via horizontal gene transfer from prokaryotes into a basal protistan. Thus, the origin of the TCAPs likely predated that of the CRF family. In the mammalian brain, TCAP-1 is transcribed independently from teneurin-1. Moreover, TCAP-1 acts on neurons by a CRF-receptor independent signal transduction pathway to regulate cellular cytoskeletal function to stimulate cell activity. Administration of synthetic TCAP-1 to rodents inhibits a number of CRF- and stress-associated behaviors via a hypothalamic-pituitary-adrenal (HPA) axis independent mechanism. PMID- 24062637 TI - Interruption of ghrelin signaling in the PVN increases high-fat diet intake and body weight in stressed and non-stressed C57BL6J male mice. AB - Chronic social stress has been associated with increased caloric intake and adiposity. These effects have been linked to stress induced changes in the secretion of ghrelin, a hormone that targets a number of brain regions to increase food intake and energy expenditure and promote increased body fat content. One of the brain sites targeted by ghrelin is the hypothalamic paraventricular nucleus (PVN), a region critical for both the regulation of the stress response and the regulation of energy balance. Given these data, we examined the contribution of ghrelin receptors in the PVN to the metabolic and behavioral changes that are seen during chronic social stress in mice. To do this, mice were implanted with cannulae attached to osmotic minipumps and delivering either vehicle or the ghrelin receptor (growth hormone secretagogue receptor) antagonist [D-Lys-3]-GHRP-6 (20 nmol/day/mouse). Following a week of recovery, half of the animals in each group were exposed to chronic social defeat stress for a period of 3 weeks whereas the other half were left undisturbed. During this time, all animals were given ad libitum access to standard laboratory chow and presented a high-fat diet for 4 h during the day. Results showed that the ghrelin receptor antagonism did not decrease stressed induced caloric intake, but paradoxically increased the intake of the high fat diet. This would suggest that ghrelin acts on the PVN to promote the intake of carbohydrate rich diets while decreasing fat intake and blockade of ghrelin receptors in the PVN leads to more consumption of foods that are high in fat. PMID- 24062638 TI - CASK regulates CaMKII autophosphorylation in neuronal growth, calcium signaling, and learning. AB - Calcium (Ca(2+))/calmodulin (CaM)-dependent kinase II (CaMKII) activity plays a fundamental role in learning and memory. A key feature of CaMKII in memory formation is its ability to be regulated by autophosphorylation, which switches its activity on and off during synaptic plasticity. The synaptic scaffolding protein CASK (calcium (Ca(2+))/calmodulin (CaM) associated serine kinase) is also important for learning and memory, as mutations in CASK result in intellectual disability and neurological defects in humans. We show that in Drosophila larvae, CASK interacts with CaMKII to control neuronal growth and calcium signaling. Furthermore, deletion of the CaMK-like and L27 domains of CASK (CASK beta null) or expression of overactive CaMKII (T287D) produced similar effects on synaptic growth and Ca(2+) signaling. CASK overexpression rescues the effects of CaMKII overactivity, consistent with the notion that CASK and CaMKII act in a common pathway that controls these neuronal processes. The reduction in Ca(2+) signaling observed in the CASK beta null mutant caused a decrease in vesicle trafficking at synapses. In addition, the decrease in Ca(2+) signaling in CASK mutants was associated with an increase in Ether-a-go-go (EAG) potassium (K(+)) channel localization to synapses. Reducing EAG restored the decrease in Ca(2+) signaling observed in CASK mutants to the level of wildtype, suggesting that CASK regulates Ca(2+) signaling via EAG. CASK knockdown reduced both appetitive associative learning and odor evoked Ca(2+) responses in Drosophila mushroom bodies, which are the learning centers of Drosophila. Expression of human CASK in Drosophila rescued the effect of CASK deletion on the activity state of CaMKII, suggesting that human CASK may also regulate CaMKII autophosphorylation. PMID- 24062640 TI - The generation of oligodendroglial cells is preserved in the rostral migratory stream during aging. AB - The subventricular zone (SVZ) is the largest source of newly generated cells in the adult mammalian brain. SVZ-derived neuroblasts migrate via the rostral migratory stream (RMS) to the olfactory bulb (OB), where they differentiate into mature neurons. Additionally, a small proportion of SVZ-derived cells contribute to the generation of myelinating oligodendrocytes. The production of new cells in the SVZ decreases during aging, affecting the incorporation of new neurons into the OB. However, the age-related changes that occur across the RMS are not fully understood. In this study we evaluate how aging affects the cellular organization of migrating neuroblast chains, the proliferation, and the fate of the newly generated cells in the SVZ-OB system. By using electron microscopy and immunostaining, we found that the RMS path becomes discontinuous and its cytoarchitecture is disorganized in aged mice (24-month-old mice). Subsequently, OB neurogenesis was impaired in the aged brain while the production of oligodendrocytes was not compromised. These findings provide new insight into oligodendrocyte preservation throughout life. Further exploration of this matter could help the development of new strategies to prevent neurological disorders associated with senescence. PMID- 24062641 TI - Seizure-like activity in hyaluronidase-treated dissociated hippocampal cultures. AB - The extracellular matrix (ECM) plays an important role in use-dependent synaptic plasticity. Hyaluronic acid (HA) is the backbone of the neural ECM, which has been shown to modulate alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptor mobility, paired-pulse depression, L-type voltage-dependent Ca(2+) channel (L-VDCC) activity, long-term potentiation and contextual fear conditioning. To investigate the role of HA in the development of spontaneous neuronal network activity, we used microelectrode array recording and Ca(2+) imaging in hippocampal cultures enzymatically treated with hyaluronidase. Our findings revealed an appearance of epileptiform activity 9 days after hyaluronidase treatment. The treatment transformed the normal network firing bursts and Ca(2+) oscillations into long-lasting "superbursts" and "superoscillations" with durations of 11-100 s. The changes in Ca(2+) transients in hyaluronidase-treated neurons were more prominent then in astrocytes and preceded changes in electrical activity. The Ca(2+) superoscillations could be suppressed by applying the L-VDCC blocker diltiazem, whereas the neuronal firing superbursts could be additionally suppressed by 6-cyano-7-nitroquinoxaline-2,3 dione as an antagonist of AMPA/kainate receptors. These results suggest that changes in the expression of HA can be epileptogenic and that hyaluronidase treatment in vitro provides a robust model for the dissection of the underlying mechanisms. PMID- 24062639 TI - K(+) channelepsy: progress in the neurobiology of potassium channels and epilepsy. AB - K(+) channels are important determinants of seizure susceptibility. These membrane proteins, encoded by more than 70 genes, make the largest group of ion channels that fine-tune the electrical activity of neuronal and non-neuronal cells in the brain. Their ubiquity and extremely high genetic and functional diversity, unmatched by any other ion channel type, place K(+) channels as primary targets of genetic variations or perturbations in K(+)-dependent homeostasis, even in the absence of a primary channel defect. It is therefore not surprising that numerous inherited or acquired K(+) channels dysfunctions have been associated with several neurologic syndromes, including epilepsy, which often generate confusion in the classification of the associated diseases. Therefore, we propose to name the K(+) channels defects underlying distinct epilepsies as "K(+) channelepsies," and introduce a new nomenclature (e.g., Kx.y channelepsy), following the widely used K(+) channel classification, which could be also adopted to easily identify other channelopathies involving Na(+) (e.g., Nav x.y-phenotype), Ca(2+) (e.g., Cav x.y-phenotype), and Cl(-) channels. Furthermore, we discuss novel genetic defects in K(+) channels and associated proteins that underlie distinct epileptic phenotypes in humans, and analyze critically the recent progress in the neurobiology of this disease that has also been provided by investigations on valuable animal models of epilepsy. The abundant and varied lines of evidence discussed here strongly foster assessments for variations in genes encoding for K(+) channels and associated proteins in patients with idiopathic epilepsy, provide new avenues for future investigations, and highlight these proteins as critical pharmacological targets. PMID- 24062642 TI - MicroRNA function is required for neurite outgrowth of mature neurons in the mouse postnatal cerebral cortex. AB - The structure of the postnatal mammalian cerebral cortex is an assembly of numerous mature neurons that exhibit proper neurite outgrowth and axonal and dendritic morphology. While many protein coding genes are shown to be involved in neuronal maturation, the role of microRNAs (miRNAs) in this process is also becoming evident. We here report that blocking miRNA biogenesis in differentiated neurons results in microcephaly like phenotypes in the postnatal mouse brain. The smaller brain defect is not caused by defective neurogenesis, altered neuronal migration or significant neuronal cell death. Surprisingly, a dramatic increase in neuronal packing density within the postnatal brain is observed. Loss of miRNA function causes shorter neurite outgrowth and smaller soma size of mature neurons in vitro. Our results reveal the impact of miRNAs on normal development of neuronal morphology and brain function. Because neurite outgrowth is critical for neuroregeneration, our studies further highlight the importance of miRNAs in the treatment of neurological diseases. PMID- 24062643 TI - Implication of fibroblast growth factors in epileptogenesis-associated circuit rearrangements. AB - The transformation of a normal brain in epileptic (epileptogenesis) is associated with extensive morpho-functional alterations, including cell death, axonal and dendritic plasticity, neurogenesis, and others. Neurotrophic factors (NTFs) appear to be very strongly implicated in these phenomena. In this review, we focus on the involvement of fibroblast growth factor (FGF) family members. Available data demonstrate that the FGFs are highly involved in the generation of the morpho-functional alterations in brain circuitries associated with epileptogenesis. For example, data on FGF2, the most studied member, suggest that it may be implicated both in seizure susceptibility and in seizure-induced plasticity, exerting different, and apparently contrasting effects: favoring acute seizures but reducing seizure-induced cell death. Even if many FGF members are still unexplored and very limited information is available on the FGF receptors, a complex and fascinating picture is emerging: multiple FGFs producing synergic or antagonistic effects one with another (and/or with other NTFs) on biological parameters that, in turn, facilitate or oppose transformation of the normal tissue in epileptic. In principle, identifying key elements in these phenomena may lead to effective therapies, but reaching this goal will require confronting a huge complexity. One first step could be to generate a "neurotrophicome" listing the FGFs (and all other NTFs) that are active during epileptogenesis. This should include identification of the extent to which each NTF is active (concentrations at the site of action); how it is active (local representation of receptor subtypes); when in the natural history of disease this occurs; how the NTF at hand will possibly interact with other NTFs. This is extraordinarily challenging, but holds the promise of a better understanding of epileptogenesis and, at large, of brain function. PMID- 24062644 TI - Alzheimer's disease and the microbiome. PMID- 24062645 TI - The role of dopamine signaling in epileptogenesis. AB - Clinical and experimental studies implicate most neuromodulatory systems in epileptogenesis. The dopaminergic system has a seizure-modulating effect that crucially depends on the different subtypes of dopamine (DA) receptors involved and the brain regions in which they are activated. Specifically, DA plays a major role in the control of seizures arising in the limbic system. Studies performed in a wide variety of animal models contributed to illustrate the opposite actions of D1-like and D2-like receptor signaling in limbic epileptogenesis. Indeed, signaling from D1-like receptors is generally pro-epileptogenic, whereas D2-like receptor signaling exerts an anti-epileptogenic effect. However, this view might appear quite simplistic as the complex neuromodulatory action of DA in the control of epileptogenesis likely requires a physiological balance in the activation of circuits modulated by these two major DA receptor subtypes, which determines the response to seizure-promoting stimuli. Here we will review recent evidences on the identification of molecules activated by DA transduction pathways in the generation and spread of seizures in the limbic system. We will discuss the intracellular signaling pathways triggered by activation of different DA receptors in relation to their role in limbic epileptogenesis, which lead to the activation of neuronal death/survival cascades. A deep understanding of the signaling pathways involved in epileptogenesis is crucial for the identification of novel targets for the treatment of epilepsy. PMID- 24062646 TI - Impairment of GABA transporter GAT-1 terminates cortical recurrent network activity via enhanced phasic inhibition. AB - In the central nervous system, GABA transporters (GATs) very efficiently clear synaptically released GABA from the extracellular space, and thus exert a tight control on GABAergic inhibition. In neocortex, GABAergic inhibition is heavily recruited during recurrent phases of spontaneous action potential activity which alternate with neuronally quiet periods. Therefore, such activity should be quite sensitive to minute alterations of GAT function. Here, we explored the effects of a gradual impairment of GAT-1 and GAT-2/3 on spontaneous recurrent network activity--termed network bursts and silent periods--in organotypic slice cultures of rat neocortex. The GAT-1 specific antagonist NO-711 depressed activity already at nanomolar concentrations (IC50 for depression of spontaneous multiunit firing rate of 42 nM), reaching a level of 80% at 500-1000 nM. By contrast, the GAT-2/3 preferring antagonist SNAP-5114 had weaker and less consistent effects. Several lines of evidence pointed toward an enhancement of phasic GABAergic inhibition as the dominant activity-depressing mechanism: network bursts were drastically shortened, phasic GABAergic currents decayed slower, and neuronal excitability during ongoing activity was diminished. In silent periods, NO-711 had little effect on neuronal excitability or membrane resistance, quite in contrast to the effects of muscimol, a GABA mimetic which activates GABAA receptors tonically. Our results suggest that an enhancement of phasic GABAergic inhibition efficiently curtails cortical recurrent activity and may mediate antiepileptic effects of therapeutically relevant concentrations of GAT-1 antagonists. PMID- 24062647 TI - Altered gamma oscillations during pregnancy through loss of delta subunit containing GABA(A) receptors on parvalbumin interneurons. AB - Gamma (gamma) oscillations (30-120 Hz), an emergent property of neuronal networks, correlate with memory, cognition and encoding. In the hippocampal CA3 region, locally generated gamma oscillations emerge through feedback between inhibitory parvalbumin-positive basket cells (PV+BCs) and the principal (pyramidal) cells. PV+BCs express delta-subunit-containing GABA(A)Rs (delta GABA(A)Rs) and NMDA receptors (NMDA-Rs) that balance the frequency of gamma oscillations. Neuroactive steroids (NS), such as the progesterone-derived (3alpha,5alpha)-3-hydroxy-pregnan-20-one (allopregnanolone; ALLO), modulate the expression of delta-GABA(A)Rs and the tonic conductance they mediate. Pregnancy produces large increases in ALLO and brain-region-specific homeostatic changes in delta-GABA(A)Rs expression. Here we show that in CA3, where most PV+ interneurons (INs) express delta-GABA(A)Rs, expression of delta-GABA(A)Rs on INs diminishes during pregnancy, but reverts to control levels within 48 h postpartum. These anatomical findings were corroborated by a pregnancy-related increase in the frequency of kainate-induced CA3 gamma oscillations in vitro that could be countered by the NMDA-R antagonists D-AP5 and PPDA. Mimicking the typical hormonal conditions during pregnancy by supplementing 100 nM ALLO lowered the gamma frequencies to levels found in virgin or postpartum mice. Our findings show that states of altered NS levels (e.g., pregnancy) may provoke perturbations in gamma oscillatory activity through direct effects on the GABAergic system, and underscore the importance of delta-GABA(A)Rs homeostatic plasticity in maintaining constant network output despite large hormonal changes. Inaccurate coupling of NS levels to delta-GABA(A)R expression may facilitate abnormal neurological and psychiatric conditions such as epilepsy, post-partum depression, and post-partum psychosis, thus providing insights into potential new treatments. PMID- 24062648 TI - Acutely increasing deltaGABA(A) receptor activity impairs memory and inhibits synaptic plasticity in the hippocampus. AB - Extrasynaptic gamma-aminobutyric acid type A (GABA(A)) receptors that contain the delta subunit (deltaGABA(A) receptors) are expressed in several brain regions including the dentate gyrus (DG) and CA1 subfields of the hippocampus. Drugs that increase deltaGABA(A) receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. Also, long term pretreatment with the deltaGABA(A) receptor-preferring agonist 4,5,6,7 tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) enhances discrimination memory and increases neurogenesis in the DG. Despite the potential therapeutic benefits of such treatments, the effects of acutely increasing deltaGABA(A) receptor activity on memory behaviors remain unknown. Here, we studied the effects of THIP (4 mg/kg, i.p.) on memory performance in wild-type (WT) and deltaGABA(A) receptor null mutant (Gabrd(-/-)) mice. Additionally, the effects of THIP on long-term potentiation (LTP), a molecular correlate of memory, were studied within the DG and CA1 subfields of the hippocampus using electrophysiological recordings of field potentials in hippocampal slices. The results showed that THIP impaired performance in the Morris water maze, contextual fear conditioning and object recognition tasks in WT mice but not Gabrd(-/-) mice. Furthermore, THIP inhibited LTP in hippocampal slices from WT but not Gabrd(-/-) mice, an effect that was blocked by GABA(A) receptor antagonist bicuculline. Thus, acutely increasing deltaGABA(A) receptor activity impairs memory behaviors and inhibits synaptic plasticity. These results have important implications for the development of therapies aimed at increasing deltaGABA(A) receptor activity. PMID- 24062650 TI - How does morality work in the brain? A functional and structural perspective of moral behavior. AB - Neural underpinnings of morality are not yet well understood. Researchers in moral neuroscience have tried to find specific structures and processes that shed light on how morality works. Here, we review the main brain areas that have been associated with morality at both structural and functional levels and speculate about how it can be studied. Orbital and ventromedial prefrontal cortices are implicated in emotionally-driven moral decisions, while dorsolateral prefrontal cortex appears to moderate its response. These competing processes may be mediated by the anterior cingulate cortex. Parietal and temporal structures play important roles in the attribution of others' beliefs and intentions. The insular cortex is engaged during empathic processes. Other regions seem to play a more complementary role in morality. Morality is supported not by a single brain circuitry or structure, but by several circuits overlapping with other complex processes. The identification of the core features of morality and moral-related processes is needed. Neuroscience can provide meaningful insights in order to delineate the boundaries of morality in conjunction with moral psychology. PMID- 24062649 TI - Shaping the aging brain: role of auditory input patterns in the emergence of auditory cortical impairments. AB - Age-related impairments in the primary auditory cortex (A1) include poor tuning selectivity, neural desynchronization, and degraded responses to low-probability sounds. These changes have been largely attributed to reduced inhibition in the aged brain, and are thought to contribute to substantial hearing impairment in both humans and animals. Since many of these changes can be partially reversed with auditory training, it has been speculated that they might not be purely degenerative, but might rather represent negative plastic adjustments to noisy or distorted auditory signals reaching the brain. To test this hypothesis, we examined the impact of exposing young adult rats to 8 weeks of low-grade broadband noise on several aspects of A1 function and structure. We then characterized the same A1 elements in aging rats for comparison. We found that the impact of noise exposure on A1 tuning selectivity, temporal processing of auditory signal and responses to oddball tones was almost indistinguishable from the effect of natural aging. Moreover, noise exposure resulted in a reduction in the population of parvalbumin inhibitory interneurons and cortical myelin as previously documented in the aged group. Most of these changes reversed after returning the rats to a quiet environment. These results support the hypothesis that age-related changes in A1 have a strong activity-dependent component and indicate that the presence or absence of clear auditory input patterns might be a key factor in sustaining adult A1 function. PMID- 24062651 TI - Caloric vestibular stimulation: interaction between somatosensory system and vestibular apparatus. PMID- 24062652 TI - Supramodal neural processing of abstract information conveyed by speech and gesture. AB - ness and modality of interpersonal communication have a considerable impact on comprehension. They are relevant for determining thoughts and constituting internal models of the environment. Whereas concrete object-related information can be represented in mind irrespective of language, abstract concepts require a representation in speech. Consequently, modality-independent processing of abstract information can be expected. Here we investigated the neural correlates of abstractness (abstract vs. concrete) and modality (speech vs. gestures), to identify an abstractness-specific supramodal neural network. During fMRI data acquisition 20 participants were presented with videos of an actor either speaking sentences with an abstract-social [AS] or concrete-object-related content [CS], or performing meaningful abstract-social emblematic [AG] or concrete-object-related tool-use gestures [CG]. Gestures were accompanied by a foreign language to increase the comparability between conditions and to frame the communication context of the gesture videos. Participants performed a content judgment task referring to the person vs. object-relatedness of the utterances. The behavioral data suggest a comparable comprehension of contents communicated by speech or gesture. Furthermore, we found common neural processing for abstract information independent of modality (AS > CS ? AG > CG) in a left hemispheric network including the left inferior frontal gyrus (IFG), temporal pole, and medial frontal cortex. Modality specific activations were found in bilateral occipital, parietal, and temporal as well as right inferior frontal brain regions for gesture (G > S) and in left anterior temporal regions and the left angular gyrus for the processing of speech semantics (S > G). These data support the idea that abstract concepts are represented in a supramodal manner. Consequently, gestures referring to abstract concepts are processed in a predominantly left hemispheric language related neural network. PMID- 24062653 TI - What the online manipulation of linguistic activity can tell us about language and thought. PMID- 24062654 TI - Task vs. rest-different network configurations between the coactivation and the resting-state brain networks. AB - There is a growing interest in studies of human brain networks using resting state functional magnetic resonance imaging (fMRI). However, it is unclear whether and how brain networks measured during the resting-state exhibit comparable properties to brain networks during task performance. In the present study, we investigated meta-analytic coactivation patterns among brain regions based upon published neuroimaging studies, and compared the coactivation network configurations with those in the resting-state network. The strength of resting state functional connectivity between two regions were strongly correlated with the coactivation strength. However, the coactivation network showed greater global efficiency, smaller mean clustering coefficient, and lower modularity compared with the resting-state network, which suggest a more efficient global information transmission and between system integrations during task performing. Hub shifts were also observed within the thalamus and the left inferior temporal cortex. The thalamus and the left inferior temporal cortex exhibited higher and lower degrees, respectively in the coactivation network compared with the resting state network. These results shed light regarding the reconfiguration of the brain networks between task and resting-state conditions, and highlight the role of the thalamus in change of network configurations in task vs. rest. PMID- 24062655 TI - Near death experiences: a multidisciplinary hypothesis. AB - Recently, we proposed a novel biophysical concept regarding on the appearance of brilliant lights during near death experiences (NDEs) (Bokkon and Salari, 2012). Specifically, perceiving brilliant light in NDEs has been proposed to arise due to the reperfusion that produces unregulated overproduction of free radicals and energetically excited molecules that can generate a transient enhancement of bioluminescent biophotons in different areas of the brain, including retinotopic visual areas. If this excess of bioluminescent photon emission exceeds a threshold in retinotopic visual areas, this can appear as (phosphene) lights because the brain interprets these intrinsic retinotopic bioluminescent photons as if they originated from the external physical world. Here, we review relevant literature that reported experimental studies (Imaizumi et al., 1984; Suzuki et al., 1985) that essentially support our previously published conception, i.e., that seeing lights in NDEs may be due to the transient enhancement of bioluminescent biophotons. Next, we briefly describe our biophysical visual representation model that may explain brilliant lights experienced during NDEs (by phosphenes as biophotons) and REM sleep associated dream-like intrinsic visual imageries through biophotons in NDEs. Finally, we link our biophysical visual representation notion to self-consciousness that may involve extremely low energy quantum entanglements. This article is intended to introduce novel concepts for discussion and does not pretend to give the ultimate explanation for the currently unanswerable questions about matter, life and soul; their creation and their interrelationship. PMID- 24062656 TI - Both novelty and expertise increase action observation network activity. AB - Our experiences with others affect how we perceive their actions. In particular, activity in bilateral premotor and parietal cortices during action observation, collectively known as the action observation network (AON), is modulated by one's expertise with the observed actions or individuals. However, conflicting reports suggest that AON activity is greatest both for familiar and unfamiliar actions. The current study examines the effects of different types and amounts of experience (e.g., visual, interpersonal, personal) on AON activation. fMRI was used to scan 16 healthy participants without prior experience with individuals with amputations (novices), 11 experienced occupational therapists (OTs) who had varying amounts of experience with individuals with amputations, and one individual born with below-elbow residual limbs (participant CJ), as they viewed video clips of goal-matched actions performed by an individual with residual limbs and by an individual with hands. Participants were given increased visual exposure to actions performed by both effectors midway through the scanning procedure. Novices demonstrated a large AON response to the initial viewing of an individual with residual limbs compared to one with hands, but this signal was attenuated after they received visual exposure to both effectors. In contrast, OTs, who had moderate familiarity with residual limbs, demonstrated a lower AON response upon initial viewing-similar to novices after they received visual exposure. At the other extreme, CJ, who has extreme familiarity with residual limbs both visually and motorically, shows a largely increased left-lateralized AON response, exceeding that of novices and experienced OTs, when viewing the residual limb compared to hand actions. These results suggest that a nuanced model of AON engagement is needed to explain how cases of both extreme experience (CJ) and extreme novelty (novices) can result in the greatest AON activity. PMID- 24062657 TI - Addiction and will. AB - A hypothesis about the neurobiological bases of drive, drive reduction and will in addictive illness is presented. Drive reduction seems to require both SEEKING and gratification. Will is the everyday term for our experience of drives functioning within us. Addictive drugs take over the will by altering neurotransmission in the SEEKING system. As a result of this biological change, psychological defenses are arrayed that allow partial gratification and reduce anxiety about the consequences of drug use. Repeated partial gratification of the addictive drive creates a cathexis to the drug and the drug seller. It also keeps the addicted person in a permanent state of SEEKING. The cathexis to the drug and drug seller creates a difficult situation for psychoanalytic therapists. The actively addicted patient will have one set of feelings for the analyst, and a split off set of feelings for the drug dealer. Addictive neuroses, which feature a split transference, are contrasted with Freud's concept of transference and narcissistic neuroses. For treatment of an actively addicted patient, the treater must negotiate the split transference. By analyzing the denial system the relationship with the drug dealer ends and the hostility involved in addictive behavior enters the transference where it can be interpreted. Selling drugs that take over the will is a lucrative enterprise. The addictive drug industry, about the size of the oil and gas industry worldwide, produces many patients in need of treatment. The marketers of addictive drugs understand the psychology of inducing initial ingestion of the drugs, and of managing their addicted populations. The neuropsychoanalytic understanding of addiction might be used to create more effective public health interventions to combat this morbid and mortal illness. PMID- 24062658 TI - Minimal self-models and the free energy principle. AB - The term "minimal phenomenal selfhood" (MPS) describes the basic, pre-reflective experience of being a self (Blanke and Metzinger, 2009). Theoretical accounts of the minimal self have long recognized the importance and the ambivalence of the body as both part of the physical world, and the enabling condition for being in this world (Gallagher, 2005a; Grafton, 2009). A recent account of MPS (Metzinger, 2004a) centers on the consideration that minimal selfhood emerges as the result of basic self-modeling mechanisms, thereby being founded on pre-reflective bodily processes. The free energy principle (FEP; Friston, 2010) is a novel unified theory of cortical function built upon the imperative that self-organizing systems entail hierarchical generative models of the causes of their sensory input, which are optimized by minimizing free energy as an approximation of the log-likelihood of the model. The implementation of the FEP via predictive coding mechanisms and in particular the active inference principle emphasizes the role of embodiment for predictive self-modeling, which has been appreciated in recent publications. In this review, we provide an overview of these conceptions and illustrate thereby the potential power of the FEP in explaining the mechanisms underlying minimal selfhood and its key constituents, multisensory integration, interoception, agency, perspective, and the experience of mineness. We conclude that the conceptualization of MPS can be well mapped onto a hierarchical generative model furnished by the FEP and may constitute the basis for higher level, cognitive forms of self-referral, as well as the understanding of other minds. PMID- 24062659 TI - Emotional modulation of experimental pain: a source imaging study of laser evoked potentials. AB - Negative emotions have been shown to augment experimental pain. As induced emotions alter brain activity, it is not clear whether pain augmentation during noxious stimulation would be related to neural activation existing prior to onset of a noxious stimulus or alternatively, whether emotional stimuli would only alter neural activity during the period of nociceptive processing. We analyzed the spatio-temporal patterns of laser evoked potentials (LEPs) occurring prior to and during the period of cortical processing of noxious laser stimuli during passive viewing of negative, positive, or neutral emotional pictures. Independent component analysis (ICA) was applied to series of source activation volumes, reconstructed using local autoregressive average model (LAURA). Pain was the strongest when laser stimuli were associated with negative emotional pictures. Prior to laser stimulus and during the first 100 ms after onset of laser stimulus, activations were seen in the left and right medial temporal cortex, cerebellum, posterior cingulate, and rostral cingulate/prefrontal cortex. In all these regions, positive or neutral pictures showed stronger activations than negative pictures. During laser stimulation, activations in the right and left anterior insula, temporal cortex and right anterior and posterior parietal cortex were stronger during negative than neutral or positive emotional pictures. Results suggest that negative emotional stimuli increase activation in the left and right anterior insula and temporal cortex, and right posterior and anterior parietal cortex only during the period of nociceptive processing. The role of background brain activation in emotional modulation of pain appears to be only permissive, and consisting in attenuation of activation in structures maintaining the resting state of the brain. PMID- 24062660 TI - Movement and afferent representations in human motor areas: a simultaneous neuroimaging and transcranial magnetic/peripheral nerve-stimulation study. AB - Neuroimaging combined with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) is an emerging technique that can examine motor-system functionality through evoked activity. However, because sensory afferents from twitching muscles are widely represented in motor areas the amount of evoked activity directly resulting from TMS remains unclear. We delivered suprathreshold TMS to left M1 or gave electrical right median nerve stimulation (MNS) in 18 healthy volunteers while simultaneously conducting functional magnetic resonance imaging and monitoring with electromyography (EMG). We examined in detail the localization of TMS-, muscle afferent- and superficial afferent-induced activity in M1 subdivisions. Muscle afferent- and TMS-evoked activity occurred mainly in rostral M1, while superficial afferents generated a slightly different activation distribution. In 12 participants who yielded quantifiable EMG, differences in brain activity ascribed to differences in movement-size were adjusted using integrated information from the EMGs. Sensory components only explained 10-20% of the suprathreshold TMS-induced activity, indicating that locally and remotely evoked activity in motor areas mostly resulted from the recruitment of neural and synaptic activity. The present study appears to justify the use of fMRI combined with suprathreshold TMS to M1 for evoked motor network imaging. PMID- 24062661 TI - Event-related potentials to unattended changes in facial expressions: detection of regularity violations or encoding of emotions? AB - Visual mismatch negativity (vMMN), a component in event-related potentials (ERPs), can be elicited when rarely presented "deviant" facial expressions violate regularity formed by repeated "standard" faces. vMMN is observed as differential ERPs elicited between the deviant and standard faces. It is not clear, however, whether differential ERPs to rare emotional faces interspersed with repeated neutral ones reflect true vMMN (i.e., detection of regularity violation) or merely encoding of the emotional content in the faces. Furthermore, a face-sensitive N170 response, which reflects structural encoding of facial features, can be modulated by emotional expressions. Owing to its similar latency and scalp topography with vMMN, these two components are difficult to separate. We recorded ERPs to neutral, fearful, and happy faces in two different stimulus presentation conditions in adult humans. For the oddball condition group, frequently presented neutral expressions (p = 0.8) were rarely replaced by happy or fearful expressions (p = 0.1), whereas for the equiprobable condition group, fearful, happy, and neutral expressions were presented with equal probability (p = 0.33). Independent component analysis (ICA) revealed two prominent components in both stimulus conditions in the relevant latency range and scalp location. A component peaking at 130 ms post stimulus showed a difference in scalp topography between the oddball (bilateral) and the equiprobable (right-dominant) conditions. The other component, peaking at 170 ms post stimulus, showed no difference between the conditions. The bilateral component at the 130-ms latency in the oddball condition conforms to vMMN. Moreover, it was distinct from N170 which was modulated by the emotional expression only. The present results suggest that future studies on vMMN to facial expressions should take into account possible confounding effects caused by the differential processing of the emotional expressions as such. PMID- 24062662 TI - Economic and evolutionary hypotheses for cross-population variation in parochialism. AB - Human populations differ reliably in the degree to which people favor family, friends, and community members over strangers and outsiders. In the last decade, researchers have begun to propose several economic and evolutionary hypotheses for these cross-population differences in parochialism. In this paper, we outline major current theories and review recent attempts to test them. We also discuss the key methodological challenges in assessing these diverse economic and evolutionary theories for cross-population differences in parochialism. PMID- 24062663 TI - Implicit and explicit social mentalizing: dual processes driven by a shared neural network. AB - Recent social neuroscientific evidence indicates that implicit and explicit inferences on the mind of another person (i.e., intentions, attributions or traits), are subserved by a shared mentalizing network. Under both implicit and explicit instructions, ERP studies reveal that early inferences occur at about the same time, and fMRI studies demonstrate an overlap in core mentalizing areas, including the temporo-parietal junction (TPJ) and the medial prefrontal cortex (mPFC). These results suggest a rapid shared implicit intuition followed by a slower explicit verification processes (as revealed by additional brain activation during explicit vs. implicit inferences). These data provide support for a default-adjustment dual-process framework of social mentalizing. PMID- 24062664 TI - Interdisciplinary research is the key. PMID- 24062665 TI - The immune hypothesis of synesthesia. PMID- 24062666 TI - Does motor imagery share neural networks with executed movement: a multivariate fMRI analysis. AB - INTRODUCTION: Motor imagery (MI) is the mental rehearsal of a motor first person action-representation. There is interest in using MI to access the motor network after stroke. Conventional fMRI modeling has shown that MI and executed movement (EM) activate similar cortical areas but it remains unknown whether they share cortical networks. Proving this is central to using MI to access the motor network and as a form of motor training. Here we use multivariate analysis (tensor independent component analysis-TICA) to map the array of neural networks involved during MI and EM. METHODS: Fifteen right-handed healthy volunteers (mean age 28.4 years) were recruited and screened for their ability to carry out MI (Chaotic MI Assessment). fMRI consisted of an auditory-paced (1 Hz) right hand finger-thumb opposition sequence (2,3,4,5; 2...) with two separate runs acquired (MI & rest and EM & rest: block design). No distinction was made between MI and EM until the final stage of processing. This allowed TICA to identify independent components (IC) that are common or distinct to both tasks with no prior assumptions. RESULTS: TICA defined 52 ICs. Non-significant ICs and those representing artifact were excluded. Components in which the subject scores were significantly different to zero (for either EM or MI) were included. Seven IC remained. There were IC's shared between EM and MI involving the contralateral BA4, PMd, parietal areas and SMA. IC's exclusive to EM involved the contralateral BA4, S1 and ipsilateral cerebellum whereas the IC related exclusively to MI involved ipsilateral BA4 and PMd. CONCLUSION: In addition to networks specific to each task indicating a degree of independence, we formally demonstrate here for the first time that MI and EM share cortical networks. This significantly strengthens the rationale for using MI to access the motor networks, but the results also highlight important differences. PMID- 24062667 TI - Modulation of cortical-subcortical networks in Parkinson's disease by applied field effects. AB - Studies suggest that endogenous field effects may play a role in neuronal oscillations and communication. Non-invasive transcranial electrical stimulation with low-intensity currents can also have direct effects on the underlying cortex as well as distant network effects. While Parkinson's disease (PD) is amenable to invasive neuromodulation in the basal ganglia by deep brain stimulation (DBS), techniques of non-invasive neuromodulation like transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) are being investigated as possible therapies. tDCS and tACS have the potential to influence the abnormal cortical-subcortical network activity that occurs in PD through sub-threshold changes in cortical excitability or through entrainment or disruption of ongoing rhythmic cortical activity. This may allow for the targeting of specific features of the disease involving abnormal oscillatory activity, as well as the enhancement of potential cortical compensation for basal ganglia dysfunction and modulation of cortical plasticity in neurorehabilitation. However, little is currently known about how cortical stimulation will affect subcortical structures, the size of any effect, and the factors of stimulation that will influence these effects. PMID- 24062669 TI - Flaws in current human training protocols for spontaneous Brain-Computer Interfaces: lessons learned from instructional design. AB - While recent research on Brain-Computer Interfaces (BCI) has highlighted their potential for many applications, they remain barely used outside laboratories. The main reason is their lack of robustness. Indeed, with current BCI, mental state recognition is usually slow and often incorrect. Spontaneous BCI (i.e., mental imagery-based BCI) often rely on mutual learning efforts by the user and the machine, with BCI users learning to produce stable ElectroEncephaloGraphy (EEG) patterns (spontaneous BCI control being widely acknowledged as a skill) while the computer learns to automatically recognize these EEG patterns, using signal processing. Most research so far was focused on signal processing, mostly neglecting the human in the loop. However, how well the user masters the BCI skill is also a key element explaining BCI robustness. Indeed, if the user is not able to produce stable and distinct EEG patterns, then no signal processing algorithm would be able to recognize them. Unfortunately, despite the importance of BCI training protocols, they have been scarcely studied so far, and used mostly unchanged for years. In this paper, we advocate that current human training approaches for spontaneous BCI are most likely inappropriate. We notably study instructional design literature in order to identify the key requirements and guidelines for a successful training procedure that promotes a good and efficient skill learning. This literature study highlights that current spontaneous BCI user training procedures satisfy very few of these requirements and hence are likely to be suboptimal. We therefore identify the flaws in BCI training protocols according to instructional design principles, at several levels: in the instructions provided to the user, in the tasks he/she has to perform, and in the feedback provided. For each level, we propose new research directions that are theoretically expected to address some of these flaws and to help users learn the BCI skill more efficiently. PMID- 24062668 TI - Exploring Links between Genotypes, Phenotypes, and Clinical Predictors of Response to Early Intensive Behavioral Intervention in Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is amongst the most familial of psychiatric disorders. Twin and family studies have demonstrated a monozygotic concordance rate of 70-90%, dizygotic concordance of around 10%, and more than a 20-fold increase in risk for first-degree relatives. Despite major advances in the genetics of autism, the relationship between different aspects of the behavioral and cognitive phenotype and their underlying genetic liability is still unclear. This is complicated by the heterogeneity of autism, which exists at both genetic and phenotypic levels. Given this heterogeneity, one method to find homogeneous entities and link these with specific genotypes would be to pursue endophenotypes. Evidence from neuroimaging, eye tracking, and electrophysiology studies supports the hypothesis that, building on genetic vulnerability, ASD emerges from a developmental cascade in which a deficit in attention to social stimuli leads to impaired interactions with primary caregivers. This results in abnormal development of the neurocircuitry responsible for social cognition, which in turn adversely affects later behavioral and functional domains dependent on these early processes, such as language development. Such a model begets a heterogeneous clinical phenotype, and is also supported by studies demonstrating better clinical outcomes with earlier treatment. Treatment response following intensive early behavioral intervention in ASD is also distinctly variable; however, relatively little is known about specific elements of the clinical phenotype that may predict response to current behavioral treatments. This paper overviews the literature regarding genotypes, phenotypes, and predictors of response to behavioral intervention in ASD and presents suggestions for future research to explore linkages between these that would enable better identification of, and increased treatment efficacy for, ASD. PMID- 24062670 TI - Functional Imaging of the Human Brainstem during Somatosensory Input and Autonomic Output. AB - Over the past half a century, many investigations in experimental animal have explored the functional roles of specific regions in the brainstem. Despite the accumulation of a considerable body of knowledge in, primarily, anesthetized preparations, relatively few studies have explored brainstem function in awake humans. It is important that human brainstem function is explored given that many neurological conditions, from obstructive sleep apnea, chronic pain, and hypertension, likely involve significant changes in the processing of information within the brainstem. Recent advances in the collection and processing of magnetic resonance images have resulted in the possibility of exploring brainstem activity changes in awake healthy individuals and in those with various clinical conditions. We and others have begun to explore changes in brainstem activity in humans during a number of challenges, including cutaneous and muscle pain, as well as during maneuvers that evoke increases in sympathetic nerve activity. More recently we have successfully recorded sympathetic nerve activity concurrently with functional magnetic resonance imaging of the brainstem, which will allow us, for the first time to explore brainstem sites directly responsible for conditions such as hypertension. Since many pathophysiological conditions no doubt involve changes in brainstem function and structure, defining these changes will likely result in a greater ability to develop more effective treatment regimens. PMID- 24062671 TI - Self-processing and the default mode network: interactions with the mirror neuron system. AB - Recent evidence for the fractionation of the default mode network (DMN) into functionally distinguishable subdivisions with unique patterns of connectivity calls for a reconceptualization of the relationship between this network and self referential processing. Advances in resting-state functional connectivity analyses are beginning to reveal increasingly complex patterns of organization within the key nodes of the DMN - medial prefrontal cortex and posterior cingulate cortex - as well as between these nodes and other brain systems. Here we review recent examinations of the relationships between the DMN and various aspects of self-relevant and social-cognitive processing in light of emerging evidence for heterogeneity within this network. Drawing from a rapidly evolving social-cognitive neuroscience literature, we propose that embodied simulation and mentalizing are processes which allow us to gain insight into another's physical and mental state by providing privileged access to our own physical and mental states. Embodiment implies that the same neural systems are engaged for self- and other-understanding through a simulation mechanism, while mentalizing refers to the use of high-level conceptual information to make inferences about the mental states of self and others. These mechanisms work together to provide a coherent representation of the self and by extension, of others. Nodes of the DMN selectively interact with brain systems for embodiment and mentalizing, including the mirror neuron system, to produce appropriate mappings in the service of social-cognitive demands. PMID- 24062672 TI - Behavioral and neural interaction between spatial inhibition of return and the Simon effect. AB - It has been well documented that the anatomically independent attention networks in the human brain interact functionally to achieve goal-directed behaviors. By combining spatial inhibition of return (IOR) which implicates the orienting network with some executive function tasks (e.g., the Stroop and the flanker tasks) which implicate the executive network, researchers consistently found that the interference effects are significantly reduced at cued compared to uncued locations, indicating the functional interaction between the two attention networks. However, a unique, but consistent effect is observed when spatial IOR is combined with the Simon effect: the Simon effect is significantly larger at the cued than uncued locations. To investigate the neural substrates underlying this phenomenon, we orthogonally combined the spatial IOR with the Simon effect in the present event-related fMRI study. Our behavioral data replicated previous results by showing larger Simon effect at the cued location. At the neural level, we found shared spatial representation system between spatial IOR and the Simon effect in bilateral posterior parietal cortex (PPC); spatial IOR specifically activated bilateral superior parietal cortex while the Simon effect specifically activated bilateral middle frontal cortex. Moreover, left precentral gyrus was involved in the neural interaction between spatial IOR and the Simon effect by showing significantly higher neural activity in the "Cued_Congruent" condition. Taken together, our results suggest that due to the shared spatial representation system in the PPC, responses were significantly facilitated when spatial IOR and the Simon effect relied on the same spatial representations, i.e., in the "Cued_Congruent" condition. Correspondingly, the sensorimotor system was significantly involved in the "Cued_Congruent" condition to fasten the responses, which indirectly resulted in the enhanced Simon effect at the cued location. PMID- 24062673 TI - Intrinsic functional network organization in high-functioning adolescents with autism spectrum disorder. AB - Converging theories and data suggest that atypical patterns of functional and structural connectivity are a hallmark neurobiological feature of autism. However, empirical studies of functional connectivity, or, the correlation of MRI signal between brain regions, have largely been conducted during task performance and/or focused on group differences within one network [e.g., the default mode network (DMN)]. This narrow focus on task-based connectivity and single network analyses precludes investigation of whole-brain intrinsic network organization in autism. To assess whole-brain network properties in adolescents with autism, we collected resting-state functional connectivity MRI (rs-fcMRI) data from neurotypical (NT) adolescents and adolescents with autism spectrum disorder (ASD). We used graph theory metrics on rs-fcMRI data with 34 regions of interest (i.e., nodes) that encompass four different functionally defined networks: cingulo-opercular, cerebellar, fronto-parietal, and DMN (Fair etal., 2009). Contrary to our hypotheses, network analyses revealed minimal differences between groups with one exception. Betweenness centrality, which indicates the degree to which a seed (or node) functions as a hub within and between networks, was greater for participants with autism for the right lateral parietal (RLatP) region of the DMN. Follow-up seed-based analyses demonstrated greater functional connectivity in ASD than NT groups between the RLatP seed and another region of the DMN, the anterior medial prefrontal cortex. Greater connectivity between these regions was related to lower ADOS (Autism Diagnostic Observation Schedule) scores (i.e., lower impairment) in autism. These findings do not support current theories of underconnectivity in autism, but, rather, underscore the need for future studies to systematically examine factors that can influence patterns of intrinsic connectivity such as autism severity, age, and head motion. PMID- 24062674 TI - Effects of pro-cholinergic treatment in patients suffering from spatial neglect. AB - Spatial neglect is a neurological condition characterized by a breakdown of spatial cognition contralateral to hemispheric damage. Deficits in spatial attention toward the contralesional side are considered to be central to this syndrome. Brain lesions typically involve right fronto-parietal cortices mediating attentional functions and subcortical connections in underlying white matter. Convergent findings from neuroimaging and behavioral studies in both animals and humans suggest that the cholinergic system might also be critically implicated in selective attention by modulating cortical function via widespread projections from the basal forebrain. Here we asked whether deficits in spatial attention associated with neglect could partly result from a cholinergic deafferentation of cortical areas subserving attentional functions, and whether such disturbances could be alleviated by pro-cholinergic therapy. We examined the effect of a single-dose transdermal nicotine treatment on spatial neglect in 10 stroke patients in a double-blind placebo-controlled protocol, using a standardized battery of neglect tests. Nicotine-induced systematic improvement on cancellation tasks and facilitated orienting to single visual targets, but had no significant effect on other tests. These results support a global effect of nicotine on attention and arousal, but no effect on other spatial mechanisms impaired in neglect. PMID- 24062675 TI - MEG studies of motor cortex gamma oscillations: evidence for a gamma "fingerprint" in the brain? AB - The human motor cortex exhibits transient bursts of high frequency gamma oscillations in the 60-90 Hz range during movement. It has been proposed that gamma oscillations generally reflect local intracortical activity. However, movement-evoked gamma is observed simultaneously in both cortical and subcortical (basal ganglia) structures and thus appears to reflect long-range cortical subcortical interactions. Recent evidence suggests that gamma oscillations do not simply reflect sensory reafference, but have a facilitative role in movement initiation. Here we summarize contributions of MEG to our understanding of movement-evoked gamma oscillations, including evidence that transient gamma bursts during the performance of specific movements constitutes a stereotyped spectral and temporal pattern within individuals-a gamma "fingerprint"-that is highly stable over time. Although their functional significance remains to be fully understood, movement-evoked gamma oscillations may represent frequency specific tuning within cortical-subcortical networks that can be monitored non invasively using MEG during a variety of motor tasks, and may provide important information regarding cortical dynamics of ongoing motor control. PMID- 24062676 TI - Perspective taking in language: integrating the spatial and action domains. AB - Language is an inherently social behavior. In this paper, we bring together two research areas that typically occupy distinct sections of the literature: perspective taking in spatial language (whether people represent a scene from their own or a different spatial perspective), and perspective taking in action language (the extent to which they simulate an action as though they were performing that action). First, we note that vocabulary is used inconsistently across the spatial and action domains, and propose a more transparent vocabulary that will allow researchers to integrate action- and spatial-perspective taking. Second, we note that embodied theories of language comprehension often make the narrow assumption that understanding action descriptions involves adopting the perspective of an agent carrying out that action. We argue that comprehenders can adopt embodied action-perspectives other than that of the agent, including those of the patient or an observer. Third, we review evidence showing that perspective taking in spatial language is a flexible process. We argue that the flexibility of spatial-perspective taking provides a means for conversation partners engaged in dialogue to maximize similarity between their situation models. These situation models can then be used as the basis for action language simulations, in which language users adopt a particular action-perspective. PMID- 24062677 TI - Two-point orientation discrimination versus the traditional two-point test for tactile spatial acuity assessment. AB - Two-point discrimination is widely used to measure tactile spatial acuity. The validity of the two-point threshold as a spatial acuity measure rests on the assumption that two points can be distinguished from one only when the two points are sufficiently separated to evoke spatially distinguishable foci of neural activity. However, some previous research has challenged this view, suggesting instead that two-point task performance benefits from an unintended non-spatial cue, allowing spuriously good performance at small tip separations. We compared the traditional two-point task to an equally convenient alternative task in which participants attempt to discern the orientation (vertical or horizontal) of two points of contact. We used precision digital readout calipers to administer two interval forced-choice versions of both tasks to 24 neurologically healthy adults, on the fingertip, finger base, palm, and forearm. We used Bayesian adaptive testing to estimate the participants' psychometric functions on the two tasks. Traditional two-point performance remained significantly above chance levels even at zero point separation. In contrast, two-point orientation discrimination approached chance as point separation approached zero, as expected for a valid measure of tactile spatial acuity. Traditional two-point performance was so inflated at small point separations that 75%-correct thresholds could be determined on all tested sites for fewer than half of participants. The 95% correct thresholds on the two tasks were similar, and correlated with receptive field spacing. In keeping with previous critiques, we conclude that the traditional two-point task provides an unintended non-spatial cue, resulting in spuriously good performance at small spatial separations. Unlike two-point discrimination, two-point orientation discrimination rigorously measures tactile spatial acuity. We recommend the use of two-point orientation discrimination for neurological assessment. PMID- 24062678 TI - Dissociation in Optokinetic Stimulation Sensitivity between Omission and Substitution Reading Errors in Neglect Dyslexia. AB - Although omission and substitution errors in neglect dyslexia (ND) patients have always been considered as different manifestations of the same acquired reading disorder, recently, we proposed a new dual mechanism model. While omissions are related to the exploratory disorder which characterizes unilateral spatial neglect (USN), substitutions are due to a perceptual integration mechanism. A consequence of this hypothesis is that specific training for omission-type ND patients would aim at restoring the oculo-motor scanning and should not improve reading in substitution-type ND. With this aim we administered an optokinetic stimulation (OKS) to two brain-damaged patients with both USN and ND, MA and EP, who showed ND mainly characterized by omissions and substitutions, respectively. MA also showed an impairment in oculo-motor behavior with a non-reading task, while EP did not. The two patients presented a dissociation with respect to their sensitivity to OKS, so that, as expected, MA was positively affected, while EP was not. Our results confirm a dissociation between the two mechanisms underlying omission and substitution reading errors in ND patients. Moreover, they suggest that such a dissociation could possibly be extended to the effectiveness of rehabilitative procedures, and that patients who mainly omit contralesional-sided letters would benefit from OKS. PMID- 24062679 TI - Compositionality in neural control: an interdisciplinary study of scribbling movements in primates. AB - This article discusses the compositional structure of hand movements by analyzing and modeling neural and behavioral data obtained from experiments where a monkey (Macaca fascicularis) performed scribbling movements induced by a search task. Using geometrically based approaches to movement segmentation, it is shown that the hand trajectories are composed of elementary segments that are primarily parabolic in shape. The segments could be categorized into a small number of classes on the basis of decreasing intra-class variance over the course of training. A separate classification of the neural data employing a hidden Markov model showed a coincidence of the neural states with the behavioral categories. An additional analysis of both types of data by a data mining method provided evidence that the neural activity patterns underlying the behavioral primitives were formed by sets of specific and precise spike patterns. A geometric description of the movement trajectories, together with precise neural timing data indicates a compositional variant of a realistic synfire chain model. This model reproduces the typical shapes and temporal properties of the trajectories; hence the structure and composition of the primitives may reflect meaningful behavior. PMID- 24062680 TI - Anisotropic connectivity implements motion-based prediction in a spiking neural network. AB - Predictive coding hypothesizes that the brain explicitly infers upcoming sensory input to establish a coherent representation of the world. Although it is becoming generally accepted, it is not clear on which level spiking neural networks may implement predictive coding and what function their connectivity may have. We present a network model of conductance-based integrate-and-fire neurons inspired by the architecture of retinotopic cortical areas that assumes predictive coding is implemented through network connectivity, namely in the connection delays and in selectiveness for the tuning properties of source and target cells. We show that the applied connection pattern leads to motion-based prediction in an experiment tracking a moving dot. In contrast to our proposed model, a network with random or isotropic connectivity fails to predict the path when the moving dot disappears. Furthermore, we show that a simple linear decoding approach is sufficient to transform neuronal spiking activity into a probabilistic estimate for reading out the target trajectory. PMID- 24062681 TI - A model-based prediction of the calcium responses in the striatal synaptic spines depending on the timing of cortical and dopaminergic inputs and post-synaptic spikes. AB - The dopamine-dependent plasticity of the cortico-striatal synapses is considered as the cellular mechanism crucial for reinforcement learning. The dopaminergic inputs and the calcium responses affect the synaptic plasticity by way of the signaling cascades within the synaptic spines. The calcium concentration within synaptic spines, however, is dependent on multiple factors including the calcium influx through ionotropic glutamate receptors, the intracellular calcium release by activation of metabotropic glutamate receptors, and the opening of calcium channels by EPSPs and back-propagating action potentials. Furthermore, dopamine is known to modulate the efficacies of NMDA receptors, some of the calcium channels, and sodium and potassium channels that affect the back propagation of action potentials. Here we construct an electric compartment model of the striatal medium spiny neuron with a realistic morphology and predict the calcium responses in the synaptic spines with variable timings of the glutamatergic and dopaminergic inputs and the postsynaptic action potentials. The model was validated by reproducing the responses to current inputs and could predict the electric and calcium responses to glutamatergic inputs and back-propagating action potential in the proximal and distal synaptic spines during up- and down states. We investigated the calcium responses by systematically varying the timings of the glutamatergic and dopaminergic inputs relative to the action potential and found that the calcium response and the subsequent synaptic potentiation is maximal when the dopamine input precedes glutamate input and action potential. The prediction is not consistent with the hypothesis that the dopamine input provides the reward prediction error for reinforcement learning. The finding suggests that there is an unknown learning mechanisms at the network level or an unknown cellular mechanism for calcium dynamics and signaling cascades. PMID- 24062682 TI - A hexapod walker using a heterarchical architecture for action selection. AB - Moving in a cluttered environment with a six-legged walking machine that has additional body actuators, therefore controlling 22 DoFs, is not a trivial task. Already simple forward walking on a flat plane requires the system to select between different internal states. The orchestration of these states depends on walking velocity and on external disturbances. Such disturbances occur continuously, for example due to irregular up-and-down movements of the body or slipping of the legs, even on flat surfaces, in particular when negotiating tight curves. The number of possible states is further increased when the system is allowed to walk backward or when front legs are used as grippers and cannot contribute to walking. Further states are necessary for expansion that allow for navigation. Here we demonstrate a solution for the selection and sequencing of different (attractor) states required to control different behaviors as are forward walking at different speeds, backward walking, as well as negotiation of tight curves. This selection is made by a recurrent neural network (RNN) of motivation units, controlling a bank of decentralized memory elements in combination with the feedback through the environment. The underlying heterarchical architecture of the network allows to select various combinations of these elements. This modular approach representing an example of neural reuse of a limited number of procedures allows for adaptation to different internal and external conditions. A way is sketched as to how this approach may be expanded to form a cognitive system being able to plan ahead. This architecture is characterized by different types of modules being arranged in layers and columns, but the complete network can also be considered as a holistic system showing emergent properties which cannot be attributed to a specific module. PMID- 24062683 TI - Value and reward based learning in neurorobots. PMID- 24062684 TI - Age-related vulnerability in the neural systems supporting semantic processing. AB - Our ability to form abstract representations of objects in semantic memory is crucial to language and thought. The utility of this information relies both on the representations of sensory-motor feature knowledge stored in long-term memory and the executive processes required to retrieve, manipulate, and evaluate this semantic knowledge in a task-relevant manner. These complementary components of semantic memory can be differentially impacted by aging. We investigated semantic processing in normal aging using functional magnetic resonance imaging (fMRI). Young and older adults were asked to judge whether two printed object names match on a particular feature (for example, whether a tomato and strawberry have the same color). The task thus required both retrieval of relevant visual feature knowledge of object concepts and evaluating this information. Objects were drawn from either natural kinds or manufactured objects, and were queried on either color or shape in a factorial design. Behaviorally, all subjects performed well, but older adults could be divided into those whose performance matched that of young adults (better performers) and those whose performance was worse (poorer performers). All subjects activated several cortical regions while performing this task, including bilateral inferior and lateral temporal cortex and left frontal and prefrontal cortex. Better performing older adults showed increased overall activity in bilateral premotor cortex and left lateral occipital cortex compared to young adults, and increased activity in these brain regions relative to poorer performing older adults who also showed gray matter atrophy in premotor cortex. These findings highlight the contribution of domain-general executive processing brain regions to semantic memory, and illustrate differences in how these regions are recruited in healthy older adults. PMID- 24062686 TI - The concept of: Generic drugs and patented drugs vs. brand name drugs and non proprietary (generic) name drugs. PMID- 24062685 TI - Enhancing verbal episodic memory in older and young subjects after non-invasive brain stimulation. AB - Memory is the capacity to store, maintain, and retrieve events or information from the mind. Difficulties in verbal episodic memory commonly occur in healthy aging. In this paper, we assess the hypothesis that anodal transcranial direct current stimulation (tDCS) applied over the dorsolateral prefrontal cortex (DLPFC) or over the parietal cortex (PARC) could facilitate verbal episodic memory in a group of 32 healthy older adults and in a group of 32 young subjects relative to a sham stimulation using a single-blind randomized controlled design. Each participant underwent two sessions of anodal tDCS (left and right) and one session of sham stimulation. Overall, our results demonstrated that, in young and in older subjects, anodal tDCS applied during the retrieval phase facilitates verbal episodic memory. In particular, we found that tDCS applied over the left and right regions (DLPFC and PARC) induced better performance in young participants; only tDCS applied over the left regions (DLPFC and PARC) increased retrieval in older subjects. These results suggest that anodal tDCS can be a relevant tool to modulate the long-term episodic memory capacities of young and older subjects. PMID- 24062687 TI - Telaprevir or boceprevir for hepatitis C treatment: a first survey on pharmacoutilization. PMID- 24062688 TI - The investigation of sudden arrhythmic death syndrome (SADS)-the current approach to family screening and the future role of genomics and stem cell technology. AB - SADS is defined as sudden death under the age of 40 years old in the absence of structural heart disease. Family screening studies are able to identify a cause in up to 50% of cases-most commonly long QT syndrome (LQTS), Brugada and early repolarization syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT) using standard clinical screening investigations including pharmacological challenge testing. These diagnoses may be supported by genetic testing which can aid cascade screening and may help guide management. In the current era it is possible to undertake molecular autopsy provided suitable samples of DNA can be obtained from the proband. With the evolution of rapid sequencing techniques it is possible to sequence the whole exome for candidate genes. This major advance offers the opportunity to identify novel causes of lethal arrhythmia but also poses the challenge of managing the volume of data generated and evaluating variants of unknown significance (VUS). The emergence of induced pluripotent stem cell technology could enable evaluation of the electrophysiological relevance of specific ion channel mutations in the proband or their relatives and will potentially enable screening of idiopathic ventricular fibrillation survivors combining genetic and electrophysiological studies in derived myocytes. This also could facilitate the assessment of personalized preventative pharmacological therapies. This review will evaluate the current screening strategies in SADS families, the role of molecular autopsy and genetic testing and the potential applications of molecular and cellular diagnostic strategies on the horizon. PMID- 24062689 TI - The developmental basis of adult arrhythmia: atrial fibrillation as a paradigm. AB - Normal cardiac rhythm is one of the most fundamental physiologic phenomena, emerging early in the establishment of the vertebrate body plan. The developmental pathways underlying the patterning and maintenance of stable cardiac electrophysiology must be extremely robust, but are only now beginning to be unraveled. The step-wise emergence of automaticity, AV delay and sequential conduction are each tightly regulated and perturbations of these patterning events is now known to play an integral role in pediatric and adult cardiac arrhythmias. Electrophysiologic patterning within individual cardiac chambers is subject to exquisite control and is influenced by early physiology superimposed on the underlying gene networks that regulate cardiogenesis. As additional cell populations migrate to the developing heart these too bring further complexity to the organ, as it adapts to the dynamic requirements of a growing organism. A comprehensive understanding of the developmental basis of normal rhythm will inform not only the mechanisms of inherited arrhythmias, but also the differential regional propensities of the adult heart to acquired arrhythmias. In this review we use atrial fibrillation as a generalizable example where the various factors are perhaps best understood. PMID- 24062690 TI - A new mathematical approach for qualitative modeling of the insulin-TOR-MAPK network. AB - In this paper we develop a novel mathematical model of the insulin-TOR-MAPK signaling network that controls growth. Most data on the properties of the insulin and MAPK signaling networks are static and the responses to experimental interventions, such as knockouts, overexpression, and hormonal input are typically reported as scaled quantities. The modeling paradigm we develop here uses scaled variables and is ideally suited to simulate systems in which much of the available data are scaled. Our mathematical representation of signaling networks provides a way to reconcile theory and experiments, thus leading to a better understanding of the properties and function of these signaling networks. We test the performance of the model against a broad diversity of experimental data. The model correctly reproduces experimental insulin dose-response relationships. We study the interaction between insulin and MAPK signaling in the control of protein synthesis, and the interactions between amino acids, insulin and TOR signaling. We study the effects of variation in FOXO expression on protein synthesis and glucose transport capacity, and show that a FOXO knockout can partially rescue protein synthesis capacity of an insulin receptor (INR) knockout. We conclude that the modeling paradigm we develop provides a simple tool to investigate the qualitative properties of signaling networks. PMID- 24062691 TI - Overview on how oncogenic Kras promotes pancreatic carcinogenesis by inducing low intracellular ROS levels. AB - Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease without clearly known disease causes. Recent epidemiological and animal studies suggest that the supplementation of dietary antioxidants (e.g., vitamins C and E) decreases cancer risk, implying that increased reactive oxygen species (ROS) may play a role in pancreatic carcinogenesis. However, oncogenic Kras mutations (e.g., Kras(G12D)), which are present in more than 90% of PDAC, have been proven to foster low intracellular ROS levels. Here, oncogenic Kras activates expression of a series of anti-oxidant genes via Nrf2 (nuclear factor, erythroid derived 2, like 2) and also mediates an unusual metabolic pathway of glutamine to generate NADPH. This can then be used as the reducing power for ROS detoxification, leading collectively to low ROS levels in pancreatic pre-neoplastic cells and in cancer cells. In adult stem cells and cancer stem cells, low ROS levels have been associated with the formation of a proliferation-permissive intracellular environment and with perseverance of self-renewal capacities. Therefore, it is conceivable that low intracellular ROS levels may contribute significantly to oncogenic Kras-mediated PDAC formation. PMID- 24062692 TI - Nicotinic acetylcholine receptors mediate lung cancer growth. AB - Ion channels modulate ion flux across cell membranes, activate signal transduction pathways, and influence cellular transport-vital biological functions that are inexorably linked to cellular processes that go awry during carcinogenesis. Indeed, deregulation of ion channel function has been implicated in cancer-related phenomena such as unrestrained cell proliferation and apoptotic evasion. As the prototype for ligand-gated ion channels, nicotinic acetylcholine receptors (nAChRs) have been extensively studied in the context of neuronal cells but accumulating evidence also indicate a role for nAChRs in carcinogenesis. Recently, variants in the nAChR genes CHRNA3, CHRNA5, and CHRNB4 have been implicated in nicotine dependence and lung cancer susceptibility. Here, we silenced the expression of these three genes to investigate their function in lung cancer. We show that these genes are necessary for the viability of small cell lung carcinomas (SCLC), the most aggressive type of lung cancer. Furthermore, we show that nicotine promotes SCLC cell viability whereas an alpha3beta4-selective antagonist, alpha-conotoxin AuIB, inhibits it. Our findings posit a mechanism whereby signaling via alpha3/alpha5/beta4-containing nAChRs promotes lung carcinogenesis. PMID- 24062694 TI - Role of Per1 and the mineralocorticoid receptor in the coordinate regulation of alphaENaC in renal cortical collecting duct cells. AB - Renal function and blood pressure (BP) exhibit a circadian pattern of variation, but the molecular mechanism underlying this circadian regulation is not fully understood. We have previously shown that the circadian clock protein Per1 positively regulates the basal and aldosterone-mediated expression of the alpha subunit of the renal epithelial sodium channel (alphaENaC). The mechanism of this regulation has not been determined however. To further elucidate the mechanism of mineralocorticoid receptor (MR) and Per1 action, site-directed mutagenesis, DNA pull-down assays and chromatin immunoprecipitation (ChIP) methods were used to investigate the coordinate regulation of alphaENaC by Per1 and MR. Mutation of two circadian response E-boxes in the human alphaENaC promoter abolished both basal and aldosterone-mediated promoter activity. DNA pull down assays demonstrated the interaction of both MR and Per1 with the E-boxes from the alphaENaC promoter. These observations were corroborated by ChIP experiments showing increased occupancy of MR and Per1 on an E-box of the alphaENaC promoter in the presence of aldosterone. This is the first report of an aldosterone mediated increase in Per1 on a target gene promoter. Taken together, these results demonstrate the novel finding that Per1 and MR mediate the aldosterone response of alphaENaC through DNA/protein interaction in renal collecting duct cells. PMID- 24062693 TI - Factors that regulate insulin producing cells and their output in Drosophila. AB - Insulin-like peptides (ILPs) and growth factors (IGFs) not only regulate development, growth, reproduction, metabolism, stress resistance, and lifespan, but also certain behaviors and cognitive functions. ILPs, IGFs, their tyrosine kinase receptors and downstream signaling components have been largely conserved over animal evolution. Eight ILPs have been identified in Drosophila (DILP1-8) and they display cell and stage-specific expression patterns. Only one insulin receptor, dInR, is known in Drosophila and most other invertebrates. Nevertheless, the different DILPs are independently regulated transcriptionally and appear to have distinct functions, although some functional redundancy has been revealed. This review summarizes what is known about regulation of production and release of DILPs in Drosophila with focus on insulin signaling in the daily life of the fly. Under what conditions are DILP-producing cells (IPCs) activated and which factors have been identified in control of IPC activity in larvae and adult flies? The brain IPCs that produce DILP2, 3 and 5 are indirectly targeted by DILP6 and a leptin-like factor from the fat body, as well as directly by a few neurotransmitters and neuropeptides. Serotonin, octopamine, GABA, short neuropeptide F (sNPF), corazonin and tachykinin-related peptide have been identified in Drosophila as regulators of IPCs. The GABAergic cells that inhibit IPCs and DILP release are in turn targeted by a leptin-like peptide (unpaired 2) from the fat body, and the IPC-stimulating corazonin/sNPF neurons may be targeted by gut-derived peptides. We also discuss physiological conditions under which IPC activity may be regulated, including nutritional states, stress and diapause induction. PMID- 24062695 TI - Perinatal programming of obesity: an introduction to the topic. PMID- 24062696 TI - Dyadic social interaction as an alternative reward to cocaine. AB - Individuals suffering from substance use disorders often show severely impaired social interaction, preferring drugs of abuse to the contact with others. Their impaired social interaction is doubly harmful for them as (1) therapy itself is based and dependent on social interaction and as (2) social interaction is not available to them as an "alternative", i.e., non-drug reward, decreasing their motivation to stop drug use. We therefore developed an animal experimental model to investigate the neurobiology of dyadic social interaction- vs. cocaine reward. We took care to avoid: (a) engaging sexual attraction-related aspects of such a social interaction and (b) hierarchical difference as confounding stimuli. The cocaine- or social interaction stimulus was offered - in a mutually exclusive setting - within the confines of a conditioned place preference (CPP) apparatus. In our paradigm, only four 15-min episodes of social interaction proved sufficient to (i) switch the rats' preference from cocaine-associated contextual stimuli to social interaction CPP and (ii) inhibit the subsequent reacquisition/reexpression of cocaine CPP. This behavioral effect was paralleled by a reversal of brain activation (i.e., EGR1 expression) in the nucleus accumbens, the central and basolateral amygdala, and the ventral tegmental area. Of relevance for the psychotherapy of addictive disorders, the most rewarding sensory component of the composite stimulus "social interaction" was touch. To test our hypothesis that motivation is encoded in neuron ensembles dedicated to specific reward scenarios, we are currently (1) mapping the neural circuits involved in cocaine- vs. social-interaction reward and (2) adapting our paradigm for C57BL/6 mice to make use of the plethora of transgenic models available in this species. PMID- 24062697 TI - Active metabolites as antidepressant drugs: the role of norquetiapine in the mechanism of action of quetiapine in the treatment of mood disorders. AB - Active metabolites of some antipsychotic drugs exhibit pharmacodynamic and pharmacokinetic properties that may be similar to or differ from the original compound and that can be translated by a different profile of responses and interactions to clinical level. Some of these antipsychotics' active metabolites might participate in mechanisms of antidepressant activity, as m chlorophenylpiperazine (aripiprazole), 9-OH-risperidone and norquetiapine. Norquetiapine exhibits distinct pharmacological activity from quetiapine and plays a fundamental role in its antidepressant efficacy. In this review, we analyze the differential pharmacological aspects between quetiapine and norquetiapine, both from the pharmacokinetic and pharmacodynamic perspectives (affinity for dopaminergic, noradrenegic, and/or serotonergic receptors, etc.), as well as differential neuroprotective role. The pharmacological differences between the two drugs could explain the differential clinical effect, as well as some differences in tolerability profile and drug interactions. The available data are sufficient to arrive at the conclusion that antidepressant activity of quetiapine is mediated, at least in part, by the active metabolite norquetiapine, which selectively inhibits noradrenaline reuptake, is a partial 5-HT1A receptor agonist, and acts as an antagonist at presynaptic alpha2, 5-HT2C, and 5-HT7 receptors. PMID- 24062698 TI - The Role of Genetic Sex in Affect Regulation and Expression of GABA-Related Genes Across Species. AB - Although circulating hormones and inhibitory gamma-aminobutyric acid (GABA) related factors are known to affect mood, considerable knowledge gaps persist for biological mechanisms underlying the female bias in mood disorders. Here, we combine human and mouse studies to investigate sexual dimorphism in the GABA system in the context of major depressive disorder (MDD) and then use a genetic model to dissect the role of sex-related factors in GABA-related gene expression and anxiety-/depressive-like behaviors in mice. First, using meta-analysis of gene array data in human postmortem brain (N = 51 MDD subjects, 50 controls), we show that the previously reported down-regulation in MDD of somatostatin (SST), a marker of a GABA neuron subtype, is significantly greater in women with MDD. Second, using gene co-expression network analysis in control human subjects (N = 214; two frontal cortex regions) and expression quantitative trait loci mapping (N = 170 subjects), we show that expression of SST and the GABA-synthesizing enzymes glutamate decarboxylase 67 (GAD67) and GAD65 are tightly co-regulated and influenced by X-chromosome genetic polymorphisms. Third, using a rodent genetic model [Four Core Genotypes (FCG) mice], in which genetic and gonadal sex are artificially dissociated (N >= 12/group), we show that genetic sex (i.e., X/Y chromosome) influences both gene expression (lower Sst, Gad67, Gad65 in XY mice) and anxiety-like behaviors (higher in XY mice). This suggests that in an intact male animal, the observed behavior represents the outcomes of male genetic sex increasing and male-like testosterone decreasing anxiety-like behaviors. Gonadal sex was the only factor influencing depressive-like behavior (gonadal males < gonadal females). Collectively, these combined human and mouse studies provide mechanistic insight into sexual dimorphism in mood disorders, and specifically demonstrate an unexpected role of male-like factors (XY genetic sex) on GABA related genes and anxiety-like behaviors. PMID- 24062699 TI - Cholinergic Enhancement of Brain Activation in Mild Cognitive Impairment during Episodic Memory Encoding. AB - OBJECTIVE: To determine the physiological impact of treatment with donepezil (Aricept) on neural circuitry supporting episodic memory encoding in patients with amnestic mild cognitive impairment (MCI) using functional magnetic resonance imaging (fMRI). METHODS: Eighteen patients with MCI and 20 age-matched healthy controls (HC) were scanned twice while performing an event-related verbal episodic encoding task. MCI participants were scanned before treatment and after approximately 3 months on donepezil; HC were untreated but rescanned at the same interval. Voxel-level analyses assessed treatment effects on activation profiles in MCI patients relative to retest changes in non-treated HC. Changes in task related connectivity in medial temporal circuitry were also evaluated, as were associations between brain activation, task-related functional connectivity, task performance, and clinical measures of cognition. RESULTS: At baseline, the MCI group showed reduced activation during encoding relative to HC in the right medial temporal lobe (MTL; hippocampal/parahippocampal) and additional regions, as well as attenuated task-related deactivation, relative to rest, in a medial parietal lobe cluster. After treatment, the MCI group showed normalized MTL activation and improved parietal deactivation. These changes were associated with cognitive performance. After treatment, the MCI group also demonstrated increased task-related functional connectivity from the right MTL cluster seed region to a network of other sites including the basal nucleus/caudate and bilateral frontal lobes. Increased functional connectivity was associated with improved task performance. CONCLUSION: Pharmacologic enhancement of cholinergic function in amnestic MCI is associated with changes in brain activation and functional connectivity during episodic memory processing which are in turn related to increased cognitive performance. fMRI is a promising biomarker for assessing treatment related changes in brain function. PMID- 24062700 TI - Chronic Ketamine Reduces the Peak Frequency of Gamma Oscillations in Mouse Prefrontal Cortex Ex vivo. AB - Abnormalities in EEG gamma band oscillations (GBO, 30-80 Hz) serve as a prominent biomarker of schizophrenia (Sz), associated with positive, negative, and cognitive symptoms. Chronic, subanesthetic administration of antagonists of N methyl-D-aspartate receptors (NMDAR), such as ketamine, elicits behavioral effects, and alterations in cortical interneurons similar to those observed in Sz. However, the chronic effects of ketamine on neocortical GBO are unknown. Thus, here we examine the effects of chronic (five daily i.p. injections) application of ketamine (5 and 30 mg/kg) and the more specific NMDAR antagonist, MK-801 (0.02, 0.5, and 2 mg/kg), on neocortical GBO ex vivo. Oscillations were generated by focal application of the glutamate receptor agonist, kainate (KA), in coronal brain slices containing the prelimbic cortex. This region constitutes the rodent analog of the human dorsolateral prefrontal cortex, a brain region strongly implicated in Sz-pathophysiology. Here we report the novel finding that chronic ketamine elicits a reduction in the peak oscillatory frequency of KA elicited oscillations (from 47 to 40 Hz at 30 mg/kg). Moreover, the power of GBO in the 40-50 Hz band was reduced. These findings are reminiscent of both the reduced resonance frequency and power of cortical oscillations observed in Sz clinical studies. Surprisingly, MK-801 had no significant effect, suggesting care is needed when equating Sz-like behavioral effects elicited by different NMDAR antagonists to alterations in GBO activity. We conclude that chronic ketamine in the mouse mimics GBO abnormalities observed in Sz patients. Use of this ex vivo slice model may be useful in testing therapeutic compounds which rescue these GBO abnormalities. PMID- 24062702 TI - Short term memory for serial order: unraveling individual differences in the use of processes and changes across tasks. AB - In this study we investigated whether we could distinguish the use of specific verbal and visual short term memory (STM) processes in children, or whether the differences in memory performance could be interpreted only in terms of quantitative differences. First, the number of processes involved in the responses on six STM tasks (serial order reconstruction) of 210 primary school children aged 5-12 years was examined by means of latent states. The number of items to reconstruct was manipulated to unravel quantitative differences in responses (high or low performance), and the similarity of the items was manipulated to distinguish qualitative differences in responses (verbal or visual processing). Furthermore, we examined how children changed from one type of process to another on tasks with list lengths of 3, 5, and 7 items by means of the dynamics between the latent states using a latent Markov model. The results showed that two latent states representing the use of specific verbal and visual STM processes could be distinguished on all the tasks. Moreover, two latent states showing merely differences in performance were also found. These findings underline the value of latent variable models to unravel differences between as well as within individuals in the use of cognitive processes. PMID- 24062701 TI - Gone in a flash: manipulation of audiovisual temporal integration using transcranial magnetic stimulation. AB - While converging evidence implicates the right inferior parietal lobule in audiovisual integration, its role has not been fully elucidated by direct manipulation of cortical activity. Replicating and extending an experiment initially reported by Kamke et al. (2012), we employed the sound-induced flash illusion, in which a single visual flash, when accompanied by two auditory tones, is misperceived as multiple flashes (Wilson, 1987; Shams et al., 2000). Slow repetitive (1 Hz) TMS administered to the right angular gyrus, but not the right supramarginal gyrus, induced a transient decrease in the Peak Perceived Flashes (PPF), reflecting reduced susceptibility to the illusion. This finding independently confirms that perturbation of networks involved in multisensory integration can result in a more veridical representation of asynchronous auditory and visual events and that cross-modal integration is an active process in which the objective is the identification of a meaningful constellation of inputs, at times at the expense of accuracy. PMID- 24062703 TI - Transfer of motor and perceptual skills from basketball to darts. AB - The quiet eye is a perceptual skill associated with expertise and superior performance; however, little is known about the transfer of quiet eye across domains. We attempted to replicate previous skill-based differences in quiet eye and investigated whether transfer of motor and perceptual skills occurs between similar tasks. Throwing accuracy and quiet eye duration for skilled and less skilled basketball players were examined in basketball free throw shooting and the transfer task of dart throwing. Skilled basketball players showed significantly higher throwing accuracy and longer quiet eye duration in the basketball free throw task compared to their less-skilled counterparts. Further, skilled basketball players showed positive transfer from basketball to dart throwing in accuracy but not in quiet eye duration. Our results raise interesting questions regarding the measurement of transfer between skills. PMID- 24062704 TI - Neural correlates of phonetic convergence and speech imitation. AB - Speakers unconsciously tend to mimic their interlocutor's speech during communicative interaction. This study aims at examining the neural correlates of phonetic convergence and deliberate imitation, in order to explore whether imitation of phonetic features, deliberate, or unconscious, might reflect a sensory-motor recalibration process. Sixteen participants listened to vowels with pitch varying around the average pitch of their own voice, and then produced the identified vowels, while their speech was recorded and their brain activity was imaged using fMRI. Three degrees and types of imitation were compared (unconscious, deliberate, and inhibited) using a go-nogo paradigm, which enabled the comparison of brain activations during the whole imitation process, its active perception step, and its production. Speakers followed the pitch of voices they were exposed to, even unconsciously, without being instructed to do so. After being informed about this phenomenon, 14 participants were able to inhibit it, at least partially. The results of whole brain and ROI analyses support the fact that both deliberate and unconscious imitations are based on similar neural mechanisms and networks, involving regions of the dorsal stream, during both perception and production steps of the imitation process. While no significant difference in brain activation was found between unconscious and deliberate imitations, the degree of imitation, however, appears to be determined by processes occurring during the perception step. Four regions of the dorsal stream: bilateral auditory cortex, bilateral supramarginal gyrus (SMG), and left Wernicke's area, indeed showed an activity that correlated significantly with the degree of imitation during the perception step. PMID- 24062705 TI - Asymmetry in infants' selective attention to facial features during visual processing of infant-directed speech. AB - Two experiments used eye tracking to examine how infant and adult observers distribute their eye gaze on videos of a mother producing infant- and adult directed speech. Both groups showed greater attention to the eyes than to the nose and mouth, as well as an asymmetrical focus on the talker's right eye for infant-directed speech stimuli. Observers continued to look more at the talker's apparent right eye when the video stimuli were mirror flipped, suggesting that the asymmetry reflects a perceptual processing bias rather than a stimulus artifact, which may be related to cerebral lateralization of emotion processing. PMID- 24062706 TI - Desynchronization and rebound of beta oscillations during conscious and unconscious local neuronal processing in the macaque lateral prefrontal cortex. AB - Accumulating evidence indicates that control mechanisms are not tightly bound to conscious perception since both conscious and unconscious information can trigger control processes, probably through the activation of higher-order association areas like the prefrontal cortex. Studying the modulation of control-related prefrontal signals in a microscopic, neuronal level during conscious and unconscious neuronal processing, and under control-free conditions could provide an elementary understanding of these interactions. Here we performed extracellular electrophysiological recordings in the macaque lateral prefrontal cortex (LPFC) during monocular physical alternation (PA) and binocular flash suppression (BFS) and studied the local scale relationship between beta (15-30 Hz) oscillations, a rhythmic signal believed to reflect the current sensory, motor, or cognitive state (status-quo), and conscious or unconscious neuronal processing. First, we show that beta oscillations are observed in the LPFC during resting state. Both PA and BFS had a strong impact on the power of this spontaneous rhythm with the modulation pattern of beta power being identical across these two conditions. Specifically, both perceptual dominance and suppression of local neuronal populations in BFS were accompanied by a transient beta desynchronization followed by beta activity rebound, a pattern also observed when perception occurred without any underlying visual competition in PA. These results indicate that under control-free conditions, at least one rhythmic signal known to reflect control processes in the LPFC (i.e., beta oscillations) is not obstructed by local neuronal, and accordingly perceptual, suppression, thus being independent from temporally co-existing conscious and unconscious local neuronal representations. Future studies could reveal the additive effects of motor or cognitive control demands on prefrontal beta oscillations during conscious and unconscious processing. PMID- 24062707 TI - Physical exercise speeds up motor timing. AB - THIS STUDY AIMED TO EXAMINE EFFECT OF PHYSICAL EXERCISE ON MOTOR TIMING: personal, maximum and "once per second" tapping. The acute effect was examined by comparing the baseline tapping with that after acute exercise in 9 amateur athletes, 8 elite synchronous swimmers and 9 elite biathletes. Then the baseline tapping was compared among athletes of different sports and professional levels (15 elite biathletes, 27 elite cross-country skiers, 15 elite synchronous swimmers and 9 amateur wrestlers) with a control group (44 non-athletes) not involved in regular exercise to examine the sport-specific or long-term effects. Maximum and "once per second" tapping speed increased after acute physical exercise and were also faster in elite athletes compared to controls during the baseline condition. However, personal tapping tempo was not affected by exercise. In addition, physical exercise had no effects on the variability of the intertap interval. The accuracy of "once per second" tapping differentiates controls and amateur wrestlers from elite synchronous swimmers and skiers suggesting sport specific adaptations to play a role. It is concluded that acute physical exercise selectively speeds up motor timing but does not affect its variability and accuracy, and this speeding-up is suggested to transfer into a long-term effect in elite athletes. PMID- 24062708 TI - Symptoms of depression as reported by Norwegian adolescents on the Short Mood and Feelings Questionnaire. AB - The present study investigated sex-differences in reports of depressive symptoms on a Norwegian translation of the short version of the Mood and Feelings Questionnaire (SMFQ). The sample comprised 9702 Norwegian adolescents (born 1993 1995, 54.9% girls), mainly attending highschool. A set of statistical analyses were run to investigate the dimensionality of the SMFQ. Girls scored significantly higher than boys on the SMFQ and used the most severe response category far more frequently. Overall, the statistical analyses supported the essential unidimensionality of SMFQ. However, the items with the highest loadings according to the bifactor analysis, reflecting problems related to tiredness, restlessness and concentration difficulties, indicated that some of the symptoms may both be independent of and part of the symptomatology of depression. Measurement invariance analysis showed that girls scored slightly higher on some items when taking the latent variable into account; girls had a lower threshold for reporting mood problems and problems related to tiredness than boys, who showed a marginally lower threshold for reporting that no-one loved them. However, the effect on the total SMFQ score was marginal, supporting the use of the Norwegian translation of SMFQ as a continuous variable in further studies of adolescents. PMID- 24062709 TI - The IAT shows no evidence for Kandinsky's color-shape associations. AB - In the early twentieth century, the Bauhaus revolutionized art and design by using simple colors and forms. Wassily Kandinsky was especially interested in the relationship of these two visual attributes and postulated a fundamental correspondence between color and form: yellow triangle, red square and blue circle. Subsequent empirical studies used preference judgments to test Kandinsky's original color-form combinations, usually yielding inconsistent results. We have set out to test the validity of these postulated associations by using the Implicit Association Test. Participants pressed one of two buttons on each trial. On some trials they classified shapes (e.g., circle or triangle). On interleaved trials they classified colors (e.g., blue or yellow). Response times should theoretically be faster when the button mapping follows Kandinsky's associations: For example, when the left key is used to report blue or circle and the right is used for yellow and triangle, than when the response mapping is the opposite of this (blue or triangle, yellow or circle). Our findings suggest that there is no implicit association between the original color-form combinations. Of the three combinations we tested, there was only a marginal effect in one case. It can be concluded that the IAT does not support Kandinsky's postulated color form associations, and that these are probably not a universal property of the visual system. PMID- 24062710 TI - A motivation model for interaction between parent and child based on the need for relatedness. AB - In parent-child communication, emotions are evoked by various types of intrinsic and extrinsic motivation. Those emotions encourage actions that promote more interactions. We present a motivation model of infant-caregiver interactions, in which relatedness, one of the most important basic psychological needs, is a variable that increases with experiences of emotion sharing. Besides being an important factor of pleasure, relatedness is a meta-factor that affects other factors such as stress and emotional mirroring. The proposed model is implemented in an artificial agent equipped with a system to recognize gestures and facial expressions. The baby-like agent successfully interacts with an actual human and adversely reacts when the caregiver suddenly ceases facial expressions, similar to the "still-face paradigm" demonstrated by infants in psychological experiments. In the simulation experiment, two agents, each controlled by the proposed motivation model, show relatedness-dependent emotional communication that mimics actual human communication. PMID- 24062711 TI - Descriptive vs. inferential cheating. PMID- 24062712 TI - The virtual brain: 30 years of video-game play and cognitive abilities. AB - Forty years have passed since video-games were first made widely available to the public and subsequently playing games has become a favorite past-time for many. Players continuously engage with dynamic visual displays with success contingent on the time-pressured deployment, and flexible allocation, of attention as well as precise bimanual movements. Evidence to date suggests that both brief and extensive exposure to video-game play can result in a broad range of enhancements to various cognitive faculties that generalize beyond the original context. Despite promise, video-game research is host to a number of methodological issues that require addressing before progress can be made in this area. Here an effort is made to consolidate the past 30 years of literature examining the effects of video-game play on cognitive faculties and, more recently, neural systems. Future work is required to identify the mechanism that allows the act of video-game play to generate such a broad range of generalized enhancements. PMID- 24062713 TI - Grounding clinical and cognitive scientists in an interdisciplinary discussion. AB - In most clinical approaches the body receives little attention. In cognitive science, in contrast, the embodied and grounded perspective, which emphasizes the importance of the body, has been intensively explored over the last decade. The present article aims to engage theorists of embodied cognition and clinical experts in a discussion encouraging them to consider the insights that may arise from each other's approaches. In a review of the cognitive and clinical literature substantial overlap is revealed between cognitive and clinical domains. PMID- 24062714 TI - A follow-up study of first episode major depressive disorder. Impairment in inhibition and semantic fluency-potential predictors for relapse? AB - The present study investigated the Executive Functions (EF) of inhibition, mental flexibility and phonemic and semantic fluency in a 1-year follow-up assessment of patients diagnosed with first episode Major Depressive Disorder (MDD). In the acute phase, the patient group performed significantly poorer compared to the control group (CG) in inhibition and semantic fluency. The present study pursued these findings from the acute phase to see if the impairment seen in inhibition and semantic fluency in the acute phase normalized or persisted in the follow-up assessment. In addition, the present study investigated the association between poor inhibition and semantic fluency performance and the experience of relapse during the 1-year period. Twenty eight patients and 28 individually matched control subjects were included. EF was reassessed using three tests from the Delis Kaplan Executive Function System (D-KEFS). RESULTS: There was a significant decrease in depression severity score from the acute phase, showing that most of the patients were in remission in the follow-up assessment. RESULTS showed a sustained impairment in inhibition and semantic fluency in the patient group. However, the performance in inhibition was more severe when an additional requirement of mental flexibility was included. There were no group differences in the other EF functions measured. Further, patients with a relapse in the course of 1 year performed significantly poorer in inhibition/switching at inclusion compared to patients that did not relapse and the CG. This relationship was not found for semantic fluency. Poor performance in inhibition and semantic fluency are prolonged despite symptom reduction in patients with a first episode of MDD. Moreover, although based on a small sample of patients, the present study showed that there may be a relationship between impaired ability in the EF of inhibition/switching and vulnerability for the experience of relapse. PMID- 24062715 TI - Audiovisual integration: an introduction to behavioral and neuro-cognitive methods. PMID- 24062716 TI - A highly compliant serpentine shaped polyimide interconnect for front-end strain relief in chronic neural implants. AB - While the signal quality of recording neural electrodes is observed to degrade over time, the degradation mechanisms are complex and less easily observable. Recording microelectrodes failures are attributed to different biological factors such as tissue encapsulation, immune response, and disruption of blood-brain barrier (BBB) and non-biological factors such as strain due to micromotion, insulation delamination, corrosion, and surface roughness on the recording site (1-4). Strain due to brain micromotion is considered to be one of the important abiotic factors contributing to the failure of the neural implants. To reduce the forces exerted by the electrode on the brain, a high compliance 2D serpentine shaped electrode cable was designed, simulated, and measured using polyimide as the substrate material. Serpentine electrode cables were fabricated using MEMS microfabrication techniques, and the prototypes were subjected to load tests to experimentally measure the compliance. The compliance of the serpentine cable was numerically modeled and quantitatively measured to be up to 10 times higher than the compliance of a straight cable of same dimensions and material. PMID- 24062717 TI - Neuro-modulating effects of honokiol: a review. AB - Honokiol is a poly-phenolic compound that exerts neuroprotective properties through a variety of mechanisms. It has therapeutic potential in anxiety, pain, cerebrovascular injury, epilepsy, and cognitive disorders including Alzheimer's disease. It has been traditionally used in medical practices throughout much of Southeast Asia, but has now become more widely studied due to its pleiotropic effects. Most current research regarding this compound has focused on its chemotherapeutic properties. However, it has the potential to be an effective neuroprotective agent as well. This review summarizes what is currently known regarding the mechanisms involved in the neuroprotective and anesthetic effects of this compound and identifies potential areas for further research. PMID- 24062718 TI - Disentangling hippocampal shape anomalies in epilepsy. AB - Drug-resistant temporal lobe epilepsy (TLE) and epileptic syndromes related to malformations of cortical development (MCD) are associated with complex hippocampal morphology. The contribution of volume and position to the overall hippocampal shape in these conditions has not been studied. We propose a surface based framework to localize volume changes through measurement of Jacobian determinants, and quantify fine-scale position and curvature through a medial axis model. We applied our methodology to T1-weighted 3D volumetric MRI of 88 patients with TLE and 78 patients with MCD, including focal cortical dysplasia (FCD, n = 29), heterotopia (HET, n = 40), and polymicrogyria (PMG, n = 19). Patients were compared to 46 age- and sex-matched healthy controls. Surface-based analysis of volume in TLE revealed severe ipsilateral atrophy mainly along the rostro-caudal extent of the hippocampal CA1 subfield. In MCD, patterns of volume changes included bilateral CA1 atrophy in HET and FCD, and left dentate hypertrophy in all three groups. The analysis of curvature revealed medial bending of the posterior hippocampus in TLE, whereas in MCD there was a supero medial shift of the hippocampal body. Albeit hippocampal shape anomalies in TLE and MCD result from a combination of volume and positional changes, their nature and distribution suggest different pathogenic mechanisms. PMID- 24062719 TI - Corrigendum: Dense Array EEG Source Estimation in Neocortical Epilepsy. AB - [This corrects the article on p. 42 in vol. 4, PMID: 23717298.]. PMID- 24062720 TI - Spontaneous cervical artery dissection: the borgess classification. AB - BACKGROUND AND PURPOSE: The pathogenesis of spontaneous cervical artery dissections (sCAD) and its best medical treatment are debated. This may be due to a lack of clear classification of sCAD. We propose the new Borgess classification of sCAD, based on the presence or absence of intimal tear as depicted on imaging studies and effect on blood flow. MATERIALS AND METHODS: This is a single-center investigator-initiated registry on consecutive patients treated for sCAD. In the Borgess classification, type I dissections have intact intima and type II dissections have an intimal tear. RESULTS: Forty-four patients and 52 dissected arteries were found. Forty-nine of 52 dissections (93%) were treated with dual anti-platelet therapy. Twenty-one of 52 dissections were type I; 31 were type II. Type I dissections were more likely to present with ischemic symptoms [stroke, transient ischemic attack (TIA)] (p = 0.001). More type I dissections occurred in the vertebral artery, while more type II dissections occurred in the internal carotid artery (p < 0.001). Follow-up averaged 18.1 months (range: 3-108 months) with no recurrent ischemic events (stroke, TIA), deaths, or hemorrhage. Forty-six vessels had 6 month follow-up on medical treatment; 19/46 (41%) healed. Type I dissections were more likely to heal than type II (p < 0.001). CONCLUSION: The two dissection types in the Borgess classification appear to relate to clinical presentation and rate of healing, making the classification useful in clinical management. Dual anti-platelet therapy for sCAD seems to have a very low risk of subsequent stroke; however, a large prospective study is needed to investigate the best treatment. PMID- 24062722 TI - Non-Linear EMG Parameters for Differential and Early Diagnostics of Parkinson's Disease. AB - The pre-clinical diagnostics is essential for management of Parkinson's disease (PD). Although PD has been studied intensively in the last decades, the pre clinical indicators of that motor disorder have yet to be established. Several approaches were proposed but the definitive method is still lacking. Here we report on the non-linear characteristics of surface electromyogram (sEMG) and tremor acceleration as a possible diagnostic tool, and, in prospective, as a predictor for PD. Following this approach we calculated such non-linear parameters of sEMG and accelerometer signal as correlation dimension, entropy, and determinism. We found that the non-linear parameters allowed discriminating some 85% of healthy controls from PD patients. Thus, this approach offers considerable potential for developing sEMG-based method for pre-clinical diagnostics of PD. However, non-linear parameters proved to be more reliable for the shaking form of PD, while diagnostics of the rigid form of PD using EMG remains an open question. PMID- 24062721 TI - The Enemy within: Propagation of Aberrant Corticostriatal Learning to Cortical Function in Parkinson's Disease. AB - Motor dysfunction in Parkinson's disease is believed to arise primarily from pathophysiology in the dorsal striatum and its related corticostriatal and thalamostriatal circuits during progressive dopamine denervation. One function of these circuits is to provide a filter that selectively facilitates or inhibits cortical activity to optimize cortical processing, making motor responses rapid and efficient. Corticostriatal synaptic plasticity mediates the learning that underlies this performance-optimizing filter. Under dopamine denervation, corticostriatal plasticity is altered, resulting in aberrant learning that induces inappropriate basal ganglia filtering that impedes rather than optimizes cortical processing. Human imaging suggests that increased cortical activity may compensate for striatal dysfunction in PD patients. In this Perspective article, we consider how aberrant learning at corticostriatal synapses may impair cortical processing and learning and undermine potential cortical compensatory mechanisms. Blocking or remediating aberrant corticostriatal plasticity may protect cortical function and support cortical compensatory mechanisms mitigating the functional decline associated with progressive dopamine denervation. PMID- 24062723 TI - Munc13-1 Translocates to the Plasma Membrane in a Doc2B- and Calcium-Dependent Manner. AB - Munc13-1 is a presynaptic protein activated by calcium, calmodulin, and diacylglycerols (DAG) that is known to enhance vesicle priming. Doc2B is another presynaptic protein that translocates to the plasma membrane (PM) upon elevation of internal calcium concentration ([Ca(2+)]i) to the submicromolar range, and increases both spontaneous and asynchronous release in a calcium-dependent manner. We speculated that Doc2B also recruits Munc13-1 to the PM since these two proteins have been shown to interact physiologically and this interaction is enhanced by Ca(2+). However, this calcium-dependent co-translocation has never actually been shown. To examine this possibility, we expressed both proteins tagged to fluorescent proteins in PC12 cells and stimulated the cells to investigate the recruitment hypothesis using imaging techniques. We found that Munc13-1 does indeed translocate to the PM upon elevation in [Ca(2+)]i, but only when co-expressed with Doc2B. Interestingly, Munc13-1 co-translocates at a slower rate than Doc2B. Moreover, while Doc2B dislocates from the PM as soon as the [Ca(2+)]i returns to basal levels, Munc13-1 dislocates at a slower rate and a fraction of it accumulates on the PM. This accumulation is more pronounced under subsequent stimulations, suggesting that Munc13-1 accumulation builds up as some other factors accumulate at the PM. Munc13-1 co-translocation and accumulation was reduced when its mutant Munc13-1(H567K), which is unable to bind DAG, was co expressed with Doc2B, suggesting that Munc13-1 accumulation depends on DAG levels. These results suggest that Doc2B enables recruitment of Munc13-1 to the PM in a [Ca(2+)]i-dependent manner and offers another possible Munc13-1 regulatory mechanism that is both calcium- and Doc2B-dependent. PMID- 24062724 TI - Molecular mechanisms underlying insect behaviors: receptors, peptides, and biosynthetic pathways. PMID- 24062725 TI - The role of cyclic nucleotides in pituitary lactotroph functions. AB - Lactotrophs are one of the five secretory anterior pituitary cell types specialized to synthesize and release prolactin. In vitro, these cells fire action potentials (APs) spontaneously and the accompanied Ca(2+) transients are of sufficient amplitude to keep the exocytotic pathway, the transcription of prolactin gene, and de novo hormone synthesis continuously active. Basal cyclic nucleotide production is also substantial in cultured cells but not critical for the APs secretion/transcription coupling in lactotrophs. However, elevated intracellular cAMP levels enhance the excitability of lactotrophs by stimulating the depolarizing non-selective cationic hyperpolarization-activated cyclic nucleotide-regulated and background channels, whereas cGMP inhibits it by activating Ca(2+)-controlled K(+) channels. Elevated cAMP also modulates prolactin release downstream of Ca(2+) influx by changing the kinetic of secretory pores: stimulate at low and inhibit at high concentrations. Induction of prolactin gene and lactotroph proliferation is also stimulated by elevated cAMP through protein kinase A. Together, these observations suggest that in lactotrophs cAMP exhibits complex regulatory effects on voltage-gated Ca(2+) influx and Ca(2+)-dependent cellular processes. PMID- 24062726 TI - Inhibitors of glutamate dehydrogenase block sodium-dependent glutamate uptake in rat brain membranes. AB - We recently found evidence for anatomic and physical linkages between the astroglial Na(+)-dependent glutamate transporters (GLT-1/EAAT2 and GLAST/EAAT1) and mitochondria. In these same studies, we found that the glutamate dehydrogenase (GDH) inhibitor, epigallocatechin-monogallate (EGCG), inhibits both glutamate oxidation and Na(+)-dependent glutamate uptake in astrocytes. In the present study, we extend this finding by exploring the effects of EGCG on Na(+) dependent l-[(3)H]-glutamate (Glu) uptake in crude membranes (P2) prepared from rat brain cortex. In this preparation, uptake is almost exclusively mediated by GLT-1. EGCG inhibited l-[(3)H]-Glu uptake in cortical membranes with an IC50 value of 230 MUM. We also studied the effects of two additional inhibitors of GDH, hexachlorophene (HCP) and bithionol (BTH). Both of these compounds also caused concentration-dependent inhibition of glutamate uptake in cortical membranes. Pre-incubating with HCP for up to 15 min had no greater effect than that observed with no pre-incubation, showing that the effects occur rapidly. HCP decreased the V max for glutamate uptake without changing the K m, consistent with a non-competitive mechanism of action. EGCG, HCP, and BTH also inhibited Na(+)-dependent transport of d-[(3)H]-aspartate (Asp), a non-metabolizable transporter substrate, and [(3)H]-gamma-aminobutyric acid (GABA). In contrast to the forebrain, glutamate uptake in crude cerebellar membranes (P2) is likely mediated by GLAST (EAAT1). Therefore, the effects of these compounds were examined in cerebellar membranes. In this region, none of these compounds had any effect on uptake of either l-[(3)H]-Glu or d-[(3)H]-Asp, but they all inhibited [(3)H]-GABA uptake. Together these studies suggest that GDH is preferentially required for glutamate uptake in forebrain as compared to cerebellum, and GDH may be required for GABA uptake as well. They also provide further evidence for a functional linkage between glutamate transport and mitochondria. PMID- 24062727 TI - Lipids in Regulated Exocytosis: What are They Doing? AB - The regulated secretory pathway in neuroendocrine cells ends with the release of hormones and neurotransmitters following a rise in cytosolic calcium. This process known as regulated exocytosis involves the assembly of soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, the synaptic vesicle VAMP (synaptobrevin), and the plasma membrane proteins syntaxin and SNAP-25. Although there is much evidence suggesting that SNARE proteins play a key role in the fusion machinery, other cellular elements regulating the kinetics, the extent of fusion, and the preparation of vesicle for release have received less attention. Among those factors, lipids have also been proposed to play important functions both at the level of secretory vesicle recruitment and late membrane fusion steps. Here, we will review the latest evidence supporting the concept of the fusogenic activity of lipids, and also discuss how this may be achieved. These possibilities include the recruitment and sequestration of the components of the exocytotic machinery, regulation of protein function, and direct effects on membrane topology. PMID- 24062729 TI - Comparative genomics of freshwater Fe-oxidizing bacteria: implications for physiology, ecology, and systematics. AB - The two microaerophilic, Fe-oxidizing bacteria (FeOB) Sideroxydans ES-1 and Gallionella ES-2 have single circular chromosomes of 3.00 and 3.16 Mb that encode 3049 and 3006 genes, respectively. Multi-locus sequence analysis (MLSA) confirmed the relationship of these two organisms to one another, and indicated they may form a novel order, the Gallionellalaes, within the Betaproteobacteria. Both are adapted for chemolithoautotropy, including pathways for CO2-fixation, and electron transport pathways adapted for growth at low O2-levels, an important adaptation for growing on Fe(II). Both genomes contain Mto-genes implicated in iron-oxidation, as well as other genes that could be involved in Fe-oxidation. Nearly 10% of their genomes are devoted to environmental sensing, signal transduction, and chemotaxis, consistent with their requirement for growing in narrow redox gradients of Fe(II) and O2. There are important differences as well. Sideroxydans ES-1 is more metabolically flexible, and can utilize reduced S compounds, including thiosulfate, for lithotrophic growth. It has a suite of genes for nitrogen fixation. Gallionella ES-2 contains additional gene clusters for exopolysaccharide production, and has more capacity to resist heavy metals. Both strains contain genes for hemerythrins and globins, but ES-1 has an especially high numbers of these genes that may be involved in oxygen homeostasis, or storage. The two strains share homology with the marine FeOB Mariprofundus ferrooxydans PV-1 in CO2 fixation genes, and respiratory genes. In addition, ES-1 shares a suite of 20 potentially redox active genes with PV-1, as well as a large prophage. Combined these genetic, morphological, and physiological differences indicate that these are two novel species, Sideroxydans lithotrophicus ES-1(T) (ATCC 700298(T); JCM 14762; DSMZ 22444; NCMA B100), and Gallionella capsiferriformans ES-2(T) (ATCC 700299(T); JCM 14763; DSMZ 22445; NCMA B101). PMID- 24062730 TI - Relevance of GC content to the conservation of DNA polymerase III/mismatch repair system in Gram-positive bacteria. AB - The mechanism of DNA replication is one of the driving forces of genome evolution. Bacterial DNA polymerase III, the primary complex of DNA replication, consists of PolC and DnaE. PolC is conserved in Gram-positive bacteria, especially in the Firmicutes with low GC content, whereas DnaE is widely conserved in most Gram-negative and Gram-positive bacteria. PolC contains two domains, the 3'-5'exonuclease domain and the polymerase domain, while DnaE only possesses the polymerase domain. Accordingly, DnaE does not have the proofreading function; in Escherichia coli, another enzyme DnaQ performs this function. In most bacteria, the fidelity of DNA replication is maintained by 3'-5' exonuclease and a mismatch repair (MMR) system. However, we found that most Actinobacteria (a group of Gram-positive bacteria with high GC content) appear to have lost the MMR system and chromosomes may be replicated by DnaE-type DNA polymerase III with DnaQ-like 3'-5' exonuclease. We tested the mutation bias of Bacillus subtilis, which belongs to the Firmicutes and found that the wild type strain is AT-biased while the mutS-deletant strain is remarkably GC-biased. If we presume that DnaE tends to make mistakes that increase GC content, these results can be explained by the mutS deletion (i.e., deletion of the MMR system). Thus, we propose that GC content is regulated by DNA polymerase and MMR system, and the absence of polC genes, which participate in the MMR system, may be the reason for the increase of GC content in Gram-positive bacteria such as Actinobacteria. PMID- 24062731 TI - Yellowstone lake nanoarchaeota. AB - Considerable Nanoarchaeota novelty and diversity were encountered in Yellowstone Lake, Yellowstone National Park (YNP), where sampling targeted lake floor hydrothermal vent fluids, streamers and sediments associated with these vents, and in planktonic photic zones in three different regions of the lake. Significant homonucleotide repeats (HR) were observed in pyrosequence reads and in near full-length Sanger sequences, averaging 112 HR per 1349 bp clone and could confound diversity estimates derived from pyrosequencing, resulting in false nucleotide insertions or deletions (indels). However, Sanger sequencing of two different sets of PCR clones (110 bp, 1349 bp) demonstrated that at least some of these indels are real. The majority of the Nanoarchaeota PCR amplicons were vent associated; however, curiously, one relatively small Nanoarchaeota OTU (71 pyrosequencing reads) was only found in photic zone water samples obtained from a region of the lake furthest removed from the hydrothermal regions of the lake. Extensive pyrosequencing failed to demonstrate the presence of an Ignicoccus lineage in this lake, suggesting the Nanoarchaeota in this environment are associated with novel Archaea hosts. Defined phylogroups based on near full length PCR clones document the significant Nanoarchaeota 16S rRNA gene diversity in this lake and firmly establish a terrestrial clade distinct from the marine Nanoarcheota as well as from other geographical locations. PMID- 24062728 TI - Afferent neuronal control of type-I gonadotropin releasing hormone neurons in the human. AB - Understanding the regulation of the human menstrual cycle represents an important ultimate challenge of reproductive neuroendocrine research. However, direct translation of information from laboratory animal experiments to the human is often complicated by strikingly different and unique reproductive strategies and central regulatory mechanisms that can be present in even closely related animal species. In all mammals studied so far, type-I gonadotropin releasing hormone (GnRH) synthesizing neurons form the final common output way from the hypothalamus in the neuroendocrine control of the adenohypophysis. Under various physiological and pathological conditions, hormonal and metabolic signals either regulate GnRH neurons directly or act on upstream neuronal circuitries to influence the pattern of pulsatile GnRH secretion into the hypophysial portal circulation. Neuronal afferents to GnRH cells convey important metabolic-, stress , sex steroid-, lactational-, and circadian signals to the reproductive axis, among other effects. This article gives an overview of the available neuroanatomical literature that described the afferent regulation of human GnRH neurons by peptidergic, monoaminergic, and amino acidergic neuronal systems. Recent studies of human genetics provided evidence that central peptidergic signaling by kisspeptins and neurokinin B (NKB) play particularly important roles in puberty onset and later, in the sex steroid-dependent feedback regulation of GnRH neurons. This review article places special emphasis on the topographic distribution, sexual dimorphism, aging-dependent neuroanatomical changes, and plastic connectivity to GnRH neurons of the critically important human hypothalamic kisspeptin and NKB systems. PMID- 24062732 TI - The need to accessorize: molecular roles of HTLV-1 p30 and HTLV-2 p28 accessory proteins in the viral life cycle. AB - Extensive studies of human T-cell leukemia virus (HTLV)-1 and HTLV-2 over the last three decades have provided detailed knowledge on viral transformation, host viral interactions and pathogenesis. HTLV-1 is the etiological agent of adult T cell leukemia and multiple neurodegenerative and inflammatory diseases while HTLV 2 disease association remains elusive, with few infected individuals displaying neurodegenerative diseases similar to HTLV-1. The HTLV group of oncoretroviruses has a genome that encodes structural and enzymatic proteins Gag, Pro, and Env, regulatory proteins Tax and Rex, and several accessory proteins from the pX region. Of these proteins, HTLV-1 p30 and HTLV-2 p28 are encoded by the open reading frame II of the pX region. Like most other accessory proteins, p30 and p28 are dispensable for in vitro viral replication and transformation but are required for efficient viral replication and persistence in vivo. Both p30 and p28 regulate viral gene expression at the post-transcriptional level whereas p30 can also function at the transcriptional level. Recently, several reports have implicated p30 and p28 in multiple cellular processes, which provide novel insight into HTLV spread and survival and ultimately pathogenesis. In this review we summarize and compare what is known about p30 and p28, highlighting their roles in viral replication and viral pathogenesis. PMID- 24062733 TI - Cytokine production and signaling pathways in respiratory virus infection. AB - It has been confirmed that respiratory virus infections can induce abberant cytokine production in the host. These cytokines may be associated with both elimination of the virus and complications in the host, such as virus-induced asthma. Representative host defense mechanisms against pathogens, including bacteria and viruses, are mediated by the innate immune system. Cells of the innate immune system express essential molecules, namely pattern recognition receptors (PRRs), such as Toll-like receptors, nucleotide-binding oligomerization domain-like receptors, and retinoic acid-inducible gene-I-like receptors. These PRRs can recognize components of pathogens such as bacterial lipopolysaccharide, viral antigens, and their genomes (DNA and RNA). Furthermore, PRRs activate various signaling pathways resulting in cytokine production against pathogen infection. However, the exact mechanisms remain unknown. In this review, we mainly focus on the representative mechanisms of cytokine production through PRRs and signaling pathways due to virus infections, including respiratory virus infections. In addition, we describe the relationships between respiratory infections and virus-induced asthma. PMID- 24062734 TI - Energy-mediated vs. ammonium-regulated gene expression in the obligate ammonia oxidizing bacterium, Nitrosococcus oceani. AB - Ammonia serves as the source of energy and reductant and as a signaling molecule that regulates gene expression in obligate ammonia-oxidizing chemolithotrophic microorganisms. The gammaproteobacterium, Nitrosococcus oceani, was the first obligate ammonia-oxidizer isolated from seawater and is one of the model systems for ammonia chemolithotrophy. We compared global transcriptional responses to ammonium and the catabolic intermediate, hydroxylamine, in ammonium-starved and non-starved cultures of N. oceani to discriminate transcriptional effects of ammonium from a change in overall energy and redox status upon catabolite availability. The most highly expressed genes from ammonium- or hydroxylamine treated relative to starved cells are implicated in catabolic electron flow, carbon fixation, nitrogen assimilation, ribosome structure and stress tolerance. Catabolic inventory-encoding genes, including electron flow-terminating Complexes IV, FoF1 ATPase, transporters, and transcriptional regulators were among the most highly expressed genes in cells exposed only to ammonium relative to starved cells, although the differences compared to steady-state transcript levels were less pronounced. Reduction in steady-state mRNA levels from hydroxylamine-treated relative to starved-cells were less than five-fold. In contrast, several transcripts from ammonium-treated relative to starved cells were significantly less abundant including those for forward Complex I and a gene cluster of cytochrome c encoding proteins. Identified uneven steady-state transcript levels of co-expressed clustered genes support previously reported differential regulation at the levels of transcription and transcript stability. Our results differentiated between rapid regulation of core genes upon a change in cellular redox status vs. those responsive to ammonium as a signaling molecule in N. oceani, both confirming and extending our knowledge of metabolic modules involved in ammonia chemolithotrophy. PMID- 24062736 TI - Functional genes to assess nitrogen cycling and aromatic hydrocarbon degradation: primers and processing matter. AB - Targeting sequencing to genes involved in key environmental processes, i.e., ecofunctional genes, provides an opportunity to sample nature's gene guilds to greater depth and help link community structure to process-level outcomes. Vastly different approaches have been implemented for sequence processing and, ultimately, for taxonomic placement of these gene reads. The overall quality of next generation sequence analysis of functional genes is dependent on multiple steps and assumptions of unknown diversity. To illustrate current issues surrounding amplicon read processing we provide examples for three ecofunctional gene groups. A combination of in silico, environmental and cultured strain sequences was used to test new primers targeting the dioxin and dibenzofuran degrading genes dxnA1, dbfA1, and carAa. The majority of obtained environmental sequences were classified into novel sequence clusters, illustrating the discovery value of the approach. For the nitrite reductase step in denitrification, the well-known nirK primers exhibited deficiencies in reference database coverage, illustrating the need to refine primer-binding sites and/or to design multiple primers, while nirS primers exhibited bias against five phyla. Amino acid-based OTU clustering of these two N-cycle genes from soil samples yielded only 114 unique nirK and 45 unique nirS genus-level groupings, likely a reflection of constricted primer coverage. Finally, supervised and non-supervised OTU analysis methods were compared using the nifH gene of nitrogen fixation, with generally similar outcomes, but the clustering (non-supervised) method yielded higher diversity estimates and stronger site-based differences. High throughput amplicon sequencing can provide inexpensive and rapid access to nature's related sequences by circumventing the culturing barrier, but each unique gene requires individual considerations in terms of primer design and sequence processing and classification. PMID- 24062735 TI - Molecular epidemiology of respiratory viruses in virus-induced asthma. AB - Acute respiratory illness (ARI) due to various viruses is not only the most common cause of upper respiratory infection in humans but is also a major cause of morbidity and mortality, leading to diseases such as bronchiolitis and pneumonia. Previous studies have shown that respiratory syncytial virus (RSV), human rhinovirus (HRV), human metapneumovirus (HMPV), human parainfluenza virus (HPIV), and human enterovirus infections may be associated with virus-induced asthma. For example, it has been suggested that HRV infection is detected in the acute exacerbation of asthma and infection is prolonged. Thus it is believed that the main etiological cause of asthma is ARI viruses. Furthermore, the number of asthma patients in most industrial countries has greatly increased, resulting in a morbidity rate of around 10-15% of the population. However, the relationships between viral infections, host immune response, and host factors in the pathophysiology of asthma remain unclear. To gain a better understanding of the epidemiology of virus-induced asthma, it is important to assess both the characteristics of the viruses and the host defense mechanisms. Molecular epidemiology enables us to understand the pathogenesis of microorganisms by identifying specific pathways, molecules, and genes that influence the risk of developing a disease. However, the epidemiology of various respiratory viruses associated with virus-induced asthma is not fully understood. Therefore, in this article, we review molecular epidemiological studies of RSV, HRV, HPIV, and HMPV infection associated with virus-induced asthma. PMID- 24062737 TI - The application of next generation sequencing to the understanding of antibody repertoires. AB - In the decade since the human genome sequence was declared complete, the development of next generation sequencing (NGS) or "deep" sequencing to deliver cost-effective genomic sequencing has influenced advances beyond its primary application and changed the research landscape in many other areas. This review will survey recent applications of NGS which have broadened the understanding of natural antibody repertoires (the "antibodyome") and how these evolve in response to viral infection. We will also report examples where deep sequencing of binding populations, derived from both natural and synthetic repertoires, have been used to benefit antibody engineering. This knowledge will ultimately lead to the design of more effective biological drugs and vaccines. PMID- 24062738 TI - Structure-Based, Rational Design of T Cell Receptors. AB - Adoptive cell transfer using engineered T cells is emerging as a promising treatment for metastatic melanoma. Such an approach allows one to introduce T cell receptor (TCR) modifications that, while maintaining the specificity for the targeted antigen, can enhance the binding and kinetic parameters for the interaction with peptides (p) bound to major histocompatibility complexes (MHC). Using the well-characterized 2C TCR/SIYR/H-2K(b) structure as a model system, we demonstrated that a binding free energy decomposition based on the MM-GBSA approach provides a detailed and reliable description of the TCR/pMHC interactions at the structural and thermodynamic levels. Starting from this result, we developed a new structure-based approach, to rationally design new TCR sequences, and applied it to the BC1 TCR targeting the HLA-A2 restricted NY-ESO 1157-165 cancer-testis epitope. Fifty-four percent of the designed sequence replacements exhibited improved pMHC binding as compared to the native TCR, with up to 150-fold increase in affinity, while preserving specificity. Genetically engineered CD8(+) T cells expressing these modified TCRs showed an improved functional activity compared to those expressing BC1 TCR. We measured maximum levels of activities for TCRs within the upper limit of natural affinity, K D = ~1 - 5 MUM. Beyond the affinity threshold at K D < 1 MUM we observed an attenuation in cellular function, in line with the "half-life" model of T cell activation. Our computer-aided protein-engineering approach requires the 3D structure of the TCR-pMHC complex of interest, which can be obtained from X-ray crystallography. We have also developed a homology modeling-based approach, TCRep 3D, to obtain accurate structural models of any TCR-pMHC complexes when experimental data is not available. Since the accuracy of the models depends on the prediction of the TCR orientation over pMHC, we have complemented the approach with a simplified rigid method to predict this orientation and successfully assessed it using all non-redundant TCR-pMHC crystal structures available. These methods potentially extend the use of our TCR engineering method to entire TCR repertoires for which no X-ray structure is available. We have also performed a steered molecular dynamics study of the unbinding of the TCR-pMHC complex to get a better understanding of how TCRs interact with pMHCs. This entire rational TCR design pipeline is now being used to produce rationally optimized TCRs for adoptive cell therapies of stage IV melanoma. PMID- 24062739 TI - Human T cell aging and the impact of persistent viral infections. AB - Aging is associated with a dysregulation of the immune response, loosely termed "immunosenescence." Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected and among all participating cells it is the T cells that are most altered. There is a large body of experimental work devoted to the investigation of age associated differences in T cell phenotypes and functions in young and old individuals, but few longitudinal studies in humans actually delineating changes at the level of the individual. In most studies, the number and proportion of late-differentiated T cells, especially CD8+ T cells, is reported to be higher in the elderly than in the young. Limited longitudinal studies suggest that accumulation of these cells is a dynamic process and does indeed represent an age associated change. Accumulations of such late-stage cells may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in older people. We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. A favored hypothesis is that these events are at least partly due to the effects of the maintenance of essential immune surveillance against persistent viral infections, notably Cytomegalovirus (CMV), which may exhaust the immune system over time. It is still a matter of debate as to whether these changes are compensatory and beneficial or pathological and detrimental to the proper functioning of the immune system and whether they impact longevity. Here, we will review present knowledge of T cell changes with aging and their relation to chronic viral and possibly other persistent infections. PMID- 24062741 TI - Immunological Monitoring to Rationally Guide AAV Gene Therapy. AB - Recent successes with adeno-associated virus (AAV)-based gene therapies fuel the hope for new treatments for hereditary diseases. Pre-existing as well as therapy induced immune responses against both AAV and the encoded transgenes have been described and may impact on safety and efficacy of gene therapy approaches. Consequently, monitoring of vector- and transgene-specific immunity is mandated and may rationally guide clinical development. Next to the humoral immune response, the cellular response is central in our understanding of the host reaction in gene therapy. But in contrast to the monitoring of antibodies, which has matured over many decades, sensitive and robust monitoring of T cells is a relatively new development. To make cellular immune assessments fit for purpose, investigators need to know, control and report the critical assay variables that influence the results. In addition, the quality of immune assays needs to be continuously adjusted to allow for exploratory hypothesis generation in early stages and confirmatory hypothesis validation in later stages of clinical development. The concept of immune assay harmonization which includes use of field-wide benchmarks, harmonization guidelines, and external quality control can support the context-specific evolution of immune assays. Multi-center studies pose particular challenges to sample logistics and quality control of sample specimens. Cooperative groups need to define if immune assessments should be performed in one central facility, in peripheral labs or including a combination of both. Finally, engineered reference samples that contain a defined number of antigen-specific T cells may become broadly applicable tools to control assay performance over time or across institutions. PMID- 24062740 TI - Hypoxia and Integrin-Mediated Epithelial Restitution during Mucosal Inflammation. AB - Epithelial damage and loss of intestinal barrier function are hallmark pathologies of the mucosal inflammation associated with conditions such as inflammatory bowel disease. In order to resolve inflammation and restore intestinal integrity the mucosa must rapidly and effectively repair the epithelial barrier. Epithelial wound healing is a highly complex and co-ordinated process and the factors involved in initiating intestinal epithelial healing are poorly defined. In order for restitution to be successful there must be a balance between epithelial cell migration, proliferation, and differentiation within and adjacent to the inflamed area. Endogenous, compensatory epithelial signaling pathways are activated by the changes in oxygen tensions that accompany inflammation. These signaling pathways induce the activation of key transcription factors, governing anti-apoptotic, and proliferative processes resulting in epithelial cell survival, proliferation, and differentiation at the site of mucosal inflammation. In this review, we will discuss the primary processes involved in epithelial restitution with a focus on the role of hypoxia-inducible factor and epithelial integrins as mediators of epithelial repair following inflammatory injury at the mucosal surface. PMID- 24062742 TI - Multi Step Selection in Ig H Chains is Initially Focused on CDR3 and Then on Other CDR Regions. AB - AFFINITY MATURATION OCCURS THROUGH TWO SELECTION PROCESSES: the choice of appropriate clones (clonal selection), and the internal evolution within clones, induced by somatic hyper-mutations, where high affinity mutants are selected for. When a final population of immunoglobulin sequences is observed, the genetic composition of this population is affected by a combination of these two processes. Different immune induced diseases can result from the failure of regulation of clonal selection or of the regulation of the within clone affinity maturation. In order to understand each of these processes separately, we propose a mixed lineage tree/sequence based method to detect within clone selection as defined by the effect of mutations on the average number of offspring. Specifically, we measure the imbalance in the number of leaves in lineage trees branches following synonymous and non-synonymous (NS) mutations. If a mutation is positively selected, we expect the number of leaves in the sub-tree below this mutation to be larger than in the parallel sub-tree without the mutation. The ratio between the number of leaves in such branches following NS mutations can be used to measure selection within a clone. We apply this method to the sampled Ig repertoire from multiple healthy volunteers and show that within clone selection is positive in the CDR2 region and either positive or negative in the CDR3 and FWR3 regions. Selection occurs already at the IgM isotype level mainly in the DH gene region, with a strong negative selection in the join region. This is followed in the later memory stages in the CDR2 region. We have not studied here the FWR1 and CDR1 regions. An important advantage of this method is that it is very weakly affected by the baseline mutation model or by sampling biases, as are most synonymous to NS mutations ratio based methods. PMID- 24062743 TI - Pyrin- and CARD-only Proteins as Regulators of NLR Functions. AB - Upon activation Nod-like receptors (NLRs) assemble into multi-protein complexes such as the NODosome and inflammasome. This process relies upon homo domain interactions between the structurally related Pyrin and caspase-recruitment (CARD) domains and adaptor proteins, such as ASC, or effector proteins, such as caspase-1. Although a variety of NLRP and NLRC complexes have been described along with their activating stimuli and associated proteins, less familiar are processes limiting assembly and/or promoting dissociation of NLR complexes. Given the importance of limiting harmful, chronic inflammation, such regulatory mechanisms are significant and likely numerous. Proteins comprised of a solitary Pyrin domain (Pyrin-only) or CARD domain (CARD-only) posses an obvious potential ability to act as competitive inhibitors of NLR complexes. Indeed, both Pyrin only proteins (POPs) and CARD-only proteins (COPs) have been described as regulators of caspase-1 and/or NLR-inflammasome activation and not surprisingly as factors mediating pathogenesis. Although clear examples of pathogen encoded POPs are currently limited to members of the poxviridae, the human genome likely encodes three POPs (POP1, POP2, and a potential POP3), of which only POP2 is known to prevent NLR:ASC interaction, and three COPs (COP/Pseudo-ICE, INCA, and ICEBERG), initially described for their ability to inhibit caspase-1 activity. Surprisingly, among eukaryotic species POPs and COPs appear to be evolutionarily recent and restricted to higher primates, suggesting strong selective pressures driving their emergence. Despite the importance of understanding the regulation of NLR functions, relatively little attention has been devoted to revealing the biological impact of these intriguing proteins. This review highlights the current state of our understanding of POPs and COPs with attention to protein interaction, functions, evolution, implications for health and disease, and outstanding questions. PMID- 24062744 TI - Monitoring of pathogen-specific T-cell immune reconstitution after allogeneic hematopoietic stem cell transplantation. AB - The clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT) has been significantly improved during the last decades with regard to the reduction in organ failure, infection, and severe acute graft-versus-host disease. However, severe complications due to infectious diseases are still one of the major causes of morbidity and mortality after allogeneic HSCT, in particular in patients receiving haploidentical HSCT or cord blood transplant due to a slow and often incomplete immune reconstitution. In order to improve the immune control of pathogens without an increased risk of alloreactivity, adoptive immunotherapy using highly enriched pathogen-specific T cells offers a promising approach. In order to identify patients who are at high risk for infectious diseases, several monitoring assays have been developed with potential for the guidance of immunosuppressive drugs and adoptive immunotherapy in clinical practice. In this article, we aim to give a comprehensive overview regarding current developments of T-cell monitoring techniques focusing on T cells against viruses and fungi. In particular, we will focus on rather simple, fast, non-labor intensive, cellular assays which could be integrated in routine clinical screening approaches. PMID- 24062745 TI - Development of novel arginase inhibitors for therapy of endothelial dysfunction. AB - Endothelial dysfunction and resulting vascular pathology have been identified as an early hallmark of multiple diseases, including diabetes mellitus. One of the major contributors to endothelial dysfunction is a decrease in nitric oxide (NO) bioavailability, impaired NO signaling, and an increase in the amount of reactive oxygen species (ROS). In the endothelium NO is produced by endothelial nitric oxide synthase (eNOS), for which l-arginine is a substrate. Arginase, an enzyme critical in the urea cycle also metabolizes l-arginine, thereby directly competing with eNOS for their common substrate and constraining its bioavailability for eNOS, thereby compromising NO production. Arginase expression and activity is upregulated in many cardiovascular diseases including ischemia reperfusion injury, hypertension, atherosclerosis, and diabetes mellitus. More importantly, since the 1990s, specific arginase inhibitors such as N-hydroxy guanidinium or N-hydroxy-nor-l-arginine, and boronic acid derivatives, such as, 2(S)-amino-6-boronohexanoic acid, and S-(2-boronoethyl)-l-cysteine, that can bridge the binuclear manganese cluster of arginase have been developed. These highly potent and specific inhibitors can now be used to probe arginase function and thereby modulate the redox milieu of the cell by changing the balance between NO and ROS. Inspired by this success, drug discovery programs have recently led to the identification of alpha-alpha-disubstituted amino acid based arginase inhibitors [such as (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid], that are currently under early investigation as therapeutics. Finally, some investigators concentrate on identification of plant derived compounds with arginase inhibitory capability, such as piceatannol-3'-O-beta-d-glucopyranoside (PG). All of these synthesized or naturally derived small molecules may represent novel therapeutics for vascular disease particularly that associated with diabetes. PMID- 24062747 TI - Aberrant Type I Interferon Regulation in Autoimmunity: Opposite Directions in MS and SLE, Shaped by Evolution and Body Ecology. AB - Studying the action of mechanisms of type I interferon (IFN) provides the insight to elucidate the cause and therapy for autoimmune diseases. There are high IFN responses in some diseases such as connective tissue diseases, but low responses in multiple sclerosis. Distinct IFN features lead us to understand pathology of a spectrum of autoimmune diseases and help us to search genetic changes, gene expression, and biomarkers for diagnosis, disease progression, and treatment response. PMID- 24062746 TI - Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics. AB - The gut mucosa is constantly challenged by a bombardment of foreign antigens and environmental microorganisms. As such, the precise regulation of the intestinal barrier allows the maintenance of mucosal immune homeostasis and prevents the onset of uncontrolled inflammation. In support of this concept, emerging evidence points to defects in components of the epithelial barrier as etiologic factors in the pathogenesis of inflammatory bowel diseases (IBDs). In fact, the integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, epithelial cell integrity, as well as the production of mucus. The purpose of this review is to systematically evaluate how alterations in the aforementioned epithelial components can lead to the disruption of intestinal immune homeostasis, and subsequent inflammation. In this regard, the wealth of data from mouse models of intestinal inflammation and human genetics are pivotal in understanding pathogenic pathways, for example, that are initiated from the specific loss of function of a single protein leading to the onset of intestinal disease. On the other hand, several recently proposed therapeutic approaches to treat human IBD are targeted at enhancing different elements of gut barrier function, further supporting a primary role of the epithelium in the pathogenesis of chronic intestinal inflammation and emphasizing the importance of maintaining a healthy and effective intestinal barrier. PMID- 24062748 TI - Bacterium-like particles for efficient immune stimulation of existing vaccines and new subunit vaccines in mucosal applications. AB - The successful development of a mucosal vaccine depends critically on the use of a safe and effective immunostimulant and/or carrier system. This review describes the effectiveness and mode of action of an immunostimulating particle, derived from bacteria, used in mucosal subunit vaccines. The non-living particles, designated bacterium-like particles are based on the food-grade bacterium Lactococcus lactis. The focus of the overview is on the development of intranasal BLP-based vaccines to prevent diseases caused by influenza and respiratory syncytial virus, and includes a selection of Phase I clinical data for the intranasal FluGEM vaccine. PMID- 24062749 TI - Tissue competence imprinting and tissue residency of CD8 T cells. AB - T cell immunity is characterized by striking tissue specialization. Tissue specificity imprinting starts during priming by tissue-derived migratory dendritic cells in the non-random, specialized micro-anatomical area of the draining lymph node and is influenced by constitutive and induced cues from local environment. Besides tissue-specific effectors, memory cells also exhibit a tissue-specificity. Long-lived tissue-resident memory T cells likely play a considerable role in preventing pathogen invasion. Understanding of the mechanisms of tissue specialization of T cells is of major importance for the design of optimal vaccination strategies and therapeutic interventions in tissue/organ-specific inflammatory diseases. The present review summarizes our current knowledge and hypothesis about tissue-specificity imprinting and tissue residency of T cells. PMID- 24062750 TI - Unsolved Mysteries in NLR Biology. AB - NOD-like receptors (NLRs) are a class of cytoplasmic pattern-recognition receptors. Although most NLRs play some role in immunity, their functions range from regulating antigen presentation (NLRC5, CIITA) to pathogen/damage sensing (NLRP1, NLRP3, NLRC1/2, NLRC4) to suppression or modulation of inflammation (NLRC3, NLRP6, NLRP12, NLRX1). However, NLRP2, NLRP5, and NLRP7 are also involved in non-immune pathways such as embryonic development. In this review, we highlight some of the least well-understood aspects of NLRs, including the mechanisms by which they sense pathogens or damage. NLRP3 recognizes a diverse range of stimuli and numerous publications have presented potential unifying models for NLRP3 activation, but no single mechanism proposed thus far appears to account for all possible NLRP3 activators. Additionally, NLRC3, NLRP6, and NLRP12 inhibit NF-kappaB activation, but whether direct ligand sensing is a requirement for this function is not known. Herein, we review the various mechanisms of sensing and activation proposed for NLRP3 and other inflammasome activators. We also discuss the role of NLRC3, NLRP6, NLRP12, and NLRX1 as inhibitors and how they are activated and function in their roles to limit inflammation. Finally, we present an overview of the emerging roles that NLRP2, NLRP5, and NLRP7 play during embryonic development and postulate on the potential pathways involved. PMID- 24062751 TI - Lights, camera, and action: vertebrate skin sets the stage for immune cell interaction with arthropod-vectored pathogens. AB - Despite increasing studies targeted at host-pathogen interactions, vector-borne diseases remain one of the largest economic health burdens worldwide. Such diseases are vectored by hematophagous arthropods that deposit pathogens into the vertebrate host's skin during a blood meal. These pathogens spend a substantial amount of time in the skin that allows for interaction with cutaneous immune cells, suggesting a window of opportunity for development of vaccine strategies. In particular, the recent availability of intravital imaging approaches has provided further insights into immune cell behavior in living tissues. Here, we discuss how such intravital imaging studies have contributed to our knowledge of cutaneous immune cell behavior and specifically, toward pathogen and tissue trauma from the arthropod bite. We also suggest future imaging approaches that may aid in better understanding of the complex interplay between arthropod vectored pathogens and cutaneous immunity that could lead to improved therapeutic strategies. PMID- 24062752 TI - Interferons in Sjogren's Syndrome: Genes, Mechanisms, and Effects. AB - Sjogren's syndrome (SS) is a common, progressive autoimmune exocrinopathy distinguished by dry eyes and mouth and affects ~0.7% of the European population. Overexpression of transcripts induced by interferons (IFN), termed as an "IFN signature," has been found in SS patients. Four microarray studies have been published in SS that identified dysregulated genes within type I IFN signaling in either salivary glands or peripheral blood of SS patients. The mechanism of this type I IFN activation is still obscure, but several possible explanations have been proposed, including virus infection-initiated and immune complex-initiated type I IFN production by plasmacytoid dendritic cells. Genetic predisposition to increased type I IFN signaling is supported by candidate gene studies showing evidence for association of variants within IFN-related genes. Once activated, IFN signaling may contribute to numerous aspects of SS pathophysiology, including lymphocyte infiltration into exocrine glands, autoantibody production, and glandular cell apoptosis. Thus, dysregulation of IFN pathways is an important feature that can be potentially used as a serum biomarker for diagnosis and targeting of new treatments in this complex autoimmune disease. PMID- 24062753 TI - Photosynthetic acclimation responses of maize seedlings grown under artificial laboratory light gradients mimicking natural canopy conditions. AB - In this study we assessed the ability of the C4 plant maize to perform long-term photosynthetic acclimation in an artificial light quality system previously used for analyzing short-term and long-term acclimation responses (LTR) in C3 plants. We aimed to test if this light system could be used as a tool for analyzing redox regulated acclimation processes in maize seedlings. Photosynthetic parameters obtained from maize samples harvested in the field were used as control. The results indicated that field grown maize performed a pronounced LTR with significant differences between the top and the bottom levels of the plant stand corresponding to the strong light gradients occurring in it. We compared these data to results obtained from maize seedlings grown under artificial light sources preferentially exciting either photosystem II or photosystem I. In C3 plants, this light system induces redox signals within the photosynthetic electron transport chain which trigger state transitions and differential phosphorylation of LHCII (light harvesting complexes of photosystem II). The LTR to these redox signals induces changes in the accumulation of plastid psaA transcripts, in chlorophyll (Chl) fluorescence values F ?rm s/F ?rm m, in Chl a/b ratios and in transient starch accumulation in C3 plants. Maize seedlings grown in this light system exhibited a pronounced ability to perform both short-term and long-term acclimation at the level of psaA transcripts, Chl fluorescence values F ?rm s/F ?rm m and Chl a/b ratios. Interestingly, maize seedlings did not exhibit redox-controlled variations of starch accumulation probably because of its specific differences in energy metabolism. In summary, the artificial laboratory light system was found to be well-suited to mimic field light conditions and provides a physiological tool for studying the molecular regulation of the LTR of maize in more detail. PMID- 24062754 TI - Nitric oxide-sphingolipid interplays in plant signalling: a new enigma from the Sphinx? AB - Nitric oxide (NO) emerged as one of the major signaling molecules operating during plant development and plant responses to its environment. Beyond the identification of the direct molecular targets of NO, a series of studies considered its interplay with other actors of signal transduction and the integration of NO into complex signaling networks. Beside the close relationships between NO and calcium or phosphatidic acid signaling pathways that are now well established, recent reports paved the way for interplays between NO and sphingolipids (SLs). This mini-review summarizes our current knowledge of the influence NO and SLs might exert on each other in plant physiology. Based on comparisons with examples from the animal field, it further indicates that, although SL-NO interplays are common features in signaling networks of eukaryotic cells, the underlying mechanisms and molecular targets significantly differ. PMID- 24062755 TI - Integration of root phenes for soil resource acquisition. AB - Suboptimal availability of water and nutrients is a primary limitation to plant growth in terrestrial ecosystems. The acquisition of soil resources by plant roots is therefore an important component of plant fitness and agricultural productivity. Plant root systems comprise a set of phenes, or traits, that interact. Phenes are the units of the plant phenotype, and phene states represent the variation in form and function a particular phene may take. Root phenes can be classified as affecting resource acquisition or utilization, influencing acquisition through exploration or exploitation, and in being metabolically influential or neutral. These classifications determine how one phene will interact with another phene, whether through foraging mechanisms or metabolic economics. Phenes that influence one another through foraging mechanisms are likely to operate within a phene module, a group of interacting phenes, that may be co-selected. Examples of root phene interactions discussed are: (1) root hair length * root hair density, (2) lateral branching * root cortical aerenchyma (RCA), (3) adventitious root number * adventitious root respiration and basal root growth angle (BRGA), (4) nodal root number * RCA, and (5) BRGA * root hair length and density. Progress in the study of phenes and phene interactions will be facilitated by employing simulation modeling and near-isophenic lines that allow the study of specific phenes and phene combinations within a common phenotypic background. Developing a robust understanding of the phenome at the organismal level will require new lines of inquiry into how phenotypic integration influences plant function in diverse environments. A better understanding of how root phenes interact to affect soil resource acquisition will be an important tool in the breeding of crops with superior stress tolerance and reduced dependence on intensive use of inputs. PMID- 24062757 TI - Assessing duplication and loss of APETALA1/FRUITFULL homologs in Ranunculales. AB - Gene duplication and loss provide raw material for evolutionary change within organismal lineages as functional diversification of gene copies provide a mechanism for phenotypic variation. Here we focus on the APETALA1/FRUITFULL MADS box gene lineage evolution. AP1/FUL genes are angiosperm-specific and have undergone several duplications. By far the most significant one is the core eudicot duplication resulting in the euAP1 and euFUL clades. Functional characterization of several euAP1 and euFUL genes has shown that both function in proper floral meristem identity, and axillary meristem repression. Independently, euAP1 genes function in floral meristem and sepal identity, whereas euFUL genes control phase transition, cauline leaf growth, compound leaf morphogenesis and fruit development. Significant functional variation has been detected in the function of pre-duplication basal-eudicot FUL-like genes, but the underlying mechanisms for change have not been identified. FUL-like genes in the Papaveraceae encode all functions reported for euAP1 and euFUL genes, whereas FUL like genes in Aquilegia (Ranunculaceae) function in inflorescence development and leaf complexity, but not in flower or fruit development. Here we isolated FUL like genes across the Ranunculales and used phylogenetic approaches to analyze their evolutionary history. We identified an early duplication resulting in the RanFL1 and RanFL2 clades. RanFL1 genes were present in all the families sampled and are mostly under strong negative selection in the MADS, I and K domains. RanFL2 genes were only identified from Eupteleaceae, Papaveraceae s.l., Menispermaceae and Ranunculaceae and show relaxed purifying selection at the I and K domains. We discuss how asymmetric sequence diversification, new motifs, differences in codon substitutions and likely protein-protein interactions resulting from this Ranunculiid-specific duplication can help explain the functional differences among basal-eudicot FUL-like genes. PMID- 24062756 TI - Plant growth-promoting rhizobacteria and root system functioning. AB - The rhizosphere supports the development and activity of a huge and diversified microbial community, including microorganisms capable to promote plant growth. Among the latter, plant growth-promoting rhizobacteria (PGPR) colonize roots of monocots and dicots, and enhance plant growth by direct and indirect mechanisms. Modification of root system architecture by PGPR implicates the production of phytohormones and other signals that lead, mostly, to enhanced lateral root branching and development of root hairs. PGPR also modify root functioning, improve plant nutrition and influence the physiology of the whole plant. Recent results provided first clues as to how PGPR signals could trigger these plant responses. Whether local and/or systemic, the plant molecular pathways involved remain often unknown. From an ecological point of view, it emerged that PGPR form coherent functional groups, whose rhizosphere ecology is influenced by a myriad of abiotic and biotic factors in natural and agricultural soils, and these factors can in turn modulate PGPR effects on roots. In this paper, we address novel knowledge and gaps on PGPR modes of action and signals, and highlight recent progress on the links between plant morphological and physiological effects induced by PGPR. We also show the importance of taking into account the size, diversity, and gene expression patterns of PGPR assemblages in the rhizosphere to better understand their impact on plant growth and functioning. Integrating mechanistic and ecological knowledge on PGPR populations in soil will be a prerequisite to develop novel management strategies for sustainable agriculture. PMID- 24062759 TI - Early Cretaceous angiosperms and beetle evolution. AB - The Coleoptera (beetles) constitute almost one-fourth of all known life-forms on earth. They are also among the most important pollinators of flowering plants, especially basal angiosperms. Beetle fossils are abundant, almost spanning the entire Early Cretaceous, and thus provide important clues to explore the co evolutionary processes between beetles and angiosperms. We review the fossil record of some Early Cretaceous polyphagan beetles including Tenebrionoidea, Scarabaeoidea, Curculionoidea, and Chrysomeloidea. Both the fossil record and molecular analyses reveal that these four groups had already diversified during or before the Early Cretaceous, clearly before the initial rise of angiosperms to widespread floristic dominance. These four beetle groups are important pollinators of basal angiosperms today, suggesting that their ecological association with angiosperms probably formed as early as in the Early Cretaceous. With the description of additional well-preserved fossils and improvements in phylogenetic analyses, our knowledge of Mesozoic beetle-angiosperm mutualisms will greatly increase during the near future. PMID- 24062758 TI - Iron: an essential micronutrient for the legume-rhizobium symbiosis. AB - Legumes, which develop a symbiosis with nitrogen-fixing bacteria, have an increased demand for iron. Iron is required for the synthesis of iron-containing proteins in the host, including the highly abundant leghemoglobin, and in bacteroids for nitrogenase and cytochromes of the electron transport chain. Deficiencies in iron can affect initiation and development of the nodule. Within root cells, iron is chelated with organic acids such as citrate and nicotianamine and distributed to other parts of the plant. Transport to the nitrogen-fixing bacteroids in infected cells of nodules is more complicated. Formation of the symbiosis results in bacteroids internalized within root cortical cells of the legume where they are surrounded by a plant-derived membrane termed the symbiosome membrane (SM). This membrane forms an interface that regulates nutrient supply to the bacteroid. Consequently, iron must cross this membrane before being supplied to the bacteroid. Iron is transported across the SM as both ferric and ferrous iron. However, uptake of Fe(II) by both the symbiosome and bacteroid is faster than Fe(III) uptake. Members of more than one protein family may be responsible for Fe(II) transport across the SM. The only Fe(II) transporter in nodules characterized to date is GmDMT1 (Glycine max divalent metal transporter 1), which is located on the SM in soybean. Like the root plasma membrane, the SM has ferric iron reductase activity. The protein responsible has not been identified but is predicted to reduce ferric iron accumulated in the symbiosome space prior to uptake by the bacteroid. With the recent publication of a number of legume genomes including Medicago truncatula and G. max, a large number of additional candidate transport proteins have been identified. Members of the NRAMP (natural resistance-associated macrophage protein), YSL (yellow stripe-like), VIT (vacuolar iron transporter), and ZIP (Zrt-, Irt-like protein) transport families show enhanced expression in nodules and are expected to play a role in the transport of iron and other metals across symbiotic membranes. PMID- 24062760 TI - Facile mutant identification via a single parental backcross method and application of whole genome sequencing based mapping pipelines. AB - Forward genetic screens have identified numerous genes involved in development and metabolism, and remain a cornerstone of biological research. However, to locate a causal mutation, the practice of crossing to a polymorphic background to generate a mapping population can be problematic if the mutant phenotype is difficult to recognize in the hybrid F2 progeny, or dependent on parental specific traits. Here in a screen for leaf hyponasty mutants, we have performed a single backcross of an Ethane Methyl Sulphonate (EMS) generated hyponastic mutant to its parent. Whole genome deep sequencing of a bulked homozygous F2 population and analysis via the Next Generation EMS mutation mapping pipeline (NGM) unambiguously determined the causal mutation to be a single nucleotide polymorphisim (SNP) residing in HASTY, a previously characterized gene involved in microRNA biogenesis. We have evaluated the feasibility of this backcross approach using three additional SNP mapping pipelines; SHOREmap, the GATK pipeline, and the samtools pipeline. Although there was variance in the identification of EMS SNPs, all returned the same outcome in clearly identifying the causal mutation in HASTY. The simplicity of performing a single parental backcross and genome sequencing a small pool of segregating mutants has great promise for identifying mutations that may be difficult to map using conventional approaches. PMID- 24062761 TI - Protein intrinsic disorder in plants. AB - To some extent contradicting the classical paradigm of the relationship between protein 3D structure and function, now it is clear that large portions of the proteomes, especially in higher organisms, lack a fixed structure and still perform very important functions. Proteins completely or partially unstructured in their native (functional) form are involved in key cellular processes underlain by complex networks of protein interactions. The intrinsic conformational flexibility of these disordered proteins allows them to bind multiple partners in transient interactions of high specificity and low affinity. In concordance, in plants this type of proteins has been found in processes requiring these complex and versatile interaction networks. These include transcription factor networks, where disordered proteins act as integrators of different signals or link different transcription factor subnetworks due to their ability to interact (in many cases simultaneously) with different partners. Similarly, they also serve as signal integrators in signaling cascades, such as those related to response to external stimuli. Disordered proteins have also been found in plants in many stress-response processes, acting as protein chaperones or protecting other cellular components and structures. In plants, it is especially important to have complex and versatile networks able to quickly and efficiently respond to changing environmental conditions since these organisms cannot escape and have no other choice than adapting to them. Consequently, protein disorder can play an especially important role in plants, providing them with a fast mechanism to obtain complex, interconnected and versatile molecular networks. PMID- 24062763 TI - Silencing of the sulfur rich alpha-gliadin storage protein family in wheat grains (Triticum aestivum L.) causes no unintended side-effects on other metabolites. AB - Wheat is an important source of proteins and metabolites for human and animal nutrition. To assess the nutritional quality of wheat products, various protein and diverse metabolites have to be evaluated. The grain storage protein family of the alpha-gliadins are suggested to be the primary initiator of the inflammatory response to gluten in Celiac disease patients. With the technique of RNAi, the alpha-gliadin storage protein fraction in wheat grains was recently knocked down. From a patient's perspective, this is a desired approach, however, this study aims to evaluate whether such a down-regulation of these problematic alpha gliadins also has unintended side-effects on other plant metabolites. Such uncontrolled and unknown arbitrary effects on any metabolite in plants designated for food production would surely represent an avoidable risk for the consumer. In general, alpha-gliadins are rich in sulfur, making their synthesis and content depended of the sulfur supply. For this reason, the influence of the application of increasing sulfur amounts on the metabolome of alpha-gliadin-deficient wheat was additionally investigated because it might be possible that e.g., considerable high/low amounts of S might increase or even induce such unintended effects that are not observable under moderate S nutrition. By silencing the alpha-gliadin genes, a recently developed wheat line that lacks the set of 75 corresponding alpha-gliadin proteins has become available. The plants were subsequently tested for RNAi-induced effects on metabolites that were not directly attributable to the specific effects of the RNAi-approach on the alpha gliadin proteins. For this, GC-MS-based metabolite profiles were recorded. A comparison of wild type with gliadin-deficient plants cultivated in pot experiments revealed no differences in all 109 analyzed metabolites, regardless of the S-nutritional status. No unintended effects attributable to the RNAi-based specific genetic deletion of a storage protein fraction were observed. PMID- 24062762 TI - New clues in the nucleus: transcriptional reprogramming in effector-triggered immunity. AB - The robustness of plant effector-triggered immunity is correlated with massive alterations of the host transcriptome. Yet the molecular mechanisms that cause and underlie this reprogramming remain obscure. Here we will review recent advances in deciphering nuclear functions of plant immune receptors and of associated proteins. Important open questions remain, such as the identities of the primary transcription factors involved in control of effector-triggered immune responses, and indeed whether this can be generalized or whether particular effector-resistance protein interactions impinge on distinct sectors in the transcriptional response web. Multiple lines of evidence have implicated WRKY transcription factors at the core of responses to microbe-associated molecular patterns and in intersections with effector-triggered immunity. Recent findings from yeast two-hybrid studies suggest that members of the TCP transcription factor family are targets of several effectors from diverse pathogens. Additional transcription factor families that are directly or indirectly involved in effector-triggered immunity are likely to be identified. PMID- 24062765 TI - DNA and the law in Italy: the experience of "the Perugia case". PMID- 24062764 TI - Explosive radiation in high Andean Hypericum-rates of diversification among New World lineages. AB - The paramos, high-elevation Andean grasslands ranging from ca. 2800 m to the snow line, harbor one of the fastest evolving biomes worldwide since their appearance in the northern Andes 3-5 million years (Ma) ago. Hypericum (St. John's wort), with over 65% of its Neotropical species, has a center of diversity in these high Mountain ecosystems. Using nuclear rDNA internal transcribed spacer (ITS) sequences of a broad sample of New World Hypericum species we investigate phylogenetic patterns, estimate divergence times, and provide the first insights into diversification rates within the genus in the Neotropics. Two lineages appear to have independently dispersed into South America around 3.5 Ma ago, one of which has radiated in the paramos (Brathys). We find strong support for the polyphyly of section Trigynobrathys, several species of which group within Brathys, while others are found in temperate lowland South America (Trigynobrathys s.str.). All paramo species of Hypericum group in one clade. Within these paramo Hypericum species enormous phenotypic evolution has taken place (life forms from arborescent to prostrate shrubs) evidently in a short time frame. We hypothesize multiple mechanisms to be responsible for the low differentiation in the ITS region contrary to the high morphological diversity found in Hypericum in the paramos. Amongst these may be ongoing hybridization and incomplete lineage sorting, as well as the putative adaptive radiation, which can explain the contrast between phenotypic diversity and the close phylogenetic relationships. PMID- 24062766 TI - Evaluating statistical analysis models for RNA sequencing experiments. AB - Validating statistical analysis methods for RNA sequencing (RNA-seq) experiments is a complex task. Researchers often find themselves having to decide between competing models or assessing the reliability of results obtained with a designated analysis program. Computer simulation has been the most frequently used procedure to verify the adequacy of a model. However, datasets generated by simulations depend on the parameterization and the assumptions of the selected model. Moreover, such datasets may constitute a partial representation of reality as the complexity or RNA-seq data is hard to mimic. We present the use of plasmode datasets to complement the evaluation of statistical models for RNA-seq data. A plasmode is a dataset obtained from experimental data but for which come truth is known. Using a set of simulated scenarios of technical and biological replicates, and public available datasets, we illustrate how to design algorithms to construct plasmodes under different experimental conditions. We contrast results from two types of methods for RNA-seq: (1) models based on negative binomial distribution (edgeR and DESeq), and (2) Gaussian models applied after transformation of data (MAANOVA). Results emphasize the fact that deciding what method to use may be experiment-specific due to the unknown distributions of expression levels. Plasmodes may contribute to choose which method to apply by using a similar pre-existing dataset. The promising results obtained from this approach, emphasize the need of promoting and improving systematic data sharing across the research community to facilitate plasmode building. Although we illustrate the use of plasmode for comparing differential expression analysis models, the flexibility of plasmode construction allows comparing upstream analysis, as normalization procedures or alignment pipelines, as well. PMID- 24062767 TI - Computationally efficient permutation-based confidence interval estimation for tail-area FDR. AB - Challenges of satisfying parametric assumptions in genomic settings with thousands or millions of tests have led investigators to combine powerful False Discovery Rate (FDR) approaches with computationally expensive but exact permutation testing. We describe a computationally efficient permutation-based approach that includes a tractable estimator of the proportion of true null hypotheses, the variance of the log of tail-area FDR, and a confidence interval (CI) estimator, which accounts for the number of permutations conducted and dependencies between tests. The CI estimator applies a binomial distribution and an overdispersion parameter to counts of positive tests. The approach is general with regards to the distribution of the test statistic, it performs favorably in comparison to other approaches, and reliable FDR estimates are demonstrated with as few as 10 permutations. An application of this approach to relate sleep patterns to gene expression patterns in mouse hypothalamus yielded a set of 11 transcripts associated with 24 h REM sleep [FDR = 0.15 (0.08, 0.26)]. Two of the corresponding genes, Sfrp1 and Sfrp4, are involved in wnt signaling and several others, Irf7, Ifit1, Iigp2, and Ifih1, have links to interferon signaling. These genes would have been overlooked had a typical a priori FDR threshold such as 0.05 or 0.1 been applied. The CI provides the flexibility for choosing a significance threshold based on tolerance for false discoveries and precision of the FDR estimate. That is, it frees the investigator to use a more data-driven approach to define significance, such as the minimum estimated FDR, an option that is especially useful for weak effects, often observed in studies of complex diseases. PMID- 24062769 TI - Antimicrobial Property of Extracts of Indian Lichen against Human Pathogenic Bacteria. AB - Context. Usnea ghattensis G. Awasthi (Usneaceae) endemic fruticose lichen found growing luxuriantly in Northern Western Ghats of India, it also contains Usnic acid as a major chemical and tested against some human pathogenic bacteria. Objective. To explore antimicrobial properties of Usnea ghattensis against some human pathogenic bacteria. Materials and Methods. The lichen was extracted in acetone, methanol, and ethanol. In vitro antimicrobial activity was tested initially by Kirby-Bauer technique of disc diffusion method and was confirmed by minimum inhibitory concentration using Broth microdilution method according to the NCCLS guidelines. Results. Ethanol extract was most effective against Bacillus cereus and Pseudomonas aeruginosa with a zone of inhibition 29.8 +/- 0.6 mm and 12.3 +/- 0.5 mm diameters at a concentration of 0.2 mg/mL. Acetone and methanol extract demonstrated almost similar activity against Staphylococcus aureus and the zone of inhibition was 24.6 +/- 0.5 and 24.7 +/- 0.4 mm. Only methanol extract was showing activity against Streptococcus faecalis with a 13.5 +/- 0.8 mm zone. MIC value noted against Staphylococcus aureus and Streptococcus faecalis was 6.25 MU g/mL and 25 MU g/mL, whereas against Bacillus cereus and Pseudomonas aeruginosa, MIC calculated was 3.125 MU g/mL and 200 MU g/mL, respectively. Conclusion. The present study demonstrates the relatively higher activity of this lichen against not only gram (+) but significantly also against gram (-) bacteria. This indicates that this lichen might be a rich source of effective antimicrobial agents. PMID- 24062768 TI - Exploiting tumor epigenetics to improve oncolytic virotherapy. AB - Oncolytic viruses (OVs) comprise a versatile and multi-mechanistic therapeutic platform in the growing arsenal of anticancer biologics. These replicating therapeutics find favorable conditions in the tumor niche, characterized among others by increased metabolism, reduced anti-tumor/antiviral immunity, and disorganized vasculature. Through a self-amplification that is dependent on multiple cancer-specific defects, these agents exhibit remarkable tumor selectivity. With several OVs completing or entering Phase III clinical evaluation, their therapeutic potential as well as the challenges ahead are increasingly clear. One key hurdle is tumor heterogeneity, which results in variations in the ability of tumors to support productive infection by OVs and to induce adaptive anti-tumor immunity. To this end, mounting evidence suggests tumor epigenetics may play a key role. This review will focus on the epigenetic landscape of tumors and how it relates to OV infection. Therapeutic strategies aiming to exploit the epigenetic identity of tumors in order to improve OV therapy are also discussed. PMID- 24062770 TI - Clinical Characteristics of Endogenous Cushing's Syndrome at a Medical Center in Southern Taiwan. AB - From January 1987 to December 2011, over a total of 25 years, 84 patients with Cushing's syndrome (CS) were identified at a medical center in southern Taiwan. We observed a higher incidence of ACTH-independent CS (75%) than ACTH-dependent CS (25%). A higher incidence of adrenocortical adenoma (58.3%) than Cushing's disease (CD, 21.4%) was also found. The sensitivity of the definitive diagnostic tests for CS, including loss of plasma cortisol circadian rhythm, a baseline 24 h urinary free cortisol (UFC) value >80 MU g, and overnight and 2-day low-dose dexamethasone suppression test, was between 94.4% and 100%. For the 2-day high dose dexamethasone suppression test for the differential diagnosis of CD, the sensitivity of 0800 h plasma cortisol and 24 h UFC was 44.4% and 85.7%, respectively. For the differential diagnosis of adrenal CS, the sensitivities of the 0800 h plasma cortisol and 24 h UFC were 95.5% and 88.9%, respectively. In patients with ACTH-independent CS and ACTH-dependent CS, the baseline plasma ACTH levels were all below 29 pg/mL and above 37 pg/mL, respectively. The postsurgical hospitalization stay following retroperitoneoscopic adrenalectomy was shorter than that observed for transabdominal adrenalectomy (4.3 +/- 1.6 versus 8.8 +/- 3.7 days, P < 0.001). It was easy to develop retroperitoneal and peritoneal seeding of adrenocortical carcinoma via laparoscopic adrenalectomy. PMID- 24062771 TI - Cross-Sectional and Longitudinal Associations between Body Mass Index and Cardiometabolic Risk Factors in Adolescents in a Country of the African Region. AB - We assessed the association between several cardiometabolic risk factors (CRFs) (blood pressure, LDL-cholesterol, HDL-cholesterol, triglycerides, uric acid, and glucose) in 390 young adults aged 19-20 years in Seychelles (Indian Ocean, Africa) and body mass index (BMI) measured either at the same time (cross sectional analysis) or at the age of 12-15 years (longitudinal analysis). BMI tracked markedly between age of 12-15 and age of 19-20. BMI was strongly associated with all considered CRFs in both cross-sectional and longitudinal analyses, with some exceptions. Comparing overweight participants with those having a BMI below the age-specific median, the odds ratios for high blood pressure were 5.4/4.7 (male/female) cross-sectionally and 2.5/3.9 longitudinally (P < 0.05). Significant associations were also found for most other CRFs, with some exceptions. In linear regression analysis including both BMI at age of 12-15 and BMI at age of 19-20, only BMI at age of 19-20 remained significantly associated with most CRFs. We conclude that CRFs are predicted strongly by either current or past BMI levels in adolescents and young adults in this population. The observation that only current BMI remained associated with CRFs when including past and current levels together suggests that weight control at a later age may be effective in reducing CRFs in overweight children irrespective of past weight status. PMID- 24062772 TI - Oral glutamine is superior than oral glucose to promote glycemia recovery in mice submitted to insulin-induced hypoglycemia. AB - The effect of the oral administration of blood glucose precursors on glycemia recovery and liver glucose production in fasted mice subjected to insulin-induced hypoglycemia (IIH) was investigated. IIH was obtained with increasing doses (from 0.5 to 2.0 U.kg(-1)) of intraperitoneal regular insulin where glycemia was evaluated from 0 to 300 min after insulin injection. The dose of 1.0 U.kg(-1) showed the best results, that is, a clear glycemia recovery phase without convulsions or deaths. Thus, this dose was used in all experiments. Afterwards, mice submitted to IIH received orally by gavage: saline (control group), glucose (100 mg.kg(-1)), glycerol (100 mg.kg(-1)), lactate (100 mg.kg(-1)), alanine (100 mg.kg(-1)), or glutamine (100 mg.kg(-1)). It was observed that glutamine was more effective in promoting glycemia recovery if compared with glucose, lactate, glycerol, or alanine. In agreement with these results, the best performance in terms of liver glucose production was obtained when glutamine was used as glucose precursors. These results open perspectives for clinical studies to investigate the impact of oral administration of gluconeogenic amino acids to promote glycemia recovery during hypoglycemia. PMID- 24062773 TI - Hypoxemic Bronchiolitis Related to Major Histocompatibility Class II Deficiency. AB - Major histocompatibility complex class II expression deficiency is an autosomal recessive primary combined immunodeficiency. The prevalence of this deficiency is the highest in Mediterranean areas, especially North Africa. Early diagnosis is essential due to high mortality in the first 2 years of life. Prognosis is very poor when bone marrow transplantation cannot be performed. We report the case of an infant with major histocompatibility complex class II expression deficiency revealed by hypoxemic bronchiolitis due to Pneumocystis jiroveci. PMID- 24062774 TI - Autologous bone marrow mononuclear cell therapy for autism: an open label proof of concept study. AB - Cellular therapy is an emerging therapeutic modality with a great potential for the treatment of autism. Recent findings show that the major underlying pathogenetic mechanisms of autism are hypoperfusion and immune alterations in the brain. So conceptually, cellular therapy which facilitates counteractive processes of improving perfusion by angiogenesis and balancing inflammation by immune regulation would exhibit beneficial clinical effects in patients with autism. This is an open label proof of concept study of autologous bone marrow mononuclear cells (BMMNCs) intrathecal transplantation in 32 patients with autism followed by multidisciplinary therapies. All patients were followed up for 26 months (mean 12.7). Outcome measures used were ISAA, CGI, and FIM/Wee-FIM scales. Positron Emission Tomography-Computed Tomography (PET-CT) scan recorded objective changes. Out of 32 patients, a total of 29 (91%) patients improved on total ISAA scores and 20 patients (62%) showed decreased severity on CGI-I. The difference between pre- and postscores was statistically significant (P < 0.001) on Wilcoxon matched-pairs signed rank test. On CGI-II 96% of patients showed global improvement. The efficacy was measured on CGI-III efficacy index. Few adverse events including seizures in three patients were controlled with medications. The encouraging results of this leading clinical study provide future directions for application of cellular therapy in autism. PMID- 24062775 TI - Autoantibodies and the immune hypothesis in psychotic brain diseases: challenges and perspectives. AB - The pathophysiology of psychosis is poorly understood, with both the cognitive and cellular changes of the disease process remaining mysterious. There is a growing body of evidence that points to dysfunction of the immune system in a subgroup of patients with psychosis. Recently, autoantibodies directed against neuronal cell surface targets have been identified in a range of syndromes that feature psychosis. Of interest is the detection of autoantibodies in patients whose presentations are purely psychiatric, such as those suffering from schizophrenia. Autoantibodies have been identified in a minority of patients, suggesting that antibody-associated mechanisms of psychiatric disease likely only account for a subgroup of cases. Recent work has been based on the application of cell-based assays-a paradigm whose strength lies in the expression of putative antigens in their natural conformation on the surface of live cells. The responsiveness of some of these newly described clinical syndromes to immune therapy supports the hypothesis that antibody-associated mechanisms play a role in the pathogenesis of psychotic disease. However, further investigation is required to establish the scope and significance of antibody pathology in psychosis. The identification of a subgroup of patients with antibody-mediated disease would promise more effective approaches to the treatment of these high morbidity conditions. PMID- 24062776 TI - Elevated apoptosis and impaired proliferation contribute to downregulated peripheral gamma delta T cells in patients with systemic lupus erythematosus. AB - OBJECTIVE: To investigate the frequency of peripheral gamma delta T cells in patients with systemic lupus erythematosus (SLE) and its correlation with disease activity and to analyze the apoptotic status, proliferation ability, and intracellular cytokine profile of these cells. METHODS: Flow cytometry was performed to detect the percentage and intracellular cytokine expression of peripheral gamma delta T cells from SLE patients. Annexin-V/PI double staining was applied to determine the proportion of apoptotic gamma delta and CD3(+) T cells. gamma delta T cell proliferation was analyzed by CFSE labeling technique. RESULTS: The percentage and absolute number of gamma delta T cells were remarkably decreased in active SLE patients compared to those in inactive patients and healthy controls, with gamma delta T cell count negatively correlated with disease activity. Compared with healthy controls, peripheral gamma delta T cells from active SLE patients exhibited higher apoptotic rate and lower proliferation ability, as well as elevated expression of intracellular IFN gamma , IL-4, IL-10, and TGF- beta , but not IL-17 or Foxp3. CONCLUSION: Decreased gamma delta T cells in the peripheral blood of SLE patients might be caused by upregulated apoptosis and downregulated cell proliferation. These gamma delta T cells may secret both pro- and anti-inflammatory cytokines to perform their functions in SLE. PMID- 24062779 TI - Evaluation of Acute 13-Week Subchronic Toxicity and Genotoxicity of the Powdered Root of Tongkat Ali (Eurycoma longifolia Jack). AB - Tongkat Ali (Eurycoma longifolia) is an indigenous traditional herb in Southern Asia. Its powdered root has been processed to produce health supplements, but no detailed toxicology report is available. In this study, neither mutagenicity nor clastogenicity was noted, and acute oral LD50 was more than 6 g/kg b.w. After 4 week subacute and 13-week subchronic exposure paradigms (0, 0.6, 1.2, and 2 g/kg b.w./day), adverse effects attributable to test compound were not observed with respect to body weight, hematology, serum biochemistry, urinalysis, macropathology, or histopathology. However, the treatment significantly reduced prothrombin time, partial thromboplastin time, blood urea nitrogen, creatinine, aspartate aminotransferase, creatine phosphate kinase, lactate dehydrogenase, and cholesterol levels, especially in males (P < 0.05). These changes were judged as pharmacological effects, and they are beneficial to health. The calculated acceptable daily intake (ADI) was up to 1.2 g/adult/day. This information will be useful for product development and safety management. PMID- 24062780 TI - Anthraquinone Content in Noni (Morinda citrifolia L.). AB - Noni has been used in traditional medicine and as food for thousands of years. While the fruits serve as food and internal medicine, leaves were traditionally used only topically. In recent years, concern regarding the possible content of anthraquinones in noni has led to scrutiny by the European Food Safety Authority. Little research existed on the content of anthraquinones in different noni preparations, with no information about the potential effect of harvest and preparation methods. Our research focused on lucidin, alizarin, and rubiadin, the most important anthraquinones from a health perspective. We found that the production process (fermentation/juice production versus drying/lyophilization) has no effect on the anthraquinone content. The source product, however, does have implications: noni fruit puree from which seeds had been removed as well as consumer products produced from such puree had no detectable amounts of any anthraquinones. Products that did contain seed or leaf material in all cases did contain partly significant amounts of anthraquinones. To alleviate safety concerns, we suggest that noni products, whether fermented or unfermented juice or powder, should be derived only from fully ripe noni fruits, and that any seed material needs to be removed during the production process. PMID- 24062778 TI - In utero hepatocellular transplantation in rats. AB - This work represents a step forward in the experimental design of an in utero hepatocellular transplantation model in rats. We focused on the enrichment optimization of isolated fetal hepatocytes suspension, arranging the surgery methodology of in utero transplantation, monitoring the biodistribution of the transplanted hepatocytes, and assessing the success of the transplants. Rat fetuses have been transplanted at the 17th embryonic day (ED17) with fetal hepatocytes isolated from rats at the end of pregnancy (ED21). We assessed possible differences between lymphocyte population, CD4 positive, CD8 positive, double-positive T-cells, and anti-inflammatory cytokines interleukins 4 and 10 (IL4 and IL10) as well. Cellular viability reached the rates of 90-95%. Transplanted groups had a limited success. Transplanted hepatocytes were not able to pass through the hematoplacental barrier. The hepatocytes injected were primarily located in the liver. There was an upward trend in the whole amount of T CD4 and T CD8 cells. There was an increased IL4 in the transplanted groups observed in the pregnant rats. The possibility to induce tolerance in fetuses with a hepatocyte transplant in utero could be a key point to avoid the immunosuppression treatments which must be undergone by transplanted patients. PMID- 24062777 TI - Epstein-Barr virus in systemic autoimmune diseases. AB - Systemic autoimmune diseases (SADs) are a group of connective tissue diseases with diverse, yet overlapping, symptoms and autoantibody development. The etiology behind SADs is not fully elucidated, but a number of genetic and environmental factors are known to influence the incidence of SADs. Recent findings link dysregulation of Epstein-Barr virus (EBV) with SAD development. EBV causes a persistent infection with a tight latency programme in memory B-cells, which enables evasion of the immune defence. A number of immune escape mechanisms and immune-modulating proteins have been described for EBV. These immune modulating functions make EBV a good candidate for initiation of autoimmune diseases and exacerbation of disease progression. This review focuses on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren's syndrome (SS) and sum up the existing data linking EBV with these diseases including elevated titres of EBV antibodies, reduced T-cell defence against EBV, and elevated EBV viral load. Together, these data suggest that uncontrolled EBV infection can develop diverse autoreactivities in genetic susceptible individuals with different manifestations depending on the genetic background and the site of reactivation. PMID- 24062781 TI - Vitamin k2, a naturally occurring menaquinone, exerts therapeutic effects on both hormone-dependent and hormone-independent prostate cancer cells. AB - In recent years, several studies have shown that vitamin k2 (VK2) has anticancer activity in a variety of cancer cells. The antitumor effects of VK2 in prostate cancer are currently not known. In the present study, we sought to characterize the anticancer potential of VK2 in both androgen-dependent and -independent prostate cancer cells. Our investigations show that VK2 is able to suppress viability of androgen-dependent and androgen-independent prostate cancer cells via caspase-3 and -8 dependent apoptosis. We also show that VK2 treatment reduces androgen receptor expression and PSA secretion in androgen-dependent prostate cancer cells. Our results also implicate VK2 as a potential anti-inflammatory agent, as several inflammatory genes are downregulated in prostate cancer cells following treatment with VK2. Additionally, AKT and NF-kB levels in prostate cancer cells are reduced significantly when treated with VK2. These findings correlated with the results of the Boyden chamber and angiogenesis assay, as VK2 treatment reduced cell migration and angiogenesis potential of prostate cancer cells. Finally, in a nude mice model, VK2 administration resulted in significant inhibition of both androgen-dependent and androgen-independent tumor growth. Overall, our results suggest that VK2 may be a potential therapeutic agent in the treatment of prostate cancer. PMID- 24062783 TI - In Vitro and In Vivo Anticancer Effects of Sterol Fraction from Red Algae Porphyra dentata. AB - Porphyra dentata, an edible red macroalgae, is used as a folk medicine in Asia. This study evaluated in vitro and in vivo the protective effect of a sterol fraction from P. dentata against breast cancer linked to tumor-induced myeloid derived-suppressor cells (MDSCs). A sterol fraction containing cholesterol, beta sitosterol, and campesterol was prepared by solvent fractionation of methanol extract of P. dentata in silica gel column chromatography. This sterol fraction in vitro significantly inhibited cell growth and induced apoptosis in 4T1 cancer cells. Intraperitoneal injection of this sterol fraction at 10 and 25 mg/kg body weight into 4T1 cell-implanted tumor BALB/c mice significantly inhibited the growth of tumor nodules and increased the survival rate of mice. This sterol fraction significantly decreased the reactive oxygen species (ROS) and arginase activity of MDSCs in tumor-bearing mice. Therefore, the sterol fraction from P. dentata showed potential for protecting an organism from 4T1 cell-based tumor genesis. PMID- 24062782 TI - Neural encoding of acupuncture needling sensations: evidence from a FMRI study. AB - Deqi response, a psychophysical response characterized by a spectrum of different needling sensations, is essential for Chinese acupuncture clinical efficacy. Previous neuroimaging research works have investigated the neural correlates of an overall deqi response by summating the scores of different needling sensations. However, the roles of individual sensations in brain activity and how they interact with each other remain to be clarified. In this study, we applied fMRI to investigate the neural correlates of individual components of deqi during acupuncture on the right LV3 (Taichong) acupoint. We selected a subset of deqi responses, namely, pressure, heaviness, fullness, numbness, and tingling. Using the individual components of deqi of different subjects as covariates in the analysis of percentage change of bold signal, pressure was found to be a striking sensation, contributing to most of negative activation of a limbic-paralimbic neocortical network (LPNN). The similar or opposite neural activity in the heavily overlapping regions is found to be responding to different needling sensations, including bilateral LPNN, right orbitofrontal cortex, and bilateral posterior parietal cortex. These findings provide the neuroimaging evidence of how the individual needle sensations interact in the brain, showing that the modulatory effects of different needling sensations contribute to acupuncture modulations of LPNN network. PMID- 24062784 TI - Efficacy and Safety of Taeeumjowi-tang in Obese Korean Adults: A Double-Blind, Randomized, and Placebo-Controlled Pilot Trial. AB - Objective. The purpose of this study was to assess the efficacy and safety of Taeeumjowi-tang (TJ001) as well as to estimate obesity-related factors. Methods. This was a 12-week trial with 5 visits. A total of 102 participants of both genders were randomized to either TJ001 (n = 57) group or the placebo group (n = 55). Subjects were administered 7 g of either TJ001 or placebo 3 times a day. The primary outcome was a rate of subjects who lost 5% or more of initial weight. Secondary outcomes included anthropometric parameters, lipid profiles, and body fat composition. Results. The subject response rate of >=5% weight loss compared to baseline was similar in both groups, and no statistically significant difference was observed (P = 0.87). Changes in anthropometric parameters were greater during the first 4 weeks in the treatment group (P < 0.0001). There were no significant changes in both within groups and between groups for lipid profile and body fat composition. No adverse event was reported in either group. Conclusion. Although the difference between the groups regarding a rate of subjects who lost 5% or more of initial weight did not show statistical significance, TJ001 appears to be beneficial in safely controlling weight. PMID- 24062785 TI - Inhibition of Klebsiella pneumoniae Growth and Capsular Polysaccharide Biosynthesis by Fructus mume. AB - Klebsiella pneumoniae is the predominant pathogen isolated from liver abscess of diabetic patients in Asian countries. With the spread of multiple-drug-resistant K. pneumoniae, there is an increasing need for the development of alternative bactericides and approaches to block the production of bacterial virulence factors. Capsular polysaccharide (CPS), especially from the K1 and K2 serotypes, is considered the major determinant for K. pneumoniae virulence. We found that extracts of the traditional Chinese medicine Fructus mume inhibited the growth of K. pneumoniae strains of both serotypes. Furthermore, Fructus mume decreased the mucoviscosity, and the CPS produced in a dose-dependent manner, thus reducing bacterial resistance to serum killing. Quantitative reverse transcription polymerase chain reaction analyses showed that Fructus mume downregulated the mRNA levels of cps biosynthesis genes in both serotypes, possibly by increasing the intracellular iron concentration in K. pneumoniae. Moreover, citric acid, a major organic acid in Fructus mume extracts, was found to have an inhibitory effect on growth and CPS biosynthesis in K. pneumoniae. Taken together, our results indicate that Fructus mume not only possesses antibacterial activity against highly virulent K. pneumoniae strains but also inhibits bacterial CPS biosynthesis, thereby facilitating pathogen clearance by the host immune system. PMID- 24062786 TI - CAM and Pediatric Oncology: Where Are All the Best Cases? AB - Background. Use of complementary and alternative medicine (CAM) by children with cancer is high; however, pediatric best cases are rare. Objectives. To investigate whether best cases exist in pediatric oncology using a three-phase approach and to compare our methods with other such programs. Methods. In phase I, Children's Oncology Group (COG) oncologists were approached via email and asked to recall patients who were (i) under 18 when diagnosed with cancer, (ii) diagnosed between 1990 and 2006, (iii) had unexpectedly positive clinical outcome, and (iv) reported using CAM during or after cancer treatment. Phase II involved partnering with CAM research networks; patients who were self-identified as best cases were asked to submit reports completed in conjunction with their oncologists. Phase III extended this partnership to 200 CAM associations and training organizations. Results. In phase I, ten cases from three COG sites were submitted, and most involved use of traditional Chinese medicine to improve quality of life. Phases II and III did not yield further cases. Conclusion. Identification of best cases has been suggested as an important step in guiding CAM research. The CARE Best Case Series Program had limited success in identifying pediatric cases despite the three approaches we used. PMID- 24062787 TI - Therapeutic Effect of Chung-Pae, an Experimental Herbal Formula, on Acute Lung Inflammation Is Associated with Suppression of NF- kappa B and Activation of Nrf2. AB - Acute lung injury (ALI) is an inflammatory disease with high mortality, but therapeutics against it is unavailable. Recently, we elaborated a formula, named Chung-pae (CP), that comprises four ethnic herbs commonly prescribed against various respiratory diseases in Asian traditional medicine. CP is being administered in aerosol to relieve various respiratory symptoms of patients in our clinic. Here, we sought to examine whether CP has a therapeutic effect on ALI and to uncover the mechanism behind it. Reporter assays show that CP suppressed the transcriptional activity of proinflammatory NF- kappa B and activated that of anti-inflammatory Nrf2. Similarly, CP suppressed the expression of NF- kappa B dependent, proinflammatory cytokines and induced that of Nrf2 dependent genes in RAW 264.7. An aerosol intratracheal administration of CP effectively reduced neutrophilic infiltration and the expression of pro-inflammatory cytokines, hallmarks of ALI, in the lungs of mice that received a prior intraperitoneal injection of lipopolysaccharide. The intratracheal CP administration concomitantly enhanced the expression of Nrf2 dependent genes in the lung. Therefore, our results evidenced a therapeutic effect of CP on ALI, in which differential regulation of the two key inflammatory factors, NF- kappa B and Nrf2, was involved. We propose that CP can be a new therapeutic formula against ALI. PMID- 24062788 TI - ATF3 Protects against LPS-Induced Inflammation in Mice via Inhibiting HMGB1 Expression. AB - Lipopolysaccharide (LPS) triggers innate immunity mainly via TLR4 signaling. ATF3 is a negative regulator of TLR4 signaling. HMGB1 plays a critical role in the final step of sepsis. However, the mechanisms of ATF3 and the role of HMGB1 in regulating innate immunity-induced sepsis are incompletely understood. In this study, we found that serum HMGB1 levels were 10-fold higher in patients with sepsis than normal controls. We further demonstrated that ATF3 gene knockout in mice subjected to LPS-induced endotoxemia correlates with an increase in the mortality rate and the elevated expression of IL-6, TNF- alpha , NO, MCP-1, and HMGB1 in the lung tissues or serum. The biochemical effects of ATF3 were observed in in vitro macrophages and blocked by ATF3 siRNA treatment. We have also shown that adeno-associated virus-mediated ATF3 gene transfer protected ATF3 knockout mice from LPS-induced mortality. In addition, ATF3 knockdown increased LPS induced release of HMGB1. In conclusion, upregulation of ATF3 contributes to the reduced release of inflammatory molecules, especially HMGB1, which induced lung injury and increased the survival rate of mice after LPS challenge. Therefore, suppressing LPS-induced inflammation with ATF3 induction or ATF3 mimetics may be an important strategy for sepsis therapy. PMID- 24062789 TI - Multivariate Analysis as a Method for Evaluating the Conceptual Perceptions of Korean Medicine Students regarding Phlegm Pattern. AB - Individuals may perceive the concepts in Korean medicine pattern classification differently because it is performed according to the integration of a variety of information. Therefore, analysis about individual perspective is very important for examining the cross-sectional perspective state of Korean medicine concepts and developing both the clinical guideline including diagnosis and the curriculum of Korean medicine colleges. Moreover, because this conceptual difference is thought to begin with college education, it is worthwhile to observe students' viewpoints. So, we suggested multivariate analysis to explore the dimensional structure of Korean medicine students' conceptual perceptions regarding phlegm pattern. We surveyed 326 students divided into 5 groups based on their year of study. Data were analyzed using multidimensional scaling and factor analysis. Within-group difference was the smallest for third-year students, who have received Korean medicine education in full for the first time. With the exception of first-year students, the conceptual map revealed that each group's mean perceptions of phlegm pattern were distributed in almost linear fashion. To determine the effect of education, we investigated the preference rankings and scores of each symptom. We also extracted factors to identify latent variables and to compare the between-group conceptual characteristics regarding phlegm pattern. PMID- 24062790 TI - Chinese Medicinal Formula (MHGWT) for Relieving Diabetic Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - Objective. To investigate the effects of modified Hungqi Guizhi Wuwu Tang (MHGWT), a formula that comprises Chinese medicinal herbs, in relieving neuropathic pain in diabetics. Method. Between March 2008 and April 2009, 112 participants were randomly assigned to either the MHGWT group, whose members received MHGWT (n = 56), or the control group, whose members received a placebo (n = 56). Diabetic neuropathic pain (DNP) was rated using the 15-item Short-Form Brief Pain Inventory (SF-BPI), the 17-item Short-Form McGill Pain Questionnaire (SF-MPQ), the 13-item Modified Michigan Neuropathy Screening Instrument (MMNSI), and the 36-item "SF-36." Nerve conduction studies (NCSs) were performed before and after treatment. Results. After 12 weeks of treatment, the SF-MPQ and SF-BPI scores of the MHGWT group were significantly (P < 0.05) reduced and a significant difference between the groups was observed (P < 0.05). The levels of NCS in the MHGWT group were nonsignificantly (P > 0.05) reduced, and no significant difference in NCS level was observed between the groups (P > 0.05). Conclusions. MHGWT shows promise in relieving DNP and deserves further investigation. PMID- 24062791 TI - Doinseunggitang ameliorates endothelial dysfunction in diabetic atherosclerosis. AB - Atherosclerosis, a chronic and progressive disease characterized by vascular inflammation, is a leading cause of death in diabetes patients. Doinseunggitang (DYSGT), traditional prescription, has been used for promoting blood circulation to remove blood stasis. The aim of this study was to investigate the beneficial effects of DYSGT on endothelial dysfunction in diabetic atherosclerosis animal model. Apolipoprotein E knockout (ApoE KO) mice fed on a Western diet were treated with DYSGT (200 mg/kg/day). DYSGT significantly lowered blood glucose level and glucose tolerance as well as systolic blood pressure. Metabolic parameter showed that DYSGT markedly decreased triglyceride and LDL-cholesterol levels. In the thoracic aorta, the impairment of vasorelaxation response to acetylcholine and atherosclerotic lesion was attenuated by DYSGT. Furthermore, DYSGT restored the reduction of endothelial nitric oxide synthase (eNOS) expression, leading to the inhibition of intracellular adhesion molecule-1 (ICAM 1) and endothelin-1 (ET-1) expression. In conclusion, DYSGT improved the development of diabetic atherosclerosis via attenuation of the endothelial dysfunction, possibly by inhibiting ET-1, cell adhesion molecules, and lesion formation. Therefore, these results suggest that Korean traditional prescription Doinseunggitang may be useful in the treatment and prevention of diabetic vascular complications. PMID- 24062792 TI - Roles of chlorogenic Acid on regulating glucose and lipids metabolism: a review. AB - Intracellular glucose and lipid metabolic homeostasis is vital for maintaining basic life activities of a cell or an organism. Glucose and lipid metabolic disorders are closely related with the occurrence and progression of diabetes, obesity, hepatic steatosis, cardiovascular disease, and cancer. Chlorogenic acid (CGA), one of the most abundant polyphenol compounds in the human diet, is a group of phenolic secondary metabolites produced by certain plant species and is an important component of coffee. Accumulating evidence has demonstrated that CGA exerts many biological properties, including antibacterial, antioxidant, and anticarcinogenic activities. Recently, the roles and applications of CGA, particularly in relation to glucose and lipid metabolism, have been highlighted. This review addresses current studies investigating the roles of CGA in glucose and lipid metabolism. PMID- 24062793 TI - Differentiated Evaluation of Extract-Specific Evidence on Cimicifuga racemosa's Efficacy and Safety for Climacteric Complaints. AB - Past reviews on Cimicifuga racemosa (CR) without differentiation between extracts, quality, and indication altogether led to inconsistent data. Therefore, for the first time, we meet the requirements of the system's logic of evidence based phytotherapy by taking into consideration extracts, pharmaceutical quality (reflected in a regulatory status as medicinal product), and indication. A literature search for clinical studies examining CR's efficacy and safety for menopausal complaints was conducted. The results were sorted by type of extract, regulatory status, and indication. Accordingly, Oxford Levels of Evidence (LOE) and Grades of Recommendation (GR) were determined. CR extracts demonstrated a good to very good safety in general, on estrogen-sensitive organs and the liver. However, only registered CR medicinal products were able to prove their efficacy. Best evidence was provided by the isopropanolic CR extract (iCR): the multitude of studies including more than 11,000 patients demonstrated consistent confirmatory evidence of LOE 1b (LOE 1a for safety) leading to GR A. The studies on the ethanolic extract BNO 1055 including more than 500 patients showed exploratory evidence of LOE 2b resulting in GR B. A positive benefit-risk profile is stated and limited to Cimicifuga racemosa products holding a marketing authorisation for treating climacteric complaints. PMID- 24062794 TI - Recent progress in voice-based sasang constitutional medicine: improving stability of diagnosis. AB - Sasang constitutional medicine is a unique form of tailored medicine in traditional Korean medicine. Voice features have been regarded as an important cue to diagnose Sasang constitution types. Many studies tried to extract quantitative voice features and standardize diagnosis methods; however, they had flaws, such as unstable voice features which vary a lot for the same individual, limited data collected from only few sites, and low diagnosis accuracy. In this paper, we propose a stable diagnosis model that has a good repeatability for the same individual. None of the past studies evaluated the repeatability of their diagnosis models. Although many previous studies used voice features calculated by averaging feature values from all valid frames in monotonic utterance like vowels, we analyse every single feature value from each frame of a sentence voice signal. Gaussian mixture model is employed to deal with a lot of voice features from each frame. Total 15 Gaussian models are used to represent voice characteristics for each constitution. To evaluate repeatability of the proposed diagnosis model, we introduce a test dataset consisting of 10 individuals' voice recordings with 50 recordings per each individual. Our result shows that the proposed method has better repeatability than the previous study which used averaged features from vowels and the sentence. PMID- 24062795 TI - The effect of chinese herbal medicine on albuminuria levels in patients with diabetic nephropathy: a systematic review and meta-analysis. AB - To evaluate the effect of Chinese herbal medicine (CHM) on albuminuria levels in patients with diabetic nephropathy (DN), we performed comprehensive searches on Medline database, Cochrane Library, CNKI database, CBM database, Wanfang database, and VIP database up to December 2012. A total of 29 trials including 2440 participants with DN met the selection criteria. CHM was tested to be more effective in reducing urinary albumin excretion rate (UAER) (MD -82.95 MU g/min, [-138.64, -27.26]) and proteinuria (MD -565.99 mg/24 h, [-892.41, -239.57]) compared with placebo. CHM had a greater beneficial effect on reduction of UAER (MD -13.41 MU g/min, [-20.63, -6.19]) and proteinuria (MD -87.48 mg/24 h, [ 142.90, -32.06]) compared with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Combination therapy with CHM and ACEI/ARB showed significant improvement in UAER (MD -28.18 MU g/min, [-44.4, -11.97]), urinary albumin-creatinine ratio (MD -347.00, [-410.61, -283.39]), protein creatinine ratio (MD -2.49, [-4.02, -0.96]), and proteinuria (MD -26.60 mg/24 h, [-26.73, -26.47]) compared with ACEI/ARB alone. No serious adverse events were reported. CHM seems to be an effective and safe therapy option to treat proteinuric patients with DN, suggesting that further study of CHM in the treatment of DN is warranted in rigorously designed, multicentre, large-scale trials with higher quality worldwide. PMID- 24062796 TI - Identification of antioxidants from sequence information using naive Bayes. AB - Antioxidant proteins are substances that protect cells from the damage caused by free radicals. Accurate identification of new antioxidant proteins is important in understanding their roles in delaying aging. Therefore, it is highly desirable to develop computational methods to identify antioxidant proteins. In this study, a Naive Bayes-based method was proposed to predict antioxidant proteins using amino acid compositions and dipeptide compositions. In order to remove redundant information, a novel feature selection technique was employed to single out optimized features. In the jackknife test, the proposed method achieved an accuracy of 66.88% for the discrimination between antioxidant and nonantioxidant proteins, which is superior to that of other state-of-the-art classifiers. These results suggest that the proposed method could be an effective and promising high throughput method for antioxidant protein identification. PMID- 24062797 TI - Predicting bird song from space. AB - Environmentally imposed selection pressures are well known to shape animal signals. Changes in these signals can result in recognition mismatches between individuals living in different habitats, leading to reproductive divergence and speciation. For example, numerous studies have shown that differences in avian song may be a potent prezygotic isolating mechanism. Typically, however, detailed studies of environmental pressures on variation in animal behavior have been conducted only at small spatial scales. Here, we use remote-sensing data to predict animal behavior, in this case, bird song, across vast spatial scales. We use remotely sensed data to predict the song characteristics of the little greenbul (Andropadus virens), a widely distributed African passerine, found across secondary and mature rainforest habitats and the rainforest-savanna ecotone. Satellite data that captured ecosystem structure and function explained up to 66% of the variation in song characteristics. Song differences observed across habitats, including those between human-altered and mature rainforest, have the potential to lead to reproductive divergence, and highlight the impacts that both natural and anthropogenic change may have on natural populations. Our approach offers a novel means to examine the ecological correlates of animal behavior across large geographic areas with potential applications to both evolutionary and conservation biology. PMID- 24062798 TI - Virulence evolution of a generalist plant virus in a heterogeneous host system. AB - Modelling virulence evolution of multihost parasites in heterogeneous host systems requires knowledge of the parasite biology over its various hosts. We modelled the evolution of virulence of a generalist plant virus, Cucumber mosaic virus (CMV) over two hosts, in which CMV genotypes differ for within-host multiplication and virulence. According to knowledge on CMV biology over different hosts, the model allows for inoculum flows between hosts and for host co-infection by competing virus genotypes, competition affecting transmission rates to new hosts. Parameters of within-host multiplication, within-host competition, virulence and transmission were determined experimentally for different CMV genotypes in each host. Emergence of highly virulent genotypes was predicted to occur as mixed infections, favoured by high vector densities. For most simulated conditions, evolution to high virulence in the more competent Host 1 was little dependent on inoculum flow from Host 2, while in Host 2, it depended on transmission from Host 1. Virulence evolution bifurcated in each host at low, but not at high, vector densities. There was no evidence of between-host trade offs in CMV life-history traits, at odds with most theoretical assumptions. Predictions agreed with field observations and are relevant for designing control strategies for multihost plant viruses. PMID- 24062799 TI - Population genetics provides new insights into biomarker prevalence in dab (Limanda limanda L.): a key marine biomonitoring species. AB - Bioindicators are species for which some quantifiable aspect of its biology, a biomarker, is assumed to be sensitive to ecosystem health. However, there is frequently a lack of information on the underlying genetic and environmental drivers shaping the spatiotemporal variance in prevalence of the biomarkers employed. Here, we explore the relative role of potential variables influencing the spatiotemporal prevalence of biomarkers in dab, Limanda limanda, a species used as a bioindicator of marine contaminants. Firstly, the spatiotemporal genetic structure of dab around UK waters (39 samples across 15 sites for four years: 2005-2008) is evaluated with 16 microsatellites. Two temporally stable groups are identified corresponding to the North and Irish Seas (average between basin [Formula: see text] = 0.007; [Formula: see text] = 0.022). Secondly, we examine the association between biomarker prevalence and several variables, including genetic structuring, age and contaminant exposure. Genetic structure had significant interactive effects, together with age and some contaminants, in the prevalence of some of the biomarkers considered, namely hyperpigmentation and liver lesions. The integration of these data sets enhanced our understanding of the relationship between biomarker prevalence, exposure to contaminants and population-specific response, thereby yielding more informative predictive models of response and prospects for environmental remediation. PMID- 24062800 TI - Geographic population structure of the African malaria vector Anopheles gambiae suggests a role for the forest-savannah biome transition as a barrier to gene flow. AB - The primary Afrotropical malaria mosquito vector Anopheles gambiae sensu stricto has a complex population structure. In west Africa, this species is split into two molecular forms and displays local and regional variation in chromosomal arrangements and behaviors. To investigate patterns of macrogeographic population substructure, 25 An. gambiae samples from 12 African countries were genotyped at 13 microsatellite loci. This analysis detected the presence of additional population structuring, with the M-form being subdivided into distinct west, central, and southern African genetic clusters. These clusters are coincident with the central African rainforest belt and northern and southern savannah biomes, which suggests restrictions to gene flow associated with the transition between these biomes. By contrast, geographically patterned population substructure appears much weaker within the S-form. PMID- 24062801 TI - Fight evolution with evolution: plasmid-dependent phages with a wide host range prevent the spread of antibiotic resistance. AB - The emergence of pathogenic bacteria resistant to multiple antibiotics is a serious worldwide public health concern. Whenever antibiotics are applied, the genes encoding for antibiotic resistance are selected for within bacterial populations. This has led to the prevalence of conjugative plasmids that carry resistance genes and can transfer themselves between diverse bacterial groups. In this study, we investigated whether it is feasible to attempt to prevent the spread of antibiotic resistances with a lytic bacteriophage, which can replicate in a wide range of gram-negative bacteria harbouring conjugative drug resistance conferring plasmids. The counter-selection against the plasmid was shown to be effective, reducing the frequency of multidrug-resistant bacteria that formed via horizontal transfer by several orders of magnitude. This was true also in the presence of an antibiotic against which the plasmid provided resistance. Majority of the multiresistant bacteria subjected to phage selection also lost their conjugation capability. Overall this study suggests that, while we are obligated to maintain the selection for the spread of the drug resistances, the 'fight evolution with evolution' approach could help us even out the outcome to our favour. PMID- 24062802 TI - Genetic variation in adaptive traits and seed transfer zones for Pseudoroegneria spicata (bluebunch wheatgrass) in the northwestern United States. AB - A genecological approach was used to explore genetic variation in adaptive traits in Pseudoroegneria spicata, a key restoration grass, in the intermountain western United States. Common garden experiments were established at three contrasting sites with seedlings from two maternal parents from each of 114 populations along with five commercial releases commonly used in restoration. Traits associated with size, flowering phenology, and leaf width varied considerably among populations and were moderately correlated with the climates of the seed sources. Pseudoroegneria spicata populations from warm, arid source environments were smaller with earlier phenology and had relatively narrow leaves than those from mild climates with cool summers, warm winters, low seasonal temperature differentials, high precipitation, and low aridity. Later phenology was generally associated with populations from colder climates. Releases were larger and more fecund than most of the native ecotypes, but were similar to native populations near their source of origin. Differences among native populations associated with source climates that are logical for survival, growth, and reproduction indicate that genetic variation across the landscape is adaptive and should be considered during restoration. Results were used to delineate seed transfer zones and population movement guidelines to ensure adapted plant materials for restoration activities. PMID- 24062803 TI - Gene flow and demographic history of leopards (Panthera pardus) in the central Indian highlands. AB - Gene flow is a critical ecological process that must be maintained in order to counteract the detrimental effects of genetic drift in subdivided populations, with conservation benefits ranging from promoting the persistence of small populations to spreading adaptive traits in changing environments. We evaluated historical and contemporary gene flow and effective population sizes of leopards in a landscape in central India using noninvasive sampling. Despite the dramatic changes in land-use patterns in this landscape through recent times, we did not detect any signs that the leopard populations have been through a genetic bottleneck, and they appear to have maintained migration-drift equilibrium. We found that historical levels of gene flow (mean m h = 0.07) were significantly higher than contemporary levels (mean m c = 0.03), and populations with large effective population sizes (Satpura and Kanha Tiger Reserves) are the larger exporters of migrants at both timescales. The greatest decline in historical versus contemporary gene flow is between pairs of reserves that are currently not connected by forest corridors (i.e., Melghat-Pench m h - m c = 0.063; and Kanha Satpura m h - m c = 0.054). We attribute this reduction in gene flow to accelerated fragmentation and habitat alteration in the landscape over the past few centuries, and suggest protection of forest corridors to maintain gene flow in this landscape. PMID- 24062804 TI - The 'Dr Jekyll and Mr Hyde fungus': noble rot versus gray mold symptoms of Botrytis cinerea on grapes. AB - Many cryptic species have recently been discovered in fungi, especially in fungal plant pathogens. Cryptic fungal species co-occurring in sympatry may occupy slightly different ecological niches, for example infecting the same crop plant but specialized on different organs or having different phenologies. Identifying cryptic species in fungal pathogens of crops and determining their ecological specialization are therefore crucial for disease management. Here, we addressed this question in the ascomycete Botrytis cinerea, the agent of gray mold on a wide range of plants. On grape, B. cinerea causes severe damage but is also responsible for noble rot used for processing sweet wines. We used microsatellite genotyping and clustering methods to elucidate whether isolates sampled on gray mold versus noble rot symptoms in three French regions belong to genetically differentiated populations. The inferred population structure matched geography rather than the type of symptom. Noble rot symptoms therefore do not seem to be caused by a specific B. cinerea population but instead seem to depend essentially on microclimatic conditions, which has applied consequences for the production of sweet wines. PMID- 24062805 TI - Scaling up from greenhouse resistance to fitness in the field for a host of an emerging forest disease. AB - Forest systems are increasingly threatened by emergent, exotic diseases, yet management strategies for forest trees may be hindered by long generation times and scant background knowledge. We tested whether nursery disease resistance and growth traits have predictive value for the conservation of Notholithocarpus densiflorus, the host most susceptible to sudden oak death. We established three experimental populations to assess nursery growth and resistance to Phytophthora ramorum, and correlations between nursery-derived breeding values with seedling survival in a field disease trial. Estimates of nursery traits' heritability were low to moderate, with lowest estimates for resistance traits. Within the field trial, survival likelihood was increased in larger seedlings and decreased with the development of disease symptoms. The seed-parent family wide likelihood of survival was likewise correlated with family predictors for size and resistance to disease in 2nd year laboratory assays, though not resistance in 1st year leaf assays. We identified traits and seedling families with increased survivorship in planted tanoaks, and a framework to further identify seed parents favored for restoration. The additive genetic variation and seedling disease dynamics we describe hold promise to refine current disease models and expand the understanding of evolutionary dynamics of emergent infectious diseases in highly susceptible hosts. PMID- 24062806 TI - Adaptive evolution of a generalist parasitoid: implications for the effectiveness of biological control agents. AB - The use of alternative hosts imposes divergent selection pressures on parasitoid populations. In response to selective pressures, these populations may follow different evolutionary trajectories. Divergent natural selection could promote local host adaptation in populations, translating into direct benefits for biological control, thereby increasing their effectiveness on the target host. Alternatively, adaptive phenotypic plasticity could be favored over local adaptation in temporal and spatially heterogeneous environments. We investigated the existence of local host adaptation in Aphidius ervi, an important biological control agent, by examining different traits related to infectivity (preference) and virulence (a proxy of parasitoid fitness) on different aphid-host species. The results showed significant differences in parasitoid infectivity on their natal host compared with the non-natal hosts. However, parasitoids showed a similar high fitness on both natal and non-natal hosts, thus supporting a lack of host adaptation in these introduced parasitoid populations. Our results highlight the role of phenotypic plasticity in fitness-related traits of parasitoids, enabling them to maximize fitness on alternative hosts. This could be used to increase the effectiveness of biological control. In addition, A. ervi females showed significant differences in infectivity and virulence across the tested host range, thus suggesting a possible host phylogeny effect for those traits. PMID- 24062808 TI - Haemorrhagic cystitis due to BK virus in a child with ALL on standard chemotherapy without stem cell transplant. AB - The BK virus (BKV) is a nonenveloped double-stranded DNA virus of the polyomavirus family that primarily affects immunocompromised people. BKV infects humans at an early age. Initial infections with BKV are mainly asymptomatic and usually remain latent in the brain, peripheral blood, kidneys, and urothelium. Following the primary infection, viruses persist indefinitely as 'latent' infections of the kidney and urinary system because the virus is urotheliotropic. Reactivation of the virus infections occurs in individuals with severe immunosuppression states such as kidney and stem cell transplantation and rarely in pregnancy. In this line, BKV has been implicated as a common cause of late onset haemorrhagic cystitis (HC) in patients who have undergone stem cell transplantation. In contrast, reports of BKV-associated diseases in nontransplant paediatric patients are almost exclusively in patients with human immunodeficiency virus infection. Herein, we report the first case of a child with acute lymphoblastic leukaemia who developed BKV-associated HC without receiving stem cell transplantation while on standard maintenance chemotherapy. PMID- 24062809 TI - Measuring patient-reported outcomes in advanced gastric cancer. AB - BACKGROUND: Gastric cancer (GC), one of the most common cancers in the world, is often diagnosed at an advanced stage and associated with a poor prognosis. Quality of life and patient-reported outcomes (PROs) are important considerations when treating GC patients. The aim of this study was to identify existing PRO instruments that would be appropriate for use in GC trials. METHODS: Data were obtained from a systematic literature review and interviews with clinical experts. A literature search was conducted using OVID (EMBASE and MEDLINE) and yielded 1,008 abstracts; 92 assessed PROs in an advanced GC. RESULTS: Key symptoms and functional impacts identified through the literature and expert input included abdominal pain or pain at the site of distant metastases, dysphagia and other symptoms related to eating, and digestive symptoms. The liver and lungs were the most frequent locations of metastases, leading to dyspnea, abdominal fullness, and jaundice. Symptoms related to changes in bowel habits appeared to be more frequent and pronounced in Asian patients, possibly due to the higher prevalence of GC in the body of the stomach in this population. The five most commonly used PRO instruments were identified, but their validity in advanced-stage GC patients remains unclear. CONCLUSIONS: The symptoms and functional impacts identified here should be confirmed with robust input from advanced-stage GC patients. Optimal measurement of PROs in GC should account for patient burden and possible differences between Asian and non-Asian patients. PMID- 24062810 TI - The Ars legendi-faculty award for excellent teaching in medicine: honour and career stepping stone. PMID- 24062811 TI - The longitudinal curriculum "social and communicative competencies" within Bologna-reformed undergraduate medical education in Basel. AB - BACKGROUND: Within the Bologna reform, a longitudinal curriculum of "social and communicative competencies" (SOKO) was implemented into the new Bachelor-Master structure of undergraduate medical education in Basel (Switzerland). PROJECT DESCRIPTION: The aim of the SOKO curriculum is to enable students to use techniques of patient-centred communication to elicit and provide information to patients in order to involve them as informed partners in decision making processes. The SOKO curriculum consists of 57 lessons for the individual student from the first bachelor year to the first master year. Teaching encompasses lectures and small group learning. Didactic methods include role play, video feedback, and consultations with simulated and real patients. Summative assessment takes place in objective structured clinical examinations (OSCE). CONCLUSION: In Basel, a longitudinal SOKO curriculum based on students' cumulative learning was successfully implemented. Goals and contents were coordinated with the remaining curriculum and are regularly assessed in OSCEs. At present, most of the workload rests on the shoulders of the department of psychosomatic medicine at the university hospital. For the curriculum to be successful in the long-term, sustainable structures need to be instituted at the medical faculty and the university hospital to guarantee high quality teaching and assessment. PMID- 24062812 TI - The effects of anonymity on student ratings of teaching and course quality in a bachelor degree programme. AB - RESEARCH QUESTION: Are there any clear differences between the outcomes of anonymous and personalised student evaluations of teaching quality? METHODS: During a two-year period students were randomly divided into two separate groups, "anonymous" and "personalised", for end-of-module evaluations. The quality of the module was assessed using a standardised questionnaire. Additionally, students were given the option to add "further comments" if they wanted to highlight specifics. These optional comments were independently assessed by three people, using a five-dimensional rating instrument: positive/negative; differentiated/absolute; naming a person/general; containing an order/neutral; visually accentuated/blank. The database consisted of 615 evaluation forms, of which 306 were completed anonymously. In order to identify whether there were any differences between the anonymous and personalised data, a multivariate variance analysis was performed. Based on the scale, the answers to the questions and the quality of the comments were evaluated. Furthermore, an assessment was made to determine if there were any differences in the number of optional comments between the two groups. RESULTS: No significant differences were identified in the informative quality of data between the anonymous and personalised student evaluations. However, students in the personalised group had a tendency to include more details in their written answers. CONCLUSION: Personalised evaluations do not generate more biased results in terms of social desirability, as long as the evaluation concept is characterised by a closed-circle process and is transparent. In other words, it is imperative that the outcomes of the evaluation are reported back to the students. Moreover, there has to be an opportunity for students to discuss any further suggestions and/or future desires in an open environment. In this way the students respect and understand that their feedback is being taken seriously; consequently, they feel able to provide a constructive and honest evaluation. PMID- 24062813 TI - Increase in medical knowledge during the final year of undergraduate medical education in Germany. AB - AIMS: In Germany, the final year of undergraduate medical education ('practice year') consists of three 16-week clinical attachments, two of which are internal medicine and surgery. Students can choose a specific specialty for their third 16 week attachment. Practice year students do not receive specific teaching to prepare them for the National Licensing Examination. It is unknown whether knowledge levels increase during this year. This study aimed at assessing knowledge at the beginning and the end of the final year of medical school. METHODS: Three hundred pre-selected United States Medical Licensing Examination type items from ten medical disciplines were reviewed by ten recent medical graduates from the Netherlands and Germany. The resulting test included 150 items and was taken by 77 and 79 final year medical students from Gottingen and Hamburg at the beginning and the end of their practice year, respectively. RESULTS: Cronbach's alpha of the pre- and post-test was 0.75 and 0.68, respectively. Mean percent scores in the pre- and post-test were 63.9+/-6.9 and 69.4+/-5.7, respectively (p<0.001; effect size calculated as Cohen's d: 0.87). In individual students, post-test scores were particularly high for items related to their specific chosen specialty. CONCLUSION: The knowledge test used in this study provides a suitable external tool to assess progress of undergraduate medical students in their knowledge during the practice year. The pre-test may be used to guide individual learning behaviour during this final year of undergraduate education. PMID- 24062814 TI - Student evaluation of problem-based learning in a dental orthodontic curriculum- a pilot study. AB - OBJECTIVE: The present questionnaire survey investigated student reception of problem-based learning (PBL) in the orthodontic curriculum with regard to acceptance, sense of purpose and motivation, knowledge and understanding, as well as tutorial support. METHODS: Over a period of two terms, we compared two different didactic methods (PBL and short presentations) by randomizing the participants of a course on orthodontic diagnostics into two different groups, who inversed methods after the first term. RESULTS: The two student groups did not show any significant differences with regard to assessments or examination performance. Therefore, acceptance of the PBL concept seems to be mainly associated with the motivation of individuals to use this method. The higher the motivation, the more positive is the attitude towards the PBL concept. Students seem to work more constructively and efficiently with PBL if they can judge the concept meaningful for themselves. CONCLUSION: In consideration of the relevant literature and the present results, PBL can be principally integrated into the dental curriculum as a method of learning. However, student motivation is vital to learning success. PMID- 24062815 TI - Use of elaborate feedback and an audience-response-system in dental education. AB - INTRODUCTION: The aim of the study was to examine the effect of an elaborate feedback and an audience response system (ARS) on learning success. METHODS: Students of the 1st clinical semester were randomly assigned to a study and a control group. The randomization was carried out considering the factors of age, gender and power spectrum during preliminary dental examination. Within 10 lectures 5 multiple-choice questions were asked about the learning objectives and answered by the students using an ARS. Only the study group received an immediate comprehensive feedback on the results. A final exam at the end was carried out in order to evaluate whether the elaborate feedback leads to a successful learning. Furthermore the effect of the ARS on the lecture atmosphere was investigated. RESULT: The results of the final exams showed no significant difference between the study and the control group regarding the learning success. CONCLUSION: Although no significant effect on learning success was found, the ARS creates a more interactive, positive learning environment. PMID- 24062816 TI - Effects and sustainability of trainings for the oral and practical part of the German final exam in medicine. AB - STUDY GOALS: It is known that the manifold limitations of oral and practical examinations can be improved by specific training. With the help of an online survey, our present study analyzes the effects that can be achieved by the training conducted at the University of Ulm for examiners in the final medical examination, the long-lasting impact of the training, and differences among participant subgroups. METHOD: All 367 participants in the training at Ulm (2007- 2012) were contacted via email. Sixty-three persons responded to the survey that included 28 items concerning demographic data, effectiveness, and sustainability. RESULTS: Six main effects of the training were identified (meaning effects rated with a grade of 1 or 2 on a 6-point scale by two thirds of the participants, with 1="applicable" and 6="not applicable"; cumulated percentage of answers of 1 or 2 in parentheses): 1. Conscious handling of strengths and weaknesses of oral examinations (71%), 2. Knowledge of factors contributing to the reliability of oral/practical examinations (76%), 3. Knowledge of factors contributing to the validity of oral/practical examinations (75%), 4. Improvement of competence in task construction (68%), 5. Improvement of competence in respect to examination formalities (75%), 6. Implementation of the concept of "structured oral examinations" (a priori planning of examination subjects, tasks, levels of expectation and grading criteria) (86%). The responses of participants trained more than two years ago were not significantly different from the answers given by recently trained persons. This is an argument for the sustainability of the training effects. Furthermore, participants without relevant prior experience in oral/practical examinations profited significantly more from the trainings, especially in the areas of stress reduction, confidence in grading, and competence in critical discrimination of grading. CONCLUSION: The positive and sustained effects of the examiner training argue for continuing the training program, especially for inexperienced examiners. Expansion of the successful training program to include the first medical exam should be considered. PMID- 24062817 TI - Sustained change in didactic skills--does teacher training last? AB - Teacher training programmes are necessary assets in faculty development. Few data exist on their long-term effects on participants' teaching skills. Our aim was to study participants' didactic competencies up to four years after attending a newly established faculty development workshop at Hamburg Medical School. Of the 322 participants who attended our teacher training between 2006 and 2009, 313 received a self-assessment and evaluation questionnaire in 2010. This follow-up self-assessment (t2) was compared with their self-assessment of the same didactic competencies before (t0) and directly after (t1) the training. Correlations between participants' personal reasons to attend the workshop and their assessment of didactic competencies were investigated. Self-assessment was significantly higher at the time of follow-up (t2) for all cohorts compared to the assessment before the workshop (t0). Personal reasons for participation differed greatly between voluntary and mandatory. However, self-assessment of the didactic competencies (t2) was not different between these groups. Participants involved in objective structured clinical examinations (OSCE) rated their competency in this field higher than participants without OSCE involvement. In conclusion, teacher training can be effective in the long run even when participation is mandatory. Competencies seem to be retained best when the content of the training fits participants' teaching activities. PMID- 24062818 TI - Challenges for medical educators: results of a survey among members of the German Association for Medical Education. AB - BACKGROUND: Despite the increasing interest in medical education in the German speaking countries, there is currently no information available on the challenges which medical educators face. To address this problem, we carried out a web-based survey among the members of the Association for Medical Education (Gesellschaft fur medizinische Ausbildung, GMA). METHODS: A comprehensive survey was carried out on the need for further qualifications, expertise and the general conditions of medical educators in Germany. As part of this study, the educators were asked to list the three main challenges which they faced and which required urgent improvement. The results were analysed by means of qualitative content analysis. RESULTS: The questionnaire was completed by 147 of the 373 members on the GMA mailing list (response rate: 39%). The educators named a total of 346 challenges and emphasised the following areas: limited academic recognition for engagement in teaching (53.5% of educators), insufficient institutional (31.5%) and financial support (28.4%), a curriculum in need of reform (22.8%), insufficient time for teaching assignments (18,9%), inadequate teacher competence in teaching methods (18.1%), restricted faculty development programmes (18.1%), limited networking within the institution (11.0%), lack of teaching staff (10.2%), varying preconditions of students (8.7%), insufficient recognition and promotion of medical educational research (5.5%), extensive assessment requirements (4.7%), and the lack of role models within medical education (3.2%). CONCLUSION: The medical educators found the biggest challenges which they faced to be limited academic recognition and insufficient institutional and financial support. Consequently, improvements should be implemented to address these issues. PMID- 24062819 TI - The ZMA and the impact factor. PMID- 24062820 TI - The rapid generation of isothiocyanates in flow. AB - Isothiocyanates are versatile starting materials for a wide range of chemical reactions. However, their high nucleophilic susceptibility means they are best prepared and used immediately. We report here on a flow platform for the fast and efficient formation of isothiocyanates by the direct conversion of easily prepared chloroximes. To expedite this chemistry a flow insert cartridge containing two immobilised reagents is used to affect the chemical transformation which typically eliminates the requirements for any conventional work-up or purification of the reaction stream. PMID- 24062821 TI - Computational study of the rate constants and free energies of intramolecular radical addition to substituted anilines. AB - The intramolecular radical addition to aniline derivatives was investigated by DFT calculations. The computational methods were benchmarked by comparing the calculated values of the rate constant for the 5-exo cyclization of the hexenyl radical with the experimental values. The dispersion-corrected PW6B95-D3 functional provided very good results with deviations for the free activation barrier compared to the experimental values of only about 0.5 kcal mol(-1) and was therefore employed in further calculations. Corrections for intramolecular London dispersion and solvation effects in the quantum chemical treatment are essential to obtain consistent and accurate theoretical data. For the investigated radical addition reaction it turned out that the polarity of the molecules is important and that a combination of electrophilic radicals with preferably nucleophilic arenes results in the highest rate constants. This is opposite to the Minisci reaction where the radical acts as nucleophile and the arene as electrophile. The substitution at the N-atom of the aniline is crucial. Methyl substitution leads to slower addition than phenyl substitution. Carbamates as substituents are suitable only when the radical center is not too electrophilic. No correlations between free reaction barriers and energies (DeltaG (?) and DeltaG R) are found. Addition reactions leading to indanes or dihydrobenzofurans are too slow to be useful synthetically. PMID- 24062822 TI - Anodic coupling of carboxylic acids to electron-rich double bonds: A surprising non-Kolbe pathway to lactones. AB - Carboxylic acids have been electro-oxidatively coupled to electron-rich olefins to form lactones. Kolbe decarboxylation does not appear to be a significant competing pathway. Experimental results indicate that oxidation occurs at the olefin and that the reaction proceeds through a radical cation intermediate. PMID- 24062823 TI - A scalable synthesis of the (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5 dihydrooxazole ((S)-t-BuPyOx) ligand. AB - An efficient method for the synthesis of the (S)-4-(tert-butyl)-2-(pyridin-2-yl) 4,5-dihydrooxazole ((S)-t-BuPyOx) ligand has been developed. Inconsistent yields and tedious purification in known routes to (S)-t-BuPyOx suggested the need for an efficient, dependable, and scalable synthetic route. Furthermore, a route suitable for the synthesis of PyOx derivatives is desirable. Herein, we describe the development of a three-step route from inexpensive and commercially available picolinic acid. This short procedure is amenable to multi-gram scale synthesis and provides the target ligand in 64% overall yield. PMID- 24062824 TI - New tridecapeptides of the theonellapeptolide family from the Indonesian sponge Theonella swinhoei. AB - Chemical analysis of the organic extract of Theonella swinhoei yielded two new tridecadepsipeptides of the theonellapeptolide family, namely sulfinyltheonellapeptolide, characterized by a methylsulfinylacetyl group at the N-terminus, and theonellapeptolide If, the first member of this class of compounds to show four valine residues. The structures of the compounds, isolated along with the known theonellapeptolide Id, were determined by extensive 2D NMR and MS/MS analyses followed by application of Marfey's method. The isolated peptides exhibited moderate antiproliferative activity against HepG2 cells, a hepatic carcinoma cell line. PMID- 24062825 TI - Polymeric redox-responsive delivery systems bearing ammonium salts cross-linked via disulfides. AB - A redox-responsive polycationic system was synthesized via copolymerization of N,N-diethylacrylamide (DEAAm) and 2-(dimethylamino)ethyl methacrylate (DMAEMA). N,N'-bis(4-chlorobutanoyl)cystamine was used as disulfide-containing cross-linker to form networks by the quaternization of tertiary amine groups. The insoluble cationic hydrogels become soluble by reduction of disulfide to mercaptanes by use of dithiothreitol (DTT), tris(2-carboxyethyl)phosphine (TCEP) or cysteamine, respectively. The soluble polymeric system can be cross-linked again by using oxygen or hydrogen peroxide under basic conditions. The redox-responsive polymer networks can be used for molecular inclusion and controlled release. As an example, phenolphthalein, methylene blue and reactive orange 16 were included into the network. After treatment with DTT a release of the dye could be recognized. Physical properties of the cross-linked materials, e.g., glass transition temperature (T g), swelling behavior and cloud points (T c) were investigated. Redox-responsive behavior was further analyzed by rheological measurements. PMID- 24062826 TI - Bromination of hydrocarbons with CBr4, initiated by light-emitting diode irradiation. AB - The bromination of hydrocarbons with CBr4 as a bromine source, induced by light emitting diode (LED) irradiation, has been developed. Monobromides were synthesized with high efficiency without the need for any additives, catalysts, heating, or inert conditions. Action and absorption spectra suggest that CBr4 absorbs light to give active species for the bromination. The generation of CHBr3 was confirmed by NMR spectroscopy and GC-MS spectrometry analysis, indicating that the present bromination involves the homolytic cleavage of a C-Br bond in CBr4 followed by radical abstraction of a hydrogen atom from a hydrocarbon. PMID- 24062827 TI - Thermochemistry and photochemistry of spiroketals derived from indan-2-one: Stepwise processes versus coarctate fragmentations. AB - Coarctate reactions are defined as reactions that include atoms at which two bonds are made and two bonds are broken simultaneously. In the pursuit of the discovery of new coarctate reactions we investigate the fragmentation reactions of cyclic ketals. Three ketals with different ring sizes derived from indan-2-one were decomposed by photolysis and pyrolysis. Particularly clean is the photolysis of the indan-2-one ketal 1, which gives o-quinodimethane, carbon dioxide and ethylene. The mechanism formally corresponds to a photochemically allowed coarctate fragmentation. Pyrolysis of the five-ring ketal yields a number of products. This is in agreement with the fact that coarctate fragmentation observed upon irradiation would be thermochemically forbidden, although this exclusion principle does not hold for chelotropic reactions. In contrast, fragmentation of the seven-ring ketal 3 is thermochemically allowed and photochemically forbidden. Upon pyrolysis of 3 several products were isolated that could be explained by a coarctate fragmentation. However, the reaction is less clean and stepwise mechanisms may compete. PMID- 24062829 TI - Chemistry in flow systems III. PMID- 24062828 TI - Organocatalyzed enantioselective desymmetrization of aziridines and epoxides. AB - Enantioselective desymmetrization of meso-aziridines and meso-epoxides with various nucleophiles by organocatalysis has emerged as a cutting-edge approach in recent years. This review summarizes the origin and recent developments of enantioselective desymmetrization of meso-aziridines and meso-epoxides in the presence of organocatalysts. PMID- 24062830 TI - Gallium-containing polymer brush film as efficient supported Lewis acid catalyst in a glass microreactor. AB - Polystyrene sulfonate polymer brushes, grown on the interior of the microchannels in a microreactor, have been used for the anchoring of gallium as a Lewis acid catalyst. Initially, gallium-containing polymer brushes were grown on a flat silicon oxide surface and were characterized by FTIR, ellipsometry, and X-ray photoelectron spectroscopy (XPS). XPS revealed the presence of one gallium per 2 3 styrene sulfonate groups of the polymer brushes. The catalytic activity of the Lewis acid-functionalized brushes in a microreactor was demonstrated for the dehydration of oximes, using cinnamaldehyde oxime as a model substrate, and for the formation of oxazoles by ring closure of ortho-hydroxy oximes. The catalytic activity of the microreactor could be maintained by periodic reactivation by treatment with GaCl3. PMID- 24062831 TI - The preparation of several 1,2,3,4,5-functionalized cyclopentane derivatives. AB - With the goal of eventually synthesizing [5]radialene (3), the still missing member of the parent radialene hydrocarbons, we have prepared the pentaacetates 21 and 31, the pentabromide 29 and the hexabromide 32. In principle these should be convertible by elimination reactions to the desired target molecule. PMID- 24062832 TI - Aerobic radical multifunctionalization of alkenes using tert-butyl nitrite and water. AB - Water induces a change in the product of radical multifunctionalization reactions of aliphatic alkenes involving an sp(3) C-H functionalization by an 1,5-hydrogen shift using tert-butyl nitrite and molecular oxygen. The reaction without water, reported previously, gives nitrated gamma-lactols, whereas the reaction in the presence of water produces 4-hydroxy-5-nitropentyl nitrate or 4-hydroxy-3 nitropentyl nitrate derivatives. PMID- 24062834 TI - Gold-catalyzed intermolecular coupling of sulfonylacetylene with allyl ethers: [3,3]- and [1,3]-rearrangements. AB - Gold-catalyzed intermolecular couplings of sulfonylacetylenes with allyl ethers are reported. A cooperative polarization of alkynes both by a gold catalyst and a sulfonyl substituent resulted in an efficient intermolecular tandem carboalkoxylation. Reactions of linear allyl ethers are consistent with the [3,3] sigmatropic rearrangement mechanism, while those of branched allyl ethers provided [3,3]- and [1,3]-rearrangement products through the formation of a tight ion-dipole pair. PMID- 24062833 TI - Iron-catalyzed decarboxylative alkenylation of cycloalkanes with arylvinyl carboxylic acids via a radical process. AB - A Fe(acac)3-catalyzed decarboxylative coupling of 2-(aryl)vinyl carboxylic acids with cycloalkanes was developed by using DTBP as an oxidant through a radical process. This reaction tolerates a wide range of substrates, and products are obtained in good to excellent yields (71-95%). The reaction also shows excellent stereoselectivity, and only trans-isomers are obtained. PMID- 24062835 TI - Synthesis and quantitative structure-activity relationship study of substituted imidazophosphor ester based tetrazolo[1,5-b]pyridazines as antinociceptive/anti inflammatory agents. AB - A high-yielding general synthesis of imidazophosphor ester based tetrazolo[1,5 b]pyridazines is described. A conjugated reaction between 3,6-diazidopyridazine and different types of phosphonyl carbanion reagents followed by intramolecular cyclization afforded the target products, by using sodium ethanolate solution as a reaction medium. Among the products, five compounds, at a dose of 50 mg per kilogram body weight, showed a notable antinociceptive and anti-inflammatory activity without toxic side-effects. PMID- 24062836 TI - Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step. AB - Piperazirum, isolated from Arum palaestinum Boiss, was originally assigned as r 3,c-5-diisobutyl-c-6-isopropylpiperazin-2-one. The reported structure was synthesised diastereoselectively using a key nitro-Mannich reaction to set up the C5/C6 relative stereochemistry. The structure was unambiguously assigned by single crystal X-ray diffraction but the spectroscopic data did not match those reported for the natural product. The structure of the natural product must therefore be revised. PMID- 24062837 TI - [3 + 2]-Cycloadditions of nitrile ylides after photoactivion of vinyl azides under flow conditions. AB - The photodenitrogenation of vinyl azides to 2H-azirines by using a photoflow reactor is reported and compared with thermal formation of 2H-azirines. Photochemically, the ring of the 2H-azirines was opened to yield the nitrile ylides, which underwent a [3 + 2]-cycloaddition with 1,3-dipolarophiles. When diisopropyl azodicarboxylate serves as the dipolarophile, 1,3,4-triazoles become directly accessible starting from the corresponding vinyl azide. PMID- 24062838 TI - Gold-catalyzed cyclization of allenyl acetal derivatives. AB - The gold-catalyzed transformation of allenyl acetals into 5-alkylidenecyclopent-2 en-1-ones is described. The outcome of our deuterium labeling experiments supports a 1,4-hydride shift of the resulting allyl cationic intermediates because a complete deuterium transfer is observed. We tested the reaction on various acetal substrates bearing a propargyl acetate, giving 4-methoxy-5 alkylidenecyclopent-2-en-1-ones 4 via a degradation of the acetate group at the allyl cation intermediate. PMID- 24062839 TI - Straightforward synthesis of a tetrasaccharide repeating unit corresponding to the O-antigen of Escherichia coli O16. AB - A straightforward synthesis of the tetrasaccharide repeating unit of the O antigen of Escherichia coli O16 has been achieved following a sequential glycosylation strategy. A minimum number of steps was used for the synthesis of the target compound involving a one-pot glycosylation and a protecting group manipulation. All intermediate reactions afford their products in high yield, and the glycosylation steps are stereoselective. PMID- 24062840 TI - Zinc-gold cooperative catalysis for the direct alkynylation of benzofurans. AB - The direct alkynylation of benzofurans was achieved for the first time using the hypervalent iodine reagent 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H) one (TIPS-EBX) based on the cooperative effect between a gold catalyst and a zinc Lewis acid. High selectivity was observed for C2-alkynylation of benzofurans substituted with alkyl, aryl, halogen and ether groups. The reaction was also successful in the case of the more complex drug 8-methoxypsoralen (8-MOP). PMID- 24062841 TI - Activation of cryptic metabolite production through gene disruption: Dimethyl furan-2,4-dicarboxylate produced by Streptomyces sahachiroi. AB - At least 65% of all small molecule drugs on the market today are natural products, however, re-isolation of previously identified and characterized compounds has become a serious impediment to the discovery of new bioactive natural products. Here, genetic knockout of an unusual non-ribosomal peptide synthetase (NRPS) C-PCP-C module, aziA2, is performed resulting in the accumulation of the secondary metabolite, dimethyl furan-2,4-dicarboxylate. The cryptic metabolite represents the first non-azinomycin related compound to be isolated and characterized from the soil bacterium, S. sahachiroi. The results from this study suggest that abolishing production of otherwise predominant natural products through genetic knockout may constitute a means to "activate" the production of novel secondary metabolites that would otherwise lay dormant within microbial genome sequences. PMID- 24062842 TI - Gold(I)-catalyzed formation of furans from gamma-acyloxyalkynyl ketones. AB - Various gamma-acyloxyalkynyl ketones were efficiently converted into highly substituted furans with 2.5 mol % of triflimide (triphenylphosphine)gold(I) as a catalyst in dichloroethane at 70 degrees C. PMID- 24062843 TI - The application of a monolithic triphenylphosphine reagent for conducting Ramirez gem-dibromoolefination reactions in flow. AB - The application of a monolithic form of triphenylphosphine to the Ramirez gem dibromoolefination reaction using flow chemistry techniques is reported. A variety of gem-dibromides were synthesised in high purity and excellent yield following only removal of solvent and no further off-line purification. It is also possible to perform the Appel reaction using the same monolith and the relationship between the mechanisms of the two reactions is discussed. PMID- 24062844 TI - Flow Giese reaction using cyanoborohydride as a radical mediator. AB - Tin-free Giese reactions, employing primary, secondary, and tertiary alkyl iodides as radical precursors, ethyl acrylate as a radical trap, and sodium cyanoborohydride as a radical mediator, were examined in a continuous flow system. With the use of an automated flow microreactor, flow reaction conditions for the Giese reaction were quickly optimized, and it was found that a reaction temperature of 70 degrees C in combination with a residence time of 10-15 minutes gave good yields of the desired addition products. PMID- 24062845 TI - Gold(I)-catalysed one-pot synthesis of chromans using allylic alcohols and phenols. AB - A gold(I)-catalysed reaction of allylic alcohols and phenols produces chromans regioselectively via a one-pot Friedel-Crafts allylation/intramolecular hydroalkoxylation sequence. The reaction is mild, practical and tolerant of a wide variety of substituents on the phenol. PMID- 24062846 TI - A practical synthesis of long-chain iso-fatty acids (iso-C12-C19) and related natural products. AB - A gram-scale synthesis of terminally-branched iso-fatty acids (iso-C12-C19) was developed commencing with methyl undec-10-enoate (methyl undecylenate) (for iso C12-C14) or the C15 and C16 lactones pentadecanolide (for iso-C15-C17) and hexadecanolide (for iso-C18-C19). Central to the approaches outlined is the two step construction of the terminal isopropyl group through addition of methylmagnesium bromide to the ester/lactones and selective reduction of the resulting tertiary alcohols. Thus, the C12, C17 and C18 iso-fatty acids were obtained in three steps from commercially-available starting materials, and the remaining C13-C16 and C19 iso-fatty acids were prepared by homologation or recursive dehomologations of these fatty acids or through intercepting appropriate intermediates. Highlighting the synthetic potential of the iso-fatty acids and various intermediates prepared herein, we describe the synthesis of the natural products (S)-2,15-dimethylpalmitic acid, (S)-2-hydroxy-15-methylpalmitic acid, and 2-oxo-14-methylpentadecane. PMID- 24062847 TI - Ethyl diazoacetate synthesis in flow. AB - Ethyl diazoacetate is a versatile compound in organic chemistry and frequently used on lab scale. Its highly explosive nature, however, severely limits its use in industrial processes. The in-line coupling of microreactor synthesis and separation technology enables the synthesis of this compound in an inherently safe manner, thereby making it available on demand in sufficient quantities. Ethyl diazoacetate was prepared in a biphasic mixture comprising an aqueous solution of glycine ethyl ester, sodium nitrite and dichloromethane. Optimization of the reaction was focused on decreasing the residence time with the smallest amount of sodium nitrite possible. With these boundary conditions, a production yield of 20 g EDA day(-1) was achieved using a microreactor with an internal volume of 100 MUL. Straightforward scale-up or scale-out of microreactor technology renders this method viable for industrial application. PMID- 24062848 TI - The first example of the Fischer-Hepp type rearrangement in pyrimidines. AB - A N-nitroso moiety can be used for the activation of chloropyrimidines toward a nucleophilic substitution reaction with amines. The subsequent treatment of the obtained products with aq H2SO4 can lead to either N-denitrosation to obtain 4,6 pyrimidinediamines or to a Fischer-Hepp type rearrangement to obtain 5-nitroso 4,6-pyrimidinediamines. It was found that the outcome of the reaction strongly depends on the structure of the pyrimidines. Activation of the pyrimidine ring by three groups with a positive mesomeric effect is crucial for the intramolecular nitroso group migration. PMID- 24062849 TI - Self-assembly of 2,3-dihydroxycholestane steroids into supramolecular organogels as a soft template for the in-situ generation of silicate nanomaterials. AB - Supramolecular gels are an important and interesting class of soft materials that show great potential for many applications. Most of them have been discovered serendipitously, and understanding the supramolecular self-assembly that leads to the formation of the gel superstructure is the key to the directed design of new organogels. We report herein the organogelating property of four stereoisomers of the simple steroid 2,3-dihydroxycholestane. Only the isomer with the trans diaxial hydroxy groups had the ability to gelate a broad variety of liquids and, thus, to be a super-organogelator for hydrocarbons. The scope of solvent gelation was analysed with regard to two solvent parameters, namely the Kamlet-Taft and the Hansen solubility parameters. The best correlation was observed with the Hansen approach that revealed the existence of two clear gelation zones. We propose a general model of self-assembly through multiple intermolecular hydrogen bonds between the 1,2-dihydroxy system, which is based on experimental data and computational simulations revealing the importance of the di-axial orientation of the hydroxy groups for the one-dimensional self-assembly. Under controlled conditions, the fibrillar superstructure of the organogel was successfully used as a template for the in-situ sol-gel polymerization of tetraethoxysilane and the further preparation of silica nanotubes. We propose that the driving forces for templating are hydrogen bonding and electrostatic interactions between the anionic silicate intermediate species and the self-assembled fibrillar network. PMID- 24062850 TI - Integrating reaction and analysis: investigation of higher-order reactions by cryogenic trapping. AB - A new approach for the investigation of a higher-order reaction by on-column reaction gas chromatography is presented. The reaction and the analytical separation are combined in a single experiment to investigate the Diels-Alder reaction of benzenediazonium-2-carboxylate as a benzyne precursor with various anthracene derivatives, i.e. anthracene, 9-bromoanthracene, 9 anthracenecarboxaldehyde and 9-anthracenemethanol. To overcome limitations of short reaction contact times at elevated temperatures a novel experimental setup was developed involving a cooling trap to achieve focusing and mixing of the reactants at a defined spot in a fused-silica capillary. This trap functions as a reactor within the separation column in the oven of a gas chromatograph. The reactants are sequentially injected to avoid undefined mixing in the injection port. An experimental protocol was developed with optimized injection intervals and cooling times to achieve sufficient conversions at short reaction times. Reaction products were rapidly identified by mass spectrometric detection. This new approach represents a practical procedure to investigate higher-order reactions at an analytical level and it simultaneously provides valuable information for the optimization of the reaction conditions. PMID- 24062851 TI - Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions. AB - An apparatus is reported for real-time Raman monitoring of reactions performed using continuous-flow processing. Its capability is assessed by studying four reactions, all involving formation of products bearing alpha,beta-unsaturated carbonyl moieties; synthesis of 3-acetylcoumarin, Knoevenagel and Claisen-Schmidt condensations, and a Biginelli reaction. In each case it is possible to monitor the reactions and also in one case, by means of a calibration curve, determine product conversion from Raman spectral data as corroborated by data obtained using NMR spectroscopy. PMID- 24062852 TI - Asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates with alpha fluoro-beta-keto esters. AB - In the presence of a commercially available Cinchona alkaloid as catalyst, the asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates, with alpha fluoro-beta-keto esters as nucleophiles, have been successfully developed. A series of important fluorinated adducts, with chiral quaternary carbon centres containing a fluorine atom, was achieved in good yields (up to 93%), with good to excellent enantioselectivities (up to 96% ee) and moderate diastereoselectivities (up to 4:1 dr). PMID- 24062853 TI - Topochemical control of the photodimerization of aromatic compounds by gamma cyclodextrin thioethers in aqueous solution. AB - The formation of soluble 1:2 complexes within hydrophilic gamma-cyclodextrin (gamma-CD) thioethers allows to perform photodimerizations of aromatic guests under controlled, homogenous reaction conditions. The quantum yields for unsubstituted anthracene, acenaphthylene, and coumarin complexed in these gamma CD thioethers were found to be up to 10 times higher than in the non-complexed state. The configuration of the photoproduct reflected the configuration of the dimeric inclusion complex of the guest. Anti-parallel orientation of acenaphthylene within the CD cavity led to the exclusive formation of the anti photo-dimer in quantitative yield. Parallel orientation of coumarin within the complex of a CD thioether led to the formation of the syn head-to-head dimer. The degree of complexation of coumarin could be increased by employing the salting out effect. PMID- 24062854 TI - Synthesis of mucin-type O-glycan probes as aminopropyl glycosides. AB - The chemical synthesis of a series of mucin-type oligosaccharide fragments 1-7 containing an alpha-linked aminopropyl spacer ready for glycoarray attachment is reported. A highly convergent and stereoselective strategy that employs two different orthogonal protected galactosamine building blocks was used to access all of the targets. A tandem deprotection sequence, that did not require chromatography-based purification between steps, was employed to globally unmask all protecting groups and all final targets were isolated in good to excellent yields. PMID- 24062855 TI - Cyclization of substitued 2-(2-fluorophenylazo)azines to azino[1,2 c]benzo[d][1,2,4]triazinium derivatives. AB - Light-induced cyclization of several substituted 2-(2-fluorophenylazo)azines in the presence of Ca(2+) ions to the corresponding triazinium derivatives is investigated experimentally and computationally. The azo derivatives of 4 methylpyridine 4 undergo facile cyclization to the corresponding triazinium 1, and the rate of cyclization increases with increasing number of fluorine atoms at the benzene ring. No triazinium ions were obtained from azo derivatives of 4 cyanopyridine, pyrazine and pyrimidine, presumably due to their instability under the reaction conditions. The experimental results and mechanism are discussed with the aid of DFT computational results. PMID- 24062856 TI - Creating complexity. PMID- 24062857 TI - Continuous flow photocyclization of stilbenes - scalable synthesis of functionalized phenanthrenes and helicenes. AB - A continuous flow oxidative photocyclization of stilbene derivatives has been developed which allows the scalable synthesis of backbone functionalized phenanthrenes and helicenes of various sizes in good yields. PMID- 24062858 TI - Enantioselective synthesis of planar chiral ferrocenes via palladium-catalyzed annulation with diarylethynes. AB - When Boc-L-Val-OH was used as a ligand for the enantioselective Pd(II)-catalyzed annulation of N,N-substituted aminomethyl ferrocene derivatives with diarylethynes, ferrocenes with planar chirality could be achieved with excellent enantioselectivity (up to 99% ee). PMID- 24062859 TI - Characterization of the Stoichiometry of HMGA1/DNA Complexes. AB - High-mobility group A1 (HMGA1) non-histone chromatin architectural transcription factors regulate gene expression, embryogenesis, cell differentiation, and adaptive immune responses by binding DNA and other transcription factors. HMGA1 has also been shown to be highly over-expressed in many human cancers and is considered to be a valuable cancer biomarker. Elevated HMGA1 expression levels also make cancer cells resistant to chemotherapy. Here, HMGA1/DNA complex formation was investigated using electrophoretic mobility shift assays (EMSA). Collectively, the EMSA results indicated that full length HMGA1 mixed with DNA containing three AT-hook binding sites formed four distinct HMGA1/DNA complexes ranging in stoichiometry from 1:2 to 3:1 in HMGA1:DNA ratio. The data indicated that the distribution of complexes with different HMGA1 to DNA stoichiometries depended on the molar ratio of HMGA1 to DNA in solution, which could have significant biological implications given that HMGA1 is highly over-expressed in human cancer cells. The two naturally occurring isoforms of HMGA1, HMGA1a and HMGA1b, the latter containing an 11 amino acid deletion between the first and second AT-hooks, were observed to have slightly different DNA binding profiles. Finally, HMGA1 binding affinity to DNA was found to be influenced by the DNA A:T segment sequence context, with higher specificity be observed in HMGA1 binding to TnAn segments, which have two local minor groove minima on either side of the TpA step, compared to An:Tn segments, which have a single minor groove minimum at the 3' end of the An run, implying AT-hook binding favors narrow minor groove structure. PMID- 24062860 TI - Perioperative management of patients with rheumatic diseases. AB - This paper aims to explore the assessment of patients with rheumatologic diseases, especially rheumatoid arthritis (RA), before undergoing orthopedic surgery. Perioperative assessment ensures an early diagnosis of the patient's medical condition, overall health, medical co-morbidities, and the assessment of the risk factors associated with the proposed procedures. Perioperative assessment allows for proper postoperative management of complications and of the management of drugs such as disease-modifying anti-rheumatic drugs (DMARD) and anti-platelets, and corticosteroids. The assessment also supports follow up plans, and patient education. Perioperative assessment enables the discussion of the proposed treatment plans and the factors associated with them in each case among the different specialists involved to facilitate an appropriate early decision-making about the assessment and treatment of patients with rheumatologic diseases. It also enables the discussion of both condition and procedure with the patient to ensure a good postoperative care. The article identifies the components of perioperative medical evaluation, discusses perioperative management of co-morbidities and the management of specific clinical problems related to RA, systemic lupus erythematosus, the management of DMARDs, like methotrexate (MTX) and biologic therapies, prophylactic antibiotics, and postoperative follow up, including patient education and rehabilitation. PMID- 24062861 TI - Profiling of hla-B alleles for association studies with ankylosing spondylitis in the chinese population. AB - Human leucocyte antigen (HLA) B*27 is a susceptibility allele to ankylosing spondylitis (AS). However, major AS-associated subtypes of HLA-B*27 and other HLA B alleles vary in different ethnic populations. Herein, we examined HLA-B alleles in a total of 360 AS patients and 350 controls of Chinese Han ancestry. The HLA-B genotyping was performed with sequence-based typing (SBT) method. Six HLA-B*27 subtypes B*27:04, B*27:05, B*27:07, B*27:08, B*27:10 and B*27:15 were observed in the cohorts. HLA-B*27:04:01 and -B*27:05:02 appeared significantly increased in AS patients, which indicated as two major susceptibility alleles to AS. Homozygous B*27 was observed only in AS patients. There are 30 HLA-B alleles identified in the studies. HLA-B*15, especially B*15:01:01:01, appeared as the major allele type in the Chinese controls. Some common HLA-B alleles such as HLA B*15, B*13, B*46 and B*51 were significantly reduced in Chinese AS patients. In conclusion, the studies profiled the HLA-B alleles, and identified major susceptibility subtypes of B27 to AS in Han Chinese population. PMID- 24062862 TI - Relationship between advanced maternal age, hiesho (sensitivity to cold) and abnormal delivery in Japan. AB - BACKGROUND: In Japan, the proportion of women aged 35 and older giving birth has greatly increased in recent years, and maternal age is continuing to increase. Advanced maternal age is a risk factor for abnormal delivery, as is hiesho (sensitivity to cold). RESEARCH QUESTION: This study aimed to assess whether advanced maternal age and hiesho precipitate premature delivery, premature rupture of membranes, weak labor pains, prolonged labor and atonic bleeding. METHOD: The study design was a descriptive comparative study with a retrospective cohort group design. Subjects in this study were 2,810 Japanese women in hospital after childbirth. The research methods employed were a paper questionnaire and extraction of data from medical records. RESULTS: Comparing the rate of occurrence of abnormal delivery among women aged 35 to 39 according to whether or not they had hiesho, results were premature delivery OR: 3.51 (95% CI: 1.66 7.43), premature rupture of membranes OR: 1.25 (95% CI: 0.90-1.74), weak labor pains OR: 2.94 (95% CI: 1.65-5.24), prolonged labor OR: 2.56 (95% CI: 1.23-5.26), and atonic bleeding, OR: 1.65 (95% CI: 0.14-2.40) when hiesho was present. Among women aged 40 and over, results were premature delivery OR: 5.09 (95% CI: 1.16 22.20), premature rupture of membranes OR: 1.60 (95% CI: 0.73-3.46), weak labor pains OR: 7.02 (95% CI: 1.56-31.55), prolonged labor OR:7.19 (95% CI: 1.49-34.60) and atonic bleeding OR: 2.00 (95% CI: 0.64-6.23). CONCLUSIONS: Regardless of maternal age, the presence of hiesho is a risk factor that can precipitate premature delivery, premature rupture of membranes, weak labor pains, prolonged labor and atonic bleeding. Furthermore, hiesho coupled with advanced maternal age increases the incidence of premature delivery, weak labor pains and prolonged labor. PMID- 24062864 TI - Stable low-fouling plasma polymer coatings on polydimethylsiloxane. AB - Polydimethylsiloxane (DMS) is a popular material for microfluidics, but it is hydrophobic and is prone to non-specific protein adsorption. In this study, we explore methods for producing stable, protein resistant, tetraglyme plasma polymer coatings on PDMS by combining extended baking processes with multiple plasma polymer coating steps. We demonstrate that by using this approach, it is possible to produce a plasma polymer coatings that resist protein adsorption (<10 ng/cm(2)) and are stable to storage over at least 100 days. This methodology can translate to any plasma polymer system, enabling the introduction of a wide range of surface functionalities on PDMS surfaces. PMID- 24062863 TI - A microfluidic platform for measuring electrical activity across cells. AB - In this paper, we present a microfluidic chip that is capable of measuring electrical conductance through gap junction channels in a 2-dimensional cell sheet. The chip utilizes a tri-stream laminar flow to create a non-conductive sucrose gap between the two conducting solutions so that electrical current can pass across the sucrose gap only through the cells. Using the chip, we tested the effect of a gap junction inhibitor, 2-APB, on the electrical coupling of connexin 43 (Cx43) gap junction channels in NRK-49F cells. We found that 2-APB reversibly blocks the conductivity in a dose-dependent manner. The tri-stream chip further allows us to simultaneously follow the conductance changes and dye diffusion in real time. We show that 2-APB affects both conductance and diffusion, supporting the interpretation that both sets of data reflect the same gap junction activity. The chip provides a generic platform to investigate gap junction properties and to screen drugs that may inhibit or potentiate gap junction transmission. PMID- 24062865 TI - Full-term newborns with normal birth weight requiring special care in a resource constrained setting. AB - INTRODUCTION: The level of clinical care and facilities to support the often more viable full-term newborns with normal birth weight compared with preterm/low birth weight newborns that require special care at birth are likely to be attainable in many resource-poor settings. However, the nature of the required care is not evident in current literature. This study therefore set out to determine maternal and perinatal profile of surviving full-term newborns with normal birth weight in a poorly-resourced setting. METHODS: A retrospective cohort study of newborns with gestational age >=37 weeks and birth weight >=2500g recruited in an inner-city maternity hospital in Lagos, Nigeria. Primary factors/outcomes were determined by multivariate logistic regression analyses and population attributable risk (PAR). RESULTS: Of the 2687 full-term newborns with normal birth weight studied, 242 (9.0%) were admitted into special care baby unit (SCBU) representing 53.6% of all SCBU admissions. Fetal distress, low 5-minute Apgar scores, neonatal sepsis and hyperbilirubinemia as well as maternal factors such as primiparity, type of employment, lack of antenatal care and emergency cesarean delivery were predictive of SCBU admission. The leading contributors to SCBU admission were neonatal sepsis (PAR=96.8%), and hyperbilirubinemia (PAR=58.7%). CONCLUSION: A significant proportion of newborns requiring special care are full-term with normal birth weight and are associated with modifiable risk factors that can be effectively addressed at appropriately equipped secondary-level hospitals. Prenatal maternal education on avoidable risk factors is warranted. PMID- 24062866 TI - [Investigation and response to an outbreak of wild poliovirus in Kinshasa]. PMID- 24062867 TI - Human papilloma virus (HPV) infection is associated with HIV-1 infection and AIDS in HIV-infected adult patients from Zaria, Northern Nigeria. PMID- 24062868 TI - Pituitary macroadenoma presenting with pituitary apoplexy, acromegaly and secondary diabetes mellitus - a case report. AB - Pituitary adenomas are associated with significant morbidity. The usual symptoms on presentation are of endocrine dysfunction and mass effects. A 31-year-old African female presented with headache, irregular menses, blurring of vision in the right eye and complete loss of vision in the left eye for 1 year. She had coarse facial features, enlarged hands and feet. Her right eye had temporal hemianopia with decreased visual acuity and her left eye had no perception of light. Investigations revealed an elevated fasting blood sugar and an elevated prolactin and growth hormone level. A CT scan and MRI done showed a hemorrhagic pituitary macroadenoma. She was put on bromocriptine, ocreotide, analgesics and insulin. Thereafter, she underwent transphenoidal surgery, where near total resection of the tumor was achieved. Patient is doing well post-operatively. This case highlights the importance of the use of a high clinical index of suspicion and radiological findings in diagnosis. PMID- 24062869 TI - An unusual case of an intramuscular lipoma of the biceps brachii. AB - Lipomas are common benign neoplasms consisting of mature fatty tissue. They are usually of roundish or ovoid shape and are situated in a single anatomical region. They most frequently occur on the back and in the extremities. Most lipomas are subcutaneous and require no imaging evaluation. When deep, large and unusual in location, MRI can identify and localise these tumours and is the best exploration to differentiate lipoma and lipo-sarcoma. We describe a case of a patient with an intramuscular lipoma of the biceps brachii. PMID- 24062870 TI - A Global Review of Melanoma Follow-up Guidelines. AB - Early detection of a melanoma recurrence is a major concern for the clinician. However, the follow-up care of melanoma patients lacks a uniform approach. Different dermatological and oncological organizations have developed their own strategies of follow-up management that vary by specialty and methods of screening for recurrence. Some areas of controversy in the follow-up care of melanoma patients include providers of care, use of staging versus Breslow depth to determine follow-up, the role of imaging and laboratory tests, frequency and duration of physical exams, and psychological well-being. Studies have evaluated these aspects of follow-up management, but no consensus exists. However, it is essential for clinicians to collaborate between specialties for an effective, evidence-based approach to melanoma clinical follow-up care. PMID- 24062872 TI - Photopneumatic technology used in combination with profusion therapy for the treatment of acne. AB - BACKGROUND: Topical and oral medications, such as retinoids, benzoyl peroxide, antibiotics, and isotretinoin, have been the standard of care for the treatment of mild-to-moderate acne for the last several decades. More recently, a number of pubHshed studies on optical treatments, such as ultraviolet light, visible (blue) light, and intense pulsed Hght systems, have also shown clinical improvement in the appearance of acne. Specifically, photopneumatic technology, which utilizes gentle pneumatic energy (vacuum) to draw the target tissue into the treatment tip and then deHver broadband pulsed Hght to the dermal targets, has demonstrated marked improvement in the appearance of acne lesions and side effects associated with acne. OBJECTIVE: To demonstrate the safety and efficacy of using a combination treatment of the photopneumatic system and profusion therapy using three currently marketed topical agents for the treatment of mild-to-moderate acne on the face and/or body, including neck, chest, or back. METHODS: A prospective, multicenter, dinical trial of 41 individuals with mild-to-moderate acne was performed. Patients received up to four treatments at 1- to 2-week intervals with the photopneumatic system and profusion therapy with three separate topical agents. Study investigators and subjects evaluated dinical efficacy at 1-month and 3-month follow-up visits. RESULTS: At three months, a 69 percent reduction was noted in inflamed acne lesions and a 41-percent reduction in noninflamed acne lesions was noted by physician assessment. Additionally, at this same time point, subjects reported moderate-to-marked (26-75%) improvement in acne lesions. Eighty-one percent of subjects (22/27) were either satisfied or very satisfied with treatment outcome. There were no adverse events caused by malfunction of the device, and no serious adverse events or deaths. CONCLUSION: The results, as well as the reported patient satisfaction and safety, suggest that the treatment of acne with the photopneumatic system in combination with profusion using currently available topical acne agents demonstrated significant treatment results. PMID- 24062871 TI - The role of inflammation in the pathology of acne. AB - The conventional perspective of acne pathogenesis holds that Propionibacterium acnes colonizes the duct of the sebaceous follicle, causing an innate immune response and the progression from a so-called noninflammatory comedo to an inflammatory papule, pustule, or nodule. However, this viewpoint has come under increasing scrutiny over the last decade, as evidence has emerged supporting a role for inflammation at all stages of acne lesion development, perhaps subclinically even before comedo formation. The immunochemical pathways underlying the initiation and propagation of the inflammation in acne are complex and still being elucidated, but may involve Propionibacterium acnes as well as several inflammatory mediators and their target receptors, including cytokines, defensins, peptidases, sebum lipids, and neuropeptides. This review presents evidence to support the notion that acne is primarily an inflammatory disease, challenging the current nomenclature of noninflammatory versus inflammatory acne lesions and suggesting that the nomenclature is outdated and incorrect. The evidence in support of acne as an inflammatory disease also has clinical implications, in that anti-inflammatory drugs used to treat the disease can be expected to exert effects against all lesion stages, albeit via distinct mechanisms of anti-inflammation. PMID- 24062873 TI - Impact of botulinum toxin a on the quality of life of subjects following treatment of facial lines. AB - OBJECTIVE: To investigate quality of life and its correlation to patient satisfaction before and after treatment with botulinum toxin A. METHODS: Quality of life was assessed using the Schedule for the Evaluation of Individual Quality of Life Direct-Weighting tool. Patients identified the five areas of their life of the greatest importance to them, weighted the areas as to their relative importance, and rated their status in each area on a visual scale before treatment (old cues) and 28 days later (using both old cues and newly defined and weighted cues). At both visits, patients also rated their overall quality of life using a visual analogue scale. Patient satisfaction with their appearance was measured using a 10-point scale in conjunction with standardized photographs taken at each visit. RESULTS: Fifty-three patients (median age 39.5 years; 87% women) with moderate-to-severe wrinkles of the glabella, forehead, or crow's feet were enrolled. Treatment with incobotulinumtoxinA consistently resulted in a significant improvement in quality of life according to Schedule for the Evaluation of Individual Quality of Life Direct-Weighting tool index scores (old cues, P=0.0006; new cues P=0.0235) and patient assessment of their overall quality of life (P<0.0001 for both old and new cues). Family, work, finance, relationships, and health were the five most frequently identified cues at each assessment. No correlation between quality of life and satisfaction scores was found, although both were significantly increased after treatment. CONCLUSION: These results support the contention that quality of life is significantly improved following botulinum toxin A treatment and that consideration should be given to incorporating the measurement of quality of life as an outcome measure following botulinum toxin A treatment, especially as satisfaction does not correlate to quality of life. PMID- 24062874 TI - Easy as PIE (Postinflammatory Erythema). AB - BACKGROUND: No term exists to date describing the phenomenon of pink-to-red discoloration after an inflammatory acne lesion. OBJECTIVES: To introduce new terminology into the dermatology literature to describe erythema often seen after inflammatory acne vulgaris and to present a treatment option for this type of erythema. METHODS: New terminology describing erythema after inflammatory acne is addressed, and a treatment option for postinflammatory erythema is presented. RESULTS: Postinflammatory erythema is a new, accurate descriptor of erythema that occurs after inflammatory acne. Additionally, pulsed dye laser treatment improved postinflammatory erythema in the authors' patients. LIMITATIONS: This paper only presents anecdotal cases. CONCLUSION: The addition of postinflammatory erythema to the dermatology literature may facilitate accurate communication among providers and direct laser treatment for postinflammatory erythema. PMID- 24062875 TI - Asymptomatic petechial eruption on the lower legs. AB - The authors report an unusual case of Rocky Mountain spotted fever that presented as an asymptomatic petechial eruption on the lower legs. Rocky Mountain spotted fever is rare in New England and, as such, is typically not on the differential diagnosis when presented with such patients. What began as an asymptomatic eruption progressed to more classic signs of the disease, including a positive Rocky Mountain spotted fever titer. The patient was successfully treated with doxycydine and within a short period of time, was completely back at baseline. PMID- 24062876 TI - Ammonium-dependent shortening of CLS in yeast cells starved for essential amino acids is determined by the specific amino acid deprived, through different signaling pathways. AB - Ammonium (NH4(+)) leads to chronological life span (CLS) shortening in Saccharomyces cerevisiae BY4742 cells, particularly evident in cells starved for auxotrophy-complementing amino acids (leucine, lysine, and histidine) simultaneously. Here, we report that the effect of NH4(+) on aging yeast depends on the specific amino acid they are deprived of. Compared with no amino acid starvation, starvation for leucine alone or in combination with histidine resulted in the most pronounced NH4(+)-induced CLS shortening, whereas starvation for lysine, alone or in combination with histidine resulted in the least sensitivity to NH4(+). We also show that NH4(+)-induced CLS shortening is mainly mediated by Tor1p in cells starved for leucine or histidine but by Ras2p in cells starved for lysine, and in nonstarved cells. Sch9p protected cells from the effect of NH4(+) under all conditions tested (starved or nonstarved cells), which was associated with Sch9p-dependent Hog1p phosphorylation. Our data show that NH4(+) toxicity can be modulated through manipulation of the specific essential amino acid supplied to cells and of the conserved Ras2p, Tor1p, and Sch9p regulators, thus providing new clues to the development of environmental interventions for CLS extension and to the identification of new therapeutic targets for diseases associated with hyperammonemia. PMID- 24062877 TI - Oxidative stress is involved in the pathogenesis of Keshan disease (an endemic dilated cardiomyopathy) in China. AB - Oxidative stress and selenoprotein deficiency are thought to be associated with the pathogenesis of Keshan disease (KD). However, to our knowledge, the level of oxidative stress and expression of selenoproteins have not been investigated in the myocardium of patients with KD. In this study, 8-hydroxy-2-deoxy guanosine (8 OH-dG), a marker of oxidative stress, was used to assess the level of oxidative stress, and thioredoxin reductase 1 (TrxR1) and glutathione peroxidase 1 (GPx1) were assessed to reflect the level of selenoproteins. Myocardial samples from 8 patients with KD and 9 non-KD patients (controls) were immunohistochemically stained for 8-OH-dG, TrxR1, and GPx1. The staining intensities were subsequently quantified using Olympus Image-Pro Plus 6.0 software. The data showed that the positive rate of 8-OH-dG expression in myocardial nuclei was higher in the KD group (68.6%) than that in the control group (2.4%). In addition, a positive correlation between the positive rate of 8-OH-dG and the degree of myocardial damage was observed in the KD group. The distribution of TrxR1 and GPx-1 was not associated with the distribution of myocardial damage. The expression of these two selenoproteins was higher in the control group than that in the KD group. Our study represents the first report on the expression profiles of oxidative stress and selenoproteins in the myocardium of patients with KD. The level of oxidative stress significantly increased and was positively correlated with the degree of myocardial damage in patients with KD. The selenoproteins, TrxR1 and GPx1, may have a role in the pathogenesis of KD. PMID- 24062878 TI - Sublethal oxidative stress induces the premature senescence of human mesenchymal stem cells derived from endometrium. AB - The specific responses of mesenchymal stem cells to oxidative stress may play a crucial role in regulation of tissue homeostasis as well as regeneration of organs after oxidative injury. The responses of human endometrium-derived mesenchymal stem cells (hMESCs) to oxidative stress remain still unknown. Herein, we examined the impact of H2O2 on cell viability, induction of premature senescence, and apoptosis. hMESCs were highly resistant to H2O2 compared with human diploid fibroblasts. To test a hypothesis whether hMESCs may undergo oxidative stress-induced premature senescence, cells were briefly exposed to the sublethal H2O2 doses. H2O2-treated cells were permanently arrested, lost Ki67 proliferation marker, and exhibited a senescent phenotype including cell hypertrophy and increased SA- beta -Gal activity. Additionally, in stressed cells the expression levels of p21Cip1, SOD1, SOD2, and GPX1 were elevated. hMESCs survived under stress were not able to resume proliferation, indicating the irreversible loss of proliferative potential. While the low H2O2 doses promoted senescence in hMESCs, the higher H2O2 doses induced also apoptosis in a part of the cell population. Of note, senescent hMESCs exhibited high resistance to apoptosis. Thus, we have demonstrated for the first time that hMESCs may enter a state of premature senescence in response to sublethal oxidative stress. PMID- 24062879 TI - Ethanol and acetate acting as carbon/energy sources negatively affect yeast chronological aging. AB - In Saccharomyces cerevisiae, the chronological lifespan (CLS) is defined as the length of time that a population of nondividing cells can survive in stationary phase. In this phase, cells remain metabolically active, albeit at reduced levels, and responsive to environmental signals, thus simulating the postmitotic quiescent state of mammalian cells. Many studies on the main nutrient signaling pathways have uncovered the strong influence of growth conditions, including the composition of culture media, on CLS. In this context, two byproducts of yeast glucose fermentation, ethanol and acetic acid, have been proposed as extrinsic proaging factors. Here, we report that ethanol and acetic acid, at physiological levels released in the exhausted medium, both contribute to chronological aging. Moreover, this combined proaging effect is not due to a toxic environment created by their presence but is mainly mediated by the metabolic pathways required for their utilization as carbon/energy sources. In addition, measurements of key enzymatic activities of the glyoxylate cycle and gluconeogenesis, together with respiration assays performed in extreme calorie restriction, point to a long-term quiescent program favoured by glyoxylate/gluconeogenesis flux contrary to a proaging one based on the oxidative metabolism of ethanol/acetate via TCA and mitochondrial respiration. PMID- 24062880 TI - Familial dilated cardiomyopathy associated with congenital defects in the setting of a novel VCL mutation (Lys815Arg) in conjunction with a known MYPBC3 variant. AB - Idiopathic dilated cardiomyopathy (DCM) is a primary myocardial disorder characterized by ventricular chamber enlargement and systolic dysfunction. Twenty to fifty percent of idiopathic DCM cases are thought to have a genetic cause. Of more than 30 genes known to be associated with DCM, rare variants in the VCL and MYBPC3 genes have been reported in several cases of DCM. In this report, we describe a family with DCM and congenital abnormalities who carry a novel missense mutation in the VCL gene. More severely affected family members also possess a second missense variant in MYBPC3, raising the possibility that this variant may be a disease modifier. Interestingly, many of the affected individuals also have congenital defects, including two with bicuspid aortic valve with aortic regurgitation. We discuss the implications of the family history and genetic information on management of at-risk individuals with aortic regurgitation. PMID- 24062881 TI - Welcome to the European heart journal: acute cardiovascular care. PMID- 24062882 TI - Welcome to the ESC journal family. PMID- 24062883 TI - The treatment of acute myocardial infarction: the Past, the Present, and the Future. AB - Since Herrick's description of the clinical picture of acute myocardial infarction exactly one century ago (1912), there have been three phases of therapy: Phase 1 (1912-1961, bed rest and 'expectant' treatment); Phase 2 (1961 1974, the coronary care unit); and Phase 3 (1975-present, myocardial reperfusion). We are now on the cusp of Phase 4, which comprises efforts to reduce myocardial perfusion injury as well as regenerative medicine. PMID- 24062884 TI - Conditioning the heart to prevent myocardial reperfusion injury during PPCI. AB - For patients presenting with a ST-segment elevation myocardial infarction (STEMI), early myocardial reperfusion by primary percutaneous coronary intervention (PPCI) remains the most effective treatment strategy for limiting myocardial infarct size, preserving left ventricular systolic function, and preventing the onset of heart failure. Recent advances in PCI technology to improve myocardial reperfusion and the introduction of novel anti-platelet and anti-thrombotic agents to maintain the patency of the infarct-related coronary artery continue to optimize PPCI procedure. However, despite these improvements, STEMI patients still experience significant major adverse cardiovascular events. One major contributing factor has been the inability to protect the heart against the lethal myocardial reperfusion injury, which accompanies PPCI. Past attempts to translate cardioprotective strategies, discovered in experimental studies to prevent lethal myocardial reperfusion injury, into the clinical setting of PPCI have been disappointing. However, a number of recent proof-of-concept clinical studies suggest that the heart can be 'conditioned' to protect itself against lethal myocardial reperfusion injury, as evidenced by a reduction in myocardial infarct size. This can be achieved using either mechanical (such as ischaemic postconditioning, remote ischaemic preconditioning, therapeutic hypothermia, or hyperoxaemia) or pharmacological (such as cyclosporin-A, natriuretic peptide, exenatide) 'conditioning' strategies as adjuncts to PPCI. Furthermore, recent developments in cardiac magnetic resonance (CMR) imaging can provide a non invasive imaging strategy for assessing the efficacy of these novel adjunctive therapies to PPCI in terms of key surrogate clinical endpoints such as myocardial infarct size, myocardial salvage, left ventricular ejection fraction, and the presence of microvascular obstruction or intramyocardial haemorrhage. In this article, we review the therapeutic potential of 'conditioning' to protect the heart against lethal myocardial reperfusion injury in STEMI patients undergoing PPCI. PMID- 24062885 TI - Primary PCI during off-hours is not related to increased mortality. AB - AIM: Previous studies have shown contradictory outcomes in ST-segment elevation myocardial infarction (STEMI) patients who underwent primary percutaneous coronary intervention (pPCI) during off-hours versus regular 'office' hours. We aimed to evaluate the relationship between pPCI timing (off-hours versus regular hours) and mortality in patients with STEMI undergoing pPCI. METHODS: The study population comprised 4352 consecutive STEMI patients treated with pPCI in a high volume centre with a 24/7 programme during 2000-2009. Descriptive statistics and multivariable survival analyses were applied to evaluate the relationship between treatment during off-hours (Monday-Friday, 6.00 pm-8.00 am and weekends) versus regular hours and the incidence of all-cause mortality at 30-day and 4-year follow-up. RESULTS: A total of 2760 patients (63.4%) were treated during off hours and 1592 patients (36.6%) during regular hours. With the exception of smoking, diabetes mellitus, use of glycoprotein IIb/IIIa antagonists and calcium antagonists, no major differences in baseline characteristics were observed between the groups. Mortality at 30-day follow-up was similar in patients treated during off-hours and those treated during regular hours (7.7% vs 7.7%; hazard ratio adjusted for potential confounders 1.03; 95% CI 0.82-1.28). Four-year mortality was similar (17.3% vs 17.3%; adjusted hazard ratio 0.95; 95% CI 0.81 1.11). CONCLUSION: In STEMI patients who present during off-hours in a high volume centre with 24/7 service, pPCI provides similar survival as patients who were treated during regular hours. PMID- 24062886 TI - STEMI mortality in community hospitals versus PCI-capable hospitals: results from a nationwide STEMI network programme. AB - AIMS: Reports examining local ST elevation myocardial infarction (STEMI) networks focused mainly on percutaneous coronary intervention (PCI)-related time issues and outcomes. To validate the concept of STEMI networks in a real-world context, more data are needed on management and outcome of an unselected community based STEMI population. METHODS AND RESULTS: The current study evaluated reperfusion strategies and in-hospital mortality in 8500 unselected STEMI patients admitted to 47 community hospitals (n=3053) and 25 PCI-capable hospitals (n=5447) in the context of a nationwide STEMI network programme that started in 2007 in Belgium. The distance between the hub and spoke hospitals ranged from 2.2 to 47 km (median 15 km). A propensity score was used to adjust for differences in baseline characteristics. Reperfusion strategy was significantly different with a predominant use of primary PCI (pPCI) in PCI-capable hospitals (93%), compared to a mixed use of pPCI (71%) and thrombolysis (20%) in community hospitals. A door to-balloon time <120 min was achieved in 83% of community hospitals and in 91% of PCI-capable hospitals (p<0.0001). In-hospital mortality was 7.0% in community hospitals versus 6.7% in PCI-capable hospitals with an adjusted odds ratio of 1.1 (95% confidence interval: 0.8-1.4). Between the periods 2007-2008 and 2009-2010, the pPCI rate in community hospitals increased from 60% to 80%, whereas the proportion of conservatively managed patients decreased from 11.1% to 7.9%. CONCLUSION: In a STEMI network with >70% use of pPCI, in-hospital mortality was comparable between community hospitals and PCI-capable hospitals. Participation in the STEMI network programme was associated with an increased adherence to reperfusion guidelines over time. PMID- 24062887 TI - Stent for Life Initiative: where are we standing and where are we going? PMID- 24062888 TI - Right coronary artery dissection following blunt chest trauma. AB - Chest trauma is a major health problem with a high mortality. Myocardial infarction secondary to coronary dissection following blunt chest trauma is a rare entity. We describe the case of an inferior MI following blunt chest trauma. A 61-year-old male without any relevant medical history was transported to a hospital after a low-velocity motorcycle accident. The patient was asymptomatic before the accident. The patient developed severe chest pain and an ECG revealed inferior ST segment elevation. After ruling out aortic dissection with angio-CT, a coronary angiograph depicted a proximal occlusion of the right coronary artery. After thrombectomy, a typical image of coronary artery dissection was observed; the image persisted after several runs of thrombectomy and for that reason a bare metal stent was implanted with a good final angiographic result. Five days after admission the patient was discharged home. Cardiac contusion is not uncommon; however acute myocardial infarction is a rare complication of blunt chest trauma. Thorough evaluation with clinical suspicion can lead to optimal medical care. PMID- 24062889 TI - Recurrent spontaneous coronary artery dissection: acute management and literature review. AB - Spontaneous coronary artery dissection is a rare cause of acute presentations to the catheter laboratory. Often, the angiographic findings are subtle and may be mistaken for a plaque rupture. We descibe a case where repeat presentation revealed the diagnosis of recurrent spontaneous coronary artery dissection. PMID- 24062890 TI - Hybrid closure of postinfarction ventricular septal rupture enlargement after transcathether closure with Amplatzer occluder. AB - Ventricular septal rupture (VSR) is nowadays a rare complication of myocardial infarction (MI), but with a mortality rate still very high. Urgent surgical correction is recommended, although in specific cases percutaneous closure of a post-infarct VSR is a therapeutic option or a bridge to surgical correction. We report a case of an 80-year-old woman, with a subacute anterior MI with an antero septal VSR. Rapid clinical deterioration in a high-surgical-risk patient led us to attempt percutaneous VSR closure at day 8 post MI. A 16-mm Amplatzer post infarction (PI) muscular VSD closed the defect with intra-cardiac echocardiography guidance, that allowed conscious sedation. Clinical and haemodynamic improvement was immediate. Unfortunately, a small orifice distal to the device persisted, which enlarged to 8 mm over the following days, with a Qp/Qs shunt of 1.9. At day 17 post MI, the VSR was surgically closed by suturing the Amplatzer device to the septum. A residual shunt was evident, but with no progression, being the patient discharged in NYHA class I. Percutaneous closure of a post-MI VSR as a bridge to surgery is a therapeutic option in patients with high surgical risk, allowing haemodynamic stabilization and thus gaining time for a further surgical intervention if needed, improving these patients grim prognosis. Intra-cardiac echocardiography for monitoring the percutaneous procedure instead of a transoesophageal approach, as well as the surgical technique, make this case unique. PMID- 24062892 TI - A strategy for addressing aspirin hypersensitivity in patients requiring urgent PCI. AB - Aspirin is key to the treatment of acute myocardial infarction, particularly if stent implantation is considered. In patients with a history of hypersensitivity to aspirin, the optimal management of ST-segment elevation acute myocardial infarction is unclear. We suggest a strategy for addressing this problem by performing percutaneous coronary intervention with antiplatelet therapy by intravenous glycoprotein IIb/IIIa receptor blockers and performing rapid oral desensitization in the ensuing hours, once the patient has stabilized. PMID- 24062891 TI - Atherosclerosis, platelets and thrombosis in acute ischaemic heart disease. AB - Atherosclerosis is the underlying reason for nearly all causes of coronary artery disease and peripheral arterial disease and many cases of stroke. Atherosclerosis is a systemic inflammatory process characterised by the accumulation of lipids and macrophages/lymphocytes within the intima of large arteries. The deposition of these blood borne materials and the subsequent thickening of the wall often significantly compromise the residual lumen leading to ischaemic events distal to the arterial stenosis. However, these initial fatty streak lesions may also evolve into vulnerable plaques susceptible to rupture or erosion. Plaque disruption initiates both platelet adhesion and aggregation on the exposed vascular surface and the activation of the clotting cascade leading to the so called atherothrombotic process. Yet, platelets have also been shown to be transporters of regulatory molecules (micro-RNA), to drive the inflammatory response and mediate atherosclerosis progression. Here we discuss our current understanding of the pathophysiological mechanisms involved in atherogenesis - from fatty streaks to complex and vulnerable atheromas - and highlight the molecular machinery used by platelets to regulate the atherogenic process, thrombosis and its clinical implications. PMID- 24062893 TI - Oral antiplatelet therapy in acute coronary syndromes: update 2012. AB - Dual antiplatelet therapy (DAPT), usually consisting of clopidogrel and acetylsalicylic acid (ASA), has come into discussion in recent years due to an increasing number of major adverse cardiac events based on insufficient ADP mediated platelet inhibition with clopidogrel, mainly explained by drug interactions or genetic variants slowing or hindering the bioactivation of the prodrug clopidgrel into an active metabolite. Accordingly, new antiplatelet agents like prasugrel and ticagrelor were investigated in large prospective randomized clinical trials in patients with different entities of acute coronary syndromes (ACS). Based on their beneficial results in comparison to clopidogrel, these agents have found their way into the recent international guidelines for treatment of patients with acute coronary syndromes. Both antiplatelet agents demonstrated superiority with respect to the primary composite endpoint (cardiovascular death/non-lethal myocardial infarction/stroke). Ticagrelor even exhibited a mortality benefit over the comparator, but both compounds also increased the risk of spontaneous major bleedings to a significant extent. However, the efficacy/safety ratio of prasugrel and ticagrelor compared to clopidogrel is better. This article widens the insight into the recent changes in antiplatelet therapy in ACS by discussing the clinically most important data derived from the TRITON-TIMI 38 trial and the PLATO trial, including also the retrospective and pre-defined subgroup analyses. This article also gives information about the recommended duration of DAPT and the situation when patients who need permanent anticoagulation (e.g. in case of non-valvular atrial fibrillation) deserve also DAPT after coronary stenting ('triple therapy'). PMID- 24062894 TI - New oral anticoagulant agents after ACS. AB - Despite tremendous progress in the management of patients with an acute coronary syndrome (ACS), morbidity and mortality remains high even in stable patients after discharge. The benefit of adding vitamin K antagonists (VKA) on top of antiplatelet therapy to prevent recurrent ischaemic events after an ACS has been successfully studied in the past. Because of their need for frequent monitoring and drug and food interactions, however, systematic long-term use of VKA has not been recommended in this setting. The new oral anticoagulants offer several advantages compared to VKA, including a faster onset and offset of action and the absence of frequent monitoring. In this review, we evaluate the current evidence and practical consequences of using the oral direct thrombin inhibitor dabigatran or the oral anti factor Xa inhibitors apixaban, rivaroxaban, and darexaban in stable ACS patients. PMID- 24062895 TI - Pre-admission NT-proBNP improves diagnostic yield and risk stratification - the NT-proBNP for EValuation of dyspnoeic patients in the Emergency Room and hospital (BNP4EVER) study. AB - BACKGROUND: Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) level is useful to diagnose or exclude acutely decompensated heart failure (ADHF) in dyspnoeic patients presenting to the emergency department (ED). AIM: To evaluate the impact of ED NT-proBNP testing on admission, length of stay (LOS), discharge diagnosis and long-term outcome. METHODS: Dyspnoeic patients were randomized in the ED to NT-proBNP testing. Admission and discharge diagnoses, and outcomes were examined. RESULTS: During 17 months, 470 patients were enrolled and followed for 2.0+/-1.3 years. ADHF likelihood, determined at study conclusion by validated criteria, established ADHF diagnosis as unlikely in 86 (17%), possible in 120 (24%), and likely in 293 (59%) patients. The respective admission rates in these subgroups were 80, 91, and 96%, regardless of blinding, and 61.9% of blinded vs. 74.5% of unblinded ADHF-likely patients were correctly diagnosed at discharge (p=0.029), with similar LOS. 2-year mortality within subgroups was unaffected by test, but was lower in ADHF-likely patients with NT-proBNP levels below median (5000 pg/ml) compared with those above median (p=0.002). Incidence of recurrent cardiac events tracked NT-proBNP levels. CONCLUSION: ED NT-proBNP testing did not affect admission, LOS, 2-year survival, or recurrent cardiac events among study patients but improved diagnosis at discharge, and allowed risk stratification even within the ADHF-likely group. (ClinicalTrials.gov#NCT00271128). PMID- 24062896 TI - Happy birthday BNP. PMID- 24062897 TI - Outcomes of percutaneous femoral cannulation for venoarterial extracorporeal membrane oxygenation support. AB - INTRODUCTION: We report and examine the outcomes of emergency venoarterial extracorporeal membrane oxygenation (ECMO) support initiated via percutaneous cannulation of the femoral vessels. PATIENTS AND METHODS: Fifteen patients undergoing percutaneous venoarterial ECMO under emergency circumstances between January 2009 and July 2011 were identified. The implantation technique employed the Seldinger's technique for both arterial and venous cannulae. Whenever possible antegrade perfusion of the ipsilateral lower limb was performed through percutaneous catheterization of the superficial femoral artery (SFA). RESULTS: ECMO support was indicated mainly for cardiac arrest (n=9, 60%) or cardiogenic shock (n=4, 27%), while two (13%) patients required ECMO support for acute respiratory failure. In five (33%) patients, ECMO was implanted during cardiopulmonary resuscitation manoeuvres. ECMO support was maintained for a mean of 4.9 days. Eight patients (53%) were successfully weaned from the device. Thirty-day mortality was 53%. Seven patients (47%) suffered early complications, namely two wound infections, one thrombosis of the venous cannula, one erroneous implantation of the arterial cannula into the femoral vein, one local dissection of the femoral artery, one retroperitoneal bleeding and one acute limb ischaemia. No long-term vascular complications were noted. CONCLUSION: Percutaneous femoral cannulation for ECMO support remains a prompt approach for establishing extracorporeal circulatory support in acute cardiopulmonary failure when conditions for performing femoral vessel cut down are not optimal. However, vascular complications are frequent and carry a significant morbidity and mortality. PMID- 24062898 TI - Lactate and lactate clearance in acute cardiac care patients. AB - Hyperlactataemia is commonly used as a diagnostic and prognostic tool in intensive care settings. Recent studies documented that serial lactate measurements over time (or lactate clearance), may be clinically more reliable than lactate absolute value for risk stratification in different pathological conditions. While the negative prognostic role of hyperlactataemia in several critical ill diseases (such as sepsis and trauma) is well established, data in patients with acute cardiac conditions (i.e. acute coronary syndromes) are scarce and controversial. The present paper provides an overview of the current available evidence on the clinical role of lactic acid levels and lactate clearance in acute cardiac settings (acute coronary syndromes, cardiogenic shock, cardiac surgery), focusing on its prognostic role. PMID- 24062899 TI - Prosthetic heart valve obstruction: thrombolysis or surgical treatment? AB - Prosthetic valve thrombosis is a potentially life-threatening complication associated with high morbidity and mortality. Transthorasic and transoesophageal echocardiography play an important role to the diagnosis and provides incremental information about the optimal treatment strategy, while fluoroscopy and cardiac computed tomography may be of added value. Guidelines differ on whether surgical treatment or fibrinolysis should be the treatment of choice for the management of left-sided prosthetic valve thrombosis and these uncertainties underline the need for further prospective randomized controlled trials. Thrombus size, New York Heart Association functional class of the patient, the possible contraindications, the availability of each therapeutic option and the clinician's experience are important determinants for the management of prosthetic valve thrombosis. PMID- 24062900 TI - Detection of acute coronary occlusion in patients with acute coronary syndromes presenting with isolated ST-segment depression. AB - OBJECTIVES: This study sought to determine whether 80-lead body surface potential mapping (BSPM) would improve detection of acute myocardial infarction (AMI) and occluded culprit artery in patients presenting with ST-segment depression (STD) only on 12-lead ECG. BACKGROUND: In patients with acute coronary syndromes (ACS), the standard 12-lead ECG has limited sensitivity (50-60%) for AMI. METHODS: Consecutive patients presenting pre- and in-hospital between 2000 and 2006 with acute ischaemic-type chest pain and an initial 12-lead ECG with STD only of >= 0.05 mV in two or more contiguous leads were analysed. Flow in the culprit artery at angiography was graded using the TIMI flow grade (TFG) criteria. RESULTS: Enrolled were 410 patients: of these, 240 (59%) had an occluded culprit artery (TFG 0/1) with AMI, 80 (19%) had a patent culprit artery (TFG 2/3) with AMI, 67 (16%) had TFG 2/3 with cardiac troponin T (cTnT) <0.03 ug/l, and 23 (6%) had TFG 0/1 with cTnT < 0.03 ug/l. BSPM ST-segment elevation (STE) occurred in 267 (65%) patients. For the diagnosis of TFG 0/1 in the culprit artery and AMI, BSPM STE had sensitivity 91% and specificity 72% with STE occurring most commonly in the posterior territory (60%). Patients with TFG 0/1 and AMI were significantly more likely to suffer death or nonfatal MI at 30 days than those with TFG 2/3 and cTnT < 0.03 ug/l (adjusted hazard ratio 4.12, 95% CI 1.67-8.56, p = 0.003). CONCLUSION: Among 410 ACS patients presenting with only STD, BSPM identifies STE beyond the territory of the 12-lead ECG with sensitivity 91% and specificity 72% for diagnosis of occluded culprit artery with AMI. PMID- 24062901 TI - Impact of TIMI 3 patency before primary percutaneous coronary intervention for ST elevation myocardial infarction on clinical outcome: results from the ASSENT-4 PCI study. AB - BACKGROUND: Early restoration of blood flow of the infarct-related artery is associated with an improved outcome in patients with ST-elevation myocardial infarction (STEMI). Previous studies have shown a low mortality in patients with TIMI 3 flow before primary percutaneous coronary intervention (PCI). Most likely these patients had spontaneous recanalization of the infarct vessel and might constitute a low-risk subgroup. The purpose of the present analysis was to investigate whether TIMI 3 flow obtained with fibrinolysis before PCI is associated with a clinical outcome comparable to that in patients with spontaneous TIMI 3 flow. METHODS: Patients with STEMI <6 hours enrolled in the ASSENT-4 PCI study were randomized to facilitated PCI with tenecteplase or primary PCI. For this analysis, patients were divided into three groups according to the TIMI flow of the infarct vessel before PCI: TIMI 0/1, TIMI 2, and TIMI 3. RESULTS: From a total of 1617 patients, 861 had TIMI 0/1, 279 had TIMI 2, and 477 TIMI 3 flow. The rates of TIMI 3 flow after PCI were 84.6, 89.7, and 95.6%, respectively. Complete ST resolution was observed most often in the TIMI 3 flow group (47.5, 53.6, and 58.6%). The incidence of cardiogenic shock (6.2, 5.5, and 3.6%) and 90-day mortality (6.1, 4.7, and 4.0%) were lowest in the group with TIMI 3 patency before PCI, respectively. The rate of TIMI 3 flow before PCI was higher in the facilitated PCI group than in the primary PCI group (43.9 vs. 15.2%). The 90-day mortality in patients with TIMI 3 before PCI was identical in the facilitated and the primary PCI groups (14/353, 4.0% vs. 5/124, 4.0%). CONCLUSION: In this post-hoc analysis of ASSENT-4 PCI, TIMI grade 3 flow in the infarct-related artery before PCI, occurring either spontaneously or obtained by fibrinolysis, is associated with a higher TIMI patency after PCI, better improved ST resolution and a trend towards a favourable clinical outcome after 90 days. PMID- 24062902 TI - The management of acute myocardial infarction in the cardiological intensive care units in Italy: the 'BLITZ 4 Qualita' campaign for performance measurement and quality improvement. AB - AIM: To assess and promote compliance of Italian cardiological intensive care units (CCUs) with evidence-based guidelines for the management of acute myocardial infarction (MI). METHODS AND RESULTS: The process of diagnosis and treatment of MI was prospectively evaluated in 163 CCUs by use of 30 indicators during two enrolment phases, each followed by a feedback of both local and general performance. Overall, 5854 patients with ST-segment elevation MI (STEMI) and 5852 with non-ST-segment elevation MI (NSTEMI) were consecutively enrolled. The target for each indicator was defined as compliance with the relevant recommendations in >=90% of suitable patients and it was met for nine (30%) and 10 (33.3%) indicators in the first and second phases, respectively. Regardless of target, a significant improvement in compliance was observed in the second phase in 10 out of 30 indicators (33.3%). Use of pre-hospital ECG, expedite delivery of reperfusion therapy, dosage of antithrombotic drugs, and non-pharmacological implementation of secondary prevention were often off target. Similar in-hospital mortality was observed in phases I and II, both in patients with STEMI (4.0 vs. 4.2%, p=0.79) and NSTEMI (1.8 vs. 2.4%, p=0.11). Overall, 30-day mortality were 5.7% for patients with STEMI and 3.4% with NSTEMI. CONCLUSIONS: Performance indicators can accurately weigh the whole process of diagnosis and treatment of patients with MI and monitor the improvements in the quality of care. In our large population of consecutive patients, satisfactory 30-day outcomes were observed despite suboptimal adherence to guidelines for some indicators of recognised prognostic relevance. PMID- 24062903 TI - Early exercise stress testing is safe after primary percutaneous coronary intervention. AB - BACKGROUND: The optimal timing of exercise stress testing post primary percutaneous coronary intervention is uncertain with anecdotal evidence suggesting an increased risk of acute myocardial infarction and/or death if performed too early. This has translated into a delayed return to normal life activities following an acute myocardial infarction resulting in an increase in socio-economic burden. AIMS: We hypothesize that early (within 7 days of primary percutaneous coronary intervention) exercise stress testing is safe. METHODS: A prospective study of consecutive patients enrolled into the Cardiac Rehabilitation Program at a tertiary referral centre that underwent primary percutaneous coronary intervention, and who were able to perform a treadmill stress test were recruited. Timing of exercise stress testing was within 7 days post primary percutaneous coronary intervention and outcomes of death, acute myocardial infarction and other major adverse cardiac event were assessed 24 hours post exercise stress testing. RESULTS: Recruited patients (n=230) aged between 29 and 78 (mean age 56 +/- 10 years) with 191 being males (83%) and 39 being females (17%). While 28 patients had a positive stress test (12.2%), there were no deaths, acute myocardial infarction or any other major adverse cardiac event within 24 hours of performing the exercise stress testing. Mean METS achieved were 8.1 +/- 2.3. CONCLUSIONS: Early exercise stress testing after primary percutaneous coronary intervention appears safe. PMID- 24062905 TI - The role of the interventional cardiologist in selecting antiplatelet agents in acute coronary syndromes: a 10-question strategy. AB - Antiplatelet agents play a major role in the management of patients with acute coronary syndromes (ACS). In recent years, the most important development has been the advent of new inhibitors of adenosine 5'-diphosphate (ADP) P2Y12 receptor inhibitors, namely prasugrel and ticagrelor. The arrival of these new drugs on the market, with their specific indications and combinations with aspirin, glycoprotein IIb/IIIa inhibitors, and anticoagulants, has rendered the therapeutic arena more complex. Achieving the best combination of all these drugs for each patient requires sound knowledge of the indications of each molecule according to the clinical situation, as well as evaluation of the ischaemic and haemorrhagic risks. In practical terms, the interventional cardiologist holds the key to therapeutic decisions, based on the anatomical information obtained in the cathlab. He/she should be able to recommend an appropriate antiplatelet treatment strategy even before the patient arrives in the cathlab, or alternatively, adapt or modify treatment according to the possibilities for revascularization, and advise on long-term therapy. In this report, we describe, in ten questions, the key elements that the interventional cardiologists should be ready to answer before choosing the appropriate antiplatelet regimen, based on recent guidelines, and covering the whole spectrum of management from pre-hospital, to the cathlab, and after invasive procedures. PMID- 24062904 TI - Recurrent angina after coronary angioplasty: mechanisms, diagnostic and therapeutic options. AB - Recurrent angina in patients who underwent percutaneous coronary intervention is defined as recurrence of chest pain or chest discomfort. Careful assessment is recommended to differentiate between non-cardiac and cardiac causes. In the case of the latter, recurrent angina occurrence can be related to structural ('stretch pain', in-stent restenosis, in-stent thrombosis, incomplete revascularization, progression of coronary atherosclerosis) or functional (coronary micro-vascular dysfunction, epicardial coronary spasm) causes. Even though a complete diagnostic algorithm has not been validated, ECG exercise testing, stress imaging and invasive assessment of coronary blood flow and coronary vaso-motion (i.e. coronary flow reserve, provocation testing for coronary spasm) may be required. When repeated coronary revascularization is not indicated, therapeutic approaches should aim at targeting the underlying mechanism for the patient's symptoms using a variety of drugs currently available such as beta-blockers, calcium-channel blockers, ivabradine or ranolazine. PMID- 24062906 TI - Temporal trends in treatment of ST-elevation myocardial infarction among men and women in Switzerland between 1997 and 2011. AB - BACKGROUND: Few data are available concerning the impact of gender on temporal trends in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: All STEMI patients consecutively enrolled in the AMIS (Acute Myocardial Infarction in Switzerland) Plus project from 1997-2011 were included. Temporal trends in presentation, treatment and outcomes were analyzed using multiple logistic regressions with generalized estimations. RESULTS: Of 21,620 STEMI patients, 5786 were women and 15,834 men from 78 Swiss hospitals. Women were 8.6 years older, presented 48 minutes later with less pain, but more dyspnea, and more frequently had atrial fibrillation (5.5 vs. 3.9%, p<0.001), heart failure (Killip class >2) (9.7 vs. 7.3%, p<0.001), and moderate or severe comorbidities (24.8 vs. 18.2%, p<0.001). Women were less likely to undergo primary reperfusion treatment after adjustment for baseline characteristics and admission year (OR 0.80, 95% CI 0.71-0.90, p<0.001) or receive early and discharge drugs, such as thienopyridines, angiotensin-converting-enzyme inhibitors, angiotensin II receptor antagonists, and statins. In 1997, thrombolysis was performed in 51% of male and 39% of female patients; its use rapidly decreased during the 1990s and has now become negligible. Primary percutaneous coronary intervention increased from under 10% in both genders in 1997 to over 70% in females and over 80% in males since 2006. Patients admitted in cardiogenic shock increased by 8% per year in both genders. The incidence of both reinfarction and cardiogenic shock developing during hospitalization decreased significantly over 15 years while in hospital mortality decreased from 10 to 5% in men and from 18 to 7% in women. This corresponds to a relative reduction of 5% per year for males (OR 0.95, 95% CI 0.92-0.99, p=0.006) and 6% per year for female STEMI patients (OR 0.94, 95% CI 0.91-0.97, p<0.001). Despite higher crude in-hospital mortality, female gender per se was not an independent predictor of in-hospital mortality (OR 1.07, 95% CI 0.84-1.35, p=0.59). CONCLUSION: Substantial changes have occurred in presentation, treatment, and outcome of men and women with STEMI in Switzerland over the past 15 years. Although parallel trends were seen in both groups, ongoing disparities in certain treatments remain. However, these did not translate into worse risk-adjusted in-hospital mortality, suggesting that the gender gap in STEMI care may be closing. PMID- 24062907 TI - Mortality and ST resolution in patients admitted with STEMI: the MOMI survey of emergency service experience in a complex urban area. AB - BACKGROUND: Since 2001, the urban area of Milan has been operating a network among 23 cardiac care units, the 118 dispatch centre (national free number for medical emergencies), and the county government health agency called Group for Prehospital Cardiac Emergency. METHODS AND RESULTS: In order to monitor the network activity, time to treatment, and clinical outcome, a periodic survey, called MOMI(2), was repeated two or three times a year. Each survey lasted 30 days and was repeated in comparable periods. Data were stratified for hospital admission mode. We collected data concerning 708 consecutive ST-elevation myocardial infarction (STEMI) patients (male 72.6%; mean age 64.4 years). In these six surveys, we observed a high rate of primary percutaneous coronary intervention (73.2%) and a mortality rate of 6.3%. Using advanced statistical models, we identified age, Killip class, and the symptom onset-to-balloon time as most relevant prognostic factors. Nonparametric test showed that the modality of hospital admittance was the most critical determinant of door-to-balloon time. 12 lead ECG tele-transmission and activation of a fast track directly to the catheterization laboratory are easy action to reduce time to treatment. CONCLUSIONS: The experience of the Milan network for cardiac emergency shows how a network coordinating the community, rescue units, and hospitals in a complex urban area and making use of medical technology contributes to the health care of patients with STEMI. PMID- 24062908 TI - Reperfusion delay in patients treated with primary percutaneous coronary intervention: insight from a real world Danish ST-segment elevation myocardial infarction population in the era of telemedicine. AB - BACKGROUND: Reperfusion delay in ST-segment elevation myocardial infarction (STEMI) predicts adverse outcome. We evaluated time from alarm call (system delay) and time from first medical contact (PCI-related delay), where fibrinolysis could be initiated, to balloon inflation in a pre-hospital organization with tele-transmitted electrocardiograms, field triage and direct transfer to a 24/7 primary percutaneous coronary intervention (PPCI) center. METHODS AND RESULTS: This was a single center cohort study with long-term follow up in 472 patients. The PPCI center registry was linked by person identification number to emergency medical services (EMS) and National Board of Health databases in the period of 2005-2008. Patients were stratified according to transfer distances to PPCI into zone 1 (0-25 km), zone 2 (65-100 km) and zone 3 (101-185 km) and according to referral by pre-hospital triage. System delay was 86 minutes (interquartile range (IQR) 72-113) in zone 1, 133 (116-180) in zone 2 and 173 (145-215) in zone 3 (p<0.001). PCI-related delay in directly referred patients was 109 (92-121) minutes in zone 2, but exceeded recommendations in zone 3 (139 (121-160)) and for patients admitted via the local hospital (219 (171-250)). System delay was an independent predictor of mortality (p<0.001). CONCLUSIONS: Pre-hospital triage is feasible in 73% of patients. PCI-related delay exceeded European Society of Cardiology (ESC) guidelines for patients living >100 km away and for non-directly referred patients. Sorting the PPCI centers catchment area into geographical zones identifies patients with long reperfusion delays. Possible solutions are pharmaco-invasive regiments, research in early ischemia detection, airborne transfer and EMS personnel education that ensures pre hospital triage. PMID- 24062909 TI - New ST-depression: an under-recognized high-risk category of 'complete' ST resolution after reperfusion therapy. AB - AIM: It is not known if there is an association between resolution of ST elevation to ST-depression following fibrinolysis and 30-day mortality. METHODS: In an ECG substudy of HERO-2, which compared bivalirudin to unfractionated heparin following streptokinase in 12,556 patients with ST-elevation myocardial infarction ECGs were recorded at baseline and at 60 minutes after commencing fibrinolysis. The main outcome measure was 30-day mortality. RESULTS: Using summed ST-segment elevation and five categories of changes in the infarct leads, further ST-elevation, 0-30% ST-resolution, >30-70% (partial) ST-resolution, >70% (complete) ST-resolution, and new ST-depression occurred in 21.7, 24.9, 36.8, 14.8, and 1.8% of patients, with 30-day mortality of 12.3, 11.7, 8.0, 4.2, and 8.1%, respectively. For the comparison of new ST-depression with complete ST resolution and no ST-depression, p<0.01 with 24-hour mortality 4.5 vs. 1.3%, respectively (p=0.0003). Patients with new ST-depression had similar peak cardiac enzyme elevations as patients with complete ST-resolution without ST-depression. On multivariate analysis including summed ST-elevation at baseline, age, sex, and infarct location, new ST-depression was a significant predictor of 30-day mortality (OR 1.82, 95% CI 1.42-4.29). CONCLUSIONS: In patients with complete ST resolution following fibrinolysis, new ST-depression at 60 minutes developed in 10.8% of patients. These patients had higher mortality than patients with complete ST-resolution without ST-depression and represent a high-risk group which could benefit from rapid triage to early angiography and revascularization as appropriate. PMID- 24062910 TI - Comparing the predictive validity of three contemporary bleeding risk scores in acute coronary syndrome. AB - AIMS: Haemorrhagic complications are strongly linked with adverse outcomes in acute coronary syndrome (ACS) patients. Various risk scores (RS) are available to predict bleeding risk in these patients. We compared the performance of three contemporary bleeding RS in ACS. METHODS: We studied 4500 consecutive patients with ACS. We calculated the ACTION, CRUSADE, and Mehran et al. (2010) bleeding RS, and evaluated their performance for predicting their own major bleeding events and TIMI serious (major or minor) bleeding episodes, in patients with either non-ST-elevation ACS (NSTEACS) or ST-elevation myocardial infarction (STEMI). Calibration (Hosmer-Lemeshow test, HL) and discrimination (c-statistic) for the three RS were computed and compared. RESULTS: For RS-specific major bleeding, ACTION and CRUSADE showed the best prognostic discrimination in STEMI (c=0.734 and 0.791, respectively; p=0.04), and in NSTEACS (c=0.791 and 0.810; p=0.4); being CRUSADE significantly superior to Mehran et al. in both ACS types (p<0.05). All RS performed well in patients undergoing coronary arteriography using either a radial or femoral approach (all c>=0.718); however, their discriminative capacity was modest in patients not undergoing coronary arteriography and in those previously on oral anticoagulant (all c<0.70). For TIMI serious bleeding, ACTION and CRUSADE displayed the highest c-index values in both STEMI (0.724 and 0.703, respectively; p=0.3) and NSTEACS (c=0.733 and 0.744, respectively; p=0.6); however, calibration of ACTION was poor in both ACS types (HL p<0.05). CONCLUSIONS: Of contemporary bleeding RS, the CRUSADE score was found to be the most accurate quantitative tool for NSTEACS and STEMI patients undergoing coronary arteriography. PMID- 24062911 TI - A life-saving case of Dressler's syndrome. AB - Myocardial rupture is an uncommon and life threatening event which may occur in the setting of acute myocardial infarction. In this case report we describe a rare instance of a patient presenting with signs of ventricular rupture as a late presentation of myocardial infarction. The findings of cardiac computed tomography are demonstrated as well as intra-operative images. Despite its very high attendant mortality risk, our patient's life was saved by the earlier development of Dressler's syndrome, an intense inflammatory process in the pericardium, resulting in dense adhesions, which effectively tamponaded the leak from the ventricular free wall rupture and prevented extravasation. PMID- 24062912 TI - QRS fragmentation in patients with arrhythmogenic right ventricular cardiomyopathy and complete right bundle branch block: a risk stratification. AB - BACKGROUND: Patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) and complete right bundle branch block (RBBB) very often have recurrent ventricular tachycardia and develop biventricular heart failure in the follow up, requiring heart transplantation and/or diuretics. In other patients with ARVC/D excluding RBBB, QRS fragmentation in the S wave of right precordial leads identifies patients with recurrent ventricular tachycardia, primary ventricular fibrillation, and recurrent implantable cardioverter defibrillator discharges; QRS fragmentation >=3 leads characterized patients who died from sudden cardiac death. METHOD: In a cohort of 374 patients with ARVC/D (208 males; mean+/-SD age 46.5+/-14.8 years), there were 22 patients with complete RBBB: 17 patients with ARVD/C developed complete RBBB and had biventricular heart failure in a follow up of 4-6 years. In five patients with ARVC/D, complete RBBB was initially evident. In all patients with ARVC/D and RBBB, QRS fragmentation >=3 of all 12 ECG leads and QRS fragmentation in the S wave of right precordial leads were analysed. RESULTS: QRS fragmentation >=3 of all 12 ECG leads and in the S wave of right precordial leads were present in 16/17 patients who developed RBBB and none of the five patients with initial RBBB. In one patient with initial RBBB, QRS fragmentation >=3 leads was present (r=17.45; p<0.0001). CONCLUSION: Patients with recurrent ventricular tachycardia who develop biventricular heart failure requiring heart transplantation and/or diuretics are characterized by QRS fragmentation in the S wave of right precordial leads and >=3 of all 12 ECG leads. These results are statistically significant. Patients with initial RBBB have an overall benign prognosis. PMID- 24062913 TI - Serial measurements associated with an amelioration of acute heart failure: an analysis of repeated quantification of plasma BNP levels. AB - BACKGROUND: The magnitude of improvement of acute heart failure achieved during treatment varies greatly among patients. We examined changes in the plasma B-type natriuretic peptide (BNP) levels of patients with acute heart failure and attempted to elucidate the clinical factors associated with amelioration of acute heart failure. METHODS AND RESULTS: The study population consisted of 208 consecutive patients admitted to our institution with acute heart failure. We measured plasma BNP levels before and after treatment of acute heart failure and evaluated these levels based on median age, body mass index (BMI), creatinine (Cr) level, and left ventricular ejection fraction (EF). Plasma BNP levels before treatment were equivalent between the younger and older age groups; however, plasma BNP levels after treatment were higher in the older age group (p<0.01). Plasma BNP levels before treatment were significantly high in the lower BMI group (p<0.05) and the higher Cr group (p<0.01). Similarly, plasma BNP levels after treatment were high in both the lower BMI and higher Cr groups (p<0.01 for both). In the low EF group, plasma BNP levels before treatment were significantly high (p<0.01), while plasma BNP levels after treatment were equivalent to those in the high EF group. A multiple linear regression analysis revealed that Cr was positively correlated and BMI and EF were negatively correlated with plasma BNP levels before treatment; however, the contributions of age, BMI, and Cr in reducing plasma BNP levels were more significant after treatment. CONCLUSIONS: The contributions of clinical factors working against amelioration of heart failure vary before and after treatment. Regarding plasma BNP levels, older age, very low BMI, and the presence of renal dysfunction eventually act to prevent amelioration of acute heart failure. Systolic dysfunction does not act against amelioration of acute heart failure. PMID- 24062914 TI - Myocardial involvement in systemic capillary leak syndrome: first demonstration by pathologic findings. AB - This case vignette relates the unknown association between systemic capillary leak syndrome, namely Clarkson's syndrome, and acute cardiac dysfunction. 'Central extra-corporeal life support (ECLS)' was needed for the management of an intractable cardiogenic shock. The acute cardiac condition completely resolved within few days. Pathology showed diffuse interstitial edema within the myocardium suggestive of cardiac involvement of the disease. PMID- 24062915 TI - Myopericarditis and severe myocardial dysfunction as the initial manifestation of systemic lupus erythematosus. AB - Pericarditis is the most frequent cardiac manifestation of systemic lupus erythematosus (SLE). However, a large pericardial effusion as the initial manifestation of the disease is infrequent, especially when it is associated with myocardial damage. We describe an unusual case of a young female with pleuropericarditis and severe myocardial dysfunction as the initial manifestation of SLE. PMID- 24062916 TI - Treating volume overload in acutely decompensated heart failure: established and novel therapeutic approaches. AB - BACKGROUND: Most patients hospitalized for acutely decompensated heart failure (ADHF) present with symptoms and signs of volume overload, which is also associated with substantially high rates of death and rehospitalization in ADHF. OBJECTIVE: To review the recent experimental and clinical evidence on existing therapeutic algorithms and investigational drugs used for the treatment of volume overload in ADHF patients. METHODS: A systematic search of peer-reviewed publications was performed on Medline and EMBASE from January 1990 to March 2012. The results of unpublished trials were obtained from presentations at national and international meetings. RESULTS: Apart from intrinsic renal insufficiency and neurohormonal activation, volume overload through venous congestion may be the primary haemodynamic factor triggering the worsening of renal function in ADHF patients. It is well known that heart and kidneys are closely interrelated and an acute or chronic disorder in one organ may induce acute or chronic dysfunction in the other organ. Established therapeutic strategies, (e.g. loop diuretics, vasodilators, and inotropes), are sometimes associated with limited clinical success due to tolerance and the need for frequent up titration of the doses in order to achieve the desired effect. That leads to an increasing interest in novel options, such as the use of adenosine A1 receptor antagonists, vasopressin antagonists, and renal-protective dopamine. Initial clinical trials have shown quite encouraging results in some heart failure subpopulations but have failed to demonstrate a clear beneficial role of these agents. On the other hand, ultrafiltration appears to be a more promising therapeutic procedure that will improve volume regulation, while preserving renal and cardiac function. CONCLUSION: Further clinical studies are required in order to determine their net effect on renal function and potential cardiovascular outcomes. Until then, management of volume overload in ADHF patients remains a challenge for the clinicians. PMID- 24062917 TI - Peripheral venous blood gases and pulse-oximetry in acute cardiogenic pulmonary oedema. AB - BACKGROUND: The role of venous blood gases as an alternative to arterial blood gases in patients with severe acute heart failure has not been established. OBJECTIVE: To assess the correlation between arterial and peripheral venous blood gases together with pulse-oximetry (SpO2), as well as to estimate arterial values from venous samples in the first hours upon admission of patients with acute cardiogenic pulmonary oedema. METHODS: Simultaneous venous and arterial blood samples were extracted on admission and over the next 1, 2, 3, 4, and 10 hours. SpO2 was also registered at the same intervals. RESULTS: A total of 178 pairs of samples were obtained from 34 consecutive patients with acute cardiogenic pulmonary oedema. Arterial and venous blood gases followed a parallel course in the first hours, showing high correlation rates at all time intervals. Venous samples underestimated pH (mean difference -0.028) and overestimated CO2 (+5.1 mmHg) and bicarbonate (+1 mEq/l). Conversely, SpO2 tended to underestimate SaO2 (mean+/-SD: 93.1+/-9.1 vs. 94.2+/-8.4). Applying simple mathematical formulae based on these differences, arterial values were empirically calculated from venous samples, showing acceptable agreement in the Bland-Altman test. Likewise, a venous pH <7.32, pCO2 >51.3 mmHg, and bicarbonate <22.8 mEq/l could fairly identify arterial acidosis, either respiratory or metabolic, with a test accuracy of 92, 68, and 91%, respectively. CONCLUSIONS: In patients with cardiogenic pulmonary oedema, arterial blood gas disturbances may be estimated from peripheral venous samples. By monitoring SpO2 simultaneously, arterial punctures could often be avoided. PMID- 24062918 TI - Use of levosimendan in critically ill patients with severe aortic stenosis and left ventricular dysfunction. AB - Congestive heart failure and left ventricular dysfunction in the setting of severe aortic stenosis are associated with a high mortality rate. Evidence on optimal medical therapy is scanty. Vasodilators were traditionally considered to be contraindicated in severe aortic stenosis, albeit this concept has recently been challenged. The use of levosimendan, which has positive inotropic, vasodilatory and cardioprotective properties seems attractive. We describe a small series of exceedingly ill patients with severe aortic stenosis and left ventricular dysfunction, in different clinical settings (acute heart failure, cardiogenic shock and difficult-to-wean ventilatory support), in which levosimendan was successfully used. PMID- 24062919 TI - Synchronized defibrillation for ventricular fibrillation. AB - OBJECTIVE: Optimization of defibrillation success is important to improve efficacy and minimize post-shock sequelae. Previous work has suggested an improvement in shock success when an intracardiac shock is delivered synchronized to the upslope of a VF wave. We investigated the efficacy of transthoracic defibrillation success using a novel external biphasic defibrillator which delivers shocks synchronized to the upslope of the surface ECG. METHODS: A prospective, controlled, randomized study in a research institute laboratory of male and female pigs (54.2+/-1.8 kg). Ventricular fibrillation (VF) was induced in 10 anaesthetized and ventilated pigs. Shocks were delivered randomly from a biphasic defibrillator in synchronized or non-synchronized mode via self-adhesive electrode pads following 30 s of VF. Energy settings at 50, 70, 80, and 100J were randomly tested. VF amplitude, impedance, and shock outcome were recorded and analysed digitally. RESULTS: A total of 300 shocks were delivered. Synchronized shocks were delivered on the upslope of the VF wave in 99% of cases. There was no significant difference in shock success between shocks delivered in synchronized or non-synchronized modes (p=0.695). There was no significant difference in the amplitude of VF between successful and unsuccessful shocks (p=0.163). Furthermore, there was no association between shock success and transthoracic impedance. CONCLUSION: The novel defibrillator used in this study was able to consistently deliver shocks on the upslope portion of the VF wave but did not show an improvement in shock success. PMID- 24062920 TI - Emergency coronary angiography in comatose cardiac arrest patients: do real-life experiences support the guidelines? AB - AIMS: To describe the use of emergency coronary angiography (CAG) and primary percutaneous coronary intervention (PCI) and the association with short- and long term survival in consecutive comatose survivors after out-of-hospital cardiac arrest (OHCA). METHODS: In the period 2004-10, a total of 479 consecutive patients with OHCA of suspected cardiac cause were referred to a tertiary cardiac centre, 360 patients were comatose and admitted to the ICU for post-resuscitative care. The population was stratified in two groups according to the pattern of the first ECG obtained after re-established circulation; ST-segment elevation (STEMI, n=116) and ECG without STEMI pattern (No-STEMI, n=244). Emergency CAG (<=12 hours after OHCA) was performed at the discretion of the attending cardiologist. Primary outcome was 30-day and 1-year survival. RESULTS: Emergency CAG was performed in all patients in the STEMI group compared to 82 (34%) in the group without STEMI pattern (p<0.0001) with significant coronary lesions found in 108 (93%) compared to 43 (52%) patients, respectively (p<0.0001). Survival at 30 day according to emergency CAG vs. no emergency CAG was 65% in the STEMI group compared to 66% and 54% in the group without STEMI pattern (p log-rank=0.11). The use of emergency CAG in the group without STEMI pattern was not associated with reduced mortality (HRadjusted=0.69, 95% CI 0.4-1.2, p=0.18). CONCLUSIONS: In comatose survivors of OHCA presenting with STEMI, a high prevalence of coronary disease and culprit lesions suitable for emergency PCI was found, whereas in patients without STEMI pattern, significant coronary stenosis was less frequent. Clinical benefits of emergency CAG/PCI in comatose survivors of OHCA presenting without STEMI could not be identified. PMID- 24062921 TI - Prognostic impact of early ventricular fibrillation in patients with ST-elevation myocardial infarction treated with primary PCI. AB - AIMS: Current guidelines do not advocate implantation of cardioverter defibrillators (ICD) for survivors of ventricular fibrillation (VF) during the first 48 hours of ST-elevation myocardial infarction (STEMI). However, contemporary studies in a real-life setting with long-term follow-up are lacking. We assessed the prognostic impact of early VF in a non-selected population of STEMI patients treated with primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: Consecutive STEMI patients admitted to a Swedish tertiary care hospital during 2007-2009 were identified from the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (n=1718, age 66+/-12 years, 70% male). Patients with VF were identified from the register, and medical records were reviewed to determine the time point of VF. Patients surviving VF in the first 48 hours after symptom onset were compared with patients without VF for one-year mortality and a combined endpoint of death, resuscitated VF or appropriate ICD therapy. VF within 48 hours occurred in 7% of STEMI patients (n=121). In patients alive at 48 hours (n=1663), VF patients (n=101) had higher in-hospital mortality (12% vs. 2%, p<0.001). However, in VF patients discharged alive (n=89), mortality was low (1%) and combined endpoint rate (3%) did not differ compared with patients without VF (n=1538; 4% and 4% respectively). CONCLUSION: In a large non-selected population of STEMI patients treated with primary PCI, VF during the first 48 hours after STEMI is associated with increased in-hospital mortality but does not influence the long-term prognosis for those discharged alive. PMID- 24062922 TI - Self-referral to chest pain units: results of the German CPU-registry. AB - BACKGROUND: Chest pain units (CPUs) are increasingly established in emergency cardiology services. With improved visibility of CPUs in the population, patients may refer themselves directly to these units, obviating emergency medical services (EMS). Little is known about characteristics and outcomes of self referred patients, as compared with those referred by EMS. Therefore, we described self-referral patients enrolled in the CPU-registry of the German Cardiac Society and compared them with those referred by EMS. METHODS AND RESULTS: From 2008 until 2010, the prospective CPU-registry enrolled 11,581 consecutive patients. Of those 3789 (32.7%) were self-referrals (SRs), while 7792 (67.3%) were referred by EMS. SR-patients were significantly younger (63.6 vs. 70.1 years), had less prior myocardial infarction or coronary artery bypass surgery, but more previous percutaneous coronary interventions (PCIs). Acute coronary syndromes were diagnosed less frequently in the SR-patients (30.3 vs. 46.9%; p<0.0001). SR-patients showed ST-segment changes in their initial ECG in 19.6% of cases. EMS-patients underwent more coronary angiographies (60.0 vs. 47.5%; p<0.0001), while SR-patients underwent more stress tests (11.3 vs. 7.8%; p<0.001). PCI was performed in 32.6% of the EMS- and in 24.0% of the SR-group (p<0.0001). CONCLUSION: These data demonstrate that patients who contact a CPU as a self-referral are younger, less severely ill and have more non-coronary problems than those calling an emergency medical service. Nevertheless, 30% of self-referral patients had an acute coronary syndrome. PMID- 24062923 TI - ACHTUNG-Rule: a new and improved model for prognostic assessment in myocardial infarction. AB - BACKGROUND: THROMBOLYSIS IN MYOCARDIAL INFARCTION (TIMI), PLATELET GLYCOPROTEIN IIB/IIIA IN UNSTABLE ANGINA: Receptor Suppression Using Integrilin (PURSUIT) and Global Registry of Acute Coronary Events (GRACE) scores have been developed for risk stratification in myocardial infarction (MI). The latter is the most validated score, yet active research is ongoing for improving prognostication in MI. AIM: Derivation and validation of a new model for intrahospital, post discharge and combined/total all-cause mortality prediction - ACHTUNG-Rule - and comparison with the GRACE algorithm. METHODS: 1091 patients admitted for MI (age 68.4 +/- 13.5, 63.2% males, 41.8% acute MI with ST-segment elevation (STEMI)) and followed for 19.7 +/- 6.4 months were assigned to a derivation sample. 400 patients admitted at a later date at our institution (age 68.3 +/- 13.4, 62.7% males, 38.8% STEMI) and followed for a period of 7.2 +/- 4.0 months were assigned to a validation sample. Three versions of the ACHTUNG-Rule were developed for the prediction of intrahospital, post-discharge and combined (intrahospital plus post discharge) all-cause mortality prediction. All models were evaluated for their predictive performance using the area under the receiver operating characteristic (ROC) curve, calibration through the Hosmer-Lemeshow test and predictive utility within each individual patient through the Brier score. Comparison through ROC curve analysis and measures of risk reclassification - net reclassification improvement index (NRI) or Integrated Discrimination Improvement (IDI) - was performed between the ACHTUNG versions for intrahospital, post-discharge and combined mortality prediction and the equivalent GRACE score versions for intrahospital (GRACE-IH), post-discharge (GRACE-6PD) and post-admission 6-month mortality (GRACE-6). RESULTS: Assessment of calibration and overall performance of the ACHTUNG-Rule demonstrated a good fit (p value for the Hosmer-Lemeshow goodness-of-fit test of 0.258, 0.101 and 0.550 for ACHTUNG-IH, ACHTUNG-T and ACHTUNG-R, respectively) and high discriminatory power in the validation cohort for all the primary endpoints (intrahospital mortality: AUC ACHTUNG-IH 0.886 +/- 0.035 vs. AUC GRACE-IH 0.906 +/- 0.026; post-discharge mortality: AUC ACHTUNG-R 0.827 +/- 0.036 vs. AUC GRACE-6PD 0.811 +/- 0.034; combined/total mortality: AUC ACHTUNG-T 0.831 +/- 0.028 vs. AUC GRACE-6 0.815 +/- 0.033). Furthermore, all versions of the ACHTUNG-Rule accurately reclassified a significant number of patients in different, more appropriate, risk categories (NRI ACHTUNG-IH 17.1%, p (2-sided) = 0.0021; NRI ACHTUNG-R 22.0%, p = 0.0002; NRI ACHTUNG-T 18.6%, p = 0.0012). The prognostic performance of the ACHTUNG-Rule was similar in both derivation and validation samples. CONCLUSIONS: All versions of the ACHTUNG-Rule have shown excellent discriminative power and good calibration for predicting intrahospital, post-discharge and combined in-hospital plus post-discharge mortality. The ACHTUNG version for intrahospital mortality prediction was not inferior to its equivalent GRACE model, and ACHTUNG versions for post-discharge and combined/total mortality demonstrated apparent superiority. External validation in wider, independent, preferably multicentre, registries is warranted before its potential clinical implementation. PMID- 24062924 TI - Intra-pericardial thrombin injection for post-infarction left ventricular free wall rupture. AB - Left ventricular free wall rupture (LVFWR) is a fatal complication of acute myocardial infarction. Different modalities of treatment were previously described, including surgical intervention and medical treatment. We report a case treated with intra-pericardial thrombin injection that gave a favourable outcome for a patient who presented with LVFWR and cardiac tamponade, following acute myocardial infarction. PMID- 24062925 TI - Sequential thromboembolic events after primary angioplasty in a patient with acute anterior myocardial infarction. AB - A 65 year old man was transferred to our cath lab for primary PCI about two hours after the onset of pain in the context of acute, anterior myocardial infarction. Thrombus aspiration of the proximal LAD and balloon angioplasty with a DES implantation were performed. After a few days, although the patient was under treatment with unfractioned heparin, he sustained a transient ischemic attack. The echocardiographic study revealed a large, mobile, protruding thrombus in the apex. Four days later, the patient complained of mild abdominal pain with a gradual deterioration. Abdominal CT scan revealed embolism of the superior mesenteric artery and urgent embolectomy was scheduled. PMID- 24062926 TI - Interpretation of acute myocardial infarction with persistent 'hyperacute T waves' by cardiac magnetic resonance. AB - Peaked and tall T waves represent a hyperacute electrocardiogram (ECG) manifestation of coronary artery occlusion which usually evolves into ST-segment elevation. We sought to investigate using cardiac magnetic resonance (CMR) the myocardial tissue changes underlying an atypical ECG pattern of presentation of left anterior descending artery (LAD) occlusion consisting of persistent hyperacute T waves and mild ST-segment depression. This ECG pattern is often associated with the presence of collateral circulation, which may modulate myocyte action potential changes in response to ischemia and prevent the appearance of ST-segment elevation. However, CMR findings resembled those of typical anterior myocardial infarction with nearly transmural necrosis in the large myocardial area supplied by LAD. Accordingly, persistent hyperacute T waves should be regarded as an equivalent to ST-segment elevation and immediate reperfusion therapy should be considered. PMID- 24062927 TI - Differences in negative T waves among acute coronary syndrome, acute pulmonary embolism, and Takotsubo cardiomyopathy. AB - AIMS: Negative T waves in precordial leads often occur in patients with acute coronary syndrome (ACS), but are also found in acute pulmonary embolism (APE) and Takotsubo cardiomyopathy (TC). Because the clinical features of these two diseases mimic those of ACS, differential diagnosis is essential to select an appropriate treatment strategy improve outcomes. This study aimed to clarify the differences in negative T waves among ACS, APE and TC. METHODS AND RESULTS: We studied admission ECGs in 300 patients (198 patients with ACS caused by the left anterior descending coronary artery disease, 81 with APE and 21 with TC). All patients were admitted within 48 h from symptom onset and had negative T waves >=1.0 mm without ST-segment elevation in leads V1 to V4. The number and maximal amplitude of negative T waves were greatest in patients with TC, followed by in those with ACS, and were lowest in patients with APE (p < 0.001, respectively). The prevalence of negative T waves significantly differed in all 12 leads among the three groups (p < 0.01, respectively). Negative T waves in both leads III and V1 identified APE with 90% sensitivity and 97% specificity. Negative T waves in lead -aVR (i.e., positive T waves in lead aVR) and no negative T waves in lead V1 identified TC with 95% sensitivity and 97% specificity. These values represented the highest diagnostic accuracies. CONCLUSION: The distributions of negative T waves differed among ACS, APE and TC, and these differences were useful for differentiating among these three diseases. PMID- 24062928 TI - Organization and staffing practices in US cardiac intensive care units: a survey on behalf of the American Heart Association Writing Group on the Evolution of Critical Care Cardiology. AB - BACKGROUND: The cardiac intensive care unit (CICU) has evolved into a complex patient-care environment with escalating acuity and increasing utilization of advanced technologies. These changing demographics of care may require greater clinical expertise among physician providers. Despite these changes, little is known about present-day staffing practices in US CICUs. METHODS AND RESULTS: We conducted a survey of 178 medical directors of ICUs caring for cardiac patients to assess unit structure and physician staffing practices. Data were obtained from 123 CICUs (69% response rate) that were mostly from academic medical centres. A majority of hospitals utilized a dedicated CICU (68%) and approximately half of those hospitals employed a 'closed' unit model. In 46% of CICUs, an intensivist consult was available, but not routinely involved in care of critically ill cardiovascular patients, while 11% did not have a board certified intensivist available for consultation. Most CICU directors (87%) surveyed agreed that a closed ICU structure provided better care than an open ICU and 81% of respondents identified an unmet need for cardiologists with critical care training. CONCLUSIONS: We report contemporary structural models and staffing practices in a sample of US ICUs caring for critically ill cardiovascular patients. Although most hospitals surveyed had dedicated CICUs, a minority of CICUs employed a 'closed' CICU model and few had routine intensivist staffing. Most CICU directors agree that there is a need for cardiologists with intensivist training and expertise. These survey data reveal potential areas for continued improvement in US CICU organizational structure and physician staffing. PMID- 24062929 TI - An assessment of composite measures of hospital performance and associated mortality for patients with acute myocardial infarction. Analysis of individual hospital performance and outcome for the National Institute for Cardiovascular Outcomes Research (NICOR). AB - AIM: To investigate whether a hospital-specific opportunity-based composite score (OBCS) was associated with mortality in 136,392 patients with acute myocardial infarction (AMI) using data from the Myocardial Ischaemia National Audit Project (MINAP) 2008-2009. METHODS AND RESULTS: For 199 hospitals a multidimensional hospital OBCS was calculated on the number of times that aspirin, thienopyridine, angiotensin-converting enzyme inhibitor (ACEi), statin, beta-blocker, and referral for cardiac rehabilitation was given to individual patients, divided by the overall number of opportunities that hospitals had to give that care. OBCS and its six components were compared using funnel plots. Associations between OBCS performance and 30-day and 6-month all-cause mortality were quantified using mixed-effects regression analysis. Median hospital OBCS was 95.3% (range 75.8 100%). By OBCS, 24.1% of hospitals were below funnel plot 99.8% CI, compared to aspirin (11.1%), thienopyridine (15.1%), beta-blockers (14.7%), ACEi (19.1%), statins (12.1%), and cardiac rehabilitation (17.6%) on discharge. Mortality (95% CI) decreased with increasing hospital OBCS quartile at 30 days [Q1, 2.25% (2.07 2.43%) vs. Q4, 1.40% (1.25-1.56%)] and 6 months [Q1, 7.93% (7.61-8.25%) vs. Q4, 5.53% (5.22-5.83%)]. Hospital OBCS quartile was inversely associated with adjusted 30-day and 6-month mortality [OR (95% CI), 0.87 (0.80-0.94) and 0.92 (0.88-0.96), respectively] and persisted after adjustment for coronary artery catheterization [0.89 (0.82-0.96) and 0.95 (0.91-0.98), respectively]. CONCLUSIONS: Multidimensional hospital OBCS in AMI survivors are high, discriminate hospital performance more readily than single performance indicators, and significantly inversely predict early and longer-term mortality. PMID- 24062930 TI - Comparison of the performance of the CRUSADE, ACUITY-HORIZONS, and ACTION bleeding risk scores in STEMI undergoing primary PCI: insights from a cohort of 1391 patients. AB - AIMS: To compare the performance of the CRUSADE, ACUITY-HORIZONS, and ACTION risk models in the ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). METHODS: We studied all consecutive patients with STEMI who underwent PPCI at our institution between 2006 and 2010 (n=1391). The CRUSADE, ACUITY-HORIZONS, and ACTION risk scores were calculated based on the patients' clinical characteristics. The occurrence of in hospital major bleeding (defined as the composite of intracranial or intraocular bleeding, access site haemorrhage requiring intervention, reduction in haemoglobin >=4 g/dl without or >=3g/dl with overt bleeding source, reoperation for bleeding, or blood transfusion) reached 9.8%. Calibration and discrimination of the three risk models were evaluated by the Hosmer-Lemeshow test and the C statistic, respectively. We compared the predictive accuracy of the risk scores by the DeLong non-parametric test. RESULTS: Calibration of the three risk scores was adequate, given the non-significant results of Hosmer-Lemeshow test for the three risk models. Discrimination of CRUSADE, ACUITY-HORIZONS, and ACTION models was good (C-statistic 0.77, 0.70, and 0.78, respectively). The CRUSADE and ACTION risk scores had a greater predictive accuracy than the ACUITY-HORIZONS risk model (z=3.89, p-value=0.0001 and z=3.51, p-value=0.0004, respectively). There was no significant difference between the CRUSADE and ACTION models (z=0.63, p=0.531). CONCLUSIONS: The CRUSADE, ACUITY-HORIZONS, and ACTION scores are useful tools for the risk stratification of bleeding in STEMI treated by PPCI. Our findings favour the CRUSADE and ACTION risk models over the ACUITY-HORIZONS risk score. PMID- 24062931 TI - Management of patients with acute coronary syndromes in real-world practice in Italy: an outcome research study focused on the use of ANTithRombotic Agents: the MANTRA registry. AB - BACKGROUND: Although outcomes of acute coronary syndromes (ACS) have greatly improved, bleeding is still an issue. Thus, this study aims to evaluate in hospital management and outcomes of unselected patients with ACS focusing on antithrombotic therapies and bleeding. METHODS AND RESULTS: From 22 April 2009 to 29 December 2010, 6394 consecutive Italian patients were prospectively enrolled and followed for 6 months. Most patients (55.3%) had non-ST-elevation (NSTE) ACS. Of the ST-elevation (STE) ACS patients, 79.8% received reperfusion (mainly mechanical). In-hospital and 6-month unadjusted total mortality rates were 4.2 and 7.8% for STE-ACS and 2.5 and 6.4% for NSTE-ACS, respectively. During hospitalization, TIMI major bleeding rate was 1.2% (1.4% STE-ACS and 1.1% NSTE ACS, respectively) and TIMI minor bleeding was 3.1%. In-hospital and 6-month unadjusted total mortality rates were 3.1 and 6.7% for patients without bleeding, 1.5 and 8.6% for minor bleeding, and 19.0 and 26.6% for TIMI major bleeding, respectively (p<0.0001). Notably, TIMI major bleeding was one of the strongest predictors of the 6-month composite end point (death or reinfarction) (STE-ACS hazard ratio, HR, 2.86, 95% confidence interval, 95% CI, 1.57-5.23; NSTE-ACS HR, 2.71, 95% CI 1.52-4.80). Predictors of in-hospital TIMI major bleeding were weight (odds ratio, OR, 0.97, 95% CI 0.95-0.99), female gender (OR 1.80, 95% CI 1.09-2.96), history of peripheral vasculopathy (OR 2.95, 95% CI 1.83-4.78), switching anticoagulant therapy (OR 2.62, 95% CI 1.36-5.05), intra-aortic balloon pump implantation (OR 4.44, 95% CI 1.85-10.69), and creatinine >=2 mg/dl on admission (OR 3.68, 95% CI 1.84-7.33). CONCLUSIONS: Despite aggressive management, the rate of bleeding remains relatively low in an unselected ACS population. However, major bleeding adversely affects prognosis and physicians should tailor treatments to reduce it. PMID- 24062932 TI - Guidelines-based treatment of anaemic STEMI patients: practice patterns and effects on in-hospital mortality: a retrospective analysis from the NCDR. AB - BACKGROUND: Anaemia is associated with an increased risk for morbidity and mortality in ST-elevation myocardial infarction (STEMI) patients. While several physiological mechanisms have been proposed to explain this association, decreased receipt of guidelines-based care may also contribute. We examined the relationship between admission haemoglobin (Hgb) level, receipt of ACC/AHA guidelines-based treatments, and in-hospital outcomes among STEMI patients. We also evaluated whether administration of these treatments modified the association between anaemia and in-hospital mortality in this group. METHODS AND RESULTS: We analysed data from 92,686 patients diagnosed with STEMI included in the NCDR ACTION Registry-GWTG database from January 2007 to March 2011. Patients were stratified by initial Hgb value: 83.1% (n=77,035) were classified as non anaemic (Hgb >13.0 g/dl for men, >12.0 g/dl for women), 11.6% (n=10,710) as mildly anaemic (11.1-13.0 g/dl for men, 11.1-12.0 g/dl for women), 4.4% (n=4059) as moderately anaemic (9.1-11.0 g/dl), and 1.0% (n=882) as severely anaemic (<9.0 g/dl). Anaemia was associated with a significantly increased prevalence of other baseline comorbidities and decreased odds of receiving several class I recommended pharmacological treatments (heparin, beta-blockers, and angiotensin converting enzyme inhibitors, p<0.01). The overall use of reperfusion therapy (fibrinolytic therapy and/or percutaneous coronary intervention) was also lower in anaemic vs. non-anaemic patients (p<0.01). Anaemia was associated higher in hospital mortality risk, which remained significant after adjustment for use of guidelines-recommended therapies and interventions (p<0.01). CONCLUSIONS: In a national sample of STEMI patients, anaemia on presentation was associated with decreased receipt of ACC/AHA guidelines-based care and higher in-hospital mortality. However, the higher mortality rates could not be fully explained by differences in in-hospital treatment. PMID- 24062933 TI - Serum uric acid: a forgotten prognostic marker in acute coronary syndromes? AB - BACKGROUND: Serum uric acid (UA) has been shown to be an independent predictor of outcome in the general population and in patients with heart failure. There are, however, limited data regarding the prognostic value of UA in the context of acute coronary syndromes (ACS) particularly in medium-term follow up and the available results are contradictory. MATERIALS AND METHODS: Study of consecutive patients admitted with an ACS (with and without ST-segment elevation) at a single centre coronary care unit. Primary endpoint was all-cause mortality at 1-year follow up. We evaluated if serum UA is an independent predictor of outcome and if it has any added value on top of GRACE risk score for risk prediction. RESULTS: We included 683 patients, mean age 64+/-13 years, 69% males. In-hospital and 1 year mortality were 4.5 and 7.6% respectively. The best cut-off of UA to predict 1-year mortality was 6.25 mg/dl (sensitivity 59%, specificity 72%) and 30.2% of the patients had an increased UA according to this cut off. Independent predictors of UA were male gender (beta= 0.078), body mass index (beta=0.163), diuretics before admission (beta=0.142), and admission serum creatinine (beta=0.403). One-year mortality was significantly higher in patients with increased UA (15.5 vs. 4.2%, p<0.001; log rank, p<0.001). After adjustment, both increased UA as a categorical variable (HR 2.25, 95% CI 1.23-4.13, p=0.008) and as a continuous variable (HR 1.26, 95% CI 1.13-1.41, p<0.001) are independent predictors of mortality. The AUC increases only slightly after inclusion of UA in the model with GRACE risk score (from 0.78 to 0.79, p=0.350). Both models had a good fit; however, model fit worsened after inclusion of UA. Overall, the inclusion of UA in the original was associated with an improvement in both the net reclassification improvement (continuous NRI=44%), and the integrated discrimination improvement (IDI=0.052) suggesting effective reclassification. CONCLUSIONS: Serum UA is an independent predictor of all-cause mortality in medium-term after the whole spectrum of ACS and has an added value for risk stratification. PMID- 24062934 TI - Serum extracellular vesicle protein levels are associated with acute coronary syndrome. AB - AIMS: Biomarkers are essential in the early detection of acute coronary syndromes (ACS). Serum extracellular vesicles are small vesicles in the plasma containing protein and RNA and have been shown to be involved in ACS-related processes like apoptosis and coagulation. Therefore, we hypothesized that serum extracellular vesicle protein levels are associated with ACS. METHODS AND RESULTS: Three serum extracellular vesicle proteins potentially associated with ACS were identified with differential Q-proteomics and were evaluated in 471 frozen serum samples of ACS-suspected patients presenting to the emergency department (30% of whom had an ACS). Protein levels were measured after vesicle isolation using ExoQuick. Mean serum extracellular vesicle concentration of the different proteins was compared between ACS and non-ACS patients. Selected proteins were tested in a univariate logistic regression model, as well as in a multivariate model to adjust for cardiovascular risk factors. A separate analysis was performed in men and women. In the multivariate logistic regression analysis, polygenic immunoglobulin receptor, (pIgR; OR 1.630, p=0.026), cystatin C (OR 1.641, p=0.021), and complement factor C5a (C5a, OR 1.495, p=0.025) were significantly associated with ACS, while total vesicle protein concentration was borderline significant. The association of the individual proteins with ACS was markedly stronger in men. CONCLUSIONS: These data show that serum extracellular vesicle pIgR, cystatin C, and C5a concentrations are independently associated with ACS and that there are pronounced gender differences. These observations should be validated in a large, prospective study to assess the potential role of vesicle content in the evaluation of patients suspected of having an ACS. PMID- 24062935 TI - Left ventricular outflow tract obstruction following an uncomplicated primary percutaneous coronary intervention: a recognized but rare cause of cardiogenic shock. AB - Dynamic left ventricular outflow tract obstruction is a rare but important complication of myocardial infarction. It occurs acutely and may mimic the presentation of papillary muscle rupture or acquired ventricular septal defect. Unlike these mechanical complications, it does not require circulatory support or cardiac surgical intervention. Recognition is critical because it typically responds to volume loading and beta blockade. We report a case who displayed many classical features of this condition. PMID- 24062936 TI - Complete graft dehiscence 8 months after repair of acute type A aortic dissection. AB - Acute type A aortic dissection is a dreaded differential diagnosis of acute chest pain. Long-term outcome mainly depends on pre-existing comorbidities and post operative complications. We present a patient with aortic graft dehiscence and subsequent severe aortic regurgitation due to fungal graft infection 8 months after repair of acute type A aortic dissection. Redo aortic surgery had to be delayed for 28 days due to intracerebral haemorrhage caused by septic embolism and clipping of a mycotic left middle cerebral artery aneurysm. Surgery revealed a circumferentially detached graft at the site of the proximal anastomosis thereby forming a massive pseudoaneurysm. The patient underwent successful aortic root replacement using a Freestyle porcine root bioprosthesis (25 mm), followed by re-anastomosis of the coronary arteries and partial replacement of the ascending aorta with a 28 mm Dacron graft. The patient was discharged on day 67 in stable cardiac condition with persistent neurological deficits. This case highlights the challenging management of patients with aortic graft infection and neurological dysfunction after redissection of the ascending aorta who require redo cardiac surgery. PMID- 24062937 TI - Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving biventricular cardiomyopathy: key diagnostic features and literature review. AB - Cardiotoxicity is a rare but serious complication of hydroxychloroquine, a 4 aminoquinoline increasingly used in the treatment of rheumatological disorders. We describe typical clinical, echocardiographic, and histological features of this rare condition according to the currently available literature, illustrated with a recent new biopsy-proven case of hydroxychloroquine cardiotoxicity in a 52 year-old female with rheumatoid arthritis. Presentation in this case was of a rapidly progressive decompensated biventricular cardiomyopathy associated with recurrent biomarker elevations, conduction system disease, and possibly neuromyotoxicity. Death occurred suddenly 2 months after diagnosis despite drug discontinuation and clinical improvement. The potential role of cardiac magnetic resonance delayed gadolinium enhancement imaging in the prognosis of this toxic cardiomyopathy is also introduced. This case-based literature review highlights that, although rare, hydroxychloroquine cardiotoxicity can be fatal, particularly if irreversible histopathological changes have occurred prior to drug discontinuation. Given this, regular screening with 12-lead electrocardiography and transthoracic echocardiography to detect conduction system disease and/or biventricular morphological or functional changes should be considered in hydroxychloroquine-treated patients in addition to recommended ophthalmological screening. PMID- 24062938 TI - Heart failure due to 'stress cardiomyopathy': a severe manifestation of the opioid withdrawal syndrome. AB - Takotsubo cardiomyopathy (TTC) is a transient left ventricular (LV) dysfunction due to akinesia of the LV mid-apical segments ('apical ballooning') in the absence of critical coronary stenoses which can be complicated in the acute phase by heart failure, mitral regurgitation, life-threatening ventricular arrhythmias, or apical LV thrombosis. The syndrome is typically precipitated by intense emotional or physical stress; however, other causes of sympathetic overstimulation including administration of exogenous sympathomimetics or withdrawal of sympathetic antagonists can trigger TTC. We report the case of a patient who unexpectedly developed an 'apical ballooning' with severe reduction in the LV systolic function and heart failure after the withdrawal of methadone. The case supports the concept that increased sympathetic activity secondary to opioids withdrawal can trigger a stress-induced severe LV dysfunction. Physicians should be aware that the abrupt discontinuation of a long-term therapy with opioids may lead to serious cardiac complications. The administration of clonidine may be considered to prevent early clinical manifestations of addictive withdrawal, including TTC. PMID- 24062939 TI - Pre-operative systolic anterior motion of the mitral valve in a patient undergoing mitral valve repair. AB - A patient with myxomatous mitral valve prolapse underwent mitral mitral valve repair due to severe symptomatic mitral regurgitation. Preoperative echocardiography demonstrated systolic anterior motion of the mitral valve. This finding disappeared once spontaneous chordal rupture occurred, resulting in a flail posterior mitral leaflet. As the patient was considered at high risk of developing post-repair SAM, he was operated on using surgical techniques aimed at lowering the risk of this complication. Despite this, post-repair SAM did develop and could only be eliminated by a surgical edge-to-edge (Alfieri) repair. PMID- 24062940 TI - The structure of the COPII transport-vesicle coat assembled on membranes. AB - Coat protein complex II (COPII) mediates formation of the membrane vesicles that export newly synthesised proteins from the endoplasmic reticulum. The inner COPII proteins bind to cargo and membrane, linking them to the outer COPII components that form a cage around the vesicle. Regulated flexibility in coat architecture is essential for transport of a variety of differently sized cargoes, but structural data on the assembled coat has not been available. We have used cryo electron tomography and subtomogram averaging to determine the structure of the complete, membrane-assembled COPII coat. We describe a novel arrangement of the outer coat and find that the inner coat can assemble into regular lattices. The data reveal how coat subunits interact with one another and with the membrane, suggesting how coordinated assembly of inner and outer coats can mediate and regulate packaging of vesicles ranging from small spheres to large tubular carriers. DOI:http://dx.doi.org/10.7554/eLife.00951.001. PMID- 24062941 TI - The antigenic switching network of Plasmodium falciparum and its implications for the immuno-epidemiology of malaria. AB - Antigenic variation in the human malaria parasite Plasmodium falciparum involves sequential and mutually exclusive expression of members of the var multi-gene family and appears to follow a non-random pattern. In this study, using a detailed in vitro gene transcription analysis of the culture-adapted HB3 strain of P. falciparum, we show that antigenic switching is governed by a global activation hierarchy favouring short and highly diverse genes in central chromosomal location. Longer and more conserved genes, which have previously been associated with severe infection in immunologically naive hosts, are rarely activated, however, implying an in vivo fitness advantage possibly through adhesion-dependent survival rates. We further show that a gene's activation rate is positively associated sequence diversity, which could offer important new insights into the evolution and maintenance of antigenic diversity in P. falciparum malaria. DOI:http://dx.doi.org/10.7554/eLife.01074.001. PMID- 24062942 TI - DIFFERENCES IN IONIC CURRENTS BETWEEN CANINE MYOCARDIAL AND PURKINJE CELLS. AB - An electrophysiological analysis of canine single ventricular myocardial (VM) and Purkinje (P) cells was carried out by means of whole cell voltage clamp method. The following results in VM versus P cells were obtained. INa3 was present, had a threshold negative to the fast activating-inactivating INa1, its slow inactivation was cut off by INa1, and contributed to Na+ influx at INa1 threshold. INa1 was smaller and had a less negative threshold. There was no comparable slowly inactivating INa2, accounting for the shorter action potential. Slope conductance at resting potential was about double and decreased to a minimum value at the larger and less negative IK1 peak. The negative slope region of I-V relation was smaller during fast ramps and larger during slow ramps than in P cells, occurred in the voltage range of IK1 block by Mg2+, was not affected by a lower Vh and TTX and was eliminated by Ba2+, in contrast to P cells. ICa was larger, peaked at positive potentials and was eliminated by Ni2+. Ito was much smaller, began at more positive values, was abolished by less negative Vh and by 4-aminopyridine, included a sustained current that 4-aminopyridine decreased but did not eliminate. Steeper ramps increased IK1 peak as well as the fall in outward current during repolarization, consistent with a time-dependent block and unblock of IK1 by polyamines. During repolarization, the positive slope region was consistently present and was similar in amplitude to IK1 peak, whereas it was small or altogether missing in P cells. The total outward current at positive potentials comprised a larger IK1 component whereas it included a larger Ito and sustained current in P cells. These and other results provide a better understanding of the mechanisms underlying the action potential of VM and P cells under normal and some abnormal (arrhythmias) conditions. PMID- 24062943 TI - Beyond poiseuille: preservation fluid flow in an experimental model. AB - Poiseuille's equation describes the relationship between fluid viscosity, pressure, tubing diameter, and flow, yet it is not known if cold organ perfusion systems follow this equation. We investigated these relationships in an ex vivo model and aimed to offer some rationale for equipment selection. Increasing the cannula size from 14 to 20 Fr increased flow rate by a mean (SD) of 13 (12)%. Marshall's hyperosmolar citrate was three times less viscous than UW solution, but flows were only 45% faster. Doubling the bag pressure led to a mean (SD) flow rate increase of only 19 (13)%, not twice the rate. When external pressure devices were used, 100 mmHg of continuous pressure increased flow by a mean (SD) of 43 (17)% when compared to the same pressure applied initially only. Poiseuille's equation was not followed; this is most likely due to "slipping" of preservation fluid within the plastic tubing. Cannula size made little difference over the ranges examined; flows are primarily determined by bag pressure and fluid viscosity. External infusor devices require continuous pressurisation to deliver high flow. Future studies examining the impact of perfusion variables on graft outcomes should include detailed equipment descriptions. PMID- 24062944 TI - Ultrasound as a tool to assess body fat. AB - Ultrasound has been used effectively to assess body fat for nearly 5 decades, yet this method is not known as well as many other body composition techniques. The purpose of this review is to explain the technical principles of the ultrasound method, explain the procedures for taking a measurement and interpreting the results, evaluate the reliability and validity of this method for measuring subcutaneous and visceral adipose tissue, highlight the advantages and limitations of ultrasound relative to other body composition methods, consider its utility to clinical populations, and introduce new body composition-specific ultrasound technology. The focus of this review is adipose, although various tissue thicknesses (e.g., muscle and bone) can be measured with ultrasound. Being a portable imaging device that is capable of making fast regional estimates of body composition, ultrasound is an attractive assessment tool in instances when other methods are limited. Furthermore, much of the research suggests that it is reliable, reproducible, and accurate. The biggest limitations appear to be a lack of standardization for the measurement technique and results that are highly dependent on operator proficiency. New ultrasound devices and accompanying software designed specifically for the purpose of body composition assessment might help to minimize these limitations. PMID- 24062945 TI - Beyond the "I" in the obesity epidemic: a review of social relational and network interventions on obesity. AB - BACKGROUND: Recent research has shown the importance of networks in the spread of obesity. Yet, the translation of research on social networks and obesity into health promotion practice has been slow. OBJECTIVES: To review the types of obesity interventions targeting social relational factors. METHODS: Six databases were searched in January 2013. A Boolean search was employed with the following sets of terms: (1) social dimensions: social capital, cohesion, collective efficacy, support, social networks, or trust; (2) intervention type: intervention, experiment, program, trial, or policy; and (3) obesity in the title or abstract. Titles and abstracts were reviewed. Articles were included if they described an obesity intervention with the social relational component central. Articles were assessed on the social relational factor(s) addressed, social ecological level(s) targeted, the intervention's theoretical approach, and the conceptual placement of the social relational component in the intervention. RESULTS: Database searches and final article screening yielded 30 articles. Findings suggested that (1) social support was most often targeted; (2) few interventions were beyond the individual level; (3) most interventions were framed on behaviour change theories; and (4) the social relational component tended to be conceptually ancillary to the intervention. CONCLUSIONS: Theoretically and practically, social networks remain marginal to current interventions addressing obesity. PMID- 24062947 TI - An investigation of the glucose monitoring practices of nurses in stroke care: a descriptive cohort study. AB - Glucose derangement is commonly observed among adults admitted to hospital with acute stroke. This paper presents the findings from a descriptive cohort study that investigated the glucose monitoring practices of nurses caring for adults admitted to hospital with stroke or transient ischaemic attack. We found that a history of diabetes mellitus was strongly associated with initiation of glucose monitoring and higher frequency of that monitoring. Glucose monitoring was continued for a significantly longer duration of days for adults with a history of diabetes mellitus, when compared to the remainder of the cohort. As glucose monitoring was not routine practice for adults with no history of diabetes mellitus, the detection and treatment of hyperglycaemia and hypoglycaemia events could be delayed. There was a significant positive association between the admission hospital that is most likely to offer stroke unit care and the opportunity for glucose monitoring. We concluded that adults with acute stroke, irrespective of their diabetes mellitus status prior to admission to hospital, are vulnerable to both hyperglycaemic and hypoglycaemic events. This study suggests that the full potential of nurses in the monitoring of glucose among hospitalised adults with stroke has yet to be realised. PMID- 24062946 TI - Diet quality, measured by fruit and vegetable intake, predicts weight change in young women. AB - This study investigates the relationship between diet quality and weight gain in young women. Young women (n = 4,287, with 1,356 women identified as plausible subsample aged 27.6 +/- 1.5 years at baseline) sampled from the Australian Longitudinal Study on Women's Health study completed food frequency questionnaires in 2003, which were used to evaluate diet quality using three indices: Australian Recommended Food Score (ARFS), Australian Diet Quality Index (Aus-DQI), and Fruit and Vegetable Index (FAVI). Weight was self-reported in 2003 and 2009. Multivariate linear regression was used to examine the association between tertiles of each diet quality index and weight change from 2003 to 2009. The ARFS and FAVI were significant predictors of 6-year weight change in this group of young women, while Aus-DQI did not predict weight change (P > 0.05). In the fully adjusted model, those who were in the top tertile of the ARFS significantly gained lower weight gain compared with the lower tertile for the plausible TEI sub-sample (beta = -1.6 kg (95% CI: -2.67 to -0.56), P = 0.003). In the fully adjustment model, young women were classified in the highest FAVI tertile and gained significantly less weight than those in the lowest tertile for the plausible TEI (beta = -1.6 kg (95% CI: -2.4 to -0.3) P = 0.01). In conclusion, overall diet quality measured by the ARFS and the frequency and variety of fruit and vegetable consumption may predict long-term weight gain in young women. Therefore, health promotion programs encouraging frequent consumption of a wide variety of fruits and vegetables are warranted. PMID- 24062948 TI - The self-fulfilling prophecy of episodic memory impairment in mild cognitive impairment: do episodic memory deficits identified at classification remain evident when later examined with different memory tests? AB - Previous studies of mild cognitive impairment (MCI) have been criticised for using the same battery of neuropsychological tests during classification and longitudinal followup. The key concern is that there is a potential circularity when the same tests are used to identify MCI and then subsequently monitor change in function over time. The aim of the present study was to examine the evidence of this potential circularity problem. The present study assessed the memory function of 72 MCI participants and 50 healthy controls using an alternate battery of visual and verbal episodic memory tests 9 months following initial comprehensive screening assessment and MCI classification. Individuals who were classified as multiple-domain amnestic MCI (a-MCI+) at screening show a significantly reduced performance in visual and verbal memory function at followup using a completely different battery of valid and reliable tests. Consistent with their initial classification, those identified as nonamnestic MCI (na-MCI) or control at screening demonstrated the highest performance across the memory tasks. The results of the present study indicate that persistent memory deficits remain evident in amnestic MCI subgroups using alternate memory tests, suggesting that the concerns regarding potential circularity of logic may be overstated in MCI research. PMID- 24062949 TI - Self-management of oxaliplatin-related peripheral neuropathy in colorectal cancer survivors. AB - Purpose. The purpose of this study was to evaluate medications that cancer survivors with oxaliplatin-induced peripheral neuropathy take to control neuropathic symptom, and to explore self-management techniques used at home to provide temporary relief of painful neuropathy. This was a mixed methods, descriptive, cross-sectional study using self-reported data from colorectal cancer survivors previously treated with oxaliplatin. We analyzed demographic and medication data obtained from participants, along with written comments from an open-ended question regarding methods participants had tried to self-manage symptoms of neuropathy. Results. Twenty-nine percent of the sample reported taking some type of nutritional supplement with potential neuroprotective qualities. Opioids were being taken by 10% of the sample, and nonsteroidal anti inflammatory and over-the-counter medications were taken by 15% of participants. Twelve percent of participants were taking antidepressants and 10% were taking anticonvulsants, primarily gabapentin. Recurrent themes for nonpharmacologic treatment included avoiding the cold/keeping warm, keeping moving, massaging or rubbing the affected area, and living with it. Conclusions. Patients treated with oxaliplatin for colorectal cancer utilize a variety of traditional pharmacologic agents and nutritional supplements in an effort to self-manage neuropathic symptoms. Patients also employ a variety of home-based therapies to provide temporary relief of peripheral neuropathy symptoms. PMID- 24062951 TI - New Freedom through Medical Devices Based on the Global System for Mobile Communications: A Prospective Survey of 620 Users of the Swiss Limmex Emergency Wristwatch-An Original Study from Switzerland. AB - About 500,000 elderly people in Switzerland suffer a fall each year. Thus medical attention and help are essential for these people, who mostly live alone without a caregiver. Only 3% of people aged over 65 in Switzerland use an emergency system. Personal telehealth devices allow patients to receive enough information about the appropriate treatment, as well as followup with their doctors and reports of any emergency, in the absence of any caregiver. This increases their quality of life in a cost-effective fashion. "Limmex"-a new medical emergency watch-was launched in Switzerland in 2011 and has been a great commercial success. In this paper, we give a brief review of this watch technology, along with the results of a survey of 620 users conducted by the Department of Emergency Medicine in Bern. PMID- 24062950 TI - Proteomic Analysis of the Ontogenetic Variability in Plasma Composition of Juvenile and Adult Bothrops jararaca Snakes. AB - The ontogenetic variability in venom composition of some snake genera, including Bothrops, as well as the biological implications of such variability and the search of new molecules that can neutralize the toxic components of these venoms have been the subject of many studies. Thus, considering the resistance of Bothrops jararaca to the toxic action of its own venom and the ontogenetic variability in venom composition described in this species, a comparative study of the plasma composition of juvenile and adult B. jararaca snakes was performed through a proteomic approach based on 2D electrophoresis and mass spectrometry, which allowed the identification of proteins that might be present at different levels during ontogenetic development. Among the proteins identified by mass spectrometry, antihemorrhagic factor Bj46a was found only in adult plasma. Moreover, two spots identified as phospholipase A2 inhibitors were significantly increased in juvenile plasma, which can be related to the higher catalytic PLA2 activity shown by juvenile venom in comparison to that of adult snakes. This work shows the ontogenetic variability of B. jararaca plasma, and that these changes can be related to the ontogenetic variability described in its venom. PMID- 24062952 TI - Reduction of Cellular Lipid Content by a Knockdown of Drosophila PDP1 gamma and Mammalian Hepatic Leukemia Factor. AB - In exploring the utility of double-stranded RNA (dsRNA) injections for silencing the PAR-domain protein 1 (Pdp1) gene in adult Drosophila, we noticed a dramatic loss of fat tissue lipids. To verify that our RNAi approach produced the expected Pdp1 knockdown, the abdominal fat tissues sections were stained with PDP1 antibodies. PDP1 protein immunostaining was absent in flies injected with dsRNA targeting a sequence common to all known Pdp1 isoforms. Subsequent experiments revealed that lipid staining is reduced in flies injected with dsRNA against Pdp1 gamma (fat body specific) and not against Pdp1 epsilon (predominantly involved in circadian mechanisms). Drosophila PDP1 gamma protein shows a high homology to mammalian thyrotroph embryonic factor (TEF), albumin D site-binding protein (DBP), and hepatic leukemia factor (HLF) transcription factors. In an in vitro model of drug- (olanzapine-) induced adiposity in mouse 3T3-L1 cells, the mRNA content of HLF but not TEF and DBP was increased by the drug treatment. A knockdown of the HLF mRNA by transfecting the cultures with HLF dsRNA significantly reduced their lipid content. Furthermore, the HLF RNAi prevented olanzapine from increasing the cell lipid content. These results suggest that the PDP1/HLF system may play a role in physiological and drug-influenced lipid regulation. PMID- 24062953 TI - Diagnostic genetics at a distance: von hippel-lindau disease and a novel mutation. AB - Genetic testing at a distance is commonplace where members of a family with a segregating germline mutation are geographically separated. For the most part, this challenge is addressed through the intervention of health professionals in taking and/or processing blood samples for subsequent couriering of DNA to a referral laboratory. In some circumstances, however, the collecting of pivotal clinical material may involve direct patient involvement. We describe such a situation where noninvasive saliva samples were provided by members of a family manifesting Von Hippel-Lindau (VHL) disease. The analysis identified a novel mutation in the VHL gene that was used to exclude other family members as being at risk of VHL disease. PMID- 24062954 TI - Accuracy of positive airway pressure device-measured apneas and hypopneas: role in treatment followup. AB - Improved data transmission technologies have facilitated data collected from positive airway pressure (PAP) devices in the home environment. Although clinicians' treatment decisions increasingly rely on autoscoring of respiratory events by the PAP device, few studies have specifically examined the accuracy of autoscored respiratory events in the home environment in ongoing PAP use. "PAP efficacy" studies were conducted in which participants wore PAP simultaneously with an Embletta sleep system (Embla, Inc., Broomfield, CO), which was directly connected to the ResMed AutoSet S8 (ResMed, Inc., San Diego, CA) via a specialized cable. Mean PAP-scored Apnea-Hypopnea Index (AHI) was 14.2 +/- 11.8 (median: 11.7; range: 3.9-46.3) and mean manual-scored AHI was 9.4 +/- 10.2 (median: 7.7; range: 1.2-39.3). Ratios between the mean indices were calculated. PAP-scored HI was 2.0 times higher than the manual-scored HI. PAP-scored AHI was 1.5 times higher than the manual-scored AHI, and PAP-scored AI was 1.04 of manual scored AI. In this sample, PAP-scored HI was on average double the manual-scored HI. Given the importance of PAP efficacy data in tracking treatment progress, it is important to recognize the possible bias of PAP algorithms in overreporting hypopneas. The most likely cause of this discrepancy is the use of desaturations in manual hypopnea scoring. PMID- 24062956 TI - Preserved imitation of known gestures in children with high-functioning autism. AB - It has been suggested that children with autism are particularly deficient at imitating novel gestures or gestures without goals. In the present study, we asked high-functioning autistic children and age-matched typically developing children to imitate several types of gestures that could be either already known or novel to them. Known gestures either conveyed a communicative meaning (i.e., intransitive) or involved the use of objects (i.e., transitive). We observed a significant interaction between gesture type and group of participants, with children with autism performing known gestures better than novel gestures. However, imitation of intransitive and transitive gestures did not differ across groups. These findings are discussed in light of a dual-route model for action imitation. PMID- 24062955 TI - Modulation of vitamin d status and dietary calcium affects bone mineral density and mineral metabolism in gottingen minipigs. AB - Calcium and vitamin D deficiency impairs bone health and may cause rickets in children and osteomalacia in adults. Large animal models are useful to study experimental osteopathies and associated metabolic changes. We intended to modulate vitamin D status and induce nutritional osteomalacia in minipigs. The control group (n = 9) was fed a semisynthetic reference diet with 6 g calcium and 6,500 IU vitamin D3/kg and the experimental group (n = 10) the same diet but with only 2 g calcium/kg and without vitamin D. After 15 months, the deficient animals were in negative calcium balance, having lost bone mineral density significantly (means +/- SEM) with -51.2 +/- 14.7 mg/cm(3) in contrast to controls (-2.3 +/- 11.8 mg/cm(3)), whose calcium balance remained positive. Their osteoid surface was significantly higher, typical of osteomalacia. Their plasma 25(OH)D dropped significantly from 60.1 +/- 11.4 nmol/L to 15.3 +/- 3.4 nmol/L within 10 months, whereas that of the control group on the reference diet rose. Urinary phosphorus excretion and plasma 1,25-dihydroxyvitamin D concentrations were significantly higher and final plasma calcium significantly lower than in controls. We conclude that the minipig is a promising large animal model to induce nutritional osteomalacia and to study the time course of hypovitaminosis D and associated functional effects. PMID- 24062957 TI - Mandibular bone and soft tissues necrosis caused by an arsenical endodontic preparation treated with piezoelectric device. AB - This paper describes a case of wide mandibular bone necrosis associated with significant soft tissues injury after using an arsenical endodontic preparation in the right lower second molar for endodontic purpose. Authors debate about the hazardous effects of the arsenic paste and the usefulness of piezosurgery for treatment of this drug related bone necrosis. PMID- 24062958 TI - Primary mesenteric smooth muscle tumor: an entity with unpredictable biologic behavior. AB - Smooth muscle tumors of the mesentery are rare lesions with unpredictable, usually malignant, biologic behavior irrespective of their histologic appearance. Such case is presented here. We present a case of a large smooth muscle tumor located in the mesentery of a 48 years old patient. The histopathologic features of the surgically excised tumor were that of a benign-appearing smooth muscle tumor, either a primary mesenteric smooth muscle tumor of unknown biologic behavior or a parasitic leiomyoma. The patient was discharged 4 days after from the hospital without any early postoperative complication. Close followup was further decided. Nine months after her primary therapy, our patient is alive and with no evidence of recurrent disease. Increased awareness must be considered for large mesenteric smooth muscle tumors, because even when they present indolent histologic features, they usually behave aggressively. PMID- 24062959 TI - Advanced composite of large cell neuroendocrine carcinoma and squamous cell carcinoma: a case report of uterine cervical cancer in a virgin woman. AB - Large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is very rare and aggressive. The prognosis is very poor despite multimodal treatment. We report a virgin woman with FIGO stage 4b LCNEC of uterine cervix coexisting with squamous cell carcinoma. An early thirties virgin woman presented with 2-month history of abdominal pain. A chest X-ray showed multiple lung metastatic tumors. A vaginal smear showed malignant cells, and a biopsy specimen had features of LCNEC. The tumor showed trabecular patterns. Tumor cells possessed a moderate amount of cytoplasm, prominent nucleoli, and large nuclei. The tumor cells are stained positive for synaptophysin, chromogranin A, and neuron specific enolase (NSE). The invasive tumor cells in connection with cervical squamous epithelium were focally positive for 34bE12. We made a diagnosis of composite LCNEC and nonkeratinizing squamous cell carcinoma. High-risk HPV test was negative with hybridized captured method 2. PMID- 24062960 TI - Novel Surgical Treatment for Refractory Heel Ulcers in Werner's Syndrome. AB - Patients with Werner's syndrome frequently develop chronic leg ulcers that heal poorly. We present a patient who suffered from this rare syndrome and developed typical heel ulcers. Treatment of the ulcer is challenging, as flap options are limited over the lower third of the leg and skin grafting is not easy as there is a lack of healthy granulations. We successfully treated the ulcer with osteomyelitis by drilling the bone and applying an ultrathin split thickness skin graft with the thigh skin as the donor site. PMID- 24062961 TI - Schwannoma of the median nerve at the wrist and palmar regions of the hand: a rare case report. AB - Schwannomas are also known as neurolemmas that are usually originated from Schwann cells located in the peripheric nerve sheaths. They are the most common tumours of the hand (0.8-2%). They usually present solitary swelling along the course of the nerve however multiple lesions may be present in cases of NF type 1, familial neurofibromatosis, and sporadic schwannomatosis. Schwannomas are generally represented as an asymptomatic mass; however pain, numbness and fatigue may take place with the increasing size of the tumour. EMG (electromyelography), MRI (magnetic resonance imagination), and USG (ultrasound) are helpful in the diagnosis. Surgical removal is usually curative. In this paper, we present a 24 year-old male referred to our clinic for a lump located at the volar side of the left wrist and a lump located in his left palm and numbness at his 3rd and 4th fingers. Total excision was performed for both lesions. Histopathological examination of the masses revealed typical features of schwannoma. At the 6th month followup the patient was symptom-free except for slight paresthesia of the 3rd and the 4th fingers. For our knowledge, this is the second case in the literature presenting wrist and palm involvement of the median nerve schwannoma. PMID- 24062962 TI - Vulva fibroadenoma associated with lactating adenoma in a 26-year-old nigerian female. AB - Background. Vulva lactating adenoma is rare and may be misdiagnosed as adenocarcinoma in frozen section and aspiration cytology if breast tissue is not anticipated. Objective. To raise the awareness of lactating vulva ectopic breast lesion among clinicians and pathologists. Case Report. We present a case of vulva fibroadenoma associated with lactating adenoma in a 26-year-old Nigerian female. Conclusion. The rarity of vulva ectopic breast tissue can present a diagnostic challenge for both the clinician and the anatomical pathologist. Once excisional biopsy is done and the lesion confirmed histologically, the anxious patient can be reassured. PMID- 24062963 TI - Idiopathic omental infarction, diagnosed and managed laparoscopically: a case report. AB - Idiopathic omental infarction is a rare cause of acute abdomen in adults, and the clinical finding can mimic acute appendicitis. Although idiopathic omental infarction is uncommon, the incidence of its detection has become more frequent as a result of advances in radiological technologies. We reported on a 21-year old man who presented with sudden onset of intermittent right lower quadrant abdominal pain for seven days. The pain became more localized at the right iliac fossa (RIF) at day 2 before admission. A physical examination revealed a fever (38.2 degrees C), severe RIF tenderness, mass-like fullness, and positive rebound tenderness. A CT of the abdomen showed inflammatory changes and increased fat density mass in the right upper quadrant measuring 5 * 4 cm representing focal panniculitis. However, the appendix was visualized normally and the findings were not in favor of acute appendicitis. Diagnosis was carried on laparoscopically. Serosanguinous free fluid was found in all abdominal quadrants. A 6 * 4 cm gangrenous omental mass was noted. The omental mass was excised and an appendectomy was performed. In summary, omental infarction should be considered as a deferential diagnosis for acute right-sided abdominal pain, especially if the clinical finding does not correspond to appendicitis. PMID- 24062964 TI - Single incision laparoscopic total gastrectomy and d2 lymph node dissection for gastric cancer using a four-access single port: the first experience. AB - Single incision laparoscopic surgery (SILS) and natural orifice transluminal endoscopic surgery (NOTES) have been developed to reduce the invasiveness of laparoscopic surgery. SILS has been frequently applied in various clinical settings, such as cholecystectomy, colectomy, and sleeve gastrectomy. So far, there have been four reports on single incision laparoscopic distal gastrectomy and one report on single incision laparoscopic total gastrectomy with D1 lymph node dissection for gastric cancer. In this report, we present our single incision laparoscopic total gastrectomy with D2 lymph node dissection technique using a four-hole single port (OctoPort) in a patient with gastric cancer. PMID- 24062965 TI - Studies on interaction of buffalo brain cystatin with donepezil: an Alzheimer's drug. AB - When drugs bind to a protein, the intramolecular structures can be altered, resulting in conformational change of the protein. Donepezil, an Acetyl Cholinesterase inhibitor (AChE), is commonly prescribed to patients with Alzheimer's disease (AD) to enhance cholinergic neurotransmission. It is the "first-line" agents in the treatment of Alzheimer's disease used to improve cognitive function in the disease. In the present study, a cysteine protease inhibitor (cystatin) has been isolated from buffalo brain using alkaline treatment, 40 to 60% ammonium sulphate fractionation and gel filtration chromatography on Sephadex G-75 with % yield of 64.13 and fold purification of 384.7. The purified inhibitor (Buffalo Brain Cystatin, (BBC)) was eluted as a single papain inhibitory peak which migrated as single band on native PAGE; however, on SDS-PAGE with and without beta mercaptoethanol ( beta ME) BBC gave two bands of M W 31.6 and 12.4 KDa, respectively. The molecular weight determined by gel filtration came out to be 43.6 KDa. The UV spectra of cystatin on interaction with donepezil suggested a conformational change in the protein. The fluorescence spectra of BC-donepezil composite show structural changes indicating 40 nm red shift with significant increase in fluorescence intensity of cystatin in the presence of donepezil representing an unfolding of cystatin on interaction, which is an indication of side effect of donepezil during the use of this drug. PMID- 24062966 TI - Validation and application of a new reversed phase HPLC method for in vitro dissolution studies of rabeprazole sodium in delayed-release tablets. AB - The purpose of this study was to develop and validate a new reversed phase high performance liquid chromatographic (RP-HPLC) method to quantify in vitro dissolution assay of rabeprazole sodium in pharmaceutical tablet dosage form. Method development was performed on C 18, 100 * 4.6 mm ID, and 10 MU m particle size column, and injection volume was 20 MU L using a diode array detector (DAD) to monitor the detection at 280 nm. The mobile phase consisted of buffer: acetonitrile at a ratio of 60 : 40 (v/v), and the flow rate was maintained at 1.0 mL/min. The method was validated in terms of suitability, linearity, specificity, accuracy, precision, stability, and sensitivity. Linearity was observed over the range of concentration 0.05-12.0 MU g/mL, and the correlation coefficient was found excellent >0.999. The method was specific with respect to rabeprazole sodium, and the peak purity was found 99.99%. The method was precise and had relative standard deviations (RSD) less than 2%. Accuracy was found in the range of 99.9 to 101.9%. The method was robust in different variable conditions and reproducible. This proposed fast, reliable, cost-effective method can be used as quality control tool for the estimation of rabeprazole sodium in routine dissolution test analysis. PMID- 24062967 TI - Electroconvulsive Therapy for Long-term Mutism in a Case of Noncatatonic Paranoid Schizophrenia. AB - We report a rare case of paranoid schizophrenia presenting with continuous mutism for about three years. This 26-year-old woman with multiple Schneiderian first rank symptoms ['Schneiderian' refers to those symptoms established by the German psychiatrist Kurt Schneider for the diagnosis of schizophrenia] did not have any catatonic features, and she would fluently communicate by gesturing or writing. Since there was serious impairment in biological functions not readily correctable by antipsychotics, she was started on electroconvulsive therapy. She responded well to 14 sessions of electroconvulsive therapy along with oral haloperidol. We also discuss the cultural implications of prolonged mutism. To the best of our knowledge, this is the first case of mutism in noncatatonic paranoid schizophrenia that responded well to electroconvulsive therapy described in the literature. PMID- 24062968 TI - Adderall-induced Trichotillomania: A Case Report. AB - Adderall (dextroamphet-amine/amphetamine) is a psychostimulant medication approved by the United States Food and Drug Administration for the treatment of attention deficit hyperactivity disorder. This medication is usually well tolerated with minimal side effects. We report a case of a 12-year-old girl who was prescribed Adderall by her primary care physician to treat her attention deficit hyperactivity disorder and who subsequently developed trichotillomania. A short time following the initiation of the medication, the patient's family members noticed the patient displaying unusual hair-pulling behavior. The patient was referred to a psychiatrist for an evaluation of trichotillomania. Following a thorough evaluation, the decision was made to discontinue the Adderall and switch the patient to guanfacine. The urge to pull her hair along with her anxiety dissipated following this change. Close follow-up was maintained for over a year with both the psychiatrist and the primary care physician, and during this time the patient did not display any unusual hair pulling behaviors. This case appears to display a very unusual side effect of Adderall. PMID- 24062969 TI - Treatment of obesity and disability in schizophrenia. AB - Despite 50 years of pharmacological and psychosocial interventions, schizophrenia remains one of the leading causes of disability. The inability to function in everyday settings includes deficits in performance of social, occupational, and independent living activities. Schizophrenia is also a life-shortening illness, caused mainly by poor physical health and its complications. Dysfunctional lifestyles including sedentary behavior and lack of physical activity prevail, while treatment with adipogenic psychotropic medication interacts with poor performance in screening, monitoring, and intervention that result in shortening of life expectancies by 25 to 30 years. Disability interferes with self-care and medical care, further worsening physical health to produce a vicious cycle of disability. Further, the neurobiological impact of obesity on brain functioning is substantial and relevant to schizophrenia. Simultaneous treatment of cognitive deficits and related deficits in functional skills, ubiquitous determinants of everyday functioning in schizophrenia, and targeted interventions aimed at poor physical health, especially obesity and associated comorbidities, may lead to additive or even interactive gains in everyday functioning in patients with schizophrenia not previously realized with other interventions. PMID- 24062970 TI - Sunshine, serotonin, and skin: a partial explanation for seasonal patterns in psychopathology? AB - A number of studies indicate that there can be seasonal variations in the expression of psychiatric phenomena, especially mood and anxiety symptoms, as well as completed suicide. Indeed, in acknowledgement of the potential for seasonal effects in depressive disorders, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition indicates the specifier, "with seasonal pattern." However, the explanations for the relationships between seasonal changes and exacerbations of psychopathology remain unclear, although the empirical literature indicates that an association between sunshine and serotonin is likely. Given that the relationship between sunshine and serotonin is probably a multimediated phenomenon, one contributory facet may be the role of sunshine on human skin. Human skin has an inherent serotonergic system that appears capable of generating serotonin. In this edition of The Interface, we discuss the relationships among psychopathology, sunshine, serotonin, and the skin. PMID- 24062971 TI - Managing handoff risk in psychiatry. PMID- 24062973 TI - The role of electron-stimulated desorption in focused electron beam induced deposition. AB - We present the results of our study about the deposition rate of focused electron beam induced processing (FEBIP) as a function of the substrate temperature with the substrate being an electron-transparent amorphous carbon membrane. When W(CO)6 is used as a precursor it is observed that the growth rate is lower at higher substrate temperatures. From Arrhenius plots we calculated the activation energy for desorption, E des, of W(CO)6. We found an average value for E des of 20.3 kJ or 0.21 eV, which is 2.5-3.0 times lower than literature values. This difference between estimates for E des from FEBIP experiments compared to literature values is consistent with earlier findings by other authors. The discrepancy is attributed to electron-stimulated desorption, which is known to occur during electron irradiation. The data suggest that, of the W(CO)6 molecules that are affected by the electron irradiation, the majority desorbs from the surface rather than dissociates to contribute to the deposit. It is important to take this into account during FEBIP experiments, for instance when determining fundamental process parameters such as the activation energy for desorption. PMID- 24062972 TI - Roles of PKC and phospho-adducin in transepithelial fluid secretion by Malpighian tubules of the yellow fever mosquito. AB - The diuretic hormone aedeskinin-III is known to increase the paracellular Cl- conductance in Malpighian (renal) tubules of the mosquito Aedes aegypti via a G protein-coupled receptor. The increase serves the blood-meal-initiated diuresis and is associated with elevated levels of Ca2+ and phosphorylated adducin in the cytosol of tubule. In the present study we have cloned adducin in Aedes Malpighian tubules and investigated its physiological roles. Immunolabeling experiments are consistent with the association of adducin with the cortical cytoskeleton, especially near the apical brush border of the tubule. An antibody against phosphorylated adducin revealed the transient phosphorylation of adducin 2 min after stimulating tubules with aedeskinin-III. The PKC inhibitor bisindolylmaleimide-I blocked the phosphorylation of adducin as well as the electrophysiological and diuretic effects of aedeskinin-III. Bisindolylmaleimide I also inhibited fluid secretion in control tubules. Phorbol 12-myristate 13 acetate increased phosphorylated adducin levels in Malpighian tubules, but it inhibited fluid secretion. Thus, the phosphorylation of adducin by PKC alone is insufficient to trigger diuretic rates of fluid secretion; elevated levels of intracellular Ca2+ may also be required. The above results suggest that the phosphorylation of adducin, which is known to destabilize the cytoskeleton, may (1) facilitate the traffic of transporters into the apical brush border supporting diuretic rates of cation secretion and (2) destabilize proteins in the septate junction thereby enabling paracellular anion (Cl-) secretion at diuretic rates. Moreover, PKC and the phosphorylation of adducin play a central role in control and diuretic tubules, consistent with the dynamic behavior of both transcellular and paracellular transport pathways. PMID- 24062974 TI - Novel composite Zr/PBI-O-PhT membranes for HT-PEFC applications. AB - Novel composite membranes for high temperature polymer-electrolyte fuel cells (HT PEFC) based on a poly[oxy-3,3-bis(4'-benzimidazol-2"-ylphenyl)phtalide-5"(6") diyl] (PBI-O-PhT) polymer with small amounts of added Zr were prepared. It was shown in a model reaction between zirconium acetylacetonate (Zr(acac)4) and benzimidazole (BI) that Zr-atoms are capable to form chemical bonds with BI. Thus, Zr may be used as a crosslinking agent for PBI membranes. The obtained Zr/PBI-O-PhT composite membranes were examined by means of SAXS, thermomechanical analysis (TMA), and were tested in operating fuel cells by means of stationary voltammetry and impedance spectroscopy. The new membranes showed excellent stability in a 2000-hour fuel cell (FC) durability test. The modification of the PBI-O-PhT films with Zr facilitated an increase of the phosphoric acid (PA) uptake by the membranes, which resulted in an up to 2.5 times increased proton conductivity. The existence of an optimal amount of Zr content in the modified PBI-O-PhT film was shown. Larger amounts of Zr lead to a lower PA doping level and a reduced conductivity due to an excessively high degree of crosslinking. PMID- 24062975 TI - A nano-graphite cold cathode for an energy-efficient cathodoluminescent light source. AB - The development of new types of light sources is necessary in order to meet the growing demands of consumers and to ensure an efficient use of energy. The cathodoluminescence process is still under-exploited for light generation because of the lack of cathodes suitable for the energy-efficient production of electron beams and appropriate phosphor materials. In this paper we propose a nano graphite film material as a highly efficient cold cathode, which is able to produce high intensity electron beams without energy consumption. The nano graphite film material was produced by using chemical vapor deposition techniques. Prototypes of cathodoluminescent lamp devices with a construction optimized for the usage of nano-graphite cold cathodes were developed, manufactured and tested. The results indicate prospective advantages of this type of lamp and the possibility to provide advanced power efficiency as well as enhanced spectral and other characteristics. PMID- 24062976 TI - Femtosecond-resolved ablation dynamics of Si in the near field of a small dielectric particle. AB - In this work we analyze the ablation dynamics of crystalline Si in the intense near field generated by a small dielectric particle located at the material surface when being irradiated with an infrared femtosecond laser pulse (800 nm, 120 fs). The presence of the particle (7.9 MUm diameter) leads to a strong local enhancement (ca. 40 times) of the incoming intensity of the pulse. The transient optical response of the material has been analyzed by means of fs-resolved optical microscopy in reflection configuration over a time span from 0.1 ps to about 1 ns. Characteristic phenomena like electron plasma formation, ultrafast melting and ablation, along with their characteristic time scales are observed in the region surrounding the particle. The use of a time resolved imaging technique allows us recording simultaneously the material response at ordinary and large peak power densities enabling a direct comparison between both scenarios. The time resolved images of near field exposed regions are consistent with a remarkable temporal shift of the ablation onset which occurs in the sub-picosend regime, from about 500 to 800 fs after excitation. PMID- 24062977 TI - Apertureless scanning near-field optical microscopy of sparsely labeled tobacco mosaic viruses and the intermediate filament desmin. AB - Both fluorescence imaging and atomic force microscopy (AFM) are highly versatile and extensively used in applications ranging from nanotechnology to life sciences. In fluorescence microscopy luminescent dyes serve as position markers. Moreover, they can be used as active reporters of their local vicinity. The dipolar coupling of the tip with the incident light and the fluorophore give rise to a local field and fluorescence enhancement. AFM topographic imaging allows for resolutions down to the atomic scale. It can be operated in vacuum, under ambient conditions and in liquids. This makes it ideal for the investigation of a wide range of different samples. Furthermore an illuminated AFM cantilever tip apex exposes strongly confined non-propagating electromagnetic fields that can serve as a coupling agent for single dye molecules. Thus, combining both techniques by means of apertureless scanning near-field optical microscopy (aSNOM) enables concurrent high resolution topography and fluorescence imaging. Commonly, among the various (apertureless) SNOM approaches metallic or metallized probes are used. Here, we report on our custom-built aSNOM setup, which uses commercially available monolithic silicon AFM cantilevers. The field enhancement confined to the tip apex facilitates an optical resolution down to 20 nm. Furthermore, the use of standard mass-produced AFM cantilevers spares elaborate probe production or modification processes. We investigated tobacco mosaic viruses and the intermediate filament protein desmin. Both are mixed complexes of building blocks, which are fluorescently labeled to a low degree. The simultaneous recording of topography and fluorescence data allows for the exact localization of distinct building blocks within the superordinate structures. PMID- 24062978 TI - Nanoglasses: a new kind of noncrystalline materials. AB - Nanoglasses are a new class of noncrystalline solids. They differ from today's glasses due to their microstructure that resembles the microstructure of polycrystals. They consist of regions with a melt-quenched glassy structure connected by interfacial regions, the structure of which is characterized (in comparison to the corresponding melt-quenched glass) by (1) a reduced (up to about 10%) density, (2) a reduced (up to about 20%) number of nearest-neighbor atoms and (3) a different electronic structure. Due to their new kind of atomic and electronic structure, the properties of nanoglasses may be modified by (1) controlling the size of the glassy regions (i.e., the volume fraction of the interfacial regions) and/or (2) by varying their chemical composition. Nanoglasses exhibit new properties, e.g., a Fe90Sc10 nanoglass is (at 300 K) a strong ferromagnet whereas the corresponding melt-quenched glass is paramagnetic. Moreover, nanoglasses were noted to be more ductile, more biocompatible, and catalytically more active than the corresponding melt-quenched glasses. Hence, this new class of noncrystalline materials may open the way to technologies utilizing the new properties. PMID- 24062979 TI - 3D nano-structures for laser nano-manipulation. AB - The resputtering of gold films from nano-holes defined in a sacrificial PMMA mask, which was made by electron beam lithography, was carried out with a dry plasma etching tool in order to form well-like structures with a high aspect ratio (height/width ~ 3-4) at the rims of the nano-holes. The extraordinary transmission through the patterns of such nano-wells was investigated experimentally and numerically. By doing numerical simulations of 50-nm and 100 nm diameter polystyrene beads in water and air, we show the potential of such patterns for self-induced back-action (SIBA) trapping. The best trapping conditions were found to be a trapping force of 2 pN/W/MUm(2) (numerical result) exerted on a 50-nm diameter bead in water. The simulations were based on the analytical Lorentz force model. PMID- 24062980 TI - Role of epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma: is tumor budding the missing link? AB - Pancreatic ductal adenocarcinoma (PDAC) ranks as the fourth commonest cause of cancer death while its incidence is increasing worldwide. For all stages, survival at 5 years is<5%. The lethal nature of pancreatic cancer is attributed to its high metastatic potential to the lymphatic system and distant organs. Lack of effective therapeutic options contributes to the high mortality rates of PDAC. Recent evidence suggests that epithelial-mesenchymal transition (EMT) plays an important role to the disease progression and development of drug resistance in PDAC. Tumor budding is thought to reflect the process of EMT which allows neoplastic epithelial cells to acquire a mesenchymal phenotype thus increasing their capacity for migration and invasion and help them become resistant to apoptotic signals. In a recent study by our own group the presence and prognostic significance of tumor budding in PDAC were investigated and an association between high-grade budding and aggressive clinicopathological features of the tumors as well as worse outcome of the patients was found. The identification of EMT phenotypic targets may help identifying new molecules so that future therapeutic strategies directed specifically against them could potentially have an impact on drug resistance and invasiveness and hence improve the prognosis of PDAC patients. The aim of this short review is to present an insight on the morphological and molecular aspects of EMT and on the factors that are involved in the induction of EMT in PDAC. PMID- 24062982 TI - MITF and PAX3 Play Distinct Roles in Melanoma Cell Migration; Outline of a "Genetic Switch" Theory Involving MITF and PAX3 in Proliferative and Invasive Phenotypes of Melanoma. AB - Melanoma is a very aggressive neoplasm with a propensity to undergo progression and invasion early in its evolution. The molecular pathways underpinning invasion in melanoma are now just beginning to be elucidated, but a clear understanding of the transition from non-invasive to invasive melanoma cells remains elusive. Microphthalmia-associated transcription factor (MITF), is thought to be a central player in melanoma biology, and it controls many aspects of the phenotypic expression of the melanocytic lineage. However, recently the paired box transcription factor PAX3 was shown to transcriptionally activate POU3F2/BRN2, leading to direct repression of MITF expression. Here we present a theory to explain melanoma phenotype switching and discuss the predictions that this theory makes. One prediction is that independent and opposing roles for MITF and PAX3 in melanoma would be expected, and we present empirical evidence supporting this: in melanoma tissues PAX3 expression occurs independently of MITF, and PAX3 does not play a key role in melanoma cell proliferation. Furthermore, we show that knockdown of PAX3 inhibits cell migration in a group of "lower MITF" melanoma cell lines, while knockdown of MITF promotes cell migration in a complementary "higher MITF" group of melanoma cell lines. Moreover, the morphological effects of knocking down PAX3 versus MITF in melanoma cells were found to differ. While these data support the notion of independent roles for MITF and PAX3, additional experiments are required to provide robust examination of the proposed genetic switch theory. Only upon clear delineation of the mechanisms associated with progression and invasion of melanoma cells will successful treatments for invasive melanoma be developed. PMID- 24062981 TI - The Elephant and the Blind Men: Making Sense of PARP Inhibitors in Homologous Recombination Deficient Tumor Cells. AB - Poly(ADP-ribose) polymerase 1 (PARP1) is an important component of the base excision repair (BER) pathway as well as a regulator of homologous recombination (HR) and non-homologous end-joining (NHEJ). Previous studies have demonstrated that treatment of HR-deficient cells with PARP inhibitors results in stalled and collapsed replication forks. Consequently, HR-deficient cells are extremely sensitive to PARP inhibitors. Several explanations have been advanced to explain this so-called synthetic lethality between HR deficiency and PARP inhibition: (i) reduction of BER activity leading to enhanced DNA double-strand breaks, which accumulate in the absence of HR; (ii) trapping of inhibited PARP1 at sites of DNA damage, which prevents access of other repair proteins; (iii) failure to initiate HR by poly(ADP-ribose) polymer-dependent BRCA1 recruitment; and (iv) activation of the NHEJ pathway, which selectively induces error-prone repair in HR-deficient cells. Here we review evidence regarding these various explanations for the ability of PARP inhibitors to selectively kill HR-deficient cancer cells and discuss their potential implications. PMID- 24062983 TI - Understanding the Biology of Bone Sarcoma from Early Initiating Events through Late Events in Metastasis and Disease Progression. AB - The two most common primary bone malignancies, osteosarcoma (OS), and Ewing sarcoma (ES), are both aggressive, highly metastatic cancers that most often strike teens, though both can be found in younger children and adults. Despite distinct origins and pathogenesis, both diseases share several mechanisms of progression and metastasis, including neovascularization, invasion, anoikis resistance, chemoresistance, and evasion of the immune response. Some of these processes are well-studies in more common carcinoma models, and the observation from adult diseases may be readily applied to pediatric bone sarcomas. Neovascularization, which includes angiogenesis and vasculogenesis, is a clear example of a process that is likely to be similar between carcinomas and sarcomas, since the responding cells are the same in each case. Chemoresistance mechanisms also may be similar between other cancers and the bone sarcomas. Since OS and ES are mesenchymal in origin, the process of epithelial-to-mesenchymal transition is largely absent in bone sarcomas, necessitating different approaches to study progression and metastasis in these diseases. One process that is less well-studied in bone sarcomas is dormancy, which allows micrometastatic disease to remain viable but not growing in distant sites - typically the lungs - for months or years before renewing growth to become overt metastatic disease. By understanding the basic biology of these processes, novel therapeutic strategies may be developed that could improve survival in children with OS or ES. PMID- 24062985 TI - Chemoresistance and Cancer-Related Inflammation: Two Hallmarks of Cancer Connected by an Atypical Link, PKCzeta. AB - Atypical protein kinase C isoforms are serine threonine kinases involved in various pathological conditions. In recent years, the PKCzeta isoform has emerged as an important regulator of multiple cellular processes operating in cancer. In this review, we will focus on the PKCzeta isoform as an oxidative-sensing kinase involved in cancer-related inflammation and chemoresistance. We will discuss its nuclear localization and its possible pivotal role in connecting inflammation with drug resistance. PMID- 24062986 TI - Simulating cancer: computational models in oncology. PMID- 24062984 TI - Ways to enhance lymphocyte trafficking into tumors and fitness of tumor infiltrating lymphocytes. AB - The tumor is a hostile microenvironment for T lymphocytes. Indeed, irregular blood flow, and endothelial cell (EC) anergy that characterize most solid tumors hamper leukocyte adhesion, extravasation, and infiltration. In addition, hypoxia and reprograming of energy metabolism within cancer cells transform the tumor mass in a harsh environment that limits survival and effector functions of T cells, regardless of being induced in vivo by vaccination or adoptively transferred. In this review, we will summarize on recent advances in our understanding of the characteristics of tumor-associated neo-angiogenic vessels as well as of the tumor metabolism that may impact on T cell trafficking and fitness of tumor infiltrating lymphocytes. In particular, we will focus on how advances in knowledge of the characteristics of tumor ECs have enabled identifying strategies to normalize the tumor-vasculature and/or overcome EC anergy, thus increasing leukocyte-vessel wall interactions and lymphocyte infiltration in tumors. We will also focus on drugs acting on cells and their released molecules to transiently render the tumor microenvironment more suitable for tumor infiltrating T lymphocytes, thus increasing the therapeutic effectiveness of both active and adoptive immunotherapies. PMID- 24062987 TI - Association of endogenous retroviruses and long terminal repeats with human disorders. AB - Since the human genome sequences became available in 2001, our knowledge about the human transposable elements which comprise ~40% of the total nucleotides has been expanding. Non-long terminal repeat (non-LTR) retrotransposons are actively transposing in the present-day human genome, and have been found to cause ~100 identified clinical cases of varied disorders. In contrast, almost all of the human endogenous retroviruses (HERVs) originating from ancient infectious retroviruses lost their infectivity and transposing activity at various times before the human-chimpanzee speciation (~6 million years ago), and no known HERV is presently infectious. Insertion of HERVs and mammalian apparent LTR retrotransposons (MaLRs) into the chromosomal DNA influenced a number of host genes in various modes during human evolution. Apart from the aspect of genome evolution, HERVs and solitary LTRs being suppressed in normal biological processes can potentially act as extra transcriptional apparatuses of cellular genes by re-activation in individuals. There has been a reasonable prediction that aberrant LTR activation could trigger malignant disorders and autoimmune responses if epigenetic changes including DNA hypomethylation occur in somatic cells. Evidence supporting this hypothesis has begun to emerge only recently: a MaLR family LTR activation in the pathogenesis of Hodgkin's lymphoma and a HERV-E antigen expression in an anti-renal cell carcinoma immune response. This mini review addresses the impacts of the remnant-form LTR retrotransposons on human pathogenesis. PMID- 24062988 TI - Autotaxin Inhibition with PF-8380 Enhances the Radiosensitivity of Human and Murine Glioblastoma Cell Lines. AB - PURPOSE: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that is radio-resistant and recurs despite aggressive surgery, chemo, and radiotherapy. Autotaxin (ATX) is over expressed in various cancers including GBM and is implicated in tumor progression, invasion, and angiogenesis. Using the ATX specific inhibitor, PF-8380, we studied ATX as a potential target to enhance radiosensitivity in GBM. METHODS AND MATERIALS: Mouse GL261 and Human U87-MG cells were used as GBM cell models. Clonogenic survival assays and tumor transwell invasion assays were performed using PF-8380 to evaluate role of ATX in survival and invasion. Radiation dependent activation of Akt was analyzed by immunoblotting. Tumor induced angiogenesis was studied using the dorsal skin fold model in GL261. Heterotopic mouse GL261 tumors were used to evaluate the efficacy of PF-8380 as a radiosensitizer. RESULTS: Pre-treatment of GL261 and U87-MG cells with 1 MUM PF-8380 followed by 4 Gy irradiation resulted in decreased clonogenic survival, decreased migration (33% in GL261; P = 0.002 and 17.9% in U87-MG; P = 0.012), decreased invasion (35.6% in GL261; P = 0.0037 and 31.8% in U87-MG; P = 0.002), and attenuated radiation-induced Akt phosphorylation. In the tumor window model, inhibition of ATX abrogated radiation induced tumor neovascularization (65%; P = 0.011). In a heterotopic mouse GL261 tumors untreated mice took 11.2 days to reach a tumor volume of 7000 mm(3), however combination of PF-8380 (10 mg/kg) with irradiation (five fractions of 2 Gy) took more than 32 days to reach a tumor volume of 7000 mm(3). CONCLUSION: Inhibition of ATX by PF-8380 led to decreased invasion and enhanced radiosensitization of GBM cells. Radiation induced activation of Akt was abrogated by inhibition of ATX. Furthermore, inhibition of ATX led to diminished tumor vascularity and delayed tumor growth. These results suggest that inhibition of ATX may ameliorate GBM response to radiotherapy. PMID- 24062989 TI - Cord Blood Transplantation: Can We Make it Better? AB - Umbilical cord blood is an established source of hematopoietic stem cells for transplantation. It enjoys several advantages over bone marrow or peripheral blood, including increased tolerance for Human Leukocyte Antigen mismatches, decreased incidence of graft-versus-host disease, and easy availability. Unrelated cord blood does have limitations, however, especially in the treatment of adults. In the 24 years since the first umbilical cord blood transplant was performed, significant progress has been made, but delayed hematopoietic engraftment and increased treatment-related mortality remain obstacles to widespread use. Here we summarize the latest results of unrelated cord blood transplants, and review strategies under investigation to improve clinical outcomes. PMID- 24062990 TI - Genomic Rearrangements of PTEN in Prostate Cancer. AB - The phosphatase and tensin homolog gene (PTEN) on chromosome 10q23.3 is a negative regulator of the PIK3/Akt survival pathway and is the most frequently deleted tumor suppressor gene in prostate cancer. Monoallelic loss of PTEN is present in up to 60% of localized prostate cancers and complete loss of PTEN in prostate cancer is linked to metastasis and androgen-independent progression. Studies on the genomic status of PTEN in prostate cancer initially used a two color fluorescence in situ hybridization (FISH) assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. More recently, a four-color FISH assay containing two additional control probes flanking the PTEN locus with a lower false-positive rate was reported. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, androgen receptor, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Although less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are also known to contribute to loss of PTEN function, and ultimately to prostate cancer initiation. Overall, it is clear that PTEN is a powerful biomarker for prostate cancer. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies. PMID- 24062992 TI - Endogenous retroviruses as targets for antitumor immunity in renal cell cancer and other tumors. AB - Human endogenous retroviruses (HERVs), remnants of ancient germ-line infections with exogenous retroviruses, are estimated to comprise up to 8% of human genome. Most HERVs have accumulated mutations and deletions that prevent their expression as an infectious virus. Nevertheless, a growing number of HERV genes and proteins have been found to be expressed in different cancers, raising the possibility that HERV-derived antigens might represent excellent targets for tumor immunotherapy. Here, we review data showing HERV-encoded antigens are capable of eliciting humoral and T-cells specific antitumor immunity. We also describe a novel HERV-E that was recently found to be selectively expressed in over 80% of clear cell kidney cancer but not in normal tissues. Remarkably, the restricted expression of HERV-E in kidney tumors was found to occur as a consequence of inactivation of the von Hippel-Lindau tumor suppressor. Importantly, antigens derived from this provirus are immunogenic, stimulating cytotoxic T-cells that kill kidney cancer cells in vitro and in vivo. Taken altogether, these data suggest efforts aimed at boosting human immunity against HERV-derived antigens could be used as a strategy to treat advanced tumors including kidney cancer. PMID- 24062991 TI - PML in the Brain: From Development to Degeneration. AB - The promyelocytic leukemia (PML) protein is the main component of PML nuclear bodies, which have many functions in a wide range of cell types. Until recently, PML was not known to have a function in the nervous system or even be expressed in the brain. However, recent reports have changed that view. PML is found in neurons and functions in many aspects of the nervous system, including brain development, circadian rhythms, plasticity, and the response to proteins that cause neurodegenerative disorders. While the investigation of PML in the brain is still in its infancy, it promises to be a fascinating subject that will contribute to our understanding of the brain. Here we summarize what is known about PML expression and function in the brain and highlight both discrepancies in the field and areas that are particularly important to future research. PMID- 24062993 TI - The pathogenic Yersiniae--advances in the understanding of physiology and virulence. PMID- 24062994 TI - Injuries in the North--analysis of 20 years of surveillance data collected by the Canadian Hospitals Injury Reporting and Prevention Program. AB - BACKGROUND: Injury is a major public health concern, particularly for Canadians living in Arctic regions where the harsh physical and social conditions pose additional challenges. Surveillance data collected over the past 2 decades through the Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) provide insights into the burden of injuries in certain parts of Canada. OBJECTIVES: This study aims to summarize and compare patterns of injuries in the Northwest Territories (NWT) and Nunavut to other southern communities across Canada. METHODS: Analysis was based on CHIRPP data covering the period 1991-2010. Proportionate injury ratio (PIR) and its 95% confidence interval were used to summarize and compare the injury experience of Canadians living in the Arctic regions to other CHIRPP sites across Canada. RESULTS: Between 1991 and 2010, there were 65,116 reported injuries. Approximately 83% of the cases were unintentional in nature; however, significantly higher proportions were observed for assaults and maltreatment (PIR = 2.80, 95% CI: 2.72-2.88) among Canadians living in northern communities. Significantly higher proportions were also observed for crushing/amputations (PIR = 2.28, 95% CI: 2.14-2.44), poison/toxic effects (PIR = 1.21, 95% CI: 1.15-1.28), drowning/asphyxiations (PIR = 1.52, 95% CI: 1.33-1.74) and frostbites (PIR = 7.39, 95% CI: 6.60-8.28). The use of all terrain vehicles or snowmobiles also resulted in significantly higher proportions of injuries (PIR = 1.93, 95% CI: 1.79-2.09). CONCLUSIONS: This study contributes to the limited literature describing injuries in northern communities where the harsh physical and social climates pose additional challenges. Excesses in the proportions identified in this study could be useful in identifying strategies needed to minimize injury risks in northern communities within Canada. PMID- 24062995 TI - Enhanced topical delivery of tetrandrine by ethosomes for treatment of arthritis. AB - The purpose of this work was to explore the feasibility of ethosomes for improving the antiarthritic efficacy of tetrandrine by topical application. It was found that tetrandrine was a weak base (pK(a) = 7.06) with pH-dependent partition coefficient. The spherical-shaped ethosomes were prepared by pH gradient loading method. Ex vivo permeation and deposition behavior demonstrated that the drug flux across rat skin and deposition of the drug in rat skin for ethosomes was 2.1- and 1.7-fold higher than that of liposomes, respectively. Confocal laser scanning microscopy confirmed that ethosomes could enhance the topical delivery of the drug in terms of depth and quantity compared with liposomes. The ethosomes were shown to generate substantial enhancement of therapeutic efficacy of tetrandrine on Freund's complete adjuvant-induced arthritis with regard to liposomes. These results indicated that ethosomes would be a promising carrier for topical delivery of tetrandrine into and across the skin. PMID- 24062996 TI - Lifting the silver flakes: the pathogenesis and management of chronic plaque psoriasis. AB - Psoriasis is a common chronic inflammatory skin condition in which patients suffer from mild to chronic plaque skin plaques. The disease manifests through an excessive inflammatory response in the skin due to complex interactions between different genetic and environmental factors. Psoriasis can affect the physical, emotional, and psychosocial well-being of patients, and currently there is no cure with treatments focusing primarily on the use of anti-inflammatory agents to control disease symptoms. Traditional anti-inflammatory agents can cause immunosuppression and adverse systemic effects. Further understanding of the disease has led to current areas of research aiming at the development of selective molecular targets to suppress the pathogenic immune responses. PMID- 24062997 TI - Brain tumor classification using AFM in combination with data mining techniques. AB - Although classification of astrocytic tumors is standardized by the WHO grading system, which is mainly based on microscopy-derived, histomorphological features, there is great interobserver variability. The main causes are thought to be the complexity of morphological details varying from tumor to tumor and from patient to patient, variations in the technical histopathological procedures like staining protocols, and finally the individual experience of the diagnosing pathologist. Thus, to raise astrocytoma grading to a more objective standard, this paper proposes a methodology based on atomic force microscopy (AFM) derived images made from histopathological samples in combination with data mining techniques. By comparing AFM images with corresponding light microscopy images of the same area, the progressive formation of cavities due to cell necrosis was identified as a typical morphological marker for a computer-assisted analysis. Using genetic programming as a tool for feature analysis, a best model was created that achieved 94.74% classification accuracy in distinguishing grade II tumors from grade IV ones. While utilizing modern image analysis techniques, AFM may become an important tool in astrocytic tumor diagnosis. By this way patients suffering from grade II tumors are identified unambiguously, having a less risk for malignant transformation. They would benefit from early adjuvant therapies. PMID- 24062998 TI - The influence of chain microstructure of biodegradable copolyesters obtained with low-toxic zirconium initiator to in vitro biocompatibility. AB - Because of the wide use of biodegradable materials in tissue engineering, it is necessary to obtain biocompatible polymers with different mechanical and physical properties as well as degradation ratio. Novel co- and terpolymers of various composition and chain microstructure have been developed and applied for cell culture. The aim of this study was to evaluate the adhesion and proliferation of human chondrocytes to four biodegradable copolymers: lactide-coglycolide, lactide co-epsilon-caprolactone, lactide-co-trimethylene carbonate, glycolide-co-epsilon caprolactone, and one terpolymer glycolide-colactide-co-epsilon-caprolactone synthesized with the use of zirconium acetylacetonate as a nontoxic initiator. Chain microstructure of the copolymers was analyzed by means of 1H and 13C NMR spectroscopy and surface properties by AFM technique. Cell adhesion and proliferation were determined by CyQUANT Cell Proliferation Assay Kit. After 4 h the chondrocyte adhesion on the surface of studied materials was comparable to standard TCPS. Cell proliferation occurred on all the substrates; however, among the studied polymers poly(L-lactide-coglycolide) 85 : 15 that characterized the most blocky structure best supported cell growth. Chondrocytes retained the cell membrane integrity evaluated by the LDH release assay. As can be summarized from the results of the study, all the studied polymers are well tolerated by the cells that make them appropriate for human chondrocytes growth. PMID- 24062999 TI - The impact of hepatic steatosis on hepatic ischemia-reperfusion injury in experimental studies: a systematic review. AB - BACKGROUND: The impact of hepatic steatosis on outcome following hepatic ischemia reperfusion injury (IRI) remains controversial with conflicting clinical results. A number of experimental studies have been published examining the relationship between hepatic steatosis and IRI. This systematic review evaluates these experimental studies. METHODS: An electronic search of the Medline and Embase databases (January 1946 to June 2012) was performed to identify studies that reported relevant outcomes in animal models of hepatic steatosis subjected to IRI. RESULTS: A total of 1314 articles were identified, of which 33 met the predefined criteria and were included in the study. There was large variation in the type of animal model, duration, and type of IRI and reporting of histological findings. Increased macrovesicular steatosis (>30%) was associated with increased histological damage, liver function derangement, and reduced survival. Increased duration of warm or cold ischemia had a negative impact on all outcomes measured. Microvesicular steatosis did not influence outcome. CONCLUSIONS: Findings from this systemic review support the hypothesis that livers with >30% macrovesicular steatosis are less tolerant of IRI. Clinically, it is likely that these findings are applicable to patients undergoing hepatic resection, but further studies are required to confirm these data. PMID- 24063001 TI - Doxycycline prevents intimal hyperplasia in vitro and may improve patency of the internal thoracic artery. AB - OBJECTIVES: The development of intimal hyperplasia and graft failure is an important problem in cardiac surgery. A fundamental process in intimal hyperplasia is the degradation of extracellular matrix by metalloproteases which induces the vascular smooth-muscle cells migration and sets the scene for graft atherosclerosis. This study investigated whether doxycycline, a metalloproteases inhibitor, can prevent the intimal hyperplasia occurrence in cultured human internal mammary artery, thus extending graft patency. METHODS: Segments of internal mammary artery from 20 consecutive patients were prepared and cultured for 2 weeks in serum-supplemented medium (control) or in medium supplemented with 10-5 M and 10-6 M doxycycline concentrations. Tissues were fixed, sectioned, and stained, and neointimal thickness was measured by computer-aided image analysis. Further sections were cultured and prepared for gel enzymography to measure the matrix metalloproteinase-2 and -9 levels. RESULTS: At the end of the culture period, neointimal thickness was significantly (P = 0.001) dose-dependently reduced in samples treated with doxycycline when compared with controls. Gelatin enzymography demonstrated a reduction in values for both latent and active forms of metalloproteases. CONCLUSIONS: Doxycycline, in a model of internal mammary artery intimal hyperplasia, has a specific role in inhibiting metalloproteases activity and may prevent graft stenosis. PMID- 24063000 TI - Role of the eNOS-NO system in regulating the antiproteinuric effects of VEGF receptor 2 inhibition in diabetes. AB - Subtle perturbations in intraglomerular VEGF/VEGFR-2 signaling or in the influencing microenvironment can profoundly affect renal function, resulting in the apparently paradoxical observation that VEGF blockade attenuates proteinuria development in experimental diabetes despite exerting the opposite effect under other circumstances. In the present study, we sought to explore the role of eNOS NO activity in regulating the differential response to VEGF blockade in the diabetic and nondiabetic settings. In a rodent model of accelerated renal injury, the transgenic (mRen-2)27 (Ren-2) rat, VEGFR-2 inhibition with the small molecule vandetanib resulted in an increase in urine protein excretion preceding a subsequent rise in systolic blood pressure. When compared to their normoglycaemic counterparts, diabetic Ren-2 rats exhibited an increase in the renal expression of eNOS and in urinary excretion of nitric oxide (NO) metabolites. In contrast to the heavy proteinuria observed with vandetanib in nondiabetic TGR(mRen-2)27 rats, VEGFR-2 inhibition reduced urine protein excretion in diabetic animals, despite a comparable magnitude of histological injury. However, proteinuria was markedly increased by concomitant treatment of diabetic Ren-2 rats with vandetanib and the nitric oxide synthase inhibitor L-NAME. These observations highlight the pivotal role that the eNOS-NO system plays in regulating the biologic response to VEGF within the glomerulus. PMID- 24063002 TI - FOXP3+ T regulatory cell modifications in inflammatory bowel disease patients treated with anti-TNFalpha agents. AB - Treg modulation has been hypothesized as one of the mechanisms by which antitumor necrosis factor alpha (TNFalpha) agents exert their action in rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). However, data in IBD are still conflicting. We evaluated CD4+CD25+FOXP3+ (Tregs) by flow cytometry in peripheral blood from 32 adult IBD patient before (T0) and after the induction of anti-TNFalpha therapy (T1). Eight healthy controls (HCs) were included. We also evaluated the number of FOXP3+ cells in the lamina propria (LP) in biopsies taken in a subset of patients and controls. Treg frequencies were significantly increased in peripheral blood from our patients after anti-TNFalpha therapy compared to T0. T1 but not T0 levels were higher than HC. The increase was detectable only in clinical responders to the treatment. A negative correlation was found among delta Treg levels and the age of patients or disease duration and with the activity score of Crohn's disease (CD). No significant differences were found in LP FOXP3+ cells. Our data suggest the possibility that in IBD patients the treatment with anti-TNFalpha may affect Treg percentages and that Treg modifications may correlate with clinical response, but differently in early versus late disease. PMID- 24063003 TI - Anticestodal activity of endophytic Pestalotiopsis sp. on protoscoleces of hydatid cyst Echinococcus granulosus. AB - Surgery is still the main treatment in hydatidosis caused by Echinococcus, which is a global health problem in human and animals. So, there is need for some natural protoscolicidal agents for instillation to prevent their reoccurrence at therapeutic doses. In this present investigation, anticestodal activity of one of the endophytic fungi Pestalotiopsis sp. from Neem plant was observed on protoscoleces of hydatid cysts of Echinococcus granulosus. Viability of protoscoleces was confirmed by 0.1% aqueous eosin red stain method, where mortality was observed at different concentrations with respect to time. An average anticestodal activity was observed with different endophytic fungal strains, that is, Nigrospora (479 +/- 2.9), Colletotrichum (469 +/- 25.8), Fusarium (355 +/- 14.5), and Chaetomium (332 +/- 28.3) showing 64 to 70% protoscolicidal activity, except Pestalotiopsis sp. (581 +/- 15.0), which showed promising scolicidal activity up to 97% mortality just within 30 min of incubation. These species showed significant reduction in viability of protoscoleces. This is the first report on the scolicidal activity of endophytic Pestalotiopsis sp. We conclude that ultrastructural changes in protoscoleces were due to endophytic extract suggesting that there may be some bioactive compounds that have selective action on the tegument layer of protoscoleces. As compared with that of standard drug used, endophytic species of Neem plant shows significant anticestodal activity. PMID- 24063004 TI - The impact of thermocycling process on the dislodgement force of different endodontic cements. AB - To evaluate the effects of thermocycling (500 cycles, 5 degrees C/55 degrees C) on the push-out bond strength of calcium silicate based cements including WMTA, Nano-WMTA, and Bioaggregate to root dentin. Forty-eight dentin slices were prepared and divided into 3 groups (n = 16) and filled with Angelus WMTA, Nano WMTA, or Bioaggregate. After incubation, half of the samples were thermocycled while the other half remained untreated. Push-out bond strength was calculated, and the modes of the bond failures were determined by SEM. The highest bond strength was seen in nonthermocycled Nano-WMTA samples and the lowest in thermocycled Bioaggregate samples. The significant differences between nonthermocycled and thermocycled samples were only noticed in WMTA and Nano-WMTA groups (P < 0.001). The mode of failure for thermocycled samples of all three cements was mostly cohesive. Thermocycling process can drastically affect the push-out bond strength of calcium silicate based cements. The intrastructural damages occurred due to the thermal stresses, causing cohesive failures in set materials. Sealing property of endodontic cements which have experienced the thermal stresses can be jeopardized due to occlusal forces happening in furcation cites. PMID- 24063005 TI - Nosology of juvenile muscular atrophy of distal upper extremity: from monomelic amyotrophy to Hirayama disease--Indian perspective. AB - Since its original description by Keizo Hirayama in 1959, "juvenile muscular atrophy of the unilateral upper extremity" has been described under many nomenclatures from the east. Hirayama disease (HD), also interchangeably referred to as monomelic amyotrophy, has been more frequently recognised in the west only in the last two decades. HD presents in adolescence and young adulthood with insidious onset unilateral or bilateral asymmetric atrophy of hand and forearm with sparing of brachioradialis giving the characteristic appearance of oblique amyotrophy. Symmetrically bilateral disease has also been recognized. Believed to be a cervical flexion myelopathy, HD differs from motor neuron diseases because of its nonprogressive course and pathologic findings of chronic microcirculatory changes in the lower cervical cord. Electromyography shows features of acute and/or chronic denervation in C7, C8, and T1 myotomes in clinically affected limb and sometimes also in clinically unaffected contralateral limb. Dynamic forward displacement of dura in flexion causes asymmetric flattening of lower cervical cord. While dynamic contrast magnetic resonance imaging is diagnostic, routine study has high predictive value. There is a need to lump all the nomenclatures under the rubric of HD as prognosis in this condition is benign and prompt diagnosis is important to institute early collar therapy. PMID- 24063006 TI - Validation thin layer chromatography for the determination of acetaminophen in tablets and comparison with a pharmacopeial method. AB - Adsorption thin layer chromatography (NP-TLC) with densitometry has been established for the identification and the quantification of acetaminophen in three leading commercial products of pharmaceutical tablets coded as brand: P1 (Product no. 1), P2 (Product no. 2), and P3 (Product no. 3). Applied chromatographic conditions have separated acetaminophen from its related substances, namely, 4-aminophenol and and 4'-chloroacetanilide. UV densitometry was performed in absorbance mode at 248 nm. The presented method was validated by specificity, range, linearity, accuracy, precision, detection limit, quantitative limit, and robustness. The TLC-densitometric method was also compared with a pharmacopeial UV-spectrophotometric method for the assay of acetaminophen, and the results confirmed statistically that the NP-TLC-densitometric method can be used as a substitute method. It could be said that the validated NP-TLC densitometric method is suitable for the routine analysis of acetaminophen in quantity control laboratories. PMID- 24063007 TI - Aminopeptidase N (CD13) is involved in phagocytic processes in human dendritic cells and macrophages. AB - Aminopeptidase N (APN or CD13) is a membrane ectopeptidase expressed by many cell types, including myelomonocytic lineage cells: monocytes, macrophages, and dendritic cells. CD13 is known to regulate the biological activity of various peptides by proteolysis, and it has been proposed that CD13 also participates in several functions such as angiogenesis, cell adhesion, metastasis, and tumor invasion. We had previously reported that, in human monocytes and macrophages, CD13 modulates the phagocytosis mediated by receptors for the Fc portion of IgG antibodies (FcgammaRs). In this work, we analyzed the possible interaction of CD13 with other phagocytic receptors. We found out that the cross-linking of CD13 positively modulates the phagocytosis mediated by receptors of the innate immune system, since a significant increase in the phagocytosis of zymosan particles or heat-killed E. coli was observed when CD13 was cross-linked using anti-CD13 antibodies, in both macrophages and dendritic cells. Also, we observed that, during the phagocytosis of zymosan, CD13 redistributes and is internalized into the phagosome. These findings suggest that, besides its known functions, CD13 participates in phagocytic processes in dendritic cells and macrophages. PMID- 24063008 TI - Cordyceps sinensis increases hypoxia tolerance by inducing heme oxygenase-1 and metallothionein via Nrf2 activation in human lung epithelial cells. AB - Cordyceps sinensis, an edible mushroom growing in Himalayan regions, is widely recognized in traditional system of medicine. In the present study, we report the efficacy of Cordyceps sinensis in facilitating tolerance to hypoxia using A549 cell line as a model system. Treatment with aqueous extract of Cordyceps sinensis appreciably attenuated hypoxia induced ROS generation, oxidation of lipids and proteins and maintained antioxidant status similar to that of controls via induction of antioxidant gene HO1 (heme oxygenase-1), MT (metallothionein) and Nrf2 (nuclear factor erythroid-derived 2-like 2). In contrast, lower level of NF kappa B (nuclear factor kappaB) and tumor necrosis factor- alpha observed which might be due to higher levels of HO1, MT and transforming growth factor- beta . Further, increase in HIF1 (hypoxia inducible factor-1) and its regulated genes; erythropoietin, vascular endothelial growth factor, and glucose transporter-1 was observed. Interestingly, Cordyceps sinensis treatment under normoxia did not regulate the expression HIF1, NF kappa B and their regulated genes evidencing that Cordyceps sinensis per se did not have an effect on these transcription factors. Overall, Cordyceps sinensis treatment inhibited hypoxia induced oxidative stress by maintaining higher cellular Nrf2, HIF1 and lowering NF kappa B levels. These findings provide a basis for possible use of Cordyceps sinensis in tolerating hypoxia. PMID- 24063009 TI - Effects of gamma irradiation on bacterial microflora associated with human amniotic membrane. AB - Human amniotic membrane is considered a promising allograft material for the treatment of ocular surface reconstruction, burns, and other skin defects. In order to avoid the transmission of any diseases, grafts should be perfectly sterile. Twenty-five amniotic sacs were collected to determine the microbiological quality of human amniotic membrane, to analyze the radiation sensitivity pattern of the microorganism, and to detect the radiation decimal reduction dose (D10) values. All the samples were found to be contaminated, and the bioburden was ranged from 3.4 * 102 to 1.2 * 105 cfu/g. Initially, a total fifty bacterial isolates were characterized according to their cultural, morphological, and biochemical characteristics and then tested for the radiation sensitivity in an incremental series of radiation doses from 1 to 10 KGy. The results depict gradual decline in bioburden with incline of radiation doses. Staphylococcus spp. were the most frequently isolated bacterial contaminant in tissue samples (44%). The D10 values of the bacterial isolates were ranged from 0.6 to 1.27 KGy. Streptococcus spp. were found to be the highest radioresistant strain with the radiation sterilization dose (RSD) of 11.4 KGy for a bioburden level of 1000. To compare the differences, D10 values were also calculated by graphical evaluations of the data with two of the representative isolates of each bacterial species which showed no significant variations. Findings of this study indicate that lower radiation dose is quite satisfactory for the sterilization of amniotic membrane grafts. Therefore, these findings would be helpful to predict the efficacy of radiation doses for the processing of amniotic membrane for various purposes. PMID- 24063010 TI - The usefulness of impedance cardiography for predicting beneficial effects of cardiac rehabilitation in patients with heart failure. AB - AIM: Cardiac rehabilitation (CR) is an important part of heart failure (HF) treatment. The aim of this paper was to evaluate if thoracic fluid content (TFC) measured by impedance cardiography (ICG) is a useful parameter for predicting the outcome of CR. METHODS: Fifty HF patients underwent clinical and noninvasive haemodynamic (TFC) assessments before and after 8-week CR. RESULTS: As a result of CR, the patients' exercise tolerance improved, especially in terms of peak VO2 (18.7 versus 20.8 mL * kg-1 * min-1; P = 0.025). TFC was found to identify patients with significantly improved peak VO2 after CR. "High TFC" patients (TFC > 27.0 kOhm-1), compared to those of "low TFC" (TFC < 27.0 kOhm-1), were found to have more pronounced increase in peak VO2 (1.3 versus 3.1 mL * kg-1 * min(-1); P = 0.011) and decrease in TFC (4.0 versus 0.7 kOhm-1; P < 0.00001). On the other hand, the patients with improved peak VO2 (n = 32) differed from those with no peak VO2 improvement in terms of higher baseline TFC values (28.4 versus 25.3 kOhm-1; P = 0.039) and its significant decrease after CR (2.7 versus 0.2 kOhm-1; P = 0.012). CONCLUSIONS: TFC can be a useful parameter for predicting beneficial effects of CR worth including in the process of patients' qualification for CR. PMID- 24063012 TI - A comparison between 18F-FDG PET/CT imaging and biological and radiological findings in restaging of hepatoblastoma patients. AB - BACKGROUND: In this study we retrospectively evaluated if 18F-FDG-PET/CT provided incremental diagnostic information over CI in a group of hepatoblastoma patients performing restaging. PROCEDURE: Nine patients (mean age: 5.9 years; range: 3.1 12 years) surgically treated for hepatoblastoma were followed up by clinical examination, serum alpha-FP monitoring, and US. CI (CT or MRI) and PET/CT were performed in case of suspicion of relapse. Fine-needle aspiration biopsies (FNAB) were carried out for final confirmation if the results of CI, PET/CT, and/or alpha-FP levels were suggestive of relapse. PET/CT and CI findings were analyzed for comparison purposes, using FNAB as reference standard. RESULTS: alpha-FP level was suggestive of disease recurrence in 8/9 patients. Biopsy was performed in 8/9 cases. CI and PET/CT resulted to be concordant in 5/9 patients (CI identified recurrence of disease, but 18F-FDG-PET/CT provided a better definition of disease extent); in 4/9 cases, CI diagnostic information resulted in negative findings, whereas PET/CT correctly detected recurrence of disease. 18F-FDG-PET/CT showed an agreement of 100% (8/8) with FNAB results. CONCLUSIONS: 18F-FDG-PET/CT scan seems to better assess HB patients with respect to CI and may provide incremental diagnostic value in the restaging of this group of patients. PMID- 24063013 TI - Recent developments in production and biotechnological applications of C phycocyanin. AB - An extensive range of pigments including phycobiliproteins are present in algae. C-phycocyanin (C-PC), a phycobiliprotein, is one of the key pigments of Spirulina, a microalgae used in many countries as a dietary supplement. Algal pigments have massive commercial value as natural colorants in nutraceutical, cosmetics, and pharmaceutical industries, besides their health benefits. At present, increasing awareness of harmful effects of synthetic compounds and inclination of community towards the usage of natural products have led to the exploitation of microalgae as a source of natural pigments/colors. This review describes recent findings about the sources and production of C-PC, with emphasis on specific techniques for extraction and purification, along with potential industrial applications in diagnostics, foods, cosmetics, and pharmaceutical industries. PMID- 24063011 TI - The impact of Aspergillus fumigatus viability and sensitization to its allergens on the murine allergic asthma phenotype. AB - Aspergillus fumigatus is a ubiquitously present respiratory pathogen. The outcome of a pulmonary disease may vary significantly with fungal viability and host immune status. Our objective in this study was (1) to assess the ability of inhaled irradiation-killed or live A. fumigatus spores to induce allergic pulmonary disease and (2) to assess the extent to which inhaled dead or live A. fumigatus spores influence pulmonary symptoms in a previously established allergic state. Our newly developed fungal delivery apparatus allowed us to recapitulate human exposure through repeated inhalation of dry fungal spores in an animal model. We found that live A. fumigatus spore inhalation led to a significantly increased humoral response, pulmonary inflammation, and airway remodeling in naive mice and is more likely to induce allergic asthma symptoms than the dead spores. In contrast, in allergic mice, inhalation of dead and live conidia recruited neutrophils and induced goblet cell metaplasia. This data suggests that asthma symptoms might be exacerbated by the inhalation of live or dead spores in individuals with established allergy to fungal antigens, although the extent of symptoms was less with dead spores. These results are likely to be important while considering fungal exposure assessment methods and for making informed therapeutic decisions for mold-associated diseases. PMID- 24063014 TI - New hypothesis on pathogenesis of ovarian cancer lead to future tailored approaches. AB - In the last decades, management of epithelial ovarian cancer (EOC) has been based on the staging system of the International Federation of Gynecology and Obstetrics (FIGO), and different classifications have been proposed for EOC that take account of grade of differentiation, histological subtype, and clinical features. However, despite taxonomic efforts, EOC appears to be not a unique disease; its subtypes differ for epidemiological and genetic risk factors, precursor lesions, patterns of spread, response to chemotherapy, and prognosis. Nevertheless, carboplatin plus paclitaxel combination represents the only standard treatment in adjuvant and advanced settings. This paper summarizes theories about the classification and origin of EOC and classical and new prognostic factors. It presents data about standard treatment and novel agents. We speculate about the possibility to create tailored therapy based on specific mutations in ovarian cancer and to personalize prevention. PMID- 24063015 TI - Prevalence of occult hepatitis B virus infection in a cohort of HIV-positive patients resident in Sicily, Italy. AB - Occult hepatitis B virus (OBI) in HIV-infected groups is still debated, as well as the associated risk-factors and clinical significance. In this paper, we examined a total of 405 HBsAg-negative/HIV-infected patients enrolled from January 2007 to December 2009. Overall, the prevalence of OBI was 5.9% (95% confidence interval (CI(95%): 3.8-8.7%); it was more frequently associated with "anti-HBc alone" serological marker (11.3%; adjusted odds ratio = 3.7, CI(95%): 1.4-9.8), although it was also detected in the absence of any HBV serological marker (4.9%; CI(95%): 2.3-9.1%). A low prevalence of anti-HCV-positive patients with OBI was found (3.1%; CI(95%): 0.6-8.7%). HIV RNA plasma levels or other immunological/clinical characteristics were not significantly associated with OBI. All but one occult HBV infections were sustained by genotype D viral strains. OBI is relatively frequent in HIV-infected patients, although it does not seem to exert a relevant clinical impact. Viral genotypes in occult HBV infections reflect those circulating in the Mediterranean area. PMID- 24063016 TI - Comparative plasma exposure of albendazole after administration of rapidly disintegrating tablets in dogs. AB - The main objectives of this study were (a) to evaluate the in vitro performance of the rapid disintegration tablets as a way to improve the solid dispersions and (b) to study the in vivo pharmacokinetics of the albendazole modified formulation in dogs. Rapid disintegration of tablets seems to be a key factor for efficiency of solid dispersions with regard to improvement of the albendazole bioavailability. The in vivo assays performed on dogs showed a marked increase in drug plasma exposure when albendazole was given in solid dispersions incorporated into rapid disintegration tablets compared with conventional solid dosage form. PMID- 24063018 TI - Tobacco use among health care workers in southwestern Saudi Arabia. AB - The present study targeted health care workers (HCWs) in Governmental Hospitals and Primary Health Care Centers in Abha City, southwestern Saudi Arabia. An anonymous self-report questionnaire was used to assess tobacco use and the reasons for smoking. The present study included 736 HCWs. The overall prevalence of tobacco use amounted to 26.3% (14.8% current and 11.5% former users). In a binary logistic regression analysis, males were found significantly more prone to smoke compared to females (aOR = 3.081, 95% CI: 2.004-4.739). Similarly, parental history of tobacco use was found to be a significant risk factor (aOR = 1.540, 95% CI: 1.040-2.278). Among current users, 89.9% were interested in quitting and 66.1% tried before to quit. The prevalence of smoking among HCWs in the present study, besides being a public health problem, represents a potential barrier in involving this group as a first line for tobacco control. There is a need for a national intervention programme in the country in a tailored manner for HCWs to control tobacco use parallel to the running national program for public. These interventions should begin early in basic medical education and to be applied continually during one's medical career. PMID- 24063017 TI - Analysis of COCH and TNFA variants in East Indian primary open-angle glaucoma patients. AB - Glaucoma represents a heterogeneous group of optic neuropathies with a complex genetic basis. It is the second-largest cause of blindness in the world that reduces vision without warning and often without symptoms. Among 3 major subtypes of glaucoma, primary open-angle glaucoma (POAG) is the most common form. The focus of this study is to understand the molecular basis of the disease among Indian patients with respect to two genes, Cochlin (COCH) and tumor necrosis factor alpha (TNFA), selected based on reports of possible association with POAG. The genes were screened in patients and controls by PCR and direct sequencing. Although two novel changes (-450 C/T and -79 G/G) were identified in the 5'upstream region of COCH, no causal variant could be identified in either gene. 450 C/T was detected in 3 patients and 2 controls and -79 G/C in a single patient. Further, we did not observe significant association with the promoter SNPs of TNFA that had been previously reported to be associated with POAG pathogenesis. Thus, our study suggests lack of association of both COCH and TNFA with POAG pathogenesis. PMID- 24063019 TI - Association between Interleukin-1 gene single nucleotide polymorphisms and ischemic stroke classified by TOAST criteria in the Han population of northern China. AB - Increasing evidence suggests that IL-1 beta (C-511T) and IL-1 alpha (C-889T) genes polymorphisms are associated with the susceptibility to cardiocerebral vascular disease. In this paper, we investigated the relationships between these polymorphisms and the risk of ischemic stroke (IS) classified by TOAST criteria in the north Chinese Han population. 440 cases of IS and 486 age- and gender matched controls of Chinese Han population were enrolled. Association study showed that the TT genotype and T allele of IL-1 alpha -889 C/T were significantly associated with IS of a large artery atherosclerosis (LAA) (TT: OR = 2.01, 95% CI = 1.34-3.0, and P < 0.001; T: OR = 1.44, 95% CI = 1.18-1.78, and P = 0.001). However, there was no significant difference in the distribution of IL 1 alpha -889 C/T genotypes and allele frequencies between the two subgroups (small-artery occlusion (SVD) and cardioembolism (CE)) of IS and control groups. No significant association was also found between the IL-1 beta -511 TT genotype and T allele (TT: OR = 0.79, 95% CI = 0.56-1.11, and P = 0.175; T: OR = 0.83, 95% CI = 0.68-1.01, and P = 0.066) and IS as well as subgroups of CE and SVD. Our results implicated that IL-1 alpha -889 C/T gene polymorphism might be associated with the susceptibility to IS, especially to IS with LAA, in a north Chinese Han population. PMID- 24063021 TI - [Pediatric oncology: significative advances in past decades]. PMID- 24063020 TI - Disease modifying therapies for Alzheimer's disease targeting Abeta oligomers: implications for therapeutic mechanisms. AB - Several lines of evidence indicate that amyloid beta (Abeta), particularly Abeta oligomers (AbetaOs), plays a causative role in Alzheimer's disease. However, the mechanisms underlying the action of an anti-AbetaO antibody to clarify the toxic action of AbetaOs remain elusive. Here, we showed that the anti-AbetaO antibody (monoclonal 72D9) can modify the Abeta aggregation pathway. We also found that 72D9 directly sequesters both extracellular and intraneuronal AbetaOs in a nontoxic state. Thus, therapeutic intervention targeting AbetaOs is a promising strategy for neuronal protection in Alzheimer's disease. PMID- 24063022 TI - [The adventure of biostatistics in oncology]. PMID- 24063023 TI - [Care networks in oncology, an evidence for all?]. PMID- 24063025 TI - [Contribution of paleopathology to the knowledge of the natural history of chronic pathologies: the example of atherosclerosis]. PMID- 24063024 TI - [(R)-2-hydroxyglutarate or (R)-2HG is an oncometabolite]. PMID- 24063026 TI - [Clinical and philosophical lecture of time in cancerology]. PMID- 24063027 TI - India promises to curb acid attacks. PMID- 24063028 TI - Funding: Global Alliance for Chronic Diseases tackles diabetes. PMID- 24063029 TI - Author's response. PMID- 24063031 TI - Retraction notice to "Reduction of emetic symptoms during Cesarean delivery with antiemetics: propofol at subhypnotic dose versus traditional antiemetics" (J Clin Anesth 2003;15:423-27). PMID- 24063030 TI - Retraction notice to "Combination of granisetron and droperidol in the prevention of nausea and vomiting after middle ear surgery" (J Clin Anesth 1999;11:108-12). PMID- 24063032 TI - Retraction notice to "Influence of aging on lidocaine requirements for pain on injection of propofol" (J Clin Anesth 2006;18:526-29). PMID- 24063033 TI - Retraction notice to "Reduction of postoperative emetic episodes and analgesic requirements with dexamethasone in patients scheduled for dental surgery" (J Clin Anesth 2005;17:182-86). PMID- 24063034 TI - Author response. PMID- 24063035 TI - Tuning of cell-biomaterial anchorage for tissue regeneration. AB - Which mechanisms mediate cell attachment to biomaterials? What role does the surface charge or wettability play on cell-material anchorage? What are the currently investigated strategies to modify cell-matrix adherence spatiotemporally? Considering the development of scaffolds made of biocompatible materials to temporarily replace the structure and/or function of the extracellular matrix, focus is given to the analysis of the specific (i.e., cell adhesive peptide sequences) and unspecific (i.e., surface charge, wettability) mechanisms mediating cell-matrix interactions. Furthermore, because natural tissue regeneration is characterized by the dynamic attachment/detachment of different cell populations, the design of advanced scaffolds for tissue engineering, based in the spatiotemporal tuning of cell-matrix anchorage is discussed. PMID- 24063036 TI - Beyond the obviousness, searching for ambiguities... PMID- 24063037 TI - Visceral leishmaniasis involving the bone marrow. PMID- 24063038 TI - Dr. Weinstein replies. PMID- 24063039 TI - Dr. Harrold, et al reply. PMID- 24063040 TI - Response to: 'Association between migraine and cardiovascular mortality: Is there a temporal trend?' by Rossi et al. PMID- 24063041 TI - Response. PMID- 24063042 TI - Response. PMID- 24063043 TI - Response. PMID- 24063044 TI - Response. PMID- 24063045 TI - Response. PMID- 24063046 TI - Response. PMID- 24063047 TI - Response. PMID- 24063048 TI - Response. PMID- 24063049 TI - The pioneers who built the European Heart House: did they get it right? PMID- 24063050 TI - Response. PMID- 24063051 TI - The polypill: difficulties for the present combination of drugs. PMID- 24063052 TI - Response. PMID- 24063053 TI - Response. PMID- 24063054 TI - Rapamycin, anti-aging, and avoiding the fate of Tithonus. AB - The discovery that rapamycin increased the lifespan of mice was recognized by Science as one of the top 10 scientific breakthroughs of 2009. In addition to increasing lifespan, Neff and colleagues show that while rapamycin improves several functions/pathologies that change with age, it has little effect on the majority of the physiological and structural parameters they evaluated. What do these data tell us about the ability of rapamycin to delay aging and improve quality of life, i.e., prevent the fate of Tithonus? PMID- 24063056 TI - [The role of circulating endothelial progenitor cells in the development of vascular retinal diseases]. AB - Based on the recent reports, circulating endothelial progenitor cells play an important role in the pathogenesis of vascular-related disorders. It is suggested that ischemia triggers endothelial progenitor cells to proceed from bone marrow into peripheral blood. Consequently, the mobilized endothelial progenitor cells may contribute to neovasculogenesis within injured retina and/or choroid tissue. Hence, in the present review the potential relationship between development of vascular retinal diseases and systemic endothelial progenitor cells migration has been discussed. Understanding of all pathophysiological mechanisms underlying progressive neovascularization may lead to development of effective prevention and treatment of these disorders. Further investigations are required to elucidate precisely the role of endothelial progenitor cells in this process and to create background for therapeutic applications. PMID- 24063055 TI - The future of molecular chaperones and beyond. AB - Protection of hair cells by HSP70 released by supporting cells is reported by May et al. in this issue of the JCI. Their findings suggest a new way to reduce ototoxicity from therapeutic medications and raise larger questions about the role and integration of heat shock proteins in non-cell-autonomous responses to stress. Increasing evidence suggests an important role for extracellular heat shock proteins in both the nervous system and the immune system. The work also suggests that defective chaperones could cause ear disease and supports the potential use of chaperone therapeutics. PMID- 24063057 TI - [Keypoints in coronary endarterectomy]. PMID- 24063058 TI - Epidemiological studies on syncope--a register based approach. AB - The epidemiology and prognosis of 'fainting' or syncope has puzzled physicians over the years. Is fainting dangerous? This is a question often asked by the patient--and the answer is 'it depends on a lot of things'. The diverse pathophysiology of syncope and the underlying comorbidites of the patients play an essential role. In epidemiology these factors have major impact on the outcome of the patients. Until recently, even the definition of syncope, differed from one study to another which has made literature reviews difficult. Traditionally the data on epidemiology of syncope has been taken from smaller studies from different clinical settings with wide differences in patient morbidity. Through the extensive Danish registries we examined the characteristics and prognosis of the patients hospitalized due to syncope in a nationwide study. The aims of the present thesis were to investigate: 1) the use, validity and accuracy of the ICD 10 diagnosis of syncope R55.9 in the National Patient Registry for the use of this diagnosis in the epidemiology of syncope, 2) diagnostics used and etiology of a random selection of patients who had a discharge diagnosis of R55.9, 3) the incidence, prevalence and cardiovascular factors associated with the risk of syncope, 4) the prognosis in healthy individuals discharged after syncope, and 5) the prognosis of patients after syncope and evaluation of the CHADS2 score as a tool for short and long-term risk prediction. The first studies of the present thesis demonstrated that the ICD-10 discharge diagnosis could reliably identify a cohort of patients admitted for syncope and that the discharge code carried a high number of unexplained cases despite use of numerous tests. The last studies showed that syncope is a common cause for hospital contact in Denmark and that the risk of syncope is tightly associated with cardiovascular comorbidities and use of pharmacotherapy. Furthermore in patients with no comorbidities (or healthy individuals), syncope is a significant and independent prognostic factor of adverse cardiovascular outcome and death compared to the background population. Lastly evaluation of the CHADS2 score, as a tool for risk stratification, showed that it provided additional prognostic information on short and long-term cardiovascular mortality in syncope patients compared to controls. PMID- 24063060 TI - Best positioning for respiratory function. PMID- 24063059 TI - On the MTD paradigm and optimal control for multi-drug cancer chemotherapy. AB - In standard chemotherapy protocols, drugs are given at maximum tolerated doses (MTD) with rest periods in between. In this paper, we briey discuss the rationale behind this therapy approach and, using as example multidrug cancer chemotherapy with a cytotoxic and cytostatic agent, show that these types of protocols are optimal in the sense of minimizing a weighted average of the number of tumor cells (taken both at the end of therapy and at intermediate times) and the total dose given if it is assumed that the tumor consists of a homogeneous population of chemotherapeutically sensitive cells. A 2-compartment linear model is used to model the pharmacokinetic equations for the drugs. PMID- 24063061 TI - Car seat challenge failure. PMID- 24063062 TI - Single-family room NICU influences infant outcomes. PMID- 24063063 TI - Oxygen saturation nomogram for asymptomatic newborns. PMID- 24063064 TI - MMPs. PMID- 24063065 TI - [Anterior and posterior combined approach to cancer infiltrating the thoracic wall of the pulmonary apex region]. PMID- 24063066 TI - The author replies. PMID- 24063067 TI - [Imaging diagnosis Q & A. Cardiac papillary fibroelastoma]. PMID- 24063068 TI - A breather for Medicare: Trust Fund's solvency extended by two years. PMID- 24063069 TI - Partway across the quality chasm: Providers improve performance, but good measurement still lacking. AB - As hospital systems experience fewer adverse events, healthcare officials acknowledge there is still plenty of work that needs to be done. Dr. Harlan Krumholz, of Yale University, co-authored a report that argues that efforts to improve quality and patient safety will falter unless more attention is paid to improving performance measures. "We're making so many changes to healthcare delivery, and we need to know how our work is impacting patients." PMID- 24063070 TI - Not 'cookbook medicine': Providers face pushback in move to standardize. PMID- 24063071 TI - Why so much variation? Studies differ on causes of Medicare cost disparities. PMID- 24063072 TI - Seeking guidance: ACA still missing key regulatory details. PMID- 24063073 TI - HAIs on the downswing: Progress made, but new strategies may be needed. PMID- 24063074 TI - Efforts paying off? Readmissions drop, but hospitals hit with penalties. PMID- 24063075 TI - 'Too early to tell': Full impact of ACOs on quality unknown. PMID- 24063076 TI - Better-educated RNs filling a need. PMID- 24063077 TI - A beacon for IT: Bluford takes a high-tech, high-touch approach. PMID- 24063078 TI - The long reach of IT: Kini extends services far beyond the community. PMID- 24063079 TI - Effect of calcium and cholecalciferol supplementation on several parameters of calcium status in plasma and urine of captive Asian (Elephas maximus) and African elephants (Loxodonta africana). AB - The aim of the current study was to assess the effect of oral calcium and cholecalciferol supplementation on several parameters of calcium status in plasma and urine of captive Asian (Elephas maximus; n=10) and African elephants (Loxodonta africana; n=6) and to detect potential species differences. Calcium and cholecalciferol supplementation were investigated in a feeding trial using a crossover design consisting of five periods of 28 days each in summer. From days 28-56 (period 2), elephants were fed the Ca-supplemented diet and from days 84 112, elephants were fed the cholecalciferol-supplemented diet (period 4). The control diet was fed during the other periods and was based on their regular ration, and the study was repeated similarly during winter. Periods 1, 3, and 5 were regarded as washout periods. This study revealed species-specific differences with reference to calcium and cholecalciferol supplementation. Asian elephants showed a significant increase in mean plasma total calcium concentration following calcium supplementation during summer, suggesting summer associated subclinical hypocalcemia in Western Europe. During winter, no effect was seen after oral calcium supplementation, but a significant increase was seen both in mean plasma, total, and ionized calcium concentrations after cholecalciferol supplementation in Asian elephants. In contrast, evidence of subclinical hypocalcemia could be demonstrated neither in summer nor in winter in African elephants, although 28 days of cholecalciferol supplementation during winter reversed the decrease in plasma 1,25(OH)2-cholecalciferol and was followed by a significant increase in mean plasma total calcium concentration. Preliminary findings indicate that the advisable permanent daily intake for calcium in Asian elephants and cholecalciferol in both elephant species at least during winter might be higher than current guidelines. It is strongly recommended to monitor blood calcium concentrations and, if available, blood parathyroid hormone levels to adjust the nutritional supplementation for each individual elephant. PMID- 24063080 TI - Evaluation of a commercial bovine colostrum replacer for achieving passive transfer of immunity in springbok calves (Antidorcas marsupialis). AB - Failure of passive transfer (FPT) occurs in ruminant species when there is inadequate absorption of immunoglobulins from the colostrum. In zoologic establishments, FPT can be a common occurrence in hand-raised ruminant neonates fed insufficient amounts of colostrum replacer (CR) and/or poor-quality CR. The goals of this study were to investigate the efficacy of a commercial bovine CR at achieving adequate passive transfer of immunity and evaluate tests to assess FPT in nondomestic ruminant species. In the past several years, research in dairy calves has shown that passive transfer rates can be dramatically improved if the CR dose is doubled. The treatment group (n = 10) consisted of springbok (Antidorcas marsupialis) calves fed Land O'Lakes bovine commercial CR at a dose of > or = 4.68 g of immunoglobulin G (22 g of CR powder) per kilogram of animal's body weight divided into five feedings over 24 hr. The control group (n=7) consisted of calves that nursed from their dams. This study reported no significant difference between the proportion of calves with adequate passive transfer in the treatment (80%) and control (71%) groups (P= 1.00). Morbidity and mortality rates until weaning were 0% in both groups. The study also determined the sensitivity and specificity values (n = 37) for five serum tests (y-glutamyl transferase [GGT], globulin, glutaraldehyde coagulation [GC], sodium sulfite turbidity test, and total protein) used to determine passive transfer status in springbok calves. This study recommends the following serum tests and cutoff ranges for determining FPT in springbok calves: globulin < or = 1.85 mg/dl, GGT < or = 228.5 IU/ L, and GC > or = 28 min. PMID- 24063081 TI - Lipid blood profile in captive Brahminy kite (Haliastur indus) as a possible indication of increased susceptibility to atherosclerosis. AB - After reviewing several cases of atherosclerosis in young Brahminy kites (Haliastur indus), a genetic predisposition to atherosclerosis in this species was hypothesized. A direct relationship between plasma cholesterol levels and atherosclerosis has already been formerly demonstrated in various bird species. Therefore, to test this hypothesis, 62 blood samples were collected from hand raised birds of prey species, including five Brahminy kites, fed with whole day old chicks, in order to compare cholesterol, phospholipids, and triglycerids concentrations in serum. All birds included in the study came from the same collection. Cholesterol serum concentration in Brahminy kites was significantly higher (P < 0.001) compared to other bird of prey species. Results showed that, under study conditions, the Brahminy kite is likely to be an atherosclerosis susceptible species. However, the diet offered in this study greatly differs from the diet of wild Brahminy kites, which includes shellfish and fish. The effect of diet in captivity, especially the polyunsaturated fatty acid/saturated fatty acid ratio, still needs to be evaluated in this species. PMID- 24063082 TI - Dermatophytosis in zoo macropods: a questionnaire study. AB - Limited published data are available on dermatophytosis in zoo macropods, despite anecdotal reports of disease occurrence and recurrent mob outbreaks. The aim of this questionnaire study was to analyze data from Australian and international zoos to evaluate estimated disease prevalence in zoos housing macropods, affected macropod species, causative organisms, predisposing factors, clinical presentations, diagnostics, treatments, and disease risk management. Two questionnaires (initial detailed and subsequent brief) were distributed via email to zoo veterinarians, with an estimated response rate of 23%. The overall estimated disease prevalence from responding zoos was 28%, with 73% of responding Australian zoos and 14% of responding non-Australian zoos reporting disease. The first cases of confirmed and suspected dermatophytosis in several macropod species and in association with Trichophyton verrucosum and Trichophyton mentagrophytes var. nodulare are reported, with young red kangaroos (Macropus rufus) appearing predisposed. Diagnosis was most commonly based on fungal culture or presumptively on typical clinical signs of minimally/nonpruritic alopecia, crusting, and scaling distributed most frequently on the tail, pinnae, and hind limbs. Both disease resolution without treatment and resolution after an average of 1 to 2 mo of treatment were reported. PMID- 24063083 TI - Parasitologic and pathologic observations of the house sparrow (Passer domesticus). AB - This study describes the parasites and related pathologic observations in the house sparrow (Passer domesticus). In total, 48 birds were examined and 41 sparrows were found to be infected with one or more endoparasites (85.4%). The most common parasites were liver trematodes identified as Brachydistomum microscelis and Brachydistomum gracupicae. In addition, coccidia and a cestode (Infula spp.) were observed. In one bird, one female Tetrameres sp. and one female Microtetrameres sp. were found in the proventriculus. No blood parasite was found after examination of the blood smears. No gross pathologic lesion was seen in the organs except for the proventriculus, gut, and liver. At histologic examination small necrotic areas and inflammatory reactions were seen in the liver and the gastrointestinal system related to the parasites. Incidentally, anthracosis was diagnosed in 23 and mild pneumonia in 12 of the lungs. PMID- 24063084 TI - Physiologic and serum biochemistry values in free-ranging Hoffmann's two-toed (Choloepus hoffmanni) and brown-throated three-toed (Bradypus variegatus) sloths immobilized using dexmedetomidine and ketamine. AB - Dexmedetomidine, a highly selective alpha-2 adrenergic agonist and dextrorotary enantiomer of medetomidine, was combined with ketamine and used to immobilize 14 free-ranging Choloepus hoffmanni (Hoffmann's two-toed sloths) and 11 Bradypus variegatus (brown-throated three-toed sloths) in Upala, Costa Rica. Following intramuscular injection of ketamine (2.1 mg/kg) and dexmedetomidine (11 microg/kg), heart rate, respiratory rate, and indirect systolic blood pressure were measured every 5 min for a total of 25 min. An iStat (CG8+) was used to evaluate serum biochemical and hematologic values during anesthesia. After 30 min of anesthesia, atipamezole (0.13 mg/kg) was administered intramuscularly, which resulted in rapid and smooth recoveries. Mean heart rate and respiratory rate remained unchanged in both C. hoffmanni and B. variegatus over time. Progressive decreases in mean indirect systolic blood pressure were documented in both species. Results of this study suggest a combination of dexmedetomidne and ketamine is a safe and effective anesthetic protocol for use in free-ranging C. hoffmanni and B. variegatus. Similar to other alpha-2 adrenergic agonist-based immobilization protocols, close monitoring of cardiovascular and respiratory parameters are recommended. This study also provides serum biochemical and hematologic data in free-ranging C. hoffmanni and B. variegatus. PMID- 24063085 TI - Selected hematologic and biochemical values in subadult and adult captive fossas (Cryptoprocta ferox). AB - Hematologic and serum biochemical values were determined for 26 (16 males and 10 females) clinically healthy captive fossas (Cryptoprocta ferox) living at Zoo Duisburg, Germany. The animals were net-restrained and anesthetized with ketamine and medetomidine for a general examination. A total of 11 animals were classified as subadult (1-3 yr of age) and 15 as adult (aged between 4 and 13 yr). The results include reference intervals and analysis of sex and age differences. Levels of inorganic phosphorus, alkaline phosphatase, glutamate dehydrogenase, creatine kinase, lactate dehydrogenase, and calcium were significantly higher in the subadult group. The white blood cell count and red blood cell count were significantly lower in the adult group than among the subadult group. PMID- 24063086 TI - Isolation and characterization of a Cervidpoxvirus from a goitered gazelle (Gazella subgutturosa) from a zoologic park in Minnesota. AB - Deerpox virus (DPV) is the sole member of the newly ratified Cervidpoxvirus genus in the subfamily Chordopoxvirinae. Presented here is the first diagnostic report of isolation of DPV from a goitered gazelle (Gazella subgutturosa). A tissue homogenate was submitted by a zoologic park to the Minnesota Veterinary Diagnostic Laboratory at the University of Minnesota for poxvirus diagnostic investigation and then referred to Plum Island Foreign Animal Disease Diagnostic Laboratory for confirmation. Poxviral infection was confirmed using electron microscopy. The virus was cultured in vero cells and subjected to further diagnoses for characterization. Polymerase chain reaction targeting the major envelope (B2L) protein and RNA polymerase of parapoxviruses, and the poly-A polymerase gene of capripoxviruses, were all negative. Degenerative pan-poxvirus primers that target the DNA polymerase (DNApol) and DNA topoisomerase (DNAtopo) genes, however, successfully amplified poxviral DNA fragments. Amplification of the DNApol and DNAtopo genes yielded fragments of 543 and 344 base pairs, respectively. DNA sequence and phylogenetic analysis of each gene fragment from the gazelle isolate showed >97% identity in BLAST searches with two DPV virus strains (W848-83 and W-1170-84) isolated from North American mule deer (Odocoileus hemionus) in 1983-1984. Neighbor-joining trees indicate that the isolate is a member of the Cervidpoxvirus genus and shows a more-distant relationship to other ruminant poxviruses, namely the Capripoxvirus genus consisting of lumpy skin disease, sheeppox, and goatpox viruses. This report documents the premiere finding of DPV, a recently characterized virus, in gazelles and demonstrates the need for broadened investigation when diagnosing poxvirus infections in ruminants. PMID- 24063087 TI - Comparison of two injectable immobilization combinations in Himalayan tahr (Hemitragus jemlahicus): medetomidine, ketamine, and atipamezole versus carfentanil, xylazine, naltrexone, and atipamezole. AB - A crossover study was performed in 12 Himalayan tahr (Hemitragus jemlahicus) undergoing preshipment examinations to compare a partially reversible to a fully reversible intramuscular chemical immobilization protocol. The partially reversible protocol (MKA) consisted of induction with medetomidine (0.06 +/- 0.009 mg/kg) and ketamine (2.03 +/- 0.315 mg/kg) and antagonism by atipamezole (0.30 +/- 0.044 mg/kg). The fully reversible protocol (CXNA) consisted of induction with carfentanil (0.009 +/- 0.003 mg/kg) and xylazine (0.08 +/- 0.019 mg/kg) and antagonism by naltrexone (0.867 +/- 0.332 mg/kg) and atipamezole (0.105 +/- 0.023 mg/ kg). Animals were monitored for quality and length of induction and recovery, depth of immobilization, heart rate, respiratory rate, rectal temperature, indirect mean blood pressure (MBP), oxygen saturation, and end-tidal carbon dioxide concentration. Blood was collected for serum cortisol measurement. Significant (P < 0.05) differences included a higher MBP, higher serum cortisol, and longer recovery time with MKA compared to CXNA. In addition, the quality of induction and recovery were different. With MKA, animals ambulated less during induction, remained recumbent longer during recovery, and demonstrated more ataxia on rising. Despite differences between the protocols, both provided an acceptable level of immobilization for pre-shipment testing to be done and appeared to be safe in the study population. These differences should be taken into consideration when selecting the anesthetic protocol because either regimen may be more or less desirable for different medical or immobilization settings. PMID- 24063088 TI - Acute phase protein expression during elephant endotheliotropic herpesvirus-1 viremia in Asian elephants (Elephas maximus). AB - Infection of Asian elephants (Elephas maximus) with elephant endotheliotropic herpesvirus (EEHV) can be associated with rapid, lethal hemorrhagic disease and has been documented in elephant herds in human care and in the wild. Recent reports describe real-time quantitative polymerase chain reaction (qPCR) assays used to monitor clinically ill elephants and also to detect subclinical EEHV1 infection in apparently healthy Asian elephants. Acute phase proteins have been demonstrated to increase with a variety of infectious etiologies in domesticated mammals but have not yet been described in elephants. In addition, the immune response of Asian elephants to EEHV1 infection has not been described. In this study, whole blood and trunk wash samples representing repeated measures from eight elephants were examined for the presence of EEHV1 using a qPCR assay. Elephants were classified into groups, as follows: whole blood negative and positive and trunk wash negative and positive. Serum amyloid A (SAA) and haptoglobin (HP) levels were compared between these groups. A significant difference in SAA was observed with nearly a threefold higher mean value during periods of viremia (P=0.011). Higher values of SAA were associated with >10,000 virus genome copies/ml EEHV1 in whole blood. There were no significant differences in HP levels, although some individual animals did exhibit increased levels with infection. These data indicate that an inflammatory process is stimulated during EEHV1 viremia. Acute phase protein quantitation may aid in monitoring the health status of Asian elephants. PMID- 24063089 TI - Blood vitamins and trace elements in Northern-East African cheetahs (Acinonyx jubatus soemmeringii) in captivity in the Middle East. AB - There are few published data regarding the endangered Northern-East African cheetah (Acinonyx jubatus soemmeringii), held in captivity in the Middle East and Europe. Studies have demonstrated a high incidence of disease in captive cheetahs, in which vitamin and trace element imbalances have often been implicated. Blood vitamin and trace element reference values in cheetahs merit further investigation. In this study, blood samples were opportunistically collected from apparently healthy A. j. soemmeringii from two collections (A and B) with successful breeding programs in the United Arab Emirates. The cheetahs were fed whole prey of mixed species (and, in Collection B, goat muscle and bone as well) dusted with vitamin and mineral supplements. Mean serum vitamin and trace element values (for cheetahs > 4 mo in age) were as follows: vitamin A (retinol), 2.20 microM/L (n = 27); vitamin B1, 0.0818 microM/L (n = 45); vitamin C, 28.6 microM/L (n=10); vitamin E (alpha-tocopherol), 35.6 microM/L (n = 27); copper (Cu), 12.53 microM/L (n = 27); selenium (Se), 3.10 microM/L (n = 27); and zinc (Zn), 10.87 microM/L (n = 27). Mean values of vitamin A, vitamin E, Cu, and Zn fell within ranges of published cheetah mean values, and mean Se was lower than range values for cheetahs presented in one previous study; blood vitamin B1 and vitamin C values of cheetahs have not previously been published. The values were taken to indicate that the cheetahs' nutritional status was adequate with regard to those nutrients analyzed. Serum vitamin E was particularly high in cheetahs fed fresh whole prey, and on this basis vitamin E supplementation of fresh whole prey appeared to have been unnecessary. There were differences (P < 0.05) between collections in serum vitamin B1, vitamin E, Cu, and 10 other hematologic and biochemical parameters. Nine hematologic and blood biochemical parameters differed among age categories. PMID- 24063090 TI - A survey for Batrachochytrium dendrobatidis in endangered and highly susceptible Vietnamese salamanders (Tylototriton spp.). AB - Until now, Asian amphibians appear to have largely escaped declines driven by chytridiomycosis. Vietnamese salamanders that belong to the genus Tylototriton are rare and have a patchy distribution in mountainous areas, falling within the proposed environmental envelope of chytrid infections, surrounded by Batrachochytrium dendrobatidis infected regions. If these salamanders are susceptible to chytridiomycosis, then their populations could be highly vulnerable after the introduction of B. dendrobatidis. Examination for the presence of the chytrid fungus in skin swabs from 19 Tylototriton asperrimus and 104 Tylototriton vietnamensis by using quantitative polymerase chain reaction was performed. Susceptibility of T. asperrimus to experimental infection by using the global panzootic lineage (BdGPL) strain of B. dendrobatidis was examined. The fungus was absent in all samples from all wild salamanders examined. Inoculation with the BdGPL strain resulted in mortality of all five inoculated salamanders within 3 weeks after inoculation with infected animals that manifested severe orthokeratotic hyperkeratosis, epidermal hyperplasia, and spongiosis. Although infection by B. dendrobatidis currently appears absent in Vietnamese Tylototriton populations, the rarity of these animals, their pronounced susceptibility to chytridiomycosis, an apparently suitable environmental context and increasing likelihood of the pathogen being introduced, together suggest the need of urgent measures to avoid future scenarios of extinction as witnessed in Central America and Australia. PMID- 24063091 TI - Development of a case definition for clinical feline herpesvirus infection in cheetahs (Acinonyx jubatus) housed in zoos. AB - The identification of feline herpesvirus (FHV) infected cheetahs (Acinonyx jubatus) and characterization of shedding episodes is difficult due to nonspecific clinical signs and limitations of diagnostic tests. The goals of this study were to develop a case definition for clinical FHV and describe the distribution of signs. Medical records from six different zoologic institutions were reviewed to identify cheetahs with diagnostic test results confirming FHV. Published literature, expert opinion, and results of a multiple correspondence analysis (MCA) were used to develop a clinical case definition based on 69 episodes in FHV laboratory confirmed (LC) cheetahs. Four groups of signs were identified in the MCA: general ocular signs, serious ocular lesions, respiratory disease, and cutaneous lesions. Ocular disease occurred with respiratory signs alone, with skin lesions alone, and with both respiratory signs and skin lesions. Groups that did not occur together were respiratory signs and skin lesions. The resulting case definition included 1) LC cheetahs; and 2) clinically compatible (CC) cheetahs that exhibited a minimum of 7 day's duration of the clinical sign groupings identified in the MCA or the presence of corneal ulcers or keratitis that occurred alone or in concert with other ocular signs and skin lesions. Exclusion criteria were applied. Application of the case definition to the study population identified an additional 78 clinical episodes, which represented 58 CC cheetahs. In total, 28.8% (93/322) of the population was identified as LC or CC. The distribution of identified clinical signs was similar across LC and CC cheetahs. Corneal ulcers and/or keratitis, and skin lesions were more frequently reported in severe episodes; in mild episodes, there were significantly more cheetahs with ocular-only or respiratory-only disease. Our results provide a better understanding of the clinical presentation of FHV, while presenting a standardized case definition that can both contribute to earlier diagnoses and be used for population-level studies. PMID- 24063092 TI - The use of spirometry to evaluate pulmonary function in olive ridley sea turtles (Lepidochelys olivacea) with positive buoyancy disorders. AB - This study utilized computed spirometry to compare the pulmonary function of two stranded olive ridley sea turtles (Lepidochelys olivacea) presenting with a positive buoyancy disorder with two healthy captive olive ridley sea turtles held in a large public aquarium. Pulmonary function test (PFT) measurements demonstrated that the metabolic cost of breathing was much greater for animals admitted with positive buoyancy than for the normal sea turtles. Positively buoyant turtles had higher tidal volumes and significantly lower breathing frequency patterns with significantly higher expiration rates, typical of gasp type breathing. The resulting higher energetic cost of breathing in the diseased turtles may have a significant impact on their long-term survival. The findings represent a method for clinical respiratory function analysis for an individual animal to assist with diagnosis, therapy, and prognosis. This is the first study, to our knowledge, to evaluate objectively sea turtles presenting with positive buoyancy and respiratory disease using pulmonary function tests. PMID- 24063093 TI - Cheyletus eruditus (taurrus): an effective candidate for the biological control of the snake mite (Ophionyssus natricis). AB - The most commonly encountered ectoparasite in captive snakes is the hematophagous snake mite (Ophionyssus natricis). Infected snakes often exhibit lethargy, dysecdysis, pruritus, crusting dermatitis (sometimes progressing to abscesses), and behavioral changes (increased bathing time, rubbing against objects). Anemia and septicemia are occasional complications. Eliminating snake mites from a collection is frustrating. Insecticidal and acaricidal compounds used in mammals can be used against O. natricis infestation in reptiles, but they all are potentially neurotoxic to reptiles. The use of a biological agent to control the snake mite was first developed by using the predatory mites Hypoaspis miles and Hypoaspis aculeifer. However, no data are available regarding the potential of these mites to control O. natricis. Furthermore, the survival and predatory behavior of H. aculeifer and H. miles decreases above 28 degrees C, which is the lower value of the optimal temperature zone range required for rearing snakes. The aim of this study is to identify the ability of the predatory mite Cheyletus eruditus to control O. natricis. In the first experiment, 125 O. natricis mites where placed in separate plastic tubes together with the same number of C. eruditus mites. After 48 hr, the survival rate of snake mites was 6% compared with 92% in the control group (n = 125, P < 0,001). In the second experiment, 11 infested (average of 13 O. natricis per snake) ball pythons, with an average of 13 O. natricis per individual, were placed in separate cages with 1,000 C. eruditus mites + vermiculite After 15 days, only an average of two mites per snake remained, compared with 48 per snake in the control group (t-test, P < 0,01). PMID- 24063094 TI - Seroprevalence of Borrelia burgdorferi sensu lato in roe deer (Capreolus capreolus) from northwestern Spain. AB - In the present study, the seroprevalence of Borrelia burgdorferi sensu lato in roe deer in relation to different parameters in northwestern Spain was investigated. A total of 154 roe deer hunted between April 2007 and October 2008 from different localities of Galicia (northwest Spain) were examined. From each animal, a blood sample and all attached ticks found were collected. All the specimens for tick stages (larva, nymph, and adult) were speciated based on reference keys. Antibodies against B. burgdorferi were detected by indirect immunofluorescence (titer > or = 1:64). The percentage of roe deer seropositive for B. burgdorferi was 68.8% (106/ 154), of which 88.7% (94/106) were parasitized by ticks. Ixodes ricinus was the only species identified and was detected in 83.1% of roe deer with a mean (standard deviation [SD]) intensity of 46 +/- 47 ticks. Individual host characteristics such as age or sex did not have any effect on the prevalence of B. burgdorferi, but significant seasonal variation was observed, with higher prevalences in April-July than in August-October. Antibodies against B. burgdorferi were related to the presence of ticks. When analyzing all the factors together, the total number of ticks parasitizing roe deer was found as the most influential factor on B. burgdorferi prevalence. The results of this study have shown that roe deer in the northwest of Spain are highly exposed to B. burgdorferi and that exposure is related to the presence of I. ricinus. PMID- 24063095 TI - Prevalence of antibiotic-resistant Gram-negative bacteria associated with the red eared slider (Trachemys scripta elegans). AB - Free-ranging Red-eared Sliders (Trachemys scripta elegans) were captured from farm ponds located in the Flint Hills of Kansas and a zoo pond in Emporia, Kansas, USA, to evaluate their enteric bacterial flora and associated antibiotic resistance. Bacteria obtained from cloacal swabs were composed of six different Gram-negative genera. Although antibiotic resistance was present in turtles captured from both locations, 40 and 49% of bacteria demonstrated multiple antibiotic resistance to four of the antibiotics tested from the zoo captured and Flint Hills ponds turtles, respectively. These data illustrate environmental antibiotic resistance is widespread in the bacterial flora obtained from Red eared Sliders in east central Kansas. PMID- 24063096 TI - Characterization and cryopreservation of semen from endangered markhor goats (Capra falconeri heptneri) with evaluation of reproductive seasonality. AB - The aims of this study were to determine the reproductive seasonality of four captive markhor goats (Capra falconeri heptneri), to characterize semen collected by electroejaculation, and to compare extenders and processing techniques for semen cryopreservation. Over the course of 1 yr, mean monthly scrotal circumference, serum testosterone, and fecal testosterone were measured and found to be inversely associated with day length. Maximum scrotal circumference (25.2 +/- 0.9 cm), serum testosterone (521.0 +/- 103.4 ng/dl), and fecal testosterone (382.5 +/- 90.3 ng/g) occurred in November, when day length was short (9.7 +/- 0.1 hr). Once a month for 3 mo (December, January, and February), bucks were anesthetized for electroejaculation and semen evaluation. Semen samples were divided into six aliquots for extension and cryopreservation in soy-based Bioxcell or Tris-based extender with 5 or 15% egg yolk, with and without centrifugation. Samples were then thawed for repeat evaluation 1-3 mo later. Postthaw evaluation revealed no significant differences between centrifuged and noncentrifuged samples. Sperm in Tris 5% and 15% egg yolk displayed higher total motility at 0, 3, and 6 hr postthaw and higher progressive motility postthaw compared with sperm in Bioxcell (P < 0.05). Sperm in Bioxcell displayed higher viability than sperm in both Tris-egg yolk extenders (P < 0.01), more intact acrosomes than sperm in Tris-15% egg yolk (P < 0.05), and a tendency for more intact acrosomes than sperm in Tris-5% egg yolk (P < 0.10). Sperm in Tris-5% egg yolk tended to have a higher percentage of morphologically normal sperm compared with Bioxcell (P < 0.10). This study provides evidence that markhor goats exhibit seasonality in scrotal circumference and testosterone levels and that centrifugation may be eliminated from the processing of markhor semen. PMID- 24063097 TI - Occurrence, prevalence and intensity of internal parasite infections of African lions (Panthera leo) in enclosures at a recreation park in Zimbabwe. AB - A coprological survey was conducted to determine the types, prevalence, and intensity of infection of internal parasites in a population of captive African lions (Panthera leo) at a recreational game park in Zimbabwe. Individual fecal samples were collected on three occasions over a 4-month period from each of 30 lions (55%) out of 55 animals held. The samples were examined using flotation and sedimentation techniques to assess the presence and count of parasite eggs, oocysts, and cysts per gram of feces as well as larvae identification. The overall prevalence of helminth infections was 100% (30/30), and 80% (24/30) of fecal samples also were positive for protozoan parasite forms. Eggs of Ancylostoma spp. were found in the feces of 23 (76.7%) lions, Physaloptera sp. in 14 (46.7%) lions, Toxascaris leonina in 13 (43.3%) lions, Toxocara cati in 12 (40%) lions, and Gnathostoma spinigerum and Toxocara canis in 2 (6.7%) lions. Furthermore, eggs of Cylicospirura subequalis, Gnathostoma spp., Lagochilascaris major, Acanthocephalan and Linguatula spp. as well as larvae of Aelurostrongylus sp. were identified in the feces of one lion. Oocysts of five apicomplexan parasites and cysts of one mastigophoran protozoan parasite were recorded, namely, Cystoisospora leonina in 11 (36.7%) lions' feces, Cystoisospora spp. in 9 (30.0%) lions, Cystoisospora felis in 5 (16.7%) lions; Toxoplasma-like spp. in 5 (16.7 %) lions, and Giardia spp. in 8 (26.7%) lions. The majority of lions (28/30) showed mixed infections with different internal parasites, whereas only two animals had single parasite infections. The intensity of infection was relatively low. Some parasite forms observed and identified, such as Eimeria spp. oocysts, were spurious and probably originated from the prey species for the lions. Among the parasites identified were some of zoonotic importance that have health implications for at-risk personnel and visitors who get into contact with the animals. PMID- 24063098 TI - Efficacy of alfaxalone for intravascular anesthesia and euthanasia in blue crabs (Callinectes sapidus). AB - The objective of this study was to characterize the behavioral effects and changes in heart rate of four doses of alfaxalone delivered by intravascular injection to blue crabs (Callinectes sapidus). Thirty (male, n = 27; female, n = 3) blue crabs were randomly assigned to one of four treatment groups of alfaxalone: eight animals were assigned to each of the 5-, 10-, and 15-mg/kg treatment groups, and the remaining six animals were assigned to the 100-mg/kg group. Times for anesthetic induction and recovery periods were recorded. Righting reflex, defensive posturing, and heart rate were evaluated before, during, and after the anesthetic trial. Anesthesia was induced in all 14 animals consolidated into the high-dosage group (15 mg/kg [n = 8] and 100 mg/kg [n = 6]), which was significantly greater than 8 of 16 animals in the low-dosage group (5 mg/kg [n = 2] and 10 mg/kg [n = 6]). Median anesthesia induction time for all crabs was 0.4 min, with no significant difference in induction time between groups observed. Median recovery time was 9.4 min (n = 2), 6.1 min (n = 5), 11.3 min (n = 8), and 66.1 min (n = 5) for the 5-, 10-, 15-, and 100-mg/kg groups, respectively. Recovery times were significantly longer for crabs exposed to an induction dose of 100 mg/kg compared with the 10- and 15-mg/kg induction doses. A significant decrease in the median heart rate was observed between the baseline value and that observed at both induction and 5 min postinjection in the 100 mg/kg dose trial. Two mortalities were observed during the anesthesia trials (n = 1, 10 mg/kg; n = 1, 100 mg/kg), both associated with the autotomization of limbs. In summary, the intravascular administration of alfaxalone at 15 mg/kg provided rapid and reliable sedation, whereas alfaxalone administered at 100 mg/kg produced rapid and long lasting anesthesia. PMID- 24063099 TI - Review of 23 cases of postintubation tracheal obstructions in birds. AB - Although recognized as a potential complication after endotracheal intubation in birds, the complication rate of postintubation tracheal obstruction in this taxon is unknown. Twenty-three cases of postintubation obstruction in birds from two institutions are reported. Clinical signs were noted an average of 16.6 days postintubation and consisted primarily of indications of acute respiratory distress. Diagnosis was confirmed via tracheoscopy or radiology. Five birds died before treatment could be initiated. Medical treatment alone was successful in three birds that had mild changes consisting primarily of a luminal mucoid plug that could be manually removed without tracheal surgery but was unsuccessful in an additional six birds. Tracheal resection and anastamosis was successful in four birds and unsuccessful in five birds. Overall mortality was 70%. Postintubation tracheal obstruction in birds appears to be more common in zoo practice than is suggested by the literature, as a total of 1.8% (1.2-2.7%, 95% confidence interval) of intubations or 3.5% (2.3-5.3%, 95% confidence interval) of individual animals intubated in these institutions resulted in this complication. Multiple cases were found in Ciconiiformes (n = 4), Columbiformes (n = 4), Gruiformes (n = 4), Anseriformes (n = 3), Galliformes (n = 3), and Passeriformes (n = 2). No cases were found in Coraciiforms, Falconiforms, or Psittaciformes despite many (>40) recorded intubations. The specific cause of these lesions is unclear, but some type of tracheal mucosa trauma or irritation is suggested by histologic findings. Prevention may include selective intubation, use of a laryngeal mask airway in place of intubation, careful placement of an endotracheal tube, minimal movement of the head and neck after placement, humidification of anesthetic gases, and gentle positive-pressure ventilation. PMID- 24063100 TI - Pharmacokinetics of ceftiofur crystalline-free acid (EXCEDE sterile suspension) administered via intramuscular injection in wild California sea lions (Zalophus californianus). AB - The pharmacokinetics of ceftiofur crystalline-free acid (EXCEDE Sterile Suspension, 200 mg ceftiofur equivalents/ml) were determined for the California sea lion (Zalophus californianus). A single dose of EXCEDE was administered intramuscularly at 6.6 mg/kg to 12 wild California sea lions during rehabilitation. The first 10 animals were each assigned to two blood collection time points, with a total of 10 time points at: 6, 12, 24, 48, 72, 96, 120, 144, 168, and 192 hr after administration of the drug. An additional two animals were sampled 1, 2, 3, 4, 5, and 6 hr postinjection. Plasma was separated within 10 min of blood collection and stored at -20 degrees C until analysis. Plasma concentrations of ceftiofur, desfuroylceftiofur, and related metabolites, were determined using liquid chromatography with tandem mass spectrometry (MS). Maximum plasma concentrations of ceftiofur and related metabolites were observed 24 hr postdosing with a mean concentration of 3.6 microg/ml. The half life (60 hr) and area under the curve (270 microg x hr/ml) were also determined. These data indicate that a single dose of EXCEDE at 6.6 mg/kg i.m. would likely maintain a mean plasma drug level >0.6 microg/ml for 5 days and >0.5 microg/ml for 8 days. PMID- 24063101 TI - Diagnosis and treatment of a dermal malignant melanoma in an African lion (Panthera leo). AB - A 13-yr-old intact male African lion (Panthera leo) presented with a 4-mo history of left maxillary lip swelling. On physical examination, a 10-cm-diameter, ulcerated, round, firm, and pigmented mass at the level of the left maxillary canine tooth was noticed. All other organ systems examined were within normal limits. Multiple biopsies of the mass were collected and fixed in 10% neutral buffered formalin. Histopathologic evaluation of the biopsies revealed a malignant dermal melanoma. Hematologic and plasma biochemical parameters were within normal reference ranges. Thoracic radiographs taken 3 days following initial presentation showed no evidence of metastasis of the tumor. Computed tomography of the skull and neck was performed to evaluate local tumor invasion and to plan for hypofractionated radiation therapy. Therapy included four weekly treatments of 8 gray external-beam hypofractionated radiation and four bimonthly immunotherapy treatments. Following this treatment regime, the tumor size was reduced by 50%, and surgical excision was performed. No major side effects associated with radiation or immunotherapy were seen. Six months after diagnosis, hematologic and plasma biochemical parameters were within normal limits, thoracic radiographs showed no evidence of metastasis, and the lion showed no clinical signs of disease. The lion will continue to receive immunotherapy every 6 mo for the rest of its life. To the authors' knowledge, this is the first report of a successful treatment of a malignant dermal melanoma with external-beam hypofractionated radiation, immunotherapy, and surgical excision in an African lion. PMID- 24063102 TI - Multifocal Cryptococcus neoformans var. neoforms: infection, treatment, and monitoring by serial computed tomography in a Schmidt's red-tailed guenon (Cercopithecus ascanius schmidti). AB - A 9-yr-old, female, intact Schmidt's red-tailed guenon (Cercopithecus ascanius schmidti) presented with an acute swelling, consistent with an abscess over the right hip. Cytology, culture, and polymerase chain reaction (PCR) results from material within the abscess and serum titers were all indicative of a Cryptococcus neoformans infection. Thoracic radiographs and computed tomography (CT) revealed a consolidated right caudal lung lobe associated with an endobronchial mass. Pulmonary Cryptococcus infection and systemic disease was confirmed with positive brush cytology and bronchoalveolar lavage (BAL). Culture and sensitivity, minimum inhibitory concentration values, and serum fluconazole level results were used to develop and monitor treatment efficacy for this animal. Sequential thoracic radiographs, CT images, bronchoscopy, BAL, and serology were used to monitor response to therapy. Five months after initial diagnosis, pregnancy was confirmed and the frequency of immobilizations for recheck serology and diagnostic imaging was decreased to lessen radiation exposure and physiologic stress to the dam and fetus. Long-term administration of oral fluconazole was well accepted and effective at treating the multifocal C. neoformans infection. No long-term adverse effects of therapy were observed, and repeated diagnostics were well tolerated. Advanced imaging modalities and serum drug levels were critical to the assessment, monitoring, and treatment of infection in this animal and should be considered for other cases. PMID- 24063103 TI - Peritoneal mesothelioma in a jaguar (Panthera onca). AB - A 21-yr-old female jaguar (Panthera onca) died in a zoo in Teresina, Piaui, Brazil, following a history of abdominal distension, ascites, anorexia, and dyspnea. At necropsy, a dark red, watery, blood-tinged serous fluid was present in the abdominal cavity. The peritoneum was thick with firm, yellow, villous projections. Histologically, the tumors were composed of a biphasic population of cells, which reacted to anti-cytokeratin and anti-vimentin antibodies, consistent with a biphasic benign mesothelioma of peritoneal origin. This is the first reported case of mesothelioma in a captive jaguar. PMID- 24063104 TI - Intrahepatic cholangiocarcinoma in a captive meerkat (Suricata suricatta). AB - A 9-yr-old male meerkat (Suricata suricatta) living in captivity, with a history of anorexia, lethargy, and weight loss, was examined postmortem. Physical examination revealed poor body condition, dehydration, and icteric mucous membranes. Macroscopically, white to yellowish, multinodulated masses were found protruding from the liver. These multinodular masses were also observed in all lobes of the lungs and the mediastinal lymph nodes. Microscopic examination revealed tumors with well-circumscribed, atypical proliferating cuboidal to columnar bile duct epithelial layers arranged in solid sheets and papillary patterns. The neoplastic masses were separated by dense fibrous connective tissues and invaded the normal parenchyma. Periodic acid-Schiff-positive material was occasionally found within the lumen of tubuloacinar structures. Immunohistochemical labeling revealed that neoplastic cells were intensely positive for pan-cytokeratin, but negative for vimentin. Based on the macroscopic and microscopic findings, intrahepatic cholangiocarcinoma was diagnosed. This is the first report describing cholangiocarcinoma in a meerkat. PMID- 24063105 TI - Gastrointestinal leiomyosarcoma in a pygmy sperm whale (Kogia breviceps). AB - An adult male pygmy sperm whale (Kogia breviceps) was stranded within a tidal pool on Fernandina Beach on the north Florida Atlantic coast (USA) and expired soon after discovery. Necropsy findings included a small intestinal mass markedly expanding the intestinal wall and partially obstructing the lumen. This finding likely led to the malnutrition and ultimately the stranding of this whale. The differential diagnoses for the mass based on gross evaluation included a duodenal adenocarcinoma, leiomyoma/sarcoma, gastrointestinal stroma tumor, and benign/malignant peripheral nerve sheath tumor, previously referred to as neurofibromas or schwannomas. The mass was presumptively diagnosed as a leiomyosarcoma via routine histopathology and confirmed by immunoreactivity for desmin and smooth actin (SMA). KIT, a gene name for CD 117, was negative, excluding a gastrointestinal stromal tumor (GIST). Leiomyosarcomas have been reported within numerous wild and domestic species, although this is the first reported case of any neoplasm in a pygmy sperm whale (K. breviceps). PMID- 24063106 TI - Complex carcinoma of the mammary gland in a free-living Japanese raccoon dog (Nyctereutes procyonoides viverrinus). AB - A complex carcinoma of the mammary gland was diagnosed in a free-living old female Japanese raccoon dog (Nyctereutes procyonoides viverrinus). Invasion into lymphatic vessels and metastasis in the inguinal lymph node were observed. This is the first report of complex carcinoma of the mammary gland in a raccoon dog. PMID- 24063107 TI - Use of xylazine hydrochloride-ketamine hydrochloride for immobilization of Indian fox (Vulpes bengalensis) in field situations. AB - Reports on doses of anesthetic agents for safe and effective immobilization of most wild species occurring in India are very limited. Further, the anesthetic agents available in India for field immobilizations are limited to xylazine hydrochloride and ketamine hydrochloride. A safe and effective dosage of xylazine ketamine for Indian fox (Vulpes bengalensis) is reported, based on 37 wild Indian fox immobilizations between April 2006 and May 2007. Foxes captured for a radiotelemetry and health monitoring study were immobilized with a mixture of xylazine (2.27 +/- 0.44 mg/kg) and ketamine (13.39 +/- 2.26 mg/kg). Induction and recovery was smooth and uneventful in all foxes. The duration of anesthesia was sufficient for the fitting of radiotransmitters, morphometric measurements, and blood sampling. No life-threatening adverse effects of immobilization were documented for at least 1 mo postimmobilization. The results suggest that field immobilization of Indian foxes with 2 mg/kg xylazine and 13 mg/kg ketamine is effective and safe. PMID- 24063108 TI - Cutaneous atypical mycobacteriosis in a clouded leopard (Neofelis nebulosa). AB - A 16-yr-old male clouded leopard (Neofelis nebulosa) was presented for lethargy and anorexia. A cutaneous abdominal mass extending from the pubis to just caudal to the xiphoid process was present. A biopsy revealed histologic lesions consistent with an atypical mycobacterial infection consisting of diffuse, severe, pyogranulomatous dermatitis and panniculitis, with clear vacuoles and 3-5 microm, intravacuolar, faintly eosinophilic, filamentous bacilli that stained positively with FiteFaraco modified acid-fast stain. The clouded leopard had biochemical findings suggestive of chronic renal failure and euthanasia was elected. Histological evaluation of tissues collected at postmortem examination revealed multicentric B-cell lymphoma involving the oral cavity, liver, spleen, and multiple lymph nodes, bilateral testicular seminomas, thyroid follicular cell adenoma, thyroid C cell adenoma, and biliary cystadenomas. Bacterial culture and molecular sequencing identified the causative agent of the cutaneous abdominal mass as belonging to the Mycobacterium fortuitum group. PMID- 24063109 TI - Meningioma in a Bengal tiger (Panthera tigris tigris). AB - A 17-yr-old female ovariectomized Bengal tiger (Panthera tigris tigris) was presented dead on arrival to the Mississippi State University College of Veterinary Medicine. The tiger was a resident of a sanctuary for big cats and had a history of juvenile-onset blindness of unknown cause. The tiger suffered two seizures the morning of presentation and expired shortly after resolution of the second seizure. Gross necropsy findings included a meningioma attached to the left frontal bone and associated with the left frontal lobe. Histologically, the mass was composed of meningothelial cells arising from the meninges, forming whorls and streams. Cells often formed syncytia and psammoma bodies were present. Neoplastic cells were immunohistochemically positive for vimentin, S100, and cytokeratin, but negative for GFAP. All findings were consistent with a meningioma. This is the first documentation of a meningioma in a Bengal tiger. PMID- 24063110 TI - Salmonella enterica prevalence in leatherback sea turtles (Dermochelys coriacea) in St. Kitts, West Indies. AB - Salmonella spp. are gram-negative bacteria capable of causing diseases in a wide range of aquatic and terrestrial animals, including humans. Sea and terrestrial turtles have been recognized as carriers of this zoonotic pathogen. In this project, conventional and molecular diagnostic methods were combined to investigate the prevalence of Salmonella enterica in leatherback sea turtles (Dermochelys coriacea) that used the island of St. Kitts, West Indies as a nesting ground during 2011 (n = 21). Isolates obtained from selective media were screened and colonies suspected of being Salmonella spp. were confirmed by fluorescence resonance energy transfer polymerase chain reaction. The prevalence of S. enterica within this sample population during this period was found to be 14.2%. Moreover, due to the increasing risk of antibiotic resistance in enteric bacteria, antimicrobial susceptibility was investigated in all recovered Salmonella spp. isolates utilizing the broth microdilution method. All isolates were susceptible to the lowest concentration of kanamycin, gentamicin, ciprofloxacin, enrofloxacin, nalidixic acid, and trimethoprim/sulfamethoxazole tested. Further research should be pursued to understand the interaction of this bacterial pathogen with the environment, host, and other microbial communities, and to further develop faster, more sensitive, and more specific diagnostic methods. PMID- 24063111 TI - Congenital glycogen storage disease in a South American coati (Nasua nasua). AB - A 14-mo-old South American coati (Nasua nasua) was submitted for necropsy to the University of Kentucky Veterinary Diagnostic Laboratory. The coati had a history of progressive neurologic signs beginning 3 mo prior to euthanasia. At necropsy, the coati was in thin body condition, but no other significant findings were evident. Histopathologic findings included moderate distension of neuronal cell bodies by finely vesiculated cytoplasm within the cerebrum, cerebellum, spinal cord, and intestinal ganglia. Hepatocytes and macrophages in the lung, spleen, and liver were similarly affected. Transmission electron microscopy showed numerous electrondense membranous cytoplasmic bodies, swirls, and vesicular profiles within neuronal lysosomes in the brain. To the authors' knowledge, this is the first report of a naturally occurring congenital glycogen storage disease in a South American coati and the family Procyonidae. PMID- 24063112 TI - Esophageal adenocarcinoma in a 53-year-old mata mata turtle (Chelus fimbriatus). AB - A 53-yr-old male captive mata mata turtle (Chelus fimbriatus) was examined following sudden death. The animal was in good nutritional, muscular and postmortem condition. The esophageal wall was circumferentially expanded by a discrete, oblong, irregular, tan, and soft contiguous glandlike structure. Histologically, the mass comprised uneven, sometimes cavitated islands of polygonal neoplastic cells consistent with an esophageal adenocarcinoma. In addition, peripheral to the mass, there was glandular epithelial hyperplasia, dysplasia, and multifocal heterophilic and lymphohistiocytic adenitis. Neoplastic cells expressed pancytokeratins; however, they demonstrated no immunoreactivity to vimentin, chromogranin, synaptophysin, and thyroglobulin. Additional findings included multifocal to coalescing areas of cortical fibrosis and membranous glomerulonephritis affecting both kidneys, and a focal hepatocellular adenoma. PMID- 24063113 TI - Polycystic kidneys in the red panda (Ailurus fulgens). AB - An intact adult male 14.3-yr-old red panda (Ailurus fulgens) presented for health examination with a history of slowly progressing loss of body condition. Abdominal radiographs revealed a truncated abdomen with poor serosal abdominal detail and multiple areas of spondylosis with some collapsed intervertebral disc spaces. On computed tomography, multiple ovoid hypoattenuating lesions were seen in the left and right kidneys. Gross pathology and histopathology revealed multiple cystic lesions in the kidneys concurrent with pancreatic cysts on histopathology. To the best of the authors' knowledge, polycystic kidneys have not been reported in this species. PMID- 24063114 TI - Meningoencephalitis with secondary obstructive hydrocephalus caused by probable coccidioides species in a buff-cheeked gibbon (Nomascus gabriellae). AB - An 8-yr-old male buff-cheeked gibbon (Nomascus gabriellae) acutely developed abnormal behavior, decreased appetite, and dull mentation. Mild generalized muscle wasting and weight loss were the only other abnormalities noted on examination. Routine immunodiffusion serology for Coccidioides spp. were IgG and IgM positive. Magnetic resonance imaging of the brain was suggestive of an infectious meningoencephalitis with secondary obstructive hydrocephalus. A ventriculoperitoneal shunt was placed in standard fashion to reduce the imminent risk of mortality from increased intracranial pressure. Postoperative treatment included oral fluconazole, a tapered course of prednisolone, and physical therapy. Clinical signs improved steadily and the gibbon was fit to return to exhibit 8 wk post-shunt placement. This case of coccidioidomycosis demonstrates the complications that can occur with dissemination to the central nervous system and its management. It is the first published report describing the use of ventriculoperitoneal shunt placement in this species. PMID- 24063115 TI - Modified-closed castration: a novel technique for sea otter (Enhydra lutris nereis) orchiectomies. AB - A novel surgical technique was used in the routine castrations of two intact male southern sea otters, Enhydra lutris nereis, housed at the Georgia Aquarium (Atlanta, Georgia, USA). This technique involved incising the parietal vaginal tunic to allow placement of double ligation of the ductus deferens, testicular artery, and pampiniform plexus en masse. After ligating and transecting these structures, they were introduced back into the tunic, which was closed with a circumferential ligature. The incision site was closed in a routine manner. Both otters recovered well from the procedure. One otter had mild cutaneous dehiscence postoperatively, and the other had no obvious complications. Benefits of this procedure include reduced risk of ligature slippage or loosening and resultant hemorrhage, as provided by the traditional open portion of the castration, and decreased postoperative swelling, as provided by the closed part of the castration. To the authors' knowledge, this is the first time this technique has been described for use in sea otters. PMID- 24063116 TI - Bilateral carpal contracture in a neonatal addax (Addax nasomaculatus). AB - A neonate male addax calf displayed an inability to extend its forelimbs bilaterally (range of motion restricted to 45 degrees-50 degrees on full extension) with resultant inability to stand. Based on examination and radiographs, the congenital defect was attributed to contracted soft tissue structures (joint capsule and/or intercarpal ligaments). Splinting, support of the limbs, and physical therapy resulted in moderate improvement of the angle of contraction (full flexion to approximately 120 degrees on extension at day 10). The animal was able to walk with splints but died at 10 days from acute head trauma, presumably related to a traumatic fall caused by challenges with ambulation. Postmortem examination confirmed soft-tissue contracture of the forelimbs. Malposition of the calf in utero was considered a possible cause of the defect. PMID- 24063117 TI - Metastatic pancreatic carcinoma and bronchioloalveolar adenomas in an Egyptian fruit bat (Rousettus aegyptiacus). AB - An adult female, intact Egyptian fruit bat (Rousettus aegyptiacus) was presented for lethargy, anorexia, and markedly reduced flying activity. Physical and ultrasound examinations were suggestive of an abdominal mass with free fluid within the abdomen. Based on the poor and deteriorating clinical condition of the animal, euthanasia was elected. Gross necropsy revealed an irregular thickening at the root of the mesentery and a diffusely, dark-red liver with rounded hepatic margins. Histologic examination revealed extensive neoplastic effacement of the pancreas with invasion into the surrounding mesentery and mesenteric lymph nodes and metastatic spread to the liver. Based on the morphology of the neoplastic cells, the involvement of the pancreas, and immunohistochemistry, a diagnosis of metastatic pancreatic carcinoma was made. Additionally, two small neoplasms were identified in the lungs. These masses were distinct from the carcinoma, and their morphology was consistent with bronchioloalveolar adenomas. This is the first known report of either benign pulmonary lesions or pancreatic carcinomas in the order Chiroptera. PMID- 24063119 TI - Seroprevalence of Toxoplasma gondii infection in captive mammals in three zoos in Mexico City, Mexico. AB - Antibodies to Toxoplasma gondii were determined in 167 mammals in three zoos in Mexico City, Mexico, using the modified agglutination test (MAT). Overall, antibodies to T. gondii were found in 89 (53.3%) of the 167 animals tested. Antibodies were found in 35 of 43 wild Felidae: 2 of 2 bobcats (Lynx rufus); 4 of 4 cougars (Puma concolor); 10 of 13 jaguars (Panthera onca); 5 of 5 leopards (Panthera pardus); 7 of 7 lions (Panthera leo); 2 of 3 tigers (Panthera tigris); 2 of 3 ocelots (Leopardus pardalis); 2 of 2 Sumatran tigers (Panthera tigris sumatrae); lof 2 Jaguarundi (Herpailurus jagouaroundi); but not in 0 of 2 oncillas (Leopardus tigrinus). Such high seroprevalence in wild felids is of public health significance because of the potential of oocyst shedding. Four of 6 New World primates (2 of 2 Geoffroy's spider monkeys [Ateles geoffroyi], 1 of 3 Patas monkeys [Erythrocebus patas], and 1 of 1 white-headed capuchin [Cebus capucinus]) had high MAT titers of 3,200, suggesting recently acquired infection; these animals are highly susceptible to clinical toxoplasmosis. However, none of these animals were ill. Seropositivity to T. gondii was found for the first time in a number of species. PMID- 24063118 TI - Pelodera strongyloides infection in Pacific harbor seals (Phoca vitulina richardii) from California. AB - Skin biopsies were collected from free-ranging harbor seals (Phoca vitulina richardii) from central California (n = 53). Microscopic examination of hematoxylin and eosin-stained tissue sections revealed the presence of tightly coiled nematode larvae within the ostia of numerous hair follicles of four seals. Parasites were characterized by paired lateral alae, platymyarian musculature, and an indistinct, uninucleate digestive tract. Mild chronic superficial dermatitis and perifolliculitis were evident microscopically in association with the intrafollicular parasites. Histomorphologic features of the larvae and their presence within hair follicles are consistent with previous reports of the facultative nematode parasite Pelodera strongyloides. This is the first published report of P. strongyloides infection in any marine mammal. This parasite may be acquired by marine mammals through close contact with soil or decaying organic material and should be considered as a potential differential diagnosis for dermatitis in marine mammals that use terrestrial resting sites. PMID- 24063120 TI - Clinical challenge. Renal adenocarcinoma in a spitting cobra. PMID- 24063121 TI - Cracking the code. Top strategies for selecting appropriate E/M levels and documenting patient care. PMID- 24063122 TI - Clarifying new place of service rules. PMID- 24063123 TI - Rewarding for value. Value-based payment models healthier for patients and economically viable for PCPs, groups report. PMID- 24063124 TI - The costs of becoming patient-centered. Cost estimates based on practice size elusive, but technology still biggest expense. PMID- 24063125 TI - GERD: rising healthcare costs spark new debate, guidelines. Revised standards designed to save system money, prevent overuse of diagnostics. PMID- 24063126 TI - The art of medicine: it's still personal. PMID- 24063127 TI - Cyber insurance now a must for medical practices. PMID- 24063128 TI - [Current trend in pediatric anesthesia: preface and comments]. AB - New trend in pediatric anesthesia is described as pediatric anesthesia can be a challenge. This special article will provide anesthesiologists, especially non pediatric anesthesiologists with an update on the most important issues and the changes that have taken place over the last few years in pediatric anesthesia. Many practices are being modified in the light of research providing new knowledge, drugs and techniques. Better knowledge in current practice in pediatric anesthesia helps us to provide high-quality anesthesia care for infants and children. This article is dedicated to the memory of Dr. Yoh Horimoto, Department of Anesthesiology, Shizuoka Children's Hospital. PMID- 24063129 TI - [Preoperative assessment of children with fever and common cold: to proceed, or not to proceed, that is the question]. AB - Fever and upper respiratory tract infections (URI) are frequently-encountered preoperative comorbidities. Whether or not to proceed with anesthesia for a child with common cold is still a continuing dilemma for anesthesiologists. We, anesthesiologists often feel uncomfortable in making a decision whether or not to proceed because URI is associated with perioperative respiratory adverse events (PRAEs) and there are no definite rules to proceed with or postpone a case. Most of PRAEs are easily managed by experienced hands; however, laryngospasm or bronchospasm without early detection and immediate treatment would probably result in serious sequelae. Although several factors (e. g., asthma, infancy, endotracheal intubation, airway surgery, parental smoking, and parental confirmation of a URI, etc.) related to PRAEs have been elucidated to date, no one can guess correctly which child will suffer from adverse events. Moreover, because children per se are vulnerable to PRAEs, we cannot reduce the risk to zero even without a URI. Therefore, we should be familiarized with how to cope with PRAEs. In making a decision to proceed with or postpone the case, it is important to take various factors together into account, and the decision ultimately depends on whether or not we feel "Yes, we can". PMID- 24063130 TI - [Preoperative fasting and fluid management in pediatric patients]. AB - Preoperative fasting is principally intended to minimize the risk of pulmonary aspiration of gastric contents and facilitate the safe and efficient conduct of anesthesia. Liberalization of fasting guidelines has been implemented in most countries. In general, clear fluids are allowed up to 2h before anesthesia, and light meals up to 6h. In infants, most recommendations now allow breast milk feeding up to 4h and other kinds of milk up to 6h. Recently, the concept of preoperative oral rehydration using a carbohydrate-rich beverage up to 2h has also gained support. Drinking carbohydrate-rich fluids before elective surgery may reduce dehydration, improve hemodynamic stability under anesthesia, facilitate intravenous access, maintain glucose homeostasis, reduce patient irritability, and improve child and parent satisfaction. These guidelines apply to healthy children only. Exclusion criteria included obesity, diabetes, gastroesophageal reflux, ileus, bowel obstruction and emergency care. In particular, trauma and other emergency cases are at higher risk for aspiration regardless of fasting interval and should be managed appropriately. PMID- 24063131 TI - [Procedural sedation: an integral part of tertiary care in pediatrics]. AB - Procedural sedation and analgesia comprise an integral part of high quality tertiary care in pediatrics. All patients undergoing procedural sedation should be evaluated as extensively as in patients receiving general anesthesia, and an appropriate fasting time should also be considered. Since cardio-respiratory side effects are inevitably associated with sedative medications, (1) only medical personnel with an expertise in the use of these medications should manage procedural sedation, and (2) additionally, the choice of medication should be decided on a case-by-case basis as no single sedation recipe has proven superior to others. Analgesics should be introduced during painful procedures in order to reduce the chance of overdose by hypnotics alone. During sedation, medical staff should continuously monitor the patients so that prompt resuscitation can be provided if unexpected critical events occur. Following the procedure, medical staff should also monitor patients until full recovery is achieved. Pediatric anesthesiologists should be involved in the sedation procedure for patients with complicated medical histories. Finally, care should be taken to avoid ferrous equipment when performing sedation in an MRI suite. PMID- 24063132 TI - [Current practice of pediatric airway management]. AB - Recent advances in pediatric airway management contribute to a significant decrease in morbidity and mortality in pediatric anesthesia. This article reviews the current concept of routine and difficult pediatric airway with special emphasis on preoperative pediatric airway assessment. Newly introduced airway devices designed for pediatric patients may facilitate ventilation and intubation although their efficacy and safety profiles in routine and difficult situations remain undetermined. Based on the pediatric protocol recently published by the Difficult Airway Society (DAS), we discuss structured algorithms for unanticipated difficult pediatric airway. Simulation technology will aid acquisition and retention of pediatric airway management skills. PMID- 24063133 TI - [Parenteral fluid therapy in the pediatric surgical patient]. AB - Perioperative fluid therapy aims to provide water, electrolytes and calorie to maintain metabolic homeostasis. The landmark article in which Holliday and Segar proposed the rate and composition of parenteral maintenance fluids for hospitalized children is used to the fluid management for the pediatric surgical patient. Critically ill patients require meticulous intraoperative fluid management to avoid acidosis, hypoglycemia, hyponatremia, and hypocalcemia as well as to maintain adequate intravascular volume. The glucose, electrolyte, and intravascular volume requirements of the pediatric surgical patient may be quite different from the original population described, and consequently, use of traditional hypotonic fluids may cause complications, such as hyperglycemia and hyponatremia in the postoperative surgical patient. Routine intraoperative dextrose administration is no longer necessary. We should ultimately change our approach according to major intraoperative fluid shifts by rational, monitored, goal-directed combination of both crystalloid and colloid therapy, similar to that occurring in adult surgical patients. PMID- 24063134 TI - [Postoperative pain managements in children]. AB - The practice of pediatric pain management has made a great progress in the last decade with the development and validation of pain assessment tools specific to pediatric patients. Adequate pediatric pain management has not been advanced as that of adult analgesia due to a lack of clinical knowledge, insufficient pediatric research and the fear of opioid side effects and addiction. Even pediatric anesthesiologists have believed the myths that neonates and infants do not feel severe pain compared to adults because of immatured development of nervous system. The recognition that untreated pain is a significant cause of morbidity and even mortality after surgical trauma advanced in pediatric pain management. Accurate assessment of pain in different age groups and the effective treatment of postoperative pain are constantly being refined. Systemic opioids in patient-controlled analgesia, nonsteroidal antiinflammatory agents and regional analgesics alone or combined with additives are currently used to provide effective postoperative analgesia. These modalities are best utilized when combined in a multimodal approach to treat acute pain in perioperative pediatric patients. PMID- 24063135 TI - [Update on the practical use of new anesthetic agents]. AB - Most drugs used in practical pediatric anesthesia are off-label. Pediatric anesthesiologists and non-pediatric anesthesiologists who rarely encounter pediatric patients need to be aware of the clinical usage of these drugs based on pediatric pharmacokinetics and pharmacodynamics to ensure that children are not exposed to unnecessary risks. Clinical guidelines on anesthetic drugs have been made available on the Japanese Society of Anesthesiologists website, and anesthesiologists are encouraged to access this site at least once. Propofol is commonly used in pediatric anesthesia and sedation in several situations. However, we should always consider the possibility of propofol infusion syndrome in the case of long-term administration. Rocuronium is widely used for general anesthesia in elective surgeries, examinations, and minor procedures in pediatric patients. Rocuronium can be used for rapid sequence induction, taking into consideration the dose and duration of action. Sugammadex has recently been introduced for practice in Japan. Rocuronium and sugammadex have been used safely in pediatric patients so far, and may change the induction methods used in difficult airway patients and the management of airway emergencies. Desflurane is novel in Japan and has not been commonly used in pediatric anesthesia. Desflurane may cause very high irritability in the airway and may be used for the maintenance of anesthesia in limited situations. PMID- 24063136 TI - [Regional anesthesia and cancer immunology]. AB - Regional anesthesia has been widely applied as an excellent method for perioperative analgesia. Recent studies suggested that regional anesthesia is a promising approach to minimize the risk of surgical site infection and postoperative cancer recurrence, subsequently providing the benefits to the long term outcome. In particular, it is of great interest that regional anesthesia might be able to reduce cancer recurrence. In cancer patients, innate immunity against cancer could be depressed, resulting in the predisposition to evoke metastasis. Besides, during the perioperative periods, tumor immunity is significantly depressed due to surgical pain, activation of sympathetic nervous system, inflammatory responses, and others. In this review article, we discuss the tumor immunity during the perioperative period, with focus on the alterations of tumor immunity and regional anesthesia. PMID- 24063137 TI - [Assessment of intraoperative hemodynamics, infusion volume, urinary output and dose of circulatory drugs in general anesthesia with transversus abdominis plane block for cholecystectomy]. AB - We retrospectively reviewed intraoperative hemodynamics, infusion volume, urinary output and dose of circulatory drugs in patients undergoing cholecystectomy in 3 types of anesthesia group: General anesthesia (GA group), general anesthesia with epidural anesthesia (EPI group) and general anesthesia with transversus abdominis plane (TAP) block (TAPB group). TAP block was performed using ultrasound-guided subcostal method and 20-30 ml of ropivacaine (0.2-0.3%) was injected to TAP bilaterally. Though, the blood pressure in TAPB group was lower than that in GA group, the degree of low blood pressure was smaller than that in EPI group. Less changes in intraoperative blood pressure, infusion volume and dose of phenylephrine in TAPB group compared to those in EPI group can be the advantage of TAP block alternative to epidural anesthesia. PMID- 24063138 TI - [The factors that require short acting beta-blockers during general anesthesia using remifentanil]. AB - BACKGROUND: Short acting beta-blockers (SBB) have been utilized effectively to prevent adverse cardiac events perioperatively. After recent introduction of remifentanil in Japan, applications of SBB could have been changed because of its intense analgesic and negative chronotrophic effects. Thus, we evaluated the factors that require SBB during general anesthesia using remifentanil. MATERIALS AND METHODS: Total of 1,631 patients who had general anesthesia with remifentanil were enrolled. Groups were divided by the use of SBB. Using logistic multivariable analysis, the factors significantly increasing the chance of using SBB were evaluated including patients' characteristics, surgical procedures, and anesthetic methods. A P value < 0.05 was considered as statistical significance. RESULTS: One hundred thirty one patients received SBB perioperatively, 94 of them received only when awake and 34 of them received during remifentanil anesthesia. Emergency operation and preoperative ECG abnormalities were significant factors requiring SBB during anesthesia using remifentanil (OR; 3.0, 4.9 respectively). CONCLUSIONS: Even with use of remifentanil there are the patients, such as those under emergency operation or with ECG abnormalities who require SBB perioperatively. PMID- 24063139 TI - [Anesthetic management of a child with fibrodysplasia ossificans progressiva (FOP)]. AB - General anesthesia was successfully performed in a 9-year-old boy with FOP. FOP is a very rare inherited disease of the connective tissue, characterized by progressive heterotopic ossification of skeletal muscles, tendons, and ligaments. Trauma and invasive medical procedures can induce heterotopic ossification. Anesthetic concerns for FOP patients include particular attention to airway management and susceptibility to respiratory complications. Regarding the airway management in general anesthesia, excessive stretching of the jaw and extension of the head may lead to the ankylosis of the temporo-mandibular joint and the neck stiffness. Ankylosis of the costvertebral joints induces restrictive ventilatory impairment, which causes atelectasis and lung infection in the perioperative period. Relating to anesthetic management for a child with FOP, anesthesiologists should keep in mind the prevention of exacerbation of the symptoms and subsequent impairment of activities of daily living postoperatively. PMID- 24063140 TI - [A case of upper airway obstruction associated with flexed cervical position after posterior occipito-cervical fusion--a retrospective radiographic analysis by the O-C2 angle]. AB - A 71-year-old female developed upper airway obstruction due to flexed cervical position after posterior occipito-cervical fusion. After the operation, she was re-intubated with the air-Q intubating laryngeal airway. Revision surgery allowing the angle to return to the neutral position was performed to attenuate the overflexion of the cervical position. After revision surgery, the upper airway obstruction disappeared. From the retrospective radiographic analysis, we suggest that the decrease of 18 degrees in the O-C2 angle causes the upper airway obstruction. On the extubation after occipito-cervical fusion, we should take care of the possibility of re-intubation and its difficulty based on the O-C2 angle. PMID- 24063141 TI - [A case of a patient with Forestier's disease--intubation by Airway Scope and bronchofiberscope]. AB - Forestier's disease accompanies difficult airway management with the ossification of the anterior longitudinal ligament of the spine. The abnormalities include limited cervical mobility, constrained epiglottic elevation, exclusion of the part of aryepiglottic, recurrent nerve paralysis and thinning of respiratory tract mucosa. We planned endotracheal intubation using both AWS and bronchofiberscope in a patient with Forestier's disease. We could easily confirm his glottis by using AWS and evaluate his respiratory tract below the glottis by bronchofiberscope. We could intubate an enforced tube (internal diameter 7.5 mm) with the bronchofiberscope guidance without any complications. This procedure seems to be safe for intubation in a Forestier's disease patient. PMID- 24063142 TI - [Helicopter transportation of a sedated, mechanically ventilated patient with cervical cord injury]. AB - We report helicopter transportation of a sedated, mechanically ventilated patient with cervical cord injury. A 20-year-old male sustained traumatic injury to the cervical spinal cord during extracurricular activities in a college. On arrival at the hospital, a halo vest was placed on the patient and tracheostomy was performed. On the 38th hospital day, he was transported a distance of 520km by helicopter to a specialized hospital in Fukuoka for medical repatriation. Cabin space was narrow. Since power supply and carrying capacity were limited, battery driven and portable medical devices were used. In consideration for patient's psychological stress, he was sedated with propofol. RSS (Ramsay sedation scale) scores were recorded to evaluate whether the patient was adequately sedated during helicopter transportation. Prior to transport, we rehearsed the sedation using bispectral index monitoring (BIS) in the hospital to further ensure the patient's safety during the transport. PMID- 24063143 TI - [Hypoxia after cesarean section in a patient with myotonic dystrophy]. AB - A 28-year-old woman, 35 week-pregnant, underwent emergency cesarean section. Although she had no apparent symptoms before the operation, myotonic dystrophy was suspected from physical examination and laboratory data. The anesthesiologist in charge recognized only high creatine kinase. Combined spinal-epidural anesthesia was performed. During the operation and on the 1st postoperative day, Spo2 remained 99% with 3 l x min(-1) oxygen administration. However, on the 2nd postoperative day Spo2 decreased. The low Spo2 persisted for 4 days. Hypoventilation and difficulty in expectoration as a result of respiratory muscle weakness might have been the cause of the prolonged hypoxemia. PMID- 24063145 TI - [GlideScope AVL single-use video laryngoscope]. AB - BACKGROUND: The aim of this case series was to evaluate the performance of GlideScope AVL single-use video laryngoscope for the visualization of the glottis and endotracheal intubations. METHODS: Visualization of the glottis with GlideScope AVL single-use video laryngoscope was performed in 200 consecutive patients who required tracheal intubation for surgery. The time to complete instrumentation and the visualization of the glottis according to the Cormack Lehane grade was recorded. RESULTS: GlideScope AVL single-use video laryngoscope provided the grade I view of the glottis in 156 patients and the gradeII view in 44 patients. Intubation with GlideScope AVL single-use video laryngoscope was successful in 199 of the 200 patients. The mean (+/- SD) time for instrumentation was 38 +/- 23 s for orotracheal intubation (n = 170) and 36 +/- 16 s for nasotracheal intubation (n = 28). CONCLUSIONS: GlideScope AVL single-use video laryngoscope could be an effective aid for airway management in surgical patients. PMID- 24063144 TI - [Use of a new video-laryngoscope (McGRATH MAC) in patients with a difficult airway]. AB - We describe the clinical use of a new video-laryngoscope (McGRATH MAC, McG) in patients with a difficult airway and morbid obesity. In a patient, case no. 2, with a difficult airway, showing a Cormack-Lehane grade III view with Macintosh direct laryngoscope, the glottis opening (Cormack-Lehane grade I) was visualized with McG. McG also provided a good view of glottis opening in a patient with morbid obesity. McG will have a profound impact on the management of the difficult airway. PMID- 24063146 TI - [Family expressiveness and young children's behavior problems: role of maternal depressive symptoms and sensitivity]. AB - This longitudinal study examined relations between family expressiveness and child behavior problems. I explored how maternal depressive symptoms and sensitivity might mediate associations between family expressiveness and child behavior problems. Mothers completed the Family Expressiveness Questionnaire at 9 months, the Beck Depression Inventory at 18 months, and the Child Behavior Checklist at 30 months. Maternal sensitivity during mother-child interactions was assessed at 18 months. A path analysis revealed that maternal depressive symptoms but not maternal sensitivity mediated the effect of family expressiveness on child behavior problems, although family expressiveness was not directly related to child behavior problems. These results suggest that the family emotional climate indirectly plays a role in the child psychological functioning. PMID- 24063147 TI - [Effects of recollection and familiarity on recognition memory in the Concealed Information Test]. AB - The effects of recollection and familiarity on recognition memory in the Concealed Information Test (CIT) were investigated. In the learning phase, participants encoded 20 words that were presented in one of four frames on a personal computer screen. Next, in the recognition test, the participants were divided into "Remember judgment (Recollection)" or "Know judgment (Familiarity)" groups, based on their Remember/Know judgment when recognizing learned items. In the CIT phase, physiological responses to questions about learned (i.e., critical) and non-learned (i.e., non-critical) items were measured and recorded. The results indicated that there was a deceleration of respiration speed (RS), an increase in skin conductance response (SCR), and a drop in heart rate in responses to critical items for both groups. Furthermore, the effect sizes of RS and SCR were greater in the "Remember judgment" group compared to the "Know judgment" group. These results suggest that critical response patterns are generated by recollection and familiarity. However, the more vividly participants recognized critical items the larger were the magnitudes of RS and SCR response patterns. PMID- 24063148 TI - [Behavioral patterns of domestic terrorist groups in Japan]. AB - This study examined the behavioral patterns of Japanese extremist groups, based on 377 terror incidents that occurred in Japan between 1990 and 2010. These incidents included bombings, rocket attacks, hostage taking, and vehicle assaults. Information was drawn primarily from on-line newspaper databases. A multiple correspondence analysis was performed using five categories: extremist group identity, time of attack, target of attack, attack strategy, and method of claiming responsibility. Extremist group characteristics varied along two dimensions: the interaction level between terrorist and victim, and the indiscriminate level of use of force. We categorized multiple far-left, far right, and religious extremist groups based on these two dimensions. Our findings may help prevent terror attacks, and help identify the group responsible for a given incident. PMID- 24063149 TI - [Development of the Japanese version of the Emotion Awareness Questionnaire for junior high school students]. AB - This study reports about the development of the Japanese version of the Emotion Awareness Questionnaire for junior high school students. Emotion Awareness Questionnaire (EAQ; Rieffe, Oosterveld, Miers, Meerum Terwogt, & Ly, 2008) for children and adolescents aims not only to monitor and differentiate emotions but also to measure attitudes about emotions. It consists of six factors: differentiating emotions, verbal sharing of emotions, not hiding emotion, bodily awareness, attending to others' emotion, analyses of emotions. To examine the reliability and validity of the Japanese version of the EAQ, junior high school students (7th to 9th grades) were requested to complete the questionnaires (n = 535 in time 1, n = 537 in time 2, n = 330 in time 3). The results showed that the Japanese version of the EAQ had almost the same six-factor structure as the original one. It also had moderate internal consistency and test-retest reliability (three weeks). The validity of the scale was examined in relation to emotional intelligence, social anxiety, depression, psychological stress responses, evaluation of emotions, self esteem and sense of authenticity. The results confirmed that the Japanese version of the EAQ had good validity. PMID- 24063150 TI - [Development of the Parenting in Adolescence Scale (PAS)]. AB - The present study developed the Parenting in Adolescence Scale (PAS) based on the three-factor model of parenting by Schaefer (1965), and examined its psychometric properties. Adolescents (n = 103 junior high, 273 high school and 667 university students) completed a questionnaire. Exploratory factor analysis identified three distinct factors labeled "Acceptance" (6 items), "Psychological control" (6 items) and "Parental monitoring" (3 items). Confirmatory factor analysis demonstrated the stability of the factor structure with adequate goodness of fit indices. The three subscales of PAS had adequate internal consistency and satisfactory test-retest reliability. The three scales also correlated significantly with measures of adolescent conduct problems, peer problems, risk taking experience, prosocial behavior, self-esteem, and another parenting scale, which indicated construct and concurrent validity. The practical use of the PAS was discussed. PMID- 24063151 TI - [Character strengths and well-being in Japanese children and youth: creating good habits]. AB - Character education in the US aims to establish good habits corresponding to good character. The purpose of this study was to determine the structure of character strengths and the relations among these strengths and wellbeing in Japanese children and youth. Peterson and Seligman (2004) developed a classification of character strengths called VIA-IS. We thought, however, that VIA-IS had too many items to use with school children. We selected 15 categories and developed a questionnaire for Japanese children and youth. Fourth to eighth grade students (N = 1,351) answered questionnaires in Study 1. We found four categories of character strengths, each of which consisted of 25 items: perseverance-honesty, courage-ideas, compassion-gratitude, and fairness-care. These categories were very similar to previous research findings which simplified the categories. In Study 2, we found a positive relationship among four categories of character strengths and well-being, which we called the hope scale, life satisfaction scale, subjective happiness scale, and social support scale. We discussed what additional research was needed for establishing good habits using our categories with children and youth in schools. PMID- 24063152 TI - [Development of the Japanese Optimism and Pessimism Scale: reliability and validity]. AB - This study reports about the construction of a bidimensional measure of optimism and pessimism (defined as positive and negative outcome expectancies), called the Japanese Optimism and Pessimism Scale (J-OPS), and examines its reliability and validity. The participants were college students. The results revealed the following: (a) the J-OPS had sufficient reliability and validity, (b) optimism and pessimism were bidimensional in structure, (c) the general pattern of correlations with external criteria of psychological well-being (positive and negative affectivity). After controlling for optimism and pessimism respectively, it indicated that these two constructs were partially independent of each other. Namely, optimism, but not pessimism, was found to be a consistent predictor of positive affectivity (psychological well-being), whereas pessimism, but not optimism, was found to be a predictor of negative affectivity (psychological distress). PMID- 24063153 TI - [Relationships between redressive self-control and discounting of reward with delay or effort]. AB - Based on the Redressive subscale of the Reformative-Redressive Self-control Scale (Sugiwaka, 1995), 10 high-scoring (highest 25%: HRD group) and 9 low-scoring (lowest 25%: LRD group) college students were selected, all with Reformative subscale scores within the intermediate 50%. They were then given (1) a hypothetical delay-discounting task, where they chose between yen100,000 available after a delay and a lesser amount of money available immediately, and also (2) a hypothetical effort-discounting task, where they chose between yen100,000 available by an effort (writing a paper) and a lesser amount of money available with no effort. Using the indifference points, discount rates (k values) based on Mazur's (1987) hyperbolic equation and the areas under the curve (AUC) were calculated. The k-value was significantly smaller in the HRD group than in the LRD group for both the effort-discounting and the delay-discounting tasks. The AUC was significantly larger in the HRD group than in the LRD group for both tasks. Possible interactional processes between Reformative Self-control and Redressive Self-control affecting discounting were discussed. PMID- 24063154 TI - [Relations between reward-distribution patterns and distribution strategies: how five-year-old children distribute rewards]. AB - The relationship between children's reward-distribution judgments and their distribution strategies was investigated. Five-year-old children (N = 61) were presented with two stories where two characters made different numbers of origami stars. The children were asked to distribute different numbers of rewards to the characters: equal to (Middle-N), less than (Small-N), or more than (Large-N) the total number of stars in each story. Distribution strategies were categorized into two types: One-round, where rewards were distributed in one round only, and Cyclic, where the rewards were distributed in several cycles across the characters. In the Small-N of both stories (4 or 8 rewards), most children distributed rewards equally. When the number of rewards was 4, more than half used the One-round strategy, but when it was 8, more than half used the Cyclic strategy. In the Middle-N and Large-N conditions, most equal distributions used the Cyclic strategy, whereas almost all the proportional-equity distributions were associated with the One-round strategy, and most ordinal-equity distributions used the Cyclic strategy. The relationships between automatic/controlled reward-distribution judgments and distribution strategies were discussed. PMID- 24063155 TI - [Integration of multiple cues in judgments of agency]. AB - The sense of self-agency is the sense that "I am the one" causing an action. Previous studies showed that multiple cues (such as congruency between prediction and actual effects, and conceptual congruency between preview and effects) contributed to explicit judgments of agency. This study independently manipulated these cues to investigate how such multiple cues of agency are integrated to form an attribution of agency. The results showed that when action became a reliably predictive cue of the occurrence of the outcome through preceding learning trials, then the congruency between prediction and actual effects received a higher weighting for a judgment of agency, and conceptual congruency received a relatively lower weighting. In contrast, without a prior learning session, the conceptual congruency, instead of the congruency between prediction and actual effects, received a relatively higher weighting for a judgment of agency. These results support the optimal cue integration hypothesis that the sense of agency reflects the relative reliability of the respective agency cues in a given situation. PMID- 24063156 TI - [Trends in treatment of retinopathy of prematurity]. PMID- 24063157 TI - [Effects of optic disc size on progression of visual field defects in normal tension glaucoma]. AB - PURPOSE: To investigate the influence of optic disc area on the progression of visual field (VF) defects in normal-tension glaucoma (NTG). We evaluated the correlation between the right-left differences of the progression of VF defects and those of the intraocular pressure and the ocular anatomical factors. METHODS: Thirty two eyes of 16 NTG patients with a significant difference between the left and right optic disc area, were followed up for more than 5 years after diurnal variation analyzed with Heidelberg Retina Tomograph (HRT), and without myopic disc shape. The left and right eyes of the patients were allocated to two groups, a group with a relatively smaller eye disc and a group with relatively larger eye disc. They were studied regarding the probability of VF stability using the Kaplan-Meier life-table analysis. In addition, a comparison of clinical factors was evaluated between the two groups (Mann-Whitney U test). RESULTS: The probability of VF stability at the 107-month follow-up was 60 +/- 13% (mean +/- SE)in patients with small disc area, and 25 +/- 11% in patients with large disc area. Optic disc area was found to have significant influence on the progression of VF defects (p = 0.022, log-rank test). In clinical factors, no statistically significant difference except disc area was found between the two groups. CONCLUSIONS: These findings suggest that optic disc area is associated with the progression of VF defects in patients with NTG. PMID- 24063158 TI - [Clinical course of retinopathy of prematurity and other neonatal complications in Kobe Children's Hospital]. AB - PURPOSE: To report changes in retinopathy of prematurity (ROP) and other neonatal complications for the last 15 years CASES AND METHOD: 638 cases with a birth weight of less than 1000 g were categorized into two groups in oxygen management changes based on reduced oxygen protocol before and after change (Group A: 218 cases from 1997 to 2001, Group B: 420 cases from 2002 to 2011). Prematurity and the clinical course of ROP were reviewed. In addition, the incidence of 5 main neonatal complications before and after oxygen control criterion change was compared. RESULTS: The differences in birth weight and gestational age among the two groups were not significant (A: 765 138 g/26.5 +/- 2.2 weeks, B: 753 +/- 158 g/26.1 +/- 2.3 weeks). The incidence of ROP and the rate of treatment for ROP in Group B were significantly less than in Group A (A: 83.0%/32.6% VS B: 54.8%/ 10.0%; p < 0.01). The rate of forming a cicatricial phase severer than grade 3 was 4.1% in Group A and 1.7% in Group B (p = 0.06). The incidence of neonatal complications before and after oxygen management change was not significantly different. CONCLUSION: Incidence and treatment of ROP were improved after changing to the reduced oxygen protocol. There was no increase in neonatal complications after the management change. PMID- 24063159 TI - [Simulation of toric intraocular lens results: the effect of repeatability and increments of automated keratometry]. AB - OBJECTIVE: To study the repeatability and scale increments of automated keratometry and their influence on the use of the toric intraocular lens (IOL) and on astigmatism correction. METHOD: The study enrolled 131 eyes of 82 patients. Preoperative corneal astigmatism was measured in the different (0.01D and 0.25D) scale increment setting of automated keratometer on separate days. An arithmetic astigmatism in 0.25 D scale increment was also calculated from that of 0.01 D scale increment. These three types of corneal astigmatism were comparatively appraised with a web-based calculator, evaluating indication and style selection of the toric IOL and simulated residual astigmatism. RESULTS: Different scale increments caused no significant difference in simulated residual astigmatism. The repeatability of calculated IOL style selection and axis location was low in eyes with mild astigmatism. True standard deviation of test retest discrepancy in the size of corneal astigmatism was 0.293 D. CONCLUSION: In mild astigmatism, the effectuation of the toric IOL, such as IOL style selection and axis location, was ineffective. However, the scale increment of 0.25 D presented moderate sensitivity. The refinement of corneal astigmatism measurement and development of algorithm would be the key to more accurate astigmatism correction with a toric IOL implantation. PMID- 24063160 TI - [Long-term observation over ten years of four cases of cone dystrophy with supernormal rod electroretinogram]. AB - BACKGROUND: 'Cone dystrophy with a supernormal rod electroretinogram (ERG)' is rare form of cone dystrophy, and no longitudinal description of the disease course has been reported in a Japanese population. Here, we describe long-term courses of 10 to 15 years in four Japanese patients with mutations in the KCNV2 gene. CASES: Four patients from three families were recruited. Two were siblings (Case 1, 24 y/o women; Case 2, 17 y/o man), and two were sporadic cases (Case 3, 17 y/o women; Case 4, 21 y/o women). All the patients presented with characteristic ERG findings. There were minimal abnormalities in fundus appearance: slight mottling of retinal pigment epithelium in the macula in all four cases, and granular change in the macula in Case 4. The visual acuity in Cases 1 and 2 did not change during the follow-up period, but the acuity in Cases 3 and 4 gradually decreased. Photoreceptor abnormalities in optical coherence tomography were found in all the cases, but were more severe in Cases 3 and 4. CONCLUSION: The long-term courses in Japanese patients were variable. The OCT was helpful in evaluating the disease progression. PMID- 24063161 TI - [Effect of serum from severe burn patients on biology characteristics of human umbilical cord mesenchymal stem cells]. AB - OBJECTIVE: To investigate the effect of the serum from severe burn patients on the biology characteristics of human umbilical cord mesenchymal stem cells (hUCMSCs) in vitro, so as to explore the feasibility of hUCMSCs transplantation for treating severe burn. METHODS: The 3rd passage of hUCMSCs were randomly divided into 3 groups: 10% fetal bovine serum group (group A), 10% normal serum group (group B), and 10% burn serum group (group C). At 24 hours, 72 hours, and 6 days after culture, the cell morphology and density were observed by inverted microscope; the cell proliferation was assessed by MTT; after 6 days of culture, the cell cycle by propidium iodide staining and flow cytometry, the apoptosis by acridine orange/ ethidium bromide staining, and the cell senescence by beta galactosidase staining; the levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), platelet-derived growth factor (PDGF), and insulin-like growth factor 1 (IGF-1) in serum were detected by a double-antibody sandwich ELISA kit. RESULTS: hUCMSCs were long spindle/polygon in 3 groups. The cell fusion of group C was obviously faster than that in group A and group B. The cell proliferation curves showed that the velocity and number of cell proliferation in group C were significantly higher than those in group A and group B at 2-6 days after culture (P < 0.05). The rates of proliferation period (S) of hUCMSCs were 9.21% +/- 1.02%, 11.79% +/- 1.87%, and 20.54% +/- 2.03%, respectively in groups A, B, and C at 6 days, and group C was significantly higher than that of group A and group B (P < 0.05). The hUCMSCs showed normal morphology and structure in 3 groups, and no apoptosis cells was observed. The positive cells percentage of group C (2.6% +/- 0.1%) was significantly lower than that of group A (4.8% +/- 0.2%) and group B (3.8% +/- 0.4%) (P < 0.05). The levels of TNF-alpha, IL-1, PDGF, and IGF-1 in group C were significantly higher than those in group B (P < 0.05). CONCLUSION: The higher levels of cytokines in serum from the severe burn patients can significantly stimulate hUCMSCs proliferation, prevent cells apoptosis, and reduce cells senescence. Therefore, it is feasible to use hUCMSCs transplantation for treating severe burn patients. PMID- 24063162 TI - [Immunomodulatory effects of human placental-derived mesenchymal stem cells on immune rejection in mouse allogeneic skin transplantation]. AB - OBJECTIVE: To investigate the effect of human placental-derived mesenchymal stem cells (PMSCs) on immunological rejection in mouse allogeneic skin transplantation. METHODS: The placenta fetal tissues from voluntary donors were used to isolate and culture the PMSCs, and the 3rd passage PMSCs were used in the experiment. Thirty Vr: CD1 (ICR) mice at age of 1-2 days were used as skin donors for allogeneic skin transplantation. Thirty C57BL/6 mice at age of 6-8 weeks as recipients were made back skin defect of 12 mm in diameter and were randomly divided into 3 groups (n=10): group A, autograft; group B, allogeneic graft + PBS tail vein injection; and group C, allogeneic graft + human PMSCs (1 x 10(5) cells/mouse) tail vein injection. The flap survival was observed. At 7 days after skin transplantation, blood leukocyte counting, abdominal fluid macrophage activation, and the expression levels of interleukin 4 (IL-4), interleukin 17 (IL 17), and interferon gamma (INF-gamma) in blood and spleen were detected by ELISA and RT-PCR, respectively. RESULTS: The flap survival time was significantly longer in group A [(58.33 +/- 4.04) days] than in groups B and C [(3.80 +/- 0.92) days and (6.80 +/- 0.82) days] (P < 0.05), and in group C than in group B (P < 0.05). At 7 days after transplantation, the blood leukocyte number was (6.32 +/- 0.45) x 10(9)/L in group A, (7.45 +/- 0.52) x 10(9)/L in group B, and (6.35 +/- 0.39) x 10(9)/L in group C, and it was significantly more in group B than in groups A and C (P < 0.05). The macrophage activation rate of the abdominal fluid was 6.87% +/- 2.40% in group A, 7.84% +/- 0.44% in group B, and 15.98% +/- 2.87% in group C; group C was significantly higher than groups A and B (P < 0.01). ELISA results showed that there was no significant difference in the concentrations of IL-4 among 3 groups (P > 0.05). Compared with group B, the concentrations of IL-17 and IFN-gamma were significantly reduced in group C (P < 0.05), while the concentration of IFN-gamma was significantly increased in group B when compared with group A (P < 0.05). RT-PCR results showed that there were significant differences in the expressions of IL-4, IL-17, and IFN-gamma mRNA between groups B, C and group A (P < 0.05); the expressions of IL-4 and IFN-gamma mRNA were significantly lower in group C than in group B (P < 0.05). CONCLUSION: Human PMSCs transplantation can suppress the acute immunological rejection in allogeneic skin transplantation. The possible mechanism may be partially related to the inhibitory effect on the secretion of IL-17 and IFN-gamma. PMID- 24063163 TI - [Histological structure and cytocompatibility of novel acellular bone matrix scaffold]. AB - OBJECTIVE: To observe the histological structure and cytocompatibility of novel acellular bone matrix (ACBM) and to investigate the feasibility as a scaffold for bone tissue engineering. METHODS: Cancellous bone columns were harvested from the density region of 18-24 months old male canine femoral head, then were dealt with high-pressure water washing, degreasing, and decellularization with Trixon X-100 and sodium deoxycholate to prepare the ACBM scaffold. The scaffolds were observed by scanning electron microscope (SEM); HE staining, Hoechst 33258 staining, and sirius red staining were used for histological analysis. Bone marrow mesenchymal stem cells (BMSCs) from canine were isolated and cultured with density gradient centrifugation; the 3rd passage BMSCs were seeded onto the scaffold. MTT test was done to assess the cytotoxicity of the scaffolds. The proliferation and differentiation of the cells on the scaffold were observed by inverted microscope, SEM, and live/dead cell staining method. RESULTS: HE staining and Hoechst 33258 staining showed that there was no cell fragments in the scaffolds; sirius red staining showed that the ACBM scaffold was stained crimson or red and yellow alternating. SEM observation revealed a three dimensional interconnected porous structure, which was the microstructure of normal cancellous bone. Cytotoxicity testing with MTT revealed no significant difference in absorbance (A) values between different extracts (25%, 50%, and 100%) and H-DMEM culture media (P > 0.05), indicating no cytotoxic effect of the scaffold on BMSCs. Inverted microscope, SEM, and histological analysis showed that three dimensional interconnected porous structure of the scaffold supported the proliferation and attachment of BMSCs, which secreted abundant extracellular matrices. Live/dead cell staining results of cell-scaffold composites revealed that the cells displaying green fluorescence were observed. CONCLUSION: Novel ACBM scaffold can be used as an alternative cell-carrier for bone tissue engineering because of thoroughly decellularization, good mircostructure, non-toxicity, and good cytocompatibility. PMID- 24063164 TI - [Chondrogenesis of passaged chondrocytes induced by different dynamic loads in bioreactor]. AB - OBJECTIVE: To investigate the effect of dynamic compression and rotation motion on chondrogenesis of the 3rd passage cell-loaded three-dimensional scaffold in a joint-specific bioreactor in vitro so as to provide theoretical basis of the autologous chondrocyte transplantation in clinical practice. METHODS: Primary chondrocytes were isolated and cultured from the knee cartilage of 3-4 months old calves. The 3rd passage cells were seeded onto fibrin-polyurethane scaffolds (8 mm x 4 mm). Experiment included 5 groups: unloaded culture for 2 weeks (group A), direct load for 2 weeks (group B), unloaded culture for 4 weeks (group C), direct load for 4 weeks (group D), and unload for 2 weeks followed by load for 2 weeks (group E). The cell-scaffold was incubated in incubator (unload) or in a joint specific bioreactor (load culture). At different time points, the samples were collected for DNA and glycosaminoglycan (GAG) quantification detect; mRNA expressions of chondrogenic marker genes such as collagen type I, collagen type II, Aggrecan, cartilage oligomeric matrix protein (COMP), and superficial zone protein (SZP) were detected by real-time quantitative PCR; and histology observations were done by toluidine blue staining and immunohistochemistry staining. RESULTS: No significant difference was found in DNA content, GAG content, and the ratio of GAG to DNA among 5 groups (P > 0.05). After load, there was a large number of GAG in the medium, and the GAG significantly increased with time (P < 0.05). The mRNA expression of collagen type I showed no significant difference among 5 groups (P > 0.05). The mRNA expression of collagen type II in group B was significantly increased when compared with group A (P < 0.01), and groups D and E were significantly higher than group C (P < 0.01); the mRNA expression of Aggrecan in groups D and E were significantly increased when compared with group C (P < 0.01), and group E was significantly higher than group D (P < 0.01); the mRNA expression of COMP in group B was significantly increased when compared with group A (P < 0.01), and group E was significantly higher than group C (P < 0.01); and the mRNA expression of SZP in group E was significantly increased when compared with groups C and D (P < 0.05). The toluidine blue staining and immunohistochemistry staining displayed that synthesis and secretion of GAG could be enhanced after load; no intensity changes of collagen type I and collagen type II were observed, but intensity enhancement of Agrrecan was seen in groups D and E. CONCLUSION: Different dynamic loads can promote chondrogenesis of the 3rd passage chondrocytes. Culture by load after unload may be the best culture for chondrogenesis, while the 3rd passage chondrocytes induced by mechanical load hold less capacity of chondrogenesis. PMID- 24063165 TI - [Experimental study on CD105+/CD166+ cells and its chondrogenic potential in early osteoarthritis cartilage]. AB - OBJECTIVE: To study the variation of CD105+/CD166+ cells and its multilineage potential in early osteoarthritis (OA) cartilage so as to lay a foundation for cartilage repair and pathologic cartilage remodeling in arthritis. METHODS: The knee OA model was established in the right knee of 30 adult New Zealand rabbits (8-12 months old). The chondrocytes were harvested from normal cartilage of the left knee (group A), OA cartilage of the right knee at 2 weeks (group B), at 4 weeks (group C), and at 8 weeks (group D) after modeling, and BMSCs were used in group E for the expression of CD105 and CD166. The percentage of CD105+/CD166+ cells in each group was counted by flow cytometry, and CD105+/CD166+ cells were isolated and purified by magnetic-activated cell sorting. The expressions of CD105 and CD166 were observed in 5 groups by laser scanning confocal microscope. Chondrogenesis, osteogenesis, and adipogenesis were evaluated with Alcian blue cytochemistry and collagen type II immunohistochemistry, by detecting the deposition of calcium, and with oil red O staining, respectively. RESULTS: The percentage of CD105+/CD166+ cells in group A, B, C, and D was significantly lower than that in group E (P < 0.05); it was significantly higher in groups B, C, and D than in group A (P < 0.05), and in group D than in groups B and C (P < 0.05), but no significant difference was found between groups B and C (P > 0.05). Laser scanning confocal microscope results confirmed the expressions of CD105+ and CD166+ cells in groups A, B, C, D, and E, no obvious difference in expression was shown among 5 groups. At 1 week after chondrogenic induction, positive expressions of proteoglycan and collagen type II were observed in 5 groups, no obvious difference was noticed among 5 groups. At 2 weeks after osteogenic induction, calcium level in group E was significantly higher than that in groups A, B, C, and D (P < 0.05), but no significant different was found among groups A, B, C, and D (P > 0.05). At 4 weeks after adipogenic induction, there were more red lipid droplets in group E than in groups A, B, C, and D. CONCLUSION: CD105+/CD166+ cells in early OA cartilage increase, which show chondrogenic differentiation potential. PMID- 24063166 TI - [Preparation of spider silk protein bilayer small diameter vascular scaffold and blood compatibility analysis in vitro]. AB - OBJECTIVE: To prepare a spider silk protein bilayer small diameter vascular scaffold using electrospinning, and to observe the blood compatibility in vitro. METHODS: The Arg-Gly-Asp-recombinant spider silk protein (pNSR16), polycaprolactone (PCL), gelatin (Gt), and heparin (Hep) were blended. Spider silk protein bilayer small diameter vascular scaffold (experimental group) was prepared by electrospinning, with pNSR16 : PCL : Hep (5 : 85 : 10, W/W) hybrid electrospun solution as inner spinning solution and pNSR16 : PCL : Gt (5 : 85 : 10, W/W) hybrid electrospun solution as outer spinning solution, but pNSR16 : PCL (5 : 85, W/W) hybrid electrospun solution was used as inner spinning solution in control group. The scaffold structure of experimental group was observed under scanning electron microscope (SEM); and the hemolysis rate, recalcification clotting time, dynamic clotting time, platelet adhesion, and platelet activation in vitro were compared between 2 groups. RESULTS: SEM results showed that bilayer fibers of scaffold were quite different in experimental group; the diameter distribution of inner layer fibers was relatively uniform with small pores, however diameter difference of the outer layer fiber was relatively big with big pores. The contact angle, hemolysis rate, recalcification clotting time, and P selectin expression of scaffold were (35 +/- 3) degrees, 1.2% +/- 0.1%, (340 +/- 11) s, and 0.412 +/- 0.027 respectively in experimental group, and were (70 +/- 4) degrees, 1.9% +/- 0.1%, (260 +/- 16) s, and 0.678 +/- 0.031 respectively in control group; significant difference were found in indexes between 2 groups (P < 0.05). With the extension of time, the curve of coagulation time in experimental group sloped downward slowly and had a long time; the blood clotting index values before 30 minutes were significantly higher than those in control group (P < 0.05). Platelet adhesion test showed that the scaffold surface almost had no platelet adhesion in experimental group. CONCLUSION: The spider silk protein bilayer small diameter vascular scaffold could be prepared through electrospinning, and it has good blood compatibility in vitro. PMID- 24063167 TI - [Experimental study on co-culture of human fibroblasts on decellularized Achilles tendon]. AB - OBJECTIVE: To investigate the preparation of decellularized Achilles tendons and the effect of co-culture of human fibroblasts on the scaffold so as to provide a scaffold for the tissue engineered ligament reconstruction. METHODS: Achilles tendons of both hind limbs were harvested from 10 male New Zealand white rabbits (5-month-old; weighing, 4-5 kg). The Achilles tendons were decellularized using trypsin, Triton X-100, and sodium dodecyl sulfate (SDS), and then gross observation, histological examination, and scanning electron microscope (SEM) observation were performed; the human fibroblasts were seeded on the decellularized Achilles tendon, and then cytocompatibility was tested using the cell counting kit 8 method at 1, 3, 5, 7, and 9 days after co-culture. At 4 weeks after co-culture, SEM, HE staining, and biomechanical test were performed for observing cell-scaffold composite, and a comparison was made with before and after decellularization. RESULTS: After decellularization, the tendons had integrated aponeurosis and enlarged volume with soft texture and good toughness; there was no loose connective tissue and tendon cells between tendon bundles, the collagen fibers arranged loosely with three-dimensional network structure and more pores between tendon bundles; and it had good cytocompatibility. At 4 weeks after co-culture, cells migrated into the pores, and three-dimensional network structure disappeared. By biomechanical test, the tensile strength and Young's elastic modulus of the decellularized Achilles tendon group decreased significantly when compared with normal Achilles tendons group and cell-scaffold composite group (P < 0.05), but no significant difference was found between normal Achilles tendons group and cell-scaffold composite group (P > 0.05). There was no significant difference in elongation at break among 3 groups (P > 0.05). CONCLUSION: The decellularized Achilles tendon is biocompatible to fibroblasts. It is suit for the scaffold for tissue engineered ligament reconstruction. PMID- 24063168 TI - [Research progress of bioreactor biophysical factors in cartilage tissue engineering]. AB - OBJECTIVE: To review the recent research progress of the bioreactor biophysical factors in cartilage tissue engineering. METHODS: The related literature concerning the biophysical factors of bioreactor in cartilage tissue engineering was reviewed, analyzed, and summarized. RESULTS: Oxygen concentration, hydrostatic pressure, compressive force, and shear load in the bioreactor system have no unified standard parameters. Hydrostatic pressure and shear load have been in controversy, which restricts the application of bioreactors. CONCLUSION: The biophysical factors of broreactor in cartilage tissue engineering have to be studied deeply. PMID- 24063169 TI - [Morphologic study on rib regeneration in patients with adolescent idiopathic scoliosis after convex short length rib resection]. AB - OBJECTIVE: To compare the rib regeneration in patients with adolescent idiopathic scoliosis (AIS) after convex short length rib resection or conventional thoracoplasty. METHODS: Between January 2005 and December 2009, 36 patients with Lenke 1 AIS underwent posterior correction, instrumentation, and fusion, and the clinical data were retrospectively analyzed. Conventional thoracoplasty was performed in group A (n=14), convex short length rib resection in group B (n=22). There was no significant difference in gender, age, Cobb angle of major curve, flexibility, and preoperative rib hump between 2 groups (P > 0.05). The standing long-cassette anteroposterior and lateral X-ray films of spine were taken at 3 months, 6 months, 1 year, and 2 years respectively after operation. Rib regeneration classification established by Philips was used to analyze the rib formation. RESULTS: All patients were followed up 32 months on average (range, 24 48 months). Cobb angle of major curve and rib hump were significantly improved when compared with preoperative values in 2 groups (P < 0.05), and there was no obvious correction loss. At each time point after operation, there was no significant difference in Cobb angle of major curve between 2 groups (P > 0.05), but the rib humb of group B was significantly bigger than that of group A (P < 0.05). The rib regeneration in group B was better than that in group A, showing significant difference (P < 0.05). At 3 months after operation, 80.0% rib regeneration was below grade 4 in group A, and 96.3% rib regeneration reached grade 4 or above in group B. At 2 years after operation, 52.0% and 96.3% rib regeneration reached grade 6 or above in groups A and B, respectively. CONCLUSION: The rib regeneration in patients with AIS after convex short length rib resection is better than that after conventional thoracoplasty. PMID- 24063170 TI - [Influence on adjacent lumbar bone density after strengthening of T12, L1 segment vertebral osteoporotic compression fracture by percutaneous vertebroplasty and percutaneous kyphoplasty]. AB - OBJECTIVE: To observe the influence on adjacent lumbar bone density after strengthening of T12, L1 segment vertebral osteoporotic compression fracture by percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) in postmenopausal female. METHODS: Between January 2008 and June 2011, 59 patients with T12, L1 segment thoracolumbar osteoporotic compression fracture were treated with PVP in 29 cases (PVP group) and PKP in 30 cases (PKP group), who were in accordance with the inclusion and exclusion criteria. No significant difference was found in gender, duration of menopause, disease druation, causes of injury, fractured vertebral body, and vertebral fracture classification between 2 groups (P > 0.05). The kyphosis Cobb angle of surgical area was measured at preoperation, 1 week after operation, and last follow-up; the lower three lumbar spine bone mineral density (BMD) of the surgical area, the femoral neck BMD, and body mass index (BMI) of patients were measured at perioperative period and last follow-up to find out the statement of anti-osteoporosis; FRAX online tools were used to evaluate the probability of major osteoporotic fracture and hip fracture of the next 10 years. RESULTS: The average follow-up was 25.5 months (range, 12 48 months) in 2 groups. There was significant difference in kyphosis Cobb angle of T12, L1 between preoperation and last follow-up in 2 groups (P < 0.05); the Cobb angle of PKP group was significantly less than that of PVP group at 1 week after operation and last follow-up (P < 0.05). No significant difference was found in BMI between 2 groups, and between perioperative period and last follow up in the same group (P > 0.05). The lower three lumbar spine BMD of the surgical area and its T value at last follow-up was improved significantly when compared with BMD at perioperative period (P < 0.05); there was no significant difference in the lower three lumbar spine BMD and its T value between 2 groups at perioperative period (P > 0.05), but significant difference was found between two groups at last follow-up (P < 0.05). Difference was not significant in the femoral neck BMD and its T value between 2 groups, and between perioperative period and last follow-up in the same group (P > 0.05). The probability of major osteoporotic fracture and hip fracture of the next 10 years was not significantly different between 2 groups and between perioperative period and last follow-up in the same group (P > 0.05). CONCLUSION: The increased BMD of adjacent lumbar spine can improve the strength of the vertebral body and reduce the incidence of adjacent vertebral fracture in patients with T12, L1 segment vertebral osteoporotic compression fracture after PVP/PKP, and PKP is superior to PVP increasing BMD of adjacent lumbar spine. PMID- 24063171 TI - [Anterolateral decompression and three column reconstruction through posterior approach for treatment of unstable thoracolumbar fracture]. AB - OBJECTIVE: To discuss the effectiveness of anterolateral decompression and three column reconstruction through posterior approach for the treatment of unstable thoracolumbar fracture. METHODS: Between March 2009 and October 2011, 39 patients with unstable burst thoracolumbar fracture were treated. Of them, there were 32 males and 7 females, with an average age of 43.8 years (range, 25-68 years). The injury causes included falling from height in 17 cases, bruise in 10 cases, traffic accident in 4 cases, and other in 8 cases. The fracture was located at the T10 level in 1 case, T11 in 9 cases, T12 in 6 cases, L1 in 14 cases, L2 in 7 cases, L3 in 1 case, and L4 in 1 case. According to Frankel classification before operation, 5 cases were classified as grade A, 5 as grade B, 9 as grade C, 14 as grade D, and 6 as grade E. Before operation, the vertebral kyphosis Cobb angle was (26.7 +/- 7.1) degrees; vertebral height loss was 37.5% +/- 9.5%; and the space occupying of vertebral canal was 73.7% +/- 11.3%. The time between injury and operation was 1-4 days (mean, 2.5 days). All patients underwent anterolateral decompression of spinal canal by posterior approach and three column reconstruction. After operation, the vertebral height restoration, correction of kyphosis, decompression of the spinal canal, and the recovery of nerve function were evaluated. RESULTS: Increase of paraplegic level, urinary infection, and pressure sore occurred in 1 case, 1 case, and 2 cases, respectively; no incision infection or neurological complications was observed in the other cases, primary healing of incision was obtained. The patients were followed up 12-36 months (mean, 27 months). The patients had no aggravation of pain of low back after operation; no loosening and breaking of screws and rods occurred; no titanium alloys electrolysis and titanium cage subsidence or breakage was observed. The imaging examination showed that complete decompression of the spinal canal, satisfactory restoration of the vertebral height, and good physiological curvature of spine at 2 years after operation. At last follow-up, 1 case was classified as Frankel grade A, 2 as grade B, 2 as grade C, 10 as grade D, and 24 as grade E, which was significantly improved when compared with preoperative one (P< 0.05). At immediate after operation and last follow-up, the Cobb angle was (6.3 +/- 2.1) degrees and (6.5 +/- 2.4) degrees respectively; the vertebral height loss was 7.9% +/- 2.7% and 8.2% +/- 3.0% respectively; and the indexes were significantly improved when compared with preoperative ones (P < 0.05). CONCLUSION: The technique of anterolateral decompression and three column reconstruction through posterior approach is one perfect approach to treat unstable thoracolumbar fracture because of complete spinal cord canal decompression, three column reconstruction, and immediate recovery of the spinal stability after operation. PMID- 24063172 TI - [Novel artificial lamina for prevention of epidural adhesions after posterior cervical laminectomy]. AB - OBJECTIVE: To evaluate the application of artificial lamina of multi-amino-acid copolymer (MAACP)/nano-hydroxyapatite (n-HA) in prevention of epidural adhesion and compression of scar tissue after posterior cervical laminectomy. METHODS: Fifteen 2-year-old male goats [weighing, (30 +/- 2) kg] were randomly divided into experimental group (n=9) and control group (n=6). In the experimental group, C4 laminectomy was performed, followed by MAACP/n-HA artificial lamina implantations; in the control group, only C4 laminectomy was performed. At 4, 12, and 24 weeks after operation, 2, 2, and 5 goats in the experimental group and 2, 2, and 2 goats in the control group were selected for observation of wound infection, artificial laminar fragmentation and displacement, and its shape; Rydell's degree of adhesion criteria was used to evaluate the adhesion degree between 2 groups. X-ray and CT images were observed; at 24 weeks after operation, CT scan was used to measure the spinal canal area and the sagittal diameter of C3, C4, and C5 vertebrea, 2 normal goats served as normal group; and MRI was used to assess adhesion and compression of scar tissue on the dura and the nerve root. Then goats were sacrificed and histological observation was carried out. RESULTS: After operation, the wound healed well; no toxicity or elimination reaction was observed. According to Rydell's degree of adhesion criteria, adhesion in the experimental group was significantly slighter than that in the control group (Z= 2.52, P=0.00). X-ray and CT scan showed that no dislocation of artificial lamina occurred, new cervical bone formed in the defect, and bony spinal canal was rebuilt in the experimental group. Defects of C4 vertebral plate and spinous process were observed in the control group. At 24 weeks, the spinal canal area and sagittal diameter of C4 in the experimental group and normal group were significantly larger than those in the control group (P < 0.05), but no significant difference was found between experimental group and normal group (P > 0.05). MRI showed cerebrospinal fluid signal was unobstructed and no soft tissue projected into the spinal canal in the experimental group; scar tissue projected into the spinal canal and the dura were compressed by scar tissue in the control group. HE staining and Masson trichrome staining showed that artificial lamina had no obvious degradation with high integrity, some new bone formed at interface between the artificial material and bone in the experimental group; fibrous tissue grew into defect in the control group. CONCLUSION: The MAACP/n-HA artificial lamina could maintaine good biomechanical properties for a long time in vivo and could effectively prevent the epidural scar from growing in the lamina defect area. PMID- 24063173 TI - [Microstructural study on detrusor muscle after bladder functional reconstruction for atonic bladder caused by medullary cone injury in rats]. AB - OBJECTIVE: To study the microstructural change of detrusor muscle and neuromuscular junction (NMJ) after bladder functional reconstruction for atonic bladder caused by medullary cone injury and to discuss the feasibility of bladder functional reconstruction for improving the detrusor muscle degeneration. METHODS: A total of 104 adult female Sprague-Dawley rats (weighing, 200-250 g) were randomized divided into 3 groups: normal group (n=8), control group (n=48), and experimental group (n=48). No treatment was given in normal group; the medullary cone injury was established by sharp transection of spinal cord at L4,5 levels in control group; and the anastomosis of bilateral L5 ventral root (VR)-S2 VR and L5 dorsal root (DR)-S2 DR was performed for bladder functional reconstruction after modeling of medullary cone injury in experimental group. After operation, the survival condition of rats was observed. At 3 days and 3 consecutive days before 1, 2, 3, 4, 5, and 6 months after operation, the residual urine volume was measured; at 1, 2, 3, 4, 5, and 6 months after operation, the detrusor muscle was harvested to measure the muscle fiber cross-sectional area by HE staining, to calculate the percentage of connective tissue by Masson trichrome staining, and to observe the ultrastructure of the detrusor muscle and the NMJ by transmission electron microscope (TEM). RESULTS: Eleven rats were supplemented because of death after operation. In control group, a significant increase of the residual urine volume was observed with the extension of time (P < 0.05); in experimental group, an increase was observed at the first 3 months after operation, and then gradually decreased, showing significant differences between the other time point (P < 0.05) except between at 3 days and at 5 months after operation (P > 0.05); there was significant difference between control and experimental groups at other each time point (P < 0.05) except at 3 days, 1 month, and 2 months (P > 0.05). HE staining and Masson trichrome staining indicated that the muscle fibers arranged in disorder with gradually aggravated atrophy and gradually increased connective tissue in control group, while the shape of the detrusor muscle recovered with no increased connective tissue at 4, 5, and 6 months after operation in experimental group; there was significant difference in cross-sectional area of detrusor muscle and percentage of connective tissue between normal group and experimental group, and between normal group and control group at each time point (P < 0.05). In control group, the cross-sectional area of detrusor muscle decreased and the percentage of connective tissue increased with the extension of time (P < 0.05). In experimental group, the cross-sectional area of detrusor muscle decreased at the first 3 months and then increased, and the percentage of connective tissue increased slowly with the extension of time. There was no significant difference of cross-sectional area of detrusor muscle at the first 3 months between control and experimental groups (P > 0.05), but the values in experimental group were significantly higher than those in control group at 4, 5, and 6 months after operation (P < 0.05). There were significant differences of the percentage of connective tissue between control and experimental groups at each time point (P < 0.05). In control group, the amount of synaptic vesicles decreased in the NMJ with time passing; vacuole like structure was observed in NMJ at 3 months; there was almost no nerve ending at 6 months. In experimental group, the amount of synaptic vesicles decreased at 1 and 3 months after operation, but obviously increased at 6 months. CONCLUSION: The reconstruction of bladder function with L5 nerve roots above the paraplegic plane can effectively inhibit the degeneration of detrusor muscle and improve its microstructural changes after medullary cone injury. PMID- 24063174 TI - [Effect of femoral offset change on pain and function after total hip arthroplasty]. AB - OBJECTIVE: To investigate the effects of altering the femoral offset after total hip arthroplasty on postoperative pain and function. METHODS: A total of 162 patients undergoing single total hip arthroplasty between March 2009 and December 2011 met the inclusion criteria. According to difference of femoral offset between operative side and contralateral side, the patients were divided into 3 groups: decreased offset group (< 5 mm, 30 cases), normal offset group (-5-5 mm, 87 cases), and increased offset group (> 5 mm, 45 cases). There was no significant difference in gender, age, and disease duration among 3 groups (P > 0.05). The types of femoral stem and head prosthesis were compared among 3 groups. Short Form 12 Health Survey (SF-12) score, Western Ontario and McMaster University Osteoarthritis Index (WOMAC) score, and Harris score were used to evaluate the clinical outcomes. RESULTS: Standard offset femoral prosthesis was most used, followed by increased offset femoral prosthesis, and decreased offset femoral prosthesis was least in 3 groups. The types of femoral stem and head prosthesis showed no significant difference among 3 groups (P > 0.05). The patients were followed up 12-33 months (mean, 25 months). There was no significant difference in SF-12 score among 3 groups at 1 year after operation (P > 0.05); there was no significant difference in WOMAC pain and stiffness scores among 3 groups (P > 0.05) except WOMAC body function score (P < 0.05). According to Harris scoring criteria, the results were excellent in 13 cases, good in 8 cases, fair in 7 cases, and poor in 2 cases in decreased offset group; the results were excellent in 42 cases, good in 34 cases, fair in 9 cases, and poor in 2 cases in normal offset group; the results were excellent in 31 cases, good in 12 cases, and fair in 2 cases in increased offset group; and significant difference was found among 3 groups (Z= -3.152, P=0.008). CONCLUSION: Increased offset is more conducive to joint functional recovery and pain relief; decreased offset may lead to joint function deterioration and pain aggravation. PMID- 24063175 TI - [Application of tibial mechanical axis locator in tibial extra-articular deformity in total knee arthroplasty]. AB - OBJECTIVE: To explore the application value of self-made tibial mechanical axis locator in tibial extra-articular deformity in total knee arthroplasty (TKA) for improving the lower extremity force line. METHODS: Between January and August 2012, 13 cases (21 knees) of osteoarthritis with tibial extra-articular deformity were treated, including 5 males (8 knees) and 8 females (13 knees) with an average age of 66.5 years (range, 58-78 years). The disease duration was 2-5 years (mean, 3.5 years). The knee society score (KSS) was 45.5 +/- 15.5. Extra articular deformities included 1 case of knee valgus (2 knees) and 12 cases of knee varus (19 knees). Preoperative full-length X-ray films of lower extremities showed 10-21 degrees valgus or varus deformity of tibial extra joint. Self-made tibial mechanical axis locator was used to determine and mark coronal tibial mechanical axis under X-ray before TKA, and then osteotomy was performed with extramedullary positioning device according to the mechanical axis marker.' RESULTS: All incisions healed by first intention, without related complications of infection and joint instability. All patients were followed up 5-12 months (mean, 8.3 months). The X-ray examination showed < 2 degrees knee deviation angle in the others except 1 case of 2.9 degrees knee deviation angle at 3 days after operation, and the accurate rate was 95.2%. No loosening or instability of prosthesis occurred during follow-up. KSS score was 85.5 +/- 15.0 at last follow up, showing significant difference when compared with preoperative score (t=12.82, P=0.00). CONCLUSION: The seft-made tibial mechanical axis locator can improve the accurate rate of the lower extremity force line in TKA for tibia extra-articular deformity. PMID- 24063176 TI - [Effect of posterior cruciate ligament retaining or not on knee-joint proprioception]. AB - OBJECTIVE: To analyze the effect of the posterior cruciate ligament (PCL) retaining or not on knee-joint proprioception by comparing the proprioceptive difference between PCL retaining and no PCL retaining in total knee arthroplasty (TKA). METHODS: Between June 2009 and June 2010, 38 osteoarthritis patients meeting the inclusion criteria were divided into PCL retaining group (group A, n=19) and PCL-substituting group (group B, n=19) according to the random number table. There was no significant difference in gender, age, disease duration, the range of motion of the knee between 2 groups (P > 0.05). The effectiveness and the knee-joint proprioception were separately assessed by the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) score and the passive angle reproduction test (30, 60, and 90 degrees of knee flexion) preoperatively and 12 months postoperatively. RESULTS: All incisons healed by first intention, without complications of infection, fracture, and deep vein thrombosis of lower limb. The patients were followed up 12-17 months (mean, 14.1 months). The knee function after operation was obviously improved when compared with preoperative one; significant differences were observed in the WOMAC scores and the results of passive angle reproduction test between at preoperation and at 12 months after operation (P < 0.05), but no significant difference was found between group A and group B (P > 0.05). CONCLUSION: Whether PCL retaining or not in TKA both can improve knee-joint proprioception, and no obvious difference between them. PMID- 24063177 TI - [Biomechanical study on a novel injectable calcium phosphate cement containing poly (latic-co-glycolic acid) in repairing tibial plateau fractures]. AB - OBJECTIVE: To investigate the biomechanics of a novel injectable calcium phosphate cement (CPC) composited by poly (lactic-co-glycolic acid) (PLGA) combined with double-screw fixation in repairing Schatzker II type tibial plateau fracture, so as to provide the mechanical basis for the clinical minimally invasive treatment. METHODS: Ten matched pairs of proximal tibia specimens were harvested from 10 elderly cadavers to prepare Schatzker II type tibial plateau fracture model. Fracture was fixed by forcing injection of CPC (experimental group) or autologous cancellous bone (control group) combined with double-screw fixation. The samples underwent axial compression on MTS 858 material testing machine to measure the load-displacement, the maximum load, and compressive stiffness. RESULTS: The novel CPC had good injectable property at room temperature, which could fill in bone defect fully and permeated into the surrounding cancellous bone. The average bone mineral density of tibial metaphysis was (0.639 +/- 0.081) g/cm2 in the experimental group and (0.668 +/- 0.083) g/cm2 in the control group, showing no significant difference (t=1.012, P=0.331). The maximum load in the experimental group [(4 101 +/- 813) N] was significantly higher than that in the control group [(692 +/- 138) N] (t=3.932, P=0.001). The compressive stiffness was (1 363 +/- 362) N/mm in the experimental group and was (223 +/- 54) N/mm in the control group, showing significant difference (t=3.023, P=0.013). CONCLUSION: The novel CPC can effectively restore the biomechanical properties of tibilal plateau in repairing Schatzker II type tibial plateau fracture by means of forcing injection combining with double-screw fixation. It could be used as an effective bone substitute in the clinical application. PMID- 24063178 TI - [Treatment of adult avascular necrosis of femoral head by transplanting iliac bone flap with deep iliac circumflex vessels and cancellous bone]. AB - OBJECTIVE: To investigate the effectiveness of transplanting iliac bone flap with deep iliac circumflex vessels and cancellous bone for the treatment of adult avascular necrosis of the femoral head (ANFH). METHODS: A retrospective analysis was made on the clinical data of 685 patients (803 hips) with ANFH, who underwent iliac bone flap transplantation with deep iliac circumflex vessels and cancellous bone between March 2002 and January 2010. There were 489 males (580 hips) and 196 females (223 hips) with a mean age of 40.4 years (range, 18-63 years), including 567 unilateral cases (303 left hips and 264 right hips) and 118 bilateral cases. The causes of ANFH included alcohol-induced in 223 cases, steroid-induced in 179 cases, alcohol + steroid-induced in 21 cases, traumatic in 136 cases, acetabular dysplasia in 8 cases, bone cyst in 5 cases, septic arthritis in 2 cases, joint tuberculosis in 3 cases, rheumatoid arthritis in 5 cases, and idiopathic in 103 cases. According to Steinberg staging, 211 hips were rated as stage II, 513 hips as stage III, and 79 hips as stage IV. The preoperative Harris hip score was 60.30 +/- 7.02. RESULTS: Fat necrosis occurred in 2 cases after operation, primary healing of incision was obtained in the other cases; delayed infection, lower extremity deep vein thrombosis, and pulmonary embolism occurred in 2 cases, respectively. All patients were followed up 36-60 months (mean, 49 months). Harris hip score at last follow-up (83.50 +/- 7.31) was significantly higher than that at preoperation (t= -2 266.980, P=0.000), and the scores were significantly higher than those at preoperation in different stages (P < 0.05). The results were excellent in 523 hips, good in 185 hips, fair in 65 hips, and poor in 30 hips, and the excellent and good rate was 88.2%. X-ray examination showed bone fusion of transplanted bone flap and bone graft with an average of 4.2 months (range, 3-6 months); according to Steinberg staging, imaging stable rate was 78.3% (629/803) at last follow-up. CONCLUSION: Iliac bone flap transplantion with deep iliac circumflex vessels and cancellous bone has the advantages of complete decompression of the femoral head, exact flap blood supply, improved blood supply of the femoral head, new support for the femoral head, and participation of osteoinductive effect for the treatment of adult ANFH, so it is an effective treatment for the retention of the femoral head. PMID- 24063179 TI - [Anatomy study on micro transverse flap pedicled with superfical palmar branch of radial artery from palmar wrist]. AB - OBJECTIVE: To study the anatomical basis of micro transverse flap pedicled with the superfical palmar branch of radial artery from the palmar wrist for using this free flap to repair soft tissue defect of the finger. METHODS: Thirty-eight fresh upper limb specimens (22 males and 16 females; aged 26-72 years with an average of 36 years; at left and right sides in 19 limbs respectively) were dissected and observed under operating microscope. Two specimens were made into casting mould of artery with bones, and 2 specimens were injected with red emulsion in radial artery. Thirty-four specimens were injected with 1% gentian violet solution in the superfical palmar branch of the radial artery. A transverse oval flap in the palmar wrist was designed, the axis of the flap was the distal palmar crease. The origin, distribution, and anastomosis of the superfical palmar branch of the radial artery were observed. RESULTS: The superficial palmar branch of the radial artery was constantly existed, it usually arises from the main trunk of the radial artery, 1.09-3.60 cm to proximal styloid process of radius. There were about 2-5 branches between the origin and the tubercle of scaphoid bone. The origin diameter was 1.00-3.00 mm, and the distal diameter at the styloid process of radius was 1.00-2.90 mm. The venous return of flap passed through 2 routes, and the innervations of the flap mainly from the palmar cutaneous branch of the median nerve. The area of the flap was 4 cm x 2 cm 6 cm x 2 cm. CONCLUSION: The origin and courses of the superficial palmar branch of the radial artery is constant, and its diameter is similar to that of the digital artery. A transverse oval flap pedicled with the superfical palmar branch of radial artery in the palmar wrist can be designed to repair defects of the finger. PMID- 24063180 TI - [Modified surgical repair of severe ingrown toenail]. AB - OBJECTIVE: To summarize the effectiveness of modified surgical repair for severe ingrown toenail. METHODS: Between January 2005 and December 2010, 13 patients with severe ingrown toenail (16 toes) were treated. There were 12 males (15 toes) and 1 female (1 toe), aged 18-32 years with an average of 20 years. The disease duration was 1-15 years (mean, 2 years and 9 months). All affected toes were great toes. Ingrown toenail occurred bilaterally in 3 cases and unilaterally in 10 cases. Granulation tissue surrounding nail-edge, embedded toenail, and necrotic nail bed were completely removed; tension glue was used to make wound edge close to nail bed. RESULTS: At 3-5 days after operation, wound congestion, swelling, and exudation were improved; at 7 days, new nail bed formed; at 2 weeks, all wounds healed, and nail bed was epitheliogenic, wound edge healed well close to nail plate, and patients returned to normal life. At 6 months after nail extraction, new toenail grew and nail groove formed. No recurrent sign was found during 24-month follow-up. CONCLUSION: Modified surgical repair is one of effective methods to treat severe ingrown toenail with the advantages of good appearance and low recurrent rate. PMID- 24063181 TI - [Breast reconstruction after skin-sparing mastectomy or nipple-sparing mastectomy for breast cancer]. AB - OBJECTIVE: To evaluate the feasibility, oncological safety, and aesthetic result of skin-spring mastectomy (SSM) or nipple-spring mastectomy (NSM) in breast reconstruction of implant (permanent gel or expander) for breast cancer patients who were not fit for the breast conserving surgery (BCS). METHODS: Between October 2005 and July 2011, 89 women with breast caner underwent SSM or NSM, with an average age of 42.4 years (range, 19-55 years) and an average disease duration of 5.7 months (range, 1-24 months). The pathological examination revealed invasive ductal carcinoma in 55 cases, ductal carcinoma in situ (DCIS) in 15 cases, invasive ductal carcinoma + DCIS in 8 cases, DCIS with infiltration in 10 cases, and occult breast cancer in 1 case. According to tumor staging criterion of American Joint Committee on Cancer (AJCC), 15 cases were rated as stage 0, 51 cases as stage I, 22 cases as stage II, and 1 case as unclear. Finally, 33 patients underwent SSM and 56 patients underwent NSM according to the location and diameter of tumor and the infiltration of tumor to nipple. Secondary breast reconstruction was performed with permanent gel replacement after axillary lymph node dissection in 9 patients with positive sentinel lymph node and 1 patient with occult breast cancer; immediate breast reconstruction was performed with permanent gel in the other patients. All the patients received the chemotherapy or/and radiotherapy according to the National Comprehensive Cancer Network (NCCN) guideline. RESULTS: Complications occurred in 5 patients undergoing breast reconstruction of permanent gel after NSM, including 1 case of haemorrhage, 2 cases of infection, and 2 cases of local skin necrosis. Primary healing of incision was obtained in the others. No nipple necrosis was observed in patients undergoing NSM. All the patients were followed up 14-88 months (median, 40 months). At 10 months after operation, the aesthetic results were excellent in 40 cases, good in 33 cases, fair in 14 cases, and poor in 2 cases, with an excellent and good rate of 82%. No recurrence or metastasis was found during follow-up. CONCLUSION: The SSM or NSM is feasible and oncological safe for patients who are not fit for BCS, with satisfactory aesthetic result. PMID- 24063182 TI - [Effectiveness comparison between endovascular recanalization and open surgical revascularization to treat peripheral pseudoaneurysm]. AB - OBJECTIVE: To compare the effectiveness, complications, and follow-up results between endovascular recanalization (EVR) and open surgical revascularization (OSR) in the treatment of peripheral pseudoaneurysm, so as to provide a reference for choosing a appropriate surgical procedure. METHODS: Clinical data of 62 cases of peripheral pseudoaneurysm between January 2001 and January 2012 were analyzed retrospectively. EVR was performed in 28 patients (EVR group) and OSR in 34 patients (OSR group). There was no significant difference in gender, age, cause of injury, tumor location, and diameter of tumor between 2 groups (P > 0.05). RESULTS: The operation time, blood loss, ICU monitoring time, and hospitalization time in EVR group were significantly shorter than those in OSR group (P < 0.05). In OSR group, 12 cases (35.29%) had early postoperative complications, including 2 deaths due to acute respiratory distress syndrome, 5 cases of pulmonary infection, 3 cases of wound infection, and 2 cases of deep vein thrombosis; in EVR group, 2 cases (7.14%) had early postoperative complications, including 1 case of hematoma at puncture site and 1 case of thrombosis in stent. There was significant difference in early postoperative complication incidence between 2 groups (chi2=6.691, P=0.008). The patients were followed up 12-39 months (mean, 26 months). In OSR and EVR groups after operation, the patency rates of the reconstructed vessels were 96.88% (31/32) and 92.86% (26/28) respectively at 12 months, showing no significant difference (chi2=0.014, P=0.905); the patency rates were 89.29% (25/28) and 84.00% (21/25) respectively at 24 months, showing no significant difference (chi2=0.322, P=0.570). CONCLUSION: Compared with OSR, EVR is a minimally invasive, safe, and effective therapy for peripheral pseudoaneurysm with the advantages of less bleeding, shorter hospitalization time, and less complications. Long-term effectiveness still needs further observation, and patients have to take antiplatelet drugs for long time after EVR. PMID- 24063183 TI - [A study on residual strain of abdominal aortic aneurysm after intraperitoneal administration of saturated hydrogen saline in rats]. AB - OBJECTIVE: By observation of the diameter, progression rate, wall thickness, and the opening angle of the abnormal aortic of abdominal aortic aneurysm (AAA) in rats, to observe the effect of saturated hydrogen saline on residual strain of AAA rats, and to investigate its inhibition effect on AAA formation. METHODS: Twenty healthy male Sprague Dawley rats (weighing, 200-220 g) were randomly divided into 2 groups, which was made the AAA model by infiltration of the abdominal arota with 0.5 mol/L calcium chloride. Saturated hydrogen saline (5 mL/kg) or saline (5 mL/kg) was injected intraperitoneally in the experimental group or control group respectively, every day for 28 days. At 28 days, the diameter, progression rate, wall thickness, and opening angle of the abnormal aorta were mearsured. The aortic tissue was harvested for histological examination (HE staining and aldehyde-fuchsin staining). RESULTS: At 28 days after operation, the diameter of abnormal aorta in 2 groups were significantly higher than preoperative ones (P < 0.05), the progression rate in experimental group (65% +/- 15%) was significantly lower than that in control group (128% +/- 54%) (t=3.611, P=0.005). The opening angle and the wall thickness in experimental group were (88.78 +/- 29.20) degrees and (0.14 +/- 0.03) mm respectively, had significant differences when compared with the values in control group [(44.23 +/ 28.52) degrees and (0.36 +/- 0.05) mm respectively] (P < 0.01). The integrity and continuity of the aortic wall in experimental group were superior to that in the control group. Compared with the control group, the injury of elastic fiber in aortic wall and the infiltration of inflammation were all reduced. CONCLUSION: Saturated hydrogen saline can maintain good mechanical properties and reduce dilatation of the aorta by increasing residual strain and reducing the remodeling of it. PMID- 24063184 TI - [Technical study on inactivating/removing virus in collagen sponge]. AB - OBJECTIVE: To verify the technics of inactivating/removing virus in collagen sponge derived from bovine Achilles tendon. METHODS: Possible pathogen species were determined according to the raw material of bovine Achilles tendon used in production, then vesicular stomatitis virus (VSV), theiler's mouse encephalomyelitis virus (TEMV), pseudorabies virus (PRV), and simian vacuolating virus 40 (SV40) were selected as indicator virus. Virus suspension was prepared in accordance with Technical Standard for Disinfection. 60Co radiation 25 kGy of collagen sponge was determined as inactivating/removing virus process according to the analysis of the manufacture process, the virus inactivation/removal effect was verified by the measurement of median tissue culture infective dose (TCID50) and showed by virus reduction factor (sample average values of numerical difference before and after processing). RESULTS: Reduction factors of VSV, TEMV, PRV, and SV40 after 60Co radiation 25 kGy were 5.646, 4.792, 5.042, and 5.292 logTCID50/0.1 mL (logs), respectively. Reduction factor of each indicator virus was greater than 4 logs, showing that 60Co irradiation 25 kGy can effectively inactivate and remove viruses. CONCLUSION: 60Co radiation 25 kGy of collagen sponge derived from bovine Achilles tendon can be used as the technics of inactivating/removing virus during the preparation process of collagen sponge to guarantee the safety of the product. PMID- 24063185 TI - [Progress in stable isotope labeled quantitative proteomics methods]. AB - Quantitative proteomics is an important research field in post-genomics era. There are two strategies for proteome quantification: label-free methods and stable isotope labeling methods which have become the most important strategy for quantitative proteomics at present. In the past few years, a number of quantitative methods have been developed, which support the fast development in biology research. In this work, we discuss the progress in the stable isotope labeling methods for quantitative proteomics including relative and absolute quantitative proteomics, and then give our opinions on the outlook of proteome quantification methods. PMID- 24063186 TI - [Recent progress in multi-stage mass spectrometry-based quantitative proteomics]. AB - With the development of proteome research, quantitative proteomics is becoming a very active area of proteomics research. The development of quantitative proteomics requires the advancement of a number of mass spectrometry (MS) -based quantitative techniques. According to the mass spectrometric stage at which the peptides are quantified, MS-based quantitative methods can be divided into two categories: MS(1) -based quantitation and MS(n)-based quantitation. In this review, the progress of MS(n)-based quantitation approaches is summarized and the advantages and disadvantages are compared. The trend of MS(n)-based quantitation is also prospected. PMID- 24063187 TI - [Detection of the major milk allergen alpha-casein in food with liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode]. AB - A new method of detecting milk allergen protein in food was established. Using multiple reaction monitoring (MRM) mode in high performance liquid chromatography mass spectrometry (HPLC-MS) to detect milk allergen protein alpha-casein is successful and convenient. All transitions gave a linear response in the chosen concentration range of the milk allergen protein (between 0. 5 and 250 mg/L total soluble protein, 5 data points), and the detection limit is 0.5 mg/L of alpha casein. Food samples from markets were tested. The results showed that MRM method could be used to detect the milk allergen in food products. PMID- 24063188 TI - [Identification of methylation at lysine 27 and 36 sites in histone H3]. AB - We combined high performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) with bioinformatics tools to analyze the isobaric modified peptides which were methylated and dimethylated at either lysine (K) 27 or/and K36 from histone H3. They were identified and dissected through alignment of every fragment ion, and the two modified sites were further analyzed according to their relative intensities of MS/MS spectra. PMID- 24063189 TI - [A novel and facile microchip based on nitrocellulose membrane toward efficient capture of circulating tumor cells]. AB - A novel and facile circulating tumor cell (CTC) microchip has been developed for the isolation and detection of cancer cells. The CTC microchip was prepared based on the nitrocellulose membrane substrate, which shows high affinity to proteins and hence can adsorb antibodies naturally. We employed non-small-cells of lung cancer NCI-H1650 as target cells and testified the high capture efficacy of the CTC microchip. Furthermore, we spiked 500 cancer cells to 1 mL healthy donor's whole blood in order to simulate the detection of CTC in patient and detected 182 cancer cells ultimately, indicating the huge application potential in the future. PMID- 24063190 TI - [A novel method for absolute protein quantification using 18O isotope labeled concatamers of Q peptides combined with isotope dilution-multiple reaction monitoring mass spectrometry]. AB - A method of concatamers of Q peptides (QconCATs) protein labeled with 18O multiple reaction monitoring mass spectrometry for absolute quantification of proteins is established. The purity of the QconCAT recombinant protein was characterized by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS PAGE), and its purity was above 99%. The relative molecular mass was approximately 63.4 kDa. The peptides digested from the QconCAT recombinant protein and the extract of Thermoanaerobacter tengcongensis (TTE) were analyzed by mass spectrometry. The raw data were processed by pFind and pLabel softwares. The results showed that the efficiencies of protein digestion and the 18O labeling efficiency were able to meet the need of the protein quantification. The performance of the method was evaluated. The absolute contents of the selected proteins in TTE were determined with the relative standard deviations of less than 20% and the accuracy is high. The method not only avoid using the expensive reagent of stable isotope labeling with amino acids in cell culture (SILAC), but also provides an alternative way for the accurately absolute quantification of proteins in biological samples for quantitative proteomic research. PMID- 24063191 TI - [Preparation of organic-inorganic hybrid boronate affinity monolith via thiol-ene click reaction for specific capture of glycoproteins]. AB - A novel strategy for the preparation of the organic-inorganic hybrid boronate affinity monolith was developed via the "thiol-ene" click reaction. A thiol group modified silica monolith was first synthesized via the sol-gel process by the in situ co-condensation with tetramethoxysilane (TMOS) and 3 mercaptopropyltrimethoxysilane (MPTMS) as precursors. Then 3 acrylamidophenylboronic acid (AAPBA) was covalently immobilized on the hybrid monolith via the "thiol-ene" click reaction to form AAPBA-silica hybrid affinity monolith. The reaction conditions for the preparation of AAPBA-silica hybrid affinity monolith were optimized, including the ratio of TMOS to MPTMS, the contents of poly(ethylene glycol) (PEG) and methanol. The morphology and mechanical stability of the boronate affinity monolith were characterized and evaluated by scanning electron microscopy and Fourier-transform infrared spectroscopy. The obtained boronate affinity hybrid monolith exhibited excellent specificity toward the nucleosides containing cis-diols under neutral conditions. It was further applied to the specific capture of the glycoproteins ovalbumin and horseradish peroxidase. The method is novel and reliable, which has a great potential for the preparation of different kinds of the boronate affinity monoliths. PMID- 24063192 TI - [Comparison of one-step and two-step methods for pI determination of proteins and polypeptides by capillary isoelectric focusing]. AB - One-step and two-step capillary isoelectric focusing (clEF) methods were employed the separation and pI determination of proteins and polypeptides. The parameters affecting the analysis efficiency, such as the sample solution, injection volume, focusing voltage, focusing time and driving conditions were optimized. The comparison of the two methods for separation of cytochrome C, hemoglobin, myoglobin, transferrin, bovine serum albumin and six polypeptides showed that the one-step cIEF was simple and fast, which could determine the pI of single component as well as it was rapid for protein and polypeptide separation, but it could not get good resolution or accurate pI of each component in a mixed sample. The two-step cIEF was more complex and needed longer time, however, which could separate and exactly determine the pI of each component in the mixture, and the pI value of each component determined was consistent with that determined using a single sample. The two methods are complementary, and can be widely used in rapid and accurate determination of the pI of amphiphilic biological particles. PMID- 24063193 TI - [Characterization of stability of polypeptides and glycoproteins by capillary electrophoresis]. AB - A capillary electrophoresis (CE) method was developed for the stability characterization of polypeptides and glycoproteins. Angiotensin II (Ang II), phytagglutinin (PHA), bovine thrombin (B-Thr), human thrombin (H-Thr) and horseradish peroxidase (HRP) were used as polypeptide and glycoprotein mode molecules. The parameters affecting the analysis efficiency for Ang II, such as sample concentration, running buffer, pH and ionic strength of sample solution were optimized, as for the glycoprotein, capillary conditions, charge state of sample, running buffer and applied voltage were optimized. It showed that the Ang II was stable when kept in borate buffer (0.02 mol/L pH 7.4) at 4 degrees C for 48 h. The four glycoproteins were quite stable in borate buffer (0.2 mol/L pH 7.4) at 20, 4, -20 degrees C for 48 h, and also kept stable at - 20 degrees C when deposited over one week and less than four weeks. HRP was the only one that kept stable when deposited over two weeks and less than four weeks. This method is effective, rapid, simple and low-cost and can be widely used for the stability characterization of polypeptides and glycoproteins. PMID- 24063194 TI - [Comparison for applicability of different trilinear decomposition algorithms to liquid chromatography-mass spectrometry data measured from multiple samples]. AB - The applicability of different trilinear decomposition algorithm to LC-MS data measured from multiple samples is discussed in this paper. An actual LC-MS data set contained a low abundance peptide was adopted to make a test for these algorithms. The bilinear method was not able to handle this type of low abundance situations, and made a mathematical separation as expected. It is found out that the famous trilinear decomposition algorithm could not be used in the LC-MS data directly. The most probable reason is the sparsity property of the pure MS spectra, which means they have positive response values at some m/z coordinates where the ions emerged and zero values elsewhere. A novel algorithm named NNATLD (non-negative alternating has been designed by the present authors to make an effective trilinear decomposition for the three-way data set constructed by LC-MS data. The new algorithm adapts the property of MS spectra, saves the computing resources, and converges fast. PMID- 24063195 TI - [Determination of undecanoic acid and 13-methyl-tetradecanoic acid connected to the glyceride with internal standard method and its application to the identification of adulteration of illegal cooking oil]. AB - On the basis of the source of illegal cooking oil (heated vegetable oil and animal oil) and the important referents reflecting their sources, namely, undecanoic acid and 13-methyl-tetradecanoic acid connected to the glyceride, their corresponding ramifications in edible oil were detected with internal standard method. The sensitivity and selectivity of this method were improved by the on-line cleanup and preconcentration. The detection limits of the method were 0.070 mg/kg for undecanoic acid and 0.006 mg/kg for 13-methyl-tetradecanoic acid. Additionally, most of the normal vegetable oils have lower levels of both fatty acids than illegal cooking oils. It was suggested to evaluate the quality of edible oils to some extent on the basis of the contents of undecanoic acid and 13 methyl-tetradecanoic acid. PMID- 24063196 TI - [Application of quality by design concept for the optimization of an analytical method for rhubarb anthraquinones in rat plasma]. AB - A robust high performance liquid chromatography with fluorescence detection method (HPLC-FLD) was developed for the determination of five rhubarb anthraquinones in rat plasma using a quality by design approach. A Plackett Burman design was utilized to screen the effects of methanol content, the pH value of mobile phase, the flow rate, column temperature, and injection volume on peak resolution, number of the theoretical plate, retention time of the last eluted peak, and tailing factor. The results showed that the methanol content in mobile phase, flow rate, and column temperature were statistically significant (p < 0.05). A Box-Behnken experimental design with response surface methodology (RSM) was then utilized to evaluate the effects of these three factors on the selected responses. Derringer' s desirability function was used for the evaluation of the chromatographic goals. The optimum conditions for separation were as follows: an isocratic mobile phase consisting of methanol/0.1% H3PO4 (81.4/18. 6, v/v), a flow rate of 1.1 mL/min, and a column temperature of 31 degrees C. The excitation and emission wavelengths were 440 nm and 540 nm, respectively. The proposed method showed good prediction ability. The results clearly showed that quality by design concept could be effectively applied to optimize the HPLC method. PMID- 24063197 TI - [Simultaneous determination of ciprofloxacin and flumequine in water samples by high performance liquid chromatography]. AB - In order to meet the field sample measurements and laboratory research, a simple, stable, and popular high performance liquid chromatographic (HPLC) method was established for the determination of the concentrations of two fluoroquinolone antibiotics in water samples simultaneously and rapidly. Thus, it could provide valuable information for other scholars to study the interactions between different antibiotics. Ciprofloxacin (CIP) and flumequine (FLU) were taken as the target contaminants because of their wide application in medical career. Furthermore, this study also investigated the different types of mobile phase, different mobile phase ratios, common ions (Ca2+, Mg2+, Fe3+, Al3+, SO4(2-) and HCO3(-)) in water samples and other factors on CIP and FLU measurements with this method. The results showed that triethylamine has obvious effect on improving column efficiency. Low concentrations of ions had little effect on the test, but Fe3+ and Al3+ might cause baseline instability, because Fe3+ and Al3+ may form complexes with the surface hydroxyl groups of the stationary phase or the test components. The results may be referred by other workers for the optimization of the determination conditions. PMID- 24063198 TI - [Determination of atracurium and laudanosine in dog plasma during cardiopulmonary bypass by high performance liquid chromatography with fluorometric detection]. AB - A high performance liquid chromatographic method coupled with fluorometric detection has been developed for the determination of atracurium and its major metabolite laudanosine in dog plasma. The separation of atracurium and laudanosine was performed on an Agilent Eclipse Plus C18 column, and the mobile phase consisted of 0.03 mol/L dipotassium hydrogen phosphate and acetonitrile (72: 28, v/v) at a flow rate of 1.0 mL/min. Verapamil was used as the internal standard. The sample was extracted by dichloromethane, concentrated and dissolved in the mobile phase. The detection is performed at 240 nm for excitation and 320 nm for emission. The results showed that the linear concentration ranges of the calibration curve were 25 - 5 000 microg/L for atracurium (r = 0.999 0), and 25 - 6 000 microg/L for laudanosine (r = 0.9984). The recoveries were 92.1% - 109.5%. The limits of detection were 3 microg/L for atracurium and 1 microg/L for laudanosine. The RSDs of intra-day and inter-day were less than 10%. The stability tests under various conditions have been performed. The method is specific, sensitive and accurate in the determination of atracurium and laudanosine, and also can be used for the pharmacokinetic investigations of atracurium and laudanosine in plasma. PMID- 24063199 TI - [Simultaneous determination of tryptophan and its metabolites in plasma by high performance liquid chromatography with on-column derivatization]. AB - A high performance liquid chromatography-ultraviolet/fluorescence detection (HPLC UV/FLD) with on-column derivatization was established to simultaneously determine tryptophan (Trp), kynurenine (Kyn), 5-hydroxyindole acetic acid (5-Hiaa) and kynurenic acid (Kyna). A Hypersil C-18 column (250 mm x 4.0 mm, 5 microm) was used for the analysis at 30 degrees C. The separation was carried out with the mobile phase consisting of 250 mmol/L zinc acetate (pH 5.5) and acetonitrile (95: 5, v/v) at a flow rate of 0.8 mL/min using 3-nitrotyrosine as internal standard (IS). The excitation (Ex) and emission (Em) wavelengths were set at 278 nm (lambda(ex))/343 nm (lambda(em)) for 5-Hiaa and 244 nm (lambda(ex))/400 nm (lambda(em)) for Kyna, while the wavelengths of ultraviolet detection were set at 360 nm for Kyn and IS, 302 nm for Trp. The recoveries were in the range of 91.62% to 114.17%. The linearities were from 2.50 micromol/L to 320.00 micromol/L for Trp, 0.32 micromol/L to 15.36 micromol/L for Kyn, 3.27 nmol/L to 104.60 nmol/L for 5-Hiaa, and 14.00 nmol/L to 464.80 nmol/L for Kyna. The detection limits were 0.078 micromol/L, 0.056 micromol/L, 0.690 nmol/L and 1.290 nmol/L for Trp, Kyn, 5 Hiaa, and Kyna, respectively. Thirty plasma samples of normal pregnant women and 28 plasma samples of healthy controls were tested, and the results exhibited that the concentrations of Trp, Kyn and Kyna in the plasma of the normal pregnant women were significantly different from those of the control group (all P < 0.01). The method is simple and sensitive with good reproducibility, and it is suitable for clinical measurements. PMID- 24063200 TI - [Determination of K-ras gene mutation in colorectal cancer tissue by capillary electrophoresis]. AB - The codons 12/13 of K-ras genomic DNA from 76 colorectal cancer tissues and normal tissues were amplified by PCR. The amplified 152 samples were purified, denatured, and then detected using capillary electrophoresis (CE)-laser induced fluorescence (LIF) with single-strand conformation polymorphism (SSCP). The abnormal samples were further confirmed by direct-sequencing. The 30 patients of the 76 colorectal cancer patients were found gene mutation, of which the results of base G --> A point mutation were confirmed by the gene sequence. To detect K ras gene mutation that has important role in clinical forecast, diagnosis, therapy and prognosis, the CE-LIF with SSCP was applied for detecting K-ras gene. It becomes a promising tool to analyse K-ras gene mutation in the clinical diagnosis and therapy of colorectal cancer tissue. PMID- 24063201 TI - Preparation and evaluation of molecularly imprinted polymer of olivetol for solid phase extraction. AB - Molecularly imprinted polymer (MIP) was synthesized by bulk polymerization, using olivetol as template molecule, methyl acrylic acid (MAA) as monomer, ethylene glycol dimethacrylate (EDMA) as crosslinker, toluene and dodecanol as solvents. The resulted MIP was characterized by the equilibrium binding experiments, scanning electron microscope (SEM) and Fourier transform infrared spectrometer (FTIR). The polymer was then applied to solid phase extraction (SPE) of olivetol from spiked wheat bran samples. From the equilibrium binding experiments, it was showed that MIP had a better recognizability for the template molecule. Scatchard analysis showed that MIP had specific adsorption to olivetol with two classes of binding sites. The high and low binding sites dissociation constants were 0.021 and 1.002 mmol/L. The corresponding maximum binding capacities were 18.74 and 135.9 micromol/g, respectively. Under the optimum condition of SPE, the recoveries of olivetol on MIP cartridge were in the range of 97.8% - 98.8%. The relative standard deviations (RSDs) were 2.8% -4.2%. The linearity range was between 0.1 and 100 mg/L. The limit of detection (S/N = 3) was 0.062 mg/L. MIP cartridge showed stronger selectivity, higher recovery and purified the sample more drastically compared with non-imprinted polymer (NIP) cartridge and commercial poly (styrene/divinyl-benzene) (PLS) cartridge. PMID- 24063202 TI - [Analysis of cracking gas compressor fouling by pyrolysis gas chromatography-mass spectrometry]. AB - The fouling from the different sections of the cracked gas compressor in Daqing Petrochemical Corporation was analyzed by pyrolysis gas chromatography-mass spectrometry (Py/GC-MS). All the samples were cracked in RJ-1 tube furnace cracker at the cracking temperature of 500 degrees C, and separated with a 60 m DB-1 capillary column. An electron impact ionization (EI) source was used with the ionizing voltage of 70 eV. The results showed the formation of fouling was closely related with cyclopentadiene which accounted for about 50% of the cracking products. Other components detected were 1-butylene, propylene, methane and n-butane. This Py/GC-MS method can be used as an effective approach to analyze the causes of fouling in the petrochemical plants. PMID- 24063203 TI - [Fluctuant hypertension and platelet activation: current situations and control strategies with integrative medicine]. AB - In recent years a huge amount of clinical studies have proved that fluctuant hypertension could aggravate the damage of target organs and increase the incidence of acute cardio-/cerebrovascular events, when compared with stable hypertension [increased mean artery blood pressure (MBP)]. How to prevent and treat fluctuant hypertension and its damage of target organs has become one of the hot and difficult problems in the field of hypertension studies all over the world. Hypertensive patients often suffer from thromboembolic target organ damage. Platelet activation plays a key role in this progress, but its concrete mechanisms have not been clearly clarified. Based on the in-depth discussions on progress of fluctuant hypertension, its relationship with platelet activation and blood stasis syndrome of Chinese medicine (CM) in recent three years, we proposed, under the fluctuant hypertensive state, the prethrombotic state has occurred in the organisms, i.e., a pathological state featured by platelet activation, liable to have vulnerable thrombopoiesis, and accompanied by endothelial dysfunction. Blood stasis syndrome might occupy an important position in CM syndrome typing of fluctuant hypertension. Herbs for activating blood circulation and removing stasis might have an extensive application prospect. PMID- 24063204 TI - [Effect of tongguan capsule on the number of endothelial progenitor cells in the peripheral blood of patients with coronary artery disease after PCI]. AB - OBJECTIVE: To observe the effect of Tongguan Capsule (TC) on the number of endothelial progenitor cells (EPCs) in the peripheral blood of patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI). METHODS: Recruited were 60 CAD patients undergoing PCI who were admitted and treated at ICU and the Heart Center of Guangdong Provincial Hospital of Traditional Chinese Medicine from March to October 2010. They were assigned to the treatment group (treated by TC) and the control group (treated by placebos) according to the random digit table, 30 cases in each group. They took TC or placebos from the day of PCI, three pills each time, three times a day, for three consecutive months. The numbers of peripheral blood CD34 and vascular endothelial growth factor receptor-2 (VEGFR2) positive cells were detected before PCI and 3 months after PCI respectively. The echocardiography was performed before PCI and 3 months after PCI respectively to determinate the left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), stroke volume (SV), cardiac output (CO), and left ventricular ejection fraction (LVEF). The wall motion score index (WMSI) was assessed in the two groups. RESULTS: There was no statistical difference in the number of EPCs, LVEF,WMSI, or SV in the two groups before PCI (P > 0.05). The number of EPCs increased in both the two groups after 1 month of PCI (P < 0.05). It was obviously higher in the treatment group than in the control group (P < 0.05). The LVEF both increased in the two groups 3 months after PCI (P < 0.05, P < 0.01). The WMSI decreased and SV increased in the treatment group (P < 0.05). The improvement of LVEF and WMSI was better in the treatment group than in the control group (P < 0.05). CONCLUSION: TC could up regulate the number of EPCs in the peripheral blood of CAD patients after PCI, and improve their cardiac functions. PMID- 24063205 TI - [Optimized treatment program for unstable angina by integrative medicine based on partially observable Markov decision process]. AB - OBJECTIVE: To initially optimize comprehensive treatment program for treating and preventing unstable angina (UA) by integrative medicine (IM). METHODS: Based on partially observable Markov decision process model (POMDP), we chose 3 syndrome elements, i.e., qi deficiency, blood stasis, and phlegm turbidity from UA inpatients. The efficacy of treating UA by IM was objectively assessed by in depth data mining and analyses. RESULTS: The treatment programs for UA patients of qi deficiency syndrome, blood stasis syndrome, and phlegm turbidity syndrome were recommended as follows: nitrates +statins +clopidogrel +angiotensin II receptor blockers +heparins +Astragalus membranaceus +Condonopsis + poria and large-head atractylodes rhizome (ADR = 0.85077869); nitrates + aspirin + clopidogrel + statins + heparins + Astragalus membranaceus + safflower + peach seed + red peony root (ADR = 0.70773000); nitrates + aspirin + statins + angiotensin-converting inhibitors + snakegourd fruit + onion bulb + ternate pinellia + tangerine peel (ADR = 0.72509600). CONCLUSION: As a POMDP based optimized treatment programs for UA, it can be used as a reference for further standardization and formulation of UA program by integrative medicine. PMID- 24063206 TI - [Exploring the association rules of clinical application of shenmai injection through text mining]. AB - OBJECTIVE: To explore the rules of clinical application of Shenmai Injection (SI). METHODS: The data sets of SI were downloaded from CBM database by the method of literature retrieved from Jan. 1980 to May 2012. Rules of Chinese medical patterns, diseases, symptoms, Chinese patent medicines (CPM), and Western medicine (WM) were mined out by data slicing algorithm, and they were demonstrated in frequency tables and two-dimension based network. RESULTS: Totally 3 159 literature were recruited. Results showed that SI was most frequently correlated with stasis syndrome and deficiency syndrome. Heart failure, arrhythmia, myocarditis, myocardial infarction, and shock were core diseases treated by SI. Symptoms such as angina pectoris, fatigue, chest tightness/pain were mainly relieved by SI. For CPM, SI was most commonly used with Compound Danshen Injection, Astragalus Injection, and so on. As for WM, SI was most commonly used with nitroglycerin, fructose, captopril, and so on. CONCLUSIONS: The syndrome types and mining results of SI were the same with its instructions. Stasis syndrome was the potential Chinese medical pattern of SI. Heart failure, arrhythmia, and myocardial infarction were potential diseases treated by SI. For CPM, SI was most commonly used with Danshen Injection, Compound Danshen Injection, and so on. And for WM, SI was most commonly used with nitroglycerin, fructose, captopril, and so on. PMID- 24063207 TI - [A research of Chinese medicine diagnosis and treatment standard procedure for patients with HIV associated pruritus based on experts' questionnaires]. AB - OBJECTIVE: To establish Chinese medicine diagnosis and treatment standard procedure for patients with HIV associated pruritus. METHODS: A Chinese medicine diagnosis and treatment standard procedure for patients with HIV associated pruritus was established by literature retrieval and peer review. Two questionnaires were carried out to investigate the confirmation and advice of in group specialists to key points of the draft including diagnosis, treatment and nursing. Then the procedures were revised accordingly. RESULTS: The recovery rate of complete questionnaires in the 1st survey was 96%. Specialists confirmed more on case history and physical examinations, syndrome differentiation of three syndrome types, treatment of blood deficiency wind dryness syndrome (BDWDS) and nursing. They held different opinions on the outlines, auxiliary examinations, treatment of blood heat induced wind evil syndrome (BHWES) and wind cold and dampness accumulation syndrome (WCDAS), of which the coefficient of variations (CVs) was within 0.1603 -0.2473. The procedures were revised and the 2nd survey was launched. The recovery rate of complete questionnaires in the 2nd survey was 100%. Specialists confirmed more on case history and physical examinations, diagnostic criteria, syndrome differentiation of BDWDS and WCDAS, and treatment of BDWDS, of which CVs was 0. All indicated high agreement and good compliance. The CVs of other items were within 0.0638-0.1439, less than those of the 1st survey. The consistency of experts' opinions were somewhat improved. The contribution by one single item showed less difference in assessing the overall results in the two surveys. A new revision of the procedure was preliminarily established according to results of two surveys. CONCLUSIONS: Experts' activeness, concentration, and coordination were good in the two surveys. They had reached consensus in key points of the draft including diagnosis, treatment, and nursing. PMID- 24063208 TI - [Research on Chinese medicine syndrome distribution of asymptomatic HIV infection patients]. AB - OBJECTIVE: To explore Chinese medicine syndrome distribution laws of asymptomatic HIV infection patients. METHODS: Using Chi-square test, Chinese medicine syndrome distribution laws were compared and analyzed in 1 156 asymptomatic HIV infection patients from March 2009 to October 2011 from four aspects, i.e., age, possible infection time, disease duration, and different routes of infection. RESULTS: Qi deficiency syndrome (QDS) and internal dampness-heat accumulation syndrome (IDHAS) were dominant in all syndrome types. Along with aging, QDS showed a growing tendency, while IDHAS showed obvious declining tendency. There was no obvious change in other syndrome types. There was statistical difference in the distribution of each syndrome type among each age period (P < 0.01). Within 15 years, along with the increase of infection time, QDS showed a growing tendency, while IDHAS ratio showed an obvious declining tendency. No obvious laws were found in other syndrome types. There was statistical difference in the distribution of each syndrome type (P < 0.01). Along with the prolongation of disease duration, the case number of each syndrome showed a decreasing trend, but QDS and IDHAS still accounted for higher ratios in each stage. There was statistical difference in the distribution of each syndrome type (P < 0.01). As for infection routes, QDS was predominant in paid blood donation, blood transfusion infection, intravenous drugs. IDHAS was predominant in sexual transmit. No obvious laws were found in other syndrome types. There was statistical difference in the distribution of each syndrome type (P < 0.01). CONCLUSIONS: DIS, IDHAS, and no confirmable syndrome typing were dominant in asymptomatic HIV infection patients. Deficiency and dampness were important pathological factors for them. PMID- 24063209 TI - [Differential serum proteomic analysis of rheumatoid arthritis patients of cold dampness arthralgia spasm syndrome]. AB - OBJECTIVE: To preliminarily study the essence of rheumatoid arthritis (RA) patients of cold-dampness arthralgia spasm syndrome (CDASS) at the protein expression level. METHODS: Totally 24 RA patients were recruited from Department of Rheumatology, Affiliated Hospital of Nanjing University of Chinese Medicine from July 2009 to September 2010. They were assigned to the CDASS group and the dampness-heat arthralgia spasm syndrome (DHASS) group according to Chinese medicine syndrome typing, 12 in each group. The normal control group consisted of 12 healthy volunteers from the Health Examination Center, Affiliated Hospital of Nanjing University of Chinese Medicine. The serum proteins were compared between the CDASS group and the normal control group/the DHASS group respectively using two-dimensional gel electrophoresis. The common differential protein spots of CDASS were analyzed by mass spectrometry. The SwissProt database was inquired using Mascot Software to identify differential proteins. RESULTS: There were 81 differential protein spots between the CDASS group and the normal control group. There were 45 differential protein spots between the CDASS group and the DHASS group. Thirteen protein spots were found to be higher or lower in protein expression quantity of the CDASS group when compared with those of the other two groups. Nine differential protein spots were identified by mass spectrometry and database retrieval. It's suggested that these proteins were most likely to be related with inhibition of cellular events, such as cell proliferation, cell differentiation, and so on. CONCLUSION: 4.1 protein and DLC-1 protein were of potential significance in the diagnosis, prognostic markers, or treatment targets of RA patients of CDASS, which also provided evidence for further studies on the essence of CDASS. PMID- 24063210 TI - [Study on composing prescription laws of treating aplastic anemia by Chinese medicine using applying data mining technique]. AB - OBJECTIVE: To explore composing prescription laws of treating aplastic anemia (AA) by Chinese medicine (CM). METHODS: The literatures on treating AA by CM were recruited from various medical periodicals at home from 1979 to 2009 including China National Knowledge Infrastructure (CNKI), VIP information network, and Wangfang data knowledge service platform. The database correlated to CM features was established using the technique of computer data bank. The data mining (DM) technique was applied to analyze drugs sorts, frequency of drug application, and association degree. RESULTS: Three hundred and eleven pertinent literatures including 677 prescriptions and 254 Chinese herbs (CHs) were screened. There were 69 CHs for invigorating deficiency, 42 for heat clearing, 20 for promoting blood circulation and removing blood stasis, 16 for arresting bleeding, and 16 for relieving exterior syndrome, which occupied the top 5. The frequency of drug application of 254 CHs amounted to 7 547, in which the frequency of drug application of Mongolian milkvetch root, Rehmannia root, Suberect spatholobus stem, Hairyvein agrimonia herb, and Chinese thorowax root were 379, 248, 167, 85, and 13 respectively, and they occupied the first place of CHs for invigorating deficiency, heat clearing, promoting blood circulation and removing blood stasis, arresting bleeding, and relieving exterior syndrome, respectively. The number of the prescriptions containing 12, 10, and 11 CHs was occupied the top 3. The coverage rate of the prescription including Mongolian milkvetch root and Chinese angelica was 60%, and thus 4 core drugs groups were established covering invigorating qi and enriching the blood, reinforcing Shen and supporting yang, replenishing yin to tonify Shen, tonifying Shen to replenish essence, and invigorating qi and enriching blood respectively. Summarized were six potential composing prescription laws covering invigorating qi and enriching blood, reinforcing Shen and supporting yang, replenishing yin to tonify Shen, strengthening Pi and harmonizing Wei, tonifying the blood and promoting blood circulation, clearing away heat and toxic materials, and removing heat from the blood to stop bleeding. CONCLUSIONS: Applying DM technique, the fundamental core drugs groups consisting of Mongolian milkvetch root and Chinese angelica were discovered. The 4 core drugs groups established were in accordance with the realization of modern CM for the pathomechanism of AA. The 6 composing prescription laws summarized revealed the rules of drug application. PMID- 24063211 TI - [The distribution of Chinese medicine syndrome types in primary liver cancer and their differences of the survival time: a clinical study]. AB - OBJECTIVE: To explore the distribution of Chinese medicine (CM) syndrome types in primary liver cancer (PLC) and their differences of the survival time. METHODS: From May 2007 to March 2009, recruited were 151 PLC inpatients at Department of Tumor, Guangdong Provincial Hospital of Traditional Chinese Medicine. Their survival time were statistically calculated. Patients' average survival time and median survival time were calculated using Kaplan-Meier method. The Log-rank test was used to analyze their differences of survival time among different CM syndrome types. RESULTS: The proportion of CM syndrome types in PLC patients were ranked from high to low as follows: mutual accumulation of dampness and blood stasis syndrome [MADBSS, 43.0% (65/151)], Gan-stagnation Pi-deficiency syndrome [GSPDS, 34.4% (52/151)], qi stagnation blood stasis syndrome [QSBSS, 9.3% (14/151)], retention of damp-heat syndrome [RDHS, 8.6%(13/151)], and Gan-Shen yin deficiency syndrome [GSYDS, 4.6% (7/ 151)]. The median survival time of different CM syndrome types were ranked from longer to shorter as follows: GSPDS (14.77 months), QSBSS (6.13 months), RDHS (5.27 months), MADBSS (4.78 months), and GSYDS (0.80 months). The mean survival times were ranked from longer to shorter as follows: GSPDS (12.40 months), QSBSS (8.84 months), MADBSS (6.99 months), RDHS (7.08 months), and GSYDS (0.72 months). There was statistical difference in the difference of the survival time among different CM syndrome types (P < 0.05). CONCLUSIONS: GSPDS and MADBSS were the most common CM syndrome types in PLC patients. There was difference in the survival time between GSPDS and MADBSS/between RDHS and GSYDS. There was difference in the survival time between MADBSS and GSYDS. Patients of GSPDS might get the best prognosis, while patients of GSYDS might get the poorest prognosis. PMID- 24063212 TI - [Tongjiang granule intervened non-erosive reflux disease patients of Gan-Wei incoordination syndrome: a curative effect observation]. AB - OBJECTIVE: To assess the effectiveness of Tongjiang Granule (TJG) in treating non erosive reflux disease (NERD) of Gan-Wei incoordination syndrome (GWIS). METHODS: Totally 128 NERD patients of GWIS were recruited from outpatients or inpatients at Department of Digestive Disease, Xiyuan Hospital, China Academy of Chinese Medical Sciences from February 2009 to November 2010. They were randomly assigned to two groups using the block group in the ratio of 1:1, 64 cases in each group. Patients in the experiment group were treated with TJG, 10 g each time, three times a day, while those in the control group were treated with Omeprazole Tablet, 20 mg each time, two times a day. The treatment course of both groups was 4 weeks. The symptoms questionnaires and SF-36 quality of life scale were observed. RESULTS: Finally 114 patients completed the trial. There was statistical difference in epigastric upset, pharyngeal foreign body sensation, abdominal swelling or abdominal pain, and integral of excrement between the two groups before treatment (P < 0.05). However, there was no statistical difference in the rest indices between the two groups (P > 0.05). Compared with before treatment in the same group, the scores of each symptom or the total symptoms were somewhat improved in the two groups (P < 0.01, P < 0.05). There was statistical difference in the rest scores (P > 0.05) except the score of mental health in the experiment group (P < 0.01, P < 0.05). There was statistical difference in the rest scores (P > 0.05) except the score of physical function in the control group (P < 0.01, P < 0.05). There was statistical difference in post treatment acid reflux, irritability, depression, body pain, roles of emotions (P < 0.01, P < 0.05). The total effective rate was higher in the experimental group, showing no statistical difference when compared with that of the control group (P > 0.05). CONCLUSIONS: TJG had confirmative efficacy in treating NERD patients of GWIS. Meanwhile, it could improve their quality of life, with no obvious adverse reaction. PMID- 24063213 TI - [Expressions of TNF-alpha, IL-6, CRP, and MCP-1 in phlegm-damp constitution population detected by multiplexed Luminex assay]. AB - OBJECTIVE: To study the expression changes of tumor necrosis factor-alpha (TNF (alpha), interleukin-6 (IL-6), C-reactive protein (CRP), monocyte chemotactic protein 1 (MCP-1), and their correlation with obesity in 20 -50 years old population of phlegm-damp constitution (PDC) and of normal constitution (NC) using Luminex technique. METHODS: Totally 101 population were recruited from Health Examination Center of Puren Hospital from April to December 2011. Based on body mass index (BMI), the subjects were assigned to four groups, i.e., the obesity of PDC group (Group OBT, BMI > or = 24 kg/m2, 30 cases), the non-obesity of PDC group (Group NOBT, BMI < 24 kg/m2, 25 cases), the obesity of non-PDC group (Group OBNT, BMI > or = 24 kg/m2, 28 cases), the NC group (Group P, BMI < 24 kg/m2, 18 cases). The BMI and body fat percent (FAT%) were compared among the 4 groups. Serum levels of TNF-alpha, IL-6, CRP, and MCP-1 were measured with Luminex technique. RESULTS: BMI was significantly higher in Group OBT and Group OBNT than in Group NOBT and Group P (all P < 0.05). The FAT% was significantly higher in Group OBT and Group OBNT than in Group P (P < 0.01). The serum TNF alpha level in Group OBT was higher than in Group P (P < 0.01). The serum CRP and MCP-1 levels were significantly higher in Group OBT, NOBT, and OBNT than in Group P (P < 0.05, P < 0.01). The score for PDC was positively correlated with TNF alpha, IL-6, and MCP-1 levels (P < 0.05). CONCLUSIONS: Abnormal higher levels of inflammatory factors exist in 20 -50 years old population of PDC. Chronic inflammation exists in population of PDC and obesity people. PMID- 24063214 TI - [Effect of acupuncture combined language training on cerebral palsy children with language retardation]. AB - OBJECTIVE: To observe effects of acupuncture combined speech therapy for cerebral palsy children with linguistic retardation. METHODS: Totally 132 cerebral palsy children were randomly assigned to the speech training group (Group A, 44 cases) and the routine acupuncture combined speech training group (Group B, 44 cases), and the acupuncture combined speech training group (Group C, 44 cases). Patients in Group A received one to one training including game therapy, therapy of communication attitudes, and so on. Those in the other two groups were needed at Baihui (GV20), Sishencong (EX-HN1), the first language zone, the second language zone, and the third language zone. Those in Group B were treated with electric needling and then speech training. Those in Group C were treated with language training, while needling with needle maintaining for 40 min. All patients were treated once daily, 5 times per week, 20 times as one course of treatment, 6 courses in total. The efficacy was assessed using S-S phonetic speech developmental retardation examination (CRRC version). The development quotient (DQ) was observed referring to the Gesell intellectual development scale before treatment, after 3 and 6 treatment courses. RESULTS: Compared with Group A (the total effective rate: 51.3%, DQ value: 58.1 +/- 13.3), better effects were obtained in Group B (the total effective rate: 77.5%, DQ value: 60.4 +/- 13.5) and Group C (the total effective rate: 81.0%, DQ value: 64.0 +/- 11.6) (all P < 0.05). There was no statistical difference in the total effective rate or post treatment DQ value between Group B and Group C (P > 0.05). CONCLUSION: Acupuncture combined speech therapy showed obvious effects on cerebral palsy children with linguistic retardation. PMID- 24063215 TI - [Effects of qingxin kaiqiao recipe volatile oil on expressions of GFAP and caspase-3 in the cortex and hippocampus of AD rats]. AB - OBJECTIVE: To study effects of Qingxin Kaiqiao Recipe (QKR) and its volatile oil on the expressions of Abeta(25-35) glial fibrillary acidic protein (GFAP), beta amyloid (Abeta), beta-amyloid precursor protein (betaAPP), and Caspase-3 in the cortex and hippocampus of Alzheimer's disease (AD) rats induced by injecting Abeta(25-35) into the bilateral amygdala. METHODS: Totally 32 male SD rats were selected. The AD rat model was establish by injecting Abeta(25-35) from bilateral amygdala. After modeling they were randomly divided into the model group, the Donepezil Hydrochloride group [Donepezil Hydrochloride Tablet (1.67 mg/kg), abbreviated as the DH group], the QKR group (QKR Decoction, 12.67 mL/kg), and the volatile oil group (3.33 mL/kg), 8 rats in each group. Another 8 rats were selected as the normal control group. Equal volume of double distilled water was administered to rats in the normal control group and the model group by gastrogavage, once daily for 2 successive weeks. The Morris water maze test was performed by the end of medication. The escape latency and times of crossing the platform in the water maze test were recorded during the 1st day to the fifth day. The expressions of GFAP, Abeta, betaAPP, and Caspase-3 in the cortex and hippocampus of the rats in each group were detected by immunohistochemical assay. RESULTS: Compared with the model group, the escape latency from the 3rd day to the 5th day was shortened, the expressions of GFAP, Abeta, betaAPP, and Caspase-3 decreased in the cortex and hippocampus, the times of crossing the platform increased in each medication group, showing statistical difference (P < 0.01, P < 0.05). Compared with the DH group, the expressions of Abeta in the cortex and hippocampus decreased, and the betaAPP expression increased in the QKR group. The expressions of GFAP, betaAPP, and Caspase-3 in the cortex and hippocampus increased in the volatile oil group. The escape latency from the 3rd day to the 5th day was obviously prolonged, and the times of crossing the platform decreased in the volatile oil group, showing statistical difference (P < 0.05, P < 0.01). CONCLUSION: QKR could obviously improve the learning and memory capabilities of AD rats, which might be achieved through decreasing the expressions of GFAP, Abeta, betaAPP, and Caspase-3 in the cortex and hippocampus. PMID- 24063216 TI - [Effects of Danshen injection on glial cell line-derived neurotrophic factor mRNA of acute spinal cord injury rats and its mechanisms]. AB - OBJECTIVE: To observe effects of Danshen Injection (DSI) on glial cell line derived neurotrophic factor (GDNF) in the gray matter of acute spinal cord injury (SCI) rats and to discuss its mechanisms. METHODS: Totally 144 male SD rats were used to prepare the SCI model, and then they were randomly divided into three groups, i.e., the treatment group, the control group, and the SCI group, 48 in each group. Rats in the treatment group were intraperitoneally injected with DSI (at the daily dose of 1.78 mL/ kg), those in the control group were intraperitoneally injected with methylprednisolone (at the dose of 30 mg/kg in 23 h, the 23-h total dose calculated according to 5.4 mg/kg per hour 45 min later; injected in 4 times), but rats in the SCI group were not intervened. Besides, another 48 male SD rats were recruited as the sham-operation group (no injury of their spinal cords). The spinal motor functions were assessed on the first day, the third day, the 7th day, and the 14th day after SCI. Their expressions of GDNF mRNA were detected at the aforesaid time points. RESULTS: The successful rate of modeling was 80.54% in this experiment. Within 14 days after SCI, bleeding, edema, and neuronal necrosis were obviously less in the treatment group than in the SCI group, but with no significant difference when compared with those of the control group. Compared with the sham-operation group at the same time points, the critical angle in the tilt board test was smaller in the SCI group on the first day, the third day, the 7th day, and the 14th day after SCI. The density of GDNF mRNA immunoreactivity was higher in the SCI group than in the sham-operation group at the same time points (P < 0.01). On the 1st day after SCI, the critical angle in the tilt board test was smaller in the treatment group after treatment than before treatment (P < 0.01). The critical angle and the density of GDNF mRNA immunoreactivity were lower in the treatment group than in the control group at the same time points (P < 0.05), but they were higher in the treatment group than in the SCI group at the same time points (P < 0.01). The density of GDNF mRNA immunoreactivity was higher in the treatment group on the 3rd day after SCI than on the 1st day after SCI, and than in the SCI group on the 3rd day after SCI (P < 0.01, P < 0.05). It was lower in the treatment group than in the control group on the 3rd day after SCI (P < 0.05). The critical angle in the tilt board test was higher in the treatment group on the 7th day after SCI than on the 3rd day after SCI, and than the SCL group on the 7th day after SCI (P < 0.01), but lower than the control group (P < 0.05). The density of GDNF mRNA immunoreactivity was higher in the treatment group than in the SCI group on the 7th day after SCI (P < 0.01). The critical angle in the tilt board test was higher in the treatment group on the 14th day after SCI than on the 7th day after SCL (P < 0.01, P < 0.05). The critical angle and the density of GDNF mRNA immunoreactivity were higher in the treatment group than in the SCI group on the 14th day (P < 0.01). CONCLUSIONS: Salvia miltiorrhiza could attenuate edema and bleeding in the gray matter of SCL rats, and improve the microcirculation of the spinal cord, thus elevating the GDNF mRNA expression in the gray matter of acute SCI rats. It was an ideal drug for treating early SCI. PMID- 24063217 TI - [Effect of panax notoginseng powder on pathological features and expressions of VEGF and its receptors of chronic subdural hematoma rabbits: an experimental study]. AB - OBJECTIVE: To observe the effect of Panax notoginseng (PN) on pathological features in chronic subdural hematoma (CSDH) rabbits and its mechanisms. METHODS: A stable pathological animal model similar to CSDH in humans could be established using subdural injections of small number of blood through a subdural pre catheter in rabbits. After successful modeling, 18 rabbits were randomly divided into the model group, the low dose PN group (0.125 g/kg), and the high dose PN group (0.250 g/kg), 6 in each group. Normal saline was given to rabbits in the model group, while PN power was given to those in the PN groups by gastrogavage for 6 successive days. Pathologic features of the hematoma outer membrane were observed by HE staining. The activity of SOD and the content of MDA in the hematoma outer membrane were examined by the colorimetric method. Expressions of CD31, CD34, and VEGF in the hematoma outer membrane were observed by immunohistochemical assay. Expressions of VEGF in the peripheral blood and the subdural hematoma were detected by enzyme-linked immunosorbent assay (ELISA). Expressions of VEGFR-1 and VEGFR-2 in the hematoma outer membrane were detected by Western blot. RESULTS: Compared with the model group, the inflammatory reaction was comparatively lessen and the proliferation of the fibrous tissue was relatively mature in the low and high dose PN groups. The activity of SOD increased (P < 0.05); expressions of CD31 and CD34 were reduced (P < 0.01); VEGF expression in the residual hematoma fluid decreased (P < 0.05) in the high dose PN group. Expressions of VEGF and VEGFR-2 were all reduced in the high and low dose PN groups (P < 0. 05, P < 0.01). Compared with the low dose PN group, expressions of CD31 and CD34 were reduced (P < 0.01), and the VEGFR-2 expression was also reduced (P < 0.05) in the high dose PN group. CONCLUSIONS: PN could promote the fibrous repairing of subdural hematoma in CSDH rabbits. It also lessened inflammation and oxidative injury of the hematoma outer membrane and reduced expressions of VEGF. The pathological angiogenesis could be reduced through influencing VEGFR-2 receptor pathways, which might be an important mechanism. PMID- 24063218 TI - [Effect of PNS on the activity and content of BACE1 in the brain of SAMP8 mice with Alzheimer's disease]. AB - OBJECTIVE: To explore the effect of Panax notoginseng saponin (PNS) on the activity and content of beta-secretase in the brain of senescence accelerated mouse-prone 8 (SAMP8) mice with Alzheimer's disease. METHODS: Totally 32 SAMP8 mice were randomly divided into the normal control group, the high dose PNS group (200 mg/kg), the low dose group (100 mg/kg), and the huperzine A group (0.3 mg/kg), 8 in each group. Equal volume of double distilled water was given to those in the normal control group. All medication was given by gastrogavage, once daily for two successive months. The activity of BACE1 was assayed by direct immunofluorescent method (DIF). The content of BACE1 protein was detected by Western blot. RESULTS: The relative fluorescence units (RFU/microg) was 2.008 +/- 0.031 in the high dose PNS group, 2.221 +/- 0.029 in the low dose PNS group, and 2.267 +/- 0.076 in the huperzine A group, all lower than that in the normal control group (2.403 +/- 0.058; all P < 0.01). The content of BACE1 protein was 0.900 +/- 0.028 in the high dose PNS group, 1.000 +/- 0.032 in the low dose PNS group, and 0.837 +/- 0.080 in the huperzine A group, all lower than that in the normal control group (2.210 +/- 0.074, all P < 0.01). CONCLUSION: PNS higher than 100 mg/kg could decrease the activity of BACE1 and down-regulate the content of BACE1 protein in the brain of SAMP8 mice. PMID- 24063219 TI - [Effect of changji'an capsule on mRNA expressions of NPY and ACTH contents in brain-gut axis of IBS-D model rats]. AB - OBJECTIVE: To explore the effect of Changji'an Capsule (CA) on mRNA expressions of neuropeptide Y (NPY) in the hypothalamus and colon and serum levels of adreno cortico-tropic hormone (ACTH) in rats of diarrhea predominant irritable bowel syndrome (IBS-D) model rats. METHODS: Totally 48 SD rats were randomly divided into six groups, i.e., the normal control group, the model group, the Pinaverium Bromide group (PB, 0.018 g/kg), the high dose CA group (2.812 g/kg), the medium dose CA group (1.406 g/kg), and the low dose CA group (0.703 g/kg), 8 in each group. The IBS-D rat model was established by using separation of breast milk + stimulation of acetic acid + constraint of four limbs. Normal saline was given to rats in the normal control group and the model group. All medication lasted for 14 successive days by gastrogavage. The serum content of ACTH was detected by enzyme linked immunosorbent assay (ELISA). The expressions of NPY mRNA in the colon and the hypothalamus were detected using real-time fluorescence quantitative PCR. RESULTS: Compared with the normal control group, the serum ACTH content significantly increased (P < 0.01), the NPY mRNA expression in the colon and the hypothalamus obviously decreased (P < 0.01) in the model control group. Compared with the model group, the serum ACTH obviously decreased in the high dose CA group, the medium dose CA group, and the PB group (P < 0.01, P < 0.05). The NPY mRNA expression in the colon and the hypothalamus were obviously up regulated in the high dose CA group, the medium dose CA group, the low dose CA group, and the PB group (P < 0.05). CONCLUSIONS: CA could modulate the abnormity of brain-gut axis of IBS-D rats possibly by up-regulating NPY mRNA expressions in the hypothalamus and the colon and down-regulating the ACTH content in the hypothalamic-pituitary-adrenal axis. PMID- 24063220 TI - [Study on mRNA and protein expressions of organic anion transporting polypeptide (oatp2b1) in rats with high fat diet and overstrain induced Pi deficiency syndrome]. AB - OBJECTIVE: To explore roles of mRNA and protein expressions of organic anion transporting polypeptide (oatp2b1) of rats with high fat diet and overstrain induced Pi deficiency syndrome in the transporting of damp turbidity. METHODS: Totally 24 SD rats were randomly divided into three groups, i.e., the normal group, the overstrain group, and the high fat diet group, 8 in each group. After successful modeling, one piece of tissues such as spleen, kidney, liver, lung, stomach, small intestine, and large intestine was taken from each rat. Rats of the overstrain group were bonded by specially made bondage cylinder, 3 h each time on odd days, and forced to swim in cold water (10 +/- 1) degrees C for 7 min on even days alternatively for twelve weeks. Rats in the model group and the normal group were fed with standard routine granular forage for 12 weeks. Rats in the high fat diet group were fed with high fat forage for twelve weeks. All rats drank and ate freely. The mRNA and protein expressions of oatp2b1 were detected in the seven tissues using RT-PCR and Western blot. RESULTS: The mRNA expression of oatp2b1 in liver and kidney tissues of rats in the high fat diet group was higher when compared with that of the normal group and the overstrain group (P < 0.01, P < 0.05). The oatp2b1 mRNA expression in the normal group was sequenced from high to low as liver > lung > spleen > larger intestine > small intestine > kidney > stomach. The oatp2b1 mRNA expression in the overstrain group was sequenced from high to low as liver > lung > larger intestine > spleen > kidney > stomach > small intestine. The oatp2b1 mRNA expression in the high fat diet group was sequenced from high to low as liver > lung > spleen > small intestine > kidney > larger intestine > stomach. The oatp2b1 protein expression in the lung tissue was sequenced from high to low as the overstrain group > the normal group > the high fat diet group (P > 0.05). The oatp2b1 protein expression in the spleen tissue was sequenced from high to low as the high fat diet group > the normal group > the overstrain group (P > 0.05). The oatp2b1 protein expression in the kidney tissue was sequenced from high to low as the normal group > the overstrain group > the high fat diet group (P > 0.05). The oatp2b1 protein expression in the liver tissue was sequenced from high to low as the normal group > the high fat diet group > the overstrain group (P > 0.05). Of them, the oatp2b1 protein expressed extremely less in the stomach, large intestine, and small intestine. The oatp2b1 protein expression in the normal group was sequenced from high to low as lung >spleen > liver, kidney > stomach, larger intestine, and small intestine. The oatp2b1 protein expression in the overstrain group was sequenced from high to low as lung > spleen > kidney > liver > stomach, larger intestine, and small intestine. The oatp2b1 protein expression in the high fat diet group was sequenced from high to low as spleen > lung > kidney > liver > stomach, larger intestine, and small intestine. However, there was no statistical significance among the three groups by pair-wise comparison (P > 0.05). CONCLUSIONS: Kidney and liver might play important roles in the transportation and transformation of damp under the state of Pi deficiency syndrome. Oatp2b1 may be one of the material bases involved in the transportation and transformation of damp turbidity. Pi's function of governing transportation and transformation of damp might not only include the functions of the gastrointestinal tract, but also include partial liver and kidney functions. PMID- 24063221 TI - [Effect of acupuncture on serum MIP-2 and MIP-2 mRNA expressions in isolated Fei and Dachang of severe acute pancreatitis induced acute lung injury rats in the acute phase]. AB - OBJECTIVE: To observe effect of acupuncture on serum macrophage inflammatory protein-2 (MIP-2) and MIP-2 mRNA expressions in isolated Fei and Dachang of severe acute pancreatitis (SAP) induced acute lung injury (ALI) rats in the acute phase. METHODS: Forty male Wistar rats were randomly divided into four groups, i.e., the sham-operation group, the SAP group, the acupuncture treatment group, and the acupuncture control group, 10 in each group. The SAP model was induced by retrograde infusion of 3.5% sodium taurocholate into the pancreatobiliary duct. Under the guidance of "Fei and Dachang exterior-inferiorly related", points were acupunctured along Fei, Dachang, and Pi channels, as well as those points on the back of rats in the acupuncture treatment group 0.5 h after modeling. Besides, points were acupunctured along Fei and Pi channels, as well as those points on the back of rats in the acupuncture control group 0.5 h after modeling. Serum levels of tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO), and MIP 2 expressions were examined 6 h after modeling. Expressions of MIP-2 mRNA in isolated lung and large intestine tissues were detected by reverse transcription PCR. RESULTS: Compared with the sham-operation group, serum levels of TNF-alpha and NO, and expressions of MIP-2 and MIP-2 mRNA in isolated lung and large intestine tissues were significantly higher in the SAP group (P < 0.05). Each index was lower in the acupuncture treatment group than in the SAP group and the acupuncture control group (P < 0.05). Besides, the serum level of MIP-2 and the MIP-2 mRNA expression in isolated lung and large intestine tissues were positively correlated in all groups except the sham-operation group (P < 0.05). CONCLUSIONS: Under the guidance of "Fei and Dachang exterior-inferiorly related", acupuncture could remarkably reduce the severity of SAP induced ALI rats in the acute phase. Its mechanism might be related to suppressing over-expressions of MIP-2 mRNA in isolated lung and large intestine tissues, and lowering the serum MIP-2 expression level. PMID- 24063222 TI - [Effect of buqi tongluo jiedu recipe on HIC1 methylation level of pancreatic cancer model mice]. AB - OBJECTIVE: To observe the effect of Buqi Tongluo Jiedu Recipe (BTJR) on HIC1 methylation of pancreatic cancer mouse model. METHODS: Totally 30 nude mice were randomly divided into the normal group, the model group, and the treatment group, 10 in each group. The model was induced by cancer cell subcutaneous planting method. Mice in the treatment group were administered with BTJR (60 g crude drugs/kg, 3 mL/100 g) by gastrogavage. Equal volume of normal saline was given to those in the normal group and the model group by gastrogavage. All the intervention lasted for 14 successive days. The mice were sacrificed to death. Their tumor tissues were taken out. The HIC1 gene methylation level of each specimen was detected by nested methylation-specific polymerase chain reaction (N MSP) method. RESULTS: Compared with the model group, the HIC1 gene methylation level was lower in the treatment group (P < 0.01). Compared with the model, the HIC1 gene methylation level was even lower in the normal group (P < 0.01). CONCLUSION: BTJR could reduce HIC1 gene methylation degree of model mice, thus playing a role of molecular biologic effect in treating pancreatic cancer. PMID- 24063223 TI - [Effect of jingui shenqi pill and its disassembled recipes on ovarian functions in shen yang deficiency female rats]. AB - OBJECTIVE: To observe the effect of Jingui Shenqi Pill (JSP) and its disassembled recipes (supplementing Shen yang, supplementing Shen yin, and supplementing Shen yang and Shen yin) on ovarian functions of female rats of Shen yang deficiency syndrome (SYDS). METHODS: Totally 55 SD female rats were randomly divided into 5 groups, i.e., the normal control group, the model group, the Shen yang supplementing group, the Shen yin supplementing group, the Shen yang and Shen yin supplementing group, 11 in each group. Except the normal control group, rats in the rest group were injected with hydrocortisone at the daily dose of 25 mg/kg at the muscle of femoribus internus for 12 successive days. From the 13th day after successful modeling, rats were administered by gastrogavage with different recipes at the dose of 1 mL/100 g (2.75 g/kg Shen yang supplementing recipe; 6.25 g/kg Shen yin supplementing recipe; 6.75 g/kg JSP), once daily for 20 successive days. Equal volume of normal saline was given to those in the normal control group and the model group, once daily for 20 successive days. Blood was withdrawn from the orbit on the 2nd day after intervention. The serum estradiol (E2) and progesterone (P) were detected using ELISA. The weight of uterus and ovarian index (VI) were calculated. The pathological changes were observed by HE staining. RESULTS: The general condition of rats in the Shen yang and Shen yin supplementing group were improved. The body weight (g) was added by 35.0 +/- 12.5 in the normal control group, 16.7 +/- 7.4 in the model group, 20.2 +/- 6.9 in the Shen yang supplementing group, 18.3 +/- 3.6 in the Shen yin supplementing group, and 29.4 +/- 12.2 in the Shen yang and Shen yin supplementing group. The uterus VI (mg/100 g) was 183.4 +/- 11.6 in the normal control group,144.0 +/- 6.5 in the model group,158.7 +/- 6.3 in the Shen yang supplementing group,152.1 +/- 6.9 in the Shen yin supplementing group, and 172.8 +/- 8.1 in the Shen yang and Shen yin supplementing group. The ovarian VI (mg/100 g) were 32.9 +/- 2.4 in the normal control group, 22.6 +/- 1.1 in the model group, 25.0 +/- 1.4 in the Shen yang supplementing group, 23.0 +/- 0.4 in the Shen yin supplementing group, and 31.4 +/- 3.3 in the Shen yang and Shen yin supplementing group. Compared with the model group, the body weight and ovarian VI increased in the Shen yang supplementing group and the Shen yang and Shen yin supplementing group (P < 0.05, P < 0.01). The uterus VI increased in each medicated group (P < 0.05, P < 0.01). Compared with the Shen yang supplementing group and the Shen yin supplementing group, all indices increased in the Shen yang and Shen yin supplementing group (P < 0.05, P < 0.01). The E2 and P levels increased in the Shen yang supplementing group and the Shen yang and Shen yin supplementing group (P < 0.05, P < 0.01). The content of E2 (pg/mL) was 22.1 +/- 9.4 in the normal control group, 9.8 +/- 3.0 in the model group, 11.3 +/- 2.2 in the Shen yang supplementing group, 10.5 +/- 0.8 in the Shen yin supplementing group, and 16.0 +/- 5.5 in the Shen yang and Shen yin supplementing group. The content of P (ng/mL) was 14.6 +/- 7.5 in the normal control group, 4.3 +/- 1.8 in the model group, 8.3 +/- 2.8 in the Shen yang supplementing group, 5.9 +/- 2.9 in the Shen yin supplementing group, and 9.5 +/- 3.4 in the Shen yang and Shen yin supplementing group. Compared with the Shen yang supplementing group and the Shen yin supplementing group, the E2 level increased in the Shen yang and Shen yin supplementing group (P < 0.05, P < 0.01). Compared with the Shen yin supplementing group, the P level increased in the Shen yang and Shen yin supplementing group (P < 0.05). Compared with the model group, the ovarian follicle at each stage increased and pathological follicular ovarian follicles decreased in the Shen yang and Shen yin supplementing group (P < 0.01). Less primary follicles, secondary follicles, and mature follicles could be seen in the Shen yang supplementing group and the Shen yin supplementing group. The total numbers of all-level follicles were obviously higher in the Shen yang and Shen yin supplementing group than in the Shen yang supplementing group and the Shen yin supplementing group (P < 0.05). The number of pathological follicles was obviously less in the Shen yang and Shen yin supplementing group than in the Shen yin supplementing group (P < 0.05). CONCLUSIONS: As for SYDS, JSP and its dissembled recipes could improve damaged ovarian functions to some degree. But better effect could not be obtained by Shen yang supplementing method or Shen yin supplementing method alone. Shen yang and Shen yin supplementing method could elevate the efficacy. PMID- 24063224 TI - [Effect of Curcuma aromatica on epithelial-myofibroblast transdifferentiation of NRK-52E cells induced by TGF-beta1]. AB - OBJECTIVE: To observe the antagonist effect of Curcuma Aromatica (CA) on renal tubular epithelial-myofibroblast transdifferentiation (EMT) induced by transforming growth factor-beta1 (TGF-beta1). METHODS: Normal renal tubular epithelial NRK-52E cells in vitro cultured were randomly divided into 6 groups, i.e., the normal control group (Group C), the TGF-beta1 induced model group (Group T), the low dose CA treated group (Group E1), the moderate dose CA treated group (Group E2), the high dose CA group (Group E3), and the Benazepril Hydrochloride Tablet treated group (Group Y). Except Group C, corresponding medication (with an action of 48 h) was administered to cells in the rest groups after they were induced by TGF-beta1 for 24 h. The morphological changes were observed by inverted phase contrast microscope. The distribution of beta-actin protein was detected by immunohistochemical assay. The mRNA expressions of alpha smooth muscle actin (alpha-SMA) and E-cadherin (E-cad) were detected by real-time PCR. The concentration of fibronectin (FN) was detected by ELISA. RESULTS: After induced by TGF-beta1 for three days, hypertrophy and elongated cells in fusiform shape occurred,with increased expressions of beta-actin protein in the cytoskeletal structure (P < 0.05), bundle fibrous structure occurred inside cytoplasm with significantly up-regulated intracellular alpha-SMA mRNA expressions (P < 0.05), E-cad mRNA expression decreased (P < 0.05), the FN content in the supernate increased (P < 0.05) in Group T. Compared with Group T, partial cells in Group E1, E2, and E3 showed fibrous changes, accompanied with decreased expression of beta-actin protein and FN concentration (P < 0.05). The expression of alpha-SMA mRNA increased and the expression E-cad mRNA decreased in Group E2 and E3 (both P < 0.05). But there was no statistical difference in the expression levels of E-cad and alpha-SMA mRNA (P > 0.05). Compared with Group E1, the expression of beta-actin protein and FN concentration decreased in Group E2 and E3 (P < 0.05). The expressions of alpha-SMA mRNA decreased and E-cad mRNA increased in Group E3 (P < 0.05). Compared with Group Y, the expression of beta actin mRNA and FN concentration increased in Group E1 (P < 0.05); the expression of beta-actin mRNA increased in Group E3 (P < 0.05); the expression of E-cad mRNA decreased in Group E3 (P < 0.05). There was no statistical difference in the expression of alpha-SMA mRNA among Group E1, E2, and E3 (P > 0.05). CONCLUSION: CA could inhibit the occurrence of TGF-beta1 induced EMT, which could be used as an effective drug for treating chronic renal insufficiency. PMID- 24063225 TI - [Synergistic effect of beta-elemene injection combined paclitaxel injection on human breast cancer MB-468 cells: an in vitro study]. AB - OBJECTIVE: To observe the synergistic effect of beta-elemene Injection (betaI) combined Paclitaxel Injection (PI) on breast cancer MB-468 cells and to study possible mechanisms. METHODS: Breast cancer MB-468 cells were treated with betaI (2.5, 5.0, 10.0, 20.0, 40.0, 80.0, 160.0, 320.0, and 640.0 microg/mL), PI (0.00100, 0.00200, 0.00400, 0.00800, 0.01600, 0.03125, 0.06250, 0.12500, and 0.25000 microg/mL), and betaI combined PI for 24 h and 48 h respectively. Cell proliferation was determined using SRB assay. Cell apoptosis and cell cycle phase distribution were detected using flow cytometry. The post-intervention expressions of cell cycle proteins [cyclin-dependent kinase (CDK1), cyclin-B1, P21(cip1), and P27(kip1)] were detected by Western blot. RESULTS: Beta-elemene or paclitaxel inhibited the growth of MB-468 cell line. The IC50 and IC20 values treated with beta-elemene for 24 h were 34.20 and 52.59 microg/mL and for 48 h were 10.15 and 17.81 microg/mL respectively, while the IC50 values treated with paclitaxel for 24 h and 48 h were 2.449 and 1.698 microg/mL respectively. Beta elemene (20 and 40 microg/mL respectively) and Paclitaxel (0.016 and 0.008 microg/mL respectively) synergistically inhibited cell proliferation of MB-468 cells, with Q value > 1.15. Beta-elemene alone (52.59 microg/mL) apparently decreased the expression of cyclin-B1 protein. The expression of cyclin-B1 protein in the combined group was also lower than that in the PI group (1.698 microg/mL). The expression of P27(kip1) was up-regulated when compared with that in the betaI group or the PI group. CONCLUSION: Beta-elemene had synergistic effect with Paclitaxel, and its possible mechanism might be correlated with down regulating the cell cycle protein cyclin-B1 expression and up-regulating the P27(kip1) expression. PMID- 24063226 TI - [The application of "preventive treatment theory" in chronic airway inflammatory disease]. AB - Bronchial asthma and chronic obstructive pulmonary disease (COPD), as chronic airway inflammatory diseases, seriously threaten the health of human beings. Chinese medicine has obvious advantages in prevention and treatment of them. "Preventive treatment theory" is a sort summarization of preventive medicine in Chinese medicine. The theory is not only reflected at the disease prevention levels, also embodied in the active treatment and the rehabilitation process. It was especially deep and colorfully embodied in the prevention and treatment of chronic airway inflammatory diseases such as asthma and COPD. In this paper,clarified were the prevention and treatment targets, ways of thinking and methods in different stages of asthma and COPD from various viewpoints including prevention before disease occurrence, treating disease at disease onset, preventing the aggravation once disease occurs, and consolidation after disease occurs. We hope to improve ways of thinking and prevention and treatment levels of bronchial asthma and COPD by Chinese medicine. PMID- 24063227 TI - [The spinous process tenderness syndrome--a new naming of a series of common symptoms]. AB - The rheumatoid activity on any part of the spine may affect the surrounding nerves, causing a series of symptoms at the related region of the innervations. By pressing corresponding parts on spinous processes of patient spine, tenderness of various degrees occurs. We named this kind of symptoms as "the spinous process tenderness syndrome". Meanwhile, we borrowed laboratory and imaging examinations to diagnose and differential identify. The symptoms could be alleviated by eliminating pathogenic reasons, local resting, and anti-rheumatic drugs. PMID- 24063228 TI - [Empirical research on translation strategy of Chinese prescription nomenclature]. PMID- 24063229 TI - [Advance of Chinese medical blood stasis syndrome and TIMI risk stratification on unstable angina pectoris]. PMID- 24063230 TI - [Advance of heat-clearing recipe, blood-activating recipe, heat-clearing and blood-activating recipe in intervening COPD]. PMID- 24063231 TI - [Applications of elementary mode analysis in biological network and pathway analysis]. AB - Elementary mode analysis is the widely applied tool in metabolic pathway analysis. Studies based on elementary mode analysis (EMA) were performed for both metabolic network and signal transduction network. Its analytical objective is from cell to bioreactor, and even ecological system. EMA is available to describe biological behaviors by steady state and dynamic models. Not only microorganism metabolism but also human health could be evaluated by EMA. The algorithms and software for calculating elementary mode (EM) were analyzed. The applications of EMA are reviewed such as special metabolic pathway and robustness of metabolic network, metabolic flux decomposition, metabolic flux analysis at steady state, dynamic model and bioprocess simulation, network structure and regulation, strain design and signal transduction network. Solving combinatorial explosion, exploring the relations between EM and metabolic regulation, and improving the algorithm efficiency of strain design are important issues of EMA in future. PMID- 24063232 TI - [Porcine VHL gene cloning and construction of VHL knockdown cloned embryos]. AB - Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder and its clinical manifestation including haemangioblastomas of the central nervous system, renal cell carcinoma, haeochromocytomas, and pancreatic cyst. The deletion, mutation and promoter methylation of VHL gene can cause VHL disease. Swine is considered as an ideal model for human disease because of its physiological and anatomical similarity to human. We cloned pig VHL gene that is 2 725 bp in length. VHL highly expressed in adrenal gland, liver, pancreas, heart and testis. We designed 5 shRNAs and screened the most effective interference RNA fragment with a knockdown efficiency of 72%. Porcine embryonic fibroblasts stably transfected with pGenesil-shRNA vector were used as donor cells for nuclear transfer and there was no significant difference of embryo development compared with the control group. Moreover, VHL was efficiently knocked-down with efficiency of 71% in porcine cloned blastocyst, these results lay a solid foundation for constructing the VHL knock-down model of pig. PMID- 24063233 TI - [Growth and mutation of Escherichia coli with suicide gene circuit based on quorum sensing]. AB - Constructing robust gene circuits is a fundamental work for synthetic biology. Bacteria with suicide gene circuit based on quorum-sensing will kill themselves in a controllable pattern upon certain cell density. In the media of different IPTG inducer concentration, we observed the growth and suicidal behavior of the Escherichia coli. Top10F' with such gene circuit, screened the mutants and determined their mutated loci. The results show that, with higher IPTG concentration, the more wild type bacteria were killed; as well the mutants emerged earlier and spread over the population more quickly. The sequence of plasmids in those mutants revealed that a transposon inserted into the luxR gene and therefore disrupted Quorum-Sensing of these individuals. Furthermore, the insertion sequence of the plasmid can solely result in the mutants escaping from suicide. PMID- 24063234 TI - [Proteomic analysis of Bacillus subtilis 168 transforming cis-propenylphosphonic acid to fosfomycin]. AB - In this study, we investigated the mechanism of transformation by Bacillus subtilis strain 168 by proteomic analysis. B. subtilis strain 168 was able to stereoselectively transform cis-propenylphosphonic acid (cPPA) to fosfomycin. The maximal fosfomycin production was 816.6 microg/mL after two days cultivation, with a conversion rate of 36.05%. We separated the whole cellular proteins by two dimensional gel electrophoresis (2-DE) method, and 562 protein spots were detected in the presence of cPPA in the medium, while 527 protein spots were detected in the absence of cPPA. Of them, 98 differentially expressed protein spots were found. Among them, 52 proteins were up-regulated whereas 20 were down regulated in the presence of cPPA in the medium, and 26 induced at the presence of cPPA. The differentially expressed proteins were analyzed by combined MS and MS/MS methods. Eighty protein spots, including 45 up-regulated proteins, 17 down regulated proteins, and 18 induced by cPPA were identified. Based on the results of proteomic analysis, we postulated two steps of transformation: in the first step, cPPA was hydrated to 2-hydroxypropylphosphonic acid; in the second step, 2 hydroxypropylphosphonic acid was transformed to fosfomycin via a dehydrogenation reaction. PMID- 24063235 TI - [Regulation of isoprenoid pathway for enhanced production of linalool in Saccharomyces cerevisiae]. AB - Linalool is an important monoterpene, and widely used in food, pharmaceutical and cosmetic industry. The low concentration in plants and the difficulties in extraction restrict its large scale production. Saccharomyces cerevisiae can provide the monoterpene precursor, geranyl diphosphate (GPP) through its endogenous isoprenoid pathway. Therefore, it could be used as the host for monoterpene production. However, the weak metabolic flux through the isoprenoid pathway leads to the insufficient supply of GPP, and results in low monoterpene productivity. In order to increase the metabolic flux, we constructed the integrated expression plasmid pRS305-tHMG1 and free expression plasmid pYLIS-IDI1 to enhance the expression levels of isopentenyl diphosphate isomerase (IDI1) and a truncated 3-hydroxyl-3-methylglutaryl-CoA reductase gene (tHMG1). The two plasmids were separately transformed into S. cerevisiae CEN.PK2-1C, resulting in strains LS01 and LS02. The plasmid pYLIS-IDI1 was further transformed into strain LS01, resulting in strain LS03. GC-MS analysis showed that the linalool concentration was increased by 1.3 times and reached (127.71 +/- 7.68) microg/L. In conclusion, enhancement of the supply of GPP precursors through the regulation of isoprenoid pathway could increase the linalool production in S. cerevisiae. PMID- 24063236 TI - [Construction of synthetic promoters for Escherichia coli and application in the biosynthesis of cis,cis-muconic acid]. AB - Promoter is one of important elements for gene expression and regulation. In the construction of recombinants for metabolic engineering and synthetic biology, it is necessary to have the promoters with varying strengths for fine-tuning metabolic pathway to reach the metabolic balance, decrease the accumulation of intermediate and increase the production of target metabolite. However, the natural promoters available are not completely suitable for fine-tuning metabolic pathway due to discrete strength, lack of versatility and standardization. To deal with this problem, in this study, a new 88 bp synthetic promoter, which contains the typical -35 box, -10 box as well as ribosome bind site, was designed. Then, the promoter library was constructed by introducing some degenerate base pairs in the sequence of 6 bp in the upstream of the initial transcription site and 14 bp in spacer region between -35 and -10 box. 720 promoters with varying strengths were screened out from a library of more than 5 000 clones via the expression of red fluorescent protein mCherry under the control of the synthetic promoter. The sequence analysis based on 35 promoters with varying strengths showed the promoters with varying strengths are base preference. The purine bases in -13 site and pyrimidine bases in the transcriptional initiation sequence are of high frequency; the purine and pyrimidine bases are of the similar frequency in the spacer sequence between -35 and -10 box in strong promoter. In the end, five characterized promoters with varying strengths were selected to tune the synthetic pathway of cis,cis-muconic acid in Escherichia coli. The results showed that the promoters with varying strengths can regulate the production of cis,cis-muconic acid and the accumulation of the intermediate catechol. PMID- 24063237 TI - [Recombinant expression, purification and characterization of a novel DyP-type peroxidase in Escherichia coli]. AB - Dye-decolorizing peroxidase (DyP-type peroxidase) represents a group of heme containing peroxidases able to decolour various organic dyes, most of which are xenobiotics. To identify and characterize a new DyP-type peroxidase (ZmDyP) from Zymomonas mobilis ZM4 (ATCC 31821), ZmDyP was amplified from the genomic DNA of Z. mobilis by PCR, and cloned into the Escherichia coli expression vector pET 21b(+). Alignment of the amino acid sequence of ZmDyP with other members of the DyP-type peroxidases revealed the presence of the active site conserved residues D149, R239, T254, F256 as well as the typical GXXDG motif, indicating that ZmDyP is a new member of the Dyp-type peroxidase family. pET-21b(+) containing ZmDyP gene was expressed in E. coli by IPTG induction. The expressed enzyme was purified by Ni-Chelating chromatography. SDS-PAGE analysis of the purified enzyme revealed a molecular weight of 36 kDa, whereas activity staining gave a molecular weight of 108 kDa, suggesting that the enzyme could be a trimer. In addition, ZmDyP is a heme-containing enzyme as shown by a typical heme absorption peak of Soret band. Moreover, ZmDyP showed high catalytic efficiency with 2, 2'-Azinobis (3-ethylbenzthiazoline-6-sulphonate) as a substrate. These results enrich the pool of DyP-type peroxidases and lay a foundation for further studies. PMID- 24063238 TI - [Identification and expression analysis of WRKY transcription factors in medicinal plant Catharanthus roseus]. AB - WRKY transcription factors, one of the largest families of transcriptional regulators in plants, involve in multiple life activities including plant growth and development as well as stress responses. However, little is known about the types and functions of WRKY transcription factors in Catharanthus roseus, an important medicinal plant. In this study, we identified 47 CrWRKY transcriptional factors from 26 009 proteins in Catharanthus roseus, and classified them into three distinct groups (G1, G2 and G3) according to the structure of WRKY domain and evolution of the protein family. The expression profiling showed that these CrWRKY genes expressed in a tissue/organ specific manner. The 47 CrWRKY genes were clustered into three types of expression patterns. The first type includes the CrWRKYs highly expressed in flowers and the protoplast treated with methy jasmonate (MeJA) or yeast extraction (YE). The second type contains the CrWRKYs highly expressed in stem and hairy root. The third type represents the CrWRKYs highly expressed in root, stem, leaf, seedling and the hairy root treated by MeJA. Real time quantitative PCR was employed to further identify the expression patterns of the 16 selected CrWRKY genes in various organs, the MeJA-treated protoplasts and hairy roots of Catharanthus roseus, and similar results were obtained. Notably, the expresion of more than 1/3 CrWRKY genes were regulated by MeJA or YE, indicating that these CrWRKYs are likely involed in the signalling webs which modulate the biosynthesis of terpenoid indole alkaloid and plant responses to various stresses. The present results provide a framework for functional identification of the CrWRKYs and understanding of the regulation network of terpenoid indole alkaloid biosynthesis in Catharanthus roseus. PMID- 24063239 TI - [Enhanced SEC2 mutants and their superantigen activities]. AB - As a superantigen protein, Staphylococcal enterotoxin C2 (SEC2) activates the immune system effectively even in extremely low concentrations, and this property could be applied in adjuvant therapy against tumors and infectious diseases. In order to enhance the superantigen activity of SEC2, the residues at position 102 106 of native SEC2 were substituted for WWH, WWT and WWP by over-lap PCR, and three mutants named ST-1, ST-2 and ST-3 were obtained. Stimulating activity to murine lymphocytes proliferation and inhibiting activity to tumor cell growth of the three mutants were significantly improved compared with the native SEC2. Febrile activities of ST-1 and ST-3 were comparable with the native SEC2, but ST 2 showed markedly increased febrile activity than native SEC2. Moreover, the levels of IL-2, IFN-gamma and TNF-alpha secreted by T cells stimulated with the three mutants were significantly improved, which might be the possible reason for enhanced tumor cell growth inhibition activities. Furthermore, mVbeta8.2 gene transcription levels of murine splenocytes stimulated by the three mutants were dramatically increased compared with native SEC2, suggesting their increased affinities to TCR mVbeta8.2 molecular, which might be the main reason for their enhanced superantigen activities. PMID- 24063240 TI - [DNA prime followed by protein boost enhances the protective efficacy against Schistosoma japonicum infection in mice]. AB - Schistosomiasis japonica is an endemic, zoonotic disease of major public health importance in China. Vaccination is needed as a complementary approach to the ongoing control programs. In the present study, we determined if the efficacies of DNA vaccine encoding the SjGST and Sj32 asparaginyl endopeptidase protein could be enhanced by boosting with SjGST-32 protein vaccines. Mice were inoculated with a VR1012-SjGST-32 DNA vaccine followed by boosting with rSjGST-32 at 0, 14 and 28 d. Two weeks after the final boost, mice were challenged percutaneously with cercariae. On day 45 following the challenge, all mice were sacrificed and the numbers of recovered worms and hepatic eggs were counted. Moreover, we analyzed the immune response among various vaccination groups. The results showed that DNA vaccine efficacy was enhanced when mice were boosted with protein vaccine. Adult worm and liver egg burdens were reduced 42.3% and 59.6%, respectively. We further found that DNA vaccine followed by boosting with protein significantly increased the IgG titer and T cell proliferation over those seen in mice vaccinated solely with DNA vaccines. Furthermore, the higher level of IFN gamma expression in the splenetic CD4+ T cell showed that DNA prime-Protein boosting vaccine induced CD4+ Th1-type responses. Thus, DNA vaccine efficacy was significantly enhanced via boosting protein vaccine which might provide a basis for rational application of the Schistosoma vaccine. PMID- 24063241 TI - [Key aromatic amino acids of anti-hepatoma activity on Parasporin-2]. AB - Nine mutants (P2M1-9) were obtained using PCR with 5-BU based on DNA template (P2Y) encoding the active region of Parasporin-2. Mutant proteins were purified after expressing in E. coli BL21 cells, followed by assayed against hepatoma cells and normal liver cells by MTT. They showed diverse anti-hepatoma activities, in which two mutant proteins, P2M1 and P2M8, exhibited high cytotoxicity against hepatoma cell lines SMMC7721 and Be17402, meanwhile leaving normal liver cells Chang-liver unaffected. Structural comparison among P2Y, P2M1 and P2M8 showed that the length of beta-sheet or beta-fold, and the amount of alpha helix greatly affected the anti-hepatoma activity of Parasporin-2. Results based on amino acid alignment, molecular docking between P2Y, P2M1 or P2M8 and receptor, and mimic mutation demonstrated that amino acid residues at the sites of 52, 56, 58 and 208 on P2Y, especially the aromatic amino acids such as Trp, Phe, and Tyr were involved in the interactions. PMID- 24063242 TI - [Expression optimization and characterization of Tenebrio molitor antimicrobiol peptides TmAMP1m in Escherichia coli]. AB - To improve the expression level of tmAMP1m gene from Tenebrio molitor in Escherichia coli, we studied the effects of expression level and activity of the fusion protein HIS-TmAMP1m by conditions, such as culture temperature, inducing time and the final concentration of inductor Isopropyl beta-D thiogalactopyranoside (IPTG). We analyzed the optimum expression conditions by Tricine-SDS-PAGE electrophoresis, meanwhile, detected its antibacterial activity by using agarose cavity diffusion method. The results suggest that when inducing the recombinant plasmid with a final IPTG concentration of 0.1 mmol/L at 37 degrees C for 4 h, there was the highest expression level of fusion protein HIS TmAMP1m in Escherichia coli. Under these conditions, the expression of fusion protein accounted for 40% of the total cell lysate with the best antibacterial activity. We purified the fusion protein HIS-TmAMPlm with nickel-nitrilotriacetic acid (Ni-NTA) metal-affinity chromatography matrices. Western blotting analysis indicates that the His monoclonal antibody could be specifically bound to fusion protein HIS-TmAMPlm. After expression by inducing, the fusion protein could inhibit the growth of host cell transformed by pET30a-tmAMP1m. The fusion protein HIS-TmAMP1m had better stability and remained higher antibacterial activities when incubated at 100 degrees C for 10 h, repeated freeze thawing at -20 degrees C, dissolved in strong acid and alkali, or treated by organic solvents and protease. Moreover, the minimum inhibitory concentration results demonstrated that the fusion protein HIS-TmAMP1m has a good antibacterial activity against Staphylococcus aureus, Staphylococcus sp., Corynebacterium glutamicum, Bacillus thuringiensis, Corynebacterium sp. This study laid the foundation to promote the application of insect antimicrobial peptides and further research. PMID- 24063243 TI - [Screening and condition optimization of a strain for efficiently biotransformation of saponins in Dioscorea zingiberensis into diosgenin]. AB - Diosgenin is an important raw material in steroid hormone and widely used in pharmaceutical industry. The traditional method for diosgenin production is acidolysis, which causes serious pollution. In order to obtain a cleaner and more efficient approach of diosgenin production, a strain of Gibberella intermedia WX12 (the sexual stage of Fusarium proliferatum) was screened from the strains deposited in our laboratory. This strain converted saponins in Dioscorea zingiberensis C.H. Wright (DZW) into diosgenin. The conversion medium was optimized by statistical experimental design. The optimized conversion medium was as follows (g/L): glucose 20.6, yeast extract 5.0, NaCl 1, K2PO4 3, ZnSO4 x 7H2O 1.5 and saponins 3. Under the optimal conditions, the yield of diosgenin achieved to (31 +/- 0.3) mg/g DZW, which was 3 times higher than that of the original medium. PMID- 24063244 TI - [Cloning, expression of phospholipase A1 from Serratia liquefaciens and auto induction fermentation by lactose]. AB - To produce recombinant phospholipase A(1) (PLA(1)) by Escherichian coli, the pla gene encoding PLA(1) was amplified from Serratia liquefaciens by PCR and cloned into two vectors pET20-b(+) and pET28-a(+). The two recombinant plasmids were then transformed into E. coli BL21 (DE3) individually to express PLA(1). E. coli BL21(DE3)/pET28a-pla yielded extracellular PLA(1) with an activity of 40.8 U/mL in batch cultivations of shaken flasks by auto-induction, which was accounted for 91% of total enzyme activity. On the basis of primal auto-induction medium, the optimized fermentation medium of PLA(1) contained tryptone 10 g/L, yeast extract 5 g/L, glucose 0.8 g/L, lactose 5 g/L, Na2HPO4 25 mmol/L, KH2PO4 25 mmol/L and 1 mmol/L MgSO4 (final concentration). Glycine (7.5 g/L) was added 6 h after inoculated. After incubated at 37 degrees C for 24 h, extracellular enzyme activity reached 128.7 U/mL. PMID- 24063245 TI - [Response surface methodology to optimize marine microbe culture for producing fungi fibrinolytic compound]. AB - Response surface methodology was applied to optimize the fermentation conditions of FGFC1 (Fungi fibrinolytic compound 1). On the basis of single factor tests, response surface analysis was designed by Design-Expert, and the effects of culture time, ornithine hydrochloride addition and culture temperature on the yield of FGFC1 were studied, the predicted value and measured value were also contrasted. The results show the optimal culture conditions as follows: the culture time is 7 d, ornithine hydrochloride addition is 0.5% (M/V), culture temperature is 28 degrees C. Under these conditions, the yield of FGFC1 is 1 978.33 mg/L, which is consistent with the predicted value. It shows that the experiment is effective. PMID- 24063246 TI - Nonviral cell labeling and differentiation agent for induced pluripotent stem cells based on mesoporous silica nanoparticles. AB - The generation of induced pluripotent stem cells (iPSCs) is an innovative personalized-regenerative technology, which can transform own-self somatic cells into embryonic stem (ES)-like cells, which have the potential to differentiate into all cell types of three dermal lineages. However, how to quickly, efficiently, and safely produce specific-lineage differentiation from pluripotent state cells and iPSCs is still an open question. The objective of the present study was to develop a platform of a nonviral gene delivery system of mesoporous silica nanoparticles (MSNs) to rapidly generate iPSC-derived definitive-lineage cells, including endodermal-differentiated cells. We also evaluated the feasibility and efficiency of FITC-conjugated MSNs (FMSNs) for labeling of iPSCs and utilized the multifunctional properties of FMSNs for a suitable carrier for biomolecule delivery. We showed that FMSNs of various surface charges could be efficiently internalized by iPSCs without causing cytotoxicity. The levels of reactive oxygen species and pluripotent status, including in vitro stemness signatures and in vivo teratoma formation, remained unaltered. Notably, positive charged FMSN enhanced cellular uptake efficiency and retention time. Moreover, when using positive-charged FMSN to deliver hepatocyte nuclear factor 3beta (HNF3beta) plasmid DNA (pDNA), the treated iPSCs exhibited significantly improved definitive endoderm formation and further quickly differentiated into hepatocyte like cells with mature functions (low-density lipoprotein uptake and glycogen storage) within 2 weeks in vitro. Double delivery of pHNF3beta further improved mRNA expression levels of liver-specific genes. These findings reveal the multiple advantages of FMSNs to serve as ideal vectors not only for stem cell labeling but also for safe gene delivery to promote the production of hepatocyte like cells from iPSCs. PMID- 24063247 TI - Determining the optimal model for role-substitution in NHS dental services in the United Kingdom. AB - BACKGROUND: Role-substitution describes a model of dental care where Dental Care Professionals (DCPs) provide some of the clinical activity previously undertaken by General Dental Practitioners. This has the potential to increase technical efficiency, the capacity to care and reduce costs. Technical efficiency is defined as the production of the maximum amount of output from a given amount of input so that the service operates at the production frontier i.e. optimal level of productivity. Academic research into technical efficiency is becoming increasingly utilised in health care, although no studies have investigated the efficiency of NHS dentistry or role-substitution in high-street dental practices. The aim of this study is to examine the barriers and enablers that exist for role substitution in general dental practices in the NHS and to determine the most technically efficient model for role-substitution. METHODS/DESIGN: A screening questionnaire will be sent to DCPs to determine the type and location of role substitutive models employed in NHS dental practices in the United Kingdom (UK). Semi-structured interviews will then be conducted with practice owners, DCPs and patients at selected sites identified by the questionnaire. Detail will be recorded about the organisational structure of the dental team, the number of NHS hours worked and the clinical activity undertaken. The interviews will continue until saturation and will record the views and attitudes of the members of the dental team. Final numbers of interviews will be determined by saturation.The second work-stream will examine the technical efficiency of the selected practices using Data Envelopment Analysis and Stochastic Frontier Modeling. The former is a non-parametric technique and is considered to be a highly flexible approach for applied health applications. The latter is parametric and is based on frontier regression models that estimate a conventional cost function. DISCUSSION: Maximising health for a given level and mix of resources is an ethical imperative for health service planners. This study will determine the technical efficiency of role-substitution and so address one of the key recommendations of the Independent Review of NHS dentistry in England. PMID- 24063249 TI - Implementing an evidence-based practices training curriculum to U.S. Army child and family behavioral health providers. AB - Military Children who have experienced multiple deployments of one or both parents are more likely to have emotional and behavioral difficulties compared with their civilian peers (e.g., Chandra et al., 2010 ). The U.S. Army Medical Command has tasked the Child, Adolescent and Family Behavioral Health Office (CAF BHO) to develop programs to address the behavioral health (BH) needs of Army Children and Families. This article will describe the efforts of the CAF-BHO Training Section to disseminate and implement an evidence based practice training curriculum for Army Child and Family Behavioral Health Providers. Specifically, this article will detail: (a) the decision making strategy used to identify the training protocol for dissemination, (b) adaptations to the training program and treatment protocol to fit a Military context, and (c) efforts to implement, maximize and sustain utilization of evidence-based practices by Military BH providers over a large geographical area with limited resources. PMID- 24063250 TI - Engineered nanotopography on electrospun PLLA microfibers modifies RAW 264.7 cell response. AB - In this study, we created a new method of electrospinning capable of controlling the surface structure of individual fibers (fiber nanotopography). The nanotopographical features were created by a phase separation in the fibers as they formed. To control the phase separation, a nonsolvent (a chemical insoluble with the polymer) was added to an electrospinning solution containing poly-l lactic acid (PLLA) and chloroform. The nanotopography of electrospun fibers in the PLLA/chloroform solution was smooth. However, adding a small weight (<2% of total solution) of a single nonsolvent (water, ethanol, or dimethyl sulfoxide) generated nanoscale depressions on the surface of the fibers unique to the nonsolvent added. Additionally, nanoscale depressions on electrospun fibers were observed to change with dimethyl sulfoxide (DMSO) concentration in the PLLA/chloroform solution. A nonlinear relationship was found between the concentration of DMSO and the number and size of nanotopographical features. The surface depressions did not alter the hydrophobicity of the scaffold or degradation of the scaffold over a two-day period. To determine if fiber nanotopography altered cell behavior, macrophages (RAW 264.7 cells) were cultured on fibers with a smooth nanotopography or fibers with nanoscale depressions. RAW 264.7 cells spread less on fibers with nanoscale depressions than fibers with a smooth topography (p<0.05), but there were no differences between groups with regard to cell metabolism or the number of adherent cells. The results of this study demonstrate the necessity to consider the nanotopography of individual fibers as these features may affect cellular behavior. More importantly, we demonstrate a versatile method of controlling electrospun fiber nanotopography. PMID- 24063248 TI - The prognostic value of Her4 receptor isoform expression in triple-negative and Her2 positive breast cancer patients. AB - BACKGROUND: Not only four but rather seven different human epidermal growth factor receptor related (Her) receptor tyrosine kinases (RTKs) have been described to be expressed in a variety of normal and neoplastic tissues: Her1, Her2, Her3, and additionally four Her4 isoforms have been identified. A differential expression of Her4 isoforms does not, however, play any role in either the molecular diagnostics or treatment decision for breast cancer patients. The prognostic and predictive impact of Her4 expression in breast cancer is basically unclear. METHODS: We quantified the Her4 variants JM-a/CYT1, JM-a/CYT2, JM-b/CYT1, and JM-b/CYT2 by isoform-specific polymerase chain reaction (qPCR) in (i) triple-negative, (ii) Her2 positive breast cancer tissues and (iii) in benign breast tissues. RESULTS: In all three tissue collectives we never found the JM-b/CYT1 or the JM-b/CYT2 isoform expressed. In contrast, the two JM-a/CYT1 and JM-a/CYT2 isoforms were always simultaneously expressed but at different ratios. We identified a positive prognostic impact on overall survival (OS) in triple-negative and event-free survival (EFS) in Her2 positive patients. This finding is independent of the absolute JM-a/CYT1 to JM-a/CYT2 expression ratio. In Her2 positive patients, Her4 expression only has a favorable effect in estrogen-receptor (ER)-positive but not in ER-negative individuals. CONCLUSION: In summary, JM-a/CYT1 and JM-a/CYT2 but not JM-b isoforms of the Her4 receptor are simultaneously expressed in both triple-negative and Her2 positive breast cancer tissues. Although different expression ratios of the two JM-a isoforms did not reveal any additional information, Her4 expression basically indicates a prolonged EFS and OFS. An extended expression analysis that takes all Her receptor homologs, including the Her4 isoforms, into account might render more precisely the molecular diagnostics required for the development of optimized targeted therapies. PMID- 24063251 TI - Beyond the continuum: how molecular solvent structure affects electrostatics and hydrodynamics at solid-electrolyte interfaces. AB - Standard continuum theory fails to predict several key experimental results of electrostatic and electrokinetic measurements at aqueous electrolyte interfaces. In order to extend the continuum theory to include the effects of molecular solvent structure, we generalize the equations for electrokinetic transport to incorporate a space dependent dielectric profile, viscosity profile, and non electrostatic interaction potential. All necessary profiles are extracted from atomistic molecular dynamics (MD) simulations. We show that the MD results for the ion-specific distribution of counterions at charged hydrophilic and hydrophobic interfaces are accurately reproduced using the dielectric profile of pure water and a non-electrostatic repulsion in an extended Poisson-Boltzmann equation. The distributions of Na(+) at both surface types and Cl(-) at hydrophilic surfaces can be modeled using linear dielectric response theory, whereas for Cl(-) at hydrophobic surfaces it is necessary to apply nonlinear response theory. The extended Poisson-Boltzmann equation reproduces the experimental values of the double-layer capacitance for many different carbon based surfaces. In conjunction with a generalized hydrodynamic theory that accounts for a space dependent viscosity, the model captures the experimentally observed saturation of the electrokinetic mobility as a function of the bare surface charge density and the so-called anomalous double-layer conductivity. The two-scale approach employed here-MD simulations and continuum theory-constitutes a successful modeling scheme, providing basic insight into the molecular origins of the static and kinetic properties of charged surfaces, and allowing quantitative modeling at low computational cost. PMID- 24063252 TI - Stainless steel pinholes for fast fabrication of high-performance microchip electrophoresis devices by CO2 laser ablation. AB - With the introduction of hobby laser engravers/cutters, the use of CO2 laser micromachining on poly(methyl methacrylate) (PMMA) has the potential for flexible, low cost, rapid prototyping of microfluidic devices. Unfortunately, the feature size created by most entry-level CO2 laser micromachining systems is too large to become a functional tool in analytical microfluidics. In this paper, we report a novel method to reduce the feature size of microchannels and the bulges formed at the rim of the channel during CO2 laser micromachining by passing the laser beam through a stainless steel pinhole. Without the pinhole, the channel width was typically 300 MUm wide. However, when 50 or 35 MUm diameter pinholes were used, channel widths of 60 and 25 MUm, respectively, could be obtained. The height of the bulge deposited directly next to the channel was reduced to less than 0.8 MUm with the pinhole during ablation. Separations of fluorescent dyes on devices ablated with and without the pinhole were compared. On devices fabricated with the pinhole, the number of theoretical plates/m was 2.2-fold higher compared to devices fabricated without the pinhole, and efficiencies comparable to embossed PMMA and laser ablated glass chips were obtained. A mass-produced commercial hobby laser (retailing at ~$2500), when equipped with a $500 pinhole, represents a rapid and low-cost approach to the rapid fabrication of rigid plastic microchips including the narrow microchannels required for microchip electrophoresis. PMID- 24063253 TI - Determining attitudes toward acupuncture: a focus on older U.S. veterans. AB - OBJECTIVE: To explore whether factors related to attitudes toward acupuncture use in a population of older veterans is similar to previously identified motivators for nonveterans. METHODS: A sample of veterans was asked to complete a questionnaire, which included questions on sociodemographic traits, history of acupuncture, chronic diseases, and the Health Belief Model (HBM). Data reduction was performed by using principal components analysis to identify major factors among the HBM responses. Linear regression was performed to evaluate variables that may contribute to attitudes toward acupuncture. RESULTS: There were 402 completed questionnaires. Principal components analysis yielded three significant factors. Linear regression resulted in a model that explained 35% of the variance for positive attitudes toward acupuncture: Age, race, religion, access to acupuncture, self-efficacy for nonpharmacologic treatments, and the presence of one or more physical and mental chronic health condition were significantly related to positive attitudes toward acupuncture. CONCLUSIONS: Factors related to attitudes toward acupuncture were very similar to factors identified in other literature for nonveterans, with the exception of income and education. The findings suggest that availability of treatment influences attitudes toward acupuncture. PMID- 24063254 TI - Apomyoglobin sequesters heme from heme bound Abeta peptides. AB - A combination of absorption, electron paramagnetic resonance (EPR), and resonance Raman (rR) spectroscopy has been used to study the interaction of heme-Abeta and apomyoglobin (apoMb). The absorption spectrum of oxidized heme bound Abeta, characterized by a split Soret band at 364 and 394 nm, shifts to 408 nm on incubation with apoMb, characteristic of Myoglobin (Mb). The nu4, nu3, and nu2 bands in the rR spectrum of heme-Abeta are observed at 1376, 1495, and 1570 cm( 1), which shift to 1371, 1482, and 1563 cm(-1), respectively on incubating with apoMb, implying formation of Mb. Similarly, heme transfer from reduced heme-Abeta to apoMb resulting in the formation of deoxyMb was also observed. Thus, spectroscopic data show that apoMb can sequester heme from heme-Abeta complexes both in oxidized and in reduced forms. Heme uptake by apoMb from native heme Abeta(1-40) and Abeta(1-16) in both oxidized and reduced forms follow a biphasic reaction kinetics likely representing heme transfer from two dominating conformers of heme-Abeta in solution. The rate constants for the two steps involved in heme uptake by apoMb from heme-Abeta(1-40) are 11.5 * 10(4) M(-1) s( 1) and 7.5 * 10(3) M(-1) s(-1) while from heme-Abeta(1-16) are 6.0 * 10(4) M(-1) s(-1) and 7.5 * 10(3) M(-1) s(-1). The rate constants for heme uptake by apoMb from reduced heme-Abeta(1-40) are 3.7 * 10(4) M(-1) s(-1) and 6.8 * 10(3) M(-1) s(-1) while for reduced heme-Abeta(1-16) are 2.0 * 10(4) M(-1) s(-1) and 6.0 * 10(3) M(-1) s(-1). The heme uptake from heme-Abeta by apoMb leads to a dramatic reduction of PROS generation by the reduced heme-Abeta complexes. PMID- 24063255 TI - Stable and potent analogues derived from the modification of the dicarbonyl moiety of curcumin. AB - Curcumin has shown promising therapeutic utilities for many diseases, including cancer; however, its clinical application is severely limited because of its poor stability under physiological conditions. Here we find that curcumin also loses its activity instantaneously in a reducing environment. Curcumin can exist in solution as a tautomeric mixture of keto and enol forms, and the enol form was found to be responsible for the rapid degradation of the compound. To increase the stability of curcumin, several analogues were synthesized in which the diketone moiety of curcumin was replaced by isoxazole (compound 2) and pyrazole (compound 3) groups. Isoxazole and pyrazole curcumins were found to be extremely stable at physiological pH, in addition to reducing atmosphere, and they can kill cancer cells under serum-depleted condition. Using molecular modeling, we found that both compounds 2 and 3 could dock to the same site of tubulin as the parent molecule, curcumin. Interestingly, compounds 2 and 3 also show better free radical scavenging activity than curcumin. Altogether, these results strongly suggest that compounds 2 and 3 could be good replacements for curcumin in future drug development. PMID- 24063256 TI - Developing an early screening instrument for predicting psychological morbidity after critical illness. AB - INTRODUCTION: Guidelines recommend follow-up for patients after an intensive care unit (ICU) stay. Methods for identifying patients with psychological problems after intensive care would be of value, to optimize treatment and to improve adequate resource allocation in ICU follow-up of ICU survivors. The aim of the study was to develop a predictive screening instrument, for use at ICU discharge, to identify patients at risk for post-traumatic stress, anxiety or depression. METHODS: Twenty-one potential risk factors for psychological problems - patient characteristics and ICU-related variables - were prospectively collected at ICU discharge. Two months after ICU discharge 252 ICU survivors received the questionnaires Post-Traumatic Stress Symptom scale -10 (PTSS-10) and Hospital Anxiety and Depression Scale (HADS) to estimate the degree of post-traumatic stress, anxiety and depression. RESULTS: Of the 150 responders, 46 patients (31%) had adverse psychological outcome, defined as PTSS-10 >35 and/or HADS subscales >=8. After analysis, six predictors were included in the screening instrument: major pre-existing disease, being a parent to children younger than 18 years of age, previous psychological problems, in-ICU agitation, being unemployed or on sick-leave at ICU admission and appearing depressed in the ICU. The total risk score was related to the probability for adverse psychological outcome in the individual patient. The predictive accuracy of the screening instrument, as assessed with area under the receiver operating characteristic curve, was 0.77. When categorizing patients in three risk probability groups - low (0 to 29%), moderate (30 to 59%) high risk (60 to 100%), the actual prevalence of adverse psychological outcome in respective groups was 12%, 50% and 63%. CONCLUSION: The screening instrument developed in this study may aid ICU clinicians in identifying patients at risk for adverse psychological outcome two months after critical illness. Prior to wider clinical use, external validation is needed. PMID- 24063257 TI - Combining functional features of whole-grain barley and legumes for dietary reduction of cardiometabolic risk: a randomised cross-over intervention in mature women. AB - The usefulness of dietary strategies against cardiometabolic risk is increasingly being acknowledged. Legumes and whole grains can modulate risk markers associated with cardiometabolic diseases, but their possible additive/synergistic actions are unknown. The objective of the present study was to assess, in healthy subjects, the effect of a diet including specific whole-grain barley products and legumes with prior favourable outcomes on cardiometabolic risk parameters in semi acute studies. A total of forty-six overweight women (50-72 years, BMI 25-33 kg/m2 and normal fasting glycaemia) participated in a randomised cross-over intervention comparing a diet rich in kernel-based barley products, brown beans and chickpeas (D1, diet 1 (functional diet)) with a control diet (D2, diet 2 (control diet)) of similar macronutrient composition but lacking legumes and barley. D1 included 86 g (as eaten)/d brown beans, 82 g/d chickpeas, 58 g/d whole grain barley kernels and 216 g/d barley kernel bread. Both diets followed the Nordic Nutrition Recommendations, providing similar amounts of dietary fibre (D1: 46.9 g/d; D2: 43.5 g/d), with wheat-based products as the main fibre supplier in D2. Each diet was consumed for 4 weeks under weight-maintenance conditions. Both diets decreased serum total cholesterol, LDL-cholesterol and HDL-cholesterol levels, but D1 had a greater effect on total cholesterol and LDL-cholesterol levels (P< 0.001 and P< 0.05, respectively). D1 also reduced apoB (P< 0.001) and gamma-glutamyl transferase (P< 0.05) levels, diastolic blood pressure (P< 0.05) and the Framingham cardiovascular risk estimate (P< 0.05). D1 increased colonic fermentative activity, as judged from the higher (P< 0.001) breath hydrogen levels recorded. In conclusion, a specific barley/legume diet improves cardiometabolic risk-associated biomarkers in a healthy cohort, showing potential preventive value beyond that of a nutritionally well-designed regimen. PMID- 24063258 TI - HANDS: a tool for genome-wide discovery of subgenome-specific base-identity in polyploids. AB - BACKGROUND: The analysis of polyploid genomes is problematic because homeologous subgenome sequences are closely related. This relatedness makes it difficult to assign individual sequences to the specific subgenome from which they are derived, and hinders the development of polyploid whole genome assemblies. RESULTS: We here present a next-generation sequencing (NGS)-based approach for assignment of subgenome-specific base-identity at sites containing homeolog specific polymorphisms (HSPs): 'HSP base Assignment using NGS data through Diploid Similarity' (HANDS). We show that HANDS correctly predicts subgenome specific base-identity at >90% of assayed HSPs in the hexaploid bread wheat (Triticum aestivum) transcriptome, thus providing a substantial increase in accuracy versus previous methods for homeolog-specific base assignment. CONCLUSION: We conclude that HANDS enables rapid and accurate genome-wide discovery of homeolog-specific base-identity, a capability having multiple applications in polyploid genomics. PMID- 24063259 TI - New dihexadecyldithiophosphate SAMs on gold provide insight into the unusual dependence of adsorbate chelation on substrate morphology in SAMs of dialkyldithiophosphinic acids. AB - We report the formation and characterization of new self-assembled monolayers (SAMs) formed from dihexadecyldithiophosphate (C16)2DDP and compare their properties with those of SAMs formed from the structurally similar adsorbate dihexadecyldithiophosphinic acid (C16)2DTPA. The new (C16)2DDP SAMs were characterized using X-ray photoelectron spectroscopy, reflection-absorption infrared spectroscopy, contact angle measurements, and electrochemical impedance spectroscopy. The data indicate that (C16)2DDP forms SAMs on gold films formed by e-beam evaporation in which all adsorbates chelate to gold, in contrast to (C16)2DTPA SAMs, in which 40% of the adsorbates are monodentate. The alkyl chains of the (C16)2DDP SAM are also less densely packed and ordered than those of the (C16)2DTPA SAM. To understand these differences, we present density functional theory calculations that show that there are only minimal differences between the geometric and electronic structures of the two adsorbates and that the energetic difference between monodentate and bidentate binding of a gold(I) ion are surprisingly small for both adsorbates. This study leads to the conclusion that differences in intermolecular interactions within the SAM are the driving force for the difference in chelation between the two adsorbates. PMID- 24063260 TI - Spectrum of prostatic lesions. AB - BACKGROUND: Prostate gland of male reproductive system is about the size of walnut and surrounds the urethra. Most frequently encountered diseases affecting prostate are Prostatitis, Benign prostatic hyperplasia and Prostatic cancer .Our objective of study was to evaluate the spectrum and correlation of prostatic lesions with presenting complaints of patient. METHODS: It was a cross-sectional study conducted in Pathology Department of Dow Medical College, Dow University of Health Sciences during the period of 1st January 2010 to December 2012. Pathology department of Dow Medical College collected specimens from both Civil Hospital and Lyari General Hospital Karachi, Pakistan. Specimens were taken through transurethral resection of prostate (TURP), simple prostatectomy and radical prostatectomy. A questionnaire was made and information including name, age, ward name of hospital, laboratory number, clinical diagnosis and symptoms were noted in it. Data was entered and analyzed through SPSS 19. RESULT: During the targeted months, 48 prostatic specimens were received with a mean age of 65.7 + -7.6 years. Common presenting complains were urinary retention in 23(47.9%) patients, followed by dribbling in 12(25%). Out of 48 patients, 42 have Benign Prostatic Hyperplasia and 6 have Prostatic Adenocarcinoma. Both Benign Prostatic Hyperplasia and Prostatic Adenocarcinoma were more prevalent in the age group of 60-70 years. CONCLUSION: Frequency of prostatic cancer is on the rise and measures should be taken for its early detection. Screening protocols and awareness programs need to be introduced. Screening programs should be focused on level of androgens and molecular pathogenesis. PMID- 24063261 TI - Erythropoietin activates Keap1-Nrf2/ARE pathway in rat brain after ischemia. AB - rhEPO has previously been shown to exert neuroprotective action in focal cerebral ischemia. However, its mechanism is not clear. We established the model of permanent focal cerebral ischemia. rhEPO was administered (5000 IU/kg i.p.) 2 h later after the successful ischemia model in rhEPO group and increased translation of Nrf2 and HO-1 and decreased the H2O2 concentration in the brain confirming activation of the Keap1-Nrf2/ARE pathway. The results show that rhEPO activate Keap1-Nrf2/ARE pathway after ischemia to protect the brain tissue. PMID- 24063262 TI - Protein expression profiling of formalin-fixed paraffin-embedded tissue using recombinant antibody microarrays. AB - Proteomics, the large-scale analysis of proteins, is a rapidly evolving field with an increasing number of key clinical applications, such as diagnosis, prognosis, and classification. In order to generate complete protein expression profiles, or protein atlases, any crude sample format must be addressable in a rapid, multiplex, and sensitive manner. A common and clinically central sample format, formalin-fixed, paraffin-embedded (FFPE) tissue material, holds great potential as a source for disease-associated biomarker signatures. However, despite major efforts, extraction and subsequent profiling of proteins from FFPE tissue has proven to be challenging. In this proof-of-concept study, we have demonstrated for the first time that proteins could be extracted, labeled, and subsequently profiled in a multiplex, sensitive, and reproducible manner using recombinant scFv antibody microarrays. Thus, we have added FFPE samples to the list of sample formats available for high-throughput analysis by affinity proteomics, paving the way for the next generation of biomarker-driven discovery projects. PMID- 24063263 TI - Cataract management in juvenile idiopathic arthritis: simultaneous versus secondary intraocular lens implantation. AB - PURPOSE: To compare primary versus secondary intraocular lens (IOL) implantation after cataract removal in patients with juvenile idiopathic arthritis (JIA). METHODS: Retrospective interventional study. Data were obtained for 40 children (40 eyes) with JIA-associated uveitis operated on for cataract before the age of 16 years between January 1998 and January 2005. RESULTS: Twenty-one patients underwent primary IOL implantation at a mean age of 13.1 +/- 2.6 (9-16) years. Mean follow-up was 48.2 +/- 5.4 (35-64) months. Nineteen patients underwent cataract removal at a mean age 12.3 +/- 2.0 (9-16) years and secondary IOL implantation 13.6 +/- 0.3 (11-16) months later. Mean follow-up was 47.2 +/- 6.5 (32-64) months. BCVA difference between the two groups was significant at 24 month visit only (p = 0.001). Incidence of secondary glaucoma was significantly lower in the group that underwent secondary IOL implantation (p = 0.01). CONCLUSION: Secondary IOL implantation after cataract removal in children with JIA-related uveitis provided a significantly lower incidence of secondary glaucoma. PMID- 24063264 TI - Enhanced brain delivery of deferasirox-lactoferrin conjugates for iron chelation therapy in neurodegenerative disorders: in vitro and in vivo studies. AB - Oxidative stress associated cell damage is one of the key factors in neurodegeneration development and is highly related to the presence of transition metal ions including iron. Herein, deferasirox, a high affinity iron chelator, was conjugated to lactoferrin molecules by carbodiimide mediated coupling reaction to create a novel drug delivery system with higher brain permeability through receptor mediated transcytosis. Each lactoferrin molecule was averagely attached to 4 to 6 deferasirox molecules resulting in water-soluble conjugated nanostructures which were purified and characterized. Neuroprotective effects of lactoferrin conjugated nanostructures and their cellular uptake were evaluated in differentiated PC12 cell line, and the molecular mechanisms involved in such neuroprotection were elucidated. Lactoferrin conjugates were able to interfere in apoptotic caspase cascade by affecting the expression level of caspase-3, PARP, Bax and Bcl-2. Furthermore, an elevation in the expression level of autophagy markers including Atg7, Atg12-Atg5 and LC3-II/LC3-I ratio was observed. Intraperitoneal injection of lactoferrin conjugates was able to significantly attenuate learning deficits induced by beta amyloid injection in a rat model of Alzheimer's disease, which further confirms a potential neuroprotective effect for lactoferrin conjugated deferasirox in neurodegenerative disorder management through metal chelation therapy. PMID- 24063265 TI - Palladium-catalyzed synthesis of 2-aminobenzoxazinones by aerobic oxidative coupling of anthranilic acids and isocyanides. AB - Isocyanides have emerged as valuable C1 building blocks in palladium catalysis. Their potential has, however, mainly been exploited for the synthesis of amidines and amidine-containing heterocycles. To illustrate the broader applicability of isocyanides, we have recently developed a novel oxidative coupling of diamines and isocyanides furnishing valuable guanidine-containing heterocycles. We here report the extension of this protocol to the coupling of anthranilic acids and isocyanides leading to medicinally relevant 2-aminobenzoxazinones. This is a particularly challenging substrate class for this reaction due to the possibility of undesired decarboxylative pathways and the susceptibility of the products to nucleophilic attack. Therefore, this work underlines the generality and broad potential of the oxidative coupling of bisnucleophiles and isocyanides, facilitating the further implementation of this chemistry in library design. PMID- 24063267 TI - Psychoanalytic taste buds. PMID- 24063268 TI - The trauma of birth in its importance for psychoanalytic therapy. PMID- 24063269 TI - The problem of feminine masochism. PMID- 24063270 TI - Freud, females, childbirth, and dissidence: Margarete Hilferding, Karen Horney, and Otto Rank. AB - These three early psychoanalysts, who differed in important ways from Freud, each tried to shift his fundamental beliefs about women's bodies in basic developmental theory. This paper illustrates this point by elaborating their materials concerning the centrality of childbirth. One thematic aspect of Freud's disruptive fights with colleagues lay in his loyalty to phallocratic certainties. These problems still affect us, a century later, even in today's clinically pluralistic climate. PMID- 24063271 TI - Annotations on Artemisia. AB - To demonstrate the relevance of an artist's biography to the understanding of her creations, no instance is more persuasive than the career of the 17th-century Italian painter Artemisia Gentileschi. Numerous scholars have attempted to correlate the nature of her subject matter with the more dramatic events of her picaresque private life. A psychoanalytic effort to make such a correlation needs to go beyond discrete incidents, to reconstruct her personality and its development. Artemisia's oeuvre is tightly focused on a fantasy system of sexual irrestibility, probably based on the interactions of this motherless child with a delinquent father. Hypotheses that the artist became a vengeful victim overtook her strength, resilience, and affability. PMID- 24063272 TI - "Playing" with the couple's projective identifications: paradigmatic psychotherapy with couples. AB - This paper is an attempt to (1) expand the concept of the defense of projective identification to include everyday interactions between intimates who are not necessarily deeply disturbed, (2) show the importance of understanding projective identification inductions in couples therapy, (3) introduce a new way of working with normal/neurotic couples where there is at least some evidence of projective identification in their communication, and (4) describe the similarity of my approach with less disturbed couples to the technical modification of paradigmatic psychotherapy as employed by Modern Psychoanalysis in their work with more disturbed individual patients. PMID- 24063273 TI - Transgressors. PMID- 24063274 TI - The woman I love and the woman I cannot live without. AB - The relationship between love and the symbiotic phase of childhood is explored from a new angle in terms of a conflict between "the woman I love" and "the woman I cannot live without." Love requires dependency, but it can also lead to giving up independent existence; then it becomes inimical to the relationship. PMID- 24063275 TI - Reik, Schnitzler, Freud, and "The murderer": the limits of insight in psychoanalysis. AB - The author explores the relationships of three major figures: Theodor Reik, Arthur Schnitzler, and Sigmund Freud. He considers how Schnitzler's novella "The Murderer" impacted Reik's life in terms of both Freud's reference to the story in a session with Reik and the parallels between Reik's life and the plot of the story. PMID- 24063277 TI - The K2/Spice phenomenon: emergence, identification, legislation and metabolic characterization of synthetic cannabinoids in herbal incense products. AB - In 2008, the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) detected unregulated, psychoactive synthetic cannabinoids (SCBs) in purportedly all-natural herbal incense products (often known as K2 or Spice) that were being covertly abused as marijuana substitutes. These drugs, which include JWH-018, JWH 073 and CP-47,497, bind and activate the cannabinoid receptors CB1R and CB2R with remarkable potency and efficacy. Serious adverse effects that often require medical attention, including severe cardiovascular, gastrointestinal and psychiatric sequelae, are highly prevalent with SCB abuse. Consequently, progressively restrictive legislation in the US and Europe has banned the distribution, sale and use of prevalent SCBs, initiating cycles in which herbal incense manufacturers replace banned SCBs with newer unregulated SCBs. The contents of the numerous, diverse herbal incense products was unknown when SCB abuse first emerged. Furthermore, the pharmacology of the active components was largely uncharacterized, and confirmation of SCB use was hindered by a lack of known biomarkers. These knowledge gaps prompted scientists across multiple disciplines to rapidly (1) monitor, identify and quantify with chromatography/mass spectrometry the ever-changing contents of herbal incense products, (2) determine the metabolic pathways and major urinary metabolites of several commonly abused SCBs and (3) identify active metabolites that possibly contribute to the severe adverse effect profile of SCBs. This review comprehensively describes the emergence of SCB abuse and provides a historical account of the major case reports, legal decisions and scientific discoveries of the "K2/Spice Phenomenon". Hypotheses concerning potential mechanisms SCB adverse effects are proposed in this review. PMID- 24063279 TI - Downregulation of LIMK1 level inhibits migration of lung cancer cells and enhances sensitivity to chemotherapy drugs. AB - LIM kinase 1 (LIMK1) is a member of a novel class of serine-threonine protein kinases, which plays an important role in malignant transformation. High expression of LIM kinase 1 (LIMK1) has been detected in various invasive cancers. Here, we showed that LIMK1 was overexpressed in non-small cell lung cancer tissues (NSCLC) and cell lines. Expression of LIMK1 was detected in 115 of 150 lung cancer tissues, the frequency being more significant than in lung tissues. In addition, overexpression of LIMK1 was also associated with high TNM stage and lymph node metastasis in NSCLC patients. Moreover, RNAi-mediated suppression of LIMK1 expression markedly inhibited migration and invasion of 801D lung cancer cells. Furthermore, silencing of LIMK1 sensitized 801D cells to chemotherapeutic drugs of cisplatin and gemcitabine. These results indicate that the overexpression of LIMK1 is tightly associated with an aggressive phenotype of lung cancer cells, knockdown of LIMK1 suppressed cell migration and invasion, enhanced chemosensitivity, suggesting a potential therapeutic target for lung cancer. PMID- 24063278 TI - Regadenoson and adenosine are equivalent vasodilators and are superior than dipyridamole- a study of first pass quantitative perfusion cardiovascular magnetic resonance. AB - BACKGROUND: Regadenoson, dipyridamole and adenosine are commonly used vasodilators in myocardial perfusion imaging for the detection of obstructive coronary artery disease. There are few comparative studies of the vasodilator properties of regadenoson, adenosine and dipyridamole in humans. The specific aim of this study was to determine the relative potency of these three vasodilators by quantifying stress and rest myocardial perfusion in humans using cardiovascular magnetic resonance (CMR). METHODS: Fifteen healthy normal volunteers, with Framingham score less than 1% underwent vasodilator stress testing with regadenoson (400 MUg bolus), dipyridamole (0.56 mg/kg) and adenosine (140 MUg /kg/min) on separate days. Rest perfusion imaging was performed initially. Twenty minutes later, stress imaging was performed at peak vasodilation, i.e. 70 seconds after regadenoson, 4 minutes after dipyridamole infusion and between 3-4 minutes of the adenosine infusion. Myocardial blood flow (MBF) in ml/min/g and myocardial perfusion reserve (MPR) were quantified using a fully quantitative model constrained deconvolution. RESULTS: Regadenoson produced higher stress MBF than dipyridamole and adenosine (3.58 +/- 0.58 vs. 2.81 +/- 0.67 vs. 2.78 +/- 0.61 ml/min/g, p = 0.0009 and p = 0.0008 respectively). Regadenoson had a much higher heart rate response than adenosine and dipyridamole respectively (95 +/- 11 vs. 76 +/- 13 vs. 86 +/- 12 beats/ minute) When stress MBF was adjusted for heart rate, there were no differences between regadenoson and adenosine (37.8 +/- 6 vs. 36.6 +/- 4 MUl/sec/g, p = NS), but differences between regadenoson and dipyridamole persisted (37.8 +/- 6 vs. 32.6 +/- 5 MUl/sec/g, p = 0.03). The unadjusted MPR was higher with regadenoson (3.11 +/- 0.63) when compared with adenosine (2.7 +/- 0.61, p = 0.02) and when compared with dipyridamole (2.61 +/- 0.57, p = 0.04). Similar to stress MBF, these differences in MPR between regadenoson and adenosine were abolished when adjusted for heart rate (2.04 +/- 0.34 vs. 2.12 +/- 0.27, p = NS), but persisted between regadenoson and dipyridamole (2.04 +/- 0.34 vs. 1.77 +/- 0.33, p = 0.07) and between adenosine and dipyridamole (2.12 +/- 0.27 vs. 1.77 +/- 0.33, p = 0.01). CONCLUSIONS: Based on fully quantitative perfusion using CMR, regadenoson and adenosine have similar vasodilator efficacy and are superior to dipyridamole. PMID- 24063280 TI - Anticancer effects of cinnamic acid in lung adenocarcinoma cell line h1299 derived stem-like cells. AB - Lung cancer is a lethal solid tumor with poor prognosis because of its high metastasis and resistance to current therapies. Recently, cancer stem cells (CSCs) were suggested to be major contributors to tumorigenicity and cancer relapse. However, therapeutic targets for lung cancer-related CSCs remain undetermined. The objective of the current study was to investigate whether cinnamic acid (CINN) exerts an antitumor activity against sphere-derived lung CSCs. In this study, CSCs were isolated from the non-small cell lung cancer cell line H1299 as tumor spheres under CSC-selective conditions, and found to have increased tumorigenicity, chemoresistance, and higher expression of both embryonic stem cell-related and drug resistance-related genes compared with parental cells. These observations are consistent with the notion that CSCs are tumorigenic, display the ability to self-renew, and generate differentiated progeny that constitute the majority of cells in tumors. Treatment of sphere derived stem cells with CINN could diminish their CSC-like abilities by decreasing their proliferation and invasive abilities and facilitating their differentiation into CD133-negative cells. Furthermore, CINN treatment increased the sensitivity of CSCs to chemotherapeutic drugs through apoptosis. Of note, xenotransplantation experiments revealed that CINN combined with cisplatin had a synergistic effect in inhibiting the tumorigenicity of CSCs. In summary, our study clearly revealed the presence of a population of sphere-forming cells with stem-like properties among H1299 cells and CINN can attenuate CSC properties of this stem-like cell population. The potential of CINN should be verified further in future studies of anti-CSC therapy. PMID- 24063281 TI - Mechanical strain and growth factors regulate expression of tenascin-C by OS cells additively. AB - Osteosarcoma (OS) is a kind of malignancy wherein the tumor cells form malignant bone-like or bone tissue. Tenascin-C (TN-C), an important extracellular matrix (ECM) protein, plays an indispensable role in tumor development. However, its regulatory factors, expression, and function in OS pathological process have not been studied extensively. Expression of TN-C is induced by growth factors as well as mechanical strain in fibroblast. So we asked whether mechanical stain and growth factors could induce TN-C expression in OS as well as which pathways were involved in those processes. We found that when mechanical strain was applied to OS cells cultured on silicone membrane, TN-C mRNA and protein levels were increased 10-fold within 8 h compared to the resting control. Likewise, when epidermal growth factors (EGFs) and insulin-like growth factor (IGF-1) were added to cells, TN-C mRNA levels increased six fold and eightfold, respectively, within 24h compared to the control. Growth factors (EGF and IGF-1) and mechanical strain had additive effects on the induction of TN-C mRNA expression in OS. Both ROCK I/II inhibitor and MEK-1 inhibitor inhibited TN-C induction by EGF or IGF-1, while only ROCK-I/II inhibitor had a strong subdued effect on TN-C induction by mechanical strain. Taken together, our findings suggest that growth factors and mechanical strain can induce TN-C in OS through different pathways additively. PMID- 24063282 TI - Two-stage model of chemically induced hepatocellular carcinoma in mouse. AB - The aim of this study was to develop an efficient and reproducible mouse model for hepatocellular carcinoma (HCC) research and assess the expression of two proto-oncogenes (c-myc and N-ras) and tumor suppressor gene p53 in the carcinogenic process. In this study, we found that diethylnitrosamine initiation with CCl4 and ethanol promotion could induce a short-term, two-stage liver carcinogenesis model in male BALB/c mice, the process of hepatocarcinogenesis including liver damage, liver necrosis/cell death, liver inflammation, liver proliferation, liver hyperplasia, liver steatosis, and liver cirrhosis and hepatocellular nodules, which mimicked the usual sequence of events observed in human HCC. We also identified that the increase in expression of the p53 gene is related to the proliferation of hepatocytes, whereas overexpression of the c-myc and N-ras genes is associated with hepatocarcinogenesis. This animal model may serve as a basis for recapitulating the molecular pathogenesis of HCC seen in humans. PMID- 24063283 TI - Characterization of ovarian cancer cell metabolism and response to chemotherapy by (31)p magnetic resonance spectroscopy. AB - We aimed to characterize the (31)P magnetic resonance spectra of various ovarian cancer cell lines exhibiting differences in cytotoxic drug resistance. We examined the metabolic profile of three different ovarian cancer cell lines, OC238, A2780, and A2780-cisplatin resistant (A2780cisR), including their response to various cytotoxic drugs (paclitaxel, cisplatin, and carboplatin) by (31)P magnetic resonance spectroscopy (MRS) in vitro. In the OC238 cell line, there were higher levels of phosphorylcholine, phosphodiesters, and uridine diphosphosugar (UDPS) + nicotinamide adenine dinucleotide phosphate (NADP). In A2780 and A2780cisR cell lines, phosphocreatine gave a high signal, which was absent in the OC238 cell line. In the OC238 cell line, a significant decrease in the glycerophosphoethanolamine, glycerophosphocholine, NADP, and UDPS signals was detected following cytotoxic drug treatment, mainly in response to paclitaxel. A significant increase in the glycerophosphocholine signal was detected following exposure to paclitaxel in both A2780 and A2780cisR cell lines. NADP and UDPS signals increased in response to all drugs in the A2780 cell line; however, in the cisplatin-resistant cell line A2780cisR, no significant change in those signals was detected following cisplatin treatment. We conclude that different ovarian cancer cell lines show characteristic (31)P MRS fingerprints and specific metabolic changes in response to cytotoxic drug treatment. PMID- 24063284 TI - Enhancement of proliferation and invasion by MicroRNA-590-5p via targeting PBRM1 in clear cell renal carcinoma cells. AB - MicroRNAs (miRNAs) play an important role in cancer development. In our study, miR-590-5p is found to be upregulated in the examined renal cell carcinoma (RCC) cell lines. PBRM1 acts as tumor suppressor in RCC, and its downregulation is associated with increased proliferation and aggressive behavior in RCC. We confirmed that PBRM1 was a direct target of miR-590-5p. miR-590-5p could regulate PBRM1 mRNA and protein expressions in clear cell renal carcinoma (ccRCC) ACHN and 786-O cells. Downregulation of miR-590-5p, which resulted in increased PBRM1, inhibited proliferation and invasion of ccRCC cells. Upregulation of miR-590-5p, which resulted in decreased PBRM1, promoted proliferation and invasion of ccRCC cells. The process of miR-590-5p promoting proliferation was found to be implicated in its inhibition of G1/S transition of ccRCC cells, and the action mechanisms were involved in its downregulation of PBRM1/p21(WAF1/CIP1) expression. In conclusion, we identified the role of miR-590-5p, serving as an oncomir in ccRCC, and our findings provide a potential target for the treatment of ccRCC. PMID- 24063285 TI - Commentary on Studying circular questioning "in situ". AB - In their discursive study of circular questioning in a systemic family therapy session, the authors raise some interesting perspectives on the original Milan therapy team's guidelines for the therapist as the conductor of therapy. By emphasizing circularity from a discourse point of view, they suggest these guidelines can be used to help family members hypothesize about their own perspectives on themselves and the other family members in circular terms, and, drawing upon Cecchin's notion of neutrality, by creating a state of curiosity in their talk and maybe in their minds. Their emphasis on circularity also helps us to become more sensitive to ways in which the natural recursion in language can help us to appreciate the new guiding lines circular questions can suggest with previously spoken elements. If we follow this line of argument, then circular questions can be seen as a critical part of a therapy we can call recursive family therapy in which we use the recursive element of all natural living languages to help our clients to recursively change their language and lives naturally. PMID- 24063286 TI - Careers Beyond the Bedside: one approach to develop the ethnic minority nursing faculty pool. AB - The wide disparities in health by race and ethnicity across the nation underscore the continuing need to increase the number of racial and ethnic minorities in the nursing workforce. In their roles as educators and researchers, minority nursing faculty help to alleviate the current disconnect between health care providers and the population that nurses serve. The authors have developed a program to increase the number of minority students in the baccalaureate nursing program at their university and to prepare them to enroll in doctoral programs within 1 year of graduation. The Careers Beyond the Bedside program offers undergraduates preentry, academic enrichment, and graduate school preparation activities designed to facilitate careers as nursing faculty educators and researchers. PMID- 24063287 TI - Improvement in critical thinking dispositions of undergraduate nursing students through problem-based learning: a crossover-experimental study. AB - Critical thinking (CT) is important to nursing education and practice. Although there is evidence that active learning approaches, such as problem-based learning (PBL), are effective in developing CT dispositions, the findings are inconclusive. This study examines the effect of PBL on the development of CT dispositions in nursing students using a crossover-experimental study in a course offered to nursing students in China. All students were randomly assigned to two parallel groups, with one group receiving PBL and the other receiving lecture based learning (LBL) as a control. The CT Dispositions Inventory-Chinese Version was administered before and after the semester-long course. Data were collected at three time points. No significant differences between groups were noted in overall and sub-scale scores at baseline; however, pronounced differences in overall posttest scores existed between the PBL and LBL groups. Thus, PBL learning significantly enhanced the CT dispositions of nursing students enrolled in Medical-Surgical Nursing II. PMID- 24063288 TI - Proteolytic effect of Cynara cardunculus rennet for use in the elaboration of 'Torta del Casar' cheese. AB - The purpose of this work was to analyse the influence of rennet from different Cynara cardunculus plants, selected for its clotting and proteolytic activity on caseins, on the characteristics of manufactured 'Torta del Casar' cheeses. After classifying the cardoon according to proteolytic activity into five groups of greater or lesser activity, 16 batches of cheeses were made with rennet derived from different wild cardoon plants. We observed a major development of the proteolysis during ripening leading to the generation of non-protein nitrogen compounds. Especially noteworthy was the relationship of amino acid nitrogen (AN) generation with rennet clotting activity after 24 h of maceration, and the fact that the production of biogenic amines was not related to the proteolytic activity of the rennet. The activities of the rennet observed 'in vitro' were also developed 'in vivo' in the cheeses, with the different rennets used affecting the final sensory characteristics of cheeses. The rennet with high clotting activity after 24 h of maceration was positively correlated with the creaminess, viscosity, and acceptability of the cheese. However, the high proteolytic activity rennet negatively influenced the acidity, bitterness, and creaminess parameters. Therefore the most appropriate cardoons for making this cheese are those with higher clotting activities and moderate proteolytic activities especially on beta-casein. The use of controlled and characterised cardoons in the manufacturing process of Torta del Casar is fundamental to obtaining the homogeneous product demanded by the Torta del Casar Registry of the Protected Designation of Origin. PMID- 24063290 TI - Preparing social workers with person-centered and participant-directed services for the changing aging and disability network. PMID- 24063289 TI - Resting-state networks and the functional connectome of the human brain in agenesis of the corpus callosum. AB - The corpus callosum is the largest white matter fiber bundle connecting the two cerebral hemispheres. In this work, we investigate the effect of callosal dysgenesis on functional magnetic resonance imaging (fMRI) resting-state networks and the functional connectome. Since alternate commissural routes between the cerebral hemispheres exist, we hypothesize that bilateral cortical networks can still be maintained in partial or even complete agenesis of the corpus callosum (AgCC). However, since these commissural routes are frequently indirect, requiring polysynaptic pathways, we hypothesize that quantitative measurements of interhemispheric functional connectivity in bilateral networks will be reduced in AgCC compared with matched controls, especially in the most highly interconnected cortical regions that are the hubs of the connectome. Seventeen resting-state networks were extracted from fMRI of 11 subjects with partial or complete AgCC and 11 matched controls. The results show that the qualitative organization of resting-state networks is very similar between controls and AgCC. However, interhemispheric functional connectivity of precuneus, posterior cingulate cortex, and insular-opercular regions was significantly reduced in AgCC. The preserved network organization was confirmed with a connectomic analysis of the resting-state fMRI data, showing five functional modules that are largely consistent across the control and AgCC groups. Hence, the reduction or even complete absence of callosal connectivity does not affect the qualitative organization of bilateral resting-state networks or the modular organization of the functional connectome, although quantitatively reduced functional connectivity can be demonstrated by measurements within bilateral cortical hubs, supporting the hypothesis that indirect polysynaptic pathways are utilized to preserve interhemispheric temporal synchrony. PMID- 24063291 TI - Moderators of intervention effects on parenting practices in a randomized controlled trial in early childhood. AB - The current study examined whether parent psychological resources (parenting stress, depression, and social support from friends and family) moderated the effects of early family preventive intervention on parenting among high-risk families. Ninety-two preschool-age children (M age = 3.94 years) at familial risk for conduct problems participated in a randomized controlled trial of a family intervention to prevent conduct problems. The majority of families were African American or Latino and experienced multiple stressors associated with poverty and familial antisocial behavior. Families were randomized to a 22-session group based intervention or to a no-intervention, assessment-only control condition. Parents reported on their psychological resources (parenting stress, depression and social support from friends and family) at baseline. Parenting (responsive, harsh, stimulation for learning) was assessed through self-report and observational measures four times over 24 months. Previously-reported intervention effects on responsive parenting and stimulation for learning were moderated by depression and social support from friends, respectively, such that benefits were concentrated among those at greatest risk (i.e., depressed, limited support from friends). The intervention effect on harsh parenting was not moderated by any of the parent psychological resources examined, such that parents with high and low resources benefited comparably. Consideration of moderators of preventive intervention effects on parenting provides important information about intervention impact among families experiencing multiple barriers to engagement and effective parenting. Findings suggest that parents with diminished psychological resources are just as likely to benefit. Family focused, group-based intervention is promising for strengthening parenting among the highest risk families. PMID- 24063292 TI - Sickness certificates: what information do they provide about rehabilitation? AB - PURPOSE: To investigate whether patients are prescribed rehabilitation early in a new sick leave period, and whether this prescription is associated with sex, age, diagnosis, description of functioning and affiliation of certifying physician. METHOD: A cross-sectional study using data from sickness certificates issued during a total sick leave period, collected consecutively during 2 weeks in 2007 in Ostergotland County, Sweden. Rehabilitation prescribed in the first certificate or within 28 days after the start of sick leave was defined as early rehabilitation. RESULTS: Musculoskeletal diseases (MSD) were the largest diagnostic group, followed by mental disorders (MD). The mean duration of sick leave was 94 days (SD 139), longest for MD patients. Early rehabilitation was prescribed in 27% of all certificates and in 45% of certificates for MSD and MD diagnoses. Logistic regression analysis indicated that prescription of early rehabilitation was associated with certificates issued for MSD and MD, youngest patients, and certificates issued by primary health care physicians. The final model explained 29% of variation in the prescription of early rehabilitation. CONCLUSIONS: There is a modest prescription of early rehabilitation in sickness certificates, based on younger age and MSD or MD diagnosis. This indicates that patients' rehabilitation needs may not have been identified. IMPLICATIONS FOR REHABILITATION: Sickness certificates are the decision basis for entitlement to sickness benefits and return to work (RTW) measures conveyed between the health care, the social insurance office and employers. Sickness certificates were found to provide modest information about early rehabilitation and RTW measures, indicating that patients' rehabilitation needs may not have been identified. As a communication tool, this scarce information might have implications for the patient regarding RTW measures or work modifications. PMID- 24063293 TI - Describing the impact of aphasia on close family members using the ICF framework. AB - PURPOSE: Aphasia is a communication disorder associated with impairments in spoken language, understanding, reading and writing that impacts upon daily activities, participation in society and the quality of life of those with the condition and their family members. Despite existing literature demonstrating the pervasive and significant effects of aphasia on family members, rehabilitation programming, policy and funding are not well developed. The aim of this qualitative study was to describe the impact of aphasia on family members in the context of changes to their functioning and disability using the framework of the International Classification of Functioning, Disability and Health (ICF). Application of ICF concept of disability or "third-party disability" to family members of people with a health condition is discussed. METHOD: Twenty family members participated in individual in-depth semi-structured interviews. Interviews were analyzed using qualitative content analysis. Research codes generated were subsequently mapped to the ICF. RESULTS: The results of this study showed that family members experienced positive, neutral and/or negative changes to their body functions and activities and participation due to their significant other's aphasia. Moreover, some family members attributed the development of a health condition or exacerbation of an existing health condition to the aphasia. CONCLUSION: Interpreted within the framework of the ICF, the results of this qualitative study reveal that family members of people with aphasia experience changes to their functioning and disability, known as "third-party functioning and disability", as a consequence of the health condition of a significant other. PMID- 24063294 TI - The moderation of resilience on the negative effect of pain on depression and post-traumatic growth in individuals with spinal cord injury. AB - PURPOSE: To determine the moderating effect of resilience on the negative effects of chronic pain on depression and post-traumatic growth. METHOD: Community dwelling individuals with SCI (n = 37) were recruited at short-term admission for yearly regular health examination. Participants completed self-rating standardized questionnaires measuring pain, resilience, depression and post traumatic growth. Hierarchical linear regression analysis was performed to identify the moderating effect of resilience on the relationships of pain with depression and post-traumatic growth after controlling for relevant covariates. RESULTS: In the regression model of depression, the effect of pain severity on depression was decreased (beta was changed from 0.47 to 0.33) after entering resilience into the model. In the final model, both pain and resilience were significant independent predictors for depression (beta = 0.33, p = 0.038 and beta = -0.47, p = 0.012, respectively). In the regression model of post-traumatic growth, the effect of pain severity became insignificant after entering resilience into the model. In the final model, resilience was a significant predictor (beta = 0.51, p = 0.016). CONCLUSIONS: Resilience potentially mitigated the negative effects of pain. Moreover, it independently contributed to reduced depression and greater post-traumatic growth. Our findings suggest that resilience might provide a potential target for intervention in SCI individuals. PMID- 24063295 TI - Comparison of three immobilisation systems for radiation therapy in head and neck cancer. PMID- 24063296 TI - Pathways of [Ca2+]i rise evoked by angiotensin II in MDCK renal tubular cells. AB - The effect of angiotensin II (Ang II) on cytosolic Ca2+ concentrations ([Ca2+]i) in MDCK renal tubular cells was explored. The Ca2+-sensitive fluorescent dye fura 2 was applied to measure [Ca2+]i. Ang II at concentrations of 5-40 uM induced a [Ca2+]i rise in a concentration-dependent manner. The response was reduced partly by removing Ca2+. Ang II evoked store-operated Ca2+ entry that was inhibited by La2+ and Gd3+. In the absence of extracellular Ca2+, incubation with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) or thapsigargin abolished Ang II-induced Ca2+ release. Inhibition of phospholipase C with U73122 abolished Ang II-induced [Ca2+]i rise. Three Ang II analogues [(ASN1,VAL5)-Ang II acetate, (SAR1,THR8)-Ang II acetate, (VAL5)-Ang II acetate] failed to induce a [Ca2+]i rise. Together, in MDCK cells, Ang II induced a [Ca2+]i rise via Ca2+ entry through store-operated Ca2+ channels and phospholipase C-dependent Ca2+ release from the endoplasmic reticulum. Moreover, Ang II's amino acid sequence is important in its stimulatory effect on [Ca2+]i. PMID- 24063297 TI - Taurine exerts anti-osteoclastogenesis activity via inhibiting ROS generation, JNK phosphorylation and COX-2 expression in RAW264.7 cells. AB - Taurine is one of the abundant amino acids present in mammalian cells. It exerts various physiological actions such as wound healing, radioprotection, neuroprotection and anti-anxiety. In the present study, we sought to determine if taurine could inhibit osteoclastogenesis and explore the potential role of cyclooxygenase-2 (COX-2) and Jun N-terminal kinase (JNK) with reactive oxygen species (ROS). The level of intracellular ROS generated by lipopolysaccharide (LPS) was measured with DCFH-DA staining and fluorescence microscopic analysis was also performed in response to taurine in RAW264.7 cells. The expression of COX-2 and phosphorylation status of JNK by LPS was analyzed by Western blot analysis in the presence of taurine. Osteoclastogenesis was induced by LPS in the absence or presence of taurine and TRAP assay was performed to confirm the formation of osteoclast cells. ROS production was significantly enhanced by LPS and taurine treatment inhibited the ROS generation in a dose-dependent manner. The fluorescence microscopic analysis clearly showed the inhibition of ROS staining by taurine. Western blot analysis indicated that taurine significantly inhibited LPS induced COX-2 protein expression and it also inhibited phosphorylation of JNK. Taurine at the same concentration inhibited osteoclastogenesis induced by LPS, suggesting that taurine prevent osteoclast differentiation by inhibiting ROS generation. Inhibition of COX-2 expression and JNK phoshorylation could be an important mechanism by which taurine exerts anti osteoclastogeneis. PMID- 24063298 TI - Investigating the biological properties of carbohydrate derived fulvic acid (CHD FA) as a potential novel therapy for the management of oral biofilm infections. AB - BACKGROUND: A number of oral diseases, including periodontitis, derive from microbial biofilms and are associated with increased antimicrobial resistance. Despite the widespread use of mouthwashes being used as adjunctive measures to control these biofilms, their prolonged use is not recommended due to various side effects. Therefore, alternative broad-spectrum antimicrobials that minimise these effects are highly sought after. Carbohydrate derived fulvic acid (CHD-FA) is an organic acid which has previously demonstrated to be microbiocidal against Candida albicans biofilms, therefore, the aims of this study were to evaluate the antibacterial activity of CHD-FA against orally derived biofilms and to investigate adjunctive biological effects. METHODS: Minimum inhibitory concentrations were evaluated for CHD-FA and chlorhexidine (CHX) against a range of oral bacteria using standardised microdilution testing for planktonic and sessile. Scanning electron microscopy was also employed to visualise changes in oral biofilms after antimicrobial treatment. Cytotoxicity of these compounds was assessed against oral epithelial cells, and the effect of CHD-FA on host inflammatory markers was assessed by measuring mRNA and protein expression. RESULTS: CHD-FA was highly active against all of the oral bacteria tested, including Porphyromonas gingivalis, with a sessile minimum inhibitory concentration of 0.5%. This concentration was shown to kill multi-species biofilms by approximately 90%, levels comparable to that of chlorhexidine (CHX). In a mammalian cell culture model, pretreatment of epithelial cells with buffered CHD-FA was shown to significantly down-regulate key inflammatory mediators, including interleukin-8 (IL-8), after stimulation with a multi-species biofilm. CONCLUSIONS: Overall, CHD-FA was shown to possess broad-spectrum antibacterial activity, with a supplementary function of being able to down-regulate inflammation. These properties offer an attractive spectrum of function from a naturally derived compound, which could be used as an alternative topical treatment strategy for oral biofilm diseases. Further studies in vitro and in vivo are required to determine the precise mechanism by which CHD-FA modulates the host immune response. PMID- 24063299 TI - Metabolic engineering of Lactococcus lactis influence of the overproduction of lipase enzyme. AB - The dairy industry uses lipase extensively for hydrolysis of milk fat. Lipase is used in the modification of the fatty acid chain length, to enhance the flavours of various chesses. Therefore finding the unlimited source of lipase is a concern of dairy industry. Due to the importance of lipase, this study was an attempt to express the lipase from Burkholderia cepacia in Lactococcus lactis. To achieve this, a gene associated with lipase transport was amplified and subcloned in inducible pNZ8148 vector, and subsequently transformed into Lc. lactis NZ9000. The enzyme assay as well as SDS-PAGE and western blotting were carried out to analysis the recombinant lipase expression. Nucleotide sequencing of the DNA insert from the clone revealed that the lipase activity corresponded to an open reading frame consisting of 1092 bp coding for a 37.5-kDa size protein. Blue colour colonies on nile blue sulphate agar and sharp band on 37.5-kD size on SDS PAGE and western blotting results confirm the successful expression of lipase by Lc. lactis. The protein assay also showed high expression, approximately 152.2 MUg/ml.h, of lipase by recombinant Lc. lactis. The results indicate that Lc. lactis has high potential to overproduce the recombinant lipase which can be used commercially for industrially purposes. PMID- 24063300 TI - Impact of lower pole calculi in patients undergoing retrograde intrarenal surgery. AB - OBJECTIVE: To assess if the presence of a lower pole stone (LPS) decreases the stone-free (SF) rate following retrograde intrarenal surgery (RIRS). The second purpose was to assess the result of RIRS for LPS and to identify predictors of SF status. PATIENTS AND METHODS: We retrospectively analyzed 205 procedures in 162 patients with renal stones treated by RIRS between January 2010 and January 2013 at a single institute. The SF status was defined as no residual fragments. Independent-sample t-tests and Chi-square tests were used for comparisons of means and proportions, respectively, between patients with or without LPS. Logistic regression models were used to assess prognostic factors influencing SF status in cases of LPS. RESULTS: LPS were present in 89 (54.9%) patients. There were no differences between patients with or without LPS regarding the mean operative time (p=0.77), the surgeon's experience (p=0.522), the length of hospital stay (p=0.269), and the SF rate (p=0.224). SF status after RIRS in patients with or without LPS was 74.1% and 78% (p=0.224), respectively. In the case of LPS, the presence of multiple stones and a history of percutaneous nephrolithotomy (PCNL) were predictive factors for occurrence of residual fragments in univariate analysis (p=0.037 and p=0.015). In multivariable analysis, only the presence of multiple stones remained as a predictive factor (p=0.027; HR=3.2), whereas a trend was observed when there was a history of PCNL (p=0.07; HR=3). CONCLUSION: The presence of a LPS does not alter the SF rate of RIRS even in cases of early experience. RIRS for LPS appears to be an effective technique, but special attention should be given to patients with multiple stones and/or a history of PCNL. PMID- 24063301 TI - Coupling XRD, EXAFS, and 13C NMR to study the effect of the carbon stoichiometry on the local structure of UC(1+/-x). AB - A series of uranium carbide samples, prepared by arc melting with a C/U ratio ranging from 0.96 to 1.04, has been studied by X-ray diffraction (XRD), (13)C nuclear magnetic resonance (NMR), and extended X-ray absorption fine structure (EXAFS). XRD determines phase uniqueness and the increase of the lattice parameter versus the carbon content. In contrast, (13)C NMR detects the different carbon environments in the lattice and in this study, clearly identifies the presence of discrete peaks for carbon in the octahedral lattice site in UC and an additional peak associated with excess carbon in hyperstoichiometric samples. Two peaks associated with different levels of carbon deficiency are detected for all hypostoichiometric compositions. More than one carbon environment is always detected by (13)C NMR. This exemplifies the difficulty in obtaining a perfect stoichiometric uranium monocarbide UC(1.00). The (13)C MAS spectra of uranium carbides exhibit the effects resulting from the carbon content on both the broadening of the peaks and on the Knight shift. An abrupt spectral change occurs between hypo- and hyperstoichiometric samples. The results obtained by EXAFS highlight subtle differences between the different stoichiometries, and in the hyperstoichiometric samples, the EXAFS results are consistent with the excess carbon atoms being in the tetrahedral interstitial position. PMID- 24063302 TI - Comparison of RefSeq protein-coding regions in human and vertebrate genomes. AB - BACKGROUND: Advances in high-throughput sequencing technology have yielded a large number of publicly available vertebrate genomes, many of which are selected for inclusion in NCBI's RefSeq project and subsequently processed by NCBI's eukaryotic annotation pipeline. Genome annotation results are affected by differences in available support evidence and may be impacted by annotation pipeline software changes over time. The RefSeq project has not previously assessed annotation trends across organisms or over time. To address this deficiency, we have developed a comparative protocol which integrates analysis of annotated protein-coding regions across a data set of vertebrate orthologs in genomic sequence coordinates, protein sequences, and protein features. RESULTS: We assessed an ortholog dataset that includes 34 annotated vertebrate RefSeq genomes including human. We confirm that RefSeq protein-coding gene annotations in mammals exhibit considerable similarity. Over 50% of the orthologous protein coding genes in 20 organisms are supported at the level of splicing conservation with at least three selected reference genomes. Approximately 7,500 ortholog sets include at least half of the analyzed organisms, show highly similar sequence and conserved splicing, and may serve as a minimal set of mammalian "core proteins" for initial assessment of new mammalian genomes. Additionally, 80% of the proteins analyzed pass a suite of tests to detect proteins that lack splicing conservation and have unusual sequence or domain annotation. We use these tests to define an annotation quality metric that is based directly on the annotated proteins thus operates independently of other quality metrics such as availability of transcripts or assembly quality measures. Results are available on the RefSeq FTP site [http://ftp.ncbi.nlm.nih.gov/refseq/supplemental/ProtCore/SM1.txt]. CONCLUSIONS: Our multi-factored analysis demonstrates a high level of consistency in RefSeq protein representation among vertebrates. We find that the majority of the RefSeq vertebrate proteins for which we have calculated orthology are good as measured by these metrics. The process flow described provides specific information on the scope and degree of conservation for the analyzed protein sequences and annotations and will be used to enrich the quality of RefSeq records by identifying targets for further improvement in the computational annotation pipeline, and by flagging specific genes for manual curation. PMID- 24063303 TI - Statement of retraction: Cognitive Behaviour Therapy. PMID- 24063305 TI - New spectral deconvolution algorithms for the analysis of polycyclic aromatic hydrocarbons and sulfur heterocycles by comprehensive two-dimensional gas chromatography-quadrupole mass spectrometery. AB - New mass spectral deconvolution algorithms have been developed for comprehensive two-dimensional gas chromatography/quadrupole mass spectrometry (GC * GC/qMS). This paper reports the first use of spectral deconvolution of full scan quadrupole GC * GC/MS data for the quantitative analysis of polycyclic aromatic hydrocarbons (PAH) and polycyclic aromatic sulfur heterocycles (PASH) in coal tar contaminated soil. A method employing four ions per isomer and multiple fragmentation patterns per alkylated homologue (MFPPH) is used to quantify target compounds. These results are in good agreement with GC/MS concentrations, and an examination of method precision, accuracy, selectivity, and sensitivity is discussed. MFPPH and SIM/1-ion concentration differences are also examined. PMID- 24063304 TI - Thrombin-targeted liposomes establish a sustained localized anticlotting barrier against acute thrombosis. AB - The goal of the present work was to design and test an acute-use nanoparticle based antithrombotic agent that exhibits sustained local inhibition of thrombin without requiring a systemic anticoagulant effect to function against acute arterial thrombosis. To demonstrate proof of concept, we functionalized the surface of liposomes with multiple copies of the direct thrombin inhibitor, d phenylalanyl-l-prolyl-l-arginyl-chloromethyl ketone (PPACK), which exhibits high affinity for thrombin as a free agent but manifests too rapid clearance in vivo to be effective alone. The PPACK-liposomes were formulated as single unilamellar vesicles, with a diameter of 170.78 +/- 10.59 nm and a near neutral charge. In vitro models confirmed the inhibitory activity of PPACK-liposomes, demonstrating a KI' of 172.6 nM. In experimental clots in vitro, treatment of formed clots completely abrogated any further clotting upon exposure to human plasma. The liposomes were evaluated in vivo in a model of photochemical-induced carotid artery injury, resulting in significantly prolonged arterial occlusion time over that of controls (69.06 +/- 5.65 min for saline treatment, N = 6, 71.33 +/- 9.46 min for free PPACK treated; N = 4, 85.75 +/- 18.24 min for precursor liposomes; N = 4, 139.75 +/- 20.46 min for PPACK-liposomes; P = 0.0049, N = 6). Systemic anticoagulant profiles revealed a rapid return to control levels within 50 min, while still maintaining antithrombin activity at the injury site. The establishment of a potent and long-acting anticoagulant surface over a newly forming clot with the use of thrombin targeted nanoparticles that do not require systemic anticoagulation to be effective offers an alternative site-targeted approach to the management of acute thrombosis. PMID- 24063306 TI - A highly sensitive mixed lanthanide metal-organic framework self-calibrated luminescent thermometer. AB - A new mixed lanthanide metal-organic framework thermometer Tb0.9Eu0.1PIA with the significantly high sensitivity of 3.53% per K has been realized by making use of an organic ligand, 5-(pyridin-4-yl)isophthalate, with higher triplet state energy. PMID- 24063307 TI - Catanionic gels based on cholic acid derivatives. AB - In this paper, the preparation and characterization of an anionic and a cationic surfactant obtained by chemical modifications of a natural bile acid (cholic acid) are reported. The bile acid was modified by introducing a diamine or a dicarboxylic aromatic residue on the lateral chain. The pure cationic surfactant self-assembles in a network of fibers with a cross-section gyration radius of about 15.1 A, providing hydrogels with a pH-dependent compactness. On the other hand, the anionic molecule gives rise to prolate ellipsoid micelles. Homogeneous catanionic mixtures have also been obtained, with molar fraction of each surfactant ranging from 0.125 to 0.875. At total surfactant concentration of 0.05% (w/v), the mixtures form gels of fibrils partially arranged in secondary twisted superstructures. Comparison of this concentration with the minimum gelation concentration of the pure cationic derivative (0.16% w/v) suggests that, in the mixtures, the presence of the electrostatic component in self-assembly of the molecules allows the formation of gels starting from more dilute samples. In view of these achievements, this work suggests that catanionic mixtures can be exploited to enhance the efficiency of gelators. PMID- 24063308 TI - Hemolytic activity of venom from crown-of-thorns starfish Acanthaster planci spines. AB - BACKGROUND: The crown-of-thorns starfish Acanthaster planci is a venomous species from Taiwan whose venom provokes strong hemolytic activity. To understand the hemolytic properties of A. planci venom, samples were collected from A. planci spines in the Penghu Islands, dialyzed with distilled water, and lyophilized into A. planci spine venom (ASV) powder. RESULTS: Both crude venom and ASV cause 50% hemolysis at a concentration of 20 MUg/mL. The highest hemolytic activity of ASV was measured at pH 7.0-7.4; ASV-dependent hemolysis was sharply reduced when the pH was lower than 3 or greater than 8. There was almost no hemolytic activity when the Cu2+ concentration was increased to 10 mM. Furthermore, incubation at 100 degrees C for 30 to 60 minutes sharply decreased the hemolytic activity of ASV. After treatment with the protease alpha-chymotrypsin, the glycoside hydrolase cellulase, and the membrane component cholesterin, the hemolytic activity of ASV was significantly inhibited. CONCLUSIONS: The results of this study provide fundamental information about A. planci spine venom. The hemolytic activity was affected by pH, temperature, metal ions, EDTA, cholesterin, proteases, and glycoside hydrolases. ASV hemolysis was inhibited by Cu2+, cholesterin, alpha-chymotrypsin, and cellulose, factors that might prevent the hemolytic activity of venom and provide the medical treatment for sting. PMID- 24063309 TI - A prospective longitudinal multicentre study of health related quality of life in ICU survivors with COPD. AB - INTRODUCTION: Mortality amongst COPD patients treated on the ICU is high. Health related quality of life (HRQL) after intensive care is a relevant concern for COPD patients, their families and providers of health care. Still, there are few HRQL studies after intensive care of this patient group. Our hypothesis was that HRQL of COPD patients treated on the ICU declines rapidly with time. METHODS: Fifty-one COPD patients (COPD-ICU group) with an ICU stay longer than 24 hours received a questionnaire at 6, 12 and 24 months after discharge from ICU. HRQL was measured using two generic instruments: the EuroQoL instrument (EQ-5D and EQ VAS) and the Short Form 36 Health Survey (SF-36). The results were compared to HRQL of two reference groups from the general population; an age- and sex adjusted reference population (Non-COPD reference) and a reference group with COPD (COPD reference). RESULTS: HRQL of the COPD-ICU group at 6 months after discharge from ICU was lower compared to the COPD reference group: Median EQ-5D was 0.66 vs. 0.73, P = 0.08 and median EQ-VAS was 50 vs.55, P < 0.05. There were no significant differences in the SF-36 dimensions between the COPD-ICU and COPD reference groups, although the difference in physical functioning (PF) approached statistical significance (P = 0.059). Patients in the COPD-ICU group who were lost to follow-up after 6 months had low HRQL scores at 6 months. Scores for patients who died were generally lower compared to patients who failed to respond to the questionnaire. The PF and social functioning (SF) scores in those who died were significantly lower compared to patients with a complete follow up. HRQL of patients in the COPD-ICU group that survived a complete 24 months follow up was low but stable with no statistically significant decline from 6 to 24 months after ICU discharge. Their HRQL at 24 months was not significantly different from HRQL in the COPD reference group. CONCLUSIONS: HRQL in COPD survivors after intensive care was low but did not decline from 6 to 24 months after discharge from ICU. Furthermore, HRQL at 24 months was similar to patients with COPD who had not received ICU treatment. PMID- 24063310 TI - Challenges and ideas from a research program on high-quality, evidence-based practice in school mental health. AB - This article reviews the progression of a research program designed to develop, implement, and study the implementation of "achievable" evidence-based practices (EBPs) in schools. We review challenges encountered and ideas to overcome them to enhance this avenue of research. The article presents two federally funded randomized controlled trials involving comparison of a four-component targeted intervention (Quality Assessment and Improvement, Family Engagement and Empowerment, Modular Evidence-Based Practice, Implementation Support) versus a comparison intervention focused on personal wellness. In both studies, primary aims focused on changes in clinician attitudes and behavior, including the delivery of high-quality EBPs and secondary aims focused on student-level impacts. A number of challenges, many not reported in the literature, are reviewed, and ideas for overcoming them are presented. Given the reality that the majority of youth mental health services are delivered in schools and the potential of school mental health services to provide a continuum of mental health care from promotion to intervention, it is critical that the field consider and address the logistical and methodological challenges associated with implementing and studying EBP implementation by clinicians. PMID- 24063311 TI - Pathway-based outlier method reveals heterogeneous genomic structure of autism in blood transcriptome. AB - BACKGROUND: Decades of research strongly suggest that the genetic etiology of autism spectrum disorders (ASDs) is heterogeneous. However, most published studies focus on group differences between cases and controls. In contrast, we hypothesized that the heterogeneity of the disorder could be characterized by identifying pathways for which individuals are outliers rather than pathways representative of shared group differences of the ASD diagnosis. METHODS: Two previously published blood gene expression data sets--the Translational Genetics Research Institute (TGen) dataset (70 cases and 60 unrelated controls) and the Simons Simplex Consortium (Simons) dataset (221 probands and 191 unaffected family members)--were analyzed. All individuals of each dataset were projected to biological pathways, and each sample's Mahalanobis distance from a pooled centroid was calculated to compare the number of case and control outliers for each pathway. RESULTS: Analysis of a set of blood gene expression profiles from 70 ASD and 60 unrelated controls revealed three pathways whose outliers were significantly overrepresented in the ASD cases: neuron development including axonogenesis and neurite development (29% of ASD, 3% of control), nitric oxide signaling (29%, 3%), and skeletal development (27%, 3%). Overall, 50% of cases and 8% of controls were outliers in one of these three pathways, which could not be identified using group comparison or gene-level outlier methods. In an independently collected data set consisting of 221 ASD and 191 unaffected family members, outliers in the neurogenesis pathway were heavily biased towards cases (20.8% of ASD, 12.0% of control). Interestingly, neurogenesis outliers were more common among unaffected family members (Simons) than unrelated controls (TGen), but the statistical significance of this effect was marginal (Chi squared P < 0.09). CONCLUSIONS: Unlike group difference approaches, our analysis identified the samples within the case and control groups that manifested each expression signal, and showed that outlier groups were distinct for each implicated pathway. Moreover, our results suggest that by seeking heterogeneity, pathway-based outlier analysis can reveal expression signals that are not apparent when considering only shared group differences. PMID- 24063313 TI - Structural, optical, and improved field-emission properties of tetrapod-shaped Sn doped ZnO nanostructures synthesized via thermal evaporation. AB - High-quality tetrapod-shaped Sn-doped ZnO (T-SZO) nanostructures have been successfully synthesized via the thermal evaporation of mixed Zn and Sn powder. The effects of the Sn dopant on the morphology, microstructure, optical, and field-emission (FE) properties of T-SZO were investigated. It was found that the growth direction of the legs of T-SZO is parallel to the [0001] crystal c-axis direction and that the incorporation of Sn in the ZnO matrix increases the aspect ratio of the tetrapods, leads to blue shift in the UV region, and considerably improves the FE performance. The results also show that tetrapod cathodes with around a 0.84 atom % Sn dosage have the best FE properties, with a turn-on field of 1.95 V/MUm, a current density of 950 MUA/cm2 at a field of 4.5 V/MUm, and a field-enhancement factor as high as 9556. PMID- 24063314 TI - pH/sugar dual responsive core-cross-linked PIC micelles for enhanced intracellular protein delivery. AB - Herein, a series of biocompatible, robust, pH/sugar-sensitive, core-cross-linked, polyion complex (PIC) micelles based on phenylboronic acid-catechol interaction were developed for protein intracellular delivery. The rationally designed poly(ethylene glycol)-b-poly(glutamic acid-co-glutamicamidophenylboronic acid) (PEG-b-P(Glu-co-GluPBA)) and poly(ethylene glycol)-b-poly(l-lysine-co-epsilon-3,4 dihydroxyphenylcarboxyl-L-lysine) (PEG-b-P(Lys-co-LysCA)) copolymers were successfully synthesized and self-assembled under neutral aqueous condition to form uniform micelles. These micelles possessed a distinct core-cross-linked core shell structure comprised of the PEG outer shell and the PGlu/PLys polyion complex core bearing boronate ester cross-linking bonds. The cross-linked micelles displayed superior physiological stabilities compared with their non cross-linked counterparts while swelling and disassembling in the presence of excess fructose or at endosomal pH. Notably, either negatively or positively charged proteins can be encapsulated into the micelles efficiently under mild conditions. The in vitro release studies showed that the release of protein cargoes under physiological conditions was minimized, while a burst release occurred in response to excess fructose or endosomal pH. The cytotoxicity of micelles was determined by cck-8 assay in HepG2 cells. The cytochrome C loaded micelles could efficiently delivery proteins into HepG2 cells and exhibited enhanced apoptosis ability. Hence, this type of core-cross-linked PIC micelles has opened a new avenue to intracellular protein delivery. PMID- 24063312 TI - Prediction of 7-year psychopathology from mother-infant joint attention behaviours: a nested case-control study. AB - BACKGROUND: To investigate whether later diagnosis of psychiatric disorder can be predicted from analysis of mother-infant joint attention (JA) behaviours in social-communicative interaction at 12 months. METHOD: Using data from a large contemporary birth cohort, we examined 159 videos of a mother-infant interaction for joint attention behaviour when children were aged one year, sampled from within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Fifty three of the videos involved infants who were later considered to have a psychiatric disorder at seven years and 106 were same aged controls. Psychopathologies included in the case group were disruptive behaviour disorders, oppositional-conduct disorder, attention-deficit/hyperactivity disorder, pervasive development disorder, anxiety and depressive disorders. Psychiatric diagnoses were obtained using the Development and Wellbeing Assessment when the children were seven years old. RESULTS: None of the three JA behaviours (shared look rate, shared attention rate and shared attention intensity) showed a significant association with the primary outcome of case-control status. Only shared look rate predicted any of the exploratory sub-diagnosis outcomes and was found to be positively associated with later oppositional-conduct disorders (OR [95% CI]: 1.5 [1.0, 2.3]; p = 0.041). CONCLUSIONS: JA behaviours did not, in general, predict later psychopathology. However, shared look was positively associated with later oppositional-conduct disorders. This suggests that some features of JA may be early markers of later psychopathology. Further investigation will be required to determine whether any JA behaviours can be used to screen for families in need of intervention. PMID- 24063315 TI - Value of serial echo-guided ramp studies in a patient with suspicion of device thrombosis after left ventricular assist device implantation. AB - Thrombus formation inside of the pump is a major cause for device malfunction following the left ventricular assist device (LVAD) implantation. We recently established a novel ramp test protocol facilitating continuous bedside echo monitoring to optimize LVAD function and diagnosing device malfunctions. We describe a case of 29-year-old woman undergoing HeartMate II LVAD implantation, in whom serial ramp studies were used to diagnose intra-device thrombus after device implantation. The 1st ramp study at postoperative day (POD) 26 revealed adequate reduction in ventricular size according to the increase in LVAD speed (left ventricular end-diastolic diameter [LVEDD] at minimum and maximum speeds, 68 and 37 mm, respectively). The patient was discharged home and received routine anticoagulation maintenance therapy. However, a 2nd ramp test was performed on POD 56 due to increased lactase dehydrogenase and brain natriuretic peptide levels and showed marked increase in left ventricle (LV) chamber size without adequate response to the LVAD speed changes (LVEDD at minimum and maximum speeds, 88 and 76 mm, respectively). Given the suspicion for partial pump thrombosis, the patient was immediately hospitalized and received intravenous heparin infusion. After the optimization of the intensive anticoagulation therapy, the patient underwent a 3rd ramp study, which showed a remarkable improvement of the adequate response to LVAD speed changes. The patients eventually underwent cardiac transplant successfully, and the partial clot was found inside of the pump. This case demonstrates the usefulness of serial ramp studies in patients who are suspected to have device thrombosis. PMID- 24063317 TI - Life review and life story books for people with mild to moderate dementia: a randomised controlled trial. AB - OBJECTIVES: To evaluate the effect of different pathways for developing a life story book (LSB) for people with dementia. METHOD: Preliminary randomised control trial; 23 people with dementia in care homes (mean age 86) randomly assigned to receive either 12 individual life review sessions and co-creating a LSB or a personal LSB created by their relatives as a 'gift' RESULTS: No difference in quality of life (quality of life-Alzheimer's disease (QOL-AD)) was observed between the two groups, six weeks after having received the LSB (F(1,20) = 0.08, p = 0.77). At this point, QOL-AD had improved for both groups, but there was a significant between-group difference at an intermediate assessment immediately after the life review sessions had been completed, before the LSBs were received (F(1, 20) = 5.11, p = 0.035), in favour of life review. A similar pattern was observed on autobiographical memory (extended autobiographical memory interview), with the life review group improving significantly more than the gift group during the life review sessions, but no difference was observed once all participants had had their LSB for six weeks. After the LSBs were produced - by either pathway - quality of relationship as rated by relatives improved significantly (F(2, 39) = 19.37, p < 0.001) and staff knowledge regarding the resident and attitudes to dementia improved. CONCLUSION: The creation of LSBs - either through a life review process or by relatives without involving the person with dementia - has benefits for people with dementia, relatives and staff in care homes. However, undertaking a life review requires training and supervision. PMID- 24063318 TI - Revalidation could be abused. PMID- 24063316 TI - CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction. AB - RATIONALE: After lung transplantation, insults to the allograft generally result in one of four histopathologic patterns of injury: (1) acute rejection, (2) lymphocytic bronchiolitis, (3) organizing pneumonia, and (4) diffuse alveolar damage (DAD). We hypothesized that DAD, the most severe form of acute lung injury, would lead to the highest risk of chronic lung allograft dysfunction (CLAD) and that a type I immune response would mediate this process. OBJECTIVES: Determine whether DAD is associated with CLAD and explore the potential role of CXCR3/ligand biology. METHODS: Transbronchial biopsies from all lung transplant recipients were reviewed. The association between the four injury patterns and subsequent outcomes were evaluated using proportional hazards models with time dependent covariates. Bronchoalveolar lavage (BAL) concentrations of the CXCR3 ligands (CXCL9/MIG, CXCL10/IP10, and CXCL11/ITAC) were compared between allograft injury patterns and "healthy" biopsies using linear mixed-effects models. The effect of these chemokine alterations on CLAD risk was assessed using Cox models with serial BAL measurements as time-dependent covariates. MEASUREMENTS AND MAIN RESULTS: There were 1,585 biopsies from 441 recipients with 62 episodes of DAD. An episode of DAD was associated with increased risk of CLAD (hazard ratio, 3.0; 95% confidence interval, 1.9-4.7) and death (hazard ratio, 2.3; 95% confidence interval, 1.7-3.0). There were marked elevations in BAL CXCR3 ligand concentrations during DAD. Furthermore, prolonged elevation of these chemokines in serial BAL fluid measurements predicted the development of CLAD. CONCLUSIONS: DAD is associated with marked increases in the risk of CLAD and death after lung transplantation. This association may be mediated in part by an aberrant type I immune response involving CXCR3/ligands. PMID- 24063326 TI - Nurses to have a vital role in new inspection regime. PMID- 24063327 TI - 'Ill-informed' debate obscuring causes of strain on emergency services. PMID- 24063328 TI - Why words matter. PMID- 24063335 TI - Vantage point - we can influence the political agenda. PMID- 24063336 TI - Accounting for care. PMID- 24063340 TI - Preparing to introduce personal health budgets. AB - A large-scale study ( Forder et al 2012 ) piloting personal health budgets for people with long-term conditions found that they improved patients' quality of life and psychological wellbeing. They were cost-effective and reduced the use of other healthcare services. From April next year, people receiving NHS continuing healthcare funding will have the right to ask for personal health budgets. Some clinical commissioning groups are also introducing them for mental health service users and patients with other long-term conditions. This article outlines the benefits and challenges of introducing personal health budgets, and suggests how nursing managers can begin to consider their role in implementing them. PMID- 24063341 TI - Evaluation of organisational culture and nurse burnout. AB - A survey of nurses working with older adults across three NHS trusts was conducted to explore how perceptions of the workplace affect nurse wellbeing. Standardised validated measures were used to assess burnout, perceived organisational support and organisational culture. Significant associations were found between innovative organisational culture and nurses' sense of personal accomplishment, which reduce the likelihood of burnout. Multiple regression showed experience of burnout to be predicted by the nature of organisational culture. It seems therefore that nurses' wellbeing may be affected by their perceptions of the working environment. Applications of this knowledge and suggestions for future research are discussed. PMID- 24063342 TI - Using the 7 Habits programme to develop effective leadership. AB - This article discusses a short leadership programme for nurse and allied health professional leaders working in a community or community hospital environment in England. It describes the adoption, adaption, implementation, delivery and interim evaluation of the programme. The article sets out the background that led to adoption of the 7 Habits for Healthcare programme and discusses the concepts outlined. It also reflects on feedback from delegates between three and nine months after they completed the programme, to explore how it has influenced them professionally and personally. PMID- 24063343 TI - Back to her roots. PMID- 24063344 TI - Dicarbaporphyrinoid systems. Synthesis of oxo-adj-dibenziphlorins. AB - A series of diformylbenzophenones were generated by sequentially reacting protected bromobenzaldehydes with n-butyllithium and ethyl N,N-dimethylcarbamate. The acetal protective groups were cleaved with refluxing formic acid. Vilsmeier Haack formylation of 2,2',4,4'-tetramethoxybenzophenone also afforded a related dialdehyde. MacDonald "2 + 2" condensation of three benzophenone dialdehydes with a dipyrrylmethane gave oxophlorin analogues constructed from two benzene and two pyrrole rings. The free base oxodibenziphlorins were rather unstable in solution, and in most cases these porphyrinoids were isolated as the corresponding trifluoroacetate salts. The spectroscopic properties of 6-oxo-adj-dibenziphlorins are consistent with a nonaromatic ring system. DFT calculations indicated that the macrocycles considerably diverge from planarity, particularly when methoxy substituents are present on the arene rings. PMID- 24063345 TI - Achromobacter xylosoxidans keratitis masquerading as recurrent erosion after LASIK. AB - PURPOSE: To describe the clinical stages and management of Achromobacter xylosoxidans keratitis with post-LASIK epithelial ingrowth in two patients. METHODS: Retrospective chart review. RESULTS: Both patients had been treated with topical antibiotics and corticosteroids for several weeks prior to presentation. Examination at presentation revealed significant areas of epithelial ingrowth without signs of acute inflammation, prompting an erroneous initial diagnosis of recurrent corneal erosion. A corneal infiltrate was eventually observed and A. xylosoxidans was cultured from both patients. Clinical resolution occurred with treatment consisting of topical fortified antibiotics. In one patient, the flap was lifted to obtain cultures and irrigate the stromal bed with fortified antibiotics. CONCLUSIONS: Post-LASIK epithelial ingrowth may have served as a risk factor for A. xylosoxidans infection. Classic signs of infectious keratitis were absent, delaying the diagnosis. Three clinical stages described herein may assist the clinician with diagnosis and customized management obviating the need for penetrating keratoplasty. PMID- 24063346 TI - Guava pomace: a new source of anti-inflammatory and analgesic bioactives. AB - BACKGROUND: Guava pomace is an example of the processing waste generated after the manufacturing process from the juice industry that could be a source of bioactives. Thus, the present investigation was carried out in order to evaluate the anti-inflammatory and antinociceptive potential and determinate the main phenolic compounds of a guava pomace extract (GPE). METHODS: The anti inflammatory activity was evaluated by carrageenan, dextran, serotonin, histamine induced paw edema and neutrophils migration in the peritoneal cavity models. Acetic acid-induced abdominal writhing and formalin test were performed to investigate the antinociceptive effects. In addition, the content of total phenolic and of individual phenolic compounds was determined by GC/MS. RESULTS: GPE showed anti-inflammatory activity by carrageenan, dextran, serotonin, histamine-induced paw edema and neutrophils migration in the peritoneal cavity models (p < 0.05). GPE also demonstrated antinociceptive activity by acetic acid induced abdominal writhing and formalin test (p < 0.05). The total phenolic value was 3.40 +/- 0.09 mg GAE/g and epicatechin, quercetin, myricetin, isovanilic and gallic acids were identified by GC/MS analysis. CONCLUSIONS: The presence of bioactive phenolic compounds as well as important effects demonstrated in animal models suggest that guava pomace could be an interesting source of anti inflammatory and analgesic substances. PMID- 24063349 TI - Paradiplozoon vaalense n. sp. (Monogenea: Diplozoidae) from the gills of moggel, Labeo umbratus (Smith, 1841), in the Vaal River System, South Africa. AB - An unidentified monogenean diplozoid species was collected from the gills of moggel in the Vaal River and Vaal Dam, South Africa. Specimens were removed from gills of the hosts and observed using light and electron microscopy to compare these diplozoids with known species. The second internal transcribed spacer (ITS2) of the ribosomal gene was amplified, sequenced and compared to that of other diplozoid taxa. Morphological species delimitation was used to determine the identity of these diplozoids, but they did not match the description of any diplozoid taxa. This species is recognized by the specific size of the hooks, number of plicae in posterior and trapezoid anterior projection of the median sclerite connecting to the clamp jaws via a single sclerite, occasionally with two small additional sclerites. Genetic characteristics based on sequence data from the ITS2 region also distinguish this taxon from all other diplozoid taxa. This South African diplozoid grouped in the same clade as Paradiplozoon ichthyoxanthon Avenant-Oldewage, 2013. Data clearly indicate that diplozoids collected from moggel represent a new, distinct taxon of Paradiplozoon Akhmerov, 1974 and are described here as Paradiplozoon vaalense n. sp. PMID- 24063347 TI - Double-targeting using a TrkC ligand conjugated to dipyrrometheneboron difluoride (BODIPY) based photodynamic therapy (PDT) agent. AB - A molecule 1 (IY-IY-PDT) was designed to contain a fragment (IY-IY) that targets the TrkC receptor and a photosensitizer that acts as an agent for photodynamic therapy (PDT). Molecule 1 had submicromolar photocytotoxicities to cells that were engineered to stably express TrkC (NIH3T3-TrkC) or that naturally express high levels of TrkC (SY5Y neuroblastoma lines). Control experiments showed that 1 is not cytotoxic in the dark and has significantly less photocytotoxicity toward cells that do not express TrkC (NIH3T3-WT). Other controls featuring a similar agent 2 (YI-YI-PDT), which is identical and isomeric with 1 except that the targeting region is scrambled (a YI-YI motif, see text), showed that 1 is considerably more photocytotoxic than 2 on TrkC(+) cells. Imaging live TrkC(+) cells after treatment with a fluorescent agent 1 (IY-IY-PDT) proved that 1 permeates into TrkC(+) cells and is localized in the lysosomes. This observation indirectly indicates that agent 1 enters the cells via the TrkC receptor. Consistent with this, the dose-dependent PDT effects of 1 can be competitively reduced by the natural TrkC ligand, neurotrophin NT3. PMID- 24063350 TI - Synthesis and structural characterization of group 4 metal alkoxide complexes of N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine and their use as initiators in the ring-opening polymerization (ROP) of rac-lactide under industrially relevant conditions. AB - A series of N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine (TOEEDH4) ligand precursors and their group 4 metal complexes have been prepared. The complexes have been characterized by single-crystal X-ray diffraction and (1)H NMR spectroscopy, highlighting the ability to systematically vary the number of TOEED ligands within the system. Initial catalytic data for the solvent-free, ring opening polymerization of rac-lactide (rac-LA), a promising degradable polymer produced from renewable resources, is reported. At 135 degrees C, it has been demonstrated that the activity of the complexes is enhanced by increasing the number of labile isopropoxide groups. When the temperature was further increased to 165 degrees C, all complexes demonstrated a far higher activity irrespective of the identity of the metal or number of labile initiator groups. Polymerization kinetics were monitored in real time using FT-IR spectroscopy with a diamond composite insertion probe and Ti4(TOEED)(O(i)Pr)12 was demonstrated to convert over 95% of the rac-LA within 160 min. PMID- 24063351 TI - Assembly of amphiphilic baskets into stimuli-responsive vesicles. Developing a strategy for the detection of organophosphorus chemical nerve agents. AB - We designed basket 1 to comprise a C3-symmetric hydrophobic cage (477 A(3)) at its southern edge and three polar ammonium caps at the northern edge. This amphiphilic molecule was observed to assemble into large unilamellar vesicles (350 nm, TEM) in water and thereby entrap dimethyl phenylphosphonate (184 A(3)) in its cavity (K(app) = (1.97 +/- 0.02) * 10(3) M(-1)). The entrapment of the organophosphonate, akin to soman in size (186 A(3)), triggers the transformation of the vesicular material into nanoparticles (100 nm, TEM). Stimuli-responsive vesicles, containing baskets of type 1 in their bilayer membrane, are unique assemblies and important for obtaining novel sensing devices. PMID- 24063352 TI - Using a single product (calcipotriene/betamethasone topical suspension) vs multiple products to manage body and scalp psoriasis: comparisons in resource utilization and costs. AB - OBJECTIVES: To compare resource utilization and costs among patients who used calcipotriene/betamethasone dipropionate topical suspension (Taclonex Scalp Topical Suspension, Leo Pharma A/S) vs those who used multiple body and scalp formulations for psoriasis. RESEARCH DESIGN AND METHODS: A retrospective study using Truven Health MarketScan Commercial Database from 2006-2011 was performed to identify patients with psoriasis (ICD code 696.1x). Two study cohorts analyzed were cohort A (used body-only formulations for psoriasis and switched on the index date to using calcipotriene/betamethasone dipropionate topical suspension alone) and cohort B (used multiple body and scalp formulations for psoriasis). Patients were required to be continuously enrolled during 180-days pre- and post index periods. Multiple regression analyses adjusting for baseline demographic and clinical covariates were performed. MAIN OUTCOMES MEASURES: Number of psoriasis-related outpatient visits, total healthcare costs, psoriasis-related costs, and use of systemic agents during post-index period. RESULTS: A total of 1923 patients were identified with at least one prescription for calcipotriene/betamethasone dipropionate scalp topical suspension (cohort A = 367, cohort B = 1556). Patients using multiple medications (cohort B) were associated with 48% higher number of outpatient visits as compared with those who used a single formulation (cohort A) after controlling for baseline covariates (p < 0.001). A generalized linear model adjusting for baseline covariates showed significantly higher post-index total and psoriasis-related healthcare costs for cohort B as compared with cohort A (both p < 0.001). Patients in Cohort B also had twice the odds of using systemic agents as compared to patients in Cohort A (p < 0.001). CONCLUSIONS: Patients with body and scalp psoriasis using a single product had significantly lower overall and psoriasis-related healthcare costs, needed fewer psoriasis-related outpatient visits, and used less systemic agents during the post-index period. A lack of robust clinical measures to define the disease severity may have limited the interpretations from this study. PMID- 24063353 TI - Development of a titanium dioxide-coated microfluidic-based photocatalyst assisted reduction device to couple high-performance liquid chromatography with inductively coupled plasma-mass spectrometry for determination of inorganic selenium species. AB - We developed a selective and sensitive hyphenated system employing a microfluidic based vapor generation (VG) system in conjunction with high-performance liquid chromatography (HPLC) separation and inductively coupled plasma-mass spectrometry (ICPMS) detection for the determination of trace inorganic selenium (Se) species. The VG system exploited poly(methyl methacrylate) (PMMA) substrates of high optical quality to fabricate a microfluidic-based photocatalyst-assisted reduction device (microfluidic-based PCARD). Moreover, to reduce the consumption of photocatalysts during analytical procedures, a microfluidic-based PCARD coated with titanium dioxide nanoparticles (nano-TiO2) was employed to avoid consecutive loading. Notably, to simplify the coating procedure and improve the stability of the coating materials, a dynamic coating method was utilized. Under the optimized conditions for the selenicals of interest, the online HPLC/TiO2-coated microfluidic-based PCARD/ICPMS system enabled us to achieve detection limits (based on 3sigma) of 0.043 and 0.042 MUg L(-1) for Se(IV) and Se(VI), respectively. Both Se(IV) and Se(VI) could be efficiently vaporized within 15 s, while a series of validation experiments indicated that our proposed method could be satisfactorily applied to the determination of inorganic Se species in the environmental water samples. PMID- 24063354 TI - Use of hyaluronic acid gel in the management of cicatricial ectropion: results and complications. AB - AIMS: To report our experience using hyaluronic acid gel injection in the lower eyelid to treat cicatricial ectropion. METHODS: Clinical records and literature review. RESULTS: Between November 2009 and June 2011, 12 lower eyelids of 11 patients with cicatricial ectropion were treated with hyaluronic acid gel. All 11 patients demonstrated improvement in the eyelid position after treatment but only 3 patients (27.3%) experimented total correction after injection. Although the correction was partial in the majority of the patients, the signs and symptoms associated with conjunctival and corneal exposure improved in all patients. Seven patients (63.7%) developed irregular fullness which resolved over time, but in 4 patients (36.3%) fullness persisted for one year. CONCLUSIONS: In our experience, hyaluronic acid gel is a nonsurgical, minimally invasive and safe technique that improves cicatricial ectropion, but with a poor cosmetic result that limits its use. This treatment could be considered only in patients who decline surgery or are poor surgical candidates, as the aesthetic result would not be acceptable to many. PMID- 24063355 TI - Development of a next-generation NIL library in Arabidopsis thaliana for dissecting complex traits. AB - BACKGROUND: The identification of the loci and specific alleles underlying variation in quantitative traits is an important goal for evolutionary biologists and breeders. Despite major advancements in genomics technology, moving from QTL to causal alleles remains a major challenge in genetics research. Near-isogenic lines are the ideal raw material for QTL validation, refinement of QTL location and, ultimately, gene discovery. RESULTS: In this study, a population of 75 Arabidopsis thaliana near-isogenic lines was developed from an existing recombinant inbred line (RIL) population derived from a cross between physiologically divergent accessions Kas-1 and Tsu-1. First, a novel algorithm was developed to utilize genome-wide marker data in selecting RILs fully isogenic to Kas-1 for a single chromosome. Seven such RILs were used in 2 generations of crossing to Tsu-1 to create BC1 seed. BC1 plants were genotyped with SSR markers so that lines could be selected that carried Kas-1 introgressions, resulting in a population carrying chromosomal introgressions spanning the genome. BC1 lines were genotyped with 48 genome-wide SSRs to identify lines with a targeted Kas-1 introgression and the fewest genomic introgressions elsewhere. 75 such lines were selected and genotyped at an additional 41 SNP loci and another 930 tags using 2b RAD genotyping by sequencing. The final population carried an average of 1.35 homozygous and 2.49 heterozygous introgressions per line with average introgression sizes of 5.32 and 5.16 Mb, respectively. In a simple case study, we demonstrate the advantage of maintaining heterozygotes in our library whereby fine-mapping efforts are conducted simply by self-pollination. Crossovers in the heterozygous interval during this single selfing generation break the introgression into smaller, homozygous fragments (sub-NILs). Additionally, we utilize a homozygous NIL for validation of a QTL underlying stomatal conductance, a low heritability trait. CONCLUSIONS: The present results introduce a new and valuable resource to the Brassicaceae research community that enables rapid fine mapping of candidate loci in parallel with QTL validation. These attributes along with dense marker coverage and genome-wide chromosomal introgressions make this population an ideal starting point for discovery of genes underlying important complex traits of agricultural and ecological significance. PMID- 24063356 TI - Alkylated trihydroxyacetophenone as a MALDI matrix for hydrophobic peptides. AB - Hydrophobic peptides are difficult to detect in matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), because of the hydrophilic properties of conventional matrices and the low affinity for hydrophobic peptides. Recently, we reported on alkylated dihydroxybenzoic acid (ADHB) as a matrix additive for hydrophobic peptides; however, the peptides were detected in the rim of the matrix-analyte dried spot. Here, we report on a novel matrix, alkylated trihydroxyacetophenone (ATHAP), which is a 2,4,6-trihydroxyacetophenone derivative incorporating a hydrophobic alkyl chain on the acetyl group and thus is expected to have an affinity for hydrophobic peptides. ATHAP increased the sensitivity of hydrophobic peptides 10-fold compared with alpha-cyano-4 hydroxycinnamic acid (CHCA), in which the detection of hydrophilic peptides was suppressed. The peptides were detected throughout the entire matrix-analyte dried spot using ATHAP, overcoming the difficulty of finding a "sweet spot" when using ADHB. In addition, ATHAP functioned alone as a matrix, unlike ADHB as an additive. In phosphorylase b digests analysis, hydrophobic peptides, which were not detected with CHCA for 1 pmol, were detected with this matrix, confirming that ATHAP led to increased sequence coverage and may extend the range of target analytes in MALDI-MS. PMID- 24063359 TI - Dementia in the movies: the clinical picture. AB - OBJECTIVES: Visual media influence the general public's perceptions and attitudes regarding people with mental conditions. This qualitative study investigates the depiction accuracy of dementia's clinical features in motion pictures. METHOD: Using the search terms 'dementia', 'Alzheimer's disease' and 'senility' movies with release dates between January 2000 and March 2012 were sought on the Internet Movie Database. Based on four selection criteria 23 movies were included. Independently, three researchers watched all movies, scored symptoms, capacities, and behaviors. Scores were discussed and refined during consensus meetings, resulting in a taxonomy of clinical features. RESULTS: Various features are found, most often cognitive symptoms. Behavioral features are also shown - retiring behavior more than agitation - and various emotions, but physical symptoms are rarely depicted. Capacities are infrequently presented and are unrealistic in several of the movies. CONCLUSION: The clinical picture of dementia portrayed in fictional movies is mild and may be misleading. PMID- 24063360 TI - Randomized controlled trial of Family Nurture Intervention in the NICU: assessments of length of stay, feasibility and safety. AB - BACKGROUND: While survival rates for preterm infants have increased, the risk for adverse long-term neurodevelopmental and behavioral outcomes remains very high. In response to the need for novel, evidence-based interventions that prevent such outcomes, we have assessed Family Nurture Intervention (FNI), a novel dual mother infant intervention implemented while the infant is in the Neonatal Intensive Care Unit (NICU). Here, we report the first trial results, including the primary outcome measure, length of stay in the NICU and, the feasibility and safety of its implementation in a high acuity level IV NICU. METHODS: The FNI trial is a single center, parallel-group, randomized controlled trial at Morgan Stanley Children's Hospital for mothers and their singleton or twin infants of 26-34 weeks gestation. Families were randomized to standard care (SC) or (FNI). FNI was implemented by nurture specialists trained to facilitate affective communication between mother and infant during specified calming interactions. These interactions included scent cloth exchange, sustained touch, vocal soothing and eye contact, wrapped or skin-to-skin holding, plus family-based support interactions. RESULTS: A total of 826 infants born between 26 and 34 weeks during the 3.5 year study period were admitted to the NICU. After infant and mother screening plus exclusion due to circumstances that prevented the family from participating, 373 infants were eligible for the study. Of these, we were unable to schedule a consent meeting with 56, and consent was withheld by 165. Consent was obtained for 150 infants from 115 families. The infants were block randomized to groups of N = 78, FNI and N = 72, SC. Sixteen (9.6%) of the randomized infants did not complete the study to home discharge, 7% of those randomized to SC and 12% of FNI infants. Mothers in the intervention group engaged in 3 to 4 facilitated one- to two-hour sessions/week. Intent to treat analyses revealed no significant difference between groups in medical complications. The mean length of stay was not significantly affected by the intervention. CONCLUSION: There was no significant effect demonstrated with this intervention amount on the primary short-term outcome, length of stay. FNI can be safely and feasibly implemented within a level IV NICU. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01439269. PMID- 24063361 TI - Functional studies of Drosophila zinc transporters reveal the mechanism for dietary zinc absorption and regulation. AB - BACKGROUND: Zinc is key to the function of many proteins, but the process of dietary zinc absorption is not well clarified. Current knowledge about dietary zinc absorption is fragmented, and mostly derives from incomplete mammalian studies. To gain a comprehensive picture of this process, we systematically characterized all zinc transporters (that is, the Zip and ZnT family members) for their possible roles in dietary zinc absorption in a genetically amenable model organism, Drosophila melanogaster. RESULTS: A set of plasma membrane-resident zinc transporters was identified to be responsible for absorbing zinc from the lumen into the enterocyte and the subsequent exit of zinc to the circulation. dZip1 and dZip2, two functionally overlapping zinc importers, are responsible for absorbing zinc from the lumen into the enterocyte. Exit of zinc to the circulation is mediated through another two functionally overlapping zinc exporters, dZnT1, and its homolog CG5130 (dZnT77C). Somewhat surprisingly, it appears that the array of intracellular ZnT proteins, including the Golgi resident dZnT7, is not directly involved in dietary zinc absorption. By modulating zinc status in different parts of the body, we found that regulation of dietary zinc absorption, in contrast to that of iron, is unresponsive to bodily needs or zinc status outside the gut. The zinc transporters that are involved in dietary zinc absorption, including the importers dZip1 and dZip2, and the exporter dZnT1, are respectively regulated at the RNA and protein levels by zinc in the enterocyte. CONCLUSIONS: Our study using the model organism Drosophila thus starts to reveal a comprehensive sketch of dietary zinc absorption and its regulatory control, a process that is still incompletely understood in mammalian organisms. The knowledge gained will act as a reference for future mammalian studies, and also enable an appreciation of this important process from an evolutionary perspective. PMID- 24063362 TI - Blood transfusion for upper gastrointestinal bleeding: is less more again? AB - BACKGROUND: The hemoglobin threshold for transfusion of red blood cells in patients with acute gastrointestinal (GI) bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy. METHODS: OBJECTIVE: The objective was to prove that the restrictive threshold for red blood cell transfusion in patients with acute upper GI bleeding (UGIB) was safer and more effective than a liberal transfusion strategy. RESULTS: In total, 225 patients assigned to the restrictive strategy (51%) and 65 assigned to the liberal strategy (15%) did not receive transfusions (P <0.001). The probability of survival at 6 weeks was higher in the restrictive-strategy group than in the liberal-strategy group (95% versus 91%; hazard ratio (HR) for death with restrictive strategy, 0.55; 95% confidence interval (CI) 0.33 to 0.92; P = 0.02). Further bleeding occurred in 10% of the patients in the restrictive-strategy group and in 16% of the patients in the liberal-strategy group (P = 0.01), and adverse events occurred in 40% and 48%, respectively (P = 0.02). The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer (HR 0.70, 95% CI 0.26 to 1.25) and was significantly higher in the subgroup of patients with cirrhosis and Child Pugh class A or B disease (HR 0.30, 95% CI 0.11 to 0.85) but not in those with cirrhosis and Child-Pugh class C disease (HR 1.04, 95% CI 0.45 to 2.37). Within the first 5 days, the portal-pressure gradient increased significantly in patients assigned to the liberal strategy (P = 0.03) but not in those assigned to the restrictive strategy. CONCLUSIONS: Compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute UGIB. PMID- 24063363 TI - Divergent mechanisms for enzymatic excision of 5-formylcytosine and 5 carboxylcytosine from DNA. AB - 5-Methylcytosine (mC) is an epigenetic mark that impacts transcription, development, and genome stability, and aberrant DNA methylation contributes to aging and cancer. Active DNA demethylation involves stepwise oxidation of mC to 5 hydroxymethylcytosine, 5-formylcytosine (fC), and potentially 5-carboxylcytosine (caC), excision of fC or caC by thymine DNA glycosylase (TDG), and restoration of cytosine via follow-on base excision repair. Here, we investigate the mechanism for TDG excision of fC and caC. We find that 5-carboxyl-2'-deoxycytidine ionizes with pK(a) values of 4.28 (N3) and 2.45 (carboxyl), confirming that caC exists as a monoanion at physiological pH. Calculations do not support the proposal that G.fC and G.caC base pairs adopt a wobble structure that is recognized by TDG. Previous studies show that N-glycosidic bond hydrolysis follows a stepwise (S(N)1) mechanism, and that TDG activity increases with pyrimidine N1 acidity, that is, leaving group quality of the target base. Calculations here show that fC and the neutral tautomers of caC are acidic relative to other TDG substrates, but the caC monoanion exhibits poor acidity and likely resists TDG excision. While fC activity is independent of pH, caC excision is acid-catalyzed, and the pH profile indicates that caC ionizes in the enzyme-substrate complex with an apparent pKa of 5.8, likely at N3. Mutational analysis reveals that Asn191 is essential for excision of caC but dispensable for fC activity, indicating that N191 may stabilize N3-protonated forms of caC to facilitate acid catalysis and suggesting that N191A-TDG could potentially be useful for studying DNA demethylation in cells. PMID- 24063364 TI - microRNA-140 targets RALA and regulates chondrogenic differentiation of human mesenchymal stem cells by translational enhancement of SOX9 and ACAN. AB - Lesions of articular cartilage do not heal spontaneously. One treatment strategy would be to make cartilage in the laboratory by directed chondrogenic differentiation of mesenchymal stem cells (MSCs). To promote our understanding of the molecular control of chondrogenesis, we have compared the changes in microRNAs (miRNAs) during in vitro chondrogenesis of MSCs with those observed in uncultured and dedifferentiated articular chondrocytes (ACs). Several miRNAs showed a reciprocal relationship during the differentiation of MSCs and dedifferentiation of ACs. miR-140-5p and miR-140-3p changed the most during in vitro chondrogenesis, they were the miRNAs most highly expressed in tissue engineered chondrocytes, and they were also among the miRNAs most highly expressed in uncultured ACs. There was a 57% overlap for the 100 most highly expressed miRNAs in differentiated MSCs and uncultured ACs, but for other miRNAs, the expression pattern was quite different. We transiently and stably inhibited and overexpressed miR-140-5p and miR-140-3p in differentiating MSCs and dedifferentiating ACs, respectively, to describe global effects and identify and validate new targets. Surprisingly, SOX9 and aggrecan proteins were found to be downregulated in anti-miR-140 transduced differentiating MSCs despite unchanged mRNA levels. This suggests that miR-140 stimulates in vitro chondrogenesis by the upregulation of these molecules at the protein level. RALA, a small GTPase, was identified as a miR-140 target and knockdown experiments showed that RALA regulated SOX9 at the protein level. These observations shed new light on the effect of miR-140 for chondrogenesis in vitro and in vivo. PMID- 24063366 TI - Improved transfection in human mesenchymal stem cells: effective intracellular release of pDNA by magnetic polyplexes. AB - AIM: Magnetically guided transfection has been shown as a promising approach for the genetic modification of cells. We observed that polyethylenimine (PEI) condensed pDNA, combined with magnetic nanoparticles (MNPs) via biotin streptavidin interactions could provide higher transfection efficiency than pDNA/PEI alone, even without the application of a magnetic force. Therefore, we intended to investigate the beneficial properties of MNP-based transfection. MATERIALS & METHODS: We performed three-color fluorescent labeling of magnetic transfection complexes and traced them inside human mesenchymal stem cells over time using confocal microscopy in order to study pDNA release kinetics by colocalization studies. RESULTS: We demonstrated that MNP-combined pDNA/PEI complexes provide more rapid and efficient release of pDNA than pDNA/PEI alone, which could be explained by the retention of PEI on the surface of the MNPs due to strong biotin-streptavidin interactions. CONCLUSION: The process of pDNA liberation may significantly influence the efficiency of the transfection vector. Therefore, it should be carefully considered when creating novel gene delivery agents. PMID- 24063365 TI - Evaluation of facilitative supervision visits in primary health care service delivery in Northern Ghana. AB - BACKGROUND: In Ghana's health delivery services, facilitative supervisory visit (FSV) as a system of management is new. This paper presents the standard evaluation results of FSV, which formed an integral part of the community-based health planning services (CHPS) initiative. METHODS: The study was conducted in the Upper West Region of Ghana. The Project developed guidelines and tools for FSV for four different health system levels--regional, district, sub-district and community levels. Electronic data from all four levels representing quarterly results were compiled into their annual equivalents, and summarized graphically for comparison. RESULTS: The data show that all the nine districts embraced the FSV concept even though they differed markedly with regard to the degree of adherence to some set benchmarks. Three DHMTs (Wa Municipal, Lawra and Jirapa) were graded as good while the remaining six DHMTs were adjudged as fair in relation to management of supplies, transport and equipment, information, meeting, and technical support. CONCLUSIONS: The data further suggest that there is much to gain both individually and institutionally from FSVs. Generally, FSVs are crucial to the delivery of primary health care services in especially rural areas. PMID- 24063367 TI - Prevalence and cost of hospital medical errors in the general and elderly United States populations. AB - OBJECTIVE: The primary objective of this study was to quantify the differences in the prevalence rate and costs of hospital medical errors between the general population and an elderly population aged >=65 years. METHODS: Methods from an actuarial study of medical errors were modified to identify medical errors in the Premier Hospital Database using data from 2009. Visits with more than four medical errors were removed from the population to avoid over-estimation of cost. Prevalence rates were calculated based on the total number of inpatient visits. RESULTS: There were 3,466,596 total inpatient visits in 2009. Of these, 1,230,836 (36%) occurred in people aged >= 65. The prevalence rate was 49 medical errors per 1000 inpatient visits in the general cohort and 79 medical errors per 1000 inpatient visits for the elderly cohort. The top 10 medical errors accounted for more than 80% of the total in the general cohort and the 65+ cohort. The most costly medical error for the general population was postoperative infection ($569,287,000). Pressure ulcers were most costly ($347,166,257) in the elderly population. LIMITATIONS: This study was conducted with a hospital administrative database, and assumptions were necessary to identify medical errors in the database. Further, there was no method to identify errors of omission or misdiagnoses within the database. CONCLUSIONS: This study indicates that prevalence of hospital medical errors for the elderly is greater than the general population and the associated cost of medical errors in the elderly population is quite substantial. Hospitals which further focus their attention on medical errors in the elderly population may see a significant reduction in costs due to medical errors as a disproportionate percentage of medical errors occur in this age group. PMID- 24063368 TI - Investigation of seasonal variability of vestibular neuronitis. AB - OBJECTIVE: To determine if the incidence of vestibular neuronitis displays seasonal variation. METHODS: A retrospective case review was performed to determine the monthly and quarterly incidence of vestibular neuronitis over a 36 month period. Incidence values were compiled, and the chi-square test and Rayleigh test for circular means were used to assess for uneven distribution and seasonality, respectively. RESULTS: Fifty-two patients were diagnosed with vestibular neuronitis during the study period. The 2009-2010 study year showed uneven distribution and evidence of seasonality (R = 7.211, p < 0.001). However, the other two study years did not show statistical significance using either the chi-square test or Rayleigh test. In addition, when incidence values were aggregated across all three years of the study, neither the chi-square test nor Rayleigh test showed statistical significance. CONCLUSION: The present study found minimal evidence of seasonality in the incidence of vestibular neuronitis. These findings are consistent with studies of seasonality observed for other inner-ear disorders thought to be virally mediated. PMID- 24063370 TI - Crystalline and glassy phases in the Cs/Bi/As/S system. AB - The quaternary Cs2S/Bi/As/S system was studied in an attempt to introduce two different asymmetric but isoelectronic building units, namely, [Bi(III)(x)S(y)] and [As(III)(x)S(y)], in a single structure. Reactions with a comparatively lower equivalent of arsenic in the Cs2S/Bi/As/S mixture led to the crystalline compound Cs3Bi(AsS4)2. The structure features tetrahedral [As(V)S4](3-) connected to Bi(III) centers to give infinite (1/infinity)[Bi(AsS4)2(3-)] chains. When the basicity was raised in these low arsenic fluxes by increasing the Cs2S fraction, the crystalline compound Cs9Bi(AsS4)4, also featuring [As(V)S4](3-) anions, was formed. On the other hand, arsenic-rich mixtures of Cs2S/Bi/As/S led to the formation of the glassy phase Cs2BiAs3S7, which contains As(III) species. X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and pair distribution function (PDF) analysis indicate the presence of As(III)-containing [AsnS2n+1] fragments in the glass structure. Several glasses in the series Cs(n 1)BiAs(n)S(2n+1) were also prepared using solid-state fusion reactions. The band gaps of the Cs(n-1)BiAs(n)S(2n+1) glasses are in the range of 1.51-1.81 eV, while that of the crystalline compound Cs3Bi(AsS4)2 is ~2.33 eV. The thermal and optical behaviors of these compounds are correlated with their structures and building units. PMID- 24063369 TI - Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI). AB - Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (PfFAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations. PMID- 24063371 TI - Extraversion and behavioral activation: integrating the components of approach. AB - This investigation evaluates the structure and correlates of lower order traits related to approach, specifically, facets of extraversion and behavioral activation system (BAS) sensitivity. A 3-factor structure of approach was derived in community and clinical samples: assertiveness, enthusiasm, and sensation seeking. All factors were positively associated with Openness/Intellect scores. Enthusiasm and assertiveness were both negatively associated with Neuroticism scores, but were distinguished by associations with Agreeableness and Conscientiousness. Sensation seeking was negatively associated with Conscientiousness scores. The 3 factors demonstrated a unique profile of association with components of impulsivity. Enthusiasm and assertiveness were negatively related to psychopathological symptoms, whereas sensation seeking was largely independent of psychopathology. Results suggest that approach is associated with 3 subfactors, which differ in their pattern or magnitude of associations with other variables, thus underscoring the importance of distinguishing among them. Further, results support the construct validity of the Assertiveness and Enthusiasm aspect scales of the Big Five Aspect Scales to assess traits at this level of the personality hierarchy. PMID- 24063372 TI - Single electrode genosensor for simultaneous determination of sequences encoding hemagglutinin and neuraminidase of avian influenza virus type H5N1. AB - The duo-genosensor consisting of two different oligonucleotide probes immobilized covalently on the surface of one gold electrode via Au-S bond formation was used for simultaneous determination of two different oligonucleotide targets. One of the probes, decorated on its 5'-end with ferrocene (SH-ssDNA-Fc), is complementary to the cDNA representing a sequence encoding part of H5 hemagglutinin from H5N1 virus. The second probe, decorated on its 5'-end with methylene blue (SH-ssDNA-MB), is complementary to cDNA representing the fragment of N1 neuraminidase from the same virus. The presence of both probes on the surface of gold electrodes was confirmed with Osteryoung square-wave voltammetry (OSWV). The changes in redox activity of both redox active complexes before and after the hybridization process were used as analytical signal. The peak at +400 +/- 2 mV was observed in the presence of 40 nM ssDNA used as a target for SH ssDNA-Fc probe. This peak increased with the increase of concentration of target ssDNA. It indicates the "signal on" mode of analytical signal generation. The peak at -250 +/- 4 mV, characteristic for SH-ssDNA-MB probe, was decreasing with the increase of the concentration of the complementary ssDNA target starting from 8 to 100 nM. This indicates the generation of electrochemical signal according to the "signal off" mode. The proposed duo-genosensor is capable of simultaneous, specific, and good sensitivity probing for the sequences derived from genes encoding two main markers of the influenza virus, hemagglutinin and neuraminidase. PMID- 24063373 TI - Inverted papillomas of the nasal and paranasal sinuses that involve the ocular/adnexal region. AB - PURPOSE: To review the management of inverted papillomas presenting to oculoplastic surgeons at three institutions and the outcomes of treatment. METHODS: A retrospective review of medical notes of patients presenting with inverted papillomas that invaded the orbit during a 7-year period. RESULTS: In total, six Caucasian patients were identified, the mean age at presentation was 63 years. The presenting features were nasal blockage, epiphora, proptosis and medial canthal mass. Four were classed as Stage IV and two as Stage III disease. The sites of origin were the lateral wall of the nose, frontal sinus, ethmoidal sinus and lacrimal system. The lesions were radiologically homogenous tumours with variable degrees of nose, paranasal sinuses and orbital involvement. Four out of six had foci of malignant transformation (two with carcinoma in situ and two with invasive squamous cell carcinoma). All were treated with surgical excision and three with adjunctive radiotherapy. One patient needed orbital exentration and subsequently died from complications of the tumour bleeding. CONCLUSION: Inverted papillomas that invade the orbit are likely to be malignant and locally aggressive tumours. Early and wide surgical excision provides the best chance of removal and minimises recurrence. Radiotherapy may be a useful adjunct. Following surgical intervention, all cases require long term observation to ensure tumour control. PMID- 24063374 TI - Investigations on the interactions of proteins with polyampholyte-coated magnetite nanoparticles. AB - Magnetite nanoparticles have been widely used in biomedical applications, especially as contrast agents in magnetic resonance imaging. In this work, the antifouling property of polyampholyte-coating (poly(acrylic acid) (PAA)-co-3 (diethylamino)-propylamine (DEAPA)) is systematically demonstrated. Polyampholyte coated magnetite nanoparticles (NP1) and PAA-coated magnetite nanoparticles (NP2) were synthesized to investigate their interactions with BSA and lysozyme (LYZ) by high-resolution turbidimetric titration, dynamic light scattering (DLS), and isothermal titration calorimetry (ITC) in phosphate buffer saline (PBS) buffer with pH 7.4. The abundant carboxyl groups of NP2 and polyampholyte coating of NP1 were well proven by TGA, zeta-potential, and titration methods. Turbidity change shows that NP1 have no interaction with both proteins other than NP2 having adsorption with LYZ, which was further confirmed by DLS. Besides, ITC gives the exact enthalpy change and unveils the binding stoichiometry for each interaction. All characterizations demonstrate the antifouling property of NP1 to both negatively charged protein BSA and positively charged protein LYZ. The polyampholyte-coated magnetite nanoparticles were shown to be a promising material to eliminate the strong interaction with proteins in complex medium, for example, when it is applied for MRA contrast agents with long in vivo circulation time. PMID- 24063375 TI - Uteroplacental circulation and maternal/fetal health.. PMID- 24063377 TI - Maternal stress and placental vascular function and remodeling. AB - This review discusses the importance of placental vascular development, as reflected by placental angiogenesis and placental blood flow, to placental function in normal pregnancies. We then summarize our current understanding of how maternal stress, including inadequate maternal nutrition as well as the application of assisted reproductive technologies (ART), leads to compromised placental angiogenesis and function and the subsequent effects on fetal and neonatal growth and development. Finally, we discuss several promising therapeutic approaches to 'rescue' placental vascular development and function in compromised pregnancies, leading to improved pregnancy and postnatal outcomes. PMID- 24063379 TI - Role of chymase in preeclampsia. AB - Chymase is a chymotrypsin-like serine protease. It has been identified as a key angiotensin converting enzyme (ACE)-independent and endothelin converting enzyme (ECE)-independent converting enzyme that generates angiotensin II and endothelin 1 (ET-1). As an inflammatory protease, chymase participates in multiple inflammatory responses in the vasculature which drive cytokine production and adhesion molecule expression. Chymase is also involved in extracellular matrix remodeling in both vascular and non-vascular tissues. Consequently, chymase has been implicated in the pathogenesis of multiple cardiovascular, immune, and inflammatory diseases. Recent studies have shown that chymase expression and activity are increased in placental trophoblasts and in the maternal vascular endothelium in women diagnosed with preeclampsia, a hypertensive disorder in human pregnancy. The present review will address the potential roles of chymase mediated placental and vascular dysfunction in preeclampsia. The effects of chymase on inflammatory responses associated with endothelial activation/dysfunction in preeclampsia are also discussed. PMID- 24063378 TI - Role of endothelin in uteroplacental circulation and fetal vascular function. AB - Endothelins are 21-amino acid peptides involved in vascular homeostasis. Three types of peptide have been identified, with endothelin-1 (ET-1) being the most potent vasoconstrictor currently known. Two endothelin receptor subtypes are found in various tissues, including the brain, heart, blood vessel, lung, and placenta. The ETA-receptor is associated with vasoconstriction in vascular smooth muscle. Conversely, the ETB-receptor can elicit a vasoconstrictor effect in vascular smooth muscle and a vasodilator effect via its action in endothelial cells. Both receptors play a key role in maintaining circulatory homeostasis and vascular function. Changes in ET-1 expression are found in various disease states, and overexpression of ET-1 is observed in hypertension and preeclampsia in pregnancy. Placental localization of ET-1 implies a key role in regulating the uteroplacental circulation. Additionally, ET-1 is important in the fetal circulation and is involved in the pulmonary circulation and closure of the ductus arteriosus after birth, as well as fetal growth constriction in utero. ET receptor antagonists and nitric oxide donors may provide therapeutic potential in treating conditions associated with overexpression of ET and hypertension. PMID- 24063376 TI - Vasotrophic regulation of age-dependent hypoxic cerebrovascular remodeling. AB - Hypoxia can induce functional and structural vascular remodeling by changing the expression of trophic factors to promote homeostasis. While most experimental approaches have been focused on functional remodeling, structural remodeling can reflect changes in the abundance and organization of vascular proteins that determine functional remodeling. Better understanding of age-dependent hypoxic macrovascular remodeling processes of the cerebral vasculature and its clinical implications require knowledge of the vasotrophic factors that influence arterial structure and function. Hypoxia can affect the expression of transcription factors, classical receptor tyrosine kinase factors, non-classical G-protein coupled factors, catecholamines, and purines. Hypoxia's remodeling effects can be mediated by Hypoxia Inducible Factor (HIF) upregulation in most vascular beds, but alterations in the expression of growth factors can also be independent of HIF. PPARgamma is another transcription factor involved in hypoxic remodeling. Expression of classical receptor tyrosine kinase ligands, including vascular endothelial growth factor, platelet derived growth factor, fibroblast growth factor and angiopoietins, can be altered by hypoxia which can act simultaneously to affect remodeling. Tyrosine kinase-independent factors, such as transforming growth factor, nitric oxide, endothelin, angiotensin II, catecholamines, and purines also participate in the remodeling process. This adaptation to hypoxic stress can fundamentally change with age, resulting in different responses between fetuses and adults. Overall, these mechanisms integrate to assure that blood flow and metabolic demand are closely matched in all vascular beds and emphasize the view that the vascular wall is a highly dynamic and heterogeneous tissue with multiple cell types undergoing regular phenotypic transformation. PMID- 24063381 TI - Calcitonin gene-related family peptides in vascular adaptations, uteroplacental circulation, and fetal growth. AB - Maternal vascular adaptations, implantation of embryo, and placental growth and development are crucial for overall well-being of the fetus and are controlled by a range of signals, including growth factors and steroid hormones. The calcitonin (CT)/calcitonin gene-related peptide (CGRP) family peptides have been the focus of emerging studies, and these peptides appear to mediate some of the critical functions during pregnancy. Three peptides of the CT/CGRP family, CGRP, adrenomedullin, and intermedin, working through their overlapping receptor components, exert significant positive effects on vascular adaptations during pregnancy, uteroplacental vascular functions, and fetal growth. Many of the effects of these peptides are regulated by sex steroid hormones. Use of peptide antagonist in animals, together with genetic animal models, strongly implicates the importance of these 3 peptides in human pregnancy and related complications. However, insights into the underlying mechanisms of their actions on fetal placental growth are limited by the lack of specificity of currently available antagonists. Future studies with specific knockdown of receptor components and/or peptides should be helpful for better understanding of these mechanisms and for the development of target-specific therapies to prevent pregnancy complications. PMID- 24063380 TI - Antenatal hypoxia and pulmonary vascular function and remodeling. AB - This review provides evidence that antenatal hypoxia, which represents a significant and worldwide problem, causes prenatal programming of the lung. A general overview of lung development is provided along with some background regarding transcriptional and signaling systems of the lung. The review illustrates that antenatal hypoxic stress can induce a continuum of responses depending on the species examined. Fetuses and newborns of certain species and specific human populations are well acclimated to antenatal hypoxia. However, antenatal hypoxia causes pulmonary vascular disease in fetuses and newborns of most mammalian species and humans. Disease can range from mild pulmonary hypertension, to severe vascular remodeling and dangerous elevations in pressure. The timing, length, and magnitude of the intrauterine hypoxic stress are important to disease development, however there is also a genetic-environmental relationship that is not yet completely understood. Determining the origins of pulmonary vascular remodeling and pulmonary hypertension and their associated effects is a challenging task, but is necessary in order to develop targeted therapies for pulmonary hypertension in the newborn due to antenatal hypoxia that can both treat the symptoms and curtail or reverse disease progression. PMID- 24063383 TI - Pregnancy, programming and preeclampsia: gap junctions at the nexus of pregnancy induced adaptation of endothelial function and endothelial adaptive failure in PE. AB - The challenge of pregnancy to the mother requires that her own metabolic and endocrine needs be met while also taking on the literally growing demands of the unborn child. While all of the mother's organs require continued support, the uterus and now added placenta must also develop substantially. One critical area of adaptation is thus the ability to provide added blood flow over and above that already serving the preexisting maternal organs. Previous reviews have covered in detail how this is achieved from an endocrine or indeed vascular physiology standpoint and we will not repeat that here. Suffice it to say in addition to new vessel growth, there is also the need to achieve reduced vascular resistance through maintenance of endothelial vasodilation, particularly through NO and PGI2 production in response to multiple agonists and their associated cell signaling systems. In this review, we continue our focus on pregnancy adaptive changes at the level of cell signaling, with a particular emphasis now on the developing story of the critical role of gap junctions. Remapping of cell signaling itself beyond changes in individual hormones and respective receptors brings about global changes in cell function, and recent studies have revealed that such post receptor changes in cell signaling are equally if not more important in the process of pregnancy adaptation of endothelial function than the upregulated expression of vasodilator synthetic pathways themselves. The principle significance, however, of reviewing this aspect of pregnancy adaptation of endothelial cell function is that these same gap junction proteins that mediate pregnancy-adapted changes in vasodilatory signaling function may also be the focal point of failure in diseased pregnancy, and clues as to how and why are given by comparing studies of Cx43 functional suppression at wound sites with studies of preeclamptic pregnancy. If preeclamptic pregnancy is indeed a pregnancy misconstrued by the body in endocrine terms to be a wound, then the kinases so activated that correspondingly suppress Cx43 function in the vascular endothelium may also be valid pharmacologic targets for novel therapies in the near future. PMID- 24063384 TI - Endothelial cell function in utero-placental circulation physiology and pathophysiology. AB - Endothelial cells in the utero-placental circulation play an important physiological role in maintaining the fetoplacental vessels in a vasodilated state as these vessels are non-innervated. These endothelial cells produce both prostacyclin and nitric oxide which in addition to causing vasodilation also prevent platelet aggregation and adhesion of platelets to endothelial cells. Most investigators are of the opinion that energy metabolism of endothelial cells and ATP generation is mainly glycolytic. Glycolytic activity in endothelial cells is increased during proliferation to maintain ATP at normal levels by an increase in the expression of the glucose transporter. More recent studies have reported the existence of a functional F1F0 ATP synthase on the surface of HUVEC and it has been found to be enzymatically active in the synthesis of ATP. Additional studies utilizing very early passage HUVEC need to be carried out to ascertain the relative contribution of oxidative phosphorylation compared with the glycolytic pathway for ATP synthesis in normal pregnancy as well as in abnormal states like preeclampsia, diabetes, intrauterine injection as well as intrauterine growth restriction. PMID- 24063386 TI - Uteroplacental circulation and fetal vascular function and development. AB - Although blood flow in the placental vasculature is governed by the same physiological forces of shear, pressure and resistance as in other organs, it is also uniquely specialized on the maternal and fetal sides. At the materno-fetal interface, the independent uteroplacental and umbilicoplacental circulations must coordinate sufficiently to supply the fetus with the nutrients and substrates it needs to grow and develop. Uterine arterial flow must increase dramatically to accommodate the growing fetus. Recent evidence delineates the hormonal and endothelial mechanisms by which maternal vessels dilate and remodel during pregnancy. The umbilical circulation is established de novo during embryonic development but blood does not flow through the placenta until late in the first trimester. The umbilical circulation operates in the interest of maintaining fetal oxygenation over the course of pregnancy, and is affected differently by mechanical and chemical regulators of vascular tone compared to other organs. The processes that match placental vascular growth and fetal tissue growth are not understood, but studies of compromised pregnancies provide clues. The subtle changes that cause the failure of the normally regulated vascular processes during pregnancy have not been thoroughly identified. Likewise, practical and effective therapeutic strategies to reverse detrimental placental perfusion patterns have yet to be investigated. PMID- 24063387 TI - The effectiveness of salicylic acid plasters compared with 'usual' scalpel debridement of corns: a randomised controlled trial. AB - BACKGROUND: Corns are a common foot problem and surveys have indicated that between 14-48% of people suffer from them. Many of these will seek podiatry treatment, however there is little evidence to indicate which current treatments provide long term resolution. This study compared 'usual' treatment (enucleation with a scalpel) with the application of 40% salicylic acid plasters to corns to investigate which is the most effective in terms of clinical, economic and patient-centred outcomes. METHODS: A parallel-group randomised controlled trial was carried out in two centres where adults who presented with one or more corns and who met the inclusion criteria were allocated to either 'usual' scalpel debridement or corn plaster treatment. All participants had measurements of corn size, pain using a 100 mm visual analogue scale (VAS) and health-related quality of life (EQ-5D) measures by an independent podiatrist, blind to treatment allocation at baseline, 3, 6, 9 and 12 months. RESULTS: 202 participants were randomised to receive scalpel debridement or corn plaster treatment (101 in each group). At 3 months 34% (32/95) of corns had completely resolved in the corn plaster group compared with 21% (20/94) in the scalpel group (p = 0.044), and 83% (79/95) had reduced in size in the corn plaster group compared with 56% (53/94) in the scalpel group (p < 0.001). At 12 months, time to corn recurrence was longer in the corn plaster group (p < 0.001). Pain from the corns was significantly lower in the corn plaster group at 3 months (p < 0.001) and EQ-5D scores changed (improved), from baseline, by 0.09 (SD +/-0.31) and 0.01 (SD +/ 0.25) points in the corn plaster and scalpel groups respectively (p = 0.056). By month 12, EQ-5D scores had changed by 0.12 and -0.05 in the corn plaster and scalpel groups respectively (p = 0.005). The EQ-5D, VAS scores and the four domains of the Foot Disability Scale were similar in both groups at 3 and 12 months. The economic analysis indicated that corn plasters were a cost effective intervention. CONCLUSIONS: The use of corn plasters was associated with a higher proportion of resolved corns, a prolonged time to corn recurrence, less pain and reduced corn size over the first 6 months in comparison with 'usual' scalpel treatment and this intervention was cost effective. Used under supervision of a podiatrist on appropriate patients, corn plasters offer an effective alternative to scalpel debridement. PMID- 24063388 TI - Estimation of radiation exposure for brain perfusion CT: standard protocol compared with deviations in protocol. AB - OBJECTIVE: The purpose of this study was to measure the organ doses and estimate the effective dose for the standard brain perfusion CT protocol and erroneous protocols. MATERIALS AND METHODS: An anthropomorphic phantom with metal oxide semiconductor field effect transistor (MOSFET) detectors was scanned on a 64-MDCT scanner. Protocol 1 used a standard brain perfusion protocol with 80 kVp and fixed tube current of 200 mA. Protocol 2 used 120 kVp and fixed tube current of 200 mA. Protocol 3 used 120 kVp with automatic tube current modulation (noise index, 2.4; minimum, 100 mA; maximum, 520 mA). RESULTS: Compared with protocol 1, the effective dose was 2.8 times higher with protocol 2 and 7.8 times higher with protocol 3. For all protocols, the peak dose was highest in the skin, followed by the brain and calvarial marrow. Compared with protocol 1, the peak skin dose was 2.6 times higher with protocol 2 and 6.7 times higher with protocol 3. The peak skin dose for protocol 3 exceeded 3 Gy. The ocular lens received significant scatter radiation: 177 mGy for protocol 2 and 435 mGy for protocol 3, which were 4.6 and 11.3 times the dose for protocol 1, respectively. CONCLUSION: Compared with the standard protocol, erroneous protocols of increasing the tube potential from 80 kVp to 120 kVp will lead to a three- to fivefold increase in organ doses, and concurrent use of high peak kilovoltage with incorrectly programmed tube current modulation can increase dose to organs by 7- to 11-fold. Tube current modulation with a low noise index can lead to doses to the skin and ocular lens that are close to thresholds for tissue reactions. PMID- 24063385 TI - Potassium channels and uterine vascular adaptation to pregnancy and chronic hypoxia. AB - During a normal course of pregnancy, uterine vascular tone is significantly decreased resulting in a striking increase in uterine blood flow, which is essential for fetal development and fetal growth. Chronic hypoxia during gestation may adversely affect the normal adaptation of uterine vascular tone and increase the risk of preeclampsia and fetal intrauterine growth restriction. In this review, we present evidence that the regulation of K+ channels is an important mechanism in the adaptation of uterine vascular tone to pregnancy and hypoxia. There are four types of K+ channels identified in arterial smooth muscle cells: 1) voltage-dependent K(+) (Kv) channels, 2) Ca2+-activated K(+) (KCa) channels, 3) inward rectifier K(+) (KIR) channels, and 4) ATP-sensitive K(+) (KATP) channels. Pregnancy differentially augments the expression and activity of K(+) channels via downregulation of protein kinase C signaling in uterine and other vascular beds, leading to decreased uterine vascular tone and increased uterine blood flow. Sex steroid hormones play an important role in the pregnancy- mediated alteration of K+ channels in the uterine vasculature. In addition, chronic hypoxia alters uterine vascular K(+) channels expression and activities via modulation of steroid hormones/receptors-mediated signaling, resulting in increased uterine vascular tone during pregnancy. PMID- 24063389 TI - HIV self-testing strategy: the middle road. PMID- 24063390 TI - Genome network medicine: new diagnostics and predictive tools. PMID- 24063391 TI - Integrating next-generation sequencing into clinical cancer diagnostics. PMID- 24063392 TI - Promising early results for Alzheimer's disease blood test diagnostic. PMID- 24063393 TI - GenomEra MRSA/SA, a fully automated homogeneous PCR assay for rapid detection of Staphylococcus aureus and the marker of methicillin resistance in various sample matrixes. AB - The GenomEra MRSA/SA assay (Abacus Diagnostica, Turku, Finland) is the first commercial homogeneous PCR assay using thermally stable, intrinsically fluorescent time-resolved fluorometric (TRF) labels resistant to autofluorescence and other background effects. This fully automated closed tube PCR assay simultaneously detects Staphylococcus aureus specific DNA and the mecA gene within 50 min. It can be used for both screening and confirmation of methicillin resistant and -sensitive S. aureus (MRSA and MSSA) directly in different specimen types or from preceding cultures. The assay has shown excellent performance in comparisons with other diagnostic methods in all the sample types tested. The GenomEra MRSA/SA assay provides rapid assistance for the detection of MRSA as well as invasive staphylococcal infections and helps the early targeting of antimicrobial therapy to patients with potential MRSA infection. PMID- 24063394 TI - A changing landscape for companion diagnostics. AB - 2nd European Symposium of Biopathology Paris, France, 13-14 June, 2013 This report highlights some of the presentations and discussions at the second European Symposium of Biopathology, Paris, France, 13-14 June 2013. The symposium covered a wide range of topics in the space between molecular biology and pathology such as DNA sequencing, cancer genome interpretation, cell-free tumor DNA in plasma, molecular pathology, tissue biomarkers, biomarker discovery, companion diagnostics (CDx), drug-diagnostic co-development and targeted cancer therapy. However, in this short report, the focus will be on CDx and drug diagnostic co-development in oncology, where a new landscape seems to emerge. As discussed at the symposium, we are slowly moving away from the 'one biomarker: one drug' scenario, which has characterized the first decades of targeted cancer drug development, toward a more integrated approach with multiple biomarkers and drugs. This 'new paradigm' will likely pave the way for the introduction of multiplexing strategies in the clinic using gene expression arrays and next generation sequencing. PMID- 24063395 TI - Meeting the challenges of PET-based molecular imaging in cancer. AB - As personalized medicine becomes a reality, there is a need for specific imaging agents that reflect molecular characteristics of a cancer. Fluorodeoxyglucose is an important advance because of its sensitivity. Newer molecular imaging probes offer higher specificity and are categorized as: radiolabeled biomimetics; antibody-antibody fragments and drug-drug-like compounds. Biomimetics have high sensitivity but tend to be less specific as they often engage natural transporters and metabolic pathways. Antibodies and their fragments are specific but may be limited by slow clearance. Labeled drugs and drug-like compounds offer good specificity but may be limited in sensitivity. There are numerous challenges facing molecular imaging related to their complexity. Additionally, fear of ionizing radiation and regulatory constraints have somewhat inhibited clinical translation. However, there is reason for optimism due to economies of scale and a changing health care system, which places a premium on diagnostic accuracy. Although molecular imaging is not likely to become mainstream in the near future, its long-term prospects for doing so are excellent. PMID- 24063396 TI - Molecular methods in the diagnosis of Clostridium difficile infections: an update. AB - Nucleic acid amplification techniques (NAATs) represent a major advance in the diagnosis of Clostridium difficile (C. difficile) infection. This review analyzes the different options available for a molecular diagnosis of C. difficile infection, as well as the strengths and weaknesses of NAATs. The performances of seven commercials NAATs are compared (BD GeneOhm Cdiff, Illumigene C. difficile, Xpert C. difficile, BD Max Cdiff, Portrait Toxigenic C. difficile, ProGastro Cd, Seeplex Diarrhea ACE). The sensitivity and the rapidity of NAATs are excellent: additional efforts should focus on the discrimination between infection and colonization. Reporting the DNA load of toxigenic C. difficile in the stool sample may represent a solution. Diagnostic algorithms combining immunoassays and NAATs could also improve the specificity and reduce the global cost of this analysis. PMID- 24063397 TI - Molecular HIV screening. AB - Nuclear acid testing is more and more used for the diagnosis of infectious diseases. This paper focuses on the use of molecular tools for HIV screening. The term 'screening' will be used under the meaning of first-line HIV molecular techniques performed on a routine basis, which excludes HIV molecular tests designed to confirm or infirm a newly discovered HIV-seropositive patient or other molecular tests performed for the follow-up of HIV-infected patients. The following items are developed successively: i) presentation of the variety of molecular tools used for molecular HIV screening, ii) use of HIV molecular tools for the screening of blood products, iii) use of HIV molecular tools for the screening of organs and tissue from human origin, iv) use of HIV molecular tools in medically assisted procreation and v) use of HIV molecular tools in neonates from HIV-infected mothers. PMID- 24063382 TI - Cerebral artery signal transduction mechanisms: developmental changes in dynamics and Ca2+ sensitivity. AB - As compared to the adult, the developing fetus and newborn infant are at much greater risk for dysregulation of cerebral blood flow (CBF), with complications such as intraventricular and germinal matrix hemorrhage with resultant neurologic sequelae. To minimize this dysregulation and its consequences presents a major challenge. Although in many respects the fundamental signal transduction mechanisms that regulate relaxation and contraction pathways, and thus cerebrovascular tone and CBF in the immature organism are similar to those of the adult, the individual elements, pathways, and roles differ greatly. Here, we review aspects of these maturational changes of relaxation/contraction mechanisms in terms of both electro-mechanical and pharmaco-mechanical coupling, their biochemical pathways and signaling networks. In contrast to the adult cerebrovasculature, in addition to attenuated structure with differences in multiple cytoskeletal elements, developing cerebrovasculature of fetus and newborn differs in many respects, such as a strikingly increased sensitivity to [Ca(2+)]i and requirement for extracellular Ca(2+) for contraction. In essence, the immature cerebrovasculature demonstrates both "hyper-relaxation" and "hypo contraction". A challenge is to unravel the manner in which these mechanisms are integrated, particularly in terms of both Ca(2+)-dependent and Ca(2+)-independent pathways to increase Ca(2+) sensitivity. Gaining an appreciation of these significant age-related differences in signal mechanisms also will be critical to understanding more completely the vulnerability of the developing cerebral vasculature to hypoxia and other stresses. Of vital importance, a more complete understanding of these mechanisms promises hope for improved strategies for therapeutic intervention and clinical management of intensive care of the premature newborn. PMID- 24063398 TI - Recent progress in prostate-specific antigen and HIV proteases detection. AB - Proteases mediate a wide variety of biological events and have a critical role in the development of many diseases. Protease detection methods can be hindered by the limitation of assay safety, sensitivity, specificity, time constraints and ease of on-site analysis. Notably, the implementation of various detection methods on biosensing platforms translates them into practical biosensing applications. Currently, the detection of prostate cancer and AIDS at the earliest occasion is one of the major research obstacles. Therefore, recent advances focus on the development of portable detection systems toward point-of care testing. These detection systems should be highly sensitive and specific for the detection of their prognostic biomarkers, such as the prostate-specific antigen and HIV load assay for prostate cancer and AIDS, respectively. These methods will also facilitate decision-making on a treatment regimen. PMID- 24063400 TI - Metabolic profiling of biofluids: potential in lung cancer screening and diagnosis. AB - The knowledge that the organism's metabolome is a potentially informative mirror of the impact of disease and its dynamics has led to promising developments in cancer research, strongly geared toward the discovery of new biomarkers of disease onset and progression. The present text reviews the advances made in the last 10 years in lung cancer research making use of the metabolomics strategies, particularly concerning metabolite profiling of human biofluids (blood serum and plasma, urine and others), expected to reflect the deviant metabolic behavior of lung tumors. The main goal of this article is to provide the reader with an up-to date summary of the main metabolic variations taking place in biofluids, in relation to lung cancer, as well as of the analytical strategies employed to unveil them. Furthermore, particular needs and challenges are identified and possible developments envisaged. PMID- 24063401 TI - BCR-ABL PCR testing in chronic myelogenous leukemia: molecular diagnosis for targeted cancer therapy and monitoring. AB - The use of tyrosine kinase inhibitors (TKIs) to treat chronic myeloid leukemia (CML) represents the paradigm for modern targeted cancer therapy. Importantly, molecular monitoring using BCR-ABL real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) for assessing treatment efficacy and quantitating minimal residual disease is a major determinate of practical therapeutic decision-making in the long-term management of this now chronic disease. Herein, we present an overview of CML and the use of TKIs for targeted CML therapy, with an emphasis on the role, application and future aspects of PCR based molecular monitoring. PMID- 24063399 TI - Fractal dimension of chromatin: potential molecular diagnostic applications for cancer prognosis. AB - Fractal characteristics of chromatin, revealed by light or electron microscopy, have been reported during the last 20 years. Fractal features can easily be estimated in digitalized microscopic images and are helpful for diagnosis and prognosis of neoplasias. During carcinogenesis and tumor progression, an increase of the fractal dimension (FD) of stained nuclei has been shown in intraepithelial lesions of the uterine cervix and the anus, oral squamous cell carcinomas or adenocarcinomas of the pancreas. Furthermore, an increased FD of chromatin is an unfavorable prognostic factor in squamous cell carcinomas of the oral cavity and the larynx, melanomas and multiple myelomas. High goodness-of-fit of the regression line of the FD is a favorable prognostic factor in acute leukemias and multiple myelomas. The nucleus has fractal and power-law organization in several different levels, which might in part be interrelated. Some possible relations between modifications of the chromatin organization during carcinogenesis and tumor progression and an increase of the FD of stained chromatin are suggested. Furthermore, increased complexity of the chromatin structure, loss of heterochromatin and a less-perfect self-organization of the nucleus in aggressive neoplasias are discussed. PMID- 24063402 TI - CAWS administration increases the expression of interferon gamma and complement factors that lead to severe vasculitis in DBA/2 mice. AB - BACKGROUND: Candida albicans water-soluble fraction (CAWS), a mannoprotein-beta glucan complex obtained from the culture supernatant of C. albicans NBRC1385, causes CAWS-mediated vasculitis (CAWS-vasculitis) in B6 and DBA/2 mice with mild and lethal symptoms, respectively. Why CAWS is lethal only in DBA/2 mice remains unknown. RESULTS: We performed DNA microarray analyses using mRNA obtained from peripheral blood mononuclear cells (PBMCs) of B6 and DBA/2 mice and compared their respective transcriptomes. We found that the mRNA levels of interferon gamma (Ifng) and several genes that regulate the complement system, such as C3, C4, Cfb, Cfh, and Fcna, were increased dramatically only in DBA/2 mice at 4 and 8 weeks after CAWS administration. The dramatic increase was confirmed by quantitative real-time polymerase chain reactions (qRT-PCR). Moreover, mRNA levels of immune-related genes, such as Irf1, Irf7, Irf9, Cebpb, Ccl4, Itgam, Icam1, and IL-12rb1, whose expression levels are known to be increased by Ifng, were also increased, but only in DBA/2 mice. By contrast, the mRNA level of Dectin-2, the critical receptor for the alpha-mannans of CAWS, was increased slightly and similarly in both B6 and DBA/2 mice after CAWS administration. CONCLUSIONS: Taken together, our results suggest that CAWS administration induces Dectin-2 mediated CAWS-vasculitis in both B6 and DBA/2 mice and the expression of Ifng, but only in DBA/2 mice, which led to increased expression of C3, C4, Cfb, Cfh, and Fcna and an associated increase in lethality in these mice. This model may contribute to our understanding of the pathogenesis of severe human vasculitis. PMID- 24063403 TI - Blue light-mediated manipulation of transcription factor activity in vivo. AB - We developed a novel technique for manipulating the activity of transcription factors with blue light (termed "PICCORO") using the bacterial BLUF-type photoreceptor protein PixD. The chimeric dominant-negative T-box transcription factor No Tail formed heterologous complexes with a PixD decamer in a light dependent manner, and these complexes affected transcription repressor activity. When applied to zebrafish embryos, PICCORO permitted regulation of the activity of the mutant No Tail in response to 472-nm light provided by a light-emitting diode. PMID- 24063404 TI - Fibrinogen depletion in trauma: early, easy to estimate and central to trauma induced coagulopathy. AB - Fibrinogen is fundamental to hemostasis and falls rapidly in trauma hemorrhage, although levels are not routinely measured in the acute bleeding episode. Prompt identification of critically low levels of fibrinogen and early supplementation has the potential to correct trauma-induced coagulation and improve outcomes. Early estimation of hypofibrinogenemia is possible using surrogate markers of shock and hemorrhage; for example, hemoglobin and base excess. Rapid replacement with fibrinogen concentrate or cryoprecipitate should be considered a clinical priority in major trauma hemorrhage. PMID- 24063405 TI - Biocompatible shaped particles from dried multilayer polymer capsules. AB - We demonstrated a simple and facile approach to fabricate biocompatible monodisperse hollow microparticles of controlled geometry. The hemispherical, spherical, and cubical microparticles are obtained by drying multilayer capsules of hydrogen-bonded poly(N-vinylpyrrolidone)/tannic acid (PVPON/TA)n. Drying spherical capsules results in hemispherical particles if 15 < n < 20. This shape transformation is controlled by capsule stiffness, which is regulated by the layer number, capsule diameter, and PVPON molecular weight. Cubical and spherical hollow particles maintaining their three-dimensional shapes in the dry state are obtained if n >= 25.5. A 17-fold stiffness increase is required to lead from totally collapsed (PVPON/TA)5.5 to dried self-supporting (PVPON/TA)25.5 particles of 2 MUm in dimensions. All hollow particles could be further resuspended in aqueous solutions while retaining their shapes upon rehydration. The cell growth and viability studies using human cancer cells revealed noncytotoxic properties of the (PVPON/TA) multilayer particles. Both spherical and hemispherical capsules were internalized by macrophages with the uptake of the hemispherical particles per cell two times more efficient. The method presented here allows for a robust preparation of biocompatible shaped particles whose shape and dimensions can be easily tuned by controlling capsule size and wall thickness. The reported structures can be potentially useful for biomedical applications such as shape controlled cellular uptake and flow dynamics. PMID- 24063406 TI - Myristica fragrans seed extract protects against dextran sulfate sodium-induced colitis in mice. AB - Nutmeg (seed of Myristica fragrans [MF]) is one of the most commonly used spices in the world and also a well-known herb for the treatment of various intestinal diseases, including colitis in traditional Korean medicine. The purpose of the current study was to investigate whether water extract of MF (MFE) can protect against dextran sulfate sodium (DSS) induced colitis in a mouse model. Colitis was induced by 5% DSS in balb/c mice. MFE (100, 300 or 1000 mg/kg) was orally administered to the mice twice a day for 7 days. Body weight, colon length, clinical score, and histological score were assessed to determine the effects on colitis. Proinflammatory cytokines (interferon-gamma, tumor necrosis factor alpha, interleukin [IL]-1beta, and IL-6) were measured to investigate the mechanisms of action. MFE dose dependently inhibited the colon shortening and histological damage to the colon. However, it did not prevent weight loss. MFE also inhibited proinflammatory cytokines. The current results suggest that MFE ameliorates DSS-induced colitis in mice by inhibiting inflammatory cytokines. Further investigation, including the exact mechanisms is needed. PMID- 24063407 TI - Corn peptides protect against thioacetamide-induced hepatic fibrosis in rats. AB - Certain bioactive peptides are reported to be able to alleviate hepatic fibrosis. Our previous work has confirmed the hepatoprotective effect of corn peptides (CPs) that are prepared from a high protein by-product, corn gluten meal, on acute liver injury in an animal model. However, the antifibrotic activity of CPs remained to be elucidated. In this study, the hepatoprotective effect of CPs on thioacetamide (TAA)-induced liver fibrosis was tested. Results showed that CPs (100 mg/kg body weight) significantly decreased the levels of alanine transaminase/aspartate transaminase, laminin, type IV collagen, and type III collagen in serum and increased the serum albumin levels and total antioxidant capacity. Additionally, with CP treatment (100 mg/kg body weight), a significant decrease was observed in the levels of malondialdehyde, nitric oxide, hydroxyproline, transforming growth factor beta1, and lactate dehydrogenase activity as well as the liver index, while the activity of superoxidedismutase was significantly increased in livers. The histological and morphological analysis showed that the hepatocyte structure in CP-treated rats was superior to that of TAA-injured rats, and inflammation and fibrosis were also ameliorated. Therefore, CPs can be used as an option for prevention and adjuvant therapy of liver fibrosis. PMID- 24063409 TI - Seven-coordinate lanthanide sandwich-type complexes with a tetrathiafulvalene fused Schiff base ligand. AB - Three seven-coordinate lanthanide(III) sandwich-type mononuclear complexes with pi-conjugated TTF-Schiff base ligand H2L (L(2-) = 2,2'-((2-(4,5-bis(methylthio) 1,3-dithiol-2-ylidene)-1,3-benzodithiole-5,6-diyl)bis(nitrilomethylidyne)bis(4 chlorophenolate)) and the tripodal ligand L(OEt)(-) (L(OEt)(-) = [(eta(5) C5H5)Co(P(?O)(OEt)2)3](-)), [(L(OEt))Ln(L)].0.25H2O (Ln(3+) = Dy(3+), 1; Tb(3+), 2; Ho(3+), 3), have been synthesized and structurally characterized. All of the complexes are also characterized by absorption spectra and electrochemical, spectroelectrochemical, and magnetic studies. The Dy complex exhibits the field induced slow relaxation of magnetization with an energy barrier of 41.6 K, indicating it shows single lanthanide-based SMM behavior. Introduction of the redox-active TTF unit into the sandwich-type lanthanide(III) complexes with interesting magnetic properties renders them promising for elaboration of new hybrid inorganic-organic materials. PMID- 24063408 TI - Cardiac metabolism in a new rat model of type 2 diabetes using high-fat diet with low dose streptozotocin. AB - BACKGROUND: To study the pathogenesis of diabetic cardiomyopathy, reliable animal models of type 2 diabetes are required. Physiologically relevant rodent models are needed, which not only replicate the human pathology but also mimic the disease process. Here we characterised cardiac metabolic abnormalities, and investigated the optimal experimental approach for inducing disease, in a new model of type 2 diabetes. METHODS AND RESULTS: Male Wistar rats were fed a high fat diet for three weeks, with a single intraperitoneal injection of low dose streptozotocin (STZ) after fourteen days at 15, 20, 25 or 30 mg/kg body weight. Compared with chow-fed or high-fat diet fed control rats, a high-fat diet in combination with doses of 15-25 mg/kg STZ did not change insulin concentrations and rats maintained body weight. In contrast, 30 mg/kg STZ induced hypoinsulinaemia, hyperketonaemia and weight loss. There was a dose-dependent increase in blood glucose and plasma lipids with increasing concentrations of STZ. Cardiac and hepatic triglycerides were increased by all doses of STZ, in contrast, cardiac glycogen concentrations increased in a dose-dependent manner with increasing STZ concentrations. Cardiac glucose transporter 4 protein levels were decreased, whereas fatty acid metabolism-regulated proteins, including uncoupling protein 3 and pyruvate dehydrogenase (PDH) kinase 4, were increased with increasing doses of STZ. Cardiac PDH activity displayed a dose-dependent relationship between enzyme activity and STZ concentration. Cardiac insulin stimulated glycolytic rates were decreased by 17% in 15 mg/kg STZ high-fat fed diabetic rats compared with control rats, with no effect on cardiac contractile function. CONCLUSIONS: High-fat feeding in combination with a low dose of STZ induced cardiac metabolic changes that mirror the decrease in glucose metabolism and increase in fat metabolism in diabetic patients. While low doses of 15-25 mg/kg STZ induced a type 2 diabetic phenotype, higher doses more closely recapitulated type 1 diabetes, demonstrating that the severity of diabetes can be modified according to the requirements of the study. PMID- 24063411 TI - Esthesioneuroblastoma as an unusual cause for dystopia. AB - Abstract Esthesioneuroblastoma, also known as olfactory neuroblastoma, is an uncommon malignant neoplasm arising from the olfactory epithelium in the roof of the nasal cavity. There are very few case reports published worldwide. The common presenting symptoms of Esthesioneuroblastoma are unilateral nasal obstruction (70%), epistaxis (50%), anosmia, rhinorrhoea, facial pain, headache, excessive lacrimation and rarely proptosis and visual disturbance. Apart from being locally aggressive, it metastasizes by haematogenous and lymphatic routes. We report an extremely rare case of esthesioneuroblastoma in a 20-year-old man with orbital involvement presenting as dystopia. This rare tumour should be considered in the differential diagnosis for young patients presenting to ophthalmic outpatient department with dystopia. PMID- 24063410 TI - Patients with osteoarthritis and avascular necrosis have better functional outcomes and those with avascular necrosis worse pain outcomes compared to rheumatoid arthritis after primary hip arthroplasty: a cohort study. AB - BACKGROUND: This study was conducted to assess whether patient-reported outcomes (PROs) differ by the underlying diagnosis (rheumatoid arthritis (RA)/inflammatory arthritis, osteoarthritis (OA), avascular necrosis of bone (AVN), other) in patients undergoing primary total hip arthroplasty (THA). METHODS: We used prospectively collected data to assess the association of diagnosis with index hip function and pain. Moderate-severe activity limitation and moderate-severe pain were assessed at two- and five-year follow-up after primary THA using multivariable-adjusted logistic regression analyses. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. RESULTS: There were 5,707 primary THAs at two-years and 3,289 at five-years, 51% were women and the mean age was 65 years. The underlying diagnosis was RA in 3%, OA in 87%, AVN in 7% and other in 3%. In multivariable-adjusted analyses, compared to RA, diagnoses of OA and AVN were significantly associated with lower odds of moderate-severe activities of daily living limitations with an OR (95% CI) of 0.5 (0.3 to 0.8) (P = 0.01) and 0.4 (0.2 to 0.8) (P = 0.01), respectively, at two-years, but not at five-years, 0.7 (0.4 to 1.4) (P = 0.36) and 0.9 (0.4 to 1.8) (P = 0.78), respectively. At two years, neither OA nor AVN were significantly associated with higher odds of moderate-severe pain (1.6 (0.6 to 4.5) (P = 0.40) and 2.8 (0.9 to 8.5) (P =0 0.06)), respectively. At five-years, AVN was associated with higher odds of moderate-severe pain with OR 4.1 (1.2 to 14.1) (P = 0.02), but not OA, 2.1 (0.7 to 6.5) (P = 0.22). CONCLUSIONS: We found that patients with OA and AVN had better functional outcomes and those with AVN worse pain outcomes after primary THA, compared to patients with RA/inflammatory arthritis. Insights into mediators of these relationships are needed to better understand these associations. PMID- 24063412 TI - Are there specific relationships between symptom patterns and interpersonal problems among psychiatric outpatients? AB - Associations between symptoms and interpersonal problems, assessed with the Symptom Checklist-90 (SCL-90-R) and the Inventory of Interpersonal Problems-64 item version (IIP-64), are examined in a large psychiatric outpatient sample. On the basis of the IIP-64 scores, the sample was divided into 8 subgroups, made up of different types of predominant interpersonal problems. These octant groups were used as independent variables in analyses testing hypothesized associations with symptom subscales of the SCL-90-R. In general, strong associations between symptoms and interpersonal problems were found. In addition, hostile and paranoid ideation symptoms displayed significant differences among octant groups, and were associated with interpersonal problems of the vindictive/self-centered kind. Phobic anxiety was associated with interpersonal problems of the socially inhibited kind. Assessing specific combinations of symptoms and interpersonal problems might be useful in treatment planning and evaluation. PMID- 24063413 TI - Succession planning: a call to action for nurse executives. AB - AIM: To discuss the organisational benefits of strategic succession planning in acute care hospital settings as a responsibility of chief nurse executives. BACKGROUND: A formal succession planning process is crucial to the financial and operational viability and sustainability of acute care hospitals. A succession plan is an essential business strategy that promotes effective leadership transition and continuity while maintaining productivity. EVALUATION: Nursing and business literature were reviewed; reports contrasting institutions with and without succession plans were examined; and, operational implications were considered. KEY ISSUES: It is imperative that chief nurse executives respond to the business benefits of an effective succession planning programme, identify common barriers and solutions, and implement best practices for a successful strategic succession planning programme. CONCLUSION: A strategic succession planning programme may offer many benefits to an acute care hospital, including improved retention rates, increased staff engagement and enhanced financial performance. IMPLICATIONS FOR NURSING MANAGEMENT: Considering the ageing nursing workforce and the potential increase in demand for nursing services in the near future, nurse executives and other nurse leaders must actively engage in a formal succession planning process. A formal succession planning programme will help to provide strategic leadership continuity, operational effectiveness and improved quality of care. PMID- 24063414 TI - Posttraumatic stress and symptom improvement in Norwegian tourists exposed to the 2004 tsunami--a longitudinal study. AB - BACKGROUND: Mental health consequences of disasters are frequently studied. However, few studies have investigated symptom improvement in victims after natural disasters. This study aimed to identify predictors of 6 months post disaster stress symptoms and to study 6 months and 24 months course of symptoms among Norwegian tourists who experienced the 2004 tsunami. METHODS: Norwegian tourists (>= 18 years) who experienced the 2004 tsunami (n = 2468) were invited to return a postal questionnaire at two points of time. The first data set was collected at 6 months (T1, n = 899) and the second data set at 24 months post disaster (T2, n = 1180). The population studied consisted of those who responded at both assessments (n = 674). Impact of Event Scale Revised (IES-R) was used to measure posttraumatic stress symptoms. IES-R score >= 33 (caseness) was used to identify various symptom trajectories from T1 to T2. Multiple linear regression was used to determine predictors of posttraumatic stress at T1 and to identify variables associated with symptom improvement from T1 to T2. RESULTS: The majority was identified as non-case at both assessments (57.7%), while 20.8% of the respondents were identified as case at both assessments. Symptoms at T1 were positively related to female gender, older age, unemployment, being chased or caught by the waves, witnessing death or suffering, loss of loved ones, experiencing intense fear during the disaster, low conscientiousness, neuroticism and low levels of social support. The IES-R sum score declined from 24.6 (SD = 18.5) at T1 to 22.9 (SD = 18.3) at T2, p < 0.001. Emotional stability and high IES-R scores at T1 were positively related to symptom improvement, while received social support was not. Being referred to a mental health specialist was negatively related to symptom improvement. CONCLUSIONS: A significant minority (20-30%) among Norwegian tourists developed enduring posttraumatic stress symptoms in the aftermath of the 2004 tsunami. Tsunami exposure, peritraumatic fear, neuroticism and low levels of social support were the strongest predictors of posttraumatic stress at 6 months post-disaster. Decrease in posttraumatic stress was related to emotional stability and higher symptom levels at T1. Being referred to a mental health specialist did not facilitate symptom improvement. PMID- 24063416 TI - Deprotonation mechanism and acidity constants in aqueous solution of flavonols: a combined experimental and theoretical study. AB - Four flavonols, namely quercetin, morin, kaempferol, and myricetin, were studied using spectrophotometry (UV-vis) in aqueous solution. The study was performed varying the pH to analyze the stability of these compounds, and to estimate their acidity constants. In addition, the deprotonation mechanisms were studied using computational chemistry within the density functional theory framework. The calculations were performed in aqueous solution using the SMD continuum model, and the results are reported as deprotonation energies. Our results show that both quercetin and myricetin are highly unstable at basic pH. Kaempferol, on the other hand, is much more stable, and morin is the only one among the studied compounds that was not affected by pH. In spite of this inconvenience, their acidity constants were estimated through analysis of their decomposition kinetics, correcting the spectra accordingly, and obtaining a correlation of values between the experimentally observed pKa and the calculated DeltaG of successive deprotonations. PMID- 24063415 TI - Targeting pancreatic cancer with magneto-fluorescent theranostic gold nanoshells. AB - AIM: We report a magneto-fluorescent theranostic nanocomplex targeted to neutrophil gelatinase-associated lipocalin (NGAL) for imaging and therapy of pancreatic cancer. MATERIALS & METHODS: Gold nanoshells resonant at 810 nm were encapsulated in silica epilayers doped with iron oxide and the near-infrared (NIR) dye indocyanine green, resulting in theranostic gold nanoshells (TGNS), which were subsequently conjugated with antibodies targeting NGAL in AsPC-1 derived xenografts in nude mice. RESULTS: Anti-NGAL-conjugated TGNS specifically targeted pancreatic cancer cells in vitro and in vivo providing contrast for both NIR fluorescence and T2-weighted MRI with higher tumor contrast than can be obtained using long-circulating, but nontargeted, PEGylated nanoparticles. The nanocomplexes also enabled highly specific cancer cell death via NIR photothermal therapy in vitro. CONCLUSION: TGNS with embedded NIR and magnetic resonance contrasts can be specifically targeted to pancreatic cancer cells with expression of early disease marker NGAL, and enable molecularly targeted imaging and photothermal therapy. PMID- 24063417 TI - Preparation of asymmetric urea derivatives that target prostate-specific membrane antigen for SPECT imaging. AB - Prostate-specific membrane antigen (PSMA) has been identified as a diagnostic and therapeutic target for prostate cancer. (S)-2-[3-[(R)-1-Carboxy-2 mercaptoethyl]ureido-pentanedioic acid (Cys-CO-Glu) were used to design novel PSMA targeting probes by nucleophilic conjugate addition between cysteine and maleimide based reagents. 3 ([(123)I]IGLCE) was synthesized by this strategy and showed high affinity for PSMA. Results of binding inhibition assays of these derivatives suggested the importance of an aromatic group and succinimide moiety for high affinity. [(123)I]3 was evaluated in vivo with PSMA positive LNCaP and PSMA negative PC-3 human prostate cancer xenograft bearing mice. [(125)I]3 accumulated in LNCaP tumors but not in PC-3 tumors, and the accumulation was inhibited by 2-(phosphonomethyl)pentanedioic acid (2-PMPA). Use of [(123)I]3 provided positive images of LNCaP tumors in single photon emission tomography scans. These results warrant further evaluation of [(123)I]3 and its derivatives as radiolabeled probes for the diagnosis of prostate cancer. PMID- 24063418 TI - Risk of adolescent offspring's completed suicide increases with prior history of their same-sex parents' death by suicide. AB - BACKGROUND: To investigate the risk of completed suicide in offspring during adolescence in relation to prior history of the same-sex parent's death by suicide and other causes. METHOD: A total of 500 adolescents who died by suicide at age 15-19 years between 1997 and 2007 were identified from the Taiwan Mortality Registration (TMR). For each case, 30 age- and time-matched controls were selected randomly from all adolescents registered in the Taiwan Birth Registry (TBR). A multivariate conditional logistic regression model was used to assess the risk of adolescent completed suicide in relation to their same-sex parent. RESULTS: Adolescent suicide risk was positively associated with both paternal [odds ratio (OR) 5.38, 95% confidence interval (CI) 2.17-13.33] and maternal suicide (OR 6.59, 95% CI 1.82-23.91). The corresponding risk estimates associated with paternal and maternal deaths from non-suicidal causes were much lower, at 1.88 and 1.94 respectively. The risk of suicide in male adolescents was significantly associated with prior history of paternal death by suicide (OR 8.23, 95% CI 2.96-22.90) but not of maternal death by suicide (OR 3.50, 95% CI 0.41-30.13). On the other contrary, the risk of suicidal death in female adolescents was significantly associated with prior history of maternal suicide (OR 9.71, 95% CI 1.89-49.94) but not of paternal suicide (OR 2.42, 95% CI 0.30 19.57). However, these differences did not reach statistical significance. CONCLUSIONS: Although limited by sample size, our study indicates that adolescent offspring suicidal death is associated with prior history of their same-sex parent's death by suicide. PMID- 24063419 TI - A facile route for producing single-crystalline epitaxial perovskite oxide thin films. AB - We report how a low vacuum pressure process followed by a few-minute annealing enables epitaxial stabilization, producing high-quality, phase-pure, single crystalline epitaxial, and misfit dislocation-free BiFeO3(001) thin films on SrTiO3(001) at ~450 degrees C less than current routes. These results unambiguously challenge the widely held notion that atomic layer deposition (ALD) is not appropriate for attaining high-quality chemically complex oxide films on perovskite substrates in single-crystalline epitaxial form, demonstrating applicability as an inexpensive, facile, and highly scalable route. PMID- 24063420 TI - Efficacy and tolerability of alpha-galactosidase in treating gas-related symptoms in children: a randomized, double-blind, placebo controlled trial. AB - BACKGROUND: Gas-related symptoms represent very common complaints in children. The reduction of gas production can be considered as a valuable target in controlling symptoms. alpha-galactosidase has been shown to reduce gas production and related symptoms in adults. To evaluate the efficacy and tolerability of alpha-galactosidase in the treatment of gas-related symptoms in pediatric patients. METHODS: Single center, randomized, double-blind, placebo-controlled, parallel group study performed in tertiary care setting. Fifty-two pediatric patients (32 female, age range 4-17) with chronic or recurrent gas-related symptoms were randomized to receive placebo (n = 25) or alpha-galactosidase (n = 27). Both treatments were given as drops or tablets, according to body weight for 2 weeks. The primary endpoint was the reduction in global distress measured by the Faces Pain Scale-Revised (FPS-R) at the end of treatment compared to baseline. Secondary endpoints were the reduction in severity and frequency of gas related symptoms as recorded by parents and/or children. RESULTS: alpha galactosidase significantly reduced global distress (p = 0.02) compared to placebo. The digestive enzyme decreased the number of days with moderate to severe bloating (p = 0.03) and the proportion of patients with flatulence (p = 0.02). No significant differences were found for abdominal spasms and abdominal distension. No adverse events were reported during treatment. CONCLUSIONS: Although larger and longer trials are needed to confirm this result, alpha galactosidase seems to be a safe, well tolerated and effective treatment for gas related symptoms in the pediatric population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01595932. PMID- 24063421 TI - ARPE-19 cell uptake of small and ultrasmall superparamagnetic iron oxide. AB - PURPOSE: To investigate the cytotoxicity, cellular intake and magnetic field interaction of three superparamagnetic iron oxide (SPIO) and one ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles on ARPE-19 cells. METHODS: Two FDA-approved SPIO nanoparticles (Endorem and Lumirem), one commercial SPIO(FluidMag-L) and one FDA-approved USPIO (Feraheme) were tested. Nanoparticle suspensions were diluted and prepared in high- (1000 Fe-ug/ml) and low- (100 Fe ug/ml) dose suspensions. ARPE-19 cells were incubated in four 24-well plates and the medium changed every other day until cells attained 80% confluence. Nanoparticle cytotoxicity was evaluated using the XTT cytotoxicity assay. Cellular attraction was tested after digestion of the cells in collagenase A (1 mg/ml) overnight. A 3500 Gauss neodymium magnet was used to attract cells to the well walls. ARPE-19 cell ultrastructure was evaluated by transmission electron microscopy (TEM) to determine the specific locations of nanoparticles within the cell membranes. RESULTS: Cytotoxicity assessment by the XTT assay revealed that ARPE-19 cells that were exposed to either concentration of Endorem, FLuidMag-L, Feraheme non-conjugated with protamine and heparin or Lumirem demonstrated no statistically significant toxicity. Cells exposed to Feraheme when conjugated with protamine and heparin presented severe toxicity in both concentrations. When a magnetic field was applied, all nanoparticle-containing samples, except Feraheme non-conjugated form, were promptly attracted. TEM and prussian blue staining examination revealed that Feraheme alone was not initially capable of cellular uptake. This issue was solved by conjugating Feraheme with protamine and heparin (although cytotoxicity was found on those samples). Endorem, FLuidMag-L, Feraheme conjugated form were found within the cytoplasm of ARPE-19 cells. CONCLUSIONS: Ferahame when conjugated with protamine and heparin was cytotoxic at the higher and lower doses, as revealed by the XTT assay. Endorem and FluidMag-L were not toxic at the studied concentrations. Feraheme non-conjugated solutions and Lumirem solutions provided were harmless but were not internalized by ARPE-19 cells. All the studied nanoparticles were attracted to the magnetic field except Feraheme in the non-conjugated form. PMID- 24063422 TI - The effect of calorie restriction on the presence of apoptotic ovarian cells in normal wild type mice and low-plasma-IGF-1 Laron dwarf mice. AB - BACKGROUND: It is known that caloric restriction extends lifespan and can minimize age-related dysfunction of the reproductive system. We became interested in how caloric restriction influences apoptosis, which is a crucial process that maintains ovarian cell homeostasis. METHODS: We examined ovarian cells in: 2.5 year-old wild type mice on caloric restriction (CR) or fed ad libitum (AL) and Laron dwarf mice (GHR-KO) at the same ages on CR or fed AL. Apoptosis was assessed by histochemical analysis on paraffin sections of ovarian tissue. RESULTS: Morphological and histochemical analysis revealed that CR improved reproductive potential in 2.5-year-old WT littermates and GHR-KO female mice, as indicated by the increased number of ovarian follicles. The level of apoptosis in ovarian tissue was higher in WT mice on a CR diet compared with WT mice on the AL diet. In GHR-KO mice, the level of apoptosis in ovaries was similar for mice on CR and on AL diets and bigger than in WT mice on CR. CONCLUSIONS: Morphological and histochemical analysis revealed a younger biological age of the ovaries in 2 year-old WT littermates and GHR-KO female mice on CR compared with animals fed AL. PMID- 24063423 TI - Selumetinib in advanced non small cell lung cancer (NSCLC) harbouring KRAS mutation: endless clinical challenge to KRAS-mutant NSCLC. AB - During the past few years, oncologists have witnessed the reclassification of non small cell lung cancer (NSCLC) as not one disease, but several molecularly defined subsets of disease with relevant therapeutic implications in the field of molecularly targeted therapies. Two not very common genetically defined subsets of NSCLC, including those with EGFR or ALK activating mutations, and show high sensitivity to tyrosine-kinase inhibitors such that patients frequently have sustained clinical responses to therapy. However, the largest subset harbours an activating KRAS mutation and up to now, no successful targeted therapy has been developed for RAS-mutant lung cancer, with few compounds being assessed by clinical trials. In fact, KRAS has remained an elusive target for cancer therapy for biologic reasons. The chief value of KRAS lies in providing information about the other biomarkers that are directly druggable, that is, EGFR and ALK. The presence of mutated KRAS rules out ALK and EGFR, and KRAS may therefore form part of an efficient pathway in a testing algorithm. Currently, KRAS itself remains undruggable despite decades of effort, but attention has recently focused on inhibition of the Ras-contingent downstream signalling. Selumetinib (AZD6244; ARRY-142886) is an oral, tight-binding, uncompetitive inhibitor of mitogen activated protein kinase kinases (MEK) 1 and 2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers and currently in clinical development. The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. Recently, in a randomised, phase II trial selumetinib plus docetaxel has proven to improve progression free survival compared to docetaxel alone in previously treated patients with advanced KRAS-mutant NSCLC. PMID- 24063424 TI - Spin crossover meets diarylethenes: efficient photoswitching of magnetic properties in solution at room temperature. AB - A photoisomerizable diarylethene-derived ligand, phen*, has been successfully introduced into a spin-crossover iron(II) complex, [Fe(H2B(pz)2)2phen*] (1; pz =1 pyrazolyl). A ligand-based photocyclization (photocycloreversion) in 1 modifies the ligand field, which, in turn, results in a highly efficient paramagnetic high spin -> diamagnetic low-spin (low-spin -> high-spin) transition at the coordinated Fe(II) ion. The reversible photoswitching of the spin states, and thus the associated magnetic properties, has been performed in solution at room temperature and has been directly monitored by measuring the magnetic susceptibility via the Evans method. The observed spin-state photoconversion in 1 exceeds 40%, which is the highest value for spin-crossover molecular switches in solution at room temperature reported to date. The photoexcited state is extraordinarily thermally stable, showing a half-time of about 18 days in solution at room temperature. Because of the outstanding photophysical properties of diarylethenes, including single-crystalline photochromism, molecular switch 1 may offer a promising platform for controlling the magnetic properties in the solid state and ultimately at the single-molecule level with light at room temperature. PMID- 24063425 TI - Should we monitor vitamin B12 and folate levels in Crohn's disease patients? AB - OBJECTIVE: Crohn's disease commonly involves the small intestine, which is the site of vitamin B12 and folate absorption. Our aim was to define the prevalence of vitamin B12 and folate deficiency in patients with Crohn's disease and to identify predictive factors associated with such abnormalities. METHODS: Two years prospective study of 180 consecutive Crohn's disease patients. Vitamin B12 and folate deficiency was defined as serum levels below 200 pg/ml and 3 ng/ml, respectively. We analysed prevalence of these deficiencies and possible predictive factors including small intestine resection, disease location, activity and duration of disease. Controls were ulcerative colitis patients (n = 70). RESULTS: The prevalence of B12 deficiency in Crohn's disease was 15.6% (95%CI 9.7-20%) compared with 2.8% (95%CI 0.8-9.8%) in ulcerative colitis (p = 0.007). With regard to folate deficiency, the prevalence in patients with Crohn's disease was 22.2% (95%CI 16-28%) compared with 4.3% (95%CI 1.4-12%) in ulcerative colitis (p = 0.001); 7.8% of Crohn's disease patients had macrocytic anemia. Ileal resection was found to be a risk factor for B12 deficiency (OR 2.7; 1.2 6.7; p = 0.02), and disease activity a risk factor for folate deficiency (OR 2.4; 1.2-5.1; p = 0.01). CONCLUSION: A significant proportion of patients with Crohn's disease suffer from vitamin B12 and/or folate deficiency, suggesting that regular screening should be performed, with closer monitoring in patients with ileal resection or active disease. PMID- 24063426 TI - Preparation of ultrathin, robust protein microcapsules through template-mediated interfacial reaction between amine and catechol groups. AB - A novel approach to the synthesis of protein microcapsules is developed through template-mediated interfacial reaction. Protein-doped CaCO3 templates are first synthetized via coprecipitation and then coated with a catechol-containing alginate (AlgDA) layer. Afterward, the templates are exposed to ethylenediamine tetraacetic acid disodium (EDTA) solution to dissolve CaCO3. During CaCO3 dissolution, the generated CO2 gas pushes protein molecules moving to the AlgDA layer, and thereby Michael addition and Schiff base reactions proceed, forming the shell of protein microcapsules. Three kinds of proteins, namely, bovine serum albumin, catalase, and protamine sulfate, are utilized. The shell thickness of microcapsule varies from 25 to 82 nm as the doping amount of protein increased from 2 to 6 mg per 66 mg CaCO3. The protein microcapsules have a robust but flexible shell and can be reversibly deformed upon exposure to osmotic pressure. The bioactivity of protein microcapsules is demonstrated through enzymatic catalysis experiments. The protein microcapsules remain about 80% enzymatic activity of the equivalent free protein. Hopefully, our approach could be extended to many other applications such as drug/gene delivery, tissue scaffolds, and catalysis due to the universality of Michael reaction and Schiff base reactions. PMID- 24063427 TI - Accuracy of clinicians and models for estimating the probability that a pulmonary nodule is malignant. AB - RATIONALE: Management of pulmonary nodules depends critically on the probability of malignancy. Models to estimate probability have been developed and validated, but most clinicians rely on judgment. OBJECTIVES: The aim of this study was to compare the accuracy of clinical judgment with that of two prediction models. METHODS: Physician participants reviewed up to five clinical vignettes, selected at random from a larger pool of 35 vignettes, all based on actual patients with lung nodules of known final diagnosis. Vignettes included clinical information and a representative slice from computed tomography. Clinicians estimated the probability of malignancy for each vignette. To examine agreement with models, we calculated intraclass correlation coefficients (ICC) and kappa statistics. To examine accuracy, we compared areas under the receiver operator characteristic curve (AUC). MEASUREMENTS AND MAIN RESULTS: Thirty-six participants completed 179 vignettes, 47% of which described patients with malignant nodules. Agreement between participants and models was fair for the Mayo Clinic model (ICC, 0.37; 95% confidence interval [CI], 0.23-0.50) and moderate for the Veterans Affairs model (ICC, 0.46; 95% CI, 0.34-0.57). There was no difference in accuracy between participants (AUC, 0.70; 95% CI, 0.62-0.77) and the Mayo Clinic model (AUC, 0.71; 95% CI, 0.62-0.80; P = 0.90) or the Veterans Affairs model (AUC, 0.72; 95% CI, 0.64-0.80; P = 0.54). CONCLUSIONS: In this vignette-based study, clinical judgment and models appeared to have similar accuracy for lung nodule characterization, but agreement between judgment and the models was modest, suggesting that qualitative and quantitative approaches may provide complementary information. PMID- 24063428 TI - Computational approaches to predicting the impact of novel bases on RNA structure and stability. AB - The use of computational modeling techniques to gain insight into nucleobase interactions has been a challenging endeavor to date. Accurate treatment requires the tackling of many challenges but also holds the promise of great rewards. The development of effective computational approaches to predict the binding affinities of nucleobases and analogues can, for example, streamline the process of developing novel nucleobase modifications, which should facilitate the development of new RNAi-based therapeutics. This brief review focuses on available computational approaches to predicting base pairing affinity in RNA based contexts such as nucleobase-nucleobase interactions in duplexes and nucleobase-protein interactions. The challenges associated with such modeling along with potential future directions for the field are highlighted. PMID- 24063429 TI - Selective cytotoxicity and combined effects of camptothecin or paclitaxel with sodium-R-alpha lipoate on A549 human non-small cell lung cancer cells. AB - Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer and remains the deadliest form of cancer in the United States and worldwide. New therapies are highly sought after to improve outcome. The effect of sodium-R alpha lipoate on camptothecin- and paclitaxel-induced cytotoxicity was evaluated on A549 NSCLC and BEAS-2B "normal" lung epithelial cells. Combination indices (CI) and dose reduction indices (DRI) were investigated by studying the cytotoxicity of sodium-R-alpha lipoate (0-16 mM), camptothecin (0-25 nM) and paclitaxel (0-0.06 nM) alone and in combination. 3-(4,5-dimethylthiazol-2-Yl)-2,5 diphenyltetrazolium-bromide (MTT) was used to assess cytotoxicity. The combinational cytotoxic effects of sodium-R-alpha lipoate with camptothecin or paclitaxel were analyzed using a simulation of dose effects (CompuSyn(r) 3.01). The effects of sodium-R-alpha lipoate on camptothecin- and paclitaxel-induced cytotoxicity varied based on concentrations and treatment times. It was found that sodium-R-alpha lipoate wasn't cytotoxic toward BEAS-2B cells at any of the concentrations tested. For A549 cells, CIs [(additive (CI = 1); synergistic (CI < 1); antagonistic (CI < 1)] were lower and DRIs were higher for the camptothecin/sodium-R-alpha-lipoate combination (CI = ~0.17-1.5; DRI = ~2.2-22.6) than the paclitaxel/sodium-R-alpha-lipoate combination (CI = ~0.8-9.9; DRI = ~0.10-5.8) suggesting that the camptothecin regimen was synergistic and that the addition of sodium-R-alpha lipoate was important for reducing the camptothecin dose and potential for adverse effects. PMID- 24063431 TI - Unraveling the benzocaine-receptor interaction at molecular level using mass resolved spectroscopy. AB - The benzocaine-toluene cluster has been used as a model system to mimic the interaction between the local anesthetic benzocaine and the phenylalanine residue in Na(+) channels. The cluster was generated in a supersonic expansion of benzocaine and toluene in helium. Using a combination of mass-resolved laser based experimental techniques and computational methods, the complex was fully characterized, finding four conformational isomers in which the molecules are bound through N-H...pi and pi...pi weak hydrogen bonds. The structures of the detected isomers closely resemble those predicted for benzocaine in the inner pore of the ion channels, giving experimental support to previously reported molecular chemistry models. PMID- 24063430 TI - Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia. AB - BACKGROUND: Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood. RESULTS: We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status. CONCLUSIONS: Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment. PMID- 24063432 TI - Reference range of fetal cisterna magna volume by three-dimensional ultrasonography using the VOCAL method. AB - OBJECTIVE: To determine reference values for the fetal cisterna magna volume by three-dimensional ultrasonography (3DUS) using the virtual organ computer-aided analysis (VOCAL) method. METHODS: A cross-sectional study was conducted with 224 healthy pregnant women between 17 and 29 completed weeks. Measurement of the fetal cisterna magna volume was performed in the standard axial plane of the transverse diameter of the cerebellum through the VOCAL method with a 30 degrees angle. For the determination of reference values, polynomial regressions with adjustments by the coefficient of determination (R(2)) were held. The reliability and agreement were made by the intra-class correlation coefficient (ICC) and limits of agreement of the Bland-Altman graph. RESULTS: The average of the fetal cisterna magna volume ranged from 0.73 +/- 0.25 to 3.79 +/- 1.10 cm(3) between 17 and 29 weeks, respectively. Correlation was observed between the fetal cisterna magna volume and the gestational age (GA), best represented by a quadratic equation: -1.918+0.0284 * GA + 0.0065 * GA(2) (R(2 )= 0.67). It was observed good reliability and intra-observer agreement, with ICC = 0.92 and 95% limits of agreement (-49.7; 48.4). There was low inter-observer reliability and agreement, with ICC = 0.58 and 95% limits of agreement (-114.0; 80.2). CONCLUSION: Reference values for the fetal cisterna magna volume by 3DUS using the VOCAL method were determined and showed good agreement and intra-observer reliability. PMID- 24063433 TI - Structure-activity relationships and discovery of a G protein biased MU opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6 oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain. AB - The concept of "ligand bias" at G protein coupled receptors has been introduced to describe ligands which preferentially stimulate one intracellular signaling pathway over another. There is growing interest in developing biased G protein coupled receptor ligands to yield safer, better tolerated, and more efficacious drugs. The classical MU opioid morphine elicited increased efficacy and duration of analgesic response with reduced side effects in beta-arrestin-2 knockout mice compared to wild-type mice, suggesting that G protein biased MU opioid receptor agonists would be more efficacious with reduced adverse events. Here we describe our efforts to identify a potent, selective, and G protein biased MU opioid receptor agonist, TRV130 ((R)-30). This novel molecule demonstrated an improved therapeutic index (analgesia vs adverse effects) in rodent models and characteristics appropriate for clinical development. It is currently being evaluated in human clinical trials for the treatment of acute severe pain. PMID- 24063434 TI - Identification of myxobacteria-derived HIV inhibitors by a high-throughput two step infectivity assay. AB - BACKGROUND: Drug-resistance and therapy failure due to drug-drug interactions are the main challenges in current treatment against Human Immunodeficiency Virus (HIV) infection. As such, there is a continuous need for the development of new and more potent anti-HIV drugs. Here we established a high-throughput screen based on the highly permissive TZM-bl cell line to identify novel HIV inhibitors. The assay allows discriminating compounds acting on early and/or late steps of the HIV replication cycle. RESULTS: The platform was used to screen a unique library of secondary metabolites derived from myxobacteria. Several hits with good anti-HIV profiles were identified. Five of the initial hits were tested for their antiviral potency. Four myxobacterial compounds, sulfangolid C, soraphen F, epothilon D and spirangien B, showed EC50 values in the nM range with SI > 15. Interestingly, we found a high amount of overlapping hits compared with a previous screen for Hepatitis C Virus (HCV) using the same library. CONCLUSION: The unique structures and mode-of-actions of these natural compounds make myxobacteria an attractive source of chemicals for the development of broad spectrum antivirals. Further biological and structural studies of our initial hits might help recognize smaller drug-like derivatives that in turn could be synthesized and further optimized. PMID- 24063435 TI - A randomized controlled trial to prevent childhood obesity through early childhood feeding and parenting guidance: rationale and design of study. AB - BACKGROUND: Early and rapid growth in Infants is strongly associated with early development and persistence of obesity in young children. Substantial research has linked child obesity/overweight to increased risks for serious health outcomes, which include adverse physical, psychological, behavioral, or social consequences. METHODS/DESIGN: The goal of this study is to compare the effectiveness of structured Community Health Worker (CHW)--provided home visits, using an intervention created through community-based participatory research, to standard care received through the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) office visits in preventing the development of overweight (weight/length >= 85th percentile) and obesity (weight/length >= 95th percentile) in infants during their first 3 years of life. One hundred forty pregnant women in their third trimester (30-36 weeks) will be recruited and randomly assigned to the intervention or control group. DISCUSSION: This study will provide prospective data on the effects of an intervention to prevent childhood obesity in children at high risk for obesity due to ethnicity, income, and maternal body mass index (BMI). It will have wide-ranging applicability and the potential for rapid dissemination through the WIC program, and will demonstrate the effectiveness of a community approach though employing CHWs in preventing obesity during the first 3 years of life. This easy-to-implement obesity prevention intervention can be adapted for many locales and diverse communities and can provide evidence for policy change to influence health throughout life. TRIAL REGISTRATION: Clinical Trials Number: NCT01905072. PMID- 24063436 TI - Augmented visual feedback counteracts the effects of surface muscular functional electrical stimulation on physiological tremor. AB - BACKGROUND: Recent studies suggest that surface muscular functional electrical stimulation (FES) might suppress neurological upper limb tremor. We assessed its effects on upper limb physiological tremor, which is mainly driven by mechanical reflex oscillations. We investigated the interaction between FES and augmented visual feedback, since (a) most daily activities are performed using visual cues, and (b) augmented visual feedback exacerbates upper limb tremor. METHODS: 10 healthy subjects (23.4 +/- 7.7 years) performed 2 postural tasks with combinations of FES (4 sites; frequency of stimulation: 30 Hz; pulse width: 300 microsec; range of current delivered 10-34 mAmp) and augmented visual feedback. RESULTS: Spectral analysis of tremor showed a decrease of power spectral density to 62.18% (p = 0.01), of the integral in the 8-12 Hz frequency band to 57.67% (p = 0.003), and of tremor root mean square (RMS) to 57.16% (p = 0.002) during FES, without any changes in tremor frequency. Augmented visual feedback blocked the beneficial effect of FES, as confirmed by power spectral analysis (p = 0.01). We found a statistically significant interaction between augmented visual feedback and electrical stimulation (p = 0.039). CONCLUSIONS: Augmented visual feedback antagonizes the effects of FES on physiological tremor. The absence of changes of peak frequency argues against an effect of FES on mechanical properties of the upper limb. PMID- 24063437 TI - Primary signet ring cell carcinoma of the eyelid. AB - Primary signet ring cell carcinoma of the eyelid (PSCE) is a very rare tumour. Only a few cases having been reported to date. The majority of patients have been middle-age to elderly men. Different treatment modalities have been applied in cases of PSCE. Here, we report a case of PSCE in a man treated with orbital exenteration and radiotherapy. PMID- 24063438 TI - Computational studies of [bmim][PF6]/n-alcohol interfaces with many-body potentials. AB - In this paper, we present the results from molecular dynamics simulations of the equilibrium properties of liquid/liquid interfaces of room temperature ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]) and simple alcohols (i.e., methanol, 1-butanol, and 1-hexanol) at room temperature. Polarizable potential models are employed to describe the interactions among species. Results from our simulations show stable interfaces between the ionic liquid and n-alcohols, and we found that the interfacial widths decrease from methanol to 1-butanol systems and then increase for 1-hexanol interfaces. Angular distribution analysis reveals that the interface induces a strong orientational order of [bmim] and n-alcohol molecules near the interface, with [bmim] extending its butyl group into the alcohol phase, whereas the alcohol has the OH group pointing into the ionic liquid region, which is consistent with the recent sum frequency-generation experiments. We found the interface to have a significant influence on the dynamics of ionic liquids and n-alcohols. The orientational autocorrelation functions illustrate that [bmim] rotates more freely near the interface than in the bulk, whereas the rotation of n-alcohol is hindered at the interface. Additionally, the time scale associated with the diffusion along the interfacial direction is found to be faster for [bmim] but slowed down for n alcohols approaching the interface. We also calculate the dipole moment of n alcohols as a function of the distance normal to the interface. We found that, even though methanol and 1-butanol have different dipole moments in bulk phase, they reach a similar value at the interface. PMID- 24063439 TI - Time for Hunt to give clear steer on uniforms. PMID- 24063442 TI - Action is overdue on safe staffing guidance, RCN tells government. PMID- 24063448 TI - Staff need training to spot vision problems following acute stroke. PMID- 24063457 TI - Trusts warned to boost flu vaccine uptake, or lose share of L500m. PMID- 24063458 TI - Lobbying bill threatens our freedom of speech. AB - Stephen Wright's monthly take on nursing in the news. PMID- 24063464 TI - Acute kidney injury. PMID- 24063465 TI - 25 years of nursing success stories. AB - The nurse awards run by Nursing Standard have been showcasing quality care and innovation since 1988. Entries open on September 30 for the 25th awards, which will culminate in a reception at the Savoy hotel in London in May 2014 and a 1000 pounds GBP prize for the overall winner. PMID- 24063466 TI - The clock is ticking on dementia care excuses. AB - Alzheimer Scotland's first nurse consultant Colin MacDonald has audited dementia care in three Edinburgh hospitals and supported staff to improve care and make wards dementia-friendly. There are now 'no hiding places' for poor care. he says. PMID- 24063479 TI - The public need help in recognising who are nurses and who are not. PMID- 24063480 TI - When employers want flexibility, it is at the expense of employees. PMID- 24063484 TI - A 500-mile round trip, just for the NMC to destroy my career. PMID- 24063481 TI - Address fundamental problems before introducing revalidation. PMID- 24063485 TI - Communicating with haematology patients: a reflective account. AB - Nurses are required to keep their knowledge and skills up to date to ensure their practice is evidence-based. Reflection in and on practice can be used to ensure care provision is evidence-based, to increase self-awareness and to promote positive change. Timely communication of high-quality information tailored to patients' needs is required. When a breakdown in communication occurs in practice, it can have a negative effect on patients and the professionals providing their care. Using an example from my practice experience, this article aims to highlight the importance of communication, reflection and knowledge in nursing practice. PMID- 24063486 TI - Developing a nurse-led paracentesis service in an ambulatory care unit. AB - Ambulatory emergency care units are present in many hospitals and accommodate patients who need urgent medical assessment or procedures but do not require inpatient admission to achieve this. This article reports on a project undertaken in the ambulatory care unit at the Royal United Hospital Bath, which introduced a nurse-led paracentesis service with the intention of reducing waiting times and improving the service for patients. To evaluate the effect of the project, patient satisfaction levels and waiting times were measured before and after the introduction of nurse-led paracentesis. The results confirmed a significant reduction in waiting times after the nurse-led intervention was introduced and high levels of satisfaction. The results provide evidence that nurses are acquiring the knowledge and skills required to undertake interventional procedures that improve the patient's experience while contributing to pioneering developments in ambulatory emergency care services. PMID- 24063488 TI - Mental health in men. PMID- 24063487 TI - Assessment of suicidal intent in emergency care. AB - The assessment of suicidal intent in first-contact settings, including the emergency department, can be challenging. Inaccurate assessment can lead to increased incidence of self-harm and completion of suicide. This article focuses on factors that may affect review of this patient group, including healthcare professionals' personal and professional standards and values. Strategies to aid assessment of people presenting with suicidal ideation are discussed. PMID- 24063489 TI - An upward trajectory. PMID- 24063490 TI - When the pressure is piling up. PMID- 24063492 TI - Health and safety matters. PMID- 24063493 TI - Look after others - and yourself. PMID- 24063494 TI - Get ready and the best of luck. PMID- 24063495 TI - There is an abundance of experience, support and information for you. PMID- 24063496 TI - The educational benefits of simulated practice. PMID- 24063497 TI - Patients always know best. PMID- 24063498 TI - Better together. PMID- 24063499 TI - Figure this one out. PMID- 24063501 TI - Coping with dyslexia. PMID- 24063503 TI - Social-Interaction Knowledge Translation for In-Home Management of Urinary Incontinence and Chronic Care. AB - Although urinary incontinence (UI) can be managed conservatively, it is a principal reason for the breakdown of in-home family care. This study explored the social interaction processes of knowledge translation (KT) related to how UI management knowledge might be translated within in-home care. In-depth interview data were collected from a theoretical sample of 23 family caregivers, older home care recipients, and home care providers. Constant comparison and Glaser's analysis criteria were used to create translating knowledge through relating , a substantive theory with 10 subthemes: living with the problem; building experiential knowledge; developing comfort; easing into a working relationship; nurturing mutuality; facilitating knowledge exchange; building confidence; fi ne tuning knowledge; putting it all together; and managing in-home care. Findings inform both theory and practice of in-home UI KT, illuminating how intersubjectivity and bi-directional relational interactions are essential to translating in-home chronic care knowledge, which is largely tacit and experiential in nature. PMID- 24063504 TI - Nurse manager succession planning: synthesis of the evidence. AB - AIM: The literature supporting nurse manager succession planning is reviewed and synthesised to discover best practice for identifying and developing future nurse managers. BACKGROUND: Healthcare succession planning practices are lacking. Nurse managers are historically selected based on clinical skills and lack formal leadership preparation. EVALUATION: A systematic literature search appraises and summarises the current literature supporting nurse manager succession planning. Multiple reviewers were used to increase the reliability and validity of article selection and analysis. KEY ISSUES: New nurse managers require months to adapt to their positions. Deliberate nurse manager succession planning should be integrated in the organisation's strategic plan and provide a proactive method for identifying and developing potential leaders. CONCLUSION: Organisations that identify and develop internal human capital can improve role transition, reduce nurse manager turnover rates and decrease replacement costs. Despite the clear benefits of succession planning, studies show that resource allocation for proactive, deliberate development of current and future nurse leaders is lacking. Additionally, systematic evaluation of succession planning is limited. IMPLICATIONS FOR NURSING MANAGEMENT: Deliberate succession planning efforts and appropriate resource allocation require strategic planning and evaluation methods. Detailed evaluation methods demonstrating a positive return on investment utilising a cost-benefit analysis and empirical outcomes are necessary. PMID- 24063505 TI - Thrombin generation in acute cardioembolic and non-cardioembolic ischemic stroke. AB - OBJECTIVE: Increased thrombin generation, as measured by the Calibrated Automated Thrombogram (CAT), has recently been reported to predict ischemic stroke, especially stroke with a cardioembolic source. However, there are few studies on thrombin generation using CAT in patients with manifest ischemic stroke, particularly in patients with cardioembolic stroke not yet on anticoagulation. MATERIALS AND METHODS: Therefore, a prospective cohort study of 205 stroke patients > 45 years of age was performed. They were recruited during their hospital stay or shortly thereafter. Inclusion criteria were ischemic stroke or TIA within two weeks and no atrial fibrillation (AF) in the history or at inclusion. Patients received a thumb ECG device in order to detect silent AF. Blood samples were collected at inclusion and after 1 month. Thrombin generation in plasma after addition of tissue factor was assessed in patients and in healthy controls. RESULTS: Mean age of patients was 72 +/- 7 years and 43% were females. Peak thrombin concentrations were variable among stroke patients but overall significantly higher at both time points (p < 0.0001) compared to controls, and tended to be highest in patients in whom paroxysmal atrial fibrillation was subsequently documented. CONCLUSION: Thrombin generation in patients with acute cardioembolic and non-cardioembolic schemic stroke/TIA is variable but overall higher compared to healthy subjects. The long-term prognostic value of thrombin generation in patients with a recent ischemic stroke deserves further investigation. PMID- 24063506 TI - Binocular Alignment and Binocular Vision Therapy. More Words and Terms; Asymmetry of Binocular Vision. Strabology: Convergence Insufficiency and Excess, Duane's Syndrome. Review: Vertical Deviations. PMID- 24063507 TI - Evaluation of Binocular Vision Therapy Efficacy by 3D Video-Oculography Measurement of Binocular Alignment and Motility. AB - OBJECTIVE: To evaluate two cases of intermittent exotropia treated by vision therapy the efficacy of the treatment by complementing the clinical examination with a 3D videooculography to register and to evidence the potential applicability of this technology for such purpose. METHODS: We report the binocular alignment changes occurring after vision therapy in a woman of 36 years with an intermittent exotropia of 25 prism diopters at far and 18 PD at near and a child of 10 years with 8 PD of intermittent exotropia in primary position associated to 6 PD of left eye hypotropia. Both patients presented good visual acuity with correction in both eyes. Instability of ocular deviation was evident by VOG analysis, revealing also the presence of vertical and torsional components. Binocular vision therapy was prescribed and performed including different types of vergence, accommodation, and consciousness of diplopia training. RESULTS: After therapy, excellent ranges of fusional vergence and a to the-nose near point of convergence were obtained.The 3D VOG examination confirmed the compensation of the deviation with a high level of stability of binocular alignment. Significant improvement could be observed after therapy in the vertical and torsional components that were found to become more stable. Patients were very satisfied with the outcome obtained by vision therapy. CONCLUSION: 3D VOG is a useful technique for providing an objective register of the compensation of the ocular deviation and the stability of the binocular alignment achieved after vision therapy in cases of intermittent exotropia, providing a detailed analysis of vertical and torsional improvements. PMID- 24063508 TI - Binocular vision interference from unequal inputs in an adult patient with monocular dense acquired cataract. AB - INTRODUCTION: The effect of the unequal visual inputs in uniocular cataracts is addressed through the hypothesis that a marked inequality of the visual inputs will have an interference effect that will degrade the binocular vision relative to that of the better eye. We tested this hypothesis of reverse interference effect by both clinical and functional Magnetic Resonance Imaging assessments in an acute unilateral cataract patient. The patient was 63 year old woman who rapidly developed a dense sub-capsular cataract following steroid radio chemotherapy treatment for breast cancer. METHODS: Clinical: Ophthalmologic evaluation and distance visual acuity (both uniocular and binocular), contrast sensitivity, binocular function, ocular motility and cover test to evaluate the presence of strabismus, and a slit lamp assessment of cataract density were performed. Neuroimaging: Functional MRI was run in a 1.5T Philips Intera Master with a SENSE neurovascular coil of 8 channels. The experimental design included three conditions: a) Binocular: both eyes viewing; b) OS-mono: left eye viewing, right eye occluded by a black cover; c) OD-mono: right eye viewing, left eye occluded by a black cover. RESULTS: Clinical: The logMAR visual acuity was 0.9 OD, hand movement at one meter OS, and 0.7 for binocular viewing, that is, the binocular acuity was worse than the better eye acuity alone. As hypothesized, adding a diffuser lens and a penlight glare on the cataract eye increased the interference signal from that eye, and thus further reduced the binocular acuity to 0.4. Binocular contrast sensitivity also was worse than the OD alone. Neuroimaging: The fMRI results were consistent with the clinical findings. The number of activated voxels in the visual cortex under binocular viewing was reduced by about 40 percent relative to that for the fellow eye alone. CONCLUSION: Clinical and fMRI data were well-correlated and consistent with the prediction for the marked binocular asymmetry. The results imply that the mechanisms operating under a severe binocular vision asymmetry caused by unilateral diffusion (blur without contour perception, or light perception only) exhibit an interference effect under binocular viewing that is not seen in the case of weaker asymmetry such as in functional amblyopia, or from the extreme case of total elimination of visual input from one eye, such as in occlusion or monocular blindness. PMID- 24063509 TI - Slanted medial rectus recesection for treatment of exotropia with convergence insufficiency strabismus: a report of results in 15 cases. AB - PURPOSE: To evaluate the surgical and functional results of slanted medial rectus resection for treatment intermittent exotropia of the convergence insufficiency type. METHODS: Fifteen patients with near vision asthenopia and intermittent exotropia of the convergence insufficiency type were included in this prospective study. The upper edge of the MR was resected more than the lower edge. Slanted bilateral or unilateral medial rectus resection was performed. The mean length of follow-up was 14.9 months. RESULTS: Slanted medial rectus resection(s) caused a significant postoperative reduction in the mean distance exodeviation from 11.40 to 4.53 PD, as well as a change in the mean near exodeviation from 23.93 to 10.73 PD. Although mean near-distance difference reduced from 12.53 to 6.2 PD. In final examination, 11 patients showed surgical success rate and recurrent exotropia occurred in 4 cases. On the other hand, 13 cases had experienced significant relief from their symptoms. CONCLUSION: Slanted medial rectus resection is useful in decreasing the symptoms of intermittent exotropia of the convergence insufficiency type. However, it can result in undercorrection in larger deviations. PMID- 24063510 TI - Is y-split recession of the medial rectus muscle as effective as scleral retroequatorial myopexy of the medial rectus muscle for partially accommodative esotropia with convertgence? A report of results in 61 cases. AB - PURPOSE: To compare the results of a medial rectus (MR) Y-split recession with those of a MR retroequatorial myopexy for the treatment of partially accommodative esotropia with convergence excess. METHODS: In this retrospective study, patients who underwent bilateral MR Y-split recession or bilateral MR retroequatorial myopexy for partially accommodative esotropia with convergence excess (accommodative convergence: accommodation ratios greater than 5 prism diopters:diopters) between March 2006 and January 2011 were included. RESULTS: Sixty-one patients underwent bilateral MR Y-split recession, and 60 patients underwent retroequatorial myopexy of the bilateral MR muscles. Satisfactory binocular alignment was achieved in 77 percent of the patients who underwent MR Y split recession by the final examination and 78 percent of patients who underwent a MR retroequatorial myopexy. There was no statistically significant difference in near or distance deviation or the near-distance disparity at the postoperative 1 month or final examination. The proportions of patients who had a successful alignment at the final examination did not differ between the two groups. No patients had any complications. CONCLUSION: We determined that both the MR Y split recession and MR retroequatorial myopexy achieved satisfactory results for the treatment of partially accommodative esotropia with convergence excess though both techniques had some disadvantages. PMID- 24063511 TI - Functional Amblyopia and Deficient Binocular Vision as Initial Clinical Features in Duane's Syndrome. AB - PURPOSE: To investigate and report the clinical characteristics at initial presentation in patients who had Duane Syndrome, especially binocular vision and functional amblyopia. METHODS: The medical files of patients with Duane's syndrome were reviewed. The main outcome measures of the study were the initial clinical characteristics including amblyopia and associated risk factors including deficiences of binocular vision. RESULTS: The review identified 99 patients with Duane Syndrome. The median age of patients was 6 years. The frequency of amblyopia at initial presentation was 23 percent. Forty-five patients had measurable stereopsis and 58 patients had binocular vision fusion. CONCLUSIONS: Amblyopia and altered binocular function are important among the clinical features of Duane Syndrome which should be highlighted at initial examination. PMID- 24063512 TI - Major Review: Management of Strabismus Vertical Deviations, A- and V-Patterns and Cyclotropia Occurring after Horizontal Rectus Muscle Surgery with or without Oblique Muscle Surgery. AB - PURPOSE: To show conditions where a vertical deviation, an A- or a V-pattern or cyclotropia can appear after surgery on the horizontal rectus muscles, with or without oblique muscle surgery. Our purpose is also to show conditions when a vertical deviation can be anticipated before horizontal rectus muscle surgery and realignment of the ocular deviation. Finally, our purpose is to stress on some surgical precautions one should take to avoid such complications. CASE REPORTS: We report two cases who showed significant vertical deviations due to complications that followed surgical weakening procedures of the inferior oblique muscles. CONCLUSION: 1. Vertical deviations, A and V patterns and cyclotropia can occur, can be anticipated or can be avoided in pure horizontal rectus muscle surgeries 2. Vertical deviations are common following complicated oblique muscles surgery if the surgeon blindly sweeps the muscle hook into the area. They can be avoided if the weakening technique allows direct visualization of the inferior oblique muscle. PMID- 24063513 TI - Five-coordinate silicon(II) compounds with Si-M bonds (M = Cr, Mo, W, Fe): Bis[N,N'-diisopropylbenzamidinato(-)]silicon(II) as a ligand in transition-metal complexes. AB - Reaction of the donor-stabilized silylene 1 with [Cr(CO)6], [Mo(CO)6], [W(CO)6], or [Fe(CO)5] leads to the formation of the transition-metal silylene complexes 2 5, which contain five-coordinate silicon(II) moieties with Si-M bonds (M = Cr, Mo, W, Fe). These compounds were characterized by NMR spectroscopic studies in the solid state and in solution and by crystal structure analyses. These experimental investigations were complemented by computational studies to gain insight into the bonding situation of 2-5. The nature of the Si-M bonds is best described as a single bond. PMID- 24063514 TI - No increased risk of perforation during colonoscopy in patients undergoing Nurse Administered Propofol Sedation. AB - OBJECTIVE: Nurse Administered Propofol Sedation (NAPS) contributes to a deeper sedation of the patients, making them unable to respond to pain and an increased incidence of perforations has been speculated. The objective of this study was to evaluate the risk of perforations during colonoscopies performed with either NAPS or conventional sedation regimes. MATERIAL AND METHODS: Data were retrospectively retracted from medical journals from 1 January 2007 to 31 December 2011. All journals were examined and cross-referenced to reveal any perforations. We analyzed all colonoscopies in regard to nature of the procedure (diagnostic vs therapeutic), experience of the endoscopist and ASA-classification of the patients. RESULTS: A total of 6371 colonoscopies were performed, of which 3155 were performed under propofol sedation. There were 16 perforations (0.25%); 10 of these performed during NAPS and 6 during conventional colonoscopy (p = 0.454, OR: 1.7 (95% CI: 0.6-5.7)). There were 4874 diagnostic and 1497 therapeutic colonoscopies, with a majority of the perforations (94%) occurring during a diagnostic procedure (p = 0.389). No statistically difference was found in the incidence of perforations caused by an experienced or less experienced endoscopist (p = 0.589). CONCLUSION: The risk of colonic perforations during colonoscopy was not found to be significantly higher in patients undergoing NAPS compared to patients undergoing conventional sedation, although a tendency may exist. Furthermore, we found no correlation to neither experience of the endoscopist, nature of the procedure nor sex of the patients. Larger and prospective studies are needed to further evaluate on this subject. PMID- 24063515 TI - Uterine electric activity during the third stage of labor; a look into the physiology of a deserted stage. AB - OBJECTIVE: To evaluate uterine activity during the third stage of labor and compare it to that observed in the second stage of labor. STUDY DESIGN: Uterine electric activity was prospectively measured using electrical uterine myography (EUM) in 44 women with singleton pregnancy at term during the final 30 min of the second stage and throughout the third stage of labor. Results are reported using a scoring index of 1-5 mWS (micro-Watt-Second). Patients were stratified into two groups based on the duration of the third stage (<15 min and >=15 min) RESULTS: The mean durations of the second and third stages were 51.9 +/- 63.5 and 15.4 +/- 7.5 minutes, respectively. During the third stage, uterine activity (contractions peaks) was similar to that observed during the second stage of labor (3.43 +/- 0.64 mWS versus 3.42 +/- 0.57 mWS, p = 0.8). No correlation was found between the duration of the third stage and EUM measurements during the third (p = 0.9) or the second (p = 0.2) stages of labor. No association was found between EUM measurements during the third stage and parity, maternal age, fetal weight, duration of labor, gestational age, gravity or BMI. The rate of oxytocin use during the second stage and EUM measurements during the second or third stage did not differ among women with short versus long duration of the third stage. CONCLUSION: Uterine activity during the third stage is comparable and as intense as that occurring during the second stage. Third stage length cannot be predicted by contraction intensity during the second or third stage of labor. PMID- 24063516 TI - A vascular piece in the puzzle of adipose tissue dysfunction: mechanisms and consequences. AB - In the last years, several studies unravelled many aspects of adipose tissue pathophysiology in metabolic diseases. Some studies suggested hypoxia as one of such aspects, despite the exact mechanisms and pathophysiological significance is still partially unknown. Adipose tissue was shown to be hypoxic in obesity, mainly resulting from adipocyte hypertrophy, leading to increased activation of inflammatory pathways. In animal and cell models, hypoxia-induced inflammation was shown to lead to endocrine alterations and dysmetabolism. However, recent evidences suggest that instead of a simple low oxygenation theory, adipose tissue microvasculature may be regulated by a series of factors, including vasoactive factors like angiotensin II, angiogenesis and glycation, among others. This review summarizes the current knowledge about the role of these factors in the regulation of adipose tissue irrigation and the functional consequences of adipose tissue microvascular dysfunction. PMID- 24063517 TI - The mutational landscape of chromatin regulatory factors across 4,623 tumor samples. AB - BACKGROUND: Chromatin regulatory factors are emerging as important genes in cancer development and are regarded as interesting candidates for novel targets for cancer treatment. However, we lack a comprehensive understanding of the role of this group of genes in different cancer types. RESULTS: We have analyzed 4,623 tumor samples from thirteen anatomical sites to determine which chromatin regulatory factors are candidate drivers in these different sites. We identify 34 chromatin regulatory factors that are likely drivers in tumors from at least one site, all with relatively low mutational frequency. We also analyze the relative importance of mutations in this group of genes for the development of tumorigenesis in each site, and indifferent tumor types from the same site. CONCLUSIONS: We find that, although tumors from all thirteen sites show mutations in likely driver chromatin regulatory factors, these are more prevalent in tumors arising from certain tissues. With the exception of hematopoietic, liver and kidney tumors, as a median, the mutated factors are less than one fifth of all mutated drivers across all sites analyzed. We also show that mutations in two of these genes, MLL and EP300, correlate with broad expression changes across cancer cell lines, thus presenting at least one mechanism through which these mutations could contribute to tumorigenesis in cells of the corresponding tissues. PMID- 24063518 TI - Brain aging and dementia during the transition from late adulthood to old age: design and methodology of the "Invece.Ab" population-based study. AB - BACKGROUND: Developed countries are experiencing an unprecedented increase in life expectancy that is accompanied by a tremendous rise in the number of people with dementia. The purpose of this paper is to report on the study design and methodology of an Italian population-based study on brain aging and dementia in the elderly. This multi-domain study is structured in two phases. Our goal is to gather sufficient data to estimate the prevalence (phase I: cross-sectional study), the incidence and the progression of dementia and its subtypes as well as cognitive impairment (phase II: follow-up study) and to identify socio demographic, clinical, and lifestyle factors associated with dementia and the quality of brain aging in people aged 70-74 years, a crucial point between late adulthood and old age. METHODS/DESIGN: We chose to contact all 1773 people born between 1935-39 residing in Abbiategrasso, Milan, Italy. Those who agreed to participate in the "Invece.Ab" study were enrolled in a cross-sectional assessment and will be contacted two and four years after the initial data collection to participate in the longitudinal survey. Both the cross-sectional and longitudinal assessments include a medical evaluation, a neuropsychological test battery, several anthropometric measurements, a social and lifestyle interview, blood analyses, and the storage of a blood sample for the evaluation of putative biological markers. DISCUSSION: Now at the end of the recruitment phase, the evaluable population has amounted to 1644 people. Among these, 1321 (80.35%) of the participants have completed phase I. This high return rate was likely due to the style of recruitment and personalization of the contacts. PMID- 24063519 TI - Timely approaches to identify probiotic species of the genus Lactobacillus. AB - Over the past decades the use of probiotics in food has increased largely due to the manufacturer's interest in placing "healthy" food on the market based on the consumer's ambitions to live healthy. Due to this trend, health benefits of products containing probiotic strains such as lactobacilli are promoted and probiotic strains have been established in many different products with their numbers increasing steadily. Probiotics are used as starter cultures in dairy products such as cheese or yoghurts and in addition they are also utilized in non dairy products such as fermented vegetables, fermented meat and pharmaceuticals, thereby, covering a large variety of products.To assure quality management, several pheno-, physico- and genotyping methods have been established to unambiguously identify probiotic lactobacilli. These methods are often specific enough to identify the probiotic strains at genus and species levels. However, the probiotic ability is often strain dependent and it is impossible to distinguish strains by basic microbiological methods.Therefore, this review aims to critically summarize and evaluate conventional identification methods for the genus Lactobacillus, complemented by techniques that are currently being developed. PMID- 24063520 TI - Gadolinium complex of DO3A-benzothiazole aniline (BTA) conjugate as a theranostic agent. AB - A gadolinium complex of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) and benzothiazole-aniline (BTA) of the type [Gd(DO3A-BTA)(H2O)] has been prepared for use as a single molecule theranostic agent. The kinetic inertness and r1 relaxivity (= 3.84 mM(-1) s(-1)) of the complex compare well with those of structurally analogous Gd-DOTA. The same complex is not only tumor-specific but also intracellular, enhancing MR images of cytosols and nuclei of tumor cells such as MCF-7, MDA-MB-231, and SK-HEP-1. Both DO3A-BTA and Gd(DO3A-BTA) reveal antiproliferative activities as demonstrated by GI50 and TGI values obtainable from the cell counting kit-8 (CCK-8) assays performed on these cell lines. Ex vivo and in vivo monitoring of tumor sizes provide parallel and supportive observations for such antiproliferative activities. PMID- 24063522 TI - Spontaneous subperiosteal hematoma precipitated by anxiety attack. AB - A 60-year-old woman presented with diplopia and left periorbital edema and pressure, which developed during an anxiety attack the previous day. Examination revealed left inferotemporal globe dystopia, periorbital edema, ecchymosis, and limitation in supraduction. Orbital MRI confirmed the diagnosis of a superior subperiosteal orbital hematoma. The patient's signs and symptoms rapidly resolved with administration of oral corticosteroids. The patient remains asymptomatic with complete resolution of orbital signs at 3-month follow-up. Subperiosteal orbital hematoma (SOH) is a rare condition in which blood accumulates between the bony orbit and separated periosteum, and is often due to blunt head trauma. Non traumatic SOH (NTSOH) is exceedingly rare and usually associated with known coagulopathies or tendency to bleed. However, few cases of spontaneous NTSOH have been reported without any such predisposition and are thought to be caused by sudden elevations in intrathoracic and intracranial venous pressure such as vomiting, coughing, SCUBA diving, weight lifting and labor. We herein describe the presentation, radiography and outcome of a unique case of spontaneous NTSOH following an anxiety attack. PMID- 24063521 TI - Exergaming for balance training of elderly: state of the art and future developments. AB - Fall injuries are responsible for physical dysfunction, significant disability, and loss of independence among elderly. Poor postural control is one of the major risk factors for falling but can be trained in fall prevention programs. These however suffer from low therapy adherence, particularly if prevention is the goal. To provide a fun and motivating training environment for elderly, exercise games, or exergames, have been studied as balance training tools in the past years. The present paper reviews the effects of exergame training programs on postural control of elderly reported so far. Additionally we aim to provide an in depth discussion of technologies and outcome measures utilized in exergame studies. Thirteen papers were included in the analysis. Most of the reviewed studies reported positive results with respect to improvements in balance ability after a training period, yet few reached significant levels. Outcome measures for quantification of postural control are under continuous dispute and no gold standard is present. Clinical measures used in the studies reviewed are well validated yet only give a global indication of balance ability. Instrumented measures were unable to detect small changes in balance ability as they are mainly based on calculating summary statistics, thereby ignoring the time-varying structure of the signals. Both methods only allow for measuring balance after the exergame intervention program. Current developments in sensor technology allow for accurate registration of movements and rapid analysis of signals. We propose to quantify the time-varying structure of postural control during gameplay using low-cost sensor systems. Continuous monitoring of balance ability leaves the user unaware of the measurements and allows for generating user-specific exergame training programs and feedback, both during one game and in timeframes of weeks or months. This approach is unique and unlocks the as of yet untapped potential of exergames as balance training tools for community dwelling elderly. PMID- 24063523 TI - Comparison of five influenza surveillance systems during the 2009 pandemic and their association with media attention. AB - BACKGROUND: During the 2009 influenza pandemic period, routine surveillance of influenza-like-illness (ILI) was conducted in The Netherlands by a network of sentinel general practitioners (GPs). In addition during the pandemic period, four other ILI/influenza surveillance systems existed. For pandemic preparedness, we evaluated the performance of the sentinel system and the others to assess which of the four could be useful additions in the future. We also assessed whether performance of the five systems was influenced by media reports during the pandemic period. METHODS: The trends in ILI consultation rates reported by sentinel GPs from 20 April 2009 through 3 January 2010 were compared with trends in data from the other systems: ILI cases self-reported through the web-based Great Influenza Survey (GIS); influenza-related web searches through Google Flu Trends (GFT); patients admitted to hospital with laboratory-confirmed pandemic influenza, and detections of influenza virus by laboratories. In addition, correlations were determined between ILI consultation rates of the sentinel GPs and data from the four other systems. We also compared the trends of the five surveillance systems with trends in pandemic-related newspaper and television coverage and determined correlation coefficients with and without time lags. RESULTS: The four other systems showed similar trends and had strong correlations with the ILI consultation rates reported by sentinel GPs. The number of influenza virus detections was the only system to register a summer peak. Increases in the number of newspaper articles and television broadcasts did not precede increases in activity among the five surveillance systems. CONCLUSIONS: The sentinel general practice network should remain the basis of influenza surveillance, as it integrates epidemiological and virological information and was able to maintain stability and continuity under pandemic pressure. Hospital and virological data are important during a pandemic, tracking the severity, molecular and phenotypic characterization of the viruses and confirming whether ILI incidence is truly related to influenza virus infections. GIS showed that web-based, self-reported ILI can be a useful addition, especially if virological self-sampling is added and an epidemic threshold could be determined. GFT showed negligible added value. PMID- 24063524 TI - n-Dodecyl beta-D-maltoside specifically competes with general anesthetics for anesthetic binding sites. AB - We recently demonstrated that the anionic detergent sodium dodecyl sulfate (SDS) specifically interacts with the anesthetic binding site in horse spleen apoferritin, a soluble protein which models anesthetic binding sites in receptors. This raises the possibility of other detergents similarly interacting with and occluding such sites from anesthetics, thereby preventing the proper identification of novel anesthetic binding sites. n-Dodecyl beta-D-maltoside (DDM) is a non-ionic detergent commonly used during protein-anesthetic studies because of its mild and non-denaturing properties. In this study, we demonstrate that SDS and DDM occupy anesthetic binding sites in the model proteins human serum albumin (HSA) and horse spleen apoferritin and thereby inhibit the binding of the general anesthetics propofol and isoflurane. DDM specifically interacts with HSA (Kd = 40 MUM) with a lower affinity than SDS (Kd = 2 MUM). DDM exerts all these effects while not perturbing the native structures of either model protein. Computational calculations corroborated the experimental results by demonstrating that the binding sites for DDM and both anesthetics on the model proteins overlapped. Collectively, our results indicate that DDM and SDS specifically interact with anesthetic binding sites and may thus prevent the identification of novel anesthetic sites. Special precaution should be taken when undertaking and interpreting results from protein-anesthetic investigations utilizing detergents like SDS and DDM. PMID- 24063525 TI - Nature of the chemical bond of aqueous Fe2+ probed by soft X-ray spectroscopies and ab initio calculations. AB - Aqueous iron(II) chloride is studied by soft X-ray absorption, emission, and resonant inelastic Raman scattering techniques on the Fe L-edge and O K-edge using the liquid-jet technique. Soft X-ray spectroscopies allow in situ and atom specific probing of the electronic structure of the aqueous complex and thus open the door for the investigation of chemical bonding and molecular orbital mixing. In this work, we combine theoretical ab initio restricted active space self consistent field and local atomic multiplet calculations with experimental soft X ray spectroscopic methods for a description of the local electronic structure of the aqueous ferrous ion complex. We demonstrate that the atomic iron valence final states dominate the resonant inelastic X-ray scattering spectra of the complex over the ligand-to-metal charge transfer transitions, which indicates a weak interaction of Fe(2+) ion with surrounding water molecules. Moreover, the oxygen K-edge also shows only minor changes due to the presence of Fe(2+) implying a small influence on the hydrogen-bond network of water. PMID- 24063526 TI - Broncho-alveolar lavage (BAL) for the diagnosis of sarcoidosic uveitis. AB - PURPOSE: To evaluate the use of BAL for the diagnosis of sarcoidosic uveitis. METHODS: Retrospective study of 109 consecutive patients with uveitis and minimum 2 signs of ocular sarcoidosis who had a BAL and chest imaging. BAL(+) was defined as an alveolar (a) lymphocytosis (L) aL > 15% with aCD4/CD8 > 3.5. Serum angiotensin converting enzyme (sACE), tuberculin skin test and gallium scan were tested in 83, 95 and 24 patients. RESULTS: BAL was + in 26.6% of patients (86.2% females, mean age 50.8y) with mean aL = 46.8% and mean aCD4/CD8 = 8.5 which significantly differed form BAL(-) patients: 62.5% females, p < 0.02, mean age 43.6y, p < 0.05, mean aL = 17.2%, p < 0.001 and mean aCD4/CD8 = 1.8, p < 0.001. BAL(+) patients had 31% of bilateral hilar adenopathy (BHL(+)), and 59.1% of elevated sACE which significantly differed form BAL(-) patients: 8.8%, p = < 0.01 and 14.8% p < 0.001. CONCLUSION: Our findings suggest that BAL have a high diagnostic value and might be a useful additional test for the diagnosis of sarcoidosic uveitis, even with normal chest imaging. PMID- 24063528 TI - Cancer: tilting at windmills? AB - One of the striking characteristics of cancer cells is their phenotypic diversity and ability to switch phenotypes in response to environmental fluctuations. Such phenotypic changes (e.g. from drug-sensitive to drug-resistant), which are critical for survival and proliferation, are widely believed to arise due to mutations in the cancer cell's genome. However, there is growing concern that such a deterministic view is not entirely consistent with multiple lines of evidence which indicate that cancer can arise in the absence of mutations and can even be reversed to normalcy despite the mutations. In this Commentary, we wish to present an alternate view that highlights how stochasticity in protein interaction networks (PINs) may play a key role in cancer initiation and progression. We highlight the potential role of intrinsically disordered proteins (IDPs) and submit that targeting IDPs can lead to new insights and treatment protocols for cancer. PMID- 24063527 TI - Increased binding of stroke-induced long non-coding RNAs to the transcriptional corepressors Sin3A and coREST. AB - LncRNAs (long non-coding RNAs) are thought to play a significant role in cellular homeostasis during development and disease by interacting with CMPs (chromatin modifying proteins). We recently showed that following transient focal ischemia, the expression of many lncRNAs was altered significantly in rat brain. We currently analyzed whether focal ischemia also alters the association of lncRNAs with the CMPs Sin3A and coREST (corepressors of the RE-1 silencing transcription factor). RIP (RNA immunoprecipitation) combined with lncRNA microarray analysis showed that 177 of the 2497 lncRNAs expressed in rat cerebral cortex showed significantly increased binding to either Sin3A or coREST following ischemia compared with sham. Of these, 26 lncRNAs enriched with Sin3A and 11 lncRNAs enriched with coREST were also up-regulated in their expressions after ischemia. A majority of the lncRNAs enriched with these CMPs were intergenic in origin. Evaluation of the expression profiles of corresponding protein-coding genes showed that their expression levels correlate with those of the lncRNAs with which they shared a common locus. This is the first study to show that stroke induced lncRNAs might associate with CMPs to modulate the post-ischemic epigenetic landscape. PMID- 24063529 TI - In vitro bactericidal effects of near-ultraviolet light from light-emitting diodes on Helicobacter pylori. AB - We investigated whether near-ultraviolet light emitted from light-emitting diodes (LEDs) effects Helicobacter pylori viability and whether this new method can potentially apply to eradication therapy. Three H. pylori strains were used for near-ultraviolet (UV) LED irradiation experiments. Viability of isolates exposed to near-UV light was compared with controls by counting colony forming units. A time-dependent bactericidal effect of near-UV light was definitely observed. LED irradiation with near-UV light showed effective bactericidal activity against H. pylori strains. Eradication therapy with LED might provide a new avenue of treatment in patients refractory to eradication due to antibiotic resistance and/or adverse effects of antibiotics. PMID- 24063531 TI - Structure and intermolecular vibrations of perylene.trans-1,2-dichloroethene, a weak charge-transfer complex. AB - The vibronic spectra of strong charge-transfer complexes are often congested or diffuse and therefore difficult to analyze. We present the spectra of the pi stacked complex perylene trans-1,2-dichloroethene, which is in the limit of weak charge transfer, the electronic excitation remaining largely confined to the perylene moiety. The complex is formed in a supersonic jet, and its S0 <-> S1 spectra are investigated by two-color resonant two-photon ionization (2C-R2PI) and fluorescence spectroscopies. Under optimized conditions, vibrationally cold (T(vib) ~ 9 K) and well resolved spectra are obtained. These are dominated by vibrational progressions in the "hindered-rotation" Rc intermolecular vibration with very low frequencies of 11 (S0) and 13 cm(-1) (S1). The intermolecular Tz stretch and the Ra and Rb bend vibrations are also observed. The normally symmetry-forbidden intramolecular 1a(u) "twisting" vibration of perylene also appears, showing that the pi- stacking interaction deforms the perylene moiety, lowering its local symmetry from D2h to D2. We calculate the structure and vibrations of this complex using six different density functional theory (DFT) methods (CAM-B3LYP, BH&HLYP, B97-D3, omegaB97X-D, M06, and M06-2X) and compare the results to those calculated by correlated wave function methods (SCS-MP2 and SCS-CC2). The structures and vibrational frequencies predicted with the CAM-B3LYP and BH&HLYP methods disagree with the other calculations and with experiment. The other four DFT and the ab initio methods all predict a pi-stacked "centered" structure with nearly coplanar perylene and dichloroethene moieties and intermolecular binding energies of D(e) = -20.8 to -26.1 kJ/mol. The 000 band of the S0 -> S1 transition is red-shifted by deltanu = -301 cm(-1) relative to that of perylene, implying that the D(e) increases by 3.6 kJ/mol or 15% upon electronic excitation. The intermolecular vibrational frequencies are assigned to the calculated Rc, Tz, Ra, and Rb vibrations by comparing to the observed/calculated frequencies and S0 <-> S1 Franck-Condon factors. Of the three TD-DFT methods tested, the hybrid-meta-GGA functional M06-2X shows the best agreement with the experimental electronic transition energies, spectral shifts, and vibronic spectra, closely followed by the omegaB97X-D functional, while the M06 functional gives inferior results. PMID- 24063530 TI - Gold(I)-phosphine-N-heterocycles: biological activity and specific (ligand) interactions on the C-terminal HIVNCp7 zinc finger. AB - The syntheses and the characterization by chemical analysis, (1)H and (31)P NMR spectroscopy, and mass spectrometry of a series of linear triphenylphosphine gold(I) complexes with substituted N-heterocycle ligands (L), [(PPh3)Au(I)(L)](+), is reported. The reaction of [(PPh3)Au(L)](+) (L = Cl(-) or substituted N- heterocyclic pyridine) with the C-terminal (Cys3His) finger of HIVNCp7 shows evidence by mass spectrometry (ESI-MS) and (31)P NMR spectroscopy of a long-lived {(PPh3)Au}-S-peptide species resulting from displacement of the chloride or pyridine ligand by zinc-bound cysteine with concomitant displacement of Zn(2+). In contrast, reactions with the Cys2His2 finger-3 of the Sp1 transcription factor shows significantly reduced intensities of {(PPh3)Au} adducts. The results suggest the possibility of systematic (electronic, steric) variations of "carrier" group PR3 and "leaving" group L as well as the nature of the zinc finger in modulation of biological activity. The cytotoxicity, cell cycle signaling effects, and cellular accumulation of the series are also reported. All compounds display cytotoxicity in the micromolar range upon 96 h continuous exposure to human tumor cells. The results may have relevance for the reported inhibition of viral load in simian virus by the gold(I) drug auranofin. PMID- 24063532 TI - Filipino Health Care Aides and the Nursing Home Labour Market in Winnipeg. AB - Canada's nursing homes have become increasingly dependent on immigrant health care aides. More than any other ethnic group, Filipino women are over-represented among health care aides in the Canadian health care system. This qualitative study explored the employment experiences of Filipino health care aides in nursing homes from their own perspectives as well as those of policy stakeholders. Fourteen in-depth interviews were conducted with Filipino health care aides and long-term-care policy stakeholders in Winnipeg, Manitoba. The results indicated that migrant social networks act as pathways linking immigrant women with employment opportunities in nursing homes. The composition of the labour force is also shaped by management strategies and labour market accommodations that respond to, and reinforce, these social networks. These findings have implications for workforce planning and the quality of care provision in nursing homes. PMID- 24063533 TI - Similarity maps - a visualization strategy for molecular fingerprints and machine learning methods. AB - : Fingerprint similarity is a common method for comparing chemical structures. Similarity is an appealing approach because, with many fingerprint types, it provides intuitive results: a chemist looking at two molecules can understand why they have been determined to be similar. This transparency is partially lost with the fuzzier similarity methods that are often used for scaffold hopping and tends to vanish completely when molecular fingerprints are used as inputs to machine learning (ML) models. Here we present similarity maps, a straightforward and general strategy to visualize the atomic contributions to the similarity between two molecules or the predicted probability of a ML model. We show the application of similarity maps to a set of dopamine D3 receptor ligands using atom-pair and circular fingerprints as well as two popular ML methods: random forests and naive Bayes. An open-source implementation of the method is provided. PMID- 24063534 TI - How to diagnose the 22q11.2 deletion syndrome in patients with schizophrenia: a case report. AB - The 22q11.2 deletion syndrome is caused by a microdeletion of chromosome 22. One third of all patients with 22q11.2 deletion develop schizophrenia-like symptoms. In general, the prevalence of 22q11.2 deletion in patients with schizophrenia is 1%-2%. The 22q11.2 deletion is one of the major known genetic risk factors for schizophrenia. However, clinical differences in the phenotypes between patients with schizophrenia who are 22q11.2 deletion carriers and those who are not are still unknown. Therefore, it may be difficult to diagnose 22q11.2 deletion in patients with schizophrenia on the basis of clinical symptoms. To date, only two Japanese patients with the deletion have been identified through microdeletion studies of patients with schizophrenia in the Japanese population. Herein, we report the case study of a 48-year-old Japanese woman with 22q11.2 deletion who had a 30-year history of schizophrenia. Based on craniofacial anomalies, unpredictable agitation, hypocalcemia, and brain imaging finding, we suspected the 22q11.2 deletion in clinical populations and diagnosed the deletion using fluorescence in situ hybridization analysis. To find common phenotypes in Japanese patients with the deletion who have schizophrenia-like symptoms, we compared phenotypes among three Japanese cases. The common phenotypes were an absence of congenital cardiovascular anomalies and the presence of current findings of low intellectual ability, agitation, and hypocalcemia. We propose that hypocalcemia and agitation in patients with schizophrenia may derive from the 22q11.2 deletion, particularly when these phenotypes are coupled with schizophrenia-like symptoms. PMID- 24063535 TI - Near infrared and visible luminescence from xerogels covalently grafted with lanthanide [Sm(3+), Yb(3+), Nd(3+), Er(3+), Pr(3+), Ho(3+)] beta-diketonate derivatives using visible light excitation. AB - A series of ternary lanthanide beta-diketonate derivatives covalently bonded to xerogels (named as Ln-DP-xerogel, Ln = Sm, Yb, Nd, Er, Pr, Ho) by doubly functionalized alkoxysilane (dbm-Si) was synthesized in situ via a sol-gel process. The properties of these xerogel materials were investigated by Fourier transform infrared (FT-IR) spectroscopy, field-emission scanning electron microscopy (FE-SEM), diffuse reflectance (DR) spectroscopy, thermogravimetric analyses, and fluorescence spectroscopy. The data and analyses suggest that the lanthanide derivatives have been covalently grafted to the corresponding xerogels successfully. Of importance here is that, after excitation with visible light (400-410 nm), the xerogels all show characteristic visible (Sm(3+)) as well as near-infrared (NIR; Sm(3+), Yb(3+), Nd(3+), Er(3+), Pr(3+), Ho(3+)) luminescence of the corresponding Ln(3+) ions, which is attributed to the energy transfer from the ligands to the Ln(3+) ions via an antenna effect. Exciting with visible light is advantageous over UV excitation. Furthermore, to the best of our knowledge, it is the first observation of NIR luminescence with visible light excitation from xerogels covalently bonded with the Sm(3+), Pr(3+), and Ho(3+) derivatives. Compared to lanthanide complexes (Ln = Er, Nd, Yb) functionalized periodic mesoporous organosilica (PMO) materials that exhibit similar optical properties reported in our previous work, the Ln-DP-xerogel (Ln = Sm, Yb, Nd, Er, Pr, Ho) in this case offer advantages in terms of ease of synthesis and handling and potentially low cost for emerging technological applications. Development of near infrared luminescence of the lanthanide materials with visible light excitation is of strong interest to emerging applications such as chemosensors, laser systems, and optical amplifiers. PMID- 24063536 TI - Increased telomere length and proliferative potential in peripheral blood mononuclear cells of adults of different ages stimulated with concanavalin A. AB - BACKGROUND: Recently, a direct correlation with telomere length, proliferative potential and telomerase activity has been found in the process of aging in peripheral blood cells. The objective of the study was to evaluate telomere length and proliferative potential in peripheral blood mononuclear cells (PBMCs) after stimulation with Concanavalin A (ConA) of young adults compared with older adults. METHODS: Blood samples were obtained from 20 healthy young males (20-25 years old) (group Y) and 20 males (60-65 years old) (group O). We compared PBMC proliferation before and after stimulation with ConA. DNA was isolated from cells separated before and after culture with ConA for telomeric measurement by real time polymerase chain reaction. RESULTS: In vitro stimulation of PBMCs from young subjects induced an increase of telomere length as well as a higher replicative capacity of cell proliferation. Samples from older adults showed higher loss of telomeric DNA (p = 0.03) and higher levels of senescent (<=6.2 kb) telomeric DNA (p = 0.02) and displayed a marked decrease of proliferation capacity. Viability cell counts and CFSE tracking in 72-h-old cell cultures indicated that group O PBMCs (CD8+ and CD4+ T cells) underwent fewer mitotic cycles and had shorter telomeres than group Y (p = 0.04). CONCLUSIONS: Our findings confirm that telomere length in older-age adults is shorter than in younger subjects. After stimulation with ConA, cells are not restored to the previous telomere length and undergo replicative senescence. This is in sharp contrast to the response observed in young adults after ConA stimulation where cells increase in telomere length and replicative capacity. The mechanisms involved in this phenomenon are not yet clear and merit further investigation. PMID- 24063537 TI - Headache and comorbidity in children and adolescents. AB - Headache is one of the most common neurological symptom reported in childhood and adolescence, leading to high levels of school absences and being associated with several comorbid conditions, particularly in neurological, psychiatric and cardiovascular systems. Neurological and psychiatric disorders, that are associated with migraine, are mainly depression, anxiety disorders, epilepsy and sleep disorders, ADHD and Tourette syndrome. It also has been shown an association with atopic disease and cardiovascular disease, especially ischemic stroke and patent foramen ovale (PFO). PMID- 24063539 TI - Indolo[3,2-a]carbazoles from a deep-water sponge of the genus Asteropus. AB - Two new indolo[3,2-a]carbazoles (1, 2) were isolated from a deep-water collection of a sponge of the genus Asteropus. The structures of 1 and 2 were determined through the analysis of spectroscopic data including mass spectrometry and 2D NMR. Compound 1 showed minimum inhibitory concentrations of 25 MUg/mL against the fungal pathogen Candida albicans and 50 MUg/mL against methicillin-resistant Staphylococcus aureus (MRSA). Compounds 1 and 2 showed no cytotoxicity against the PANC1 human pancreatic carcinoma and NCI/ADR-RES ovarian adenocarcinoma cell lines at our standard test concentration of 5 MUg/mL. PMID- 24063541 TI - Anatomy of deep lateral and medial orbital walls: implications in orbital decompression surgery. AB - BACKGROUND: Isolated deep lateral and combined medial orbital wall decompressions (balanced decompression) are well accepted for treatment of disfiguring proptosis and compressive optic neuropathy in patients with Graves' orbitopathy. However, cerebrospinal fluid leakage and/or optic nerve injury occasionally occur during these operations. PURPOSE: To describe the anatomy of the deep lateral and medial orbital walls and its surgical implications in orbital decompression. METHODS: We reviewed literature on the anatomy of the deep lateral and medical orbital walls. In addition, we performed cadaver dissection and computed tomographics studies to illustrate the anatomy. RESULTS: We provided an anatomical overview and elucidated the detailed surgical anatomy of the posterior and superior borders of the deep lateral orbital wall, the posterior and accessory ethmoidal foramina, and the frontoethmoidal suture. CONCLUSIONS: The anatomy of the deep lateral and medical orbital walls presented here will warrant safe and confident performance of orbital decompression surgery. PMID- 24063540 TI - Astrocyte elevated gene-1 is associated with metastasis in head and neck squamous cell carcinoma through p65 phosphorylation and upregulation of MMP1. AB - BACKGROUND: The survival rate of head and neck squamous cell carcinoma (HNSCC) at advanced stage is poor, despite contemporary advances in treatment modalities. Recent studies have indicated that astrocyte elevated gene-1 (AEG-1), a single transmembrane protein without any known functional domains, is overexpressed in various malignancies and is implicated in both distant metastasis and poor survival. RESULTS: High expression of AEG-1 in HNSCC was positively correlated with regional lymph node metastasis and a poor 5-year survival rate. Knockdown of AEG-1 in HNSCC cell lines reduced their capacity for colony formation, migration and invasion. Furthermore, decreased tumor volume and metastatic foci were observed after knockdown of AEG-1 in subcutaneous xenografts and pulmonary metastasis assays in vivo, respectively. We also demonstrated that AEG-1 increased phosphorylation of the p65 subunit of NF-kappaB, and regulated the expression of MMP1 in HNSCC cells. Moreover, compromised phosphorylation of the p65 (RelA) subunit of NF-kappaB at serine 536 was observed upon silencing of AEG 1 in both HNSCC cell lines and clinical specimens. CONCLUSION: High expression of AEG-1 is associated with lymph node metastasis and its potentially associated mechanism is investigated. PMID- 24063542 TI - Severe HLA B27-associated uveitis complicated by hypotony, serous retinal detachment, and ciliochoroidal effusion. AB - PURPOSE: To report on severe HLA B27-associated anterior uveitis complicated by vitritis, hypotony, and serous retinal detachment. METHODS: Retrospective case series. RESULTS: Five patients with HLA B27-associated uveitis presented with an acute anterior uveitis complicated by vitritis, hypotony, serous retinal detachment, and ciliochoroidal effusion. Two patients had previously acute anterior uveitis and two suffered from HLA B27-associated systemic disease. Laboratory and imaging examinations did not reveal another cause of uveitis. Despite the aggressive treatment a prolonged and slow recovery followed. Four patients developed macular edema and one additional patient developed a macular pucker. Finally, 3 eyes improved, 2 eyes developed atrophy, and 1 was lost at 4 month follow-up with visual acuity of hand movements. CONCLUSIONS: The authors conclude that severe uveitis with a serous retinal detachment might develop in HLA B27-positive patients and may be complicated by protracted hypotony, macular edema, and poor visual outcome. PMID- 24063538 TI - Secreted phospholipase A2 is increased in meconium-stained amniotic fluid of term gestations: potential implications for the genesis of meconium aspiration syndrome. AB - BACKGROUND: Meconium-stained amniotic fluid (MSAF) represents the passage of fetal colonic content into the amniotic cavity. Meconium aspiration syndrome (MAS) is a complication that occurs in a subset of infants with MSAF. Secreted phospholipase A2 (sPLA2) is detected in meconium and is implicated in the development of MAS. The purpose of this study was to determine if sPLA2 concentrations are increased in the amniotic fluid of women in spontaneous labor at term with MSAF. MATERIALS AND METHODS: This was a cross-sectional study of patients in spontaneous term labor who underwent amniocentesis (n = 101). The patients were divided into two study groups: (1) MSAF (n = 61) and (2) clear fluid (n = 40). The presence of bacteria and endotoxin as well as interleukin-6 (IL-6) and sPLA2 concentrations in the amniotic fluid were determined. Statistical analyses were performed to test for normality and bivariate analysis. The Spearman correlation coefficient was used to study the relationship between sPLA2 and IL-6 concentrations in the amniotic fluid. RESULTS: Patients with MSAF have a higher median sPLA2 concentration (ng/mL) in amniotic fluid than those with clear fluid [1.7 (0.98-2.89) versus 0.3 (0-0.6), p < 0.001]. Among patients with MSAF, those with either microbial invasion of the amniotic cavity (MIAC, defined as presence of bacteria in the amniotic cavity), or bacterial endotoxin had a significantly higher median sPLA2 concentration (ng/mL) in amniotic fluid than those without MIAC or endotoxin [2.4 (1.7-6.0) versus 1.7 (1.3-2.5), p < 0.05]. There was a positive correlation between sPLA2 and IL-6 concentrations in the amniotic fluid (Spearman Rho = 0.3, p < 0.05). CONCLUSION: MSAF that contains bacteria or endotoxin has a higher concentration of sPLA2, and this may contribute to induce lung inflammation when meconium is aspirated before birth. PMID- 24063543 TI - A stimulatory role of ozone exposure on human natural killer cells. AB - Ozone is claimed to have beneficial effects. While studies revealed the safe therapeutic use of ozone, there are conflicting results for the link between immune system and ozone encounter. Natural killer (NK) cells are important sentinels of immunity with their cytotoxic activity and immune-regulatory potentials. This study aimed to investigate the effects of direct ozone encountering on human immune system, at cellular level. Survival, proliferative capacity and subset content of peripheral blood mononuclear cells (PBMC) were analysed. PBMC of healthy donors (n=5, mean age: 27+/-6 years) were exposed to 1, 5, 10 and 50 ug/mL doses of medical ozone, directly injected into culture wells, once, initially. 1 and 5 ug/mL doses didn't show toxic effects while 10 and 50 ug/mL doses were toxic. PBMC were cultured for 5 days following 1 and 5 ug/mL ozone encountering. 1 ug/mL dose increased numbers of CD3-CD16+/56+ NK cells among PBMC. Following stimulation with ozone, no difference was observed in basal and phytohemaglutinin-stimulated proliferative capacity. 1 and 5 ug/mL doses of ozone were found to increase NK cytotoxicity. These data indicates influential effects of transient ozone exposure on NK cells, which in turn may have a role in control of immune responses. PMID- 24063544 TI - Determinants of binge drinking in a permissive environment: focus group interviews with Dutch adolescents and parents. AB - BACKGROUND: Compared to other European countries, the Netherlands score among the highest of binge drinking rates of 16 to 18 year old adolescents. Dutch adolescents aged 16 are legally allowed to buy and consume low strength alcoholic beverages. This study focused on determinants of binge drinking in such a permissive environment from the perspectives of adolescents and parents. METHODS: Focus group interviews were conducted with adolescents aged 16 to 18 (N = 83), and parents of adolescents from this age group (N = 24). Data was analysed using thematic analyses methods. RESULTS: Most reasons adolescents mentioned for drinking were to relax, increase a good mood and to be social. Also peers around them influenced and increased adolescents' drinking. Comparing adolescents and parental statements about their perspectives how alcohol use is handled and accepted by the parents we found that generally, those perspectives match. Parents as well as adolescents stated that alcohol use is accepted by parents. However, when looking at essential details, like the acceptable amounts that children may consume, the perspectives differ enormously. Adolescents think their parents accept any amount of drinking as long as they do not get drunk, whereas parents reported acceptable limits of 1 or 2 glasses every two weeks. Parents further indicated that they felt unsupported by the Dutch policies and regulations of alcohol use. Most of them were in favour of an increase of the legal purchasing age to 18 years. CONCLUSIONS: Parents and adolescents should both be targeted in interventions to reduce alcohol use among adolescents. In particular, communication between parents and children should be improved, in order to avoid misconceptions about acceptable alcohol use. Further, adolescents should be supported to handle difficult social situations with peers where they feel obliged to drink. Additionally, revisions of policies towards a less permissive standpoint are advised to support parents and to impede availability of alcoholic beverages for adolescents/children younger than 18 years. PMID- 24063545 TI - Optimization of triplet excited state and singlet oxygen quantum yields of picolylamine-porphyrin conjugates through zinc insertion. AB - We synthesized a new class of picolylamine-porphyrin conjugates 1-3 and have investigated the effect of heavy atom insertion on their intersystem crossing efficiency through spin-orbit perturbations. By incorporating zinc ions in the core as well as periphery positions of the porphyrin ring, we have successfully optimized their triplet excited state quantum yields and their efficiency to generate singlet oxygen. Uniquely, the picolylamine-porphyrin conjugate 3 having five zinc ions exhibited a triplet excited state quantum yield of ca. 0.97 and a sensitized singlet oxygen generation yield of ca. 0.92. In contrast, the free base porphyrin derivative 1 exhibited ca. 0.64 and 0.5 of the triplet excited state and singlet oxygen quantum yields, respectively. Our results demonstrate that the insertion of zinc metal ions in the picolylamine-porphyrin conjugates not only quantitatively enhances the triplet excited state and singlet oxygen yields but also imparts hydrophilicity, thereby their potential use as sensitizers in photodynamic therapy and green photooxygenation reactions. PMID- 24063546 TI - Regulation of trehalase expression inhibits apoptosis in diapause cysts of Artemia. AB - Trehalase, which specifically hydrolyses trehalose into glucose, plays an important role in the metabolism of trehalose. Large amounts of trehalose are stored in the diapause encysted embryos (cysts) of Artemia, which are not only vital to their extraordinary stress resistance, but also provide a source of energy for development after diapause is terminated. In the present study, a mechanism for the transcriptional regulation of trehalase was described in Artemia parthenogenetica. A trehalase-associated protein (ArTAP) was identified in Artemia-producing diapause cysts. ArTAP was found to be expressed only in diapause-destined embryos. Further analyses revealed that ArTAP can bind to a specific intronic segment of a trehalase gene. Knockdown of ArTAP by RNAi resulted in the release of cysts with coarse shells in which two chitin-binding proteins were missing. Western blotting showed that the level of trehalase was increased and apoptosis was induced in these ArTAP-knockdown cysts compared with controls. Taken together, these results show that ArTAP is a key regulator of trehalase expression which, in turn, plays an important role in trehalose metabolism during the formation of diapause cysts. PMID- 24063547 TI - Gastrointestinal symptoms in patients with cirrhosis: a longitudinal study before and after liver transplantation. AB - OBJECTIVE: Gastrointestinal (GI) symptoms are common in cirrhosis and have an impact on quality of life. Their pathophysiology and their relation to energy intake have not been fully elucidated and the effect of liver transplantation on GI symptoms has not been studied. We aimed to prospectively evaluate GI symptoms and their determinants before and after transplantation and their potential relation with energy intake in cirrhosis. METHODS: A total of 108 cirrhotic liver transplant candidates completed the Gastrointestinal Symptom Rating Scale (GSRS) and the hospital anxiety and depression scale. Fasting serum glucose and insulin were measured in all patients. Serum thyrotropin, free T3/T4, cortisol, free testosterone, estradiol, dehydroepiandrosterone sulfate, interleukin-6 and tumor necrosis factor-alpha were measured in a subgroup of 80 patients. Transplant recipients were followed for 1 year. A separate cohort of 40 cirrhotic patients underwent a high-caloric satiation drinking test (SDT). RESULTS: GI symptoms were more severe in cirrhotics compared to controls from the general population. In regression analysis, the total GSRS score was independently related to lactulose, anxiety and low free testosterone (p < 0.05 for all). Four out of six GSRS domain scores improved significantly 1 year post-transplant (p < 0.05) but the total GSRS score remained higher compared to controls. GI symptoms predicted ingestion of fewer calories at SDT compared to other patients and controls (p < 0.05). CONCLUSIONS: Psychological distress, lactulose treatment and low testosterone are predictors of GI symptoms which are common among cirrhotic transplant candidates. They are also associated with decreased energy intake as measured by a SDT. GI symptoms remain of concern post-transplant. PMID- 24063549 TI - Synergistic effects of atorvastatin and all-trans retinoic acid in ameliorating animal model of multiple sclerosis. AB - One suitable approach to enhancing multiple sclerosis (MS) treatment is combination of available medications to provide more desirable outcomes. Immunomodulatory effects of atorvastatin and/or all-trans retinoic acid (ATRA) were determined in previous studies. The present study was set out to investigate the synergistic effects of combination therapy by suboptimal doses of atorvastatin and ATRA in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE was induced by MOG35-55 in female C57BL/6 mice. Therapies were initiated at day 12 post immunization when the mice developed a disability score and continued throughout the study until the day 33 when animals were sacrificed. Therapeutic treatment with half doses of atorvastatin and ATRA in combination has synergistic benefits causing the regression of clinical and neuropathological features of EAE more favorable than treatment with full doses of either drug alone. Without any advantage in anti-proliferative effect, combination treatment significantly reduced the secretion of pro-inflammatory cytokine interleukin-17 and conversely, increased the production of anti inflammatory cytokine interleukin-10 more prominent than either drug alone. Furthermore, FoxP3+Treg cells were significantly increased only in combination treatment. In conclusion, combined atorvastatin and ATRA have immunomodulatory synergistic benefits and this pharmacological approach may be as a useful strategy to control MS. PMID- 24063548 TI - PTEN phosphorylation and nuclear export mediate free fatty acid-induced oxidative stress. AB - AIM: Oxidative stress induced by free fatty acids (FFA) contributes to metabolic syndrome-associated development of cardiovascular diseases, yet molecular mechanisms remain poorly understood. This study aimed at establishing whether phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and its subcellular location play a role in FFA-induced endothelial oxidative stress. RESULTS: Exposing human endothelial cells (ECs) with FFA activated mammalian target of rapamycin (mTOR)/S6K pathway, and upon activation, S6K directly phosphorylated PTEN at S380. Phosphorylation of PTEN increased its interaction with its deubiquitinase USP7 in the nucleus, leading to PTEN deubiquitination and nuclear export. The reduction of PTEN in the nucleus, in turn, decreased p53 acetylation and transcription, reduced the expression of the p53 target gene glutathione peroxidase-1 (GPX1), resulting in reactive oxygen species (ROS) accumulation and endothelial damage. Finally, C57BL/6J mice fed with high-fat atherogenic diet (HFAD) showed PTEN nuclear export, decreased p53 and GPX1 protein expressions, elevated levels of ROS, and significant lesions in aortas. Importantly, inhibition of mTOR or S6K effectively blocked these effects, suggesting that mTOR/S6K pathway mediates HFAD-induced oxidative stress and vascular damage via PTEN/p53/GPX1 inhibition in vivo. INNOVATION: Our study demonstrated for the first time that S6K directly phosphorylated PTEN at S380 under high FFA conditions, and this phosphorylation mediated FFA-induced endothelial oxidative stress. Furthermore, we showed that S380 phosphorylation affected PTEN monoubiquitination and nuclear localization, providing the first example of coordinated regulation of PTEN nuclear localization via phosphorylation and ubiquitination. CONCLUSION: Our studies provide a novel mechanism by which hyperlipidemia causes vascular oxidative damage through the phosphorylation of PTEN, blocking of PTEN nuclear function, and inhibition of p53/GPX1 activity. PMID- 24063550 TI - Secondary Control Belief Combinations (Adjustment and Acceptance) and Well-Being in Older Adults. AB - Few studies of older individuals have directly assessed secondary control beliefs, previously defined by Morling and Evered in 2006 as a combination of psychological adjustment and acceptance. We classified older adults ( n = 223, M age = 85 years, 62% women) into three categories of secondary control beliefs: psychological adjustment only, psychological adjustment and acceptance, and neither psychological adjustment nor acceptance. Relative to individuals who emphasized beliefs about psychological adjustment only, those who emphasized a combination of secondary control beliefs (including both psychological adjustment and acceptance), reported more frequent positive emotions, greater life satisfaction, and less severe chronic conditions. Our findings have implications in both theoretical and applied contexts. Theoretically, our findings extend contemporary thinking on secondary control. In applied contexts, they suggest ways of thinking that could enhance well-being in the very old. PMID- 24063551 TI - Job satisfaction, intent to stay, and recommended job improvements: the palliative nursing assistant speaks. AB - BACKGROUND AND OBJECTIVE: There are few studies specifically focused on the job satisfaction of hospice and palliative nursing assistants (NAs). The goal of this study was to ascertain factors contributing to NAs' job satisfaction and intent to remain with their current employer, garner suggestions for improving NA jobs, and inform hospice and palliative care providers concerned about retaining qualified, satisfied NAs. METHODS: A nonexperimental, cross-sectional survey design was used to collect data from a broad sample of NAs employed in hospice and palliative care settings between December 2010 and May 2011. RESULTS AND CONCLUSIONS: This study found hospice and palliative NAs to be satisfied and committed to their jobs, which most viewed as long-term careers. However, organizations committed to recruitment and retention of committed and satisfied NAs would do well to ensure high-quality NA supervision, include NAs as valued team members, encourage positive work relationships, work to reduce problems identified by NAs as interfering with their work, and continue efforts to increase NA compensation. PMID- 24063552 TI - Could triaging family history of cancer during palliative care enable earlier genetic counseling intervention? AB - BACKGROUND: Patients are commonly referred to cancer genetics services when all affected family members are deceased. This makes genetic testing and risk assessment more difficult, reducing the benefit from screening and prophylactic treatment. METHODS: Observational, retrospective, cohort study of 508 randomly selected patients referred to a regional cancer genetics unit, using review of case notes to explore whether a simple clinical "3, 2, 1" family history rule could have been used to improve timely and appropriate referrals for genetic assessment. The 3, 2, 1 criteria are: three affected relatives with the same/associated cancers, across two generations, with at least one person affected age <50 years. RESULTS: Most (71% [362]) genetic risk assessment referrals were in unaffected individuals and 22% (80) of these were referred after all affected family members had died, including 24% (19) who lost their last remaining affected relative in the previous year. Most (59% [301]) referrals met all 3, 2, 1 criteria, and 67% of these could have been made earlier in clinical practice. A further 23% (115) met two of the three criteria. CONCLUSION: Using a simple "3, 2, 1" family rule in cancer care and particularly in palliative care could enable earlier cancer genetic risk assessment for unaffected relatives, improving the potential to benefit from targeted screening and intervention. PMID- 24063553 TI - Challenges of conducting research on cancer pain classification: how do we make sense of the outcomes? PMID- 24063554 TI - Integrating psychiatry into palliative medicine: lessons learned from our antidepressant trial. PMID- 24063555 TI - Beethoven's ode to hope. PMID- 24063559 TI - Nephelauxetic effects in the electronic spectra of Pr3+. AB - The well-known nephelauxetic series of ligands describes the change in interelectronic repulsion of the central metal ion, which is reduced on going from the vapor to crystalline state. This study examines the trends and quantifies the mechanism of this series for the lanthanide ion Pr(3+), with the 4f(2) electronic configuration. A new and concise measurement by a single parameter, sigmaee, is introduced to quantify the overall strength of interelectronic repulsion, as the alternative to the Slater parameters, F(k) (k = 2, 4, 6). Energy parameters have been derived from the literature electronic spectra of Pr(3+), in the free ion and in various crystalline hosts, with new calculations in some cases. It is found that at least the first 12 of the 13 multiplet terms of Pr(3+) must be well-determined to obtain reliable parameter values. The shifts of various energy levels for changes in the Slater parameters are not uniform in direction. For the various Pr(3+) solid-state systems, the change in sigmaee is only up to ~5%, with the magnitude of sigmaee in the order F(-) > Cl(-) > O(2-) ~ Br(-) > C, and decreasing with lower coordination number of the ligand. The decreases of the Slater parameters from the free ion values are reasonably estimated by considering the dielectric constant of the medium. In particular, the magnitude of sigmaee (and of the spin-orbit coupling constant) is proportional to the polarizability of the ligand for F(-), Cl(-), O(2-), and Br( ). The data point scatter for oxide systems is accounted for by considering the individual ligand bond distances. A fair estimation of nephelauxetic effects can be made from some luminescence transition energies, by contrast with Eu(3+) systems where crystal field effects also play a major role. In conclusion, the nephelauxetic effect of Pr(3+) is due to the polarization of the ligand by one 4f electron, and the interaction of the other electron with the induced multipolar moments, of which the dipole moment dominates. PMID- 24063556 TI - Evaluation of the Housing First program in patients with severe mental disorders in France: study protocol for a randomized controlled trial. AB - BACKGROUND: Recent studies in North American contexts have suggested that the Housing First model is a promising strategy for providing effective services to homeless people with mental illness. In the context of the highly generous French national health and social care system, which is easily accessible and does not require out-of-pocket payment, the French Health Ministry insists on rigorous techniques, including randomized protocols, to evaluate the impact of Housing First approaches in France. METHOD AND DESIGN: A prospective randomized trial was designed to assess the impact of a Housing First intervention on health outcomes and costs over a period of 24 months on homeless people with severe mental illness, compared to Treatment-As-Usual. The study is being conducted in four cities in France: Lille, Marseille, Paris and Toulouse. The inclusion criteria are as follows: over 18 years of age, absolutely homeless or in precarious housing, and possessing a 'high' level of need: diagnosis of schizophrenia or bipolar disorder and moderate to severe disability according to the Multnomah Community Ability Scale (score <= 62) and at least one of the following three criteria: 1) having been hospitalized for mental illness two or more times in any one year during the preceding five years; 2) co-morbid alcohol or substance use; and 3) having been recently arrested or incarcerated. Participants will be randomized to receiving the Housing First intervention or Treatment-As-Usual. The Housing First intervention provides immediate access to independent housing and community care. The primary outcome criterion is the use of high-cost health services (that is,, number of hospital admissions and number of emergency department visits) during the 24-month follow-up period. Secondary outcome measures include health outcomes, social functioning, housing stability and contact with police services. An evaluation of the cost-effectiveness and cost utility of Housing First will also be conducted. A total of 300 individuals per group will be included. DISCUSSION: This is the first study to examine the impact of a Housing First intervention compared to Treatment-As-Usual in France. It should provide key information to policymakers concerning the cost-effectiveness and health outcomes of the Housing First model in the French context. TRIAL REGISTRATION: The current clinical trial number is NCT01570712. PMID- 24063558 TI - Decreased fructose-1,6-bisphosphatase-2 expression promotes glycolysis and growth in gastric cancer cells. AB - BACKGROUND: Increasing evidence suggests that cancer is a metabolic disease. Here, we investigated the potential role of fructose-1,6-bisphosphatase-2 (FBP2), the enzyme that catalyses the hydrolysis of fructose-1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate in glucose metabolism, in gastric cancer (GC) development. RESULTS: Our data indicated that FBP2 was downregulated in GC tissues (86.2%, 100/116), and absent or low FBP2 expression in GC tissues was correlated with poor survival of GC patients (P = 0.019). Conversely, ectopic expression of FBP2 in GC cells activated AMP-activated protein kinase (AMPK) signalling, inhibited the Akt-mTOR pathway, suppressed glucose metabolism, enhanced apoptosis, and reduced cell proliferation. Bisulphite genomic sequencing (BGS) in gastric cancer cell lines revealed that the FBP2 promoter region was densely methylated, and treatment of GC cells with the demethylation reagent, 5 aza-2-deoxycytidine (5-Aza), led to an increase in FBP2 expression. Importantly, forced expression of FBP2 abrogated tumour formation of these GC cells in nude mice. CONCLUSION: Our results indicate that FBP2 does negatively regulate cell growth, and reduced expression of FBP2 may contribute to carcinogenesis for GC. These findings suggest that restoration of FBP2 expression can be a promising strategy for the target therapy of GC. PMID- 24063560 TI - Self-assembly of luminescent Ag nanocluster-functionalized nanowires. AB - Two different methods to self-assemble red- or yellow-luminescent nucleic acids stabilized Ag nanoclusters (NCs) nanowires are presented. By one method, the autonomous hybridization-polymerization process between two nucleic acids leads to polymer chains consisting of sequence-specific loops for the stabilization of the red- or yellow-emitting Ag NCs. By the other method, the nucleic acid triggered hybridization chain reaction (HCR) involving the cross-opening of two functional hairpins leads to sequence-specific DNA loops and a nucleic acid scaffold that stabilize the respective red- or yellow-emitting Ag NCs. The micrometer-long luminescent Ag NC-functionalized nanowires are imaged by AFM and confocal microscopy. PMID- 24063561 TI - Controlled and triggered small molecule release from a confined polymer film. AB - A device composed of a poly (N-isopropylacrylamide)-co-acrylic acid (pNIPAm-co AAc) microgel layer sandwiched between two thin Au layers (all on a glass support) was used as a novel platform for controlled and triggered small molecule delivery. Tris (4-(dimethylamino)phenyl)methylium chloride (Crystal Violet, CV), which is positively charged, was loaded into the microgel layer of the device and released in a pH dependent fashion, at a rate that could be controlled by the thickness of the Au layer coating the microgels. Specifically, at pH 6.5 (above the pKa for AAc) the microgels were negatively charged, promoting the strong interaction between the CV and the microgels, hindering its release from the layer. At pH 3.0 the microgel's AAc groups are protonated making the microgel mostly neutral, allowing CV to be released from the microgel layer at a rate that depends on the thickness of the Au covering the microgels. Specifically, devices with thin Au overlayers on the microgel layer allow CV to be released from the device faster than devices with thick Au overlayers. The ability to tune the release rate with pH and Au layer thickness is advantageous for developing implantable devices that are capable of releasing small molecule drugs in a triggered and controlled fashion. PMID- 24063562 TI - Clusters [Co(As3S3)2]2-, [Ni(As3S3)2]2-, and [{Co(en)}6(MU3-S)4(AsS3)4]2- with Co As or Ni-As bonds: solvothermal syntheses and characterizations of thioarsenates containing transition-metal complexes. AB - Solvothermal reactions of As2O3 and S with CoCl2.6H2O or NiCl2.6H2O in an aqueous solution of dien produced novel thioarsenates [Co(dien)2][Co(As3S3)2] (1) and [Ni(dien)2][Ni(As3S3)2] (2) (dien = diethylenetriamine), and the reaction with CoCl2.6H2O in an aqueous solution of en afforded complex [Hen]2[{Co(en)}6(MU3 S)4(AsS3)4] (3) (en = ethylenediamine). In 1 and 2, one transition-metal ion is coordinated by two dien ligands to form [TM(dien)2](2+) (TM = Co, Ni) complex cations. The As3S3 unit coordinates to the other TM(II) ion with both As- and S donor atoms to form the [TM(As3S3)2](2-) anionic cluster, in which TMAs2, TMAs2S2, and TMAs3S2 rings are formed. In 3, each Co(3+) ion is coordinated by an en ligand. Six Co(en) units are interlinked by four MU3-S and four AsS3 ligands to form a [{Co(en)}6(MU3-S)4(AsS3)4](2-) cluster containing an adamantane-like Co6S4 core. The AsS3 unit coordinates to Co atom in the eta(1)-As1,eta(2)-S coordination mode with As binding Co(1) and S(1) binding Co(1) and Co(2). The As3S3 and AsS3 ligands with both As- and S-donor atoms in 1-3 have never been obtained in amine solution before. The same reactions in pure dien and en solvents afforded compounds [Co(dien)2]3[As3S6]2 (4) and [Co(en)3]2As2S5 (5) containing discrete anions [As3S6](3-) and [As2S5](4-), respectively. The band gaps of 1-3 are in the range of 1.37-1.55 eV, and the band gaps of 4 and 5 are 2.24 and 2.26 eV, which show the influence of the coordination mode of thioarsenate ligands on the electronic transitions in the TM-thioarsenates. PMID- 24063564 TI - Donor-acceptor random copolyesters containing perylenebisimide (PBI) and oligo(p phenylene vinylene) (OPV) by melt condensation polymerization: energy transfer studies. AB - Novel copolyesters consisting of oligo(p-phenylene vinylene) (OPV) as donor (D) and perylenebisimide (PBI) as acceptor (A) were synthesized by melt polycondensation. Photoinduced energy transfer and photoinduced charge separation in these polyesters were studied in solution as well as in the solid state. Selective excitation of OPV moiety resulted in the energy transfer with >90% efficiency from OPV to PBI chromophore in the solution state. The direct excitation of PBI in the D-A copolyester resulted in reduced fluorescence emission of acceptor, indicating electron transfer between the D and A moieties. The effect of distance between donor and acceptor on the energy transfer efficiency from donor to acceptor was studied. Compared to a physical mixture of D and A polyesters alone, the energy transfer was 4 times more efficient in the D A copolyester, highlighting the influence of covalently linking D and A in a single polymer chain. A strong fluorescence quenching (~ 100%) of both chromophores in solid state indicated an efficient photoinduced charge transfer after photoexcitation of either D or A. Thus, OPV-PBI main chain copolyester is an excellent system for the study of energy- and electron-transfer processes in organic semiconductor. Reactive blend of D/A copolyester was also prepared by the transesterification reaction between D and A alone copolyesters. The energy transfer efficiency from D to A moiety upon selective excitation of D chromophore in the D/A copolyester blend was ~4 times higher compared to a physical mixture of D and A alone copolyesters, which gave direct proof for the transesterification reaction in polyester/polyester reactive blending. PMID- 24063563 TI - Epidemiology and impact of a multifaceted approach in controlling central venous catheter associated blood stream infections outside the intensive care unit. AB - BACKGROUND: Outside ICUs, CVC-ABSIs epidemiology and the results of strategies for their prevention are not well known. The aim of this study was to investigate the epidemiology and the impact of a multifaceted "bundle" approach in controlling CVC-ABSIs outside ICU. METHODS: From 1991 we performed prevalence studies of device and parenteral nutrition use, and prospective surveillance of all episodes of CVC-ABSIs in a 350-bed teaching hospital. CVC-ABSIs incidence/1,000 inpatient-days was calculated. An estimated CVC-ABSIs incidence/1,000 catheter-days was calculated based on the prevalence rates of catheter use and the total number of inpatient-days in each year. On november 2008, an education programme was instituted for care of catheter lines: reinforcing instructions in aseptic insertion technique, after care and hand washing; in order to assess the adherence to these measures the quantity of alcohol-based hand-rub consumption/1,000 patient-days was quoted in litres. From January 2009, a checklist intervention for CVC insertion in ICU was started: hand hygiene, using full barrier precautions, cleaning the skin with alcoholic chlorhexidine, avoiding femoral access and removing unnecessary catheters. Compliance with the central line insertion checklist was measured by real-time audits and was achieved in 80% of cases. RESULTS: Prevalence of use of CVC and parenteral nutrition was similar throughout the study. We followed-up 309 CVC ABSIs cases. Estimated CVC-ABSIs rate progressively increased to 15.1/1,000 catheter-days in 2008 (0.36/1,000 inpatient-days). After the intervention, the alcohol-based hand-rub consumption increased slightly and estimated CVC-ABSIs rate fell to 10.1 /1,000 catheter-days in last three years (0.19/1,000 inpatient days), showing a 32.9% decrease. The infection rates achieved were lower in Internal Medicine wards: decreased from 14.1/1,000 catheter-days (0.17/patient days) in 2008 to 5.2/1,000 catheter-days (0.05/1,000 inpatient-days) in last three years, showing a 63.1% decrease. In 2009, the estimated CVC-ABSIs incidence rate was significantly lower in the Internal Medicine ward compared to the Surgery ward: rate ratio (RR) = 0.14, 95%CI: 0.03-0.60), and within the Internal Medicine ward, the estimated CVC-ABSIs incidence rate was significantly lower in 2009 compared to 2008 (RR = 0.20, 95%CI: 0.04-0.91). CONCLUSION: The rate of CVC ABSIs increased outside-ICU, and the implementation of multifaceted infection control programme decreased their clinical impact. PMID- 24063565 TI - Understanding the brain-behaviour relationship in persons with ASD: implications for PECS as a treatment choice. AB - INTRODUCTION: This article presents emerging neurological findings in Autism Spectrum Disorders (ASD) with particular attention to how this information might inform treatment practices addressing communication impairments. METHODS: The article begins with a general discussion of the brain-behaviour relationship and moves to the presentation of recent research findings related to ASD. There is particular attention to individuals with autism who are either non-verbal or present emergent verbal abilities. RESULTS/DISCUSSION: A specific communication treatment, the Picture Exchange Communication System (PECS), is presented as an example of an intervention that addresses the learner needs of many individuals with ASD. The success of PECS is discussed within the context of its fit with brain-based learner characteristics. PMID- 24063567 TI - Cytotoxic oxepinochromenone and flavonoids from the flower buds of Rosa rugosa. AB - A new oxepinochromenone, rugosachromenone A (1), seven new flavonoids, rugosaflavonoids A-G (2-8), and 11 known compounds (9-19) were isolated from the flower buds of Rosa rugosa. Compound 1 is found from Nature for the first time. Compound 2 displayed cytotoxicity against NB4, SHSY5Y, and MCF7 cells with IC50 values of 2.2, 2.5, and 2.3 MUM, respectively, and 3 was toxic to A549 and MCF7 cells with IC50 values of 1.2 and 2.8 MUM, respectively. PMID- 24063568 TI - In silico characterization of a novel pathogenic deletion mutation identified in XPA gene in a Pakistani family with severe xeroderma pigmentosum. AB - BACKGROUND: Xeroderma Pigmentosum (XP) is a rare skin disorder characterized by skin hypersensitivity to sunlight and abnormal pigmentation. The aim of this study was to investigate the genetic cause of a severe XP phenotype in a consanguineous Pakistani family and in silico characterization of any identified disease-associated mutation. RESULTS: The XP complementation group was assigned by genotyping of family for known XP loci. Genotyping data mapped the family to complementation group A locus, involving XPA gene. Mutation analysis of the candidate XP gene by DNA sequencing revealed a novel deletion mutation (c.654del A) in exon 5 of XPA gene. The c.654del A, causes frameshift, which pre-maturely terminates protein and result into a truncated product of 222 amino acid (aa) residues instead of 273 (p.Lys218AsnfsX5). In silico tools were applied to study the likelihood of changes in structural motifs and thus interaction of mutated protein with binding partners. In silico analysis of mutant protein sequence, predicted to affect the aa residue which attains coiled coil structure. The coiled coil structure has an important role in key cellular interactions, especially with DNA damage-binding protein 2 (DDB2), which has important role in DDB-mediated nucleotide excision repair (NER) system. CONCLUSIONS: Our findings support the fact of genetic and clinical heterogeneity in XP. The study also predicts the critical role of DDB2 binding region of XPA protein in NER pathway and opens an avenue for further research to study the functional role of the mutated protein domain. PMID- 24063569 TI - Multicentric cohort study on the long-term efficacy and safety of electronic cigarettes: study design and methodology. AB - BACKGROUND: While electronic cigarettes are forbidden in several countries, their sales are exploding in many others. Although e-cigarettes have been proposed as long-term substitutes for traditional smoking or as a tool for smoking cessation, very scarce data are available on their efficacy and safety.We describe the protocol of a 5-year multicentric prospective study aimed to evaluate short- and long-term adherence to e-cigarette smoking and the efficacy of e-cigarettes in reducing and/or quitting traditional cigarette smoking. The study will also compare the health effects of electronic vs traditional vs mixed cigarette smoking. METHODS/DESIGN: From June to December 2013, we will enroll adult smokers of: (EC) e-cigarettes (self-reported inhaling >= 50 puffs per week since >= 6 months); (TC) traditional cigarettes (>= 1 per day since >= 6 m); (Mixed) both electronic and traditional cigarettes (>= 1 per day since >= 6 m). Eligible subjects will be requested participation through newspaper advertisements and direct contact at the shops. Each subject will have to compile a structured questionnaire at enrolment and after 6, 12, 24, 36 and 60 months. The level of carbon monoxide in expired after breath will be evaluated in all subjects declaring no traditional cigarette smoking in any follow-up phase, using portable carbon monoxide analyzers. The primary outcomes are traditional smoking cessation rates and number of smoked cigarettes. Secondary outcomes include adherence to e cigarettes, self-reported adverse events, quality of life, and time to hospital admission for one among cardiovascular diseases, chronic obstructive pulmonary diseases, cancer of the lung, esophagus, larynx, oral cavity, bladder, pancreas, kidney, stomach, cervix, and myeloid leukemia. Admissions will be checked using official discharge data of the Abruzzo Region. A minimum of 500 subjects in each group will be enrolled, for a total of 1500 participants. Cox proportional hazards analysis will be used to calculate adjusted relative hazards of smoking cessation by each variable. DISCUSSION: Data on long-term efficacy and safety of e-cigarettes will be of utmost importance to form the basis for guidelines and regulatory decisions on e-cigarettes. TRIAL REGISTRATION: The protocol has been registered (NCT01785537) and approved by the Ethics Committee of the University of Chieti (Record n. 6; 25-03-2013). PMID- 24063570 TI - Green tea polyphenol decreases the severity of portosystemic collaterals and mesenteric angiogenesis in rats with liver cirrhosis. AB - Abnormal angiogenesis in liver cirrhosis often leads to severe complications such as variceal haemorrhage and encephalopathy. Furthermore, splanchnic angiogenesis elevates portal pressure, in which angiogenic factors play pivotal roles. GTP (green tea polyphenol) extracted from Camellia sinensis has anti-angiogenic properties, but the effects on the parameters described above in cirrhosis have not been investigated. The aim of the present study was to determine the effects of GTP in cirrhosis and to investigate the underlying mechanism. Liver cirrhosis was induced in Spraque-Dawley rats by common BDL (bile duct ligation). They randomly received GTP or DW (distilled water, vehicle) for 28 days, then haemodynamic parameters, portosystemic shunting, mesenteric window vascular density, intrahepatic angiogenesis, liver fibrosis, plasma VEGF (vascular endothelial growth factor) concentration, mesenteric angiogenic factor and receptor protein expression, and serum and mesenteric oxidative stress parameters were assessed. Compared with the DW group, GTP significantly decreased portosystemic shunting, liver fibrosis, intrahepatic angiogenesis, mesenteric window vascular density, VEGF concentration and down-regulated the mesenteric HIF (hypoxia-inducible factor)-1alpha, VEGF and phospho-Akt expression. In conclusion, GTP ameliorates the severity of portosystemic shunting and mesenteric angiogenesis via the suppression of HIF-1alpha, Akt activation and VEGF. GTP appears to be an appropriate agent in controlling portal hypertension-related complications via anti-angiogenesis. PMID- 24063571 TI - Generation and characterization of a rat monoclonal antibody against the RNA polymerase protein from Dengue Virus-2. AB - Dengue virus (DENV) RNA replication requires 2 viral proteins, non-structural protein 3 (NS3) and NS5. NS5 consists of 2 functional domains: a methyltransferase (MTase) domain involved in RNA cap formation and located in the amino terminal region and a RNA-dependent RNA polymerase domain essential for virus replication and located in the carboxyl terminal region. To gain additional insight into the structural interactions between viral proteins and cellular factors involved in DENV RNA replication, we generated a panel of rat monoclonal antibodies (mAbs) against the NS5 MTase domain. Six rat mAbs were selected from 41 clones, of which clone 13G7 was further characterized. The specificity of this antibody for NS5 was demonstrated by western blot of DENV-infected cells, which revealed that this antibody recognizes all 4 DENV serotypes. Furthermore, Western blotting analysis suggested that this antibody recognizes a sequential epitope of the NS5 protein. Positive and specific staining with 13G7 was detected predominantly in nuclei of DENV-infected cells, similarly a pattern was observed in both in human and monkey cells. Furthermore, the NS5 staining co-localized with a Lamin A protein (Pierson index: 0.7). In summary, this monoclonal antibody could be used to identify and evaluate different cellular factors that may interact with NS5 during DENV replication. PMID- 24063566 TI - Sensory and motor secondary symptoms as indicators of brain vulnerability. AB - In addition to the primary symptoms that distinguish one disorder from the next, clinicians have identified, yet largely overlooked, another set of symptoms that appear across many disorders, termed secondary symptoms. In the emerging era of systems neuroscience, which highlights that many disorders share common deficits in global network features, the nonspecific nature of secondary symptoms should attract attention. Herein we provide a scholarly review of the literature on a subset of secondary symptoms--sensory and motor. We demonstrate that their pattern of appearance--across a wide range of psychopathologies, much before the full-blown disorder appears, and in healthy individuals who display a variety of negative symptoms--resembles the pattern of appearance of network abnormalities. We propose that sensory and motor secondary symptoms can be important indicators of underlying network aberrations and thus of vulnerable brain states putting individuals at risk for psychopathology following extreme circumstances. PMID- 24063572 TI - Functional microRNA library screening identifies the hypoxamir miR-24 as a potent regulator of smooth muscle cell proliferation and vascularization. AB - Smooth muscle cells (SMCs) are key components within the vasculature. Dependent on the stimulus, SMC can either be in a proliferative (synthetic) or differentiated state. Alterations of SMC phenotype also appear in several disease settings, further contributing to disease progression. AIMS: Here, we asked whether microRNAs (miRNAs, miRs), which are strong posttranscriptional regulators of gene expression, could alter SMC proliferation. Results and Innovation: Employing a robotic-assisted high-throughput screening method using miRNA libraries, we identified hypoxia-regulated miR-24 as a master regulator of SMC proliferation. Proteome profiling showed a strong miR-24-dependent impact on cellular stress-associated factors, overall resulting in reduced stress resistance. In vitro, synthetic miR-24 overexpression had detrimental effects on SMC functional capacity inducing apoptosis, migration defects, enhanced autophagy, and loss of contractile marker genes. Impaired SMC function was mediated in part by the herein identified direct target gene heme oxygenase 1. Ex vivo, miR-24 was shown to inhibit the development of vasculature in a model of engineered heart tissue. CONCLUSION: Collectively, we report the identification of the hypoxamir-24 as an inhibitor of SMC proliferation, contributing to loss of vascularization. PMID- 24063573 TI - Direct coupling of normal-phase high-performance liquid chromatography to atmospheric pressure laser ionization fourier transform ion cyclotron resonance mass spectrometry for the characterization of crude oil. AB - The high complexity of crude oil makes the use of chromatographic separation an important tool especially for sample simplification. The coupling of normal-phase high-performance liquid chromatography (HPLC) using a polar aminocyano column to a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer offers the best attributes of good separation prior to ultrahigh resolution mass spectrometry (MS) detection. Atmospheric pressure laser ionization (APLI) was used as an ionization technique to analyze the nitrogen-containing aromatic compounds in a deasphalted crude oil due to its unique selectivity toward aromatic compounds and also due to its sensitivity. Two main chromatographic peaks were observed during this separation indicating a class-based separation. Mass spectra obtained from fractions were collected along the entire retention time and compared with each other to assign the unique constituents. By coupling the HPLC system directly to the FTICR mass spectrometer, comparable ion and UV chromatograms were obtained, reflecting the scan-to-scan sensitivity of the coupling system. The results show that it is possible to calculate reconstructed class chromatograms (RCC), allowing differences in class composition to be traced along the retention time. As an example, radical and protonated nitrogen species generated by APLI were detected along the retention time which enabled a differentiation between basic and nonbasic species in the same polar peak, thus overcoming the limitation of chromatographic resolution. This report represents the first online LC-FTICR MS coupling in the field of crude oil analysis. PMID- 24063575 TI - Development of a new free radical absorption capacity assay method for antioxidants: aroxyl radical absorption capacity (ARAC). AB - A new free radical absorption capacity assay method is proposed with use of an aroxyl radical (2,6-di-tert-butyl-4-(4'-methoxyphenyl)phenoxyl radical) and stopped-flow spectroscopy and is named the aroxyl radical absorption capacity (ARAC) assay method. The free radical absorption capacity (ARAC value) of each tocopherol was determined through measurement of the radical-scavenging rate constant in ethanol. The ARAC value could also be evaluated through measurement of the half-life of the aroxyl radical during the scavenging reaction. For the estimation of the free radical absorption capacity, the aroxyl radical was more suitable than the DPPH radical, galvinoxyl, and p-nitrophenyl nitronyl nitroxide. The ARAC value in tocopherols showed the same tendency as the free radical absorption capacities reported previously, and the tendency was independent of an oxygen radical participating in the scavenging reaction and of a medium surrounding the tocopherol and oxygen radical. The ARAC value can be directly connected to the free radical-scavenging rate constant, and the ARAC method has the advantage of treating a stable and isolable radical (aroxyl radical) in a user-friendly organic solvent (ethanol). The ARAC method was also successfully applied to a palm oil extract. Accordingly, the ARAC method would be useful in free radical absorption capacity assay of antioxidative reagents and foods. PMID- 24063576 TI - Combined effect of glycine and sea salt on aerosol cloud droplet activation predicted by molecular dynamics simulations. AB - The present study illustrates the combined effect of organic and inorganic compounds on cloud droplet nucleation and activation processes representative for the marine environment. Amino acids and sea salt are common marine cloud condensation nuclei (CCN) which act as a prerequisite for growth of cloud droplets. The chemical and physical properties of these CCN play a key role for interfacial properties such as surface tension, which is important for the optical properties of clouds and for heterogeneous reactions. However, there is a lack of detailed information and in situ measurements of surface tension of such nanosized droplets. Here we present a study of the combined effect of zwitterionic glycine (ZGLY) and sea salt in nanosized water droplets using molecular dynamics simulations, where particular emphasis is placed on the surface tension for the nanosized droplets. The critical supersaturation is estimated by the Kohler equation. It is found that dissolved sea salt interacts with ZGLY through a water bridge and weakens the hydrogen bonds among ZGLYs, which has a significant effect on both surface tension and water vapor supersaturation. Clusters of glycine mixed with sea salt deliquesce more efficiently and have higher growth factors. PMID- 24063574 TI - Electrical stimulation of schwann cells promotes sustained increases in neurite outgrowth. AB - Endogenous electric fields are instructive during embryogenesis by acting to direct cell migration, and postnatally, they can promote axonal growth after injury (McCaig 1991, Al-Majed 2000). However, the mechanisms for these changes are not well understood. Application of an appropriate electrical stimulus may increase the rate and success of nerve repair by directly promoting axonal growth. Previously, DC electrical stimulation at 50 mV/mm (1 mA, 8 h duration) was shown to promote neurite outgrowth and a more pronounced effect was observed if both peripheral glia (Schwann cells) and neurons were co-stimulated. If electrical stimulation is delivered to an injury site, both the neurons and all resident non-neuronal cells [e.g., Schwann cells, endothelial cells, fibroblasts] will be treated and this biophysical stimuli can influence axonal growth directly or indirectly via changes to the resident, non-neuronal cells. In this work, non neuronal cells were electrically stimulated, and changes in morphology and neuro supportive cells were evaluated. Schwann cell response (morphology and orientation) was examined after an 8 h stimulation over a range of DC fields (0 200 mV/mm, DC 1 mA), and changes in orientation were observed. Electrically prestimulating Schwann cells (50 mV/mm) promoted 30% more neurite outgrowth relative to co-stimulating both Schwann cells with neurons, suggesting that electrical stimulation modifies Schwann cell phenotype. Conditioned medium from the electrically prestimulated Schwann cells promoted a 20% increase in total neurite outgrowth and was sustained for 72 h poststimulation. An 11-fold increase in nerve growth factor but not brain-derived neurotrophic factor or glial-derived growth factor was found in the electrically prestimulated Schwann cell conditioned medium. No significant changes in fibroblast or endothelial morphology and neuro-supportive behavior were observed poststimulation. Electrical stimulation is widely used in clinical settings; however, the rational application of this cue may directly impact and enhance neuro-supportive behavior, improving nerve repair. PMID- 24063577 TI - Controlling the levels of airborne pollen: can heterogeneous photocatalysis help? AB - Airborne pollen is a worldwide problem because is a very important allergenic agent; it can be altered only by certain microorganisms and by some oxidizers, such as reactive oxygen species (ROS). On the other hand, heterogeneous photocatalysis (HPC) arose as a promising technology for reducing the level of contaminants in the air, based on their degradation by the production of ROS. In this paper, study of the feasibility of HPC to diminish the counts of pollen is undertaken. The research has been carried out at different levels, from solutions to mortar specimens with the evidence that HPC is able to reduce the amount of pollen grains. This is a major breakthrough that opens the door to a whole field of research, already full of gaps, whose implications could be quite controversial. PMID- 24063578 TI - LIHNCS - Lugol's iodine in head and neck cancer surgery: a multicentre, randomised controlled trial assessing the effectiveness of Lugol's iodine to assist excision of moderate dysplasia, severe dysplasia and carcinoma in situ at mucosal resection margins of oral and oropharyngeal squamous cell carcinoma: study protocol for a randomised controlled trial. AB - BACKGROUND: Oral cavity and oropharynx cancer are increasing in incidence worldwide but survival outcomes have not significantly improved over the last three decades. The presence of dysplasia or carcinoma in situ at surgical margins following resection of squamous carcinoma of the mucosal surfaces of the head and neck has been shown to be associated with a higher incidence of local recurrence and reduced survival. While invasive carcinoma in mucosal surfaces can usually be distinguished from adjacent normal mucous membrane, pre-malignant disease is much less readily distinguished at operation. We describe a protocol for a randomised, controlled trial in which we will assess the effectiveness of Lugol's iodine staining in allowing visualisation and excision of cancer margin dysplasia at time of primary surgery. METHODS/DESIGN: We will recruit 300 patients diagnosed with oral cavity or oropharynx squamous cell carcinoma. All participants will be planned for primary surgery with curative intent. After completion of baseline assessment participants will be randomised into either a standard surgical treatment arm or surgical treatment including Lugol's iodine staining. DISCUSSION: This paper describes the rationale and design of a unique trial in head and neck surgical oncology. If margin dysplasia visualisation with Lugol's iodine allows complete excision of high-risk, pre-cancer mucosa at time of primary surgery, this may lead to a reduction in local recurrence and improved survival. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03712770. PMID- 24063579 TI - The role of anorectal investigations in predicting the outcome of biofeedback in the treatment of faecal incontinence. AB - OBJECTIVE: The current literature does not provide unequivocal evidence on prognostic factors of patients' response to biofeedback for management of faecal incontinence. The aim of this study was to identify independent predictors of patient response to biofeedback. MATERIAL AND METHODS: Baseline demographic characteristics, symptomatology and anorectal investigation reports of 137 patients who completed biofeedback therapy were analysed retrospectively. Short term response (<3 months) to biofeedback was assessed using subjective criteria (improvement/ no improvement). P Values < 0.05 were considered to be statistically significant. RESULTS: At univariate analysis, age, duration of symptoms, severity of faecal incontinence, mean maximum squeeze and resting pressure differed significantly (p < 0.05) were associated with patients' response. However, after performing logistic regression analysis age, duration and severity of symptoms were the only variables associated with the outcome (p Values were 0.041, 0.022 and 0.025, respectively). CONCLUSION: Three independent factors (younger age, shorter duration and lower severity of faecal incontinence) were associated with patient outcome after completing our unit's biofeedback protocol. Anorectal investigations are of questionable value in patient selection for biofeedback therapy. PMID- 24063580 TI - Syphilitic uveitis in a Singaporean population. AB - PURPOSE: To report the presentations of syphilitic uveitides in Singapore. METHODS: Retrospective noncomparative observational case series of 18 eyes from 12 patients with ocular syphilis between 2004 and 2009. RESULTS: Patients were mainly male (91.7%). Median age was 49.5 (24-84) years. Initial visual acuity varied from 6/6 to counting fingers (CF) and was >=6/12 in 7 eyes (38.8%). Blurring of vision (n = 11, 61.1%) was the most common presenting complaint. Anterior uveitis and panuveitis were both most common (n = 6, 33.3%). Treponemal and nontreponemal serologies were positive in 12 (100.0%) and 10 (83.3%) patients, respectively. Patients were treated systematically with penicillin therapy by infectious disease physicians. CONCLUSIONS: Ocular syphilis is seeing a worldwide resurgence. Although anterior uveitis and panuveitis were most common in this study, there was a large spectrum of ocular manifestations. Syphilitic uveitides can potentially cause severe loss of vision but are effectively treated by an appropriate regimen of penicillin. PMID- 24063581 TI - Nanomechanics insights into the performance of healthy and osteoporotic bones. AB - In situ nanoscopic observations of healthy and osteoporotic bone nanopillars under compression were performed. The structural-mechanical property relationship at the atomic scale suggests that cortical bone performance is correlated to the feature, arrangement, movement, distortion, and fracture of hydroxyapatite nanocrystals. Healthy bone comprising tightly bound mineral nanocrystals shows high structural stability with nanoscopic lattice distortions and dislocation activities. On the other hand, osteoporotic bone exhibits brittleness owing to the movements of dispersed minerals in and intergranular fracture along a weak organic matrix. PMID- 24063582 TI - Cytotoxic deoxybenzoins and diphenylethylenes from Arundina graminifolia. AB - Eight new C-4-alkylated deoxybenzoins (1-8), three new diphenylethylenes (9-11), and five known diphenylethylenes were isolated from Arundina graminifolia. The structures of 1-11 were elucidated by spectroscopic methods including extensive 1D and 2D NMR techniques. Compounds 9-11 are the first naturally occurring diphenylethylenes possessing a hydroxyethyl unit. Compounds 1-11 were evaluated for cytotoxicity against five human tumor cell lines. Compounds 4, 5, and 9-11 showed significant cytotoxicity against five cancer cell lines, with IC50 values ranging from 1.8 to 8.7 MUM. PMID- 24063583 TI - Odd or even? Monolayer domain size depends on diyne position in alkadiynylanthracenes. AB - 1,5-(Alkadiynyl)anthracenes self-assemble single component and multicomponent monolayers at the solution-HOPG interface. An alkadiynyl chain's kinked shape constrains the molecular structures with which it can close-pack. This affords rudimentary molecular recognition that has been used to direct self-assembly of 1 D patterned, multicomponent monolayers. The unit cell building blocks of single- and multicomponent alkadiynylanthracene monolayers repeat with high fidelity for 100s of nanometers along the side chain direction. Unit cell repeat fidelity along the orthogonal, anthracene column direction of the monolayer depends on diyne location within the side chain; even-position diyne side chains produce high fidelity of unit cell repeats and wider domain widths along the anthracene columns, whereas odd-position diyne side chains produce more frequent domain interfaces that disrupt the anthracene columns. Alkadiynylanthracene monolayers may be viewed as stacks of 1-D molecular tapes. 1-D tape molecular composition, sequence, and intratape side chain alignment are dictated by shape complementarity of the kinked alkadiynyl side chains. Stacking alignments of adjacent 1-D tapes are controlled by shape matching of tape peripheries and determine repeat fidelity along the anthracene columns. Tapes stacked with a constant intertape alignment comprise crystalline domains that repeat along the anthracene columns. The 1-D tapes formed by anthracenes with odd-position diynes have triangle wave peripheries that close-pack in multiple stacking alignments. This reduces unit cell repeat fidelity and decreases the widths of crystalline domains along the anthracene columns. Even-position diyne side chains form 1-D tapes with trapezoid wave peripheries that close-pack in only one stacking alignment. This generates higher stacking fidelity, larger domain widths, and fewer domain interfaces along the anthracene columns of even-position diyne monolayers. Even- and odd-position diyne monolayers exhibit comparable densities of interfaces between enantiotopic domains and between domains aligned along different graphite symmetry axes. These interfaces likely arise through collisions of independently nucleated/growing domains and persist for lack of kinetically competent pathways that interconvert or merge the domains. PMID- 24063584 TI - Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB2 receptors. AB - BACKGROUND: The level of expression of cannabinoid receptor type 2 (CB2R) in healthy and diseased brain has not been fully elucidated. Therefore, there is a growing interest to assess the regional expression of CB2R in the brain. Positron emission tomography (PET) is an imaging technique, which allows quantitative monitoring of very low amounts of radiolabelled compounds in living organisms at high temporal and spatial resolution and, thus, has been widely used as a diagnostic tool in nuclear medicine. Here, we report on the radiofluorination of N-aryl-oxadiazolyl-propionamides at two different positions in the lead structure and on the biological evaluation of the potential of the two tracers [18F]1 and [18F]2 as CB2 receptor PET imaging agents. RESULTS: High binding affinity and specificity towards CB2 receptors of the lead structure remained unaffected by the structural changes such as the insertion of the aliphatic and aromatic fluorine in the selected labelling sites of 1 and 2. Aliphatic and aromatic radiofluorinations were optimized, and [18F]1 and [18F]2 were achieved in radiochemical yields of >=30% with radiochemical purities of >=98% and specific activities of 250 to 450 GBq/MUmol. Organ distribution studies in female CD1 mice revealed that both radiotracers cross the blood-brain barrier (BBB) but undergo strong peripheral metabolism. At 30 min after injection, unmetabolized [18F]1 and [18F]2 accounted for 60% and 2% as well as 68% and 88% of the total activity in the plasma and brain, respectively. The main radiometabolite of [18F]2 could be identified as the free acid [18F]10, which has no affinity towards the CB1 and CB2 receptors but can cross the BBB. CONCLUSIONS: N-aryl-oxadiazolyl propionamides can successfully be radiolabelled with 18F at different positions. Fluorine substitution at these positions did not affect affinity and specificity towards CB2R. Despite a promising in vitro behavior, a rather rapid peripheral metabolism of [18F]1 and [18F]2 in mice and the generation of brain permeable radiometabolites hamper the application of these radiotracers in vivo. However, it is expected that future synthetic modification aiming at a replacement of metabolically susceptible structural elements of [18F]1 and [18F]2 will help to elucidate the potential of this class of compounds for CB2R PET studies. PMID- 24063585 TI - Anthropometry and physical activity level in the prediction of metabolic syndrome in children. AB - OBJECTIVE: To evaluate the effectiveness of anthropometric measures and physical activity level in the prediction of metabolic syndrome (MetS) in children. DESIGN: Cross-sectional study with children from public and private schools. Children underwent an anthropometric assessment, blood pressure measurement and biochemical evaluation of serum for determination of TAG, HDL-cholesterol and glucose. Physical activity level was calculated and number of steps per day obtained using a pedometer for seven consecutive days. SETTING: Vicosa, south eastern Brazil. SUBJECTS: Boys and girls (n 187), mean age 9.90 (SD 0.7) years. RESULTS: Conicity index, sum of four skinfolds, physical activity level and number of steps per day were accurate in predicting MetS in boys. Anthropometric indicators were accurate in predicting MetS for girls, specifically BMI, waist circumference measured at the narrowest point and at the level of the umbilicus, four skinfold thickness measures evaluated separately, the sum of subscapular and triceps skinfold thickness, the sum of four skinfolds and body fat percentage. CONCLUSIONS: The sum of four skinfolds was the most accurate method in predicting MetS in both genders. PMID- 24063586 TI - The challenge of matching across ages. PMID- 24063587 TI - Effect of a multivitamin preparation supplemented with phytosterol on serum lipids and infarct size in rats fed with normal and high cholesterol diet. AB - BACKGROUND: Although complex multivitamin products are widely used as dietary supplements to maintain health or as special medical food in certain diseases, the effects of these products were not investigated in hyperlipidemia which is a major risk factor for cardiovascular diseases. Therefore, here we investigated if a preparation developed for human use containing different vitamins, minerals and trace elements enriched with phytosterol (VMTP) affects the severity of experimental hyperlipidemia as well as myocardial ischemia/reperfusion injury. METHODS: Male Wistar rats were fed a normal or cholesterol-enriched (2% cholesterol + 0.25% cholate) diet for 12 weeks to induce hyperlipidemia. From week 8, rats in both groups were fed with a VMTP preparation or placebo for 4 weeks. Serum triglyceride and cholesterol levels were measured at week 0, 8 and 12. At week 12, hearts were isolated, perfused according to Langendorff and subjected to a 30-min coronary occlusion followed by 120 min reperfusion to measure infarct size. RESULTS: At week 8, cholesterol-fed rats showed significantly higher serum cholesterol level as compared to normal animals, however, serum triglyceride level did not change. VMTP treatment significantly decreased serum cholesterol level in the hyperlipidemic group by week 12 without affecting triglyceride levels. However, VMTP did not show beneficial effect on infarct size. The inflammatory marker hs-CRP and the antioxidant uric acid were also not significantly different. CONCLUSIONS: This is the first demonstration that treatment of hyperlipidemic subjects with a VMTP preparation reduces serum cholesterol, the major risk factor for cardiovascular disease; however, it does not provide cardioprotection. PMID- 24063588 TI - The increase of microRNA-21 during lung fibrosis and its contribution to epithelial-mesenchymal transition in pulmonary epithelial cells. AB - BACKGROUND: The excess and persistent accumulation of fibroblasts due to aberrant tissue repair results in fibrotic diseases such as idiopathic pulmonary fibrosis. Recent reports have revealed significant changes in microRNAs during idiopathic pulmonary fibrosis and evidence in support of a role for microRNAs in myofibroblast differentiation and the epithelial-mesenchymal transition in the context of fibrosis. It has been reported that microRNA-21 is up-regulated in myofibroblasts during fibrosis and promotes transforming growth factor-beta signaling by inhibiting Smad7. However, expression changes in microRNA-21 and the role of microRNA-21 in epithelial-mesenchymal transition during lung fibrosis have not yet been defined. METHODS: Lungs from saline- or bleomycin-treated C57BL/6 J mice and lung specimens from patients with idiopathic pulmonary fibrosis were analyzed. Enzymatic digestions were performed to isolate single lung cells. Lung epithelial cells were isolated by flow cytometric cell sorting. The expression of microRNA-21 was analyzed using both quantitative PCR and in situ hybridization. To induce epithelial-mesenchymal transition in culture, isolated mouse lung alveolar type II cells were cultured on fibronectin-coated chamber slides in the presence of transforming growth factor-beta, thus generating conditions that enhance epithelial-mesenchymal transition. To investigate the role of microRNA-21 in epithelial-mesenchymal transition, we transfected cells with a microRNA-21 inhibitor. Total RNA was isolated from the freshly isolated and cultured cells. MicroRNA-21, as well as mRNAs of genes that are markers of alveolar epithelial or mesenchymal cell differentiation, were quantified using quantitative PCR. RESULTS: The lung epithelial cells isolated from the bleomycin-induced lung fibrosis model system had decreased expression of epithelial marker genes, whereas the expression of mesenchymal marker genes was increased. MicroRNA-21 was significantly upregulated in isolated lung epithelial cells during bleomycin-induced lung fibrosis and human idiopathic pulmonary fibrosis. MicroRNA-21 was also upregulated in the cultured alveolar epithelial cells under the conditions that enhance epithelial-mesenchymal transition. Exogenous administration of a microRNA-21 inhibitor prevented the increased expression of vimentin and alpha-smooth muscle actin in cultured primary mouse alveolar type II cells under culture conditions that induce epithelial mesenchymal transition. CONCLUSIONS: Our experiments demonstrate that microRNA-21 is increased in lung epithelial cells during lung fibrosis and that it promotes epithelial-mesenchymal transition. PMID- 24063589 TI - Highly efficient cadmium-free quantum dot light-emitting diodes enabled by the direct formation of excitons within InP@ZnSeS quantum dots. AB - We demonstrate bright, efficient, and environmentally benign InP quantum dot (QD) based light-emitting diodes (QLEDs) through the direct charge carrier injection into QDs and the efficient radiative exciton recombination within QDs. The direct exciton formation within QDs is facilitated by an adoption of a solution processed, thin conjugated polyelectrolyte layer, which reduces the electron injection barrier between cathode and QDs via vacuum level shift and promotes the charge carrier balance within QDs. The efficient radiative recombination of these excitons is enabled in structurally engineered InP@ZnSeS heterostructured QDs, in which excitons in the InP domain are effectively passivated by thick ZnSeS composition-gradient shells. The resulting QLEDs record 3.46% of external quantum efficiency and 3900 cd m(-2) of maximum brightness, which represent 10-fold increase in device efficiency and 5-fold increase in brightness compared with previous reports. We believe that such a comprehensive scheme in designing device architecture and the structural formulation of QDs provides a reasonable guideline for practical realization of environmentally benign, high-performance QLEDs in the future. PMID- 24063590 TI - Assembly of multivalent protein ligands and quantum dots: a multifaceted investigation. AB - The development of multivalent protein ligands for nanoparticles lags behind that of multidentate polymers and small-molecule ligands largely because of a lack of thorough understanding of the interaction between nanoparticles and multimeric proteins. Guided by protein crystal structures, we have harnessed recombinant technology to develop a collection of mCherry fused multimeric proteins with different spatial distributions of the quantum dot (QD)-binding sequence, hexahistidine tag (histag). All of the proteins can behave as ligands to assemble with ZnS-CdSe QDs through metal-affinity-driven self-assembly. We have observed that protein shape and geometry greatly affect the stoichiometry and stability of their assemblies with QDs. We also demonstrate a peptide-induced structural transition of a nanobelt protein that preorganizes the QD-binding sites and effects a more efficient assembly with QDs. This work reports the first multifaceted investigation on how multivalent proteins, in particular, dimers, tetramers, and linear multidentate proteins, assemble with QDs. It also manifests our capability of harnessing structural and conformational information about proteins to design multivalent protein ligands for QD surface functionalization. PMID- 24063591 TI - Fourier transform infrared studies of ammonia photochemistry in solid parahydrogen. AB - We present 193 nm in situ photochemical studies of NH3 isolated in solid parahydrogen (pH2) at 1.8 K using Fourier Transform Infrared (FTIR) spectroscopy. By recording FTIR spectra during and after irradiation we are able to identify and assign a number of rovibrational transitions to ortho-NH2(X(2)B1) and NH(X(3)Sigma(-)). Spectroscopic analysis shows that these two radical species rotate freely in solid pH2 and that effects of the unpaired electron spin remain essentially unchanged from the gas phase. We provide detailed mechanistic studies that show the nascent ortho-NH2 photoproduct is rapidly cooled within the pH2 matrix to the ground vibrational and rotational state before (1) subsequent photodissociation or (2) tunneling-driven reaction (k(tun) = 1.88(17) min(-1)) with the pH2 host to produce ortho-NH3 in a defect site. Once the ortho-NH3 is produced in this defect site it slowly converts (k(conv) = 7.72(51) * 10(-3) min( 1)) back to a single substitution site even at 1.8 K. We demonstrate the in situ photolysis of NH3 can be utilized to generate NH doped pH2 solids that are relatively stable at low temperature. However, the ortho-NH2 + pH2 -> ortho-NH3 + H back reaction substantially limits the sequential two-photon conversion of NH3 to NH. These studies also reveal that extended photolysis of the NH3/pH2 system results in the generation of high concentrations of orthohydrogen that must result from repeated cycles of photodissociation and NH2 back reaction within the pH2 host. PMID- 24063593 TI - Are rehabilitation services following stroke accessed equitably in Australia?: findings from the psychosocial outcomes in stroke (POISE) cohort study. AB - BACKGROUND: Stroke recovery is generally optimised through the provision of multidisciplinary rehabilitation. However not much is known about how equitably such services are utilised. This study examines the determinants of physiotherapy and speech therapy utilisation in rehabilitation within a cohort of young stroke survivors in Australia. METHODS: Psychosocial Outcomes in StrokE (POISE) was a three-year prospective observational study involving stroke survivors between the ages of 18 and 65 years recruited within 28 days of stroke. It was conducted in 20 stroke units in Australia. Participants were interviewed at 28 days (baseline), 6 and 12 months after stroke about their demographic and socioeconomic background, economic and health outcomes and the use of services. The primary outcome in this paper is utilisation of rehabilitation in the 12 months after stroke. RESULTS: Of 414 participants, 254 (61%) used some rehabilitation in the 12 months post stroke. The strongest predictor of use of these rehabilitation services was dependency at 28 days, as assessed by need for assistance in activities of daily living (OR=33.1; p<0.0001). Other significant variables were two dimensions of social capital--an individuals' ability to make important decisions, which had a negative relationship (OR = 0.43; p=0.04) and number of close friends (OR= 1.042; p=0.02). CONCLUSION: These findings demonstrate that socio-demographic factors exert little influence on the use of rehabilitation services in working age stroke patients and that the use of such services is primarily determined by 'need'. Such findings suggest that services are being provided equitably. TRIAL REGISTRATION: ANZCTRN12608000459325. PMID- 24063594 TI - Expression kinetics of miRNA involved in dermal toluene 2,4-diisocyanate sensitization. AB - Allergic disease is an important occupational health concern, with work-related asthma and allergic contact dermatitis being the most frequently diagnosed occupational illnesses. Diisocyanates, particularly toluene 2,4-diisocyanate (TDI), have been the leading cause of occupational asthma for many years. Understanding the mechanisms behind allergic disease is critical for treatment and prevention. Recently, the study of post-transcriptional regulation by microRNAs (miRNA) has shed light on mechanisms of allergic disease. The present studies report the expression of miRNA during the sensitization phase of an allergic response to TDI in a murine model. Female BALB/c mice were dermally exposed to TDI (0.1-15% [v/v]) or vehicle. RNA was isolated from superficial parotid lymph nodes at timepoints between 1 h and 15 days post-exposure and then miRNA expression was analyzed using array and real-time quantitative PCR analysis. Consistent changes in miRNA expression were identified for miR-21, miR 22, miR-27b, miR-31, miR-126, miR-155, miR-210, and miR-301a. Following TDI exposure, peak expression was observed by Day 4 for the majority of miRNA evaluated with trends in expression correlated to exposure concentration. Confirmed and predicted targets were identified using Diana-microT, miRanda, miRwalk, and Targetscan algorithms. Evaluation of mRNA expression of cytokine and transcription factor targets suggests that miRNA may have a central role early in TDI sensitization. Understanding the role of these miRNA and their specific mechanism of action in sensitization to TDI may provide pertinent information for the identification of other chemical sensitizers while also contributing to the treatment and prevention of allergic disease. PMID- 24063595 TI - Chemical allergy in humans: fresh perspectives. AB - There is considerable interest in the immunobiological processes through which the development of allergic sensitization to chemicals is initiated and orchestrated. One of the most intriguing issues is the basis for the elicitation by chemical sensitizers of different forms of allergic reaction; that is, allergic contact dermatitis or sensitization of the respiratory tract associated with occupational asthma. Studies in rodents have revealed that differential forms of allergic sensitization to chemicals are, in large part at least, a function of the selective development of discrete functional sub-populations of CD4(+) and CD8(+) T-lymphocytes. Evidence for a similar association of chemical allergy in humans with discrete T-lymphocyte populations is, however, limited. It is of some interest, therefore, that two recent articles from different teams of investigators have shed new light on the role of polarized T-lymphocyte responses in the development of allergic contact dermatitis and occupational asthma in humans. The implications for understanding of chemical allergy in humans are explored in this Commentary. PMID- 24063596 TI - Angiotensin II and the ERK pathway mediate the induction of leptin by mechanical cyclic stretch in cultured rat neonatal cardiomyocytes. AB - Mechanical cyclic stretch of cardiomyocytes causes cardiac hypertrophy through cardiac-restricted gene expression. Leptin induces cardiomyocyte hypertrophy in response to myocardial stress. In the present study, we evaluated the expression of leptin under cyclic stretch and its role in regulating genetic transcription in cardiomyocytes. Cultured rat neonatal cardiomyocytes were subjected to cyclic stretch, and the expression levels of leptin, ROS (reactive oxygen species) and AngII (angiotensin II) were evaluated. Signal transduction inhibitors were used to identify the pathway of leptin expression. EMSAs were used to identify the binding of leptin/STAT3 (signal transducer and activator of transcription 3) and luciferase assays were used to identify the transcription of leptin in cardiomyocytes. The study also used an in vivo model of AV (aortocaval) shunt in rats to investigate leptin, ROS and AngII expression. Leptin and leptin receptor levels increased after cyclic stretch with the earlier expression of AngII and ROS. Leptin expression was suppressed by AngII receptor blockers, an ROS scavenger [NAC (N-acetylcysteine)], an ERK (extracellular-signal-regulated kinase) pathway inhibitor (PD98059) and ERK siRNA. Binding of leptin/STAT3 was identified by EMSAs, and luciferase assays confirmed the transcription of leptin in neonatal cardiomyocytes after cyclic stretch. Increased MHC (myosin heavy chain) expression and [3H]-proline incorporation in cardiomyocytes was detected after cyclic stretch, which were inhibited by leptin siRNA and NAC. The in vivo model of AV shunt also demonstrated increased levels of plasma and myocardial leptin, ROS and AngII expression after cyclic stretch. Mechanical cyclic stretch in cardiomyocytes increased leptin expression mediated by the induction of AngII, ROS and the ERK pathway to cause cardiomyocyte hypertrophy. Myocardial hypertrophy can be identified by increased transcriptional activity and an enhanced hypertrophic phenotype of cardiomyocytes. PMID- 24063592 TI - Circadian redox and metabolic oscillations in mammalian systems. AB - SIGNIFICANCE: A substantial proportion of mammalian physiology is organized around the day/night cycle, being regulated by the co-ordinated action of numerous cell-autonomous circadian oscillators throughout the body. Disruption of internal timekeeping, by genetic or environmental perturbation, leads to metabolic dysregulation, whereas changes in metabolism affect timekeeping. RECENT ADVANCES: While gene expression cycles are essential for the temporal coordination of normal physiology, it has become clear that rhythms in metabolism and redox balance are cell-intrinsic phenomena, which may regulate gene expression cycles reciprocally, but persist in their absence. For example, a circadian rhythm in peroxiredoxin oxidation was recently observed in isolated human erythrocytes, fibroblast cell lines in vitro, and mouse liver in vivo. CRITICAL ISSUES: Mammalian timekeeping is a cellular phenomenon. While we understand many of the cellular systems that contribute to this biological oscillation's fidelity and robustness, a comprehensive mechanistic understanding remains elusive. Moreover, the formerly clear distinction between "core clock components" and rhythmic cellular outputs is blurred since several outputs, for example, redox balance, can feed back to regulate timekeeping. As with any cyclical system, establishing causality becomes problematic. FUTURE DIRECTIONS: A detailed molecular understanding of the temporal crosstalk between cellular systems, and the coincidence detection mechanisms that allow a cell to discriminate clock-relevant from irrelevant stimuli, will be essential as we move toward an integrated model of how this daily biological oscillation works. Such knowledge will highlight new avenues by which the functional consequences of circadian timekeeping can be explored in the context of human health and disease. PMID- 24063597 TI - Microbial community in the soil determines the forest recovery post-exposure to gamma irradiation. AB - Exposure of an ecosystem to ionizing radiation remains a possibility either due to accidents involving nuclear fuel rods or contamination with high-level radioactive wastes. While the short and long-term effect of ionizing radiation on higher eukaryotes has been well documented, we do not have an understanding on the recovery of the microbial community post radiation. Here we report that at a site within Brookhaven National Laboratory that was radiated from 1961 to 1978 with gamma rays (Gamma Forest), the ecosystem has not yet fully recovered from the effects of radiation. The current vegetation type in the Gamma Forest varies as one goes away from the source of ionizing radiation, with the region closest to the source having no vegetation. The microbial tag-encoded FLX amplicon pyrosequencing analysis of the soil from different regions suggests that the current microbial community structure is identical in all the Zones. When soil samples from each vegetation zone of the Gamma Forest were radiated with 1.8 kGy gamma radiation and survival microbial community analyzed, clear difference in the microbial communities were observed. It is evident based on the experimental data that the colonization of soil with Nitrosomonadaceae is critical for the higher plants in pine barrens to reestablish and grow after the area had been exposed to ionizing radiation. PMID- 24063598 TI - Surface modification of polypyrrole/biopolymer composites for controlled protein and cellular adhesion. AB - The ability to control the interaction between proteins and cells with biomaterials is critical for the effective application of materials for a variety of biomedical applications. Herein, the surface modification of the biological dopant dextran sulphate-doped polypyrrole (PPy-DS) with poly(ethylene glycol) to generate a biomaterial interface that is highly resistant to protein and cellular adhesion is described. Thiolated poly(ethylene glycol) (PEG-thiol) was covalently bound to PPy-DS backbone via a thiol-ene reaction. The surface resistance to an extracellular matrix protein fibronectin increased with increasing molecular weight and concentration of PEG-thiol, and was further optimised via increasing the reaction temperature and the pH of the reactant aqueous solution. Optimised surface modification conditions substantially reduced interfacial protein adsorption, with the complete inhibition of adhesion and colonisation by primary mouse myoblasts. PEG-thiol-modified inherently conducting polymers are highly protein resistant multifunctional materials that are promising compounds for a range of biomedical and aquatic applications. PMID- 24063599 TI - An exceptional case of full-thickness macular hole closure in a patient with Behcet disease. AB - PURPOSE: To present a case of a full-thickness macular hole closure in a patient with Behcet uveitis. DESIGN: A 23-year-old-male patient with Behcet Disease had clinically inactive uveitis with topical steroids, oral azathiopurine and cyclosporine until he developed a retinal infiltrate in the left eye which evolved into a full-thickness macular hole during the follow-up. METHODS: Strict control of inflammation and subsequent vitrectomy was planned. Meanwhile another attack of panuveitis developed in the left eye and subcutaneous Interferon alfa 2b interferon treatment was initiated. RESULTS: After 2 months, the patient was clinically inactive with complete closure of the macular hole. CONCLUSIONS: Strict control of inflammation may result in closure of the macular hole and avoid the need for vitrectomy. PMID- 24063600 TI - Association mapping of starch physicochemical properties with starch biosynthesizing genes in waxy rice (Oryza sativa L.). AB - Waxy (glutinous) rice is widely used in traditional foods, and understanding the genetic bases of its diverse physicochemical properties will contribute to breeding of new waxy rice with unique qualities. The objective of this study was to investigate the genetic relationship between the starch biosynthesis related genes and the physicochemical properties of waxy rice using association mapping. A total of 36 molecular markers representing 18 genes were used to genotype 50 waxy rice accessions for which starch properties were previously available. Most of the starch properties differed between high and low gelatinization temperature (GT) groups, whereas most traits were similar between the low-GT indica rice and low-GT japonica rice, suggesting GT was the main determinant of the starch quality of waxy rice. Association mapping indicated that the starch properties of waxy rice were mainly controlled by starch synthase IIa (SSIIa or SSII-3, a major gene responsible for the gelatinization temperature) and SSI. It was found that gene-gene interactions were also important for the genetic control of starch properties of waxy rice. This study suggests that application of the functional SNPs of SSIIa in molecular breeding may facilitate quality improvement of waxy rice. PMID- 24063601 TI - Does age affect symptom recovery after sports-related concussion? A study of high school and college athletes. AB - OBJECT: Sport-related concussions (SRCs) in high school and college athletes represent a significant public health concern. Research suggests that younger athletes fare worse symptomatically than older athletes after an SRC. Using reliable change index (RCI) methodology, the authors conducted a study to determine if there are age-related differences in number, severity, and resolution of postconcussion symptoms. METHODS: Between 2009 and 2011, baseline measures of neurocognitive functions and symptoms in high school and college athletes were entered into a regional database. Seven hundred forty of these athletes later sustained an SRC. Ninety-two athletes in the 13- to 16-year-old group and 92 athletes in the 18- to 22-year-old group were matched for number of prior concussions, sex, biopsychosocial variables, and days to first postconcussion testing and symptom assessment. A nonparametric Mann-Whitney U test was used to compare the severity of each of 22 symptoms comprising the Total Symptom Scale (TSS) at baseline and first postconcussion test. To obtain a family wise p value of 0.05 for each test, the significance level for each symptom comparison was set at an alpha of 0.05/22 = 0.0023. The number of days to return to baseline TSS score was compared using the RCI methodology, set at the 80% confidence interval, equal to a change in raw score of 9.18 points on the TSS. RESULTS: There was no statistically significant difference in symptom presence, symptom severity, and total symptoms between the age groups at baseline or at postconcussion testing. There was no statistically significant difference in return to baseline symptom scores between the age groups. CONCLUSIONS: Using RCI methodology, there was no statistically significant difference between younger and older athletes in return to baseline symptoms postconcussion. PMID- 24063602 TI - Ru/ITO: a carbon-free cathode for nonaqueous Li-O2 battery. AB - Ru nanoparticles deposited on a conductive support indium tin oxide (Ru/ITO) were applied as a carbon-free cathode in a nonaqueous Li-O2 battery. The Li-O2 battery with Ru/ITO showed much lower charging overpotentials and better cycling performance at 0.15 mA/cm(2) than those with Super P (SP) and SP loaded with Ru nanoparticles (Ru/SP) as the cathodes. The carbon-free cathode Ru/ITO can effectively reduce formation of Li2CO3 or other Li carbonates in a discharging process, which cannot be completely decomposed upon charging, in comparison with the carbon based cathode. The improved performance of Ru/ITO can be attributed to the superior catalytic activity of Ru nanoparticles toward oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) and the absence of carbon that has been reported to react with Li2O2 to form Li2CO3. PMID- 24063603 TI - Cancer-testis gene expression is associated with the methylenetetrahydrofolate reductase 677 C>T polymorphism in non-small cell lung carcinoma. AB - BACKGROUND: Tumor-specific, coordinate expression of cancer-testis (CT) genes, mapping to the X chromosome, is observed in more than 60% of non-small cell lung cancer (NSCLC) patients. Although CT gene expression has been unequivocally related to DNA demethylation of promoter regions, the underlying mechanism leading to loss of promoter methylation remains elusive. Polymorphisms of enzymes within the 1-carbon pathway have been shown to affect S-adenosyl methionine (SAM) production, which is the sole methyl donor in the cell. Allelic variants of several enzymes within this pathway have been associated with altered SAM levels either directly, or indirectly as reflected by altered levels of SAH and Homocysteine levels, and altered levels of DNA methylation. We, therefore, asked whether the five most commonly occurring polymorphisms in four of the enzymes in the 1-carbon pathway associated with CT gene expression status in patients with NSCLC. METHODS: Fifty patients among a cohort of 763 with NSCLC were selected based on CT gene expression status and typed for five polymorphisms in four genes known to affect SAM generation by allele specific q-PCR and RFLP. RESULTS: We identified a significant association between CT gene expression and the MTHFR 677 CC genotype, as well as the C allele of the SNP, in this cohort of patients. Multivariate analysis revealed that the genotype and allele strongly associate with CT gene expression, independent of potential confounders. CONCLUSIONS: Although CT gene expression is associated with DNA demethylation, in NSCLC, our data suggests this is unlikely to be the result of decreased MTHFR function. PMID- 24063604 TI - Long-term reduction in poly(dimethylsiloxane) surface hydrophobicity via cold plasma treatments. AB - Poly(dimethylsiloxane), PDMS, a versatile elastomer, is the polymer of choice for microfluidic systems. It is inexpensive, relatively easy to pattern, and permeable to oxygen. Unmodified PDMS is highly hydrophobic. It is typically exposed to an oxygen plasma to reduce this hydrophobicity. Unfortunately, the PDMS surface soon returns to its original hydrophobic state. We present two alternative plasma treatments that yield long-term modification of the wetting properties of a PDMS surface. An oxygen plasma pretreatment followed by exposure to a SiCl4 plasma and an oxygen-CCl4 mixture plasma both cause a permanent reduction in the hydrophobicity of the PDMS surface. We investigate the properties of the plasma-treated surfaces with X-ray photoelectron spectroscopy (XPS) and contact angle measurements. We propose that the plasma treated PDMS surface is a dynamic mosaic of high- and low-contact-angle functionalities. The SiCl4 and CCl4 plasmas attach polar groups that block coverage of the surface by low-molecular-weight groups that exist in PDMS. We describe an application that benefits from these new plasma treatments, the use of a PDMS stencil to form dense arrays of DNA on a surface. PMID- 24063605 TI - STAT3 regulation by S-nitrosylation: implication for inflammatory disease. AB - AIMS: S-nitrosylation and S-glutathionylation, redox-based modifications of protein thiols, are recently emerging as important signaling mechanisms. In this study, we assessed S-nitrosylation-based regulation of Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway that plays critical roles in immune/inflammatory responses and tumorigenesis. RESULTS: Our studies show that STAT3 in stimulated microglia underwent two distinct redox dependent modifications, S-nitrosylation and S-glutathionylation. STAT3 S nitrosylation was associated with inducible nitric oxide synthase (iNOS)-produced nitric oxide (NO) and S-nitrosoglutathione (GSNO), whereas S-glutathionylation of STAT3 was associated with cellular oxidative stress. NO produced by iNOS or treatment of microglia with exogenous GSNO inhibited STAT3 activation via inhibiting STAT3 phosphorylation (Tyr(705)). Consequently, the interleukin-6 (IL 6)-induced microglial proliferation and associated gene expressions were also reduced. In cell-free kinase assay using purified JAK2 and STAT3, STAT3 phosphorylation was inhibited by its selective preincubation with GSNO, but not by preincubation of JAK2 with GSNO, indicating that GSNO-mediated mechanisms inhibit STAT3 phosphorylation through S-nitrosylation of STAT3 rather than JAK2. In this study, we identified that Cys(259) was the target Cys residue of GSNO mediated S-nitrosylation of STAT3. The replacement of Cys(259) residue with Ala abolished the inhibitory role of GSNO in IL-6-induced STAT3 phosphorylation and transactivation, suggesting the role of Cys(259) S-nitrosylation in STAT3 phosphorylation. INNOVATION: Microglial proliferation is regulated by NO via S nitrosylation of STAT3 (Cys(259)) and inhibition of STAT3 (Tyr(705)) phosphorylation. CONCLUSION: Our results indicate the regulation of STAT3 by NO based post-translational modification (S-nitrosylation). These findings have important implications for the development of new therapeutics targeting STAT3 for treating diseases associated with inflammatory/immune responses and abnormal cell proliferation, including cancer. PMID- 24063606 TI - Trends in thinness prevalence among adolescents in ten European countries and the USA (1998-2006): a cross-sectional survey. AB - OBJECTIVE: To describe the prevalence of 'graded thinness' in children aged 11, 13 and 15 years in eleven developed countries and to identify trends in the prevalence of 'thinness' (BMI < 17 kg/m2 at age 18 years) by age and gender. DESIGN: Cross-sectional study using data collected through self-reported questionnaires. SETTING: Data were taken from the 1997/1998, 2001/2002 and 2005/2006 surveys of the Health Behaviours in School-aged Children (HBSC) Study. SUBJECTS: Children and adolescents from ten European countries and the USA (n 158 000). RESULTS: Prevalence of grades 1, 2 and 3 of thinness was higher among 11 year-old students compared with the 13- and 15-year-olds in all countries. A higher prevalence of thinness was observed in girls than in boys. Since 1998 the prevalence of thinness decreased steadily in Czech boys and girls, while it increased for French girls. In the total European sample of females, thinness decreased from 1998 to 2006 (chi 2 for trend, P < 0.01). Age-adjusted logistic regression analysis showed that Czech boys and girls, and Flemish and American girls were less likely to be thin in 2006 than in 1998; while a noteworthy increment, even if borderline significant, was observed for French girls with a 41% increase in the likelihood to be thin. CONCLUSIONS: Our findings suggest that thinness is an important overlooked phenomenon with wide variation in prevalence and trends across developed countries. It deserves further longitudinal studies in a multinational context that could increase the understanding of the factors associated with thinness and contribute to developing preventive and nutritional programmes targeted at controlling obesity and chronic diseases, while monitoring thinness. PMID- 24063607 TI - A modular framework for biomedical concept recognition. AB - BACKGROUND: Concept recognition is an essential task in biomedical information extraction, presenting several complex and unsolved challenges. The development of such solutions is typically performed in an ad-hoc manner or using general information extraction frameworks, which are not optimized for the biomedical domain and normally require the integration of complex external libraries and/or the development of custom tools. RESULTS: This article presents Neji, an open source framework optimized for biomedical concept recognition built around four key characteristics: modularity, scalability, speed, and usability. It integrates modules for biomedical natural language processing, such as sentence splitting, tokenization, lemmatization, part-of-speech tagging, chunking and dependency parsing. Concept recognition is provided through dictionary matching and machine learning with normalization methods. Neji also integrates an innovative concept tree implementation, supporting overlapped concept names and respective disambiguation techniques. The most popular input and output formats, namely Pubmed XML, IeXML, CoNLL and A1, are also supported. On top of the built-in functionalities, developers and researchers can implement new processing modules or pipelines, or use the provided command-line interface tool to build their own solutions, applying the most appropriate techniques to identify heterogeneous biomedical concepts. Neji was evaluated against three gold standard corpora with heterogeneous biomedical concepts (CRAFT, AnEM and NCBI disease corpus), achieving high performance results on named entity recognition (F1-measure for overlap matching: species 95%, cell 92%, cellular components 83%, gene and proteins 76%, chemicals 65%, biological processes and molecular functions 63%, disorders 85%, and anatomical entities 82%) and on entity normalization (F1 measure for overlap name matching and correct identifier included in the returned list of identifiers: species 88%, cell 71%, cellular components 72%, gene and proteins 64%, chemicals 53%, and biological processes and molecular functions 40%). Neji provides fast and multi-threaded data processing, annotating up to 1200 sentences/second when using dictionary-based concept identification. CONCLUSIONS: Considering the provided features and underlying characteristics, we believe that Neji is an important contribution to the biomedical community, streamlining the development of complex concept recognition solutions. Neji is freely available at http://bioinformatics.ua.pt/neji. PMID- 24063609 TI - Enhanced kinetics of pseudo first-order hydrolysis in liquid phase coexistent with ice. AB - The reaction rate of the hydrolysis of fluorescein diacetate (FDA) is several times larger in the frozen state than that in the unfrozen solution of the same composition at the same temperature. The freeze concentration of reactants in the liquid phase expelled form ice crystals cannot explain the kinetic enhancement of pseudo first order reactions such as the FDA hydrolysis. However, the reaction rate increases as the freeze concentration ratio becomes larger at a constant temperature. Direct pH measurements have revealed that the basicity of the liquid phase is unchanged at any concentration ratio, suggesting that the reactivity enhancement is not caused by increased basicity. The reaction rate enhancement is clearly related to the size of the space in which the liquid phase is confined upon freezing. The ice wall itself or the water structure formed near the wall should thus be responsible for this kinetic enhancement. PMID- 24063608 TI - Intermittent preventive treatment: efficacy and safety of sulfadoxine pyrimethamine and sulfadoxine-pyrimethamine plus piperaquine regimens in schoolchildren of the Democratic Republic of Congo: a study protocol for a randomized controlled trial. AB - BACKGROUND: In malaria endemic areas, schoolchildren usually have asymptomatic malaria infections and consequently remain untreated. Therefore, intermittent preventive treatment with sulfadoxine-pyrimethamine in schoolchildren would be a plausible strategy in malaria stable transmission areas to prevent anaemia and malnutrition. However, in contrast to infancy and pregnancy, antimalaria intermittent preventive treatment in children has been barely investigated. As the implementation of intermittent preventive treatment may be challenged by sulfadoxine-pyrimethamine resistance, sulfadoxine-pyrimethamine combined with piperaquine may be a better alternative than sulfadoxine-pyrimethamine monotherapy. A clinical trial is being conducted to assess the efficacy and safety of intermittent preventive treatments versus controls in Democratic Republic of Congo (DRCongo) schoolchildren and their impact on sulfadoxine pyrimethamine resistance. METHODS/DESIGN: A phase IIIb, randomised, controlled trial will enroll asymptomatic schoolchildren. For interventions, sulfadoxine pyrimethamine is compared to sulfadoxine-pyrimethamine plus piperaquine and to a control group. The two treatments are given four-monthly from baseline for a year as a single dose for sulfadoxine-pyrimethamine and two doses at 24-hour intervals for piperaquine. All participants receive praziquantel and albendazole as mass treatment for helminthiasis at enrolment. The primary endpoint is haemoglobin concentration change at 12 months follow-up. Secondary endpoints are malaria parasite load and malaria prevalence, at baseline and at month 12. Malaria and helminthiasis incidence will be monitored throughout the study. Statistical analysis will use multilevel modelling due to repeated measurements and clustering effect of participants. DISCUSSION: The very few studies on intermittent preventive treatment in schoolchildren in malaria stable transmission areas have contradictory results. This randomised controlled trial is unique in comparing efficacy and safety of a prophylactic combination therapy to monotherapy or a control group after 12 months follow-up. Resistance markers for sulfadoxine-pyrimethamine (including break through parasitaemias) will also be recorded. Its uniqueness lies also in the fact that we use piperaquine, a long acting antimalarial, in combination with sulfadoxine-pyrimethamine. Artemisinin derivatives have been excluded as it is part of the treatment policies in virtually all malaria endemic countries. Our findings may, therefore, contribute to the public health of youngsters who fail to thrive and grow due to multiple morbidities. TRIAL REGISTRATION: NCT01722539; PACTR201211000449323. PMID- 24063610 TI - Strategies for recruiting injection drug users for HIV prevention services in Delhi, India. AB - BACKGROUND: We utilized multiple recruitment approaches to recruit IDUs in a longitudinal cohort study to examine HIV incidence and behavior change pre- and post-introduction of comprehensive HIV prevention services. METHODS: IDUs were recruited through peer referral, targeted outreach by outreach workers (ORWs) and as walk-in clients at drop-in centers. Participants received monetary compensation for participation (USD 0.80). Participants were given recruitment coupons to recruit peers (regardless of recruitment method). For peer referral, participants received a food coupon, as secondary compensation, for each peer he/she successfully recruited. We report the profile of IDUs by recruitment method, based on the baseline behavioral survey and HIV test results. Cost per IDU recruited by recruitment method was also calculated. RESULTS: A total of 3,818 IDUs were recruited between May 2011 and October 2011. More than half of the study participants were recruited through targeted outreach (ORW: 53.6%; peer referral: 26.3%; walk-ins: 20.1%). Of the participants who were given recruitment coupons, 92.7% recruited no peers. Those who successfully recruited at least one peer were significantly more likely to be in a stable living accommodation compared to those who did not recruit any peers (51.1% versus 42.7%; p < 0.05). Only 45.9% of the food coupons were claimed for successful recruitment of peers. Peer-referred IDUs were more likely to be living with family or relatives (50.7% versus ORW: 40.1% and walk-in: 39.8%; p < 0.001) rather than on the street or shared housings compared to the other two recruitment modes. Walk-ins were more likely than peer-referred and ORW-referred IDUs to be HIV-positive (walk-ins: 26.1%; peer-referred: 19.1%; ORW: 19.9%; p < 0.01) and have risky injection practices (walk-ins: 62.2%; ORW: 57.0%; peer-referred: 58.6%; p < 0.05). The cost per IDU recruited through ORW referral method was the most costly at USD 16.30, followed by peer-referral at USD 8.40 and walk-in at USD 7.50. CONCLUSION: When recruiting a large number of IDUs, using multiple recruitment modes is ideal with regard to diversification of IDU characteristics and risk profile. Although it was the most costly, ORW recruitment was more effective than the other two methods. Lack of monetary compensation for successful recruitment of peers may have hampered peer-referral. PMID- 24063611 TI - microRNA profiles in coeliac patients distinguish different clinical phenotypes and are modulated by gliadin peptides in primary duodenal fibroblasts. AB - CD (coeliac disease) is a frequent autoimmune disorder of the small bowel, which is characterized by an immunological reaction against gluten and transglutaminase in genetically predisposed subjects. However, the molecular determinants underpinning CD pathogenesis are yet to be fully elucidated and little data are available about the involvement of miRNAs (microRNAs) in CD. In the present study, the duodenal mucosa miRNA expression was profiled in adult untreated CD presenting with a classic phenotype or iron-deficiency anaemia, treated patients with or without duodenal normalization, and non-CD subjects as controls. Deregulation of seven miRNAs (miR-31-5p, miR-192-3p, miR-194-5p, miR-551a, miR 551b-5p, miR-638 and miR-1290) was determined in a larger series of CD patients with different clinical phenotypes compared with non-CD subjects. These seven microRNAs were then analysed in duodenal fibroblasts obtained from CD patients and incubated with gliadin peptides (13- and 33-mer). The miRNA cluster miR 192/194, involved in matrix remodelling, was deregulated in CD according to the different clinical presentations, and miR-192-3p levels were modulated by gliadin peptides in vitro. In conclusion, the analysis of miRNAs deserves further consideration for its potential use in the treatment and management of CD. PMID- 24063612 TI - Immunoassay for lead ions: analysis of spiked food samples. AB - A rapid, simple, and reliable competitive immunoassay was developed for measurement of lead ions in spiked food samples. Avian antibodies were produced against Pb(II). Since lead ions are too small to elicit an immune response, the metal was coupled to protein carrier Bovine Serum Albumin (BSA) using a bifunctional chelator 1-(4-isothiocyanobenzyl) ethylenediamine N,N,N',N' tetraacetic acid (ITCBE). Poultry birds (layers) were immunized with this Pb(II) ITCBE-BSA immunoconjugate and avian antibodies (IgY) were isolated from egg yolk. This avian antibody (IgY) produced recognized Pb(II)-ITCBE complexes as capture reagent. The assay depended on a competitive binding reaction between the antibody and Pb(II). Antibody reaction was optimized for different concentrations of antigen and antibody dilutions. Cross reactivity with other metals were below 1% in competitive ELISA. The detection range and the detection limit were 0.02 1000 mg . kg-1 and 0.2 mg . kg-1, respectively. Spike recovery studies in different food samples showed that the avian antibodies could recognize Pb(II) in food samples without much matrix effect. PMID- 24063613 TI - In vitro neutralization of HCV by goat antibodies against peptides encompassing regions downstream of HVR-1 of E2 glycoprotein. AB - This article aims at testing several in vitro systems with various viral sources and cell lines for propagation of HCV to evaluate goat antibodies raised against three E2 epitopes in viral neutralization experiments. Four human cell lines (Huh 7, Huh-7.5, HepG2, and CaCo2) were tested using two different HCV viral sources; Genotype 4 infected sera and J6/JFH HCV cc particles. Neutralization capacity of goat Abs against conserved E2 epitopes; p412 (a.a 412-419), p517 (a.a 517-531), and p430 (a.a 430-447) were examined in the above mentioned in vitro systems. Although infection with patients' sera seems to mimic the in vitro situation, it has limited replication rates as compared with HCV cc particularly in Huh7.5 cells. Non-HCV adapted Huh-7 cells were also found susceptible for transfection with J6/JFH virus but at much slower kinetics. The results of the neutralization assay showed that anti p412 and anti p517 were highly neutralizing to HCVcc. Our data demonstrate that antibodies directed against the viral surface glycoprotein E2 reduced the infectivity of the J6/JFH virus and are promising agents for immunotherapy and HCV vaccine development. PMID- 24063614 TI - The in vitro effects of artificial and natural sweeteners on the immune system using whole blood culture assays. AB - This article investigates the effects of commercially available artificial (aspartame, saccharin, sucralose) and natural sweeteners (brown sugar, white sugar, molasses) on the immune system. Human whole blood cultures were incubated with various sweeteners and stimulated in vitro with either phytohemagglutinin or endotoxin. Harvested supernatants were screened for cytotoxicity and cytokine release. Results showed that none of the artificial or natural sweeteners proved to be cytotoxic, indicating that no cell death was induced in vitro. The natural sweetener, sugar cane molasses (10 ug/mL), enhanced levels of the inflammatory biomarker IL-6 while all artificial sweeteners (10 ug/mL) revealed a suppressive effect on IL-6 secretion (P < 0.001). Exposure of blood cells to sucralose containing sweeteners under stimulatory conditions reduced levels of the biomarker of humoral immunity, Interleukin-10 (P < 0.001). The cumulative suppression of Interleukin-6 and Interleukin-10 levels induced by sucralose may contribute to the inability in mounting an effective humoral response when posed with an exogenous threat. PMID- 24063615 TI - Tylosin content in meat and honey samples over a two-year period in Croatia. AB - A total of 646 meat and 96 honey samples were examined over a 2-year period for the presence of tylosin residues. ELISA method used was validated according to the criteria of Commission Decision 2002/657/EC established for qualitative screening methods. The CCbeta values were 32.1 ug kg-1 in muscle and 24.4 ug kg-1 in honey. The recoveries from spiked samples ranged from 66.4-118.6%, with a coefficient of variation between 12.6% and 18.6%. All the investigated samples showed no presence of tylosin. Calculated estimated daily intakes show exposure levels lower than the acceptable daily intakes set by World Health Organization. PMID- 24063616 TI - PSMA/PSA ratio evaluated by immunohistochemistry may improve diagnosis of prostate cancer. AB - Prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) measured in serum are not fully satisfactory as biomarkers of prostate cancer (PC). Results obtained in this article indicated that PSMA/PSA ratio evaluated by immunohistochemistry in normal prostate (NP), benign prostatic hyperplasia (BPH), and PC at the individual level could be a useful tool for diagnosis and prognosis of PC. PSMA and PSA were equally expressed in NP and the PSMA/PSA ratio was 1.22 +/- 0.15. Data also indicated that PSMA/PSA ratio fluctuates in BPH and PC compared to NP. In BPH, the PSMA/PSA ratio was around 0.47 +/- 0.02, whereas it's significantly increased in PC, about 4.95 +/- 0.83. In parallel, the highest PSMA/PSA ratio was associated with high intratumoral angiogenesis in PC patients with (PSMA+,PSA+) profile. PMID- 24063617 TI - Mouse monoclonal antibody towards e1 specific epitope blocks viral entry and intracellular viral replication in vitro. AB - We characterized viral neutralization by a murine monoclonal antibody (mAb315) developed against conserved E1 specific epitope aa 315-323 at pre- and post binding steps of infection into Huh7 cells. Detection of native virus in infected Huh7 cells by mAb315 were demonstrated by immunostaining. Inhibitions of viral entry by three different concentrations of mAb315 were measured by intracellular amplification of HCV RNA post infection. HCV RNA positive sera from 24 patients were used to infect Huh7 cell line in absence or presence of mouse monoclonal antibody produced in Balb/c mice or culture supernatant of mouse hybrid cells. Monoclonal Ab mAb315 could detect synthetic peptide p315 adsorbed on peripheral human lymphocytes by flow cytometry and showed high immuno reactivity to E1 viral antigen in infected Huh7 cells by immunostaining. Antibody-mediated neutralization assays demonstrated the ability of mAb315 to block HCV binding/entry to target cells at 0.73 mg/mL ascitic fluid or 250 ug/mL culture supernatant of mouse hybrid cells. Sixteen of 24 infected sera could infect Huh7 cells (67%). Binding/entry of HCV was completely blocked by mAb315 in 11/16 cases (69%). These findings suggest that mAb315 can induce HCV neutralization in vitro, which makes it a candidate for developing HCV therapeutic antibodies. PMID- 24063618 TI - Relevance of molecular tests for HTLV-1 infection as confirmatory tests after the first sero-screening. AB - The diagnosis of human T-cell leukemia virus type-1 (HTLV-1) infection has been widely examined by serologics. In the first screening tests, serological false negative and positive samples have been reduced thanks to advances in assay techniques that apply new emission agents and sensors. On the other hand, western blot (WB) remains problematic. For example, WB analysis yields many samples equivalent to antibody positive ones. To reduce the need for WB, an alternative testing strategy is required to detect HTLV-1 infection. Polymerase chain reaction (PCR) for the HTLV-1 provirus has recently been recommended for a final diagnosis of infection. However, although PCR is thought to be one element, the validation of detection performance for HTLV-1 infection between serological and molecular testing is not always clear. Thus, this study aimed to evaluate the accuracy and test the validity of an improved methodology for serological detection of HTLV-infection, as well as that of PCR. In conclusion, the high values of kappa-statistics are expected to deliver high quality in chemiluminescent enzyme immunoassay (or chemiluminescent immunoassay), while the problems with WB assays remain to be elucidated. As an alternative to WB, a combination of real-time qPCR and nested PCR is proposed as a suitable confirmatory test. PMID- 24063619 TI - Advantageous sensitivity in the DNA homolog of the RNA dopamine aptamer. AB - A competitive enzyme-linked aptamer assay for DA was performed by using two aptamers, individually; one is a 57 mer-RNA aptamer and the other is its homolog DNA aptamer. The difference between the RNA aptamer and the DNA aptamer are based on their particular nucleotides. It is known that the lack of a hydroxyl group in the 2' position of DNA is related with its chemical and biological stability. Thus, the use of the DNA homolog of the RNA aptamer could improve the affinity toward DA due to stability and finally, lower the detection limit. In this paper, we report advantageous sensitivity and specificity of its homolog DNA aptamer assay as compared to the RNA aptamer assay. Both aptamer assays were performed with 0.01 ug mL-1 of each aptamer and 1.205 * 10-8 M DA-HRP conjugate using the optimized method. A dose-response curve was constructed, and the limit of detection for the DA was determined as 6.3 * 10-8 M for RNA aptamer assay, and 3.2 * 10-12 M for the homolog DNA aptamer assay, respectively. These results demonstrated that the assay sensitivity was more than 104 times improved with the DNA homolog of the RNA aptamer compared to its original RNA aptamer obtained through SELEX process. Also these results confirmed that the DNA homolog of the RNA aptamer can maintained the binding site and retained a function in both structure. Thus, the switching to the DNA version of RNA aptamer is possible to bind more stably and still able to bind to dopamine. PMID- 24063620 TI - Investigation of the relation between anaerobic bacteria genus clostridium and late-onset autism etiology in children. AB - The aim of this study was to investigate the relation between the etiology of late-onset childhood autism and anaerobic bacteria. Thirty children diagnosed with autistic disorder and control group have been included in the study. 3-(3 hydroxy phenyl)-3-hydroxypropionic acid (HPHPA) excretion rates which is a metabolic product of the genus Clostridium, were measured via mass spectrometry gas chromatography (MS-GC) method from urine samples. When the assayed average HPHPA values compared with each group, a statistically significant difference was found (p < 0.05). Data obtained from this study support the existence of a significant correlation between autism etiology and anaerobic bacteria. PMID- 24063621 TI - Potential for novel MUC1 glycopeptide-specific antibody in passive cancer immunotherapy. AB - MUC1 is an important target for antibodies in passive cancer immunotherapy. Antibodies against mucin glycans or mucin peptide backbone alone may give rise to cross reactivity with normal tissues. Therefore, attempts to identify antibodies against cancer-specific MUC1 glycopeptide epitopes havebeen made. We recently demonstrated that a monoclonal antibody against the immunodominant Tn-MUC1 (GalNAc-alpha-MUC1) antigen induced ADCC in breast cancer cell lines, suggesting the feasibility of targeting combined glycopeptide epitopes in future passive cancer immunotherapy. PMID- 24063622 TI - Associations of sedentary behavior and physical activity with psychological distress: a cross-sectional study from Singapore. AB - BACKGROUND: Emerging evidence suggests the adverse association between sedentary behaviour (SB) with physical and mental health, but few studies have investigated the relationship between volume of physical activity and psychological distress. The present study examined the independent and interactive associations of daily SB and weekly level of moderate to vigorous physical activity (MVPA) with psychological distress in a multi-ethnic Asian population. METHODS: De-identified data of 4,337 adults (18-79 years old) on sedentary behaviors, physical activity patterns, psychological distresses, and other relevant variables were obtained from the Singapore Ministry of Health's 2010 National Health Survey. Psychological distress was assessed using General Health Questionnaire-12 (GHQ 12), whereas total daily SB and total weekly volume (MET/minutes) of MVPA were estimated using the Global Physical Activity Questionnaire version 2 (GPAQ v2). Multivariate logistic regression analyses were carried out to estimate the odds ratios (95% confidence intervals) of the independent and interactive relationships of SB and MVPA with prevalence of psychological distress. RESULTS: The category of high SB was positively associated with increased odds (OR = 1.29, 1.04-1.59) for psychological distress, whereas the category of active was inversely associated with lower odds (OR = 0.73, 0.62-0.86) for psychological distress. Multivariate analyses for psychological distress by combined daily SB and weekly MVPA levels showed inverse associations between middle SB and active categories (OR = 0.58, 0.45 - 0.74) along with low SB and active categories (OR = 0.61, 0.47-0.80). CONCLUSIONS: The present population-based cross-sectional study indicated that in the multi-ethnic Asian society of Singapore, a high level of SB was independently associated with psychological distress and meeting the recommended guidelines for physical activity along with <= 5 h/day of SB was associated with the lowest odds of psychological distress. PMID- 24063623 TI - Effect of simultaneous inhibition of starch branching enzymes I and IIb on the crystalline structure of rice starches with different amylose contents. AB - Mutating or inhibiting genes encoding starch branching enzymes (SBEs) can increase the amylose content (AC) of cereals. We analyzed endosperm starches from three rice cultivars with different ACs and from transgenic lines derived from them. The transgenic lines had simultaneously inhibited SBE I and IIb genes. Compared with the starch from their wild-type parents, the starch from transgenic lines showed significantly increased apparent ACs and lamella size and decreased relative crystallinity, double helix content, and lamellar peak scattering intensity, and altered short-range ordered structure in the external region. These changes were more prominent in the line derived from the high-AC cultivar than in those derived from waxy and low-AC cultivars. Inhibiting both SBE I and IIb changed the crystalline structure of starch from A-type to CA-type in lines derived from waxy and low-AC cultivars, and from A-type to C-type in that derived from the high-AC cultivar. PMID- 24063624 TI - Safety and efficacy of statin treatment alone and in combination with fibrates in patients with dyslipidemia: a meta-analysis. AB - BACKGROUND: Dyslipidemia is a major risk factor for cardiovascular disease and is treated with many effective lipid-lowering agents. Statins are often used alone or in combination with fibrates. Combination therapy is more effective due to their comparative actions, but the increased incidence of side effects should be considered carefully. RESEARCH DESIGN AND METHODS: A meta-analysis of published data was conducted to compare the safety and efficacy of statins alone versus statins plus fibrates in patients with dyslipidemia. In total, nine articles were assessed for efficacy analysis and ten articles were assessed for safety analysis. RESULTS: In the efficacy analysis, a combination of statins and fibrates provided significantly greater reductions in total cholesterol (SE = 0.430; 95% CI 0.315-0.545), LDL cholesterol (SE = 0.438; 95% CI 0.321-0.555) and triglycerides (SE = 0.747; 95% CI 0.618-0.876), and a significantly greater increase in HDL cholesterol (SE = 0.594; 95% CI 0.473-0.715) than treatment with statins alone. In the safety analysis, treatment with statins alone was associated with a significant reduction in the numbers of total adverse events (RR = 0.665; 95% CI 0.539-0.819), liver-related adverse events (RR = 0.396; 95% CI 0.206-0.760) and kidney-related adverse events (RR = 0.146; 95% CI 0.075 0.285). CONCLUSION: We suggest that treatment with statins plus fibrates provides clinical benefits over treatment with statins alone but increased risks, especially of hepatic or renal side effects, should be monitored carefully. PMID- 24063625 TI - Pluripotent reprogramming and lineage reprogramming: promises and challenges in cardiovascular regeneration. AB - Cardiovascular disease is a leading cause of death in industrialized countries. Scientists are trying to generate cardiomyocytes in vitro and in vivo to repair damaged heart tissue. Pluripotent reprogramming brings an alternative source of embryonic-like stem cells, and the possibility of regenerating mammalian tissues by first reverting somatic cells to induced pluripotent stem cells, followed by redifferentiating these cells into cardiomyocytes. More recently, lineage reprogramming of fibroblasts directly into functional cardiomyocytes has been reported. The procedure does not involve reverting cells back to a pluripotent stage, and, thus, would presumably reduce tumorigenic potential. Interestingly, lineage reprogramming could be used for in situ conversion of cell fate. Moreover, zebrafish-like regenerative mechanism in mammalian heart tissue, which was observed in mice within the first week of postpartum, should be further addressed. Here, we review the landmark progresses of the two major reprogramming strategies, compare their pros and cons in cardiovascular regeneration, and forecast the future directions of cardiac repair. PMID- 24063626 TI - Evaluation of the ability of C. albicans to form biofilm in the presence of phage resistant phenotypes of P. aeruginosa. AB - Pseudomonas aeruginosa and Candida albicans are disparate microbial species, but both are known to be opportunistic pathogens frequently associated with nosocomial infections. The aim of this study was to provide a better understanding of the interactions between these microorganisms in dual-species biofilms. Several bacteriophage-resistant P. aeruginosa phenotypes have been isolated and were used in dual-species mixed-biofilm studies. Twenty-four and 48 h mixed-biofilms were formed using the isolated phenotypes of phage-resistant P. aeruginosa and these were compared with similar experiments using other P. aeruginosa strains with a defined lipopolysaccharide (LPS) deficiency based on chromosomal knockout of specific LPS biosynthetic genes. Overall, the results showed that the variants of phage-resistant P. aeruginosa and LPS mutants were both less effective in inhibiting the growth of C. albicans in mixed-biofilms compared to the wild-type strains of P. aeruginosa. Conversely, the proliferation of P. aeruginosa was not influenced by the presence of C. albicans. In conclusion, the ability of strains of P. aeruginosa to inhibit the formation of a biofilm of C. albicans appears to be correlated with the LPS chain lengths of phenotypes of P. aeruginosa, suggesting that LPS has a suppressive effect on the growth of C. albicans. PMID- 24063627 TI - The development and predictive value of gestures in very-low-birth-weight children: a longitudinal study. AB - The present study analysed the development of gestures between 0;9-1;3 years, and the predictive value of this development for language skills at 2;0 in very-low birth-weight (VLBW) children. Participants were 32 VLBW children and their 35 controls. The data on gestures was gathered using the Finnish version of the Communicative Development Inventory (FinCDI). At 2;0, the language skills of the children were assessed using the Reynell Developmental Language Scales (RDLS III) and the FinCDI. The number of acquired gestures was lower in the VLBW children than in the controls. The development of gestures correlated significantly with later expressive language in both groups, but significant correlations between the development of gestures and later receptive language development were detected only in the VLBW group. When the predictive value of gestures and early expressive and receptive lexicon with regard to later language skills were analysed, the development of gestures at 1;3 had good predictive value for poor language performance at 2;0. In addition, a small receptive lexicon size at 1;0 and at 1;3 was also a good predictor for later language performance. The development of gestures and receptive lexicon thus jointly provide clinically valuable information on the emerging language skills of VLBW children. PMID- 24063628 TI - The 100 top-cited classic papers in hand surgery. AB - The number of citations that a published article has received reflects the importance that paper has on that area of practice. In hand surgery, it is unknown which journal articles are cited most frequently. The purpose of this study was to identify and analyze the characteristics of the top 100 papers in the field of hand surgery. The 100 most cited papers were identified in the following journals; the Journal of Hand Surgery (American volume), the Journal of Hand Surgery (European volume), the Journal of Hand Surgery (British and European volume), The Scandinavian Journal of Plastic and Reconstructive and Hand Surgery, Hand Clinics, and the Journal of Plastic Surgery and Hand Surgery. The articles were ranked in order of the number of citations received. These classic 100 papers were analyzed for article type, their journal distribution, as well as geographic and institutional origin. PMID- 24063629 TI - Cu-catalyzed fluorination of diaryliodonium salts with KF. AB - A mild Cu-catalyzed nucleophilic fluorination of unsymmetrical diaryliodonium salts with KF is described. This protocol preferentially fluorinates the smaller aromatic ligand on iodine(III). The reaction exhibits a broad substrate scope and proceeds with high chemoselectivity and functional group tolerance. DFT calculations implicate a Cu(I)/Cu(III) catalytic cycle. PMID- 24063631 TI - Bilateral optic neuritis--the only ocular finding in a case of subacute sclerosing panencephalitis. AB - Subacute sclerosing panencephalitis is a rare disease of central nervous system caused by defective measles virus. Chorioretinitis with macular involvement is the mostly observed ocular finding in the disease. Other reported ocular findings in the disease are cortical blindness, hemianopsia, nystagmus, extraocular muscle paresis and optic atrophy. We present a rare case of subacute sclerosing panencephalitis with isolated bilateral optic neuritis as the only ocular finding without macular involvement. PMID- 24063630 TI - Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. AB - BACKGROUND: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S. METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites. RESULTS: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 * 10-15), versus 3/9 in AA (p= 0.03 to 6 * 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only. CONCLUSIONS: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium. PMID- 24063632 TI - Protein Ser/Thr phosphatase-6 is required for maintenance of E-cadherin at adherens junctions. AB - BACKGROUND: Epithelial tissues depend on intercellular homodimerization of E cadherin and loss of E-cadherin is central to the epithelial to mesenchymal transition seen in multiple human diseases. Signaling pathways regulate E cadherin function and cellular distribution via phosphorylation of the cytoplasmic region by kinases such as casein kinases but the protein phosphatases involved have not been identified. RESULTS: This study shows protein Ser/Thr phosphatase-6 catalytic subunit (PP6c) is expressed in epithelial tissue and its mRNA and protein are robustly up-regulated in epithelial cell lines at high vs. low density. PP6c accumulates at adherens junctions, not tight junctions, co immunoprecipitates with E-cadherin-catenin complexes without a canonical SAPS subunit, and associates directly with the E-cadherin cytoplasmic tail. Inducible shRNA knockdown of PP6c dispersed E-cadherin from the cell surface and this response was reversed by chemical inhibition of casein kinase-1 and prevented by alanine substitution of Ser846 in murine E-cadherin. CONCLUSIONS: PP6c associates with E-cadherin in adherens junctions and is required to oppose casein kinase-1 to maintain cell surface localization of E-cadherin. There is feedback signaling to enhance PP6c transcription and boost protein levels in high density epithelial cells. PMID- 24063633 TI - Thailand special recruitment track of medical students: a series of annual cross sectional surveys on the new graduates between 2010 and 2012. AB - BACKGROUND: Comprehensive policies for rural retention of medical doctor and other health professional, including education strategy and mandatory service, have been implemented in Thailand since the 1970s. This study compared the rural attitudes, intention to fulfil mandatory rural service and competencies between medical graduates' from two modes of admission, normal and special tracks. METHODS: Three cross-sectional, self-administered questionnaire surveys were conducted in April 2010, 2011 and 2012. The questionnaire was distributed to all new medical graduates in the annual Ministry of Public Health meeting to allocate workplaces for the 3-year mandatory service. FINDINGS: The majority of students were recruited through the normal track (56 to 77%) from medical schools in Bangkok (56 to 66%), having mostly attended secondary schools in Bangkok. A majority of special track graduates came from secondary schools in provincial cities (76 to 79%). All three batches came from well-educated parents.A slight difference in rural attitudes was observed between tracks. Univariable analysis found statistical associations between the intention to fulfil the 3-year obligation and special track recruitment and attributes on rural exposure. Multivariable analysis showed that graduates recruited through the special track had a 10 to 15% higher probability of fulfilling the mandatory service.Special track graduates scored higher on four out of five competencies, notably procedural skills, but normal track graduates had higher competency on clinical knowledge in major clinical subjects. CONCLUSION: Since special track recruitment resulted in a higher probability of fulfilling mandatory service and competency, increasing the proportion of special track recruitment and improving the effectiveness of policies addressing physician shortage were recommended. PMID- 24063634 TI - Problems and solutions to filling the drying drug pipeline for psychiatric disorders: a report from the inaugural 2012 CINP Think Tank. AB - The inaugural Collegium Internationale Neuro-Psychopharmacologicum (CINP) Think Tank, a small open meeting sponsored by the CINP, discussed impediments to developing new drugs for psychiatric disorders and approaches to overcome these impediments. Whilst neuropsycharmacology has a rich pharmacopeia (current treatments benefiting many individuals), issues of treatment resistance, sub optimal response and unwanted side effects remain problematic. Many scientific, economic and social issues are impeding the development of drugs (e.g. higher risk of failure, placebo effects, problematic regulatory environments, pressures imposed by patent protection, downward pressure on reimbursements and financial, legal and social risk aversion). A consensus of the meeting was that efforts to understanding the core pathophysiology of psychiatric disorders are fundamental to increasing the chance of developing new drugs. However, findings from disorders such as Huntington's chorea, have shown that knowing the cause of a disorder may not reveal new drug targets. By contrast, clinically useful biomarkers that define target populations for new drugs and models that allow findings to be accurately translated from animals to humans will increase the likelihood of developing new drugs. In addition, a greater accent on experimental medicine, creative clinical investigations and improved communication between preclinical neuropsychopharmacologists, clinicians committed to neuropsychopharmacological research, industry and the regulators would also be a driver to the development of new treatments. Finally, it was agreed that the CINP must continue its role as a conduit facilitating vibrant interactions between industry and academia as such communications are a central component in identifying new drug targets, developing new drugs and transitioning new drugs into the clinic. PMID- 24063635 TI - Efficacy and tolerability of lanthanum carbonate in treatment of hyperphosphatemia patients receiving dialysis--a systematic review and meta analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the efficacy and tolerability of lanthanum carbonate (LC) in the treatment of hyperphosphatemia in dialysis patients. METHOD: Multiple databases were used to recruit the published clinical randomized controlled trials (RCTs) comparing LC with placebo for hyperphosphatemia in dialysis patients from inception to March 2013. Results were expressed using standardized mean difference (SMD) for continuous variables and pooled odd ratios (OR) for dichotomous outcomes. Study quality was assessed according to Cochrane Handbook 5.1 guidelines and statistical analysis was performed using RevMan 5.2 software. RESULTS: A total of 950 patients in seven placebo-controlled RCTs were included. Results showed that LC could effectively controlled hyperphosphatemia compared with placebo (SMD -1.06, 95% CI -1.27- -0.86, P < 0.00001). The proportion of subjects reaching the target in the LC group was higher than that in the placebo group (OR 6.88, 95% CI 4.39-10.78, P < 0.00001). LC-treated patients showed less change in serum PTH and Ca * Pi product from baseline compared to the placebo group (SMD -0.21, 95% CI -0.48-0.06, P = 0.007; SMD -0.90, 95% CI -1.13- -0.66, P < 0.00001, respectively). LC-treated patients experienced more side-effects, like vomiting and nausea, than controls (OR 3.10, 95% CI 1.35-7.08, P = 0.007; OR 2.74, 95% CI 1.22-6.19, P = 0.02, respectively). But overall, the incidence of drug-related adverse events was similar between placebo- and LC-treated patients (OR 1.21, 95% CI 0.66-2.22, P = 0.54). CONCLUSION: In the treatment of hyperphosphatemia in dialysis patients, LC is well tolerated and more effective than placebo during short-term trials. Furthermore, it helps to maintain PTH and Ca * Pi product levels within recommended ranges. LC is an ideal choice for second-line treatment of hyperphosphatemia after therapy failure or other contraindication for calcium agents. Its long-term security still needs further research. PMID- 24063636 TI - Solution-processed Fe3O4 magnetic nanoparticle thin film aligned by an external magnetostatic field as a hole extraction layer for polymer solar cells. AB - We report, for the first time, the effect of a solution-processed Fe3O4 magnetic nanoparticle (MNP) thin film and a Fe3O4 MNP thin film aligned by an external magnetostatic field, used as a hole extraction layer (HEL), respectively, in polymer solar cells (PSCs). The thin film of a Fe3O4 MNP shows a smoother surface, better transparency, and higher electrical conductivity than that of a poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) thin layer. Moreover, the thin film of a Fe3O4 MNP aligned by an external magnetostatic field possesses an enhanced electrical conductivity and lower internal series resistance, thus leading to greater than 13% enhancement in the power conversion efficiency of PSCs than those using a PEDOT:PSS thin film. It was also found that PSCs incorporated with a Fe3O4 MNP shows better stability compared with those using PEDOT:PSS as an anode buffer layer. These results demonstrated that utilization of a Fe3O4 MNP as a HEL in PSCs blazes a trail to achieve highly efficient and long-time-stable devices. PMID- 24063637 TI - Tolerance of the invasive tunicate Styela clava to air exposure. AB - Styela clava is a subtidal invasive marine species in Northern Europe, Atlantic Canada, Australia and New Zealand. It grows attached to solid substrata, including boat hulls, ropes, moorings, piers and aquaculture equipment, all of which can aid its spread to new locations. It interferes with feeding of mussels and oysters, and increases their harvesting costs. Being subtidal, it could be assumed that tunicates would rapidly die in air and thus exposure to air would be a practical method to prevent their spread on boats and equipment. This study tested their survival when exposed to air for up to (1) 120 h at a constant temperature of 10 degrees C, (2) shade ambient 15-27 degrees C, and (3) full sun ambient 15-29 degrees C. Humidity was consistently high (78-100%). The results indicated that survival was longer when the air temperature was cooler. Larger individuals of S. clava generally survived for longer out of seawater than smaller individuals. The results predict that two weeks of exposure to air for two weeks could be an effective management method to eradicate S. clava from marine equipment when the air temperature is 10 degrees C. However, drying time would be less under conditions of low humidity and under direct sunlight. PMID- 24063638 TI - Mechanism of iron carbonyl-catalyzed hydrogenation of ethylene. 1. Theoretical exploration of molecular pathways. AB - The hydrogenation of alkenes catalyzed by metal carbonyls is an intricate process involving reactions of various isomers of labile pi- and sigma-complexes, hydrides, dihydrides, and their radicals. Two general mechanisms have been suggested in the literature regarding the catalytic hydrogenation of simple alkenes by photochemically activated iron pentacarbonyl: a molecular mechanism that involves the sequential replacement of two carbonyl ligands by hydrogen and unsaturated ligands, and a radical mechanism involving the EPR-identified iron carbonyl hydride radicals. Even though significant results were obtained in numerous experiments and few theoretical studies, these mechanisms remain phenomenological, without detailed information regarding the potential energy surfaces (PES) and the elementary processes. Several major issues also remain open. It is still unclear, for instance, whether the ethane can be formed via a monomolecular reaction of ethyl hydride isomer intermediates HFe(CO)3(C2H5) or the only way to produce C2H6 is a bimolecular reaction assisted by a second ethylene. It is also uncertain if a dihydride or a dihydrogen complex is operating in olefin hydrogenation. To gain insight into these processes, a detailed theoretical examination of various PES for gas-phase reactions of ethylene with potential metallocomplex reagents to primary and secondary products (both singlet and triplet electronic states) was performed using DFT and ab initio methods. Calculations have been carried out for a set of reactions of ethylene with all possible isomers of tricarbonyliron hydrogenates, viz., dihydrides of trans-, cis-, and gauche-configurations (isomers with respect to the two hydridic atoms), and two nonclassical singlet and two triplet dihydrogen complexes, some of them being identified for the first time. The hydrogenation pathways (both molecular and radical) are shown to be strongly stereoselective and dependent on the spin configurations of the initial reagents. The combination of various dihydride isomers with C2H4 as separate reaction channels allowed us to explore relevant PES cross sections and to identify corresponding stereoregulated elementary processes. The reaction channels can alternatively start from the association of ethylene with dihydrogen tricarbonyliron complexes and may involve intersystem crossings with triplet pathways, followed by that of the corresponding singlet PES. Various interconversion and isomerization processes involving single-olefin adducts were found to precede the major ethane elimination reactions (through both monomolecular and second-ethylene-assisted pathways). Monomolecular processes are suggested to occur under appropriate conditions. The stereospecific mechanistic results and thermochemical parameters constitute a basis for developing detailed kinetic models for iron-carbonyl catalysis. PMID- 24063640 TI - Shear-induced structures and thickening in fumed silica slurries. AB - Chemical mechanical polishing (CMP) is an essential technology used in the semiconductor industry to polish and planarize a variety of materials for the fabrication of microelectronic devices (e.g., computer chips). During the high shear (~1,000,000 s(-1)) CMP process, it is hypothesized that individual slurry particles are driven together to form large agglomerates (>=0.5 MUm), triggering a shear thickening effect. These shear-induced agglomerates are believed to cause defects during polishing. In this study, we examined the shear thickening of a 25 wt % fumed silica slurry with 0.17 M added KCl using in situ small-angle light scattering during rheological characterization (rheo-SALS). The salt-adjusted slurry displays a ~3-fold increase in viscosity at a critical shear rate of 20,000 s(-1) during a stepped shear rate ramp from 100 to 25,000 s(-1). As the shear rate is reduced back to 100 s(-1), the slurry displays irreversible thickening behavior with a final viscosity that is 100-times greater than the initial viscosity. Corresponding rheo-SALS images indicate the formation of micrometer scale structures (2-3 MUm) that directly correlate with the discontinuous and irreversible shear thickening behavior of the fumed silica slurry; these micrometer scale structures are 10-times the nominal particle diameter (~0.2 MUm). The scattering patterns from the 25 wt % slurry were corroborated through rheo-SALS examination of 27 and 29 wt % slurries (C(KCl) = 0.1 M). All slurries, regardless of ionic strength and solids loading, display scattering patterns that are directly associated with the observed thickening behavior. Scattering was only observable during and after thickening (i.e., no scattering was detected in the absence of thickening). This work serves as the first in situ observation of micrometer scale structures within the fumed silica CMP slurry while under shear. PMID- 24063639 TI - The mini-gastric bypass in the management of morbid obesity in Prader-Willi syndrome: a viable option? AB - AIMS: To test the efficacy of the mini-gastric bypass (MGB) in the treatment of morbid obesity related to the Prader-Willi Syndrome (PWS). PATIENTS AND METHODS: Three young male patients (mean age 15.6 years) complaining with PWS were treated by MGB with the aim to improve morbid obesity associated with the syndrome. Preoperative body mass index was 51 +/- 4.13 kg/m(2). Two patients suffered from both hypertension and frequent sleep apnea crises. The mean preoperative level of fasting plasma acyl ghrelin was 1417.26 +/- 289.37 pg/ml. All patients underwent a laparoscopic MGB. RESULTS: The postoperative period was uneventful and all patients were discharged on the fifth postoperative day. The patients suffering from both hypertension and respiratory crises are now free from receiving any therapeutic support. When measured, the postoperative level of fasting plasma acyl ghrelin decreased to 675.5, 524.6, and 353.1 pg/ml, respectively. An excess weight loss of 79% has been recorded at two years so far. To date, no nutritional impairment, weight regain, or need for revision surgery has been recorded. CONCLUSION: MGB appears to provide an effective weight reduction in patients suffering from PWS without determining significant nutritional impairment or weight regain. Larger studies are however required. PMID- 24063641 TI - Fluorescence approach for measuring anthocyanins and derived pigments in red wine. AB - A novel fluorescence approach to monitor the evolution of anthocyanins and derivatives in red wine was developed. Some red table wines and Port wine with different vintage years were first tested with the aim to determine the ideal fluorescent conditions. The fluorescence contribution of both monomeric and polymeric anthocyanins was studied by comparing their emission spectra. By measuring the F700/F560 ratio on different wine samples and applying an inverted exponential function, it was possible to estimate the monomeric/polymeric anthocyanin absorbance ratio that is proportional to the relative content of the two classes of compounds. The methodology was further developed by using pure compounds representative of monomeric anthocyanins and anthocyanin-pyruvic acid adducts, namely, by using malvidin-3-O-glucoside and vitisin A. A fluorescence excitation ratio (FER350/550) was considered for estimating the absorbance ratio between vitisin A and malvidin-3-O-glucoside. Overall, this work aims to use fluorescence to monitor the evolution of anthocyanin derivatives and to distinguish them from their anthocyanin precursors, thereby allowing the evolution of anthocyanin pigments during wine aging to be monitored, but it also may be useful to determine age markers or even geographical markers. PMID- 24063642 TI - The "BIG BIRD" of the "YELLOW YOUNG" man: do nontarget properties cascade? AB - This study investigated whether in speech production object properties flow in a cascaded manner or whether cascaded processing is restricted to the object's identity. In Experiments 1 and 2, participants saw pictured objects and had to state either their size (GRAND or PETIT-meaning big and small) or their name. The size of the objects varied as a function of the way they were presented on the computer screen (Experiment 1) or their real size in the world (Experiment 2). In Experiment 3, faces of young and old men were coloured in yellow or in green. The task was to name either the colour (JAUNE or VERT, meaning yellow and green, respectively) or the age (JEUNE or VIEUX, meaning young and old, respectively) of the face. In Experiments 1 and 2, no reliable effects of phonological relatedness ("GORILLE-grand"-a big gorilla) were found on the object-naming latencies. However, size-naming latencies were shorter when the adjective shared the initial phoneme of the picture name (i.e., "GRAND-gorille") than when it did not (i.e., "GRAND-dinosaure"-saying "big" in response to a big dinosaur). In Experiment 3, phonological overlap did not affect colour naming latencies, or age naming latencies. Overall, these findings strongly suggest that cascaded processing is restricted to the object's identity in conceptually driven naming tasks. PMID- 24063643 TI - Sulfoxide-directed enantioselective synthesis of functionalized tetrahydropyridines. AB - The highly selective base-promoted cyclization of enantiopure sulfinyl dienamines provides stereodefined sulfinyl 1,2,3,6-tetrahydropyridines (dr up to 99:1). Subsequent sigmatropic rearrangement affords tetrahydropyridin-3-ols in good yields and selectivities. PMID- 24063644 TI - Preventive effect of nucleoprotein on hindlimb unloading-induced capillary regression in rat soleus muscle. AB - We investigated the preventive effects of nucleoprotein on capillary regression and mitochondrial dysfunction induced by unloading in the soleus muscle of rats. Nucleoprotein is a supplement made from soft roe of salmon, and its major components are nucleotides and protamine. Adult male Sprague-Dawley rats were divided randomly into control, hindlimb unloading (HU), and hindlimb unloading plus nucleoprotein administration (HU+ NP) groups. Hindlimb unloading was carried out for 2 weeks in the rats belonging to the HU and the HU+ NP groups. The rats of the HU+ NP group were administered nucleoprotein (500 mg/kg) using a feeding needle twice a day for 2 weeks. Hindlimb unloading resulted in capillary regression, decreased succinate dehydrogenase activity of the muscle fiber, and decreased PGC-1alpha expression in the soleus muscle. These effects were prevented by administration of nucleoprotein. Nucleoprotein appears to prevent capillary regression and mitochondrial dysfunction caused by unloading of the skeletal muscle. Therefore, nucleoprotein supplementation may be an effective therapy for maintaining capillary network and mitochondrial metabolism of the muscle fiber during an unloading period. PMID- 24063645 TI - Classification and phylogeny of sika deer (Cervus nippon) subspecies based on the mitochondrial control region DNA sequence using an extended sample set. AB - To further refine the classification and phylogeny of sika deer subspecies, the well-annotated sequences of the complete mitochondrial DNA (mtDNA) control region of 13 sika deer subspecies from GenBank were downloaded, aligned and analyzed in this study. By reconstructing the phylogenetic tree with an extended sample set, the results revealed a split between Northern and Southern Mainland Asia/Taiwan lineages, and moreover, two subspecies, C.n.mantchuricus and C.n.hortulorum, were existed in Northern Mainland Asia. Unexpectedly, Dybowskii's sika deer that was thought to originate from Northern Mainland Asia joins the Southern Mainland Asia/Taiwan lineage. The genetic divergences were ranged from 2.1% to 4.7% between Dybowskii's sika deer and all the other established subspecies at the mtDNA sequence level, which suggests that the maternal lineage of uncertain sika subspecies in Europe had been maintained until today. This study also provides a better understanding for the classification, phylogeny and phylogeographic history of sika deer subspecies. PMID- 24063646 TI - Neuromuscular adaptations after a rehabilitation program in patients with chronic low back pain: case series (uncontrolled longitudinal study). AB - BACKGROUND: To investigate the impact of a short-term multimodal rehabilitation program for patients with low back pain (LBP) on trunk muscle reflex responses and feedforward activation induced by postural perturbations. METHODS: Case series (uncontrolled longitudinal study). Thirty chronic patients with LBP (21 women and 19 men, mean age 42.6 +/- 8.6 years, mean weight 73 +/- 14 kg, mean height 174 +/- 10 cm) were included. The intervention consisted in a 5-day program including therapeutic education sessions (360 min), supervised abdominal and back muscle strength exercises (240 min), general aerobic training (150 min), stretching (150 min), postural education (150 min) and aqua therapy (150 min). Feedforward activation level and reflex amplitude determined by surface electromyographic activity triggered by postural perturbations were recorded from abdominal and paraspinal muscles in unexpected and expected conditions. Subjects were tested before, just after and again one month after the rehabilitation program. RESULTS: No main intervention effect was found on feedforward activation levels and reflex amplitudes underlining the absence of changes in the way patients with LBP reacted across perturbation conditions. However, we observed a shift in the behavioral strategy between conditions, in fact feedforward activation (similar in both conditions before the program) decreased in the unexpected condition after the program, whereas reflex amplitudes became similar in both conditions. CONCLUSIONS: The results suggest that a short-term rehabilitation program modifies trunk behavioral strategies during postural perturbations. These results can be useful to clinicians for explaining to patients how to adapt to daily life activities before and after rehabilitation. PMID- 24063647 TI - Mental, social, and physical well-being in New Hampshire, Oregon, and Washington, 2010 Behavioral Risk Factor Surveillance System: implications for public health research and practice related to Healthy People 2020 foundation health measures on well-being. AB - BACKGROUND: Well-being is now accepted as one of four cross-cutting measures in gauging progress for Healthy People 2020. This shift to population indicators of well-being redresses notions of health that have focused on absence of illness (negative health) as a primary or sufficient indicator of positive functioning. The purpose of this study was to estimate mental, social, and physical well-being in three US states using new measures piloted on the 2010 Behavioral Risk Factor Surveillance Survey System (BRFSS). Baseline estimates were provided for states overall, and within states for demographic subgroups, those with chronic health conditions or disabilities, and those with behavioral risk factors. METHODS: Ten validated questions designed to assess mental (e.g., satisfaction with life, satisfaction with life domains, happiness), physical (e.g., satisfaction with energy level), and social dimensions (e.g., frequency of social support) of well being were selected with state input for inclusion on BRFSS. 18,622 individuals responded to the BRFSS surveys administered by New Hampshire (N = 3,139), Oregon (N = 2,289), and Washington (N = 13,194). Multivariate adjusted proportions of positive responses to well-being items were examined. RESULTS: After adjustment for confounders, about 67% of adults in these states had high levels of well being, including >80% reporting experiencing happiness. Most adults were satisfied with their work, neighborhood, and education, but significant differences were seen in subgroups. Well-being differed by demographic characteristics such as marital status, health behaviors, chronic conditions, and disability status, with those who reported a disability and smokers consistently experiencing the worst well-being. CONCLUSIONS: Well-being is accepted as one of four cross-cutting measures in gauging progress for Healthy People 2020. Well being differs by important sociodemographic factors and health conditions (e.g., age, employment, smoking, disability status). These findings provide baseline estimates for the three states to use in gauging improvements in well-being and can serve as a model for other state-level or national surveillance systems. These findings also assist states in identifying vulnerable subgroups who may benefit from potential interventions such as those in the National Prevention Strategy that focus on enhancing well-being where such disparities exist. PMID- 24063648 TI - Reliability of self-administered Work Ability Index questionnaire among Korean workers. AB - Although the Work Ability Index (WAI) has been used in many countries, its reliability is yet to be validated in Korea. In our study, test-retest results of WAI total score, WAI category and seven subscales were compared. The correlation coefficients of WAI total score and subscales 1 and 2 between test and retest were 0.70, 0.80 and 0.63, respectively. The kappa values on WAI category, subscales 4, 5, 6 and 7 were 0.52, 0.32, 0.31, 0.48 and 0.85, respectively. The results of our reliability test show that WAI scores of female, younger and private company workers were found to be higher than those of male, older and public company workers, respectively. We conclude that overall test-retest reliability of WAI in Korea is acceptable. Another notable observation from our study is that work ability dimension (subscales 1, 2 and 7) had a higher reliability, whereas health dimension (subscales 3-6) had a lower reliability. PMID- 24063649 TI - Unusual multifocal intraosseous papillary intralymphatic angioendothelioma (Dabska tumor) of facial bones: a case report and review of literature. AB - Papillary intralymphatic angioendothelioma (PILA) or Dabska tumor is extremely rare, and often affects the skin and subcutaneous tissues of children. Since its first description by Dabska, only a few intraosseous cases have been described in the literature and none of them presents with multifocal osteolytic lesion of bones. We present a case of unusual multifocal intraosseous PILA in facial bones occurring in a 1 year 3 month old male child. Computed tomography (CT) scan revealed multifocal osteolytic lesions were located at the left zygoma, left orbital bone and right maxillary. Histologically, the lesions were ill-defined and composed of multiple delicate interconnecting vascular channels with papillae formation which projected into the lumen lined by atypical plumped endothelial cells. The vascular channels were also lined by plump cuboidal endothelial cells with focal hobnailed or "match-head" appearance. In some areas, endothelial cells formed solid-appearing aggregates with vessel lumens. By immunohistochemistry, the tumor cells were positive for CD31, CD34 and D2-40 at varying intensity. A final diagnosis of intraosseous PILA was made. To the best of our knowledge, this case is the first case of primary multifocal osseous PILA. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1919488629100787. PMID- 24063650 TI - Preparation of protein-like silver-cysteine hybrid nanowires and application in ultrasensitive immunoassay of cancer biomarker. AB - Novel protein-like silver-cysteine hybrid nanowires (p-SCNWs) have been synthesized by a green, simple, nontemplate, seedless, and one-step aqueous-phase approach. AgNO3 and l-cysteine were dissolved in distilled water, forming Ag cysteine precipitates and HNO3. Under vigorous stirring, the pH of the solution was rapidly adjusted to 9.0 by addition of concentrated sodium hydroxide solution, leading to quick dissolution of the Ag-cysteine precipitates and sudden appearance of white precipitates of p-SCNWs. The p-SCNWs are monodispersed nanowires with diameter of 100 nm and length of tens of micrometers, and have abundant carboxyl (-COOH) and amine (-NH2) groups at their surfaces, large amounts of peptide-linkages and S-bonding silver ions (Ag(+)) inside, making them look and act like Ag-hybrid protein nanostructures. The abundant -COOH and -NH2 groups at the surfaces of p-SCNWs have been found to facilitate the reactions between the p-SCNWs and proteins including antibodies. Furthermore, the fact that the p-SCNWs contain large amounts of silver ions enables biofunctionalized p SCNWs to be excellent signal amplifying chemiluminescence labels for ultrasensitive and highly selective detection of important antigens, such as cancer biomarkers. In this work, the immunoassay of carcinoembryonic antigen (CEA) in human serum was taken as an example to demonstrate the immunoassay applications of antibody-functionalized p-SCNWs. By the novel p-SCNW labels, CEA can be detected in the linear range from 5 to 400 fg/mL with a limit of detection (LOD) of 2.2 fg/mL (at signal-to-noise ratio of 3), which is much lower than that obtained by commercially available enzyme-linked immunosorbent assay (ELISA). Therefore, the synthesized p-SCNWs are envisioned to be an excellent carrier for proteins and related immunoassay strategy would have promising applications in ultrasensitive clinical screening of cancer biomarkers for early diagnostics of cancers. PMID- 24063651 TI - Evidence for the occurrence of two sympatric sibling species within the Anopheles (Kerteszia) cruzii complex in southeast Brazil and the detection of asymmetric introgression between them using a multilocus analysis. AB - BACKGROUND: Anopheles (Kerteszia) cruzii (Diptera: Culicidae) is a primary vector of human and simian malaria parasites in southern and southeastern Brazil. Earlier studies using chromosome inversions, isoenzymes and a number of molecular markers have suggested that An. cruzii is a species complex. RESULTS: In this study, a multilocus approach using six loci, three circadian clock genes and three encoding ribosomal proteins, was carried out to investigate in more detail the genetic differentiation between the An. cruzii populations from Florianopolis Santa Catarina (southern Brazil) and Itatiaia-Rio de Janeiro States (southeastern Brazil). The analyses were performed first comparing Florianopolis and Itatiaia, and then comparing the two putative sympatric incipient species from Itatiaia (Itatiaia A and Itatiaia B). The analysis revealed high FST values between Florianopolis and Itatiaia (considering Itatiaia A and B together) and also between the sympatric Itatiaia A and Itatiaia B, irrespective of their function. Also, using the IM program, no strong indication of migration was found between Florianopolis and Itatiaia (considering Itatiaia A and B together) using all loci together, but between Itatiaia A and Itatiaia B, the results show evidence of migration only in the direction of Itatiaia B. CONCLUSIONS: The results of the multilocus analysis indicate that Florianopolis and Itatiaia represent different species of the An. cruzii complex that diverged around 0.6 Mya, and also that the Itatiaia sample is composed of two sympatric incipient species A and B, which diverged around 0.2 Mya. Asymmetric introgression was found between the latter two species despite strong divergence in some loci. PMID- 24063652 TI - On the contribution of biomass burning to POPs (PAHs and PCDDs) in air in Africa. AB - Forest, savannah, and agricultural fires in the tropics and subtropics are sources for widespread pollution and release many organic substances into the air and soil, including persistent organic pollutants, i.e., polychlorinated dibenzo p-dioxins and dibenzofurans (PCDD/Fs) and polycyclic aromatic hydrocarbons (PAHs). The significance of this source for the exposure of humans and the environment in Africa toward phenanthrene, fluoranthene, pyrene, benzo(a)pyrene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, and octachlorodibenzo-p-dioxin is studied using daily global emissions from vegetation fires observed by satellite and a global multicompartment chemistry transport model. Near-ground atmospheric concentrations of model-predicted vegetation fire related concentrations of PAHs and PCDDs were in the 10-1000 and 10(-5)-10(-3) pg m(-3) ranges, respectively. Vegetation fires in Africa are found to emit 180 +/- 25 kg yr(-1) of PCDD/Fs. By comparison with observations, it is found that fires explain 1-10% of the PCDD (5% of 2,3,7,8- tetrachlorodibenzo-p dioxin) concentrations in the rural and background atmosphere of sub-Saharan Africa. The contribution of vegetation fires to exposure to PAH is probably >10%, but cannot be quantified due to lack of knowledge with regard to both emission factors and photochemistry. A sensitivity analysis suggests that the heterogeneous reaction of PAHs with ozone is effectively limiting atmospheric lifetime and long-range transport. PMID- 24063653 TI - High-resolution sizing of monolayer-protected gold clusters by differential centrifugal sedimentation. AB - Differential centrifugal sedimentation (DCS) has been applied to accurately size ligand-protected gold hydrosols in the 10 to 50 nm range. A simple protocol is presented to correct for particle density variations due to the presence of the ligand shell, which is formed here by either polyethylene glycol-substituted alkane thiols (PEG-alkane thiols) of different chain length or oligopeptides. The method gives reliable data for all particle sizes investigated and lends itself to rapid routine sizing of nanoparticles. Unlike TEM, DCS is highly sensitive to small changes in the thickness of the organic ligand shell and can be applied to monitor shell thickness variations of as little as 0.1 nm on particles of a given core size. PMID- 24063654 TI - HIF-1alpha C1772T polymorphism and gastrointestinal tract cancer risk: a meta analysis and meta-regression analysis. AB - OBJECTIVE: Recent evidence suggests that genetic variations in the hypoxia inducible factor-1alpha (HIF-1alpha) gene may have an impact on an individual's susceptibility to gastrointestinal tract (GIT) cancer; but individually published results are inconclusive. This meta-analysis aims to derive a precise estimation of the association between a common polymorphism (C1772T; rs11549465 C>T) in the HIF-1alpha gene and susceptibility to GIT cancer. METHODS: An extensive literature search was conducted for appropriate articles published before May 1st, 2013. This meta-analysis was performed using the STATA 12.0 software. The crude odds ratio with 95% confidence interval was calculated. RESULTS: Six case control studies were assessed with a total of 911 GIT cancer patients and 2774 healthy controls. Our meta-analysis indicated that the C variant of HIF-1alpha C1772T polymorphism appeared to confer an increased risk for GIT cancer. Further subgroup analyses indicated that the C variant of HIF-1alpha C1772T polymorphism may increase the risk of GIT cancer among Asian populations, but not among Caucasian populations. Univariate and multivariate meta-regression analyses confirmed that differences in ethnicity and cancer type are the major sources of heterogeneity. No publication bias was detected in this meta-analysis. CONCLUSION: The current meta-analysis suggests that the C variant of HIF-1alpha C1772T polymorphism may increase the risk of GIT cancer, especially among Asian populations. PMID- 24063655 TI - Ethnic variation in oral cleft occurrence in denmark 1981-2002. AB - Objective : To examine differences in oral cleft (OC) occurrence based on maternal only and parental country of origin in Denmark from 1981 to 2002. Methods : Data on all live births from the Danish Medical Birth Register from 1981 to 2002 were linked with the Danish Facial Cleft Database. Cleft cases were categorized into isolated and nonisolated cleft lip with or without palate (CL/P) and cleft palate only (CP). Birth prevalence was calculated as cases per 1,000 live born children by maternal country of origin, world region, and mixed parental groups. Results : We identified 3094 OC cases among 1,319,426 live births. Danish-born women had an OC birth prevalence of 2.38 with a 95% confidence interval (CI) (2.29-2.47) and foreign-born women a significant lower prevalence of 2.01 (CI, 1.77-2.27). This difference was explained by a lower isolated CL/P birth prevalence among foreign-born women of 0.97 (CI, 0.81-1.16) versus 1.35 (CI, 1.28-1.41). No significant differences were seen for the remaining subtypes. Parents with the same foreign country of origin had a lower overall OC (1.63; CI, 1.35-1.94) and isolated CL/P (0.76; CI, 0.57-0.99) birth prevalence than Danish-born parents. This was not the case for any of the mixed parental groups. Overall and subtype prevalence rates varied according to maternal categories of world region. Conclusion : In this study we found differences in OC occurrence among all live births in the Danish population based on maternal country of origin from 1981 to 2002. Danish-born women had higher OC and isolated CL/P birth prevalence compared with foreign-born women. PMID- 24063656 TI - Full state-resolved energy gain profiles of CO2 from collisions with highly vibrationally excited molecules. II. Energy-dependent pyrazine (E = 32,700 and 37,900 cm(-1)) relaxation. AB - The full state-resolved distribution of scattered CO2 (00(0)0) molecules from collisions with highly vibrationally excited pyrazine (E = 32,700 cm(-1)) is reported and compared to previous studies on pyrazine (E = 37,900 cm(-1)) to investigate how internal energy content impacts the dynamics for collisional quenching of high energy molecules [J. Phys. Chem. A 2010, 113, 1569]. Nascent rotational and translational energy profiles for scattered CO2 (00(0)0) molecules with J = 2-72 were measured using high-resolution transient infrared absorption and combined with earlier results for the J = 56-78 states [J. Chem. Phys. 1999, 111, 7373]. The product translational energy for individual J-states increases by 50% for a 16% increase in donor vibrational energy. The nascent rotational distribution for scattered CO2 is biexponential, comprising 77% nearly elastic collisions and 23% inelastic collisions. The spread of the rotational distribution is sensitive to donor energy, but the branching ratio for elastic and inelastic collisions is the same for both donor energies. The measured collision rates are close to the Lennard-Jones values and are only weakly dependent on changes in donor energy. The nascent energy gain distribution function P(DeltaE) depends strongly on the energy, and this energy dependence is stronger than the linear dependence seen in multicollision energy transfer studies for pyrazine(E) + CO2 collisions. PMID- 24063657 TI - A PARK2 polymorphism associated with delayed neuropsychological sequelae after carbon monoxide poisoning. AB - BACKGROUND: Delayed neuropsychological sequelae (DNS) are the most severe and clinically intractable complications following acute carbon monoxide (CO) poisoning. Symptoms of DNS often resemble those of Parkinson's disease (PD), suggesting shared neurological deficits. Furthermore, Parkinson protein 2 (PARK2) mutations are associated with PD and other neurodegenerative diseases. The association signal was detected between PARK2 and DNS after acute CO poisoning in our DNA pooling base genome-wide association study. METHODS: Two PARK2 single nucleotide polymorphisms (SNPs), rs1784594 (C/T allele) and rs1893895 (G/A allele), selected from DNA pooling base genome-wide association study, were genotyped by in 514 CO poisoning patients using polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLPs). The patient group consisted of 231 patients with DNS and 283 patients with no signs of lasting neurological damage (control population). RESULTS: The frequency of the rs1784594 T allele was significantly lower in the DNS population (OR = 1.42, 95%CI: 1.08 - 1.87), as was the TT vs. CC genotype (OR = 1.95, 95%CI: 1.15 - 3.23) and the TT vs. CT + CC frequency (OR = 1.68, 95%CI: 1.32 - 2.49) compared to controls. Association analysis revealed a significant association between DNS and rs1784594 (P < 0.01) but not rs1893895 (P > 0.05). In female cases, the T allele frequency of rs1784594 was significantly lower in DNS patients compared to female controls (OR = 1.48, 95%CI: 1.01 - 2.17). CONCLUSION: These data suggest that the allelic variant of rs1784594 is a risk factor for DNS following acute CO poisoning, especially in females. The PARK2 protein may modulate the susceptibility to DNS, underscoring the importance of examining the relationship between other PARK2 polymorphisms and clinical outcome following CO poisoning. PMID- 24063658 TI - Single ZnO microrod ultraviolet photodetector with high photocurrent gain. AB - An Ag/ZnO microrod/Ag ultraviolet photodetector is fabricated, the ZnO microrod shows a hexagonal whispering gallery cavity structure. Upon a 325 nm ultraviolet illumination, the device shows a high sensitivity of 4 * 10(4) A/W and a high photocurrent gain of 1.5 * 10(5) at 5 V bias. Under different illumination power P, the photocurrent Ilight obeys a power law relation Ilight ? P(0.69). The high performance is probably attributed to a Schottky barrier at Ag/ZnO interface and optical whispering gallery mode effect in the ZnO microrod. PMID- 24063659 TI - The face inversion effect--parts and wholes: individual features and their configuration. AB - The face inversion effect (FIE) is a reduction in recognition performance for inverted faces (compared to upright faces) that is greater than that typically observed with other stimulus types (e.g., houses). The work of Diamond and Carey, suggests that a special type of configural information, "second-order relational information" is critical in generating this inversion effect. However, Tanaka and Farah concluded that greater reliance on second-order relational information did not directly result in greater sensitivity to inversion, and they suggested that the FIE is not entirely due to a reliance on this type of configural information. A more recent review by McKone and Yovel provides a meta-analysis that makes a similar point. In this paper, we investigated the contributions made by configural and featural information to the FIE. Experiments 1a and1b investigated the link between configural information and the FIE. Remarkably, Experiment 1b showed that disruption of all configural information of the type considered in Diamond and Carey's analysis (both first and second order) was effective in reducing recognition performance, but did not significantly impact on the FIE. Experiments 2 and 3 revealed that face processing is affected by the orientation of individual features and that this plays a major role in producing the FIE. The FIE was only completely eliminated when we disrupted the single feature orientation information in addition to the configural information, by using a new type of transformation similar to Thatcherizing our sets of scrambled faces. We conclude by noting that our results for scrambled faces are consistent with an account that has recognition performance entirely determined by the proportion of upright facial features within a stimulus, and that any ability to make use of the spatial configuration of these features seems to benefit upright and inverted normal faces alike. PMID- 24063661 TI - Statistical analyses of monozygotic and dizygotic twinning rates. AB - The French mathematician Bertillon reasoned that the number of dizygotic (DZ) pairs would equal twice the number of twin pairs of unlike sexes. The remaining twin pairs in a sample would presumably be monozygotic (MZ). Weinberg restated this idea and the calculation has come to be known as Weinberg's differential rule (WDR). The keystone of WDR is that DZ twin pairs should be equally likely to be of the same or the opposite sex. Although the probability of a male birth is greater than .5, the reliability of WDR's assumptions has never been conclusively verified or rejected. Let the probability for an opposite-sex (OS) twin maternity be pO , for a same-sex (SS) twin maternity pS and, consequently, the probability for other maternities 1 - pS - pO . The parameter estimates $?hat p_O$ and $?hat p_S$ are relative frequencies. Applying WDR, the MZ rate is m = pS - pO and the DZ rate is d = 2pO , but the estimates $?hat m$ and $?hat d$ are not relative frequencies. The maximum likelihood estimators $?hat p_S$ and $?hat p_O$ are unbiased, efficient, and asymptotically normal. The linear transformations $?hat m = ?hat p_S - ?hat p_O$ and ${?skew6?hat d} = 2?hat p_O$ are efficient and asymptotically normal. If WDR holds they are also unbiased. For the tests of a set of m and d rates, contingency tables cannot be used. Alternative tests are presented and the models are applied on published data. PMID- 24063660 TI - Structure and inducing tumor cell apoptosis activity of polysaccharides isolated from Lentinus edodes. AB - In this study, five novel polysaccharides SLNT1, SLNT2, JLNT1, JLNT2, and JLNT3 were isolated from the fruit body of Lentinus edodes. Chemical and physical analyses showed that the five polysaccharides consist of glucose with the structure of beta-(1->3)-d-glucose main chains and beta-(1->6)-d-glucose side chains. Moreover, all of them had triple-helical conformation and different molecular weight distributions. Animal studies further demonstrated that the antitumor effects were remarkably improved by SLNT1 and JLNT1 treatments with the inhibitory rates of 65.41% and 61.07% in H22-bearing mice, respectively. Additionally, both of them significantly increased the levels of serum IL-2 and TNF-alpha production and induced the tumor cell apoptosis. Taken together, our findings revealed that the involved antitumor mechanisms possibly in part were mediated not only by enhancing the immunity but also by directly killing the tumor and the induction of tumor cell apoptosis in H22-bearing mice. PMID- 24063662 TI - A novel liver parenchyma transection technique using locking straight rigid ties. An experimental study in pigs. AB - INTRODUCTION: Technological advances have led to the development of many devices used in liver resections. However, no single transection tool is uniformly considered to be better than the others. This study aimed to develop an effective, fast, and cost-efficient technique for hepatic parenchymal transection. MATERIALS AND METHODS: A liver parenchyma compression device in the form of a locking straight rigid tie (LoStRiT) was newly developed. Twelve pigs were distributed into two groups. The control group ( n = 6) comprised animals that underwent hepatectomy using the standard Kelly-clysis technique. The study group (n = 6) comprised animals that underwent hepatectomy using sequential LoStRiT mechanisms. The transection speed, blood loss, and biloma formation were recorded. RESULTS: The mean parenchymal transection speed was 1.27 +/- 0.27 cm(2)/min for the control group and 2.39 +/- 0.56 cm(2)/min for the LoStRiT group ( p = .003). The mean blood loss per kilogram of body weight was 9.8 +/- 5.2 ml/kg for the control group and 3.9 +/- 0.9 ml/kg for the LoStRiT group ( p = .040). No bilomas were identified. CONCLUSION: LoStRiT hepatectomy appears to be effective, fast, and reproducible in a porcine model of liver resection. Further development of this novel and potentially cost-efficient technique includes construction of the device using absorbable materials. PMID- 24063663 TI - Psychosocial benefits of cross-ethnic friendships in urban middle schools. AB - To examine the unique functions of same- and cross-ethnic friendships, Latino (n = 536) and African American (n = 396) sixth-grade students (Mage = 11.5 years) were recruited from 66 classrooms in 10 middle schools that varied in ethnic diversity. Participants reported on the number of same- and cross-ethnic friends, perceived vulnerability, friendship quality, and the private regard dimension of ethnic identity. Whereas same-ethnic friendships were uniquely associated with stronger private regard, more ethnic diversity and cross-ethnic friendships were uniquely associated with less perceived vulnerability. Multilevel structural equation modeling tested whether cross-ethnic friendships mediated the diversity vulnerability relation. Although cross-ethnic friendships did not significantly mediate this relation at the classroom level, these friendships predicted less vulnerability at the individual student level. PMID- 24063664 TI - A structural equation modelling approach to predicting adoption of a patient handling intervention developed for EMS providers. AB - Patient-handling tasks are integral to Emergency Medical Service (EMS) work as are the musculoskeletal injuries associated with these tasks. The aim of this study was to develop and test a structural equation model that describes the interactions between previously identified factors that contribute to the adoption of a specific ergonomics intervention designed for EMS work. EMS responders (n = 187), from six different organisations, participated in a 2-month longitudinal study following the introduction of a foldable patient transfer board (slide-board) designed to assist with lateral patient transfers. Surveys administered at baseline, after 1 month and after 2 months sampled factors potentially influencing EMS responders' adoption decisions. Perceived ergonomics advantage, which was influenced by access and storage concerns and prior tool experience, contributed most strongly to intention to use at the end of the first month and to the emergence of champions, which contributed to the intention to use at the end of the second month. PMID- 24063665 TI - Anodic passivation of tin by alkanethiol self-assembled monolayers examined by cyclic voltammetry and coulometry. AB - The self-assembly of medium chain length alkanethiol monolayers on polycrystalline Sn electrodes has been investigated by cyclic voltammetry and coulometry. These studies have been performed in order to ascertain the conditions under which their oxidative deposition can be achieved directly on the oxide-free Sn surface, and the extent to which these electrochemically prepared self-assembled monolayers (SAMs) act as barriers to surface oxide growth. This work has shown that the potentials for their oxidative deposition are more cathodic (by 100-200 mV) than those for Sn surface oxidation and that the passivating abilities of these SAMs improve with increasing film thickness (or chain length). Oxidative desorption potentials for these films have been observed to shift more positively, and in a highly linear fashion, with increasing film thickness (~75 mV/CH2). Although reductive desorption potentials for the SAMs are in close proximity to those for reduction of the surface oxide (SnOx), little or no SnOx formation occurs unless the potential is made sufficiently anodic that the monolayers start to be removed oxidatively. Our coulometric data indicate that the charge involved with alkanethiol reductive desorption or oxidative deposition is consistent with the formation of a close-packed monolayer, given uncertainties attributable to surface roughness and heterogeneity phenomena. These experiments also reveal that the quantity of charge passed during oxidative desorption is significantly larger than what would be predicted for simple alkylsulfinate or alkylsulfonate formation, suggesting that oxidative removal involves a more complex oxidation mechanism. Analogous chronocoulometric experiments for short-chain alkanethiols on polycrystalline Au electrodes have evidenced similar oxidative charge densities. This implies that the mechanism for oxidative desorption on both surfaces may be very similar, despite the significant differences in the inherent dissolution characteristics of the two materials at the anodic potentials employed. PMID- 24063666 TI - Long-term outcome of intravitreal triamcinolone acetonide injection for the treatment of uveitis attacks in Behcet disease. AB - PURPOSE: To evaluate the long-term efficacy and safety of intravitreal triamcinolone acetonide (IVTA) injection for posterior segment inflammation in Behcet disease (BD) patients. METHODS: The authors reviewed the medical records of BD patients who underwent IVTA injection (4 mg/0.1 mL) for posterior uveitis attack unresponsive to systemic immunosuppression and were followed up for more than 24 months. RESULTS: Forty-nine patients (49 eyes) were included. Mean best corrected visual acuity improved from 0.89 logMAR units to 0.70, 0.64 at 12, 24 months, respectively. Complete inflammation control was achieved in 87.0% of patients, but 60.0% of them experienced relapse within 12 months. For phakic eyes, cumulative probabilities for cataract surgery were 13.8%, 48.9%, and 60.2% at 12, 24, and 36 months, respectively. Intraocular pressure elevation exceeding 21 mmHg was noted in 40.8%. CONCLUSIONS: In Behcet uveitis attack that is unresponsive or intolerant to systemic medications, IVTA injection is an effective therapeutic option, although ocular complications could limit its efficacy and repeatability. PMID- 24063667 TI - Selective, on-resin N-methylation of peptide N-trifluoroacetamides. AB - Mild and efficient methods for site-specific methylation of peptide backbone amides are important tools for chemists seeking to modulate the pharmacokinetic properties of peptide drugs. The Mitsunobu reaction was used to selectively methylate N-trifluoroacetamide (Tfa) protected peptides on-resin. The Tfa group was removed quickly and completely by reduction with excess NaBH4, and it was shown to be orthogonal to many of the protecting groups used in solid-phase peptide synthesis. PMID- 24063669 TI - [Ileo-anal pouch for inflammatory intestinal disease]. AB - The surgical treatment of choice for ulcerative colitis is colectomy followed by ileostomy or the construction of an ileo-anal pouch, which results in an improvement in quality of life. The pouch can be constructed in one operation after a total colectomy or in two steps: first, constructing an ileostomy after a subtotal colectomy and second, constructing the pouch after a proctectomy. The most common pouch-related diseases include surgical complications such as abscesses, fistulas and leaks, and inflammatory complications like pouchitis, cuffitis and Crohn's disease of the pouch. The most important diagnostic tool to differentiate between the often difficult to distinguish pouch-related diseases is a pouchoscopy. There are no evidence-based treatment strategies for pouch related diseases due to the lack of large randomized placebo-controlled trials. Pouch-related diseases can lead to pouch failure which may require surgical reintervention with revision or excision of the pouch. PMID- 24063671 TI - [Arterial thrombosis due to heparin induced thrombocytopenia]. AB - BACKGROUND: Type II heparin induced thrombocytopenia (HIT) is a procoagulant disorder that is caused by IgG-antibodies against platelet factor 4 (PF4)-heparin (H) complex. Clotting tendency is also increased. This is characterized by a >= 50% decrease in platelet count between 5-10 days after exposure to unfractionated or low-molecular weight heparin. CASE DESCRIPTION: A 49-year-old woman presented with neurological symptoms and pain in her right hand shortly after hospitalisation in Spain. She had an ischaemic CVA and arterial perfusion difficulties in her right arm due to a large thrombus in the aortic arch and some of its branches. She was treated with thrombolytic therapy and dalteparin. Based on initially mild thrombocytopenia that progressed rapidly after admission and her 7-day exposure to enoxaparin during the previous hospital admission, we diagnosed heparin induced thrombocytopenia (HIT) with arterial thrombosis. CONCLUSION: It can be difficult to diagnose HIT. A clinical probability score based on clinical parameters and laboratory results is useful in this. Quick diagnosis and treatment are of great importance because of the high risk of complications. PMID- 24063668 TI - Molecular imaging of labile iron(II) pools in living cells with a turn-on fluorescent probe. AB - Iron is an essential metal for living organisms, but misregulation of its homeostasis at the cellular level can trigger detrimental oxidative and/or nitrosative stress and damage events. Motivated to help study the physiological and pathological consequences of biological iron regulation, we now report a reaction-based strategy for monitoring labile Fe(2+) pools in aqueous solution and living cells. Iron Probe 1 (IP1) exploits a bioinspired, iron-mediated oxidative C-O bond cleavage reaction to achieve a selective turn-on response to Fe(2+) over a range of cellular metal ions in their bioavailable forms. We show that this first-generation chemical tool for fluorescence Fe(2+) detection can visualize changes in exchangeable iron stores in living cells upon iron supplementation or depletion, including labile iron pools at endogenous, basal levels. Moreover, IP1 can be used to identify reversible expansion of labile iron pools by stimulation with vitamin C or the iron regulatory hormone hepcidin, providing a starting point for further investigations of iron signaling and stress events in living systems as well as future probe development. PMID- 24063672 TI - [Organ donation after active euthanasia in a patient with a neurodegenerative disease]. AB - In countries where active euthanasia by a physician is allowed under law - Belgium and the Netherlands - physicians are sometimes confronted with patients who want to donate organs after active euthanasia has been performed. This combination of procedures has been reported in Belgium, and this article is the first description of such a case in the Netherlands. It concerns a patient with a neurodegenerative disease who donated organs after euthanasia. The combination of two complex and controversial procedures - active euthanasia and organ donation - raises important ethical, legal and practical issues. It is suggested that with a thorough preparation and a strict separation of both procedures, organ donation after active euthanasia can strengthen patient autonomy and increase the number of donated organs. PMID- 24063673 TI - [Perianal fistulae and abscesses in children: consider Crohn's disease]. AB - While perianal fistulae and abscesses in infants usually occur as an isolated phenomenon, in older children Crohn's disease might be the underlying etiologic factor. We present four children of different ages with recurrent perianal fistulae and abscesses. Only after the diagnosis Crohn's disease was established and adequate treatment was initiated, the perianal lesions disappeared without further surgical treatment. Perianal fistulae and abscesses in older children should raise the suspicion of Crohn's disease, in which case therapy is indicated to induce and maintain remission of the underlying disease instead of surgical intervention. PMID- 24063674 TI - [A woman with abdominal pain, nausea and vomiting]. AB - A 82-year-old female came to the emergency department because of abdominal pain, nausea and vomiting. Physical examination was suggestive of ileus. CT imaging of the abdomen showed a sciatic hernia. Familiarity with this rare pelvic floor herniation is essential for making the diagnosis. PMID- 24063675 TI - [Ileo-anal pouch in patients with ulcerative colitis; preferably with laparoscopic surgery and in a centre of expertise]. AB - If the colon and rectum need to be removed in patients with ulcerative colitis, it is preferable to create an ileo-anal pouch to restore continuity of the intestinal tract. The surgical approach and the centre at which the patient can best have his surgery are still under debate. Laparoscopy seems to be the best approach due to faster recovery, better fertility preservation, less adhesion formation and fewer incisional hernias. The procedure should be performed in a tertiary referral centre with an annual volume of more than 20 cases. PMID- 24063676 TI - [Is surgical scientific research substandard?]. AB - Randomized controlled trials (RCTs) are the gold standard for establishing the efficacy of surgical interventions. As the trial results are frequently incorporated in clinical guidelines, proper methodology and reporting of RCTs are essential. Trial protocol registration has been introduced, with the aim of improving the latter. A recent study by Hannink and colleagues showed that the quality of registration of surgical RCTs published in surgical journals was inferior to those published in medical journals. In addition, there was a discrepancy between registered and published outcome in approximately 50% of surgical trials. In this comment we critically assess the quality of surgical journals and surgical scientific research. Although there is still room for improvement, we conclude that major quality improvements have been made in these fields, such as the adoption of trial protocol registration by the editorial boards of high-impact surgical journals and the establishment of multidisciplinary study groups, which assure the future of evidence-based surgery. PMID- 24063677 TI - [Closure of patent foramen ovale after a TIA or minor ischaemic stroke; yet another logical, but unnecessary treatment]. AB - Recently, three randomised clinical trials have demonstrated that percutaneous closure of a patent foramen ovale (PFO) should not routinely be recommended for patients with a TIA or a minor ischaemic stroke, which was deemed to be caused by a PFO. Although the procedure is feasible and carries a low complication rate, it should be considered unnecessary in most patients, because of its benign prognosis with respect to future ischaemic stroke during optimal medical therapy. Cardiologists and neurologists have the difficult task of identifying the few patients with a TIA or minor ischaemic stroke who might benefit from closure of a PFO. Possibly, the procedure should be performed only in patients with recurrent cerebral ischaemic events, a large right-to-left shunt and a relatively high risk for deep venous thrombosis. PMID- 24063678 TI - The effects of commercially available footwear on foot pain and disability in people with gout: a pilot study. AB - BACKGROUND: There is limited evidence on non-pharmacological interventions for gout. The aim of the study was to determine whether a footwear intervention can reduce foot pain and musculoskeletal disability in people with gout. METHODS: Thirty-six people with gout participated in a prospective intervention study over 8 weeks. Participants selected one of 4 pairs of shoes and thereafter wore the shoes for 8 weeks. The primary outcome was foot pain using a 100 mm visual analogue scale. Secondary outcomes related to function and disability were also analysed. RESULTS: The Cardio Zip shoe was selected by 58% of participants. Compared with baseline, overall scores for all shoes at 8-weeks demonstrated a decrease in foot pain (p = 0.03), general pain (p = 0.012), Health Assessment Questionnaire (HAQ)-II (p = 0.016) and Leeds Foot Impact Scale (LFIS) impairment subscale (p = 0.03). No significant differences were observed in other patient reported outcomes including patient global assessment, LFIS activity subscale, and Lower Limb Task Questionnaire subscales (all p > 0.10). We observed significant improvements between baseline measurements using the participants' own shoes and the Cardio Zip for foot pain (p = 0.002), general pain (p = 0.001), HAQ-II (p = 0.002) and LFIS impairment subscale (p = 0.004) after 8 weeks. The other three shoes did not improve pain or disability. CONCLUSIONS: Footwear with good cushioning, and motion control may reduce foot pain and disability in people with gout. PMID- 24063679 TI - How to regulate neutrophils in gout. AB - Most research in gout has concentrated on the proinflammatory mechanisms to explain the inflammation that is generated when leucocytes are in contact with monosodium urate crystals. However, the episodic nature of gout and the absence of inflammation even when crystals are present suggest that there are natural counter-regulatory mechanisms to limit the inflammatory response. Gagne and colleagues showed that myeloid inhibitory C-type lectin, a C-type lectin inhibitory receptor expressed on neutrophils, modulates monosodium urate-induced neutrophil responses in vitro. PMID- 24063681 TI - Pt-Cu bimetallic alloy nanoparticles supported on anatase TiO2: highly active catalysts for aerobic oxidation driven by visible light. AB - Visible light irradiation (lambda > 450 nm) of Pt-Cu bimetallic alloy nanoparticles (~3-5 nm) supported on anatase TiO2 efficiently promotes aerobic oxidation. This is facilicated via the interband excitation of Pt atoms by visible light followed by the transfer of activated electrons to the anatase conduction band. The positive charges formed on the nanoparticles oxidize substrates, and the conduction band electrons reduce molecular oxygen, promoting photocatalytic cycles. The apparent quantum yield for the reaction on the Pt-Cu alloy catalyst is ~17% under irradiation of 550 nm monochromatic light, which is much higher than that obtained on the monometallic Pt catalyst (~7%). Cu alloying with Pt decreases the work function of nanoparticles and decreases the height of the Schottky barrier created at the nanoparticle/anatase heterojunction. This promotes efficient electron transfer from the photoactivated nanoparticles to anatase, resulting in enhanced photocatalytic activity. The Pt-Cu alloy catalyst is successfully activated by sunlight and enables efficient and selective aerobic oxidation of alcohols at ambient temperature. PMID- 24063680 TI - Integration of molecules and new fossils supports a Triassic origin for Lepidosauria (lizards, snakes, and tuatara). AB - BACKGROUND: Lepidosauria (lizards, snakes, tuatara) is a globally distributed and ecologically important group of over 9,000 reptile species. The earliest fossil records are currently restricted to the Late Triassic and often dated to 227 million years ago (Mya). As these early records include taxa that are relatively derived in their morphology (e.g. Brachyrhinodon), an earlier unknown history of Lepidosauria is implied. However, molecular age estimates for Lepidosauria have been problematic; dates for the most recent common ancestor of all lepidosaurs range between approximately 226 and 289 Mya whereas estimates for crown-group Squamata (lizards and snakes) vary more dramatically: 179 to 294 Mya. This uncertainty restricts inferences regarding the patterns of diversification and evolution of Lepidosauria as a whole. RESULTS: Here we report on a rhynchocephalian fossil from the Middle Triassic of Germany (Vellberg) that represents the oldest known record of a lepidosaur from anywhere in the world. Reliably dated to 238-240 Mya, this material is about 12 million years older than previously known lepidosaur records and is older than some but not all molecular clock estimates for the origin of lepidosaurs. Using RAG1 sequence data from 76 extant taxa and the new fossil specimens two of several calibrations, we estimate that the most recent common ancestor of Lepidosauria lived at least 242 Mya (238 249.5), and crown-group Squamata originated around 193 Mya (176-213). CONCLUSION: A Early/Middle Triassic date for the origin of Lepidosauria disagrees with previous estimates deep within the Permian and suggests the group evolved as part of the faunal recovery after the end-Permain mass extinction as the climate became more humid. Our origin time for crown-group Squamata coincides with shifts towards warmer climates and dramatic changes in fauna and flora. Most major subclades within Squamata originated in the Cretaceous postdating major continental fragmentation. The Vellberg fossil locality is expected to become an important resource for providing a more balanced picture of the Triassic and for bridging gaps in the fossil record of several other major vertebrate groups. PMID- 24063682 TI - Cleft palate surgery: an evaluation of length of stay, complications, and costs by hospital type. AB - OBJECTIVE: The purpose of this study was to assess length of stay (LOS), complication rates, costs, and charges of cleft palate repair by various hospital types. We hypothesized that pediatric hospitals would have shorter LOS, fewer complications, and lower costs and charges. METHODS: Patients were identified by ICD-9-CM code for cleft palate repair (27.62) using databases from the Agency for Health Research and Quality Healthcare Cost and Utilization Project Kids' Inpatient Database from 1997, 2000, 2003, and 2006. Patient characteristics (age, race, gender, insurer, comorbidities) and facility resources (hospital beds, cleft palate surgery volume, nurse-to-bed ratio, pediatric intensive care unit [PICU], PICU intensivist, burn unit) were examined. Hospitals types included pediatric hospitals, general hospitals, and nonaccredited children's hospital. For each hospital type, mean LOS, extended LOS (LOS > 2), and complications were assessed. RESULTS: A total of 14,153 patients had cleft repair with a mean LOS of 2 days (SD, 0.04), mortality 0.01%, transfusion 0.3%, and complication <3%. Pediatric hospitals had fewer patients with extended hospital stays. Patients with an LOS >2 days were associated with fourfold higher complications. Comorbidities increased the relative rate of LOS >2 days by 90%. Pediatric hospitals had the highest comorbidities, yet 35% decreased the relative rate of LOS >2 days. Median total charges of $10,835 increased to $15,104 with LOS >2 days; median total costs of $4367 increased to $6148 with a LOS >2 days. CONCLUSION: Pediatric hospitals had higher comorbidities yet shorter LOS. Pediatric resources significantly decreased the relative rate of LOS >2 days. Median costs and charges increased by 41% with LOS >2 days. Further research is needed to understand additional aspects of pediatric hospitals associated with lower LOS. PMID- 24063683 TI - Hydrazone radical promoted vicinal difunctionalization of alkenes and trifunctionalization of allyls: synthesis of pyrazolines and tetrahydropyridazines. AB - The intramolecular addition of hydrazone radicals to carbon-carbon double bonds was achieved by using TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or DIAD (diisopropyl azodicarboxylate) as the hydrazone radical initiator as well as the carbon radical scavenger. Consequently, alkenes were difunctionalized to afford pyrazolines and tetrahydropyridazines via C-N forming 5-exo-trig and 6-exo-trig cyclizations, respectively, and allyls were trifunctionalized to afford pyrazolines via C-N forming tandem 1,5-H-shift/5-exo-trig cyclizations under metal-free neutral conditions. PMID- 24063684 TI - Impaired binding of standard initiation factors eIF3b, eIF4G and eIF4B to domain V of the live-attenuated coxsackievirus B3 Sabin3-like IRES--alternatives for 5'UTR-related cardiovirulence mechanisms. AB - Internal ribosome entry site (IRES) elements fold into highly organized conserved secondary and probably tertiary structures that guide the ribosome to an internal site of the RNA at the IRES 3'end. The composition of the cellular proteome is under the control of multiple processes, one of the most important being translation initiation. In each poliovirus Sabin vaccine strain, a single point mutation in the IRES secondary-structure domain V is a major determinant of neurovirulence and translation attenuation. Here we are extrapolating poliovirus findings to a genomic related virus named coxsackievirus B3 CVB3); a causative agent of viral myocarditis. We have previously reported that Sabin3-like mutation (U473 -> C) introduced in the domain V sequence of the CVB3 IRES led to a defective mutant with a serious reduction in translation efficiency and ribosomal initiation complex assembly, besides an impaired RNA-protein binding pattern. With the aim to identify proteins interacting with both CVB3 wild-type and Sabin3 like domain V RNAs and to assess the effect of the Sabin3-like mutation on these potential interactions, we have used a proteomic approach. This procedure allowed the identification of three RNA-binding proteins interacting with the domain V: eIF4G (p220), eIF3b (p116) and eIF4B (p80). Moreover, we report that this single nucleotide exchange impairs the interaction pattern and the binding affinity of these standard translation initiation factors within the IRES domain V of the mutant strain. Taken together, these data indicate how this decisive Sabin3-like mutation mediates viral translation attenuation; playing a key role in the understanding of the cardiovirulence attenuation within this construct. Hence, these data provide further evidence for the crucial role of RNA structure for the IRES activity, and reinforce the idea of a distribution of function between the different IRES structural domains. VIRTUAL SLIDE: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6160165131045880. PMID- 24063685 TI - Long non-coding RNA expression profile in human gastric cancer and its clinical significances. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) are prevalently transcribed in the genome yet their potential roles in human cancers are not well understood. The aim of the present study was to determine the lncRNA expression profile in gastric cancer and its potential clinical value. METHODS: The global lncRNA expression profile in gastric cancer was measured by lncRNA microarray. Levels of two representative lncRNAs, H19 and uc001lsz, were confirmed by real-time reverse transcriptase-polymerase chain reaction. The relationship between their levels and clinicopathological factors of patients with gastric cancer was explored. A receiver operating characteristic (ROC) curve was constructed for differentiating gastric cancer from benign gastric diseases. RESULTS: Total of 135 lncRNAs, which differential expression levels between tumor and non-tumorous tissues were more than twofold, were found (GEO No. GSE47850). The most down-regulated lncRNAs in gastric cancer tissues were FER1L4, uc001lsz, BG491697, AF131784, uc009ycs, BG981369, AF147447, HMlincRNA1600, and AK054588; while the most up-regulated ones were H19, HMlincRNA717, BM709340, BQ213083, AK054978, and DB077273. H19 was found highly expressed in stomach and liver cancer cell lines, while lowly expressed in lung cancer and prostate cancer cell lines. Uc001lsz was lowly expressed in gastric, lung and liver cancer cell lines, while highly expressed in prostate cancer. The areas under ROC curves were up to 0.613, 0.751, and 0.761 for H19, uc001lsz, and the combination, respectively. CONCLUSIONS: The lncRNA expression profile in gastric cancer suggests the potential roles of lncRNAs in gastric cancer occurrence and development. The overexpression of H19 in gastric cancer suggests that H19 may be participated in gastric cancer. The reduced expression of uc001lsz in gastric cancer cell lines and tissues, its associations with TNM stage, and its dysregulation in early cancer and precancerous lesions suggest that uc001lsz may be a potential marker for the diagnosis of early gastric cancer. PMID- 24063687 TI - Age-related differences in attentional bias for emotional faces. AB - Past research suggests an aging-related positivity effect in orienting to faces. However, these studies have eschewed direct comparison of orienting when positive and negative faces are presented simultaneously, thereby potentially underestimating the degree to which emotional valence influences such effects. In the current study younger and older adults viewed face pairs for 1000 ms, and upon face-pair offset indicated the location of a dot that appeared in the former location of one of the faces, to assess attentional orienting. When shown negative-neutral pairs, both age groups were biased to attend to negative faces, but when shown positive-negative pairs only younger adults showed a bias toward negative; older adults showed a lack of orienting toward either emotional face. Results suggest younger adults have a negativity bias in attention orienting regardless of the valence of nearby stimuli, whereas older adults show an absence of this bias when positive information is present. PMID- 24063689 TI - What is in a name? Renaming schizophrenia as a starting point for moving ahead with its re-conceptualization. PMID- 24063688 TI - Genetic analysis of the FBXO42 gene in Chinese Han patients with Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD), the second most common neurodegenerative disease, is characterized by loss of dopaminergic neurons in the substantia nigra. The clinical manifestations of PD encompass a variety of motor and non motor symptoms. Mutations in the F-box protein 7 gene (FBXO7) have been identified to cause Parkinsonian-pyramidal syndrome, an autosomal recessive form of Parkinsonism. The F-box protein 42 gene (FBXO42), a paralog of the FBXO7 gene, is involved in the ubiquitin-proteasome system that may play a role in the pathogenesis of PD. METHODS: To determine whether the FBXO42 gene is associated with PD, we performed a systematic genetic analysis of the FBXO42 gene in 316 PD patients and 295 gender-, age-, and ethnicity-matched normal controls. RESULTS: We identified a novel variant c.1407T>C (p.S469S) and three known single nucleotide variants, including rs2273311, rs12069239 and rs35196193 in the FBXO42 gene in PD patient group. None of the three known variants displayed statistically significant difference in either genotypic or allelic distributions between patient and control groups (all P > 0.05). Haplotype analysis showed that a common haplotype (G-C-G) for the three single nucleotide variants conferred a 1.69-fold increased risk for PD (P = 0.008 after Bonferroni correction, OR = 1.69, 95% CI = 1.06-2.71). CONCLUSIONS: Our findings suggest that a haplotype of the FBXO42 gene might be associated with a higher susceptibility to PD. PMID- 24063686 TI - Role of fibrinogen in cerebrovascular dysfunction after traumatic brain injury. AB - Traumatic brain injury (TBI) has been associated with various neurological disorders. However, the role of cerebrovascular dysfunction and its mechanisms associated with TBI are still not well understood. Inflammation is the main cause of vascular dysfunction. It affects properties of blood components and the vascular wall leading to changes in blood flow and in interaction of blood components and vascular endothelium exacerbating microcirculatory complications during inflammatory diseases. One of the markers of inflammation is a plasma adhesion protein, fibrinogen (Fg). At elevated levels, Fg can also cause inflammatory responses. One of the manifestations of inflammatory responses is an increase in microvascular permeability leading to accumulation of plasma proteins in the subendothelial matrix and causing vascular remodelling. This has a most devastating effect on cerebral circulation after TBI that is accompanied with an elevation of plasma level of Fg and with an increased cerebrovascular permeability in injury penumbra impairing the normal healing process. This study reviews cerebrovascular alterations after TBI, considers the consequences of increased blood-brain barrier permeability, defines the role of elevated level of Fg and discusses the potential mechanisms of its action leading to vascular dysfunction, which subsequently can cause impairment in neuronal function. Thus, possible mechanisms of vasculo-neuronal dysfunction after TBI are considered. PMID- 24063690 TI - The effect of melatonin on a dorsal skin flap model. AB - BACKGROUND: Melatonin (Mel) has a very potent antioxidant activity, depending mainly on its capacity to act as an electron donor. Recently, the antioxidant property of Mel has been much emphasized. In this study, the dorsal skin flap model was used to investigate the effect of Mel in flap viability in rats. MATERIAL AND METHODS: Totally 28 Wistar Albino rats were divided into four groups: control group (C) (n = 7), local treatment group (L) (n = 7), systemic low-dose melatonin treatment group (LT) (n = 7), and systemic high-dose melatonin treatment group (HT) (n = 7). The necrosis rate of the skin flaps was observed seven days after the operation by a blinded observer. Oxidative stress was assessed by determining malondialdehyde (MDA) level, and effects of melatonin on antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) were measured. Vascularity, epithelial thickness, and fibroblast proliferation of dorsal skin flaps were assessed histologically. RESULTS: Amount of MDA were found significantly lower (p < .05), and the flap viability, CAT, SOD, vascularity, fibroblast proliferation, and epithelial thickness were found significantly higher (p < .05) in groups HT than in groups C, L, and LT statistically. CONCLUSION: Our results showed that the usage on different doses of melatonin could play an important role in the process of flap viability and further studies will focus on these areas of interest. PMID- 24063691 TI - Task difficulty and response complexity modulate affective priming by emotional facial expressions. AB - In this study we used an affective priming task to address the issue of whether the processing of emotional facial expressions occurs automatically independent of attention or attentional resources. Participants had to attend to the emotion expression of the prime face, or to a nonemotional feature of the prime face, the glasses. When participants attended to glasses (emotion unattended), they had to report whether the face wore glasses or not (the glasses easy condition) or whether the glasses were rounded or squared (the shape difficult condition). Affective priming, measured on valence decisions on target words, was mainly defined as interference from incongruent rather than facilitation from congruent trials. Significant priming effects were observed just in the emotion and glasses tasks but not in the shape task. When the key-response mapping increased in complexity, taxing working memory load, affective priming effects were reduced equally for the three types of tasks. Thus, attentional load and working memory load affected additively to the observed reduction in affective priming. These results cast some doubts on the automaticity of processing emotional facial expressions. PMID- 24063692 TI - Outbreak of multidrug-resistant acute postoperative endophthalmitis due to Enterobacter aerogenes. AB - PURPOSE: To report the clinical features, management, and outcome of 7 cases of culture-proven multidrug-resistant Enterobacter postoperative endophthalmitis following cataract surgery. METHODS: Medical records of 7 cases of acute postoperative endophthalmitis after uneventful cataract surgery were reviewed. Details regarding age, gender, visual acuity and clinical features at presentation, microbiological profile, treatment interventions, and visual acuity and clinical features at 1 week, 1 month, and 3 months follow-up were collected. RESULTS: All patients reported decreased visual acuity and pain as presenting symptoms. All patients were resistant to intravitreal antibiotics such as vancomycin (1 mg/0.1 mL) and ceftazidime (2.25 mg/0.1 mL). Culture of aqueous and vitreous sample was positive for Enterobacter aerogenes and sensitive to co trimoxazole, cefoperazone-sulbactam, imipenem-meropenem, and piperacillin tazobactem. Two patients with panophthalmitis and no perception of light underwent evisceration. Three patients had visual acuity of >=6/24 at the final follow-up. CONCLUSION: Multidrug-resistant Enterobacter acute postoperative endophthalmitis has a poor prognosis if not intercepted early. PMID- 24063694 TI - Photophysical studies of bioconjugated ruthenium metal-ligand complexes incorporated in phospholipid membrane bilayers. AB - The luminescent, mono-diimine ruthenium complexes [(H)Ru(CO)(PPh3)2(dcbpy)][PF6] (1) (dcbpy = 4,4'-dicarboxy-2,2'-bipyridyl) and [(H)Ru(CO)(dppene)(5-amino-1,10 phen)][PF6] (2) (dppene = bis(diphenylphosphino)ethylene; phen = phenanthroline) were conjugated with 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (DPPE) and with cholesterol in the case of complex 2. Using standard conjugation techniques, compound 1 gives the bis-lipid derivative [(H)Ru(CO)(PPh3)2(dcbpy-N DPPE2)][PF6] (3), while 2 provides the monolipid conjugate [(H)Ru(CO)(dppene)(1,10-phen-5-NHC(S)-N-DPPE)][PF6] (4) and the cholesterol derivative [(H)Ru(CO)(dppene)(1,10-phen-5-NHC(O)Ocholesteryl)][PF6] (5). These compounds were characterized by spectroscopic methods, and their photophysical properties were measured in organic solvents. The luminescence of lipid conjugates 3 and 4 is quenched in organic solvents while compound 4 shows a weak, short-lived, blue-shifted emission in aqueous solution. The cholesterol conjugate 5 shows the long-lived, microsecond-time scale emission associated with triplet metal-to-ligand charge-transfer excited states. Incorporation of conjugate 3 in lipid bilayer vesicles restores the luminescence, but with blue shifts (~80 nm) accompanied by nanosecond-time scale lifetimes. In the vesicles conjugate 4 shows a short-lived and blue-shifted emission similar to that observed in solution but with increased intensity. Conjugation of the complex [(H)Ru(CO)(PhP2C2H4C(O)O-N succinimidyl)2(bpy)][PF6] (6") (bpy = 2,2'-bipyridyl) with DPPE gives the phosphine-conjugated complex [(H)Ru(CO)(PhP2C2H4C(O)-N-DPPE)2(bpy)][PF6] (7). Complex 7 also exhibits a short-lived and blue-shifted emission in solution and in vesicles as observed for complexes 3 and 4. We have also conjugated the complex [Ru(bpy)2(5-amino-1,10-phen)][PF6]2 (8) with both cholesterol (9) and DPPE (10). Neither complex 9 nor the previously reported complex 10 exhibited the blue shifts observed for complexes 3 and 4 when incorporated into large unilamellar vesicles (LUVs). The anisotropies of the emissions of complexes 3, 4, and 7 were also measured in LUVs, and those of complex 5 were measured in both glycerol and LUVs. High fundamental anisotropies were observed for complexes 3, 4, and 7. PMID- 24063695 TI - Systematic review and meta-analysis of the efficacy and safety of alendronate and zoledronate for the treatment of postmenopausal osteoporosis. AB - The aim of this meta-analysis was to evaluate the efficacy and safety of two bisphosphonates (alendronate and zoledronate) in the treatment of postmenopausal osteoporosis. The incidence of fractures was considered as primary endpoint. Only randomized trials with a follow-up period of 1 year or more were included in this systematic review and meta-analysis. We excluded studies that included patients with secondary osteoporosis especially in relation to therapy with corticosteroids or other drugs or diseases known to affect bone mineral density. Studies published as subgroup analysis, extension studies, economic evaluations, and comparisons with active control were excluded. The methodological quality of controlled clinical trials that met these inclusion criteria was evaluated. No studies were excluded from analysis due to lack of quality. The risk ratio of hip, vertebral and wrist fractures for alendronate were 0.61 [95% confidence interval (CI) 0.40-0.93], 0.54 (95% CI 0.44-0.66) and 0.65 (95% CI 0.33-1.25), respectively. Zoledronate risk ratio was 0.62 (95% CI 0.46-0.82) and 0.38 (95% CI 0.22-0.67) for hip and vertebral fractures, respectively. PMID- 24063697 TI - Design and fabrication of biosensing interface for waveguide-mode sensor. AB - In order to develop a biosensing system with waveguide-mode sensor, fabrication of a biosensing interface on the silica surface of the sensing chip was carried out using triethoxysilane derivatives with anti-leptin antibody. Triethoxysilane derivatives bearing succinimide ester and oligoethylene glycol moieties were synthesized to immobilize the antibody and to suppress nonspecific adsorption of proteins, respectively. The chip modified with triethoxysilane derivatives bearing oligoethylene glycol moiety suppressed nonspecific adsorption of proteins derived from human serum effectively by rinse with PBS containing surfactant (0.05% Tween 20). On the other hand, it was confirmed that antibody was immobilized on the chip by immersion into antibody solution to show response of antigen-antibody reaction, where the chip was modified with triethoxysilane derivatives bearing succinimide ester moiety. When the interface was fabricated with antibody and a mixture of triethoxysilane derivatives bearing succinimide ester and oligoethylene glycol moieties, the response of antigen-antibody reaction depended on composition of the mixture and enhanced with the increase of ratio for triethoxysilane derivatives bearing succinimide ester moiety reflecting the antibody concentration immobilized on the chip. While introduction of excess triethoxysilane derivatives bearing succinimide ester moiety induced nonspecific adsorption of proteins derived from human serum, the immobilized antibody on the chip kept its activity after 1-month storage in a refrigerator. Taking into consideration those factors, the biosensing interface was fabricated using triethoxysilane derivatives with anti-leptin antibody to examine performance of the waveguide-mode sensor. It was found that the detection limits for human leptin were 50 ng/mL in PBS and 100 ng/mL in human serum. The results demonstrate that the waveguide-mode sensor powered by the biosensing interface fabricated with those triethoxysilane derivatives and antibody has potential to detect several tens of nanograms per milliliter of biomarkers in human serum with an unlabeled detection method. PMID- 24063699 TI - Micro/nano-structured polypyrrole surfaces on oxidizable metals as smart electroswitchable coatings. AB - Polypyrrole (PPy) films were electrodeposited from a pyrrole/sodium salicylate solution in water, through two-dimensional (2-D) polystyrene (PS) templates self assembled on various oxidizable metals, after which the template was removed by dissolution in tetrahydrofuran (THF). The resulting PPy films were analyzed by scanning electron microscopy and atomic force microscopy. Two-dimensional PPy honeycomb structures are obtained on copper or mild steel by using PS spheres of various sizes. The morphology of these structures was controlled electrochemically, as an increase in the polymerization charge does not disturb the PPy honeycomb arrangement, leading instead to the formation of deeper pores accompanied by a change in their diameter. The hydrophobicity of the reduced micro-structured PPy surface is much greater than that of a bulk PPy film generated on the same metal. Reversible electro-switching of the wettability was obtained with marked variation of the apparent contact angle upon PPy oxido reduction, and an important effect of film micro-structuration upon the wettability range. PMID- 24063698 TI - Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. AB - INTRODUCTION: This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral poly(ADPribose) polymerase (PARP) inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). METHODS: Eligible patients who had received <=1 prior cytotoxic regimen for mTNBC were treated with olaparib 200 mg bid continuously plus weekly paclitaxel 90 mg/m2 for three weeks per four-week cycle. Dose modifications in a large proportion of patients due to neutropenia resulted in enrollment of a second cohort of patients who, if they experienced grade >=2 neutropenia in cycle 1, received granulocyte-colony stimulating factor, which was continued prophylactically in subsequent cycles. All patients had measurable disease; tumor responses were evaluated according to RECIST (version 1.0). RESULTS: Nineteen patients (cohort 1, n = 9; cohort 2, n = 10) received treatment; 15 had received prior taxane chemotherapy. The most frequent adverse events were diarrhea (n = 12, 63%), nausea (n = 11, 58%) and neutropenia (n = 11, 58%). Seven neutropenia events were reported in cohort 1 (four grade >=3) and four in cohort 2 (two grade >=3, including one event of febrile neutropenia). The median (range) dose intensity of paclitaxel was 57% (26 to 100%) in cohort 1 and 73% (29 to 100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression. CONCLUSIONS: The combination of olaparib and weekly paclitaxel was complicated by a significant clinical interaction, with higher-than-expected rates of neutropenia despite secondary prophylaxis. Given the encouraging response rate, alternative scheduling and dosing strategies should be considered (funded by AstraZeneca; ClinicalTrials.gov, NCT00707707). PMID- 24063700 TI - Fast GPU-based CT reconstruction applied in ablation treatment for hepatocellular carcinoma. AB - OBJECTIVE: To develop an image visualization system based on graphic processing unit (GPU) hardware acceleration for clinical use in hepatocellular carcinoma (HCC) interventional planning. METHODS: We developed a liver tumor planning tool to assist the physician in providing patient-specific analysis and visualization. We employed a spatial distance computation algorithm to determine the spatial location of tumors and their relation to the main hepatic vessels. GPU hardware acceleration was implemented for rapid calculation of the spatial distance from the tumor surface to the surrounding vascular territories. RESULTS: The algorithm for spatial distance provided an accurate minimum value for the distance from the tumor surface to the surrounding duct system as well as the region of interest (ROI). Analyzing the data (mean CPU time = 43.14 +/- 29.34; mean GPU time = 0.41 +/- 0.38) using an independent samples t-test, the result showed a remarkable difference (p < 0.001). Thus, GPU hardware acceleration performed the distance arithmetic at higher rates than conventional CPUs. CONCLUSIONS: The visual assistance tool performs as an intuitive and objective module in clinical cases, and is expected to help physicians achieve a more reliable treatment in liver tumor patients. As such, we believe it represents an improvement in image guided preoperative planning. PMID- 24063701 TI - Trends in thyroid cancer incidence in Texas from 1995 to 2008 by socioeconomic status and race/ethnicity. AB - BACKGROUND: Thyroid cancer incidence is increasing, potentially due to enhanced diagnostic practices. However, access to healthcare may be dependent on socioeconomic status (SES) and race/ethnicity. Consequently, certain segments of the population may experience thyroid cancer overdiagnosis as a result of greater access to and use of enhanced diagnostic technology. The current study examined trends by SES in thyroid cancer incidence at the census tract level from 1995 to 2008 for the population of Texas, as well as by racial/ethnic subgroup. METHODS: Joinpoint regressions were used to examine incidence trends over time by SES for the study population, and for the non-Hispanic white, non-Hispanic black, and Hispanic subgroups separately. Other race/ethnicities were not adequately represented for subgroup analyses. RESULTS: There were 22,390 incident thyroid cancer cases (65.0% white, 6.7% black, 24.3% Hispanic, 4.1% Asian/other races; 85.9% papillary histology). The low SES group experienced a steady increase in incidence since 1995 (6.7% per year, p<0.05), whereas incidence among the high SES group has increased at a rate of 8.6% per year since 1999 (p<0.05). The joinpoint projected incidence trends for the low and high SES groups were significantly different (p=0.047). Whites experienced a steady increase in incidence over time among both high and low SES groups (7.6% per year p<0.05), whereas blacks and Hispanics of higher SES had a much more pronounced increase in incidence over time relative to their lower SES counterparts (blacks=12.8% vs. 4.1%; Hispanics=11.2% vs. 8.3%, p<0.05). For blacks and Hispanics, joinpoint projected incidence trends for the low and high SES groups were significantly different from one another (p<0.001-0.004). CONCLUSIONS: These results identify groups experiencing the greatest problem of increasing thyroid cancer incidence, and raise concern that greater access to healthcare may be accompanied by thyroid cancer overdiagnosis. A dual focus on delineating and preventing disease-related causal factors and focusing clinical attention on avoiding overdiagnosis among certain populations (e.g., high SES) may be advisable to address thyroid cancer in Texas. Clinicians are encouraged to adhere to ATA/NCCN guidelines when choosing patients for thyroid ultrasound, selecting which nodules to examine, and deciding which patients should proceed to biopsy. PMID- 24063702 TI - Synthesis of plantazolicin analogues enables dissection of ligand binding interactions of a highly selective methyltransferase. AB - A convergent strategy for the synthesis of truncated analogues of plantazolicin (PZN), a member of the thiazole/oxazole-modified microcin (TOMM) class of natural products, has been developed. These N-terminal mono-, tri-, and pentazole substructures of PZN were utilized to probe the substrate requirements and thermodynamic ligand binding parameters of an unusually selective PZN methyltransferase (BamL) by isothermal titration calorimetry. Our results demonstrate that the presence of a single N-terminal azole permits efficient processing by BamL; however, the substrate binding becomes stronger with increased polyazole chain length. PMID- 24063703 TI - Errorless (re)learning of daily living routines by a woman with impaired memory and initiation: transferrable to a new home? AB - PRIMARY OBJECTIVE: To use errorless learning to train a memory- and initiation impaired woman on two activities of daily living routines and then to transfer these routines to a new home. RESEARCH DESIGN: Single case quasi-experimental. METHODS AND PROCEDURES: Over 9 months, a young woman with an anterior cerebral haemorrhagic stroke (secondary to a ruptured arteriovenous malformation) was trained on routines of morning self-care and diabetes management, involving extensive practice on a structured series of steps with intervention as needed to prevent errors. Once routines were established, family members were trained in the supervision and rating of the routines at home. Following discharge, caregivers continued to monitor the routines daily for 3 months. MAIN OUTCOMES: Errorless learning of self-care and diabetes routines was successful. The routines were transferred to a new home environment and maintained at a near perfect level over a 3-month follow-up period. The patient remained severely memory-impaired, indicating that her functional gains were not attributable to any recovery of her memory abilities over time. CONCLUSIONS: This case offers evidence that even people with severe memory and initiation impairments can be trained on new routines using errorless learning and that, once learned, these routines can be carried out in novel contexts. PMID- 24063704 TI - Serum anti-carbonic anhydrase antibodies and oxidant-antioxidant balance in patients with acute anterior uveitis. AB - PURPOSE: To study the existence of anti-carbonic anhydrase antibodies (anti-CA I&II) in acute anterior uveitis (AAU) patients and to analyze the relationship between the levels of these antibodies and the total antioxidant capacity (TAC), total oxidant capacity (TOC), oxidative stress index (OSI), and malondialdehyde (MDA) level. METHODS: Forty-five AAU cases and 43 healthy controls were enrolled in this prospective study. RESULTS: The average anti-CA I and II antibody levels were 0.433 +/- 0.306 and 0.358 +/- 0.261 IU/mL, respectively, in the AAU group and 0.275 +/- 0.147 and 0.268 +/- 0.108 IU/mL, respectively, in the control group (p = 0.004 and p = 0.036, respectively). In addition, it was found that the TOC, OSI, and MDA levels in the AAU subjects were statistically significantly higher than those of the control subjects. CONCLUSIONS: These results suggest that autoimmune responses against CA I and CA II and an altered serum oxidant antioxidant balance may be involved in the pathogenesis of AAU. PMID- 24063705 TI - How the dynamics of the metal-binding loop region controls the acid transition in cupredoxins. AB - Many reduced cupredoxins undergo a pH-dependent structural rearrangement, triggered by protonation of the His ligand belonging to the C-terminal hydrophobic loop, usually termed the acid transition. At variance with several members of the cupredoxin family, the acid transition is not observed for azurin (AZ). We have addressed this issue by performing molecular dynamics simulations of AZ and four mutants, in which the C-terminal loop has been replaced with those of other cupredoxins or with polyalanine loops. All of the loop mutants undergo the acid transition in the pH range of 4.4-5.5. The main differences between AZ and its loop mutants are the average value of the active site solvent accessible surface area and the extent of its fluctuations with time, together with an altered structure of the water layer around the copper center. Using functional mode analysis, we found that these variations arise from changes in nonbonding interactions in the second coordination sphere of the copper center, resulting from the loop mutation. Our results strengthen the view that the dynamics at the site relevant for function and its surroundings are crucial for protein activity and for metal-containing electron transferases. PMID- 24063706 TI - [Pig methicillin-resistant Staphylococcus aureus: stop the contagion now]. PMID- 24063707 TI - [Acute treatment of hypo- and hypernatremia]. PMID- 24063708 TI - [Prevalence of methicillin resistant Staphylococcus aureus is increasing in Danish farming]. AB - Since 2001 livestock-associated methicillin resistant Staphylococcus aureus (LA MRSA) has increased in Denmark. Transmission to people happens by contact with livestock and mainly pigs. The prevalence in animals is not known but the bacterial reservoir is huge. The incidence of human isolates is increasing. However, LA-MRSA seems to be less virulent than non-LA-MRSA. Well-designed studies focusing on LA-MRSA infection, carrier status and risk factors in populations at risk are needed in order to provide solid data of the health consequences due to this rural, mainly occupational exposure. PMID- 24063709 TI - [Central pontin myelinolysis]. AB - Initially central pontin myelinolysis was associated with alcoholism and later with hyponatraemia and particularly the correction rate. The diagnosis is made by characteristic symptoms and cerebral MRI with areas of hyperintensity on T2 weighted images. Outcome varies, mortality is high and most survivors have some degree of neurological deficit. There is no treatment and supportive therapy remains the only option with possible recovery within 6-8 weeks. Hyponatraemia can safely be corrected at a rate of no more than 10 mmol/l within the first 24 hours and 18 mmol/l within 48 hours. PMID- 24063710 TI - [Severe hyponatraemia to terlipressin treatment]. AB - Terlipressin is a vasopressin analogue. The clinical effect is attributable to affinity to vasopressin-1a receptors. However, it also has affinity to renal vasopressin-2 receptors, which can lead to water retention and dilutional hyponatraemia. We report a case of severe hyponatraemia secondary to terlipressin treatment. A 60-year-old woman with bleeding oesophageal varices was treated with terlipressin 2 mg every fourth hour. After 24 hours of treatment she was somnolent, and the sodium concentration had dropped from 127 mmol/l to 107 mmol/l. Hyponatraemia is an important adverse event in terlipressin treatment, and serum sodium should be monitored closely. PMID- 24063712 TI - [Development of central pontin myelinolysis in a patient with light hyponatraemia]. AB - Central pontin myelinolysis has since the 1970s been correlated with hyponatraemia. A 56-year-old woman was admitted to hospital after a few days of diminished capacity and acute disorientation and respiratory distress. Initially, her alcohol overconsumption was not recognised. She presented with only a light hyponatraemia and sepsis. Following fluid resuscitation she developed hypernatraemia and was later diagnosed with osmotic demyelination syndrome. Despite several weeks of therapy the outcome was fatal. PMID- 24063711 TI - [Hyponatraemia as the cause of severe cerebral symptoms]. AB - Hyponatraemia with severe symptoms is a medical emergency that warrants swift action. Treatment can be delayed and/or insufficient if a systematic approach fails. We present two cases of severe symptomatic hyponatraemia: 1) Seizures treated with antiepileptics and isotonic saline, which fails to increase the plasma [Na+]/reveal the symptoms and 2) coma treated successfully with infusions of hypertonic saline boluses. Effective treatment is simple and involves management of airway, breathing and circulation together with bolus infusions of hypertonic saline to ensure controllable plasma [Na+] increase. PMID- 24063713 TI - [Severe hypernatraemia can be treated with continuous veno-venous haemodialysis]. AB - Hypernatraemia is a common and potentially serious condition in the intensive care unit (ICU). We present a case, a 84-year-old man, who was admitted to the ICU with septic shock due to pneumonia. After successful fluid resuscitation and antibiotic treatment the patient was stable, but severely oedematose and developed hypernatraemia (S-Na 165 mmol/l) with cerebral symptoms. Urine-Na was very low. The condition was successfully treated with continuous veno-venous haemodialysis (CVVHD), adding extra Na to the dialysate in order to correct the hypernatraemia at a rate of 8-15 mmol/l per day. Correction of hypernatremia using CVVHD is effective and safe. PMID- 24063714 TI - [Cardiac transplantation]. AB - More than 100,000 heart transplants have been performed worldwide since 1967. Surgical and medical procedures have improved and median survival in many centres including those participating in Scandiatransplant now exceed 13 years. The article reviews current indications and contraindications for cardiac transplantation and highlights improvements in donor selection, organ preservation, surgical techniques, immunosuppression, and rejection surveillance. PMID- 24063715 TI - [Bilateral rupture of the Achilles tendons after treatment with ciprofloxacin]. AB - We report a case of spontaneous non-traumatic bilateral rupture of the Achilles tendons following ciprofloxacin treatment. A 54-year-old man presented with spontaneous Achilles tendon rupture on the left side, tendinitis and partial tear on the right side following few days of treatment with ciprofloxacin 500 mg twice daily and long-term treatment with prednisolon 10 mg once daily. This rare side effect caused by concurrent treatment with steroids and ciprofloxacin should be kept in mind. Any signs of tendinitis following this treatment should arouse the physicians' suspicion towards ciprofloxacin. PMID- 24063716 TI - [Heterotopic ossification]. PMID- 24063717 TI - Australian and Pacific contributions to the genetic diversity of Norfolk Island feral chickens. AB - BACKGROUND: Norfolk Island has a population of feral chickens which could be the result of domestic stock introduced onto the island by British settlers in 1788. However, there is ongoing debate about their origins because multiple human arrivals to the island may have brought chickens with them. Here we investigate the genetic origins of these feral chickens by sequencing their mitochondrial control region. We infer their phylogenetic relationships using a large dataset of novel sequences from Australian mainland domestic chickens and published sequences from around the world. RESULTS: Eleven control region haplotypes were found among the Norfolk Island feral and Australian mainland domestic chickens. Six of the Norfolk Island haplotypes fall within haplogroup E, but given the worldwide distribution of this haplogroup, the putative European origin of these chickens requires further investigation. One haplotype common among Norfolk Island and Australian samples belonged to a subgroup of haplogroup D, which appears to be restricted to chickens from Indonesia, Vanuatu and Guam. CONCLUSIONS: Our data show that at least two mitochondrial DNA haplogroups (D and E) have contributed to the genetic make-up of Norfolk Island feral chickens. In addition, we have provided insights into the discrete geographical distribution and diversity of the chicken haplogroup D. In view of the worldwide interest in the characterisation of poultry resources, further assessment of chicken populations of Island Southeast Asia and the Pacific region is warranted. PMID- 24063718 TI - Social support in depression: structural and functional factors, perceived control and help-seeking. AB - Aims. This study examined the associations of social support, loneliness and locus of control with depression and help-seeking in persons with major depression. Methods. Twelve-month help-seeking for emotional problems was assessed in a cross-sectional 2006 Estonian Health Survey. Non-institutionalized individuals aged 18-84 years (n = 6105) were interviewed. A major depressive episode was assessed using the Mini-International Neuropsychiatric Interview. Factors describing social support, social and emotional loneliness and locus of control were assessed, and their associations with depression were analysed. The associations with reported help-seeking behaviour among people identified as having a major depressive episode (n = 343) were explored. Results. Low frequency of contacts with one's friends and parents, emotional loneliness, external locus of control and emotional dissatisfaction with couple relations were significant factors predicting depression in the multivariate model. External locus of control was associated with help-seeking in the depressed sample. Interactions of emotional loneliness, locus of control and frequency of contacts with parents significantly predicted help-seeking in the depressed sample. Conclusions. Depression is associated with structural and functional factors of social support and locus of control. Help-seeking of depressed persons depends on locus of control, interactions of emotional loneliness, locus of control and contacts with the parental family. PMID- 24063719 TI - Development of the Post Cardiac Surgery (POCAS) prognostic score. AB - INTRODUCTION: The risk of mortality in cardiac surgery is generally evaluated using preoperative risk-scale models. However, intraoperative factors may change the risk factors of patients, and the organism functionality parameters determined upon ICU admittance could therefore be more relevant in deciding operative mortality. The goals of this study were to find associations between the general parameters of organism functionality upon ICU admission and the operative mortality following cardiac operations, to develop a Post Cardiac Surgery (POCAS) Scale to define operative risk categories and to validate an operative mortality risk score. METHODS: We conducted a prospective study, including 920 patients who had undergone cardiac surgery with cardiopulmonary bypass. Several parameters recorded on their ICU admission were explored, looking for a univariate and multivariate association with in-hospital mortality (90 days). In-hospital mortality was 9%. Four independent factors were included in the POCAS mortality risk model: mean arterial pressure, bicarbonate, lactate and the International Normalized Ratio (INR). The POCAS scale was compared with four other risk scores in the validation series. RESULTS: In-hospital mortality (90 days) was 9%. Four independent factors were included in the POCAS mortality risk model: mean arterial pressure, bicarbonate ratio, lactate ratio and the INR. The POCAS scale was compared with four other risk scores in the validation series. Discriminatory power (accuracy) was defined with a receiver-operating characteristics (ROC) analysis. The best accuracy in predicting in-hospital mortality (90 days) was achieved by POCAS. The areas under the ROC curves of the different systems analyzed were 0.890 (POCAS), followed by 0.847 (Simplified Acute Physiology Score (SAP II)), 0.825 (Sepsis-related Organ Failure Assessment (SOFA)), 0.768 (Acute Physiology and Chronic Health Evaluation (APACHE II)), 0.754 (logistic EuroSCORE), 0.714 (standard EuroSCORE) and 0.699 (Age, Creatinine, Ejection Fraction (ACEF) score). CONCLUSIONS: Our new system to predict the operative mortality risk of patients undergoing cardiac surgery is better than others used for this purpose (SAP II, SOFA, APACHE II, logistic EuroSCORE, standard EuroSCORE, and ACEF score). Moreover, it is an easy-to-use tool since it only requires four risk factors for its calculation. PMID- 24063720 TI - Signal amplification via biological self-assembly of surface-engineered quantum dots for multiplexed subattomolar immunoassays and apoptosis imaging. AB - The parallel and highly sensitive detection of biomolecules is of paramount importance to understand biological functions at the single cell level and for various medical diagnoses. Surface-engineered semiconductor quantum dots (QDs) have been demonstrated to act as a signal amplifiable reporter in immunoassays. This takes advantage of the QDs' robustness against self-quenching in proximity and the tunability of their surface properties. A streptavidin (SA) and biotin QD conjugate pair containing a zwitterionic surface modification was designed for QD self-assembly with minimal nonspecific adsorption. Typical sandwich-type immunoassay procedures were adopted, and the targeted protein binding events were effectively transduced and amplified by the fluorescence of the SA-biotin QD conjugates. The detection limit of myoglobin in 100% serum was determined to be at the subattomolar (tens of copies per milliliter) level, which was achieved by using 100 cycles of the layer-by-layer QD assembly. Adsorption kinetics studies and Monte Carlo simulations revealed that this highly sensitive signal amplification was accomplished by the zwitterionic surface, which gave equilibrium constants 5 orders of magnitude larger for specific binding than for nonspecific binding. The QD conjugates showed an effective multivalency of two, which resulted in a broad linear dynamic range spanning 9 orders of magnitude of target protein concentrations. The assay can be highly miniaturized and multiplexed, and as a proof-of-concept, parallel and rapid detection of four different cancer markers has been successfully demonstrated. To demonstrate that this QD signal amplification can be a universal platform, sensitive imaging and early detection of apoptotic cells were also showcased. PMID- 24063722 TI - Reply to comment on "Partition coefficient measurements in picoliter drops using a segmented flow microfluidic device". PMID- 24063721 TI - Subjective outcome related to donor site morbidity after sural nerve graft harvesting: a survey in 41 patients. AB - BACKGROUND: The sural nerve is the most commonly used nerve for grafting severe nerve defects. Our aim was to evaluate subjective outcome in the lower leg after harvesting the sural nerve for grafting nerve defects. METHODS: Forty-six patients were asked to fill in a questionnaire to describe symptoms from leg or foot, where the sural nerve has been harvested to reconstruct an injured major nerve trunk. The questionnaire, previously used in patients going through a nerve biopsy, consists of questions about loss of sensation, pain, cold intolerance, allodynia and present problems from the foot. The survey also contained questions (visual analogue scales; VAS) about disability from the reconstructed nerve trunk. RESULTS: Forty-one out of 46 patients replied [35 males/6 females; age at reconstruction 23.0 years (10-72); median (min-max), reconstruction done 12 (1.2 39) years ago]. In most patients [37/41 cases (90%)], the sural nerve graft was used to reconstruct an injured nerve trunk in the upper extremity, mainly the median nerve [19/41 (46%)].In 38/41 patients, loss of sensation, to a variable extent, in the skin area innervated by the sural nerve was noted. These problems persisted at follow up, but 19/41 noted that this area of sensory deficit had decreased over time. Few patients had pain and less than 1/3 had cold intolerance. Allodynia was present in half of the patients, but the majority of them considered that they had no or only slight problems from their foot. None of the patients in the study required painkillers. Eighty eight per cent would accept an additional sural nerve graft procedure if another nerve reconstruction procedure is necessary in the future. CONCLUSIONS: Harvesting of the sural nerve for reconstruction nerve injuries results in mild residual symptoms similar to those seen after a nerve biopsy; although nerve biopsy patients are less prone to undergo an additional biopsy. PMID- 24063730 TI - Pore-size dependent protein adsorption and protection from proteolytic hydrolysis in tailored mesoporous silica particles. AB - Protein adsorption and interactions with mesoporous silica are of interest for a broad range of applications including drug delivery, chemical synthesis, biosensors, and bioseparations. A major challenge in designing mesoporous silica supports for tailored protein interaction is the differentiation of protein interactions at the surface of the particle from interactions within the pore, important features when considering mesoporous silica as a protective support for active proteins. In this investigation, the location of Enhanced Green Fluorescent Proteins (EGFPs) adsorbed on tailored mesoporous silica particles is examined as a function of pore diameter using proteolytic hydrolysis to distinguish between accessible and inaccessible proteins. Pore size control is achieved by tuning the hydrothermal aging temperature (60-110 degrees C) during synthesis, where the synthesis results in 5-15 MUm diameter spherical particles appropriate for imaging by confocal scanning laser microscopy (CSLM). In low pH environments, EGFP unfolds within pores and on the surface of particles, rendering it susceptible to proteolytic hydrolysis by the protease Pepsin A. Upon return to neutral pH, un-hydrolyzed EGFP regains its fluorescence and can be visualized within the mesoporous particles. The pore-size dependent loading and protection of EGFP (2.4 nm diameter*4.2 nm) from proteolytic attack by Pepsin A (7.3 nm*3.6 nm*5.4 nm) is demonstrated by the retention of fluorescence in 7.3 nm pores. Larger-pored materials (>9 nm) provide diminishing protection for EGFP, and the protection is greatly reduced with increasing pore size and pore size distribution breadth. Proteolytic hydrolysis is used to delineate the activity of pore-loaded versus surface-bound proteins and to establish that there is an optimal pore diameter for loading EGFP while protecting it from attack by a larger proteolytic enzyme. PMID- 24063731 TI - Acid catalyzed ring transformation of benzofurans to tri- and tetrasubstituted furans. AB - An unusual Bronsted acid catalyzed benzofuran ring opening and furan ring closure sequence for the formation of tri- and tetrasubstituted furans is presented. Benzofuranyl carbinols and 1,3-dicarbonyls in the presence of a catalytic amount of an acid generated functionalized, polysubstituted furans in good to excellent yields via an unusual benzofuran ring opening and furan recyclization process. This reaction is found to be general even on furyl carbinols; however, it generates the rearranged polysubstituted furans in moderate yields. PMID- 24063732 TI - Anatomical, functional, physiological and behavioural aspects of the development of mastication in early childhood. AB - Mastication efficiency is defined as the efficiency of crushing food between the teeth and manipulating the resulting particles to form a swallowable food bolus. It is dependent on the orofacial anatomical features of the subject, the coordination of these anatomical features and the consistency of the food used during testing. Different measures have been used to indirectly quantify mastication efficiency as a function of children's age such as observations, food bolus characterisation, muscle activity measurement and jaw movement tracking. In the present review, we aim to describe the changes in the oral physiology (e.g. bone and muscle structure, teeth and soft tissues) of children and how these changes are associated with mastication abilities. We also review previous work on the effect of food consistency on children's mastication abilities and on their level of texture acceptance. The lack of reference foods and differences in testing methodologies across different studies do not allow us to draw conclusions about (1) the age at which mastication efficiency reaches maturity and (2) the effect of food consistency on the establishment of mature mastication efficiency. The effect of food consistency on the development of children's mastication efficiency has not been tested widely. However, both human and animal studies have reported the effect of food consistency on orofacial development, suggesting that a diet with harder textures enhances bone and muscle growth, which could indirectly lead to better mastication efficiency. Finally, it was also reported that (1) children are more likely to accept textures that they are able to manipulate and (2) early exposure to a range of textures facilitates the acceptance of foods of various textures later on. Recommending products well adapted to children's mastication during weaning could facilitate their acceptance of new textures and support the development of healthy eating habits. PMID- 24063734 TI - Synthesis, structural characterization, and electrochemical properties of dinuclear Ni/Mn model complexes for the active site of [NiFe]-hydrogenases. AB - Four new dinuclear Ni/Mn model complexes RN(PPh2)2Ni(MU-SEt)2(MU-Cl)Mn(CO)3 (7, R = p-MeC6H4CH2; 8, R = EtO2CCH2) and RN(PPh2)2Ni(MU-SEt)2(MU-Br)Mn(CO)3 (9, R = p MeC6H4CH2; 10, R = EtO2CCH2) have been prepared via the four separated step reactions involving six new precursors RN(PPh2)2 (1, R = p-MeC6H4CH2; 2, R = EtO2CCH2), RN(PPh2)2NiCl2 (3, R = p-MeC6H4CH2; 4, R = EtO2CCH2), and RN(PPh2)2Ni(SEt)2 (5, R = p-MeC6H4CH2; 6, R = EtO2CCH2). The Et3N-assisted aminolysis of Ph2PCl with p-MeC6H4CH2NH2 or EtO2CCH2NH2.HCl in CH2Cl2 gave the azadiphosphine ligands 1 and 2 in 38% and 53% yields, whereas the coordination reaction of 1 or 2 with NiCl2.6H2O in CH2Cl2/MeOH afforded the mononuclear Ni dichloride complexes 3 and 4 in 59% and 78% yields, respectively. While thiolysis of 3 or 4 with EtSH under the assistance of Et3N in CH2Cl2 produced the mononuclear Ni dithiolate complexes 5 and 6 in 64% and 68% yields, further treatment of 5 and 6 with Mn(CO)5Cl or Mn(CO)5Br resulted in formation of the dinuclear Ni/Mn model complexes 7-10 in 31-73% yields. All the new compounds 1-10 have been structurally characterized, while model complexes 7 and 9 have been found to be catalysts for HOAc proton reduction to hydrogen under CV conditions. PMID- 24063733 TI - Detection of the GPI-anchorless prion protein fragment PrP226* in human brain. AB - BACKGROUND: The accumulation of the misfolded forms of cellular prion protein, i.e. prions (PrPSc), in the brain is one of the crucial characteristics of fatal neurodegenerative disorders, called transmissible spongiform encephalopathies (TSEs). Cellular prion protein is normally linked to the cell surface by the glycosylphosphatidylinositol (GPI) anchor. There is accumulating evidence that the GPI-anchorless prion protein may act as an accelerator of formation and propagation of prions. In the TSE affected human brain we have previously discovered a novel GPI-anchorless prion protein fragment, named PrP226*, which ends with the tyrosine 226. This fragment can be labeled specifically by the monoclonal antibody V5B2. METHODS: We developed a DELFIA based assay for quick and sensitive detection of the PrP226* fragment in human brain tissue homogenates. By calculating the ratio between the signals of native (N) and denatured (D) samples applied to the assay we were able to observe significant difference between 24 TSE affected brains and 10 control brains. The presence of PrP226* in brain tissue was confirmed by western blot. RESULTS: Our results demonstrate that PrP226* is present in small quantities in healthy human brain, whereas in degenerated brain it accumulates in prion aggregates, proportionally to PrPSc. Samples with high D/N ratio generally comprised more proteinase K resistant PrP, while no correlation was found between the quantity of PrP226* and standard classification of Creutzfeldt-Jakob disease (CJD). CONCLUSIONS: In the present study we show that the PrP226* fragment accumulates in prion aggregates and after being released from them by a denaturation procedure, could serve as a proteinase K digestion independent biomarker for human TSEs. The PrP226* assay described in this paper offers a tool to follow and study this unique anchorless PrP fragment in various parts of human brain and possibly also in other tissues and body fluids. PMID- 24063735 TI - Lymphocytic infiltration in the cutaneous lymphoma microenvironment after injection of TG1042. AB - BACKGROUND: Primary cutaneous lymphomas (CLs), characterized by an accumulation of clonal T or B lymphocytes preferentially localized in the skin, have been successfully treated with interferons (IFNs) which counterbalance the Th2 immunosuppressive state associated with this pathology. In a phase I/II clinical trial, we correlated the local immune infiltrate and the anti-tumor effects of repeated intralesional administrations of an adenovirus vector expressing human interferon-gamma (IFN-g) termed TG1042, in patients with advanced primary cutaneous T-cell lymphomas (CTCL) or multilesional cutaneous B-cell lymphomas (CBCL). METHODS: For each patient, variation in time of specific lymphocyte populations, defined by immunohistochemical stainings, was assessed in biopsies of injected lesions. For each patient, the change in local immune response was associated with the patient's objective response at the end of the study. RESULTS: Immunohistochemical analyses of biopsies indicate that infiltration of CD8+ T lymphocytes and of TIA-1+ cytotoxic T-cells in lesions injected with TG1042 correlates with clinical benefit. CONCLUSIONS: These data suggest for the first time that a CD8+ cytotoxic infiltrate, induced by local expression of IFN-g correlates with a clinical response. TRIAL REGISTRATION: The phase I step (TG1042.01) does not have a registration number. The phase II step (TG1042.06) registration number was NCT00394693. PMID- 24063736 TI - Targeting the chemokine receptor system. PMID- 24063737 TI - Therapeutic targeting of chemokine receptors by small molecules. PMID- 24063738 TI - Targeting chemokines and chemokine receptors with antibodies. PMID- 24063739 TI - Why and how to find neutraligands targeting chemokines? PMID- 24063740 TI - Targeting chemokine-glycan interactions: the CellJammer((r)) technology platform. PMID- 24063741 TI - Peptidylarginine deiminases: physiological function, interaction with chemokines and role in pathology. PMID- 24063742 TI - C(X)CR in silico: Computer-aided prediction of chemokine receptor-ligand interactions. PMID- 24063743 TI - NMR in the analysis of functional chemokine interactions and drug discovery. PMID- 24063744 TI - Unnatural amino acids for the study of chemokine receptor structure and dynamics. PMID- 24063745 TI - Pattern recognition correlating materials properties of the elements to their kinetics for the hydrogen evolution reaction. AB - Here we demonstrate the use of a previously reported pattern recognition algorithm to evaluate correlations between 50 different materials properties of the elements and their kinetics for the hydrogen evolution reaction in acid. We determined that the melting point and bulk modulus of the elements quantitatively gave the highest correlations of all materials properties investigated. We also showed that the melting point and bulk modulus correlations held true for a popular hydrogen evolution catalysts alloy, NiMo, and a previously untested material, MoSi2. In addition, we quantified the previously known relationship between the d-band center of an element and its kinetics for hydrogen evolution, and found that the melting point and bulk modulus correlations have correlations that are similar to but slightly stronger than those of the d-band center. PMID- 24063747 TI - Persistent abdominal pain over uterine scar during labor as a predictor of delivery complications. AB - OBJECTIVE: To evaluate the significance of persistent lower abdominal pain in women with previous cesarean delivery. METHODS: Various maternal outcomes were compared between women who underwent repeated cesareans owing to persistent lower abdominal pain (study group) and women who underwent repeated cesareans without persistent abdominal pain (control group). RESULTS: The incidence of uterine rupture was significantly higher in the study group than in the control group (8/81 [9.9%] vs 0/119 [0.0%]; P<0.001). While all women with persistent lower abdominal pain and uterine rupture had an additional sign or symptom, only 6/73 (8.2%) women with persistent abdominal pain without uterine rupture had any additional symptoms (P<0.001). There was no difference in incidence of uterine scar dehiscence between the groups. However, the hospitalization period was significantly longer in the study group (4 vs 3.7days; P<0.05). Trial of labor was a contributing factor to uterine rupture. CONCLUSION: Isolated persistent lower abdominal pain in women with previous cesarean is a poor indicator of uterine rupture. However, the positive predictive value for uterine rupture is 57% when an additional sign or symptom is present. Dehiscence of the uterine scar is relatively common and it is not associated with persistent abdominal pain. PMID- 24063749 TI - The importance of interpersonal communication in poison centers. AB - BACKGROUND: Poison control center (PCC) personnel face many challenges in communicating with callers and with each other. The purpose of this study was to identify interpersonal communication issues that affect the work environment within PCCs. METHODS: As part of a larger questionnaire study distributed electronically to members of the American Association of Poison Control Centers (AAPCC) to assess communication training needs for PCCs, three questions were included to assess interpersonal communication within the work environment: (1) How important is interpersonal communication within your center to a positive work environment? (not at all to extremely important, 1-7); (2) How disruptive is interpersonal communication to your work? (not at all to extremely disruptive, 1 7); and (3) What communication issues do you find most disruptive to your work? (free-text response). Descriptive and qualitative content analyses were used to identify themes in responses. RESULTS: A total of 537 responses were received from SPIs, directors, medical directors, and other PCC staff. Interpersonal communication within the PCC was rated as extremely important to a positive work environment (median = 7 and IQR = 6-7; 62.3% rated as extremely important). Interpersonal communication was rated as less than moderately disruptive on average (median = 3 and IQR = 2-4). Free-text responses were received from 335 (62%) respondents. Free-text comments were broadly categorized as relating to PCC personnel and work environment and issues related to PCC callers. Categories that emerged from the PCC personnel and work environment category included the following: poor interpersonal communication (n = 104; 31%); background noise (n = 96; 29%); poor work procedures (n = 51; 15%); and poor management communication (n = 38; 11%). CONCLUSION: Interpersonal communication within PCCs was considered to be important for a positive work environment. Although not found to be strongly disruptive by most respondents, several specific interpersonal communication issues were identified by PCC personnel as disruptive to their work. PMID- 24063748 TI - Statistical design for biospecimen cohort size in proteomics-based biomarker discovery and verification studies. AB - Protein biomarkers are needed to deepen our understanding of cancer biology and to improve our ability to diagnose, monitor, and treat cancers. Important analytical and clinical hurdles must be overcome to allow the most promising protein biomarker candidates to advance into clinical validation studies. Although contemporary proteomics technologies support the measurement of large numbers of proteins in individual clinical specimens, sample throughput remains comparatively low. This problem is amplified in typical clinical proteomics research studies, which routinely suffer from a lack of proper experimental design, resulting in analysis of too few biospecimens to achieve adequate statistical power at each stage of a biomarker pipeline. To address this critical shortcoming, a joint workshop was held by the National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), and American Association for Clinical Chemistry (AACC) with participation from the U.S. Food and Drug Administration (FDA). An important output from the workshop was a statistical framework for the design of biomarker discovery and verification studies. Herein, we describe the use of quantitative clinical judgments to set statistical criteria for clinical relevance and the development of an approach to calculate biospecimen sample size for proteomic studies in discovery and verification stages prior to clinical validation stage. This represents a first step toward building a consensus on quantitative criteria for statistical design of proteomics biomarker discovery and verification research. PMID- 24063750 TI - Ataxin-3 is a multivalent ligand for the parkin Ubl domain. AB - The ubiquitin signaling pathway consists of hundreds of enzymes that are tightly regulated for the maintenance of cell homeostasis. Parkin is an E3 ubiquitin ligase responsible for conjugating ubiquitin onto a substrate protein, which itself can be ubiquitinated. Ataxin-3 performs the opposing function as a deubiquitinating enzyme that can remove ubiquitin from parkin. In this work, we have identified the mechanism of interaction between the ubiquitin-like (Ubl) domain from parkin and three C-terminal ubiquitin-interacting motifs (UIMs) in ataxin-3. (1)H-(15)N heteronuclear single-quantum coherence titration experiments revealed that there are weak direct interactions between all three individual UIM regions of ataxin-3 and the Ubl domain. Each UIM utilizes the exposed beta-grasp surface of the Ubl domain centered around the I44 patch that did not vary in the residues involved or the surface size as a function of the number of ataxin-3 UIMs involved. Further, the apparent dissociation constant for ataxin-3 decreased as a function of the number of UIM regions used in experiments. A global multisite fit of the nuclear magnetic resonance titration data, based on three identical binding ligands, resulted in a KD of 669 +/- 62 MUM for each site. Our observations support a multivalent ligand binding mechanism employed by the parkin Ubl domain to recruit multiple UIM regions in ataxin-3 and provide insight into how these two proteins function together in ubiquitination-deubiquitination pathways. PMID- 24063751 TI - Ecotoxicological risk assessment linked to the discharge by hospitals of bio accumulative pharmaceuticals into aquatic media: The case of mitotane. AB - The release of hospital wastewater into the urban sewer networks contributes to the general contamination of aquatic media by pharmaceutical residues. These residues include bio-accumulative pharmaceuticals that lead to increased risk for ecosystems because they can concentrate in organisms and food chains, and therefore reach toxic levels. In order to assess the ecotoxicological risks linked to this particular category of residues, we have developed a specific method, by combining a theoretical calculation of pollutant concentrations in organisms to estimate Body Residue (BR), and ecotoxicity biomarkers in fish cell lines, enabling the calculation of a Critical Body Residue (CBR). This method finally results in the calculation of a specific risk quotient (Qb=BR/CBR), characterizing the risk linked to this type of pollutant. This method was applied to mitotane, a bio-accumulative pharmaceutical typically found in hospital wastewater, in the framework of an exposure scenario corresponding to the discharge of all the hospital wastewaters into the Rhone River which flows through the city of Lyon, France. This approach leads to risk quotients (Qb and Qbg) much higher than those found with the classical approach, i.e. Q=PEC/PNEC (Predictive Environmental Concentration/Predictive Non Effect Concentration)=0.0006. This difference in the appreciation of risk is important when using cytotoxicity as the criterion for measuring the toxicity of mitotane (Qb=0.056) and it is even greater when the criterion used is genotoxicity (Qbg=6.8). This study must be now consolidated by taking the biomagnification of the pharmaceuticals into consideration. PMID- 24063752 TI - A web-based telemedicine system for low-resource settings 13 years on: insights from referrers and specialists. AB - BACKGROUND: One way to tackle health inequalities in resource-poor settings is to establish links between doctors and health professionals there and specialists elsewhere using web-based telemedicine. One such system run by the Swinfen Charitable Trust has been in existence for 13 years which is an unusually long time for such systems. OBJECTIVE: We wanted to gain some insights into whether and how this system might be improved. METHODS: We carried out a survey by questionnaire of referrers and specialists over a six months period. RESULTS: During the study period, a total of 111 cases were referred from 35 different practitioners, of whom 24% were not doctors. Survey replies were received concerning 67 cases, a response rate of 61 per cent. Eighty-seven per cent of the responding referrers found the telemedicine advice useful, and 78% were able to follow the advice provided. As a result of the advice received, the diagnosis was changed in 22% of all cases and confirmed in a further 18 per cent. Patient management was changed in 33 per cent. There was no substantial difference between doctors and non-doctors. During the study period, the 111 cases were responded to by 148 specialists, from whom 108 replies to the questionnaire were received, a response rate of 73 per cent. About half of the specialists (47%) felt that their advice had improved the management of the patients. There were 62 cases where it was possible to match up the opinions of the referrer and the consultants about the value of a specific teleconsultation. In 34 cases (55%) the referrers and specialists agreed about the value. However, in 28 cases (45%) they did not: specialists markedly underestimated the value of a consultation compared to referrers. Both referrers and specialist were extremely positive about the system which appears to be working well. Minor changes such as a clearer referral template and an improved web interface for specialists may improve it. PMID- 24063753 TI - Enantioenriched bifunctional crotylsilanes for the asymmetric synthesis of orthogonally protected 2-methyl-1,3-diols. AB - Enantiomerically pure alpha-substituted crotylsilane reagents I and ent-I undergo asymmetric aldehyde crotylation followed by Ir(I)-catalyzed diastereoselective allylic etherification to give a variety of orthogonally protected 2-methyl-1,3 diols at the synthetically useful level of yields and stereoselectivity. The reagents are air-stable and bifunctional so that they can be used in these reactions sequentially without recourse to functional group adjustments. PMID- 24063754 TI - Online and splitless NanoLC * CapillaryLC with quadrupole/time-of-flight mass spectrometric detection for comprehensive screening analysis of complex samples. AB - A novel multidimensional separation system based on online comprehensive two dimensional liquid chromatography and hybrid high-resolution mass spectrometry has been developed for the qualitative screening analysis and characterization of complex samples. The core of the system is a consistently miniaturized two dimensional liquid chromatography that makes the rapid second dimension compatible with mass spectrometry without the need for any flow split. Elevated temperature, ultrahigh pressure, and a superficially porous sub-3-MUm stationary phase provide a fast second dimension separation and a sufficient sampling frequency without a first dimension flow stop. A highly loadable porous graphitic carbon stationary phase is employed in the first dimension to implement large volume injections that help countervailing dilution caused by the sampling process between the two dimensions. Exemplarily, separations of a 99-component standard mixture and a complex wastewater sample were used to demonstrate the performance of the dual-gradient system. In the second dimension, 30 s gradients at a cycle time of 1 min were employed. One multidimensional separation took 80 90 min (~120 min including extended hold and re-equilibration in the first dimension). This approach represents a cost-efficient alternative to online LC * LC strategies working with conventionally sized columns in the rapid second dimension, as solvent consumption is drastically decreased and analytes still are detectable at environmentally relevant concentrations. PMID- 24063755 TI - Acquired drusenoid deposits on infrared imaging as a sign of vitreoretinal lymphoma. PMID- 24063757 TI - Improved estimation of inbreeding and kinship in pigs using optimized SNP panels. AB - BACKGROUND: Traditional breeding programs consider an average pairwise kinship between sibs. Based on pedigree information, the relationship matrix is used for genetic evaluations disregarding variation due to Mendelian sampling. Therefore, inbreeding and kinship coefficients are either over or underestimated resulting in reduction of accuracy of genetic evaluations and genetic progress. Single nucleotide polymorphism (SNPs) can be used to estimate pairwise kinship and individual inbreeding more accurately. The aim of this study was to optimize the selection of markers and determine the required number of SNPs for estimation of kinship and inbreeding. RESULTS: A total of 1,565 animals from three commercial pig populations were analyzed for 28,740 SNPs from the PorcineSNP60 Beadchip. Mean genomic inbreeding was higher than pedigree-based estimates in lines 2 and 3, but lower in line 1. As expected, a larger variation of genomic kinship estimates was observed for half and full sibs than for pedigree-based kinship reflecting Mendelian sampling. Genomic kinship between father-offspring pairs was lower (0.23) than the estimate based on pedigree (0.26). Bootstrap analyses using six reduced SNP panels (n = 500, 1000, 1500, 2000, 2500 and 3000) showed that 2,000 SNPs were able to reproduce the results very close to those obtained using the full set of unlinked markers (n = 7,984-10,235) with high correlations (inbreeding r > 0.82 and kinship r > 0.96) and low variation between different sets with the same number of SNPs. CONCLUSIONS: Variation of kinship between sibs due to Mendelian sampling is better captured using genomic information than the pedigree-based method. Therefore, the reduced sets of SNPs could generate more accurate kinship coefficients between sibs than the pedigree-based method. Variation of genomic kinship of father-offspring pairs is recommended as a parameter to determine accuracy of the method rather than correlation with pedigree-based estimates. Inbreeding and kinship coefficients can be estimated with high accuracy using >=2,000 unlinked SNPs within all three commercial pig lines evaluated. However, a larger number of SNPs might be necessary in other populations or across lines. PMID- 24063756 TI - Implementation of evidence-based practice across medical, nursing, pharmacological and allied healthcare professionals: a questionnaire survey in nationwide hospital settings. AB - BACKGROUND: Implementation of evidence-based practice (EBP) is regarded as core competence to improve healthcare quality. In the current study, we investigated the EBP of six groups of professionals: physicians, nurses, pharmacists, physical therapists, technicians, and other allied healthcare personnel. METHODS: A structured questionnaire survey of regional hospitals throughout Taiwan was conducted by post in 2011. Questionnaires were mailed to all healthcare workers of 11 randomly selected hospitals. Linear and logistic regression models were used to examine predictors for implementing EBP. RESULTS: In total, 6,160 returned questionnaires, including 645 from physicians, 4,206 from nurses, 430 from pharmacists, 179 from physical therapists, 537 from technicians, and 163 from other allied healthcare professionals, were valid for the analysis. Physicians and pharmacists were more aware of EBP than were the other professional groups (p < 0.001). Positive attitudes toward and beliefs in EBP were significantly lower among nurses than in the other groups (p < 0.001). Physicians had more sufficient knowledge and skills of EBP than did the other professionals (p < 0.001); in addition, they implemented EBP for clinical decision-making more often and perceived fewer personal barriers to EBP (p < 0.001). Multivariate logistic regression analyses showed that EBP implementation was associated with the following characteristics of participants: EBP training, having a faculty position, academic degree, one's profession, and perceptions (beliefs, attitudes, knowledge, skills and barriers). CONCLUSIONS: This study depicts various levels of EBP implementation among medical, nursing, pharmacological, and allied healthcare personnel. There were significant differences in their implementation of EBP. We observed that certain factors were associated with EBP implementation, including personal backgrounds and perceptions toward EBP. The data suggest that strategies for enhancing EBP implementation should differ for various groups of professionals. PMID- 24063759 TI - Organocatalytic Michael addition/intramolecular Julia-Kocienski olefination for the preparation of nitrocyclohexenes. AB - An asymmetric organocatalytic [3 + 3] annulation strategy based on a Michael addition/intramolecular Julia-Kocienski olefination sequence has been developed for the synthesis of 4-substituted-5-nitrocyclohex-1-ene compounds. The strategy is an alternative to the direct reluctant enantioselective Diels-Alder approach. The potential of the methodology has been demonstrated with a concise enantioselective formal synthesis of trandolapril. PMID- 24063760 TI - Probing the oxidation chemistry of half-sandwich iridium complexes with oxygen atom transfer reagents. AB - The new complexes [Ir(Cp*)(phpy)3,5-bis(trifluoromethyl)benzonitrile](+) (1 NCAr(+)) and [Ir(Cp*)(phpy)(styrene)](+) (1-Sty(+), Cp* = eta(5) pentamethylcyclopentadienyl, phpy = 2-phenylene-kappaC(1')-pyridine-kappaN) were prepared as analogues of reported iridium water oxidation catalysts, to study their reactions with oxygen atom transfer (OAT) reagents at low temperatures. In no case was the desired product, an Ir(V)oxo complex, observed by spectroscopy. Instead, ligand oxidation was implicated. Oxidation of 1-NCAr(+) with the OAT reagent dimethyldioxirane (DMDO) yielded dioxygen when analyzed by GC, but formation of a heterogeneous or paramagnetic species was simultaneously observed. This amplifies uncertainty over the actual identity of iridium catalysts in the harsh oxidizing conditions required for water oxidation. Catalyst stability was then assessed for a reported styrene epoxidation mediated by [Ir(Cp*)(phpy)(OH2)](+) (1-OH2(+)). It was found that the OAT reagent iodosobenzene (PhIO) extensively oxidized the organic ligands of 1-OH2(+). Acetic acid was detected as a decomposition product. In addition, both the molecular structure and the aqueous electrochemistry of 1-OH2(+) are described for the first time. Oxidative scans revealed rapid decomposition of the complex. All of the above experiments indicate that degradation of the organic ligands in catalysts built with the Ir(Cp*)(phpy) framework are facile under oxidizing conditions. In separate experiments designed to promote ligand substitution, an unexpected silver-bridged, dinuclear Ir(III) species with terminal hydrides, [{Ir(Cp*)(phpy)H}2Ag](+) (2), was discovered. The source of Ag(+) for complex 2 was identified as AgCl. PMID- 24063758 TI - A chemically synthesized capture agent enables the selective, sensitive, and robust electrochemical detection of anthrax protective antigen. AB - We report on a robust and sensitive approach for detecting protective antigen (PA) exotoxin from Bacillus anthracis in complex media. A peptide-based capture agent against PA was developed by improving a bacteria display-developed peptide into a highly selective biligand through in situ click screening against a large, chemically synthesized peptide library. This biligand was coupled with an electrochemical enzyme-linked immunosorbent assay utilizing nanostructured gold electrodes. The resultant assay yielded a limit of detection of PA of 170 pg/mL (2.1 pM) in buffer, with minimal sensitivity reduction in 1% serum. The powdered capture agent could be stably stored for several days at 65 degrees C, and the full electrochemical biosensor showed no loss of performance after extended storage at 40 degrees C. The engineered stability and specificity of this assay should be extendable to other cases in which biomolecular detection in demanding environments is required. PMID- 24063761 TI - Hands-off linear interaction energy approach to binding mode and affinity estimation of estrogens. AB - With this work we target the development of a predictictive model for the identification of small molecules which bind to the estrogen receptor alpha and, thus, may act as endocrine disruptors. We propose a combined thermodynamic approach for the estimation of preferential binding modes along with corresponding free energy differences using a linear interaction energy (LIE) ansatz. The LIE model is extended by a Monte Carlo approach for the computation of conformational entropies as recently developed by our group. Incorporating the entropy contribution substantially increased the correlation with experimental affinity values. Both squared coefficients for the fitted data as well as the more meaningful leave-one-out cross-validation of predicted energies were elevated up to r(Fit)2 = 0.87 and q(LOO)2 = 0.82, respectively. All calculations have been performed on a set of 31 highly diverse ligands regarding their structural properties and affinities to the estrogen receptor alpha. Comparison of predicted ligand orientations with crystallographic data retrieved from the Protein database pdb.org revealed remarkable binding mode predictions. PMID- 24063762 TI - Epilepsy and vitamin D. AB - Several disorders, both systemic and those of the nervous system, have been linked with vitamin D deficiency. Neurological disorders with a vitamin D link include but are not limited to multiple sclerosis, Alzheimer and Parkinson disease, as well as cerebrovascular disorders. Epilepsy which is the second leading neurological disorder received much less attention. We review evidence supporting a link between vitamin D and epilepsy including those coming from ecological as well as interventional and animal studies. We also assess the literature on the interaction between antiepileptic drugs and vitamin D. Converging evidence indicates a role for vitamin D deficiency in the pathophysiology of epilepsy. PMID- 24063763 TI - Survival of patients with operable breast cancer (Stages I-III) at a Brazilian public hospital--a closer look into cause-specific mortality. AB - BACKGROUND: Breast cancer incidence is increasing. The survival rate varies and is longer in high-income countries. In Brazil, lower-income populations rely on the Unified Public Health System (Sistema Unico de Saude, SUS) for breast cancer care. The goal of our study is to evaluate the survival of patients with operable breast cancer stages I-III at a Brazilian public hospital that treats mostly patients from the SUS. METHODS: A cohort study of patients who underwent surgery for breast cancer treatment at the Clinical Hospital of the Federal University of Minas Gerais from 2001 to 2008 was performed, with a population of 897 cases. Information on tumor pathology and staging, as well as patients' age and type of health coverage (SUS or private system) was collected. A probabilistic record linkage was performed with the database of the Mortality Information System to identify patients who died by December 31th, 2011. The basic cause of death was retrieved, and breast cancer-specific survival rates were estimated with the Kaplan-Meier method. The Cox proportional hazards model was used for univariate and multivariate analysis of factors related to survival. RESULTS: A total of 282 deaths occurred during the study's period, 228 of them due to breast cancer. Five year breast cancer-specific survival rates were 95.5% for stage I, 85.1% for stage II and 62.1% for stage III disease. Patients from the SUS had higher stages at diagnosis (42% was in stage III, and from the private system only 17.6% was in this stage), and in the univariate but not multivariate analysis, being treated by the SUS was associated with shorter survival (hazard ratio, HR = 2.22, 95% CI 1.24-3.98). In the multivariate analysis, larger tumor size, higher histologic grade, higher number of positive nodes and age older than 70 years were associated with a shorter breast cancer-specific survival. CONCLUSIONS: Five-year breast cancer survival was comparable to other Brazilian cohorts. Patients treated by the SUS, rather than by the private system, had shorter survival times, mostly due to higher initial stage of the disease. PMID- 24063764 TI - Bioorthogonal layer-by-layer encapsulation of pancreatic islets via hyperbranched polymers. AB - Encapsulation of viable tissues via layer-by-layer polymer assembly provides a versatile platform for cell surface engineering, with nanoscale control over the capsule properties. Herein, we report the development of a hyperbranched polymer based, ultrathin capsule architecture expressing bioorthogonal functionality and tailored physiochemical properties. Random carbodiimide-based condensation of 3,5 dicarboxyphenyl glycineamide on alginate yielded a highly branched polysaccharide with multiple, spatially restricted, and readily functionalizable terminal carboxylate moieties. Poly(ethylene glycol) (PEG) was utilized to link azido end groups to the structured alginate. Together with a phosphine-functionalized poly(amidoamine) dendrimer, nanoscale layer-by-layer coatings, covalently stabilized via Staudinger ligation, were assembled onto solid surfaces and pancreatic islets. The effects of electrostatic and/or bioorthogonal covalent interlayer interactions on the resulting coating efficiency and stability, as well as pancreatic islet viability and function, were studied. These hyperbranched polymers provide a flexible platform for the formation of covalently stabilized, ultrathin coatings on viable cells and tissues. In addition, the hyperbranched nature of the polymers presents a highly functionalized surface capable of bioorthogonal conjugation of additional bioactive or labeling motifs. PMID- 24063766 TI - Another review on triple negative breast cancer. Are we on the right way towards the exit from the labyrinth? AB - Triple negative breast cancer is a heterogeneous group of tumors, lacking the expression of estrogen, progesterone and HER-2 receptors. As frequency, it accounts about 15-20% of all breast cancers. Although in the last years there was a "boom" in publishing over this issue, multiple molecular classifications being elaborated, "the triple negative breast cancer odyssey " is still far away from ending, as the complicated molecular pathways of pathogenesis and drug resistance mechanisms remain yet insufficiently explored. The aim of this review is presentation of molecular signatures that could predict outcome and drug resistance in triple negative breast cancer. PMID- 24063768 TI - The study of multireactional electrochemical interfaces via a tip generation/substrate collection mode of scanning electrochemical microscopy: the hydrogen evolution reaction for Mn in acidic solution. AB - We report a new method of scanning electrochemical microscopy (SECM) that can be used to separate multireactional electrochemical interfaces, i.e., electrodes at which two or more reactions occur (and hence two partial currents flow) at the same time. This was done with a modified tip generation/substrate collection mode where the two reactions occur on the tip electrode, and the substrate electrode is held at a potential to collect only one of the products, allowing the determination of the individual partial currents. Thus, by using the substrate electrode current and the difference between the tip and substrate electrode currents, the two reactions occurring on the tip electrode can be separated. As a test case for this new method, we investigated proton reduction on Mn, a reaction that, because of the highly corrosive nature of Mn, to our knowledge has never before been directly measured. This test was carried out using a Mn tip electrode and a Pt substrate electrode. Using a three-dimensional COMSOL Multiphysics simulation, we were able to accurately determine the tip/substrate distance with this electrode, and by fitting simulations to experimental data, we were able to determine an exchange current density, log(j(0)) = -4.7 +/- 0.7 A cm(-2), for proton reduction on Mn in strong acid. This result corrects a literature value and was used in a pattern recognition algorithm reported in a companion manuscript. PMID- 24063765 TI - Genetic variance in nitric oxide synthase and endothelin genes among children with and without endothelial dysfunction. AB - BACKGROUND: The presence of endothelial dysfunction (ED) constitutes an early risk factor for cardiovascular disease (CVD) in children. Nitric oxide (NO) and endothelin (EDN) are generated in endothelial cells and are critical regulators of vascular function, with ED resulting from an imbalance between these two molecules. We hypothesized that genetic variants in NO synthase and EDN isoforms and its receptors (EDNRA and EDNRB) may account for a proportion of the risk for ED in developing children. METHODS: Consecutive children (ages 5-10 years) were prospectively recruited from the community. Time to peak post-occlusive reperfusion (Tmax) was considered as the indicator of either normal endothelial function (NEF; Tmax < 45 sec) or ED (Tmax >= 45 sec). Lipid profiles, high sensitivity C-reactive protein (hsCRP), fasting glucose and insulin were assayed using ELISA. Genomic DNA from peripheral blood was extracted and genotyped for NOS1 (209 SNPs), NOS2 (122 SNPs), NOS3 (50 SNPs), EDN1 (43 SNPs), EDN2 (48 SNPs), EDN3 (14 SNPs), EDNRA (27 SNPs), and EDNRB (23 SNPs) using a custom SNPs array. Linkage disequilibrium was analyzed using Haploview version 4.2 software. RESULTS: The relative frequencies of SNPs were evaluated in 122 children, 84 with NEF and 38 with ED. The frequencies of NOS1 (11 SNPs), and EDN1 (2 SNPs) were differentially distributed between NEF vs. ED, and no significant differences emerged for all other genes. Significant SNPs for NOS1 and EDN1 SNPs were further validated with RT-PCR. CONCLUSIONS: Genetic variants in the NOS1 and EDN1 genes appear to account for important components of the variance in endothelial function, particularly when concurrent risk factors such as obesity exist. Thus, analysis of genotype-phenotype interactions in children at risk for ED will be critical for more accurate formulation of categorical CVD risk estimates. PMID- 24063767 TI - Age and sex differences in the incorporation of EPA and DHA into plasma fractions, cells and adipose tissue in humans. AB - The aim of the present study was to determine whether age and sex influence both the status and incorporation of EPA and DHA into blood plasma, cells and tissues. The study was a double-blind, randomised, controlled intervention trial, providing EPA plus DHA equivalent to 0, 1, 2 or 4 portions of oily fish per week for 12 months. The participants were stratified by age and sex. A linear regression model was used to analyse baseline outcomes, with covariates for age or sex groups and by adjusting for BMI. The change in outcomes from baseline to 12 months was analysed with additional adjustment for treatment and average compliance. Fatty acid profiles in plasma phosphatidylcholine, cholesteryl esters, NEFA and TAG, mononuclear cells (MNC), erythrocyte membranes, platelets, buccal cells (BU) and adipose tissue (AT) were determined. At baseline, EPA concentrations in plasma NEFA and DHA concentrations in MNC, BU and AT were higher in females than in males (all P< 0.05). The concentrations of EPA in AT (P= 0.003) and those of DHA in plasma TAG (P< 0.01) and AT (P< 0.001) were higher with increasing age. Following 12-month supplementation with EPA plus DHA, adjusted mean difference for change in EPA concentrations in plasma TAG was significantly higher in females than in males (P< 0.05) and was greater with increasing age (P= 0.02). Adjusted mean difference for change in DHA concentrations in AT was significantly smaller with increasing age (P= 0.02). Although small differences in incorporation with age and sex were identified, these were not of sufficient magnitude to warrant a move away from population level diet recommendations for n-3 PUFA. PMID- 24063769 TI - Acquisition of early auditory milestones with a cochlear implant. AB - OBJECTIVE: Speech acquisition after cochlear implant is a long process. Various studies have followed the auditory milestones in the early period after implantation. The aim of the present study was to track the development of hearing skills in the early period after cochlear implantation and evaluate which factors influence the process. METHODS: 195 records of children implanted in the Hadassah Medical Center were examined retrospectively. Data on etiology, age at implantation and type of implant were collected. In addition, information on the rate of progress was measured: the first time that there was detection and identification of Ling sounds, the first time it was possible to obtain SDT (speech detection threshold), SRT (speech reception threshold) and an audiogram, and the first accurate repetition of VCV (vowel consonant vowel) sounds. RESULTS: Results show a consistent pattern of auditory milestone acquisition similar to that of normal development, from milestones that do not require decoding beginning with SDT, detection of Ling sounds followed by an audiogram which requires cooperation, to tasks that involve decoding starting with SRT and repetition of Ling sounds and finally VCV repetition. The children implanted before 24 months of age achieved the auditory milestones later than children implanted between 2 and 6 years, apparently since these tasks involve cognitive abilities which are not yet developed in the youngest children. Previous hearing experience improved the rate of acquisition of the auditory milestones and progress was faster in the second implanted ear compared to the first implanted ear. CONCLUSION: More research is needed to address the relationship between acquisition of early auditory milestones and performance with the cochlear implant later on in life. PMID- 24063770 TI - Persistent petrosquamosal sinus: underlying cause of otitic hydrocephalus with lateral sinus thrombosis. AB - Lateral sinus thrombosis (LST) occurs when a middle ear infection disseminates directly via bone erosion or disseminates indirectly through the venous networks. The petrosquamosal sinus (PSS) is the residual accessory dural sinus connecting intracranial to extracranial drainage. This report describes a case of a patient with persistent PSS running through the mastoid in context of otitic hydrocephalus with LST. To identify PSS, enhanced CT and reconstructed image from CT venography were more useful than MRI. The possibility of persistent PSS running through the mastoid should be considered if LST without marked inflammation and bone erosion is noted. PMID- 24063771 TI - Intralesional cidofovir as adjuvant for the successful management of aggressive respiratory papillomatosis in an infant. AB - Recurrent respiratory papillomatosis (RRP) in young children is frequently characterized by a recalcitrant course and need for multiple surgeries. Periodic surgical debulking and ablation is the mainstay of therapy as a cure for RRP rarely occurs. Benefits of adjuvant treatment with local injection of cidofovir in aggressive cases of RRP have been reported in both children and adults. However, a consensus on initiation, dosage, or scheduling of this drug has not been established in the very young patient. Literature on successful remission in children less than 1 year of age is not available. One such case of an infant with aggressive RRP treated with local adjuvant cidofovir is described herein. PMID- 24063774 TI - Enhanced visualization of small peptides absorbed in rat small intestine by phytic-acid-aided matrix-assisted laser desorption/ionization-imaging mass spectrometry. AB - Enhanced visualization of small peptides absorbed through a rat intestinal membrane was achieved by matrix-assisted laser desorption/ionization time-of flight imaging mass spectrometry (MALDI-IMS) with the aid of phytic acid as a matrix additive. Penetrants through intestinal peptide transporter 1, i.e., glycyl-sarcosine (Gly-Sar, 147.1 m/z) and antihypertensive dipeptide, Val-Tyr (281.2 m/z), were chosen for MALDI-IMS. The signal-to-noise (S/N) ratios of dipeptides Gly-Sar and Val-Tyr were seen to increase by 2.4- and 8.0-fold, respectively, when using a 2',4',6'-trihydroxyacetophenone (THAP) matrix containing 5.0 mM phytic acid, instead of the THAP matrix alone. Owing to the phytic-acid-aided MALDI-IMS method, Gly-Sar and Val-Tyr absorbed in the rat intestinal membrane were successfully visualized. The proposed imaging method also provided useful information on intestinal peptide absorption; to some extent, Val-Tyr was rapidly hydrolyzed to Tyr by peptidases located at the intestinal microvillus during the absorption process. In conclusion, the strongly acidic additive, phytic acid, is beneficial for enhancing the visualization of small peptides using MALDI-IMS, owing to the suppression of ionization interfering salts in the tissue. PMID- 24063773 TI - A streamlined implementation of the glutamine synthetase-based protein expression system. AB - BACKGROUND: The glutamine synthetase-based protein expression system is widely used in industry and academia for producing recombinant proteins but relies on the cloning of transfected cells, necessitating substantial investments in time and handling. We streamlined the production of protein-producing cultures of Chinese hamster ovary cells using this system by co-expressing green fluorescent protein from an internal ribosomal entry site and selecting for high green fluorescent protein-expressing cells using fluorescence-activated cell sorting. RESULTS: Whereas other expression systems utilizing green fluorescent protein and fluorescence-activated cell sorting-based selection have relied on two or more sorting steps, we obtained stable expression of a test protein at levels >50% of that of an "average" clone and ~40% that of the "best" clone following a single sorting step. Versus clone-based selection, the principal savings are in the number of handling steps (reduced by a third), handling time (reduced by 70%), and the time needed to produce protein-expressing cultures (reduced by ~3 weeks). Coupling the glutamine synthetase-based expression system with product independent selection in this way also facilitated the production of a hard-to assay protein. CONCLUSION: Utilizing just a single fluorescence-activated cell sorting-based selection step, the new streamlined implementation of the glutamine synthetase-based protein expression system offers protein yields sufficient for most research purposes, where <10 mg/L of protein expression is often required but relatively large numbers of constructs frequently need to be trialed. PMID- 24063775 TI - Comparison of outcomes between conventional lumbar fenestration discectomy and minimally invasive lumbar discectomy: an observational study with a minimum 2 year follow-up. AB - BACKGROUND: Different surgical techniques for lumbar discectomy are in vogue. This study compares the outcomes of two techniques for lumbar discectomy, viz. micro lumbar discectomy (LD) and conventional fenestration discectomy. MATERIALS AND METHODS: Sixty-six patients who had single-level 'virgin' lumbar disc herniation with unilateral radicular symptoms were included. Of these, 39 had undergone MLD while 27 had undergone fenestration. Outcomes were measured using the visual analogue scale (VAS) for back and leg pain, Japanese Orthopedic Association (JOA) score, Roland-Morris score (RM) improvement and North American Spine Society (NASS) score. All quantitative data were summarised using mean and standard deviation, and qualitative data using proportions. Significance of differences across the two groups in terms of mean scores was assessed using independent sample t test, and the improvement within the same groups was measured using paired t test. Multiple linear regression analysis was done to assess independent predictors of improvement. RESULTS: The MLD group showed statistically better outcomes with regard to improvement in JOA score at 6 weeks, 6 months and 2 years. Mean (SD) VAS for lower back ache at 6 weeks, 6 months, and 2 years was better for the MLD group. But the difference noted in VAS for leg pain was not statistically significant across the groups (P = 0.133). The improvement noted in JOA at 2 years postoperatively compared to the preoperative score was 13.67 (2.89) in the MLD group and 12.11 (3.30) in the macrodiscectomy group (P = 0.046).The mean (SD) RM improvement for the MLD group was 79.24% (8.96%) vs 71.72% (16.53), P = 0.02, in the macrodiscectomy group. Mean NASS score for the MLD group was 2.74 vs 2.96 in the conventional group (P = 0.407).The type of surgery was the significant predictor of improvement in JOA score (P = 0.046) even after adjusting for age, sex, level of lesion and the initial JOA score. MLD as the surgical procedure (P = 0.002) and a lower initial JOA score (P = 0.006) were found significantly contributing to the RM improvement. CONCLUSION: The study shows that both MLD and fenestration give comparable results at short-term follow-up. There is statistically significant improvement in MLD with regard to improvement in JOA, VAS and RM scores at 2 years. However, the difference is not large and may not be clinically significant. PMID- 24063776 TI - Investigating short- and long-term transfer effects of a Taiji beginner course in participants' daily life. AB - OBJECTIVE: In recent years research investigating various health benefits of Taiji practice has markedly increased. Despite this growing scientific interest, essential questions such as to what extent a Taiji course may exert noticeable effects in participants' everyday life, what these effects are, and how and where potential transfer effects occur, have hardly been considered. The aim of our study was to explore transfer effects from a Taiji course into participants' daily lives. METHODS: We conducted a longitudinal observational study in 45 healthy participants at the end of their three-month Taiji beginner course (tp1) and at two months (tp2) as well as one year after course completion (tp3). Participants were asked to report their Taiji practice behavior at all time points, as well as to rate and describe perceived transfer effects of Taiji course contents on their daily life at tp1 and tp3. RESULTS: Transfer effects were reported by 91.1% of all respondents after course completion (tp1) and persisted in 73.3% at the one-year follow-up assessment (tp3), counting "increase of self-efficacy", "improvement of stress management", and "increase of body awareness" as the most frequently mentioned effects. Transfer effects predominantly occurred in participants' work and social environments, as well as during everyday activities in public areas. While self-reliant Taiji practice frequency significantly decreased from 82.2% at tp1 to 55.6% at tp3 (P < 0.001), the magnitude of self-reported transfer effects did not (P = 0.35). As explorative analyses revealed, regular Taiji course attendance was highly correlated with stronger transfer effects at tp1 (r = 0.51; P < 0.001) and tp3 (r = 0.35; P = 0.020). Participants reporting high self-reliant Taiji practice frequency at tp2 were likely to maintain a regular practice routine at tp3 (r = 0.42; P < 0.004), whereas self-reliant practice frequency and transfer effects at tp1 were positively correlated with self-reliant practice frequency at tp3 on a trend level (r < 0.27; P > 0.08). CONCLUSION: Our data underline the importance of regular course participation for pronounced and long lasting transfer effects into participants' everyday life. We discuss that several context and process related aspects of a Taiji intervention are potentially relevant factors for enhancement of transfer effect. PMID- 24063777 TI - A study on drug utilization and prescription habits of physicians in a government homeopathic hospital in West Bengal, India. AB - OBJECTIVE: Improper prescribing habits and inappropriate drug use lead to serious health and economic consequences. This study was undertaken to evaluate drug utilization services and prescription patterns of homeopathic doctors in a government homeopathic teaching hospital in India. METHODS: No standardized homeopathic drug use indicators are available. The researchers used indicators for health care setting (drug availability)-modified prescribing indicators and patient care indicators, based on World Health Organization's core drug use indicators. A cross-sectional, prospective, institutional, observational study of 2-month duration with record analysis was conducted on 600 patients visiting seven different outpatient departments (OPDs) for the first time at Mahesh Bhattacharyya Homeopathic Medical College and Hospital, Howrah, West Bengal, India, using the developed indicators. RESULTS: Overall availability of prescribed drugs was quite satisfactory (92.28%). Centesimal potencies accounted for the majority of prescriptions (74.76%). There was a poor record of diagnosis (39.17%) except in the OPDs of Gynecology and Obstetrics (68.48%, P < 0.01) and Dermatology (64.58%, P < 0.01). Records of investigational findings and ongoing therapies, if any, were also poor except OPDs of Gynecology and Obstetrics, and Pediatrics. Structure of prescriptions was maintained satisfactorily in all the OPDs. Though tendency of using 'individualized homeopathy' predominated, there also existed the use of 'polypharmacy'. Mean consultation time was 5.9 min. Labeling was extremely poor and is an area needing improvement. The prescriptions were highly legible. CONCLUSION: This was a preliminary study, conducted for the first time in homeopathy using newly developed indicators that yield meaningful results. Further studies are necessary in order to evaluate the different factors involved and to plan future interventions to improve the quality of care in healthcare settings. PMID- 24063778 TI - Difference between the effects of one-site and three-site abdominal hot-stone stimulation on the skin-temperature changes of the lower limbs. AB - OBJECTIVE: To determine whether any difference exists in the skin-temperature responses of the lower limbs to hot-stone application relative to one-site and three-site abdominal application. METHODS: Twenty-five female students participated in experimental sessions after a random allocation: 14 participants received a hot-stone application on the umbilicus, superior-umbilicus, and inferior-umbilicus regions (hereafter referred to as the three-site stimulation group); and 11 participants received the hot-stone application on the umbilicus region only (hereafter referred to as the one-site stimulation group). Heated stones were applied for 9 min to participants in both groups. Four arbitrary frames (the lower leg, ankle, proximal foot, and distal foot regions) were created in order to observe and analyze the skin temperature of a lower limb using a thermograph. Observation periods were as follows: before hot-stone stimulation, immediately after stimulation, and 5, 10, 15, and 20 min after stimulation. RESULTS: There was a significant offset interaction of distal foot skin temperature between the groups. The left-side distal foot skin temperature increased at 15 and 20 min following the three-site abdominal hot-stone stimulation. The right-side distal foot skin temperature increased immediately and at 5, 10, 15, and 20 min following the three-site abdominal hot-stone stimulation. No significant change in distal foot skin temperature was observed following the one-site stimulation. CONCLUSION: Lower-limb skin temperature was altered following hot-stone stimulation applied to the abdomen, and the one-site stimulation and three-site stimulation yielded different distal foot skin temperature reactions. PMID- 24063779 TI - Effects of cosmetics containing purified honeybee (Apis mellifera L.) venom on acne vulgaris. AB - OBJECTIVE: Acne vulgaris is a chronic dermatologic problem with multiple factors involved in its pathogenesis. Alternative solutions to acne treatment were instigated by antibiotic resistance despite of its extensive use. Purified bee venom (PBV) has been proposed as a promising candidate for that purpose. The present study was designed to confirm the antibacterial effect of PBV and access the efficacy of cosmetics containing PBV in subjects with acne vulgaris. METHODS: The skin bacterium Propionibacterium acnes was incubated with PBV at various concentrations and bacterial growth was evaluated using the colony forming unit (CFU) assay. The mechanism of PBV employed in killing P. acnes was examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). In addition, a total of 12 subjects were randomized in a double-blind, controlled trial to receive either cosmetics containing PBV or cosmetics without PBV for two weeks. Evaluations included lesion counts and skin microorganism. RESULTS: PBV exhibited antimicrobial activity in a concentration-dependent manner, reducing the number of P. acnes CFU by approximately 6 logs at a concentration of 0.5 mg. When PBV concentration was higher than 1.0 mg, no P. acnes colonies were spotted on an agar. TEM and SEM of untreated P. acnes illustrated the normal pleomorphic structure, whereas the PBV-treated bacterium lost the integrity of surface architecture. Significant difference (P=0.027) in the grading levels based on numbers of lesion counts for inflammatory and noninflammatory was observed in favour of the PBV group compared with the control group. In terms of average decrement of skin microorganism, subjects receiving cosmetics containing PBV experienced a significant 57.5% decrease of adenosine triphosphate levels, whereas participants receiving cosmetics without PBV experienced a nonsignificant decrease of 4.7%. CONCLUSION: These results show that the in vitro actions of antimicrobial activity of PBV were translated in vivo. Cosmetics containing PBV provided a certain degree of efficacy in terms of lesion counts and skin microorganism concentration compared with cosmetics without PBV in subjects with acne vulgaris. PBV may be a good candidate compound for developing therapeutic drug for the treatment of acne vulgaris. PMID- 24063780 TI - Cardioprotection of Shenfu preparata on cardiac myocytes through cytochrome P450 2J3. AB - OBJECTIVE: To evaluate whether Shenfu injection (SFI) protects against cardiac myocyte injury induced by Fupian injection (FPI) in vitro. METHODS: H9c2 cells were separately treated with FPI, Renshen injection (RSI) and SFI. Cell viability, lactate dehydrogenase (LDH) release, spontaneous beating rate of primative cardical cells, caspase-3/7 activity, cell apoptosis, and cytochrome P450 2J3 (CYP2J3) mRNA expression were analyzed. RESULTS: The viability of H9c2 cells treated with SFI (37 and 75 mg/mL) was significantly higher than that of H9c2 cells treated with FPI (25 and 50 mg/mL) (P<0.05, P<0.01, respectively). LDH activity of H9c2 cells treated with SFI (75 mg/mL) was significantly decreased (P<0.01) compared with that of H9c2 cells treated with FPI (50 mg/mL). SFI (150 mg/mL) significantly attenuated FPI (100 mg/mL)-induced spontaneous beating rate decrease in primary myocardial cells after 4-hour treatment. Compared with FPI (12 and 25 mg/mL), SFI (18 and 37 mg/mL) treatment could effectively reverse the change of caspase-3/7 activity (P<0.01 and P<0.01, respectively). Compared with FPI (6 and 25 mg/mL), apoptotic cells decreased significantly (P<0.05, P<0.01, respectively) when H9c2 cells were incubated with SFI (9 and 37 mg/mL). The expression of CYP2J3 mRNA was down-regulated by FPI, while RSI and SFI could up regulate the expression of CYP2J3 (P<0.01), which suggested the potential mechanism of protection of RSI against cardiac myocyte damage induced by FPI treatment. CONCLUSION: These observations indicate that SFI has the potential to exert cardioprotective effects against FPI toxicity. The effect was possibly correlated with the activation of CYP2J3. PMID- 24063781 TI - Effects of rutin on oxidative stress in mice with kainic acid-induced seizure. AB - OBJECTIVE: Flavonoids are present in foods such as fruits and vegetables. Several studies have demonstrated a relationship between the consumption of flavonoid rich foods and prevention of human disease, including neurodegenerative disorders. We assessed the effect of rutin (quercetin-3-O-rutinoside) on oxidative stress in kainic acid (KA)-induced seizure. METHODS: Thirty-six BALB/c mice were randomly divided into three groups. In the control group, saline (intra peritoneal, i.p.) was administered for 7 d, and on the last day, KA (10 mg/kg, i.p.) was injected 30 min after administration of saline. In rutin groups, mice were pretreated with rutin (100 and 200 mg/kg, i.p.) for 7 d, and on the last day, KA (10 mg/kg, i.p.) was injected 30 min after administration of rutin. Subsequently, behavioural changes were observed in mice. Lipid peroxidation and oxidative stress were measured respectively in the early and late phases after KA induced seizures. RESULTS: Seizure scores in the rutin groups were significantly lower than those in the control group (P < 0.01). Furthermore, rutin dose dependently inhibited the number of wet-dog shakes (WDS) (P < 0.05). Malondialdehyde level in the hippocampus of the rutin groups was significantly lower than that in the hippocampus of the control group on days 1 and 21 after KA administration. In the rutin groups, the thiol levels observed on day 1 after KA administration were higher than that in the control group (P < 0.01). CONCLUSION: These results indicate that rutin has potential anticonvulsant and antioxidative activities against oxidative stress in KA-induced seizure in mice. PMID- 24063782 TI - Preliminary pharmacological evaluation of Alocasia indica Schott tuber. AB - OBJECTIVE: To elucidate potential antioxidant, antidiarrheal, cytotoxic, and antibacterial activities of the ethanol extract of Alocasia indica Schott tuber in different experimental models established in vitro and in vivo. METHODS: In vitro antioxidant activity was evaluated by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging assay. Phenolic content was estimated by using Folin Ciocalteu's reagent while reducing ability was measured by ferric reducing power assay. In vivo antidiarrheal studies were carried out in mice, and the activity was evaluated in castor oil and magnesium sulfate-induced diarrhea. Disk diffusion assay was utilized to determine antibacterial activity against a number of pathogenic bacterial strains. Acute toxicity test was carried out to measure the safe doses for the extract. RESULTS: In DPPH radical-scavenging assay, the extract exhibited strong radical-scavenging activity with the 50% inhibitory concentration value of 42.66 MUg/mL. Total phenolic content was found to be 542.26 mg gallic acid equivalent per 100 g of dried tuber extract, whereas flavonoid content was found to be 4.30 mg quercetin equivalent/g of dried tuber extract. In reducing power assay, the extract showed strong reducing power in a concentration-dependent manner. The extract significantly (P < 0.01) enhanced the latent period and decreased defecation in both castor oil- and magnesium sulfate induced diarrhea. The extract also lessened gastrointestinal motility in mice. Potential antibacterial activity was exhibited by the extract against all the tested bacterial strains in disk diffusion assay. The 50% lethal concentration against brine shrimp nauplii was 81.09 MUg/mL. CONCLUSION: The results demonstrated that the ethanol extract of A. indica has potential antioxidant, antidiarrheal, cytotoxic, and antibacterial activity. PMID- 24063783 TI - An improved association-mining research for exploring Chinese herbal property theory: based on data of the Shennong's Classic of Materia Medica. AB - Knowledge Discovery in Databases is gaining attention and raising new hopes for traditional Chinese medicine (TCM) researchers. It is a useful tool in understanding and deciphering TCM theories. Aiming for a better understanding of Chinese herbal property theory (CHPT), this paper performed an improved association rule learning to analyze semistructured text in the book entitled Shennong's Classic of Materia Medica. The text was firstly annotated and transformed to well-structured multidimensional data. Subsequently, an Apriori algorithm was employed for producing association rules after the sensitivity analysis of parameters. From the confirmed 120 resulting rules that described the intrinsic relationships between herbal property (qi, flavor and their combinations) and herbal efficacy, two novel fundamental principles underlying CHPT were acquired and further elucidated: (1) the many-to-one mapping of herbal efficacy to herbal property; (2) the nonrandom overlap between the related efficacy of qi and flavor. This work provided an innovative knowledge about CHPT, which would be helpful for its modern research. PMID- 24063784 TI - Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: diseases in external medicine (Part 4). PMID- 24063785 TI - Molecular clues about the dystrophin-neuronal nitric oxide synthase interaction: a theoretical approach. AB - Dystrophin is a large skeletal muscle protein located at the internal face of the plasma membrane and interacting with membrane phospholipids and a number of cytosolic proteins. Binding of neuronal nitric oxide synthase (nNOS) to dystrophin appears to be crucial for exercise-induced increases in blood supply in muscle cells. By contrast, utrophin, the developmental homologous protein of dystrophin, does not display nNOS interaction. Recent in vitro and in vivo experiments showed that the dystrophin region involved in nNOS binding is located in spectrin-like repeats R16 and R17 of its filamentous central domain. Using homology modeling and atomistic molecular dynamics simulation, we compared the structural organization and surface potentials of dystrophin, utrophin, and chimeric fragments, thus revisiting the dystrophin-nNOS binding region. Our simulation results are in good agreement with experimental data. They provide a three-dimensional representation of the repeats and give insight into the molecular organization of the regions involved in dystrophin-nNOS interaction. This study also further elucidates the physical properties crucial for this interaction, particularly the presence of a large hydrophobic patch. These results will be helpful to improving our understanding of the phenotypic features of patients bearing mutations in the nNOS-binding region of dystrophin. PMID- 24063786 TI - Systemic side effects of antiviral therapy in a patient with acute retinal necrosis. AB - PURPOSE: To report a case of Acute Retinal Necrosis (ARN)-developed nephrotoxicity during intravenous acyclovir treatment and toxic hepatitis during oral valacyclovir treatment. DESIGN: Interventional case report. METHODS: Retrospective chart review. RESULTS: A 45-year-old male with ARN treated with intravenous acyclovir developed nephrotoxicity. After switching to oral valacyclovir, toxic hepatitis developed. Both renal and liver function tests returned to normal levels after drug cessation CONCLUSIONS: Although rare, clinicians should be aware of the potential nephrotoxic and hepatotoxic side effects of antiviral therapy during ARN treatment. PMID- 24063787 TI - Computational prediction of associations between long non-coding RNAs and proteins. AB - BACKGROUND: Though most of the transcripts are long non-coding RNAs (lncRNAs), little is known about their functions. lncRNAs usually function through interactions with proteins, which implies the importance of identifying the binding proteins of lncRNAs in understanding the molecular mechanisms underlying the functions of lncRNAs. Only a few approaches are available for predicting interactions between lncRNAs and proteins. In this study, we introduce a new method lncPro. RESULTS: By encoding RNA and protein sequences into numeric vectors, we used matrix multiplication to score each RNA-protein pair. This score can be used to measure the interactions between an RNA-protein pair. This method effectively discriminates interacting and non-interacting RNA-protein pairs and predicts RNA-protein interactions within a given complex. Applying this method on all human proteins, we found that the long non-coding RNAs we collected tend to interact with nuclear proteins and RNA-binding proteins. CONCLUSIONS: Compared with the existing approaches, our method shortens the time for training matrix and obtains optimal results based on the model being used. The ability of predicting the associations between lncRNAs and proteins has also been enhanced. Our method provides an idea on how to integrate different information into the prediction process. PMID- 24063788 TI - Activity ex vivo of cytotoxic drugs in patient samples of peritoneal carcinomatosis with special focus on colorectal cancer. AB - BACKGROUND: The optimal choice of cytotoxic drugs for intraperitoneal chemotherapy (IPC) in conjunction with cytoreductive surgery (CRS) for treatment of peritoneal carcinomatosis (PC) is poorly defined. We investigated drug sensitivity ex vivo in patient samples of various PC tumor types and correlated clinical outcome to drug sensitivity within the subset of PC from colorectal cancer (CRC). METHODS: PC tissue samples (n = 174) from mesothelioma, pseudomyxoma peritonei (PMP), ovarian cancer, CRC or appendix cancer were analyzed ex vivo for sensitivity to oxaliplatin, cisplatin, mitomycin C, melphalan, irinotecan, docetaxel, doxorubicin and 5-FU. Clinicopathological variables and outcome data were collected for the CRC subset. RESULTS: Mesothelioma and ovarian cancer were generally more drug sensitive than CRC, appendix cancer and PMP. Oxaliplatin showed the most favorable ratio between achievable IPC concentration and ex vivo drug sensitivity. Drug sensitivity in CRC varied considerably between individual samples. Ex vivo drug sensitivity did not obviously correlate to time-to-progression (TTP) in individual patients. CONCLUSIONS: Drug-sensitivity varies considerably between PC diagnoses and individual patients arguing for individualized therapy in IPC rather than standard diagnosis-specific therapy. However, in the current paradigm of treatment according to diagnosis, oxaliplatin is seemingly the preferred drug for IPC from a drug sensitivity and concentration perspective. In the CRC subset, analysis of correlation between ex vivo drug sensitivity and TTP was inconclusive due to the heterogeneous nature of the data. PMID- 24063789 TI - Development and validation of an advanced anisotropic visco-hyperelastic human brain FE model. AB - This paper proposes the implementation of fractional anisotropy and axonal fiber orientation from diffusion tensor imaging (DTI) of 12 healthy patients into an existing human FE head model to develop a more realistic brain model with advanced constitutive laws. Further, the brain behavior was validated in terms of brain strain against experimental data published by Hardy et al. (2001, 2007) and for brain pressure against Nahum et al. (1977) experimental impacts. A reasonable agreement was observed between the simulation and experimental data. Results showed the feasibility of integrating axonal direction information into FE analysis and established the context of computation of axonal elongation in case of head trauma. PMID- 24063790 TI - Over-expression of LGR5 correlates with poor survival of colon cancer in mice as well as in patients. AB - Leucine-rich repeat-containing G protein-coupled receptor 5(LGR5) was identified as the stem cell marker of colon cancer stem cells(CSCs),which were considered as the main criminal cells initiation and reinitiation of colon cancer. We intended to demonstrate and further explain the relationship between LGR5 and colon cancer in mice model and patients. In our research, we used transcriptional methods and immunohistochemistry to investigate the LGR5 gene and protein expression, examined proliferating cell nuclear antigen(PCNA) and Ki67 which were the classic markers for cell proliferation in LGR5 protein positive and negative colon cancer among mice model and patients. Our results showed that LGR5 mRNA and protein expression was significantly over-expressed in 193/366 patients and 24/40mice model with primary colon cancer contrasted with matched normal tissues; significantly higher LGR5 gene expression was detected in pT4 cases than that in pT3 cases; PCNA and Ki67 expression was much more increase in colon cancer cells with positive LGR5 expression than those with negative LGR5 expression;LGR5 positive cancer not only in mice model but also in patients have shorter survival rate compared with LGR5 negative cancer. All our study manifested that LGR5 took on an important effect in the initiation and progression of colon cancer, provided also more helpful evidence for clinical diagnosis and an useful indicator for adjuvant therapy. PMID- 24063791 TI - Educator informed practice within a triadic preceptorship model. AB - Preceptorships have long been a subject of scholarship with proven effectiveness in preparing nursing students to transition into beginning graduate nurses. Nursing research has predominantly focused on the dyadic preceptor-student relationship. The triadic pedagogical relationship between educator-student preceptor has garnered less attention and inquiry. Nurse educators' experience in preceptorships is under reported. Through a process of scholarly inquiry, nurse educators from one western Canada School of Nursing documented their experiences and professional judgment in facilitating preceptorships over one semester. In the context of the anticipated exodus of nursing experts in the midst of rapidly changing healthcare delivery, this paper recommends a reemphasis on preceptorships as a triadic pedagogical relationship. Educator informed practices that foster triadic relationships in preceptorships include attending to distant relationships, being mindful of the influence of continuity, recognizing a preceptor's proficiency, responding to rapidly changing and complex environments, facilitating common understanding through communication, and integrating practice and education performance expectations. PMID- 24063792 TI - Challenging clinical learning environments: experiences of undergraduate nursing students. AB - Clinical learning is an essential component of becoming a nurse. However at times, students report experiencing challenging clinical learning environments (CCLE), raising questions regarding the nature of a challenging clinical learning environment, its impact on students' learning and how students might respond within a CCLE. Using an Interpretive Descriptive study design, researchers held focus groups with 54 students from two Canadian sites, who self-identified as having experienced a CCLE. Students defined a CCLE as affected by relationships in the clinical area and by the context of their learning experiences. CCLE decreased students' learning opportunities and impacted on them as persons. As students determined which relationships were challenging, they tapped other resources and they used strategies to rebuilt, reframe, redirect and/or retreat relative to the specific challenge. Relationships also acted as buffers to unsupportive practice cultures. Implications for practice and research are addressed. PMID- 24063793 TI - Virtual reality disaster training: translation to practice. AB - Disaster training is crucial to the mitigation of both mortality and morbidity associated with disasters. Just as clinical practice needs to be grounded in evidence, effective disaster education is dependent upon the development and use of andragogic and pedagogic evidence. Educational research findings must be transformed into useable education strategies. Virtual reality simulation is a teaching methodology that has the potential to be a powerful educational tool. The purpose of this article is to translate research findings related to the use of virtual reality simulation in disaster training into education practice. The Ace Star Model serves as a valuable framework to translate the VRS teaching methodology and improve disaster training of healthcare professionals. Using the Ace Star Model as a framework to put evidence into practice, strategies for implementing a virtual reality simulation are addressed. Practice guidelines, implementation recommendations, integration to practice and evaluation are discussed. It is imperative that health educators provide more exemplars of how research evidence can be moved through the various stages of the model to advance practice and sustain learning outcomes. PMID- 24063794 TI - Pharmacologic treatment of sport-related concussion: a review. AB - The goals of the current study were to review the published research over the past decade and to summarize the findings related to pharmacologic approaches in the treatment of sport-related concussion (SRC). PubMed searches across all databases were employed using combinations of the key words and search phrases ''concussion,'' ''mild traumatic brain injury,'' ''pharmacology,'' ''treatment,'' and ''sports,'' along with specific classes of pharmacologic agents. The few studies found were based primarily on clinician experience, with frequent reference to animal models. No clinical pharmacologic trials of SRC were found. The pharmacologic treatment of SRC remains focused on specific symptoms, and there is as yet no evidence-based treatment. On the basis of the limited published research, the authors offer some preliminary guidelines regarding the use of pharmacologic therapies in SRC. PMID- 24063795 TI - Necrotizing soft tissue infections of the upper extremity: a case series. AB - Four cases of necrotizing soft tissue infections of the upper extremity are presented. Each involved minor wounds to the hand that gradually progressed to fulminant infection. Two of the patients reported a history of alcohol abuse. One patient had psychiatric illness that led to delay in recognizing the infection and seeking intervention. The causative organism in all cases was group A beta hemolytic streptococcus. Fortunately, none of the patients suffered loss of the affected extremity, although long-term function is limited. The necrotizing soft tissue infection encountered in these cases represents a less severe presentation than classic necrotizing fasciitis. Necrotizing soft tissue infections are properly recognized as a spectrum of disease and can, as in these cases, follow a prolonged progression with limited systemic involvement. The current literature regarding diagnosis and treatment of necrotizing soft tissue infections is reviewed. PMID- 24063796 TI - Complications of hip and knee joint replacement in solid-organ transplant patients. AB - This study investigated complication rates for 68 solid-organ transplant patients who had undergone 94 primary hip or knee joint replacements at a single institution from 1995 to 2008. There was a deep infection rate of 6.8% in the transplant patients compared to a 1.9% deep infection rate for all primary joint replacement patients at the Medical University of South Carolina over the same time period (odds ratio 4.48). All four infections in the transplant group occurred in diabetic patients. The joint revision rate for transplant patients was 13% (deep infection 6.8%, aseptic loosening 5.1%, instability 1.7%). Other complications included superficial infections (5.1%), deep venous thromboses (3.4%), and a nonfatal pulmonary embolus (1.7%). The deep infection rate for joint replacement in solid-organ transplant patients was higher than rates reported by most similar studies, and diabetic patients may be at particular risk. PMID- 24063797 TI - Plate position and angular stability: mechanical comparison in sawbone osteotomy models. AB - Proximal metatarsal osteotomies are inherently unstable and difficult to fix. The purpose of this study was to compare the mechanical stiffness in sawbone models of medially versus dorsally placed plates and then to compare semilocked versus nonlocked plates in different osteotomy configurations. Thirty sawbone models were constructed, fixed either with titanium self-locking or steel mini-fragment plates. They were divided in groups and their stiffness was measured. The stiffness of any model fixed with medial titanium or steel plates was on average 158% and 228% greater, respectively, compared to dorsal plates. Adding a dorsal shelf of bone to a proximal closing wedge osteotomy increases its stiffness. Using locked plates increased the mechanical stiffness in only one configuration. The article suggests that models fixed with medial plates have greater resistance to failure than models fixed with dorsal plates. Using locked plates does not increase the mechanical stiffness of the construct. PMID- 24063798 TI - Supraclavicular long thoracic nerve decompression for traumatic scapular winging. AB - Scapular winging resulting from long thoracic nerve palsy is a painful, disabling condition often associated with periscapular weakness and decreased active shoulder range of motion. Observation, therapy, and symptomatic treatment have customarily been the recommended treatment, often with disappointing results. Recently, encouraging results have been reported following decompression of the long thoracic nerve. Six patients who underwent a supraclavicular long thoracic nerve decompression from 2008 to 2010 for painful posttraumatic scapular winging were identified retrospectively. Four males and two females with a mean age of 28 years at the time of surgery were treated for an average of 9 months following injury. Mean follow-up was 16 months following surgery. All patients had decreased pain, disability, and scapular winging, and improved shoulder range of motion. One patient had recurrence following a second injury. This procedure has resulted in good outcomes without the morbidity associated with tendon or nerve transfer. PMID- 24063799 TI - Effect of cyclic strain on tensile properties of a naturally derived, decellularized tendon scaffold seeded with allogeneic tenocytes and associated messenger RNA expression. AB - Naturally derived tendon scaffolds have the potential to improve the treatment of flexor tendon injuries. Seeded and unseeded tendon scaffolds were maintained in the presence or absence of physiologic strain for 7 days. After 7 days, the tensile properties and associated messenger RNA expression were compared. Seeded scaffolds maintained in the absence of strain had significantly lower tensile properties than unseeded tendons and fresh-frozen tendons. The loss of tensile properties was associated with elevated matrix metalloproteinase-2 and collagen III expression. Tensile properties of seeded scaffolds maintained in the presence of strain for 7 days after seeding did not differ from those of fresh-frozen tendons. This study demonstrates that the tensile properties of seeded, naturally derived tendon scaffolds will degrade rapidly in the absence of cyclic strain. Seeded scaffolds used for tendon reconstruction should be maintained under cyclic strain to maintain essential tensile properties. PMID- 24063800 TI - Botox as an adjuvant to tendon transfer for foot drop. AB - The authors' hypothesis was that weakening the gastrocnemius muscle at the time of tendon transfer will reduce the risk of rupture and facilitate faster rehabilitation with increased active dorsiflexion and improved overall outcome, because the transferred tendon is spared the antagonistic effect of the gastrocnemius during the early recovery period. A retrospective chart review identified 12 patients who underwent a tibialis posterior tendon (PTT) transfer with gastrocnemius Botox injection for foot drop. All statistical analyses were conducted using SAS version 9.2 (SAS Institute, Inc., Cary, North Carolina). There were no failures or tendon ruptures. All patients had zero dorsiflexion (DF) strength preoperatively, and those with DF strength documented postoperatively had a mean DF strength at final clinical evaluation of 3.9 (p < .001) with a mean active DF of 4 degrees . It was concluded that gastrocnemius chemodenervation with Botox at the time of PTT transfer is a safe and effective means of restoring active dorsiflexion. PMID- 24063801 TI - Stemmed knee replacement in a patient with an irremovable tibial nail. AB - A patient with a cemented centrally located intramedullary tibial nail that occluded the proximal tibial canal underwent knee reconstruction with a total knee design utilizing a custom hollow tibial stem. In this oncology case, a rotating-hinge knee design was used that incorporates an intra-articular inverted post-in-channel central rotational post design. This design allowed for a rather straightforward reconstruction that functioned well for 3 years. Although rarely encountered, utilization of a hollow-stemmed tibial total knee component may allow salvage of an extremity with central occlusion of the proximal tibial canal. PMID- 24063802 TI - Glenoid component failure after total shoulder arthroplasty with migration of the component into posterior subcutaneous tissue: a case report. AB - Glenoid component loosening is the most frequently cited complication related to total shoulder arthroplasty (TSA). The mechanism behind glenoid loosening remains an area of active investigation. Distant migration of the implant following loosening has not been described. Both glenoid implant removal and revision have demonstrated successful results following symptomatic loosening. This report presents the case of a 61-year-old female who experienced a complete glenoid component dissociation following TSA with migration of the implant into the subcutaneous tissue of the posterior shoulder. The patient underwent implant removal without glenoid revision and has experienced an excellent outcome at midterm follow-up. Although glenoid component loosening remains the most common complication associated with TSA, this particular scenario and the subsequent management have not been previously reported. PMID- 24063803 TI - Attrition tendinitis of long head of biceps brachii in relation to humeral head osteonecrosis: case report. AB - This case report identifies a 41-year-old male patient who developed anterior shoulder pain in the setting of humeral head osteonecrosis. As a consequence of the cartilage degeneration, multiple loose bodies formed and migrated into the bicipital tendon sheath, causing attrition tendinitis, which was a feature of the clinical presentation. The patient was treated by a combination of arthroscopic glenohumeral joint debridement and open tenodesis of the biceps using a suture anchor. Follow-up revealed asymptomatic shoulder function by 18 months. This is the first report in the literature of bicipital tendinitis in the context of avascular necrosis of the shoulder. PMID- 24063806 TI - The function of Notch signalling in segment formation in the crustacean Daphnia magna (Branchiopoda). AB - Ten years ago we showed for the first time that Notch signalling is required in segmentation in spiders, indicating the existence of similar mechanisms in arthropod and vertebrate segmentation. However, conflicting results in various arthropod groups hampered our understanding of the ancestral function of Notch in arthropod segmentation. Here we fill a crucial data gap in arthropods and analyse segmentation in a crustacean embryo. We analyse the expression of homologues of the Drosophila and vertebrate segmentation genes and show that members of the Notch signalling pathway are expressed at the same time as the pair-rule genes. Furthermore, inactivation of Notch signalling results in irregular boundaries of the odd-skipped-like expression domains and affects the formation of segments. In severe cases embryos appear unsegmented. We suggest two scenarios for the function of Notch signalling in segmentation. The first scenario agrees with a segmentation clock involving Notch signalling, while the second scenario discusses an alternative mechanism of Notch function which is integrated into a hierarchical segmentation cascade. PMID- 24063805 TI - Planarian MBD2/3 is required for adult stem cell pluripotency independently of DNA methylation. AB - Planarian adult stem cells (pASCs) or neoblasts represent an ideal system to study the evolution of stem cells and pluripotency as they underpin an unrivaled capacity for regeneration. We wish to understand the control of differentiation and pluripotency in pASCs and to understand how conserved, convergent or divergent these mechanisms are across the Bilateria. Here we show the planarian methyl-CpG Binding Domain 2/3 (mbd2/3) gene is required for pASC differentiation during regeneration and tissue homeostasis. The genome does not have detectable levels of 5-methylcytosine (5(m)C) and we find no role for a potential DNA methylase. We conclude that MBD proteins may have had an ancient role in broadly controlling animal stem cell pluripotency, but that DNA methylation is not involved in planarian stem cell differentiation. PMID- 24063807 TI - FGF4 is a limiting factor controlling the proportions of primitive endoderm and epiblast in the ICM of the mouse blastocyst. AB - The primitive endoderm (PE) and epiblast (EPI) are two lineages derived from the inner cell mass (ICM) of the E3.5 blastocyst. Although it has been shown that FGF signaling is necessary and sufficient for PE specification in the ICM, it is unknown what mechanisms control the PE/EPI proportion in the embryo. Because modulation of FGF signaling alone is sufficient to convert all ICM cells to either PE or EPI, a model has been proposed in which the amount of FGF in the embryo controls the PE/EPI proportion. To test this model, we reduced the amount of FGF4, the major FGF in the preimplantation embryo, using various genotypes of Fgf4 mutants. We observed a maternal contribution of Fgf4 in PE specification, but it was dispensable for development. In addition, upon treatment of Fgf4 mutant embryos with exogenous FGF4, we observed a progressive increase of PE proportions in an FGF4 dose dependent manner, regardless of embryo genotype. We conclude that the amount of FGF4 is limited and regulates PE/EPI proportions in the mouse embryo. PMID- 24063808 TI - Lentil-based diets attenuate hypertension and large-artery remodelling in spontaneously hypertensive rats. AB - Hypertension is a major risk factor for CVD, the leading cause of mortality worldwide. The prevalence of hypertension is expected to continue increasing, and current pharmacological treatments cannot alleviate all the associated problems. Pulse crops have been touted as a general health food and are now being studied for their possible effects on several disease states including hypertension, obesity and diabetes. In the present study, 15-week-old spontaneously hypertensive rats (SHR) were fed diets containing 30% w/w beans, peas, lentils, chickpeas, or mixed pulses or a pulse-free control diet for 4 weeks. Normotensive Wistar-Kyoto (WKY) rats were placed on a control diet. Pulse wave velocity (PWV) was measured weekly, while blood pressure (BP) was measured at baseline and week 4. Fasting serum obtained in week 4 of the study was analysed for circulating lipids. A histological analysis was carried out on aortic sections to determine vascular geometry. Of all the pulse varieties studied, lentils were found to be able to attenuate the rise in BP in the SHR model (P< 0.05). Lentils were able to decrease the media:lumen ratio and media width of the aorta. The total cholesterol (TC), LDL-cholesterol (LDL-C) and HDL-cholesterol levels of rats fed the pulse-based diets were found to be lower when compared with those of the WKY rat and SHR controls (P< 0.05). Although all pulses reduced circulating TC and LDL-C levels in the SHR, only lentils significantly reduced the rise in BP and large-artery remodelling in the SHR, but had no effect on PWV. These results indicate that the effects of lentils on arterial remodelling and BP in the SHR are independent of circulating LDL-C levels. PMID- 24063810 TI - Facile one-pot synthesis of Fe3O4@Au composite nanoparticles for dual-mode MR/CT imaging applications. AB - A facile one-pot hydrothermal approach to synthesizing Fe3O4@Au composite nanoparticles (CNPs) for dual-mode magnetic resonance (MR) and computed tomography (CT) imaging applications is reported. In this work, polyethyleneimine (PEI) partially modified with poly(ethylene glycol) monomethyl ether (mPEG) was used as a stabilizer to form gold NPs (mPEG-PEI.NH2-Au NPs) with the assistance of sodium borohydride reduction. The mPEG-PEI.NH2-Au NPs were then mixed with iron(II) salt in a basic aqueous solution followed by treatment under an elevated temperature and pressure. This hydrothermal process led to the formation of Fe3O4@Au-mPEG-PEI.NH2 CNPs. The remaining PEI amine groups were finally acetylated to reduce the surface positive charge of the CNPs. The formed Fe3O4@Au mPEG-PEI.NHAc (Fe3O4@Au) CNPs were characterized via different techniques. The combined in vitro cell viability assay, cell morphology observation, flow cytometry, and hemolysis assay data show that the formed Fe3O4@Au CNPs are noncytotoxic and hemocompatible in the given concentration range. MR and CT imaging data reveal that the formed Fe3O4@Au CNPs have a relatively high r2 relaxivity (146.07 mM(-1) s(-1)) and good X-ray attenuation property, which enables their uses as contrast agents for MR imaging of mouse liver and CT imaging of rat liver and aorta. The Fe3O4@Au CNPs developed via the facile one pot approach may have promising potential for the dual-mode MR/CT imaging of different biological systems. PMID- 24063809 TI - Augmentation therapy for alpha-1 antitrypsin deficiency: towards a personalised approach. AB - BACKGROUND: Intravenous augmentation therapy is the only specific treatment available for emphysema associated with alpha-1 antitrypsin deficiency. Despite large observational studies and limited interventional studies there remains controversy about the efficacy of this treatment due to the impracticality of conducting adequately powered studies to evaluate the rate of decline in lung function, due to the low prevalence and the slow progression of the disease. However, measurement of lung density by computed tomography is a more specific and sensitive marker of the evolution of emphysema and two small placebo controlled clinical trials have provided evidence supporting a reduction in the rate of decline in lung density with augmentation therapy. THE PROBLEM: Where augmentation therapy has become available there has been little consideration of a structured approach to therapy which is often introduced on the basis of functional impairment at diagnosis. Data from registries have shown a great variability in the evolution of lung disease according to patient acquisition and the presence of recognised risk factors. Avoidance of risk factors may, in many cases, stabilise the disease. Since augmentation therapy itself will at best preserve the presenting level of lung damage yet require intravenous administration for life with associated costs, identification of patients at risk of continued rapid or long term progression is essential to select those for whom this treatment can be most appropriate and hence generally more cost-effective. This represents a major reconsideration of the current practice in order to develop a consistent approach to management world wide. PURPOSE OF THIS REVIEW: The current review assesses the evidence for efficacy of augmentation therapy and considers how the combination of age, physiological impairment, exacerbation history and rate of decline in spirometry and other measures of emphysema may be used to improve therapeutic decision making, until a reliable predictive biomarker of the evolution of lung impairment can be identified. In addition, individual pharmacokinetic studies may permit the selection of the best regimen of administration for those who need it. SUMMARY: The rarity and variable characteristics of the disease imply the need for an individualised approach to therapy in specialised centres with sufficient experience to apply a systematic approach to monitoring and management. PMID- 24063811 TI - A test of agent-based models as a tool for predicting patterns of pathogen transmission in complex landscapes. AB - BACKGROUND: Landscape complexity can mitigate or facilitate host dispersal, influencing patterns of pathogen transmission. Spatial transmission of pathogens through landscapes, therefore, presents an important but not fully elucidated aspect of transmission dynamics. Using an agent-based model (LiNK) that incorporates GIS data, we examined the effects of landscape information on the spatial patterns of host movement and pathogen transmission in a system of long tailed macaques and their gut parasites. We first examined the role of the landscape to identify any individual or additive effects on host movement. We then compared modeled dispersal distance to patterns of actual macaque gene flow to both confirm our model's predictions and to understand the role of individual land uses on dispersal. Finally, we compared the rate and the spread of two gastrointestinal parasites, Entamoeba histolytica and E. dispar, to understand how landscape complexity influences spatial patterns of pathogen transmission. RESULTS: LiNK captured emergent properties of the landscape, finding that interaction effects between landscape layers could mitigate the rate of infection in a non-additive way. We also found that the inclusion of landscape information facilitated an accurate prediction of macaque dispersal patterns across a complex landscape, as confirmed by Mantel tests comparing genetic and simulated dispersed distances. Finally, we demonstrated that landscape heterogeneity proved a significant barrier for a highly virulent pathogen, limiting the dispersal ability of hosts and thus its own transmission into distant populations. CONCLUSIONS: Landscape complexity plays a significant role in determining the path of host dispersal and patterns of pathogen transmission. Incorporating landscape heterogeneity and host behavior into disease management decisions can be important in targeting response efforts, identifying cryptic transmission opportunities, and reducing or understanding potential for unintended ecological and evolutionary consequences. The inclusion of these data into models of pathogen transmission patterns improves our understanding of these dynamics, ultimately proving beneficial for sound public health policy. PMID- 24063812 TI - Oxytocin receptor blockade reduces acquisition but not retrieval of taste aversion and blunts responsiveness of amygdala neurons to an aversive stimulus. AB - When gastrointestinal sickness induced by toxin injection is associated with exposure to novel food, the animal acquires a conditioned taste aversion (CTA). Malaise is accompanied by a surge in oxytocin release and in oxytocin neuronal activity; however, it is unclear whether oxytocin is a key facilitator of aversion or merely its marker. Herein we investigated whether blockade of the oxytocin receptor with the blood-brain barrier penetrant oxytocin receptor antagonist L-368,899 is detrimental for the acquisition and/or retrieval of lithium chloride (LiCl)-dependent CTA to a saccharin solution in mice. We also examined whether L-368,899 given prior to LiCl affects neuronal activity defined through c-Fos immunohistochemistry in select brain sites facilitating CTA acquisition. L-368,899 given prior to LiCl caused a 30% increase in saccharin solution intake in a two-bottle test, but when the antagonist was administered before the two-bottle test, it failed to diminish the retrieval of an existing CTA. LiCl administration increased c-Fos expression in the hypothalamic paraventricular and supraoptic nuclei, area postrema, nucleus of the solitary tract and basolateral and central (CNA) nuclei of the amygdala. L-368,899 injected before LiCl reduced the number of c-Fos positive CNA neurons and brought it down to levels similar to those observed in mice treated only with L-368,899. We conclude that oxytocin is one of the key components in acquisition of LiCl induced CTA and the aversive response can be alleviated by the oxytocin receptor blockade. Oxytocin receptor antagonism blunts responsiveness of CNA to peripherally injected LiCl. PMID- 24063813 TI - Different patterns of gene structure divergence following gene duplication in Arabidopsis. AB - BACKGROUND: Divergence in gene structure following gene duplication is not well understood. Gene duplication can occur via whole-genome duplication (WGD) and single-gene duplications including tandem, proximal and transposed duplications. Different modes of gene duplication may be associated with different types, levels, and patterns of structural divergence. RESULTS: In Arabidopsis thaliana, we denote levels of structural divergence between duplicated genes by differences in coding-region lengths and average exon lengths, and the number of insertions/deletions (indels) and maximum indel length in their protein sequence alignment. Among recent duplicates of different modes, transposed duplicates diverge most dramatically in gene structure. In transposed duplications, parental loci tend to have longer coding-regions and exons, and smaller numbers of indels and maximum indel lengths than transposed loci, reflecting biased structural changes in transposed duplications. Structural divergence increases with evolutionary time for WGDs, but not transposed duplications, possibly because of biased gene losses following transposed duplications. Structural divergence has heterogeneous relationships with nucleotide substitution rates, but is consistently positively correlated with gene expression divergence. The NBS-LRR gene family shows higher-than-average levels of structural divergence. CONCLUSIONS: Our study suggests that structural divergence between duplicated genes is greatly affected by the mechanisms of gene duplication and may be not proportional to evolutionary time, and that certain gene families are under selection on rapid evolution of gene structure. PMID- 24063814 TI - Cyr61 induces the expression of monocyte chemoattractant protein-1 via the integrin alphanubeta3, FAK, PI3K/Akt, and NF-kappaB pathways in retinal vascular endothelial cells. AB - Diabetes causes a number of metabolic and physiological abnormalities in the retina. Many of the molecular and physiological abnormalities that develop during diabetic retinopathy are due to inflammation. Monocyte chemoattractant protein-1 (MCP-1) is an important factor involved in diabetic retinopathy. In a previous study, we found that cysteine-rich 61 (Cyr61), an important angiogenic factor, also plays an important role in diabetic retinopathy. In addition to the direct effects of Cyr61, we observed that Cyr61 can induce the expression of MCP-1. However, the mechanism through which this occurs is not completely understood in chorioretinal vascular endothelial cells. We therefore investigated the effects of Cyr61 on MCP-1 expression in this cell type. Cyr61 stimulated the expression of MCP-1 at the mRNA, protein, and secreted protein levels in a dose-dependent and time-dependent manner. Both total MCP-1 levels and secreted MCP-1 levels were attenuated during the response to Cyr61 stimulation by pretreatment with integrin alphanubeta3-blocking antibodies, a FAK inhibitor (PF573228), a PI3K inhibitor (LY294002), and an Akt inhibitor (A6730). Electrophoretic mobility shift assays revealed that the above inhibitors suppressed the activation of NF-kappaB. Additionally, deletion of the NF-kappaB-binding element in the MCP-1 gene promoter led to a decrease in expression in luciferase reporter assays. These results show that the induction of MCP-1 by Cyr61 is mediated through the activation of the integrin alphanubeta3, FAK, PI3K/Akt, and IKK/NF-kappaB pathways in chorioretinal vascular endothelial cells. PMID- 24063815 TI - Expression profile-dependent improvement of insulin sensitivity by gene delivery of interleukin-6 in a mouse model of type II diabetes. AB - Type II diabetes is one of the most problematic metabolic disorders and is associated with secondary conditions such as heart disease and eye complications. Interleukin-6 (IL-6), a multifunctional cytokine, could influence conditions of altered glucose metabolism such as insulin resistance in diabetic patients. However, a consensus about the role of IL-6 on glucose metabolism has not been reached. The aim of the present study is to investigate whether the expression of IL-6 affects glucose metabolism in diet-induced obesity (DIO) mice, a model of type II diabetes and obesity, using gene delivery of IL-6. DIO mice received hydrodynamic or intramuscular injection of IL-6-expressing plasmid to investigate the importance of the site of IL-6 expression. DIO mice that received a sustained IL-6 gene transfer showed similar glucose levels to lean mice in a glucose tolerance test. DIO mice exhibited reduced food intake and low body and epididymal fat weights after IL-6 gene transfer. IL-6 gene delivery reduced the mRNA expression of metabolism-related genes in the liver, skeletal muscle, and adipose tissue of DIO mice. The metabolic status of DIO mice receiving intramuscular injections was moderately better than that of DIO mice receiving hydrodynamic injections. The infiltration of inflammatory cells into the sites where the IL-6-expressing plasmid DNA was delivered was observed. Transient expression of IL-6 had limited effects on all parameters examined. These results indicate that the expression of IL-6 has an effect on obesity and the metabolism of glucose and lipid in diabetic mice and that the expression site of IL-6 is not an important factor. PMID- 24063816 TI - Thermal pretreatment and hydraulic retention time in continuous digesters fed with sewage sludge: assessment using the ADM1. AB - Thermal pretreatment is an interesting technique not only for increasing sludge biodegradability, leading to higher methane productivity, but also for improving degradation rates, allowing full-scale plants to reduce the size of digesters. In this study, the Anaerobic Digestion Model No. 1 (ADM1) was used as a tool to assess the effects of thermal pretreatment and hydraulic retention time (HRT) on the performance of three pilot-scale digesters fed with mixed sludge with/without pretreatment applied to the waste activated sludge fraction. Calibration procedures using batch tests showed an increase of up to five times in the model disintegration coefficient due to the pretreatment, and the validations performed presented good accuracy with the experimental data, with under/overestimation lower than 15% in both average and global accumulated CH4 productions. Therefore, the ADM1 demonstrated its feasibility and usefulness in predicting and assessing the behavior of the digesters under these conditions. PMID- 24063817 TI - Effective reduction of enteric methane production by a combination of nitrate and saponin without adverse effect on feed degradability, fermentation, or bacterial and archaeal communities of the rumen. AB - This study evaluated the effects of Quillaja saponin (0.6 and 1.2g/L), propynoate (4 and 8mM), and nitrate (5 and 10mM), alone or in combinations, on methanogenesis, fermentation, bacterial and archaeal communities, and abundances of select ruminal microbial populations. All treatment decreased methane production, but combination of all three inhibitors at high dose achieved the greatest inhibition (85%). Propynoate, alone or in combination with nitrate or saponin, decreased feed degradability and total volatile fatty acid (TVFA) concentrations. However, saponin and nitrate alone at high dose and in combination at low dose inhibited methanogenesis substantially while increasing feed degradability and TVFA concentrations. The abundances of methanogens were lowered by all inhibitors except saponin alone. Fibrobacter succinogenes and Ruminococcus flavefaciens were increased by saponin, both alone and in combination with nitrate, but inhibited by propynoate. Combination of saponin and nitrate may have practical application in mitigating methane emission from ruminants. PMID- 24063818 TI - Effect of the combined physical and chemical treatments with microbial fermentation on corn straw degradation. AB - In order to improve corn straw degradation, steam explosion, sodium hydroxide soaking and Aspergillus oryzae fermentation were used. The optimal sodium hydroxide pretreatment condition for lignin degradation was obtained. The degradation rates of hemicellulose, cellulose and lignin were 54.68%, 17.76% and 33.14% for the exploded straw (P<0.05); 67.92%, 2.44% (P>0.05) and 76.54% for the alkali-treated straw (P<0.05); 75.98%, 39.93% and 77.88% for the exploded and alkali-treated straw (P<0.05), respectively. The following microbial fermentation could degrade hemicellulose and cellulose further (P<0.05). Cellulase, amylase and protease activities produced during microbial fermentation in the pretreated corn straw were lower than that in the untreated one (P<0.05); however, glucose content was increased by microbial fermentation (P<0.05). It can be concluded that the combined treatments of steam explosion, sodium hydroxide and microbial fermentation will be a good method for straw degradation. PMID- 24063819 TI - Decolorisation of piggery wastewater to stimulate the production of Arthrospira platensis. AB - The aim of this study was to evaluate the potential of color removal methods for enhancing the growth rate and biomass yield of Arthrospira produced using piggery wastewater as a nutrient source. Color could be removed from the piggery wastewater by means of oxidation (H2O2-UV) or by means of positively charged flocculants (e.g., ferric chloride, magnesium hydroxide), biopolymers (chitosan, cationic starch) or adsorbents (hydrotalcite). Some methods remove not only color but also phosphate (e.g., hydrotalcite) while other do not affect phosphate concentrations (e.g., chitosan). Color removal using chitosan resulted in a doubling of initial growth rate and a 50% increase in final biomass yield of Arthrospira produced on piggery wastewater. Color removal using hydrotalcite resulted in a low biomass yield of Arthrospira due to phosphate limitation. PMID- 24063820 TI - Intensity of blue LED light: a potential stimulus for biomass and lipid content in fresh water microalgae Chlorella vulgaris. AB - Light quality and the intensity are key factors which render microalgae as a potential source of biodiesel. In this study the effects of various intensities of blue light and its photoperiods on the growth and lipid content of Chlorella vulgaris were investigated by using LED (Light Emitting Diode) in batch culture. C. vulgaris was grown for 13 days at three different light intensities (100, 200 and 300 MUmol m(-2)s(-1)). Effect of three different light and dark regimes (12:12, 16:08 and 24:00 h Light:Dark) were investigated for each light intensity at 25 degrees C culture temperature. Maximum lipid content (23.5%) was obtained due to high efficiency and deep penetration of 200 MUmol m(-2)s(-1) of blue light (12:12 L:D) with improved specific growth (1.26 d(-1)) within reduced cultivation time of 8 days. White light could produce 20.9% lipid content in 10 days at 16:08 h L:D. PMID- 24063821 TI - Evaluation of multi-brush anode systems in microbial fuel cells. AB - The packing density of anodes in microbial fuel cells (MFCs) was examined here using four different graphite fiber brush anode configurations. The impact of anodes on performance was studied in terms of carbon fiber length (brush diameter), the number of brushes connected in parallel, and the wire current collector gage. MFCs with different numbers of brushes (one, three or six) set perpendicular to the cathode all produced similar power densities (1200 +/- 40 mW/m(2)) and coulombic efficiencies (60% +/- 5%). Reducing the number of brushes by either disconnecting or removing them reduced power, demonstrating the importance of anode projected area covering the cathode, and therefore the need to match electrode projected areas to maintain high performance. Multi-brush reactors had the same COD removal as single-brush systems (>90%). The use of smaller Ti wire gages did not affect power generation, which will enable the use of less metal, reducing material costs. PMID- 24063822 TI - Optimization of parameters for anaerobic co-metabolic degradation of TBBPA. AB - The addition of different carbon and nitrogen sources can promote tetrabromobisphenol A degradation to varying degrees under co-metabolism process. A kinetic model was developed to evaluate the degradation efficiency using different carbon and nitrogen sources. Sodium formate was found to be the best carbon source for tetrabromobisphenol A degradation. The degradation rate reached 96.2% with a half-life of 4.1d. Nitrogen supplementation can also accelerate tetrabromobisphenol A degradation. Organic nitrogen is generally better than inorganic nitrogen. A response surface methodology based on the central composite design was applied to determine the optimum conditions. It showed that concentration of sodium formate, yeast extraction, tetrabromobisphenol A, and inoculum size of microorganism were important factors, and the interaction between either of two variables played different roles. Under the optimum conditions (sodium formate 11.5mg/L, yeast extraction 2.5mg/L, TBBPA 1.1mg/L and inoculum size 3.4%), TBBPA degradation rate reached the maximum. PMID- 24063823 TI - Engineering and adaptive evolution of Escherichia coli W for L-lactic acid fermentation from molasses and corn steep liquor without additional nutrients. AB - The D-lactic acid producing strain, Escherichia coli HBUT-D, was reengineered for L(+)-lactic acid fermentation by replacing the D-lactate dehydrogenase gene (ldhA) with an L(+)-lactate dehydrogenase gene (ldhL) from Pedicoccus acidilactici, followed by adaptive evolution in sucrose. The resulting strain, WYZ-L, has enhanced expression of the sucrose operon (cscA and cscKB). In 100 g L(-1) of sucrose fermentation using mineral salt medium, WYZ-L produced 97 g L( 1) of l(+)-lactic acid, with a yield of 90%, a maximum productivity of 3.17 g L( 1)h(-1) and an optical purity of greater than 99%. In fermentations using sugarcane molasses and corn steep liquor without additional nutrients, WYZ-L produced 75 g L(-1) of l(+)-lactic acid, with a yield of 85%, a maximum productivity of 1.18 g L(-1)h(-1), and greater than 99% optical purity. These results demonstrated that WYZ-L has the potential to use waste molasses and corn steep liquor as a resource for L(+)-lactic acid fermentation. PMID- 24063824 TI - A giant saphenous vein graft aneurysm causing left internal mammary artery to left anterior descending artery graft compression. AB - Saphenous vein graft aneurysm is a rare complication after coronary artery bypass surgery. It is defined as a localized dilatation of the vessel to 1.5* the expected normal diameter. We report a case of 67-year-old man who presented with angina 23 years after coronary artery bypass graft. He was found to have a giant saphenous vein graft aneurysm to diagonal artery compressing the left internal mammary artery graft to the left anterior descending artery. The patient underwent aneurysm resection with satisfactory outcome. PMID- 24063825 TI - Comparison of right versus left ventricular strain analysis as a predictor of outcome in patients with systolic heart failure referred for heart transplantation. AB - The aim of the present study was to explore the relation between right ventricular (RV) and left ventricular (LV) echocardiographic parameters with clinical outcome in patients with advanced heart failure referred for cardiac transplantation. Ninety-eight consecutive patients with advanced systolic heart failure, referred for cardiac transplant evaluation, were enrolled. All patients were prospectively followed for the development of new outcome events, which included hospitalization for acute heart failure, cardiovascular death, heart transplantation, intra-aortic balloon pump implantation, and ventricular assist device implantation. Conventional transthoracic echocardiography was performed in all subjects. RV longitudinal strain (RVLS) by speckle-tracking echocardiography was assessed by averaging all segments in apical 4-chamber view (global RVLS) and by averaging RV free-wall segments (free-wall RVLS). LV global longitudinal and global circumferential strains were also calculated. Of the 98 subjects at baseline, 46 had 67 new events during a mean follow-up of 1.5 +/- 0.9 years. Free wall RVLS, global RVLS, N-terminal fragment of the prohormone brain natriuretic peptide, RV fractional area change, and LV end-diastolic volume were independently predictive of combined outcomes (all p <0.0001). The overall performance for the prediction of cardiovascular events was greatest for free wall RVLS (area under the curve free-wall RVLS: 0.87; global RVLS: 0.67; RV fractional area change: 0.60; N-terminal fragment of the prohormone brain natriuretic peptide, 0.62; global circumferential strain: 0.55; global longitudinal strain: 0.35; and LV ejection fraction: 0.26). Free-wall RVLS showed the highest adjusted hazards ratio. A graded association between the grade of RV dysfunction and the risk of cardiovascular events was only evident for free-wall RVLS and global RVLS. In conclusion, in patients referred for heart transplantation, RVLS is a stronger predictor of outcome than LV longitudinal strain and other conventional parameters, providing a stronger prognostic stratification. PMID- 24063826 TI - Radiofrequency-intravascular ultrasound assessment of lesion coverage after angiography-guided emergent percutaneous coronary intervention in patients with non-ST elevation myocardial infarction. AB - Using radiofrequency-intravascular ultrasound (VH-IVUS), we have previously demonstrated that in 50% of patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention with optimal angiographic result, the stent does not fully cover the whole VH-IVUS derived thin-cap fibroatheroma (VH-TCFA) related to the culprit lesion. Presently, we set out to extend these findings to 20 patients with non-STEMI with Thrombolysis In Myocardial Infarction flow 3 in the infarct-related artery before intervention who were then treated with angiography-guided direct stent implantation. The lesion was imaged with VH-IVUS before and after intervention, but the results were blinded to the operator. Plaque rupture site was identified in 8 lesions (40%), all proximal to the minimum lumen area (MLA) site. The maximum necrotic core site was found proximal to MLA in 18 lesions and at the MLA in 2 lesions. Although the plaque rupture site was fully covered with the stent in all lesions, an uncovered VH-TCFA was found in 7 lesions (35%), 4 in the proximal reference segment, 1 in the distal reference segment, and 2 in both the proximal and distal reference segments. In conclusion, in 35% of patients with non-STEMI undergoing angiography-guided emergent percutaneous coronary intervention, the stent does not fully cover a VH-TCFA related to the culprit lesion. PMID- 24063827 TI - Comparison of the degree of platelet aggregation inhibition with prasugrel versus clopidogrel and clinical outcomes in patients with unprotected left main disease treated with everolimus-eluting stents. AB - The everolimus-eluting stent (EES) performs better than the first generation drug eluting stent. Prasugrel compared with clopidogrel in acute coronary syndromes treated invasively is associated with improved clinical outcome and decreased risk of stent thrombosis. The aim of the study was to compare the clinical outcome and degree of platelet aggregation inhibition of patients treated with EES for unprotected left main disease (ULMD) and receiving clopidogrel or prasugrel. Patients receiving an EES for ULMD and with low residual platelet reactivity on clopidogrel or prasugrel treatment were included in the analysis. The primary end point of the study was the composite of cardiac mortality and myocardial infarction at 1 year. The secondary end point was the degree of platelet aggregation inhibition as assessed by light transmittance aggregometry. From January 2009 to December 2011, 252 patients with low residual platelet reactivity on thienopyridine treatment were treated with EES for ULMD. Of these, 104 patients received clopidogrel and 148 received prasugrel. The primary end point rate was lower in the prasugrel group compared with clopidogrel group: 1.3% and 9.6%, respectively (p = 0.002). Residual platelet reactivity was less in the prasugrel group compared with clopidogrel group (adenosine diphosphate 10 MUmol/L 37 +/- 17% and 45 +/- 15%, respectively, p <0.001). At multivariate analysis, prasugrel treatment was related to the primary end point (hazard ratio 0.17; 95% confidence interval 0.04 to 0.77, p = 0.022). In conclusion, in patients treated with EES for ULMD, prasugrel compared with clopidogrel is associated with increased platelet aggregation inhibition and a better clinical outcome. PMID- 24063828 TI - Outcomes of adolescents and adults undergoing primary Fontan procedure. AB - Patients who have undergone the Fontan procedure in later adolescence and adulthood represent a unique population at risk for significant morbidity and mortality. The optimal strategy for long-term management of such patients is unknown. The aim of this study was to evaluate outcomes of patients who had undergone Fontan surgery later in life, focusing on late survivorship, mode of death, and predictors of mortality. Eighty-eight patients were identified who had their initial Fontan operation from 1973 to 2007 at >=15 years of age. A standardized tiered contact protocol was followed to capture the recent health status of each patient; the probability of survival was 83%, 71%, and 66% at 5, 10, and 15 years of follow-up, respectively. Despite focused efforts, the modes of death were not available in 48% of the patients. A prolonged intensive care unit stay at the time of operation was the single predictor of mortality (p = 0.0123). In conclusion, this investigation highlights the significant mortality that exists in patients who undergo a Fontan procedure later in life and the difficulties in achieving standardized medical follow-up for this high-risk group of patients. PMID- 24063829 TI - The Bjork-Shiley convexo-concave heart valve experience from the perspective of the supervisory panel. AB - The 20-year activities of a medical supervisory panel appointed under the terms of a settlement agreement of the Bowling v. Pfizer class action suit involving the Bjork-Shiley convexo-concave (BSCC) heart valve are detailed. Of approximately 86,000 valves implanted, catastrophic failure of the valve was reported in 663 patients from 1978 to 2012. In 1994, a 7-member medical panel consisting of cardiologists, cardiovascular surgeons, epidemiologists, and a nontechnical chairman was appointed by the federal court. The panel collected clinical and manufacturing data, supported epidemiologic studies assessing risk factors for valve fracture, and developed guidelines for payment for explanting potentially defective valves in patients. Three sets of guidelines, based on comparisons of estimated risks of valve fracture versus risks of valve replacement surgery, were issued by the panel to help guide patients and their physicians in decisions about explanting valves. In addition, the panel supported research directed at identifying valves at risk for outlet strut fracture. The primary techniques evaluated included analyzing acoustic signals from the valves, imaging valves for potential cracks in the struts, and structural analyses of Bjork-Shiley convexo-concave valves, but none proved applicable for large-scale surveillance of the patient population. The panel also became a patient advocate and acted as an intermediary between the manufacturer and the attorneys initiating the legal settlement. The panel's experiences may help inform future strategies for guideline development for other medical devices or procedures involving risk-benefit comparisons. PMID- 24063830 TI - Efficacy and safety of ezetimibe added to atorvastatin versus atorvastatin uptitration or switching to rosuvastatin in patients with primary hypercholesterolemia. AB - Hypercholesterolemic patients (n = 1,547) at high atherosclerotic cardiovascular disease risk with low-density lipoprotein cholesterol (LDL-C) levels >=100 and <=160 mg/dl while treated with atorvastatin 10 mg/day entered a multicenter, randomized, double-blind, active-controlled, clinical trial using two 6-week study periods. Period I compared the efficacy/safety of (1) adding ezetimibe 10 mg (ezetimibe) to stable atorvastatin 10 mg, (2) doubling atorvastatin to 20 mg, or (3) switching to rosuvastatin 10 mg. Subjects in the latter 2 groups who persisted with elevated LDL-C levels (>=100 and <=160 mg/dl) after period I, entered period II; subjects on atorvastatin 20 mg had ezetimibe added to their atorvastatin 20 mg, or uptitrated their atorvastatin to 40 mg; subjects on rosuvastatin 10 mg switched to atorvastatin 20 mg plus ezetimibe or uptitrated their rosuvastatin to 20 mg. Some subjects on atorvastatin 10 mg plus ezetimibe continued the same treatment into period II. At the end of period I, ezetimibe plus atorvastatin 10 mg reduced LDL-C significantly more than atorvastatin 20 mg or rosuvastatin 10 mg (22.2% vs 9.5% or 13.0%, respectively, p <0.001). At the end of period II, ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than atorvastatin 40 mg (17.4% vs 6.9%, p <0.001); switching from rosuvastatin 10 mg to ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than uptitrating to rosuvastatin 20 mg (17.1% vs 7.5%, p <0.001). Relative to comparative treatments, ezetimibe added to atorvastatin 10 mg (period I) or atorvastatin 20 mg (period II) produced significantly greater percent attainment of LDL-C targets <100 or <70 mg/dl, and significantly greater percent reductions in total cholesterol, non-high-density lipoprotein cholesterol, most lipid and lipoprotein ratios, and apolipoprotein B (except ezetimibe plus atorvastatin 20 vs atorvastatin 40 mg). Reports of adverse experiences were generally similar among groups. In conclusion, treatment of hypercholesterolemic subjects at high cardiovascular risk with ezetimibe added to atorvastatin 10 or 20 mg produced significantly greater improvements in key lipid parameters and significantly greater attainment of LDL-C treatment targets than doubling atorvastatin or switching to (or doubling) rosuvastatin at the compared doses. PMID- 24063831 TI - Prognostic value of frontal QRS-T angle in patients without clinical evidence of cardiovascular disease (from the Multi-Ethnic Study of Atherosclerosis). AB - Abnormal frontal QRS-T angle on a 12-lead electrocardiogram is associated with incident coronary heart disease and total mortality in a biracial cohort, but there have been no studies to date examining QRS-T angle's prognostic value across multiple ethnicities. We studied 6,814 participants (52.7% women, mean age 62 years) from Multi-Ethnic Study of Atherosclerosis, a multiethnic cohort aged 45 to 84 years free of clinical cardiovascular disease (CVD) at enrollment. Baseline examination included measurement of traditional risk factors and 12-lead electrocardiograms. Frontal QRS-T axis was defined as normal (less than seventy fifth percentile), borderline (seventy-fifth to ninety-fifth percentile), or abnormal (ninety-fifth percentile or more), and participants were followed for the composite end point of incident CVD events: cardiovascular death, myocardial infarction, angina pectoris, or heart failure. After 7.6 years of follow-up, there were 444 total events. Borderline (HR [hazard ratio] 1.37, 95% confidence interval [CI] 1.10 to 1.70) and abnormal QRS-T angles (HR 2.2, 95% CI 1.63 to 2.97) were associated with incident CVD events in multivariate-adjusted models. However, after adjusting for T-wave abnormalities, there was no statistically significant association of either borderline (HR 1.12, 95% CI 0.90 to 1.41) or abnormal (HR 1.31, 95% CI 0.93 to 1.84) QRS-T angle with incident CVD events. Abnormal frontal QRS-T angle predicts incident CVD events in a multiethnic population, and this increased risk is primarily mediated through T-wave abnormalities. QRS-T angle provides an easily interpretable continuous marker of abnormal ventricular repolarization that can aid the everyday clinician in risk prediction. PMID- 24063832 TI - Effect of body mass index on 30- and 365-day complication and survival rates of transcatheter aortic valve implantation (from the FRench Aortic National CoreValve and Edwards 2 [FRANCE 2] registry). AB - The "obesity paradox" that patients with high body mass index (BMI) have good prognoses remains controversial. This study aimed to assess the impact of BMI on clinical outcomes in patients who underwent transcatheter aortic valve implantation (TAVI). Data from the French national TAVI registry were collected for 3,072 patients who underwent TAVI from January 2010 to October 2011. The patients were categorized into 4 groups according to BMI (kg/m(2)): underweight (<18.5 kg/m(2)), normal weight (18.5 to 25 kg/m(2)), overweight (25 to 30 kg/m(2)), and obese (>30 kg/m(2)). Thereafter, clinical outcomes were compared among the 4 groups. The BMI distribution was 3.1% (n = 95), 44.1% (n = 1,355), 34.2% (n = 1,050), and 18.6% (n = 572). Although the 4 groups greatly differed in baseline clinical background, they had similar procedural success rates (95.8%, 97.1%, 97.3%, and 95.6%, p = 0.23). Major vascular complication was significantly associated with the underweight patients after adjusting for the other potential confounders (odds ratio 2.33, 95% confidence interval 1.17 to 4.46, p = 0.016). The cumulative postoperative survival rates were increasing across the 4 groups at 30 days (83.2%, 88.9%, 91.6%, and 93.0%, p = 0.003) and 1 year (67.9%, 73.6%, 77.4%, and 80.3%, p = 0.006). In a multivariate Cox regression analysis, the overweight and obese patients were independently associated with superior cumulative survival rate at 1 year (hazard ratios 0.74 and 0.71, 95% confidence intervals 0.57 to 0.97 and 0.59 to 0.87, p = 0.050 and 0.029, respectively). In conclusion, major morbidity and 1-year mortality were less in overweight and obese patients than those classified as normal weight even in a TAVI cohort. PMID- 24063833 TI - Percutaneous coronary intervention for multiple chronic total occlusions. AB - No data exist about successful percutaneous coronary intervention (PCI) and clinical outcome in patients with multiple coronary chronic total occlusions (CTOs). The aim of this study was to determine the impact on cardiac mortality of PCI of multiple CTOs. The Florence CTO PCI registry includes patients treated with drug-eluting stent for at least 1 CTO. From this registry, we examined consecutive patients with >=2 CTOs. Patients were stratified into successful PCI of all attempted CTOs and partially successful PCI (1 CTO PCI successful) or failed PCI (no CTO PCI success) groups. The primary end point of the study was cardiac mortality. Of 1,035 patients with CTO, 120 (11.6%) underwent PCI for >=2 CTOs for a total of 249 CTOs. CTO PCI was successful in 195 CTOs (78.3%), and in 76 patients (63.3%), PCI was successful in all attempted lesions, whereas in 34 patients, CTO PCI was partially successful and in 10, completely unsuccessful. Cardiac mortality at 12 months was lower in the CTO PCI success group than CTO PCI failure or partial success group (1.3% vs 11.3%; p = 0.025). The 2-year survival rate was lower in patients with a complete coronary revascularization compared with those with incomplete revascularization (96 +/- 3% vs 78 +/- 7%; p = 0.002); completeness of revascularization was inversely related to the risk of death (hazard ratio 0.10; p = 0.029). In patients with multiple CTOs, a successful PCI of all CTOs was associated with increased survival and completeness of revascularization was a strong predictor of survival. PMID- 24063834 TI - Trends in myocardial infarction rates and case fatality by anatomical location in four United States communities, 1987 to 2008 (from the Atherosclerosis Risk in Communities Study). AB - Although the incidence of and mortality after ST-segment elevation myocardial infarction (STEMI) is decreasing, time trends in anatomical location of STEMI and associated short-term prognosis have not been examined in a population-based community study. We determined 22-year trends in age- and race-adjusted gender specific incidences and 28-day case fatality of hospitalized STEMI by anatomic infarct location among a stratified random sample of 35- to 74-year-old residents of 4 communities in the Atherosclerosis Risk in Communities study. STEMI infarct location was assessed by 12-lead electrocardiograms from the hospital record and was coded as anterior, inferior, lateral, and multilocation STEMIs using the Minnesota code. From 1987 to 2008, a total of 4,845 patients had an incident STEMI; 37.2% were inferior STEMI, 32.8% were anterior, 16.8% occurred in multiple infarct locations, and 13.2% were lateral STEMI. For inferior, anterior, and lateral STEMIs in both men and women, significant decreases were observed in the age-adjusted annual incidence and the associated 28-day case fatality. In contrast, for STEMI in multiple infarct locations, neither the annual incidence nor the 28-day case fatality changed over time. The age- and race-adjusted annual incidence and associated 28-day case fatality of STEMI in anterior, inferior, and lateral infarct locations decreased during 22 years of surveillance; however, no decrease was observed for STEMI in multiple infarct locations. In conclusion, our findings suggest that there is room for improvement in the care of patients with multilocation STEMI. PMID- 24063835 TI - Comparison of dual versus triple antiplatelet therapy after drug-eluting stent according to stent length (from the pooled analysis of DECLARE trials). AB - There are no practical criteria for the use of triple antiplatelet therapy after drug-eluting stent (DES) implantation. In our present report, pooled analysis of 3 randomized studies in patients with diabetes mellitus (Drug-Eluting Stenting Followed by Cilostazol treatment reduces LAte Restenosis in patients with diabetes mellitus trial) and long coronary narrowings (Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients with Long Coronary Lesions trials I and II) compared triple (aspirin, clopidogrel, and cilostazol; triple group, n = 700) and dual antiplatelet therapies (aspirin and clopidogrel; dual group, n = 699) after DES implantation. Among pooled population (n = 1,399 patients), 1,173 patients with follow-up angiography were divided into 3 stent length categories (<=20, 20 to 40, and >40 mm). There was no statistical significance of in-stent restenosis (ISR) in <=20- and 20- to 40-mm categories between 2 groups. However, ISR rate was significantly reduced in triple versus dual group in >40-mm stent length category (12.4% vs 22.1%, p = 0.008). In diabetic patients, triple group also showed significant reduction in the ISR rate in >40-mm stent length category (15.4% vs 32.3%, p = 0.003). According to postprocedural minimal lumen diameter, triple group showed a trend toward a lower ISR than that of the dual group in all categories (p = 0.033 for <=2.5 mm, p = 0.087 for 2.5 to 3.0 mm, and p = 0.119 for >3.0 mm). In conclusion, the triple group had a significantly reduced ISR in patients with >40-mm stent length after DES implantation compared with the dual group. Therefore, this suggestion for use of triple antiplatelet therapy could be easily applied after DES implantation in routine clinical practice. PMID- 24063836 TI - Long-term outcomes of patients sent emergently to the catheterization laboratory for possible primary percutaneous coronary intervention. AB - Current guidelines advocate primary percutaneous coronary intervention as the therapy of choice for ST-segment elevation myocardial infarction (STEMI) when available. Little is known about the outcomes of patients without a culprit lesion after referral for primary percutaneous coronary intervention for a presumed STEMI. Subjects were identified within a registry containing consecutive patients who underwent emergent angiography for a potential STEMI from October 2008 to July 2012. Vital status was obtained from the medical record and Social Security Death Index. Cox proportional hazards models were created to evaluate the relation between the angiographic findings and cardiovascular outcomes, including major adverse cardiovascular events (MACE) and mortality. Among 539 patients who underwent emergent angiography, 65 (12%) had no coronary artery disease (CAD), 110 (20%) had CAD without a culprit lesion, and 364 (68%) had a culprit lesion. Kaplan-Meier analysis of MACE demonstrated that patients with CAD who lack a culprit lesion had a similar rate of MACE to those with a culprit lesion (p = 0.64), and both groups had significantly increased risk compared with those with no CAD (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.01 to 3.41 and HR 2.0, 95% CI 1.15 to 3.54, respectively). Kaplan-Meier analysis of mortality illustrated a nonsignificant trend toward increased mortality in patients having a culprit lesion (HR 1.7, 95% CI 0.59 to 4.80) and those having CAD without a culprit lesion (HR 1.2, 95% CI 0.39 to 3.81) compared with those with no CAD. In conclusion, patients found to have CAD without a culprit lesion in emergent angiography after a presumptive STEMI diagnosis have similar long term rates of MACE compared with those requiring emergent revascularization. PMID- 24063837 TI - Age-dependent effect of left ventricular ejection fraction on long-term mortality in patients with heart failure (from the Heart Failure Survey in ISrael). AB - Contemporary heart failure (HF) therapies have not resulted in improved outcomes among patients with HF and preserved left ventricular ejection fraction (LVEF). We sought to evaluate the differential effect of LVEF on long-term mortality after hospitalization for acute decompensated HF in a real-world setting. All cause mortality at 4 years after hospitalization for HF was assessed by LVEF (categorized as preserved [>=50%], mildly [40% to 49%], moderately [30% to 39%], and severely [<30%] reduced) among 1,620 patients enrolled in the Heart Failure Survey in ISrael. Among the study patients, 30% had preserved LVEF and 20%, 25%, and 25%, had mild, moderate, and severe reductions in LVEF, respectively. Multivariate analysis showed that patients with preserved LVEF had a similar risk of long-term mortality as patients with mild or moderate reduction in LVEF (hazard ratio [HR] 0.92 [p = 0.40] and 1.01 [p = 0.90], respectively) while severely reduced LVEF conferred increased increase rate compared with preserved LVEF (HR 1.20, p = 0.04). Interaction term analysis showed that the risk associated with severely reduced LVEF was evident only among patients <=75 years (HR 1.49, p = 0.003), whereas among older patients, there was no difference in the risk of long-term mortality between those with preserved versus severely reduced LVEF (HR 1.02 [p = 0.86]; p value for age-by-LVEF interaction = 0.03). In conclusion, patients hospitalized for HF who have preserved LVEF experience similar long-term mortality as patients with mild or moderate reductions in LVEF, whereas severely reduced LVEF remains an independent predictor of long-term mortality in this population. The differential effect of LVEF on long-term mortality is significantly attenuated in the older age group. PMID- 24063838 TI - Obstacles encountered in developing an adult congenital heart disease program. AB - More adults than children are now living in the United States with congenital heart disease (CHD). To accommodate the needs of this burgeoning population, there are an increasing number of centers providing care for adults with CHD. We sought to identify pertinent obstacles encountered in the development of a newly established adult CHD program. A survey regarding CHD knowledge, insurance, and cardiovascular counseling was provided to new clinic patients aged >=18 years. Crosstab correlations were performed to identify relations among categorical variables. Of 145 subjects (54% women; mean age 31 +/- 11 years), 84% had at least moderately complex CHD. Household income was <$40,000 for 51% of subjects. There were a significantly greater number of adults, aged 30 to 54 years, with public insurance compared with the national average (p = 0.005). Of 83% of subjects reporting CHD knowledge, 71% correctly identified their defect. Self reported CHD knowledge correlated positively with higher education (p = 0.019), higher income (p = 0.036), health maintenance organization or preferred provider organization insurance (p = 0.01), and higher level of CHD complexity (p = 0.012); however, none of these factors significantly affected correct identification of one's CHD. In fact, patients with the most complex disease were the least likely to correctly identify their defects. In general, cardiovascular and sexual health screening was lacking. In conclusion, adult patients with CHD require robust ancillary services and special attention to lifelong insurance and counseling. Implementation of a health-care strategy to identify patients' needs can help to overcome socioeconomic obstacles and contribute to the success of the newly established adult CHD program. PMID- 24063839 TI - Outcome after ST elevation myocardial infarction in patients with cancer treated with primary percutaneous coronary intervention. AB - The simultaneous occurrence of cancer and coronary heart disease is increasing in the Western world. Nevertheless, the influence of cancer on ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) has not been investigated extensively. This multicenter registry included patients with STEMI treated with primary PCI from 2006 to 2009. Patients were stratified according to history of cancer, and primary focus lay on all-cause and cardiac mortalities during 1-year follow-up. Adjusted effect sizes were calculated using Cox proportional hazard models. In total, 208 patients had a history of cancer (diagnosed <=6 months ago in 20.7%, 6 months to 3 years ago in 21.7%, and >3 years ago in 57.6%) and 3,215 patients had no history of cancer. Chemotherapy had been administered previously to 23% of patients with cancer. Patients with cancer were older, more frequently women, and more commonly known with previous myocardial infarction or anemia. Reperfusion rates were similar after PCI. Patients with cancer showed greater all-cause (17.4% vs 6.5% in other patients) and cardiac mortalities at 1 year (10.7% vs 5.4% in other patients) because of high early cardiac death (23.8%) in recently diagnosed patients with cancer. After adjustment, a recent cancer diagnosis predicted cardiac mortality at 7 days (hazard ratio 3.34, 95% confidence interval 1.57 to 7.08). The adverse prognosis was partly explained by anemia and occurrence of cardiogenic shock, whereas outcome was independent of cancer treatment. In conclusion, patients with cancer showed greater mortality after STEMI. A cancer diagnosis in the 6 months before primary PCI was strongly associated with early cardiac mortality. PMID- 24063840 TI - Comparison of Zotarolimus-Eluting stent versus Sirolimus-Eluting stent for de novo coronary artery disease in patients with diabetes mellitus from the ESSENCE DIABETES II trial. AB - Angiographic and clinical outcomes remain relatively unfavorable for diabetic patients even after the use of drug-eluting stent. This prospective, multicenter, randomized study compared the relative efficacy and safety of resolute zotarolimus-eluting stent (R-ZES) and sirolimus-eluting stent (SES) implantation in diabetic patients with coronary artery disease. The primary end point was noninferiority of angiographic in-segment late loss at 9 months. Clinical events were also monitored for at least 12 months. Patient recruitment was prematurely stopped after enrollment of 256 patients (127 in R-ZES group and 129 in SES) because of discontinuing production of SES. The R-ZES was noninferior to the SES for 9-month in-segment late loss (0.34 +/- 0.30 vs 0.39 +/- 0.43 mm; difference 0.048; 95% confidence interval -0.157 to 0.061; upper 1-sided 95% confidence interval 0.044; p <0.001 for noninferiority). In addition, in-stent late loss (0.22 +/- 0.29 vs 0.21 +/- 0.40 mm, p = 0.849) and the rates of in-segment (1.2% vs 6.7%, p = 0.119) and in-stent (1.2% vs 3.3%, p = 0.621) binary restenoses were similar between the 2 groups. At 12 months, there were no statistical differences between the 2 groups in the incidence of any clinical outcomes (death, myocardial infarction, stent thrombosis, ischemia-driven target lesion revascularization, ischemia-driven target vessel revascularization, and composite outcomes). In conclusion, despite having reduced power because of early study termination, our study suggests that the R-ZES has noninferior angiographic outcomes at 9 months to the SES in diabetic patients with coronary artery disease. PMID- 24063841 TI - Relation of conjugated bilirubin concentrations to the presence of coronary artery calcium. AB - Whether conjugated bilirubin concentration, resulting from hepatic UDP glucuronosyltransferase 1 A1 activity, is associated with cardiovascular disease is unknown. Our aim was to investigate the relation between serum conjugated bilirubin concentrations and coronary artery calcium score (CACS) as a measure of preclinical atherosclerosis. Data were analyzed from an occupational cohort of 14,583 subjects who underwent a cardiac computed tomographic estimation of CACS and measurements of risk factors. Logistic regression was used to describe associations between bilirubin concentrations and CACS. The proportion of subjects with a CACS >0 (total: men = 1,351, women = 111) decreased across increasing conjugated bilirubin quartiles (men p <0.001, women p = 0.005). After adjustment for age, gender, waist, systolic blood pressure, smoking, exercise, alcohol, homeostatic model assessment of insulin resistance, glucose, triglyceride, high- and low-density lipoprotein cholesterols, high-sensitivity C reactive protein, lipoprotein (a), ferritin, fatty liver, cerebrovascular accident, coronary artery disease, hypertension, and diabetes, there was an inverse independent association between conjugated bilirubin and CACS >0 (odds ratio 0.76, 95% confidence interval 0.64 to 0.92, p = 0.004, for top vs bottom quartile). After further adjustment for estimated glomerular filtration rate, the odds ratio was 0.83 (95% confidence interval 0.69 to 0.99), p = 0.04. Exclusion of subjects with a high bilirubin (total >1.3 mg/dl) did not attenuate the association. In conclusion, there was a strong inverse and independent relation between conjugated bilirubin and CACS. The mechanism behind this association is not clear and may not be causal, but the effects of glucuronidation on cardiovascular disease risk should be tested. PMID- 24063842 TI - Comparison of predictors of heart failure-related hospitalization or death in patients with versus without preserved left ventricular ejection fraction. AB - Heart failure with preserved ejection fraction (HFpEF) is recognized as a major cause of cardiovascular morbidity and mortality. An ability to identify patients with HFpEF who are at increased risk for adverse outcomes can facilitate their more careful management. We studied the patients having heart failure (HF) using data from the Heart Failure Adherence and Retention Trial (HART). HART enrolled 902 patients in the New York Heart Association (NYHA) class II or III who had been recently hospitalized for HF to study the impact of self-management counseling on the primary outcome of death or HF hospitalization. In HART, 208 patients had HFpEF and 692 had HF with reduced ejection fraction (HFrEF) and were followed for a median of 1,080 days. Two final multivariate models were developed. In patients having HFpEF, predictors of primary outcome were male gender (odds ratio [OR] 3.45, p = 0.004), NYHA class III (OR 3.05, p = 0.008), distance covered on a 6-minute walk test (6-MWT) of <620 feet (OR 2.81, p = 0.013), and <80% adherence to prescribed medications (OR 2.61, p = 0.018). In patients having HFrEF, the predictors were being on diuretics (OR 3.06, p = 0.001), having >=3 co-morbidities (OR 2.11, p = 0.0001), distance covered on a 6 MWT of <620 feet (OR 1.94, p = 0.001), NYHA class III (OR 1.90, p = 0.001), and age >65 years (OR 1.63, p = 0.01). In conclusion, indicators of functional status (6-MWT and NYHA class) were common to both patients with HFpEF and those with HFrEF, whereas gender and adherence to prescribed therapy were unique to patients having HFpEF in predicting death or HF hospitalization. PMID- 24063843 TI - Relation between white blood cell count and final infarct size in patients with ST-segment elevation acute myocardial infarction undergoing primary percutaneous coronary intervention (from the INFUSE AMI trial). AB - Although it has been shown that elevated white blood cell count (WBCc) on presentation is associated with an increased risk of cardiac mortality in patients with ST-segment elevation myocardial infarction (STEMI), the responsible mechanisms are unknown. We therefore sought to investigate whether elevated WBCc is associated with increased infarct size measured with cardiac magnetic resonance imaging 30 days after primary percutaneous coronary intervention in the Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction trial. INFUSE AMI randomized patients with STEMI and proximal or mid-left anterior descending coronary artery occlusion to bolus intracoronary abciximab versus no abciximab and to manual aspiration versus no aspiration. WBCc at hospital admission was available in 407 of 452 randomized patients. Patients were stratified according to tertiles of WBCc. At 30 days, a significant stepwise increase in infarct size (percentage of total left ventricular mass) was apparent across tertiles of increasing WBCc (median [interquartile range] for tertiles I vs II vs III = 11.2% [3.8% to 19.6%] vs 17.5% [0.5% to 22.9%] vs 19.1% [13.7 to 26.0], respectively, p <0.0001). Absolute infarct mass in grams and abnormal wall motion score were also significantly increased across tertiles of WBC. By multivariate linear regression analysis, WBCc was an independent predictor of infarct size along with intracoronary abciximab randomization, age, time from symptom onset to first device, proximal left anterior descending location, and baseline TIMI flow of 0/1. In conclusion, in patients with anterior wall STEMI, an elevated admission WBCc is a powerful independent predictor of infarct size measured with cardiac magnetic resonance imaging 30 days after primary percutaneous coronary intervention. PMID- 24063844 TI - Foodweb transfer, sediment transport, and biological impacts of emerging and legacy organic contaminants in the lower Columbia River, Oregon and Washington, USA: USGS Contaminants and Habitat (ConHab) Project. PMID- 24063846 TI - The Official Positions of the International Society for Clinical Densitometry: vertebral fracture assessment. AB - Vertebral fracture assessment (VFA) is a low-cost method of accurately identifying individuals who have clinically unrecognized or undocumented vertebral fractures at the time of bone density test. Because prevalent vertebral fractures predict subsequent fractures independent of bone mineral density and other clinical risk factors, their recognition is an important part of strategies to identify those who are at high risk of fracture, so that prevention therapies for those individuals can be implemented. The 2007 Position Development Conference developed detailed guidelines regarding the indications for acquisition of, and interpretation and reporting of densitometric VFA tests. The purpose of the 2013 VFA Task Force was to simplify the indications for VFA yet keep them evidence based. The Task Force reviewed the literature published since the 2007 Position Development Conference and developed prediction models based on 2 large cohort studies (the Study of Osteoporotic Fractures and the Osteoporotic Fractures in Men Study) and the densitometry database of the University of Chicago. Based on these prediction models, indications for VFA were reduced to a simplified set of criteria based on age, historical height loss, use of systemic glucocorticoid therapy, and self-reported but undocumented prior vertebral fracture. PMID- 24063845 TI - Divergent effects of obesity on bone health. AB - Historically, obesity was thought to be advantageous for maintaining healthy bones due to the greater bone mineral density observed in overweight individuals. However, recent observations of increased fracture in some obese individuals have led to concern that common metabolic complications of obesity, such as type 2 diabetes, metabolic syndrome, impaired glucose tolerance, insulin resistance, hyperglycemia, and inflammation may be associated with poor bone health. In support of this hypothesis, greater visceral fat, a hallmark of insulin resistance and metabolic syndrome, is associated with lower bone mineral density. Research is needed to determine if and how visceral fat and/or poor metabolic health are causally associated with bone health. Clinicians should consider adding a marker metabolic health, such as waist circumference or fasting plasma glucose concentration, to other known risk factors for osteoporosis and fracture. PMID- 24063847 TI - Calcium primer: current controversies and common clinical questions. AB - The use of calcium supplements has recently come under fire because of studies purportedly showing a relationship to cardiovascular events. Although the conclusions made sensational headlines in the popular press, numerous editorials and convincing scientific evidence to the contrary went unnoticed. This controversy and others, such as the relationship of proton-pump inhibitors and osteoporosis, caffeine consumption and the risk of calciuria, and the effects of loop diuretics on fracture risk, are common clinical queries of both primary care physicians and subspecialists. The purpose of this article, therefore, is to provide a concise review of select literature pertinent to current clinical practice and to provide no-nonsense recommendations for common clinical dilemmas regarding calcium supplementation. PMID- 24063848 TI - Relation of genetic profile and novel circulating biomarkers with coronary plaque phenotype as determined by intravascular ultrasound: rationale and design of the ATHEROREMO-IVUS study. AB - AIMS: The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis - Intravascular Ultrasound (ATHEROREMO-IVUS) study aims to investigate the relations of genetic profile and novel circulating biomarkers with coronary plaque phenotype and vulnerability as determined by intravascular ultrasound (IVUS). METHODS AND RESULTS: ATHEROREMO-IVUS is a prospective, observational cohort study of 846 patients with stable angina pectoris or acute coronary syndrome (ACS) who are referred for coronary angiography. Prior to the catheterisation procedure, blood samples are drawn for biomarker measurements and genetic analyses. During the catheterisation procedure, IVUS is performed in a non-culprit coronary artery. The primary endpoint is the presence of vulnerable plaque as determined by IVUS virtual histology. Secondary endpoints include the incidence of major adverse cardiac events during long-term follow-up. CONCLUSIONS: Results from ATHEROREMO-IVUS are expected to improve our knowledge of the role of genetic profile and circulating biomarkers in relation to the development of atherosclerosis and vulnerable plaques. Assessment and early validation of the prognostic value of novel biomarkers and intracoronary imaging techniques will be performed. (ClinicalTrials.gov number: NCT01789411). PMID- 24063849 TI - Looking back and looking forward. PMID- 24063850 TI - Practice patterns of mitochondrial disease physicians in North America. Part 2: treatment, care and management. AB - Mitochondrial medicine is a young subspecialty. Clinicians have limited evidence based guidelines on which to formulate clinical decisions regarding diagnosis, treatment and management for patients with mitochondrial disorders. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice including diagnosis, preventive care and treatment, as provided by various mitochondrial disease providers in North America. In this second of two reports, we present data related to clinical practice that highlight the challenges clinicians face in the routine care of patients with established mitochondrial disease. Concerning variability in treatment and preventative care approaches were noted. We hope that sharing this information will be a first step toward formulating a set of consensus criteria and establishing standards of care. PMID- 24063851 TI - A new mutation in MT-ND1 m.3928G>C p.V208L causes Leigh disease with infantile spasms. AB - New mutations in mitochondrial DNA encoded genes of complex I are rarely reported. An infant developed Leigh disease with infantile spasms. Complex I enzyme activity was deficient and response to increasing coenzyme Q concentrations was reduced. Complex I assembly was intact. A new mutation in MT ND1 m.3928G>C p.V208L, affecting a conserved amino acid in a critical domain, part of the coenzyme Q binding pocket, was present at high heteroplasmy. The unaffected mother did not carry measurable mutant mitochondrial DNA, but concern remained for gonadal mosaicism. Prenatal testing was possible for a subsequent sibling. The ND1 p.V208L mutation causes Leigh disease. PMID- 24063853 TI - Evidence-based medicine and the role of the private sector in assisted reproduction: a response to Dr Fishel's commentary 'Evidenced-based medicine and the role of the National Health Service in assisted reproduction'. AB - We respond to Dr Fishel's commentary on evidenced-based medicine in assisted reproduction and the role of the UK's National Health Service. We agree that proper randomised clinical trials are not easy to set up or execute. Recruitment is also challenging but requires that all personnel involved in the study, clinicians, embryologists and nurses, agree with its aims and buy in to the need for an answer. Those who believe fervently in the method under scrutiny prior to the availability of robust evidence are likely to undermine the success of any trial. New technologies are not necessarily better technologies. Neither is the supposed 'logic' of a treatment nor anecdotal clinical experience a substitute for evidence properly gained and fairly demonstrated. Dr Fishel would agree that the first obligation of healthcare professionals, whether they are in the public or private sector, is not to do harm to their patients. Adopting new interventions without rigorous assessment of the potential for harm flies in the face of this basic principle. PMID- 24063854 TI - The presence of tumour-associated lymphocytes confers a good prognosis in pancreatic ductal adenocarcinoma: an immunohistochemical study of tissue microarrays. AB - BACKGROUND: Tumour-associated lymphocytes (TALs) have been linked with good prognosis in several solid tumours. This study aimed to evaluate the prognostic significance of CD3, CD8 and CD20 positive lymphocytes in pancreatic ductal adenocarcinoma. METHODS: After histological re-evaluation of the tumours of 81 patients who underwent surgical resection for exclusively pancreatic ductal adenocarcinoma, tissue micro-arrays (TMA) were constructed and immunohistochemistry was performed for CD3, CD8 and CD20. The number of lymphocytes within specific tumour compartments (i.e. stromal and intratumoural) was quantified. X-tile software (Yale School of Medicine, CT, USA) was used to stratify patients into 'high' and 'low' for each of the lymphocytes stained and their association with survival. Receiver operating curves (ROC) were constructed to evaluate the association between the TALs, alone and in combination, with clinicopathological features. RESULTS: CD3 and CD8 positive lymphocytes were associated with grade of tumour differentiation. The presence of intratumoural CD3 positive cells was associated with improved survival (p = 0.028), and intratumoural and stromal CD3 in combination also correlated with improved survival (p = 0.043). When CD20 positive lymphocyte levels were high, survival improved (p = 0.029) and similar results were seen for CD20 in combination with intratumoural CD3 (p = 0.001) and stromal CD8 (p = 0.013). CONCLUSIONS: This study has shown a correlation between the presence of TALs and survival in pancreatic ductal adenocarcinoma. PMID- 24063856 TI - Reply to the letter: "nationwide survey of Arima syndrome: revised diagnostic criteria from epidemiological analysis". PMID- 24063855 TI - RNA silencing of genes involved in Alzheimer's disease enhances mitochondrial function and synaptic activity. AB - An age-dependent increase in mRNA levels of the amyloid precursor protein (APP), the microtubule-associated protein Tau, and voltage-dependent anion channel 1 (VDAC1) genes are reported to be toxic to neurons affected by Alzheimer's disease (AD). However, the underlying toxic nature of these genes is not completely understood. The purpose of our study was to determine the effects of RNA silencing of APP, Tau, and VDAC1 genes in AD pathogenesis. Using human neuroblastoma (SHSY5Y) cells, we first silenced RNA for APP, Tau, and VDAC1 genes, and then performed real-time RT-PCR analysis to measure mRNA levels of 34 genes that are involved in AD pathogenesis. Using biochemical assays, we also assessed mitochondrial function by measuring levels of H2O2 production, lipid peroxidation, cytochrome c oxidase activity, ATP production, and GTPase enzymatic activity. We found that increased mRNA expression of synaptic function and mitochondrial fission genes, and reduced levels of mitochondrial fusion genes in RNA silenced the SHSY5Y cells for APP, Tau and VDAC1 genes relative to the control SHSY5Y cells. In addition, RNA-silenced APP, Tau, and VDAC1 genes in SHSY5Y cells showed reduced levels of H2O2 production, lipid peroxidation, fission-linked GTPase activity, and increased cytochrome oxidase activity and ATP production. These findings suggest that a reduction of human APP, Tau, and VDAC1 may enhance synaptic activity, may improve mitochondrial maintenance and function, and may protect against toxicities of AD-related genes. Thus, these findings also suggest that the reduction of APP, Tau, and VDAC1 mRNA expressions may have therapeutic value for patients with AD. PMID- 24063858 TI - Roll out of intraveneous artesunate under named patient programmes in the Netherlands, Belgium and France. AB - BACKGROUND: Intravenous (IV) artesunate is the treatment of choice for severe malaria. In Europe, this treatment is only available in a few countries via named patient programmes (NPPs). As a case study, the legal and organisational aspects and pharmacovigilance of these NPPs and possibilities for harmonisation within the EU were studied over time and space using IV artesunate (Malacef) in the Netherlands, Belgium and France. METHODS: The legal base and organisation of NPPs in the Netherlands, Belgium and France were studied. The diffusion and cumulative availability of IV artesunate and the pharmacovigilance components were compared among the three countries using distribution data from the period 2007 through 2012. RESULTS: Artesunate has quickly gained acceptance for treating severe malaria in the Netherlands, whereas both Belgium and France have introduced this treatment more hesitantly. This difference in acceptance is due to differences in the implementation of NPP legislation among the countries. France currently has a proactive system in which treatment requires the permission for each patient and an intensive follow-up protocol. On the other hand, Belgium and Dutch NPPs are more dependent on the investigators' initiative and are therefore potentially faster and more flexible, facilitating the discovery of adverse effects that have not been reported by more formal comparative clinical trials. CONCLUSIONS: NPPs provide a unique opportunity to study both the benefits and risks of unregistered products for treating rare diseases, provided that the patients are actively vigilated. Thus, we recommend that NPPs should be harmonised throughout Europe in order to ensure equal availability of treatment and therapeutic benefit to all Europeans without compromising patient safety. PMID- 24063857 TI - The predictive value of a change in natural killer cell activity for delirium. AB - PURPOSE: Few studies looking for an effective biomarker to predict delirium have been performed. This study was designed to investigate whether a change in inflammatory status, indicated by blood natural killer (NK) cell activity, predicts delirium. METHODS: This prospective study, performed in 4 university and 1 general hospital from September, 2011 to October, 2012, included 29 patients. Eligible patients were 65-89years old, newly and emergently admitted. Patients were assessed daily, up to 7days, for occurrence of DSM-IV-defined delirium. The main outcome measure was change in blood NK cell activity between the first and second mornings after admission. RESULTS: The mean change in blood NK cell activity on the second morning, compared to the first morning, in patients developing delirium (n=9) was significantly greater than that in patients without delirium (n=20) (6.0% [SD 8.4] vs. -1.4% [9.0], respectively, t=2.10, P=0.045). Significant difference between the groups was still found after adjusting for age, the history of previous delirium, and the Clinical Dementia Rating score (F=6.63, P=0.017). Of note is that 8 of 9 (89%) patients developing delirium had increased blood NK cell activity, as did only 8 of 20 (40%) patients without delirium, giving measurement of this parameter, for distinguishing the two groups, a sensitivity of 89%, specificity 60%, positive predictive value 50%, negative predictive value 92%, positive likelihood ratio 2.22, and negative likelihood ratio 0.19. When combining this predictor with another predictor, a Delirium Rating Scale-Revised-98 severity score of 5 or more at baseline, positive and negative likelihood ratios were 7.80 and 0.24, respectively. CONCLUSION: Increase in blood NK cell activity may be associated with developing delirium. Further studies including larger numbers of patients are needed to justify the preventive use of drugs for patients meeting criteria for both predictors. PMID- 24063859 TI - Low doses amino-bisphosphonates stimulate keratinocytes growth inactivating glucocorticoid receptor. AB - Amino-bisphosphonates (N-BPs) have a wide range of clinical applications to treat bone diseases. Their activity lowered farnesyl pyrophosphate (FPP) endogenous levels by inhibiting FPP synthase. In epithelial cells it has been demonstrated that FPP reduces both cell proliferation and migration activting glucocorticoid receptor. In this study two N-BPs (zoledronate and neridronate) used at low concentrations (100 nM to 10 MUM) are able to stimulate human keratinocytes proliferation reducing glucocorticoid receptor activation. PMID- 24063861 TI - Fifteen-minute consultation: congenital nasolacrimal duct obstruction. PMID- 24063860 TI - Overall survival for sorafenib plus interleukin-2 compared with sorafenib alone in metastatic renal cell carcinoma (mRCC): final results of the ROSORC trial. AB - BACKGROUND: The ROSORC trial, a randomised, phase II trial comparing sorafenib plus interleukin (IL-2) versus sorafenib alone as first-line treatment of metastatic renal cell carcinoma (mRCC) failed to demonstrate differences in progression-free survival (PFS). Updated overall survival (OS) results are reported. PATIENTS AND METHODS: In this study, 128 patients were randomised to receive sorafenib 400 mg twice daily plus subcutaneous IL-2 4.5 million international units (MIU) five times per week for 6 weeks every 8 weeks (arm A) or sorafenib alone (arm B). OS was estimated with the Kaplan-Meier method and compared with the two-sided log-rank test. RESULTS: After a median follow-up of 58 months (interquartile range: 28-63 months), the median OS was 38 and 33 months in arms A and B, respectively (P = 0.667). The 5-year OS was 26.3% [95% confidence interval (CI) 15.9-43.5) and 23.1% (95% CI 13.2-40.5) for the combination- and single-agent arm, respectively. Most of the patients who were refractory to first-line treatment were subsequently treated with different targeted agents; they had a median survival greater than expected. CONCLUSIONS: This outcome suggests a synergistic effect of the subsequent therapies following sorafenib failure. CLINICALTRIALSGOV IDENTIFIER: NCT00609401. PMID- 24063862 TI - Enigmatic cerebrospinal fluid-contacting neurons arise even after the termination of neurogenesis in the rat spinal cord during embryonic development and retain their immature-like characteristics until adulthood. AB - Despite the abundance of cerebrospinal fluid-contacting neurons (CSF-cNs) lining the central canal of the spinal cord of mammals, little information is known regarding the phenotype and fate of these cells during development and in adulthood. Using immunofluorescence of spinal cord tissue of rats from the first postnatal day (P1) until the end of the 5th postnatal week (P36), we observed that these neurons show both immature (doublecortin+, beta-III-tubulin+, neurofilament 200 kDa-) and more mature (weak NeuN+, P2X2+, GAD65+) characteristics during the first postnatal weeks. Because of the gradually decreasing number of CSF-cNs in the central canal lining during development, we were also interested in the migration potential of these cells. However, the assessment of the number of CSF-cNs in the lining of the central canal during postnatal development revealed that this decline is most likely associated with the growth of the spinal cord. Lastly, to reveal the birth date of CSF-cNs, we performed 5-bromo-2-deoxyuridine administration and colocalization analyses. We found that production of these cells appears from day 12 of embryonic development (E12) until E22. The vast majority of CSF-contacting neurons arise on E14 and E15. In contrast with other types of spinal neurons, the production of CSF-cNs is not restricted to a particular neuroepithelial region and occurs even after what is thought to be the termination of neurogenesis. PMID- 24063863 TI - Sirtuin 6 nuclear localization at cortical brain level of young diabetic mice: an immunohistochemical study. AB - A study was conducted to assess the physiopathological significance of sirtuin 6 (SIRT6) at the brain cortical level. We analyzed the specific expression and subcellular localization of SIRT6 in young db/db mice, an experimental animal model of type II Diabetes mellitus. We analyzed the cytoarchitecture of the brain cortex, evaluated SIRT6 expression and its localization by immunohistochemistry comparing db/db mice to lean control mice, examining the six cortical layers and the motor and somatosensory cortex. Finally, we calculated a SIRT6 labeling index. We observed the absence of significant morphological differences between lean and db/db mice, indicating that young db/db mice showed a neuronal morphology and distribution similar to that of lean mice and also normal brain tissue architecture with intact cortical layers. Moreover, sirtuin 6 is mainly localized in the nucleus of both lean and db/db mice. In particular, the db/db mice showed few positive cells compared to lean control mice in all cortical layers. We found a lower sirtuin 6 labeling index without significant differences between the motor and somatosensory cortex. Our findings contribute to further understanding the sirtuin 6 immunohistochemical changes in the early stages of type II Diabetes mellitus and propose its possible implication in the pathogenic processes associated with Diabetes mellitus and diabetes-induced neurodegeneration. PMID- 24063864 TI - Spatiotemporal expression of retrogene-host pair Mcts2/H13 in mouse embryo, and Mcts2 has no influence on H13 transcription pattern in NIH/3T3 cells. AB - Mcts2 and H13 comprise an imprinted retrogene-host gene pair. Imprinted genes have been proved to be closely related with embryo development. In order to understand its expression relationship during embryo development and influence of the retrogene on the host gene, we studied expression patterns in mouse embryos and transcriptional interference in a cell culture system. The present study determined the spatio-temporal expression pattern of Mcts2 and H13 from embryonic day 9.5 to 15.5. A similar expression pattern between Mcts2 and H13 was observed in mouse embryogenesis by in situ hybridization and real-time PCR, these two genes were extensively expressed in the neural tissues at mid-embryonic stages. As the embryo development proceeded, H13 and Mcts2 were widely detected throughout the developing organism, especially highly expressed in brain. Moreover, neither over expression nor knockdown of Mcts2 has any significant detectable effect on H13 expression in NIH/3T3 cells. In addition, transcriptional up-regulation of Mcts2 caused by demethylation of DMR in the Mcts2 promoter was not directly associated with the H13 transcription in NIH/3T3 cells treated by 5-Aza-cdR. The regulatory relationship between H13 transcripts and the promoter methylation status of Mcts2 was complex, demonstrating host/retrogene relationship may not be limited to the imprinted locus. PMID- 24063865 TI - Long-term treatment with temozolomide in malignant glioma. AB - Six months of maintenance temozolomide (TMZ) following concurrent TMZ chemotherapy and radiation therapy has become the standard of care in the treatment of glioblastoma. In addition, TMZ has also been used to treat other forms of glioma although less evidence of efficacy exists. TMZ administration longer than 6months is common in clinical practice, but it is unusual for the drug to be administered longer than 1 to 2years. We report five patients who received long-term treatment with TMZ chemotherapy at normal dosing levels. One of these patients was diagnosed with glioblastoma, two with anaplastic astrocytoma, one with gliosarcoma, and one with oligo-astrocytoma. The length of treatment in our group of patients ranged from 45 to 85 cycles of TMZ. Common Terminology Criteria for Adverse Events (CTCAE) developed by The National Cancer Institute was used to classify toxicity. Two patients experienced no toxicity per CTCAE guidelines. One patient experienced grade I thrombocytopenia, one developed grade I leukopenia, and one experienced both grade I thrombocytopenia and grade I nausea, all which resolved with either withholding TMZ for 1month or supportive treatment. Our report provides evidence that long-term TMZ chemotherapy is a therapeutic option when appropriately monitored. PMID- 24063866 TI - Diagnosis and management of pouch outlet obstruction caused by common anatomical problems after restorative proctocolectomy. AB - BACKGROUND AND AIMS: Efferent limb syndrome (ELS) after S pouch and pouch-rectal anastomosis (PRA) after J pouch are common anatomical problems after restorative proctocolectomy that lead to pouch outlet obstruction. This study was aimed to evaluate the frequency, diagnosis and management of ELS and PRA. METHODS: Consecutive patients diagnosed with ELS or PRA at our Pouch Center from 2002 to 2011 were included. Demographic, clinical, endoscopic, and radiographic features together with its management and outcomes were studied. RESULTS: A total of 26 patients met the inclusion criteria, 17 (65.4%) were male. Eleven patients (42.3%) had ELS and 15 (57.7%) had PRA. The median length of the efferent limb/rectal stump for all patients was 6.0 (interquartile range [IQR]: 5.0-8.8) cm, 7.0 (IQR: 5.0-9.0) cm and 6.0 (IQR: 5.0-10.5) cm for S and J pouch patients, respectively (P=0.025). Dyschezia (n=15, 57.7%) was the most common presenting symptom, followed by bloating (n=9, 34.6%), abdominal pain (n=9, 34.6%), the sense of incomplete evacuation (n=7, 26.9%) and perianal discomfort (n=3, 11.5%). A greater number of patients in the ELS group had dyschezia compared to the PRA group (90.9% vs. 33.3%, P=0.005). More patients in the ELS group had a sense of incomplete evacuation than those in the PRA group (45.5% vs. 13.3%, P=0.10). Ten patients (90.9%) in the ELS group and 5 patients in the PRA group (33.3%) required surgical intervention (P=0.005). After a mean follow-up of 3.4 +/- 1.4 years, 7 (87.5%) of the 8 patients, who underwent redo pouch construction with efferent limb/rectal stump excision, maintained a functional pouch. CONCLUSIONS: Patients with ELS or PRA often presented with debilitating symptoms. ELS occurred more frequently in S pouch patients than PRA in J pouch patients. Surgical intervention might be needed, especially for the ELS patients. PMID- 24063867 TI - Evaluation of children with urinary tract infection--impact of the 2011 AAP guidelines on the diagnosis of vesicoureteral reflux using a historical series. AB - OBJECTIVE: To clarify the impact of the updated American Academy of Pediatrics guidelines for the evaluation of children presenting with initial febrile urinary tract infection (UTI) on the diagnosis of vesicoureteral reflux (VUR) in children with normal renal sonograms. MATERIALS AND METHODS: Children with VUR followed between 2002 and 2004 were evaluated using criteria specified in the AAP guidelines. A total of 49 children (42 girls) who were 2-24 months of age at diagnosis of VUR made following initial febrile UTI were included. RESULTS: 40.8% of ultrasounds were abnormal. While children with abnormal ultrasounds were more likely to have scintigraphic evidence of renal damage than children with normal ultrasounds (50% vs 17%, p = 0.026), one third of the children with abnormal renal scans had normal RBUS. There was no statistically significant difference in diagnosis of grade 3 or higher VUR between groups (p = 0.136). CONCLUSIONS: Most children in this series would not have been diagnosed with VUR after initial febrile UTI. More worrisome, 17.2% of children with normal ultrasound had renal injury identified on renal scanning, and 62.1% had grade 3 or higher VUR. These findings reinforce concerns that the new guidelines may miss or delay diagnosis of clinically significant VUR. PMID- 24063868 TI - Abnormal fat distribution in PMM2-CDG. AB - We hypothesize that abnormal fat distribution, a common feature of PMM2-CDG, is associated with abnormal perinatal hormone regulation. We assessed 32 cases with PMM2-CDG, for the comorbidity of hypoglycemia/hyperinsulinism and fat pads. Ninety percent of patients with hypoketotic hypoglycemia and/or hyperinsulinism had abnormal fat distribution, while normoglycemic patients showed this feature in 50% of the cases. This statistically significant difference suggests an etiological role of the insulin receptor in developing abnormal fat distribution in PMM2-CDG. PMID- 24063869 TI - Daily electromyography in females with Parkinson's disease: a potential indicator of frailty. AB - Females with Parkinson's disease (PD) are at increased risk for frailty, yet are often excluded from frailty studies. Daily electromyography (EMG) recordings of muscle activity can dissociate stages of frailty and indicate functional decline in non-neurological conditions. The purpose of this investigation was to determine whether muscle activity can be used to identify frailty phenotypes in females with PD. EMG during a typical 6.5-h day was examined in biceps brachii, triceps brachii, vastus lateralis and biceps femoris on less-affected PD side. Muscle activity was quantified through burst (>2% maximum exertion, >0.1s) and gap characteristics (<1% maximum exertion, >0.1s). Differences across frailty phenotype (nonfrail, prefrail, frail) and muscle (biceps brachii, BB; triceps brachii, TB; vastus lateralis, VL; biceps femoris, BF) were evaluated with a 2 way repeated measure ANOVA for each burst/gap characteristic. Thirteen right handed females (mean=67 +/- 8 years) were classified as nonfrail (n = 4), prefrail (n = 6), and frail (n = 3) according to the Cardiovascular Health Study frailty index (CHSfi). Frail females had 73% decreased gaps and 48% increased burst duration compared with nonfrail. Decreased gaps may be interpreted as reduced muscle recovery time, which may result in earlier onset fatigue and eventually culminating in frailty. Longer burst durations suggest more muscle activity is required to initiate movement leading to slower movement time in frail females with PD. This is the first study to use EMG to dissociate frailty phenotypes in females with PD during routine daily activities and provides insight into how PD-associated motor declines contributes to frailty and functional decline. PMID- 24063871 TI - Quantification of scientific output in cardiovascular medicine: a perspective based on global data. AB - AIMS: We sought to explore whether global and regional scientific output in cardiovascular medicine is associated with economic variables and follows the same trend as medicine and as science overall. METHODS AND RESULTS: We registered the number of documents, number of citations, citations per document and the h index for the first 50 countries according to the h-index (a measure to evaluate both the productivity and impact of the publications) in cardiovascular medicine. Economic variables (gross domestic product [GDP] per capita, % expenditure of the GDP in research and development [R&D] and health) were obtained from the World Bank, the UNESCO, and the World Health Organization. In total, the scientific output in cardiology showed the same position as in medicine and science overall (mean difference vs. medicine -0.9+/-5.3o, p=0.25 vs. science -0.7+/-5.3o, p=0.39). We found significant correlations between the h-index and the % GDP expenditure in R&D (r=0.67, p<0.001), and the % GDP expenditure in health (r=0.71, p<0.0001). Overall, there was a 21.4% (interquartile range 3.7; 55.0) increase in the % GDP expenditure in R&D between 1996 and 2007. Emerging economies showed the larger growth in % GDP expenditure in health and R&D. CONCLUSIONS: The global situation of scientific output in cardiovascular medicine is highly polarised and closely related to economic indicators. Emergent economies, with higher rates of GDP growth and increasingly larger expenditures for R&D and healthcare, are expected to show a visible escalation in the scientific global picture in the near future. PMID- 24063870 TI - Falls efficacy and self-rated health in older African American adults. AB - Fear of falling and mobility restrictions have a significant negative impact on the quality of life of older adults. Because older African American adults are at increased risk for various modifiable health problems, understanding potential constraints on their overall health and mobility is critical in this population. The current study investigated this issue by analyzing a dataset of 449 older African American adults (mean age=72.3 years) living in Detroit. We characterized and investigated the relationships among the following falls- and health-related variables: previous falls, falls efficacy, mobility, self-rated health (SRH), and depression and well-being. As a whole, participants reported moderate health and well-being, little depression, few mobility problems (mean=8.4/40), and very high falls efficacy (mean=94.9/100) despite the fact that a quarter of the sample experienced a fall within the past year. Correlation results indicated that previous falls, falls efficacy, mobility, SRH and depression and well-being were all inter-related. Regression analyses revealed that higher falls efficacy was more closely associated with better SRH than was having previously fallen. Findings suggest that improving falls efficacy in older African American adults may be beneficial to their mobility and overall health and well-being. Further, by asking a single-item SRH question, clinicians may be able to quickly identify older African American adults who have low falls efficacy and are at high risk for falling. PMID- 24063872 TI - Acute dystonic reaction caused by gabapentin. PMID- 24063873 TI - "Synchronous" multifocal necrotizing fasciitis. AB - BACKGROUND: Necrotizing fasciitis (NF) is an infection of the soft tissue, and is fatal if not promptly and aggressively treated. Although it is rare, it is not exceptional; nevertheless, its presentation may be misleading and may delay the diagnosis. We highlight the possible synchronous development of NF in multiple noncontiguous areas. CASE REPORT: A 44-year-old diabetic man with no history of trauma complained of nonspecific lower back pain, which he treated with analgesics and oral antibiotics. Erythema at the left arm appeared, and the general condition worsened. The patient was admitted to the Emergency Department, and NF was diagnosed at the right gluteus and left arm. CONCLUSION: "Synchronous" multifocality is not an expected presentation of NF, and it complicates the diagnosis and delays treatment, with a potentially negative impact on outcome. PMID- 24063874 TI - Giant hepatic artery aneurysm: a fatal evolution. PMID- 24063875 TI - Recognizing cardiac syncope in patients presenting to the emergency department with trauma. AB - BACKGROUND: Cardiac syncope is associated with poor outcomes and may result in traumatic injuries. In patients presenting to the emergency department (ED) with trauma, recognizing the cause of syncope is particularly challenging. Also, clinical markers to identify cardiac syncope are not well established. STUDY OBJECTIVES: We sought to evaluate clinical markers that could identify cardiac syncope in patients with traumatic falls derived from a large urban trauma database. METHODS: All patients presenting to the ED during a 10-year study period with a traumatic fall were identified retrospectively. The subset of patients with syncope was ascertained by chart review and defined as cardiac syncope (e.g., presence of dysrhythmia, valvular abnormality), non-cardiac syncope (e.g., vasovagal, neurological), or syncope of unknown cause. RESULTS: Of the 5420 patients with traumatic falls, 180 (3.3%) patients with syncope were identified. Among the 180 patients with syncope, the cause was identified as cardiac in 24 (13%), noncardiac in 58 (32%), and unknown in 98 (54%). Three independent predictors (i.e., risk factors) of cardiac syncope were identified: age >65 years, presence of coronary artery disease, and pathological Q waves. Presence of at least one risk factor accurately predicted cardiac syncope in this population, with a sensitivity of 100%, a specificity of 43%, and a negative predictive value of 100% (area under the receiver operating characteristic curve: 0.80 +/- 0.04). CONCLUSION: In patients with traumatic falls and syncope, simple clinical and electrocardiographical variables may identify patients with cardiac causes of syncope. Proper identification of cardiac syncope in this population can potentially prevent recurrence of life-threatening traumatic injury. PMID- 24063876 TI - Acute aortic pathology, Munchausen syndrome, and confirmation bias. AB - BACKGROUND: Munchausen syndrome is a psychiatric disease characterized by pathological lying and malingering. Patients who are affected can set up such complex and compelling clinical scenarios that they can lead to a bias in the diagnostic process and even to unnecessary surgery. CASE REPORTS: Two cases of Munchausen syndrome misrepresenting acute aortic dissection are reported. The two cases occurred at two different institutions where there was considerable expertise in the management of aortic pathology. In both patients, a wrong diagnosis of acute aortic syndrome was made, leading to unnecessary surgery. CONCLUSIONS: Retrospective analysis of the clinical events and the diagnostic process suggests that a confirmation bias played a major role in determining the misdiagnosis. The same mistake is likely to have occurred in the only other case reported in the literature. PMID- 24063877 TI - Female patient self-diagnosis compared with emergency physician diagnosis of urinary tract infection. AB - BACKGROUND: Urinary tract infection (UTI) is a common emergency department (ED) complaint and self-diagnosis may be possible. OBJECTIVE: The objective was to compare female patient self-diagnosis compared with emergency physician (EP) diagnosis of UTI. METHODS: This was a prospective cohort study in a single urban ED. Women aged 18-64 years with a chief complaint of UTI, urinary frequency, or dysuria who presented to an urban academic ED were enrolled in a convenience sample fashion. Patients completed a written four-question survey by an ED greeter before triage. Charts of respondents were reviewed for demographic, laboratory, and EP diagnosis. RESULTS: Fifty women were enrolled; 100% of patients who were approached participated in the study. Mean age was 33.7 years (standard deviation 13.8). Forty-three patients (86%) had a history of UTI. Forty one patients (82%) thought they had a UTI on the index visit. Thirty patients (60%) preferred to buy over-the-counter antibiotics for their symptoms instead of seeing a doctor. Fifteen patients (30%) identified a specific antibiotic they would take. Of the 41 patients who thought they had a UTI, 25 (61%) were given that diagnosis. Of the 30 patients who would have preferred over-the-counter antibiotics, 20 (67%) were actually prescribed them. Agreement between EP and women's final impressions was low (kappa = 0.11). CONCLUSIONS: There was poor agreement between EP diagnosis and self-diagnosis of UTI. In our ED population, women should be encouraged to seek medical attention to confirm the diagnosis. PMID- 24063878 TI - Emergency department patient knowledge, opinions, and risk tolerance regarding computed tomography scan radiation. AB - BACKGROUND: Computed tomography (CT) scanning use for emergency department (ED) patients has increased exponentially since its inception. STUDY OBJECTIVES: This study aimed to determine what patients view as the risk of radiation from CT scans, their risk tolerance and preference for alternative testing, and their opinions about informed consent and malpractice regarding CT scans. METHODS: A 25 question survey was administered to a random convenience sample of ED patients aged >= 18 years by trained research associates. RESULTS: There were 487 patients approached to be surveyed; 78 patients were excluded, leaving 409 patients (84.0%) responding. Mean patient age was 40.5 (standard deviation [SD] 16.8) years, and 51.5% were female. Three hundred ninety of 409 (95.4%) believed doctors should explain the risks and benefits of CT, and 316/409 (77.3%) thought an informed consent form should be signed. One hundred seventy-nine of 409 (43.8%) patients recognized that there was more radiation from a CT scan than a single chest x-ray study. Three hundred twenty-four of 409 (79.2%) preferred CT angiography over lumbar puncture to exclude subarachnoid hemorrhage. To diagnose appendicitis, 199/409 (48.7%) preferred an ultrasound first even if it meant needing a subsequent confirmatory CT, and 193/409 (47.2%) preferred a CT right away. One hundred sixty-nine of 409 (41.3%) patients would still like to have a CT scan of the head after head trauma even if their physician did not believe the test was indicated. CONCLUSION: This study elucidates patient preference and knowledge regarding CT scans. Overall, patients have a poor understanding of CT scan radiation, and desire to have risks explained to them as informed consent prior to the scan. PMID- 24063879 TI - Patients overwhelmingly prefer inpatient boarding to emergency department boarding. AB - BACKGROUND: Boarding of admitted patients in the emergency department (ED) is a major cause of crowding. One alternative to boarding in the ED, a full-capacity protocol where boarded patients are redeployed to inpatient units, can reduce crowding and improve overall flow. OBJECTIVE: Our aim was to compare patient satisfaction with boarding in the ED vs. inpatient hallways. METHODS: We performed a structured telephone survey regarding patient experiences and preferences for boarding among admitted ED patients who experienced boarding in the ED hallway and then were subsequently transferred to inpatient hallways. Demographic and clinical characteristics, as well as patient preferences, including items related to patient comfort and safety using a 5-point scale, were recorded and descriptive statistics were used to summarize the data. RESULTS: Of 110 patients contacted, 105 consented to participate. Mean age was 57 +/- 16 years and 52% were female. All patients were initially boarded in the ED in a hallway before their transfer to an inpatient hallway bed. The overall preferred location after admission was the inpatient hallway in 85% (95% confidence interval 75-90) of respondents. In comparing ED vs. inpatient hallway boarding, the following percentages of respondents preferred inpatient boarding with regard to the following 8 items: rest, 85%; safety, 83%; confidentiality, 82%; treatment, 78%; comfort, 79%; quiet, 84%; staff availability, 84%; and privacy, 84%. For no item was there a preference for boarding in the ED. CONCLUSIONS: Patients overwhelmingly preferred the inpatient hallway rather than the ED hallway when admitted to the hospital. PMID- 24063880 TI - A systematic review of emergency department interventions for college drinkers. AB - BACKGROUND: Alcohol use in college-age individuals is associated with increased injury risk. Many college drinkers end up in the emergency department (ED) as a result of their drinking, providing a unique opportunity to intervene. OBJECTIVE: This systematic review evaluates the existing evidence for the use of brief ED interventions for alcohol use in the college-age population. METHODS: A systematic search of on-line databases was conducted. Articles were limited to those in English published since 1990. Studies were included if they specifically studied 18- to 20-year-old alcohol users, if they were performed in an ED or acute care setting, and if an intervention regarding alcohol use was attempted. RESULTS: There were 400 studies identified; 60 abstracts were reviewed, 18 full text articles were evaluated, and 7 met the inclusion criteria for review. Eligible studies focused on alcohol use only, except for one study that addressed alcohol and other drug use. All examined changes in alcohol intake patterns as a primary outcome, and most also looked for reductions in alcohol-related harm. Each found reductions in alcohol intake patterns or reductions in alcohol-related harm in the intervention group, although some between-group differences were not statistically significant reductions. CONCLUSION: Seven studies were identified that measured the outcomes of ED interventions for alcohol use in the college-age population. The studied interventions showed promise but had variable success. More research is needed to establish short- and long-term efficacy, specifically in high-risk underage college students. PMID- 24063882 TI - Traumatic ventral hernia: the seat-belt sign. PMID- 24063881 TI - Patient and provider perceptions of why patients seek care in emergency departments. AB - BACKGROUND: Little is known about why patients choose emergency departments (EDs) to receive care. OBJECTIVE: Our aim was to measure the distribution and frequency of the stated reasons why patients choose the ED for care and why primary care physicians (PCPs) think their patients utilize the ED. METHODS: The authors conducted a survey of patients presenting to an ED with 92,000 annual visits. Appropriate parametric tests were used for univariate and multivariate analysis and results were presented as frequencies with 95% confidence intervals. The authors also performed a cross-sectional survey of PCPs through a web-based survey. RESULTS: Of the 1515 patients approached, 1083 (71%) agreed to participate and 1062 (98%) of them completed the survey. The most common reason patients gave for coming to the ED was their belief that their problem was serious (61%), followed by being referred (35%). In addition, 48% came at the advice of a provider, family member, or friend. By self-report, 354 (33%) patients attempted to reach their PCPs and 306 (86%) of them were successful. Two hundred and seventy-five PCPs were also surveyed. The most frequent reasons PCPs thought their patients came to an ED were that the patient chose to go on their own (80%) and the patients felt that they were too sick to be seen in the PCP's office (80%). CONCLUSIONS: The majority of patients stated that the most common reason for seeking care in an ED was that they thought their problem was serious. Almost half sought ED care on the advice of a family member, friend, or health care provider, and a sizable minority were actually referred in by a health care provider. PCPs agree that most patients come to EDs because they believe they are too sick to be seen in their office or become sick after office hours. PMID- 24063883 TI - Influence of skin penetration enhancers on skin barrier function and skin protease activity. AB - In order to overcome the skin's excellent barrier function formulation scientists often employ skin penetration enhancers (SPEs) in topical and transdermal formulations. The effects of these compounds on skin health is still not well understood at the molecular level. The aim of the present work was to probe the effects of some common SPEs on desquamatory protease activity in healthy skin. The SPEs studied were isopropyl myristate (IPM), propylene glycol, (PG), propylene glycol laurate (PGL) and TranscutolTM (TC). Occluded infinite doses of each SPE were applied to human volunteers for 24 h. Transepidermal water loss (TEWL) measurements were taken before and after application of SPEs. Tape strips were collected from the treated sites to determine protein content and the activity of two desquamatory proteases kallikrein 5 (KLK5) and kallikrein 7 (KLK7). TEWL values were also measured after tape stripping. PG was found to elevate both TEWL values and KLK7 activity to a significant extent (p<0.05). No significant effects were observed for the other SPEs. The ability of PG to alter the skin barrier at the macroscopic level and the influence of the molecule on protease activity reported here may have implications for its use in topical formulations used for the management of impaired skin barrier function such as atopic eczema or psoriasis. PMID- 24063884 TI - Human genetic data reveal contrasting demographic patterns between sedentary and nomadic populations that predate the emergence of farming. AB - Demographic changes are known to leave footprints on genetic polymorphism. Together with the increased availability of large polymorphism data sets, coalescent-based methods allow inferring the past demography of populations from their present-day patterns of genetic diversity. Here, we analyzed both nuclear (20 noncoding regions) and mitochondrial (HVS-I) resequencing data to infer the demographic history of 66 African and Eurasian human populations presenting contrasting lifestyles (nomadic hunter-gatherers, nomadic herders, and sedentary farmers). This allowed us to investigate the relationship between lifestyle and demography and to address the long-standing debate about the chronology of demographic expansions and the Neolithic transition. In Africa, we inferred expansion events for farmers, but constant population sizes or contraction events for hunter-gatherers. In Eurasia, we inferred higher expansion rates for farmers than herders with HVS-I data, except in Central Asia and Korea. Although isolation and admixture processes could have impacted our demographic inferences, these processes alone seem unlikely to explain the contrasted demographic histories inferred in populations with different lifestyles. The small expansion rates or constant population sizes inferred for herders and hunter-gatherers may thus result from constraints linked to nomadism. However, autosomal data revealed contraction events for two sedentary populations in Eurasia, which may be caused by founder effects. Finally, the inferred expansions likely predated the emergence of agriculture and herding. This suggests that human populations could have started to expand in Paleolithic times, and that strong Paleolithic expansions in some populations may have ultimately favored their shift toward agriculture during the Neolithic. PMID- 24063886 TI - Stiffness map of the grasping contact areas of the human hand. AB - The elasticity and damping of the soft tissues of the hand contribute to dexterity while grasping and also help to stabilise the objects in manipulation tasks. Although some previous works have studied the force-displacement response of the fingertips, the responses in all other regions of the hand that usually participate in grasping have not been analysed to date. In this work we performed experimental measurements in 20 subjects to obtain a stiffness map of the different grasping contact areas of the human hand. A force-displacement apparatus was used to simultaneously measure force and displacement at 39 different points on the hand at six levels of force ranging from 1N to 6N. A non linear force-displacement response was found for all points, with stiffness increasing with the amount of force applied. Mean stiffness for the different points and force levels was within the range from 0.2N/mm to 7.7N/mm. However, the stiffness range and variation with level of force were found to be different from point to point. A total of 13 regions with similar stiffness behaviours were identified. The stiffness in the fingertips increased linearly with the amount of force applied, while in the palm it remained more constant for the range of forces considered. It is hypothesised that the differences in the stiffness behaviour from one region to another allow these regions to play different roles during grasping. PMID- 24063885 TI - Changes in nasal airflow and heat transfer correlate with symptom improvement after surgery for nasal obstruction. AB - Surgeries to correct nasal airway obstruction (NAO) often have less than desirable outcomes, partly due to the absence of an objective tool to select the most appropriate surgical approach for each patient. Computational fluid dynamics (CFD) models can be used to investigate nasal airflow, but variables need to be identified that can detect surgical changes and correlate with patient symptoms. CFD models were constructed from pre- and post-surgery computed tomography scans for 10 NAO patients showing no evidence of nasal cycling. Steady-state inspiratory airflow, nasal resistance, wall shear stress, and heat flux were computed for the main nasal cavity from nostrils to posterior nasal septum both bilaterally and unilaterally. Paired t-tests indicated that all CFD variables were significantly changed by surgery when calculated on the most obstructed side, and that airflow, nasal resistance, and heat flux were significantly changed bilaterally as well. Moderate linear correlations with patient-reported symptoms were found for airflow, heat flux, unilateral allocation of airflow, and unilateral nasal resistance as a fraction of bilateral nasal resistance when calculated on the most obstructed nasal side, suggesting that these variables may be useful for evaluating the efficacy of nasal surgery objectively. Similarity in the strengths of these correlations suggests that patient-reported symptoms may represent a constellation of effects and that these variables should be tracked concurrently during future virtual surgery planning. PMID- 24063888 TI - Kinetic study of the thermal denaturation of a hyperthermostable extracellular alpha-amylase from Pyrococcus furiosus. AB - Hyperthermophilic enzymes are of industrial importance and interest, especially due to their denaturation kinetics at commercial sterilisation temperatures inside safety indicating time-temperature integrators (TTIs). The thermal stability and irreversible thermal inactivation of native extracellular Pyrococcus furiosus alpha-amylase were investigated using differential scanning calorimetry, circular dichroism and Fourier transform infrared spectroscopy. Denaturation of the amylase was irreversible above a Tm of approximately 106 degrees C and could be described by a one-step irreversible model. The activation energy at 121 degrees C was found to be 316kJ/mol. Using CD and FT-IR spectroscopy it was shown that folding and stability greatly increase with temperature. Under an isothermal holding temperature of 121 degrees C, the structure of the PFA changes during denaturation from an alpha-helical structure, through a beta-sheet structure to an aggregated protein. Such data reinforces the use of P. furiosus alpha-amylase as a labile species in TTIs. PMID- 24063889 TI - Insights in progressive myoclonus epilepsy: HSP70 promotes cystatin B polymerization. AB - Cystatin B (CSTB) is an anti-protease frequently mutated in progressive myoclonus epilepsy (EPM1), a devastating degenerative disease. This work shows that rat CSTB is an unstable protein that undergoes structural changes following the interaction with a chaperone, either prokaryotic or eukaryotic. Both the prokaryotic DnaK and eukaryotic HSP70 promote CSTB polymerization. Denaturated CSTB is polymerized by the chaperone alone. Native CSTB monomers are more stable than denatured monomers and require Cu(2+) for chaperone-dependent polymerization. Cu(2+) interacts with at least two conserved histidines, at positions 72 and 95 modifying the structure of native monomeric CSTB. Subsequently, CSTB becomes unstable and readily responds to the addition of DnaK or HSP70, generating polymers. This reaction depends strictly on the presence of this divalent metal ion and on the presence of one cysteine in the protein chain. The cysteine deletion mutant does not polymerize. We propose that Cu(2+) modifies the redox environment of the protein, allowing the oxidation of the cysteine residue of CSTB that triggers polymerization. These polymers are sensitive to reducing agents while polymers obtained from denatured CSTB monomers are DTT resistant. We propose that the Cu(2+)/HSP70 dependent polymers are physiological and functional in eukaryotic cells. Furthermore, while monomeric CSTB has anti protease function, it seems likely that polymeric CSTB fulfils different function(s). PMID- 24063890 TI - Structural insights into the interaction of human S100B and basic fibroblast growth factor (FGF2): Effects on FGFR1 receptor signaling. AB - S100B is a calcium sensing protein belonging to the S100 protein family with intracellular and extracellular roles. It is one of the EF hand homodimeric proteins, which is known to interact with various protein targets to regulate varied biological functions. Extracellular S100B has been recently reported to interact with FGF2 in a RAGE-independent manner. However, the recognition mechanism of S100B-FGF2 interaction at the molecular level remains unclear. In this study, the critical residues on S100B-FGF2 interface were mapped by combined information derived from NMR spectroscopy and site directed mutagenesis experiments. Utilizing NMR titration data, we generated the structural models of S100B-FGF2 complex from the computational docking program, HADDOCK which were further proved stable during 15ns unrestrained molecular dynamics (MD) simulations. Isothermal titration calorimetry studies indicated S100B interaction with FGF2 is an entropically favored process implying dominant role of hydrophobic contacts at the protein-protein interface. Residue level information of S100B interaction with FGF2 was useful to understand the varied target recognition ability of S100B and further explained its role in effecting extracellular signaling diversity. Mechanistic insights into the S100B-FGF2 complex interface and cell-based assay studies involving mutants led us to conclude the novel role of S100B in FGF2 mediated FGFR1 receptor inactivation. PMID- 24063891 TI - Inflammatory response after spinal cord injury. PMID- 24063892 TI - Nanotoxicology. PMID- 24063893 TI - RNAi-mediated silencing of Myc transcription inhibits stem-like cell maintenance and tumorigenicity in prostate cancer. AB - Several studies link disease progression, recurrence, and treatment failures to the cancer stem-like cell (CSC) subpopulation within the heterogeneous tumor cell population. Myc is a transcription factor having a central function in stem cell biology and in human cancers. Hence, Myc represents an attractive target to develop CSC-specific therapies. Recent findings suggest that Myc transcription can be silenced using an RNA interference (RNAi)-based strategy that targets noncoding promoter-associated RNA (paRNA) overlapping the transcription start site. In this study, we investigated the effects of silencing Myc transcription on prostate CSC in cell culture and xenograft models of human prostate cancer. Treatment with an effective promoter-targeting siRNA reduced the fraction of CSCs, leading to reduced self-renewal, tumor-initiating, and metastatic capability. Combined analysis of stem-like cells and senescence markers indicated that Myc silencing triggered a phenotypic shift and senescence in the CSC subpopulation. Notably, systemic delivery of the promoter-targeting siRNA in the xenograft model produced a striking suppression in the development of prostate tumors. Our results support a pivotal role for Myc in CSC maintenance and show that Myc targeting via RNAi-based transcriptional silencing can trigger CSC senescence and loss of their tumor-initiating capability. More generally, our findings demonstrate the efficacy of RNAi-based transcriptional strategies and the potential to target regulatory noncoding paRNAs for therapeutic applications. PMID- 24063895 TI - [Introduction]. PMID- 24063894 TI - Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization. AB - Kinase domain mutations of the EGF receptor (EGFR) are common oncogenic events in lung adenocarcinoma. Here, we explore the dependency upon asymmetric dimerization of the kinase domain for activation of lung cancer-derived EGFR mutants. We show that whereas wild-type EGFR and the L858R mutant require dimerization for activation and oncogenic transformation, the exon 19 deletion, exon 20 insertion, and L858R/T790M EGFR mutants do not require dimerization. In addition, treatment with the monoclonal antibody, cetuximab, shrinks mouse lung tumors induced by the dimerization-dependent L858R mutant, but exerts only a modest effect on tumors driven by dimerization-independent EGFR mutants. These data imply that different EGFR mutants show differential requirements for dimerization and that disruption of dimerization may be among the antitumor mechanisms of cetuximab. PMID- 24063896 TI - [Biochemical and pharmacological features of telaprevir]. AB - Telaprevir is the first of a new generation of drugs based on blocking the NS3-4A protease of hepatitis C virus (HCV), which is essential for viral reproduction, and is especially active against genotype 1 HCV. However, to be effective, telaprevir must be combined with pegylated interferon and ribavirin for 12 weeks. Telaprevir has poor solubility in water and tends to crystallize, properties that hamper its formulation as a drug intended for oral delivery. This agent is efficiently absorbed after oral administration, but only if administered with food (not low in fat), since fasting intake markedly reduces systemic exposure. The total daily dose is 2,250 mg. Because of its pharmacokinetics, telaprevir has been designed for administration every 8 hours but efficacy is maintained in a twice-daily dosing regimen. Dose adjustment is not required in compensated liver cirrhosis. Because it is a substrate and potent inhibitor of CYP3A4 and glycoprotein P, telaprevir has multiple drug-drug interactions. The IL-28B genotype has little influence on the likelihood of response to telaprevir triple combination therapy. PMID- 24063897 TI - [Telaprevir in treatment-naive patients with HCV monoinfection]. AB - Chronic hepatitis due to the hepatitis C virus (HCV) infection affects nearly 180 million people worldwide. This infection is curable. Until 1 year ago, the only treatment for genotype 1 HCV was the combination of pegylated interferon and ribavirin, which was only moderately effective (40-50%). The introduction of new antiviral agents, such as telaprevir, represents a change of paradigm and has revolutionized the treatment of this infection. This drug has increased the likelihood of viral response (to 80%) and has allowed treatment length to be shortened in more than 50% of patients. New stopping rules have been developed to avoid the development of resistances. Finally, special attention should be paid to potentially serious adverse effects, particularly anemia and cutaneous alterations. PMID- 24063898 TI - [Telaprevir in HCV-monoinfected patients with failure to prior treatment]. AB - The introduction of telaprevir in the therapeutic armamentarium for hepatitis C virus infection is a major advance, even in patients unresponsive to prior treatment with interferon and ribavirin. In this group of patients, sustained viral response is achieved in more than 80% of those with recurrence and who received triple therapy. In partial responders, more than half achieve cure with the triple combination of pegylated interferon, ribavirin and telaprevir. Unfortunately, the results are less good in null responders, especially given that many are of a certain age and have advanced fibrosis. Patients in this group should be carefully selected to identify those most likely to derive a benefit from triple therapy. PMID- 24063899 TI - [Clinical use of telaprevir: stopping rules, predicting response, treatment length, and management of adverse effects]. AB - Triple combination therapy with pegylated interferon, ribavirin and telaprevir is currently considered the gold standard for the treatment of chronic hepatitis C virus (HCV) infection. The most important features are an increase in rates of sustained viral response (74-79% vs 46% with pegylated interferon and ribavirin), as well as the possibility of early cessation of ineffective therapy due to the application of futility rules at weeks 4 and 12 (HCV-RNA > 1,000 UI/ml), and the possibility of selecting candidates for the shortest treatments due to the clinical significance of extended rapid viral response (undetectable HCV-RNA at weeks 4 and 12 of triple therapy). Treatment length is mainly based on the stage of fibrosis and prior response to pegylated interferon and ribavirin. Thus, in both treatment-naive patients and patients with recurrence after pegylated interferon therapy, the duration of treatment is 24 or 48 weeks (unless cirrhosis is present), depending on the presence of extended rapid viral response, while in cirrhotic patients and null responders, treatment length is 48 weeks. The main adverse effects of telaprevir therapy are anemia and skin rash. If these effects occur, the main measures that should be adopted are reduction of the ribavirin dose in anemia, and close monitoring and treatment cessation in skin rash, depending on its spread and severity. PMID- 24063900 TI - [Telaprevir resistance]. AB - Telaprevir is an extremely potent antiviral drug. However, as with other direct acting antiviral agents against the hepatitis C virus (HCV), this potency can be compromised by the rapid emergence of resistance mutations. This phenomenon is favored by the high rate of HCV replication, the lack of corrective activity to HCV polymerase errors, a low genetic barrier to resistance, and poor treatment adherence. Like other HCV protease inhibitors, telaprevir has a low genetic barrier to resistance. Phase II/III clinical trials (ADVANCE, ILLUMINATE and REALIZE) have characterized resistance to telaprevir in combination with pegylated interferon and ribavirin both genotypically and phenotypically. Mutations are selected mainly in positions 36, 54, 55, 155 and 156. The resistance profile depends on the genetic subtype of HCV, with selection of mutations in positions 36 and 155 for subtype 1a and in positions 36, 54, 55 and 156 for subtype 1b. The V36M+R155K and A156F/T/V variants confer a high degree of resistance (>25-fold increase), while the impact on resistance of other mutations such as V36A/G/M, T54A/S, R155G/K/M/T and A156S is lower (3-25- fold increase). The presence of polymorphisms or mutations associated with telaprevir resistance is very low (< 1%), especially for mutations with a higher impact on resistance. There is a high degree of cross resistance among protease inhibitors. However, the rapid reversion of telaprevir resistance mutations after the end of treatment could allow the use of "recycling" strategies with protease inhibitors. PMID- 24063901 TI - [Safety and efficacy of telaprevir in patients with HIV and hepatitis C virus coinfection]. AB - Related to the use of telaprevir in patients with HIV and genotype 1 hepatitis C virus, there is available data from a phase IIb clinical trial in patients not previously treated for HCV, study 110; and preliminary data from a real practice study in patients with previous failure to a HCV treatment, study ARNSHC26 (TelapreVIH). Additionally, there are two ongoing phase III studies in coinfected patients, C3008 and 115, both in naive and previously treated patients. In the 110 study, rates of sustained viral response (SVR) in patients receiving the triple combination of pegylated interferon + ribavirin + telaprevir was 74%. This SVR rate is similar to those reported in treatment-naive patients with genotype 1 HCV monoinfection who received pegylated interferon + ribavirin + telaprevir. Similarly, the adverse effects in this trial did not differ from those found in patients with genotype 1 HCV monoinfection. Telaprevir has been approved for use in patients with HCV genotype 1 monoinfection by the European Commission through a centralized procedure. Telaprevir label includes data on coinfected patients, covering efficacy, security, and practical management with different antirretroviral drugs. The Spanish Agency for Medications and Health Care Products has established recommendations that regulate and allow the use of telaprevir in patients with HIV/HCV genotype 1 coinfection. The most important restrictions on the use of telaprevir established by the Agency are as follows: a) patients with stage F3-F4 liver fibrosis on liver biopsy or liver stiffness >= 9.5kPa can be treated; b) in the absence of advanced fibrosis, telaprevir can be used to treat severe extrahepatic manifestations of HCV infection; c) patients with cirrhosis must have Child-Pugh stage A. PMID- 24063903 TI - [Conclusions]. PMID- 24063902 TI - [Pharmacokinetic interactions of telaprevir with other drugs]. AB - Telaprevir is a new direct-acting antiviral drug for the treatment of hepatitis C virus (HCV) infection and is both a substrate and an inhibitor of cytochrome P450 (CYP450) isoenzymes. With the introduction of this new drug, assessment of drug drug interactions has become a key factor in the evaluation of patients under treatment for HCV infection. During the treatment of this infection, many patients require other drugs to mitigate the adverse effects of anti-HCV drugs and to control other comorbidities. Moreover, most patients coinfected with HIV and HCV require antiretroviral therapy during treatment for HCV. Physicians should therefore be familiar with the pharmacokinetic properties of direct-acting antivirals for HCV treatment and their potential drug-drug interactions. The present article reviews the available information to date on the interactions of telaprevir with other drugs and provides recommendations for daily clinical practice. PMID- 24063904 TI - Probabilities of dying from cancer and other causes in French cancer patients based on an unbiased estimator of net survival: a study of five common cancers. AB - BACKGROUND: Net survival is the survival that would be observed if cancer were the only possible cause of death. Although it is an important epidemiological tool allowing temporal or geographical comparisons, it cannot inform on the "crude" probability of death of cancer patients; i.e., when taking into account other possible causes of deaths. METHODS: In this work, we provide estimates of the crude probabilities of death from cancer and from other causes as well as the probability of being alive up to ten years after cancer diagnosis according to the age and year of diagnosis. Based on a flexible excess hazard model providing unbiased estimates of net survival, our methodology avoids the pitfalls associated with the use of the cause of death. We used data from FRANCIM, the French network of cancer registries, and studied five common cancer sites: head and neck, breast, prostate, lung, and colorectal cancers. RESULTS: For breast, prostate, and colorectal cancers, the impact of the other causes on the total probability of death increased with the age at diagnosis whereas it remained negligible for lung and head and neck cancers whatever the age. For breast, prostate, and colorectal cancer, the more recently was the cancer diagnosed, the less was the probability of death from cancer. CONCLUSION: The crude probability of death is an intuitive concept that may prove particularly useful in choosing an appropriate treatment, or refining the indication of a screening strategy by allowing the clinician to estimate the proportion of cancer patients who will die specifically from cancer. PMID- 24063905 TI - Equilibrium, kinetic and thermodynamic studies of uranium biosorption by calcium alginate beads. AB - Calcium alginate beads are potential biosorbent for radionuclides removal as they contain carboxyl groups. However, until now limited information is available concerning the uptake behavior of uranium by this polymer gel, especially when sorption equilibrium, kinetics and thermodynamics are concerned. In present work, batch experiments were carried out to study the equilibrium, kinetics and thermodynamics of uranium sorption by calcium alginate beads. The effects of initial solution pH, sorbent amount, initial uranium concentration and temperature on uranium sorption were also investigated. The determined optimal conditions were: initial solution pH of 3.0, added sorbent amount of 40 mg, and uranium sorption capacity increased with increasing initial uranium concentration and temperature. Equilibrium data obtained under different temperatures were fitted better with Langmuir model than Freundlich model, uranium sorption was dominated by a monolayer way. The kinetic data can be well depicted by the pseudo second-order kinetic model. The activation energy derived from Arrhenius equation was 30.0 kJ/mol and the sorption process had a chemical nature. Thermodynamic constants such as DeltaH(0), DeltaS(0) and DeltaG(0) were also evaluated, results of thermodynamic study showed that the sorption process was endothermic and spontaneous. PMID- 24063906 TI - Effects of accompanying anions on cesium retention and translocation via droplets on soybean leaves. AB - Plant foliar uptake and translocation is an important pathway for the migration of radiocesium to the human diet. This study reports the effects of accompanying anions ( [Formula: see text] , [Formula: see text] , [Formula: see text] , and I( )) on cesium retention and translocation. An experiment to simulate cesium retention and translocation was conducted in a greenhouse by applying droplets of stable cesium solutions to the upper surface of four soybean [Glycine max (L.) Merr.] trifoliate leaves. The average percentages of cesium retention with the accompanying anions [Formula: see text] , [Formula: see text] , [Formula: see text] , and I(-) on the leaves were 7.2, 21.5, 49.3, and 10.2%, respectively. Retention values of the four treatments were stable during the 3-day exposure period, indicating that cesium could be absorbed and penetrate the cuticle quickly once it was dissolved. Scanning electron microscopy coupled with energy dispersive X-ray microanalysis showed that particles containing cesium remained on the leaf surfaces after washing. Also, nano-sized particles containing cesium were observed inside the leaf tissues. Cesium concentrations in the uncontaminated leaves, pods, stems, and roots increased during the study period indicating cesium redistribution from the contaminated leaves. PMID- 24063907 TI - Further SAR studies on bicyclic basic merbarone analogues as potent antiproliferative agents. AB - Pyrimidopyrimidine derivatives 1 were prepared as rigid thioanalogues of merbarone (a catalytic topoisomerase II inhibitor) and screened as antiproliferative agents against different tumor cell lines. A number of the synthesized compounds emerged as cytotoxic in cell-based assays (MT-4, HeLa and MCF-7 cells) at low micromolar concentrations. In a National Cancer Institute screening, selected member of the series showed a broad spectrum of antiproliferative activity against various tumours (melanoma, renal, CNS, colon and breast cancers). The acid-base and steric properties of the substituent at position 7 of the pyrimidopyrimidine scaffold deeply affected potency. Enzymatic assays evidenced that a subset of tested derivatives efficiently inhibit topoisomerase IIalpha accordingly to merbarone mechanism of action. However this property does not fully rationalize the cytotoxicity data of the full ligand panel, suggesting that different target(s) should be additionally involved. PMID- 24063908 TI - 'Click' synthesized sterol-based cationic lipids as gene carriers, and the effect of skeletons and headgroups on gene delivery. AB - In this work, we have successfully prepared a series of new sterol-based cationic lipids (1-4) via an efficient 'Click' chemistry approach. The pDNA binding affinity of these lipids was examined by EB displacement and agarose-gel retardant assay. The average particle sizes and surface charges of the sterol based cationic lipids/pDNA lipoplexes were analyzed by dynamic laser light scattering instrument (DLS), and the morphologies of the lipoplexes were observed by atomic force microscopy (AFM). The cytotoxicity of the lipids were examined by MTT and LDH assay, and the gene transfection efficiencies of these lipid carriers were investigated by luciferase gene transfection assay in various cell lines. In addition, the intracellular uptake and trafficking/localization behavior of the Cy3-DNA loaded lipoplexes were preliminarily studied by fluorescence microscopy. The results demonstrated that the pDNA loading capacity, lipoplex particle size, zeta potential and morphology of the sterol lipids/pDNA lipoplexes depended largely on the molecular structure factors including sterol-skeletons and headgroups. Furthermore, the sterol-based lipids showed quite different cytotoxicity and gene transfection efficacy in A549 and HeLa cells. Interestingly, it was found that the cholesterol-bearing lipids 1 and 2 showed 7 10(4) times higher transfection capability than their lithocholate-bearing counterparts 3 and 4 in A549 and HeLa cell lines, suggested that the gene transfection capacity strongly relied on the structure of sterol skeletons. Moreover, the study on the structure-activity relationships of these sterol-based cationic lipid gene carriers provided a possible approach for developing low cytotoxic and high efficient lipid gene carriers by selecting suitable sterol hydrophobes and cationic headgroups. PMID- 24063909 TI - Sodium butyrate and short chain fatty acids in prevention of travellers' diarrhoea: a randomized prospective study. AB - INTRODUCTION: Travellers' diarrhoea (TD) remains a considerable concern among international travellers. Known methods of prevention include dietary precautions, administration of vaccines and antibiotic agents. AIM: To assess the efficacy of sodium butyrate (SB) and short-chain fatty acids (SCFA) in prevention of TD. MATERIAL AND METHODS: 67 adult patients planning to travel to subtropical countries were originally enrolled in the study. After eliminating 7 patients for not fulfilling the inclusion criteria, 60 patients were randomized into a study group receiving SB with SCFA and a placebo group. Patients were requested to complete previously distributed questionnaire daily. After elimination of 18 patients who did not return questionnaires, 42 patients completed the study (22 study, 20 placebo). RESULTS: In comparison to the control arm, the study arm noted significantly reduced occurrence of TD (4.5% vs. 40%, p = 0.008), was associated with a significant decrease in number of stools per day in travellers (1.9 vs. 4.2, p = 0.04), as well as a decrease in gastrointestinal symptoms including pain, bloating and nausea with fevers (0.7 vs. 1.4, p = 0.01). We recorded a trend towards decrease in diarrhoea related utilization of medical care in subjects from the study arm. There were no adverse effects noted regarding the use of SB and SCFA. CONCLUSIONS: Administration of SB with SCFA decreases occurrence of travellers' diarrhoea. It is safe and may constitute a new method of travellers' diarrhoea prevention. PMID- 24063910 TI - When a misperception favors a tragedy: Carlos Chagas and the Nobel Prize of 1921. AB - Carlos Chagas, the discoverer of Chagas' disease was nominated to the Nobel Prize in 1921, but none did win the prize in that year. As a leader of a young scientist team, he discovered all aspects of the new disease from 1909 to 1920. It is still obscure why he did not win the Nobel Prize in 1921. Chagas was discarded by Gunnar Hedren on April 16, 1921. Hedren should have made a written report about the details of his evaluation to the Nobel Committee. However, such a document has not been found in the Nobel Committee Archives. No evidence of detractions made by Brazilian scientists on Chagas was found. Since Chagas nomination was consistent with the Nobel Committee requirements, as seen in the presentation letter by until now unknown Cypriano de Freitas, it become clear that Chagas did not win the Nobel Prize exclusively because the Nobel Committee did not perceive the importance of his discovery. Thus, it would be fair a posthumous Nobel Prize of 1921 to Carlos Chagas. A diploma of the Nobel Prize, as precedent with Dogmack in 1947, would recognize the merit of the scientist who made the most complete medical discovery of all times. PMID- 24063911 TI - Reply to: "Zimarino M et al. The adequacy of myocardial revascularization in patients with multivessel coronary artery disease". PMID- 24063912 TI - Effects of ranolazine in symptomatic patients with stable coronary artery disease. A systematic review and meta-analysis. AB - BACKGROUND: Ranolazine (R), as add-on therapy in symptomatic patients with chronic stable coronary artery disease (CAD), has been tested in randomized clinical studies. Aim of the study was to assess in a meta-analysis the effects of R on angina, nitroglycerin consumption, functional capacity, electrocardiographic signs of ischemia and hemodynamic parameters in patients with chronic CAD. METHODS: Randomized trials assessing the effects of R compared to control on exercise duration, time to onset of angina, time to 1mm ST-segment depression, weekly nitroglycerin consumption and weekly angina frequency were included in the analysis. The effects of R compared to control on heart rate and blood pressure were also analyzed. RESULTS: Six trials enrolling 9223 patients were included in the analysis. At trough and peak levels, R compared to control significantly improved exercise duration, time to onset of angina and time to 1mm ST-segment depression. Additionally, R compared to control significantly reduced weekly angina frequency and weekly nitroglycerin consumption. Finally, R compared to control did not significantly reduce supine systolic and diastolic blood pressure as well as heart rate, standing heart rate and diastolic blood pressure, whereas it modestly reduced standing systolic blood pressure. At sensitivity analysis, results were not influenced by concomitant background therapy. CONCLUSIONS: In symptomatic patients with chronic CAD, R, added to conventional therapy, effectively reduces angina frequency and sublingual nitroglycerin consumption while prolonging exercise duration as well as time to onset of ischemia and to onset of angina with no substantial effects on blood pressure and heart rate. PMID- 24063913 TI - Improved two-year outcomes after drug-eluting versus bare-metal stent implantation in women and men with large coronary arteries: importance of vessel size. AB - OBJECTIVES: To investigate the importance of vessel size on outcome differences by comparing the effects of drug-eluting stents (DES) versus bare-metal stents (BMS) in women and men with large coronary vessels. METHODS: All 2314 BASKET PROVE patients randomized to DES versus BMS were followed for 2 years with a primary endpoint of major adverse cardiac events (MACE: cardiac death, non-fatal myocardial infarction, target-vessel revascularization). Cox proportional hazard models were used to evaluate the relative risk for women and men, respectively. All comparisons were adjusted for vessel size. RESULTS: Age, risk factors and complexity of coronary artery disease differed between women and men. DES reduced MACE rates at 2 years compared to BMS--in women: 4% vs. 15%, p<0.0001 with a hazard ratio (HR) of 0.27 (0.15-0.51), and men: 6% vs. 10%, p=0.003 (HR=0.60 (0.43-0.84)), respectively. The association persisted in both women (HR=0.25 (0.13-0.46)) and men (HR=0.60 (0.42-0.84)) following multivariable adjustments. A significant gender-treatment interaction was present (p=0.02). The reduced risk of MACE following DES vs. BMS implantation was present until 6 months in both women (HR=0.15 (0.06-0.36)) and men (HR=0.32 (0.17-0.59)) and remained significant until 2 years in women (HR=0.36 (0.15-0.87)), but not in men (HR=0.87 (0.49-1.55)). CONCLUSIONS: In women and men with similarly sized large coronary arteries, DES reduced 2-year MACE rates compared to BMS, but the significant gender-treatment interaction indicated a greater benefit of DES in women. Thus, factors other than vessel size seem to determine this gender difference. PMID- 24063914 TI - Non-invasive 24 hour ambulatory monitoring of aortic wave reflection and arterial stiffness by a novel oscillometric device: the first feasibility and reproducibility study. AB - BACKGROUND: Surrogates of aortic wave reflection and arterial stiffness, such as augmentation index (AIx), augmentation pressure, pulse wave velocity (PWV) and pulse pressure amplification (PPampl) are independent predictors of cardiovascular risk. A novel ambulatory, brachial cuff-based oscillometric device has been recently developed and validated, yielding 24-h assessment of the aforementioned parameters (Mobilo-O-Graph). Aim of this study was to investigate the feasibility and reproducibility of wave reflection and arterial stiffness estimation by pulse wave analysis using this device. METHODS: Thirty treated or untreated hypertensives (mean age: 53.6 +/- 11.6 years, 17 men) had test-retest 24-h monitoring one week apart using the test device. RESULTS: Mean numbers of valid aortic readings per subject, between test and retest, were comparable. Approximately 12 aortic readings per subject (17%) were not feasible or valid. No differences were observed for any 24-h parameter between the two assessments. Bland-Altman plots showed no systemic difference, while the limits of agreement for each parameter indicated high reproducibility (AIx: -7.2 to 8.2%, AP: -3.7 to 4.1mm Hg, PWV: -0.39 to 0.41 m/s, PPampl: -0.08 to 0.06). This was further verified by intraclass correlation coefficients which were >0.8 for each parameter. CONCLUSIONS: Non-invasive 24-h estimation of wave reflection and arterial stiffness indices, derived by the test device, appear to be highly reproducible. Future studies should investigate whether these measurements have additive prognostic value for cardiovascular risk stratification, beyond common brachial blood pressure measurements or single estimations of wave reflection and PWV at office settings. PMID- 24063915 TI - Abnormal heart rate recovery on exercise in ankylosing spondylitis. AB - OBJECTIVES: This study evaluated the heart rate recovery response in ankylosing spondylitis (AS) patients and control subjects. BACKGROUND: Delayed heart rate recovery after exercise reflects AD and independently predicts adverse cardiac outcome. METHODS: Fifty-one patients with AS and 50 age- and matched controls received electrocardiography, echocardiography, and treadmill exercise testing. The heart rate recovery (HRR) index was calculated as the reduction in heart rate from the rate at peak exercise to the rate at the 1st (HRR1), 2nd (HRR2), 3rd (HRR3) and 5th (HRR5) minute after the cessation of exercise stress testing. RESULTS: There were significant differences in HRR1 and HRR2 indices between patients and controls (24.8 +/- 12.1 vs 34.9 +/- 11.0; p<0.001 and 41.2 +/- 14.2 vs 54.3 +/- 11.8; p<0.001, beats/min, respectively). Similarly, HRR3 and HRR5 indices were lower in patients than controls (51.3 +/- 15.1 vs 65.2 +/- 14.0; p<0.001 and 61.0 +/- 14.2 vs 76.1 +/- 14.8; p<0.001). In addition, exercise capacity was markedly lower (8.1 +/- 2.0 vs 10.5 +/- 2.5 METs; p<0.001) in AS than controls. CONCLUSION: The HRR index is impaired in AS patients, implying the occurrence of autonomic dysfunction even without active joint disease or frank cardiac involvement. PMID- 24063916 TI - Management of stroke as described by Ibn Sina (Avicenna) in the Canon of Medicine. AB - Stroke or cerebrovascular accident (CVA) is caused by a disturbance of the blood supply to the brain and an accruing loss of brain function. The first recorded observations were in 2455 BC and it has been studied intensely by ancient physicians throughout history. In the early medieval period, Ibn Sina (980-1025 AD) called stroke sekteh and described it extensively. Some of Ibn Sina's definitions and his etiology of stroke are based on humoral theories and cannot be compared with medical current concepts, but most of his descriptions concur with current definitions. This review examines the definition and etiology, clinical manifestations, prognosis, differential diagnosis, and interventions for stroke based on Ibn Sina's epic work, Canon of Medicine. The pharmacological effects of medicinal herbs suggested by Ibn Sina for stroke are examined in light of current knowledge. PMID- 24063917 TI - T1 and T2 mapping for tissue characterization of cardiac myxoma. PMID- 24063918 TI - Effects of slow breathing rate on blood pressure and heart rate variabilities. PMID- 24063919 TI - Digoxin use is associated with increased risk of stroke in patients with non valvular atrial fibrillation--a nationwide population-based cohort study. PMID- 24063920 TI - Evaluation of therapeutic effect and cytokine change during transplacental Digoxin treatment for fetal heart failure associated with fetal tachycardia, a case-control study. PMID- 24063921 TI - Robotically assisted ablation of atrial fibrillation: a systematic review and meta-analysis. AB - BACKGROUND: Robotic systems are becoming increasingly common in complex ablation procedures. We conducted systematic review and meta-analysis on the procedural outcomes of Magnetic Navigation System (MNS) in comparison to conventional catheter navigation for atrial fibrillation (AF) ablation. METHODS: An electronic search was performed using multiple databases between 2002 & 2012. Outcomes were: acute and long-term success, complications, total procedure, ablation and fluoroscopic times. RESULTS: Fifteen studies (11 nonrandomized controlled studies & 4 case series) involving 1647 adult patients were identified. In comparison between MNS and conventional groups, a tendency towards higher acute success was noted with conventional group but with similar long-term freedom from AF (95% vs. 97%, odds ratio (OR) 0.25 (95% confidence interval [CI] 0.06; 1.04, p=0.057); 73% vs. 75%, OR 0.92 (95% CI 0.69; 1.24, p=0.59), respectively). A significantly shorter fluoroscopic time was achieved with MNS (57 vs. 86 min, standardized difference in means (SDM) -0.90 (95% CI -1.68; -0.12, p=0.024)). Longer total procedure and ablation times were noted with MNS (286 vs. 228 min, SDM 0.7 (95% CI 0.28; 1.12, p=0.001); 67 vs. 47 min, SDM 0.79 (95% CI 0.18; 1.4, p=0.012), respectively). Overall complication rate was similar (2% vs. 5%, OR 0.48 (95% CI 0.18; 1.26, p=0.135)), however rate of significant pericardial complication defined either as tamponade or effusion requiring intervention/hospitalization was significantly lower in MNS (0.3% vs. 2.5%, p=0.005). CONCLUSIONS: Our results suggest that MNS has similar rates of success and possibly superior safety outcomes when compared to conventional manual catheter ablation for AF. PMID- 24063922 TI - Predictors of cardiovascular complication in patients with diabetes mellitus: a 5 year follow-up study in a multiethnic population of Singapore: CREDENCE II study. PMID- 24063923 TI - Temporary coronary sinus pacing to allow hip surgery in a patient with drug refractory incessant ventricular tachycardia. PMID- 24063924 TI - Cardiac cachexia is associated with right ventricular failure and liver dysfunction. AB - BACKGROUND: The mechanisms involved in cardiac cachexia remain poorly understood. We examined the association of right ventricular (RV) and hepatic dysfunction with cardiac cachexia. METHODS: We prospectively enrolled 118 patients with left ventricular ejection fraction (LVEF) <=40%, which were subgrouped as follows: New York Heart Association (NYHA) class II (n=59), NYHA class III without cachexia (n=41) and NYHA class III with cachexia (n=18). All patients underwent blood collection, echocardiography and exercise testing. RESULTS: Reduced systolic RV function (tricuspid annular plane systolic excursion [TAPSE] <=15 mm), was present in 80% of cachectic patients. When comparing NYHA class II patients vs. non-cachectic and cachectic NYHA class III patients we found a stepwise decrease in systolic RV function (TAPSE 19 [16-23] vs. 16 [13-19] vs. 14 [9-15] mm, respectively; p<0.001) and an increase in right atrial pressure (RAP; >10 mm Hg: 6.8 vs. 27.5 vs. 75.0%, respectively; p<0.001), indicating a higher degree of congestive right HF in cardiac cachexia. Systolic and diastolic function of the left ventricle did not differ between non-cachectic and cachectic patients in NYHA class III. Serum alkaline phosphatase and direct bilirubin correlated with TAPSE and RAP, and were highest in cachectic patients (all p <= 0.002), suggesting cholestatic dysfunction due to liver congestion. In multivariable regression analysis, RV dysfunction, cholestatic liver parameters and albumin were independently associated with the presence of cardiac cachexia. CONCLUSION: Patients with cardiac cachexia display a more pronounced degree of right HF, cholestatic liver dysfunction and hypoalbuminemia compared to non-cachectic patients of similar LVEF and NYHA class. PMID- 24063925 TI - Long-term prognostic value of diastolic exercise echocardiography. PMID- 24063927 TI - Treatment failure of low molecular weight heparin in post-surgery orthopedic case. PMID- 24063926 TI - Same wrist intervention via the cubital (ulnar) artery in case of radial puncture failure for percutaneous cardiac catheterization or intervention: the multicenter SWITCH registry. AB - AIMS: The radial approach is safer than the femoral for percutaneous coronary procedures. However its feasibility is lower, mainly for technical issues, often related to failure to puncture or cannulate the radial artery. The ulnar approach is a valid alternative to radial. We aimed to test the incidence, feasibility and safety of a direct homolateral ulnar approach in case of failed radial sheath insertion. METHODS AND RESULTS: Five operators collected their 1-year activity (diagnostic and interventional) with focus on entry site. Entry site choice was left to operators' discretion. In case of failed radial sheath insertion, an attempt to cannulate the homolateral ulnar artery was mandated, if ulnar pulse was present. All patients in whom this attempt was performed were followed until discharge. Out of 2403 procedures (1271 interventions), the final successful entry site was radial in 66.5%, femoral in 31.0%, ulnar in 2.1% and brachial in 0.4%. Radial failure occurred in 117 patients (6.9%). In 75 patients, the radial failure was not due to sheath insertion (which was successful), but to lack of catheter support or to tortuosity of the subclavian/brachial arteries. In the remaining 42 (35.9% of all radial failures), a homolateral ulnar approach was attempted. A successful cannulation of the ulnar artery occurred in 36 patients (85.7%) with further performance of the complete procedure. Concerning local complications, 1 radial pseudo-aneurysm (treated with additional compression) occurred, while no cases of early hand ischemia were reported. CONCLUSIONS: In this multicenter registry, in case of failed radial sheath insertion, switching directly to the homolateral ulnar artery for percutaneous coronary procedures is feasible and it appears to be safe, without cases of symptomatic hand ischemia. PMID- 24063928 TI - Retroperitoneal hematoma counterpart of transradial coronary angiography: retropleural hematoma. PMID- 24063929 TI - Recording the insula during ictal asystole. PMID- 24063931 TI - Ectopic fat and cardiometabolic and vascular risk. AB - Given that the variation in how regional adipose tissue handles and stores excess dietary energy has substantial cardiometabolic implications, ectopic fat distribution might be an important predictor of cardiometabolic and vascular risk, in addition to overall obesity itself. Conceptually, ectopic fat depots may be divided into systemically acting fat depots and locally acting fat depots. Systemically acting fat depots include visceral fat, fat in the liver, muscle, or neck, and subcutaneous fat. Accumulation in the abdominal visceral area, compared with overall obesity, has an equally or more important role in the development of cardiometabolic risk. Fat depots in liver/muscle tissue cause adverse cardiometabolic effects by affecting energy metabolism. Fat depots in lower-body subcutaneous areas may be protective regarding cardiometabolic risk, by trapping remnant energy. Fat accumulation in the neck is a unique type of fat depot that may increase cardiovascular risk by increasing insulin resistance. Locally acting fat depots include pericardial fat, perivascular fat, and renal sinus fat. These fat depots have effects primarily on adjacent anatomic organs, directly via lipotoxicity and indirectly via cytokine secretion. Pericardial fat is associated with coronary atherosclerosis. Perivascular fat may play an independent role in adverse vascular biology, including arterial stiffness. Renal sinus fat is a unique fat depot that may confer additional cardiometabolic risk. Thus, ectopic fat depots may contribute to the understanding of the link between body composition and cardiometabolic risk. In this review, we focus on the role and clinical implications of ectopic fat depots in cardiometabolic and vascular risk. PMID- 24063930 TI - Preprocedural high-sensitive troponin predicts survival after transcatheter aortic valve implantation (TAVI). PMID- 24063932 TI - A proposal for a new scoring system in the prediction of catheter ablation outcomes: promising results from the Turkish Cryoablation Registry. AB - BACKGROUND: Although cryoballoon based catheter ablation is an effective therapeutic option in atrial fibrillation (AF), a significant amount of patients failed to remain in sinus rhythm at long term follow-up. Appropriate selection of patients for catheter ablation reduces unnecessary interventions and prevents complications related with catheter ablation. The purpose of our study is to propose a new scoring system in the prediction of recurrence after AF ablation with cryoballoon. METHOD: A total of 236 patients (54% male, age 54.6 +/- 10.45 years and 79.6% paroxysmal) with symptomatic AF underwent an index cryoablation. The first 3 months after AF ablation is defined as blanking period. Predictors of AF recurrence after cryoablation were analyzed with multivariate Cox regression analysis. BASE-AF2 score [acronym stands for Body mass index >28 kg/m(2) (1); Atrial dilatation >40 mm (1); current Smoking (1); Early recurrence (1); duration of AF history >6 years (1) and non-paroxysmal type (1) of AF] is identified by the total number of significant predictors of recurrence in each patient (range=0 6). RESULTS: At median 20 (range: 12-30) months follow-up, 74.5% of the patients were free from AF recurrence. Of these patients, 64 (27.1%) patients had a BASE AF2 score of >=3. Patients with AF recurrence had a higher mean BASE-AF2 score (3.27+/-0.82 vs. 1.1 +/- 0.95, p<0.001) compared to patients without AF recurrence. ROC analysis showed that a BASE-AF2 score of >=3 well predicted AF recurrence with a sensitivity of 80.8% and a specificity of 91.6% (AUC=0.94; 95% CI: 0.89-0.97, p<0.001). A BASE-AF2 score of >=3 was found to be an independent predictor of AF recurrence (HR: 3.34, 95% CI: 2.34-4.76, p=0.001). CONCLUSION: BASE-AF2, which was identified as a new scoring system, has well predicted AF recurrence and could be helpful in selecting appropriate patients for interventional strategy. PMID- 24063934 TI - Reply: To PMID 24063935. PMID- 24063933 TI - Time course of electrocardiographic changes in transient left ventricular ballooning syndrome. AB - BACKGROUND: We sought to describe, for the first time, in detail the time course of electrocardiographic (ECG) changes in transient left ventricular ballooning syndrome (TLVBS) from acute onset until 1 year after presentation. METHODS: The serial ECGs of all patients identified with TLVBS who presented to our cardiology department from August 1998 to August 2012 were analyzed, from admission to 1 year follow-up, with respect to time from onset of symptoms. RESULTS: In total, 145 TLVBS episodes were identified in 139 patients. In 53% of patients, ST segment elevation was present in the first 3h after symptom onset, after which there was a steady decline with complete resolution in all patients by 1 month. The presence of T wave inversion (TWI), with or without ST segment depression, was most prevalent between day 1 (60%) and day 30 (71%) from symptom onset, with 17% of patients still exhibiting TWI after 6 to 12 months. At 1 year, approximately 80% of patients had no significant residual ST-T wave changes. In 86% of patients, there was prolongation of the corrected QT (QTc) interval in the acute phase, with normalization of all QTc intervals by day 14. CONCLUSIONS: During the early phase, ECG mimics acute ST elevation myocardial infarction with initial regional ST segment elevation progressing to T wave inversion with or without ST depression. In the majority of patients, significant QTc interval prolongation occurs in the early phase, normalizing by day 14. PMID- 24063935 TI - Periprostatic fat area is an independent factor that prolonged operative time in laparoscopic radical prostatectomy. AB - OBJECTIVE: To evaluate the effect of visceral obesity on surgical outcomes in laparoscopic radical prostatectomy (LRP). METHODS: Visceral fat area (VFA) and periprostatic fat area (PPFA) were used as index of visceral obesity. In addition to VFA and PPFA, age, body mass index (BMI), prostate weight, cross-section area of Retzius space, history of previous abdominal surgery, repeated transrectal needle biopsy, and neoadjuvant hormone therapy were recorded. LRP was separated into 7 steps (1: port insertion and lymph node dissection, 2: endopelvic fascia incision, 3: dorsal vein complex ligation, 4: prostate dissection from bladder neck, 5: dissection of seminal vesicle and vas deferens, 6: prostate dissection from rectum, and 7: vesicourethral anastomosis). Potential factors that prolonged total operative time (OT), pneumoperitoneum time, and duration of each step were assessed by multivariate logistic regression analysis. The association between visceral obesity and other surgical outcomes was also evaluated. RESULTS: One hundred sixteen LRPs were performed by a single experienced surgeon. High PPFA and prostate weight were independent factors that prolonged total OT and pneumoperitoneum time. High BMI was not a factor. PPFA affected steps 1, 4, 5, and 6, and prostate weight affected prolonged steps 5 and 6. Estimated blood loss, duration of urethral catheterization, postoperative hospital stay, perioperative complications, and margin status were not affected by visceral obesity. CONCLUSION: PPFA was more useful to accurately predict prolonged OT than VFA or BMI. Safety and margin status were not compromised even in high PPFA group when operations were performed by an experienced surgeon. PMID- 24063936 TI - Editorial comment. PMID- 24063937 TI - Editorial comment. PMID- 24063938 TI - A novel skin management scheme in surgery of epispadias undergoing Cantwell Ransley repair: a technique to improve the aesthetics and minimize complications. AB - OBJECTIVE: To describe a new scheme of skin cover in epispadias repair to improve the aesthetic results and minimize complications. PATIENTS AND METHODS: In the last 4 years, 7 male continent epispadias (aged 2-5 years) undergoing Cantwell Ransley repair received a new technique of skin cover. After a U-shaped incision along the margin of urethral plate, a transverse incision beginning at the margin of urethral plate 7-10 mm proximal to the corona was carried along the prepucial edge upto the corresponding point at urethral plate margin on the other side. The prepuce was split into a dorsal flap attached to the corona and a ventral flap continuous with penile skin. After subdartos degloving, incision through median raphe upto penoscrotal junction bifurcated the penile skin-dartos complex. After Cantwell-Ransley repair, reverse advancement of inner prepucial flap provided skin cover to most of the ventral aspect of penile shaft. Dorsal midline union of bifurcated penile skin-dartos flaps provided dorsolateral cover. At ventral midline, limited joining of penile skin-dartos flaps at penoscrotal junction and anchoring to corpus spongiosum created penoscrotal angle with shaft cover at penoscrotal junction. Lateral margins of dorsal and ventral skin cover were joined. RESULTS: There was no flap necrosis, penile rotation, or recurrent chordee. Symmetrical distribution of skin and automatic creation of partial prepucial hood provided gratifying aesthetic appearance. One coronal sulcus fistula was repaired. CONCLUSION: This simple and reproducible skin management scheme in epispadias repair helps in providing aesthetically pleasing skin cover, penoscrotal angle, penopubic angle, and prepucial hood with minimum complications. PMID- 24063939 TI - Effect of supine vs prone position on outcomes of percutaneous nephrolithotomy in staghorn calculi: results from the Clinical Research Office of the Endourology Society Study. AB - OBJECTIVE: To analyze the effect of patient positioning on outcomes of percutaneous nephrolithotomy (PNL) among patients with staghorn stones. The choice of optimal position for these patients undergoing PNL remains challenging. No previous studies exclusively addressing this point have been performed. METHODS: From November 2007 to December 2009, prospective data were collected by the Clinical Research Office of the Endourological Society. We included all patients with staghorn stones. Patients were divided on the basis of the position used during PNL (prone/supine). Patient characteristics, stone burden, operative details, and outcomes were compared. Multivariate analysis was performed to evaluate the relationship between patient position and stone-free rate and complication rate adjusting for number of access puncture sites. RESULTS: A total of 1079 PNLs were performed in prone and 232 in supine positions. There were no differences in comorbidities or preoperative stone burden. A higher percentage of patients in the prone position had access through the upper pole (P <.001). Surgical time was shorter (P <.001) and stone-free rate was higher (P <.001) for patients in the prone position. There were no differences in complication rates. In multivariate analysis, patients in prone position had a higher stone-free rates (P = .0013) after adjusting for the method used for determining stone-free status and number of renal access. CONCLUSION: Higher stone-free rates are achieved in the prone position during PNL for patients with staghorn calculi. Complication rates were similar for both positions. PMID- 24063940 TI - Relationship of estimated glomerular filtration rate with lower urinary tract symptoms/benign prostatic hyperplasia measures in middle-aged men with moderate to severe lower urinary tract symptoms. AB - OBJECTIVE: To evaluate the relationship of the glomerular filtration rate (GFR) and lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia measures in middle-aged men. METHODS: A total of 1400 male police officers with moderate and severe LUTS (international prostate symptoms score [IPSS] >7) and aged 40-59 years who had participated in a health examination were included. LUTS/benign prostatic hyperplasia was measured with IPSS, transrectal ultrasonography, uroflowmetry, and postvoid residual urine volume. We estimated the GFR using the Chronic Kidney Disease Epidemiology Collaboration equation. Spearman correlation tests and multiple linear regression tests were used to evaluate the relationship. RESULTS: The median age was 50.0 years, and the median GFR was 85.3 mL/min/1.73 m(2). The GFR showed a significant positive correlation with the maximal flow rate (Qmax; r = .112; P <.001). However, there was no significant correlation of GFR with IPSS (r = -.018; P = .493), total prostate volume (r = .032; P = .237), and postvoid residual (r = -.066; P = .051). After adjusting for age, body mass index (BMI), and metabolic syndrome, only Qmax showed a positive correlation with GFR (beta = .114; P = .003). CONCLUSION: Qmax demonstrated a significant correlation with GFR in middle-aged men with moderate to severe LUTS in this study. Our data suggest that improved clinical attention is required for patients with LUTS and a low Qmax. PMID- 24063941 TI - Reply: To PMID 24063936. PMID- 24063942 TI - Does consuming the recommend daily level of fiber prevent Crohn's disease? PMID- 24063943 TI - Novel antithrombotic challenges: head, heart, and guts. PMID- 24063944 TI - The other genome: mitochondrial DNA and protection from experimental colitis. PMID- 24063945 TI - Compressive fatigue life of subchondral bone of the metacarpal condyle in thoroughbred racehorses. AB - In racehorses, fatigue related subchondral bone injury leads to overt fracture or articular surface collapse and subsequent articular cartilage degeneration. We hypothesised that the fatigue behaviour of equine subchondral bone in compression follows a power law function similar to that observed in cortical and trabecular bone. We determined the fatigue life of equine metacarpal subchondral bone in vitro and investigated the factors influencing initial bone stiffness. Subchondral bone specimens were loaded cyclically in compression [54MPa (n=6), 66MPa (n=6), 78MPa (n=5), and 90MPa (n=6)] until failure. The fatigue life curve was determined by linear regression from log transformed number of cycles to failure and load. A general linear model was used to investigate the influence of the following variables on initial Young's Modulus: age (4-8years), specimen storage time (31-864days), time in training since most recent rest period (6 32weeks), limb, actual density (1.6873-1.8684g/cm(3)), subchondral bone injury grade (0-3), and cause of death (fatigue injury vs. other). Number of cycles to failure was (median, range) 223,603, 78,316-806,792 at 54MPa; 69,908, 146-149,855 at 66MPa; 13204, 614-16,425 at 78MPa (n=3); and 4001, 152-11,568 at 90MPa. The fatigue life curve was sigma=112.2-9.6 log10Nf, (R(2)=0.52, P<0.001), where Nf is number of cycles to failure and sigma is load. Removal of the three horses with the highest SCBI grade resulted in: sigma=134.2-14.1 log10Nf, (R(2)=0.72, P<0.001). Initial Young's Modulus (mean+/-SD) was 2500+/-494MPa (n=22). Actual density (rho) was the only variable retained in the model to describe initial Young's Modulus (E): E=-8196.7+5880.6rho, (R(2)=0.34, P=0.0044). The fatigue behaviour of equine subchondral bone in compression is similar to that of cortical and trabecular bone. These data can be used to model the development of SCBI to optimize training regimes. PMID- 24063946 TI - Trends in osteoporosis treatment with oral and intravenous bisphosphonates in the United States, 2002-2012. AB - Bisphosphonates have been widely prescribed to postmenopausal women for treatment and prevention of osteoporosis. Given a background of reports of recent safety problems, questions about optimal duration of use, and the patent expiration of Fosamax in February 2008, we accessed data from pharmaceutical marketing research databases to describe trends in dispensed prescriptions and sales of oral bisphosphonates, characteristics of patients and prescribers, and sales of intravenous bisphosphonates for osteoporosis treatment. An estimated 21.3million prescriptions for oral bisphosphonates were dispensed in U.S. retail pharmacies in 2002 that increased 46% to a peak of 31.0million in 2007 and 2008, and declined by 53% in a four year-period to 14.7million in 2012. Sales data (number of packages sold in all settings of care) showed parallel trends (66% increase from 2002 through 2007 and 51% decrease from 2007 through 2012). Similarly, intravenous bisphosphonate sales for osteoporosis treatment grew 3.8-fold from 149.5 thousand packages in 2007 to 561.6 thousand in 2010, followed by a 22% decrease in 2012. Data from an ongoing monthly office-based survey indicated physicians mentioned oral bisphosphonates primarily in visits of older aged Caucasian women with lower body mass for osteoporosis. Frequencies of oral bisphosphonate mentions increased between 2002 and 2012 in visits of Asians and for osteopenia diagnoses. These data indicate a substantial decline in prescriptions and sales of oral (since 2007-2008) and intravenous (since 2010) bisphosphonates for osteoporosis treatment in the United States. Reasons for, and implications of, the decline should be considered for future research. PMID- 24063949 TI - Cross-talk between estradiol receptor and EGFR/IGF-IR signaling pathways in estrogen-responsive breast cancers: focus on the role and impact of proteoglycans. AB - In hormone-dependent breast cancer, estrogen receptors are the principal signaling molecules that regulate several cell functions either by the genomic pathway acting directly as transcription factors in the nucleus or by the non genomic pathway interacting with other receptors and their adjacent pathways like EGFR/IGFR. It is well established in literature that EGFR and IGFR signaling pathways promote cell proliferation and differentiation. Moreover, recent data indicate the cross-talk between ERs and EGFR/IGFR signaling pathways causing a transformation of cell functions as well as deregulation on normal expression pattern of matrix molecules. Specifically, proteoglycans, a major category of extracellular matrix (ECM) and cell surface macromolecules, are modified during malignancy and cause alterations in cancer cell signaling, affecting eventually functional cell properties such as proliferation, adhesion and migration. The on going strategies to block only one of the above signaling effectors result cancer cells to overcome such inactivation using alternative signaling pathways. In this article, we therefore review the underlying mechanisms in respect to the role of ERs and the involvement of cross-talk between ERs, IGFR and EGFR in breast cancer cell properties and expression of extracellular secreted and cell bound proteoglycans involved in cancer progression. Understanding such signaling pathways may help to establish new potential pharmacological targets in terms of using ECM molecules to design novel anticancer therapies. PMID- 24063947 TI - The plastic nature of the human bone-periodontal ligament-tooth fibrous joint. AB - This study investigates bony protrusions within a narrowed periodontal ligament space (PDL-space) of a human bone-PDL-tooth fibrous joint by mapping structural, biochemical, and mechanical heterogeneity. Higher resolution structural characterization was achieved via complementary atomic force microscopy (AFM), nano-transmission X-ray microscopy (nano-TXM), and microtomography (MicroXCTTM). Structural heterogeneity was correlated to biochemical and elemental composition, illustrated via histochemistry and microprobe X-ray fluorescence analysis (MU XRF), and mechanical heterogeneity evaluated by AFM-based nanoindentation. Results demonstrated that the narrowed PDL-space was due to invasion of bundle bone (BB) into PDL-space. Protruded BB had a wider range with higher elastic modulus values (2-8GPa) compared to lamellar bone (0.8-6GPa), and increased quantities of Ca, P and Zn as revealed by MU-XRF. Interestingly, the hygroscopic 10-30MUm interface between protruded BB and lamellar bone exhibited higher X-ray attenuation similar to cement lines and lamellae within bone. Localization of the small leucine rich proteoglycan biglycan (BGN) responsible for mineralization was observed at the PDL-bone interface and around the osteocyte lacunae. Based on these results, it can be argued that the LB-BB interface was the original site of PDL attachment, and that the genesis of protruded BB identified as protrusions occurred as a result of shift in strain. We emphasize the importance of bony protrusions within the context of organ function and that additional study is warranted. PMID- 24063948 TI - Metaphyseal and diaphyseal bone loss in the tibia following transient muscle paralysis are spatiotemporally distinct resorption events. AB - When the skeleton is catabolically challenged, there is great variability in the timing and extent of bone resorption observed at cancellous and cortical bone sites. It remains unclear whether this resorptive heterogeneity, which is often evident within a single bone, arises from increased permissiveness of specific sites to bone resorption or localized resorptive events of varied robustness. To explore this question, we used the mouse model of calf paralysis induced bone loss, which results in metaphyseal and diaphyseal bone resorption of different timing and magnitude. Given this phenotypic pattern of resorption, we hypothesized that bone loss in the proximal tibia metaphysis and diaphysis occurs through resorption events that are spatially and temporally distinct. To test this hypothesis, we undertook three complimentary in vivo/MUCT imaging studies. Specifically, we defined spatiotemporal variations in endocortical bone resorption during the 3weeks following calf paralysis, applied a novel image registration approach to determine the location where bone resorption initiates within the proximal tibia metaphysis, and explored the role of varied basal osteoclast activity on the magnitude of bone loss initiation in the metaphysis using MUCT based bone resorption parameters. A differential response of metaphyseal and diaphyseal bone resorption was observed throughout each study. Acute endocortical bone loss following muscle paralysis occurred almost exclusively within the metaphyseal compartment (96.5% of total endocortical bone loss within 6days). Using our trabecular image registration approach, we further resolved the initiation of metaphyseal bone loss to a focused region of significant basal osteoclast function (0.03mm(3)) adjacent to the growth plate. This correlative observation of paralysis induced bone loss mediated by basal growth plate cell dynamics was supported by the acute metaphyseal osteoclastic response of 5-week vs. 13-month-old mice. Specifically, MUCT based bone resorption rates normalized to initial trabecular surface (BRRBS) were 3.7-fold greater in young vs. aged mice (2.27+/-0.27MUm(3)/MUm(2)/day vs. 0.60+/ 0.44MUm(3)/MUm(2)/day). In contrast to the focused bone loss initiation in the metaphysis, diaphyseal bone loss initiated homogeneously throughout the long axis of the tibia predominantly in the second week following paralysis (81.3% of diaphyseal endocortical expansion between days 6 and 13). The timing and homogenous nature are consistent with de novo osteoclastogenesis mediating the diaphyseal resorption. Taken together, our data suggests that tibial metaphyseal and diaphyseal bone loss induced by transient calf paralysis are spatially and temporally discrete events. In a broader context, these findings are an essential first step toward clarifying the timing and origins of multiple resorptive events that would require targeting to fully inhibit bone loss following neuromuscular trauma. PMID- 24063950 TI - Seroprevalence and correlates of Toxoplasma gondii infection in domestic sheep in Michoacan State, Mexico. AB - Toxoplasma gondii infection in sheep is of public health and economic importance. Seroprevalence of T. gondii infection and correlates were determined in 405 sheep from 7 farms in 4 geographical regions in Michoacan State, Mexico using the modified agglutination test (MAT). General sheep and environmental characteristics were obtained by a questionnaire. All sheep were raised in semi extensive conditions in temperate climate. Antibodies to T. gondii were found in 121 (29.9%) of the 405 sheep with MAT titers of 1:25 in 46, 1:50 in 20, 1:100 in 7, 1:200 in 5, 1:400 in 7, 1:800 in 11, 1:1600 in 5, and 1:3200 or higher in 20. Seropositivity did not vary significantly with age, sex or breed. In contrast, seroprevalence varied among farms, geographic region, municipality, altitude, mean annual temperature, and mean annual rainfall. The median seroprevalence in farms was 32.6% (range 7.1-71.4%). Sheep raised in farms at >=1900 m above sea level had a higher seroprevalence (44.1%) than those in farms at lower sea level (16.3%). Sheep raised in municipalities with <=17.7 degrees C mean annual temperature had a higher seroprevalence (37.2%) than those in municipalities with higher mean annual temperature (14.1%). Sheep raised in a municipality with 600 mm of mean annual rainfall had a higher seroprevalence (71.4%) than municipalities with higher mean annual rainfall (29.1%). This is the first report on the seroprevalence and correlates of T. gondii infection in sheep in Michoacan State, Mexico. The role of environmental characteristics for T. gondii infection in sheep deserves further research. PMID- 24063951 TI - A novel approach for FE-SEM imaging of wood-matrix polymer interface in a biocomposite. AB - Understanding the interface between polymer and biomass in composite products is important for developing high performance products, as the quality of adhesion at the interface determines composite properties. For example, with greater stiffness compared to polymer matrix, such as that of high density polyethylene, the wood component enhances stiffness of wood-polymer composites, provided there is good adhesion between composite components. However, in composites made from wood flour (wood particles) and synthetic resins it is often difficult to clearly resolve particle-matrix interfaces in the conventionally employed microscopy method that involves SEM examination of fractured faces of composites. We developed a novel approach, where composites made from high density polyethylene and wood flour were examined and imaged with a FE-SEM (field emission scanning electron microscope) in transverse sections cut through the composites. Improved definition of the interface was achieved using this approach, which enabled a more thorough comparison to be made of the features of the interface between wood particles and the matrix in composites with and without a coupling agent, as it was possible to clearly resolve the interfaces for particles of all sizes, from large particles consisting of many cells down to tiny cell wall fragments, particularly in composites that did not incorporate the coupling agent used to enhance particle adhesion with the matrix polymer. The method developed would be suitable particularly for high definition SEM imaging of a wide range of composites made combining wood and agricultural residues with synthetic polymers. PMID- 24063952 TI - [Acute neurological deficit, pleural chest pain and trifascicular block: presentation of a case of atypical infectious endocarditis]. PMID- 24063953 TI - Fe biogeochemistry in reclaimed acid mine drainage precipitates--implications for phytoremediation. AB - At a 50-year-old coal mine drainage barrens in central Pennsylvania, USA, we evaluated the biogeochemistry of acidic, Fe(III)oxy(hydr)oxide precipitates in reclaimed plots and compared them to untreated precipitates in control areas. Reclaimed plots supported successional vegetation that became established after a one-time compost and lime treatment in 2006, while control plots supported biological crusts. Precipitates were sampled from moist yet unsaturated surface layers in an area with lateral subsurface flow of mine drainage above a fragipan. Fe(II) concentrations were three- to five-fold higher in reclaimed than control precipitates. Organically bound Fe and amorphous iron oxides, as fractions of total Fe, were also higher in reclaimed than control precipitates. Estimates of Fe-reducing and Fe-oxidizing bacteria were four- to tenfold higher in root adherent than both types of control precipitates. By scaling up measurements from experimental plots, total Fe losses during the 5-yr following reclamation were estimated at 45 t Fe ha(-1) yr(-1). PMID- 24063954 TI - Developmental changes in melanophores and their asymmetrical responsiveness to melanin-concentrating hormone during metamorphosis in barfin flounder (Verasper moseri). AB - Barfin flounder larvae exhibit unique black coloration, as well as left-right asymmetry in juvenile stage as in other flatfish. In this study, we first assessed the changes in melanophores with development and then investigated their responsiveness to melanin-concentrating hormone (MCH) during metamorphosis. Larval-type melanophores appeared on both sides of the body before metamorphosis, whereas adult-type melanophores appeared only on the ocular side after metamorphosis. Even in the individuals of this species displaying black coloration, the density of larval-type melanophores was similar to that in transparent larvae of other species. However, unlike in transparent larvae, larval-type melanophores completely dispersed in the black larvae of this species. Therefore, the black coloration during larval stages was mainly due to dispersion, and not the density, of larval-type melanophores. In vitro MCH treatment revealed, for the first time, the responsiveness of melanophores in larval stages. On the ocular side, larval-type melanophores aggregated against MCH during larval stages, while, in the larvae at later metamorphic stages and in juveniles, larval-type melanophores did not aggregate, although aggregation of adult-type melanophores was noted. In contrast, on the blind side, the responsiveness of larval-type melanophores to MCH was consistently present from larval to juvenile stages. The metamorphic transition of MCH responsiveness from larval- to adult-type melanophores only on the ocular side suggests the larval (therefore, immature) nature of the blind side skin. We propose that the inhibited development, and thus the retention of the larval-type skin leads to the formation of the blind side characteristics and is the central mechanism for the flatfish asymmetry. PMID- 24063955 TI - An improved algorithm for model-based analysis of evoked skin conductance responses. AB - Model-based analysis of psychophysiological signals is more robust to noise - compared to standard approaches - and may furnish better predictors of psychological state, given a physiological signal. We have previously established the improved predictive validity of model-based analysis of evoked skin conductance responses to brief stimuli, relative to standard approaches. Here, we consider some technical aspects of the underlying generative model and demonstrate further improvements. Most importantly, harvesting between-subject variability in response shape can improve predictive validity, but only under constraints on plausible response forms. A further improvement is achieved by conditioning the physiological signal with high pass filtering. A general conclusion is that precise modelling of physiological time series does not markedly increase predictive validity; instead, it appears that a more constrained model and optimised data features provide better results, probably through a suppression of physiological fluctuation that is not caused by the experiment. PMID- 24063956 TI - Membrane perforation and recovery dynamics in microbubble-mediated sonoporation. AB - Transient sonoporation can essentially be epitomized by two fundamental processes: acoustically induced membrane perforation and its subsequent resealing. To provide insight into these processes, this article presents a new series of direct evidence on the membrane-level dynamics during and after an episode of sonoporation. Our direct observations were obtained from anchored fetal fibroblasts whose membrane topography was imaged in situ using real-time confocal microscopy. To facilitate controlled sonoporation at the single-cell level, microbubbles that can passively adhere to the cell membrane were first introduced at a 1:1 cell-to-bubble ratio. Single-pulse ultrasound exposure (1-MHz frequency, 10-cycle pulse duration, 0.85-MPa peak negative pressure in situ) was then applied to trigger microbubble pulsation/collapse, which, in turn, instigated membrane perforation. With this protocol, five membrane-level phenomena were observed: (i) localized perforation of the cell membrane was synchronized with the instant of ultrasound pulsing; (ii) perforation sites with temporal peak area <30 MUm(2) were resealed successfully; (iii) during recovery, a thickened pore rim emerged, and its temporal progression corresponded with the pore closure action; (iv) membrane resealing, if successful, would generally be completed within 1 min of the onset of sonoporation, and the resealing time constant was estimated to be below 20 s; (v) membrane resealing would fail for overly large pores (>100 MUm(2)) or in the absence of extracellular calcium ions. These findings serve to underscore the spatiotemporal complexity of membrane level dynamics in sonoporation. PMID- 24063957 TI - Induction of endoplasmic reticulum stress by sonoporation: linkage to mitochondria-mediated apoptosis initiation. AB - The use of cavitational means to create transient membrane pores on living cells (i.e., sonoporation) may potentially induce a broad range of downstream bio effects that disrupt the functioning of various organelles. Here we observed that on HL-60 leukemia cells, sonoporation may induce endoplasmic reticulum (ER) stress on a time-lapse basis and, in turn, signal the mitochondria to commit a cell toward apoptosis. Our observations were derived from in vitro ultrasound exposure experiments performed on HL-60 cells in the presence of lipid-shelled microbubbles (1:1 cell-to-bubble ratio; 1-MHz frequency; 0.45-MPa in situ peak negative pressure; 100-cycle pulse length; 1-kHz pulse repetition frequency; 60-s exposure period). Using flow cytometry, we found that sonoporated cells exhibited a progressive loss of functional ER mass over a 6-h period. Also, post-exposure Western blot assays (between 0 and 24 h) revealed various indications of post sonoporation ER stress: (i) upregulation of ER-resident enzymes responsible for catalyzing protein folding; (ii) activation of trans-ER-membrane stress sensors; (iii) increased expression of ER-induced regulatory proteins that mediate pro apoptotic signals to the mitochondria. These results corresponded to flow cytometry observations that depicted a progressive depolarization of a sonoporated cell's mitochondrial outer membrane potential. They were also consistent with another Western blot assay that found, in sonoporated cells, a time-lapse increase of caspase-9 (a mitochondria-activated apoptosis initiator protein). Taken together, our findings indicate that sonoporation may upset ER homeostasis, and this may ultimately result in initiation of apoptosis. PMID- 24063958 TI - Histotripsy cardiac therapy system integrated with real-time motion correction. AB - Histotripsy has shown promise in non-invasive cardiac therapy for neonatal and fetal applications. However, for cardiac applications in general, and especially in the adult heart, cardiac and respiratory motion may affect treatment accuracy and efficacy. In this article, we describe a histotripsy-mediated cardiac therapy system integrated with a fast motion tracking algorithm and treatment monitoring using ultrasound imaging. Motion tracking is performed by diamond search block matching in real-time ultrasound images using a reference image of the moving target, refined by Kalman filtering. As proof of feasibility, this algorithm was configured to track 2-D target motion and then electronically adjust the focus of a 1-MHz annular therapy array to correct for axial motion. This integrated motion tracking system is capable of sub-millimeter accuracy for displacements of 0-15 mm and velocities of 0-80 mm/s, with a maximum error less than 3 mm. Tissue phantom tests indicated that treatment efficiency and lesion size using motion tracking over displacements of 0-15 mm and velocities of 0-42 mm/s are comparable to those achieved when treating stationary targets. In vivo validation was conducted in an open-chest canine model, where the system provided 24 min of motion-corrected histotripsy therapy in the live beating heart, generating a targeted lesion on the atrial septum. Based on this proof of feasibility and the natural extension of these techniques to three dimensions, we anticipate a full motion correction system would be feasible and beneficial for non-invasive cardiac therapy. PMID- 24063959 TI - Fully automatic plaque segmentation in 3-D carotid ultrasound images. AB - Automatic segmentation of the carotid plaques from ultrasound images has been shown to be an important task for monitoring progression and regression of carotid atherosclerosis. Considering the complex structure and heterogeneity of plaques, a fully automatic segmentation method based on media-adventitia and lumen-intima boundary priors is proposed. This method combines image intensity with structure information in both initialization and a level-set evolution process. Algorithm accuracy was examined on the common carotid artery part of 26 3-D carotid ultrasound images (34 plaques ranging in volume from 2.5 to 456 mm(3)) by comparing the results of our algorithm with manual segmentations of two experts. Evaluation results indicated that the algorithm yielded total plaque volume (TPV) differences of -5.3 +/- 12.7 and -8.5 +/- 13.8 mm(3) and absolute TPV differences of 9.9 +/- 9.5 and 11.8 +/- 11.1 mm(3). Moreover, high correlation coefficients in generating TPV (0.993 and 0.992) between algorithm results and both sets of manual results were obtained. The automatic method provides a reliable way to segment carotid plaque in 3-D ultrasound images and can be used in clinical practice to estimate plaque measurements for management of carotid atherosclerosis. PMID- 24063960 TI - Enhancement of adenovirus delivery after ultrasound-stimulated therapy in a cancer model. AB - Improving the efficiency of adenovirus (Ad) delivery to target tissues has the potential to advance the translation of cancer gene therapy. Ultrasound (US) stimulated therapy uses microbubbles (MBs) exposed to low-intensity US energy to improve localized delivery. We hypothesize that US-stimulated gene therapy can improve Ad infection in a primary prostate tumor through enhanced tumor uptake and retention of the Ad vector. In vitro studies were performed to analyze the degree of Ad infectivity after application of US-stimulated gene therapy. A luciferase-based Ad on a ubiquitous cytomegalovirus (CMV) promoter (Ad5/3-CMV Luc) was used in an animal model of prostate cancer (bilateral tumor growth) to evaluate Ad transduction efficiency after US-stimulated therapy. Bioluminescence imaging was employed for in vivo analysis to quantify Ad infection within the tumor. In vitro studies revealed no difference in Ad transduction between groups receiving US-stimulated therapy using high, low or sham US intensity exposures at various multiplicities of infection (MOIs) (p = 0.80). In vivo results indicated that tumors receiving US-stimulated therapy after intra-tumoral injection of Ad5/3-CMV-Luc (1 * 10(6) plaque-forming units) exhibited a 95.1% enhancement in tumor delivery compared with control tumors receiving sham US (p = 0.03). US stimulated therapy has significant potential to immediately affect Ad-based cancer gene therapy by improving virus bioavailability in target tissues. PMID- 24063961 TI - Shear wave velocity measurements for differential diagnosis of solid breast masses: a comparison between virtual touch quantification and virtual touch IQ. AB - This study compared the diagnostic performance of two shear wave speed measurement techniques in 81 patients with 83 solid breast lesions. Virtual Touch Quantification, which provides single-point shear wave speed measurement capability (SP-SWS), was compared with Virtual Touch IQ, a new 2-D shear wave imaging technique with multi-point shear wave speed measurement capability (2D SWS). With SP-SWS, shear wave velocity was measured within the lesion ("internal" value) and the marginal areas ("marginal" value). With 2D-SWS, the highest velocity was measured. The marginal values obtained with the SP-SWS and 2D-SWS methods were significantly higher for malignant lesions and benign lesions, respectively (p < 0.0001). Sensitivity, specificity and accuracy were 86% (36/42), 90% (37/41) and 88% (73/83), respectively, for SP-SWS, and 88% (37/42), 93% (38/41) and 90% (75/83), respectively, for 2D-SWS. It is concluded that 2D SWS is a useful diagnostic tool for differentiating malignant from benign solid breast masses. PMID- 24063962 TI - Evaluation of real-time tissue sono-elastography in the assessment of 214 breast lesions: limitations of this method resulting from different histologic subtypes, tumor size and tumor localization. AB - Real-time sono-elastography is an ultrasound-based technique used to estimate tissue elasticity. Several publications have reported that this method has the ability to differentiate between malignant and benign breast lesions. However, on the basis of current literature, sono-elastography returned false-negative results in 25% of cases with certain lesions, such as mucinous carcinoma. Our data indicate that elastography has higher specificity (96.5% vs. 84.4%) and lower sensitivity (86.9% vs. 93.9%) than B-mode ultrasound. Our evidence suggests that elastography performs significantly worse in lesions >=20 mm in diameter (sensitivity = 61.1%, specificity = 97.2%) than in lesions <20 mm in diameter (sensitivity = 92.6%, specificity = 96.2%). Furthermore, elastography returned false-negative results in all cases mucinous carcinoma. Finally, in eight cases we obtained a valid elastogram. Our data indicate that this finding is probably due to tumor depth. PMID- 24063963 TI - Test-retest reliability and the minimal detectable change for achilles tendon length: a panoramic ultrasound assessment. AB - The purpose of the present study was to examine test-retest reliability and minimal detectable change (MDC) values for Achilles tendon (AT) length determined using panoramic ultrasound (US) imaging. Seventeen men (age = 21.0 +/- 2.3 y) visited the laboratory on two separate days, where AT length was examined along the mid-longitudinal axis of the right lower leg with a portable B-mode panoramic US device. These measures were found to have acceptable reliability with intra class correlation coefficient (ICC) and standard error of measurement (SEM) values of 0.954 and 4.43 mm (SEM% of the mean = 2.37%), respectively. In addition, the MDC for the panoramic US assessment of AT length was 12.27 mm (MDC% of the mean = 6.57%). These findings suggest that panoramic US imaging is a reliable technique for detection of clinically relevant changes in AT length and may therefore be a practical and time-efficient clinical tool for future studies examining AT length in vivo. PMID- 24063964 TI - Adaptive wavelet packet-based de-speckling of ultrasound images with bilateral filter. AB - A new adaptive wavelet packet-based approach to minimize speckle noise in ultrasound images is proposed. This method combines wavelet packet thresholding with a bilateral filter. Here, the best bases after wavelet packet decomposition are selected by comparing the first singular value of all sub-bands, and the noisy coefficients are thresholded using a modified NeighShrink technique. The algorithm is tested with various ultrasound images, and the results, in terms of peak signal-to-noise ratio and mean structural similarity values, are compared with those for some well-known de-speckling techniques. The simulation results indicate that the proposed method has better potential to minimize speckle noise and retain fine details of the ultrasound image. PMID- 24063966 TI - Laparoscopic versus robotic radical hysterectomy after neoadjuvant chemotherapy in locally advanced cervical cancer: a case control study. AB - OBJECTIVE: To compare the surgical outcome of robotic radical hysterectomy (RRH) versus laparoscopic radical hysterectomy (LRH) for the treatment of locally advanced cervical cancer (LACC) after neoadjuvant chemotherapy (NACT). MATERIALS AND METHODS: From August 1st 2010 to July 1st 2012 a prospective data collection of women undergoing RRH for cervical cancer stage FIGO IB2 to IIB, after neoadjuvant chemotherapy, was conducted at National Cancer Institute "Regina Elena" of Rome. All patients deemed operable underwent class C1 RRH with pelvic lymphadenectomy within 4 weeks from the last chemotherapy cycle. RESULTS: A total of 25 RRH were analyzed, and compared with 25 historic LRH cases. The groups did not differ significantly in body mass index, stage, histology, number of pelvic lymph nodes removed. The median operative time was the same in the two groups with 190 min respectively. The median estimated blood loss (EBL) was statistically significant in favor of RRH group. Median length of stay was shorter, for the RRH group (4 versus 6 days, P = 0.28). There was no significant difference in terms of intraoperative and postoperative complications between groups but in the RRH group we observed a greater number of total complications compared to the control group. CONCLUSION: This study shows that RRH is safe and feasible in LACC after NACT compare to LRH. However, a comparison of oncologic outcomes and cost-benefit analysis is still needed and it has to be carefully evaluated in the future. PMID- 24063967 TI - Massive endoprosthetic replacement for bone metastases resulting from renal cell carcinoma: factors influencing patient survival. AB - BACKGROUND: Surgery remains the main treatment of bone metastases due to renal cell carcinoma (RCC). We reviewed 135 patients treated with resection and endoprosthetic replacement (EPR) and examined clinico-pathological factors predicting survival. METHODS: Surgical and oncological outcomes were examined using a prospectively maintained database between 1976 and 2012. Survival rates were calculated by Kaplan-Meier method. Multivariate analyses were performed to investigate factors predictive of increased survival. RESULTS: At diagnosis, 81 patients had synchronous RCC and bone metastases and the remaining developed metachronous metastases after primary treatment for RCC. The majority were solitary tumours (75%) and 77% had >= one concurrent visceral metastases. The median age at surgery was 61 years old (IQR 53-69). The median follow-up was 20 months (IQR 10-43) and the overall survival was 72% at one-year. This declined to 45% and 28% at three and five-years, respectively. After adjustments for prognostic factors, there was an increased risk of death in patients with multiple skeletal metastases (HR = 2), >=one visceral metastases (HR = 3) and local recurrence (HR = 3) (all p <= 0.01). Ten patients required revision (7%) and the risk of revision was 4% at one-year and remained low at 8% from two years postoperatively. CONCLUSION: Patients with solitary bone lesions and no visceral metastases should be considered for bone resection and EPR. As survival beyond one-year can be expected in a majority of patients and the risk of further surgery after EPR is low, patients with multiple skeletal metastases and visceral metastases should also be considered. PMID- 24063968 TI - A causal role for circulating miR-34b in osteosarcoma. AB - PURPOSE: To investigate the associations between plasma miR-34b/c expression levels and osteosarcoma (OS). SUBJECTS AND METHODS: A case-control study was conducted in 133 patients with OS and 133 controls. MiR-34b/c levels were detected by quantitative reverse transcriptase polymerase chain reaction (qRT PCR) assays. Genotyping of SNP rs4938723 was done using the TaqMan assay. The causal association was examined by mendelian randomization analysis. RESULTS: Plasma miR-34b level was significantly lower in OS patients than in controls (P = 0.001). Expression levels of miR-34b in OS tissues decreased (P = 3.22 * 10(-4)) and was significantly related with its expression in plasma (r = 0.21, P = 0.004). Compared with wild-type TT genotype, the variant genotypes of rs4938723 TC/CC were significantly associated with increased OS risk (TC vs. TT: OR, 1.97 [95% CI: 1.40-2.55], P = 0.021; CC vs. TT: OR, 2.76 [95% CI: 2.00-3.53], P = 0.009; TC + CC vs. TT: OR, 2.16 [95% CI: 1.61-2.70], P = 0.006), consistent with its decreased effect on plasma miR-34b (TC vs. TT: -0.32 (-0.43, -0.21), P < 0.001; CC vs. TT: -0.70 (-0.84, -0.56), P < 0.001; TC + CC vs. TT: -0.42 (-0.53, 0.32), P < 0.001). Adjustment for miR-34b completely abolished the association between SNP rs4938723 and OS risk (P > 0.05). In addition, plasma expression levels of miR-34b were significantly decreased in the metastatic patients compared with that in the non-metastatic ones (P = 0.004). CONCLUSION: Plasma miR 34b was causally associated with OS risk and related with its metastatic status, suggesting that plasma miR-34b might be a novel biomarker and a potential treatment target for OS. PMID- 24063969 TI - Multidisciplinary care of gastrointestinal stromal tumour: a review and a proposal for a pre-treatment classification. AB - The introduction of receptor tyrosine kinase inhibitors (TKIs) has revolutionized the management of gastrointestinal stromal tumour (GIST). Strong evidence supports the use of imatinib as first-line treatment in metastatic or unresectable tumours and its efficacy in the post-operative adjuvant setting has been confirmed by phase III trials. There are a number of reports concerning the administration of imatinib in the pre-operative setting, however, the heterogeneity of the terminology used and the indications for pre-operative treatment make it difficult to determine the true value of pre-operative imatinib. Larger studies, or a phase III trial could be helpful but patient accrual and standardization of care could be difficult. We propose a pre treatment classification of GIST in order to facilitate the comparison and collection of data from different institutions, and overcome the difficulties related to accrual. Moreover, in the current era of multidisciplinary treatment of GIST, an appropriate classification is mandatory to properly design clinical trials and plan stage-adapted treatment. PMID- 24063970 TI - Prognostic value of the IASLC/ATS/ERS classification in stage I lung adenocarcinoma patients--based on a hospital study in China. AB - AIMS: We investigated the relationship between predominant subtype, according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Lung Adenocarcinoma Classification, and prognosis in stage I lung adenocarcinoma in Zhejiang Cancer Hospital. METHODS: Two hundred and sixty-one patients with stage I lung adenocarcinoma, operated in Zhejiang Cancer Hospital, were identified between 2000 and 2010. Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis. RESULTS: None of the cases were adenocarcinoma in situ and six were minimally invasive adenocarcinomas. Two hundred and fifty-five cases were invasive adenocarcinoma. Of those, 80, 76, 42, 34, 19, and 4 were papillary predominant, acinar predominant, micropapillary predominant, solid predominant, lepidic predominant subtypes, and variants of invasive adenocarcinoma, respectively. Patients with micropapillary and solid predominant tumors had a significantly worse disease-free survival as compared to those with other subtypes predominant tumors (p < 0.001). Multivariate analysis revealed that the new classification was an independent predictor of the disease-free and overall survival (p = 0.002 and 0.015). CONCLUSION: The predominant subtype in the primary tumor was associated with prognosis in resected stage I lung adenocarcinoma. PMID- 24063971 TI - Effectiveness of routine follow-up in the detection of contralateral breast cancer in young women with early breast cancer. AB - BACKGROUND: The purpose of the study was to determine the effectiveness of routine follow-up to detect contralateral breast cancer (CBC) in young women. METHODS: We used the data of the population-based Eindhoven Cancer Registry, which covers the southern part of the Netherlands. Between 1988 and 2005, 1451 women aged <= 40 years were treated for early-stage breast cancer with breast conserving treatment or mastectomy. RESULTS: Of the 94 patients who developed CBC 17 had an in situ carcinoma. Fifty-seven CBCs (61%) were diagnosed more than 5 years after the primary tumour. Forty-two CBCs (45%) were detected during routine follow-up visits, while 52 (55%) presented between two visits. Of the CBC diagnosed between two visits, only 27 (60%) were visible on mammography. Of the invasive CBCs more than 25% was larger than 2 cm in diameter and in 34% positive axillary lymph nodes were found. CONCLUSIONS: These figures indicate that routine follow-up does not guarantee early detection of CBC in young women with breast cancer. PMID- 24063972 TI - Comparison of TNF antagonism by etanercept and dexamethasone on airway epithelium and remodeling in an experimental model of asthma. AB - BACKGROUND: The aim of the study was to compare the influence of TNF antagonism and corticosteroid treatment on epithelial, smooth muscle and basement membrane component of airway remodeling in an experimental murine model of chronic asthma. METHODS: We used 30 BALB/c mice. Group 1 not exposed to ovalbumin or any medication was designated as control group. Chronic asthma model was achieved in the other three groups with intraperitoneal (IP) and inhaled ovalbumin. Then, Group 2 received IP saline, Group 3 received IP dexamethasone and Group 4 received IP etanercept. Epithelial, subepithelial smooth muscle and basement membrane thickness as well as goblet cells and mast cells were examined on samples isolated from left lung. RESULTS: Etanercept treatment led to thinner epithelial and basement membrane layer and lower goblet and mast cell number than untreated asthmatic mice (p<0.001, p=0.001, p=0.005 and p=0.03 respectively). Neither epithelial and basement membrane thickness nor mast cell number was different among mice treated with etanercept and dexamethasone (p=0.38, p=0.79 and p=0.51 respectively). However, etanercept group was associated with thicker subepithelial muscle layer but lower goblet cell number (p<0.001 and p=0.04 respectively) than dexamethasone group. CONCLUSIONS: Corticosteroids are more effective in decreasing smooth muscle mass while TNF antagonists in reducing goblet cell number in animal model of asthma. Therefore, further research is needed to assess the synergistic use of TNF antagonism and dexamethasone for more rational remodeling control. PMID- 24063973 TI - The long-term psychiatric and medical prognosis of perinatal mental illness. AB - The perinatal period provides an important window into a woman's long-term health. Perinatal mental illness is a common condition conferring potential serious long-term psychiatric and medical consequences for the mother and family. It is known that childbirth acts as a powerful trigger for depressive episodes in some women, and that women with histories of a mood disorder are particularly vulnerable. Some evidence links perinatal mental illness with obstetrical complications and reduced lactation initiation and duration. Therefore, perinatal mental illness may be a marker for long-term risk, and may contribute directly to subsequent cardiometabolic disease through both neuroendocrine mechanisms and the effects of mental illness on health behaviours. In clinical practice, these associations underscore the importance of screening and treating women with perinatal mental illness to ensure best possible long-term outcomes. Early screening and treatment may both mitigate the primary disease process and reduce the risk of comorbid medical conditions. PMID- 24063975 TI - Elevated titers of anti-thyroperoxidase antibodies in patients with multiple system atrophy: a pilot study. AB - OBJECTIVES: Multiple system atrophy (MSA) is a neurodegenerative disease characterized by progressive neuronal loss and alpha-synuclein deposition in oligodendroglial cells in the central nervous system. The cause of MSA remains essentially unknown. A cerebellar syndrome was associated with autoimmune thyroid disease in some cases, apparently not related to MSA and was partially responsive to immunomodulatory therapy. PATIENTS AND METHODS: 28 euthyroid patients who fulfilled the diagnostic criteria for probable MSA, 11 with MSA-cerebellar type (MSA-C), 17 with MSA-parkinsonian type (MSA-P), 28 patients with Parkinson's disease (PD) and 26 normal euthyroid controls were tested the for serum levels of anti-thyroperoxidase antibodies (anti-TPO) and anti-thyroglobulin (Anti-TG) antibodies (Ab). RESULTS: The laboratory results were statistically similar in all three groups, but 3 MSA-C patients had highly elevated anti-TPO Ab titers. CONCLUSION: We identified the presence of elevated anti-TPO levels in a small subgroup of MSA-C patients but neither in MSA-P or PD patients nor in healthy controls. These findings may suggest an autoimmune etiology in some cases of MSA C. PMID- 24063974 TI - Influence of VMH fuel sensing on hypoglycemic responses. AB - Hypoglycemia produces complex neural and hormonal responses that restore glucose levels to normal. Glucose, metabolic substrates and their transporters, neuropeptides and neurotransmitters alter the firing rate of glucose-sensing neurons in the ventromedial hypothalamus (VMH); these monitor energy status and regulate the release of neurotransmitters that instigate a suitable counter regulatory response. Under normal physiological conditions, these mechanisms maintain blood glucose concentrations within narrow margins. However, antecedent hypoglycemia and diabetes can lead to adaptations within the brain that impair counter-regulatory responses. Clearly, the mechanisms employed to detect and regulate the response to hypoglycemia, and the pathophysiology of defective counter-regulation in diabetes, are complex and need to be elucidated to permit the development of therapies that prevent or reduce the risk of hypoglycemia. PMID- 24063976 TI - Safety and immunogenicity of inactivated poliovirus vaccine based on Sabin strains with and without aluminum hydroxide: a phase I trial in healthy adults. AB - BACKGROUND: An inactivated poliovirus vaccine (IPV) based on attenuated poliovirus strains (Sabin-1, -2 and -3) was developed for technology transfer to manufacturers in low- and middle income countries in the context of the Global Polio Eradication Initiative. METHOD: Safety and immunogenicity of the Sabin-IPV was evaluated in a double-blind, randomized, controlled, phase I 'proof-of concept' trial. Healthy male adults received a single intramuscular injection with Sabin-IPV, Sabin-IPV adjuvanted with aluminum hydroxide or conventional IPV. Virus-neutralizing titers against both Sabin and wild poliovirus strains were determined before and 28 days after vaccination. RESULTS: No vaccine-related serious adverse events were observed, and all local and systemic reactions were mild or moderate and transient. In all subjects, an increase in antibody titer for all types of poliovirus (both Sabin and wild strains) was observed 28 days after vaccination. CONCLUSION: Sabin-IPV and Sabin-IPV adjuvanted with aluminum hydroxide administered as a booster dose were equally immunogenic and safe as conventional IPV. EudraCTnr: 2010-024581-22, NCT01708720. PMID- 24063978 TI - Enhancing neutralizing antibody production by an interferon-inducing porcine reproductive and respiratory syndrome virus strain. AB - Porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) continues to cause substantial economic losses to the global swine industry. PRRSV appears to inhibit synthesis of type I interferons (IFNs), such as IFN-alpha and -beta, which are critical for the innate immunity and play an important role in the modulation of adaptive immunity. An atypical PRRSV strain, A2MC2, is able to induce type I IFNs in vitro. In this study, A2MC2 induction of neutralizing antibodies in vivo was compared with the Ingelvac PRRS modified live virus (MLV) vaccine strain and VR-2385 (a moderate virulent strain). Three-week-old pigs were exposed to these PRRSV strains via intranasal or intramuscular routes to also account for a possible effect of inoculation routes. The interferon-inducing A2MC2 resulted in earlier onset and significantly higher levels of PRRSV neutralizing antibodies than the MLV. In addition, the A2MC2-induced neutralizing antibodies were capable of neutralizing VR-2385, a heterologous strain. The pigs exposed via intranasal route had higher titers of neutralizing antibodies than those injected via intramuscular route. Macroscopic and microscopic lung lesions 14 days post-exposure indicated that A2MC2 had similar virulence in vivo as VR 2385. Pulmonary alveolar macrophages (PAMs) collected during the necropsy 14 days post-exposure in the A2MC2 group had higher level expression of IFN-gamma than the MLV group. These results indicate that A2MC2 can be further explored for development of an improved vaccine against PRRS. PMID- 24063977 TI - NDV-3 protects mice from vulvovaginal candidiasis through T- and B-cell immune response. AB - We have previously reported that vaccination with rAls3p-N protein of Candida albicans, formulated with alum adjuvant (also designated as NDV-3) protects immunocompetent mice from, lethal disseminated candidiasis and mucosal oropharyngeal candidiasis. NDV-3 vaccine was recently, tested in a Phase 1 clinical trial and found to be safe, well-tolerated, and induced robust humoral and, cellular immune responses with increased interferon (IFN)-gamma and interleukin (IL)-17 secretion. In preparation for a Phase 2 clinical trial against vulvovaginal candidiasis (VVC), we evaluated NDV-3, efficacy in a murine VVC model. Here, NDV-3 induced a strong immune response characterized by high, anti-rAls3p-N serum IgG and vaginal IgA titers. Furthermore, moderate doses of the vaccine (a range of 1-30MUg given subcutaneously [SQ] or 0.3-10MUg given intramuscularly [IM]) elicited a 10-1000 fold, decrease in vaginal fungal burden vs. control (mice injected with alum adjuvant alone) in both inbred, and outbred mice infected with different clinical C. albicans isolates. Additionally, NDV-3 required both, T and B lymphocytes for efficacy in reducing C. albicans tissue burden, which is followed by a reduction, in neutrophil influx to the affected site. Finally, anti-rAls3p-N antibodies enhanced the ex vivo killing, of C. albicans by neutrophils primed with IFN-gamma. These data indicate that NDV-3 protects mice, from VVC by a mechanism that involves the concerted priming of both humoral and adaptive immune, responses. PMID- 24063979 TI - Hedgehog-signaling is upregulated in non-producing human adrenal adenomas and antagonism of hedgehog-signaling inhibits proliferation of NCI-H295R cells and an immortalized primary human adrenal cell line. AB - Hedgehog (Hh)-signaling pathway is important in embryonic development. Activation of Hh-signaling is associated with tumorigenesis. Recent studies demonstrate that Hh-signaling is involved in the development of the adrenal gland in mice and is important in regulating adrenal proliferation. We studied the expression of Sonic hedgehog (SHH), Smoothened (SMO), Patched1 (PTCH1) and GLI family zinc finger 1 (GLI1) in human adrenal and in adrenocortical tumors using immunohistochemistry and semi-quantitative reverse transcriptase-polymerase chain reaction. Modulation of GLI1 and SMO messenger ribonucleic acid (mRNA) expression was investigated with forskolin. The role of Hh-signaling was studied in NCI-H295R cells and in an immortalized primary cell line using the Hh-agonist smoothened agonist (SAG) and the Hh-antagonist cyclopamine. The Hh-pathway components SHH, GLI1, PTCH1 and SMO were detectable in all adrenal glands. While in cortisol-producing adenomas (CPA), Hh-signaling expression levels were comparable to that in normal adrenal cortex, a much higher mRNA expression of GLI1, SMO and SHH was observed in non producing adenomas (NPA). Interestingly, stimulation of cultured adrenal cells with forskolin led to a decrease in expression of GLI1 and SMO mRNAs. Antagonism of Hh-signaling resulted in a lower proliferation rate of adrenocortical cells, while Hh-agonism had no significant effect on adrenal cell proliferation. Our data show Hh-signaling activity in adult adrenal glands. Activation of the PKA pathway results in lower expression of Hh-signaling proteins. This might explain the lower expression of the Hh components GLI1 and SMO in CPA in comparison to the higher expression in NPA. Hh-signaling might be involved in the tumorigenesis of NPA. PMID- 24063980 TI - Reply to Yamamoto et al. PMID- 24063981 TI - A novel multimodal chromatography based single step purification process for efficient manufacturing of an E. coli based biotherapeutic protein product. AB - Methionine oxidized, reduced and fMet forms of a native recombinant protein product are often the critical product variants which are associated with proteins expressed as bacterial inclusion bodies in E. coli. Such product variants differ from native protein in their structural and functional aspects, and may lead to loss of biological activity and immunogenic response in patients. This investigation focuses on evaluation of multimodal chromatography for selective removal of these product variants using recombinant human granulocyte colony stimulating factor (GCSF) as the model protein. Unique selectivity in separation of closely related product variants was obtained using combined pH and salt based elution gradients in hydrophobic charge induction chromatography. Simultaneous removal of process related impurities was also achieved in flow through leading to single step purification process for the GCSF. Results indicate that the product recovery of up to 90.0% can be obtained with purity levels of greater than 99.0%. Binding the target protein at pH10(7)g/mol), affecting rheological properties of the rubber. Thus, determinations of M and size distribution of these microgels are critical in performance evaluation and control for SSBR. We employ thermal field-flow fractionation (ThFFF), combined with online multi-angle light scattering (MALS), as most suited for characterization of solutions containing the microgels since they can be characterized in toto without removing the microgels from the solution. ThFFF-MALS was applied for characterization of linear and branched SBR materials from various commercial sources, and the results were compared to those from size-exclusion chromatography (SEC). ThFFF provides higher resolution than SEC for high molecular fractions and allowed gel content to be measured. The gel content was determined by subtracting the amount of sol from total injection mass, and was measured to be 10-15%. We infer from the characterization results that the microgel content may not be correlated to the microstructure, the styrene and vinyl content of butadiene but to the fraction of high molecular weight in SSBR. Finally, the macromolecular structure and the content of microgel (larger than about 100nm) were found to significantly affect various rheological parameters such as viscosity, mechanical and dynamic properties. PMID- 24063985 TI - Successful local control of cutaneous Merkel cell carcinoma on the eyelid with CyberKnife radiosurgery. PMID- 24063986 TI - Analgesia induced by 2- or 100-Hz electroacupuncture in the rat tail-flick test depends on the anterior pretectal nucleus. AB - AIMS: The anterior pretectal nucleus (APtN) and electroacupuncture (EA) activate descending mechanisms to modulate nociceptive inputs in the spinal dorsal horn. This study examines qualitatively whether mechanisms in the APtN participate in the EA-induced analgesia in rats. MAIN METHODS: The tail-flick test was utilized to examine the changes produced by non-selective antagonists of serotonergic (methysergide, 37 pg), muscarinic (atropine, 10 ng) and opioid (naloxone, 10 ng) receptors; selective antagonists against MU (CTOP, 6.4 MUg), delta (ICI174,864, 6.9 MUg) or kappa (nor-BNI, 7.3 MUg); 5HT1 (methiothepin, 0.47 MUg), 5HT2 (ketanserin, 5.4 MUg), or 5HT3 (MDL 72222, 15.7 MUg); and GABAA (bicuculline, 150 ng) receptors injected into the dorsal (d) or ventral (v) APtN on the antinociception induced by a 20-min EA applied at 2- or 100-Hz frequency to the Zusanli and Sanyinjiao acupoints. KEY FINDINGS: The 2-Hz EA-induced analgesia was blocked by naloxone, CTOP or atropine, was less intense after bicuculline, was shorter after methysergide or methiothepin in dAPtN, and was less intense after methysergide, methiothepin and bicuculline in vAPtN. The 100-Hz EA-induced analgesia was less intense after methysergide, methiothepin and CTOP in vAPtN, and remained unchanged after injection of the antagonists into the dAPtN. SIGNIFICANCE: The 2-Hz EA-induced analgesia utilizes cholinergic muscarinic, MU opioid, GABAA and 5-HT1 mechanisms in the dAPtN and MU-opioid and 5-HT1 mechanisms in the vAPtN, while 100-Hz EA-induced analgesia utilizes MU-opioid and 5-HT1 mechanisms in the vAPtN but does not utilize them in the dAPtN. PMID- 24063987 TI - Berberine counteracts enhanced IL-8 expression of AGS cells induced by evodiamine. AB - AIMS: Although showing an anti-tumor activity, evodiamine also up-regulated IL-8 production of human gastric cancer AGS cells. This study aimed to assess this effect and to examine whether co-administration with berberine counteracts it. MAIN METHODS: MTT assay was used to assess the cell proliferation and adhesive ability. Flow cytometry was performed to measure the cell cycle distribution. Wound healing assay was used to detect the migration ability of cells. IL-8 production was determined by ELISA. Levels of mRNA expression of IL-8, VCAM-1 and ICAM-1 were measured by real-time PCR. Molecular pathways involved were evaluated by ELISA and western-blotting methods. KEY FINDINGS: Evodiamine triggered proliferative inhibition and cell cycle arrest, and decreased migration of AGS cells. IL-8 expression and the adhesive ability of AGS cells to HUVECs were significantly increased by evodiamine, but were inhibited after being co-treated with berberine in AGS cells. As IL-8 was neutralized, increased adhesion of AGS cells to HUVECs induced by evodiamine was abolished. Berberine significantly suppressed the up-regulation of VCAM-1 and the down-regulation of ICAM-1 induced by evodiamine. Evodiamine provoked IL-8 secretion via ERK1/2, SAPK/JNK, JAK2 and AP-1 pathways which could be counteracted by berberine. SIGNIFICANCE: Although showing anti-proliferative and anti-migratory activities in AGS cells, evodiamine displayed a potential tendency to promote metastasis of gastric cancer cells by increasing IL-8 secretion and adhesion molecules. However, berberine could counteract the side-effect and simultaneously keep anti-proliferative and anti migratory properties of evodiamine on AGS cells, which reduces the risk to use evodiamine in therapy of gastric cancers. PMID- 24063988 TI - The effects of bilateral lesions of the mesencephalic trigeminal sensory nucleus on nocturnal feeding and related behaviors in mice. AB - AIMS: The mesencephalic trigeminal sensory nucleus (Me5), which receives signals originating from oral proprioceptors and projects its fibers to the hypothalamus, regulates mastication and modulates satiation. Because the Me5 neurons display circadian rhythms in circadian mPer1 gene expression and bilateral Me5 lesions change feeding and exploratory behavior profiles, we speculated that Me5 may influence the daily timing of feeding. Therefore, we explored the effects of bilateral caudal Me5 lesions on the circadian profiles of feeding and its related behaviors. MAIN METHODS: We measured the activities of feeding, drinking, and locomotion for 24h using an automated feeding behavior measurement apparatus and analyzed the mRNA expression levels of hypothalamic orexigenic and anorexigenic signaling molecules in both Me5-lesioned and sham-operated mice. KEY FINDINGS: Food and water intake and locomotor activity decreased significantly in Me5 lesioned mice during the dark phase without affecting these total indexes when measured over the entire day. Analysis of the mRNA expression levels of hypothalamic orexigenic and anorexigenic signaling molecules showed that prepro orexin (orexin) mRNA in the perifornical area was significantly decreased during the dark phase only in Me5-lesioned mice. SIGNIFICANCE: Bilateral caudal Me5 lesions alter the nocturnal properties of food and water intake and locomotor activity in mice and decrease the mRNA expression level of orexin in the perifornical area during the dark phase. These results suggest that Me5 activity may influence the nocturnal properties of feeding and its related behaviors by adjusting the activity of orexin neurons in the perifornical area. PMID- 24063989 TI - Low doses of curcumin protect alcohol-induced liver damage by modulation of the alcohol metabolic pathway, CYP2E1 and AMPK. AB - AIMS: This study investigated the hepatoprotective effects of low doses of curcumin against liver damage induced by chronic alcohol intake and a high-fat diet. We also examined several potential underlying mechanisms including action on alcohol metabolism, antioxidant activity, AMPK level and lipid metabolism. MAIN METHOD: Alcohol (25% v/v, 5 g/kg body weight) was orally administered once a day for 6 weeks to mice fed a high-fat diet with or without two different doses of curcumin (0.02% and 0.05%, wt/wt). KEY FINDINGS: Curcumin significantly decreased the plasma aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and alkaline phosphatase activities (p<0.05) and prevented hepatic steatosis compared with the alcohol control group. Curcumin significantly reversed the alcohol-induced inhibition of the alcohol dehydrogenase, aldehyde dehydrogenase 2 and antioxidant enzyme activities as well as the activation of cytochrome P4502E1 and promotion of lipid peroxidation (p<0.05). Curcumin significantly increased the hepatic total AMPK protein level and concomitantly suppressed the fatty acid synthase and phosphatidate phosphohydrolase activities compared with the alcohol control group (p<0.05). Furthermore, curcumin significantly lowered the plasma leptin, free fatty acids and triglycerides levels and hepatic lipid levels (p<0.05). SIGNIFICANCE: These findings indicate that low doses of curcumin may protect against liver damage caused by chronic alcohol intake and a high-fat diet partly by modulating the alcohol metabolic enzyme activity, the antioxidant activity and the lipid metabolism. Therefore, curcumin may provide a promising natural therapeutic strategy against liver disease. PMID- 24063990 TI - Plant pararetroviruses: replication and expression. AB - True retroviruses are not known in plants; however, plant pararetroviruses (caulimoviridae) share many retroviral properties, replicating by transcription in the nucleus followed by reverse transcription in the cytoplasm. Pararetroviruses have circular DNA genomes that do not integrate into the host genome, and display several unique expression strategies. Typical of plant pararetroviral pregenomic RNA is a highly structured leader of about 600nt long that is bypassed by scanning ribosomes. Caulimoviruses and Soymoviruses have a further interesting translation mechanism: at least six of the seven open reading frames are translated via polycistronic translation mediated by a specific transactivator (TAV), which modifies the translation complex. TAV also forms large intracellular inclusion bodies, which are the site of translation and virus assembly. PMID- 24063991 TI - Low education level of nursing home staff in Chinese nursing homes. PMID- 24063993 TI - A virtual reality-integrated program for improving social skills in patients with schizophrenia: a pilot study. AB - BACKGROUND AND OBJECTIVES: Social skills training (SST) intervention has shown its efficacy to improve social dysfunction in patients with psychosis; however the implementation of new skills into patients' everyday functioning is difficult to achieve. In this study, we report results from the application of a virtual reality (VR) integrated program as an adjunct technique to a brief social skills intervention for patients with schizophrenia. It was predicted that the intervention would improve social cognition and performance of patients as well as generalisation of the learned responses into patient's daily life. METHODS: Twelve patients with schizophrenia or schizoaffective disorder completed the study. They attended sixteen individual one-hour sessions, and outcome assessments were conducted at pre-treatment, post-treatment and four-month follow up. RESULTS: The results of a series of repeated measures ANOVA revealed significant improvement in negative symptoms, psychopathology, social anxiety and discomfort, avoidance and social functioning. Objective scores obtained through the use of the VR program showed a pattern of learning in emotion perception, assertive behaviours and time spent in a conversation. Most of these gains were maintained at four-month follow-up. LIMITATIONS: The reported results are based on a small, uncontrolled pilot study. Although there was an independent rater for the self-reported and informant questionnaires, assessments were not blinded. CONCLUSIONS: The results showed that the intervention may be effective for improving social dysfunction. The use of the VR program contributed to the generalisation of new skills into the patient's everyday functioning. PMID- 24063994 TI - Conradi-Hunermann-Happle syndrome with cervical stenosis. PMID- 24063995 TI - Eco-efficient ultrasonic responsive synthesis of pyrimidines/pyridines. AB - Using ultrasound irradiation, two simple one-pot multicomponent methods are described for syntheses of highly functionalized pyrimidine/pyridine derivatives in excellent yields in the presence of NaOH at room temperature. While one route involved aromatic aldehyde, thiourea and acetoacetanilide, the other employed aromatic aldehyde, malononitrile and benzyl mercaptane or EtOH. These approaches afford several advantages over former and contemporary reaction methodologies in terms of operational simplicity, simple work-up procedure, higher yield, short reaction time and environment friendly protocols. PMID- 24063997 TI - Low concentration of PDGF-AB shows synergism with IFN-alpha in induction of IFN beta and -gamma in MRC5 fibroblasts. AB - Platelet-derived growth factor (PDGF) is a potent mediator of fibroblast proliferation and chemotaxis. Also it has been reported as a strong suppressor of interferon (IFN) expression. IFN-alpha has opposite effect on fibroblast function and IFN induction. Here is our early report on the effect of low concentration of PDGF-AB alone or in combination with IFN-alpha on IFN mRNA production in MRC5 fibroblasts. MRC5 cells incubated with IFN-alpha or PDGF-AB, alone or in combination, produced significant induction of IFN-alpha, -beta and -gamma mRNA in comparison with untreated cells. The induction was dose-dependent, with higher effect in cells treated with lower concentrations of PDGF-AB. Also, low concentration of PDGF-AB showed synergism with IFN-alpha in IFN-beta and -gamma induction. Results presented here open new possibilities in multi-cytokine therapy and expand previous results on PDGF activity. PMID- 24063996 TI - Docosahexaenoic acid complexed to albumin provides neuroprotection after experimental stroke in aged rats. AB - Recently we have shown that docosahexaenoic acid complexed to albumin (DHA-Alb) is neuroprotective after experimental stroke in young rats. The purpose of this study was to determine whether treatment with DHA-Alb would be protective in aged rats after focal cerebral ischemia. Isoflurane/nitrous oxide-anesthetized normothermic (brain temperature 36-36.5 degrees C) Sprague-Dawley aged rats (18 months old) received 2h middle cerebral artery occlusion (MCAo) by poly-l-lysine coated intraluminal suture. The neurological status was evaluated during occlusion (60min) and on days 1, 2, 3 and 7 after MCAo; a grading scale of 0-12 was employed. DHA (5mg/kg), Alb (0.63g/kg), DHA-Alb (5mg/kg+0.63g/kg) or saline was administered i.v. 3h after onset of stroke (n=8-10 per group). Ex vivo T2 weighted imaging (T2WI) of the brains was conducted on an 11.7T MRI on day 7 and 3D reconstructions were generated. Infarct volumes and number of GFAP (reactive astrocytes), ED-1 (activated microglia/microphages), NeuN (neurons)-positive cells and SMI-71 (positive vessels) were counted in the cortex and striatum at the level of the central lesion. Physiological variables were entirely comparable between groups. Animals treated with DHA-Alb showed significantly improved neurological scores compared to vehicle rats; 33% improvement on day 1; 39% on day 2; 41% on day 3; and 45% on day 7. Total and cortical lesion volumes computed from T2WI were significantly reduced by DHA-Alb treatment (62 and 69%, respectively). In addition, treatment with DHA-Alb reduced cortical and total brain infarction while promoting cell survival. We conclude that DHA-Alb therapy is highly neuroprotective in aged rats following focal cerebral ischemia and has potential for the effective treatment of ischemic stroke in aged individuals. PMID- 24063998 TI - Interleukin-1 beta in unstimulated whole saliva is a potential biomarker for oral squamous cell carcinoma. AB - The objective of this study was to evaluate cytokines in unstimulated whole saliva (UWS) of oral squamous cell carcinoma (OSCC) patients as compared to those with pre- and post-operation for evaluation as markers of OSCC. Sixteen OSCC patients were included in this study. Cytokine concentrations in resting saliva were measured using a Bio-Plex suspension array system. Only interleukin-1 (IL-1) beta showed significantly different cytokine concentration in saliva between pre- and post-operation. IL-1 beta was released from cultured OSCC cells confirmed by ELISA and immunohistochemistry. From this study, IL-1 beta in UWS may be useful for detection of early stage OSCC. More studies are needed to accept the utility of IL-1 beta in UWS for predicting, diagnosis and evaluation of OSCC. PMID- 24063999 TI - Clinical significance of both tumor and stromal expression of components of the IL-1 and TNF-alpha signaling pathways in prostate cancer. AB - IL-1 and TNF-alpha, the two major proinflammatory cytokines, have been involved in initiation and progression of several malignancies. They could influence the biological behavior of prostatic tumors and patient outcome, and could be useful as prognostic factors. This study evaluated the prognostic capability for biochemical progression after radical prostatectomy of expression of IL-1, TNF alpha and related signaling components, in the tumor and surrounding stroma, as well as its correlation with other clinicopathological features. Expression of IL 1alpha, IL-1beta, IL-1Ra, IL-1RI, IL-1RII, IRAK-1, TRAF6, TNF-alpha, TNFRI and TRAF2 was analyzed by immunohistochemistry in radical prostatectomy samples from 93 prostate cancer patients. Spearman's test, Kaplan-Meier curves, and univariate and multivariate Cox proportional hazard regression analyses were performed. Expression of TNF-alpha, TNFRI, TRAF2, ILRI, IRAK-1 and TRAF6 correlated with at least one clinicopathological feature (clinical T stage, pathological T stage, preoperative serum PSA or Gleason score). Increased tumor expression of TNF alpha, TNFRI and IL-1RI, and reduced tumor expression of IRAK-1 were significantly correlated with a poor prognosis in univariate analysis. Reduced stromal expression of IL-1beta and IL-1RII, and increased stromal expression of IRAK-1 were also adverse prognostic factors in univariate analysis. Remarkably, tumor IL-1beta and stromal IL-1RII and IRAK-1 remained as independent prognostic factors after adjustment for preoperative serum PSA, pathological T stage and Gleason score in multivariate Cox models. Our results suggest that prostatic expression of TNF-alpha, IL-1beta and related signaling proteins (TNFRI, IL-1RI, IL-1RII and IRAK-1) predicts clinical outcome in prostate cancer, and support the involvement of TNF-alpha and IL-1beta signaling in prostate cancer progression. PMID- 24064000 TI - Dissimilar cytokine patterns in different human liver and colon cancer cell lines. AB - An accurate and simultaneous estimate of cellular levels of a large cytokine number is very useful to obtain information about an organ dysfunction leading to cancer because through the understanding of the evolution of cytokine patterns we can recognize and predict the disease progression. Cancer cell lines are commonly used to study the cancer microenvironment, to analyze their chemosensitivity and carcinogenesis as well as to test in vitro the effect of molecules, such as drugs or anti-oxidants, on the inflammation status and its progression. We noted that various cell lines commonly used as a model for studies on liver and colon cancer possess different patterns of cytokines. This aspect may generate data not comparable in laboratories using different cell lines; thus, to investigate the origin of these abnormalities we compared the cell lines HepG2 and Huh7, and HT 29 and HCT-116, for liver and colon cancer, respectively. In this context we have evaluated and compared the levels of cytokines, chemokines and growth factors in the supernatants of these cellular lines. Our aim was to identify what cytokines were significantly different correlating similarities and differences to the specific inflammation status of each cellular model of cancer. PMID- 24064001 TI - Identification of novel and zoonotic Cryptosporidium species in fish from Papua New Guinea. AB - There is still limited information on the distribution of Cryptosporidium species and genotypes in fish. The present study investigated the prevalence of Cryptosporidium species in cultured freshwater (n=132), wild freshwater (n=206) and wild marine (n=276) fish in Papua New Guinea (PNG) by PCR screening at the 18S rRNA locus. A total of seven fish (2 cultured freshwater, 1 wild freshwater and 4 wild marine fish) were identified as positive for Cryptosporidium. Specifically, Cryptosporidium was found in four different host species (Nile tilapia, Oreochromis niloticus; silver barb, Puntius gonionotus; mackerel scad, Decapterus maracellus and oblong silver biddy, Gerres oblongus), giving an overall prevalence of 1.14% (95% CI: 0.3-2%, n=7/614). Of the seven positive isolates, five were identified as C. parvum and two were a novel piscine genotype, which we have named piscine genotype 8. Piscine genotype 8 was identified in two marine oblong silver biddies and exhibited 4.3% genetic distance from piscine genotype 3 at the 18S locus. Further subtyping of C. parvum isolates at the 60 kDa glycoprotein (gp60) locus identified 3 C. parvum subtypes (IIaA14G2R1, IIaA15G2R1 and IIaA19G4R1) all of which are zoonotic and a C. hominis subtype (IdA15G1). The zoonotic Cryptosporidium were identified in fish samples from all three groups; cultured and wild freshwater and wild marine fish. Detection of Cryptosporidium among aquaculture fingerlings warrants further research to gain a better understanding of the epidemiology of Cryptosporidium infection in cultured fish. The identification of zoonotic Cryptosporidium genotypes in fish from PNG has important public health implications and should be investigated further. PMID- 24064002 TI - Absence of Fms-like tyrosine kinase 3 ligand (Flt3L) signalling protects against collagen-induced arthritis. AB - OBJECTIVE: Comprehending the mechanisms that regulate activation of autoreactive T cells and B cell antibody production is fundamental for understanding the breakdown in self-tolerance and development of autoimmunity. Here we studied the role of Fms-like tyrosine kinase 3 ligand (Flt3L) signalling in the pathogenesis of collagen-induced arthritis (CIA). METHODS: CIA was induced in mice lacking Flt3L (Flt3L(-/-)) and wild-type (WT) littermates (C57/BL6, 8-10 weeks old). Mice were killed in the initial phase (acute phase: experiment 1) and late phase (chronic phase: experiment 2) of the disease. Arthritis severity was assessed using a semiquantitative scoring system (0-4), and histological analysis of cellular infiltration, cartilage destruction and peptidoglycan loss was performed. Phenotypic and functional analysis of T and B cells, FoxP3 expression, activation and lymphocyte costimulatory markers, and cytokine production were performed ex vivo by flow cytometry in lymph nodes. Serum collagen type II (CII) specific antibodies were measured by ELISA. RESULTS: Flt3L(-/-) mice showed a marked decrease in clinical arthritis scores and incidence of arthritis in both acute and chronic phases of CIA compared with WT mice. Moreover, decreased synovial inflammation and joint destruction was observed. Both the magnitude and quality of T cell responses were altered in Flt3L(-/-). In the acute phase, the amount of CII-specific IgG2a antibodies was lower in Flt3L(-/-) than WT mice. CONCLUSIONS: These results strongly suggest a role for Flt3L signalling in the development of arthritis. PMID- 24064004 TI - Physicochemical investigation of mixed surfactant microemulsions: water solubilization, thermodynamic properties, microstructure, and dynamics. AB - In this contribution, we report on a systematic investigation of phase behavior and solubilization of water in water-in-heptane or decane aggregates stabilized by mixtures of polyoxyethylene (20) cetyl ether (Brij-58) and cetyltrimethylammonium bromide (CTAB) surfactants with varying compositions in conjugation with 1-pentanol (Pn) at fixed surfactant(s)/Pn ratio and temperature. Synergism in water solubilization was evidenced by the addition of CTAB to Brij 58 stabilized system in close proximity of equimolar composition in both oils. An attempt has been made to correlate composition dependent water solubilization and volume induced conductivity studies to provide insight into the solubilization mechanism of these mixed systems. Conductivity studies reveal the ascending curve in water solubilization capacity-(Brij-58:CTAB, w/w) profile as the interdroplet interaction branch indicating percolation of conductance and the descending curve is a curvature branch due to the rigidity of the interface in these systems. The microstructure of these systems as a function of surfactant composition has been determined by dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR) measurements. FTIR study reveals increase and decrease in relative population of bound and bulk-like water, respectively, with increase in Brij-58:CTAB (w/w). DLS measurements showed that the droplet hydrodynamic diameter (Dh) decreases significantly with the increase in Brij-58:CTAB (w/w). Further, the interfacial composition and energetic parameters for the transfer of Pn from bulk oil to the interface were evaluated by the dilution method. Formation of temperature-insensitive microemulsions and temperature invariant droplet sizes are evidenced in the vicinity of the equimolar composition. The results are interpreted in terms of a proposed mechanism. PMID- 24064005 TI - Highly selective dopamine electrochemical sensor based on electrochemically pretreated graphite and nafion composite modified screen printed carbon electrode. AB - Herein, we report a highly selective dopamine electrochemical sensor based on electrochemically pretreated graphite/nafion composite modified screen printed carbon (SPC) electrode. Electrochemically activated graphite/nafion composite was prepared by using a simple electrochemical method. Scanning electron microscope (SEM) used to characterize the surface morphology of the fabricated composite electrode. The SEM result clearly indicates that the graphitic basal planes were totally disturbed and leads to the formation of graphite nanosheets. The composite modified electrode showed an enhanced electrocatalytic activity toward the oxidation of DA when compared with either electrochemical pretreated graphite or nafion SPC electrodes. The fabricated composite electrode exhibits a good electrocatalytic oxidation toward DA in the linear response range from 0.5 to 70 MUM with the detection limit of 0.023 MUM. The proposed sensor also exhibits very good selectivity and stability, with the appreciable sensitivity. In addition, the proposed sensor showed satisfactory recovery results toward the commercial pharmaceutical DA samples. PMID- 24064003 TI - Validation of a score tool for measurement of histological severity in juvenile dermatomyositis and association with clinical severity of disease. AB - OBJECTIVES: To study muscle biopsy tissue from patients with juvenile dermatomyositis (JDM) in order to test the reliability of a score tool designed to quantify the severity of histological abnormalities when applied to biceps humeri in addition to quadriceps femoris. Additionally, to evaluate whether elements of the tool correlate with clinical measures of disease severity. METHODS: 55 patients with JDM with muscle biopsy tissue and clinical data available were included. Biopsy samples (33 quadriceps, 22 biceps) were prepared and stained using standardised protocols. A Latin square design was used by the International Juvenile Dermatomyositis Biopsy Consensus Group to score cases using our previously published score tool. Reliability was assessed by intraclass correlation coefficient (ICC) and scorer agreement (alpha) by assessing variation in scorers' ratings. Scores from the most reliable tool items correlated with clinical measures of disease activity at the time of biopsy. RESULTS: Inter- and intraobserver agreement was good or high for many tool items, including overall assessment of severity using a Visual Analogue Scale. The tool functioned equally well on biceps and quadriceps samples. A modified tool using the most reliable score items showed good correlation with measures of disease activity. CONCLUSIONS: The JDM biopsy score tool has high inter- and intraobserver agreement and can be used on both biceps and quadriceps muscle tissue. Importantly, the modified tool correlates well with clinical measures of disease activity. We propose that standardised assessment of muscle biopsy tissue should be considered in diagnostic investigation and clinical trials in JDM. PMID- 24064006 TI - More than a gut feeling: predicting surgical necrotising enterocolitis. PMID- 24064007 TI - Waist belt and central obesity cause partial hiatus hernia and short-segment acid reflux in asymptomatic volunteers. AB - OBJECTIVE: There is a high incidence of inflammation and metaplasia at the gastro oesophageal junction (GOJ) in asymptomatic volunteers. Additionally, the majority of patients with GOJ adenocarcinomas have no history of reflux symptoms. We report the effects of waist belt and increased waist circumference (WC) on the physiology of the GOJ in asymptomatic volunteers. DESIGN: 12 subjects with normal and 12 with increased WC, matched for age and gender were examined fasted and following a meal and with waist belts on and off. A magnet was clipped to the squamo-columnar junction (SCJ). Combined assembly of magnet-locator probe, 12 channel pH catheter and 36-channel manometer was passed. RESULTS: The waist belt and increased WC were each associated with proximal displacement of SCJ within the diaphragmatic hiatus (relative to upper border of lower oesophageal sphincter (LOS), peak LOS pressure point and pressure inversion point, and PIP (all p<0.05). The magnitude of proximal migration of SCJ during transient LOS relaxations was reduced by 1.6-2.6 cm with belt on versus off (p=0.01) and in obese versus non-obese (p=0.04), consistent with its resting position being already proximally displaced. The waist belt, but not increased WC, was associated with increased LOS pressure (vs intragastric pressure) and movement of pH transition point closer to SCJ. At 5 cm above upper border LOS, the mean % time pH <4 was <4% in all studied groups. Acid exposure 0.5-1.5 cm above SCJ was increased, with versus without, belt (p=0.02) and was most marked in obese subjects with belt. CONCLUSIONS: Our findings indicate that in asymptomatic volunteers, waist belt and central obesity cause partial hiatus herniation and short-segment acid reflux. This provides a plausible explanation for the high incidence of inflammation and metaplasia and occurrence of neoplasia at the GOJ in subjects without a history of reflux symptoms. PMID- 24064008 TI - Squamous cell carcinoma possibly originating from a granuloma following vaccination with Bacille Calmette-Guerin. PMID- 24064009 TI - New and emerging drug molecules against obesity. AB - Obesity has become a growing pandemic of alarming proportions in the developed and developing countries over the last few decades. The most perturbing fact regarding obesity is the increased predisposition for coronary artery disease, congestive heart failure and sudden cardiac death. The modest efficacy of current anti-obesity agents such as orlistat and the increasing withdrawals of several anti-obesity agents such as sibutramine, rimonabant have led to huge gaps in the pharmacotherapy of obesity. Lorcaserin and Phentermine-topiramate combination (phen-top) are two drugs approved by US FDA in 2012. Lorcaserin, a 5HT2C agonist has moderate efficacy with an acceptable safety profile. Clinical trials with Phen-top have shown a reasonable efficacy but at the cost of risks such as teratogenicity and psychiatric disturbances. Cetilistat, a lipase inhibitor is claimed to have superior safety profile to orlistat and is in phase 3 clinical trials. Other promising anti-obesity molecules acting on the gut which are in clinical trials include exenatide and liraglutide. Drugs which act on the monoaminergic and opioid systems include bupropion-naltrexone and bupropion zonisamide. Other novel first-in-class drugs which have been explored and have limited success in early clinical development include velneperit, tesofensine, and beloranib. Tesofensine is a triple monoamine re-uptake inhibitor, velneperit acts as a neuropeptide Y5 receptor antagonist and beloranib is a methionine amino peptidase 2 inhibitor. Novel targets such as histamine H3 receptor, VEGF, matrix metalloproteinase, sirtuin receptors are also being investigated. This review is an attempt to describe the new and emerging molecules that are in clinical development for obesity. PMID- 24064010 TI - Circadian variation of stent thrombosis and the effect of more robust platelet inhibition: a post hoc analysis of the TRITON-TIMI 38 trial. AB - BACKGROUND: The well-described morning peak in the onset of acute coronary syndromes has been partly attributed to increased platelet activity upon arising. It has been suggested that stent thrombosis (ST) exhibits a similar pattern. We assessed whether a diurnal variation in ST occurs, and whether more robust antiplatelet therapy with prasugrel (vs clopidogrel) can attenuate a morning excess. METHODS AND MATERIALS: Patients from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial (N = 13 608) with adjudicated ST classified per the Academic Research Consortium definitions of definite (N = 135) and probable (N = 27) were grouped into prespecified 8-hour intervals by time of onset: early (6 am-2 pm), late-day (2 pm-10 pm), and overnight (10 pm-6 am). We compared the rates per 1000 patients of ST across time intervals and stratified by treatment and stent type. RESULTS: A diurnal variation in definite/probable ST was observed with rates of 6.5, 3.7, and 2.1 for early, late-day, and overnight intervals, respectively (P < .001), per 1000 patients treated. A sensitivity analysis excluding periprocedural acute-ST (<24 hours after index percutaneous coronary intervention [PCI]) resulted in similar findings (5.2, 2.5, and 1.8 per 1000, P < .001). The circadian variation in ST was observed in patients on clopidogrel (9.7, 4.8, and 3.1 per 1000, P < .001) with the highest rate of ST early in the day. Patients on prasugrel also demonstrated a circadian variation with particularly low rates of overnight ST (3.4, 3.0, and 1.1 per 1000, P = .020). CONCLUSIONS: In TRITON-TIMI 38 trial, the timing of ST exhibited a significant diurnal variation similar to that seen with onset of other acute coronary syndromes. ST occurred less frequently among patients randomized to prasugrel compared to clopidogrel with the greatest absolute reduction (6.2 per 1000 patients) in events earlier in the day when platelet activity is known to be highest. PMID- 24064011 TI - Taxonomy of auto-inflammatory diseases: time to consider changing some names. PMID- 24064012 TI - Up-regulation of Th17 and related cytokines in Behcet's disease corresponding to disease activity. AB - OBJECTIVES: The IL-23/IL-17 pathway is implicated in the development of certain inflammatory diseases. The aim of the present study was to investigate the expression of Th17 and related cytokines according to clinical activity in Behcet's disease (BD). METHODS: Peripheral blood mononuclear cells (PBMCs) from eleven patients with active BD, eleven patients with inactive BD, ten patients with recurrent aphthous ulcers, and ten healthy controls were cultured and stained with the appropriate fluorescent antibodies for analysis by flow cytometry. ELISA assays were utilized to determine the concentrations of IL-17, IFN-gamma, IL-23, and IL-12/23p40 in serum and culture supernatants. IL-12p35, IL 12/23p40, and IL-23p19 transcript levels in PBMCs were measured by real-time PCR. RESULTS: Significantly higher frequencies of IL-17 and IFN-gamma expressing CD4(+) T cells were observed in patients with active BD compared with control groups. Similarly, levels of IL-17, IL-23, IL-12/23p40, and IFN-gamma in serum and supernatants were significantly elevated in patients with BD despite the fact that IL-12p35 and IL-12/23p40 mRNA expression in PBMCs was up-regulated in the inactive BD group. In the same patient, the frequency of IL-17 expressing cells decreased when the BD disease activity was stabilised. CONCLUSIONS: The results of this study suggest that up-regulated IL-17 expression may be associated with clinical activity of BD. PMID- 24064013 TI - Current trends in colchicine treatment in familial Mediterranean fever. AB - OBJECTIVES: Since the publication of the first reports on the efficiency of colchicine in familial Mediterranean fever (FMF), very few randomised studies have investigated issues related to its long-term use. Thus, different approaches taken by physicians involved in FMF care, are exclusively empiric, emulative, and based on case-reports or case-series. Problems such as colchicine intolerance and colchicine resistance have not been solved yet. This paper aims to evaluate trends in colchicine therapy among physicians taking care of FMF patients around the world. METHODS: We conducted a survey by sending questionnaires to FMF research and treatment centres in Europe and Asia. Many issues (such as dosages, schedules, side effects, interactions, efficacy and toxicity monitoring, definition of colchicine intolerance, colchicine resistance and responsiveness, etc) have been investigated. When more than 70% of physicians responded giving similar answers to an item, the response was considered as a 'trend'. A comparison between answers of physicians from FMF-prevalent and non-prevalent countries was also made. RESULTS: Thirty-five physicians from 11 countries filled the questionnaires, taking care of a total of more than 15000 FMF patients (pts). Different approaches were evident among the various physicians. Statistically significant different approaches between physicians from FMF-prevalent countries with respect to those from non-prevalent countries were found in items like colchicine during pregnancy, severity score and blood tests for disease monitoring. No consensus was found regarding the definition of colchicine resistance. CONCLUSIONS: The current study demonstrated significant variations in the strategy of colchicine therapy for FMF around the world and re-emphasised the need for standardised definitions of colchicine resistance and colchicine intolerance. PMID- 24064014 TI - TIR-domain-containing adaptor protein gene TIRAP S180L polymorphism is not increased in Behcet's disease patients in two ethnic cohorts. AB - OBJECTIVES: The single nucleotide polymorphism (SNP) of TIRAP (Serine 180 leucine, S180L) that is shown to be associated with Behcet's disease (BD) in a European-derived cohort, but not in Middle Eastern patients is investigated in two other populations. METHODS: Two cohorts of BD patients and controls from Turkey (n=797) and Italy (n=633) were genotyped by sequence specific primer polymerase chain reaction (SSP-PCR) or TaqMan q-PCR assays. RESULTS: Genotype and allele frequencies in TIRAP S180L (rs8177374) were not different between BD patients and controls in either ethnicity. Furthermore, a meta-analysis between the Turkish and the Italian BD cohorts did not reveal an association between this non-synonymous SNP in TIRAP and BD (meta-analysis OR=0.94, meta-analysis p=0.61, Q statistic heterogeneity p=0.11). CONCLUSIONS: TIRAP S180L gene polymorphism, which was previously shown to be associated with BD in a Caucasian population, has been replicated in either Turkish or Italian population in our study. PMID- 24064015 TI - Vitamin B12 levels in familial Mediterranean fever patients treated with colchicine. AB - OBJECTIVES: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterised by paroxysmal attacks of serosal inflammation. Colchicine is highly effective in preventing these attacks but it may also disrupt the intestinal absorption of vitamin B12. We hypothesised that patients treated with colchicine for a prolonged period could develop deficiency of the vitamin. METHODS: Ninety-five adult FMF patients on regular colchicine treatment for at least 2 years and age and sex-matched 90 healthy controls were enrolled and complete blood count with platelets, vitamin B12 and folic acid were measured in each person. We also investigated 15 adult FMF patients who were not yet on colchicine. RESULTS: The mean vitamin B12 values were not significantly different between the groups (352.12 (SD=171.62) pg/mL vs. 360.96 (SD=146.53) pg/mL, p=0.71), but there were significantly more vitamin B12 deficient cases among FMF patients (12 vs. 3; p=0.021) and 3 out of these 12 had megaloblastic anaemia. None of the vitamin B12 deficient controls had anaemia. We could not identify any disorder which might have causative effect for the deficiency among this subgroup. The mean vitamin B12 value of 15 colchicine-naive cases was not significantly different from patients on colchicine (p=0.356). CONCLUSIONS: We did not observe significant vitamin B12 deficiency among colchicine-treated FMF patients but some cases may be more prone to developing this potentially serious disorder. PMID- 24064016 TI - MEFV gene mutations and their clinical significance in Korean patients with adult onset Still's disease. AB - OBJECTIVES: Adult-onset Still's disease (AOSD) and periodic fever syndrome share clinical features in some aspects. Familial Mediterranean fever (MEFV) is a typical periodic fever syndrome and MEFV gene mutations may contribute to the clinical features of certain rheumatic diseases. The purpose of this study is to research the incidence and clinical utility of MEFV gene mutations in Korean AOSD patients. METHODS: The study included 96 AOSD patients and 165 healthy controls. In both groups, genomic DNA was isolated and genotyped using restriction fragment length polymorphism for 5 MEFV gene mutations (E148Q, P369S, M680I, V726A and M694V). In the AOSD patients, the clinical significance of MEFV mutation was assessed by the laboratory and clinical features. RESULTS: M680I, V726A and M694V were not found in both groups. P369S was detected in 7 (7.3%) AOSD patients and 10 (6.1%) healthy controls. E148Q mutation was found in 77 (46.7%) among healthy controls with 6 QQ and 44 (45.8%) of AOSD patients with 5 QQ, respectively. The allele frequency of E148Q was 0.25 in AOSD patients, and that of P369S was 0.04. However, there was no significant difference in most clinical manifestations and laboratory findings by the presence and absence of E148Q mutation. CONCLUSIONS: MEFV mutations including E148Q mutation were not associated with the development of AOSD patients in Korea. Although high incidence of E148Q mutation was found, E148Q mutation did not show major effect on the clinical features of AOSD. But we need to look for association with clinical response to certain treatments and long-term prognosis. PMID- 24064017 TI - Fever in Behcet's syndrome. AB - OBJECTIVES: Fever is taken to be rare in Behcet's syndrome (BS) and when present it is usually considered to be associated with vascular disease. The aim of this study was to formally investigate the presence of fever as a clinical feature in BS patients and suitable controls. METHODS: The study consisted of 2 parts. In the first part, 500 patients with BS, 94 with familial Mediterranean fever (FMF), 100 with ankylosing spondylitis (AS), and 72 with systemic lupus erythematosus (SLE) along with 100 healthy controls (HC) were surveyed with the help of a questionnaire for the history of periodic fever episodes. In the second part, body temperature was measured in 98 newly diagnosed BS patients having at least one active BS lesion and 61 HC. Temperature was measured 3 times and the highest reading was used in the analyses. RESULTS: First part: history of fever episodes was present in 22% patients with BS, 87% with FMF, 33% with SLE and 8% with AS. None of the HC recalled a fever episode. Patients with BS who reported fever episodes were more likely to have major organ involvement such as vascular, neurological or joint involvement. Second part: The mean body temperature reading was similar (albeit statistically different) among patients with BS (36.72+/ 0.42oC) compared to that of the HC (36.56+/- 0.27oC) (p=0.004). CONCLUSIONS: In this study, 22% of patients with BS reported a history of fever episodes. As previously reported, fever attacks seemed to be associated strongly with vascular, neurological or joint involvement. The increase in temperature accompanying active BS lesions was modest even when the highest values were considered. PMID- 24064018 TI - The prevalence of atopy in patients with familial Mediterranean fever and Behcet's disease. AB - OBJECTIVES: The purpose of this study is to investigate the prevalence of atopy in patients with Behcet's disease (BD) and familial Mediterranean fever (FMF). METHODS: In this study, 42 BD patients, 40 FMF patients and 49 healthy subjects were included. The skin test was applied to the whole group. If one or more allergen response was equal or greater than histamine response, it was accepted as atopy. At the same time, total serum IgE and peripheral blood eosinophil levels were also determined. RESULTS: The frequency of atopy was found to be 2.4% (1/42 patients) in BD patients and 5% (2/40 patients) in FMF patients and 16.3% (8/49 individuals) in healthy controls. In the BD patients, positivity to skin prick test was significantly lower than the control group (p=0.035). The mean serum total IgE level and eosinophil counts did not differ between the three groups. In 33.3% of BD patients, 39.8% of FMF patients and 20.8% of controls levels of IgE lower than 20 kU/L were found (both groups p<0.05). CONCLUSIONS: The related conditions with Th-2 cell response such as atopy seem to be low frequency in BD and FMF patients. PMID- 24064020 TI - Patient-driven assessment of disease activity in Behcet's syndrome: cross cultural adaptation, reliability and validity of the Turkish version of the Behcet's Syndrome Activity Score. AB - OBJECTIVES: The Behcet's Syndrome Activity Score (BSAS) is the first patient reported outcome measure developed to assess the global disease activity in patients with Behcet's syndrome (BS). We aimed to evaluate the reliability and validity of the Turkish version of BSAS for measuring disease activity in BS. We further investigated the performance of Routine Assessment of Patient Index Data (RAPID)3, a patient-reported index originally developed for rheumatoid arthritis, in BS patients. METHODS: Patients seen consecutively at a tertiary Rheumatology Centre were requested to complete BSAS and multidimensional health assessment questionnaire (MDHAQ). Besides, all attending physicians filled the Behcet's Disease Current Activity Form (BDCAF). Descriptive statistics and Pearson correlation coefficients were calculated accordingly for the reliability and validity assessments of BSAS. RESULTS: A total of 104 patients completed all three assessments. The test-retest reliability of BSAS has a good level (ICC=0.84, 95% CI [0.69-0.94]). The mean scores for BSAS, BDCAF and RAPID3 were 39+/-20.8, 3.2+/-1.4 and 9.2+/-5.6, respectively. BSAS was correlated with BDCAF moderately (r=0.587), while it was moderately correlated with RAPID3 (r=0.648). The correlation between the RAPID3 and BDCAF was moderate (r=0.403), but lower as compared to the correlations between the other instruments. CONCLUSIONS: We found that the BSAS has modest correlation with BDCAF and is a reliable and valid patient reported measure of disease activity that can be used to assess patients with BS. An outcome score composed of only patient-derived observations may have the additional advantage of being easier to use in a routine care setting. Demonstration of a moderate level of correlation between RAPID3 and BDCAF (close to the level of weak relationship), suggests that RAPID3 likely needs more investigations before recommending its use in BS. PMID- 24064019 TI - Lectin-like oxidised LDL receptor-1 as a marker of endothelial dysfunction in Behcet's disease. AB - OBJECTIVES: The aim of this study was to examine the distribution of lectin-like oxidised LDL receptor-1 (LOX-1) levels in patients with active BD, possible association of LOX-1 with the oxidised LDL (oxLDL), endothelial nitric oxide synthase (eNOS), nitric oxide (NO), endothelin-1 (ET-1) levels, and to characterise the differences between patients with active BD and those with systemic lupus erythematosus( SLE) in terms of these parameters compared with healthy controls. METHODS: A total of 30 patients with active BD, 22 patients with SLE as patients controls, and 30 healthy subjects were enrolled in this study. RESULTS: Significantly lower eNOS ve NO levels were observed in patients with BD and SLE compared with healthy controls. oxLDL, LOX-1 ve ET-1 levels were significantly increased in active periods of patients with BD and SLE compared with healthy control. There was no significant difference in oxLDL levels between subjects with BD and SLE. LOX-1 levels were significantly higher in active periods of patients with BD than in SLE , ET-1 levels were significantly lower. CONCLUSIONS: Endothelial dysfunction parameters are elevated in patients with BD having active disease. The necessary measures should be considered in terms of risk of atherosclerosis in BD, especially for the early identification of endothelial damage by looking at LOX-1 levels. PMID- 24064021 TI - The expression of transmembrane and soluble CXCL16 and the relation with interferon-alpha secretion in patients with Behcet's disease. AB - OBJECTIVES: CXCL16 is a member of CXC chemokine, which is synthesised in plasmacytoid dendritic cell as a transmembrane molecule. Transmembrane CXCL16 on plasmacytoid dendritic cell plays a role in binding, uptaking and accumulation of CpG D ODN in early endosomes rather then lysosomal vesicles, thereby causing a high level of interferon-alpha secretion. Previously, we disclosed pronounced interferon-alpha production from these cells in patients with Behcet's disease. The aim of this study was to investigate the relation between the secretion of IFN-alpha and the expression of CXCL16 on surface of plasmacytoid dendritic cell from patients with Behcet's disease, and compare it with patients with ankylosing spondylitis and healthy controls. METHODS: The study population consisted of 73 cases (35 with Behcet's disease, 19 with ankylosing spondylitis and 19 controls). We investigated the expression of CXCL16 on surface of plasmacytoid dendritic cells by flow cytometry, and the serum levels of IFN-alpha and CXCL16 with ELISA. RESULTS: Serum levels of IFN-alpha in patients with Behcet's disease were significantly higher than the controls (p=0.009), and than patients with ankylosing spondylitis, but not statistically significant (p=0.124). Serum levels of CXCL16 in patients with Behcet's disease and patients with ankylosing spondylitis were significantly higher than controls (p=0.009, p=0.003, respectively). We found no difference in the percentage and MFI of plasmacytoid dendritic cells and CD123+CXCL16+ cells determined by flow cytometry among the study and control groups. In patients with Behcet's disease, a positive correlation was found between the percentage of plasmacytoid dendritic cells and CD123+CXCL16+ cells (p<0.001). Furthermore, there was also a positive correlation between the percentage of plasmacytoid dendritic cells and serum levels of CXCL16 in patients with ankylosing spondylitis (p=0.001). In addition, there was a positive correlation between the percentage of CD123+CXCL16+ cells and serum levels of IFN-alpha in Behcet's disease group (p=0.034). We could not find any significant difference in other comparisons. CONCLUSIONS: We suggested that the expression of transmembrane CXCL16 on surface of plasmacytoid dendritic cell might contribute to high serum IFN-alpha levels seen in patients with BD. PMID- 24064022 TI - Macrophage activation syndrome as the initial manifestation of tumour necrosis factor receptor 1-associated periodic syndrome (TRAPS). AB - An 11-year-old Turkish girl from a non-consanguineous family was suffering from joint pain, fever, hepatosplenomegaly, and respiratory insufficiency. Laboratory abnormalities were thrombocytopenia, elevated levels of serum transaminases, lactate dehydrogenase, and C-reactive protein (up to 193 mg / l), a hyperferritinaemia of 8030 ng/ml, and an increased sCD25. The tentative diagnosis of macrophage activation syndrome (MAS) was confirmed by the detection of a histiocytosis with haemophagocytosis in the bone marrow. Treatment with dexamethasone, cyclosporine A, and VP16 was successful. However, the diagnosis of MAS on the background of a systemic juvenile idiopathic arthritis was questionable because of recurrent, spontaneously remitting fever phases of 5 to 7 days duration without an obvious infectious aetiology. A positive family history of febrile episodes in three consecutive generations raised the suspicion of a dominantly inherited disease. Genetic studies revealed a likely pathogenetically relevant E56D/p.Glu85Asp mutation in exon 3 of the TNFRSF1A gene. Alterations of the MEFV gene, in contrast, were not found. To our knowledge, this is the first case of a macrophage activation syndrome as the initial manifestation of TRAPS. Similar case reports in patients with the far more common familial Mediterranean fever (FMF) have been published already. PMID- 24064023 TI - Familial Mediterranean fever: a critical digest of the 2012-2013 literature. AB - The year 2012-2013 has been a fertile one in the area of FMF inquiry. Recent studies have led to further insight into the possible mechanisms whereby pyrin mutations might cause the auto-inflammatory phenotype that is characteristic of FMF. Evidence-based guidelines for diagnosis of FMF, including the role of genetic testing, have become available. Risks for colchicine resistance have been partially defined, and a randomised, controlled trial showing efficacy of an interleukin-1 antagonist for treatment of colchicine-resistant or intolerant FMF patients was reported. In this review, we summarise these and other salient findings from the recent FMF literature, and discuss their significance for the clinician. PMID- 24064024 TI - Behcet's syndrome: a critical digest of the 2012-2013 literature. AB - Recent work on the epidemiology of Behcet's syndrome confirm the previous contention that the prevalence increases from North to South and that the disease follows a more severe course in patients with an early age of onset, also when specifically studied in patients with eye and gastrointestinal involvement. Imputation analyses of genome wide association studies revealed new associations such as ERAP-1, CCR1-CCR3, KLRC4 and STAT4. Further work suggested that the BS associated variant of STAT4 is not related to the previously reported one associated with autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. The prognosis of eye involvement seems to have improved over the last decade with better visual acuity and less frequent severe complications in patients reported in the 2000s compared to the 1990s. Immunosuppresssives and corticosteroids were observed to improve the outcome of cardiac involvement in BS. Recurrence and complications were common in these patients when surgery was performed without immunosuppressives. The cognitive dysfunction in BS patients with neurological involvement seemed to be severely impaired and worse than that of multiple sclerosis patients, suggesting a more severe 'frontal'-executive dysfunction. Gastrointestinal involvement seemed to be brought to a remission in the majority of BS within 5 years, with about one fourth of the patients following a relapsing or chronic disease course. TNF-alpha inhibitors have become standard treatment for patients resistant to conventional immunosuppressives. Switching to another biologic can be effective when the first or even the second biologic agent fails or is stopped due to adverse events. PMID- 24064025 TI - Inherited autoinflammatory diseases: a critical digest of the recent literature. AB - In this paper we provide a critical digest of the recent literature on inherited autoinflammatory diseases. We reviewed all the articles published during the last 24 months on monogenic autoinflammatory diseases and selected the most relevant studies regarding the pathogenesis, clinical aspects and management of these conditions. In particular, we focused the attention on the more frequent conditions, familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS) and TNF-receptor associated periodic syndrome (TRAPS). PMID- 24064026 TI - Is recurrent aseptic meningitis a manifestation of familial Mediterranean fever? A systematic review. AB - OBJECTIVES: Familial Mediterranean fever (FMF) causes recurrent episodes of fever and painful serositis. It has been suggested that FMF can cause recurrent aseptic meningitis (RAM). Due to the rarity of both diseases, this claim cannot be assessed with epidemiological methods. We therefore decided to perform a systematic review of the literature to assess the number and validity of published case reports. METHODS: Medline, Embase, Pascal, Web of Science and the proceedings of relevant conferences were searched. Two independent investigators selected reports asserting RAM in FMF patients, abstracted data and rated the strength of evidence with a custom tool designed to assess: (a) the diagnosis of FMF; (b) the diagnosis of RAM; and (c) the link between FMF and RAM. A causal link was supported by (i) evidence of inflammation and/or clinical FMF features during episodes of RAM; (ii) effectiveness of colchicine to prevent further bouts of meningitis; and (iii) the exclusion of other causes of RAM. RESULTS: Among 944 retrieved references, 917 were rejected by title and abstract screening and 15 after full text review. The strength of evidence of 12 alleged cases of RAM due to FMF was assessed. FMF was unsupported in 4 cases and RAM in 3 further cases. Four of the 5 remaining cases did not provide adequate evidence to support a causal relationship between FMF and RAM. CONCLUSIONS: The possibility of RAM due to FMF is poorly supported by a single fairly documented case report that does not, however, meet current diagnostic standards. PMID- 24064027 TI - Interleukin-6 targeting therapy in familial Mediterranean fever. PMID- 24064028 TI - Anakinra for resistant Behcet uveitis: why not? PMID- 24064029 TI - A case of Behcet's disease with development of MS-like lesions in the CNS and spinal cord. PMID- 24064030 TI - Rare NLRP12 variants associated with the NLRP12-autoinflammatory disorder phenotype: an Italian case series. PMID- 24064032 TI - Mutation effects of C2+ ion irradiation on the greasy Nitzschia sp. AB - Screening and nurturing algae with high productivity, high lipid content and strong stress resistance are very important in algae industry. In order to increase the lipid content, the Nitzschia sp. was irradiated with a 3MeV C(2+) beam. The sample pretreatment method was optimized to obtain the best mutagenic condition and the survival ratio curve. The positive mutants with a significant improvement in lipid content were screened and their C(2+) mutagenic effects were analyzed by comparing the greasiness and growth characteristics with the wild type algae. Results showed that when the Nitzschia sp. was cultivated in nutritious medium containing 10% glycerol solution, and dried on the filter for 5 min after centrifugation, the realization of the microalgae heavy ion mutagenesis could be done. The survival ratio curve caused by C(2+) irradiation was proved to be "saddle-shaped". A positive mutant was screened among 20 survivals after irradiation, the average lipid content of the mutation increased by 9.8% than the wild type after 4 generations. But the growth rate of the screened mutation didn't change after the heavy ion implantation compared to the wild type algae. PMID- 24064031 TI - Metabolic syndrome induces inflammation and impairs gonadotropin-releasing hormone neurons in the preoptic area of the hypothalamus in rabbits. AB - Rabbits with high fat diet (HFD)-induced metabolic syndrome (MetS) developed hypogonadotropic hypogonadism (HH) and showed a reduced gonadotropin-releasing hormone (GnRH) immunopositivity in the hypothalamus. This study investigated the relationship between MetS and hypothalamic alterations in HFD-rabbits. Gonadotropin levels decreased as a function of MetS severity, hypothalamic gene expression of glucose transporter 4 (GLUT4) and interleukin-6 (IL-6). HFD determined a low-grade inflammation in the hypothalamus, significantly inducing microglial activation, expression and immunopositivity of IL-6, as well as GLUT4 and reduced immunopositivity for KISS1 receptor, whose mRNA expression was negatively correlated to glucose intolerance. Correcting glucose metabolism with obetcholic acid improved hypothalamic alterations, reducing GLUT4 and IL-6 immunopositivity and significantly increasing GnRH mRNA, without, however, preventing HFD-related HH. No significant effects at the hypothalamic level were observed after systemic anti-inflammatory treatment (infliximab). Our results suggest that HFD-induced metabolic derangements negatively affect GnRH neuron function through an inflammatory injury at the hypothalamic level. PMID- 24064033 TI - Influence of denture supporting tissue properties on pressure-pain threshold- measurement in dentate subjects. AB - PURPOSE: The present study was designed to clarify the relationship between the properties of the palatal mucosa and the pressure-pain threshold. METHODS: Three parts of the palatal mucosa of 17 dentate subjects were measured: the median part of the palate, the lateral part of the first molar, and the midpoint between these two parts. The subjects were instructed to press a pushbutton when he or she felt pressure-pain. The probe pressure was gradually increased (1N/s). The thickness (T) (mm) and elasticity (E) (MPa) were used as the parameters of the properties of the palatal mucosa, whereas pressure (P) (MPa), compressibility (C) (%), and subsidence (S) (mm) were used as the parameters of the pressure-pain threshold. The Shapiro-Wilk test was used to consider the data of distribution of normality for each measurement point, as obtained from the 17 subjects. A Kruskal Wallis test and a Wilcoxon signed rank test were performed for multiple comparisons, the Bonferroni method was used to compensate for the P-value. Spearman's rank correlation coefficient was calculated. RESULTS: T correlated with the values of S at the median points (P=0.001) and midpoints (P=0.011). CONCLUSION: Thickness can be an index of the amount of relief where pain is caused easily. In addition, modulus of elasticity is important as an indicator of the bearing ability of denture support tissues, it is necessary to consider how to evaluate the modulus of elasticity and to evaluate the relationship between the parameters of the pain threshold. PMID- 24064034 TI - Muscular heat and mechanical pain sensitivity after lengthening contractions in humans and animals. AB - Mechanical sensitivity of muscle nociceptors was previously shown to increase 2 days after lengthening contractions (LC), but heat sensitivity was not different despite nerve growth factor (NGF) being upregulated in the muscle during delayed onset muscle soreness (DOMS). The discrepancy of these results and lack of other reports drove us to assess heat sensitivity during DOMS in humans and to evaluate the effect of NGF on the heat response of muscle C-fibers. Pressure pain thresholds and pain intensity scores to intramuscular injection of isotonic saline at 48 degrees C and capsaicin were recorded in humans after inducing DOMS. The response of single unmyelinated afferents to mechanical and heat stimulations applied to their receptive field was recorded from muscle-nerve preparations in vitro. In humans, pressure pain thresholds were reduced but heat and capsaicin pain responses were not increased during DOMS. In rats, the mechanical but not the heat sensitivity of muscle C-fibers was increased in the LC group. NGF applied to the receptive field facilitated the heat sensitivity relative to the control. The absence of facilitated heat sensitivity after LC, despite the NGF sensitization, may be explained if the NGF concentration produced after LC is not sufficient to sensitize nociceptor response to heat. PERSPECTIVE: This article presents new findings on the basic mechanisms underlying hyperalgesia during DOMS, which is a useful model to study myofascial pain syndrome, and the role of NGF on muscular nociception. This might be useful in the search for new pharmacologic targets and therapeutic approaches. PMID- 24064035 TI - Motor dysfunction of complex regional pain syndrome is related to impaired central processing of proprioceptive information. AB - Our understanding of proprioceptive deficits in complex regional pain syndrome (CRPS) and its potential contribution to impaired motor function is still limited. To gain more insight into these issues, we evaluated accuracy and precision of joint position sense over a range of flexion-extension angles of the wrist of the affected and unaffected sides in 25 chronic CRPS patients and in 50 healthy controls. The results revealed proprioceptive impairment at both the patients' affected and unaffected sides, characterized predominantly by overestimation of wrist extension angles. Precision of the position estimates was more prominently reduced at the affected side. Importantly, group differences in proprioceptive performance were observed not only for tests at identical percentages of each individual's range of wrist motion but also when controls were tested at wrist angles that corresponded to those of the patient's affected side. More severe motor impairment of the affected side was associated with poorer proprioceptive performance. Based on additional sensory tests, variations in proprioceptive performance over the range of wrist angles, and comparisons between active and passive displacements, the disturbances of proprioceptive performance most likely resulted from altered processing of afferent (and not efferent) information and its subsequent interpretation in the context of a distorted "body schema." PERSPECTIVE: The present results point at a significant role for impaired central processing of proprioceptive information in the motor dysfunction of CRPS and suggest that therapeutic strategies aimed at identification of proprioceptive impairments and their restoration may promote the recovery of motor function in CRPS patients. PMID- 24064036 TI - Chromatin immunoprecipitation and deep sequencing in Xenopus tropicalis and Xenopus laevis. AB - Chromatin immunoprecipitation and deep sequencing (ChIP-SEQ) represents a powerful tool for identifying the genomic targets of transcription factors, chromatin remodeling factors, and histone modifications. The frogs Xenopus laevis and Xenopus tropicalis have historically been outstanding model systems for embryology and cell biology, with emerging utility as highly accessible embryos for genome-wide studies. Here we focus on the particular strengths and limitations of Xenopus cell biology and genomics as they apply to ChIP-SEQ, and outline a methodology for ChIP-SEQ in both species, providing detailed strategies for sample preparation, antibody selection, quality control, sequencing library preparation, and basic analysis. PMID- 24064037 TI - Pseudophosphatases: methods of analysis and physiological functions. AB - Protein tyrosine phosphatases (PTPs) are key enzymes in the regulation of cellular homeostasis and signaling pathways. Strikingly, not all PTPs bear enzymatic activity. A considerable fraction of PTPs are enzymatically inactive and are known as pseudophosphatases. Despite the lack of activity they execute pivotal roles in development, cell biology and human disease. The present review is focused on the methods used to identify pseudophosphatases, their targets, and physiological roles. We present a strategy for detailed enzymatic analysis of inactive PTPs, regulation of inactive PTP domains and identification of binding partners. Furthermore, we provide a detailed overview of human pseudophosphatases and discuss their regulation of cellular processes and functions in human pathologies. PMID- 24064039 TI - Environmental genotoxicity and cytotoxicity in flounder (Platichthys flesus), herring (Clupea harengus) and Atlantic cod (Gadus morhua) from chemical munitions dumping zones in the southern Baltic Sea. AB - The data on environmental genotoxicity and cytotoxicity levels as well as on genotoxicity risk in flounder (Platichthys flesus), herring (Clupea harengus) and cod (Gadus morhua) collected in 2010-2012 at 42 stations located in chemical munitions dumping areas of the southern Baltic Sea are presented. The frequency of micronuclei, nuclear buds and nucleoplasmic bridges in erythrocytes was used as genotoxicity endpoint and the induction of fragmented-apoptotic, bi-nucleated and 8-shaped erythrocytes as cytotoxicity endpoint. The most significantly increased geno-cytotoxicity levels were determined in fish collected near known chemical munitions dumpsites. Extremely high genotoxicity risk for flounder were identified at 21 out of 24 stations, for herring at 29 out of 31 and for cod at 5 out of 10 stations studied. The reference level of genotoxicity was not recorded at any of the stations revealing that in the sampling area fish were affected generally. PMID- 24064040 TI - A multi-criteria evaluation system for marine litter pollution based on statistical analyses of OSPAR beach litter monitoring time series. AB - During the last decades, marine pollution with anthropogenic litter has become a worldwide major environmental concern. Standardized monitoring of litter since 2001 on 78 beaches selected within the framework of the Convention for the Protection of the Marine Environment of the North-East Atlantic (OSPAR) has been used to identify temporal trends of marine litter. Based on statistical analyses of this dataset a two-part multi-criteria evaluation system for beach litter pollution of the North-East Atlantic and the North Sea is proposed. Canonical correlation analyses, linear regression analyses, and non-parametric analyses of variance were used to identify different temporal trends. A classification of beaches was derived from cluster analyses and served to define different states of beach quality according to abundances of 17 input variables. The evaluation system is easily applicable and relies on the above-mentioned classification and on significant temporal trends implied by significant rank correlations. PMID- 24064041 TI - SCIMITAR: subject-carried implant monitoring inductive telemetric ambulatory reader for remote data acquisition from implanted orthopaedic prostheses. AB - This work describes the functions of the external, portable part of a telemetry system for powering and interrogating implantable electrical devices built within orthopaedic implants for real-time data acquisition of strain, load, temperature, humidity and other relevant data (e.g. from inertial sensors). The system contains a battery powered inductive energiser and demodulator to remotely power the implant electronics and demodulate the signals transmitted from the implanted device. Due to the housing of the internal coil, sufficient inductive coupling is obtained between the external and internal tuned circuits to enable simultaneous power and data transmission over the same inductive link. The actual performance of this system when used with one specific implant was studied, and some correspondence made to the relevant theory. Performance factors relating to both power efficiency and data reconstruction were identified. PMID- 24064042 TI - What do hospital mortality rates tell us about quality of care? AB - Hospital mortality rates could be useful indicators of quality of care, but careful statistical analysis is required to avoid erroneously attributing variation in mortality to differences in health care when it is actually due to differences in case mix. The summary hospital mortality indicator is currently used by the English National Health Service (NHS). It adjusts mortality rates up to 30 days after discharge for patient age, sex, type of admission, year of discharge, comorbidity, deprivation and diagnosis. Such risk-adjustment methods have been used to identify poor performance, most notably at mid-Staffordshire NHS Foundation Trust, but their use is subject to a number of limitations. Studies exploring whether variation in risk-adjusted mortality can be explained by variation in healthcare have reached conflicting conclusions. Furthermore, concerns have been raised that the proportion of preventable deaths among hospital admissions is too small to produce a reliable 'signal' in risk-adjusted mortality rates. This provides hospital managers, regulators and clinicians with a considerable dilemma. Variation in mortality rates cannot be ignored, as they might indicate unacceptable variation in healthcare and avoidable mortality, but they also cannot be reliably used to judge the quality of healthcare, based on current evidence. PMID- 24064043 TI - Bowing, kneeling and 'prostration': athlete's collapse patterns during sudden cardiac arrhythmia/arrest on the field of play. AB - BACKGROUND: Sudden cardiac arrest (SCA) on the field of play remains one of the most tragic and challenging events for a team physician. Even with robust regular preparticipation cardiac screening we cannot prevent all cases of SCA. Ability to recognise imminent cardiac arrest occurring on the field of play remains an important step in managing this condition without delay. METHODS: You Tube was searched for video clips clearly depicting the sequence of an athlete's collapse of cardiac origin. A pattern of collapse was subsequently analysed. RESULTS: 13 cases were available for public viewing on You Tube and demonstrated the final position of collapse. 12 collapses had full video footage of athlete's fall. All athletes were men. 84.6% (11) cases were from football (soccer). 15.4% (2) of cases were from martial arts. In 10 out of 12 cardiac event cases (83.3%) bowing and/or kneeling were followed by decubitus position. 58.3% (7) of cases demonstrated bowing at the beginning of collapse. 58.3% (7) cases had kneeling as an element of collapse. 61.5% (8 out of 13 cases) of casualties adopted position of 'prostration' (ie, prone) as final stage of collapse. CONCLUSIONS: When on the field of play, in the absence of head injury, athletes displaying bowing and/or kneeling positions followed by collapse should be assumed to have a life threatening cardiac event. Final position of 'prostration' was adopted in over half of cardiogenic collapses. A sports medicine professional should bear this in mind and target his/her assessment and treatment accordingly. When attending such casualties, a defibrillator must be taken to the collapsed player. PMID- 24064044 TI - Reducing delay to stroke thrombolysis--lessons learnt from the Stroke 90 Project. AB - BACKGROUND: The Stroke 90 Project was implemented to reduce delays to stroke thrombolysis and involved 7 hospitals and 2 ambulance services in the Avon, Gloucester, Wiltshire and Somerset regional network. Interventions included a direct to CT (DtoCT) protocol for paramedics to transport patients directly to the CT scanner. Coincidentally, there were severe winter pressures on all participating emergency departments during this period. METHODS: Comparison of data from 2 groups across all 7 hospitals: preintervention (n=136) and postintervention patients (n=215) thrombolysed from August 2012 to January 2013. The chi(2) test, t tests, multiple and linear regression were used for analysis. RESULTS: Ambulance transport times were 56.8 min for preintervention versus 57.5 min for postintervention patients (p=0.78). 11.7% of preintervention patients received thrombolysis within 90 min of call for help versus 23.7% of postintervention cases (p=0.0135). 44% of postintervention patients entered the DtoCT pathway and achieved a mean reduction in door to CT time of 17 min (95% CI 11.5 to 21.5; p<0.0001) and a 19 min reduction in door to needle time (95% CI 10.8 to 26.8; p<0.0001). CT to needle times were 43.8 min preintervention and 42.1 min postintervention (p=0.57). CONCLUSIONS: The DtoCT pathway was successful in reducing delays to thrombolysis and should be implemented routinely. The call to door and CT to needle times were not improved by our interventions and further work is required to streamline these. Factors beyond the control of most hospitals may play a role in delaying treatment, but local changes can be implemented to mitigate this. PMID- 24064045 TI - Doxorubicin induces cell death in breast cancer cells regardless of Survivin and XIAP expression levels. AB - Breast cancer is the leading cause of deaths in women around the world. Resistance to therapy is the main cause of treatment failure and still little is known about predictive biomarkers for response to systemic therapy. Increasing evidence show that Survivin and XIAP overexpression is closely associated with chemoresistance and poor prognosis in breast cancer. However, their impact on resistance to doxorubicin (dox), a chemotherapeutic agent widely used to treat breast cancer, is poorly understood. Here, we demonstrated that dox inhibited cell viability and induced DNA fragmentation and activation of caspases-3, -7 and -9 in the breast cancer-derived cell lines MCF7 and MDA-MB-231, regardless of different p53 status. Dox exposure resulted in reduction of Survivin and XIAP mRNA and protein levels. However, when we transfected cells with a Survivin encoding plasmid, we did not observe a cell death-resistant phenotype. XIAP and Survivin silencing, either alone or in combination, had no effect on breast cancer cells sensitivity towards dox. Altogether, we demonstrated that breast cancer cells are sensitive to the chemotherapeutic agent dox irrespective of Survivin and XIAP expression levels. Also, our findings suggest that dox-mediated modulation of Survivin and XIAP might sensitize cells to taxanes when used in a sequential regimen. PMID- 24064046 TI - Arterial complications in patients undergoing extracorporeal membrane oxygenation via femoral cannulation. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides continuous cardiopulmonary support on a long-term basis. It has been speculated that patients undergoing ECMO via femoral arterial cannulation are more likely to develop peripheral vascular complications. The purpose of this study was to evaluate the incidence of peripheral vascular complications in this group of patients and outline the modalities used for treatment. METHODS: Data were collected for all patients who had femoral artery cannulation for ECMO therapy from June 2008 to October 2011. Primary outcome was any vascular complication. Secondary outcomes were 30-day mortality and amputation. Operative reports were reviewed to analyze the surgical procedures implied for treating vascular complications. RESULTS: One hundred one patients underwent ECMO therapy during the period of study; 63.4% were male with an average age of 47.7 years. Mean length of hospital stay was 19.8 days and average length of time on the ECMO device was 7.33 days. Indications for ECMO included cardiogenic shock in 61 patients (60.4%), pulmonary failure in 37 (36.6%), and combined cardiac and pulmonary failure in 3 (3%). Overall mortality comprised 42 patients (42%). Risk factors for peripheral arterial disease included hypertension (32%), diabetes mellitus (21.8%), hyperlipidemia (21.7%), and smoking (19.8%). Eighteen patients (17.8%) developed peripheral vascular complications (confidence interval 10-25%). Among the patients who developed vascular complications, 78% were male and average length of time on the device was 7.16 days. Indications for ECMO were cardiac failure in 13 (72%) and pulmonary failure in 5 (28%). Two (11%) were managed nonoperatively and 16 (89%) needed surgical intervention, 8 (44.44%) of whom required femoral endarterectomy with patch angioplasty. One patient required below-knee amputation. None required distal bypass. Mortality among patients with vascular complications was 28% (P = 0.30). Indications for use of ECMO in these patients included cardiogenic shock in 13 (72%) and pulmonary failure in 5 (28%). The mortality rate was 58% among diabetic patients and 34% in nondiabetic patients (P = 0.007). CONCLUSIONS: Vascular complications occur in less then 20% of ECMO patients with the majority requiring femoral reconstruction. Development of vascular complications does not appear to increase risk of amputation or mortality. Among those patients who develop vascular complications, the most common indication for ECMO is cardiogenic shock. PMID- 24064047 TI - Ugandan opinion-leaders' knowledge and perceptions of unsafe abortion. AB - While laws in Uganda surrounding abortion remain contradictory, a frequent interpretation of the law is that abortion is only allowed to save the woman's life. Nevertheless abortion occurs frequently under unsafe conditions at a rate of 54 abortions per 1000 women of reproductive age annually, taking a large toll on women's health. There are an estimated 148,500 women in Uganda who experience abortion complications annually. Understanding opinion leaders' knowledge and perceptions about unsafe abortion is critical to identifying ways to address this public health issue. We conducted in-depth, semi-structured interviews with 41 policy-makers, cultural leaders, local politicians and leaders within the health care sector in 2009-10 at the national as well as district (Bushenyi, Kamuli and Lira) level to explore their knowledge and perceptions of unsafe abortion and the potential for policy to address this issue. Only half of the sample knew the current law regulating abortion in Uganda. Respondents understood that the result of the current abortion restrictions included long-term health complications, unwanted children and maternal death. Perceived consequences of increasing access to safe abortion included improved health as well as overuse of abortion, marital conflict and less reliance on preventive behaviour. Opinion leaders expressed the most support for legalization of abortion in cases of rape when the perpetrator was unknown. Understanding opinion leaders' perspectives on this politically sensitive topic provides insight into the policy context of abortion laws, drivers behind maintaining the status quo, and ways to improve provision under the law: increase education among providers and opinion leaders. PMID- 24064048 TI - Hydrogen peroxide production and free radical-mediated cell stress in Mycoplasma bovis pneumonia. AB - Mycoplasma bovis causes chronic pneumonia and polyarthritis in feedlot cattle. M. bovis infects the lungs of most feedlot cattle, but the majority of calves never develop disease. Competing explanations are that some strains of M. bovis are more virulent than others or, alternatively, that calves require some other abnormality to be present in order for M. bovis to cause disease. We hypothesize that H2O2 production is an important virulence factor of M. bovis, causing oxidative injury to lung tissue. A second hypothesis is that isolates associated with caseonecrotic bronchopneumonia have an increased capacity for H2O2 production. Immunohistochemical markers of oxidative stress (4-hydroxynonenal, HN) and nitrative stress (3-nitrotyrosine, NT) were compared in lungs of calves with caseonecrotic bronchopneumonia characteristic of M. bovis infection, with other forms of bronchopneumonia or with non-inflamed lungs. HN and NT were identified in M. bovis pneumonia, mainly in foci of caseous necrosis. HN was not observed in inflamed non-necrotic tissue in lesions typical of pneumonic pasteurellosis. H2O2 production by M. bovis was identified, but the levels did not differ in isolates from calves with caseonecrotic bronchopneumonia compared with those with non-inflamed lungs or other forms of pneumonia. These findings provide evidence that oxidative and nitrative injury contribute to the formation of the caseonecrotic lesions that are characteristic of M. bovis pneumonia and that production of H2O2 by M. bovis may contribute to this oxidative injury. PMID- 24064049 TI - Immunohistochemical expression of markers of immaturity in sertoli and seminal cells in canine testicular atrophy. AB - During maturation from fetal to adult testis, both Sertoli cells (SCs) and germ cells (GCs) switch from an immature to a mature immunophenotype. Immature canine SCs express cytokeratins (CKs), desmin (DES), vimentin (VIM), anti-Mullerian hormone (AMH) and inhibin (INH)-alpha, while mature SCs retain only expression of VIM. Immature GCs express placental alkaline phosphatase (PLAP), which is lost in spermatocytes. Re-expression of markers of immaturity has been observed in human atrophic testes and in human and canine testicular tumours. In human medicine, testicular atrophy is considered a risk factor for testicular cancer. In the present study 13 canine atrophic testes were examined immunohistochemically. VIM was expressed in the SCs of all cases, while CK, DES, INH-alpha and AMH were expressed in a variable percentage of SCs in two, five, five and eight cases, respectively. PLAP was expressed by single GCs in one case. Markers of immaturity are therefore expressed by SCs and GCs in canine atrophic testes. Similar results were reported previously in canine testicular neoplasia, suggesting that testicular atrophy may represent a risk factor for tumour development in the dog. PMID- 24064050 TI - Standardization of therapeutic, urinary gonadotrophins: an update on the use and availability of International Standards for Menotrophin. AB - The potencies of therapeutic preparations of gonadotrophins of human, urinary origin, which comprise a heterogenous mix of isoforms with follicle-stimulating hormone (FSH) and luteinizing hormone (LH) bioactivities, are standardized by WHO International Standards (IS). We report here, the evaluation, through an international collaborative study, of a candidate preparation, coded 10/286, to replace the 4th IS, 98/704, for human, urinary FSH and LH (Menotrophin) which has been used for many years for the potency assignment of therapeutic preparations using bioassays. The mean FSH and LH bioactivities of 10/286, determined by in vivo bioassays in terms of 98/704, were 183 IU per ampoule (95% confidence limits 165-202) and 177 IU per ampoule (95% confidence limits 159-197), respectively. PMID- 24064057 TI - Emerging role of sirtuins on tumorigenesis: possible link between aging and cancer. AB - Aging is the strongest risk factor for cancer development, suggesting that molecular crosstalks between aging and tumorigenesis exist in many cellular pathways. Recently, Sirtuins (Sirt1-7), the mammalian homologues of aging-related sir2alpha in yeast, have been shown to modulate several major cellular pathways, such as DNA repair, inflammation, metabolism, cell death, and proliferation in response to diverse stresses, and may serve as a possible molecular link between aging and tumorignenesis. In addition, growing evidence suggests that sirtuins are directly implicated in the development of cancer, and they can act as either a tumor suppressor or promoter, depending on the cellular context and tumor types. While the functions of Sirt1 in tumorigenesis have been reported and reviewed in many studies, the connection between sirtuins 2-7 and the development of cancer is less established. Thus, this review will present the recent updates on the emerging roles of Sirt2-7 members in carcinogenesis. PMID- 24064058 TI - Splicing and alternative splicing in rice and humans. AB - Rice is a monocot gramineous crop, and one of the most important staple foods. Rice is considered a model species for most gramineous crops. Extensive research on rice has provided critical guidance for other crops, such as maize and wheat. In recent years, climate change and exacerbated soil degradation have resulted in a variety of abiotic stresses, such as greenhouse effects, lower temperatures, drought, floods, soil salinization and heavy metal pollution. As such, there is an extremely high demand for additional research, in order to address these negative factors. Studies have shown that the alternative splicing of many genes in rice is affected by stress conditions, suggesting that manipulation of the alternative splicing of specific genes may be an effective approach for rice to adapt to abiotic stress. With the advancement of microarrays, and more recently, next generation sequencing technology, several studies have shown that more than half of the genes in the rice genome undergo alternative splicing. This mini review summarizes the latest progress in the research of splicing and alternative splicing in rice, compared to splicing in humans. Furthermore, we discuss how additional studies may change the landscape of investigation of rice functional genomics and genetically improved rice. PMID- 24064059 TI - CD83 expression induced by CpG-DNA stimulation in a macrophage cell line RAW 264.7. AB - CpG-DNA has various immunomodulatory effects in dendritic cells, B cells, and macrophages. While induction of cytokines by CpG-DNA has been well documented in macrophages, the expression of costimulatory molecules in CpG-DNA treated macrophages has not yet been defined. Therefore, we investigated the effects of CpG-DNA on the expression of costimulatory molecules in RAW 264.7 cells. The surface expression of CD80 was slightly increased and CD83 expression was significantly increased in response to CpG-DNA. However, the expression of CD86 and MHC class II was not changed. As expression of CD83 mRNA was also increased by CpG-DNA, CD83 expression is regulated at a transcriptional level. To understand the contribution of signaling pathways to CD83 induction, we used pathway specific inhibitors. The NF-kappaB inhibitor significantly reduced surface expression of CD83 as well as phagocytic activity of RAW 264.7 cells. Therefore, CD83 expression may contribute to the immunostimulatory effects of CpG DNA in macrophage cells. PMID- 24064060 TI - Dexamethasone induces the expression of LRRK2 and alpha-synuclein, two genes that when mutated cause Parkinson's disease in an autosomal dominant manner. AB - LRRK2 (leucine-rich repeat kinase 2) has been identified as a gene corresponding to PARK8, an autosomal-dominant gene for familial Parkinson's disease (PD). LRRK2 pathogenic-specific mutants induce neurotoxicity and shorten neurites. To elucidate the mechanism underlying LRRK2 expression, we constructed the LRRK2 promoter-luciferase reporter and used it for promoter analysis. We found that the glucocorticoid receptor (GR) transactivated LRRK2 in a ligand-dependent manner. Using quantitative RT-PCR and Western analysis, we further showed that treatment with dexamethasone, a synthetic GR ligand, induced LRRK2 expression at both the transcriptional and translational levels, in dopaminergic MN9D cells. Dexamethasone treatment also increased expression of alpha alpha-synuclein, another PD causative gene, and enhanced transactivation of the alpha-synuclein promoter-luciferase reporter. In addition, dexamethasone treatment to MN9D cells weakly induced cytotoxicity based on an LDH assay. Because glucocorticoid hormones are secreted in response to stress, our data suggest that stress might be a related factor in the pathogenesis of PD. PMID- 24064061 TI - Induction of transforming growth factor-beta 1 by androgen is mediated by reactive oxygen species in hair follicle dermal papilla cells. AB - The progression of androgenetic alopecia is closely related to androgen-inducible transforming growth factor (TGF)-beta1 secretion by hair follicle dermal papilla cells (DPCs) in bald scalp. Physiological levels of androgen exposure were reported to increase reactive oxygen species (ROS) generation. In this study, rat vibrissae dermal papilla cells (DP-6) transfected with androgen receptor showed increased ROS production following androgen treatment. We confirmed that TGF beta1 secretion is increased by androgen treatment in DP-6, whereas androgen inducible TGF-beta1 was significantly suppressed by the ROS-scavenger, N-acetyl cysteine. Therefore, we suggest that induction of TGF-beta1 by androgen is mediated by ROS in hair follicle DPCs. PMID- 24064062 TI - Anti-wrinkle effect of bone morphogenetic protein receptor 1a-extracellular domain (BMPR1a-ECD). AB - Bone morphogenetic proteins (BMPs) have diverse and important roles in the proliferation and differentiation of adult stem cells in our tissues. Especially, BMPs are well known to be the main inducers of bone formation, by facilitating both proliferation and differentiation of bone stem cells. Interestingly, in skin stem cells, BMPs repress their proliferation but are indispensable for the proper differentiation into several lineages of skin cells. Here, we tested whether BMP antagonists have an effect on the prevention of wrinkle formation. For this study we used an in vivo wrinkle-induced mouse model. As a positive control, retinoic acid, one of the top anti-wrinkle effectors, showed a 44% improvement compared to the non-treated control. Surprisingly, bone morphogenetic protein receptor 1a extracellular domain (BMPR1a-ECD) exhibited an anti-wrinkle effect which was 6 fold greater than that of retinoic acid. Our results indicate that BMP antagonists will be good targets for skin or hair diseases. PMID- 24064064 TI - Basal blood corticosterone level is correlated with susceptibility to chronic restraint stress in mice. AB - Corticosterone is released in response to stress and manifests as various bodily stress responses in rodents. While corticosterone reflects acute adaptive responses, how the basal steady-state corticosterone level relates to the subsequent stress response is largely unknown. Here, we investigated how basal corticosterone levels can affect the susceptibility to chronic restraint stress in mice. We designed a longitudinal experiment, enabling us to compare the basal corticosterone level and the subsequent response to repeated restraint stress within the same animal. We found that the mice had differential changes in plasma corticosterone levels, which either increased or decreased, with exposure to chronic stress. These differential changes reflected the differential stress susceptibility of the mice, as evaluated by changes in body weight. The extent of the changes in corticosterone level during chronic stress exposure was predicted by the basal corticosterone level. In addition, the behavioral consequence of chronic stress was also correlated with the basal corticosterone level prior to chronic stress experience. These data reveal that the basal steady-state corticosterone level is a predictor of stress susceptibility or resilience to subsequent stress exposures. PMID- 24064063 TI - PIDD mediates and stabilizes the interaction between RAIDD and caspase-2 for the PIDDosome assembly. AB - The PIDDosome, which is an oligomeric signaling complex composed of PIDD, RAIDD and caspase-2, can induce proximity-based dimerization and activation of caspase 2. In the PIDDosome assembly, the adaptor protein RAIDD interacts with PIDD and caspase-2 via CARD:CARD and DD:DD, respectively. To analyze the PIDDosome assembly, we purified all of the DD superfamily members and performed biochemical analyses. The results revealed that caspase-2 CARD is an insoluble protein that can be solubilized by its binding partner, RAIDD CARD, but not by full-length RAIDD; this indicates that full-length RAIDD in closed states cannot interact with caspase-2 CARD. Moreover, we found that caspase-2 CARD can be solubilized and interact with full-length RAIDD in the presence of PIDD DD, indicating that PIDD DD initially binds to RAIDD, after which caspase-2 can be recruited to RAIDD via a CARD:CARD interaction. Our study will be useful in determining the order of assembly of the PIDDosome. PMID- 24064065 TI - Safety of 5 kHz tACS. AB - BACKGROUND: Sinusoidal transcranial alternating current stimulation (tACS) at 5 kHz applied for 10 min at 1 mA intensity over the hand area of the primary motor cortex (M1) results in sustained changes in cortical excitability as previously demonstrated. OBJECTIVE: Here we have assessed safety aspects of this stimulation method by measuring neuron-specific enolase (NSE) levels, examining electroencephalogram (EEG) traces and analyzing anatomical data by using magnetic resonance imaging (MRI). METHODS: Altogether 18 healthy volunteers participated in the study. tACS was applied at 5 kHz for a duration of 10 min over the left M1 at an intensity of 1 mA. RESULTS: After stimulation no significant changes were detected in NSE levels, no structural alterations were observed in the anatomical scans and no pathological changes were found in the EEG recordings. CONCLUSIONS: Our data imply that the application of tACS is safe at least within these parameters and with these applied protocols. PMID- 24064067 TI - Electrophysiological markers of biological motion and human form recognition. AB - Current models suggest that human form and motion information are initially processed through separate pathways, then integrated in action perception. Testing such a sequential model requires techniques with high temporal resolution. Prior work demonstrated sensitivity of a posterior temporal event related potential (ERP) effect - the N2 - to biological motion, but did not test whether the N2 indexes biological motion perception specifically, or human form/action perception more generally. We recorded ERPs while participants viewed stimuli across 3 blocks: (1) static (non-moving) point-light displays of humans performing actions; (2) static stick figures with clear forms; and (3) point light biological motion. A similar sequence of ERP components was elicited by human forms in all blocks (stationary and moving), and reliably discriminated between human and scrambled forms. The N2 showed similar scalp distribution and sensitivity to stimulus manipulations for both stick figures and biological motion, suggesting that it indexes integration of form and motion information, rather than biological motion perception exclusively - and that form and motion information are therefore integrated by approximately 200ms. We identified a component subsequent to the N2, which we label the medial parietal positivity/ventral-anterior negativity (MPP/VAN), that was also sensitive to both human form and motion information. We propose that the MPP/VAN reflects higher order human action recognition that occurs subsequent to the integration of form and motion information reflected by the N2. PMID- 24064066 TI - Neuroinflammation in healthy aging: a PET study using a novel Translocator Protein 18kDa (TSPO) radioligand, [(18)F]-FEPPA. AB - One of the cellular markers of neuroinflammation is increased microglia activation, characterized by overexpression of mitochondrial 18kDa Translocator Protein (TSPO). TSPO expression can be quantified in-vivo using the positron emission tomography (PET) radioligand [(18)F]-FEPPA. This study examined microglial activation as measured with [(18)F]-FEPPA PET across the adult lifespan in a group of healthy volunteers. We performed genotyping for the rs6971 TS.PO gene polymorphism to control for the known variability in binding affinity. Thirty-three healthy volunteers (age range: 19-82years; 22 high affinity binders (HAB), 11 mixed affinity binders (MAB)) underwent [(18)F]-FEPPA PET scans, acquired on the High Resolution Research Tomograph (HRRT) and analyzed using a 2 tissue compartment model. Regression analyses were performed to examine the effect of age adjusting for genetic status on [(18)F]-FEPPA total distribution volumes (VT) in the hippocampus, temporal, and prefrontal cortex. We found no significant effect of age on [(18)F]-FEPPA VT (F (1,30)=0.918; p=0.346), and a significant effect of genetic polymorphism (F (1,30)=8.767; p=0.006). This is the first in-vivo study to evaluate age-related changes in TSPO binding, using the new generation TSPO radioligands. Increased neuroinflammation, as measured with [(18)F]-FEPPA PET was not associated with normal aging, suggesting that healthy elderly individuals may serve as useful benchmark against patients with neurodegenerative disorders where neuroinflammation may be present. PMID- 24064068 TI - Why size matters: differences in brain volume account for apparent sex differences in callosal anatomy: the sexual dimorphism of the corpus callosum. AB - Numerous studies have demonstrated a sexual dimorphism of the human corpus callosum. However, the question remains if sex differences in brain size, which typically is larger in men than in women, or biological sex per se account for the apparent sex differences in callosal morphology. Comparing callosal dimensions between men and women matched for overall brain size may clarify the true contribution of biological sex, as any observed group difference should indicate pure sex effects. We thus examined callosal morphology in 24 male and 24 female brains carefully matched for overall size. In addition, we selected 24 extremely large male brains and 24 extremely small female brains to explore if observed sex effects might vary depending on the degree to which male and female groups differed in brain size. Using the individual T1-weighted brain images (n=96), we delineated the corpus callosum at midline and applied a well-validated surface-based mesh-modeling approach to compare callosal thickness at 100 equidistant points between groups determined by brain size and sex. The corpus callosum was always thicker in men than in women. However, this callosal sex difference was strongly determined by the cerebral sex difference overall. That is, the larger the discrepancy in brain size between men and women, the more pronounced the sex difference in callosal thickness, with hardly any callosal differences remaining between brain-size matched men and women. Altogether, these findings suggest that individual differences in brain size account for apparent sex differences in the anatomy of the corpus callosum. PMID- 24064069 TI - Numerical ordering and symbolic arithmetic share frontal and parietal circuits in the right hemisphere. AB - A prominent proposal in numerical cognition states that our mental calculation abilities are grounded in the approximate number system (ANS). Recently, it was proposed that this association is mediated by numerical ordering abilities. As a first step in elucidating the neural correlates of this link this study tested which areas in the human brain carry information common to both calculation and numerical ordering. While lying in an MR scanner 17 healthy participants (a) decided whether or not a given number triplet was presented in numerically ascending order, and (b) solved simple addition and subtraction problems. Standard general linear model analyses revealed a largely overlapping network in fronto-parietal regions for both tasks. By analyzing the spatial information over voxels using a whole-brain searchlight algorithm we identified a right hemispheric network comprising areas along the intraparietal sulcus and in the inferior frontal cortex which was similarly involved in order judgments and symbolic arithmetic. Functional and anatomical characteristics of this network make it a candidate for linking the ANS to mental arithmetic. PMID- 24064070 TI - Testing the model of caudo-rostral organization of cognitive control in the human with frontal lesions. AB - The cascade model of cognitive control, mostly relying on functional neuroimaging studies, stipulates that the lateral frontal cortex (LFC) is organized as a cascade of executive processes involving three levels of cognitive control, implemented in distinct LFC areas from the premotor to the anterior prefrontal regions. The present experiment tested this model in patients with LFC lesions and studied the hierarchy of executive functions along the caudo-rostral axis, i.e. the respective roles of the different LFC areas in the control of behavior. Voxel-based lesion-symptom mapping and region of interest group analyses were conducted in 32 patients with focal LFC lesions who performed cognitive tasks assessing the cascade model. We first showed that three different LFC areas along the caudo-rostral axis subserved three distinct control levels, whose integrity is necessary for adaptive behavior. Second, we found that prefrontal cognitive control has an asymmetric organization: higher control processes involving more anterior prefrontal regions rely on the integrity of lower control processes in more posterior regions, while lower control processes can operate irrespective of the integrity of higher control processes. Altogether, these findings support a caudo-rostral cascade of executive processes from premotor to anterior prefrontal regions. PMID- 24064072 TI - Development of deactivation of the default-mode network during episodic memory formation. AB - Task-induced deactivation of the default-mode network (DMN) has been associated in adults with successful episodic memory formation, possibly as a mechanism to focus allocation of mental resources for successful encoding of external stimuli. We investigated developmental changes of deactivation of the DMN (posterior cingulate, medial prefrontal, and bilateral lateral parietal cortices) during episodic memory formation in children, adolescents, and young adults (ages 8-24), who studied scenes during functional magnetic resonance imaging (fMRI). Recognition memory improved with age. We defined DMN regions of interest from a different sample of participants with the same age range, using resting-state fMRI. In adults, there was greater deactivation of the DMN for scenes that were later remembered than scenes that were later forgotten. In children, deactivation of the default-network did not differ reliably between scenes that were later remembered or forgotten. Adolescents exhibited a pattern of activation intermediate to that of children and adults. The hippocampal region, often considered part of the DMN, showed a functional dissociation with the rest of the DMN by exhibiting increased activation for later remembered than later forgotten scene that was similar across age groups. These findings suggest that development of memory ability from childhood through adulthood may involve increased deactivation of the neocortical DMN during learning. PMID- 24064071 TI - Task preparation processes related to reward prediction precede those related to task-difficulty expectation. AB - Recently, attempts have been made to disentangle the neural underpinnings of preparatory processes related to reward and attention. Functional magnetic resonance imaging (fMRI) research showed that neural activity related to the anticipation of reward and to attentional demands invokes neural activity patterns featuring large-scale overlap, along with some differences and interactions. Due to the limited temporal resolution of fMRI, however, the temporal dynamics of these processes remain unclear. Here, we report an event related potentials (ERP) study in which cued attentional demands and reward prospect were combined in a factorial design. Results showed that reward prediction dominated early cue processing, as well as the early and later parts of the contingent negative variation (CNV) slow-wave ERP component that has been associated with task-preparation processes. Moreover these reward-related electrophysiological effects correlated across participants with response time speeding on reward-prospect trials. In contrast, cued attentional demands affected only the later part of the CNV, with the highest amplitudes following cues predicting high-difficulty potential-reward targets, thus suggesting maximal task preparation when the task requires it and entails reward prospect. Consequently, we suggest that task-preparation processes triggered by reward can arise earlier, and potentially more directly, than strategic top-down aspects of preparation based on attentional demands. PMID- 24064074 TI - Qualification of fMRI as a biomarker for pain in anesthetized rats by comparison with behavioral response in conscious rats. AB - fMRI can objectively measure pain-related neural activities in humans and animals, providing a valuable tool for studying the mechanisms of nociception and for developing new analgesics. However, due to its extreme sensitivity to subject motion, pain fMRI studies are performed in animals that are immobilized, typically with anesthesia. Since anesthesia could confound the nociceptive processes, it is unknown how well nociceptive-related neural activities measured by fMRI in anesthetized animals correlate with nociceptive behaviors in conscious animals. The threshold to vocalization (VT) in response to an increasing noxious electrical stimulus (NES) was implemented in conscious rats as a behavioral measure of nociception. The antinociceptive effect of systemic (intravenous infusion) lidocaine on NES-induced fMRI signals in anesthetized rats was compared with the corresponding VT in conscious rats. Lidocaine infusion increased VT and suppressed the NES-induced fMRI signals in most activated brain regions. The temporal characteristics of the nociception signal by fMRI and by VT in response to lidocaine infusion were highly correlated with each other, and with the pharmacokinetics (PK) of lidocaine. These results indicate that the fMRI activations in these regions may be used as biomarkers of acute nociception in anesthetized rats. Interestingly, systemic lidocaine had no effect on NES-induced fMRI activations in the primary somatosensory cortex (S1), a result that warrants further investigation. PMID- 24064073 TI - Using single-trial EEG to predict and analyze subsequent memory. AB - We show that it is possible to successfully predict subsequent memory performance based on single-trial EEG activity before and during item presentation in the study phase. Two-class classification was conducted to predict subsequently remembered vs. forgotten trials based on subjects' responses in the recognition phase. The overall accuracy across 18 subjects was 59.6% by combining pre- and during-stimulus information. The single-trial classification analysis provides a dimensionality reduction method to project the high-dimensional EEG data onto a discriminative space. These projections revealed novel findings in the pre- and during-stimulus periods related to levels of encoding. It was observed that the pre-stimulus information (specifically oscillatory activity between 25 and 35Hz) 300 to 0ms before stimulus presentation and during-stimulus alpha (7-12Hz) information between 1000 and 1400ms after stimulus onset distinguished between recollection and familiarity while the during-stimulus alpha information and temporal information between 400 and 800ms after stimulus onset mapped these two states to similar values. PMID- 24064075 TI - Leading the follower: an fMRI investigation of dynamic cooperativity and leader follower strategies in synchronization with an adaptive virtual partner. AB - From everyday experience we know that it is generally easier to interact with someone who adapts to our behavior. Beyond this, achieving a common goal will very much depend on who adapts to whom and to what degree. Therefore, many joint action tasks such as musical performance prove to be more successful when defined leader-follower roles are established. In the present study, we present a novel approach to explore the mechanisms of how individuals lead and, using functional magnetic resonance imaging (fMRI), probe the neural correlates of leading. Specifically, we implemented an adaptive virtual partner (VP), an auditory pacing signal, with which individuals were instructed to tap in synchrony while maintaining a steady tempo. By varying the degree of temporal adaptation (period correction) implemented by the VP, we manipulated the objective control individuals had to exert to maintain the overall tempo of the pacing sequence (which was prone to tempo drift with high levels of period correction). Our imaging data revealed that perceiving greater influence and leading are correlated with right lateralized frontal activation of areas involved in cognitive control and self-related processing. Using participants' subjective ratings of influence and task difficulty, we classified a subgroup of our cohort as "leaders", individuals who found the task of synchronizing easier when they felt more in control. Behavioral tapping measures showed that leaders employed less error correction and focused more on self-tapping (prioritizing the instruction to maintain the given tempo) than on the stability of the interaction (prioritizing the instruction to synchronize with the VP), with correlated activity in areas involved in self-initiated action including the pre supplementary motor area. PMID- 24064077 TI - Bacterial sinusitis can be a focus for initial lung colonisation and chronic lung infection in patients with cystic fibrosis. AB - A major purpose of treating patients with cystic fibrosis (CF) is to prevent or delay chronic lung infections with CF-pathogenic Gram-negative bacteria. In the intermittent stage, bacteria can usually be eradicated from the lungs with antibiotics, but following eradication, the next lung colonisations often occur with bacteria of identical genotype. This may be due to re-colonisation from the patient's paranasal sinuses. In our study, we found that approximately two-thirds of CF patients having sinus surgery (FESS) had growth of CF-lung-pathogenic Gram negative bacteria in their sinuses (Pseudomonas aeruginosa, Achromobacter xylosoxidans, Burkholderia cepacia complex). The environment in the sinuses is in many ways similar to that of the lower respiratory tract, e.g. low oxygen concentration in secretions. Sinus bacteria are more difficult to eradicate than in the lungs, thus, having good conditions for adapting to the environment in the lungs. In the presence of bacteria, the environment of the sinuses differs from that of the lower respiratory tract by having a higher immunoglobulin A (IgA): IgG ratio, and reduced inflammation. We found a significant correlation between the concentration of IgA against P. aeruginosa (standard antigen and alginate) in nasal secretions and saliva and CF patients' infection status (not lung colonised, intermittently colonised or chronically lung-infected with P. aeruginosa). This supports the hypothesis that infections often originate in the sinuses and can be a focus for initial lung colonisation or for maintaining lung infections in CF patients. We are confident that anti-P. aeruginosa IgA can be used as an early supplementary tool to diagnose P. aeruginosa colonisation; P. aeruginosa being the microorganism causing most morbidity and mortality in CF patients. This is important since urgent treatment reduces morbidity when CF patients are early colonised with P. aeruginosa, however, there is a lack of diagnostic tools for detecting the early colonisation in the lungs and in the sinuses. We initiated a treatment strategy for CF patients to prevent sino-nasal bacteria being seeded into the lower airways: we recommended extensive functional endoscopic FESS with creation of sufficient drainage from all involved sinuses with subsequent i.v. antibiotics and at least 6 months of twice daily nasal irrigation with saline and antibiotics. By this strategy, sinus bacteria could be eradicated in a large proportion of patients. Essentially, growth of CF pathogenic bacteria from the lower respiratory tract was decreased following the treatment. Furthermore, a number of patients have been free from CF-pathogenic bacteria for more than one year after FESS, and thus re-classified as "not lung colonised". We also corroborated that CF patients obtain an improved quality of life and reduction in their symptoms of chronic rhinosinusitis after FESS. It is primarily intermittently lung colonised CF patients with CF-pathogenic bacteria in their sinuses that seem to benefit from the treatment strategy. This is in accordance with the fact that we did not see a significant increase in lung function and only a small decrease in specific antibodies after FESS; a high systemic immune and inflammatory response and a decreasing lung function is generally not present in patients who primarily have sinus CF-pathogenic bacteria. It is important that guidelines are created for how CF patients with CF pathogenic bacteria in the sinuses are to be treated, including criteria for who may likely benefit from FESS, and who may be treated exclusively with conservative therapy, e.g. saline and antibiotic irrigations. PMID- 24064078 TI - Fibrous hyperplasia involving the orifice of Stensen's duct. AB - This study aimed to describe the clinical features and surgical management of fibrous hyperplasia involving the orifice of Stensen's duct. The clinical data of three patients (one male and two females) were collected and analyzed to characterize this lesion. The lesions surrounding the orifice of Stensen's duct were painless and without obvious causes. The patients' clinical features included sensation of a foreign body and an awkward bite during mastication. All patients received surgical management to resect the polyp and reconstruct the orifice of Stensen's duct. The ducts were preserved intact and parotid glands functioned normally after 12-18 months follow-up. In conclusion, the key point for surgical management of fibrous hyperplasia involving Stensen's duct is to keep the duct intact and unobstructed in consideration of its particular location. PMID- 24064079 TI - Management of right heart thrombi associated with acute pulmonary embolism: is there no room for surgical embolectomy? PMID- 24064080 TI - Pacemaker interrogation showing virtually no ventricular pacing in a ventricular pacing dependent patient: what is the explanation? PMID- 24064081 TI - Catheter ablation of electrical storm triggered by monomorphic ventricular ectopic beats after myocardial infarction. PMID- 24064082 TI - Successful ablation of cavo-tricuspid isthmus dependent atrial flutter in a patient with Senning operation. PMID- 24064083 TI - [Recurrent myocardial infarction in a young patient with PAI-1 4G/4G mutation]. PMID- 24064084 TI - An acute coronary syndrome patient: is this atherosclerosis? PMID- 24064085 TI - Cardiovascular risk factors in Turkey. PMID- 24064086 TI - Appropriate methodology is essential for accurate conclusions. PMID- 24064087 TI - Increased mean platelet volume in patients with familial Mediterranean fever may not be a marker of atherosclerosis risk. PMID- 24064088 TI - Mean platelet volume in patients with idiopathic and ischemic cardiomyopathy. PMID- 24064089 TI - Epicardial adipose tissue measurement: inexpensive, easy accessible and rapid practical method. PMID- 24064090 TI - LDL cholesterol measurement in terms of CHOLINDEX. PMID- 24064091 TI - Does left ventricular function deteriorate in patients with nasal polyposis? PMID- 24064092 TI - [The heart project: a cost-effective method to save a life]. PMID- 24064093 TI - Atypical presentation of adult celiac disease: myocarditis and liver abnormality. PMID- 24064094 TI - Diffuse coronary ectasia and acute coronary syndrome in a young man. Who is guilty? Cannabis, smoking or dyslipidemia? PMID- 24064095 TI - [High dose cytosin arabinoside induced sinus bradycardia in a Hodgkin's lymphoma patient]. PMID- 24064096 TI - [Medium-long term follow-up results of valvular pulmonary stenosis in Turkish children]. PMID- 24064098 TI - Multimodality imaging of persistent left superior vena cava and an absent right superior vena cava in a patient with dextrocardia. PMID- 24064097 TI - An adult patient with coexistence of coarctation of aorta and patent ductus arteriosus: multimodality imaging. PMID- 24064099 TI - Mitral valve perforation from aortic insufficiency. PMID- 24064100 TI - Giant aneurysm with thrombosis refractory to medical therapy due to Kawasaki disease. PMID- 24064101 TI - Right ventricular penetration and acute cardiac tamponade caused by sewing needle in a woman under antipsychotherapeutic treatment. PMID- 24064102 TI - Acute myocardial infarction caused by severe muscular bridges of the left anterior descending artery and diagonal branch: a very unusual cause of myocardial infarction. PMID- 24064103 TI - Tako-tsubo-like cardiomyopathy induced by pheochromocytoma crisis. PMID- 24064104 TI - Pulmonary artery sling and tracheal bronchus in an infant with severe respiratory distress. PMID- 24064105 TI - Interatrial septal mass. Lipomatous hypertrophy of interatrial septum. PMID- 24064106 TI - Almanac 2013: novel non-coronary cardiac interventions. AB - Recent innovations in interventional cardiology have dramatically expanded the therapeutic options for patients with cardiac conditions. Interventional cardiology is no longer limited to the treatment of coronary artery disease but allows also treatment of valvular disease, stroke prevention, hypertension, etc. One of the most important new treatment options is the percutaneous treatment for aortic valve stenosis (transcatheter aortic valve implantation), since aortic valve disease is a rather common problem in elderly patients, with many of them at high risk for surgery. Similarly, mitral regurgitation is often associated with comorbidities which make surgery high risk. The MitraClip is a promising percutaneous alternative to surgical valve repair or replacement. Other procedures discussed in this review are the percutaneous left atrial appendage closure as a non-pharmacologic therapy to prevent strokes, and renal denervation for resistant hypertension. This review explains the basic principles of these procedures, the most important clinical evidence, and also provides additional recent clinical data on each of these them. PMID- 24064107 TI - The relation between location of paravalvular leakage and time to reoperation after mitral valve replacement. AB - OBJECTIVE: A relation between the location of the paravalvular leakage (PVL) and time to reoperation after mitral mechanical valve replacement was investigated. METHODS: In an observational retrospective study plan, from 59 patients who underwent reoperation only 47 patients having clinical and echocardiographic follow-up for five years were included into study. Depending on echocardiographic evaluation of location of leak, patients were divided into Group 1 (Leaflet) and Group 2 (Commissural). Demographics, preoperative variables, causes of reoperation, the time period between diagnosis of PVL and reoperation were recorded. Unpaired t test or Mann-Whitney U test were used for comparison of variables between groups. RESULTS: A PVL was diagnosed after a median time of 180 days (range: 1 day-28 years) after the first mitral valve replacement. The median follow-up period was 5 years (range; 1-16 years). Age, gender, left ventricular ejection function, number and size of leaks did not differ between groups (p>0.05). The time period between diagnosis and reoperation time was longer in Group 1 in comparison to Group 2 (39.0 +/- 9.9 vs. 19.5 +/- 12.8 months, p=0.002). The 30-day mortality for valve reoperation was 4.3% (2/47). In Group 1, 2 patients (2/21, 9.8%) died whereas, no death was observed in Group 2 (0/26, 0%) (p=0.002). CONCLUSION: The time period between diagnosis and reoperation was longer in leaflet leak group in comparison to commissural leak group. We suggest echocardiographic evaluation should include location of the paravalvular leakage during follow-up of patients with PVL after mitral valve replacement. PMID- 24064108 TI - Late stent malapposition combined by thrombus resolution after primary stenting in acute myocardial infarction: optical coherence tomography findings. PMID- 24064109 TI - Infusions of ascorbic acid into the medial preoptic area facilitate appetitive sexual behavior in the female rat. AB - Ascorbic acid (AA), also known as Vitamin C, enhances dopamine (DA) transmission in mesolimbic and nigrostriatal terminals and augments DA-mediated behaviors. It is not yet known whether AA has a similar influence in other DA terminals, in particular terminals of the incertohypothalamic system that modulate the function of the medial preoptic area (mPOA). In female rats, DA in the mPOA plays a critical role in the generation of appetitive sexual responses, notably solicitations, hops, and darts, and we have shown previously that the role of DA in this region on female sexual behavior changes depending on the hormonal profile of the female. Since AA has often been used as a vehicle control in the examination of rat sexual behavior, the present study examined the effect of infusions of AA to the mPOA of sexual experienced ovariectomized rats under two hormonal conditions: partially-primed with estradiol benzoate (EB) alone or fully primed with EB and progesterone. Relative to saline baselines, females under both hormonal conditions displayed a significant increase in appetitive sexual behaviors following infusions of AA. No difference in lordosis behavior was observed following AA infusions relative to saline baselines. We suggest that the mechanism by which AA infusions to the mPOA increase appetitive sexual behaviors in female rats may be through dose-dependent DA receptor interactions, possibly through both presynaptic release mechanisms and postsynaptic DA D1-related messenger systems. PMID- 24064110 TI - Hybrid pig versus Gottingen minipig-derived cartilage and chondrocytes show pig line-dependent differences. AB - Minipigs are widely used as a large animal model for cartilage repair. However, many in vitro studies are based on porcine chondrocytes derived from abundantly available premature hybrid pigs. It remains unclear whether pig line-dependent differences exist which could limit the comparability between in vitro and in vivo results using either hybrid or miniature pig articular chondrocytes. Porcine knee joint femoral cartilage was isolated from 3- to 5-month-old hybrid pigs and Gottingen minipigs. Cartilage from both pig lines was analysed for thickness, zonality, cell content, size and proteoglycan deposition. Cultured articular chondrocytes from both pig lines were investigated for gene and/or protein expression of cartilage-specific proteins such as type II collagen, aggrecan, the chondrogenic transcription factor Sox9, non-specific type I collagen and the cell matrix receptor beta1-integrin. Cartilage was significantly thinner in the miniature pig compared to the hybrid pig, but the differences between the medial and lateral femur condyles did not reach a significant level. Knee joint cartilage zone formation started only in the minipig, whereas cellularity and cell diameters were comparable in both pig lines. Blood vessels could be detected in the hybrid pig but not the minipig cartilage. Sulphated proteoglycan deposition was more pronounced in cartilage zones II-IV of both pig lines. Minipig chondrocytes expressed type II and I collagen, Sox9 and beta1-integrin at a higher level than hybrid pig chondrocytes. These distinct line-dependent differences should be considered when using hybrid pig-derived chondrocytes for tissue engineering and Gottingen minipigs as a large animal model. PMID- 24064111 TI - Head drops in advanced Huntington's disease. PMID- 24064112 TI - Aquaporins in cancer. AB - BACKGROUND: The aquaporins (AQPs) are a family of 13 small hydrophobic integral transmembrane water channel proteins involved in transcellular and transepithelial water movement, transport of fluid and cell migration. SCOPE OF THE REVIEW: This review article summarizes our knowledge concerning the involvement of AQPs in tumor growth, angiogenesis and metastatic process. MAJOR CONCLUSIONS: Tumor cells types express AQPs and a positive correlation exists between histological tumor grade and the AQP expression. Moreover, AQPs are involved also in tumor edema formation and angiogenesis in several solid and hematological tumors. GENERAL SIGNIFICANCE: AQPs inhibition in endothelial and tumor cells might limit tumor growth and spread, suggesting a potential therapeutic use in the treatment of tumors. This article is part of a Special Issue entitled Aquaporins. PMID- 24064113 TI - Turner syndrome and autoimmune diseases: record-linkage study. AB - BACKGROUND: There is increasing evidence that Turner syndrome is associated with an elevated risk of a range of autoimmune disorders. We aimed to document this in a national study. METHOD: Use of a record-linked dataset of all hospital admissions in England, 1999-2011, to construct a retrospective cohort of people with Turner syndrome and a control cohort of people without it. Statistical follow-up to identify the occurrence of 29 separate autoimmune disorders in each cohort. Calculation of rate ratios, comparing the Turner and control cohorts. RESULTS: In the Turner syndrome cohort (2459 people), rate ratios were elevated for 16 of the 29 conditions. Examples included coeliac disease (rate ratio 14.0, 95% CI 10.2 to 18.8), Crohn's disease (5.3, 3.5 to 7.8), ulcerative colitis (3.9, 2.3 to 6.1), hypothyroidism (8.8, 7.8 to 9.9) and hyperthyroidism (4.9, 3.2 to 7.1). CONCLUSIONS: The increased risk of autoimmune disorders in people with Turner syndrome covers a wide range of conditions. PMID- 24064114 TI - Synthesis and anti-tumor evaluation of B-ring substituted steroidal pyrazoline derivatives. AB - The synthesis and anti-tumor activity screening of new steroidal derivatives (4 18) containing pharmacologically attractive pyrazoline moieties are performed. During in vitro anticancer evaluation, the newly synthesized compounds displayed moderate to good cytotoxicity on cervical and leukemia cancer cell lines. In addition these compounds were found to be nontoxic to normal cell (PBMCs) (IC50>50 MUM). The structure-activity relationship is also discussed. The most effective anticancer compound 9 was found to be active with IC50 value of 10.6 MUM. It demonstrated significant antiproliferative influence on Jurkat cell lines. The morphological changes and growth characteristics of HeLa cells treated with compound 4 were analyzed by means of SEM. PMID- 24064115 TI - Teachable moments for burn injury prevention. PMID- 24064116 TI - Burn surface area calculation: what do we need in future. PMID- 24064117 TI - [Study on activation of benzo(a)pyrene and DNA damage mediated by lipoxygenase in human bronchial epithelial cells]. AB - OBJECTIVE: The oxidation of benzo (a) pyrene mediated by 5-lipoxygenase (5-LOX) were investigated in HBE cells in order to provide further proof that lipoxygenase is the alternative pathway for the oxidation of xenobiotics. METHODS: Enzymic experiment: Soybean lipoxygenase (SLO), substrate (benzo[a] pyrene) and other component react in the enzymic system and the reaction product are detected by spectrophotometry. At the same time, in vitro detect of benzo (a) pyrene-DNA adducts with a UV spectrophotometer and HPLC. Cellular experiment: After HBE cells exposure to different poison (B[a]P 4, 8, 16, 32, 64, 128umol/L, AA-861, naproxen or alpha- naphthoflavone 0.1, 1, 10 umol/L) for 24 hours, the effect of benzo (a) -pyrene on cell survival rate were assessed by reductions of tetrazolium dye (MTT) and flow cytometry in cultured HBE cells, and the protein expressions of 5-lipoxygenase in the cells are tested by western-blot, and the DNA damages by the single cell gel electrophoresis. And then, the effect of the specific inhibitor of 5-lipoxygenase (AA-861) on 5-lipoxygenase protein expression and DNA damage in the cells are detected. RESULTS: SLO can catalyze the co-oxidation of benzo (a) pyrene to generate benzo (a) pyrene-7,8-epoxide in the presence of hydrogen peroxide. GTP can inhibit the reaction , the IC50 value is 0.46 mg/L, the model equation is Probit (P) = 0.8985+2.6824 Log (dose). SLO can catalyze the co-oxidation of benzo (a) pyrene to generate a new product, but fail to form DNA adducts in vitro. HBE cell viability decreased with the benzo (a) pyrene concentration increased , but AA-861 and naproxen can inhibit it. Flow cytometry and single cell gel electrophoresis experiments show, Benzo (a) pyrene can induce 5-lipoxygenase protein expression, but AA-861 cannot in HBE. Benzo (a) pyrene causes toxic action and DNA damage in HBE, which can significantly inhibit by AA-861, the difference is statistically significant (P < 0.05). CONCLUSIONS: The co-oxidate of benzo (a) pyrene by 5-LOX turns into electrophiles that covalently bind to DNA and induce DNA damage, which can be significantly inhibited by AA-861. PMID- 24064118 TI - [Protective performance and subjective evaluation of N95 filtering-facepiece respirators]. AB - OBJECTIVE: To evaluate the protective performance of N95 filtering-facepiece respirators (FFRs) used widely in China and to investigate participants' subjective evaluation about them. METHODS: Four models (A1, A2, B1, B2) of N95 FFRs from two manufactures were chosen to measure the filter penetration and inhalation resistance. Inward leakage was measured by Condensation Nuclei Counting method (CNC) in 50 participants selected using the Chinese respirator fit test panel. Each participant was asked subjective feelings after wearing a respirator by questionnaire survey. RESULTS: The filter penetration and inhalation resistance of four FFRs complied with national standard (GB 2626 2006). The geometric mean fit factors (GMFFs) for four models were 20.9, 14.6, 74.0, 49.1 and there passing rates were 4%, 4%, 42%, 10%. All of four models had bad seal performance, especially the passing rate of A1 and A2 were lower than 10%. The self-feelings about the resistance for FFRs had no significant difference (P > 0.05). The results indicated that B (B1 and B2) has a better fit than A (A1 and A2) according to participants' subject evaluation (P < 0.05). The folding style respirator (B2) was significant more comfortable than the cup style respirator (B1). The subjective feeling of respirators leakage by participant was poor consistent with objective inward leakage test. The kappa index was 0.067 (95%CI: -0.029~0.163, P = 0.18) and the consistent rate was 50%. CONCLUSION: The poor seal performance was the biggest problem of N95 FFRs in Chinese market. Respirators should be resigned or improved rely on Chinese facial features. Dust workers should choice a fit respirator according to the result of objective leakage test rather than subjective feeling of leakage. PMID- 24064119 TI - [Effect of N-acetyl-seryl-aspartyl-lysyl-proline on differentiation from pulmonary fibroblast to myofibroblast mediated by Rho-associated coiled-coil forming protein kinase pathway]. AB - OBJECTIVE: To investigate whether N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) can inhibit the differentiation of pulmonary fibroblasts into myofibroblasts by regulating Rho-associated coiled-coil forming protein kinase (ROCK) pathway mediated by transforming growth factor-beta1 (TGF-beta1). METHODS: Primary culture of pulmonary fibroblasts was performed by trypsinization method. Four generations of pulmonary fibroblasts were divided into control group, TGF-beta induced differentiation group, Y-27632 treatment group, and Ac-SDKP treatment group. The intracellular distributions of ROCK, serum response factor (SRF), and alpha-smooth muscle actin (alpha-SMA) were observed by confocal laser scanning microscopy. The protein expression of ROCK, SFR, alpha-SMA, and type I and type III collagen in pulmonary fibroblasts was measured by Western blot. The mRNA expression of ROCK, SFR, and alpha-SMA was measured by real-time quantitative PCR. RESULTS: Compared with the control group, the pulmonary fibroblasts stimulated by TGF-beta1 had a lot of alpha-SMA antibody-labeled myofilaments in parallel or cross arrangement, as observed by confocal laser scanning microscopy, and the mRNA and protein expression of ROCK, SRF, and alpha-SMA and protein expression of type I and type III collagen increased significantly after 6, 12, and 24 h of stimulation (P < 0.05). Compared with the TGF-beta1-induced differentiation group, the Y-27632 treatment group and Ac-SDKP treatment group had significantly decreased mRNA and protein expression of ROCK, SRF, and alpha SMA and protein expression of type I and type III collagen at the same time point (P < 0.05). CONCLUSION: Ac-SDKP can inhibit the differentiation of pulmonary fibroblasts into myofibroblasts and the synthesis of collagen in rats by regulating the ROCK pathway mediated by TGF-beta1. That may be one of the mechanisms by which Ac-SDKP acts against (silicotic) pulmonary fibrosis. PMID- 24064120 TI - [Changes of centrosome and related protein in malignant transformation of BEAS-2B cell induced by coal tar pitch smoke extracts]. AB - OBJECTIVE: To analyze the centrosome abnormalities in the malignant transformation of human bronchial epithelial cells (BEAS-2B) induced by coal tar pitch smoke extracts and to investigate the role and action mechanism of centrosome in the lung cancer induced by coal tar pitch. METHODS: Medium temperature coal tar pitch smoke extracts were used to treat immortalized human bronchial epithelial cells (BEAS-2B) and establish a malignant transformation model. The treated BEAS-2B cells were used as exposure group, and solvent control group and normal control group were also set for passage culture. The changes of centrosome in BEAS-2B cells seeded on coverslips were evaluated by indirect immunofluorescence assay. The mRNA expression of p53, p21, and cyclin E in BEAS 2B cells was measured by real-time quantitative RT-PCR, and their protein levels in BEAS-2B cells seeded on coverslips were measured by semiquantitative immunohistochemical analysis. RESULTS: The overall rate of centrosome abnormalities in BEAS-2B cells at passage 20 was 6.56+/-1.01% in the exposure group, significantly higher than those in the normal control group (3.40+/-0.86%) and solvent control group (3.14+/-0.59%) (P < 0.05). In addition, the exposure group had a significantly higher overall rate of centrosome abnormalities in BEAS 2B cells at passage 30 compared with the normal control group and solvent control group (22.39+/-9.5% vs 4.34+/-1.04%, P < 0.05; 22.39+/-9.5% vs 4.33+/-1.20%, P < 0.05). Compared with the normal control group and solvent control group, the exposure group had significantly decreased mRNA and protein expression of p53 and significantly increased mRNA and protein expression of cyclin E in BEAS-2B cells at passages 20 and 30 (P < 0.05). CONCLUSION: Centrosome abnormalities occur before the malignant transformation in BEAS-2B cells treated with coal tar pitch smoke extracts, and they may be mediated by the p53/p21/cyclin E signaling pathway. PMID- 24064121 TI - [Two family members all elevated blood lead the investigation]. PMID- 24064122 TI - [Value of arterial lactic acid and buffer excess in predicting the prognosis of patients with paraquat poisoning]. AB - OBJECTIVE: To investigate the early prognostic values of arterial lactate and base excess (BE) in patients with paraquat poisoning. METHODS: Seventy-five patients with paraquat poisoning were divided into sudden death group (n = 10) who died within 24 h after admission, recent death group (n = 31) who died more than 24 h after admission, and survival group (n = 34). Arterial lactate and BE were measured on admission and at 24 h after admission. The prognostic values of arterial lactate and BE were analyzed. RESULTS: The arterial lactate measured on admission was significantly higher in the sudden death group than in the recent death group and survival group (P < 0.01), but there was no significant difference in arterial lactate between the recent death group and survival group (P = 0.309). The BE measured on admission was significantly lower in the sudden death group than in the recent death group and survival group, and it was significantly lower in the recent death group than in the survival group (P < 0.01 or P < 0.05). At 24 h after admission, the recent death group had a significantly higher arterial lactate (P < 0.01) and a significantly lower BE (P < 0.01), as compared with the survival group. The logistic regression analysis showed that the two indices were significantly associated with prognosis (P < 0.01). On admission, the areas under the receiver operating characteristic (ROC) curve (AUCs) of arterial lactate and BE for predicting death were 0.692 and 0.787, respectively, and the cut-off values were 3.25 mmol/L and -1.75 mmol/L, respectively; the AUCs of arterial lactate and BE for predicting sudden death were 0.995 and 1, respectively, and the cut-off values were 7.1 mmol/L and -12.8 mmol/L, respectively. At 24 h after admission, the AUCs of arterial lactate and BE for predicting death were 0.743 and 0.822, respectively, and the cut-off values were 2.15 mmol/L and -5.55 mmol/L, respectively. CONCLUSION: Arterial lactate and BE have certain values in predicting the death, especially the sudden death, in patients with acute paraquat poisoning. PMID- 24064123 TI - [Effect of tube voltage on digital chest radiograph for phantom and occupational exposed workers]. AB - OBJECTIVE: To explore the image quality of different tube voltage on digital chest radiograph for contrast detail phantom (CDRAD2.0) and occupational exposed workers. METHODS: The CDRAD2.0 phantom DR images of high KV and different tube voltages were analyzed by 3 readers, image quality figure (IQF) were calculated and compared; at the same time 136 exposed workers were examined with high-kV and DR chest radiograph of different tube voltages. Contrast to high-KV images, 10 anatomic sites were scored .The image differences were compared between DR and high-kV. RESULTS: On CDRAD2.0 phantom, the IQF value of DR images in 3 readers were minimum in the condition of 120 kV, average value was 22.25. The analysis of variance in model with random effects, the mean IQF value of different tube voltage DR image had a significant difference (F = 13.775, P<0.01); By Dunnett t tests analysis, the mean IQF value of DR image in 120 kV and high kilovoltage had no difference (t = -0.58, P = 0.979); On clinical cases, the DR image of 120 kV showed the closest anatomy to the high KV, the mean had no significant difference with 0 (P > 0.05) with single sample t test. CONCLUSION: On the CDRAD2.0 phantom or clinical exposed workers, the DR image quality of 120 kV tube voltage equals to high-KV basically. PMID- 24064125 TI - [The long-term therapeutic effects of silicosis by repeat the whole lung lavage]. AB - OBJECTIVE: To preliminary study the long term therapeutic effects of repeat the whole lung lavage (RWLL) in the treatment of silicosis. METHODS: A total of 60 patients with silicosis in the same stone mine were randomly and equally divided into repeat the whole lung Lavage (RWLL) group and whole lung Lavage (WLL) group based on silicosis staging, age and working age of dust exposure. Comparative analysis was performed to evaluate the long-term therapeutic efficacy and safety of RWLL. The cell count and SiO2 content were measured in twice right lung bronchoalveolar lavage fluid(BALF) of the RWLL group. RESULTS: Four years after treatment, the cough and asthma improvement rates of the RWLL group were 68.4% and 75.0% higher than those (52.4%and 57.9%) of the WLL group (P > 0.05). Six years after treatment, the asthma improvement rate (70.0%) of the RWLL group was significantly higher than that (36.8%) of the WLL group (P < 0.05). The RWLL group showed slight decrease in forced vital capacity (FVC) and forced expiratory volume in one second (FEV1.0) after treatment (P > 0.05), while the WLL group showed significant decrease in FVC and FEV1.0 in the six years after treatment (P<0.05). Four and Six years after treatment, the RWLL group had higher no change rate and lower progression rate and significant progression rate than the WLL group in terms of chest X-ray (P>0.05). In the RWLL group,the first time the right lung BALF test showed a number of cells 6.71*10(7)~2.14*10(9)/L, average 4.50*10(8)/L, pulmonary alveoli macrophages (PAM) ratio of 0.873~0.980, average 0.954 and SiO2 content of 18~104.7 mg, average 93.7 mg; the second test showed a number of cells 5.71*10(6)~1.30*10(9)/L, average 9.12*10(7)/L; PAM ratio 0.710~0.926, average 0.870 and SiO2 content of 6~90.2 mg, average 46.2 mg. The RWLL group happened hemoptysis, chest pain one case in perioperative period, the incidence of 6.7%. The RWLL group complicated by left pneumothorax, pulmonary infection one case and the WLL group complicated by one case of lung cancer in a year of follow-up. CONCLUSION: RWLL is reasonable and safe treatment which could help to further improve the long-term effects of WLL for silicosis. PMID- 24064124 TI - [Experimental treatment of pulmonary interstitial fibrosis with human umbilical cord blood mesenchymal stem cells]. AB - OBJECTIVE: To investigate the therapeutic effect and possible action mechanism of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) in the treatment of bleomycin-induced pulmonary fibrosis in rats. METHODS: The second generation of hUCB-MSCs was cultured to the fourth generation. Sixty healthy male Sprague Dawley rats (clean grade) were randomly and equally divided into 4 groups: bleomycin group, stem cell treatment group, dexamethasone treatment group, and negative control group. A pulmonary fibrosis model was established by intratracheal instillation of bleomycin in the bleomycin group, stem cell treatment group, and dexamethasone treatment group. The stem cell treatment group was injected with stem cells labeled with 5-bromo-2-deoxyuridine (Brdu) via the caudal vein immediately after the model was established. The dexamethasone treatment group was intraperitoneally injected with dexamethasone for 7 d from the next day after the model was established. The negative control group was given an equal volume of normal saline by intra-tracheal instillation. In each group, 5 rats were sacrificed in the 7th, 14th, and 28th days. The expression of transforming growth factor beta1 (TGF-beta1) and Brdu-labeled stem cells were observed by HE and Masson staining and immunohistochemistry. Lung hydroxyproline content was determined by acid hydrolysis. RESULTS: The stem cell treatment groups had Brdu-labeled stem cells seen in lung tissue in the 7th, 14th, and 28th days. Compared with the negative control group, the bleomycin group, stem cell treatment group, and dexamethasone treatment group had significantly increased scores of alveolitis and pulmonary fibrosis (P < 0.05). In the 7th, 14th, and 28th days, the scores of alveolitis in stem cell treatment group and dexamethasone treatment group were significantly lower than those in bleomycin group (P < 0.05); in the 28th day, the scores of pulmonary fibrosis in stem cell treatment group and dexamethasone treatment group were significantly lower than that in bleomycin group (P < 0.05). There were no significant differences in scores of alveolitis and pulmonary fibrosis between the dexamethasone treatment group and stem cell treatment group (P > 0.05). Compared with the bleomycin group, the stem cell treatment group and dexamethasone treatment group had significantly decreased number of TGF-beta1-positive cells and hydroxyproline content in lung tissue at all time points (P < 0.05). There were no significant differences in number of TGF-beta1-positive cells and hydroxyproline content in lung tissue between the stem cell treatment group and dexamethasone treatment group (P > 0.05). CONCLUSION: hUCB-MSCs can be transplanted into damaged lung tissue and effectively reduce alveolitis and pulmonary fibrosis in the early stage of pulmonary fibrosis. The action mechanism of hUCB-MSCs may involve inhibiting the expression of TGF-beta1 and reducing the formation of collagen. PMID- 24064126 TI - [Current situation of awareness and use of banned pesticides among vegetable greenhouse farmers in a town of Ledu County, China]. AB - OBJECTIVE: To investigate the awareness and use of banned pesticides among vegetable greenhouse farmers in a town of Ledu County, Qinghai Province, China and to provide a basis for the management and control of banned pesticides. METHODS: Local residents who lived in a town of Ledu County for more than 5 years were selected as subjects in August 2012. A questionnaire survey was conducted in 267 vegetable greenhouse farmers who were selected from five villages of the town by cluster random sampling. RESULTS: Of the 267 subjects, 249 (93.26%) completed and returned the questionnaires. Eighty-seven (34.9%) of the 249 subjects were aware of banned pesticides, and the banned pesticide awareness rate varied significantly among the subjects with different education levels (chi(2) = 11.061, P = 0.011). Only education level entered the regression equation in non conditional logistic regression analysis. Only five (2.0%) of the 249 subjects knew the banned pesticides as well as the details. All the 249 subjects used banned pesticides to varying degrees in the past 5 years. Only 9.0% (17/189) of the vegetable greenhouse farmers knew the time pesticides were initially banned in China. CONCLUSION: The banned pesticide awareness rate is relatively low in the town of Ledu County, and this rate is influenced by education level. It is needed to spread the knowledge and hazards of banned pesticides. PMID- 24064127 TI - [Results of miner's health check in coal mine]. PMID- 24064128 TI - [Study on the morbidity of pneumoconiosis complicated with pulmonary tuberculosis in coal miners of a city]. PMID- 24064129 TI - [Study of genotoxicity and oxidative stress induced by copper oxide nanoparticles in mice]. AB - OBJECTIVE: To investigate the genotoxicity and oxidative stress induced by copper oxide nanoparticles in mice. METHODS: Thirty mice were randomly divided into control group and low- and high-dose exposure groups. The low- and high-dose exposure groups were given copper oxide nanoparticles (50 and 150 mg/kg) by a single intraperitoneal injection, while the control group was given an equal volume of normal saline containing 0.05%Tween 80. The micronucleus rate of reticulocytes in peripheral blood from the caudal vein and urinary 8-hydroxy deoxyguanosine (8-OH-dG) level were measured before and at 24, 48, and 72 h after exposure. All the mice were sacrificed at 72 h after exposure, the liver, kidney, and femoral marrow were taken for DNA extraction, and 8-OH-dG in DNA was quantified. RESULTS: The micronucleus rates of peripheral blood reticulocytes in low-dose exposure group at 48 h (3.11+/-1.460/00 and in high-dose exposure group at 24 and 48 h (4.25+/-0.43) and 5.42+/-0.760/00) were significantly increased compared with those before exposure (1.55+/-0.390/00 and 1.11+/-0.190/00) and those in control group (1.55+/-0.280/00 and 1.00+/-0.670/00) (P < 0.05 or P < 0.01). The urinary 8-OH-dG levels (ng/mg creatinine) in low- and high-dose exposure groups at all time points were significantly increased compared with those before exposure and those in control group (P < 0.05 or P < 0.01). The low- and high-dose exposure groups had significantly higher content of 8-OH-dG in liver DNA than the control group (4.53+/-1.27 and 7.69+/-2.78 vs 0.85+/-0.14, P < 0.01). CONCLUSION: Copper oxide nanoparticles cause genotoxicity and increase oxidative stress in mice. PMID- 24064130 TI - [Effects of ozone exposure on percentage of CD4(+)CD25(high)Foxp(3+) regulatory T cells and mRNA expression of Foxp3 in asthmatic rats]. AB - OBJECTIVE: To investigate the effects of low-concentration ozone exposure on the percentage of CD4(+)CD25(high)Foxp(3+) regulatory T cells and the mRNA expression of transcription factor Foxp3 in asthmatic rats. METHODS: Sixty male Wistar rats were randomly divided into 4 groups (n = 15 for each): normal control group, ovalbumin (OVA) exposure group, ozone exposure group, and OVA+ozone exposure group. The OVA exposure group was sensitized and challenged with OVA to establish an asthma model; the normal control group inhaled aerosolized saline; the ozone exposure group inhaled low-concentration ozone; the OVA+ozone exposure group inhaled low-concentration ozone before being challenged with aerosolized OVA every day. The percentage of CD4(+)CD25(high)Foxp(3+) regulatory T cells in CD4(+) T cells was determined by flow cytometry. The levels of interferon-gamma (INF-gamma) and interleukin 4 (IL-4) in peripheral blood and lung tissue were measured by enzyme-linked immunosorbent assay. The mRNA expression of Foxp3 in lung tissue was measured by PCR. RESULTS: The percentages of CD4(+)CD25(high)Foxp(3+) regulatory T cells in OVA exposure group (6.12+/-1.03%) and ozone exposure group (5.87+/-1.26%) were significantly lower than that in normal control group (9.85+/-1.34%), and the percentage of CD4(+)CD25(high)Foxp(3+) regulatory T cells in OVA+ozone exposure group (3.31+/ 0.85%) was significantly lower than those in normal control group and OVA exposure group (P < 0.01). The levels of IL-4 in plasma and lung tissue in OVA exposure group (plasma: 21.83+/-5.12 ng/L; lung tissue: 0.89+/-0.13 ng/L) were significantly higher than those in normal control group (plasma: 10.58+/-2.73 ng/L; lung tissue: 0.32+/-0.11 ng/L) (P < 0.01). The levels of IL-4 in plasma and lung tissue in OVA+ozone exposure group (plasma: 35.47+/-7.24 ng/L; lung tissue: 1.50+/-0.42 ng/L) were significantly higher than those in normal control group and OVA exposure group (P < 0.01). The levels of INF-gamma in plasma and lung tissue in OVA exposure group (plasma: 61.78+/-23.45 ng/L; lung tissue: 0.69+/ 0.21 ng/L] were significantly lower than those in normal control group [plasma: 158.89+/-60.23 ng/L; lung tissue: 1.86+/-0.29) (P < 0.01). The levels of INF gamma in plasma and lung tissue in OVA+ozone exposure group (plasma: 10.28+/-2.63 ng/L; lung tissue: 0.41+/-0.12 ng/L) were significantly lower than those in normal control group and OVA exposure group (P < 0.01). The mRNA expression of Foxp3 was significantly lower in the OVA+ ozone exposure group than in the normal control group (P < 0.05). CONCLUSION: Low-concentration ozone exposure may decrease the number of CD4(+)CD25(high)Foxp(3+) regulatory T cells and inhibit the mRNA expression of Foxp3 to promote Th1/Th2 imbalance in asthmatic rats, suggesting that ozone exposure may be one of factors that induce asthma attack. PMID- 24064131 TI - [The clinical pathological analysis of 14 autopsy cases of pneumoconiosis]. AB - OBJECTIVE: To investigate the histopathological features, complications, diagnosis, and differential diagnosis of coal workers' pneumoconiosis (CWP). METHODS: The lung tissue sections from 14 autopsy cases of CWP were subjected to HE staining and observed under a light microscope, and a retrospective analysis was performed considering the occupational history and clinical features. RESULTS: The 14 cases were 46-71 years of age (mean, 57.7 years). Two cases were diagnosed as dust reaction, 1 case as simple CWP (stage I anthracosilicosis), and 11 cases as complicated CWP (9 cases of stage II anthracosilicosis, 1 case of stage III anthracosilicosis, and 1 case of stage III silicosis). Twelve cases were complicated by chronic bronchitis and emphysema, 8 cases by pulmonary heart disease, 4 cases by pulmonary tuberculosis, 3 cases by liver cirrhosis and liver cancer with pulmonary metastases, and 2 cases by cerebral hemorrhage. CONCLUSION: Among patients with CWP, the pathological changes of lung tissue become more complex with increasing years of dust exposure. Coal macule is the common pathological feature of CWP, and dust nodules and massive fibrosis are the necessary indices of pathological diagnosis. PMID- 24064132 TI - [Drug resistance of imipenem-resistant Gram-negative bacilli in coal worker's pneumoconiosis chronic obstructive pulmonary disease patients with lower respiratory tract infection]. AB - OBJECTIVE: To investigate the drug resistance of imipenem-resistant (IR) Gram negative bacilli (GNB) in coal workers' pneumoconiosis (CWP)-chronic obstructive pulmonary disease (COPD) patients with lower respiratory tract infection (LRTI) and to provide a basis for clinical treatment. METHODS: Sixty-six strains of IR GNB were isolated from the sputum of CWP-COPD patients with LRTI, and the bacterial spectrum was investigated. The drug resistance of bacterial strains was studied by KB disk diffusion method. RESULTS: Among the 66 strains of IR-GNB, 29 (43.9%) were Pseudomonas aeruginosa, 17 (25.8%) were Acinetobacter baumannii, and 11 (16.7%) were Stenotrophomonas maltophilia. The drug sensitivity test showed that all bacteria had high drug resistance; Pseudomonas aeruginosa had a susceptibility rate higher than 50% to ciprofloxacin, polymyxin B, fosfomycin, and amikacin, Acinetobacter baumannii had a susceptibility rate higher than 55% to fosfomycin, polymyxin B, and cefoperazone/sulbactam, Stenotrophomonas maltophilia had a susceptibility rate higher than 50% to cotrimoxazole, ciprofloxacin, piperacillin/tazobactam, levofloxacin, polymyxin B, and cefoperazone/sulbactam, and Pseudomonas cepacia had a susceptibility rate higher than 50% to piperacillin/tazobactam, ciprofloxacin, cefoperazone/sulbactam, and polymyxin B. CONCLUSION: The main species of IR-GNB are such non-fermentative bacteria as Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia in CWP-COPD patients with LRTI. These bacteria have high drug resistance and are sensitive to only a limited range of antibiotics. PMID- 24064133 TI - [The effect of emergency hemoperfusion for the drug ingredients of acute hypnotic poisoning]. PMID- 24064134 TI - [A case report of Naja atra bitten poisoning in northern China]. PMID- 24064135 TI - [UV-Spectrophotometric determination of metronidazole in poisoned blood]. PMID- 24064136 TI - [Determination method for 17 pesticides in common in whole blood by gas chromatography coupled to mass spectrometry with solid-phase extraction sample cleanup]. AB - OBJECTIVE: To establish a method for simultaneous determination of 17 common pesticides in whole blood by solid phase extraction-gas chromatography-mass spectrometry (SPE-GC-MS). METHODS: Whole blood samples were treated by extraction with acetonitrile, and the obtained extract was cleaned up using an Oasis HLB SPE cartridge; pesticides were separated by GC and quantitatively analyzed by MS with selected ion monitoring. RESULTS: The concentrations of 17 pesticides in whole blood were 1.0-5.0 mg/L, and the recovery rate was 41.3-102.1%, with a relative standard deviation of less than 10%in most pesticides. The 17 pesticides showed a good linear relationship between concentration and peak area within 0.5-5.0 mg/L, with a correlation coefficient of 0.9945-0.9994. The limit of detection and limit of quantification were 0.02-0.05 mg/L and 0.05-0.09 mg/L, respectively. CONCLUSION: With this method, 17 pesticides in whole blood can be well separated and determined. This method has high sensitivity, accuracy, and precision and can be used for identification and quantification of multiple pesticides in blood samples. PMID- 24064137 TI - [The mechanism of paraquat poisoning]. PMID- 24064138 TI - [Nanoparticle exposure assessment and control in workplace]. PMID- 24064139 TI - [The mechanism and application of suppressive oligodeoxynucleotides on silica induced alveoli inflammation]. PMID- 24064140 TI - Identification and testing of early indicators for N leaching from urine patches. AB - Nitrogen leaching from urine patches has been identified as a major source of nitrogen loss under intensive grazing dairy farming. Leaching is notoriously variable, influenced by management, soil type, year-to-year variation in climate and timing and rate of urine depositions. To identify early indicators for the risk of N leaching from urine patches for potential usage in a precision management system, we used the simulation model APSIM (Agricultural Production Systems SIMulator) to produce an extensive N leaching dataset for the Waikato region of New Zealand. In total, nearly forty thousand simulation runs with different combinations of soil type and urine deposition times, in 33 different years, were done. The risk forecasting indicators were chosen based on their practicality: being readily measured on farm (soil water content, temperature and pasture growth) or that could be centrally supplied to farms (such as actual and forecast weather data). The thresholds of the early indicators that are used to forecast a period for high risk of N leaching were determined via classification and regression tree analysis. The most informative factors were soil temperature, pasture dry matter production, and average soil water content in the top soil over the two weeks prior to the urine N application event. Rainfall and air temperature for the two weeks following urine deposition were also important to fine-tune the predictions. The identified early indicators were then tested for their potential to predict the risk of N leaching in two typical soils from the Waikato region in New Zealand. The accuracy of the predictions varied with the number of indicators, the soil type and the risk level, and the number of correct predictions ranged from about 45 to over 90%. Further expansion and fine-tuning of the indicators and the development of a practical N risk tool based on these indicators is needed. PMID- 24064141 TI - Solar photo-Fenton mineralization of antipyrine in aqueous solution. AB - The mineralization of an aqueous solution of antipyrine (C11H12N2O), an emerging contaminant, using a solar photocatalytic oxidation process assisted with ferrioxalate was evaluated in a compound parabolic collector (CPC) pilot plant. Under the selected operating conditions ([H2O2] = 250 ppm, [Fe] = 14 ppm, pH = 2.7, and [(COOH)2.2H2O] = 80 ppm), 60% of TOC is removed just 5 min after treating an aqueous solution containing 50 ppm of antipyrine. The addition of oxalic acid up to a maximum concentration of 80 ppm significantly increases the mineralization rate during the first 15 min of the reaction. The synergism between the solar and dark H2O2/ferrioxalate process was quantified at 79%, calculated from the pseudo first-order mineralization rate constants. The operational costs due to the consumption of electrical energy, reagents and catalysts were calculated from the optimal conditions and compared with a novel sono-photocatalytic process using artificial UV-light. The results showed that the ferrioxalate-assisted solar photo-Fenton process was economically feasible, being able to achieve up to 60% mineralization with a total cost of 4.5 cent ?/g TOC removed (1.1 ?/m(3)). PMID- 24064142 TI - Assessment of soil pollution based on total petroleum hydrocarbons and individual oil substances. AB - Different oil products like gasoline, diesel or heavy oils can cause soil contamination. The assessment of soils exposed to oil products can be conducted through the comparison between a measured concentration and an intervention value (IV). Several national policies include the IV based on the so called total petroleum hydrocarbons (TPH) measure. However, the TPH assessment does not indicate the individual substances that may produce contamination. The soil quality assessment can be improved by including common hazardous compounds as polycyclic aromatic hydrocarbons (PAHs) and aromatic volatile hydrocarbons like benzene, toluene, ethylbenzene and xylenes (BTEX). This study, focused on 62 samples collected from different sites throughout The Netherlands, evaluates TPH, PAH and BTEX concentrations in soils. Several indices of pollution are defined for the assessment of individual variables (TPH, PAH, B, T, E, and X) and multivariables (MV, BTEX), allowing us to group the pollutants and simplify the methodology. TPH and PAH concentrations above the IV are mainly found in medium and heavy oil products such as diesel and heavy oil. On the other hand, unacceptable BTEX concentrations are reached in soils contaminated with gasoline and kerosene. The TPH assessment suggests the need for further action to include lighter products. The application of multivariable indices allows us to include these products in the soil quality assessment without changing the IV for TPH. This work provides useful information about the soil quality assessment methodology of oil products in soils, focussing the analysis into the substances that mainly cause the risk. PMID- 24064144 TI - A bioinformatics-based update on microRNAs and their targets in rainbow trout (Oncorhynchus mykiss). AB - MicroRNAs (miRNAs) participate in various vitally biological processes via controlling target genes activity and thousands of miRNAs have been identified in many species to date, including 18,698 known animal miRNA in miRBase. However, there are only limited studies reported in rainbow trout (Oncorhynchus mykiss) especially via the computational-based approaches. In present study, we systematically investigated the miRNAs in rainbow trout using a well-developed comparative genome-based homologue search. A total of 196 potential miRNAs, belonging to 124 miRNA families, were identified, most of which were firstly reported in rainbow trout. The length of miRNAs ranged from 17 to 24 nt with an average of 20 nt while the length of their precursors varied from 47 to 152 nt with an average of 85 nt. The identified miRNAs were not evenly distributed in each miRNA family, with only one member per family for a majority, and multiple members were also identified for several families. Nucleotide U was dominant in the pre-miRNAs with a percentage of 30.04%. The rainbow trout pre-miRNAs had relatively high negative minimal folding free energy (MFE) and adjusted MFE (AMFE). Not only the mature miRNAs but their precursor sequences are conserved among the living organisms. About 2466 O. mykiss genes were predicted as potential targets for 189 miRNAs. Gene Ontology (GO) analysis showed that nearly 2093, 2107, and 2081 target genes are involved in cellular component, molecular function, and biological processes respectively. KEGG pathway enrichment analysis illuminated that these miRNAs targets might regulate 105 metabolic pathways, including those of purine metabolism, nitrogen metabolism, and oxidative phosphorylation. This study has provided an update on rainbow trout miRNAs and their targets, which represents a foundation for future studies. PMID- 24064143 TI - Effect of a GFOD2 variant on responses in total and LDL cholesterol in Mexican subjects with hypercholesterolemia after soy protein and soluble fiber supplementation. AB - BACKGROUND: Although dietary treatments can successfully reduce blood lipids in hypercholesterolemic subjects, individual variation in that response has on occasion been linked to allelic differences. SNP rs12449157 has shown association with HDL-C concentrations in GWAS and falls in the glucose-fructose oxidoreductase domain containing 2 (GFOD2) locus. Of interest, previous data suggest that this SNP may be under environmentally driven selection. Thus, the aim of this study was to assess if rs12449157 may mediate the response of lipid traits to a dietary supplementation (DS) with soy protein and soluble fiber in a Mexican population with hypercholesterolemia. METHODS: Forty-one subjects with hypercholesterolemia were given a low saturated fat diet (LSFD) for 1 month, followed by a LSFD+DS that included 25 g of soy protein and 15 g of soluble fiber (S/SF) daily for 2 months. Anthropometric, clinical, biochemical and dietary variables were determined. We analyzed the gene-diet interaction between the GFOD2 genotype, with the minor allele frequency of 0.24, and the DS on total cholesterol (TC) and LDL-C concentrations. RESULTS: Hypercholesterolemic subjects with GFOD2 rs12449157 G allele had higher serum TC and LDL-C at the baseline and showed a greater response to the LSCD+S/SF (-83.9 and -57.5mg/dl, respectively) than those with GFOD2 AA genotype (-40.1 and -21.8 mg/dl, respectively) (P=0.006 for TC, 0.025 for LDL-C, respectively). CONCLUSION: The observed differences in allele-driven, diet-induced changes in blood lipids may be the result of a recent environmentally driven selection on the rs12449157 minor allele. Variation in the GFOD2 gene contributes to the genetic basis for a differential response to a cholesterol- or lipid-lowering diet. PMID- 24064145 TI - Cloning, distribution and effects of fasting status of melanocortin 4 receptor (MC4R) in Schizothorax prenanti. AB - Melanocortin 4 receptor (MC4R) has an important role in the regulation of energy homeostasis in both mammals and fish. In this study, MC4R was characterized in S. prenanti (Schizothorax prenanti) and designated as SpMC4R. SpMC4R cDNA is composed of 1004 nucleotides with a 978 nucleotide open reading frame encoding a protein of 326 amino acids. The SpMC4R contained predicted regions that were structural features of MCR subtypes of vertebrates. In addition, phylogenetic analyses suggested that S. prenanti MC4R was closely related to fish MC4Rs. The SpMC4R mRNA was detected in embryos at developmental stages. Further, its mRNA was detectable in unfertilized eggs. Using real-time RT-PCR, MC4R is widely expressed, with highest levels of expression in brain and ovary. An experiment was conducted to determine the expression profile of MC4R during short-term and long-term fasting of the brain. The expression level of MC4R in unfed fish was significantly increased at 6, 9 and 24h post-fasting (hpf) and 14days fasting than in fed fish, this suggests that MC4R is conserved peptide that might be involved in the regulation of food intake and other physiological function in S. prenanti. PMID- 24064146 TI - [Interposition of the small intestine between the colon and the rectum as a way of achieving a pelvic anastomosis without pressure]. AB - PURPOSE: There are some circumstances in which the descending colon does not reach the pelvis to complete a colorectal anastomosis without tension. Re establishing intestinal continuity by interposing small bowel as a bridge between the colon and the rectum could be an acceptable surgical alternative. METHODS: We describe the interposition of one or two segments of small bowel as a way of restoring continuity of the colon and rectum in three patients in whom it was not possible to perform a colorectal anastomosis without tension due to ischaemic colon, synchronous cancer or difficulty in accessing the supramesocolic space, respectively. RESULTS: Intestinal continuity was re-established in all patients with no significant morbidity and good intestinal function. CONCLUSION: The interposition of small bowel segments between the colon and the rectum should be considered a valid surgical option when it is not possible to achieve a well perfused, tension-free pelvic colorectal anastomosis. PMID- 24064147 TI - [Giant pelvic hibernoma]. PMID- 24064149 TI - Two members of the Ustilago maydis velvet family influence teliospore development and virulence on maize seedlings. AB - Members of the fungal-specific velvet protein family regulate sexual and asexual spore production in the Ascomycota. We predicted, therefore, that velvet homologs in the basidiomycetous plant pathogen Ustilago maydis would regulate sexual spore development, which is also associated with plant disease progression in this fungus. To test this hypothesis, we studied the function of three U. maydis velvet genes, umv1, umv2 and umv3. Using a gene replacement strategy, deletion mutants were made in all three genes in compatible haploid strains, and additionally for umv1 and umv2 in the solopathogenic strain, SG200. None of the mutants showed novel morphological phenotypes during yeast-like, in vitro growth. However, the Deltaumv1 mutants failed to induce galls or teliospores in maize. Chlorazol black E staining of leaves infected with Deltaumv1 dikaryons revealed that the Deltaumv1 hyphae did not proliferate normally and were blocked developmentally before teliospore formation. The Deltaumv2 mutants were able to induce galls and teliospores in maize, but were slow to do so and thus reduced in virulence. The Deltaumv3 mutants were not affected in teliospore formation or disease progression. Complementation of the Deltaumv1 and Deltaumv2 mutations in the SG200 background produced disease indices similar to those of SG200. These results indicate that two U. maydis velvet family members, umv1 and umv2, are important for normal teliospore development and disease progression in maize seedlings. PMID- 24064148 TI - The promotion of mandibular defect healing by the targeting of S1P receptors and the recruitment of alternatively activated macrophages. AB - Endogenous signals originating at the site of injury are involved in the paracrine recruitment, proliferation, and differentiation of circulating progenitor and diverse inflammatory cell types. Here, we investigate a strategy to exploit endogenous cell recruitment mechanisms to regenerate injured bone by local targeting and activation of sphingosine-1-phosphate (S1P) receptors. A mandibular defect model was selected for evaluating regeneration of bone following trauma or congenital disease. The particular challenges of mandibular reconstruction are inherent in the complex anatomy and function of the bone given that the area is highly vascularized and in close proximity to muscle. Nanofibers composed of poly(DL-lactide-co-glycolide) (PLAGA) and polycaprolactone (PCL) were used to delivery FTY720, a targeted agonist of S1P receptors 1 and 3. In vitro culture of bone progenitor cells on drug-loaded constructs significantly enhanced SDF1alpha mediated chemotaxis of bone marrow mononuclear cells. In vivo results show that local delivery of FTY720 from composite nanofibers enhanced blood vessel ingrowth and increased recruitment of M2 alternatively activated macrophages, leading to significant osseous tissue ingrowth into critical sized defects after 12 weeks of treatment. These results demonstrate that local activation of S1P receptors is a regenerative cue resulting in recruitment of wound healing or anti-inflammatory macrophages and bone healing. Use of such small molecule therapy can provide an alternative to biological factors for the clinical treatment of critical size craniofacial defects. PMID- 24064152 TI - Partial anomalous pulmonary vein connection in a 15-year-old patient. PMID- 24064150 TI - Birth status, child growth, and adult outcomes in low- and middle-income countries. AB - OBJECTIVE: To assess the impact of being born preterm or small for gestational age (SGA) on several adult outcomes. STUDY DESIGN: We analyzed data for 4518 adult participants in 5 birth cohorts from Brazil, Guatemala, India, the Philippines, and South Africa. RESULTS: In the study population, 12.8% of males and 11.9% of females were born preterm, and 26.8% of males and 22.4% of females were born term but SGA. Adults born preterm were 1.11 cm shorter (95% CI, 0.57 1.65 cm), and those born term but SGA were 2.35 cm shorter (95% CI, 1.93-2.77 cm) compared with those born at term and appropriate size for gestational age. Blood pressure and blood glucose level did not differ by birth category. Compared with those born term and at appropriate size for gestational age, schooling attainment was 0.44 years lower (95% CI, 0.17-0.71 years) in those born preterm and 0.41 years lower (95% CI, 0.20-0.62 years) in those born term but SGA. CONCLUSION: Being born preterm or term but SGA is associated with persistent deficits in adult height and schooling, but is not related to blood pressure or blood glucose level in low- and middle-income settings. Increased postnatal growth is associated with gains in height and schooling regardless of birth status, but not with increases in blood pressure or blood glucose level. PMID- 24064151 TI - Use of magnetic resonance elastography to assess hepatic fibrosis in children with chronic liver disease. AB - Management of pediatric chronic liver disease is limited by lack of validated noninvasive biomarkers of histologic severity. We demonstrate that magnetic resonance elastography is feasible and accurate in detecting significant hepatic fibrosis in a case series of 35 children with chronic liver disease, including severely obese children. PMID- 24064153 TI - Self assembled homodinuclear dithiocarbamates: one pot synthesis and spectral characterization. AB - Several self assembled homodinuclear complexes of the type [M2(Ldtc)2.4H2O] derived from quadridentate ligand (Ldtc), where Ldtc = 2 aminobenzoylhydrazidebis(dithiocarbamate) and M = Mn(II), Fe(II), Co(II), Ni(II), Cu(II) and Zn(II) have been reported. The in situ procedure gives high yield with the formation of single product as evident by TLC and various other physicochemical techniques. Elemental analysis, TGA, (1)H NMR, (13)C NMR, ESI mass spectrometry, EPR, UV-vis. and IR spectroscopy were used to characterize the homodinuclear complexes. The spectroscopic evidences and room temperature magnetic moment values suggest that all the complexes have octahedral geometry around the transition metal atom. A symmetrical bidentate coordination of the dithiocarbamato moiety has been observed in all the complexes. The energy minimized structure of the molecule also showed that each metal atom acquires a distorted octahedral geometry. The complexes exhibit a three-step thermolytic pattern and are non-electrolyte in nature. PMID- 24064154 TI - How to read a citation: contemplating the meanings of references in scientific papers. PMID- 24064155 TI - Developing a road map for success in esthetics. PMID- 24064156 TI - Universal materials--do they really exist? PMID- 24064157 TI - Management of a 3-canal mandibular premolar in a patient with unusual root canal anatomy in all mandibular premolars. AB - Endodontic treatment of mandibular premolars can be difficult due to their aberrant root canal anatomy. Successful nonsurgical root canal treatment requires knowledge of basic root and root canal morphology, and possible anatomical variations of the root canal system. Mandibular second premolars usually have a single root and a single canal, and the presence of 3 canals in separate roots is very rare. Nonsurgical endodontic treatment of such teeth is a challenge. This article presents a rare case of a mandibular second premolar with 3 root canals in separate roots and its endodontic management, with a special emphasis on radiographic interpretation and access refinement during treatment. PMID- 24064158 TI - Influence of periodontal biotype on the presence of interdental papillae. AB - The absence of interdental papillae can be a negative influence in aesthetics. Periodontal biotype (PB) is one of the factors that can possibly influence this relation and has to be considered in periodontal diagnosis and treatment planning. The objective of this study was to evaluate the influence of the periodontal biotype on the presence and absence of interdental papillae. Forty seven patients were included in this transversal clinical study. The PB, presence and height of interdental papilla, loss of papillary height, and the distance between the base of the contact point and bone crest (CP-BC) were evaluated. The chi-square test was used to verify the significance level of the PB distribution frequency between groups. The Mann-Whitney test was used to compare the CP-BC measures between the different PB groups, and the correlation test was used to verify the relation between the CP-BC distance and the presence of papillae. The thin PB group presented a significantly higher presence of papillae (71.1%) than did the thick PB group (59.6%, P < 0.05). An inverse and proportional correlation between the CP-BC distance and the presence of papillae was found. The authors concluded that the PB influenced the presence and height of interdental papillae. PMID- 24064159 TI - A randomized controlled clinical trial evaluating the effectiveness of an external mandibular support device during dental care for patients with temporomandibular disorders. AB - This study tested a jaw support device for patients receiving dental care while suffering from temporomandibular joint pain. This crossover randomized trial used 31 subjects with jaw pain. Subjects underwent 2 consecutive dental scaling sessions of 30 minutes each. For each subject, the device was used for 1 of the sessions. Subjects completed questionnaires regarding jaw pain and jaw fatigue before and after each session. Multivariate analyses were performed to assess the device's effectiveness in preventing the aggravation of pain and fatigue during dental treatment. Statistically significant differences were found for jaw pain (P = 0.001), and fatigue (P = 0.04), indicating the effectiveness of the device. Based on the results, supporting the mandible of patients with temporomandibular disorders during dental treatments may prevent further pain. PMID- 24064160 TI - Bilateral lymphoepithelial cyst of the tongue: a case report. AB - A lymphoepithelial cyst (LC) is a rare occurrence in the oral cavity, lined by a keratinized stratified squamous epithelium that is surrounded by diffuse lymphoid tissue, that often contains lymphoid follicles. The clinical aspect of oral LC includes an asymptomatic yellowish nodule (less than 10 mm) with regular surface and soft consistency. It usually affects the floor of the mouth and the ventral and posterolateral surfaces of the tongue in adult male patients. To date, approximately 280 cases of LC in the oral cavity have been reported in the literature; however, none of them appear bilaterally. This article presents the histopathological and immunohistochemical findings of a unique bilateral LC in the posterolateral region of the tongue. PMID- 24064161 TI - Effects of mixing technique on bubble formation in alginate impression material. AB - Previous studies have found that variations in mixing technique can influence the porosity content of alginate impression material. The aim of this study was twofold: determine whether bubble formation in alginate is influenced by the sequence of water/powder addition prior to mixing, and to compare 4 different mixing techniques. Manual spatulation, an automated spinning bowl, a centrifugal mixer and a vacuum mixer were evaluated for the resulting porosity in the set alginate. It was found that adding powder first, versus water first, made no difference in the bubble content using the 3 automated mixing techniques (P = 0.714). However, porosity was significantly less for powder-first trials using manual spatulation (P < 0.05). It was also found that surface porosity in the resulting impressions was significantly less for centrifugal and vacuum mixing when compared to manual spatulation, while internal porosity was significantly less for centrifugal mixing compared to all other mixing techniques (P < 0.05). The centrifugal mixing and vacuum mixing techniques required the least amount of mixing time. PMID- 24064162 TI - Simple method for fabricating a cast partial framework obturator for lifelike appearance: a case report. AB - Defects can form after tumors in the maxillary region are resected surgically. Maxillofacial defects can affect a patient's physical, psychological, and social status. Surgery reduces the residual teeth and tissue's ability to provide optimal cross-arch support, stability, and retention. The design of the obturator can improve the esthetics of the prosthesis and give it a more lifelike appearance. This case report describes the fabrication of a cast metal framework design for a partial obturator prosthesis in a maxillectomy patient. PMID- 24064163 TI - Should acid etching be performed prior to nonvital bleaching? AB - This study sought to measure the microtensile bond strength of a nanofilled composite resin to human dentin after phosphoric acid etching followed by nonvital bleaching. Scanning electron microscopy was used to analyze fracture modes. Twenty extracted sound human maxillary premolars were prepared for Class I defects and assigned randomly to 4 groups (n = 5): Group 1 (control group) samples were unbleached and had no previous acid etching; Group 2 samples were bleached only, Group 3 samples were acid-etched for 15 seconds prior to bleaching, and Group 4 samples were acid-etched for 30 seconds prior to bleaching. There were no statistically significant differences of bond strength values among Groups 1-3; however, the mean values of Group 4 were statistically lower compared with the other groups. PMID- 24064164 TI - Coronal microleakage of 3 temporary filling materials used for endodontic treatment: an in vitro study. AB - Most root canal treatments are performed over multiple appointments. The temporary sealing material used between sessions must have sealing properties capable of preventing microleakage. This study assessed the degree of microleakage of temporary sealing materials according to time spent blocking the access cavity. Endodontic treatments with a standardized protocol were performed on 63 healthy, single-rooted, caries-free human teeth. The teeth were divided randomly into 5 groups. Groups 1-3 were each treated with 1 of 3 sealing materials, while Group 4 and 5 served as positive and negative controls, respectively. Data was obtained and analyzed with nonparametric tests (Kruskal Wallis and Chi-square). Results indicated statistically significant differences between materials and the degree of microleakage (P = 0.000). All 3 sealing materials allowed microleakage within 48 hours, with glass ionomer cement demonstrating the most microleakage. PMID- 24064165 TI - Comparative study of a wireless digital system and 2 PSP digital systems on proximal caries detection and pixel values. AB - This study compared the radiographic image quality of 2 photostimulable phosphor (PSP) plate systems with a radiographic system against a complementary metal oxide silicon (CMOS) system. Using the 3 digital systems, 160 approximal surfaces were radiographed under standardized conditions. Using a 5-point scale, 6 observers scored the resulting images for the presence of caries. The presence of caries was validated histologically, and the image receptors were evaluated using receiver operating characteristic curve analysis. The digital systems were used to take radiographs of an aluminum step wedge for objective analysis with pixel density measurements. The mean pixel values were analyzed statistically using the Kruskal-Wallis test and Dunn multiple comparison test (P < 0.01). The performance of the new CMOS system was comparable to the PSP plate systems and radiographic film. PMID- 24064166 TI - Management of phenytoin-induced gingival enlargement: a case report. AB - Gingival enlargements may adversely affect speech, mastication, tooth eruption, and esthetics. These enlargements can occur as a result of the administration of certain anticonvulsants, immunosuppressants, and calcium channel blockers. The present case report describes the treatment of a patient with a phenytoin-induced gingival enlargement. A case of gingival enlargement should be treated in a step wise manner, including consultation with the patient's physician, substitution of the drug, nonsurgical therapy, surgical therapy (if needed), and supportive periodontal therapy after every 3 months. In this case, healing was uneventful, and no recurrences occurred 3 months postoperatively. PMID- 24064167 TI - Surgical management of multiple myeloma in the mandible: a case report. AB - Multiple myeloma (MM), solitary bone plasmacytoma, and extramedullary plasmacytoma are different types of plasma cell neoplasia, which is a lymphoid neoplastic proliferation of beta-cells. While MM is most frequently seen in the vertebrae and long bones, 30% of MM cases are found in the jaws. This case report presents a 58-year-old man with mandibular swelling; his medical history indicated he had a fracture of the humerus 1 month earlier. Panoramic radiography revealed a radiolucent lesion in the mandibular posterior region. Biopsy was performed and the histopathological examination indicated plasmocytoma. However, given the patient's dental and medical history, and the presence of multiple osteolytic lesions, the final diagnosis was MM. The patient underwent chemotherapy for the MM. To treat the pathological fracture of the jaw, a hemimandibulectomy was followed by the installation of a reconstructive plate. PMID- 24064168 TI - Bond strength of resin cements to zirconia conditioned with primers. AB - New ceramic primers, which reportedly enhance bonding of resin cements to zirconia, have been marketed recently. The purpose of this study was to compare the shear bond strength of 3 resin cements to zirconia conditioned with 4 ceramic primers. Zirconia blocks were conditioned with 4 different primers (Z-Prime Plus, MonoBond Plus, CLEARFIL CERAMIC PRIMER, and AZ Primer) or no primer (control). The zirconia blocks were placed in a jig, and 1 of 3 resin cements (Multilink Automix, RelyX Unicem, Panavia F 2.0) were mixed, injected into a mold, and light cured. The specimens were tested in shear on a universal testing machine after 24 hours of storage in distilled water. The shear bond strength of the resin cements to zirconia varied based on the type of primer. Z-Prime Plus provided the highest shear bond strength to zirconia, and was significantly greater than the control (no primer) with all 3 resin cements. PMID- 24064169 TI - Alteration of lingual frenum. Intraoral syphilis. PMID- 24064170 TI - Giant cemento-ossifying fibroma of the mandible: a rare case. AB - The World Health Organization classifies cemento-ossifying fibroma (COF) as a fibro-osseous neoplasm included among the nonodontogenic tumors derived from the mesenchymal blast cells of the periodontal ligament, with a potential for forming fibrous tissue, cementum and bone, or a combination of such elements. These are slow-growing lesions, and are more frequent in women, between the third and fourth decades of life. Case reports of massive expansile COFs (measuring more than 10 cm) are rarely reported in the literature. This article aims to describe a case of giant cemento-ossifying fibroma with radiographic and 3D CT features in a 34 year old female patient, who came with the complaint of progressive swelling of the face which had started 6 years earlier. PMID- 24064171 TI - Clinical fractures of veneered zirconia single crowns. AB - Crowns made from an yttria-stabilized tetragonal zirconia polycrystals (3Y-TZP) core with a porcelain veneer have shown high clinical failure rates. Manifestations of clinical failure in veneering ceramic ranges from a single chip to an extended fracture. Core failures are uncommon but usually are catastrophic. This article examines the possible causes of failure in zirconia systems and presents a case report involving the diagnosis and repair of three different types of failure in six 3Y-TZP/porcelain crowns. PMID- 24064172 TI - Pigmented lesion with characteristics of malignancy: a case report. AB - Pigmentations of the oral mucosa include a range of lesions or conditions that manifest as changes in the color of oral tissues; these changes may show melanocytic activity. A melanotic macule is a small, well-circumscribed melanocytic benign lesion. It can occur on the lips and intraorally and ranges in color from brown to black. Microscopically, it is characterized by elevated levels of melanin production by basal melanocytes, which appear normal in terms of number, morphology, and distribution. A 48-year-old woman sought treatment for a pigmented lesion that had been present for 4 months. Intraoral examination revealed a non-homogenous brownish spot (measuring 0.7 cm) with irregular borders on the left side of the soft palate. Since the lesion had an atypical clinical appearance, melanocytic nevus, oral melanoacanthoma, and oral malignant melanoma were considered in differential diagnoses. After an incisional biopsy, the lesion was diagnosed as a melanotic macule. Due to their varying clinical appearance, benign pigmented lesions can be mistaken for malignant tumors, especially when the lesions exhibit similar coloration, symmetry, and borders. Through this report on a case with atypical clinical characteristics, we aim to reinforce the ubiquitous nature of oral pigmented lesions, and the importance of employing different approaches to diagnosing these lesions. PMID- 24064173 TI - Vertical ridge augmentation using sandwich osteotomy: 2 case reports. AB - The placement of dental implants in atrophic jaws is a challenging procedure due to inadequate bone quantity. This anatomic limitation can be overcome by various treatment methods such as onlay bone graft, inlay bone graft (known as sandwich osteotomy), and distraction osteogenesis. Two female patients with complaints of atrophic mandible were included in this study. Both patients were treated with a segmental mandibular sandwich osteotomy with interpositional grafts. This is called a sandwich osteotomy technique because a section of the jaw bone is separated from the main part and a bone graft is inserted between the 2 parts. The postoperative period was uneventful, and sufficient bone gain was obtained in both patients. Sandwich osteotomy is an effective technique to gain vertical bone height in atrophic jaws. PMID- 24064174 TI - A rare case of recurring calcifying epithelial odontogenic cyst in the maxillary sinus: a case report and literature review. AB - Calcifying epithelial odontogenic cyst (CEOC) is an odontogenic cyst with epithelial lining. CEOC is a rare entity that occurs in a wide age range, does not show any gender predilection, and accounts for only 1% of all jaw cysts. The lesion generally occurs in the region anterior to maxillary and mandibular molars and either intraosseously or extraosseusly. This entity might present as a cystic or solid lesion. Enucleation is the recommended treatment for a simple, unicystic CEOC. A case of recurring CEOC in the right maxilla antrum is presented here. The patient presented to the authors after postsurgical recurrence. The case was evaluated thoroughly, and the cyst was resolved. PMID- 24064175 TI - The absolute contraindication for using nitrous oxide with intraocular gases and other dental considerations associated with vitreoretinal surgery. AB - Nitrous oxide is absolutely contraindicated after vitreoretinal surgery that uses intraocular gas, as the mixture of gas and nitrous oxide can cause catastrophic vision loss. Professional awareness and communication are vital to prevent this iatrogenic complication. This case report identifies a side effect of vitreoretinal surgery with a benign outcome--specifically, a referred pain or pressure from left eye surgery or an associated gas bubble to the upper left quadrant. Such cases underscore the need for a dentist and staff to inquire about all ocular procedures to avoid patient vision loss due to nitrous oxide. Dentists should communicate with the patient's opthalmologist before proceeding with any dental procedure. PMID- 24064176 TI - Conservative treatment of an aggressive odontogenic tumor: a case report. AB - An ameloblastoma is a polymorphic, benign, locally invasive tumor made up of odontogenic epithelium, clinically characterized by slow, progressive, painless growth. There are reports in the literature on the treatment of ameloblastomas with aggressive mural invasion through resections, in order to minimize recurrence. However, different approaches may be used at the bone level, such as curettage combined with a chemical fixative (Carnoy's solution), cryotherapy, or thermal cauterization. The findings of this case report demonstrate that the use of Carnoy's solution following the enucleation of a unicysticameloblastoma with mural invasion may be a treatment alternative with a low rate of recurrence, as well as a reduced rate of postoperative complications, a reduction in costs, and preservation of both esthetics and function. PMID- 24064177 TI - Hospital washbasin water: risk of Legionella-contaminated aerosol inhalation. AB - The contamination of aerosols by washbasin water colonized by Legionella in a hospital was evaluated. Aerosol samples were collected by two impingement technologies. Legionella was never detected by culture in all the (aerosol) samples. However, 45% (18/40) of aerosol samples were positive for Legionella spp. by polymerase chain reaction, with measurable concentrations in 10% of samples (4/40). Moreover, immunoassay detected Legionella pneumophila serogroup 1 and L. anisa, and potentially viable bacteria were seen on viability testing. These data suggest that colonized hospital washbasins could represent risks of exposure to Legionella aerosol inhalation, especially by immunocompromised patients. PMID- 24064179 TI - Selective activation of the latissimus dorsi and the inferior fibers of trapezius at various shoulder angles during isometric pull-down exertion. AB - The aim of this study was to determine the effect of isometric pull down exercise on muscle activity with shoulder elevation angles of 60 degrees , 90 degrees , and 120 degrees and sagittal, scapular, and frontal movement planes, by electromyography (EMG) of the latissimus dorsi, inferior fibers of trapezius, and latissimus dorsi/inferior fibers of trapezius activity ratio. Fourteen men performed nine conditions of isometric pull down exercise (three conditions of shoulder elevation * three conditions of movement planes). Surface EMG was used to collect data from the latissimus dorsi and inferior fibers of trapezius during exercise. Two-way repeated analysis of variance with two within-subject factors (shoulder elevation angles and planes of movement) was used to determine the significance of the latissimus dorsi and inferior fibers of trapezius activity and latissimus dorsi/inferior fibers of trapezius activity ratio. The latissimus dorsi activity and ratio between the latissimus dorsi and the inferior fibers of trapezius were significantly decreased as shoulder elevation angle increased from 60 degrees to 120 degrees . The inferior fibers of trapezius activity was significantly increased with shoulder elevation angle. The EMG activity and the ratios were not affected by changes in movement planes. This study suggests that selective activation of the latissimus dorsi is accomplished with a low shoulder elevation angle, while the inferior fibers of the trapezius are activated with high shoulder elevation angles. PMID- 24064180 TI - The effectiveness of stretch-shortening cycling in upper-limb extensor muscles during elite cross-country skiing with the double-poling technique. AB - This investigation was designed to evaluate the effectiveness of stretch shortening cycling (SSC(EFF)) in upper-limb extensor muscles while cross-country skiing using the double-poling technique (DP). To this end, SSC(EFF) was analyzed in relation to DP velocity and performance. Eleven elite cross-country skiers performed an incremental test to determine maximal DP velocity (V(max)). Thereafter, cycle characteristics, elbow joint kinematics and poling forces were monitored on a treadmill while skiing at two sub-maximal and racing velocity (85% of V(max)). The average EMG activities of the triceps brachii and latissimus dorsi muscles were determined during the flexion and extension sub-phases of the poling cycle (EMG(FLEX), EMG(EXT)), as well as prior to pole plant (EMG(PRE)). SSC(EFF) was defined as the ratio of aEMG(FLEX) to aEMG(EXT). EMG(PRE) and EMG(FLEX) increased with velocity for both muscles (P < 0.01), as did SSC(EFF) (from 0.9 +/- 0.3 to 1.3 +/- 0.5 for the triceps brachii and from 0.9 +/- 0.4 to 1.5 +/- 0.5 for the latissimus dorsi) and poling force (from 253 +/- 33 to 290 +/ 36N; P < 0.05). Furthermore, SSC(EFF) was positively correlated to Vmax, to EMG(PRE) and EMG(FLEX) (P < 0.05). The neuromuscular adaptations made at higher velocities, when more poling force must be applied to the ground, exert a major influence on the DP performance of elite cross-country skiers. PMID- 24064181 TI - A preliminary descriptive analysis of Corneal Transplant Registry of National Eye Bank in India. AB - PURPOSE: To describe and analyze the Corneal Transplant Registry of National Eye Bank and also evaluate graft outcomes in India. METHODS: All patients who underwent corneal transplant at our center within six months of setting up of Corneal Transplant Registry and installation of database at National Eye Bank were included in the study. The established database was analyzed for utilization, donor and recipient details and graft outcomes. Outcome was assessed at the end of one year follow up. The influence of various donor and recipient factors affecting outcome were evaluated. Visual outcome was analyzed in terms of shift in visual handicap category. Statistical tests like analysis of variance, Kruskal-Wallis test and Chi square tests were applied for determination of clinical significance wherever required. RESULTS: 326 corneas were received from 168 donors; of these, 234 (71.7%) were utilized for transplantation. Out of 177 patients with adequate (one year) follow up (75.6% patients), optical corneal replacement was performed in106 patients and therapeutic keratoplasty in71. 78% (82/106) patients in the optical group retained clear grafts at the end of follow up. 59.7% (49 of 82) of patients who attained clear grafts belonged to visual disability category 3 or worse pre-operatively. 59.1% of these achieved BCVA of >=6/60 at the end of follow up; thus shifting up their visual handicap category. Primary graft failure was found to be associated with full thickness keratoplasty and not with lamellar procedures (p<0.05) and occurred in 4.2% patients (5) with optical corneal replacement whereas 7.5% patients (8) developed secondary graft failure. Age of donor (p=0.54), death enucleation time (p>0.05), cause of donor death (p=0.15), type of surgical procedures (p=0.538) and indication for surgery did not have any significant effect on outcome. 76% patients who underwent therapeutic graft achieved elimination of corneal infection. CONCLUSIONS: The development of corneal graft registry established an effective means to evaluate our corneal transplantation services. Outcomes of sight restoring corneal transplants performed were comparable to results of graft registries from developed nations. PMID- 24064182 TI - The Antipsychotics and Sexual Functioning Questionnaire (ASFQ): preliminary evidence for reliability and validity. AB - The aim of this study is to describe the psychometric properties of the Antipsychotics and Sexual Functioning Questionnaire (ASFQ). Internal reliability, test-retest reliability, inter-rater reliability, validity and sensitivity to change were calculated in a sample of 30 patients with schizophrenia or a schizophrenia spectrum disorder using antipsychotics. The ASFQ is a semistructured interview, with good face validity and content validity, that takes on average about 10min to complete. The ASFQ has good internal reliability (Cronbach's alpha 0.84) and good test-retest reliability (mean Spearman's rho=.76). The inter-rater reliability is good for questions about libido, orgasm, erection and ejaculation. Correlation coefficients for calculating convergent validity were modest to good when comparing the ASFQ with the corresponding items on the Subject's Response to Antipsychotics (SRA) questionnaire and the Arizona Sexual Experience Scale (ASEX). Based on preliminary evidence, it can be concluded that the Antipsychotics and Sexual Functioning Questionnaire has reasonable reliability and is available for clinical use and research. PMID- 24064183 TI - 5-HT1A receptor antagonists reduce food intake and body weight by reducing total meals with no conditioned taste aversion. AB - Serotonin acts through receptors controlling several physiological functions, including energy homeostasis regulation and food intake. Recent experiments demonstrated that 5-HT1A receptor antagonists reduce food intake. We sought to examine the microstructure of feeding with 5-HT1A receptor antagonists using a food intake monitoring system. We also examined the relationship between food intake, inhibition of binding and pharmacokinetic (PK) profiles of the antagonists. Ex vivo binding revealed that, at doses used in this study to reduce food intake, inhibition of binding of a 5-HT1A agonist by ~40% was reached in diet-induced obese (DIO) mice with a trend for higher binding in DIO vs. lean animals. Additionally, PK analysis detected levels from 2 to 24h post-compound administration. Male DIO mice were administered 5-HT1A receptor antagonists LY439934 (10 or 30 mg/kg, p.o.), WAY100635 (3 or 10mg/kg, s.c.), SRA-333 (10 or 30 mg/kg, p.o.), or NAD-299 (3 or 10mg/kg, s.c.) for 3 days and meal patterns were measured. Analyses revealed that for each antagonist, 24-h food intake was reduced through a specific decrease in the total number of meals. Compared to controls, meal number was decreased 14-35% in the high dose. Average meal size was not changed by any of the compounds. The reduction in food intake reduced body weight 1-4% compared to Vehicle controls. Subsequently, a conditioned taste aversion (CTA) assay was used to determine whether the feeding decrease might be an indicator of aversion, nausea, or visceral illness caused by the antagonists. Using a two bottle preference test, it was found that none of the compounds produced a CTA. The decrease in food intake does not appear to be a response to nausea or malaise. These results indicate that 5-HT1A receptor antagonist suppresses feeding, specifically by decreasing the number of meals, and induce weight loss without an aversive side effect. PMID- 24064184 TI - In vitro endocrine disruption and TCDD-like effects of three novel brominated flame retardants: TBPH, TBB, & TBCO. AB - The novel brominated flame retardants (NBFRs), 2-ethylhexyl-2,3,4,5 tetrabromobenzoate (TBB), Bis(2-ethylhexyl)-2,3,4,5-tetrabromophtalate (TBPH), and 1,2,5,6-tetrabromocyclooctane (TBCO) are components of flame retardant mixtures including Firemaster 550 and Saytex BC-48. Despite the detection of these NBFRs in environmental and biotic matrices, studies regarding their toxicological effects are poorly represented in the literature. The present study examined endocrine disruption by these three NBFRs using the yeast YES/YAS reporter assay and the mammalian H295R steroidogenesis assay. Activation of the aryl hydrocarbon receptor (AhR) was also assessed using the H4IIE reporter assay. The NBFRs produced no TCDD-like effects in the H4IIE assay or agonistic effects in the YES/YAS assays. TBB produced a maximal antiestrogenic effect of 62% at 0.5mgL(-1) in the YES assay while TBPH and TBCO produced maximal antiandrogenic effects of 74% and 59% at 300mgL(-1) and 1500mgL(-1), respectively, in the YAS assay. Significant effects were also observed in the H295R assay. At 0.05mgL(-1), 15mgL(-1), and 15mgL(-1) TBB, TBPH, and TBCO exposures, respectively resulted in a 2.8-fold, 5.4-fold, and 3.3-fold increase in concentrations of E2. This is one of the first studies to demonstrate the in vitro endocrine disrupting potentials of TBB, TBPH, and TBCO. PMID- 24064185 TI - Alzheimer's disease susceptibility variants in the MS4A6A gene are associated with altered levels of MS4A6A expression in blood. AB - An increased risk of developing Alzheimer's disease (AD) has previously been found to be associated with variants at the MS4A6A locus. We sought to identify which genes and transcripts in this region have altered expression in AD and mild cognitive impairment (MCI) and are influenced by the AD risk variant(s), as a first step to understanding the molecular basis of AD susceptibility at this locus. Common variants located within highly expressed MS4A6A transcripts were significantly associated with AD and MS4A6A expression levels in blood from MCI and AD subjects (p < 0.05, rs610932, rs7232, rs583791). More copies of the protective (minor) allele were associated with lower MS4A6A expression of each transcript (e.g., p = 0.019; rs610932-total MS4A6A). Furthermore, in heterozygous AD subjects, relative expression of the protective allele of V4-MS4A6A transcripts was lower (p < 0.008). Irrespective of genotype, MS4A6A transcripts were increased in blood from people with AD (p < 0.003), whereas lower expression of full length V1-MS4A6A (p = 0.002) and higher expression of V4-MS4A6A (p = 1.8 * 10(-4)) were observed in MCI, relative to elderly controls. The association between genotype and expression was less consistent in brain, although BA9 did have a similar genotype association with V4-MS4A6A transcripts as in blood. MS4A6A transcripts were widely expressed in tissues and cells, with the exception of V4-MS4A6A, which was not expressed in neuronal cells. Together these results suggest that high levels of MS4A6A in emerging AD pathology are detrimental. Persons with MCI may lower MS4A6A expression to minimize detrimental disease associated MS4A6A activity. However, those with the susceptibility allele appear unable to decrease expression sufficiently, which may explain their increased risk for developing AD. Inhibiting MS4A6A may therefore promote a more neuroprotective phenotype, although further work is needed to establish whether this is the case. PMID- 24064186 TI - miR128 up-regulation correlates with impaired amyloid beta(1-42) degradation in monocytes from patients with sporadic Alzheimer's disease. AB - Alzheimer's disease (AD), the most common form of dementia in elderly individuals, is characterized by neurofibrillary tangles, extracellular amyloid beta (Abeta) plaques and neuroinflammation. New evidence has shown that the lysosomal system might be a crossroad in which etiological factors in AD pathogenesis converge. This study shows that several lysosomal enzymes, including Cathepsin B, D, S, beta-Galactosidase, alpha-Mannosidase, and beta Hexosaminidase, were less expressed in monocytes and lymphocytes from patients with a clinical diagnosis of AD dementia compared with cells from healthy controls. In vitro experiments of gain and loss of function suggest that down regulation is a direct consequence of miR-128 up-regulation found in AD-related cells. The present study also demonstrates that miR-128 inhibition in monocytes from AD patients improves Abeta(1-42) degradation. These results could contribute to clarify the molecular mechanisms that affect the imbalanced Abeta production/clearance involved in the pathogenesis of AD. PMID- 24064188 TI - Social and self-reflective use of a Web-based personally controlled health management system. AB - BACKGROUND: Personally controlled health management systems (PCHMSs) contain a bundle of features to help patients and consumers manage their health. However, it is unclear how consumers actually use a PCHMS in their everyday settings. OBJECTIVE: To conduct an empirical analysis of how consumers used the social (forum and poll) and self-reflective (diary and personal health record [PHR]) features of a Web-based PCHMS designed to support their physical and emotional well-being. METHODS: A single-group pre/post-test online prospective study was conducted to measure use of a Web-based PCHMS for physical and emotional well being needs during a university academic semester. The PCHMS integrated an untethered PHR with social forums, polls, a diary, and online messaging links with a health service provider. Well-being journeys additionally provided information to encourage engagement with clinicians and health services. A total of 1985 students and staff aged 18 and above with access to the Internet were recruited online, of which 709 were eligible for analysis. Participants' self reported well-being, health status, health service utilization, and help-seeking behaviors were compared using chi-square, McNemar's test, and Student's t test. Social networks were constructed to examine the online forum communication patterns among consumers and clinicians. RESULTS: The two PCHMS features that were used most frequently and considered most useful and engaging were the social features (ie, the poll and forum). More than 30% (213/709) of participants who sought well-being assistance during the study indicated that other people had influenced their decision to seek help (54.4%, 386/709 sought assistance for physical well-being; 31.7%, 225/709 for emotional well-being). Although the prevalence of using a self-reflective feature (diary or PHR) was not as high (diary: 8.6%, 61/709; PHR: 15.0%, 106/709), the proportion of participants who visited a health care professional during the study was more than 20% greater in the group that did use a self-reflective feature (diary: P=.03; PHR: P<.001). CONCLUSIONS: There was variation in the degree to which consumers used social and self-reflective PCHMS features but both were significantly associated with increased help-seeking behaviors and health service utilization. A PCHMS should combine both self-reflective as well as socially driven components to most effectively influence consumers' help-seeking behaviors. PMID- 24064189 TI - Expressive writing as a brief intervention for reducing drinking intentions. AB - The present study examined the effectiveness of expressive writing in reducing drinking behavior. We expected that students prompted to write about negative drinking experiences would show greater decreases in future drinking intentions compared to the neutral and the positive writing conditions. We also expected that decreases in drinking intentions following the writing prompts might differ based on current drinking and AUDIT scores. Participants included 200 (76% female) undergraduates who completed measures of their current drinking behavior. They were then randomly assigned to either write about: a time when they had a lot to drink that was a good time (Positive); a time when they had a lot to drink that was a bad time (Negative); or their first day of college (Neutral), followed by measures assessing intended drinking over the next three months. Results revealed that participants intended to drink significantly fewer drinks per week and engage in marginally fewer heavy drinking occasions after writing about a negative drinking occasion when compared to control. Interactions provided mixed findings suggesting that writing about a positive event was associated with higher drinking intentions for heavier drinkers. Writing about a negative event was associated with higher intentions among heavier drinkers, but lower intentions among those with higher AUDIT scores. This research builds on previous expressive writing interventions by applying this technique to undergraduate drinkers. Preliminary results provide some support for this innovative strategy but also suggest the need for further refinement, especially with heavier drinkers. PMID- 24064190 TI - Social influence on temptation: perceived descriptive norms, temptation and restraint, and problem drinking among college students. AB - Temptation and restraint have long been associated with problematic drinking. Among college students, social norms are one of the strongest predictors of problematic drinking. To date, no studies have examined the association between temptation and restraint and perceived descriptive norms on drinking and alcohol related problems among college students. The purpose of this study was to examine whether perceived descriptive norms moderated the relationship between temptation and restraint and drinking outcomes among college students. Participants were 1095 college students from a large, public, culturally-diverse, southern university who completed an online survey about drinking behaviors and related attitudes. Drinks per week and alcohol-related problems were examined as a function of perceived descriptive norms, Cognitive Emotional Preoccupation (CEP) (temptation), and Cognitive Behavioral Control (CBC) (restraint). Additionally, drinking outcomes were examined as a function of the two-way interactions between CEP and perceived descriptive norms and CBC and perceived descriptive norms. Results indicated that CEP and perceived descriptive norms were associated with drinking outcomes. CBC was not associated with drinking outcomes. Additionally, perceived descriptive norms moderated the association between CEP and drinks per week and CEP and alcohol-related problems. There was a positive association between CEP and drinks per week and CEP and alcohol-related problems, especially for those higher on perceived descriptive norms. College students who are very tempted to drink may drink more heavily and experience alcohol-related problems more frequently if they have greater perceptions that the typical student at their university/college drinks a lot. PMID- 24064191 TI - Student drinking patterns and blood alcohol concentration on commercially organised pub crawls in the UK. AB - BACKGROUND: Commercial student pub crawls are associated with high levels of alcohol consumption, and are of growing concern amongst public health and student bodies. However, little is currently known about drinking behaviours whilst participating in these events. METHODS: A questionnaire was implemented amongst 227 students attending commercial pub crawls across three UK events. Questions established alcohol consumption patterns up to the point of interview and throughout the remaining night out, and pub crawl experience. Breathalyser tests were used to measure breath alcohol concentration (converted to blood alcohol concentration [BAC]) at interview. Analyses used chi squared, Mann-Whitney U, Kruskal-Wallis and logistic regression. RESULTS: 94.3% of participants had consumed alcohol, 90.9% of whom reported preloading. Drinkers reported consuming a median of 10.0 alcohol units (80g of pure alcohol) up to the point of interview (range one-40.6), with estimated total consumption over the evening exceeding 16units (range three-70.6). Median BAC of drinkers at the time of interview was 0.10%BAC (range 0.00-0.27). High BAC (>0.08%; at interview) was associated with having not eaten food in the four hours prior (AOR 4.8, p<0.01), time spent drinking (AOR 1.4, p<0.01) and number of units drank per hour (AOR 1.2, p<0.01). CONCLUSIONS: Measures to prevent high levels of alcohol consumption before and during commercial pub crawls should aim to alter drinking behaviours such as preloading and rapid and excessive drinking. Organisers, local authorities, universities and students should all be involved in ensuring the effective management of pub crawls, including implementation of harm prevention measures. PMID- 24064192 TI - Sport-related achievement motivation and alcohol outcomes: an athlete-specific risk factor among intercollegiate athletes. AB - Intercollegiate athletes report greater alcohol consumption and more alcohol related problems than their non-athlete peers. Although college athletes share many of the same problems faced by non-athletes, there are some consequences that are unique to athletes. Studies have demonstrated that alcohol negatively affects athletic performance including increased dehydration, impeded muscle recovery, and increased risk for injury. Beyond risk factors for alcohol misuse that may affect college students in general, research has begun to examine risk factors that are unique to collegiate athletes. For example, research has found that off season status, the leadership role, and athlete-specific drinking motives are associated with increased alcohol use. Given these findings, it is possible that other athlete-specific variables influence alcohol misuse. One such variable may be sport achievement orientation. The purpose of the current study was to examine the relationship between sport achievement orientation and alcohol outcomes. Given previous research regarding seasonal status and gender, these variables were examined as moderators. Varsity athletes (n=263) completed the Sport Orientation Questionnaire, which assesses sport-related achievement orientation on three scales (Competitiveness, Win Orientation, and Goal Orientation). In addition, participants completed measures of alcohol use and alcohol-related problems. Results indicated that Competitiveness, Win Orientation, and Goal Orientation were all significantly associated with alcohol use, but not alcohol related problems. Moreover, these relationships were moderated by seasonal status and gender. These interactions, clinical implications, and limitations are discussed. PMID- 24064193 TI - A person-centered approach to understanding negative reinforcement drinking among first year college students. AB - The current study used a person-centered approach (i.e. latent profile analysis) to identify distinct types of college student drinkers based on the predictions of motivational, social learning, and stress and coping theories of maladaptive drinking. A large sample (N=844; 53% female) of first-year undergraduates from two institutions, public and private, who reported consuming one or more drinks in the last three months completed measures of depressive and anxiety symptoms, positive alcohol-outcome expectancies, negative life events, social support, drinking motives, drinking level and drinking-related problems. Latent profile analysis revealed a small subgroup of individuals (n=81, 9%) who conformed to the anticipated high-risk profile; specifically, this group demonstrated high levels of negative affect, coping motives, drinks per week, and drinking-related problems. However, additional groups emerged that showed patterns inconsistent with the proposed vulnerability profile (e.g., high negative affect, positive expectancies, and negative life events, but relatively low drinking levels). Findings from our person-centered approach showing the presence of groups both consistent and inconsistent with the predictions of motivational, social learning, and stress and coping theories highlight the need to identify and target certain college students for prevention and intervention of negative affect-related drinking. PMID- 24064194 TI - Personality, cognition and hazardous drinking: Support for the 2-Component Approach to Reinforcing Substances Model. AB - Personality and cognitive processes are both related to alcohol use and misuse. A recent model of hazardous drinking referred, the 2-CARS model, postulates two major pathways to hazardous drinking. One pathway primarily involves the association between Reward Drive and Positive Outcome Expectancies, the second involves the association between Rash Impulsiveness and Drinking Refusal Self Efficacy. In previous tests of the model, Drinking Refusal Self-Efficacy was found to have the most proximal impact on drinking, being directly influenced by Rash Impulsiveness, and indirectly influenced by Reward Drive through Positive Outcome Expectancies. The aim of the current study was to test the 2-CARS model in a larger independent sample. Results found that individuals with a strong Reward Drive showed higher Positive Outcome Expectancies, while individuals high in Rash Impulsiveness were more likely to report reduced Drinking Refusal Self Efficacy. The present results also showed a theoretically unexpected pathway with a direct association between Rash Impulsiveness and Positive Outcome Expectancies. However, overall the results support the view that a greater understanding of hazardous drinking can be achieved by investigating the relationship between these personality and cognitive variables. PMID- 24064195 TI - Embryonic DNA methylation: insights from the genomics era. AB - DNA methylation is an epigenetic mark associated with transcriptional repression and essential for proper vertebrate development. Because of its association with human development and disease, DNA methylation has stayed in the research focus for almost half a century. However, it is only since very recently that we are able to generate genome-wide maps of this mark and gain insight into the many roles DNA methylation plays during the vertebrate life cycle. The recent adaptation of next-generation sequencing technologies to global DNA methylation profiling has spurred a flurry of studies conducted on various model systems. The recent publications of zebrafish base-pair resolution methylomes provided key advances in our understanding of how DNA methylation is remodeled during early vertebrate embryogenesis and highlighted important differences in developmental strategies between mammals and lower vertebrates. Here, we review our understanding of the role of DNA methylation during vertebrate development and discuss the insights obtained from almost a decade of methylome studies. PMID- 24064196 TI - Extramedullary chronic lymphocytic leukemia: systematic analysis of cases reported between 1975 and 2012. AB - The prognostic significance of extra-medullary chronic lymphocytic leukemia (EM CLL) is unknown. We conducted a Medline database systematic search analyzing English language articles published between 1975 and 2012 identifying 192 cases. Patients with EM-CLL were more commonly treated than not (p < .001). Skin and central nervous system (CNS) were the most commonly reported sites of organ involvement. Survival after diagnosis of EM-CLL appeared to depend on the site of EM involvement. Prospective evaluation and further studies of EM-CLL are warranted. PMID- 24064197 TI - Immunological challenges for peptide-based immunotherapy in glioblastoma. AB - Glioblastoma is the most aggressive primary tumor of the central nervous system with a medium overall survival of 7-15 months after diagnosis. Since tumor cells penetrate the surrounding brain tissue, complete surgical resection is impossible and tumor recurrence is almost a certainty. New treatment modalities are therefore needed, and these should be able to trace, identify, and kill dispersed tumor cells with great accuracy. Immunological approaches in principle meet these needs. Unfortunately, due to profound tumor-associated mechanisms of immunosuppression and -evasion, immunotherapeutic strategies like peptide vaccination have so far not been translated into clinical success. If future, peptide-based vaccination approaches shall be successful in glioblastoma therapy, multiple questions need to be solved including identification of suitable antigens, route and mode of vaccination, preparation of the tumor-bearing "host" and antagonizing, as much as this is possible, glioblastoma-associated mechanisms of immune evasion and poor vaccination response. In this review we will address the immunological challenges of glioblastoma and discuss key aspects that have rendered successful immunotherapy difficult in the past. PMID- 24064198 TI - Altered neural correlates of affective processing after internet-delivered cognitive behavior therapy for social anxiety disorder. AB - Randomized controlled trials have yielded promising results for internet delivered cognitive behavior therapy (iCBT) for patients with social anxiety disorder (SAD). The present study investigated anxiety-related neural changes after iCBT for SAD. The amygdala is a critical hub in the neural fear network, receptive to change using emotion regulation strategies and a putative target for iCBT. Twenty-two subjects were included in pre- and post-treatment functional magnetic resonance imaging at 3T assessing neural changes during an affective face processing task. Treatment outcome was assessed using social anxiety self reports and the Clinical Global Impression-Improvement (CGI-I) scale. ICBT yielded better outcome than ABM (66% vs. 25% CGI-I responders). A significant differential activation of the left amygdala was found with relatively decreased reactivity after iCBT. Changes in the amygdala were related to a behavioral measure of social anxiety. Functional connectivity analysis in the iCBT group showed that the amygdala attenuation was associated with increased activity in the medial orbitofrontal cortex and decreased activity in the right ventrolateral and dorsolateral (dlPFC) cortices. Treatment-induced neural changes with iCBT were consistent with previously reported studies on regular CBT and emotion regulation in general. PMID- 24064199 TI - Combined geochemical and electrochemical methodology to quantify corrosion of carbon steel by bacterial activity. AB - The availability of respiratory substrates, such as H2 and Fe(II,III) solid corrosion products within nuclear waste repository, will sustain the activities of hydrogen-oxidizing bacteria (HOB) and iron-reducing bacteria (IRB). This may have a direct effect on the rate of carbon steel corrosion. This study investigates the effects of Shewanella oneidensis (an HOB and IRB model organism) on the corrosion rate by looking at carbon steel dissolution in the presence of H2 as the sole electron donor. Bacterial effect is evaluated by means of geochemical and electrochemical techniques. Both showed that the corrosion rate is enhanced by a factor of 2-3 in the presence of bacteria. The geochemical experiments indicated that the composition and crystallinity of the solid corrosion products (magnetite and vivianite) are modified by bacteria. Moreover, the electrochemical experiments evidenced that the bacterial activity can be stimulated when H2 is generated in a small confinement volume. In this case, a higher corrosion rate and mineralization (vivianite) on the carbon steel surface were observed. The results suggest that the mechanism likely to influence the corrosion rate is the bioreduction of Fe(III) from magnetite coupled to the H2 oxidation. PMID- 24064200 TI - Immunoglobulin A nephropathy: insights and progress. PMID- 24064201 TI - Delivery of ibuprofen to the skin. AB - Ibuprofen (IBU) has been available as a topical skin preparation for more than two decades. Its primary indication is for the relief of pain and inflammation in rheumatic disease and other musculoskeletal conditions. This article reviews the various formulation strategies which have been investigated for percutaneous IBU delivery to date. The focus is on studies which have been conducted with IBU in the free base form on human or porcine skin as data from other species are known to overestimate likely permeation in man. Emerging technologies for enhanced dermal delivery of IBU are considered including methods which require physical disruption of the membrane. The role of biophysical techniques such as Confocal Raman Spectroscopy in the rational development of IBU formulations is also discussed. PMID- 24064202 TI - Propofol and fentanyl take longer for induction of anesthesia in aortic regurgitation: a case-controlled prospective study. AB - OBJECTIVES: This study was conducted to determine if induction time of anesthesia in patients with aortic regurgitation (AR) is different from patients with a normal aortic valve (AV). DESIGN: A prospective, case-control study. SETTING: A single institutional study conducted in a tertiary care teaching hospital. PARTICIPANTS: Twenty-four male patients scheduled for cardiac surgery, group I (n = 12) patients with competent AV and group 2 (n = 12) with severe AR. INTERVENTIONS: General anesthesia was induced by intravenous infusion of propofol and fentanyl. MEASUREMENTS AND MAIN RESULTS: Continuous measurements of heart rate, intra-arterial blood pressure, and bispectral index were recorded. Induction doses of propofol and fentanyl were analyzed and compared. There was significant difference between the 2 groups in terms of induction time of anesthesia (mean +/- SD 308 +/- 68.2 seconds in group 1 v 445 +/- 97.9 seconds in group 2). The patients in group 2 (AR) required significantly larger doses of propofol (0.91 +/- 0.40 mg/kg) than the patients in group 1 (0.49 +/- 0.17 mg/kg). Similarly, fentanyl dose was increased in the group 2 patients (20.8 +/- 15.9 ug/kg) compared with the group 1 patients (9.2 +/- 2.9 ug/kg). CONCLUSION: The authors concluded that there was a significant prolongation of the induction time of anesthesia and the need of larger doses of propofol and fentanyl by slow intravenous infusion regimen in patients with AR compared with patients with a competent aortic valve. PMID- 24064203 TI - Cardiac surgery and C1-inhibitor deficiency. PMID- 24064204 TI - Impact of guideline implementation on transfusion practices in a surgical intensive care unit. AB - BACKGROUND: Anemia is a common clinical problem in cardiac surgery patients in the postoperative period and may result in transfusion in up to 90% of this population. There is tremendous variation in transfusion rates by hospital and individual physician. It is unknown if implementation of a clinical practice guideline lowers unnecessary transfusion in hospital practices that already have a restrictive transfusion culture . OBJECTIVE: To evaluate transfusion practice before and after implementation of a clinical practice guideline. DESIGN: Pre/post intervention study. SETTING: Sixteen bed surgical intensive care unit in an academic hospital. PARTICIPANTS: Four hundred ninety-five adult patients undergoing cardiac surgery. INTERVENTIONS: Implementation of an anemia clinical practice guideline reinforced with education and retrospective audit/feedback. MEASUREMENTS AND MAIN RESULTS: A total of 252 pre-intervention and 243 postintervention cases were examined. Unnecessary transfusion occurred in 14.7% of pre-intervention patients and decreased to a rate of 8.1% after guideline implementation (p = 0.016). CONCLUSIONS: This study suggests that clinical guideline implementation utilizing guideline development, education, and compliance audit/feedback may reduce unnecessary transfusion in cardiac surgery patients. A fully powered prospective trial would be necessary to validate these findings. PMID- 24064205 TI - Catalysis of nitrite generation from nitroglycerin by glyceraldehyde-3-phosphate dehydrogenase (GAPDH). AB - Vascular relaxation to nitroglycerin (glyceryl trinitrate; GTN) requires its bioactivation by mechanisms that remain controversial. We report here that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalyzes the release of nitrite from GTN. In assays containing dithiothreitol (DTT) and NAD(+), the GTN reductase activity of purified GAPDH produces nitrite and 1,2-GDN as the major products. A vmax of 2.6nmolmin(-)(1)mg(-)(1) was measured for nitrite production by GAPDH from rabbit muscle and a GTN KM of 1.2mM. Reductive denitration of GTN in the absence of DTT results in dose- and time-dependent inhibition of GAPDH dehydrogenase activity. Disulfiram, a thiol-modifying drug, inhibits both the dehydrogenase and GTN reductase activity of GAPDH, while DTT or tris(2 carboxyethyl)phosphine reverse the GTN-induced inhibition. Incubation of intact human erythrocytes or hemolysates with 2mM GTN for 60min results in 50% inhibition of GAPDH's dehydrogenase activity, indicating that GTN is taken up by these cells and that the dehydrogenase is a target of GTN. Thus, erythrocyte GAPDH may contribute to GTN bioactivation. PMID- 24064206 TI - Sulfation of beta-chitosan and evaluation of biological activity from gladius of Sepioteuthis lessoniana. AB - beta-Chitosan extracted from the gladius of Sepioteuthis lessoniana was sulfated with chlorosufonic acid. The structural features of sulfated chitosan were analyzed by NMR spectroscopy. The elemental composition was analyzed using elemental analyzer. The molecular weight of sulfated chitosan estimated through viscometry was calculated as 12.47 * 10(4) Da. The water solubility of sulfated chitosan was found to be 81%. The sulfated chitosan was able to scavenge the DPPH, superoxide and hydroxyl radicals and the inhibitory concentration (IC50) of those free radicals was found to be 4, 0.428 and 0.473 mg/ml respectively. Sulfated chitosan also showed reducing and chelating property. The IC50 value of reducing and chelating ability was found to be 0.316 and 5.64 mg/ml respectively. The anticoagulant activity was determined for human plasma with respect to activated partial thromboplastin time and prothrombin time and it was 7.13 IU and 1.26 IU, respectively. PMID- 24064207 TI - Leucaena sp. recombinant cinnamyl alcohol dehydrogenase: purification and physicochemical characterization. AB - Cinnamyl alcohol dehydrogenase is a broad substrate specificity enzyme catalyzing the final step in monolignol biosynthesis, leading to lignin formation in plants. Here, we report characterization of a recombinant CAD homologue (LlCAD2) isolated from Leucaena leucocephala. LlCAD2 is 80 kDa homo-dimer associated with non covalent interactions, having substrate preference toward sinapaldehyde with Kcat/Km of 11.6*10(6) (M(-1) s(-1)), and a possible involvement of histidine at the active site. The enzyme remains stable up to 40 degrees C, with the deactivation rate constant (Kd(*)) and half-life (t1/2) of 0.002 and 5h, respectively. LlCAD2 showed optimal activity at pH 6.5 and 9 for reduction and oxidation reactions, respectively, and was stable between pH 7 and 9, with the deactivation rate constant (Kd(*)) and half-life (t1/2) of 7.5*10(-4) and 15 h, respectively. It is a Zn-metalloenzyme with 4 Zn(2+) per dimer, however, was inhibited in presence of externally supplemented Zn(2+) ions. The enzyme was resistant to osmolytes, reducing agents and non-ionic detergents. PMID- 24064208 TI - Blunted reward responsiveness in remitted depression. AB - Major depressive disorder has been associated with blunted responsiveness to rewards, but inconsistencies exist whether such abnormalities persist after complete remission. To address this issue, across two independent studies, 47 adults with remitted major depressive disorder (rMDD) and 37 healthy controls completed a Probabilistic Reward Task, which used a differential reinforcement schedule of social or monetary feedback to examine reward responsiveness (i.e., ability to modulate behavior as a function of reinforcement history). Relative to controls, adults with rMDD showed blunted reward responsiveness. Importantly, a history of depression predicted reduced reward learning above and beyond residual depressive (including anhedonic) symptoms and perceived stress. Findings indicate that blunted reward responsiveness endures even when adults are in remission and might be a trait-related abnormality in MDD. More research is warranted to investigate if blunted reward responsiveness may predict future depressive episodes and whether targeting reward-related deficits may prevent the re occurrence of the disorder. PMID- 24064209 TI - Isolation, characterisation and cDNA sequencing of a new form of parvalbumin from carp semen. AB - Parvalbumins (Pv) are calcium-binding proteins present mainly in the muscle and nervous system where they act as a Ca(2+) buffer. Our previous work demonstrated the presence of Pv-I in carp semen and indicated the presence of a second Pv (Pv II). The purpose of the present work was to identify, purify and determine the full-length cDNA sequence of Pv-II from carp testis. Pv-II from seminal plasma was purified by ion-exchange chromatography (IEC) and preparative electrophoresis, while the Pv-II from spermatozoa was purified by IEC, gel filtration and preparative electrophoresis. The purified Pv-II was submitted to an analysis of molecular mass, isoelectric point (pI), amino-acid sequence and oligomerisation ability. The amino-acid sequence was used to construct primers and obtain the full-length cDNA sequence of seminal-specific Pv-II from carp testis. Analysis of the cDNA sequence indicated that carp-testis Pv-II was distinct from carp-muscle parvalbumins. Pv-II was distinct from Pv-I regarding sequence, molecular mass and pI. Both parvalbumins had the ability to form oligomers or to bind to other proteins. Carp seminal plasma had a protective effect against parvalbumin oligomerisation. Pv-II underwent post-translational modification such as n-acetylation and cysteinylation. The present study is the first to report the full-length cDNA sequence of parvalbumin from carp testis. PMID- 24064210 TI - Desensitization and internalization of endothelin receptor A: impact of G protein coupled receptor kinase 2 (GRK2)-mediated phosphorylation. AB - Endothelin receptor A (ETA), a G protein-coupled receptor, mediates endothelin signaling, which is regulated by GRK2. Three Ser and seven Thr residues recently proven to be phosphoacceptor sites are located in the C-terminal extremity (CTE) of the receptor following its palmitoylation site. We created various phosphorylation-deficient ETA mutants. The phospholipase C activity of mutant receptors in HEK-293 cells was analyzed during continuous endothelin stimulation to investigate the impact of phosphorylation sites on ETA desensitization. Total deletion of phosphoacceptor sites in the CTE affected proper receptor regulation. However, proximal and distal phosphoacceptor sites both turned out to be sufficient to induce WT-like desensitization. Overexpression of the Galphaq coupling-deficient mutant GRK2-D110A suppressed ETA-WT signaling but failed to decrease phospholipase C activity mediated by the phosphorylation-deficient mutant ETA-6PD. In contrast, GRK2-WT acted on both receptors, whereas the kinase inactive mutant GRK2-D110A/K220R failed to inhibit signaling of ETA-WT and ETA 6PD. This demonstrates that ETA desensitization involves at least two autonomous GRK2-mediated components: 1) a phosphorylation-independent signal decrease mediated by blocking of Galphaq and 2) a mechanism involving phosphorylation of Ser and Thr residues in the CTE of the receptor in a redundant fashion, able to incorporate either proximal or distal phosphoacceptor sites. High level transfection of GRK2 variants influenced signaling of ETA-WT and ETA-6PD and hints at an additional phosphorylation-independent regulatory mechanism. Furthermore, internalization of mRuby-tagged receptors was observed with ETA-WT and the phosphorylation-deficient mutant ETA-14PD (lacking 14 phosphoacceptor sites) and turned out to be based on a phosphorylation-independent mechanism. PMID- 24064211 TI - The Geminin and Idas coiled coils preferentially form a heterodimer that inhibits Geminin function in DNA replication licensing. AB - Geminin is an important regulator of proliferation and differentiation in metazoans, which predominantly inhibits the DNA replication licensing factor Cdt1, preventing genome over-replication. We show that Geminin preferentially forms stable coiled-coil heterodimers with its homologue, Idas. In contrast to Idas-Geminin heterodimers, Idas homodimers are thermodynamically unstable and are unlikely to exist as a stable macromolecule under physiological conditions. The crystal structure of the homology regions of Idas in complex with Geminin showed a tight head-to-head heterodimeric coiled-coil. This Idas-Geminin heterodimer binds Cdt1 less strongly than Geminin-Geminin, still with high affinity (~30 nm), but with notably different thermodynamic properties. Consistently, in Xenopus egg extracts, Idas-Geminin is less active in licensing inhibition compared with a Geminin-Geminin homodimer. In human cultured cells, ectopic expression of Idas leads to limited over-replication, which is counteracted by Geminin co expression. The properties of the Idas-Geminin complex suggest it as the functional form of Idas and provide a possible mechanism to modulate Geminin activity. PMID- 24064212 TI - Aspergillus niger beta-glucosidase has a cellulase-like tadpole molecular shape: insights into glycoside hydrolase family 3 (GH3) beta-glucosidase structure and function. AB - Aspergillus niger is known to secrete large amounts of beta-glucosidases, which have a variety of biotechnological and industrial applications. Here, we purified an A. niger beta-glucosidase (AnBgl1) and conducted its biochemical and biophysical analyses. Purified enzyme with an apparent molecular mass of 116 kDa forms monomers in solution as judged by native gel electrophoresis and has a pI value of 4.55, as found for most of the fungi of beta-glucosidases. Surprisingly, the small angle x-ray experiments reveal that AnBgl1 has a tadpole-like structure, with the N-terminal catalytic domain and C-terminal fibronectin III like domain (FnIII) connected by the long linker peptide (~100 amino acid residues) in an extended conformation. This molecular organization resembles the one adopted by other cellulases (such as cellobiohydrolases, for example) that frequently contain a catalytic domain linked to the cellulose-binding module that mediates their binding to insoluble and polymeric cellulose. The reasons why AnBgl1, which acts on the small soluble substrates, has a tadpole molecular shape are not entirely clear. However, our enzyme pulldown assays with different polymeric substrates suggest that AnBgl1 has little or no capacity to bind to and to adsorb cellulose, xylan, and starch, but it has high affinity to lignin. Molecular dynamics simulations suggested that clusters of residues located in the C-terminal FnIII domain interact strongly with lignin fragments. The simulations showed that numerous arginine residues scattered throughout the FnIII surface play an important role in the interaction with lignin by means of cation-pi stacking with the lignin aromatic rings. These results indicate that the C terminal FnIII domain could be operational for immobilization of the enzyme on the cell wall and for the prevention of unproductive binding of cellulase to the biomass lignin. PMID- 24064213 TI - The same major histocompatibility complex polymorphism involved in control of HIV influences peptide binding in the mouse H-2Ld system. AB - Single-site polymorphisms in human class I major histocompatibility complex (MHC) products (HLA-B) have recently been shown to correlate with HIV disease progression or control. An identical single-site polymorphism (at residue 97) in the mouse class I product H-2L(d) influences stability of the complex. To gain insight into the human polymorphisms, here we examined peptide binding, stability, and structures of the corresponding L(d) polymorphisms, Trp(97) and Arg(97). Expression of L(d)W97 and L(d)R97 genes in a cell line that is antigen processing competent showed that L(d)R97 was expressed at higher levels than L(d)W97, consistent with enhanced stability of self-peptide.L(d)R97 complexes. To further examine peptide-binding capacities of these two allelic variants, we used a high affinity pep-L(d) specific probe to quantitatively examine a collection of self- and foreign peptides that bind to L(d). L(d)R97 bound more effectively than L(d)W97 to most peptides, although L(d)W97 bound more effectively to two peptides. The results support the view that many self-peptides in the L(d) system (or the HLA-B system) would exhibit enhanced binding to Arg(97) alleles compared with Trp(97) alleles. Accordingly, the self-peptide.MHC-Arg(97) complexes would influence T-cell selection behavior, impacting the T-cell repertoire of these individuals, and could also impact peripheral T cell activity through effects of self-peptide.L(d) interacting with TCR and/or CD8. The structures of several peptide.L(d)R97 and peptide.L(d)W97 complexes provided a framework of how this single polymorphism could impact peptide binding. PMID- 24064214 TI - Specificity determinants for lysine incorporation in Staphylococcus aureus peptidoglycan as revealed by the structure of a MurE enzyme ternary complex. AB - Formation of the peptidoglycan stem pentapeptide requires the insertion of both L and D amino acids by the ATP-dependent ligase enzymes MurC, -D, -E, and -F. The stereochemical control of the third position amino acid in the pentapeptide is crucial to maintain the fidelity of later biosynthetic steps contributing to cell morphology, antibiotic resistance, and pathogenesis. Here we determined the x-ray crystal structure of Staphylococcus aureus MurE UDP-N-acetylmuramoyl-L-alanyl-D glutamate:meso-2,6-diaminopimelate ligase (MurE) (E.C. 6.3.2.7) at 1.8 A resolution in the presence of ADP and the reaction product, UDP-MurNAc-L-Ala gamma-D-Glu-L-Lys. This structure provides for the first time a molecular understanding of how this Gram-positive enzyme discriminates between L-lysine and D,L-diaminopimelic acid, the predominant amino acid that replaces L-lysine in Gram-negative peptidoglycan. Despite the presence of a consensus sequence previously implicated in the selection of the third position residue in the stem pentapeptide in S. aureus MurE, the structure shows that only part of this sequence is involved in the selection of L-lysine. Instead, other parts of the protein contribute substrate-selecting residues, resulting in a lysine-binding pocket based on charge characteristics. Despite the absolute specificity for L lysine, S. aureus MurE binds this substrate relatively poorly. In vivo analysis and metabolomic data reveal that this is compensated for by high cytoplasmic L lysine concentrations. Therefore, both metabolic and structural constraints maintain the structural integrity of the staphylococcal peptidoglycan. This study provides a novel focus for S. aureus-directed antimicrobials based on dual targeting of essential amino acid biogenesis and its linkage to cell wall assembly. PMID- 24064215 TI - Binding of complement inhibitor C4b-binding protein to a highly virulent Streptococcus pyogenes M1 strain is mediated by protein H and enhances adhesion to and invasion of endothelial cells. AB - Streptococcus pyogenes AP1, a strain of the highly virulent M1 serotype, uses exclusively protein H to bind the complement inhibitor C4b-binding protein (C4BP). We found a strong correlation between the ability of AP1 and its isogenic mutants lacking protein H to inhibit opsonization with complement C3b and binding of C4BP. C4BP bound to immobilized protein H or AP1 bacteria retained its cofactor activity for degradation of (125)I-C4b. Furthermore, C4b deposited from serum onto AP1 bacterial surfaces was processed into C4c/C4d fragments, which did not occur on strains unable to bind C4BP. Recombinant C4BP mutants, which (i) lack certain CCP domains or (ii) have mutations in single aa as well as (iii) mutants with additional aa between different CCP domains were used to determine that the binding is mainly mediated by a patch of positively charged amino acid residues at the interface of domains CCP1 and CCP2. Using recombinant protein H fragments, we narrowed down the binding site to the N-terminal domain A. With a peptide microarray, we identified one single 18-amino acid-long peptide comprising residues 92-109, which specifically bound C4BP. Biacore was used to determine KD = 6 * 10(-7) M between protein H and a single subunit of C4BP. C4BP binding also correlated with elevated levels of adhesion and invasion to endothelial cells. Taken together, we identified the molecular basis of C4BP protein H interaction and found that it is not only important for decreased opsonization but also for invasion of endothelial cells by S. pyogenes. PMID- 24064216 TI - Mutations in intracellular loops 1 and 3 lead to misfolding of human P glycoprotein (ABCB1) that can be rescued by cyclosporine A, which reduces its association with chaperone Hsp70. AB - P-glycoprotein (P-gp) is an ATP binding cassette transporter that effluxes a variety of structurally diverse compounds including anticancer drugs. Computational models of human P-gp in the apo- and nucleotide-bound conformation show that the adenine group of ATP forms hydrogen bonds with the conserved Asp 164 and Asp-805 in intracellular loops 1 and 3, respectively, which are located at the interface between the nucleotide binding domains and transmembrane domains. We investigated the role of Asp-164 and Asp-805 residues by substituting them with cysteine in a cysteine-less background. It was observed that the D164C/D805C mutant, when expressed in HeLa cells, led to misprocessing of P-gp, which thus failed to transport the drug substrates. The misfolded protein could be rescued to the cell surface by growing the cells at a lower temperature (27 degrees C) or by treatment with substrates (cyclosporine A, FK506), modulators (tariquidar), or small corrector molecules. We also show that short term (4-6 h) treatment with 15 MUM cyclosporine A or FK506 rescues the pre-formed immature protein trapped in the endoplasmic reticulum in an immunophilin-independent pathway. The intracellularly trapped misprocessed protein associates more with chaperone Hsp70, and the treatment with cyclosporine A reduces the association of mutant P-gp, thus allowing it to be trafficked to the cell surface. The function of rescued cell surface mutant P-gp is similar to that of wild-type protein. These data demonstrate that the Asp-164 and Asp-805 residues are not important for ATP binding, as proposed earlier, but are critical for proper folding and maturation of a functional transporter. PMID- 24064219 TI - Biochemical analysis and structure determination of bacterial acetyltransferases responsible for the biosynthesis of UDP-N,N'-diacetylbacillosamine. AB - UDP-N,N'-diacetylbacillosamine (UDP-diNAcBac) is a unique carbohydrate produced by a number of bacterial species and has been implicated in pathogenesis. The terminal step in the formation of this important bacterial sugar is catalyzed by an acetyl-CoA (AcCoA)-dependent acetyltransferase in both N- and O-linked protein glycosylation pathways. This bacterial acetyltransferase is a member of the left handed beta-helix family and forms a homotrimer as the functional unit. Whereas previous endeavors have focused on the Campylobacter jejuni acetyltransferase (PglD) from the N-linked glycosylation pathway, structural characterization of the homologous enzymes in the O-linked glycosylation pathways is lacking. Herein, we present the apo-crystal structures of the acetyltransferase domain (ATD) from the bifunctional enzyme PglB (Neisseria gonorrhoeae) and the full-length acetyltransferase WeeI (Acinetobacter baumannii). Additionally, a PglB-ATD structure was solved in complex with AcCoA. Surprisingly, this structure reveals a contrasting binding mechanism for this substrate when compared with the AcCoA bound PglD structure. A comparison between these findings and the previously solved PglD crystal structures illustrates a dichotomy among N- and O-linked glycosylation pathway enzymes. Based upon these structures, key residues in the UDP-4-amino and AcCoA binding pockets were mutated to determine their effect on binding and catalysis in PglD, PglB-ATD, and WeeI. Last, a phylogenetic analysis of the aforementioned acetyltransferases was employed to illuminate the diversity among N- and O-linked glycosylation pathway enzymes. PMID- 24064218 TI - ETS-1-mediated transcriptional up-regulation of CD44 is required for sphingosine 1-phosphate receptor subtype 3-stimulated chemotaxis. AB - Sphingosine-1-phosphate (S1P)-regulated chemotaxis plays critical roles in various physiological and pathophysiological conditions. S1P-regulated chemotaxis is mediated by the S1P family of G-protein-coupled receptors. However, molecular details of the S1P-regulated chemotaxis are incompletely understood. Cultured human lung adenocarcinoma cell lines abundantly express S1P receptor subtype 3 (S1P3), thus providing a tractable in vitro system to characterize molecular mechanism(s) underlying the S1P3 receptor-regulated chemotactic response. S1P treatment enhances CD44 expression and induces membrane localization of CD44 polypeptides via the S1P3/Rho kinase (ROCK) signaling pathway. Knockdown of CD44 completely diminishes the S1P-stimulated chemotaxis. Promoter analysis suggests that the CD44 promoter contains binding sites of the ETS-1 (v-ets erythroblastosis virus E26 oncogene homolog 1) transcriptional factor. ChIP assay confirms that S1P treatment stimulates the binding of ETS-1 to the CD44 promoter region. Moreover, S1P induces the expression and nuclear translocation of ETS-1. Knockdown of S1P3 or inhibition of ROCK abrogates the S1P-induced ETS-1 expression. Furthermore, knockdown of ETS-1 inhibits the S1P-induced CD44 expression and cell migration. In addition, we showed that S1P3/ROCK signaling up regulates ETS-1 via the activity of JNK. Collectively, we characterized a novel signaling axis, i.e., ROCK-JNK-ETS-1-CD44 pathway, which plays an essential role in the S1P3-regulated chemotactic response. PMID- 24064220 TI - Oxytocin sharpens self-other perceptual boundary. AB - Recent cross-species research has demonstrated that the neurohormone oxytocin plays a key role in social interaction and cognitive processing of others' emotions. Whereas oxytocin has been shown to influence social approach, trust, and bond formation, a potential role of the oxytocinergic system in blurring or enhancing the ability to differentiate between one's self and other's related stimuli is unknown. Thus, we investigated whether oxytocin affects the ability to differentiate between self- and other-related stimuli using a facial morphing procedure. In a placebo-controlled, double-blind study, 44 healthy men received either 24 IU oxytocin or placebo intranasally. After 45 min, we measured participants' ability to differentiate their own identity while viewing a photo of themselves morphing into the photo of an unfamiliar face. Oxytocin administration shortened the latency of self-other differentiation. Additionally, when asked to rate the pleasantness of the unmorphed photos, the oxytocin-treated participants rated their own and the unfamiliar face as comparably pleasant. Oxytocin increases the ability to recognize differences between self and others and increases positive evaluation of others. Our findings are consistent with the hypothesis that impaired oxytocin signaling may be involved in the development and manifestation of human psychopathologies in which self-recognition is altered. PMID- 24064217 TI - Characterization of a membrane-active peptide from the Bordetella pertussis CyaA toxin. AB - Bordetella pertussis, the pathogenic bacteria responsible for whooping cough, secretes several virulence factors, among which is the adenylate cyclase toxin (CyaA) that plays a crucial role in the early stages of human respiratory tract colonization. CyaA invades target cells by translocating its catalytic domain directly across the plasma membrane and overproduces cAMP, leading to cell death. The molecular process leading to the translocation of the catalytic domain remains largely unknown. We have previously shown that the catalytic domain per se, AC384, encompassing residues 1-384 of CyaA, did not interact with lipid bilayer, whereas a longer polypeptide, AC489, spanning residues 1-489, binds to membranes and permeabilizes vesicles. Moreover, deletion of residues 375-485 within CyaA abrogated the translocation of the catalytic domain into target cells. Here, we further identified within this region a peptidic segment that exhibits membrane interaction properties. A synthetic peptide, P454, corresponding to this sequence (residues 454-485 of CyaA) was characterized by various biophysical approaches. We found that P454 (i) binds to membranes containing anionic lipids, (ii) adopts an alpha-helical structure oriented in plane with respect to the lipid bilayer, and (iii) permeabilizes vesicles. We propose that the region encompassing the helix 454-485 of CyaA may insert into target cell membrane and induce a local destabilization of the lipid bilayer, thus favoring the translocation of the catalytic domain across the plasma membrane. PMID- 24064221 TI - Cumulative estrogen exposure, number of menstrual cycles, and Alzheimer's risk in a cohort of British women. AB - The effect of estrogen on Alzheimer's Disease (AD) risk has received substantial research and media attention, especially in terms of hormone replacement therapy. But reproductive history is also an important modifier of estrogenic exposure, and deserves further investigation. Importantly, there is wide variation in reproductive patterns that modifies estrogen exposure during the reproductive span, which previous AD studies have not incorporated into their calculations. We measured degree of Alzheimer's-type dementia in a cohort of elderly British women, and collected detailed reproductive and medical history information, which we used to estimate number of months with estrogen exposure and number of months with menstrual cycles. Using Cox proportional-hazards models, we find that longer duration of estrogen exposure may have a protective effect against AD risk, such that for every additional month with estrogen, women experienced on average a 0.5% decrease in AD risk (N=89, p=0.02). More menstrual cycles may also have a protective effect against AD risk, although this result was of borderline statistical significance (p<0.10). These results build upon previous methodologies by taking into account a variety of parameters including oral contraceptive use, breastfeeding, post-partum anovulation, abortions, and miscarriages. Additionally, Cox models revealed that longer reproductive span, age>21 at first birth, and more months in lifetime spent pregnant had protective effects against AD risk. PMID- 24064222 TI - Protection from inflammatory bowel disease and colitis-associated carcinogenesis with 4-vinyl-2,6-dimethoxyphenol (canolol) involves suppression of oxidative stress and inflammatory cytokines. AB - Oxidative stress is associated with various pathological processes including inflammatory bowel disease, which is a major cause of colon cancer. Here, we examined the antioxidative and anti-inflammatory effects of 4-vinyl-2,6 dimethoxyphenol (canolol), a potent antioxidant compound obtained from crude canola oil. Oral administration of 2% dextran sulfate sodium (DSS) resulted in the progression of colitis with shortening of the large bowel length. Administering a diet containing canolol significantly suppressed pathogenesis; diarrhea markedly improved and the length of large bowel returned to almost normal. Pathological examination clearly revealed improvement of colonic ulcers. Production of inflammatory cytokines, i.e. interleukin-12 and tumor necrosis factor-alpha, was significantly increased during this pathological process; their production was markedly inhibited by canolol. In the azoxymethane/DSS-induced colon cancer model, mice receiving canolol had a reduced occurrence of cancer, to 60%, compared with control mice, 100% of which had colon cancer. The numbers of tumors in each mouse were also significantly reduced in mice receiving the canolol-containing diet (5.6+/-2.0) compared with azoxymethane/DSS control mice (10.8+/-4.2). No apparent toxicity of canolol was observed. Moreover, inflammatory cytokines (i.e. cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-alpha) and oxidative responding molecules, i.e. heme oxygenase-1, in colon were suppressed during this treatment. In a mouse colon 26 solid tumor model, canolol significantly suppressed cyclooxygenase-2 expression; however, no significant tumor growth inhibition was observed, suggesting that canolol preferably shows chemopreventive effects during the stages of initiation/promotion. Canolol may, thus, be considered a potential cancer preventive agent or supplement. PMID- 24064223 TI - JWA inhibits melanoma angiogenesis by suppressing ILK signaling and is an independent prognostic biomarker for melanoma. AB - Melanoma is the deadliest cutaneous malignancy because of its high incidence of metastasis. Melanoma growth and metastasis relies on sustained angiogenesis; therefore, inhibiting angiogenesis is a promising approach to treat metastatic melanoma. JWA is a novel microtubule-associated protein and our previous work revealed that JWA inhibited melanoma cell invasion and metastasis. However, the role of JWA in melanoma angiogenesis and the prognostic value are still unknown. Here, we report that JWA in melanoma cells significantly inhibited the tube formation of endothelial cells. In addition, JWA regulated integrin-linked kinase (ILK) through integrin alphaVbeta3 and such regulation was achieved through the transcription factor Sp1. Notably, both in vitro and in vivo angiogenesis assays revealed that JWA dramatically suppressed melanoma angiogenesis by inhibiting ILK signaling. Furthermore, we examined the expression of JWA protein in a large set of melanocytic lesions (n = 505) at different stages by tissue microarray and found an inverse correlation between JWA expression and melanoma progression (P = 5 * 10(-6)). Importantly, reduced JWA expression was correlated with a poorer overall, and disease-specific 5 year survival of patients (P = 0.001 and 0.007, respectively). Multivariate Cox regression analyses indicated that JWA was an independent prognostic marker for melanoma patients. Moreover, we found a significant negative correlation between JWA and ILK in melanoma biopsies, and their concomitant expression was closely correlated with melanoma patient survival (P = 0.004), further indicating the regulation of ILK expression by JWA is critical in melanoma. Taken together, our data highlight the function of JWA in melanoma angiogenesis and reveal the clinical prognostic value of JWA. PMID- 24064224 TI - miR-200b suppresses invasiveness and modulates the cytoskeletal and adhesive machinery in esophageal squamous cell carcinoma cells via targeting Kindlin-2. AB - To further our understanding of the pathobiology of esophageal squamous cell carcinoma (ESCC), we previously performed microRNA profiling that revealed downregulation of miR-200b in ESCC. Using quantitative real-time PCR applied to 88 patient samples, we confirmed that ESCC tumors expressed significantly lower levels of miR-200b compared with the respective adjacent benign tissues (P = 0.003). Importantly, downregulation of miR-200b significantly correlated with shortened survival (P = 0.025), lymph node metastasis (P = 0.002) and advanced clinical stage (P = 0.020) in ESCC patients. Quantitative mass spectrometry identified 57 putative miR-200b targets, including Kindlin-2, previously implicated in the regulation of tumor invasiveness and actin cytoskeleton in other cell types. Enforced expression of miR-200b mimic in ESCC cells led to a decrease of Kindlin-2 expression, whereas transfection of miR-200b inhibitor induced Kindlin-2 expression. Furthermore, transfection of miR-200b mimic or knockdown of Kindlin-2 in ESCC cells decreased cell protrusion and focal adhesion (FA) formation, reduced cell spreading and invasiveness/migration. Enforced expression of Kindlin-2 largely abrogated the inhibitory effects of miR-200b on ESCC cell invasiveness. Mechanistic studies revealed that Rho-family guanosine triphosphatases and FA kinase mediated the biological effects of the miR-200b Kindlin-2 axis in ESCC cells. To conclude, loss of miR-200b, a frequent biochemical defect in ESCC, correlates with aggressive clinical features. The tumor suppressor effects of miR-200b may be due to its suppression of Kindlin-2, a novel target of miR-200b that modulates actin cytoskeleton, FA formation and the migratory/invasiveness properties of ESCC. PMID- 24064225 TI - Blushing primary cardiac angiosarcoma. PMID- 24064226 TI - Physical activity and atrial fibrillation. PMID- 24064227 TI - The effects of gender and age on occurrence of clinically suspected myocarditis in adulthood. AB - OBJECTIVE: To study the effects of gender and age on occurrence of myocarditis. DESIGN: Nationwide, multicentre registry study in Finland. SETTING: All medical hospital admissions (n=1 698 397) of patients aged >= 16 years during 9.5 years in 29 hospitals. PATIENTS: 3198 myocarditis patients. RESULTS: Myocarditis was more common in men (76.61%; 95% CI 75.11% to 78.05%) than in women (23.39%; 95% CI 21.95% to 24.89%, p<0.0001). Median age of patients was 33 years (IQR 23-50 years). Male patients were significantly younger than females (mean age 34.1 +/- SD 15.1 vs 49.0 +/- 18.7 years, p<0.0001). In men, occurrence was highest at 16 20 yrs of age, with a linear decline to elderliness (r=-0.95, p<0.0001). By contrast, myocarditis affected women more evenly at all ages with highest occurrence at the age of 56-60 years. Myocarditis caused 0.19% (95% CI 0.18% to 0.19%) of all medical admissions, and 0.48% (95% CI 0.46% to 0.49%) of admissions due to cardiovascular reasons with an inverse logarithmic association with age (r=-0.97, p<0.0001). Admissions were more commonly caused by myocarditis in men (risk ratio 3.11; 95% CI 2.87 to 3.38, p<0.0001). CONCLUSIONS: Men are significantly more susceptible to myocarditis than women. Young men are especially at risk for acquiring myocarditis, while women are affected most commonly at the postmenopausal age. The proportion of hospital admissions caused by myocarditis has an inverse, logarithmic association with age. PMID- 24064228 TI - Strategic target temperature management in myocardial infarction--a feasibility trial. AB - OBJECTIVE: The purpose of this study was to demonstrate the feasibility of a combined cooling strategy started out of hospital as an adjunctive to percutaneous coronary intervention (PCI) in the treatment of ST-elevation acute coronary syndrome (STE-ACS). DESIGN: Non-randomised, single-centre feasibility trial. SETTING: Department of emergency medicine of a tertiary-care facility, Medical University of Vienna, Vienna, Austria. In cooperation with the Municipal ambulance service of the city of Vienna. PATIENTS: Consecutive patients with STE ACS presenting to the emergency medical service within 6 h after symptom onset. INTERVENTIONS: Cooling was initiated with surface cooling pads in the out-of hospital setting, followed by the administration of 1000-2000 mL of cold saline at hospital arrival and completed by endovascular cooling in the catheterisation laboratory. MAIN OUTCOME MEASURES: Feasibility of lowering core temperature below 35.0 degrees C prior to immediately performed revascularisation. Safety and tolerability of the cooling procedure. RESULTS: In enrolled 19 patients (one woman, median age 51 years (IQR 45-59)), symptom onset to first medical contact (FMC) was 45 min (IQR 31-85). A core temperature below 35.0 degrees C at reperfusion of the culprit lesion was achieved in 11 patients (78%) within 100 min (IQR 90-111) after FMC without any cooling-related serious adverse event. Temperature could be lowered from baseline 36.4 degrees C (IQR 36.2-36.5 degrees C) to 34.4 degrees C (IQR 34.1-35.0 degrees C) at the time of reperfusion. CONCLUSIONS: With limitations an immediate out-of-hospital therapeutic hypothermia strategy was feasible and safe in patients with STE-ACS undergoing primary PCI. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov/ct2/show/NCT01864343; clinical trials unique identifier: NCT01864343. PMID- 24064229 TI - Cardiac arrest in concomitant Wolff-Parkinson-White syndrome and early repolarisation: is pathway ablation enough? PMID- 24064231 TI - 5alpha-Reductase inhibitor is less effective in men with small prostate volume and low serum prostatic specific antigen level. AB - BACKGROUND/PURPOSE: Large total prostate volumes (TPVs) or high serum prostate specific antigen (PSA) levels indicate high-risk clinical progression of benign prostatic hyperplasia. This prospective study investigated the treatment outcome of combined 5alpha-reductase inhibitor and alpha-blocker in patients with and without large TPVs or high PSA levels. METHODS: Men aged >= 45 years with International Prostate Symptom scores (IPSS) >= 8, TPV >= 20 mL, and maximum flow rate <= 15 mL/s received a combination therapy (dutasteride plus doxaben) for 2 years. Patients with baseline PSA >= 4 ng/mL underwent prostatic biopsy for excluding malignancy. The changes in the parameters from baseline to 24 months after combination therapy were compared in those with and without TPV >= 40 mL or PSA levels >= 1.5 ng/mL. RESULTS: A total of 285 patients (mean age 72 +/- 9 years) completed the study. Combination therapy resulted in significant continuous improvement in IPSS, quality of life index, maximum flow rate, and postvoid residual (all p < 0.0001) regardless of baseline TPV or PSA levels. However, only patients with baseline TPV >= 40 mL had significant improvements in IPSS-storage subscore, voided volume, reduction in TPV, transitional zone index, and PSA levels. In addition, patients with baseline TPV < 40 mL and PSA < 1.5 ng/mL had neither a reduction in TPV nor a decrease in serum PSA level. CONCLUSION: A high TPV indicates more outlet resistance, whereas elevated serum PSA level reflects glandular proliferation. Thus, patients with TPV<40 mL and low PSA levels has less benefit from 5alpha-reductase inhibitor therapy. The therapeutic effect of combined treatment may arise mainly from the alpha-blocker in these patients. PMID- 24064230 TI - New developments of alignment-free sequence comparison: measures, statistics and next-generation sequencing. AB - With the development of next-generation sequencing (NGS) technologies, a large amount of short read data has been generated. Assembly of these short reads can be challenging for genomes and metagenomes without template sequences, making alignment-based genome sequence comparison difficult. In addition, sequence reads from NGS can come from different regions of various genomes and they may not be alignable. Sequence signature-based methods for genome comparison based on the frequencies of word patterns in genomes and metagenomes can potentially be useful for the analysis of short reads data from NGS. Here we review the recent development of alignment-free genome and metagenome comparison based on the frequencies of word patterns with emphasis on the dissimilarity measures between sequences, the statistical power of these measures when two sequences are related and the applications of these measures to NGS data. PMID- 24064232 TI - Deciphering the combination principles of Traditional Chinese Medicine from a systems pharmacology perspective based on Ma-huang Decoction. AB - ETHNOPHARMACOLOGY RELEVANCE: The main therapeutic concept in Traditional Chinese Medicine (TCM) is herb formula, which treats various diseases via potential herb interactions to maximize the efficacy and minimize the adverse effects. However, the combination principle of herb formula still remains a mystery due to the lack of appropriate methods. METHODS: A systems pharmacology method integrating the pharmacokinetic analysis, drug targeting, and drug-target-disease network is developed to dissect this rule embedded in the herbal formula. All these are exemplified by a representative TCM formula, Ma-huang decoction, made up of four botanic herbs. RESULTS: Based on the deep investigation of the function and compatibility of each herb, in a molecular/systems level, we demonstrate the different pharmacological roles that each herb might play in the prescription. By the way of enhancing the bioavailability and/or making the pharmacological synergy among different herbs, the four herbs effectively combine together to be suitable for treating diseases. CONCLUSIONS: The present work lays foundations for a more comprehensive understanding of the combination rule of TCM, which might also be beneficial to drug development and applications. PMID- 24064233 TI - Dietary Hizikia fusiformis glycoprotein-induced IGF-I and IGFBP-3 associated to somatic growth, polyunsaturated fatty acid metabolism, and immunity in juvenile olive flounder Paralichthys olivaceus. AB - This study was aimed to examine the effect of dietary glycoprotein extracted from the sea mustard Hizikia fusiformis (Phaeophyceae: Sargassaceae) as a dietary supplement on growth performance in association with somatotropin level, proximate compositions, and immunity in juvenile olive flounder Paralichthys olivaceus. Water-ethanol extracted glycoprotein from H. fusiformis was supplemented to three fishmeal-based diets at the concentration of 0, 5, and 10gkg(-1) diet (designated as H0, H5, and H10, respectively). After a 12week-long feeding trial, growth performance and biochemical responses were analyzed including proximate composition, and whole body amino acids and fatty acids. We also measured plasma insulin like growth factor (IGF), IGF-binding protein (IGFBP) and interleukin (IL). The fish fed H5 showed the greatest weight gain among the dietary treatments. In parallel with the growth, the fish fed the diets containing H. fusiformis glycoprotein showed an increased plasma IGF-I activity and increased expression of 43-kDa IGFBP-3 compared to that in the control, whereas an opposite trend was observed for 34-kDa IGFBP-1. Although no differences were found in the level of whole body linoleic acid (C18:2n-6) and linolenic acid (C18:3n-3) among treatments, increases in arachidonic acid (ARA, C20:4n-6), eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) were observed in fish fed H5 compared to control. IL-2 and -6 levels increased significantly in fish fed H10 compared to those in the control indicating increased immunity. These results suggest that supplementation of H. fusiformis glycoprotein in fish diet may be beneficial for fish growth and immunity in juvenile olive flounder. PMID- 24064235 TI - Expression of immune system-related genes during ontogeny in experimentally wounded common carp (Cyprinus carpio) larvae and juveniles. AB - We investigated the effect of full-thickness incisional wounding on expression of genes related to the immune system in larvae and juveniles of common carp (Cyprinus carpio). The wounds were inflicted by needle puncture immediately below the anterior part of the dorsal fin on days 7, 14, 28 and 49 after fertilization. We followed the local gene expression 1, 3 and 7 days after wounding by removing head and viscera before extracting RNA from the remaining part of the fish, including the wound area. In addition, we visually followed wound healing. Overall the wounds had regenerated to a point where they were microscopically indistinguishable from normal tissue by day 3 post-wounding in all but the juvenile carp wounded on day 49 post-fertilization. In these juveniles the wounded area was still visible even 7 days post-wounding. On the transcriptional level a very limited response was observed in the investigated genes as a result of the wounding. HSP70 was downregulated 1 and 3 days post-wounding in the smallest larvae. However, HSP70 was differentially expressed at different time points in a similar manner in wounded and mock-wounded groups, thus suggesting a stress effect of the handling, which may have overshadowed some transcriptional effects of the wounding. MMP-9, TGF-beta1 and IgZ1 were slightly but significantly upregulated at few time-points, while no effect of wounding was detected on the expression of IgM, C3, IL-1beta and IL-6 family member M17. PMID- 24064236 TI - Development and validation of a delirium predictive score in older people. AB - BACKGROUND: delirium is frequently under diagnosed in older hospitalised patients. Predictive models have not been widely incorporated in clinical practice. OBJECTIVE: to develop and validate a predictive score for incident delirium. DESIGN AND SETTING: two consecutive observational prospective cohorts (development and validation) in a university affiliated hospital. SUBJECTS: inpatients 65 years and older. METHODS: in the development cohort patients were assessed within the first 48 h of admission, and every 48 h thereafter, using the confusion assessment method to diagnose delirium and data were collected on comorbidity, illness severity, functional status and laboratory. Delirium predictive score (DPS) was constructed in the development cohort using variables associated with incident delirium in the multivariate analysis (P < 0.05), and then tested in a validation cohort of comparable patients, admitted without delirium. Receiver operating characteristic (ROC) analysis and likelihood ratio (LR) were calculated. RESULTS: the development cohort included 374 patients, incident delirium occurred in 25. After multivariate analysis incident delirium was independently associated with lower functional status (Barthel Index) and a proxy for dehydration (elevated urea to creatinine ratio). Using these variables, DPS was constructed with a performance in the ROC curve area of 0.86 (95% CI: 0.82-0.91) and (-) LR = 0.16 and (+) LR = 3.4. The validation cohort included 104 patients and the performance of the score was ROC 0.78 (95% CI: 0.66-0.90). CONCLUSIONS: This simple predictive model highlights functional status and a proxy for dehydration as a useful tool for identifying older patients that may benefit from close monitoring and preventive care for early diagnosis of delirium. PMID- 24064237 TI - Trajectories of social activities from middle age to old age and late-life disability: a 36-year follow-up. AB - OBJECTIVES: to examine the association between 34-year trajectories of social activity, from middle age to old age and late-life disability. METHODS: data from the Swedish Level of Living Survey (LNU) and the Swedish Panel Study of the Oldest Old (SWEOLD) were used. LNU data from 1968, 1981, 1991 and 2000 were merged with SWEOLD data from 1992, 2002 and 2004 to create a longitudinal data set with five observation periods. Trajectories of social activities covered 1968 2002, and late-life disability was measured in 2004. The sample consisted of 729 individuals aged 33-61 at baseline (1968), who participated in at least four observation periods and who were free from mobility limitations at baseline. Four trajectories of social activity were identified and used as predictors of late life disability. RESULTS: reporting low/medium levels of social activity from mid life to old age was the most common trajectory group. Persons reporting continuously low/medium or decreasing levels of social activity had higher odds ratios for late-life disability (OR = 2.33 and OR = 2.15, respectively) compared with those having continuously high levels of activity, even when adjusting for age, sex and mobility limitations, and excluding persons with baseline mobility limitations. CONCLUSIONS: results suggest that the disability risk associated with social activities is related to recent levels of activity, but also that risk may accumulate over time, as indicated by the higher disability risk associated with the continuously low/medium level social activity trajectory. PMID- 24064239 TI - Knottins: disulfide-bonded therapeutic and diagnostic peptides. PMID- 24064238 TI - Peptides or modified peptides as drug molecules. PMID- 24064240 TI - Discovery and applications of naturally occurring cyclic peptides. PMID- 24064241 TI - Opioid peptides: potential for drug development. PMID- 24064242 TI - Pepducins: lipopeptide allosteric modulators of GPCR signaling. PMID- 24064243 TI - All-hydrocarbon stapled peptides as Synthetic Cell-Accessible Mini-Proteins. PMID- 24064244 TI - Beyond cell penetrating peptides: designed molecular transporters. PMID- 24064245 TI - End-capped alpha-helices as modulators of protein function. PMID- 24064246 TI - beta-Hairpin protein epitope mimetic technology in drug discovery. PMID- 24064247 TI - A handful of promises. PMID- 24064248 TI - Alterations in excitatory and inhibitory brainstem interneuronal circuits in fibromyalgia: evidence of brainstem dysfunction. AB - OBJECTIVE: Patients with fibromyalgia syndrome (FMS) perceive stimuli differently and show altered cortical sensory representation maps following peripheral stimulation. Altered sensory gating may play a causal role. METHODS: Blink reflex, blink reflex excitability recovery, and prepulse inhibition of the blink reflex - representing brainstem excitability - were assessed in 10 female patients with FMS and 26 female healthy controls. RESULTS: Unconditioned blink reflex characteristics (R1 latency and amplitude, R2 and R2c latency and area under-the-curve) did not differ significantly between patients and controls. Blink reflex excitability recovery was enhanced in patients versus controls at all intervals tested. Prepulses significantly suppressed R2 area and increased R2 latency in patients and controls. However, R2 area suppression was significantly less in patients than in controls (patients: to 80.0 +/- 28.9%, controls: to 47.8 +/- 21.7%). The general pattern of corresponding changes in R2c was similar. CONCLUSIONS: Blink reflex is normal, whereas blink reflex excitability recovery is enhanced and blink reflex prepulse inhibition is reduced in patients with FMS, suggesting functional changes at the brainstem level in FMS. SIGNIFICANCE: Reduced blink reflex prepulse inhibition concurs with altered sensory gating in patients with FMS. PMID- 24064249 TI - Regional homogeneity abnormalities in patients with transient ischaemic attack: a resting-state fMRI study. AB - OBJECTIVE: To investigate regional activity abnormalities in the resting state in patients with transient ischaemic attack (TIA) using a regional homogeneity (ReHo) method combined with functional magnetic resonance imaging (fMRI) and to examine the relationship between regional activity abnormalities and clinical variables. METHODS: Resting-state fMRI was conducted in 21 patients with right sided TIA and in 21 healthy volunteers. The ReHo was calculated to assess the strength of the local signal synchrony and was compared between the two groups. RESULTS: Compared with the controls, the TIA patients exhibited a decreased ReHo in the right dorsolateral prefrontal cortex (dlPFC), the right inferior prefrontal cortex (iPFC), the right ventral anterior cingulate cortex (vACC) and the right dorsal posterior cingulate cortex (dPCC). In addition, the mean ReHo values in the right dlPFC and the right iPFC were significantly correlated with the Montreal Cognitive Assessment (MoCA) in TIA patients. CONCLUSIONS: Neural activities in the resting state are changed in TIA patients even without visible ischaemic lesions on conventional MRI. The positive correlation between the ReHo of resting-state fMRI and cognition suggests that ReHo could be a promising tool to observe the neurobiological consequences of TIA. SIGNIFICANCE: The present study revealed abnormal local synchronisation of spontaneous neural activities in patients with TIA. PMID- 24064251 TI - Steroid receptor-DNA interactions: toward a quantitative connection between energetics and transcriptional regulation. AB - Steroid receptors comprise an evolutionarily conserved family of transcription factors. Although the qualitative aspects by which individual receptors regulate transcription are well understood, a quantitative perspective is less clear. This is primarily because receptor function is considerably more complex than that of classical regulatory factors such as phage or bacterial repressors. Here we discuss recent advances in placing receptor-specific transcriptional regulation on a more quantitative footing, specifically focusing on the role of macromolecular interaction energetics. We first highlight limitations and challenges associated with traditional approaches for assessing the role of energetics (more specifically, binding affinity) with functional outcomes such as transcriptional activation. We next demonstrate how rigorous in vitro measurements and straightforward interaction models quantitatively relate energetics to transcriptional activity within the cell, and follow by discussing why such an approach is unexpectedly effective in explaining complex functional behavior. Finally, we examine the implications of these findings for considering the unique gene regulatory properties of the individual receptors. PMID- 24064250 TI - Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways. AB - E2A is a member of the E-protein family of transcription factors. Previous studies have reported context-dependent regulation of E2A-dependent transcription. For example, whereas the E2A portion of the E2A-Pbx1 leukemia fusion protein mediates robust transcriptional activation in t(1;19) acute lymphoblastic leukemia, the transcriptional activity of wild-type E2A is silenced by high levels of corepressors, such as the AML1-ETO fusion protein in t(8;21) acute myeloid leukemia and ETO-2 in hematopoietic cells. Here, we show that, unlike the HEB E-protein, the activation domain 1 (AD1) of E2A has specifically reduced corepressor interaction due to E2A-specific amino acid changes in the p300/CBP and ETO target motif. Replacing E2A-AD1 with HEB-AD1 abolished the ability of E2A-Pbx1 to activate target genes and to induce cell transformation. On the other hand, the weak E2A-AD1-corepressor interaction imposes a critical importance on another ETO-interacting domain, downstream ETO-interacting sequence (DES), for corepressor-mediated repression. Deletion of DES abrogates silencing of E2A activity by AML1-ETO in t(8;21) leukemia cells or by ETO-2 in normal hematopoietic cells. Our results reveal an E2A-specific mechanism important for its context-dependent activation and repression function, and provide the first evidence for the differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways. PMID- 24064252 TI - Comparison of three indirect calorimetry devices and three methods of gas collection: a prospective observational study. AB - BACKGROUND & AIMS: Indirect calorimetry was performed for a long time with the DeltatracII((r)) device (Datex, Finland), considered as a reference but no longer produced. This study aims at comparing the energy expenditure (EE), the volume of oxygen (VO2) and carbon dioxide (VCO2) measured by two new available indirect calorimeters, the QuarkRMR((r)) (Cosmed, Italy) and the CCMexpress((r)) (MedGraphic,USA), using three different methods of gas collection, with the DeltatracII((r)) in healthy subjects. METHODS: Twenty-four healthy subjects (15 women and 9 men, age 53 +/- 15 yrs, mean BMI 25.5 +/- 7.1 kg/m(2)) underwent measurements of EE with DeltatracII((r)) using canopy, QuarkRMR((r)) using canopy and CCMexpress((r)) using canopy, face tent and facemask. All measurements were performed for 10 min in random order. Results are presented as mean +/- SD and compared by linear regression, repeated measure one-way ANOVA with Bonferroni's post hoc test and Bland & Altman test. RESULTS: EE was 1630 +/- 340 kcal for DeltatracII((r)) and 1607 +/- 307 kcal, 1741 +/- 360 kcal, 1666 +/- 315 and 1626 +/- 336 kcal for QuarkRMR((r)) and CCMexpress((r)) with canopy, face tent and facemask, respectively (p = 0.001). Compared to DeltatracII((r)), Bland & Altman test showed a mean EE difference (2SD) of 24(220)kcal for QuarkRMR((r)), and 111(260) kcal, -36(304) kcal, 5(402) kcal for CCMexpress((r)) with canopy, face tent and facemask, respectively. There was no systematic over- or underestimation with any device or gas collection method. CONCLUSION: Mean EE was similar between QuarkRMR((r)) and DeltatracII((r)) but not between CCMexpress((r)), in any mode of gas collection, and DeltatracII((r)). Bland & Altman test shows a large variability in EE differences with both devices compared to DeltatracII((r)), highlighting the need for refining their accuracy. PMID- 24064253 TI - Adherence to the Mediterranean diet is associated with the severity of non alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Nutrition has been proposed as a potential environmental factor affecting the risk of non-alcoholic fatty liver disease (NAFLD). In the present study, the impact of adherence to the Mediterranean diet (MD) on the presence and severity of NAFLD was explored. METHODS: Seventy-three consecutive adult patients with recent NAFLD diagnosis were included. Adherence to the MD was estimated with MedDietScore. Demographic and anthropometric data, body composition analysis and several biochemical and inflammatory markers were estimated. Liver stiffness measurements by transient elastography were available in 58 patients and liver biopsies in 34 patients. Fifty-eight patients were matched with 58 healthy controls in terms of age, sex and body mass index. RESULTS: MedDietScore was negatively correlated to patients' serum alanine aminotransferase (p = 0.03) and insulin levels (p = 0.001), insulin resistance index (p = 0.005) and severity of steatosis (p = 0.006) and positively to serum adiponectin levels (p = 0.04). Patients with non-alcoholic steatohepatitis (NASH) exhibited lower adherence to MD (29.3 +/- 3.2 vs. 34.1 +/- 4.4, p = 0.004) compared to those with simple fatty liver. Logistic regression analysis revealed that one unit increase in the MedDietScore was associated with 36% lower likelihood of having NASH (odds ratio: 0.64, 95% confidence interval: 0.45-0.92), after adjusting for sex and abdominal fat level. No difference in the MedDietScore was observed between patients and controls. CONCLUSIONS: Higher adherence to the Mediterranean diet is not associated with lower likelihood of having NAFLD, but it is associated with less degree of insulin resistance and less severe liver disease among patients with NAFLD. PMID- 24064254 TI - The roles of LSD1-mediated epigenetic modifications in maintaining the pluripotency of bladder cancer stem cells. AB - Bladder cancer stem cells (BCSCs) may be the source for tumorigenesis, recurrence, and resistance to treatment of bladder carcinoma. Lysine-specific demethylase 1 (LSD1) plays crucial roles in the pluripotency maintenance of embryonic and cancer stem cells through the epigenetical modification of the associated genes, such as the regulation of bivalent domain at regulatory region of the developmental genes. It has also been found that LSD1 expression is elevated in clinical bladder cancer tissues compared with in normal tissues, and LSD1 knock down could significantly result in the suppression of bladder cancer cell line proliferation. Furthermore, results from our unpublished study showed that elevated levels of LSD1 are highly associated with the grades of the cancers, and more interestingly, LSD1 was mainly presented in the basal layer of bladder carcinoma tissue, co-localizing with BCSCs. Thus we hypothesized that LSD1 is mainly expressed in BCSCs in bladder cancer tissues, and LSD1-mediated epigenetic modification of the developmental genes may play important roles in maintaining pluripotency of BCSCs. LSD1 may become a reliable prognostic indicator and could serve as a molecular target in bladder cancer therapy. PMID- 24064255 TI - Phylogenetic relationships among Neoechinorhynchus species (Acanthocephala: Neoechinorhynchidae) from North-East Asia based on molecular data. AB - Phylogenetic and statistical analyses of DNA sequences of two genes, cytochrome oxidase subunit 1 (cox 1) of the mitochondrial DNA and 18S subunit of the nuclear ribosomal RNA (18S rRNA), was used to characterize Neoechinorhynchus species from fishes collected in different localities of North-East Asia. It has been found that four species can be clearly recognized using molecular markers Neoechinorhynchus tumidus, Neoechinorhynchus beringianus, Neoechinorhynchus simansularis and Neoechinorhynchus salmonis. 18S sequences ascribed to Neoechinorhynchus crassus specimens from North-East Asia were identical to those of N. tumidus, but differed substantially from North American N. crassus. We renamed North-East Asian N. crassus specimens to N. sp., although the possibility that they represent a subspecies of N. tumidus cannot be excluded, taking into account a relatively small distance between cox 1 sequences of North-East Asian specimens of N. crassus and N. tumidus. Maximum likelihood, maximum parsimony and Bayesian inference analyses were performed for phylogeny reconstruction. All the phylogenetic trees showed that North-East Asian species of Neoechinorhynchus analyzed in this study represent independent clades, with the only exception of N. tumidus and N. sp. for 18S data. Phylogenetic analysis has shown that the majority of species sampled (N. tumidus+N. sp., N. simansularis and N. beringianus) are probably very closely related, while N. salmonis occupies separate position in the trees, possibly indicating a North American origin of this species. PMID- 24064256 TI - Hybrid brain-computer interfaces and hybrid neuroprostheses for restoration of upper limb functions in individuals with high-level spinal cord injury. AB - BACKGROUND: The bilateral loss of the grasp function associated with a lesion of the cervical spinal cord severely limits the affected individuals' ability to live independently and return to gainful employment after sustaining a spinal cord injury (SCI). Any improvement in lost or limited grasp function is highly desirable. With current neuroprostheses, relevant improvements can be achieved in end users with preserved shoulder and elbow, but missing hand function. OBJECTIVE: The aim of this single case study is to show that (1) with the support of hybrid neuroprostheses combining functional electrical stimulation (FES) with orthoses, restoration of hand, finger and elbow function is possible in users with high-level SCI and (2) shared control principles can be effectively used to allow for a brain-computer interface (BCI) control, even if only moderate BCI performance is achieved after extensive training. PATIENT AND METHODS: The individual in this study is a right-handed 41-year-old man who sustained a traumatic SCI in 2009 and has a complete motor and sensory lesion at the level of C4. He is unable to generate functionally relevant movements of the elbow, hand and fingers on either side. He underwent extensive FES training (30-45min, 2-3 times per week for 6 months) and motor imagery (MI) BCI training (415 runs in 43 sessions over 12 months). To meet individual needs, the system was designed in a modular fashion including an intelligent control approach encompassing two input modalities, namely an MI-BCI and shoulder movements. RESULTS: After one year of training, the end user's MI-BCI performance ranged from 50% to 93% (average: 70.5%). The performance of the hybrid system was evaluated with different functional assessments. The user was able to transfer objects of the grasp-and release-test and he succeeded in eating a pretzel stick, signing a document and eating an ice cream cone, which he was unable to do without the system. CONCLUSION: This proof-of-concept study has demonstrated that with the support of hybrid FES systems consisting of FES and a semiactive orthosis, restoring hand, finger and elbow function is possible in a tetraplegic end-user. Remarkably, even after one year of training and 415 MI-BCI runs, the end user's average BCI performance remained at about 70%. This supports the view that in high-level tetraplegic subjects, an initially moderate BCI performance cannot be improved by extensive training. However, this aspect has to be validated in future studies with a larger population. PMID- 24064257 TI - Methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson's disease: a meta-analysis. AB - BACKGROUND: The association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson's disease (PD) was controversial in previous studies. The present study was therefore designed to investigate a more reliable estimate. METHODS: 15 studies were identified by a search of PubMed, EBMBASE, PDGENE, Elsevier, Springer Link, CBM (Chinese Biomedical Database), CNKI (Chinese National Knowledge Infrastructure), VIP (Chinese), and Wanfang (Chinese) databases, up to April 2013. Odds ratios (ORs) with corresponding 95% confidence interval (CI) were calculated using fixed effects model or random effects model. The subgroup analyses were made on the ethnicity. RESULTS: MTHFR C677T polymorphism had a significant association with susceptibility to PD in all genetic models (for T vs. C: OR=1.24, 95% CI=1.11 1.38; for TT+CT vs. CC: OR=1.27, 95% CI=1.10-1.46; for TT vs. CC: OR=1.56, 95% CI=1.22-1.98; for TT vs. CT+CC: OR=1.43, 95% CI=1.14-1.79). Subgroup analyses by ethnicity revealed that the association between the MTHFR C677T polymorphism and PD existed in Caucasian population and Asian population. However, no association was detected between the MTHFR A1298C polymorphism and PD. CONCLUSIONS: Results from this meta-analysis supported that the MTHFR C677T polymorphism was associated with an increased risk of PD. The MTHFR A1298C polymorphism may not increase the susceptibility to PD. Further studies are required to confirm our findings. PMID- 24064258 TI - Clinico-electrophysiological profile and predictors of functional outcome in Guillain-Barre syndrome (GBS). AB - INTRODUCTION: Guillain-Barre syndrome (GBS) is an acute polyradiculoneuropathy with varied severity of presentation. AIMS: To study the clinical and electrophysiological profile of patients with GBS and to determine the factors associated with poor functional outcome and need for mechanical ventilation. SETTINGS AND DESIGN: It was a hospital-based prospective observational study. METHODS AND MATERIAL: 90 patients with GBS diagnosed as per Asbury and Cornblath criteria were enrolled and followed up for 6 months. Various epidemiological, clinical and electrophysiological parameters were evaluated. Hughes motor scale was used to measure functional outcome. Factors associated with poor functional outcome and need for mechanical ventilation were determined. RESULTS: 90 patients (56 males; 34 females; mean age of 29.3+/-15.2 years) were enrolled in this study. Amongst these 6 (6.7%) patients died during in-hospital stay. Antecedent infection was present in 29 (32.2%), autonomic dysfunction in 31 (34.4%), bulbar palsy in 21 (23.3%), neck flexor weakness in 52 (57.8%). 60 cases (66.7%) were of axonal variety and 30 (33.3%) of demyelinating variety. On univariate analysis, predictors associated with poor functional outcome at 6 months were autonomic dysfunction (p=0.013), neck flexor weakness (p=0.009), requirement of ventilatory assistance (p=<0.001), MRC sum score<30 on admission (p=<0.001) and axonal pattern on electrophysiological assessment (p=<0.001). On multivariate analysis, MRC sum score<30 on admission (p=0.007) and axonal pattern on electrophysiological assessment (p=<0.001) were independently associated with poor functional outcome at 6 months. Factors associated with need for mechanical ventilation were presence of autonomic dysfunction (p=<0.001), cranial nerve palsy including facial palsy (p=<0.001) and bulbar palsy (p=0.002), neck flexor weakness (p=<0.001), low MRC sum score (<30) (p=0.001), and low proximal CPN CMAP amplitude to distal CPN CMAP amplitude ratio (p=0.042); none of them being significant on multivariate analysis. CONCLUSIONS: Detailed evaluation of the clinical and electrophysiological profile may help in predicting the functional outcome and need for mechanical ventilation in patients with GBS. PMID- 24064259 TI - Depressed mood and quality of life after subarachnoid hemorrhage. AB - BACKGROUND: Cognitive impairment is widely considered the main cause of disability and handicap after subarachnoid hemorrhage (SAH). The impact of depression on recovery after SAH remains poorly defined. We sought to determine the frequency of post-SAH depression, identify risk factors for its development, and evaluate the impact of depression on quality of life (QOL) during the first year of recovery. METHODS: We prospectively studied 216 of 534 SAH patients treated between July 1996 and December 2001 with complete one-year follow-up data. Depression was evaluated with the Center for Epidemiological Studies Depression (CES-D) scale, cognitive status with the Telephone Interview for Cognitive Status (TICS), and QOL with the Sickness Impact Profile (SIP) 3 and 12 months after SAH. RESULTS: Depressed mood occurred in 47% of patients during the first year of recovery; 26% were depressed at both 3 and 12 months. Non-white ethnicity predicted early (3 month) and late (12 month) depressions; early depression was also predicted by previously-diagnosed depression, cigarette smoking, and cerebral infarction, whereas late depression was predicted by prior social isolation and lack of medical insurance. Depression was associated with inferior QOL in all domains of the SIP, and changes in depression status were associated with striking parallel changes in QOL, disability, and cognitive function during the first year of recovery. CES-D scores accounted for over 60% of the explained variance in SIP total scores, whereas TICS performance accounted for no more than 6%. CONCLUSION: Depression affects nearly half of SAH patients during the first year of recovery, and is associated with poor QOL. Systematic screening and early treatment for depression are promising strategies for improving outcome after SAH. PMID- 24064261 TI - Compliance of LC50 and NOEC data with Benford's Law: an indication of reliability? AB - Reliability of research data is essential, especially when potentially far reaching conclusions will be based on them. This is also, amongst others, the case for ecotoxicological data used in risk assessment. Currently, several approaches are available to classify the reliability of ecotoxicological data. The process of classification, such as using the Klimisch score, is time consuming and focuses on the application of standardised protocols and the documentation of the study. The presence of irregularities and the integrity of the performed work, however, are not addressed. The present study shows that Benford's Law, based on the occurrence of first digits following a logarithmic scale, can be applied to ecotoxicity test data for identifying irregularities. This approach is already successfully applied in accounting. Benford's Law can be used as reliability indicator, in addition to existing reliability classifications. The law can be used to efficiently trace irregularities in large data sets of interpolated (no) effect concentrations such as LC50s (possibly the result of data manipulation), without having to evaluate the source of each individual record. Application of the law to systems in which large amounts of toxicity data are registered (e.g., European Commission Regulation concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals) can therefore be valuable. PMID- 24064260 TI - Methyl jasmonate as modulator of Cd toxicity in Capsicum frutescens var. fasciculatum seedlings. AB - Methyl jasmonate (MeJA) elicits protective effects as form of plant response to abiotic stress. However, related studies on plant response to metal stress are insufficient. This study aimed to examine the effects of MeJA on growth and physiological responses of Capsicum frutescens seedlings exposed to cadmium (Cd) stress. The study was performed in an artificial climate chamber. Results showed that 50 mg L-1 Cd significantly impaired the growth of the seedlings by increasing leaf MDA content and decreasing chlorophyll b. These effects were significantly mitigated by MeJA at low concentrations (0.1 umol L-1). The dry weights of different plant parts, chlorophyll content, and leaf catalase and ascorbate peroxidase activities were increased by a low MeJA concentration (0.1 umol L-1) but were decreased by a high MeJA concentration (1000 umol L-1). Significant increases in endogenous jasmonic acid were observed at 48 h after the samples were treated with Cd and 0.1 umol L-1 MeJA. These results suggested that low exogenous MeJA concentrations exhibited protective effects on the growth and physiology of C. frutescens seedlings under Cd stress. PMID- 24064262 TI - Influences of chlorpyrifos on antioxidant enzyme activities of Nilaparvata lugens. AB - The brown planthoppers (Nilaparvata lugens, BPH) resistant to chlorpyrifos were selected in laboratory for eight generations. In the full course, the successive changes of activities of SOD, CAT and POD were analyzed. The analyses revealed that increasing of LD50 value was parallel to increasing of SOD, CAT, and POD, all of which increased gradually generation by generation. qRT-PCR showed that CAT was not directly involved in chlorpyrifos detoxification, but could be transcriptionally induced by chlorpyrifos. The results showed that the change of CAT activity was high correlated with chlorpyrifos toxicity in the full course, indicating that CAT played very important role in BPH antioxidant defense. It was suggested that the significant induction of CAT activity could contribute to enhancing antioxidant capacity in BPH and its population growth. CAT as an oxidative stress biomarker was recommended. PMID- 24064264 TI - Morbidity risks among older adults with pre-existing age-related diseases. AB - Multi-morbidity is common among older adults; however, for many aging-related diseases there is no information for U.S. elderly population on how earlier manifested disease affects the risk of another disease manifested later during patient's lifetime. Quantitative evaluation of risks of cancer and non-cancer diseases for older adults with pre-existing conditions is performed using the Surveillance, Epidemiology, and End Results (SEER) Registry data linked to the Medicare Files of Service Use (MFSU). Using the SEER-Medicare data containing individual records for 2,154,598 individuals, we empirically evaluated age patterns of incidence of age-associated diseases diagnosed after the onset of earlier manifested disease and compared these patterns with those in general population. Individual medical histories were reconstructed using information on diagnoses coded in MFSU, dates of medical services/procedures, and Medicare enrollment/disenrollment. More than threefold increase of subsequent diseases risk was observed for 15 disease pairs, majority of them were i) diseases of the same organ and/or system (e.g., Parkinson disease for patients with Alzheimer disease, HR=3.77, kidney cancer for patients with renal failure, HR=3.28) or ii) disease pairs with primary diseases being fast-progressive cancers (i.e., lung, kidney, and pancreas), e.g., ulcer (HR=4.68) and melanoma (HR=4.15) for patients with pancreatic cancer. Lower risk of subsequent disease was registered for 20 disease pairs, mostly among patients with Alzheimer's or Parkinson's disease, e.g., decreased lung cancer risk among patients with Alzheimer's (HR=0.64) and Parkinson's (HR=0.60) disease. Synergistic and antagonistic dependences in geriatric disease risks were observed among US elderly confirming known and detecting new associations of wide spectrum of age-associated diseases. The results can be used in optimization of screening, prevention and treatment strategies of chronic diseases among U.S. elderly population. PMID- 24064266 TI - Optimizing the physical form - opportunities and limitations. PMID- 24064265 TI - Formulation technologies to overcome poor drug-like properties. PMID- 24064267 TI - The use of amorphous solid dispersions: A formulation strategy to overcome poor solubility and dissolution rate. PMID- 24064268 TI - Overcoming poor oral bioavailability using nanoparticle formulations - opportunities and limitations. PMID- 24064270 TI - Insight of current technologies for oral delivery of proteins and peptides. PMID- 24064269 TI - Lipid-based formulations for oral delivery of lipophilic drugs. PMID- 24064271 TI - Overcoming poor permeability: translating permeation enhancers for oral peptide delivery. PMID- 24064272 TI - Overcoming poor permeability - the role of prodrugs for oral drug delivery. PMID- 24064273 TI - Smart polymers for peptide and protein parenteral sustained delivery. PMID- 24064274 TI - Formulation technologies to overcome unfavorable properties of peptides and proteins for pulmonary delivery. PMID- 24064275 TI - Peptide and protein transdermal drug delivery. PMID- 24064276 TI - Enhanced brain drug delivery: safely crossing the blood-brain barrier. PMID- 24064277 TI - Enhanced permeability and retention effect for selective targeting of anticancer nanomedicine: are we there yet? PMID- 24064278 TI - siRNA as a conventional drug in the clinic? Challenges and current technologies. PMID- 24064279 TI - Anodal tDCS over SMA decreases the probability of withholding an anticipated action. AB - Previous research has shown that the supplementary motor area (SMA) is critical in movement inhibition. Recently it was shown that applying transcranial direct current stimulation (tDCS) over SMA affected participants' ability to inhibit their movement in a stop-signal reaction time task (Hsu et al. [11]). Of interest in the current study was whether modulating SMA excitability using tDCS would have similar effects in an anticipation-timing stop-signal task. Participants performed 2 sessions each consisting of a pre- and post-tDCS block of 160 trials in which they were instructed to extend their wrist concurrently with the arrival of a pointer to a target (i.e., a clock hand reaching a set position). In 20% of trials (stop trials) the pointer stopped 80, 110, 140, 170, or 200 ms prior to the target, and on these trials participants were instructed to inhibit their movement if possible. Anodal and cathodal tDCS (separated by at least 48 h) was applied for each participant between the pre- and post-tDCS blocks. No change in the proportion of successfully inhibited movements on stop trials was found following cathodal tDCS (p>.05). However, anodal tDCS resulted in a decreased proportion of successfully inhibited movements on stop trials (p=002), and an earlier movement onset on control trials (p<.01). This suggests that the SMA may be more involved in initiation than in inhibition of anticipatory movements. Furthermore these data suggest that differences in initiation and inhibitory processes exist between stop-signal reaction time and anticipation-timing stop signal tasks. PMID- 24064280 TI - Icaritin opposes the development of social aversion after defeat stress via increases of GR mRNA and BDNF mRNA in mice. AB - Icariin is a major constituent of flavonoids isolated from Herba Epimedii. Several previous studies have demonstrated the antidepressant-like effects of icariin. After oral administration of icariin, 19 metabolites of icariin were detected in rat plasma. Icaritin is one such of metabolite of icariin. In this study, a chronic social defeat protocol is used as a mouse model for depression, and the effects of icaritin administration on social avoidance are investigated. The data indicates that icaritin (5mg/kg and 10mg/kg) oral administration opposes the development of social aversion after defeat stress. In vitro corticosterone sensitivity assay demonstrated that icaritin partially restored social defeat induced impairment of glucocorticoid sensitivity. The expressions of GR mRNA and BDNFmRNA in the hippocampus were increased after icaritin treatment. Meanwhile, the social defeat-induced increases in CRH mRNA in hypothalamus were restored by icaritin administration. Our data also suggests that icaritin administration remarkably attenuated the increases in serum IL-6 and TNF-alpha level that occur following exposure to social defeat. In conclusion, icaritin is a novel antidepressant. It partially restored social defeat-induced impairment of glucocorticoid sensitivity, HPA axis hyperactivity. These effects are at least partially attributed to normalization of the GR function and increases in BDNF expression. PMID- 24064281 TI - Alcohol consumption and psychological distress in adolescents: a multi-country study. AB - PURPOSE: To examine the association between alcohol use and psychological distress among adolescents in a range of developing countries. METHODS: Secondary data analysis of the Global School-Based Student Health Survey was conducted using nationally representative data from 12 developing countries: Botswana, Grenada, Indonesia, Kenya, Myanmar, the Philippines, Saint Lucia, Saint Vincent and the Grenadines, the Seychelles, Thailand, Trinidad and Tobago, and Uganda. The surveys were conducted between 2003 and 2008 and involved 32,001 adolescents primarily aged 13-15 years. We used multivariate logistic regression analysis to determine the association between alcohol use and psychological distress. RESULTS: The prevalence of past 30-day alcohol use and lifetime drunkenness varied widely across countries, as did the occurrence of psychological distress (anxiety-induced sleeplessness and/or depression). The risk of psychological distress was significantly higher among adolescents when using alcohol in all countries except Myanmar. In nine of the 12 countries, past 30-day alcohol use was associated with psychological distress, while students who had been drunk at least once in their lifetime had an increased risk of experiencing psychological distress in 11 of the study countries. CONCLUSIONS: The high prevalence of alcohol use among adolescents and the strength of the association with psychological distress present a major public health challenge in developing countries. The urgent need to reduce adolescent alcohol use necessitates the implementation of context- and culture-specific strategies that reduce the physical availability of alcohol. PMID- 24064282 TI - Factors associated With Medicaid providers' recommendation of the HPV vaccine to low-income adolescent girls. AB - PURPOSE: Human papillomavirus (HPV) vaccination in the United States remains a public health challenge with vaccine rates of 50%. Although health care providers can facilitate HPV vaccination, several factors may impede their ability to universally recommend the vaccine. To maximize the potential of HPV vaccines, it is important to understand challenges providers face in the clinical environment. The study sought to identify factors associated with recommendation of the HPV vaccine for low-income adolescents in the early (9-10), target (11-12), early adolescent catch-up (13-14), and late adolescent catch-up (15-17) vaccination groups. METHODS: Surveys were mailed between October 2009 and April 2010 to a random sample of Florida-based physicians serving Medicaid-enrolled adolescents. Data were analyzed in 2013. RESULTS: Among early adolescents, discomfort discussing sexually transmitted infections (STIs) with teens (odds ratio [OR] = 1.75), difficulty ensuring vaccine completion (OR = .73), and discomfort discussing STIs with parents (OR = .44) were associated with recommendation. For target adolescents, discomfort discussing STIs with teens (OR = 2.45), time constraints (OR = .70), vaccine efficacy concerns (OR = .65), discomfort discussing STIs with parents (OR = .33), obstetrics/gynecology (OR = .25) and family medicine (OR = .24) specialty, and non-Hispanic black patient (OR = .15) were associated with recommendation. In early catch-up adolescents, concerns that teens will practice riskier behaviors (OR = .57), discomfort discussing STIs with parents (OR = .47), and family medicine specialty (OR = .20) were associated with recommendation. For late catch-up adolescents, family medicine specialty (OR = .13) was associated with recommendation. CONCLUSIONS: Modifiable factors that impede or influence provider recommendations of HPV vaccines can be addressed through intervention. Overall, findings suggest that efforts should focus on sexuality communication and family medicine specialty. PMID- 24064283 TI - Application of transmission electron tomography for modeling the renal corpuscle. AB - Structural alteration to the microanatomical organization of the glomerular filtration barrier results in proteinuria. Conventional transmission electron microscopy is an important diagnostic tool to assess the degree of ultrastructural damage of the corpusclar filtration unit. However, this approach lacks the ability to collect accurate stereological insights in a relative large tissue volume. Transmission electron tomography offers the ability to gather three-dimensional information with relative ease. Therefore, this contribution aims to highlight what electron tomography can bring to the pathologist in this challenging area of diagnostic practice. Kidney tissue was prepared for routine ultrastructural transmission electron microscopy investigation. Three-dimensional data stacks were automatically acquired by tilting semi-thin sections of 270 nm in an angular range of typically -60 degrees to +60 degrees with 1 degrees increment. Subsequently, models of the filtration unit were produced by computer assisted tracking of structures of interest. This short report illustrates the capability that transmission electron tomography can offer in the fine structure function assessment of the porous fenestrated glomerular capillary endothelium, the underlying basement membrane and the podocyte filtration slits. Furthermore, this approach allows the generation of morphometric data about size, shape and volume alterations of the kidney's filtration barrier at the nanoscale. PMID- 24064284 TI - Elevated cerebrospinal fluid nitrite level in human immunodeficiency virus infected patients with neurosyphilis. AB - BACKGROUND/PURPOSE: Human immunodeficiency virus (HIV) and syphilis coinfection is a common phenomenon. A percentage of neurosyphilis cases is asymptomatic in HIV-infected patients. The diagnosis of neurosyphilis is more difficult because of the alteration of cerebrospinal fluid (CSF) presentation by the HIV itself. The CSF levels of the degradation products of nitric oxide (NO; e.g., nitrate and nitrite) are reportedly elevated in animals and patients with bacterial meningitis. We hypothesized that an elevated CSF nitrite concentration may be present in patients coinfected with HIV and neurosyphilis. METHODS: This cohort study was conducted from January 2007 to June 2008. Forty patients were enrolled and included seven patients in the control group and 33 HIV-infected patients with or without syphilis. Nitrite levels in the serum and the CSF were measured by using the Griess assay. RESULTS: The CSF nitrite levels were significantly higher in HIV-infected patients with neurosyphilis, compared to the control group or patients with HIV infection only or patients with HIV and syphilis coinfection (p = 0.026). The CSF nitrite levels were correlated with the CSF white blood cell counts (Spearman correlation test, r(2) = 0.324; p < 0.001). There was no significant difference between different groups in serum nitrite levels. CONCLUSION: Marked elevation of CSF nitrite level was observed in HIV-infected patients with neurosyphilis. PMID- 24064285 TI - Risk factors for Clostridium difficile-associated diarrhea among hospitalized adults with fecal toxigenic C. difficile colonization. AB - BACKGROUND: Patients with toxigenic Clostridium difficile colonization (tCDC) are at risk of developing C. difficile-associated diarrhea (CDAD). However, the risk factors of hospitalized patients with tCDC developing CDAD are not clear. METHODS: We conducted an 18-month prospective study at a medical ward in a district hospital in southern Taiwan. Within 48 hours of admission, weekly stool samples from asymptomatic hospitalized patients were obtained to detect fecal CDC. A polymerase chain reaction for tcdB was performed to determine toxigenic isolates. CDAD was diagnosed if the patient had diarrhea and toxigenic C. difficile present in a stool sample. RESULTS: A total 483 patients with stool samples were eligible for the study. Eighty-six (17.8%) patients had tCDC after screening, of whom 14 (16.3%) developed CDAD during follow-up. Among those with tCDC, patients with subsequent CDAD were more likely to have diabetes mellitus (p = 0.01) and to have received piperacillin-tazobactam (p = 0.04), or proton-pump inhibitors (PPIs; p = 0.04) than those without developing CDAD. The variables were statistically significant as determined by multivariate analysis. However, the 60-day crude mortality rates among tCDC patients with and without subsequent development of CDAD were similar. CONCLUSION: Diabetes mellitus and recent receipt of piperacillin-tazobactam or PPIs are independent risk factors for the development of CDAD among hospitalized patients with tCDC. PMID- 24064287 TI - Autoimmune diseases-related arthritis in HIV-infected patients in the era of highly active antiretroviral therapy. AB - BACKGROUND: Autoimmune diseases-related arthritis has been rarely reported in HIV 1-infected patients. We aimed to investigate the incidence and clinical manifestations of autoimmune diseases-related arthritis in HIV-infected patients in the era of highly active antiretroviral therapy (HAART) in Taiwan. METHODS: We retrospectively reviewed medical records of all HIV-infected patients who had a diagnosis of autoimmune arthritis between 1993 and 2013. Demographic characteristics, clinical manifestations, serial CD4 and CD8 lymphocyte counts and plasma HIV viral loads, HLA-B27 status, and treatment response to HIV and rheumatic diseases were recorded. RESULTS: During the 20-year study period, totally 26 HIV-infected patients with autoimmune arthritis (0.7%) were diagnosed among 3623 HIV-infected patients. There were 18 patients with ankylosing spondylitis (AS), six with rheumatoid arthritis (RA), one with psoriatic arthritis, and one with Sjogren's syndrome. HLA-B27 antigens were all detected positive of AS patients. Fifteen patients (57.7%) developed autoimmune arthritis after HAART was initiated. The median age and CD4(+) T lymphocyte counts at the diagnosis of autoimmune arthritis were 35 (20-62 years) and 406 (3-695 cells/MUL), respectively. Three patients had typical presentations of Reiter's syndrome. Both AS and RA patients achieved a good virological response with undetectable plasma HIV RNA load 12 months after receiving HAART(85.71% vs. 80%, respectively, p = 0.999). The treatment response to antirheumatic medications were similar between AS patients and RA patients (77.8% vs. 50%, p = 0.3068), but seems to be better than that reported for the general population (30-40%). CONCLUSION: A low prevalence of autoimmune arthritis among HIV-infected patients in the era of HAART was similar to that of the general Taiwanese population. Clinical manifestations of HIV-infected patients were similar to those described in HIV-uninfected patients. However, the treatment response to antirheumatic agents was better in HIV-infected patients in our study. PMID- 24064286 TI - Clinical characteristics and risk factors for mortality in cefepime-resistant Pseudomonas aeruginosa bacteremia. AB - BACKGROUND: To identify the clinical characteristics and risk factors for mortality of patients with cefepime-resistant Pseudomonas aeruginosa (FRPa) bacteremia. METHODS: This retrospective study analyzed adult patients with FRPa bacteremia hospitalized between January 2006 and December 2011. RESULTS: Seventy eight patients (46 male, 32 female; mean age: 72.2 +/- 14.1 years) were included. Of them, 46 (59.0%) had ventilator use and 45 (57.7%) had intensive care unit stay. All the bacteremia episodes were health-care associated or hospital acquired, and 55.1% of FRPa blood isolates were multidrug resistant. The sources of bacteremia were identified in 42 patients (53.8%), with pneumonia being the most common one (28/42; 66.7%). The mean interval between admission and the sample date of the first FRPa-positive blood culture was 45.8 +/- 52.6 days. The mean Pittsburgh bacteremia score was 5.0 +/- 3.4. The 15-day and 30-day mortality rates were 50.0% and 65.4%, respectively. Patients (41; 52.6%) on appropriate antibiotic therapy within 72 hours of the first FRPa-positive blood culture had a higher 30-day survival rate than those without (48.8% vs. 18.9%, p = 0.011 by log rank test). Multivariate analyses revealed that a higher Pittsburgh bacteremia score was an independent risk factor for either 15-day (p = 0.002) or 30-day mortality (p = 0.010), and appropriate antibiotic therapy within 72 hours was an independent protecting factor for either 15-day (p = 0.049) or 30-day mortality (p = 0.017). CONCLUSION: FRPa bacteremia had a high mortality rate. The disease severity and appropriate antimicrobial therapy within 72 hours of positive blood culture were related to the patients' outcome. PMID- 24064288 TI - Virulence factors of uropathogenic Escherichia coli of urinary tract infections and asymptomatic bacteriuria in children. AB - BACKGROUND/PURPOSE: The clinical aspects of virulence genes of uropathogenic Escherichia coli (UPEC) are not fully understood. This study compared the presence of virulence genes in UPEC isolated from urinary tract infections (UTIs) and asymptomatic bacteriuria (ABU) in children. METHODS: The study included children with UTI (n = 15) or ABU (n = 49) treated at Chung-Ang University Yongsan Hospital between 2010 and 2011. The strains were acquired from each urine sample collected, and 18 major virulence genes were detected by polymerase chain reaction. Antimicrobial susceptibility of all UPEC isolates was determined. RESULTS: Sixty-four E. coli strains were isolated from the urine samples. The most commonly identified virulence gene in both groups was fimH (100.0% in the UTI group and 95.9% in the ABU group). The UTI isolates showed a higher prevalence of papEF and fyuA, and a lower prevalence of feoB than ABU isolates (p < 0.01 for all). The profile of virulence gene, fimH(+)kpsMTII(+)feoB(+) also showed a significant difference between the two groups (p < 0.01). Isolates from ABU were more resistant to most antimicrobials tested. The presence of papEF, feoB, and fyuA also correlated with the antimicrobial susceptibility of UPEC. CONCLUSION: The virulence gene repertoire was different in the UPEC of UTI and ABU. The papEF, feoB, and fyuA genes showed meaningful differences between the two groups and may have an important role in the pathogenesis of overt UTI. PMID- 24064289 TI - Evolution of carbapenem resistance in Acinetobacter baumannii: an 18-year longitudinal study from a medical center in northern Taiwan. AB - BACKGROUND: Carbapenem-resistant Acinetobacter baumannii has emerged as an important cause of nosocomial infections with high morbidity and mortality. The carbapenemases, especially class D carbapenem-hydrolyzing oxacillinases (CHDLs), play an important role, but the relationship between their prevalence trend and carbapenem resistance remains unclear. MATERIALS AND METHODS: Between 1995 and 2012, we collected 667 isolates of A. baumannii from a single medical center in northern Taiwan. Pulsed-field gel electrophoresis (PFGE) was used to determine clonality. Antimicrobial susceptibility was determined. Carbapenemase genes and associated genetic structures were detected by polymerase chain reaction. RESULTS: Isolates were heterogeneous on PFGE. Susceptibility to carbapenem decreased steadily over the study period from 88.1% (2001-2003) to <25% (2010 2012), whereas the isolates remained susceptible to colistin (nearly 100%) and partially susceptible to tigecycline (80%). Starting in 2001, isolates carrying the ISAba1-blaOXA-51-like allele were consistently identified. Isolates containing the transposons Tn2006 or Tn2008 first appeared in 2007 with increasing carriage rates from 17.5% (2007-2009) to 50.0% (2010-2012). The IS1008 DeltaISAba3-blaOXA-58-like, blaOXA-72 and metallo-beta-lactamase genes were detected only sporadically. Isolates carrying CHDL genes were resistant to multiple drugs, including carbapenem, but remained susceptible to colistin (100.0%). CONCLUSION: Increased carbapenem resistance in A. baumannii may be caused by the increased prevalence of isolates containing the ISAba1-blaOXA-51 like allele and the transposons Tn2006 and Tn2008. PMID- 24064290 TI - Comparative antimicrobial efficacy of alcohol-based hand rub and conventional surgical scrub in a medical center. AB - BACKGROUND: Hand hygiene is the cornerstone of aseptic techniques to reduce surgical site infection. Conventional surgical scrub is effective for disinfecting a surgeon's hands. However, the compliance of conventional scrub may be hindered by skin damage, allergy, and time. Alcohol-based hand rub has a satisfactory antimicrobial effect, but mostly in laboratory settings. Our aim was to compare a conventional surgical scrub with an alcohol-based hand rub to evaluate antimicrobial efficacy. METHODS: From June 1, 2010 to July 31, 2011, 128 healthcare workers were enrolled in the study. They used an alcohol-based hand rub or a conventional surgical scrub as preoperative hand antisepsis during their routine practice. Hand sampling for cultures were performed before and after operations. Positive culture plates were further processed for pathogen identification. RESULTS: The culture positive rate of the alcohol-based hand rub was 6.2% before operations and 10.8% after operations. Both rates were lower than the conventional surgical scrub [47.6% before operations (p < 0.001) and 25.4% after operations (p = 0.03)]. The most identified pathogens were Gram-positive with coagulase-negative staphylococci being the major pathogen. Multivariate analysis showed that prior hand condition (p = 0.21) and type of surgery such as cardiovascular surgery (p = 0.12) were less relevant, but the alcohol-based hand rub was a significant protective factor for positive hand cultures. CONCLUSION: The alcohol-based hand rub was more efficacious for surgical antisepsis and had sustained efficacy, compared to conventional surgical scrub. We suggest that alcohol-based hand rubs could be an alternative surgical antiseptic in the operative theater. PMID- 24064291 TI - Higher rate of hepatitis events in patients with human immunodeficiency virus, hepatitis B, and hepatitis D genotype II infection: a cohort study in a medical center in southern Taiwan. AB - BACKGROUND: The epidemiology and impact of hepatitis delta virus (HDV) on hepatic outcomes and virological and immunological responses to highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) patients coinfected with hepatitis B virus (HBV) in northern Taiwan have been reported. However, the epidemiology and impact of HDV infection in HIV-HBV coinfection patients in southern Taiwan remains uncertain. METHODS: In this cohort study, a total of 64 HIV patients coinfected with HBV were identified between January 1, 2009 and May 30, 2012. The seroprevalence of anti-HDV antibodies, HDV genotyping, clinical manifestations and hepatic outcomes were compared between the patients with and without HDV coinfection, and laboratory examinations and hepatic outcomes were recorded. RESULTS: Among the 64 HIV patients coinfected with HBV, seven were seropositive for HDV (10.9%). There were no statistically significant differences in risk factors for acquiring HIV infection. During a median observation period of 27.8 months, the adjusted hazard ratio of HDV and HBV genotype (type B vs. non-type B) on hepatitis flare-ups were 62.132 (p = 0.04) and 0.028 (p = 0.01), respectively. All seven patients had genotype II and were HDV viremic. The phylogenetic tree analysis and clinical history evaluation did not identify any clusters of HDV infection. CONCLUSION: HDV infection resulted in higher rate of hepatitis flare-ups, but it did not have a statistical significance on HIV progression and immunological response to HAART. Whether higher rate of HDV viremia has worse impact on the hepatic outcomes requires further investigation. PMID- 24064292 TI - Epidemiology and risk factors of community-onset urinary tract infection caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae in a medical center in Taiwan: a prospective cohort study. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing pathogens have been increasingly identified in community-onset urinary tract infection (UTI). This study was conducted to determine the epidemiology and risk factors of community onset UTI caused by ESBL-producing pathogens, and to determine the correlation of antimicrobial resistance with ESBL detected by phenotypic and genotypic methods. METHODS: The study was conducted from December 2010 to January 2012. Patients with community-onset UTI caused by Enterobacteriaceae were enrolled from the emergency department. The production of ESBL was determined by the phenotypic method (using the combined disk test) or by the genotypic method (using polymerase chain reaction detection). The patients' medical records were reviewed and risk factors were analyzed by multivariate analysis. RESULTS: A total of 376 patients were enrolled and 393 isolates from urine culture were analyzed. Escherichia coli was the most commonly isolated species (259/393 isolates; 65.9%), followed by Klebsiella pneumoniae (42/393 isolates; 10.7%). Fifty-three (13.5%) isolates were phenotypically positive for ESBL production. Nine (2.3%) isolates were phenotypically positive for both ESBL and AmpC beta-lactamase (AmpC) production. Nasogastric tube placement [odds ratio (OR) 2.230; 95% confidence interval (CI) 1.244-3.997; p = 0.007] and hospitalization within the previous 3 months (OR 2.567, 95% CI 1.448-4.551, p = 0.001) were independently associated with the acquisition of ESBL-producing pathogens in community-onset UTI. The ESBL phenotype had a better correlation with resistance to third generation cephalosporins, compared to the ESBL-positive genotype. CONCLUSION: In our study, nasogastric tube placement and hospitalization within the previous 3 months were significantly associated with the acquisition of ESBL-producing pathogens in community-onset UTI. PMID- 24064293 TI - Clinical characteristics, microbiology, and outcomes of prosthetic joint infection in Taiwan. AB - BACKGROUND: Prosthetic joint infection (PJI) after total knee or hip replacement is a devastating complication associated with substantial morbidity and economic cost. The incidence of prosthetic joint infection is increasing as the use of mechanical joint replacement increases. The treatment approach to prosthetic joint infection is based on different clinical situations such as a patient's comorbidities, epidemic microbiology data, and surgical procedures. The aim of our study was to understand clinical characteristics of prosthetic joint infection, the microbiology of the prosthetic joint infection, and the outcomes of different treatment strategies during 2006-2011. METHODS: We retrospectively collected cases of prosthetic joint infection in the National Taiwan University Hospital between January 1, 2006 and December 31, 2011. The patients' characteristics, microbiology, outcomes, and factors associated with treatment success were recorded. RESULTS: One hundred and forty-four patients were identified as having PJI. Of these, 92 patients were entered into per-protocol analysis. Staphylococcus aureus was the most common causative organism (29.9%), followed by coagulase-negative Staphylococci (16.7%), and Enterococci (9.7%). The overall treatment success rate was 50%. Patients who received a two-stage revision had a better outcome, compared to patients who underwent other types of surgeries (70% vs. 32.7%, respectively; p < 0.001). In multivariate analysis, the two-stage revision was significantly associated with treatment success (odds ratio = 3.923, 95% confidence interval = 1.53-10.04). CONCLUSION: Our study demonstrates that Staphylococcus aureus was the most common causative organisms in PJI. Performing two-stage revisions was significantly associated with a better outcome. PMID- 24064294 TI - Drug susceptibility and treatment response of common urinary tract infection pathogens in children. AB - BACKGROUND/PURPOSE: To document the trends of sensitivity and to find whether it is necessary to change antibiotics in selected patients according to the sensitivity test results in our clinical practice. METHODS: We collected urine culture results from 0-18-year-old patients in the National Taiwan University Hospital from January 1, 2003 to October 31, 2012. Their medical chart was reviewed to identify true pathogens responsible for their urinary tract infection (UTI). We checked the percentage of susceptibility of these pathogens to ampicillin, amoxicillin-clavulanate (AMC), cefazolin, cefmetazole, ceftriaxone, gentamicin, and trimethoprim-sulfamethoxazole (TMP-SMX) according to the Clinical and Laboratory Standards Institute (CLSI) guideline. The extended-spectrum-beta lactamases (ESBLs) rate was also checked. In addition, we reviewed the treatment response of different antibiotics. Defervescence within 48 hours after initial antibiotics use was considered responsive. RESULTS: A total of 7758 urine cultures positive for Escherichia coli infection were collected during the 10 year period. The E. coli cefazolin susceptibility rate was 62-73% during 2003 2010, but it dropped to 23% in 2011 and 28% in 2012 after the new CLSI guideline (M100-S21) was released. However, other antibiotics did not show a significant difference. In UTI caused by E. coli, on average, the sensitivity rates for various antibiotics were as follows: cefmetazole, 90%; ceftriaxone, 85%; gentamicin, 77%; AMC, 61%; TMP-SMX, 47%; and ampicillin, 20%. The ESBL rate was also found to increase (2-11%; p < 0.01). The overall response rate of UTI caused by E. coli to first-line antibiotics such as first-generation cephalosporin and/or gentamicin was 78%. CONCLUSION: The susceptibility of common urinary tract pathogens to cefazolin has decreased dramatically since 2010. This trend may be due to the change in the CLSI guideline. Although the susceptibility rate to first-line empirical antibiotics shows a decreasing trend, we found that the clinical response was acceptable for our first-line empirical antibiotics. PMID- 24064295 TI - A population-based analysis of children with pneumonia among intensive care units in Taiwan. AB - BACKGROUND: Pneumonia is a major diagnosis in children that requires intensive care and is a major cause of mortality in critically ill children. A survey on current epidemiology and case fatality-associated conditions is crucial for the care of critically ill children with pneumonia in an intensive care unit (ICU). METHODS: The sex, age, seasonality of admission, area of distribution, and case fatality rate of children younger than 18 years who had pneumonia and were admitted to an ICU during the period 2006-2010 were obtained from the National Health Insurance Research Database (NHIRD) of Taiwan. The enrolled children were grouped by age (0-2 years, 3-5 years, 6-11 years, and 12-17 years). The need for invasive procedures such as endotracheal tube (ET) insertion, mechanical ventilation (MV), tracheostomy, central venous catheter (CVC) insertion, chest tube insertion/drainage, chest surgery, and extracorporeal membranous oxygenation (ECMO) were analyzed to clarify their association with case fatality in critically ill children with pneumonia. RESULTS: Of the 12,577 children enrolled, 7131 (56.7%) were boys and 5446 (43.3%) were girls. The younger age groups had more cases of pneumonia, but less often required invasive procedures. Children 0 2 years old (n = 6083) accounted for approximately one-half (48.4%) of all enrolled children. This group had the lowest case fatality rate (3.1%; 187/6083 children) and lowest need for invasive procedures (31.1%; 1892/6083 children), whereas children in the 12-17 year-old group had the highest case fatality rate (9.9%; 140/1417 children) and the highest need for invasive procedures (59.8%; 847/1417 children) (p < 0.001). The percentage of pneumonia cases was highest in the spring (30.1%) and lowest in the summer (21.7%). The invasive procedures associated with case fatality were ET/MV (OR, 14.31; p < 0.001), CVC insertion (OR, 7.46; p < 0.001), ECMO intervention (OR, 4.59; p < 0.001), and chest tube insertion/drainage (OR, 1.87; p < 0.001). CONCLUSION: The number of cases of pneumonia that required ICU admission was greater among younger children than among older children. Factors associated with the higher case fatality rate included older age at presentation, the need for invasive procedures (e.g., ET/MV, CVC insertion, chest tube insertion/drainage, and ECMO), underlying comorbidities and complications. PMID- 24064296 TI - Loss of beta2-spectrin prevents cardiomyocyte differentiation and heart development. AB - AIMS: beta2-Spectrin is an actin-binding protein that plays an important role in membrane integrity and the transforming growth factor (TGF)-beta signalling pathway as an adaptor for Smads. Loss of beta2-spectrin in mice (Spnb2(-/-)) results in embryonic lethality with gastrointestinal, liver, neural, and heart abnormalities that are similar to those in Smad2(+/-)Smad3(+/-) mice. However, to date, the role of beta2-spectrin in embryogenesis, particularly in heart development, has been poorly delineated. Here, we demonstrated that beta2 spectrin is required for the survival and differentiation of cardiomyocytes, and its loss resulted in defects in heart development with failure of ventricular wall thickening. METHODS AND RESULTS: Disruption of beta2-spectrin in primary muscle cells not only inhibited TGF-beta/Smad signalling, but also reduced the expression of the cardiomyocyte differentiation markers Nkx2.5, dystrophin, and alpha-smooth muscle actin (alpha-SMA). Furthermore, cytoskeletal networks of dystrophin, F-actin, and alpha-SMA in cardiomyocytes were disorganized upon loss of beta2-spectrin. In addition, deletion of beta2-spectrin in mice (Spnb2(tm1a/tm1a)) prevented proper development of the heart in association with disintegration of dystrophin structure and markedly reduced survival. CONCLUSION: These data suggest that beta2-spectrin deficiency leads to inactivation of TGF beta/Smad signalling and contributes to dysregulation of the cell cycle, proliferation, differentiation, and the cytoskeletal network, and it leads to defective heart development. Our data demonstrate that beta2-spectrin is required for proper development of the heart and that disruption of beta2-spectrin is a potential underlying cause of congenital heart defects. PMID- 24064297 TI - A capillary electrophoresis-based enzyme assay for kinetics and inhibition studies of carbonic anhydrase. AB - In the current study, capillary electrophoresis (CE)-based enzyme assay for characterization and inhibition study of bovine carbonic anhydrase II (bCA II) was developed. The developed method is the first CE assay for carbonic anhydrase (CA). The method was optimized in order to get short analysis time, minimal sample volume consumption, and high resolution of substrate and product. The CE conditions were optimized as follows: fused-silica capillary (30 cm effective length*75 MUm i.d.), pressure injection for 5s, 20mM sodium borate buffer (pH 9.0), constant voltage of 15 kV, constant capillary temperature of 25 degrees C, and detection at 260 nm. For precise measurements, uridine was used as an internal standard during optimization of the CE methods. The limits of detection and quantification for p-nitrophenyl acetate (p-NPA) were 3.01 and 9.12 MUM, respectively, whereas for p-nitrophenolate they were 2.05 and 6.22 MUM, respectively. The performance of the developed method was confirmed by determination of kinetic parameters (i.e., K(m) and V(max) of bCA for p-NPA); the inhibition constant (K(i)) was determined for furosemide, a standard inhibitor of CA. The new method proved to be fast and efficient, and it can be used for the investigation of inhibitors of all isoforms of CAs. PMID- 24064298 TI - Degradation of chloroanilines by toluene dioxygenase from Pseudomonas putida T57. AB - In this study, we investigated the ability of Pseudomonas putida toluene dioxygenase to oxidize chloroanilines. Toluene-induced P. putida T57 cells degraded 4-chloroaniline (4CA) more rapidly than toluene-non-induced cells, suggesting that toluene dioxygenase pathway was involved in 4CA degradation. Escherichia coli harboring P. putida T57 genes encoding toluene dioxygenase complex (todC1C2BA) showed 4CA degradation activity, demonstrating that toluene dioxygenase oxidizes 4CA. Thin-layer chromatography (TLC) and mass spectrometry (MS) analyses identified 4-chlorocatechol and 2-amino-5-chlorophenol as reaction products, suggesting that toluene dioxygenase catalyzes both 1,2- and 2,3 dioxygenation of 4CA. A plasmid containing the entire tod operon (todC1C2BADE) was introduced to P. putida T57 to enhance its ability to degrade 4CA. Resulting P. putida T57 (pHK-C1C2BADE) showed 250-fold higher 4CA degradation activity than P. putida T57 parental strain. P. putida T57 (pHK-C1C2BADE) degraded 2 chloroaniline (2CA), 3-chloroaniline (3CA), and 3,4-dichloroaniline (34DCA) as well as 4CA, but not 3,5-dichloroaniline (35DCA). The order of the degradation rate was: 4CA > 3CA > 2CA > 34DCA. PMID- 24064299 TI - Bacterial pyruvate production from alginate, a promising carbon source from marine brown macroalgae. AB - Marine brown macroalgae is a promising source of material for biorefining, and alginate is one of the major components of brown algae. Despite the huge potential availability of alginate, no system has been reported for the production of valuable compounds other than ethanol from alginate, hindering its further utilization. Here we report that a bacterium, Sphingomonas sp. strain A1, produces pyruvate from alginate and secretes it into the medium. High aeration and deletion of the gene for d-lactate dehydrogenase are critical for the production of high concentrations of pyruvate. Pyruvate concentration and productivity were at their maxima (4.56 g/l and 95.0 mg/l/h, respectively) in the presence of 5% (w/v) initial alginate, whereas pyruvate produced per alginate consumed and % of theoretical yield (0.19 g/g and 18.6%, respectively) were at their maxima at 4% (w/v) initial alginate. Concentration of pyruvate decreased after it reached its maximum after cultivations for 2 or 3 days at 145 strokes per minute. Our study is the first report to demonstrate the production of other valuable compounds than ethanol from alginate, a promising marine macroalgae carbon source. PMID- 24064300 TI - Cell dispersion culture for the effective growth of Humicola insolens and efficient enzyme production. AB - We have developed a method for the effective growth of Humicola insolens conducive to efficient enzyme production using a medium containing glucose as a carbon source and extruded soybean meal (ExSBM) as a nitrogen source. Enzymes from Humicola sp. hold promise for biomass degradation, especially of lignocellulosic materials such as rice straw, wood chips, and corn stover. The strain, however, is hard to disperse, so an aggregated form of the fungus in a liquid culture media is generally used, resulting in poor control of the growth process and low enzyme production. This has greatly limited the utilization of this strain, in spite of its potential as an enzyme producer. Surprisingly, the addition of ExSBM improves mycelium dispersion and enzyme production of H. insolens, and the dispersive effect is applicable to other fungi such as Trichoderma and Aspergillus sp. In contrast, defatted soybean meal not treated with an extrusion process has little effect on mycelium cohesion. It therefore appears that the specific three-dimensional structure of ExSBM arising from the extrusion process provides a favorable environment for cell growth, since the composition of ExSBM and soybean meal is essentially identical. The optimum medium for cell dispersion culture essentially consisted of 5% glucose and 0.3% ExSBM. PMID- 24064302 TI - New insight into the structure, reaction mechanism, and biological functions of neutral ceramidase. AB - Ceramidase (CDase) is an enzyme that hydrolyzes the N-acyl linkage between the sphingoid base and fatty acid of ceramide. These enzymes are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasma membrane as a type II membrane protein. The X-ray crystal structure of neutral CDase was recently solved, uncovering a unique structure and reaction mechanism for the enzyme. Neutral CDase contains a zinc ion in the active site that functions as a catalytic center, and the hydrolysis of the N-acyl linkage in ceramide proceeds through a mechanism that is similar to that described for zinc dependent carboxypeptidase. This review describes the structure, reaction mechanism, and biological functions of neutral CDase in association with the molecular evolution, topology, and mechanical conformation. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology. PMID- 24064301 TI - Sphingosine 1-phosphate (S1P) induces COX-2 expression and PGE2 formation via S1P receptor 2 in renal mesangial cells. AB - Understanding the mechanisms of sphingosine 1-phosphate (S1P)-induced cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) formation in renal mesangial cells may provide potential therapeutic targets to treat inflammatory glomerular diseases. Thus, we evaluated the S1P-dependent signaling mechanisms which are responsible for enhanced COX-2 expression and PGE2 formation in rat mesangial cells under basal conditions. Furthermore, we investigated whether these mechanisms are operative in the presence of angiotensin II (Ang II) and of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). Treatment of rat and human mesangial cells with S1P led to concentration-dependent enhanced expression of COX-2. Pharmacological and molecular biology approaches revealed that the S1P dependent increase of COX-2 mRNA and protein expression was mediated via activation of S1P receptor 2 (S1P2). Further, inhibition of Gi and p42/p44 MAPK signaling, both downstream of S1P2, abolished the S1P-induced COX-2 expression. In addition, S1P/S1P2-dependent upregulation of COX-2 led to significantly elevated PGE2 levels, which were further potentiated in the presence of Ang II and IL-1beta. A functional consequence downstream of S1P/S1P2 signaling is mesangial cell migration that is stimulated by S1P. Interestingly, inhibition of COX-2 by celecoxib and SC-236 completely abolished the migratory response. Overall, our results demonstrate that extracellular S1P induces COX-2 expression via activation of S1P2 and subsequent Gi and p42/p44 MAPK-dependent signaling in renal mesangial cells leading to enhanced PGE2 formation and cell migration that essentially requires COX-2. Thus, targeting S1P/S1P2 signaling pathways might be a novel strategy to treat renal inflammatory diseases. PMID- 24064303 TI - Experiences of mothers of infants with congenital heart disease before, during, and after complex cardiac surgery. AB - OBJECTIVE: Experiences of mothers of infants undergoing complex heart surgery were explored to build evidence-based family-centered interventions. BACKGROUND: Congenital heart disease is the most frequent birth defect in the United States and is common worldwide. METHODS: Eight mothers recalled through journal entries their experiences of the days before, during, and after their infant's surgery and shared advice for other mothers. Colaizzi's phenomenological method was utilized for data analysis. A validation survey of seven additional mothers from a support group occurred via email. RESULTS: Six themes were identified and validated: Feeling Intense Fluctuating Emotion; Navigating the Medical World; Dealing with the Unknown; Facing the Possibility of My Baby Dying, Finding Meaning and Spiritual Connection, and the umbrella theme of Mothering Through It All. CONCLUSIONS: Through a clearer understanding of experiences as described by mothers, health-care providers may gain insight as to how to better support mothers of infants undergoing heart surgery. PMID- 24064304 TI - Modified dextrose prolotherapy for recurrent temporomandibular joint dislocation. AB - Conservative interventions with simple procedures and predictable benefits are expected by patients with recurrent dislocation of the temporomandibular joint (TMJ). We have introduced a modified technique of prolotherapy that comprises injection of lignocaine and 50% dextrose at a single site in the posterior periarticular tissues. We studied the effects in 45 younger patients (age range 17-59 years) with non-neurogenic recurrent dislocation of the TMJ, and confirmed the therapeutic effect after more than a year's follow-up. There were appreciable improvements in the number of episodes of dislocation and clicking after the injection. The overall success rate, defined as the absence of any further dislocation or subluxation for more than 6 months, was 41/45 (91%). Of the 41 rehabilitated patients, 26 (63%) required a single injection, 11 (27%) had 2 treatments, and 4 (10%) needed a third injection. All patients tolerated the injections well. The modified dextrose prolotherapy is simple, safe, and cost effective for the treatment of recurrent dislocation of the TMJ. PMID- 24064306 TI - Editorial. PMID- 24064307 TI - Serendipity and VZV drug discovery. PMID- 24064305 TI - Confirmation of in vitro and clinical safety assessment of behentrimonium chloride-containing leave-on body lotions using post-marketing adverse event data. AB - Behentrimonium chloride (BTC) is a straight-chain alkyltrimonium chloride compound commonly used as an antistatic, hair conditioning, emulsifier, or preservative agent in personal care products. Although the European Union recently restricted the use of alkyltrimonium chlorides and bromides as preservatives to <=0.1%, these compounds have been safely used for many years at <=5% in hundreds of cosmetic products for other uses than as a preservative. In vitro, clinical, and controlled consumer usage tests in barrier-impaired individuals were conducted to determine if whole body, leave-on skin care products containing 1-5% BTC cause dermal irritation or any other skin reaction with use. BTC-containing formulations were predicted to be non-irritants by the EpiDerm(r) skin irritation test and the bovine corneal opacity and permeability (BCOP)/chorioallantoic membrane vascular assay (CAMVA) ocular irritation test battery. No evidence of allergic contact dermatitis or cumulative dermal irritation was noted under the exaggerated conditions of human occlusive patch tests. No clinically assessed or self-reported adverse reactions were noted in adults or children with atopic, eczematous, and/or xerotic skin during two-week and four-week monitored home usage studies. These results were confirmed by post marketing data for five body lotions, which showed only 0.69 undesirable effects (mostly skin irritation) reported per million shipped consumer units during 2006 2011; a value consistent with a non-irritating body lotion. No serious undesirable effects were reported during in-market use of the products. Therefore, if formulated in appropriate conditions at 1-5%, BTC will not cause dermal irritation or delayed contact sensitization when used in a whole-body, leave-on product. PMID- 24064308 TI - Practical considerations for developing nucleoside reverse transcriptase inhibitors. PMID- 24064309 TI - Structural biology of the hepatitis C virus proteins. PMID- 24064310 TI - Fueling HIV-1 integrase drug design with structural insights. PMID- 24064311 TI - De novo computer-aided design of novel antiviral agents. PMID- 24064312 TI - In silico virtual screening approaches for anti-viral drug discovery. PMID- 24064314 TI - Taking pictures to take control: Photovoice as a tool to facilitate empowerment among poor and racial/ethnic minority women with HIV. AB - Poor and racial/ethnic minority women comprise the majority of women living with HIV (WLH) in the United States. Race, gender, class, and HIV-based stigmas and inequities limit women's powers over their health and compromise their quality of life. To help WLH counter this powerlessness, we implemented a Photovoice project, called Picturing New Possibilities (PNP), and explored how women experienced empowerment through Photovoice. PNP participants (n = 30) photographed their life experiences, attended 3 group discussions and a community exhibit of their photos, and completed a follow-up interview. We used strategies of Grounded Theory to identify key empowerment themes. Participants described empowerment through enhanced self-esteem, self-confidence, critical thinking skills, and control. Our findings suggest that Photovoice is an important tool for WLH. It offers women a way to access internal strengths and use these resources to improve their quality of life and health. PMID- 24064315 TI - Protein export through the bacterial flagellar type III export pathway. AB - For construction of the bacterial flagellum, which is responsible for bacterial motility, the flagellar type III export apparatus utilizes both ATP and proton motive force across the cytoplasmic membrane and exports flagellar proteins from the cytoplasm to the distal end of the nascent structure. The export apparatus consists of a membrane-embedded export gate made of FlhA, FlhB, FliO, FliP, FliQ, and FliR and a water-soluble ATPase ring complex consisting of FliH, FliI, and FliJ. FlgN, FliS, and FliT act as substrate-specific chaperones that do not only protect their cognate substrates from degradation and aggregation in the cytoplasm but also efficiently transfer the substrates to the export apparatus. The ATPase ring complex facilitates the initial entry of the substrates into the narrow pore of the export gate. The export gate by itself is a proton-protein antiporter that uses the two components of proton motive force, the electric potential difference and the proton concentration difference, for different steps of the export process. A specific interaction of FlhA with FliJ located in the center of the ATPase ring complex allows the export gate to efficiently use proton motive force to drive protein export. The ATPase ring complex couples ATP binding and hydrolysis to its assembly-disassembly cycle for rapid and efficient protein export cycle. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey. PMID- 24064317 TI - Risk of local failure in breast cancer patients with lobular carcinoma in situ at the final surgical margins: is re-excision necessary? AB - PURPOSE: To compare the outcome of patients with invasive breast cancer both with and without lobular carcinoma in situ (LCIS)-positive/close surgical margins after breast-conserving treatment. METHODS AND MATERIALS: We retrospectively studied 2358 patients with T1-T2 invasive breast cancer treated with lumpectomy and radiation therapy from January 1980 to December 2009. Median age was 57 years (range, 24-91 years). There were 82 patients (3.5%) with positive/close LCIS margins (<0.2 cm) and 2232 patients (95.7%) with negative margins. A total of 1789 patients (76%) had negative lymph nodes. Patients who received neoadjuvant chemotherapy were excluded. A total of 1783 patients (76%) received adjuvant systemic therapy. Multivariable analysis (MVA) was performed using Cox's proportional hazards model. RESULTS: The 5-year cumulative incidence of locoregional recurrence (LRR) was 3.2% (95% confidence interval [CI] 2.5%-4.1%) for the 2232 patients with LCIS-negative surgical margins (median follow-up 104 months) and 2.8% (95% CI 0.7%-10.8%) for the 82 patients with LCIS-positive/close surgical margins (median follow-up 90 months). This was not statistically significant (P=.5). On MVA, LCIS-positive margins after the final surgery were not associated with increased risk of LRR (hazard ratio [HR] 3.4, 95% CI 0.5 24.5, P=.2). Statistically significant prognostic variables on Cox's MVA for risk of LRR included systemic therapy (HR 0.5, 95% CI 0.33-0.75, P=.001), number of positive lymph nodes (HR 1.11, 95% CI 1.05-1.18, P=.001), menopausal status (HR 0.96, 95% CI 0.95-0.98, P=.001), and histopathologic grade (grade 3 vs grade 1/2) (HR 2.6, 95% CI 1.4-4.7, P=.003). CONCLUSION: Our results suggest that the presence of LCIS at the surgical margin after lumpectomy does not increase the risk of LRR or the final outcome. These findings suggest that re-excision or mastectomy in patients with LCIS-positive/close final surgical margins is unnecessary. PMID- 24064316 TI - Effects of altered levels of extracellular superoxide dismutase and irradiation on hippocampal neurogenesis in female mice. AB - PURPOSE: Altered levels of extracellular superoxide dismutase (EC-SOD) and cranial irradiation have been shown to affect hippocampal neurogenesis. However, previous studies were only conducted in male mice, and it was not clear if there was a difference between males and females. Therefore, female mice were studied and the results compared with those generated in male mice from an earlier study. METHODS AND MATERIALS: Female wild-type, EC-SOD-null (KO), and EC-SOD bigenic mice with neuronal-specific expression of EC-SOD (OE) were subjected to a single dose of 5-Gy gamma rays to the head at 8 weeks of age. Progenitor cell proliferation, differentiation, and long-term survival of newborn neurons were determined. RESULTS: Similar to results from male mice, EC-SOD deficiency and irradiation both resulted in significant reductions in mature newborn neurons in female mice. EC-SOD deficiency reduced long-term survival of newborn neurons whereas irradiation reduced progenitor cell proliferation. Overexpression of EC SOD corrected the negative impacts from EC-SOD deficiency and irradiation and normalized the production of newborn neurons in OE mice. Expression of neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 were significantly reduced by irradiation in wild-type mice, but the levels were not changed in KO and OE mice even though both cohorts started out with a lower baseline level. CONCLUSION: In terms of hippocampal neurogenesis, EC-SOD deficiency and irradiation have the same overall effects in males and females at the age the studies were conducted. PMID- 24064318 TI - Can we predict plan quality for external beam partial breast irradiation: results of a multicenter feasibility study (Trans Tasman Radiation Oncology Group Study 06.02). AB - PURPOSE: Partial breast irradiation (PBI) after lumpectomy may be an option for selected patients with early breast cancer. A feasibility study of accelerated PBI delivered using external beam 3-dimensional conformal radiation therapy (RT) was undertaken at 8 Australasian centers. The present study evaluated the impact of patient, tumor, and RT technique-related factors on the quality of RT plans as determined by the dose-volume parameters of organs at risk. METHODS AND MATERIALS: Forty-eight patients were enrolled in the study. All RT plans were centrally reviewed using predefined dosimetric criteria before commencement and after completion of protocol therapy. The RT plans of 47 patients met the dose volume constraints, and all 47 patients received PBI to a prescribed dose of 38.5 Gy in 10 fractions. The RT plan quality was determined by volumes of the ipsilateral whole breast, lung, and heart that received 50% and 95%; 30%; and 5% of the prescribed dose, respectively. Patient, tumor, and RT technique-related factors were investigated for association with the parameters of RT plan quality. RESULTS: The ratio of the planning target volume to the ipsilateral whole-breast volume was significantly associated with the ipsilateral breast doses on multiple variable analyses. The distance of the postlumpectomy surgical cavity from the heart and lung were predictive for heart and lung doses, respectively. A distance between surgical cavity and heart of >4 cm typically resulted in <1% of the heart volume receiving 5 Gy or less. It was more difficult to meet the heart dose constraint for left-sided and medially located tumors. CONCLUSIONS: Partial breast irradiation using 3-dimensional conformal RT was feasible within the study constraints. The ratio of planning target volume to ipsilateral whole-breast volume and the distance of surgical cavity from the heart were significant predictors of the quality of treatment plan for external beam PBI. PMID- 24064319 TI - Evaluation of fractional regional ventilation using 4D-CT and effects of breathing maneuvers on ventilation. AB - PURPOSE: Current implementations of methods based on Hounsfield units to evaluate regional lung ventilation do not directly incorporate tissue-based mass changes that occur over the respiratory cycle. To overcome this, we developed a 4 dimensional computed tomography (4D-CT)-based technique to evaluate fractional regional ventilation (FRV) that uses an individualized ratio of tidal volume to end-expiratory lung volume for each voxel. We further evaluated the effect of different breathing maneuvers on regional ventilation. The results from this work will help elucidate the relationship between global and regional lung function. METHODS AND MATERIALS: Eight patients underwent 3 sets of 4D-CT scans during 1 session using free-breathing, audiovisual guidance, and active breathing control. FRV was estimated using a density-based algorithm with mass correction. Internal validation between global and regional ventilation was performed by use of the imaging data collected during the use of active breathing control. The impact of breathing maneuvers on FRV was evaluated comparing the tidal volume from 3 breathing methods. RESULTS: Internal validation through comparison between the global and regional changes in ventilation revealed a strong linear correlation (slope of 1.01, R2 of 0.97) between the measured global lung volume and the regional lung volume calculated by use of the "mass corrected" FRV. A linear relationship was established between the tidal volume measured with the automated breathing control system and FRV based on 4D-CT imaging. Consistently larger breathing volumes were observed when coached breathing techniques were used. CONCLUSIONS: The technique presented improves density-based evaluation of lung ventilation and establishes a link between global and regional lung ventilation volumes. Furthermore, the results obtained are comparable with those of other techniques of functional evaluation such as spirometry and hyperpolarized-gas magnetic resonance imaging. These results were demonstrated on retrospective analysis of patient data, and further research using prospective data is under way to validate this technique against established clinical tests. PMID- 24064320 TI - Self-reported cognitive outcomes in patients with brain metastases before and after radiation therapy. AB - PURPOSE: Patients with brain metastases may experience treatment-related cognitive deficits. In this study, we prospectively assessed the self-reported cognitive abilities of patients with brain metastases from any solid primary cancer before and after irradiation of the brain. METHODS AND MATERIALS: The treatment group (TG) consisted of adult patients (n=50) with brain metastases who received whole or partial irradiation of the brain without having received prior radiation therapy (RT). The control group (CG) consisted of breast cancer patients (n=27) without cranial involvement who were treated with adjuvant RT. Patients were recruited between May 2008 and December 2010. Self-reported cognitive abilities were acquired before RT and 6 weeks, 3 months, and 6 months after irradiation. The information regarding the neurocognitive status was collected by use of the German questionnaires for self-perceived deficits in attention (FEDA) and subjectively experienced everyday memory performance (FEAG). RESULTS: The baseline data showed a high proportion of self-perceived neurocognitive deficits in both groups. A comparison between the TG and the CG regarding the course of self-reported outcomes after RT showed significant between-group differences for the FEDA scales 2 and 3: fatigue and retardation of daily living activities (P=.002) and decrease in motivation (P=.032) with an increase of attention deficits in the TG, but not in the CG. There was a trend towards significance in FEDA scale 1: distractibility and retardation of mental processes (P=.059) between the TG and the CG. The FEAG assessment presented no significant differences. An additional subgroup analysis within the TG was carried out. FEDA scale 3 showed significant differences in the time-related progress between patients with whole-brain RT and those receiving hypofractionated stereotactic RT (P=.025), with less decrease in motivation in the latter group. CONCLUSION: Self-reported attention declined in patients with brain metastases after RT to the brain, whereas it remained relatively stable in breast cancer patients. PMID- 24064321 TI - Combined treatment effects of radiation and immunotherapy: studies in an autochthonous prostate cancer model. AB - PURPOSE: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. METHODS AND MATERIALS: Transgenic mice expressing a model antigen under a prostate specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. RESULTS: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. CONCLUSIONS: Our preclinical model establishes a potential role for the use of combined radiation immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting. PMID- 24064322 TI - Volume-based parameters of 18F-fluorodeoxyglucose positron emission tomography/computed tomography improve disease recurrence prediction in postmastectomy breast cancer patients with 1 to 3 positive axillary lymph nodes. AB - PURPOSE: To determine whether volume-based parameters on pretreatment (18)F fluorodeoxyglucose positron emission tomography/computed tomography in breast cancer patients treated with mastectomy without adjuvant radiation therapy are predictive of recurrence. METHODS AND MATERIALS: We retrospectively analyzed 93 patients with 1 to 3 positive axillary nodes after surgery, who were studied with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography for initial staging. We evaluated the relationship between positron emission tomography parameters, including the maximum standardized uptake value, metabolic tumor volume (MTV), and total lesion glycolysis (TLG), and clinical outcomes. RESULTS: The median follow-up duration was 45 months. Recurrence was observed in 11 patients. Metabolic tumor volume and TLG were significantly related to tumor size, number of involved nodes, nodal ratio, nuclear grade, estrogen receptor (ER) status, and triple negativity (TN) (all P values were <.05). In receiver operating characteristic curve analysis, MTV and TLG showed better predictive performance than tumor size, ER status, or TN (area under the curve: 0.85, 0.86, 0.79, 0.74, and 0.74, respectively). On multivariate analysis, MTV was an independent prognostic factor of locoregional recurrence-free survival (hazard ratio 34.42, 95% confidence interval 3.94-882.71, P=.0008) and disease-free survival (DFS) (hazard ratio 13.92, 95% confidence interval 2.65-103.78, P=.0018). The 3-year DFS rate was 93.8% for the lower MTV group (<53.1; n=85) and 25.0% for the higher MTV group (>=53.1; n=8; P<.0001, log-rank test). The 3-year DFS rate for patients with both ER-positive status and MTV<53.1 was 98.2%; and for those with ER-negative status and MTV>=53.1 it was 25.0% (P<.0001). CONCLUSIONS: Volume-based parameters improve recurrence prediction in postmastectomy breast cancer patients with 1 to 3 positive nodes. The addition of MTV to ER status or TN has potential benefits to identify a subgroup at higher risk for recurrence. PMID- 24064324 TI - The effect of composition on mechanical properties of brushite cements. AB - Due to a fast setting reaction, good biological properties, and easily available starting materials, there has been extensive research within the field of brushite cements as bone replacing material. However, the fast setting of brushite cement gives them intrinsically low mechanical properties due to the poor crystal compaction during setting. To improve this, many additives such as citric acid, pyrophosphates, and glycolic acid have been added to the cement paste to retard the crystal growth. Furthermore, the incorporation of a filler material could improve the mechanical properties when used in the correct amounts. In this study, the effect of the addition of the two retardants, disodium dihydrogen pyrophosphate and citric acid, together with the addition of beta-TCP filler particles, on the mechanical properties of a brushite cement was investigated. The results showed that the addition of low amounts of a filler (up to 10%) can have large effects on the mechanical properties. Furthermore, the addition of citric acid to the liquid phase makes it possible to use lower liquid to-powder ratios (L/P), which strongly affects the strength of the cements. The maximal compressive strength (41.8MPa) was found for a composition with a molar ratio of 45:55 between monocalcium phosphate monohydrate and beta-tricalcium phosphate, an L/P of 0.25ml/g and a citric acid concentration of 0.5M in the liquid phase. PMID- 24064323 TI - Hydrophobic variants of ganglio-tripod amphiphiles for membrane protein manipulation. AB - Membrane proteins operate in unique cellular environments. Once removed from their native context for the purification that is required for most types of structural or functional analyses, they are prone to denature if not properly stabilized by membrane mimetics. Detergent micelles have prominently been used to stabilize membrane proteins in aqueous environments as their amphipathic nature allows for shielding of the hydrophobic surfaces of these bio-macromolecules while supporting solubility and monodispersity in water. This study expands the utility of branched diglucoside-bearing tripod agents, designated ganglio-tripod amphiphiles, with introduction of key variations in their hydrophobic sections and shows how these latter elements can be fine-tuned to maximize membrane protein solubilization while preserving characteristics of these molecules that afford stabilization of rather fragile assemblies. Their efficacy rivals benchmark detergents heavily used today, such as n-dodecyl-beta-d-maltoside. PMID- 24064325 TI - The French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD REIN) cohort study. AB - BACKGROUND: While much has been learned about the epidemiology and treatment of end-stage renal disease (ESRD) in the last 30 years, chronic kidney disease (CKD) before the end-stage has been less investigated. Not enough is known about factors associated with CKD progression and complications, as well as its transition to ESRD. We designed the CKD-renal epidemiology and information network (REIN) cohort to provide a research platform to address these key questions and to assess clinical practices and costs in patients with moderate or advanced CKD. METHODS: A total of 46 clinic sites and 4 renal care networks participate in the cohort. A stratified selection of clinic sites yields a sample that represents a diversity of settings, e.g. geographic region, and public versus for-profit and non-for-profit private clinics. In each site, 60-90 patients with CKD are enrolled at a routine clinic visit during a 12-month enrolment phase: 3600 total, including 1800 with Stage 3 and 1800 with Stage 4 CKD. Follow-up will continue for 5 years, including after initiation of renal replacement therapy. Data will be collected from medical records at inclusion and at yearly intervals, as well as from self-administered patient questionnaires and provider-level questionnaires. Patients will also be interviewed at baseline, and at 1, 3 and 5 years. Healthcare costs will also be determined. Blood and urine samples will be collected and stored for future studies on all patients at enrolment and at study end, and at 1 and 3 years in a subsample of 1200. CONCLUSIONS: The CKD-REIN cohort will serve to improve our understanding of the biological, clinical and healthcare system determinants associated with CKD progression and adverse outcomes as well as of international variations in collaboration with the CKD Outcome and Practice Pattern Study (CKDopps). It will foster CKD epidemiology and outcomes research and provide evidence to improve the health and quality of life of patients with CKD and the performances of the healthcare system in this field. PMID- 24064326 TI - Performance of estimated glomerular filtration rates to monitor change in renal function in kidney transplant recipients. AB - BACKGROUND: Glomerular filtration rate estimates (e-GFR) are often used to evaluate the changes in renal function, but have not been validated for this purpose in kidney transplant recipients (KTRs). The aim of this study was to evaluate the validity of e-GFR for monitoring serial changes in renal function in KTR using directly measured GFR by inulin clearance (I-GFR) as the reference standard. METHODS: Performances of inverse serum creatinine (1/creat) and Cockcroft and Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration formulas were assessed to estimate the changes in I-GFR. RESULTS: A total of 1935 I-GFR clearance procedures were performed in 631 KTRs who underwent serial measurements between 2003 and 2009. The baseline median I-GFR were 51.0 mL/min/1.73 m(2) (confidence interval 95%: 23-84 mL/min/1.73 m(2)]. The performances of 1/creat and formulas for detecting the I GFR variations between two consecutive measurements (n = 1304) were similar. To detect the variations of <20% (increase or decrease), sensitivities ranged between 50 and 56%, and specificities between 64 and 69%. To detect the variations >20% (increase or decrease), sensitivities ranged between 27% and 39%, and specificities between 88 and 97%. Bland-Altman plots confirmed the scattering of values for individual patients. CONCLUSIONS: In a population of Caucasian KTRs, the mean changes in GFR are correctly estimated whatever the formula used in the range of 23-84 mL/min/1.73 m(2) and can thus be applied in population studies. However, in clinical practice, individual changes in GFR evaluated by formulas should be interpreted with caution in KTRs. PMID- 24064328 TI - The role of transesophageal echocardiography in clinical use. AB - Transesophageal echocardiography (TEE) is not only an invaluable diagnostic tool for cardiac patients, but also is essential for cardiac monitoring in critically ill patients in cardiac and non-cardiac surgery settings and in the differential diagnosis of unexplained hemodynamic collapse. The advantage of TEE over transthoracic echocardiography (TTE) is usually clearer images, especially when viewing structures that are difficult to see transthoracically. TEE is essential in monitoring adult and congenital heart surgery perioperatively. The adequacy of the repair can be ensured immediately through a review of TEE images directly after surgery. Although TEE is considered to be relatively safe and noninvasive, TEE-associated complications, such as esophageal laceration, must be taken seriously. Recently, real-time three-dimensional (3D) TEE imaging has played an important role defining valvular and congenital abnormalities and aiding in operative and percutaneous repair. PMID- 24064327 TI - The mitochondrial uncoupler 2,4-dinitrophenol attenuates sodium nitroprusside induced toxicity in Drosophila melanogaster: potential involvement of free radicals. AB - The toxicity of sodium nitroprusside (SNP) (an inducer of oxidative/nitrosative stress) and the attenuation of SNP effects by 2,4-dinitrophenol (DNP) (that induces mild uncoupling of respiration) were evaluated in the Drosophila melanogaster model system. Fly larvae were raised on food supplemented with 1.0 mM SNP, 0.5 or 1.25 mM DNP, or with mixtures 1.0 mM SNP plus 0.5 or 1.25 mM DNP. Food supplementation with SNP decreased larval viability and pupation height whereas supplementation with DNP substantially reversed these changes. Biochemical analyses of oxidative stress markers and activities of antioxidant and associated enzymes were carried out on 2-day-old flies emerged from control larvae and larvae fed on food supplemented with SNP, DNP, or SNP/DNP mixtures. Larval exposure to SNP lowered activities of aconitase, while the presence of DNP reduced the negative impact of SNP by raising aconitase activity back to near control levels. Larval treatment with SNP also elevated the contents of carbonyl protein, uric acid and low molecular mass thiols and produced higher activities of superoxide dismutase, glutathione S-transferase, glucose-6-phosphate dehydrogenase and thioredoxin reductase in adult flies. However, the presence of DNP in the food mixtures prevented SNP-induced changes in thioredoxin reductase and glucose-6-phosphate dehydrogenase activities, as well as uric acid and low molecular-mass thiol content. The potential mechanisms by which DNP exerts protective effects against SNP toxicity are discussed. PMID- 24064329 TI - The epidermal growth factor receptor-tyrosine kinase inhibitor era has changed the causes of death of patients with advanced non-small-cell lung cancer. AB - BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR TKIs) are effective against tumor EGFR-mutated non-small cell lung cancer (NSCLC). Patients with the tumor EGFR-activating mutation (EGFRmu) had superior survival, compared to patients with EGFR wild-type tumors (EGFRwt). Many patients with the EGFRmu have had disease progression with EGFR-TKI treatment because of central nervous system (CNS) metastases. The objective of this retrospective study was to compare the causes of death in patients with a known tumor EGFR mutation status who had been treated with EGFR-TKIs. METHODS: We retrospectively reviewed the chart records of our patients with advanced NSCLC who had received diagnosis, treatment, and supportive and hospice care in our hospital between July 2005 and June 2010. The tumor EGFR mutation status was analyzed by using a DNA sequence method. All enrolled patients had a documented cause of death. RESULTS: Ninety-four patients had documented tumor EGFR data, had received EGFR TKI treatment (either erlotinib or gefitinib), and were with or without previous or salvage systemic chemotherapy. Of the 94 patients, 36 patients had EGFRwt and 58 patients had EGFRmu. The overall patient survival after starting EGFR-TKI treatment was significantly longer in the EGFRmu patients (median 17.2 months) than in the EGFRwt patients (median 11.6 months; p = 0.0058). Twenty-nine patients died of CNS metastases and 65 died of organ failure (other than the CNS). Patients who died of CNS metastases had undergone EGFR-TKI treatment significantly longer than patients who died of other organ failure (median, 8 months vs. 1.9 months; p = 0.0003) with a hazard ratio of 2.308 [95% confidence interval (C.I.), 1.452-3.668; p = 0.0004]. A significantly higher proportion of EGFRmu patients (26 of 58 patients; 44.8%) than EGFRwt patients (3 of 36 patients; 8.3%) (p < 0.001) died of CNS metastases. CONCLUSION: The EGFRmu NSCLC patients survived longer and had a significantly higher probability of mortality due to CNS metastases, compared to the EGFRwt patients. This change in the causes of death was noted after the era of EGFR-TKI treatment, and will have an important impact on the strategies and management of supportive and hospice care for patients. PMID- 24064330 TI - Smiles may go unseen in generalized social anxiety disorder: evidence from binocular rivalry for reduced visual consciousness of positive facial expressions. AB - Research has demonstrated increased attention to negative social cues and reduced attention to positive social cues in generalized social anxiety disorder (GSAD), but little is known about whether GSAD also involves differences in lower levels of visual processing. This study explored visual experience in GSAD compared to participants with generalized anxiety disorder (GAD) and healthy controls using binocular rivalry. Participants were presented with dissimilar images to each eye, and the two images competed for perceptual dominance. Consistent with the hypothesis that GSAD involves a reduced visual salience for positive social cues, we found that smiling faces were dominant for significantly shorter durations in GSAD compared to GAD and controls. Contrasting with our hypothesis of greater visual salience of negative social cues, we found no difference in negative stimuli salience. These findings are consistent with the broader view that a perceiver's affective state directly influences the content of visual consciousness. PMID- 24064331 TI - Responses to voluntary hyperventilation in children with separation anxiety disorder: implications for the link to panic disorder. AB - BACKGROUND: Biological theories on respiratory regulation have linked separation anxiety disorder (SAD) to panic disorder (PD). We tested if SAD children show similarly increased anxious and psychophysiological responding to voluntary hyperventilation and compromised recovery thereafter as has been observed in PD patients. METHODS: Participants were 49 children (5-14 years old) with SAD, 21 clinical controls with other anxiety disorders, and 39 healthy controls. We assessed cardiac sympathetic and parasympathetic, respiratory (including pCO2), electrodermal, electromyographic, and self-report variables during baseline, paced hyperventilation, and recovery. RESULTS: SAD children did not react with increased anxiety or panic symptoms and did not show signs of slowed recovery. However, during hyperventilation they exhibited elevated reactivity in respiratory variability, heart rate, and musculus corrugator supercilii activity indicating difficulty with respiratory regulation. CONCLUSIONS: Reactions to hyperventilation are much less pronounced in children with SAD than in PD patients. SAD children showed voluntary breathing regulation deficits. PMID- 24064332 TI - Autonomic responses and neural-cardiac coupling during individually tailored symptom provocation in obsessive-compulsive disorder. AB - Elevated anxiety in obsessive-compulsive disorder (OCD) has been linked to cortico-limbic hyperactivation, whereas hyperarousal of the autonomous nerve system (ANS) has inconsistently been found. We investigate ANS functioning during symptom provocation with individually tailored OCD-relevant pictures in 14 unmedicated patients and 14 controls and link it to activation in brain areas involved in ANS regulation. In addition to OCD-triggers, aversive and neutral control stimuli were included. Both groups showed increased skin conductance and heart rate changes to aversive control stimuli, whereas only patients demonstrated augmented skin conductance responses to OCD-triggers. Overall ANS hyperarousal in patients relative to controls was found at trend level. Activity in limbic and paralimbic areas in OCD patients was increased to both generally aversive and OCD-relevant stimuli, whereas dorsolateral prefrontal cortex (DLPFC) hyperactivation, covarying with cardiac responses in patients but not in controls, was present for disorder-relevant triggers only. Despite the small study group, these preliminary findings suggest ANS hyperactivity during OCD symptom provocation that could reflect arousal to the perceived threatening value of OCD-triggers and might mediate elevated anxiety. PMID- 24064333 TI - PTSD's underlying symptom dimensions and relations with behavioral inhibition and activation. AB - Reinforcement sensitivity theory (RST) stipulates that individuals have a behavioral activation system (BAS) guiding approach (rewarding) behaviors (Gray, 1971, 1981), and behavioral inhibition system (BIS) guiding conflict resolution between approach and avoidance (punishment) behaviors (Gray & McNaughton, 2000). Posttraumatic stress disorder (PTSD) severity overall relates to both BIS (e.g., Myers, VanMeenen, & Servatius, 2012; Pickett, Bardeen, & Orcutt, 2011) and BAS (Pickett et al., 2011). Using a more refined approach, we assessed specific relations between PTSD's latent factors (Simms, Watson, & Doebbeling, 2002) and observed variables measuring BIS and BAS using 308 adult, trauma-exposed primary care patients. Confirmatory factor analysis and Wald chi-square tests demonstrated a significantly greater association with BIS severity compared to BAS severity for PTSD's dysphoria, avoidance, and re-experiencing factors. Further, PTSD's avoidance factor significantly mediated relations between BIS/BAS severity and PTSD's dysphoria factor. PMID- 24064334 TI - Trauma experience in children and adolescents: an assessment of the effects of trauma type and role of interpersonal proximity. AB - The psychiatric sequelae associated with childhood experience(s) of trauma is complex and distinguishable from that of adult trauma exposure. Categories of impairment associated with experiences of early trauma include internalizing and externalizing emotional and behavioral problems, posttraumatic stress symptomatology, and dissociation. The present study assessed the relationship between the type of trauma experience (i.e., non-interpersonal or interpersonal) and the manifestation of a wide range of psychiatric symptomatology using prospective longitudinal data from a community sample of ethnically diverse children and adolescents (N=1676; ages 4-18). The study also examined the relationship between different types of trauma experiences (e.g., direct, vicarious, interpersonal) and levels of various symptom domains (e.g., anxiety, posttraumatic stress, conduct problems). A number of factors relevant to the relationship between early trauma experience and subsequent impairment including temperament, socioeconomic status, sex, and age were included in the analyses. Results indicated that interpersonal traumas involving significant interpersonal proximity were associated with externalizing problems (i.e., oppositional defiant and conduct problems). Direct trauma experiences and emotionality were positively associated with almost all symptom domains. Implications for the relationship between trauma and developmental psychopathology are discussed. PMID- 24064336 TI - Overexpression of synphilin-1 promotes clearance of soluble and misfolded alpha synuclein without restoring the motor phenotype in aged A30P transgenic mice. AB - Lewy bodies and neurites are the pathological hallmark of Parkinson's disease. These structures are composed of fibrillized and ubiquitinated alpha-synuclein suggesting that impaired protein clearance is an important event in aggregate formation. The A30P mutation is known for its fast oligomerization, but slow fibrillization rate. Despite its toxicity to neurons, mechanisms involved in either clearance or conversion of A30P alpha-synuclein from its soluble state into insoluble fibrils and their effects in vivo are poorly understood. Synphilin 1 is present in Lewy bodies, interacting with alpha-synuclein in vivo and in vitro and promotes its sequestration into aggresomes, which are thought to act as cytoprotective agents facilitating protein degradation. We therefore crossed animals overexpressing A30P alpha-synuclein with synphilin-1 transgenic mice to analyze its impact on aggregation, protein clearance and phenotype progression. We observed that co-expression of synphilin-1 mildly delayed the motor phenotype caused by A30P alpha-synuclein. Additionally, the presence of N- and C-terminal truncated alpha-synuclein species and fibrils were strongly reduced in double transgenic mice when compared with single-transgenic A30P mice. Insolubility of mutant A30P and formation of aggresomes was still detectable in aged double transgenic mice, paralleled by an increase of ubiquitinated proteins and high autophagic activity. Hence, this study supports the notion that co-expression of synphilin-1 promotes formation of autophagic-susceptible aggresomes and consecutively the degradation of human A30P alpha-synuclein. Notably, although synphilin-1 overexpression significantly reduced formation of fibrils and astrogliosis in aged animals, a similar phenotype is present in single- and double-transgenic mice suggesting additional neurotoxic processes in disease progression. PMID- 24064335 TI - Meta-analysis of genome-wide association data identifies novel susceptibility loci for obesity. AB - Obesity is a major public health problem with strong genetic determination. Multiple genetic variants have been implicated for obesity by conducting genome wide association (GWA) studies, primarily focused on body mass index (BMI). Fat body mass (FBM) is phenotypically more homogeneous than BMI and is more appropriate for obesity research; however, relatively few studies have been conducted on FBM. Aiming to identify variants associated with obesity, we carried out meta-analyses of seven GWA studies for BMI-related traits including FBM, and followed these analyses by de novo replication. The discovery cohorts consisted of 21 969 individuals from diverse ethnic populations and a total of over 4 million genotyped or imputed SNPs. The de novo replication cohorts consisted of 6663 subjects from two independent samples. To complement individual SNP-based association analyses, we also carried out gene-based GWA analyses in which all variations within a gene were considered jointly. Individual SNP-based association analyses identified a novel locus 1q21 [rs2230061, CTSS (Cathepsin S)] that was associated with FBM after the adjustment of lean body mass (LBM) (P = 3.57 * 10(-8)) at the genome-wide significance level. Gene-based association analyses identified a novel gene NLK (nemo-like kinase) in 17q11 that was significantly associated with FBM adjusted by LBM. In addition, we confirmed three previously reported obesity susceptibility loci: 16q12 [rs62033400, P = 1.97 * 10(-14), FTO (fat mass and obesity associated)], 18q22 [rs6567160, P = 8.09 * 10(-19), MC4R (melanocortin 4 receptor)] and 2p25 [rs939583, P = 1.07 * 10(-7), TMEM18 (transmembrane protein 18)]. We also found that rs6567160 may exert pleiotropic effects to both FBM and LBM. Our results provide additional insights into the molecular genetic basis of obesity and may provide future targets for effective prevention and therapeutic intervention. PMID- 24064337 TI - Neuronal accumulation of glucosylceramide in a mouse model of neuronopathic Gaucher disease leads to neurodegeneration. AB - Gaucher disease has recently received wide attention due to the unexpected discovery that it is a genetic risk factor for Parkinson's disease. Gaucher disease is caused by the defective activity of the lysosomal enzyme, glucocerebrosidase (GCase; GBA1), resulting in intracellular accumulation of the glycosphingolipids, glucosylceramide and psychosine. The rare neuronopathic forms of GD (nGD) are characterized by profound neurological impairment and neuronal cell death. We have previously described the progression of neuropathological changes in a mouse model of nGD. We now examine the relationship between glycosphingolipid accumulation and initiation of pathology at two pre-symptomatic stages of the disease in four different brain areas which display differential degrees of susceptibility to GCase deficiency. Liquid chromatography electrospray ionization tandem mass spectrometry demonstrated glucosylceramide and psychosine accumulation in nGD brains prior to the appearance of neuroinflammation, although only glucosylceramide accumulation correlated with neuroinflammation and neuron loss. Levels of other sphingolipids, including the pro-apoptotic lipid, ceramide, were mostly unaltered. Transmission electron microscopy revealed that glucosylceramide accumulation occurs in neurons, mostly in the form of membrane delimited pseudo-tubules located near the nucleus. Highly disrupted glucosylceramide-storing cells, which are likely degenerating neurons containing massive inclusions, numerous autophagosomes and unique ultrastructural features, were also observed. Together, our results indicate that a certain level of neuronal glucosylceramide storage is required to trigger neuropathological changes in affected brain areas, while other brain areas containing similar glucosylceramide levels are unaltered, presumably because of intrinsic differences in neuronal properties, or in the neuronal environment, between various brain regions. PMID- 24064338 TI - Hindbrain noradrenergic input to the hypothalamic PVN mediates the activation of oxytocinergic neurons induced by the satiety factor oleoylethanolamide. AB - Oleoylethanolamide (OEA) is a gut-derived endogenous lipid that stimulates vagal fibers to induce satiety. Our previous work has shown that peripherally administered OEA activates c-fos transcription in the nucleus of the solitary tract (NST) and in the paraventricular nucleus (PVN), where it enhances oxytocin (OXY) expression. The anorexigenic action of OEA is prevented by the intracerebroventricular administration of a selective OXY receptor antagonist, suggesting a necessary role of OXYergic mediation of OEA's effect. The NST is the source of direct noradrenergic afferent input to hypothalamic OXY neurons, and therefore, we hypothesized that the activation of this pathway might mediate OEA effects on PVN neurons. To test this hypothesis, we subjected rats to intra-PVN administration of the toxin saporin (DSAP) conjugated to an antibody against dopamine-beta-hydroxylase (DBH) to destroy hindbrain noradrenergic neurons. In these rats we evaluated the effects of OEA (10 mg/kg, ip) on feeding behavior, on c-Fos and OXY immunoreactivity in the PVN, and on OXY immunoreactivity in the posterior pituitary gland. We found that the DSAP lesion completely prevented OEA's effects on food intake, on Fos and OXY expression in the PVN, and on OXY immunoreactivity of the posterior pituitary gland; all effects were maintained in sham-operated rats. These results support the hypothesis that noradrenergic NST PVN projections are involved in the activation of the hypothalamic OXY system, which mediates OEA's prosatiety action. PMID- 24064339 TI - Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes. AB - Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG + IGT is unknown. Twenty-four older (66.7 +/- 0.8 yr) obese (34.2 +/- 0.9 kg/m(2)) adults were categorized as IFG (n = 8), IGT (n = 8), or IFG + IGT (n = 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12 wk of exercise (60 min/day for 5 days/wk at ~85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU.m(2).min( 1)) with [6,6-(2)H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG + IGT (P < 0.05). Exercise reduced glucose iAUCOGTT in IGT only (P < 0.05), and the decrease in glucose iAUCOGTT was inversely correlated with the increase in peripheral but not hepatic insulin sensitivity (P < 0.01). Increased clamp-derived peripheral insulin sensitivity was also correlated with enhanced metabolic flexibility, reduced fasting RQ, and higher nonoxidative glucose disposal (P < 0.05). Adults with IFG + IGT had smaller gains in clamp-derived peripheral insulin sensitivity and metabolic flexibility, which was related to blunted improvements in postprandial glucose. Additional work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training. PMID- 24064340 TI - Altered body composition and energy expenditure but normal glucose tolerance among humans with a long-chain fatty acid oxidation disorder. AB - The development of insulin resistance has been associated with impaired mitochondrial fatty acid oxidation (FAO), but the exact relationship between FAO capacity and glucose metabolism continues to be debated. To address this controversy, patients with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency underwent an oral glucose tolerance test (OGTT) and measurement of energy expenditure, body composition, and plasma metabolites. Compared with controls, patients with LCHAD deficiency had a trend toward higher total body fat and extramyocellular lipid deposition but similar levels of intramyocelluar and intrahepatic lipids. Resting energy expenditure was similar between the groups, but respiratory quotient was higher and total energy expenditure was lower in LCHAD-deficient patients compared with controls. High-molecular-weight (HMW) adiponectin levels were lower and plasma long-chain acylcarnitines were higher among LCHAD-deficient patients. Fasting and post-OGTT levels of glucose, insulin, and ghrelin, along with estimates of insulin sensitivity, were the same between the groups. Despite decreased capacity for FAO, lower total energy expenditure and plasma HMW adiponectin, and increased plasma acylcarnitines, LCHAD-deficient patients exhibited normal glucose tolerance. These data suggest that inhibition of the FAO pathway in humans is not sufficient to induce insulin resistance. PMID- 24064342 TI - Seminoma with bronchial involvement and superior vena cava syndrome: a rare combination. AB - We describe the case of a 45-year-old male who was admitted with clinical signs of superior vena cava syndrome (SVCS). Physical examination showed collar of Stokes and extensive collateral circulation in the neck and anterosuperior thoracic region, as well as a large testicular mass. Fibrobronchoscopy revealed an endobronchial tumour, histopathologically diagnosed as seminoma, with the same characteristics as the testicular biopsy. Treatment was initiated with surgery, chemotherapy and radiotherapy, resulting in a major clinical improvement. We indicate the importance of considering SVCS as an entity related with less common neoplasms such as germ cell tumours. PMID- 24064341 TI - Defective prolactin signaling impairs pancreatic beta-cell development during the perinatal period. AB - Prolactin (PRL) and placental lactogens stimulate beta-cell replication and insulin production in pancreatic islets and insulinoma cells through binding to the PRL receptor (PRLR). However, the contribution of PRLR signaling to beta-cell ontogeny and function in perinatal life and the effects of the lactogens on adaptive islet growth are poorly understood. We provide evidence that expansion of beta-cell mass during both embryogenesis and the postnatal period is impaired in the PRLR(-/-) mouse model. PRLR(-/-) newborns display a 30% reduction of beta cell mass, consistent with reduced proliferation index at E18.5. PRL stimulates leucine incorporation and S6 kinase phosphorylation in INS-1 cells, supporting a role for beta-cell mTOR signaling in PRL action. Interestingly, a defect in the development of acini is also observed in absence of PRLR signaling, with a sharp decline in cellular size in both endocrine and exocrine compartments. Of note, a decrease in levels of IGF-II, a PRL target, in the Goto-Kakizaki (GK) rat, a spontaneous model of type 2 diabetes, is associated with a lack of PRL-mediated beta-cell proliferation in embryonic pancreatic buds. Reduced pancreatic IGF-II expression in both rat and mouse models suggests that this factor may constitute a molecular link between PRL signaling and cell ontogenesis. Together, these results provide evidence that PRL signaling is essential for pancreas ontogenesis during the critical perinatal window responsible for establishing functional beta cell reserve. PMID- 24064343 TI - Iodine mobilization in groundwater system at Datong basin, China: evidence from hydrochemistry and fluorescence characteristics. AB - Characterizing the speciation of iodine in groundwater is essential for understanding its hydrogeochemical behavior in aquifer systems. To quantify the variations in iodine speciation and assess factors controlling the distribution and transformation of iodine, 82 groundwater samples and 1 rain water were collected from the Datong basin, northern China in this study. Factor analysis (FA) and excitation emission matrix with parallel factor analysis (EEM-PARAFAC) were used to clarify the potential relationships among iodine species and other hydrochemical parameters. The iodine concentrations of groundwater range from 6.23 to 1380 MUg L(-1) with 47% of samples exceeding its drinking water level of 150 MUg L(-1) as recommended by the Chinese government. 57% of samples have ratios of iodate to total iodine greater than 60%, while iodide as the major species in 22% of the samples. Significant amounts of organic iodine with concentrations higher than 100 MUg L(-1) were observed in 9 groundwater samples. Redox conditions of groundwater system strongly affect iodine concentration and speciation of inorganic iodine in groundwater, and extremely reducing condition restricts the iodine release from sediments into groundwater. The results of FA show that iodine mobilization in groundwater is related to the nature of dissolved organic matter. EEM-PARAFAC model demonstrates the dominance of terrestrial DOM sources and the presence of microbial activities in groundwater system of the Datong basin. It is proposed that degradation of organic matter and reductive dissolution of iron oxyhydroxides are major hydrogeochemical processes responsible for the mobilization of iodine release and the genesis of organic iodine. PMID- 24064344 TI - Multiple exposures to airborne pollutants and hospital admissions due to diseases of the circulatory system in Santiago de Chile. AB - BACKGROUND: High concentrations of various air pollutants have been associated with hospitalization due to development and exacerbation of cardiovascular diseases. OBJECTIVES: We aimed to assess associations between airborne exposures by particulate matter as well as gaseous air pollutants and hospital admissions due to different cardiovascular disease groups in Santiago de Chile. METHODS: The study was performed in the metropolitan area of Santiago de Chile during 2004 2007. We applied a time-stratified case-crossover analysis taking temporal variation, meteorological conditions and autocorrelation into account. We computed associations between daily ambient concentrations of carbon monoxide (CO), nitrogen dioxide (NO2), particulate matter (PM10 and PM2.5--particulate matter with aerodynamic diameters less than 10 or 2.5 MUm, respectively) or ozone (O3) and hospital admissions for cardiovascular illnesses. RESULTS: We found for CO, NO2, PM10 and PM2.5 adverse relationships to cardiovascular admissions while effect strength and lag depended on the pollutant and on the disease group. By trend, in 1-pollutant models most adverse pollutants were NO2 and particulate matter (PM10 and PM2.5) followed by CO, while in 2-pollutant models effects of PM10 persisted in most cases whereas other effects weakened. In addition the strongest effects seemed to be immediate or with a delay of up to 2 days. Adverse effects of ozone could not be detected. CONCLUSIONS: Our results provided evidence for adverse health effects of combined exposure to airborne pollutants. Different pollutants accounted for varying adverse effects within different cardiovascular disease groups. Taking case numbers and effect strength of all cardiovascular diseases into account, mitigation measures should address all pollutants but especially NO2, PM10, and CO. PMID- 24064345 TI - Effects of rainfall events on the occurrence and detection efficiency of viruses in river water impacted by combined sewer overflows. AB - Rainfall events can introduce large amount of microbial contaminants including human enteric viruses into surface water by intermittent discharges from combined sewer overflows (CSOs). The present study aimed to investigate the effect of rainfall events on viral loads in surface waters impacted by CSO and the reliability of molecular methods for detection of enteric viruses. The reliability of virus detection in the samples was assessed by using process controls for virus concentration, nucleic acid extraction and reverse transcription (RT)-quantitative PCR (qPCR) steps, which allowed accurate estimation of virus detection efficiencies. Recovery efficiencies of poliovirus in river water samples collected during rainfall events (<10%) were lower than those during dry weather conditions (>10%). The log10-transformed virus concentration efficiency was negatively correlated with suspended solid concentration (r(2)=0.86) that increased significantly during rainfall events. Efficiencies of DNA extraction and qPCR steps determined with adenovirus type 5 and a primer sharing control, respectively, were lower in dry weather. However, no clear relationship was observed between organic water quality parameters and efficiencies of these two steps. Observed concentrations of indigenous enteric adenoviruses, GII-noroviruses, enteroviruses, and Aichi viruses increased during rainfall events even though the virus concentration efficiency was presumed to be lower than in dry weather. The present study highlights the importance of using appropriate process controls to evaluate accurately the concentration of water borne enteric viruses in natural waters impacted by wastewater discharge, stormwater, and CSOs. PMID- 24064346 TI - Associations between lung function and alcohol consumption--assessed by both a questionnaire and a blood marker. AB - BACKGROUND: Studies on the influence of alcohol consumption on lung function have shown conflicting results. Self-reported alcohol consumption may be inaccurate. This study used both a validated alcohol questionnaire and a blood marker of heavy alcohol consumption, and examined potential associations with different lung physiological variables. METHODS: The study population (450 subjects) answered an alcohol questionnaire (AUDIT-C) and performed spirometry, body plethysmography and a test for diffusing capacity for CO (DL,CO). Carbohydrate deficient transferrin (CDT), a clinically used blood marker for identifying heavy alcohol consumption, and C-reactive protein (CRP), a marker of systemic inflammation were analysed. RESULTS: Using AUDIT-C, 407 subjects were alcohol drinkers and 29 non-drinkers. Of the alcohol drinkers, 224 subjects were "hazardous drinkers" and 183 "moderate drinkers". Thirty-four subjects had a CDT >=2.0% (=heavy drinkers). There was no difference in lung function between hazardous and moderate drinkers. Heavy drinkers had lower DL,CO (74% vs 83% PN, p = 0.003), more symptoms of chronic bronchitis (p = 0.001) and higher AUDIT-C scores (p < 0.001) than non-heavy drinkers. After adjustments (pack years and CRP) the difference in DL,CO (p = 0.037) remained. Multiple regression showed an association between CDT and both FEV1 (p = 0.004) and DL,CO (p = 0.012) in all alcohol drinkers, but not in never-smokers. The AUDIT-C score was associated with CDT (also after adjustments, p < 0.001) but not with any lung function variable. CONCLUSION: The results from this study suggest that alcohol and particularly heavy drinking has an independent additive negative effect on lung function in smokers. PMID- 24064347 TI - A pilot study assessing the effect of bronchodilator on dynamic hyperinflation in LAM. AB - INTRODUCTION: Positive responses to bronchodilators (BDs) on spirometry can be found in up to 30% of patients with lymphangioleiomyomatosis (LAM). However, no previous studies have investigated the impact of BDs on exercise outcomes, including dynamic hyperinflation (DH). METHODS: A randomised, double-blind, placebo-controlled, crossover trial was conducted on 38 patients with LAM, comparing inhaled placebo versus salbutamol. Pulmonary function tests and a cycle endurance test at 75% of the maximal work capacity, with evaluation of DH by serial measurement of inspiratory capacity (IC), which was the primary endpoint, were performed after each intervention. RESULTS: Although salbutamol produced a slight improvement in airway obstruction, compared with placebo, there was no significant variation in resting IC or air trapping. A total of 18% of the patients met the criteria for a positive response to BD. During submaximal exercise, BD did not reduce DH or dyspnoea nor did it improve exercise tolerance in the entire population. In addition, BD produced only slight improvement in FEV1 and air trapping in patients who had DH during incremental cardiopulmonary exercise testing, without the beneficial effects on exercise outcomes. CONCLUSIONS: Although salbutamol produced a slight improvement in airway obstruction, it did not lead to a reduction in DH or increase in exercise tolerance in patients with LAM. CLINICAL TRIAL REGISTRATION: Brazilian Registry of Clinical Trials (ReBEC); www.ensaiosclinicos.gov.br; registration number: RBR 49sk2j. PMID- 24064349 TI - Co-stimulation with bone morphogenetic protein-9 and FK506 induces remarkable osteoblastic differentiation in rat dedifferentiated fat cells. AB - Dedifferentiated fat (DFAT) cells, which are isolated from mature adipocytes using the ceiling culture method, exhibit similar characteristics to mesenchymal stem cells, and possess adipogenic, osteogenic, chondrogenic, and myogenic potentials. Bone morphogenetic protein (BMP)-2 and -9, members of the transforming growth factor-beta superfamily, exhibit the most potent osteogenic activity of this growth factor family. However, the effects of BMP-2 and BMP-9 on the osteogenic differentiation of DFAT remain unknown. Here, we examined the effects of BMP-2 and BMP-9 on osteoblastic differentiation of rat DFAT (rDFAT) cells in the presence or absence of FK506, an immunosuppressive agent. Co stimulation with BMP-9 and FK506 induced gene expression of runx2, osterix, and bone sialoprotein, and ALP activity compared with BMP-9 alone, BMP-2 alone and BMP-2+FK506 in rDFAT cells. Furthermore, it caused mineralization of cultures and phosphorylation of smad1/5/8, compared with BMP-9 alone. The ALP activity induced by BMP-9+FK506 was not influenced by addition of noggin, a BMP antagonist. Our data suggest that the combination of BMP-9 and FK506 potently induces osteoblastic differentiation of rDFAT cells. PMID- 24064350 TI - The cAMP response element binding protein (CREB) is activated by insulin-like growth factor-1 (IGF-1) and regulates myostatin gene expression in skeletal myoblast. AB - Myostatin, a member of the Transforming Growth Factor beta (TGF-beta) superfamily, plays an important role as a negative regulator of skeletal muscle growth and differentiation. We have previously reported that IGF-1 induces a transient myostatin mRNA expression, through the activation of the Nuclear Factor of Activated T cells (NFAT) in an IP3/calcium-dependent manner. Here we examined the activation of CREB transcription factor as downstream targets of IGF-1 during myoblast differentiation and its role as a regulator of myostatin gene expression. In cultured skeletal myoblast, IGF-1 induced the phosphorylation and transcriptional activation of CREB via IGF-1 Receptor/Phosphatidylinositol 3 Kinase (PI3K)/Phospholipase C gamma (PLC gamma), signaling pathways. Also, IGF-1 induced calcium-dependent molecules such as Calmodulin Kinase II (CaMK II), Extracellular signal-regulated Kinases (ERK), Protein Kinase C (PKC). Additionally, we examined myostatin mRNA levels and myostatin promoter activity in differentiated myoblasts stimulated with IGF-1. We found a significant increase in mRNA contents of myostatin and its reporter activity after treatment with IGF-1. The expression of myostatin in differentiated myoblast was downregulated by the transfection of siRNA-CREB and by pharmacological inhibitors of the signaling pathways involved in CREB activation. By using pharmacological and genetic approaches together these data demonstrate that IGF-1 regulates the myostatin gene expression via CREB transcription factor during muscle cell differentiation. PMID- 24064351 TI - Co-culture with neurotrophic factor secreting cells induced from adipose-derived stem cells: promotes neurogenic differentiation. AB - Adipose-derived stem cells (ADSCs) and bone marrow stem cells (BMSCs) can be equally proper in the treatment of neurodegenerative diseases. However, ADSCs have practical benefits. In this study, we attempted to induce the secretion of neurotrophic factors (NTF) in human ADSCs. We then evaluated the effects of co culture with NTF secreting cells in neural differentiation of human ADSCs. Isolated human ADSCs were induced to neurotrophic factors secreting cells. To evaluate the in vitro effects of NTF-secreting ADSCs on neurogenic differentiation of ADSCs, we used neurogenic induction medium (control group), the combination of neurogenic medium and conditioned medium, or co-cultured NTF secreting ADSCs which were encapsulated in alginate beads (co-culture) for 7 days. ELISA showed increased (by about 5 times) release of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in NTF-secreting ADSCs compared to human ADSCs. Real time RT-PCR analysis revealed that NTF-secreting ADSCs highly expressed NGF and BDNF. In addition, co-culture with NTF-secreting ADSCs could also promote neuronal differentiation relative to gliogenesis. Overall, NTF-secreting ADSCs secrete a range of growth factors whose levels in culture could promote neuronal differentiation and could support the survival and regeneration in a variety of neurodegenerative diseases. PMID- 24064352 TI - Microglial activation of p38 contributes to scorpion envenomation-induced hyperalgesia. AB - Intraplantar (i.pl.) injection of BmK I, a receptor site 3-specific modulator of voltage-gated sodium channels (VGSCs) from the venom of scorpion Buthus martensi Karsch (BmK), was shown to induce long-lasting and spontaneous nociceptive responses as demonstrated through experiments utilizing primary thermal and mirror-imaged mechanical hypersensitivity with different time course of development in rats. In this study, microglia was activated on both sides of L4 L5 spinal cord by i.pl. injection of BmK I. Meanwhile, the activation of p38/MAPK in L4-L5 spinal cord was found to be co-expressed with OX-42, the cell marker of microglia. The unilateral thermal and bilateral mechanical pain hypersensitivity of rat induced by BmK I was suppressed in a dose-dependent manner following pretreatment with SB203580 (a specific inhibitor of p-p38). Interestingly, microglia activity was also reduced in the presence of SB203580, which suggests that BmK I-induced microglial activation is mediated by p38/MAPK pathway. Combined with previously published literature, the results of this study demonstrate that p38-dependent microglial activation plays a role in scorpion envenomation-induced pain-related behaviors. PMID- 24064354 TI - Haematopoietic differentiation is inhibited when Notch activity is enhanced in FLK1(+) mesoderm progenitors. AB - Notch signalling has been implicated during haematopoietic development in vivo and in the differentiation of haematopoietic cells from pluripotent cells in vitro. However interpretation of data from many of these studies has been complicated by the heterogeneous nature of cell populations under study and by the fact that the Notch pathway is active during embryogenesis prior to the development of the haematopoietic system. To define the role of Notch signalling in more precise cell populations during the early stages of haematopoietic development within the aorta-gonad-mesonephros (AGM) microenvironment we co cultured differentiating ESCs on a stromal cell line derived from this region of the embryo. Our co-culture system had no effect on the production of FLK1(+) mesoderm progenitor cells but promoted their subsequent haematopoietic differentiation. We assessed the role of Notch signalling on haematopoietic differentiation of isolated FLK1(+) cells. Notch activity is dynamic and drops to basal levels as FLK1(+) cells commit to a haematopoietic fate. Further reduction of Notch activity by the inducible expression of dominant negative MAML had no functional consequences. In contrast, induction of Notch activity using an inducible NotchIC expression system had an inhibitory effect on haematopoietic differentiation. We used a Cre-mediated recombination strategy whereby NotchIC expressing cells were marked with the hCD2 receptor and observed a reduction in the number of multi-lineage and myeloid colonies derived from NotchIC(+) compared to NotchIC(-) FLK1(+) cells isolated from the same culture. We believe that our culture system represents a good model for haematopoietic development within the AGM microenvironment and our data suggest that haematopoietic commitment of FLK1(+) cells in this setting occurs when Notch activity is below a specific threshold. PMID- 24064353 TI - Protein phosphatase 2A family members (PP2A and PP6) associate with U1 snRNP and the spliceosome during pre-mRNA splicing. AB - Protein phosphorylation and dephosphorylation are both important for multiple steps in the splicing pathway. Members of the PP1 and PP2A subfamilies of phospho serine/threonine phosphatases play essential but redundant roles in the second step of the splicing reaction. PP6, a member of the PP2A subfamily, is the mammalian homolog of yeast Sit4p and ppe1, which are involved in cell cycle regulation; however, the involvement of PP6 in the splicing pathway remains unclear. Here we show that PP2A family members physically associate with the spliceosome throughout the splicing reaction. PP2A holoenzyme and PP6 were found stably associated with U1 snRNP. Together our findings indicate that these phosphatases regulate splicing catalysis involving U1 snRNP and suggest an important evolutionary conserved role of PP2A family phosphatases in pre-mRNA splicing. PMID- 24064355 TI - Sample size and threshold estimation for clinical trials with predictive biomarkers. AB - With the increasing availability of newly discovered biomarkers personalized drug development is becoming more commonplace. Unless evidence of the dependence of clinical benefit on biomarker classification is a priori unequivocal, personalized drug development needs to jointly investigate treatments and biomarkers in clinical trials. Motivated by the development of contemporary cancer treatments, we propose targeting three main questions sequentially in order to determine (1) whether a drug is efficacious, (2) whether a biomarker can personalize treatment, and (3) how to define personalization. For time-to-event data satisfying the Cox proportional hazards model, we show that (1) and (2) may not directly involve the variance of an interaction term but of a contrast with smaller variance. An asymptotically exact covariance matrix for the parameter vector in the CPH model is derived to construct sample size formulae and an inference approach for thresholds of continuous biomarkers. The covariance matrix also reveals strategies for greater efficiency in trial design, for example, when the biomarker is binary or does not modulate the effect of treatment in the control arm. We motivate our approach by studying the outcome of a contemporary cancer study. PMID- 24064356 TI - Hindbrain catecholamine neurons control rapid switching of metabolic substrate use during glucoprivation in male rats. AB - Using the retrogradely transported immunotoxin, antidopamine beta-hydroxylase saporin (DSAP), we showed previously that hindbrain catecholamine neurons innervating corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus are required for glucoprivation-induced corticosterone secretion. Here, we examine the metabolic consequences of the DSAP lesion in male rats using indirect calorimetry. Rats injected into the paraventricular nucleus of the hypothalamus with DSAP or saporin (SAP) control did not differ in energy expenditure or locomotor activity under any test condition. However, DSAP rats had a persistently higher respiratory exchange ratio (RER) than SAPs under basal conditions. Systemic 2-deoxy-D-glucose did not alter RER in DSAP rats but rapidly decreased RER in SAP controls, indicating that this DSAP lesion impairs the ability to switch rapidly from carbohydrate to fat metabolism in response to glucoprivic challenge. In SAP controls, 2-deoxy-D glucose-induced decrease in RER was abolished by adrenalectomy but not adrenal denervation. Furthermore, dexamethasone, a synthetic glucocorticoid, decreased RER in both SAP and DSAP rats. Thus, rapid switching of metabolic substrate use during glucoprivation appears to be due to impairment of the catecholamine mediated increase in corticosterone secretion. Sustained elevation of basal RER in DSAP rats indicates that catecholamine neurons also influence metabolic functions that conserve glucose under basal conditions. PMID- 24064357 TI - GATA4 and GATA6 silencing in ovarian granulosa cells affects levels of mRNAs involved in steroidogenesis, extracellular structure organization, IGF-I activity, and apoptosis. AB - Knockdown of the transcription factors GATA4 and GATA6 in granulosa cells (GCs) impairs folliculogenesis and induces infertility. To investigate the pathways and genes regulated by these factors, we performed microarray analyses on wild-type GCs or GCs lacking GATA4, GATA6, or GATA4/6 (G4(gcko), G6(gcko), and G4/6(gcko)) after in vivo treatment with equine chorionic gonadotropin. GATA4 deletion affected a greater number of genes than GATA6, which correlates with the subfertility observed in G4(gcko) mice and the normal reproductive function found in G6(gcko) animals. An even greater number of genes were affected by the deletion of both factors. Moreover, the expression of FSH receptor, LH receptor, inhibin alpha and beta, versican, pregnancy-associated plasma protein A, and the regulatory unit 2b of protein kinase A, which are known to be crucial for ovarian function, was greatly affected in double GATA4 and GATA6 knockouts when compared with single GATA-deficient animals. This suggests that GATA4 and GATA6 functionally compensate for each other in the regulation of key ovarian genes. Functional enrichment revealed that ovulation, growth, intracellular signaling, extracellular structure organization, gonadotropin and growth factor actions, and steroidogenesis were significantly regulated in G4/6(gcko) mice. The results of this analysis were confirmed using quantitative polymerase chain reaction, immunohistochemical, and biological assays. Treatment of GCs with cAMP/IGF-I, to bypass FSH and IGF-I signaling defects, revealed that most of the affected genes are direct targets of GATA4/6. The diversity of pathways affected by the knockdown of GATA underscores the important role of these factors in the regulation of GC function. PMID- 24064358 TI - Nesfatin-1 in human and murine cardiomyocytes: synthesis, secretion, and mobilization of GLUT-4. AB - Nesfatin-1, a satiety-inducing peptide identified in hypothalamic regions that regulate energy balance, is an integral regulator of energy homeostasis and a putative glucose-dependent insulin coadjuvant. We investigated its production by human cardiomyocytes and its effects on glucose uptake, in the main cardiac glucose transporter GLUT-4 and in intracellular signaling. Quantitative RT-PCR, Western blots, confocal immunofluorescence microscopy, and ELISA of human and murine cardiomyocytes and/or cardiac tissue showed that cardiomyocytes can synthesize and secrete nesfatin-1. Confocal microscopy of cultured cardiomyocytes after GLUT-4 labeling showed that nesfatin-1 mobilizes this glucose transporter to cell peripherals. The rate of 2-deoxy-D-[(3)H]glucose incorporation demonstrated that nesfatin-1 induces glucose uptake by HL-1 cells and cultured cardiomyocytes. Nesfatin-1 induced dose- and time-dependent increases in the phosphorylation of ERK1/2, AKT, and AS160. In murine and human cardiac tissue, nesfatin-1 levels varied with diet and coronary health. In conclusion, human and murine cardiomyocytes can synthesize and secrete nesfatin-1, which is able to induce glucose uptake and the mobilization of the glucose transporter GLUT-4 in these cells. Nesfatin-1 cardiac levels are regulated by diet and coronary health. PMID- 24064359 TI - PPARgamma activation inhibits growth and survival of human endometriotic cells by suppressing estrogen biosynthesis and PGE2 signaling. AB - Endometriosis is a chronic inflammatory disease of reproductive age women leading to chronic pelvic pain and infertility. Current antiestrogen therapies are temporizing measures, and endometriosis often recurs. Potential nonestrogenic or nonsteroidal targets are needed for treating endometriosis. Peroxisome proliferator-activated receptor (PPAR)gamma, a nuclear receptor, is activated by thiazolidinediones (TZDs). In experimental endometriosis, TZDs inhibit growth of endometriosis. Clinical data suggest potential use of TZDs for treating pain and fertility concurrently in endometriosis patients. Study objectives were to 1) determine the effects of PPARgamma action on growth and survival of human endometriotic epithelial and stromal cells and 2) identify the underlying molecular links between PPARgamma activation and cell cycle regulation, apoptosis, estrogen biosynthesis, and prostaglandin E2 biosynthesis and signaling in human endometriotic epithelial and stromal cells. Results indicate that activation of PPARgamma by TZD ciglitazone 1) inhibits growth of endometriotic epithelial cells 12Z up to 35% and growth of endometriotic stromal cells 22B up to 70% through altered cell cycle regulation and intrinsic apoptosis, 2) decreases expression of PGE2 receptors (EP)2 and EP4 mRNAs in 12Z and 22B cells, and 3) inhibits expression and function of P450 aromatase mRNA and protein and estrone production in 12Z and 22B cells through EP2 and EP4 in a stromal epithelial cell-specific manner. Collectively, these results indicate that PGE2 receptors EP2 and EP4 mediate actions of PPARgamma by incorporating multiple cell signaling pathways. Activation of PPARgamma combined with inhibition of EP2 and EP4 may emerge as novel nonsteroidal therapeutic targets for endometriosis associated pain and infertility, if clinically proven safe and efficacious. PMID- 24064360 TI - Regulation of LH receptor mRNA binding protein by miR-122 in rat ovaries. AB - LH receptor (LHR) expression in the ovary is regulated by the RNA binding protein, (LHR mRNA binding protein [LRBP]), which has been identified as being mevalonate kinase. This study examined the role of microRNA miR-122 in LRBP mediated LHR mRNA expression. Real-time PCR analysis of ovaries from pregnant mare serum gonadotropin/human chorionic gonadotropin (hCG)-primed female rats treated with hCG to down-regulate LHR expression showed that an increase in miR 122 expression preceded LHR mRNA down-regulation. The expression of miR-122 and its regulation was confirmed using fluorescent in situ hybridization of the frozen ovary sections using 5'-fluorescein isothiocyanate-labeled miR-122 locked nucleic acid probe. The increased expression of miR-122 preceded increased expression of LRBP mRNA and protein, and these increases were followed by LHR mRNA down-regulation. Inhibition of protein kinase A (PKA) and ERK1/2 signaling pathways by H89 and UO126, respectively, attenuated the hCG-mediated up regulation of miR-122 levels. This was also confirmed in vitro using human granulosa cells. These results suggest the possibility that hCG-mediated miR-122 expression is mediated by the activation of cAMP/PKA/ERK signaling pathways. Inhibition of miR-122 by injection of the locked nucleic acid-conjugated antagomir of miR-122 abrogated the hCG-mediated increases in LRBP protein expression. Because it has been previously shown that miR-122 regulates sterol regulatory element-binding proteins (SREBPs) and SREBPs, in turn, regulate LRBP expression, the role of SREBPs in miR-122-mediated increase in LRBP expression was then examined. The levels of active forms of both SREBP-1a and SREBP-2 were increased in response to hCG treatment, and the stimulatory effect was sustained up to 4 hours. Taken together, our results suggest that hCG-induced down regulation of LHR mRNA expression is mediated by activation of cAMP/PKA/ERK pathways to increase miR-122 expression, which then increases LRBP expression through the activation of SREBPs. PMID- 24064361 TI - Dlk1 up-regulates Gli1 expression in male rat adrenal capsule cells through the activation of beta1 integrin and ERK1/2. AB - The development and maintenance of the zones of the adrenal cortex and their steroidal output are extremely important in the control of gluconeogenesis, the stress response, and blood volume. Sonic Hedgehog (Shh) is expressed in the adrenal cortex and signals to capsular cells, which can respond by migrating into the cortex and converting into a steroidogenic phenotype. Delta-like homologue 1 (Dlk1), a member of the Notch/Delta/Serrate family of epidermal growth factor like repeat-containing proteins, has a well-established role in inhibiting adipocyte differentiation. We demonstrate that Shh and Dlk1 are coexpressed in the outer undifferentiated zone of the male rat adrenal and that Dlk1 signals to the adrenal capsule, activating glioma-associated oncogene homolog 1 transcription in a beta1 integrin- and Erk1/2-dependent fashion. Moreover, Shh and Dlk1 expression inversely correlates with the size of the zona glomerulosa in rats after manipulation of the renin-angiotensin system, suggesting a role in the homeostatic maintenance of the gland. PMID- 24064363 TI - Sex difference in urocortin production is contributory to the gender disparity in a rat model of vasculitis induced by sodium laurate. AB - Cardiovascular diseases, the most common leading death diseases, occur more in men than women of the same ages. Increasing evidence shows that urocortin (Ucn1), an autocrine or paracrine pro-inflammatory factor, can be regulated by sex hormones. The purpose of the study is to investigate the role of Ucn1 in gender disparity in a sodium laurate-induced vasculitis model. Rats exhibited visible signs of vasculitis on the 14th day after sodium laurate injection. Inflammatory states of the rat femoral artery were observed by histological examination. Significant gender disparity, with the symptoms much grosser in males than females, was seen. In males, the serum levels of Ucn1, prostaglandin estradiol, and soluble intercellular adhesion molecule-1 and the expressions of Ucn1, cyclooxygenase-2, and intercellular adhesion molecule-1 in femoral artery were higher than those in females. Orchidectomy significantly ameliorated the symptoms of vasculitis accompanied with a decrease in the plasma Ucn1 level. However, estradiol supplement after orchidectomy failed to improve the inflammatory states further. In females, ovariectomy and/or dihydrotestosterone supplement significantly increased Ucn1 level and exacerbated symptoms of vasculitis. Furthermore, ip administration of rabbit antiserum to Ucn1 almost abolished the gender differences in vasculitis. These results demonstrated that vasculitis of this model is androgen-responsive and hormonal manipulation by surgical orchidectomy could substantially attenuate the symptoms of vasculitis. Moreover, Ucn1 is a contributory factor to the gender disparity in vasculitis and dihydrotestosterone-promoted Ucn1 secretion exacerbated the development of vasculitis. PMID- 24064364 TI - Maternal undernutrition programs tissue-specific epigenetic changes in the glucocorticoid receptor in adult offspring. AB - Epidemiological data indicate that an adverse maternal environment during pregnancy predisposes offspring to metabolic syndrome with increased obesity, and type 2 diabetes. The mechanisms are still unclear although epigenetic modifications are implicated and the hypothalamus is a likely target. We hypothesized that maternal undernutrition (UN) around conception in sheep would lead to epigenetic changes in hypothalamic neurons regulating energy balance in the offspring, up to 5 years after the maternal insult. We found striking evidence of decreased glucocorticoid receptor (GR) promoter methylation, decreased histone lysine 27 trimethylation, and increased histone H3 lysine 9 acetylation in hypothalami from male and female adult offspring of UN mothers. These findings are entirely compatible with the increased GR mRNA and protein observed in the hypothalami. The increased GR predicted the decreased hypothalamic proopiomelanocortin expression and increased obesity that we observed in the 5-year-old adult males. The epigenetic and expression changes in GR were specific to the hypothalamus. Hippocampal GR mRNA and protein were decreased in UN offspring, whereas pituitary GR was altered in a sex-specific manner. In peripheral polymorphonuclear leukocytes there were no changes in GR methylation or protein, indicating that this epigenetic analysis did not predict changes in the brain. Overall, these results suggest that moderate changes in maternal nutrition, around the time of conception, signal life-long and tissue specific epigenetic alterations in a key gene regulating energy balance in the hypothalamus. PMID- 24064366 TI - Delayed ischemic stroke following spontaneous thrombosis of an arteriovenous malformation. AB - Spontaneous obliteration of an arteriovenous malformation (SOAVM) is a rare event that is not completely understood. Less than 100 cases of SOAVMs have been reported in the literature. We present a unique case of a middle-aged patient with spontaneous obliteration of a cerebral arteriovenous malformation (AVM) who developed an ischemic stroke due to thrombosis of the stagnant proximal segment of the inferior branch of the middle cerebral artery feeder. Although the pathophysiology is not well understood, the arterial feeder hemodynamic changes post SOAVM may behave similarly to what occurs in rare cases after surgical resection of AVMs. Our case raises the hypothesis that stagnation of flow in spontaneous AVM obliteration may lead to delayed ischemic stroke in the territory of the feeding artery. PMID- 24064365 TI - Prolactin activates ERalpha in the absence of ligand in female mammary development and carcinogenesis in vivo. AB - Resistance of estrogen receptor positive (ERalpha+) breast cancers to antiestrogens is a major factor in the mortality of this disease. Although activation of ERalpha in the absence of ligand is hypothesized to contribute to this resistance, the potency of this mechanism in vivo is not clear. Epidemiologic studies have strongly linked prolactin (PRL) to both development of ERalpha+ breast cancer and resistance to endocrine therapies. Here we employed genetically modified mouse models to examine the ability of PRL and cross talk with TGFalpha to activate ERalpha, using a mutated ERalpha, ERalpha(G525L), which is refractory to endogenous estrogens. We demonstrate that PRL promotes pubertal ERalpha-dependent mammary ductal elongation and gene expression in the absence of estrogen, which are abrogated by the antiestrogen, ICI 182,780 (ICI). PRL and TGFalpha together reduce sensitivity to estrogen, and 30% of their combined stimulation of ductal proliferation is inhibited by ICI, implicating ligand independent activation of ERalpha as a component of their interaction. However, PRL/TGFalpha-induced heterogeneous ERalpha+ tumors developed more rapidly in the presence of ICI and contained altered transcripts for surface markers associated with epithelial subpopulations and increased signal transducer and activator of transcription 5b expression. Together, these data support strong interactions between PRL and estrogen on multiple levels. Ligand-independent activation of ERalpha suggests that PRL may contribute to resistance to antiestrogen therapies. However, these studies also underscore ERalpha-mediated moderation of tumor phenotype. In light of the high expression of PRL receptors in ERalpha+ cancers, understanding the actions of PRL and cross talk with other oncogenic factors and ERalpha itself has important implications for therapeutic strategies. PMID- 24064367 TI - Construction of a shuttle vector for use in Riemerella anatipestifer. AB - Riemerella anatipestifer causes epizootic infectious disease in poultry and serious economic losses, especially to the duck industry. Four complete genome sequences of R. anatipestifer strains are now available. However, functional studies have been limited by the lack of an effective shuttle vector. In this study, we constructed a shuttle vector, pRES, which was able to transfer plasmid DNA between Escherichia coli and R. anatipestifer strains. The vector contains the putative replication origin from R. anatipestifer plasmid pRA7026 and a ColE1 ori for replication in R. anatipestifer and E. coli respectively. In addition, it contains oriT for transferring the vector into R. anatipestifer by conjugation, and the putative promoter of the streptothricin resistance gene of plasmid pRA0726 for heterologous gene expression in R. anatipestifer. The vector pRES will be useful in the investigation of gene function in R. anatipestifer. PMID- 24064362 TI - A role for glucocorticoids in stress-impaired reproduction: beyond the hypothalamus and pituitary. AB - In addition to the well-characterized role of the sex steroid receptors in regulating fertility and reproduction, reproductive events are also mediated by the hypothalamic-pituitary-adrenal axis in response to an individual's environment. Glucocorticoid secretion in response to stress contributes to the well-characterized suppression of the hypothalamic-pituitary-gonadal axis through central actions in the hypothalamus and pituitary. However, both animal and in vitro studies indicate that other components of the reproductive system are also regulated by glucocorticoids. Furthermore, in the absence of stress, it appears that homeostatic glucocorticoid signaling plays a significant role in reproduction and fertility in all tissues comprising the hypothalamic-pituitary gonadal axis. Indeed, as central regulators of the immune response, glucocorticoids are uniquely poised to integrate an individual's infectious, inflammatory, stress, nutritional, and metabolic status through glucocorticoid receptor signaling in target tissues. Endocrine signaling between tissues regulating the immune and stress response and those determining reproductive status provides an evolutionary advantage, facilitating the trade-off between reproductive investment and offspring fitness. This review focuses on the actions of glucocorticoids in tissues important for fertility and reproduction, highlighting recent studies that show glucocorticoid signaling plays a significant role throughout the hypothalamic-pituitary-gonadal axis and characterizing these effects as permissive or inhibitory in terms of facilitating reproductive success. PMID- 24064368 TI - A systematic review of air pollution as a risk factor for cardiovascular disease in South Asia: limited evidence from India and Pakistan. AB - Cardiovascular diseases (CVD) are major contributors to mortality and morbidity in South Asia. Chronic exposure to air pollution is an important risk factor for cardiovascular diseases, although the majority of studies to date have been conducted in developed countries. Both indoor and outdoor air pollution are growing problems in developing countries in South Asia yet the impact on rising rates of CVD in these regions has largely been ignored. We aimed to assess the evidence available regarding air pollution effects on CVD and CVD risk factors in lower income countries in South Asia. A literature search was conducted in PubMed and Web of Science. Our inclusion criteria included peer-reviewed, original, empirical articles published in English between the years 1990 and 2012, conducted in the World Bank South Asia region (Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka). This resulted in 30 articles. Nine articles met our inclusion criteria and were assessed for this systematic review. Most of the studies were cross-sectional and examined measured particulate matter effects on CVD outcomes and indicators. We observed a bias as nearly all of the studies were from India. Hypertension and CVD deaths were positively associated with higher particulate matter levels. Biomarkers of oxidative stress such as increased levels of P-selection expressing platelets, depleted superoxide dismutase and reactive oxygen species generation as well as elevated levels of inflammatory-related C-reactive protein, interleukin-6 and interleukin-8 were also positively associated with biomass use or elevated particulate matter levels. An important outcome of this investigation was the evidence suggesting important air pollution effects regarding CVD risk in South Asia. However, too few studies have been conducted. There is as an urgent need for longer term investigations using robust measures of air pollution with different population groups that include a wider range of air pollutants and outcomes, including early indicators of CVD. These regions are facing burdens from increasing urbanization, air pollution and populations, generally weaker health infrastructure, aging populations and increased incidence of non communicable diseases, included CVD. The extent to which the problem of air pollution and CVD will impact these countries will depend largely on the information available to inform policy and programs, which are still lacking, political will as well as social and economic development. PMID- 24064369 TI - Theory of mind deficit in subjects with alcohol use disorder: an analysis of mindreading processes. AB - AIM: The aim of the study was to investigate multidimensional Theory of Mind (ToM) abilities in subjects with alcohol use disorder (AUD). METHOD: A semi structured interview and a set of brief stories were used to investigate different components of the participants' ToM, namely first- vs. third-person, egocentric vs. allocentric, first- vs. second-order ToM in 22 persons with AUD plus an equal number of healthy controls. Participants were administered the Theory of Mind Assessment Scale (Th.o.m.a.s., Bosco et al., 2009a) and the Strange Stories test ( Happe et al., 1999). RESULTS: Persons with AUD performed worse than controls at all ToM dimensions. The patterns of differences between groups varied according to the Th.o.m.a.s. dimension investigated. In particular persons with AUD performed worse at third-person than at first-person ToM, and at the allocentric than at the egocentric perspective. CONCLUSION: These findings support the hypothesis that the ability to understand and ascribe mental states is impaired in AUD. Future studies should focus on the relevance of the different ToM impairments as predictors of treatment outcome in alcoholism, and on the possibility that rehabilitative interventions may be diversified according to ToM assessment. PMID- 24064370 TI - Do prenatal immune activation and maternal iron deficiency interact to affect neurodevelopment and early behavior in rat offspring? AB - Infection and iron deficiency are common during pregnancy and studies have described altered brain development in the offspring as a result of these individual maternal exposures. Both exposures have been identified as risk factors for schizophrenia yet they have never been modeled simultaneously. We developed a rat model of prenatal immune activation on a background of maternal iron deficiency to determine whether these factors interact to affect neurodevelopment and early behavior in offspring. Pregnant rats were placed on iron sufficient (IS) or iron deficient (ID) diets from E2 to P7, and administered LPS or saline on E15/16. Iron was reduced in liver, spleen, serum and placenta from ID dams by E15. LPS administration on E15 caused greater induction of serum interleukin-6 and tumor necrosis factor-alpha in ID dams compared to IS dams. Offspring (P0, P7) from ID dams had reduced iron in spleen, liver and brain compared to IS, which normalized by P21. Pups from ID dams showed differences in forelimb grasp and acoustic startle, whilst pups from LPS dams displayed differences in grip ability, geotaxis reflex, cliff avoidance and acoustic startle. Offspring from LPS dams displayed reduced locomotor activity at P7 and P60; offspring from ID dams showed no change. Our findings show effects of prenatal LPS and maternal iron deficiency were additive, such that offspring exposed to both insults displayed more neurodevelopmental abnormalities than offspring exposed to one alone. Yet surprisingly there was no interaction between factors, suggesting independent mechanisms of action. PMID- 24064371 TI - Laparoscopic and hand-assisted deep enteroscopy with polypectomy in Peutz-Jeghers syndrome. PMID- 24064372 TI - Modelling bioaccumulation of oil constituents in aquatic species. AB - Crude oil poses a risk to marine ecosystems due to its toxicity and tendency to accumulate in biota. The present study evaluated the applicability of the OMEGA model for estimating oil accumulation in aquatic species by comparing model predictions of kinetic rates (absorption and elimination) and bioconcentration factors (BCF) with measured values. The model was a better predictor than the means of the measurements for absorption and elimination rate constants, but did not outperform the mean measured BCF. Model estimates and measurements differed less than one order of magnitude for 91%, 80% and 61% of the absorption and elimination rates and BCFs of all oil constituents, respectively. Of the "potentially modifying" factors: exposure duration, biotransformation, molecular mass, and water temperature, the last two tended to influence the performance of the model. Inclusion of more explanatory variables in the bioaccumulation model, like the molecular mass, is expected to improve model performance. PMID- 24064373 TI - Use of skin and blubber tissues of small cetaceans to assess the trace element content of internal organs. AB - In order to evaluate the use of biopsy samples as non-destructive tool for assessing trace element concentrations in small cetaceans, the concentrations of 14 trace elements were determined in skin, blubber, liver and kidneys of four species of small cetaceans (i.e. common dolphin Delphinus delphis, harbour porpoise Phocoena phocoena, bottlenose dolphin Tursiops truncatus and striped dolphin Stenella coeruleolba), stranded and/or by-caught along the NE Atlantic Ocean coast between 2001 and 2008. Only Cu, Fe, Hg, Mn, Ni and Zn were above the detection limit of the instruments and showed recoveries satisfactory enough to be interpreted. Among these trace elements, Hg was the only one showing a significant correlation between concentrations in and those in liver and kidneys. In consequence skin and blubber can only be used as non-invasive monitoring tissues to investigate Hg bioaccumulation in internal tissues for cetacean populations. PMID- 24064374 TI - Changes in zooplankton communities along a mercury contamination gradient in a coastal lagoon (Ria de Aveiro, Portugal). AB - The main objective of this paper was to evaluate the impact of mercury on the zooplankton communities' structure and functioning and their bioaccumulation patterns along a contamination gradient in a temperate coastal lagoon. Our results demonstrated that total abundance was not negatively affected by Hg contamination, since the most contaminated areas presented the highest values, being the copepod Acartia tonsa the dominant species, which means that it is a very well adapted and tolerant species to mercury. Nevertheless, negative effects were observed in terms of species diversity, since the most contaminated areas presented the lowest values of species richness, evenness and heterogeneity. Moreover, the spatial mercury gradient was reflected on the bioaccumulation patterns of the zooplankton communities. This reinforces the idea that zooplankton can be considered as an important vehicle of mercury transfer through the food pelagic web since it constitutes a primordial food resource for several commercial fish species. PMID- 24064376 TI - Assessing the perception and reality of arguments against thermal waste treatment plants in terms of property prices. AB - The thermal processing of waste materials, although considered to be an essential part of waste management, is often sharply contested in the UK. Arguments such as health, depletion of resources, cost, noise, odours, traffic movement and house prices are often cited as reasons against the development of such facilities. This study aims to review the arguments and identify any effect on property prices due to the public perception of the plant. A selection of existing energy from waste (EfW) facilities in the UK, operational for at least 7 years, was selected and property sales data, within 5 km of the sites, was acquired and analysed in detail. The locations of the properties were calculated in relation to the plant using GIS software (ArcGIS) and the distances split into 5 zones ranging from 0 to 5 km from the site. The local property sale prices, normalised against the local house price index, were compared in two time periods, before and after the facility became operational, across each of the 5 zones. In all cases analysed no significant negative effect was observed on property prices at any distance within 5 km from a modern operational incinerator. This indicated that the perceived negative effect of the thermal processing of waste on local property values is negligible. PMID- 24064375 TI - Agricultural waste as household fuel: techno-economic assessment of a new rice husk cookstove for developing countries. AB - In many rural contexts of the developing world, agricultural residues and the organic fraction of waste are often burned in open-air to clear the lands or just to dispose them. This is a common practice which generates uncontrolled emissions, while wasting a potential energy resource. This is the case of rice husk in the Logone Valley (Chad/Cameroon). In such a context household energy supply is a further critical issue. Modern liquid fuel use is limited and traditional solid fuels (mainly wood) are used for daily cooking in rudimentary devices like 3-stone fires, resulting in low efficiency fuel use, huge health impacts, increasing exploitation stress for the local natural resources. Rice husk may be an alternative fuel to wood for household energy supply. In order to recover such a biomass, the authors are testing a proper stove with an original design. Its lay-out (featuring a metal-net basket to contain the fuel and a chimney to force a natural air draft) allows a mix of combustion/gasification of the biomass occurring in a completely burning fire, appropriate for cooking tasks. According to results obtained with rigorous test protocols (Water Boiling Test), different lay-outs have been designed to improve the performance of the stove. Technical and economic issues have been addressed in the development of such a model; building materials have been chosen in order to guarantee a cost as low as possible, using locally available items. The feasibility of the introduction of the stove in the studied context was assessed through an economic model that keeps into account not only the technology and fuel costs, but also the energy performance. According to the model, the threshold for the trade-off of the stove is the use of rice husk to cover 10-15% of the household energy needs both with traditional fireplaces or with improved efficiency cookstoves. The use of the technology proposed in combination with improved woodstove would provide householders with an appropriate and convenient cooking technology portfolio, increasing the opportunities of choice of the preferred energy system for the user and allowing significant savings for the family budget (up to 50% of the total annual cooking energy expenditure). The proposed model may be used also as a tool for the evaluation of the affordability or for the comparison of different cooking technologies also in other similar contexts, given their specific techno-economic parameter values. PMID- 24064377 TI - Long-term comparison of everolimus-eluting stents with sirolimus- and paclitaxel eluting stents for percutaneous coronary intervention of saphenous vein grafts. AB - AIMS: Newer-generation everolimus-eluting stents (EES) have been shown to improve clinical outcomes compared with early-generation sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) in patients undergoing percutaneous coronary intervention (PCI). Whether this benefit is maintained among patients with saphenous vein graft (SVG) disease remains controversial. METHODS AND RESULTS: We assessed cumulative incidence rates (CIR) per 100 patient years after inverse probability of treatment weighting to compare clinical outcomes. The pre specified primary endpoint was the composite of cardiac death, myocardial infarction (MI), and target vessel revascularisation (TVR). Out of 12,339 consecutively treated patients, 288 patients (5.7%) underwent PCI of at least one SVG lesion with EES (n=127), SES (n=103) or PES (n=58). Up to four years, CIR of the primary endpoint were 58.7 for EES, 45.2 for SES and 45.6 for PES with similar adjusted risks between groups (EES vs. SES; HR 0.94, 95% CI: 0.55-1.60, EES vs. PES; HR 1.07, 95% CI: 0.60-1.91). Adjusted risks showed no significant differences between stent types for cardiac death, MI and TVR. CONCLUSIONS: Among patients undergoing PCI for SVG lesions, newer-generation EES have similar safety and efficacy to early-generation SES and PES during long-term follow-up to four years. PMID- 24064378 TI - Novel human astrovirus strains showing multiple recombinations within highly conserved ORF1b detected from hospitalized acute watery diarrhea cases in Kolkata, India. AB - Human astroviruses (HAstVs) associated with acute watery diarrhea among hospitalized infants, children and adults as sole or mixed infection, were earlier reported from Kolkata, India. Further, novel recombinations have been detected through sequencing of the highly conserved ORF1b (RdRp) region of seven human astrovirus strains in Kolkata, India. Primers were designed and the ORF1b region was amplified by RT-PCR and sequenced. To examine the evolutionary pressures influencing the evolution of human astroviruses we implemented evolutionary genetics analysis. Maximum recombination break points detected in Kolkata strain IDH1300 were 8 and a single break point location was detected at 1205nt position. Partition-wise phylogenetic analyses of the IDH1300 Kolkata strain did not show close homology to the reference strains. Further phylogenetic analyses of full length ORF1b region of the seven human astrovirus strains showed that they formed a close cluster with each other and displayed a separate lineage in comparison to reference human astrovirus strains worldwide. This study shows the emergence of novel recombinant human astrovirus strains in Kolkata, India, warranting stringent surveillance to monitor the genetic diversity of human astrovirus strains infecting different age groups. PMID- 24064379 TI - Urinary concentrations of organophosphate pesticide metabolites in adults in Israel: demographic and dietary predictors. AB - Exposure to organophosphate pesticides (OPs) in agricultural and urban populations has been associated with a range of adverse health effects. The purpose of the current study was to estimate exposure to OPs in the general adult population in Israel and to determine dietary and demographic predictors of exposure. We measured six non-specific organophosphate pesticide metabolites (dialkyl phosphates) in urine samples collected from 247 Israeli adults from the general population. We collected detailed demographic and dietary data from these individuals, and explored associations between demographic and dietary characteristics and urinary dialkyl phosphate concentrations. OP metabolites were detectable in all urine samples. Concentrations of several dialkyl phosphate metabolites (dimethylphosphate, dimethylthiophosphate, diethylphosphate) were high in our study population relative to the general populations in the US and Canada and were comparable to those reported in 2010 in France. Total dialkyl phosphates were higher in individuals with fruit consumption above the 75th percentile. In a multivariate analysis, total molar dialkyl phosphate concentration increased with age and was higher in individuals with high income compared to individuals with the lowest income. Total diethyl metabolite concentrations were higher in females and in study participants whose fruit consumption was above the 75th percentile. In conclusion, we found that levels of exposure to OP pesticides were high in our study population compared to the general population in the US and Canada and that intake of fruits is an important source of exposure. PMID- 24064380 TI - Relative effects of educational level and occupational social class on body concentrations of persistent organic pollutants in a representative sample of the general population of Catalonia, Spain. AB - Scant evidence is available worldwide on the relative influence of occupational social class and educational level on body concentrations of persistent organic pollutants (POPs) in the general population. The objective was to analyse such influence in a representative sample of the general population of Catalonia, Spain. Participants in the Catalan Health Interview Survey aged 18-74 were interviewed face-to-face, gave blood, and underwent a physical exam. The role of age, body mass index (BMI), and parity was analysed with General Linear Models, and adjusted geometric means (GMs) were obtained. Crude (unadjusted) concentrations were higher in women and men with lower education, and in women, but not men, in the less affluent social class. After adjusting for age, in women there were no associations between POP levels and social class or education. After adjusting for age and BMI, men in the less affluent class had higher p,p' DDE concentrations than men in class I (p-value=0.016), while men in class IV had lower HCB than men in the upper class (p-value<0.03). Also in contrast with some expectations, positive associations between education and POP levels were observed after adjusting for age and BMI in men; e.g., men with university studies had higher HCB concentrations than men with first stage of primary schooling (adjusted GM 153.9 and 80.5ng/g, respectively) (p-value<0.001). When education and social class were co-adjusted for, some positive associations with education in men remained statistically significant, whereas class remained associated only with p,p'-DDE. Educational level influenced blood concentrations of POPs more than occupational social class, especially in men. In women, POP concentrations were mainly explained by age/birth cohort, parity and BMI. In men, while concentrations were also mainly explained by age/birth cohort and BMI, both social class and education showed positive associations. Important characteristics of socioeconomic groups as age and BMI may largely explain crude differences among such groups in internal contamination by POPs. The absence of clear patterns of relationships between blood concentrations of POPs and indicators of socioeconomic position may fundamentally be due to the widespread, lifelong, and generally invisible contamination of human food webs. Decreasing historical trends would also partly explain crude socioeconomic differences apparently due to birth cohort effects. PMID- 24064381 TI - Rare serotype occurrence and PFGE genotypic diversity of Streptococcus agalactiae isolated from tilapia in China. AB - Previously, we reported 10 PEGE types of 85 tilapia Streptococcus agalactiae (GBS), which shifted from Streptococcus iniae in China, by using PEGE method. Presently, larger and more representative tilapia GBS were isolated, for the first time in China, to characterize their serotypes and genetic diversities more precisely than had done before. 168 GBS strains were distributed in five provinces of China, in which Guangdong, Guangxi and Hainan were the major ones, holding 36.9% (62/168), 37.5% (63/168) and 19.6% (33/168), respectively. Serotypes, Ia, Ib and III, were observed in these strains and the most predominant one was Ia (95.2%), which mainly distributed in Guangdong, Guangxi and Hainan. Ia initially occurred in 2009, it shoot up to 32.1% in 2010, but decreased to 16.1% in 2011 before went up to 45.2% in 2012. Ib sporadically occurred during 2007-2011, III only occurred in 2012. 14 different PFGE types, including 4 new types (N, O, P and Q), were observed, in which B, D, F and G were the predominant types, holding 83.9% (141/168) of the total GBS strains. Ia corresponded to 11 PFGE types (A-H, N-P), in which type D predominated (51%). Ib represented 3 genotypes (I, J and Q) and III harbored only 2 genotypes (N and F). Type N and F synchronously presented in Ia and III. In summary, the genetic diversity of tilapia GBS varied by serotypes and changed with geographical locations and years. Although Ia still predominated, new rare serotype III already occurred in China. PMID- 24064382 TI - Oxidative stress enhances Axl-mediated cell migration through an Akt1/Rac1 dependent mechanism. AB - Persistent oxidative stress is common in cancer cells because of abnormal generation of reactive oxygen species (ROS) and has been associated with malignant phenotypes, such as chemotherapy resistance and metastasis. Both overexpression of Axl and abnormal ROS elevation have been linked to cell transformation and increased cell migration. However, the relationship between Axl and ROS in malignant cell migration has not been previously evaluated. Using an in vitro human lung cancer model, we examined the redox state of lung adenocarcinoma cell lines of low metastatic (CL1-0) and high metastatic (CL1-5) potentials. Here we report that Axl activation elicits ROS accumulation through the oxidase-coupled small GTPase Rac1. We also observed that oxidative stress could activate Axl phosphorylation to synergistically enhance cell migration. Further, Axl signaling activated by H2O2 treatment results in enhancement of cell migration via a PI3K/Akt-dependent pathway. The kinase activity of Axl is required for the Axl-mediated cell migration and prolongs the half-life of phospho-Akt under oxidative stress. Finally, downregulation of Akt1, but not Akt2, by RNAi in Axl-overexpressing cells inhibits the amount of activated Rac1 and the ability to migrate induced by H2O2 treatment. Together, these results show that a novel Axl-signaling cascade induced by H2O2 treatment triggers cell migration through the PI3K/Akt1/Rac1 pathway. Elucidation of redox regulation in Axl-related malignant migration may provide new molecular insights into the mechanisms underlying tumor progression. PMID- 24064384 TI - Concreteness effects in single-meaning, multi-meaning and newly acquired words. AB - This study examined the extent to which concreteness influences the acquisition and subsequent processing of novel (low frequency) concepts. Participants were trained on 70 rare English words (35 concrete, 35 abstract) paired with definitions. ERPs were then recorded while participants performed a semantic categorisation (concrete vs. abstract) and a lexical decision task on single meaning, multi-meaning and the newly acquired words. During training there was a significant effect of concreteness, in that participants were more successful at acquiring concrete concepts. In both the semantic categorisation and the lexical decision task, concreteness effects were evident in the behavioural and in the ERP data for all word types, with concrete words eliciting more negative waveforms than abstract words in the N400 time window. Behaviourally, participants experienced greater difficulty in judging the concreteness of multi meaning words, yet concreteness effects in the N400 were equally strong for all three word types across both tasks. These findings indicate that concreteness represents a fundamental distinction in the way that items are represented in memory, which is independent of the participant's perceived judgement. They further demonstrate that novel concepts can be acquired rapidly after minimal training, and that the neurophysiological correlates associated with processing novel words are modulated by the specific nature of the conceptual characteristics assigned to the word. PMID- 24064383 TI - CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis. AB - Ethanol-inducible cytochrome P450 2E1 (CYP2E1) contributes to increased oxidative stress and steatosis in chronic alcohol-exposure models. However, its role in binge ethanol-induced gut leakiness and hepatic injury is unclear. This study was aimed at investigating the role of CYP2E1 in binge alcohol-induced gut leakiness and the mechanisms of steatohepatitis. Female wild-type (WT) and Cyp2e1-null mice were treated with three doses of binge ethanol (WT-EtOH or Cyp2e1-null-EtOH) (6g/kg oral gavage at 12-h intervals) or dextrose (negative control). Intestinal histology of only WT-EtOH exhibited epithelial alteration and blebbing of lamina propria, and liver histology obtained at 6h after the last ethanol dose showed elevated steatosis with scattered inflammatory foci. These were accompanied by increased levels of serum endotoxin, hepatic enterobacteria, and triglycerides. All these changes, including the intestinal histology and hepatic apoptosis, determined by TUNEL assay, were significantly reversed when WT-EtOH mice were treated with the specific inhibitor of CYP2E1 chlormethiazole and the antioxidant N-acetylcysteine, both of which suppressed oxidative markers including intestinal CYP2E1. WT-EtOH also exhibited elevated amounts of serum TNF-alpha, hepatic cytokines, CYP2E1, and lipid peroxidation, with decreased levels of mitochondrial superoxide dismutase and suppressed aldehyde dehydrogenase 2 activity. Increased hepatocyte apoptosis with elevated levels of proapoptotic proteins and decreased levels of active (phosphorylated) p-AKT, p-AMPK, and peroxisome proliferator activated receptor-alpha, all of which are involved in fat metabolism and inflammation, were observed in WT-EtOH. These changes were significantly attenuated in the corresponding Cyp2e1-null-EtOH mice. These data indicate that both intestinal and hepatic CYP2E1 induced by binge alcohol seems critical in binge alcohol-mediated increased nitroxidative stress, gut leakage, and endotoxemia; altered fat metabolism; and inflammation contributing to hepatic apoptosis and steatohepatitis. PMID- 24064385 TI - Temporospatial expression and cellular localization of VGLUT3 in the rat cochlea. AB - Vesicular glutamate transporter 3 (VGLUT3) plays an important role in hearing, and VGLUT3 knockout mice are deaf. However, the mechanisms whereby VGLUT3 exerts its effects in the cochlea are not well established. Elucidating the developmental and aging dynamics of VGLUT3 localization and expression in the cochlea would aid a functional understanding of auditory glutamatergic transmission. In this study, we characterized the expression of VGLUT3 in rat auditory epithelium and spiral ganglion cells (SGCs) during postnatal development and with age using immunohistochemistry and quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). We observed VGLUT3 expression in cochlea inner hair cells (IHCs) and SGCs as early as postnatally, and its expression increased gradually with maturity. However, the expression of VGLUT3 in the IHCs decreased in the aging rats compared to postnatal day 60 (P60), and VGLUT3 was still expressed in the remaining SGCs in the aging rats. VGLUT3 immunopositive punctate structures were only found in the cytoplasm of SGCs, not IHCs, at P7, or later. Variation in VGLUT3 mRNA expression evaluated by quantitative real time RT-PCR was consistent with the immunohistochemical data except for no statistical difference between P60 and aging rats in the whole cochlea level. Our data suggest that VGLUT3 likely has developmental and physiological roles in the rat cochlea during postnatal development as well as later in life. VGLUT3 may have additional unknown roles in SGCs besides glutamate transport. PMID- 24064386 TI - A dynamical systems approach to understanding self-regulation in smoking cessation behavior change. AB - INTRODUCTION: Self-regulation, a key component of the addiction process, has been challenging to model precisely in smoking cessation settings, largely due to the limitations of traditional methodological approaches in measuring behavior over time. However, increased availability of intensive longitudinal data (ILD) measured through ecological momentary assessment facilitates the novel use of an engineering modeling approach to better understand self-regulation. METHODS: Dynamical systems modeling is a mature engineering methodology that can represent smoking cessation as a self-regulation process. This article shows how a dynamical systems approach effectively captures the reciprocal relationship between day-to-day changes in craving and smoking. Models are estimated using ILD from a smoking cessation randomized clinical trial. RESULTS: A system of low order differential equations is presented that models cessation as a self regulatory process. It explains 87.32% and 89.16% of the variance observed in craving and smoking levels, respectively, for an active treatment group and 62.25% and 84.12% of the variance in a control group. The models quantify the initial increase and subsequent gradual decrease in craving occurring postquit as well as the dramatic quit-induced smoking reduction and postquit smoking resumption observed in both groups. Comparing the estimated parameters for the group models suggests that active treatment facilitates craving reduction and slows postquit smoking resumption. CONCLUSIONS: This article illustrates that dynamical systems modeling can effectively leverage ILD in order to understand self-regulation within smoking cessation. Such models quantify group-level dynamic responses in smoking cessation and can inform the development of more effective interventions in the future. PMID- 24064388 TI - Percutaneous closure of large femoral artery access with Prostar XL in thoracic endovascular aortic repair. AB - OBJECTIVES: To investigate the technical success rate of Prostar XL for closure of large (>=20F) femoral vascular access sites in thoracic endovascular aortic repair (TEVAR) procedures. METHODS: This was a single-center consecutive case series. All TEVAR procedures at Uppsala University Hospital 2006-2010 were registered prospectively. Reoperations and cases with open closure technique were excluded. Primary (early) technical failure was defined as closure failure requiring immediate (on-table) open surgical repair; late access-related complication occurred thereafter. The medical records, pre- and postoperative computed tomography images were reviewed retrospectively. RESULTS: A total of 164 TEVAR procedures were identified, of which 118 (71%) had a median 22F (range 20 26F) access site sealed with tandem Prostar XL. The indications for TEVAR were dissection (47%), aneurysm (42%), trauma (8%), and miscellaneous (3%). Median follow-up time was 10 months (range 1-62). Primary technical failure occurred in 10 of 118 (8%). These cases were converted to cut-downs and surgical repair (n = 7), femoral fascia suturing (n = 2), and external compression with the Femo-Stop device (n = 1). Hypertension was associated with primary failure (p = .005), and a trend was observed for high age (p = .078) and increased groin subcutaneous fat layer (p = .077). Late access-related complications included pseudo-aneurysms (n = 12), small hematomas (n = 7), superficial groin infections (n = 2), and deep venous thrombosis (n = 1). None of the late complications required surgical treatment. CONCLUSIONS: The access closure technique with tandem Prostar XL for large access sites during TEVAR is safe, in experienced hands. Few technical failures and few late complications occur, and they are usually benign. PMID- 24064389 TI - Commentary regarding "Percutaneous closure of large femoral artery access with ProStar XL in thoracic endovascular aortic repair". PMID- 24064390 TI - Resuscitation in the perinatal period. PMID- 24064391 TI - Age related changes in aminergic system and behavior following lead exposure: protection with essential metal supplements. AB - Age related impairments in behavioral functions following lead (Pb) exposure have been linked to changes in neurotransmitter levels in brain regions. In the present study, we have evaluated the protective effect of a mixture of essential elements containing calcium, zinc and iron against Pb-induced long-term effects on aminergic system and behavior of rats. Rats were lactationally exposed to Pb (0.2%) or Pb acetate together with nutrient metal mixture (0.02% Ca, Zn and Fe) in drinking water of the mother from postnatal day (PND) 1 to PND 21. Increases in synaptosomal dopamine, epinephrine, norepinephrine and serotonin levels and decrease in mitochondrial monoamine oxidase (MAO) in cortex, cerebellum, and hippocampus regions were observed following Pb exposure in different age groups (PND 45, 4, 12 and 18 months) of rats. The alterations were greater in hippocampus than cortex and cerebellum. Total locomotor activity, exploratory and open field behaviors were also altered following Pb exposure. However, the alterations were maximum in PND 45 coinciding with greater blood Pb levels observed in PND 45. These data suggest that, Pb exposure induced age dependent alterations in motor behavior and synaptosomal aminergic system were significantly reversed with the supplementation of nutrient metal mixture suggesting therapeutic nature of essential metal supplements against Pb-induced toxicity. PMID- 24064392 TI - Chicken DT40 cell line lacking DJ-1, the gene responsible for familial Parkinson's disease, displays mitochondrial dysfunction. AB - Parkinson's disease (PD) is the most common neurodegenerative movement disorder mainly due to gradual loss of dopaminergic neurons in the substantia nigra. Although the causative genes for autosomal recessive PD, Parkin, PINK1 and DJ-1, share a common pathway, at least in part, in mitochondrial quality control and protein quality control, their precise relationship remains elusive. Previous studies suggested the limitation of gene-modified mice model to solve this problem. DT40 is an avian leukosis virus-induced chicken B cell line with an exceptionally high ratio of targeted to random DNA integration, which enables efficient targeted disruption of multiple genes of interest. We generated DJ-1 deficient DT40 cells and analyzed PD-related phenotypes. These cells exhibited vulnerability to oxidative stress, mitochondrial dysfunction and fragmentation. Importantly, we showed that mitochondrial membrane potential and morphology are available for the phenotype analysis in DT40. These results suggest that genetically engineered DT40 cells would serve as a relevant model of PD, and help understand the genetic and functional relationship among multiple causative genes. Furthermore, in line with the recent concept of PD as a systemic disorder, elucidating the pathomechanism of PD using DT40 would lead to the development of noninvasive diagnostic tools and drug screening assays using patient-derived lymphocytes. PMID- 24064393 TI - Who was Dr. Guillotin and why he should be remembered. PMID- 24064394 TI - Proper catheter selection for needle thoracostomy: a height and weight-based criteria. AB - BACKGROUND: Obesity increases the incidence of mortality in trauma patients. Current Advanced Trauma Life Support guidelines recommend using a 5-cm catheter at the second intercostal (ICS) space in the mid-clavicular line to treat tension pneumothoraces. Our study purpose was to determine whether body mass index (BMI) predicted the catheter length needed for needle thoracostomy. METHODS: We retrospectively reviewed trauma patients undergoing chest computed tomography scans January 2004 through September 2006. A BMI was calculated for each patient, and the chest wall thickness (CWT) at the second ICS in the mid-clavicular line was measured bilaterally. Patients were grouped by BMI as underweight (<= 18.5 kg/m2), normal weight (18.6-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), or obese (>= 30 kg/m(2)). RESULTS: Three hundred twenty-six patients were included in the study; 70% were male. Ninety-four percent of patients experienced blunt trauma. Sixty-three percent of patients were involved in a motor vehicle collision. The average BMI was 29 [SD 7.8]. The average CWT was 6.2 [SD 1.9]cm on the right and 6.3 [SD 1.9]cm on the left. As BMI increased, a statistically significant (p<0.0001) CWT increase was observed in all BMI groups. There were no significant differences in ISS, ventilator days, ICU length of stay, or overall length of stay among the groups. CONCLUSION: As BMI increases, there is a direct correlation to increasing CWT. This information could be used to quickly select an appropriate needle length for needle thoracostomy. The average patient in our study would require a catheter length of 6-6.5 cm to successfully decompress a tension pneumothorax. There are not enough regionally available data to define the needle lengths needed for needle thoracostomy. Further study is required to assess the feasibility and safety of using varying catheter lengths. PMID- 24064395 TI - Difficulties of triage in mass casualties incident. PMID- 24064396 TI - Enteroendocrine cell signalling via the vagus nerve. AB - Nutrient delivery to the gut activates neuroendocrine mechanisms that control digestion and energy intake and utilisation. These include the release from enteroendocrine cells of mediators including 5HT, CCK, GLP-1, PYY and ghrelin that act on vagal afferent neurons regulating food intake and autonomic reflexes controlling motility, secretion, inflammatory responses and mucosal defence. The mediators may act locally on vagal afferent fibres running close to their cell of origin, or distally after delivery in the circulation. Recent work indicates that the signalling mechanisms are strongly influenced by nutrient status. Thus, both food withdrawal and diet-induced obesity alter the sensitivity of vagal afferent neurons to stimulation as well as their patterns of expression of receptors and neuropeptide transmitters. Normally, leptin potentiates vagal afferent stimulation by CCK but this is lost in obesity. Recent studies suggest changes in the gut microbiota in obesity lead to increased LPS which suppresses leptin effects on vagal afferent neurons. There are obvious limitations to direct studies of vagal afferent signalling in man but recent work indicates fMRI brain imaging of CNS responses to CCK and ghrelin is feasible, informative and provides opportunities for future progress in human studies of gut-brain signalling. PMID- 24064397 TI - Enteroendocrine hormone mimetics for the treatment of obesity and diabetes. AB - The utilisation of gastrointestinal-derived hormones as treatment options for obesity-diabetes has been well publicised. This has been fuelled by the synthesis of longer-acting peptide forms and beneficial altered secretion of gut hormones following certain gastric bypass surgeries. The aim of this review is to highlight the potential of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and oxyntomodulin (OXM) as treatments for obesity-diabetes. To date, long-acting GLP-1 receptor mimetics have achieved clinical utility for diabetes. GIP, CCK and OXM molecules appear to offer promising new classes of drugs. Furthermore, recent observations suggest significant potential for concurrent modulation of numerous receptor sub-families in the treatment of obesity-diabetes. Thus, gut hormones offer an expanding family of druggable targets for obesity-diabetes. PMID- 24064398 TI - Anxiety, stress and perfectionism in bipolar disorder. AB - BACKGROUND: Previous reports have highlighted perfectionism and related cognitive styles as a psychological risk factor for stress and anxiety symptoms as well as for the development of bipolar disorder symptoms. The anxiety disorders are highly comorbid with bipolar disorder but the mechanisms that underpin this comorbidity are yet to be determined. METHOD: Measures of depressive, (hypo)manic, anxiety and stress symptoms and perfectionistic cognitive style were completed by a sample of 142 patients with bipolar disorder. Mediation models were used to explore the hypotheses that anxiety and stress symptoms would mediate relationships between perfectionistic cognitive styles, and bipolar disorder symptoms. RESULTS: Stress and anxiety both significantly mediated the relationship between both self-critical perfectionism and goal attainment values and bipolar depressive symptoms. Goal attainment values were not significantly related to hypomanic symptoms. Stress and anxiety symptoms did not significantly mediate the relationship between self-critical perfectionism and (hypo)manic symptoms. LIMITATIONS: 1. These data are cross-sectional; hence the causality implied in the mediation models can only be inferred. 2. The clinic patients were less likely to present with (hypo)manic symptoms and therefore the reduced variability in the data may have contributed to the null findings for the mediation models with (hypo) manic symptoms. 3. Those patients who were experiencing current (hypo)manic symptoms may have answered the cognitive styles questionnaires differently than when euthymic. CONCLUSION: These findings highlight a plausible mechanism to understand the relationship between bipolar disorder and the anxiety disorders. Targeting self-critical perfectionism in the psychological treatment of bipolar disorder when there is anxiety comorbidity may result in more parsimonious treatments. PMID- 24064399 TI - Cartilage oligomeric matrix protein (COMP)-mediated cell differentiation to proteolysis mechanism networks from human normal adjacent tissues to lung adenocarcinoma. AB - BACKGROUND: To understand cartilage oligomeric matrix protein (COMP) mechanism network from human normal adjacent tissues to lung adenocarcinoma. METHODS: COMP complete different activated (all no positive correlation, Pearson CC < 0.25) and uncomplete (partly no positive correlation except COMP, Pearson CC < 0.25) network were identified in higher lung adenocarcinoma compared with lower human normal adjacent tissues from the corresponding COMP-stimulated (>=0.25) or inhibited (Pearson CC <= -0.25) overlapping molecules of Pearson correlation coefficient (CC) and GRNInfer, respectively. COMP complete different activated and inhibited (all no positive correlation, Pearson CC < 0.25) mechanisms networks of higher lung adenocarcinoma and lower human normal adjacent tissues were constructed by integration of Pearson CC, GRNInfer and GO. As visualized by integration of GO, KEGG, GenMAPP, BioCarta and Disease, we deduced COMP complete different activated and inhibited network in higher lung adenocarcinoma and lower human normal adjacent tissues. RESULTS: As visualized by GO, KEGG, GenMAPP, BioCarta and disease database integration, we proposed mainly that the mechanism and function of COMP complete different activated network in higher lung adenocarcinoma was involved in COMP activation with matrix-localized insulin-like factor coupling carboxypeptidase to metallopeptidase-induced proteolysis, whereas the corresponding inhibited network in lower human normal adjacent tissues participated in COMP inhibition with nucleus-localized vasculogenesis, B and T cell differentiation and neural endocrine factors coupling pyrophosphatase mediated proteolysis. However, COMP complete different inhibited network in higher lung adenocarcinoma included COMP inhibition with nucleus-localized chromatin maintenance, licensing and assembly factors coupling phosphatase inhibitor to cytokinesis regulators-mediated cell differentiation, whereas the corresponding activated network in lower human normal adjacent tissues contained COMP activation with cytolplasm-localized translation elongation factor coupling fucosyltransferase to ubiquitin-protein ligase-induced cell differentiation. CONCLUSION: COMP different networks were verified not only by complete and uncomplete COMP activated or inhibited networks within human normal adjacent tissues or lung adenocarcinoma, but also by COMP activated and inhibited network between human normal adjacent tissues and lung adenocarcinoma. PMID- 24064400 TI - Facial and neck hematoma after carotid artery stenting: an uncommon misadventure in endovascular carotid revascularization. AB - The complication rates of carotid artery stenting (CAS) vary from 3.0% to 4.4%, and most commonly include ischemic stroke, intracranial hemorrhage, or groin complications. We present the rare complication of a patient who underwent CAS for a symptomatic 90% left internal carotid artery stenosis and developed an expanding cervical hematoma after the procedure with imminent respiratory compromise. After intubation, an arteriogram revealed perforation of the external carotid artery trunk, proximal to the origin of the internal maxillary artery. The artery was subsequently embolized and the hematoma resolved without further intervention. We present a potential catastrophic complication and suggest potential causes and treatment options available. PMID- 24064401 TI - Cardiac tamponade following traumatic rupture of a mediastinal mature teratoma. PMID- 24064403 TI - What is this? VT versus SVT. AB - We present a patient who had a wide QRS tachycardia; it was initially difficult to determine whether it was superventricular tachycardia (SVT) or ventricular tachycardia (VT). By some criteria (sinus capture beats, pseudo-delta waves and wide QRS) the patient's ECG was suggestive of VT of epicardial origin. On the coronary angiogram it was found that this patient had significant coronary artery disease. He was stented with three stents and later had a full electrophysiological study .We present here the ECGs and the differential diagnosis and a brief review of the diagnostic features of epicardial VT. PMID- 24064404 TI - The catastrophic basilar artery occlusion. PMID- 24064405 TI - Isolated oculomotor nerve palsy due to common carotid artery occlusion. PMID- 24064407 TI - Dynamic eye socket reconstruction after extended total maxillectomy using temporalis transfer. AB - The functional and cosmetic results of the reconstructive surgery after extended total maxillectomy greatly depend on the quality of the orbital reconstruction. In order to achieve good orbital reconstruction, we developed the dynamic eye socket reconstruction using temporalis transfer. In this report, I will present the details of the technique, including tips and innovations for dynamic eye socket reconstruction.Two patients (2 males, aged 70 and 72 years old) who underwent extensive resection of midfacial tumours were treated with dynamic eye socket reconstruction using temporalis transfer. The follow up period was 16 and 102 months. No acute complications were observed. The movements of the upper/lower eyelids including crow's feet were observed and a good shape in the reconstructed medial/lateral canthal area was maintained in all patients.This procedure provides both the eyelids with movement and also a good shape in the reconstructed medial/lateral canthal region. Furthermore, it contributes to achieving satisfactory functional and cosmetic results in the orbital reconstruction. PMID- 24064406 TI - Crystallographic model validation: from diagnosis to healing. AB - Model validation has evolved from a passive final gatekeeping step to an ongoing diagnosis and healing process that enables significant improvement of accuracy. A recent phase of active development was spurred by the worldwide Protein Data Bank requiring data deposition and establishing Validation Task Force committees, by strong growth in high-quality reference data, by new speed and ease of computations, and by an upswing of interest in large molecular machines and structural ensembles. Progress includes automated correction methods, concise and user-friendly validation reports for referees and on the PDB websites, extension of error correction to RNA and error diagnosis to ligands, carbohydrates, and membrane proteins, and a good start on better methods for low resolution and for multiple conformations. PMID- 24064408 TI - Visual search and attention in five-year-old very preterm/very low birth weight children. AB - INTRODUCTION: This study aimed to establish visual search performance and attention functioning in very preterm/very low birth weight (VP/VLBW) children using novel and well established measures, and to study their contribution to intellectual functioning. METHODS: Visual search and attention network efficiency were assessed in 108 VP/VLBW children and 72 age matched term controls at 5.5 years corrected age. Visual search performance was investigated with a newly developed paradigm manipulating stimulus density and stimulus organization. Attention functioning was studied using the Attention Network Test (ANT). Intellectual functioning was measured by a short form of the Wechsler Preschool and Primary Scale of Intelligence. Data were analyzed using ANOVAs and multiple regression analyses. RESULTS: Visual search was less efficient in VP/VLBW children as compared to term controls, as indicated by increased search time (0.31 SD, p = .04) and increased error rate (0.36 SD, p = .02). In addition, VP/VLBW children demonstrated poorer executive attention as indicated by lower accuracy for the executive attention measure of the ANT (0.61 SD, p < .001). No differences were found for the alerting (0.06 SD, p = .68) and orienting attention measures (0.13 SD, p = .42). Visual search time and error rate, and executive attention, collectively, accounted for 14% explained variance in full scale IQ (R(2) = .14, p < .001). DISCUSSION: VP/VLBW children were characterized by less efficient visual search ability and reduced executive attention. Visual attention dysfunctions contributed to intelligence, suggesting the opportunity to improve intellectual functioning by using interventions programs that may enhance attention capacities. PMID- 24064409 TI - Spatiotemporal cortical activation underlies the Muller-Lyer illusion: an event related potentials study. AB - Event-related brain potentials (ERPs) were used to examine the electrophysiological correlates of the visual illusion effect in the Muller-Lyer illusion tasks. The participants were presented with the context of a horizontal line with two symmetric inward-pointing arrowheads or outward-pointing arrowheads, and then, they were asked to indicate whether they perceived an increase or a decrease in the line length. The behavioral results showed that there were significant differences among the four types of tasks, which meant that participants could understand different mean illusion magnitudes. The ERP results showed that both the illusion-45 and the illusion-135 elicited a more negative ERP deflection (N180-280) than did the illusion-225 and illusion-315 between 180 and 280 ms. In addition, the strong illusion stimuli elicited a more positive ERP deflection (P280-450) than did the weak illusion stimuli between 280 and 450 ms after the onset of the stimuli. Dipole source analysis of the difference wave (illusion-135-illusion-225) indicated that one generator localized in the left lateral occipital cortex and the difference wave (illusion 45-illusion-135) indicated that one generator localized in the left lingual gyrus. Our results led us to conclude that the ERP deflection in the different illusory strength might be related to the theory of attention resource distribution or because of the inverse optics problem. Then, the early visual areas lateral occipital cortex and the lingual gyrus near to the visual cortex could contribute to integrated processing in the illusory contours and top-down control processing because of the visual experiences. PMID- 24064410 TI - Combining findings from gaze and electroencephalography recordings to study timing in a visual tracking task. AB - Electroencephalography (EEG) and gaze data have traditionally been separated in neurocognitive studies because of the artefacts that even small controlled eye movements produce. Study of gaze control in a visual tracking task provides information about an individual's prospective control. By including gaze events in the EEG analysis, we studied prospective control and its neural correlates during deceleration in a visual tracking task. Adult participants followed with their gaze a small car moving horizontally on a large screen, where the final approach of the car was temporarily occluded, and pushed a button to stop the car at the reappearance point. Two gaze events, the behavioural push button response and the nonbehavioural stimulus onset, were used to time-lock the averaged event related potential (ERP) waveform. A significant effect of deceleration on peak amplitude in parietal channel Pz (P<0.05) was found when ERP waveforms were time locked to the prospective gaze shift over the occluder. The peak decreased in amplitude as car deceleration increased when participants successfully stopped the car, indicating successful deceleration discrimination. No such effect was found when ERP waveforms were time-locked to any of the other events. Thus, a traditional stimulus onset time-locking procedure is likely to distort the averaged signal and consequently hide important Pz-peak amplitude differences on the prospective timing of decelerating object motion during occlusion. This study shows the importance of including behavioural data when studying neural correlates of prospective control and proposes active incorporation of behavioural data into the EEG analysis. PMID- 24064411 TI - Neuroplastic effects of music lessons on hippocampal volume in children with congenital hypothyroidism. AB - Children with congenital hypothyroidism (CH) who experience a neonatal thyroid hormone deficiency have reduced hippocampal volumes compared with healthy controls. Interestingly, evidence suggests that musical training can contribute to structural plasticity in a number of brain areas, including the hippocampus. Therefore, we investigated whether taking music lessons could ameliorate the volumetric reductions of the hippocampus in children with CH. Left and right hippocampal volumes were measured in four groups of children: children with CH with and without music lessons, and healthy controls with and without music lessons. We found that the volume of the right hippocampus was comparable between children with CH who had taken music lessons and the healthy controls. Children with CH who had not taken music lessons had reduced hippocampal volumes compared with the other three groups. These results suggest that music lessons may induce structural neuroplasticity in children with atypical hippocampal development because of early thyroid hormone deficiencies. PMID- 24064412 TI - From DSM-IV to DSM-5: changes to eating disorder diagnoses. AB - PURPOSE OF REVIEW: This article reviews the modifications to eating disorders that appear in the 'Feeding and Eating Disorders' chapter of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). These modifications include the addition of three disorders (avoidant/restrictive food intake disorder, rumination disorder, and pica) previously described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) section 'Feeding and Eating Disorders of Infancy or Early Childhood'; clarifications and modifications to anorexia nervosa and bulimia nervosa; and the inclusion of binge eating disorder as a formal diagnosis. RECENT FINDINGS: Research suggests that the majority of individuals seeking treatment for an eating disorder are classified as eating disorder not otherwise specified based on DSM-IV criteria. Using DSM-5 criteria, many of these individuals will be reassigned to a diagnosis with greater clinical utility. A large body of research also supports the inclusion of binge eating disorder as a formal diagnosis. SUMMARY: The changes to eating disorders, recommended by the Eating Disorders Work Group, aim to clarify existing criteria and to decrease the frequency with which individuals are assigned to the heterogeneous residual category, eating disorder not otherwise specified, which provides little clinical utility. PMID- 24064413 TI - Sexuality and couple intimacy in dementia. AB - PURPOSE OF REVIEW: The review assesses recent research and its impact on understanding of intimacy and sexuality in older adults with dementia. RECENT FINDINGS: There is no universally accepted definition of inappropriate sexual behaviors (ISBs), but they have been divided into overt acts associated with increased libido and uninhibited sexual behaviors directed at oneself or other people. Couples affected by dementia frequently maintain physical intimacy. Nonintercourse intimate activities may be preferred over intercourse. Early therapeutic interventions may assist partners in modifying activities, behaviors, and expectations about the future of the relationship. Inappropriate sexual behaviors are commonly due to the disruption of interconnected brain structures. Trauma to the temporal lobes may lead to hypersexuality and ISB. Trauma to the limbic system can produce changes in sexual preference. Both temporal and frontotemporal dementias, or either of them, often present with socially and sexually inappropriate behaviors. Huntington's disease can exhibit hypersexuality, pedophilia, promiscuity, and marital infidelity. The involvement of the medial striatum of the basal ganglia in this disease explains the prevalence of ISB. There is no consensus regarding first-line pharmacotherapy for ISB. Little information is known about the adverse effects. SUMMARY: Clinicians and society need to consider how dementia might affect physical intimacy. PMID- 24064414 TI - Molecularly imprinted micro solid-phase extraction technique coupled with complementary molecularly imprinted polymer-sensor for ultra trace analysis of epinephrine in real samples. AB - A simple hyphenation approach was adopted to obtain a new molecularly imprinted micro solid-phase extraction fiber (as a selective extraction tool) and complementary molecularly imprinted polymer coated pencil graphite electrode (as a detection tool) for the selective and sensitive analysis of epinephrine, which is a disease biomarker prevalent at ultra trace level in biological fluids. In both extraction and detection processes, the functionalized multiwalled carbon nanotubes (CNT-mers) were preferred to multiwalled carbon nanotubes (unmodified) in order to obtain a stable homogeneously dispersed imprinted polymer matrix of better electroconductivity and adsorptive characteristics. The hyphenation of both tools helped dual pre-concentration of epinephrine so as to achieve the stringent limit [limit of detection: 0.002 ng mL(-1), S/N=3] of clinical detection, without any problems of non-specific contributions and cross reactivity. PMID- 24064415 TI - A simple one-step modification of various materials for introducing effective multi-functional groups. AB - Covalent immobilization of various biomolecules is a desired strategy for bio multifunctional surface modification. Multi-functionalization of a material surface is considered to be the premise of immobilizing a variety of biomolecules. However, currently adopted methods, used to introduce proper reactive functional groups on material surfaces, mostly are hard to be carried out and frequently can only introduce insufficient functional groups. In this work, we successfully develop the films (GAHD films) prepared via the simple copolymerization of gallic acid (GA) and hexamethylenediamine (HD), which can be deposited on different kinds of material surfaces including metals, ceramics and polymers by a one-step dip-coating method. Moreover, these copolymerized GAHD films possess high concentration of multi-functional groups like carboxyl (COOH), primary amine (-NH2) and quinone groups on the surfaces. Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) results prove either the occurrence of Michael addition reaction, Schiff base reaction in the film-forming process, or the existence of COOH, NH2 and quinone groups on the surfaces. The maximum contents of carboxyl and amine on the GAHD film are 24.9 nmol/cm(2) and 31.7 nmol/cm(2) respectively. After dynamical immersion for 30 days, slight swellings can be observed, which reveals that the GAHD films possess good stability. Moreover, Heparin (Hep), fibronectin (Fn) and laminin (Ln) are successfully immobilized on the GAHD film surfaces. The results of cell counting kit-8 (CCK-8) and rhodamine fluorescence photograph indicate that the 1:1.62 GAHD film has good cytocompatibility. PMID- 24064416 TI - BioServices: a common Python package to access biological Web Services programmatically. AB - MOTIVATION: Web interfaces provide access to numerous biological databases. Many can be accessed to in a programmatic way thanks to Web Services. Building applications that combine several of them would benefit from a single framework. RESULTS: BioServices is a comprehensive Python framework that provides programmatic access to major bioinformatics Web Services (e.g. KEGG, UniProt, BioModels, ChEMBLdb). Wrapping additional Web Services based either on Representational State Transfer or Simple Object Access Protocol/Web Services Description Language technologies is eased by the usage of object-oriented programming. AVAILABILITY AND IMPLEMENTATION: BioServices releases and documentation are available at http://pypi.python.org/pypi/bioservices under a GPL-v3 license. PMID- 24064417 TI - BSeQC: quality control of bisulfite sequencing experiments. AB - MOTIVATION: Bisulfite sequencing (BS-seq) has emerged as the gold standard to study genome-wide DNA methylation at single-nucleotide resolution. Quality control (QC) is a critical step in the analysis pipeline to ensure that BS-seq data are of high quality and suitable for subsequent analysis. Although several QC tools are available for next-generation sequencing data, most of them were not designed to handle QC issues specific to BS-seq protocols. Therefore, there is a strong need for a dedicated QC tool to evaluate and remove potential technical biases in BS-seq experiments. RESULTS: We developed a package named BSeQC to comprehensively evaluate the quality of BS-seq experiments and automatically trim nucleotides with potential technical biases that may result in inaccurate methylation estimation. BSeQC takes standard SAM/BAM files as input and generates bias-free SAM/BAM files for downstream analysis. Evaluation based on real BS-seq data indicates that the use of the bias-free SAM/BAM file substantially improves the quantification of methylation level. AVAILABILITY AND IMPLEMENTATION: BSeQC is freely available at: http://code.google.com/p/bseqc/. PMID- 24064418 TI - CPPpred: prediction of cell penetrating peptides. AB - Cell penetrating peptides (CPPs) are attracting much attention as a means of overcoming the inherently poor cellular uptake of various bioactive molecules. Here, we introduce CPPpred, a web server for the prediction of CPPs using a N-to 1 neural network. The server takes one or more peptide sequences, between 5 and 30 amino acids in length, as input and returns a prediction of how likely each peptide is to be cell penetrating. CPPpred was developed with redundancy reduced training and test sets, offering an advantage over the only other currently available CPP prediction method. PMID- 24064419 TI - An alignment-free test for recombination. AB - MOTIVATION: Why recombination? is one of the central questions in biology. This has led to a host of methods for quantifying recombination from sequence data. These methods are usually based on aligned DNA sequences. Here, we propose an efficient alignment-free alternative. RESULTS: Our method is based on the distribution of match lengths, which we look up using enhanced suffix arrays. By eliminating the alignment step, the test becomes fast enough for application to whole bacterial genomes. Using simulations we show that our test has similar power as established tests when applied to long pairs of sequences. When applied to 58 genomes of Escherichia coli, we pick up the strongest recombination signal from a 125 kb horizontal gene transfer engineered 20 years ago. AVAILABILITY AND IMPLEMENTATION: We have implemented our method in the command-line program rush. Its C sources and documentation are available under the GNU General Public License from http://guanine.evolbio.mpg.de/rush/. PMID- 24064420 TI - QSSPN: dynamic simulation of molecular interaction networks describing gene regulation, signalling and whole-cell metabolism in human cells. AB - MOTIVATION: Dynamic simulation of genome-scale molecular interaction networks will enable the mechanistic prediction of genotype-phenotype relationships. Despite advances in quantitative biology, full parameterization of whole-cell models is not yet possible. Simulation methods capable of using available qualitative data are required to develop dynamic whole-cell models through an iterative process of modelling and experimental validation. RESULTS: We formulate quasi-steady state Petri nets (QSSPN), a novel method integrating Petri nets and constraint-based analysis to predict the feasibility of qualitative dynamic behaviours in qualitative models of gene regulation, signalling and whole-cell metabolism. We present the first dynamic simulations including regulatory mechanisms and a genome-scale metabolic network in human cell, using bile acid homeostasis in human hepatocytes as a case study. QSSPN simulations reproduce experimentally determined qualitative dynamic behaviours and permit mechanistic analysis of genotype-phenotype relationships. AVAILABILITY AND IMPLEMENTATION: The model and simulation software implemented in C++ are available in supplementary material and at http://sysbio3.fhms.surrey.ac.uk/qsspn/. PMID- 24064421 TI - Methods and challenges in timing chromosomal abnormalities within cancer samples. AB - MOTIVATION: Tumors acquire many chromosomal amplifications, and those acquired early in the lifespan of the tumor may be not only important for tumor growth but also can be used for diagnostic purposes. Many methods infer the order of the accumulation of abnormalities based on their occurrence in a large cohort of patients. Recently, Durinck et al. (2011) and Greenman et al. (2012) developed methods to order a single tumor's chromosomal amplifications based on the patterns of mutations accumulated within those regions. This method offers an unprecedented opportunity to assess the etiology of a single tumor sample, but has not been widely evaluated. RESULTS: We show that the model for timing chromosomal amplifications is limited in scope, particularly for regions with high levels of amplification. We also show that the estimation of the order of events can be sensitive for events that occur early in the progression of the tumor and that the partial maximum likelihood method of Greenman et al. (2012) can give biased estimates, particularly for moderate read coverage or normal contamination. We propose a maximum-likelihood estimation procedure that fully accounts for sequencing variability and show that it outperforms the partial maximum-likelihood estimation method. We also propose a Bayesian estimation procedure that stabilizes the estimates in certain settings. We implement these methods on a small number of ovarian tumors, and the results suggest possible differences in how the tumors acquired amplifications. AVAILABILITY AND IMPLEMENTATION: We provide implementation of these methods in an R package cancerTiming, which is available from the Comprehensive R Archive Network (CRAN) at http://CRAN.R-project.org/. PMID- 24064422 TI - BCov: a method for predicting beta-sheet topology using sparse inverse covariance estimation and integer programming. AB - MOTIVATION: Prediction of protein residue contacts, even at the coarse-grain level, can help in finding solutions to the protein structure prediction problem. Unlike alpha-helices that are locally stabilized, beta-sheets result from pairwise hydrogen bonding of two or more disjoint regions of the protein backbone. The problem of predicting contacts among beta-strands in proteins has been addressed by several supervised computational approaches. Recently, prediction of residue contacts based on correlated mutations has been greatly improved and finally allows the prediction of 3D structures of the proteins. RESULTS: In this article, we describe BCov, which is the first unsupervised method to predict the beta-sheet topology starting from the protein sequence and its secondary structure. BCov takes advantage of the sparse inverse covariance estimation to define beta-strand partner scores. Then an optimization based on integer programming is carried out to predict the beta-sheet connectivity. When tested on the prediction of beta-strand pairing, BCov scores with average values of Matthews Correlation Coefficient (MCC) and F1 equal to 0.56 and 0.61, respectively, on a non-redundant dataset of 916 protein chains known with atomic resolution. Our approach well compares with the state-of-the-art methods trained so far for this specific task. AVAILABILITY AND IMPLEMENTATION: The method is freely available under General Public License at http://biocomp.unibo.it/savojard/bcov/bcov-1.0.tar.gz. The new dataset BetaSheet1452 can be downloaded at http://biocomp.unibo.it/savojard/bcov/BetaSheet1452.dat. PMID- 24064423 TI - Accurate prediction of bacterial type IV secreted effectors using amino acid composition and PSSM profiles. AB - MOTIVATION: Various human pathogens secret effector proteins into hosts cells via the type IV secretion system (T4SS). These proteins play important roles in the interaction between bacteria and hosts. Computational methods for T4SS effector prediction have been developed for screening experimental targets in several isolated bacterial species; however, widely applicable prediction approaches are still unavailable RESULTS: In this work, four types of distinctive features, namely, amino acid composition, dipeptide composition, .position-specific scoring matrix composition and auto covariance transformation of position-specific scoring matrix, were calculated from primary sequences. A classifier, T4EffPred, was developed using the support vector machine with these features and their different combinations for effector prediction. Various theoretical tests were performed in a newly established dataset, and the results were measured with four indexes. We demonstrated that T4EffPred can discriminate IVA and IVB effectors in benchmark datasets with positive rates of 76.7% and 89.7%, respectively. The overall accuracy of 95.9% shows that the present method is accurate for distinguishing the T4SS effector in unidentified sequences. A classifier ensemble was designed to synthesize all single classifiers. Notable performance improvement was observed using this ensemble system in benchmark tests. To demonstrate the model's application, a genome-scale prediction of effectors was performed in Bartonella henselae, an important zoonotic pathogen. A number of putative candidates were distinguished. AVAILABILITY: A web server implementing the prediction method and the source code are both available at http://bioinfo.tmmu.edu.cn/T4EffPred. PMID- 24064424 TI - Development of an amplified luminescent proximity homogeneous assay for quantitative determination of hepatitis B surface antigen in human serum. AB - BACKGROUND: Hepatitis B virus (HBV) poses a serious risk to human health and the hepatitis B surface antigen (HBsAg) is a popular biomarker in the diagnosis of HBV infection. A quantitative method with a high degree of accuracy, sensitivity and throughput is needed. METHODS: A novel amplified luminescent proximity homogeneous assay (AlphaLISA) was developed for HBsAg determination. A set of monoclonal antibodies was screened against the main subtypes of HBsAg (adr, ay) to confirm the assay's sensitivity to mutants. Technological processes and reaction conditions were optimized and the assay performance was evaluated. RESULTS: HBsAg concentrations were determined within a linear range of 0.04 to 100 IU ml(-1). The detection sensitivity was established as 0.01 IU ml(-1). Assay sensitivity to mutant HBsAg was achieved through antibody screening. The results demonstrate that the reproducibility, recovery, and specificity of this assay for HBsAg were better than acceptable. Compared with the commercial light-initiated chemiluminescence assay, the correlation coefficient of the novel assay was established as 0.921. CONCLUSIONS: The novel AlphaLISA developed in this study has shorter incubation time and easier protocol than the ones of conventional ELISA. It could be used for the clinical determination of HBsAg in human serum. We established a platform for further development of other biomarkers. PMID- 24064425 TI - Increased Th22 cells as well as Th17 cells in patients with adult T-cell acute lymphoblastic leukemia. AB - BACKGROUND: Immune regulation is important for the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). Th22 cells are recently-identified CD4(+) T cells that implicated in the pathogenesis of many hematological diseases, such as AML. However, the role of Th22 cells in the pathophysiology of T-ALL remains unclear. We examined the Th22, Th17 and Th1 cell frequencies in peripheral blood of T-ALL patients. METHODS: We studied 24 newly-diagnosed (ND), 17 morphologic complete remission (CR) T-ALL patients and 30 healthy controls. Th subsets were examined by flow cytometry. Plasma IL-22 and IL-17 concentrations were measured by ELISA. Transcription factor RORC, T-bet and AHR mRNA expressions were examined by RT PCR. RESULTS: Th22, Th17 frequencies, plasma IL-22 concentration and AHR expression were significantly increased in ND or CR T-ALL patients compared with controls. Moreover, Th22 showed positive correlation with Th17 or Th1 cells in T ALL patients. However, a significant decrease of IL-17 concentration, Th1 frequency and T-bet expression was found in ND or CR ALL patients compared with controls. Furthermore, Th17 cells showed positive correlation but Th1 cells showed negative correlation with white blood cell counts. CONCLUSION: The profile of Th subsets was distinct for T-ALL patients and showed some correlations with clinical index, which suggest that these Th subsets may be implicated in the pathogenesis of T-ALL and be reasonable targets for therapeutic intervention. PMID- 24064426 TI - Natural history of optical coherence tomography-detected non-flow-limiting edge dissections following drug-eluting stent implantation. AB - AIMS: Angiographic evidence of edge dissections has been associated with a risk of early stent thrombosis. Optical coherence tomography (OCT) is a high resolution technology detecting a greater number of edge dissections- particularly non-flow-limiting--compared to angiography. Their natural history and clinical implications remain unclear. The objectives of the present study were to assess the morphology, healing response, and clinical outcomes of OCT detected edge dissections using serial OCT imaging at baseline and at one year following drug-eluting stent (DES) implantation. METHODS AND RESULTS: Edge dissections were defined as disruptions of the luminal surface in the 5 mm segments proximal and distal to the stent, and categorised as flaps, cavities, double-lumen dissections or fissures. Qualitative and quantitative OCT analyses were performed every 0.5 mm at baseline and one year, and clinical outcomes were assessed. Sixty-three lesions (57 patients) were studied with OCT at baseline and one-year follow-up. Twenty-two non-flow-limiting edge dissections in 21 lesions (20 patients) were identified by OCT; only two (9%) were angiographically visible. Flaps were found in 96% of cases. The median longitudinal dissection length was 2.9 mm (interquartile range [IQR] 1.6-4.2 mm), whereas the circumferential and axial extensions amounted to 1.2 mm (IQR: 0.9-1.7 mm) and 0.6 mm (IQR: 0.4-0.7 mm), respectively. Dissections extended into the media and adventitia in seven (33%) and four (20%) cases, respectively. Eighteen (82%) OCT detected edge dissections were also evaluated with intravascular ultrasound which identified nine (50%) of these OCT-detected dissections. No stent thrombosis or target lesion revascularisation occurred up to one year. At follow-up, 20 (90%) edge dissections were completely healed on OCT. The two cases exhibiting persistent dissection had the longest flaps (2.81 mm and 2.42 mm) at baseline. CONCLUSIONS: OCT-detected edge dissections which are angiographically silent in the majority of cases are not associated with acute stent thrombosis or restenosis up to one-year follow-up. PMID- 24064427 TI - Improving Process Evaluations of Health Behavior Interventions: Learning From the Social Sciences. AB - This article reflects on the current state of process evaluations of health behavior interventions and argues that evaluation practice in this area could be improved by drawing on the social science literature to a greater degree. While process evaluations of health behavior interventions have increasingly engaged with the social world and sociological aspects of interventions, there has been a lag in applying relevant and potentially useful approaches from the social sciences. This has limited the scope for health behavior process evaluations to address pertinent contextual issues and methodological challenges. Three aspects of process evaluations are discussed: the incorporation of contexts of interventions; engagement with the concept of "process" in process evaluation; and working with theory to understand interventions. Following on from this, the article also comments on the need for new methodologies and on the implications for addressing health inequalities. PMID- 24064428 TI - Effects of Time Frame on the Recall Reliability of CFS Symptoms. AB - This study serves as an investigation of the reliability of symptom data as reported by individuals with chronic fatigue syndrome (CFS), across three recall time frames (the past week, the past month, and the past 6 months), and at two assessment points (with 1 week in between each assessment). Multilevel model analyses were used to determine the optimal recall time frame, in terms of test retest reliability, for each of the Fukuda et al. (1994) case defining symptoms. Results suggested that the optimal time frame for reliably reporting CFS symptoms was six months for sore throat, lymph node pain, muscle pain, post-exertional malaise, headaches, memory/concentration difficulties, and unrefreshing sleep. For joint pain, the optimal time frame was one month. Researchers who are interested in the assessment of CFS symptoms need to take recall time frame into account, especially when the intended goal is to standardize and improve the methods used to reliably and accurately diagnose this complex illness. PMID- 24064429 TI - Expanding assessments of translational research programs: supplementing metrics with value judgments. AB - The University of Washington (UW) Institute for Translational Health Sciences (ITHS), funded by a Clinical and Translational Sciences Award program, has supplemented its initial Kellogg Logic Model-based program evaluation with the eight judgment-based evaluative elements of the World Health Organization's (WHO) Health Services Assessment Model. This article describes the relationship between the two models, the rationale for the decision to supplement the evaluation with WHO evaluative elements, the value-added results of the WHO evaluative elements, and plans for further developing the WHO assessments. PMID- 24064430 TI - Investigating the psychometric properties of the Rosenberg Self-Esteem scale for South African residents of Greater Pretoria. AB - Interviewers administered the Rosenberg Self-Esteem scale (RSES) to five groups of Black (formal township and informal settlement), White, Indian, and mixed race adult residents of Greater Pretoria. The results demonstrated that the RSES was psychometrically sound for the five groups. The minimal effects of sociodemographic characteristics on global self-esteem showed that the RSES and its two dimensions, self-competence (SC) and self-liking (SL), were suitable in this setting. All five groups scored above the theoretical midpoint of the RSES, indicating that generally positive self-evaluations appear to be universal. The relationships between positively and negatively worded items, SC, and SL attested to the following: internal structure reliability, congruence between positive and negative items, no negative biases in response, and concordance between SC and SL dimensions. The significant differences between informal settlement residents and the other four groups on global self-esteem, positively and negatively worded items, and SC and SL were possibly due to physiological needs taking precedence over higher order needs. PMID- 24064431 TI - Methods for identifying translational researchers. AB - There is currently no generally accepted method for identifying the community of translational researchers when evaluating Clinical and Translational Science Centers. We use data from the multiyear evaluation of the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) to investigate the complexities of reliably identifying translational researchers. We use three methods to identify translational researchers: (1) participating in CCTS services and programs; (2) self-identifying as a translational researcher; and (3) engaging in activities that are characteristic of translational science. We find little overlap of these differently defined research groups. We conclude with a discussion of how the findings suggest challenges for evaluating translational science programs and the need for better definition, communication, and demonstration of translational science for scientists and evaluators. PMID- 24064432 TI - Assessing and evaluating multidisciplinary translational teams: a mixed methods approach. AB - A case report illustrates how multidisciplinary translational teams can be assessed using outcome, process, and developmental types of evaluation using a mixed-methods approach. Types of evaluation appropriate for teams are considered in relation to relevant research questions and assessment methods. Logic models are applied to scientific projects and team development to inform choices between methods within a mixed-methods design. Use of an expert panel is reviewed, culminating in consensus ratings of 11 multidisciplinary teams and a final evaluation within a team-type taxonomy. Based on team maturation and scientific progress, teams were designated as (a) early in development, (b) traditional, (c) process focused, or (d) exemplary. Lessons learned from data reduction, use of mixed methods, and use of expert panels are explored. PMID- 24064433 TI - Comments on Graves' hyperthyroidism-induced psychosis treated with aripiprazole: a case report. PMID- 24064434 TI - Clostridium difficile-associated diarrhea: role of the pharmacist in the health system. PMID- 24064436 TI - Antibiotic-associated diarrhea: a refresher on causes and possible prevention with probiotics--continuing education article. AB - Antibiotic-associated diarrhea (AAD) describes any unexplained diarrhea associated with the use of an antibiotic. AAD also includes infection caused by Clostridium difficile, however this organism only accounts for a small percentage of diarrhea caused by antibiotics. AAD can be caused by multiple other organisms including C perfringens, S aureus, and Candida. Some antibiotics are more likely to cause non-C difficile AAD, such as erythromycin and the penicillin class. AAD develops through the loss of normal flora and reduced colonic bacterial carbohydrate metabolism during antibiotic administration. There is an increasing interest in the use of probiotics for the prevention of AAD. There are several meta-analyses that report a relative risk reduction of AAD with the use of probiotics during antibiotic administration. Interpretation of these studies has been challenging due to the heterogeneity and size of the patient populations, unclear probiotic regimen, and unclear safety profile. Since AAD can be a reason for a patient to become non-compliant or receive incomplete treatment, clinicians should monitor for this potential adverse effect caused by antibiotics. PMID- 24064437 TI - Role of fidaxomicin for the treatment of Clostridium difficile infection. AB - Clostridium difficile is a gram-negative, anaerobic, spore-forming emerging pathogen within health care systems and community-based populations that has a high associated morbidity and mortality as well as cost for the health care system. Recent studies reported high rates of recurrence thus a need for new pharmacological agents to treat C difficile infections (CDIs). Fidaxomicin is a novel macrocyclic antibiotic, originally isolated from fermentation broth of Dactylosporangium aurantiacum spp Hamdenensis, with selective spectrum, unique pharmacokinetic and pharmacodynamics profile, adverse effect profile, efficacy, and role in the treatment of and time to recurrent CDI. Fidaxomicin data have similar clinical cure, when compared to vancomycin, with lower recurrence rates and higher global cure rates in non-BI/NAP1/027 strains. Fidaxomicin also lacks activity against gram-negative bacteria; hence, its potential effect on resistance development among enteric bacteria appears to be low. It appears to have minimal need for renal or hepatic adjustments and minimal concerns for drug drug interactions. Overall, fidaxomicin has been generally well tolerated with the most common adverse effects reported as mild gastrointestinal complaints. Fidaxomicin appears to have a role in the treatment of CDI with potential lower rates of recurrence, especially in patients with severe disease or risk factors for recurrent CDI. PMID- 24064435 TI - Epidemiology of Clostridium difficile infection. AB - There has been dramatic change in the epidemiology of Clostridium difficile infection (CDI) since the turn of the 21st century noted by a marked increase in incidence and severity, occurring at a disproportionately higher frequency in older patients. Historically considered a nosocomial infection associated with antibiotic exposure, CDI has now also emerged in the community in populations previously considered low risk. Emerging risk factors and disease recurrence represent continued challenges in the management of CDI. The increased incidence and severity associated with CDI has coincided with the emergence and rapid spread of a previously rare strain, ribotype 027. Recent data from the United States and Europe suggest that the incidence of CDI may have reached a crescendo in the recent years and is perhaps beginning to plateau. The acute care direct costs of CDI were estimated to be US$4.8 billion in 2008. However, nearly all the published studies have focused on CDI diagnosed and treated in the acute care hospital setting and fail to measure the burden outside the hospital, including recently discharged patients, outpatients, and those in long-term care facilities. Enhanced surveillance methods are needed to monitor the incidence, to identify populations at risk, and to characterize the molecular epidemiology of strains causing CDI. PMID- 24064439 TI - Response letter to: the Hispanic paradox further unraveled? PMID- 24064438 TI - Challenges in predicting the effects of climate change on Schistosoma mansoni and Schistosoma haematobium transmission potential. AB - Climate change will inevitably influence both the distribution of Schistosoma mansoni and Schistosoma haematobium and the incidence of schistosomiasis in areas where it is currently endemic, and impact on the feasibility of schistosomiasis control and elimination goals. There are several limitations of current models of climate and schistosome transmission, and substantial gaps in empirical data that impair model development. In this review we consider how temperature, precipitation, heat waves, drought, and flooding could impact on snail and schistosome population dynamics. We discuss how widely used degree day models of schistosome development may not be accurate at lower temperatures, and highlight the need for further research to improve our understanding of the relationship between air and water temperature and schistosome and snail development. PMID- 24064440 TI - Cost effectiveness of endosonography versus surgical staging in potentially resectable lung cancer: a health economics analysis of the ASTER trial from a European perspective. AB - In the ASTER study, mediastinal staging was more accurate for patients randomised to combined endobronchial and endoscopic ultrasound, followed by surgical staging if endoscopy was negative, versus surgical staging alone. Here, we report survival, quality of life and cost effectiveness up to 6 months, for the UK, The Netherlands and Belgium, separately. Survival in the two arms of the study was similar. In all three countries, the endosonography strategy had slightly higher quality-adjusted life years over 6 months, and was cheaper. Therefore, based on clinical accuracy and cost effectiveness, we conclude that mediastinal staging should commence with endosonography. PMID- 24064441 TI - High treatment success in children treated for multidrug-resistant tuberculosis: an observational cohort study. AB - BACKGROUND: Few studies have described the management of multidrug-resistant (MDR) tuberculosis (TB) in children and evidence-based guidance on management is lacking. We describe the presentation, treatment and outcome in children treated for severe and non-severe MDR-TB in Cape Town, South Africa. METHODS: We conducted an observational cohort study of all children (<15 years) treated for MDR-TB if routinely initiated on treatment between January 2009 and December 2010. Treatment was based on local standard of care, based on international guidelines. Data were collected through family interviews and folder review. Standardised definitions were used for diagnosis, severity of disease, adverse events and outcome. RESULTS: Of 149 children started on MDR-TB treatment, the median age was 36 months (IQR 16-66), 32 (22%; of 146 tested) had HIV infection and 59 (40%) had a confirmed diagnosis. Ninety-four (66%) children were treated with an injectable drug and the median total duration of treatment was 13 months (IQR 11-18). Thirty-six (24%) children were cured, 101 (68%) probably cured, 1 (1%) was transferred out, 8 (5%) were lost to follow-up and 3 (2%) died. Children with severe disease were older (54 months (IQR 18-142) vs 31.5 months (IQR 17.5 53.5); p=0.012), more commonly had HIV infection (OR 6.25; 95% CI 2.50 to 15.6; p<0.001) and were more likely to die (p=0.008). DISCUSSION: A confirmed diagnosis of MDR-TB is not possible in all cases but this should not impede the treatment of MDR-TB in children. More than 90% of children with MDR-TB can be successfully treated. Non-severe disease could be successfully treated with reduced treatment duration. PMID- 24064442 TI - An adaptable architecture for patient cohort identification from diverse data sources. AB - OBJECTIVE: We define and validate an architecture for systems that identify patient cohorts for clinical trials from multiple heterogeneous data sources. This architecture has an explicit query model capable of supporting temporal reasoning and expressing eligibility criteria independently of the representation of the data used to evaluate them. METHOD: The architecture has the key feature that queries defined according to the query model are both pre and post-processed and this is used to address both structural and semantic heterogeneity. The process of extracting the relevant clinical facts is separated from the process of reasoning about them. A specific instance of the query model is then defined and implemented. RESULTS: We show that the specific instance of the query model has wide applicability. We then describe how it is used to access three diverse data warehouses to determine patient counts. DISCUSSION: Although the proposed architecture requires greater effort to implement the query model than would be the case for using just SQL and accessing a data-based management system directly, this effort is justified because it supports both temporal reasoning and heterogeneous data sources. The query model only needs to be implemented once no matter how many data sources are accessed. Each additional source requires only the implementation of a lightweight adaptor. CONCLUSIONS: The architecture has been used to implement a specific query model that can express complex eligibility criteria and access three diverse data warehouses thus demonstrating the feasibility of this approach in dealing with temporal reasoning and data heterogeneity. PMID- 24064443 TI - Sociotechnical challenges to developing technologies for patient access to health information exchange data. AB - BACKGROUND: Providing patients with access to their medical data is widely expected to help educate and empower them to manage their own health. Health information exchange (HIE) infrastructures could potentially help patients access records across multiple healthcare providers. We studied three HIE organizations as they developed portals to give consumers access to HIE data previously exchanged only among healthcare organizations. OBJECTIVE: To follow the development of new consumer portal technologies, and to identify barriers and facilitators to patient access to HIE data. METHODS: Semistructured interviews of 15 key informants over a 2-year period spanning the development and early implementation of three new projects, coded according to a sociotechnical framework. RESULTS: As the organizations tried to develop functionality that fully served the needs of both providers and patients, plans were altered by technical barriers (primarily related to data standardization) and cultural and legal issues surrounding data access. Organizational changes also played an important role in altering project plans. In all three cases, patient access to data was significantly scaled back from initial plans. CONCLUSIONS: This prospective study revealed how sociotechnical factors previously identified as important in health information technology success and failure helped to shape the evolution of three novel consumer informatics projects. Barriers to providing patients with seamless access to their HIE data were multifactorial. Remedies will have to address technical, organizational, cultural, and other factors. PMID- 24064444 TI - Classification of medication incidents associated with information technology. AB - INTRODUCTION: Information technology (IT) plays a pivotal role in improving patient safety, but can also cause new problems for patient safety. This study analyzed the nature and consequences of a large sample of IT-related medication incidents, as reported by healthcare professionals in community pharmacies and hospitals. METHODS: The medication incidents submitted to the Dutch central medication incidents registration (CMR) reporting system were analyzed from the perspective of the healthcare professional with the Magrabi classification. During classification new terms were added, if necessary. MAIN MEASURES: The principal source of the IT-related problem, nature of error. Additional measures: consequences of incidents, IT systems, phases of the medication process. RESULTS: From March 2010 to February 2011 the CMR received 4161 incidents: 1643 (39.5%) from community pharmacies and 2518 (60.5%) from hospitals. Eventually one of six incidents (16.1%, n=668) were related to IT; in community pharmacies more incidents (21.5%, n=351) were related to IT than in hospitals (12.6%, n=317). In community pharmacies 41.0% (n=150) of the incidents were about choosing the wrong medicine. Most of the erroneous exchanges were associated with confusion of medicine names and poor design of screens. In hospitals 55.3% (n=187) of incidents concerned human-machine interaction-related input during the use of computerized prescriber order entry. These use problems were also a major problem in pharmacy information systems outside the hospital. CONCLUSIONS: A large sample of incidents shows that many of the incidents are related to IT, both in community pharmacies and hospitals. The interaction between human and machine plays a pivotal role in IT incidents in both settings. PMID- 24064445 TI - Protective effects of alkaloid compounds from Nelumbinis Plumula on tert-butyl hydroperoxide-induced oxidative stress. AB - This study was conducted to investigate the effect of Nelumbinis Plumula total alkaloid (NPA) and its main alkaloid components on oxidative stress induced by tert-butyl hydroperoxide (t-BHP) in the human hepatocellular HepG2 cell line. According to HPLC analysis, several major alkaloid compounds such as liensinine, isoliensinine and neferine were present in NPA. The cytotoxic effects in 0.55 mM t-BHP-induced HepG2 cells were significantly inhibited by NPA and the major compound in NPA, neferine, showed the strongest activities. The protective effect of neferine against oxidative stress induced by t-BHP may be associated with decreased ROS formation, TBARS generation, LDH release and increased GSH levels, suggesting their involvement of the cytoprotective on oxidative stress. The effects were comparable with quercetin, which was used as positive control. Overall, total alkaloid and alkaloid compounds from Nelumbinis Plumula displayed a significant cytoprotective effect against oxidative stress. Further study is needed to elucidate the relationship between the chemical structures of the components in NPA and their protective effect on oxidative stress. PMID- 24064446 TI - Coverage dependent variation of the adsorption structure of 2 thiophenecarboxaldehyde on the Ge(100)-2 * 1 reconstructed surface. AB - High-resolution photoemission spectroscopy (HRPES) measurements were collected and density functional theory (DFT) calculations were performed to track the exposure-dependent variation of the adsorption structure of 2 thiophenecarboxaldehyde (C4H3SCHO: TPCA) on the Ge(100) 2 * 1 reconstructed surface at room temperature. In an effort to identify the most probable adsorption structures on the Ge(100)-2 * 1 reconstructed surface, we deposited TPCA molecules at low exposure and at high exposure and compared the differences between the electronic features measured using HRPES. The HRPES data suggested three possible adsorption structures of TPCA on the Ge(100)-2 * 1 reconstructed surface, and DFT calculations were used to determine the plausibility of these structures. HRPES analysis corroborated by DFT calculations, indicated that an S dative bonded structure is the most probable adsorption structure at relatively low exposure levels, the [4 + 2] cycloadduct structure is the second most probable structure, and the [2 + 2]-C=O cycloadduct structure is the least probable structure on the Ge(100)-2 * 1 reconstructed surface at relatively high exposure levels. PMID- 24064447 TI - Bioactive flavone-C-glycosides of the African medicinal plant Biophytum umbraculum. AB - Three flavone-C-glycosides-cassiaoccidentalin A (1), isovitexin (2) and isoorientin (3)-were isolated from the ethyl acetate (EtOAc) soluble fraction of the methanol crude extract of the African medicinal plant Biophytum umbraculum, This is the first report of these compounds in this plant. All compounds were identified by spectroscopic analysis and comparison with published data. Isoorientin (3) and the EtOAc extract showed the greatest antioxidant activity in the DPPH assay as well as the strongest inhibition of xanthine oxidase (XO) and 15-lipoxygenase (15-LO). From these results, the extract of B. umbraculum might be a valuable source of flavone C-glycosides. PMID- 24064448 TI - Volatile organic compounds obtained by in vitro callus cultivation of Plectranthus ornatus Codd. (Lamiaceae). AB - Plectranthus spp (Lamiaceae) are plants of economic importance because they are sources of aromatic essential oils and are also cultivated and several species of this genus are used as folk medicines. This paper describes the effects of different concentrations of the 2,4-dichlorophenoxyacetic acid (2,4-D) and 1 naphthaleneacetic acid (NAA) on the induction of callus from nodal segments of Plectranthus ornatus Codd and in the production of volatile organic compounds (monoterpenes and sesquiterpenes). The 20 and 40 day calli were subjected to solid phase micro extraction (HS-SPME) and submitted to GCMS analysis. Variations in VOCs between the samples were observed and, a direct relationship was observed between of the major constituent detected (alpha-terpinyl acetate) and the monoterpenes alpha-thujene, alpha-pinene, beta-pinene, camphene, sabinene and alpha-limonene that were present in the volatile fractions. Besides alpha terpinyl acetate, isobornyl acetate and alpha-limonene were also major constituents. Variations were observed in VOCs in the analyzed periods. The best cultivation media for the production of VOCs was found to be MS0 (control). Moderate success was achieved by treatment with 2.68 uM and 5:37 uM NAA (Group 2). With 2,4-D (9.0 uM), only the presence of alpha-terpinyl acetate and isocumene were detected and, with 2.26 uM of 2,4-D was produced mainly alpha terpinyl acetate, alpha-thujene and beta-caryophyllene (16.2%). The VOC profiles present in P. ornatus were interpreted using PCA and HCA. The results permitted us to determine the best cultivation media for VOC production and, the PCA and HCA analysis allowed us to recognize four groups among the different treatments from the compounds identified in this set of treatments. PMID- 24064449 TI - Palladium-catalyzed synthesis of natural and unnatural 2-, 5-, and 7-oxygenated carbazole alkaloids from N-arylcyclohexane enaminones. AB - A palladium-catalyzed synthesis of the carbazole framework is described, including the preparation of 2-, 5-, and 7-oxygenated natural and unnatural carbazole alkaloids. A series of N-arylcyclohexane enaminones, generated by condensation of cyclohexane-1,3-dione with diverse anilines, were aromatized by a Pd(0)-catalyzed thermal treatment to afford the corresponding diarylamines. The latter were submitted to a Pd(II)-catalyzed cyclization and methylation processes to provide the desired carbazoles, including clausine V. Following an inverse strategy, a new and short total synthesis of glycoborine is also reported. PMID- 24064450 TI - Bioactive protopanaxatriol type saponins isolated from the roots of Panax notoginseng (Burk.) F. H. Chen. AB - Seven new protopanaxatriol type saponins, 20S-sanchirhinosides A1 (1), A2 (2), A3 (3), A4 (4), A5 (5), and A6 (6), and sanchirhinoside B (7) were obtained as minor constituents from the root extract of Panax notoginseng (Burkill, F. H. Chen), which showed protection effects against antimycin A induced mitochondrial oxidative stress. Their structures were elucidated by chemical and spectroscopic methods (IR, HRESI-TOF-MS, 1D and 2D NMR). Among them, compounds 4, 6 and 7 showed significant protective effects against antimycin A-induced L6 cell injury. PMID- 24064451 TI - Isolation and identification of two novel attractant compounds from Chinese cockroach (Eupolyphaga sinensis Walker) by combination of HSCCC, NMR and CD techniques. AB - High-speed counter-current chromatography (HSCCC) with a two-phase solvent system composed of n-hextane-ethyl acetate-methanol-water (1.5:1:1.5:1, v/v/v/v) was applied to the isolation and purification of attractants from Chinese cockroach, Eupolyphaga sinensis Walker. Two new attractants with attractant activity towards the male insects were obtained from the extract sample in a one-step separation. Their purities were determined by HPLC. Subsequent MS, NMR and CD analyses have led to the characterization of (R)-3-ethyl-6,8-dihydroxy-7-methyl-3,4 dihydroisochromen-1-one (1) and (R)-6,8-dihydroxy-3,7-dimethyl-3,4 dihydroisochromen-1-one (2), two novel isocumarin type attractants. Based on these results, it is concluded that HSCCC is a viable separation method option for purifying insect attractants, while effectively maintaining the attracting activity of the isolates. This is the first attempt to apply counter-current chromatography technique to separate attractants from Chinese cockroach. PMID- 24064452 TI - Revealing the properties of plant defensins through dynamics. AB - Defensins are potent, ancient natural antibiotics that are present in organisms ranging from lower organisms to humans. Although the structures of several defensins have been well characterized, the dynamics of only a few have been studied. This review discusses the diverse dynamics of two plant defensins for which the structure and dynamics have been characterized, both in the free state and in the presence of target membranes. Multiple motions are observed in loops and in secondary structure elements and may be related to twisting or breathing of the alpha-helix and beta-sheet. This complex behavior is altered in the presence of an interface and is responsive to the presence of the putative target. The stages of membrane recognition and disruption can be mapped over a large time scale range, demonstrating that defensins in solution exist as an ensemble of different conformations, a subset of which is selected upon membrane binding. Therefore, studies on the dynamics have revealed that defensins interact with membranes through a mechanism of conformational selection. PMID- 24064453 TI - Dillapiole, isolated from Peperomia pellucida, shows gastroprotector activity against ethanol-induced gastric lesions in Wistar rats. AB - Peperomia pellucida is a plant used in traditional medicine to treat gastric ulcers. Although this gastroprotective activity was reported, the active compounds have not been identified. Therefore, the aim herein was to identify the most active compound in the gastroprotective activity of P. pellucida using an ethanol-induced gastric ulcer experimental rat model. A gastroprotective effect was observed when the hexane and dichloromethane extracts were tested, with the higher effect being obtained with the dichloromethane extract (82.3 +/- 5.6%) at 100 mg/kg. Dillapiole was identified as the most active compound in this extract. Although there have been previous reports on dillapiole, this is the first on its gastroprotective activity. Rats treated with this compound at 3, 10, 30 and 100 mg/kg showed 23.1, 56.1, 73.2 and 85.5% gastroprotection, respectively. The effect elicited by dillapiole at 100 mg/kg was not attenuated by pretreatment with indomethacin (10 mg/kg, s.c.), a prostaglandin synthesis blocker, NG-nitro-l arginine methyl ester (70 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, or N-ethylmaleimide (10 mg/kg, s.c.), a blocker of sulfhydryl groups. This suggests that the gastroprotective mechanism of action of dillapiole does not involve prostaglandins, NO or sulfhydryl groups. PMID- 24064454 TI - Anticancer and antifungal compounds from Aspergillus, Penicillium and other filamentous fungi. AB - This review covers important anticancer and antifungal compounds reported from filamentous fungi and in particular from Aspergillus, Penicillium and Talaromyces. The taxonomy of these fungi is not trivial, so a focus of this review has been to report the correct identity of the producing organisms based on substantial previous in-house chemotaxonomic studies. PMID- 24064455 TI - A new lignan glucoside from the whole plants of Salvia scapiformis. AB - Phytochemical investigation of the whole plants of Salvia scapiformis Hance afforded eight compounds, including one new lignan, (+)-8alpha-hydroxypinoresinol 8-O-[6''-O-(4'''-hydroxybenzoyl)]-beta-d-glucopyranoside (1), four known lignans, (+)-8alpha-hydroxy-pinoresinol-8-O-beta-d-glucopyranoside (2), (+)-8alpha hydroxypinoresinol (3), (+)-pinoresinol (4), and (+)-medioresinol (5), and three known triterpenoids, ursolic acid (6), 4-epi-niga-ichigoside F1 (7), and niga ichigoside F1 (8). Their structures were determined on the basis of extensive spectroscopic analyses and comparison with spectroscopic data in the literature. The absolute configuration of the new compound 1 was determined by chemical transformation and GC analysis. PMID- 24064456 TI - Bioactivity-guided fractionation of physical fatigue-attenuating components from Rubus parvifolius L. AB - Alleviation of fatigue has been emerging as a serious issue that requires urgent attention. Health professionals and sports physiologists have been looking for active natural products and synthetic compounds to overcome fatigue in humans. This study was designed to define the anti-fatigue property of Rubus parvifolius L. (RPL) by characterization of active constituents using a mouse forced swimming test model. Four RPL fractions with different polarities containing anti-fatigue activity were sequentially isolated from the n-butanol RPL extract, followed by elution of 50% ethanol-water fraction from D101 macroporous resin chromatography to obtain nigaichigoside F1, suavissimoside R1 and coreanoside F1. Active constituents of the 50% ethanol-water eluate of RPL were total saponins. The fractions were examined based on the effect on weight-loaded swimming capacity of mice. Serum levels of urea nitrogen (SUN), triglyceride fatty acids (TG), lactate dehydrogenase (LDH), lactic acid (LA), ammonia and hepatic glycogen (HG) were also examined for potential mechanisms underlying the anti-fatigue effect of RPL extracts. During the experiment, two inflammatory markers, interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha) in serum, were measured. We found that total saponins from RPL possess potent capabilities to alleviate mouse fatigue induced by forced swimming and that nigaichigoside F1 was responsible for the pharmacological effect. The underlying mechanisms include delays of SUN and LA accumulation, a decrease in TG level by increasing fat consumption, increases in HG and LDH so that lactic acid accumulation and ammonia in the muscle were reduced, and suppression of increased immune activation and inflammatory cytokine production. Our findings will be helpful for functional identification of novel anti-fatigue components from natural medicinal herbs. PMID- 24064457 TI - A modular approach to triazole-containing chemical inducers of dimerisation for yeast three-hybrid screening. AB - The yeast three-hybrid (Y3H) approach shows considerable promise for the unbiased identification of novel small molecule-protein interactions. In recent years, it has been successfully used to link a number of bioactive molecules to novel protein binding partners. However despite its potential importance as a protein target identification method, the Y3H technique has not yet been widely adopted, in part due to the challenges associated with the synthesis of the complex chemical inducers of dimerisation (CIDs). The development of a modular approach using potentially "off the shelf" synthetic components was achieved and allowed the synthesis of a family of four triazole-containing CIDs, MTX-Cmpd2.2-2.5. These CIDs were then compared using the Y3H approach with three of them giving a strong positive interaction with a known target of compound 2, TgCDPK1. These results showed that the modular nature of our synthetic strategy may help to overcome the challenges currently encountered with CID synthesis and should contribute to the Y3H approach reaching its full potential as an unbiased target identification strategy. PMID- 24064458 TI - Do dopamine gene variants and prenatal smoking interactively predict youth externalizing behavior? AB - Externalizing behaviors (encompassing antisocial, impulsive, and substance use behaviors) are pervasive and impairing across a multitude of settings and developmental contexts. These behaviors, though often investigated separately, are highly comorbid. Prenatal tobacco exposure in interaction with various genetic influences has predicted later externalizing behavior, and recent evidence supports investigating sex differences in these patterns. In the current study, we extend this work by (a) examining two functional genetic markers in the dopamine system: the transporter gene (DAT1) and the dopamine receptor D4 gene (DRD4) in interaction with prenatal tobacco exposure to predict a latent composite of externalizing behavior and (b) testing whether these patterns differ by sex of youth in a community sample of adolescents (n=176). The relatively small sample is partially offset by high quality, multi-method prospective measurement. We assessed prenatal tobacco exposure using prospective repeated cotinine-corrected reports and externalizing behaviors were assessed utilizing multiple measures across three waves. The interaction between DAT1 (but not DRD4) and prenatal tobacco exposure was statistically significant in boys, and patterns appeared to differ by sex. Risk for externalizing behaviors for exposed boys increased linearly as a function of the 10r DAT1 allele. For exposed girls, there was a trend such that DAT1 heterozygotes had a marginally higher risk than homozygotes. This pattern was not explained by passive gene-environment correlation. Elucidating sex-specific pathways through which early adverse exposures and genetic susceptibilities contribute to externalizing behavior can inform early targeted prevention efforts for those children at highest risk. PMID- 24064459 TI - Cofactoring and dimerization of proteinase-activated receptors. AB - Proteinase-activated receptors (PARs) are G protein-coupled receptors that transmit cellular responses to extracellular proteases and have important functions in vascular physiology, development, inflammation, and cancer progression. The established paradigm for PAR activation involves proteolytic cleavage of the extracellular N terminus, which reveals a new N terminus that functions as a tethered ligand by binding intramolecularly to the receptor to trigger transmembrane signaling. Most cells express more than one PAR, which can influence the mode of PAR activation and signaling. Clear examples include murine PAR3 cofactoring of PAR4 and transactivation of PAR2 by PAR1. Thrombin binds to and cleaves murine PAR3, which facilitates PAR4 cleavage and activation. This process is essential for thrombin signaling and platelet activation, since murine PAR3 cannot signal alone. Although PAR1 and PAR4 are both competent to signal, PAR1 is able to act as a cofactor for PAR4, facilitating more rapid cleavage and activation by thrombin. PAR1 can also facilitate PAR2 activation through a different mechanism. Cleavage of the PAR1 N terminus by thrombin generates a tethered ligand domain that can bind intermolecularly to PAR2 to activate signaling. Thus, PARs can regulate each other's activity by localizing thrombin when in complex with PAR3 and PAR4 or by cleaved PAR1, providing its tethered ligand domain for PAR2 activation. The ability of PARs to cofactor or transactivate other PARs would necessitate that the two receptors be in close proximity, likely in the form of a heterodimer. Here, we discuss the cofactoring and dimerization of PARs and the functional consequences on signaling. PMID- 24064461 TI - Modulation of motor cortex excitability in obsessive-compulsive disorder: an exploratory study on the relations of neurophysiology measures with clinical outcome. AB - Low-frequency repetitive transcranial magnetic stimulation (rTMS) to supplementary motor area (SMA) showed clinical benefit in obsessive-compulsive disorder (OCD). Here we tested whether clinical improvement was associated with enhanced cortical inhibition as measured by single and paired-pulse TMS variables. In 18 OCD patients receiving 4 weeks of either active or sham rTMS in a double-blind randomized trial, we assessed bilateral resting and active motor thresholds (RMT and AMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). We tested correlations between changes in Yale-Brown Obsessive Compulsive Scale-Self-report (Y-BOCS-SR), Clinical Global Impression-Severity subscale (CGI-S) and cortical excitability measures. Active rTMS increased right hemisphere RMT whose change correlated with Y-BOCS-SR improvement. Baseline RMT hemispheric asymmetry, defined as the difference between left and right hemispheres RMT, and its normalization after active rTMS correlated with Y-BOCS-SR and CGI-S improvements. Active rTMS also increased right hemisphere SICI whose change correlated with Y BOCS-SR and CGI-S at week 4, and with normalization of baseline RMT hemispheric asymmetry. Treatment-induced changes in cortical excitability measures are consistent with an inhibitory action of SMA rTMS on dysfunctional motor circuits in OCD. Correlations of neurophysiology measures with therapeutic outcome are supportive of the role of SMA in the modulation of OCD symptoms. PMID- 24064462 TI - PTSD symptom dimensions and their relationship to functioning in World Trade Center responders. AB - Post-traumatic stress disorder (PTSD) symptoms are common among responders to the 9/11 attacks on the World Trade Center and can lead to impairment, yet it is unclear which symptom dimensions are responsible for poorer functioning. Moreover, how best to classify PTSD symptoms remains a topic of controversy. The present study tested competing models of PTSD dimensions and then assessed which were most strongly associated with social/occupational impairment, depression, and alcohol abuse. World Trade Center responders (n=954) enrolled in the Long Island site of the World Trade Center Health Program between 2005 and 2006 were administered standard self-report measures. Confirmatory factor analysis confirmed the superiority of four-factor models of PTSD over the DSM-IV three factor model. In selecting between four-factor models, evidence was mixed, but some support emerged for a broad dysphoria dimension mapping closely onto depression and contributing strongly to functional impairment. This study confirmed in a new population the need to revise PTSD symptom classification to reflect four dimensions, but raises questions about how symptoms are categorized. Results suggest that targeted treatment of symptoms may provide the most benefit, and that treatment of dysphoria-related symptoms in disaster relief workers may have the most benefit for social and occupational functioning. PMID- 24064463 TI - Theory of mind and central coherence in eating disorders: two sides of the same coin? AB - The aim of this study was to evaluate central coherence and theory of mind (ToM) and explore the relationships between these domains in patients with eating disorders (ED). ToM and central coherence were assessed in 72 women [24 with anorexia nervosa (AN), 24 with bulimia nervosa (BN) and 24 healthy controls (HC)]. The Reading the Mind in the Eyes (RME) and the Faux Pas Test (FPT) to measure ToM, and the copy strategy of the Rey-Osterrieth Complex Figure Test to assess central coherence were used. It was observed that patients with ED had a decrease in central coherence skills compared with the control group; that patients with anorexia had a poor performance on RME ToM task compared with BN patients and HCs, and also that these measures were related in both clinical groups. The statistically significant correlation between them suggests that the central coherence and ToM measures might involve common cognitive processes. These results provide a better understanding of the nature of the socio-cognitive deficits observed in patients with eating disorders. PMID- 24064464 TI - The association between psychosis proneness and sensory gating in cocaine dependent patients and healthy controls. AB - This was a naturalistic study of 23 abstinent cocaine-dependent patients and 38 controls who were studied using a paired-stimulus paradigm to elicit three mid latency auditory evoked responses (MLAERs), namely, the P50, N100, and P200. Sensory gating was defined as the ratio of the S2 amplitude to the S1 amplitude. Psychosis-proneness was assessed using four Chapman psychosis proneness scales measuring perceptual aberration, magical ideation, social anhedonia, and physical anhedonia. Omnibus correlations based upon the entire sample revealed significant and differential relationships between the MLAER components and psychosis proneness. Social Anhedonia scale scores accounted for the largest proportion of variance in the P50 gating ratio, while Perceptual Aberration scores accounted for the largest proportion of variance in P200 gating. Psychosis proneness and sensory gating appear to be associated. In particular, poorer P50 gating is related to higher scores on the Social Anhedonia scale in healthy controls and across mixed samples of cocainede-pendent patients and controls. These findings hold significance for the further understanding of the relationship between deficient sensory gating ability and the propensity to developing psychotic symptoms in a vulnerable population like cocaine-dependent individuals. PMID- 24064466 TI - NMR spectroscopic and MS/MS spectrometric characterization of a new lipopeptide antibiotic bacillopeptin B1 produced by a marine sediment-derived Bacillus amyloliquefaciens SH-B74. PMID- 24064460 TI - Interrogating tumor metabolism and tumor microenvironments using molecular positron emission tomography imaging. Theranostic approaches to improve therapeutics. AB - Positron emission tomography (PET) is a noninvasive molecular imaging technology that is becoming increasingly important for the measurement of physiologic, biochemical, and pharmacological functions at cellular and molecular levels in patients with cancer. Formation, development, and aggressiveness of tumor involve a number of molecular pathways, including intrinsic tumor cell mutations and extrinsic interaction between tumor cells and the microenvironment. Currently, evaluation of these processes is mainly through biopsy, which is invasive and limited to the site of biopsy. Ongoing research on specific target molecules of the tumor and its microenvironment for PET imaging is showing great potential. To date, the use of PET for diagnosing local recurrence and metastatic sites of various cancers and evaluation of treatment response is mainly based on [(18)F]fluorodeoxyglucose ([(18)F]FDG), which measures glucose metabolism. However, [(18)F]FDG is not a target-specific PET tracer and does not give enough insight into tumor biology and/or its vulnerability to potential treatments. Hence, there is an increasing need for the development of selective biologic radiotracers that will yield specific biochemical information and allow for noninvasive molecular imaging. The possibility of cancer-associated targets for imaging will provide the opportunity to use PET for diagnosis and therapy response monitoring (theranostics) and thus personalized medicine. This article will focus on the review of non-[(18)F]FDG PET tracers for specific tumor biology processes and their preclinical and clinical applications. PMID- 24064467 TI - Evidence of pre-synaptic dopaminergic deficit in a patient with a novel progranulin mutation presenting with atypical parkinsonism. AB - Parkinsonism can be the presenting feature of frontotemporal dementia due to Progranulin (GRN) mutations or develop over the course of the disease, mimicking idiopathic Parkinson's disease or atypical parkinsonism. Here we report on a patient carrying a novel GRN mutation who presented with asymmetric parkinsonism and developed cognitive decline and language alterations two years later. Brain MRI showed mild asymmetric fronto-parietal atrophy. Single-photon emission computed tomography with I123 ioflupane (DAT-Scan) demonstrated reduced tracer uptake in the left putamen. Larger studies are needed to clarify whether presynaptic dopaminergic deficit is present in all GRN mutation carriers or only in those with parkinsonism. PMID- 24064465 TI - Molecular imaging for cancer diagnosis and surgery. AB - Novel molecular imaging techniques have the potential to significantly enhance the diagnostic and therapeutic approaches for cancer treatment. For solid tumors in particular, novel molecular enhancers for imaging modalities such as US, CT, MRI and PET may facilitate earlier and more accurate diagnosis and staging which are prerequisites for successful surgical therapy. Enzymatically activatable "smart" molecular MRI probes seem particularly promising because of their potential to image tumors before and after surgical removal without re administration of the probe to evaluate completeness of surgical resection. Furthermore, the use of "smart" MR probes as part of screening programs may enable detection of small tumors throughout the body in at-risk patient populations. Dual labeling of molecular MR probes with fluorescent dyes can add real time intraoperative guidance facilitating complete tumor resection and preservation of important structures. A truly theranostic approach with the further addition of therapeutic agents to the molecular probe for adjuvant therapy is conceivable for the future. PMID- 24064468 TI - A new algorithm for predicting time to disease endpoints in Alzheimer's disease patients. AB - BACKGROUND: The ability to predict the length of time to death and institutionalization has strong implications for Alzheimer's disease patients and caregivers, health policy, economics, and the design of intervention studies. OBJECTIVE: To develop and validate a prediction algorithm that uses data from a single visit to estimate time to important disease endpoints for individual Alzheimer's disease patients. METHOD: Two separate study cohorts (Predictors 1, N = 252; Predictors 2, N = 254), all initially with mild Alzheimer's disease, were followed for 10 years at three research centers with semiannual assessments that included cognition, functional capacity, and medical, psychiatric, and neurologic information. The prediction algorithm was based on a longitudinal Grade of Membership model developed using the complete series of semiannually-collected Predictors 1 data. The algorithm was validated on the Predictors 2 data using data only from the initial assessment to predict separate survival curves for three outcomes. RESULTS: For each of the three outcome measures, the predicted survival curves fell well within the 95% confidence intervals of the observed survival curves. Patients were also divided into quintiles for each endpoint to assess the calibration of the algorithm for extreme patient profiles. In all cases, the actual and predicted survival curves were statistically equivalent. Predictive accuracy was maintained even when key baseline variables were excluded, demonstrating the high resilience of the algorithm to missing data. CONCLUSION: The new prediction algorithm accurately predicts time to death, institutionalization, and need for full-time care in individual Alzheimer's disease patients; it can be readily adapted to predict other important disease endpoints. The algorithm will serve an unmet clinical, research, and public health need. PMID- 24064469 TI - C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: a genotype-phenotype correlation study. AB - Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as the most common pathogenic mutation in families with autosomal dominant frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. Herein we investigated frequency and penetrance of the C9ORF72 hexanucleotide repeat pathological expansion in a large cohort of familial and sporadic FTLD and related disorders (FTLD and related disorders, n = 388; Controls, n = 201). Moreover, we weighed the impact of C9ORF72 genotype on clinical phenotype taking into account the hexanucleotide repeat units number as a possible disease modifier. In our cohort, the C9ORF72 pathological expansion: (i) showed a prevalence of 7.5%; (ii) showed a full penetrance by the age of 80; (iii) was rarely found in sporadic patients; (iv) was solely associated with FTLD; (v) was mainly associated with bvFTD clinical subtype; and (vi) was associated with earlier age of onset in the youngest generation compared with the previous generation within a pedigree. Interestingly, intermediate C9ORF72 expansion had a risk effect in familial/sporadic FTLD. Eventually, the C9ORF72 repeat units number influenced the disease phenotype in terms of age of onset and associated clinical subtype. Genome-wide studies in well characterized clinical cohorts will be essential in order to decipher pathways of disease expression in C9ORF72 associated neurodegeneration. PMID- 24064471 TI - Investing in biomedical research is important. PMID- 24064470 TI - Quantitative prediction of individual psychopathology in trauma survivors using resting-state FMRI. AB - Neuroimaging techniques hold the promise that they may one day aid the clinical assessment of individual psychiatric patients. However, the vast majority of studies published so far have been based on average differences between groups. This study employed a multivariate approach to examine the potential of resting state functional magnetic resonance imaging (MRI) data for making accurate predictions about psychopathology in survivors of the 2008 Sichuan earthquake at an individual level. Resting-state functional MRI data was acquired for 121 survivors of the 2008 Sichuan earthquake each of whom was assessed for symptoms of post-traumatic stress disorder (PTSD) using the 17-item PTSD Checklist (PCL). Using a multivariate analytical method known as relevance vector regression (RVR), we examined the relationship between resting-state functional MRI data and symptom scores. We found that the use of RVR allowed quantitative prediction of clinical scores with statistically significant accuracy (correlation=0.32, P=0.006; mean squared error=176.88, P=0.001). Accurate prediction was based on functional activation in a number of prefrontal, parietal, and occipital regions. This is the first evidence that neuroimaging techniques may inform the clinical assessment of trauma-exposed individuals by providing an accurate and objective quantitative estimation of psychopathology. Furthermore, the significant contribution of parietal and occipital regions to such estimation challenges the traditional view of PTSD as a disorder specific to the fronto-limbic network. PMID- 24064472 TI - Emergency medicine trainees' confidence in psychiatric assessments. PMID- 24064474 TI - Impact of stent overlap on long-term clinical outcomes in patients treated with newer-generation drug-eluting stents. AB - AIMS: Early-generation drug-eluting stent (DES) overlap (OL) is associated with impaired long-term clinical outcomes whereas the impact of OL with newer generation DES is unknown. Our aim was to assess the impact of OL on long-term clinical outcomes among patients treated with newer-generation DES. METHODS AND RESULTS: We analysed the three-year clinical outcomes of 3,133 patients included in a prospective DES registry according to stent type (sirolimus-eluting stents [SES; N=1,532] versus everolimus-eluting stents [EES; N=1,601]), and the presence or absence of OL. The primary outcome was a composite of death, myocardial infarction (MI), and target vessel revascularisation (TVR). The primary endpoint was more common in patients with OL (25.1%) than in those with multiple DES without OL (20.8%, adj HR=1.46, 95% CI: 1.03-2.09) and patients with a single DES (18.8%, adj HR=1.74, 95% CI: 1.34-2.25, p<0.001) at three years. A stratified analysis by stent type showed a higher risk of the primary outcome in SES with OL (28.7%) compared to other SES groups (without OL: 22.6%, p=0.04; single DES: 17.6%, p<0.001), but not between EES with OL (22.3%) and other EES groups (without OL: 18.5%, p=0.30; single DES: 20.4%, p=0.20). CONCLUSIONS: DES overlap is associated with impaired clinical outcomes during long-term follow-up. Compared with SES, EES provide similar clinical outcomes irrespective of DES overlap status. PMID- 24064476 TI - Self-assembly of manganese doped zinc sulfide quantum dots/CTAB nanohybrids for detection of rutin. AB - Quantum dots (QDs) nanohybrids are an effective route to obtain new property of materials, and are very significant for developing specific materials and improving the performance of existing QDs materials. The objectives of this work are to prepare MPA-capped Mn-doped ZnS QDs/CTAB nanohybrids (MPA: 3 mercaptopropionic acid; CTAB: cetyltrimethyl ammonium bromide) through electrostatic self-assembly, to investigate the formation mechanism and the Room Temperature Phosphorescenee (RTP) changes, and to explore the possibility of their application in detection of rutin. As a result, MPA-capped Mn-doped ZnS QDs/CTAB nanohybrids greatly improve the rutin detection ability of QDs and provide an important method for developing more convenient and effective rutin detection sensor. The sensor for rutin gave a detection limit of 0.037 mg L(-1) and two linear ranges from 0.05 to 0.5 mg L(-1) and from 0.5 to 5 mg L(-1), and thus can be expanded to selective detection of other substances. Since the present QDs-based RTP method does not need deoxidants or other inducers as conventional RTP detection methods, and avoids interference from autofluorescence and the scattering light of the matrix that are encountered in spectrofluorometry, this method can be used to detect the content of rutin in body fluid. PMID- 24064475 TI - Improving sensitivity of gold nanoparticle based fluorescence quenching and colorimetric aptasensor by using water resuspended gold nanoparticle. AB - Gold nanoparticles (AuNPs) based fluorescence quenching or colorimetric aptasensor have been developed for many analytes recently largely because of the ease of detection, high sensitivity, and potential for high-throughput analysis. However, the effects of remnant non-AuNPs components in the colloid gold solution on these assays performance remain unclear. For the first time, we demonstrated that the remnant sodium citrate and the reaction products of three acids play counteractive roles in AuNPs based fluorescence quenching and colorimetric aptasensor in three ways in this study. First, the remnant sodium citrate in the colloid gold solution could increase the fluorescence intensity of FAM labeled on the aptamer that reduce the efficiency of AuNPs fluorescent quenching. Second, the reaction products of citric acid, HCl and ketoglutaric acid reduce the fluorescence recovery by quenching the fluorescence of FAM labeled on the aptamer dissociated from the surface of AuNPs upon addition of target. Lastly, the reaction products of three acids reduce the pH value of the colloid gold solution that reduce the sensitivity of AuNPs based colorimetric aptasensor by increasing the adsorption of aptamer to surface of AuNPs. With sulfadimethoxine and thrombin as model analytes, we found that water resuspended AuNPs can significantly increase the sensitivity by more than 10-fold for AuNPs based fluorescence quenching aptasensor. In the AuNPs based colorimetric aptasensor for sulfadimethoxine using the water resuspended AuNPs, the sensitivity also was increased by 10-fold compared with that of original AuNPs. The findings in this study provide theoretical guidance for further improving AuNPs based fluorescent quenching and colorimetric aptasensor by adjusting the composition of AuNPs solution. PMID- 24064477 TI - A sensitive and reliable dopamine biosensor was developed based on the Au@carbon dots-chitosan composite film. AB - A novel composite film of Au@carbon dots (Au@CDs)-chitosan (CS) modified glassy carbon electrode (Au@CDs-CS/GCE) was prepared in a simple manner and applied in the sensitive and reliable determination of dopamine (DA). The CDs had carboxyl groups with negative charge, which not only gave it have good stability but also enabled interaction with amine functional groups in DA through electrostatic interaction to multiply recognize DA with high specificity, and the Au nanoparticle could make the surface of the electrode more conductive. Compared with the bare GCE, CS/GCE, and CDs-CS/GCE electrodes, the Au@CDs-CS/GCE had higher catalytic activity toward the oxidation of DA. Furthermore, Au@CDs-CS/GCE exhibited good ability to suppress the background current from large excess ascorbic acid (AA) and uric acid (UA). Under the optimal conditions, selective detection of DA in a linear concentration range of 0.01-100.0 MUM was obtained with the limit of 0.001 MUM (3S/N). At the same time, the Au@CDs-CS/GCE was also applied to the detection of DA content in DA's injection with satisfactory results, and the biosensor could keep its activity for at least 2 weeks. PMID- 24064478 TI - Effect of insulin glargine on endogenous insulin secretion and beta-cell function in Japanese type 2 diabetic patients using oral antidiabetic drugs. AB - The aim of the present study was to evaluate the effect of insulin glargine (Gla) (as part of basal-supported oral therapy) on endogenous insulin secretion and beta-cell function in type 2 diabetic patients. In 33 insulin-naive patients showing poor glycemic control on treatment with sulfonylurea (SU)-based OADs without DPP4 inhibitors, once-daily injection of Gla was added without changing OADs, and the dose of Gla was titrated to attain a fasting plasma glucose (FPG) <110 mg/dL over 24 weeks. Morning meal tests were done at baseline, 12 weeks and 24 weeks. FPG and 2-hour plasma glucose (2HPG) and serum C-peptide (FCPR and 2HCPR) were measured 3 times, while serum intact proinsulin (FPI and 2HPI) was measured at baseline and 24 weeks. Levels of FPG, FCPR, 2HPG, and HbA1c were significantly reduced from baseline at 24 weeks (176+/-52 to 117+/-27 mg/dL, p<0.01; 2.0+/-0.9 to 1.6+/-1.0 ng/mL, p<0.01; 257+/-53 to 202+/-27 mg/dL, p<0.01; and 8.4+/-0.9 to 7.3+/-0.6%, p<0.01, Mean+/-SD), but 2HCPR was unchanged. The patients were divided into two groups depending on whether FPG at 24 weeks was <110 mg/dL or not: attained group (n=15) and not attained group (n=18). The dose of Gla did not differ between the two groups, but the 2HPI/2HCPR ratio at 24 weeks showed a significant decrease from baseline in the attained group. Supplementation with Gla improved glycemic control and maintained intrinsic basal insulin secretion, without changing 2-hour postprandial secretion. Achieving good glycemic control with an FPG<110 mg/dL by adding Gla decreased the 2HPI/2HCPR ratio at 24 weeks. PMID- 24064479 TI - An image correction protocol to reduce distortion for 3-T stereotactic MRI. AB - BACKGROUND: Image distortion limits application of direct 3-T magnetic resonance imaging for stereotactic functional neurosurgery. OBJECTIVE: To test the application of a method to correct and curtail image distortion of 3-T magnetic resonance images. METHODS: We used a phantom head model mounted on a platform with the dimensions and features of a stereotactic frame. The phantom was scanned within the head coil of a Philips Achieva 3T X series (Philips Medical Systems, Eindhoven, the Netherlands). For each scan, 2 images were obtained-the normal and the reversed images. We applied the inverted gradient correction protocol to produce a corrected x, y, and z coordinates. We applied the Cronbach test or coefficient of reliability to assess the internal consistency of the data. RESULTS: For all analyzed data, the P value was >.05, indicating that the differences among the observers were not statistically significant. Moreover, the data rectification proved to be effective, as the average distortion after correction was 1.05 mm. The distortion varied between 0.7 mm and 3.7 mm, depending on the target location. CONCLUSION: This study examined a rectifying technique for correcting geometric distortion encountered in magnetic resonance images related to static field inhomogeneities (resonance offsets), and the technique proved to be highly successful in producing consistently accurate stereotactic target registration. The technique is applicable to all routinely used spin-echo MRI. PMID- 24064480 TI - Extended subtemporal transtentorial approach to the anterior incisural space and upper clival region: experience with posterior circulation aneurysms. AB - BACKGROUND: Although most posterior circulation aneurysms are currently treated by endovascular means, some are not amenable to this treatment modality. The narrow working window afforded by the anterolateral and lateral surgical approaches often translates into suboptimal visualization and limited maneuverability. OBJECTIVE: We present a modified technique of tentorial incision and reflection that optimizes the exposure achieved with the traditional subtemporal approach and report our clinical experience in a series of posterior circulation aneurysms. METHODS: Retrospective review of patients operated via an extended subtemporal transtentorial approach for posterior circulation aneurysms. The modified tentorial incision implies dissection of the trochlear nerve along its dural canal up to its entrance into the cavernous sinus and incision of a tentorial flap that extends up to Meckel cave, which is then reflected far anterolaterally. Clinical and radiological data were reviewed. RESULTS: This series comprises 18 patients (21 procedures). Ten patients presented (56%) with a subarachnoid hemorrhage. Aneurysms most frequently arose from the basilar tip (61%) and were of small size (50%) and saccular morphology (72%). Two patients underwent surgery following unsuccessful endovascular treatment. Aneurysm treatment was successful on the first attempt in 90% (19/21) and after a second attempt in 10% (2/21). Documented postoperative palsies of the oculomotor (n = 3) and trochlear (n = 1) nerves were all transient. No procedure-related mortality occurred. CONCLUSION: This modified technique of tentorial incision and reflection optimizes visibility, anatomic orientation, and maneuverability by increasing the rostrocaudal and anterolateral exposure obtained via the extended subtemporal transtentorial route without permanent postoperative trochlear nerve deficit. PMID- 24064484 TI - A 3-dimensional transnasal endoscopic journey through the paranasal sinuses and adjacent skull base: a practical and surgery-oriented perspective. AB - An endoscopic approach through the transnasal corridor is currently the treatment of choice in the management of benign sinonasal tumors, cerebrospinal fluid leaks, and pituitary lesions. Moreover, this approach can be considered a valid option in the management of selected sinonasal malignancies extending to the skull base, midline meningiomas, parasellar lesions such as craniopharyngioma and Rathke cleft cyst, and clival lesions such as chordoma and ecchordosis. Over the past decade, strict cooperation between otorhinolaryngologists and neurosurgeons and acquired surgical skills, together with high-definition cameras, dedicated instrumentation, and navigation systems, have made it possible to broaden the indications of endoscopic surgery. Despite these improvements, depth perception, as provided by the use of a microscope, was still lacking with this technology. The aim of the present project is to reveal new perspectives in the endoscopic perception of the sinonasal complex and skull base thanks to 3-dimensional endoscopes, which are well suited to access and explore the endonasal corridor. In the anatomic dissection herein, this innovative device came across with sophisticated and long-established fresh cadaver preparation provided by one of the most prestigious universities of Europe. The final product is a 3-dimensional journey starting from the nasal cavity, reaching the anterior, middle, and posterior cranial fossae, passing through the ethmoidal complex, paranasal sinuses, and skull base. Anatomic landmarks, critical areas, and tips and tricks to safely dissect delicate anatomic structures are addressed through audio comments, figures, and their captions. PMID- 24064485 TI - Complex middle cerebral artery aneurysm: 3-dimensional operative video. PMID- 24064483 TI - Diffusion tensor imaging of the spinal cord: insights from animal and human studies. AB - Diffusion tensor imaging (DTI) provides a measure of the directional diffusion of water molecules in tissues. The measurement of DTI indexes within the spinal cord provides a quantitative assessment of neural damage in various spinal cord pathologies. DTI studies in animal models of spinal cord injury indicate that DTI is a reliable imaging technique with important histological and functional correlates. These studies demonstrate that DTI is a noninvasive marker of microstructural change within the spinal cord. In human studies, spinal cord DTI shows definite changes in subjects with acute and chronic spinal cord injury, as well as cervical spondylotic myelopathy. Interestingly, changes in DTI indexes are visualized in regions of the cord, which appear normal on conventional magnetic resonance imaging and are remote from the site of cord compression. Spinal cord DTI provides data that can help us understand underlying microstructural changes within the cord and assist in prognostication and planning of therapies. In this article, we review the use of DTI to investigate spinal cord pathology in animals and humans and describe advances in this technique that establish DTI as a promising biomarker for spinal cord disorders. PMID- 24064486 TI - In reply. PMID- 24064487 TI - In reply. PMID- 24064488 TI - Letter to the editor re: "performance of flow cytometry to screen urine for bacteria and white blood cells prior to urine culture". PMID- 24064489 TI - Product of serum calcium and phosphorus (Ca * PO4) as predictor of cardiovascular disease risk in predialysis patients. AB - OBJECTIVES: The mortality rate of chronic kidney disease (CKD) patients is very high due to cardiovascular diseases (CVD) which cannot be fully justified by traditional CVD markers. Since, mineral bone disorder is common in CKD, product of serum calcium and phosphorus (Ca * PO4) can be a predictor of future CVD. So, our study aims to assess the utility of higher Ca * PO4 in prediction of CVD risk in predialysis CKD patients. DESIGN AND METHODS: 150 CKD patients defined by NKF KDOQI guideline not undergoing dialysis were recruited. Anthropometric and electrocardiographic parameters were recorded. We evaluated CVD risk by: i) Biochemical CVD markers, ii) NCEP ATP III guideline postulated risk factors and iii) Framingham risk scores. RESULTS: Higher Ca * PO4 is associated with presence of Left Ventricular Hypertrophy, oxidative stress, microinflammation, hyperhomocysteinemia, hypercholesterolemia, hypertriglyceridemia and increased LDLc. Compared to cases with Ca * PO4 <55 mg2/dL2, cases with >=55 mg2/dL2 had relative risk (RR) of 1.82 (95% CI 1.25-2.64) for CVD, 3.24 (95% CI 2.37-4.41) for stroke and 2.43 (95% CI 1.37-4.31) for coronary heart disease (CHD). Moreover, compared to lowest quartile of Ca x PO4, the highest quartile group had RR of 2.13 (95% CI 1.06-4.28) for CVD, 2.61(95% CI 1.80-3.75) for stroke and 2.84 (95% CI 1.15-7.0) for CHD. CONCLUSION: In predialysis patients, higher Ca * PO4 is independent predictor of CVD risk. PMID- 24064490 TI - Non-invasive measurement of cerebral oxygen metabolism in the mouse brain by ultra-high field (17)O MR spectroscopy. AB - To assess cerebral energetics in transgenic mouse models of neurologic disease, a robust, efficient, and practical method for quantification of cerebral oxygen consumption is needed. (17)O magnetic resonance spectroscopy (MRS) has been validated to measure cerebral metabolic rate of oxygen (CMRO2) in the rat brain; however, mice present unique challenges because of their small size. We show that CMRO2 measurements with (17)O MRS in the mouse brain are highly reproducible using 16.4 Tesla and a newly designed oxygen delivery system. The method can be utilized to measure mitochondrial function in mice quickly and repeatedly, without oral intubation, and has numerous potential applications to study cerebral energetics. PMID- 24064491 TI - Underestimation of the pentose-phosphate pathway in intact primary neurons as revealed by metabolic flux analysis. AB - The rates of glucose oxidized at glycolysis and pentose-phosphate pathway (PPP) in neurons are controversial. Using [3-(3)H]-, [1-(14)C]-, and [6-(14)C]glucose to estimate fluxes through these pathways in resting, intact rat cortical primary neurons, we found that the rate of glucose oxidized through PPP was, apparently, ~14% of total glucose metabolized. However, inhibition of PPP rate-limiting step, glucose-6-phosphate (G6P) dehydrogenase, increased approximately twofold the glycolytic rate; and, knockdown of phosphoglucose isomerase increased ~1.8-fold the PPP rate. Thus, in neurons, a considerable fraction of fructose-6-phosphate returning from the PPP contributes to the G6P pool that re-enters PPP, largely underestimating its flux. PMID- 24064492 TI - Cerebral oxygen metabolism in neonatal hypoxic ischemic encephalopathy during and after therapeutic hypothermia. AB - Pathophysiologic mechanisms involved in neonatal hypoxic ischemic encephalopathy (HIE) are associated with complex changes of blood flow and metabolism. Therapeutic hypothermia (TH) is effective in reducing the extent of brain injury, but it remains uncertain how TH affects cerebral blood flow (CBF) and metabolism. Ten neonates undergoing TH for HIE and seventeen healthy controls were recruited from the NICU and the well baby nursery, respectively. A combination of frequency domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) systems was used to non-invasively measure cerebral hemodynamic and metabolic variables at the bedside. Results showed that cerebral oxygen metabolism (CMRO2i) and CBF indices (CBFi) in neonates with HIE during TH were significantly lower than post-TH and age-matched control values. Also, cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2) were significantly higher in neonates with HIE during TH compared with age-matched control neonates. Post-TH CBV was significantly decreased compared with values during TH whereas SO2 remained unchanged after the therapy. Thus, FDNIRS-DCS can provide information complimentary to SO2 and can assess individual cerebral metabolic responses to TH. Combined FDNIRS-DCS parameters improve the understanding of the underlying physiology and have the potential to serve as bedside biomarkers of treatment response and optimization. PMID- 24064493 TI - Cerebral hemodynamic and ventilatory responses to hypoxia, hypercapnia, and hypocapnia during 5 days at 4,350 m. AB - This study investigated the changes in cerebral near-infrared spectroscopy (NIRS) signals, cerebrovascular and ventilatory responses to hypoxia and CO2 during altitude exposure. At sea level (SL), after 24 hours and 5 days at 4,350 m, 11 healthy subjects were exposed to normoxia, isocapnic hypoxia, hypercapnia, and hypocapnia. The following parameters were measured: prefrontal tissue oxygenation index (TOI), oxy- (HbO2), deoxy- and total hemoglobin (HbTot) concentrations with NIRS, blood velocity in the middle cerebral artery (MCAv) with transcranial Doppler and ventilation. Smaller prefrontal deoxygenation and larger DeltaHbTot in response to hypoxia were observed at altitude compared with SL (day 5: DeltaHbO2-0.6+/-1.1 versus -1.8+/-1.3 MUmol/cmper mm Hg and DeltaHbTot 1.4+/-1.3 versus 0.7+/-1.1 MUmol/cm per mm Hg). The hypoxic MCAv and ventilatory responses were enhanced at altitude. Prefrontal oxygenation increased less in response to hypercapnia at altitude compared with SL (day 5: DeltaTOI 0.3+/-0.2 versus 0.5+/ 0.3% mm Hg). The hypercapnic MCAv and ventilatory responses were decreased and increased, respectively, at altitude. Hemodynamic responses to hypocapnia did not change at altitude. Short-term altitude exposure improves cerebral oxygenation in response to hypoxia but decreases it during hypercapnia. Although these changes may be relevant for conditions such as exercise or sleep at altitude, they were not associated with symptoms of acute mountain sickness. PMID- 24064494 TI - Molecular alterations in the hippocampus after experimental subarachnoid hemorrhage. AB - Patients with aneurysmal subarachnoid hemorrhage (SAH) frequently have deficits in learning and memory that may or may not be associated with detectable brain lesions. We examined mediators of long-term potentiation after SAH in rats to determine what processes might be involved. There was a reduction in synapses in the dendritic layer of the CA1 region on transmission electron microscopy as well as reduced colocalization of microtubule-associated protein 2 (MAP2) and synaptophysin. Immunohistochemistry showed reduced staining for GluR1 and calmodulin kinase 2 and increased staining for GluR2. Myelin basic protein staining was decreased as well. There was no detectable neuronal injury by Fluoro Jade B, TUNEL, or activated caspase-3 staining. Vasospasm of the large arteries of the circle of Willis was mild to moderate in severity. Nitric oxide was increased and superoxide anion radical was decreased in hippocampal tissue. Cerebral blood flow, measured by magnetic resonance imaging, and cerebral glucose metabolism, measured by positron emission tomography, were no different in SAH compared with control groups. The results suggest that the etiology of loss of LTP after SAH is not cerebral ischemia but may be mediated by effects of subarachnoid blood such as oxidative stress and inflammation. PMID- 24064496 TI - Diet-induced obesity suppresses expression of many proteins at the blood-brain barrier. AB - The blood-brain barrier (BBB) is a regulatory interface between the central nervous system and the rest of the body. However, BBB changes in obesity and metabolic syndrome have not been fully elucidated. We hypothesized that obesity reduces energy metabolism in the cerebral microvessels composing the BBB, reflected by downregulation of protein expression and function. We performed comparative proteomic analyses in enriched microvessels from the cerebral cortex of mice 2 months after ingestion of a high-fat diet or regular rodent chow. In mice with diet-induced obesity (DIO), there was downregulation of 47 proteins in the cerebral microvessels, including cytoskeletal proteins, chaperons, enzymes, transport-related proteins, and regulators for transcriptional and translational activities. Only two proteins, involved in messenger RNA (mRNA) transport and processing, were upregulated. The changes of these proteins were further validated by quantitative polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining of freshly isolated microvessels, in samples obtained from different batches of mice. The predominant downregulation suggests that DIO suppresses metabolic activity of BBB microvessels. The finding of a hypometabolic state of the BBB in mice at the chronic stage of DIO is unexpected and unprecedented; it may provide novel mechanistic insight into how obesity influences CNS function via regulatory changes of the BBB. PMID- 24064497 TI - Theoretical exploration of structures and electronic properties of double electron oxidized guanine-cytosine base pairs with intriguing radical-radical interactions. AB - We present a computational study of the double-electron oxidized guanine-cytosine base pair as well as its deprotonated derivatives, focusing on their structural and electronic properties. Some novel electromagnetic characteristics are found. A hydrazine-like (N-N) cross-linked structure between the G and C radical moieties is the lowest-energy one for the [GC](2+) complexes. Double-electron oxidation can considerably destabilize the GC unit and leads to a barrier hindered dissociation channel with negative dissociation energy. This channel is governed by a balance between electrostatic repulsion and attractive hydrogen bonding interaction co-existing between G(+) and C(+). The proton/electron transfer reactions in the double-electron oxidized Watson-Crick base pair occur through a proton transfer induced charge migration mechanism. For the deprotonated [GC](2+) derivative, the [G(-H(+))C](+) series prefers to accompany by transfer of an electron from the G to C moiety when the G(+) is deprotonated, and its highest-doubly occupied molecular orbital mainly localizes over the C moiety with a pi-bonding character. For the diradical G(+)C(-H) series in which the C moiety is deprotonated, the two unpaired electrons reside one on each moiety in the pi system. The diradical base pairs possess open-shell broken symmetry singlet states, and their magnetic coupling interactions are controlled by both intra- and inter-molecular interactions. The double-electron oxidized Watson-Crick base pair shows strong antiferromagnetic coupling, whereas the magnetic interactions of other diradical derivatives are relatively weak. This study highlights the crucial role of H-bonding in determining the magnetic interactions. PMID- 24064499 TI - Desulfuration of 2-thiouridine with hydrogen peroxide in the physiological pH range 6.6-7.6 is pH-dependent and results in two distinct products. AB - The 2-thiomodified nucleosides, located at first position of tRNAs anticodon, may constitute a primary target for oxidative attack under conditions of oxidative stress. Desulfuration of 2-thiouridine (S2U) was investigated in the (1)H NMR scale in the presence of 100mM H2O2 and phosphate buffer in the physiological pH range, from pH 6.6 to 7.6. The obtained data demonstrate an intriguing result that within one unit of the pH range uridine is the major product of the S2U desulfuration in the pH 7.6, while the 4-pyrimidinone nucleoside (H2U) is dominant in pH 6.6. The possible desulfuration pathway and the biological importance of the transformation of S2U either to U or H2U are discussed in the context of the tRNA oxidative damage. PMID- 24064498 TI - New beta-phospholactam as a carbapenem transition state analog: Synthesis of a broad-spectrum inhibitor of metallo-beta-lactamases. AB - In an effort to test whether a transition state analog is an inhibitor of the metallo-beta-lactamases, a phospholactam analog of carbapenem has been synthesized and characterized. The phospholactam 1 proved to be a weak, time dependent inhibitor of IMP-1 (70%), CcrA (70%), L1 (70%), NDM-1 (53%), and Bla2 (94%) at an inhibitor concentration of 100MUM. The phospholactam 1 activated ImiS and BcII at the same concentration. Docking studies were used to explain binding and to offer suggestions for modifications to the phospholactam scaffold to improve binding affinities. PMID- 24064495 TI - The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage. AB - The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions. PMID- 24064500 TI - Lead optimization of an acylhydrazone scaffold possessing antiviral activity against Lassa virus. AB - Previously we reported the optimization of antiviral scaffolds containing benzimidazole and related heterocycles possessing activity against a variety of arenaviruses. These series of compounds were discovered through an HTS campaign of a 400,000 small molecule library using lentivirus-based pseudotypes incorporated with the Lassa virus envelope glycoprotein (LASV GP). This screening also uncovered an alternate series of very potent arenavirus inhibitors based upon an acylhydrazone scaffold. Subsequent SAR analysis of this chemical series involved various substitutions throughout the chemical framework along with assessment of the preferred stereochemistry. These studies led to an optimized analog (ST-161) possessing subnanomolar activity against LASV and submicromolar activity against a number of other viruses in the Arenaviridae family. PMID- 24064501 TI - Synthesis and activity of a folate targeted monodisperse PEG camptothecin conjugate. AB - A folate targeted camptothecin small molecule drug conjugate (SMDC) was synthesized using a monodisperse PEG spacer linked to folate via a releasable disulfide carbonate linker. Cell cytotoxicity in human KB cells exhibited an IC50 of 6nM. Importantly, activity of the prodrug was blocked by excess folate, demonstrating receptor-mediated celluar uptake of the PEG conjugate. PMID- 24064503 TI - Oxidant-resistant imaging and ratiometric luminescence detection by selective oxidation of silver nanodots. AB - Reactive oxygen species selectively accelerated transitions between various silver nanodots. The blue was developed as an oxidant-resistant imaging agent and analyte reporter. In addition to the spectral response of nanodots to ROS, silver nanodots were formulated to detect analytes with excellent selectivity and picomolar detection limit when coupled to glucose oxidase. PMID- 24064504 TI - Tau and beyond for Alzheimer's disease. PMID- 24064502 TI - Academic Achievement Among Juvenile Detainees. AB - The literature has long pointed to heightened frequencies of learning disabilities (LD) within the population of law offenders; however, a systematic appraisal of these observations, careful estimation of these frequencies, and investigation of their correlates and causes have been lacking. Here we present data collected from all youth (1,337 unique admissions, mean age 14.81, 20.3% females) placed in detention in Connecticut (January 1, 2010-July 1, 2011). All youth completed a computerized educational screener designed to test a range of performance in reading (word and text levels) and mathematics. A subsample (n = 410) received the Wide Range Achievement Test, in addition to the educational screener. Quantitative (scale-based) and qualitative (grade-equivalence-based) indicators were then analyzed for both assessments. Results established the range of LD in this sample from 13% to 40%, averaging 24.9%. This work provides a systematic exploration of the type and severity of word and text reading and mathematics skill deficiencies among juvenile detainees and builds the foundation for subsequent efforts that may link these deficiencies to both more formal, structured, and variable definitions and classifications of LD, and to other types of disabilities (e.g., intellectual disability) and developmental disorders (e.g., ADHD) that need to be conducted in future research. PMID- 24064506 TI - Hyperphosphorylation results in tau dysfunction in DNA folding and protection. AB - Hyperphosphorylation of tau occurs in preclinical and clinical stages of Alzheimer's disease (AD), and hyperphosphorylated tau is the main constituent of the paired helical filaments in the brains of mild cognitive impairment and AD patients. While most of the work described so far focused on the relationship between hyperphosphorylation of tau and microtubule disassembly as well as axonal transport impairments, both phenomena ultimately leading to cell death, little work has been done to study the correlation between tau hyperphosphorylation and DNA damage. As we showed in this study, tau hyperphosphorylation and DNA damage co-occurred under formaldehyde treatment in N2a cells, indicating that phosphorylated tau (p-Tau) induced by formaldehyde may be involved in DNA impairment. After phosphorylation, the effect of tau in preventing DNA from thermal denaturation was diminished, its ability to accelerate DNA renaturation was lost, and its function in protecting DNA from reactive oxygen species (ROS) attack was impaired. Thus, p-Tau is not only associated with the disassembly of the microtubule system, but also plays a crucial role in DNA impairment. Hyperphosphorylation-mediated dysfunction of tau protein in prevention of DNA structure from damage under the attack of ROS may provide novel insights into the mechanisms underlying tauopathies. PMID- 24064509 TI - Extension of the crosstalk cancellation method in ultrasonic transducer arrays from the harmonic regime to the transient one. AB - This paper describes a procedure to extend the crosstalk correction method presented in a previous paper [A. Bybi, S. Grondel, J. Assaad, A.-C. Hladky Hennion, M. Rguiti, Reducing crosstalk in array structures by controlling the excitation voltage of individual elements: a feasibility study, Ultrasonics, 53 (6) (2013) 1135-1140] from the harmonic regime to the transient one. For this purpose a part of an ultrasonic transducer array radiating in water is modeled around the frequency 0.5 MHz using the finite element method. The study is carried out at low frequency in order to respect the same operating conditions than the previous paper. This choice facilitated the fabrication of the transducer arrays and the comparison of the numerical results with the experimental ones. The modeled array is composed of seventeen elements with the central element excited, while the others are grounded. The matching layers and the backing are not taken into account which limits the crosstalk only to the piezoelectric elements and fluid. This consideration reduces the structure density mesh and results in faster computation time (about 25 min for each configuration using a computer with a processor Intel Core i5-3210M, frequency 2.5 GHz and having 4 Go memory (RAM)). The novelty of this research work is to prove the efficiency of the crosstalk correction method in large frequency band as it is the case in medical imaging. The numerical results show the validity of the approach and demonstrate that crosstalk can be reduced by at least 13 dB in terms of displacement. Consequently, the directivity pattern of the individual element can be improved. PMID- 24064510 TI - Comparison of two empiric antibiotic regimen in late onset neonatal sepsis--a randomized controlled trial. AB - OBJECTIVE: To compare the effectiveness of two antibiotic regimens among neonates with late onset sepsis (LOS). METHODS: This randomized controlled trial conducted in a tertiary care teaching hospital, South India, included 90 babies with LOS. Detailed history, examination and appropriate investigations were done for all the babies. Cloxacillin + Amikacin were administered to 40 and Cefotaxime + Gentamicin to 50 babies. Outcomes including mortality, complications and treatment failure were evaluated. Chi-square test was used for categorical variables and Student's unpaired t-test for continuous variables. RESULTS: LOS had a male preponderance, and median time of onset was 13 days. Mortality was more among low birth weight babies irrespective of the antibiotics. Predominant bacteria isolated were coagulase-negative staphylococci (26.67%), Escherichia coli (13.33%) and Streptococcus pneumoniae (13.33%). Complications, mortality and cost were similar in both regimens. CONCLUSION: There was no significant difference between the two antibiotic regimens with regard to outcome of LOS. PMID- 24064512 TI - Dendritic cells: tracing the origins of cDCs. PMID- 24064511 TI - A randomized, placebo-controlled phase I study assessing the safety and immunogenicity of a Pseudomonas aeruginosa hybrid outer membrane protein OprF/I vaccine (IC43) in healthy volunteers. AB - INTRODUCTION: IC43 is a recombinant outer membrane protein-based vaccine against Pseudomonas aeruginosa (P. aeruginosa) consisting of OprF- and OprI- epitopes (Opr, outer membrane protein; OprF/I, OprF/OprI hybrid vaccine) with an N terminal His 6 tag (Met-Ala-(His)6-OprF190-342-OprI21-83). OBJECTIVES: The study aimed to confirm the optimal dose of IC43 in adults with regard to immunogenicity, safety, and tolerability after vaccination with three different dosages of IC43, compared with placebo, and to investigate a potential immune enhancing effect of the adjuvant, aluminum hydroxide. Subjects were randomly allocated in a 1:1:1:1:1 ratio to one of five treatment groups: 50, 100, or 200 ug IC43 with adjuvant, 100 ug IC43 without adjuvant, or placebo (0.9% sodium chloride) and two intramuscular injections were given in the deltoid region 7 d apart. RESULTS: The primary immunogenicity analysis of OprF/I-specific IgG antibody titers on day 14 demonstrated statistically significant differences among treatment groups (P<0.0001), with a significantly higher immune response detected in each IC43 treatment group compared with placebo. From day 0 to day 14, a >=4-fold increase in OprF/I-specific immunoglobulin G (IgG) antibody titers were observed in>90% of subjects in all IC43 treatment groups in the per-protocol (PP) and intention-to-treat (ITT) populations; a >=50-fold titer increase was observed in 42.6% subjects including all IC43 treatment groups. On day 90, OprF/I specific IgGs started to decline in all IC43 treatment groups but remained significantly higher until 6 mo compared with placebo. Assessment of functional antibody induction by opsonophagocytic assay (OPA) followed a similar pattern compared with OprF/I-specific IgG kinetics. At day 14, a >=2-fold increase in OPA titer was observed in 54.5% subjects within all IC43 treatment groups. An increase in antibody avidity index was observed after the second vaccination. At day 14, >96% of subjects in each IC43 treatment group had detectable OprF/I specific IgG antibodies. Anti-histidine IgG antibody titers peaked on day 14 and were reduced on day 90 in all IC43 treatment groups. OprF/I-specific IgG secreted by antibody-secreting cell (ASC) was detected in all IC43 groups by B-cell ELIspot after the second vaccination and up to 6 mo. All vaccinations were safe and well tolerated up to the maximum cumulative dosage of 400 ug IC43. CONCLUSION: IC43 doses equal to or greater than 50 ug were sufficient to induce a plateau of IgG antibody responses in healthy volunteers. Higher doses, whether adjuvanted or non-adjuvanted, were not more effective. METHODS: In this phase I, randomized, placebo-controlled, observer-blinded, multicenter clinical trial, 163 healthy volunteers (18-65 y) were randomly assigned to five treatment groups (1:1:1:1:1). Three groups received IC43 with adjuvant: 50 ug (n=32), 100 ug (n=33), or 200 ug (n=33). One group received IC43 100 ug without adjuvant (n=32), and one group received placebo (0.9% sodium chloride) (n=33). Each subject received two intramuscular vaccinations, separated by a 7-d interval (days 0 and 7) (Fig. 1). Humoral immune response was assessed by measurement of outer membrane protein F/I (OprF/I)-specific antibodies determined by enzyme-linked immunosorbent assay (ELISA), anti-histidine antibodies determined by ELISA, and functional antibody activity determined by opsonophagocytic assay (OPA), up to 6 mo post-vaccination. Antibody avidity was measured on days 7 and 14 from samples that had detectable vaccine antibody-specific immunoglobulin G (IgG) antibody titers. At the Austrian site only, the B-cell ELIspot assay was used to determine specific ASC responses. Safety was assessed using adverse event monitoring and clinical laboratory tests. Local and systemic tolerability was recorded in a subject diary for 7 d after each vaccination and by investigators up to 6 mo post vaccination. PMID- 24064515 TI - Macrophages: metabolic master prompts a change of tack. PMID- 24064517 TI - B cell development: a window of opportunity. PMID- 24064519 TI - Comparison of sagittal subluxation in two different three-component total ankle replacement systems. AB - BACKGROUND: Malalignment following total ankle arthroplasty (TAA) has been reported in 4% to 45% of patients. However, all reports to date have been related to coronal deformity. This study compared sagittal malalignment between the Mobility and Hintegra total ankle systems and assessed the positional stability of the implant components over time. METHODS: The study included 50 cases each of total ankle replacement arthroplasty with the Hintegra and Mobility total ankle systems performed between May 2008 and June 2010. The Mobility group included 24 men and 25 women, and the mean age was 60.3 years (range, 50.7-70.0 years). The Hintegra group included 25 men and 25 women, and the mean age was 59.8 years (range, 50.8-68.7 years). The 2 groups did not differ in terms of gender (P = .76) or age (P = .77). Three independent observers with different levels of training evaluated the radiographs and performed the measurements independently. Each observer evaluated the radiographs twice at a 6-week interval to determine the intraobserver reliability, and the anteroposterior offset ratio was evaluated. RESULTS: The anteroposterior offset ratio intra- and interobserver reliabilities all showed good or excellent levels of agreement in the Hintegra total ankle system and the Mobility total ankle system. With respect to the stability of sagittal translation of the talus, the Mobility system (0.08 +/- 0.07 immediately, 0.0 +/- 0.07 at 6 weeks postoperatively, and 0.01 +/- 0.07 at 1 year postoperatively) was better than the Hintegra system (0.20 +/- 0.08 immediately, 0.18 +/- 0.11 at 6 weeks postoperatively, and 0.15 +/- 0.10 at 1 year postoperatively) (P < .0001). CONCLUSIONS: The Mobility system had less sagittal malalignment of the talus than the Hintegra system. Consequently, when treating ankles in patients with osteoarthritis using the Hintegra system, one must pay careful attention to sagittal malalignment during surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 24064520 TI - Glomerular function time trends in long-term survivors of childhood cancer: a longitudinal study. AB - BACKGROUND: Impaired glomerular function is one of the health problems affecting childhood cancer survivors (CCS). It is unclear whether glomerular function deteriorates or recovers. We investigated time trends and predictors of glomerular function in CCS. METHODS: We evaluated repeated observations of estimated glomerular filtration rate (GFR) and glomerular dysfunction (GFR <90 mL/min/1.73 m(2)) among adult five-year CCS treated in the EKZ/AMC between 1966 and 2003. Ifosfamide, cisplatin, carboplatin, high-dose (HD) methotrexate, HD cyclophosphamide, radiotherapy to the kidney region, and nephrectomy (i.e., potentially nephrotoxic therapy) were investigated as predictors of glomerular function patterns over time in multivariable longitudinal analyses. RESULTS: At a median follow-up of 21 years after diagnosis, glomerular function was assessed in 1,122 CCS aged >=18 years. CCS treated with potentially nephrotoxic therapy had a significantly lower GFR and higher glomerular dysfunction probability up to 35 years after cancer diagnosis compared with CCS treated without nephrotoxic therapy (P < 0.001). Especially ifosfamide, cisplatin, and nephrectomy were associated with worse glomerular function that persisted during the entire follow up period (P < 0.001). Glomerular function deteriorated over time in all CCS (P < 0.001). CCS treated with higher doses of cisplatin seem to have a higher deterioration rate as compared with other CCS (P < 0.005). CONCLUSIONS: The loss in glomerular function starts early, especially for CCS treated with ifosfamide, higher doses of cisplatin, and nephrectomy, and seems to be persistent. We have an indication that CCS treated with higher doses of cisplatin experience faster decline than other CCS. IMPACT: As glomerular function continues to deteriorate, CCS are at risk for premature chronic renal failure. PMID- 24064518 TI - Autophagy in infection, inflammation and immunity. AB - Autophagy is a fundamental eukaryotic pathway that has multiple effects on immunity. Autophagy is induced by pattern recognition receptors and, through autophagic adaptors, it provides a mechanism for the elimination of intracellular microorganisms. Autophagy controls inflammation through regulatory interactions with innate immune signalling pathways, by removing endogenous inflammasome agonists and through effects on the secretion of immune mediators. Moreover, autophagy contributes to antigen presentation and to T cell homeostasis, and it affects T cell repertoires and polarization. Thus, as we discuss in this Review, autophagy has multitiered immunological functions that influence infection, inflammation and immunity. PMID- 24064521 TI - Metabolic dysregulation of the insulin-glucose axis and risk of obesity-related cancers in the Framingham heart study-offspring cohort (1971-2008). AB - BACKGROUND: Obesity-related dysregulation of the insulin-glucose axis is hypothesized in carcinogenesis. We studied impaired fasting glucose (IFG) and other markers of insulin-glucose metabolism in the Framingham Heart Study Offspring Cohort, which uniquely tracks these markers and cancer >37 years. METHODS: Participants were recruited between 1971 and 1975 and followed until 2008 (n = 4,615; mean age 66.8 years in 2008). Serum glucose, insulin, and hemoglobin A1c were determined from fasting blood in quart-annual exams. Lifestyle and demographic information was self-reported. HRs and 95% confidence intervals (CI) of cancer risk were computed using time-dependent survival analysis (SASv9.3), while accounting for temporal changes for relevant variables. RESULTS: We identified 787 obesity-related cancers, including 136 colorectal, 217 breast, and 219 prostate cancers. Absence versus presence of IFG 10 to 20 years and 20+ years before the event or last follow-up was associated with 44% (95% CI, 1.15-1.79) and 57% (95% CI, 1.17-2.11) increased risk of obesity-related cancers, respectively. When time-dependent variables were used, after adjusting for age, sex, smoking, alcohol, and body mass index, IFG was associated with a 27% increased risk of obesity-related cancer (HR = 1.27; CI, 1.1-1.5). Associations were stronger in smokers (HR = 1.41; CI, 1.13-1.76). Increased risk was noted among persons with higher insulin (HR = 1.47; CI, 1.15-1.88) and hemoglobin A1c (HR = 1.54; CI, 1.13-2.10) for the highest (>= 5.73%) versus lowest (<= 5.25%) category. A >2-fold increase in colorectal cancer risk was observed for all blood biomarkers of insulin-glucose metabolism, particularly with earlier IFG exposure. Nonsignificant increased risk of breast and prostate cancer was observed for blood biomarkers. CONCLUSIONS: Earlier IFG exposure (>10 years before) increased obesity-related cancer risk, particularly for colorectal cancer. IMPACT: Our study explicitly recognizes the importance of prolonged IFG exposure in identifying links between glucose dysregulation and obesity-related cancers. PMID- 24064524 TI - Monovision surgery in myopic presbyopes: visual function and satisfaction. AB - PURPOSE: To describe our experience with monovision excimer laser correction in individuals with myopic presbyopia. METHODS: This prospective interventional case series was conducted in a private refractive surgery center on 40 patients with presbyopia aged 40 years and older, who were treated with monovision refractive surgery between 2010 and 2011. The dominant eye was corrected for distance vision and the nondominant eye was corrected for near vision, with anisometropia of >=1.00 diopters (D). All patients underwent comprehensive objective and subjective visual assessments, including a questionnaire that was filled out preoperatively and at 6 and 12 months postoperatively. The primary outcomes were preoperative and postoperative refraction, binocular visual acuity, stereopsis, contrast sensitivity, glare, and questionnaire results. RESULTS: The 1-year follow-up was completed by 38 patients (95%). Preoperative and 1-year postoperative refraction of the distance eye spherical equivalent (SE), anisometropia SE, and uncorrected visual acuity were -4.05 +/- 1.94 and -0.01 +/- 0.22 D, 0.45 +/- 0.50 and 1.73 +/- 0.56 D, and 0.87 +/- 0.2 and 0.09 +/- 0.11 logMAR, respectively. Best-corrected visual acuity was unchanged. Both mean distance and near stereopsis decreased, from 52 to 142 seconds of arc and from 54 to 57 seconds of arc, respectively. Contrast sensitivity and glare decreased significantly. Patient satisfaction improved from 41.5 +/- 30.4% to 85.2 +/- 5.0% (range, 40 to 100%) at the 1-year follow-up. CONCLUSIONS: Monovision excimer laser correction provides both effective and satisfactory results and should be considered as an option for individuals with myopic presbyopia suitable for, and interested in, refractive surgery. PMID- 24064526 TI - Optic disc drusen in a child: diagnosis using noninvasive imaging tools. AB - PURPOSE: To describe a case of bilateral optic nerve head drusen (ONHD) in a pediatric patient and the complementary use of advanced noninvasive imaging techniques to confirm this diagnosis. CASE REPORT: A 15-year-old female adolescent with type 1 diabetes and no ocular history was seen at a routine screening without complaints. Visual acuity was 20/20 bilaterally, and visual fields using frequency doubling technology (Zeiss Humphrey Systems, Dublin, CA) were within normal limits. Fundus photography (CX-1 Mydriatic/Non-Mydriatic Hybrid Digital Retinal Camera, Canon, Toyko, Japan) showed slight elevation of the left disc margin, with lack of physiologic cup, elevation of the inferior neuroretinal rim, and no swelling of the nerve fiber layer. Fundus autofluorescence image of the left eye showed hyperfluorescence in the inferior optic disc. Red/green/blue channel separation analysis using the blue channel (Eye-Q software, Canon, Irvine, CA) showed elevation of the nerve fiber layer without obscuration of small vessels surrounding the left optic disc. Embossed technique highlighted the drusen in the left disc. B-scan ultrasound (Eye Cubed, Ellex, Adelaide, Australia) showed a hyperechoic focus on the optic disc with posterior shadowing and corresponding spike on A-scan in both eyes, indicative of bilateral drusen. Optical coherence tomography (RTVue, Optovue, Fremont, CA) showed an elevation in the ONH corresponding to the drusen. CONCLUSIONS: The complementary use of noninvasive imaging modalities such as fundus autofluorescence, red/green/blue separation, B-scan, and optical coherence tomography is important in confirming the diagnosis of ONHD in pediatric patients. They allow us to rule out more serious conditions and avoid unnecessary, costly, and invasive investigative procedures, relieving young patients and their families of potential financial and emotional burdens. PMID- 24064528 TI - Self-assembly of C4H-type hydrogenated graphene. AB - We demonstrate by molecular dynamic (MD) simulations that patterned partially hydrogenated graphene (C4H) can self-assemble at room temperature. The main driving force of the self-assembly of C4H is due to the one-sided distribution of hydrogen and the corresponding asymmetric orientation of sp(3) bonding, there exists strong electrostatic repulsion between the relatively close H atoms. The simulations show that C4H can self-assemble into various carbon nanoscroll (CNS) structures, this is mainly controlled by its geometry (size and aspect ratio). And the carbon nanotube (CNT) is a good candidate to activate and guide C4H to form CNS, whose core size can be controlled. Meanwhile, a novel CNT/C4H core/shell composite nanostructure is also formed. The theoretical results shed important light on a feasible approach to fabricate high-quality CNS and other novel nanostructures including core/shell structures, which hold great potential applications in optics, optoelectronic devices, hydrogen storage, sensors, and energy storage in supercapacitors or batteries. PMID- 24064529 TI - Stochastic modeling of short-term exposure close to an air pollution source in a naturally ventilated room: an autocorrelated random walk method. AB - For an actively emitting source such as cooking or smoking, indoor measurements have shown a strong "proximity effect" within 1 m. The significant increase in both the magnitude and variation of concentration near a source is attributable to transient high peaks that occur sporadically-and these "microplumes" cause great uncertainty in estimating personal exposure. Recent field studies in naturally ventilated rooms show that close-proximity concentrations are approximately lognormally distributed. We use the autocorrelated random walk method to represent the time-varying directionality of indoor emissions, thereby predicting the time series and frequency distributions of concentrations close to an actively emitting point source. The predicted 5-min concentrations show good agreement with measurements from a point source of CO in a naturally ventilated house-the measured and predicted frequency distributions at 0.5- and 1-m distances are similar and approximately lognormal over a concentration range spanning three orders of magnitude. By including the transient peak concentrations, this random airflow modeling method offers a way to more accurately assess acute exposure levels for cases where well-defined airflow patterns in an indoor space are not available. PMID- 24064530 TI - Complexities of sibling analysis when exposures and outcomes change with time and birth order. AB - In this study, we demonstrate the complexities of performing a sibling analysis with a re-examination of associations between cell phone exposures and behavioral problems observed previously in the Danish National Birth Cohort. Children (52,680; including 5441 siblings) followed up to age 7 were included. We examined differences in exposures and behavioral problems between siblings and non siblings and by birth order and birth year. We estimated associations between cell phone exposures and behavioral problems while accounting for the random family effect among siblings. The association of behavioral problems with both prenatal and postnatal exposure differed between siblings (odds ratio (OR): 1.07; 95% confidence interval (CI): 0.69-1.66) and non-siblings (OR: 1.54; 95% CI: 1.36 1.74) and within siblings by birth order; the association was strongest for first born siblings (OR: 1.72; 95% CI: 0.86-3.42) and negative for later-born siblings (OR: 0.63; 95% CI: 0.31-1.25), which may be because of increases in cell phone use with later birth year. Sibling analysis can be a powerful tool for (partially) accounting for confounding by invariant unmeasured within-family factors, but it cannot account for uncontrolled confounding by varying family level factors, such as those that vary with time and birth order. PMID- 24064531 TI - Determinants of personal exposure to some carcinogenic substances and nitrogen dioxide among the general population in five Swedish cities. AB - Environmental levels of airborne carcinogenic and related substances are comparatively better known than individual exposure and its determinants. We report on a personal monitoring program involving five Swedish urban populations. The aim of the program was to investigate personal exposure to benzene, 1,3 butadiene, formaldehyde, and nitrogen dioxide (NO2). The measurements were performed among 40 inhabitants during seven consecutive days, in one urban area each year, during 2000-2008. The estimated population exposure levels were 1.95 MUg/m(3) for benzene, 0.56 MUg/m(3) for 1,3-butadiene, 19.4 MUg/m(3) for formaldehyde, and 14.1 MUg/m(3) for NO2. Statistical analysis using a mixed effects model revealed that time spent in traffic and time outdoors contributed to benzene and 1,3- butadiene exposure. For benzene, refueling a car was an additional determinant influencing the exposure level. Smoking or environmental tobacco smoke were significant determinants of exposure to NO2, benzene, and 1,3 butadiene. Those with a gas stove had higher NO2 exposure. Living in a single family house increased the exposure to formaldehyde significantly. In a variance component model, the between-subject variance dominated for 1,3-butadiene and formaldehyde, whereas the between-city variance dominated for NO2. For benzene, the between-subject and between-cities variances were similar. PMID- 24064532 TI - Development and evaluation of alternative approaches for exposure assessment of multiple air pollutants in Atlanta, Georgia. AB - Measurements from central site (CS) monitors are often used as estimates of exposure in air pollution epidemiological studies. As these measurements are typically limited in their spatiotemporal resolution, true exposure variability within a population is often obscured, leading to potential measurement errors. To fully examine this limitation, we developed a set of alternative daily exposure metrics for each of the 169 ZIP codes in the Atlanta, GA, metropolitan area, from 1999 to 2002, for PM(2.5) and its components (elemental carbon (EC), SO(4)), O(3), carbon monoxide (CO), and nitrogen oxides (NOx). Metrics were applied in a study investigating the respiratory health effects of these pollutants. The metrics included: (i) CS measurements (one CS per pollutant); (ii) air quality model results for regional background pollution; (iii) local scale AERMOD air quality model results; (iv) hybrid air quality model estimates (a combination of (ii) and (iii)); and (iv) population exposure model predictions (SHEDS and APEX). Differences in estimated spatial and temporal variability were compared by exposure metric and pollutant. Comparisons showed that: (i) both hybrid and exposure model estimates exhibited high spatial variability for traffic-related pollutants (CO, NO(x), and EC), but little spatial variability among ZIP code centroids for regional pollutants (PM(2.5), SO(4), and O(3)); (ii) for all pollutants except NO(x), temporal variability was consistent across metrics; (iii) daily hybrid-to-exposure model correlations were strong (r>0.82) for all pollutants, suggesting that when temporal variability of pollutant concentrations is of main interest in an epidemiological application, the use of estimates from either model may yield similar results; (iv) exposure models incorporating infiltration parameters, time-location-activity budgets, and other exposure factors affect the magnitude and spatiotemporal distribution of exposure, especially for local pollutants. The results of this analysis can inform the development of more appropriate exposure metrics for future epidemiological studies of the short-term effects of particulate and gaseous ambient pollutant exposure in a community. PMID- 24064533 TI - Individual whole-body concentration of 137Cesium is associated with decreased blood counts in children in the Chernobyl-contaminated areas, Ukraine, 2008-2010. AB - The Narodichesky region, Zhitomir Oblast, Ukraine, is situated ~80 km from the Chernobyl Nuclear Power Plant, which exploded in 1986 and polluted the environment. A previous study found that children living in villages with high activity of (137)Cesium (Cs) in the soil had decreased levels of hemoglobin, erythrocytes and thrombocytes. These findings motivated the present study that used a more comprehensive exposure assessment, including individual whole-body concentrations (WBC) of (137)Cs (Bq/kg). This cross-sectional sample examined between 2008-2010, included 590 children in the age 0-18 years. Children with higher individual log(WBC) activity in the body had significantly decreased hemoglobin, erythrocyte and thrombocyte counts. The effect of log(WBC) on decreased thrombocyte count was only seen in children older than 12 years. The average village activity of (137)Cs (kBq/m(2)) in soil was associated with decreased blood counts only indirectly, through (137)Cs in the body as an intermediate variable. Children in this study were born at least 4 years after the accident and thus exposed to low doses of ionizing radiation from (137)Cs. This cross-sectional study indicates that low levels may be associated with decreased blood counts, but we cannot exclude that these results are due to residual confounding factors. PMID- 24064535 TI - Incidence, predictive factors and haemodynamic consequences of acute stent recoil following transcatheter aortic valve implantation with a balloon-expandable valve. AB - AIMS: The elastic behaviour (acute recoil) of a valve prosthesis stent following transcatheter aortic valve implantation (TAVI) is unknown. This study sought to determine the occurrence, severity, predictive factors and haemodynamic consequences of acute recoil following TAVI. METHODS AND RESULTS: A prospective angiographic analysis of the stent frame dimensions in 111 consecutive patients who underwent TAVI with a balloon-expandable valve (36 Edwards SAPIEN; 75 SAPIEN XT) was performed. Acute recoil was defined as the difference between minimal lumen diameter (MLD) at full balloon expansion and immediately after balloon deflation. MLD during balloon inflation was significantly larger than MLD after balloon deflation (23.40+/-2.31 mm vs. 22.29+/-2.21 mm, p<0.001), which represented an absolute and percent decrease in stent dimension of 1.10+/-0.40 mm and 4.70+/-1.76%, respectively. In the multivariate analysis, the predictors of larger recoil were a higher prosthesis/annulus ratio (r2=0.0624, p=0.015) and the SAPIEN XT prosthesis (r2=0.1276, p=0.001). No significant changes in haemodynamic performance were observed at discharge and follow-up in patients with larger recoil. CONCLUSIONS: TAVI with a balloon-expandable valve was systematically associated with a certain degree of valve stent recoil after balloon deflation. A higher degree of valve oversizing and the SAPIEN XT prosthesis predicted a larger degree of stent recoil. PMID- 24064536 TI - Constructing stem cell microenvironments using bioengineering approaches. AB - Within the adult organism, stem cells reside in defined anatomical microenvironments called niches. These architecturally diverse microenvironments serve to balance stem cell self-renewal and differentiation. Proper regulation of this balance is instrumental to tissue repair and homeostasis, and any imbalance can potentially lead to diseases such as cancer. Within each of these microenvironments, a myriad of chemical and physical stimuli interact in a complex (synergistic or antagonistic) manner to tightly regulate stem cell fate. The in vitro replication of these in vivo microenvironments will be necessary for the application of stem cells for disease modeling, drug discovery, and regenerative medicine purposes. However, traditional reductionist approaches have only led to the generation of cell culture methods that poorly recapitulate the in vivo microenvironment. To that end, novel engineering and systems biology approaches have allowed for the investigation of the biological and mechanical stimuli that govern stem cell fate. In this review, the application of these technologies for the dissection of stem cell microenvironments will be analyzed. Moreover, the use of these engineering approaches to construct in vitro stem cell microenvironments that precisely control stem cell fate and function will be reviewed. Finally, the emerging trend of using high-throughput, combinatorial methods for the stepwise engineering of stem cell microenvironments will be explored. PMID- 24064537 TI - Pancreastatin is an endogenous peptide that regulates glucose homeostasis. AB - Pancreastatin (PST) is a regulatory peptide containing 49 amino acids, first isolated from porcine pancreas. Intracellular and extracellular processing of the prohormone Chromogranin A (Chga) results various bioactive peptides of which PST has dysglycemic activity. PST regulates glucose, lipid, and protein metabolism in liver and adipose tissues. It also regulates the secretion of leptin and expression of leptin and uncoupling protein 2 in adipose tissue. In Chga knockout mice, PST induces gluconeogenesis in the liver. PST reduces glucose uptake in mice hepatocytes and adipocytes. In rat hepatocytes, PST induces glycogenolysis and glycolysis and inhibits glycogen synthesis. In rat adipocytes, PST inhibits lactate production and lipogenesis. These metabolic effects are confirmed in humans. In the dual signaling mechanism of PST receptor, mostly PST activates Galphaq/11 protein leads to the activation of phospholipase C beta3-isoform, therefore increasing cytoplasmic free calcium and stimulating protein kinase C. PST inhibits the cell growth in rat HTC hepatoma cells, mediated by nitric oxide and cyclic GMP production. Elevated levels of PST correlating with catecholamines have been found in gestational diabetes and essential hypertension. Rise in the blood PST level in Type 2 diabetes suggests that PST is a negative regulator of insulin sensitivity and glucose homeostasis. PMID- 24064539 TI - Cell signalling: Linking JNK and Hippo signalling. PMID- 24064538 TI - Functions and mechanics of dynein motor proteins. AB - Fuelled by ATP hydrolysis, dyneins generate force and movement on microtubules in a wealth of biological processes, including ciliary beating, cell division and intracellular transport. The large mass and complexity of dynein motors have made elucidating their mechanisms a sizable task. Yet, through a combination of approaches, including X-ray crystallography, cryo-electron microscopy, single molecule assays and biochemical experiments, important progress has been made towards understanding how these giant motor proteins work. From these studies, a model for the mechanochemical cycle of dynein is emerging, in which nucleotide driven flexing motions within the AAA+ ring of dynein alter the affinity of its microtubule-binding stalk and reshape its mechanical element to generate movement. PMID- 24064541 TI - Cell cycle: Cyclin A corrections. PMID- 24064540 TI - Regenerating the skin: a task for the heterogeneous stem cell pool and surrounding niche. AB - In the past years, our view of the molecular and cellular mechanisms that ensure the self-renewal of the skin has dramatically changed. Several populations of stem cells have been identified that differ in their spatio-temporal contribution to their compartment in steady-state and damaged conditions, suggesting that epidermal stem cell heterogeneity is far greater than previously anticipated. There is also increasing evidence that these different stem cells require a tightly controlled spatial and temporal communication between other skin residents to carry out their function. PMID- 24064542 TI - Telomeres: Plan B for staying long. PMID- 24064543 TI - Determinants of influenza vaccination uptake among Italian healthcare workers. AB - We analyzed seasonal influenza vaccination coverage among the Italian healthcare workers (HCW) in order to identify socio-demographic and clinical determinants of vaccination. We used data from the survey "Health and health care use in Italy," which comprised interviews of 5,336 HCWs For each respondent, information on socioeconomic, health conditions, self-perceived health and smoking status were obtained. After bivariate analysis, we used multilevel regression models to assess determinants of immunization. Overall 20.8% of HCWs (95%CI 19.7-21.9) reported being vaccinated against seasonal influenza. After controlling for potential confounders, multilevel regression revealed that older workers have a higher likelihood of vaccine uptake (OR = 6.07; 95% CI 4.72-7.79). Conversely, higher education was associated with lower vaccine uptake (OR = 0.65; 95% IC 0.50 0.83). Those suffering from diabetes (OR = 2.07; 95% CI 1.19-1.69), COPD (OR = 1.95; 95% CI 1.31-2.89) and cardiovascular diseases (OR = 1.48 95% CI 1.11-1.96) were more likely to be vaccinated. Likewise, smokers, or former smokers receive more frequently the vaccination (OR = 1.40; 95% CI 1.15-1.70; OR = 1.54; 95% CI 1.24-1.91, respectively) compared with never-smokers as well as those HCWs reporting fair or poor perceived health status (ORs of 1.68, 95% CI 1.30-2.18). Vaccine coverage among HCWs in Italy remains low, especially among those with no comorbidities and being younger than 44 y old. This behavior not only raises questions regarding healthcare organization, infection control in healthcare settings and clinical costs, but also brings up ethical issues concerning physicians who seem not to be very concerned about the impact of the flu on themselves, as well as on their patients. Influenza vaccination campaigns will only be effective if HCWs understand their role in influenza transmission and prevention, and realize the importance of vaccination as a preventive measure. PMID- 24064544 TI - Updating diabetic retinopathy screening lists using automatic extraction from GP patient records. AB - OBJECTIVES: Diabetic Retinopathy screening services aim to reduce the risk of sight loss amongst patients with diabetes. The rising incidence of diabetes in England and the operational need to ensure the accuracy and timeliness of screening lists led to a pilot study of electronic extraction of data from primary care. This study aimed to evaluate the effectiveness of updating the single collated list of patients eligible for diabetic eye screening using extracts from electronic patient records in primary care. SETTING AND METHODS: The Gloucestershire Diabetic Eye Screening Programme (GDESP) provides screening for 85 General Practices in the county. Of these, 54 using Egton Medical Information Systems (EMIS) practice management system software agreed to participate in this study. The screening list held in 2009 by the Gloucestershire DESP of 14,209 patients known to have diabetes was audited against a list created with automatic extraction from General Practice records of patients marked with the diabetes Read Code C10. Those subsequently screened and referred to the Hospital Eye service were followed up. RESULTS: The Gloucestershire DESP manual list covering the 54 EMIS practices comprised 14,771 people with diabetes. The audit process identified an additional 709 (4.8%) patients coded C10, including 23 diagnosed more than 5 years ago, and 20 patients under the age of 20 who were diagnosed more than a year ago. CONCLUSION: Automatic extraction of data from General Practice identified 709 patients coded as having diabetes not previously known to the Gloucestershire DESP. PMID- 24064545 TI - Dietary intake of vitamins A, C, and E and the risk of colorectal adenoma: a meta analysis of observational studies. AB - To comprehensively summarize the association between dietary intake of vitamins A, C, and E and the risk of colorectal adenoma (CRA), the precursor of colorectal cancer, relevant studies were identified in MEDLINE and EMBASE up to 31 October 2012. Summary relative risks (SRRs) with 95% confidence intervals (CIs) were pooled with a random-effects model. Between-study heterogeneity was assessed using Cochran's Q and I statistics. A total of 13 studies with 3832 CRA cases were included in this meta-analysis. On the basis of the highest versus lowest analysis, dietary intake of vitamin C reduced the risk of CRA by 22% (SRRs 0.78, 95% CIs: 0.62-0.98). Subgroup analyses showed that this relation was not modified by BMI, smoking status, and dietary energy intake. Further, dietary intake of beta-carotene was also inversely associated with the risk of CRA. However, dietary intake of vitamins A and E was not associated with the risk of CRA in overall and subgroup analyses (vitamin A: SRRs 0.87, 95% CIs: 0.67-1.14; vitamin E: SRRs 0.87, 95% CIs: 0.69-1.10). Our results indicate that dietary intake of vitamin C and beta-carotene, but not vitamins A and E, could reduce the risk of CRA. However, these associations seem to be limited. Further investigation using large samples and a rigorous methodology is warranted. PMID- 24064546 TI - Overexpression of S100A9 in human glioma and in-vitro inhibition by aspirin. AB - Our previous work has shown that S100A9 promotes the growth of glioma cells. The aim of this study was to investigate S100A9 expression in glioma cells and to explore the potential of NSAIDs in the inhibition of S100A9. The levels of S100A9 were analyzed in five normal human brain tissues and 109 astrocytomas by immunohistochemical analysis. In addition, S100A9 levels were detected in normal human astrocytes, glioma cell lines, and six pairs of matched astrocytoma tissues by reverse transcription-PCR or western blotting analysis. After treatment with 4, 8, and 16 mmol/l aspirin, cell viability, early apoptosis rate, and S100A9 levels were quantified. Cell viability and the changes in S100A9 levels were also examined in glioma cells exposed to a cyclooxygenase-2 inhibitor, NS-398, alone and in combination with prostaglandin E2. We found that S100A9 was upregulated in astrocytomas and was significantly (P<0.05) correlated with histologic grades. S100A9 protein levels were also elevated in six astrocytomas compared with matched adjacent noncancerous tissues. Both S100A9 mRNA and protein levels were higher in glioma cell lines than in normal human astrocytes (P<0.05). Aspirin treatment inhibited cell proliferation and caused early apoptosis in glioma, coupled with reduced S100A9 levels. Treatment with NS-398 decreased cell growth and expression of S100A9 in glioma cells; these effects were partially reversed by exogenous prostaglandin E2. These results suggest overexpression of S100A9 in glioma cells. Aspirin may be a novel candidate for targeted prevention of S100A9 overexpression in glioma cells. PMID- 24064547 TI - VBNC Legionella pneumophila cells are still able to produce virulence proteins. AB - Legionella pneumophila is the agent responsible for legionellosis. Numerous bacteria, including L. pneumophila, can enter into a viable but not culturable (VBNC) state under unfavorable environmental conditions. In this state, cells are unable to form colonies on standard medium but are still alive. Here we show that VBNC L. pneumophila cells, obtained by monochloramine treatment, were still able to synthesize proteins, some of which are involved in virulence. Protein synthesis was measured using (35)S-labeling and the proteomes of VBNC and culturable cells then compared. This analysis allowed the identification of nine proteins that were accumulated in the VBNC state. Among them, four were involved in virulence, i.e., the macrophage infectivity potentiator protein, the hypothetical protein lpl2247, the ClpP protease proteolytic subunit and the 27 kDa outer membrane protein. Others, i.e., the enoyl reductase, the electron transfer flavoprotein (alpha and beta subunits), the 50S ribosomal proteins (L1 and L25) are involved in metabolic and energy production pathways. However, resuscitation experiments performed with Acanthamoeba castellanii failed, suggesting that the accumulation of virulence factors by VBNC cells is not sufficient to maintain their virulence. PMID- 24064548 TI - An anaerobic two-layer permeable reactive biobarrier for the remediation of nitrate-contaminated groundwater. AB - In this paper, an anaerobic two-layer permeable reactive biobarrier system consisting of an oxygen-capturing layer followed by a biodegradation layer was designed firstly for evaluating the remediation effectiveness of nitrate contaminated groundwater. The first layer filling with granular oxygen-capturing materials is used to capture dissolved oxygen (DO) in groundwater in order to create an anaerobic condition for the microbial denitrification. Furthermore, it can also provide nutrition, such as carbon and phosphorus, for the normal metabolism of immobilized denitrifying bacteria filled in the second layer. The second layer using granular activated carbon as microbial carrier is able to biodegrade nitrate entering the barrier system. Batch experiments were conducted to identify the effect of DO on microbial denitrification, oxygen-capturing performance of zero valent iron (ZVI) powder and the characteristics of the prepared oxygen-capturing materials used to stimulate growth of denitrifying bacteria. A laboratory-scale experiment using two continuous upflow stainless steel columns was then performed to evaluate the feasibility of this designed system. The first column was filled with granular oxygen-capturing materials prepared by ZVI powder, sodium citrate as well as other inorganic salts, etc. The second column was filled with activated carbon immobilizing denitrifying microbial consortium. Simulated nitrate-contaminated groundwater (40 mg NO3-N/L, pH 7.0) with 6 mg/L of DO content was pumped into this system at a flow rate of 235 mL/d. Samples from the second column were analyzed for nitrate and its major degradation byproduct. Results showed that nitrate could be removed more than 94%, and its metabolic intermediate, nitrite, could also be biodegraded further in this passive system. Further study is necessary in order to evaluate performance of its field application. PMID- 24064549 TI - Tracing biofouling to the structure of the microbial community and its metabolic products: a study of the three-stage MBR process. AB - The biofouling characteristics of a sequential anoxic/aerobic-membrane bioreactor (A/O MBR) were analyzed during the three-stage process (fast-slow-fast transmembrane pressure (TMP) increasing). The results indicated: during the stage 1 (before day 1), the microbial communities in the activated sludge (AS), cake sludge (CS) and biofilm (BF) were similar to each other, and the adsorption of microbes and the metabolic products was the main factor that led to TMP increase; during the stage 2 (between day 1 and day 7), the cake layer begun to form and the TMP continued to rise gradually at a reduced rate compared to stage 1, at this point a characteristic microbial community colonized the CS with microorganisms such as Saprospiraceae and Comamonadaceae thriving on the membrane surface (BF) probably due to greater nutrient availability, and the predominance of these species in the microbial population led to the accumulation of biofouling metabolic products in the CS, which resulted in membrane fouling and the associated rise in TMP; during the final stage (after day 7), the biofilm had matured, and the activity of anaerobes stimulated cake compaction. The statistical analysis showed a correlation between the TMP changing rate and the carbonhydrates of soluble microbial products (SMPc) content in the CS. When the SMPc concentration rose slowly there was a low level of biofouling. However, when the SMPc accumulating rate was greater, it resulted in the more severe biofouling associated with the TMP jump. Furthermore, the correlation coefficient for the TMP increase and protein concentrations of extracellular polymeric substances (EPSp) in the CS was highly significant. The cluster analysis suggested that the AS microbial community remained stable during the three TMP change stages, while the CS and BF community were changed accompanied with the TMP change. The interaction between the microbial communities and the metabolic products lead to the significant correlation between them. The EPSp in conjunction with the SMPc were the main factors that accelerate the membrane fouling. The rapid rise of SMPc triggered a sudden increase in the TMP, while the accumulation of EPSp caused the sustained rise in TMP. PMID- 24064550 TI - NOM degradation during river infiltration: effects of the climate variables temperature and discharge. AB - Most peri-alpine shallow aquifers fed by rivers are oxic and the drinking water derived by riverbank filtration is generally of excellent quality. However, observations during past heat waves suggest that water quality may be affected by climate change due to effects on redox processes such as aerobic respiration, denitrification, reductive dissolution of manganese(III/IV)- and iron(III)(hydr)oxides that occur during river infiltration. To assess the dependence of these redox processes on the climate-related variables temperature and discharge, we performed periodic and targeted (summer and winter) field sampling campaigns at the Thur River, Switzerland, and laboratory column experiments simulating the field conditions. Typical summer and winter field conditions could be successfully simulated by the column experiments. Dissolved organic matter (DOM) was found not to be a major electron donor for aerobic respiration in summer and the DOM consumption did not reveal a significant correlation with temperature and discharge. It is hypothesized that under summer conditions, organic matter associated with the aquifer material (particulate organic matter, POM) is responsible for most of the consumption of dissolved oxygen (DO), which was the most important electron acceptor in both the field and the column system. For typical summer conditions at temperatures >20 degrees C, complete depletion of DO was observed in the column system and in a piezometer located only a few metres from the river. Both in the field system and the column experiments, nitrate acted as a redox buffer preventing the release of manganese(II) and iron(II). For periodic field observations over five years, DO consumption showed a pronounced temperature dependence (correlation coefficient r = 0.74) and therefore a seasonal pattern, which seemed to be mostly explained by the temperature dependence of the calculated POM consumption (r = 0.7). The river discharge was found to be highly and positively correlated with DO consumption (r = 0.85), suggesting an enhanced POM input during flood events. This high correlation could only be observed for the low-temperature range (T < 15 degrees C). For temperatures >15 degrees C, DO consumption was already high (almost complete) and the impact of discharge could not be resolved. Based on our results, we estimate the risk for similar river-infiltration systems to release manganese(II) and iron(II) to be low during future average summer conditions. However, long-lasting heat waves might lead to a consumption of the nitrate buffer, inducing a mobilization of manganese and iron. PMID- 24064551 TI - Long-term motor cortical map changes following unilateral lesion of the hand representation in the motor cortex in macaque monkeys showing functional recovery of hand functions. AB - PURPOSE: How are motor maps modified within and in the immediate vicinity of a damaged zone in the motor cortex of non-human primates? METHODS: In eight adult macaque monkeys subjected to a restricted chemical lesion of the hand area in the primary motor cortex (M1), motor maps were established using intracortical micro stimulation (ICMS) techniques. The monkeys were subdivided into five animals without treatment, whereas three monkeys received an anti-Nogo-A antibody treatment. RESULTS: Following permanent M1 injury, the lesion territory became largely non micro-excitable several months post-lesion, in spite of some recovery of hand function. Few sites within the lesion territory remained excitable, though irrespective to the degree of functional recovery. Around the lesion in M1, there was no reallocation of proximal shoulder/arm territories into distal hand functions. However, ICMS delivered at supra-threshold intensities in these proximal territories elicited digit movements. Post-lesion ICMS thresholds to elicit movements of forelimb muscle territories increased, independently from the degree of functional recovery. Further behavioural evidence for an enhancement of functional recovery promoted by the anti-Nogo-A antibody treatment is provided. CONCLUSION: The degree of functional recovery is not related to a reorganization of motor maps within, and in the vicinity of, a M1 lesion. PMID- 24064552 TI - Study on UV-shielding mechanism of layered double hydroxide materials. AB - The development of UV-shielding materials has attracted considerable attention in the field of coatings and sunscreen. This paper reports the UV-shielding mechanism of layered double hydroxide (LDH) materials in terms of chemical composition, structure and morphology, by using (LDH/PAA)n films (n stands for bilayer number) through alternate LBL assembly of LDH nanoparticles and poly(acrylic acid) (PAA) on quartz substrates as a model system. A combination investigation based on experimental and theoretical study demonstrates that the maximum UV scattering can be achieved when lambda/d ~ 1.98; the introduction of Zn element is an effective way to tune the electron structure, band gap, transition mode and resulting UV-shielding property of LDH materials. A UV shielding efficiency as high as 95% can be obtained by modulating the particle size, composition and thickness of the LDHs. Furthermore, the UV anti-aging capacity of LDH-modified bitumen was studied, which demonstrates a large improvement in UV-resistance performance of bitumen by the incorporation of LDH materials. Therefore, this work systematically discloses the relationship between UV-shielding property and chemical/structural parameters of LDH materials, which can be potentially used as anti-aging agents in various organic matrices and polymer areas. PMID- 24064554 TI - Selective one-pot syntheses of Pt(II)-Cu(I) heterobimetallic complexes of 4,5 diazafluorenide derivatives. AB - We report both the stepwise and one-pot syntheses of Pt(II)-Cu(I) hetero dinuclear complexes using 4,5-diazafluorenide (L(-)) and 9-(2 (diphenylphosphino)ethyl)-4,5-diazafluorenide (L(p)(-)) as binucleating ligands. In the case of L(p)(-), the tethered phosphine arm helps anchor the Pt(II) centre onto the carbon site of the diazafluorenide and the Cu(I) centre is bound to the N,N-chelate site. In the case of L(-), the Cu(I) centre is bound to the carbon site of diazafluorenide and the Pt(II) centre is coordinated to the N,N-chelate site. PMID- 24064555 TI - Light-controlled ion channels formed by amphiphilic small molecules regulate ion conduction via cis-trans photoisomerization. AB - Light-regulated ion channel-transport across lipid bilayers was realized using structurally simple azobenzene-based amphiphilic small molecules. UV or visible irradiation triggers molecular photoisomerization, which induces structural and membrane affinity changes in self-assembled channels, thus resulting in light regulated ion transmembrane transport. PMID- 24064553 TI - Dysregulation of Ca(v)1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2. AB - Mutations in the gene encoding Cav 1.4, CACNA1F, are associated with visual disorders including X-linked incomplete congenital stationary night blindness type 2 (CSNB2). In mice lacking Cav 1.4 channels, there are defects in the development of "ribbon" synapses formed between photoreceptors (PRs) and second order neurons. However, many CSNB2 mutations disrupt the function rather than expression of Cav 1.4 channels. Whether defects in PR synapse development due to altered Cav 1.4 function are common features contributing to the pathogenesis of CSNB2 is unknown. To resolve this issue, we profiled changes in the subcellular distribution of Cav 1.4 channels and synapse morphology during development in wild-type (WT) mice and mouse models of CSNB2. Using Cav 1.4-selective antibodies, we found that Cav 1.4 channels associate with ribbon precursors early in development and are concentrated at both rod and cone PR synapses in the mature retina. In mouse models of CSNB2 in which the voltage-dependence of Cav 1.4 activation is either enhanced (Cav 1.4I756T) or inhibited (CaBP4 KO), the initial stages of PR synaptic ribbon formation are largely unaffected. However, after postnatal day 13, many PR ribbons retain the immature morphology. This synaptic abnormality corresponds in severity to the defect in synaptic transmission in the adult mutant mice, suggesting that lack of sufficient mature synapses contributes to vision impairment in Cav 1.4I756T and CaBP4 KO mice. Our results demonstrate the importance of proper Cav 1.4 function for efficient PR synapse maturation, and that dysregulation of Cav 1.4 channels in CSNB2 may have synaptopathic consequences. PMID- 24064556 TI - Modifiable factors associated with tuberculosis disease in children: a case control study. AB - We conducted a case-control study among children in Lima, Peru to identify factors associated with tuberculosis disease. Known close contact with someone with tuberculosis disease, prior hospitalization, and history of anemia were associated with a higher tuberculosis disease rate. Consumption of fruits/vegetables >=5 days/week was associated with a lower rate. Isoniazid uptake was low among children with a known contact. PMID- 24064557 TI - Toxoplasmosis in pregnancy in an area with low seroprevalence: is prenatal screening still worthwhile? AB - BACKGROUND: The effectiveness of Toxoplasma gondii (Tg) screening during pregnancy in areas with a low prevalence of the infection is debated. We investigate the Tg serological status, the rate of primary infection in a cohort of pregnant women and the rate of congenital toxoplasmosis among their infants during a 3-year period in an urban area with low Tg prevalence. METHODS: Demographic and Tg serological data for all pregnant women delivering from January 2009 to December 2011 were collected. All pregnant women with primary Tg infection during pregnancy and their infants were included in the study. RESULTS: In early pregnancy, 10,347 women underwent prenatal screening and 2308 (22.3%) had anti-Tg. The seroprevalence among non-native women was significantly higher than that among native women [32.8% vs. 19.1%, relative risk: 1.71, P < 0.001]. The incidence rate of primary Tg infection during pregnancy was 0.77%. Immigrant women were more likely to be infected during pregnancy than Italian women (relative risk: 4.88, P < 0.001). Tg infection was more frequent in women coming from Africa, Asia, Eastern Europe and South America. The CT incidence rate was 0.06%. All congenitally infected infants were born to immigrant mothers. CONCLUSIONS: Tg infection during pregnancy and congenital disease are more frequent in non-native mothers and their infants. Measures to prevent Tg exposition must be carefully explained to pregnant women, with a focus on specific habits in non-native women. Prenatal screening is still effective to select women for prenatal therapy aiming to decrease vertical transmission and to identify foetuses/newborns with congenital disease that could benefit from pre/postnatal antiparasitic therapy. PMID- 24064558 TI - Predictors and outcomes of viridans group streptococcal infections in pediatric acute myeloid leukemia: from the Canadian infections in AML research group. AB - BACKGROUND: Viridans group streptococci (VGS) cause significant morbidity in children treated for acute myeloid leukemia (AML). Our goals were to determine the occurrence and impact of these infections in children treated for AML and to understand the factors that increase the risk of VGS infections and viridans streptococcal shock syndrome (VSSS) in this population. METHODS: We conducted a retrospective, population-based cohort study that included children <=18 years of age with de novo AML treated at 15 Canadian centers. We evaluated factors related to VGS infection and VSSS. RESULTS: Among 341 children with AML, VGS occurred in 78 (22.9%) children over the entire course of therapy and 16 had recurrent episodes. VGS infection occurred in 97 of 1277 courses of chemotherapy (7.6%). VSSS occurred in 19.6% of these episodes and included 11 patients who required intensive care services with 2 VGS infections resulting in death. In multiple regression analysis, factors independently related to VGS included treatment on a Medical Research Council-based protocol (odds ratio (OR) 2.87, 95% confidence interval (CI) 1.53-5.39; P = 0.001), cytarabine dose per gram/m2 (OR 1.04, 95% CI 1.01-1.07; P = 0.002) and prolonged neutropenia (OR 1.58, 95% CI: 0.97-2.56; P = 0.06). None of the evaluated factors were predictive of VSSS. CONCLUSIONS: VGS infections occur in 7.6% of chemotherapy courses and remain an important cause of morbidity and even mortality in children being treated for AML. Interventions to reduce VGS need to be identified. PMID- 24064559 TI - Epidemiologic features of Kawasaki disease in South Korea: data from nationwide survey, 2009-2011. AB - BACKGROUND: To assess the recent epidemiologic features of Kawasaki disease (KD) in South Korea from the nationwide survey conducted between 2009 and 2011. METHODS: We collected data regarding the incidence, symptoms, treatment and coronary complications associated with acute KD by sending questionnaires to the 100 hospitals that have pediatric residency programs from 2009 to 2011. RESULTS: We received complete responses from 73 hospitals and partial responses from 14 hospitals. A total of 13,031 patients of KD were reported from the 87 hospitals (3941 in 2009, 4635 in 2010 and 4455 in 2011). The male to female ratio was 1.44:1, and the median age at diagnosis was 28 months. From the questionnaires with complete responses, we noted that the incidence of KD per 100,000 children <5 years of age was 115.4 in 2009, 132.9 in 2010 and 134.4 in 2011 (average rate, 127.7). KD occurred more frequently during summer (June, July and August) and during winter (December and January). The recurrence rate was 3.83%. The standard dose of intravenous immunoglobulin was administered to 93.6% of the patients, and nonresponder rate was 11.6%. Coronary aneurysm occurred in 1.9% of the patients and giant aneurysm developed in 26 patients (0.26%) over 3 years, and 2 patients had myocardial infarction. No mortality was reported. CONCLUSIONS: The average annual incidence of KD in South Korea has continuously increased to 134.4 per 100,000 children <5 years of age in 2011, which is the second highest incidence of KD worldwide, following its incidence in Japan. PMID- 24064560 TI - Different penetrance of disseminated infections caused by nontuberculous Mycobacteria in Mendelian susceptibility to mycobacterial disease associated with a novel mutation. AB - Deficiency in the interleukin12/INFgamma pathway is a genetic condition that predisposes to some infections, including nontuberculous mycobacteria infection and extraintestinal salmonellosis. We report 2 cases in sisters who were diagnosed with a genetic defect caused by a new mutation in Interleukin-12 receptor beta1 chain (IL12Rbeta1) leading to different clinical presentations and responses to therapy. PMID- 24064561 TI - Comparison of Mycobacterium lentiflavum and Mycobacterium avium-intracellulare complex lymphadenitis. AB - BACKGROUND: Mycobacterium lentiflavum is considered a rare pathogen causing nontuberculous mycobacterial (NTM) lymphadenitis. METHODS: A multicenter, retrospective study was performed in immunocompetent children <14 years of age with microbiologically confirmed NTM lymphadenitis treated at 6 hospitals in Madrid, Spain, during 2000-2010. We compared children with M. lentiflavum and Mycobacterium avium-intracellulare complex infection. RESULTS: Forty-five microbiologically confirmed NTM lymphadenitis patients were identified: 19 (45.2%) caused by M. avium-intracellulare complex, 17 (40.5%) by M. lentiflavum, 1 by both and 5 by other mycobacteria. Out of 17 M. lentiflavum cases, 14 were diagnosed in the past 5 years. Regarding M. lentiflavum cases, median age was 23 months. Submandibular nodes were the most frequently involved (76.5%), with multiple locations seen in 41% of the children and spontaneous drainage in 41% of them. Drug susceptibility tests were performed in 14 isolates and showed a complete susceptibility to clarithromycin and cycloserine, whereas 93% were resistant to rifampin, 33% to quinolones and full resistance to other tested antimycobacterial drugs was detected. All but 1 child required surgery and 11 were treated additionally with various drug combinations. Total resolution was achieved in 50% of children within 6 months.Compared with M. avium-intracellulare complex cases, children were younger and laterocervical nodes were significantly less frequently involved. No statistically significant differences were found related to clinical characteristics, treatment and outcome. CONCLUSIONS: M. lentiflavum is an emerging pathogen producing NTM lymphadenitis in Madrid. PMID- 24064563 TI - Detection of respiratory viral infections in neonates treated for suspicion of nosocomial bacterial sepsis: a feasibility study. AB - There is a lack of knowledge concerning the frequency and significance of respiratory viral infections that occur in the neonatal intensive care unit. In the present study, all neonates with suspected nosocomial bacterial sepsis were screened for a panel of respiratory viruses. Respiratory viral infections were detected in 10% of these cases. This was comparable with the frequency of a blood culture-proven sepsis. PMID- 24064566 TI - Regulation of prostate cancer cell migration toward bone marrow stromal cell conditioned medium by Wnt5a signaling. AB - Bone is a major site of metastasis for several types of malignant tumor. Specific interactions between tumor cells and the bone microenvironment contribute to the tendency of tumors to metastasize to bone. Furthermore, Wnt5a participates in the progression of several types of malignant tumor. This study investigates the role of Wnt5a in the migration of the prostate cancer (PCa) cell line PC3 toward bone marrow stromal cell (BMSC)-conditioned medium (CM). The expression of 22 genes associated with bone metastasis was measured in three PCa cell lines (LNCaP, PC3 and DU145). Subsequently, the proliferation and migration capacities of PC3 cells treated either with small interfering RNA (siRNA) against Wnt5a or with recombinant mouse (rm) Wnt5a were analyzed with alamarBlue and transwell assays. BMSC-CM was collected to evaluate its effect on PC3 cell migration. Also, the expression of Wnt5a in BMSCs was knocked down prior to collection of the CM to evaluate its effects on the migration of PC3 cells. Significantly higher levels of Wnt5a mRNA expression were identified in the PC3 cells, compared with those in LNCaP and DU145 cells. Silencing Wnt5a expression with siRNA reduced the migration capacity of PC3 cells by 50%. The addition of rmWnt5a improved the migration capacity of PC3 cells in a concentration-dependent manner. PC3 cells preferred to migrate toward BMSC-CM than toward the control. CM from Wnt5a siRNA treated BMSCs significantly reduced PC3 cell migration. Wnt5a promotes PC3 cell migration toward BMSC-CM, indicating that Wnt5a is a potential therapeutic target for the treatment of advanced PCa. PMID- 24064567 TI - Multilayer polymer thin films for fabrication of ordered multifunctional polymer nanocomposites. AB - Here, we describe a novel and versatile approach for fabrication of multilayer polymeric thin films with a tunable, ordered periodic structure in each layer using self-assembly of block copolymers. Different functional nanomaterials are selectively introduced in different layers with controlled arrays and network formation resulting in ordered multifunctional nanocomposite thin films. PMID- 24064568 TI - A case of intraosseous microcystic meningioma without a mass lesion. AB - Both intraosseous and microcystic meningiomas are rare tumor types. We report the case of a 66-year-old woman with intraosseous microcystic meningioma without a mass lesion. She presented with a rare intraosseous microcystic meningioma manifesting as pain. Radiological examination revealed an osteolytic lesion in the right parietal bone. Magnetic resonance (MR) images showed iso- to hypointensity on T1-weighted images and hyperintensity on T2-weighted images corresponding to the lesion. T1-weighted MR imaging with gadolinium enhancement better defined the marginal area. The inner table of the skull was disrupted prominently, and both sides of the outer table were eroded. There was fluid leakage during surgery but no obvious tumor mass. Histological examination revealed microcystic meningioma in the inner part of the defective bone. A macroscopic lesion was not found, because most of the tumor comprised microcysts, and their contents leaked out during the surgical procedure. Intraosseous microcystic meningioma may be considered as one of the differential diagnoses when the intraosseous tumor in the skull has fluid leakage and does not have a mass lesion during the surgery. PMID- 24064569 TI - Optimized endoscopic autofluorescence spectroscopy for the identification of premalignant lesions in Barrett's oesophagus. AB - OBJECTIVE: Fluorescence spectroscopy has the potential to detect early cellular changes in Barrett's oesophagus before these become visible. As the technique is based on varying concentrations of intrinsic fluorophores, each with its own optimal excitation wavelength, it is important to assess the optimal excitation wavelength(s) for identification of premalignant lesions in patients with Barrett's oesophagus. METHODS: The endoscopic spectroscopy system used contained five (ultra)violet light sources (lambdaexc=369-416 nm) to generate autofluorescence during routine endoscopic surveillance. Autofluorescence spectroscopy was followed by a biopsy for histological assessment and spectra correlation. Three intensity ratios (r1, r2, r3) were calculated by dividing the area, A, under the spectral curve of selected emission wavelength ranges for each spectrum generated by each excitation wavelength lambdaexc as follows (Equation is included in full-text article.). Double intensity ratios were calculated using two excitation wavelengths. RESULTS: Fifty-eight tissue areas from 22 patients were used for autofluorescence spectra analysis. Excitation with 395, 405 or 410 nm showed a significant (P<=0.0006) differentiation between intestinal metaplasia and grouped high-grade dysplasia/early carcinoma for intensity ratios r2 and r3. A sensitivity of 80.0% and specificity of 89.5% with an area under the ROC curve of 0.85 was achieved using 395 nm excitation and intensity ratio r3. CONCLUSION: Double excitation showed no additional value over single excitation. The combination of 395 nm excitation and intensity ratio r3 showed optimal conditions to discriminate nondysplastic from early neoplasia in Barrett's oesophagus. PMID- 24064570 TI - Chlorogenic acid alters the biological characteristics of basophil granulocytes by affecting the fluidity of the cell membrane and triggering pseudoallergic reactions. AB - It is not clear whether pseudoallergic reactions are caused by similar mechanisms as type I allergic reactions. 3-Caffeoylquinic acid (chlorogenic acid) is an active ingredient in traditional Chinese medicines used for antibacterial, anti inflammatory and cholagogic purposes. It is assumed to be the reason for the high allergic reaction rates associated with certain traditional Chinese medicine injection solutions. The aim of the present study was to investigate the possible mechanisms through which chlorogenic acid triggers pseudoallergic reactions. The fluidity of the cell membrane was investigated using fluorescence recovery after photobleaching. Western blot analysis was used to measure the phosphorylation levels of the Spleen tyrosine kinase (Syk) protein and Fluo-3/AM fluorescent probes were used to investigate the influx of calcium ions. In addition, fluorescence microscopy and phalloidin were used to determine F-actin depolymerization levels. The secretion rate of beta-hexosaminidase by RBL-2H3 cells clearly increased following treatment with chlorogenic acid and the levels of cytoskeletal disintegration were also markedly increased. Furthermore, we detected an increase in the intracellular calcium ion concentration along with distinct changes in Syk protein phosphorylation and cellular F-actin. These changes indicated that chlorogenic acid affected the restructuring of the cytoskeleton and played a role in cell degranulation. In conclusion, chlorogenic acid may lead to the aggregation of lipid rafts on the cell membrane surface by altering RBL-2H3 cell membrane fluidity, thus triggering Syk-related signal transduction and inducing a truncated type I like allergic reaction. PMID- 24064572 TI - Iron deficiency in heart failure: a practical guide. AB - Iron is an element necessary for cells due to its capacity of transporting oxygen and electrons. One of the important co-morbidities in heart failure is iron deficiency. Iron has relevant biological functions, for example, the formation of haemoglobin, myoglobin and numerous enzymatic groups. The prevalence of iron deficiency increases with the severity of heart failure. For a long time, the influence of iron deficiency was underestimated especially in terms of worsening of cardiovascular diseases and of developing anaemia. In recent years, studies with intravenous iron agents in patients with iron deficiency and cardiovascular diseases indicated new insights in the improvement of therapy. Experimental studies support the understanding of iron metabolism. Many physicians remain doubtful of the use of intravenous iron due to reports of side effects. The aim of this review is to describe iron metabolism in humans, to highlight the influence of iron deficiency on the course and symptoms of heart failure, discuss diagnostic tools of iron deficiency and provide guidance on the use of intravenous iron. PMID- 24064571 TI - Childhood overweight/obesity and pediatric asthma: the role of parental perception of child weight status. AB - Childhood obesity and asthma are on the rise in the U.S. Clinical and epidemiological data suggest a link between the two, in which overweight and obese children are at higher risk for asthma. Prevention of childhood obesity is preferred over treatment, however, in order to be receptive to messages, parents must perceive that their child is overweight. Many parents do not accurately assess their child's weight status. Herein, the relation between parental perceptions of child weight status, observed body mass index (BMI) percentiles, and a measure of child feeding practices were explored in the context of asthma, food allergy, or both. Out of the children with asthma or food allergy that were classified as overweight/obese by BMI percentiles, 93% were not perceived as overweight/obese by the parent. Mean scores for concern about child weight were higher in children with both asthma and food allergy than either condition alone, yet there were no significant differences among the groups in terms of pressure to eat and restrictive feeding practices. In summary, parents of children with asthma or food allergy were less likely to recognize their child's overweight/obese status and their feeding practices did not differ from those without asthma and food allergy. PMID- 24064573 TI - Xylo-oligosaccharides and inulin affect genotoxicity and bacterial populations differently in a human colonic simulator challenged with soy protein. AB - High dietary intakes of some protein sources, including soy protein, can increase colonic DNA damage in animals, whereas some carbohydrates attenuate this. We investigated whether inulin and xylo-oligosaccharides (XOS) could be protective against DNA strand breaks by adding them to a human colonic simulator consisting of a proximal vessel (PV) (pH 5.5) and a distal vessel (DV) (pH 6.8) inoculated with human faeces and media containing soy protein. Genotoxicity of the liquid phase and microbial population changes in the vessels were measured. Soy protein (3%) was fermented with 1% low amylose cornstarch for 10 day followed by soy protein with 1% XOS or 1% inulin for 10 day. Inulin did not alter genotoxicity but XOS significantly reduced PV genotoxicity and increased DV genotoxicity. Inulin and XOS significantly increased butyrate concentration in the DV but not PV. Numbers of the key butyrate-producing bacterium Faecalibacterium prausnitzii were significantly increased in the PV and DV by inulin but significantly decreased by XOS in both vessels. Other bacteria examined were also significantly impacted by the carbohydrate treatments or by the vessel (i.e., pH). There was a significant overall inverse correlation between levels of damage induced by the ferments and levels of sulphate-reducing bacteria, Bacteroides fragilis, and acetate. In conclusion, dietary XOS can potentially modulate the genotoxicity of the colonic environment and specific bacterial groups and short chain fatty acids may mediate this. PMID- 24064575 TI - Application of the Rasch model to measuring the performance of cognitive radios. AB - Cognitive radios (CRs) are recent technological developments that rely on artificial intelligence to adapt a radio's performance to suit environmental demands, such as sharing radio frequencies with other radios. Measuring the performance of the cognitive engines (CEs) that underlie a CR's performance is a challenge for those developing CR technology. This simulation study illustrates how the Rasch model can be applied to the evaluation of CRs. We simulated the responses of 50 CEs to 35 performance tasks and applied the Random Coefficients Multidimensional Multinomial Logit Model (MRCMLM) to those data. Our results indicate that CEs based on different algorithms may exhibit differential performance across manipulated performance task parameters. We found that a multidimensional mixture model may provide the best fit to the simulated data and that the two algorithms simulated may respond to tasks that emphasize achieving high levels of data throughput coupled with lower emphasis on power conservation differently than they do to other combinations of performance task characteristics. PMID- 24064576 TI - Properties of Rasch residual fit statistics. AB - This paper examines the residual-based fit statistics commonly used in Rasch measurement. In particular, the paper analytically examines some of the theoretical properties of the residual-based fit statistics with a view to establishing the inferences that can be made using these fit statistics. More specifically, the relationships between the distributional properties of the fit statistics and sample size are discussed; some research that erroneously concludes that residual-based fit statistics are unstable is reviewed; and finally, it is analytically illustrated that, for dichotomous items, residual based fit statistics provide a measure of the relative slope of empirical item characteristic curves. With a clear understanding of the theoretical properties of the fit statistics, the use and limitations of these statistics can be placed in the right light. PMID- 24064577 TI - Validating workplace performance assessments in health sciences students: a case study from speech pathology. AB - Valid assessment of health science students' ability to perform in the real world of workplace practice is critical for promoting quality learning and ultimately certifying students as fit to enter the world of professional practice. Current practice in performance assessment in the health sciences field has been hampered by multiple issues regarding assessment content and process. Evidence for the validity of scores derived from assessment tools are usually evaluated against traditional validity categories with reliability evidence privileged over validity, resulting in the paradoxical effect of compromising the assessment validity and learning processes the assessments seek to promote. Furthermore, the dominant statistical approaches used to validate scores from these assessments fall under the umbrella of classical test theory approaches. This paper reports on the successful national development and validation of measures derived from an assessment of Australian speech pathology students' performance in the workplace. Validation of these measures considered each of Messick's interrelated validity evidence categories and included using evidence generated through Rasch analyses to support score interpretation and related action. This research demonstrated that it is possible to develop an assessment of real, complex, work based performance of speech pathology students, that generates valid measures without compromising the learning processes the assessment seeks to promote. The process described provides a model for other health professional education programs to trial. PMID- 24064578 TI - Rasch analysis for the evaluation of rank of student response time in multiple choice examinations. AB - The availability of computerized testing has broadened the scope of person assessment beyond the usual accuracy-ability domain to include response time analyses. Because there are contexts in which speed is important, e.g. medical practice, it is important to develop tools by which individuals can be evaluated for speed. In this paper, the ability of Rasch measurement to convert ordinal nonparametric rankings of speed to measures is examined and compared to similar measures derived from parametric analysis of response times (pace) and semi parametric logarithmic time-scaling procedures. Assuming that similar spans of the measures were used, non-parametric methods of raw ranking or percentile ranking of persons by questions gave statistically acceptable person estimates of speed virtually identical to the parametric or semi-parametric methods. Because no assumptions were made about the underlying time distributions with ranking, generality of conclusions was enhanced. The main drawbacks of the non-parametric ranking procedures were the lack of information on question duration and the overall assignment by the model of variance to the person by question interaction. PMID- 24064574 TI - Activation and regulation of the pattern recognition receptors in obesity-induced adipose tissue inflammation and insulin resistance. AB - Obesity-associated chronic tissue inflammation is a key contributing factor to type 2 diabetes mellitus, and a number of studies have clearly demonstrated that the immune system and metabolism are highly integrated. Recent advances in deciphering the various immune cells and signaling networks that link the immune and metabolic systems have contributed to our understanding of the pathogenesis of obesity-associated inflammation. Other recent studies have suggested that pattern recognition receptors in the innate immune system recognize various kinds of endogenous and exogenous ligands, and have a crucial role in initiating or promoting obesity-associated chronic inflammation. Importantly, these mediators act on insulin target cells or on insulin-producing cells impairing insulin sensitivity and its secretion. Here, we discuss how various pattern recognition receptors in the immune system underlie the etiology of obesity-associated inflammation and insulin resistance, with a particular focus on the TLR (Toll like receptor) family protein Radioprotective 105 (RP105)/myeloid differentiation protein-1 (MD-1). PMID- 24064579 TI - Assessing DIF among small samples with separate calibration t and Mantel-Haenszel chi2 statistics in the Rasch model. AB - The National Council Licensure Examination (NCLEX) program has evaluated differential item functioning (DIF) using the Mantel-Haenszel (M-H) chi-square statistic. Since a Rasch model is assumed, DIF implies a difference in item difficulty between a reference group, e.g., White applicants, and a focal group, e.g., African-American applicants. The National Council of State Boards of Nursing (NCSBN) is planning to change the statistic used to evaluate DIF on the NCLEX from M-H to the separate calibration t-test (t). In actuality, M-H and t should yield identical results in large samples if the assumptions of the Rasch model hold (Linacre and Wright, 1989, also see Smith, 1996). However, as is true throughout statistics, "how large is large" is undefined, so it is quite possible that systematic differences exist in relatively smaller samples. This paper compares M-H and t in four sets of computer simulations. Three simulations used a ten-item test with nine fair items and one potentially containing DIF. To address instability that may result from a ten-item test, the fourth used a 30-item test with 29 fair items and one potentially containing DIF. Depending upon the simulation, the magnitude of population DIF (0, .5, 1.0, and 1.5 z-score units), the ability difference between the focal and reference group (-1, 0, and 1 z score units), the focal group size (0, 10, 20, 40, 50, 80, 160, and 1000), and the reference group size (500 and 1000) were varied. The results were that: (a) differences in estimated DIF between the M-H and t statistics are generally small, (b) t tends to estimate lower chance probabilities than M-H with small sample sizes, (c) neither method is likely to detect DIF, especially when it is of slight magnitude in small focal group sizes, and (d) M-H does marginally better than t at detecting DIF but this improvement is also limited to very small focal group sizes. PMID- 24064580 TI - Application of latent variable model in Rosenberg self-esteem scale. AB - Latent Variable Models (LVM) are applied to Rosenberg Self-Esteem Scale (RSES). Parameter estimations automatically give negative signs hence no recoding is necessary for negatively scored items. Bad items can be located through parameter estimate, item characteristic curves and other measures. Two factors are extracted with one on self-esteem and the other on the degree to take moderate views, with the later not often being covered in previous studies. A goodness-of fit measure based on two-way margins is used but more works are needed. Results show that scaling provided by models with more formal statistical ground correlated highly with conventional method, which may provide justification for usual practice. PMID- 24064581 TI - A rasch analysis of the statistical anxiety rating scale. AB - The conceptualization of a distinct construct known as statistics anxiety has led to the development of numerous rating scales, including the Statistical Anxiety Rating Scale (STARS), designed to assess levels of statistics anxiety. In the current study, the STARS was administered to a sample of 423 undergraduate and graduate students from a midsized, western United States university. The Rasch measurement rating scale model was used to analyze scores from the STARS. Misfitting items were removed from the analysis. In general, items from the six subscales represented a broad range of abilities, with the major exception being a lack of items at the lower extremes of the subscales. Additionally, a differential item functioning (DIF) analysis was performed across sex and student classification. Several items displayed DIF, which indicates subgroups may ascribe different meanings to those items. The paper concludes with several recommendations for researchers considering using the STARS. PMID- 24064583 TI - Root bark extracts of Juncus effusus and Paeonia suffruticosa protect salivary gland acinar cells from apoptotic cell death induced by cis-platinum (II) diammine dichloride. AB - Cis-platinum (II) diammine dichloride (CDDP) is a platinum-based anticancer agent, and is often used for chemotherapy for malignant tumors, albeit CDDP has serious side-effects, including xerostomia (dry mouth). Since patients with xerostomia have reduced quality of life, it is urgent and important to identify nontoxic and natural agents capable of reducing the adverse effect of chemotherapy on salivary gland function. Therefore, we commenced an institutional collaborative project in which candidates of herbal extracts were selected from more than 400 bioactive herbal products for their potential therapeutic effects not only on xerostomia, but also on oral diseases. In the present study, we report on two Chinese medical herbal extracts from the root barks of Juncus effusus and Paeonia suffruticosa. The two extracts showed a protective effect in NS-SV-Ac cells from the cytotoxicity and apoptosis caused by CDDP. The effect was dependent on the p53 pathway, protein kinase B/Akt 1 and mitochondrial apoptosis related proteins (i.e. Bcl-2 and Bax), but was not dependent on nuclear factor kappaB. Notably, the apoptosis-protective effect of the extracts was not observed in adenocystic carcinoma cell lines. Although these extracts have been utilized in traditional Chinese medicine for hundreds of years, there are no reports to our knowledge, on their therapeutic effects on xerostomia. Thus, in the present study, we elucidated the potency of these herbal extracts as novel candidates for xerostomia to improve the quality of life of patients undergoing chemotherapy. PMID- 24064585 TI - Oxidative stability and chemical safety of mayonnaise enriched with grape seed extract. AB - Grape seed extract (GSE), a by-product from the wine industry, was explored for its use as enrichment to mayonnaise, due to its potential health effects. Mayonnaises were enriched with 0 mg GSE per mL, 0.5 mg GSE per mL (~0.050%), 0.9 mg GSE per mL (~0.10%) and 1.4 mg GSE per mL (~0.15%) during preparation and stored in the dark at room temperature for 8 weeks. The antioxidative capacity of the mayonnaises was evaluated by their ability to scavenge the stable radical TEMPO by electron spin resonance (ESR) spectroscopy. The oxidative stability of the mayonnaises was determined by the content of lipid hydroperoxides (peroxide value, POV), the content of conjugated diene hydroperoxides and the content of thiobarbituric acid reactive substances (TBARS). The highest antioxidative capacity and the lowest content of lipid hydroperoxides and TBARS were found in the mayonnaise with the highest percentage of GSE (0.15%). Therefore, the oxidative stability of the mayonnaises enriched with GSE was slightly improved through storage. However, mayonnaise without GSE had the highest sensorial acceptability compared to mayonnaise enriched with GSE. In the Artemia salina assay, a fast screening method for overall toxicity, the death rate of brine shrimps larvae was found to increase for increasing percentage of GSE. A level of 0.05% GSE in mayonnaise is concluded not to constitute any toxicological risks, but to provide significant protection against oxidation during storage. PMID- 24064587 TI - Neurodevelopmental disorders: super sonic. PMID- 24064591 TI - Cognitive neuroscience: oxytocin and serotonin make it worthwhile. PMID- 24064592 TI - Correlation of a self-report and direct measure of physical activity level in the electron-beam tomography and risk assessment among Japanese and US Men in the post World War II birth cohort (ERA JUMP) study. AB - BACKGROUND: Physical activity (PA) is complex and a difficult behavior to assess as there is no ideal assessment tool(s) that can capture all contexts of PA. Therefore, it is important to understand how different assessment tools rank individuals. We examined the extent to which self-report and direct assessment PA tools yielded the same ranking of PA levels. METHODS: PA levels were measured by the Modifiable Activity Questionnaire (MAQ) and pedometer at baseline among 855 white (W), African-American (AA), Japanese-American (JA), and Korean (K) men (mean age 45.3 years) in 3 geographic locations in the ERA JUMP study. RESULTS: Korean men were more active than W, AA, and JA men, according to both the MAQ and pedometer (MAQ total PA [mean +/- SD]: 41.6 +/- 17.8, 20.9 +/- 9.9, 20.0 +/- 9.1, and 29.4 +/- 10.3 metabolic equivalent [MET] hours/week, respectively; pedometer: 9584.4 +/- 449.4, 8363.8 +/- 368.6, 8930.3 +/- 285.6, 8335.7 +/- 368.6 steps/day, respectively). Higher levels of total PA in Korean men, as shown by MAQ, were due to higher occupational PA. Spearman correlations between PA levels reported on the MAQ and pedometer indicated positive associations ranging from rho = 0.29 to 0.42 for total activity, rho = 0.13 to 0.35 for leisure activity, and rho = 0.10 to 0.26 for occupational activity. CONCLUSIONS: The 2 assessment methods correlated and were complementary rather than interchangeable. The MAQ revealed why Korean men were more active. In some subpopulations it may be necessary to assess PA domains other than leisure and to use more than 1 assessment tool to obtain a more representative picture of PA levels. PMID- 24064593 TI - Molecular interactions between serum albumin proteins and Keggin type polyoxometalates studied using luminescence spectroscopy. AB - The interaction between the plenary Keggin H3PW12O40, lacunary Keggin K7PW11O39 and the Eu(III)-substituted Keggin K4EuPW11O39 (Eu-Keggin) type polyoxometalates (POMs), and the proteins human and bovine serum albumin (HSA and BSA) was studied using steady state and time-resolved Eu(III) luminescence and tryptophan (Trp) fluorescence spectroscopy. The excitation spectrum of the Eu-Keggin POM is dominated by a ligand-to-metal charge transfer band at 291 nm. In the absence of proteins, the number of water molecules coordinated in the first coordination sphere of the Eu(III) center of Eu-Keggin was determined to be 4, indicating that Eu(III) occurs as a 1 : 1 isomer in solution. In the presence of HSA or BSA, the number of coordinated water molecules decreased to 0 and 1, respectively, suggesting interaction between the Eu-Keggin POM and the protein surface. As a result of this interaction, a five-fold increase of the hypersensitive (5)D0 -> (7)F2 transition in the luminescence intensity was observed for the Eu-Keggin-HSA complex. The association constants were calculated to be 1.5 * 10(2) M(-1) and 2.0 * 10(3) M(-1) for the Eu-Keggin-HSA and Eu-Keggin-BSA complexes, respectively. Tryptophan fluorescence quenching studies were performed and the quenching constants were calculated using a Stern-Volmer analysis. The obtained values of the quenching constants were 6.1 * 10(4) M(-1) and 2.0 * 10(6) M(-1) for the Eu-Keggin-HSA and Eu-Keggin-BSA complexes, respectively. The surface map of both proteins shows that the cavity containing the tryptophan has a positive surface potential, providing a specific binding site at the surface of albumin proteins for the negatively charged POM. PMID- 24064594 TI - Copper-catalyzed direct oxysulfonylation of alkenes with dioxygen and sulfonylhydrazides leading to beta-ketosulfones. AB - The first copper-catalyzed oxysulfonylation reaction of alkenes with dioxygen and sulfonylhydrazides for the construction of beta-ketosulfones has been developed under mild conditions without any ligand or additive. PMID- 24064595 TI - Fluidic automation of nitrate and nitrite bioassays in whole blood by dissolvable film based centrifugo-pneumatic actuation. AB - This paper demonstrates the full centrifugal microfluidic integration and automation of all liquid handling steps of a 7-step fluorescence-linked immunosorbent assay (FLISA) for quantifying nitrate and nitrite levels in whole blood within about 15 min. The assay protocol encompasses the extraction of metered plasma, the controlled release of sample and reagents (enzymes, co factors and fluorescent labels), and incubation and detection steps. Flow control is implemented by a rotationally actuated dissolvable film (DF) valving scheme. In the valves, the burst pressure is primarily determined by the radial position, geometry and volume of the valve chamber and its inlet channel and can thus be individually tuned over an extraordinarily wide range of equivalent spin rates between 1,000 RPM and 5,500 RPM. Furthermore, the vapour barrier properties of the DF valves are investigated in this paper in order to further show the potential for commercially relevant on-board storage of liquid reagents during shelf-life of bioanalytical, ready-to-use discs. PMID- 24064596 TI - Narrow and deep fano resonances in a rod and concentric square ring-disk nanostructures. AB - Localized surface plasmon resonances (LSPRs) in metallic nanostructures have been studied intensely in the last decade. Fano interference is an important way to decrease the resonance linewidth and enhance the spectral detection resolution, but realizing a Fano lineshape with both a narrow linewidth and high spectral contrast-ratio is still challenging. Here we propose a metallic nanostructure consisting of a concentric square ring-disk (CSRD) nanostructure and an outside nanorod. Fano linewidth and spectral contrast ratio can be actively manipulated by adjusting the gap between the nanorod and CSRD, and by adjusting the gap between the ring and disk in CSRD. When the gap size in CSRD is reduced to 5 nm, the quadrupolar Fano linewidth is of 0.025 eV, with a contrast ratio of 80%, and the figure of merit reaches 15. PMID- 24064597 TI - Measuring accurate body parameters of dressed humans with large-scale motion using a Kinect sensor. AB - Non-contact human body measurement plays an important role in surveillance, physical healthcare, on-line business and virtual fitting. Current methods for measuring the human body without physical contact usually cannot handle humans wearing clothes, which limits their applicability in public environments. In this paper, we propose an effective solution that can measure accurate parameters of the human body with large-scale motion from a Kinect sensor, assuming that the people are wearing clothes. Because motion can drive clothes attached to the human body loosely or tightly, we adopt a space-time analysis to mine the information across the posture variations. Using this information, we recover the human body, regardless of the effect of clothes, and measure the human body parameters accurately. Experimental results show that our system can perform more accurate parameter estimation on the human body than state-of-the-art methods. PMID- 24064598 TI - An oil fraction neural sensor developed using electrical capacitance tomography sensor data. AB - This paper presents novel research on the development of a generic intelligent oil fraction sensor based on Electrical Capacitance Tomography (ECT) data. An artificial Neural Network (ANN) has been employed as the intelligent system to sense and estimate oil fractions from the cross-sections of two-component flows comprising oil and gas in a pipeline. Previous works only focused on estimating the oil fraction in the pipeline based on fixed ECT sensor parameters. With fixed ECT design sensors, an oil fraction neural sensor can be trained to deal with ECT data based on the particular sensor parameters, hence the neural sensor is not generic. This work focuses on development of a generic neural oil fraction sensor based on training a Multi-Layer Perceptron (MLP) ANN with various ECT sensor parameters. On average, the proposed oil fraction neural sensor has shown to be able to give a mean absolute error of 3.05% for various ECT sensor sizes. PMID- 24064599 TI - Study of the effect of the strategy of heating on the mudejar church of Santa Maria in Ateca (Spain) for preventive conservation of the altarpiece surroundings. AB - The mudejar church of Santa Maria (Ateca) is valuable for its architecture and the altarpiece contained inside. Ateca is a village with continental climate characterized by cold winters and hot summers. In this paper we are interested in analysing the effect of temperature and relative humidity (RH) changes produced by the heating system on the altarpiece. Therefore, a monitoring system of 15 temperature and 15 relative humidity sensors was installed with a recording frequency of a data point per minute. The main contribution of this paper is the quantitative study of the effect of the heating system on the thermo-hygrometric parameters using statistical techniques such as ANOVA, mean daily trajectories or bivariate plots, and the proposal of an innovative dynamic contour plot. As results, the heating system produces a substantial increase (decrease) of temperature (RH) causing an hourly variation of these physical parameters detrimental to the conservation of the altarpiece, especially in its higher areas. PMID- 24064601 TI - Sensors systems for the automation of operations in the ship repair industry. AB - Hull cleaning before repainting is a key operation in the maintenance of ships. For years, a method to improve such operation has been sought by means of the robotization of techniques such as grit blasting and ultra high pressure water jetting. Despite this, it continues to be standard practice in shipyards that this process is carried out manually because the developed robotized systems are too expensive to be widely accepted by shipyards. We have chosen to apply a more conservative and realistic approach to this problem, which has resulted in the development of several solutions that have been designed with different automation and operation range degrees. These solutions are fitted with most of the elements already available in many shipyards, so the installation of additional machinery in the workplace would not be necessary. This paper describes the evolutionary development of sensor systems for the automation of the preparation process of ship hull surfaces before the painting process is performed. Such evolution has given rise to the development of new technologies for coating removal. PMID- 24064600 TI - A new position measurement system using a motion-capture camera for wind tunnel tests. AB - Considering the characteristics of wind tunnel tests, a position measurement system that can minimize the effects on the flow of simulated wind must be established. In this study, a motion-capture camera was used to measure the displacement responses of structures in a wind tunnel test, and the applicability of the system was tested. A motion-capture system (MCS) could output 3D coordinates using two-dimensional image coordinates obtained from the camera. Furthermore, this remote sensing system had some flexibility regarding lab installation because of its ability to measure at relatively long distances from the target structures. In this study, we performed wind tunnel tests on a pylon specimen and compared the measured responses of the MCS with the displacements measured with a laser displacement sensor (LDS). The results of the comparison revealed that the time-history displacement measurements from the MCS slightly exceeded those of the LDS. In addition, we confirmed the measuring reliability of the MCS by identifying the dynamic properties (natural frequency, damping ratio, and mode shape) of the test specimen using system identification methods (frequency domain decomposition, FDD). By comparing the mode shape obtained using the aforementioned methods with that obtained using the LDS, we also confirmed that the MCS could construct a more accurate mode shape (bending-deflection mode shape) with the 3D measurements. PMID- 24064602 TI - Crack orientation and depth estimation in a low-pressure turbine disc using a phased array ultrasonic transducer and an artificial neural network. AB - Stress corrosion cracks (SCC) in low-pressure steam turbine discs are serious hidden dangers to production safety in the power plants, and knowing the orientation and depth of the initial cracks is essential for the evaluation of the crack growth rate, propagation direction and working life of the turbine disc. In this paper, a method based on phased array ultrasonic transducer and artificial neural network (ANN), is proposed to estimate both the depth and orientation of initial cracks in the turbine discs. Echo signals from cracks with different depths and orientations were collected by a phased array ultrasonic transducer, and the feature vectors were extracted by wavelet packet, fractal technology and peak amplitude methods. The radial basis function (RBF) neural network was investigated and used in this application. The final results demonstrated that the method presented was efficient in crack estimation tasks. PMID- 24064603 TI - A dry membrane protection technique to allow surface acoustic wave biosensor measurements of biological model membrane approaches. AB - Model membrane approaches have attracted much attention in biomedical sciences to investigate and simulate biological processes. The application of model membrane systems for biosensor measurements is partly restricted by the fact that the integrity of membranes critically depends on the maintenance of an aqueous surrounding, while various biosensors require a preconditioning of dry sensors. This is for example true for the well-established surface acoustic wave (SAW) biosensor SAM(r)5 blue. Here, a simple drying procedure of sensor-supported model membranes is introduced using the protective disaccharide trehalose. Highly reproducible model membranes were prepared by the Langmuir-Blodgett technique, transferred to SAW sensors and supplemented with a trehalose solution. Membrane rehydration after dry incorporation into the SAW device becomes immediately evident by phase changes. Reconstituted model membranes maintain their full functionality, as indicated by biotin/avidin binding experiments. Atomic force microscopy confirmed the morphological invariability of dried and rehydrated membranes. Approximating to more physiological recognition phenomena, the site directed immobilization of the integrin VLA-4 into the reconstituted model membrane and subsequent VCAM-1 ligand binding with nanomolar affinity were illustrated. This simple drying procedure is a novel way to combine the model membrane generation by Langmuir-Blodgett technique with SAW biosensor measurements, which extends the applicability of SAM(r)5 blue in biomedical sciences. PMID- 24064605 TI - Crop biometric maps: the key to prediction. AB - The sustainability of agricultural production in the twenty-first century, both in industrialized and developing countries, benefits from the integration of farm management with information technology such that individual plants, rows, or subfields may be endowed with a singular "identity." This approach approximates the nature of agricultural processes to the engineering of industrial processes. In order to cope with the vast variability of nature and the uncertainties of agricultural production, the concept of crop biometrics is defined as the scientific analysis of agricultural observations confined to spaces of reduced dimensions and known position with the purpose of building prediction models. This article develops the idea of crop biometrics by setting its principles, discussing the selection and quantization of biometric traits, and analyzing the mathematical relationships among measured and predicted traits. Crop biometric maps were applied to the case of a wine-production vineyard, in which vegetation amount, relative altitude in the field, soil compaction, berry size, grape yield, juice pH, and grape sugar content were selected as biometric traits. The enological potential of grapes was assessed with a quality-index map defined as a combination of titratable acidity, sugar content, and must pH. Prediction models for yield and quality were developed for high and low resolution maps, showing the great potential of crop biometric maps as a strategic tool for vineyard growers as well as for crop managers in general, due to the wide versatility of the methodology proposed. PMID- 24064604 TI - Static hyperspectral fluorescence imaging of viscous materials based on a linear variable filter spectrometer. AB - This paper presents a low-cost hyperspectral measurement setup in a new application based on fluorescence detection in the visible (Vis) wavelength range. The aim of the setup is to take hyperspectral fluorescence images of viscous materials. Based on these images, fluorescent and non-fluorescent impurities in the viscous materials can be detected. For the illumination of the measurement object, a narrow-band high-power light-emitting diode (LED) with a center wavelength of 370 nm was used. The low-cost acquisition unit for the imaging consists of a linear variable filter (LVF) and a complementary metal oxide semiconductor (CMOS) 2D sensor array. The translucent wavelength range of the LVF is from 400 nm to 700 nm. For the confirmation of the concept, static measurements of fluorescent viscous materials with a non-fluorescent impurity have been performed and analyzed. With the presented setup, measurement surfaces in the micrometer range can be provided. The measureable minimum particle size of the impurities is in the nanometer range. The recording rate for the measurements depends on the exposure time of the used CMOS 2D sensor array and has been found to be in the microsecond range. PMID- 24064606 TI - Activation of carbon-hydrogen bonds and dihydrogen by 1,2-CH-addition across metal-heteroatom bonds. AB - The controlled conversion of hydrocarbons to functionalized products requires selective C-H bond cleavage. This perspective provides an overview of 1,2-CH addition of hydrocarbons across d(0) transition metal imido complexes and compares and contrasts these to examples of analogous reactions that involve later transition metal amide, hydroxide and alkoxide complexes with d(6) and d(8) metals. PMID- 24064607 TI - Sharing new ideas and giving them wings: introducing innovation reports. PMID- 24064608 TI - Why medical educators should continue to focus on clinical outcomes. PMID- 24064609 TI - In reply. PMID- 24064610 TI - An ethical argument for preserving medical trainee authorship. PMID- 24064611 TI - We must make the cost of medical education reasonable for everyone. PMID- 24064612 TI - In reply. PMID- 24064613 TI - Prediction bias in the MCAT exam. PMID- 24064614 TI - Desperately seeking Flexner: time to reemphasize basic science in medical education. PMID- 24064616 TI - Medicine and the arts. Aesthetics and the academic medical center by Joseph J Fins. Commentary. PMID- 24064618 TI - 2013 humanism in medicine essay contest: third place: the good doctor. PMID- 24064619 TI - What about the soul? PMID- 24064620 TI - AM last page: avoiding five common pitfalls of experimental research in medical education. PMID- 24064622 TI - Integrated analyses of microRNA and mRNA expression profiles in aggressive papillary thyroid carcinoma. AB - microRNAs (miRNAs) are involved in the pathogenesis of diverse human cancers through its target genes, including papillary thyroid cancer (PTC). However, there are few studies regarding associations between clinicopathological features of PTC with the expression of specific miRNAs and its potential target genes. In the present study, analysis of miRNA was integrated with mRNA expression profiles in aggressive PTC. miRNA and gene expression arrays were used to identify a subset of differentially expressed miRNAs and mRNAs between aggressive and non aggressive PTCs. These miRNAs and mRNAs were further validated by qPCR in a cohort of 20 PTCs with extrathyroidal invasion and/or distant metastases, and 20 PTCs with no extrathyroidal invasion. The target of these miRNAs was determined by luciferase reporter and bioinformatic analysis. The miRNA arrays identified 14 upregulated miRNAs and 10 downregulated miRNAs in aggressive compared with non aggressive PTCs. Significant miRNA deregulation was confirmed in the validation cohort, with upregulation of miR-146b-5p and miR-221/222 and downregulation of miR-16 and miR-613 in aggressive PTCs. The gene arrays identified 2000 differentially expressed genes, in which TIMP3, ZNFR3, FN1 and ITGA2 were observed to be target genes inversely correlated with miR-221/222, miR-146b-5p, miR-613 and miR-16, respectively. The results of the present study indicated the potential importance of miR-221/222, miR-146b-5p, miR-16 and miR-613 in determining the aggressive properties of PTC by targeting TIMP3, ZNFR3, FN1 and ITGA2, respectively. Additional studies should be conducted to confirm the results. PMID- 24064623 TI - Editor's commentary. PMID- 24064621 TI - An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions. AB - Oncogenic subtypes in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are used for risk stratification. However, a significant number of BCP ALL patients are still genetically unassigned. Using array-comparative genomic hybridization in a selected BCP-ALL cohort, we characterized a recurrent V(D)J mediated intragenic deletion of the ERG gene (ERG(del)). A breakpoint-specific PCR assay was designed and used to screen an independent non-selected cohort of 897 children aged 1-17 years treated for BCP-ALL in the EORTC-CLG 58951 trial. ERG(del) was found in 29/897 patients (3.2%) and was mutually exclusive of known classifying genetic lesions, suggesting that it characterized a distinct leukemia entity. ERG(del) was associated with higher age (median 7.0 vs. 4.0 years, P=0.004), aberrant CD2 expression (43.5% vs. 3.7%, P<0.001) and frequent IKZF1 Delta4-7 deletions (37.9% vs. 5.3%, P<0.001). However, ERG(del) patients had a very good outcome, with an 8-year event-free survival (8-y EFS) and an 8-year overall survival of 86.4% and 95.6%, respectively, suggesting that the IKZF1 deletion had no impact on prognosis in this genetic subtype. Accordingly, within patients with an IKZF1 Delta4-7 deletion, those with ERG(del) had a better outcome (8-y EFS: 85.7% vs. 51.3%; hazard ratio: 0.16; 95% confidence interval: 0.02-1.20; P=0.04). These findings have implications for further stratification including IKZF1 status. PMID- 24064624 TI - Science and evidence: separating fact from fiction. AB - Evidence-based medicine (EBM) is the integration of individual clinical expertise with the best available research evidence from systematic research and the patient's values and expectations. A hierarchy of evidence can be used to assess the strength upon which clinical decisions are made. The efficient approach to finding the best evidence is to identify systematic reviews or evidence-based clinical practice guidelines. Respiratory therapies that evidence supports include noninvasive ventilation for appropriately selected patients, lung protective ventilation, and ventilator discontinuation protocols. Evidence does not support use of weaning parameters, albuterol for ARDS, and high frequency oscillatory ventilation for adults. Therapy with equivocal evidence includes airway clearance, selection of an aerosol delivery device, and PEEP for ARDS. Although all tenets of EBM are not universally accepted, the principles of EBM nonetheless provide a valuable approach to respiratory care practice. PMID- 24064625 TI - The scientific basis for protocol-directed respiratory care. AB - As defined by the American Association for Respiratory Care, respiratory care protocols are "guidelines, usually written in algorithmic form, for providing respiratory therapy services." The need for protocols has been framed by the frequent occurrence of misallocation of respiratory care, consisting both of over ordering (ie, prescribing respiratory care that is unlikely to confer benefit) and under-ordering services (ie, failing to prescribe services that would be expected to offer benefit). In this context, the current paper reviews available studies regarding the effectiveness of respiratory care protocols. Such studies can be organized into those assessing respiratory care treatments in the ICU, and those addressing non-ICU respiratory care. In the ICU, studies have addressed sampling both ABGs and liberating patients from mechanical ventilation; in the latter activity, multiple concordant randomized controlled trials have shown that weaning protocols implemented by respiratory therapists and/or nurses can accelerate patients' liberation from mechanical ventilation, with shorter stay and lower cost. Outside of the ICU, studies have addressed the effectiveness of respiratory care protocols in guiding the use of supplemental oxygen, bronchopulmonary hygiene, bronchodilator use, and of assessing patient for step down unit placement. All such studies have shown that respiratory care protocols are effective. Furthermore, 2 concordant randomized controlled trials have shown that comprehensive respiratory care protocol programs can enhance the allocation of respiratory care services, with concomitant savings and no excess adverse outcomes. Overall, while the overwhelming weight of available evidence supports the effectiveness of respiratory care protocols, gaps in current understanding remain, especially regarding settings outside the acute care hospital (eg, geriatric care, palliative care, and extended care facilities). In the same spirit that engendered the Sugarloaf Conference to assess the effectiveness of respiratory care, further assessment of the effectiveness of respiratory care protocols is encouraged and expected. PMID- 24064626 TI - Airway clearance therapy: finding the evidence. AB - Disease processes can impair ciliary function, alter secretion production and mucus rheology, and interfere with the cough reflex. Airway clearance therapy has been a cornerstone of therapy aimed at minimizing the devastating effects of airway obstruction, infection, and inflammation due to mucus stasis on the conducting airways and lung parenchyma. Although challenges to performing clinical studies evaluating the effectiveness of airway clearance therapeutic modalities exist, resources are available in the literature. In addition to device evaluations and original clinical research, the expert opinion, systematic reviews, and evidence-based practice guidelines can be found. These tools can be used to develop protocols and pathways to guide our practice. Monitoring and reporting patient, process, and financial outcomes are essential steps germane to the implementation of evidence-based care. PMID- 24064627 TI - Evidence for oxygen use in the hospitalized patient: is more really the enemy of good? AB - Oxygen in arguably one of the most frequently utilized drugs in modern healthcare, but is often administered to patients at caregivers' discretion with scant evidence as to its efficacy or safety. Although oxygen is administered for varied medical conditions in the hospital setting, published literature supports the use of oxygen to reverse hypoxemia, for trauma victims with traumatic brain injury and hemorrhagic shock, for resuscitation during cardiac arrest, and for carbon monoxide poisoning. Oxygen should be titrated to target an S(pO2) of 94 98%, except with carbon monoxide poisoning (100% oxygen), ARDS (88-95%), those at risk for hypercapnia (S(pO2) 88-92%), and premature infants (S(pO2) 88-94%). Evidence for use with other conditions for which oxygen is administered relies on anecdotal experiences, case reports, or small, underpowered studies. Definitive conclusions for oxygen use in these conditions where efficacy and/or safety are uncertain will require large randomized controlled clinical trials. PMID- 24064628 TI - Too passive to prevent ventilator-associated pneumonia. PMID- 24064629 TI - Endotracheal suctioning may or may not have an impact, but it does depend on what you measure! PMID- 24064630 TI - Long-term oxygen therapy: in a perfect world. PMID- 24064631 TI - SpCO: let's not throw the baby out with the bath water. PMID- 24064632 TI - SpCO: let's not throw the baby out with the bath water--reply. PMID- 24064633 TI - SpCO: let's not throw the baby out with the bath water--reply. PMID- 24064634 TI - Anxiety disorders in patients with COPD. PMID- 24064635 TI - Anxiety disorders in patients with COPD--reply. PMID- 24064636 TI - Rejection of a manuscript. PMID- 24064637 TI - Trends in biomedical communication. PMID- 24064638 TI - Translocation of gut flora and its role in sepsis. AB - Bacterial translocation is the invasion of indigenous intestinal bacteria through the gut mucosa to normally sterile tissues and the internal organs. Sometimes instead of bacteria, inflammatory compounds are responsible for clinical symptoms as in systemic inflammatory response syndrome (SIRS). The difference between sepsis and SIRS is that pathogenic bacteria are isolated from patients with sepsis but not with those of SIRS. Bacterial translocation occurs more frequently in patients with intestinal obstruction and in immunocompromised patients and is the cause of subsequent sepsis. Factors that can trigger bacterial translocation from the gut are host immune deficiencies and immunosuppression, disturbances in normal ecological balance of gut, mucosal barrier permeability, obstructive jaundice, stress, etc. Bacterial translocation occurs through the transcellular and the paracellular pathways and can be measured both directly by culture of mesenteric lymph nodes and indirectly by using labeled bacteria, peripheral blood culture, detection of microbial DNA or endotoxin and urinary excretion of non metabolisable sugars. Bacterial translocation may be a normal phenomenon occurring on frequent basis in healthy individuals without any deleterious consequences. But when the immune system is challenged extensively, it breaks down and results in septic complications at different sites away from the main focus. The factors released from the gut and carried in the mesenteric lymphatics but not in the portal blood are enough to cause multi-organ failure. Thus, bacterial translocation may be a promoter of sepsis but not the initiator. This paper reviews literature on the translocation of gut flora and its role in causing sepsis. PMID- 24064639 TI - First case series of emerging Rickettsial neonatal sepsis identified by polymerase chain reaction-based deoxyribonucleic acid sequencing. AB - PURPOSE: To detect and identify the aetiological agent in the peripheral blood from the cases of neonatal sepsis. MATERIALS AND METHODS: Four neonates from geographically different regions of South India presented with signs of neonatal sepsis and all the routine clinical and laboratory investigations were performed. Blood culture by Bac T Alert 3D was negative. To establish the aetiology, polymerase chain reaction (PCR) for eubacterial genome and subsequent amplification with Gram positive and Gram negative primers were performed followed by deoxyribonucleic acid (DNA) sequencing. RESULTS: PCR for the detection of eubacterial genome was positive in all the four neonates and further amplification with designed Gram positive and Gram negative primers revealed the presence of Gram negative bacteria. The amplicons were identified as Orientia tsutsugamushi in three neonates and Coxiella burnetti in the other neonate. Multalin analysis was done to further characterise the strain variation among the three strains. CONCLUSION: PCR-based DNA sequencing is a rapid and reliable diagnostic tool to identify the aetiological agents of neonatal sepsis. This is the first case series of emerging Rickettsial neonatal sepsis in India . PMID- 24064640 TI - Genotypes of hepatitis C virus in the Indian sub-continent: a decade-long experience from a tertiary care hospital in South India. AB - BACKGROUND: Hepatitis C virus (HCV) is a leading cause of chronic liver disease (CLD) that can progress to cirrhosis and hepatocellular carcinoma. Genotypes of HCV can vary in pathogenicity and can impact on treatment outcome. OBJECTIVES: To study the different genotypes among patients with HCV related CLD attending a tertiary care hospital in south India during 2002-2012. STUDY DESIGN: Study subjects were those referred to clinical virology from the liver clinic. Genotyping was performed using the genotype specific core primers in nested polymerase chain reaction (PCR), 5' non-coding regions based PCR- restriction fragment length polymorphism and NS5B sequencing methods. With the latter method, obtained sequences were compared with published GenBank sequences to determine the genotype. RESULTS: Of the 451 samples tested, HCV genotype 3 was found to be the most predominant (63.85%). Other genotypes detected were genotype 1 (25.72%), genotype 2 (0.002%), genotype 4 (7.5%) and genotype 6 (2.7%). Genotype 3 was the common genotype in patients from Eastern India while genotype 1 and 4 were mainly seen in South Indian patients. Genotype 6 was seen exclusively in patients from North-Eastern India. Two other patients were infected with recombinants of genotype 1 and 2. CONCLUSIONS: In this study spanning a decade, HCV genotype 3 and genotype 1 were found to be the predominant genotypes in the Indian sub continent. Genotype 4 and genotype 6 appeared to show some geographic restriction. A continued monitoring of HCV genotypes is essential for the optimum management of these chronically infected patients. In addition, knowledge of circulating genotypes could impact on future vaccine formulations. PMID- 24064641 TI - A study of changing trends of prevalence and genotypic distribution of hepatitis C virus among high risk groups in North India. AB - PURPOSE: Hepatitis C virus (HCV) has emerged as a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. There is a great variability in HCV's geographical presence, transmission routes, genotypic distribution etc., in studied populations. We undertook this study in a North Indian hospital on patients of chronic liver disease to observe any emerging trend in risk groups, transmission patterns, genotypic distribution of the virus in this geographical region and its correlation with viral load. MATERIALS AND METHODS: There were 54 anti-HCV positive patients including 31 HCV Ribonucleic acid (RNA) positive patients were included in the study. HCV genotyping was carried out by restriction fragment length polymorphism (RFLP) followed by direct sequencing of the core region. Viral load estimation was carried out by Taqman real time polymerase chain reaction system. RESULTS: In 45/54 (83.3%) anti-HCV positive patients, iatrogenic procedures were responsible for transmission with blood transfusion alone responsible in 36/54 (67%). Genotype 3 was observed to be the commonest type found in all risk groups followed by type 1 and 2. Subtype 3b (35.5%) was found more prevalent than subtype 3a. A higher frequency of subtype 1b (19.4%) was also seen. Genotype 1 was associated with a significantly higher viral load compared to genotypes 3 and 2. No significant difference was observed in the biochemical profile among the three genotypes except for the levels of the enzyme, aspartate aminotransferase (AST). CONCLUSIONS: Iatrogenic procedures, especially contaminated blood transfusion etc., still contributes significantly to the pool of HCV infection. Genotype 3 is the predominant genotype in North India, though the subtype distribution within genotype 3 may be changing. The association of severe liver disease is significantly more with genotype 1 as evidenced by higher viral load and deranged AST levels. PMID- 24064642 TI - Mutation analysis of hepatitis B virus reverse transcriptase region among untreated chronically infected patients in Ahvaz city (South-West of Iran). AB - BACKGROUND: It has been revealed that mutations can occur spontaneously and naturally in HBV reverse transcriptase (RT) region among untreated patients. These HBV mutants pre-exist as minor viral population in naive patients and can emerge as major viral population, conferring drug resistance and treatment failure. OBJECTIVES: The aim of this study was to investigate and identify prevalent mutations of RT region of hepatitis B virus genome in patients with chronic hepatitis B (CHB) untreated with antiviral drugs in South-West of Iran. MATERIALS AND METHODS: A total of 45 cases with CHB who did not receive the treatment of lamivudine and any other antivirus drugs within the last one year were randomly chosen. After sample collection and HBV DNA extraction, RT region was amplified by polymerase chain reaction (PCR). Then PCR products were sequenced and HBV RT region mutations and amino acid changes were analyzed either manually or using web-based programs, on the basis of comparison of the obtained sequences with a set of HBV reference sequences. RESULTS: A total of 23 (51.1%) mutations and amino acid changes were detected in studied 45 untreated patients. Of these, 3 (6.6%) patients had primary resistance mutation (rtM204I, rtA181T and rtA181S) and 20 (44.4%) patients had secondary resistance mutations. CONCLUSION: High prevalence of mutations was found in HBV RT region of untreated patients. Most of these mutations were associated with resistance to adefovir and one patient had primary resistance mutation to lamivudine. Awareness of these resistance patterns might help in the antiviral therapy and for predicting clinical outcomes. PMID- 24064643 TI - Diagnostic appraisal of simultaneous application of two nested PCRs targeting MPB64 gene and IS6110 region for rapid detection of M. tuberculosis genome in culture proven clinical specimens. AB - BACKGROUND: Early diagnosis of tuberculosis is critical for its effective management and prevention. Several gene amplification methods are used in the detection of tubercle bacilli from clinical specimens. MPB64 gene and IS6110 region have been identified as potential gene targets for the specific detection of Mycobacterium tuberculosis from direct clinical specimens. OBJECTIVE: The present study was conducted to evaluate the diagnostic utility of simultaneous application of two nested polymerase chain reaction (nPCRs) targeting MPB64 and IS6110 region for the detection of M. tuberculosis genome. MATERIALS AND METHODS: A total of 100 and 354 clinical specimens from the control group and clinically suspected tuberculosis patients, respectively, were included in the study. nPCRs targeting MPB64 and IS6110 region were performed. RESULTS AND CONCLUSION: All of the 100 clinical specimens from the control group were negative for both nPCRs. Out of the 354 clinical specimens, 339 were positive for both culture and nPCRs, 10 and 5 were positive for culture, and nPCR targeting IS6110 and MPB64 regions, respectively. To conclude, nPCRs targeting MPB64 and IS6110 region are reliable and specific targets when applied simultaneously on clinical specimens to attain 100% sensitivity for the detection of M. tuberculosis genome. PMID- 24064644 TI - Evaluation of multiplex polymerase chain reaction utilising multiple targets in Mycobacterium tuberculosis direct test negative but culture positive cases: a potential method for enhancing the diagnosis of tuberculosis. AB - PURPOSE: To evaluate multiplex Polymerase Chain Reaction (MPCR) utilising multiple targets (IS6110, Protein b [Pab] and MPB64 genes) in Mycobacterium tuberculosis Direct Test (MTD) negative but culture positive cases and comparison of MPCR with Real-Time polymerase chain reaction (RT-PCR) for diagnosis of tuberculosis. MATERIALS AND METHODS: MPCR was carried out on 28 culture positive sputum samples. Out of 28 culture positive samples, 17 were originally reported, as MTD test negative and 11 were MTD test positive, respectively. The results of MPCR were compared with RT-PCR. To check the specificity of the tests, MPCR and RT-PCR were also evaluated with 16 non-tuberculous mycobacterial (NTM) isolates. RESULTS: Out of 28 culture positive sputum samples, MPCR was positive in all 28/28 samples, whereas RT-PCR was positive in 27/28 samples and MTD test was originally tested positive in six sputum samples and on repeating MTD testing, five more sputum samples were positive and thus total number of MTD positive were 11/28 sputum samples, respectively. All the tests were negative on evaluation with all the 16 NTMs, thus giving specificity of 100% to all the tests; sensitivity of MPCR, RT-PCR and MTD tests were 100%, 96.42% and 39.28%, respectively, in these specifically selected samples. CONCLUSIONS: MPCR may be an important tool in the rapid diagnosis of tuberculosis especially in disease endemic, resource limited countries. PMID- 24064645 TI - Study of the role of efflux pump in ciprofloxacin resistance in Salmonella enterica serotype Typhi. AB - PURPOSE: There are increasing reports on failure of clinical response to ciprofloxacin in typhoid fever despite the strain being sensitive to drug in in vitro using standard guidelines and showing mutations in DNA gyrase. But this increased MIC and clinical failures with ciprofloxacin are not always co-related with mutations presently identified in gyrA and parC genes. This shows that there may be other mechanisms such as an active drug efflux pump responsible as has been shown in other Enterobacteriaceae. This study was carried out to determine the role of efflux pump in Salmonella Typhi isolates. MATERIALS AND METHODS: Total 25 already characterized nalidixic acid sensitive and nalidixic acid resistant S. Typhi strains with different range of ciprofloxacin MIC were included to study the role of efflux pump in the presence of CCCP (efflux pump inhibitor). For genotypic characterization, the entire acrR gene was sequenced to confirm the presence of any mutation in the gene. RESULTS: The MIC of ciprofloxacin remained same in the presence and absence of CCCP in the studied strains and no significant mutations were found in the acrR gene in any of the isolates studied. CONCLUSIONS: No role of efflux pump in ciprofloxacin resistance was found in strains studied. There is a need to explore further mechanism of ciprofloxacin resistance in Salmonella Typhi. PMID- 24064646 TI - Unusual causes of fungal rhinosinusitis: a study from a tertiary care centre in South India. AB - PURPOSE: The frequency of mycotic infections of the nose and paranasal sinuses has been increasing over the past three decades. Apart from the common causes of fungal rhinosinusitis such as Aspergillus species and Penicillium species, there have been reports of rare and unusual fungi isolated from India and other countries. OBJECTIVE: The objective of this study is to find out the prevalence of fungal infections of the nose and paranasal sinuses caused by unusual fungal isolates at a tertiary care teaching hospital in South India. MATERIALS AND METHODS: Duration of the study period was from April 2009 to March 2010. Specimens were collected from the nose and paranasal sinuses of all clinically and radiologically diagnosed cases of rhinosinusitis. All the clinical specimens were processed by standard methods for fungal culture. This included initial screening by 10% potassium hydroxide, inoculation of the specimen onto Sabouraud dextrose agar and incubation at 25 degrees C and 37 degrees C, followed by slide culture and other special techniques wherever necessary. Histopathological examination was also performed for the specimens. RESULTS: A total of 60 specimens were received for fungal culture from cases of rhinosinusitis during the period, out of which 45 showed no growth. There were nine cases of Aspergillus flavus, 1 each of Aspergillus fumigatus and Penicillium species. The rest four specimens grew rare fungal isolates, i.e. Acremonium sp., Scedosporium apiospermun, Cladosporium cladosporioides and Lasiodiplodia theobromae. Histopathological findings were also positive for these four cases. CONCLUSION: Apart from the common causes, unusual fungal pathogens were isolated from cases of rhinosinusitis during the study period, which is in accordance with similar reports from other parts of India and some other countries. PMID- 24064647 TI - Class 1 integrons contributes to antibiotic resistance among clinical isolates of Escherichia coli producing extended-spectrum beta-lactamases. AB - OBJECTIVES: The objective of this study is to determine the prevalence of antibiotic resistance factors, including the production of extended-spectrum beta lactamases (ESBLs) and the presence of class 1 integrons among Escherichia coli isolated from clinical specimens. MATERIALS AND METHODS: Bacterial species identification was performed using a VITEK-2 system (VITEK2 GN-card; bioMerieux, France). Antimicrobial susceptibility testing was determined using the disk diffusion method according to the 2010 Clinical and Laboratory Standards Institute guidelines. Polymerase chain reaction (PCR) was used to detect integrons and amplify variable regions of the bla TEM, bla SHV and bla CTX-M genes. Gene cassettes were detected by deoxyribonucleic acid sequencing. RESULTS: In this study, 58% (100/172) of clinical E. coli isolates were identified as ESBL producers. We found that 90% of the ESBL-producing E. coli isolates harbored the blaCTX-M gene, whereas only 59% and 32% possessed the blaTEM and blaSHV genes respectively. The presence of class 1 integrons was based on the detection of the integrase gene by PCR. A total of 69% of the ESBL-producing isolates were integron-positive. Resistance to 10 antibiotics, including quinolones, sulfonamides and beta-lactam/enzyme inhibitors, was significantly higher in the class 1 integron-positive isolates (P < 0.05). The occurrence of class 1 integrons in blaTEM , blaSHV and blaCTX-M gene carriers was 72.9%, 84.4% and 68.9%, respectively. Class 1 integrons were detected in 61.5% of the isolates with only one ESBL genotype, but in 69.0% and 92.3% of the isolates with two or three different ESBL genotypes, respectively. CONCLUSIONS: Our findings indicate that clinical strains of bacteria with multiple ESBL genotypes may have greater opportunities to carry class 1 integrons. PMID- 24064648 TI - Mortality due to septicemia at a level 1 Indian trauma care centre: an epidemiological analysis. AB - Trauma contributes to a significant proportion of mortality and morbidity in the economically productive age group of 15-45 years. Infections are the second most important cause of death in trauma patients after head injury. Despite advances in trauma care, deaths due to septicemia are increasing. An epidemiological study of septicemia-related deaths were conducted at a level 1 Trauma Centre from January 2011 to December 2011. A total of 201 patients died due to suspected septicemia. The average age of the deceased trauma victims was 35.9 years and the median length of stay in hospital before death was 27 days. In our study, a high proportion of patients had grown pathogens in significant counts from respiratory specimens (36%) and blood (23%) during ante-mortem period, which may have contributed to their fatal outcome. Infections are one of the most common and fatal complications following trauma and complicate the recovery of a significant number of injured patients. PMID- 24064649 TI - Anaerobes in nosocomial and community acquired pleural infections. AB - Anaerobes are important causes of pleural space infections. The aim of the study is to evaluate the role of the anaerobic bacteria in pleural infections. The study involved 278 consecutive clinical samples sent to the Clinical Microbiology Laboratory of Tertiary Chest Hospital. Anaerobes were isolated in 39 community acquired and five nosocomial cases out of 278 anaerobic cultivations (15.8%). Total of 56 anaerobe strains were identified and 21 aerobes were accompanied to anaerobic isolates. Aerobe isolates were associated with anaerobic microorganisms in 19 cases (43.2%). Bacteroides species (21.4%) and Pseudomonas aeruginosa (33.3%) were the most common anaerobic and aerobic isolates. PMID- 24064650 TI - Mutation in katG315 is, possibly, a good prognostic marker for treatment with second-line drugs in multi-drug resistant tuberculosis: a preliminary study. AB - The aim of this study was to explore baseline data, laboratory and molecular analyses to determine if any could serve as potential prognostic marker(s) for treatment response to second line tuberculosis regimens. Of a total number of 50 multi-drug resistant tuberculosis (MDR-TB) patients starting second-line drug MDR TB treatment in Iraq, only 21 showed treatment adherence and thus, included in this study. Response to treatment was monitored for 11 months by sputum microscopy and culture. We explored baseline data, laboratory and molecular analyses to determine if any could serve as potential prognostic marker(s) for treatment response. Highly significant association (P = 0.019) was detected between mutations in katG315 codon and good response to second-line anti-TB drugs. Spoligotyping and mycobacterial interspersed repetitive unit variable number tandem repeat confirmed that katG315-mutatnt isolates were genotypically unrelated. The katG315 mutation is a potential prognostic marker for treatment response to second-line anti-tuberculosis drugs. One possible explanation of our results is that the katG315-mutants are sensitive to bacterial killing by "oxidative killing.". PMID- 24064651 TI - Rhinoentomophthoromycosis: a rare case report. AB - Entomophthoromycosis is chronic granulomatous fungal infection with varied presentation as subcutaneous,mucocutaneous and visceral infections. The majority of the subcutaneous infection caused by entomophthoralean fungi involves Basidiobolus spp, C. coronatus, or C. incongruous. A case of rhinoentomophthoromycosis in an immunocompetent male involving maxillary sinus and nose is presented. The patient was clinically diagnosed as malignancy of nose but microscopy and histopathology of the aspirate clinched the diagnosis. The patient responded to antifungal therepy. PMID- 24064652 TI - Subcutaneous dirofilariasis. AB - Subcutaneous Human Dirofilariasis is an uncommon zoonotic infection caused by Dirofilariarepens. The reports of this infection in humans in India are limited, although increasingly being reported worldwide. We report a case of Dirofilariasis with subcutaneous presentation from the state of Meghalaya and to emphasize the importance of considering this entity in the differential diagnosis of patients presenting with subcutaneous nodules. PMID- 24064653 TI - Cupriavidus pauculus (Ralstonia paucula) concomitant meningitis and septicemia in a neonate: first case report from India. AB - Ralstonia paucula (formerly classified as CDC (Centre for Disease Control) group IVc-2, Wautersia paucula; recently renamed as Cupriavidus pauculus) is an environmental Gram-negative bacillus isolated from water sources and can cause serious human infections. Patients recover bacteriologically indicating low virulence. A total of 32 cases have been reported world-wide, but no isolation has ever been reported from cerebrospinal fluid or in India. The first case of R. paucula meningitis and septicemia is being reported here along with the brief summary of cases reported world-wide. PMID- 24064654 TI - Unusual manifestation of Salmonella enterica serotype enteritidis infection in a case of Langerhans cell histiocytosis. AB - Nontyphoidal Salmonella (NTS) are established foodborne pathogens, most commonly reported in cases of gastroenteritis. These pathogens are however, increasingly being implicated in cases of bacteraemia and other extraintestinal manifestations. We report a case of a scalp abscess due to Salmonella enterica serotype Enteritidis, which is a serotype of NTS, in a child suffering from a haematologic malignancy. The child was on steroid and anticancer chemotherapy and developed the abscess secondary to bacteraemia with Salmonella Enteritidis. The abscess was drained and resolved following a course of intravenous antibiotic treatment. PMID- 24064655 TI - Infected primary hydatid cyst located in the Sartorius muscle. AB - Primary intramuscular hydatid cyst should be considered for the differential diagnosis of cystic soft tissue masses especially in the endemic areas though primary muscular hydatidosis is a rare clinical entity. We aimed to report the case of a 30-year-old female patient with infected primary intramuscular hydatid cyst located in the sartorius muscle. PMID- 24064656 TI - Occurrence and characterisation of CTX-M enzymes in Enterobacteriaceae isolated from intensive care units of a Turkish university hospital. PMID- 24064657 TI - Clinical and laboratory evidence of Trichomonas vaginalis infection among women of reproductive age in rural area of Malwa region of Punjab. PMID- 24064658 TI - Comparison of results obtained with different volumes of whole blood in human immunodeficiency virus-1 deoxyribonucleic acid polymerase chain reaction technique. PMID- 24064659 TI - Weak positive band by immunochromatographic test in pregnancy-associated malaria: a diagnostic dilemma. PMID- 24064660 TI - In-vitro susceptibility to colistin and tigecycline in New Delhi metallo-beta lactamase-1 producing Enterobacteriaceae. PMID- 24064661 TI - Prevalence of extended-spectrum-beta-lactamase and metallo-beta-lactamase producing multi drug resistance gram- negative bacteria from urinary isolates. PMID- 24064662 TI - First case of acute haemorrhagic leucoencephalitis following Plasmodium vivax infection: comment. PMID- 24064663 TI - Vitamin D binding protein plays an important role in the progression of endometriosis. AB - Endometriosis, characterized by the growth of the endometrial gland and stroma outside the uterine cavity, is a gynecological disorder affecting 6-10% of women of reproductive age. However, the pathogenesis of endometriosis and the molecular mechanisms involved in the progression of this disease remain to be clarified. Therefore, in this study two-dimensional gel electrophoresis (2-DE) combined with mass spectrometry (MS) were applied to explore endometrial proteins with a role in the progression of endometriosis. Expression of global proteins in ectopic endometrial tissue (n=13; endometriosis group) was compared with that of the normal endometrial tissue (n=6; control group). Sixteen differently expressed proteins, including Vitamin D binding protein (DBP), with various functions were primarily identified in the ectopic endometrial tissue. DBP was confirmed to be significantly increased in the ectopic endometrial tissue compared with that in the normal endometrial tissue (P<0.05). Results of the present study therefore showed that DBP may play an important role in the progression of endometriosis. PMID- 24064664 TI - Silencing of RegIV by shRNA causes the loss of stemness properties of cancer stem cells in MKN45 gastric cancer cells. AB - Regenerating islet-derived family member 4 (RegIV) is overexpressed in several types of tumours, including pancreatic and gastric cancer (GC). However, the role it plays in gastric cancer stem cells (GCSCs) remains unknown. The present study tested the hypothesis that the silencing of RegIV by shRNA in GC cells may cause the loss of their stemness properties, indicating the inhibition of growth, proliferation and increased sensitivity to chemoradiation-induced cell death. MKN45 poorly differentiated human GC cells were propagated as mammospheres in stem cell culture conditions. Mammospheres were identified as CSCs using generally acknowledged CSC markers such as CD44. A panel of 21-nucleotide shRNAs were designed to target RegIV gene expression. Several shRNA constructs were identified that led to significant reduction in RegIV mRNA expression. Furthermore, the stemness properties of control mammospheres and RegIV knockdown mammospheres were compared by tumourigenicity assay in vivo and plate colony formation assay in vitro. Finally, we evaluated the treatment response in both mammospheres which underwent chemoradiation. The knockdown expression of RegIV by shRNA deprived CSCs of their stemness properties and increased the effectiveness of cell killing following chemoradiation. Inhibition of endogenous RegIV expression may be a new therapeutic strategy for human GC. PMID- 24064665 TI - Thermoresponsive poly(ionic liquid) hydrogels. AB - A new series of LCST ILs have been copolymerised with crosslinkers of varying length to afford the first ever thermoresponsive poly(ionic liquid)-based hydrogels. These hydrogels exhibit surprisingly broad LCST and volume transition behaviour compared to standard thermoresponsive gels and linear ILs. PMID- 24064666 TI - Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology. AB - Resolution of severe Respiratory Syncytial Virus (RSV)-induced bronchiolitis is mediated by alternatively activated macrophages (AA-Mphi) that counteract cyclooxygenase (COX)-2-induced lung pathology. Herein, we report that RSV infection of 5-lipoxygenase (LO)(-/-) and 15-LO(-/-) macrophages or mice failed to elicit AA-Mphi differentiation and concomitantly exhibited increased COX-2 expression. Further, RSV infection of 5-LO(-/-) mice resulted in enhanced lung pathology. Pharmacologic inhibition of 5-LO or 15-LO also blocked differentiation of RSV-induced AA-Mphi in vitro and, conversely, treatment of 5-LO(-/-) macrophages with downstream products, lipoxin A4 and resolvin E1, but not leukotriene B4 or leukotriene D4, partially restored expression of AA-Mphi markers. Indomethacin blockade of COX activity in RSV-infected macrophages increased 5-LO and 15-LO, as well as arginase-1 mRNA expression. Treatment of RSV infected mice with indomethacin also resulted not only in enhanced lung arginase 1 mRNA expression and decreased COX-2, but also decreased lung pathology in RSV infected 5-LO(-/-) mice. Treatment of RSV-infected cotton rats with a COX-2 specific inhibitor resulted in enhanced lung 5-LO mRNA and AA-Mphi marker expression. Together, these data suggest a novel therapeutic approach for RSV that promotes AA-Mphi differentiation by activating the 5-LO pathway. PMID- 24064667 TI - Highly prevalent colorectal cancer-infiltrating LAP+ Foxp3- T cells exhibit more potent immunosuppressive activity than Foxp3+ regulatory T cells. AB - Although elevated CD4+Foxp3+ regulatory T cell (Treg) frequencies within tumors are well documented, the functional and phenotypic characteristics of CD4+Foxp3+ and CD4+Foxp3- T cell subsets from matched blood, healthy colon, and colorectal cancer require in-depth investigation. Flow cytometry revealed that the majority of intratumoral CD4+Foxp3+ T cells (Tregs) were Helios+ and expressed higher levels of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and CD39 than Tregs from colon and blood. Moreover, ~30% of intratumoral CD4+Foxp3- T cells expressed markers associated with regulatory functions, including latency-associated peptide (LAP), lymphocyte activation gene-3 (LAG-3), and CD25. This unique population of cells produced interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta), and was ~50-fold more suppressive than Foxp3+ Tregs. Thus, intratumoral Tregs are diverse, posing multiple obstacles to immunotherapeutic intervention in colorectal malignancies. PMID- 24064668 TI - IgA subclass switch recombination in human mucosal and systemic immune compartments. AB - Human immunoglobulin A (IgA) comprises two IgA subclasses, IgA1 and IgA2, whose distribution has been shown by immunohistochemistry to be different in various body compartments. In comparison with systemic immune compartments, we investigated the IgA switch profiles at the molecular level in salivary and lacrimal glands, nasal mucosa, and proximal and distal gut mucosa. Direct switching from IgM to IgA1 or IgA2 predominated in all immune compartments analyzed. Similar composition of the SMU-Salpha1 and SMU-Salpha2 junctions was observed, including microhomology usage, which suggested that there is no major difference in the actual recombination mechanism utilized during IgA subclass switching. The proportion of IgA1/IgA2 switch recombination events largely paralleled the previously published immunohistochemical representation of IgA1(+) and IgA2(+) plasma cells, implying that the local subclass distribution generally reflects precommitted memory/effector B cells that have undergone IgA subclass switching before extravasation at the effector site. The extremely low or undetectable levels of activation-induced cytidine deaminase (AID) and Ialpha-CMU circle transcripts in intestinal lamina propria samples as compared with Peyer's patches suggest that the cellular IgA subclass distribution outside of organized gut-associated lymphoid tissue is only to a minor extent, if at all, influenced by in situ switching. PMID- 24064669 TI - Transcription of RORgammat in developing Th17 cells is regulated by E-proteins. AB - In the present study we investigated the molecular mechanisms regulating the expression of RAR-related orphan receptor gamma t (RORgammat), the central factor controlling interleukin (IL)-17 transcription and Th17 differentiation. In key studies, we found that cells from mice with major deletions of E-protein transcription factors, E2A and HEB, display greatly reduced RORgammat/IL-17 expression and that E-protein-deficient mice exhibit greatly diminished IL-17 dependent inflammation in experimental allergic encephalitis models. In additional studies, we unexpectedly found that cells from mice with deletion of Id3, a protein that inhibits E-protein binding to DNA, display diminished RORgammat/IL-17 expression and mice deficient in this protein exhibit decreased Th17-mediated inflammation in a cell-transfer colitis model. The explanation of these initially paradoxical findings came from studies showing that Id3 deficiency leads to increased IL-4-induced GATA-3 expression, the latter a negative regulator of RORgammat transcription; thus, increased Id3 expression likely has a net positive effect on RORgammat expression via its inhibition of IL 4 production. Finally, we found that both E-proteins and Id3 are upregulated in tandem by the cytokines that induce Th17 differentiation, transforming growth factor-beta, and IL-6, implying that these transcription factors are critical regulators of Th17 induction. PMID- 24064671 TI - From infection to immunotherapy: host immune responses to bacteria at the bladder mucosa. AB - The pathogenesis of urinary tract infection and mechanisms of the protective effect of Bacillus Calmette-Guerin (BCG) therapy for bladder cancer highlight the importance of studying the bladder as a unique mucosal surface. Innate responses to bacteria are reviewed, and although our collective knowledge remains incomplete, we discuss how adaptive immunity may be generated following bacterial challenge in the bladder microenvironment. Interestingly, the widely held belief that the bladder is sterile has been challenged recently, indicating the need for further study of the impact of commensal microorganisms on the immune response to uropathogen infection or intentional instillation of BCG. This review addresses the aspects of bladder biology that have been well explored and defines what still must be discovered about the immunobiology of this understudied organ. PMID- 24064670 TI - Lung niches for the generation and maintenance of tissue-resident memory T cells. AB - The extent to which tissue-specific viral infections generate memory T cells specifically adapted to and maintained within the target infection site is unknown. Here, we show that respiratory virus-specific memory T cells in mice and humans are generated and maintained in compartmentalized niches in lungs, distinct from populations in lymphoid tissue or circulation. Using a polyclonal mouse model of influenza infection combined with an in vivo antibody labeling approach and confocal imaging, we identify a spatially distinct niche in the lung where influenza-specific T-cell responses are expanded and maintained long term as tissue-resident memory (T(RM)) CD4 and CD8 T cells. Lung T(RM) are further distinguished from circulating memory subsets in lung and spleen based on CD69 expression and persistence independent of lymphoid stores. In humans, influenza specific T cells are enriched within the lung T(RM) subset, whereas memory CD8 T cells specific for the systemic virus cytomegalovirus are distributed in both lung and spleen, suggesting that the site of infection affects T(RM) generation. Our findings reveal a precise spatial organization to virus-specific T-cell memory, determined by the site of the initial infection, with important implications for the development of targeted strategies to boost immunity at appropriate tissue sites. PMID- 24064673 TI - Detecting low-level flexibility using residual dipolar couplings: a study of the conformation of cellobiose. AB - We have developed novel NMR methods for the measurement of heteronuclear residual dipolar couplings (RDCs) in molecules with severely overlapping NMR resonances. These and other methods enabled us to obtain 31 RDCs for alpha-D-cellobiose and 24 RDCs for beta-D-cellobiose. The interpretation of the data in the approximation of a rigid disaccharide structure, using RDCs and interglycosidic (3)J coupling constants, yielded conformation that is very close to that determined using X-ray crystallography. However, depending on which ring was used to calculate the order parameters, the dihedral angle psiH varied up to 30 degrees or 40 degrees , while the phiH angle was always the same. This indicates residual flexibility of the glycosidic linkage between the two monosaccharide rings and was observed for both alpha- and beta-D-cellobiose. The RDC analysis using rigid fragments rather than a complete molecule has thus shown that the glycosidic bond of cellobiose is not completely rigid and exhibits low-level flexibility. The sources of this flexibility are discussed and evidence presented to support a hypothesis that it is associated with the psi more than the phi angle. PMID- 24064672 TI - Airway structural cells regulate TLR5-mediated mucosal adjuvant activity. AB - Antigen-presenting cell (APC) activation is enhanced by vaccine adjuvants. Most vaccines are based on the assumption that adjuvant activity of Toll-like receptor (TLR) agonists depends on direct, functional activation of APCs. Here, we sought to establish whether TLR stimulation in non-hematopoietic cells contributes to flagellin's mucosal adjuvant activity. Nasal administration of flagellin enhanced T-cell-mediated immunity, and systemic and secretory antibody responses to coadministered antigens in a TLR5-dependent manner. Mucosal adjuvant activity was not affected by either abrogation of TLR5 signaling in hematopoietic cells or the presence of flagellin-specific, circulating neutralizing antibodies. We found that flagellin is rapidly degraded in conducting airways, does not translocate into lung parenchyma and stimulates an early immune response, suggesting that TLR5 signaling is regionalized. The flagellin-specific early response of lung was regulated by radioresistant cells expressing TLR5 (particularly the airway epithelial cells). Flagellin stimulated the epithelial production of a small set of mediators that included the chemokine CCL20, which is known to promote APC recruitment in mucosal tissues. Our data suggest that (i) the adjuvant activity of TLR agonists in mucosal vaccination may require TLR stimulation of structural cells and (ii) harnessing the effect of adjuvants on epithelial cells can improve mucosal vaccines. PMID- 24064674 TI - Nano-volume drop patterning for rapid on-chip neuronal connect-ability assays. AB - The ability of neurons to extend projections and to form physical connections among them (i.e., "connect-ability") is altered in several neuropathologies. The quantification of these alterations is an important read-out to investigate pathogenic mechanisms and for research and development of neuropharmacological therapies, however current morphological analysis methods are very time intensive. Here, we present and characterize a novel on-chip approach that we propose as a rapid assay. Our approach is based on the definition on a neuronal cell culture substrate of discrete patterns of adhesion protein spots (poly-d lysine, 23 +/- 5 MUm in diameter) characterized by controlled inter-spot separations of increasing distance (from 40 MUm to 100 MUm), locally adsorbed in an adhesion-repulsive agarose layer. Under these conditions, the connect-ability of wild type primary neurons from rodents is shown to be strictly dependent on the inter-spot distance, and can be rapidly documented by simple optical read outs. Moreover, we applied our approach to identify connect-ability defects in neurons from a mouse model of 22q11.2 deletion syndrome/DiGeorge syndrome, by comparative trials with wild type preparations. The presented results demonstrate the sensitivity and reliability of this novel on-chip-based connect-ability approach and validate the use of this method for the rapid assessment of neuronal connect-ability defects in neuropathologies. PMID- 24064675 TI - Artificial daylight photodynamic therapy with "non-inflammatory" doses of hexyl aminolevulinate only marginally delays SCC development in UV-exposed hairless mice. AB - Photodynamic therapy (PDT) is effective for actinic keratoses, but is associated with pain and post-treatment inflammation. Daylight-mediated PDT and PpIX precursors at low concentrations reduce pain and inflammation intensity. The objective was to evaluate the effect of repeated low-concentration PDT combined with artificial daylight on SCC development. Mice (n = 265) were exposed to simulated solar UV-irradiation (UVR) 3 times weekly mimicking "summer-dose" exposure (3 SED). Selected groups of mice received a "winter-dose"-exposure (0.6 SED) for the first 90 days. PDT was delivered with 0.1%, 0.05% and 0.02% hexyl aminolevulinate (HAL) cream and artificial daylight for 2.5 hours (6 J cm(-2)) in different treatment regimes (1-3 times weekly, 45-days intervals, days 1-180 and from day 180 onwards). The primary end-point was the time to first SCC (1 mm diameter). 0.1% HAL-PDT given 3 times weekly slightly delayed SCC development and induced minimal inflammation. In winter- and summer UVR-treatment regimes, 0.1% HAL PDT delayed the time to first SCC compared to control UVR and placebo-PDT when mice were PDT-treated on days 1-180 (median 213 vs. 199 days, p = 0.011) and from day 180 onwards (median 218 vs. 199 days, p = 0.006). PDT with 0.05% and 0.02% HAL did not influence SCC development (medians 206 days, p = ns). In summer UVR-exposed mice, 0.1% HAL-PDT marginally postponed the time to first SCC compared to control UVR (median 160 days) when treatments were given 3 times weekly for 180 days (median 166, p = 0.01), but not for 90 days (median 161, p = 0.112). In conclusion, repeated low-concentration HAL-PDT combined with artificial daylight is well-tolerated, but only marginally delays SCC development in mice. PMID- 24064676 TI - Involvement of histone H3 phosphorylation through p38 MAPK pathway activation in casticin-induced cytocidal effects against the human promyelocytic cell line HL 60. AB - The effect of casticin was investigated by focusing on cell viability, apoptosis induction and cell cycle arrest in HL-60 cells. Casticin induced a dose- and time dependent decrease in cell viability associated with apoptosis induction and G2/M cell cycle arrest. The addition of SB203580, an inhibitor for p38 mitogen activated protein kinase (MAPK), but not SP600125 [c-Jun NH2-terminal protein kinase (JNK) inhibitor] and PD98059 [extracellular signal-regulated kinase (ERK) inhibitor], abrogated casticin-induced cell cycle arrest and apoptosis associated with the activation of caspases including caspase-8, -9 and -3. Endogenous p38 MAPK activation was observed in untreated cells based on the detection of the expression levels of phospho-p38 MAPK, whereas casticin did not affect the degree of p38 MAPK activation. Interestingly, the addition of SB203580 suppressed casticin-induced phosphorylation of histone H3, a downstream molecule of the p38 MAPK signaling pathway and known to be involved in chromosome condensation during mitosis. More importantly, casticin induced upregulation of intracellular ATP levels. Although casticin induced intracellular reactive oxygen species, antioxidants failed to block casticin-mediated cytotoxicity, indicating that casticin-induced cytotoxicity appears to be independent of reactive oxygen species generation. Based on the fact that SB203580 has been reported to compete with ATP for binding to the active form of p38 MAPK, and consequently blocks the p38 MAPK activity in activating downstream molecules, these results suggest that casticin induces cytotoxicity associated with apoptosis and cell cycle arrest in HL-60 cells through the p38 MAPK pathway, in which intracellular ATP levels and phosphorylation of histone H3 play critical roles. PMID- 24064677 TI - The glucagon-like peptide-1 receptor agonist, liraglutide, attenuates the progression of overt diabetic nephropathy in type 2 diabetic patients. AB - Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Glucagon-like peptide-1 (GLP-1) is one of the incretins, gut hormones released from the intestine in response to food intake. GLP-1 receptor (GLP-1R) agonists have been used to treat type 2 diabetes. Here, we studied the effect of the administration of a GLP-1R agonist, liraglutide, on proteinuria and the progression of overt DN in type 2 diabetic patients. Twenty-three type 2 diabetic patients with overt DN, who had already been treated with blockade of renin angiotensin system under dietary sodium restriction, were given liraglutide for a period of 12 months. Treatment with liraglutide caused a significant decrease in HbA1c from 7.4 +/- 0.2% to 6.9 +/- 0.3% (p = 0.04), and in body mass index (BMI) from 27.6 +/- 0.9 kg/m2 to 26.5 +/- 0.8 kg/m2 after 12 months (p < 0.001), while systolic blood pressure did not change. The progression of DN was determined as the rate of decline in estimated glomerular filtration rate (eGFR). The 12-month administration of liraglutide caused a significant decrease in proteinuria from 2.53 +/- 0.48 g/g creatinine to 1.47 +/- 0.28 g/g creatinine (p = 0.002). The administration of liraglutide also substantially diminished the rate of decline in eGFR from 6.6 +/- 1.5 mL/min/1.73 m2/year to 0.3 +/- 1.9 mL/min/1.73 m2/year (p = 0.003). Liraglutide can be used not only for reducing HbA1c and BMI, but also for attenuating the progression of nephropathy in type 2 diabetic patients. PMID- 24064679 TI - Mature BDNF promotes the growth of glioma cells in vitro. AB - High-grade glioma is incurable and is associated with a short survival time and a poor prognosis. There are two forms of brain-derived neurotrophic factor (BDNF), proBDNF and mature BDNF, which exert opposite effects. Their diverse actions are mediated through two different transmembrane receptor signalling systems: p75NTR and TrkB. The important roles of the BDNF/TrkB signalling system in tumour cell proliferation and survival have been demonstrated. However, few studies have been able to distinguish mature BDNF from proBDNF due to the limitation of specific antibodies. Using specific proBDNF antibodies, we demonstrated that the proBDNF/p75NTR pathway appears to inhibit malignant glioma cell growth and migration. In the present study using specific mature BDNF antibodies, we found that mature BDNF inhibited C6 glioma cell apoptosis and increased cell growth and migration in vitro. Our data suggest that the counterbalance between mature BDNF and proBDNF may regulate tumour growth. PMID- 24064680 TI - Construction of a recombinant eukaryotic human ZHX1 gene expression plasmid and the role of ZHX1 in hepatocellular carcinoma. AB - The zinc-fingers and homeoboxes protein 1 (ZHX1) consists of 873 amino acid residues, is localized in the cell nucleus and appears to act as a transcriptional repressor. Previous studies have shown that ZHX1 interacts with nuclear factor Y subunit alpha (NF-YA), DNA methyltransferases (DNMT) 3B and ZHX2, all of which are involved in tumorigenesis. However, the exact role of ZHX1 in tumorigenesis remains unknown. The aim of the current study was to construct a recombinant eukaryotic expression plasmid containing the human ZHX1 (hZHX1) gene and to investigate the biological activities of ZHX1 in hepatocellular carcinoma (HCC). Reverse transcription-polymerase chain reaction (RT-PCR) was used to amplify the N- and C-terminal fragments (ZHX1-N and ZHX1-C, respectively) of the hZHX1 gene. The two PCR fragments were cloned into the pEASY-T1 vector and subcloned into the pcDNA3 plasmid to generate a recombinant pcDNA3-ZHX1 plasmid. Following identification by enzyme digestion and DNA sequencing, the recombinant pcDNA3-ZHX1 plasmid was transfected into SMMC-7721 cells. The level of ZHX1 expression was detected by RT-PCR and western blot analysis. Cell growth curve assays were used to evaluate the effect of ZHX1 on cell proliferation. Moreover, the differential expression of ZHX1 between cancer and adjacent cirrhotic liver tissue was investigated by quantitative PCR (qPCR). Enzyme digestion and DNA sequencing confirmed the successful construction of the recombinant plasmid, pcDNA3-ZHX1. qPCR and western blot analysis demonstrated that ZHX1 was efficiently expressed in SMMC-7721 cells and overexpression of ZHX1 may inhibit the proliferation of SMMC-7721 cells. In addition, reduced ZHX1 expression is widespread among cancer tissues from HCC patients. In conclusion, a recombinant eukaryotic expression plasmid, pcDNA3-ZHX1, was successfully constructed. In addition, the current results indicate that a low expression of ZHX1 may be responsible for hepatocarcinogenesis. PMID- 24064681 TI - Nonsynonymous polymorphisms of the PDLIM5 gene association with the occurrence of both bipolar disorder and schizophrenia. AB - Two single nucleotide polymorphisms of PDLIM5, rs7690296 and rs11097431, were genotyped using Mass-Array SNP genotyping by Sequenom technology in 244 bipolar disorder patients, 471 schizophrenia patients, and 601 control individuals who were Malay, Chinese, and Indian ethnic groups in the Malaysian population. A significant association was observed in allele frequency between the rs7690296 polymorphism and bipolar disorder in the Indian ethnic group [P=0.02, adjusted odds ratio (OR) 0.058, 95% confidence interval (CI) 0.36-0.93]. A significant association was also observed between the rs7690296 polymorphism and schizophrenia under the recessive model for both Malay (P=0.02, adjusted OR 1.86, 95% CI 1.12-3.10) and Indian (P=0.02, adjusted OR 1.92, 95% CI 1.10-3.37) ethnic groups. However, no association was detected between the rs11097431 polymorphism either with bipolar disorder or with schizophrenia. Therefore, it can be deduced that the nonsynonymous rs7690296 polymorphism could play an important role in the pathophysiology of both bipolar disorder and schizophrenia. PMID- 24064682 TI - Rare variants analysis of neurexin-1beta in autism reveals a novel start codon mutation affecting protein levels at synapses. AB - Neurexins are synaptic plasma membrane proteins encoded by three genes (NRXN1, 2, -3) with alternative promoters. Mutations in neurexin genes have been identified in different neurodevelopmental disorders, including autism. Recently, two point mutations altering the translation initiation site of NRXN1beta (c. 3G>T and c.3G>T) have been described in patients with autism and mental retardation. In this study, we analyzed the NRXN1beta gene in a sample of 153 patients with autism. We report the identification of a novel mutation, c.3G>A (p.Met1), affecting the translation initiation site. Expression analysis showed that the c.3G>A mutation switches the translation start site of NRXN1beta to an in-frame downstream methionine and decreases synaptic levels of the mutant protein in cultured neurons. These data reinforce a role for synaptic defects of NRXN1beta in neurodevelopmental disorders. PMID- 24064683 TI - Association study of ABCA7 and NPC1 polymorphisms with Alzheimer's disease in Chinese Han ethnic population. PMID- 24064684 TI - Blood glucose in multiparous women influences offspring birth size but not size at 2 years of age. AB - BACKGROUND: Gestational diabetes is associated with increased birth size. Blood glucose concentrations within the nondiabetic range affect birth size but whether this influences postnatal growth is unclear. METHODS: We measured fasting blood glucose concentrations (FBG) in 1650 singleton Caucasian pregnancies at 12 and 28 weeks' gestation and related values to birth weight and weight at 12 and 24 months of age. Pregnancies complicated by antepartum hemorrhage, gestational diabetes, preeclampsia, and prematurity were excluded. RESULTS: Mean maternal age was 30 years and 49% were primiparous. There was a weak relationship between birth weight (z score) and FBG at 12 (r = 0.1; P = .006) and 28 (r = 0.1; P < .001) weeks. FBG at 12 and 28 were correlated (r = 0.3; P < .001). Mothers at 12 and 28 weeks of pregnancy with higher FBG were shorter and heavier. The relationship between FBG at 12 and 28 weeks and birth weight was not observed in primiparous women and FBG was not associated with weight at any postnatal time point. CONCLUSIONS: These data suggest that in a low-risk United Kingdom pregnancy cohort FBG concentrations in the nondiabetic range affect birth weight in multiparous women. The effect is small (50 g change in birth weight/1 mmol/L FBG change) and does not persist into postnatal life. This implies a limited role for maternal glucose status within the normal range in determining size in infancy. PMID- 24064685 TI - Clinical review: Lifecycle of polycystic ovary syndrome (PCOS): from in utero to menopause. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is diagnosed during the reproductive years when women present with 2 of 3 of the following criteria: 1) irregular menstrual cycles or anovulation, 2) hyperandrogenism, and 3) PCO morphology. However, there is evidence that PCOS can be identified from early infancy to puberty based on predisposing environmental influences. There is also increasing information about the PCOS phenotype after menopause. The goal of this review is to summarize current knowledge about the appearance of PCOS at different life stages and the influence of reproductive maturation and senescence on the PCOS phenotype. EVIDENCE: PubMed, the bibliography from the Evidence-Based PCOS Workshop, and the reference lists from identified manuscripts were reviewed. EVIDENCE SYNTHESIS: The current data suggest that daughters of women with PCOS have a greater follicle complement and mild metabolic abnormalities from infancy. PCOS is often diagnosed in puberty with the onset of hyperandrogenism and may be preceded by premature pubarche. During the reproductive years, there is a gradual decrease in the severity of the cardinal features of PCOS. Menopausal data suggest that the majority of women who had PCOS during their reproductive years continue to manifest cardiovascular risk factors. However, the majority do not present an increased risk for cardiovascular morbidity and mortality, perhaps because women with no history of PCOS may catch up after menopause. CONCLUSION: The current data provide a comprehensive starting point to understand the phenotype of PCOS across the lifespan. However, limitations such as a bias of ascertainment in childhood, age-based changes during reproductive life, and the small numbers studied during menopause point to the need for additional longitudinal studies to expand the current knowledge. PMID- 24064686 TI - Acute severe hypercalcemia after traumatic fractures and immobilization in hypophosphatasia complicated by chronic renal failure. AB - CONTEXT: Hypophosphatasia (HPP) features deficient activity of the "tissue nonspecific" isoenzyme of alkaline phosphatase (TNSALP) due to loss-of-function mutation(s) within the TNSALP gene. Consequently, inorganic pyrophosphate, a TNSALP substrate and inhibitor of mineralization, accumulates extracellularly. This can cause rickets or osteomalacia. OBJECTIVE: We report a 55-year-old man with HPP and chronic renal failure (CRF) requiring hemodialysis who developed severe hypercalcemia acutely after traumatic fractures and immobilization. He manifested HPP in childhood and in middle age received hemodialysis for CRF attributed to hypertension and anti-inflammatory medication. He took 2 g of calcium carbonate orally each day to bind dietary phosphorus, but never aluminum hydroxide or any form of vitamin D. Pretrauma serum levels of calcium spanned 8.4 10.7 mg/dL (normal [Nl], 8.6-10.3), inorganic phosphate 5.8-6.4 mg/dL (Nl, 2.5 4.5), and PTH 63-75 pg/mL (Nl, 10-55). RESULTS: Rapid succession falls fractured multiple major bones. Six hours later, he became confused. Serum calcium was 14.9 mg/dL, ionized calcium was 7.4 mg/dL (Nl, 4.5-5.1), and PTH was 16 pg/mL. Hemodialysis quickly corrected his hypercalcemia and confusion. Low serum alkaline phosphatase persisted, and follow-up skeletal histopathology showed that his osteomalacia was severe. CONCLUSION: Hemodialysis does not heal the skeletal disease of HPP. During sudden fracture immobilization in HPP, sufficient calcium can emerge from bone, perhaps from a rapidly exchangeable calcium pool, to cause acute severe hypercalcemia if the kidneys cannot compensate for the mineral efflux. Hence, we worry that acute hypercalcemia might accompany sudden immobilization in CRF patients without HPP if they have adynamic bone disease. PMID- 24064687 TI - Iodine contributes to thyroid autoimmunity in humans by unmasking a cryptic epitope on thyroglobulin. AB - CONTEXT: The mechanisms linking thyroid autoimmunity and iodine use in humans are unknown. OBJECTIVE: Our aim was to correlate iodine intake, thyroid autoimmunity, and recognition of thyroglobulin (Tg) epitopes after implementation of iodine prophylaxis. SETTING: The general community living in an Italian village was evaluated. MAIN OUTCOME MEASURES: Thyroglobulin autoantibodies (TgAb), thyroperoxidase autoantibodies (TPOAb), and urinary iodine excretion were assessed in 906 iodized salt users (IS-users) and 389 nonusers (IS-nonusers). Ultrasound (US) was performed to identify thyroid hypoechogenicity, suggestive of Hashimoto thyroiditis (HT). TgAb epitope pattern in 16 IS-users and 17 IS nonusers was evaluated by an inhibition binding assay to Tg, using human monoclonal TgAb-Fab directed to A, B, C, and D epitopes on Tg. RESULTS: Median urinary iodine excretion was slightly higher in IS-users than in IS-nonusers (112.0 MUg/L vs 86.5 MUg/L; P < .01). TgAb, and not TPOAb, was more frequent in IS-users (18.9% vs 13.6%, P = .02). HT-US was found in 87 subjects, among whom both positive TgAb (58.4% vs 31.8%, P = .03) and TPOAb (61.5% vs 45.4%. P = .04) were more frequent in IS-users. In this group significantly higher serum levels of TgAb (median 108 U/mL vs 30 U/mL; P = .02), but not of TPOAb, were present. Iodized salt use had no effect on the 1208 non HT-US subjects. TgAb directed to the epitope B of Tg were more frequent in IS-users than in IS-nonusers (27.5% vs 3.0%, P = .047). CONCLUSIONS: Iodine-induced thyroid autoimmunity is related to TgAb and the unmasking of a cryptic epitope on Tg contributes to this relationship in humans. PMID- 24064689 TI - Effects of odanacatib on BMD and safety in the treatment of osteoporosis in postmenopausal women previously treated with alendronate: a randomized placebo controlled trial. AB - CONTEXT: Odanacatib (ODN) is a selective cathepsin K inhibitor being developed to treat osteoporosis. OBJECTIVE: The effects of ODN were evaluated on bone mineral density (BMD), biochemical markers of bone turnover, and safety in patients previously treated with alendronate. DESIGN: This was a randomized, double-blind, placebo-controlled, 24-month study. SETTING: The study was conducted at private or institutional practices. PARTICIPANTS: Postmenopausal women (n = 243) >= 60 years of age with low BMD at the total hip, femoral neck, or trochanter (T-score <=-2.5 but >-3.5 without prior fracture or <=-1.5 but >-3.5 with prior fracture) on alendronate for >= 3 years. INTERVENTION: The intervention included ODN 50 mg or placebo weekly. MAIN OUTCOME MEASURES: The primary end point was percentage change from baseline of femoral neck BMD at month 24. BMD was assessed by dual energy x-ray absorptiometry at baseline and 6, 12, and 24 months. Biochemical markers of bone turnover (serum C-telopeptides of type 1 collagen, urinary N telopeptides of type 1 collagen, serum bone specific alkaline phosphatase, and serum N-terminal propeptide of type 1 collagen) were measured at baseline and 3, 6, 12, 18, and 24 months. RESULTS: In the ODN group, BMD changes from baseline at the femoral neck, trochanter, total hip, and lumbar spine at 24 months (1.7%, 1.8%, 0.8%, and 2.3%, respectively) were significantly different from the placebo group. ODN significantly decreased urinary N-telopeptides of type 1 collagen to creatinine ratio and significantly increased serum N-terminal propeptide of type 1 collagen compared with placebo. Serum C-telopeptides of type 1 collagen was unexpectedly increased with ODN treatment. The safety profile appeared similar between groups. CONCLUSIONS: ODN provided incremental BMD gains in osteoporotic women after alendronate treatment. PMID- 24064688 TI - Increased AKT or MEK1/2 activity influences progesterone receptor levels and localization in endometriosis. AB - CONTEXT: Endometriosis is characterized by progesterone resistance and hyperactivity of the AKT and MAPK pathways. Kinases can cause posttranslational modifications of the progesterone receptor (PR) to influence cellular localization and protein stability. OBJECTIVE: The objective of this study was to determine whether the increased AKT or MAPK kinase-1/2 (MEK1/2) activity observed in endometriotic stromal cells (OSIS) from ovarian endometriomas influences levels of PR protein. In turn, the effects of inhibiting AKT or MEK1/2 in the presence of the progestin R5020 on cell viability were investigated. RESULTS: Inhibiting AKT with MK-2206 or MEK1/2 with U0126 for 24 hours in the absence of R5020 increased total and nuclear PRA and PRB protein levels in OSIS but not in eutopic endometrial stromal cells from disease-free patients from disease-free patients. MK-2206 and R5020 decreased OSIS viability and increased apoptosis. Trends toward decreased volumes of sc grafted endometriosis tissues were demonstrated with MK-2206 and progesterone. CONCLUSIONS: Inhibition of AKT or MEK1/2 increased total and nuclear PR protein in OSIS. MK-2206 and R5020 decreased OSIS viability and increased apoptosis. The AKT and MAPK pathways may be potential molecular targets for the treatment of endometriosis. PMID- 24064690 TI - Regional and overall aortic function in nondiabetic individuals with insulin resistance and normal glucose tolerance. AB - CONTEXT: Insulin resistance is associated with altered vascular function in diabetes. OBJECTIVE: The objective of the study was to define the overall and regional aortic function as well as the changes of aortic function over time in nondiabetic individuals with insulin resistance and a normal oral glucose tolerance test (OGTT). DESIGN: This was a cross-sectional and longitudinal analysis with 12 months follow-up. SETTING: The setting of the study was in primary care. PATIENTS: Nondiabetic individuals (n = 181, mean age 42 +/- 8 y) with a normal OGTT and insulin resistance as defined by the insulin sensitivity index (ISI) participated in the study. INTERVENTIONS: ISI was estimated from serial measurements of plasma insulin and glucose during an iv glucose tolerance test. Ascending and abdominal aortic distensibility (AoD) and stiffness index beta (AoSI) were assessed using echocardiography. Carotid-to-femoral artery pulse wave velocity (PWVc-f; an index of overall aortic function) was measured from carotid and femoral arteries Doppler flow velocities recorded simultaneously with an electrocardiogram. Associations between ISI, AoD, AoSI, and PWVc-f were assessed using linear regression analyses and ANOVA. Differences between baseline and 12 months were compared using a paired t test. MAIN OUTCOME MEASURES: AoD and AoSI associations as well as changes over a 12-month period in relation to ISI were measured. RESULTS: Ascending AoD (P = .01) and ascending AoSI (P = .025) were significantly associated with ISI; in contrast, abdominal AoD and AoSI and PWVc-f did not. Changes in AoD, AoSI, and PWVc-f over time were more prominent in individuals with low ISI compared with those with high ISI. CONCLUSIONS: The significant associations between ISI and aortic function suggest that insulin resistance may affect the cardiovascular system, even when OGTT is normal. PMID- 24064691 TI - Genomic basis of aromatase excess syndrome: recombination- and replication mediated rearrangements leading to CYP19A1 overexpression. AB - CONTEXT: Genomic rearrangements at 15q21 have been shown to cause overexpression of CYP19A1 and resultant aromatase excess syndrome (AEXS). However, mutation spectrum, clinical consequences, and underlying mechanisms of these rearrangements remain to be elucidated. OBJECTIVE: The aim of the study was to clarify such unsolved matters. DESIGN, SETTING, AND METHODS: We characterized six new rearrangements and investigated clinical outcome and local genomic environments of these rearrangements and of three previously reported duplications/deletions. RESULTS: Novel rearrangements included simple duplication involving exons 1-10 of CYP19A1 and simple and complex rearrangements that presumably generated chimeric genes consisting of the coding region of CYP19A1 and promoter-associated exons of neighboring genes. Clinical severities were primarily determined by the copy number of CYP19A1 and the property of the fused promoters. Sequences at the fusion junctions suggested nonallelic homologous recombination, nonhomologous end-joining, and replication-based errors as the underlying mechanisms. The breakpoint-flanking regions were not enriched with GC content, palindromes, noncanonical DNA structures, or known rearrangement associated motifs. The rearrangements resided in early-replicating segments. CONCLUSIONS: These results indicate that AEXS is caused by duplications involving CYP19A1 and simple and complex rearrangements that presumably lead to the usage of cryptic promoters of several neighboring genes. Our data support the notion that phenotypes depend on the dosage of CYP19A1 and the characteristics of the fused promoters. Furthermore, we show that the rearrangements in AEXS are generated by both recombination- and replication-mediated mechanisms, independent of the known rearrangement-inducing DNA features or late-replication timing. Thus, AEXS represents a unique model for human genomic disorders. PMID- 24064692 TI - Comparison of elastographic strain index and thyroid fine-needle aspiration cytology in 631 thyroid nodules. AB - CONTEXT: Ultrasound (US) elastography (USE) was recently been reported as a sensitive, noninvasive tool for identifying thyroid cancer. However, the accuracy of this technique is hampered by the intra- and interoperator variability, some US features of the nodule, and the coexistence of autoimmune thyroid disease (ATD). OBJECTIVES: The purpose of this article was to assess the accuracy of USE findings in the differential diagnosis of thyroid nodules compared with other US features to evaluate its feasibility in the presence of ATDs and identify the strain index (SI) cutoff with the highest diagnostic performance. DESIGN: We evaluated 528 consecutive patients for a total of 661 thyroid nodules. All nodules underwent fine-needle aspiration cytology (FNAC) and USE evaluation. The SI was calculated as a ratio of the nodule strain divided by the strain of the softest part of the surrounding normal tissue. RESULTS: The median SI value was significantly higher in THY4 and THY5 than in THY2 nodules in ATD-positive, ATD negative, and ATD-unknown patients. The cutoff of SI for malignancy was estimated to be 2.905 by receiver operating characteristic curve analysis in a screening set (379 FNAC results), and then tested in a replication set (252 FNAC results). In all cases, a SI value of >= 2.905 conferred to the nodule a significantly greater probability of being malignant. This SI cutoff had the greatest area under the curve, sensitivity, and negative predictive value, compared with the conventional US features of malignancy. CONCLUSION: The elastographic SI has a high sensitivity, specificity, and negative predictive value for the diagnosis of thyroid malignancy both in the presence and in the absence of ATD. If our data on USE are also confirmed in THY3 nodules, FNAC could be avoided in a number of thyroid nodules with certain features. PMID- 24064693 TI - Beneficial and adverse effects of testosterone on the cardiovascular system in men. AB - CONTEXT: The widespread use of T therapy, particularly in aging males, necessitates knowledge of the relationship between T and the cardiovascular system. EVIDENCE ACQUISITION: The review is based on a 1970 to 2013 PubMed search with terms related to androgens in combination with cardiovascular disease, including T, dihydrotestosterone, trial, mortality, cardiovascular disease, myocardial infarction, blood pressure, endothelial function, dyslipidemia, thrombosis, ventricular function, and arrhythmia. Original articles, systematic reviews and meta-analyses, and relevant citations were screened. EVIDENCE SYNTHESIS: Low T has been linked to increased blood pressure, dyslipidemia, atherosclerosis, arrhythmia, thrombosis, endothelial dysfunction, as well as to impaired left ventricular function. On the one hand, a modest association is suggested between low endogenous T and incident cardiovascular disease or cardiovascular mortality, implying unrecognized beneficial T effects, residual confounding, or a relationship with health status. On the other hand, treatments with T to restore "normal concentrations" have so far not been proven to be beneficial with respect to cardiovascular disease; neither have they definitely shown specific adverse cardiovascular effects. The cardiovascular risk-benefit profile of T therapy remains largely evasive in view of a lack of well-designed and adequately powered randomized clinical trials. CONCLUSIONS: The important knowledge gap as to the exact relationship between T and cardiovascular disease would support a cautious, restrained approach to T therapy in aging men, pending clarification of benefits and risks by adequately powered clinical trials of sufficient duration. PMID- 24064694 TI - Sex differences in insulin resistance and cardiovascular disease risk. AB - CONTEXT: The possibility that differences in insulin sensitivity explain why women, especially younger women, have a lower cardiovascular disease (CVD) risk than men remains an unsettled issue. OBJECTIVE: The objective of this study was to evaluate whether sex disparities in CVD risk are associated with differences in insulin resistance. DESIGN/SETTING/PARTICIPANTS: This was a cross-sectional study of women (n = 468) and men (n = 354) who had the measurement of CVD risk factors and steady-state plasma glucose (SSPG) concentration (insulin resistance) using the insulin suppression test. The population was also divided by median age (51 y) to evaluate the effect of age on sex differences. MAIN OUTCOME MEASURES/RESULTS: In general, the SSPG concentration was similar between sexes. At higher BMI (>=30 kg/m(2)), women had significantly lower SSPG concentration than men (sex * BMI interaction, P = .001). However, sex differences in CVD risk factors were not due to differences in SSPG but accentuated by a higher degree of insulin resistance in younger (age < 51 y) but not older (>= 51 y) individuals. In younger individuals, women had significantly (P <= .007) lower diastolic blood pressure and fasting glucose and triglyceride concentration compared with men in SSPG tertile 3 (most insulin resistant) but not in tertile 1 (least insulin resistant). Older women had lower diastolic blood pressure compared with men, regardless of SSPG. High-density lipoprotein cholesterol remained higher in women, regardless of age or SSPG. CONCLUSIONS: The female advantage is not due to a difference in insulin action but results from an attenuation of the relationship between insulin resistance and CVD risk, especially in younger individuals. PMID- 24064696 TI - Flexible and robust MoS2-graphene hybrid paper cross-linked by a polymer ligand: a high-performance anode material for thin film lithium-ion batteries. AB - A flexible and robust MoS2-graphene hybrid paper with an excellent lithium storage capacity is fabricated through cross-linking by a polymer ligand, PEO, and shows potential for the development of high-performance film anodes. PMID- 24064695 TI - Calcium and vitamin d supplementation in postmenopausal women. AB - CONTEXT: Bone health is influenced by the intake of both calcium and vitamin D. OBJECTIVE: Our objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration. INTERVENTIONS: Subjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 MUg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months. MAIN OUTCOME MEASURES: Serum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured. RESULTS: Before study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium. CONCLUSIONS: Fasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 MUg vitamin D3/d does not. PMID- 24064697 TI - [Investigation of polymer gel dosimetry for small circular irradiated fields]. AB - Polymer gels can be used as tissue equivalent dosimeters, and polymer gel dosimetry can be employed without perturbation of the radiation field. In this study, polymer gel dosimetry was used for small circular irradiation fields 10-30 mm in diameter using a radiation planning system. The irradiated gels were compared with planned data for a 50% dose width of 6 Gy dose maximum, and for the dose difference between gels and planned data over an 80% dose maximum area. The present study investigated magnetic resonance imaging (MRI) conditions based on an optimal dose-R2 calibration curve. The average difference between the full width half maximum of the 50% dose width between gels and planned data was 11%. The average dose difference over 80% of the dose was 5.6%. Optimal dose-R2 calibration curves were acquired using images with echo times of 30 and 60 ms. For cases of larger thicknesses and an increasing number of averages, the coefficients of variance of the curves were smaller than under other conditions. Compared to other traditional dosimetric tools, polymer gels have the advantage of providing three-dimensional dosimetric data. An arbitrary profile from the gel's data can be compared with the profile of the planned data. In the future, new gel dosimeters will be needed that demonstrate improved dose evaluation under 1 Gy and stability in high dose areas. PMID- 24064698 TI - [Basic research for development of pinhole camera using a Geiger Mueller counter]. AB - To visualize the scattered X-ray distribution in the diagnosis domain, we examined whether a Geiger Mueller (GM) counter could be applied to a pinhole camera as an X-ray detector. The GM counter detects radiation at certain detection points. To obtain two-dimensional images using the GM counter, the detector needs to be moved two-dimensionally. We constructed an apparatus using industrial actuators to move the detector. To investigate the usability of the developed apparatus, the scattered X-rays from the phantom were measured using the GM counter. The images obtained were then compared with those measured using the phosphor plate. Our results demonstrated that the GM counter can detect low count-rate radiation, but further research will be needed to obtain clear two dimensional images. In this paper, we propose that the GM counter can be used as a complementary detector to a phosphor plate. PMID- 24064699 TI - [Development of an experimental apparatus for energy calibration of a CdTe detector by means of diagnostic X-ray equipment]. AB - Diagnostic X-ray equipment was used to develop an experimental apparatus for calibrating a CdTe detector. Powder-type samples were irradiated with collimated X-rays. On excitation of the atoms, characteristic X-rays were emitted. We prepared Nb2O5, SnO2, La2O3, Gd2O3, and WO3 metal oxide samples. Experiments using the diagnostic X-ray equipment were carried out to verify the practicality of our apparatus. First, we verified that the collimators involving the apparatus worked well. Second, the X-ray spectra were measured using the prepared samples. Finally, we analyzed the spectra, which indicated that the energy calibration curve had been obtained at an accuracy of +/-0.06 keV. The developed apparatus could be used conveniently, suggesting it to be useful for the practical training of beginners and researchers. PMID- 24064702 TI - [Power to the people]. PMID- 24064703 TI - On the role of guests in enforcing the mechanism of action of gated baskets. AB - We designed and prepared a spacious and gated basket of type 2 (V = 318 A(3)) in ten synthetic steps. With the assistance of (1)H NMR spectroscopy, we found that the pyridine gates at the rim of 2 form a seam of N-H???N hydrogen bonds, thereby adopting right- (P) and left-handed (M) helical arrangements. The recognition characteristics of the smaller basket 1 (V = 226 A(3)) and the larger 2 for various solvents as guests were quantified by (1)H NMR spectroscopy in CD2Cl2 (61 A(3)), CDCl3 (75 A(3)), CFCl3 (81 A(3)) and CCl4 (89 A(3)); the apparent guest binding equilibria Ka were found to be inversely proportional to the affinity of bulk solvents KS for populating each host. The rate of the P/M racemization (krac, s(-1)) was, for both 1 and 2, studied in all four solvents using dynamic NMR spectroscopy. From these experiments, two isokinetic relationships (DeltaS++P/M vs. DeltaH++P/M) were identified with each one corresponding to a different mechanism of P/M racemization. A computational study (B3LYP/6 31+G**//PM6) of 1 and 2 in the gas phase indicates two competing racemization pathways: (a) RM1-2 describes a pivoting of a single gate followed by the rotation of the remaining two gates, while (b) RM3 depicts simultaneous (geared) rotation of all three gates. The racemization of the larger basket 2, in all four solvents (packing coefficient, PC = 0.19-0.28), conformed to one isokinetic relationship, which also coincided with the operation of the smaller basket 1 in CD2Cl2 (PC = 0.27). However, in CDCl3, CFCl3 and CCl4 (PC = 0.33-0.39), the mode of action of 1 appears to correlate with a different isokinetic relationship. Thus, we propose that the population of the basket's inner space (PC) determines the mechanism of P/M racemization. When PC < 0.3, the mechanism of operation is RM1-2, whereas, a greater packing, represented when PC > 0.3, enforces the geared RM3 mechanistic alternative. PMID- 24064704 TI - Optimal periodic perfusion strategy for robust long-term microfluidic cell culture. AB - Long-term cell culture in microfluidic devices is an essential prerequisite for "on a chip" biological and physiological based studies. We investigated how medium delivery, from continuous to periodic perfusion, affects long-term cell cultures in a microfluidic platform. Computational simulations suggested that different delivery strategies result in different temporal profiles of accumulation and washing out of endogenous (EnF) and exogenous (ExF) factors, respectively. Thus, cultures exposed to the same overall amount of medium with different temporal profiles were analysed in terms of homogeneity, cell morphology and phenotype. Murine and human cell lines (C2C12 and HFF) and mouse embryonic stem cells (mESC) were cultured in microfluidic channels. An ad hoc experimental setup was developed to perform continuous and periodic medium delivery into the chip, tuning the flow rate, the perfusion time, and the interval of perfusion while using the same amount of medium volume. Periodic medium delivery with a short perfusion pulse ensured cell homogeneity compared to standard cell culture. Conversely, a continuous flow resulted in cell heterogeneity, with abnormal morphology and vesiculation. Only dramatic and unfeasible increasing of perfused medium volume in the continuous configuration could rescue normal cell behaviour. Consistent results were obtained for C2C12 and HFF. In order to extend these results to highly sensitive cells, mESC were cultured for 6 days in the microfluidic channels. Our analysis demonstrates that a periodic medium delivery with fast pulses (with a frequency of 4 times per day) resulted in a homogeneous cell culture in terms of cell viability, colony morphology and maintenance of pluripotency markers. According to experimental observations, the computational model provided a rational description of the perfusion strategies and of how they deeply shape the cell microenvironment in microfluidic cell cultures. These results provide new insight to define optimal strategies for homogeneous and robust long-term cell culture in microfluidic systems, an essential prerequisite for lab on chip cell-based applications. PMID- 24064706 TI - Polymorphisms within Toll-like receptors are associated with systemic lupus erythematosus in a cohort of Danish females. AB - OBJECTIVES: Toll-like receptors (TLRs) are pattern-associated receptors in innate immunity that may be involved in the recognition of self-antigens and the production of pathogenic autoantibodies. This study was undertaken to examine whether polymorphisms of TLR genes are associated with SLE and to determine the expression of various TLRs in peripheral blood mononuclear cells (PBMCs) of patients with SLE. METHODS: The TLR polymorphisms in a cohort of 143 Danish lupus patients and 432 healthy Danish blood donors were analysed. Groups were age matched. Genotyping for the TLR single-nucleotide polymorphisms (SNPs) was performed using Sequenom Multiplex technology. In addition, the mRNA expression of TLRs in PBMCs from 56 SLE patients and 56 healthy controls was studies by quantitative real-time PCR. RESULTS: We found a genetic association with SLE and three SNPs located within the TLR3, TLR8 and TLR9 genes (rs3775291, P = 0.006; rs37648, P = 0.013; rs352143, P < 0.02). Furthermore, the relative TLR7, TLR8, IFN-alpha and LY6E mRNA expression levels were significantly higher in SLE patients than in healthy controls (P < 0.0001, P < 0.0001, P = 0.0004 and P < 0.0001, respectively). CONCLUSION: These results obtained from a female lupus population of Danish ancestry suggest that variations in TLR3, TLR8 and TLR9 genes are implicated in the pathogenesis of the disease. If these polymorphisms are associated with innate immune dysfunction they may add to the growing field of theoretically well founded new therapeutic targets. PMID- 24064707 TI - Effects of iptycene scaffolds on the photoluminescence of N,N dimethylaminobenzonitrile and its analogues. AB - To understand the effect of iptycene scaffolds on the locally excited (LE) and intramolecular charge transfer (ICT) fluorescence of aminobenzonitriles, a series of triptycene and pentiptycene derivatives were synthesized and their molecular structures and photophysical properties were characterized and compared with the parent phenylene systems, 4-(N-methylamino)benzonitrile (MABN), 4-(N,N dimethylamino)benzonitrile (DMABN), and 4-(N-phenylamino)benzonitrile (PABN). The iptycene effect does not change the nature of the fluorescing states for each amino donor system, i.e., the MA, PA, and DMA series display LE-only, ICT-only, and LE-ICT dual fluorescences, respectively. However, the iptycene scaffolds impose a significant modification of the absorption and emission spectra, fluorescence quantum efficiency and lifetimes, and the interplay of LE and ICT states. The observed iptycene effect has been discussed with three factors: (1) steric effect on increasing the amino twist angle, (2) steric shielding of solvation to the aminobenzonitrile core, and (3) hyperconjugation interactions of the aminobenzonitrile core with the peripheral phenylene groups of iptycene. PMID- 24064708 TI - Context Dependent Effects of Chimeric Peptide Morpholino Conjugates Contribute to Dystrophin Exon-skipping Efficiency. AB - We have recently reported that cell-penetrating peptides (CPPs) and novel chimeric peptides containing CPP (referred as B peptide) and muscle-targeting peptide (referred as MSP) motifs significantly improve the systemic exon-skipping activity of morpholino phosphorodiamidate oligomers (PMOs) in dystrophin deficient mdx mice. In the present study, the general mechanistic significance of the chimeric peptide configuration on the activity and tissue uptake of peptide conjugated PMOs in vivo was investigated. Four additional chimeric peptide-PMO conjugates including newly identified peptide 9 (B-9-PMO and 9-B-PMO) and control peptide 3 (B-3-PMO and 3-B-PMO) were tested in mdx mice. Immunohistochemical staining, RT-PCR and western blot results indicated that B-9-PMO induced significantly higher level of exon skipping and dystrophin restoration than its counterpart (9-B-PMO), further corroborating the notion that the activity of chimeric peptide-PMO conjugates is dependent on relative position of the tissue targeting peptide motif within the chimeric peptide with respect to PMOs. Subsequent mechanistic studies showed that enhanced cellular uptake of B-MSP-PMO into muscle cells leads to increased exon-skipping activity in comparison with MSP-B-PMO. Surprisingly, further evidence showed that the uptake of chimeric peptide-PMO conjugates of both orientations (B-MSP-PMO and MSP-B-PMO) was ATP- and temperature-dependent and also partially mediated by heparan sulfate proteoglycans (HSPG), indicating that endocytosis is likely the main uptake pathway for both chimeric peptide-PMO conjugates. Collectively, our data demonstrate that peptide orientation in chimeric peptides is an important parameter that determines cellular uptake and activity when conjugated directly to oligonucleotides. These observations provide insight into the design of improved cell targeting compounds for future therapeutics studies.Molecular Therapy-Nucleic Acids (2013) 2, e124; doi:10.1038/mtna.2013.51; published online 24 September 2013. PMID- 24064709 TI - Structures and properties of a BEDT-TTF-based organic charge transfer salt and the zwitterion of ferrocenesulfonate. AB - The structure and properties of a new semiconducting BEDT-TTF-based charge transfer salt containing the ferrocenesulfonate (Fc-SO3(-)) anion, alpha-(BEDT TTF)2Fc-SO3.2.5H2O, are described. The structure and magnetic properties of a zwitterion of ferrocenesulfonate, Fc(+)-SO3(-), are also reported. PMID- 24064710 TI - Maternal anxiety and infants' hippocampal development: timing matters. AB - Exposure to maternal anxiety predicts offspring brain development. However, because children's brains are commonly assessed years after birth, the timing of such maternal influences in humans is unclear. This study aimed to examine the consequences of antenatal and postnatal exposure to maternal anxiety upon early infant development of the hippocampus, a key structure for stress regulation. A total of 175 neonates underwent magnetic resonance imaging (MRI) at birth and among them 35 had repeated scans at 6 months of age. Maternal anxiety was assessed using the State-Trait Anxiety Inventory (STAI) at week 26 of pregnancy and 3 months after delivery. Regression analyses showed that antenatal maternal anxiety did not influence bilateral hippocampal volume at birth. However, children of mothers reporting increased anxiety during pregnancy showed slower growth of both the left and right hippocampus over the first 6 months of life. This effect of antenatal maternal anxiety upon right hippocampal growth became statistically stronger when controlling for postnatal maternal anxiety. Furthermore, a strong positive association between postnatal maternal anxiety and right hippocampal growth was detected, whereas a strong negative association between postnatal maternal anxiety and the left hippocampal volume at 6 months of life was found. Hence, the postnatal growth of bilateral hippocampi shows distinct responses to postnatal maternal anxiety. The size of the left hippocampus during early development is likely to reflect the influence of the exposure to perinatal maternal anxiety, whereas right hippocampal growth is constrained by antenatal maternal anxiety, but enhanced in response to increased postnatal maternal anxiety. PMID- 24064712 TI - Valproic acid inhibits the growth of HeLa cervical cancer cells via caspase dependent apoptosis. AB - Valproic acid (VPA) as a histone deacetylase (HDAC) inhibitor has an anticancer effect. In the present study, we evaluated the effects of VPA on the growth and death of HeLa cervical cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH). Dose- and time-dependent growth inhibition was observed in HeLa cells with an IC50 of approximately 10 mM at 24 h. DNA flow cytometric analysis indicated that 10 mM VPA induced a G2/M phase arrest of the cell cycle. This agent also induced apoptosis, which was accompanied by the cleavage of PARP, the activation of caspase-3, -8 and -9, and the loss of mitochondrial membrane potential (MMP; ?Psim). All the tested caspase inhibitors significantly prevented HeLa apoptotic cell death induced by VPA, whereas TNF-alpha intensified the apoptotic cell death. With respect to ROS and GSH levels, VPA increased ROS levels and induced GSH depletion. However, N-acetyl cysteine (NAC; an antioxidant) and L-buthionine sulfoximine (BSO; a GSH synthesis inhibitor) did not significantly affect cell death in VPA-treated HeLa cells. In conclusion, VPA inhibits the growth of HeLa cervical cancer cells via caspase-dependent apoptosis and the growth inhibition is independent of ROS and GSH level changes. PMID- 24064711 TI - Genotyping serotonin transporter polymorphisms 5-HTTLPR and rs25531 in European- and African-American subjects from the National Institute of Mental Health's Collaborative Center for Genomic Studies. AB - A number of studies have suggested DNA sequence variability in the serotonin transporter gene (SLC6A4) between European-American (EA) and African-American (AA) populations, which could be clinically important, given the central role SLC6A4 has in serotonin transmission. However, these studies have had relatively small samples, used self-reported measures of race, and have only tested the promoter-linked polymorphism 5-HTTLPR. Here we genotype 5-HTTLPR and rs25531, a neighboring functional polymorphism, in 954 AA and 2622EA subjects from a National Institute of Mental Health repository sample. Genotyping was performed using fragment analysis by capillary electrophoresis. AA, as compared with EA, groups had lower frequencies of the S allele (0.25 vs 0.43) and SS genotype (0.06 vs 0.19) at 5-HTTLPR, and higher rates of the G allele at rs25531 (0.21 vs 0.075). A rare xL variant at 5-HTTLPR was also more common among AAs (0.017 vs 0.008). When the polymorphisms were redefined into a high- and low-transcription haplotypes, the AA group showed significantly fewer low-transcription variants (chi(2)=4.8, P=0.03). No genotypes were associated with major depression, any anxiety disorder, or neuroticism in either EA or AA populations. This is the largest study to show SLC6A4 genotype differences between EA and AA populations, and the first to include rs25531. Lack of associations with clinical outcomes may reflect untested moderating environmental influences. PMID- 24064713 TI - Anesthetic approach to high-risk patients and prolonged awake craniotomy using dexmedetomidine and scalp block. AB - BACKGROUND: Awake craniotomy with intraoperative speech or motor testing is relatively contraindicated in cases requiring prolonged operative times and in patients with severe medical comorbidities including anxiety, anticipated difficult airway, obesity, large tumors, and intracranial hypertension. The anesthetic management of neurosurgical patients who possess these contraindications but would be optimally treated by an awake procedure remains unclear. METHODS: We describe a new anesthetic approach for awake craniotomy that did not require any airway manipulation, utilizing a bupivacaine-based scalp nerve block, and dexmedetomidine as the primary hypnotic-sedative agent. Using this technique, we provided optimal operative conditions to perform awake craniotomy facilitating safe tumor resection, while utilizing intraoperative electrocorticography for motor and speech mapping in a cohort of 10 patients at a high risk for airway compromise and complications associated with patient comorbidities. RESULTS: All patients underwent successful awake craniotomy, intraoperative mapping, and tumor resection with adequate sedation for up to 9 hours (median 3.5 h, range 3 to 9 h) without any loss of neurological function, airway competency, or the need to provide any active rescue airway management. We report 4 of these cases that highlight our experience: 1 case required prolonged surgery because of the complexity of tumor resection and 3 patients had important medical comorbidities and/or relative contraindication for an awake procedure. CONCLUSIONS: Dexmedetomidine, with concurrent scalp block, is an effective and safe anesthetic approach for awake craniotomy. Dexmedetomidine facilitates the extension procedure complexity and duration in patients who might traditionally not be considered to be candidates for this procedure. PMID- 24064714 TI - Can baroreflex sensitivity and heart rate variability predict late neurological outcome in patients with traumatic brain injury? AB - BACKGROUND: Previous studies have suggested that depressed heart rate variability (HRV) and baroreflex sensitivity (BRS) are associated with early mortality and morbidity in patients with acute brain injuries of various etiologies. The aim of the present study was to assess changes in HRV and BRS in isolated traumatic brain injury (TBI), with the hypothesis that measurement of autonomic nervous system dysfunction can provide prognostic information on late neurological outcome. MATERIALS AND METHODS: Nineteen patients with TBI, requiring mechanical ventilation, sedation and analgesia, and with arterial and intracranial pressure monitoring for at least 1 week, were included. Physiological and treatment variables were collected and power spectral analyses of HRV and BRS analyses in time domain were performed daily. HRV in the high-frequency (HF) and low frequency (LF) domains, as well as LF/HF ratio and total power, were investigated. The power of these variables to predict poor (Glasgow Outcome Scale Extended [GOSE] score <5), late (1 y) neurological outcome was assessed. RESULTS: Total power, LF, HF, and BRS were all significantly depressed in patients with GOSE score <5. This difference could not be explained by a more severe brain injury at admission or more extensive use of sedative or analgesic drugs. The autonomic variables predicted the late neurological outcome with areas under the receiver-operating curves between 0.78 and 0.83 (sensitivity: 0.63 to 0.88 and specificity: 0.73 to 0.82). CONCLUSIONS: HRV and BRS measures in TBI patients during intensive care treatment, including sedative, analgesic, and vasoactive drugs, may identify patients with poor late neurological outcome. PMID- 24064715 TI - Extracorporeal membrane oxygenation support as a life-saving measure for acute respiratory distress syndrome after craniectomy. PMID- 24064716 TI - Reply: To PMID 23764717. PMID- 24064717 TI - The effect of aflatoxin-B1 on red drum (Sciaenops ocellatus) and assessment of dietary supplementation of NovaSil for the prevention of aflatoxicosis. AB - Aflatoxin B1 (AFB1) is a potent carcinogen that causes growth stunting, immunosuppression and liver cancer in multiple species. The recent trend of replacing fishmeal with plant-based proteins in fish feed has amplified the AFB1 exposure risk in farm-raised fish. NovaSil (NS), a calcium montmorillonite clay, has previously been shown to reduce AFB1 bioavailability safely and efficaciously in several mammalian species. This study was designed to: (1) evaluate AFB1 impact on cultured red drum, Sciaenops ocellatus, over the course of seven weeks; and (2) assess NS supplementation as a strategy to prevent aflatoxicosis. Fish were fed diets containing 0, 0.1, 0.25, 0.5, 1, 2, 3, or 5 ppm AFB1. Two additional treatment groups were fed either 5 ppm AFB1 + 1% NS or 5 ppm AFB1 + 2% NS. Aflatoxin B1 negatively impacted red drum weight gain, survival, feed efficiency, serum lysozyme concentration, hepatosomatic index (HSI), whole-body lipid levels, liver histopathological scoring, as well as trypsin inhibition. NovaSil inclusion in AFB1-contaminated diets improved weight gain, feed efficiency, serum lysozyme concentration, muscle somatic index, and intraperitoneal fat ratios compared to AFB1-treated fish. Although not significant, NS reduced AFB1-induced histopathological changes in the liver and decreased Proliferating Cell Nuclear Antigen (PCNA) staining. Importantly, NS supplementation improved overall health of AFB1-exposed red drum. PMID- 24064718 TI - Canine cyanotoxin poisonings in the United States (1920s-2012): review of suspected and confirmed cases from three data sources. AB - Cyanobacteria (also called blue-green algae) are ubiquitous in aquatic environments. Some species produce potent toxins that can sicken or kill people, domestic animals, and wildlife. Dogs are particularly vulnerable to cyanotoxin poisoning because of their tendency to swim in and drink contaminated water during algal blooms or to ingestalgal mats.. Here, we summarize reports of suspected or confirmed canine cyanotoxin poisonings in the U.S. from three sources: (1) The Harmful Algal Bloom-related Illness Surveillance System (HABISS) of the National Center for Environmental Health (NCEH), Centers for Disease Control and Prevention (CDC); (2) Retrospective case files from a large, regional veterinary hospital in California; and (3) Publicly available scientific and medical manuscripts; written media; and web-based reports from pet owners, veterinarians, and other individuals. We identified 231 discreet cyanobacteria harmful algal bloom (cyanoHAB) events and 368 cases of cyanotoxin poisoning associated with dogs throughout the U.S. between the late 1920s and 2012. The canine cyanotoxin poisoning events reviewed here likely represent a small fraction of cases that occur throughout the U.S. each year. PMID- 24064720 TI - Influence of carbohydrates on secondary metabolism in Fusarium avenaceum. AB - Fusarium avenaceum is a widespread pathogen of important crops in the temperate climate zones that can produce many bioactive secondary metabolites, including moniliformin, fusarin C, antibiotic Y, 2-amino-14,16-dimethyloctadecan-3-ol (2 AOD-3-ol), chlamydosporol, aurofusarin and enniatins. Here, we examine the production of these secondary metabolites in response to cultivation on different carbon sources in order to gain insight into the regulation and production of secondary metabolites in F. avenaceum. Seven monosaccharides (arabinose, xylose, fructose, sorbose, galactose, mannose, glucose), five disaccharides (cellobiose, lactose, maltose, sucrose and trehalose) and three polysaccharides (dextrin, inulin and xylan) were used as substrates. Three F. avenaceum strains were used in the experiments. These were all able to grow and produce aurofusarin on the tested carbon sources. Moniliformin and enniatins were produced on all carbon types, except on lactose, which suggest a common conserved regulation mechanism. Differences in the strains was observed for production of fusarin C, 2-AOD-3-ol, chlamydosporol and antibiotic Y, which suggests that carbon source plays a role in the regulation of their biosynthesis. PMID- 24064719 TI - Update on staphylococcal superantigen-induced signaling pathways and therapeutic interventions. AB - Staphylococcal enterotoxin B (SEB) and related bacterial toxins cause diseases in humans and laboratory animals ranging from food poisoning, acute lung injury to toxic shock. These superantigens bind directly to the major histocompatibility complex class II molecules on antigen-presenting cells and specific Vbeta regions of T-cell receptors (TCR), resulting in rapid hyper-activation of the host immune system. In addition to TCR and co-stimulatory signals, proinflammatory mediators activate signaling pathways culminating in cell-stress response, activation of NFkappaB and mammalian target of rapamycin (mTOR). This article presents a concise review of superantigen-activated signaling pathways and focuses on the therapeutic challenges against bacterial superantigens. PMID- 24064722 TI - Generation and characterization of a polyclonal antibody against human high mobility group box 4. AB - A human high mobility group box 4 (hHMGB4) expression construct (pET-28a/hHMGB4) was generated by cloning the hHMGB4 full-length cDNA in the expression vector pET 28a(+). The hHMGB4 fusion protein with His6-Tag was prepared using E.coli BL21 (DE3) transformed with pET-28a/hHMGB4 and purified via preparative SDS-PAGE plus electroelution. Immunization of rabbits with the purified hHMGB4 generated polyclonal antibodies. The titer of the antiserum was determined to be 1:102,400 by ELISA analysis. Western blotting analysis showed that the antibody specifically recognized the recombinant hHMGB4 protein and also the endogenous hHMGB4 protein in prostate cancer cells. In addition, immunohistochemical staining analysis using the prepared antibody revealed marked hHMGB4 staining in the nuclei of the human prostate tissue. These data demonstrate that the anti hHMGB4 polyclonal antibody may be a useful reagent for the functional study of hHMGB4. PMID- 24064723 TI - Footprinting molecular electrostatic potential surfaces for calculation of solvation energies. AB - A liquid is composed of an ensemble of molecules that populate a large number of different states, so calculation of the solvation energy of a molecule in solution requires a method for summing the interactions with the environment over all of these states. The surface site interaction model for the properties of liquids at equilibrium (SSIMPLE) simplifies the surface of a molecule to a discrete number of specific interaction sites (SSIPs). The thermodynamic properties of these interaction sites can be characterised experimentally, for example, through measurement of association constants for the formation of simple complexes that feature a single H-bonding interaction. Correlation of experimentally determined solution phase H-bond parameters with gas phase ab initio calculations of maxima and minima on molecular electrostatic potential surfaces (MEPS) provides a method for converting gas phase calculations on isolated molecules to parameters that can be used to estimate solution phase interaction free energies. This approach has been generalised using a footprinting technique that converts an MEPS into a discrete set of SSIPs (each described by a polar interaction parameter, epsiloni). These SSIPs represent the molecular recognition properties of the entire surface of the molecule. For example, water is described by four SSIPs, two H-bond donor sites and two H-bond acceptor sites. A liquid mixture is described as an ensemble of SSIPs that represent the components of the mixture at appropriate concentrations. Individual SSIPs are assumed to be independent, so speciation of SSIP contacts can be calculated based on properties of the individual SSIP interactions, which are given by the sum of a polar (epsiloniepsilonj) and a non-polar (E(vdW)) interaction term. Results are presented for calculation the free energies of transfer of a range of organic molecules from the pure liquid into water, from the pure liquid into n-hexadecane, from n-hexadecane into water, from n-octanol into water, and for the transfer of water from pure water into a range of organic liquids. The agreement with experiment is accurate to within 1.6-3.9 kJ mol(-1) root mean square difference, which suggests that the SSIMPLE approach is a promising method for estimation of solvation energies in more complex systems. PMID- 24064721 TI - Signaling cascades of Pasteurella multocida toxin in immune evasion. AB - Pasteurella multocida toxin (PMT) is a protein toxin found in toxigenic strains of Pasteurella multocida. PMT is the causative agent for atrophic rhinitis in pigs, a disease characterized by loss of nasal turbinate bones due to an inhibition of osteoblast function and an increase in osteoclast activity and numbers. Apart from this, PMT acts as a strong mitogen, protects from apoptosis and has an impact on the differentiation and function of immune cells. Many signaling pathways have been elucidated, however, the effect of these signaling cascades as a means to subvert the host's immune system are just beginning to unravel. PMID- 24064725 TI - The solar exposure time required for vitamin D3 synthesis in the human body estimated by numerical simulation and observation in Japan. AB - Although the importance of solar radiation for vitamin D3 synthesis in the human body is well known, the solar exposure time required to prevent vitamin D deficiency has not been determined in Japan. This study attempted to identify the time of solar exposure required for vitamin D3 synthesis in the body by season, time of day, and geographic location (Sapporo, Tsukuba, and Naha) using both numerical simulations and observations. According to the numerical simulation for Tsukuba at noon in July under a cloudless sky, 3.5 min of solar exposure are required to produce 5.5 MUg vitamin D3 per 600 cm2 skin corresponding to the area of a face and the back of a pair of hands without ingestion from foods. In contrast, it took 76.4 min to produce the same quantity of vitamin D3 at Sapporo in December, at noon under a cloudless sky. The necessary exposure time varied considerably with the time of the day. For Tsukuba at noon in December, 22.4 min were required, but 106.0 min were required at 09:00 and 271.3 min were required at 15:00 for the same meteorological conditions. Naha receives high levels of ultraviolet radiation allowing vitamin D3 synthesis almost throughout the year. PMID- 24064724 TI - Curcumin suppresses proliferation and induces apoptosis of human hepatocellular carcinoma cells via the wnt signaling pathway. AB - Curcumin from the rhizome of Curcuma longa (zingiberaceae) has been reported to be a chemopreventive agent that affects cell proliferation by arresting the cell cycle in G2 and modulating the wnt signaling pathway. We found that curcumin inhibits proliferation and induces apoptosis of human hepatocellular carcinoma (HCC) cells in a concentration-dependent manner. We identified that curcumin interrupts wnt signaling by decreasing beta-catenin activity, which in turn suppresses the expression of beta-catenin target genes (c-myc, VEGF and cyclin D1). Our results from molecular simulation of curcumin binding to Dvl2 protein and from binding free energy calculations suggest that curcumin may prevent axin recruitment to cellular membrane in order to maintain the functional beta-catenin destruction complex in normal cells. This results in beta-catenin being unable to accumulate in the nucleus, depriving the protein of its ability to bind with lymphoid enhancer factor/T cell-specific transcription factor (Lef/Tcf) and repressing its activation of target gene transcription. This may be one mechanism through which curcumin inhibits proliferation and induces apoptosis of HCC cells. PMID- 24064726 TI - Effects of green-leafy vegetable intake on postprandial glycemic and lipidemic responses and alpha-tocopherol concentration in normal weight and obese men. AB - Vegetable consumption has been encouraged as a component of nutritional education for obese and insulin-resistant patients. However, the benefits of vegetable intake in a therapeutic diet on postprandial glycemic and lipidemic responses have not been clarified. We studied the effects of the intake of spinach, a green leafy vegetable rich in dietary fiber and alpha-tocopherol, with a fat-rich meal on postprandial glycemic and lipidemic changes. Fourteen normal weight and 10 obese men consumed three test meals of bread, as a control, bread and butter, and bread and butter with boiled spinach. Blood samples were obtained prior to and 30, 60, 120, 180 and 240 min after consuming the test meals. Compared with the bread meal, consumption of the bread and butter meal showed a reduced peak glucose response at 30 min in normal (p<0.05) but not in obese subjects. The increase in triglyceride and decrease in LDL-cholesterol were greater after the butter-containing meal than after the bread meal (p<0.05). The alpha tocopherol/lipid level decreased and remained low after the bread and butter meal, but the decrease was smaller with the spinach-containing meal in obese subjects (p<0.05). These results suggest that green-leafy vegetable intake with a fat-rich meal is effective for supplying postprandial alpha-tocopherol in obese subjects, but consumption of a regular-sized dish cannot be expected to improve abnormal postprandial hyperglycemic or hyperlipidemic responses. PMID- 24064727 TI - Sweet potato [Ipomoea batatas (L.) Lam. "Tainong 57"] starch improves insulin sensitivity in high-fructose diet-fed rats by ameliorating adipocytokine levels, pro-inflammatory status, and insulin signaling. AB - The aim of this study was to investigate the effects of low-glycemic index (GI) sweet potato starch on adipocytokines, pro-inflammatory status, and insulin signaling in the high-fructose diet-induced insulin-resistant rat. We randomly divided 24 insulin-resistant rats and 16 normal rats into two groups fed a diet containing 575 g/kg of starch: a low-GI sweet potato starch (S) or a high-GI potato starch (P). The four experimental groups were labeled as follows: insulin resistant P (IR-P), insulin-resistant S (IR-S), normal P (N-P) and normal S (N S). After 4 wk on the experimental diets, an intraperitoneal glucose tolerance test (IPGTT) was conducted, and the homeostasis model assessment (HOMA), adipocytokines, pro-inflammatory cytokines levels, and insulin signaling-related protein expression were measured. The homeostasis model assessment values were significantly lower in the IR-S than in the IR-P group, suggesting that insulin sensitivity was improved among sweet potato starch-fed rats. Levels of tumor necrosis factor-alpha, interleukin-6, resistin, and retinol binding protein-4 were significantly lower in the IR-S versus the IR-P group, indicating an improvement of pro-inflammatory status in sweet potato starch-fed rats. The sweet potato starch diet also significantly enhanced the protein expression of phospho Tyr-insulin receptor substrate-1 and improved the translocation of glucose transporter 4 in the skeletal muscle. Our results illustrated that sweet potato starch feeding for 4 wk can improve insulin sensitivity in insulin-resistant rats, possibly by improving the adipocytokine levels, pro-inflammatory status, and insulin signaling. PMID- 24064728 TI - Usual dietary intakes of selected trace elements (Zn, Cu, Mn, I, Se, Cr, and Mo) and biotin revealed by a survey of four-season 7-consecutive day weighed dietary records in middle-aged Japanese dietitians. AB - We aimed to identify food sources of selected trace elements (Zn, Cu, Mn, I, Se, Cr, Mo) and biotin in the Japanese diet and to assess usual dietary intakes based on the ratios of within-person to between-person variance. Subjects were 98 middle-aged dietitians living in central Japan who participated in a survey of four-season 7 consecutive day weighed diet records. Based on the latest Standard Tables of Food Composition in Japan published in 2010, food sources of selected nutrients were located according to a contribution analysis, and computed usual dietary intakes. Dietary intakes were checked with the Dietary Reference Intakes for Japanese 2010. Prevalence of inadequacy in a group was determined using the Estimated Average Requirement cut-point method. The major contributors to selected trace elements and biotin were not only meat and milk, but also traditional Japanese food items, including rice, tofu and tofu products, fish, seaweed, chicken eggs, fermented soy bean seasonings, and green tea. Medians of usual intakes were estimated for Zn (men 8.9 mg, women 8.4 mg), Cu (1.32 mg, 1.21 mg), Mn (3.73 mg, 3.76 mg), I (312 MUg, 413 MUg), Se (97 MUg, 94 MUg), Cr (10 MUg, 9 MUg), Mo (226 MUg, 184 MUg), and biotin (51.7 MUg, 47.6 MUg). The prevalence of inadequacy of dietary intakes was high for Zn, Cu and Cr. Regarding I, the proportion above the Tolerant Upper Level was overestimated based on the crude mean value. We first identified food sources of selected trace elements and biotin in the Japanese diet, and assessed the usual intakes. PMID- 24064729 TI - Effect of 48-h food deprivation on the expressions of myosin heavy-chain isoforms and fiber type-related factors in rats. AB - The primary aim of this study was to examine the effects of 48-h food deprivation on rat skeletal muscle fiber type, according to myosin heavy-chain (MyHC) isoform composition and some metabolism-related factors in both slow-type dominant and fast-type dominant muscle tissues. Male Wistar rats (7 wk old) were treated with 48-h food deprivation or ad libitum feeding as control. After the treatment, the soleus muscle (slow-type dominant) and the extensor digitorum longus (EDL, fast type dominant) were excised. We found that 48-h food deprivation did not affect MyHC composition in either the soleus or EDL, compared with fed rats by electrophoretic separation of MyHC isoforms. However, 48-h food deprivation significantly increased the mRNA expression of fast-type MyHC2B in the EDL muscle. Moreover, food deprivation increased fatty acid metabolism, as shown by elevated levels of related serum energy substrates and mRNA expression of mitochondrial uncoupling protein (UCP) 3 and lipoprotein lipase (LPL) in both the soleus and EDL. UCP3 and LPL are generally expressed at higher levels in slow type fibers. Furthermore, we found that food deprivation significantly decreased the protein amounts of PGC1alpha and phosphorylated FOXO1, which are known as skeletal muscle fiber type regulators. In conclusion, 48-h food deprivation increased mRNA expression of fast-type MyHC isoform and oxidative metabolism related factors in EDL, whereas MyHC composition at the protein level did not change in either the soleus or EDL. PMID- 24064730 TI - Resting energy expenditure (REE) in six- to seventeen-year-old Japanese children and adolescents. AB - Accurate estimation of resting energy expenditure (REE) in children and adolescents is important to establish estimated energy requirements for the Japanese population. Our objectives were 1) to determine the REE of 6- to 17-y old Japanese children and adolescents by indirect calorimetry in order to estimate energy expenditure for this group, 2) to compare measured REE with predicted REE to determine the accuracy of predictive equations of REE for Japanese children and adolescents, and 3) to derive new predictive equations for REE for Japanese children and adolescents based on measured REE. REE was measured in 221 Japanese children and adolescents, aged 6 to 17 y old (113 boys and 108 girls) using a ventilated indirect calorimeter. Anthropometric and body composition measurements were also performed. REE expressed as absolute values increased with age in both genders, and there was a significant difference between genders in the 12-17 y age group. REE was strongly correlated with body weight (BW) and fat-free mass (FFM). REE adjusted for BW or FFM decreased with age in both genders, and a gender difference was still observed in the 12-17 y age group after this adjustment. The highest accuracy of prediction was achieved using the Dietary Reference Intake for Japanese (1969) for boys and the Molnar equation for girls. Step-down multiple regression analysis was carried out using either a combination of age, gender, BW, and height, or a combination of age, gender, FFM, and fat mass (FM). The predictive equation accounted for 75% (R2) and 76% of the variance, respectively. In conclusion, absolute REE increased and REE adjusted for BW or FFM decreased with age. The major determinant of REE was FFM, but significant gender differences were observed in the 12-17 y range for both absolute REE and adjusted REE. PMID- 24064731 TI - Evaluation of the prevalence of iodine intakes above the tolerable upper intake level from four 3-day dietary records in a Japanese population. AB - The Japanese population routinely consumes iodine-rich seaweed, thereby probably making Japan the nation with the highest iodine intake worldwide. The present study aimed to estimate the duration of dietary records (DRs) needed to calculate the usual iodine intake and to ascertain the frequency of iodine intakes above the tolerable upper intake level (UL) in the Dietary Reference Intakes for Japanese. Four 3-d DRs for the 4 seasons within a year were collected for 55 men and 58 women. On the basis of analysis of variance, the total variance in iodine intake was classified into inter-individual and intra-individual components. The frequency of appearance for high iodine intakes was estimated. The most commonly consumed types of iodine-containing food items were seaweed, milk and milk products, fish and shellfish, and tofu. The percentage contribution of intra individual variance was markedly greater than that of inter-individual variance, and the excessive iodine intake was intermittent rather than continuous. The duration for which dietary records were required to assess the usual intake of iodine within 10% of their true mean was 6,276 d for men and 4,953 d for women. The period that transpired until a value was exceeded once was 6.3 d/occurrence for values above UL (2,200 MUg), 8.5 d/occurrence for values above 3,000 MUg, 9.8 d/occurrence for values above 4,000 MUg, 11.2 d/occurrence for values above 5,000 MUg, and 16.7 d/occurrence for values above 10,000 MUg. To avoid errors in interpretation, it is inappropriate to assess the habitual nutrient intake of a nutrient that is intermittently consumed at maximal levels. It is important to assess the iodine intake in consideration of the range of the nutrient intake and of the time period in which the upper limit is exceeded. PMID- 24064733 TI - Genetic variants of the fatty acid desaturase gene cluster are associated with plasma LDL cholesterol levels in Japanese males. AB - Fatty acid (FA) compositions in tissues are related to metabolic disorders, and consequently the appropriate management of underlying FA compositions in tissues is considered to be important. However, the relationship among the serum lipid profiles, the FA composition of the red blood cell (RBC) membranes and genetic variations in the fatty acid desaturase (FADS) genes in Japanese men is unclear. In this study, the subjects recruited were 137 Japanese men, 40 to 60 y old, who had a regular health checkup. Their serum lipid profile and the relative FA composition of the RBC membranes were measured. They were genotyped for the single nucleotide polymorphisms (SNPs) rs174553, rs174546, rs99780 and rs174583 in FADS gene. Multiple regression analysis was conducted to detect the relationship among hyperlipidemia, the FA composition of the RBC and the FADS genotypes. As a result, the homozygous genotype for the minor alleles in rs174553, rs174546, rs99780 were found to be associated with lower low-density lipoprotein cholesterol (LDL-C) levels and a lower LDL-C/total-cholesterol ratio. The homozygous genotype for the minor alleles reduced the risk of high LDL-C level (R2=0.50, beta=-0.20, p=0.009), whereas, the arachidonic acid (AA) levels in the carriers of the homozygous genotype for the minor alleles tended to be lower compared with the carriers of the major alleles. However, no significant differences were observed in any FA level among the three genotypes for four SNPs. These results indicate that the appropriate management of serum LDL-C levels depending on genetic predisposition in FADS genotypes should be encouraged. PMID- 24064732 TI - Isoflavones derived from soy beans prevent MuRF1-mediated muscle atrophy in C2C12 myotubes through SIRT1 activation. AB - Proinflammatory cytokines are factors that induce ubiquitin-proteasome-dependent proteolysis in skeletal muscle, causing muscle atrophy. Although isoflavones, as potent antioxidative nutrients, have been known to reduce muscle damage during the catabolic state, the non-antioxidant effects of isoflavones against muscle atrophy are not well known. Here we report on the inhibitory effects of isoflavones such as genistein and daidzein on muscle atrophy caused by tumor necrosis factor (TNF)-alpha treatment. In C2C12 myotubes, TNF-alpha treatment markedly elevated the expression of the muscle-specific ubiquitin ligase MuRF1, but not of atrogin-1, leading to myotube atrophy. We found that MuRF1 promoter activity was mediated by acetylation of p65, a subunit of NFkappaB, a downstream target of the TNF-alpha signaling pathway; increased MuRF1 promoter activity was abolished by SIRT1, which is associated with deacetylation of p65. Of interest, isoflavones induced expression of SIRT1 mRNA and phosphorylation of AMP kinase, which is well known to stimulate SIRT1 expression, although there was no direct effect on SIRT1 activation. Moreover, isoflavones significantly suppressed MuRF1 promoter activity and myotube atrophy induced by TNF-alpha in C2C12 myotubes. These results suggest that isoflavones suppress myotube atrophy in skeletal muscle cells through activation of SIRT1 signaling. Thus, the efficacy of isoflavones could provide a novel therapeutic approach against inflammation related muscle atrophy. PMID- 24064734 TI - Altitudinal variation of antioxidant components and capability in Indocalamus latifolius (Keng) McClure leaf. AB - Indocalamus latifolius (Keng) McClure leaf is a popular food material in East Asia due to its antioxidant and anticorrosive activities. To utilize it more effectively, we investigated the discrepancy of antioxidant activities and active compound content in Indocalamus latifolius leaf along with the altitude change. Total flavonoids, phenolics, titerpenoids and eight characteristic active constituents, i.e, orientin, isoorientin, vitexin, homovitexin, p-coumaric acid, chlorogenic acid, caffeic acid, and ferulic acid, were determined by UV spectrophotometer and synchronous RP-HPLC, respectively. Antioxidant activity was measured using DPPH and FRAP methods. Our data showed that the content of TP and TF, DPPH radical scavenging ability and ferric reduction power of Indocalamus latifolius leaf changed as altitude altered, with the trends of decreasing gradually when lower than 700 m and then increasing to 1,000 m. Chlorogenic acid and orientin were the main characteristic compounds in Indocalamus latifolius leaf and were also affected by altitude. Our result indicated that higher altitude with an adverse environment is conducive to secondary metabolite accumulation for Indocalamus latifolius. It would provide a theoretical basis to regulate the leaf collection conditions in the industrial use of Indocalamus latifolius leaf. PMID- 24064735 TI - Changes in plasma pyridoxal 5'-phosphate concentration during pregnancy stages in Japanese women. AB - Most Japanese women do not consume the estimated average requirement of vitamin B6 (1.7 mg/d) during pregnancy. Nevertheless, these deficiencies are not reported. We investigated a nutritional biomarker of vitamin B6 in pregnant Japanese women as well as their vitamin B6 intakes. Vitamin B6 intakes in the first, second, and third trimesters of pregnancy, and 1 mo after delivery were 0.79+/-0.61 (n=56), 0.81+/-0.29 (n=71), 0.90+/-0.35 (n=92), and 1.00+/-0.31 (n=44) mg/d, respectively. Plasma pyridoxal 5'-phosphate (PLP) concentrations in the first, second, and third trimesters of pregnancy, and 1 mo after delivery were 57.1+/-27.6 (n=56), 23.3+/-16.7 (n=71), 18.3+/-12.5 (n=92), and 43.9+/-33.4 (n=44) nmol/L, respectively. The plasma concentrations significantly decreased in the second and third trimesters of pregnancy compared to values from the first trimester (p<0.05), and these concentrations returned to the values of the first trimester of pregnancy 1 mo after birth. PMID- 24064736 TI - The relationship between dietary vitamin A intake and the levels of sialic acid in the breast milk of lactating women. AB - Sialic acid (SA) is an important nutrient but few studies have examined the link between dietary intake and breast milk sialic acid. The purpose of this observational study was to assess the potential relationship between human breast milk sialic acid levels and dietary nutrition intake 40 d postpartum. The study population included 90 healthy women who were lactating. Human breast milk SA concentrations were measured using fluorescence detector-high performance liquid chromatography (HPLC-FLD) analysis and nutritional intake was estimated by a computerized validated food frequency questionnaire. SA in human breast milk was bound to free oligosaccharides (82.35%), protein (15.27%) and free sialic acid (2.37%). The findings of this study indicate that subjects with higher milk SA levels showed statistically higher levels of vitamin A compared with subjects with lower SA levels (423.48+/-172.29 vs. 602.22+/-126.46 MUg/d, p=0.000). In addition, there was a certain association (standardized coefficients=0.713; p=0.000) between breast milk SA and vitamin A intake in healthy young subjects. This study demonstrated that dietary vitamin A intake has a certain relationship with breast milk SA concentrations. This may be attributed to the influence of vitamin A on sialic acid glycoprotein and sialic acid mucopolysaccharide in the human body or the common food sources for vitamin A and sialic acid. Additional study is required to further investigate this relationship. PMID- 24064737 TI - The maximum single dose of resistant maltodextrin that does not cause diarrhea in humans. AB - The objective of the present study was to determine the maximum dose of resistant maltodextrin (Fibersol)-2, a non-viscous water-soluble dietary fiber), that does not induce transitory diarrhea. Ten healthy adult subjects (5 men and 5 women) ingested Fibersol-2 at increasing dose levels of 0.7, 0.8, 0.9, 1.0, and 1.1 g/kg body weight (bw). Each administration was separated from the previous dose by an interval of 1 wk. The highest dose level that did not cause diarrhea in any subject was regarded as the maximum non-effective level for a single dose. The results showed that no subject of either sex experienced diarrhea at dose levels of 0.7, 0.8, 0.9, or 1.0 g/kg bw. At the highest dose level of 1.1 g/kg bw, no female subject experienced diarrhea, whereas 1 male subject developed diarrhea with muddy stools 2 h after ingestion of the test substance. Consequently, the maximum non-effective level for a single dose of the resistant maltodextrin Fibersol-2 is 1.0 g/kg bw for men and >1.1 g/kg bw for women. Gastrointestinal symptoms were gurgling sounds in 4 subjects (7 events) and flatus in 5 subjects (9 events), although no association with dose level was observed. These symptoms were mild and transient and resolved without treatment. PMID- 24064738 TI - Identification of carbonyl reductase 1 as a resveratrol-binding protein by affinity chromatography using 4'-amino-3,5-dihydroxy-trans-stilbene. AB - The mechanisms by which resveratrol (3,4',5-trihydroxy-trans-stilbene) elicits diverse health benefits remain unclear because the intracellular target molecules of resveratrol are poorly defined. We screened resveratrol-binding proteins from lysates of MCF-7 breast cancer cells using resveratrol-affinity resin, which was constructed by immobilizing 4'-amino-3,5-dihydroxy-trans-stilbene on activated CH Sepharose. On SDS-PAGE, two bands were detected as proteins that specifically bound to the resveratrol-affinity resin. One of these, a 30-kDa protein, was identified as human carbonyl reductase 1 (CBR1) by hybrid linear ion trap/time-of flight mass spectrometry. Similarly, recombinant CBR1 bound to the resveratrol affinity resin in the absence of resveratrol, but not in the presence of resveratrol. Among its activities, CBR1 catalyzes a NADPH-dependent reduction of the anticancer drug doxorubicin to the cardiotoxin doxorubicinol. The effects of doxorubicin on viability of MCF-7 cells were enhanced by resveratrol, 3,5 dihydroxy-4'-methoxy-trans-stilbene, 3,4'-dihydroxy-5-methoxy-trans-stilbene, and 4'-amino-3,5-dihydroxy-trans-stilbene at concentrations of 1 and 10 MUM. Resveratrol and these derivatives inhibited CBR1 activities to a similar degree at concentrations of 100 and 200 MUM. However, 3,5-dimethoxy-4'-hydroxy-trans stilbene and m-hydroquinone had no influence on doxorubicin cytotoxicity or CBR1 activity. Resveratrol inhibited CBR1 activity through an apparent mix of competitive (Ki=55.8 MUM) and noncompetitive (alphaKi=164 MUM; alpha=2.98) inhibition kinetics. These results indicate that (i) resveratrol enhances the cytotoxic effects of doxorubicin on MCF-7 cells; (ii) the moiety that contains the 3,5-dihydroxyl groups of resveratrol, but not the m-hydroquinone structure alone, is required to bind CBR1; and (iii) resveratrol acts as a mixed-type inhibitor of CBR1 activity on doxorubicin. PMID- 24064739 TI - Vitamin B6 and its effect on systemic carcinogenesis. PMID- 24064740 TI - Longitudinal association of C-reactive protein and lung function over 13 years: The EPIC-Norfolk study. AB - Chronic obstructive pulmonary disease is known to be associated with systemic inflammation. We examined the longitudinal association of C-reactive protein (CRP) and lung function in a cohort of 18,110 men and women from the European Prospective Investigation Into Cancer in Norfolk who were 40-79 years of age at baseline (recruited in 1993-1997) and followed-up through 2011. We assessed lung function by measuring forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) at baseline, 4 years, and 13 years. Serum CRP levels were measured using a high-sensitivity assay at baseline and the 13-year follow up. Cross-sectional and longitudinal associations of loge-CRP and lung function were examined using multivariable linear mixed models. In the cross-sectional analysis, 1-standard-deviation increase in baseline loge-CRP (about 3-fold higher CRP on the original milligrams per liter scale) was associated with a -86.3 mL (95% confidence interval: -93.9, -78.6) reduction in FEV1. In longitudinal analysis, a 1-standard-deviation increase in loge-CRP over 13 years was also associated with a -64.0 mL (95% confidence interval: -72.1, -55.8) decline in FEV1 over the same period. The associations were similar for FVC and persisted among lifetime never-smokers. Baseline CRP levels were not predictive of the rate of change in FEV1 or FVC over time. In the present study, we found longitudinal observational evidence that suggested that increases in systemic inflammation are associated with declines in lung function. PMID- 24064741 TI - Regression calibration in nutritional epidemiology: example of fat density and total energy in relationship to postmenopausal breast cancer. AB - Regression calibration using biomarkers provides an attractive approach to strengthening nutritional epidemiology. We consider this approach to assessing the relationship of fat and total energy consumption with postmenopausal breast cancer. In analyses that included fat density data, biomarker-calibrated total energy was positively associated with postmenopausal breast cancer incidence in cohorts of the US Women's Health Initiative from 1994-2010. The estimated hazard ratio for a 20% increment in calibrated food frequency questionnaire (FFQ) energy was 1.22 (95% confidence interval (CI): 1.15, 1.30). This association was not evident without biomarker calibration, and it ceased to be apparent following control for body mass index (weight (kg)/height (m)(2)), suggesting that the association is mediated by body fat deposition over time. The hazard ratio for a corresponding 40% increment in FFQ fat density was 1.05 (95% CI: 1.00, 1.09). A stronger fat density association, with a hazard ratio of 1.19 (95% CI: 1.00, 1.41), emerged from analyses that used 4-day food records for dietary assessment. FFQ-based analyses were also carried out by using a second dietary assessment in place of the biomarker for calibration. This type of calibration did not correct for systematic bias in energy assessment, but may be able to accommodate the "noise" component of dietary measurement error. Implications for epidemiologic applications more generally are described. PMID- 24064743 TI - Snippets from the past: is Flint, Michigan, the birthplace of the case-control study? AB - In the summer of 1924, an outbreak of scarlet fever occurred in Flint, Michigan. Unable to trace it to the usual causes, particularly fresh milk, the Michigan Department of Health used a novel approach to disentangle the enigma: The 116 cases of scarlet fever were compared with 117 "controls" selected from neighbors of the quarantined cases and from patients at the City Health Center who had been treated for ailments unrelated to scarlet fever. The extraordinary culprit was ice cream, which had a frequent/occasional/none consumption prevalence of 60%, 34%, and 6% among the cases and 24%, 51%, and 25% among the controls, respectively. The 1925 report reads, "Detailed epidemiological investigation, by means of case histories and control histories on well persons, confirmed early suspicions and established the fact that the epidemic was spread by ice cream" (Am J Hyg. 1925;5(5):669-681). This forgotten epidemiologic study is the oldest study using the case-control design to have been resurrected thus far. The case control study design may have been conceived simultaneously, but independently and for different purposes, in England (Janet Lane-Claypon's 1926 report on the determinants of breast cancer) and the United States. PMID- 24064742 TI - Do psychosocial stress and social disadvantage modify the association between air pollution and blood pressure?: the multi-ethnic study of atherosclerosis. AB - Researchers have theorized that social and psychosocial factors increase vulnerability to the deleterious health effects of environmental hazards. We used baseline examination data (2000-2002) from the Multi-Ethnic Study of Atherosclerosis. Participants were 45-84 years of age and free of clinical cardiovascular disease at enrollment (n = 6814). The modifying role of social and psychosocial factors on the association between exposure to air pollution comprising particulate matter less than 2.5 um in aerodynamic diameter (PM2.5) and blood pressure measures were examined using linear regression models. There was no evidence of synergistic effects of higher PM2.5 and adverse social/psychosocial factors on blood pressure. In contrast, there was weak evidence of stronger associations of PM2.5 with blood pressure in higher socioeconomic status groups. For example, those in the 10th percentile of the income distribution (i.e., low income) showed no association between PM2.5 and diastolic blood pressure (b = -0.41 mmHg; 95% confidence interval: -1.40, 0.61), whereas those in the 90th percentile of the income distribution (i.e., high income) showed a 1.52-mmHg increase in diastolic blood pressure for each 10 ug/m(3) increase in PM2.5 (95% confidence interval: 0.22, 2.83). Our results are not consistent with the hypothesis that there are stronger associations between PM2.5 exposures and blood pressure in persons of lower socioeconomic status or those with greater psychosocial adversity. PMID- 24064744 TI - Age-period-cohort analysis of trends in amyotrophic lateral sclerosis in Denmark, 1970-2009. AB - Amyotrophic lateral sclerosis (ALS) is a disease of the motor neuron with poorly understood etiology. Recent studies have suggested that the incidence rate of ALS and the rate of death from ALS are increasing, but it is unclear whether this is due to changing exposures or improvements in diagnosis. We used age-period-cohort models to investigate trends in ALS incidence (hospitalization) from 1982 to 2009 and ALS mortality from 1970 to 2009 in Denmark. Among those 45 years of age or older, 4,265 deaths (incidence rate = 5.35 per 100,000 person-years) and 3,228 incident diagnoses (incidence rate = 5.55 per 100,000 person-years) were recorded. Age-adjusted mortality rates increased by an average of 3.0% annually between 1970 and 2009 and by an average of 2.1% annually after 1982. Age-period cohort analyses suggested that the full age-period-cohort model provided the best fit to the mortality data (P < 0.001), although restriction to the post-1982 period suggested that the age-cohort model provided the best fit. Age-adjusted incidence rates increased by 1.6% annually after 1982 (P < 0.001), which was best explained by the age-period model, with borderline significant cohort effects (P = 0.08). A consistent finding regardless of parameterization or data subset appeared to be an increase in ALS incidence and mortality rate with later birth cohorts, up to a birth year of at least 1910. PMID- 24064745 TI - Income inequality among American states and the incidence of major depression. AB - BACKGROUND: Although cross-sectional and ecological studies have shown that higher area-level income inequality is related to increased risk for depression, few longitudinal studies have been conducted. This investigation examines the relationship between state-level income inequality and major depression among adults participating in a population-based, representative longitudinal study. METHODS: We used data from the National Epidemiologic Survey on Alcohol and Related Conditions (n=34 653). Respondents completed structured diagnostic interviews at baseline (2001-2002) and follow-up (2004-2005). Weighted multilevel modelling was used to determine if U.S. state-level income inequality (measured by the Gini coefficient) was a significant predictor of depression at baseline and at follow-up, while controlling for individual-level and state-level covariates. We also repeated the longitudinal analyses, excluding those who had a history of depression or at baseline, in order to test whether income inequality was related to incident depression. RESULTS: State-level inequality was associated with increased incidence of depression among women but not men. In comparison to women residing in states belonging to the lowest quintile of income inequality, women were at increased risk for depression in the second (OR=1.18, 95% CI 0.86 to 1.62), third (OR=1.22, 95% CI 0.91 to 1.62), fourth (OR=1.37, 95% CI 1.03 to 1.82) and fifth (OR=1.50, 95% CI 1.14 to 1.96) quintiles at follow-up (p<0.05 for the linear trend). CONCLUSIONS: Living in a state with higher income inequality increases the risk for the development of depression among women. PMID- 24064746 TI - Asymmetric domino synthesis of indanes bearing four contiguous stereocentres catalyzed by sub-mol% loadings of a squaramide in minutes. AB - An efficient diastereo- and enantioselective synthesis of polyfunctionalized indanes bearing four contiguous stereogenic centres in generally very short reaction times and sub-mol% squaramide catalyst loadings has been developed. The novel methodology creates a maximum of two stereocentres per bond formation via an organocatalytic Michael-Henry domino reaction. PMID- 24064747 TI - Dosimetric definitions of total lung volumes in calculating parameters predictive for radiation-induced pneumonitis. AB - OBJECTIVES: The volume of normal lung receiving 20 Gy (V20) and the mean lung dose (MLD) represent dosimetric parameters used for identifying risk of radiation pneumonitis. However, the total lung volume for dosimetric analysis has been defined differently. Herein we investigate to quantify the dosimetric differences when analysis is based on either definition (ie, excluding planning target volume [PTV] vs. gross tumor volume [GTV] from the total bilateral lung volume). METHODS: Sixty-one patients with lung cancer who had undergone definitive radiation therapy were retrospectively reviewed. Dosimetric parameters were calculated when excluding GTV or PTV from the total bilateral lung volume. RESULTS: Median GTV to PTV margin was 1.3 cm (range, 0.4 to 3.8 cm). Median heterogeneity-corrected RT dose was 74 Gy with the median GTV of 110 mL (range, 13.79 to 665.8 mL) and the median PTV of 346 mL (range, 39.8 to 1258 mL).The MLD, V5, V10, V20, and V30 were all slightly higher and significant when excluding GTV from the total bilateral lung volume compared with similar dosimetric parameters when excluding PTV (P<0.001). Average MLD was 14.8 and 16.7 Gy when excluding PTV and GTV, respectively. Mean V5, V10, V20, and V30 were 49.8%, 38%, 25%, and 18.8% when excluding PTV versus 51.3%, 40%, 28%, and 21.5% when excluding GTV. There were 4 patients with clinical pneumonitis and all had the V20>23% when excluding the PTV versus the V20>27% when excluding the GTV from total bilateral lung volume. CONCLUSIONS: A small but significant difference exists between the 2 approaches used to calculate dosimetric variables for lung dose. This difference should be taken into account when comparing dosimetric information between different institutions and when optimizing treatment plans. PMID- 24064748 TI - Clinical Impact of Percutaneous Transhepatic Insertion of Metal Biliary Endoprostheses for Palliation of Jaundice and Facilitation of Chemotherapy. AB - OBJECTIVE: To describe the technique and report on the clinical benefit of percutaneous transhepatic metal biliary endoprosthesis (TMBE) placement for the palliation of malignant biliary obstruction (MBO). MATERIALS AND METHODS: This is a retrospective single-center case series of 31 TMBE placements between October 2007 and October 2011 in 29 patients with inoperable MBO who failed endoscopic drainage and were not candidates for surgical resection. The mean age was 66.4 years. Eastern Cooperative Oncology Group performance scores were <=2 in all patients. Data on procedural success, clinical and radiologic markers of stent patency, procedure-related complications, return to medically treatable status, benefit from chemotherapy, and survival were recorded. RESULTS: All TMBE procedures were successful with no major procedure-related complications, and all patients improved clinically. Mean preprocedural and postprocedural bilirubin concentrations were 228.9+/-138.4 and 39.9.0+/-33.6 MUmol/L, respectively (P<0.0001). Mean overall survival and occlusion-free survival were 9.355+/-2.425 months (95% confidence interval [4.60-14.12]) and 4.678+/-0.720 months (95% confidence interval [3.27-6.09]), respectively. Chemotherapy was initiated or reinstated in 16 patients (55%), 7 of whom (44%) demonstrated stable disease or partial response. Three patients were lost to follow-up. CONCLUSIONS: TMBE provides acceptable palliation for patients with inoperable MBO who have failed endoscopic drainage. Stents appear to remain patent for the remainder of the patient's life in most cases and may facilitate the first induction or reinstatement of chemotherapy with further clinical response in some patients. PMID- 24064749 TI - Time to Nadir PSA: Of Popes and PSA--The Immortality Bias. AB - OBJECTIVES: The objective of the study was to investigate prostate-specific antigen (PSA) nadir (nPSA) and time to nPSA (TnPSA) as prognostic variables for outcomes after definitive high-dose (>75 Gy) external beam radiation therapy (RT) without androgen deprivation therapy while correcting for immortal-time bias. METHODS: nPSA and TnPSA were available for 410 patients. nPSA and TnPSA's impact on freedom from biochemical failure, freedom from metastasis, and prostate cancer specific survival was assessed on univariate and multivariate analysis using Kaplan-Meier and Cox proportional hazards regression. Outcomes were also evaluated relative to the time since achieving nPSA and not relative to the time of RT, given the intrinsic time bias in TnPSA. RESULTS: Median nPSA was 0.7 ng/mL (interquartile range: 0.4 to 1.1), with a median TnPSA of 25.0 months (IQR: 15.0 to 40.0). On univariate analysis both nPSA and TnPSA were predictive of all endpoints: freedom from biochemical failure, freedom from metastasis, and prostate cancer-specific survival, as categorical (all P<0.0001) and continuous (all P<0.01) variables. However, after adjusting for immortal-time bias the benefit of long TnPSA was mostly lost. On Cox proportional hazards, a TnPSA<12 months did have worse prognosis for biochemical failure and distant metastasis as compared with longer TnPSA, but for those who achieved nadir >12 months from the time of RT the TnPSA was no longer prognostic. CONCLUSIONS: For dose-escalated RT a lower nPSA is prognostic, but the benefit of a long TnPSA is largely an immortal-time bias and that a longer TnPSA is not in and of itself a significant favorable factor except as compared with those with the shortest TnPSA of <12 months. PMID- 24064750 TI - The Natural History, Treatment Pattern, and Outcomes of Patients With Micropapillary Bladder Carcinoma. AB - OBJECTIVE: Micropapillary bladder carcinoma (MPBC) is a rare variant of urothelial cancer. Most literature on MPBC is from case series reports. This study's objective was to examine the epidemiology, natural history, and prognostic factors of MPBC using a population-based registry, in addition to a literature review. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database identified 98 histologically confirmed MPBC patients from 2001 and 2007. In addition, 213 MPBC cases were identified in published literature. The clinical, demographic characteristics, treatment, and survival outcomes were compared between these 2 cohorts. RESULTS: Among patients identified in SEER, MPBC accounted for approximately 0.01% of primary bladder tumors, with the median age of 72 years (range, 26 to 95 y). Among the MPBC cases, 56.1% had muscle invasive disease, 75.5% had poor or undifferentiated histology, and 30.6% underwent a radical or partial cystectomy. The 1-, 3-, and 5-year overall survival rates for the SEER cohort were estimated at 84.5%, 57.3%, and 42.3%, respectively. Using multivariate analysis, tumor stage and marital status were the most significant predictors for cancer-specific survival. When comparing published single-institution studies to the SEER cohort, significant differences existed in demographic characteristics including age at diagnosis, male-to-female ratio, tumor stage, cystectomy treatment, and survival outcomes, likely reflecting differences in practice patterns. CONCLUSIONS: This is the first population-based study to analyze MPBC's epidemiology, tumor characteristics, and survival rates. Emphases on early detection, cystectomy, and multimodality in treatment are needed. PMID- 24064751 TI - The Integration of Multimodality Care for the Treatment of Small Cell Lung Cancer in a Rural Population and Its Impact on Survival. AB - OBJECTIVES: Many factors and disparities contribute to the multidisciplinary management of small cell lung cancer (SCLC). Our objective was to conduct a cancer registry analysis of patients with SCLC in Kentucky to identify factors affecting treatment choice and mortality. METHODS: Database collection was done through the Kentucky Cancer Registry, which is part of the Surveillance, Epidemiology, and End Results program. Patients diagnosed between 1995 and 2008, diagnosed with SCLC, and AJCC stage I through IV were included. Statistical analyses were performed to identify variables affecting initial treatment choice and survival. RESULTS: Analysis evaluated 4814 patients from the Kentucky Cancer Registry. For extensive stage, age (P<0.001) and urban versus rural county (P=0.03) were significantly associated with the type of treatment received. Age was the only variable impacting treatment choice in limited-stage patients. Limited stage patients were more likely to receive chemotherapy and radiation (chemoRT; 54.6% vs. 46.5%). On multivariate analysis, for extensive stage patients, age at diagnosis, male sex, and treatments other than chemoRT were variables associated for increased risk of death. In limited stage patients, increasing age, and treatments other than chemoRT were variables associated with increased risk of death. Survival was significantly improved in both limited stage and extensive stage patients that received chemoRT compared with chemotherapy only, radiation only, or no treatment. CONCLUSIONS: Treatment with chemoRT was associated with improved survival in patients with limited and extensive stage SCLC. In these patients, socioeconomic, racial, or geographic factors did not impact the type of treatment received or survival. PMID- 24064752 TI - Pancreatectomy Versus Conservative Management for Pancreatic Cancer: A Question of Lead-time Bias. AB - OBJECTIVES: Pancreatectomy is regarded as the only curative treatment for cancer of the pancreas. A population-based study was conducted to examine its efficacy within the general community. METHODS: Overall and cancer-specific survivals were compared between individuals treated with pancreatectomy and those managed nonsurgically. Kaplan-Meier analysis was used, based on both time from diagnosis and attained age (age at diagnosis plus time from diagnosis). RESULTS: A total of 7830 Surveillance Epidemiology and End Results cases of localized cancer of the pancreatic head were retrieved, diagnosed from 2000 to 2008. Median follow-up was 12 months; the pancreatectomy cohort was 5 years younger and had 7-fold less stage III disease. Overall and cancer-specific survivals were 17% and 21% at 5 years from time of diagnosis in the pancreatectomy cohort versus 2% and 4% in the nonsurgical cohort, respectively (P<0.001). However, the overall and cancer specific survival curves were nearly superimposed on each other when based on attained age. Moreover, the proportion of deaths attributable to pancreatic cancer exceeded 85% in both cohorts. CONCLUSIONS: A lead-time bias is hypothesized to explain the survival discrepancies seen between time from diagnosis and attained age analyses; the pancreatectomy cohort was diagnosed earlier, with less disease. If most of these individuals had occult metastases at diagnosis, which manifested later and caused death at similar ages as the nonsurgical cohort, their survival from time of diagnosis would appear speciously improved. A randomized controlled trial would be necessary to confirm whether or not the survival advantage ascribed to pancreatectomy should be attributed to lead-time bias. PMID- 24064753 TI - Radioembolization With Yttrium-90 Resin Microspheres in Hepatocellular Carcinoma: A Multicenter Prospective Study. AB - OBJECTIVES: The aim of this prospective study was to reveal the efficacy and safety of Yttrium-90 (Y) radioembolization in Korean patients with hepatocellular carcinoma (HCC). METHODS: A total of 40 HCC patients were prospectively recruited from 7 centers. The response to treatment was assessed on the basis of the modified Response Evaluation Criteria in Solid Tumors criteria. The time to progression and overall survival were also evaluated, and the assessment of safety was done according to National Cancer Institute Common Terminology Criteria, Version 3.0. RESULTS: Forty-two treatments of Y radioembolization were carried out. Median follow-up was 29 months. At 3 months, the complete response, partial response (PR), and stable disease were seen in 4 (10.0%), 19 (47.5%), and 15 (37.5%) patients, respectively. The response rate was 57.5% (23/40), and disease control rate was 95% (38/40) at 3 months. The response rate at 6 months was 63.9% (23/36), and disease control rate was 83.3% (30/36). The median time to progression was 18 months. During follow-up, 10 HCC-related deaths occurred and the 3-year survival rate was 75%. In 19 patients with Barcelona Clinic Liver Cancer-B stage, the 3-year survival rate was 50%. The tumor number (>5) was the only significant predictor associated with survival. The most common adverse event was abdominal pain of mild to moderate degree, and all the complications were manageable. Twenty-six (65%) patients underwent other treatments such as transarterial chemoembolization because of local progression or remnant viable lesion. CONCLUSIONS: Y radioembolization might be a safe and effective treatment modality in intermediate-stage to advanced-stage HCC. PMID- 24064754 TI - Surgical Treatment of Gastrointestinal Stromal Tumors Located in the Stomach in the Imatinib Era. AB - BACKGROUND: Imatinib has changed the treatment of gastrointestinal stromal tumors (GISTs). Preoperative imatinib treatment can be administered to patients with locally advanced disease to reduce the risk of incomplete resection, tumor spill, and lessen the extent of resection. In metastatic GIST, surgery follows imatinib in responding patients with resectable disease. In this study, the outcome of surgically treated patients with a gastric GIST with and without preoperative imatinib was investigated. METHODS: Patients surgically treated for a gastric GIST at our institute between 1999 and 2011 were included. Patient data were retrieved from a prospectively maintained database. RESULTS: A consecutive series of 47 patients was identified: 17 patients were treated with primary surgery (group 1) and 30 patients received imatinib before surgery (group 2). Preoperative imatinib led to a 33% reduction in tumor size. All patients in group 1 and 23 patients (77%) in group 2 had a complete resection (R0) without tumor spill. At a median follow-up of 30 months, 4 patients in group 2 had died of GIST. In these 4 patients, either the resection had been irradical or tumor spill had occurred, and 3 of them had radiologic progressive disease at the time of surgery. CONCLUSIONS: In this surgical series of gastric GIST patients, preoperative imatinib led to a major reduction in tumor size. Irradical resection, tumor spill, and progressive disease at the time of surgery were associated with poor prognosis. PMID- 24064755 TI - Early, Prophylactic Thyroidectomy in Hereditary Medullary Thyroid Carcinoma: A 26 year Monoinstitutional Experience. AB - PURPOSE: Prophylactic thyroidectomy has been encouraged for children with REarranged during Transfection (RET) germline mutations to prevent the onset, persistence, or recurrence of medullary thyroid carcinoma (MTC). The American Thyroid Association (ATA) recently published guidelines on the timing of prophylactic thyroidectomy. Our aim here was to seek information on the optimal timing of surgery for carriers of RET gene mutations with no clinical evidence of disease, bearing in mind the ATA recommendations. METHODS: From 1986 to 2012, total thyroidectomy was performed at our institute on 31 carriers of RET gene mutations, 28 of them found on family screening in the post-RET era, and the other 3 under 20 years of age and classified as "early cases" in the pre-RET era. The following parameters were studied: age at surgery, MTC risk, basal calcitonin (bCT) and pentagastrin-stimulated calcitonin (sCT), surgery outcomes, and persistence of disease. RESULTS: By family, the most prevalent mutation was codon 634 (30%) RET mutation. The youngest MTC patient was 5 years old. Overall, MTC was found in 68% of cases; 52% of the sample had a normal bCT and 25% had an sCT unresponsive to pentagastrin. The only factor predicting the risk of MTC at final histology was an ATA-RET risk level C. On receiver oparating curves analysis, a cutoff at age over 24 years predicted (P=0.06) a yield of MTC in the resected specimen. Interestingly, none of the patients with MTC had nodal involvement (0/21 patients with MTC). Yet, none of the patients had permanent nerve palsy, and only 1 patient had permanent hypocalcemia. bCT was normal postoperatively and during the follow-up in all but 3 patients. CONCLUSIONS: It is noteworthy that the yield of cancer in removed thyroid was 100% for codon 634 (9/9 patients, 5 families) and for codons 891 and 768 (2/2 patients in each of the 2 families with those codon mutations), followed by 67% for codon 609 (4/6 patients, 1 family), and 60% for codon 618 (3/5 patients in 4 families) RET mutation. In cases of ATA RET levels B and C, waiting for an increase in bCT and/or sCT may not guarantee that prophylactic surgery is performed before MTC develops (which would assure patients a life free of diseases and a less-invasive surgical procedure, without any need for central lymph-node dissection). PMID- 24064756 TI - Pain Intensity and Pain Interference in Patients With Lung Cancer: A Pilot Study of Biopsychosocial Predictors. AB - OBJECTIVE: To explore biopsychosocial factors (beliefs, depression, catastrophizing cytokines) in individuals newly diagnosed with lung cancer and no pain to determine their relationship at diagnosis and across time and to determine whether these factors contribute to pain intensity or pain interference with function at pain onset. MATERIALS AND METHODS: A longitudinal, exploratory, pilot study was implemented in a private medical center and a VA medical center in the southeast. Twelve subjects not experiencing pain related to cancer of the lung or its treatment were recruited. A Karnofsky status of 40% and hemoglobin of 8 g were required. Five questionnaires were completed and 10 mL of blood was drawn at baseline; 4 questionnaires and blood draws were repeated monthly for 5 months. One baseline questionnaire and a pain assessment were added at final. Demographic, clinical, and questionnaire data were summarized; standardized scale scores were calculated. RESULTS: Biopsychosocial scores that were low at baseline increased from T1-T4 but decreased slightly T5-T6. Individuals with higher pain intensity and higher pain interference at final had higher psychosocial scores at baseline than individuals with lower pain intensity and lower pain interference at final. CONCLUSIONS: Unrelated to disease stage, metastasis, or treatment, unique levels of biopsychosocial factors are observed in patients newly diagnosed with lung cancer who report higher levels of pain intensity and higher levels of pain interference at the time pain occurs. Replication studies are needed to validate this response pattern and determine the value of repeated individual assessments. PMID- 24064757 TI - Safety of Abiraterone Acetate in Castration-resistant Prostate Cancer Patients With Concomitant Cardiovascular Risk Factors. AB - OBJECTIVES: The aim of this study was to evaluate the safety profile of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) men with cardiovascular comorbidity, as little conclusive safety data are available in this patient subset. PATIENTS AND METHODS: A retrospective analysis of mCRPC patients with controlled cardiovascular comorbidities, receiving AA 1000 mg administered orally once daily and prednisone 5 mg twice daily, between April 2011 and July 2012, was performed. All clinical and instrumental variables and toxicity data were analyzed by descriptive statistics: mean, standard deviation, minimum and maximum values for continuous variables, and absolute and relative frequencies for categorical variables. RESULTS: A total of 51 mCRPC patients were evaluated. Metastatic sites included the bone (74%), lungs, and liver (26%). All patients were previously treated with at least 2 lines of hormone and 1 docetaxel based chemotherapy. Preexisting cardiac risk factors included hypertension (41%), cardiac ischemia (12%), arrhythmias (6%), dislipidemia (18%), and hyperglycemia (30%). No grade 3-4 adverse events were observed. Grade 1-2 adverse events included fluid retention (18%), asthenia (15%), and hypertension (16%). Median progression-free survival was 5.1 months (95% confidence interval, 0.5-12). Prostate specific antigen assessment revealed a good overall disease control rate (64%). CONCLUSIONS: AA appears to be safe and well tolerated even in patients with cardiovascular comorbidities or with increased risk factors for cardiovascular diseases. PMID- 24064758 TI - Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study. AB - BACKGROUND: Temozolomide (TMZ) administered daily with radiation therapy (RT) for 6 weeks, followed by adjuvant TMZ for 6 cycles, is the standard therapy for newly diagnosed glioblastoma (GBM) patients. Although TMZ is considered to be a safe drug, it has been demonstrated to cause severe myelotoxicity; in particular, some case reports and small series studies have reported severe myelotoxicity developing during TMZ and concomitant RT. We performed a prospective study to analyze the incidence of early severe myelotoxicity and its possible clinical and genetic factors. PATIENTS AND METHODS: From November 2010 to July 2012, newly diagnosed GBM patients were enrolled. They were eligible for the study if they met the following criteria: pathologically proven GBM, age 18 years and older, an Eastern Cooperative Oncology Group performance status of 0 to 2, adequate renal and hepatic function, and adequate blood cell counts before starting TMZ plus RT. Grading of hematologic toxicity developing during radiation and TMZ was based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Clinical factors from all patients were recorded. The methylation status and polymorphic variants of O-methylguanine-DNAmethyl-transferase gene in peripheral blood mononuclear cells, and polymorphic genetic variants of genes involved in the pharmacokinetics and pharmacodynamics of TMZ, were analyzed. For genetic analyses, patients with toxicity were matched (1:2) for age, performance status, anticonvulsants, and proton pump inhibitors with patients without myelotoxicity. RESULTS: We enrolled 87 consecutive GBM patients: 32 women and 55 men; the average age was 60 years. During TMZ and RT, 4 patients (5%) showed grade 3-4 myelotoxicity, and its median duration was 255 days. Predictor factors of severe myelotoxicity were female sex, pretreatment platelet count of <=3,00,000/mm, methylated O-methylguanine-DNA methyltransferase promoter in the hematopoietic cell system, and specific polymorphic variants of the cytochrome P450 oxidoreductase and methionine adenosyltransferase 1A genes. CONCLUSIONS: Although we studied a small population, we suggest that both clinical and genetic factors might simultaneously be associated with severe myelosuppression developed during TMZ plus RT. However, our results deserve validation in larger prospective studies and, if the factors associated with severe myelotoxicity are validated, dose adjustments of TMZ for those patients may reduce the risk of severe myelotoxicity during the concomitant treatment. PMID- 24064759 TI - Multispecialist Care and Mortality in Hepatocellular Carcinoma. AB - PURPOSE: Multidisciplinary physician care has increased for many cancers yet little evidence exists for hepatocellular carcinoma (HCC). The purpose of this study was to explore the association between multispecialist care and mortality in HCC. METHODS: Treated patients with an HCC primary diagnosis from 2000 to 2007 were studied using Surveillance, Epidemiology, and End Results-Medicare data. A surrogate variable for multidisciplinary care was defined-multispecialist care-as the number of disciplines among surgeons, radiology oncologist, intervention radiologist, hematologist/medical oncologist, gastroenterologist, and generalist in the pretreatment period. Multivariate survival analysis was conducted and adjusted for selection and survival bias. RESULTS: Of 3588 treated HCC patients, 1434 (40%) saw 1, 1343 (37%) saw 2, and 811 (23%) saw 3 or more specialists. Patients with multispecialist care received treatment that differed from patients who saw a single specialist. In propensity score-adjusted survival analysis, patients who saw 3 or more specialist types were associated with 10% (P=0.04) reduced mortality, compared with those who saw 1 specialist. When stratified by treatment received, patients on chemotherapy who saw 3 or more specialist types were associated with 28% (P=0.002) reduced mortality, compared with those who saw 1 specialist. CONCLUSIONS: Multispecialist care for treated HCC patients was associated with reduced mortality, particularly among chemotherapy recipients. While adjusting for selection and survival bias, our study is limited in capturing a causal relationship between coordinated multidisciplinary care and mortality. Our findings may provide support for the development of coordinated care delivery models but should be confirmed through more rigorous examination in future studies. PMID- 24064760 TI - Resveratrol suppresses the STAT3 signaling pathway and inhibits proliferation of high glucose-exposed HepG2 cells partly through SIRT1. AB - Hepatocellular carcinoma is the most common type of liver cancer. The risk of hepatocellular carcinoma for type 2 diabetic patients is greater than that for non-diabetic individuals although the mechanism is unclear. The cancer suppressor resveratrol inhibits cancer cell proliferation partly through the STAT3 signaling pathway. However, the effects of resveratrol on STAT3 in high glucose-exposed HepG2 cells and the role of SIRT1 are not clear to date. The aim of the present study was to investigate the effects of resveratrol on STAT3 and SIRT1 regarding the proliferation of high glucose-exposed HepG2 cells. HepG2 cells were cultured in DMEM containing glucose (2.8, 5.5 and 25 mM) and resveratrol (0, 10 and 100 uM). HepG2 cell proliferation and viability were analyzed by MTT assays. The levels of p-STAT3 and SIRT1 were analyzed by western blotting, and RT-PCR methods were used to detect the transcription levels of cyclin B1, cyclin D1, VEGF and MMP-9. SIRT1-specific short-interfering RNA was used to investigate the role of SIRT1 in p-STAT3 signaling. A high glucose concentration (25 mM) induced HepG2 cell proliferation. This effect was suppressed by resveratrol (100 uM), and the effect on the p-STAT3 signaling pathway was found to be SIRT1-dependent. Our findings may provide new insights into the mechanism by which resveratrol suppresses HepG2 cell proliferation under conditions of high glucose. Furthermore, this information may provide the basis for a novel therapeutic strategy for hepatocellular carcinoma patients suffering from either diabetes or hyperglycemia. PMID- 24064761 TI - Design of a single-step immunoassay principle based on the combination of an enzyme-labeled antibody release coating and a hydrogel copolymerized with a fluorescent enzyme substrate in a microfluidic capillary device. AB - A combination of an enzyme-labeled antibody release coating and a novel fluorescent enzyme substrate-copolymerized hydrogel in a microchannel for a single-step, no-wash microfluidic immunoassay is demonstrated. This hydrogel discriminates the free enzyme-conjugated antibody from an antigen-enzyme conjugated antibody immunocomplex based on the difference in molecular size. A selective and sensitive immunoassay, with 10-1000 ng mL(-1) linear range, is reported. PMID- 24064763 TI - New metal-organic frameworks based on 2,5-thiophenedicarboxylate and pyridine- or imidazole-based spacers: syntheses, topological structures, and properties. AB - Solvothermal reactions of 2,5-thiophenedicarboxylate (H2tdc) and N-auxiliary ligands in the presence of cobalt(II), zinc(II) and cadmium(II) salts have given rise to seven new metal-organic frameworks, namely, [Co2(tdc)2(bpp)2(H2O).(H2O)]n (bpp = 1,3-bis(4-pyridyl)propane) (1), [Cd(tdc)(bpp)(H2O).(H2O)2]n (2), [Zn2(tdc)2(bbi)2.(H2O)2]n (bbi = 1,1'-(1,4-butanediyl)bis(imidazole)) (3), [Co4(tdc)3(bimb)4(H2O)5.(tdc).(DMF).(H2O)2]n (bimb = 4,4'-bis(1 imidazolyl)biphenyl) (4), [Zn4(O)(tdc)3(bimb)4.(H2O)5.25.(CH3OH)]n (5), [Cd4(tdc)4(bimb)6.(H2O)2.(CH3OH)2.(DMF)4] (6) and [Co2(tdc)2(tib)2.(H2tdc).(DMF)2] (tib = 1,3,5-tris(1-imidazolyl)benzene) (7), which exhibit structural diversity. Compounds 1-3 display 3D 2-fold interpenetrating 8-connected tsi net, 2D 4-connected sql net, and 3D 5-fold interpenetrating 4-connected dia net, respectively; while compound 4 features an extremely rare 3D 7-connected hxg-d cationic net and compound 5 adopts a 3D trinodal (4,4,6)-connected net with a new topology structure. For compounds 6 and 7, the topology in the structures were determined as 3D 3-fold interpenetrating 5 connected bnn net and 3D 2-fold interpenetrating binodal (3,5)-connected net, respectively. In the solid state, complexes 1, 4 and 5 exhibit nonlinear optical properties, and complex 5 has also been evaluated as a promising visible-light driven photocatalyst for degradation of organic pollutants. The magnetic investigation of complexes 1 and 4 shows that there exists spin-canted antiferromagnetism for 1, whereas strong antiferromagnetic interaction and/or the depopulation of the higher energy Kramers doublets of the Co(II) centers are dominant in 4. PMID- 24064762 TI - Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. AB - The antioxidant tempol reduces obesity in mice. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-beta-muricholic acid (T-beta-MCA). T-beta-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist, which is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signalling in the intestine. High-fat diet-fed intestine-specific Fxr null (Fxr(DeltaIE)) mice show lower diet-induced obesity, similar to tempol treated wild-type mice. Further, tempol treatment does not decrease weight gain in Fxr(DeltaIE) mice, suggesting that the intestinal FXR mediates the anti obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signalling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs. PMID- 24064764 TI - Long-term outcome of splenectomy in advanced cirrhotic patients with hepatocellular carcinoma and thrombocytopenia. AB - Splenectomy may be a treatment option in hepatocellular carcinoma (HCC) and cirrhosis when there is no potential donor for liver transplantation. We retrospectively investigated the long-term outcome of splenectomy on survival in advanced cirrhotic patients with HCC and thrombocytopenia. Between 1999 and 2009, 46 cirrhotic patients with thrombocytopenia (Child-Pugh class B or C) who underwent splenectomy for the simultaneous or secondary treatment of HCC at our institute were evaluated. The 1-, 3-, and 5-year survival rates were 93.5, 76.0, and 37.9%, respectively. Splenectomy resulted in a significant reduction in mean portal venous pressure from 21.2 to 16.8 mmHg and improvements in liver function tests such as total bilirubin, prothrombin time, platelet count, Child-Pugh score for 3 years, and albumin for 2 years. The mean frequency of treatment for HCC recurrence after surgery was 3.0 times (range 1-11). Seven patients out of 16 scheduled for Interferon (IFN) therapy after surgery achieved a sustained virological response (SVR). Multivariate analysis identified SVR after IFN therapy as an independent significant prognostic factor (Hazard ratio 0.18, 95%CI 0.03-0.65, P=0.006). Postoperative complications including liver failure (n=1), portal thrombosis (n=7), ascites (n=5), and bacterial infections (n=4) were observed in 14 patients (30%). Splenectomy can be a feasible supportive therapy for the continuation of anticancer therapy and completion of IFN therapy based on improvements in liver function and thrombocytopenia with minimum complications in patients with HCC and advanced cirrhosis with no potential donor. PMID- 24064765 TI - New vascular ring connectors in surgery for intramural haematoma of the abdominal aorta progressing to rupture. AB - Aortic intramural haematoma is similar to classic aortic dissection, which causes a life-threatening medical condition, and immediate diagnosis and treatment are crucial. The optimal therapy for intramural haematoma of the abdominal aorta remains controversial. Conservative medical management is usually the first choice of treatment for uncomplicated cases. Surgical intervention is usually required for complicated intramural haematomas of the abdominal aorta, including conventional open repair and endovascular treatment with stent-grafts. A new vascular ring connector that achieves a quick, blood-sealed and sutureless anastomosis has been designed for aortic dissection. We herein report a case of intramural haematoma of the abdominal aorta, progressing to rupture on day 14 after onset, which had successful aortic repair with the new vascular ring connector. The new vascular ring connector could be an alternative method for the treatment of complicated intramural haematomas of the abdominal aorta. PMID- 24064766 TI - Endovascular stent-graft repair for abdominal aortic aneurysm in a patient with a short and severely angulated proximal aortic neck. AB - Serious anatomical limitations to endovascular aortic aneurysm repair (EVAR) are mostly related to the anatomical characteristics of the proximal neck of the aneurysm. A 75-year-old male was referred for management of an incidentally found large asymptomatic infra-renal saccular abdominal aortic aneurysm. Its proximal aortic neck was short and severely angulated. We performed successful EVAR in this patient without surgical intervention. PMID- 24064767 TI - Salt of the earth: ethylene promotes salt tolerance by enhancing Na/K homeostasis. PMID- 24064768 TI - An Arabidopsis soil-salinity-tolerance mutation confers ethylene-mediated enhancement of sodium/potassium homeostasis. AB - High soil Na concentrations damage plants by increasing cellular Na accumulation and K loss. Excess soil Na stimulates ethylene-induced soil-salinity tolerance, the mechanism of which we here define via characterization of an Arabidopsis thaliana mutant displaying transpiration-dependent soil-salinity tolerance. This phenotype is conferred by a loss-of-function allele of ethylene overproducer1 (ETO1; mutant alleles of which cause increased production of ethylene). We show that lack of ETO1 function confers soil-salinity tolerance through improved shoot Na/K homeostasis, effected via the ethylene resistant1-constitutive triple response1 ethylene signaling pathway. Under transpiring conditions, lack of ETO1 function reduces root Na influx and both stelar and xylem sap Na concentrations, thereby restricting root-to-shoot delivery of Na. These effects are associated with increased accumulation of respiratory burst oxidase homolog F (RBOHF) dependent reactive oxygen species in the root stele. Additionally, lack of ETO1 function leads to significant enhancement of tissue K status by an RBOHF independent mechanism associated with elevated high-affinity K(+) TRANSPORTER5 transcript levels. We conclude that ethylene promotes soil-salinity tolerance via improved Na/K homeostasis mediated by RBOHF-dependent regulation of Na accumulation and RBOHF-independent regulation of K accumulation. PMID- 24064771 TI - Citrate induces apoptosis of the acute monocytic leukemia U937 cell line through regulation of HIF-1alpha signaling. AB - The present study aimed to investigate the anti-tumor effect of citrate on acute monocytic leukemia (AML) and its mechanisms. The apoptosis of the AML cell line, U937, was assessed by MTT and Hoechst staining, the expression of Bcl-2, caspases 3 and -9, hypoxia-inducible factor 1alpha (HIF-1alpha) and its target gene GLUT 1, were assayed by western blotting and the role of HIF-1alpha was evaluated through siRNA. The results showed that citrate inhibits the expression of Bcl-2, while it induces the activation of caspases-3 and -9. In addition, citrate induces U937 apoptosis in a dose- and time-dependent manner by regulating the expression of HIF-1alpha and its downstream target GLUT-1. The results suggest that citrate performs an anti-acute monocytic leukemia action by targeting HIF 1alpha signaling and may be a promising clinical approach. PMID- 24064769 TI - Ethylene-insensitive3 is a senescence-associated gene that accelerates age dependent leaf senescence by directly repressing miR164 transcription in Arabidopsis. AB - Numerous endogenous and environmental signals regulate the intricate and highly orchestrated process of plant senescence. Ethylene is a well-known inducer of senescence, including fruit ripening and flower and leaf senescence. However, the underlying molecular mechanism of ethylene-induced leaf senescence remains to be elucidated. Here, we examine ethylene-insensitive3 (EIN3), a key transcription factor in ethylene signaling, and find that EIN3 is a functional senescence associated gene. Constitutive overexpression or temporary activation of EIN3 is sufficient to accelerate leaf senescence symptoms. Conversely, loss of EIN3 and EIN3-Like1 (its close homolog) function leads to a delay in age-dependent and ethylene-, jasmonic acid-, or dark-induced leaf senescence. We further found that EIN3 acts downstream of ORESARA2 (ORE2)/ORE3/EIN2 to repress miR164 transcription and upregulate the transcript levels of ORE1/NAC2, a target gene of miR164. EIN3 directly binds to the promoters of microRNA164 (miR164), and this binding activity progressively increases during leaf ageing. Genetic analysis revealed that overexpression of miR164 or knockout of ORE1/NAC2 represses EIN3-induced early-senescence phenotypes. Collectively, our study defines a continuation of the signaling pathway involving EIN2-EIN3-miR164-NAC2 in regulating leaf senescence and provides a mechanistic insight into how ethylene promotes the progression of leaf senescence in Arabidopsis thaliana. PMID- 24064772 TI - Downregulation of CD147 expression by RNA interference inhibits HT29 cell proliferation, invasion and tumorigenicity in vitro and in vivo. AB - We investigated the effect of CD147 silencing on HT29 cell proliferation and invasion. We constructed a novel short hairpin RNA (shRNA) expression vector pYr mir30-shRNA. The plasmid was transferred to HT29 cells. The expression of CD147, MCT1 (lactate transporters monocarboxylate transporter 1) and MCT4 (lactate transporters monocarboxylate transporter 4) were monitored by quantitative PCR and western blotting, respectively. The MMP-2 (matrix metalloproteinase-2) and MMP-9 (matrix metalloproteinase-9) activities were determined by gelatin zymography assay, while the intracellular lactate concentration was determined by the lactic acid assay kit. WST-8 assay was used to determine the HT29 cell proliferation and the chemosensitivity. Invasion assay was used to determine the invasion of HT29 cells. In addition, we established a colorectal cancer model, and detected CD147 expression in vivo. The results showed that the expression of CD147 and MCT1 was significantly reduced at both mRNA and protein levels, and also the activity of MMP-2 and MMP-9 was reduced. The proliferation and invasion were decreased, but chemosensitivity to cisplatin was increased. In vivo, the CD147 expression was also significantly decreased, and reduced the tumor growth after CD147 gene silencing. The results demonstrated that silencing of CD147 expression inhibited the proliferation and invasion, suggesting CD147 silencing might be an adjuvant gene therapy strategy to chemotherapy. PMID- 24064770 TI - The brassinosteroid insensitive1-like3 signalosome complex regulates Arabidopsis root development. AB - Brassinosteroid (BR) hormones are primarily perceived at the cell surface by the leucine-rich repeat receptor-like kinase brassinosteroid insensitive1 (BRI1). In Arabidopsis thaliana, BRI1 has two close homologs, BRI1-LIKE1 (BRL1) and BRL3, respectively, which are expressed in the vascular tissues and regulate shoot vascular development. Here, we identify novel components of the BRL3 receptor complex in planta by immunoprecipitation and mass spectrometry analysis. Whereas BRI1 associated kinase1 (BAK1) and several other known BRI1 interactors coimmunoprecipitated with BRL3, no evidence was found of a direct interaction between BRI1 and BRL3. In addition, we confirmed that BAK1 interacts with the BRL1 receptor by coimmunoprecipitation and fluorescence microscopy analysis. Importantly, genetic analysis of brl1 brl3 bak1-3 triple mutants revealed that BAK1, BRL1, and BRL3 signaling modulate root growth and development by contributing to the cellular activities of provascular and quiescent center cells. This provides functional relevance to the observed protein-protein interactions of the BRL3 signalosome. Overall, our study demonstrates that cell specific BR receptor complexes can be assembled to perform different cellular activities during plant root growth, while highlighting that immunoprecipitation of leucine-rich repeat receptor kinases in plants is a powerful approach for unveiling signaling mechanisms with cellular resolution in plant development. PMID- 24064773 TI - Effects on presenteeism and absenteeism from a 1-year workplace randomized controlled trial among health care workers. AB - OBJECTIVES: It is unknown whether workplace interventions successfully improving health outcomes can also provide concurrent improvements in presenteeism and absenteeism. METHODS: A 1-year cluster randomized controlled trial was conducted on 144 employees at a care unit in Denmark. The intervention consisted of calorie limited diet, physical exercise, and cognitive behavioral training during working hours 1 hour per week. The reference group was offered presentations about healthy lifestyle. Absenteeism and presenteeism (productivity, workability, and sickness absence) were recorded at baseline and after 3 and 12 months of intervention. RESULTS: In intention-to-treat analysis, a significant effect of the intervention was found for productivity after 3 months. Nevertheless, after 12 months no significant effects on absenteeism or presenteeism were found. CONCLUSIONS: This study suggests that a worksite intervention, despite successfully reducing overweight, does not induce lasting improvements on absenteeism or presenteeism. PMID- 24064774 TI - Investigating work conditions and burnout at three hierarchical levels. AB - OBJECTIVE: To investigate the differences and the association between work conditions and symptoms of burnout at the three hierarchical levels: subordinates, first-line managers, and middle managers. METHODS: Analyses were based on questionnaire data from 4096 employees in nine organizations, containing three hierarchical levels: subordinates (n = 3659), first-line managers (n = 345), and middle managers (n = 92). RESULTS: Work conditions were found to differ between the three hierarchical levels, mostly between subordinates and managers. Managers experienced fewer symptoms of burnout than subordinates. Furthermore, the association between work conditions and burnout differed for subordinates, first-line managers, and middle managers. CONCLUSIONS: Occupational health research needs to focus more on differences between hierarchical levels regarding work conditions and burnout. PMID- 24064775 TI - A more generalizable method to evaluate the association between commonly reported health risks and health care expenditures among employers of all sizes. AB - OBJECTIVE: To evaluate the association between health risks and health care expenditures for employers of all sizes, generalizing to all employees, even those who did not complete a health risk assessment (HRA). METHODS: Health risk assessments were obtained from 169,693 insured employees and spouses. Total health care expenditures were measured before HRA completion. Propensity score weighting, adjusting for HRA nonresponse, and multivariate regression analyses were used to estimate the relationship between health risks and health care expenditures. RESULTS: These at-risk categories were significantly associated with increased health care expenditures: elevated blood pressure, body weight and cholesterol, medication/drug use for relaxation, physical inactivity, and stress. CONCLUSIONS: The large sample size, the use of data from small firms, and generalizability made this study unique. Targeted programs that promote management of health risks could result in health care cost savings for employers of all sizes. PMID- 24064776 TI - Oregon indigenous farmworkers: results of promotor intervention on pesticide knowledge and organophosphate metabolite levels. AB - OBJECTIVES: To examine changes in health beliefs, pesticide safety knowledge, and biomarkers of pesticide exposure in indigenous farmworkers who received enhanced pesticide safety training compared with those receiving the standard training. METHODS: Farmworkers in Oregon were randomly assigned to either a promotors pesticide safety training program or a standard video-based training. Spot urine samples were analyzed for dialkyl phosphate urinary metabolites. Pre /postintervention questionnaires were used to measure pesticide safety knowledge, health beliefs, and work practices. RESULTS: Baseline to follow-up improvements in total pesticide knowledge scores were higher in the promotor group than in the standard video group. Pairwise differences in mean concentrations of dialkyl phosphate metabolite levels showed declines from baseline to follow-up for both intervention groups. CONCLUSIONS: Results showed reductions in pesticide exposure in indigenous-language speaking farmworkers who received enhanced pesticide safety training. PMID- 24064777 TI - Hypothyroidism and pesticide use among male private pesticide applicators in the agricultural health study. AB - OBJECTIVE: Evaluate the association between thyroid disease and use of insecticides, herbicides, and fumigants/fungicides in male applicators in the Agricultural Health Study. METHODS: We examined the association between use of 50 specific pesticides and self-reported hypothyroidism, hyperthyroidism, and "other" thyroid disease among 22,246 male pesticide applicators. RESULTS: There was increased odds of hypothyroidism with ever use of the herbicides 2,4-D (2,4 dichlorophenoxyacetic acid), 2,4,5-T (2,4,5-trichlorophenoxyacetic acid), 2,4,5 TP (2,4,5-trichlorophenoxy-propionic acid), alachlor, dicamba, and petroleum oil. Hypothyroidism was also associated with ever use of eight insecticides: organochlorines chlordane, dichlorodiphenyltrichloroethane (DDT), heptachlor, lindane, and toxaphene; organophosphates diazinon and malathion; and the carbamate carbofuran. Exposure-response analysis showed increasing odds with increasing level of exposure for the herbicides alachlor and 2,4-D and the insecticides aldrin, chlordane, DDT, lindane, and parathion. CONCLUSION: There is an association between hypothyroidism and specific herbicides and insecticides in male applicators, similar to previous results for spouses. PMID- 24064779 TI - The association between body mass index status and sick leave and the role of emotional exhaustion-a mediation analysis among a representative sample of dutch employees. AB - OBJECTIVE: To investigate the associations between body mass index (BMI) and sick leave, and the mediating role of emotional exhaustion. METHODS: Data were collected from a large survey among Dutch employees (n = 35,022). The causal pathway approach consisting of four regression analyses was applied. RESULTS: In women, moderate overweight and obesity were associated with higher sick leave; in men, obesity, but not moderate overweight, was associated with higher sick leave. Obese workers were at increased risk for emotional exhaustion. Emotional exhaustion was also associated with higher sick leave rates. Adjustment for emotional exhaustion in the association between BMI and sick leave hardly changed the effect size and significance remained. CONCLUSIONS: The association between BMI status and sick leave can be explained partially by the presence of emotional exhaustion. Workplace health promotion initiatives should take this into account. PMID- 24064778 TI - Construction workers struggle with a high prevalence of mental distress, and this is associated with their pain and injuries. AB - OBJECTIVES: We aimed to investigate how mental distress was associated with pain and injuries in a convenience sample of construction workers. METHODS: A cross sectional, mental health assessment was conducted in a convenience sample of construction workers (N = 172). A subsample participated in a clinical interview (n = 10). We used a cutoff (1.50 or greater) on Hopkins Symptom Checklist-25 to determine substantial mental distress and determined associations with pain and injury outcomes. RESULTS: The prevalence of substantial mental distress was 16% in the workers. This was supported by follow-up clinical interviews where 9 of 10 workers fulfilled the criteria for a mental disorder. Substantial mental distress was associated with both injury rate and self-reported pain. CONCLUSION: This pilot study strongly suggests the need for rigorous studies on construction worker mental health and how it affects their work and well-being. PMID- 24064781 TI - Differential effects of mental and physical health and coping style on work ability: a 1-year follow-up study among aging workers. AB - OBJECTIVE: This study examines whether mental and physical health relate differently to work ability and whether these associations vary with coping style. METHODS: A 1-year longitudinal study was conducted among 8842 employees aged 45 to 64 years from the Study on Transitions in Employment, Ability and Motivation. On-line questionnaires measured self-perceived mental and physical health at baseline and coping and work ability at follow-up. The data were analyzed using hierarchical regression analysis. RESULTS: Active coping and good mental and especially physical health predicted high work ability at follow-up. Avoidant coping was negatively related to work ability. Seeking support was unrelated to work ability. Interaction effects of coping and health on work ability were weak. CONCLUSIONS: Successful coping styles and good health predict high work ability, and thus, promoting such factors can help improve sustainable employability. PMID- 24064780 TI - The mental vitality @ work study: effectiveness of a mental module for workers' health surveillance for nurses and allied health care professionals on their help seeking behavior. AB - OBJECTIVES: To study the effectiveness of a mental module for workers' health surveillance for health care workers. METHODS: Nurses and allied health care professionals from one organization were cluster-randomized at ward level to an intervention or control group. The intervention included screening for work functioning impairments and mental health complaints. Positively screened workers were invited to visit their occupational physician. Outcome measures, including help-seeking behavior, work functioning, and mental health, were assessed at baseline, 3-month follow-up, and 6-month follow-up. RESULTS: An effect of study group * time interaction on help-seeking behavior was found (P = 0.02). Workers in the intervention group showed less work functioning impairments over time than the control group (P = 0.04). CONCLUSION: The module can be used to stimulate help seeking from the occupational physician and to improve functioning in workers with mild to moderate work functioning, mental health complaints, or both. TRIAL NUMBER: NTR2786. PMID- 24064782 TI - A practical measure of workplace resilience: developing the resilience at work scale. AB - OBJECTIVE: To develop an effective measure of resilience at work for use in individual work-related performance and emotional distress contexts. METHODS: Two separate cross-sectional studies investigated: (1) exploratory factor analysis of 45 items putatively underpinning workplace resilience among 397 participants and (2) confirmatory factor analysis of resilience measure derived from Study 1 demonstrating a credible model of interaction, with performance outcome variables among 194 participants. RESULTS: A 20-item scale explaining 67% of variance, measuring seven aspects of workplace resilience, which are teachable and capable of conscious development, was achieved. A credible model of relationships with work engagement, sleep, stress recovery, and physical health was demonstrated in the expected directions. CONCLUSION: The new scale shows considerable promise as a reliable instrument for use in the area of employee support and development. PMID- 24064783 TI - Patient handling in the veterans health administration: facilitating change in the health care industry. AB - OBJECTIVE: To describe a 15-year process creating an industry standard of practice without regulatory support through organizational leadership. METHODS: Description of the development and rollout of a safe patient-handling program, including the initial scientific development, a cultural history, and agency data. RESULTS: Patient-handling injuries represent more than 20% of injuries to nurses. These declined by more than 40% throughout the program. In parallel, program scope and implementation evolved through collaboration across facility program managers in one organization, among various organizations, and between users and equipment manufacturers. Program success required a shift from a technology focus to culture change and behaviors. CONCLUSION: Program evolution arises from collaborative practice and interactions between individual practitioners, organizational needs and interests, and manufacturers. Creation of a public forum was critical to changes in a meanwhile internationally accepted standard. PMID- 24064784 TI - Electronic medical record use among US occupational medicine physicians: a national survey. AB - OBJECTIVE: To examine the use of electronic medical records (EMRs) among US occupational medicine physicians (OMPs). METHODS: An electronic- and paper-based survey was conducted among OMPs using an anonymous self-administered questionnaire. RESULTS: The OMPs reported using an EMR for billing purposes only (14.6%), clinical purposes only (27.8%), or both (39.3%) with the total EMR use of 81.7%. About 60% were satisfied with their EMRs, and 64% to 66% believed that EMRs improve safety and quality of medical care. Among OMPs not using EMR, 17% reported that they were likely to adopt an EMR in the year after the survey, whereas 47% were very unlikely to do so. CONCLUSIONS: Occupational physicians' use of EMRs was relatively high. They also seemed to be satisfied with their EMRs and believed that EMRs improve both safety and quality of clinical care. PMID- 24064785 TI - Changes in psychosocial work exposures among employees between 2005 and 2010 in 30 countries in Europe. AB - OBJECTIVE: The aim was to assess the changes in psychosocial work factors among European employees between 2005 and 2010. METHODS: The study samples came from the European Working Conditions Survey, involving 23,580 and 32,516 employees in 2005 and 2010, respectively, from 30 European countries. The psychosocial work factors studied were based on job strain and effort-reward imbalance models, and more recent factors. Multilevel linear and logistic regression models were used. Differences according to occupations and countries were tested. RESULTS: Results were mixed with improvement for some factors and decline for other factors. Some countries and occupations were more likely to be affected by negative changes, especially low-skilled employees. CONCLUSION: Prevention policies at the workplace should take into account that the degradation of some psychosocial work factors may be sharper for some countries and occupations. PMID- 24064786 TI - Association of brominated trihalomethane and haloacetic acid exposure with fetal growth and preterm delivery in Massachusetts. AB - OBJECTIVES: We examined the relationship between adverse reproductive outcomes and exposure to several disinfection by-products including haloacetic acids (HAAs), trihalomethanes (THMs), and the brominated THMs sum (THMBr). METHODS: Second- and third-trimester exposure scores were estimated from quarterly town level average THM and HAA concentration data and were examined relative to mean birth weight (BWT), small for gestational age (SGA), and preterm delivery (PTD). RESULTS: We found an increased risk of PTD for second-trimester chloroform, bromodichloromethane, and all HAA exposure metrics (adjusted odds ratio range: 1.04 to 1.15), but detected no associations for SGA and third-trimester exposures. Mean BWT deficits were observed across all HAA (26 to 33 g) and THMBr (11 to 23 g) exposure categories. CONCLUSIONS: We detected consistent associations for adjusted mean BWT and THMBr exposures; these data reinforce the need to consider different disinfection by-product exposure metrics in epidemiological studies. PMID- 24064787 TI - Work-related and health care cost burden of community-acquired pneumonia in an employed population. AB - OBJECTIVE: To estimate community-acquired pneumonia (CAP) incidence, turnover, episode length, inpatient length-of-stay, and cost burden. METHODS: Using 2007 to 2010 employee demographic, payroll, and claims data, CAP episodes were identified in employees aged 18 to 64 years. Semiannual medical, drug, sick leave, short term disability (STD), long-term disability, and workers' compensation costs and absence days were compared between employees with and without CAP (controls) using two-part regression modeling. RESULTS: In a population of 250,000, the number of CAP episodes per 100,000 employees was 628. The incidence rate increased with age and comorbidity. CAP employees' turnover rate nearly doubled that of controls (P < 0.01). In every age and risk group, employees with CAP had significantly (P < 0.01) higher medical and drug costs than controls and double the STD costs and days (P < 0.05). CONCLUSIONS: CAP and underlying comorbidity are associated with increased medical, pharmacy, and STD costs and employee turnover rates. PMID- 24064788 TI - Robust visible light photoswitching with ortho-thiol substituted azobenzenes. AB - Introduction of S-ethyl groups in all four ortho positions of azobenzene prevents reduction of the azo group by intracellular glutathione, while enhancing the absorptivity to ~10,000 M(-1) cm(-1) in the blue and green regions of the visible spectrum. cis-to-trans isomerization occurs thermally on the minutes timescale. Further, this substitution pattern permits switching with red light, a color that is more penetrating through biological tissues than other parts of the visible spectrum. PMID- 24064789 TI - Low incidence of an altered endometrial epidermal growth factor (EGF) profile in repeat breeder Holstein heifers and differential effect of parity on the EGF profile between fertile Holstein (dairy) and Japanese Black (beef) cattle. AB - A high incidence (about 70%) of alteration in endometrial epidermal growth factor (EGF) profile, i.e., loss of 2 peaks on days 2-4 and 13-14, has been linked to a reduced fertility in multiparous repeat breeder Holstein cows. However, the EGF profile in Holstein heifers and other breeds (types) of cattle has not been investigated. In study 1, EGF concentrations were determined using endometrial tissues obtained by biopsy on days 3, 7 and 14 from 84 fertile Holstein heifers to obtain a normal range and 53 repeat breeder Holstein heifers to estimate incidence of alterations in the EGF profile. In repeat breeder heifers, EGF concentrations were similar to fertile controls on 3 days and five animals (9.4%) had an altered EGF profile with EGF concentrations below the normal range on days 3 and 14. In study 2, EGF concentrations on day 3 were repeatedly examined from the nulliparous period to the third postpartum period in 28 Holstein (dairy) and 47 Japanese Black (beef) cattle. The effect of parity on EGF concentrations on day 3 was different between Holstein and Japanese Black cattle. In Japanese Black cows, the EGF concentrations were consistently high throughout the study period, while in Holstein cows, the EGF concentrations decreased after the second calving. In conclusion, unlike multiparous repeat breeder Holstein cows, an altered EGF profile may not be a major cause of repeat breeding in Holstein heifers, and the peak EGF concentrations around day 3 may decrease even in fertile populations of multiparous dairy cows, but not in beef cows. PMID- 24064791 TI - Deep mutational scanning of an RRM domain of the Saccharomyces cerevisiae poly(A) binding protein. AB - The RNA recognition motif (RRM) is the most common RNA-binding domain in eukaryotes. Differences in RRM sequences dictate, in part, both RNA and protein binding specificities and affinities. We used a deep mutational scanning approach to study the sequence-function relationship of the RRM2 domain of the Saccharomyces cerevisiae poly(A)-binding protein (Pab1). By scoring the activity of more than 100,000 unique Pab1 variants, including 1246 with single amino acid substitutions, we delineated the mutational constraints on each residue. Clustering of residues with similar mutational patterns reveals three major classes, composed principally of RNA-binding residues, of hydrophobic core residues, and of the remaining residues. The first class also includes a highly conserved residue not involved in RNA binding, G150, which can be mutated to destabilize Pab1. A comparison of the mutational sensitivity of yeast Pab1 residues to their evolutionary conservation reveals that most residues tolerate more substitutions than are present in the natural sequences, although other residues that tolerate fewer substitutions may point to specialized functions in yeast. An analysis of ~40,000 double mutants indicates a preference for a short distance between two mutations that display an epistatic interaction. As examples of interactions, the mutations N139T, N139S, and I157L suppress other mutations that interfere with RNA binding and protein stability. Overall, this study demonstrates that living cells can be subjected to a single assay to analyze hundreds of thousands of protein variants in parallel. PMID- 24064792 TI - Characterization of acute and chronic neuropathies induced by oxaliplatin in mice and differential effects of a novel mitochondria-targeted antioxidant on the neuropathies. AB - BACKGROUND: Oxaliplatin, a chemotherapeutic agent used for the treatment of colorectal cancer, induces dose-limiting neuropathy that compromises quality of life. This study aimed to reproduce, in mice, patients' symptoms of oxaliplatin induced neuropathy and to observe effects of SS-31, a mitochondria-targeted antioxidant on the neuropathy. METHODS: Neuropathy was induced by single or repeated injections of oxaliplatin. Cold and mechanical hypersensitivities were assessed by 15 degrees C-cold plate, temperature preference, and von Frey tests. Morphology of peripheral nerves and dorsal root ganglions, expression of spinal cord c-Fos, density of intraepidermal nerve fibers, and levels of dorsal root ganglion-reactive oxygen/nitrogen species were examined. SS-31 was administered concomitantly or after oxaliplatin injections. RESULTS: Single injection of oxaliplatin induced cold hypersensitivity in forepaws but not in hind paws which resolved within days (maximal forepaw shakes: 28 +/- 1.5 vs. 9.3 +/- 1.6/150 s, mean +/- SEM, P < 0.001, n = 6 per group). Oxaliplatin-administered mice disfavored 10 degrees and 15 degrees C plates more than control. Paw stimulation at 15 degrees C induced c-Fos-positive cells within superficial laminae of the dorsal horn in C7-T1 segments. Weekly administrations induced gradual development of persistent mechanical allodynia in the hind paws (minimal mechanical threshold: 0.19 +/- 0.08 vs. 0.93 +/- 0.11 g, P < 0.001, n = 10 per group). Microscopy revealed no overt morphological changes in peripheral nerves and dorsal root ganglions. Concomitant SS-31 administration with repeated oxaliplatin administration attenuated both cold and mechanical hypersensitivity. Decrease in intraepidermal nerve fibers and increase in dorsal root ganglion-reactive oxygen/nitrogen species were also attenuated. Acute SS-31 administration after symptoms were established reversed only cold hypersensitivity. CONCLUSION: This model of oxaliplatin-induced neuropathy mimicked patients' conditions. SS-31 has potentials to prevent both acute and chronic neuropathies but is only helpful in treatment of acute neuropathy. (Anesthesiology 2014; 120:459-73). PMID- 24064795 TI - Genome sequencing of West Nile Virus from human cases in Greece, 2012. AB - A West Nile Virus (WNV) lineage 2 strain, named Nea Santa-Greece-2010, has been demonstrated to be responsible for the large outbreaks of neuroinvasive disease (WNND) that have been occurring in Greece since 2010, based on sequence similarities of viral isolates identified between 2010-2012. However, knowledge on the evolution of this strain is scarce because only partial WNV genome sequences are available from Greece. The aim of this study was to get the complete genome sequence of WNV from patients with infection. To this aim, plasma and urine samples collected during the 2012 Greek outbreak were retrospectively investigated. Full WNV genome sequence was obtained from a patient with WNND. The genome had 99.7% sequence identity to Nea Santa, higher than to other related WNV lineage 2 strains, and five amino acid changes apparently not relevant for viral pathogenicity or fitness. In addition, infection by WNV lineage 2 was confirmed in additional nine patients with WNND; in three of them the infection with WNV Nea Santa was demonstrated by sequencing. In conclusion, this study characterized for the first time a WNV full genome from a patient with WNND from Greece, demonstrated the persistence of the Nea Santa strain, and suggested that the virus might have locally evolved. PMID- 24064793 TI - Non-simian foamy viruses: molecular virology, tropism and prevalence and zoonotic/interspecies transmission. AB - Within the field of retrovirus, our knowledge of foamy viruses (FV) is still limited. Their unique replication strategy and mechanism of viral persistency needs further research to gain understanding of the virus-host interactions, especially in the light of the recent findings suggesting their ancient origin and long co-evolution with their nonhuman hosts. Unquestionably, the most studied member is the primate/prototype foamy virus (PFV) which was originally isolated from a human (designated as human foamy virus, HFV), but later identified as chimpanzee origin; phylogenetic analysis clearly places it among other Old World primates. Additionally, the study of non-simian animal FVs can contribute to a deeper understanding of FV-host interactions and development of other animal models. The review aims at highlighting areas of special interest regarding the structure, biology, virus-host interactions and interspecies transmission potential of primate as well as non-primate foamy viruses for gaining new insights into FV biology. PMID- 24064796 TI - Increased detection of Sin Nombre hantavirus RNA in antibody-positive deer mice from Montana, USA: evidence of male bias in RNA viremia. AB - Hantaviruses are widespread emergent zoonotic agents that cause unapparent or limited disease in their rodent hosts, yet cause acute, often fatal pulmonary or renal infections in humans. Previous laboratory experiments with rodent reservoir hosts indicate that hantaviruses can be cleared from host blood early in the infection cycle, while sequestered long term in various host organs. Field studies of North American deer mice (Peromyscus maniculatus), the natural reservoir of Sin Nombre hantavirus, have shown that viral RNA can be transiently detected well past the early acute infection stage, but only in the minority of infected mice. Here, using a non-degenerate RT-PCR assay optimized for SNV strains known to circulate in Montana, USA, we show that viral RNA can be repeatedly detected on a monthly basis in up to 75% of antibody positive deer mice for periods up to 3-6 months. More importantly, our data show that antibody positive male deer mice are more than twice as likely to have detectable SNV RNA in their blood as antibody positive females, suggesting that SNV-infected male deer mice are more likely to shed virus and for longer periods of time. PMID- 24064797 TI - Kinematic analysis of the posterior cruciate ligament, part 1: the individual and collective function of the anterolateral and posteromedial bundles. AB - BACKGROUND: The posterior cruciate ligament (PCL) is composed of 2 functional bundles and has an essential role in knee function and stability. There is, however, a limited understanding of the role of each individual bundle through the full range of knee flexion. HYPOTHESIS: Both bundles provide restraint to posterior tibial translation across a full range of knee flexion. At higher angles of knee flexion (>90 degrees ), the intact PCL also imparts significant rotational stability. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty matched-paired, human cadaveric knees (mean age, 55.2 years; range, 51-59 years; 6 male and 4 female pairs) were used to evaluate the kinematics of an intact, anterolateral bundle (ALB) sectioned, posteromedial bundle (PMB) sectioned, and complete PCL sectioned knee. A 6 degree of freedom robotic system was used to assess knee stability with an applied 134-N posterior tibial load, 5-N.m external and internal rotation torques, 10-N.m valgus and varus torques, and a coupled 100 N posterior tibial load and 5-N external rotation torque at 0 degrees , 15 degrees , 30 degrees , 45 degrees , 60 degrees , 75 degrees , 90 degrees , 105 degrees , and 120 degrees . RESULTS: All sectioned states had significant increases compared with intact in posterior translation, internal rotation, and external rotation at all tested flexion angles, with the exception of the ALB sectioned state at 75 degrees of flexion for external rotation. The significant increases (mean +/- standard deviation) in posterior translation during a 134-N posterior tibial load at 90 degrees of flexion were 0.9 +/- 0.6 mm, 2.6 +/- 1.8 mm, and 11.7 +/- 4.0 mm for the PMB, ALB, and complete PCL sectioned states, respectively, compared with the intact state. The largest significant increases in internal rotation were in the PMB and complete PCL sectioned states at 105 degrees of flexion, 1.3 degrees +/- 1.0 degrees and 2.8 degrees +/- 2.1 degrees , respectively. CONCLUSION: Both the ALB and the PMB assume a significant role in resisting posterior tibial translation, at all flexion angles, suggesting a codominant relationship. The PCL provided a significant constraint to internal rotation beyond 90 degrees of flexion. CLINICAL RELEVANCE: This information broadens the understanding of native knee kinematics and provides a template for the evaluation of single- and double-bundle PCL reconstructions. PMID- 24064794 TI - Regulated transport into the nucleus of herpesviridae DNA replication core proteins. AB - The Herpesvirdae family comprises several major human pathogens belonging to three distinct subfamilies. Their double stranded DNA genome is replicated in the nuclei of infected cells by a number of host and viral products. Among the latter the viral replication complex, whose activity is strictly required for viral replication, is composed of six different polypeptides, including a two-subunit DNA polymerase holoenzyme, a trimeric primase/helicase complex and a single stranded DNA binding protein. The study of herpesviral DNA replication machinery is extremely important, both because it provides an excellent model to understand processes related to eukaryotic DNA replication and it has important implications for the development of highly needed antiviral agents. Even though all known herpesviruses utilize very similar mechanisms for amplification of their genomes, the nuclear import of the replication complex components appears to be a heterogeneous and highly regulated process to ensure the correct spatiotemporal localization of each protein. The nuclear transport process of these enzymes is controlled by three mechanisms, typifying the main processes through which protein nuclear import is generally regulated in eukaryotic cells. These include cargo post-translational modification-based recognition by the intracellular transporters, piggy-back events allowing coordinated nuclear import of multimeric holoenzymes, and chaperone-assisted nuclear import of specific subunits. In this review we summarize these mechanisms and discuss potential implications for the development of antiviral compounds aimed at inhibiting the Herpesvirus life cycle by targeting nuclear import of the Herpesvirus DNA replicating enzymes. PMID- 24064799 TI - Unified approach to multipolar polarisation and charge transfer for ions: microhydrated Na+. AB - Electrostatic effects play a large part in determining the properties of chemical systems. In addition, a treatment of the polarisation of the electron distribution is important for many systems, including solutions of monatomic ions. Typically employed methods for describing polarisable electrostatics use a number of approximations, including atom-centred point charges and polarisation methods that require iterative calculation on the fly. We present a method that treats charge transfer and polarisation on an equal footing. Atom-centred multipole moments describe the charge distribution of a chemical system. The variation of these multipole moments with the geometry of the surrounding atoms is captured by the machine learning method kriging. The interatomic electrostatic interaction can be computed using the resulting predicted multipole moments. This allows the treatment of both intra- and interatomic polarisation with the same method. The proposed method does not return explicit polarisabilities but instead, predicts the result of the polarisation process. An application of this new method to the sodium cation in a water environment is described. The performance of the method is assessed by comparison of its predictions of atomic multipole moments and atom-atom electrostatic interaction energies to exact results. The kriging models are able to predict the electrostatic interaction energy between the ion and all water atoms within 4 kJ mol(-1) for any of the external test set Na(+)(H2O)6 configurations. PMID- 24064798 TI - An INHIBIT logic gate from a thiophene derivative using iron and zinc ions as the input: tuning the efficiency on moving from naphthalene to anthracene to pyrene for the green luminescent detection of the intracellular iron. AB - A pyrene-thiophene conjugate has been used for the efficient detection of intracellular irons through the generation of bright green luminescence. Amongst three different probes being reported, it is observed that the efficiency for the naked eye green luminescent detection of iron increases on moving from naphthalene to anthracene to pyrene. The developed technique may be very useful to monitor iron and zinc supplementation as single micronutrients in living systems through the construction of an INHIBIT logic gate. PMID- 24064801 TI - Human impacts drive a global topographic signature in tree cover. AB - The Anthropocene is a geological epoch marked by major human influences on processes in the atmosphere, biosphere, hydrosphere and geosphere. One of the most dramatic features of the Anthropocene is the massive alteration of the Earth's vegetation, including forests. Here we investigate the role of topography in shaping human impacts on tree cover from local to global scales. We show that human impacts have resulted in a global tendency for tree cover to be constrained to sloped terrain and losses to be concentrated on flat terrain. This effect increases in strength with increasing human pressure and is most pronounced in countries with rapidly growing economies, limited human population stress and highly effective governments. These patterns likely reflect the relative inaccessibility of sloped topography and have important implications for conservation and modelling of future tree cover. PMID- 24064800 TI - Caudatin inhibits human hepatoma cell growth and metastasis through modulation of the Wnt/beta-catenin pathway. AB - In the present study, we investigated the antitumor activity of caudatin in the human hepatoma cell line SMMC-7721 by analysis of cell viability, cell cycle distribution, apoptosis and metastasis. The results showed that caudatin impaired the cell viability and inhibited the growth of SMMC-7721 cells in a time- and dose-dependent manner and resulted in cell cycle arrest in the G2 phase. In addition, SMMC-7721 cells, treated with caudatin exhibited typical characteristics of apoptosis. Furthermore, caudatin treatment resulted in a decrease in beta-catenin and GSK3beta in SMMC-7721 cells, with a concomitant reduction in metastatic capability and expression of Wnt signaling pathway targeted genes including cox-2, mmp-2 and mmp-9. Our findings revealed that caudatin inhibits human hepatoma cell growth and metastasis by targeting the GSK3beta/beta-catenin pathway and suppressing VEGF production. PMID- 24064802 TI - [RUNX family genes and hematopoiesis]. PMID- 24064803 TI - [Clinical application strategy by iPS cells]. PMID- 24064804 TI - [Deep sequencing]. PMID- 24064805 TI - [Roles of transcription factors in normal and leukemic hematopoiesis]. PMID- 24064806 TI - [Regulation and disorders of granulopoiesis]. PMID- 24064807 TI - [Guidelines for the diagnosis and management of bone marrow failure syndrome]. PMID- 24064808 TI - Anemia of inflammation: clinical insights from mechanisms. PMID- 24064809 TI - [Metabolomic analysis of human blood, plasma and red blood cells in comparison with eukaryotic microbe]. PMID- 24064810 TI - [The legend of erythropoietin: from purification to molecular cloning]. PMID- 24064811 TI - [Fanconi anemia and the molecular mechanism of the repair of DNA crosslinks]. PMID- 24064812 TI - [Guideline for AML]. PMID- 24064813 TI - [AML stem cell]. PMID- 24064814 TI - [Genetic alterations in AML]. PMID- 24064815 TI - [New clinical evidence and drugs]. PMID- 24064816 TI - [Myelodysplastic syndrome, a guide for clinical practice]. PMID- 24064817 TI - [3rd generation ABL kinase inhibitor and Philadelphia chromosome positive leukemia]. PMID- 24064818 TI - [Genomic abnormalities and pathophysiology in myelodysplastic syndrome]. PMID- 24064819 TI - [Molecular biology and new drug therapy for myeloproliferative neoplasm]. PMID- 24064821 TI - A novel BIM deletion polymorphism: implications and lessons for cancer targeted therapies. PMID- 24064820 TI - [CML stem cells]. PMID- 24064823 TI - The biology and treatment of myelodysplastic syndromes. PMID- 24064822 TI - [Therapeutic drug management of BCR-ABL tyrosine kinase inhibitor for chronic myeloid leukemia patients]. PMID- 24064824 TI - [Guideline, acute lymphoblastic leukemia]. PMID- 24064825 TI - [The guideline for patients with follicular lymphoma]. PMID- 24064826 TI - [Japanese Society of Hematology, clinical practice guideline: diffuse large B cell lymphoma]. PMID- 24064827 TI - [Guideline for T/NK-cell lymphoma]. PMID- 24064828 TI - [Treatment strategy for lymphoma of childhood, adolescent and young adult]. PMID- 24064829 TI - [The role of chromosomal translocations in the pathogenesis of B-cell lymphomas]. PMID- 24064830 TI - [Genetic mutations in malignant lymphoma: the molecular and clinical significances and the application for development of molecular targeting therapeutics]. PMID- 24064831 TI - [New drugs in development for lymphomas in Japan]. PMID- 24064832 TI - [ATL progress 2013]. PMID- 24064833 TI - Management of adult patients with Philadelphia positive acute lymphoblastic leukemia. PMID- 24064834 TI - Chronic lymphocytic leukemia (CLL): a model for understanding and treating chronic B-cell malignancies. PMID- 24064835 TI - Extranodal lymphomas. PMID- 24064836 TI - [JSH guideline for multiple myeloma]. PMID- 24064837 TI - [Multiple myeloma: chromosomal abnormalities, clinical features and prognosis]. PMID- 24064838 TI - [Molecular oncogenesis of multiple myeloma]. PMID- 24064839 TI - [Renal impairment in multiple myeloma and related disorders]. PMID- 24064840 TI - [Diagnostic approaches to bleeding disorders]. PMID- 24064841 TI - [Atypical hemolytic uremic syndrome]. PMID- 24064842 TI - [Acquired coagulant factor inhibitors]. PMID- 24064843 TI - Thrombopoietin Receptor Agonists for the treatment of ITP. PMID- 24064844 TI - [A historical glance at hemophilia]. PMID- 24064845 TI - [Vaccination after stem cell transplantation]. PMID- 24064846 TI - [Prophylaxis and treatment for invasive fungal infection: update]. PMID- 24064847 TI - [Virus infection after allogeneic hematopoietic stem cell transplantation]. PMID- 24064848 TI - [Antigen presentation and graft-versus-host disease]. PMID- 24064849 TI - [Pathophysiology and management of transplantation associated TMA]. PMID- 24064850 TI - [Engraftment failure following umbilical cord blood transplantation]. PMID- 24064851 TI - [Indication for platelet transfusion and a new preventive measures for adverse reactions]. PMID- 24064852 TI - [Common variable immunodeficiency: the spectrum of disease manifestations and molecular basis of the disorder]. PMID- 24064853 TI - [The clinical condition and diagnosis of EBV-T/NK-LPD (CAEBV, EBV-HLH etc.)]. PMID- 24064854 TI - [Molecular biology in childhood acute lymphoblastic leukemia (ALL)]. PMID- 24064855 TI - [Tumor lysis syndrome]. PMID- 24064856 TI - [Febrile neutropenia]. PMID- 24064857 TI - Coupling reaction of thioamides with sulfonyl azides: an efficient catalyst-free click-type ligation under mild conditions. AB - We report a coupling reaction of thioamides and sulfonyl azides to generate sulfonyl amidines in the absence of any activation additives. The reaction progresses in various solvents under mild conditions. Water exhibits the highest performance with respect to efficiency. PMID- 24064859 TI - Gender issues in solid organ donation and transplantation. AB - Gender as a critical, intrinsic, non-immunologic factor plays a pivotal role in the field of transplantation. The gender of donors and recipients is involved in the entire process, including organ donation and transplant surgery. This review article aims to summarize the literature related to the role of gender in solid organ donation and transplantation and to unveil the underlying mechanism by which gender mismatch between donor and recipient impacts transplant rejection. A systematic search was conducted through PubMed by using the following key words: "gender", or "sex", and "transplant", "organ donation" for published articles. The prima facie evidence demonstrated that females are more likely to donate their organs and are less willing than males to accept transplant surgery; however, their donated liver organs will have a higher risk of graft failure compared with males. With respect to kidney, heart, and lung transplantations, the role of gender remains controversial. Results of animal studies support the negative impact of gender mismatch on allograft function. In conclusion, our present study advances the knowledge of gender issues in the field of solid organ donation and transplantation. In general, gender mismatch is not advantageous to transplant outcome, as evidenced by many aspects of biological investigations on immunogenicity of H-Y antigen to females. Therefore, gender issues should be highlighted and an a priori intervention is needed to improve graft survival in clinical practice. PMID- 24064860 TI - Design, calibration and validation of a novel 3D printed instrumented spatial linkage that measures changes in the rotational axes of the tibiofemoral joint. AB - An accurate axis-finding technique is required to measure any changes from normal caused by total knee arthroplasty in the flexion-extension (F-E) and longitudinal rotation (LR) axes of the tibiofemoral joint. In a previous paper, we computationally determined how best to design and use an instrumented spatial linkage (ISL) to locate the F-E and LR axes such that rotational and translational errors were minimized. However, the ISL was not built and consequently was not calibrated; thus the errors in locating these axes were not quantified on an actual ISL. Moreover, previous methods to calibrate an ISL used calibration devices with accuracies that were either undocumented or insufficient for the device to serve as a gold-standard. Accordingly, the objectives were to (1) construct an ISL using the previously established guidelines,(2) calibrate the ISL using an improved method, and (3) quantify the error in measuring changes in the F-E and LR axes. A 3D printed ISL was constructed and calibrated using a coordinate measuring machine, which served as a gold standard. Validation was performed using a fixture that represented the tibiofemoral joint with an adjustable F-E axis and the errors in measuring changes to the positions and orientations of the F-E and LR axes were quantified. The resulting root mean squared errors (RMSEs) of the calibration residuals using the new calibration method were 0.24, 0.33, and 0.15 mm for the anterior-posterior, medial-lateral, and proximal-distal positions, respectively, and 0.11, 0.10, and 0.09 deg for varus-valgus, flexion-extension, and internal-external orientations, respectively. All RMSEs were below 0.29% of the respective full-scale range. When measuring changes to the F-E or LR axes, each orientation error was below 0.5 deg; when measuring changes in the F-E axis, each position error was below 1.0 mm. The largest position RMSE was when measuring a medial-lateral change in the LR axis (1.2 mm). Despite the large size of the ISL, these calibration residuals were better than those for previously published ISLs, particularly when measuring orientations, indicating that using a more accurate gold standard was beneficial in limiting the calibration residuals. The validation method demonstrated that this ISL is capable of accurately measuring clinically important changes (i.e. 1 mm and 1 deg) in the F-E and LR axes. PMID- 24064861 TI - Custom tailoring multiple droplets one-by-one. AB - We report automated generation of arbitrary sequences of multiple microdroplets with online and individual control over the number of cores and volumes of all the constituents (cores and shells) of each of the multiple droplets. We show that a given sequence of volumes of the cores always folds to the same final three-dimensional architecture. The method presents the first proof-of-concept for the ability to design the three-dimensional structure of multiple droplets. We discuss the potential use of the technique in the formulation of predetermined distribution of drug release capsules and for automated generation of functional chemical microdroplet networks. PMID- 24064862 TI - P53 regulates the migration of mesenchymal stromal cells in response to the tumor microenvironment through both CXCL12-dependent and -independent mechanisms. AB - Mesenchymal stromal cells (MSCs) are multipotent fibroblast-like cells located in the bone marrow that localize to areas of tissue damage including wounds and solid tumors. Within the tumor microenvironment, MSCs adopt the phenotype of carcinoma-associated fibroblasts (CAFs) and stimulate tumor growth. Production of the chemokine CXCL12, also known as stromal cell-derived factor 1 (SDF-1), by MSCs is required for their in vitro migration in response to tumor cells and has also been implicated in stimulation of tumor growth. The tumor suppressor p53 regulates cellular migration, CXCL12 production and the promotion of tumor growth by carcinoma-associated fibroblasts (CAFs). We investigated the role of p53 in MSC migration to tumors. P53 inhibits the migration of MSCs in response to tumor cells in conjunction with a decrease in CXCL12 transcription. Conversely, decreased p53 activity leads to enhanced MSC migration. Interestingly, increased p53 activity inhibits MSC migration even in the context of high concentrations of exogenous CXCL12. These data show that stromal p53 status impacts the recruitment of MSCs to solid tumors through both regulation of CXCL12 production as well as other mechanisms. Stromal p53 may influence other important aspects of tumor biology such as tumor growth and metastasis through mechanisms distinct from CXCL12. PMID- 24064863 TI - Enantioselective synthesis of encecaline-derived potent antimalarial agents. AB - The high antiplasmodial activity of racemic benzylamines rac-1 and rac-2 stimulated the synthesis of pure enantiomers. Ellman's chiral sulfinamides (S)-6 and (R)-6 were used as chiral auxiliaries. Condensation of prochiral ketone 5 with enantiomerically pure sulfinamides (S)-6 and (R)-6 and subsequent NaBH4 reduction provided predominantly unlike configured diastereomers (S,R)-8 and (R,S)-8 (ratio unlike-8:like-8 = 90:10). The same transformation of phenol 4 led to the diastereomeric sulfinamides (S,R)-12 and (S,S)-12 in the ratio 60:40. Acid hydrolysis of the diastereomerically pure sulfinamides followed by monobenzylation yielded the enantiomerically pure benzylamines (R)-1, (S)-1, (R) 2 and (S)-2. The enantiomeric purity of the products was proven by chiral HPLC and the absolute configuration by CD-spectroscopy. Generally, benzylamines with (R)-configuration show higher antiplasmodial activity than their corresponding (S)-configured enantiomers. Phenol (R)-2 represents a very potent lead against P. falciparum, with an IC50 value of only 0.026 MUM against the NF54 strain. The very high eudismic ratio of 34 indicates the enantioselective interaction of phenol (R)-2 with a particular target protein of P. falciparum. PMID- 24064864 TI - Pericardiocentesis in trauma: a systematic review. AB - BACKGROUND: Pericardiocentesis (PCC) had been taught as a mandatory skill in the Advanced Trauma Life Support (ATLS(r)) course as a bridge to definitive surgical therapy for traumatic pericardial tamponade since its inception in 1978. Immediate thoracotomy for penetrating trauma to the heart and chest has resulted in the decreased use of PCC in trauma. PCC is now offered as an optional skill in the ninth edition of the ATLS(r). A review of the literature regarding the use and effectiveness of PCC in traumatic pericardial tamponade in the modern era is necessary to better define its current role in trauma care. METHODS: Scientific publications from 1970 to 2010 involving PCC after trauma were identified. The Preferred Reporting Items for Systematic reviews and Meta-Analyses was used. Human studies describing acute traumatic tamponade were included. Publications involving nontraumatic or chronic pericardial tamponade from effusions caused by inflammatory, infectious, or neoplastic etiology were excluded. Publications were categorized by level of evidence. RESULTS: Of the 135 publications identified, 27 were included, composing of 2,094 trauma patients with suspected cardiac tamponade. The reported use of PCC decreased from 45.9% of patients in the period 1970 to 1979 down to 6.4% of patients in the period between 2000 and 2010 (p < 0.05). Reported rates describing the use of PCC as the sole intervention decreased from 13.7% in the period 1970 to 1979 to 2.1% in the period 2000 to 2010 (p < 0.05). Survival analysis after PCC was possible for 380 patients. Overall survival following PCC was 83.4% (n = 317) and 91.8% (n = 145) when used as the sole intervention. In patients who received PCC then thoracotomy, survival rate was 79.5% (n = 178). CONCLUSION: Studies on the use of PCC for trauma are limited and biased toward survivors. The reported survival rate is high. There remains a limited role for PCC in nontrauma centers where definitive surgical management is not immediately available and transport time to a higher level of care facility supports the use of temporary decompression by PCC. LEVEL OF EVIDENCE: Systematic review, level III. PMID- 24064865 TI - Mild and moderate pediatric traumatic brain injury: replace routine repeat head computed tomography with neurologic examination. AB - BACKGROUND: Opinion is divided on the role of routine repeat head computed tomography (RHCT) for guiding clinical management in pediatric patients with blunt head trauma. We hypothesize that routine RHCT does not lead to change in management in mild and moderate traumatic brain injury (TBI). METHODS: This is a 3-year retrospective study of all patients of age 2 years to 18 years with blunt TBI admitted to our Level 1 trauma center with an abnormal head CT. Indications for RHCT (routine vs. neurologic deterioration) and their findings (progression or improvement) were recorded. Neurosurgical intervention was defined as extraventricular drain placement, craniectomy, or craniotomy. Primary outcome was a change in management after RHCT. RESULTS: A total of 291 pediatric patients were identified; of which 191 patients received an RHCT. Routine RHCT did not lead to neurosurgical intervention in the mild and moderate TBI group. In patients who received RHCT due to neurologic decline (n = 7), radiographic progression was seen on 85% of the patients (n = 6), with subsequent neurosurgical interventions in three patients. Two of these patients had a Glasgow Coma Scale (GCS) score of less than 8 at admission. CONCLUSION: Our study showed that the neurologic examination can be trusted and is reliable in pediatric blunt TBI patients in determining when an RHCT scan is necessary. We recommend that RHCT is required routinely in patients with intracranial hemorrhage with GCS score of 8 or less and in patients with GCS greater than 8 and that RHCT be performed only when there are clinical indications. LEVEL OF EVIDENCE: Diagnostic/therapeutic study, level IV. PMID- 24064866 TI - Strong ion difference and gap predict outcomes after adult burn injury. AB - BACKGROUND: The strong ion difference (SID) (apparent [SIDa] and effective [SIDe]) and strong ion gap (SIG) provide a comprehensive method of evaluating acid-base status in critically ill patients. The SID is the difference between strong cations and strong anions in plasma, while the SIG demonstrates the presence of unmeasured ions. This approach accounts for changes in a patient's protein status, which is particularly important in those with burn injuries. We hypothesized that the SIDa, SIDe, and SIG during the first 72 hours after admission would be predictive of mortality in burn patients. METHODS: This study is a retrospective review of adults with 20% or greater total body surface area burns admitted during a 7-year period to a regional burn center. SIDa, SIDe, and SIG were calculated at admission and for the first 3 days. These results were then compared with Acute Physiology and Chronic Health Evaluation II (APACHE II) and sepsis-related organ failure assessment (SOFA) scores. RESULTS: A total of 113 patients met the criteria and had full data sets, with mean +/- SEM age of 45.4 +/- 1.4 years and total body surface area burn of 41.4% +/- 1.6%. Mortality was 27.4%. At admission, APACHE II remained most predictive of mortality (p = 0.006). However, admission SIG (SIDa - SIDe) was also predictive of mortality on multivariate analysis (odds ratio, 1.11). Day 1 SIDa (Na+ + K+ + Ca2+ + Mg2+ - Cl ) and SIDe ([1,000 * 2.46 * 10(-11) * PaCO2/10(-pH)] + [[albumin] * (0.123 * pH - 0.631)] + [[PO4] * (0.309) * pH - 0.469)]) were also associated with mortality (odds ratio, 1.16 and 1.13 respectively), and SIDe with length of stay and ventilator days (p < 0.05). CONCLUSION: The SID and SIG are predictive of mortality, hospital length of stay, and ventilator days in adult burn patients. They also elucidate complex acid-base disorders. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 24064867 TI - Compliance of randomized controlled trials in trauma surgery with the CONSORT statement. AB - BACKGROUND: Randomized controlled trials (RCTs) are the criterion standard for assessing new interventions. However, bias can result from poor reporting, which also makes critical appraisal and systematic review challenging. The Consolidated Standards of Reporting Trials (CONSORT) criteria for nonpharmacological trials published in 2008 provided a set of 23 mandatory items that should be reported in an RCT. This is the first study to assess the compliance of RCTs in trauma with the CONSORT criteria for nonpharmacological trials. METHODS: The MEDLINE database was searched using the MeSH term wounds and injuries for English-language articles published between January 2009 and December 2011. Relevant articles were scored by two reviewers and compared against surrogate markers of article quality (such as journal impact factor). RESULTS: Eighty-three articles were deemed suitable for inclusion. The mean CONSORT score was 11.2 of 23 items (49%; range, 3.38-18.17). Compliance was poorest for items relating to the adherence of care providers (0%), abstract (5%), and implementation of randomization (6%). Only 40% declared conflicts of interest, 73% declared permission from an ethics review committee, 43% declared sources of funding, and 10% stated a trial registry number. There was a significant correlation between the CONSORT score and the impact factor of the publishing journal (rho = 0.37, p = 0.0006) but not for the number of patients or authors or single versus multicentre trials CONCLUSION: The reporting quality of RCTs in trauma surgery needs improvement. We suggest ways by which this could be improved including the following: better education, awareness, and a cohesive strategy among all stakeholders and the hard wiring of compliance through electronic journal submission systems. PMID- 24064868 TI - Combat injury coding: a review and reconfiguration. AB - BACKGROUND: The current civilian Abbreviated Injury Scale (AIS), designed for automobile crash injuries, yields important information about civilian injuries. It has been recognized for some time, however, that both the AIS and AIS-based scores such as the Injury Severity Score (ISS) are inadequate for describing penetrating injuries, especially those sustained in combat. Existing injury coding systems do not adequately describe (they actually exclude) combat injuries such as the devastating multi-mechanistic injuries resulting from attacks with improvised explosive devices (IEDs). METHODS: After quantifying the inapplicability of current coding systems, the Military Combat Injury Scale (MCIS), which includes injury descriptors that accurately characterize combat anatomic injury, and the Military Functional Incapacity Scale (MFIS), which indicates immediate tactical functional impairment, were developed by a large tri service military and civilian group of combat trauma subject-matter experts. Assignment of MCIS severity levels was based on urgency, level of care needed, and risk of death from each individual injury. The MFIS was developed based on the casualty's ability to shoot, move, and communicate, and comprises four levels ranging from "Able to continue mission" to "Lost to military." Separate functional impairments were identified for injuries aboard ship. Preliminary evaluation of MCIS discrimination, calibration, and casualty disposition was performed on 992 combat-injured patients using two modeling processes. RESULTS: Based on combat casualty data, the MCIS is a new, simpler, comprehensive severity scale with 269 codes (vs. 1999 in AIS) that specifically characterize and distinguish the many unique injuries encountered in combat. The MCIS integrates with the MFIS, which associates immediate combat functional impairment with minor and moderate-severity injuries. Predictive validation on combat datasets shows improved performance over AIS-based tools in addition to improved face, construct, and content validity and coding inter-rater reliability. Thus, the MCIS has greater relevance, accuracy, and precision for many military-specific applications. CONCLUSION: Over a period of several years, the Military Combat Injury Scale and Military Functional Incapacity Scale were developed, tested and validated by teams of civilian and tri-service military expertise. MCIS shows significant promise in documenting the nature, severity and complexity of modern combat injury. PMID- 24064869 TI - Current concepts in the management of biologic and chemical warfare causalities. PMID- 24064870 TI - The swinging pendulum: a national perspective of nonoperative management in severe blunt liver injury. AB - BACKGROUND: Despite a shift toward nonoperative management (NOM) of blunt liver trauma, severe injuries continue to require operative management. Our objective was to examine current trends of NOM for severe blunt liver injury from a national perspective. METHODS: Patients with blunt liver injury with Abbreviated Injury Scale (AIS) score of 4 or greater and no other major solid organ injury or pelvic fracture were identified in the National Trauma Data Bank 2002 to 2008. Attempted NOM was defined as no surgery in 6 hours or less. Failed NOM was defined as surgery in greater than 6 hours. Cox regression evaluated the association of NOM outcome with 30-day mortality after controlling for injury severity and center. Logistic regression was used to define independent predictors of failed NOM. Annual attempted and failed NOM rates were compared during the study period. RESULTS: A total of 3,627 patients were identified with a median Injury Severity Score (ISS) of 29 (interquartile range, 20-38) and 20% mortality. Early operative management occurred in 20%, while initial NOM occurred in 73% of the patients. Of these, 93% had successful NOM, and 7% had failed NOM. Failed NOM was an independent predictor of mortality (hazard ratio, 1.7; 95% confidence interval, 1.1-2.6; p = 0.01). Increasing age, male sex, increasing ISS, decreasing Glasgow Coma Scale (GCS) score, hypotension, and hepatic angioembolization were independent predictors of failed NOM. The rate of attempted and failed NOM increased during the study period (p < 0.01). CONCLUSION: NOM for isolated severe blunt liver injury is increasing nationally with similar increment in failure. Failed NOM was associated with higher mortality. Several predictors of failed NOM were identified including age, sex, ISS, GCS, and hypotension. These factors may allow for better patient selection and improved outcomes. LEVEL OF EVIDENCE: Therapeutic study, level IV; prognostic/epidemiologic study, level III. PMID- 24064871 TI - Splenectomy in patients with traumatic brain injury: protective or harmful? A National Trauma Data Bank analysis. AB - BACKGROUND: Experimental data have demonstrated a potential survival benefit for animals undergoing splenectomy immediately after traumatic brain injury. The aim of this study was to investigate the effect of splenectomy on survival in patients with moderate or severe traumatic brain injury (TBI). METHODS: This is a National Trauma Data Bank (2002-2009) analysis and included patients sustaining moderate or severe blunt head trauma (head Abbreviated Injury Scale [AIS] score, 3-5), with an associated splenic injury and an exploratory laparotomy. The population was divided into two arms: those that had a splenectomy and those who did not. The primary outcome was in-hospital mortality. Logistic regression was performed to adjust for factors that were significantly different between the study groups. RESULTS: During the 9-year study period, 2,625 patients met the criteria for inclusion in the analysis. Of these, 1,450 (55%) had a splenectomy, and 1,175 (45%) did not. Mortality was 13% for the splenectomized compared with 9% for the nonsplenectomized population (p = 0.001). After logistic regression, mortality remained significantly higher in the splenectomized population (adjusted odds ratio [AOR], 1.62; 95% confidence interval [CI], 1.16-2.26; p = 0.005). After stratification according to the severity of brain injury, the association between splenectomy and increased mortality persisted for both patients with moderate head injury (8% vs. 6%; AOR, 2.43; 95% CI, 1.26-4.71; p = 0.008) and for patients with severe head injury (17% vs. 10%; AOR, 1.49; 95% CI, 1.03-2.19; p = 0.036). CONCLUSION: Splenectomy was independently associated with increased mortality in patients with moderate or severe TBI. This finding warrants further investigation regarding splenic preservation in patients with TBI. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 24064872 TI - Contemporary trends in the immediate surgical management of renal trauma using a national database. AB - BACKGROUND: The National Trauma Data Bank was used to analyze open surgical management of renal trauma during the first 24 hours of hospital admission, excluding those who were treated with conservative measures. A descriptive analysis of initial management trends following renal trauma was also performed as a secondary analysis. METHODS: With the use of the National Trauma Data Bank, patients with renal injuries were identified, and Abbreviated Injury Scale (AIS) codes were stratified to a corresponding American Association for the Surgery of Trauma (AAST) renal injury grade. Trends in initial management were assessed using the following initial treatment categories: observation, minimally invasive surgery, and open renal surgery. Analysis of initial open surgery was further examined according to etiology of injury (blunt vs. penetrating), type of open renal surgery, concomitant abdominal surgery, patient demographics, and time to surgery. RESULTS: A total of 9,002 renal injuries (0.3%) were mapped to an AAST renal grade. Of these, 1,183 patients underwent open surgery for their renal injury in the first 24 hours. There were 773 penetrating and 410 blunt injuries within this cohort. The majority of surgical patients sustained a high-grade renal injury (AAST Grades 4-5, 64%). The overall nephrectomy rate in the first 24 hours was 54% and 83% for the penetrating and blunt groups, respectively. While the overall nephrectomy rate for AAST Grade 1 to 3 renal injuries in the first 24 hours was low (1.8%), the nephrectomy rate was higher in the setting of an exploratory laparotomy (30%). Of those undergoing renal surgery in the first 24 hours, 86% had concomitant surgery performed for other abdominal injuries. Mean time from emergency department presentation to surgery was less for penetrating trauma. CONCLUSION: Of the patients requiring open surgery for renal trauma within 24 hours of admission, nephrectomy is the most common surgery. Continued effort to reduce nephrectomy rates following abdominal trauma is necessary. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 24064873 TI - Real-time heart rate entropy predicts the need for lifesaving interventions in trauma activation patients. AB - BACKGROUND: Heart rate complexity (HRC), commonly described as a "new vital sign," has shown promise in predicting injury severity, but its use in clinical practice has been precluded by the absence of real-time data. This study was conducted to evaluate the utility of real-time, automated, instantaneous, hand held heart rate entropy analysis in predicting the need for lifesaving interventions (LSIs). We hypothesized that real-time HRC would predict LSIs. METHODS: Prospective enrollment of patients who met criteria for trauma team activation was conducted at a Level I trauma center (September 2011 to February 2012). A novel, hand-held, portable device was used to measure HRC (by sample entropy) and time-domain heart rate variability continuously in real time for 2 hours after the moment of presentation. Electric impedance cardiography was used to determine cardiac output. Patients who received an LSI were compared with patients without any intervention (non-LSI). Multivariable analysis was performed to control for differences between the groups. RESULTS: Of 82 patients enrolled, 21 (26%) received 67 LSIs within 24 hours of hospital arrival. Initial systolic blood pressure was similar in both groups. LSI patients had a lower Glasgow Coma Scale (GCS) score (9.2 [5.1] vs. 14.9 [0.2], p < 0.0001). The mean (SD) HRC value on presentation was 0.8 (0.6) in the LSI group compared with 1.5 (0.6) in the non LSI group (p < 0.0001). With the use of logistic regression, initial HRC was the only significant predictor of LSI. A cutoff value for HRC of 1.1 yields sensitivity, specificity, negative predictive value, and positive predictive value of 86%, 74%, 94%, and 53%, respectively, with an accuracy of 77% for predicting an LSI. CONCLUSION: Decreased HRC on hospital arrival is an independent predictor of the need for LSI in trauma activation patients. Real time HRC may be a useful adjunct to standard vital signs monitoring and predicts LSIs. LEVEL OF EVIDENCE: Prognostic and diagnostic study, level III. PMID- 24064874 TI - Chest x-ray as a screening tool for blunt thoracic trauma in children. AB - BACKGROUND: With the increasing use of thoracic computed tomography (CT) to screen for injuries in pediatric blunt thoracic trauma (BTT), we determined whether chest x-ray (CXR) and other clinical and epidemiologic variables could be used to predict significant thoracic injuries, to inform the selective use of CT in pediatric BTT. We further queried if these were discrepant from factors associated with the decision to obtain a thoracic CT. METHODS: This retrospective cohort study included cases of BTT from three Level I pediatric trauma centers between April 1999 and March 2008. Pre-CT epidemiologic, clinical, and radiologic variables associated with CT findings of any thoracic injury or a significant thoracic injury as well as the decision to obtain a thoracic CT were determined using logistic regression. RESULTS: Of 425 patients, 40% patients had a significant thoracic injury, 49% had nonsignificant thoracic injury, and 11% had no thoracic injury at all. Presence of hydrothorax and/or pneumothorax on CXR significantly increased the likelihood of significant chest injury visualized by CT (adjusted odds ratio 10.8; 95% confidence interval, 6.5-18), as did the presence of isolated subcutaneous emphysema (adjusted odds ratio, 19.8; 95% confidence interval, 2.3-168). Although a normal CXR finding was not statistically associated with a reduced risk of significant thoracic injury, 8 of the 9 cases with normal CXR findings and significant injuries involved occult pneumothoraces or hemothoraces not requiring intervention. Converse to features suggesting increased risk of significant injury, the decision to obtain a thoracic CT was only associated with later period in the study and obtaining a CT scan of another body region. CONCLUSION: CXR can be used to screen for significant thoracic injuries and direct the selective use of thoracic CT in pediatric BTT. Prospective studies are needed to validate these findings and develop guidelines that include CXR to define indications for thoracic CT in pediatric BTT. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 24064875 TI - Characterizing vasopressin and other vasoactive mediators released during resuscitation of trauma patients. AB - BACKGROUND: We sought to perform the first characterization of vasopressin and other vasoactive mediators released during resuscitation of hypotensive trauma patients. METHODS: This institutional review board-approved study was conducted under waiver of consent. Adults with clinical evidence of acute traumatic injury and systolic blood pressure less than or equal to 90 mm Hg within 1 hour of arrival were evaluated at our Level I trauma center. Two hundred three patients were screened with 50 enrolled from February 2010 to February 2011. Demographic information was also collected. Blood samples were obtained at 0, 30, 60, 90, 120, and 240 minutes after arrival, and assays were performed for vasopressin, angiotensin II, epinephrine, and cortisol. We assessed the significance of variation in these vasoactive mediators with injury and transfusion of more than 600 mL, with adjustment for time using repeated-measures linear models in log units. RESULTS: We found that vasopressin (p = 0.005) and epinephrine (p = 0.01) increased significantly with injury, while angiotensin (p = 0.60) and cortisol (p = 0.46) did not and that vasopressin (p < 0.001) and epinephrine (p = 0.004) increased significantly in patients requiring transfusion of more than 600 mL but angiotensin II (p = 0.11) and cortisol (p = 0.90) did not. Relatively low levels of vasopressin (<30 pg/mL) were observed at least once during the first 2 hours in 88% of trauma patients, and abnormally low epinephrine levels (<100 pg/mL) were observed at least once during the first 2 hours in 18% of trauma patients. CONCLUSION: This is the first clinical trial to serially evaluate vasopressin and other vasoactive mediators following trauma during the resuscitation phase. Vasopressin, in particular, and epinephrine seem to be the key mediators produced in the human response to severe injury. A deficiency of vasopressin may contribute to intractable shock after trauma. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 24064876 TI - Admission ASIA motor score predicting the need for tracheostomy after cervical spinal cord injury. AB - BACKGROUND: Respiratory compromise and the need for tracheostomy are common after cervical spinal cord injury (cSCI). The purpose of the study was to evaluate if admission American Spinal Injury Association (ASIA) motor score is associated with the need for tracheostomy following cSCI. METHODS: The trauma registry identified patients with isolated cSCI during a 3-year period. Patients with an Abbreviated Injury Scale score greater than 3 in other body regions were excluded. Medical records were reviewed for demographics, admission ASIA motor score, ASIA Impairment Scale (AIS), anatomic level of injury, need for a tracheostomy, and length of stay (LOS). Logistic regression models were constructed to examine the effect of admission ASIA motor scores on the outcome of tracheostomy. Cox proportional hazards models were fit to determine risk factors for time to tracheostomy. RESULTS: A total of 128 patients were identified. Seventy-four patients had a tracheostomy performed on mean (SD) hospital Day 9 (4). Median admission ASIA motor score was 22.0 (interquartile range [IQR], 8-54). Median anatomic level of injury was 5 (IQR, 4-6). Patients requiring tracheostomy had significantly lower median admission ASIA motor score (9 [IQR, 3-17] vs. 57 [IQR, 30-77], p < 0.001) and were more likely to be an AIS A. There was no difference in median anatomic level of injury (5 [IQR, 4-5.8] vs. 5 [IQR, 4-6], p = nonsignificant). ASIA motor scores less than 10 had an unadjusted odds ratio for requiring tracheostomy of 56 (95 confidence interval, 7 426). Following adjustment for independent risk factors, the odds ratio for ASIA motor score less than 10 remained statistically significant at 22 (confidence interval, 3-180). Among patients with incomplete cSCI, ASIA motor scores increased significantly from AIS B to AIS D, while Injury Severity Score (ISS), LOS and intensive care unit LOS declined significantly. Of those patients without a tracheostomy, 100% had an ASIA motor score greater than 10, 98% had an ASIA motor score greater than 20, and 86% had an ASIA motor score greater than 25. Among patients with an ASIA motor score less than 10, 100% had a tracheostomy; among patients with an ASIA motor score less than 20, 96% had a tracheostomy. Among patients with a tracheostomy, 91% were an AIS B or C, while 85% of patients classified as AIS D did not have a tracheostomy. CONCLUSION: Tracheostomy after cSCI is common. Lower admission ASIA motor score and "complete" cSCI are significantly associated with the need for tracheostomy. Anatomic level of injury was not associated with tracheostomy after cSCI. Classification of incomplete patients by AIS indicates that ASIA motor score may be used as a surrogate for grade of injury. When looking only at patients with an "incomplete" cSCI, those with an admission ASIA score of less than 10 should have an early tracheostomy. Those with an AIS D scale should not be considered for early tracheostomy. LEVEL OF EVIDENCE: Therapeutic/care management, level II. PMID- 24064877 TI - Early application of airway pressure release ventilation may reduce mortality in high-risk trauma patients: a systematic review of observational trauma ARDS literature. AB - BACKGROUND: Adult respiratory distress syndrome is often refractory to treatment and develops after entering the health care system. This suggests an opportunity to prevent this syndrome before it develops. The objective of this study was to demonstrate that early application of airway pressure release ventilation in high risk trauma patients reduces hospital mortality as compared with similarly injured patients on conventional ventilation. METHODS: Systematic review of observational data in patients who received conventional ventilation in other trauma centers were compared with patients treated with early airway pressure release ventilation in our trauma center. Relevant studies were identified in a PubMed and MEDLINE search from 1995 to 2012 and included prospective and retrospective observational and cohort studies enrolling 100 or more adult trauma patients with reported adult respiratory distress syndrome incidence and mortality data. RESULTS: Early airway pressure release ventilation as compared with the other trauma centers represented lower mean adult respiratory distress syndrome incidence (14.0% vs. 1.3%) and in-hospital mortality (14.1% vs. 3.9%). CONCLUSION: These data suggest that early airway pressure release ventilation may prevent progression of acute lung injury in high-risk trauma patients, reducing trauma-related adult respiratory distress syndrome mortality. LEVEL OF EVIDENCE: Systematic review, level IV. PMID- 24064878 TI - Safety and efficacy of pharmacologic thromboprophylaxis following blunt head injury: a systematic review. AB - BACKGROUND: Patients with blunt head injury are at high risk of venous thromboembolism. However, pharmacologic thromboprophylaxis (PTP) may cause progression of intracranial hemorrhage, and clinicians must often weigh up the risks and benefits. This review aimed to determine whether adding PTP to mechanical prophylaxis confers net benefit or harm and the optimal timing, dose, and agent for PTP in patients with blunt head injury. METHODS: We searched MEDLINE, EMBASE, The Cochrane Library Central Register of Controlled Trials (CENTRAL), and www.clinicaltrials.gov on April 24, 2013, to identify controlled studies and ongoing trials that assessed the efficacy or safety of thromboprophylaxis interventions in the early management of head-injured patients. Studies were classified based on types of interventions and comparisons, and the quality of included studies was assessed using Cochrane risk of-bias tool and the Newcastle-Ottawa Quality Assessment Scale. We intended to undertake a meta-analysis if studies were sufficiently similar. RESULTS: Sixteen studies met the inclusion criteria, including four randomized controlled trials. At least two randomized controlled trials were at high risk of bias owing to inadequate randomization and concealment of allocation, and observational studies were potentially confounded by substantial differences between comparison groups. Heterogeneity of included studies precluded meta-analysis. Results were mixed, with some studies supporting and others refuting addition of PTP to mechanical interventions. Little evidence was available about dose or choice of agent. The safety and efficacy of early PTP in patients without early progression of hemorrhage is unclear. CONCLUSION: There is currently insufficient evidence to guide thromboprophylaxis in patients with blunt head injury. Standardized definitions and outcome measurements would facilitate comparison of outcomes across future studies. Studies in mixed populations should report head-injured specific subgroup data. Future randomized controlled trials should investigate the efficacy and safety of early pharmacologic prophylaxis in addition to mechanical intervention. LEVEL OF EVIDENCE: Systematic review, level IV. PMID- 24064880 TI - Does perioperative systemic infection or fever increase surgical infection risks after internal fixation of femur and tibia fractures in an intensive care polytrauma unit? AB - BACKGROUND: We hypothesized that internal fixation procedures performed on trauma intensive care unit (ICU) patients with systemic infections, some also febrile, would be at increased risk for deep infection. METHODS: A total of 128 patients (mean age, 37.4 years; mean Injury Severity Score [ISS], 34.7) admitted to the ICU with 179 femur or tibia fractures developed systemic infections. Systemic infections included sepsis, pneumonia, urinary tract infections, abdominal infections, and wound infections remote to the fracture. Of the fractures, 33 open and 146 closed underwent 150 intramedullary and 29 plate fixation procedures. Data were gathered regarding antibiotic use, systemic infection timing in relation to the date of fixation, and whether fever (>38.2 degrees C) was present within 24 hours of fixation. Patients were followed up for a mean of 491 days. RESULTS: Twenty-eight procedures were performed a mean of 4.7 days after the diagnosis of a systemic infection, and 151 were performed a mean of 9.3 days before the diagnosis. Forty-five procedures were performed in patients who were febrile within 24 hours. Of the 179 procedures, 10 (5.6%) developed a deep infection. Four patients' implant infection was potentially hematogenously seeded with the same organism as their systemic infection. Neither the timing of the systemic infection in relation to the fixation procedure nor the presence of fever within 24 hours of fixation, days of preoperative antibiotics, location of the fracture, type of fixation (intramedullary nail vs. plate fixation), or type of systemic infection was significantly associated with the development of an infection. The only significant risk factor for developing an orthopedic infection was an open fracture (p < 0.001). CONCLUSION: Internal fixation performed in ICU patients with fever or in close conjunction to the diagnosis of systemic infection led to a 5.6% infection rate, which compares favorably with historic infection rates for fixation of open or closed tibia and femur fractures. LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 24064879 TI - Perioperative supplemental oxygen to reduce surgical site infection after open fixation of high-risk fractures: a randomized controlled pilot trial. AB - BACKGROUND: Higher concentrations of fraction of inspired oxygen (FIO2) have been shown to be associated with lower risk for surgical site infection in multiple studies outside the domain of orthopedic surgery. We evaluated the efficacy of high FIO2 administered during the perioperative period to reduce the rate of surgical site infection after open fixation of lower-extremity fractures at high risk of infection. METHODS: We conducted a randomized controlled, parallel design, double-blind study. Patients sustaining high-energy tibial plateau, tibial pilon, and calcaneus fractures treated in a staged fashion were selected for enrollment because these injuries are associated with high risk of infection. The study population included 222 patients with 235 fractures. Consenting patients were randomized by random number sequence to either the treatment or the control group. Treatment group patients received 80% FIO2 intraoperatively and for 2 hours afterward. Control group patients received 30% FIO2 during the same period. Surgeons, patients, and personnel who performed wound assessments were blinded to group assignment. The primary outcome measure was surgical site infection as defined by the Centers for Disease Control criteria for postoperative wound infection. RESULTS: The overall rates of postoperative surgical site infection were 12% (14 of 119 fractures) in the treatment group and 16% (19 of 116 fractures) in the control group (p = 0.31). Multivariate analysis, accounting for risk factors for infection, yielded the closest to a statistically significant reduction in the odds of infection with treatment (odds ratio, 0.54; p = 0.17). No treatment-associated events were observed. CONCLUSION: Use of a high concentration of FIO2 during the perioperative period is safe and shows a trend toward reduction of surgical site infection in patients undergoing open operative fixation of high-energy traumatic lower-extremity fractures. Further study in a larger patient population is indicated. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 24064881 TI - Let technology do the work: Improving prediction of massive transfusion with the aid of a smartphone application. AB - BACKGROUND: The use of massive transfusion protocols (MTPs) is now common in civilian trauma settings, and early activation of MTP has been shown to increase survival of MTP recipients. Numerous MTP prediction tools have been developed; however, they are often cumbersome to use efficiently or have traded predictive power for ease of use. We hypothesized that a highly accurate predictor of massive transfusion could be created and incorporated into a smartphone application that would provide an additional tool for clinicians to use in directing the resuscitation of critically injured patients. METHODS: Data from all trauma admissions since the inception of MTP were put in place at Grady Memorial Hospital in Atlanta, Georgia, were collected. A predictive model was developed using the least absolute shrinkage and selection operator (LASSO) and 10-fold cross validation. Data were resampled over 500 iterations, each using a unique and random subset of 80% of the data for model training and 20% for validation. RESULTS: The trauma registry contained 13,961 cases between 2007 and November 2011, of which 10,900 were complete and 394 received MTP. Of 44 input terms, only the mechanism of injury, heart rate, systolic blood pressure, and base deficit were found to be important predictors of massive transfusion. Our model has an area under the receiver operating curve of 0.96 (against data not used during model training) and accurately predicted MTP status for 97% of all patients. The model accurately discriminated full MTPs from MTP activations that did not meet criteria for massive transfusion. While complex to calculate by hand, our model has been packaged into a mobile application, allowing for efficient use while minimizing potential for user error. CONCLUSION: We have developed a highly accurate model for the prediction of massive transfusion that has potential to be easily accessed and used within a simple and efficient mobile application for smartphones. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 24064882 TI - Risky drinking among parents of pediatric trauma patients. AB - BACKGROUND: Unintentional injury is the leading cause of death for children in the United States. An association between parental alcohol use and the frequency and severity of childhood injuries has been found; however, research is limited. The purpose of this study was to (1) describe demographics, child safety behaviors, and parental risky behaviors for a pediatric trauma patient population and (2) assess the relationship between positive screen results for risky drinking in parents and demographic and child safety behaviors. METHODS: Data were collected from a sample of parents of a child younger than 15 years who was admitted to an urban children's hospital for treatment for an unintentional injury. Data were analyzed using descriptive statistics, bivariate analyses, and logistic regression. RESULTS: A total of 926 parents of 693 patients were included in this study. Of the families who completed the survey, 37.1% (n = 257) had at least one parent screening positive for risky alcohol use. When looking at patients who ride bicycles, a little more than half (55.1%) were reported as consistently using a helmet. Results showed that inconsistent helmet use was associated with a higher likelihood of at least one parent screening positive for risky drinking (odds ratio, 1.58; 95% confidence interval, 1.06-2.36; p <= 0.05). CONCLUSION: Helmet use is a known prevention method of head injuries resulting from bicycle crashes. However, improvements need to be made on how to disseminate this information to parents and how to locate and intervene with the parents who have children that are at an increased risk of injury and injury recidivism. Using screening and brief intervention programs may assist in locating and reducing the potential of recurring visits by at-risk patients such as those in this sample who had at least one parent screening positive for risky drinking. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 24064883 TI - Gender impacts mortality after traumatic brain injury in teenagers. AB - BACKGROUND: Gender may influence outcomes following traumatic brain injury (TBI) although the mechanism is unknown. Animal TBI studies suggest that gender differences in endogenous hormone production may be the source. Limited retrospective clinical studies on gender present varied conclusions. Pediatric patients represent a unique population as pubescent children experience up regulation of endogenous hormones that varies dramatically by gender. Younger children do not have these hormonal differences. The aim of this study was to compare pubescent and prepubescent females with males after isolated TBI to identify independent predictors of mortality. METHODS: We performed a retrospective review of the National Trauma Data Bank Research Data Sets from 2007 and 2008 looking at all blunt trauma patients 18 years or younger who required hospital admission after isolated, moderate-to-severe TBI, defined as head Abbreviated Injury Scale (AIS) score 3 or greater. We excluded all individuals with AIS score of 3 or greater for any other region to limit the confounding effect of comorbidities. Based on the median age of menarche, we defined two age groups as follows: prepubescent (0-12 years) and pubescent (>12 years). Analysis was performed to compare trauma profiles and outcomes between groups. Our primary outcome measure was in-hospital mortality. RESULTS: A total of 20,280 patients met inclusion criteria; 10,135 were prepubescent, and 10,145 were pubescent. Overall mortality was 6.9%, and lower mortality was noted among prepubescent patients compared with pubescent (5.2% vs. 8.6%, p < 0.0001). Although female gender did not predict reduced mortality in the prepubescent cohort (adjusted odds ratio, 1.05; 95% confidence interval, 0.85-1.30; p = 0.63), female gender was associated with reduced mortality in the pubescent (adjusted odds ratio, 0.78; 95% confidence interval, 0.65-0.93; p = 0.007). CONCLUSION: In contrast to prepubescent female gender, pubescent female gender predicts reduced mortality following isolated, moderate-to-severe TBI. Endogenous hormonal differences may be a contributing factor and require further investigation. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 24064884 TI - Who needs an orthopedic trauma surgeon? An analysis of US national injury patterns. AB - BACKGROUND: Many hospitals in the United States are seeking to obtain and maintain trauma credentialing. Assessment of trauma center success has traditionally focused on mortality without directed measure of surgical subspecialization. However, survival alone may not be a sufficient marker of success with modern health care. The purpose of this study was to determine the number of trauma patients nationally who would benefit from subspecialized care by an orthopedic traumatologist. METHODS: A list of musculoskeletal DRG International Classification of Diseases-9th Rev. codes representing injuries warranting care by subspecialized orthopedic traumatologists was generated by survey to each of two cohorts: one consisting of 10 subspecialized orthopedic traumatologists and one consisting of 10 nontraumatologists. The 2006 National Inpatient Sample data set was used to estimate the national volume of patients sustaining an orthopedic injury and the number requiring subspecialty orthopedic trauma care, as defined by the DRG International Classification of Diseases-9th Rev. lists generated by our survey. RESULTS: Survey response rate was 100%. In 2006, 2,068,349 patients sustained a traumatic injury; 46.7% of these had an orthopedic injury. Our cohort of subspecialized orthopedic traumatologists identified 25.7% of all trauma patients as requiring an orthopedic traumatologist. Our cohort of general orthopedists identified 13.5% of all trauma patients as requiring an orthopedic traumatologist. Rates of polytrauma, injury severity, and treatment at trauma centers were similar between the two groups. CONCLUSION: Between 13.5% and 25.7% of all injured patients should, if resources permit, receive subspecialty orthopedic trauma care. The magnitude of this figure highlights the importance, from a public health perspective, of policy interventions aimed at better coordinating the field of orthopedic traumatology. Detailed outcome measures beyond mortality and triage guidelines suggesting which patients should receive subspecialty orthopedic trauma care should be developed. In addition, resources, including fellowship training, should be allocated in a methodical manner that matches supply to the national demand for this type of care. LEVEL OF EVIDENCE: Economic/decision analysis, level IV. PMID- 24064885 TI - Obesity and overweight as a risk factor for pneumonia in polytrauma patients: a retrospective cohort study. AB - BACKGROUND: Obesity is a growing problem in western societies. The aim of this retrospective cohort study was to determine the association between the overweight and obese polytrauma patients and pneumonia after injury. METHODS: A total of 628 patients with an Injury Severity Score (ISS) of 16 or greater and 16 years or older were included in this retrospective study. The sample was subdivided into three groups as follows: body mass index (BMI) of less than 25 kg/m2; BMI of 25 kg/m2 to 30 kg/m2; and BMI more than 30 kg/m2. The Murray score was assessed at admission and at its maximum during hospitalization to determine pulmonary problems. Pneumonia was defined as bacteriologically positive sputum with appropriate radiologic and laboratory changes (C-reactive protein and interleukin 6). Data are given as mean +/- SEM. One-way analysis of variance and the Kruskal-Wallis test were used for the analyses, and the significance level was set at p < 0.05; Bonferroni-Dunn test was performed as post hoc analysis. RESULTS: The Abbreviated Injury Scale (AIS) score for the thorax was 3.2 +/- 0.1 in the group with a BMI of less than 25 kg/m2, 3.3 +/- 0.1 in the group with a BMI of 25 kg/m2 to 30 kg/m2, and 2.8 +/- 0.2 in the group with BMI of more than 30 kg/m2 (p = 0.044). The Murray score at admission was elevated with increasing BMI (0.8 +/- 0.8 for BMI < 25 kg/m2, 0.9 +/- 0.9 for BMI 25-30 kg/m2, and 1.0 +/- 0.8 for BMI > 30 kg/m2; p = 0.137); the maximum Murray score during hospitalization revealed significant differences (1.2 +/- 0.9 for BMI < 25 kg/m2, 1.6 +/- 1.0 for BMI 25-30 kg/m2, and 1.5 +/- 0.9 for BMI > 30 kg/m2; p < 0.001). The incidence of pneumonia also increased with increasing BMI (1.6% for BMI < 25 kg/m2, 2.0% for BMI 25-30 kg/m2, and 3.1% for BMI > 30 kg/m2; p = 0.044). CONCLUSION: Obesity leads to an increased incidence of pneumonia in a polytrauma situation. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level IV. PMID- 24064886 TI - The impact of liver cirrhosis on outcomes in trauma patients: a prospective study. AB - BACKGROUND: The adverse effects of liver cirrhosis on outcomes following trauma has been established in retrospective series. In this study, however, we set out to evaluate prospectively the in-hospital outcome measures in this subgroup of trauma patients. METHODS: Prospective observational study of all patients admitted to the surgical intensive care unit of a Level I trauma center from January 2008 to December 2011. Cirrhotic trauma cases were matched with noncirrhotic controls in a 1:2 ratio. Matching criteria included age, sex, injury mechanism, vital signs at admission, Abbreviated Injury Scale (AIS) score for all body regions, and Injury Severity Score (ISS). Outcomes included in-hospital morbidity and mortality. RESULTS: During the 4-year study period, 92 (0.8%) of the 12,102 trauma admissions had liver cirrhosis. After matching, no differences with regard to demographic and clinical injury characteristics were noted comparing the cases and controls. The overall complication rate in cases and controls was 31.5% and 7.1%, respectively (p < 0.001). In-hospital mortality was significantly higher for cirrhotic patients compared with their noncirrhotic counterparts (20.7 vs. 6.5%, p = 0.001). Within the cirrhotic group, mortality increased significantly from 8.0% in Child-Pugh Class A to 32.3% in Class B and 45.5% in Class C (p = 0.003). Likewise, mortality was significantly higher for patients with a Model for End-Stage Liver Disease (MELD) score of 10 or greater versus less than 10 (30.0% vs. 9.5%; odds ratio, 4.07; 95% confidence interval, 1.23-13.45; p = 0.016). CONCLUSION: In this prospective investigation, liver cirrhosis is associated with adverse outcomes following trauma. Both stepwise increasing Child-Pugh and MELD scores predicted adjusted adverse outcomes. Injured patients with cirrhosis warrant aggressive monitoring and instant treatment after injury. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 24064887 TI - The effect of trauma center care on pediatric injury mortality in California, 1999 to 2011. AB - BACKGROUND: Trauma centers (TCs) have been shown to decrease mortality in adults, but this has not been demonstrated at a population level in all children. We hypothesized that seriously injured children would have increased survival in a TC versus nontrauma center (nTC), but there would be no increased benefit from pediatric-designated versus adult TC care. METHODS: This was a retrospective study of the unmasked California Office of Statewide Health and Planning Department patient discharge database (1999-2011). DRG International Classification of Diseases-9th Rev. (ICD-9) diagnostic codes indicating trauma were identified for children (0-18 years), and injury severity was calculated from ICD-9 codes using validated algorithms. To adjust for hospital case mix, we selected patients with ICD-9 codes that were capable of causing death and which appeared at both TCs and nTCs. Instrumental variable (IV) analysis using differential distance between the child's residence to a TC and to the nearest hospital was applied to further adjust for unobservable differences in TC and nTC populations. Instrumental variable regression models analyzed the association between mortality and TC versus nTC care as well as for pediatric versus adult TC designations, adjusting for demographic and clinical variables. RESULTS: Unadjusted mortality for the entire population of children with nontrivial trauma (n = 445,236) was 1.2%. In the final study population (n = 77,874), mortality was 5.3%, 3.8% in nTCs and 6.1% in TCs. IV regression analysis demonstrated a 0.79 percentage point (95% confidence interval, -0.80 to -0.30; p = 0.044) decrease in mortality for children cared for in TC versus nTC. No decrease in mortality was demonstrated for children cared for in pediatric versus adult TCs. CONCLUSION: Our IV TC outcome models use improved injury severity and case mix adjustment to demonstrate decreased mortality for seriously injured California children treated in TCs. These results can be used to take evidence-based steps to decrease disparities in pediatric access to, and subsequent outcomes for, trauma care. LEVEL OF EVIDENCE: Therapeutic/care management, level III. PMID- 24064888 TI - Measurable outcomes of quality improvement using a daily quality rounds checklist: two-year prospective analysis of sustainability in a surgical intensive care unit. AB - BACKGROUND: The use of a "quality rounds checklist" (QRC) is an effective tool for improving compliance with evidence-based preventative measures and outcomes in the surgical intensive care unit (SICU). Our aim was to evaluate the long-term sustainability and outcome impact of this quality improvement strategy. METHODS: Prospective observational study evaluates the use of the QRC in the SICU from July 2009 to June 2011. Daily compliance with evidence-based prophylactic measures was assessed using the QRC and reviewed monthly at a multidisciplinary meeting. Logistic regression was performed to evaluate patterns of compliance over time. Current compliance was compared with previously reported rates, and the impact on outcomes including catheter-related blood stream infection and ventilator-associated pneumonia rates was examined. RESULTS: Over 2 years, 2,472 patients were admitted to the SICU. Mean (SD) age was 42.2 (22.4) years, 79% were male, and 35% had an Injury Severity Score (ISS) of greater than 15. The rate of compliance with head-of-bed elevation significantly improved during the study period (p = 0.01 for trend), with an overall compliance of 97%. Both deep venous thrombosis prophylaxis and gastrointestinal bleed prophylaxis compliance remained stable, with overall rates of 98% and 96%, respectively. The use of sedation holidays also remained stable, with an overall compliance rate of 94%. Compared with our previously published data, the compliance rates with preventative measures were stable or significantly improved; the incidence of catheter-related blood stream infections was lower (0.85/1,000 vs. 4.98/1,000 catheter days, p < 0.001); and the incidence of ventilator-associated pneumonia downtrended (1.66/1,000 vs. 8.74/1,000 ventilator days, p = 0.07). CONCLUSION: Two years after implementation of a QRC, sustainable high rates of compliance with clinically relevant preventative measures in a SICU was demonstrated with minimal fading of clinically relevant outcomes. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 24064889 TI - Efficiency of a four-item posttraumatic stress disorder screen in trauma patients. AB - BACKGROUND: One of the most common barriers identified by physicians who fail to screen for posttraumatic stress disorder (PTSD) in trauma patients is time constraint. We hypothesized the four-question Primary Care-PTSD screen (PC-PTSD) was an acceptable alternative to the commonly used 17-question Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C). METHODS: Consecutive trauma patients admitted to a Level I trauma center were given the PCL-C at the time of hospitalization. The four questions of the PC-PTSD are contained within the PCL C. A positive PC-PTSD screen result was an endorsement of least three of the four questions. An overall score of greater than 44 on the PCL-C indicated a positive screen result. Sensitivity and specificity comparisons were made between the PCL C and the PC-PTSD. RESULTS: Data were collected from 1,347 patients hospitalized for injury. The PC-PTSD identified 17.22% of patients with PTSD risk, and the PCL C identified 16.10% at risk. Before discharge, the PC-PTSD has reasonable sensitivity in capturing the population at risk PTSD symptoms. CONCLUSION: In trauma patients before hospital discharge, the PC-PTSD is comparable with the PCL C. Although some sensitivity is lost,the PC-PTSD is a shorter screen, and the loss of sensitivity may be offset by an increased frequency of administration. LEVEL OF EVIDENCE: Diagnostic test, level III. PMID- 24064890 TI - Insurance status is a predictor of failure to rescue in trauma patients at both safety net and non-safety net hospitals. AB - BACKGROUND: Disparities in outcomes for uninsured trauma patients have been well documented. This study investigates whether failure to rescue (FTR) is a driver of mortality disparities after injury and whether patients treated at hospitals with a large volume of uninsured patients are more likely to die after complication. METHODS: A retrospective cohort study that analyzed patient records included in the National Trauma Data Bank from years 2008 to 2010 was performed. Hierarchical logistic regression was used to examine the probability that insurance type would be associated with complications, FTR, and in-hospital mortality while controlling for injury severity, mechanism of trauma, age, sex, race, comorbidities, head injury, hypotension, and hospital clustering. Additional regression models that stratified insurance subgroups and hospital subgroups were also performed. RESULTS: The uninsured patients had the lowest likelihood of developing a complication, and publicly insured patients were most likely to develop a complication compared with privately insured patients (uninsured odds ratio [OR], 0.86; government OR, 1.44). Despite having a lower risk of complication, the uninsured group was significantly more likely to experience FTR than publicly or privately insured patients (OR, 1.34). There was no significant difference in the FTR outcome between private and publicly insured patients. Both the uninsured and publicly insured patients were significantly more likely to die in the hospital than privately insured patients (uninsured OR, 1.26l; government OR, 1.17). There were no differences in complications, FTR, or mortality between safety net and non-safety net hospitals. CONCLUSION: The uninsured patients are more likely to experience FTR than the privately insured patients. Resources should be focused on this patient population to prevent complications and to study the reasons for higher mortality in these patients after they experience a complication. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 24064891 TI - Appropriate use of helicopter emergency medical services for transport of trauma patients: guidelines from the Emergency Medical System Subcommittee, Committee on Trauma, American College of Surgeons. PMID- 24064892 TI - Is viscoelastic evidence of hyperfibrinolysis the ideal indicator for tranexamic acid administration in trauma? PMID- 24064893 TI - Re: Is viscoelastic evidence of hyperfibrinolysis the ideal indicator for tranexamic acid administration in trauma? PMID- 24064894 TI - Experimental evaluation of the Combat Ready Clamp. PMID- 24064895 TI - Outcome criteria such as massive transfusion are inadequate for matching and result in questionable conclusions. PMID- 24064896 TI - Re: Outcome criteria such as massive transfusion are inadequate for matching and result in questionable conclusions. PMID- 24064897 TI - Major burn injuries and early coagulation dysfunction. PMID- 24064900 TI - Acute compartment syndrome in haemophilia. AB - Acute compartment syndrome (ACS) is characterized by an increase in pressure (intramuscular pressure) within a muscle compartment, which reduces capillary perfusion threatening tissue survival. Persistence of this increased pressure for a few hours will result in necrosis of muscle and nerve tissue, with contracture in the affected limb and permanent loss of function. For that reason, early treatment and diagnosis of ACS is fundamental. Diagnosis should be based on physical examination (pain on stretching the involved muscles) and on an objective measurement of the limb perfusion pressure (DBP minus intramuscular pressure) within the affected compartment. To obtain a reliable clinical diagnosis, the patient must be evaluated every 1-2 h. In children and in unconscious patients, where the level of pain cannot be appropriately determined, an accurate clinical diagnosis is unfeasible, hence the importance of measuring compartment pressure. A fasciotomy should be performed when the limb perfusion pressure is less than 30 mmHg when averaged over a 12-h period (monitored every 1-2 h). Only 16 studies have been published on haemophilic patients with ACS, which report on a total of 34 cases. If symptoms or pressure measurements are suggestive of ACS, an extensive fasciotomy will be required. Unfortunately, fasciotomy is not exempt from complications such as the need of subsequent surgery because of a delay in wound healing, the need of a skin graft, pain, cosmetic problems, nerve injury, permanent muscle weakness and chronic venous insufficiency. Overlooked compartment syndrome remains one of most common causes of malpractice lawsuits. In haemophilia, adequate substitution of coagulation factor must be the first step. The main principle of surgical treatment is an extensive fasciotomy. PMID- 24064901 TI - Heparin toxicity in cell culture: a critical link in translation of basic science to clinical practice. AB - Heparin is a universal drug used frequently for its anticoagulant effects. The variabilities in distribution and tendency of heparin to accumulate in tissues cause increased tissue concentrations despite normal serum levels. We aimed to underline the toxic effects of heparin in cell culture make projections for clinical applications. L929 mouse fibroblastic cell line was plated in 96-well culture plates at an initial density of 5000 cells/well. Heparin was prepared in 10 different concentrations (10-300 units/well). Following 3 days of incubation, viabilities were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for each concentration in each day and compared. The viability of cells decreased significantly with increasing doses of heparin; at least 50 units/well in the first and second days and at least 20 units/well in the third day (P < 0.05 for each). There was statistically significant difference when the viabilities of cells treated with same heparin concentration in different days were compared (P < 0.05). The authors clearly demonstrated the toxic effects of heparin in cell culture, toxic effects increased as the dose increased. To prevent the unwanted clinical side-effects of heparin further studies should be made and more accurate testing methods should be developed to determine the effective tissue concentration of heparin. PMID- 24064902 TI - Low intraindividual variability of activated partial thromboplastin time revealed in a population of 10,487 control individuals. AB - The activated partial thromboplastin time (aPTT) is a routine coagulation test that reflects the activities of multiple coagulation proteins. Given the known genetic elements underlying the different coagulation factor activities, a low intraindividual variability is expected in aPTT values, but has not been demonstrated in a large population. In this regard, we evaluated the intraindividual variability of aPTT by analyzing serial aPTTs from a large population. The study population consisted of control individuals who had three or more consecutive aPTT values at at least 6-month intervals at a single institution. The coefficient of variation of serial aPTT values was determined in each control individual, and the mean value of the coefficient of variations in the control population was calculated. The aPTT values from a total of 10,487 individuals [mean age 57 years (range 21-93 years); male-to-female ratio 1 : 0.9] were included. The mean value of the coefficient of variation of aPTTs in those individuals was 3.75%, which indicates a very low intraindividual variability. This is the first study to demonstrate a low intraindividual variability of aPTT in a large population. The result supports the previous notion that aPTT is a genetically determined parameter and has potential clinical implications. PMID- 24064903 TI - Acquired hemophilia A in a patient associated with community-acquired pneumonia. AB - Acquired hemophilia A (AHA) is a rare disease induced by autoantibodies to factor VIII (FVIII) and may be correlated with pregnancy, underlying malignancies, autoimmune diseases or drug administration. An 81-year-old man who presented with cough, expectoration, hemoptysis and multiple ecchymoses was diagnosed with community-acquired pneumonia by computed tomography scan. Respiratory symptoms were ameliorated after the application of antibiotics. Despite repeated infusion of fresh frozen plasma and cryoprecipitate, his prolonged activated partial thromboplastin time (APTT) maintained in the 75-110-s range and ecchymoses were not ameliorated. Then, he was transferred to the department of hematology. Based on a prolonged APTT, decreased level of FVIII and presence of antibodies against FVIII, the patient was diagnosed with AHA. Then the patient was treated with activated prothrombin complex concentrates, prednisone and intravenous immunoglobulin, resulting in a complete remission of the bleeding, recovering the FVIII level and negativity for FVIII antibody titers. Here, we investigate this novel case retrospectively and review the relevant literature. PMID- 24064904 TI - An importance of identification of double variant methylenetetrahydrofolate reductase gene C677T and A1298C in cis configuration for pharmacogenetic studies. PMID- 24064906 TI - Rutin and quercetin show greater efficacy than nifedipin in ameliorating hemodynamic, redox, and metabolite imbalances in sodium chloride-induced hypertensive rats. AB - Rutin and quercetin were investigated for their effects on blood pressure and antioxidant defense system of rats fed with 8% sodium chloride-supplemented diet (high salt diet) for 6 weeks. Animals fed with high salt diet demonstrated an increase in systolic, diastolic, pulse, and mean arterial blood pressures (p < 0.05) as well as lipid peroxidation but decreases in the activities of antioxidant enzymes compared with control group. Groups post-treated with rutin and quercetin for 2 weeks showed significant reversals in the values of these indices compared with the group fed with only the high salt diet but not post treated. The high salt diet also led to significant increase in serum glucose, urea, creatinine, triglycerides, low-density-lipoprotein, and total cholesterol concentrations. Treatment with rutin and quercetin ameliorated the effects of high salt diet on these biochemical indices. The reference standard, nifedipin was less effective than rutin and quercetin. The results of this study highlight the risk of high salt consumption on cardiovascular health and the potent antioxidant and antihypertensive property of rutin and quercetin. PMID- 24064905 TI - Effect of DNA damage response by quinazolinone analogue HMJ-38 on human umbilical vein endothelial cells: evidence for gammaH2A.X and DNA-PK-dependent pathway. AB - The present study aims to explore the mechanism of quinazolinone analogue HMJ-38 induced DNA damage in endothelial cells in vitro. We attempt to evaluate the antiangiogenetic response utilizing human umbilical vein endothelial cells (HUVECs). Herein, the results demonstrated that HMJ-38 incubation triggered DNA damage behavior and showed a longer DNA migration in HUVECs based on the comet assay and the analysis of DNA agarose gel electrophoresis to contact DNA smears. We further gained to determine a marker of DNA double strand breaks, phosphorylated histone H2A.X (Ser139) (gammaH2A.X), in HMJ-38-treated HUVECs by flow cytometry and Western blotting assay. We consider that HMJ-38 has caused an increase in gammaH2A.X, and DNA damage seemed to mediate through DNA-dependent serine/threonine protein kinase (DNA-PK) binding to Ku70/Ku80 as well as advanced activated p-Akt (Ser473) and stimulated phosphorylated glycogen synthase kinase 3beta (p-GSK-3beta) conditions in HUVECs. Importantly, the effect of above DNA damage response was prevented by N-acetyl-l-cysteine (a reactive oxygen species scavenger), and NU7026 (a DNA-PK inhibitor) could attenuate DNA-PK catalytic subunit and phosphorylation of H2A.X on Ser139 expression in comparison with HMJ 38 alone treated HUVECs. Therefore, HMJ-38-provoked DNA damage stress in HUVECs probably led to the activation of gammaH2A.X/DNA-PK/GSK-3beta signaling. In summary, our novel finding provides more information addressing the pharmacological approach of newly synthesized HMJ-38 for further development and therapeutic application in antiangiogenetic effect of cancer chemotherapy. PMID- 24064907 TI - Protective effect of gallic acid on alloxan-induced oxidative stress and osmotic fragility in rats. AB - In the present study, we investigated the antioxidant effect of gallic acid (GA) on membrane lipid peroxidation and osmotic fragility in alloxan-induced diabetic Wistar rats. GA was administered orally at doses of 5, 10, and 20 mg/kg body weight for 45 days, after which liver and kidney tissues were analyzed for the degree of lipid peroxidation, reduced glutathione, and the activities of antioxidants such as catalase, superoxide dismutase, and glutathione peroxidase. Administration of GA to alloxan-induced diabetic rats reduced the blood glucose level with an increase in the level of insulin. Liver and kidney tissues from diabetic animals exhibited disturbances in antioxidant defense compared with normal rats. GA at a dose of 20 mg/kg b.w. showed a significant effect than that of the other doses. In addition, the results revealed that GA protected the integrity of erythrocyte membrane in diabetic rats as demonstrated by lower percentage of hemolysis and resistance to hydrogen peroxide-induced peroxidation. The anti-hyperglycemic activity of GA in alloxan-induced diabetic rats was also comparable with glibenclamide, a reference drug. These results suggest that GA could provide a beneficial effect on diabetes by decreasing oxidative stress related diabetic complications. PMID- 24064908 TI - Molecular characterization of photosensitizer-mediated photodynamic therapy by gene expression profiling. AB - Photodynamic therapy (PDT) is a novel cancer treatment based on the tumor specific accumulation of a photosensitizer followed by irradiation with visible light, which induces selective tumor cell death via production of reactive oxygen species. To elucidate the underlying mechanisms, microarray analysis was used to analyze the changes in gene expression patterns during PDT induced by various photosensitizers. Cancer cells were subjected to four different photosensitizer mediated PDT and the resulting gene expression profiles were compared. We identified many differentially expressed genes reported previously as well as new genes for which the functionfunctions in PDT are still unclear. Our current results not only advance the general understanding of PDT but also suggest that distinct molecular mechanisms are involved in different photosensitizer-mediated PDT. Elucidating the signaling mechanisms in PDT will provide information to modulate the antitumor effectiveness of PDT using various photosensitizers. PMID- 24064909 TI - Cardioprotective effects of fish omega-3 fatty acids on doxorubicin-induced cardiotoxicity in rats. AB - The aim of this study was to investigate the protective effects of fish omega-3 (n-3) fatty acids on doxorubicin (DOX)-induced acute cardiotoxicity. A total of 24 rats were divided into three groups: control, DOX-treated, and DOX treated with fish n-3 fatty acids. Control group received 0.4 ml/kg/day of saline intragastrically. The rats in the fish n-3 fatty acid-pretreated group were given 400 mg/kg/day fish n-3 fatty acids for 30 days by intragastric intubation. To induce acute cardiotoxicity, DOX (30 mg/kg) was injected intraperitoneally by a single dose and the rats were killed after 48 h. DOX treatment caused severe damage in heart tissues. Disorganization of myocardial muscle fibers, myofibrillar loss, and cardiotoxic myocardial fibers with cytoplasmic vacuoles were seen. Fish n-3 fatty acid-treated rats showed an improved histological appearance in the DOX-treated group. Our data indicate a significant reduction in the activity of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling in cardiomyocytes of the DOX-treated group with fish n-3 fatty acids therapy. The DOX-treated with fish n-3 fatty acids group showed a significant decrease in malondialdehyde levels, and an increase in superoxide dismutase and glutathione peroxidase activities in comparison with the DOX-treated group. This study showed that fish n-3 fatty acids may be a suitable cardioprotector against acute toxic effects of DOX. PMID- 24064910 TI - The serum levels of adiponectin and leptin in mustard lung patients. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) due to sulfur mustard (SM), known as mustard lung, is an important late pulmonary complication of SM poisoning. Due to the possible role of systemic inflammation in mustard lung, we evaluated the serum levels of adiponectin and leptin in these patients. MATERIALS AND METHODS: Thirty nonsmoker mustard lung patients in stable phase were enrolled into this study. Also, 30 COPD and 21 healthy participants were entered as control groups. Complete lung function tests were performed in the participants. The serum levels of adiponectin and leptin were measured in all groups. RESULTS: There were no statistically significant differences in mean adiponectin and leptin levels among the groups (p = 0.38 and p = 0.35, respectively). There was a downward trend in leptin to adiponectin ratio from lower to higher stages of global initiative for chronic obstructive lung disease guidelines in mustard lung patients, which was not statistically significant (p = 0.8). CONCLUSION: Our results showed that there is no difference in mean adipokine levels in stable mustard lung patients compared with control groups. There was a foot-point in the alterations of serum adipokines regarding the severity of COPD, which needs to be documented by larger sample group. PMID- 24064911 TI - CD14 regulates gastric cancer cell epithelial-mesenchymal transition and invasion in vitro. AB - Cluster of differentiation 14 (CD14) protein functions as a co-receptor with either the Toll-like receptor TLR4 or MD-2 in the detection of bacterial lipopolysaccharide (LPS) and plays a role in the innate immune system. Recently, it was shown to have effects on the regulation of epithelial-mesenchymal transition (EMT). Thus, the present study investigated the effects of CD14 knockdown on the regulation of gastric cancer cell EMT and invasive capacity following treatment with or without LPS. Knockdown of CD14 expression using CD14 shRNA in MGC-803 cells significantly enhanced E-cadherin expression, but reduced N-cadherin and vimentin expression in both LPS-treated and untreated cells. Morphologically, the phenotype of LPS-treated CD14-knockdown cells was altered to a sporadic long spindle shape. Moreover, TNF-alpha-treated cells were further elongated, connections between cells were reduced, the gap between the cells was increased and the cells were transformed into mesenchymal cells. Furthermore, the invasive capacity of CD14-knockdown cells was significantly lower compared to that of the negative control shRNA-transfected MGC-803 cells. LPS-treated CD14 knockdown cells had significantly lower levels of tumor cell invasive ability when compared to the LPS-treated parental MGC-803 cells. However, addition of TNF alpha to LPS-treated CD14-knockdown cells significantly increased tumor cell invasion. This study demonstrated that CD14 promoted tumor cell EMT and invasion through TNF-alpha, whereas knockdown of CD14 expression inhibited gastric cancer cell invasion and EMT. PMID- 24064912 TI - Exploration of the supramolecular interactions involving tris-dipicolinate lanthanide complexes in protein crystals by a combined biostructural, computational and NMR study. AB - Incorporating in a non-covalent manner lanthanide derivatives into protein crystals has shown to be of prime interest for X-ray crystallography, insofar as these versatile compounds can co-crystallize with proteins through supramolecular interactions, in addition to being strong anomalous scatterers for anomalous based diffraction techniques. In this paper, the selective affinity of tris dipicolinate lanthanide complexes for cationic amino-acid residues is explored, using a panel of experimental (X-ray diffraction, NMR titration) and theoretical methods that provides access to an accurate description of the interaction process. PMID- 24064914 TI - Interaction between the quorum sensing and stringent response regulation systems in the enterohemorrhagic Escherichia coli O157:H7 EDL933 strain. AB - In order to investigate the interaction of well-known regulation systems, quorum sensing and stringent response for the expression of virulence genes in enterohemorrhagic Escherichia coli (EHEC), E. coli strains with mutations in the two regulation systems, DeltaluxS (ECM101) and DeltaluxSDeltarelADeltaspoT (ECM201), and DeltaluxS complemented strain to ECM201 (ECM202) were created from EHEC O157:H7 EDL933. Phenotypic characterization revealed that mutations in the stringent response system (ECM201 and ECM202) influenced the metabolic (defective utilization of arabinose and L-sorbose), enzymatic activities (decreased trypsin activity, and increased alpha-glucosidase activity) and motility. Our results suggest that quorum sensing interacts with stringent response regulation system. PMID- 24064913 TI - Development of a general methodology for labelling peptide-morpholino oligonucleotide conjugates using alkyne-azide click chemistry. AB - We describe a general methodology for fluorescent labelling of peptide conjugates of phosphorodiamidate morpholino oligonucleotides (PMOs) by alkyne functionalization of peptides, subsequent conjugation to PMOs and labelling with a fluorescent compound (Cy5-azide). Two peptide-PMO (PPMO) examples are shown. No detrimental effect of such labelled PMOs was seen in a biological assay. PMID- 24064915 TI - Purification and characterization of thermostable agarase from Bacillus sp. BI-3, a thermophilic bacterium isolated from hot spring. AB - An extracellular agarase was purified from Bacillus sp. BI-3, a thermophilic agar degrading bacterium isolated from a hot spring in Indonesia. The purified agarase revealed a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, with an apparent molecular mass of 58 kDa. The optimum pH and temperature of the agarase were 6.4 and 70 degrees C, respectively. The activity of the agarase was stable at high temperatures, and more than 50% activity was retained at 80 degrees C for 15 min. Furthermore, the enzyme was stable in the pH range of 5.8-8.0, and more than 60% of the residual activity was retained. Significant activation of the agarase was observed in the presence of K(+), Na(+), Ca(2+), Mg(2+), and Sr(2+); on the other hand, Ba(2+), Zn(2+), Cu(2+), Mn(2+), Co(2+), Fe(2+), and EDTA inhibited or inactivated the enzyme activity. The components of the hydrolytic product analyzed by thin-layer chromatography showed that the agarase mainly produced neoagarobiose. This study is the first to present evidence of agarolytic activity in aerobic thermophilic bacteria. PMID- 24064916 TI - Enhancement of herboxidiene production in Streptomyces chromofuscus ATCC 49982. AB - Structurally, herboxidiene contains the tetrahydropyran acetic acid moiety and a side chain including a conjugated diene, and has been isolated from Streptomyces chromofuscus ATCC 49982. Its production was significantly elevated nearly 13.5 fold (0.74 g/l) in a medium supplemented with glycerol (medium No. 6A6), and was more efficacious (1.08 g/l; 19.8-fold) in fed-batch fermentation at 36 h in medium No. 6A6, from Streptomyces chromofuscus. For further enhancement, regulatory genes metK1-sp and afsR-sp from Streptomyces peucetius were overexpressed using an expression vector, pIBR25, and similarly ACCase from Streptomyces coelicolor and two genes, metK1-sp and afsR-sp, were also overexpressed using an integration vector, pSET152, under the control of the strong ermE* promoter in Streptomyces chromofuscus. Only the recombinant strains S. chromofuscus SIBR, S. chromofuscus GIBR, and S. chromofuscus AFS produced more herboxidiene than the parental strain in optimized medium No. 6A6 with an increment of 1.32-fold (0.976 g/l), 3.85-fold (2.849 g/l), and 1.7-fold(1.258 g/l) respectively. PMID- 24064917 TI - Characterization of an antibiotic produced by Bacillus subtilis JW-1 that suppresses Ralstonia solanacearum. AB - Bacillus subtilis JW-1 was isolated from rhizosphere soil as a potential biocontrol agent of bacterial wilt caused by Ralstonia solanacearum. Seed treatment followed by a soil drench application with this strain resulted in >80% reduction in bacterial wilt disease compared with that in the untreated control under greenhouse conditions. The antibacterial compound produced by strain JW-1 was purified by bioactivity-guided fractionation. Based on mass spectroscopy and nuclear magnetic resonance spectral data ((1)H, (13)C, (1)H-(1)H correlation spectroscopies, rotating frame nuclear Overhauser effect spectroscopy, and heteronuclear multiple-bond correlation spectroscopy), the structure of this compound was elucidated as a cyclic lipopeptide composed of a heptapeptide (Gln Leu-Leu-Val-Asp-Leu-Leu) bonded to a beta-hydroxy-iso-hexadecanoic acid arranged in a lactone ring system. PMID- 24064918 TI - Biotransformation of rosamicin antibiotic into 10,11-dihydrorosamicin with enhanced in vitro antibacterial activity against MRSA. AB - A biotransformation approach using microbes as biocatalysts can be an efficient tool for the targeted modification of existing antibiotic chemical scaffolds to create previously uncharacterized therapeutic agents. By employing a recombinant Streptomyces venezuelae strain as a microbial catalyst, a reduced macrolide, 10,11-dihydrorosamicin, was created from rosamicin macrolide. Its chemical structure was spectroscopically elucidated, and the new rosamicin analog showed 2 4-fold higher antibacterial activity against two strains of methicillin-resistant Staphylococcus aureus compared with its parent rosamicin. This kind of biocatalytic approach is able to expand existing antibiotic entities and can also provide more diverse therapeutic resources. PMID- 24064919 TI - The effect of spent medium recycle on cell proliferation, metabolism and baculovirus production by the lepidopteran Se301 cell line infected at very low MOI. AB - The aim of this paper was to study the effect of spent medium recycle on Spodoptera exigua Se301 cell line proliferation, metabolism, and baculovirus production when grown in batch suspension cultures in Ex-Cell 420 serum-free medium. The results showed that the recycle of 20% of spent medium from a culture in mid-exponential growth phase improved growth relative to a control culture grown in fresh medium. Although both glucose and glutamine were still present at the end of the growth phase, glutamate was always completely exhausted. The pattern of the specific glucose and lactate consumption and production rates, as well as the specific glutamine and glutamate consumption rates, suggests a metabolic shift at spent medium recycle values of over 60%, with a decrease in the efficiency of glucose utilization and an increase in glutamate consumption to fuel energy metabolism. Baculovirus infection provoked a change in the metabolic pattern of Se301 cells, although a beneficial effect of spent medium recycle was also observed. Both growth rate and maximum viable cell density decreased relative to uninfected cultures. The efficiency of glucose utilization was dramatically reduced in those cultures containing the lowest percentages of spent medium, whereas glutamine and glutamate consumption was modulated, thereby suggesting that infected cells were devoted to virus replication, retaining their ability to incorporate the nutrients required to support viral replication. Recycle of 20% of spent medium increased baculovirus production by around 90%, thus showing the link between cell growth and baculovirus production. PMID- 24064921 TI - Protein O-fucosyltransferase 1: a potential diagnostic marker and therapeutic target for human oral cancer. AB - Protein O-fucosyltransferase 1 (POFUT1) is the enzyme that adds O-fucose through O-glycosidic linkage to conserved serine or threonine residues in the epidermal growth factor-like repeats of a number of cellular surface and secreted proteins. Our previous study using microarray technology showed that significant upregulation of POFUT1 occurs in oral squamous cell carcinoma (OSCC)-derived cell lines compared to human normal oral keratinocytes. The aim of the present study was to examine the status of POFUT1 mRNA and protein expression in OSCC-derived cell lines and human primary OSCCs. POFUT1 mRNA was upregulated significantly (P<0.05 for both comparisons) in five OSCC-derived cell lines and primary OSCCs using quantitative reverse transcriptase-polymerase chain reaction. Immunohistochemistry data indicated that POFUT1 protein expression levels were consistent with mRNA expression status in OSCC-derived cell lines and primary OSCCs. Furthermore, POFUT1 expression status was correlated significantly (P=0.048) with the primary tumor size. The proliferation of POFUT1 knockdown cells was inhibited significantly compared with that of control cells. These results indicated that POFUT1 expression can contribute to cancer progression and that POFUT1 may serve as a diagnostic marker and a therapeutic target for OSCCs. PMID- 24064922 TI - Autophagy as a novel strategy for treatment of gastric cancer: a hypothesis. AB - Gastric cancer is the second most frequent cause of cancer-related death in the world and also causes much morbidity. The acquired resistance of cancer cells to drug reagents is becoming a major obstacle for successful cancer therapy. Recently, many studies have revealed that macroautophagy (here referred to as autophagy) may be a prosurvival factor and protect the cancer cell from the development of drug-induced death. Thus, we propose that autophagy may play an important role in the resistance of gastric cancer to therapy. Although the exact role of autophagy in tumor cells is still unclear and further studies are needed to prove the role of autophagy in gastric cancer, recent research findings suggest a new direction in investigating the mechanism underlying resistance of gastric cancer to therapy. PMID- 24064924 TI - Emotion self-regulation and empathy depend upon longer stimulus exposure. AB - Observation of others in pain induces positive elevation (pain effect) in late event-related potentials (ERP). This effect is associated with top-down attention regulating processes. It has previously been shown that stimulus exposure duration can affect top-down attentional modulation of response to threat-related stimuli. We investigated the effect of exposure duration on ERP response to others in pain. Two late ERP components, P3 and late positive potentials (LPP), from 18 healthy people were measured while they viewed pictures of hands in painful or neutral situations for either 200 or 500 ms, during two task conditions (pain judgment and counting hands). P3 and LPP pain effects during the pain judgment condition were significantly greater with 500 ms than 200 ms stimulus presentation. Ours is the first study to suggest that engagement of empathy-related self-regulatory processes reflected in late potentials requires longer exposure to the pain-related stimulus. Although this is important information about the relationship between early sensory and subsequent brain processing, and about engagement of self-regulatory processes, the neural basis of this time-dependence remains unclear. It might be important to investigate the relationship between stimulus duration and empathic response in clinical populations where issues of self-regulation, empathic response and speed of information processing exist. PMID- 24064925 TI - Plant micro- and nanomechanics: experimental techniques for plant cell-wall analysis. AB - In the last few decades, micro- and nanomechanical methods have become increasingly important analytical techniques to gain deeper insight into the nanostructure and mechanical design of plant cell walls. The objective of this article is to review the most common micro- and nanomechanical approaches that are utilized to study primary and secondary cell walls from a biomechanics perspective. In light of their quite disparate functions, the common and opposing structural features of primary and secondary cell walls are reviewed briefly. A significant part of the article is devoted to an overview of the methodological aspects of the mechanical characterization techniques with a particular focus on new developments and advancements in the field of nanomechanics. This is followed and complemented by a review of numerous studies on the mechanical role of cellulose fibrils and the various matrix components as well as the polymer interactions in the context of primary and secondary cell-wall function. PMID- 24064927 TI - Accelerating the domestication of a bioenergy crop: identifying and modelling morphological targets for sustainable yield increase in Miscanthus. AB - To accelerate domestication of Miscanthus, an important energy crop, 244 replicated genotypes, including two different species and their hybrids, were analysed for morphological traits and biomass yield over three growing seasons following an establishment phase of 2 years in the largest Miscanthus diversity trial described to date. Stem and leaf traits were selected that contributed both directly and indirectly to total harvested biomass yield, and there was variation in all traits measured. Morphological diversity within the population was correlated with dry matter yield (DMY) both as individual traits and in combination, in order to determine the respective contributions of the traits to biomass accumulation and to identify breeding targets for yield improvement. Predictive morphometric analysis was possible at year 3 within Miscanthus sinensis genotypes but not between M. sinensis, Miscanthus sacchariflorus, and interspecific hybrids. Yield is a complex trait, and no single simple trait explained more than 33% of DMY, which varied from 1 to 5297 g among genotypes within this trial. Associating simple traits increased the power of the morphological data to predict yield to 60%. Trait variety, in combination, enabled multiple ideotypes, thereby increasing the potential diversity of the crop for multiple growth locations and end uses. Both triploids and interspecific hybrids produced the highest mature yields, indicating that there is significant heterosis to be exploited within Miscanthus that might be overlooked in early selection screens within years 1-3. The potential for optimizing biomass yield by selecting on the basis of morphology is discussed. PMID- 24064926 TI - Proteome and metabolome profiling of cytokinin action in Arabidopsis identifying both distinct and similar responses to cytokinin down- and up-regulation. AB - In plants, numerous developmental processes are controlled by cytokinin (CK) levels and their ratios to levels of other hormones. While molecular mechanisms underlying the regulatory roles of CKs have been intensely researched, proteomic and metabolomic responses to CK deficiency are unknown. Transgenic Arabidopsis seedlings carrying inducible barley cytokinin oxidase/dehydrogenase (CaMV35S>GR>HvCKX2) and agrobacterial isopentenyl transferase (CaMV35S>GR>ipt) constructs were profiled to elucidate proteome- and metabolome-wide responses to down- and up-regulation of CK levels, respectively. Proteome profiling identified >1100 proteins, 155 of which responded to HvCKX2 and/or ipt activation, mostly involved in growth, development, and/or hormone and light signalling. The metabolome profiling covered 79 metabolites, 33 of which responded to HvCKX2 and/or ipt activation, mostly amino acids, carbohydrates, and organic acids. Comparison of the data sets obtained from activated CaMV35S>GR>HvCKX2 and CaMV35S>GR>ipt plants revealed unexpectedly extensive overlaps. Integration of the proteomic and metabolomic data sets revealed: (i) novel components of molecular circuits involved in CK action (e.g. ribosomal proteins); (ii) previously unrecognized links to redox regulation and stress hormone signalling networks; and (iii) CK content markers. The striking overlaps in profiles observed in CK-deficient and CK-overproducing seedlings might explain surprising previously reported similarities between plants with down- and up-regulated CK levels. PMID- 24064928 TI - Associations of TP53 mutations, codon 72 polymorphism and human papillomavirus in head and neck squamous cell carcinoma patients. AB - To investigate the possible associations between mutations in TP53 and phenotypes of single-nucleotide polymorphisms (SNPs) in codon 72 (SNP72) with the expression profiles of p53 and human papillomavirus (HPV) infection, 93 pathologically diagnosed head and neck squamous cell carcinomas (HNSCCs) were included for study. Using PCR and direct sequencing, 45 TP53 mutations in 35 cases (37.6%) were confirmed out of the 93 HNSCCs. P53 immunohistochemistry (IHC) confirmed 34 (36.6%) cases with positive staining, including 22 cases with strong and 12 with weak positivity. IARC database and software analysis showed similar results that most of the mutated p53 proteins lost their normal function. Further statistical analysis found a negative correlation between p53 IHC and HPV IHC in the tissues from the group of other HNSCCs (of various sites other than the larynx) but not in the tissues from the laryngeal carcinomas. Analyses of SNP72 showed that the patients with the Arg phenotype had a significantly older age at disease onset when compared to patients with the Pro phenotype, particularly in the group of other HNSCCs. In addition, all cases with strong staining for p53 in the laryngeal carcinoma group had the Pro phenotype and all tumors with poor pathological differentiation in the group of other HNSCCs had the Pro phenotype. These data indicate that the profiles of TP53 mutations, SNP72 polymorphism, p53 IHC and HPV E6 IHC are distinct between the groups of laryngeal carcinoma and other HNSCCs. PMID- 24064929 TI - A member of the heavy metal P-type ATPase OsHMA5 is involved in xylem loading of copper in rice. AB - Heavy metal-transporting P-type ATPase (HMA) has been implicated in the transport of heavy metals in plants. Here, we report the function and role of an uncharacterized member of HMA, OsHMA5 in rice (Oryza sativa). Knockout of OsHMA5 resulted in a decreased copper (Cu) concentration in the shoots but an increased Cu concentration in the roots at the vegetative stage. At the reproductive stage, the concentration of Cu in the brown rice was significantly lower in the mutants than in the wild-type rice; however, there was no difference in the concentrations of iron, manganese, and zinc between two independent mutants and the wild type. The Cu concentration of xylem sap was lower in the mutants than in the wild-type rice. OsHMA5 was mainly expressed in the roots at the vegetative stage but also in nodes, peduncle, rachis, and husk at the reproductive stage. The expression was up-regulated by excess Cu but not by the deficiency of Cu and other metals, including zinc, iron, and manganese, at the vegetative stage. Analysis of the transgenic rice carrying the OsHMA5 promoter fused with green fluorescent protein revealed that it was localized at the root pericycle cells and xylem region of diffuse vascular bundles in node I, vascular tissues of peduncle, rachis, and husk. Furthermore, immunostaining with an antibody against OsHMA5 revealed that it was localized to the plasma membrane. Expression of OsHMA5 in a Cu transport-defective mutant yeast (Saccharomyces cerevisiae) strain restored the growth. Taken together, OsHMA5 is involved in loading Cu to the xylem of the roots and other organs. PMID- 24064930 TI - Initial events during the evolution of C4 photosynthesis in C3 species of Flaveria. AB - The evolution of C4 photosynthesis in many taxa involves the establishment of a two-celled photorespiratory CO2 pump, termed C2 photosynthesis. How C3 species evolved C2 metabolism is critical to understanding the initial phases of C4 plant evolution. To evaluate early events in C4 evolution, we compared leaf anatomy, ultrastructure, and gas-exchange responses of closely related C3 and C2 species of Flaveria, a model genus for C4 evolution. We hypothesized that Flaveria pringlei and Flaveria robusta, two C3 species that are most closely related to the C2 Flaveria species, would show rudimentary characteristics of C2 physiology. Compared with less-related C3 species, bundle sheath (BS) cells of F. pringlei and F. robusta had more mitochondria and chloroplasts, larger mitochondria, and proportionally more of these organelles located along the inner cell periphery. These patterns were similar, although generally less in magnitude, than those observed in the C2 species Flaveria angustifolia and Flaveria sonorensis. In F. pringlei and F. robusta, the CO2 compensation point of photosynthesis was slightly lower than in the less-related C3 species, indicating an increase in photosynthetic efficiency. This could occur because of enhanced refixation of photorespired CO2 by the centripetally positioned organelles in the BS cells. If the phylogenetic positions of F. pringlei and F. robusta reflect ancestral states, these results support a hypothesis that increased numbers of centripetally located organelles initiated a metabolic scavenging of photorespired CO2 within the BS. This could have facilitated the formation of a glycine shuttle between mesophyll and BS cells that characterizes C2 photosynthesis. PMID- 24064931 TI - Repeated targeting of the same hosts by a brood parasite compromises host egg rejection. AB - Cuckoo eggs famously mimic those of their foster parents to evade rejection from discriminating hosts. Here we test whether parasites benefit by repeatedly parasitizing the same host nest. This should make accurate rejection decisions harder, regardless of the mechanism that hosts use to identify foreign eggs. Here we find strong support for this prediction in the African tawny-flanked prinia (Prinia subflava), the most common host of the cuckoo finch (Anomalospiza imberbis). We show experimentally that hosts reject eggs that differ from an internal template, but crucially, as the proportion of foreign eggs increases, hosts are less likely to reject them and require greater differences in appearance to do so. Repeated parasitism by the same cuckoo finch female is common in host nests and likely to be an adaptation to increase the probability of host acceptance. Thus, repeated parasitism interacts with egg mimicry to exploit cognitive and sensory limitations in host defences. PMID- 24064932 TI - Ratcheted electrophoresis for rapid particle transport. AB - Ratcheted electrophoresis of contact-charged particles allows for high speed transport through microfluidic channels over large distances and even against fluid flows. Using a set of predictive design heuristics, we demonstrate an extension of this microfluidic ratchet to separate conductive particles from a particle suspension. PMID- 24064933 TI - Pain and recovery after total knee arthroplasty: a 12-month follow-up after a prospective randomized study evaluating Nefopam and Ketamine for early rehabilitation. AB - OBJECTIVES: Ketamine and nefopam has been documented to decrease pain intensity and improve rehabilitation after total knee arthroplasty (TKA). We conducted a follow-up study of a previously randomized clinical trial to determine the prevalence and risk factors of chronic pain 1 year after TKA and to assess the role of perioperative administration of ketamine and nefopam. MATERIALS AND METHODS: The original randomized, double-blind trial evaluated postoperative pain in 75 patients scheduled for TKA who received either a 48-hour infusion of ketamine or nefopam compared with placebo. The current study has evaluated patients at 6 and 12 months for the presence of chronic pain defined as a visual analogue scale >=40 mm during a stair-climbing test. Other outcomes were incidence of neuropathic pain evaluated (DN4 score), active flexion of the knee, and functional outcome (KOOS-PS score). RESULTS: A total of 69 patients completed the trial. The prevalence of chronic pain at 12 months was 17.4% (95% confidence interval [CI], 10.2%-27.9%) without difference between the ketamine (12.5%), nefopam (13.7%), and placebo groups (26.1%). Prevalence of neuropathic pain was 10.2% (95% CI, 3%-17.3%). Ketamine reduced DN4 scores (P=0.02), increased knee flexion (P=0.0007), and KOOS-PS scores (P<0.0001) compared with placebo. A visual analogue scale score >=60 mm in the postoperative period was the only risk factor associated with the occurrence of chronic pain (odds ratio 4.54; 95% CI, 1.17 17.67). DISCUSSION: After TKA, the intensity of postoperative pain is a risk factor of chronic pain on movement. Intraoperative ketamine seems to improve long term results of rehabilitation in this setting. PMID- 24064934 TI - Preferences, experience, and attitudes in the management of chronic pain and depression: a comparison of physicians and medical students. AB - OBJECTIVES: The current study investigated clinicians' treatment preferences for chronic pain and depression and the extent to which these preferences were related to clinicians' experience and attitudes. METHODS: Eighty-five participants (50 physicians, 35 medical students) made treatment recommendations for 8 virtual patients with chronic low back pain and depression. The 10 treatment options included pharmacological and nonpharmacological approaches. Participants also provided information about their clinical experience and completed measures assessing their attitudes toward patients with pain and depression. RESULTS: The highest recommended treatments were over-the-counter medications and topical modalities, whereas "no intervention," referral to a pain specialist, and opioid medication received the lowest ratings. Physicians gave higher ratings to physical therapy (P<0.05) and lifestyle activities (P<0.05) than did medical students. Students reported more negative attitudes about patients with depression (P<0.05) than did physicians. After controlling for participants' attitudes, the treatment preference*training level interaction was no longer significant (P>0.05). DISCUSSION: Physicians and medical students shared a general preference for "low-risk," self-management approaches for chronic pain and depression; however, they differed in their recommendations for some specific treatments. Participants' attitudes toward patients with pain and depression were associated with their preferences and accounted for the differences in their treatment decisions. These results suggest a need for early and continuing education to reduce clinicians' negative attitudes toward and improve the management of patients with chronic pain and depression. PMID- 24064935 TI - Outcome of smooth surface tunnel porous polyethylene orbital implants (Medpor SST) in children with retinoblastoma. AB - AIM: To evaluate the surgical outcome after the insertion of smooth surface tunnel porous polyethylene orbital implants (Medpor SST) in children with retinoblastoma. METHODS: 44 consecutive children with retinoblastoma who underwent primary enucleation and Medpor SST implantation at Seoul National University Hospital from November 2004 to August 2009, with at least 24 months of follow-up were included. A retrospective review of cases was performed. RESULTS: Mean age at the time of surgery was 24.7 months (range 1-65 months). The diameter of the spherical implant was 20 mm in 36 patients (81.8%) and 18 mm in 8 patients (18.2%). During a mean follow-up period of 60.1 months (range 26-93 months), there were no cases of implant exposure, extrusion or infection. Transient conjunctival thinning developed in three patients, but all resolved with conservative treatment. Anophthalmic socket complications such as lower lid malposition (retraction or entropion) (n=10, 22.7%), blepharoptosis (n=8, 18.2%) and enophthalmos (n=2, 4.5%) developed, but most showed acceptable cosmesis. CONCLUSIONS: Medpor SST is relatively safe, allowing for a mean follow-up of 5 years in terms of implant exposure, and may be a good choice of orbital implant for children with retinoblastoma. PMID- 24064936 TI - Why do people present late with advanced glaucoma? A qualitative interview study. AB - OBJECTIVE: To explore the presentation behaviours and pathways to detection of adults who first presented to UK hospital eye services with severe glaucoma. DESIGN: Semistructured interviews, based on models of diagnostic delay, to obtain a descriptive self-reported account of when and how participants' glaucoma was detected. RESULTS: 11 patients participated (five in Aberdeen, six in Huddersfield). Four participants reported that the optometry appointment at which their glaucoma was detected was their first ever eye test or their first for over 10 years. Seven participants reported attending regular routine optometrist appointments. Their self-reported experiences and pathways to detection describe a variety of missed detection opportunities and delayed referral and treatment. CONCLUSIONS: The qualitative data suggest that late detection of glaucoma can result from delays at the patient level but, although based on a small sample, delays also occurred at the healthcare provider (system) level both in terms of accuracy of case detection and effective referral. We suggest that current attempts to address the significant burden of over-referral of glaucoma suspects to hospital eye services (a large proportion of which are false positives) must also focus on the issue of false negatives and on reducing missed detection and service delays. PMID- 24064937 TI - Pupillographic evaluation of relative afferent pupillary defect in glaucoma patients. AB - AIM: To evaluate the association between the magnitude of relative afferent pupillary defect (RAPD) and the laterality of visual fields in glaucoma patients using pupillography. METHODS: Evaluations were made with an RAPDx (Konan Medical USA, Irvine, California, USA), which is designed to analyse pupil responses to multiple colour stimuli (white, red, green, blue, and yellow) at multiple controlled stimulus intensities. Humphrey automated perimetry (SITA standard 30 2) was performed to determine mean deviations (MDs), which were used to evaluate associations between MD differences (better eye MD-worse eye MD) and RAPDx amplitude and latency measurements in pupil response to multiple colour stimuli. RESULTS: 58 glaucoma patients (35 men, 23 women; mean age: 62.6+/-12.8 years; range 28-88 years) were enrolled. The MD values were -2.00+/-3.1 (range -9.64 to 2.33) dB in the better eyes and -8.17+/-7.1 (range -26.33 to 1.07) dB in the worse eyes. The differences in MD values (better eye MD-worse eye MD) were 6.17+/ 6.1 (range 0.05-26.41) dB. The results of linear regression analysis between the log-scaled RAPD amplitudes and differences in MD values were as follows: white: R(2)=0.45 (p<0.001), red: R(2)=0.18 (p=0.002), green: R(2)=0.30 (p<0.001), blue: R(2)=0.29 (p<0.001), and yellow: R(2)=0.32 (p<0.001). The log-scaled RAPD latencies and the differences in MD values were: white: R(2)=0.17 (p=0.001), red: R(2)=0.03 (p=0.22), green: R(2)=0.01 (p=0.52), blue: R(2)=0.1 (p=0.02), and yellow: R(2)=0.05 (p=0.11). CONCLUSIONS: The log-scaled RAPD amplitudes correlated moderately with the differences in MD values, but the log-scaled RAPD latencies showed a weaker correlation. Stimulation with white light produced the strongest correlation with differences in MD values. PMID- 24064939 TI - Pars plana vitrectomy to repair retinal detachment following brachytherapy for uveal melanoma. AB - AIMS: Retinal detachment can develop following brachytherapy for uveal melanoma. This complication may result in substantial visual loss and poses a significant therapeutic dilemma due to the required surgical intervention for correction of the detachment. We report the incidence of retinal detachment in eyes treated with brachytherapy for posterior uveal melanoma and the outcome of pars plana vitrectomy in those eyes. METHODS: Patients who developed tractional or combined tractional-rhegmatogenous retinal detachment following brachytherapy for posterior uveal melanoma in a single referral centre were retrospectively evaluated. Clinical findings, demographics, and ophthalmic imaging findings were recorded, as well as the manner of treatment and its success. RESULTS: Seven of the 473 posterior uveal melanoma patients (1.48%), who were treated between 2000 and 2011 with brachytherapy, developed tractional or combined tractional rhegmatogenous retinal detachment. Retinal detachment developed at a mean of 50.1 months (range 3.5-120 months) following brachytherapy. All patients underwent pars plana vitrectomy. Retinas remained attached in each of the cases. In five of seven patients there was substantial improvement in visual acuity following repair of the retinal detachment. No tumour growth or dissemination were observed during the mean follow-up of 18.4 months after vitrectomy (range 10-36 months). CONCLUSIONS: Tractional and tractional-rhegmatogenous retinal detachment are rare complications of treated uveal melanoma. Pars plana vitrectomy appears to be an effective and safe procedure in such cases. PMID- 24064938 TI - Association of blood and ocular perfusion pressure with structural glaucomatous progression by flicker chronoscopy. AB - BACKGROUND: Vascular risk factors have been associated with glaucomatous visual field progression. AIM: We determined the relationship between vascular risk factors and structural glaucomatous progression using serial flicker chronoscopy images. METHODS: Two glaucoma fellowship-trained ophthalmologists, masked to temporal sequence, independently graded serial flicker chronoscopy images from one eye of a cohort of glaucoma patients for features of structural progression in this retrospective cohort study. After adjudication, simple and multiple logistic models were constructed to determine variables associated with increased odds of progression, including systolic blood pressure (BP), diastolic BP and mean ocular perfusion pressure. RESULTS: Seventy-two eyes of 72 patients were analysed. Patients with any form of structural progression (n=40) were older (67.0 vs 58.8 years; p=0.005) and had lower diastolic BP (71.8 vs 76.5 mm Hg; p=0.02) than patients without progression (n=32). In the univariable model, diastolic BP was associated with progressive retinal nerve fibre layer (RNFL) loss (OR=0.2 per 10 mm Hg, 95% CI 0.1 to 0.6, p<0.006) and neuroretinal rim loss (OR=0.4 per 10 mm Hg, 95% CI 0.2 to 0.8, p<0.01). Diastolic BP was also significant in the multivariable model for RNFL loss (p=0.009) and neuroretinal rim loss (p=0.003). CONCLUSIONS: This study is the first to use structural progression and flicker chronoscopy to identify vascular glaucoma risk factors. Older age and lower diastolic BP were associated with progression. By multivariable analysis diastolic BP was associated with RNFL and neuroretinal rim loss. These findings suggest that diastolic BP is associated with structural glaucomatous progression which may have implications for management. PMID- 24064940 TI - Endophthalmitis following intravitreal anti-VEGF injections in ambulatory surgical centre facility: incidence, management and outcome. PMID- 24064941 TI - The effect of steep Trendelenburg positioning on intraocular pressure and visual function during robotic-assisted radical prostatectomy. AB - BACKGROUND: To evaluate intraocular pressure (IOP) changes in patients undergoing robotic-assisted radical prostatectomy and to evaluate complications from increased IOP. METHODS: Thirty-one eyes scheduled for robotic prostatectomy were included. Perioperative IOP measurements were performed as follows: prior to induction of anaesthesia while supine and awake (T1); immediately post-induction while supine (T2); every hour from 0 to 5 h while anaesthetised in a steep Trendelenburg position (T3-T8); prior to awakening while supine (T9); and 30 min after awakening while supine (T10). A complete ophthalmic examination including visual acuity and retinal nerve fibre layer thickness (RNFL) was performed at enrolment and 1 month postoperatively. RESULTS: Average IOP (mm Hg) for each time point was as follows: T1=18.0, T2=9.8, T3=18.9, T4=21.6, T5=22.5, T6=22.3, T7=24.2, T8=24.0, T9=15.7 and T10=17.9. The proportion of eyes with intraoperative IOP ?30 mm Hg were as follows: T3=0%, T4=3.23%, T5=9.68%, T6=6.45%, T7=22.22%, and T8=25%. Maximum IOP was 36 mm Hg. Mean visual acuity (logarithm of the minimal angle of resolution) and RNFL showed no statistically significant difference before and after operation and no other ocular complications were found at final examination. CONCLUSIONS: While IOP increased in a time-dependent fashion in anesthaetised patients undergoing robotic-assisted radical prostatectomy in a steep Trendelenburg position, visual function showed no significant change postoperatively and no complications were seen. Steep Trendelenburg positioning during time-limited procedures appears to pose little or no risk from IOP increases in patients without pre-existing ocular disease. PMID- 24064942 TI - Capsular bag stability and posterior capsule opacification of a plate-haptic design microincision cataract surgery intraocular lens: 3-year results of a randomised trial. AB - PURPOSE: To compare capsular bag stability and posterior capsule opacification (PCO) of a plate-haptic intraocular lens (IOL) and a standard three-piece open loop-haptic IOL of the same acrylic material. METHODS: In this randomised bilateral patient-masked and examiner-masked study, each patient received a microincision cataract surgery IOL (MICS IOL; Acri.Smart 46S=CT SHERIS 209M) in one eye and a small incision cataract surgery IOL (SICS IOL; AcriLyc 53N = CT 53N, both Carl Zeiss Meditec AG, Germany) as a control in the contralateral eye. Follow-up examinations were performed 1 h, 1 week, 1 month, 1 year and 3 years postoperatively. Anterior chamber depth (ACD) was measured and retroillumination images were performed at all postoperative follow-ups. Furthermore, uncorrected and corrected distance visual acuity, autorefraction and subjective refraction were assessed. RESULTS: In total, 50 eyes of 25 patients were included. The ACD difference between the MICS IOL and the SICS IOL was not significant at any time point (p>0.05). Distance-corrected visual acuity at the 3-year follow-up was similar and not significantly different between the groups (p=0.48). Mean AQUA score in the MICS IOL group and in the SICS IOL group at the 3-year follow-up was 2.3 (SD +/-2.3) and 2.1 (SD +/-2.2), respectively (p=0.79). CONCLUSIONS: The investigated hydrophilic acrylic plate-haptic MICS IOL with a hydrophobic surface showed comparable results concerning capsular bag stability and PCO rates up to 3 years compared with a SICS IOL of the same material. PMID- 24064943 TI - Ocular surface squamous neoplasia: analysis of 78 cases from a UK ocular oncology centre. AB - BACKGROUND/AIMS: Ocular surface squamous neoplasia (OSSN) is a spectrum of disease, on which few large series have been published, none in particular, from the UK. The purpose of this study is to describe experience of this condition from a UK national ocular oncology centre, including statistical analysis to elucidate factors significant in recurrence. METHODS: Retrospective review of case notes, clinical photographs and histopathology reports. RESULTS: 78 cases were included, of which 10 (12.8%) recurred during the follow-up time (mean 37 months). The 1-year recurrence rate was 10.9%, and 5-year recurrence rate was 18.5% using Kaplan-Meier analysis, with a mean time to recurrence of 9.5 months. Significant factors in recurrence were tumour size and first treatment given. Grade of OSSN, including presence of invasive disease and positive biopsy margins were not found to be statistically significant in recurrence. CONCLUSIONS: OSSN in an uncommon disease in the UK population. However, when managed appropriately in a specialist centre, it is associated with good outcomes, even in recurrence situations. PMID- 24064944 TI - Prospective study of sentinel lymph node biopsy for conjunctival melanoma. AB - BACKGROUND: To report our experience with sentinel lymph node biopsy for staging patients with conjunctival melanoma. METHODS: A prospective review of patients with conjunctival melanoma who underwent sentinel lymph node biopsy at St Bartholomew's Hospital from May 2008 to May 2012. The selection criterion for sentinel node biopsy depended on the tumour thickness (>=2 mm) and location of the conjunctival melanoma. The main outcome measures were the incidence of sentinel lymph node positivity and the procedure-related complications. RESULTS: In 4 years, 26 out of 70 patients met the selection criteria for sentinel lymph node biopsy. 4 patients declined and 22 patients consented for the procedure. Technetium-99m failed to identify a sentinel lymph node in four of the 22 patients (18%). Of the remaining 18 patients, two were found to have subclinical micrometastasis in regional lymph nodes. Median follow-up was 20 months (range 6 36 months). No false-negative events were observed. Complications of the procedure included transient blue staining of the epibulbar surface in five patients and transient facial nerve palsy in one patient. CONCLUSIONS: Sentinel lymph node biopsy is a safe procedure with minimal complications. It should be considered for the staging of conjunctival melanomas, especially melanomas in non limbal location or conjunctival melanomas >=2 mm thick. PMID- 24064947 TI - Laser speckle contrast imaging of blood flow in rat retinas using an endoscope. AB - Laser speckle contrast imaging (LSCI) offers a cost-effective means to image blood flow in vivo. However, it is not commonly used to image rodent retinas because of the challenges associated with imaging through the curved cornea and delivering light through the highly scattering lens. A solution to overcome these problems by using LSCI in conjunction with an endoscope to obtain high spatiotemporal blood flow images is described. Its utility is demonstrated by imaging blood flow changes in rat retinas using hyperoxic, hypercapnic, and visual (flicker) stimulations. Hypercapnia increases blood flow, hyperoxia decreases blood flow, and visual stimulation increases blood flow in the retina relative to basal conditions. The time-to-peak of the LSCI response to visual stimulation is also measured. This approach may prove useful to investigate dysregulation in blood flow-evoked responses in retinal diseases and to evaluate treatment strategies in rodents. PMID- 24064948 TI - Tissue deoxygenation kinetics induced by prolonged hypoxic exposure in healthy humans at rest. AB - This study aimed to investigate the effects of sustained hypoxic exposure on cerebral and muscle oxygenation and cardiorespiratory function at rest. Eleven healthy subjects inhaled a normobaric hypoxic (FiO2=0.12) or normoxic (FiO2=0.21) gas mixture for 4 h at rest, on two separated blinded sessions. Arterial oxygen saturation (SpO2), heart rate variability (HRV), end-tidal CO2 (EtCO2), and oxygenation of quadriceps muscle, prefrontal and motor cortices assessed by near infrared spectroscopy (NIRS) were measured continuously during each session. Acute mountain sickness symptoms were evaluated at the end of each session. During a hypoxic session, SpO2 reduction (~13%) plateaued after 20 min, while deoxygenation pattern took 30 to 40 min at the cerebral sites to plateau (+5.3+/ 1.6 MUMol of deoxygenated-hemoglobin). Deoxygenation was more pronounced in the cerebral cortex compared to the muscle (+2.1+/-2.3 MUMol of deoxygenated hemoglobin), and NIRS-derived tissue perfusion index showed distinct profiles between the muscle (hypoperfusion) and the brain (hyperperfusion) with prolonged hypoxia. Changes in tissue oxygenation were not associated with cardiorespiratory responses (e.g., HRV, EtCO2) and altitude sickness symptom appearance during hypoxic sessions. These data demonstrate that sustained hypoxia elicits time delay in changes between arterial and tissue (especially cerebral) oxygenation, as well as a tissue-specific sensitivity. PMID- 24064950 TI - Infrared spectroscopic analysis of human and bovine articular cartilage proteoglycans using carbohydrate peak or its second derivative. AB - Fourier transform infrared (FTIR) microspectroscopy has been used to estimate the spatial proteoglycan (PG) and collagen contents in articular cartilage (AC). However, it is not clear whether the results of FTIR analyses are consistent between different species. Our aim was to clarify how three different FTIR PG parameters in use, i.e., the integrated absorbance in the carbohydrate region, the carbohydrate/amide I ratio, and the second derivative peak at 1062 cm-1, can indicate the densitometrically assessed (reference method) spatial PG content in a sample set consisting of osteoarthritic human and bovine AC samples. The results show that all the parameters can accurately reflect the PG content, when the species are analyzed separately. When all samples are pooled, the correlation with the reference method is high (r=0.760, n=104) for the second derivative peak at 1062 cm-1 and is significantly lower (p<0.05) for the carbohydrate region (r=0.587, n=104) and for the carbohydrate/amide I ratio (r=0.579, n=104). Therefore, the analysis of the carbohydrate region may provide inconsistent results, if the cartilage samples from different species are in use. Based on the present study, second derivative analysis yields more consistent results for human and bovine cartilages. PMID- 24064949 TI - Targeting telomere-containing chromosome ends with a near-infrared femtosecond laser to study the activation of the DNA damage response and DNA damage repair pathways. AB - Telomeres are at the ends of chromosomes. Previous evidence suggests that laser induced deoxyribose nucleic acid (DNA) breaks at chromosome ends during anaphase results in delayed cytokinesis. A possible explanation for this delay is that the DNA damage response (DDR) mechanism has been activated. We describe a live imaging method to study the effects of DDR activation following focal point near infrared femtosecond laser microirradiation either at a single chromosome end or at a chromosome arm in mitotic anaphase cells. Laser microirradiation is used in combination with dual fluorescent labeling to monitor the co-localization of double-strand break marker gammaH2AX along with the DDR factors in PtK2 (Potorous tridactylus) cells. Laser-induced DNA breaks in chromosome ends as well as in chromosome arms results in recruitment of the following: poly(ADP-ribose) polymerase 1, checkpoint sensors (p-Chk1, p-Chk2), DNA repair protein Ku70/Ku80, and proliferating cell nuclear antigen. However, phosphorylated p53 at serine 15 is detected only at chromosome ends and not at chromosome arms. Full activation of DDR on damaged chromosome ends may explain previously published results that showed the delay of cytokinesis. PMID- 24064951 TI - Epigallocatechin-3-gallate and trichostatin A synergistically inhibit human lymphoma cell proliferation through epigenetic modification of p16INK4a. AB - DNA methylation and histone deacetylation play important roles in the occurrence and development of cancers by inactivating the expression of tumor suppressors, including p16(INK4a), a cyclin-dependent kinase inhibitor. The present study investigated the effect of epigallocatechin-3-gallate (EGCG) alone or in combination with trichostatin A (TSA) on p16(INK4a) gene expression and growth in human malignant lymphoma CA46 cells. CA46 cell viability and cell cycle were analyzed; methylation of the p16(INK4a) gene was assessed by nested methylation specific PCR (n-MSP). p16(INK4a )mRNA and protein expression was determined by real-time quantitative PCR and western blot analyses, respectively. Both EGCG and TSA alone inhibited CA46 cell proliferation; the combined treatment (6 ug/ml EGCG and 15 ng/ml TSA) significantly reduced CA46 cell proliferation from 24 to 96 h (all P<0.001). Cells treated with 24 ug/ml EGCG or the combination treatment (6 ug/ml EGCG and 15 ng/ml TSA) had lower proliferative indices when compared to the other groups. Co-treatment with EGCG and TSA decreased p16(INK4a) gene methylation, which coincided with increased p16(INK4a) mRNA and protein expression. Thus, EGCG and TSA synergistically reactivate p16(INK4a) gene expression in part through reducing promoter methylation, which may decrease CA46 cell proliferation. PMID- 24064952 TI - The expression pattern of Nischarin after lipopolysaccharides (LPS)-induced neuroinflammation in rats brain cortex. AB - OBJECTIVE: To investigate whether Nischarin participated in neuronal apoptosis induced by neuroinflammation and via the phosphatidylinositol 3-kinase (PI3K) and PKB-dependent pathway. MATERIAL: Use of male Sprague-Dawley rats, rat pheochromocytoma (PC12), and murine microglial cells (BV-2). Treatment lipopolysaccharides (LPS) were injected into the brain lateral ventricle of the rat. The BV-2 cells were treated by LPS. The PC12 cells were pretreated by or not pretreated by conditioned media and siRNA. METHODS: Western blotting was used for analyzing the expression level of Nischarin, pAKT, BAD and Bcl-2. Immunohistochemistry and immunofluorescence were used to perform the morphology and localization of Nischarin. The siRNA could down-regulate the protein level of endogenous Nischarin. RESULTS: The expression level of Nischarin was elevated after LPS injection; meanwhile, Nischarin was located in the neuron. Nischarin was involved in regulating the PI3K/PKB patway. CONCLUSION: Nischarin might be involved in mediating the process of PI3K/PKB pathway-dependent neuronal apoptosis. After the silencing of Nischarin in cultured PC12 (pheochromocytoma) by siRNA, these results showed that it would induce a reduction of pAKT and Bcl-2 proteins expression; meanwhile, it induces an increase of BAD and active caspase 3. PMID- 24064953 TI - Case-control study of the association between malignant brain tumours diagnosed between 2007 and 2009 and mobile and cordless phone use. AB - Previous studies have shown a consistent association between long-term use of mobile and cordless phones and glioma and acoustic neuroma, but not for meningioma. When used these phones emit radiofrequency electromagnetic fields (RF EMFs) and the brain is the main target organ for the handheld phone. The International Agency for Research on Cancer (IARC) classified in May, 2011 RF-EMF as a group 2B, i.e. a 'possible' human carcinogen. The aim of this study was to further explore the relationship between especially long-term (>10 years) use of wireless phones and the development of malignant brain tumours. We conducted a new case-control study of brain tumour cases of both genders aged 18-75 years and diagnosed during 2007-2009. One population-based control matched on gender and age (within 5 years) was used to each case. Here, we report on malignant cases including all available controls. Exposures on e.g. use of mobile phones and cordless phones were assessed by a self-administered questionnaire. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index using the whole control sample. Of the cases with a malignant brain tumour, 87% (n=593) participated, and 85% (n=1,368) of controls in the whole study answered the questionnaire. The odds ratio (OR) for mobile phone use of the analogue type was 1.8, 95% confidence interval (CI)=1.04 3.3, increasing with >25 years of latency (time since first exposure) to an OR=3.3, 95% CI=1.6-6.9. Digital 2G mobile phone use rendered an OR=1.6, 95% CI=0.996-2.7, increasing with latency >15-20 years to an OR=2.1, 95% CI=1.2-3.6. The results for cordless phone use were OR=1.7, 95% CI=1.1-2.9, and, for latency of 15-20 years, the OR=2.1, 95% CI=1.2-3.8. Few participants had used a cordless phone for >20-25 years. Digital type of wireless phones (2G and 3G mobile phones, cordless phones) gave increased risk with latency >1-5 years, then a lower risk in the following latency groups, but again increasing risk with latency >15-20 years. Ipsilateral use resulted in a higher risk than contralateral mobile and cordless phone use. Higher ORs were calculated for tumours in the temporal and overlapping lobes. Using the meningioma cases in the same study as reference entity gave somewhat higher ORs indicating that the results were unlikely to be explained by recall or observational bias. This study confirmed previous results of an association between mobile and cordless phone use and malignant brain tumours. These findings provide support for the hypothesis that RF-EMFs play a role both in the initiation and promotion stages of carcinogenesis. PMID- 24064954 TI - Rediscovery of the microbial world in microbial ecology. PMID- 24064956 TI - Phosphazene-catalyzed intramolecular cyclization of nitrogen-tethered alkynyl esters. AB - Intramolecular cyclization of nitrogen-tethered alkynyl esters catalyzed by phosphazene organosuperbases P2-tBu and P4-tBu was investigated. Both acyclic and cyclic substrates underwent 5-exo-dig and 5-endo-dig cyclization. This reaction is a rare example of the intramolecular addition of enolates of simple esters to alkynes. PMID- 24064958 TI - Stable platinum nanoparticles on specific MgAl2O4 spinel facets at high temperatures in oxidizing atmospheres. AB - The development of thermally stable, nanometer-sized precious metal-based catalysts remains a daunting challenge. Such materials, especially those based on the use of costly platinum metal, are essential and, to date, non-replaceable for a large number of industrially important catalytic processes. Here we report a well-defined cuboctahedral MgAl2O4 spinel support material that is capable of stabilizing platinum particles in the range of 1-3 nm on its relatively abundant {111} facets during extremely severe aging at 800 degrees C in air for 1 week. The aged catalysts retain platinum dispersions of 15.9% with catalytic activities for methanol oxidation being ~80% of that of fresh ones, whereas a conventional Pt/gamma-Al2O3 catalyst is severely sintered and nearly inactive. We reveal the origin of the markedly superior ability of spinel {111} facets, resulting from strong interactions between spinel surface oxygens and epitaxial platinum {111} facets, inspiring the rational design of anti-sintering supported platinum group catalysts. PMID- 24064959 TI - 15N NMR spectroscopic and theoretical GIAO-DFT studies for the unambiguous characterization of disubstituted 1,2,3-triazoles. AB - The 1,2,3-triazole ring has recently attracted a renewed interest as a structural scaffold with many applications in different fields. However, very often, the unambiguous assignment of the correct structure is not an easy task, and the development of robust characterization methodologies is needed. Herein, the three possible isomeric forms of disubstituted 1,2,3-triazole (1,4- or 1,5- or 2,4 disubstituted derivatives) have been characterized and distinguished by routine (1)H/(15)N gHMBC experiments at (15)N natural abundance. The calculated (GIAO B3LYP/6-311++G**) (15)N NMR chemical shifts showed good agreement with the experimental values, further supporting their unambiguous structural characterization. PMID- 24064957 TI - Allogeneic tumor cell vaccines: the promise and limitations in clinical trials. AB - The high mortality rate associated with cancer and its resistance to conventional treatments such as radiation and chemotherapy has led to the investigation of a variety of anti-cancer immunotherapies. The development of novel immunotherapies has been bolstered by the discovery of tumor-associated antigens (TAAs), through gene sequencing and proteomics. One such immunotherapy employs established allogeneic human cancer cell lines to induce antitumor immunity in patients through TAA presentation. Allogeneic cancer immunotherapies are desirable in a clinical setting due to their ease of production and availability. This review aims to summarize clinical trials of allogeneic tumor immunotherapies in various cancer types. To date, clinical trials have shown limited success due potentially to extensive degrees of inter- and intra-tumoral heterogeneity found among cancer patients. However, these clinical results provide guidance for the rational design and creation of more effective allogeneic tumor immunotherapies for use as monotherapies or in combination with other therapies. PMID- 24064962 TI - Evaluation of pump pulsation in respirable size-selective sampling: part I. Pulsation measurements. AB - Pulsations generated by personal sampling pumps modulate the airflow through the sampling trains, thereby varying sampling efficiencies, and possibly invalidating collection or monitoring. The purpose of this study was to characterize pulsations generated by personal sampling pumps relative to a nominal flow rate at the inlet of different respirable cyclones. Experiments were conducted using a factorial combination of 13 widely used sampling pumps (11 medium and 2 high volumetric flow rate pumps having a diaphragm mechanism) and 7 cyclones [10-mm nylon also known as Dorr-Oliver (DO), Higgins-Dewell (HD), GS-1, GS-3, Aluminum, GK2.69, and FSP-10]. A hot-wire anemometer probe cemented to the inlet of each cyclone type was used to obtain pulsation readings. The three medium flow rate pump models showing the highest, a midrange, and the lowest pulsations and two high flow rate pump models for each cyclone type were tested with dust-loaded filters (0.05, 0.21, and 1.25mg) to determine the effects of filter loading on pulsations. The effects of different tubing materials and lengths on pulsations were also investigated. The fundamental frequency range was 22-110 Hz and the magnitude of pulsation as a proportion of the mean flow rate ranged from 4.4 to 73.1%. Most pump/cyclone combinations generated pulse magnitudes >=10% (48 out of 59 combinations), while pulse shapes varied considerably. Pulsation magnitudes were not considerably different for the clean and dust-loaded filters for the DO, HD, and Aluminum cyclones, but no consistent pattern was observed for the other cyclone types. Tubing material had less effect on pulsations than tubing length; when the tubing length was 183cm, pronounced damping was observed for a pump with high pulsation (>60%) for all tested tubing materials except for the Tygon Inert tubing. The findings in this study prompted a further study to determine the possibility of shifts in cyclone sampling efficiency due to sampling pump pulsations, and those results are reported subsequently. PMID- 24064963 TI - Evaluation of pump pulsation in respirable size-selective sampling: part II. Changes in sampling efficiency. AB - This second, and concluding, part of this study evaluated changes in sampling efficiency of respirable size-selective samplers due to air pulsations generated by the selected personal sampling pumps characterized in Part I (Lee E, Lee L, Mohlmann C et al. Evaluation of pump pulsation in respirable size-selective sampling: Part I. Pulsation measurements. Ann Occup Hyg 2013). Nine particle sizes of monodisperse ammonium fluorescein (from 1 to 9 MUm mass median aerodynamic diameter) were generated individually by a vibrating orifice aerosol generator from dilute solutions of fluorescein in aqueous ammonia and then injected into an environmental chamber. To collect these particles, 10-mm nylon cyclones, also known as Dorr-Oliver (DO) cyclones, were used with five medium volumetric flow rate pumps. Those were the Apex IS, HFS513, GilAir5, Elite5, and Basic5 pumps, which were found in Part I to generate pulsations of 5% (the lowest), 25%, 30%, 56%, and 70% (the highest), respectively. GK2.69 cyclones were used with the Legacy [pump pulsation (PP) = 15%] and Elite12 (PP = 41%) pumps for collection at high flows. The DO cyclone was also used to evaluate changes in sampling efficiency due to pulse shape. The HFS513 pump, which generates a more complex pulse shape, was compared to a single sine wave fluctuation generated by a piston. The luminescent intensity of the fluorescein extracted from each sample was measured with a luminescence spectrometer. Sampling efficiencies were obtained by dividing the intensity of the fluorescein extracted from the filter placed in a cyclone with the intensity obtained from the filter used with a sharp edged reference sampler. Then, sampling efficiency curves were generated using a sigmoid function with three parameters and each sampling efficiency curve was compared to that of the reference cyclone by constructing bias maps. In general, no change in sampling efficiency (bias under +/-10%) was observed until pulsations exceeded 25% for the DO cyclone. However, for three models of pumps producing 30%, 56%, and 70% pulsations, substantial changes were confirmed. The GK2.69 cyclone showed a similar pattern to that of the DO cyclone, i.e. no change in sampling efficiency for the Legacy producing 15% pulsation and a substantial change for the Elite12 producing 41% pulsation. Pulse shape did not cause any change in sampling efficiency when compared to the single sine wave. The findings suggest that 25% pulsation at the inlet of the cyclone as measured by this test can be acceptable for the respirable particle collection. If this test is used in place of that currently in European standards (EN 1232-1997 and EN 12919-1999) or is used in any International Organization for Standardization standard, then a 25% pulsation criterion could be adopted. This work suggests that a 10% criterion as currently specified in the European standards for testing may be overly restrictive and not able to be met by many pumps on the market. Further work is recommended to determine which criterion would be applicable to this test if it is to be retained in its current form. PMID- 24064964 TI - Current and emerging challenges of field effect transistor based bio-sensing. AB - Field-effect-transistor (FET) based electrical signal transduction is an increasingly prevalent strategy for bio-sensing. This technique, often termed "Bio-FETs", provides an essentially label-free and real-time based bio-sensing platform effective for a variety of targets. This review highlights recent progress and challenges in the field. A special focus is on the comprehension of emerging nanotechnology-based approaches to facilitate signal-transduction and amplification. Some new targets of Bio-FETs and the future perspectives are also discussed. PMID- 24064965 TI - Molecular-based diagnosis of bacteremia in the setting of fever with or without neutropenia in pediatric hematology-oncology patients. AB - BACKGROUND: Prompt evaluation and appropriate treatment with wide-spectrum antibiotics is considered mandatory for febrile oncology patients especially during neutropenia. Central venous catheters are widely used in pediatric oncology patients and are often the source of infections. Patients are usually admitted for follow-up and administration of antibiotics. Aims were to assess the efficacy of the polymerase chain reaction (PCR) method in identifying bacteria in blood samples as compared with standard blood cultures. METHODS: This was a prospective study, which included all patients with central venous catheters admitted to the pediatric hematology-oncology department over the 14-month period. Demographic, clinical, and laboratory variables were compared in bacteremic and nonbacteremic patients. Standard microbiological cultures were compared using the PCR technique. RESULTS: From September 2004 to November 2005, 148 blood cultures (70 patients) were evaluated. Positive blood cultures were detected on 21 (18.3%) occasions. PCR had sensitivity of 46%, specificity of 98%, positive predictive value 86%, and negative predictive value 89%. The PCR identified fastidious bacteria in 2 occasions when standard cultures were negative. CONCLUSIONS: Inspite of low sensitivity, PCR may help with early identification of bacteremia. Improving this technology is warranted. PMID- 24064966 TI - Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells. AB - An elevated rate of glucose consumption and the dependency on aerobic glycolysis for ATP generation have long been observed in cancer cells, a phenomenon known as the Warburg effect. the altered energy metabolism in cancer cells provides an attractive opportunity for developing novel cancer therapeutic strategies. Lactate dehydrogenase (LDH), which catalyzes the transformation of pyruvate to lactate, plays a vital role in the process of glycolysis. It has been reported that the level of LDH-A expression is increased both in head and neck cancer cells and in the blood serum of nasopharyngeal carcinoma (NPC) patients, and is associated with poor prognosis. However, the effect of LDH-A inhibition on NPC cells remains unknown. Here, in the present study, we found that oxamate, a classical inhibitor of LDH-A, suppressed cell proliferation in a dose- and time dependent manner both in CNE-1 and CNE-2 cells, two NPC cancer cell lines. LDH inhibition by oxamate induced G2/M cell cycle arrest via downregulation of the CDK1/cyclin B1 pathway and promoted apoptosis through enhancement of mitochondrial ROS generation. N-acetylcysteine, a specific scavenger of ROS, significantly blocked the growth inhibition effect induced by oxamate. We also identified that oxamate increased sensitivity to ionizing radiation in the two NPC cancer cell lines. Furthermore, we verified similar results in tumor xenograft models. collectively, these results suggest that LDH-A may serve as a promising therapeutic target for NPC treatment. PMID- 24064967 TI - Characterization of brivanib therapy response in hepatocellular carcinoma xenografts using 1H HR-MAS spectroscopy and histopathology. AB - Angiogenesis inhibition is an attractive therapeutic strategy in the management of solid tumors. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are key factors in growth and neovascularization of hepatocellular carcinoma (HCC). Brivanib is a novel, orally available dual tyrosine kinase inhibitor that selectively targets the key angiogenesis receptors VEGF-R2, FGF-R1 and FGF-R2. Recently, high-resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS MRS) has provided the opportunity to investigate more detailed metabolic profiles from intact tissue specimens that are correlated with histopathology and is thus, a promising tool for monitoring changes induced by treatment. In the present study, 1H HR-MAS MRS and immunohistochemistry were used to investigate the antitumor efficacy of brivanib in HCC xenograft models. Tumor growth was significantly suppressed in brivanib-treated mice compared with the controls and treatment was associated with the inhibition of angiogenesis, increased apoptosis and inhibition of cell proliferation. Furthermore, HR-MAS techniques showed altered metabolic profiles between the two groups. HR-MAS spectra demonstrated a significant decrease in choline metabolite levels in the treated groups, concurrent with decreased cell proliferation and increased apoptosis. The results showed that 1H HR-MAS MRS provides quantitative metabolite information that may be used to analyze the efficacy of brivanib treatment in Hep3B tumor xenografts. Thus, the HR-MAS MRS technique may be a complementary method to support histopathological results and increase its potential for use in the clinic. PMID- 24064968 TI - The impact of supportive nursing care on the needs of men with prostate cancer: a study across seven European countries. AB - BACKGROUND: Prostate cancer is for many men a chronic disease with a long life expectancy after treatment. The impact of prostate cancer therapy on men has been well defined, however, explanation of the consequences of cancer treatment has not been modelled against the wider variables of long-term health-care provision. The aim of this study was to explore the parameters of unmet supportive care needs in men with prostate cancer in relation to the experience of nursing care. METHODS: A survey was conducted among a volunteer sample of 1001 men with prostate cancer living in seven European countries. RESULTS: At the time of the survey, 81% of the men had some unmet supportive care needs including psychological, sexual and health system and information needs. Logistic regression indicated that lack of post-treatment nursing care significantly predicted unmet need. Critically, men's contact with nurses and/or receipt of advice and support from nurses, for several different aspects of nursing care significantly had an impact on men's outcomes. CONCLUSION: Unmet need is related not only to disease and treatment factors but is also associated with the supportive care men received. Imperative to improving men's treatment outcomes is to also consider the access to nursing and the components of supportive care provided, especially after therapy. PMID- 24064969 TI - Treatment costs associated with interventional cancer clinical trials conducted at a single UK institution over 2 years (2009-2010). AB - BACKGROUND: The conduct of clinical trials should be an integral part of routine patient care. Treating patients in trials incurs additional costs over and above standard of care (SOC), but the extent of the cost burden is not known. We undertook a retrospective cost attribution analysis to quantitate the treatment costs associated with cancer clinical trial protocols conducted over a 2 year period. METHODS: All patients entered into oncology (non-haematology) clinical trials involving investigational medicinal products in 2009 and 2010 in a single UK institution were identified. The trial protocols on which they were treated were analysed to identify the treatment costs for the experimental arm(s) of the trial and the equivalent SOC had the patient not been entered in the trial. The treatment cost difference was calculated by subtracting the experimental treatment cost from SOC cost. For randomised trials, an average treatment cost was estimated by taking into account the number of arms and randomisation ratio. An estimate of the annual treatment costs was calculated. RESULTS: A total of 357 adult oncology patients were treated on 53 different trial protocols: 40 phase III, 2 randomised II/III and 11 phase II design. A total of 27 trials were academic, non-commercial sponsored trials and 26 were commercial sponsored trials. When compared with SOC, the average treatment cost per patient was an excess of L431 for a non-commercial trial (range L6393 excess to L6005 saving) and a saving of L9294 for a commercial trial (range L0 to L71,480). There was an overall treatment cost saving of L388,719 in 2009 and L496,556 in 2010, largely attributable to pharmaceutical company provision of free drug supplies. CONCLUSION: On an average, non-commercial trial protocols were associated with a small per patient excess treatment cost, whereas commercial trials were associated with a substantially higher cost saving. Taking into account the total number of patients recruited annually, treatment of patients on clinical trial protocols was associated with considerable cost savings across both the non commercial and commercial portfolio. PMID- 24064970 TI - ERCC1 is a prognostic biomarker in locally advanced head and neck cancer: results from a randomised, phase II trial. AB - BACKGROUND: Cisplatin-radiotherapy is a preferred standard for locally advanced, head and neck squamous cell carcinoma (HNSCC). However, the cisplatin attributable survival benefit is small and toxicity substantial. A biomarker of cisplatin resistance could guide treatment selection and spare morbidity. The ERCC1-XPF nuclease is critical to DNA repair pathways resolving cisplatin-induced lesions. METHODS: In a phase II trial, patients with untreated Stage III-IVb HNSCC were randomised to cisplatin-radiotherapy with/without erlotinib. Archived primary tumours were available from 90 of 204 patients for this planned substudy. Semi-quantitative ERCC1 protein expression (H-score) was determined using the FL297, 4F9, and 8F1 antibodies. The primary analysis evaluated the relationship between continuous ERCC1 protein expression and progression-free survival (PFS). Secondary analyses included two pre-specified ERCC1 cutpoints and performance in HPV-associated disease. RESULTS: Higher ERCC1 expression was associated with inferior PFS, as measured by the specific antibodies FL297 (HR=2.5, 95% CI=1.1 5.9, P=0.03) and 4F9 (HR=3.0, 95% CI=1.2-7.8, P=0.02). Patients with increased vs decreased/normal ERCC1 expression experienced inferior PFS (HR=4.8 for FL297, P=0.003; HR=5.5 for 4F9, P=0.007). This threshold remained prognostic in HPV associated disease. CONCLUSION: ERCC1-XPF protein expression by the specific FL297 and 4F9 antibodies is prognostic in patients undergoing definitive cisplatin-radiotherapy for HNSCC, irrespective of HPV status. PMID- 24064972 TI - Spindle cell morphology is related to poor prognosis in vulvar squamous cell carcinoma. AB - BACKGROUND: Vulvar cancer is the fourth most common gynaecological malignancy, with an annual incidence of 2 out of 100,000 women. Although most cases of early stage vulvar cancer have a good prognosis, recurrence and rapid tumour progression can occur. We investigated the prevalence of spindle cell morphology in vulvar cancer and its association with survival. METHODS: This retrospective cohort study included 108 patients with primary vulvar squamous cell carcinoma who were treated at the Leiden University Medical Center during 2000-2009. Paraffin-embedded tissue was examined for the presence of spindle cell morphology. Survival and histology data were compared between cases with spindle and without spindle cell morphology. RESULTS: Twenty-two (20%) tumours showed spindle cells infiltrating the stromal tissue. All spindle cell tumours were human papillomavirus (HPV) negative. Spindle cell morphology was strongly associated with poor prognosis and with a high risk of lymph node involvement at the time of diagnosis (relative risk 2.26 (95% CI 1.47-3.47)). Five-year disease specific survival was lower in patients with vs without spindle cell morphology (45.2% vs 79.7%, respectively; P=0.00057). CONCLUSION: Vulvar spindle cell morphology occurs frequently and seems to develop through the non-HPV pathway. It is associated with a worse prognosis than conventional vulvar squamous cell carcinoma. PMID- 24064971 TI - Response of high-risk of recurrence/progression bladder tumours expressing sialyl Tn and sialyl-6-T to BCG immunotherapy. AB - BACKGROUND: High risk of recurrence/progression bladder tumours is treated with Bacillus Calmette-Guerin (BCG) immunotherapy after complete resection of the tumour. Approximately 75% of these tumours express the uncommon carbohydrate antigen sialyl-Tn (Tn), a surrogate biomarker of tumour aggressiveness. Such changes in the glycosylation of cell-surface proteins influence tumour microenvironment and immune responses that may modulate treatment outcome and the course of disease. The aim of this work is to determine the efficiency of BCG immunotherapy against tumours expressing sTn and sTn-related antigen sialyl-6-T (s6T). METHODS: In a retrospective design, 94 tumours from patients treated with BCG were screened for sTn and s6T expression. In vitro studies were conducted to determine the interaction of BCG with high-grade bladder cancer cell line overexpressing sTn. RESULTS: From the 94 cases evaluated, 36 had recurrence after BCG treatment (38.3%). Treatment outcome was influenced by age over 65 years (HR=2.668; (1.344-5.254); P=0.005), maintenance schedule (HR=0.480; (0.246 0.936); P=0.031) and multifocality (HR=2.065; (1.033-4.126); P=0.040). sTn or s6T expression was associated with BCG response (P=0.024; P<0.0001) and with increased recurrence-free survival (P=0.001). Multivariate analyses showed that sTn and/or s6T were independent predictive markers of recurrence after BCG immunotherapy (HR=0.296; (0.148-0.594); P=0.001). In vitro studies demonstrated higher adhesion and internalisation of the bacillus to cells expressing sTn, promoting cell death. CONCLUSION: s6T is described for the first time in bladder tumours. Our data strongly suggest that BCG immunotherapy is efficient against sTn- and s6T-positive tumours. Furthermore, sTn and s6T expression are independent predictive markers of BCG treatment response and may be useful in the identification of patients who could benefit more from this immunotherapy. PMID- 24064973 TI - Comment on 'Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102)'. PMID- 24064974 TI - Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research. AB - BACKGROUND: Lymph node density (LND) has previously been reported to reliably predict recurrence risk and survival in oral cavity squamous cell carcinoma (OSCC). This multicenter international study was designed to validate the concept of LND in OSCC. METHODS: The study included 4254 patients diagnosed as having OSCC. The median follow-up was 41 months. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional control and distant metastasis rates were calculated using the Kaplan-Meier method. Lymph node density (number of positive lymph nodes/total number of excised lymph nodes) was subjected to multivariate analysis. RESULTS: The OS was 49% for patients with LND?0.07 compared with 35% for patients with LND>0.07 (P<0.001). Similarly, the DSS was 60% for patients with LND?0.07 compared with 41% for those with LND>0.07 (P<0.001). Lymph node density reliably stratified patients according to their risk of failure within the individual N subgroups (P=0.03). A modified TNM staging system based on LND ratio was consistently superior to the traditional system in estimating survival measures. CONCLUSION: This multi-institutional study validates the reliability and applicability of LND as a predictor of outcomes in OSCC. Lymph node density can potentially assist in identifying patients with poor outcomes and therefore for whom more aggressive adjuvant treatment is needed. PMID- 24064975 TI - Surface proteomic analysis of osteosarcoma identifies EPHA2 as receptor for targeted drug delivery. AB - BACKGROUND: Osteosarcoma (OS) is the most common bone tumour in children and adolescents. Despite aggressive therapy regimens, treatment outcomes are unsatisfactory. Targeted delivery of drugs can provide higher effective doses at the site of the tumour, ultimately improving the efficacy of existing therapy. Identification of suitable receptors for drug targeting is an essential step in the design of targeted therapy for OS. METHODS: We conducted a comparative analysis of the surface proteome of human OS cells and osteoblasts using cell surface biotinylation combined with nano-liquid chromatography - tandem mass spectrometry-based proteomics to identify surface proteins specifically upregulated on OS cells. This approach generated an extensive data set from which we selected a candidate to study for its suitability as receptor for targeted treatment delivery to OS. First, surface expression of the ephrin type-A receptor 2 (EPHA2) receptor was confirmed using FACS analysis. Ephrin type-A receptor 2 expression in human tumour tissue was tested using immunohistochemistry. Receptor targeting and internalisation studies were conducted to assess intracellular uptake of targeted modalities via EPHA2. Finally, tissue micro arrays containing cores of human OS tissue were stained using immunohistochemistry and EPHA2 staining was correlated to clinical outcome measures. RESULTS: Using mass spectrometry, a total of 2841 proteins were identified of which 156 were surface proteins significantly upregulated on OS cells compared with human primary osteoblasts. Ephrin type-A receptor 2 was highly upregulated and the most abundant surface protein on OS cells. In addition, EPHA2 was expressed in a vast majority of human OS samples. Ephrin type-A receptor 2 effectively mediates internalisation of targeted adenoviral vectors into OS cells. Patients with EPHA2 positive tumours showed a trend toward inferior overall survival. CONCLUSION: The results presented here suggest that the EPHA2 receptor can be considered an attractive candidate receptor for targeted delivery of therapeutics to OS. PMID- 24064976 TI - Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes. AB - BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour, predominantly affecting children and adolescents. Cancer cell line models are required to understand the underlying mechanisms of tumour progression and for preclinical investigations. METHODS: To identify cell lines that are well suited for studies of critical cancer-related phenotypes, such as tumour initiation, growth and metastasis, we have evaluated 22 osteosarcoma cell lines for in vivo tumorigenicity, in vitro colony-forming ability, invasive/migratory potential and proliferation capacity. Importantly, we have also identified mRNA and microRNA (miRNA) gene expression patterns associated with these phenotypes by expression profiling. RESULTS: The cell lines exhibited a wide range of cancer-related phenotypes, from rather indolent to very aggressive. Several mRNAs were differentially expressed in highly aggressive osteosarcoma cell lines compared with non-aggressive cell lines, including RUNX2, several S100 genes, collagen genes and genes encoding proteins involved in growth factor binding, cell adhesion and extracellular matrix remodelling. Most notably, four genes-COL1A2, KYNU, ACTG2 and NPPB-were differentially expressed in high and non-aggressive cell lines for all the cancer-related phenotypes investigated, suggesting that they might have important roles in the process of osteosarcoma tumorigenesis. At the miRNA level, miR-199b-5p and mir-100-3p were downregulated in the highly aggressive cell lines, whereas miR-155-5p, miR-135b-5p and miR-146a-5p were upregulated. miR-135b-5p and miR-146a-5p were further predicted to be linked to the metastatic capacity of the disease. INTERPRETATION: The detailed characterisation of cell line phenotypes will support the selection of models to use for specific preclinical investigations. The differentially expressed mRNAs and miRNAs identified in this study may represent good candidates for future therapeutic targets. To our knowledge, this is the first time that expression profiles are associated with functional characteristics of osteosarcoma cell lines. PMID- 24064978 TI - Reply: 'Comment on Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102)'. PMID- 24064977 TI - Photodynamic therapy plus regulatory T-cell depletion produces immunity against a mouse tumour that expresses a self-antigen. AB - BACKGROUND: Photodynamic therapy (PDT) can lead to development of antigen specific immune response and PDT-mediated immunity can be potentiated by T regulatory cell (Treg) depletion. We investigated whether the combination of PDT with cyclophosphamide (CY) could foster immunity against wild-type tumours expressing self-antigen (gp70). METHODS: Mice with CT26 tumours were treated with PDT alone or in combination with low-dose CY. T regulatory cell numbers and transforming growth factor-beta (TGF-beta) levels were measured at several time points after treatment. Mice cured by PDT+CY were rechallenged with CT26 and monitored for long-term survival. RESULTS: Photodynamic therapy+CY led to complete tumour regression and long-term survival in 90% of treated mice while the absolute numbers of Treg decreased after PDT+CY and the TGF-beta levels were reduced to a level comparable to naive mice. Sixty-five percent of the mice treated with PDT+CY that survived over 90 days tumour free rejected the rechallenge with the same tumour when a second dose of CY was administered before rechallenge but not without. CONCLUSION: Administration of CY before PDT led to depletion of Treg and potentiated PDT-mediated immunity, leading to long-term survival and development of memory immunity that was only uncovered by second Treg depletion. PMID- 24064979 TI - Montreal prognostic score: estimating survival of patients with non-small cell lung cancer using clinical biomarkers. AB - BACKGROUND: For evidence-based medical practice, well-defined risk scoring systems are essential to identify patients with a poor prognosis. The objective of this study was to develop a prognostic score, the Montreal prognostic score (MPS), to improve prognostication of patients with incurable non-small cell lung cancer (NSCLC) in everyday practice. METHODS: A training cohort (TC) and a confirmatory cohort (CC) of newly diagnosed patients with NSCLC planning to receive chemotherapy were used to develop the MPS. Stage and clinically available biomarkers were entered into a Cox model and risk weights were estimated. C statistics were used to test the accuracy. RESULTS: The TC consisted of 258 patients and the CC consisted of 433 patients. Montreal prognostic score classified patients into three distinct groups with median survivals of 2.5 months (95% confidence interval (CI): 1.8, 4.2), 8.2 months (95% CI: 7.0, 9.4) and 18.2 months (95% CI: 14.0, 27.5), respectively (log-rank, P<0.001). Overall, the C-statistics were 0.691 (95% CI: 0.685, 0.697) for the TC and 0.665 (95% CI: 0.661, 0.670) for the CC. CONCLUSION: The MPS, by classifying patients into three well-defined prognostic groups, provides valuable information, which physicians could use to better inform their patients about treatment options, especially the best timing to involve palliative care teams. PMID- 24064981 TI - Landscape composition has limited impact on local genetic structure in mountain clover, Trifolium montanum L. AB - Semi-dry grasslands in the European Alps have been increasingly fragmented over the last 150 years. Few studies have investigated the implications of landscape configuration for genetic structure and gene flow among remnant habitat patches. Conservation management of semi-dry grassland plants rarely accounts for possible effects of major landscape elements, such as forest patches, as barriers to gene flow and dispersal via seed and pollen, despite their potential importance for biodiversity conservation. Using 1416 individuals from 61 sampling sites across 2 valleys in South-Eastern Switzerland and Amplified fragment length polymorphism (AFLP) fingerprints, we applied a spatial strip and a circle approach to determine the impact of different landscape elements on genetic differentiation in the semi-dry grassland herb Trifolium montanum (mountain clover). Overall genetic differentiation among sampling sites was low (overall F ST = 0.044). Forest area had no effect on gene flow at the landscape scale, but area of semi dry grassland, the potential habitat of T. montanum, road area, and altitude influenced genetic differentiation among sampling sites. The observed pattern of genetic differentiation suggests that a future increase in forest area, due to land use abandonment, at least in the short term, are unlikely to directly impact patterns of genetic variation in T. montanum. PMID- 24064980 TI - Low activity of select Hsp104 mutants is sufficient to propagate unstable prion variants. AB - The molecular chaperone network plays a critical role in the formation and propagation of self-replicating yeast prions. Not only do individual prions differ in their requirements for certain chaperones, but structural variants of the same prion can also display distinct dependences on the chaperone machinery, specifically Hsp104. The AAA+ ATPase Hsp104 is a disaggregase required for the maintenance of most known yeast prions. As a key component in the propagation of prions, understanding how Hsp104 differs in its interaction with specific variants is crucial to understanding how prion variants may be selected or evolve. Here, we investigate two novel mutations in Hsp104, hsp104-G254D, and hsp104-G730D, which allow us to elucidate some mechanistic features of Hsp104 disaggregation and its requirement for activity in propagating specific prion variants. Both Hsp104 mutants propagate the [PSI+] prion to some extent, but show a high rate of prion loss. Both Hsp104-G254D and Hsp104-G730D display reduced biochemical activity, yet differ in their ability to efficiently resolubilize disordered, heat-aggregated substrates. Additionally, both mutants impair weak [PSI+] propagation, but are capable of propagating the less stable strong [PSI+] variant to some extent. One of the Hsp104 mutants also has the ability to propagate one variant of the [RNQ+] prion. Thus, our data suggest that changes in Hsp104 activity limit substrate disaggregation in a manner that depends more on the stability of the substrate than the nature of the aggregated species. PMID- 24064982 TI - Molecular determinants of common gating of a ClC chloride channel. AB - Uniquely, the ClC family harbours dissipative channels and anion/H(+) transporters that share unprecedented functional characteristics. ClC-1 channels are homodimers in which each monomer supports an identical pore carrying three anion-binding sites. Transient occupancy of the extracellular binding site by a conserved glutamate residue, E232, independently gates each pore. A common gate, the molecular basis of which is unknown, closes both pores simultaneously. Mutations affecting common gating underlie myotonia congenita in humans. Here we show that the common gate likely occludes the channel pore via interaction of E232 with a highly conserved tyrosine, Y578, at the central anion-binding site. We also identify structural linkages important for coordination of common gating between subunits and modulation by intracellular molecules. Our data reveal important molecular determinants of common gating of ClC channels and suggest that the molecular mechanism is an evolutionary vestige of coupled anion/H(+) transport. PMID- 24064984 TI - Enhancement of the photocytotoxic efficiency of sub-12 nm therapeutic polymeric micelles with increased co-localisation in mitochondria. AB - We engineered phototherapeutic sub-12 nm-sized polymeric micelles to treat malignant brain tumours (MBTs). The engineered nanoparticles in MBT cells enhanced the photocytotoxic efficiency more than 2.5-fold compared with parental and PEGylated photosensitisers (PSs). Increased subcellular co-localisation of PSs in mitochondria was observed. PMID- 24064987 TI - The utility of short message service (SMS) texts to remind patients at higher risk of STIs and HIV to reattend for testing: a controlled before and after study. AB - BACKGROUND: Patients attending for sexually transmitted infection (STI)/HIV testing may be at continuing risk of infection and advised to return for retesting at a later date. OBJECTIVES: To measure the impact of short message service (SMS) text reminders on the reattendance rates of patients who require repeat STI testing. METHODS: Reattendance rates were measured for two groups of higher risk patients: those listed for routine SMS text reminders in 2012 and a control group of patients from 2011 with the same risk profile who had not received any active recall. Reattendance was counted if it was within 4 months of the end of the episode of care. RESULTS: Reattendance rates were not statistically different between the text group 32% (89/274) and the control group 35% (92/266). Reattendance also was not statistically different between the text and control groups respectively in patients with the following risks: recent chlamydia 43/121 (36%) versus 41/123 (33%), recent gonorrhoea 4/21 (19%) versus 7/21 (33%), recent emergency contraception 27/60 (45%) versus 25/56 (45%) and other risks 7/27 (26%) versus 9/26 (35%). High rates of STIs were found in patients who reattended in both the text group (13/90, 14%) and control group (15/91, 17%) and at even higher rates at reattendance if the reason for recall was chlamydia infection at the initial visit: 9/43 (21%) in the text group and 10/41 (24%) in the control group. CONCLUSIONS: SMS texts sent as reminders to patients at higher risk of STIs and HIV did not increase the reattendance rate, when compared with standard advice, in this service which already has a high reattendance rate. STI rates were high in those patients who reattended. PMID- 24064986 TI - HIV prevalence and related risk behaviours among female partners of male injecting drugs users in Iran: results of a bio-behavioural survey, 2010. AB - OBJECTIVE: Sexual partners of injecting drug users (IDUs) are at high risk of HIV infection, yet data for such populations are scarce worldwide, particularly in the Middle East and North African region. This study measured and compared the prevalence of HIV, hepatitis C (HCV), hepatitis B (HBV) and related behavioural factors in male IDUs (MIDUs), their main female sexual partners who were also injecting drug users (FIDUPs) and their main non-injecting female partners (FNIDUPs). METHOD: Using convenience sampling, MIDUs were recruited at drop-in health centres in three cities (Tehran, Mashhad and Shiraz), who in turn recruited their main female partners. Behavioural data were collected using a standard questionnaire, and blood samples were drawn for HIV and HCV antibody testing and HBV surface antigen. RESULTS: HIV prevalence was 9.4% (95% CI 2.96% to 26.2%) among MIDUs (n=226), 7.7% (95% CI 1.9% to 26.3%) among FIDUPs (n=42) and 2.8% (95% CI 0.65% to 11.3%) among FNIDUPs (n=184). HCV prevalence was 38.6% (95% CI 20.3% to 60.7%) among MIDUs, 36.6% (95% CI 13.6% to 67.9%) among FIDUPs and 8.4% (95% CI 5.67% to 12.4%) among FNIDUPs. HBV surface antigen prevalence was 3.6% (95% CI 1.5% to 8.3%), 7.3% (95% CI 1.9% to 24.8%) and 1.1% (95% CI 0.3% to 4.7%), respectively. Among MIDUs, 19.5% (95% CI 3.4% to 62.2%) had a history of sexual contact with other men. Mean age at first sexual contact in MIDUs was 19.2 years (95% CI 18.6 to 25.2) and in FIDUPs and FNIDUPs 16.4 years (95% CI 14.1 to 22.1) and 18.2 years (95% CI 15.7 to 23.1), respectively. FIDUPs and FNIDUPs had a higher mean number of sexual partners (other than their main partner) in the previous month than MIDUs (5.5 (95% CI 0 to 14.1) and 2.5 (95% CI 1.1 to 4) vs 1.3 (95% CI 0.37 to 2.2), respectively). FIDUPs tended to use drugs before or during sex with their main and casual partners more often than MIDUs (with main partner: 69% (95% CI 41.5% to 87.5%) vs 54.4% (95% CI 27% to 79.4%), respectively, and with casual partners: 47.6% (95% CI 13.1% to 84.6%) vs 34.1% (95% CI 10% to 70.6%), respectively); however, the differences were not statistically significant. CONCLUSIONS: Female partners of MIDUs in Iran and elsewhere are an under studied group. The high rate of HIV, HCV and HBV infection among females who are partners of MIDUs points to the necessity of appropriate injection and sexual risk reduction interventions among this group, to prevent acquisition of HIV, HCV and HBV and their onward transmission to other male partners. PMID- 24064988 TI - Evaluation of potential sewage contamination by fecal sterol biomarkers adsorbed in natural biofilms. AB - The use of biofilms for adsorption of sterols was investigated for the first time to evaluate sewage contamination in the Barigui River, Curitiba (Brazil). The characteristics of a biofilm that favor its use in monitoring include the relatively rapid development of biofilms and their capacity to sorb hydrophobic compounds. Some fecal sterols considered to be biomarkers for human and animal feces have relatively high octanol-water partitioning coefficients (log KOW); thus, sterols were expected to be readily sorbed in the biofilms. The biofilms were developed on glass plates (0.48 m(2)) previously coated with a fine layer of stearic acid and supported by a PVC tube that was submersed in the river 20 cm above the river bottom. After a certain period of incubation time, the biofilm growth was scraped from the plates and analyzed for the following fecal steroids: coprostanol (5beta-cholestan-3beta-ol), epicoprostanol (5beta-cholestan-3alpha ol), cholesterol (5,6-cholesten-3beta-ol), cholestanol (5alpha-cholestan-3beta ol), stigmastanol (24beta-ethyl-5alpha-cholestan-3beta-ol) and coprostanone (5beta-cholestan-3-one). Six samples were collected between March 2012 and June 2012. All analyzed compounds were detected, and in general, cholesterol was present in high amounts (23 160-41.9 ng g(-1) dry biofilm). Variation among campaigns was observed in the distribution of sterols, with cholestanol showing the least variation among the samples. Sterol ratios that are commonly used for evaluating sewage contamination were calculated; these ratios indicated some periods of potential sewage influence. However, these sterol ratios are intended to be applied primarily for sediments and not for biological compartments; thus, the results must be carefully interpreted. Biofilms developed under natural conditions can be a tool for monitoring some important sterols that are used as biomarkers of fecal pollution. PMID- 24064989 TI - Assessing of heavy metal concentrations in the tissues of Rutilus rutilus caspicus and Neogobius gorlap from Miankaleh international wetland. AB - The concentrations of four heavy metals (Pb, Cd, Ni and Cr) were measured in tissues of pelagic (Rutilus caspicus) and benthic (Neogobius gorlap) fishes from the Miankaleh international wetland. The maximum concentrations of Pb, Cd, Ni, and Cr (2.06, 1.20, 1.14 and 0.70 MUg g(-1), respectively) were measured in the liver of N. gorlap, while the lowest concentrations were measured in muscle tissue collected from R. caspicus (Pb 0.67; Cd 0.25; Ni 0.21 and Cr 0.08 MUg g( 1)). The mean concentrations of metals in liver of R. caspicus and N. gorlap followed a trend where Pb > Cd > Ni > Cr, whereas in R. caspicus and N. gorlap gills and N. gorlap muscle the following trend was observed Pb > Ni > Cd > Cr. The data of presented study show that the liver and gill tissues have higher metal concentrations than muscle and also the metal concentrations in tissues of N. gorlap (benthic) were higher in comparison with R. caspicus (pelagic). PMID- 24064992 TI - Apples: Thomas Worthington Whittredge. PMID- 24064993 TI - Questions linger about health premiums in new exchanges. PMID- 24064983 TI - Initiation of mRNA decay in bacteria. AB - The instability of messenger RNA is fundamental to the control of gene expression. In bacteria, mRNA degradation generally follows an "all-or-none" pattern. This implies that if control is to be efficient, it must occur at the initiating (and presumably rate-limiting) step of the degradation process. Studies of E. coli and B. subtilis, species separated by 3 billion years of evolution, have revealed the principal and very disparate enzymes involved in this process in the two organisms. The early view that mRNA decay in these two model organisms is radically different has given way to new models that can be resumed by "different enzymes-similar strategies". The recent characterization of key ribonucleases sheds light on an impressive case of convergent evolution that illustrates that the surprisingly similar functions of these totally unrelated enzymes are of general importance to RNA metabolism in bacteria. We now know that the major mRNA decay pathways initiate with an endonucleolytic cleavage in E. coli and B. subtilis and probably in many of the currently known bacteria for which these organisms are considered representative. We will discuss here the different pathways of eubacterial mRNA decay, describe the major players and summarize the events that can precede and/or favor nucleolytic inactivation of a mRNA, notably the role of the 5' end and translation initiation. Finally, we will discuss the role of subcellular compartmentalization of transcription, translation, and the RNA degradation machinery. PMID- 24064994 TI - Low diastolic blood pressure and chronic kidney disease are associated with increased mortality. PMID- 24064995 TI - ICMJE: All authors of medical journal articles have "responsibility to stand by the integrity of the entire work". PMID- 24065006 TI - The evolving role and value of libraries and librarians in health care. PMID- 24065005 TI - Patient-reported outcome alerts: ethical and logistical considerations in clinical trials. PMID- 24065007 TI - A piece of my mind. Crossing boundaries--violation or obligation? PMID- 24065008 TI - Insulin pump therapy with automated insulin suspension: toward freedom from nocturnal hypoglycemia. PMID- 24065009 TI - High-stakes diagnostic decision rules for serious disorders: the Ottawa subarachnoid hemorrhage rule. PMID- 24065010 TI - Effect of sensor-augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial. AB - IMPORTANCE: Hypoglycemia is a critical obstacle to the care of patients with type 1 diabetes. Sensor-augmented insulin pump with automated low-glucose insulin suspension has the potential to reduce the incidence of major hypoglycemic events. OBJECTIVE: To determine the incidence of severe and moderate hypoglycemia with sensor-augmented pump with low-glucose suspension compared with standard insulin pump therapy. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial involving 95 patients with type 1 diabetes, recruited from December 2009 to January 2012 in Australia. INTERVENTIONS: Patients were randomized to insulin pump only or automated insulin suspension for 6 months. MAIN OUTCOMES AND MEASURES: The primary outcome was the combined incidence of severe (hypoglycemic seizure or coma) and moderate hypoglycemia (an event requiring assistance for treatment). In a subgroup, counterregulatory hormone responses to hypoglycemia were assessed using the hypoglycemic clamp technique. RESULTS: Of the 95 patients randomized, 49 were assigned to the standard-pump (pump-only) therapy and 46 to the low-glucose suspension group. The mean (SD) age was 18.6 (11.8) years; duration of diabetes, 11.0 (8.9) years; and duration of pump therapy, 4.1 (3.4) years. The baseline rate of severe and moderate hypoglycemic events in the pump only group was 20.7 vs 129.6 events per 100 patient months in the low-glucose suspension group. After 6 months of treatment, the event rates decreased from 28 to 16 in the pump-only group vs 175 to 35 in the low-glucose suspension group. The adjusted incidence rate per 100 patient-months was 34.2 (95% CI, 22.0-53.3) for the pump-only group vs 9.5 (95% CI, 5.2-17.4) for the low-glucose suspension group. The incidence rate ratio was 3.6 (95% CI, 1.7-7.5; P <.001). There was no change in glycated hemoglobin in either group: mean, 7.4 (95% CI, 7.2-7.6) to 7.4 (95% CI, 7.2-7.7) in the pump-only group vs mean, 7.6 (95%, CI, 7.4-7.9) to 7.5 (95% CI, 7.3-7.7) in the low-glucose suspension group. Counterregulatory hormone responses to hypoglycemia were not changed. There were no episodes of diabetic ketoacidosis or hyperglycemia with ketosis. CONCLUSIONS AND RELEVANCE: Sensor augmented pump therapy with automated insulin suspension reduced the combined rate of severe and moderate hypoglycemia in patients with type 1 diabetes. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12610000024044. PMID- 24065011 TI - Clinical decision rules to rule out subarachnoid hemorrhage for acute headache. AB - IMPORTANCE: Three clinical decision rules were previously derived to identify patients with headache requiring investigations to rule out subarachnoid hemorrhage. OBJECTIVE: To assess the accuracy, reliability, acceptability, and potential refinement (ie, to improve sensitivity or specificity) of these rules in a new cohort of patients with headache. DESIGN, SETTING, AND PATIENTS: Multicenter cohort study conducted at 10 university-affiliated Canadian tertiary care emergency departments from April 2006 to July 2010. Enrolled patients were 2131 adults with a headache peaking within 1 hour and no neurologic deficits. Physicians completed data forms after assessing eligible patients prior to investigations. MAIN OUTCOMES AND MEASURES: Subarachnoid hemorrhage, defined as (1) subarachnoid blood on computed tomography scan; (2) xanthochromia in cerebrospinal fluid; or (3) red blood cells in the final tube of cerebrospinal fluid, with positive angiography findings. RESULTS: Of the 2131 enrolled patients, 132 (6.2%) had subarachnoid hemorrhage. The decision rule including any of age 40 years or older, neck pain or stiffness, witnessed loss of consciousness, or onset during exertion had 98.5% (95% CI, 94.6%-99.6%) sensitivity and 27.5% (95% CI, 25.6%-29.5%) specificity for subarachnoid hemorrhage. Adding "thunderclap headache" (ie, instantly peaking pain) and "limited neck flexion on examination" resulted in the Ottawa SAH Rule, with 100% (95% CI, 97.2%-100.0%) sensitivity and 15.3% (95% CI, 13.8%-16.9%) specificity. CONCLUSIONS AND RELEVANCE: Among patients presenting to the emergency department with acute nontraumatic headache that reached maximal intensity within 1 hour and who had normal neurologic examination findings, the Ottawa SAH Rule was highly sensitive for identifying subarachnoid hemorrhage. These findings apply only to patients with these specific clinical characteristics and require additional evaluation in implementation studies before the rule is applied in routine clinical care. PMID- 24065012 TI - Repeat bone mineral density screening and prediction of hip and major osteoporotic fracture. AB - IMPORTANCE: Screening for osteoporosis with bone mineral density (BMD) is recommended for older adults. It is unclear whether repeating a BMD screening test improves fracture risk assessment. OBJECTIVES: To determine whether changes in BMD after 4 years provide additional information on fracture risk beyond baseline BMD and to quantify the change in fracture risk classification after a second BMD measure. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study involving 310 men and 492 women from the Framingham Osteoporosis Study with 2 measures of femoral neck BMD taken from 1987 through 1999. MAIN OUTCOMES AND MEASURES: Risk of hip or major osteoporotic fracture through 2009 or 12 years following the second BMD measure. RESULTS: Mean age was 74.8 years. The mean (SD) BMD change was -0.6% per year (1.8%). Throughout a median follow-up of 9.6 years, 76 participants experienced an incident hip fracture and 113 participants experienced a major osteoporotic fracture. Annual percent BMD change per SD decrease was associated with risk of hip fracture (hazard ratio [HR], 1.43 [95% CI, 1.16 to 1.78]) and major osteoporotic fracture (HR, 1.21 [95% CI, 1.01 to 1.45]) after adjusting for baseline BMD. At 10 years' follow-up, 1 SD decrease in annual percent BMD change compared with the mean BMD change was associated with 3.9 excess hip fractures per 100 persons. In receiver operating characteristic (ROC) curve analyses, the addition of BMD change to a model with baseline BMD did not meaningfully improve performance. The area under the curve (AUC) was 0.71 (95% CI, 0.65 to 0.78) for the baseline BMD model compared with 0.68 (95% CI, 0.62 to 0.75) for the BMD percent change model. Moreover, the addition of BMD change to a model with baseline BMD did not meaningfully improve performance (AUC, 0.72 [95% CI, 0.66 to 0.79]). Using the net reclassification index, a second BMD measure increased the proportion of participants reclassified as high risk of hip fracture by 3.9% (95% CI, -2.2% to 9.9%), whereas it decreased the proportion classified as low risk by -2.2% (95% CI, -4.5% to 0.1%). CONCLUSIONS AND RELEVANCE: In untreated men and women of mean age 75 years, a second BMD measure after 4 years did not meaningfully improve the prediction of hip or major osteoporotic fracture. Repeating a BMD measure within 4 years to improve fracture risk stratification may not be necessary in adults this age untreated for osteoporosis. PMID- 24065015 TI - Necrotic black eschars on the lower extremities in a 57-year-old woman with ovarian cancer. PMID- 24065014 TI - A 91-year-old woman with difficult-to-control hypertension: a clinical review. AB - IMPORTANCE: Hypertension is common among people older than 65 years, affecting nearly two-thirds of men and three-fourths of women by age 75 years. Treatment goals and medication selection for this population may differ from those for younger patients. OBJECTIVE: To discuss the presentation, pathophysiology, and optimal treatment of hypertension among elderly persons. EVIDENCE REVIEW: MEDLINE was searched from 1990 to 2013. A hand search of bibliographies from guidelines and review articles from 2000 to 2013 was also used to identify studies of hypertension treatment in patients older than 65 years. FINDINGS: Hypertension in elderly people differs from that in younger people in that (1) hypertension is predominantly systolic because of vascular stiffness; (2) it is associated with reduced baroreflex sensitivity, which increases blood pressure variability and vulnerability to hypotension during common daily activities; (3) it is associated with cognitive and functional decline as well as adverse cardiovascular outcomes; and (4) hypertension may be beneficial in frail people older than 85 years. Treatment of healthy patients up to age 85 years with most antihypertensive medications reduces cardiovascular morbidity and mortality and possibly cognitive and functional decline. CONCLUSION AND RELEVANCE: Although patients in their 90s have not been studied, any ambulatory and independent patient older than 80 years should have multiple blood pressure measurements taken during their usual daily activities, and if these show persistent hypertension, these patients should be treated judiciously. PMID- 24065013 TI - Effects of intensive diet and exercise on knee joint loads, inflammation, and clinical outcomes among overweight and obese adults with knee osteoarthritis: the IDEA randomized clinical trial. AB - IMPORTANCE: Knee osteoarthritis (OA), a common cause of chronic pain and disability, has biomechanical and inflammatory origins and is exacerbated by obesity. OBJECTIVE: To determine whether a >=10% reduction in body weight induced by diet, with or without exercise, would improve mechanistic and clinical outcomes more than exercise alone. DESIGN, SETTING, AND PARTICIPANTS: Single blind, 18-month, randomized clinical trial at Wake Forest University between July 2006 and April 2011. The diet and exercise interventions were center-based with options for the exercise groups to transition to a home-based program. Participants were 454 overweight and obese older community-dwelling adults (age >=55 years with body mass index of 27-41) with pain and radiographic knee OA. INTERVENTIONS: Intensive diet-induced weight loss plus exercise, intensive diet induced weight loss, or exercise. MAIN OUTCOMES AND MEASURES: Mechanistic primary outcomes: knee joint compressive force and plasma IL-6 levels; secondary clinical outcomes: self-reported pain (range, 0-20), function (range, 0-68), mobility, and health-related quality of life (range, 0-100). RESULTS: Three hundred ninety-nine participants (88%) completed the study. Mean weight loss for diet + exercise participants was 10.6 kg (11.4%); for the diet group, 8.9 kg (9.5%); and for the exercise group, 1.8 kg (2.0%). After 18 months, knee compressive forces were lower in diet participants (mean, 2487 N; 95% CI, 2393 to 2581) compared with exercise participants (2687 N; 95% CI, 2590 to 2784, pairwise difference [Delta](exercise vs diet )= 200 N; 95% CI, 55 to 345; P = .007). Concentrations of IL-6 were lower in diet + exercise (2.7 pg/mL; 95% CI, 2.5 to 3.0) and diet participants (2.7 pg/mL; 95% CI, 2.4 to 3.0) compared with exercise participants (3.1 pg/mL; 95% CI, 2.9 to 3.4; Delta(exercise vs diet + exercise) = 0.39 pg/mL; 95% CI, -0.03 to 0.81; P = .007; Delta(exercise vs diet )= 0.43 pg/mL; 95% CI, 0.01 to 0.85, P = .006). The diet + exercise group had less pain (3.6; 95% CI, 3.2 to 4.1) and better function (14.1; 95% CI, 12.6 to 15.6) than both the diet group (4.8; 95% CI, 4.3 to 5.2) and exercise group (4.7; 95% CI, 4.2 to 5.1, Delta(exercise vs diet + exercise) = 1.02; 95% CI, 0.33 to 1.71; P(pain) = .004; 18.4; 95% CI, 16.9 to 19.9; Delta(exercise vs diet + exercise), 4.29; 95% CI, 2.07 to 6.50; P(function )< .001). The diet + exercise group (44.7; 95% CI, 43.4 to 46.0) also had better physical health-related quality of life scores than the exercise group (41.9; 95% CI, 40.5 to 43.2; Delta(exercise vs diet + exercise) = 2.81; 95% CI, -4.76 to -0.86; P = .005). CONCLUSIONS AND RELEVANCE: Among overweight and obese adults with knee OA, after 18 months, participants in the diet + exercise and diet groups had more weight loss and greater reductions in IL 6 levels than those in the exercise group; those in the diet group had greater reductions in knee compressive force than those in the exercise group. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00381290. PMID- 24065016 TI - Prevalence of reduced estimated glomerular filtration rate among the oldest old from 1988-1994 through 2005-2010. PMID- 24065017 TI - Timing of tracheostomy. PMID- 24065018 TI - Timing of tracheostomy. PMID- 24065019 TI - Controversy over contraception coverage. PMID- 24065020 TI - Timing of tracheostomy--reply. PMID- 24065021 TI - Controversy over contraception coverage--reply. PMID- 24065022 TI - Controversy over contraception coverage. PMID- 24065023 TI - Focusing on the body of evidence. PMID- 24065025 TI - Focusing on the body of evidence--reply. PMID- 24065024 TI - Controversy over contraception coverage--reply. PMID- 24065027 TI - Health and finance. PMID- 24065028 TI - JAMA patient page. Vascular screening. PMID- 24065029 TI - Radical trachelectomy: the first step of fertility preservation in young women with cervical cancer (Review). AB - Radical trachelectomy (RT) can be performed vaginally or abdominally (laparotomic, laparoscopic or robotic). The aim of this systematic review was to compare all techniques in terms of surgical complications, disease recurrence and subsequent fertility/pregnancy outcomes. A total of 1293 RTs were analyzed (FIGO stage: IA1-IIA). The most frequent surgical complications do not differ from the ones of radical hysterectomy. The recurrence risk is approximately 3% (range 0 16.8%). The majority of women conceive spontaneously: 284 pregnancies with 173 live births. The most frequent pregnancy complication was miscarriage and chorioamnionitis. RT appears to be a safe option for eligible women who intend to maintain their future pregnancy desire. PMID- 24065031 TI - The press, press releases, and raising unwarranted expectations. PMID- 24065032 TI - Over-diagnosis estimate from The Independent UK Panel on Breast Cancer Screening is based on unsuitable data. PMID- 24065030 TI - Functional evaluation of autism-associated mutations in NHE9. AB - NHE9 (SLC9A9) is an endosomal cation/proton antiporter with orthologues in yeast and bacteria. Rare, missense substitutions in NHE9 are genetically linked with autism but have not been functionally evaluated. Here we use evolutionary conservation analysis to build a model structure of NHE9 based on the crystal structure of bacterial NhaA and use it to screen autism-associated variants in the human population first by phenotype complementation in yeast, followed by functional analysis in primary cortical astrocytes from mouse. NHE9-GFP localizes to recycling endosomes, where it significantly alkalinizes luminal pH, elevates uptake of transferrin and the neurotransmitter glutamate, and stabilizes surface expression of transferrin receptor and GLAST transporter. In contrast, autism associated variants L236S, S438P and V176I lack function in astrocytes. Thus, we establish a neurobiological cell model of a candidate gene in autism. Loss-of function mutations in NHE9 may contribute to autistic phenotype by modulating synaptic membrane protein expression and neurotransmitter clearance. PMID- 24065034 TI - Effects of smoking habit on the prevalence of atrial fibrillation in Japanese patients with special reference to sex differences. AB - BACKGROUND: Tobacco smoking is a well-known risk factor for cardiovascular disease, but controversial results have been reported regarding its relationship with atrial fibrillation (AF). Moreover, no study on the relationship between smoking and AF has yet been undertaken in a Japanese context. METHODS AND RESULTS: We used data from the Shinken Database 2004-2011 (men/women, n=10,714/6,803, respectively), which included all new patients attending the Cardiovascular Institute between June 2004 and March 2012. AF was diagnosed in 1,698 and 598 men and women, respectively. In men, smokers were more prevalent in the AF than in the non-AF group (54.5% vs. 44.7%), whereas in women the prevalence of smokers was similar between AF and non-AF groups (14.4% vs. 15.4%). This discrepancy between the sexes seems to derive from a characteristic distribution pattern of smoking habit in women. After adjustment for various cofactors, smoking was independently associated with AF (odds ratio 1.54; 95% confidence interval 1.35-1.75; P<0.001) without a significant interaction between sex categories (P=0.195). CONCLUSIONS: Smoking was independently associated with AF without a significant interaction between sex categories among Japanese patients visiting a cardiovascular hospital. Further studies using a prospective cohort design are required to confirm a causal link between smoking and AF in Japanese patients. PMID- 24065035 TI - Genetic detection of Pseudomonas spp. in commercial Amazonian fish. AB - Brazilian freshwater fish caught from large drainages like the River Amazon represent a million ton market in expansion, which is of enormous importance for export to other continents as exotic seafood. A guarantee of bacteriological safety is required for international exports that comprise a set of different bacteria but not any Pseudomonas. However, diarrhoea, infections and even septicaemia caused by some Pseudomonas species have been reported, especially in immune-depressed patients. In this work we have employed PCR-based methodology for identifying Pseudomonas species in commercial fish caught from two different areas within the Amazon basin. Most fish caught from the downstream tributary River Tapajos were contaminated by five different Pseudomonas species. All fish samples obtained from the River Negro tributary (Manaus markets) contained Pseudomonas, but a less diverse community with only two species. The most dangerous Pseudomonas species for human health, P. aeruginosa, was not found and consumption of these fish (from their Pseudomonas content) can be considered safe for healthy consumers. As a precautionary approach we suggest considering Pseudomonas in routine bacteriological surveys of imported seafood. PMID- 24065036 TI - Appraisal of hygiene indicators and farming practices in the production of leafy vegetables by organic small-scale farmers in uMbumbulu (Rural KwaZulu-Natal, South Africa). AB - During October, November and December 2011 (when highest sales of Agri-Hub fresh produce are observed), irrigation water, compost, lettuce and spinach sampled from four different farmer cooperatives supplying the local Agri-Hub in uMbumbulu (KwaZulu-Natal, South Africa) were analyzed monthly for the presence of total and fecal coliforms and Escherichia coli using the most probable number (MPN) technique. The pH values for all irrigation water samples analyzed were within the acceptable range of 6.5-8.5 for agricultural use. Fecal coliform levels were <1,000 MPN per 100 mL irrigation water and <1,000 MPN per g of compost. The vegetables produced by Agri-Hub small-scale farmers met the requirements for total coliforms of <200/g set by the South African Department of Health at the time of sampling. E. coli MPN values for irrigation water and vegetables were below the limit of detection. In addition, the farming practices of 73 farmers were assessed via a survey. The results revealed that more than 40% of farmers used microbiologically safe tap water for irrigation and that trained farmers have a significantly better understanding of the importance of production hygiene than untrained farmers. These results reiterate the importance of interventions that build capacity in the area of food safety and hygiene of small-scale farmers for market access of formal value chains. PMID- 24065037 TI - New Zealand's drug development industry. AB - The pharmaceutical industry's profitability depends on identifying and successfully developing new drug candidates while trying to contain the increasing costs of drug development. It is actively searching for new sources of innovative compounds and for mechanisms to reduce the enormous costs of developing new drug candidates. There is an opportunity for academia to further develop as a source of drug discovery. The rising levels of industry outsourcing also provide prospects for organisations that can reduce the costs of drug development. We explored the potential returns to New Zealand (NZ) from its drug discovery expertise by assuming a drug development candidate is out-licensed without clinical data and has anticipated peak global sales of $350 million. We also estimated the revenue from NZ's clinical research industry based on a standard per participant payment to study sites and the number of industry sponsored clinical trials approved each year. Our analyses found that NZ's clinical research industry has generated increasing foreign revenue and appropriate policy support could ensure that this continues to grow. In addition the probability-based revenue from the out-licensing of a drug development candidate could be important for NZ if provided with appropriate policy and financial support. PMID- 24065038 TI - Lung deposition analyses of inhaled toxic aerosols in conventional and less harmful cigarette smoke: a review. AB - Inhaled toxic aerosols of conventional cigarette smoke may impact not only the health of smokers, but also those exposed to second-stream smoke, especially children. Thus, less harmful cigarettes (LHCs), also called potential reduced exposure products (PREPs), or modified risk tobacco products (MRTP) have been designed by tobacco manufacturers to focus on the reduction of the concentration of carcinogenic components and toxicants in tobacco. However, some studies have pointed out that the new cigarette products may be actually more harmful than the conventional ones due to variations in puffing or post-puffing behavior, different physical and chemical characteristics of inhaled toxic aerosols, and longer exposure conditions. In order to understand the toxicological impact of tobacco smoke, it is essential for scientists, engineers and manufacturers to develop experiments, clinical investigations, and predictive numerical models for tracking the intake and deposition of toxicants of both LHCs and conventional cigarettes. Furthermore, to link inhaled toxicants to lung and other diseases, it is necessary to determine the physical mechanisms and parameters that have significant impacts on droplet/vapor transport and deposition. Complex mechanisms include droplet coagulation, hygroscopic growth, condensation and evaporation, vapor formation and changes in composition. Of interest are also different puffing behavior, smoke inlet conditions, subject geometries, and mass transfer of deposited material into systemic regions. This review article is intended to serve as an overview of contributions mainly published between 2009 and 2013, focusing on the potential health risks of toxicants in cigarette smoke, progress made in different approaches of impact analyses for inhaled toxic aerosols, as well as challenges and future directions. PMID- 24065040 TI - Size dependent reduction-oxidation-reduction behaviour of cobalt oxide nanocrystals. AB - Morphologically similar cobalt oxide nanoparticles (Co3O4) of four different sizes (3 nm, 6 nm, 11 nm and 29 nm) with narrow size distribution were prepared by subtle variation of synthesis conditions. These nanoparticles were used as model materials to understand the structural and morphological changes that occur to cobalt oxide during sequential reduction, oxidation and further re-reduction process as a function of the initial size of cobalt oxide. On reduction, spherical cobalt nanoparticles were obtained independent of the original size of cobalt oxide. In contrast, subsequent oxidation of the metal particles led to solid spheres, hollow spheres or core-shell structures depending on the size of the initial metal particle. Further re-reduction of the oxidized structures was also observed to be size dependent. The hollow oxide shells formed by the large particles (29 nm) fragmented into smaller particles on reduction, while the hollow shells of the medium sized particles (11 nm) did not re-disperse on further reduction. Similarly, no re-dispersion was observed in the case of the small particles (6 nm). This model study provides useful insights into the size dependent behavior of metal/metal oxide particles during oxidation/reduction. This has important implications in petrochemical industry where cobalt is used as a catalyst in the Fischer-Tropsch process. PMID- 24065039 TI - Genetic analysis of West Nile virus isolates from an outbreak in Idaho, United States, 2006-2007. AB - West Nile virus (WNV) appeared in the U.S. in 1999 and has since become endemic, with yearly summer epidemics causing tens of thousands of cases of serious disease over the past 14 years. Analysis of WNV strains isolated during the 2006 2007 epidemic seasons demonstrates that a new genetic variant had emerged coincidentally with an intense outbreak in Idaho during 2006. The isolates belonging to the new variant carry a 13 nt deletion, termed ID-Delta13, located at the variable region of the 3'UTR, and are genetically related. The analysis of deletions and insertions in the 3'UTR of two major lineages of WNV revealed the presence of conserved repeats and two indel motifs in the variable region of the 3'UTR. One human and two bird isolates from the Idaho 2006-2007 outbreaks were sequenced using Illumina technology and within-host variability was analyzed. Continued monitoring of new genetic variants is important for public health as WNV continues to evolve. PMID- 24065041 TI - White light emission based on a single component Sm(iii) framework and a two component Eu(iii)-doped Gd(iii) framework constructed from 2,2'-diphenyl dicarboxylate and 1H-imidazo[4,5-f][1,10]-phenanthroline. AB - New 1D lanthanide-organic frameworks, [Ln(dpdc)1.5(IP)(H2O)]n (Ln = Sm 1, Eu 2, Gd 3; dpdc = 2,2'-diphenyldicarboxylate and IP = 1H-imidazo[4,5-f][1,10] phenanthroline), were synthesized. White light emission was realized by two approaches: a single component Sm(iii) framework and a two-component Eu(iii) doped Gd(iii) framework. PMID- 24065042 TI - Efficient delivery of miR-122 to regulate cholesterol metabolism using a non covalent peptide-based strategy. AB - MicroRNAs (miRNAs) are small non-coding RNAs that are important in the pathogenesis of multiple diseases and, therefore, may represent a novel class of targets for therapeutic intervention. However, like the majority of oligonucleotide-based strategies, there are obstacles to their clinical application, including poor cellular uptake due to the low permeability of the cell membrane to negatively charged molecules. MPG is a 27-residue peptide vector which contains a hydrophobic domain derived from the fusion sequence of HIV-1 gp41 and a hydrophilic domain derived from the nuclear localization sequence of SV40 T-antigen. MPG is one of the most promising tools for the non-invasive cellular import of oligonucleotides and analogs. In the present study, a non covalent peptide-based strategy was used for the efficient delivery of the miRNA 122 (miR-122) mimic and inhibitor into mouse liver cell lines, mouse primary hepatocytes and C. elegans, without any associated cytotoxicity. Moreover, high performance liquid chromatography analysis determined that MPG and MPGDeltaNLS delivered the miR-122 mimic and inhibitor into mouse liver cells and effectively regulated cholesterol levels. The results demonstrated that MPG family members may be used for the efficient delivery of miR-122 to regulate cholesterol metabolism, and that this cell-penetrating peptide-based technology may be beneficial for further biological applications of RNA therapeutics in vivo. PMID- 24065043 TI - Oxidative stress and inflammation in obesity after taurine supplementation: a double-blind, placebo-controlled study. AB - PURPOSE: Some researchers found decreased levels of plasma taurine in obese subjects and animals, and reduced expression of an important enzyme of taurine synthesis. These evidences, coupled with the metabolic imbalance of obesity and the possible anti-inflammatory and antioxidant effects of taurine, highlighted the use of taurine as a supplement in obesity treatment. The aim of the present study was to investigate whether taurine supplementation, associated with nutritional counseling, modulates oxidative stress, inflammatory response, and glucose homeostasis in obese women. METHODS: A randomized double-blind placebo controlled study was conducted with 16 women with obesity diagnosis and 8 women in the normal weight range. The obese volunteers were matched by age and body mass index and randomly assigned to either the placebo (3 g/day starch flour) or taurine (3 g/day taurine) group. The study lasted 8 weeks, and the experimental protocol included nutritional assessment and determination of plasma sulfur amino acids, insulin, and adiponectin, serum glycemia, and markers of inflammatory response and oxidative stress. RESULTS: Plasma taurine levels were significantly decreased (41%) in the obese volunteers. Both the placebo and taurine groups showed significant reduction in weight (3%), with no differences between groups. Different from placebo, taurine-supplemented group showed significant increase in plasma taurine (97%) and adiponectin (12%) and significant reduction in the inflammatory marker hs-C-reactive protein (29%) and in the lipid peroxidation marker thiobarbituric acid reactive substances (TBARS) (20%). CONCLUSIONS: Eight weeks of taurine supplementation associated with nutritional counseling is able to increase adiponectin levels and to decrease markers of inflammation (high sensitivity C-reactive protein) and lipid peroxidation (TBARS) in obese women. PMID- 24065044 TI - Phyllodes tumor in survivors of childhood osteosarcoma: a single institution's experience. AB - We evaluate the incidence of second neoplasms in 86 patients with osteosarcoma (OS) of the extremities treated with different protocols of adjuvant chemotherapy. Three patients developed phyllodes tumors as the second neoplasm. One of these patients simultaneously developed a third cancer with therapy related acute myeloid leukemia. The sites of primary OS were the tibia (2) and humerus (1). None had received prior radiotherapy before excision of phyllodes tumor. All the patients were female with a median age of 21.7 years at the time of presentation. As yet, that precise causation is unclear, but it can increase our understanding of carcinogenic processes, in general. PMID- 24065045 TI - Acute pain relief after Mantram meditation in children with neuroblastoma undergoing anti-GD2 monoclonal antibody therapy. AB - Nonpharmacologic, mind-body interventions are used to reduce anxiety in pediatric patients. Anti-ganglioside GD2 monoclonal antibody (anti-GD2 MoAb 3F8) therapy is the standard of care for high-risk neuroblastoma and pain is its major side effect. We performed a retrospective analysis of children undergoing anti-GD2 MoAb 3F8 treatment who received guided meditation. Meditation involved concentrating on the repetition of rhythmic, melodic sounds purported to slow breathing and induce a relaxation response. A total of 71% patients completed a session at first (n=19) or second attempt (n=5). Patients received fewer analgesic doses to manage anti-GD2 MoAb 3F8-induced pain when participating in meditation (n=17, mean=-0.4 dose, P<0.01). Mantram meditation is a feasible outpatient intervention associated with reduced analgesic requirements. PMID- 24065046 TI - Juvenile xanthogranuloma: diverse presentations of noncutaneous disease. AB - Juvenile xanthogranulomas (JXGs) are benign cutaneous lesions of childhood that often spontaneously involute. They rarely present as a noncutaneous tumors. However, JXG tumors have been described in numerous noncutaneous anatomic sites, presenting with a variety of symptoms. The severity of symptoms and accurate preoperative diagnosis of JXG should determine operative and nonoperative treatment options of these uncommon, benign, and self-limiting tumors. We report 3 cases of symptomatic, noncutaneous JXG from disparate anatomic sites all treated with aggressive surgical resection. PMID- 24065047 TI - Regio- and stereoselective synthesis of spirooxindole 1'-nitro pyrrolizidines with five concurrent stereocenters under aqueous medium and their bioprospection using the zebrafish (Danio rerio) embryo model. AB - A highly regio- and stereoselective method has been developed and expanded for the synthesis of a 20-membered library of spirooxindole 1'-nitro pyrrolizidines via 1,3-dipolar cycloaddition of azomethine ylides, generated in situ by a decarboxylative route from a common set of diverse isatins and L-proline derivatives, with substituted beta-nitrostyrenes under aqueous medium. Among various reaction conditions, water proved to be necessary for the interaction of the reagents as well as heating the reaction at 90 degrees C for one hour, during which time the desired products were obtained in good yields and with excellent regio- and stereoselectivities. We subsequently applied in silico drug discovery computational methods to (i) identify the ADME properties, based on Lipinski's rule, (ii) screen the toxicological profile, and (iii) predict the penetration through the blood brain barrier (BBB) of the synthesized compounds. Next, the LC50 values of all these spirocyclic oxindoles were determined in zebrafish embryos cultured individually in buffer solutions of each compound and, finally, the phenotypes induced by these molecules in the zebrafish embryos at concentrations below their LC50 were analyzed at 48, 72 and 96 hours post fertilization. PMID- 24065048 TI - Coronary spasms, cardiomyopathy, and Churg-Strauss syndrome : a case report. PMID- 24065049 TI - [Therapeutic management of non-valvular atrial fibrillation. Update 2013]. AB - In western countries one in ten of elderly persons (> 65 years old) will develop atrial fibrillation. The main goal in atrial fibrillation therapy is the prophylaxis of thromboembolic complications through anticoagulation according to the individual risk profile (CHA2DS2-Vasc score) of patients and treatment of cardiovascular comorbidities. Symptoms during atrial fibrillation guide the further therapeutic concept. Doctors can deploy a rate control strategy with a heart rate at rest less than 110/min and/or a rhythm control strategy with cardioversion, antiarrhythmic drugs and catheter ablation to alleviate complaints. To what extent maintaining the sinus rhythm improves the prognosis of atrial fibrillation patients is part of ongoing trials. PMID- 24065050 TI - Demographic change and its impact on the health-care budget for heart failure inpatients in Germany during 1995-2025. AB - AIMS: Demographic change affects the health system in many countries. Heart failure is used as an example in demonstrating the effects of these changing demographics. METHODS: We analyzed trends for demographic change and their effects on heart failure and its costs over the period 1995-2025. RESULTS: Changing demographics are associated with higher treatment costs. The number of patients with heart failure is expected to increase by 61.8 % overall and as much as 74.6 % among the population aged over 65 years. The number of hospital admissions due to heart failure is forecast to increase to 448,752 in 2025. The cost of inpatient treatment will also rise by almost 50 % to around 1.80 billion in 2025. CONCLUSION: It is important to reduce the number of inpatient cases; this can be achieved, for example, by the implementation of adequate guideline-oriented patient-care programs, as well as patient education for the improvement of therapy adherence. PMID- 24065052 TI - Manganese and cobalt binding in a multi-histidinic fragment. AB - The binding of Mn(II) and Co(II) ions to a multi-histidinic peptide, the three repeats (T1R2S3R4S5H6T7S8E9G10)3 portion of Cap43 protein, has been studied. Potentiometric measurements have been used to investigate the protonation equilibria and stoichiometry of the species obtained in a wide range of pH and at a 1 : 1 ligand-to-metal molar ratio. NMR, UV-visible and EPR spectroscopy techniques have been used to investigate the role of multi-histidinic and glutamate sites in coordinating metal ions. (1)H-(1)H TOCSY, (1)H-(13)C HSQC multidimensional NMR techniques were performed to understand the details of metal binding sites and the conformational behaviour of the peptide. The effects of the peptide titration with the two metals have been followed by paramagnetic selective line-broadening in the 1D NMR spectra and the signals' disappearance in the 2D (1)H-(13)C HSQC and (1)H-(1)H TOCSY. Both ions showed common binding donor atoms: the main manganese and cobalt binding centre of the peptide fragment is associated with histidine and glutamate residues. The specific perturbation of NMR resonances indicated that the coordination involves imidazole Nepsilon of histidine and carboxyl gamma-O of glutamate residue. All the three imidazole Nepsilon of His6, His16 and His26, as well as carboxyl gamma-O of Glu9, Glu19 and Glu29, in an octahedral arrangement are involved in the coordination in the physiological pH range. The involvement of hydroxyl gamma-O from the threonine (or serine) side chain can also be observed. Manganese and cobalt complexation induces important structural changes within the C-terminal portion of the ligand, constraining it to leave its disordered conformation. A model of the structure of manganese and cobalt species can be obtained from our data. PMID- 24065051 TI - Characterization of the pumpkin Translationally-Controlled Tumor Protein CmTCTP. AB - In higher plants, the phloem plays a central role in the delivery of nutrients and signals from source to sink tissues. These signals likely coordinate different aspects of plant development, as well as its response to environmental cues. Although some phloem-transported proteins and RNAs may function as signaling molecules in plants, their mode of action remains poorly understood. Previous analysis of transcripts from CMV-infected pumpkin (Cucurbita maxima cv Big Max) identified a Translationally-Controlled Tumor Protein (TCTP) mRNA homolog, designated CmTCTP. In the present work this transcript was analyzed in terms of its expression pattern. This RNA accumulates, both in healthy and CMV infected plants, in developing and mature phloem in petiole and roots, as well as in apices at high levels. The protein was present at lower levels in most cell types, and almost no signal was detected in apices, suggesting translational regulation of this RNA. Additionally, CmTCTP harbored by Agrobacterium rhizogenes is capable of inducing whole plant regeneration. These data suggest a role for CmTCTP in growth regulation, possibly through long-distance signaling. PMID- 24065053 TI - Synthesis, structural characterization and photoluminescence property of three Zn(2+)/Mn(2+)-acylhydrazidate complexes and two acylhydrazide molecules. AB - By employing the hydrothermal in situ acylation of N2H4 with aromatic polycarboxylic acids, three new acylhydrazidate-containing complexes [Zn(N2H4)(dphkh)].H2O (dphkh = 4,4'-diphthalhydrazidatoketone hydrazone) 1, [Zn(npth)2] (npth = naphthalhydrazidate) 2 and [Mn(mpdh)2(H2O)2].2H2O 4, and two new acylhydrazide molecules [bpth].0.5H2O (bpth = 3,3'-biphthalhydrazide) 3 and [(chpth)2] (chpth = 4-chloro-5-hydrazinophthalhydrazide) 5 were obtained. It is noteworthy that (i) compound 1 is a layered Zn(2+) coordination polymer with a mixed ligand of dphkh and N2H4. The nucleophilic addition of the keto spacer with N2H4 also occurred, forming the ketone hydrazone; (ii) compound 2 is a unique example of a npth-extended coordination polymer, exhibiting a double-chain structure; (iii) apart from the acylation of N2H4 with dcpha (dcpha = 4,5 dichlorophthalic acid), one Cl was substituted by N2H4, generating a new monoacylhydrazide molecule of compound 5. The solid-state photoluminescence analysis revealed that compounds 1 and 5 exhibit strong luminescence with the maximum at 490 nm for 1 and 535 nm for 5, whereas compounds 2 and 3 show weaker emissions with the peaks at 510 nm for 2 and 440 nm for 3. PMID- 24065054 TI - Chronic ethanol consumption decreases serum sulfatide levels by suppressing hepatic cerebroside sulfotransferase expression in mice. AB - Epidemiological studies demonstrate a possible relationship between chronic ethanol drinking and thrombotic diseases, such as myocardial infarction and stroke. However, the precise mechanism for this association remains unclear. Sulfatides are endogenous glycosphingolipids composed of ceramide, galactose, and sulfate, known to have anti-thrombotic properties. Low (0.5 g/kg/day), middle (1.5 g/kg/day), and high (3.0 g/kg/day) doses of ethanol were administered for 21 days intraperitoneally to female wild-type mice, and serum/liver sulfatide levels were measured. No significant changes in cholesterol and triglycerides were seen in serum and liver by ethanol treatment. However, serum/liver sulfatide levels were significantly decreased by middle- and high-dose ethanol treatment, likely due to downregulation of hepatic cerebroside sulfotransferase (CST) levels. Marked decreases in the expression of catalase and superoxide dismutases and ensuing increases in lipid peroxides were also observed in the livers of mice with middle- and high-dose ethanol treatment, suggesting the association between the suppression of hepatic CST expression and enhancement of oxidative stress. Furthermore, serum levels of tissue factor, a typical pro-coagulant molecule, were significantly increased in the mice with middle- and high-dose ethanol treatment showing decreases in serum sulfatide levels. Collectively, these results demonstrate that chronic ethanol consumption reduces serum sulfatide levels by increasing oxidative stress and decreasing the expression of CST in the liver. These findings could provide a mechanism by which chronic ethanol drinking increases thrombotic events. PMID- 24065055 TI - In vitro reactivation kinetics of paraoxon- and DFP-inhibited electric eel AChE using mono- and bis-pyridinium oximes. AB - Oxime-assisted reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) is a crucial step in the post-inhibitory treatment of OP intoxication. The limited efficacy of oxime reactivators for all OP nerve agents and pesticides led to the development of various novel oximes and their thorough kinetic investigations. Hence, in the present investigation, we have tested 10 structurally different pyridinium oxime-based reactivators for their in vitro potency to reactivate paraoxon- and DFP-inhibited electric eel AChE. From structure activity relationship point of view, various oximes such as mono quaternary (2-PAM, K100, K024) and bis-quaternary symmetric (obidoxime, TMB-4) and asymmetric (K027, K048, K203, K618, K628) oximes bearing different connecting linkers (oxybismethylene, trimethylene, propane, butane, butene, and xylene) have been studied. The observed kinetic data demonstrate that not only the position of oxime group is decisive for the increased reactivation ability of oximes, but the role of connecting linker is also significant. Oximes with aliphatic linkers are superior reactivators than the oximes with unsaturated and aromatic linkers. The optimal chain length for plausible reactivation ability for paraoxon- and DFP inhibited AChE is 3 or 4 carbon-carbon connecting linker between prydinium rings. PMID- 24065059 TI - ACC synthase and its cognate E3 ligase are inversely regulated by light. AB - 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS) is the key enzyme in ethylene biosynthesis, catalyzing the conversion of S-adenosylmethionine (AdoMet) to ACC, which is the immediate precursor of ethylene. The regulation of ACS protein stability plays an important role in controlling ethylene biosynthesis. We have recently shown that 14-3-3 positively regulates ACS protein stability by both a direct effect and via downregulation of the stability of the E3 ligases regulating its turnover, Ethylene Overproducer1 (ETO1)/ETO1-like (EOL). Here, we report that treatment of etiolated Arabidopsis seedlings with light rapidly increases the stability of ACS5 protein. In contrast, light destabilizes the ETO1/EOLs proteins, suggesting that light acts to increase ethylene biosynthesis in part through a decrease in the level of the ETO1/EOL proteins. This demonstrates that the ETO1/EOLs are regulated in response to at least one environmental cue and that their regulated degradation may represent a novel input controlling ethylene biosynthesis. PMID- 24065060 TI - Nutritional risk of European elderly. AB - BACKGROUND/OBJECTIVES: The elderly constitute a population group with a high prevalence of non-communicable chronic diseases and high risk of malnutrition. The aim of this study was to identify factors associated to nutritional risk in free-living European elderly. SUBJECTS/METHODS: The sample included 644 European citizens, free living in the community, aged 65 years or more. The sample was quota controlled for age groups (65-74, >=75 years), gender (male/female) and living circumstances (living alone/with others). Logistic regression was performed to identify factors associated with nutritional risk. RESULTS: Several variables regarding socio-demographic characteristics, food choice, health status and the satisfaction with food-related life were included in the analysis. According to the recoded score of the 'Determine your nutritional health' (NSI checklist), 53% of the elderly were at nutritional risk. Nutritional risk was more likely to occur in elderly who considered that it was more important to choose foods 'easy to chew'; with lower average number of fruit and vegetables (F&V) intake episodes and lower score for general health. It was also found in non-married participants; those that did not identify changes in their appetite; and those that felt changes in health status. In this sample, the lowest nutritional risk was found for body mass index (BMI) around 18.5 kg/m(2). Country of residence, gender and age were not found to have a significant effect on nutritional risk. CONCLUSIONS: Attention should be drawn to the living circumstances, changes in appetite or health, the general heath perception, F&V intake, choice of foods easy to chew and having a low or high BMI. PMID- 24065061 TI - The effectiveness of a physical activity and nutrition education program in the prevention of overweight in schoolchildren in Criciuma, Brazil. AB - BACKGROUND/OBJECTIVES: The objectives of this study were to evaluate nutritional status, aptitude and physical activity at the beginning and end of the nutrition education and physical activity intervention program as compared with a control group. METHODS: We conducted a 28-week quasi-experimental study involving 238 students (108 in the intervention group (IG) and 130 in the control group (CG)). The IG participated in curricular and extracurricular activities for nutrition education (50 min once a week) and physical activity (50 min twice a week), and the CG participated only in curricular activities. Nutritional status was determined using body mass index, according to the WHO 2007 curve. The effect of the intervention program was evaluated using a model of generalized estimating equations. RESULTS: Among overweight students, a greater reduction in percentile of BMI was observed in the IG (64.6%) compared with CG (36.4%), P=0.001. Improvement in nutritional status occurred in 26.2% of IG versus 10.4% of CG (P=0.014). The IG showed a significant increase in the amount of moderate or vigorous physical activity (P=0.012), whereas in the control group the increase was not significant (P=0.810). In three physical fitness tests, the IG showed significant improvements in performance (P<0.001), whereas the control group's performance was worse in the final evaluation. CONCLUSIONS: The intervention program had a positive effect on overweight, with significant improvements in nutritional status and physical fitness. PMID- 24065063 TI - What are key factors influencing malnutrition screening in community-dwelling elderly populations by general practitioners? A large cross-sectional survey in two areas of France. AB - BACKGROUND/OBJECTIVES: Malnutrition is associated with a high morbi-mortality in elderly populations and their institutionalization at an early stage. The incidence is well known despite being often under-diagnosed in primary care. General practitioners (GPs) have a key role in home care. What are the factors affecting malnutrition-screening implementation by French GPs? SUBJECTS/METHODS: We conducted a cross-sectional survey in two areas in the southeast of France (Savoie and Isere). In May 2008, an anonymized survey was sent by e-mail and/or post to all GPs with a large clinical practice. Two months later, reminder letters were sent. Potential barriers were measured by dichotomous scale. On GPs' characteristics (socio-demographic, medical training, geriatric practice and knowledge), multiple regression logistic was performed to identify others factors affecting malnutrition screening. RESULTS: In all, 493 GPs (26.85%) answered and 72.2% felt that malnutrition screening was useful although only 26.6% implemented it each year and 11.9% every 2-5 years. The main barriers to the implementation were patient selection (60.4%) and forgetting to screen (26.6%). Minor barriers were lack of knowledge (19.5%) or time (15%). New factors were identified: unsuitable working conditions (19.1%), insufficient motivation (6.8%) or technical support (7.2%). The quality of malnutrition information received was found to be the only promoter of annual screening (odds ratio=1.44 (1.087-1.919); P=0.011). CONCLUSIONS: This survey is the first in France to reveal GPs' factors affecting malnutrition implementation. New obstacles were identified in this survey. The hope of implementing regular malnutrition screening by GPs seems to lie with the quality of malnutrition information received. PMID- 24065062 TI - Diagnosis of gastroesophageal reflux and anti-reflux procedures among Polish children with gastrostomies: a 10-year nationwide analysis. AB - BACKGROUND/OBJECTIVES: To analyse the approach to diagnose gastroesophageal reflux (GER) and the qualification criteria for anti-reflux (AR) procedures in Polish children fed via gastrostomy between 2000 and 2010. SUBJECTS/METHODS: An electronic questionnaire containing questions on the demographic and clinical data of patients with gastrostomies was distributed to six Polish centres of nutritional therapy. The portion pertaining to GER included data on clinical exponents, diagnostic procedures (pH-metry, pH-impedance, scintigraphy and upper gastrointestinal (GI) series) and AR. RESULTS: In total, 348 children (M199/F149; age at gastrostomy 5.78+/-5.49 years) were included. Data on the diagnosis of GER and the AR criteria were available for 343 and 336 subjects, respectively. Percutaneous endoscopic gastrostomy was performed in 258/348 patients (74.1%), while surgery was performed in 80/348 patients (23%). The data from 10/348 (2.9%) cases were unavailable. At least one of the tests for GER was conducted in 177/343 (51.6%) of patients: pH-metry in 74/343 (21.6%), pH-impedance in 17/343 (5.0%), scintigraphy in 60/343 (17.5%) and upper GI series in 102/343 (29.7%). GER was reported in 114/343 cases (33.2%), and fundoplication was performed in 87 children (76.3% of patients with GER). The highest congruence between a positive test result and the decision to perform fundoplication was documented in cases of scintigraphy and upper GI series (P=0.00000 and P=0.00191, respectively). A significant increase in the prevalence of simultaneous gastrostomy and AR was observed over the decade analysed (r=0.8, P=0.009). This study revealed a centre specific attitude towards the diagnosis of GER and the assessment of qualifications for fundoplication in Polish gastrostomy-fed children. CONCLUSIONS: The unified diagnostic algorithm of GER and the universal qualification criteria for AR procedures need to be defined for gastrostomy-fed children. PMID- 24065064 TI - Response to cameron et al. PMID- 24065065 TI - Effects of the menopausal transition on dietary intake and appetite: a MONET Group Study. AB - BACKGROUND/OBJECTIVE: The purpose of this study was to investigate changes in dietary intake and appetite across the menopausal transition. SUBJECTS/METHODS: This was a 5-year observational, longitudinal study on the menopausal transition. The study included 94 premenopausal women at baseline (age: 49.9+/-1.9 years; BMI: 23.3+/-2.3 kg/m2). Body composition (dual-energy X-ray absorptiometry), appetite (visual analogue scale), eating frequency, energy intake (EI) and macronutrient composition (7-day food diary and buffet-type meal) were measured annually. RESULTS: Repeated-measures analyses revealed that total EI and carbohydrate intake from food diary decreased significantly over time in women who became postmenopausal by year 5 (P>0.05) compared with women in the menopausal transition. In women who became postmenopausal by year 5, fat and protein intakes decreased across the menopausal transition (0.05>P<0.01). Although a decrease in % fat intake was observed during the menopausal transition (P<0.05), this variable was significantly increased in the postmenopausal years (P<0.05). Spontaneous EI and protein intake also declined over time and were higher in the years preceding menopause onset (P<0.05). Desire to eat, hunger and prospective food consumption increased during the menopausal transition and remained at this higher level in the postmenopausal years (0.05>P<0.001). Fasting fullness decreased across the menopausal transition (P<0.05). CONCLUSION: These results suggest that menopausal transition is accompanied with a decrease in food intake and an increase in appetite. PMID- 24065066 TI - Lower dietary vitamin E intake during the second trimester is associated with insulin resistance and hyperglycemia later in pregnancy. AB - BACKGROUND/OBJECTIVES: Beneficial effects of vitamin E on insulin sensitivity have been reported in observational and short-term intervention studies in non pregnant populations. We aimed to investigate whether dietary vitamin E intake during the second trimester would be associated with glucose metabolism later in pregnancy and whether this association would be influenced by an insulin sensitizing hormone adiponectin. SUBJECTS/METHODS: Women with singleton pregnancies (n=205) underwent a 3-h oral glucose tolerance test at 30 weeks gestation and were asked to recall second trimester dietary intake. RESULTS: Higher dietary vitamin E intake was associated with lower fasting glucose, lower HOMA insulin resistance, and higher Matsuda insulin sensitivity index after covariate adjustment including serum adiponectin among women consuming daily multivitamin supplements (all P<=0.03). CONCLUSIONS: Lower dietary vitamin E intake during the second trimester is associated with hyperglycemia and insulin resistance later in pregnancy among women consuming daily multivitamin supplementations. Further, these associations are not influenced by adiponectin. PMID- 24065067 TI - Factors influencing thyroid volume in Chinese children. AB - BACKGROUND/OBJECTIVES: This paper aims to compare children's thyroid volume (Tvol) by age and gender in Zhejiang province in order to explore the factors influencing Tvol in this area. SUBJECTS/METHODS: This survey was a cross sectional survey of a provincial representative sample of Zhejiang province children aged 6-12 years. The children were asked to provide a urine sample for the determination of urinary iodine concentration (UIC) and thyroid ultrasonography was performed for the determination of Tvol. RESULTS: The median (25th, 75th percentile) of UIC in children aged 6-12 years in Zhejiang province was found to be 170.0(111.2, 244.4) MUg/l. The median (25th, 75th percentile) of Tvols was found to be 3.1(2.3, 4.2) ml. There were significant differences among the different age groups on BSA (Z=-17.911, P=0.000) and Tvol (Z=-1.996, P=0.046) but not on UIC and body mass index (P>0.05). Tvol was in significant association with BSA (P=0.000) but was not associated with UIC (P>0.05). Age, gender and BSA were significant in multiple linear regression (P<0.05). CONCLUSIONS: The median UIC of children aged 6-12 years falls in the optimal iodine status as recommended by WHO/UNICEF/ICCIDD. However, urinary iodine nutritional status had little effect on the Tvol in children aged 6-12 years in Zhejiang province. Age, gender and BSA were the influencing factors of Tvol. PMID- 24065068 TI - Comment on 'General and abdominal obesity parameters and their combination in relation to mortality: a systematic review and meta-regression analysis'. PMID- 24065069 TI - CD39/CD73 and the imbalance of Th17 cells and regulatory T cells in allergic asthma. AB - In the immune system, CD4+CD25+Foxp3+ regulatory T cells (Tregs) maintain self tolerance and Th17 cells mediate inflammatory responses. CD39 is expressed on the surface of a subset of naturally occurring human Tregs that are important in constraining pathogenic Th17 cells. Additional studies have shown that Tregs differentiate into interleukin-17 (IL-17)+Foxp3+ T cells. Our previous study indicated an imbalance of Th17 and Tregs in allergic asthma; however, the underlying mechanisms remain poorly understood. Using quantitative PCR (qPCR), CD39 and CD73 mRNA levels in CD4+ T cells were investigated. Flow cytometry was used to analyze the proportion of IL-17+Foxp3+ T cells, and CD39 and CD73 expressed by CD4+ T cells and Tregs in the peripheral blood of the subjects. The results of the present study demonstrated an increased frequency of CD4+Foxp3+IL 17+ T cells in moderate to severe asthma. A deficiency in CD39 expressed on the surface of CD4+ T cells and Tregs was observed in asthma patients. The expression of CD39 and CD73 on the surface of CD4+ T cells and Tregs was negatively correlated with the number of Th17 cells. These results indicated that the plasticity of Tregs transforming to IL-17+Foxp3+CD4+ T cells, the reduced frequency of CD39+ Tregs and less effective suppression of IL-17 production by residual CD39+ Tregs leads to an imbalance of Th17 and Tregs in asthma. Therefore, enhanced CD39 activity is hypothesized to prevent the progression of asthma. PMID- 24065071 TI - B-DNA characteristics are preserved in double stranded d(A)3.d(T)3 and d(G)3.d(C)3 mini-helixes: conclusions from DFT/M06-2X study. AB - We report the results of the first comprehensive DFT study on the d(A)3.d(T)3 and d(G)3.d(C)3 nucleic acid duplexes. The ability of mini-helixes to preserve the conformation of B-DNA in the gas phase and under the influence of such factors as: solvent, uncompensated charge, and counter-ions was evaluated using M06-2X functional with 6-31G(d,p) basis set. The accuracy of the models was ascertained based on their ability to reproduce key structural features of natural B-DNA. Analysis of the helicity suggests that the helical conformations adopt geometrical parameters which are close to those of the B-DNA form. The torsion angles fall somewhere between the values observed for BI/BII conformational classes. The comparative analysis of parameters of isolated Watson-Crick base pairs versus B-DNA-like conformations indicates the same tendency of base-pair polarization and hydration. Specifically, effects of polarization of nucleobases in continuum type dielectric medium mimicking water are stronger than those caused by the presence of backbone. Polar environment as well as the presence of counterions stabilizes duplexes, facilitating helix formation. Substantial conformational changes of nucleotides upon duplex formation decrease the binding energy. In spite of structural and energetic changes, the placement of a mini helix into the gas phase does not lead to significant disruption of the structure. On the contrary, the duplex preserves its helicity and the strands remain bound. PMID- 24065070 TI - Female patients with late-onset legg-calve-perthes disease are frequently gymnasts: is there a mechanical etiology for this subset of patients? AB - BACKGROUND: The cause of Legg-Calve-Perthes disease (LCPD) is unknown. We have observed a relatively high prevalence of female gymnasts presenting with LCPD. The purpose of this study was to determine: (1) the percentage of LCPD patients exposed to high-level gymnastics training, (2) the demographics of this subset of patients, and (3) their clinical outcomes. METHODS: Several adolescent female gymnasts presented to our clinic with recent-onset LCPD. We reviewed our cases to discern the prevalence and treatment of the disorder in this patient cohort. From 1999 to 2010, 572 patients were evaluated for a diagnosis of LCPD at our tertiary referral center. Clinical records were retrospectively reviewed. Of those, 13 patients had a history of gymnastics participation with 8 patients (all females) having competitive participation. RESULTS: For females aged 10 years and older presenting with LCPD, 7 of 9 patients (78%) were involved in high-level competitive gymnastics. These patients had disease onset between 10 and 12 years of age (mean, 11 y). Competitive gymnasts represented 6.6% (8 of 120) of females with LCPD and 1.4% (8 of 572) of all patients evaluated with LCPD during the study period. Only 1 of 111 females below 10 years with LCPD participated in competitive gymnastics (chi, P<0.0001).Patients underwent a variety of treatments. Two patients underwent nonoperative treatment, and the remainder underwent surgical management. All 7 gymnasts had a Stulberg IV result. In the nongymnast group of females 10 years and older, there were 1 Stulberg III result and 1 Stulberg IV result. CONCLUSIONS: At our center, competitive gymnasts comprise >75% of the female patients over the age of 10 who presented with late onset LCPD. Results in general were poor. Further studies are needed to explore the association between the physical demands of advanced gymnastic training and the development of LCPD in this subset of patients. LEVEL OF EVIDENCE: IV, case series. PMID- 24065072 TI - Electric field-controlled rippling of graphene. AB - Metal-graphene interfaces generated by electrode deposition induce barriers or potential modulations influencing the electronic transport properties of graphene based devices. However, their impact on the local mechanical properties of graphene is much less studied. Here we show that graphene near a metallic interface can exhibit a set of ripples self-organized into domains whose topographic roughness is controlled by the tip bias of a scanning tunneling microscope. The reconstruction from topographic images of graphene bending energy maps sheds light on the local electro-mechanical response of graphene under STM imaging and unveils the role of the stress induced by the vicinity of the graphene-metal interface in the formation and the manipulation of these ripples. Since microscopic rippling is one of the important factors that limit charge carrier mobility in graphene, the control of rippling with a gate voltage may have important consequences in the conductance of graphene devices where transverse electric fields are created by contactless suspended gate electrodes. This opens up also the possibility to dynamically control the local morphology of graphene nanomembranes. PMID- 24065073 TI - Super liquid-repellent gas membranes for carbon dioxide capture and heart-lung machines. AB - In a gas membrane, gas is transferred between a liquid and a gas through a microporous membrane. The main challenge is to achieve a high gas transfer while preventing wetting and clogging. With respect to the oxygenation of blood, haemocompatibility is also required. Here we coat macroporous meshes with a superamphiphobic-or liquid repellent-layer to meet this challenge. The superamphiphobic layer consists of a fractal-like network of fluorinated silicon oxide nanospheres; gas trapped between the nanospheres keeps the liquid from contacting the wall of the membrane. We demonstrate the capabilities of the membrane by capturing carbon dioxide gas into a basic aqueous solution and in addition use it to oxygenate blood. Usually, blood tends to clog membranes because of the abundance of blood cells, platelets, proteins and lipids. We show that human blood stored in a superamphiphobic well for 24 h can be poured off without leaving cells or adsorbed protein behind. PMID- 24065074 TI - Synthesis of beta-diketiminate-ligated bimetallic and monometallic lanthanide amide complexes and their reactivity with isoprene and AlMe3. AB - The amine elimination of lanthanide tris(amide) complexes with the phenylene bridged bis(beta-diketiminate) ligands PARA(Me)-H2, META(Me)-H2 and PARA(Pr)-H2 (PARA(Me)-H2 = 2[2,6-Me2C6H3NHC(Me)C(H)C(Me)N]-(para-phenylene), META(Me)-H2 = 2[2,6-Me2C6H3NHC(Me)C(H)C(Me)N]-(meta-phenylene), PARA(Pr)-H2 = 2[2,6 (i)Pr2C6H3NHC(Me)C(H)C(Me)N]-(para-phenylene)), and the mono-beta-diketiminate ligand L(2,6-iPr2)Ph-H (2,6-(i)Pr2C6H3)NHC(Me)CHC(Me)N(C6H5)) afforded the bimetallic lanthanide amide complexes PARA(Me)-{Ln[N(SiMe3)2]2}2 (Ln = Y (1), Sm (2)), META(Me)-{Y[N(SiMe3)2]2}2 (3), PARA(Pr)-{Ln[N(HSiMe2)2]2}2 (Ln = Y (4), Sm (5)), and the monomeric complexes L(2,6-iPr2)Ph-Y[N(SiMe3)2]2 (6) and L(2,6 iPr2)Ph-Y[N(HSiMe2)2]2 (7). In the presence of AlR3 and on activation with 1 equiv. of [Ph3C][B(C6F5)4], complexes 1-7 showed a high activity toward the 1,4 selective polymerization of isoprene. The heterometallic Y/Al methyl complex [L(2,6-iPr2)Ph]Y[(MU-Me)2AlMe2]2 (8) was prepared to elucidate the real active precursor in the polymerization. PMID- 24065075 TI - Body composition for health and performance: a survey of body composition assessment practice carried out by the Ad Hoc Research Working Group on Body Composition, Health and Performance under the auspices of the IOC Medical Commission. AB - BACKGROUND: Successful performers in weight-sensitive sports are characterised by low body mass (BM) and fat content. This often requires chronic energy restriction and acute weight loss practices. AIM: To evaluate current use of body composition (BC) assessment methods and identify problems and solutions with current BC approaches. METHODS: A 40-item survey was developed, including demographic and content questions related to BC assessment. The survey was electronically distributed among international sporting organisations. Frequencies and chi(2) analyses were computed. RESULTS: 216 responses were received, from 33 countries, representing various institutions, sports and competitive levels. Of the sample, 86% of respondents currently assess BC, most frequently using skinfolds (International Society for the Advancement of Kinanthropometry (ISAK): 50%; non-ISAK, conventional: 40%; both: 28%), dual energy X-ray absorptiometry (38%), bioelectrical impedance (29%), air displacement plethysmography (17%) and hydrostatic weighing (10%). Of those using skinfolds, more at the international level used ISAK, whereas conventional approaches were more reported at regional/national level (p=0.006). The sport dietitian/nutritionist (57%) and physiologist/sports scientist (54%) were most frequently the professionals assessing BC, followed by MDs and athletic trainers, with some reporting coaches (5%). 36% of 116 respondents assessed hydration status and more (64%) did so at international than regional/national level (36%, p=0.028). Of 125 participants answering the question of whether they thought that BC assessment raised problems, 69% said 'yes', with most providing ideas for solutions. CONCLUSIONS: Results show high use of BC assessment but also a lack of standardisation and widespread perception of problems related to BM and BC in sport. Future work should emphasise standardisation with appropriate training opportunities and more research on BC and performance. PMID- 24065076 TI - Arne Ljungqvist: the great fighter against doping. PMID- 24065077 TI - How BJSM embraces the power of social media to disseminate research. PMID- 24065078 TI - Is surgery effective for deep posterior compartment syndrome of the leg? A systematic review. AB - BACKGROUND: Results of surgery for lower leg deep posterior chronic exertional compartment syndrome (dp-CECS) are inferior compared to other types of CECS. Factors influencing suboptimal surgical results are unknown. The purpose of this systematic review was to provide a critical analysis of the existing literature on the surgical management of dp-CECS aimed at identifying parameters determining surgical results. METHODS: A literature search was performed using Pubmed, EMBASE, MEDLINE and CINAHL (EBSCO). Studies including surgical results for dp CECS were systematically reviewed. RESULTS: 7 studies of level III evidence reporting on a total of 131 patients met inclusion criteria (>5 patients, reporting intracompartmental pressures (ICP), clearly stating postoperative outcome). Only four studies strictly adhered to predefined ICP criteria. Cutoff ICP levels varied widely among the 7 studies. Surgical procedures ranged from a superficial crural fasciotomy to multiple fasciotomies of various deep posterior compartments. No single surgical procedure proved superior. Prolonged high ICP levels following provocation were associated with postoperative success. Success rates after fasciotomy were modest ranging from 30% to 65%. Risk factors for failure of surgery were not identified. CONCLUSIONS: The quality of studies reporting on surgery for dp-CECS is poor. Prospective, controlled or randomised studies are lacking. Diagnostic criteria and surgical techniques are diverse. As functional results of current management regimes are disappointing, future studies of dp-CECS should focus on optimising diagnostic criteria and standardisation of treatment modalities. PMID- 24065079 TI - Determination of the prevalence of Helicobacter heilmannii-like organisms type 2 (HHLO-2) infection in humans and dogs using non-invasive genus/species-specific PCR in Korea. AB - Helicobacter spp. may have multiple routes of transmission. It is unclear, however, whether the agent is zoonotic and therefore transmitted from an animal reservoir, including dogs. The aim of this population-based study was to assess the relationship between pet ownership or frequent exposure to dogs and Helicobacter spp. infection, especially focusing on HHLO-2 (Helicobacter heilmannii-like organisms type 2) in saliva and feces samples in Korea, using non invasive genus/species-specific PCR. One hundred twenty-four eligible human subjects and 39 dogs participated in this study. Relativity of contact with dogs and Helicobacter spp. infection diagnosed by genus-specific PCR showed a statistically significant result (P<0.01), but in the relativity analyses between contact with dogs and H. pylori, H. felis and H. bizzozeronii infections diagnosed using species-specific PCR, only Helicobacter felis showed a statistically significant result. Although H. pylori infection showed a statistically significant relativity, no statistically significant association was found between veterinarian subjects and Helicobacter. spp., H. felis and H. bizzozeronii infections. On performing risk factor analyses of HHLO-2 infection by transmission, using matching species, between HHLO-2-positive dog owners and HHLO-2-positive dogs, Helicobacter felis infection showed an extremely significant relativity (P<0.0001), and Helicobacter bizzozeronii may also be a possible significant risk factor (P<0.01). These results suggest that HHLO-2 infection might be a zoonotic infection, because continuous contact with dogs was proved to be correlated with human H. felis and H. bizzozeronii infections in this study. PMID- 24065080 TI - Erythrophagocytosis enhances heme-dependent cytotoxicity of antimalarial drugs in canine histiocytic sarcoma cell line DH82. AB - Antimalarial drugs, dihydroartemisinin (DHA) and artesunate (ATS), exhibit iron dependent cytotoxicity in tumor cells. We hypothesized that erythrophagocytic uptake of heme-iron enhances the cytotoxicity of DHA and ATS. Erythrophagocytic (EP) treatment of the canine histiocytic sarcoma cell line DH82 markedly increased the cytotoxicity of DHA and ATS compared to controls. Succinyl acetone, an inhibitor of intracellular heme synthesis, decreased the cytotoxicity of DHA and ATS in normal cells, but this change was not observed in EP cells. These results suggest that exogenous heme derived from erythrocytes can enhance the cytotoxicity of DHA and ATS. Furthermore, our study suggests that heme could be a novel component of tumor treatment in veterinary medicine. PMID- 24065081 TI - Nested PCR detection and phylogenetic analysis of Babesia bovis and Babesia bigemina in cattle from Peri-urban localities in Gauteng Province, South Africa. AB - Babesia bovis and Babesia bigemina are tick-borne hemoparasites causing babesiosis in cattle worldwide. This study was aimed at providing information about the occurrence and geographical distribution of B. bovis and B. bigemina species in cattle from Gauteng province, South Africa. A total of 268 blood samples collected from apparently healthy animals in 14 different peri-urban localities were tested using previously established nested PCR assays for the detection of B. bovis and B. bigemina species-specific genes encoding rhoptry associated protein 1 (RAP-1) and SpeI-AvaI restriction fragment, respectively. Nested PCR assays revealed that the overall prevalence was 35.5% (95% confidence interval [CI]=+/- 5.73) and 76.1% (95% CI=+/- 5.11) for B. bovis and B. bigemina, respectively. PCR results were corroborated by sequencing amplicons of randomly selected samples. The neighbor-joining trees were constructed to study the phylogenetic relationship between B. bovis and B. bigemina sequences of randomly selected isolates. Analysis of phylogram inferred with B. bovis RAP-1 sequences indicated a close relationship between our isolates and GenBank strains. On the other hand, a tree constructed with B. bigemina gp45 sequences revealed a high degree of polymorphism among the B. bigemina isolates investigated in this study. Taken together, the results presented in this work indicate the high incidence of Babesia parasites in cattle from previously uncharacterised peri-urban areas of the Gauteng province. These findings suggest that effective preventative and control measures are essential to curtail the spread of Babesia infections among cattle populations in Gauteng. PMID- 24065082 TI - Functional and morphological variety in trunk muscles of Urodela. AB - Trunk musculature in Urodela species varies by habitat. In this study, trunk musculature was examined in five species of adult salamanders representing three different habitats: aquatic species, Amphiuma tridactylum and Necturus maculosus; semi-aquatic species, Cynops pyrrhogaster; terrestrial species, Hynobius nigrescens and Ambystoma tigrinum. More terrestrial species have heavier dorsal and ventral trunk muscles than more aquatic forms. By contrast, the lateral hypaxial musculature was stronger in more aquatic species. The number of layers of lateral hypaxial musculature varied among Urodela species and did not clearly correlate with their habitats. The M. rectus abdominis was separated from the lateral hypaxial musculature in both terrestrial and semi-aquatic species. In aquatic species, M. rectus abdominis was not separated from lateral hypaxial musculature. Lateral hypaxial musculature differed in thickness among species and was relatively thinner in terrestrial species. In more terrestrial species, dorsal muscles may be used for stabilization and ventral flexing against gravity. Ventral muscle may be used in preventing dorsally concave curvature of the trunk by dorsal muscles and by weight. The lengthy trunk supported by limbs needs muscular forces along the ventral contour line in more terrestrial species. And, the locomotion on well-developed limbs seems to lead to a decrease of the lateral hypaxial musculature. PMID- 24065083 TI - Development of an ELISA using a recombinant P46-like lipoprotein for diagnosis of Mycoplasma pulmonis infection in rodents. AB - Mycoplasma pulmonis is one of the most prevalent bacterial pathogens that infects laboratory mice and rats. To develop an M. pulmonis-specific antigen for serological diagnosis, we cloned the cDNA of P46-like lipoprotein (P46L), an M. pulmonis putative periplasmic protein. P46L is a homolog of P46, an M. hyopneumoniae antigen. We produced recombinant P46L fused to glutathione S transferase (GST) in Escherichia coli. Immunoblot analysis revealed that sera from Mycoplasma-infected mice and rats contained anti-P46L antibodies. We developed an ELISA using the recombinant P46L-GST protein as an antigen. Thirteen of the 14 samples from rats naturally infected with M. pulmonis were determined to be positive according to the commercial ELISA (MONILISA Myco) and positive by our ELISA. Furthermore, 18/19 samples from mice experimentally infected with M. pulmonis were positive using our P46L-GST ELISA. In contrast, only 8/19 samples from infected mice were positive by the commercial ELISA. Our results indicate that P46L-GST was an appropriate antigen for developing a serological test to determine M. pulmonis infection in laboratory mice and rats. PMID- 24065085 TI - Detection and confirmation of Mycobacterium avium subsp. paratuberculosis in direct quantitative PCR positive fecal samples by the manual fluorescent MGIT culture system. AB - An efficient protocol for the manual fluorescent MGIT culture system combined with rapid confirmation of Mycobacterium avium subsp. paratuberculosis (MAP) growth in the broth culture was established and evaluated for the detection of viable MAP in direct quantitative PCR (QPCR) positive bovine feces. Manually detected fluorescence emissions from MGIT tubes were analyzed objectively using an open source software, ImageJ. For molecular confirmation of MAP growth, DNA samples harvested by simply boiling the broth, an inexpensive and time- and labor saving DNA preparation method, yielded adequate results. The sheep strain of MAP required longer incubation time relative to the cattle strain, suggesting that the MGIT system may not support well the growth of ovine isolates as described previously. Of 61 direct QPCR positive bovine feces, the recovery rate of MAP in the MGIT system (62.3%) was significantly higher (P<0.05) than that using 7H10 agar-based slants (44.3%). The time to obtain a final result for fecal culture by the MGIT system was several weeks earlier compared to solid media. In MGIT culture positive samples, the time to detect fluorescence was correlated with the DNA quantity detected in fecal QPCR. As a positive result in the direct fecal QPCR test does not mean fecal excretion of viable MAP, bacterial isolation by fecal culture could be conducted to verify the QPCR result. For this purpose, the manual MGIT system is a sensitive and rapid culture method at least for bovine samples. PMID- 24065084 TI - Induction of beige-like adipocytes in 3T3-L1 cells. AB - There are two types of brown adipocytes: classical brown adipocytes that form the brown fat depots and beige adipocytes that emerge in the white fat depots. Beige adipocytes have a low level of uncoupling protein 1 (Ucp1) expression in the basal state, but Ucp1 expression is increased in response to beta adrenergic receptor activation. The present study explored the factors responsible for the differentiation of 3T3-L1 white preadipocytes to beige adipocytes. Significant expression of Ucp1 was not detected under any tested conditions in the absence of isoproterenol (Iso), an agonist of beta adrenergic receptor. Iso-induced Ucp1 expression was significantly higher in the cells treated with a mixture of triiodothyronine (T3) and 3-isobutyl-1-methylxanthine (IBMX) for days 0-8 than in the control cells. Chronic IBMX treatment was indispensable for the enhanced Iso induced Ucp1 expression, and treatment with additional rosiglitazone (Rosi) for days 0-8 further increased the Ucp1 expression. Recently, genes were identified that are predominantly expressed in beige adipocytes, which were induced from stromal vascular cells in white fat depots. However, the expression levels of the beige adipocyte-selective genes in the adipocytes induced by the mixture of T3, IBMX and Rosi did not differ from those in the control adipocytes. The present study indicates that 3T3-L1 cells can differentiate to beige-like adipocytes by prolonged treatment with the mixture of T3, IBMX and Rosi and that the gene expression profile of the adipocytes is distinct from those previously induced from white fat depots. PMID- 24065086 TI - Correlation and prognostic value of osteopontin and Bcl-2 in hepatocellular carcinoma patients after curative resection. AB - Osteopontin (OPN) may facilitate tumorigenesis and metastasis through prevention of tumor cells from apoptosis. Although previous studies have suggested involvement of enhanced Bcl-2 protein family expression, the role of OPN together with Bcl-2 in hepatocellular carcinoma (HCC) remains unknown. In this study, we used western blotting to detect the OPN and Bcl-2 expression levels in cell lines with different OPN backgrounds and HCC tissues, and tumor tissue microarrays to examine OPN and Bcl-2 expression levels in 454 HCC cases. The Kaplan-Meier method and log-rank test were applied to investigate the predictive values of OPN and Bcl-2 in HCC patients. In vitro assays indicated that OPN expression increased concordantly with increasing metastatic potential in MHCC97-H, MHCC97-L, HepG2 and SMMC-7721 cell lines by western blotting, whereas Bcl-2 expression declined. In addition, Bcl-2 was highly upregulated in OPN knockdown MHCC97-H cell lines. Furthermore, in HCC tissues, it was confirmed that OPN levels were also significantly higher in recurrent tumor tissues compared to non-recurrent tissues by western blotting (p<0.001), whereas the contrary occurred in Bcl-2 (p=0.046). Using immunohistochemistry analysis, patients with higher OPN levels had significantly shorter median survival time and recurrence time compared to the lower ones, although the opposite occurred in Bcl-2 levels. Of note, when OPN and Bcl-2 were combined, we found that the co-index of OPN/Bcl-2 was an independent prognostic factor for both overall survival (p<0.001) and time to recurrence (p<0.001). Our findings demonstrate that OPN/Bcl-2 expression is a promising independent predictor of recurrence and survival in HCC. Additionally, Bcl-2 levels may be regulated by OPN in the HCC microenvironment. PMID- 24065087 TI - Characterization of anticonvulsant and antiepileptogenic potential of thymol in various experimental models. AB - The present study was to investigate the anticonvulsant and antiepileptogenic potential of thymol. Anticonvulsant activity of thymol (5-100 mg/kg i.p.) was studied using maximal electroshock, pentylenetetrazole (PTZ), strychnine and 4 aminopyridine (4-AP) models. Thymol at the selected dose was also studied for its effect on locomotion. Antiepileptogenic property of thymol (5-25 mg/kg) was evaluated using PTZ-induced kindling model along with its effect on malondialdehyde and glutathione levels. Thymol (50 and 100 mg/kg, i.p.) showed anticonvulsant activity against maximal electroshock and pentylenetetrazole (66.66 and 83.33 % protection at 50 and 100 mg/kg, respectively) model but not against strychnine and 4-aminopyridine models. Thymol exhibited decreased locomotor activity in dose-dependent manner at the same dose range. Thymol at the dose of (25 mg/kg, i.p.) significantly decreased the seizure score, increased glutathione levels and decreased malondialdehyde levels in pentylenetetrazole induced kindling model. Thymol exhibited significant anticonvulsant and antiepileptogenic property. PMID- 24065088 TI - The transcription activation and homodimerization of Lotus japonicus Nod factor Signaling Pathway2 protein. AB - The legume-rhizobia symbioses lead to the formation of a novel adaptive complex organ, termed the root nodule, which arises from cortical cell division and rhizobial infection in the root. Lipochitin oligosaccarides, Nod-Factors (NFs) secreted by rhizobia, are responsible for the onset of nodule development. Here we describe the characterization of Lotus japonicas, Nod factor Signaling Pathway2 (LjNSP2) protein that belongs to the plant GRAS family of transcription factors. Yeast two-hybrid analysis indicates that LjNSP2 alone has a transcription-stimulating ability and for this the SH2(src-homology2)-like domain, vital for function of STAT proteins is required. The ADG4 (the activation domain of GAL4)-LjNSP2 fusion coupled with BDG4 (the DNA binding domain of GAL4) LjNSP2 increased the expression level, whereas the ADG4-Ljnsp2-1 mutant fusion did not, indicating that LjNSP2 interacts with itself to form a homodimer and this depends on the SH2-like domain. Based on the evidence, we discuss the action of LjNSP2, compared with that of the family of animal-specific STAT transcription factors, which induce developmental programmes in response to external stimuli. PMID- 24065090 TI - The characterisation of pluripotent and multipotent stem cells using Fourier transform infrared microspectroscopy. AB - Fourier transform infrared (FTIR) microspectroscopy shows potential as a benign, objective and rapid tool to screen pluripotent and multipotent stem cells for clinical use. It offers a new experimental approach that provides a holistic measurement of macromolecular composition such that a signature representing the internal cellular phenotype is obtained. The use of this technique therefore contributes information that is complementary to that acquired by conventional genetic and immunohistochemical methods. PMID- 24065092 TI - Materials characterization of Feraheme/ferumoxytol and preliminary evaluation of its potential for magnetic fluid hyperthermia. AB - Feraheme, is a recently FDA-cleared superparamagnetic iron oxide nanoparticle (SPION)-based MRI contrast agent that is also employed in the treatment of iron deficiency anemia. Feraheme nanoparticles have a hydrodynamic diameter of 30 nm and consist of iron oxide crystallites complexed with a low molecular weight, semi-synthetic carbohydrate. These features are attractive for other potential biomedical applications such as magnetic fluid hyperthermia (MFH), since the carboxylated polymer coating affords functionalization of the particle surface and the size allows for accumulation in highly vascularized tumors via the enhanced permeability and retention effect. This work presents morphological and magnetic characterization of Feraheme by transmission electron microscopy (TEM), Energy dispersive X-ray spectroscopy (EDX), and superconducting quantum interference device (SQUID) magnetometry. Additionally, the results of an initial evaluation of the suitability of Feraheme for MFH applications are described, and the data indicate the particles possess promising properties for this application. PMID- 24065091 TI - Quorum quenching enzymes and their application in degrading signal molecules to block quorum sensing-dependent infection. AB - With the emergence of antibiotic-resistant strains of bacteria, the available options for treating bacterial infections have become very limited, and the search for a novel general antibacterial therapy has received much greater attention. Quorum quenching can be used to control disease in a quorum sensing system by triggering the pathogenic phenotype. The interference with the quorum sensing system by the quorum quenching enzyme is a potential strategy for replacing traditional antibiotics because the quorum quenching strategy does not aim to kill the pathogen or limit cell growth but to shut down the expression of the pathogenic gene. Quorum quenching enzymes have been identified in quorum sensing and non-quorum sensing microbes, including lactonase, acylase, oxidoreductase and paraoxonase. Lactonase is widely conserved in a range of bacterial species and has variable substrate spectra. The existence of quorum quenching enzymes in the quorum sensing microbes can attenuate their quorum sensing, leading to blocking unnecessary gene expression and pathogenic phenotypes. In this review, we discuss the physiological function of quorum quenching enzymes in bacterial infection and elucidate the enzymatic protection in quorum sensing systems for host diseases and their application in resistance against microbial diseases. PMID- 24065093 TI - Oleic acid increases synthesis and secretion of VEGF in rat vascular smooth muscle cells: role of oxidative stress and impairment in obesity. AB - Obesity is characterized by poor collateral vessel formation, a process involving vascular endothelial growth factor (VEGF) action on vascular smooth muscle cells (VSMC). Free fatty acids are involved in the pathogenesis of obesity vascular complications, and we have aimed to clarify whether oleic acid (OA) enhances VEGF synthesis/secretion in VSMC, and whether this effect is impaired in obesity. In cultured aortic VSMC from lean and obese Zucker rats (LZR and OZR, respectively) we measured the influence of OA on VEGF-A synthesis/secretion, signaling molecules and reactive oxygen species (ROS). In VSMC from LZR we found the following: (a) OA increases VEGF-A synthesis/secretion by a mechanism blunted by inhibitors of Akt, mTOR, ERK-1/2, PKC-beta, NADPH-oxidase and mitochondrial electron transport chain complex; (b) OA activates the above mentioned signaling pathways and increases ROS; (c) OA-induced activation of PKC-beta enhances oxidative stress, which activates signaling pathways responsible for the increased VEGF synthesis/secretion. In VSMC from OZR, which present enhanced baseline oxidative stress, the above mentioned actions of OA on VEGF-A, signaling pathways and ROS are impaired: this impairment is reproduced in VSMC from LZR by incubation with hydrogen peroxide. Thus, in OZR chronically elevated oxidative stress causes a resistance to the action on VEGF that OA exerts in LZR by increasing ROS. PMID- 24065094 TI - Spectroscopic studies of model photo-receptors: validation of a nanosecond time resolved micro-spectrophotometer design using photoactive yellow protein and alpha-phycoerythrocyanin. AB - Time-resolved spectroscopic experiments have been performed with protein in solution and in crystalline form using a newly designed microspectrophotometer. The time-resolution of these experiments can be as good as two nanoseconds (ns), which is the minimal response time of the image intensifier used. With the current setup, the effective time-resolution is about seven ns, determined mainly by the pulse duration of the nanosecond laser. The amount of protein required is small, on the order of 100 nanograms. Bleaching, which is an undesirable effect common to photoreceptor proteins, is minimized by using a millisecond shutter to avoid extensive exposure to the probing light. We investigate two model photoreceptors, photoactive yellow protein (PYP), and alpha-phycoerythrocyanin (alpha-PEC), on different time scales and at different temperatures. Relaxation times obtained from kinetic time-series of difference absorption spectra collected from PYP are consistent with previous results. The comparison with these results validates the capability of this spectrophotometer to deliver high quality time-resolved absorption spectra. PMID- 24065095 TI - Potential of the angiotensin receptor blockers (ARBs) telmisartan, irbesartan, and candesartan for inhibiting the HMGB1/RAGE axis in prevention and acute treatment of stroke. AB - Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs. PMID- 24065097 TI - Emulsifying activity and stability of a non-toxic bioemulsifier synthesized by Microbacterium sp. MC3B-10. AB - A previously reported bacterial bioemulsifier, here termed microbactan, was further analyzed to characterize its lipid component, molecular weight, ionic character and toxicity, along with its bioemulsifying potential for hydrophobic substrates at a range of temperatures, salinities and pH values. Analyses showed that microbactan is a high molecular weight (700 kDa), non-ionic molecule. Gas chromatography of the lipid fraction revealed the presence of palmitic, stearic, and oleic acids; thus microbactan may be considered a glycolipoprotein. Microbactan emulsified aromatic hydrocarbons and oils to various extents; the highest emulsification index was recorded against motor oil (96%). The stability of the microbactan-motor oil emulsion model reached its highest level (94%) at 50 degrees C, pH 10 and 3.5% NaCl content. It was not toxic to Artemia salina nauplii. Microbactan is, therefore, a non-toxic and non-ionic bioemulsifier of high molecular weight with affinity for a range of oily substrates. Comparative phylogenetic assessment of the 16S rDNA gene of Microbacterium sp. MC3B-10 with genes derived from other marine Microbacterium species suggested that this genus is well represented in coastal zones. The chemical nature and stability of the bioemulsifier suggest its potential application in bioremediation of marine environments and in cosmetics. PMID- 24065098 TI - A polymorphism at the 3'-UTR region of the aromatase gene is associated with the efficacy of the aromatase inhibitor, anastrozole, in metastatic breast carcinoma. AB - Estrogen-related genes and the fat mass and obesity-associated (FTO) gene play a critical role in estrogen metabolism, and those polymorphisms are associated with a poor prognosis in breast cancer. However, little is known about the association between these polymorphisms and the efficacy of anastrozole. The aim was to investigate the impact of the genetic polymorphisms, CYP19A1, 17-beta-HSD-1 and FTO, on the response to anastrozole in metastatic breast carcinoma (MBC) and to evaluate the impact of those polymorphisms on various clinicopathologic features. Two-hundred seventy-two women with hormone receptor-positive MBC treated with anastrozole were identified retrospectively. DNA was extracted from peripheral blood and genotyped for five variants in three candidate genes. Time to progression was improved in patients carrying the variant alleles of rs4646 when compared to patients with the wild-type allele (16.40 months versus 13.52 months; p = 0.049). The rs4646 variant alleles were significantly associated with longer overall survival (37.3 months versus 31.6 months; p = 0.007). This relationship was not observed with the rs10046, rs2830, rs9926298 and rs9939609 polymorphisms. The findings of this study indicate that rs4646 polymorphism in the CYP19A1 gene may serve as a prognostic maker of the response to anastrozole in patients with MBC who are treated with anastrozole. PMID- 24065096 TI - The clinical utilization of circulating cell free DNA (CCFDNA) in blood of cancer patients. AB - Qualitative and quantitative testing of circulating cell free DNA (CCFDNA) can be applied for the management of malignant and benign neoplasms. Detecting circulating DNA in cancer patients may help develop a DNA profile for early stage diagnosis in malignancies. The technical issues of obtaining, using, and analyzing CCFDNA from blood will be discussed. PMID- 24065099 TI - Minor role of mitochondrial respiration for fatty-acid induced insulin secretion. AB - An appropriate insulin secretion by pancreatic beta-cells is necessary to maintain glucose homeostasis. A rise in plasma glucose leads to increased metabolism and an elevated cytoplasmic ATP/ADP ratio that finally triggers insulin granule exocytosis. In addition to this triggering pathway, one or more amplifying pathways-activated by amino acids or fatty acid-enhance secretion by promoting insulin granule recruitment to, and priming at, the plasma membrane. The aim of this study was to clarify the impact of the mitochondrial respiratory activity on fatty acid-induced insulin secretion that was assessed by an extracellular flux analyzer. Treatment of isolated mouse islets with glucose (20 mM) increased insulin secretion 18-fold and correlated with ATP-synthesizing respiration. Furthermore, oxygen consumption rate (OCR) significantly increased by 62% in response to glucose, whereas the addition of palmitate resulted only in a minor increase of OCR at both 2.8 mM (11%) and 20 mM glucose (21%). The addition of palmitate showed a pronounced increase of coupling efficiency (CE) at 2.8 mM glucose but no further insulin secretion. However, treatment with palmitate at 20 mM glucose increased insulin secretion about 32-fold accompanied by a small increase in CE. Thus, fatty acid induced respiration has a minor impact on insulin secretion. Our data clearly demonstrate that fatty acids in contrast to glucose play a minor role for respiration-mediated insulin secretion. In the presence of high glucose, fatty acids contribute partially to amplifying pathways of insulin secretion by further increasing mitochondrial activity in the islets of Langerhans. PMID- 24065100 TI - hnRNP A1: the Swiss army knife of gene expression. AB - Eukaryotic cells express a large variety of RNA binding proteins (RBPs), with diverse affinities and specificities towards target RNAs. These proteins play a crucial role in almost every aspect of RNA biogenesis, expression and function. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a complex and diverse family of RNA binding proteins. hnRNPs display multiple functions in the processing of heterogeneous nuclear RNAs into mature messenger RNAs. hnRNP A1 is one of the most abundant and ubiquitously expressed members of this protein family. hnRNP A1 plays multiple roles in gene expression by regulating major steps in the processing of nascent RNA transcripts. The transcription, splicing, stability, export through nuclear pores and translation of cellular and viral transcripts are all mechanisms modulated by this protein. The diverse functions played by hnRNP A1 are not limited to mRNA biogenesis, but extend to the processing of microRNAs, telomere maintenance and the regulation of transcription factor activity. Genomic approaches have recently uncovered the extent of hnRNP A1 roles in the development and differentiation of living organisms. The aim of this review is to highlight recent developments in the study of this protein and to describe its functions in cellular and viral gene expression and its role in human pathologies. PMID- 24065101 TI - Biochemistry and molecular biology of carotenoid biosynthesis in chili peppers (Capsicum spp.). AB - Capsicum species produce fruits that synthesize and accumulate carotenoid pigments, which are responsible for the fruits' yellow, orange and red colors. Chili peppers have been used as an experimental model for studying the biochemical and molecular aspects of carotenoid biosynthesis. Most reports refer to the characterization of carotenoids and content determination in chili pepper fruits from different species, cultivars, varieties or genotypes. The types and levels of carotenoids differ between different chili pepper fruits, and they are also influenced by environmental conditions. Yellow-orange colors of chili pepper fruits are mainly due to the accumulation of alpha- and beta-carotene, zeaxanthin, lutein and beta-cryptoxanthin. Carotenoids such as capsanthin, capsorubin and capsanthin-5,6-epoxide confer the red colors. Chromoplasts are the sites of carotenoid pigment synthesis and storage. According to the most accepted theory, the synthesis of carotenoids in chili peppers is controlled by three loci: c1, c2 and y. Several enzymes participating in carotenoid biosynthesis in chili pepper fruits have been isolated and characterized, and the corresponding gene sequences have been reported. However, there is currently limited information on the molecular mechanisms that regulate this biosynthetic pathway. Approaches to gain more knowledge of the regulation of carotenoid biosynthesis are discussed. PMID- 24065102 TI - Exposure to enriched environment decreases neurobehavioral deficits induced by neonatal glutamate toxicity. AB - Environmental enrichment is a popular strategy to enhance motor and cognitive performance and to counteract the effects of various harmful stimuli. The protective effects of enriched environment have been shown in traumatic, ischemic and toxic nervous system lesions. Monosodium glutamate (MSG) is a commonly used taste enhancer causing excitotoxic effects when given in newborn animals. We have previously demonstrated that MSG leads to a delay in neurobehavioral development, as shown by the delayed appearance of neurological reflexes and maturation of motor coordination. In the present study we aimed at investigating whether environmental enrichment is able to decrease the neurobehavioral delay caused by neonatal MSG treatment. Newborn pups were treated with MSG subcutaneously on postnatal days 1, 5 and 9. For environmental enrichment, we placed rats in larger cages, supplemented with different toys that were altered daily. Normal control and enriched control rats received saline treatment only. Physical parameters such as weight, day of eye opening, incisor eruption and ear unfolding were recorded. Animals were observed for appearance of reflexes such as negative geotaxis, righting reflexes, fore- and hindlimb grasp, fore- and hindlimb placing, sensory reflexes and gait. In cases of negative geotaxis, surface righting and gait, the time to perform the reflex was also recorded daily. For examining motor coordination, we performed grid walking, footfault, rope suspension, rota-rod, inclined board and walk initiation tests. We found that enriched environment alone did not lead to marked alterations in the course of development. On the other hand, MSG treatment caused a slight delay in reflex development and a pronounced delay in weight gain and motor coordination maturation. This delay in most signs and tests could be reversed by enriched environment: MSG-treated pups kept under enriched conditions showed no weight retardation, no reflex delay in some signs and performed better in most coordination tests. These results show that environmental enrichment is able to decrease the neurobehavioral delay caused by neonatal excitotoxicity. PMID- 24065103 TI - Basic amino acid residues of human eosinophil derived neurotoxin essential for glycosaminoglycan binding. AB - Human eosinophil derived neurotoxin (EDN), a granule protein secreted by activated eosinophils, is a biomarker for asthma in children. EDN belongs to the human RNase A superfamily possessing both ribonucleolytic and antiviral activities. EDN interacts with heparin oligosaccharides and heparin sulfate proteoglycans on bronchial epithelial Beas-2B cells. In this study, we demonstrate that the binding of EDN to cells requires cell surface glycosaminoglycans (GAGs), and the binding strength between EDN and GAGs depends on the sulfation levels of GAGs. Furthermore, in silico computer modeling and in vitro binding assays suggest critical roles for the following basic amino acids located within heparin binding regions (HBRs) of EDN 34QRRCKN39 (HBR1), 65NKTRKN70 (HBR2), and 113NRDQRRD119 (HBR3) and in particular Arg35, Arg36, and Arg38 within HBR1, and Arg114 and Arg117 within HBR3. Our data suggest that sulfated GAGs play a major role in EDN binding, which in turn may be related to the cellular effects of EDN. PMID- 24065104 TI - Voltage-gated potassium channel Kv1.3 is highly expressed in human osteosarcoma and promotes osteosarcoma growth. AB - Deregulation of voltage-gated potassium channel subunit Kv1.3 has been reported in many tumors. Kv1.3 promotes tumorigenesis by enhancing cell proliferation while suppressing apoptosis. However, the expression and function of Kv1.3 in osteosarcoma are unknown. In the present study, we detected the expression of Kv1.3 in human osteosarcoma cells and tissues by RT-PCR, Western blot and immunohistochemistry. We further examined cell proliferation and apoptosis in osteosarcoma MG-63 cells and xenografts following knockdown of Kv1.3 by short hairpin RNA (shRNA). We found that Kv1.3 was upregulated in human osteosarcoma. Knockdown of Kv1.3 significantly suppressed cell proliferation and increased apoptosis as demonstrated by enhanced cleavage of poly (ADP-ribose) polymerase (PARP) and the activation of Caspase-3/7. Furthermore, adenovirus delivered shRNA targeting Kv1.3 significantly inhibited the growth of MG-63 xenografts. Taken together, our results suggest that Kv1.3 is a novel molecular target for osterosarcoma therapy. PMID- 24065105 TI - The consequence of oncomorphic TP53 mutations in ovarian cancer. AB - Ovarian cancer is the most lethal gynecological malignancy, with an alarmingly poor prognosis attributed to late detection and chemoresistance. Initially, most tumors respond to chemotherapy but eventually relapse due to the development of drug resistance. Currently, there are no biological markers that can be used to predict patient response to chemotherapy. However, it is clear that mutations in the tumor suppressor gene TP53, which occur in 96% of serous ovarian tumors, alter the core molecular pathways involved in drug response. One subtype of TP53 mutations, widely termed gain-of-function (GOF) mutations, surprisingly converts this protein from a tumor suppressor to an oncogene. We term the resulting change an oncomorphism. In this review, we discuss particular TP53 mutations, including known oncomorphic properties of the resulting mutant p53 proteins. For example, several different oncomorphic mutations have been reported, but each mutation acts in a distinct manner and has a different effect on tumor progression and chemoresistance. An understanding of the pathological pathways altered by each mutation is necessary in order to design appropriate drug interventions for patients suffering from this deadly disease. PMID- 24065106 TI - Receptor-targeted, magneto-mechanical stimulation of osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. AB - Mechanical cues are employed to promote stem cell differentiation and functional tissue formation in tissue engineering and regenerative medicine. We have developed a Magnetic Force Bioreactor (MFB) that delivers highly targeted local forces to cells at a pico-newton level, utilizing magnetic micro- and nano particles to target cell surface receptors. In this study, we investigated the effects of magnetically targeting and actuating specific two mechanical-sensitive cell membrane receptors-platelet-derived growth factor receptor alpha (PDGFRalpha) and integrin alphanubeta3. It was found that a higher mineral-to matrix ratio was obtained after three weeks of magneto-mechanical stimulation coupled with osteogenic medium culture by initially targeting PDGFRalpha compared with targeting integrin alphanubeta3 and non-treated controls. Moreover, different initiation sites caused a differentiated response profile when using a 2-day-lagged magneto-mechanical stimulation over culture periods of 7 and 12 days). However, both resulted in statistically higher osteogenic marker genes expression compared with immediate magneto-mechanical stimulation. These results provide insights into important parameters for designing appropriate protocols for ex vivo induced bone formation via magneto-mechanical actuation. PMID- 24065107 TI - Oxidative stress in the pathogenesis of keratoconus and Fuchs endothelial corneal dystrophy. AB - Due to its localization and function, the cornea is regularly exposed to sunlight and atmospheric oxygen, mainly dioxygen, which produce reactive oxygen species (ROS). Therefore, corneal cells are particularly susceptible to oxidative stress. The accumulation of ROS in the cornea may affect signal transduction, proliferation and may also promote cell death. The cornea has several enzymatic and non-enzymatic antioxidants involved in ROS scavenging, but in certain conditions they may not cope with oxidative stress, leading to diseases of the eye. Keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD) are multifactorial diseases of the cornea, in which pathogenesis is not fully understood. However, increased levels of oxidative stress markers detected in these disorders indicate that oxidative stress may play an important role in their development and progression. These markers are: (i) decreased levels of non enzymatic antioxidants, and (ii) decreased expression of genes encoding antioxidative enzymes, including thioredoxin reductase, peroxiredoxins, superoxide dismutase, glutathione S-transferase, and aldehyde dehydrogenase. Moreover, the FECD endothelium displays higher levels of oxidative DNA damage, especially in mitochondrial DNA (mtDNA), whereas KC cornea shows abnormal levels of some components of oxidative phosphorylation encoded by mtDNA. In this review we present some considerations and results of experiments supporting the thesis on the important role of oxidative stress in KC and FECD pathology. PMID- 24065109 TI - Transcriptome-wide single nucleotide polymorphisms (SNPs) for abalone (Haliotis midae): validation and application using GoldenGate medium-throughput genotyping assays. AB - Haliotis midae is one of the most valuable commercial abalone species in the world, but is highly vulnerable, due to exploitation, habitat destruction and predation. In order to preserve wild and cultured stocks, genetic management and improvement of the species has become crucial. Fundamental to this is the availability and employment of molecular markers, such as microsatellites and single nucleotide (SNPs). Transcriptome sequences generated through sequencing-by synthesis technology were utilized for the in vitro and in silico identification of 505 putative SNPs from a total of 316 selected contigs. A subset of 234 SNPs were further validated and characterized in wild and cultured abalone using two Illumina GoldenGate genotyping assays. Combined with VeraCode technology, this genotyping platform yielded a 65%-69% conversion rate (percentage polymorphic markers) with a global genotyping success rate of 76%-85% and provided a viable means for validating SNP markers in a non-model species. The utility of 31 of the validated SNPs in population structure analysis was confirmed, while a large number of SNPs (174) were shown to be informative and are, thus, good candidates for linkage map construction. The non-synonymous SNPs (50) located in coding regions of genes that showed similarities with known proteins will also be useful for genetic applications, such as the marker-assisted selection of genes of relevance to abalone aquaculture. PMID- 24065110 TI - Germ-line deletion in DICER1 revealed by a novel MLPA assay using synthetic oligonucleotides. AB - DICER1 is an endoribonuclease responsible for the production of mature microRNAs which are small, single-stranded RNA molecules that regulate gene expression post transcriptionally by binding to mRNA and repressing the expression of target genes. Germ-line mutations in DICER1 are responsible for a rare cancer syndrome, including tumors that can co-occur with multinodular goiter (MNG). Using Sanger sequencing, we screened all DICER1 exons and intron boundaries in 20 suspected mutation carriers: nine with ovarian sex cord-stromal tumors (including Sertoli Leydig cell tumors (SLCTs)), five with pleuropulmonary blastoma, one with cystic nephroma, one with nasal chondromesenchymal hamartoma and four with more than one manifestation suggestive of a germ-line DICER1 mutation. All were negative for any apparently deleterious variants. We developed a Multiplex Ligation-based Probe Amplification assay for DICER1 to screen for large deletions or duplications. Synthetic oligonucleotides were designed to cover all exons in three probe-mixes. In a child with a SLCT and MNG, and in her mother and brother (both diagnosed with MNG), we identified a heterozygous germ-line deletion of approximately 3 kilobases that eliminates exon 21 of DICER1 and two-thirds of intron 21, accompanied by an insertion of a G nucleotide at the 3' end of the deletion (c.3270-6_4051-1280delinsG). This allele is expressed in the patient's cDNA, creating an out-of-frame deletion predicted to result in a truncated protein (r.3270_4050del; p.Tyr1091Ser*28). Our novel finding of a disease-causing large deletion in DICER1 emphasizes the need to include assays that can detect rearrangements, duplications and deletions in any DICER1 screening protocol. PMID- 24065111 TI - Incidental findings: the time is not yet ripe for a policy for biobanks. AB - Incidental findings (IFs) are acknowledged to be among the most important ethical issues to consider in biobank research. Genome-wide association studies and disease-specific genetic research might reveal information about individual participants that are not related to the research purpose, but may be relevant to those participants' future health. In this article, we provide a synopsis of arguments for and against the disclosure of IFs in biobank research. We argue that arguments that do not distinguish between communications about pathogenic conditions and complex genetic risk for diseases fail, as preferences and decisions may be far more complex in the latter case. The principle of beneficence, for example, often supports the communication of incidentally discovered diseases, but if communication of risk is different, the beneficence of such communication is not equally evident. By conflating the latter form of communication with the former, the application of ethical principles to IFs in biobank research sometimes becomes too easy and frictionless. Current empirical surveys of people's desire to be informed about IFs do not provide sufficient guidance because they rely on the same notion of risk communication as a form of communication about actual health and disease. Differently designed empirical research and more reflection on biobank research and genetic risk information is required before ethical principles can be applied to support the adoption of a reasonable and comprehensive policy for handling IFs. PMID- 24065108 TI - Choosing an appropriate infection model to study quorum sensing inhibition in Pseudomonas infections. AB - Bacteria, although considered for decades to be antisocial organisms whose sole purpose is to find nutrients and multiply are, in fact, highly communicative organisms. Referred to as quorum sensing, cell-to-cell communication mechanisms have been adopted by bacteria in order to co-ordinate their gene expression. By behaving as a community rather than as individuals, bacteria can simultaneously switch on their virulence factor production and establish successful infections in eukaryotes. Understanding pathogen-host interactions requires the use of infection models. As the use of rodents is limited, for ethical considerations and the high costs associated with their use, alternative models based on invertebrates have been developed. Invertebrate models have the benefits of low handling costs, limited space requirements and rapid generation of results. This review presents examples of such models available for studying the pathogenicity of the Gram-negative bacterium Pseudomonas aeruginosa. Quorum sensing interference, known as quorum quenching, suggests a promising disease-control strategy since quorum-quenching mechanisms appear to play important roles in microbe-microbe and host-pathogen interactions. Examples of natural and synthetic quorum sensing inhibitors and their potential as antimicrobials in Pseudomonas related infections are discussed in the second part of this review. PMID- 24065112 TI - Copy number variants in patients with short stature. AB - Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes. PMID- 24065113 TI - Do BRCA1/2 mutations and low FMR1 alleles interact or not? PMID- 24065114 TI - The FMR1 CGG repeat test is not a candidate prescreening tool for identifying women with a high probability of being carriers of BRCA mutations. AB - The identification of women with a high probability of being carriers of pathogenic BRCA mutation is not straightforward and a major improvement would be the availability of markers of mutations that could be directly evaluated in individuals asking for genetic testing. The FMR1 gene testing was recently proposed as a candidate prescreening tool because an association between BRCA pathogenic mutations and FMR1 genotypes with 'low alleles' (CGG repeat number <26) was observed. To confirm this hypothesis, we evaluated the distribution of FMR1 alleles and genotypes between BRCA mutation carriers and non-carriers in a cohort of 147 Italian women, free of cancer or affected by breast and/or ovarian cancer, who were tested for the presence of BRCA mutation in a clinical setting. The distribution of FMR1 CGG repeat numbers in the two groups was similar (lower allele median/mean were 30/27.4 and 30/27.9, respectively; Mann-Whitney test P=0.997) and no difference in the FMR1 genotype distribution was present (chi(2)=0.503, d.f.=2, P=0.78). This result is in contrast with literature data and suggests that FMR1 genetic testing is not a candidate BRCA prescreening tool. PMID- 24065115 TI - A computational study of the protonation of simple amines in water clusters. AB - The microsolvation study of a group of amines with a variable number of water molecules was performed by conducting a theoretical analysis of the properties of the clusters formed by the amines with up to seven molecules of water. We describe the microsolvation of several amines focusing on the dissociation of a water molecule that transfers a proton to the amine and forms a hydroxide ion. Ab initio calculations were performed on these clusters employing the DFT/B3LYP and MP2 methods with the 6-311++G(2d,p) basis set. Several stationary points for each cluster were thus located and characterized as minima from frequency calculations. Intermolecular BSSE corrected interaction energies were obtained. The protonation mechanism of the amines was examined in terms of some parameters that include the lengths of the bonds involved in the process of proton transfer and the frequencies associated with certain O-H and N-H stretching modes. On the basis of the calculations, all studied amines present similar behavior but trimethylamine, whose limitations to be integrated in the water hydrogen bond network cause the instability of some of their complexes. The cyclic configurations are the most stable structures up to five water molecules due to the presence of cooperative effects associated with the hydrogen bonds of water molecules. However, when the number of water molecules increases the spatial forms become the most stable configurations. The dissociated forms were not found to have the most stable configuration in any of the studied systems but energetic differences between the dissociated and non-dissociated forms decrease with the number of water molecules. PMID- 24065116 TI - Performance enhancement of metal nanowire transparent conducting electrodes by mesoscale metal wires. AB - For transparent conducting electrodes in optoelectronic devices, electrical sheet resistance and optical transmittance are two of the main criteria. Recently, metal nanowires have been demonstrated to be a promising type of transparent conducting electrode because of low sheet resistance and high transmittance. Here we incorporate a mesoscale metal wire (1-5 MUm in diameter) into metal nanowire transparent conducting electrodes and demonstrate at least a one order of magnitude reduction in sheet resistance at a given transmittance. We realize experimentally a hybrid of mesoscale and nanoscale metal nanowires with high performance, including a sheet resistance of 0.36 Omega sq(-1) and transmittance of 92%. In addition, the mesoscale metal wires are applied to a wide range of transparent conducting electrodes including conducting polymers and oxides with improvement up to several orders of magnitude. The metal mesowires can be synthesized by electrospinning methods and their general applicability opens up opportunities for many transparent conducting electrode applications. PMID- 24065118 TI - Antitumor effects of telomerase-specific replication-selective oncolytic viruses for adenoid cystic carcinoma cell lines. AB - We evaluated the antitumor effect of a telomerase-specific replication-selective adenovirus (Telomelysin, OBP-301) for adenoid cystic carcinoma (ACC) in vitro and in vivo. Adenovirus E1 gene expression was controlled by human telomerase reverse transcription (hTERT). Infection of ACC cells by OBP-301 induced high E1A mRNA expression and subsequent oncolytic cell death in a dose-dependent manner. Using OBP-401 (TelomeScan), a genetically engineered adenovirus that carries the GFP gene under the control of the cytomegalovirus (CMV) promoter at the deleted E3 region of OBP-301, ACC cells expressed bright GFP fluorescence as early as 12 h after OBP-401 infection. The fluorescence intensity gradually increased in a time dependent manner, followed by rapid cell death due to the cytopathic effect of OBP-401, as evidenced by the floating, highly light-refractive cells using phase contrast microscopy. Effects of intratumorally injected OBP-401 against established Acc2 xenograft tumors were seen in BALB/c nu/nu mice. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Our data clearly indicated that telomerase-specific oncolytic adenoviruses have significant therapeutic potential against human ACC in vitro and in vivo. These results suggest that treatment with OBP-301 and OBP-401 may improve the quality of life of oral cancer patients. PMID- 24065117 TI - Enhanced stem cell migration mediated by VCAM-1/VLA-4 interaction improves cardiac function in virus-induced dilated cardiomyopathy. AB - Endogenous circulation of bone marrow-derived cells (BMCs) was observed in patients with dilated cardiomyopathy (DCM) who showed cardiac upregulation of Vascular Cell Adhesion Protein-1 (VCAM-1). However, the underlying pathophysiology is currently unknown. Thus, we aimed to analyze circulation, migration and G-CSF-based mobilization of BMCs in a murine model of virus-induced DCM. Mice with coxsackievirus B3 (CVB3) induced DCM and healthy controls were analyzed regarding their myocardial homing factors by PCR. To determine cardiac VCAM-1 expression ELISA and immunohistochemistry were applied. Flow cytometry was performed to analyze BMCs. Cardiac diameters and function were evaluated by echocardiography before and 4 weeks after G-CSF treatment. In murine CVB3-induced DCM an increase of BMCs in peripheral blood and a decrease of BMCs in bone marrow was observed. We found an enhanced migration of Very Late Antigen-4 (VLA-4+) BMCs to the diseased heart overexpressing VCAM-1 and higher numbers of CD45-CD34-Sca 1+ and CD45-CD34-c-kit+ cells. Mobilization of BMCs by G-CSF boosted migration along the VCAM-1/VLA-4 axis and reduced apoptosis of cardiomyocytes. Significant improvement of cardiac function was detected by echocardiography in G-CSF-treated mice. Blocking VCAM-1 by a neutralizing antibody reduced the G-CSF-dependent effects on stem cell migration and cardiac function. This is the first study showing that in virus-induced DCM VCAM-1/VLA-4 interaction is crucial for recruitment of circulating BMCs leading to beneficial anti-apoptotic effects resulting in improved cardiac function after G-CSF-induced mobilization. PMID- 24065119 TI - Effects of shuangtengbitong tincture on collagen-induced arthritis in rats. AB - Shuangtengbitong tincture (STBT), a clinical prescription from the Fujian University of Traditional Chinese Medicine (TCM) Affiliated People's Hospital (Fuzhou, China), has been used in the treatment of rheumatoid arthritis (RA) for ~10 years. The aim of the current study was to confirm the anti-RA effect of STBT and to evaluate the potential mechanisms underlying collagen-induced arthritis (CIA) in rats. CIA model Wistar rats were induced with bovine type II collagen. The rats were immunized with CIA and were treated with STBT (0.5 and 2 ml/injection) and votalin (~1 cm/injection) continuously for ~1 month. Following treatment, the pathological sections of CIA rat joints were observed by hematoxylin and eosin staining, expression of toll-like receptor-4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear transcription factor-kappaB (NF-kappaB) were investigated by western blot analysis and reverse transcription polymerase chain reaction (RT-PCR) analysis. Following treatment, STBT significantly suppressed paw swelling (P<0.05) compared with the model group and increased body weight. STBT also reversed pathological changes, STBT-treated rats showed a significant improvement of synovial hyperplasia, inflammatory infiltration, and cartilage and bone destruction. The levels of protein and mRNA expression of TLR4, MyD88 and NF-kappaB were markedly suppressed in the synovial tissue of STBT- and votalin-treated rats. In addition, STBT showed marked inhibition of the levels of protein and mRNA expression of TLR4, MyD88 and NF kappaB at an STBT volume ranging between 1 and 4 ml/day, indicating that the inhibition was volume dependent. These results show that STBT inhibits CIA and may be correlated with TLR4, MyD88 and NF-kappaB expression. PMID- 24065120 TI - Zinc complexes containing asymmetrical N,N,O-tridentate ligands and their application in lactide polymerization. AB - A series of zinc complexes based on asymmetrical N,N,O-tridentate ligands were prepared via binaphthyl diamine derivatives. These complexes were characterized and employed as catalysts in lactide polymerization. The X-ray diffraction analyses revealed that molecular structures of 1b and 2b were mononuclear complexes with zinc atoms in distorted octahedral geometries. Upon co-catalysis with isopropanol, complex 2a showed the highest activity among these zinc complexes for the ring-opening polymerization of L-lactide, and complex 3a exhibited the highest stereoselectivity for the ring-opening polymerization of rac-lactide affording substantially isotactic polylactide (PLA) with a P(m) of 0.62. The polymerization kinetics using 2a as a catalyst was studied in detail. The kinetics of the polymerization results revealed that the rates of polymerization were first-order both in the monomer and the catalyst, and there was a linear relationship between the L-LA conversion and the number-average molecular weight of PLA with a narrow molecular distribution (1.07-1.17). The activation energy (31.49 kJ mol(-1)) was deduced according to the Arrhenius equation. PMID- 24065121 TI - DNA-enhanced peroxidase-like activity of layered double hydroxide nanosheets and applications in H2O2 and glucose sensing. AB - LDH nanosheets were obtained via continuous impaction and exfoliation by herring sperm DNA molecules using a constant vibration method. DNA-LDH nanohybrids were composed by electrostatic forces and they exhibited DNA-enhanced peroxidase-like activity. The morphology and structure of DNA-LDH nanohybrids were analyzed by transmission electron microscopy (TEM), selected-area electron diffraction (SAED), X-ray diffraction (XRD), and atomic force microscopy (AFM) characterization. On the basis of the high catalytic activity of DNA/CuAl-LDH nanosheets, a rapid, sensitive, and convenient approach was developed for colorimetric detection of H2O2 and blood glucose. This method can be potentially applied in medical diagnostics and biotechnology fields. PMID- 24065122 TI - A selective fluorescent chemosensor for phosphoserine. AB - A fluorescent chemosensor for the detection of phosphoserine is reported. The ditopic sensor features a phosphate-coordinating zinc(II)-dipicolylamine (Zn(2+) DPA) unit tethered to an amine-binding coumarin aldehyde fluorophore. With phosphoserine, the sensor demonstrates a 30-fold fluorescence enhancement under buffered aqueous conditions. PMID- 24065123 TI - Novel risk factors for lymph node metastasis in early invasive colorectal cancer: a multi-institution pathology review. AB - BACKGROUND: Novel risk factors for lymph node metastasis (LNM) in T1 colorectal cancer (CRC) have been recently proposed, but most have not been implemented because of the lack of validation. Here we determined the value of poorly differentiated clusters (PDCs) in a multi-institutional cohort of T1 CRC cases. METHODS: A pathology review involving 30 institutions was conducted for 3556 T1 CRCs. PDC was defined as malignant clusters comprising >=5 cells and lacking a glandular formation. The ability to identify LNM risk was compared using Akaike's information criterion (AIC). RESULTS: PDC was observed in 1401 tumors (39.4 %), including 94 (17.8 %) with <1000 um submucosal invasion and 1307 (43.2 %) with >=1000 um submucosal invasion (P < 0.0001). The incidence of LNM was higher in PDC-positive tumors (17.4 %) than in PDC-negative tumors (6.9 %; P < 0.0001), and PDCs had an adverse impact on LNM irrespective of the degree of submucosal invasion. Grade 3, vascular invasion, budding, and submucosal invasion depth were also significant factors (all, P < 0.0001). AIC of risk factor to identify LNM risk was most favorable for vascular invasion (2273.4), followed by PDC (2357.4); submucosal invasion depth (2429.1) was the most unfavorable. Interinstitutional judgment disparities were smaller in PDC (kappa, 0.51) than vascular invasion (0.33) or tumor grade (0.48). CONCLUSIONS: PDC is a promising new parameter with good ability to identify LNM risk. Use of its appropriate judgment criteria will enable us determine whether an observational policy can be safely applied following local tumor excision in T1 CRC cases. PMID- 24065124 TI - Thrombocytopenia in pegylated interferon and ribavirin combination therapy for chronic hepatitis C. AB - BACKGROUND: This study aimed to examine the therapeutic effect and prognostic indicators of pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy in thrombocytopenic patients with chronic hepatitis C, hepatitis C virus (HCV)-related cirrhosis, and those who underwent splenectomy or partial splenic embolization (PSE). METHODS: Of 326 patients with HCV-related chronic liver disease (252 with genotype 1b and 74 with genotype 2a/2b) treated with PEG IFN/RBV, 90 were diagnosed with cirrhosis. RESULTS: Regardless of the degree of thrombocytopenia, the administration rate was significantly higher in the splenectomy/PSE group compared to the cirrhosis group. However, in patients with genotype 1b, the sustained virological response (SVR) rate was significantly lower in the cirrhosis and the splenectomy/PSE groups compared to the chronic hepatitis group. No cirrhotic patients with platelets less than 80,000 achieved an SVR. Patients with genotype 2a/2b were more likely to achieve an SVR than genotype 1b. Prognostic factors for SVR in patients with genotype 1b included the absence of esophageal and gastric varices, high serum ALT, low AST/ALT ratio, and the major homo type of the IL28B gene. Splenectomy- or PSE-facilitated induction of IFN in patients with genotype 2a/2b was more likely to achieve an SVR by an IFN dose maintenance regimen. Patients with genotype 1b have a low SVR regardless of splenectomy/PSE. In particular, patients with a hetero/minor type of IL28B did not have an SVR. CONCLUSIONS: Splenectomy/PSE for IFN therapy should be performed in patients expected to achieve a treatment response, considering their genotype and IL28B. PMID- 24065125 TI - Rapid high-throughput genotyping of HBV DNA using a modified hybridization extension technique. AB - China has the highest incidence of hepatitis B virus (HBV) infection worldwide. HBV genotypes have variable impacts on disease pathogenesis and drug tolerance. We have developed a technically simple and accurate method for HBV genotyping that will be applicable to pre-treatment diagnosis and individualized treatment. Multiple sequence alignments of HBV genomes from GenBank were used to design primers and probes for genotyping of HBV A through H. The hybridization was carried out on nitrocellulose (NC) membranes with probes fixed in an array format, which was followed by hybrid amplification by an extension step with DNA polymerase to reinforce the double-stranded DNA hybrids on the NC membrane and subsequent visualization using an avidin-biotin system. Genotyping results were confirmed by DNA sequencing and bioinformatics analysis using the National Center for Biotechnology Information genotyping database, and compared with results from the line probe assay. The data show that multiple sequence alignment defined a 630 bp region in the HBV PreS and S regions that was suitable for genotyping. All genotyping significant single nucleotides in the region were defined. Two-hundred and-ninety-one HBV-positive serum samples from Northwest Chinese patients were genotyped, and the genotyping rate from the new modified hybridization-extension method was 100% compared with direct sequencing. Compared with line probe assay, the newly developed method is superior, featuring reduced reaction time, lower risk of contamination, and increased accuracy for detecting single nucleotide mutation. In conclusion, a novel hybridization-extension method for HBV genotyping was established, which represents a new tool for accurate and rapid SNP detection that will benefit clinical testing. PMID- 24065126 TI - RNAtomy of the Spliceosome's heart. PMID- 24065127 TI - Lncing protein translation to metastasis. PMID- 24065128 TI - How unfinished business from S-phase affects mitosis and beyond. AB - The eukaryotic cell cycle is conventionally viewed as comprising several discrete steps, each of which must be completed before the next one is initiated. However, emerging evidence suggests that incompletely replicated, or unresolved, chromosomes from S-phase can persist into mitosis, where they present a potential threat to the faithful segregation of sister chromatids. In this review, we provide an overview of the different classes of loci where this 'unfinished S phase business' can lead to a variety of cytogenetically distinct DNA structures throughout the various steps of mitosis. Furthermore, we discuss the potential ways in which cells might not only tolerate this inevitable aspect of chromosome biology, but also exploit it to assist in the maintenance of genome stability. PMID- 24065129 TI - IFNbeta-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. AB - A single high dose of interferon-beta (IFNbeta) activates powerful cellular responses, in which many anti-viral, pro-apoptotic, and anti-proliferative proteins are highly expressed. Since some of these proteins are deleterious, cells downregulate this initial response rapidly. However, the expression of many anti-viral proteins that do no harm is sustained, prolonging a substantial part of the initial anti-viral response for days and also providing resistance to DNA damage. While the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase, the related factor un phosphorylated ISGF3 (U-ISGF3), formed by IFNbeta-induced high levels of IRF9 and STATs 1 and 2 without tyrosine phosphorylation, drives the second prolonged response. The U-ISGF3-induced anti-viral genes that show prolonged expression are driven by distinct IFN stimulated response elements (ISREs). Continuous exposure of cells to a low level of IFNbeta, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase in other IFNbeta-induced proteins, and to constitutive resistance to DNA damage. PMID- 24065130 TI - Amyloid-beta oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. AB - Mislocalization and aggregation of Abeta and Tau combined with loss of synapses and microtubules (MTs) are hallmarks of Alzheimer disease. We exposed mature primary neurons to Abeta oligomers and analysed changes in the Tau/MT system. MT breakdown occurs in dendrites invaded by Tau (Tau missorting) and is mediated by spastin, an MT-severing enzyme. Spastin is recruited by MT polyglutamylation, induced by Tau missorting triggered translocalization of TTLL6 (Tubulin-Tyrosine Ligase-Like-6) into dendrites. Consequences are spine loss and mitochondria and neurofilament mislocalization. Missorted Tau is not axonally derived, as shown by axonal retention of photoconvertible Dendra2-Tau, but newly synthesized. Recovery from Abeta insult occurs after Abeta oligomers lose their toxicity and requires the kinase MARK (Microtubule-Affinity-Regulating-Kinase). In neurons derived from Tau-knockout mice, MTs and synapses are resistant to Abeta toxicity because TTLL6 mislocalization and MT polyglutamylation are prevented; hence no spastin recruitment and no MT breakdown occur, enabling faster recovery. Reintroduction of Tau re-establishes Abeta-induced toxicity in TauKO neurons, which requires phosphorylation of Tau's KXGS motifs. Transgenic mice overexpressing Tau show TTLL6 translocalization into dendrites and decreased MT stability. The results provide a rationale for MT stabilization as a therapeutic approach. PMID- 24065132 TI - Nociception coma scale-revised scores correlate with metabolism in the anterior cingulate cortex. AB - BACKGROUND: The Nociception Coma Scale-Revised (NCS-R) was recently validated to assess possible pain perception in patients with disorders of consciousness. OBJECTIVE: To identify correlations between cerebral glucose metabolism and NCS-R total scores. METHODS: [18F]-fluorodeoxyglucose positron emission tomography, NCS R, and Coma Recovery Scale-Revised assessments were performed in 49 patients with disorders of consciousness. RESULTS: We identified a significant positive correlation between NCS-R total scores and metabolism in the posterior part of the anterior cingulate cortex, known to be involved in pain processing. No other cluster reached significance. No significant effect of clinical diagnosis (vegetative/unresponsive vs minimally conscious states), etiology or interval since insult was observed. CONCLUSIONS: Our data support the hypothesis that the NCS-R total scores are related to cortical processing of nociception and may constitute an appropriate behavioral tool to assess, monitor, and treat possible pain in brain-damaged noncommunicative patients with disorders of consciousness. Future studies using event-related functional magnetic resonance imaging should investigate the correlation between NCS-R scores and brain activation in response to noxious stimulation at the single-subject level. PMID- 24065131 TI - Antagonistic functions between the RNA chaperone Hfq and an sRNA regulate sensitivity to the antibiotic colicin. AB - The RNA chaperone Hfq is a key regulator of the function of small RNAs (sRNAs). Hfq has been shown to facilitate sRNAs binding to target mRNAs and to directly regulate translation through the action of sRNAs. Here, we present evidence that Hfq acts as the repressor of cirA mRNA translation in the absence of sRNA. Hfq binding to cirA prevents translation initiation, which correlates with cirA mRNA instability. In contrast, RyhB pairing to cirA mRNA promotes changes in RNA structure that displace Hfq, thereby allowing efficient translation as well as mRNA stabilization. Because CirA is a receptor for the antibiotic colicin Ia, in addition to acting as an Fur (Ferric Uptake Regulator)-regulated siderophore transporter, translational activation of cirA mRNA by RyhB promotes colicin sensitivity under conditions of iron starvation. Altogether, these results indicate that Fur and RyhB modulate an unexpected feed-forward loop mechanism related to iron physiology and colicin sensitivity. PMID- 24065133 TI - Spatial and temporal variability of metals in inter-tidal beach sediment of Mumbai, India. AB - Nine metals were monitored in the beach sediment in Mumbai from May 2011 to March 2012 to evaluate the spatial and temporal distributions. The average heavy metal concentrations exhibited the following order: Fe > Mn > Cr > Co > Ni > Pb > Zn > Cu > Cd for the four sampling sites. The mean concentrations (+/- SD) of Fe, Mn, Cr, Co, Ni, Pb, Zn, Cu and Cd were estimated to be 31.15 +/- 10.02 g kg(-1), 535.04 +/- 76.42, 151.98 +/- 97.90, 92.76 +/- 14.18, 67.52 +/- 11.32, 59.57 +/- 15.19, 54.65 +/- 15.01, 32.24 +/- 8.07 and 18.75 +/- 1.76 mg kg(-1), respectively. The results indicated that the sediments were polluted with Cd, Cr, Co and Pb due to high anthropogenic influences. Spatial variation of metals revealed that most of the metals were high in Dadar beach and low in Aksa beach. Cd was the highest contaminant metal studied with a mean contamination factor of 93.75. The pollution load indices of the studied beaches ranged from 1.63 (Aksa) to 1.91 (Dadar) and indicated that the beach sediments were polluted with heavy metals. The heavy metal contents increased in relation to monsoon, and most of the heavy metals showed significantly high concentrations in November during the post-monsoon. The statistical analysis revealed significant effect of study site on all the metals studied. Further, there was a significant difference on metal accumulation on bimonthly basis in relation to weather pattern in Mumbai beaches. PMID- 24065134 TI - Spectrophotometeric determination of trace amounts of Al3+ ion in water samples after cloud point extraction using quinizarin as a complexing agent. AB - In this study, cloud point extraction was used for the preconcentration of Al(3+) ion after the complex formation with 1,4-dihydroxy-9,10-anthraquinone (Quinizarin [QUIN]), and subsequent analysis by spectrophotometeric method, using Triton X 114 as surfactant. The optimal extraction and reaction conditions were studied (i.e., pH = 5.5, 0.1 mM QUIN, Triton X-114 = 0.1% (w/v)), and the analytical characteristics of the method (e.g., limit of detection, linear range, preconcentration, and enrichment factors) were obtained. Linearity was obeyed in the range of 3.33-166.67 ng ml(-1) of Al(3+) ion. The detection limit of the method was 2.09 ng ml(-1) for Al(3+) ion. The interference effect of some anions and cations was also tested. The method was applied to determine Al(3+) ion in water samples. PMID- 24065135 TI - Determination and study on dissipation and residue of bismerthiazol and its metabolite in Chinese cabbage and soil. AB - A simple and accurate method for the determination of bismerthiazol and its metabolite 2-amino-5-mercapto-1,3,4-thiadiazole was developed in Chinese cabbage and soil by high-performance liquid chromatography-diode array detection in this study. The limits of detection were 0.06 mg/kg for bismerthiazol and 0.03 mg/kg for 2-amino-5-mercapto-1,3,4-thiadiazole, respectively. Recoveries of cabbage and soil were investigated at three spiking levels and were in the range of 84.0 96.0% for bismerthiazol and 71.0-74.6% for 2-amino-5-mercapto-1,3,4-thiadiazole, with relative standard deviations below 7.0%. For field experiments, the half life of bismerthiazol was 2.4-2.5 days in Chinese cabbage and 2.5-4.8 days in soil at the two experimental locations in China. Dissipation residues of 2-amino 5-mercapto-1,3,4-thiadiazole were lower than 0.72 mg/kg. Terminal residues of bismerthiazol and its metabolite were less than 3.0 and 0.3 mg/kg in Chinese cabbage, respectively. No bismerthiazol or metabolite residues were detected in soil on days 5, 7, 10, and 14 after the last spraying at the two dosage levels. PMID- 24065136 TI - Development of a finite element human head model partially validated with thirty five experimental cases. AB - This study is aimed to develop a high quality, extensively validated finite element (FE) human head model for enhanced head injury prediction and prevention. The geometry of the model was based on computed tomography (CT) and magnetic resonance imaging scans of an adult male who has the average height and weight of an American. A feature-based multiblock technique was adopted to develop hexahedral brain meshes including the cerebrum, cerebellum, brainstem, corpus callosum, ventricles, and thalamus. Conventional meshing methods were used to create the bridging veins, cerebrospinal fluid, skull, facial bones, flesh, skin, and membranes-including falx, tentorium, pia, arachnoid, and dura. The head model has 270,552 elements in total. Thirty five loading cases were selected from a range of experimental head impacts to check the robustness of the model predictions based on responses including the brain pressure, relative skull-brain motion, skull response, and facial response. The brain pressure was validated against intracranial pressure data reported by Nahum et al. (1977, "Intracranial Pressure Dynamics During Head Impact," Proc. 21st Stapp Car Crash Conference, SAE Technical Paper No. 770922) and Trosseille et al. (1992, "Development of a F.E.M. of the Human Head According to a Specific Test Protocol," Proc. 36th Stapp Car Crash Conference, SAE Technical Paper No. 922527). The brain motion was validated against brain displacements under sagittal, coronal, and horizontal blunt impacts performed by Hardy et al. (2001, "Investigation of Head Injury Mechanisms Using Neutral Density Technology and High-Speed Biplanar X-Ray," Stapp Car Crash Journal, 45, pp. 337-368; and 2007, "A Study of the Response of the Human Cadaver Head to Impact," Stapp Car Crash Journal, 51, pp. 17-80). The facial bone responses were validated under nasal impact (Nyquist et al. 1986, "Facial Impact Tolerance and Response," Proc. 30th Stapp Car Crash Conference, SAE Technical Paper No. 861896), zygoma and maxilla impact (Allsop et al. 1988, "Facial Impact Response - A Comparison of the Hybrid III Dummy and Human Cadaver," Proc. 32nd Stapp Car Crash Conference, SAE Technical Paper No. 881719)]. The skull bones were validated under frontal angled impact, vertical impact, and occipital impact (Yoganandan et al. 1995, "Biomechanics of Skull Fracture," J Neurotrauma, 12(4), pp. 659-668) and frontal horizontal impact (Hodgson et al. 1970, "Fracture Behavior of the Skull Frontal Bone Against Cylindrical Surfaces," 14th Stapp Car Crash Conference, SAE International, Warrendale, PA). The FE head model was further used to study injury mechanisms and tolerances for brain contusion (Nahum et al. 1976, "An Experimental Model for Closed Head Impact Injury," 20th Stapp Car Crash Conference, SAE International, Warrendale, PA). Studies from 35 loading cases demonstrated that the FE head model could predict head responses which were comparable to experimental measurements in terms of pattern, peak values, or time histories. Furthermore, tissue-level injury tolerances were proposed. A maximum principal strain of 0.42% was adopted for skull cortical layer fracture and maximum principal stress of 20 MPa was used for skull diploe layer fracture. Additionally, a plastic strain threshold of 1.2% was used for facial bone fracture. For brain contusion, 277 kPa of brain pressure was calculated from reconstruction of one contusion case. PMID- 24065137 TI - [Annual Report 2011 of the German pacemaker and defibrillator register: Section pacemakers and AQUA-Institute for Applied Quality Improvement and Research in Health Care]. PMID- 24065138 TI - Assessment of biological characteristics of adipose tissue-derived stem cells co labeled with Molday ION Rhodamine BTM and green fluorescent protein in vitro. AB - The current study aimed to investigate adipose tissue-derived stem cells (ADSCs) in vivo by multimodality imaging following implantation for cellular therapy. The biological characteristics of ADSCs co-labeled with Molday ION Rhodamine BTM (MIRB) and green fluorescent protein (GFP) were studied in vitro. Following rat ADSC isolation and culture, a combined labeling strategy for ADSCs based on genetic modification of the reporter gene GFP with lentiviral vector expression enhancement and physical MIRB labeling was performed. Cell viability, proliferation, membrane-bound antigens and multiple differentiation ability were compared between the labeled and unlabeled ADSCs. The ADSCs were successfully labeled with GFP and MIRB, showing various fluorescent colors for marker identification. The fluorescence emitted by the GFP protein was sustained and exhibited stable expression, while MIRB fluorescence decreased with time. Compared with the unlabeled ADSCs, no significant differences were detected in cell viability, proliferation, membrane-bound antigens and multiple differentiation ability in the co-labeled samples (P>0.05). No significant effects on the biophysical properties of ADSCs were observed following co labeling with lentiviral vectors encoding the gene for emerald green fluorescent protein and MIRB. The ADSCs were able to be efficiently tracked in vitro and in vivo by multimodality imaging thus, the co-labeling approach provides a novel strategy for therapeutic gene studies. PMID- 24065139 TI - Safety of veralipride for the treatment of vasomotor symptoms of menopause. AB - OBJECTIVE: Veralipride is a nonhormonal option for the treatment of vasomotor symptoms of menopause. Incidence of adverse events in a Mexican population and drug compliance according to correct use were evaluated. METHODS: We carried out a longitudinal, prospective, and analytical study in Mexican women who received veralipride to treat symptoms of menopause from 2011 to 2012. There were 386 treatment cycles; 272 were assigned to dosing schedule 1, which included 20 days of treatment with 10 days of suspension, and 114 were assigned to dosing schedule 2, which included 5 days of treatment and 2 days of suspension. RESULTS: A total of 57 adverse events were registered during the 386-month treatment. For the 20 * 10 dosing schedule, the highest incidence was observed for anxiety (2.2%), drowsiness, and weakness (1.5%); for the 5 * 2 dosing schedule, the highest incidence was observed for drowsiness (5.3%) and headache (2.6%). The Hamilton Depression Rating Scale was used to assess the presence and severity of depression; improvement was noted. The Unified Parkinson's Disease Rating Scale was used to assess neurological movement disorders; no adverse neurological events were detected. Based on the assessments of both women and physicians, the highest frequency was observed for "very satisfied" (45.5% and 52.3%, respectively), followed by "satisfied" (23.9% and 27.3%, respectively). CONCLUSIONS: Both dosing schedules show acceptable safety profiles for up to 6 months of use when used according to the contraindications in the current prescribing information for standard use (2012) and recent medical literature. PMID- 24065140 TI - Melatonin in perimenopausal and postmenopausal women: associations with mood, sleep, climacteric symptoms, and quality of life. AB - OBJECTIVE: Melatonin synthesis and secretion are partly modulated by estrogen and progesterone. Changes in melatonin concentrations, possibly related to the menopausal transition, may be associated with climacteric mood, sleep, and vasomotor symptoms. The aims of this study were to compare the serum concentrations of melatonin in perimenopausal and postmenopausal women and to evaluate melatonin's influence on mood, sleep, vasomotor symptoms, and quality of life. METHODS: We analyzed the data of 17 healthy perimenopausal women (aged 43 51 y) and 18 healthy postmenopausal women (aged 58-71 y) who participated in a prospective study. On study night (9:00 pm-9:00 am), serum melatonin was sampled at 20-minute (9:00 pm-12:00 midnight; 6:00-9:00 am) and 1-hour (12:00 midnight 6:00 am) intervals. Questionnaires were used to assess depression (Beck Depression Inventory), anxiety (State-Trait Anxiety Inventory), insomnia and sleepiness (Basic Nordic Sleep Questionnaire [BNSQ]), subjective sleep quality, vasomotor symptoms, and quality of life (EuroQoL). RESULTS: Postmenopausal women had lower nighttime serum melatonin concentrations than perimenopausal women. The duration of melatonin secretion tended to be shorter in postmenopause, whereas melatonin peak time did not differ. Mean melatonin concentrations and exposure levels did not correlate with follicle-stimulating hormone level, estradiol level, body mass index, Beck Depression Inventory score, State-Trait Anxiety Inventory score, BNSQ insomnia score, BNSQ sleepiness score, subjective sleep score, climacteric vasomotor score, or quality of life. In perimenopause, the later is the melatonin peak, the higher is the level of anxiety (P = 0.022), and the longer is the melatonin secretion, the better is the quality of life (P < 0.001). CONCLUSIONS: Longitudinal research is needed to better understand the possible contributory role of menopause in lower melatonin levels. PMID- 24065142 TI - Focus issue: networking cancer treatment strategies. AB - Receptor tyrosine kinases and the signaling networks that they control contribute to cancer and resistance to therapies. Therefore, understanding these networks, how they vary within and among tumors and how they adapt to enable cancer cells to circumvent treatment, should lead to more effective therapeutic strategies in treating the diverse disease that is cancer. As Science Signaling highlights in this week's issue, systems biology and computational biology are shining light on these complex networks and enabling integration of diverse information about genetics, proteomics, and network activity to effectively predict therapeutic response and identify key components to target for intervention. PMID- 24065141 TI - REG Ialpha gene expression is linked with the poor prognosis of lung adenocarcinoma and squamous cell carcinoma patients via discrete mechanisms. AB - The aim of the present study was to evaluate the effects of the REG Ialpha and REG Ibeta genes on lung cancer cell lines, and thereafter, the expression of REG family genes (REG Ialpha, REG Ibeta, REG III, HIP/PAP and REG IV) in lung cancer in relation to patient prognosis was evaluated. Lung adenocarcinoma (AD) and squamous cell carcinoma (SCC) cell lines expressing REG Ialpha or REG Ibeta (HLC 1 REG Ialpha/Ibeta and EBC-1 REG Ialpha/Ibeta) were established, and cell number, cell invasive activity, and anchorage-independent cell growth were compared with these variables in the control cells. The expression levels of REG family genes were evaluated by real-time RT-PCR in surgically resected lung cancers, and disease-specific survival (DSS) curves were generated. The HLC-1 REG Ialpha/Ibeta cell line showed significant increases in cell number and anchorage-independent cell growth compared with the control cells. EBC-1 REG Ialpha/Ibeta cells showed significant increases in cell invasive activity and anchorage-independent cell growth as compared with the control cells. Except for the REG Ibeta gene, expression of other REG family genes was observed in the surgically resected samples; however, DSS was significantly worse only in stage I patients who were positive for REG Ialpha expression than in patients who were negative for REG Ialpha expression. The effects of REG Ialpha on AD and SCC cells were different in the in vitro study, and a correlation between REG Ialpha expression and patient prognosis was noted in the in vivo study. Therefore, overexpression of REG Ialpha is a risk factor for poor prognosis caused by discrete mechanisms in AD and SCC patients. PMID- 24065143 TI - mTORC1 status dictates tumor response to targeted therapeutics. AB - Genomics has revolutionized and personalized our approach to cancer therapy, with clinical trials now frequently involving patient stratification based on tumor genotype. Rational drug design specifically targeting the most common genetic events and aberrantly regulated pathways in human cancers makes this approach possible. However, our understanding of the wiring of oncogenic signaling networks and the key downstream effectors driving human cancers is incomplete, limiting our ability to predict clinical responses or identify mechanisms of resistance to targeted therapeutics. Recent studies in independent cancer lineages driven by distinct oncogenic signaling events point to a common downstream target, the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1), which dictates the cellular and clinical response to pathway-specific inhibitors. mTORC1 is a highly integrated signaling node that promotes anabolic cell growth and proliferation and lies downstream of multiple oncogenes and tumor suppressors, including those influencing the PI3K-Akt and RAS-RAF-MEK-ERK pathways. Studies are now suggesting that to effectively target the major oncogenic signaling pathway in a given tumor, mTORC1 must be inhibited, and that its sustained activation is a major mechanism of resistance to such targeted therapies. PMID- 24065144 TI - What lies beneath: looking beyond tumor genetics shows the complexity of signaling networks underlying drug sensitivity. AB - The identification of "driver mutations" in cancers initiated rapid development of targeted drugs for the clinic. Despite promising outcomes initially in patients, the ultimate success of oncogene-targeted drugs has been hampered by the redundancy and remarkable complexity of cellular signaling pathways. Two studies in Science Signaling show that understanding these intricate networks and considering them during tumor classification and drug design can better predict drug response. These studies exemplify the potential of using systems analysis and computational modeling approaches to improve therapeutic strategies and outcomes in cancer patients. PMID- 24065145 TI - Profiles of Basal and stimulated receptor signaling networks predict drug response in breast cancer lines. AB - Identifying factors responsible for variation in drug response is essential for the effective use of targeted therapeutics. We profiled signaling pathway activity in a collection of breast cancer cell lines before and after stimulation with physiologically relevant ligands, which revealed the variability in network activity among cells of known genotype and molecular subtype. Despite the receptor-based classification of breast cancer subtypes, we found that the abundance and activity of signaling proteins in unstimulated cells (basal profile), as well as the activity of proteins in stimulated cells (signaling profile), varied within each subtype. Using a partial least-squares regression approach, we constructed models that significantly predicted sensitivity to 23 targeted therapeutics. For example, one model showed that the response to the growth factor receptor ligand heregulin effectively predicted the sensitivity of cells to drugs targeting the cell survival pathway mediated by PI3K (phosphoinositide 3-kinase) and Akt, whereas the abundance of Akt or the mutational status of the enzymes in the pathway did not. Thus, basal and signaling protein profiles may yield new biomarkers of drug sensitivity and enable the identification of appropriate therapies in cancers characterized by similar functional dysregulation of signaling networks. PMID- 24065146 TI - Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets. AB - Dedifferentiated liposarcoma (DDLS) is a rare but aggressive cancer with high recurrence and low response rates to targeted therapies. Increasing treatment efficacy may require combinations of targeted agents that counteract the effects of multiple abnormalities. To identify a possible multicomponent therapy, we performed a combinatorial drug screen in a DDLS-derived cell line and identified cyclin-dependent kinase 4 (CDK4) and insulin-like growth factor 1 receptor (IGF1R) as synergistic drug targets. We measured the phosphorylation of multiple proteins and cell viability in response to systematic drug combinations and derived computational models of the signaling network. These models predict that the observed synergy in reducing cell viability with CDK4 and IGF1R inhibitors depends on the activity of the AKT pathway. Experiments confirmed that combined inhibition of CDK4 and IGF1R cooperatively suppresses the activation of proteins within the AKT pathway. Consistent with these findings, synergistic reductions in cell viability were also found when combining CDK4 inhibition with inhibition of either AKT or epidermal growth factor receptor (EGFR), another receptor similar to IGF1R that activates AKT. Thus, network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer specific signaling mechanisms and aid in the design of effective combination therapies. PMID- 24065147 TI - Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. AB - Receptor tyrosine kinases (RTKs) are activated by somatic genetic alterations in a subset of cancers, and such cancers are often sensitive to specific inhibitors of the activated kinase. Two well-established examples of this paradigm include lung cancers with either EGFR mutations or ALK translocations. In these cancers, inhibition of the corresponding RTK leads to suppression of key downstream signaling pathways, such as the PI3K (phosphatidylinositol 3-kinase)/AKT and MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase) pathways, resulting in cell growth arrest and death. Despite the initial clinical efficacy of ALK (anaplastic lymphoma kinase) and EGFR (epidermal growth factor receptor) inhibitors in these cancers, resistance invariably develops, typically within 1 to 2 years. Over the past several years, multiple molecular mechanisms of resistance have been identified, and some common themes have emerged. One is the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective RTK. A second is activation of alternative RTKs that maintain the signaling of key downstream pathways despite sustained inhibition of the original drug target. Indeed, several different RTKs have been implicated in promoting resistance to EGFR and ALK inhibitors in both laboratory studies and patient samples. In this mini review, we summarize the concepts underlying RTK-mediated resistance, the specific examples known to date, and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance. PMID- 24065148 TI - Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) infection caused severe pneumonia and multiorgan dysfunction and had a higher crude fatality rate (around 50% vs. 10%) than SARS coronavirus (SARS-CoV) infection. To understand the pathogenesis, we studied viral replication, cytokine/chemokine response, and antigen presentation in MERS-CoV-infected human monocyte-derived macrophages (MDMs) versus SARS-CoV-infected MDMs. Only MERS-CoV can replicate in MDMs. Both viruses were unable to significantly stimulate the expression of antiviral cytokines (interferon alpha [IFN-alpha] and IFN-beta) but induced comparable levels of tumor necrosis factor alpha and interleukin 6. Notably, MERS-CoV induced significantly higher expression levels of interleukin 12, IFN-gamma, and chemokines (IP-10/CXCL-10, MCP-1/CCL-2, MIP-1alpha/CCL-3, RANTES/CCL-5, and interleukin 8) than SARS-CoV. The expression of major histocompatibility complex class I and costimulatory molecules were significantly higher in MERS-CoV infected MDMs than in SARS-CoV-infected cells. MERS-CoV replication was validated by immunostaining of infected MDMs and ex vivo lung tissue. We conclusively showed that MERS-CoV can establish a productive infection in human macrophages. The aberrant induction of inflammatory cytokines/chemokines could be important in the disease pathogenesis. PMID- 24065149 TI - Alternative mutational pathways to increased vancomycin resistance in MRSA. PMID- 24065150 TI - Gold nanorods as multifunctional probes in a liquid crystalline DNA matrix. AB - We show how a single gold nanorod can serve as a multifunctional probe in an organized DNA matrix. Polarization analysis of two-photon luminescence excited with a femtosecond laser enables imaging of the orientation of a single nanorod, which reports the orientation of DNA strands. Carefully controlled photoinduced heating by the same laser is able to degrade the DNA matrix in a highly localized volume. PMID- 24065151 TI - Increasing burden, younger age at onset and worst metabolic control in migrant than in Italian children with type 1 diabetes: an emerging problem in pediatric clinics. AB - To assess burden and clinical features of type 1 diabetes in migrant with respect to Italian children. Prevalent children with type 1 diabetes were identified through a multicenter study, including 46 pediatric outpatients diabetic clinics. A nested case-control study was also performed, comparing features at diabetes onset and after 1 year of insulin treatment in 84 migrants and 75 Italian children with onset in 2011, matched for age and sex. Out of 7,812 children cared for by pediatric diabetologists, 761 (10%) were migrant and 548 of them were born in Italy. Age at diagnosis was lower in migrants born in Italy (5.1 years, interquartile range (IQR) 2.2-7.7) than in those born in their original countries (7.8 years, IQR 5.3-10.3) and in Italians (9.8 years, IQR 5.9-13.0, p < 0.001). At diabetes onset, migrants had lower frequencies of positivities of markers of beta-cell autoimmunity (96 vs. 99.5%, p < 0.01), higher values of weight loss (11 vs. 7%, p < 0.01), HbA1c (70 vs. 58 mmol/mol, p < 0.001), and insulin requirement (0.70 +/- 0.03 vs. 0.63 +/- 0.10 UI/kg/die, p = 0.05) and lower levels of 25-OH vitamin D3 (15.0 +/- 2.8 vs. 20.8 +/- 1.3, p = 0.03). Moreover, they experienced higher frequencies of hospitalizations during the first year of disease (19.2 vs. 2.7%, p < 0.001). Burden of type 1 diabetes in migrant children is increasing in Italy, with younger age at onset and different clinical features than in Italian children. Higher hospitalization rates and poorer glycemic control over the first year underline that approach to diabetes care in migrants needs to be improved. PMID- 24065152 TI - Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue. AB - AIMS/HYPOTHESIS: Insulin therapy in patients with type 2 diabetes mellitus is accompanied by weight gain characterised by an increase in abdominal fat mass. The expansion of adipose tissue mass is generally paralleled by profound morphological and inflammatory changes. We hypothesised that the insulin associated increase in fat mass would also result in changes in the morphology of human subcutaneous adipose tissue and in increased inflammation, especially when weight gain was excessive. METHODS: We investigated the effects of weight gain on adipocyte size, macrophage influx, and mRNA expression and protein levels of key inflammatory markers within the adipose tissue in patients with type 2 diabetes mellitus before and 6 months after starting insulin therapy. RESULTS: As expected, insulin therapy significantly increased body weight. At the level of the subcutaneous adipose tissue, insulin treatment led to an influx of macrophages. When comparing patients gaining no or little weight with patients gaining >4% body weight after 6 months of insulin therapy, both subgroups displayed an increase in macrophage influx. However, individuals who had gained weight had higher protein levels of monocyte chemoattractant protein-1, TNF-alpha and IL-1beta after 6 months of insulin therapy compared with those who had not gained weight. CONCLUSIONS/INTERPRETATION: We conclude that insulin therapy in patients with type 2 diabetes mellitus improved glycaemic control but also induced body weight gain and an influx of macrophages into the subcutaneous adipose tissue. In patients characterised by a pronounced insulin-associated weight gain, the influx of macrophages into the adipose tissue was accompanied by a more pronounced inflammatory status. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00781495. FUNDING: The study was funded by European Foundation for the Study of Diabetes and the Dutch Diabetes Research Foundation. PMID- 24065155 TI - The simple hydrothermal synthesis of Ag-ZnO-SnO2 nanochain and its multiple applications. AB - In this article, we report the fabrication of a stable Ag-ZnO-SnO2 nanochain by template free hydrothermal method and its photocatalytic activity for the first time. This composite material represents a potential new class of photocatalysts with enhanced light absorption, hydrophobic and electronic properties of ZnO. This catalyst has been characterized by X-ray diffraction (XRD), high resolution scanning electron microscopy (HRSEM), field emission scanning electron microscopy (FESEM), elemental mapping, energy dispersive spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), UV-Vis diffuse reflectance spectroscopy (DRS) and photoluminescence spectroscopy (PL). XRD and elemental mapping reveal the presence of SnO2 and Ag in the catalyst. Ag-ZnO-SnO2 has increased absorption in the visible region when compared to ZnO. This three component nano junction system exhibits enhanced photocatalytic activity for the degradation of azo dyes, Acid Black 1 (AB 1) and Acid Violet 7 (AV 7) under UV light (365 nm), far exceeding those of the single and two component systems. Ag-ZnO-SnO2 is found to be reusable without appreciable loss of catalytic activity up to four runs. Based on the band gap energies of ZnO and SnO2, a mechanism is proposed for the photodegradation of dyes. Hydrophobicity and photoconductivity of Ag-ZnO-SnO2 have been evaluated. Nanochain exhibiting higher positive photoconductivity can be useful for soliton wave communication as well as solar cell applications. Our results provide some new insights on the fabrication of Ag-ZnO-SnO2 and its performance as an active photocatalyst, self cleaning and conducting material. PMID- 24065153 TI - HbA1c, fasting and 2 h plasma glucose in current, ex- and never-smokers: a meta analysis. AB - AIMS/HYPOTHESIS: The relationships between smoking and glycaemic variables have not been well explored. We compared HbA1c, fasting plasma glucose (FPG) and 2 h plasma glucose (2H-PG) in current, ex- and never-smokers. METHODS: This meta analysis used individual data from 16,886 men and 18,539 women without known diabetes in 12 DETECT-2 consortium studies and in the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) and Telecom studies. Means of three glycaemic variables in current, ex- and never-smokers were modelled by linear regression, with study as a random factor. The I (2) statistic was used to evaluate heterogeneity among studies. RESULTS: HbA1c was 0.10% (95% CI 0.08, 0.12) (1.1 mmol/mol [0.9, 1.3]) higher in current smokers and 0.03% (0.01, 0.05) (0.3 mmol/mol [0.1, 0.5]) higher in ex-smokers, compared with never-smokers. For FPG, there was no significant difference between current and never-smokers (-0.004 mmol/l [-0.03, 0.02]) but FPG was higher in ex-smokers (0.12 mmol/l [0.09, 0.14]). In comparison with never-smokers, 2H-PG was lower ( 0.44 mmol/l [-0.52, -0.37]) in current smokers, with no difference for ex-smokers (0.02 mmol/l [-0.06, 0.09]). There was a large and unexplained heterogeneity among studies, with I (2) always above 50%; I (2) was little changed after stratification by sex and adjustment for age and BMI. In this study population, current smokers had a prevalence of diabetes that was 1.30% higher as screened by HbA1c and 0.52% lower as screened by 2H-PG, in comparison with never-smokers. CONCLUSION/INTERPRETATION: Across this heterogeneous group of studies, current smokers had a higher HbA1c and lower 2H-PG than never-smokers. This will affect the chances of smokers being diagnosed with diabetes. PMID- 24065154 TI - Maternal diabetes in pregnancy and offspring cognitive ability: sibling study with 723,775 men from 579,857 families. AB - AIMS/HYPOTHESIS: The aim of this study was to investigate the association between maternal diabetes in pregnancy and offspring cognitive ability and also to assess whether the association was due to intrauterine mechanisms or shared familial characteristics. METHODS: We linked national registers and conducted a prospective cohort study of singleton Swedish-born men to explore associations between maternal pregnancy diabetes and educational achievement at age 16 years, the age of completing compulsory education in Sweden (n = 391,545 men from 337,174 families, graduating in 1988-1997 and n = 326,033 men from 282,079 families, graduating in 1998-2009), and intelligence quotient (IQ) at the mandatory conscription examination at 18 years of age (n = 664,871 from 543,203 families). RESULTS: Among non-siblings, maternal diabetes in pregnancy was associated with lower offspring cognitive ability even after adjustment for maternal age at birth, parity, education, early-pregnancy BMI, offspring birth year, gestational age and birthweight. For example, in non-siblings, the IQ of men whose mothers had diabetes in their pregnancy was on average 1.36 points lower (95% CI -2.12, -0.60) than men whose mothers did not have diabetes. In comparison, we found no such association within sibships (mean difference 1.70; 95% CI -1.80, 5.21). CONCLUSIONS/INTERPRETATION: The association between maternal diabetes in pregnancy and offspring cognitive outcomes is likely explained by shared familial characteristics and not by an intrauterine mechanism. PMID- 24065156 TI - Conformations of D-xylose: the pivotal role of the intramolecular hydrogen bonding. AB - Crystalline samples of D-xylose have been vaporized by laser ablation and probed in the gas phase using Fourier transform microwave spectroscopy. The rotational spectrum revealed the existence of two alpha-D-xylopyranose conformers stabilized by the anomeric effect and cooperative hydrogen bond networks. The experiment spectroscopically tracked fine structural changes upon clockwise and counterclockwise arrangements of the OH groups in the observed conformers. The five monosubstituted (13)C species of the most abundant conformer cc-alpha-(4)C1 have also been observed in their natural abundance, and its structure has been derived. This work demonstrates the pivotal role that the intramolecular hydrogen bonding network plays in the conformational behavior of free monosaccharides. PMID- 24065157 TI - Glycosylated porphyra-334 and palythine-threonine from the terrestrial cyanobacterium Nostoc commune. AB - Mycosporine-like amino acids (MAAs) are water-soluble UV-absorbing pigments, and structurally different MAAs have been identified in eukaryotic algae and cyanobacteria. In this study novel glycosylated MAAs were found in the terrestrial cyanobacterium Nostoc commune (N. commune). An MAA with an absorption maximum at 334 nm was identified as a hexose-bound porphyra-334 derivative with a molecular mass of 508 Da. Another MAA with an absorption maximum at 322 nm was identified as a two hexose-bound palythine-threonine derivative with a molecular mass of 612 Da. These purified MAAs have radical scavenging activities in vitro, which suggests multifunctional roles as sunscreens and antioxidants. The 612-Da MAA accounted for approximately 60% of the total MAAs and contributed approximately 20% of the total radical scavenging activities in a water extract, indicating that it is the major water-soluble UV-protectant and radical scavenger component. The hexose-bound porphyra-334 derivative and the glycosylated palythine-threonine derivatives were found in a specific genotype of N. commune, suggesting that glycosylated MAA patterns could be a chemotaxonomic marker for the characterization of the morphologically indistinguishable N. commune. The glycosylation of porphyra-334 and palythine-threonine in N. commune suggests a unique adaptation for terrestrial environments that are drastically fluctuating in comparison to stable aquatic environments. PMID- 24065158 TI - Silaffins of diatoms: from applied biotechnology to biomedicine. AB - Silaffins are involved in the formation of the cell walls of diatoms. It is known that silaffins can precipitate silica in vitro, forming nano- and micro-particles in the shape of spheres and plates containing many pores. It is important to note that the deposition of silica and the particle morphology in the presence of silaffins affects chemical and physical agents (e.g., peptides, polyamines, phosphate, nitrogen, and the mechanical changes of the reaction mixture). It is believed that silaffins act as an organic matrix for silica-genesis and that silica pore size should reflect the pattern of a matrix. Here, biotechnology related to silaffins is discussed in the context of "a hypothesis of silaffin matrix" and "the LCPA-phosphate model". We discuss the most promising area of silaffin biotechnology--the development of production methods for silicon structures with desired shapes and nanostructural properties that can be used to create biocompatible materials. PMID- 24065159 TI - Towards the small and the beautiful: a small dibromotyrosine derivative from Pseudoceratina sp. sponge exhibits potent apoptotic effect through targeting IKK/NFkappaB signaling pathway. AB - A dibromotyrosine derivative, (1'R,5'S,6'S)-2-(3',5'-dibromo-1',6'-dihydroxy-4' oxocyclohex-2'-enyl) acetonitrile (DT), was isolated from the sponge Pseudoceratina sp., and was found to exhibit a significant cytotoxic activity against leukemia K562 cells. Despite the large number of the isolated bromotyrosine derivatives, studies focusing on their biological mechanism of action are scarce. In the current study we designed a set of experiments to reveal the underlying mechanism of DT cytotoxic activity against K562 cells. First, the results of MTT cytotoxic and the annexin V-FITC/PI apoptotic assays, indicated that the DT cytotoxic activity is mediated through induction of apoptosis. This effect was also supported by caspases-3 and -9 activation as well as PARP cleavage. DT induced generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP) as indicated by flow cytometric assay. The involvement of ROS generation in the apoptotic activity of DT was further corroborated by the pretreatment of K562 cells with N-acetyl cysteine (NAC), a ROS scavenger, which prevented apoptosis and the disruption of MMP induced by DT. Results of cell-free system assay suggested that DT can act as a topoisomerase II catalytic inhibitor, unlike the clinical anticancer drug, etoposide, which acts as a topoisomerase poison. Additionally, we found that DT treatment can block IKK/NFkappaB pathway and activate PI3K/Akt pathway. These findings suggest that the cytotoxic effect of DT is associated with mitochondrial dysfunction-dependent apoptosis which is mediated through oxidative stress. Therefore, DT represents an interesting reference point for the development of new cytotoxic agent targeting IKK/NFkappaB pathway. PMID- 24065160 TI - Sarcophyolides B-E, new cembranoids from the soft coral Sarcophyton elegans. AB - Four new cembrane-type diterpenoids, sarcophyolides B-E (1-4), along with 11 known analogues were isolated from the soft coral Sarcophyton elegans. The structures of new compounds 1-4 were established on the basis of spectroscopic analysis and chemical conversion. The new cembranoids sarcophyolides B (1) and lobocrasol were found to exhibit potent inhibition against A2780 human ovarian tumor cells. PMID- 24065161 TI - Influence of lipid A acylation pattern on membrane permeability and innate immune stimulation. AB - Lipid A, the hydrophobic anchor of lipopolysaccharide (LPS), is an essential component in the outer membrane of Gram-negative bacteria. It can stimulate the innate immune system via Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD2), leading to the release of inflammatory cytokines. In this study, six Escherichia coli strains which can produce lipid A with different acylation patterns were constructed; the influence of lipid A acylation pattern on the membrane permeability and innate immune stimulation has been systematically investigated. The lipid A species were isolated and identified by matrix assisted laser ionization desorption-time of flight/tandem mass spectrometry. N-Phenyl naphthylamine uptake assay and antibiotic susceptibility test showed that membrane permeability of these strains were different. The lower the number of acyl chains in lipid A, the stronger the membrane permeability. LPS purified from these strains were used to stimulate human or mouse macrophage cells, and different levels of cytokines were induced. Compared with wild type hexa-acylated LPS, penta-acylated, tetra-acylated and tri-acylated LPS induced lower levels of cytokines. These results suggest that the lipid A acylation pattern influences both the bacterial membrane permeability and innate immune stimulation. The results would be useful for redesigning the bacterial membrane structure and for developing lipid A vaccine adjuvant. PMID- 24065162 TI - Marine derived hamacanthins as lead for the development of novel PDGFRbeta protein kinase inhibitors. AB - In this study, we report on pyrazin-2(1H)-ones as lead for the development of potent adenosine triphosphate (ATP) competitive protein kinase inhibitors with implications as anti-cancer drugs. Initially, we identified the pyrazin-2(1H)-one scaffold from hamacanthins (deep sea marine sponge alkaloids) by Molecular Modeling studies as core binding motif in the ATP pocket of receptor tyrosine kinases (RTK), which are validated drug targets for the treatment of various neoplastic diseases. Structure-based design studies on a human RTK member PDGFR (platelet-derived growth factor receptor) suggested a straight forward lead optimization strategy. Accordingly, we focused on a Medicinal Chemistry project to develop pyrazin-2(1H)-ones as optimized PDGFR binders. In order to reveal Structure-Activity-Relationships (SAR), we established a flexible synthetic route via microwave mediated ring closure to asymmetric 3,5-substituted pyrazin-2(1H) ones and produced a set of novel compounds. Herein, we identified highly potent PDGFR binders with IC50 values in an enzymatic assay below uM range, and possessing significant activity against PDGFR dependent cancer cells. Thus, marine hamacanthin-derived pyrazin-2(1H)-ones showing interesting properties as lead for their further development towards potent PDGFR-inhibitors. PMID- 24065164 TI - Cyclodextrin formulation of the marine natural product pseudopterosin A uncovers optimal pharmacodynamics in proliferation studies of human umbilical vein endothelial cells. AB - Pseudopterosin A (PsA) treatment of growth factor depleted human umbilical vein endothelial cell (HUVEC) cultures formulated in hydroxypropyl-beta-cyclodextrin (HPbetaCD) for 42 h unexpectedly produced a 25% increase in cell proliferation (EC50 = 1.34 * 10-8 M). Analysis of dose response curves revealed pseudo-first order saturation kinetics, and the uncoupling of cytotoxicity from cell proliferation, thereby resulting in a widening of the therapeutic index. The formulation of PsA into HPbetaCD produced a 200-fold increase in potency over a DMSO formulation; we propose this could result from a constrained presentation of PsA to the receptor, which would limit non-specific binding. These results support the hypothesis that the non-specific receptor binding of PsA when formulated in DMSO has ostensibly masked prior estimates of specific activity, potency, and mechanism. Collectively, these results suggest that the formulation of PsA and compounds of similar chemical properties in HPbetaCD could result in significant pharmacological findings that may otherwise be obscured when using solvents such as DMSO. PMID- 24065163 TI - Epigonal conditioned media from bonnethead shark, Sphyrna tiburo, induces apoptosis in a T-cell leukemia cell line, Jurkat E6-1. AB - Representatives of Subclass Elasmobranchii are cartilaginous fish whose members include sharks, skates, and rays. Because of their unique phylogenetic position of being the most primitive group of vertebrates to possess all the components necessary for an adaptive immune system, the immune regulatory compounds they possess may represent the earliest evolutionary forms of novel compounds with the potential for innovative therapeutic applications. Conditioned medium, generated from short term culture of cells from the epigonal organ of bonnethead sharks (Sphyrna tiburo), has been shown to have potent reproducible cytotoxic activity against a variety of human tumor cell lines in vitro. Existing data suggest that epigonal conditioned medium (ECM) exerts this cytotoxic activity through induction of apoptosis in target cells. This manuscript describes apoptosis induction in a representative tumor cell line, Jurkat E6-1, in response to treatment with ECM at concentrations of 1 and 2 mg/mL. Data indicate that ECM exposure initiates the mitochondrial pathway of apoptosis through activation of caspase enzymes. Future purification of ECM components may result in the isolation of an immune-regulatory compound with potential therapeutic benefit for treatment of human cancer. PMID- 24065165 TI - Adverse effect of antifouling compounds on the reproductive mechanisms of the ascidian Ciona intestinalis. AB - Fertilization and embryo development that occur in sea water are sensitive to xenobiotics from anthropogenic sources. In this work, we evaluated the influence of two antifouling biocides, tributyltin (TBT) and diuron, on the reproductive mechanisms of the marine invertebrate Ciona intestinalis. By using electrophysiological techniques, we examined the impact of these compounds on the electrical properties of the mature oocytes and of events occurring at fertilization. With different toxicity assays, we studied the effect of the two biocides on the gametes by evaluating fertilization rate and embryo development. Results show that sodium (Na+) currents were significantly reduced by either of the two biocides, whereas conductance was significantly increased. The fertilization current frequency and amplitude, fertilization rate and larval development were affected only by TBT. This study suggests that: (i) the two biocides affect either the electrical properties of the oocyte plasma membrane and the reproductive success representing a risk factor for the survival of the species exposed to environmental pollution; (ii) the ascidian Ciona intestinalis may represent a good model organism to test toxicity of marine pollutants. Possible mechanisms of action of the two biocides are discussed. PMID- 24065167 TI - Response to Ijaz S, et al. "Night-shift work and breast cancer--a systematic review and meta-analysis". PMID- 24065166 TI - Limited impact of 2 g/day omega-3 fatty acid ethyl esters (Omacor(r)) on plasma lipids and inflammatory markers in patients awaiting carotid endarterectomy. AB - The objective of this study was to determine the effects of prescription omega-3 (n-3) fatty acid ethyl esters (Omacor(r)) on blood pressure, plasma lipids, and inflammatory marker concentrations in patients awaiting carotid endarterectomy. Patients awaiting carotid endarterectomy (n = 121) were randomised to Omacor(r) or olive oil as placebo (2 g/day) until surgery (median 21 days). Blood pressure, plasma lipids, and plasma inflammatory markers were determined. There were significant decreases in systolic and diastolic blood pressure and in plasma triglyceride, total cholesterol, low density lipoprotein-cholesterol, soluble vascular cellular adhesion molecule 1, and matrix metalloproteinase 2 concentrations, in both groups. The extent of triglyceride lowering was greater with Omacor(r) (25%) compared with placebo (9%). Soluble E-selectin concentration was significantly decreased in the Omacor(r) group but increased in the placebo group. At the end of the supplementation period there were no differences in blood pressure or in plasma lipid and inflammatory marker concentrations between the two groups. It is concluded that Omacor(r) given at 2 g/day for an average of 21 days to patients with advanced carotid atherosclerosis lowers triglycerides and soluble E-selectin concentrations, but has limited broad impact on the plasma lipid profile or on inflammatory markers. This may be because the duration of intervention was too short or the dose of n-3 fatty acids was too low. PMID- 24065169 TI - Multifunctional MnO2 nanosheet-modified Fe3O4@SiO2/NaYF4:Yb, Er nanocomposites as novel drug carriers. AB - We report on a novel drug carrier which is based on the combination of magnetic and upconversion (UC) emission of Fe3O4@SiO2/NaYF4:Yb, Er (MSU) hybrids modified with MnO2 nanosheets (MSU/MnO2). The MSU hybrids were fabricated by covalently linking amino-modified Fe3O4@SiO2 particles with carboxyl-functionalized NaYF4:Yb, Er particles. The Fe3O4 core and the NaYF4:Yb, Er shell functioned successfully for magnetic targeting and fluorescence imaging, respectively. MnO2 nanosheets served as drug carriers and UC luminescence quenchers. The drug can be released by introducing glutathione (GSH) which reduces MnO2 to Mn(2+), and at the same time, UC luminescence can be turned on. These results clearly show that these MSU/MnO2 nanocomposites are promising platforms which can be applied to construct a smart drug delivery system with magnetic targeting and GSH stimulation, as well as tracking by UC luminescence. PMID- 24065170 TI - Assessing leg length after fixation of comminuted femur fractures. AB - BACKGROUND: Nailing comminuted femur fractures may result in leg shortening, producing significant complications including pelvic tilt, narrowing of the hip joint space, mechanical and functional changes in gait, an increase in energy expenditures, and strains on spinal ligaments, leading to spinal deformities. The frequency of this complication in patients managed with an intramedullary (IM) nail for comminuted diaphyseal fractures is unknown. QUESTIONS/PURPOSES: We therefore determined (1) the frequency of LLDs, (2) whether a specific fracture pattern was associated with LLDs, (3) the frequency of reoperation, and (4) whether revision fixation ultimately corrected the LLD. METHODS: We studied 83 patients with 91 AO/OTA Type B or Type C fractures fixed with either an antegrade or retrograde IM nail from July 2002 through December 2005. There were 60 males and 23 females, with a mean age of 30 years (range, 15-79 years). All underwent a digitized CT scan in the immediate postoperative period. Measurements of both legs were performed. Any fixation producing a discrepancy and requiring a return to surgery was identified. RESULTS: An mean LLD of 0.58 cm was found in 98% of the patients, but only six (7%) patients had an LLD of greater than 1.25 cm. No fracture pattern or the presentation of bilateral injuries demonstrated a greater incidence of LLD. Of the patients with LLD, two patients refused further surgery while the remaining four patients, two Type B and two Type C fractures, ultimately underwent revision fixation. Repeat CT scans after revision surgery of all four patients demonstrated a residual LLD of only 0.2 cm. CONCLUSIONS: Postoperative CT scans appear to be an efficient method to measure femoral length after IM nailing. Although residual LLDs may be common in comminuted femurs treated with IM nails, most LLDs do not appear to be functionally relevant. When an LLD of greater than 1.5 cm is identified, it should be discussed with the patient, who should be told that potential complications may occur with larger LLDs and that sometimes patients may benefit from repeat surgery. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 24065171 TI - Treatment and displacement affect the reoperation rate for femoral neck fracture. PMID- 24065172 TI - Does an unloader brace reduce knee loading in normally aligned knees? AB - BACKGROUND: Unloading knee braces often are used after tibiofemoral articular cartilage repair. However, the experimental basis for their use in patients with normal tibiofemoral alignment such as those undergoing cartilage repair is lacking. QUESTIONS/PURPOSES: The purpose of this study was to investigate the effect of varus and valgus adjustments to one commercially available unloader knee brace on tibiofemoral joint loading and knee muscle activation in populations with normal knee alignment. METHODS: The gait of 20 healthy participants (mean age 28.3 years; body mass index 22.9 kg/m(2)) was analyzed with varus and valgus knee brace conditions and without a brace. Spatiotemporal variables were calculated as were knee adduction moments and muscle activation during stance. A directed cocontraction ratio was also calculated to investigate the relative change in the activation of muscles with medial (versus lateral) moment arms about the knee. Group differences were investigated using analysis of variance. The numbers available would have provided 85% power to detect a 0.05 increase or decrease in the knee adduction moment (Nm/kg*m) in the braced condition compared with the no brace condition. RESULTS: With the numbers available, there were no differences between the braced and nonbraced conditions in kinetic or muscle activity parameters. Both varus (directed cocontraction ratio 0.29, SD 0.21, effect size 0.95, p = 0.315) and valgus (directed cocontraction ratio 0.28, SD 0.24, effect size 0.93, p = 0.315) bracing conditions increased the relative activation of muscles with lateral moment arms compared with no brace (directed cocontraction ratio 0.49, SD 0.21). CONCLUSIONS: Results revealed inconsistencies in knee kinetics and muscle activation strategies after varus and valgus bracing conditions. Although in this pilot study the results were not statistically significant, the magnitudes of the observed effect sizes were moderate to large and represent suitable pilot data for future work. Varus bracing increased knee adduction moments as expected; however, they produced a more laterally directed muscular activation profile. Valgus bracing produced a more laterally directed muscular activation profile; however, it increased knee adduction moments. CLINICAL RELEVANCE: When evaluating changes in knee kinetics and muscle activation together, this study demonstrated conflicting outcomes and questions the efficacy for the use of unloader bracing for people with normally aligned knees such as those after articular cartilage repair. PMID- 24065174 TI - Debate: Gun control in the United States. PMID- 24065173 TI - Coexisting lumbar spondylosis in patients undergoing TKA: how common and how serious? AB - BACKGROUND: Information on the coexistence of lumbar spondylosis and its influence on overall levels of pain and function in patients with advanced knee osteoarthritis (OA) undergoing total knee arthroplasty (TKA) would be valuable for patient consultation and management. QUESTIONS/PURPOSES: The purposes of this study were to document the prevalence and severity of coexisting lumbar spondylosis in patients with advanced knee OA undergoing TKA and to determine whether the coexisting lumbar spondylosis at the time of TKA adversely affects clinical scores in affected patients before and 2 years after TKA. METHODS: Radiographic lumbar spine degeneration and lumbar spine symptoms including lower back pain, radiating pain at rest, and radiating pain with activity were assessed in 225 patients undergoing TKA. In addition, the WOMAC score and the SF-36 scores were evaluated before and 2 years after TKA. Potential associations of radiographic lumbar spine degeneration and lumbar spine symptom severities with pre- and postoperative WOMAC subscales and SF-36 scores were examined. RESULTS: All 225 patients had radiographic degeneration of the lumbar spine, and the large majority (89% [200 of 225]) had either moderate or severe spondylosis (72% and 17%, respectively). A total of 114 patients (51%) had at least one moderate or severe lumbar spine symptom. No association was found between radiographic severity of lumbar spine degeneration and pre- and postoperative clinical scores. In terms of lumbar spine symptoms, more severe symptoms were likely to adversely affect the preoperative WOMAC and SF-36 physical component summary (PCS) scores, but most of these adverse effects improved by 2 years after TKA with the exception of the association between severe radiating pain during activity and a poorer postoperative SF-36 PCS score (regression coefficient = -5.41, p = 0.015). CONCLUSIONS: Radiographic lumbar spine degeneration and lumbar spine symptoms are common among patients with advanced knee OA undergoing TKA. Severe lumbar spine symptoms (visual analog scale score of >= 7) were likely to adversely affect the preoperative clinical scores of patients undergoing TKA; however, most of the adverse effects were not found 2 years after TKA. Nevertheless, because preexisting severe radiating pain during activity may be a source of a poorer outcome after TKA, careful patient consultation regarding this potential poorer prognosis after TKA needs to be provided to the patient with this symptom. PMID- 24065175 TI - Tuning molecular interactions in lipid-oligonucleotides assemblies via locked nucleic acid (LNA)-based lipids. AB - Hybrid nucleotide-lipids containing locked nucleic acid (LNA) show enhanced hybridization properties with complementary single strand RNAs compared to DNA lipid analogues. The LNA adenosine lipid features unique binding properties with a high binding affinity for poly-uridine and the entropically driven formation of a stable complex (K(d) ~ 43 nM). Enhanced hybridization properties of LNA-based lipids should be applicable for the development of oligonucleotide (ON) delivery systems or as small molecule binders to RNA for novel therapeutic strategies. PMID- 24065176 TI - Human tandem-repeat-type galectins bind bacterial non-betaGal polysaccharides. AB - Galectins are multifunctional effectors, for example acting as regulators of cell growth via protein-glycan interactions. The observation of capacity to kill bacteria for two tandem-repeat-type galectins, which target histo-blood epitopes toward this end (Stowell et al. Nat. Med. 16:295-301, 2010), prompted us to establish an array with bacterial polysaccharides. We addressed the question whether sugar determinants other than beta-galactosides may be docking sites, using human galectins-4, -8, and -9. Positive controls with histo-blood group ABH epitopes and the E. coli 086 polysaccharide ascertained the suitability of the set-up. Significant signal generation, depending on type of galectin and polysacchride, was obtained. Presence of cognate beta-galactoside-related epitopes within a polysaccharide chain or its branch will not automatically establish binding properties, and structural constellations lacking galactosides, like rhamnan, were found to be active. These data establish the array as valuable screening tool, giving direction to further functional and structural studies. PMID- 24065177 TI - Effects and mechanisms of curcumin and basil polysaccharide on the invasion of SKOV3 cells and dendritic cells. AB - In the present study, a polysaccharide extract was obtained from Ocimum basilicum (basil polysaccharide, BPS) and the effects of curcumin and BPS on the invasion activity of the SKOV3 ovarian cancer cells and human monocyte-derived dendritic cells (DCs) were investigated. SKOV3 cells and immature or mature DCs were treated with 50 uM curcumin or 100 ug/ml BPS. A transwell invasion assay demonstrated that curcumin and BPS differentially regulate the invasion of SKOV3 cells and DCs. Curcumin significantly decreased the invasion of SKOV3 cells and immature and mature DCs, while BPS only decreased SKOV3 cell invasion. Osteopontin (OPN) mRNA and protein expression were significantly reduced in curcumin and BPS-treated SKOV3 cells and curcumin-treated DCs. Furthermore, flow cytometry showed that curcumin significantly inhibited the surface expression of CD44 in SKOV3 cells and DCs, while BPS had a minimal effect on CD44 expression. Matrix metallopeptidase-9 (MMP-9) mRNA and protein expression were also reduced in all curcumin-treated cells and BPS-treated SKOV3 cells. The results indicated that curcumin and BPS regulated invasion of SKOV3 cells and DCs by distinctly downregulating OPN, CD44 and MMP-9 expression. Therefore, Curcumin and BPS may be suitable candidates for DC-based vaccines for ovarian cancer immunotherapy. PMID- 24065178 TI - Genetically engineered pig models for diabetes research. AB - Diabetes mellitus (DM) has emerged into a steadily increasing health problem and the predicted future dimension of the global DM epidemic is alarming: an increase from currently 346 million to over 400 million affected people worldwide by the year 2030 was extrapolated. Thus concerted research efforts are imperative to gain insight into disease mechanisms and to expand the basis for development of preventive and therapeutic strategies. Diabetic rodent models have traditionally been used to follow these goals, but have limitations for translational research. The pig is another classical animal model for diabetes research. Genetic engineering now facilitates tailoring pig models which mimic human disease mechanisms at the molecular level. This article reviews the existing genetically engineered pig models for diabetes research and their current and future applications. Further, the potential role of the pig as donor of pancreatic islets for xenotransplantation or as host for growing human pancreas is outlined. PMID- 24065179 TI - Genetic and epigenetic changes in a genomic region containing MIR172 in Arabidopsis allopolyploids and their progenitors. AB - Combination of divergent genomes in allopolyploids creates genome-wide gene expression changes including many miRNA targets in Arabidopsis allotetraploids relative to the parents Arabidopsis thaliana and Arabidopsis arenosa. Here we report expression and epigenetic changes in a chromosomal region containing the MIR172b locus in the allotetraploids. Although mature miRNA sequences are conserved, A. thaliana and A. arenosa miRNA loci diverge rapidly in sequence and expression. Among four MIR172 loci in Arabidopsis, the level of nucleotide sequence divergence between A. thaliana and A. arenosa MIR172 loci is 15-25%, which is higher than that of protein-coding genes (~5%). MIR172b locus and its flanking genes in A. arenosa were expressed at low levels relative to that in A. thaliana, which is associated with hypermethylation of this region in the allotetraploids. Consistently with this notion, pri-miR172 transcripts in the allotetraploids were primarily derived from the A. thaliana MIR172b locus. Expression of homoeologous alleles in miR172 target loci is associated with allelic loss, allelic changes in outcrossing A. arenosa or repression of A. thaliana alleles. These data suggest that gene expression changes in this homoeologous region are associated with genetic diversity and epigenetic variation of miRNA genes and their targets in allopolyploids. PMID- 24065180 TI - Speciation of two desert poplar species triggered by Pleistocene climatic oscillations. AB - Despite the evidence that the Pleistocene climatic fluctuations have seriously affected the distribution of intraspecific diversity, less is known on its impact on interspecific divergence. In this study, we aimed to test the hypothesis that the divergence of two desert poplar species Populus euphratica Oliv. and P. pruinosa Schrenk. occurred during the Pleistocene. We sequenced 11 nuclear loci in 60 individuals from the two species to estimate the divergence time between them and to test whether gene flow occurred after species separation. Divergence time between the two species was estimated to be 0.66-1.37 million years ago (Ma), a time at which glaciation was at its maximum in China and deserts developed widely in central Asia. Isolation-with-Migration model also indicated that the two species had diverged in the presence of gene flow. We also detected evidence of selection at GO in P. euphratica and to a lesser extent at PhyB2. Together, these results underscore the importance of Pleistocene climate oscillations in triggering plant speciation as a result of habitats divergence. PMID- 24065181 TI - Contemporary pollen-mediated gene immigration reflects the historical isolation of a rare, animal-pollinated shrub in a fragmented landscape. AB - Fragmentation is generally considered to have negative impacts on widespread outbreeders but impacts on gene flow and diversity in patchy, naturally rare, self-compatible plant species remain unclear. We investigated diversity, gene flow and contemporary pollen-mediated gene immigration in the rare, narrowly distributed endemic shrub Calothamnus quadrifidus ssp. teretifolius. This taxon occurs in an internationally recognized biodiversity hotspot subjected to recent human-induced fragmentation and the condition of the remnants ranges from intact to highly degraded. Using microsatellites, we found that inbreeding, historically low gene flow and significant population differentiation have characterized the genetic system of C. quadrifidus ssp. teretifolius. Inbreeding arises from self pollination, a small amount of biparental inbreeding and significant correlation of outcross paternity but fecundity was high suggesting populations might have purged their lethals. Paternity analyses show that pollinators can move pollen over degraded and intact habitat but populations in both intact and degraded remnants had few pollen parents per seed parent and low pollen immigration. Genetic diversity did not differ significantly between intact and degraded remnants but there were signs of genetic bottlenecks and reduced diversity in some degraded remnants. Overall, our study suggests human-induced fragmentation has not significantly changed the mating system, or pollen immigration to, remnant populations and therefore genetic connectivity need not be the highest conservation priority. Rather, for rare species adapted to higher levels of inbreeding, conservation efforts may be best directed to managing intact habitats and ecosystem processes. PMID- 24065182 TI - Evolution of body shape in sympatric versus non-sympatric Tropheus populations of Lake Tanganyika. AB - Allopatric speciation often yields ecologically equivalent sister species, so that their secondary admixis enforces competition. The shores of Lake Tanganyika harbor about 120 distinct populations of the cichlid genus Tropheus, but only some are sympatric. When alone, Tropheus occupies a relatively broad depth zone, but in sympatry, fish segregate by depth. To assess the effects of competition, we studied the partial co-occurrence of Tropheus moorii 'Kaiser' and 'Kirschfleck' with Tropheus polli. A previous study demonstrated via standardized breeding experiments that some observed differences between Tropheus 'Kaiser' living alone and in sympatry with T. polli have a genetic basis despite large scale phenotypic plasticity. Using geometric morphometrics and neutral genetic markers, we now investigated whether sympatric populations differ consistently in body shape from populations living alone and if the differences are adaptive. We found significant differences in mean shape between non-sympatric and sympatric populations, whereas all sympatric populations of both color morphs clustered together in shape space. Sympatric populations had a relatively smaller head, smaller eyes and a more anterior insertion of the pectoral fin than non-sympatric populations. Genetically, however, non-sympatric and sympatric 'Kaiser' populations clustered together to the exclusion of 'Kirschfleck'. Genetic distances, but not morphological distances, were correlated with geographic distances. Within- and between-population covariance matrices for T. moorii populations deviated from proportionality. It is thus likely that natural selection acts on both phenotypic plasticity and heritable traits and that both factors contribute to the observed shape differences. The consistency of the pattern in five populations suggests ecological character displacement. PMID- 24065183 TI - Genome-wide association study of handedness excludes simple genetic models. AB - Handedness is a human behavioural phenotype that appears to be congenital, and is often assumed to be inherited, but for which the developmental origin and underlying causation(s) have been elusive. Models of the genetic basis of variation in handedness have been proposed that fit different features of the observed resemblance between relatives, but none has been decisively tested or a corresponding causative locus identified. In this study, we applied data from well-characterised individuals studied at the London Twin Research Unit. Analysis of genome-wide SNP data from 3940 twins failed to identify any locus associated with handedness at a genome-wide level of significance. The most straightforward interpretation of our analyses is that they exclude the simplest formulations of the 'right-shift' model of Annett and the 'dextral/chance' model of McManus, although more complex modifications of those models are still compatible with our observations. For polygenic effects, our study is inadequately powered to reliably detect alleles with effect sizes corresponding to an odds ratio of 1.2, but should have good power to detect effects at an odds ratio of 2 or more. PMID- 24065184 TI - Ternary alloyed AgCl(x)Br(1-x) nanocrystals: facile modulation of electronic structures toward advanced photocatalytic performance. AB - Manipulating the electronic structure of semiconductor photocatalysts represents an ideal approach for the exploration and development of photocatalysis. However, it still remains a challenge in terms of silver halide photocatalysts. Herein, we report ternary alloyed AgClxBr1-x nanocrystals (NCs) synthesized by controlling the crystal growth process within a facile microemulsion system. The alloyed NCs crystallize in a homogeneous rock-salt crystal structure and possess tunable bandgaps from 2.5 to 3.0 eV obtained by varying the halogen mole ratios (Cl/Br). Their photocatalytic activities for dye degradation and CO2 reduction are found to depend strongly on the chemical compositions, and among them, the AgCl0.75Br0.25 sample exhibits the highest activity (about 2-4 times higher than AgCl and AgBr). Further theoretical calculations demonstrate that a decrease of the ratios of Cl/Br lowers the levels of the conduction band minimum and thereby narrows the bandgaps. Combining the theoretical and experimental results, the highest activity can be rationally ascribed to the optimum conduction band levels, which balances the overall effect of bandgap, electronic coupling and redox potential. This methodological exploration of engineering the bandgap of silver halide materials is a step forward toward the development of advanced photocatalysts and will shed light on devising various semiconductor photocatalytic systems. PMID- 24065185 TI - Tandem Michael addition/isocyanide insertion into the C-C bond: a novel access to 2-acylpyrroles and medium-ring fused pyrroles. AB - A new reaction model, tandem Michael addition/formal isocyanide insertion into the acyl C-C bond, has been developed. Thus, a series of 2-acylpyrroles and seven /eight-membered ring fused pyrroles were synthesized from the reaction of methyl isocyanides with enones in a single operation. PMID- 24065186 TI - 14-3-3beta regulates the proliferation of glioma cells through the GSK3beta/beta catenin signaling pathway. AB - We previously demonstrated that 14-3-3beta is overexpressed in astrocytomas; however, the underlying mechanisms are poorly understood. Based on the reported multiple functions of 14-3-3beta, we hypothesized that it interacts with glycogen synthase kinase 3 beta (GSK3beta), which regulates beta-catenin-mediated oncogene expression and contributes to tumorigenesis and astrocytoma progression. To test these hypotheses, we used 14-3-3beta overexpression vectors and small interfering RNA (siRNA) transfection in the human normal astrocyte cell line SVGp12 and the glioma cell line U87, respectively. The results showed that overexpression of 14 3-3beta promoted the proliferation of SVGp12 cells, while knockdown of 14-3-3beta inhibited the proliferation of U87 cells as analyzed by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and bromodeoxyuridine (BrdU) assays. In Flag-tagged 14-3-3beta-overexpressing cells, GSK3beta was co immunoprecipitated with 14-3-3beta using a Flag antibody. Knockdown of beta catenin by siRNA blocked cell proliferation induced by overexpression of 14-3 3beta. Furthermore, overexpression of 14-3-3beta suppressed the phosphorylation of beta-catenin leading to its accumulation and nuclear translocation as revealed by western blot analysis. In addition, beta-catenin nuclear translocation induced by overexpression of 14-3-3beta activated the transcription of oncogenes including c-myc and cyclin D1. Collectively, these results revealed that 14-3 3beta regulates the proliferation of astrocytes and glioma cells through the GSK3beta/beta-catenin signaling pathway. The delineated mechanism of 14-3-3beta may be responsible for the tumorigenesis and progression of human astrocytomas. Thus, new therapeutic strategies or drugs aimed at 14-3-3beta may have potential for the treatment of human astrocytomas. PMID- 24065187 TI - Initial experiences with endoscopic rhino-neurosurgery in Amsterdam. AB - Endoscopic surgery of the skull base has been on the rise for several years. Endoscopic access for surgery can be achieved from the frontal sinus anteriorly along the skull base to the odontoid process posterior inferiorly. An endoscope is inserted through one nasal corridor and allows visualization of the working field and up to three surgical instruments can be used to address the lesion. This is called the "two nostrils-four hands technique". This is a retrospective study of 67 cases. Setting of the study is an Amsterdam University hospital. Cases were identified in the department of otorhinolaryngology and department of neurosurgery database. All patients operated between 1 January, 2008 and 1 February, 2012 with pituitary tumours that extend beyond the sella, sinonasal tumours and all non-pituitary skull-base tumours were included. Mean tumour diameter was 3.8 cm. We performed a near-to-gross total resection in 92% of cases where we intended to perform a total resection. The most frequent complication was CSF leakage. This study demonstrates that this technique is safe and reliable. What is needed is a dedicated team, which includes a dedicated anesthesiologist, endocrinologist, ophthalmologist, and radiation oncologist. PMID- 24065188 TI - The EGFR-mTOR pathway and laryngeal cancer angiogenesis. AB - Epidermal growth factor receptor (EGFR) is a trans-membrane tyrosine kinase taking part in cell transformation and tumor progression. One of the downstream pathways controlled by EGFR involves the mammalian target of rapamycin (mTOR), a proto-oncogene activated in several cell functions. Recent evidence seems to confirm that both EGFR and mTOR regulate angiogenesis. The aim of this study was to investigate the expression of EGFR and mTOR in laryngeal squamous cell carcinoma (LSCC) cells in a retrospective clinical setting and their correlation with tumor neo-angiogenesis, judged on the grounds of CD105-assessed microvascular density (MVD), and prognosis. We considered 76 consecutive patients with LSCC treated with surgery alone. Immunohistochemical expressions of EGFR, mTOR, and CD105 were measured using image analysis and findings underwent statistical analysis using univariate and multivariate models. We found that nodal status correlated significantly with patient prognosis in terms of disease free survival (DFS) (p = 0.01). There was a strong direct correlation between mTOR and EGFR expression (p = 0.0003), and between mTOR and CD105-assessed MVD (p = 0.0025). Patients with a CD105-assessed MVD >5.28 % had a significantly higher recurrence rate (RR) (p = 0.026), and a significantly shorter DFS (p = 0.025). On multivariate analysis, only N stage [hazard ratio (HR) 3.54, p = 0.009] and CD105 assessed MVD (HR 2.87, p = 0.027) maintained their independent prognostic significance in terms of DFS. Judging from our promising findings, the EGFR-mTOR pathway should be investigated further to understand its role in LSCC neo angiogenesis. PMID- 24065189 TI - Comparison of HPV prevalence in HNSCC patients with regard to regional and socioeconomic factors. AB - HPV infection is considered as an independent risk factor for head and neck squamous cell carcinomas (HNSCC). Due to highly variable prevalence results in numerous studies, it is, however, difficult to estimate the relevance of HPV infection as risk factor for a specific patient collective. This study aimed to elucidate the disparities of HPV prevalence by analyzing socioeconomically and regionally different patient collectives. Two age, gender, stage and tumor location matched cohorts of 18 private health insured (PHIP) and 16 statutory health insured patients (SIP) suffering from an oropharyngeal squamous cell carcinoma (OSCC) and treated at a university hospital were screened for p16 overexpression and HPV infection by immunohistochemistry and PCR. In addition 85 HNSCC patients of an otolaryngology private practice (PPP) in a rural area were screened for p16 overexpression and positive cases were tested for HPV infection. HPV prevalence was 72.2% in the PHIP collective in comparison to 25.0% (p = 0.015) in the SIP collective with a significantly improved 5-year overall survival (p = 0.003) of the PHIP collective. The total HPV prevalence of PPP group was 7.1% with the highest infection rate in tonsillar carcinomas (33.3%) and a larger percentage of female patients in the HPV positive group (p = 0.037). This study shows that variable HPV infection rates in HNSCC can be caused by the selection of particular patient collectives, which suggest taking socioeconomic and regional factors into account for a decision on HPV testing, if it is not performed on a routine basis. PMID- 24065190 TI - Influence of surface properties of Merocel(r) (polyvinyl acetal) and silicone nasal splints on biofilm formation. AB - The objective of the study was to investigate biofilm formation on Merocel((r)) and silicone nasal splint after nasal septal surgery. 50 patients who were scheduled to undergo nasal septal surgery were included in this study. The patients were randomized into receiving an insert of Merocel((r)) or silicone splint after septoplasty. In group 1 (8 females, 17 males) and group 2 (10 females, 15 males), Merocel ((r)) packs or silicone splints were inserted into nasal cavities at the end of the procedures, respectively. All packs were removed 48 h after insertion, and samples were taken from the packs under sterilized conditions. Scanning electron microscopy was performed to observe biofilm formation on the surfaces of Merocel((r)) and silicone splints. Biofilm formation was observed in 25 (100%) and 3 (12%) of the Merocel((r)) and silicone splint samples, respectively. Our study revealed that biofilm formation on Merocel((r)) packs is significantly higher than silicone splints, mainly due to the different texture and surface properties of these materials. Considering the hazardous effects of biofilm formation on humans, our observations in this study may guide surgeons to choose the most appropriate packing material after nasal septal surgery. PMID- 24065192 TI - Risk for re-expansion pulmonary edema following spontaneous pneumothorax. AB - PURPOSE: Re-expansion pulmonary edema is an uncommon condition that occurs when a collapsed lung is expanded. The aim of the present study was to investigate the incidence and risk factors associated with re-expansion pulmonary edema which may occur as a complication when carrying out treatment for spontaneous pneumothorax. METHODS: A total of 462 patients with spontaneous pneumothorax treated with chest tube drainage in inpatient settings at the Nissan Tamagawa Hospital during the 6 year period between January 2007 and December 2012 were retrospectively evaluated. The data were analyzed to identify any clinical differences between the patients with and without re-expansion pulmonary edema. RESULTS: Re-expansion pulmonary edema occurred on 30 (6.5 %) of the 462 patients. The duration of lung collapse in the patients with re-expansion pulmonary edema was longer than that observed in the patients without re-expansion pulmonary edema. (7.7 +/- 9.1 and 2.4 +/- 4.6 days). This difference was statistically significant (P < 0.0001). The extent of lung collapse in the patients with re-expansion pulmonary edema was more severe than that observed in the patients without re-expansion pulmonary edema. This difference was also statistically significant (P = 0.004). CONCLUSIONS: The results suggest that treating spontaneous pneumothorax using chest tube drainage requires careful consideration in view of the relatively high incidence of re-expansion pulmonary edema, especially in cases associated with long periods of lung collapse or large spontaneous pneumothoraxes. PMID- 24065193 TI - Clinicopathological analysis of small-sized anterior mediastinal tumors. AB - PURPOSE: The purpose of this study was to determine the clinicopathological findings and prognosis of small-sized anterior mediastinal tumors (SSAMTs). METHODS: A retrospective study was conducted on 43 patients who underwent surgery between January 1989 and December 2011 for SSAMTs. RESULTS: From the preoperative radiological findings, the tumors were classified into solid (n = 28) and cystic lesions (n = 15). The pathological diagnoses of the solid lesions included thymoma (n = 24), thymic carcinoma (n = 1), mucosa-associated lymphoid tissue lymphoma (n = 1), teratoma (n = 1) and neurofibroma (n = 1), and those of the cystic lesions included thymic cysts (n = 8), thymoma (n = 3), bronchogenic cysts (n = 2), teratoma, (n = 1) and a pericardial cyst (n = 1). The 27 thymomas were composed of stages I (n = 22), II (n = 3), III (n = 1) and IVb (n = 1). The overall survival in the 43 patients was 97.1 % at 5 years. In the 28 patients with solid lesions, the overall survival was 95.8 % at 5 years. All patients with cystic lesions were still alive at the last follow-up. CONCLUSION: Cystic lesions of SSAMTs were benign lesions or stage I thymoma, and most of the solid lesions of SSAMTs were stage I or II thymomas. SSAMTs are good candidates for video assisted thoracic surgery procedures, as conversion to sternotomy can be selected based on the intraoperative findings of pericardial invasion and a rapid pathological diagnosis of thymic carcinoma. PMID- 24065194 TI - Clinical experience using a tensor fascia lata flap in oncology patients. AB - PURPOSE: The tensor fascia lata (TFL) flap is used to reconstruct various anatomical structures in different regions of the body. We herein describe the use of TFL flaps for a variety of indications, and discuss the results of such procedures with respect to postoperative complications in oncology patients. METHODS: We reviewed 15 oncology patients who were treated with TFL flaps. RESULTS: The lesions were located in the groin in five patients, the lower abdomen in five, and the buttocks, ischium, shoulder, thigh and upper abdomen in one patient each. Abdominal wall reconstruction was performed in nine patients. Three patients underwent resection of femoral vessels and the tumor in the groin, followed by a vascular graft implant. In these patients, the combined flaps were transferred to reconstruct the defects. Nine patients developed complications. No total flap loss occurred in any patient. CONCLUSIONS: Postoperative complications, such as necrosis in the distal part of the flap (33 %) and ventral hernias (11 %) were seen, but these percentages were comparable to those seen in previous reports. Our review shows that the TFL flap is useful to reconstruct the defects in various anatomical sites in oncology patients. PMID- 24065195 TI - High expression of MACC1 predicts poor prognosis in patients with osteosarcoma. AB - Increasing evidence has demonstrated that high metastasis-associated in colon cancer-1 (MACC1) level is tightly associated with the development, progression, and poor prognosis of a variety of tumors. However, the relationship between MACC1 and the occurrence, development, and progression of osteosarcoma (OS) remains to be clarified. To facilitate and deepen the understanding of the associations of MACC1 with the development and progression of OS, in the current study, we detected the expressions of MACC1 mRNA and protein, and investigated the relationship between MACC1 expression and prognosis of the patients with OS. Our findings demonstrated that expressions of MACC1 mRNA and protein in OS tissues were significantly higher than those in paired normal bone tissues (P < 0.05). Additionally, the level of MACC1 mRNA in the patients with higher clinical stage and distant metastasis was markedly higher than those with lower clinical stage and without metastasis (P < 0.05). Furthermore, high MACC1 level was closely correlated with clinical stage and distant metastasis (P < 0.05), but not related to the patients' age, gender, tumor size, and anatomical location (P > 0.05). Stepwise investigation revealed that survival time of the patients with high MACC1 level was obviously lower than that with low MACC1 level (P < 0.05). Collectively, our data suggest that MACC1 may play important roles in the development and progression of OS, and thus may be considered as a novel molecular target for therapy of the patients with OS. PMID- 24065196 TI - Biological significance of promoter hypermethylation of p14/ARF gene: relationships to p53 mutational status in Tunisian population with colorectal carcinoma. AB - One of the most important pathways which are frequently affected in colorectal cancer is p53/ (MDM2)/p14ARF pathway. We aim to determine the methylation pattern of p14/ARF in relation to mutation of p53. This correlation was studied to investigate whether their alterations could be considered as a predictor factor of prognosis in colorectal cancer and whether it can be useful in early-stage diagnosis. Statistical analyses show that p14/ARF hypermethylation was correlated with rectum location (p = 0.004), primary TNM stage (p = 0.016), and advanced Astler-Coller stage (p = 0.024). The RT-PCR that revel 31 % of patients did not express p14/ARF mRNA or at very low level. A high concordance between CpG hypermethylation and the low levels (p < 0.005) was shown. In addition, our analyses demonstrate that patients with mutation in the p53 gene have a lack of the protein expression (p < 0.005). This category with negative expression of p53 had a shorter survival rate (p < 0.005). On the one hand, MSP pattern of p14/ARF were correlated with a lack of p53 expression (p = 0.007). We found that p53/p14ARF pathway was frequently deregulated among our patients. In our study, we demonstrate that hypermethylation of p14/ARF occurs early during CRC tumorogenesis. However, we did not find correlation between p14/ARF and survival. These results suggest that p14/ARF methylation pattern may constitute a predictor factor of CRC in early stage but it could not be considered as a prognostic factor. On the other hand and because of the reversibility of the methylation mechanism, it may be appropriate to target the demethylation of p14/ARF to develop new drogues for CRC. PMID- 24065197 TI - CDKN2A exon-wise deletion status and novel somatic mutations in Indian glioma patients. AB - Over the years, deletions of CDKN2A (p16) tumor suppressor gene has been studied using FISH and multiplex PCR, with major focus on exon 2 in various cancers, and the frequency of mutation is found to be varied in different studies. In this study, we analyzed the deletion status of all three exons of p16 and frequency of exon 2 somatic point mutations in glioma from the Indian population and its clinical implications. Multiplex PCR was carried out in order to check deletion of all 3 exons in 50 glioma samples. Nonconventional PCR-SSCP analysis and sequencing was done to identify mutations in 48 cases. Deletion of at least one of the three exons of p16 INK4A was observed in ten cases (20 %). The frequencies of exon-wise deletions were 10 % for exon 1, 4 % for exon 2, and 8 % for exon 3. Two out of 48 samples were positive for mutations in p16 exon 2. One sample had a transition of G to C on position 147 with a codon change TGG to TGC which does not contribute to the protein structure. Another sample had a transversion of A to G on the position 154 with a codon change ATG to GTG with change in amino acid methionine to valine in 52nd position. Deletion pattern was found to be varied in three exons. Frequency of p16 gene mutation was less in the Indian population (4.2 %), and this mutation does not contribute to any remarkable change in protein structure. PMID- 24065198 TI - Interaction among Caveolin-1 genotypes (rs3807987/rs7804372), H. pylori infection, and risk of gastric cancer in a Chinese population. AB - Caveolin-1, a candidate tumor suppressor, interacts with a number of transducing molecules and plays a regulatory role in several signaling pathways. Recently, a study revealed that Cav-1 G14713A (rs3807987)/T29107A (rs7804372) polymorphisms might be associated with the susceptibility to certain cancers. In this study, we evaluated the interaction among Caveolin-1 genotypes (rs3807987/rs7804372) and Helicobacter pylori infection and increased risk of gastric cancer among the Chinese population. Blood specimens were collected from 412 gastric cancer cases to 412 noncancer controls between January 2004 and December 2012 in Liaoning Province, China. Caveolin-1 genotypes (rs3807987/rs7804372) were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Enzyme-linked immunosorbent assays were used to measure serum levels of anti-H. pylori IgG. Odds ratio and 95 % confidence interval were calculated using multivariate logistic regression adjusted by sex and age. There were significant differences between gastric cancer and control groups in the distribution of their genotypes and allelic frequencies of the Cav-1 G14713A (rs3807987) and T29107A (rs7804372) polymorphisms, respectively. An elevated risk of gastric cancer was observed in patients with H. pylori infection combined with the Cav-1 G14713A, but not T29107A genotypes. The A allele of G14713A shows an interaction with H. pylori infection that increases the risk of gastric cancer. PMID- 24065199 TI - Tumor cell uptake of 99mTc-labeled 1-thio-beta-D-glucose and 5-thio-D-glucose in comparison with 2-deoxy-2-[18F]fluoro-D-glucose in vitro: kinetics, dependencies, blockage and cell compartment of accumulation. AB - PURPOSE: This study was conducted to investigate the capacity of (99m)Tc-labeled 1-thio-beta-D-glucose ((99m)Tc-1-TG) and 5-thio-D-glucose ((99m)Tc-5-TG) to act as a marker for glucose metabolism in tumor cells in vitro. PROCEDURES: We investigated the cellular uptake of (99m)Tc-1-TG, (99m)Tc-5-TG, and 2-deoxy-2 [(18)F]fluoro-D-glucose((18)F-FDG) in a human colorectal carcinoma and human lung adenocarcinoma cell line (HCT-116, A549) at different time points and varying glucose/insulin concentrations and under transporter blockage by cytochalasin-B and phloretin. Cell compartment analysis was performed. RESULTS: A significant uptake and time dependency thereof, a significant uptake dependency on glucose and insulin and a significant uptake inhibition by cytochalasin-B for (99m)Tc-1 TG and (99m)Tc-5-TG, was shown. Albeit substantial, the uptake was less pronounced in (99m)Tc-1-TG and (99m)Tc-5-TG compared with (18)F-FDG. (99m)Tc-1-TG and (99m)Tc-5-TG showed a higher accumulation in the cell membranes compared with (18)F-FDG. CONCLUSION: Tc-1-TG and (99m)Tc-5-TG showed an uptake in vitro with glucose analog characteristics but with membranous accumulation. Tumor imaging should be investigated in an animal model. PMID- 24065200 TI - Comparison of USPIO-enhanced MRI and Gd-DTPA enhancement during the subacute stage of focal cerebral ischemia in rats. AB - BACKGROUND: Being one class of magnetic resonance imaging (MRI) contrast agents, ultrasmall superparamagnetic particles of iron oxides (USPIO) bear the potential to study neuroinflammation following stroke, but there is still debate over whether the iron oxides particles may enter the brain tissue passively over a damaged blood-brain barrier (BBB). PURPOSE: To compare the enhancement patterns of USPIO and gadopentate dimeglumine (Gd-DTPA) during the subacute stage of focal cerebral ischemia, to examine the relationship between USPIO enhancement and BBB disturbance, as well as with neuroinflammatory cell response. MATERIAL AND METHODS: Multiple MR sequences were obtained on days 3 and 6 after transient middle cerebral artery occlusion induced in rats with and without the application of USPIO and Gd-DTPA. The enhancement patterns of the two contrast agents were compared and correlated to histology, including IgG for BBB permeability, Prussian Blue staining for iron particle detection, and CD68 immunohistochemistry staining to identify macrophage/microglia. RESULTS: Gd-DTPA enhancement depicted BBB breakdown being in line with IgG leakage. The USPIO enhanced images demonstrated both diffuse and focal signal alteration in ischemic lesions. The diffuse enhanced pattern had a similar spatial and temporal profile as with Gd DTPA enhancement. In addition, focal enhanced signal loss was visible on T1-, T2 , and T2*-weighted images, with a peak tendency of MR signal loss, macrophage/microglia concentration and iron particle accumulation at a later phase of the study. CONCLUSION: After focal cerebral ischemia, Gd-DTPA-enhanced MRI showed a higher sensitivity in detecting BBB alterations than did USPIO enhancement. USPIO provided complementary information regarding inflammatory cell activity in neuroinflammatory to cerebral ischemia that had not been visualized using conventional Gd-DTPA. The assessment using multiple MR parameters may identify intracellular and extracellular USPIO in vivo. PMID- 24065201 TI - 64-section multidetector CT angiography for evaluation of intracranial aneurysms: comparison with 3D rotational angiography. AB - BACKGROUND: To assess the diagnostic performance of 64-section computed tomography angiography (CTA) for detection of cerebral aneurysms by comparison with the new gold standard three-dimensional (3D) digital subtraction angiography (DSA). MATERIAL AND METHODS: A total of 128 patients who underwent both 64 section CTA and 3D DSA for suspected intracranial aneurysms were included. The location, size, and shape of the aneurysm were assessed and compared with 3D DSA results. The sensitivity, specificity, positive and negative predictive values of 64-section CTA were calculated by using 3D DSA as reference standard. RESULTS: According to the reference standard, a total of 145 aneurysms were detected at 3D DSA in 118 patients. Of these 145 aneurysms, 64-section CTA detected 139 aneurysms in 118 patients. The sensitivity of CTA for detection of aneurysm was 95.8% on a per-aneurysm basis. All missed aneurysms were non-causative very small aneurysms in patients harboring multiple aneurysms. On a per-patient basis, the sensitivity, specificity, positive and negative predictive values were 100%. CONCLUSION: Compared with the new gold standard 3D DSA, 64-section CTA offers high sensitivity and specificity for detection of intracranial aneurysms. It could be readily used as a screening imaging method for detection of intracranial aneurysms. PMID- 24065202 TI - Functional outcomes according to the size of the gastric remnant and the type of reconstruction following distal gastrectomy for gastric cancer: an investigation including total gastrectomy. AB - OBJECTIVE: In gastric cancer, various methods of gastric resection have been devised according to the location of the primary tumor and the depth of invasion. Functional outcomes were compared among different types of reconstruction following open 2/3- or 4/5 distal gastrectomy for gastric cancer. METHODS: Resection and reconstruction were performed by one of the following three methods, depending on the depth of cancer invasion and the date of the procedure relative to the introduction of Roux-en-Y reconstruction: distal 2/3 gastrectomy with Roux-en-Y reconstruction (1/3 Roux-en-Y, n = 30); distal 4/5 gastrectomy with Roux-en-Y reconstruction (1/5 Roux-en-Y, n = 15) and distal 2/3 gastrectomy with Billroth I reconstruction (1/3B1, n = 30). Open total gastrectomy with Roux en-Y reconstruction (total gastrectomy with RY reconstruction, n = 30) was taken as the control procedure. RESULTS: Comparison of postoperative/preoperative body weight ratios and food intake ratios revealed better preservation among patients with a larger remnant stomach (the 1/3 Roux-en-Y and 1/3B1 groups), regardless of the reconstruction. The gastric emptying pattern in larger remnant stomach groups was milder than in the 1/5 Roux-en-Y and total gastrectomy with RY reconstruction groups. Reflux esophagitis was often observed on endoscopy in the 1/3B1 group. CONCLUSIONS: Better functional outcomes were observed in patients with a large remnant stomach regardless of the reconstruction. PMID- 24065203 TI - Cobalt phosphonates based on 4-(ethoxycarbonyl)naphthalen-1-yl)phosphonic acid. AB - The first examples of metal phosphonates based on 4-(ethoxycarbonyl)naphthanen-1 yl)phosphonic acid (4-cnppH2) are reported, namely, Co(4-cnpp) (1), Co2(4 cnpp)2(dptz) (2) and Co2(4-cnpp)2(4,4'-bpy)(H2O) (3) (dptz = 3,6-di(pyridin-3-yl) 1,2,4,5-tetrazine, 4,4'-bpy = 4,4'-bipyridine). The cobalt atoms are four coordinated with distorted tetrahedral geometries in both 1 and 2, while five coordinated with a distorted trigonal bipyramidal environment in compound 3. Compound 1 shows a layer structure in which the inorganic layers made up of edge sharing {CoNO3} dimers and {PO3C} linkages are separated by the organic groups of the 4-cnpp(2-) ligands. Compound 2 displays a different type of layer structure, where the ladder-like chains composed of corner-sharing {CoNO3} and {PO3C} tetrahedra are connected by dptz ligands with the organic groups of the 4-cnpp(2 ) ligands pendent on the two sides of the layer. In 3, similar ladder-like chains of corner-sharing {CoNO4} and {PO3C} are also found except that the cobalt atoms within the chain are further bridged by a coordinated water molecule. The chains are cross-linked by 4,4'-bpy, leading to a three-dimensional open-framework structure. Magnetic studies reveal that dominant antiferromagnetic interactions are mediated between the Co(II) ions in all three cases. PMID- 24065204 TI - Effect of icariin on cell proliferation and the expression of bone resorption/formation-related markers in human periodontal ligament cells. AB - Periodontitis is a common destructive inflammatory disease that leads to changes in the tooth-supporting tissues. Human periodontal ligament cells are essential in periodontal tissue regeneration. The traditional Chinese medicine icariin promoted bone formation, stimulated the osteogenic differentiation of preosteoblastic cells and inhibited osteoclast differentiation and bone resorption. Thus, in the present study, the effect of icariin on cell proliferation and the expression of osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB ligand (RANKL), core binding factor alpha1 (Cbfa1) and osteocalcin (OC) was investigated in human periodontal ligament cells, by an MTT assay, qPCR and western blot analysis. The results demonstrated that icariin promoted cell proliferation in a dose- and time-dependent manner, upregulated OPG, Cbfa1 and OC expression, and downregulated RANKL production and the RANKL/OPG expression ratio. This suggested the potential value of icariin in treating alveolar bone resorption and promoting periodontal tissue regeneration, due to its ability to stimulate the proliferation and osteogenic differentiation of human periodontal ligament cells and inhibit osteoclast differentiation. PMID- 24065205 TI - Novel mutation in exon 56 of the dystrophin gene in a child with Duchenne muscular dystrophy. AB - Duchenne type muscular dystrophy (DMD) is an allelic X-linked recessive disorder caused by mutations in the gene encoding dystrophin. Genotype analysis has shown that deletion mutations account for approximately 65% of all cases, and 5-10% are duplications, while the remaining 30% of affected individuals may have smaller mutations, including point mutations, small deletions or small insertions. In this study, we present the case of a 4-year-old boy with typical clinical features of DMD, who developed normally until the age of 2. However, at age 3 he presented his first symptom, a tendency to fall, had difficulty in rising from the floor and in walking on his toes. At age 4 he had a waddling gait and could no longer climb stairs. A physical examination revealed proximal muscle weakness, calf hypertrophy, deep tendon hyporflexia and a positive Gower's sign. To identify the disease-causing gene in the proband, all coding regions (exons 1-79) of the dystrophin gene were PCR-amplified and sequenced. A novel duplication (c.8284dupA) in exon 56 of the dystrophin gene was identified, which was predicted to generate a frameshift mutation and create a premature termination codon (p.Ile2762Asnfs*10). This mutation was further confirmed by single-strand conformation polymorphism (SSCP) analysis, which revealed an extra band found in exon 56 of the dystrophin in the proband; however, this was not present in his family members or in the 100 matched normal controls. The data presented in this study may aid in expanding the spectrum of mutations causing DMD. To our knowledge, we demonstrate for the first time that a small duplication mutation can cause severe DMD. PMID- 24065206 TI - A multicomponent snapshot of pharmaceuticals and pesticides in the river Meuse basin. AB - The river Meuse serves as a drinking-water source for more than 6 million people in France, Belgium, and The Netherlands. Pharmaceuticals and pesticides, both designed to be biologically active, are important classes of contaminants present in this river. The variation in the presence of pharmaceuticals in time and space in the Dutch part of the Meuse was studied using a multicomponent analytical method for pharmaceuticals combined with univariate and multivariate statistical analyses of the results. Trends and variation in time in the presence of pharmaceuticals were investigated in a dead-end side stream of the Meuse that serves as an intake point for the production of drinking water, and 93% of the selected compounds were detected. Highest concentrations were found for the antidiabetic metformin. Furthermore, a spatial snapshot of the presence of pharmaceuticals and pesticides was made along the river Meuse. Principal component analysis was successfully applied to reveal that wastewater-treatment plant effluent and water composition at the Belgian border were the main factors determining which compounds are found at different locations. The Dutch part of the river basin appeared responsible for approximately one-half of the loads of pharmaceuticals and pesticides discharged by the Meuse into the North Sea. The present study showed that multicomponent monitoring in combination with principal component analysis is a powerful tool to provide insight into contamination patterns in surface waters. PMID- 24065207 TI - Absence of evidence for enhanced benefit of antibiotic therapy on recurrent acute rhinosinusitis episodes: a systematic review of the evidence base. AB - OBJECTIVE: To systematically review the evidence base on the effectiveness of short-course antibiotic therapy in adult patients with a recurrent episode of acute rhinosinusitis as part of a disease pattern on severity and duration of symptoms and recurrences. DATA SOURCES: PubMed, EMBASE, and the Cochrane Library. REVIEW METHODS: A comprehensive search was performed up to March 21, 2013. Articles reporting studies on the effects of short-course antibiotic therapy compared with placebo in patients with recurrent acute rhinosinusitis were included. For included articles, the design of reported studies was assessed for directness of evidence and risk of bias. RESULTS: In total, 3473 unique publications were retrieved, of which 30 were considered eligible based on title and abstract screening. In addition, 8 eligible articles were retrieved using cross-reference checking. Based on full-text evaluation, none of the retrieved 38 articles satisfied our predefined selection criteria. They did not compare antibiotic treatment with placebo, excluded patients with recurrent acute rhinosinusitis, or did not report findings for a subgroup of patients with recurrent acute rhinosinusitis. CONCLUSION AND RECOMMENDATION: To date, there is no evidence available on differences in effect of antibiotic therapy in primary or sporadic and recurrent episodes of acute rhinosinusitis. As such, decisions for or against initial antibiotic therapy in patients with recurring episodes of acute rhinosinusitis should be based on the same criteria used in managing primary or sporadic episodes of uncomplicated acute rhinosinusitis. PMID- 24065208 TI - The subalar graft and its role in nasal tip medialization and improved nostril symmetry. AB - OBJECTIVES: Relationships between nasal axis deviation and lower midfacial asymmetry or hypoplasia have been established in prior studies. We describe our experience with the subalar grafting technique in addressing nasal tip deviation associated with facial asymmetry. Indications in using this graft in isolation or in conjunction with other tip modification techniques are also investigated. STUDY DESIGN: Retrospective case series. SETTING: Academic medical center. SUBJECTS AND METHODS: Thirty-seven consecutive patients from a single surgeon (R.W.W.) treated using subalar grafting are evaluated for correction. Various measurements from preoperative and postoperative photographs are analyzed to determine the effectiveness of this intervention. RESULTS: Statistically significant correlations between improvement in nasal axis and alar-facial angle on base view (AFAB) (P < .001) and between alar-facial angle on frontal view (AFAF) (P = .017) were observed. In addition, a significant correlation between AFAB improvement and AFAF normalization was observed (P < .001). The improved nostril symmetry was significantly correlated with base view correction and was not the result of general improvements in nasal deviation. CONCLUSION: While measuring the independent effects of subalar grafting is limited due to contaminant procedures, it can be recognized as a foundation rhinoplasty technique that, in conjunction with septoplasty, provides medialization of the tip in patients with facial asymmetry. Furthermore, aesthetic correction of nostril horizontal dystopia and/or nostril "show" is achieved with the proper application of this technique. This correction represents a unique intervention in rhinoplasty and should be considered a second indication for its use. PMID- 24065209 TI - Secondary acquired cholesteatoma after adenoidectomy and myringotomy. PMID- 24065210 TI - Successful CO2 laser ablation of true vocal fold microaneurysm in a patient with Ehlers-Danlos syndrome. PMID- 24065212 TI - Analytical analysis of the generic SET and RESET characteristics of electrochemical metallization memory cells. AB - We report on an analytical model which describes the bipolar resistive switching in electrochemical metallization cells. To simulate the resistive switching, we modeled the growth and dissolution of a metallic filament together with electron tunneling between the growing filament and the counter electrode. The model accounts for the controllability of the low resistive state and the RESET current by tuning the SET current. By analytical analysis the relevant conditions for these generic characteristics are identified. In addition, an explanation for the asymmetry in the SET and RESET switching characteristics is presented. The results of the analytical analysis is generalized to all types of ReRAMs. PMID- 24065211 TI - Dual-sugar imaging using isonitrile and azido-based click chemistries. AB - We report the first account of metabolically labelling N-acetylglucosamine, in conjunction with either N-acetylgalactosamine or N-acetylmannosamine using a combination of isonitrile- and azide-based chemistries. With the appropriately labelled fluorescent probe molecules, that react with either the azido or isonitrile groups, the method enabled co-visualisation of cancer cell glycoproteins. PMID- 24065213 TI - The distinct mechanisms of the antitumor activity of emodin in different types of cancer (Review). AB - Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. The inhibitory effect of emodin on mammalian cell cycle modulation in specific oncogene-overexpressing cells has formed the basis for using this compound as an anticancer drug. Previous reviews have summarized the antitumor properties of emodin. However, the specific molecular mechanisms of emodin-mediated tumor inhibition have not been completely elucidated over the last 5 years. Recently, there has been great progress in the preclinical study of the anticancer mechanisms of emodin. Our recent study revealed that emodin has therapeutic effects on pancreatic cancer through various antitumor mechanisms. Notably, the therapeutic efficacy of emodin in combination with chemotherapy was found to be higher than the comparable single chemotherapeutic regime, and the combination therapy also exhibited fewer side effects. Despite these encouraging results, further investigation is warranted as emodin has been shown to modulate one or more key regulators of cancer growth. This review provides an overview of the distinct mechanisms of anticancer action of emodin in different body systems identified over the past 5 years. These new breakthrough findings may have important implications for targeted cancer therapy and for the future clinical use of emodin. PMID- 24065214 TI - Combination of optic disc rim area and retinal nerve fiber layer thickness for early glaucoma detection by using spectral domain OCT. AB - BACKGROUND: To compare the diagnostic ability of optic disc rim area (RA), retinal nerve fiber layer thickness (RNFLT), and their combination on sector based analysis of spectral domain optical coherence tomography (Cirrus OCT) in discriminating subjects with early-stage open angle glaucoma (OAG) from normal subjects. METHODS: RA and RNFLT of 78 early OAG and 80 normal subjects were measured on Cirrus OCT at the global area, 4 quadrants, 12 clock hours, and 7 + 11 o'clock (a sector that includes 7 and 11 o'clock). A new parameter, RR (a multiplication of the RA and RNFLT) was derived to identify the best combination of the two parameters. Areas under the receiver operating characteristics curves (AUCs) of RA, RNFLT, and RR were compared. RESULTS: AUCs of RA were larger than those of RNFLT at nasal quadrant, at 1-5 o'clock on Cirrus OCT (all P values < 0.05). At the remaining areas, the two parameters were not significantly different on both devices (all P values > 0.05). RR had significantly larger AUCs than those of both RA and RNFLT at 7 + 11 o'clock (0.931 for RA, 0.933 for RNFLT, and 0.968 for RR) and global area (0.914 for RA, 0.905 for RNFLT, and 0.935 for RR), which were the two areas with largest AUCs. CONCLUSIONS: RR outperformed both RA and RNFLT of the Cirrus OCT, especially at areas with diagnostic importance. This suggests that combinations of RA and RNFLT by sector-based analysis of Cirrus OCT would be promising to determine early glaucoma. PMID- 24065216 TI - Complete genome sequences of two iflaviruses from the brown planthopper, Nilaparvata lugens. AB - The complete genome sequences of two new iflaviruses (genus Iflavirus, family Iflaviridae) were determined. These viral sequences were first identified in RNA seq contig sequences of Nilaparvata lugens in two distinct colonies: Izumo and Kagoshima. The accuracy of the contig sequences of the two viruses was verified by restriction enzyme digestion of RT-PCR products from viruliferous insects. RT PCR of RNA extracted from honeydews after viruliferous insect feeding detected the expected viral products, which suggested that viruses were excreted into the honeydews by the insects. Since we previously designated a similar iflavirus as "Nilaparvata lugens honeydew virus 1", the two new viruses have been tentatively named "Nilaparvata lugens honeydew virus 2" and "Nilaparvata lugens honeydew virus 3". The identity of the putative amino acid sequences of the capsid proteins of these viruses met the criterion for iflavirus species demarcation. Therefore, these two viruses are suggested to be members of distinct species in the genus Iflavirus. PMID- 24065215 TI - Impact of SOX18 expression in cancer cells and vessels on the outcome of invasive ductal breast carcinoma. AB - PURPOSE: SOX18 is a transcription factor known to be involved in hair follicle, blood and lymphatic vessel development, as well as wound healing processes (together with SOX7 and SOX17). In addition, it has been reported that SOX18 may affect the growth of cancer cells in vitro. Until now, the exact role of SOX18 expression in invasive ductal breast carcinoma (IDC) has remained unknown. METHODS: In this study, we have investigated SOX18 expression in cancer cells and endothelial cells in 122 IDC samples using immunohistochemistry (IHC). SOX18 expression was also determined using real-time PCR and Western blotting in a series of breast cancer-derived cell lines (i.e., MCF-7, BT-474, SK-BR-3, MDA-MB 231, BO2). RESULTS: Using IHC, we observed SOX18 nuclear expression in cancer cells, as well as in blood and lymphatic vessels of the IDC samples tested. SOX18 expression in the IDC samples correlated with a higher malignancy grade (Grade 2 and Grade 3 versus Grade 1; p = 0.02 and p = 0.009, respectively) and VEGF-D expression (r = 0.27, p = 0.007). SOX18 expression was also associated with HER2 positivity (p = 0.02). A significantly higher SOX18 expression was found in the HER2-positive cell line BT-474, and a significantly lower expression in the triple negative cell lines MDA-MB-231 and BO2. Laser capture microdissection of IDC samples revealed significantly higher mRNA SOX7, SOX17 and SOX18 expression levels in the vessels as compared to the cancer cells (p = 0.02 and p = 0.0002, p < 0.0001, respectively). SOX18 positive intratumoral and peritumoral microvessel counts (MVC) were associated with higher malignancy grades (p = 0.04 and p = 0.02, respectively). Moreover, peritumoral SOX18 positive MVC were found to act as an independent marker for a poor prognosis (p = 0.04). CONCLUSION: SOX18 expression may serve as a marker for a poor prognosis in IDC. PMID- 24065217 TI - The new era of hepatitis C treatment: still the tip of the iceberg? PMID- 24065218 TI - Treatment of ischemic colonic anastomoses with systemic transplanted bone marrow derived mesenchymal stem cells. AB - BACKGROUND: The aim of the study is to investigate the healing effect of the bone marrow derived mesenchymal stem cells (BM-MSCs) on ischemic colon anastomosis in systemic application and to recovery the adverse effect of ischemia. MATERIALS AND METHODS: Fourty male Wistar Albino rats weigthing 250-300 g were divided into four equal groups (n=10 Group 1: control; ischemic left colonic anastomoses (4th day); Group 2: control; ischemic left colonic anastomoses (7th day); Group 3: ischemic left colonic anastomoses + systemic transplanted BM-MSCs (4th day); Group 4: ischemic left colonic anastomoses + systemic transplanted BM-MSCs (7th day). BMSCs labelled with bromodeoxyuridine (BrdU) were transplanted into the vena cava. Group 1 and group 3 were killed four days after surgery. In group 2 and group 4 were sacrificed seven days after the surgical procedure. Histopathological features, hydroxyproline levels in the tissue, and anastomotic strength were investigated. RESULTS: There was no mortality all of the groups.The mean bursting pressures of ischemic colonic anastomoses in group 3 were higher than in control group 1 (4th day). We found significantly higher hydroxyproline values in group 3 and were significantly higher in group 4 than in control groups. We investigated the early period of wound healing (4th day and 7th day). When comparing between group 1 and group 3, we found higher levels for all of the histological parameters except inflammation in group 3. On day 7, when comparing between group 2 and group 4, we found higher levels for parameters of necrosis, collagen deposition. CONCLUSIONS: BM-MSCs therapy significantly accelerated all of the healing parameters for ischemic colonic anastomosis except for inflammation on fourth day. On the seventh day, BM-MSCs augmented the levels of the hydroxyproline. Histological parameters, necrosis and collagen deposition were also found to be important for healing of ischemic colonic anastomoses. However, they did not accelerate the others histological parameters especially angiogenesis. PMID- 24065219 TI - Evaluation of the effects of hyperbaric oxygen treatment and enoxaparin on left colon anastomosis. An experimental study. AB - BACKGROUND: Surgical interventions on left colon lead to high morbidity. The problems in wound healing are the main cause of this morbidity. Hypoxia retards wound healing and hyperbaric oxygen treatment (HBOT) has an anti-hypoxic effect. MATERIALS AND METHODS: In this experimental study we divided eighty Wistar albino rats into eight groups and numbered between 1 and 8. Normal (non-ischemic) and ischemic left colon anastomosis were performed in the first and second four groups respectively. HBOT and subcutaneous enoxaparin were applied to the groups separately and in combination for four days, except the control groups. (Group-1 and Group-5). We measured anastomotic bursting pressures and performed pathological examinations besides electron microscopic study in one sample from each group after sacrificing the rats on the fourth day. RESULTS: There were no statistically significant differences in bursting pressures when we compared Group-1 with other non-ischemic groups, and Group-5 with Group-6, but there were statistically significant differences when we compared Group-5 with Group-7 and 8. In pathological examination, there were no statistically significant differences between the groups concerning necrosis, epithelization, granulation tissue formation and collagen deposition. Statistically significant differences were found in the scores of neovascularization when we compared Group-1 with Group-3 and 4, and Group-5 with Group-8. Electron microscopic evaluation revealed a prominent increase both in neovascularization and collagen fibers in the samples taken from the groups received enoxaparine and hyperbaric oxygen treatment in combination. CONCLUSIONS: These findings suggest that HBOT increases neovascularization and bursting pressures in ischemic colon anastomosis in contrast with enoxaparin. PMID- 24065220 TI - Pneumatosis intestinalis: a rare cause of lower gastrointestinal bleeding. AB - Pneumatosis intestinalis is an uncommon condition characterized by the presence of gas in the bowel wall. We present the case of a 49-year-old man admitted to our Clinic for his 4 day long haematochezia. Colonoscopy revealed pneumatosis coli as a cause of the lower gastrointestinal bleeding. A wide range of diagnostic methods didn't show any underlying disease related to the bleeding, other than the presence of gas. Patient is reported in order to draw attention to the primary pneumatosis coli presented as a rare cause of haematochezia. PMID- 24065221 TI - The impact of metabolic syndrome on carotid intima media thickness. AB - OBJECTIVES: Metabolic syndrome (MetS) is a cluster of metabolic abnormalities involving several cardiovascular risk factors. Carotid intima media thickness (CIMT) is an important early screening tool to assess subclinical manifestation of cardiovascular and metabolic diseases. We aimed to investigate the impact of MetS on CIMT in a large scaled community based study. METHODS: The study was conducted on 2102 participants. Carotid intima media thickness was measured in all of the participants. The study sample was divided into 4 groups; Group 1 subjects with a body mass index (BMI) < 25.0 kg/m2 [n = 499 (MetS- = 488, MetS+ = 11)], Group 2 BMI between 25.0 and 29.9 kg/m2 [n = 693 (MetS- = 559, MetS+ = 134)], Group 3 BMI between >= 30 kg/m2 and 39.9 kg/m2 [n = 822 (MetS- = 375, MetS+ = 477)], and Group 4 BMI >= 40 kg/m2 [n = 88 (MetS- = 27, MetS+ = 61)]. RESULTS: Carotid intima media thickness was higher in the individuals with MetS compared to their normal counterparts. Furthermore, the subgroup analysis showed that CIMT values in Group 1 (0.55+/-0.18 vs 0.82+/-0.70; p < 0.001), Group 2 (0.59+/-0.20 vs 0.68+/-0.18; p < 0.001) and Group 3 (0.61+/-0.15 vs 0.65+/-0.18; p < 0.001) were significantly higher in subjects with MetS compared to their normal counterparts, whereas the values were similar in Group 4 (0.62+/-0.13 vs 0.65+/-0.17; p = 0.363). CONCLUSIONS: Carotid intima media thickness of overweight, obese and normal weight individuals without MetS were lower than their counterparts with MetS. MetS had no impact on CIMT in morbid obese individuals possibly due to established insulin resistance earlier than MetS. PMID- 24065222 TI - Fibrosis in heart failure subtypes. AB - BACKGROUND: The differences in concentrations of biomarkers between heart failure patients with dilated cardiomyopathy (HF-D) and with ischemic cardiomyopathy (HF I) have yet to be defined. The objectives of this study were to compare the concentrations and correlation of biomarkers of inflammation, extracellular matrix (ECM) turnover and oxidative stress parameters between these populations. PATIENTS AND METHODS: Our study consisted of 36 subjects with HF-D (LVSD = 47.2 +/- 7.3 mm, LVDD = 65.1 +/- 6.3 mm), 44 subjects with HF-I (LVSD = 38.0 +/- 4.4 mm, LVDD = 58.5 +/- 6.0 mm) and 38 controls without heart failure. Concentrations of matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, MMP-13, Galectin-3, prolidase, TNF-alpha, and oxidative stress index (OSI) were measured. RESULTS: Serum levels of MMP-2, MMP-9, and prolidase were significantly increased in HF-I group compared to healthy controls (p = 0.039, 0.019, 0.012 respectively), whereas the increases in MMP-1 and MMP-13 were not significant. This significance was stronger in the HF-D group than the HF-I group (p = 0.004, 0.001, 0.002 respectively). TNF-alpha, a marker of inflammation, was significantly increased in heart failure (p = 0.004) but there was no difference between HF-D and HF-I groups; however, Galectin-3 was significantly increased in the HF-D group compared to the HF-I group (p = 0.005). OSI showed the same response pattern as TNF-alpha (p = 0.019, 0.002 respectively). There was a positive correlation of MMP-9 levels with prolidase activity (r = 0.612, p: 0.003). CONCLUSIONS: MMPs and Galectin-3 are important in cardiac remodeling; prolidase may share an undefined role in fibrosis in heart failure and may have a role in the diffuse fibrosis of heart failure. PMID- 24065223 TI - Effects of pleural opening on respiratory function tests in cardiac surgery: a prospective study. AB - PURPOSE: To show the effects on lung function of the opening pleura in patients undergoing cardiac surgery. SUBJECTS AND METHODS: 66 patients were included. Patients were allocated into two groups. In group 1 (n=21) pleura was intact, in group 2 (n=45) pleura was opened. Both groups were compared prospectively in terms of preoperative and on the post-operative 5th day pulmonary function tests (PFT), preoperative, postoperative first and fifth day arterial blood gas analysis, preoperative and postoperative first day mixt venous oxygen saturation, bleeding, operation periods, pulmonary complications, intensive care and hospital stay period and mortality. RESULTS: There was significant decrease in all PFT indicators on 5th post-operative day in group 2 (p < 0.01). Although there was a significant decrease in FEV1 on 5th post-operative day in group 1 (p < 0.001), other pulmonary functions parameters were not change significantly (p > 0.025). In group 2 much more decline in pulmonary function test parameters than group 1 were observed (p < 0.05). There was not statistically significant difference in blood gas analysis and mixed venous oxygen saturation values in group 1 (p > 0.05). But in group 2 except pH and PaCO2, other blood gas measurements were significantly decreased on the postoperative first and fifth day (p < 0.008). In group 2 except pH and PCO2, other parameters were less than the other Group (p < 0.01). The drained amount was still significantly higher in group 2 (p < 0.001). The frequency of the revision due to bleeding was observed much more in group 2. CONCLUSIONS: Protection of the integrity of pleura may have positive effects on pulmonary functions in cardiac surgery. PMID- 24065224 TI - Molecular changes of mesenchymal stromal cells in response to dexamethasone treatment. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into a variety of cell types. The MSCs can be activated and mobilized if needed. AIM: This study aimed to investigate the response mechanism of MSCs under Dexamethasone (Dex) treatment by combining MSCs microarray and bioinformatics methods. MATERIALS AND METHODS: We downloaded the gene expression profile of rat's MSCs challenge with or without Dex (GSE3339) from Gene Expression Omnibus database, including 2 Dex treated samples and 3 untreated samples. The differentially expressed genes (DEGs) were identified by packages in R language. Then, Gestalt (Genomic Sequence Total Analysis and Lookup Tool) and EASE (Expression Analysis Systematic Explorer) to were employed to obtain the molecular events of MSCs under Dex treatment. RESULTS: A total of 17 genes were identified as DEGs between untreated and treated samples, and they were significant enriched in immune response and cell differentiation. The C3 gene was the common candidate gene selected from two different algorithms, and 24 conserved sites were identified in the 3'UTR of C3 gene. CONCLUSIONS: Genes associated with immune response and cell differentiation were dysregulated in MSCs under Dex. PMID- 24065225 TI - Doxorubicin-induced apoptosis in H9c2 cardiomyocytes by NF-kappaB dependent PUMA upregulation. AB - OBJECTIVE: The cardiotoxicity of doxorubicin limits its clinical use in the treatment of a variety of solid tumors and malignant hematologic disease. Although the mechanism by which it causes cardiac injury is not yet known, apoptosis has been regarded as one of mechanisms underlying the cardiotoxic effects of doxorubicin. In the present study, we investigates the mechanisms of doxorubicin-induced apoptosis in H9c2 cardiomyocytes by NF-kappaB dependent PUMA upregulation. MATERIALS AND METHODS: H9c2 cardiac myocytes was treated with 5-50 mM concentration of doxorubicin for 72 hours. p65 siRNA or PUMA siRNA was transfected into H9c2 cardiac myocytes, then treated with 50 mM doxorubicin for 72 hours. Apoptotic cells were detected using Flow cytometric analysis. MTT cytotoxicity test was used to detect the effect of doxorubicin on H9c2 cardiac myocytes. PUMA expression was detected by western blot assay. NF-kappaB binding activities was detected using electrophoretic mobility shift assays (EMSA). RESULTS: Doxorubicin promotes apoptosis and inhibits proliferation in H9c2 cardiac myocytes in a dose and time-dependent way. Doxorubicin treatment increased NF-kappaB binding activities and PUMA expression. Inhibition of p65 by p65 siRNA decreased PUMA expression of doxorubicin-induced. Furthermore, p65 siRNA or PUMA siRNA-mediated suppression of p65 or PUMA results in inhibition of apoptosis of doxorubicin-induced. CONCLUSIONS: It is demonstrated that PUMA is a direct target of NF-kappaB and mediates doxorubicin-induced apoptosis in vitro. PMID- 24065226 TI - Presence of low lipid levels in patients with Behcet' s disease as a protector against atherosclerosis. AB - BACKGROUND: A relapsing systemic inflammatory process is a well-known feature of Behcet's disease. Because systemic inflammation and dyslipidemia are involved in the pathogenesis of atherosclerosis, Behcet's disease may play a part in the development of atherosclerosis. Lipid profile in Behcet's disease and the development of atherosclerosis remain to be controversial. In order to learn more about this relationship, our study compared blood lipid levels in healthy controls to those in patients with Behcet's disease during both their active and inactive stages. PATIENTS AND METHODS: Between December 2010 and March 2012, this prospective, observational study was designed to evaluate three groups The study included 91 Behcet's patients (36 in active and 55 in inactive period) and 61 healthy control subjects matched for age, gender, and body mass index. Data from lipid profiles included total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein. Acute phase reactants were also recorded, including high sensitive C-reactive protein and erythrocyte sedimentation rate levels. RESULTS: Total cholesterol, low density lipoprotein, and high density lipoprotein cholesterol levels of patients in active stage were significantly lower than those in inactive stage, while total cholesterol and low density lipoprotein levels were lower in the control group (p < 0.05). CONCLUSIONS: Patients with Behcet's disease in the active period may be less susceptible to atherogenic events as compared with the controls and those in the inactive period of the disease. PMID- 24065227 TI - JNK phosphorylation promotes natural degeneration of cervical endplate chondrocytes by down-regulating expression of ANK. AB - BACKGROUND: Endplate degeneration leads to accelerated degeneration of the intervertebral disc. The importance of endplate chondrocytes in this process is unclear. Many cellular processes in chondrocytes are controlled by activated c Jun N-terminal kinases (JNK) and protein kinase B (AKT). However, the involvement of their pathways in the degeneration process needs to be elucidated. AIM: To study activation of JNK and AKT signaling pathways and their significance for degeneration of endplate chondrocytes, as well as involvement of progressive ankylosis protein (ANK) in this process. MATERIALS AND METHODS: Rat primary chondrocytes were grown to confluence and subcultured until passage 4. Morphological appearances (microscope, hematoxylin & eosin staining, toluidine blue staining) and proliferation rates of cells (MTT test) were observed. Further, levels of type II collagen, aggrecan, phosphorylated JNK and AKT, total JNK, AKT and ANK were evaluated by qPCR, flow cytometry and Western blot assays. Furthermore, inhibition experiments with SP600125, the JNK inhibitor, were carried out in the passage 4 cells to assess the effects of the JNK pathway on natural degeneration of endplate chondrocytes. RESULTS: The proliferative speed of endplate chondrocytes progressively decreased during passaging. Expressions of type II collagen and aggrecan were significantly decreased with cells at higher passages. Furthermore, phosphorylation of JNK, but not AKT, was significantly up regulated and accompanied by reduced ANK expression. Inhibition of the JNK pathway increased expression of type II collagen, aggrecan and ANK and facilitated proliferation rates. CONCLUSIONS: Phosphorylation of JNK promotes natural degeneration of cervical endplate chondrocytes, likely by down-regulating ANK expression. PMID- 24065228 TI - Switching from immediate release to sustained release methylphenidate in the treatment of children and adolescents with attention deficit/hyperactivity disorder. AB - BACKGROUND: Switching from Immediate Release Methylphenidate (MPH-IR) to a sustained release formulation in treatment of attention deficit/hyperactivity disorder (ADHD) is often required to provide better compliance and convenience. However; the switch has been reported to be not always successful and small doses of MPH-IR may be added to sustained release preparations when its effect wears off. SUBJECTS AND METHODS: In this survey, clinical case notes of 77 subjects aged 6-18 years who had been switched from MPH-IR to Concerta XL were retrospectively analyzed to demonstrate the effectiveness of the switch. The impact of adding MPH-IR to Concerta XL on the outcome was evaluated. RESULTS: Switch to Concerta XL alone was successful in 94% of cases and all 23 (100%) subjects who had MPH-IR added to Concerta XL showed good response to the switch. However; more than 43% of the subjects required additional doses of MPH-IR and 55% needed a larger than recommended equivalent doses of Concerta XL for a successful switch. CONCLUSIONS: Higher than equivalent doses of Concerta XL or an additional dose of MPH-IR may be required for a successful switch from immediate to sustained release methylphenidate. PMID- 24065229 TI - Platelet function in euthyroid patients undergoing thyroidectomy in women. AB - BACKGROUND: Several studies have reported several platelet abnormalities in patients with sub-clinical or overt thyroid dysfunctions. The primary mechanism that affects the hemostatic balance is excess or deficiency of thyroid hormones. The different ways of thyroid gland to the platelet function are not yet clearly understood. The relationship between in the thyroid gland and platelet activation without thyroid hormones has not been studied yet. AIM: The aim of our study is to determine the platelet function in euthyroid patients undergoing thyroidectomy in females. PATIENTS AND METHODS: The study group includes 52 female euthyroid patients undergoing thyroidectomy. The control group consisted with 21 healthy euthyroid female. Platelet count (PC), platelet mass (PM), mean platelet volume (MPV), and platelet distribution width (PDW) were measured. PM was calculated by multiplying MPV and PLT. RESULTS: MPV (8.4 +/- 1.3 versus 7.9 +/- 0.8) and PDW (17.8 +/- 1 versus 17.6 +/- 0.8) values were similar between the two groups. CONCLUSIONS: Thyroid gland does not directly affect platelet activation. Accordingly, platelet abnormalities of thyroid disease can be considered to be independent of the underlying thyroid tissue. This finding suggests that association between thyroid diseases and platelet function is dependent on the status of thyroid hormones. PMID- 24065230 TI - Kaposi' s sarcoma in HIV-positive patients: the state of art in the HAART-era. AB - Kaposi's sarcoma (KS) is a multicentric angioproliferative cancer of endothelial origin typically occurring in the context of immunodeficiency, i.e. coinfection with Human Immonodeficiency Virus (HIV) or transplantation. The incidence of KS has dramatically decreased in both US and Europe in the Highly Active Antiretroviral Therapy (HAART) era. However, KS remains the second most frequent tumor in HIV-infected patients worldwide and it has become the most common cancer in Sub-Saharan Africa. In 1994, Yuan Chang et al discovered a novel gamma herpesvirus in biopsy specimens of human KS. Epidemiologic studies showed that KS associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) was the etiological agent associated with all subtypes of KS. KS has a variable clinical course ranging from very indolent forms to a rapidly progressive disease. HAART represents the first treatment step for slowly progressive disease. Chemotherapy (CT) plus HAART is indicated for visceral and/or rapidly progressive disease. The current understanding of KS as a convergence of immune evasion, oncogenesis, inflammation and angiogenesis has prompted investigators to develop target therapy, based on anti-angiogenic agents as well as metalloproteinase and cytokine signaling pathway inhibitors. These drugs may represent effective strategies for patients with AIDS-associated KS, which progress despite chemotherapy and/or HAART. In this review, we focus on the current state of knowledge on KSHV epidemiology, pathogenesis and therapeutic options. PMID- 24065231 TI - Application of acrylic spacers for long bone defects after tumoral resections. AB - INTRODUCTIONS: Tumoral resections pose serious challenges because sufficient removal has to be balanced against function preservation. A particular type of resection is encountered when the tumor is located in the diaphysis. It can lead to an important gap which cannot always amend to bone grafting in the same procedure. PATIENTS AND METHODS: The aim of the paper is to evaluate the long term outcome of segmental bone loss in patients with malignant tumors removed from diaphyseal regions and treated by intramedullary nailing and polymethylmethacrylate spacer. The limb function was then evaluated using a range of motion by the Musculoskeletal Tumor Score (MSTS) and the perceived quality of life measured by the EORTC QLQ-C30. RESULTS: There were no immediate postoperative local or systemic complications and no failures of the nail/cement construct. All cases were allowed immediate weight bearing (lower limb) and none were immobilized (upper limb). The average length of the bone defect was 9 (6-14) centimeters. The average follow-up was 2.5 (1-4) years. CONCLUSIONS: Polymethylmethacrylate cement spacers, over intramedullary nailing, have statistically proved a feasible and inexpensive procedure with limited complications, low surgical stress and favorable functional outcomes. It can be a definitive therapy for advanced cases, as well as temporary solution which can be successfully converted to secondary bone grafting. PMID- 24065232 TI - S100A4 regulates migration and invasion in hepatocellular carcinoma HepG2 cells via NF-kappaB-dependent MMP-9 signal. AB - BACKGROUND AND OBJECTIVES: We previously showed that the calcium-binding protein S100A4 is overexpressed and related to metastasis in hepatocellular carcinoma (HCC). However, whether S100A4 participates in the regulation of metastasis and its mechanisms in HCC is mostly unknown. Given the associations of S100A4, nuclear factor-kB (NF-kB/RelA) and MMP-9 with metastasis in a variety of malignancies, we explored a potential role of S100A4 in HCC metastasis and its mechanism. METHODS: 20 patients with HCC invasion (Lymph node metastasis, microvascular invasion, major portal vein invasion and intrahepatic metastasis) and 20 patients without HCC invasion were included. These tissues were detected for the expression of S100A4, NF-kB/RelA and MMP-9 by immunohistochemistry and quantitative real time polymerase chain reaction (Q-PCR). Correlation between the expressions of S100A4, NF-kB/RelA and MMP-9 with the invasion was analysed. The expressions of S100A4, nuclear factor-kB and MMP-9 was evaluated in HepG2 cells by western blot and immunohistochemistry. HepG2 cells were stably transfected with S100A4-specific small interfering RNA (S100A4 siRNA) to knockdown of S100A4, then transiently transfected with S100A4 cDNA to rescure the S100A4 level and evaluated for effects on invasion and expression analysis for molecules involved in invasion. After the HepG2 cells recurred the S100A4 levels, the HepG2 cells was treated with 5 uM Pyrrolidine Dithiocarbamate (PDTC) (a selective NF kappa B inhibitor) to inhibit the NF-kB activity, or treated with Batimast (BB94: a MMPs inhibitor) to inhibit the MMP-9 activity. The expression analysis for molecules involved in invasion was analyzed. RESULTS: A significant increase of S100A4, NF kB/RelA and MMP-9 expression in HCC tissues with invasion than that of without invasion. A positive correlation was observed between S100A4, NF-kB/RelA, MMP-9 and invasion, respectively. In addition, S100A4 was positively correlated with NF kB and MMP-9. S100A4 siRNA mediated knockdown of S100A4 in HepG2 cells resulted in significant reduction in the NF-kB activity and MMP-9 expression, and dramatically decreased its invasion. Moreover, the HepG2 cell metastatic potential was rescued by overexpression of S100A4 completely, at the same time, the NF-kB activity and MMP-9 expression was also increased. Pretreatment with PDTC or BB94 was observed to significantly reduce NF-kB activity and MMP-9 expression and dramatically decreased S100A4 -induced invasion. CONCLUSIONS: Our findings indicate that S100A4 contributes to HCC metastasis by activation of NF kB dependent MMP-9 expression, suggesting S100A4 as a novel diagnostic biomarker and therapeutic target in HCC. PMID- 24065233 TI - Diagnostic accuracy of Cyfra 21-1 for head and neck squamous cell carcinoma: a meta-analysis. AB - BACKGROUND AND OBJECTIVES: The role of Cyfra 21-1 in diagnosing squamous cell carcinoma of head and neck is not yet clear. The present meta-analysis aimed to establish the overall diagnostic accuracy of Cyfra 21-1 for head and neck squamous cell carcinoma. METHODS: After a systematic literature review and selection of English language studies, sensitivity, specificity and other measures of accuracy of Cyfra 21-1 in the diagnosis of head and neck squamous cell carcinoma were pooled using random effects models. Summary receiver operating characteristic curve was used to summarize overall diagnostic performance. Publication bias was examined by Deeks' funnel plot. RESULTS: Thirteen studies with 2269 subjects met the inclusion criteria for the analysis. The pooled sensitivity and specificity of Cyfra 21-1 for diagnosing head and neck squamous cell carcinoma were 0.51 (95%CI: 0.48-0.54) and 0.97 (95%CI: 0.95-0.98), respectively. The positive likelihood ratio was 10.11 (95%CI: 6.50-15.71), negative likelihood ratio was 0.52 (95%CI: 0.41-0.66) and diagnostic odds ratio was 25.60 (95%CI: 13.39-48.96). The area under the summary receiver operating characteristic curve was 0.94. CONCLUSIONS: The evidence from current meta analysis suggests Cyfra 21-1 plays a valuable role in the diagnosis of head and neck squamous cell carcinoma with high specificity. The results of tumor marker assays should be interpreted in parallel with clinical findings and the results of conventional tests. PMID- 24065234 TI - The evaluation of MDCT and quantitative first-pass perfusion in lung cancers. AB - OBJECTIVES: The aim of this study was the in vivo evaluation of tumor angiogenesis in lung cancers grouped according to their histopathological diagnosis, localization and necrosis characteristics determined using CT first pass parameters. MATERIALS AND METHODS: The study was performed between January and April 2012 on 44 patients consisting of 38 males and 6 females who were diagnosed with lung cancer as a result of cytological and/or histopathological evaluations. Patients who had not received radiotherapy and/or chemotherapy previously were included in the study. Images were obtained for each patient by using the 64-detector MDCT scanner. Colored perfusion maps were created from the obtained images. Perfusion parameter measurements were performed by placing ROI at 3 different locations in the solid sections, avoiding the necrotic cystic areas of the masses. Obtained BV, BF, TTP, and MTT perfusion parameters were recorded. RESULTS: The BF values of central and peripherally located lung cancers that showed normal distribution were found to be statistically significantly different. No statistically significant difference was found between TTP values. The BV values of central and peripherally located lung cancers that did not show normal distribution showed a statistically significant difference. There was a statistically significant difference between the BV and BF values of lung cancer with and without necrosis that did not show a normal distribution and the BV and BF values of lung cancers with and without necrosis. CONCLUSIONS: Non-invasive evaluation of tumor perfusion of first-pass perfusion CT in lung cancers provides valuable information about tumor angiogenesis. However, we believe that peripheral and solid lung cancers will benefit more from treatments such as anti angiogenetic drugs, radiotherapy and chemotherapy more than the centrally located and necrotic lung cancers and that perfusion CT will play a greater role in the evaluation of the efficiency of these treatments in the future. PMID- 24065235 TI - The evaluation of selected serum mineral concentrations and their association with insulin resistance in obese adolescents. AB - BACKGROUND: In obesity, elevated insulin resistance is observed, which may be associated with disturbances in mineral status in the body. The few studies concerning the status of minerals and their relationships with insulin resistance and body composition in adolescent populations have brought inconclusive results. AIM: of this study is, thus, to assess serum mineral concentration in obese adolescents, and to evaluate their potential association with insulin resistance. SUBJECTS AND METHODS: Seventy-eight obese adolescents and 20 healthy volunteers aged 12-18 years were recruited for the study. Selected anthropometrical measurements and levels of iron, zinc, copper, calcium, and magnesium were assessed in serum. Insulin resistance in the participants was evaluated according to the homeostatic model of assessment for insulin resistance (HOMA-IR) protocol. Levels of iron, zinc, copper, calcium, and magnesium were assessed in serum. RESULTS: Obese subjects had significantly higher HOMA-IR indices than the control group. Compared to healthy subjects, the serum concentration of zinc, calcium, and magnesium was significantly lower in obese subjects. A significant inverse relation was found between HOMA-IR and zinc levels in serum. CONCLUSIONS: Obese adolescents have a poorer mineral status (especially zinc) than adolescents of normal weight, which can contribute to insulin resistance. PMID- 24065236 TI - Exome sequencing reveals new insights into the progression of abdominal aortic aneurysm. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a multi-factorial disease and its underlying pathogenesis remains poorly understood. AIM: We aim to search for the underlying etiology of AAA using whole exome sequencing and gene expression analysis. MATERIALS AND METHODS: We performed whole exome sequencing for AAA and adjacent normal abdominal aorta tissue from one male AAA patient. Further gene expression analysis using downloaded dataset from the GEO database was also carried out to explore the underlying molecular mechanisms. RESULTS: A total of 5.97 Gb clean data were generated for the two samples, achieving a mean depth of coverage of 31.96 and 32.88 for the AAA and normal samples, respectively. We identified 203 somatic variants and confirmed 34 protein-altering somatic mutations in 25 genes. Among the confirmed variants, 11 mutations were not reported in the dbSNP database before. According to the literature review, none of these 25 genes were reportedly associated with AAA. CONCLUSIONS: Our findings here may provide potential targets for effective prevention of human AAA development and progression. PMID- 24065237 TI - Neutrophil lymphocyte ratio should be assessed together with other inflammatory markers and confounding factors. PMID- 24065238 TI - Serum alpha-fetoprotein in patients with nonalcoholic fatty liver disease. PMID- 24065239 TI - Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. AB - The management of chronic lymphocytic leukemia (CLL) is undergoing profound changes. Several new drugs have been approved for CLL treatment (fludarabine, bendamustine, and the monoclonal antibodies alemtuzumab, rituximab, and ofatumumab) and many more drugs are in advanced clinical development to be approved for this disease. In addition, the extreme heterogeneity of the clinical course and our improved ability to foresee the prognosis of this leukemia by the use of clinical, biological, and genetic parameters now allow us to characterize patients with a very mild onset and course, an intermediate prognosis, or a very aggressive course with high-risk leukemia. Therefore, it becomes increasingly challenging to select the right treatment strategy for each condition. This article summarizes the currently available diagnostic and therapeutic tools and gives an integrated recommendation of how to manage CLL in 2013. Moreover, I propose a strategy how we might integrate the novel agents for CLL therapy into sequential treatment approaches in the near future. PMID- 24065240 TI - von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. AB - von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder. The disease represents a range of quantitative and qualitative pathologies of the adhesive glycoprotein von Willebrand factor (VWF). The pathogenic mechanisms responsible for the type 2 qualitative variants of VWF are now well characterized, with most mutations representing missense substitutions influencing VWF multimer structure and interactions with platelet GPIbalpha and collagen and with factor VIII. The molecular pathology of type 3 VWD has been similarly well characterized, with an array of different mutation types producing either a null phenotype or the production of VWF that is not secreted. In contrast, the pathogenetic mechanisms responsible for type 1 VWD remain only partially resolved. In the hemostasis laboratory, the measurement of VWF:Ag and VWF:RCo are key components in the diagnostic algorithm for VWD, although the introduction of direct GPIbalpha-binding assays may become the functional assay of choice. Molecular genetic testing can provide additional benefit, but its utility is currently limited to type 2 and 3 VWD. The treatment of bleeding in VWD involves the use of desmopressin and plasma-derived VWF concentrates and a variety of adjunctive agents. Finally, a new recombinant VWF concentrate has just completed clinical trial evaluation and has demonstrated excellent hemostatic efficacy and safety. PMID- 24065241 TI - Molecular approaches for improved clotting factors for hemophilia. AB - Hemophilia is caused by a functional deficiency of one of the coagulation proteins. Therapy for no other group of genetic diseases has seen the progress that has been made for hemophilia over the past 40 years, from a life expectancy in 1970 of ~20 years for a boy born with severe hemophilia to essentially a normal life expectancy in 2013 with current prophylaxis therapy. However, these therapies are expensive and require IV infusions 3 to 4 times each week. These are exciting times for hemophilia because several new technologies that promise extended half-lives for factor products, with potential for improvements in quality of life for persons with hemophilia, are in late-phase clinical development. PMID- 24065242 TI - Blood spotlight on leukocytes and obesity. AB - The rise of obesity and its attendant pathological sequelae, including type 2 diabetes and coronary artery disease, constitute an ongoing public health catastrophe in both the developed and, more recently, the developing world. Although the underlying pathophysiology is complex, chronic low-grade inflammation has emerged as a central driver of both primary metabolic dysfunction and subsequent tissue failure. Importantly, this inflammation has been shown to arise as a consequence of both the disruption of homeostatic tissue resident leukocytes and the recruitment of antagonistic effector cells from the circulation. In this review, we discuss the roles of visceral adipose tissue's salient leukocyte lineages in the transition to obesity and highlight key points at which this emerging immune axis may be manipulated for therapeutic effect. PMID- 24065243 TI - Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. AB - Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.39-0.86; P = .007), and relapse after, but not before, 1 year posttransplant (RR = 0.23; 95% CI: 0.08-0.65; P = .006), and better leukemia-free survival (RR = 0.70; 95% CI: 0.55-0.88; P = .003) and survival (RR = 0.68; 95% CI: 0.52-0.88; P = .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first CR. PMID- 24065244 TI - Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response. AB - Platelets are a reservoir for angiogenic proteins that are secreted in a differentially regulated process. Because of the propensity for clotting, patients with malignancy are often anticoagulated with heparin products, which paradoxically offer a survival benefit by an unknown mechanism. We hypothesized that antithrombotic agents alter the release of angiogenesis regulatory proteins from platelets. Our data revealed that platelets exposed to heparins released significantly decreased vascular endothelial growth factor (VEGF) in response to adenosine 5'-diphosphate or tumor cells (MCF-7 cells) and exhibited a decreased angiogenic potential. The releasate from these platelets contained decreased proangiogenic proteins. The novel anticoagulant fondaparinux (Xa inhibitor) demonstrated a similar impact on the platelet angiogenic potential. Because these anticoagulants decrease thrombin generation, we hypothesized that they disrupt signaling through the platelet protease-activated receptor 1 (PAR1) receptor. Addition of PAR1 antagonists to platelets decreased VEGF release and angiogenic potential. Exposure to a PAR1 agonist in the presence of anticoagulants rescued the angiogenic potential. In vivo studies demonstrated that platelets from anticoagulated patients had decreased VEGF release and angiogenic potential. Our data suggest that the mechanism by which antithrombotic agents increase survival and decrease metastasis in cancer patients is through attenuation of platelet angiogenic potential. PMID- 24065245 TI - Strengths and weaknesses of microarray approaches to detect Pseudo-nitzschia species in the field. AB - The planktonic diatom genus Pseudo-nitzschia contains several genetically closely related species. Some of these can produce domoic acid, a potent neurotoxin. Thus, monitoring programs are needed to screen for the presence of these toxic species. Unfortunately, many are impossible to distinguish using light microscopy. Therefore, we assessed the applicability of microarray technology for detection of toxic and non-toxic Pseudo-nitzschia species in the Gulf of Naples (Mediterranean Sea). Here, 11 species have been detected, of which at least 5 are potentially toxic. A total of 49 genus- and species-specific DNA probes were designed in silico against the nuclear LSU and SSU rRNA of 19 species, and spotted on the microarray. The microarray was tested against total RNA of monoclonal cultures of eight species. Only three of the probes designed to be species-specific were indeed so within the limits of our experimental design. To assess the effectiveness of the microarray in detecting Pseudo-nitzschia species in environmental samples, we hybridized total RNA extracted from 11 seasonal plankton samples against microarray slides and compared the observed pattern with plankton counts in light microscopy and with expected hybridization patterns obtained with monoclonal cultures of the observed species. Presence of species in field samples generally resulted in signal patterns on the microarray as observed with RNA extracted from cultures of these species, but many a-specific signals appeared as well. Possible reasons for the numerous cross reactions are discussed. Calibration curves for Pseudo-nitzschia multistriata showed linear relationship between signal strength and cell number. PMID- 24065246 TI - Shifts and stasis in marine HAB monitoring in New Zealand. AB - This review article outlines harmful algal bloom (HAB) monitoring practices in New Zealand and highlights the shift from light microscope (LM)-based identification and quantification of the early 1990s to the use of molecular tools to support the HAB monitoring programmes two decades later. Published research and available client information from the monitoring programmes have been reviewed; HAB events and programme changes are highlighted. The current HAB monitoring practices allow for rapid determination of potential biotoxin issues for the shellfish industry and of potential ichthyotoxic events for finfish farmers. The use of molecular tools, including quantitative PCR, has improved risk assessments for those HAB species that are difficult to differentiate to species level using LM. This has enabled rapid feedback to aquaculture managers during HAB events. Tests for biotoxins in flesh remain the regulatory tools for commercially harvested shellfish, but this is supported by the weekly phytoplankton monitoring data. Recreational (non-commercial) shellfish harvesting and commercial finfish aquaculture rely solely on phytoplankton monitoring to assess the biotoxin risk. HAB monitoring in New Zealand continues to maintain internationally recognised standards, and the government-funded research programmes feed the latest knowledge and technical methods into the programmes. The early dependence on light microscopy continues but is now supported by molecular tools, with a view to employing multi-species detection systems in the future. The traditional mouse bioassay test has been fully replaced by chemical tests. PMID- 24065247 TI - Crosstalk between dopamine receptors and the Na+/K+-ATPase (review). AB - Dopamine (DA) receptors, which belong to the G protein-coupled receptor family, are the target of ~50% of all modern medicinal drugs and constitute a large and diverse class of proteins whose primary function is to transduce extracellular stimuli into intracellular signals. Na+/K+-ATPase (NKA) is ubiquitous and crucial for the maintenance of intracellular ion homeostasis and excitability. Furthermore, it plays a critical role in diverse effects, including clinical cardiotonic and cardioprotective effects, ischemic preconditioning in the brain, natriuresis, lung edema clearance and other processes. NKA regulation is of physiological and pharmacological importance and has species- and tissue-specific variations. The activation of DA receptors regulates NKA expression/activity and trafficking in various tissues and cells, for example in the kidney, lung, intestine, brain, non-pigmented ciliary epithelium and the vascular bed. DA receptor-mediated regulation of NKA mediates a diverse range of cellular responses and includes endocytosis/exocytosis, phosphorylation/dephosphorylation of the alpha subunit of NKA and multiple signaling pathways, including phosphatidylinositol (PI)-phospholipase C/protein kinase (PK) C, cAMP/PKA, PI3K, adaptor protein 2, tyrosine phosphatase and mitogen-activated protein kinase/extracellular signal-regulated protein kinase. Furthermore, in brain and HEK293T cells, D1 and D2 receptors exist in a complex with NKA. Among D1 and D2 receptors and NKA, regulations are reciprocal, which leads to crosstalk between DA receptors and NKA. In the present study, the current understanding of signaling mechanisms responsible for the crosstalk between DA receptors and NKA, as well as with specific consequent functions, is reviewed. PMID- 24065248 TI - Sonography: first-line modality in the diagnosis of acute colonic diverticulitis? PMID- 24065249 TI - Findings and implications of focal fatty sparing of the liver at follow-up: a preliminary study based on sonography, computed tomography, and magnetic resonance imaging. AB - OBJECTIVES: The purpose of this study was to investigate the stability of focal fatty sparing of the liver and its clinical implications. METHODS: This prospective study consisted of 2 parts. In the first part, patients who underwent sonography and computed tomography (CT) or magnetic resonance imaging (MRI) were selected, and abnormal findings including focal and diffuse liver abnormalities were documented. In the second part, patients with nonalcoholic hepatic steatosis and focal fatty sparing were included and underwent follow-up with sonography in the second and third years (study interval, 34-37 months; mean +/- SD, 35.9 +/- 1.14 months). Some cases of focal fatty sparing that were not appreciable on sonography in the third year were reevaluated with CT. RESULTS: A total of 6781 patients with nonalcoholic hepatic steatosis and focal abnormalities were found among 35,337 people undergoing liver sonography; 2133 underwent CT, MRI, biopsy, or a combination thereof. Eighty-nine of those patients (63 male and 26 female; mean age, 37.6 +/- 17.5 years; range, 18-72 years) with hepatic steatosis and focal fatty sparing were finally included. In the second part of the study, focal fatty sparing was appreciable on follow-up sonography in 78 cases (87.6%) and 61 cases (68.5%) in the second and third years, respectively. The hepatic steatosis resolved in the third year in 4 patients, and 26 of 28 cases (92.8%) of focal fatty sparing that were not appreciable on follow-up sonography were found on CT in the third year. CONCLUSIONS: Focal fatty sparing may change with fatty liver changes over time, and it is sometimes not appreciable on sonography, although it is often evident on CT. These findings imply that if differentiation between focal fatty sparing and a tumor is undetermined and follow-up is performed, should any change occur, then an abnormality that is no longer appreciable at follow-up is probably focal fatty sparing rather than a true tumor. PMID- 24065251 TI - Evaluation of the fetal heart at 14 to 18 weeks' gestation in fetuses with a screening nuchal translucency greater than or equal to the 95th percentile. AB - OBJECTIVES: The purpose of this study was to determine whether normal fetal cardiac anatomy could be successfully demonstrated and congenital heart disease detected transabdominally at 14 to 18 weeks' gestation in fetuses with a nuchal translucency greater than or equal to the 95th percentile. METHODS: In this retrospective chart review, grayscale images, Z scores, and Doppler evaluations, including pulsed, color, and spectral Doppler imaging, were reviewed to determine whether fetal heart evaluation findings at 14 to 18 weeks' gestation were normal or abnormal. RESULTS: Normal cardiac anatomy was successfully evaluated in 32 of 33 normal cases; only an aortic arch and a ductal arch were not successfully visualized in 1 case. Major congenital heart disease was detected prenatally in 4 abnormal cases. CONCLUSIONS: The fetal heart can be successfully evaluated at an earlier gestational age but may be dependent on the skill of the sonographer and reading physician. Maternal decisions can be made earlier in gestation, before the pregnancy is obvious, and can allow planning for a pregnancy that will need to be delivered at a medical center that has a level 3 nursery. PMID- 24065250 TI - Size discrepancy between sonographic and computed tomographic/magnetic resonance imaging measurement of hepatocellular carcinoma: the necessity of tumor size measurement standardization. AB - OBJECTIVES: There is no standardized method for size measurement of hepatocellular carcinoma. The purpose of this study was to evaluate whether the size and stage of hepatocellular carcinoma differ according to the imaging modality. METHODS: This retrospective study was approved by our Institutional Review Board, and written informed consent was waived. Patients with hepatocellular carcinoma who underwent either computed tomography (CT) or magnetic resonance imaging (MRI) along with planning sonography for radiofrequency ablation on the same day were included. A total of 113 patients with 127 hepatocellular carcinomas were included. The sizes of the tumors were measured and the tumor stages were assessed on CT/MRI and sonography. The results were compared by a t test, Bland-Altman limits of agreement, and a McNemar test. RESULTS: There was a significant difference in the hepatocellular carcinoma size between CT/MRI and sonographic measurements (mean difference, 0.26 cm; P < .0001). The sizes of 102 tumors (80.3%) were larger on sonography than on CT/MRI. Twelve tumors (9.5%) were the same size and 13 (10.2%) were smaller on sonography than on CT/MRI. There was also difference in the tumor stage (very early or not) between CT/MRI and sonography (P= .006, McNemar test). The stage was discordant in 16 of 127 tumors (12.6%). Among 69 tumors at the very early stage on CT/MRI, 14 (20.3%) were beyond the very early stage on sonography. CONCLUSIONS: The size of hepatocellular carcinoma measured on sonography tends to be larger than on CT/MRI; therefore, the tumor stage can differ between sonography and CT/MRI. PMID- 24065252 TI - Comparison of cervical lengths using transabdominal and transvaginal sonography in midpregnancy. AB - OBJECTIVES: Cervical length assessment is helpful to predict and prevent preterm birth. However, transvaginal sonography is not easy to perform. The aim of this study was to investigate the relationship and discrepancies between cervical lengths measured by transabdominal and transvaginal sonography in midpregnancy. METHODS: Transabdominal and transvaginal cervical lengths were measured in 255 pregnant women between 20 and 29 gestational weeks. The discrepancies in cervical lengths between the two methods were analyzed for the following maternal and fetal conditions: (1) vertex versus breech fetal presentation, (2) whether the fetal presenting part overlay the cervical internal os, (3) whether both the internal os and external os were visible or only the internal os was clearly visible, (4) maternal bladder filling status, (5) maternal age, (6) parity, and (7) gestational age. RESULTS: The mean cervical lengths were not significantly different (mean +/- SD, 3.88 +/- 0.73 cm on transabdominal sonography and 3.93 +/ 0.72 cm on transvaginal sonography; P = .129; Pearson r = 0.75). The 5th percentile transabdominal cervical length was 26.0 mm, and the transvaginal length was 27.8 mm. There were significant discrepancies between the two methods in the cases in which a fetal presenting part overlay the internal os, in the cases in which the external os was not clearly visible, and in primiparous women. Transabdominal cervical measurements were consistently shorter than transvaginal measurements in the cases with discrepancies. CONCLUSIONS: Transabdominal cervical length measurements are correlated with transvaginal measurements overall, and the transabdominal length is consistently shorter than the transvaginal length in cases with discrepancies. Transabdominal sonography could be used as a cervical length screening tool. PMID- 24065253 TI - Reference ranges for fetal septum primum excursion from 14 to 40 weeks' gestation. AB - OBJECTIVES: The purpose of this study was to establish reference ranges for septum primum excursion and the septum primum excursion index. METHODS: Normal singleton pregnancies with certain dates from 14 to 40 weeks' gestation were enrolled to acquire spatiotemporal image correlation volume data sets. The stored data sets were subsequently displayed offline to measure septum primum excursion and the left atrium diameter. The measured values were regressed to identify the best-fitted model as a function of gestational age and biparietal diameter. RESULTS: A total of 624 volumes were successfully measured, and normal reference ranges for predicting means and standard deviations of septum primum excursion and the septum primum excursion index were established based on best-fitted equations. The septum primum excursion index was relatively constant throughout pregnancy (mean +/- SD, 0.474 +/- 0.082), whereas septum primum excursion increased with gestational age and biparietal diameter as follows: (1) septum primum excursion = -6.30 + 0.667 * gestational age - 0.009 * gestational age(2); SD of septum primum excursion = 0.219 + 0.02 * gestational age; and (2) septum primum excursion = -3.342 + 1.933 * biparietal diameter - 0.102 * biparietal diameter(2); SD of septum primum excursion = 0.330 + 0.065 * biparietal diameter. Percentile charts for predicting septum primum excursion and equations for Z score calculation were also provided. CONCLUSIONS: Normal reference ranges for fetal septum primum excursion and the septum primum excursion index have been provided. These normative data may be useful tools for assessment of hemodynamics through the foramen ovale or left ventricular diastolic function. PMID- 24065254 TI - Musculoskeletal ultrasound training and competency assessment program for rheumatology fellows. AB - OBJECTIVES: The purpose of this study was to establish standards for musculoskeletal ultrasound competency through knowledge and skills testing using criterion-referenced methods. METHODS: Two groups of rheumatology fellows trained in musculoskeletal ultrasound through a standardized curriculum, which required submission of ultrasound studies for review over 8 months. Both groups then completed written and practical examinations in musculoskeletal ultrasound. Instructors, advanced users, and intermediate users of musculoskeletal ultrasound served as comparison groups. A passing score (competency) was established for the written examination by the Angoff procedure and for the practical examination by the borderline method. RESULTS: Thirty-eight fellows (19 in each group) took the final examination. Five fellows failed the written examination, and 1 failed the practical examination, whereas none of the advanced users failed. Written examination scores did not differ between the two fellow groups (74% versus 70%; P > .05), were reliable, and were able to discriminate between the intermediate and advanced groups. Practical and written examination results correlated in both groups (first group, r = 0.70; P = .0008; second group, r = 0.59; P = .009). CONCLUSIONS: Criterion-referenced methods were used for the first time to determine fellow musculoskeletal ultrasound competency. The examination used to determine competency was reproducible, was reliable, and could differentiate musculoskeletal ultrasound users with different levels of experience. Most rheumatology fellows completing our program passed the written and practical examinations, suggesting achievement of basic musculoskeletal ultrasound competency. PMID- 24065255 TI - Movement of the ulnar nerve at the elbow: a sonographic study. AB - OBJECTIVES: The aim of this study was to measure the degree of movement of the ulnar nerve in the cubital tunnel using sonography in patients with ulnar neuropathy at the elbow compared to a healthy control group. METHODS: We examined the ulnar nerve in the cubital tunnel using sonography with the elbow extended and then flexed in 26 patients with ulnar neuropathy and 13 control participants. The distance from the ulnar nerve to the skin, medial epicondyle, and tip of olecranon at the inlet of the cubital tunnel and the distance from the ulnar nerve to the skin and olecranon recess at the outlet of the cubital tunnel were measured when the elbow was extended and flexed, respectively. Displacement of the ulnar nerve during elbow extension and flexion between patients with ulnar neuropathy and controls was compared. RESULTS: There was significantly greater displacement of the ulnar nerve to the medial epicondyle at the inlet of the cubital tunnel in the patients with ulnar neuropathy (mean +/- SD, 4.22 +/- 3.79 mm) compared to the controls (1.76 +/- 1.51 mm) during elbow extension and flexion (P = .008). CONCLUSIONS: A significantly greater degree of movement of the ulnar nerve occurs in patients with ulnar neuropathy at the elbow compared to healthy people, as determined by sonography. PMID- 24065256 TI - Carotid intima-media thickness in patients with carpal tunnel syndrome. AB - OBJECTIVES: We measured the carotid intima-media thickness, a surrogate marker of early atherosclerosis, in patients with carpal tunnel syndrome compared to a control group to evaluate the risk of atherosclerotic disease. METHODS: Between January 2011 and December 2011, female patients presenting to the outpatient neurology clinic for pain and paresthesia in the hands were screened for study enrollment. Patients 30 years or older were eligible for the study if they did not have a history of stroke or cardiovascular disease. RESULTS: During the study period, 111 patients (58 in the carpal tunnel syndrome group and 53 in the control group) were enrolled, with a mean age of 56 years (range, 32-79 years). There were no significant differences in baseline characteristics except maximum carotid intima-media thickness and body mass index. The maximum intima-media thickness was greater in the carpal tunnel syndrome group (mean +/- SD, 1.05 +/- 0.17 mm) than the control group (0.85 +/- 0.22 mm; P < .0001). The body mass index was greater among the controls (P = .012). Simple linear regression analysis revealed that age (P < .0001), carpal tunnel syndrome (P < .0001), hypertension (P = .022), and systolic blood pressure (P = .034) were statistically significantly associated with increased intima-media thickness. Multiple linear regression analysis revealed that hypertension (P = .033), systolic blood pressure (P = .022), age (P < .0001), and carpal tunnel syndrome (P < .0001) were significantly associated with increased intima-media thickness, with carpal tunnel syndrome being the most influential factor (beta = 0.489). CONCLUSIONS: The maximum carotid intima-media thickness was significantly increased in patients with carpal tunnel syndrome compared to controls. Chronic inflammation beyond the traditional cardiovascular risk factors might be related to increased carotid intima-media thickness in patients with carpal tunnel syndrome. PMID- 24065257 TI - Transcranial Doppler investigation of hemodynamic alterations associated with blunt cervical vascular injuries in trauma patients. AB - OBJECTIVES: Blunt cervical vascular injuries, often missed with current screening methods, have substantial morbidity and mortality, and there is a need for improved screening. Elucidation of cerebral hemodynamic alterations may facilitate serial bedside monitoring and improved management. Thus, the objective of this study was to define cerebral flow alterations associated with single blunt cervical vascular injuries using transcranial Doppler sonography and subsequent Doppler waveform analyses in a trauma population. METHODS: In this prospective pilot study, patients with suspected blunt cervical vascular injuries had diagnoses by computed tomographic angiography and were examined using transcranial Doppler sonography to define cerebral hemodynamics. Multiple vessel injuries were excluded for this analysis, as the focus was to identify hemodynamic alterations from isolated injuries. The inverse damping factor characterized altered extracranial flow patterns; middle cerebral artery flow velocities, the pulsatility index, and their asymmetries characterized altered intracranial flow patterns. RESULTS: Twenty-three trauma patients were evaluated: 4 with single internal carotid artery injuries, 5 with single vertebral artery injuries, and 14 without blunt cervical vascular injuries. All internal carotid artery injuries showed a reduced inverse damping factor in the internal carotid artery and dampened ipsilateral mean flow and peak systolic velocities in the middle cerebral artery. Vertebral artery injuries produced asymmetry of a similar magnitude in the middle cerebral artery mean flow velocity with end-diastolic velocity alterations. CONCLUSIONS: These data indicate that extracranial and intracranial hemodynamic alterations occur with internal carotid artery and vertebral artery blunt cervical vascular injuries and can be quantified in the acute injury phase by transcranial Doppler indices. Further study is required to elucidate cerebral flow changes resulting from a single blunt cervical vascular injury, which may guide future management to preserve cerebral perfusion after trauma. PMID- 24065258 TI - Corticomedullary strain ratio: a quantitative marker for assessment of renal allograft cortical fibrosis. AB - OBJECTIVES: To quantitatively assess the correlation between the corticomedullary strain ratio and cortical fibrosis in renal transplants. METHODS: Using quasistatic ultrasound elasticity imaging, we prospectively assessed the corticomedullary strain ratio in renal allografts of 33 patients who underwent renal transplant sonography and biopsy. Based on Banff score criteria for renal cortical fibrosis, 33 allografts were divided into 2 groups: group 1 (n = 19), with mild (<25%) fibrosis; and group 2 (n = 14), with moderate (>26%) fibrosis. We used 2-dimensional speckle-tracking software to perform offline analysis of cortical and medullary strain induced by external compression by the ultrasound transducer. We then calculated the corticomedullary strain ratio (cortical normalized strain/medullary normalized strain; normalized strain = developed strain/applied strain [deformation from the abdominal wall to the pelvic muscles]). An unpaired 2-tailed t test was used to determine differences in normalized strain and the strain ratio between the groups. Receiver operating characteristic curve analysis was performed to determine the best strain ratio cutoff value for identifying moderate fibrosis. RESULTS: Normalized strain differed between the cortex and medulla (mean +/- SD: group 1, 4.58 +/- 2.02 versus 2.58 +/- 1.38; P = .002; group 2, 1.71 +/- 0.42 versus 2.60 +/- 0.87; P = .0011). The strain ratio in group 1 was higher than in group 2 (2.06 +/- 1.33 versus 0.70 +/- 0.20; P = .0007). The area under the receiver operating characteristic curve was 0.964. The sensitivity and specificity of a strain ratio cutoff value of 0.975 for determining moderate fibrosis were 92.9% and 94.7%, respectively. CONCLUSIONS: Strain values vary in different compartments of the kidney. The corticomedullary strain ratio on ultrasound elasticity imaging decreases with increasing renal cortical fibrosis, which makes it potentially useful as a noninvasive quantitative marker for monitoring the progression of fibrosis in renal transplants. PMID- 24065259 TI - Role of dynamic contrast-enhanced sonography for characterization and monitoring of extramedullary myeloma: comparison with serologic data. AB - OBJECTIVE: To measure blood perfusion in extramedullary myeloma by contrast enhanced sonography, correlate it with specific hematologic parameters, and determine their utility for local and systemic response monitoring. METHODS: Twenty-five consecutive patients (14 male and 11 female; median age, 68 years) with extramedullary myeloma were included. After intravenous administration of 2.4 mL of sulfur hexafluoride, extramedullary myeloma masses were examined for 60 seconds. All patients underwent contrast-enhanced sonography at baseline, and 15 were monitored additionally (3 weeks during therapy). Average peak perfusion, regional blood flow (RBF), and regional blood volume (RBV) were calculated. Baseline perfusion parameters were compared with short-term follow-up sonographic data and serologic biomarkers (M gradient). For validation of extramedullary myeloma and systemic myeloma, patients underwent midterm (<3 months) imaging and serologic diagnosis. RESULTS: Patients with baseline beta2-microglobulin (B2M) greater than 3.5 mg/L (n = 17) showed higher perfusion parameters compared with baseline B2M less than 3.5 mg/L (n = 8). At short-term follow-up, patients were classified by serologic criteria as responders (n = 9) and nonresponders (n = 6) and by sonographic criteria as responders (n = 10) and nonresponders (n = 5). In sonographic responders, mean peak, RBV, and RBF dropped from 59.13, 1446.09, and 71.52 (artificial units) at baseline to 29.30, 364.19, and 34.64 at follow-up (P < .05), whereas in nonresponders, perfusion parameters increased from 33.18, 789.82, and 36.92 at baseline to 51.14, 1491.06, and 65.34 at follow-up (P > .05). Prediction of a midterm course of systemic myeloma using serologic data yielded sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 0.66, 0.77, 0.66, and 0.77, whereas sonographic results (judged by RBV) yielded values of 0.66, 0.55, 0.5, and 0.71. Separate prediction of a local (extramedullary myeloma) response by sonography yielded sensitivity, specificity, PPV, and NPV of 0.8, 1.0, 1.0, and 0.71. CONCLUSIONS: Contrast enhanced sonography is a valuable tool for short-term monitoring of the treatment response in extramedullary myeloma. PMID- 24065260 TI - Ultrasound backscatter microscopy for imaging of oral carcinoma. AB - OBJECTIVES: Ultrasound backscatter microscopy (UBM), or ultrasound biomicroscopy, is a noninvasive, label-free, and ionizing radiation-free technique allowing high resolution 3-dimensional structural imaging. The goal of this study was to evaluate UBM for resolving anatomic features associated with squamous cell carcinoma of the oral cavity. METHODS: The study was conducted in a hamster buccal pouch model. A carcinogen was topically applied to cheeks of 14 golden Syrian hamsters. Six additional hamsters served as healthy controls. A high frequency (41 MHz, 6-mm focal depth, lateral and axial resolutions of 65 and 37 MUm, respectively) UBM system was used for scanning the oral cavity after 14 weeks of carcinogen application. Histologic analyses were conducted on scanned regions. RESULTS: The histologic structure of buccal tissue and microvasculature networks could be visualized from the UBM images. Epithelial and mucosal hypertrophy and neoplastic changes were identified in animals subjected to the carcinogen. In animals with invasive squamous cell carcinoma, lesion development and destruction of the structural integrity of tissue layers were noted. CONCLUSIONS: In this pilot study, UBM generated sufficient contrast for morphologic features associated with oral carcinoma compared to healthy tissue. This modality may present a practical technique for detection of oral neoplasms that is potentially translatable to humans. PMID- 24065261 TI - Evaluation of a hydrogen peroxide-based system for high-level disinfection of vaginal ultrasound probes. AB - OBJECTIVES: Because of the complex process and the risk of errors associated with the glutaraldehyde-based solutions previously used at our institution for disinfection, our department has implemented a new method for high-level disinfection of vaginal ultrasound probes: the hydrogen peroxide-based Trophon system (Nanosonics, Alexandria, New South Wales, Australia). The aim of this study was to compare the time difference, safety, and sonographers' satisfaction between the glutaraldehyde-based Cidex (CIVCO Medical Solutions, Kalona, IA) and the hydrogen peroxide-based Trophon disinfection systems. METHODS: The Institutional Review Board approved a 14-question survey administered to the 13 sonographers in our department. Survey questions addressed a variety of aspects of the disinfection processes with graded responses over a standardized 5-point scale. A process diagram was developed for each disinfection method with segmental timing analysis, and a cost analysis was performed. RESULTS: Nonvariegated analysis of the survey data with the Wilcoxon signed rank test showed a statistical difference in survey responses in favor of the hydrogen peroxide-based system over the glutaraldehyde-based system regarding efficiency (P = .0013), ease of use (P = .0013), ability to maintain work flow (P = .026), safety (P = .0026), fixing problems (P = .0158), time (P = .0011), and overall satisfaction (P = .0018). The glutaraldehyde-based system took 32 minutes versus 14 minutes for the hydrogen peroxide-based system; the hydrogen peroxide-based system saved on average 7.5 hours per week. The cost of the hydrogen peroxide based system and weekly maintenance pays for itself if 1.5 more ultrasound examinations are performed each week. CONCLUSIONS: The hydrogen peroxide-based disinfection system was proven to be more efficient and viewed to be easier and safer to use than the glutaraldehyde-based system. The adoption of the hydrogen peroxide-based system led to higher satisfaction among sonographers. PMID- 24065262 TI - Diagnostic efficacy of contrast-enhanced sonography by combined qualitative and quantitative analysis in breast lesions: a comparative study with magnetic resonance imaging. AB - OBJECTIVES: The purpose of this study was to evaluate the diagnostic efficacy of contrast-enhanced sonography for differentiation of breast lesions by combined qualitative and quantitative analyses in comparison to magnetic resonance imaging (MRI). METHODS: Fifty-six patients with American College of Radiology Breast Imaging Reporting and Data System category 3 to 5 breast lesions on conventional sonography were evaluated by contrast-enhanced sonography and MRI. A comparative analysis of diagnostic results between contrast-enhanced sonography and MRI was conducted in light of the pathologic findings. RESULTS: Pathologic analysis showed 26 benign and 30 malignant lesions. The predominant enhancement patterns of the benign lesions on contrast-enhanced sonography were homogeneous, centrifugal, and isoenhancement or hypoenhancement, whereas the patterns of the malignant lesions were mainly heterogeneous, centripetal, and hyperenhancement. The detection rates for perfusion defects and peripheral radial vessels in the malignant group were much higher than those in the benign group (P < .05). As to quantitative analysis, statistically significant differences were found in peak and time-to-peak values between the groups (P < .05). With pathologic findings as the reference standard, the sensitivity, specificity, and accuracy of contrast enhanced sonography and MRI were 90.0%, 92.3%, 91.1% and 96.7%, 88.5%, and 92.9%, respectively. The two methods had a concordant rate of 87.5% (49 of 56), and the concordance test gave a value of kappa = 0.75, indicating that there was high concordance in breast lesion assessment between the two diagnostic modalities. CONCLUSIONS: Contrast-enhanced sonography provided typical enhancement patterns and valuable quantitative parameters, which showed good agreement with MRI in diagnostic efficacy and may potentially improve characterization of breast lesions. PMID- 24065263 TI - Quantification of ultrasound correlation-based flow velocity mapping and edge velocity gradient measurement. AB - This study investigated the use of ultrasound speckle decorrelation- and correlation-based lateral speckle-tracking methods for transverse and longitudinal blood velocity profile measurement, respectively. By studying the blood velocity gradient at the vessel wall, vascular wall shear stress, which is important in vascular physiology as well as the pathophysiologic mechanisms of vascular diseases, can be obtained. Decorrelation-based blood velocity profile measurement transverse to the flow direction is a novel approach, which provides advantages for vascular wall shear stress measurement over longitudinal blood velocity measurement methods. Blood flow velocity profiles are obtained from measurements of frame-to-frame decorrelation. In this research, both decorrelation and lateral speckle-tracking flow estimation methods were compared with Poiseuille theory over physiologic flows ranging from 50 to 1000 mm/s. The decorrelation flow velocity measurement method demonstrated more accurate prediction of the flow velocity gradient at the wall edge than the correlation based lateral speckle-tracking method. The novelty of this study is that speckle decorrelation-based flow velocity measurements determine the blood velocity across a vessel. In addition, speckle decorrelation-based flow velocity measurements have higher axial spatial resolution than Doppler ultrasound measurements to enable more accurate measurement of blood velocity near a vessel wall and determine the physiologically important wall shear. PMID- 24065264 TI - Influence of gain adjustment on 3-dimensional power Doppler indices and on spatiotemporal image correlation volumetric pulsatility indices using a flow phantom. AB - Spatiotemporal image correlation can be used to acquire 3-dimensional power Doppler information across a single cardiac cycle. Assessment and comparison of the systolic and diastolic components of the data sets allow measurement of the recently introduced "volumetric pulsatility index" (vPI) through algorithms comparable with those used in 2-dimensional Doppler waveform analysis. The vPI could potentially overcome the dependency on certain machine settings, such as power, color gain, pulse repetition frequency, and attenuation, since these factors would affect the power Doppler signal equally throughout the cardiac cycle. The objective of this study was to compare the effect of color gain on the vascularization index (VI), vascularization-flow index (VFI), and vPI using an in vitro flow phantom model. We separated gains into 3 bands: -8 to -1 (no noise), 1 to +5 (low noise), and +5 to +8 (obvious noise). The vPI was determined from the 3-dimensional VI or VFI using the formula vPI = (maximum - minimum)/mean. Using no-noise gains, we observed that although the VI and VFI increased linearly with gain, the vPI was substantially less dependent on this adjustment. The VI and VFI continued to increase linearly with gain, whereas the vPI decreased slightly using low-noise gains. When gain was increased above the lower limit of obvious noise (+5), the VI and VFI increased noticeably, and there were marked reductions in both vPI values. We conclude that the vPI is less affected by changes in color gain than the VI and VFI at no-noise gains. PMID- 24065265 TI - How to measure substantia nigra hyperechogenicity in Parkinson disease: detailed guide with video. AB - The detection of an enlarged echogenic size ("hyperechogenicity") of the substantia nigra on transcranial sonography is increasingly used for the early and differential diagnosis of Parkinson disease. However, the diagnostic value of substantia nigra sonography depends on the quality of its execution. This article with an accompanying video presents a step-by-step description and demonstration of ultrasound system settings, typical errors in assessment of the substantia nigra, planimetric measurement of substantia nigra echogenicity according to current guidelines, and its diagnostic implications in 2 exemplary patients with parkinsonism. Published cutoff values for grading substantia nigra hyperechogenicity with different ultrasound systems and novel technologies are reviewed. PMID- 24065266 TI - A novel technique for teaching challenging ultrasound-guided breast procedures to radiology residents. AB - Ultrasound-guided breast interventions (core biopsies, needle-wire localizations, and fine-needle cyst aspirations) are common procedures performed by radiologists. Residents must gain competency in these interventions during training. Phantoms and simulations have been advocated for teaching interventions, and various systems are available for standard breast interventions. However, simulations for difficult/high-risk interventions are not readily available. We describe an inexpensive method for simulating difficult ultrasound-guided breast procedures, including masses over breast implants, deep masses along the chest wall, and lymph nodes adjacent to axillary vessels. PMID- 24065267 TI - High-intensity focused ultrasound ablation for treatment of hepatocellular carcinoma and hypersplenism: preliminary study. AB - The purpose of this work was to preliminarily investigate the efficacy and safety of high-intensity focused ultrasound treatment of hepatocellular carcinoma and hypersplenism. Nine patients with hepatocellular carcinoma complicated by hypersplenism (5 male and 4 female; median age, 56 years; range, 51-66 years) were treated with ultrasound-guided high-intensity focused ultrasound. Complications were recorded. Laboratory examination and magnetic resonance imaging were used to evaluate the efficacy. After high-intensity focused ultrasound treatment, mean spleen ablation +/- SD of 28.76% +/- 6.1% was discovered; meanwhile, the white blood cell count, platelet count, and liver function of the patients were substantially improved during the follow-up period. In addition, symptoms such as epistaxis and gingival bleeding were ameliorated or even eliminated, and the quality of life was improved. Follow-up imaging showed a nonperfused volume in the spleen and an absence of a tumor blood supply at the treated lesions in the liver. For the first time to our knowledge, high-intensity focused ultrasound ablation was used to treat hepatocellular carcinoma complicated by hypersplenism. High-intensity focused ultrasound may be an effective and safe alternative for treatment of hepatocellular carcinoma complicated by hypersplenism, but further studies are necessary to clarify the mechanisms. PMID- 24065268 TI - First-trimester sonographic findings associated with a Dandy-Walker malformation and inferior vermian hypoplasia. AB - We report 2 cases in which first-trimester measurements of the intracranial translucency and the brain stem-to-occipital bone diameter were markedly enlarged. This finding was thought to represent an abnormal fourth ventricle cisterna magna complex. Subsequently, the diagnoses of a Dandy-Walker malformation with partial vermian agenesis in 1 case and inferior vermian hypoplasia in the other were established and confirmed by either postmortem autopsy or postnatal magnetic resonance imaging. These cases suggest that evaluation of the fourth ventricle-cisterna magna complex, by measuring the intracranial translucency or brain stem-to-occipital bone diameter may identify some cases with structural malformations of the cerebellum as early as the first trimester. PMID- 24065269 TI - Novel use of contrast-enhanced sonography in the diagnosis of central uterine necrosis following embolization for postpartum hemorrhage. AB - Since 2007, we have identified 2 cases of central uterine necrosis after uterine arterial embolization for postpartum hemorrhage. Contrast-enhanced sonography showed an absence of enhancement of the internal myometrium. Magnetic resonance imaging with gadolinium confirmed the diagnosis. The images obtained for the first case were corroborated by histologic analysis from a hysterectomy done for sepsis. For the second case, contrast-enhanced sonography performed during a follow-up period of conservative treatment revealed a reduction of necrosis. Our study shows that contrast-enhanced sonography seems to be a useful examination as an adjunct to grayscale and power Doppler imaging in the diagnosis and follow-up of uterine necrosis. PMID- 24065270 TI - Fractured intrauterine device copper sheath with an intact polyethylene core. PMID- 24065271 TI - Four consecutive recurrent cesarean scar pregnancies in a single patient. PMID- 24065272 TI - Measuring pain perceptions and medication taking behavior at the end of life: a pilot study. AB - BACKGROUND: Understanding why some patients with terminal illness are reluctant to take sufficient medication to control pain is critical to effective pain management. OBJECTIVE: As a first step toward exploring the pain medication taking behavior of palliative care patients, this pilot study tested a survey regarding pain medication adherence, medication beliefs, and quality of life (QoL). DESIGN: Convenience sample; survey. SETTING/SUBJECTS: Six patients receiving inpatient Palliative Care consultations at an academic medical center answered questions about their outpatient pain medication-taking behavior. MEASUREMENTS: Medication Adherence Report Scale (MARS), Beliefs about Medications Questionnaire (BMQ), Brief Pain Inventory (BPI), closed-response items from a pain medication adherence study in terminally ill patients, the McGill Quality of Life Questionnaire (McGill), and demographic items. RESULTS: The battery of questionnaires took approximately 53 minutes; five of six participants were able to complete all items. Respondents reported moderate to severe pain (mean 4.3/10 for pain on average; 7/10 for worst pain in past 24 hours), and excellent medication adherence. When asked how much relief was provided by pain therapies, respondents reported a mean 73% (range 50-100%) relief. They expressed little concern about addiction, but more concern about medication-induced nausea and constipation. Overall QoL was good (mean 6.8/10, range 5-10, higher score better), with notably high scores in existential and support domains. CONCLUSIONS: Inpatients receiving palliative care consultation were able to complete interviewer-administered questionnaires regarding their pain perceptions, medications, and QoL. Further studies using these instruments are feasible and could inform shared decision making about pain management. PMID- 24065273 TI - Aquaporin-9 downregulation prevents steatosis in oleic acid-induced non-alcoholic fatty liver disease cell models. AB - Aquaporin-9 (AQP9) is an aquaglyceroporin that acts as the adipose glycerol channel. However, the role of AQP9 in steatosis in non-alcoholic fatty liver disease (NAFLD) has not yet been fully elucidated. In the present study, the coding sequence of the AQP9 gene was obtained from LO2 cells by RT-PCR, and cloned into the pEGFP-N1 vector. Short hairpin RNA (shRNA) targeting the AQP9 gene was inserted into the pGenesil-1 vector. Recombinant plasmids were confirmed by enzyme digestion and sequence analysis, and transfected into cell models (derived from LO2 cells) of oleic acid-induced NAFLD. Our results demonstrated that AQP9 recombinant plasmids can be effectively expressed in cell models of NAFLD. Furthermore, in comparison with the control group, AQP9 overexpression significantly increased intracellular lipid content, triglyceride (TG), free fatty acid (FFA) and glycerol levels; however, the silencing of AQP9 exerted the opposite effects. Taken together, recombinant plasmids used to induce AQP9 overexpression and to silence AQP9 expression were successfully constructed. AQP9 overexpression aggravated the degree of steatosis; however, the silencing of AQP9 alleviated these effects. Based on these data, we suggest that AQP9 may serve as a novel molecular target for therapeutic intervention in NAFLD. PMID- 24065274 TI - Development of a simple, repeatable, and cost-effective extracellular matrix for long-term xeno-free and feeder-free self-renewal of human pluripotent stem cells. AB - Given the potential importance of human pluripotent stem cells (hPSCs) in translational research and regenerative medicine, the aim of the present study was to develop a simple, safe, and cost-effective substrate to expand hPSCs. We report the development of an extracellular matrix (ECM), designated "RoGel," based on conditioned medium (CM) of human fibroblasts under serum- and xeno-free culture conditions. The long-term self-renewal of hPSCs on RoGel was also assessed. The results showed that self-renewal, pluripotency, plating efficiency, and cloning efficiency of hPSCs on this newly developed ECM were similar to those of Matrigel, the conventional mouse-cell line-derived ECM. The cells had the capability to passage mechanically on a cold surface, which resulted in their long-term maintenance with normal karyotype. We have demonstrated that CM-coated plates preserved for 1 year at room temperature maintained the capability of hPSC expansion. This ECM provides an attractive hPSC culture platform for both research and future therapeutic applications. PMID- 24065275 TI - First evidence of the interaction between deleted in malignant brain tumor 1 and galectin-3 in the mammalian oviduct. AB - The oviduct supports the transport and final maturation of gametes, and harbors fertilization and early embryo development. The oviductal epithelium is responsible for providing the correct environment for these processes. Deleted in malignant brain tumor 1 (DMBT1) is expressed by multiple organisms and several cell types, and the interaction of the rabbit ortholog of DMBT1 with galectin-3 (gal-3) modulates the polarity of epithelial cells. This interaction has not yet been shown in locations other than rabbit kidney and human-cultured endothelial cells. DMBT1 and gal-3 also protect epithelial layers from pathogens and trauma, and are innate immunity components. DMBT1 has been detected in the porcine oviduct, and gal-3 has been reported in the Fallopian tube and in the cow oviduct. Interaction between both proteins would show a probable physiological function in the female reproductive tract. This work describes the presence and co-localization of DMBT1 and gal-3 mainly in the apical region of the epithelial cells of the Fallopian tube and the porcine oviduct, and co-immunoprecipitation in membrane-enriched epithelial cell extracts from the porcine oviduct. The findings strongly support a functional interaction in the mammalian oviduct, suggestive of a role on epithelial protection and homeostasis, which might be related to epithelium-gamete interaction. PMID- 24065277 TI - Female sex hormones regulate the Th17 immune response to sperm and Candida albicans. AB - STUDY QUESTION: What role do female sex hormones play in the antisperm immune response? SUMMARY ANSWER: We found that sperm induce a Th17 immune response and that estradiol down-regulates the antisperm Th17 response by dendritic cells. WHAT IS KNOWN ALREADY: Estradiol down-regulates the immune response to several pathogens and impairs the triggering of dendritic cell maturation by microbial products. STUDY DESIGN, SIZE, DURATION: Ex vivo and in vivo murine models of vaginal infection with sperm and Candida albicans were used to study the induction of Th17 and its hormonal regulation. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed the induction of Th17 cytokines and T cells in splenocytes obtained from BALB/c mice challenged with sperm and C. albicans. For the in vivo vaginal infection models, we used ovariectomized mice treated with vehicle, estradiol or progesterone, and we assessed the effect of these hormones on the immune response in the lymph nodes. MAIN RESULTS AND THE ROLE OF CHANCE: Th17 cytokines and T cells were induced by sperm antigens in both ex vivo and in vivo experiments. Estrus levels of estradiol down-regulated the Th17 response to sperm and C. albicans in vivo. LIMITATIONS, REASONS FOR CAUTION: This study was conducted using murine models; whether or not the results are applicable to humans is not known. WIDER IMPLICATIONS OF THE FINDINGS: Our results describe an adaptive mechanism that reconciles immunity and reproduction and further explains why unregulated Th17 could be linked to infertility and recurrent infections. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research grants from the Instituto de Salud Carlos III (ISCIII) (PI10/00897) and Fundacion Mutua Madrilena to M.R. M.R. holds a Miguel Servet contract from the ISCIII (CP08/00228). M.A.M.-F. was supported by (ISCIII) INTRASALUD PI09/02029. We have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not required. PMID- 24065278 TI - Template-constrained cyclic sulfopeptide HIV-1 entry inhibitors. AB - Template-constrained cyclic sulfopeptides that inhibit HIV-1 entry were rationally designed based on a loop from monoclonal antibody (mAb) 412d. A focused set of sulfopeptides was synthesized using Fmoc-Tyr(SO3DCV)-OH (DCV = 2,2 dichlorovinyl). Three cyclic sulfopeptides that inhibit entry of HIV-1 and complement the activity of known CCR5 antagonists were identified. PMID- 24065279 TI - An electrophysiological approach using 3D electroanatomical mapping system for catheter-based renal denervation: the first Polish experience. PMID- 24065280 TI - Ventricular septal rupture after blunt chest trauma. PMID- 24065281 TI - [Optimal model of comprehensive rehabilitation and secondary prevention]. PMID- 24065282 TI - HSP70 and modified HPV 16 E7 fusion gene without the addition of a signal peptide gene sequence as a candidate therapeutic tumor vaccine. AB - Millions of women are currently infected with high-risk human papillomavirus (HPV), which is considered to be a major risk factor for cervical cancer. Thus, it is urgent to develop therapeutic vaccines to eliminate the established infections or HPV-related diseases. In the present study, using the mycobacterium tuberculosis heat shock protein 70 (MtHSP70) gene linked to the modified HPV 16 E7 (mE7) gene, we generated two potential therapeutic HPV DNA vaccines, mE7/MtHSP70 and SigmE7/MtHSP70, the latter was linked to the signal peptide gene sequence of human CD33 at the upstream of the fusion gene. We found that vaccination with the mE7/MtHSP70 DNA vaccine induced a stronger E7-specific CD8+ T cell response and resulted in a more significant therapeutic effect against E7 expressing tumor cells in mice. Our results demonstrated that HSP70 can play a more important role in mE7 and MtHSP70 fusion DNA vaccine without the help of a signal peptide. This may facilitate the use of HSP70 and serve as a significant reference for future study. PMID- 24065283 TI - Reading direction and the central perceptual span: evidence from Arabic and English. AB - In English and other alphabetic languages read from left to right, useful information acquired during each fixational pause is generally reported to extend much further to the right of each fixation than to the left. However, the asymmetry of the perceptual span for alphabetic languages read in the opposite direction (i.e., from right to left) has received very little attention in empirical research. Accordingly, we investigated the perceptual span for Arabic, which is one of the world's most widely read languages and is read from right to left, using a gaze-contingent window paradigm in which a region of text was displayed normally around each point of fixation, while text outside this region was obscured. Skilled Arabic readers who were bilingual in Arabic and English read Arabic and English sentences while a window of normal text extended symmetrically 0.5(o) to the left and right of fixation or asymmetrically, by increasing this window to 1.5(o) or 2.5(o) to either the left or the right. When English was read, performance across window conditions was superior when windows extended rightward. However, when Arabic was read, performance was superior when windows extended leftward and was essentially the reverse of that observed for English. These findings show for the first time that a leftward asymmetry in the central perceptual span occurs when Arabic is read and, for the first time in over 30 years, provide a new indication that the perceptual span for alphabetic languages is modified by the overall direction of reading. PMID- 24065284 TI - Effects of face and inanimate-object contexts on stimulus-response compatibility. AB - Prior studies have shown that a left-right spatial compatibility effect occurs for vertically oriented stimuli relative to a background context of a face rotated 90 degrees clockwise or counterclockwise from upright. For stimuli presented at the location of the eyes, the mapping of the right eye to a right response and the left eye to a left response, as would be viewed by the participant, yields better performance than does the opposite mapping. An issue of current interest in social cognition is whether animate objects are processed differently from inanimate ones. We investigated this issue in two experiments in which we compared the compatibility effects obtained with inanimate objects to those obtained with animate, face stimuli. The results showed left-right compatibility effects from the participant's perspective for vehicles and faces from frontal and profile views, as well as for a road sign. Our findings indicate that coding of stimulus location relative to an external frame of reference is not restricted to face backgrounds. PMID- 24065285 TI - S-shaped learning curves. AB - In this article, learning curves for foreign vocabulary words are investigated, distinguishing between a subject-specific learning rate and a material-specific parameter that is related to the complexity of the items, such as the number of syllables. Two experiments are described, one with Turkish words and one with Italian words. In both, S-shaped learning curves were observed, which were most obvious if the subjects were not very familiar with the materials and if they were slow learners. With prolonged learning, the S shapes disappeared. Three different mathematical functions are proposed to explain these S-shaped curves. A further analysis clarifies why S-shaped learning curves may go unnoticed in many experiments. PMID- 24065287 TI - Nanostructured TiO2 surfaces promote polarized activation of microglia, but not astrocytes, toward a proinflammatory profile. AB - Activation of glial cells, including astrocytes and microglia, has been implicated in the inflammatory responses underlying brain injury and neurodegenerative diseases including Alzheimer's and Parkinson's diseases. The classic activation state (M1) is characterized by high capacity to present antigens, high production of nitric oxide (NO) and reactive oxygen species (ROS) and proinflammatory cytokines. Classically activated cells act as potent effectors that drive the inflammatory response and may mediate detrimental effects on neural cells. The second phenotype (M2) is an alternative, apparently beneficial, activation state, more related to a fine tuning of inflammation, scavenging of debris, promotion of angiogenesis, tissue remodeling and repair. Specific environmental chemical signals are able to induce these different polarization states. We provide here evidence that nanostructured substrates are able, exclusively in virtue of their physical properties, to push microglia toward the proinflammatory activation phenotype, with an efficacy which reflects the graded nanoscale rugosity. The acquisition of a proinflammatory phenotype appears specific for microglia and not astrocytes, indicating that these two cell types, although sharing common innate immune responses, respond differently to external physical stimuli. PMID- 24065288 TI - Purification and characterization of an antifungal chitinase from Citrobacter freundii str. nov. haritD11. AB - The purpose of the research was to study the purification and partial characterization of antifungal alkaline chitinase from a newly isolated Citrobacter freundii haritD11. The enzyme was purified in a three-step procedure involving ammonium sulfate precipitation, dialysis, and Sephadex G-100 gel filtration chromatography. The enzyme was shown to have a relative high molecular weight of 64 kDa by sodium dodecyl sulfate polyacrylamide gel electrophoresis and was purified 7.3-fold with a yield of 18.8 %. It was most active at 35 degrees C, pH 8.0, with colloid chitin as substrate and was very stable at alkaline pH contradicting the characteristic that most of the bacterial chitinases are active at acidic pH. Further, the purified chitinase exhibited remarkable antifungal activity against pathogenic fungi Aspergillus flavus MTCC 2798 and Aspergillus niger MTCC 9652 showing diametric inhibition zones of 27 mm and 21 mm, respectively. PMID- 24065289 TI - Internal jugular and vertebral vein volume flow in patients with clinically isolated syndrome or mild multiple sclerosis and healthy controls: results from a prospective sonographer-blinded study. AB - OBJECTIVES & METHODS: We evaluated internal jugular vein and vertebral vein volume flow using ultrasound, in patients with clinically isolated syndrome or mild multiple sclerosis and controls, to determine whether volume flow was different between the two groups. RESULTS: In patients and controls, internal jugular vein volume flow increased from superior to inferior segments, consistent with recruitment from collateral veins. Internal jugular vein and vertebral vein volume flow were greater on the right in supine and sitting positions. Internal jugular vein volume flow was higher in the supine posture. Vertebral vein volume flow was higher in the sitting posture. Regression analyses of cube root transformed volume flow data, adjusted for supine/sitting, right/left and internal jugular vein/vertebral vein, revealed no significant difference in volume flow in patients compared to controls. CONCLUSIONS: Our findings further refute the concept of venous obstruction as a causal factor in the pathogenesis of multiple sclerosis. Control volume flow data may provide useful normative reference values. PMID- 24065290 TI - On the link between action planning and motor imagery: a developmental study. AB - We examined the link between action planning and motor imagery in 6- and 8-year old children. Action planning efficiency was assessed with a bar transport task. Motor imagery and visual imagery abilities were measured using a hand mental rotation task and a number (i.e., non-body stimuli) mental rotation task, respectively. Overall, results showed that performance varied with age in all tasks, performance being progressively refined with development. Importantly, action planning performance was correlated with motor imagery, whereas no relationship was evident between action planning and visual imagery at any age. The results showed that the ability to engage sensorimotor mechanisms when solving a motor imagery task was concomitant with action planning efficiency. The present work is the first demonstration that evaluating the consequences of the upcoming action in grasping depends on children's abilities to mentally simulate the response options to choose the most efficient grasp. PMID- 24065291 TI - Selective changes in cerebellar-cortical processing following motor training. AB - The aim of this study was to investigate the effect of varying stimulation rate and the effects of a repetitive typing task on the amplitude of somatosensory evoked potential (SEP) peaks thought to relate to cerebellar processing. SEPs (2,000 sweep averages) were recorded following median nerve stimulation at the wrist at frequencies of 2.47, 4.98, and 9.90 Hz from 12 subjects before and after a 20-min repetitive typing task. Typing and error rate were recorded 2-min pre- and post-typing task. Effect of stimulation rate was analysed with ANOVA followed by pairwise comparisons (paired t tests). Typing effects were analysed by performing two-tailed paired t tests. Increasing stimulation frequency significantly decreased the N30 SEP peak amplitude (p < 0.02). Both the 4.98 and 9.90 Hz rates lead to significantly smaller N30 peak amplitudes compared to the 2.47 Hz (p <= 0.01). The N24 amplitude significantly increased following the typing task for both 4.98 and 2.47 Hz (p <= 0.025). In contrast, there was a highly significant decrease (p < 0.001) in the N18 peak amplitude post-typing at all frequencies. Typing rate increased (p < 0.001) and error rate decreased (p < 0.05) following the typing task. The results suggest that the N24 SEP peak amplitude is best recorded at 4.98 Hz since the N30 amplitude decreases and no longer contaminates the N24 peak, making the N24 visible and easier to measure, while still enabling changes due to repetitive activity to be measured. The decrease in N18 amplitude along with an increase in N24 amplitude with no change in N20 amplitude may be explained by the intervention reducing inhibition at the level of the cuneate nucleus and/or interior olives leading to alterations in cerebellar-cortical processing. PMID- 24065292 TI - Beneficial effects of lifelong caloric restriction on endothelial function are greater in conduit arteries compared to cerebral resistance arteries. AB - Endothelial dysfunction occurs in conduit and cerebral resistance arteries with advancing age. Lifelong caloric restriction (CR) can prevent the onset of age related dysfunction in many tissues, but its effects on cerebral resistance artery function, as compared with conduit artery function, have not been determined. We measured endothelium-dependent dilation (EDD) in the carotid artery and middle cerebral artery (MCA) from young (5-7 months), old ad libitum fed (AL, 29-32 months), and old lifelong CR (CR, 40 % CR, 29-32 months) B6D2F1 mice. Compared with young, EDD for old AL was 24 % lower in the carotid and 47 % lower in the MCA (p < 0.05). For old CR, EDD was not different from young in the carotid artery (p > 0.05), but was 25 % lower than young in the MCA (p < 0.05). EDD was not different between groups after NO synthase inhibition with N(omega) nitro-L-arginine methyl ester in the carotid artery or MCA. Superoxide production by the carotid artery and MCA was greater in old AL compared with young and old CR (p < 0.05). In the carotid, incubation with the superoxide scavenger TEMPOL improved EDD for old AL (p > 0.05), with no effect in young or old CR (p > 0.05). In the MCA, incubation with TEMPOL or the NADPH oxidase inhibitor apocynin augmented EDD in old AL (p < 0.05), but reduced EDD in young and old CR (p < 0.05). Thus, age-related endothelial dysfunction is prevented by lifelong CR completely in conduit arteries, but only partially in cerebral resistance arteries. These benefits of lifelong CR on EDD result from lower oxidative stress and greater NO bioavailability. PMID- 24065294 TI - Four weeks of combination exercise training improved executive functions, episodic memory, and processing speed in healthy elderly people: evidence from a randomized controlled trial. AB - Previous reports have described that long-term combination exercise training improves cognitive functions in healthy elderly people. This study investigates the effects of 4 weeks of short-term combination exercise training on various cognitive functions of elderly people. We conducted a single-blinded randomized controlled trial with two parallel groups. Sixty-four healthy older adults were assigned randomly to a combination exercise training group or a waiting list control group. Participants in the combination exercise training group participated in the combination exercise training (aerobic, strength, and stretching exercise trainings) 3 days per week during 4 weeks (12 workouts total). The waiting list control group did not participate in the combination exercise training. Measures of the cognitive functions (executive functions, episodic memory, working memory, reading ability, attention, and processing speed) were conducted before and after training. Results showed that the combination exercise training improved executive functions, episodic memory, and processing speed compared to those attributes of the waiting list control group. This report was the first of a study demonstrating the beneficial effects of short-term combination exercise training on diverse cognitive functions of elderly people. Our study provides important evidence of the short-term combination exercise's effectiveness. PMID- 24065295 TI - Green tea with high-density catechins improves liver function and fat infiltration in non-alcoholic fatty liver disease (NAFLD) patients: a double blind placebo-controlled study. AB - Catechins, a major component of green tea extract, have anti-hyperlipidemic effects. The present study investigated the effects of consumption of green tea with high-density catechins in non-alcoholic fatty liver disease (NAFLD) patients. Seventeen patients with NAFLD consumed green tea with high-density catechins, low-density catechins or a placebo for 12 weeks in a randomized double blind study. Ultrasonography and computed tomography (CT) were performed at baseline and after 12 weeks. Serum alanine aminotransferase (ALT) levels and urine 8-isoprostane were monitored and compared to baseline at 4, 8 and 12 weeks. Body fat was significantly decreased in the high-density catechin group compared with the placebo and low-density catechin groups after 12 weeks of consumption. All the patients in the high-density catechin group showed a significantly improved liver-to-spleen CT attenuation ratio compared with the placebo and low density catechin groups after 12 weeks of consumption. The high-density catechin group significantly decreased serum ALT levels and reduced urinary 8-isoprostane excretion compared with the placebo and low-density catechin group after 12 weeks of consumption. Based on a reduced proportion of body fat as estimated by bioimpedance measurement, increased liver-to-spleen CT attenuation ratio, decreased serum ALT levels and reduced urinary 8-isoprostane excretion, we concluded that 12 weeks of 700 ml per day of green tea containing >1 g catechin improved liver fat content and inflammation by reducing oxidative stress in patients with NAFLD. PMID- 24065293 TI - Independent skewing of the T cell and NK cell compartments associated with cytomegalovirus infection suggests division of labor between innate and adaptive immunity. AB - Cytomegalovirus (CMV) infection induces profound changes in different subsets of the cellular immune system. We have previously identified an immune risk profile (IRP) where CMV-associated changes in the T cell compartment, defined as a CD4/CD8 ratio < 1, are associated with increased mortality in elderly people. Since natural killer (NK) cells have an important role in the defense against viral infections, we examined whether the expansion of CD8 + T cells seen in individuals with CD4/CD8 ratio < 1 is coupled to a parallel skewing of the NK cell compartment. A number of 151 subjects were examined with CMV serology and a flow cytometry panel for assessment of T cell and NK cell subsets. CMV seropositive individuals had higher frequencies of CD57 + and NKG2C + NK cells and lower frequencies of NKG2A + NK cells, in line with a more differentiated NK cell compartment. Intriguingly, however, there was no correlation between CD4/CD8 ratio and NK cell repertoires among CMV-seropositive donors, despite the profound skewing of the T cell compartment in the group with CD4/CD8 ratio < 1. Conversely, donors with profound expansion of NK cells, defined as NKG2C + NK cells with high expression of CD57 and ILT-2, did not display more common changes in their T cell repertoire, suggesting that NK cell expansion is independent of the T cell-defined IRP. Altogether, these results indicate that the effect of CMV on CD8 T cells and NK cells is largely nonoverlapping and independent. PMID- 24065297 TI - Long-term mechanical circulatory support for advanced heart failure: 'the tide is turning'. PMID- 24065299 TI - Combined effect and mechanism of acidity and lead ion on soybean biomass. AB - Heavy metal pollution and soil acidification are serious global environmental issues. The combined pollution from acidification and heavy metal has become a new environmental issue in regions where the two issues simultaneously occur. However, studies on combined pollution are still limited. In the current study, we investigated the combined effect and mechanism of acidity and heavy metal [lead ion (Pb(2+))] on soybean biomass as well as on growth, nitrogen nutrition, and antioxidant system in soybean roots. Results showed that the combined treatment with acidity and Pb(2+) decreased the soybean biomass. At pH 4.5, the soybean biomass in the combined treatment with acidity and 0.9 mmol L(-1) Pb(2+) was lower than that in the combined treatment with acidity and Pb(2+) at 0.3 or 1.5 mmol L(-1). This result was also observed at pH 3.5 and 3.0. The combined treatment with acidity and Pb(2+) also resulted in the following consequences: root growth inhibition; decrease in nitrate, ammonium, and malondialdehyde contents; increase in nitrite reductase activity; and decrease in peroxidase activity. The extent at which the test indexes decreased/increased in the combined treatment was higher than that in the single acidity treatment. The correlation analysis results indicated that the decrease in the soybean biomass in the combined treatment with acidity and Pb(2+) resulted from the decrease in the root growth, nitrate-nitrogen assimilation, and peroxidase activity. PMID- 24065300 TI - Mechanism of the inhibition of the STAT3 signaling pathway by EGCG. AB - Signal transducer and activator of transcription 3 (STAT3) is an oncogene that promotes cell survival, proliferation, and motility. In the present study, we explored the mechanism involved in the inhibition by epigallocatechin-3-gallate (EGCG) of STAT3 signaling as detected by surface plasmon resonance (SPR)-binding assays and in silico docking. Stat3-binding assay indicated that EGCG significantly interrupted Stat3 peptide binding at micromolar concentrations, and the docking experiments indicated that EGCG had a strong interaction with Arg 609, one of the key residues in the STAT3 SH2 domain that contributes greatly to Stat3 and phosphorylated peptide binding. Following treatment of the hepatocellular carcinoma cell lines BEL-7402 and QGY-7703 with EGCG, in vitro, EGCG significantly suppressed cell proliferation as detected by MTT assay, induced apoptosis as detected by flow cytometry, dramatically lowered the expression levels of phosphorylated Stat3 proteins (p-Stat3) as determined by immunoblot detection, and inhibited the expression of multiple genes including Bcl-xL, c-Myc, VEGF and cyclin D1 as demonstrated by RT-PCR analysis. In conclusion, our research data indicate that the anticancer function of green tea results from the inhibition of the STAT3 signaling pathway by EGCG. PMID- 24065302 TI - [Imaging in organic mitral regurgitation. Expert consensus statement of the Polish Clinical Forum for Cardiovascular Imaging]. PMID- 24065301 TI - Selective and specific inhibition of If with ivabradine for the treatment of coronary artery disease or heart failure. AB - Heart rate is an important contributor in the pathophysiology of both coronary artery disease (CAD) and heart failure (HF). Ivabradine is an anti-anginal and anti-ischaemic agent, which selectively and specifically inhibits the I f current in the sino-atrial node and provides pure heart rate reduction without altering other cardiac parameters, including conduction, and without directly affecting other haemodynamic parameters. It is approved for the treatment of CAD and HF. This article summarises the pharmacological properties, pharmacokinetics, clinical efficacy and tolerability of ivabradine in the treatment of CAD and HF, and presents evidence demonstrating that the pharmacological and clinical properties and clinical efficacy of ivabradine make it an important therapeutic choice for patients with stable CAD or HF. The positive effect of ivabradine on angina pectoris symptoms and its ability to reduce myocardial ischemia make it an important agent in the management of patients with stable CAD or chronic HF. Further studies are underway to add to the already robust evidence of ivabradine for the prevention of cardiovascular events in patients with CAD but without clinical HF. The SIGNIFY (Study assessInG the morbidity-mortality beNefits of the I f inhibitor ivabradine in patients with coronarY artery disease) trial includes patients with stable CAD and an LVEF above 40 %, with no clinical sign of HF, and is investigating the long-term effects (over a period of 48 months) of ivabradine in a large study population. So far, this study has included more than 19,000 patients from 51 countries. PMID- 24065303 TI - Non-ST elevation myocardial infarction in a patient with severe degenerative aortic stenosis. AB - Among heterogeneous groups of patients admitted to the catheterisation laboratory due to non-ST elevation myocardial infarction (NSTEMI), there are increasing numbers with coexisting valvular heart diseases. A 66-year-old man was transferred to our centre with a diagnosis of NSTEMI. Immediate echocardiogram was performed in which a left ventricular ejection fraction (LVEF) of 50% with regional wall motion abnormalities and aortic stenosis was present. Urgent coronary angiography showed near total occlusion (99% stenosis) in the mid segment of the left circumflex artery. During the same procedure, we performed percutaneous coronary intervention of the infarct-related artery (IRA) with direct bare metal stent implantation. An optimal distal flow in the IRA (TIMI 3) was achieved. An echocardiography assessment performed the next day revealed an improvement of the LVEF (from 50% to 61%) and severe aortic stenosis with maximum transaortic pressure gradient of 123 mm Hg (mean 69.6 mm Hg) and aortic valve area 0.8 cm2. Adhering to the Heart Team's recommendation, surgical aortic valve replacement (AVR) was planned for eight weeks after hospital discharge. We considered the possibility of changing the qualification of urgent AVR, so bare metal stent implantation seems to be the optimal treatment strategy for this patient. PMID- 24065304 TI - [Unusual epicardial location of ventricular ectopy in left ventricular outflow tract, cured with RF ablation from the great cardiac vein]. AB - The case report refers to a 54-year-old woman with a drug-refractory premature ventricular contractions (total number of ventricular ectopy: 40,851 beats/24 h) where an ectopy focus was localised in epicardial part of the left ventricular outflow tract. Successful radiofrequency ablation with the open-irrigated-tip catheter was performed at the site of earliest activation in the great cardiac vein. PMID- 24065305 TI - Bone disease in patients awaiting liver transplantation. Has the situation improved in the last two decades? AB - In recent years, there has been speculation about the possibility of a reduction in the incidence of fractures after liver transplantation (LT) because of changes in the characteristics of candidates and the use of different immunosuppressive therapies. We analyzed the characteristics of LT candidates (CTC) and compared them with historical data from a group of LT candidate patients (HTC). Data from 60 CTC patients consecutively included in a screening program of metabolic bone disease were compared with data from 60 HTC patients prospectively evaluated between 1992 and 1993. In all patients, we analyzed the clinical and laboratory characteristics, bone mineral density (BMD) dual-energy X-ray absorptiometry, and skeletal fractures. Patients in the CTC group were older than patients in the HTC group. The CTC group had lower femoral neck T scores. No differences were observed between groups in the proportion of patients with osteoporosis (22 vs. 30 %, p = ns) or fractures (36 vs. 33 %, p = ns). The percentage of patients with normal BMD decreased from 38 to 20 %. 25(OH)D values were low in both groups. Only 7.5 % of the CTC patients received calcium and/or vitamin D supplementation. The prevalence of fractures among CTC patients was similar to that seen two decades ago. At present, candidates for LT are older and have lower femoral bone mass. Vitamin D deficiency remains frequent; however, calcium and/or vitamin D supplementation is uncommon. PMID- 24065306 TI - Differential expression of rat hippocampal microRNAs in two rat models of chronic pain. AB - The two most common forms of chronic pain are inflammatory pain and neuropathic pain. Nevertheless, the underlying mechanisms of these pain conditions and their therapeutic responses are poorly understood. MicroRNAs (miRNAs) negatively regulate cell genes, and thus control cell proliferation, inflammation and metabolism. In the present study, we examined gene expression in the hippocampus of rats in two models of chronic pain. In addition, we used the left hindpaw procedure to identify differences in the bilateral hippocampus. We divided the rats into the 4 following groups: the group with chronic constriction injury (CCI), the sham-operated group, the group injected with complete Freund's adjuvant (CFA) and the group injected with normal saline. miRNA expression profiles were analyzed using TaqMan low-density array (TLDA). We observed 54 miRNAs (22.7%) in the rats with CCI rats that were differentially expressed, including 7 miRNAs that were downregulated compared with the sham-operated rats. In the CFA-injected rats, 40 miRNAs (16.8%) were differentially expressed, including 8 miRNAs that were downregulated compared with the normal saline injected rats. Pearson's correlation co-efficient for all detected miRNAs in the rat hippocampus failed to identify differences between the hippocampi bilaterally. An unsupervised cluster analysis produced separate clusters between the control and experimental groups. In this study, we demonstrate the differential expression of hippocampal miRNAs in two rat models of chronic pain; however, no significant differences were observed bilaterally in hippocampal miRNA expression. Further research is required to determine the correlation among miRNAs, messenger RNAs (mRNAs) and proteins. PMID- 24065307 TI - Intranuclear cytoplasmic inclusions in cytologically suspicious or malignant thyroid nodules: identification and correlation with echogenicity and size of the nodules. AB - Intranuclear inclusions (ICI) represent one cytological feature suggestive of malignancy. The aims of this study are (1) to correlate ICI with size and echogenicity of the thyroid nodules that, at fine-needle aspiration cytology (FNAC), are suspiciously malignant (THY4) or malignant (THY5); and (2) to ascertain whether ICI alone or combined with some ultrasonography (US) characteristics would help in predicting malignancy. We studied 90 consecutive thyroid nodules (THY4 n = 60 or THY5 n = 30) from 90 patients, who subsequently underwent thyroidectomy. Prior to thyroidectomy, all 90 nodules were examined by the US-guided FNAC. A cytology/histology correlation was performed. The results showed that 70 nodules were cancerous (82.2 %, THY4 = 73.3 %, THY5 = 100 %). ICI positive (ICI+) were 53/90 nodules (THY4 = 48.3 %, THY5 = 80.0 %), of which three (all THY4) were benign. The maximum diameter was smaller in the 53 ICI +ve than in the 37 ICI -ve nodules (14.2 +/- 5.4 vs. 20.0 +/- 9.4 mm, P = 0.0001; median volume 1.32 vs. 4.03 ml). In the THY4 smaller hypoechoic nodules, malignancy rate was 95 % with greater probability to detect ICI compared with non-hypoechoic nodules of >20 mm in maximum diameter (31 (75.6 %) vs. 4 (23.5 %), P = 0.0002). Based on the results, we conclude that ICI detection is associated with relatively smaller size and hypoechoic appearance in THY4 or THY5 nodules. In the THY4 nodules, when coupled with these US characteristics, ICI identification selects lesions with high chances of malignancy. PMID- 24065308 TI - Functional thyrotropin receptor expression in the ventricle and the effects on ventricular BNP secretion. AB - Elevated thyrotropin (TSH) and hypercholesterolemia commonly coexist in patients with subclinical hypothyroidism, which can cause and aggravate heart disease. However, it is unclear whether TSH has a direct effect on cardiac function. To determine the expression of the thyrotropin receptor (TSHR) and the effects of TSH on ventricular function, we analyzed the ventricular tissues and thyroid glands from normal rats and mice and the H9c2 cardiomyocyte cell line. The results revealed that TSHR was expressed at the transcriptional and protein levels by PCR, immunoblotting, immunohistochemistry and immunofluorescence. The mRNA levels of beta-MHC and the expression of pCREB and HMGCR in the ventricle were significantly lower in Tshr (-/-) mice than in wild-type (WT) mice (p < 0.05), but serum NT-proBNP levels were similar between WT and Tshr (-/-) mice. After synchronization, H9c2 cells were stimulated with several concentrations of TSH for various time periods. TSH up-regulated beta-MHC mRNA expression in H9c2 cells. Cyclic adenosine monophosphate (cAMP) production and downstream signaling, such as pCREB and HMGCR expression and NT-proBNP secretion, increased in dose- and time-dependent manners. The TSH-stimulated effects were suppressed by an adenylyl cyclase inhibitor, a protein kinase A (PKA) inhibitor and HMGCR inhibitors (all p < 0.05). The data indicate functional TSHR is expressed in ventricular myocytes and mediates TSH-induced BNP secretion and HMGCR up regulation through the cAMP/PKA/pCREB signaling pathway. Our findings suggest a potentially novel pathophysiological role of TSH in heart failure-associated hypothyroidism. PMID- 24065309 TI - Metastatic small cell neuroendocrine carcinoma of the pelvic floor. PMID- 24065310 TI - Metabolic syndrome and cancer: holistic or reductionist? AB - Metabolic syndrome has become a major public health problem worldwide and represents a common clinical condition in countries with a high incidence of obesity and western dietary patterns. Metabolic syndrome associates with common cancers at many sites, including liver, colorectal, and bladder cancers in men, and endometrial, pancreatic, breast post-menopausal, and colorectal cancers in women. However, the role played by each single component of the syndrome on cancer risk is still unclear. For endometrial cancer, obesity and/or high circumference waist explain all the risk associated with the full metabolic syndrome, while for post-menopausal breast cancer, the risk conveyed by metabolic syndrome appears to be greater than its parts, as no single component explains the full risk associated with the syndrome. Future research should cover other avenues in order to elucidate the complexity of biological processes linking metabolic syndrome and cancer. PMID- 24065311 TI - Insulin sensitivity in normocalcaemic primary hyperparathyroidism. PMID- 24065312 TI - Additive effect of heavy metals on metabolic syndrome in the Korean population: the Korea National Health and Nutrition Examination Survey (KNHANES) 2009-2010. AB - There have been increasing concerns regarding health problems due to endocrine disrupting chemicals (EDCs). We investigated association of heavy metals, including lead, mercury, and cadmium, with metabolic syndrome (MS) and its individual components in the Korean population. Participants included 1,961 males and 1,989 females 20 years of age or older from the fourth and fifth Korea National Health and Nutritional Examination Surveys of the Korean population (2009 and 2010). We examined the relationship of blood lead, mercury, and cadmium levels with MS and the additive effect of three heavy metals on MS after adjustment for age, sex, body mass index (BMI), region, smoking, alcohol consumption, and regular exercise. Blood concentration of lead showed a significant but modest association with prevalence of MS (P = 0.04). Other heavy metals did not show such a relationship with MS. When the participants were classified according to the sum of category numbers of the three heavy metals, adjusted odds ratios were 1.0, 1.355, 1.638, and 1.556 (P < 0.01). Among components of MS, significant relationship of the sum of heavy metals with hypertension and elevated triglyceride was demonstrated. Blood concentration of lead was positively associated with the prevalence of MS. Of particular interest, cumulative effect of a mixture of lead, mercury, and cadmium on prevalence of MS was stronger than the sum of effect of each heavy metal. Accumulative effect of exposure to heavy metals could be more additive or synergistic than individual exposure in the general population. PMID- 24065313 TI - Elastographic presentation of medullary thyroid carcinoma. AB - Aim of the study was to evaluate the elastographic appearance of medullary thyroid carcinoma (MTC) by a retrospective evaluation of 18 nodules histologically proven as MTC. Free-hand qualitative elastography was performed using Hitachi Logos EUB 7500. The elasticity score (ES), was assessed based on a colour elastogram, the blue colour being correlated with hard tissue, red colour with soft tissue, and green with intermediate hardness. Nodules were classified into four classes. A alleged diagnosis of malignancy was assigned to nodules with ES3 or 4 and a presumptive diagnosis of benignity was assigned to nodules with an ES1 or 2. More than half (55.6 %) of MTCs have a low-intermediate grade of elasticity. The hardest lesions (ES4) were those with ultrasonographic features highly suspicious for malignancy. In conclusion, most of MTCs present an elastographic pattern of benignity. Therefore, qualitative elastography does not add useful information in pointing out MTC on the basis of its hardness. Our data suggest a marginal role for this technique in MTC evaluation. PMID- 24065314 TI - Predictors of relapse in problem gambling: a prospective cohort study. AB - To explore the variation of predictors of relapse in treatment and support seeking gamblers. A prospective cohort study with 158 treatment and support seeking problem gamblers in South Australia. Key measures were selected using a consensus process with international experts in problem gambling and related addictions. The outcome measures were Victorian Gambling Screen (VGS) and behaviours related to gambling. Potential predictors were gambling related cognitions and urge, emotional disturbance, social support, sensation seeking traits, and levels of work and social functioning. Mean age of participants was 44 years (SD = 12.92 years) and 85 (54 %) were male. Median time for participants enrollment in the study was 8.38 months (IQR = 2.57 months). Patterns of completed measures for points in time included 116 (73.4 %) with at least a 3 month follow-up. Using generalised mixed-effects regression models we found gambling related urge was significantly associated with relapse in problem gambling as measured by VGS (OR 1.29; 95 % CI 1.12-1.49) and gambling behaviours (OR 1.16; 95 % CI 1.06-1.27). Gambling related cognitions were also significantly associated with VGS (OR 1.06; 95 % CI 1.01-1.12). There is consistent association between urge to gamble and relapse in problem gambling but estimates for other potential predictors may have been attenuated because of methodological limitations. This study also highlighted the challenges presented from a cohort study of treatment and support seeking problem gamblers. PMID- 24065315 TI - The moderating effect of gender on the relation between expectancies and gambling frequency among college students. AB - Compared to college females, college males are more likely to report frequent gambling. Research on gambling outcome expectancies has shown that expectations about gambling influence gambling behavior and that endorsement of particular expectancies differs by gender. Knowledge regarding the differential predictive utility of specific gambling expectancies based on gender would help to determine how beliefs about gambling may be fundamentally different for men and women. The present study explored whether gender moderates the relation between gambling expectancy and gambling frequency in a college sample. 421 college students completed an online survey that included questions about their demographics, gambling frequency, and gambling expectancies. Hierarchical regression analyses indicated that gender moderated the relations between the expectancies of social consequences, material gain, and gambling frequency. For females, greater endorsement of social consequences predicted less frequent gambling. For both males and females, greater endorsement of material gain predicted more frequent gambling. The current findings can help inform prevention and intervention efforts by identifying gambling expectations that are differentially related to college student gambling behavior choices. PMID- 24065316 TI - Prehypertension, hypertension, and the risk of acute myocardial infarction in HIV infected and -uninfected veterans. AB - BACKGROUND: Compared to uninfected people, human immunodeficiency virus (HIV) infected individuals may have an increased risk of acute myocardial infarction (AMI). Currently, HIV-infected people are treated to the same blood pressure (BP) goals (<140/90 or <130/80 mm Hg) as their uninfected counterparts. Whether HIV infected people with elevated BP have excess AMI risk compared to uninfected people is not known. This study examines whether the association between elevated BP and AMI risk differs by HIV status. METHODS: The Veterans Aging Cohort Study Virtual Cohort (VACS VC) consists of HIV-infected and -uninfected veterans matched 1:2 on age, sex, race/ethnicity, and clinical site. For this analysis, we analyzed 81 026 people with available BP data from VACS VC, who were free of cardiovascular disease at baseline. BP was the average of the 3 routine outpatient clinical measurements performed closest to baseline (first clinical visit after April 2003). BP categories used in the analyses were based on criteria of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Analyses were performed using Cox proportional hazards regression. RESULTS: Over 5.9 years (median), 860 incident AMIs occurred. Low/high prehypertensive and untreated/treated hypertensive HIV-infected individuals had increased AMI risk compared to uninfected, untreated normotensive individuals (hazard ratio [HR], 1.60 [95% confidence interval {CI}, 1.07-2.39]; HR, 1.81 [95% CI, 1.22-2.68]; HR, 2.57 [95% CI, 1.76-3.76]; and HR, 2.76 [95% CI, 1.90-4.02], respectively). CONCLUSIONS: HIV, prehypertensive BP, and hypertensive BP were associated with an increased risk of AMI in a cohort of HIV-infected and -uninfected veterans. Future studies should prospectively investigate whether HIV interacts with BP to further increase AMI risk. PMID- 24065320 TI - Recalcitrant pseudotumoral anogenital herpes simplex virus type 2 in HIV-infected patients: evidence for predominant B-lymphoplasmocytic infiltration and immunomodulators as effective therapeutic strategy. AB - BACKGROUND: In patients with human immunodeficiency virus (HIV) infection, genital herpetic lesions may be extensive and tend to persist for longer periods; in addition, atypical hypertrophic, ulcerative, or pseudotumor forms have been reported, frequently showing resistance to acyclovir (ACV) treatment. METHODS: Between 2003 and 2011, 10 HIV-1-infected patients presenting with chronic pseudotumoral anogenital herpes simplex type 2 (HSV-2) infections were studied. RESULTS: All patients developed chronic, hypertrophic HSV-2 anogenital lesions with multilesional presentation in 7 cases and involvement of 2 anatomical sites in 6 of them. At the time of diagnosis, the median CD3(+)CD4(+) absolute blood count was 480.5 cells/uL (range, 165-632 cells/uL), whereas the plasma HIV load was undetectable in all cases. Histopathologic analysis of lesion biopsies showed a moderately dense dermal polytypic plasma cell infiltrate. Detection of HSV-2 by culture and/or polymerase chain reaction was positive for all patients, with evidence for ACV-resistant strains in 6 of 8 cases. In addition, viral resistance to ACV was found only in HSV-2 isolated from ulcerative lesions, whereas purely pseudotumoral ones harbored sensitive strains. Durable control was observed with HSV DNA polymerase inhibitors in only 2 cases, and the immunomodulators imiquimod and thalidomide allowed 5 patients to reach sustained complete response. CONCLUSIONS: HSV-2-related pseudolymphoma in HIV-infected patients is characterized by a predominant polyclonal lymphoplasmacytic infiltration, and is frequently refractory to antiherpetic drugs. Immunomodulatory therapeutic strategies using thalidomide showed consistent efficacy, and should be considered early during the course of disease. PMID- 24065317 TI - A 24-week treatment strategy with pegylated interferon/ribavirin in HIV/hepatitis C virus genotype 3-coinfected patients who achieved a rapid virologic response results in a high sustained virologic response rate. AB - We designed a study to evaluate the efficacy of a 24-week treatment strategy in HIV/hepatitis C virus (HCV) genotype 3-coinfected patients achieving rapid virologic response for a first HCV treatment with pegylated interferon plus ribavirin (peg-IFN/RBV). Our results suggest that a shorter course of peg-IFN/RBV therapy may be sufficient in this population. PMID- 24065321 TI - Preventive therapy for child contacts of multidrug-resistant tuberculosis: a prospective cohort study. AB - BACKGROUND: Evidence is limited to guide the management of children exposed to multidrug-resistant (MDR) tuberculosis. We aimed to study the tolerability and toxicity of a standard preventive therapy regimen given to children exposed to infectious MDR tuberculosis, and explore risk factors for poor outcome. METHODS: In this prospective cohort study in the Western Cape, South Africa, children <5 years of age, or human immunodeficiency virus (HIV)-positive children aged <15 years, were recruited from May 2010 through April 2011 if exposed to an ofloxacin susceptible, MDR tuberculosis source case. Children were started on preventive therapy as per local guidance: ofloxacin, ethambutol, and high-dose isoniazid for 6 months. Standardized measures of adherence and adverse events were recorded; poor outcome was defined as incident tuberculosis or death from any cause. RESULTS: One hundred eighty-six children were included, with a median age of 34 months (interquartile range, 14-47 months). Of 179 children tested for HIV, 9 (5.0%) were positive. Adherence was good in 141 (75.8%) children. Only 7 (3.7%) children developed grade 3 adverse events. One child (0.5%) died and 6 (3.2%) developed incident tuberculosis during 219 patient-years of observation time. Factors associated with poor outcome were age <1 year (rate ratio [RR], 10.1; 95% confidence interval [CI], 1.65-105.8; P = .009), HIV-positive status (RR, 10.6; 95% CI, 1.01-64.9; P = .049), exposure to multiple source cases (RR, 6.75; 95% CI, 1.11-70.9; P = .036) and poor adherence (RR, 7.50; 95% CI, 1.23-78.7; P = .026). CONCLUSIONS: This 3-drug preventive therapy regimen was well tolerated and few children developed tuberculosis or died if adherent to therapy. The provision of preventive therapy to vulnerable children following exposure to MDR tuberculosis should be considered. PMID- 24065323 TI - Editorial commentary: variant Influenza A(H3N2) virus: looking through a glass, darkly. PMID- 24065324 TI - Respiratory syncytial virus lower respiratory disease in hematopoietic cell transplant recipients: viral RNA detection in blood, antiviral treatment, and clinical outcomes. AB - BACKGROUND: Respiratory syncytial virus (RSV) pneumonia after hematopoietic cell transplant (HCT) is associated with severe morbidity. Although RSV RNA has been detected in serum from patients with RSV lower respiratory disease (LRD) after HCT, the association with clinical outcomes has not been well established in multivariable models. Additionally, the role of antiviral treatment in HCT recipients has not been previously analyzed in multivariable models. METHODS: We retrospectively identified HCT recipients with virologically confirmed RSV LRD and tested stored plasma/serum samples by quantitative reverse transcription polymerase chain reaction for RSV RNA. Risk factors for RSV RNA detection and the impact of RSV RNA in serum and antiviral therapy on outcomes were analyzed using multivariable Cox models. RESULTS: RSV RNA was detected in plasma or serum from 28 of 92 (30%) patients at a median of 24.5 days following HCT and 2 days following LRD. In multivariable models, neutropenia, monocytopenia, thrombocytopenia, and mechanical ventilation increased the risk of plasma/serum RSV RNA detection; lymphopenia and steroid use did not. RSV RNA detection increased the risk of overall mortality in multivariable models (adjusted hazard ratio [aHR], 2.09 [P = .02]), whereas treatment with aerosolized ribavirin decreased the risk of overall mortality and pulmonary death (aHR, 0.33 [P = .001] and aHR 0.31 [P = .003], respectively). CONCLUSIONS: RSV RNA detection in plasma or serum may be a marker for lung injury and poor outcomes in HCT recipients with RSV LRD. Treatment with aerosolized ribavirin appeared to be protective against overall and pulmonary mortality. PMID- 24065322 TI - Outbreak of variant influenza A(H3N2) virus in the United States. AB - BACKGROUND: Variant influenza virus infections are rare but may have pandemic potential if person-to-person transmission is efficient. We describe the epidemiology of a multistate outbreak of an influenza A(H3N2) variant virus (H3N2v) first identified in 2011. METHODS: We identified laboratory-confirmed cases of H3N2v and used a standard case report form to characterize illness and exposures. We considered illness to result from person-to-person H3N2v transmission if swine contact was not identified within 4 days prior to illness onset. RESULTS: From 9 July to 7 September 2012, we identified 306 cases of H3N2v in 10 states. The median age of all patients was 7 years. Commonly reported signs and symptoms included fever (98%), cough (85%), and fatigue (83%). Sixteen patients (5.2%) were hospitalized, and 1 fatal case was identified. The majority of those infected reported agricultural fair attendance (93%) and/or contact with swine (95%) prior to illness. We identified 15 cases of possible person-to-person transmission of H3N2v. Viruses recovered from patients were 93%-100% identical and similar to viruses recovered from previous cases of H3N2v. All H3N2v viruses examined were susceptible to oseltamivir and zanamivir and resistant to adamantane antiviral medications. CONCLUSIONS: In a large outbreak of variant influenza, the majority of infected persons reported exposures, suggesting that swine contact at an agricultural fair was a risk for H3N2v infection. We identified limited person-to-person H3N2v virus transmission, but found no evidence of efficient or sustained person-to-person transmission. Fair managers and attendees should be aware of the risk of swine-to-human transmission of influenza viruses in these settings. PMID- 24065325 TI - Persistent coma in Strongyloides hyperinfection syndrome associated with persistently increased ivermectin levels. PMID- 24065326 TI - Changes in the timing of antiretroviral therapy initiation in HIV-infected patients with tuberculosis in Uganda: a study of the diffusion of evidence into practice in the global response to HIV/AIDS. AB - BACKGROUND: We aimed to determine the extent to which emerging evidence and changing guidelines regarding timing of antiretroviral therapy (ART) among human immunodeficiency virus (HIV)-infected patients with tuberculosis influenced "real world" clinical practice in Uganda. METHODS: We evaluated ART-naive, HIV-infected adults starting tuberculosis therapy at 2 HIV clinics in Uganda between 26 August 2006 and 29 September 2012. We used multivariate regression to calculate associations between 4 calendar periods reflecting publication of seminal clinical studies or changes in guidelines and timing of ART after tuberculosis therapy initiation. RESULTS: For patients with CD4 counts <50 cells/uL, the fraction starting ART within 14 and 30 days of initiating tuberculosis therapy increased from 7% to 14% and from 14% to 86% over the period of observation. The fraction of patients with CD4 counts >50 cells/uL starting ART within 60 days increased from 16% to 28%. After adjustment for sociodemographic factors, when comparing the most recent with the earliest calendar period, the rate of ART initiation increased by 4.57-fold (95% confidence interval [CI], 1.76-fold to 11.86-fold) among patients with baseline CD4 counts <= 50 cells/uL and by 5.43 fold (95% CI, 3.16- fold to 9.31-fold) among those with baseline CD4 counts >50 cells/uL. CONCLUSIONS: We observed large changes in clinical practice during a period of emerging data and changing guidelines among HIV-infected patients with tuberculosis. Nonetheless, a significant proportion of individuals with higher CD4 cell counts do not start ART within recommended time frames. Targeted dissemination and implementation efforts are still needed to achieve target levels in practice. PMID- 24065328 TI - Drug resistance in patients with leprosy in the United States. AB - Molecular drug susceptibility testing was performed on 39 US patients with leprosy. Of these, 2 had dapsone-resistant Mycobacterium leprae and 1 of these patients also had rifampin-resistant M. leprae. Even though antileprosy drug resistance occurs in this leprosy population, resistance does not appear to be a major problem. PMID- 24065327 TI - Point-of-care diagnosis and prognostication of cryptococcal meningitis with the cryptococcal antigen lateral flow assay on cerebrospinal fluid. AB - The cryptococcal antigen (CRAG) lateral flow assay (LFA) had 100% sensitivity and specificity on cerebrospinal fluid samples. Pretreatment LFA titers correlated with quantitative cultures (R(2) = 0.7) and predicted 2- and 10-week mortality. The CRAG LFA is an accurate diagnostic assay for CSF and should be considered for point-of-care diagnosis of cryptococcal meningitis. PMID- 24065330 TI - Consideration of prophylactic antibiotic therapy during an outbreak of Legionnaires' disease. PMID- 24065329 TI - The quad pill, a once-daily combination therapy for HIV infection. AB - The quad pill is the newest single-pill, once-daily option for the treatment of human immunodeficiency virus (HIV) type 1 infection. In addition to tenofovir difumarate (TDF) and emtricitabine (FTC), the quad pill includes cobicistat (COBI; an inactivator of cytochrome P450 isoenzyme CYP3A without anti-HIV activity) and a new integrase inhibitor, elvitegravir (EVG). The quad does not have drug interactions with H2-receptor antagonists or proton pump inhibitors, does not cause central nervous system (CNS) side effects, and is pregnancy category B. It does have substantial drug interactions with medications that are metabolized using CYP3A and causes reversible declines in estimated glomerular filtration rate (eGFR) owing to inhibition of renal tubule transport of creatinine. In clinical trials, the virologic and immunologic efficacy of the quad pill is equivalent to that of other comparator regimens with low rates of discontinuation. The major side effect is nauseam which is self-limited, and the primary mutations associated with treatment failure frequently lead to cross resistance with raltegravir (RAL). PMID- 24065331 TI - Causes of death and characteristics of decedents with viral hepatitis, United States, 2010. AB - BACKGROUND: Previous research indicates that the mortality burden from viral hepatitis is growing, particularly among middle-aged persons. To monitor progress toward prevention goals, it is important to continue to document characteristics and comortalities of these deaths. This study sought to examine demographic characteristics and the most frequent causes of death among decedents with a viral hepatitis-related death. METHODS: A cross-sectional study was performed on approximately 2.4 million death records from 2010. We calculated mortality rates for decedents with and without hepatitis A, B, and C virus (HAV, HBV, and HCV) and relative risks for the most frequently cited conditions in decedents with and without HBV and HCV. RESULTS: In 2010, there were 18 473 (0.7%) deaths with HAV, HBV, and HCV listed among causes of death, disproportionately in those aged 45-64 years. Among the 10 frequent causes of death, decedents listing HBV or HCV died, on average, 22-23 years earlier than decedents not listing these infections. HBV- and HCV-infected decedents aged 45-64 years had an increased risk of having the following conditions reported than decedents without these infections: cancer of liver and intrahepatic bile duct; fibrosis, cirrhosis, and other liver diseases; alcohol-related liver disease; gastrointestinal hemorrhage; human immunodeficiency infection; acute and unspecified renal failure; and septicemia (HCV only). CONCLUSIONS: Decedents with other causes of death that include HBV or HCV died 22-23 years earlier than decedents not listing these infections. These data suggest and support the need for prevention, early identification, and treatment of HBV and HCV. PMID- 24065332 TI - Editorial commentary: including the X-factor: toward patient-centered prevention of urinary tract infection. PMID- 24065333 TI - Recurrent urinary tract infections among women: comparative effectiveness of 5 prevention and management strategies using a Markov chain Monte Carlo model. AB - BACKGROUND: Recurrent urinary tract infections (UTIs) are a common problem among women. However, comparative effectiveness strategies for managing recurrent UTIs are lacking. METHODS: We performed a systematic literature review of management of women experiencing >=3 UTIs per year. We then developed a Markov chain Monte Carlo model of recurrent UTI for each management strategy with >=2 adequate trials published. We simulated a cohort that experienced 3 UTIs/year and a secondary cohort that experienced 8 UTIs/year. Model outcomes were treatment efficacy, patient and payer cost, and health-related quality of life. RESULTS: Five strategies had >=2 clinical trials published: (1) daily antibiotic (nitrofurantoin) prophylaxis; (2) daily estrogen prophylaxis; (3) daily cranberry prophylaxis; (4) acupuncture prophylaxis; and (5) symptomatic self-treatment. In the 3 UTIs/year model, nitrofurantoin prophylaxis was most effective, reducing the UTI rate to 0.4 UTIs/year, and the most expensive to the payer ($821/year). All other strategies resulted in payer cost savings but were less efficacious. Symptomatic self-treatment was the only strategy that resulted in patient cost savings, and was the most favorable strategy in term of cost per quality-adjusted life-year (QALY) gained. CONCLUSIONS: Daily antibiotic use is the most effective strategy for recurrent UTI prevention compared to daily cranberry pills, daily estrogen therapy, and acupuncture. Cost savings to payers and patients were seen for most regimens, and improvement in QALYs were seen with all. Our findings provide clinically meaningful data to guide the physician-patient partnership in determining a preferred method of prevention for this common clinical problem. PMID- 24065334 TI - Effects of immunocompromise and comorbidities on pneumococcal serotypes causing invasive respiratory infection in adults: implications for vaccine strategies. AB - BACKGROUND: The 13-valent pneumococcal conjugate vaccine (PCV13) has recently been approved for use in immunocompromised adults. However, it is unclear whether there is an association between specific underlying conditions and infection by individual serotypes. The objective was to determine the prevalence of serotypes covered by PCV13 in a cohort of patients with invasive pneumococcal disease of respiratory origin and to determine whether there are specific risk factors for each serotype. METHODS: An observational study of adults hospitalized with invasive pneumococcal disease in 2 Spanish hospitals was conducted during the period 1996-2011. A multinomial regression analysis was performed to identify conditions associated with infection by specific serotypes (grouped according their formulation in vaccines and individually). RESULTS: A total of 1094 patients were enrolled; the infecting serotype was determined in 993. In immunocompromised patients, 64% of infecting serotypes were covered by PCV13. After adjusting for age, smoking, alcohol abuse, and nonimmunocompromising comorbidities, the group of serotypes not included in either PCV13 or PPV23 were more frequently isolated in patients with immunocompromising conditions and cardiopulmonary comorbidities. Regarding individual serotypes, 6A, 23F, 11A, and 33F were isolated more frequently in patients with immunocompromise and specifically in some of their subgroups. The subgroup analysis showed that serotype10A was also associated with HIV infection. CONCLUSIONS: Specific factors related to immunocompromise seem to determine the appearance of invasive infection by specific pneumococcal serotypes. Although the coverage of serotypes in the 13-valent conjugate pneumococcal vaccine (PCV13) was high, some non-PCV13 emergent serotypes are more prevalent in immunocompromised patients. PMID- 24065336 TI - Yield of contact investigations in households of patients with drug-resistant tuberculosis: systematic review and meta-analysis. AB - Contact investigations among individuals living with drug-susceptible tuberculosis patients (source cases) have shown a high yield of tuberculosis disease and latent tuberculosis, but the yield of such investigations in households of drug-resistant tuberculosis source cases is unknown. In this systematic review and meta-analysis, we found 25 studies that evaluated a median of 111 (interquartile range, 21-302) household contacts of drug-resistant tuberculosis source cases. The pooled yield was 7.8% (95% CI, 5.6%-10.0%) for active tuberculosis and 47.2% (95% CI, 30.0%-61.4%) for latent tuberculosis, although there was significant statistical heterogeneity (P < .0001). More than 50% of secondary cases with drug susceptibility test results were concordant with those of the source case. Among studies that followed household members, the majority of secondary cases were detected within 1 year of the source case's diagnosis. Household contact investigation around drug-resistant tuberculosis patients is a high-yield intervention for detection of drug-resistant tuberculosis and prevention of ongoing transmission. PMID- 24065339 TI - Thermodynamic modeling of chromium: strong and weak magnetic coupling. AB - As chromium is a decisive ingredient for stainless steels, a reliable understanding of its thermodynamic properties is indispensable. Parameter-free first-principles methods have nowadays evolved to a state allowing such thermodynamic predictions. For materials such as Cr, however, the inclusion of magnetic entropy and higher order contributions such as anharmonic entropy is still a formidable task. Employing state-of-the-art ab initio molecular dynamics simulations and statistical concepts, we compute a set of thermodynamic properties based on quasiharmonic, anharmonic, electronic and magnetic free energy contributions from first principles. The magnetic contribution is modeled by an effective nearest-neighbor Heisenberg model, which itself is solved numerically exactly by means of a quantum Monte Carlo method. We investigate two different scenarios: a weak magnetic coupling scenario for Cr, as usually presumed in empirical thermodynamic models, turns out to be in clear disagreement with experimental observations. We show that instead a mixed Hamiltonian including weak and strong magnetic coupling provides a consistent picture with good agreement to experimental thermodynamic data. PMID- 24065340 TI - [What does obesity paradox mean in coronary heart disease?]. PMID- 24065337 TI - An integrated approach to the biomechanics and motor control of cricket fast bowling techniques. AB - To date, scientific investigations into the biomechanical aspects of cricket fast bowling techniques have predominantly focused on identifying the mechanical factors that may predispose fast bowlers to lower back injury with a relative paucity of research being conducted on the technical features that underpin proficient fast bowling performance. In this review paper, we critique the scientific literature examining fast bowling performance. We argue that, although many published investigations have provided some useful insights into the biomechanical factors that contribute to a high ball release speed and, to a lesser extent, bowling accuracy, this research has not made a substantive contribution to knowledge enhancement and has only had a very minor influence on coaching practice. To significantly enhance understanding of cricket fast bowling techniques and, therefore, have greater impact on practice, we recommend that future scientific research adopts an interdisciplinary focus, integrating biomechanical measurements with the analytical tools and concepts of dynamical systems motor control theory. The use of qualitative (topological) analysis techniques, in particular, promises to increase understanding of the coordinative movement patterns that define 'technique' in cricket fast bowling and potentially help distinguish between functional and dysfunctional aspects of technique for individual fast bowlers. PMID- 24065341 TI - [Does this stimulator/defibrillator work correctly? Not always does 2+2=4...]. PMID- 24065342 TI - Ventricular fibrillation with a 2:1 conduction block over the right ventricle in a Brugada syndrome patient. PMID- 24065343 TI - Ruptured aneurysm of the sinus of Valsalva manifesting as acute heart failure. PMID- 24065344 TI - Injured workers' assessment of vocational rehabilitation services before and after retraining. AB - PURPOSE: Workers' compensation-based vocational rehabilitation (VR) programs are costly and challenging to operate effectively. This study aimed to: (1) describe injured workers' assessment of Washington State's VR system before and after vocational retraining, (2) describe the factors affecting injured worker satisfaction with VR services, and (3) gather suggestions for program improvement from injured workers. METHODS: Telephone surveys were conducted in two distinct samples: (1) 361 workers were interviewed after determination of retraining eligibility but before retraining plan development, and (2) 360 workers were interviewed after cessation of vocational services and claim closure. RESULTS: Injured workers interviewed before retraining were more often satisfied with the VR system (69 %) than were those interviewed after VR services ended (46 %). Although 55 % were initially somewhat/very certain they would return to work (RTW) after retraining, only 21 % had RTW 3-6 months after claim closure. Poor health, poor functional ability, and multiple retraining attempts were significantly associated with dissatisfaction. Suggestions for program improvement fell most frequently into the following areas: (1) more training choices, more worker input into the retraining goal, and/or a better fit of the retraining goal with the workers' experience and abilities (25 %); (2) listen to, respect, and/or understand the worker with regard to their interests, goals, and limitations (17 %); and (3) more support with job placement, work re-entry skills, and RTW in general (9 %). CONCLUSIONS: There is substantial room for improvement in worker satisfaction with VR. Injured workers' feedback may facilitate identification of opportunities to improve the VR process and RTW outcomes. PMID- 24065345 TI - Functional annulus remodelling using a prosthetic ring in tricuspid aortic valve repair: mid-term results. AB - OBJECTIVES: The functional aortic valve annulus (FAVA) is a complex unit with proximal (aorto-ventricular junction) and distal (sinotubular junction) components. The aim of our study was to evaluate the impact of the total FAVA remodelling, using a prosthetic ring, on mid-term clinical and echocardiographic results after aortic valve repair. METHODS: Since February 2003, 250 patients with tricuspid aortic valve insufficiency (AI) underwent aortic valve repair. FAVA dilatation was treated by prosthetic ring in 52 patients, by isolated subcommissural plasty in 62, by subcommissural plasty plus ascending aortic replacement in 57 and by David's reimplantation procedure in 79. Survival rate and freedom from recurrent AI greater than or equal to moderate were evaluated by Kaplan-Meier. RESULTS: Overall late survival was 90.4%. Late cardiac-related deaths occurred in 15 patients. At follow-up, 36 (16%) patients had recurrent AI greater than or equal to moderate because of cusp reprolapse and/or FAVA redilatation. Freedom from recurrent AI was significantly higher for patients who underwent David's procedure or FAVA remodelling by prosthetic ring than those who underwent isolated subcommissural plasty (P < 0.01) or subcommissural plasty plus ascending aortic replacement (P = 0.02). There was no statistical difference between David's procedure and prosthetic ring annuloplasty (P = 0.26). CONCLUSION: FAVA remodelling using a prosthetic ring is a safe procedure in aortic valve repair surgery thanks to long-term annulus stabilization and it is a pliable alternative to David's procedure in selected patients. This technique may be used in all patients with slight root dilatation to avoid aggressive root reimplantation. We also recommended total FAVA annuloplasty in all patients who underwent aortic valve repair to improve long-term repair results. PMID- 24065346 TI - Social value orientation: theoretical and measurement issues in the study of social preferences. AB - What motivates people when they make decisions and how those motivations are potentially entangled with concerns for others are central topics for the social, cognitive, and behavioral sciences. According to the postulate of narrow self interest, decision makers have the goal of maximizing personal payoffs and are wholly indifferent to the consequences for others. The postulate of narrow self interest-which has been influential in economics, psychology, and sociology-is precise and powerful but is often simply wrong. Its inadequacy is well known and efforts have been made to develop reliable and valid measurement methods to quantify the more nuanced social preferences that people really have. In this paper, we report on the emergence and development of the predominant conceptualization of social preferences in psychology: social value orientation (SVO). Second, we discuss the relationship between measurement and theory development of the SVO construct. We then provide an overview of the literature regarding measurement methods that have been used to assess individual variations in social preferences. We conclude with a comparative evaluation of the various measures and provide suggestions regarding the measures' constructive use in building psychologically realistic theories of people's social preferences. PMID- 24065347 TI - Lipomatous hypertrophy of the interatrial septum: a possibly neglected cause of sudden cardiac death. PMID- 24065348 TI - Ensuring integrity of forensic data in a shared practice environment. PMID- 24065349 TI - In consideration of subspecialty training in forensic anthropology for pathologists. PMID- 24065350 TI - Disgust, contempt, and anger and the stereotypes of obese people. AB - PURPOSE: Emotions form an important part of stereotyping and prejudice, but little is known about how intergroup emotions are associated with anti-fat prejudice. This study examined the relation between negative intergroup emotions (disgust, contempt, and anger) and the stereotypes of obese people. METHOD: A community sample (n = 380) and an undergraduate sample (n = 96) rated obese people on common obesity stereotypes (e.g., lazy, sloppy), and also indicated the extent to which they felt disgust, contempt, and anger toward obese people. RESULTS: In both samples, participants reported feeling more disgust and contempt than anger toward obese people. Furthermore, regression analyses indicated that disgust was a significant positive predictor of obesity stereotypes, but contempt and anger were not. CONCLUSION: Overall, these findings provide further evidence that disgust plays an important role in prejudice toward obese people. PMID- 24065352 TI - Cardiac involvement of lung cancer mimicking myocardial infarction. PMID- 24065351 TI - Loss of control eating and weight outcomes after bariatric surgery: a study with a Portuguese sample. AB - The present study aim is to investigate the frequency of loss of control eating (LOC) episodes in three groups with different assessment times: one before, one at short and one at long-term after bariatric surgery; as well as to explore the association of postoperative problematic eating behaviors and weight outcomes and psychological characteristics. This cross-sectional study compared a group of preoperative bariatric surgery patients (n = 176) and two postoperative groups, one at short-term with <2 years follow-up (n = 110), and one at long-term >2 years follow-up (n = 53). Assessments included the EDE diagnostic interview and a set of self-report measures assessing eating disordered symptomatology, depression, and body image. We found the presence of LOC in 26.7 and 16.9 % of the pre-operative and long-term patients, respectively, and in about 11.8% of the short-term patients. One patient (0.9%) reported objective binge eating episodes at short-time, but subjective binge eating episodes were present in about 10% of the patients in all groups. LOC eating was related with the highest BMIs, the least weight loss, most weight regain, and most psychological impairment in the long-term assessments, but not at short-term. Despite the lower frequencies of disordered eating behavior in the short-term group, patients reporting LOC seem to represent a subgroup of individuals with poorest outcomes after surgery and most psychological distress. PMID- 24065353 TI - Association of common variants in KIF21B and ankylosing spondylitis in a Chinese Han population: a replication study. AB - KIF21B polymorphisms were found associated with susceptibility to multiple sclerosis and ankylosing spondylitis (AS) in populations of white European ancestry. We aimed to replicate the association of polymorphisms around KIF21B and AS in a Chinese Han population. This case-control study included 665 patients with AS and 1,042 healthy controls genotyped for seven single nucleotide polymorphisms (SNPs) of KIF21B--rs12118246, rs4915464, rs502658, rs10494829, rs12089839, rs6687260, and rs957957--by TaqMan genotyping assay; statistical analyses involved the use of PLINK. We also estimated the linkage disequilibrium and haplotypes of these SNPs. Two SNPs--rs502658 (allelic p = 0.0002, odds ratio [OR] 0.60, 95 % confidence interval [95 % CI] 0.47-0.76) and rs10494829 (allelic p = 0.003, OR 1.30, 95 % CI 1.12-1.52)--were significantly associated with AS in the Chinese Han population. In addition, a linear regression test showed that they have independent contribution to disease susceptibility. For both SNPs, haplotype AT was strongly associated with AS and increased the risk of the disease (p = 0.045, OR 1.183, 95 % CI 1.004-1.395), and the genotype GC reduced the risk (p = 0.011, OR 0.715, 95 % CI 0.55-0.928). This work identified a significant association of two SNPs in KIF21B and AS in the Chinese Han population. KIF21B may play an important role in the pathogenesis of AS in the Chinese population and might be a new therapeutic target for AS. PMID- 24065354 TI - Genome-wide association study of chronic hepatitis B virus infection reveals a novel candidate risk allele on 11q22.3. AB - BACKGROUND: Hepatitis B virus (HBV) affects millions of people worldwide. While some people are able to clear the virus following the first encounter, those who develop chronic infection manifest remarkable clinical heterogeneity that ranges from asymptomatic carrier state to cirrhosis and hepatocellular carcinoma. Despite extensive studies, little is known about genetic host factors that influence the outcome of chronic HBV infection. Thus, we conducted this study to investigate the genetic risk of developing active liver disease among chronic carriers of HBV. METHODS: In this study, we conducted a genome-wide association study (GWAS) on a cohort of patients with chronic HBV infection. RESULTS: One particular SNP that is 16 kb upstream of Ferredoxin 1 was found to have an association with complicated chronic HBV infection (cirrhosis and hepatocellular carcinoma) that reached GWAS significance, and was successfully validated on an independent set of samples. CONCLUSIONS: This first GWAS in an Arab population further demonstrates the utility of this approach in elucidating the genetic risk of HBV infection-related complications and highlights the advantage of conducting GWAS in different ethnicities to achieve that goal. PMID- 24065355 TI - A novel mutation in KIAA0196: identification of a gene involved in Ritscher Schinzel/3C syndrome in a First Nations cohort. AB - BACKGROUND: Ritscher-Schinzel syndrome (RSS) is a clinically heterogeneous disorder characterised by distinctive craniofacial features in addition to cerebellar and cardiac anomalies. It has been described in different populations and is presumed to follow autosomal recessive inheritance. In an effort to identify the underlying genetic cause of RSS, affected individuals from a First Nations (FN) community in northern Manitoba, Canada, were enrolled in this study. METHODS: Homozygosity mapping by SNP array and Sanger sequencing of the candidate genes in a 1Mb interval on chromosome 8q24.13 were performed on genomic DNA from eight FN RSS patients, eight of their parents and five unaffected individuals (control subjects) from this geographic isolate. RESULTS: All eight patients were homozygous for a novel splice site mutation in KIAA0196. RNA analysis revealed an approximate eightfold reduction in the relative amount of a KIAA0196 transcript lacking exon 27. A 60% reduction in the amount of strumpellin protein was observed on western blot. CONCLUSIONS: We have identified a mutation in KIAA0196 as the cause of the form of RSS characterised in our cohort. The ubiquitous expression and highly conserved nature of strumpellin, the product of KIAA0196, is consistent with the complex and multisystem nature of this disorder. PMID- 24065356 TI - CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome. AB - BACKGROUND: Russell Silver syndrome (RSS) leads to prenatal and postnatal growth retardation. About 55% of RSS patients present a loss-of-methylation of the paternal ICR1 domain on chromosome 11p15. CDKN1C is a cell proliferation inhibitor encoded by an imprinted gene in the 11p15 ICR2 domain. CDKN1C mutations lead to Beckwith Wiedemann syndrome (BWS, overgrowth syndrome) and in IMAGe syndrome which associates growth retardation and adrenal insufficiency. We searched for CDKN1C mutations in a cohort of clinically diagnosed RSS patients with no molecular anomaly. METHOD: The coding sequence and intron-exon boundaries of CDKN1C were analysed in 97 RSS patients. The impact of CDKN1C variants on the cell cycle in vitro were determined by flow cytometry. Stability of CDKN1C was studied by western immunoblotting after inhibition of translation with cycloheximide. RESULTS: We identified the novel c.836G>[G;T] (p.Arg279Leu) mutation in a familial case of intrauterine growth retardation (IUGR) with RSS phenotype and no evidence of IMAGe. All the RSS patients inherited this mutation from their mothers (consistent with monoallelic expression from the maternal allele of the gene). A mutation of this amino acid (p.Arg279Pro) has been reported in cases of IMAGe. Functional analysis showed that Arg279Leu (RSS) did not affect the cell cycle, whereas the Arg279Pro mutation (IMAGe) led to a gain of function. Arg279Leu (RSS) led to an increased stability which could explain an increased activity of CDKN1C. CONCLUSIONS: CDKN1C mutations cause dominant maternally transmitted RSS, completing the molecular mirror with BWS. CDKN1C should be investigated in cases with family history of RSS. PMID- 24065357 TI - Absence of strong magnetic fluctuations in FeP-based systems LaFePO and Sr2ScO3FeP. AB - We report neutron inelastic scattering measurements on polycrystalline LaFePO and Sr2ScO3FeP, two members of the iron phosphide families of superconductors. No evidence is found for any magnetic fluctuations in the spectrum of either material in the energy and wavevector ranges probed. Special attention is paid to the wavevector at which spin-density-wave-like fluctuations are seen in other iron-based superconductors. We estimate that the magnetic signal, if present, is at least a factor of four (Sr2ScO3FeP) or seven (LaFePO) smaller than in the related iron arsenide and chalcogenide superconductors. These results suggest that magnetic fluctuations are not as influential on the electronic properties of the iron phosphide systems as they are in other iron-based superconductors. PMID- 24065358 TI - Process parameter optimization for hydantoinase-mediated synthesis of optically pure carbamoyl amino acids of industrial value using Pseudomonas aeruginosa resting cells. AB - Hydantoinase-mediated enzymatic synthesis of optically pure carbamoyl amino acids was investigated as an environmentally friendly, energy-efficient alternative to the otherwise energy-intensive, polluting chemical synthesis. Hydantoinase producing bacterial strain was identified as Pseudomonas aeruginosa by 16S rRNA gene sequencing and biochemical profiling using the BIOLOG Microbial Identification System. Hydantoinase activity was assessed using hydantoin analogs and 5-monosubstituted hydantoins as substrates in a colorimetric assay. The hydantoinase gene was PCR amplified using gene-specific primers and sequenced on an automated gene analyzer. Hydantoinase gene sequence of P. aeruginosa MCM B-887 revealed maximum homology of only 87 % with proven hydantoinase gene sequences in GenBank. MCM B-887 resting cells converted >99 % of substrate into N-carbamoyl amino acids under optimized condition at 42 degrees C, pH 8.0, and 100 mM substrate concentration in <120 min. Hydantoin hydrolyzing activity was D selective and included broad substrate profile of 5-methyl hydantoin, 5-phenyl hydantoin, 5-hydroxyphenyl hydantoin, o-chlorophenyl hydantoin, as well as hydantoin analogs such as allantoin, dihydrouracil, etc. MCM B-887 resting cells may thus be suitable for bio-transformations leading to the synthesis of optically pure, unnatural carbamoyl amino acids of industrial importance. PMID- 24065359 TI - Viability of calcifying bacterial formulations in fly ash for applications in building materials. AB - Evidence of bacterial involvement in precipitation of calcium carbonates has brought a revolution in the field of applied microbiology, geotechnical sciences, environmental and civil engineering with its marked success in restoration of various building materials. For applications of these calcite binder-producing bacterial cultures, different expensive carrier materials have been used but their high costs have come in the way of their successful commercialization. In the present study, we have explored the potential of cheap industrial by-product fly ash as a carrier material for bacterial cells and investigated the viability of calcifying bacterial isolates: Bacillus megaterium, Bacillus cereus, and Lysinibacillus fusiformis in fly ash carrier at varying temperatures and moisture conditions along with biomineralization efficacy of these formulations. We used laser scanning confocal microscopy to analyze the viability of bacteria by florescent dye 5-cyano-2,3-ditolyl tetrazolium chloride (CTC) along with the plate count method. Results revealed that fly ash successfully served as an effective carrier material and bacterial formulations stored at 4 degrees C provided longer shelf life than those stored at higher temperatures. Up to 10(6) cfu/g was found to sustain in all formulations at 4 degrees C compared to 10(4) 10(5) cfu/g in case of higher temperatures up to 1 year. For 4 degrees C, higher moistures (50 %) were found to provide better survivability while for higher temperatures, lower moistures (30 %) favored higher viability. The biomineralization capability of fresh and formulated bacterial cells was compared on the basis of precipitation of carbonates and it was found that carbonate precipitation efficacy of formulated bacterial cells was comparable to fresh bacterial cells. PMID- 24065360 TI - Developmental functional adaptation to high altitude: review. AB - Various approaches have been used to understand the origins of the functional traits that characterize the Andean high-altitude native. Based on the conceptual framework of developmental functional adaptation which postulates that environmental influences during the period of growth and development have long lasting effects that may be expressed during adulthood, we initiated a series of studies addressed at determining the pattern of physical growth and the contribution of growth and development to the attainment of full functional adaptation to high-altitude of low and high altitude natives living under rural and urban conditions. Current research indicate that: (a) the pattern of growth at high altitude due to limited nutritional resources, physical growth in body size is delayed but growth in lung volumes is accelerated because of hypoxic stress); (b) low-altitude male and female urban natives can attain a full functional adaptation to high altitude by exposure to high-altitude hypoxia during the period of growth and development; (c) both experimental studies on animals and comparative human studies indicate that exposure to high altitude during the period of growth and development results in the attainment of a large residual lung volume; (d) this developmentally acquired enlarged residual lung volume and its associated increase in alveolar area when combined with the increased tissue capillarization and moderate increase in red blood cells and hemoglobin concentration contributes to the successful functional adaptation of the Andean high-altitude native to hypoxia; and (e) any specific genetic traits that are related to the successful functional adaptation of Andean high-altitude natives have yet to be identified. PMID- 24065361 TI - Bone mineral density changes in lactating adolescent mothers during the first postpartum year. AB - OBJECTIVES: This study aimed to compare changes in whole body bone mineral density (wbBMD) during the first postpartum year in adolescent mothers with those of nulliparous adolescents. METHODS: The study included 21 adolescent mothers and 16 nulliparous adolescent non-indigenous Mexican women (State of Sonora) from a low income level. All mothers were assessed at 15 days (0.5 months), 3 months, and 6 months postpartum; 16 were measured at 12 months postpartum. Nulliparous adolescents were assessed in the same periods. Multiple regression models was used to assess adjusted associations of changes in wbBMD (by DPX-MD+ densitometer) with dietary calcium and physical activity assessments (estimated using pre-tested questionnaires), post menarche years, and number of breast feedings. RESULTS: At baseline, no differences were observed between nulliparous and adolescent mothers regarding age, post-menarche years, or BMD values. Changes in wbBMD of -0.56% and 0.77% were observed in mothers and nulliparous adolescents, respectively, after the first 3 months (P = 0.006). Changes in wbBMD in mothers were associated with number of breast feedings and changes in BMI. At 12 months postpartum, the BMD of adolescent mothers was similar to that of nulliparous adolescents. CONCLUSIONS: At 1 year postpartum, adolescent mothers exhibited BMD similar to those of nulliparous adolescents. This result is likely attributable to the breastfeeding practices adopted by mothers during late adolescence. PMID- 24065362 TI - Male scarcity is associated with higher prevalence of premature gestation and low birth weight births across the United States. AB - OBJECTIVES: Modern adverse birth outcomes may partially result from mechanisms evolved to evaluate environmental conditions and regulate maternal investment trade-offs. Male scarcity in a population is associated with a cluster of characteristics related to higher mating effort and lower paternal investment. We predicted that modern populations with male scarcity would have shorter gestational times and lower birth weights on average. METHODS: We compared US Centers for Disease Control and Prevention county-aggregated year 2000 birth records with US Decennial Census data. We combined these data in a path model with the degree of male scarcity and known socio-economic predictors of birth outcomes as exogenous predictors of prematurity and low birth weight, with single mother households as a proportion of families with children as a mediator (N = 450). RESULTS: Male scarcity was directly associated with higher rates of low birth weight. Male scarcity made significant indirect predictions of rates of prematurity and low birth weight, as mediated by the proportion of families headed by single mothers. Aggregate socio-economic status also indirectly predicted birth outcomes, as mediated by the proportion of families headed by single mothers, whereas the proportion African American retained both direct and indirect predictions of adverse birth outcomes. CONCLUSIONS: Male scarcity influences life history tradeoffs, with consequences for important social and public health issues such as adverse birth outcomes. PMID- 24065363 TI - Association of self-reported familial history of cardiometabolic disease with metabolic syndrome in apparently healthy urban Colombian men. AB - OBJECTIVES: Evidence about the relationship between familial history (FH) of cardiometabolic disease (CMD) and metabolic syndrome (MetS) in Latin American populations is scarce. The aim of this study was to evaluate the relationship of FH of CMD and of dyslipidemia and obesity with MetS in healthy men. METHODS: One hundred-twenty one individuals were recruited. Waist circumference and blood pressure were measured by a trained researcher using standard techniques. Glycemia and lipid profile were determined by colorimetric assays. A survey to record personal data and family antecedents in siblings, aunts/uncles, parents, and grandparents was conducted by trained interviewers. RESULTS: Individuals having three or more familial antecedents were associated with high triglycerides level even after adjusting by age, sedentarism, fat and carbohydrates intake, and alcohol consumption. After adjusting for the same variables, FH of dyslipidemia and hypertension was also associated with high triglycerides levels and elevated waist circumference, respectively. The FH of stroke was associated with high blood pressure after adjusting for the rest of familial antecedents, and with MetS in all adjustment models. DISCUSSION: the findings of association of this study together with the previous reports are evidence of the importance of hereditary component as independent predictor of cardiovascular risk factors and its clustering, as well as of possible specific association patterns between FH of CMD and MetS depending on evaluated population in terms of ethnic groups and geographic region. Further studies are required in other populations, as well as exploration of genetic markers of CMD regarding to MetS. PMID- 24065364 TI - Impact of sarcopenia on outcomes following intra-arterial therapy of hepatic malignancies. AB - BACKGROUND: Assessment of patient performance status is often subjective. Sarcopenia--measurement of muscle wasting--may be a more objective means to assess performance status and therefore mortality risk following intra-arterial therapy (IAT). METHODS: Total psoas area (TPA) was measured on cross-sectional imaging in 216 patients undergoing IAT of hepatic malignancies between 2002 and 2012. Sarcopenia was defined as TPA in the lowest sex-specific quartile. Impact of sarcopenia was assessed relative to other clinicopathological factors. RESULTS: Indications for IAT included hepatocellular carcinoma (51 %), intrahepatic cholangiocarcinoma (13 %), colorectal liver metastasis (7 %), or other metastatic disease (30 %). Median TPA among men (568 mm(2)/m(2)) was greater than women (413 mm(2)/m(2)). IAT involved conventional chemoembolization (54 %), drug-eluting beads (40 %), or yttrium-90 (6 %). Median tumor size was 5.8 cm; most patients had multiple lesions (74 %). Ninety-day mortality was 9.3 %; 3 year survival was 39 %. Factors associated with risk of death were tumor size (HR = 1.84) and Child's score (HR = 2.15) (all P < 0.05). On multivariate analysis, sarcopenia remained independently associated with increased risk of death (lowest vs. highest TPA quartile, HR = 1.84; P = 0.04). Sarcopenic patients had a 3-year survival of 28 vs. 44 % for non-sarcopenic patients. CONCLUSIONS: Sarcopenia was an independent predictor of mortality following IAT with sarcopenic patients having a twofold increased risk of death. Sarcopenia is an objective measure of frailty that can help clinical decision-making regarding IAT for hepatic malignancies. PMID- 24065365 TI - Long-term results of seton placement for fistula-in-ano in infants. AB - BACKGROUND: The present study aimed to assess the long-term results of seton placement for fistula-in-ano (FIA) in infants. METHODS: Data of patients aged <1 year who presented to our department with perianal abscess (PA) between January 2006 and February 2010 were retrospectively reviewed. Our standard initial treatment for PA was incision and drainage. Patients with systemic diseases and inflammatory bowel diseases were excluded. RESULTS: Ninety-five patients were treated for PA and/or FIA during the 5-year period, and follow-up data were available for 90 patients. The mean follow-up duration in these patients was 49.8 +/- 11.4 months, and mean age at presentation was 3.1 +/- 2.7 months. Of the 90 patients, 36 (40%) developed FIA (39 lesions) and underwent seton placement. The condition healed in a mean period of 6.3 +/- 4.0 weeks after the placement of a cutting seton. Healing of the fistula was achieved in 35 (97.2%) of 36 patients after the initial seton procedure, and one patient who showed recurrence underwent a second seton placement, resulting in successful healing of the FIA after 5 weeks. CONCLUSIONS: The long-term success of seton placement indicates that this procedure should be a treatment option for FIA in infants. PMID- 24065366 TI - Risk factors associated with 30-day postoperative readmissions in major gastrointestinal resections. AB - PURPOSE: Preventable readmissions represent a major burden on the health care system and risk stratification of patients can help direct costly resources. This study examines patient characteristics, surgical factors, and postoperative complications associated with 30-day postoperative readmissions in gastrointestinal (GI) resections. METHODS: Inpatients undergoing major GI surgery were selected from the 2011 American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database. Resections were classified into foregut, small bowel, colorectal, liver, and pancreatic using Current Procedural Terminology (CPT) codes. Postoperative complications were divided into pre- and post-discharge groups using time to complication and discharge. Univariate analysis compared patient and surgical characteristics and pre-discharge complications with 30-day unplanned readmission rates. Factors with a p value <0.1 were included in multivariate logistic regression. A p value <0.05 was considered statistically significant. RESULTS: For 42,609 patients undergoing GI resection, the overall 30-day unplanned readmission rate was 12.3 % ranging from 11.8 % for colorectal resections to 16.3 % for pancreatic resections. Major predictors of 30-day readmissions included pre-discharge major complications (odds ratio [OR] = 1.28, 95 % confidence interval [CI] 1.18-1.39, p < 0.0001), chronic steroid use (OR = 1.67, 95 % CI 1.50-1.86, p < 0.0001), operative time >=4 h (OR = 1.45, 95 % CI 1.35-1.56, p < 0.0001) and discharge to a facility other than home (OR = 1.37, 95 % CI 1.23-1.50, p < 0.0001). CONCLUSIONS: Unplanned 30-day readmissions represent a major clinical and financial concern, but some may be foreseeable and potentially modifiable. This model provides insight into factors that could inform resource utilization and postoperative care to help prevent readmissions in select GI surgical patients. PMID- 24065369 TI - Migraine predicts hypertension--a cohort study of the Finnish working-age population. AB - BACKGROUND: Migraine has been suggested to be associated with hypertension. The aim of the present 5-year prospective cohort study was to examine whether self reported migraine in 1998 predicted hypertension in 2003 in a Finnish working-age population. METHODS: This cohort study consisted of 13 454 randomly selected initially non-hypertensive working-age participants of the prospective postal survey of the Health and Social Support. A total of 13 426 responses of the initial participants were linked with the register data of the Social Insurance Institution on the special reimbursement medication for hypertension. The outcome variable, hypertension, was determined according to the survey data and the register data of the Social Insurance Institution. The statistical analysis was carried out using logistic regression. RESULTS: In a multivariate model adjusted for gender, age, occupational training, living alone, metabolic equivalent of task, body mass index and alcohol consumption, self-reported migraine predicted hypertension (odds ratio 1.39; 95% confidence interval 1.19-1.64) for the self reported and (odds ratio 1.42; 95% confidence interval 1.13-1.77) for the register data of the Social Insurance Institution. CONCLUSION: The findings may indicate a focus on hypertension screening for the working-age population with migraine. PMID- 24065368 TI - Fully covered self-expanding metal stents are effective for benign esophagogastric disruptions and strictures. AB - PURPOSE: Self-expanding fully covered metal stents (CSs) are ideal for use in benign esophagogastric disease. We reviewed our experience with CS to evaluate outcomes, to determine a role for CS in a standard treatment for benign esophageal conditions, and to compare our results with recently published studies. METHODS: We performed a retrospective chart review from 2005 to 2012. RESULTS: A total of 57 CSs were placed in 44 patients. Indications were stricture (11 patients), anastomotic leak (20), perforation (7), and tracheoesophageal fistulae (6). For GI tract disruptions, open repair or diversion was avoided in 31/33 patients (93.9 %) but required an associated drainage procedure in 22/33 (67 %) patients. Resolution does not depend on achieving radiological control with 6/26 (23 %) having evidence of a persistent leak. Benign strictures were dilated at a mean of 3.7 times prior to stenting. Adjunctive intra-mucosal steroid injections were used in 8/11 patients. Stents were removed at a mean of 33 days. At a mean of 283 days of follow-up, 6/11 (54.5 %) had symptom resolution. The most common complication was stent migration occurring in 17.5 % of patients overall. CONCLUSION: Covered stents are an effective adjunct in the management of benign upper gastrointestinal tract fistulae, leaks, perforations and benign strictures. PMID- 24065370 TI - The inability to pay for health services in Central and Eastern Europe: evidence from six countries. AB - BACKGROUND: Out-of-pocket payments for health services constitute a major financial burden for patients in Central and Eastern European (CEE) countries. Individuals who are unable to pay use different coping strategies (e.g. borrowing money or foregoing service utilization), which can have negative consequences on their health and social welfare. This article explores patients' inability to pay for outpatient and hospital services in six CEE countries: Bulgaria, Hungary, Lithuania, Poland, Romania and Ukraine. METHODS: The analysis is based on quantitative data collected in 2010 in nationally representative surveys. Two indicators of inability to pay were considered: the need to borrow money or sell assets and foregoing service utilization. Statistical analyses were applied to investigate associations between the indicators of inability to pay and individual characteristics. RESULTS: Patient payments are most common in Bulgaria, Ukraine, Romania and Lithuania and often include informal payments. Romanian and, particularly, Ukrainian patients most often face difficulties to pay for health services (with approximately 40% of Ukrainian payers borrowing money or selling assets to cover hospital payments and approximately 60% of respondents who need care foregoing services). Inability to pay mainly affects those with poor health and low incomes. CONCLUSION: Widespread patient payments constitute a major financial barrier to health service use in CEE. There is a need to formalize them where they are informal and to take measures to protect vulnerable population groups, especially those with limited possibilities to deal with payment difficulties. PMID- 24065371 TI - Preventing obesity in infants and toddlers in child care: results from a pilot randomized controlled trial. AB - Few interventions have focused on very young children for obesity prevention. This study evaluated a pilot intervention to improve the nutrition and physical activity environments of child care centers serving infants and toddlers. This randomized controlled trial took place in 32 centers in Boston, Massachusetts. The intervention aimed to improve policies and practices related to nutrition and physical activity within the center. For the outcome, observers assessed center environments using the Environment and Policy Assessment and Observation (EPAO) instrument (range 0-320 points) at baseline and the 6-month follow-up. We fit linear regression models with change in EPAO score from baseline to follow-up, controlling for potential confounders for total score, nutrition sub-score, and physical activity sub-score. Intervention centers had a mean (SD) of 98.2 (144.8) children enrolled, while control centers had 59.2 (34.5). In intervention centers, 47.5% of children were white, compared to 46.2% in controls. Fewer intervention centers had outdoor play areas on site (75 vs. 100%) but more had indoor play space (67 vs. 25%). At baseline, intervention centers had a mean (SD) EPAO score of 134.5 (7.0) points and controls had 146.8 (4.8) points. Compared with controls, intervention centers improved their EPAO scores at follow-up by 18.5 points (95% CI 0.1, 37.0; p = 0.049), chiefly through greater improvement in physical activity (12.2; 95% CI -1.6, 26.0; p = 0.075) and not nutrition (6.4; 95% CI -7.1, 19.8; p = 0.385). The pilot showed promise as an intervention to improve center environments, but future studies should include child-level outcomes. PMID- 24065372 TI - p53 pathway activation by telomere attrition in X-DC primary fibroblasts occurs in the absence of ribosome biogenesis failure and as a consequence of DNA damage. AB - BACKGROUND: Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome with high clinical heterogeneity. Various mutations have been reported in DC patients, affecting genes that code for components of H/ACA ribonucleoproteins, proteins of the telomerase complex and components of the shelterin complex. OBJECTIVES: We aim to clarify the role of ribosome biogenesis failure in senescence induction in X-DC since some studies in animal models have reported a decrease in ribosome biogenesis as a major role in the disease. METHODS: Dyskerin was depleted in normal human fibroblasts by expressing two DKC1 shRNAs. Common changes in gene expression profile between these dyskerin-depleted cells and X-DC fibroblasts were analyzed. RESULTS: Dyskerin depletion induced early activation of the p53 pathway probably secondary to ribosome biogenesis failure. However, the p53 pathway in the fibroblasts from X-DC patients was activated only after an equivalent number of passes to AD-DC fibroblasts, in which telomere attrition in each division rendered shorter telomeres than control fibroblasts. Indeed, no induction of DNA damage was observed in dyskerin-depleted fibroblasts in contrast to X-DC or AD-DC fibroblasts suggesting that DNA damage induced by telomere attrition is responsible for p53 activation in X-DC and AD-DC fibroblasts. Moreover, p53 depletion in senescent DC fibroblasts rescued their proliferative capacity and reverted the morphological changes produced after prolonged culture. CONCLUSIONS: Our data indicate that ribosome biogenesis do not seem to play an important role in dyskeratosis congenita, conversely increasing DNA damage and activation of p53 pathway triggered by telomere shortening is the main activator of cell senescence. PMID- 24065374 TI - The utility of immunohistochemistry for providing genetic information on tumors. AB - With advances in immunohistochemical technology and growing knowledge of the molecular genetics of tumors, immunohistochemistry is playing an increasingly important role in providing genetic information for tumors. Specific chromosomal translocations can be demonstrated through detection of the protein product of one of the genes involved in gene fusion (such as BCL2, cyclin D, and ALK). Some mutations can be detected by (1) aberrant localization of the protein product (such as beta-catenin and nucleophosmin), (2) abnormal accumulation of the protein product as a result of stabilization of the protein (such as p53), and (3) mutation-specific antibodies directed against the mutant protein (such as isocitrate dehydrogenase gene R132H mutation, epidermal growth factor receptor gene L858R and exon 19 deletion mutations, and BRAF gene V600E mutation). Gene deletion or loss of function can be demonstrated by the loss of immunostaining for the protein product (such as mismatch repair proteins in microsatellite unstable tumors, E-cadherin in lobular carcinoma of the breast, and INI1 in rhabdoid tumors, atypical teratoid/rhabdoid tumors, and epithelioid sarcomas). Gene amplification can be demonstrated by overexpression of the protein product (such as HER2 in breast and gastric cancers, and MDM2 or CDK4 in well differentiated/dedifferentiated liposarcomas). Viruses associated with tumors can be demonstrated directly (such as Epstein-Barr virus latent membrane protein-1 in Hodgkin lymphomas, human herpesvirus 8 in Kaposi sarcomas, and Merkel cell polyomavirus in Merkel cell carcinomas) or by a surrogate marker (such as p16 in human papillomavirus infection). In this review, examples are given to illustrate the principles and pitfalls of these applications. PMID- 24065373 TI - Object shape and orientation do not routinely influence performance during language processing. AB - The role of visual representations during language processing remains unclear: They could be activated as a necessary part of the comprehension process, or they could be less crucial and influence performance in a task-dependent manner. In the present experiments, participants read sentences about an object. The sentences implied that the object had a specific shape or orientation. They then either named a picture of that object (Experiments 1 and 3) or decided whether the object had been mentioned in the sentence (Experiment 2). Orientation information did not reliably influence performance in any of the experiments. Shape representations influenced performance most strongly when participants were asked to compare a sentence with a picture or when they were explicitly asked to use mental imagery while reading the sentences. Thus, in contrast to previous claims, implied visual information often does not contribute substantially to the comprehension process during normal reading. PMID- 24065375 TI - Predictors of high platelet reactivity during aspirin treatment in patients with type 2 diabetes. AB - BACKGROUND: Diabetes mellitus type 2 (DM2) is associated with high platelet reactivity both in patients who do not receive antiplatelet drugs and in those treated with acetylsalicylic acid (ASA). The pathomechanism of this phenomenon has not been fully understood. AIM: 1. To evaluate variability of platelet reactivity in patients with DM2 treated with oral antidiabetic drugs and receiving chronic ASA therapy. 2. To identify independent predictors of high platelet reactivity during ASA therapy in patients with DM2. METHODS: We studied 171 patients with DM2 treated with oral antidiabetic drugs and receiving long term treatment with 75 mg of ASA daily, selected among the participants of the prospective AVOCADO study. Platelet function was simultaneously evaluated using 4 methods: 1. measurement of serum thromboxane B2 (TXB2) concentration; 2. measurement of urinary 11-dehydrothromboxane B2 (11-dhTXB2) concentration; 3. VerifyNow(r) automated analyser; 4. PFA-100(r) automated analyser.High platelet reactivity was defined as at least 3 of the following criteria: 1. serum TXB2 concentration in the upper quartile;2. urinary 11-dhTXB2 concentration in the upper quartile; 3. value >= 550 aspirin reaction units (ARU) by VerifyNow(r);4. collagen-epinephrine closure time (CEPI-CT) below median of readings other than 300 s by PFA-100(r). In all patients, DM2 control was evaluated, insulin resistance was measured using HOMA-IR, and routine laboratory tests were performed, including full blood count, renal function parameters, and inflammation markers. RESULTS: Mean patient age was 67.8 years, and median duration of DM2 was 5 years. We found poor agreement between different tests of platelet function. ARU >= 550 (VerifyNow(r)) was found in 14.0% of patients, and CEPI-CT below median of readings other than 300 s (PFA-100(r)) was found in 32.8% of patients. Our criteria of high platelet reactivity were met by 9.9% of patients. In multivariate logistic regression analysis, independent predictors of high platelet reactivity despite ASA therapy included chronic heart failure, current smoking, and higher leukocyte count. CONCLUSIONS: 1. Patients with DM2 are characterised by large variability of platelet reactivity, with little agreement between various methods. 2. Smoking, chronic heart failure, and subclinical inflammation may be associated with high platelet reactivity in patients with DM2 treated with ASA. PMID- 24065376 TI - Ablation of atrioventricular nodal reentrant tachycardia: predictors of long-term success. AB - BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT) is the commonest regular supraventricular tachyarrhythmia. Ablation in the area of slow pathway (SP) has been successfully implemented in everyday clinical electrophysiological practice for more than 20 years. Although the procedure is generally regarded as effective and safe, data on long-term effects and predictors of success or failure are incomplete. AIM: To identify predictors of successful AVNRT ablation. METHODS: The study group consisted of 359 patients (105 males, mean age 51.1 +/- 16.7 years) who underwent AVNRT radiofrequency ablation using typical combined electrophysiological and anatomical approach. RESULTS: Acute success was achieved in 342 (95%) patients, including 187 (52%) with SP ablation and 155 (43%) with SP modification. Patients with SP modification were younger, had shorter AVNRT cycle length, less often had typical echo, and had more frequent isoproterenol usage after ablation. Long-term follow-up data was available for 308 patients (86% of the total study group). During the mean follow-up of 52.9 +/- 27.3 months (median 48, range 12-130 months), 22 patients experienced AVNRT recurrences (long-term efficacy 93%). These patients had less often complete SP abolition than SP modification (27% vs. 56%, p < 0.001) and typical jump (vs. no jump or multiple jumps) at baseline (74% vs. 89%, p < 0.06) than patients without recurrences. Multivariate Cox regression analysis showed that typical jump was associated with a favourable outcome (HR 5.8, 95% CI 0.44-3.1, p = 0.0089). There were no significant differences in the use of 2 or > 2 electrode approaches between patients with or without AVNRT recurrences. CONCLUSIONS: Typical jump and complete SP elimination are associated with a better outcome. A 2-electrode approach is as effective as > 2 electrode approach. The electrophysiological profile of patients in whom complete SP elimination was achieved may differ from that of patients in whom only SP modification was possible. PMID- 24065377 TI - Multidetector computed tomographic anatomy of the coronary sinus in patients with supraventricular reentrant tachycardia. AB - BACKGROUND: In a number of previous studies it has been observed that coronary sinus (CS) ostium was larger and cannulation was easier in patients with atrioventricular nodal reentrant tachycardia (AVNRT). AIM: To investigate the size and morphology of CS in AVNRT patients and compare them to those of atrioventricular reentrant tachycardia (AVRT) patients and a control group using multidetector computed tomography (MDCT), which is a non-invasive technique. METHODS: Eighteen consecutive patients with AVNRT who were scheduled for catheter ablation in our institution constituted the study population. Sixteen patients with AVRT and 16 patients without supraventricular arrhythmia who underwent MDCT for other indications comprised the control group. A conventional transthoracic echocardiography was performed to all patients. The diameter of the CS at ostium as well as at 5, 10, and 15 mm inside the CS were measured on MDCT images. The CS was also categorised according to its morphology, as to whether it had a windsock shape or a tubular shape. RESULTS: The AVNRT, AVRT and control groups were similar with regard to age, gender, body surface area and echocardiographic parameters. The size of the CS ostium was 10.9 +/- 3.0, 11.1 +/- 3.9 and 12.5 +/- 3.6 mm for the AVNRT, AVRT and control groups, respectively (p = 0.393). There was no significant difference in the size of the CS from the ostium until 15 mm into the CS between the AVNRT, AVRT and control groups. The number of patients with windsock or tubular CS morphology were also similar between the three groups. CONCLUSIONS: Contrary to previous reports, the CS size and morphology of patients with AVNRT did not differ from that of AVRT or control patients. PMID- 24065378 TI - Chemical crystallography before X-ray diffraction. PMID- 24065379 TI - Fungating mass as first presentation of advanced breast cancer. PMID- 24065380 TI - Capsule commentary on Paradies et al., 'a systematic review of the extent and measurement of healthcare provider racism'. PMID- 24065382 TI - Capsule commentary on Radin, pitfalls in hemoglobin A1c measurement: when results may be misleading. PMID- 24065381 TI - Helicobacter pylori: evidence-based review with a focus on immigrant populations. AB - Helicobacter pylori has been causally linked to a number of diseases, including peptic ulcer disease, gastric adenocarcinoma, mucosa-associated lymphoid tissue lymphoma, and dyspepsia. It is the most prevalent bacterial pathogen in humans, and while the overall prevalence in the United States is about 30 %, the distribution is heterogeneous amongst different ethnic groups. Recent immigrants from high prevalence areas such as Korea, Japan, and China bear an increased burden of its disease and complications. There is clear evidence that treatment of H. pylori resolves peptic ulcer disease, and increasing evidence for protection against development of gastric adenocarcinoma. However, H. pylori treatment failure is common and alternative regimens may be necessary. The following case-based review will highlight these issues, including the epidemiology of H. pylori in the immigrant population, an approach to dyspepsia, and the role of H. pylori in gastric adenocarcinoma. PMID- 24065383 TI - Light availability prevails over soil fertility and structure in the performance of Asian knotweeds on riverbanks: new management perspectives. AB - Asian knotweeds (Fallopia spp.) are considered one of the world's most invasive species. Restoring habitats dominated by these exotic species requires a better understanding of the importance of abiotic factors controlling the invasive knotweeds performance. We used observational data obtained on the embankment of the Isere River (France) to study the performance of Fallopia spp. under different soil, light, and disturbance conditions. On the Isere riverbanks, light intensity assessed by light quantity transmitted through canopy was the most important factor explaining the variability observed on knotweed performance expressed as above-ground biomass per square meter. Asian knotweeds were more productive under intensive light conditions. Alternatively other factors such as mowing (twice a year), soil fertility, soil texture, position on the bank or exposure to the sun had no significant effect on knotweed biomass production. We conclude that decreasing light resources, for example, by increasing competitive pressure on sites dominated by Asian knotweeds could be included in management plans to control the populations of this invasive taxon. PMID- 24065384 TI - Perspectives on disconnects between scientific information and management decisions on post-fire recovery in Western US. AB - Environmental regulations frequently mandate the use of "best available" science, but ensuring that it is used in decisions around the use and protection of natural resources is often challenging. In the Western US, this relationship between science and management is at the forefront of post-fire land management decisions. Recent fires, post-fire threats (e.g. flooding, erosion), and the role of fire in ecosystem health combine to make post-fire management highly visible and often controversial. This paper uses post-fire management to present a framework for understanding why disconnects between science and management decisions may occur. We argue that attributes of agencies, such as their political or financial incentives, can limit how effectively science is incorporated into decision-making. At the other end of the spectrum, the lack of synthesis or limited data in science can result in disconnects between science based analysis of post-fire effects and agency policy and decisions. Disconnects also occur because of the interaction between the attributes of agencies and the attributes of science, such as their different spatial and temporal scales of interest. After offering examples of these disconnects in post-fire treatment, the paper concludes with recommendations to reduce disconnects by improving monitoring, increasing synthesis of scientific findings, and directing social science research toward identifying and deepening understanding of these disconnects. PMID- 24065385 TI - The Maine Vernal Pool Mapping and Assessment Program: engaging municipal officials and private landowners in community-based citizen science. AB - The Vernal Pool Mapping and Assessment Program (VPMAP) was initiated in 2007 to create a vernal pool database as a planning tool to foster local compliance with new state vernal pool regulations. In the northeastern United States, vernal pools are seasonal wetlands that provide critical breeding habitat for a number of amphibians and invertebrates and provide important resting and foraging habitat for some rare and endangered state-listed species. Using participant observation, interviews, and focus groups, we examined the engagement of municipal officials and private landowners in VPMAP. Important outcomes of municipal and landowner engagement included mobilization of town support for proactive planning, improved awareness and understanding of vernal pools, and increased interactions between program coordinators, municipal officials, and private landowners. Challenges to municipal and landowner engagement included an inconsistency in expectations between coordinators and municipal officials and a lack of time and sufficient information for follow-up with landowners participating in VPMAP. Our study highlights the importance of developing relationships among coordinators, municipal officials, and private landowners in facilitating positive outcomes for all stakeholders and for effective resource management. We suggest an expanded citizen science model that focuses on improving two-way communication among project coordinators, municipal officials, and local citizens and places communication with private landowners on par with volunteer citizen scientist recruitment and field training. Lessons learned from this research can inform the design and implementation of citizen science projects on private land. PMID- 24065386 TI - Elastic and vibrational properties of group IV semiconductors in empirical potential modelling. AB - We have developed an interatomic potential that with a single set of parameters is able to accurately describe at the same time the elastic, vibrational and thermodynamics properties of semiconductors. The simultaneous inclusion of radial and angular forces of the interacting atom pairs (short range) together with the influence of the broken crystal symmetry when the atomic arrangement is out of equilibrium (long range) results in correct predictions of all of the phonon dispersion spectrum and mode-Gruneisen parameters of silicon and germanium. The long range interactions are taken into account up to the second nearest neighbours, to correctly influence the elastic and vibrational properties, and therefore represent only a marginal computational cost compared to the full treatment of other proposed potentials.Results of molecular dynamics simulations are compared with those of ab initio calculations, showing that when our proposed potential is used to perform the initial stages of the structural relaxation, a significant reduction of the computational time needed during the geometry optimization of density functional theory simulations is observed. PMID- 24065388 TI - Activation of proMMP-2 by U46619 occurs via involvement of p(38)MAPK-NFkappaB MT1MMP signaling pathway in pulmonary artery smooth muscle cells. AB - We investigated the mechanism by which TxA2 mimetic, U46619, activates proMMP-2 in bovine pulmonary artery smooth muscle cells. Our study showed that treatment of the cells with U46619 caused an increase in the expression and subsequently activation of proMMP-2 in the cells. Pretreatment with p(38)MAPK inhibitor, SB203580; and NF-kappaB inhibitor, Bay11-7082 inhibited the expression and activation of proMMP-2 induced by U46619. U46619 also induced increase in MT1-MMP expression, which was inhibited upon pretreatment with SB203580 and Bay11-7082. U46619 treatment to the cells stimulated p(38)MAPK activity as well as NF-kappaB activation by IkappaB-alpha phosphorylation, translocation of NF-kappaBp65 subunit from cytosol to nucleus and subsequently, by increasing its DNA-binding activity. Induction of NF-kappaB activation seems to be mediated through IKK, as transfection of cells with either IKKalpha or IKKbeta siRNA prevented U46619 induced phosphorylation of IkappaB-alpha and NF-kappaBp65 DNA-binding activity. U46619 treatment to the cells also downregulated the TIMP-2 level. Pretreatment of the cells with SB203580 and Bay11-7082 did not show any discernible change in TIMP-2 level by U46619. Overall, U46619-induced activation of proMMP-2 is mediated via involvement of p(38)MAPK-NFkappaB-MT1MMP signaling pathway with concomitant downregulation of TIMP-2 expression in bovine pulmonary artery smooth muscle cells. PMID- 24065387 TI - Rad51 expression is a useful predictive factor for the efficacy of neoadjuvant chemoradiotherapy in squamous cell carcinoma of the esophagus. AB - BACKGROUND: Neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) is beneficial in the setting of a complete pathological response. Rad51 expression affects both chemo- and radiosensitivity in many cancers; however, its role in ESCC is unclear. METHODS: Rad51 expression was investigated by immunohistochemical staining with resected specimens in 89 ESCC patients who underwent surgery without preoperative therapy. The association with Rad51 and clinicopathological factors was assessed. The expression of Rad51 was also investigated in pretreatment biopsy specimens in 39 ESCC patients who underwent surgery after NACRT and compared with the pathological response to NACRT. RESULTS: Lymph node metastasis was more frequently observed in Rad51 positive cases than negative cases (58.5 vs. 30.6%, P = 0.0168) in patients treated with surgery alone. Disease-specific survival was decreased in Rad51 positive cases compared to Rad51-negative cases (5 year survival: 79.6 vs. 59.3%, P = 0.0324). In NACRT patients, completed pathological responses were more frequently observed in Rad51-negative cases than in Rad51-positive cases (68.8 vs. 46.5%, P = 0.0171). CONCLUSIONS: Rad51 expression in ESCC was associated with lymph node metastasis and poor survival. Additionally, Rad51 expression in pretreatment biopsy specimens was a predictive factor for the response to NACRT. PMID- 24065389 TI - LPS stimulates MUC5AC expression in human biliary epithelial cells: whether there exists a possible pathway of PKC/NADPH/ROS? AB - Previous studies have shown that lipopolysaccharide (LPS) can upregulate MUC5AC in airway epithelial cells. However, the relationship and mechanism between bacterial infection and altered mucus secretion in the biliary tract remains unclear. Human biliary epithelial cells were induced by LPS, H2O2 production in the cell supernatants were detected by specific kit and expression of MUC5AC were detected by real-time PCR, Western blot, and immunohistochemistry. H2O2 production increased in a dose-dependent manner, LPS upregulate MUC5AC expression in both mRNA and protein level while specific inhibitors can reduce this high expression. Reactive oxygen species participates in the process of LPS by upregulating MUC5AC secretion. Moreover, PKC and NADPH oxidase regulate MUC5AC production in LPS-challenged human biliary epithelial cells. PMID- 24065390 TI - Knockdown of p62/sequestosome 1 attenuates autophagy and inhibits colorectal cancer cell growth. AB - p62/sequestosome-1 is a multifunctional adapter protein implicated in selective autophagy, cell signaling pathways, and tumorigenesis, and plays an important role at the crossroad between autophagy and cancer. But, the connection between autophagy and cancer is complex and in some cases contradictory. Human colorectal cancer tissues from patients were analyzed for expression of p62 and Microtubule associated protein light chain 3 (LC3, an autophagosome marker) using immunostaining, western blotting, real-time PCR, and confocal microscopy. To study the effects of p62 on autophagy and cell growth, shRNA for p62 was applied and cell growth curve was monitored in human colorectal cancer cell. In vivo experiments were done using the mouse xenograft model. We showed that up regulated expression of p62 and LC3 in colorectal cancer tissues. We also demonstrated that specifically knockdown the expression of p62 showed significantly inhibitory effects not only on autophagy activation, but also on tumor growth both in vitro and xenograft tumors model. The ectopic overexpression of p62 and autophagy activation contributes to colorectal tumorigenesis. p62 and autophagy will be therapy targets for the treatment of colorectal cancer. PMID- 24065391 TI - Evaluation of the anti-atherogenic potential of chrysin in Wistar rats. AB - Hypercholesterolemia is one of the major risk factors that precipitate coronary heart disease and atherosclerosis. Oxidative stress is believed to contribute to the pathogenesis of hypercholesterolemic atherosclerosis; hence, various antioxidant compounds are being evaluated for potential anti-atherogenic effects. In the present study, the putative anti-atherogenic and antioxidant efficacy of a flavonoid, chrysin, was evaluated in an experimental model of atherosclerosis. In male, albino Wistar rats fed an atherogenic diet for 45 days and treated with saline, significantly higher mean levels of serum lipid profile parameters (total cholesterol, triglycerides, low-density, and very low-density lipoprotein cholesterol), lower mean levels of high-density lipoprotein cholesterol and higher mean serum levels of hepatic marker enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase) were observed when compared with the levels in rats fed a control diet. In addition, significantly lower mean hepatic levels of lipoprotein lipase, 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) and non-enzymatic antioxidants (reduced glutathione, and vitamins C and E), and a significantly higher mean level of hepatic malondialdehyde (MDA) were noted in comparison to the values in control rats. In atherogenic diet-fed rats that received chrysin orally (200 mg/kg b.wt) for 15 days, starting 30 days after the start of the atherogenic diet, significantly lower mean serum levels of lipid profile parameters (except for HDL-cholesterol which was elevated), hepatic marker enzymes, and significantly higher mean hepatic levels of LPL, HMG-CoA reductase, enzymatic, and non-enzymatic antioxidants and significantly lower mean levels of hepatic MDA were noted, compared to the values in atherogenic diet-fed, saline-treated rats. Histopathological studies appeared to suggest the protective effect of chrysin on the hepatic tissue and aorta of atherosclerotic rats. These results suggest that chrysin has anti-atherogenic potential in an experimental setting. PMID- 24065392 TI - Parthenolide induces apoptosis by activating the mitochondrial and death receptor pathways and inhibits FAK-mediated cell invasion. AB - The natural product parthenolide induces apoptosis in cancer cells. However, the mechanism of apoptosis in ovarian cancer cells exposed to parthenolide is not clear. In addition, it is unclear whether parthenolide-induced apoptosis is mediated by the formation of reactive oxygen species and the depletion of GSH contents, and the effect of parthenolide on the invasion and migration of human epithelial ovarian cancer cells has not been studied. Therefore, we investigated the effects of parthenolide exposure on apoptosis, cell adhesion, and migration using the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. The results suggest that parthenolide may induce apoptotic cell death in ovarian carcinoma cell lines by activating the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The apoptotic effect of parthenolide appears to be mediated by the formation of reactive oxygen species and the depletion of GSH. Parthenolide inhibited fetal bovine serum-induced cell adhesion and migration of OVCAR-3 cells, possibly through the suppression the focal adhesion kinase dependent activation of cytoskeletal-associated components. Therefore, parthenolide might be beneficial in the treatment of epithelial ovarian adenocarcinoma and combination therapy. PMID- 24065393 TI - Insulin-like growth factor 1 opposes the effects of C-reactive protein on endothelial cell activation. AB - Emerging evidence demonstrates that high plasma C-reactive protein (CRP) levels or low plasma insulin-like growth factor 1 (IGF-1) concentrations may be separately associated with the increased risk of coronary artery disease or myocardial infarction. Interestingly, animal model studies and epidemiological investigations indicate that circulating IGF-1 and CRP levels have an inverse correlation. The present study aims to evaluate if IGF-1 can directly oppose the effects of CRP on endothelial cell (EC) activation. We found that IGF-1 rescues endothelial nitric oxide synthase activity and decreases the release of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 from ECs. We also showed that IGF-1 antagonizes the effects of CRP by activating the PI3K/Akt pathway and suppressing the JNK/c-Jun and MAPK p38/ATF2 signaling pathways, rather than inhibiting ERK1/2 activity. These findings provide evidence of the physiopathological mechanisms of endothelial activation and novel insights into the protective properties of IGF-1. PMID- 24065401 TI - Comprehensive survivorship care with cost and revenue analysis. AB - PURPOSE: The 2015 Commission on Cancer standards require that cancer survivors receive an individualized survivorship care plan (SCP). To meet this new standard, St Luke's Mountain States Tumor Institute (MSTI), with support from the National Community Cancer Centers Program, implemented a successful survivorship model. PATIENTS AND METHODS: At MSTI, the patient's SCP is prepared in the electronic health record by a registered health information technician. This document is reviewed during an appointment with a nurse practitioner and social worker. The provider's dictation is mailed to the primary care physician with the SCP. From August 2011 to Oct 2012, 118 patients with breast cancer were seen for survivorship appointments. Medical record audit and follow-up telephone call were completed to evaluate patient survivorship needs and satisfaction with the appointment. Patient accounts were reviewed for reimbursement. RESULTS: From medical record review, the most common patient concerns were weight management (35%), fatigue (30%), sexuality (27%), anxiety (23%), caregiver stress (17%), and depression (16%). Telephone calls showed high patient satisfaction and understanding. Patients rated the following statements on a Likert scale from 1 (strongly disagree) to 5 (strongly agree): I understand my treatment summary and care plan (88% strongly agree or agree), and I feel the survivorship visit met my survivorship needs (86% strongly agree or agree). At 1 month, 80% of participants were still working on wellness goals. Patient accounts analysis showed revenue covered costs. CONCLUSION: Survivorship care at MSTI meets new standards, allows for patient engagement and satisfaction, and improves care coordination. Costs are covered by reimbursement. PMID- 24065403 TI - [Role of academic medicine for innovations in development of drugs and biomedicine technology]. PMID- 24065402 TI - Antiemetic guideline consistency and incidence of chemotherapy-induced nausea and vomiting in US community oncology practice: INSPIRE Study. AB - PURPOSE: Consensus guidelines for preventing chemotherapy-induced nausea and vomiting (CINV) are variably implemented in practice. The purpose of this study was to evaluate the impact of guideline-consistent/guideline-inconsistent CINV prophylaxis (GCCP/GICP) on the incidence of no CINV after cycle 1 of highly or moderately emetogenic chemotherapy (HEC or MEC). PATIENTS AND METHODS: This prospective observational study enrolled chemotherapy-naive adult outpatients who received single-day HEC or MEC at four oncology practice networks, all using electronic health record (EHR) systems, in Georgia, Tennessee, and Florida. Results from the Multinational Association of Supportive Care in Cancer Antiemesis Tool, a validated tool to measure CINV, administered 5 to 8 days postchemotherapy, were merged with EHR data. The primary end point, no CINV, defined as no emesis and no clinically significant nausea (score < 3 on 0-10 scale), was compared between cohorts using logistic regression. RESULTS: A total of 1,295 patients were enrolled (mean age, 59.3 years; 70.0% female; 35.5% HEC). The overall prevalence of GCCP was 57.3%. When corticosteroids were prescribed on days 2 to 4 after all HEC, GCCP for HEC increased from 28.7% to 89.8%; when NK1 receptor antagonists were prescribed after all MEC, GCCP for MEC increased from 73.1% to 97.8%. Over 5 days postchemotherapy, the incidence of no CINV was significantly higher in the GCCP cohort than the GICP cohort (53.4% v 43.8%; P < .001). The adjusted odds of no CINV with GCCP was 1.31 (95% CI, 1.07 to 1.69; P = .037). CONCLUSION: Increased adherence to antiemetic guidelines could significantly reduce the incidence of CINV after HEC and MEC. PMID- 24065404 TI - [Monitoring of coagulation during treatment with direct oral anticoagulants]. PMID- 24065405 TI - [Dignity of thyroid nodules: diagnostic gain by molecular fine needle aspiration cytology]. PMID- 24065406 TI - [Mobility in old age: aspects of training in independently living older people]. PMID- 24065407 TI - [Gastrointestinal stromal tumors (GIST)]. PMID- 24065408 TI - [Rare pathogens causing pneumonia]. PMID- 24065409 TI - [Advanced and terminal heart failure in the light of new guidelines and innovative treatment options]. PMID- 24065410 TI - [Primary and secondary glomerular diseases]. PMID- 24065411 TI - [Targeted treatment of advanced lung cancer]. PMID- 24065412 TI - [Psoriatic arthritis and general recommendations for targeted therapy of spondyloarthritis]. PMID- 24065413 TI - [Alcohol-induced hepatitis]. PMID- 24065414 TI - [79-year-old woman with pelvic pain]. PMID- 24065415 TI - [BNP elevation due to a subdural hematoma - misled by a biomarker]. AB - HISTORY AND ADMISSION FINDINGS: A 73-year-old man with a mechanical aortic valve and a history of congestive heart failure was admitted to our hospital with an unspecifically reduced general condition. Physical examination was normal according to age apart from mechanic valve closure tones and a 2/6 sytolic murmur at Erb's point. INVESTIGATIONS: Inflammation markers were elevated (leukocytosis 22 100/MUl, CRP 22 mg/dl ), there was mild anemia (hemoglobin 9.7 mg/dl) and digitoxin blood level was increased to 56 MUg/l (therapeutic range 10-30 MUg/l). Because NT-proBNP was highly elevated, further diagnostics focused on cardiac causes of BNP elevation despite missing clinical symptoms. Transesophageal echocardiography was inconspicuous and blood cultures were negative. Therefore an infection of unknown origin or an emerging endocarditis were presumed. TREATMENT AND COURSE: Pragmatic treatment with antibiotics and diuretics as well as discontinuation of digitoxin led to normalization of leukocytes, CRP and digitoxin levels. But the patient's general condition deteriorated further, NT proBNP rose to 37731 pg/ml and the patient became disoriented. On thorough questioning the patient's relatives stated that he had fallen 6 weeks previously. Computed tomography then revealed a large chronic subdural hematoma which had caused the NT-proBNP elevation. The patient was operated successful. CONCLUSION: In patients with elevated BNP and atypical symptoms neurological causes should be considered. PMID- 24065416 TI - [Levamethadone as substitution treatment of opioid-dependent patients]. PMID- 24065417 TI - The impact of skin grafting on the quality of life and self-esteem of patients with venous leg ulcers. AB - BACKGROUND: The assessment of health-related quality of life in patients with venous leg ulcers provides important information for clinical decision making, evaluation of therapeutic benefits, and prediction of survival probabilities. METHODS: Health-related quality of life and self-esteem were assessed using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) and the Rosenberg self-esteem (RSE) scale, respectively, in patients with venous leg ulcers treated with split-thickness skin grafts. One hundred patients with venous leg ulcers and indication for skin grafting were divided into two groups of 50 patients each: the control group (patients who received conservative treatment) and surgery group (patients who received split-thickness skin grafts). RESULTS: Patients in the surgery group reported significantly higher SF-36 scores (better health status) than controls one month after surgery, as well as 90 and 180 days postoperatively (p < 0.002). The mean total RSE score was significantly lower (indicating higher self-esteem) in the surgery group (mean RSE score, 17.54) than in the control group (mean RSE score, 24.22). CONCLUSIONS: Split-thickness skin grafting resulted in better health-related quality of life and self-esteem in patients with venous leg ulcers than did compression therapy with Unna's boot. PMID- 24065418 TI - Evaluating the incidence, clinical significance and predictors for vocal cord palsy and incidental laryngopharyngeal conditions before elective thyroidectomy: is there a case for routine laryngoscopic examination? AB - BACKGROUND: Routine preoperative laryngeal examination remains controversial. We aimed to assess the utility of preoperative routine flexible laryngoscopy (FL) by looking at the incidence, clinical significance and predictors for preoperative vocal cord paresis (VCP) and incidental laryngopharyngeal conditions (LPC) in our consecutive cohort. METHODS: A total of 302 patients underwent laryngeal examination by an independent otorhinolaryngologist and were specifically asked about voice/swallowing symptoms suggestive of VCP 1 day before surgery. As well as vocal cord (VC) mobility, the naso-pharynx and larynx were examined using FL. Any VCP and/or LPC was recorded. VCP was defined as reduced or absent movement in one or more VC. An LPC was considered clinically significant if the ensuing thyroidectomy was changed or deferred. RESULTS: Seven (2.3 %) patients had preoperative VCP, while an additional seven patients had an incidental LPC. Of the seven VCPs, five were caused by previous thyroidectomy, while two were caused by a benign goitre. The incidence of asymptomatic VCP in a previously non operated cohort was 1/245 (0.41 %). Voice/swallowing symptoms (p = 0.033) and previous thyroidectomy (p < 0.001) were the two significant predictors for VCP. The seven incidental LPCs were vallecular cyst (n = 1), VC scar and polyp (n = 2), nasopharyngeal cyst and polyp (n = 3) and redundant arytenoid mucosa (n = 1); however, as they were benign, all seven patients proceeded to thyroidectomy as planned. CONCLUSIONS: Given the low incidence (0.41 %) of asymptomatic VCP in a previously non-operated cohort and that none of the seven LPCs were considered clinically significant, routine preoperative laryngoscopic examination should be reserved for those with previous thyroidectomy and/or voice/swallowing symptoms. PMID- 24065419 TI - Backbone 1H, 13C and 15N assignments of yeast Ump1, an intrinsically disordered protein that functions as a proteasome assembly chaperone. AB - Eukaryotic proteasome assembly is a highly organized process mediated by several proteasome-specific chaperones, which interact with proteasome assembly intermediates. In yeast, Ump1 and Pba1-4 have been identified as assembly chaperones that are dedicated to the formation of the proteasome 20S catalytic core complex. The crystal structures of Pba chaperones have been reported previously, but no detailed information has been provided for the structure of Ump1. Thus, to better understand the mechanisms underlying Ump1-mediated proteasome assembly, we characterized the conformation of Ump1 in solution using NMR. Backbone chemical shift data indicated that Ump1 is an intrinsically unstructured protein and largely devoid of secondary structural elements. PMID- 24065420 TI - Structure and function of large arteries in hypertension in relation to oxidative stress markers. AB - BACKGROUND: The relationship between hypertension and oxidative stress remains unexplained. Nevertheless, it is well established that reactive oxygen species have an influence on the arterial wall, endothelial function and therefore determine blood pressure. AIM: The evaluation of selected oxidative stress markers in hypertensive patients and an assessment of the relationship between oxidative stress markers and the arterial structure and function. We also aimed to investigate whether the influence of oxidative stress on remodelling of arteries, their structural and functional changes is independent of hypertension or is related to hypertension. METHODS: Altogether 217 subjects (114 female, 103 male) were enrolled from hypertensive families. The mean age was 45.5 +/- 16 years, and the group included 155 hypertensives. In every subject, the pulse wave velocity and intima-media thickness (IMT) in carotid arteries were measured as well as selected oxidative stress markers such as asymmetric dimethylarginin (ADMA), symmetric dimethylarginin (SDMA), advanced oxidation protein products (AOPP) and oxidised low density lipoproteins (ox-LDL). RESULTS: The results of multivariate analysis show that in hypertensive patients: the ADMA level increased with increasing peripheral pulse pressure (b = 0.003; p < 0.001), and AOPP was related to higher carotid IMT (b = 0.91; p = 0.036). In normotensive subjects, the following associations were found: between ADMA and central pulse pressure (b = 0.006; p = 0.008), between SDMA and the peripheral augmentation index (b = -0.03; p = 0.014), between AOPP and the peripheral augmentation index (b = 0.011; p = 0.04), and between ox-LDL/LDL ratio and the peripheral augmentation index (b = -0.025; p = 0.004). The SDMA/ADMA ratio was associated with estimated glomerular filtration rate in both groups (b = -0.0061; p < 0.0001 and b = -0.005; p < 0.017, respectively). In hypertensives, we observed a relation with peripheral pulse pressure (b = -0.0067; p = 0.0143). Moreover, in normotensives there was an association between the SDMA/ADMA ratio and uric acid (b = 1.3629; p = 0.046). CONCLUSIONS: We found that the influence of oxidative stress on the structure and function of large arteries was independent of hypertension. Therefore oxidative stress may play a significant role in the development of arterial stiffness. Higher oxidative stress is associated with more advanced arterial remodelling in hypertension. PMID- 24065421 TI - Effects of six-week cardiac rehabilitation and exercise on adiponectin in patients with acute coronary syndrome. AB - BACKGROUND: Increased adiponectin is a result of an anti-arteriosclerotic effect and is related to the prevention of arteriosclerosis. However, it is uncertain whether cardiac rehabilitation and exercise (CRE) increase adiponectin in patients after acute coronary syndrome (ACS). AIM: To assess the effects of CRE intervention on adiponectin in patients after ACS. METHODS: Forty four patients participated in a cardiac rehabilitation programme after receiving percutaneous coronary intervention. The participants were divided into either an intervention (CRE) or a control (CON) group. Assessments were made at baseline and six weeks after the intervention for adiponectin, interleukin-6 (IL-6), tumour necrosis factor-a (TNF-a); high sensitivity C-reactive protein (hs-CRP), waist-to-hip ratio (WHR), and exercise duration. RESULTS: After six weeks of exercise training, adiponectin significantly increased in both CRE and CON (p < 0.001 and p = 0.009, respectively). Adiponectin showed a significantly greater increase in CRE than in CON (p = 0.032). Significant differences were not observed in IL-6, TNF-a, and hs-CRP between the groups. However, VO(2max) and exercise duration significantly increased in CRE (p < 0.001). Significant increases in VO(2max) and exercise duration were also observed in CRE but not in CON (p < 0.001). WHR significantly decreased in CRE, with no significant change in CON (p < 0.05). The difference in adiponectin between the groups showed a significantly inverse relationship with the difference in WHR (R2 = -0.376, p = 0.034). CONCLUSIONS: Adiponectin and cardiopulmonary fitness were significantly increased in CRE after six weeks of intervention. Although reductions in inflammatory markers were not observed, a significant inverse correlation was observed between the changes in adiponectin and WHR in CRE. Therefore, six weeks of short-term CRE intervention had a significant anti-inflammatory effect. PMID- 24065422 TI - Association of red blood cell distribution width with plasma lipids in a general population of unselected outpatients. AB - BACKGROUND AND AIM: Increased values of red blood cell distribution width (RDW) are frequent in patients suffering from cardiovascular disorders, and are associated with traditional or less conventional risk factors. Nevertheless, limited and controversial information exists on the association between anisocytosis and plasma lipids. METHODS: We performed a retrospective search to retrieve test results of RDW and plasma lipids of unselected outpatients aged 18 years or older referred for routine testing over a six-month period. No restrictive inclusion or exclusion criteria were applied for extracting data of total cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, total to HDL-cholesterol ratio (COL/HDL) and atherogenic index of plasma (AIP). Cumulative results were retrieved for 4,874 outpatients (2,150 men, 2,724 women). RESULTS: A significantly higher median RDW was found in females than in males (13.2 vs. 13.1; p < 0.01). After stratification of the study population into RDW quartiles, significant differences were observed in all parameters, except triglycerides and COL/HDL in men. RDW was negatively correlated with haemoglobin and mean corpuscular volume (MCV), and positively associated with age. After comparison of lipid values across RDW quartiles by multivariate logistic regression adjusted for age, haemoglobin and MCV, the RDW was negatively associated with HDL-cholesterol (OR 3.20 in females and OR 1.67 in males), and positively associated with AIP (1.53 in females and 1.43 in males), hypertriglyceridaemia (OR 1.66) and COL/HDL (OR 1.28) in women. CONCLUSIONS: Higher RDW is associated with a globally unfavourable lipid profile, especially in women. PMID- 24065423 TI - The effect of leukocyte reduction filters on inflammatory mediator release during coronary artery bypass grafting. AB - BACKGROUND: Extracorporeal circulation used during coronary artery bypass grafting triggers systemic inflammatory response with neutrophil activation which adversely affects ischaemic/reperfused myocardium. One method of myocardial protection during cardiac surgery is the use of blood cardioplegia. Its protective effect is related to cardiac cooling and metabolism reduction, oxygen supply from erythrocytes, and reactive oxygen species scavenging. However, blood cardioplegia is also associated with myocardial damage induced by undesirable morphotic blood elements. AIM: To evaluate the effect of the use of leukocyte reduction filters on the activity of polymorphonuclear neutrophils (PMN) in patients undergoing surgical myocardial revascularisation. PMN activity was evaluated based on measurements of plasma activity of granulocyte enzymes, lysozyme and beta-glucuronidase. METHODS: We studied 40 patients who underwent myocardial revascularisation using extracorporeal circulation. Patients were randomly assigned to two equal groups: in Group I, blood cardioplegia was administered using leukocyte reduction filters, and in Group II, leukocyte reduction filters were not used for blood cardioplegia. Measurements were performed in plasma of arterial and coronary sinus blood samples collected before aortic clamping, immediately after unclamping, and after 25 min of reperfusion. In addition, blood cardioplegic solution samples were collected in Group I from the lines proximal and distal to the filter during first and last administration. Plasma levels of lysozyme and beta-glucuronidase were determined using previously described methods. RESULTS: We found a significant decrease in PMN count in filtered blood cardioplegic solution during its first administration (0.27 +/- 0.07 G/L) compared to samples collected before filter passage (1.73 +/- 0.049 G/L). Also during last administration, PMN count in filtered blood cardioplegic solution was decreased compared to samples collected before filter passage (0.66 +/- 0.35 G/L vs. 3.64 +/- 1.14 G/L, respectively). Significantly lower (p < 0.02) plasma beta-glucuronidase levels were found in arterial blood samples in Group I compared to Group II (5.59 +/- 1.63 MUg/mL immediately after aortic unclamping and 6.59 +/- 1.98 MUg/mL after 25 min of reperfusion in Group I vs. 10.19 +/- 2.66 and 12.83 +/- 1.88 MUg/mL, respectively, in Group II). Beta-glucuronidase levels in coronary sinus blood samples collected after aortic unclamping and at the end of reperfusion were significantly higher in Group II compared to Group I (p < 0.04). In Group I, plasma lysozyme levels in arterial and venous blood samples did not show significant changes during the surgery. In contrast, plasma lysozyme level in coronary sinus blood samples at the end of reperfusion in Group II was significantly higher compared to that in pre-clamping samples (p < 0.014). CONCLUSIONS: With the use of leukocyte reduction filters, we found significantly lower beta-glucuronidase levels in arterial and coronary sinus blood samples. These findings seem to confirm reduced PMN activation and/or reduced myocardial infiltration by activated PMN. Plasma levels of lysozyme, a characteristic product of PMN degranulation, did not show significant differences between the study groups. PMID- 24065424 TI - [Heart failure as an independent prognostic factor for endovascular method of abdominal aortic aneurysm treatment]. AB - Endovascular aneurysm repair (EVAR) has been accepted as an alternative to traditional open surgery in selected patients. Now it is a widely accepted standard. In case of contraindications for open repair, after accomplishing including criteria for EVAR, the patient can be treated by this method. Despite the minimally invasiveness of this treatment, several complications may occur during or after EVAR. Complications arise from the limitations of the method and improper patient selection. We report a case of patient with heart failure and complications after EVAR. PMID- 24065425 TI - [Clinical utility of computed tomography in diagnosing sinus venosus atrial septal defect]. AB - We present a case of 51-year-old patient after surgical closure of atrial septal defect several years ago. Enlarged right ventricle, right atrium and pulmonary hypertension were found on routine transthoracic echocardiography. Transesophageal echocardiography revealed sinus venosus atrial septal defect. Partial anomalous pulmonary venous drainage was suspected. Only the computed tomography with contrast agent let us establish final diagnosis. PMID- 24065426 TI - Early neurological complications after transcatheter closure of atrial septal defect with nitinol wire mesh occluder. AB - Atrial septal defect (ASD) was closed percutaneously in an 18-year-old boy with a 27 mm nitinol wire mesh occluder according to standard procedures. Three hours after the procedure, he presented anxiety attacks, aggression, a vacant stare and a verbal/speaking disorder. Small ischaemic stroke localised in the right temporal/parietal region of the central nervous system was confirmed by computed tomography examination. Activated partial thromboplastin time was then 54 s despite continuous heparin infusion. Heparin dose was increased and symptomatic treatment was introduced (mannitol, furosemide, propofol, haloperidol). The next day, all symptoms disappeared. He remained in good clinical condition, without neurological disorders 1.5 months after the procedure. Complications related to transcatheter ASD closure still exist despite the fulfillment of standard procedural criteria. Frequent coagulogical examinations during and after the procedure are necessary. Close observation and follow-up of treated patients is mandatory. PMID- 24065427 TI - Investigating hypokalaemia. PMID- 24065428 TI - Testicular germ cell tumours. PMID- 24065429 TI - Female genital mutilation/cutting. PMID- 24065430 TI - US House passes bill that would defund Affordable Care Act. PMID- 24065431 TI - Private provider clarifies its position on Bournemouth and Poole hospitals merger. PMID- 24065432 TI - Doctors plan to relaunch smartphone app after being cleared of plagiarism. PMID- 24065433 TI - Bad medicine: monitoring patients' drugs. PMID- 24065434 TI - BMA appeals for release of Canadian doctor held in Egypt. PMID- 24065435 TI - GMC drops cases against doctors who worked at Stafford Hospital. PMID- 24065437 TI - MSM and drug use: A latent class analysis of drug use and related sexual risk behaviors. AB - This study examined patterns of drug use among gay men and other men who have sex with men (MSM) to identify sub-categories of men whose drug use and sexual behavior place them at especially high risk for HIV. A latent class analysis of a sample of MSM yielded a four-class model with two distinct high drug use sub groups: one whose drug use concentrated on "sex-drugs" (SDU); and a distinct polydrug use class that showed higher probabilities of using all other drugs assessed. Comparative follow-up analyses indicated the SDU group was also more likely to engage in particular potentially high-risk sexual behaviors, be older, and to be HIV positive. Implications of distinguishing between patterns of drug use for HIV-risk prevention efforts with MSM are discussed. PMID- 24065436 TI - Peer social support is associated with recent HIV testing among young black men who have sex with men. AB - Resiliency factors such as social support have been associated with more frequent HIV testing among MSM. We examined the association between social support and delayed HIV testing in the context of structural discrimination and individual factors among young Black MSM. We combined two independent cross-sectional samples recruited 1 year apart from a venue-based, modified time-location sampling study of young Black MSM aged 18-29 years in the US South. Our subsample (N = 813) was men who self-reported not being HIV positive and who indicated they had one or more male sex partners in the past 2 months. Using a social epidemiology framework we estimated associations of structural (racism and homophobia), social (social support from other Black MSM friends) and individual factors with delayed HIV testing (>6 months ago) using logistic regression. Bivariate analyses demonstrated that individual level variables as well as experiences of racism (OR 1.20, 95% CI 1.02-1.41) and homophobia (OR 1.49, 95 % CI 1.02-2.17) were associated with higher risk of delayed HIV testing. Receiving social support from other Black MSM friends was associated with lower risk of delayed HIV testing (OR 0.80, 95 % CI 0.67-0.95). In multivariable models, social support remained significantly associated with lower risk of delayed HIV testing after inclusion of structural and individual level variables. Social support has a positive and robust association with HIV testing among young Black MSM. Whether community building and development of resiliency factors can overcome structural, social, and individual-level barriers to HIV prevention and care for young Black MSM warrants further study. PMID- 24065439 TI - Genetic risk score does not predict the outcome of obesity surgery. AB - BACKGROUND: We evaluated the benefit of using combined genetic risk score (GRS) of known single nucleotide polymorphisms (SNPs) for body mass index (BMI) and waist/hip ratio (WHR) in the prediction of weight loss and weight regain after obesity surgery. METHODS: A total of 163 consecutive morbidly obese individuals undergoing Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) in a single bariatric center in Finland were recruited. Fasting blood samples were drawn after 12 h of fasting before and 1 year after bariatric operation. Data for weight regain and medication were collected with a questionnaire after 3.1 +/- 2.7 years (mean +/- SD) follow-up. Nonalcoholic steatohepatitis (NASH) was diagnosed with liver histology. Twenty BMI- and 13 WHR-related SNPs were genotyped. Linear regression was used to identify factors predicting weight loss and weight regain. RESULTS: Lower baseline BMI predicted greater decline in BMI (p = 0.0005) and excess weight loss (EWL) (p = 0.009). In the multiple linear regression analysis age and BMI, explained the variance of EWL during the first year while GRS, sex, fasting plasma glucose, serum insulin and NASH diagnosis did not have any effect. None of the baseline clinical variables explained BMI regain. The combined GRS did not associate with weight or BMI at baseline, with 1 year changes or with weight regain between 1 year and an average of 3.1 years follow-up. CONCLUSIONS: In our study, we found that the genotype risk score does not predict weight loss after obesity surgery while lower baseline BMI predicted the greater weight loss. PMID- 24065440 TI - Predominant gray matter volume loss in patients with end-stage renal disease: a voxel-based morphometry study. AB - To investigate the pattern of brain volume changes in patients with end-stage renal disease (ESRD) using voxel-based morphometry (VBM) and correlation with clinical and neuropsychological (NP) tests. Fifty seven ESRD patients with no anatomical abnormalities in conventional magnetic resonance imaging [24 patients with abnormal NP scores, 16 male, 39 +/- 12 years; 33 patients with normal NP scores, 23 male, 35 +/- 9.7 years] and 22 age- and gender-matched healthy controls (14 male, 36 +/- 10.1 years) were recruited in this study. Results from VBM analysis were analyzed with ANOVA test among 3 groups (controls, minimal nephro-encephalopathy group, non-nephro-encephalopathy group). Multiple linear regression analysis was used to investigate the effect of serum urea and creatinine, and dialysis duration on the brain volumes in ESRD patients. Correlation analysis was performed to investigate the association between NP scores with the brain volumes in ESRD patients. Compared with healthy controls, ESRD patients showed diffusely decreased gray matter volume that further decreased in the presence of encephalopathy. Multiple linear regression results showed that serum urea was negatively associated with changes in gray matter volume in many regions, while dialysis duration was negatively associated with some white matter volume changes (All P < 0.05, AlphaSim correction). NP scores correlated with some decreased gray matter volume in ESRD patients (All P < 0.05, AlphaSim correction). No correlation was found between white matter volume and any NP test scores in ESRD patients. This study found predominantly decreased gray matter volume in ESRD patients, which was associated with neurocognitive dysfunction. Serum urea level may be a risk factor for decreased gray matter in ESRD patients. PMID- 24065441 TI - Magnetic interactions in exchange-coupled yet unbiased IrMn/NiCu bilayers. AB - This paper reports experimental and model magnetization results obtained on exchange-coupled ferromagnet/antiferromagnet (FM/AF) bilayers that show zero net bias. The coercivity of the films, either irradiated with He or implanted with Ge ions at 40 keV, varies significantly with the fluence used. We employed the remanence plots technique in order to estimate the nature of the interactions present and check if there exists a correlation between their type and the coercivity variations. The analysis of the remanence plots through numerical simulations based on the Landau-Lifshitz-Gilbert equation demonstrated that outcomes of interactions within the FM layer could be distinguished from those coming from coupling at the FM/AF interface and that demagnetizing interaction effects could be achieved without the presence of dipolar interactions. Our findings indicate that such experiments could give selective information on modifications caused by a post-deposition treatment in each layer of the film. PMID- 24065442 TI - Clinical and procedural characteristics associated with higher radiation exposure during percutaneous coronary interventions and coronary angiography. AB - BACKGROUND: We aim to study the clinical and procedural characteristics associated with higher radiation exposure in patients undergoing percutaneous coronary interventions (PCIs) and coronary angiography. METHODS AND RESULTS: Our present study included all coronary angiography and PCI procedures in 5 PCI centers in the Western part of Sweden, between January 1, 2008, and January 19, 2012. The radiation exposure and clinical data were collected prospectively in these 5 PCI centers in Sweden as part of the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). A prediction model was made for the radiation exposure (dose-area product) expressed in Gy.cm(2). A total of 20 669 procedures were included in the present study, consisting of 9850 PCI and 10 819 coronary angiography procedures. In multivariable analyses, body mass index (beta=1.04; confidence interval [CI], 1.04-1.04; P<0.001); history of coronary artery bypass graft surgery (beta=1.32; CI, 1.28-1.32; P<0.001); 2, 3, or 4 treated lesions (2 treated lesions: beta=1.95; CI, 1.84-2.03; P<0.001; 3 treated lesions: beta=2.34; CI, 2.16-2.53; P<0.001; and 4 treated lesions: beta=2.83; CI, 2.53-3.16; P<0.001); and chronic total occlusion lesions (beta=1.39; CI, 1.31-1.48; P<0.001) were associated with the highest radiation exposure. After adjusting for procedural complexity, radial access route was not associated with increased radiation exposure (beta=1.00; CI, 0.98-1.03; P=0.67). CONCLUSIONS: In the largest study population to assess radiation exposure, we found that high body mass index, history of coronary artery bypass graft surgery, number of treated lesions, and chronic total occlusions were associated with the highest patient radiation exposure. Radial access site was not associated with higher radiation exposure when compared with femoral approach. PMID- 24065443 TI - Effect on platelet reactivity from a prasugrel loading dose after a clopidogrel loading dose compared with a prasugrel loading dose alone: Transferring From Clopidogrel Loading Dose to Prasugrel Loading Dose in Acute Coronary Syndrome Patients (TRIPLET): a randomized controlled trial. AB - BACKGROUND: Adding a prasugrel loading dose (LD) to a clopidogrel LD could be desirable because clopidogrel may fail to provide adequate levels of platelet inhibition in patients with acute coronary syndrome undergoing percutaneous coronary intervention. METHODS AND RESULTS: The pharmacodynamic response of prasugrel 60 mg ld alone was compared with prasugrel 60 mg or 30 mg added 24 hours to clopidogrel 600 mg in Transferring From Clopidogrel Loading Dose To Prasugrel Loading Dose In Acute Coronary Syndrome Patients study: a multicenter, randomized, double-blind, double-dummy, 3-arm, parallel, active-comparator controlled study. Two hundred eighty-two patients were randomized to 3 LD strategies: placebo plus prasugrel 60 mg, clopidogrel 600 mg plus prasugrel 60 mg, or clopidogrel 600 mg plus prasugrel 30 mg. Platelet function was assessed using VerifyNow P2Y12 Reaction Units (PRU) immediately before prasugrel LD, and 2, 6, 24, and 72 hours after prasugrel LD in 149 patients with evaluable platelet function studies. At 6 hours after the prasugrel 60 mg LD, the least squares mean (95% confidence interval) difference between placebo/prasugrel 60 mg and clopidogrel 600 mg/prasugrel 60 mg (primary outcome) was 22.2 (-11.0 to 55.5; P=0.19; least squares mean PRU 57.9 versus 35.6, respectively). For clopidogrel 600 mg/prasugrel 30 mg (least squares mean PRU, 53.9), the difference was 3.9 ( 28.2 to 36.1; P=0.81) versus placebo/prasugrel 60 mg. No significant differences in PRU were observed at any time point across the 3 groups. There were few bleeding events observed regardless of treatment. CONCLUSIONS: Platelet reactivity with prasugrel 60 mg LD added to clopidogrel 600 mg LD was not significantly different compared with prasugrel 60 mg LD alone in acute coronary syndrome patients undergoing percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01115738. PMID- 24065444 TI - Risk of coronary artery compression among patients referred for transcatheter pulmonary valve implantation: a multicenter experience. AB - BACKGROUND: The Melody transcatheter pulmonary valve (TPV) was approved for implantation in obstructed right ventricular outflow tract conduits in 2010 after a multicenter trial demonstrating improvements in conduit obstruction, regurgitation, and right ventricular pressure. A recognized risk and contraindication to TPV implantation is the demonstration of coronary artery (CA) compression during balloon angioplasty or stent placement in the overlying conduit. This study is the first to characterize the risk of CA compression in this population. METHODS AND RESULTS: From 2007 to 2012, 404 patients underwent 407 catheterizations for potential TPV implantation (median age, 18 years) at 4 centers. Three hundred forty-three patients (85%) underwent valve implantation. Twenty-one patients (5%) had evidence of CA compression with simultaneous right ventricular outflow tract angioplasty and CA angiography. Sixty-eight patients (17%) had abnormal CA anatomy. Fifteen of 21 (71%) patients with CA compression had abnormal CA anatomy. Eight patients with tetralogy of Fallot and 7 patients with transposition of the great arteries demonstrated compression. Of the 34 patients with tetralogy of Fallot and abnormal CA, 7 (21%) demonstrated CA compression. CONCLUSIONS: CA compression following TPV implantation can be catastrophic. CA compression was observed in 5% of patients during test balloon angioplasty. No patients in this study developed clinically apparent CA compression after TPV implantation. CA compression was significantly associated with the presence of abnormal CA anatomy, especially in patients with tetralogy of Fallot or transposition of the great arteries. Preimplantation coronary angiography with simultaneous test angioplasty is an important step to evaluate for the presence of CA compression during TPV implantation. PMID- 24065445 TI - Excimer laser-assisted removal of embedded inferior vena cava filters: a single center prospective study. AB - BACKGROUND: Although chronically implanted inferior vena cava filters may result in filter-related morbidity, there is currently no routine option for removing such filters when they become firmly embedded along the vena cava endothelium. METHODS AND RESULTS: During a 3-year period, 100 consecutive patients were prospectively enrolled in a single-center study. There were 42 men and 58 women (mean age, 46 years; limits, 18-76 years). Retrieval indications included filter related acute inferior vena cava thrombosis, chronic inferior vena cava occlusion, and pain from retroperitoneal or bowel penetration. Filter retrieval was also performed to prevent risks from prolonged implantation and to potentially eliminate the need for lifelong anticoagulation. After standard methods failed, photothermal tissue ablation was attempted with a laser sheath powered by a 308-nm xenon chloride excimer laser. Applied forces were recorded with a digital tension meter before and during laser activation. Laser-assisted retrieval was successful in 98.0% (95% confidence interval [CI], 93.0%-99.8%) with mean implantation of 855 days (limits, 37-6663 days; >18 years). The following filter types were encountered in this study: Gunther-Tulip (n=34), Celect (n=12), Option (n=17), Optease (n=20, 1 failure), TrapEase (n=6, 1 failure), Simon-Nitinol (n=1), 12F Stainless Steel Greenfield (n=4), and Titanium Greenfield (n=6). The average force during failed standard retrievals was 7.2 versus 4.6 pounds during laser-assisted retrievals (P<0.0001). The major complication rate was 3.0% (95% CI, 0.6%-8.5%), the minor complication rate was 7.0% (95% CI, 0.3%-13.9%), and there were 4 adverse events (2 coagulopathic hemorrhages, 1 renal infarction, and 1 cholecystitis; 4.0%; 95% CI, 1.1%-9.9%) at mean follow-up of 500 days (limits, 84-1079 days). Scar tissue ablation was histologically confirmed in 96.0% (95% CI, 89.9%-98.9%). Successful retrieval allowed cessation of anticoagulation in 30 of 30 (100%) patients and alleviated morbidity in 23 of 24 patients (96%). CONCLUSIONS: Excimer laser-assisted removal is effective in removing embedded inferior vena cava filters refractory to standard retrieval and high force. This method can be safely used to prevent and alleviate filter-related morbidity. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01158482. PMID- 24065446 TI - Sex-related differences in outcomes after transcatheter aortic valve implantation: a systematic review and meta-analysis. AB - BACKGROUND: There were considerable discrepancies with regard to sex-related differences in complications and prognosis after transcatheter aortic valve implantation. METHODS AND RESULTS: The Cochrane library and PubMed online databases were searched. Articles reporting sex-specific post-transcatheter aortic valve implantation complications and mortality were identified. Two authors selected studies and extracted data independently. Random- and fixed effects models were used depending on between-study heterogeneity. There were 27 articles, a total of 9118 patients, enrolled in our systematic review and meta analysis, including 4176 men and 4942 women. Pooled analyses suggested considerable sex-related differences in complications and early as well as midterm outcomes after transcatheter aortic valve implantation. The difference in the risk for heart block requiring permanent pacemaker implantation was noted to be significant only in the subgroup of the CoreValve-dominating studies (pooled risk ratio [RR, men versus women], 1.29; 95% confidence interval [CI], 1.13 1.47). Although men had significantly lower risks for major/life-threatening bleeding (pooled RR, 0.81; 95% CI, 0.68-0.96) and major vascular complications (pooled RR, 0.49; 95% CI, 0.37-0.66), they had poorer prognosis. In fact, male sex was associated with significantly higher risks for deaths at both 30 days (RR, 1.37; 95% CI, 1.07-1.76) and 1 year (RR, 1.30; 95% CI, 1.14-1.49). CONCLUSIONS: Although men had lower risks for major/life-threatening bleeding and major vascular complications after transcatheter aortic valve implantation, they had less favorable short-term and midterm survival. PMID- 24065447 TI - Increased thin-cap neoatheroma and periprocedural myocardial infarction in drug eluting stent restenosis: multimodality intravascular imaging of drug-eluting and bare-metal stents. AB - BACKGROUND: Re-endothelialization is delayed after drug-eluting stent (DES) implantation. In this setting, neointima is more prone to become lipid laden and develop neoatherosclerosis (NA), potentially increasing plaque vulnerability. METHODS AND RESULTS: Optical coherence tomography and near-infrared spectroscopy with intravascular ultrasound were used to characterize NA in 65 (51 DES and 14 bare-metal stents) consecutive symptomatic patients with in-stent restenosis. Median duration poststent implantation was 33 months. Optical coherence tomography-verified NA was observed in 40 stents with in-stent restenosis (62%), was more prevalent in DES than bare-metal stents (68% versus 36%; P=0.02), and demonstrated significantly higher prevalence of thin-cap neoatheroma (47% versus 7%; P=0.01) in DES. Near-infrared spectroscopy assessment demonstrated that the total lipid core burden index (34 [interquartile range, 12-92] versus 9 [interquartile range, 0-32]; P<0.001) and the density of lipid core burden index (lipid core burden index/4 mm, 144 [interquartile range, 60-285] versus 26 [interquartile range, 0-86]; P<0.001) were higher in DES compared with bare-metal stents. Topographically, NA was classified as I (thin-cap NA), II (thick-cap NA), and III (peri-strut NA). Type I thin-cap neoatheroma was more common in DES (20% versus 3%; P=0.01) and in areas of the stented segment without significant in stent restenosis (71%). Periprocedural myocardial infarction occurred only in DES (11 versus 0; P=0.05), of which 6 (55%) could be attributed to segments with >70% in-stent restenosis. By logistic regression, prior DES was the only independent predictor of both NA (odds ratio, 7.0; 95% confidence interval, 1.7-27; P=0.006) and periprocedural myocardial infarction (odds ratio, 1.8; 95% confidence interval, 1.1-2.4; P=0.05). CONCLUSIONS: In-stent thin-cap neoatheroma is more prevalent, is distributed more diffusely across the stented segment, and is associated with increased periprocedural myocardial infarction in DES compared with bare-metal stents. These findings support NA as a mechanism for late DES failure. PMID- 24065448 TI - Microfluidics as a tool for C. elegans research. AB - Microfluidics has emerged as a set of powerful tools that have greatly advanced some areas of biological research, including research using C. elegans. The use of microfluidics has enabled many experiments that are otherwise impossible with conventional methods. Today there are many examples that demonstrate the main advantages of using microfluidics for C. elegans research, achieving precise environmental conditions and facilitating worm handling. Examples range from behavioral analysis under precise chemical or odor stimulation, locomotion studies in well-defined structural surroundings, and even long-term culture on chip. Moreover, microfluidics has enabled coupling worm handling and imaging thus facilitating genetic screens, optogenetic studies, and laser ablation experiments. In this article, we review some of the applications of microfluidics for C. elegans research and provide guides for the design, fabrication, and use of microfluidic devices for C. elegans research studies. PMID- 24065450 TI - [Computer-aided design of selective ligands binding to G protein-coupled receptors]. PMID- 24065449 TI - An immunohistochemical panel for reliable differentiation of salivary duct carcinoma and mucoepidermoid carcinoma. AB - Salivary duct carcinoma is a highly aggressive salivary gland malignancy that may be misdiagnosed as high-grade mucoepidermoid carcinoma. We utilized tissue microarrays with 78 examples of mucoepidermoid carcinoma and 47 salivary duct carcinomas to evaluate the utility of an immunohistochemical panel consisting of androgen receptor, Her2/neu, p63, and cytokeratin 5/6 in distinguishing these entities. Among all cases in the cohorts, androgen receptor was highly specific for salivary duct carcinoma, while cytokeratin 5/6 and p63 were specific for mucoepidermoid carcinoma. While the rate of unequivocal Her2/neu overexpression among the salivary duct carcinomas was low (8.9 %), discrimination of salivary duct carcinoma was enhanced when this marker was used in combination with androgen receptor due to profound sensitivity. The immunohistochemical panel was particularly efficacious at distinguishing the problematic subset of high-grade mucoepidermoid carcinomas from salivary duct carcinoma. Utilization of this set of immunohistochemical markers allows reliable differentiation of salivary duct and mucoepidermoid carcinoma, a distinction with important prognostic and therapeutic implications. PMID- 24065451 TI - Subjectively homogeneous noise over written text as a tool to investigate the perceptual mechanisms involved in reading. AB - In an effort to understand the factors influencing text legibility in natural reading, we adapted the visual spread method (Poirier, Gosselin, & Arguin, 2008) to natural text. Stimuli were sentences conforming to MNREAD standards (Legge, Ross, Luebker, & LaMay 1989) mixed with dynamic probabilistic noise-i.e., each pixel in the image is associated with a probability that its polarity is inverted on a given refresh cycle of the display screen. Noise level varied continuously over the image as initially determined by Gaussian-filtered noise. Participants adjusted noise levels in the text using the mouse until the text appeared homogenously noisy. We assume that participants increased (or decreased) noise at locations where stimulus features were easy (or difficult) to encode and thus that local noise settings correlate with legibility. Data from 11 participants and 30 sentences revealed interesting effects, demonstrating the validity of the method for assessing the impact of various factors on noise resistance in natural text. For example, participants increased noise over (a) spaces and adjacent letters, (b) the second half of words, (c) words with more orthographic neighbors but fewer phonological neighbors, (d) less useful word types, (e) less complex letters, and (f) diagnostic letters (a novel metric). Our observations also offer significant insights on constraints acting upon letter identification as well as on higher-level processes that are involved in reading. PMID- 24065452 TI - Reassessing the reliability of the salivary cortisol assay for the diagnosis of Cushing syndrome. AB - OBJECTIVE: The cortisol concentration in saliva is 10-fold lower than total serum cortisol and accurately reflects the serum concentration, both levels being lowest around midnight. The salivary cortisol assay measures free cortisol and is unaffected by confounding factors. This study analysed published data on the sensitivity and specificity of salivary cortisol levels in the diagnosis of Cushing syndrome. METHODS: Data from studies on the use of different salivary cortisol assay techniques in the diagnosis of Cushing syndrome, published between 1998 and 2012 and retrieved using Ovid MEDLINE(r), were analysed for variance and correlation. RESULTS: For the 11 studies analysed, mean sensitivity and specificity of the salivary cortisol assay were both >90%. Repeated measurements were easily made with this assay, enabling improved diagnostic accuracy in comparison with total serum cortisol measurements. CONCLUSIONS: This analysis confirms the reliability of the saliva cortisol assay as pragmatic tool for the accurate diagnosis of Cushing syndrome. With many countries reporting a rising prevalence of metabolic syndrome, diabetes and obesity--in which there is often a high circulating cortisol level--salivary cortisol measurement will help distinguish these states from Cushing syndrome. PMID- 24065453 TI - Prognostic significance of serum microRNA-210 levels in nonsmall-cell lung cancer. AB - OBJECTIVE: To investigate the levels of microRNA-210 (miR-210) in the serum of patients with nonsmall-cell lung cancer (NSCLC) and to determine whether there was a correlation with the prognosis of NSCLC patients following cisplatin-based chemotherapy. METHODS: Quantitative real-time reverse transcription-polymerase chain reaction was used to measure the serum levels of miR-210 in patients with NSCLC and healthy age-matched control subjects. Correlations between serum miR 210 levels and clinicopathological factors and prognosis were investigated. RESULTS: Serum miR-210 was significantly upregulated in 60 patients with NSCLC compared with 30 healthy control subjects. Higher serum miR-210 levels were significantly correlated with the clinical stage and the presence of regional lymph node metastasis in patients with NSCLC. Serum miR-210 levels in patients that achieved a partial response following cisplatin-based chemotherapy were significantly lower than in patients with stable or progressive disease, and were similar to those in healthy control subjects. CONCLUSIONS: These findings suggest that serum miR-210 levels might be a novel diagnostic and prognostic marker of NSCLC. PMID- 24065454 TI - Predictive value of procalcitonin for excluding bloodstream infection: results of a retrospective study and utility of a rapid, quantitative test for procalcitonin. AB - OBJECTIVES: To assess retrospectively the diagnostic value of procalcitonin (PCT) in excluding suspected bloodstream infection, establish cut-off values for PCT levels, and compare PCT with other clinical markers. METHODS: The predictive accuracy of different continuous parameters was estimated by univariate analysis of the area under the receiver operating characteristic curve. Optimized cut-off points for the parameters were selected according to the maximum Youden index values, which in turn were used to define positive and negative predictive values of different parameters in diagnosing bloodstream infection. RESULTS: The PCT level yielded a statistically significant area under the receiver operating characteristic curve of 0.765, with a best cut-off value of 0.80 ng/ml (83% sensitivity; 65% specificity, Youden index, J = 0.48). Positive and negative predictive values at this cut-off value were 38% and 94%, respectively. Mann Whitney U-test revealed significantly higher values for PCT, C-reactive protein and percentage of neutrophils, but not for white blood cell count, in patients with bloodstream infection. CONCLUSIONS: The serum PCT level can potentially be used as surrogate marker to exclude bacteraemia and to inform critical management decisions regarding antibiotic usage, in patients admitted with suspected bloodstream infection. PMID- 24065455 TI - Influence of caffeic acid phenethyl ester on bone healing in a rat model. AB - OBJECTIVE: To examine the effects of caffeic acid phenethyl ester (CAPE; a component of honey bee-hive propolis with antioxidant, anti-inflammatory, antiviral and anticancer properties) on bone regeneration and fibrotic healing in a rat model. METHODS: Male Sprague-Dawley rats (n = 63; mean age 7 weeks; weight 280-490 g) were randomly divided into three groups: A, cranial defect with no bone healing treatment (n = 21); B, cranial defect treated with CAPE (n = 21); C, cranial defect treated with CAPE and beta-tricalcium phosphate/hydroxyl apatite (n = 21). Rats were anaesthetized with ketamine (8 mg/100 g) by intraperitoneal injection and a cranial critical size bone defect was created. Following surgery, CAPE (10 umol/kg) was administered by daily intraperitoneal injection. Seven rats in each group were killed at days 7, 15 and 30 following surgery. Bone regeneration, fibrotic healing and osteoblast activity were evaluated by histopathology. RESULTS: Statistically significant differences in healing were found between all groups. There were no statistically significant within-group differences between day 7 and 15. At day 30, bone healing scores were significantly higher in groups B and C compared with group A. CONCLUSION: CAPE significantly improved bone-defect healing in a rat model, suggesting that CAPE has beneficial effects on bone healing. PMID- 24065456 TI - Magnetic resonance imaging, magnetic resonance arthrography and ultrasonography for assessing rotator cuff tears in people with shoulder pain for whom surgery is being considered. AB - BACKGROUND: Shoulder pain is a very common symptom. Disorders of the rotator cuff tendons due to wear or tear are among the most common causes of shoulder pain and disability. Magnetic resonance imaging (MRI), magnetic resonance arthrography (MRA) and ultrasound (US) are increasingly being used to assess the presence and size of rotator cuff tears to assist in planning surgical treatment. It is not known whether one imaging method is superior to any of the others. OBJECTIVES: To compare the diagnostic test accuracy of MRI, MRA and US for detecting any rotator cuff tears (i.e. partial or full thickness) in people with suspected rotator cuff tears for whom surgery is being considered. SEARCH METHODS: We searched the Cochrane Register of Diagnostic Test Accuracy Studies, MEDLINE, EMBASE, and LILACS from inception to February 2011. We also searched trial registers, conference proceedings and reference lists of articles to identify additional studies. No language or publication restrictions were applied. SELECTION CRITERIA: We included all prospective diagnostic accuracy studies that assessed MRI, MRA or US against arthroscopy or open surgery as the reference standard, in people suspected of having a partial or full thickness rotator cuff tear. We excluded studies that selected a healthy control group, or participants who had been previously diagnosed with other specific causes of shoulder pain such as osteoarthritis or rheumatoid arthritis. Studies with an excessively long period (a year or longer) between the index and reference tests were also excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on study characteristics and results of included studies, and performed quality assessment according to QUADAS criteria. Our unit of analysis was the shoulder. For each test, estimates of sensitivity and specificity from each study were plotted in ROC space and forest plots were constructed for visual examination of variation in test accuracy. Meta-analyses were performed using the bivariate model to produce summary estimates of sensitivity and specificity. We were unable to formally investigate potential sources of heterogeneity because of the small number of studies. MAIN RESULTS: We included 20 studies of people with suspected rotator cuff tears (1147 shoulders), of which six evaluated MRI and US (252 shoulders), or MRA and US (127 shoulders) in the same people. Many studies had design flaws, with the potential for bias, thus limiting the reliability of their findings. Overall, the methodological quality of the studies was judged to be low or unclear. For each test, we observed considerable heterogeneity in study results, especially between studies that evaluated US for the detection of full thickness tears and studies that evaluated MRA for the detection of partial thickness tears. The criteria for a positive diagnostic test (index tests and reference standard) varied between studies.Meta-analyses were not possible for studies that assessed MRA for detection of any rotator cuff tears or partial thickness tears. We found no statistically significant differences in sensitivity or specificity between MRI and US for detecting any rotator cuff tears (P = 0.13), or for detecting partial thickness tears (P = 1.0). Similarly, for the comparison between MRI, MRA and US for detecting full thickness tears, there was no statistically significant difference in diagnostic performance (P = 0.7). For any rotator cuff tears, the summary sensitivity and specificity were 98% (95% CI 92% to 99%) and 79% (95% CI 68% to 87%) respectively for MRI (6 studies, 347 shoulders), and 91% (95% CI 83% to 95%) and 85% (95% CI 74% to 92%) respectively for US (13 studies, 854 shoulders). For full thickness tears, the summary sensitivity and specificity were 94% (95% CI 85% to 98%) and 93% (95% CI 83% to 97%) respectively for MRI (7 studies, 368 shoulders); 94% (95% CI 80% to 98%) and 92% (95% CI 83% to 97%) respectively for MRA (3 studies, 183 shoulders); and 92% (95% CI 82% to 96%) and 93% (95% CI 81% to 97%) respectively for US (10 studies, 729 shoulders).Because few studies were direct head-to-head comparisons, we could not perform meta-analyses restricted to these studies. The test comparisons for each of the three classifications of the target condition were therefore based on indirect comparisons which may be prone to bias due to confounding. AUTHORS' CONCLUSIONS: MRI, MRA and US have good diagnostic accuracy and any of these tests could equally be used for detection of full thickness tears in people with shoulder pain for whom surgery is being considered. The diagnostic performance of MRI and US may be similar for detection of any rotator cuff tears. However, both MRI and US may have poor sensitivity for detecting partial thickness tears, and the sensitivity of US may be much lower than that of MRI. The strength of evidence for all test comparisons is limited because most studies were small, heterogeneous and methodologically flawed, and there were few comparative studies. Well designed studies that directly compare MRI, MRA and US for detection of rotator cuff tears are needed. PMID- 24065457 TI - The sensitivity of an interferon-gamma release assay in microbiologically confirmed pediatric tuberculosis. AB - This study aimed at determining the sensitivity of a whole blood interferon-gamma release assay (IGRA) among children with microbiologically confirmed tuberculosis in a high-burden country. Children with a diagnosis of tuberculosis based on clinical and radiographic assessment were tested with an IGRA in addition to microbiologic examination of appropriate specimens for acid-fast bacilli, mycobacterial rRNA, and observation for growth of Mycobacterium tuberculosis on appropriate culture media. Of the 405 children with a clinical diagnosis of tuberculosis, 91 (22.5 %) had microbiologically confirmed tuberculosis, of whom 81 were tested with an IGRA. A positive result was obtained in 43 (sensitivity 53.1 %, 95 % confidence interval 42.3 to 63.6 %), uninfluenced by age, sex, or disease manifestation. CONCLUSIONS: The sensitivity of a whole blood interferon gamma release assay in microbiologically confirmed pediatric tuberculosis was low. An IGRA cannot, thus, be used as rule-in test, but it might be useful to rule in tuberculosis among children in whom tuberculosis is notoriously difficult to confirm microbiologically. PMID- 24065458 TI - The organizational social context of mental health medicaid waiver programs with family support services: implications for research and practice. AB - Peer family support specialists (FSS) are parents with practical experience in navigating children's mental health care systems who provide support, advocacy, and guidance to the families of children who need mental health services. Their experience and training differ from those of formally trained mental health clinicians, creating potential conflicts in priorities and values between FSS and clinicians. We hypothesized that these differences could negatively affect the organizational cultures and climates of mental health clinics that employ both FSS and mental health clinicians, and lower the job satisfaction and organizational commitment of FSS. The Organizational Social Context measure was administered on site to 209 FSS and clinicians in 21 mental health programs in New York State. The study compared the organizational-level culture and climate profiles of mental health clinics that employ both FSS and formally trained clinicians to national norms for child mental health clinics, assessed individual level job satisfaction and organizational commitment as a function of job (FSS vs. clinician) and other individual-level and organizational-level characteristics, and tested whether FSS and clinicians job attitudes were differentially associated with organizational culture and climate. The programs organizational culture and climate profiles were not significantly different from national norms. Individual-level job satisfaction and organizational commitment were unrelated to position (FSS vs. clinician) or other individual-level and organizational-level characteristics except for culture and climate. Both FSS' and clinicians' individual-level work attitudes were associated similarly with organizational culture and climate. PMID- 24065459 TI - A philosophical defense of the idea that we can hold each other in personhood: intercorporeal personhood in dementia care. AB - Since John Locke, regnant conceptions of personhood in Western philosophy have focused on individual capabilities for complex forms of consciousness that involve cognition such as the capability to remember past events and one's own past actions, to think about and identify oneself as oneself, and/or to reason. Conceptions of personhood such as Locke's qualify as cognition-oriented, and they often fail to acknowledge the role of embodiment for personhood. This article offers an alternative conception of personhood from within the tradition of phenomenology of the body. The article presents a phenomenological analysis of joint musical activity in dementia care and outlines an intercorporeal conception of personhood based on this analysis. It also provides a philosophical basis for the idea that others can hold us in personhood, and it questions a strict one body-one-person logic that has pertained in much personhood debate. PMID- 24065460 TI - Rapid pannus formation after few months of obstructing aortic mechanical prosthesis. AB - We report a rare case of a prosthetic aortic valve obstruction due to pannus formation only 3 months following aortic and mitral valve replacement. Fragments of asymmetrical pannus formation affected one of the leaflets of the bi-leaflet mechanical valve; the leaflet appeared immobile due to pannus ingrowth into the mechanical skeleton resulting in encroachment of the leaflet, which in turn became immobile. The patient successfully underwent emergency redo-aortic valve replacement. PMID- 24065461 TI - Contribution of embryology in the understanding of cervical venous system anatomy within and around the transverse foramen: a review of the classical literature. AB - Anatomic arrangement of venous system within the transverse foramen is a controversial topic among authors. Precise knowledge of this arrangement is necessary in imaging where vertebral artery dissection is suspected, as well as in surgical approaches of cervical spine. This knowledge objective cannot be achieved without a prerequisite knowledge of primitive venous system. We present here an update on the development of the transverse foramen venous system through a literature review. Our review of the classical literature aimed at synthesis of available related embryological knowledge and relating this synthesis to cervical vertebrae anatomy. Our findings with regard to different primitive descriptions were consistent and often complementary across the studies. The description has varied from a single vertebral vein to a single vein divided at certain areas, or even to a confluence of venous plexus. In this manner, the embryonic knowledge for instance on venous system can help us to better understand the segmental development of vertebral veins and their plexus arrangement. Furthermore, the cranial-caudal embryology, in particular of the nervous system, conveys the initial plexiform arrangement of vertebral veins, which ends into a single venous trunk joining the subclavian vein. PMID- 24065462 TI - Bilateral anomalous high position of the mandibular foramen: a case report. AB - The inferior alveolar nerve block is one of the most common techniques for delivering dental anesthesia. Its success depends on placing the needle tip in close proximity to the mandibular foramen (MF). In certain cases, however, this nerve block fails, even when performed by the most experienced clinician. Anatomical variability may be one source of local anesthetic failure and includes bone and nerve variations. A case is presented of a bilateral anomalous high position of the MF, identified from the panoramic radiograph. An adjusted anesthetic technique (the Vazirani-Akinosi technique) was used to achieve local anesthesia before extraction of a lower second molar following an unsuccessful conventional indirect technique with a higher entry point. A description of the embryological basis for the anomalous high positioned MF and its impact from a practical and clinical perspective, with particular reference to local anatomy, is included. PMID- 24065463 TI - Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality. AB - RATIONALE: The Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID 1) study was a phase 1/phase 2 first-in-human clinical gene therapy trial using an adeno-associated virus serotype 1 (AAV1) vector carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a) in patients with advanced heart failure. The study explored potential benefits of the therapy at 12 months, and results were previously reported. OBJECTIVE: To report long-term (3-year) clinical effects and transgene expression in the patients in CUPID 1. METHODS AND RESULTS: A total of 39 patients with advanced heart failure who were on stable, optimal heart failure therapy were randomized to receive intracoronary infusion of AAV1/SERCA2a in 1 of 3 doses (low-dose, 6*10(11) DNase-resistant particles; mid-dose, 3*10(12) DNase-resistant particles; and high-dose, 1*10(13) DNase-resistant particles) versus placebo. The following recurrent cardiovascular and terminal events were tracked for 3 years in all groups: myocardial infarction, worsening heart failure, heart failure-related hospitalization, ventricular assist device placement, cardiac transplantation, and death. The number of cardiovascular events, including death, was highest in the placebo group, high but delayed in the low- and mid-dose groups, and lowest in the high-dose group. Evidence of long-term transgene presence was also observed in high-dose patients. The risk of prespecified recurrent cardiovascular events was reduced by 82% in the high-dose versus placebo group (P=0.048). No safety concerns were noted during the 3-year follow-up. CONCLUSIONS: After a single intracoronary infusion of AAV1/SERCA2a in patients with advanced heart failure, positive signals of cardiovascular events persist for years. PMID- 24065464 TI - Olfactory neuroblastoma (esthesioneuroblastoma): towards minimally invasive surgery and multi-modality treatment strategies - an updated critical review of the current literature. AB - Olfactory neuroblastoma (esthesioneuroblastoma) was first described by Berger and Luc in 1924. It is considered to be an uncommon malignancy of the nasal cavity. The tumor arises from the specialized sensory epithelial olfactory cells, normally situated at the upper part of the nasal cavity, including the superior nasal concha, the roof of the nose and the cribriform plate. The imaging modalities of choice are computed tomography (CT) and magnetic resonance imaging (MRI). Combination of surgery and radiotherapy (either conventional radiotherapy or stereotactic radiosurgery), with or without chemotherapy is considered to be the standard of care for primary site disease by the majority of researchers. Combined transfacial and neurosurgical conventional approaches are also adopted in many reported cases, mainly due to the endocranial extension and the close anatomic relationship of esthesioneuroblastomas with the ethmoid roof and cribriform plate. Recent literature supports that endoscopic resection correlates with similar oncologic control rates compared with conventional open surgery, provided that basic oncologic surgical principles with clearance of margins and intradural dissection (when required) are completely maintained. PMID- 24065465 TI - Cisplatin: process and future. AB - One of the most important anticancer agents is cisplatin (CDDP). Numerous studies with a CDDP-based combination have been reported over the last 30 years. The use of CDDP in the 1980s and 1990s showed responses in advanced stage non-small-cell lung cancer (NSCLC). Over the years it was found that the side effects of this agent (particularly nephrotoxicity) were a common problem. Agents such as carboplatin, taxanes, gemcitabine, irinotecan and pemetrexed proved to be effective in NSCLC with reduced or no nephrotoxicity. The administration of these newer agents improved several side effects, but without improving efficacy. When prophylactic (adjuvant) treatment for NSCLC was introduced, CDDP was the agent selected, which indicated the value of the drug. Recently, a novel formulation of CDDP, liposomal cisplatin, which has shown very low toxicity, no nephrotoxicity and equal effectiveness was produced; its importance is its higher effectiveness than standard CDDP in lung adenocarcinoma. PMID- 24065466 TI - Pharmacogenomics: current applications and future prospects towards personalized therapeutics. AB - Personalized Medicine is more than just a metabolic activity of a person. Pharmacogenomics, pharmacogenetics, pharmacoproteomics, and metabolomics play an important role in the development of personalized medicines. Personalized medicine uses information about a person's genes, proteins, enzyme activities, and cellular environment to diagnose and treat disease, cancer included. A major problem of personalized medicine is the fact that there is no portable bedside and low-cost bioanalytical technology that can be used in close proximity to the patient. This technology could play a significant role in defining the dosage setting for subsets of the population. The success of the personalized therapy is possible through the application of technology, which can provide a bridge between metabolism status and an individual's response to a particular drug and therapeutic modality. PMID- 24065467 TI - The importance of COX-2 expression as prognostic factor in early breast cancer. AB - PURPOSE: A number of studies have been carried out, showing that the risk for breast carcinoma is decreased in those using non-steroidal anti-inflammatory drugs (NSAIDs). Increased cyclooxygenase-2 (COX-2) level is considered as a factor indicating poor prognosis and responsible for angiogenesis, increased cellular proliferation, apoptotic defect and aromatase enzyme induction. For this reason the level of COX-2 might have a prognostic and predictive value in breast cancer as well. This question has become the basis of the present study. METHODS: Eighty-eight female patients with early stage breast cancer being under adjuvant anthracycline based chemotherapy were prospectively recruited. The patient age, body weight, menopausal status, tumor size and grade as well as axillary lymph node involvement were recorded. Routine pathological examination was performed, and COX-2, CerbB2 (HER2), estrogen (ER) and progesterone receptors (PR) levels in breast cancer tissue were determined immunohistochemically. RESULTS: Multivariate analysis confirmed the independent predictive value of both menopausal status and ER expression for overall survival (OS) (p=0.009, HR=1.92, and p=0.014, HR=0.20, respectively). A negative correlation was observed between COX-2 levels and the levels of ER and PR (p=0.006, R= -0.303, and p=0.004, R=-0.312, respectively) whereas no significant correlation was observed concerning CerbB2. No statistically significant correlation was determined between COX-2 levels and the disease-free (DFS) and OS rates. CONCLUSION: Further studies investigating the role of COX- 2 levels in breast cancer progression are needed. PMID- 24065469 TI - CHEK2 1100delC and Del5395bp mutations in BRCA-negative individuals from Serbian hereditary breast and ovarian cancer families. AB - PURPOSE: Hereditary breast/ovarian cancer (HBOC) occurs in families with several members affected. Most HBOC is caused by mutations in high penetrance BRCA genes accounting for about 5% of all breast cancers. There is a large number of genes with moderate or low penetrance, contributing to non-BRCA aggregation of breast and ovarian cancers. In the present study, we evaluated the presence and frequency of 1100delC and Del5395 mutations in CHEK2 gene in Serbian BRCA negative HBOC cases. METHODS: We analyzed 57 BRCA-negative subjects from high risk breast/ovarian cancer families from Serbia for CHEK2 1100delC and Del5395 mutations. We used two multiplex allele specific PCR in order to detect them. All suspected positive cases were compared with controls and confirmed by DNA sequencing. RESULTS: 1100delC was not detected in the tested group. However, we detected one Del5395 mutation in a female diagnosed with breast cancer at the age of 32 and with apparent family history of breast cancer (her mother and sister were diagnosed with breast cancer at 42 and 39 years of age, respectively). The frequency of Del5395 mutation in our tested group was 1.7% (1/57). CONCLUSIONS: 1100delC variant in CHEK2 gene was not present in the tested subjects from HBOC families in Serbia. However, the finding of Del5395 mutation does not allow us to discard a possible involvement of this gene in breast cancer susceptibility in Serbian population. It would be of great interest to assess the distribution of this large deletion in other countries from the Balkan region in order to assess its geographical distribution and possible founder effect. PMID- 24065468 TI - Duration of anti-HER2 blockage therapy may improve survival in HER2 positive metastatic breast carcinoma patients. AB - PURPOSE: The duration of anti-HER2 blockage therapy in metastatic breast cancer patients is still unclear. We aimed to evaluate the effect of the anti-HER2 blockage therapy duration and other factors on survival in HER2 positive metastatic breast carcinoma (MBC) patients. METHODS: The medical records of 193 HER2 positive MBC patients, who did not have the opportunity to receive adjuvant trastuzumab therapy but had received trastuzumab in the metastatic setting were retrospectively evaluated. RESULTS: The median age at diagnosis was 45.0 years (range 21-83). Ninety-two (47.7%) patients received palliative trastuzumab < 6 months median, whereas 101 patients received trastuzumab >= 6 months median. The median number of trastuzumab cycles was 8 (range 1-51). Median survival after breast cancer recurrence was 31.0 months (range 24.3-37.7). The duration of trastuzumab therapy had a significant impact on the prognosis of recurrent breast cancer (22.0 vs 49.0 months, for <= 6 months of treatment duration, respectively; p<0.0001). Survival after breast cancer recurrence for the patients who received lapatinib plus capecitabine vs those who did not was significantly different (59 patients, p=0.005). Moreover, there was a statistically significant relationship between prolonged lapatinib plus capecitabine combination therapy and improved survival after disease recurrence (p=0.022). In the multivariate Cox regression analysis, treatment with trastuzumab > 6 months (p=0.003) was the only independent prognostic factor for survival after breast cancer recurrence. CONCLUSION: The duration of anti-HER2 blockage therapies, especially with trastuzumab, seems to improve survival of HER2-positive metastatic breast cancer patients who were not previously treated with adjuvant trastuzumab, regardless of other therapies. PMID- 24065470 TI - The importance of pre-operative needle core breast biopsy results on resected tissue volume, margin status, and cosmesis. AB - PURPOSE: This study aimed to evaluate the relationship between pre-operative image-guided large needle core biopsy (LNCB) histopathology results and surgical resection volumes in breast conserving surgery (BCS), with attention to both margin status and cosmetic outcome. METHODS: Breast volumes (BV) were calculated using the elliptical cone based formula on mammography images for each patient. Initial resected volume (IRV), final resected volume (FRV), and resected volume ratio (RVR) were calculated and compared according to histopathological diagnosis and cosmetic outcomes. Final pathology results were classified as benign, high risk lesion (HRL), ductal carcinoma in situ (DCIS), or invasive cancer. The cosmetic results were graded based on the Harvard breast cosmesis grading scale. RESULTS: A total of 217 women underwent BCS by the same experienced breast surgeon. The resected volumes (mean, cm3) were higher among patients who underwent LNCB than those who did not (54.3 vs 26.5 ;p=0.005). The LNCB diagnoses were 16% benign, 19% HRLs, 16% DCIS, and 49% invasive cancers. Reexcision rates were 15.6% and 25.8% for DCIS and invasive cancer, respectively. Cosmesis was excellent in 79.8%. Age, pathological tumor size, IRV and FRV were different among the benign, HRLs and carcinoma groups (p= 0.001). CONCLUSION: The diagnosis of carcinoma by LNCB leads to the planning of a wider resection, but the need for reexcision is no different than less resection. HRLs are best approached with diagnostic excision, as there is no strong evidence that larger resections reduce the incidence of involved resection margins. PMID- 24065471 TI - Variations in tumor marker levels in metastatic breast cancer patients according to tumor subtypes. AB - PURPOSE: To investigate whether serum CA 15-3 and CEA levels show differences among subgroups of breast cancer patients at the time of diagnosis of early-stage disease and at disease relapse. METHODS: Patients with metastatic breast cancer diagnosed from 2000 to 2010 were retrospectively analyzed. Data were obtained from medical charts. CA 15-3 and CEA levels of patients with metastatic disease at the time of diagnosis or who relapsed during follow-up were evaluated. Four different breast cancer subtypes were defined: estrogen receptor (ER) and/or progesterone receptor (PR) positive and HER-2 negative (luminal A), ER and/or PR positive and HER-2 positive (luminal B), ER and PR negative and HER-2 positive (HER-2 overexpressing) and triple negative (ER, PR and HER-2 negative). Fifty eight (13.7%) of the patients were metastatic at the time of diagnosis. RESULTS: 423 metastatic breast cancer patients were included. Of the patients, 232 (54.8%) had luminal A disease, 70 (16.5%) luminal B, 53 (12.5%) HER-2 overexpressing, and 68 (16.1%) triple negative disease. Preoperative CA 15-3 levels were raised in 48.1% of the luminal A group, in 42.8% of the luminal B group, in 26.0% of the HER-2 overexpressing group, and in 33.3% of the triple negative group. CA 15-3 levels after relapse were raised in 44.5% of the luminal A group, in 33.3% of the luminal B, in 28.9% of the HER-2 overexpressing, and in 38.8% of the triple negative group. Preoperative CEA levels were elevated in 44.3% of the luminal A group, in 28.5% of the luminal B, in 43.4% of the HER-2 overexpressing, and in 14.3% of the triple negative group. CEA levels after relapse were raised in 60.8%, 54.7%, 51.1%, and 36.0% of the patients in the 4 subgroups, respectively. CONCLUSION: This study showed that there are differences between the breast cancer subgroups in terms of tumor marker levels in metastatic breast cancer patients. Tumor marker elevation was lower in the triple negative group as compared to the luminal groups. Monitoring CEA levels in luminal A group may be beneficial in determining early relapses. However, this retrospective study requires further prospective confirmative cohort studies. PMID- 24065472 TI - Oxidative and antioxidative status after anthracyclinebased chemotherapy in breast cancer patients. AB - PURPOSE: The present study was undertaken to evaluate the effects of adjuvant anthracycline-based chemotherapy on thiobarbituric acid reactive substances (TBARS) and superoxide dismutase (SOD) levels in patients with breast cancer who had undergone surgery. METHODS: Body mass index (BMI), serum lipids (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides), serum TBARS and SOD values were assessed in 30 patients with stage III breast cancer receiving adjuvant anthracycline- based chemotherapy. RESULTS: Anthracycline-based chemotherapy had no effect on BMI, blood pressure and lipid profile. A significant elevation was noted in TBARS (5.5+/-0.6 vs 5.9+/-0.9 MUmol/L; p=0.038) and a significant reduction to baseline values in SOD levels (226.5+/ 61.0 vs 203.1+/-48.3 U/mL; p=0.03) in patients following 6 cycles of adjuvant chemotherapy. CONCLUSION: The TBARS levels increased, whereas the SOD levels descreased after anthracycline-based chemotherapy. We suggest that oxidative stress is not always detrimental, as it can be beneficial in cancer treatment. PMID- 24065473 TI - Hormone receptor and HER2 status in patients with breast cancer by races in southeastern Turkey. AB - PURPOSE: Hormone receptor (HR) status is a prognostic factor in women with breast cancer and differs among different ethnic groups. HR status among Turkish, Kurdish and Arabic women with breast cancer living in Turkey is unknown and in this study we investigated the relationship between HR and HER2 status and race. METHODS: FA total of 648 women with breast cancer (Turkish 438, Kurdish 174, Arabic 35 and Armenian 1) living in southeastern Turkey and referred to the Department of Radiation Oncology between July 2006-July 2012 were included in the study. Patients were categorized into 4 groups according to their HR status. Estrogen receptor (ER) and progesterone receptor (PR) positive (ER+/PR+), ER positive and PR negative (ER+/PR-), ER negative and PR positive (ER-/PR+) and ER and PR negative (ER-/PR-). Human epidermal growth factor receptor 2 (HER2) status was recorded immunohistochemically (IHC) as negative (0 and 1+), and positive (3+). Statistical analysis included ER, PR, HER2, triple subtypes (combination of ER, PR and HER2), and race. RESULTS: The median age at diagnosis was 48 years (range 20-83). ER+, PR+ and HER2+ patients were 453 (70%), 470 (72.6%) and 206 (32.1%), respectively. ER+/PR+ rates among Turkish and Arabic patients were similar, but were higher than Kurdish patients (p<0.002). Triple-negative (ER-/PR /HER2-) rates among Kurdish and Arabic patients were similar, but were higher than Turkish patients (p=0.04). CONCLUSION: Turkish, Kurdish and Arabic women with breast cancer in southeastern Turkey differed by HR status. Compared to Turkish and Arabic patients, Kurdish patients had more unfavorable prognostic factors. PMID- 24065474 TI - Procalcitonin in patients with colorectal cancer. AB - PURPOSE: Bacterial translocation (BT) is common in colon cancer patients and may be associated with increased occurrence of septic complications as well as with adverse oncologic outcomes. The aim of the present study was to correlate the BT detectable through peritoneal lavage culture or identified by abnormal inflammatory parameters with the clinicopathologic parameters and the short-term prognosis in a prospective series of patients. METHODS: Fifty-four consecutive patients with histologically proven colorectal cancer were included in this prospective study. White blood cells (WBC), erythrocyte sedimentation rate (ESR) and serum levels of procalcitonin (PCT) and C-reactive protein (CRP) were determined and cultures from peritoneal lavage were collected immediately after laparotomy. RESULTS: Positive PCT was detected in 31 (55.3%) patients while positive cultures were obtained in 6 (11%) patients. Significant positive correlation of PCT with inflammation markers was noticed. Patients with distant metastases had higher serum PCT levels than patients without distant metastases (p=0.01). Borderline statistical significance was found between PCT and tumor grade (p=0.09). PCT was not correlated with the cultures of the lavage or the outcome. CONCLUSION: PCT is an adequate inflammatory marker, able to preoperatively discriminate patients with bacterial systemic inflammatory reaction due to BT. However, the clinical consequence of BT may be minimal as is shown by the lack of association of PCT or positive peritoneal lavage cultures with time to discharge, complications and short-term survival. PMID- 24065475 TI - Chemotherapy compliance, tolerance and efficacy in elderly and non-elderly patients with metastatic colorectal cancer: a single institution comparative study. AB - PURPOSE: To evaluate whether elderly patients with metastatic colorectal cancer (mCRC) receive chemotherapy of suboptimal intensity and duration, mainly due to fears of poor compliance and/or excessive toxicity. METHODS: We carried out a retrospective analysis in a series of 94 mCRC patients. Using the cut-off of 70 years, we compared elderly patients with their younger counterparts in terms of treatment delivery [type, dose intensity (DI), relative dose intensity (RDI), duration], chemotherapy toxicity and efficacy [objective response rate (ORR), overall survival (OS) and progression-free survival (PFS)]. RESULTS: Complete data were available for 72 patients (76.6%) among which 38 (52.8%) were elderly. As compared to the younger, elderly patients were more likely to receive single agent chemotherapy (13.1 vs 0%, p<0.001). The mean number of chemotherapy cycles was 6.2 for the elderly and 8.3 for the non-elderly patients who received either the FOLFOX or FOLFIRI regimen (p=0.142) and 5.1 vs 5.0 for those who received either the XELOX or XELIRI regimen, respectively (p=0.831). In oxaliplatin containing regimens, elderly patients received 42.8% of the planned dose, as compared to 78.4% for the younger ones (p=0.012). DI for oxaliplatin was higher in non-elderly than in the elderly (46.66 mg/ m(2)/week vs 32.47 mg/m(2)/week, p=0.008). No difference was observed in the rate of severe (grade III-IV) toxicities. ORR, PFS and OS were similar between the two groups. CONCLUSION: Despite the inferior type and intensity of chemotherapy, elderly patients derived equivalent benefit to their younger counterparts. These data further support the use of optimal chemotherapy in elderly patients with mCRC. PMID- 24065476 TI - AKAP12/Gravin gene expression in colorectal cancer: clinical importance and review of the literature. AB - PURPOSE: : Colorectal cancer (CRC) is a common and potentially lethal disease. A number of genetic aberrations is known to take place in colorectal carcinogenesis, which leads to progressive alteration of normal mechanisms controlling cell growth. A-kinase-anchoring protein 12 (AKAP12) plays a role in cell proliferation, angiogenesis and cytoskeletal remodeling. The purpose of this study was to demonstrate the role of the AKAP12 gene expression in CRC patients and to determine its relationship (if any) with prognosis. METHODS: AKAP12 gene expression was investigated by immunohistochemistry. RESULTS: A total of 55 patients (63.6% males, 36.4% females) with histologically confirmed CRC were studied. Normal intestinal epithelium showed weak basal staining, dysplastic areas were stained mildly, whereas all of the cancer cells were stained completely with AKAP12. CONCLUSION: AKAP12 gene seems to play a role in colorectal carcinogenesis. PMID- 24065477 TI - Safety and efficacy of addition of bevacizumab to oxaliplatin-based preoperative chemotherapy in colorectal cancer with liver metastasis- a single institution experience. AB - PURPOSE: To evaluate the safety and efficacy of the addition of bevacizumab to oxaliplatin-based preoperative chemotherapy in metastatic colorectal cancer (mCRC) patients. METHODS: Between August 2008 and December 2011, 51 patients with histologically documented CRC and liver metastases were treated with first-line oxaliplatin-based therapy plus bevacizumab: FOLFOX 4 (oxaliplatin, folinic acid and 5-FU) plus bevacizumab or OXFL mod.Mayo (folinic acid, oxaliplatin and 5-FU) plus bevacizumab. RESULTS: The mean patient age was 59.69+ 9.38 years (range 38 78) and 34 (66.67%) were male. Complete response (CR) was achieved in 7 (13.73%) patients, partial response (PR) in 29 (56. 86%) and stable disease (SD) in 6 (11.76%); progressive disease (PD) was registered in 9 (17.65%) patients. Disease control rate was 82.36% (42 patients). Liver resections were performed in 37 (72.55%) patients vs those without resection (p<0.01). The same regimen without bevacizumab was administered postoperatively to 18 (42. 86%) patients. The mean progression free survival (PFS) was 9.90+/-7.07 months (range 3-26) and was significantly longer in patients with postoperative therapy (p<0.001). Treatment related toxicity appeared in 28 (54. 90%) patients vs those who did not (p<0.001) Independent of grade, nausea (19.61%), leucopenia (17.65%) and peripheral neuropathy (17.65%) were the most frequent toxicities. Chemotherapy was postponed in 9 (17.65%) patients due to grade 3-4 toxicities. The most frequent grade 3 or 4 toxicities were leucopenia (5.88%) and hypertension (3.92%). CONCLUSION: Bevacizumab plus oxaliplatin-based treatment is safe and efficient as preoperative treatment of mCRC with primarily unresectable liver metastases. Liver resection could offer a possibility for long-term survival in these patients. PMID- 24065478 TI - Survival analysis of metastatic colorectal cancer patients who were treated with the five major therapeutic agents over the course of disease. AB - PURPOSE: Exposure to all active agents may be more important than specific sequence of drug administration in the treatment of patients with metastatic colorectal cancer (mCRC). The purpose of this study was to evaluate the overall survival (OS) of mCRC patients who were treated with all 5 major therapeutic agents used in this malignancy. METHODS: We retrospectively reviewed the medical records of 395 mCRC patients referred to our clinic. The study included patients who received 5-fluorouracil (5-FU)-, irinotecan- or oxaliplatin-based chemotherapy and at least 3 cycles of bevacizumab and 4 weeks of cetuximab sequentially in various combinations. RESULTS: Forty mCRC patients received the 5 major therapeutic agents effectively and sequentially, and their mean OS was 26.43+/-2.04 months. The 3- and 4- year OS survival rates were 26.7% and 16.7%, respectively. When survival analysis was limited to the metastatic patients with at least 6 cycles of bevacizumab therapy in addition to standard duration of other chemotherapeutic agents (N=33), the mean OS was 26.7+/-2.38 months. With a further survival analysis limited to metastatic patients who were treated with at least both 6 cycles of bevacizumab and 8 weeks of cetuximab in addition to other therapies (N=17), the mean OS was 44.8+/-11.03 months. CONCLUSION: This study demonstrated that in mCRC patients there may be a significant survival advantage if an adequate tumor response was achieved with all major therapeutic agents. Therefore, we believe that we should treat our patients with the 5 major therapeutic drugs as effectively as possible. PMID- 24065479 TI - ErbB2, ErbB3 and ErbB4 expression in urothelial tumors of the upper urinary tract and their prognostic significance. AB - PURPOSE: ErbB family represents a promising therapeutic target in upper urinary tract urothelial carcinoma (UUTUC). Our study aimed to correlate ErbB2, ErbB3 and ErbB4 expression in UUTUC with other clinicopathological parameters as well as patient outcome. METHODS: ErbB2, ErbB3 and ErbB4 were immunohistochemically assessed in 99 consecutive UUTUC specimens. RESULTS: With a median follow-up of 52.5 months (range 1-127) 28 patients (28.3%) died 1-95 months after the first surgical treatment and the mean survival was 18.9-24.2 months. ErbB2, ErbB3 and ErbB4 expression was positive in 64.8, 19.5, and 20.8% of the tumors, respectively. Combined expression of all 3 receptors was found in 7.9% of the tumors, combined expression of 2 receptors in 14.5% and 48.7% expressed at least one ErbB receptor. No ErbB expression was found in 28.9% of the tumors. We found no significant correlation between ErbB2, ErbB3 and ErbB4 expression with tumor stage, grade, recurrence or cancer specific survival apart from the inverse relation between ErbB2 expression and time to recurrence (p=0.027). CONCLUSION: Of the 3 receptors evaluated, neither ErbB3 nor ErbB4 showed any prognostic significance in the UUTUC. ErbB2, however, was inversely associated with recurrence and needs further evaluation in well-designed, prospective, randomized trials. PMID- 24065480 TI - Evaluation of the clinical value of the newly identified urine biomarker HIST1H4K for diagnosis and prognosis of prostate cancer in Bulgarian patients. AB - PURPOSE: Searching for diagnostic and prognostic biomarkers for prostate cancer (PC) is main public health priority. DNA methylation in body fluids is a stable, easily detectable and promising PC biomarker. The major advantages of urine-based assays are their noninvasive nature and the ability to monitor PC with heterogeneous foci. The aim of this study was to determine the diagnostic value of the recently identified candidate PC biomarker HIST1H4K. METHODS: We investigated DNA methylation of HIST1H4K in urine samples from 57 PC patients, 29 controls with benign prostatic hyperplasia (BPH) and 50 young asymptomatic men (YAM) by MethyLight real-time PCR. RESULTS: The frequency of HIST1H4K promoter hypermethylation significantly discriminated PC patients from YAM (AUC =0.763; 95% CI 0.672-0.839; p<0.0001), but did not show any statistical difference between PC patients and BPH controls (AUC=0.513, 95% CI 0.402-0.622; p=0.8255). HIST1H4K could not outperform the prostatic specific antigen (PSA) in our sample (AUC=0.785; 95% CI 0.679-0.870; p<0.0001). Methylation of HIST1H4K showed significant correlation with aging (r=0.5418; p<0.0001), but with no other clinicopathological characteristics. CONCLUSION: The results suggest that the promoter hypermethylation of HIST1H4K is rather due to aging than related to prostate carcinogenesis. To elucidate this observation analysis of larger samples is needed. PMID- 24065481 TI - Treatment of high risk prostate cancer with combined radiotherapy and hormonal treatment- results and identification of factors influencing outcome. AB - PURPOSE: The aim of this work was to prospectively analyze the outcome of combined hormonal treatment and radical radiotherapy in high risk non metastatic prostate cancer patients (T1=4, N0-1, M0). METHODS: Between April 2003 and December 2007 196 patients with high risk prostate cancer were treated with curative intent. The treatment consisted of 2-month neoadjuvant hormonal treatment (LHRH analog), radical radiotherapy (68-78 Gy, conformal technique) and an optional 2-year adjuvant hormonal treatment. RESULTS: The median follow up time was 59 months. Fiveyear overall survival was 86% and 5-year biochemical disease free survival (DFS) 70%. Factors found to be statistically significant relative to outcomes were Gleason score (p=0.017), initial PSA value (p=0.039) and adjuvant hormonal treatment (p=0.035). There was no significant association between radiotherapy dose or volume and biochemical DFS (bDFS). Late genitourinary and gastrointestinal toxicity was acceptable. CONCLUSION: Treatment combining hormonal therapy and radical radiotherapy can be recommended for this subgroup of prostate cancer patients. Adjuvant hormonal treatment should also be used. PMID- 24065482 TI - Effect of trichosanthin on apoptosis and telomerase activity of nasopharyngeal carcinomas in nude mice. AB - PURPOSE: To evaluate the effect of trichosanthin (TCS) on telomerase activity and apoptosis in nasopharyngeal carcinoma cells implanted into nude mice. METHODS: Nude mice implanted with CNE1 and CNE2 nasopharyngeal carcinoma cell lines were randomly divided into 3 groups, including TCS group, control group (treatment with saline only), and cyclophosphamide (CTX) group. The weight of mice and the tumor volume were measured. The ultra-microstructural changes were observed by transmission electron microscope. Expression of Bcl-2 and Bax were investigated by immunohistochemistry. Apoptosis of CNE1 and CNE2 cells was determined by the TUNEL method, and telomerase activity by TRAP-ELISA. RESULTS: Compared with the normal control group (saline group), TCS significantly inhibited the growth of both CNE1 and CNE2 tumor cells. CTX also inhibited the growth of both CNE1 and CNE2 tumor cells but this inhibition was slightly slower compared with the TCS. CONCLUSION: TCS suppresses the growth of CNE1 and CNE2 cells lines in vivo. Its anticancer effects were associated with induction of apoptosis and, at least partially, with suppression of telomerase activity. PMID- 24065483 TI - Laryngeal dysplasia: a long-term follow-up study. AB - PURPOSE: To assess the progression of precancerous laryngeal lesions to squamous cell carcinoma (SCC), defined by specific histopathological criteria, in patients with longterm follow-up. METHODS: Patients with laryngeal dysplasia, followed/ treated between 1985 and 2008, were retrospectively evaluated and classified according to the World Health Organization classification system (WHO). The investigated outcome parameters were progression of dysplasia to SCC, time interval to malignant transformation and continuation of smoking as potential risk factors. RESULTS: Fifty-nine patients were studied. Progression of dysplasia to SCC between the first and the final histological examination was statistically significant (p<0.0001). Malignant transformation appeared in 29 patients (49.2%). Serious dysplasia was more likely to progress to SCC (64.8%) compared to mild (41.7%) or moderate (44.4%) (p<0.0001). However, the time interval needed in these 29 cases to progress to cancer was not statistically related to the initial histological diagnosis. Continuation of smoking did not affect the progression of disease. However, the mean time from dysplasia to laryngeal cancer was much longer in patients who quitted smoking (33.5 months) vs those who continued smoking (19.5 months), with a marginal statistical difference (p=0.057). CONCLUSION: All patients with laryngeal dysplasia should be followed up at regular intervals. The progression of dysplasia to SCC did not seem to be directly related to the continuation of smoking or not. However, large long-term follow- up studies taking into account the degree of exposure (e.g. time of exposure, number of cigarettes) are needed in order to clarify risk factors and proper management. Consensus guidelines in diagnosis, follow-up, and treatment would improve substantially the current clinical practice. PMID- 24065484 TI - Therapeutic effect of laparoscopy-assisted D2 radical gastrectomy in 106 patients with advanced gastric cancer. AB - PURPOSE: To explore the feasibility and short-term effect of laparoscopy-assisted D2 radical gastrectomy for advanced gastric cancer. METHODS: A total of 239 patients with advanced gastric cancer underwent D2 radical gastrectomy between March 2009 and June 2011, from which 106 patients underwent laparoscopic surgery (laparoscopy group) and 133 patients underwent open surgery (open surgery group). The intraoperative and postoperative condition, number of lymph node removed, complications and mortality rates between the two groups were compared. RESULTS: The operation time (268+/-51 min) and the number of lymph node removed (29.1+6.1) in the laparoscopy group were comparable with the operation time (268+/-49 min) and the number of lymph node removed (30.2+/-7.0) in the open surgery group, while there were significant differences in the intraoperative bleeding (134+/-66 vs 289+/-139 ml), intraoperative blood infusion cases (5 vs 19), time to first postoperative flatus (3.4+/-0.9 vs 5.0+/-1.4 days), time to first taking liquid food (7.3+/-1.3 vs 8.1+/-1.4 days) and postoperative hospital stay (12.8+/-2.6 vs 14.5+/-3.1 days) between the two groups (p<0.05). These results favored the laparoscopy group. The incidence of postoperative complications in the laparoscopy and open surgery group were 14.1 and 24.8, respectively (p<0.05). Compared with the open surgery, the laparoscopic surgery significantly reduced the incidence of pulmonary infection (p<0.05). There was no significant difference in the postoperative short-term survival rate between the two groups (p>0.05). CONCLUSION: Laparoscopy-assisted D2 gastrectomy for advanced gastric cancer is advantageous in terms of safety and feasibility, rapid postoperative recovery and few complications. Both groups gave comparable results in terms of lymph node dissection and short-term survival. PMID- 24065485 TI - KLF4 expression and apoptosis-related markers in gastric cancer. AB - PURPOSE: To correlate the expression of Kruppel-like factor 4 (KLF4) with clinicopathological properties of gastric cancer (GC) and to evaluate any possible correlation between KLF4 expression and the expression of apoptosis related markers p53, Fas, Bcl-2, survivin and FLICE inhibitory protein (Flip-l). METHODS: Formalin-fixed, paraffin-embedded tissue specimens obtained from 96 patients with GC who had undergone gastric surgery were analyzed for pathological parameters, while KLF4, p53, Fas, Bcl-2, survivin and Flip-l expression was assessed by immunohistochemistry. RESULTS: TKLF4 immunohistochemical staining was noted in 78.1% of the cases. Strong positivity was found in 15.6% and weak in 62.5% of the samples. Positive expression of p53, Fas, Bcl-2, survivin, Flip-l was found in 56.2%, 44.8%, 15.6%, 41.7% and 38.5% of the samples, respectively. KLF4 expression was significantly associated with p53 nuclear staining and Fas immunoreactivity. p53-positive tumors demonstrated more often high KLF4 staining compared to p53-negative tumors. Fas-positive tumors were associated with decreased KLF4 expression. Logistic regression analysis of apoptosis-related markers to KLF4 expression revealed that Fas positivity significantly decreased the probability of strong KLF4 expression, and inversely, Bcl-2 expression improved the prediction of KLF4 staining. When all 5 predictive variables were considered together (p53, Fas, survivin, Bcl-2, Flip-l) they significantly predicted the type of KLF4 expression in GC cells (p=0.019). CONCLUSION: Our results suggest that the decrease or loss of KLF4 expression correlates with diffuse-type GC and immunoreactivity to Fas, and are inversely linked with p53 nuclear accumulation. The significance of KLF4 in GC requires further studies and should be more thoroughly investigated for potential use in the evaluation and better stratification of GC patients. PMID- 24065486 TI - Correlation of the ICG test with risk factors and postoperative outcomes following hepatic resection. AB - PURPOSE: Liver failure is a major cause of early mortality following hepatectomy. The future-remnant liver function is an important factor when assessing the risk for postoperative liver functional impairment. Several techniques have been established for this evaluation, including the indocyanine green (ICG) test. The aim of this study was to evaluate the ICG clearance in patients scheduled for liver resection regarding perioperative and postoperative risk factors. METHODS: Thirty-one patients, scheduled for liver resection, underwent the ICG test. Peri operative and postoperative variables were recorded and analyzed using non parametric tests. RESULTS: Procedures extended from wedge excisions to extended hepatectomies. Plasma disappearance rate (PDR) was found positively correlated with total blood loss, transfusion and operation duration. There were 11 primary hepatic malignancies, including hepatocellular carcinomas and cholangiocarcinomas, 13 metastatic carcinomas, mainly of colorectal origin, and 7 benign lesions. The uninvolved liver parenchyma was normal in 20 (64. 5%) cases. Two patients died due to myocardial infarction and postoperative liver failure, respectively. CONCLUSION: The role of residual liver function and particularly the hepatic reserve assessment on liver surgery may be of most benefit in the routine stratification of risk, enabling surgical procedures to be performed with safety. The ICG clearance markers were found significantly correlated with perioperative risk factors in histologically "normal" liver parenchyma. In addition to computed tomographic (CT) volumetry, functional assessment of the hepatic reserve with the ICG test may persuade the preoperative planning and prevent postoperative liver failure. PMID- 24065487 TI - In which cases surgical gastrostomy and jejunostomy techniques are inevitable? AB - PURPOSE: This study investigated the surgical gastrostomy and jejunostomy procedures in cancer patients who needed nutritional support and endoscopy was unattainable. METHODS: Operation time and procedure, anesthesia and tube types, procedure-specific and surgical complications, and tube replacement at the follow up period were retrospectively analyzed. RESULTS: 109 patients (44 female, 65 male, mean age 50.9 years, range 14-87) were subjected to surgical gastrostomy/ jejunostomy. Ninety-three (85.4%) patients had head-neck and gastrointestinal cancers. In 94 (86.2%) patients endoscopy was impossible due to obstruction of the esophagus and stomach. Gastrostomy/jejunostomy was combined with other surgical procedures in 12 (11 %) patients. Procedure- related complications occurred in 22 (20.7%) patients. Early 30-day mortality occurred in 12 (11 %) cases. The median follow up period was 3.6 months (range 0-18). CONCLUSION: Obstructing cancer, obesity or previous laparotomy make the use of endoscopic techniques impossible. For these patients, surgical gastrostomy/jejunostomy is safe with acceptable complication rates and improves the treatment outcomes with nutritional support. PMID- 24065488 TI - Radiation enhancing effects with the combination of sanazole and irinotecan in hypoxic HeLa human cervical cancer cell line. AB - PURPOSE: This study was conducted to determine the synergistic radiation sensitizing effects of the combination of sanazole and irinotecan in hypoxic cervical cancer HeLa human tumor cell line. METHODS: The 3-(4,5 dimethylthiazol-2 yl)-2,5 diphenyltetrazolium bromide (MTT) assay was used to evaluate the number of surviving cells. Cell cycle was determined by flow cytometry. Surviving cell fractions were determined by the standard in vitro colony formation assay. RESULTS: The MTT assay showed that the presence of irinotecan with or without sanazole reduced significantly the cells' viability. Flow cytometry demonstrated that the combination of sanazole and irinotecan led to more HeLa cells blocked in G(2) phase. Cell colony formation assay indicated that the radiosensitivity of hypoxic HeLa cells was enhanced by sanazole and/or irinotecan. CONCLUSION: This study showed that the radiation enhancing effects produced by the combination sanazole and irinotecan was significant in hypoxic HeLa cells, which were arrested in the G(2) phase of the cell cycle. This study may provide a new combination modality of radiosensitizers in the radiotherapy of cervical cancer. PMID- 24065489 TI - Evaluation of linear accelerator-based stereotactic radiosurgery in the management of meningiomas: a single center experience. AB - PURPOSE: Stereotactic radiosurgery (SRS) has emerged as a viable alternative to surgery in the management of meningioma through exploiting the advantage of being minimally invasive with few complications and acceptable local control rates. The aim of this study was to evaluate the efficiency of linear accelerator (LINAC) based SRS in the management of meningiomas and to report our experience using this sophisticated technique. METHODS: Between July 1998 and March 2012, 79 patients (42 female, 37 male) were treated using LINAC-based SRS in the Department of Radiation Oncology, Gulhane Military Medical Academy. Median dose was 13 Gy (range 10- 16) prescribed to the 80-95% isodose line encompassing the target. RESULTS: Median follow-up time was 53 months (range 9-112). Median tumor volume was 3.43 cc (range 0.3-14.1). Local tumor control was 89.7% in the 68 patients with adequate follow-up. CONCLUSION: LINAC-based SRS offers a safe and effective treatment alternative to surgery in intracranial meningiomas with high local control rates and low morbidity. PMID- 24065490 TI - EMortality from cancer of the lung in Serbia. AB - PURPOSE: To estimate the death rates for lung cancer and their secular trends in the population of Serbia, excluding the autonomous province of Kosovo and Metohia, over the 1991-2009 period. METHODS: A descriptive epidemiological method was employed. Trend of the lung cancer mortality rates was estimated using joinpoint linear regression analysis. An average annual percentage of change (AAPC) was computed for trend using linear models assuming a Poisson distribution, and the corresponding 95% confidence interval (CI). RESULTS: The mortality rate from lung cancer in Serbia ranks as the highest in the world, and it has been increasing continuously from 1991 (AAPC = + 1.9; 95% CI=1.7-2.2). A significant increase in mortality was present in both the male population (AAPC = + 1.4; 95% CI=1.2-1.6), and the female population (AAPC = + 3.9; 95% CI=3.6-4.3). However, a significant decline in lung cancer mortality in men was seen in some age groups. In young men (35-39 and 40-44 years age groups), lung cancer death rates decreased continuously from 1991, by - 5.1% and - 2.6% per year, respectively. Among men in the 45-49 years age group, a marked increase of lung cancer mortality was observed from 1991 to 1998 (by + 6.5% per year), followed by significant decrease (- 1.9% per year). Among women, only in the youngest age group (35-39 years) a declining trend was present (- 0.6% per year), yet without significance. CONCLUSION: Lung cancer mortality rates in Serbia indicate the importance of consistent application of measures of primary and secondary prevention that have been proven effective in other countries. PMID- 24065491 TI - Prognostic importance of the nutritional status and systemic inflammatory response in non-small cell lung cancer. AB - PURPOSE: Despite all primary prevention and therapeutic efforts around the world, non-small cell lung cancer (NSCLC) continues to be an important public health problem. In the treatment of patients, laboratory parameters can be used for the determination of treatment intensity. These laboratory parameters should be easily accessible, cheap and easy to use. For this purpose, the prognostic importance in NSCLC of serum albumin levels, neutrophil-lymphocyte ratio (NLR) and thrombocyte-lymphocyte ratio (TLR) was investigated in the present study. METHODS: Serum albumin levels and body mass index (BMI) were used to determine the nutritional status and NLR and TLR were used to determine the systemic inflammatory response (SIR). RESULTS: While median survival was 9.1 months in hypoalbuminemic patients, it was 16.4 months in normoalbuminemic patients (p=0.002). The relationship of positive or negative NLR as an indicator of SIR with median survival was statistically significant (p=0.006). While median survival was 7.8 months for patients with NLR >=5, it was 14.7 for the patients with NLR <5 (p=0.006). TLR as a SIR indicator was not connected with median survival (p=0.072). CONCLUSION: Serum albumin, indicating the nutritional status and the NLR as an indicator of SIR, are significantly related with prognosis in locally advanced and metastatic NSCLC. Serum albumin measurement and calculation of NLR are easily accessible, cheap and easy to use laboratory methods. We consider that serum albumin levels and NLR can be utilized in the treatment planning of NSCLC patients. PMID- 24065492 TI - Central lymph node metastasis in cN0 papillary thyroid carcinoma. AB - PURPOSE: To evaluate the predictive factors of central lymph node (CLN) metastasis and the relationship between the number of metastatic CLN and risk factors for recurrence or metastasis in papillary thyroid carcinoma (PTC) patients. METHODS: Patients with PTC who had undergone subtotal or total thyroidectomy and ipsilateral CLN dissection were retrospectively reviewed. According to the number of metastatic CLN, patients were divided into 3 Groups: Group A: N=0; Group B: N=1-2; Group C: N >=3. RESULTS: Occult ipsilateral CLN metastasis was present in 34.2% (78/228) of the patients. Univariate analysis revealed that ipsilateral CLN metastasis was significantly higher in younger patients (age <45 years), in those with maximal carcinoma diameter >=1 cm and in those who presented with extrathyroid extension of carcinoma. Multivariate analysis showed tumor size and age were independent risk factors for ipsilateral CLN metastasis. Patient group distribution was as follows: Group A: N=150 (65.8%); Group B: N=50 (21.9%); Group C: N=28 (12.3%). Tumor size increased as the number of metastatic CLN increased, but age decreased when the number of metastatic CLN increased. Patients with CLN metastasis (Group B and C) had larger tumor size than those without metastasis. For patients with extrathyroid extension, patients in Group C had a significant odds ratio (0.215, p<0.05). CONCLUSION: A maximal carcinoma diameter >=1 cm and younger age are associated with a higher rate of ipsilateral CLN metastasis in unilateral PTC patients. Prophylactic ipsilateral CLN dissection may be effective in the management of these patients. The number of metastatic CLN is negatively associated with prognostic factors including age, tumor size and extrathyroid extension. PMID- 24065493 TI - The role of flow cytometry in the diagnosis of non- Hodgkin's lymphoma, Hodgkin's lymphoma, granulomatous inflammation and reactive lymph node specimens. AB - PURPOSE: In this study we aimed to compare the flow cytometry (FC) results of patients with B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, granulomatous inflammation and reactive lymph node and investigate the role of FC in malignant or non malignant conditions. METHODS: Ninety patients were divided into 5 groups according to histopathology results. Patients were compared according to cytokeratin and positivity percentage of the following surface markers: CD45, CD19, CD5, CD19-CD5, CD4, CD8, CD3,CD16-CD56, CD10, CD10-CD19, CD23, CD20, CD4 CD8, CD3-CD16-56, CD30, CD38, kappa and lambda light chains, CD20-CD23. Patients were also compared according to the intensity of the expression (exp) of same markers. ROC curve analysis was performed for CD19+ cell percentage, CD38 exp, kappa/lambda and lambda/kappa ratios. RESULTS: 1) Kappa/lambda and lambda/kappa ratios can distinguish B cell lymphoma from T cell lymphoma, Hodgkin's lymphoma, granulomatous inflammation and reactive lymph node; 2) CD19+ cell percentage can distinguish T cell lymphoma from Hodgkin's lymphoma, granulomatous inflammation and reactive lymph node; 3) CD38 exp can partly distinguish B cell lymphoma from T cell lymphoma, Hodgkin's lymphoma, granulomatous inflammation and reactive lymph node and T cell lymphoma from granulomatous inflammation, T cell lymphoma from reactive lymph node, Hodgkin's lymphoma from reactive lymph node. CONCLUSION: Flow cytometry has a role in distinguishing lymphomas from non malignant lesions. PMID- 24065494 TI - Informing cancer patient based on his type of personality: the suspicious (paranoid) patient. AB - Imparting bad news had always been an unpleasant task for the physician, as shown from ancient years to our days. In the healthcare sector and as far as the cancer patient is concerned, the imparting of bad news is performed by the patient's doctor within a therapeutic relationship of course. The fundamental question is how a therapist could tailor the information to any patient and if "Is it possible to determine who should be told what, when and how ?". The aim of this paper was to describe the suspicious character or type of personality thoroughly so that any physician can make a diagnosis and tailor the information strategy to the patient's needs. As method of research was used the qualitative method through groups with doctors and nurses, while research within groups lasted for 5 years. The degree of informing of the suspicious personality in the range "minimal - small - medium - large - very large" is : the degree of denial varies between large and very large. The degree of informing varies between medium and small and sometimes minimal. Informing the Family: The hardest family to deal with. Pay attention to litigious mania. Avoid confrontation or be drawn into agreeing with the family views. PMID- 24065495 TI - The influence of distressing symptoms to levels of depression in cancer patients. AB - PURPOSE: Our objectives were to identify the depression and the distressing symptoms in younger and elderly advanced cancer patients. METHODS: : The instruments that have been used were the Beck Depression Inventory (BDI) for younger patients, the Geriatric Depression Scale (GDS) for geriatric patients and the M. D. Anderson Symptom Inventory (MDASI) for the severity and impact of cancer-related symptoms. RESULTS: A trend for significant correlation was found between the GDS and MDASI symptoms for nausea (p=0.058), while a significant correlation was observed for increased sadness (p=0.011), increased constipation (p=0.021), interference of symptoms in mood (p=0.012) and in relations with people (p=0.007); interference of symptoms in mood was the most important risk factor. For younger patients, many statistically significant associations were found between distressing symptoms and depression; however, interference of symptoms in mood (p=0.045) was the only important risk factor. CONCLUSION: Health care professionals should take into consideration the risk factors for depressive symptoms suggesting a holistic care in advanced cancer patients. PMID- 24065496 TI - An evaluation of lifestyle changes in cancer patients after diagnosis. AB - PURPOSE: Cancer is an increasingly important health problem, and is second only to cardiovascular disease as cause of death. Cancer diagnosis causes significant changes in patients and their families, and social relationships are affected. For this reason, we examined the lives of patients subsequent to their diagnosis and sought to determine any changes in their lifestyles. METHODS: Between March 16th and September 30th, 2011, a questionnaire consisting of 20 questions was distributed via a face-to-face interview to 150 patients at the Marmara University Hospital Oncology Unit. Each patient was queried during the administration of his/her chemotherapy. Six of the questions were independent choices, and 14 were dependent (multiple choice). A Local Ethics Committee approval was obtained. RESULTS: Of the 150 patients, 70 (46%) were male and 80 female, and their median age was 55 years (range: 22-82). Following their diagnosis, 71% of males and 50% of females reported that they were complying with guidelines for a healthy lifestyle, and 19% of the patients said that they were eating healthier food. At the time they filled in the questionnaire, 61% said that they were hopeful; however, close to 10% said that they felt hopeless. Approximately 53% of the participants said that following their diagnosis they had a more sympathetic view of the underserved and underprivileged. CONCLUSIONS: It was surprising that an unexpectedly high percentage of the respondents reported that they did not make any changes in their lifestyles after their diagnosis of cancer, including eating healthier food. It appears Turkish cancer patients are coping with cancer in different means and ways than we expected of them. PMID- 24065497 TI - Depression and anxiety in cancer patients and their relatives. AB - PURPOSE: To investigate the depression and anxiety levels and the factors that affect patients receiving chemotherapy and their relatives with the Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI) scoring system. METHODS: 330 patients and 330 relatives of these patients were enrolled in this study. The study forms including the questions regarding the patient demographic characteristics, BDI, and STAI were completed during face-to-face interviews by trained interviewers for the determination of the psychological status of the patients and their relatives. BDI and STAI were validated for Turkish population by studies made before. RESULTS: According to BDI scale, 96 (29.1%) patients had mild and 60 (18.2%) had severe depression. Seventy-one (21.5%) relatives had mild and 24 (7.3%) had severe depression. Anxiety evaluation was made by STAI scale and a statistical difference emerged between patients and relatives (patients: 44.93+/-8.8 vs relatives: 43.27+/-8.5, p=0.015). The depression and anxiety levels were higher in women, in people with low socio-economic level, in people having a time period between diagnosis and participation in the study longer than 6 months, and in people having relapsing disease. CONCLUSION: Since there are many emotional and psychological disorders in patients and their relatives, much attention should be paid in order to diagnose and treat their psychiatric disorders and enough information about their disease should be given. PMID- 24065498 TI - Impaired coronary flow reserve in metastatic cancer patients treated with sunitinib. AB - PURPOSE: Hypertension is one of the major side effects of sunitinib, an angiogenesis inhibitor used in the treatment of metastatic renal cell carcinomas (mRCC) and gastrointestinal stromal tumors (GIST). Endothelial dysfunction, an early and reversible event in the pathogenesis of atherosclerosis, is suggested to be one of the possible underlying mechanisms of hypertension caused by angiogenesis inhibitors. Coronary flow reserve (CFR) measurement by trans thoracic Doppler echocardiography (TTDE) reflects coronary microvascular and endothelial functions, as a cheaper and an easy screening test. We have used TTDE to evaluate endothelial function and coronary microvascular function in mRCC and GIST patients under sunitinib treatment. METHODS: Eighteen metastatic cancer patients (16 mRCC and 2 GIST) on sunitinib treatment and 27 healthy subjects were enrolled in this cross-sectional study. Thyroid stimulating hormone (TSH), lipid profile, creatinine, hemoglobin, glucose, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anthropometric and physical parameters of patients were recorded. CFR recordings were performed by the Vivid 7 echocardiography device. RESULTS: CFR was significantly lower in patients when compared with controls (1.82+/-0.4 vs 2.71+/-0.8, respectively; p < 0.001). Impaired CFR was found in 13 (72%) patients whereas all controls had normal CFR values. CFR was inversely correlated with the duration of sunitinib treatment (r=-0.36, p =0.01), high sensitivite (hs) CRP (r = -0.574, p =0.01) and ESR (r = - 0.5, p = 0.02). CONCLUSION: Our findings indicate that CFR is significantly impaired in cancer patients on sunitinib treatment. There is an inverse correlation between CFR and duration of sunitinib treatment and inflammation markers. PMID- 24065499 TI - Risk factors for recurrence and survival in patients with primary retroperitoneal tumors. AB - PURPOSE: Postoperative recurrence remains the major cause of death in patients with primary retroperitoneal tumors (PRT). This study aimed at investigating the potential biological and surgical factors associated with postoperative recurrence and survival in PRT patients. METHODS: Retrospective data were collected from 231 PRT patients from January 1980 and December 2005 from the General Hospital of PLA and Beijing Shijitan Hospital. Recurrence-free survival (RFS) was determined with the Kaplan-Meier method and Cox model. Clinicopathologocal and surgical variables were analyzed to determine their impact on the outcome of PRT. RESULTS: The median follow-up period was 35 months (range 1-221). The most common histological subtype was liposarcoma (N=93, 40.3%), followed by malignant fibrous histiocytoma (MFH; N=46, 19.9%). Eighty eight patients had local recurrence (71%) and 36 (29%) developed distant metastasis. On multivariate analysis, the surgical margin status and histological type were associated with postoperative recurrence. Patients with liposarcoma and MFH had significantly increased postoperative recurrence rate (p=0.008 and p=0.002, respectively). The overall survival in PRT patients was comparable between the incomplete resection group and the complete resection group (p=0.060), but significantly associated with the surgical resection (p=0.045). CONCLUSIONS: Our results demonstrate that high tumor grade, histological subtype, incomplete resection and positive residual margins are strongly associated with PRT recurrence. Resection should be considered in patients with PRT for improving overall survival while prolonging RFS after resection. PMID- 24065500 TI - Magnetic resonance imaging and image analysis of post - radiation changes of bone marrow in patients with skeletal metastases. AB - PURPOSE: To evaluate the post-radiation lesions of the bone marrow with magnetic resonance imaging (MRI) and image analysis in patients with bone metastases undergoing radiation therapy (RT). METHODS: Thirty-five patients with bone metastases were studied from June 2008 to December 2010. All patients had osseous metastases from various primary malignancies and underwent palliative RT. MRI was performed in a Philips Gyroscan Intera 1T scanner at the beginning of RT and 12 18 days later. T1-TSE, T2-TSE and short tau inversion recovery (STIR) sequences were used. All images obtained were evaluated for early post-radiation lesions. Additionally, 1st and 2nd order textural features were extracted from these images and were introduced into a probabilistic neural network (PNN) classifier in order to create an automated classification system for those lesions. RESULTS: Changes of signal intensity in T1-TSE, T2-TSE and STIR sequences were evaluated for the presence of edema, fatty conversion of the bone marrow or areas of hemorrhage within the limits of the irradiated area. The automated classification system showed positive results in correctly discriminating the post-radiation lesions that MRI revealed. The overall classification accuracy for discriminating between pre-radiation and post-radiation lesions was 93.2%. Furthermore, the overall classification accuracy for discriminating between post-radiation lesions was 86.67%. CONCLUSION: It seems that MRI can evaluate the degree of early therapy-induced bone marrow lesions observed during the first 18 days from the beginning of RT. The proposed neural network-based classification system might be used as an assisting tool for the characterization of these lesions. PMID- 24065501 TI - Legal, cultural and ethical considerations on the informing of the cancer patient: a perspective from Greece. AB - PURPOSE: To discuss the current official legal position of the Greek Council and the official international statement on the subject, as well as the emerging cultural and moral aspects on the issue of informing the cancer patient. METHODS: Perusal of national and international legal and ethics sources, under a multidisciplinary perspective. RESULTS: According to the Council of State of Greece the violation of informing the patient by the physician constitutes urban liability and disciplinary offence. The Greek Code of Medical Ethics declares that the physician is obliged to inform his patient about his health and respect the desire of the patient who decides not to be informed. The UNESCO declaration does not seem to clarify the subject. In Greece, physicians have the tendency to tell the truth more often today than in the past, reflecting the global tendency, although the majority still discloses the truth to the next of kin. The difference in the tactics of informing in several nations reflects huge cultural, social, economic and religious differences in each society. CONCLUSION: Well informed and knowledgeable health-care and legal professionals, alongside with patients and ethical directors, should sit at the same table in order to productively discuss the most sensitive matters of the contemporary medical practice. PMID- 24065502 TI - Medullary carcinoma of the breast: a brief report from a tertiary care center. PMID- 24065503 TI - Successful treatment of benign metastasizing leiomyoma with oral alternated chemotherapeutic agents. PMID- 24065504 TI - Lung tuberculosis causing false positivity on positron emission tomography. PMID- 24065505 TI - Does trastuzumab-emtansine have better cardiac safety profile in contrast to trastuzumab? PMID- 24065506 TI - Re-irradiation for recurrent head and neck carcinomas (by Dr. Peponi et al). PMID- 24065507 TI - Reply to Dr. Jon Cacicedo Fernandez de Bobadilla. PMID- 24065508 TI - Significance of the resection margin and risk factors for close or positive resection margin in patients undergoing breast-conserving surgery (by Drs Gatek and Vrana). PMID- 24065509 TI - Reply to Dr. Charalampos Seretis. PMID- 24065510 TI - Aretaeus of Cappadocia and the first accurate description of uterine carcinoma. AB - In our article we present the work on uterine cancer of the distinguished physician Aretaeus of Cappadocia. Uterine cancer was known since antiquity and its presence is testified in ancient Egyptian and Greek medical writings. However in the 2nd century AD Aretaeus provided the first accurate description of uterine cancer, dividing it in two forms, an ulcerated and a non ulcerated, both painful and fatal. PMID- 24065511 TI - [Endophthalmitis as a serious complication of intravitreal drug delivery]. AB - BACKGROUND: Endophthalmitis, regarded as a severe complication, can occur after intraocular injection of drugs (IVI). At present only few reports exist on the development of this disease, although recently the number of intraocular injections to treat especially age-related macular degenerations is increasing considerably. METHODS: In this paper we present our results of a retrospective study of 27 patients suffering from endophthalmitis after IVI. Treatment had been performed between January 2008 and March 2012. The indications for IVI were as follows: age-related macular degeneration 19, venous branch occlusion 1, diabethic retinopathies 6, uveitis 1. The following drugs were injected: bevacizumab in 8, Rranibizumab in 19 patients. The following data were assessed: incubation time, best corrected visual acuity that had been determined before treatment and later 3, 6 and 9 months after therapeutic vitrectomy. Additionally we describe the ophthalmoscopic changes and the results of bacteriological studies. RESULTS: Endophthalmitis was diagnosed 5.8 days after IVI on average. The vision of all patients had only been hand movements during the first examination. During the observation time the postoperative visual acuity could be improved only to 1/35 on average. During vitrectomy in 24 out of 27 patients a whitish retinal infiltration could be observed. 18 of 27 patients showed a hypopyon during slit lamp examination. 11 patients developed a retinal detachment and one eye had to be enucleated. CONCLUSIONS: Endophthalmitis must be regarded as a severe complication causing a high risk of retinal detachment with permanent loss of visual acuity. Retinal infiltrations and haemorrhages occur already in the early stages and cause finally a very poor prognosis. The incubation time as a rule amounts to 6 days. The increasing number of IVI and the high risk of damaged retinal structures due to intraocular infections should make postoperative retinal follow-up examinations mandatory, especially during the first 6 days. PMID- 24065512 TI - [Applications of optical coherence tomography (OCT) in neuro-ophthalmology]. AB - Optical coherence tomography (OCT) has revolutionised ophthalmology. Due to modern instruments with extremely high resolution there are more and more applications also in neuro-ophthalmological disorders. This review gives an overview on typical changes in OCT for the following diseases: autosomal dominant optic atrophy, Leber hereditary optic neuropathy, toxic, traumatic and compressive optic neuropathy, optic nerve drusen, anterior ischaemic optic neuropathy, optic disc pit, papilledema, optic neuritis (isolated or associated with multiple sclerosis or neuromyelitis optica), neurodegenerative diseases and hereditary retinal diseases. A diagnosis exclusively based on an OCT examination is not always possible, but in several diseases there are pathognomonic changes that directly lead to the correct diagnosis. Particularly with the often complex settings in neuro-ophtalmology the OCT should be seen as a supplementary modality and not as a replacement for other techniques. PMID- 24065513 TI - PET/CT in malignant lymphoma: basic information, clinical application, and proposal. AB - Coregistered fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) provides functional and morphologic data useful for the management of lymphoma. PET/CT is a promising tool in initial staging/re-staging, monitoring post-treatment recurrence/exacerbation, and evaluating prognosis at mid-treatment use [interim PET/CT (iPET/CT)]. Many multicenter studies are currently underway to investigate the effectiveness and safety of stratified treatment protocols using iPET/CT. Thus, the establishment of a system focusing on standardization of image quality through established protocols for scanning or quality control (QC) of the acquired data and organization of a core laboratory facility to promote standardization would be beneficial. Uniformity of image quality across multiple institutions can be guaranteed through optimization of imaging conditions and appropriate QC of PET/CT scanners to ensure standardization. Further research is required to ensure the standardization of PET/CT protocols used in the management of malignant lymphoma. PMID- 24065514 TI - Enlargement of bilateral kidneys by infiltration of leukemic cells in acute lymphoblastic leukemia at relapse after allogeneic hematopoietic stem cell transplantation. PMID- 24065515 TI - Understanding the lived experience of Latino adolescent and young adult survivors of childhood cancer. AB - PURPOSE: The purpose of this study was to investigate the experience of surviving cancer for Latino adolescents and young adult (AYA) survivors of pediatric cancer. METHODS: Using a phenomenological approach, this study focused on the experience of cancer survivorship through in-depth interviews with 14 Latino AYA survivors (16-29 years) diagnosed as young children (0-15 years) and at least 1 year post-treatment RESULTS: Four essential themes about the Latino AYA experience as childhood cancer survivors emerged from analysis: borrowed strength of family and hospital staff; sustained positive attitude; perceived vulnerability; branded a cancer survivor. According to these participants, the lived experience of surviving cancer was predominately positive. These emerging adults were able to focus on the positive lessons learned from their cancer experience such as the importance of personal relationships and an optimistic outlook on life. Yet, it was clear that long after these survivors had been labeled "cured" by the medical team, cancer continued to be a large part of their existence. CONCLUSIONS: The results indicate that these emerging adults faced their cancer experience with optimism, leaned on relationships with family and health care professionals, and demonstrated resilience through their cancer treatment and beyond. IMPLICATIONS FOR CANCER SURVIVORS: This unique description of Latino survivors' experiences demonstrates that they simultaneously face uncertainty and identify positive influences of the cancer experience in particular unwavering familial support. These findings provide opportunities for health care providers to better understand this rapidly growing population and to create culturally resonant programs that can promote their long-term health and well being. PMID- 24065516 TI - Retained rectal foreign body with rectal perforation; a complication of the traditional management of haemorrhoids: a case report. AB - Retained rectal foreign bodies are most commonly seen in homosexuals and after assault. A few have been reported after self-treatment of anorectal conditions and prostatic massage. Harmful traditional medical practices have been reported in many communities in Africa but therapeutic anal insertion of foreign bodies for the management of haemorrhoids is rare. We present a patient with features of peritonitis following insertion of a wine bottle into his rectum in an attempt to manage his prolapsed haemorrhoids. PMID- 24065517 TI - Congenital vivax malaria: rare or underdiagnosed infection. AB - Congenital malaria is a rare disease both in endemic and non-endemic areas. It is seldom suspected due to its rarity and the fact that its signs and symptoms may be similar to those with neonatal sepsis. Furthermore, clues such as a history of maternal travel to an endemic area during pregnancy or any malaria symptoms may not always be revealed. The situation is further complicated by subjective smear tests and an expensive rapid diagnostic test, especially in developing countries where affordability is an issue. We call attention to the need to consider the diagnosis of malaria in neonates who present with signs and symptoms often confused with sepsis, to enable a quick diagnosis and treatment in order to reduce mortality. PMID- 24065518 TI - Tuberculosis presenting as mediastinal and lung mass radiologically: a case report. AB - Mediastinal and lung masses are commonly encountered. The causes range from benign to malignant lesions to which infective lesions contribute to some extent. The conditions presenting as a lung mass with metastatic mediastinal mass are usually indications of malignancy. Tuberculosis is an uncommon cause of such presentations. We report a case of a 53-year-old man who presented with a lung mass with conglomerate lymph nodal mass which was later confirmed as tuberculosis on histopathological examination. PMID- 24065519 TI - EGCG suppresses Fused Toes Homolog protein through p53 in cervical cancer cells. AB - The anticarcinogenic actions of epigallocatechin-3-gallate (EGCG), one of the main ingredients of green tea, against various cancer types including cervical cancer are well documented. Studies pertaining to the exact molecular mechanism by which EGCG induces cancer cell growth inhibition needs to be investigated extensively. In the present study, we observed a stupendous dose dependent reduction in the protein expression of Fused Toes Homolog (FTS) after treatment with EGCG at 1, 10, 25 and 50 MUM. Further, we were interested in finding out whether the decrease in the protein expression of FTS was due to decreased mRNA synthesis. Real time reverse transcriptase polymerase chain reaction results revealed a similar dose dependent reduction in the FTS mRNA after EGCG treatment. Chromatin immunoprecipitation analysis revealed the interaction between p53 and the promoter region of FTS. A dose dependent increase in this interaction was evidenced at 25 and 50 MUM EGCG treatment. p53 silencing increased the expression of FTS and also decreased the reduction in the levels of FTS expression after EGCG treatment. The decrease in the levels of FTS was more significant at 25 and 50 MUM and is associated with reduced physical interaction of FTS with Akt, phosphorylation of Akt and survival of HeLa cells. Collectively, these results conclude that EGCG induced anti-proliferative action in the cervical cancer cell involves reduced mRNA expression of FTS through p53. PMID- 24065521 TI - Genetic diversity of MYH3 gene associated with growth and carcass traits in Chinese Qinchuan cattle. AB - MYH3, whose function is to convert chemical energy to mechanical energy through ATP hydrolysis, is mainly expressed in skeletal muscle at various stages and is indispensable in the procedure of development of skeletal muscle and heart. In the study, genetic variations and genotypes of MYH 3 gene in a total of 365 Qinchuan cattles were analyzed by polymerase chain reaction-restriction fragment length polymorphism, as well as verified the effect on growth and carcass traits. After PCR products were digested by restriction enzymes, eight SNPs were identified and individuals were genotyped. It showed that the SNPs at nucleotides were all in low linkage disequilibrium, therefore no dominated haplotype was found in the population. The result of statistic analysis indicated seven SNPs were significantly associated with growth and carcass traits (P < 0.05, N = 365) except locus G13791A. To sum up, the result of the study proved that polymorphisms in MYH3 gene are associated with the growth performance of Chinese Qinchuan cattle, so the variations of the gene could be used as possible molecular assisted-makers in the beef cattle breeding program and management. PMID- 24065520 TI - Genetic variants in transforming growth factor-beta gene (TGFB1) affect susceptibility to schizophrenia. AB - Immense body of evidence indicates that dysfunction of immune system is implicated in the etiology of schizophrenia. The immune theory of schizophrenia is supported by alterations in cytokine profile in the brain and peripheral blood. Given the strong genetic background of schizophrenia, it might be assumed that aberrant production of cytokines might be the consequence of genetic factors. This study aimed at investigating the association between schizophrenia susceptibility and selected functional polymorphisms in genes encoding cytokines including: interleukin-2 (IL2 -330T>G, rs2069756), interleukin-6 (IL-6 -174G>C, rs1800795), interferon-gamma (IFNG +874T>A, rs2430561) as well as for the first time transforming growth factor-beta1 (TGFB1 +869T>C, rs1800470 and +916G>C, rs1800471). We recruited 151 subjects with schizophrenia and 279 controls. There was a significant difference in the genotype distribution and allelic frequency of the TGFB1 +869T>C between patients with schizophrenia and healthy controls (p < 0.05). The risk of schizophrenia was more than two-fold higher in carriers of T allele (CT+TT genotypes) than individuals with CC genotype. Given documented gender differences in incidence of schizophrenia, we conducted separate analyses of male and female participants. We have shown that the association was significant in females, while in males it reached a trend toward statistical significance. To the best of our knowledge, it is the first report showing the association between TGFB1 +869T>C polymorphism and schizophrenia. PMID- 24065522 TI - The short chain cell-permeable ceramide (C6) restores cell apoptosis and perifosine sensitivity in cultured glioblastoma cells. AB - Primary glioblastoma multiforme is the most malignant form of astrocytic tumor with an average survival of approximately 12-14 months. The combination of novel Akt inhibitors with anti-cancer therapeutics has achieved improved anti-tumor efficiency. In the current study, we examined the synergistic anti-cancer ability of Akt inhibitor perifosine in combination with short-chain ceramide (C6) against glioblastoma cells (U87MG and U251MG), and studied the underlying mechanisms. We found that perifosine, which blocked Akt/mammalian target of rapamycin activation, only induced moderate cell death and few cell apoptosis in cultured glioblastoma cells. On the other hand, perifosine administration induced significant protective autophagy, which inhibited cell apoptosis induction. Inhibition of autophagy by 3-methyaldenine or by autophagy-related gene-5 RNA interference significantly enhanced perifosine-induced apoptosis and cytotoxicity. We found that the short chain cell-permeable ceramide (C6) significantly enhanced cytotoxic effects of perifosine in cultured glioblastoma cells. For mechanism study, we observed that ceramide (C6) inhibited autophagy induction to restore cell apoptosis and perifosine sensitivity. In conclusion, our study suggests that autophagy inhibition by ceramide (C6) restores perifosine induced apoptosis and cytotoxicity in glioblastoma cells. PMID- 24065523 TI - FFAs and adipokine-mediated regulation of hsa-miR-143 expression in human adipocytes. AB - Accumulating evidence suggests that microRNAs (miRNAs) play an important role in regulating the pathways in adipose tissue that control processes such as adipogenesis, insulin resistance, and inflammation. MiR-143 is a well characterized miRNA involved in adipogenesis and may be involved in regulating insulin resistance. Free fatty acids (FFAs) and adipokines, such as tumor necrosis factor-alpha (TNF-alpha), leptin, resistin, and interleukin-6 (IL-6), have already been identified as main regulators of obesity and insulin sensitivity. Therefore, we studied the effects of these inflammatory cytokines on the expression of miR-143. FFAs, resistin, and leptin downregulated miR-143 expression in human adipocytes, whereas TNF-alpha and IL-6 had little effect on miR-143 expression. These results suggest that the expression of miR-143 is affected by a variety of factors that are related to insulin sensitivity. Therefore, miR-143 may be an important mediator in the development of obesity related insulin resistance. PMID- 24065524 TI - Genetic analysis of prolactin gene in Pakistani cattle. AB - Prolactin (PRL) is a polypeptide hormone, secreted mainly by the anterior pituitary gland. It is involved in many endocrine activities. The key functions of PRL are related to reproduction and lactation in mammals. To ascertain the presence of polymorphisms in the bovine PRL gene (bPRL), the bPRL gene was sequenced. Five mutations were identified in exonic region and eleven in associated intronic regions in 100 cattle from four Pakistani cattle breeds. Haplotype of predicted amino acid changes represent a common alteration at codon 222 from R-Arginine into K-Lysine in all four breeds. Significant statistical variations were observed in the distribution of single nucleotide polymorphism (SNP) in various cattle populations. However, on basis of present study, an association of these SNPs with milk performance traits in four Pakistani cow breeds cannot be truly replicated but at least can be effective DNA markers for some of the breeds studied. Linkage analysis between these SNPs on larger populations can be useful for the association with milk production traits. Furthermore, present study may be used for marker-assisted selection and management in cattle breeding program in local cattle breeds. PMID- 24065525 TI - Species-specific ITS primers for the identification of Picoa juniperi and Picoa lefebvrei and using nested-PCR for detection of P. juniperi in planta. AB - Desert truffles, hypogeous Pezizales (Ascomycota), are difficult to identify due to evolutionary convergence of morphological characters among taxa that share a similar habitat and mode of spore dispersal. Also, during their symbiotic phase, these are barely distinguishable morphologically, and molecular probes are needed for their identification. We have developed a PCR-based method for the identification of Picoa juniperi and Picoa lefebvrei based on internal transcribed spacers of rDNA. Two PCR primers specific for P. lefebvrei (FLE/RLE) and two specific for P. juniperi (FJU/RJU) were designed. A collection of samples from different geographical areas representing diversity of these species were examined for unique regions of internal transcribed spacers 1, 2 and 5.8S gene of rDNA (ITS) compared to other closely related species. Annealing temperatures and extension times were optimized for each set of primers for maximum specificity and efficiency. They proved to be efficient to specifically detect the presence of P. juniperi and P. lefebvrei by PCR and neither set amplified purified DNA from other truffle species as well as some ascomycetous fungi. The partial small subunit of ribosomal DNA genes of P. juniperi were amplified with the genomic DNA extracted from Helianthemum ledifolium var. ledifolium roots by nested polymerase chain reaction (PCR) using the universal fungal primer pair ITS1/ITS4 and specific primer pair FTC/RTC, which was designed based on internal transcribed spacer 1, 2 and 5.8S gene of rDNA sequences of P juniperi. The nested-PCR was sensitive enough to re-amplify the direct-PCR product, resulting in a DNA fragment of 426 bp. The efficacy of nested-PCR showed that it could re-amplify the direct-PCR product and detect 200 fg genomic DNA. PMID- 24065526 TI - Molecular characterization and expression analysis of three hypoxia-inducible factor alpha subunits, HIF-1alpha, -2alpha and -3alpha in hypoxia-tolerant Indian catfish, Clarias batrachus [Linnaeus, 1758]. AB - The present study aimed at characterization of three HIF-alpha subunits, HIF 1alpha -2alpha and -3alpha from hypoxia-tolerant Clarias batrachus, as well as to elucidate their expression pattern under short and long-term hypoxic conditions and identification of biomarker candidate. The complete cDNAs of HIF-1alpha, 2alpha and -3alpha were 2,833, 4,270 and 3,256 bp in length, encoding 774, 818 and 628 amino acid residues, respectively. In C. batrachus, HIF-alpha subunits were structurally similar in DNA binding, dimerization, degradation and transcriptional activation domains, but differed in their oxygen-dependent degradation domains. Presence of c-Jun N-terminal kinase binding domain in HIF alpha subunits was reported here for the first time in fish. In adult C. batrachus, three HIF-alpha mRNAs were detected in different tissues under normoxic conditions, however HIF-1alpha was highly expressed in all the tissues studied, in comparison to HIF-2alpha and -3alpha. Short-term hypoxia exposure caused significant increase in three HIF-alpha transcripts in brain, liver and head kidney, while after long-term hypoxia exposure, significant up-regulation of HIF-1alpha in spleen and -2alpha in muscle was observed and HIF-3alpha significantly down-regulated in head kidney. These observations suggest that the differential expression of HIF-alpha subunits in C. batrachus was hypoxic time period dependent and may play specialized roles in adaptive response to hypoxia. HIF-2alpha, with its highly elevated expression in muscle tissues, can be a robust biomarker candidate for exposure to hypoxic environment. PMID- 24065527 TI - ELISA examining urinary angiotensinogen as a potential indicator of intrarenal renin-angiotensin system (RAS) activity: a clinical study of 128 chronic kidney disease patients. AB - In the current study, we measured urinary angiotensinogen (AGT) through enzyme linked immunoadsordent assay (ELISA) and analyzed its correlation with intrarenal renin-angiotensin system (RAS) activity in 128 chronic kidney disease (CKD) patients. Urinary and plasma renin activity, AGT, angiotensin II (Ang II) and aldosterone levels were also measured by radioimmunoassay (RIA) or ELISA in these participants. Further, the expression level of intrarenal renin, AGT, Ang II and Ang II receptors were examined by immunohistochemistry staining (IHCS) in 72 CKD patients. Their correlations with urinary AGT were also analyzed. We found that the urinary AGT level was positively correlated with hypertension (rho = 0.28, P < 0.01), urinary protein (r = 0.38, P < 0.01), urinary Ang II (r = 0.29, P < 0.05), urinary type IV collagen (Col IV) (r = 0.56, P < 0.01), and was negatively correlated with estimated glomerular filtration rate (eGFR) (r = -0.28, P < 0.01), urinary sodium (r = -0.22, P < 0.05) and serum AGT (r = -0.27, P < 0.01). Multiple regression analysis indicated low serum AGT (P < 0.01), high urinary protein (P < 0.01), high urinary Ang II (P < 0.05) and high urinary Col IV (P < 0.01) were correlated significantly with high urinary AGT. Urinary AGT level was positively correlated with intrarenal expression level of AGT (rho = 0.46, P < 0.01), Ang II (rho = 0.56, P < 0.01) and Ang II type 1 receptor (rho = 0.32, P < 0.01), as detected by IHCS. Together, these data suggest that urinary AGT might be a potential biomarker of intrarenal RAS and Ang II activities in CKD patients. PMID- 24065528 TI - Lack of association of lysyl oxidase (LOX) gene polymorphisms with intracranial aneurysm in a south Indian population. AB - Intracranial aneurysm (IA) accounts for 85 % of haemorrhagic stroke and is mainly caused due to weakening of arterial wall. Lysyl oxidase (LOX) is a cuproenzyme involved in cross linking structural proteins collagen and elastin, thus providing structural stability to artery. Using a case-control study design, we tested the hypothesis whether the variants in LOX gene flanking the two LD block, can increase risk of aSAH among South Indian patients, either independently, or by interacting with other risk factors of the disease. SNPs were genotyped by fluorescence-based competitive allele-specific PCR (KASPar) chemistry. We selected 200 radiologically confirmed aneurysmal cases and 235 ethnically and age and gender matched controls from the Dravidian Malayalam speaking population of South India. We observed marked interethnic differences in the genotype distribution of LOX variants when compared to Japanese and African populations. However, there was no significant association with any of the LOX variants with IA. This study also could not observe any significant role of LOX polymorphisms in influencing IA either directly or indirectly through its confounding factors such as hypertension and gender in South Indian population. PMID- 24065529 TI - Different anti-apoptotic effects of normal and asthmatic serum on normal eosinophil apoptosis depending on house dust mite-specific IgE. AB - We investigated the effect of asthmatic serum on constitutive eosinophil apoptosis in normal subjects. Eosinophil apoptosis in normal subjects was inhibited by asthmatic serum but not normal serum. In a detailed analysis based on the presence of house dust mite (HDM) IgE, HDM IgE-positive (+) asthmatic serum was more effective for eosinophil apoptosis than that of HDM IgE-negative ( ) asthmatic serum. HDM IgE+ asthmatic serum inhibited both HDM IgE- and HDM IgE+ normal eosinophil apoptosis, and HDM IgE- asthmatic serum suppressed eosinophil apoptosis of HDM IgE+ normal. HDM IgE- normal serum did not inhibit either HDM IgE- or HDM IgE+ normal eosinophil apoptosis, and HDM IgE+ normal serum inhibited HDM IgE+ normal eosinophil apoptosis. The kind of HDM IgE (Dermatophagoides pteronissinus-specific IgE and Dermatophagoides farinae-specific IgE) was not related to the effect of asthmatic serum on eosinophil apoptosis. Extracts of DP and DF, Der p1, and Der p2, were not effective for eosinophil apoptosis. HDM IgE+ asthmatic serum inhibited cleavage of procaspase 9 and procaspase 3. Asthmatic serum induced Akt and ERK phosphorylation, and ERK activation was suppressed by AKTi. Taken together, asthmatic serum inhibited normal eosinophil apoptosis via PI3K/Akt/ERK cascade. The novel approach taken in this study provided better insight into HDM-associated anti-apoptotic mechanism of eosinophils in patients with asthma. PMID- 24065530 TI - Evaluation of tumor suppressor gene expressions and aberrant methylation in the colon of cancer-induced rats: a pilot study. AB - Altered expression and methylation pattern of tumor suppressor and DNA repair genes, in particular involved in mismatch repair (MMR) pathway, frequently occur in primary colorectal (CRC) tumors. However, little is known about (epi)genetic changes of these genes in precancerous and early stages of CRC. The aim of this pilot study was to analyze expression profile and promoter methylation status of important tumor suppressor and DNA repair genes in the early stages of experimentally induced colorectal carcinogenesis. Rats were treated with azoxymethane (AOM), dextran sodium sulphate (DSS) or with their combination, and sacrificed 1 or 4 months post-treatment period. The down-regulation of Apc expression in left colon, detectable in animals treated with DSS-AOM and sacrificed 1 month after the end of treatment, represents most early marker of the experimental colorectal carcinogenesis. Significantly reduced gene expressions were also found in 5 out of 7 studied MMR genes (Mlh1, Mlh3, Msh3 Pms1, Pms2), regarding the sequential administration of DSS-AOM at 4 months since the treatment. Strong down-regulation was also discovered for Apc, Apex1, Mgmt and TP53. Tumors developed in rectum-sigmoid region displayed significantly lower Apc and Pms2 expressions. The decreased expression of studied genes was not in any case associated with aberrant methylation of promoter region. Present data suggest that down-regulation of Apc and MMR genes are prerequisite for the development of CRC. In this study we addressed for the first time early functional alterations of tumor suppressor genes with underlying epigenetic mechanisms in experimentally induced CRC in rats. PMID- 24065531 TI - Impact of matrix metalloproteinase-8 gene variations on the risk of thoracic aortic dissection in a Chinese Han population. AB - The importance of matrix metalloproteinase 8 (MMP8) expression during the progression of thoracic aortic dissection (TAD) has been recently emphasized. Genetic variations that affect proteinase expression or activity might contribute to the pathogenesis of TAD. In this study, we investigated whether the MMP8 C 799T genotype is associated with TAD. The frequency distributions of the MMP8 C 799T polymorphism were determined by direct sequencing. Associations between the polymorphism and disease progression in TAD were investigated. The level of plasma and tissue MMP8 was measured by enzyme-linked immunosorbent assay and western blotting. The MMP8 C-799T polymorphism was significantly associated with susceptibility to disease progression in TAD patients (n = 152) than in controls (n = 147) (P = 0.004, OR = 0.62, 95 % CI 0.45-0.86). The TT homozygotes had a significantly higher risk of TAD compared to C allele carriers in a logistic regression model, after adjustment for the conventional risk factors for TAD. The plasma MMP8 concentration was significantly higher in TAD patients compared to control patients (P < 0.05). TT genotypes had increased MMP8 levels compared to CC and CT genotype carriers in both TAD and control subjects (P < 0.05). The C 799T polymorphism in the MMP8 promoter is part of the genetic variation underlying the susceptibility of individuals to the progression of TAD. PMID- 24065532 TI - Starfish polysaccharides downregulate metastatic activity through the MAPK signaling pathway in MCF-7 human breast cancer cells. AB - We investigated the effects of starfish (Asterina pectinifera) polysaccharides on metastatic activity in MCF-7 estrogen receptor (ER)-positive human breast cancer cells. In wound healing assay, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell migration was dose-dependently decreased by the starfish polysaccharides (PS). Transcription of aromatase, which catalyzes estrogen synthesis from androgen, was reduced by PS. Also, transcription of TPA-induced cyclooxygenase-2 (COX-2), which enhances breast cancer progression and metastasis via the increase of prostaglandin E2 biosynthesis, was downregulated by the PS in a dose-dependent manner. PS decreased the expression and activity of matrix metalloproteinase (MMP)-9, an important factor in the degradation of basement membrane and extracellular matrix in the metastasis process. In contrast, mRNA expression of tissue inhibitor of matrix metalloproteinase (TIMP)-1, a MMP inhibitor, was increased by 10-120 MUg/ml of PS but not that of TIMP-2. We also found that PS reversed the phosphorylations of p38, ERK and JNK but not IkappaBalpha and NF kappaB. These results demonstrate that PS successfully inhibits PKC-mediated cell migration and metastatic activities in MCF-7 ER-positive human breast cancer cells via downregulation of MMP-9 activity mediated by TIMP-1 upregulation and inhibition of aromatase and COX-2 expression. Also, COX-2 and MMP-9 expressions are attenuated through the inhibition of AP-1 transcription activity via the downregulation of c-Jun expression regulated by p38, ERK and JNK signaling. In conclusion, the present investigation shows that PS may prevent COX-2- and MMP-9 mediated metastatic activities in MCF-7 ER-positive breast cancer cells through the downregulation of MAPK signaling pathways. PMID- 24065533 TI - The HTLV-1 HBZ protein inhibits cyclin D1 expression through interacting with the cellular transcription factor CREB. AB - Human T cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that can cause adult T-cell leukemia (ATL) and other diseases. The HTLV-1 bZIP factor (HBZ), which is encoded by an mRNA of the opposite polarity of the viral genomic RNA, interacts with several transcription factors and is involved in T cell proliferation, viral gene transcription and cellular transformation. Cyclin D1 is a pivotal regulatory protein involved in cell cycle progression, and its depressed expression correlates with cell cycle prolongation or arrested at the G1/S transition. In our present study, we observed that HBZ expression suppressed cyclin D1 level. To investigate the role of HBZ on cyclin D1 depression, we transduced HBZ with lentivirus vector into 293T cells, CEM cells and Jurkat cells. The results of Western blot, RT-PCR and luciferase assays showed that transcriptional activity of the cyclin D1 promoter was suppressed by the bZIP domain of HBZ (HBZ-bZIP) through cyclic AMP response element (CRE) site. Immunoprecipitation and GST pull-down assays showed the binding of HBZ-bZIP to CRE-binding protein (CREB), which confirmed that the cyclin D1 promoter activity inhibition via the CRE-site was mediated by HBZ-bZIP. The results suggested that HBZ suppressed cyclin D1 transcription through interactions with CREB and along with other viral protein, HBZ may play a causal role for leukemogenesis. PMID- 24065534 TI - Rs2200733 and rs10033464 on chromosome 4q25 confer risk of cardioembolic stroke: an updated meta-analysis. AB - A recent genome-wide association study elucidated that 4q25 was implicated in ischemic stroke, but subsequent studies showed inconsistent results. In order to get coincident conclusion, we investigated two SNPs (rs2200733, rs10033464) on chromosome 4q25 in 1,388 stroke patients and 1,629 controls from Chinese Han population and then performed a meta-analysis. Although we failed to detect any association between 4q25 and stroke in our case-control study, meta-analysis revealed that rs2200733 showed association with overall stroke (OR 1.18, 95 % CI 1.08-1.27), but not for rs10033464. Subsequently subgroup analysis indicated that both rs2200733 and rs10033464 conferred increased risk for cardioembolic stroke (CE stroke) (for rs2200733, OR 1.38, 95 % CI 1.26-1.51; for rs10033464, OR 1.14, 95 % CI 1.02-1.26), while rs2200733 was marginal associated with non-CE stroke (OR 1.09, 95 % CI 1.02-1.16). our results demonstrated that two SNPs (rs2200733 and rs1003346) on chromosome 4q25 were limited to the stroke of cardioembolic etiology. To confirm this conclusion, well-designed studies with larger sample size involving case-control populations with homogeneous ancestry warrant to be conducted in the future. PMID- 24065535 TI - Association between CYP1A1 polymorphisms and esophageal cancer: a meta-analysis. AB - Cytochrome P4501A1 (CYP1A1) enzyme is a member of the CYP superfamily of enzymes. CYP1A1 A2455G and T3801C are two most commonly studied polymorphisms loci. Previous studies have reported that CYP1A1 polymorphisms increase esophageal cancer (EC) risk. However, the results remain controversial and ambiguous. To further investigate the association between CYP1A1 polymorphisms (A2455G and T3801C) and EC risk. A meta-analysis was performed to investigate the association between CYP1A1 polymorphisms and EC risk. A total of 13 articles (A2455G and T3801C: 2 papers, A2455G: 8 papers, T3801C: 3 papers) from the PubMed containing information on the CYP1A1 polymorphisms and EC were included in this meta analysis, with summational sample size of 1,881 EC cases and 3,786 controls. Stratified analysis was performed to evaluate the ethnicity (Caucasians and Asian) and histopathology type (esophageal squamous cell carcinoma and esophageal adenocarcinoma) effect. No obvious publication bias in the two polymorphisms was observed. Our meta-analysis revealed a significant association between the A2455G polymorphism and EC (OR = 1.55 per A allele, 95 % CI 1.29-1.85, P < 0.001). Stratification analysis by ethnicity and histopathology type showed significant association in the population of Asian origin (OR = 1.55, 95 % CI 1.28-1.89, P < 0.001) and in histopathology type of ESCC (OR = 1.40, 95 % CI 1.19-1.65, P < 0.001). We didn't observe the significant association between CYP1A1 T3801C polymorphism and EC. We observed a difference of allele frequencies between Caucasian and Asian population in the meta-analysis. The allele frequencies in our meta-analysis were consistent with the allele frequencies in 1000 Genome Project. Our meta-analysis demonstrated distinct evidence that CYP1A1 A2455G polymorphism was associated with the risk of EC. PMID- 24065536 TI - Isolation and characterization of a novel PDR-type ABC transporter gene PgPDR3 from Panax ginseng C.A. Meyer induced by methyl jasmonate. AB - In order to screen novel genes involved in the biosynthesis and accumulation of ginsenosides in ginseng for investigating the molecular mechanism of ginsenosides accumulation, the differential expression analysis was performed by cDNA amplified fragment length polymorphism (cDNA-AFLP) in methyl jasmonate (MeJA) treated ginseng suspension cells and untreated controls. Twenty-five transcript derived-fragments (TDFs) were obtained and 14 of them was involved in secondary metabolite biosynthesis, transportation, signal transduction and stress response. PgTDF3 (JK974248) was detected in MeJA-treated ginseng cells and its full-length cDNA was subsequently isolated. The gene designated PgPDR3 (GenBank accession number KC013238) has 4515 bp in length containing a 4137 bp open reading frame (ORF). The deduced amino acid sequence of PgPDR3 shares high similarity to other plant pleiotropic drug resistance (PDR) transporters and have the characteristic domain of plant PDR transporter Walker A, Walker B and ABC signature both at the N- and C-terminal ends respectively. RT-PCR and quantitative real-time PCR (qRT PCR) analysis indicated that PgPDR3 was expressed at a high level in the roots and adventitious roots compared to leaves, seeds and buds, and the expression was induced strongly by MeJA in a time-dependent manner, as it is well known MeJA is a signaling molecule that mediates the biosynthesis and accumulation of secondary metabolites. These results demonstrate a potential role of the PgPDR3 gene in the accumulation of secondary metabolites in MeJA-induced ginseng. PMID- 24065537 TI - Association between clinical expression and molecular heterogeneity in beta thalassemia Tunisian patients. AB - Beta-thalassemia is the most frequent hereditary blood disorder in Tunisia because of its geographic localization and history. This pathology is characterized by a complex multisystem process with genetic and biochemical interactions. The aim of this work was to establish phenotype/genotype association through studying the distribution and the relationship between beta thalassemia and alpha-thalassemia mutations and three polymorphic markers: the C > T polymorphism at -158 of the Ggamma gene, the RFLP haplotype and the repeated sequence (AT)xTy in the beta globin silencer, in two groups of beta-thalassemia major and beta-thalassemia intermedia (TI) patients. Statistical analysis has shown that moderate expression seen in TI patients was significantly associated to beta(+) -87 (C -> G), -30 (T -> A) and IVSI-6 (T -> C) mutations, haplotypes VIII, IX and Nb and to XmnI polymorphism. The regression analysis of combined genotypes (mutation/XmnI/RFLP haplotype) revealed that they contribute to justify 17.1 % of clinical expression diversity (p < 0.05). Among the studied genotypes the XmnI polymorphism seems to be the most determinant modulating factor, followed by the beta-thalassemia mutation and RFLP haplotype. Our findings highlight the heterogeneity of molecular background of beta-thalassemia that would be responsible of clinical variability. PMID- 24065538 TI - Association between the -1438G/A and T102C polymorphisms of 5-HT2A receptor gene and obstructive sleep apnea: a meta-analysis. AB - The serotonin 2A (5-HT2A) receptor has been implicated in obstructive sleep apnea (OSA). Single nucleotide polymorphisms (SNPs) in the 5-HT2A gene have been found in OSA, the most common being -1438G/A and T102C; however, studies of the association between 5-HT2A SNPs and OSA risk have reported inconsistent findings. A meta-analysis was performed to quantitatively review the association between 1438G/A and T102C SNPs and OSA. Five studies, including 791 subjects for -1438G/A genotype and 1,068 subjects for T102C genotype, were selected. Pooled data analysis of the -1438G/A genotype indicated a significantly increased OSA risk was associated with two variant genotypes (AA vs. AG+GG: OR 3.023, 95 % CI 2.169 4.213, P = 0.506 for heterogeneity; A allele carriers vs. GG: OR 1.938, 95 % CI 0.879-4.274, P = 0.012 for heterogeneity). Stratification analysis by gender supported the association in males, but not females. For the T102C genotype, no significantly increased OSA risk was associated with the two variant genotypes (CC vs. CT+TT: OR 1.065, 95 % CI 0.787-1.442, P = 0.361 for heterogeneity; C allele carriers vs. TT: OR 0.979, 95 % CI 0.737-1.3, P = 0.9 for heterogeneity).In conclusions, meta-analysis indicated that the -1438G/A, and not T102C, polymorphism of 5-HT2A is a positive risk factor of OSA, especially in males. PMID- 24065539 TI - Long non-coding genes implicated in response to stripe rust pathogen stress in wheat (Triticum aestivum L.). AB - The non-protein-coding genes have been reported as a critical control role in the regulation of gene expression in abiotic stress. We previously identified four expressed sequence tags numbered S18 (EL773024), S73 (EL773035), S106 (EL773041) and S108 (EL773042) from a SSH-cDNA library of bread wheat Shaanmai 139 infected with Puccinia striiformis f. sp. tritici (Pst). Here, we isolated four cDNA clones and referred them as TalncRNA18, TalncRNA73, TalncRNA106 and TalncRNA108 (GenBank: KC549675-KC549678). These cDNA separately consisted of 1,393, 667, 449 and 647 nucleotides but without any open reading frame. The alignment result showed that TalncRNA18 is a partial cDNA of E3 ubiquitin-protein ligase UPL1-like gene, TalncRNA73 is an antisense transcript of hypothetical protein, TalncRNA108 is a homolog to RRNA intron-encoded homing endonuclease, and lncRNA106 had no similarly sequence. Quantitative RT-PCR studies confirmed that these four lncRNAs were differentially expressed in three near isogenic lines. TalncRNA108 was significantly stepwise decreased at early stage of inoculation with Pst, while the others were upregulated, especially at 1 and 3 dpi (days post-inoculation). Using Chinese Spring nulli-tetrasomic lines and its ditelosomic lines, TalncRNA73 and TalncRNA108 were located to wheat chromosome 7A and the short arm of chromosome 4B, respectively, while TalncRNA18 and TalncRNA106 were located to chromosome 5B. Comparing the sequence of DNA and cDNA of four lncRNAs with polymerase chain reaction primers, the results showed that all of them have no introns. The kinetics analyses of lncRNAs expression as a result of pathogen challenge in immune resistant genotype indicated that they may play the roles of modulating or silencing the protein-coding gene into pathogen-defence response. PMID- 24065540 TI - MMP-2, TNF-alpha and NLRP1 polymorphisms in Chinese patients with ankylosing spondylitis and rheumatoid arthritis. AB - Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are autoimmune, inflammatory diseases with substantial genetic contributions. Matrix metalloproteinase (MMP)-2, tumor necrosis factor (TNF)-alpha and NLR family pyrin domain-containing 1 (NLRP1) play important roles in the immune response. We studied the MMP-2 rs243865 C/T, TNF-alpha rs1800629 A/G, NLRP1 rs878329 C/G and NLRP1 rs6502867 C/T polymorphisms in a Chinese cohort of 520 patients with RA, 100 with AS and 520 controls. Genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Using the MMP-2 rs243865 CC homozygote genotype as the reference group, the CT and TT/CT genotypes were associated with significantly reduced risks of AS. However, logistic regression analyses revealed that the MMP-2 rs243865 C/T polymorphism was not associated with risk of RA. TNF-alpha rs1800629 A/G, NLRP1 rs878329 C/G and NLRP1 rs6502867 C/T polymorphisms were not associated with risk of RA or AS. These findings suggest that the MMP-2 rs243865 C/T polymorphism is associated with AS development. PMID- 24065541 TI - Characterization and expression of Rubisco activase genes in Ipomoea batatas. AB - Two-dimensional electrophoresis, coupled with MALDI-TOF-MS, was used to identify differentially expressed proteins between young and mature leaves of sweet potato [Ipomoea batatas (L.) Lam]. The results showed that there were 25 differential proteins between young and mature leaves. The Rubisco activase (RCA) that catalyzes the activation of Rubisco in vivo and plays a crucial role in photosynthesis was among these 25 proteins. So far, little was known about the molecular biology of RCA in sweet potato. Here, this research reports the cloning and characterization of two genes encoding the short isoform and the long isoform of sweet potato RCAs. Analysis of DNA sequences of RCA suggested that the corresponding mRNAs were transcribed from two different genes. To study the roles of these two RCA isoforms in photosynthesis, we investigated the expression patterns of these RCA genes at the mRNA and protein levels every 2 h in a photoperiod and under different temperatures conditions. The results indicated that these two RCA isoforms may play different roles in regulating photosynthesis and they may be regulated by light, heat or both. In addition, there were interactions between Rubisco large subunit (RBCl) and short isoform RCA (RCAs) as well as RCAs and long isoform RCA (RCAl), but no interaction between RBCl and RCAl, implying they might form a sandwich-like structure (RBCl-RCAs-RCAl), at least in yeast cells. These results provided new information on the modulation of RCA genes in sweet potato, which could be useful in improving photosynthesis and plant growth in sweet potato. PMID- 24065542 TI - Identification and expression of an encoding steroid receptor coactivator (SRA) in amphioxus (Branchiostoma japonicum). AB - Steroid receptor coactivator (SRA), a class of genes encoding both functional RNA and protein, has been shown to be present in vertebrates but little is known in invertebrates. Here we isolated a cDNA encoding a SRA homolog from amphioxus Branchiostoma japonicum, named AmphiSRA. The cDNA contained a 525 bp open reading frame corresponding to a deduced protein of 174 amino acids with a predicted molecular mass of ~21 kDa. Phylogenetic analysis showed that AmphiSRA was located at the base of its vertebrate counterparts, suggesting that it represents the archetype of vertebrate SRA. The genomic DNA sequence of AmphiSRA contained four exons and three introns, which was similar to B. floridae SRA exon/intron organization. The recombinant SRAP expressed in vitro shows a band with a molecular mass of 21 kDa and western blot confirmed it, which proved it is an encoding isoform. AmphiSRA is found to display a tissue specific expression pattern, with a predominant expression in gill, intestine, testis, neural tube and notochord. The whole-mount in situ hybridization demonstrated the expression of AmphiSRA in all the stages of development assayed. These implicated that SRA maybe play an important role during embryonic development of cephalochordate amphioxus. PMID- 24065543 TI - Genetic association study of adaptor protein complex 4 with cerebral palsy in a Han Chinese population. AB - Adaptor protein complex 4 (AP-4) plays a key role in vesicle formation, trafficking, and sorting processes that are critical for brain development and function. AP-4 consists of four subunits encoded by the AP4E1, AP4B1, AP4M1, and AP4S1 genes. A number of studies have pointed to the involvement of AP-4-mediated vesicular trafficking pathways in the etiology of cerebral palsy (CP), the most notable of which are the causative mutations that have recently been identified in each of the AP-4 genes in different CP families. We postulated, therefore, that variations in AP-4 genes might influence an indivual's susceptibility to CP. In the present study, 16 SNPs were genotyped among 517 CP patients and 502 healthy controls from the Han Chinese population. We systematically analyzed the association of the AP4E1, AP4B1, AP4M1, and AP4S1 genes with CP on the basis of clinical characteristics. No significant associations were found between these variants and the overall risk of CP. Subgroup analysis showed that rs1217401 of AP4B1 was significantly associated with CP as a sequela of hypoxic-ischemic encephalopathy (HIE) (CP + HIE) (allele: p = 0.042151; genotype: p = 4.46 * 10( 6)). Our results indicate that the 16 variants studied in the genes of the four subunits of AP-4 have no detectable effects on the overall susceptibility to CP, but AP4B1 appears to be a susceptibility gene for CP + HIE in the Han Chinese population. PMID- 24065544 TI - Molecular cloning, expression, purification and characterization of thioredoxin from Antarctic sea-ice bacteria Pseudoalteromonas sp. AN178. AB - Thioredoxin (Trx) is a highly conserved and multi-functional protein that plays a pivotal role in maintaining the redox state of the cell and in protecting the cell against oxidative stress. Trx gene from Antarctic sea-ice bacteria Pseudoalteromonas sp. AN178 was cloned and expressed as soluble protein in Escherichia coli (designated as PsTrx). Trx gene consisted of an open reading frame of 324-bp nucleotides encoding a protein of 108 amino acids with a calculated molecular mass of 11.88 kDa. The deduced protein included the conserved Cys-Gly-Pro-Cys active-site sequence. After purification by a single step Ni-NTA affinity chromatography, recombinant PsTrx with a high specific activity of 96.67 U/mg was obtained. The purified PsTrx had an optimal temperature and pH of 25 degrees C and 7.0, respectively, and showed about 55 % of the residual catalytic activity even at 0-10 degrees C. It had high tolerance to a wide range of NaCl concentrations (0-2 M NaCl) and was stable in the presence of H2O2. This research suggested that PsTrx displayed unique catalytic properties. PMID- 24065545 TI - Large BRCA1 and BRCA2 genomic rearrangements in Polish high-risk breast and ovarian cancer families. AB - BRCA1 and BRCA2 are two major genes associated with familial breast and ovarian cancer susceptibility. In Poland standard BRCA gene test is usually limited to Polish founder BRCA1 mutations: 5382insC, C61G and 4153delA. To date, just a few single large genomic rearrangements (LGRs) of BRCA1 gene have been reported in Poland. Here we report the first comprehensive analysis of large mutations in BRCA1 and BRCA2 genes in this country. We screened LGRs in BRCA1 and BRCA2 genes by multiplex ligation-dependent probe amplification in 200 unrelated patients with strong family history of breast/ovarian cancers and negative for BRCA1 Polish founder mutations. We identified three different LGRs in BRCA1 gene: exons 13-19 deletion, exon 17 deletion and exon 22 deletion. No LGR was detected in BRCA2 genes. Overall, large rearrangements accounted for 3.7 % of all BRCA1 mutation positive families in our population and 1.5 % in high-risk families negative for Polish founder mutation. PMID- 24065546 TI - Y chromosome diversity and paternal origin of Chinese cattle. AB - To determine the Y chromosome genetic diversity and paternal origin of Chinese cattle, 369 bulls from 17 Chinese native cattle breeds and 30 bulls from Holstein and four bulls from Burma were analyzed using a recently discovered USP9Y marker that could distinguish between taurine and indicine cattle more efficiently. In total, the taurine Y1, Y2 haplogroup and indicine Y3 haplogroup were detected in 7 (1.9 %), 193 (52.3 %) and 169 (45.8 %) individuals of 17 Chinese native breeds, respectively, although these frequencies varied amongst the Chinese native cattle breeds examined. Y2 dominates in northern China (91.4 %), while Y3 dominates in southern China (81.2 %). Central China is an admixture zone with Y2 predominating overall (72.0 %). Our results demonstrate that Chinese cattle have two paternal origins, one from B. taurus (Y2) and the other from B. indicus (Y3). The Y1 haplogroup may originate from the imported beef cattle breeds in western countries. The geographical distributions of the Y2 and Y3 haplogroup frequencies reveal a pattern of male indicine introgression from south to north China, and male taurine introgression from north to south China. PMID- 24065547 TI - Testosterone promotes vascular endothelial cell migration via upregulation of ROCK-2/moesin cascade. AB - Cross-sectional studies have demonstrated a reverse relationship between serum level of testosterone (T) and the incidence rate of cardiovascular disease in men, indicating that T exerts beneficial effects in cardiovascular system. However, the endothelial effects of T are poorly understood. Actin remodeling is essential for endothelial cell movement and vascular repair and this process is controlled by the actin-binding protein moesin. In the present study, we studied the effects of T on actin remodeling, moesin expression and phosphorylation, as well as cell migration in cultured human umbilical endothelial cells (hUVECs). We found that T provoked the formation of cortical actin complexes and membrane protrusions in endothelial cells. Treatment with T induced dose- and time dependent increase of moesin expression and phosphorylation, which was inhibited by the addition of androgen receptor antagonist hydroxyflutamide (HF). Moreover, T enhanced ROCK-2 activity. The ROCK-2 inhibitor Y27632 or the transfection of ROCK-2 siRNA largely inhibited T-induced moesin expression and phosphorylation, indicating that ROCK-2 pathway is crucial for these effects. T promoted endothelial cell migration, which was inhibited by the addition of HF or Y27632. In conclusion, T induces actin cytoskeleton remodeling by regulating moesin expression and activation, resulting in enhanced endothelial cell migration. Our work adds new insights into endothelial mechanisms of T, which is relevant for its vascular actions. PMID- 24065548 TI - Protective effect of mitochondrial ferritin on cytosolic iron dysregulation induced by doxorubicin in HeLa cells. AB - Doxorubicin (DOX) is an anticancer drug with cardiotoxic side effects mostly caused by iron homeostasis dysregulation. Mitochondria are involved in iron trafficking and mitochondrial ferritin (FtMt) was shown to provide protection against cellular iron imbalance. Therefore, we hypothesized that FtMt overexpression could limit DOX effects on iron homeostasis. Heart's homogenates of DOX-treated C57BL/6 mice were analyzed for cytosolic and mitochondrial iron related proteins' expression and activity, revealing high cytosolic ferritin and ferritin-bound iron, low transferrin-receptor 1 and a strong hepcidin upregulation. Mitochondrial iron-related proteins (aconitase, succinate dehydrogenase, frataxin) seemed, however, unaffected, although a partial inactivation of superoxide dismutase 2 was detected. Importantly, the ectopic expression of FtMt in human HeLa cells partially reverted DOX-induced iron imbalance. Our results, while confirming DOX effects on iron homeostasis, demonstrate that DOX affects more cytosolic than mitochondrial iron metabolism both in murine hearts and human HeLa cells and that FtMt overexpression is able to prevent most of these effects in HeLa cells. PMID- 24065549 TI - Cell death-inducing DFFA-like effector c (CIDEC/Fsp27) gene: molecular cloning, sequence characterization, tissue distribution and polymorphisms in Chinese cattles. AB - Cell death-inducing DFFA-like effector c (CIDEC) protein, also known as fat specific protein 27 (Fsp27), is localized to lipid droplets. CIDEC protein is required for unilocular lipid droplet formation and optimal energy storage in addition to controlling lipid metabolism in adipocytes and hepatocytes. Research found that Ad-36 could induce lipid droplets in the cultured skeletal muscle cells and this process may be mediated by promoting CIDEC expression. The content of intermuscular fat is an important index for evaluation of beef quality, so the CIDEC gene appeared to be a candidate gene for regulation of intermuscular fat, however similar research for the bovine CIDEC gene is lacking. This paper examined the tissue expression profile of CIDEC gene in cattle using real-time RT PCR to suggest that bovine CIDEC is highly expressed in adipose tissue. In addition, the Bovine CIDEC gene was cloned and inserted into the eukaryotic expression vector pET-28a(+), whereupon recombinant bovine CIDEC protein was induced and identified by Western-blot. A phylogenetic analysis showed that the animo acid sequence of bovine CIDEC was closer to mammalian CIDEC than rasorial CIDEC. We found ten single nucleotide polymorphisms sites (SNPs) in bovine CIDEC gene, of which SNP 2, 3, 4, 6 and 9, and SNP 8 and 10 were in complete linkage disequilibrium, respectively. SNP 1, 2 and 10 were used in further haplotype studies. Eight different haplotypes were identified in 973 cattle, of which haplotype 8 predominated with frequencies ranging from 42.90 to 54.30 %. This research provides a basis for future functional studies of CIDEC in cattle. PMID- 24065550 TI - Interventions for promoting habitual exercise in people living with and beyond cancer. AB - BACKGROUND: The beneficial effects of regular exercise for people living with or beyond cancer are becoming apparent. However, how to promote exercise behaviour in sedentary cancer cohorts is not as well understood. A large majority of people living with or recovering from cancer do not meet exercise recommendations. Hence, reviewing the evidence on how to promote and sustain exercise behaviour is important. OBJECTIVES: To assess the effects of interventions to promote exercise behaviour in sedentary people living with and beyond cancer and to address the following questions: Which interventions are most effective in improving aerobic fitness and skeletal muscle strength and endurance? What adverse effects are attributed to different exercise interventions? Which interventions are most effective in improving exercise behaviour amongst patients with different cancers? Which interventions are most likely to promote long-term (12 months or longer) exercise behaviour? What frequency of contact with exercise professionals is associated with increased exercise behaviour? What theoretical basis is most often associated with increased exercise behaviour? What behaviour change techniques are most often associated with increased exercise behaviour? SEARCH METHODS: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 8, 2012), MEDLINE, EMBASE, AMED, CINAHL, PsycLIT/PsycINFO, SportDiscus and PEDro from inception to August 2012. We also searched the grey literature, wrote to leading experts in the field, wrote to charities and searched reference lists of other recent systematic reviews. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) that compared an exercise intervention with a usual care approach in sedentary people over the age of 18 with a homogenous primary cancer diagnosis. DATA COLLECTION AND ANALYSIS: Two review authors working independently (LB and KH) screened all titles and abstracts to identify studies that might meet the inclusion criteria, or that cannot be safely excluded without assessment of the full text (e.g. when no abstract is available). All eligible papers were formally abstracted by at least two members of the review author team working independently (LB and KH) and using the data collection form. When possible, and if appropriate, we performed a fixed-effect meta-analysis of study outcomes. For continuous outcomes (e.g. cardiorespiratory fitness), we extracted the final value, the standard deviation of the outcome of interest and the number of participants assessed at follow-up in each treatment arm, to estimate standardised mean difference (SMD) between treatment arms. SMD was used, as investigators used heterogeneous methods to assess individual outcomes. If a meta analysis was not possible or was not appropriate, we synthesised studies as a narrative. MAIN RESULTS: Fourteen trials were included in this review, involving a total of 648 participants. Only studies involving breast, prostate or colorectal cancer were identified as eligible. Just six trials incorporated a target level of exercise that could meet current recommendations. Only three trials were identified that attempted to objectively validate independent exercise behaviour with accelerometers or heart rate monitoring. Adherence to exercise interventions, which is crucial for understanding treatment dose, is often poorly reported. It is important to note that the fundamental metrics of exercise behaviour (i.e. frequency, intensity and duration, repetitions, sets and intensity of resistance training), although easy to devise and report, are seldom included in published clinical trials.None of the included trials reported that 75% or greater adherence (the stated primary outcome for this review) of the intervention group met current aerobic exercise recommendations at any given follow-up. Just two trials reported six weeks of resistance exercise behaviour that would meet the guideline recommendations. However, three trials reported adherence of 75% or greater to an aerobic exercise goal that was less than the current guideline recommendation of 150 minutes per week. All three incorporated both supervised and independent exercise components as part of the intervention, and none placed restrictions on the control group in terms of exercise behaviour. These three trials shared programme set goals and the following behaviour change techniques: generalisation of a target behaviour; prompting of self-monitoring of behaviour; and prompting of practise. Despite the uncertainty surrounding adherence in many of the included trials, interventions caused improvements in aerobic exercise tolerance at 8 to 12 weeks (from 7 studies, SMD 0.73, 95% confidence interval (CI) 0.51 to 0.95) in intervention participants compared with controls. At six months, aerobic exercise tolerance was also improved (from 5 studies, SMD 0.70, 95% CI 0.45 to 0.94), but it should be noted that four of the five trials used in this analysis had a high risk of bias, hence caution is warranted in interpretation of results. Attrition over the course of these interventions is typically low (median 6%). AUTHORS' CONCLUSIONS: Interventions to promote exercise in cancer survivors who report better levels of adherence share some common behaviour change techniques. These involve setting programme goals, prompting practise and self-monitoring and encouraging participants to attempt to generalise behaviours learned in supervised exercise environments to other, non-supervised contexts. However, expecting most sedentary survivors to achieve current guideline recommendations of at least 150 minutes per week of aerobic exercise is likely to be unrealistic. As with all well-designed exercise programmes in any context, prescriptions should be designed around individual capabilities, and frequency, duration and intensity or sets, repetitions, intensity or resistance training should be generated on this basis. PMID- 24065551 TI - Parent psychological functioning and communication predict externalizing behavior problems after pediatric traumatic brain injury. AB - OBJECTIVE: Adolescents sustaining traumatic brain injury (TBI) show increased prevalence of behavior problems. This study investigated the associations of parent mental health, family functioning, and parent-adolescent interaction with adolescent externalizing behavior problems in the initial months after TBI, and examined whether injury severity moderated these associations. METHODS: 117 parent-adolescent dyads completed measures of family functioning, adolescent behavior, and parent mental health an average of 108 days post-TBI. Dyads also engaged in a 10-min video-recorded problem-solving activity coded for parent behavior and tone of interaction. RESULTS: Overall, higher ratings of effective parent communication were associated with fewer externalizing behavior problems, whereas poorer caregiver psychological functioning was associated with greater adolescent externalizing behaviors. Results failed to reveal moderating effects of TBI severity on the relationship between socio-environmental factors and behavior problems. CONCLUSIONS: Interventions targeting parent communication and/or improving caregiver psychological health may ameliorate potential externalizing behavior problems after adolescent TBI. PMID- 24065552 TI - Bring in universal mental health checks in schools. PMID- 24065553 TI - Should hospitals provide all patients with single rooms? PMID- 24065554 TI - Too much angioplasty. PMID- 24065555 TI - Invasive crayfish reduce food limitation of alien American mink and increase their resilience to control. AB - Trophic relationships between invasive species in multiply invaded ecosystems may reduce food limitation relative to more pristine ecosystems and increase resilience to control. Here, we consider whether invasive predatory American mink Neovison vison are trophically subsidized by invasive crayfish. We collated data from the literature on density and home range size of mink populations in relation to the prevalence of crayfish in the diet of mink. We then tested the hypothesis that populations of an invasive predator reach higher densities and are more resilient to lethal control when they have access to super-abundant non native prey, even in the absence of changes in density dependence, hence compensatory capacity. We found a strong positive relationship between the proportion of crayfish in mink diet and mink population density, and a negative relationship between the proportion of crayfish in mink diet and mink home range size, with crayfish contribution to mink diet reflecting their abundance in the ecosystem. We then explored the consequence of elevated mink density by simulating a hypothetical eradication program with a constant harvest in a Ricker model. We found that mink populations were more resilient to harvest in the presence of crayfish. As a result, the simulated number of mink harvested to achieve eradication increased by 500% in the presence of abundant crayfish if carrying capacity increased by 630%. This led to a threefold increase in time to eradication under a constant harvest and an approximately 20-fold increase in the cumulative management cost. Our results add to evidence of inter-specific positive interactions involving invasive species, and our simple model illustrates how this increases management cost. PMID- 24065557 TI - Old world versus new world: life-history alterations in a successful invader introduced across Europe. AB - We examined differences in pumpkinseed (Lepomis gibbosus) life-history traits between native North American and introduced European populations, and tested three life-history predictions related to the effect of temperature, growth, waterbody size, and the presence/absence of predators on native and non-native populations. Pumpkinseed populations exhibit more 'opportunistic' traits (earlier maturity, smaller size at maturity, and higher reproductive allocation) in their introduced European range than those in their native range. Predictions of life history traits were improved when indicators of juvenile growth rate (mean length at age 2), waterbody size (surface area), and thermal regime (air temperature degree-days above 10 degrees C) were incorporated into models along with continental location, but European pumpkinseed populations exhibit more opportunistic life-history traits than North American populations even when these factors are accounted for. Native pumpkinseed in waterbodies containing piscivores mature later and at a larger size, and have lower gonadosomatic indices than those in waterbodies lacking piscivores, whereas there is no significant difference in the same three life-history traits between European waterbodies containing or lacking piscivores. Because congeneric competitors of the pumpkinseed are absent from Europe, the apparent absence of a predator life history effect there could also be due to the absence of the major sunfish competitors. In either case, the evolution and maintenance of more opportunistic traits in European pumpkinseed can likely be attributed to enemy release, and this may explain the successful establishment and spread of pumpkinseed in many parts of Europe. PMID- 24065556 TI - Interactions among resource partitioning, sampling effect, and facilitation on the biodiversity effect: a modeling approach. AB - Resource partitioning, facilitation, and sampling effect are the three mechanisms behind the biodiversity effect, which is depicted usually as the effect of plant species richness on aboveground net primary production. These mechanisms operate simultaneously but their relative importance and interactions are difficult to unravel experimentally. Thus, niche differentiation and facilitation have been lumped together and separated from the sampling effect. Here, we propose three hypotheses about interactions among the three mechanisms and test them using a simulation model. The model simulated water movement through soil and vegetation, and net primary production mimicking the Patagonian steppe. Using the model, we created grass and shrub monocultures and mixtures, controlled root overlap and grass water-use efficiency (WUE) to simulate gradients of biodiversity, resource partitioning and facilitation. The presence of shrubs facilitated grass growth by increasing its WUE and in turn increased the sampling effect, whereas root overlap (resource partitioning) had, on average, no effect on sampling effect. Interestingly, resource partitioning and facilitation interacted so the effect of facilitation on sampling effect decreased as resource partitioning increased. Sampling effect was enhanced by the difference between the two functional groups in their efficiency in using resources. Morphological and physiological differences make one group outperform the other; once these differences were established further differences did not enhance the sampling effect. In addition, grass WUE and root overlap positively influence the biodiversity effect but showed no interactions. PMID- 24065558 TI - Life history traits associated with body size covary along a latitudinal gradient in a generalist grasshopper. AB - Animal body size often varies systematically along latitudinal gradients, where individuals are either larger or smaller with varying season length. This study examines ecotypic responses by the generalist grasshopper Melanoplus femurrubrum (Orthoptera: Acrididae) in body size and covarying, physiologically based life history traits along a latitudinal gradient with respect to seasonality and energetics. The latitudinal compensation hypothesis predicts that smaller body size occurs in colder sites when populations must compensate for time constraints due to short seasons. Shorter season length requires faster developmental and growth rates to complete life cycles in one season. Using a common garden experimental design under laboratory conditions, we examined how grasshopper body size, consumption, developmental time, growth rate and metabolism varied among populations collected along an extended latitudinal gradient. When reared at the same temperature in the lab, individuals from northern populations were smaller, developed more rapidly, and showed higher growth rates, as expected for adaptations to shorter and generally cooler growing seasons. Temperature dependent, whole organism metabolic rate scaled positively with body size and was lower at northern sites, but mass-specific standard metabolic rate did not differ among sites. Total food consumption varied positively with body size, but northern populations exhibited a higher mass-specific consumption rate. Overall, compensatory life history responses corresponded with key predictions of the latitudinal compensation hypothesis in response to season length. PMID- 24065560 TI - Closure of a coronary to pulmonary artery fistula by radiofrequency catheter ablation in the pulmonary artery. PMID- 24065559 TI - Strategies for non-resectable head and neck cancer. AB - OPINION STATEMENT: Treatment of unresectable, locally advanced head and neck cancer consists of many different options, all of them based on radiotherapy. The main variable is represented by chemotherapy, i.e., the way in which chemotherapy is combined with radiation. More recently, the combination of cetuximab and radiotherapy emerged as a new treatment opportunity and induction chemotherapy, with the combination of docetaxel, cisplatin, and 5-fluoruracil, gained a renewed interest. Concurrent chemoradiation is based on the most robust evidence and is regarded as the leading standard of care for unresectable locally advanced head and neck cancer. Unfortunately, chemoradiation is hampered by severe toxicity and patients must be selected carefully before treatment. The experience of the staff (medical oncologists, radiation oncologists, and nurses), and in particular its familiarity with toxicity management, as well the structural facilities, play an important role in the final outcome. When the patient is unfit for chemoradiation, or when experienced staff or adequate structures are unavailable, induction chemotherapy, cetuximab and radiotherapy, or radiotherapy alone are all evidence-based alternative options. The choice among them will be based on the clinical condition of the patient, the physician's experience, and the patient's preference. Whatever is the treatment of choice, it is important to involve a multidisciplinary staff in the management of these patients. Indeed, also unresectable patients may require supportive surgical interventions before or during treatment, or removal of residual disease after treatment. PMID- 24065561 TI - Secondary suturing compared to non-suturing for broken down perineal wounds following childbirth. AB - BACKGROUND: Each year approximately 350,000 women in the United Kingdom and millions more worldwide, experience perineal suturing following childbirth. The postpartum management of perineal trauma is a core component of routine maternity care. However, for those women whose perineal wound dehisces (breaks down), the management varies depending on individual practitioners preferences as there is limited scientific evidence and no clear guidelines to inform best practice. For most women the wound will be managed expectantly whereas, others may be offered secondary suturing. OBJECTIVES: To evaluate the therapeutic effectiveness of secondary suturing of dehisced perineal wounds compared to non-suturing (healing by secondary intention, expectancy). SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2013) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials of secondary suturing of dehisced perineal wounds (second-, third- or fourth-degree tear or episiotomy), following wound debridement and the removal of any remaining suture material within the first six weeks following childbirth compared with non suturing. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion. Two review authors independently assessed trial quality and extracted data. Data were checked for accuracy. MAIN RESULTS: Two small studies of poor methodological quality including 52 women with a dehisced and/or infected episiotomy wound at point of entry have been included.Only one small study presented data in relation to wound healing at less than four weeks, (the primary outcome measure for this review), although no reference was made to demonstrate how healing was measured. There was a trend to favour this outcome in the resuturing group, however, this difference was not statistically significant (risk ratio (RR) 1.69, 95% confidence interval (CI) 0.73 to 3.88, one study, 17 women).Similarly, only one trial reported on rates of dyspareunia (a secondary outcome measure for this review) at two months and six months with no statistically significant difference between both groups; two months, (RR 0.44, 95% CI 0.18 to 1.11, one study, 26 women) and six months, (RR 0.39, 95% CI 0.04 to 3.87, one study 32 women). This trial also included data on the numbers of women who resumed sexual intercourse by two months and six months. Significantly more women in the secondary suturing group had resumed intercourse by two months (RR 1.78, 95% CI 1.10 to 2.89, one study, 35 women), although by six months there was no significant difference between the two groups (RR 1.08, 95% CI, 0.91 to 1.28).Neither of the trials included data in relation to the following prespecified secondary outcome measures: pain at any time interval; the woman's satisfaction with the aesthetic results of the perineal wound; exclusive breastfeeding; maternal anxiety or depression. AUTHORS' CONCLUSIONS: Based on this review, there is currently insufficient evidence available to either support or refute secondary suturing for the management of broken down perineal wounds following childbirth. There is an urgent need for a robust randomised controlled trial to evaluate fully the comparative effects of both treatment options. PMID- 24065562 TI - The contributions of Lindon Eaves to psychiatric genetics. PMID- 24065563 TI - Are bottom-up and top-down traits in dual-systems models of risky behavior genetically distinct? AB - Numerous dual-systems models of personality have been posited, which propose that behavior is influenced by two complementary systems. A bottom-up system is characterized by emotion-based drive (e.g., urge for rewarding experience), and a top-down system is characterized by the ability to control those urges. Although evidence suggests that these two systems are distinct and may be important in explaining some behaviors, these constructs are also moderately correlated. Notably, there has been little molecular or behavior genetic research on the genetic distinctness of the two systems central to the dual-systems model. The current study used a national twin sample to investigate the degree to which bottom-up and top-down systems, measured here as personality traits of sensation seeking and lack of planning, respectively, covary through genetic and environmental influences. Whereas the overlap between these systems was primarily comprised of unshared environmental influences (e.g., measurement error and unshared systematic variation) in females, a statistically significant proportion of the overlap was accounted for by genetic factors in men. Further, the genetic factors for these systems were moderately to highly correlated in men (rG = 0.62 0.79). These results provide clear support for a dual-systems model in women; however, these systems appear to share some common genetic influences in men. PMID- 24065564 TI - Shared environmental influences on personality: a combined twin and adoption approach. AB - In the past, shared environmental influences on personality traits have been found to be negligible in behavior genetic studies (e.g., Bouchard and McGue, J Neurobiol 54:4-45, 2003). However, most studies have been based on biometrical modeling of twins only. Failure to meet key assumptions of the classical twin design could lead to biased estimates of shared environmental effects. Alternative approaches to the etiology of personality are needed. In the current study we estimated the impact of shared environmental factors on adolescent personality by simultaneously modeling both twin and adoption data. We found evidence for significant shared environmental influences on Multidimensional Personality Questionnaire Absorption (15% variance explained), Alienation (10%), Harm Avoidance (14%), and Traditionalism (26%) scales. Additionally, we found that in most cases biometrical models constraining parameter estimates to be equal across study type (twins vs. adoptees) fit no worse than models allowing these parameters to vary; this suggests that results converge across study design despite the potential (sometimes opposite) biases of twin and adoption studies. Thus, we can be more confident that our findings represent the true contribution of shared environmental variance to personality development. PMID- 24065565 TI - Pathogenic analysis of Vibrio alginolyticus infection in a mouse model. AB - Vibrio alginolyticus is a Gram-negative halophilic bacterium and has been recognized as an opportunistic pathogen to both humans and marine animals. So far, most studies have been focused on marine animals and few reports have been aimed at mammals, including human. In this study, we first established a mouse model to understand the pathogenic mechanism of V. alginolyticus infection. After infection via intraperitoneal injection, hematological and liver function indicators were evaluated and serum interleukin (IL)-1beta and IL-6 expression were detected by ELISA. Furthermore, we compared the virulence of two V. alginolyticus strains, ATCC17749T and E0666. The results demonstrated that V. alginolyticus infection causes robust lung and liver damage and induces changes in IL-1beta, IL-6, hematological, and liver indicators. In addition, the ATCC17749T strain appeared to be more virulent than the E0666 strain. Better understanding of the pathogenic mechanism of V. alginolyticus infection should guide effective prevention and therapy for V. alginolyticus infection. PMID- 24065566 TI - Long-term use of flupirtine leads to withdrawal symptoms and is associated with dependency. AB - This is the case of a 44-year-old woman, who was treated as an inpatient because of withdrawal symptoms like sweating, tremors, sleeping disorders and irritability after long-term use of flupirtine. She recovered by symptom-based application of pipamperone within 72 h after flupirtine cessation. PMID- 24065567 TI - Early improvement and serum concentrations of citalopram to predict antidepressant drug response of patients with major depression. AB - INTRODUCTION: Post hoc analyses of clinical trials have shown that early improvement around day 14 is highly predictive for later response. More-over, evidence has been given that sufficiently high concentrations of antidepressant drugs in blood are required to attain response. In this study, we determined cut off levels for citalopram serum concentrations and clinical improvement during the early phase of treatment to predict later response and the predictive power of these measures either alone or in combination. METHODS: Inpatients with depressive disorder according to ICD-10 who received citalopram were included. Psychopathology was assessed by the 17-item Hamilton Depression (HAMD-17) rating scale, and serum concentrations of citalopram were measured in weekly intervals. RESULTS: The analysis included 55 inpatients. Receiver operating characteristics analysis revealed for citalopram a serum concentration of 53 ng/ml on day 7 and a clinical improvement of 24% on the HAMD-17 scale on day 14 as significant cut-off values to predict response after 5 weeks of treatment. Both measures taken together predicted response on week 5 with 73% sensitivity and 85% specificity with an odds ratio of 14.6. DISCUSSION: It is concluded that treatment with citalopram should be guided by symptom rating at baseline and on day 14 and serum concentration determination on day 7. PMID- 24065568 TI - Radiosurgery for central neurocytoma: long-term outcome and failure pattern. AB - Despite the favorable outcomes of radiosurgery for central neurocytoma (CN), these results are based on case series that included a limited number of patients and short follow-up periods because of the scarcity of CN. Because CN is a benign tumor with an indolent clinical course, long-term follow-up and analysis of failure pattern are required for the establishment of the role of radiosurgery in the management of CN. Twenty consecutive patients (10 patients who received Gamma Knife radiosurgery (GKRS) as a primary treatment and 10 patients who received GKRS as a secondary treatment) with a radiological follow-up period >=36 months were included in this study. The mean radiological follow-up duration was 100 months (range 43-149 months). The mean tumor volume was 10.4 cm(3) (range 0.4 36.4 cm(3)) and the mean marginal dose was 15.4 Gy (range 9-20 Gy). Local control failure was found in six patients at the last radiological follow-up. Overall actuarial local control rates were 89.5 % at 5 years and 83.1 % at 10 years. The primary GKRS group included two cases with local failure, with cyst formation or local recurrence. In contrast, in the secondary GKRS group, local control failure was found in four cases (including three cases with an "out-of-field recurrence" pattern) and occurred earlier compared with the primary GKRS group. Our study suggests that GKRS could be a primary or secondary treatment option for CN. However, long-term radiological follow-up is mandatory. In particular, more careful consideration during margin delineation and planning procedure is required in the secondary GKRS group. PMID- 24065569 TI - The temozolomide derivative 2T-P400 inhibits glioma growth via administration route of intravenous injection. AB - The aim of this study is to investigate the inhibitory effects of 2T-P400, a derivative of temozolomide (TMZ), on glioma growth. SHG-44 and U373 human glioblastoma cell lines and SHG-44 cell subcutaneous and intracranial xenograft mouse models were used as the model system for these studies. Cell growth was analyzed using MTT assay. For intracranial glioma xenograft model, mouse brains were obtained and made as paraffin section for immunohistochemical staining. Tumor volume was calculated with this formula: tumor volume = length * width2/ 2. The results showed that 2T-P400 or TMZ significantly inhibits cell growth in a concentration dependent manner with the IC50 values of 12.90 +/- 1.05 or 9.73 +/- 2.12 MUg/ml on SHG-44 cell line and 13.12 +/- 0.86 or 10.13 +/- 1.02 MUg/ml on U373 cell line respectively. In SHG-44 cell subcutaneous xenograft model, the tumor volume of 2T-P400 or TMZ treated group was 1,062.12 +/- 204.76 or 803.59 +/ 110.32 mm3 respectively, which was significantly smaller than that in physiological saline (with volume of 1,968.85 +/- 348.37 mm3) treated group. In intracranial xenograft model, the tumor volume of 2T-P400 or TMZ group was 6.12 +/- 1.69 or 5.58 +/- 1.45 mm3 respectively, significantly smaller than that in physiological saline group of 33.08 +/- 6.88 mm3. Moreover, polyethylene glycol 400 (PEG400) exhibited no significant tumor growth inhibition. Our results indicated that 2T-P400 posses the same growth inhibitory effect as TMZ on glioblastoma cell lines and the subcutaneously and intracranially transplanted gliomas in xenograft mouse models. It may be a suitable alternate of TMZ for the treatment of glioma via intravenous administration route. PMID- 24065570 TI - Breast cancer brain metastases responding to primary systemic therapy with T-DM1. PMID- 24065571 TI - First-principles electronic structure study of rhizoferrin and its Fe(III) complexes. AB - We have determined the structure and coordination chemistry of rhizoferrin (Rf), which is a particular type of siderophore, and its Fe(III) complexes using density functional theory calculations. Our results show that the Fe(III) ion binds in an octahedral coordination, with a low-spin (S = 1/2) charge-neutral chiral complex having the largest binding energy of the investigated complexes. We have also calculated nuclear magnetic resonance parameters, such as chemical shifts for (1)H and (13)C, and indirect nuclear spin-spin couplings for (1)H-(1)H and (13)C-(1)H in free Rf and in a low-spin neutral Rf metal complex, as well as nuclear quadrupole interaction parameters, such as asymmetry parameter and nuclear quadrupole coupling constants for (14)N. Our calculated values for the chemical shifts for free Rf are in excellent agreement with experimental data while the calculated NMR parameters for Fe(III) complexes are predictions for future experimental work. PMID- 24065572 TI - Developmental neurotoxicity of cadmium on enzyme activities of crucial offspring rat brain regions. AB - Cadmium (Cd) is an environmental contaminant known to exert significant neurotoxic effects on both humans and experimental animals. The aim of this study was to shed more light on the effects of gestational (in utero) and lactational maternal exposure to Cd (50 ppm of Cd as Cd-chloride in the drinking water) on crucial brain enzyme activities in important rat offspring brain regions (frontal cortex, hippocampus, hypothalamus, pons and cerebellum). Our study provides a brain region-specific view of the changes in the activities of three crucial brain enzymes as a result of the developmental neurotoxicity of Cd. Maternal exposure to Cd during both gestation and lactation results into significant changes in the activities of acetylcholinesterase and Na(+),K(+)-ATPase in the frontal cortex and the cerebellum of the offspring rats, as well as in a significant increase in the hippocampal Mg(2+)-ATPase activity. These brain region-specific findings underline the need for further research in the field of Cd-induced developmental neurotoxicity. Deeper understanding of the mechanisms underlying the neurodevelopmental deficits taking place due to in utero and early age exposure to Cd could shed more light on the causes of its well-established cognitive implications. PMID- 24065573 TI - Modeling greenup date of dominant grass species in the Inner Mongolian Grassland using air temperature and precipitation data. AB - This work was undertaken to examine the combined effect of air temperature and precipitation during late winter and early spring on modeling greenup date of grass species in the Inner Mongolian Grassland. We used the traditional thermal time model and developed two revised thermal time models coupling air temperature and precipitation to simulate greenup date of three dominant grass species at six stations from 1983 to 2009. Results show that climatic controls on greenup date of grass species were location-specific. The revised thermal time models coupling air temperature and precipitation show higher simulation parsimony and efficiency than the traditional thermal time model for five of 11 data sets at Bayartuhushuo, Xilinhot and Xianghuangqi, whereas the traditional thermal time model indicates higher simulation parsimony and efficiency than the revised thermal time models coupling air temperature and precipitation for the other six data sets at E'ergunayouqi, Ewenkeqi and Chaharyouyihouqi. The mean root mean square error of the 11 models is 4.9 days. Moreover, the influence of late winter and early spring precipitation on greenup date seems to be stronger at stations with scarce precipitation than at stations with relatively abundant precipitation. From the mechanism perspectives, accumulated late winter and early spring precipitation may play a more important role as the precondition of forcing temperature than as the supplementary condition of forcing temperature in triggering greenup. Our findings suggest that predicting responses of grass phenology to global climate change should consider both thermal and moisture scenarios in some semiarid and arid areas. PMID- 24065578 TI - Old and new challenges in hemophilia management. PMID- 24065579 TI - Think about it: FMR1 gene mosaicism. AB - Fragile X syndrome (FXS) is one of the most frequent causes of mental retardation, intellectual disability, and autism. Most cases are the result of an expansion of the CGG trinucleotide repeat in the 5' untranslated region of the FMR1 gene and the subsequent functional loss of the related protein. We describe the case of a 4-year-old boy who clinically presents mild psychomotor delay without any major clinical dysmorphisms. Molecular analysis of the FMR1 gene showed mosaicism in terms of size and methylation, with one normal and 1 fully mutated allele, which is very rare in this syndrome. Physicians should therefore consider a diagnosis of FXS even if the patient's phenotype is mild. Although rare, diagnosing this condition has important consequences for the patient's rehabilitation and the family planning of parents and relatives. PMID- 24065580 TI - Prevalence of Sleep Disturbances in Children With Neurofibromatosis Type 1. AB - Children with neurodevelopmental disorders are at increased risk for sleep issues, which affect quality of life, cognitive function, and behavior. To determine the prevalence of sleep problems in children with the common neurodevelopmental disorder neurofibromatosis type 1, a cross-sectional study was performed on 129 affected subjects and 89 unaffected siblings, age 2 to 17 years, using the Sleep Disturbance Scale for Children questionnaire. Children with neurofibromatosis type 1 were significantly more likely to have disturbances in initiating and maintaining sleep, arousal, sleep-wake transition, and hyperhidrosis, but not problems with abnormal sleep breathing, or excessive somnolence. Although the overall sleep scores were higher in children with neurofibromatosis type 1, this was not related to a coexisting attention deficit disorder, cognitive impairment, or stimulant medication use. Collectively, these results demonstrate that children with neurofibromatosis type 1 are more likely to have sleep disturbances, and support the use of appropriate interventions for this at-risk population. PMID- 24065581 TI - Posterior Reversible Encephalopathy Syndrome in Children: Case Series and Systematic Review. AB - To study presentations and outcome of posterior reversible encephalopathy syndrome in children, we retrospectively analyzed 14 patients admitted to our pediatric intensive care unit. We further assessed 94 additional pediatric cases from a systematic review. Our patients had a mean age of 11.6 years. Their precipitating factors were hypertension (100%), immunosuppressants (71%), antineoplastic agents (21%), and hemodialysis (14%). Initial neurologic manifestations included seizures (100%), mental change (100%), headache (79%), and visual disturbance (57%). After prompt diagnosis by magnetic resonance imaging (MRI) with intensive management, all patients had complete clinical recovery with subsequent radiologic resolution. Systemic literature review indicated that seizures (90%), hypertension (85%), and atypical neuroimaging findings (80%) are common presentations in childhood posterior reversible encephalopathy syndrome. We conclude that in children presenting with seizures and hypertension, a pediatric neurologist should consider posterior reversible encephalopathy syndrome within a comprehensive differential diagnosis of acute encephalopathy. Early recognition and intensive care are essential to ensure complete neurologic recovery in children with posterior reversible encephalopathy syndrome. PMID- 24065582 TI - Functional relapses in pediatric multiple sclerosis. AB - Multiple sclerosis in children is characterized by more frequent relapses than in adult patients. Diagnosing and treating youth with multiple sclerosis present a number of challenges including differentiating organic relapses from functional symptoms. However, there is no literature describing coexistence of functionality in pediatric multiple sclerosis. Here, we report 2 cases in which inconsistency between clinical history, physical examination, imaging, and atypical disease progression led to suspicion of functional relapses. The purpose of this study is to raise awareness of functional relapses, as prompt recognition can prevent overtreatment and iatrogenic risks in children and adolescents with multiple sclerosis. Underlying psychiatric issues also need to be addressed. PMID- 24065583 TI - Patient transition from a free clinic to a medical home. PMID- 24065585 TI - Variation in diffusion of gases through PDMS due to plasma surface treatment and storage conditions. AB - Polydimethylsiloxane (PDMS) is a commonly used polymer in the fabrication of microfluidic devices due to such features as transparency, gas permeability, and ease of patterning with soft lithography. The surface characteristics of PDMS can also be easily changed with oxygen or low pressure air plasma converting it from a hydrophobic to a hydrophilic state. As part of such a transformation, surface methyl groups are removed and replaced with hydroxyl groups making the exposed surface to resemble silica, a gas impermeable substance. We have utilized Platinum(II)-tetrakis(pentaflourophenyl)porphyrin immobilized within a thin (~1.5 um thick) polystyrene matrix as an oxygen sensor, Stern-Volmer relationship, and Fick's Law of simple diffusion to measure the effects of PDMS composition, treatment, and storage on oxygen diffusion through PDMS. Results indicate that freshly oxidized PDMS showed a significantly smaller diffusion coefficient, indicating that the SiO2 layer formed on the PDMS surface created an impeding barrier. This barrier disappeared after a 3-day storage in air, but remained significant for up to 3 weeks if PDMS was maintained in contact with water. Additionally, higher density PDMS formulation (5:1 ratio) showed similar diffusion characteristics as normal (10:1 ratio) formulation, but showed 60 % smaller diffusion coefficient after plasma treatment that never recovered to pre treatment levels even after a 3-week storage in air. Understanding how plasma surface treatments contribute to oxygen diffusion will be useful in exploiting the gas permeability of PDMS to establish defined normoxic and hypoxic oxygen conditions within microfluidic bioreactor systems. PMID- 24065586 TI - Validation of anatomical models to study aerosol deposition in human nasal cavities. AB - PURPOSE: Intranasal deposition of aerosols is often studied using in vitro nasal cavity models. However, the relevance of these models to predict in vivo human deposition has not been validated. This study compared in vivo nasal aerosol deposition and in vitro deposition in a human plastinated head model (NC1) and its replica constructed from CT-scan (NC2). METHODS: Two nebulizers (Atomisor Sonique(r) and Easynose(r)) were used to administer a 5.6 MUm aerosol of (99m)Tc DTPA to seven healthy volunteers and to the nasal models. Aerosol deposition was quantified by gamma-scintigraphy in the nasal, upper nasal cavity and maxillary sinus (MS) regions. The distribution of aerosol deposition was determined along three nasal cavity axes (x, y and z). RESULTS: There was no significant difference regarding aerosol deposition between the volunteers and NC1. Aerosol deposition was significantly lower in NC2 than in volunteers regarding nasal region (p < 0.05) but was similar for the upper nasal cavity and MS regions. Mean aerosol distribution for NC1 came within the standard deviation (SD) of in vivo distribution, whereas that of NC2 was outside the in vivo SD for x and y axes. CONCLUSIONS: In conclusion, nasal models can be used to predict aerosol deposition produced by nebulizers, but their performance depends on their design. PMID- 24065587 TI - Zanamivir conjugated to poly-L-glutamine is much more active against influenza viruses in mice and ferrets than the drug itself. AB - PURPOSE: Previously, polymer-attached zanamivir had been found to inhibit influenza A viruses in vitro far better than did small-molecule zanamivir (1) itself. The aim of this study was to identify in vitro-using the plaque reduction assay-a highly potent 1-polymer conjugate, and subsequently test its antiviral efficacy in vivo. METHODS: By examining the structure-activity relationship of 1 polymer conjugates in the plaque assay, we have determined that the most potent inhibitor against several representative influenza virus strains has a neutral high-molecular-weight backbone and a short alkyl linker. We have examined this optimal polymeric inhibitor for efficacy and immunogenicity in the mouse and ferret models of infection. RESULTS: 1 attached to poly-L-glutamine is an effective therapeutic for established influenza infection in ferrets, reducing viral titers up to 30-fold for 6 days. There is also up to a 190-fold reduction in viral load when the drug is used as a combined prophylactic/therapeutic in mice. Additionally, we see no evidence that the drug conjugate stimulates an immune response in mice upon repeat administration. CONCLUSIONS: 1 attached to a neutral high-molecular-weight backbone through a short alkyl linker drastically reduced both in vitro and in vivo titers compared to those observed with 1 itself. Thus, further development of this polymeric zanamivir for the mitigation of influenza infection seems warranted. PMID- 24065588 TI - Preparation, characterization, and evaluation of dipfluzine-benzoic acid co crystals with improved physicochemical properties. AB - PURPOSE: To prepare and characterize the co-crystal of dipfluzine and benzoic acid. To investigate the feasibility of the co-crystal for improving solubility and a faster dissolution rate in vitro and evaluate the bioavailability and tissue distribution of co-crystal in vivo. METHODS: A novel dipfluzine-benzoic acid co-crystal prepared using the solvent-assisted co-grinding and the solvent ultrasonic methods were identified and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), as well as Raman, solid-state nuclear magnetic resonance (ssNMR), and terahertz (THz) spectroscopy. Pharmacokinetics and tissue distribution were tested in vivo using murine models. Statistics analysis for dissolution data of co-crystal in vitro and animal experiment data in vivo were evaluated using t test. RESULTS: Results of PXRD and DSC identified the dipfluzine-benzoic acid co crystals were formed with a molar ratio of 1:2. The IR, Raman, and ssNMR spectra verified the formation of O-H . . . O and O-H . . . F hydrogen bonds. The complex constant, K, was evaluated to be 10(9) orders of magnitude with Delta r G < 0. The co-crystal solubility, the rate of drug dissolution and the relative bioavailability were approximately 500 times, five times and double that of dipfluzine, respectively. Increased solubility of co-crystal did not reduce distribution in the brain; the mean concentrations in the brain increased, but the differences had no statistic significance (p > 0.05). CONCLUSIONS: The co crystal of dipfluzine-benzoic acid improved the physicochemical properties of dipfluzine, such as solubility and dissolution rate. Furthermore, the increased relative bioavailability of co-crystal indicated the potential use in further clinical study. PMID- 24065589 TI - Magnetic targeting of novel heparinized iron oxide nanoparticles evaluated in a 9L-glioma mouse model. AB - PURPOSE: A novel PEGylated and heparinized magnetic iron oxide nano-platform (DNPH) was synthesized for simultaneous magnetic resonance imaging (MRI) and tumor targeting. METHODS: Starch-coated magnetic iron oxide nanoparticles ("D") were crosslinked, aminated (DN) and then simultaneously PEGylated and heparinized with different feed ratios of PEG and heparin (DNPH1-4). DNPH products were characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and superconducting quantum interference device (SQUID). The magentic targeting of DNPH3, with appropriate amounts of conjugated PEG and heparin, in a mouse 9L-glioma subcutaneous tumor model was confirmed by magnetic resonance imaging (MRI)/electron spin resonance (ESR). RESULTS: DNPH3 showed long circulating properties in vivo (half-life >8 h, more than 60-fold longer than that of parent D) and low reticuloendothelial system (RES) recognition in liver and spleen. Protamine, a model cationic protein, was efficiently loaded onto DNPH3 with a maximum loading content of 26.4 MUg/mg Fe. Magnetic capture of DNPH3 in tumor site with optimized conditions (I.D. of 12 mg/kg, targeting time of 45 min) was up to 29.42 MUg Fe/g tissue (12.26% I.D./g tissue). CONCLUSION: DNPH3 showed the potential to be used as a platform for cationic proteins for simultaneous tumor targeting and imaging. PMID- 24065591 TI - PLGA/liposome hybrid nanoparticles for short-chain ceramide delivery. AB - PURPOSE: Rapid premature release of lipophilic drugs from liposomal lipid bilayer to plasma proteins and biological membranes is a challenge for targeted drug delivery. The purpose of this study is to reduce premature release of lipophilic short-chain ceramides by encapsulating ceramides into liposomal aqueous interior with the aid of poly (lactic-coglycolicacid) (PLGA). METHODS: BODIPY FL labeled ceramide (FL-ceramide) and BODIPY-TR labeled ceramide (TR-ceramide) were encapsulated into carboxy-terminated PLGA nanoparticles. The negatively charged PLGA nanoparticles were then encapsulated into cationic liposomes to obtain PLGA/liposome hybrids. As a control, FL-ceramide and/or TR ceramide co-loaded liposomes without PLGA were prepared. The release of ceramides from PLGA/liposome hybrids and liposomes in rat plasma, cultured MDA-MB-231 cells, and rat blood circulation was compared using fluorescence resonance energy transfer (FRET) between FL-ceramide (donor) and TR-ceramide (acceptor). RESULTS: FRET analysis showed that FL-ceramide and TR-ceramide in liposomal lipid bilayer were rapidly released during incubation with rat plasma. In contrast, the FL-ceramide and TR ceramide in PLGA/liposome hybrids showed extended release. FRET images of cells revealed that ceramides in liposomal bilayer were rapidly transferred to cell membranes. In contrast, ceramides in PLGA/liposome hybrids were internalized into cells with nanoparticles simultaneously. Upon intravenous administration to rats, ceramides encapsulated in liposomal bilayer were completely released in 2 min. In contrast, ceramides encapsulated in the PLGA core were retained in PLGA/liposome hybrids for 4 h. CONCLUSIONS: The PLGA/liposome hybrid nanoparticles reduced in vitro and in vivo premature release of ceramides and offer a viable platform for targeted delivery of lipophilic drugs. PMID- 24065590 TI - Antiangiogenic effect of docetaxel and everolimus as individual and dual-drug loaded micellar nanocarriers. AB - PURPOSE: The in vitro inhibitory effect of Docetaxel (DTX) and Everolimus (EVR) alone and together in poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b PLA) nanocarriers on angiogenic processes and acute toxicity in mice was evaluated. METHODS: PEG-b-PLA DTX and/or EVR nanocarriers were characterized for size, drug loading, stability, and drug release. Cell proliferation, tubule formation, and migration studies were performed in Human Umbilical Vein Endothelial Cells (HUVEC) and Maximum Tolerated Doses (MTD) studies were in mice. RESULTS: DTX and EVR loading was 1.93 and 2.00 mg/mL respectively with similar solubilities for dual-drug micelles. All micelles were below 30 nm with diffusion controlled drug release. The IC50 for DTX, EVR micelles were, 6.80 +/- 0.67, 18.57 +/- 2.86 and 0.65 +/- 0.11 nM respectively with a synergistic inhibitory effect for dual-drug nanocarriers. Significant inhibition of tube formation occurred upon treatment with dual-drug nanocarriers as compared to individual micelles. EVR presence in dual-drug nanocarriers was able to significantly increase the inhibition of the migration of HUVEC by DTX. The MTDs for EVR, DTX and dual-drug micelles were 50, 30 and 20 mg/kg for each respectively. CONCLUSIONS: DTX-EVR dual-drug nanocarriers have antiangiogenic effects in vitro mediated through cellular angiogenic process and possess clinically relevant MTD. PMID- 24065592 TI - A neonatal amikacin covariate model can be used to predict ontogeny of other drugs eliminated through glomerular filtration in neonates. AB - PURPOSE: Recently, a covariate model characterizing developmental changes in clearance of amikacin in neonates has been developed using birth bodyweight and postnatal age. The aim of this study was to evaluate whether this covariate model can be used to predict maturation in clearance of other renally excreted drugs. METHODS: Five different neonatal datasets were available on netilmicin, vancomycin, tobramycin and gentamicin. The extensively validated covariate model for amikacin clearance was used to predict clearance of these drugs. In addition, independent reference models were developed based on a systematic covariate analysis. RESULTS: The descriptive and predictive properties of the models developed using the amikacin covariate model were good, and fairly similar to the independent reference models (goodness-of-fit plots, NPDE). Moreover, similar clearance values were obtained for both approaches. Finally, the same covariates as in the covariate model of amikacin, i.e. birth bodyweight and postnatal age, were identified on clearance in the independent reference models. CONCLUSIONS: This study shows that pediatric covariate models may contain physiological information since information derived from one drug can be used to describe other drugs. This semi-physiological approach may be used to optimize sparse data analysis and to derive individualized dosing algorithms for drugs in children. PMID- 24065595 TI - Functional magnetic nanoparticles for non-viral gene delivery and MR imaging. AB - Gene therapy is becoming a promising strategy to treat various kinds of genetic and acquired diseases. However, the development of safe, efficient, and targetable gene delivery systems remains a major challenge in gene therapy. The unique material characteristics of magnetic nanoparticles (MNPs), including high surface area, facile surface modification, controllable size, and excellent magnetic properties, make them promising candidates for gene delivery. The engineered MNPs with modifiable functional surfaces and bioactive cores can result in several advantageous diagnostic and therapeutic properties including enhanced magnetic resonance imaging (MRI) signal intensity, long permeation and retention in the circulatory system, specific delivery of therapeutic genes to target sites. In this review, the updated research on the preparation and surface modification of MNPs for gene delivery is summarized. PMID- 24065594 TI - Pharmacokinetics and pharmacodynamics of CD4-anchoring bi-functional fusion inhibitor in monkeys. AB - PURPOSE: This study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a chimeric protein, CD4-anchoring bi-functional fusion inhibitor (CD4-BFFI), in monkeys and assess the feasibility for HIV-1 treatment in humans. METHODS: The serum concentrations of CD4-BFFI and CD4 receptors were determined and modeled using a target-mediated drug disposition (TMDD) model following intravenous administration of 1 or 10 mg/kg in monkeys. In vitro CD4 internalization was examined in human peripheral blood mononuclear cells. RESULTS: Noncompartmental analysis showed a decrease in clearance (1.35 to 0.563 mL/h/kg) and an increase in half-lives (35 to 50 h) with increasing doses. Dose dependent CD4 occupancy was observed. The TMDD model reasonably captured the PK/PD profiles and suggested greater degradation rate constant for the free CD4 than the bound CD4. In vitro assay showed CD4-BFFI did not reduce the internalization of cell surface CD4. The simulated serum concentrations of CD4 BFFI were 20-fold above its in vitro IC50 for HIV-1 at 3 mg/kg weekly or biweekly following subcutaneous administration in humans. CONCLUSIONS: The TMDD modeling and in vitro CD4 internalization study indicate that CD4-BFFI does not induce CD4 internalization and CD4-BFFI short half-life is likely due to normal CD4 internalization. The simulated human PK supports CD4-BFFI as a promising anti-HIV 1 agent. PMID- 24065593 TI - Oxidation of therapeutic proteins and peptides: structural and biological consequences. AB - Oxidation is a common degradation pathway that affects therapeutic proteins and peptides during production, purification, formulation, transportation, storage and handling of solid and liquid preparations. In the present work we review the scientific literature about structural and biological consequences of protein/peptide oxidation. Representative examples are discussed of specific products whose oxidation has been recently studied, including monoclonal antibodies, calcitonin, granulocyte colony-stimulating factor, growth hormone, insulin, interferon alpha and beta, oxytocin and parathyroid hormone. These examples illustrate that oxidation often leads to modifications of higher-order structures, including aggregate induction, and can generate products that are pharmacokinetically different, biologically less active and/or potentially more immunogenic than their native counterpart. It is therefore crucially important during the pharmaceutical development of therapeutic proteins and peptides to comprehensively characterize oxidation products and evaluate the impact of oxidation-induced structural modifications on the biological properties of the drug. PMID- 24065596 TI - Effects of hepatic ischemia-reperfusion injury on the P-glycoprotein activity at the liver canalicular membrane and blood-brain barrier determined by in vivo administration of rhodamine 123 in rats. AB - PURPOSE: To investigate the effects of normothermic hepatic ischemia-reperfusion (IR) injury on the activity of P-glycoprotein (P-gp) in the liver and at the blood-brain barrier (BBB) of rats using rhodamine 123 (RH-123) as an in vivo marker. METHODS: Rats were subjected to 90 min of partial ischemia or sham surgery, followed by 12 or 24 h of reperfusion. Following intravenous injection, the concentrations of RH-123 in blood, bile, brain, and liver were used for pharmacokinetic calculations. The protein levels of P-gp and some other transporters in the liver and brain were also determined by Western blot analysis. RESULTS: P-gp protein levels at the liver canalicular membrane were increased by twofold after 24 h of reperfusion. However, the biliary excretion of RH-123 was reduced in these rats by 26%, presumably due to IR-induced reductions in the liver uptake of the marker and hepatic ATP concentrations. At the BBB, a 24% overexpression of P-gp in the 24-h IR animals was associated with a 30% decrease in the apparent brain uptake clearance of RH-123. The pharmacokinetics or brain distribution of RH-123 was not affected by the 12-h IR injury. CONCLUSIONS: Hepatic IR injury may alter the peripheral pharmacokinetics and brain distribution of drugs that are transported by P-gp and possibly other transporters. PMID- 24065597 TI - Electrosprayed microparticles with loaded pDNA-calcium phosphate nanoparticles to promote the regeneration of mature blood vessels. AB - PURPOSE: The lack of control over microvasculature formation remains a key roadblock to the therapeutic vascularization and regeneration of functional tissues. In the current study, the integration of plasmid DNA (pDNA) condensation and electrospraying technologies was proposed to promote the regeneration of mature blood vessels through injectable or infusible administration of microparticles. METHODS: Calcium phosphate (CP) nanoparticles with encapsulated plasmids encoding vascular endothelial growth factors (pVEGF) and basic fibroblast growth factor (pbFGF) were synthesized using reverse microemulsions. Electrosprayed microparticles with the loading of CP-pDNA nanoparticles were evaluated on both endothelial cells and smooth muscle cells and after subcutaneous infusion into animals. RESULTS: CP-pDNA nanoparticles was obtained with an average size of around 110 nm and electrosprayed into microparticles, resulting in high loading efficiency and extended protection on pDNA from external DNase environment. The inoculation of poly(ethylene glycol) into microparticle matrices realized a gradual release for 4 weeks of CP-pDNA nanoparticles, leading to an incremental transfection efficiency and strong secretion of extracellular matrices. After subcutaneous infusion of microparticles with encapsulated both CP-pVEGF and CP-pbFGF nanoparticles, significantly higher densities of blood vessels were achieved than those containing individual nanoparticles, and induced a rapid generation of mature blood vessels with few cytotoxicity and inflammation reactions. CONCLUSIONS: Electrosprayed microparticle with CP-pDNA nanoparticles encapsulated promoted the formation of vascular networks, providing clinical relevance for therapeutic vascularization and regeneration of functional tissues after injection to ischemic sites or entrapment into tissue engineering scaffolds. PMID- 24065599 TI - Different pharmaceutical products need similar terminology. AB - In the last decade, discussions on the development of the regulatory framework of generic versions of complex drugs such as biologicals and non-biological complex drugs have attracted broad attention. The terminology used is far from harmonized and can lead to multiple interpretations of legal texts, reflection papers, and guidance documents regarding market introduction as well as reimbursement. This article describes the meaning of relevant terms in different global regions (Europe, USA, WHO) and offers a proposal for a globally accepted terminology regarding (non-) biological complex drugs. PMID- 24065598 TI - Effect of rhamnolipids on permeability across Caco-2 cell monolayers. AB - PURPOSE: This report describes the effect of rhamnolipids (RLs), an amphiphilic biosurfactant produced by the bacterium Pseudomonas aeruginosa, on the integrity and permeability across Caco-2 cell monolayers. METHODS: We measured the trans epithelial electrical resistance (TEER) and permeability of [(14)C]mannitol across Caco-2 cell monolayers upon incubation with 0.01-5.0% v/v RLs as a function of incubation time (30, 60, 90, and 120 min). We also studied the recovery of RL-treated Caco-2 cell monolayers upon incubation with Kaempferol, which is a natural flavonoid that promotes the assembly of the tight junctions. RESULTS: TEER of Caco-2 cell monolayers incubated with 0.01-5.0% v/v RLs solution dropped to 80-28% of that of untreated cells. Decline in TEER was associated with an increase in [(14)C]mannitol permeability as a function of RLs concentration and incubation time with Caco-2 cells. Incubation of RLs-treated Caco-2 cell monolayers with normal culture medium for 48 h did not restore barrier integrity. Whereas, incubation of a RLs-treated Caco-2 cells with culture medium containing Kaempferol for 24 h restored barrier function indicated by the higher TEER and lower [(14)C]mannitol permeability values. CONCLUSIONS: These results show the ability of RLs to modulate the integrity and permeability of Caco-2 cell monolayers in a concentration- and time-dependent fashion, which suggest their potential to function as a non-toxic permeation enhancer. PMID- 24065600 TI - How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider. AB - The aim of this critical review is to reach a global consensus regarding the introduction of follow-on versions of nonbiological complex drugs (NBCD). A nonbiological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by state of the art physicochemical analytical means and where the clinical meaning of the differences is not known. The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation. The challenges posed by the development of follow-on versions of NBCD are illustrated in this paper by discussing the 'families' of liposomes, iron-carbohydrate ('iron-sugar') drugs and glatiramoids. It is proposed that the same principles for the marketing authorization of copies of NBCD as for biosimilars be used: the need for animal and/or clinical data and the need to show similarity in quality, safety and efficacy. The regulatory approach of NBCD will have to take into consideration the specific characteristics of the drugs, their formulation and manufacturing process and the resulting critical attributes to achieve their desired quality, safety and efficacy. As with the biosimilars, for the NBCD product, family specific methods should be evaluated and applied where scientifically proven, including sophisticated quality methods, pharmacodynamic markers and animal models. Concerning substitution and interchangeability of NBCD, it is also advisable to take biosimilars as an example, i.e. (1) substitution without the involvement of a healthcare professional should be discouraged to ensure traceability of the treatment of individual patients, (2) keep an individual patient on a specific treatment if the patient is doing well and only switch if unavoidable and (3) monitor the safety and efficacy of the new product if switching occurs. PMID- 24065601 TI - Development of pulmonary arteries after a central end-to-side shunt in patients with pulmonary atresia, ventricular septal defect, and diminutive pulmonary arteries. AB - AIM: To evaluate the development of pulmonary arteries (PAs) in patients with pulmonary atresia, ventricular septal defect, and diminutive PAs by using a central end-to-side shunt. METHODS: A total of 103 consecutive patients (71 male and 32 female) with pulmonary atresia, ventricular septal defect, and diminutive PAs received a central end-to-side shunt between PA and aorta from May 2004 to December 2010. The age and weight ranged between 2 to 86 months and 2.5 to 21.5 kg, respectively. Overall 79 patients with main PA diameters less than 4 mm received a central end-to-side shunt between PA and aorta, and 24 patients with main PAs absence received a modified central shunt between PA branches and aorta. RESULTS: There were no deaths during operation and follow-up. Compared with preoperative measures, total PA index increased from mean value 68.8 +/- 11.4 mm2/m2 to 129.1 +/- 24.9 mm2/m2 (p < 0.001). The increased PA index change at the time of 6 months or final repair after shunt completion was 87.7 +/- 27.4% (27 150%). By multivariate regression analysis, age at shunt, shunt procedure, and number of major aortopulmonary collateral arteries were correlated with increasing PA index change. CONCLUSION: The central end-to-side shunt promoted sufficient growth of the diminutive central PAs, especially in infant patients. Due to the risk of a distortion of pulmonary branches, the authors interposed a modified procedure for patients with main PAs absence by anastomosis of left PA and right PA directly in an end-to-side fashion to the both lateral wall of ascending aorta. It is technically easy to perform, warrants low risk of shunt thrombosis, and flow restriction in the early postoperative period. PMID- 24065602 TI - Interleukin-1 receptor-related protein ST2 and mitral valve repair outcome in patients with chronic degenerative mitral regurgitation. AB - BACKGROUND: ST2 is a member of the interleukin-1 receptor family that is markedly upregulated in cultured cardiomyocytes subjected to mechanical strain. Serum soluble ST2 (sST2) levels can be detected in patients with acute myocardial infarction and severe chronic heart failure. This study sought to assess for the first time the activation of the ST2 pathway in patients with severe chronic degenerative mitral regurgitation. MATERIALS AND METHODS: Serum sST2 levels were measured in 20 patients scheduled for mitral valve (MV) repair at baseline, at the end of the intervention, on postoperative day 1, at hospital discharge, and after 6 months. Patients also underwent measurement of N-terminal pro-brain natriuretic peptide and echocardiographic evaluation at each time point. RESULTS: At baseline, sST2 was detected in 10 (50%) patients (mean value, 60 +/- 74 pg/mL; range, 0-234 pg/mL; median, 8 pg/mL). MV repair was performed successfully in all patients. Cardiac surgery with cardiopulmonary bypass was associated with a rapid and transient increase in sST2 levels. Patients with baseline higher versus lower sST2 levels (>= 8 vs. < 8 pg/mL) had significantly higher levels of sST2 on postoperative day 1 (1,050 +/- 593 vs. 440 +/- 312 pg/mL; p = 0.009). At follow up, patients with preoperative sST2 >= 8 pg/mL had significantly higher ejection fraction (EF) (64.7 +/- 5.8 vs. 57.6 +/- 5.9; p = 0.03) and lower left ventricular end-diastolic diameter (LVEDD) (50.6 +/- 5.8 vs. 56 +/- 4.2; p = 0.03) compared with patients with preoperative sST2 < 8 pg/mL. CONCLUSION: Preoperative ST2 activation, evidenced by the presence of serum sST2 levels, is present in half of the patients with chronic degenerative mitral regurgitation and is associated with higher levels of EF and lower levels of LVEDD after MV repair. PMID- 24065603 TI - Assessment of stroke and concomitant cerebrovascular disease with heart disease requires invasive treatment: analysis of 249 consecutive patients with heart disease. AB - PURPOSE: The aim of this study was to analyze the relationships of cerebrovascular disease (CVD), heart problems, and stroke in patients who required an invasive cardiac procedure. MATERIALS AND METHODS: We enrolled 249 consecutive patients who required to or underwent invasive cardiac treatment and divided into a non-CVD group (n = 116) and a CVD group (n = 133). The latter group was divided into a coronary artery disease (CAD) group (n = 118) and a non CAD group such as cardiac structural lesions (n = 15). RESULTS: No significant relationship with significant cerebrovascular stenosis was observed in either the CADs or non-CADs. The incidence of past stroke was significantly higher in the CVD group than that in the non-CVD group (12.8 vs. 3.4%; p = 0.017). Previous stroke event had increased odds of having significant cerebrovascular stenosis (odds ratio, 3.919, p = 0.006). In patients with both cardiac disease and the CVD, perioperative stroke was only one case (0.9%). The main source of stroke was cardiogenic in the immediate results and cerebrovascular lesions in the delayed results (1-12 months). CONCLUSION: The risk of perioperative stroke was very low in combined cardiac disease and the CVD. However, for preventing ischemic stroke due to the predetected cerebrovascular lesions, precautionary efforts could be needed for patients undergoing an invasive cardiac procedure, and concomitant cerebrovascular lesions should be considered as main source of delayed ischemic stroke. PMID- 24065605 TI - Mood and anxiety problems in perinatal Indigenous women in Australia, New Zealand, Canada, and the United States: a critical review of the literature. AB - We conducted a review of research literature related to anxiety, depression, and mood problems in Indigenous women in Canada, the United States (including Hawaii), Australia, and New Zealand. Quantitative and qualitative research studies published between 1980 and March 2010 were reviewed. The initial search revealed 396 potential documents, and after being checked for relevance by two researchers, data were extracted from 16 quantitative studies, one qualitative research article, and one dissertation. Depression is a common problem in Indigenous pregnant and postpartum women; however, the prevalence and correlates of anxiety and mood disorders are understudied. The review identified four key areas where further research is needed: (a) longitudinal, population-based studies; (b) further validation and modification of appropriate screening tools; (c) exploration of cultural diversity and meaning of the lived experiences of antenatal and postpartum depression, anxiety, and mood disorders; and (d) development of evidence-informed practices for researchers and practitioners through collaborations with Aboriginal communities to better understand and improve mental health of women of childbearing age. PMID- 24065604 TI - Small bowel amyloidosis. AB - Amyloidosis often involves the gastrointestinal tract. The small intestine is the most commonly involved gastrointestinal site. Gastrointestinal manifestations of amyloidosis involvement of the small intestine include diarrhea, gastrointestinal bleeding, and obstruction. High index of suspicion leading to early diagnosis is important in tailoring appropriate therapeutic management of these patients. PMID- 24065606 TI - The intergenerational effects of Indian Residential Schools: implications for the concept of historical trauma. AB - The current paper reviews research that has explored the intergenerational effects of the Indian Residential School (IRS) system in Canada, in which Aboriginal children were forced to live at schools where various forms of neglect and abuse were common. Intergenerational IRS trauma continues to undermine the well-being of today's Aboriginal population, and having a familial history of IRS attendance has also been linked with more frequent contemporary stressor experiences and relatively greater effects of stressors on well-being. It is also suggested that familial IRS attendance across several generations within a family appears to have cumulative effects. Together, these findings provide empirical support for the concept of historical trauma, which takes the perspective that the consequences of numerous and sustained attacks against a group may accumulate over generations and interact with proximal stressors to undermine collective well-being. As much as historical trauma might be linked to pathology, it is not possible to go back in time to assess how previous traumas endured by Aboriginal peoples might be related to subsequent responses to IRS trauma. Nonetheless, the currently available research demonstrating the intergenerational effects of IRSs provides support for the enduring negative consequences of these experiences and the role of historical trauma in contributing to present day disparities in well being. PMID- 24065607 TI - A comparison of the prevalence and risk factors of suicidal ideation and suicide attempts in two American Indian population samples and in a general population sample. AB - The current study aimed to examine whether the prevalence and risk factors for suicidal ideation and attempts differ when comparing two American Indian reservation samples to the U.S. general population. Data were from the baseline nationally representative National Comorbidity Survey (N = 5,877) and the representative American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project (AI-SUPERPFP; N = 3,084). Face-to-face interviews were conducted using the fully structured World Health Organization Composite International Diagnostic Interview. American Indians from these Northern Plains and Southwest tribes appeared significantly less likely to have suicidal thoughts in their lifetime when compared with the general population, odds ratio (OR) of 0.49 (99% CI [0.36, 0.66]) and 0.36 (99% CI [0.25, 0.51]), respectively. However, members of the Northern Plains tribe were more likely to have attempted suicide in their lifetime compared with the general population (OR = 1.96, 99% CI [1.45, 2.65]). Suicide attempts without suicidal ideation were more common in the two American Indian samples than in the general population. In contrast, correlates of suicidal behavior appear quite similar when comparing the groups. Increased attention is needed to determine why rates of ideation and attempts may differ in American Indians when compared with the general population. PMID- 24065608 TI - Physiological and phenotypic characteristics of late survivors of tetralogy of fallot repair who are free from pulmonary valve replacement. AB - BACKGROUND: Pulmonary valve replacement (PVR) after repair of tetralogy of Fallot is commonly required and is burdensome. Detailed anatomic and physiologic characteristics of survivors free from late PVR and with good exercise capacity are not well described in a literature focusing on the indications for PVR. METHODS AND RESULTS: Survival and freedom from PVR were tracked in 1085 consecutive patients receiving standard tetralogy of Fallot repair in a single institution from 1964 to 2009. Of 152 total deaths, 100 occurred within the first postoperative year. Surviving patients between 10 and 50 years of age had an annual risk of death of 4 (confidence limit, 2.8-5.4) times that of normal contemporaries. To date, 189 patients have undergone secondary PVR at mean age of 20+/-13 years (36% of those alive at 40 years of age). A random sample of 50 survivors (age, 4-57 years) free from PVR underwent cardiovascular magnetic resonance, echocardiography, and exercise testing. These patients had mildly dilated right ventricles (right ventricular end-diastolic volume=101+/-26 mL/m(2)) with good systolic function (right ventricular ejection fraction=59+/ 7%). Most had exercise capacity within normal range (z peak o2=-0.91+/-1.3; z e/ co2=0.20+/-1.5). In patients >35 years of age with normal exercise capacity, there was mild residual right ventricular outflow tract obstruction (mean gradient, 24+/-13 mm Hg), pulmonary annulus diameters <0.5z, and unobstructed branch pulmonary arteries. CONCLUSIONS: An important proportion of patients require PVR late after tetralogy of Fallot repair. Patients surviving to 35 years of age without PVR and with a normal exercise capacity may have had a definitive primary repair; their right ventricular outflow tracts are characterized by mild residual obstruction and pulmonary annulus diameter <0.5z. PMID- 24065609 TI - Indications for pulmonary valve replacement in repaired tetralogy of fallot: the quest continues. PMID- 24065610 TI - Atrium-specific Kir3.x determines inducibility, dynamics, and termination of fibrillation by regulating restitution-driven alternans. AB - BACKGROUND: Atrial fibrillation is the most common cardiac arrhythmia. Ventricular proarrhythmia hinders pharmacological atrial fibrillation treatment. Modulation of atrium-specific Kir3.x channels, which generate a constitutively active current (I(K,ACh-c)) after atrial remodeling, might circumvent this problem. However, it is unknown whether and how I(K,ACh-c) contributes to atrial fibrillation induction, dynamics, and termination. Therefore, we investigated the effects of I(K,ACh-c) blockade and Kir3.x downregulation on atrial fibrillation. METHODS AND RESULTS: Neonatal rat atrial cardiomyocyte cultures and intact atria were burst paced to induce reentry. To study the effects of Kir3.x on action potential characteristics and propagation patterns, cultures were treated with tertiapin or transduced with lentiviral vectors encoding Kcnj3- or Kcnj5-specific shRNAs. Kir3.1 and Kir3.4 were expressed in atrial but not in ventricular cardiomyocyte cultures. Tertiapin prolonged action potential duration (APD; 54.7+/-24.0 to 128.8+/-16.9 milliseconds; P<0.0001) in atrial cultures during reentry, indicating the presence of I(K,ACh-c). Furthermore, tertiapin decreased rotor frequency (14.4+/-7.4 to 6.6+/-2.0 Hz; P<0.05) and complexity (6.6+/-7.7 to 0.6+/-0.8 phase singularities; P<0.0001). Knockdown of Kcnj3 or Kcnj5 gave similar results. Blockade of I(K,ACh-c) prevented/terminated reentry by prolonging APD and changing APD and conduction velocity restitution slopes, thereby altering the probability of APD alternans and rotor destabilization. Whole-heart mapping experiments confirmed key findings (e.g., >50% reduction in atrial fibrillation inducibility after I(K,ACh-c) blockade). CONCLUSIONS: Atrium specific Kir3.x controls the induction, dynamics, and termination of fibrillation by modulating APD and APD/conduction velocity restitution slopes in atrial tissue with I(K,ACh-c). This study provides new molecular and mechanistic insights into atrial tachyarrhythmias and identifies Kir3.x as a promising atrium-specific target for antiarrhythmic strategies. PMID- 24065611 TI - Endothelial junctional adhesion molecule-a guides monocytes into flow-dependent predilection sites of atherosclerosis. AB - BACKGROUND: Junctional adhesion molecule (JAM)-A expressed in endothelial, epithelial, and blood cells can regulate permeability and leukocyte extravasation. Atherosclerosis develops at sites of disturbed flow in large arteries, but the mechanisms guiding inflammatory cells into these predilection sites remain unknown. METHODS AND RESULTS: To characterize cell-specific functions of JAM-A in atherosclerosis, we used apolipoprotein E-deficient mice with a somatic or endothelium-specific deficiency in JAM-A and bone marrow chimeras with JAM-A-deficient leukocytes. We show that impaired JAM-A expression in endothelial cells reduced mononuclear cell recruitment into the arterial wall and limited atherosclerotic lesion formation in hyperlipidemic mice. In contrast, JAM-A deficiency in bone marrow cells impeded monocyte de-adhesion, thereby increasing vascular permeability and lesion formation, whereas somatic JAM-A deletion revealed no significant effects. Regions with disturbed flow displayed a focal enrichment and luminal redistribution of endothelial JAM-A and were preferentially protected by its deficiency. The functional expression and redistribution of endothelial JAM-A was increased by oxidized low-density lipoprotein, but confined by atheroprotective laminar flow through an upregulation of microRNA (miR)-145, which repressed JAM-A. CONCLUSIONS: Our data identify endothelial JAM-A as an important effector molecule integrating atherogenic conditions to direct inflammatory cell entry at predilection sites of atherosclerosis. PMID- 24065612 TI - New breast screening leaflet still denies women the full picture, says critic. PMID- 24065613 TI - Are you 45% more likely to die in a UK hospital rather than a US hospital? PMID- 24065614 TI - Children will suffer most as climate change increases in coming decades, say scientists. PMID- 24065615 TI - Anti-atherogenic effects of methotrexate carried by a lipid nanoemulsion that binds to LDL receptors in cholesterol-fed rabbits. AB - PURPOSE: Nanoemulsions (LDE) with a lipid composition resembling that of LDL can concentrate in aortic lesions and when associated with anti-blastic agents, such as paclitaxel or etoposide, decrease atherosclerotic lesions induced in rabbits. Our aim was to test the association of a lipophilic derivative of methotrexate, didodecyl-methotrexate (ddMTX) to LDE on the lesions and on the expression of pro inflammatory and anti-inflammatory genes. METHODS: Twenty male New Zealand rabbits were fed 1 % cholesterol diet for 60 days. Starting from day 30, 10 animals were treated with 4 weekly LDE-ddMTX injections (4 mg/kg, I.V.) and 10 with LDE injections (20 mg LDE total lipid mass/kg). RESULTS: LDE-ddMTX reduced the size of the lesion areas by 65 % and the intima-media ratio by 2-fold. Reduction of intimal macrophage was 67 % and of apoptotic cells was 88 %. Smooth muscle cells migration into the intima was unaffected. LDE-ddMTX treatment diminished metalloproteinase-9 in the intima. In aortas of atherosclerotic rabbits, downregulation of 6 pro-inflammatory genes, TNF-alpha, MCP-1, IL-1beta, IL-18, MMP-9, MMP-12 and upregulation of the anti-inflammatory IL-10 gene were observed. Incubation of LDE-ddMTX with HUVEC cells led to downregulation of TNF alpha IL1-beta VAP-1, TLR2 and CXCL2. CONCLUSIONS: LDE-ddMTX is potentially useful to threat atherosclerosis by acting on inflammatory processes which are instrumental in the development of the disease. PMID- 24065616 TI - Nasally located ectopic ACTH-secreting pituitary adenoma (EAPA) causing Nelson's syndrome: diagnostic challenges. AB - PURPOSE: We report the first case of an Ectopic adrenocorticotrophin (ACTH) secreting pituitary adenoma (EAPA) located within the posterior nasal septum associated with Nelson's syndrome, which eluded diagnosis for over a decade. In this report, we explore the reasons for such diagnostic difficulty and suggest ways in which an earlier diagnosis may be made. METHODS AND RESULTS: A 19 years old Lebanese man presented in 2000, with overt Cushing's syndrome confirmed with markedly elevated urine free cortisols and failed dexamethasone suppression tests. An unsuppressed ACTH and a possible 5 mm adenoma on MRI (Magnetic Resonance Imaging) pituitary suggested Cushing's disease. The patient underwent trans-sphenoidal surgery (TSS), but histology revealed normal pituitary tissue and Cushing's syndrome persisted. A repeat MRI pituitary showed no anomaly, and extensive investigations failed to locate an ectopic lesion. Subsequently a bilateral adrenalectomy was performed. Over the ensuing years, the patient developed Nelson's syndrome with hyperpigmentation and markedly elevated ACTH levels. Repeated high dose dexamethasone suppression tests, corticotrophin releasing hormone (CRH) tests, and CRH stimulated inferior petrosal sinus samplings (IPSS) suggested a pituitary origin of the ACTH. Two further TSS were unsuccessful. The pituitary was irradiated. Subsequent review of his previous MRIs revealed an enlarging mass within the posterior nasal septum, which was excised in 2011. The histology confirmed the diagnosis of an EAPA within the nasal septum. CONCLUSION: Ectopic ACTH-secreting pituitary adenomas can occur not only along the developmental route of Rathke's pouch, but other aberrant locations giving a clinical and biochemical picture identical to Cushing's disease or Nelson's syndrome. Clinicians should suspect an EAPA, when a central ACTH source seems to be apparent with no obvious pituitary adenoma. A detailed MRI involving possible EAPA sites aids in locating these unusual lesions. PMID- 24065617 TI - Effects of dobutamine stress on cardiac contraction synchronism in a canine model. AB - In cardiac resynchronization therapy, many devices need to be optimized to take into account the magnitude and characteristics of patients' ventricular mechanical dyssynchrony. The optimization process is mostly performed at rest; however, mechanical resynchronization might be more important under stress, while patients need to improve their cardiac efficiency. The objective of this study was to observe if levels of cardiac stress could modify the ventricular contraction synchronism. Cardiac stress was induced with dobutamine infusion in eight healthy canine subjects. Hemodynamic and ventricular synchronism assessments were performed by left ventricular pressure measurements and radionuclide tomographic-gated blood pools. Cardiac output increased from 2.8 +/- 1.0 at rest to 5.7 +/- 2.2 L min(-1) at 20 ug kg(-1) min(-1), while the ventricular performance (dP/dtmax) increased from 1588 +/- 374 to 8004 +/- 710 mmHg s(-1). At baseline, the interventricular delay (in degrees) was -6.3 +/- 2.6 degrees , the left ventricle contraction preceding the right. The delay significantly increased to -21.6 +/- 3.1 degrees with dobutamine stress (p < 0.0001). On assessment of the left intraventricular synchrony, septal-to-lateral delay was -6.9 +/- 5.1 degrees at baseline which revealed a preceded contraction of the left lateral wall from the septum. Cardiac stress produced a significant modulation (p = 0.01), with an inversion of the contraction pattern, the septum contraction preceding the lateral wall contraction by 15.5 +/- 5.6 degrees at maximum dobutamine infusion; a significant linear trend (p < 0.001) was found between cardiac stress levels and septal-to-lateral delays. Cardiac activity levels modified the ventricular synchronism supporting the fact that optimizations of cardiac resynchronization devices could be improved by taking cardiac stress into account. PMID- 24065618 TI - Evaluation of docosahexaenoic acid in a dog model of hypertension induced left ventricular hypertrophy. AB - Marine n-3 polyunsaturated fatty acids alter cardiac phospholipids and prevent cardiac pathology in rodents subjected to pressure overload. This approach has not been evaluated in humans or large animals with hypertension-induced pathological hypertrophy. We evaluated docosahexaenoic acid (DHA) in old female dogs with hypertension caused by 16 weeks of aldosterone infusion. Aldosterone induced hypertension resulted in concentric left ventricular (LV) hypertrophy and impaired diastolic function in placebo-treated dogs. DHA supplementation increased DHA and depleted arachidonic acid in cardiac phospholipids, but did not improve LV parameters compared to placebo. Surprisingly, DHA significantly increased serum aldosterone concentration and blood pressure compared to placebo. Cardiac mitochondrial yield was decreased in placebo-treated hypertensive dogs compared to normal animals, which was prevented by DHA. Extensive analysis of mitochondrial function found no differences between DHA and placebo groups. In conclusion, DHA did not favorably impact mitochondrial or LV function in aldosterone hypertensive dogs. PMID- 24065619 TI - Evaluation of YO-PRO-1 as an early marker of apoptosis following radiofrequency ablation of colon cancer liver metastases. AB - Radiofrequency (RF) ablation (RFA) is a minimally invasive treatment for colorectal-cancer liver metastases (CLM) in selected nonsurgical patients. Unlike surgical resection, RFA is not followed by routine pathological examination of the target tumor and the surrounding liver tissue. The aim of this study was the evaluation of apoptotic events after RFA. Specifically, we evaluated YO-PRO-1 (YP1), a green fluorescent DNA marker for cells with compromised plasma membrane, as a potential, early marker of cell death. YP1 was applied on liver tissue adherent on the RF electrode used for CLM ablation, as well as on biopsy samples from the center and the margin of the ablation zone as depicted by dynamic CT immediately after RFA. Normal pig and mouse liver tissues were used for comparison. The same samples were also immunostained for fragmented DNA (TUNEL assay) and for active mitochondria (anti-OxPhos antibody). YP1 was also used simultaneously with propidium iodine (PI) to stain mouse liver and samples from ablated CLM. Following RFA of human CLM, more than 90 % of cells were positive for YP1. In nonablated, dissected pig and mouse liver however, we found similar YP1 signals (93.1 % and 65 %, respectively). In samples of intact mouse liver parenchyma, there was a significantly smaller proportion of YP1 positive cells (22.7 %). YP1 and PI staining was similar for ablated CLM. However in dissected normal mouse liver there was initial YP1 positivity and complete absence of the PI signal and only later there was PI signal. CONCLUSION: This is the first time that YP1 was applied in liver parenchymal tissue (rather than cell culture). The results suggest that YP1 is a very sensitive marker of early cellular events reflecting an early and widespread plasma membrane injury that allows YP1 penetration into the cells. PMID- 24065620 TI - Definition of research misconduct: problem on "definition" or "user"? PMID- 24065621 TI - 1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous Neuroprotectant and MAO inhibitor with antidepressant-like properties in the rat. AB - Oxidative stress is a major contributing factor in a range of brain pathologies and in the etiology of depression. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous substance which is present in the mammalian brain and exhibits neuroprotective, and monoamine oxidase (MAO)-inhibiting properties. In the present study, in order to investigate the potential role of 1MeTIQ as an antidepressant, we tested antidepressant-like effects of 1MeTIQ in comparison with desipramine (a classic antidepressant) in the forced swimming test (FST), and using HPLC methodology, we measured the concentrations of monoamines (dopamine, noradrenaline, serotonin) and the rate of their metabolism. 1MeTIQ given alone as well as in combination with desipramine produced an antidepressant like effect and decreased the immobility time in the FST. Neurochemical data have shown that 1MeTIQ like desipramine, activated the noradrenergic system. However, the mechanism of action of 1MeTIQ is broader than the actions of desipramine, and 1MeTIQ inhibits the MAO-dependent oxidation of dopamine and serotonin in all investigated structures. We can conclude that 1MeTIQ exhibits antidepressant-like activity in the FST in the rat. The mechanism of its antidepressant action differs from desipramine and seems to be mostly associated with the inhibition of the catabolism of monoamines and their increased concentrations in the brain. 1MeTIQ seems to be very beneficial from the clinical point of view as a reversible MAO inhibitor with a significant antidepressant effects. PMID- 24065623 TI - Protocol to assess the neurophysiology associated with multi-segmental postural coordination. AB - Anticipatory postural adjustments (APAs) stabilize potential disturbances to posture caused by movement. Impaired APAs are common with disease and injury. Brain functions associated with generating APAs remain uncertain due to a lack of paired tasks that require similar limb motion from similar postural orientations, but differ in eliciting an APA while also being compatible with brain imaging techniques (e.g., functional magnetic resonance imaging; fMRI). This study developed fMRI-compatible tasks differentiated by the presence or absence of APAs during leg movement. Eighteen healthy subjects performed two leg movement tasks, supported leg raise (SLR) and unsupported leg raise (ULR), to elicit isolated limb motion (no APA) versus multi-segmental coordination patterns (including APA), respectively. Ground reaction forces under the feet and electromyographic activation amplitudes were assessed to determine the coordination strategy elicited for each task. Results demonstrated that the ULR task elicited a multi segmental coordination that was either minimized or absent in the SLR task, indicating that it would serve as an adequate control task for fMRI protocols. A pilot study with a single subject performing each task in an MRI scanner demonstrated minimal head movement in both tasks and brain activation patterns consistent with an isolated limb movement for the SLR task versus multi-segmental postural coordination for the ULR task. PMID- 24065625 TI - Diabetes mellitus and aortic aneurysm rupture: a favorable association? AB - INTRODUCTION: Recent reports suggest that diabetic patients are relatively unlikely to have abdominal aortic aneurysms (AAAs). This retrospective study assesses the relationship between diabetes mellitus (DM) and aortic aneurysm rupture. METHODS: Patients with a diagnosis of any aortic aneurysm during a 10 year period were identified from our records. Patients with diagnoses of aortic aneurysm (thoracic, thoracoabdominal, and abdominal, treated and untreated) were included. Patients with nonatheromatous aneurysms (transection, dissection, mycotic, or isolated iliac) were excluded. RESULTS: In all, 1830 patients with nonruptured aneurysms and 232 ruptured aneurysms were included giving a total of 2062 patients with aortic aneurysms (abdominal, thoracic, and thoracoabdominal). Of these 1830, 225 (12.3%) patients with nonruptured aneurysm were diabetic; however, only 13 (5.6%) of the 232 patients with ruptured aortic aneurysm were diabetic (odds ratio [OR] = 0.42; confidence interval [CI]: 0.23-0.75, P = .004). Considering only those with AAAs, 184 (12.4%) of the 1482 nonruptured AAA were diabetic; however, only 12 (6.4%) of the 188 patients with ruptured AAA were diabetic (OR = 0.48 [CI: 0.26-0.88], P = .02). In this study group, the odds of dying due to aneurysm rupture in the diabetic group are significantly lower compared to the nondiabetic groups (OR = 0.31 [CI: 0.13-0.69], P = .004), despite the finding that diabetic patients had almost the same life expectancy as nondiabetic patients (DM, 73 years [67-80] vs non-DM, 75 years [68-82] P = .23). CONCLUSIONS: Diabetic patients with aortic aneurysms are significantly less likely to present with rupture or to die from aneurysm rupture when compared to nondiabetic patients with aortic aneurysms. We have identified association only, not causality. However, it is plausible that DM, or the treatment of DM, may have a protective effect on aortic aneurysm rupture. PMID- 24065626 TI - Changes in hypothalamus-pituitary-adrenal axis following transient ischemic attack. AB - Acute brain ischemia caused by transient ischemic attack initiates a complex sequence of events in the central nervous system and hypothalamic-pituitary adrenal (HPA) axis which may ultimately culminate in neuronal and cell damage. The brain is highly susceptible to ischemia and in response to stress shows changes in morphology and chemistry that are largely reversible. These responses are known to modify the function of the HPA axis, but their mechanisms are not yet clear. Duration and size of the HPA axis activation are regulated by corticotropin-releasing hormone, vasopressin (AVP), and glucocorticoids, including cortisol. Numerous studies suggest that activation of these hormones following brain ischemia can result in neurohormonal dysfunction that can exacerbate long-term prognosis following stroke. These studies represent evidence that changes in the HPA axis play an important role in brain ischemia. PMID- 24065622 TI - Role of oxytocin signaling in the regulation of body weight. AB - Obesity and its associated metabolic disorders are growing health concerns in the US and worldwide. In the US alone, more than two-thirds of the adult population is classified as either overweight or obese [1], highlighting the need to develop new, effective treatments for these conditions. Whereas the hormone oxytocin is well known for its peripheral effects on uterine contraction during parturition and milk ejection during lactation, release of oxytocin from somatodendrites and axonal terminals within the central nervous system (CNS) is implicated in both the formation of prosocial behaviors and in the control of energy balance. Recent findings demonstrate that chronic administration of oxytocin reduces food intake and body weight in diet-induced obese (DIO) and genetically obese rodents with impaired or defective leptin signaling. Importantly, chronic systemic administration of oxytocin out to 6 weeks recapitulates the effects of central administration on body weight loss in DIO rodents at doses that do not result in the development of tolerance. Furthermore, these effects are coupled with induction of Fos (a marker of neuronal activation) in hindbrain areas (e.g. dorsal vagal complex (DVC)) linked to the control of meal size and forebrain areas (e.g. hypothalamus, amygdala) linked to the regulation of food intake and body weight. This review assesses the potential central and peripheral targets by which oxytocin may inhibit body weight gain, its regulation by anorexigenic and orexigenic signals, and its potential use as a therapy that can circumvent leptin resistance and reverse the behavioral and metabolic abnormalities associated with DIO and genetically obese models. PMID- 24065624 TI - First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors. AB - PURPOSE: This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Resminostat was administered orally once-daily on days 1 to 5 every 14 days at 5 dose levels between 100 and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed. RESULTS: Nineteen patients (median age 58 years, range 39-70) were treated. At 800 mg, 1 patient experienced grade 3 nausea and vomiting, grade 2 liver enzyme elevation, and grade 1 hypokalemia and thrombocytopenia; these were declared as a combined DLT. No other DLT was observed. Although an MTD was not reached and patients were safely dosed up to 800 mg, 3 of 7 patients treated with 800 mg underwent dose reductions after the DLT-defining period due to cumulative gastrointestinal toxicities and fatigue. All toxicities resolved following drug cessation. No grade 4 treatment-related adverse event was observed. The pharmacokinetic profile was dose-proportional with low inter-patient variability. Pharmacodynamic inhibition of HDAC enzyme was dose-dependent and reached 100% at doses >=400 mg. Eleven heavily pretreated patients had stable disease and 1 patient with metastatic thymoma had a 27% reduction in target lesion dimensions. CONCLUSIONS: Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels >=400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1 to 5 every 14 days. PMID- 24065627 TI - Mean platelet volume is elevated in patients with low high-density lipoprotein cholesterol. AB - A low high-density lipoprotein cholesterol (HDL-C) level is a predictor of increased cardiovascular risk. We assessed the mean platelet volume (MPV) in patients with low HDL-C. We studied 59 patients with low HDL-C (HDL-C <=35 mg/dL) and 56 control participants (HDL-C levels >35 mg/dL) with similar cardiovascular risk factors. As expected, HDL-C was significantly lower among the patients with low HDL-C than that of the control group (32 +/- 3 vs 51 +/- 5 mg/dL, respectively; P < .001). Platelet count was significantly lower among the patients with low HDL-C than that of the control group (213 +/- 60 vs 285 +/- 75 * 10(9)/L, respectively; P < .001). The MPV was significantly higher among the patients with low HDL-C than that of the control group (8.7 +/- 0.6 vs 7.1 +/- 0.5 fL, respectively; P < .001). We have shown that MPV was significantly elevated in patients with low HDL-C compared with control participants. PMID- 24065628 TI - The anatomical compartments and their connections as demonstrated by ectopic air. AB - Air/gas outside the aero-digestive tract is abnormal; depending on its location, it is usually called emphysema, referring to trapped air/gas in tissues, or ectopic air/gas. It can be associated to a wide range of disorders, and although it usually is an innocuous condition, it should prompt a search for the underlying aetiology, since some of its causes impose an urgent treatment. In rare instances, it may itself represent a life-threatening condition, depending on the site involved and how quickly it evolves. Abnormal air/gas beyond viscera and serosal spaces, reaches its location following some anatomic boundaries, such as fascia, which may help search the source; however if the air pressure exceeds the strength of the tissues, or the time between the aggression and the imaging is too long, the air/gas is almost everywhere, which may hinder its cause. Good knowledge of the anatomic spaces and how they connect between them facilitates the quick detection of the cause. Teaching points * Ectopic air can be depicted on conventional radiographs; but CT is more sensitive and accurate * Visceral and retropharyngeal spaces directly communicate with mediastinum * Renal fascia is a single multilaminated structure, which contains potential space. PMID- 24065629 TI - Radiography, tomosynthesis, CT and MRI in the evaluation of pulmonary cystic fibrosis: an untangling review of the multitude of scoring systems. AB - OBJECTIVE: The first radiographic scoring system for pulmonary cystic fibrosis was presented in 1958. Since then a multitude of scoring systems for radiography and computed tomography (CT) have been presented, recently also for tomosynthesis and magnetic resonance imaging (MRI). The aim of the current review was to analyse and compare the plethora of scoring systems for cystic fibrosis, especially regarding which scoring components are considered most important. METHODS: Four scoring systems for chest radiography, one for tomosynthesis, eight for CT and one for MRI were compared regarding components evaluated and their terminology; the areas scored; scoring levels; the weighting of each component in percentage of the total score; and the calculations for the final score. RESULTS: In most radiological scoring systems the lungs are evaluated for increased volume, bronchial wall thickening, bronchiectasis, mucus plugging, atelectasis and consolidation. In addition, for instance abscesses, bullae, septal thickening, mosaic perfusion, ground glass opacities and air trapping are evaluated in some CT scoring systems. Pleural affection and perfusion defects are scored on MRI. CONCLUSIONS: Bronchiectasis alone, or in combination with mucus plugging, is given the highest weighting in most scoring systems and is thus commonly considered to be the most significant finding when evaluating cystic fibrosis lung disease. TEACHING POINTS: * Scoring of examinations is used for comparison of outcome in studies. * Scoring of examinations can also be used for monitoring disease progression. * Cystic fibrosis can be scored on radiography, tomosynthesis, CT or MRI. * The typical imaging findings of cystic fibrosis depend on the imaging modality used. * Bronchiectasis is commonly considered the most significant finding when scoring cystic fibrosis. PMID- 24065630 TI - An association between peptidoglycan synthesis and organization of the Streptococcus pyogenes ExPortal. AB - The ExPortal of Streptococcus pyogenes is a focal microdomain of the cytoplasmic membrane that clusters the translocons of the general secretory pathway with accessory factors to facilitate the maturation of secreted polypeptides. While it is known that the ExPortal is enriched in anionic lipids, the mechanisms that organize the ExPortal are poorly understood. In the present study, we examined the role of the cell wall in organizing and maintaining the ExPortal. Removal of the cell wall resulted in a loss of ExPortal focal integrity accompanied by the circumferential redistribution of ExPortal lipid and protein components. A similar loss occurred upon treatment with gallidermin, a nonpermeabilizing lantibiotic that targets the lipid II precursor of peptidoglycan synthesis, and this treatment disrupted the secretion of several ExPortal substrates. Furthermore, several enzymes involved in the membrane-associated steps of lipid II synthesis, including MraY and MurN, were found to localize to a single discrete focus in the membrane that was coincident with the focal location of the secretory translocons and the anionic lipid microdomain. These data suggest that the ExPortal is associated with the site of peptidoglycan precursor synthesis and that peptidoglycan biogenesis influences ExPortal organization. These data add to an emerging literature indicating that cell wall biogenesis, cell division, and protein secretion are spatially coorganized processes. IMPORTANCE: Since Gram positive bacteria lack a periplasmic space, they lack a protected compartment to spatially coordinate interaction between newly secreted proteins and the factors required to process them. This represents a significant problem for pathogens that depend on the secretion of toxins and cell wall-associated adhesins to cause disease. Streptococci solve this dilemma by restricting secretion and processing factors to a defined region of the membrane. However, the mechanisms that promote restriction are not understood. In this study, we show that restriction of these factors in the pathogen Streptococcus pyogenes is intimately linked with the presence of the cell wall and its synthesis. Furthermore, several cell wall synthesis proteins are also restricted to the site of protein secretion. This study contributes to our understanding of how the Gram-positive cell is organized to coordinate protein secretion and biogenesis with cell wall synthesis and to the ongoing development of antibiotics that target these processes. PMID- 24065631 TI - Basal levels of (p)ppGpp in Enterococcus faecalis: the magic beyond the stringent response. AB - The stringent response (SR), mediated by the alarmone (p)ppGpp, is a conserved bacterial adaptation system controlling broad metabolic alterations necessary for survival under adverse conditions. In Enterococcus faecalis, production of (p)ppGpp is controlled by the bifunctional protein RSH (for "Rel SpoT homologue"; also known as RelA) and by the monofunctional synthetase RelQ. Previous characterization of E. faecalis strains lacking rsh, relQ, or both revealed that RSH is responsible for activation of the SR and that alterations in (p)ppGpp production negatively impact bacterial stress survival and virulence. Despite its well-characterized role as the effector of the SR, the significance of (p)ppGpp during balanced growth remains poorly understood. Microarrays of E. faecalis strains producing different basal amounts of (p)ppGpp identified several genes and pathways regulated by modest changes in (p)ppGpp. Notably, expression of numerous genes involved in energy generation were induced in the rsh relQ [(p)ppGpp(0)] strain, suggesting that a lack of basal (p)ppGpp places the cell in a "transcriptionally relaxed" state. Alterations in the fermentation profile and increased production of H2O2 in the (p)ppGpp(0) strain substantiate the observed transcriptional changes. We confirm that, similar to what is seen in Bacillus subtilis, (p)ppGpp directly inhibits the activity of enzymes involved in GTP biosynthesis, and complete loss of (p)ppGpp leads to dysregulation of GTP homeostasis. Finally, we show that the association of (p)ppGpp with antibiotic survival does not relate to the SR but rather relates to basal (p)ppGpp pools. Collectively, this study highlights the critical but still underappreciated role of basal (p)ppGpp pools under balanced growth conditions. IMPORTANCE: Drug resistant bacterial infections continue to pose a significant public health threat by limiting therapeutic options available to care providers. The stringent response (SR), mediated by the accumulation of two modified guanine nucleotides collectively known as (p)ppGpp, is a highly conserved stress response that broadly remodels bacterial physiology to a survival state. Given the strong correlation of the SR with the ability of bacteria to survive antibiotic treatment and the direct association of (p)ppGpp production with bacterial infectivity, understanding how bacteria produce and utilize (p)ppGpp may reveal potential targets for the development of new antimicrobial therapies. Using the multidrug-resistant pathogen Enterococcus faecalis as a model, we show that small alterations to (p)ppGpp levels, well below concentrations needed to trigger the SR, severely affected bacterial metabolism and antibiotic survival. Our findings highlight the often-underappreciated contribution of basal (p)ppGpp levels to metabolic balance and stress tolerance in bacteria. PMID- 24065632 TI - Genes required for aerial growth, cell division, and chromosome segregation are targets of WhiA before sporulation in Streptomyces venezuelae. AB - WhiA is a highly unusual transcriptional regulator related to a family of eukaryotic homing endonucleases. WhiA is required for sporulation in the filamentous bacterium Streptomyces, but WhiA homologues of unknown function are also found throughout the Gram-positive bacteria. To better understand the role of WhiA in Streptomyces development and its function as a transcription factor, we identified the WhiA regulon through a combination of chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray transcriptional profiling, exploiting a new model organism for the genus, Streptomyces venezuelae, which sporulates in liquid culture. The regulon encompasses ~240 transcription units, and WhiA appears to function almost equally as an activator and as a repressor. Bioinformatic analysis of the upstream regions of the complete regulon, combined with DNase I footprinting, identified a short but highly conserved asymmetric sequence, GACAC, associated with the majority of WhiA targets. Construction of a null mutant showed that whiA is required for the initiation of sporulation septation and chromosome segregation in S. venezuelae, and several genes encoding key proteins of the Streptomyces cell division machinery, such as ftsZ, ftsW, and ftsK, were found to be directly activated by WhiA during development. Several other genes encoding proteins with important roles in development were also identified as WhiA targets, including the sporulation-specific sigma factor sigma(WhiG) and the diguanylate cyclase CdgB. Cell division is tightly coordinated with the orderly arrest of apical growth in the sporogenic cell, and filP, encoding a key component of the polarisome that directs apical growth, is a direct target for WhiA-mediated repression during sporulation. IMPORTANCE: Since the initial identification of the genetic loci required for Streptomyces development, all of the bld and whi developmental master regulators have been cloned and characterized, and significant progress has been made toward understanding the cell biological processes that drive morphogenesis. A major challenge now is to connect the cell biological processes and the developmental master regulators by dissecting the regulatory networks that link the two. Studies of these regulatory networks have been greatly facilitated by the recent introduction of Streptomyces venezuelae as a new model system for the genus, a species that sporulates in liquid culture. Taking advantage of S. venezuelae, we have characterized the regulon of genes directly under the control of one of these master regulators, WhiA. Our results implicate WhiA in the direct regulation of key steps in sporulation, including the cessation of aerial growth, the initiation of cell division, and chromosome segregation. PMID- 24065633 TI - Less is more: Burkholderia pseudomallei and chronic melioidosis. AB - The Gram-negative bacterium Burkholderia pseudomallei is the causative agent of melioidosis, a serious infectious disease of humans and animals. Once considered an esoteric tropical disease confined to Southeast Asia and northern Australia, research on B. pseudomallei has recently gained global prominence due to its classification as a potential bioterrorism agent by countries such as the United States and also by increasing numbers of case reports from regions where it is not endemic. An environmental bacterium typically found in soil and water, assessing the true global prevalence of melioidosis is challenged by the fact that clinical symptoms associated with B. pseudomallei infection are extremely varied and may be confused with diverse conditions such as lung cancer, tuberculosis, or Staphyloccocus aureus infection. These diagnostic challenges, coupled with lack of awareness among clinicians, have likely contributed to underdiagnosis and the high mortality rate of melioidosis, as initial treatment is often either inappropriate or delayed. Even after antibiotic treatment, relapses are frequent, and after resolution of acute symptoms, chronic melioidosis can also occur, and the symptoms can persist for months to years. In a recent article, Price et al. [mBio 4(4):e00388-13, 2013, doi:10.1128/mBio.00388 13] demonstrate how comparative genomic sequencing can reveal the repertoire of genetic changes incurred by B. pseudomallei during chronic human infection. Their results have significant clinical ramifications and highlight B. pseudomallei's ability to survive in a wide range of potential niches within hosts, through the acquisition of genetic adaptations that optimize fitness and resource utilization. PMID- 24065634 TI - The circadian clock in oral health and diseases. AB - Most physiological processes in mammals display circadian rhythms that are driven by the endogenous circadian clock. This clock is comprised of a central component located in the hypothalamic suprachiasmatic nucleus and subordinate clocks in peripheral tissues. Circadian rhythms sustain 24-hour oscillations of a large number of master genes controlling the correct timing and synchronization of diverse physiological and metabolic processes within our bodies. This complex regulatory network provides an important communication link between our brain and several peripheral organs and tissues. At the molecular level, circadian oscillations of gene expression are regulated by a family of transcription factors called "clock genes". Dysregulation of clock gene expression results in diverse human pathological conditions, including autoimmune diseases and cancer. There is increasing evidence that the circadian clock affects tooth development, salivary gland and oral epithelium homeostasis, and saliva production. This review summarizes current knowledge of the roles of clock genes in the formation and maintenance of oral tissues, and discusses potential links between "oral clocks" and diseases such as head and neck cancer and Sjogren's syndrome. PMID- 24065635 TI - Comparison of long-term survival of implants and endodontically treated teeth. AB - The outcomes of both dental implants and endodontically treated teeth have been extensively studied. However, there is still a great controversy over when to keep a natural tooth and when to extract it for a dental implant. This article reviews the benefits and disadvantages of both treatment options and discusses success vs. survival outcomes, as well as the impact of technical advances for modern endodontics and endodontic microsurgery on the long-term prognosis of tooth retention. PMID- 24065636 TI - Self-reported measures for surveillance of periodontitis. AB - The purpose of this study was to evaluate the performance of self-reported measures in predicting periodontitis in a representative US adult population, based on 2009-2010 National Health and Nutrition Examination Survey (NHANES) data. Self-reported gum health and treatment history, loose teeth, bone loss around teeth, tooth not looking right, and use of dental floss and mouthwash were obtained during in-home interviews and validated against full-mouth clinically assessed periodontitis in 3,743 US adults 30 years and older. All self-reported measures (> 95% item response rates) were associated with periodontitis, and bivariate correlations between responses to these questions were weak, indicating low redundancy. In multivariable logistic regression modeling, the combined effects of demographic measures and responses to 5 self-reported questions in predicting periodontitis of mild or greater severity were 85% sensitive and 58% specific and produced an 'area under the receiver operator characteristic curve' (AUROCC) of 0.81. Four questions were 95% sensitive and 30% specific, with an AUROCC of 0.82 in predicting prevalence of clinical attachment loss >= 3 mm at one or more sites. In conclusion, self-reported measures performed well in predicting periodontitis in US adults. Where preferred clinically based surveillance is unattainable, locally adapted variations of these self-reported measures may be a promising alternative for surveillance of periodontitis. PMID- 24065637 TI - Isolation and characterization of polymorphic microsatellite loci in the ridgetail white prawn Exopalaemon carinicauda. AB - The ridgetail white prawn Exopalaemon carinicauda is one of the major economic shrimp species cultured in China. In this study, 30 microsatellite loci were isolated and characterized for the ridgetail white prawn E. carinicauda using a microsatellite-enriched library. Polymorphisms were tested in 30 individuals from a single wild population. The number of alleles at each locus ranged from 2 to 14. The observed and expected heterozygosities varied from 0.1000 to 0.8000 and from 0.2299 to 0.9228, respectively. The PIC value ranged from 0.2002 to 0.8939. These new loci will be useful in the study of population genetic structure and genetic diversity in this species. PMID- 24065638 TI - Significance of linkage disequilibrium heterogeneous patterns in the 21q22.3 region for mapping 21 trisomy individuals. AB - Recombination patterns can be indirectly inferred by means of linkage disequilibrium (LD) estimates, since LD is negatively correlated with genetic distance. However, LD does not necessarily have absolute correspondence with genetic distance. We estimated LD at 5 loci located in the 21q22.3 region. These STRs (D21S1440, D21S168, D21S1260, D21S1446, and D21S1411) covered 8.81 Mb of the 21q22.3 region. They were genotyped by conventional PCR. Similar size samples previously validated by sequencing were used as a genotyping control. Three hundred and sixty-nine individuals (62 families) living in Guadalajara, Mexico, were included. As an inclusion criterion, each family had a positive paternity test by autosomal markers for the CODIS core loci. Two hundred and thirty phase known haplotypes were identified by familial segregation. Only those haplotypes whose frequency was higher than 4% were taken into account for LD estimation, expressed as Lewontin's D' coefficient and Bonferroni's correction P values. For all 5 loci, the genetic distributions were in agreement with Hardy-Weinberg expectations. Heterozygosity and haplotype diversity were >= 0.69 and 99.58%, respectively. D21S1440-D21S168 (4.51 cM) and D21S1446-D21S1411 (4.58 cM) marker haplotype frequencies were significantly different from those expected by random distribution. The remaining haplotypes, including those with minimal inter distance (D21S1260-D21S1446, 1.44 Mb), did not show LD. The 5 STRs at the 21q22.3 region in this Mexican population showed a non-homogeneous LD pattern, which demonstrates that recombination or linkage should not be assumed solely on the basis of genetic distance. PMID- 24065639 TI - Genetic variations in the active efflux pump genes acrA/B and tolC in different drug-induced strains of Escherichia coli CVCC 1547. AB - This study aimed to investigate the properties of mutations of the active efflux pump genes acrA/B and tolC in Escherichia coli CVCC 1547 when induced by different drugs. The mutations were isolated in vitro by exposing E. coli CVCC 1547 to stepwise increases in the concentration of ceftriaxone (CRO), amikacin (AMK), or ciprofloxacin. The results showed that the minimum inhibitory concentrations for the corresponding drugs increased, as did the minimum inhibitory concentrations for other fluoroquinolones and beta-lactam drugs that were not inducers. DNA sequence analyses of the acrA/B and tolC genes of the mutants and comparison with the parent strain revealed that genetic variations had occurred. Three point mutations resulted in amino acid changes in the proteins expressed. Specifically, strain CRO10 had a mutation in acrA, A309G, that resulted in a Thr-103 to Ala substitution, and a mutation in tolC, G735A, that changed Ala-245 to Thr; strain AMK20 (and AMK30) had a Val-447 to Ile amino acid change in acrB. In addition to the missense mutations in these strains, we detected 7, 20, and 15 nonsense mutations in acrA, acrB, and tolC, respectively. To sum up, multiple genetic sequence variations and some changes in amino acid sequences were detected when E. coli CVCC 1547 was challenged in vitro with CRO, AMK, or ciprofloxacin. These changes may have given rise to multidrug-resistant strains. PMID- 24065640 TI - Development and characterization of microsatellite primers in Pogostemon cablin (Lamiaceae). AB - Microsatellite primers were developed and optimized for patchouli (Pogostemon cablin) to characterize the patchouli Active Germplasm Bank of Universidade Federal de Sergipe. Creation of a genomic library for patchouli enabled the design of 12 microsatellite primers. Six of these microsatellites were polymorphic, revealing two well-defined groups of individuals that possess exclusive alleles. The data allowed us to characterize the patchouli active Germplasm Bank, identify its genetic diversity, and provide new information for researching this species. PMID- 24065641 TI - A novel insertion mutation in the ADAR1 gene of a Chinese family with dyschromatosis symmetrica hereditaria. AB - Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant pigmentary genodermatosis, characterized by a mixture of hyperpigmented and hypopigmented macules that are mainly present on the dorsal portions of the extremities. The DSH locus was mapped to chromosome 1q11-q12 and, subsequently, pathogenic mutations in the double-stranded RNA-specific adenosine deaminase (ADAR1) gene were identified. We performed a mutational analysis of the ADAR1 gene in a Chinese family that included three individuals affected with typical DSH phenotypes. Mutations within the entire coding region and the exon-intron boundaries of ADAR1 were detected and confirmed by polymerase chain reaction and direct sequencing, respectively. An insertion mutation within exon 12, c.3035_3036insC (p.P1012fsX1017), was identified in all family members affected by DSH, but not in the healthy members or 100 unrelated controls. This finding improves our understanding of the role of ADAR1 in DSH. PMID- 24065642 TI - Use of molecular markers to compare Fusarium verticillioides pathogenic strains isolated from plants and humans. AB - Fusarium verticillioides is a pathogen of agriculturally important crops, especially maize. It is considered one of the most important pathogens responsible for fumonisin contamination of food products, which causes severe, chronic, and acute intoxication in humans and animals. Moreover, it is recognized as a cause of localized infections in immunocompetent patients and disseminated infections among severely immunosuppressed patients. Several molecular tools have been used to analyze the intraspecific variability of fungi. The objective of this study was to use molecular markers to compare pathogenic isolates of F. verticillioides and isolates of the same species obtained from clinical samples of patients with Fusarium mycoses. The molecular markers that we used were inter simple sequence repeat markers (primers GTG5 and GACA4), intron splice site primer (primer EI1), random amplified polymorphic DNA marker (primer OPW-6), and restriction fragment length polymorphism-internal transcribed spacer (ITS) from rDNA. From the data obtained, clusters were generated based on the UPGMA clustering method. The amplification products obtained using primers ITS4 and ITS5 and loci ITS1-5.8-ITS2 of the rDNA yielded fragments of approximately 600 bp for all the isolates. Digestion of the ITS region fragment using restriction enzymes such as EcoRI, DraI, BshI, AluI, HaeIII, HinfI, MspI, and PstI did not permit differentiation among pathogenic and clinical isolates. The inter-simple sequence repeat, intron splice site primer, and random amplified polymorphic DNA markers presented high genetic homogeneity among clinical isolates in contrast to the high variability found among the phytopathogenic isolates of F. verticillioides. PMID- 24065643 TI - IL-10 promoter SNPs and susceptibility to leprosy in ethnic groups from southwest China. AB - The purpose of this study was to determine whether interleukin-10 (IL-10) promoter polymorphisms are associated with leprosy or their subtypes in ethnic groups from southwest China. Genotyping using TaqMan(r) SNP Genotyping Master Mix and ABI 7500 real-time PCR system was performed for IL-10 T3575A, G2849A, C2763A, A1082G, C819T, and C592A in 189 healthy controls (40 +/- 18 years) and 193 patients (46 +/- 18 years) with leprosy [multibacillary, N = 131; paucibacillary (PB), N = 62]. The allelic frequencies of -2763C (97.9 vs 94.0%, P = 0.0074) and 1082A (92.8 vs 88.6%, P = 0.0452) in leprosy patients were significantly higher than in control subjects. The genetic frequency of -2763CC and -1082AA was not only significantly higher among leprosy patients than among control subjects [odds ratio (OR) = 3.33, 95% confidence interval (95%CI) = 1.39-7.99, P = 0.0071 and OR = 1.76, 95%CI = 1.02-3.03, P = 0.0420, respectively] but also significantly higher among PB patients than among control subjects (OR = 2.46, 95%CI = 1.22-4.96, P = 0.0115 and OR = 5.58, 95%CI = 2.06-15.12, P = 0.0007, respectively). The frequency of IL-10 haplotype 3575A/2849G/2763A/1082G/819C/592C was significantly higher among leprosy patients (OR = 5.57, 95%CI = 1.13-27.52, P = 0.0351) and PB patients (OR = 10.5, 95%CI = 1.36- 81.05, P = 0.0241) than among control subjects. IL-10 promoter -2763C/CC,-1082A/AA and haplotype 3575A/2849G/2763A/1082 G/819C/592C are associated with susceptibility to leprosy and the PB subtype in southwest China. PMID- 24065644 TI - Analysis of fusion gene expression in prostate tumors by using single-end reads. AB - Fusion gene expression, a kind of chromosome rearrangement mode, has been strongly linked to prostate cancer diagnosis and prognosis as well as to the Gleason score and the American Joint Committee on Cancer stage assessment. In combination with traditional methods for locating fusion genes and scoring their association with cancer cell growth, proliferation, and invasion through the basement membrane, the emerging high-throughput sequencing technologies offer a panorama of fusion genes in a genome and facilitate the discovery of new fusion modes. We describe here a method for using single-end reads to analyze fusion gene expression in prostate tumors. We obtained the fusion gene expression profiling of prostate tumors, clustered them into several biological pathways, highlighted three "rediscovered" fusion genes (TMPRSS2-ERG, KLK2, and KLK3) and proved the reliability of our method. PMID- 24065645 TI - In situ analysis of apoptosis in Aspergillus nidulans with ethidium bromide and acridine orange. AB - Apoptosis and necrosis are among several types of cell death. We stained the nuclei of Aspergillus nidulans grown in micro-colonies with ethidium bromide and acridine orange to detect in situ apoptosis. Suspensions of conidia from 5-day old colonies of the A. nidulans strains biA1methG1, G422, CLC100, and CLB3 were each put into two tubes. The suspension of one tube was irradiated with ultraviolet light for 20 s, whereas the other tube was not exposed to irradiation. The two suspensions were inoculated in complete liquid medium and 50 uL samples were placed on sterilized cover slips, spread on the surface of solid culture media on Petri dishes. After the micro-colonies were formed, the material on the cover slips was stained with ethidium bromide and acridine orange, placed on the lamina and observed under a fluorescence microscope. This staining method was efficient in discriminating normal nuclei from those going apoptosis and necrosis. Results have shown that irradiation provokes apoptosis but does not induce necrosis. There were no differences between the three strains and all data were considered to be statistically significant. PMID- 24065647 TI - Agrobacterium tumefaciens-mediated genetic transformation of the Taxol-producing endophytic fungus Ozonium sp EFY21. AB - An efficient Agrobacterium tumefaciens-mediated genetic transformation method was successfully established for a newly isolated Taxol-producing fungus, Ozonium sp EFY21. A specific hygromycin B resistance expression vector, pCAMBIA1304'AN7-1, was constructed for fungal transformation. Key factors affecting transformation efficiency were thoroughly investigated and optimized. PCR amplification and Southern hybridization were used to verify the transformation events. This study should pave the way for future genetic modification studies of Ozonium sp EFY21. PMID- 24065646 TI - In silico prediction of conserved vaccine targets in Streptococcus agalactiae strains isolated from fish, cattle, and human samples. AB - Streptococcus agalactiae (Lancefield group B; group B streptococci) is a major pathogen that causes meningoencephalitis in fish, mastitis in cows, and neonatal sepsis and meningitis in humans. The available prophylactic measures for conserving human and animal health are not totally effective and have limitations. Effective vaccines against the different serotypes or genotypes of pathogenic strains from the various hosts would be useful. We used an in silico strategy to identify conserved vaccine candidates in 15 genomes of group B streptococci strains isolated from human, bovine, and fish samples. The degree of conservation, subcellular localization, and immunogenic potential of S. agalactiae proteins were investigated. We identified 36 antigenic proteins that were conserved in all 15 genomes. Among these proteins, 5 and 23 were shared only by human or fish strains, respectively. These potential vaccine targets may help develop effective vaccines that will help prevent S. agalactiae infection. PMID- 24065648 TI - Protein synthesis and degradation gene SNPs related to feed intake, feed efficiency, growth, and ultrasound carcass traits in Nellore cattle. AB - We looked for possible associations of SNPs in genes related to protein turnover, with growth, feed efficiency and carcass traits in feedlot Nellore cattle. Purebred Nellore bulls and steers (N = 290; 378 +/- 42 kg body weight, 23 months +/- 42 days old) were evaluated for daily feed intake, body weight gain (BWG), gross feed efficiency, feed conversion ratio, partial efficiency of growth, residual feed intake (RFI), ultrasound backfat, rump fat, and ribeye area. Genotypes were obtained for SNPs in the growth hormone receptor (GHR-1 and GHR 2); calpain (CAPN4751); calpastatin (UoGCAST); ubiquitin-conjugating enzyme 2I (UBE2I-1 and UBE2I-2); R3H domain containing 1 (R3HDM1-1, -2, -3, and -4), ring finger protein 19 (RNF19); proteasome 26S subunit, non-ATPase, 13 (PSMD13); ribosomal protein, large, P2 (RPLP2); and isoleucine-tRNA synthetase 2, mitochondrial (IARS2) genes. Allelic substitution, additive and dominant effects were tested and molecular breeding values were computed. CAPN4751, GHR-1 and -2, IARS2, R3HDM1-4, and UoGCAST were found to be normally segregating polymorphisms. Additive and dominance effects were observed on BWG, feed efficiency and carcass traits, although dominant effects predominated. Significant allelic substitution effects were observed for CAPN4751, GHR-1 and -2, and UoGCAST on BWG, gross feed efficiency, RFI, and carcass traits, under single- or multiple-marker analyses. Correlations between molecular breeding values and phenotypes were low, excepted for RFI, based on allelic substitution estimates obtained by stepwise linear regression. We conclude that SNPs in genes related to protein turnover are related to economically important traits in Nellore cattle. PMID- 24065649 TI - Single-nucleotide polymorphism of the pri-miR-34b/c gene is not associated with susceptibility to congenital heart disease in the Han Chinese population. AB - Recent evidence has shown that the microRNA polymorphism may play an important role in the susceptibility to congenital heart disease (CHD). A potentially functional SNP rs4938723 (T>C) in the promoter region of pri-miR-34b/c might affect transcription factor GATA binding and therefore pri-miR-34b/c expression. We genotyped the pri-miR-34b/c polymorphism in a case-control study of 590 patients and 672 controls in a Han Chinese population and assessed the effects of the pri-miR-34b/c polymorphism on CHD susceptibility by TaqMan SNP genotyping assay. There was no association between the pri-miR-34b/c polymorphism and the risk of CHD in both genotype and allelic frequency. In a subsequent analysis of the association between this polymorphism and CHD classification, there was still no significant difference in both genotype and allelic frequency. Our results suggest that the pri-miR-34b/c polymorphism rs4938723 is not associated with susceptibility to sporadic CHD in the Han Chinese population. PMID- 24065650 TI - Rescue from dominant follicle atresia by follicle-stimulating hormone in mice. AB - We investigated the effects of follicle-stimulating hormone (FSH) on atresia of the dominant follicle and changes in relevant apoptosis genes in granulosa cells of dominant follicles regulated by FSH in vivo. Four-week-old mice were administered FSH by intraperitoneal injection to induce follicular maturation. Granulosa cells of dominant follicles were collected at 48, 72, and 96 h after the first FSH injection. Phosphate-buffered saline was injected as a control. The mRNA levels of relevant granulosa cell apoptosis genes were examined by real-time quantitative polymerase chain reaction, and apoptosis of granulosa cells in dominant ovarian follicles was determined by the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Apoptosis in granulosa cells of dominant follicles was almost TUNEL-negative at 48, 72-66, 72, and 96-90 h after the first FSH injection, but granulosa cell apoptosis in dominant follicles was clearly detected at 96, 102, and 102-96 h by TUNEL. The BIM, caspase-3, and caspase-9 mRNA expression levels were significantly lower after FSH treatment at 72-66 and 96-90 h, compared with that at 72 and 96 h (P < 0.05). Caspase-8 and FasL mRNA expressions did not respond to FSH. FSH rescued granulosa cells from apoptosis when the relevant apoptosis genes were upregulated in early atretic follicles. FSH did not rescue granulosa cells from apoptosis if the DNA was cut into fragments by endonucleases. Thus, the rescue by FSH of granulosa cells from apoptosis and dominant follicle atresia may be accomplished by inhibition of apoptosis in mitochondria. PMID- 24065651 TI - Genomic in situ hybridization in plants. AB - Genomic in situ hybridization (GISH), which is a modification of fluorescent in situ hybridization, has been widely used in the study of plants. It has become one of the most important techniques for molecular cytogenetics. GISH is a technique that allows distinguishing the genomes in a cell. With this technique, it is possible to differentiate the genomes in a hybrid; consequently, this tool has been applied to the study of hybrid lineages, genetic improvement programs, and studies of the evolution of polyploids. Moreover, GISH can be applied to the analysis of the meiotic behavior in hybrids and polyploids, providing information concerning the relationship between species. This review presents the wide application of this technique in plants. PMID- 24065652 TI - Microsatellite usefulness is independent of phylogenetic distance in Tyrant flycatchers (Aves: Tyrannidae): a test using two globally threatened species. AB - Tyrant flycatchers (Aves: Tyrannidae) are endemic to the New World, and many species of this group are threatened or near-threatened at the global level. The aim of this study was to test the 18 microsatellite markers that have been published for other Tyrant flycatchers in the Strange-tailed Tyrant (Alectrurus risora) and the Sharp-tailed Tyrant (Culicivora caudacuta), two endemic species of southern South American grasslands that are classified as vulnerable. We also analyzed the usefulness of loci in relation to phylogenetic distance to the source species. Amplification success was high in both species (77 to 83%) and did not differ between the more closely and more distantly related species to the source species. Polymorphism success was also similar for both species, with 9 and 8 loci being polymorphic, respectively. An increased phylogenetic distance thus does not gradually lead to allelic or locus dropouts, implying that in Tyrant flycatchers, the published loci are useful independent of species relatedness. PMID- 24065653 TI - Rituximab regulates the expression of the Raf kinase inhibitor protein via NF kappaB in renal tissue of rats with diabetic nephropathy. AB - This study aimed to investigate the expression levels of the Raf kinase inhibitor protein (RKIP) and NF-kappaB in renal tissues of diabetic nephropathy (DN) rats, and to determine the underlying molecular targets of rituximab (RTX), with the goal of developing new clinical treatment selection for DN. Sprague-Dawley rats were randomly divided into a normal group (N), a DN group (M), and an RTX treatment group (D). Blood glucose and 24-h urine protein levels of rats were determined. The expression levels of RKIP and NF-kappaB in glomerular tissues were determined by immunohistochemistry staining and Western blotting. Comparisons between the M and N groups revealed that the concentrations of blood glucose and 24-h urine protein were significantly increased by DN (P < 0.01), and the expression levels of RKIP and NF-kappaB were significantly decreased and increased (P < 0.05), respectively. In the D group, the expression levels of RKIP and NF-kappaB were, respectively, upregulated and downregulated by RTX, and the concentrations of 24-h urine protein were also decreased by RTX. These results suggest that expression levels of RKIP might be regulated by RTX via NF-kappaB. This pathway could play an important role in the development and pathogenesis of DN. Therefore, RTX could be selected for clinical treatment of DN. PMID- 24065655 TI - Meta-analysis of association of common variants in the KCNJ11-ABCC8 region with type 2 diabetes. AB - KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11) and ABCC8 (ATP-binding cassette, subfamily C (CFTR/MRP), member 8) have been studied for association with type 2 diabetes in various ethnic populations with contradictory results. We performed a comprehensive meta-analysis for KCNJ11 rs5219, rs5210, rs5215, and ABCC8 rs757110 to evaluate the effect of these regions on genetic susceptibility for type 2 diabetes. Forty-one case-control association studies of KCNJ11 and ABCC8 polymorphisms with type 2 diabetes, including 61,879 subjects, were identified and used in our meta-analysis. Combined odds ratios (OR) of associations of this disease with the rs5219 T, rs5210 G, rs5215 G, and rs757110 G alleles were 1.15 [95% confidence interval (95%CI) = 1.10-1.21, P < 0.0001], 1.16 (95%CI = 1.08-1.24, P = 0.023), 1.08 (95%CI = 1.02-1.13, P = 0.006), and 1.12 (95%CI = 1.07-1.18, P < 0.0001), respectively. The effect of allele T of rs5219 was similar (OR = 1.16) in Europeans and Japanese. However, rs5219 was not associated with type 2 diabetes in the Chinese Han population. Our meta-analysis demonstrated that KCNJ11 and ABCC8 polymorphisms are associated with risk for type 2 diabetes in the global population. Comparative genomics and bioinformatics analyses revealed that rs5210 is located within a conserved 3'-UTR, and that allele A may abolish the binding site of hsa-miR-1910 that the risk allele G possesses. PMID- 24065654 TI - PANNOTATOR: an automated tool for annotation of pan-genomes. AB - Due to next-generation sequence technologies, sequencing of bacterial genomes is no longer one of the main bottlenecks in bacterial research and the number of new genomes deposited in public databases continues to increase at an accelerating rate. Among these new genomes, several belong to the same species and were generated for pan-genomic studies. A pan-genomic study allows investigation of strain phenotypic differences based on genotypic differences. Along with a need for good assembly quality, it is also fundamental to guarantee good functional genome annotation of the different strains. In order to ensure quality and standards for functional genome annotation among different strains, we developed and made available PANNOTATOR (http://bnet.egr.vcu.edu/iioab/agenote.php), a web based automated pipeline for the annotation of closely related and well-suited genomes for pan-genome studies, aiming at reducing the manual work to generate reports and corrections of various genome strains. PANNOTATOR achieved 98 and 76% of correctness for gene name and function, respectively, as result of an annotation transfer, with a similarity cut-off of 70%, compared with a gold standard annotation for the same species. These results surpassed the RAST and BASys softwares by 41 and 21% and 66 and 17% for gene name and function annotation, respectively, when there were reliable genome annotations of closely related species. PANNOTATOR provides fast and reliable pan-genome annotation; thereby allowing us to maintain the research focus on the main genotype differences between strains. PMID- 24065657 TI - Skeletal muscle calcium channel ryanodine and the development of pale, soft, and exudative meat in poultry. AB - The development of pale, soft, and exudative (PSE) breast fillet meat has become an economic burden for the poultry industry worldwide. PSE meat results in 1.0 1.5% loss in moisture and carcass weight, and a 2010 estimate of the Brazilian annual production put the economic loss due to PSE at over US$30 million. In the USA, PSE has caused an annual loss of up to US$200 million to the poultry industries. The underlying causes of the color abnormality in PSE meat are not fully understood. However, the likely physiological origin of PSE broiler meat is an excessive release of Ca(2+) promoted by a genetic mutation of the ryanodine receptor (RYR), a Ca(2+)-channel protein in the skeletal muscle sarcoplasmic reticulum. In pigs, the genetic cause of PSE meat has been identified as a point mutation in the RYR1 gene at nucleotide 1843, which causes an amino acid substitution (Arg615 to Cys615) in the RYR. This mutation leads to an alteration in Ca(2+) homeostasis, hypermetabolism, intense muscle contraction, and malignant hyperthermia in pigs susceptible to porcine stress syndrome. An understanding of this process represents the basis for breeding strategies aimed at eliminating the RYR1 mutation from global pig populations, a strategy that the poultry industry intends to emulate. The aim of this study was to review the subject, with an emphasis on the most recent developments in the field. PMID- 24065656 TI - Temporal variations of Hsp60 and HSF-1 in primary rat myocardial cells in vitro under heat stress. AB - The mechanisms involved in sudden animal death due to acute heart failure during heat stress are not well understood. We examined the relationship between heat stress-induced variations of protective Hsp60 and expression of its regulatory factor, HSF-1, in heat-stressed primary myocardial cells of neonatal rats in vitro through cardiac enzyme detection, immunoblotting, immunocytochemistry, and qPCR. Increases in cardiac damage-related enzyme levels demonstrated injury to myocardial cells after heat exposure at 42 degrees C. Hsp60 expression levels fluctuated during heat stress; they decreased significantly after 20 min, then increased at 120 min and decreased again at 360 min after initiation of heat stress. The highest levels of Hsp60 were observed at 240 min, while the lowest were at 60 min. Damage to myocardial cells was characterized by increases in cardiac enzyme levels and low levels of Hsp60 due to functional disorder of myocardial cells at early stages of heat stress. However, the significant induction of hsp60 mRNA levels from the beginning up to 240 min of heat stress was not consistent with the classic regulatory mechanisms that link transcription and translation, suggesting that Hsp60 expression is delayed due to loss of Hsp60 during the early stages of heat stress. hsf-1 mRNA levels were significantly increased from 10 min of heat stress; however, HSF-1 protein levels did not simultaneously increase, indicating that HSF-1 is not the sole regulator of Hsp60 expression. PMID- 24065658 TI - Identification and assessment of differentially expressed genes involved in growth regulation in Apostichopus japonicus. AB - Rapid and efficient growth is a major consideration and challenge for global mariculture. The differential growth rate of the sea cucumber, Apostichopus japonicus, has significantly hampered the total production of the industry. In the present study, forward and reverse suppression subtractive hybridization libraries were constructed and sequenced from a fast-growth group and a slow growth group of the sea cucumber. A total of 142 differentially expressed sequence tags (ESTs) with insertions longer than 150 bp were identified and further analyzed. Fifty-seven of these ESTs (approximately 40%) were functionally annotated for cell structure, energy metabolism, immunity response, and growth factor categories. Six candidate genes, arginine kinase, cytochrome c oxidase subunit I, HSP70, beta-actin, ferritin, and the ADP-ribosylation factor, were further validated by quantitative PCR. Significant differences were found between the fast- and slow-growth groups (P < 0.05) for the expression levels of arginine kinase, cytochrome c oxidase, HSP70, the ADP-ribosylation factor, and beta-actin. However, no significant difference was observed for ferritin. Our results provide promising candidate gene markers for practical size screening, and also further promote marker-assisted selective breeding of this species. PMID- 24065659 TI - MicroRNA-199a-3p is downregulated in gastric carcinomas and modulates cell proliferation. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate the translation of targeted mRNAs. An increasing amount of evidence indicates that miRNAs play important role in cancer pathogenesis, apoptosis, proliferation, and differentiation as oncogenes or tumor suppressors. Recently, miRNA-199a has been shown to be involved in many human cancers, although the role of miRNA-199a-3p in gastric cancer has not yet been evaluated. In the present study, the expression of miRNA-199a-3p was found to be significantly downregulated in human gastric cancer tissues and cells. miRNA-199a-3p induced anti-proliferation effects on human gastric cancer cells. Furthermore, using quantitative RT-PCR (real-time polymerase chain reaction) and luciferase reporter assays, mTOR was identified as a direct target gene of miRNA-199a-3p that is downregulated by it. In conclusion, our findings suggest that miRNA-199a-3p is associated with human gastric cancer through its ability to decrease cancer cell proliferation and target the mTOR signaling pathway, and, therefore, may provide a novel therapeutic target for the treatment of human gastric cancer. PMID- 24065660 TI - Genotoxicity in oral epithelial cells in children caused by nickel in metal crowns. AB - The micronucleus (MN) assay evaluates the effects of low doses of genotoxic carcinogens and can detect structural lesions that survive mitotic cycles. The objective of this study was to determine both the genotoxicity of nickel (Ni) in buccal epithelial cells and the urinary excretion of Ni in children with metal crowns. This was a prospective longitudinal study based on 37 patients selected at the Facultad de Odontologia de la Universidad Autonoma de Coahuila. MN assays were performed using buccal cells from the 37 patients, and Ni levels were determined from urine samples using inductively coupled plasma mass spectrometry at 1 (basal value), 15, and 45 days following the placement of crowns in each patient. Ni urinary excretion levels increased from 2.12 +/- 1.23 to 3.86 +/- 2.96 mg Ni/g creatinine (P < 0.05) and the frequency of exposed micronuclei increased from 4.67 +/- 0.15 to 6.78 +/- 0.167/1000 cells (P < 0.05) between 1 and 45 days post-crown placement. These results suggest that odontological exposure to metal crowns results in genotoxic damage at the cellular level of the oral mucosa and an increase in the urinary excretion of Ni within 45 days of exposure. PMID- 24065661 TI - Incidence of bovine leukocyte adhesion deficiency, complex vertebral malformation, and deficiency of uridine-5-monophosphate synthase carriers in Brazilian Girolando cattle. AB - Among the various hereditary diseases that have been widely studied in dairy cattle, bovine leukocyte adhesion deficiency (BLAD), deficiency of uridine-5 monophosphate synthase (DUMPS), and complex vertebral malformation (CVM) are noteworthy because of their high impact on overall herd productivity as a consequence of increased calf mortality. The aim of this study was to verify the frequency of carriers of BLAD, CVM, and DUMPS mutant alleles in cows and bulls from the National Girolando Progeny Test carried out in Brazil by using polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific PCR assays. A total of 777 animals were genotyped for BLAD, 783 for CVM, and 122 for DUMPS. The frequencies of carriers for BLAD and CVM were 0.77 and 1.53%, respectively, whereas no carriers of DUMPS were observed. PMID- 24065662 TI - Identification of naturalized goat breeds under conservation from northeastern Brazil using chromosomal markers. AB - In order to provide the first cytogenetic data of naturalized and threatened goat breeds from northeastern Brazil, cytogenetic analyses were carried out in individuals of Repartida and Moxoto breeds raised in Bahia and Ceara States. Males and females of both breeds had 2n = 60, with 29 autosomal acrocentric pairs plus the sex chromosome pair. The number of nucleolar organizer region (NOR) bearing chromosomes ranged from 6 to 8 per metaphase in Moxoto and Repartida goats, respectively. The active NORs in Repartida individuals were located exclusively at the terminal regions of the long arms, as usually detected in Bovidae. Otherwise, Moxoto specimens presented a large autosomal pair with NORs on short arms. GC-rich heterochromatin was detected at the centromeres in both breeds, although polymorphic terminal C-bands were visualized on pair 25 in Moxoto. In addition, GC-rich regions were detected at the terminal regions of the long arms of a single pair in Repartida and of 20 chromosomes in Moxoto goats. The differences in both the number and/or position of Ag-NORs and GC-rich sites between Repartida and Moxoto breeds represent efficient cytogenetic markers that can be used in the identification and conservation of the genetic integrity of each lineage. In spite of the small effective population size of these breeds, chromosomal abnormalities related to drift or inbreeding effects were absent in the samples analyzed. PMID- 24065663 TI - Identification of a new locus conferring antixenosis to the brown planthopper in rice cultivar Swarnalata (Oryza sativa L.). AB - The brown planthopper [Nilaparvata lugens (Stal); BPH] has caused severe damage to rice production. The identification of resistance genes and the development of BPH-resistant varieties are economical and effective ways to manage this pest. Using an F2 population from a cross between the Indica cultivars 93-11 and Swarnalata, we mapped the Qbph-8 locus to a 7.3-cM region on chromosome 8 in two tests, flanked by the markers RM339 and RM515. In this population, Qbph-8 explained 7.7 and 6.6% of the phenotypic variance of BPH preference in both tests. In the BPH host choice test, the average number of settled BPHs on the Qbph-8 plants was less than that on the 93-11 plants over the 24- to 120-h observation period. Furthermore, less BPH insects were observed on the BPH6+Qbph 8 plant compared with the BPH6 plant or Qbph-8 plant, indicating a stronger antixenotic effect shown in the gene pyramiding plants. Hence, this locus can be pyramided with other BPH resistance genes and applied to breed-resistant varieties, which possibly can improve the resistance level and durable resistance to the BPH. PMID- 24065664 TI - Antibacterial activity of leaf extract of Breonadia salicina (Rubiaceae), an endangered medicinal plant of Saudi Arabia. AB - Wild plants can contain bioactive compounds with potential activity against disease-causing microorganisms. In the Kingdom of Saudi Arabia, there are many plant species that may have antibacterial, antifungal, or antiviral activities, among other properties. We extracted bioactive compounds with methanol as well as with water from leaves of Breonadia salicina, which is an endangered plant found in the wild in Saudi Arabia. These extracts were tested against the bacteria Bacillus subtilis, Pseudomonas aeruginosa, Shigella sonnei, Escherichia coli, and Staphylococcus aureus. Both extracts showed antibacterial activity against all of the microorganisms, and thus, B. salicina leaf extract has potential as an antimicrobial agent for the preservation of foods, instead of synthetic chemical compounds. We found that the methanolic leaf extract was more effective than the aqueous crude extract against B. subtilis, P. aeruginosa, and S. aureus. PMID- 24065665 TI - Relationships among lipid peroxidation, SOD enzyme activity, and SOD gene expression profile in Lycopersicum esculentum L. exposed to cold stress. AB - The current study was designed to evaluate lipid peroxidation (via malondialdehyde) levels, the superoxide dismutase (SOD) gene expression profile, and SOD enzyme activity in tomato plants (Lycopersicum esculentum L.) subjected to different time periods of cold stress (control, 2, 4, 6, 8, and 10 days). Results revealed that maximum lipid peroxidation occurred in plants exposed to cold stress for 10 days, and SOD enzyme activity gradually increased with increasing exposure to cold stress. The level of mRNA increased within 4 days of cold treatment. After this period, the level tended to decrease and reached a minimum by the eighth day. A complex gene expression profile was determined, which was not statistically significant until the eighth day. At the 10th day of cold treatment, the mRNA level of SOD increased and changes between the 8th and 10th day were found to be statistically significant at the P < 0.05 level. These results suggest that the SOD gene and enzyme play a key role in resistance to cold stress conditions in tomato plants. PMID- 24065666 TI - Complete mitochondrial genomes reveal phylogeny relationship and evolutionary history of the family Felidae. AB - Many mitochondrial DNA sequences are used to estimate phylogenetic relationships among animal taxa and perform molecular phylogenetic evolution analysis. With the continuous development of sequencing technology, numerous mitochondrial sequences have been released in public databases, especially complete mitochondrial DNA sequences. Using multiple sequences is better than using single sequences for phylogenetic analysis of animals because multiple sequences have sufficient information for evolutionary process reconstruction. Therefore, we performed phylogenetic analyses of 14 species of Felidae based on complete mitochondrial genome sequences, with Canis familiaris as an outgroup, using neighbor joining, maximum likelihood, maximum parsimony, and Bayesian inference methods. The consensus phylogenetic trees supported the monophyly of Felidae, and the family could be divided into 2 subfamilies, Felinae and Pantherinae. The genus Panthera and species tigris were also studied in detail. Meanwhile, the divergence of this family was estimated by phylogenetic analysis using the Bayesian method with a relaxed molecular clock, and the results shown were consistent with previous studies. In summary, the evolution of Felidae was reconstructed by phylogenetic analysis based on mitochondrial genome sequences. The described method may be broadly applicable for phylogenetic analyses of anima taxa. PMID- 24065667 TI - Transcriptome network-based method to identify genes associated with unruptured intracranial aneurysms. AB - Intracranial aneurysm is a balloon or sac-like dilatation of blood vessels inside the brain. Despite their importance, the biological mechanisms of intracranial aneurysms are not totally understood. We used public genome-wide gene expression profile data to identify potential genes that are involved in intracranial aneurysm in order to construct a regulation network. Some of the transcription factors and target genes that we identified in this network had been identified as related to intracranial aneurysm in previous studies. We found additional transcription factors and target genes that are apparently related to intracranial aneurysm with this method. The confirmation of previously identified genes and transcription factors supports the usefulness of this transcriptome network analysis for the identification of candidate genes involved in intracranial aneurysm. PMID- 24065668 TI - Simple-sequence repeat markers of Cattleya coccinea (Orchidaceae), an endangered species of the Brazilian Atlantic Forest. AB - Microsatellite markers were developed for the endangered Brazilian orchid species Cattleya coccinea to describe its genetic diversity and structure and to support conservation studies. Nine microsatellite loci were isolated and characterized using an enriched genomic library. All loci are polymorphic at least in the 2 populations sampled, except for loci Cac05 and Cac09 for the Petropolis population. The mean number of alleles per locus was 8.8 between populations. The mean values of the observed and expected heterozygosities were 0.541 (ranging from 0 to 1) and 0.639 (ranging from 0 to 0.9), respectively. Cross amplifications were performed in 7 additional Epidendroideae species, and at least 2 loci were successful in 3 additional Cattleya species, Epidendrum secundum, and Brasiliorchis gracilis. All markers described herein will be useful in further studies evaluating the genetic diversity, population dynamics, and conservation genetics of C. coccinea and related species. PMID- 24065669 TI - Association between single nucleotide polymorphisms of the osteoprotegerin gene and postmenopausal osteoporosis in Chinese women. AB - Osteoporosis is an important and common complex health problem, particularly in postmenopausal women. It is characterized by a reduction in bone mineral density (BMD) and a deterioration of bone microarchitecture with a consequent increase of fracture risk. The osteoprotegerin (OPG) gene is considered to play an important role in the pathogenesis of osteoporosis. We analyzed SNPs of the OPG gene and associations between these polymorphisms and BMD in 399 Chinese postmenopausal women. BMD was quantified at the lumbar spine (L2-4), femoral neck, and total hip. The g.2264T>C and g.27676A>C SNPs were detected by PCR-RFLP and DNA sequencing methods. A significant association with spine BMD was found for g.27676A>C. The spine BMD value for subjects with genotype AA was significantly higher than those with genotypes GA and AA. No significant association was detected between any of the SNP marker genotypes and the other traits. We conclude that g.27676A>C in the OPG gene affects spine BMD and that the C allele is associated with increased risk for osteoporosis in Chinese postmenopausal women. PMID- 24065670 TI - Isolation and identification of new pollen-specific SFB genes in Japanese apricot (Prunus mume). AB - SFB, a candidate gene for the pollen S gene, has been identified in several species of Prunus (Rosaceae). We isolated 5 new SFB alleles from 6 Japanese apricot (Prunus mume) lines using a specific Prunus SFB primer pair (SFB-C1F and Pm-Vb), which was designed from conserved regions of Prunus SFB. The nucleotide sequences of these SFB genes were submitted to the GenBank database. The 5 new SFB alleles share typical structural features with SFB alleles from other Prunus species and were found to be polymorphic, with 67.08 to 96.91% amino acid identity. These new SFB alleles were specifically expressed in the pollen. We conclude that the PmSFB alleles that we identified are the pollen S determinants of Japanese apricot; they have potential as a tool for studies of the mechanisms of pollen self-incompatibility. PMID- 24065672 TI - Cloning and molecular characterization of a cDNA encoding a small GTPase from Hevea brasiliensis. AB - Small GTPases play a critical role in the regulation of a range of cellular processes including growth, differentiation, and intracellular transportation. The cDNA encoding a small GTPase, designated as HbGTPase1, was isolated from Hevea brasiliensis. HbGTPase1 was 882 bp long containing a 612-bp open reading frame encoding a putative protein of 203 amino acids, flanked by an 83-bp 5' untranslated region (UTR) and a 187-bp 3'-UTR. The predicted molecular mass of HbGTPase1 is 22.62 kDa, with an isoelectric point of 5.06. The HbGTPase1 protein was predicted to possess the conserved functional regions of the small GTPase superfamily of proteins. Quantitative polymerase chain reaction analysis revealed that HbGTPase1 was constitutively expressed in all tissues tested. HbGTPase1 transcripts accumulated at relatively low levels in the flower, latex, and leaves, while HbGTPase1 transcripts accumulated at relatively high levels in bark. Transcription of HbGTPase1 in the latex was induced by jasmonate. PMID- 24065671 TI - DNA detection of Clostridium difficile infection based on real-time resistance measurement. AB - We used a newly developed electrochemical method, real-time resistance measurement, based on loop-mediated isothermal amplification (LAMP), with real time resistance monitoring and derivative analysis. DNA extracted from specimens was amplified through LAMP reaction. The 2 products of LAMP, DNA and pyrophosphate, both are negative ions; they combine with positive dye (crystal violet) and positive ions (Mg(2+)), which leads to an increase in the resistivity of the reaction liquid. The changes of resistivity were measured in real-time with a specially designed resistance electrode, to detect Clostridium difficile DNA. We found that electrochemical detection of C. difficile could be completed in 0.5-1 h, with a detection limit of 10(2) CFU/mL, with high accuracy (95.0%), sensitivity (91.1%), and specificity (97.3%) compared to PCR methods. C. difficile is commonly associated with antibiotic-induced diarrhea. Due to the difficulty in performing anaerobic culture and cytotoxicity neutralization assays, a simple, rapid, sensitive, and accurate method is preferred. We conclude that real-time resistance measurement is a rapid, sensitive, and stable method for the diagnosis of C. difficile infection that could be applied to gene chips and pocket instruments. PMID- 24065673 TI - Genetic diversity of Palestine landraces of faba bean (Vicia faba) based on RAPD markers. AB - Until now, neither phenotypic nor molecular approaches have been used to characterize the landraces of Palestine faba beans (Vicia faba). We used PCR based RAPD markers to determine the genetic diversity and relatedness among 26 Palestinian faba bean landraces (traditional farmers' varieties) from 8 localities in the West Bank, Palestine. In tests with 37 primers, 14 generated no polymorphic bands, 12 exhibited weak and unclear products, and 11 primers produced good amplification products with high intensity and pattern stability. Ninety-four DNA fragments (loci) were detected, with an average of 8.54 loci per primer and size ranging from 160 to 1370 bp. A minimum of 4 and a maximum of 14 DNA fragments were obtained using (OPA-05 and OPA-09) and (BC-261) primers, respectively. The maximum percentage of polymorphic markers was 71.4 (BC-298) and the minimum was 50.0 (OPA-05, -09, -16). The 11 primers exhibited relatively high collective resolving power (Rp) values of 26.316, and varied from 0.154 for the OPA-09 primer to 5.236 for the BC-261, with an overall mean of 2.392. The primers BC-261, -322, and -298 were found to be the most useful RAPD primers to assess the genetic diversity of Palestinian faba beans, as they revealed relatively high Rp rates (5.236, 3.618, and 3.150, respectively). Based on the Jaccard coefficient, the genetic distance ranged from 0.358 to 0.069, with a mean of 0.213. We conclude that the RAPD technique is useful for determining genetic diversity and for developing suitable fingerprints for faba bean landraces grown in Palestine. PMID- 24065674 TI - Lack of association of functional UCP2 -866G/A and Ala55Val polymorphisms and type 2 diabetes in the Chinese population based on a case-control study and a meta-analysis. AB - Uncoupling protein 2 (UCP2) is a mitochondrial transporter protein and can affect the function of beta-cells. We investigated a possible association between functional UCP2 -866G/A and Ala55Val polymorphisms and type 2 diabetes in 715 Hubei Han Chinese. No significant association was found, either for the -866G/A polymorphism (allele, P = 0.254; genotype, P = 0.508) or for the Ala55Val polymorphism (allele, P = 0.250; genotype, P = 0.896). Then, we reviewed the association of UCP2 -866G/A and Ala55Val polymorphisms with type 2 diabetes susceptibility in the Chinese population with a meta-analysis. Our meta-analysis, which included 3643 Chinese, further confirmed a lack of association of -866G/A and Ala55Val with type 2 diabetes (additive model: -866G/A, odds ratio = 1.09, 95% confidence interval = 0.94-1.27, P = 0.25; Ala55Val, odds ratio = 1.21, 95% confidence interval = 0.85-1.72, P = 0.28). Based on our case-control study and meta-analysis, we conclude that UCP2 Ala55Val and -866G/A polymorphisms are not significantly associated with type 2 diabetes risk in the Chinese population. PMID- 24065675 TI - Molecular characterization of Aspergillus flavus and aflatoxin contamination of wheat grains from Saudi Arabia. AB - Twelve species belonging to six fungal genera were found to be associated with wheat (Triticum aestivum L.) grain samples collected from three main regions in Saudi Arabia. The most common genera (average frequency) were Aspergillus (14.3%), Fusarium (29.1%), Penicillium (9.3%), and Alternaria (8.2%). Nineteen isolates of Aspergillus flavus were screened for their ability to produce aflatoxins using HPLC. Thirteen isolates produced aflatoxins ranging from 0.5 to 2.6 ug/kg. Inter-simple sequence repeats (ISSR), and random amplified polymorphic DNA (RAPD) molecular markers were used, with the aim of genetically characterizing strains of A. flavus to discriminate between aflatoxigenic and non aflatoxigenic isolates. RAPD and ISSR analysis revealed a high level of genetic diversity in the A. flavus population, useful for genetic characterization. Clustering based on RAPD and ISSR dendograms was unrelated to geographic origin. RAPD and ISSR markers were not suitable to discriminate aflatoxigenic and non aflatoxigenic isolates, but ISSR primers were better compared to RAPD. PMID- 24065676 TI - Association analysis of yield and fiber quality traits in Gossypium barbadense with SSRs and SRAPs. AB - Cotton is an important cash crop. Mining for quantitative trait loci related to yield and fiber quality traits using association analysis has many advantages for cotton research. In this study, 170 simple sequence repeats (SSRs) and 258 sequence-related amplified polymorphisms (SRAPs) were used to analyze the association of 3 yield component traits and 5 fiber quality traits of 55 Gossypium barbadense accessions in 2009 and 2010. Principal component analysis of SSRs and SRAPs showed 3 and 2 subgroups, respectively. The boundaries between the SRAP groups were much more defined than those of the SSRs. A mixed linear model was used to analyze association of yield and fiber quality traits with SSRs and SRAPs. A total of 72 loci were detected, including 28 loci of SSRs and 44 loci of SRAPs; 26 of these loci were related to yield component traits, and 46 of these loci were related to fiber quality traits. The mean phenotypic variations explained in the SSR and SRAP analysis were 8.89 and 8.61%, respectively. The locus with the highest phenotypic variation explained was NAU1164 (23.33%), which was related to fiber uniformity. The comparison of association results between the two datasets showed that mining quantitative trait loci using association analysis was more efficient with SRAPs than with SSRs. PMID- 24065677 TI - Construction of recombinant adenoviruses carrying the optimal shRNA template against goat PTHrP and successful suppression of PTHrP expression in mammary epithelial cells. AB - Parathyroid hormone-related protein (PTHrP) is a protein member of the parathyroid hormone family that regulates the dynamic balance between blood and bone calcium during lactation. However, the mechanism of its regulation is not very clear. In order to establish a framework for further functional studies of the PTHrP gene in goat mammary gland epithelial cells during the lactation period, PTHrP cDNA was isolated from Xinong Saanen dairy goats. Its coding sequence is 534 bp in size. We also designed a short hairpin RNA (shRNA) to efficiently inhibit PTHrP expression and constructed recombinant adenoviruses carrying a template encoding this shRNA (AD-PTHrP-322) using the Block-iT shRNA interference system. Finally, the inhibition of PTHrP expression by the recombinant adenoviruses was confirmed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blotting. qRT-PCR results showed that the expression of PTHrP mRNA in mammary epithelial cells was downregulated by 29.2, 68.1, and 82.6% 24, 48, and 72 h after the cells were infected with AD PTHrP-322, respectively. Western blotting also showed that the expression of PTHrP was reduced in a time-dependent manner. These results suggest that AD-PTHrP 322 significantly inhibits the expression of PTHrP. PMID- 24065678 TI - Association between a polymorphism of the alpha-lactalbumin gene and milk production traits in Chinese Holstein cows. AB - The traits particularly important for milk production include milk yield, protein percentage, fat percentage, and the somatic cell score. Alpha-lactalbumin (alpha LA) is an important whey protein of cow milk, and is also present in the milk of many other mammalian species. In this study, we analyzed the genetic polymorphisms of the alpha-LA gene and their relationship to milk production traits (milk yield, protein percentage, fat percentage, and somatic cell score) in Chinese Holstein cows. The goal of this study was to contribute further molecular genetic information related to dairy cattle, to determine the molecular markers that are most closely linked with milk production traits, and to provide a scientific basis for the improvement of economically relevant traits in cows. Fluorescence-based conformation-sensitive gel electrophoresis, DNA sequencing, and ligation detection reaction techniques were used to analyze genetic variations of the alpha-LA gene (5'-UTR, exons 1, 2, 3, 4, and 3'-UTR) in 923 Chinese Holstein cows. One novel single nucleotide polymorphism (SNP), alpha LA2516, was identified in exon 4 of the alpha-LA gene. Allele frequencies were as follows: T 0.674, C 0.326. Association analysis revealed that alpha-LA2516 was not associated with milk yield, protein percentage, fat percentage, or somatic cell score (P > 0.05). These findings suggest that the SNP alpha-LA2516 in the alpha-LA gene likely does not have potential as a molecular marker for milk production traits in Chinese Holstein cows. PMID- 24065679 TI - Effect of muscle-fiber type on glycogenin-1 gene expression and its relationship with the glycolytic potential and pH of pork. AB - This study analyzed the effect of muscle-fiber type composition on glycogenin-1 (GYG) gene expression and its impact on pH. The longissimus dorsi (LD) muscle contains more type IIB fibers (75.10%) than does the psoas major (PM) muscle (41.58%), while the PM has more type I (3.65 vs 0.94%), type IIA (34.15 vs 10.63%), and type IIX (20.62 vs 13.33%) fibers. Compared with PM, glycolytic potential (GP), pH45 min, and DeltapH from 45 min to 24 h post-mortem were all relatively higher in LD. Glycogen metabolites (lactate and GP) were negatively correlated with pH24 h and positively correlated with DeltapH. Expression of GYG was generally higher in LD. GYG expression was positively correlated with glycogen metabolite (lactate and GP) content and DeltapH, and was negatively correlated with pH24 h. These data confirm that the muscle-fiber type and GP have significant effects on ultimate pH and pH decline, and suggest that expression of GYG in muscles is related to the metabolism of glycogen and may impact GP, DeltapH, and ultimate pH. High expression of GYG was associated with a high glycogen content, large pH decline, and low ultimate pH in muscles post-mortem. PMID- 24065680 TI - Role of a homozygous A(TA)7TAA promoter polymorphism and an exon 1 heterozygous frameshift mutation UGT1A1 in Crigler-Najjar syndrome type II in a Thai neonate. AB - Crigler-Najjar syndrome is a rare autosomal recessive disease caused by mutations in the UGT1A1 gene. These mutations result in the deficiency of UGT1A1, a hepatic enzyme essential for bilirubin conjugation. This report describes the case of a 4 month-old boy with the cardinal symptoms of Crigler-Najjar syndrome type II. Molecular genetic analysis showed a homozygous UGT1A1 promoter mutation [A(TA)7TAA] and a heterozygous insertion of 1 adenosine nucleotide between positions 353 and 354 in exon 1 of UGT1A1 that caused a frameshift with a premature stop codon. PMID- 24065681 TI - Comparative analysis of myostatin gene and promoter sequences of Qinchuan and Red Angus cattle. AB - To better understand the function of the myostatin gene and its promoter region in bovine, we amplified and sequenced the myostatin gene and promoter from the blood of Qinchuan and Red Angus cattle by using polymerase chain reaction. The sequences of Qinchuan and Red Angus cattle were compared with those of other cattle breeds available in GenBank. Exon splice sites were confirmed by mRNA sequencing. Compared to the published sequence (GenBank accession No. AF320998), 69 single nucleotide polymorphisms (SNPs) were identified in the Qinchuan myostatin gene, only one of which was an insertion mutation in Qinchuan cattle. There was a 16-bp insertion in the first 705-bp intron in 3 Qinchuan cattle. A total of 7 SNPs were identified in exon 3, in which the mutation occurred in the third base of the codon and was synonymous. On comparing the Qinchuan myostatin gene sequence to that of Red Angus cattle, a total of 50 SNPs were identified in the first and third exons. In addition, there were 18 SNPs identified in the Qinchuan cattle promoter region compared with those of other cattle compared to the Red Angus cattle myostatin promoter region. breeds (GenBank accession No. AF348479), but only 14 SNPs when compared to the Red Angus cattle myostatin promoter region. PMID- 24065682 TI - Assessment of clinical scoring systems for the diagnosis of Williams-Beuren syndrome. AB - Williams-Beuren syndrome (WBS) is a genetic disorder characterized by physical and intellectual developmental delay, associated with congenital heart disease and facial dysmorphism. WBS is caused by a microdeletion on chromosome 7 (7q11.23), which encompasses the elastin (ELN) gene and about 27 other genes. The gold standard for WBS laboratory diagnosis is FISH (fluorescence in situ hybridization), which is very costly. As a possible alternative, we investigated the accuracy of three clinical diagnostic scoring systems in 250 patients with WBS diagnosed by FISH. We concluded that all three systems could be used for the clinical diagnosis of WBS, but they all gave a low percentage of false-positive (6.0-9.2%) and false-negative (0.8-4.0%) results. Therefore, their use should be associated with FISH testing. PMID- 24065683 TI - Genetic variability in Melipona scutellaris from Reconcavo, Bahia, Brazil. AB - Bees play a key role in pollination and thereby help maintain plant diversity. The stingless bee Melipona scutellaris is an important pollinator in northeastern Brazil because it is endemic to this region. Both deforestation and timber harvesting have reduced the nesting sites for this species, thus reducing its population and range. Genetic studies may help reverse this process by providing important tools for their proper management with a view to conservation of this species. Microsatellite markers have proven to be ideal for mapping genes and population genetic studies. Our aim was to study, using microsatellite markers, the interpopulation genetic variability of M. scutellaris in different parts of the Reconcavo region in Bahia State, Brazil. In all, 95 adult workers from 11 localities in Reconcavo Baiano (Amargosa, Cabaceiras do Paraguacu, Conceicao da Feira, Conceicao do Almeida, Domingos Macedo Costa, Governador Mangabeira, Jaguaripe, Jiquirica, Maragojipe, Sao Felipe, and Vera Cruz) were analyzed using 10 pairs of microsatellite primers developed for different Meliponini species. The total number of alleles, allele richness, and genetic diversity ranged from 2 to 7 per locus (average = 4.4), 1.00 to 4.88, and 0.0 to 0.850, respectively. The expected and observed heterozygosities varied from 0.0 to 0.76 and 0.0 to 0.84, respectively. No locus showed deviation from the expected frequencies in the chi square test or linkage disequilibrium. The fixation index, analysis of molecular variance, and unweighted pair-group method using the arithmetic average revealed the effects of human activities on the populations of M. scutellaris, as little genetic structure was detected. PMID- 24065684 TI - Association between the TRAIL single nucleotide polymorphism rs1131580 and type 2 diabetes mellitus in a Han Chinese population. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is expressed in different tissues and cells, including the pancreas and lymphocytes, and it can selectively induce apoptosis in tumor cells but not in most normal cells. TRAIL plays critical roles in type 1 diabetes mellitus, and is involved in type 2 diabetes mellitus (T2DM). We recently discovered the association of nonalcoholic fatty liver disease, a risk factor for T2DM, with a single nucleotide polymorphism (SNP) in the TRAIL (TNFSF10) gene at site 1595C/T (rs1131580), indicating the possible association of T2DM with this TRAIL polymorphism. The aim of this study was to investigate the relationship of the TRAIL SNP at site 1595C/T (rs1131580) with T2DM susceptibility and the biometabolic parameters of T2DM in a Han Chinese population. The polymerase chain reaction-restriction fragment length polymorphism method was used to genotype SNP rs1131580 in 292 patients with T2DM and 266 healthy controls. We found that the frequency of the CC genotype and that of the C allele of rs1131580 were significantly higher in T2DM patients than in the control group. Additionally, the triglyceride and serum creatinine levels of T2DM patients with the CC genotype were significantly higher than those of patients with the TT genotype. Thus, the CC genotype of the TRAIL SNP at 1595C/T (rs1131580) confers increased susceptible to T2DM in a Han Chinese population from Shandong Province. These data suggest that the CC genotype at this SNP is related to diabetic severity and it might be a candidate for the prognostic assessment of T2DM. PMID- 24065685 TI - Fourteen years after the Shahid-Rajaei dam construction: an evaluation of morphometric and genetic differentiation between isolated up- and downstream populations of Capoeta capoeta gracilis (Pisces: Cyprinidae) in the Tajan River of Iran. AB - We evaluated the effects of the Shahid-Rajaei dam, 14 years after its construction, on morphometric and genetic divergence between up- and downstream populations of the Iranian fish Siah-Mahi (Capoeta capoeta gracilis). Sixty-six specimens were analyzed. There were significant differences between the 2 groups in the means of 16 morphometric characters (univariate analysis). In discriminant function analysis, the proportion of individuals classified into their original groups was 97 and 100% for up- and downstream populations, respectively. Principal component analysis of morphometric data demonstrated that the up- and downstream samples of Siah-Mahi are clearly distinct. In the genetic analysis, 6 informative primers produced 89 polymorphic bands with 95% polymorphism. In association analysis between morphological and genetic data, 63 of 89 genetic markers were significantly correlated with the 16 morphometric characters. We conclude that these are 2 morphologically and genetically distinct populations of C. c. gracilis, probably due to limited downstream dispersal and elimination of upstream migration. PMID- 24065686 TI - Odorant receptor genes are expressed in olfactory neuroblastoma. AB - Olfactory neuroblastoma (ONB) is a malignant tumor found in the human nasal cavity. These tumors are rare and poorly characterized at the molecular level. In this study, we asked whether olfactory-specific genes are expressed in ONBs by using reverse-transcriptase-polymerase chain reaction. We found that the olfactory marker protein and the RIC-8B genes, which are specifically expressed in mature olfactory neurons, are expressed in ONBs. Importantly, we also found that ONBs express a large variety of odorant receptor genes, representative of different odorant receptor gene subfamilies. Our results show that the ONBs express genes that are normally expressed in mature olfactory neurons and indicate that they are derived from progenitor or immature cells in the olfactory epithelium and not from a clonal expansion of a single or few mature olfactory neurons. PMID- 24065687 TI - Effect of atorvastatin on left atrial function of patients with paroxysmal atrial fibrillation. AB - The aim of this study was to evaluate the effects of atorvastatin on left atrial (LA) function in paroxysmal atrial fibrillation patients. Fifty-eight paroxysmal atrial fibrillation patients were divided into two groups (treatment and control groups). The echocardiography parameters, including LA active emptying volume (LAAEV), LA active emptying fraction, LA maximum volume, LA total emptying volume, LA total emptying fraction, and LA ejection force (LAEF), were measured before treatment, and then 12 and 18 months after treatment. Compared to pre treatment levels, the parameters reflecting LA pump function, such as LAAEV and LAEF, decreased significantly in treatment groups 12 months after treatment (P < 0.05). LAAEV and LAEF significantly increased 18 months after treatment (P < 0.05), and the indicators reflecting LA reservoir function, such as maximum volume, total emptying volume, and total emptying fraction increased significantly 18 months after treatment (P < 0.05). Compared with pre-treatment levels, LAAEV and LAEF decreased significantly 18 months after treatment in the control group (P < 0.05). These results demonstrated that long-term atorvastatin treatment could ameliorate the function of the atrium sinistrum. PMID- 24065688 TI - Mitochondrial and nuclear genes as the cause of complex I deficiency. AB - Multiple sclerosis (MS) is an immunological inflammatory disease of the central nervous system. The pathogenesis of MS is incompletely understood, but various studies have suggested that mitochondrial dysfunction is associated with the disease. Mitochondria are among the main cellular sources of reactive oxygen and nitrogen species, and they play a pivotal role in many neuro-pathological conditions. The mitochondrial nuclear subunit of complex I gene in mitochondria may play a role in MS, and understanding this role may provide rationale for novel approaches to treatment of the disease and the development of novel therapies. We designed a molecular study to demonstrate biochemical defects in complex I activity and found some novel nucleotide substitutions in mitochondrial DNA that might be involved in the pathogenesis of MS. The mitochondrial complex subunit I sequence was amplified and sequenced in MS patients. Although no reported pathogenic mutations were found in these patients, other studies have clearly indicated that the mitochondrial nuclear complex subunit I gene plays a significant role in MS pathogenesis. PMID- 24065689 TI - Characterization and molecular mapping of a dwarf mutant in wheat. AB - A spontaneous dwarf mutant of wheat was found in an F5 generation line derived from a cross between Huamai No. 9 and Een No. 1 in 1998; it was named Huaai 01. We characterized the genetic pattern of Huaai 01 and mapped the gene controlling the dwarf trait. This dwarf mutant was found insensitive to exogenous gibberellic acid treatment, based on the length of the first leaf and the coleoptile at the seedling stage, suggesting that it plays a crucial role in the gibberellin response pathway. Genetic analysis revealed that a single gene that is partially recessive controls the dwarf phenotype in Huaai 01. We named the dwarfing gene Rht-B2. Simple sequence repeats (SSR) were examined as identifying markers linked to the Rht-B2 gene in an F2 population. We screened 904 pairs of primers and identified 5 SSR markers linked to the Rht-B2 gene. Two markers, barc1096 and xgwm495, were located on the flanking region of the Rht-B2 gene at genetic distances of 2.9 and 3.3 cM, respectively. Based on published SSR linkage data for wheat, the Rht-B2 gene was mapped to the long arm of chromosome 4B. This identification and characterization of the Rht-B2 dwarfing gene will facilitate its utilization in wheat breeding. PMID- 24065690 TI - Decision-making processes for the uptake and implementation of family-based therapy by eating disorder treatment teams: a qualitative study. AB - OBJECTIVE: To explore the decision-making processes involved in the uptake and implementation of evidence-based treatments (EBTs), namely, family-based treatment (FBT), among therapists and their administrators within publically funded eating disorder treatment programs in Ontario, Canada. METHOD: Fundamental qualitative description guided sampling, data collection, and analytic decisions. Forty therapists and 11 administrators belonging to a network of clinicians treating eating disorders completed an in-depth interview regarding the decision making processes involved in EBT uptake and implementation within their organizations. Content analysis and the constant comparative technique were used to analyze interview transcripts, with 20% of the data independently double-coded by a second coder. RESULTS: Therapists and their administrators identified the importance of an inclusive change culture in evidence-based practice (EBP) decision-making. Each group indicated reluctance to make EBP decisions in isolation from the other. Additionally, participants identified seven stages of decision-making involved in EBT adoption, beginning with exposure to the EBT model and ending with evaluating the impact of the EBT on patient outcomes. Support for a stage-based decision-making process was in participants' indication that the stages were needed to demonstrate that they considered the costs and benefits of making a practice change. Participants indicated that EBTs endorsed by the Provincial Network for Eating Disorders or the Academy for Eating Disorders would more likely be adopted. DISCUSSION: Future work should focus on integrating the important decision-making processes identified in this study with known implementation models to increase the use of low-cost and effective treatments, such as FBT, within eating disorder treatment programs. PMID- 24065691 TI - SUS-BAR: a database of pig proteins with statistically validated structural and functional annotation. AB - Given the relevance of the pig proteome in different studies, including human complex maladies, a statistical validation of the annotation is required for a better understanding of the role of specific genes and proteins in the complex networks underlying biological processes in the animal. Presently, approximately 80% of the pig proteome is still poorly annotated, and the existence of protein sequences is routinely inferred automatically by sequence alignment towards preexisting sequences. In this article, we introduce SUS-BAR, a database that derives information mainly from UniProt Knowledgebase and that includes 26 206 pig protein sequences. In SUS-BAR, 16 675 of the pig protein sequences are endowed with statistically validated functional and structural annotation. Our statistical validation is determined by adopting a cluster-centric annotation procedure that allows transfer of different types of annotation, including structure and function. Each sequence in the database can be associated with a set of statistically validated Gene Ontologies (GOs) of the three main sub ontologies (Molecular Function, Biological Process and Cellular Component), with Pfam functional domains, and when possible, with a cluster Hidden Markov Model that allows modelling the 3D structure of the protein. A database search allows some statistics demonstrating the enrichment in both GO and Pfam annotations of the pig proteins as compared with UniProt Knowledgebase annotation. Searching in SUS-BAR allows retrieval of the pig protein annotation for further analysis. The search is also possible on the basis of specific GO terms and this allows retrieval of all the pig sequences participating into a given biological process, after annotation with our system. Alternatively, the search is possible on the basis of structural information, allowing retrieval of all the pig sequences with the same structural characteristics. PMID- 24065693 TI - An integrative review: work environment factors associated with physical activity among white-collar workers. AB - The purpose of this review is to synthesize the research evidence for the role of the work environment-workplace physical activity policies and resources and job strain factors-in explaining physical activity in white-collar workers. White collar workers are at risk for developing a sedentary lifestyle, which contributes to all-cause mortality. Understanding how work environment can influence worker physical activity is important for the development of effective interventions. We reviewed 15 research articles that describe the relationship between work environment factors and physical activity in predominantly white collar workers. Relatively consistent evidence was found for the effects of supportive workplace policies and resources. Weak evidence was found for the effects of job strain. Both work environment factors have the potential to influence physical activity but require further exploration to fully understand their contribution to physical activity in white-collar workers. Limitations and implications are discussed. PMID- 24065694 TI - Duration of untreated psychosis in a high-income versus a low- and middle-income region. AB - OBJECTIVE: Most data on duration of untreated psychosis (DUP) derives from high income countries. An inverse relationship between DUP and income and a longer DUP in low- and middle-income (LAMI) countries has been reported. The aim of this study was to compare DUP in a high-income country with that in a LAMI country using the same methodology. METHODS: The sample consisted of in- and outpatients, aged 15-35 years for the Vienna site and 18-35 years for the Pakistani sites, with first-episode psychosis (FEP). DUP was evaluated using psychiatric interviews, medical charts and the Nottingham Onset Schedule. Differentiated reporting of duration of untreated illness (DUI) from prodrome to start of treatment, and DUP from manifest psychotic symptoms to start of treatment was ensured. Primary outcome measures, DUI and DUP, were measured at a 0.025 level of significance. RESULTS: Thirty-one FEP patients in Vienna (mean age 20.03 years, SD 4.2) and 60 FEP patients from the Pakistani sites (mean age 26.15 years, SD 5.29) participated. The mean age in Vienna was younger due to the different age range inclusion criteria. The severity of psychopathology was more pronounced in the Pakistani sample. Log DUP was significantly different between groups (i.e. longer in the Pakistani sample (p=0.001)). Log DUI showed a trend for longer duration in the Vienna sample; however, this did not reach statistical significance (p=0.036). The severity of positive psychotic symptoms was associated with length of DUI in both regions. CONCLUSION: The longer DUP in Pakistan confirms the need to provide affordable treatment for psychosis for young FEP patients in Pakistan and in other LAMI countries. The relatively long period from prodrome to treatment initiation in both regions underlines the need to further establish low-threshold early intervention strategies in order to increase detection rates and reduce factors limiting patients seeking treatment. PMID- 24065692 TI - Quantitative molecular phenotyping of gill remodeling in a cichlid fish responding to salinity stress. AB - A two-tiered label-free quantitative (LFQ) proteomics workflow was used to elucidate how salinity affects the molecular phenotype, i.e. proteome, of gills from a cichlid fish, the euryhaline tilapia (Oreochromis mossambicus). The workflow consists of initial global profiling of relative tryptic peptide abundances in treated versus control samples followed by targeted identification (by MS/MS) and quantitation (by chromatographic peak area integration) of validated peptides for each protein of interest. Fresh water acclimated tilapia were independently exposed in separate experiments to acute short-term (34 ppt) and gradual long-term (70 ppt, 90 ppt) salinity stress followed by molecular phenotyping of the gill proteome. The severity of salinity stress can be deduced with high technical reproducibility from the initial global label-free quantitative profiling step alone at both peptide and protein levels. However, an accurate regulation ratio can only be determined by targeted label-free quantitative profiling because not all peptides used for protein identification are also valid for quantitation. Of the three salinity challenges, gradual acclimation to 90 ppt has the most pronounced effect on gill molecular phenotype. Known salinity effects on tilapia gills, including an increase in the size and number of mitochondria-rich ionocytes, activities of specific ion transporters, and induction of specific molecular chaperones are reflected in the regulation of abundances of the corresponding proteins. Moreover, specific protein isoforms that are responsive to environmental salinity change are resolved and it is revealed that salinity effects on the mitochondrial proteome are nonuniform. Furthermore, protein NDRG1 has been identified as a novel key component of molecular phenotype restructuring during salinity-induced gill remodeling. In conclusion, besides confirming known effects of salinity on gills of euryhaline fish, molecular phenotyping reveals novel insight into proteome changes that underlie the remodeling of tilapia gill epithelium in response to environmental salinity change. PMID- 24065695 TI - Ethical dilemma in consultation-liaison psychiatry. PMID- 24065696 TI - Opportunistic pathology-based screening for diabetes. AB - OBJECTIVE: To determine the potential of opportunistic glycated haemoglobin (HbA1c) testing of pathology samples to detect previously unknown diabetes. DESIGN: Pathology samples from participants collected for other reasons and suitable for HbA1c testing were utilised for opportunistic diabetes screening. HbA1c was measured with a Biorad Variant II turbo analyser and HbA1c levels of >=6.5% (48 mmol/mol) were considered diagnostic for diabetes. Confirmation of previously unknown diabetes status was obtained by a review of hospital medical records and phone calls to general practitioners. SETTING: Hospital pathology laboratory receiving samples from hospital-based and community-based (CB) settings. PARTICIPANTS: Participants were identified based on the blood sample collection location in the CB, emergency department (ED) and inpatient (IP) groups. Exclusions pretesting were made based on the electronic patient history of: age <18 years, previous diabetes diagnosis, query for diabetes status in the past 12 months, evidence of pregnancy and sample collected postsurgery or transfusion. Only one sample per individual participant was tested. RESULTS: Of the 22 396 blood samples collected, 4505 (1142 CB, 1113 ED, 2250 IP) were tested of which 327 (7.3%) had HbA1c levels >=6.5% (48 mmol/mol). Of these 120 (2.7%) were determined to have previously unknown diabetes (11 (1%) CB, 21 (1.9%) ED, 88 (3.9%) IP). The prevalence of previously unknown diabetes was substantially higher (5.4%) in hospital-based (ED and IP) participants aged over 54 years. CONCLUSIONS: Opportunistic testing of referred pathology samples can be an effective method of screening for diabetes, especially in hospital-based and older persons. PMID- 24065697 TI - Measuring a caring culture in hospitals: a systematic review of instruments. AB - OBJECTIVE: To identify instruments or components of instruments that aim to measure aspects of a caring culture-shared beliefs, norms and values that direct professionals and managers to act caring in hospitals, and to evaluate their psychometric properties. DESIGN: Systematic review. DATA SOURCES: PubMed, CINAHL, EMBASE, PsychInfo, Web of Science and the International bibliography of the Social Sciences. STUDY SELECTION: Peer-reviewed articles describing (components of) instruments measuring aspects of a caring culture in a hospital setting. Studies had to report psychometric data regarding the reliability or validity of the instrument. Potentially useful instruments that were identified after the title and abstract scan were assessed on relevance by an expert panel (n=12) using the RAND-modified Delphi procedure. RESULTS: Of the 6399 references identified, 75 were examined in detail. 7 studies each covering a unique instrument met our inclusion criteria. On average, 24% of the instrument's items were considered relevant for measuring aspects of the hospital's caring culture. Studies showed moderate-to-high validity and reliability scores. Validity was addressed for 6 of the 7 instruments. Face, content (90%) and construct (60%) validity were the most frequently reported psychometric properties described. One study (14%) reported discriminant validity of the instrument. Reliability data were available for all of the instruments. Internal consistency was the most frequently reported psychometric property for the instruments and demonstrated by: a Cronbach's alpha coefficient (80%), subscale intercorrelations (60%), and item-total correlations (40%). CONCLUSIONS: The ultimate standard for measuring a caring culture in hospitals does not exist. Existing instruments provide partial coverage and lack information on discriminant validity, responsiveness and feasibility. Characteristics of the instruments included in this review could provide useful input for the design of a reliable and valid instrument for measuring a caring culture in hospitals. PMID- 24065698 TI - Trends in age at first hospital admission in relation to trends in life expectancy in Swedish men and women above the age of 60. AB - OBJECTIVES: To examine whether the first admission to hospital after the age of 60 has been postponed to higher ages for men and women in Sweden, in line with the shift in mortality. DESIGN: This nationwide observational study was based on data obtained from national registries in Sweden. The study cohort was created by linking the Register of the Total Population in Sweden with the National Patient Register and the Swedish Cause of Death Register. SETTING: The entire Swedish population born between 1895 and 1950 was followed up between 1987 and 2010 with respect to hospital admissions and deaths using the national registry data. PRIMARY OUTCOME MEASURES: The time from age 60 until the first admission to the hospital, regardless of the diagnosis, and the time from age 60 until death (remaining life expectancy, LE) were estimated for the years 1995-2010. The difference between these two measures was also estimated for the same period. RESULTS: Between 1995 and 2010 mortality as well as first hospital admission shifted to higher ages. The average time from age 60, 70, 80 and 90 until the first hospital admission increased at all ages. The remaining LE at age 60, 70 and 80 increased for men and women. For the 90-year-olds it was stable. CONCLUSIONS: In Sweden, the first hospital admission after the age of 60 has been pushed to higher ages in line with mortality for the ages 60 and above. First admission to the hospital could indicate the onset of first severe morbidity; however, the reorganisation of healthcare may also have influenced the observed trends. PMID- 24065699 TI - Trial-based cost-effectiveness analysis comparing surgical and endoscopic drainage in patients with obstructive chronic pancreatitis. AB - OBJECTIVE: Published evidence indicates that surgical drainage of the pancreatic duct was more effective than endoscopic drainage for patients with chronic pancreatitis. This analysis assessed the cost-effectiveness of surgical versus endoscopic drainage in obstructive chronic pancreatitis. DESIGN: This trial-based cost-utility analysis (ISRCTN04572410) was conducted from a UK National Health Service (NHS) perspective and during a 79-month time horizon. During the trial the details of the diagnostic and therapeutic procedures, and pancreatic insufficiency were collected. The resource use was varied in the sensitivity analysis based on a review of the literature. The health outcome was the Quality Adjusted Life Year (QALY), generated using EQ-5D data collected during the trial. There were no pancreas-related deaths in the trial. All-cause mortality from the trial was incorporated into the QALY estimates in the sensitivity analysis. SETTING: Hospital. PARTICIPANTS: Patients with obstructive chronic pancreatitis. PRIMARY AND SECONDARY OUTCOME MEASURES: Costs, QALYs and cost-effectiveness. RESULTS: The result of the base-case analysis was that surgical drainage dominated endoscopic drainage, being both more effective and less costly. The sensitivity analysis varied mortality and resource use and showed that the surgical option remained dominant in all scenarios. The probability of cost effectiveness for surgical drainage was 100% for the base case and 82% in the assessed most conservative case scenario. CONCLUSIONS: In obstructive chronic pancreatitis, surgical drainage is highly cost-effective compared with endoscopic drainage from a UK NHS perspective. PMID- 24065700 TI - Targeted interventions for patellofemoral pain syndrome (TIPPS): classification of clinical subgroups. AB - INTRODUCTION: Patellofemoral pain (PFP) can cause significant pain leading to limitations in societal participation and physical activity. An international expert group has highlighted the need for a classification system to allow targeted intervention for patients with PFP; we have developed a work programme systematically investigating this. We have proposed six potential subgroups: hip abductor weakness, quadriceps weakness, patellar hypermobility, patellar hypomobility, pronated foot posture and lower limb biarticular muscle tightness. We could not uncover any evidence of the relative frequency with which patients with PFP fell into these subgroups or whether these subgroups were mutually exclusive. The aim of this study is to provide information on the clinical utility of our classification system. METHODS AND ANALYSIS: 150 participants will be recruited over 18 months in four National Health Services (NHS) physiotherapy departments in England. INCLUSION CRITERIA: adults 18-40 years with PFP for longer than 3 months, PFP in at least two predesignated functional activities and PFP elicited by clinical examination. EXCLUSION CRITERIA: prior or forthcoming lower limb surgery; comorbid illness or health condition; and lower limb training or pregnancy. We will record medical history, demographic details, pain, quality of life, psychomotor movement awareness and knee temperature. We will assess hip abductor and quadriceps weakness, patellar hypermobility and hypomobility, foot posture and lower limb biarticular muscle tightness. The primary analytic approach will be descriptive. We shall present numbers and percentages of participants who meet the criteria for membership of (1) each of the subgroups, (2) none of the subgroups and (3) multiple subgroups. Exact (binomial) 95% CIs for these percentages will also be presented. ETHICS AND DISSEMINATION: This study has been approved by National Research Ethics Service (NRES) Committee North West-Greater Manchester North (11/NW/0814) and University of Central Lancashire (UCLan) Built, Sport, Health (BuSH) Ethics Committee (BuSH 025). An abstract has been accepted for the third International Patellofemoral Pain Research Retreat, Vancouver, September 2013. PMID- 24065701 TI - Evaluation of the validity of the Multidimensional Personality Questionnaire Simplified-Wording Form (MPQ-SF) in adolescents with treatment histories. AB - The Multidimensional Personality Questionnaire (MPQ) is a widely used personality assessment instrument informing lower- and higher-order personality dimensions. Despite recent developments of brief (MPQ-BF) and simplified wording (MPQ-SF) forms, there is relatively little work on the utility and validity of the MPQ in younger samples with lower reading levels. This study is the first to assess the reliability, factor structure, and criterion validity of the MPQ-SF in a sample of treatment-referred mid-adolescents (N = 105; 12-17 years). Results suggest adequate reliabilities for most of the lower-order primary scales and support a three-factor structure of the MPQ-SF, consistent with previous research with adult and college-aged samples. However, there were also notable cross-loadings for particular scales, which we discuss in relation to the four-factor MPQ model and the Five Factor Model of Personality. Relationships between MPQ personality dimensions and psychopathology using youth, parent, and clinician-rated psychopathology indices supported criterion-related validity. Together, these results confirm the utility of the MPQ in youth with treatment histories. PMID- 24065702 TI - Reliability and validity of the personality inventory for DSM-5 (PID-5): predicting DSM-IV personality disorders and psychopathy in community-dwelling Italian adults. AB - In order to assess the internal consistency, factor structure, and ability to recover DSM-IV personality disorders (PDs) of the Personality Inventory for DSM-5 (PID-5) scales, 710 Italian adult community dwelling volunteers were administered the Italian translation of the PID-5, as well as the Italian translation of the Personality Diagnostic Questionnaire-4+ (PDQ-4+). Cronbach's alpha values were >.70 for all PID-5 facet scales and greater than .90 for all PID-5 domain scales. Parallel analysis and confirmatory factor analysis supported the theoretical five factor model of the PID-5 trait scales. Regression analyses showed that both PID 5 trait and domain scales explained a substantial amount of variance in the PDQ 4+ PD scales, with the exception of the Passive-Aggressive PD scale. When the PID 5 was administered to a second independent sample of 389 Italian adult community dwelling volunteers, the basic psychometric properties of the scale were replicated. In this second sample, the PID-5 trait and domain scales proved to be significant predictors of psychopathy measures. As a whole, the results of the present study support the hypothesis that the PID-5 is a reliable instrument which is able to recover DSM-IV PDs, as well as to capture personality pathology that is not included in the DSM-IV (namely, psychopathy). PMID- 24065703 TI - Forkhead box O1 is a repressor of basal and GnRH-induced Fshb transcription in gonadotropes. AB - Synthesis of the gonadotropin beta-subunits is tightly controlled by a complex network of hormonal signaling pathways that may be modulated by metabolic cues. Recently, we reported that insulin regulates FOXO1 phosphorylation and cellular localization in pituitary gonadotropes and that FOXO1 overexpression inhibits Lhb transcription. In the current study, we investigated whether FOXO1 modulates Fshb synthesis. Here, we demonstrate that FOXO1 represses basal and GnRH-induced Fshb transcription in LbetaT2 cells. In addition, we show that PI3K inhibition, which increases FOXO1 nuclear localization, results in decreased Fshb mRNA levels in murine primary pituitary cells. FOXO1 also decreases transcription from the human FSHB promoter, suggesting that FOXO1 regulation of FSHB transcription may be conserved between rodents and humans. Although the FOXO1 DNA-binding domain is necessary for suppression of Fshb, we do not observe direct binding of FOXO1 to the Fshb promoter, suggesting that FOXO1 exerts its effect through protein protein interactions with transcription factors required for Fshb synthesis. FOXO1 suppression of basal Fshb transcription may involve PITX1 because PITX1 interacts with FOXO1, FOXO1 repression maps to the proximal Fshb promoter containing a PITX1-binding site, PITX1 induction of Fshb or a PITX1 binding element in CV-1 cells is decreased by FOXO1, and FOXO1 suppresses Pitx1 mRNA and protein levels. GnRH induction of an Fshb promoter containing a deletion at -50/ 41 or -30/-21 is not repressed by FOXO1, suggesting that these two regions may be involved in FOXO1 suppression of GnRH-induced Fshb synthesis. In summary, our data demonstrate that FOXO1 can negatively regulate Fshb transcription and suggest that FOXO1 may relay metabolic hormonal signals to modulate gonadotropin production. PMID- 24065704 TI - Regulation of hypothalamic corticotropin-releasing hormone transcription by elevated glucocorticoids. AB - Negative glucocorticoid feedback is essential for preventing the deleterious effects of excessive hypothalamic pituitary adrenal axis axis activation, with an important target being CRH transcription in the hypothalamic paraventricular nucleus. The aim of these studies was to determine whether glucocorticoids repress CRH transcription directly in CRH neurons, by examining glucocorticoid effects on glucocorticoid receptor (GR)-CRH promoter interaction and the activation of proteins required for CRH transcription. Immunoprecipitation of hypothalamic chromatin from intact or adrenalectomized rats subjected to either stress or corticosterone injections showed minor association of the proximal CRH promoter with the GR compared with that with phospho-CREB (pCREB). In contrast, the Period-1 (Per1, a glucocorticoid-responsive gene) promoter markedly recruited GR. Stress increased pCREB recruitment by the CRH but not the Per1 promoter, irrespective of circulating glucocorticoids. In vitro, corticosterone pretreatment (30 minutes or 18 hours) only slightly inhibited basal and forskolin stimulated CRH heteronuclear RNA in primary hypothalamic neuronal cultures and CRH promoter activity in hypothalamic 4B cells. In 4B cells, 30 minutes or 18 hours of corticosterone exposure had no effect on forskolin-induced nuclear accumulation of the recognized CRH transcriptional regulators, pCREB and transducer of regulated CREB activity 2. The data show that inhibition of CRH transcription by physiological glucocorticoids in vitro is minor and that direct interaction of GR with DNA in the proximal CRH promoter may not be a major mechanism of CRH gene repression. Although GR interaction with distal promoter elements may have a role, the data suggest that transcriptional repression of CRH by glucocorticoids involves protein-protein interactions and/or modulation of afferent inputs to the hypothalamic paraventricular nucleus. PMID- 24065706 TI - Manual ventilation therapy and aggressive potassium supplementation in the management of respiratory failure secondary to severe hypokalaemia in a cat with exocrine pancreatic insufficiency. AB - A domestic shorthair cat was referred for progressive muscle weakness and dyspnoea. The cat had a 2-month history of severe weight loss, small intestinal diarrhoea, polyphagia and polyuria/polydipsia. Biochemical analysis and venous blood gas evaluation revealed severe hypokalaemia [1.7 mmol/l; reference interval (RI): 3.5-5.1 mmol/l] and hypoventilation (partial pressure of carbon dioxide = 68 mmHg; RI: 34-38 mmHg). Aggressive potassium supplementation was initiated. The cat was manually ventilated until serum potassium increased to 3 mmol/l. A diagnosis of exocrine pancreatic insufficiency (EPI) was made based on clinical signs and serum feline trypsin-like immunoreactivity (0.1 MUg/l; RI: 12-82 MUg/l). Medical management of the EPI resulted in clinical recovery. PMID- 24065705 TI - Transgenic muscle-specific Nor-1 expression regulates multiple pathways that effect adiposity, metabolism, and endurance. AB - The mRNA encoding Nor-1/NR4A3 is rapidly and strikingly induced by beta2 adrenergic signaling in glycolytic and oxidative skeletal muscle. In skeletal muscle cells, Nor-1 expression is important for the regulation of oxidative metabolism. Transgenic skeletal muscle-specific expression of activated Nor-1 resulted in the acquisition of an endurance phenotype, an increase in type IIA/X oxidative muscle fibers, and increased numbers of mitochondria. In the current study, we used dual-energy x-ray absorptiometry and magnetic resonance imaging analysis to demonstrate decreased adiposity in transgenic (Tg) Nor-1 mice relative to that in wild-type littermates. Furthermore, the Tg-Nor-1 mice were resistant to diet-induced weight gain and maintained fasting glucose at normoglycemic levels. Expression profiling and RT-quantitative PCR analysis revealed significant increases in genes involved in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation, and glycogen synthesis, in concordance with the lean phenotype. Moreover, expression profiling identified several Z-disc and sarcomeric binding proteins that modulate fiber type phenotype and endurance, eg, alpha-actinin-3. In addition, we demonstrated that the Tg-Nor-1 mouse line has significantly higher glycogen content in skeletal muscle relative to that in wild-type littermates. Finally, we identified a decreased NAD(+)/NADH ratio with a concordant increase in peroxisome proliferator-activated receptor gamma coactivator-1alpha1 protein/mRNA expression. Increased NADH was associated with an induction of the genes involved in the malate-aspartate shuttle and a decrease in the glycerol 3-phosphate shuttle, which maximizes aerobic ATP production. In conclusion, skeletal muscle specific Nor-1 expression regulates genes and pathways that regulate adiposity, muscle fiber type metabolic capacity, and endurance. PMID- 24065707 TI - Risk factors for urinary tract infection with multiple drug-resistant Escherichia coli in cats. AB - The emergence of multiple drug-resistant (MDR) bacteria is a growing public health problem. The objective of this retrospective study was to identify risk factors associated with MDR Escherichia coli infection of the urinary tract in cats. All cats presenting with an E coli urinary infection between March 2010 and December 2012 were included and divided into two groups: an MDR group and a non MDR group. The effects of different variables on the occurrence of an MDR E coli infection were evaluated: age, sex, additional diseases, number of antibiotics and number of days of hospitalisation. Fifty-two cats were identified (10 MDR and 42 non-MDR). The number of antibiotic groups used within the last 3 months was associated with an increased risk of MDR E coli urinary infection (P = 0.007). The association of the number of days of hospitalisation within the last 3 months and the increased risk of MDR E coli urinary infection did not reach significance (P = 0.090). This study provides evidence that systematic urinary culture with antibiotic sensitivity testing should be recommended when treating urinary tract infections if antibiotics have been prescribed within the past 3 months. Moreover, the selection of MDR bacteria through antibiotic use should be considered as a potential risk associated with treatment. PMID- 24065708 TI - Flow cytometric immunophenotyping of feline bone marrow cells and haematopoietic progenitor cells using anti-human antibodies. AB - There is a paucity of species-specific antibodies available for feline haematopoietic conditions. The purpose of this study was to broaden the panel of antibodies available for use in the immunophenotypic characterisation of feline haematopoietic cells by testing clones of anti-human monoclonal antibodies (mAbs) on normal, neoplastic and cultured feline haematopoietic progenitors to determine cross-reactivity to feline counterparts. In this study, 24 clones of anti-human mAbs were tested on normal or neoplastic feline bone marrow and peripheral blood cells. Six of these mAbs, including anti-cluster of differentiation (CD)61, anti CD18, anti-CD14, anti-CD235a, anti-CD41 and anti-CD29, cross-reacted with normal feline bone marrow cells, whereas anti-CD33 and anti-CD117 cross-reacted with the blast cells in the bone marrow of two cats with myelodysplastic syndrome, and anti-CD71, anti-235a, anti-41 and anti-42 cross-reacted with immature erythroid cells in a cat with erythroleukaemia. In a feline immunodeficiency virus-positive cat, bone marrow cells were labelled with anti-CD33, anti-14 and anti-45. Anti CD18, anti-CD14, anti-CD41 and anti-CD61 also reacted with the peripheral blood cells of the healthy cats. The feline haematopoietic progenitors formed colonies in the methylcellulose-based semisolid medium with significant enrichment of colony-forming unit-granulocyte, monocyte and burst-forming unit-erythroid. A panel of six anti-feline mAbs (anti-CD21-like, anti-T lymphocytes, anti-CD172a, anti-granulocyte, anti-CD45-like and anti-CD18) and eight anti-human antibodies (anti-CD71, anti-CD33, anti-CD235a, anti-CD41, anti-CD61, anti-CD117, anti-CD38 and anti-CD34) were used for the immunophenotypic characterisation of the feline bone marrow progenitors. CD45, CD33, CD235a and CD18 were expressed by the feline haematopoietic progenitor cells, with the highest expression level for CD45. PMID- 24065709 TI - Gastric cylicospirurosis in a domestic cat from Italy. AB - A gastric nodule was found in a cat examined following a car accident. Cytological examination showed a mixed, mainly eosinophilic, inflammation with reactive fibroblasts and ovoidal elements resembling nematode eggs. The cat was euthanased because of rapid worsening of clinical signs due to secondary injuries, and the gastric nodule was excised for examination. The intramural mass was smooth and spherical, with an intact mucosal surface and a little opening from which several reddish worms were extruding. Histopathological examination confirmed severe reactive fibroplasia and inflammation, surrounding sections of a nematode worm. The latter was then identified with polymerase chain reaction as belonging to the Cylicospirura genus. Cylicospirura species worms should be considered in the differential diagnosis of gastric nodules in the cat. PMID- 24065710 TI - Effect of insular injury on autonomic functions in patients with ruptured middle cerebral artery aneurysms. AB - BACKGROUND AND PURPOSE: Insular injuries are known to cause autonomic derangements. Patients with ruptured middle cerebral artery aneurysms frequently develop temporal hematomas (THs) in addition to subarachnoid hemorrhages, and those with TH may sustain autonomic derangements more frequently than those without TH. Hemispheric lateralization in autonomic derangements has been reported in patients with insular ischemic stroke, and this study was conducted to clarify whether such lateralization was also observed in patients with TH resulting from middle cerebral artery aneurysm rupture. METHODS: A retrospective analysis on the medical records of 79 patients with ruptured middle cerebral artery aneurysms was performed on the basis of lateralization and presence of TH. They were quadrichotomized as left TH+ (LTH+; n=17), right TH+ (n=25), left TH- (n=15), and right TH- (n=22). Comparisons, mainly between LTH+ and right TH+, were made on demographic variables, autonomic/cardiac parameters, plasma catecholamine and glucose levels, and outcomes. RESULTS: There were no significant differences in demographic or cardiac parameters between the 2 groups. Systolic blood pressures were lower in LTH+ (139+/-34 versus 174+/-47 mm Hg; P=0.05). The LTH+ group also tended to be more bradycardiac (80+/-19 versus 101+/-22 bpm; P=0.13). The LTH+ group exhibited significantly lower plasma norepinephrine (1008+/-975 versus 2549+/-2133 pg/mL; P=0.03) and glucose levels (9.3+/-1.8 versus 12.2+/-4.5 mmol/L; P=0.04). However, in-hospital mortality did not differ significantly (41% versus 44%; P=1.00). CONCLUSIONS: Lateralization of autonomic derangements observed might not have had a significant effect on the outcomes. Nevertheless, autonomic derangements associated with insular injury should be considered in the management of subarachnoid hemorrhage patients with TH. PMID- 24065711 TI - Burden and outcome of prevalent ischemic brain disease in a national acute stroke registry. AB - BACKGROUND AND PURPOSE: Previous overt stroke and subclinical stroke are frequent in patients with stroke; yet, their clinical significance and effects on stroke outcome are not clear. We studied the burden and outcome after acute ischemic stroke by prevalent ischemic brain disease in a national registry of hospitalized patients with acute stroke. METHODS: Patients with ischemic stroke in the National Acute Stroke Israeli prospective hospital-based registry (February to March 2004, March to April 2007, and April to May 2010) with information on previous overt stroke and subclinical stroke per computed tomography/MRI (n=3757) were included. Of them, a subsample (n=787) was followed up at 3 months. Logistic regression models were computed for outcomes in patients with prior overt stroke or subclinical stroke, compared with patients with first stroke, adjusting for age, sex, vascular risk factors, stroke severity, and clinical classification. RESULTS: Two-thirds of patients had a prior overt stroke or subclinical stroke. Death rates were similar for patients with and without prior stroke. Adjusted odds ratios (OR; 95% confidence interval [CI]) for disability were increased for patients with prior overt stroke (OR, 1.31; 95% CI, 1.03-1.66) and subclinical stroke (OR, 1.45; 95% CI, 1.16-1.82). Relative odds of Barthel Index<=60 for patients with prior overt stroke (OR, 2.04; 95% CI, 1.14-3.68) and with prior subclinical stroke (OR, 2.04; 95% CI, 1.15-3.64) were twice higher than for patients with a first stroke. ORs for dependency were significantly increased for patients with prior overt stroke (OR, 1.95; 95% CI, 1.19-3.20) but not for those with subclinical stroke (OR, 1.36; 95% CI, 0.84-2.19). CONCLUSIONS: In our national cohort of patients with acute ischemic stroke, nearly two thirds had a prior overt stroke or subclinical stroke. Risk of poor functional outcomes was increased for patients with prior stroke, both overt and subclinical. PMID- 24065712 TI - Thrombolysis for acute ischemic stroke in patients with cancer: a population study. AB - BACKGROUND AND PURPOSE: The safety of thrombolysis for acute stroke in patients with cancer is not well established. Our aim is to study the outcomes after thrombolysis in patients with stroke with cancer. METHODS: Patients with acute ischemic stroke who received thrombolysis were identified from the 2009 and 2010 Nationwide Inpatient Sample. Patients with cancer-associated strokes and noncancer strokes were compared based on demographics, comorbidities, and outcomes. RESULTS: Of the 32 576 strokes treated with thrombolysis, cancer associated strokes had significantly higher comorbidity indices overall, but fewer vascular risk factors than noncancer strokes. There was no difference in the rates of home discharge and in-hospital mortality, after adjusting for confounders. Subgroup analysis showed that compared with liquid cancers, patients with solid tumors had worse home discharge (odds ratio, 0.178; 95% confidence interval, 0.109-0.290; P<0.001) and higher in-hospital mortality (odds ratio, 3.018; 95% confidence interval, 1.37-6.646; P=0.006) after thrombolysis. Metastatic cancers had poorest outcomes, but intracerebral hemorrhage rates were similar. CONCLUSIONS: Thrombolytic therapy for acute stroke in patients with cancer is not associated with increased risk of intracerebral hemorrhage or in hospital mortality. However, careful consideration of the cancer subtype may help delineate the subset of patients with poor response to thrombolysis. Prospective confirmation is warranted. PMID- 24065714 TI - Tackling transitions in patient care: the process of medication reconciliation. PMID- 24065713 TI - Stroke unit care benefits patients with intracerebral hemorrhage: systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Patients with any type of stroke managed in organized inpatient (stroke unit) care are more likely to survive, return home, and regain independence. However, it is uncertain whether these benefits apply equally to patients with intracerebral hemorrhage and ischemic stroke. METHODS: We conducted a secondary analysis of a systematic review of controlled clinical trials comparing stroke unit care with general ward care, including only trials published after 1990 that could separately report outcomes for patients with intracerebral hemorrhage and ischemic stroke. We performed random-effects meta analyses and tested for subgroup interactions by stroke type. RESULTS: We identified 13 trials (3570 patients) of modern stroke unit care that recruited patients with intracerebral hemorrhage and ischemic stroke, of which 8 trials provided data on 2657 patients. Stroke unit care reduced death or dependency (risk ratio [RR], 0.81; 95% confidence interval [CI], 0.471-0.92; P=0.0009; I2=60%) with no difference in benefits for patients with intracerebral hemorrhage (RR, 0.79; 95% CI, 0.61-1.00) than patients with ischemic stroke (RR, 0.82; 95% CI, 0.70-0.97; Pinteraction=0.77). Stroke unit care reduced death (RR, 0.79; 95% CI, 0.64-0.97; P=0.02; I2=49%) to a greater extent for patients with intracerebral hemorrhage (RR, 0.73; 95% CI, 0.54-0.97) than patients with ischemic stroke (RR, 0.82; 95%, CI 0.61-1.09), but this difference was not statistically significant (Pinteraction=0.58). CONCLUSIONS: Patients with intracerebral hemorrhage seem to benefit at least as much as patients with ischemic stroke from organized inpatient (stroke unit) care. PMID- 24065715 TI - Concomitant occurrence of different trigeminal autonomic cephalalgias: a case series and review of the literature. AB - INTRODUCTION: The trigeminal autonomic cephalalgias (TACs) subsume four primary headache disorders. Hemicrania continua is increasingly regarded as an additional TAC. In rare cases patients may present with two different TACs or a TAC and hemicrania continua. CASES: We report four patients with two different TACs or one TAC and hemicrania continua. Two patients presented with cluster headache and paroxysmal hemicrania, one patient with cluster headache and hemicrania continua, and one patient suffered from cluster headache and SUNCT. DISCUSSION: While the International Classification of Headache Disorders (ICHD-II) proposes specific diagnostic criteria, the variability of clinical presentation may make clear diagnosis difficult. All patients fulfilled the ICHD-II criteria. The manifestation of two different TACs or hemicrania continua in one patient is uncommon but possible and should be taken into account especially when chronic headache patients present with changing headache symptoms. PMID- 24065716 TI - Migraine and serotonin: the quest for the Holy Grail goes on. PMID- 24065717 TI - Formaldehyde degradation in Corynebacterium glutamicum involves acetaldehyde dehydrogenase and mycothiol-dependent formaldehyde dehydrogenase. AB - Corynebacterium glutamicum, a Gram-positive soil bacterium belonging to the actinomycetes, is able to degrade formaldehyde but the enzyme(s) involved in this detoxification process were not known. Acetaldehyde dehydrogenase Ald, which is essential for ethanol utilization, and FadH, characterized here as NAD-linked mycothiol-dependent formaldehyde dehydrogenase, were shown to be responsible for formaldehyde oxidation since a mutant lacking ald and fadH could not oxidize formaldehyde resulting in the inability to grow when formaldehyde was added to the medium. Moreover, C. glutamicum DeltaaldDeltafadH did not grow with vanillate, a carbon source giving rise to intracellular formaldehyde. FadH from C. glutamicum was purified from recombinant Escherichia coli and shown to be active as a homotetramer. Mycothiol-dependent formaldehyde oxidation revealed Km values of 0.6 mM for mycothiol and 4.3 mM for formaldehyde and a Vmax of 7.7 U mg(-1). FadH from C. glutamicum also possesses zinc-dependent, but mycothiol independent alcohol dehydrogenase activity with a preference for short chain primary alcohols such as ethanol (Km = 330 mM, Vmax = 9.6 U mg(-1)), 1-propanol (Km = 150 mM, Vmax = 5 U mg(-1)) and 1-butanol (Km = 50 mM, Vmax = 0.8 U mg(-1)). Formaldehyde detoxification system by Ald and mycothiol-dependent FadH is essential for tolerance of C. glutamicum to external stress by free formaldehyde in its habitat and for growth with natural substrates like vanillate, which are metabolized with concomitant release of formaldehyde. PMID- 24065718 TI - Repertoire of malic enzymes in yeast and fungi: insight into their evolutionary functional and structural significance. AB - Malic enzyme (ME) is one of the important enzymes for furnishing the cofactor NAD(P)H for the biosynthesis of fatty acids and sterols. Due to the existence of multiple ME isoforms in a range of oleaginous microbes, a molecular basis for the evolutionary relationships amongst the enzymes in oleaginous fungi was investigated using sequence analysis and structural modelling. Evolutionary distance and structural characteristics were used to discriminate the MEs of yeasts and fungi into several groups. Interestingly, the NADP(+)-dependent MEs of Mucoromycotina had an unusual insertion region (FLxxPG) that was not found in other fungi. However, the subcellular compartment of the Mucoromycotina enzyme could not be clearly identified by an analysis of signal peptide sequences. A constructed structural model of the ME of Mucor circinelloides suggested that the insertion region is located at the N-terminus of the enzyme (aa 159-163). In addition, it is presumably part of the dimer interface region of the enzyme, which might provide a continuously positively charged pocket for the efficient binding of negatively charged effector molecules. The discovery of the unique structure of the Mucoromycotina ME suggests the insertion region could be involved in particular kinetics of this enzyme, which may indicate its involvement in the lipogenesis of industrially important oleaginous microbes. PMID- 24065719 TI - Maternal anxiety and breastfeeding: findings from the MAVAN (Maternal Adversity, Vulnerability and Neurodevelopment) Study. AB - BACKGROUND: Maternal anxiety and depression may impair maternal intention, motivation, and self-efficacy in multiple domains associated with child health including breastfeeding. OBJECTIVE: We tested the hypothesis that mothers who experience substantial anxiety during pregnancy or the postpartum period are at increased risk for reduced initiation, exclusivity, and continuation of breastfeeding. METHODS: We obtained data on 255 Canadian pregnant women from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) study recruited between June 2004 and February 2009. We utilized data collected from 18 to 23 weeks gestation through 12 months postpartum. Multivariate logistic regression was used to assess whether scores on the Hamilton Anxiety Scale (HAM-A) and State Trait Anxiety Inventory (STAI) were associated with initiation, exclusivity, and continuation of breastfeeding. RESULTS: Prenatal anxiety was not associated with breastfeeding outcomes. In adjusted models, a single point increase in HAM-A scores at 3 months postpartum was associated with an 11% reduction in the odds of exclusive breastfeeding at 6 months (adjusted odds ratio [aOR] = 0.89; 95% CI, 0.80-0.99). A single point increase in STAI State and STAI Trait scores at 3 months postpartum was associated with a 4% (aOR = 0.96; 95% CI, 0.92-0.99) and 7% (aOR = 0.93; 95% CI, 0.86-1.00) reduction, respectively, in the odds of any breastfeeding at 12 months. CONCLUSION: Our findings suggest a relationship between maternal anxiety and reduced exclusivity and continuation of breastfeeding. Maternal anxiety should be actively monitored and managed appropriately in the postpartum period to support optimal breastfeeding practices. PMID- 24065720 TI - Revealing the invisible: the paradox of picturing a phantom limb. AB - Illustrations of phantom limbs are intriguing as they depict an invisible perception. But such illustrations are also important: they provide a form of objectivity to phenomena, which particularly in the past, have often stretched credulity. Acknowledging the paradox of using images to reveal an absent though sensate body part, depictions of phantom limbs are discussed from the neurological perspective, starting with medieval pictures that showed the miraculous restoration of limbs, and which possibly represented pictorial metaphors for a phantom limb. Centuries later, phantom limbs-whether resulting from amputation or deafferentation-became illustrated, and some reasons for their illustration are considered. Although often depicted by others, the most precise and perhaps revealing illustrations of these phantoms have been those made when patients guide the artist, or draw the phantom themselves. In the case of phantom pains, the painful component too is sometimes illustrated, again, as with the miraculous, in metaphorical terms. More recently, depictions of phantoms have also been revealing in studies of some underlying mechanisms of phantom phenomena, notably in demonstrating novel patterns of referred sensations after amputation and attributable to cortical plasticity. Mention is made of photographs of phantom hands visualized using a mirror box, such visualization recalling full circle the miraculous restoration of limbs pictured in the past. The nature of the outline of the phantom is included in a discussion of demarcation of an invisible body part, before concluding that images of phantom limbs provide an invaluable background to understanding and studying these remarkable sensory phenomena. PMID- 24065721 TI - Circular inferences in schizophrenia. AB - A considerable number of recent experimental and computational studies suggest that subtle impairments of excitatory to inhibitory balance or regulation are involved in many neurological and psychiatric conditions. The current paper aims to relate, specifically and quantitatively, excitatory to inhibitory imbalance with psychotic symptoms in schizophrenia. Considering that the brain constructs hierarchical causal models of the external world, we show that the failure to maintain the excitatory to inhibitory balance results in hallucinations as well as in the formation and subsequent consolidation of delusional beliefs. Indeed, the consequence of excitatory to inhibitory imbalance in a hierarchical neural network is equated to a pathological form of causal inference called 'circular belief propagation'. In circular belief propagation, bottom-up sensory information and top-down predictions are reverberated, i.e. prior beliefs are misinterpreted as sensory observations and vice versa. As a result, these predictions are counted multiple times. Circular inference explains the emergence of erroneous percepts, the patient's overconfidence when facing probabilistic choices, the learning of 'unshakable' causal relationships between unrelated events and a paradoxical immunity to perceptual illusions, which are all known to be associated with schizophrenia. PMID- 24065722 TI - Factors that determine penumbral tissue loss in acute ischaemic stroke. AB - The goal of acute stroke treatment with intravenous thrombolysis or endovascular recanalization techniques is to rescue the penumbral tissue. Therefore, knowing the factors that influence the loss of penumbral tissue is of major interest. In this study we aimed to identify factors that determine the evolution of the penumbra in patients with proximal (M1 or M2) middle cerebral artery occlusion. Among these factors collaterals as seen on angiography were of special interest. Forty-four patients were included in this analysis. They had all received endovascular therapy and at least minimal reperfusion was achieved. Their penumbra was assessed with perfusion- and diffusion-weighted imaging. Perfusion weighted imaging volumes were defined by circular singular value decomposition deconvolution maps (Tmax > 6 s) and results were compared with volumes obtained with non-deconvolved maps (time to peak > 4 s). Loss of penumbral volume was defined as difference of post- minus pretreatment diffusion-weighted imaging volumes and calculated in per cent of pretreatment penumbral volume. Correlations between baseline characteristics, reperfusion, collaterals, time to reperfusion and penumbral volume loss were assessed using analysis of covariance. Collaterals (P = 0.021), reperfusion (P = 0.003) and their interaction (P = 0.031) independently influenced penumbral tissue loss, but not time from magnetic resonance (P = 0.254) or from symptom onset (P = 0.360) to reperfusion. Good collaterals markedly slowed down and reduced the penumbra loss: in patients with thrombolysis in cerebral infarction 2 b-3 reperfusion and without any haemorrhage, 27% of the penumbra was lost with 8.9 ml/h with grade 0 collaterals, whereas 11% with 3.4 ml/h were lost with grade 1 collaterals. With grade 2 collaterals the penumbral volume change was -2% with -1.5 ml/h, indicating an overall diffusion-weighted imaging lesion reversal. We conclude that collaterals and reperfusion are the main factors determining loss of penumbral tissue in patients with middle cerebral artery occlusions. Collaterals markedly reduce and slow down penumbra loss. In patients with good collaterals, time to successful reperfusion accounts only for a minor fraction of penumbra loss. These results support the hypothesis that good collaterals extend the time window for acute stroke treatment. PMID- 24065724 TI - The corpus callosum of Albert Einstein's brain: another clue to his high intelligence? PMID- 24065725 TI - Transcriptomic indices of fast and slow disease progression in two mouse models of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis is heterogeneous with high variability in the speed of progression even in cases with a defined genetic cause such as superoxide dismutase 1 (SOD1) mutations. We reported that SOD1(G93A) mice on distinct genetic backgrounds (C57 and 129Sv) show consistent phenotypic differences in speed of disease progression and life-span that are not explained by differences in human SOD1 transgene copy number or the burden of mutant SOD1 protein within the nervous system. We aimed to compare the gene expression profiles of motor neurons from these two SOD1(G93A) mouse strains to discover the molecular mechanisms contributing to the distinct phenotypes and to identify factors underlying fast and slow disease progression. Lumbar spinal motor neurons from the two SOD1(G93A) mouse strains were isolated by laser capture microdissection and transcriptome analysis was conducted at four stages of disease. We identified marked differences in the motor neuron transcriptome between the two mice strains at disease onset, with a dramatic reduction of gene expression in the rapidly progressive (129Sv-SOD1(G93A)) compared with the slowly progressing mutant SOD1 mice (C57-SOD1(G93A)) (1276 versus 346; Q-value <= 0.01). Gene ontology pathway analysis of the transcriptional profile from 129Sv-SOD1(G93A) mice showed marked downregulation of specific pathways involved in mitochondrial function, as well as predicted deficiencies in protein degradation and axonal transport mechanisms. In contrast, the transcriptional profile from C57-SOD1(G93A) mice with the more benign disease course, revealed strong gene enrichment relating to immune system processes compared with 129Sv-SOD1(G93A) mice. Motor neurons from the more benign mutant strain demonstrated striking complement activation, over-expressing genes normally involved in immune cell function. We validated through immunohistochemistry increased expression of the C3 complement subunit and major histocompatibility complex I within motor neurons. In addition, we demonstrated that motor neurons from the slowly progressing mice activate a series of genes with neuroprotective properties such as angiogenin and the nuclear factor (erythroid-derived 2)-like 2 transcriptional regulator. In contrast, the faster progressing mice show dramatically reduced expression at disease onset of cell pathways involved in neuroprotection. This study highlights a set of key gene and molecular pathway indices of fast or slow disease progression which may prove useful in identifying potential disease modifiers responsible for the heterogeneity of human amyotrophic lateral sclerosis and which may represent valid therapeutic targets for ameliorating the disease course in humans. PMID- 24065723 TI - Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification. AB - Idiopathic basal ganglia calcification is characterized by mineral deposits in the brain, an autosomal dominant pattern of inheritance in most cases and genetic heterogeneity. The first causal genes, SLC20A2 and PDGFRB, have recently been reported. Diagnosing idiopathic basal ganglia calcification necessitates the exclusion of other causes, including calcification related to normal ageing, for which no normative data exist. Our objectives were to diagnose accurately and then describe the clinical and radiological characteristics of idiopathic basal ganglia calcification. First, calcifications were evaluated using a visual rating scale on the computerized tomography scans of 600 consecutively hospitalized unselected controls. We determined an age-specific threshold in these control computerized tomography scans as the value of the 99th percentile of the total calcification score within three age categories: <40, 40-60, and >60 years. To study the phenotype of the disease, patients with basal ganglia calcification were recruited from several medical centres. Calcifications that rated below the age-specific threshold using the same scale were excluded, as were patients with differential diagnoses of idiopathic basal ganglia calcification, after an extensive aetiological assessment. Sanger sequencing of SLC20A2 and PDGFRB was performed. In total, 72 patients were diagnosed with idiopathic basal ganglia calcification, 25 of whom bore a mutation in either SLC20A2 (two families, four sporadic cases) or PDGFRB (one family, two sporadic cases). Five mutations were novel. Seventy-one per cent of the patients with idiopathic basal ganglia calcification were symptomatic (mean age of clinical onset: 39 +/- 20 years; mean age at last evaluation: 55 +/- 19 years). Among them, the most frequent signs were: cognitive impairment (58.8%), psychiatric symptoms (56.9%) and movement disorders (54.9%). Few clinical differences appeared between SLC20A2 and PDGFRB mutation carriers. Radiological analysis revealed that the total calcification scores correlated positively with age in controls and patients, but increased more rapidly with age in patients. The expected total calcification score was greater in SLC20A2 than PDGFRB mutation carriers, beyond the effect of the age alone. No patient with a PDGFRB mutation exhibited a cortical or a vermis calcification. The total calcification score was more severe in symptomatic versus asymptomatic individuals. We provide the first phenotypical description of a case series of patients with idiopathic basal ganglia calcification since the identification of the first causative genes. Clinical and radiological diversity is confirmed, whatever the genetic status. Quantification of calcification is correlated with the symptomatic status, but the location and the severity of the calcifications don't reflect the whole clinical diversity. Other biomarkers may be helpful in better predicting clinical expression. PMID- 24065726 TI - Clinical presentation and diagnostic work-up of isolated oesophageal lung in a neonate. PMID- 24065727 TI - Glucose monitoring in neonates: need for accurate and non-invasive methods. AB - Neonatal hypoglycaemia can lead to devastating consequences. Thus, constant, accurate and safe glucose monitoring is imperative in neonatal care. However, point-of-care (POC) devices for glucose testing currently used for neonates were originally designed for adults and do not address issues specific to neonates. This review will address currently available monitoring options and describe new methodologies for non-invasive glucose monitoring in newborns. PMID- 24065728 TI - Five-minute parameter of thromboelastometry is sufficient to detect thrombocytopenia and hypofibrinogenaemia in patients undergoing liver transplantation. AB - BACKGROUND: Early detection of coagulopathy is important to prevent bleeding during liver transplantation (LT). Rotation thromboelastometry (ROTEM((r))) provides the earliest parameter of clot amplitudes at 5 min (A5). We evaluated whether A5 correlates with platelet count (PLT) and fibrinogen concentration (Fib) and can predict thrombocytopenia and hypofibrinogenaemia in hypocoagulable patients undergoing living-donor LT (LDLT). METHODS: A total of 3446 retrospective ROTEM((r)) measurements, including 1139 EXTEM, 1182 INTEM, and 1125 FIBTEM, with simultaneously measured PLT and Fib, were analysed during LDLT in 239 patients. The correlations between A5 and maximum clot firmness (MCF) index, PLT, and Fib were calculated. Receiver operating characteristic analysis with area under the curve (AUC) was used to assess A5 thresholds predictive of PLT and Fib. RESULTS: The median PLT was 47 000 mm(-3) and the median Fib was 100 mg dl( 1) during LDLT. The A5 parameters of EXTEM (A5EXTEM) and INTEM (A5INTEM) were highly correlated with MCF (r=0.96 and r=0.95, respectively), PLT (r=0.76 and r=0.77, respectively), and Fib (r=0.63 and r=0.64, respectively). A5 of FIBTEM (A5FIBTEM) was also correlated with MCF (r=0.91) and Fib (r=0.75). A5EXTEM thresholds of 15 and 19 mm predicted PLT<30 000 mm(-3) (AUC=0.90) and <50 000 mm( 3) (AUC=0.87), respectively, whereas A5FIBTEM 4 mm predicted Fib<100 mg dl(-1) (AUC=0.86). Biases from A5EXTEM and A5FIBTEM to their MCFs were 16.4 and 1.3 mm, respectively. CONCLUSIONS: A5 as an early variable of clot firmness is effective in detecting critically low PLT and Fib. A5 can therefore be a reliable fast index guiding transfusion therapy in hypocoagulable patients undergoing LDLT. PMID- 24065729 TI - Clinical decision-making augmented by simulation training: neural correlates demonstrated by functional imaging: a pilot study. AB - BACKGROUND: Investigation of the neuroanatomical basis of clinical decision making, and whether this differs when students are trained via online training or simulation training, could provide valuable insight into the means by which simulation training might be beneficial. METHODS: The aim of this pilot prospective parallel group cohort study was to investigate the neural correlates of clinical decision-making, and to determine if simulation as opposed to online training influences these neural correlates. Twelve third-year medical students were randomized into two groups and received simulation-based or online-based training on anaphylaxis. This was followed by functional magnetic resonance imaging scanning to detect brain activation patterns while answering multiple choice questions (MCQs) related to anaphylaxis, and unrelated non-clinical (control) questions. Performance in the MCQs, salivary cortisol levels, heart rate, and arterial pressure were also measured. RESULTS: Comparing neural responses to clinical and non-clinical questions (in all participants), significant areas of activation were seen in the ventral anterior cingulate cortex and medial prefrontal cortex. These areas were activated in the online group when answering action-based questions related to their training, but not in the simulation group. The simulation group tended to react more quickly and accurately to clinical MCQs than the online group, but statistical significance was not reached. CONCLUSIONS: The activation areas seen could indicate increased stress when answering clinical questions compared with general non-clinical questions, and in the online group when answering action-based clinical questions. These findings suggest simulation training attenuates neural responses related to stress when making clinical decisions. PMID- 24065730 TI - Time-dependent modulation of muscarinic m1/m3 receptor signalling by local anaesthetics. AB - BACKGROUND: Signalling of several G-protein-coupled receptors of the Gq/11 family is time-dependently inhibited by local anaesthetics (LAs). Since LA-induced modulation of muscarinic m1 and m3 receptor function may explain their beneficial effects in clinical practice, such as decreased postoperative cognitive dysfunction or less bronchoconstriction, we studied how prolonged exposure affects muscarinic signalling (Wang D, Wu X, Li J, Xiao F, Liu X, Meng M. The effect of lidocaine on early postoperative cognitive dysfunction after coronary artery bypass surgery. Anesth Analg 2002; 95: 1134-41; Groeben H, Silvanus MT, Beste M, Peters J. Combined lidocaine and salbutamol inhalation for airway anesthesia markedly protects against reflex bronchoconstriction. Chest 2000; 118: 509-15). METHODS: A two-electrode voltage clamp was used to assess the effects of lidocaine or its permanently charged analogue QX314 on recombinantly expressed m1 and m3 receptors in Xenopus oocytes. Antisense knock-down of functional Galphaq protein and inhibition of protein kinase C (PKC) served to define mechanisms and sites of action. RESULTS: Lidocaine affected muscarinic signalling in a biphasic way: an initial decrease in methylcholine bromide-elicited m1 and m3 responses after 30 min, followed by a significant increase in muscarinic responses after 8 h. Intracellularly injected QX314 time-dependently inhibited muscarinic signalling, but had no effect in Galphaq-depleted oocytes. PKC-antagonism enhanced m1 and m3 signalling, but completely abolished the LA-induced increase in muscarinic responses, unmasking an underlying time-dependent inhibition of m1 and m3 responses after 8 h. CONCLUSIONS: Lidocaine modulates muscarinic m1 and m3 receptors in a time- and Galphaq-dependent manner, but this is masked by enhanced PKC activity. The biphasic time course may be due to interactions of LAs with an extracellular receptor domain, modulated by PKC activity. Prolonged exposure to LAs may not benefit pulmonary function, but may positively affect postoperative cognitive function. PMID- 24065731 TI - Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M mediated resistance in NSCLC. AB - Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR(T790M) mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC. SIGNIFICANCE: We report the preclinical development of a novel covalent inhibitor, CO-1686, that irreversibly and selectively inhibits mutant EGFR, in particular the T790M drug-resistance mutation, in NSCLC models. CO-1686 is the fi rst drug of its class in clinical development for the treatment of T790M-positive NSCLC, potentially offering potent inhibition of mutant EGFR while avoiding the on-target toxicity observed with inhibition of the WT EGFR. PMID- 24065732 TI - Punctuated emergences of genetic and phenotypic innovations in eumetazoan, bilaterian, euteleostome, and hominidae ancestors. AB - Phenotypic traits derive from the selective recruitment of genetic materials over macroevolutionary times, and protein-coding genes constitute an essential component of these materials. We took advantage of the recent production of genomic scale data from sponges and cnidarians, sister groups from eumetazoans and bilaterians, respectively, to date the emergence of human proteins and to infer the timing of acquisition of novel traits through metazoan evolution. Comparing the proteomes of 23 eukaryotes, we find that 33% human proteins have an ortholog in nonmetazoan species. This premetazoan proteome associates with 43% of all annotated human biological processes. Subsequently, four major waves of innovations can be inferred in the last common ancestors of eumetazoans, bilaterians, euteleostomi (bony vertebrates), and hominidae, largely specific to each epoch, whereas early branching deuterostome and chordate phyla show very few innovations. Interestingly, groups of proteins that act together in their modern human functions often originated concomitantly, although the corresponding human phenotypes frequently emerged later. For example, the three cnidarians Acropora, Nematostella, and Hydra express a highly similar protein inventory, and their protein innovations can be affiliated either to traits shared by all eumetazoans (gut differentiation, neurogenesis); or to bilaterian traits present in only some cnidarians (eyes, striated muscle); or to traits not identified yet in this phylum (mesodermal layer, endocrine glands). The variable correspondence between phenotypes predicted from protein enrichments and observed phenotypes suggests that a parallel mechanism repeatedly produce similar phenotypes, thanks to novel regulatory events that independently tie preexisting conserved genetic modules. PMID- 24065733 TI - Genomic correlates of relationship QTL involved in fore- versus hind limb divergence in mice. AB - Divergence of serially homologous elements of organisms is a common evolutionary pattern contributing to increased phenotypic complexity. Here, we study the genomic intervals affecting the variational independence of fore- and hind limb traits within an experimental mouse population. We use an advanced intercross of inbred mouse strains to map the loci associated with the degree of autonomy between fore- and hind limb long bone lengths (loci affecting the relationship between traits, relationship quantitative trait loci [rQTL]). These loci have been proposed to interact locally with the products of pleiotropic genes, thereby freeing the local trait from the variational constraint due to pleiotropic mutations. Using the known polymorphisms (single nucleotide polymorphisms [SNPs]) between the parental strains, we characterized and compared the genomic regions in which the rQTL, as well as their interaction partners (intQTL), reside. We find that these two classes of QTL intervals harbor different kinds of molecular variation. SNPs in rQTL intervals more frequently reside in limb-specific cis regulatory regions than SNPs in intQTL intervals. The intQTL loci modified by the rQTL, in contrast, show the signature of protein-coding variation. This result is consistent with the widely accepted view that protein-coding mutations have broader pleiotropic effects than cis-regulatory polymorphisms. For both types of QTL intervals, the underlying candidate genes are enriched for genes involved in protein binding. This finding suggests that rQTL effects are caused by local interactions among the products of the causal genes harbored in rQTL and intQTL intervals. This is the first study to systematically document the population level molecular variation underlying the evolution of character individuation. PMID- 24065736 TI - Multicentric Castleman's disease presenting with recurrent infections, rash, and malnutrition. PMID- 24065735 TI - The landscape of nucleotide polymorphism among 13,500 genes of the conifer picea glauca, relationships with functions, and comparison with medicago truncatula. AB - Gene families differ in composition, expression, and chromosomal organization between conifers and angiosperms, but little is known regarding nucleotide polymorphism. Using various sequencing strategies, an atlas of 212k high confidence single nucleotide polymorphisms (SNPs) with a validation rate of more than 92% was developed for the conifer white spruce (Picea glauca). Nonsynonymous and synonymous SNPs were annotated over the corresponding 13,498 white spruce genes representative of 2,457 known gene families. Patterns of nucleotide polymorphisms were analyzed by estimating the ratio of nonsynonymous to synonymous numbers of substitutions per site (A/S). A general excess of synonymous SNPs was expected and observed. However, the analysis from several perspectives enabled to identify groups of genes harboring an excess of nonsynonymous SNPs, thus potentially under positive selection. Four known gene families harbored such an excess: dehydrins, ankyrin-repeats, AP2/DREB, and leucine-rich repeat. Conifer-specific sequences were also generally associated with the highest A/S ratios. A/S values were also distributed asymmetrically across genes specifically expressed in megagametophytes, roots, or in both, harboring on average an excess of nonsynonymous SNPs. These patterns confirm that the breadth of gene expression is a contributing factor to the evolution of nucleotide polymorphism. The A/S ratios of Medicago truncatula genes were also analyzed: several gene families shared between P. glauca and M. truncatula data sets had similar excess of synonymous or nonsynonymous SNPs. However, a number of families with high A/S ratios were found specific to P. glauca, suggesting cases of divergent evolution at the functional level. PMID- 24065737 TI - Can the Newest Vital Sign be used to assess health literacy in children and adolescents? AB - CONTEXT: We evaluated the validity of the Newest Vital Sign (NVS) as a brief screen for health literacy in children. OBJECTIVES: To (a) test the hypothesis that child performance on the NVS correlates with performance on a test of child reading comprehension and (b) establish age-based cutoffs for expected performance on the NVS. DESIGN: Children aged 7 to 17 years were administered the NVS followed by the Gray Silent Reading Test (GSRT). RESULTS: The NVS score correlated strongly with GSRT score (rho = 0.71, P < .0001) and increased with age. Children aged 7 to 9 years had a median NVS score of 1 (interquartile range = 1-2); children aged 10 to 17 years had a median score of 3 (interquartile range = 2-4), P < .0001. CONCLUSION: The NVS performs well in this population. Children aged 10 to 17 years with an NVS score lower than 2 may have low health literacy. PMID- 24065738 TI - Earlobe anomalies in children. PMID- 24065734 TI - Transposable elements: powerful contributors to angiosperm evolution and diversity. AB - Transposable elements (TEs) are a dominant feature of most flowering plant genomes. Together with other accepted facilitators of evolution, accumulating data indicate that TEs can explain much about their rapid evolution and diversification. Genome size in angiosperms is highly correlated with TE content and the overwhelming bulk (>80%) of large genomes can be composed of TEs. Among retro-TEs, long terminal repeats (LTRs) are abundant, whereas DNA-TEs, which are often less abundant than retro-TEs, are more active. Much adaptive or evolutionary potential in angiosperms is due to the activity of TEs (active TE Thrust), resulting in an extraordinary array of genetic changes, including gene modifications, duplications, altered expression patterns, and exaptation to create novel genes, with occasional gene disruption. TEs implicated in the earliest origins of the angiosperms include the exapted Mustang, Sleeper, and Fhy3/Far1 gene families. Passive TE-Thrust can create a high degree of adaptive or evolutionary potential by engendering ectopic recombination events resulting in deletions, duplications, and karyotypic changes. TE activity can also alter epigenetic patterning, including that governing endosperm development, thus promoting reproductive isolation. Continuing evolution of long-lived resprouter angiosperms, together with genetic variation in their multiple meristems, indicates that TEs can facilitate somatic evolution in addition to germ line evolution. Critical to their success, angiosperms have a high frequency of polyploidy and hybridization, with resultant increased TE activity and introgression, and beneficial gene duplication. Together with traditional explanations, the enhanced genomic plasticity facilitated by TE-Thrust, suggests a more complete and satisfactory explanation for Darwin's "abominable mystery": the spectacular success of the angiosperms. PMID- 24065741 TI - Cardiac patients who completed a longitudinal psychosocial study had a different clinical and psychosocial baseline profile than patients who dropped out prematurely. AB - Non-response is a serious threat to the external validity of longitudinal psychosocial studies. Little is known about potential systematic differences between patients with coronary artery disease who complete a psychosocial study and those who drop out prematurely due to non-response, or whether drop-outs may have a different cardiovascular risk. We studied a cohort of 1132 consecutive patients undergoing percutaneous coronary intervention (PCI). At baseline, all patients completed the Hospital Anxiety and Depression Scale (HADS) and the Type D Scale (DS14). At 12 months follow-up, 70.8% (n = 802) of patients completed both questionnaires, while 29.2% (n = 330) dropped out. We observed significant differences in socio-demographic, clinical, and psychological baseline characteristics between completers and drop-outs. Drop-outs were younger, more likely to smoke, but less often prescribed cardiovascular medications, including calcium antagonists and angiotensin-converting enzyme inhibitors, as compared with completers. Drop-outs more often had depression, anxiety, and negative affectivity, as compared with completers (all p-values <0.05). After a median follow-up of 4 years, we found no significant differences in mortality risk between completers and drop-outs (6.5 vs. 7.3%; adjusted HR 1.34, 95% CI 0.82 2.19, respectively). In conclusion, a possible attrition bias occurred, as drop outs and completers differed systematically on some socio-demographic, clinical, and psychological baseline characteristics. Despite these differences, this did not translate into a poorer short-term prognosis, as there were no differences in the mortality risk of completers vs. drop-outs after a median follow-up of 4 years. In future prospective studies, attention should be paid to attrition bias, and its possible impact on study results and implications should be discussed. PMID- 24065739 TI - Cathepsin C is a tissue-specific regulator of squamous carcinogenesis. AB - Serine and cysteine cathepsin (Cts) proteases are an important class of intracellular and pericellular enzymes mediating multiple aspects of tumor development. Emblematic of these is CtsB, reported to play functionally significant roles during pancreatic islet and mammary carcinogenesis. CtsC, on the other hand, while up-regulated during pancreatic islet carcinogenesis, lacks functional significance in mediating neoplastic progression in that organ. Given that protein expression and enzymatic activity of both CtsB and CtsC are increased in numerous tumors, we sought to understand how tissue specificity might factor into their functional significance. Thus, whereas others have reported that CtsB regulates metastasis of mammary carcinomas, we found that development of squamous carcinomas occurs independently of CtsB. In contrast to these findings, our studies found no significant role for CtsC during mammary carcinogenesis but revealed squamous carcinogenesis to be functionally dependent on CtsC. In this context, dermal/stromal fibroblasts and bone marrow-derived cells expressed increased levels of enzymatically active CtsC that regulated the complexity of infiltrating immune cells in neoplastic skin, development of angiogenic vasculature, and overt squamous cell carcinoma growth. These studies highlight the important contribution of tissue/microenvironment context to solid tumor development and indicate that tissue specificity defines functional significance for these two members of the cysteine protease family. PMID- 24065740 TI - H3.3 actively marks enhancers and primes gene transcription via opening higher ordered chromatin. AB - The histone variants H3.3 and H2A.Z have recently emerged as two of the most important features in transcriptional regulation, the molecular mechanism of which still remains poorly understood. In this study, we investigated the regulation of H3.3 and H2A.Z on chromatin dynamics during transcriptional activation. Our in vitro biophysical and biochemical investigation showed that H2A.Z promoted chromatin compaction and repressed transcriptional activity. Surprisingly, with only four to five amino acid differences from the canonical H3, H3.3 greatly impaired higher-ordered chromatin folding and promoted gene activation, although it has no significant effect on the stability of mononucleosomes. We further demonstrated that H3.3 actively marks enhancers and determines the transcriptional potential of retinoid acid (RA)-regulated genes via creating an open chromatin signature that enables the binding of RAR/RXR. Additionally, the H3.3-dependent recruitment of H2A.Z on promoter regions resulted in compaction of chromatin to poise transcription, while RA induction results in the incorporation of H3.3 on promoter regions to activate transcription via counteracting H2A.Z-mediated chromatin compaction. Our results provide key insights into the mechanism of how histone variants H3.3 and H2A.Z function together to regulate gene transcription via the modulation of chromatin dynamics over the enhancer and promoter regions. PMID- 24065742 TI - Relationships between consumption of alcoholic beverages and healthy foods: the French supermarket cohort of 196,000 subjects. AB - AIMS: Moderate alcohol consumption is associated with reduced risk of cardiovascular disease. Related dietary habits and lifestyle may bias assessment of the relationship between alcohol intake and health status. We examined the relationship between key features relating to the consumption of alcoholic beverages and individual profiles of objective food purchases. METHODS AND RESULTS: Data were collected on regular clients of a large supermarket chain implanted across France (n = 196,604). Food items purchased were classified into three categories: (1) healthy foods; (2) unhealthy foods; and (3) others. Wine consumers favoured purchase of healthy foods more often than others, whereas the lowest level of healthy food purchasers was associated with consumption of beer and aniseed-based beverages. Bordeaux wine purchasers spent less in their average budget than the whole population for nine out of the 11 unhealthy food categories. Conversely, the budget was markedly higher in non-alcohol purchasers as compared to the whole population for seven out of the 11 unhealthy foods. The ratio of the budget for healthy to that for unhealthy foods was also distinct between the groups, being highest for wine and lowest for beer. In the subgroup of non-alcohol consumers, this ratio was intermediate but significantly lower relative to values in the five subcategories of wine purchasers. CONCLUSIONS: Marked differences in the profile of the purchase of healthy versus unhealthy food products as a function of the subcategory of alcoholic beverage consumed were documented, revealing a critical unidentified confounding feature in analyses of the potential relationship between alcohol consumption and protection against cardiovascular disease. PMID- 24065743 TI - Outcome of three very different treatments for thumb CMC joint arthritis. PMID- 24065744 TI - Commentary on Young et al. Paediatric hand fractures. PMID- 24065745 TI - Re: Stevenson et al. An objective assessment of safety to drive in an upper limb cast. J Hand Surg Eur. 2013, 38: 321-4. PMID- 24065746 TI - Paul R. Manske 2013 award for the best upper extremity congenital research manuscript. PMID- 24065747 TI - Cochrane corner: local corticosteroid injection for carpal tunnel syndrome. AB - BACKGROUND: Carpal tunnel syndrome is a clinical syndrome manifested by signs and symptoms of irritation of the median nerve at the carpal tunnel in the wrist. Local corticosteroid injection for carpal tunnel syndrome has been studied but its effectiveness is unknown. OBJECTIVES: To evaluate the effectiveness of local corticosteroid injection for carpal tunnel syndrome versus placebo injection or other non-surgical interventions. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Trials register (searched May 2006), MEDLINE (searched January 1966 to May 2006), EMBASE (searched January 1980 to May 2006) and CINAHL (searched January 1982 to May 2006). SELECTION CRITERIA: Randomized or quasi-randomized studies. DATA COLLECTION AND ANALYSIS: Three authors independently selected the trials and rated their overall quality. Relative risks and 95% confidence intervals were calculated for each trial and summary relative risks and 95% confidence intervals were also calculated. PMID- 24065748 TI - Impact Factor 1.112 for Interactive CardioVascular and Thoracic Surgery: a well deserved recognition for all contributors. PMID- 24065749 TI - eComment. Postoperative atrial fibrillation: a robust human model of atrial fibrillation genesis? PMID- 24065750 TI - eComment. Coronary artery dilatation: ectasia or aneurysm. PMID- 24065751 TI - eComment. Renal dysfunction may predict early and late cardiovascular events. PMID- 24065752 TI - eComment. A significance of intra-abdominal pressure in cardiovascular patients. PMID- 24065753 TI - eComment. Intra-abdominal hypertension and abdominal compartment syndrome in cardiac surgery patients. PMID- 24065754 TI - eComment. Trifecta: the latest generation of bioprosthetic aortic valves. PMID- 24065755 TI - eComment. Atrial fibrillation in patients undergoing thoracic surgery. PMID- 24065756 TI - eComment. Autologous pericardium is superior to conventional bovine patch in congenital heart disease reconstructive surgery: an appraisal for tissueengineered xenograft. PMID- 24065757 TI - eComment. Preoperative levosimendan administration in cardiac surgery patients. PMID- 24065758 TI - eComment. Levosimendan in adult patients undergoing cardiac surgery. PMID- 24065759 TI - eComment. Consider trying levosimendan. PMID- 24065760 TI - eComment. Adjustable tricuspid annuloplasty for functional tricuspid regurgitation. PMID- 24065761 TI - eComment. Beyond the tricuspid annuloplasty techniques. PMID- 24065762 TI - eComment. Traumatic ascending aortic transection. PMID- 24065763 TI - eComment. Aortic aneurysms secondary to tuberculosis. PMID- 24065764 TI - eComment. Fatal purulent mediastinitis after endobronchial ultrasound-guided transbronchial needle aspiration and mediastinoscopy. PMID- 24065765 TI - Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. AB - Somatic mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 occur frequently in acute myeloid leukemia (AML) and other cancers. These genes encode neomorphic proteins that produce the presumed oncometabolite 2-hydroxyglutarate (2-HG). Despite the prospect of treating AML and other cancers by targeting IDH mutant proteins, it remains unclear how these mutants affect tumor development and maintenance in vivo, and no cancer models exist to study the action of IDH2 mutants in vivo. We show that IDH2 mutants can cooperate with oncogenic Flt3 or Nras alleles to drive leukemia in mice by impairing the differentiation of cells of the myeloid lineage. Pharmacologic or genetic inhibition of IDH2 triggers the differentiation and death of AML cells, albeit only with prolonged IDH2 inhibition. In contrast, inhibition of the bromodomain-containing protein Brd4 triggers rapid differentiation and death of IDH2 mutant AML. Our results establish a critical role for mutant IDH2 in leukemogenesis and tumor maintenance and identify an IDH-independent strategy to target these cancers therapeutically. PMID- 24065766 TI - Induction of sarcomas by mutant IDH2. AB - More than 50% of patients with chondrosarcomas exhibit gain-of-function mutations in either isocitrate dehydrogenase 1 (IDH1) or IDH2. In this study, we performed genome-wide CpG methylation sequencing of chondrosarcoma biopsies and found that IDH mutations were associated with DNA hypermethylation at CpG islands but not other genomic regions. Regions of CpG island hypermethylation were enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. In murine 10T1/2 mesenchymal progenitor cells, expression of mutant IDH2 led to DNA hypermethylation and an impairment in differentiation that could be reversed by treatment with DNA-hypomethylating agents. Introduction of mutant IDH2 also induced loss of contact inhibition and generated undifferentiated sarcomas in vivo. The oncogenic potential of mutant IDH2 correlated with the ability to produce 2-hydroxyglutarate. Together, these data demonstrate that neomorphic IDH2 mutations can be oncogenic in mesenchymal cells. PMID- 24065767 TI - Exchange of associated factors directs a switch in HBO1 acetyltransferase histone tail specificity. AB - Histone acetyltransferases (HATs) assemble into multisubunit complexes in order to target distinct lysine residues on nucleosomal histones. Here, we characterize native HAT complexes assembled by the BRPF family of scaffold proteins. Their plant homeodomain (PHD)-Zn knuckle-PHD domain is essential for binding chromatin and is restricted to unmethylated H3K4, a specificity that is reversed by the associated ING subunit. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as catalytic acetyltransferase subunit. Interestingly, while the previously reported HBO1 complexes containing JADE scaffold proteins target histone H4, the HBO1-BRPF1 complex acetylates only H3 in chromatin. We mapped a small region to the N terminus of scaffold proteins responsible for histone tail selection on chromatin. Thus, alternate choice of subunits associated with HBO1 can switch its specificity between H4 and H3 tails. These results uncover a crucial new role for associated proteins within HAT complexes, previously thought to be intrinsic to the catalytic subunit. PMID- 24065768 TI - Spliceosome-mediated decay (SMD) regulates expression of nonintronic genes in budding yeast. AB - We uncovered a novel role for the spliceosome in regulating mRNA expression levels that involves splicing coupled to RNA decay, which we refer to as spliceosome-mediated decay (SMD). Our transcriptome-wide studies identified numerous transcripts that are not known to have introns but are spliced by the spliceosome at canonical splice sites in Saccharomyces cerevisiae. Products of SMD are primarily degraded by the nuclear RNA surveillance machinery. We demonstrate that SMD can significantly down-regulate mRNA levels; splicing at canonical splice sites in the bromodomain factor 2 (BDF2) transcript reduced transcript levels roughly threefold by generating unstable products that are rapidly degraded by the nuclear surveillance machinery. Regulation of BDF2 mRNA levels by SMD requires Bdf1, a functionally redundant Bdf2 paralog that plays a role in recruiting the spliceosome to the BDF2 mRNA. Interestingly, mutating BDF2 5' splice site and branch point consensus sequences partially suppresses the bdf1Delta temperature-sensitive phenotype, suggesting that maintaining proper levels of Bdf2 via SMD is biologically important. We propose that the spliceosome can also repress protein-coding gene expression by promoting nuclear turnover of spliced RNA products and provide an insight for coordinated regulation of Bdf1 and Bdf2 levels in the cell. PMID- 24065769 TI - Mechanistic insights into CED-4-mediated activation of CED-3. AB - Programmed cell death in Caenorhabditis elegans requires activation of the caspase CED-3, which strictly depends on CED-4. CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. Despite recent advances, major questions remain unanswered. Importantly, how CED-4 recognizes CED-3 and how such binding facilitates CED-3 activation remain completely unknown. Here we demonstrate that the L2' loop of CED-3 directly binds CED-4 and plays a major role in the formation of an active CED-4-CED-3 holoenzyme. The crystal structure of the CED-4 apoptosome bound to the L2' loop fragment of CED-3, determined at 3.2 A resolution, reveals specific interactions between a stretch of five hydrophobic amino acids from CED-3 and a shallow surface pocket within the hutch of the funnel-shaped CED-4 apoptosome. Structure-guided biochemical analysis confirms the functional importance of the observed CED-4-CED-3 interface. Structural analysis together with published evidence strongly suggest a working model in which two molecules of CED-3 zymogen, through specific recognition, are forced into the hutch of the CED-4 apoptosome, consequently undergoing dimerization and autocatalytic maturation. The mechanism of CED-3 activation represents a major revision of the prevailing model for initiator caspase activation. PMID- 24065772 TI - Flavobacterium tructae sp. nov. and Flavobacterium piscis sp. nov., isolated from farmed rainbow trout (Oncorhynchus mykiss). AB - Four Gram-staining-negative, catalase- and oxidase-positive, pale-orange pigmented bacterial strains (435-08(T), 47B-3-09, 412R-09(T) and 60B-3-09) were isolated from diseased rainbow trout. Analysis of their 16S rRNA gene sequences suggested their adscription to the genus Flavobacterium. Strains formed two phylogenetic groups represented by strains 435-08(T) and 47B-3-09 (group A), and strains 412R-09(T) and 60B-3-09 (group B) displaying 16S rRNA sequence similarities greater than 99.8-99.9% within their respective groups. Strain 435 08(T) exhibited the highest levels of similarity with Flavobacterium aquidurense WB-1.1.56(T) (98.6% sequence similarity) and strain 412R-09(T) with Flavobacterium frigidimaris KUC-1(T) and Flavobacterium aquidurense WB-1.1.56(T) (98.9% and 98.6% sequence similarity, respectively). DNA-DNA hybridization studies showed low levels of relatedness between strain 435-08(T) and strain 412R 09(T) and between both strains and the most closely related species of the genus Flavobacterium. The genomic DNA G+C contents of strains 435-08(T) and 412R-09(T) were 36.2 and 34.3 mol%, respectively. The predominant respiratory quinone of both strains was MK-6 and the major fatty acids were iso-C(15 : 0), C(16 : 1)omega7c and C(15 : 0). The two groups of strains could be distinguished from each other and from related species of the genus Flavobacterium by a number of phenotypic properties. Phylogenetic, genotypic and phenotypic evidence indicated that strains of groups A and B represent two novel species of the genus Flavobacterium, for which the names Flavobacterium tructae sp. nov. (type strain 435-08(T) = CECT 7791(T) = CCUG 60100(T)) and Flavobacterium piscis sp. nov. (type strain 412R-09(T) = CECT 7911(T) = CCUG 60099(T)) are proposed. PMID- 24065770 TI - De- and repolarization mechanism of flagellar morphogenesis during a bacterial cell cycle. AB - Eukaryotic morphogenesis is seeded with the establishment and subsequent amplification of polarity cues at key times during the cell cycle, often using (cyclic) nucleotide signals. We discovered that flagellum de- and repolarization in the model prokaryote Caulobacter crescentus is precisely orchestrated through at least three spatiotemporal mechanisms integrated at TipF. We show that TipF is a cell cycle-regulated receptor for the second messenger--bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP)--that perceives and transduces this signal through the degenerate c-di-GMP phosphodiesterase (EAL) domain to nucleate polar flagellum biogenesis. Once c-di-GMP levels rise at the G1 -> S transition, TipF is activated, stabilized, and polarized, enabling the recruitment of downstream effectors, including flagellar switch proteins and the PflI positioning factor, at a preselected pole harboring the TipN landmark. These c-di GMP-dependent events are coordinated with the onset of tipF transcription in early S phase and together enable the correct establishment and robust amplification of TipF-dependent polarization early in the cell cycle. Importantly, these mechanisms also govern the timely removal of TipF at cell division coincident with the drop in c-di-GMP levels, thereby resetting the flagellar polarization state in the next cell cycle after a preprogrammed period during which motility must be suspended. PMID- 24065773 TI - Nonlabens antarcticus sp. nov., a psychrophilic bacterium isolated from glacier ice, and emended descriptions of Nonlabens marinus Park et al. 2012 and Nonlabens agnitus Yi and Chun 2012. AB - A Gram-negative, proteorhodopsin-containing, orange pigmented, rod-shaped and strictly aerobic bacterium, designated strain AKS622(T), was isolated from a glacier core collected from the coast of King George Island, Antarctica. 16S rRNA gene sequence analysis revealed that strain AKS622(T) was affiliated to the genus Nonlabens of the family Flavobacteriaceae and showed highest similarity to Nonlabens marinus S1-08(T) (97.9%). The level of DNA-DNA relatedness between strain AKS622(T) and N. marinus S1-08(T) was 46%. Optimal growth of strain AKS622(T) was observed at pH 7.0, at 15 degrees C and with 2.0% NaCl. The predominant cellular fatty acids were anteiso-C(15 : 0), iso-C(16 : 0), iso-C(16 : 0) 3-OH, C17:0 2-OH and summed feature 3 (comprising C(16 : 1)omega7c and/or C(16 : 1)omega6c). The DNA G+C content was 37.9 mol%. The major respiratory quinone was MK-6. Phosphatidylethanolamine, four unidentified glycolipids, three unidentified aminolipids and one unidentified lipid were detected as major polar lipids. On the basis of the data from this polyphasic taxonomic study, it was concluded that strain AKS622(T) represents a novel species within the genus Nonlabens, for which the name Nonlabens antarcticus sp. nov. is proposed. The type strain is AKS622(T) ( = KCCM 43019(T) = JCM 14068(T)). Emended descriptions of N. marinus Park et al. 2012 and Nonlabens agnitus Yi and Chun 2012 are given. PMID- 24065774 TI - Chromosome-wide profiling of X-chromosome inactivation and epigenetic states in fetal brain and placenta of the opossum, Monodelphis domestica. AB - Evidence from a few genes in diverse species suggests that X-chromosome inactivation (XCI) in marsupials is characterized by exclusive, but leaky inactivation of the paternally derived X chromosome. To study the phenomenon of marsupial XCI more comprehensively, we profiled parent-of-origin allele-specific expression, DNA methylation, and histone modifications in fetal brain and extra embryonic membranes in the gray, short-tailed opossum (Monodelphis domestica). The majority of X-linked genes (152 of 176 genes with trackable SNP variants) exhibited paternally imprinted expression, with nearly 100% of transcripts derived from the maternal allele; whereas 24 loci (14%) escaped inactivation, showing varying levels of biallelic expression. In addition to recently reported evidence of marsupial XCI regulation by the noncoding Rsx transcript, strong depletion of H3K27me3 at escaper gene loci in the present study suggests that histone state modifications also correlate strongly with opossum XCI. In contrast to mouse, the opossum did not show an association between X-linked gene expression and promoter DNA methylation, with one notable exception. Unlike all other X-linked genes examined, Rsx was differentially methylated on the maternal and paternal X chromosomes, and expression was exclusively from the inactive (paternal) X chromosome. Our study provides the first comprehensive catalog of parent-of-origin expression status for X-linked genes in a marsupial and sheds light on the regulation and evolution of imprinted XCI in mammals. PMID- 24065775 TI - Random replication of the inactive X chromosome. AB - In eukaryotic cells, genomic DNA replicates in a defined temporal order. The inactive X chromosome (Xi), the most extensive instance of facultative heterochromatin in mammals, replicates later than the active X chromosome (Xa), but the replication dynamics of inactive chromatin are not known. By profiling human DNA replication in an allele-specific, chromosomally phased manner, we determined for the first time the replication timing along the active and inactive chromosomes (Xa and Xi) separately. Replication of the Xi was different from that of the Xa, varied among individuals, and resembled a random, unstructured process. The Xi replicated rapidly and at a time largely separable from that of the euchromatic genome. Late-replicating, transcriptionally inactive regions on the autosomes also replicated in an unstructured manner, similar to the Xi. We conclude that DNA replication follows two strategies: slow, ordered replication associated with transcriptional activity, and rapid, random replication of silent chromatin. The two strategies coexist in the same cell, yet are segregated in space and time. PMID- 24065777 TI - The impact of pedestrian countdown signals on pedestrian-motor vehicle collisions: a reanalysis of data from a quasi-experimental study. AB - OBJECTIVE: To perform a more sophisticated analysis of previously published data that advances the understanding of the efficacy of pedestrian countdown signal (PCS) installation on pedestrian-motor vehicle collisions (PMVCs), in the city of Toronto, Canada. METHODS: This is an updated analysis of the same dataset from Camden et al. A quasi-experimental design was used to evaluate the effect of PCS on PMVC. A Poisson regression analysis, using a one-group comparison of PMVC, pre PCS installation to post-PCS installation was used, controlling for season and temporal effects. The outcome was the frequency of reported PMVC (January 2000 December 2009). Similar models were used to analyse specific types of collisions defined by age of pedestrian, injury severity, and pedestrian and vehicle action. Incidence rate ratios with 95% CI are presented. RESULTS: This analysis included 9262 PMVC, 2760 during or after PCS installation, at 1965 intersections. There was a 26% increase in the rate of collisions, pre to post-PCS installation (incidence rate ratio=1.26, 95% CI 1.11 to 1.42). CONCLUSIONS: The installation of PCS at 1965 signalised intersections in the city of Toronto resulted in an increase in PMVC rates post-PCS installation. PCSs may have an unintended consequence of increasing pedestrian-motor vehicle collisions in some settings. PMID- 24065778 TI - 'Do as we say, not as we do:' a cross-sectional survey of injuries in injury prevention professionals. AB - BACKGROUND: As the leading cause of death and among the top causes of hospitalisation in Canadians aged 1-44 years, injury is a major public health concern. Little is known about whether knowledge, training and understanding of the underlying causes and mechanisms of injury would help with one's own prevention efforts. Based on the Theory of Planned Behaviour, we hypothesised that injury prevention professionals would experience fewer injuries than the general population. METHODS: An online cross-sectional survey was distributed to Canadian injury prevention practitioners, researchers and policy makers to collect information on medically attended injuries. Relative risk of injury in the past 12 months was calculated by comparing the survey data with injury incidence reported by a comparable subgroup of adults from the (Canadian Community Health Survey (CCHS)) from 2009 to 2010. RESULTS: We had 408 injury prevention professionals complete the survey: 344 (84.5%) women and 63 (15.5%) men. In the previous 12 months, 86 individuals reported experiencing at least one medically attended injury (21,235 people per 100,000 people); with sports being the most common mechanism (41, 33.6%). Fully 84.8% individuals from our sample believed that working in the field had made them more careful. After accounting for age distribution, education level and employment status, injury prevention professionals were 1.69 (95% CI 1.41 to 2.03) times more likely to be injured in the past year. INTERPRETATION: Despite their convictions of increasing their own safety behaviour and that of others, injury prevention professionals' knowledge and training did not help them prevent their own injuries. PMID- 24065776 TI - Small RNA profiling of Xenopus embryos reveals novel miRNAs and a new class of small RNAs derived from intronic transposable elements. AB - Small RNA control of gene expression is critical for developmental processes in vertebrate embryos. To determine the dynamics of small RNA expression and to uncover novel small RNAs in the early vertebrate embryo, we performed high throughput sequencing of all small RNAs in Xenopus tropicalis embryos at three developmental time points and in dissected halves of gastrula embryos. This analysis allowed us to identify novel microRNAs and we show that microRNA expression is highly dynamic and spatially localized in early embryos. In addition, we have developed a microRNA prediction pipeline and demonstrate that it has the power to predict new miRNAs that are experimentally detectable in frogs, mice, and humans. By combining the small RNA sequencing with mRNA profiling at the different developmental stages, we identify a new class of small noncoding RNAs that we name siteRNAs, which align in clusters to introns of protein-coding genes. We show that siteRNAs are derived from remnants of transposable elements present in the introns. We find that genes containing clusters of siteRNAs are transcriptionally repressed as compared with all genes. Furthermore, we show that this is true for individual genes containing siteRNA clusters, and that these genes are enriched in specific repressive histone modifications. Our data thus suggest a new mechanism of siteRNA-mediated gene silencing in vertebrates, and provide an example of how mobile elements can affect gene regulation. PMID- 24065779 TI - What is the value and impact of the safety World Conference? Evaluators' reflections of safety 2012. AB - Using survey and documentary information collected as part of an evaluation of the 2012 conference, this paper reflects upon the value of the 2012 World Conference to attendees of the event. The results are discussed in the context of questions about what the purpose of conference is to the world injury prevention community and how they are organised. The evaluators challenge the community and future organisers to clarify what the purpose of these events are to better inform future evaluation activities. PMID- 24065781 TI - Chemical modifications on siRNAs avoid Toll-like-receptor-mediated activation of the hepatic immune system in vivo and in vitro. AB - OBJECTIVES: The therapeutic application of small interfering RNAs (siRNAs) is limited by the induction of severe off-target effects, especially in the liver. Therefore, we assessed the potential of differently modified siRNAs to induce the hepatic innate immune system in vitro and in vivo. METHODS: Primary isolated liver cells were transfected with siRNAs against apolipoprotein B1 (APOB1), luciferase (LUC) or galactosidase (GAL). For in vivo use, siRNAs were formulated in lipid nanoparticles (LNPs) and administered intravenously to C57BL/6 mice. Liver tissue was collected 6-48 h after injection and knock-down efficiency or immune responses were determined by quantitative reverse-transcription-linked PCR. RESULTS: Unmodified GAL siRNA transiently induced the expression of TNF alpha, IL-6, IL-10, IFN-beta and IFN-sensitive gene 15 in vivo, whereas a formulation of 2'-O-methylated-LUC siRNA had no such effects. Formulation of unmodified APOB1-specific siRNA suppressed APOB1 mRNA levels by ~80% in the liver 48h after application. The results were paralleled in vitro, where transfection of liver cells with unmodified siRNAs, but not with chemically modified siRNAs, led to cell-type-specific induction of immune genes. These immune responses were not observed in MYD88-deficient mice or in chloroquine-treated cells in vitro. CONCLUSIONS: Our data indicate that siRNAs activate endosomal Toll-like receptors in different liver-derived cell types to various degrees, in vitro. LNP formulated siRNA selectively leads to hepatic knock-down of target genes in vivo. Here, off-target immune responses are restricted to non-parenchymal liver cells. However, 2'-O-methyl modifications of siRNA largely avoid immune-stimulatory effects, which is a crucial prerequisite for the development of safe and efficient RNA-interference-based therapeutics. PMID- 24065780 TI - Integrating clinical services for HIV, tuberculosis, and cryptococcal disease in the developing world: a step forward with 2 novel diagnostic tests. AB - The success of antiretroviral therapy (ART) programs in the developing world is limited by the lack of adequate diagnostic tests to screen for life-threatening opportunistic infections such as tuberculosis (TB) and cryptococcal disease. Furthermore, there is an increasing need for implementation research in measuring the effectiveness of currently available rapid diagnostic tests. The recently developed lateral flow assays for both cryptococcal disease and TB have the potential to improve care and greatly reduce the time to initiation of ART among individuals who need it the most. However, we caution that the data on feasibility and effectiveness of these assays are limited and such research agendas must be prioritized. PMID- 24065782 TI - Glucose metabolism in critically ill patients: are incretins an important player? AB - Critical illness afflicts millions of people worldwide and is associated with a high risk of organ failure and death or an adverse outcome with persistent physical or cognitive deficits. Spontaneous hyperglycemia is common in critically ill patients and is associated with an adverse outcome compared to normoglycemia. Insulin is used for treating hyperglycemia in the critically ill patients but may be complicated by hypoglycemia, which is difficult to detect in these patients and which may lead to serious neurological sequelae and death. The incretin hormone, glucagon-like peptide (GLP) 1, stimulates insulin secretion and inhibits glucagon release both in healthy individuals and in patients with type 2 diabetes (T2DM). Compared to insulin, GLP-1 appears to be associated with a lower risk of severe hypoglycemia, probably because the magnitude of its insulinotropic action is dependent on blood glucose (BG). This is taken advantage of in the treatment of patients with T2DM, for whom GLP-1 analogs have been introduced during the recent years. Infusion of GLP-1 also lowers the BG level in critically ill patients without causing severe hypoglycemia. The T2DM and critical illness share similar characteristics and are, among other things, both characterized by different grades of systemic inflammation and insulin resistance. The GLP-1 might be a potential new treatment target in critically ill patients with stress induced hyperglycemia. PMID- 24065783 TI - Prenatal alcohol exposure and offspring cognition and school performance. A 'Mendelian randomization' natural experiment. AB - BACKGROUND: There is substantial debate as to whether moderate alcohol use during pregnancy could have subtle but important effects on offspring, by impairing later cognitive function and thus school performance. The authors aimed to investigate the unconfounded effect of moderately increased prenatal alcohol exposure on cognitive/educational performance. METHODS: We used mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) and performed both conventional observational analyses and Mendelian randomization using an ADH1B variant (rs1229984) associated with reduced alcohol consumption. Women of White European origin with genotype and self-reported prenatal alcohol consumption, whose offspring's IQ score had been assessed in clinic (N=4061 pairs) or Key Stage 2 (KS2) academic achievement score was available through linkage to the National Pupil Database (N=6268), contributed to the analyses. RESULTS: Women reporting moderate drinking before and during early pregnancy were relatively affluent compared with women reporting lighter drinking, and their children had higher KS2 and IQ scores. In contrast, children whose mothers' genotype predisposes to lower consumption or abstinence during early pregnancy had higher KS2 scores (mean difference +1.7, 95% confidence interval +0.4, +3.0) than children of mothers whose genotype predisposed to heavier drinking, after adjustment for population stratification. CONCLUSIONS: Better offspring cognitive/educational outcomes observed in association with prenatal alcohol exposure presumably reflected residual confounding by factors associated with social position and maternal education. The unconfounded Mendelian randomization estimates suggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes. PMID- 24065784 TI - Outcomes assessment of a pharmacist-directed seamless care program in an ambulatory oncology clinic. AB - The primary goal of seamless care is improved patient outcomes and improved standards of care for patients with cancer. The pharmacy service of the Newfoundland Cancer Treatment and Research Foundation conducted a randomized control study that measured clinical and humanistic outcomes of a pharmacist directed seamless care program in an ambulatory oncology clinic. This article focuses on the intervention group, particularly the identification of drug related problems (DRPs) and utilization of health care services as well the satisfaction of 3 types of health professionals with the services provided by the pharmacist-directed seamless care program. Overall, the seamless care pharmacist (SCP) identified an average of 3.7 DRPs per intervention patient; the most common DRP reported was a patient not receiving or taking a drug therapy for which there is an indication. The SCP identified more DRPs in patients receiving adjuvant treatment compared to those receiving palliative treatment. On average, family physicians, oncology nurses, and hospital pharmacists were satisfied with the SCP intervention indicating that they agreed the information collected and distributed by the SCP was useful to them. Pharmacist-directed seamless care services in an ambulatory oncology clinic have a significant impact on clinical outcomes and processes of patient care. The presence of a SCP can help identify and resolve DRPs experienced by patients in an outpatient oncology clinic, ensuring that patients are receiving the highest standard of care. PMID- 24065785 TI - Hunting habits of lions. PMID- 24065789 TI - Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50% of filtered glucose load in humans. AB - Inhibitors of sodium-glucose cotransporter 2 (SGLT2) are a novel class of antidiabetes drugs, and members of this class are under various stages of clinical development for the management of type 2 diabetes mellitus (T2DM). It is widely accepted that SGLT2 is responsible for >80% of the reabsorption of the renal filtered glucose load. However, maximal doses of SGLT2 inhibitors fail to inhibit >50% of the filtered glucose load. Because the clinical efficacy of this group of drugs is entirely dependent on the amount of glucosuria produced, it is important to understand why SGLT2 inhibitors inhibit <50% of the filtered glucose load. In this Perspective, we provide a novel hypothesis that explains this apparent puzzle and discuss some of the clinical implications inherent in this hypothesis. PMID- 24065788 TI - Sugar, uric acid, and the etiology of diabetes and obesity. AB - The intake of added sugars, such as from table sugar (sucrose) and high-fructose corn syrup has increased dramatically in the last hundred years and correlates closely with the rise in obesity, metabolic syndrome, and diabetes. Fructose is a major component of added sugars and is distinct from other sugars in its ability to cause intracellular ATP depletion, nucleotide turnover, and the generation of uric acid. In this article, we revisit the hypothesis that it is this unique aspect of fructose metabolism that accounts for why fructose intake increases the risk for metabolic syndrome. Recent studies show that fructose-induced uric acid generation causes mitochondrial oxidative stress that stimulates fat accumulation independent of excessive caloric intake. These studies challenge the long standing dogma that "a calorie is just a calorie" and suggest that the metabolic effects of food may matter as much as its energy content. The discovery that fructose-mediated generation of uric acid may have a causal role in diabetes and obesity provides new insights into pathogenesis and therapies for this important disease. PMID- 24065790 TI - Diabetes and the heart: is there objective evidence of a human diabetic cardiomyopathy? PMID- 24065791 TI - Can ADAMTS13 lead us to the paradise of personalized medicine? PMID- 24065792 TI - A new home for pancreatic islet transplants: the bone marrow. PMID- 24065793 TI - How sweet it is: intestinal sweet taste receptors in type 2 diabetes. PMID- 24065794 TI - Genetic dissection of diabetes: facing the giant. PMID- 24065798 TI - Comment on: Butler et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 2013;62:2595 2604. PMID- 24065795 TI - Assessing the human gut microbiota in metabolic diseases. AB - Recent findings have demonstrated that the gut microbiome complements our human genome with at least 100-fold more genes. In contrast to our Homo sapiens-derived genes, the microbiome is much more plastic, and its composition changes with age and diet, among other factors. An altered gut microbiota has been associated with several diseases, including obesity and diabetes, but the mechanisms involved remain elusive. Here we discuss factors that affect the gut microbiome, how the gut microbiome may contribute to metabolic diseases, and how to study the gut microbiome. Next-generation sequencing and development of software packages have led to the development of large-scale sequencing efforts to catalog the human microbiome. Furthermore, the use of genetically engineered gnotobiotic mouse models may increase our understanding of mechanisms by which the gut microbiome modulates host metabolism. A combination of classical microbiology, sequencing, and animal experiments may provide further insights into how the gut microbiota affect host metabolism and physiology. PMID- 24065799 TI - Comment on: Butler et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 2013;62:2595 2604. PMID- 24065800 TI - Response to comments on: Butler et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 2013;62:2595-2604. PMID- 24065801 TI - Comment on: Tessari et al. Roles of insulin, age, and asymmetric dimethylarginine on nitric oxide synthesis in vivo. Diabetes 2013;62:2699-2708. PMID- 24065802 TI - Response to comment on: Tessari et al. Roles of insulin, age, and asymmetric dimethylarginine on nitric oxide synthesis in vivo. Diabetes 2013;62:2699-2708. PMID- 24065803 TI - Comment on: Selvin et al. sRAGE and risk of diabetes, cardiovascular disease, and death. Diabetes 2013;62:2116-2121. PMID- 24065804 TI - Comment on: Selvin et al. sRAGE and risk of diabetes, cardiovascular disease, and death. Diabetes 2013;62:2116-2121. PMID- 24065805 TI - Response to comments on: Selvin et al. sRAGE and risk of diabetes, cardiovascular disease, and death. Diabetes 2013;62:2116-2121. PMID- 24065806 TI - Episcleral venous pressure and IOP responses to central electrical stimulation in the rat. AB - PURPOSE: Histological evidence suggests a role for the central nervous system in controlling episcleral venous pressure (EVP). Based on prior studies that identified candidate regions in the brain stem, the present study assessed the effect of electrical stimulation at the location of the superior salivatory nucleus (SSN) on EVP in rats. METHODS: Male Sprague-Dawley rats (n = 11) were anesthetized using pentobarbital sodium (50 mg/kg intraperitoneally initially, supplemented intravenously [IV] as needed) and paralyzed with gallamine triethiodide (1 mg/kg, IV). The animals were artificially ventilated and the femoral artery and vein were cannulated for blood pressure measurement and drug administration. Carotid blood flow was measured with an ultrasound flow probe and heart rate with a cardiotachometer. IOP was measured through a cannula in the vitreous compartment and EVP was measured through a micropipette in episcleral veins using the servonull technique. After a craniotomy was performed, a unipolar stainless steel electrode was inserted into the brainstem at the coordinates of the SSN using a stereotactic instrument. Stimulations were performed at 20Hz, 9 MUA, 1 ms pulse duration, and 200 pulses. RESULTS: Stimulation at the SSN coordinates increased IOP from 10.6 +/- 0.4 to 11.8 +/- 0.6 mm Hg (P < 0.01) and EVP from 7.8 +/- 1.3 to 10.7 +/- 1.1 mm Hg (P < 0.01). Mean arterial pressure, carotid blood flow, and heart rate remained unaltered. CONCLUSIONS: The present study indicates that the SSN may participate in regulating EVP. PMID- 24065808 TI - High resolution OCT quantitative analysis of the space between the IOL and the posterior capsule during the early cataract postoperative period. AB - PURPOSE: We quantitatively characterized the space between the IOL and the posterior capsule (IOL-PC space) during the early postphacoemulsification period, using high resolution optical coherence tomography (OCT). METHODS: We recruited 30 eyes of 30 patients who underwent phacoemulsification and randomly divided them into two groups. Acrysof Natural IQ IOLs were implanted in one group (n = 15), and Adapt-AO IOLs were implanted into the other (n = 15). A custom-built OCT instrument was used to image the IOL-PC space at 1 day, 1 week, and 1 month after surgery. Slit-lamp examination and auto refraction were performed at each visit. RESULTS: The IOL-PC spaces in the IQ group were 0.72 +/- 0.35, 0.40 +/- 0.24, and 0.23 +/- 0.16 mm(2) at 1 day, 1 week, and 1 month after surgery, respectively. At each of these times, the values for the AO group were significantly smaller (P < 0.001). Compared to 1 day after surgery, significant changes in the ACDs and refractive errors occurred up to 1 month postoperatively in the IQ group; however, changes in the ACD and refractive error were significant only at 1 week in the AO group. CONCLUSIONS: The decreases in IOL-PC space and in ACD during the early postoperative period were associated with a myopic shift. It appeared that the different IOL designs had a role in closure of the IOL-PC space. High resolution OCT was suitable for quantitative analysis of IOL-PC space. (ClinicalTrials.gov number, NCT01605812.). PMID- 24065807 TI - Optic nerve inflammation and demyelination in a rodent model of nonarteritic anterior ischemic optic neuropathy. AB - PURPOSE: Optic nerve (ON) ischemia associated with nonarteric anterior ischemic optic neuropathy (NAION) results in axon and myelin damage. Myelin damage activates the intraneural Ras homolog A (RhoA), contributing to axonal regeneration failure. We hypothesized that increasing extrinsic macrophage activity after ON infarct would scavenge degenerate myelin and improve postischemic ON recovery. We used the cytokine granulocyte-macrophage colony stimulating factor (GM-CSF) to upregulate ON macrophage activity, and evaluated GM-CSF's effects after ON ischemia in the NAION rodent model (rAION). METHODS: Following rAION induction, GM-CSF was administered via intraventricular injection. Retinal ganglion cell (RGC) stereologic analysis was performed 1 month postinduction. The retinae and optic nerve laminae of vehicle- and GM-CSF-treated animals were examined immunohistochemically and ultrastructurally using transmission electron microscopy (TEM). RhoA activity was analyzed using a rhotekin affinity immunoanalysis and densitometry. Isolated ONs were analyzed functionally ex vivo by compound action potential (CAP) analysis. RESULTS: Rodent NAION produces ON postinfarct demyelination and myelin damage, functionally demonstrable by CAP analysis and ultrastructurally by TEM. Granulocyte-macrophage colony-stimulating factor increased intraneural inflammation, activating and recruiting endogenous microglia, with only a moderate amount of exogenous macrophage recruitment. Treatment with GM-CSF reduced postinfarct intraneural RhoA activity, but did not neuroprotect RGCs after rAION. CONCLUSIONS: Sudden ON ischemia results in previously unrecognized axonal demyelination, which may have a clinically important role in NAION-related functional defects and recovery. Granulocyte-macrophage colony-stimulating factor is not neuroprotective when administered directly to the optic nerve following ON ischemia, and does not improve axonal regeneration. It dramatically increases ON-microglial activation and recruitment. PMID- 24065809 TI - Ocular anterior segment biometry and high-order wavefront aberrations during accommodation. AB - PURPOSE: We investigated the relationships between the ocular anterior segment biometry and the ocular high-order aberrations (HOAs) during accommodation by combined ultralong scan depth optical coherence tomography (UL-OCT) and wavefront sensor. METHODS: We enrolled 35 right eyes of young healthy subjects (21 women and 14 men; age, 25.6 +/- 3.1 years; spherical equivalent refractive error, -0.41 +/- 0.59 diopters [D]). A custom-built UL-OCT and a wavefront sensor were combined. They were able to image the ocular anterior segment and to measure the HOAs during accommodation. The differences in the biometric dimensions and in the HOAs between the nonaccommodative and accommodative states were compared, and the relationships between them were investigated. RESULTS: Compared to the nonaccommodative condition, anterior chamber depth, pupil diameter, and radii of the crystalline lens surface curvatures decreased significantly, while the lens thickness and root-mean-square of high-order aberration (HORMS) of fixed 3-mm pupil size increased under the accommodative stimulus (P < 0.01). A negative correlation was found between the change in the radius of the lens anterior surface curvature and the change in HORMS (r = -0.370, P = 0.014). For nonaccommodative and accommodative conditions, HORMS for a fixed pupil size was correlated negatively with pupil diameter (r = -0.532 and -0.801, respectively, P < 0.01). CONCLUSIONS: The anterior segment biometry and the HOAs changed significantly during accommodation. The increase in HOAs mainly was due to the increased convexity of the anterior surface of the lens during accommodation. Contraction of the pupil may help to decrease HOAs. PMID- 24065810 TI - The effects of age on lens transport. AB - PURPOSE: Age-related nuclear cataracts involve denaturation and aggregation of intracellular proteins. We have documented age-dependent changes in membrane transport in the mouse lens to see what might initiate changes in the intracellular milieu. METHODS: Microelectrode-based intracellular impedance studies of intact lenses were used to determine gap junction coupling conductance, fiber and surface cell membrane conductances, effective extracellular resistivity, and intracellular voltage. Fiber cell connexin expression was detected by Western blotting. Intracellular hydrostatic pressure was measured with a microelectrode/manometer system. Concentrations of intracellular sodium and calcium were measured by intracellular injection of sodium-binding benzofuran isophthalate and Fura2, respectively. RESULTS: In adult lenses, as age increased: fiber cell gap junction coupling conductance declined significantly, correlating with decreases in Cx46 and Cx50 labeling in Western blots; fiber and surface cell membrane conductances did not change systematically; effective extracellular resistivity increased monotonically; center to surface gradients for intracellular pressure, sodium, calcium, and voltage all increased, but in an interdependent manner that moderated changes. In newborn pup lenses, there were changes that did not simply fit with the above paradigm. CONCLUSIONS: In newborn pup lenses, the observed changes may relate to growth factors that are not related to age-dependent changes seen in adult lenses. The major change in adult lenses was an age-dependent decrease in gap junction coupling, probably due to oxidative damage leading to degradation of connexin proteins. These changes clearly lead to compromise of intracellular homeostasis and may be a causal factor in age-related nuclear cataracts. PMID- 24065811 TI - Imaging microscopic pigment chemistry in conjunctival melanocytic lesions using pump-probe laser microscopy. AB - PURPOSE: To report the application of a novel imaging technique, pump-probe microscopy, to analyze patterns of pigment chemistry of conjunctival melanocytic lesion biopsies. METHODS: Histopathologic specimens of eight previously excised conjunctival melanocytic lesions were analyzed with pump-probe microscopy. The technique uses a laser scanning microscope with a two-color pulsed laser source to distinguish hemoglobin, eumelanin, and pheomelanin pigment based on differences in transient excited state and ground state photodynamics. The pump probe signatures of conjunctival melanins were compared with cutaneous melanins. The distributions of hemoglobin, eumelanin, and pheomelanin were analyzed, and pump-probe images were correlated with adjacent hematoxylin and eosin (H&E) stained sections. RESULTS: The pump-probe signatures of conjunctival melanins are similar, but not identical to cutaneous melanins. In addition, there are qualitative and quantitative differences in the structure and pigment chemistry of conjunctival benign nevi, primary acquired melanosis of the conjunctiva (PAM), and conjunctival melanomas. The pump-probe images correlated well with histopathologic features observed in the adjacent H&E-stained sections, and provided a label-free means of discerning conjunctival anatomic features and pathologic benign or malignant tissue. CONCLUSIONS: Pump-probe laser microscopy shows promise as an adjuvant diagnostic tool in evaluation of ocular melanocytic lesions based on morphologic correlation with the histopathology results and pigment chemistry. This initial study suggests systematic differences in pigmentation patterns among conjunctival benign nevi, primary acquired melanosis, and melanomas. In addition, pump-probe microscopy has the potential for use as a noninvasive "in vivo" optical biopsy technique to aid clinical and surgical management of conjunctival melanocytic lesions. PMID- 24065812 TI - Suppression of IL-22-producing T helper 22 cells by RPE cells via PD-L1/PD-1 interactions. AB - PURPOSE: To determine whether RPE cells can suppress a novel T helper subset, the Th22 cells, via costimulatory interactions. METHODS: Primary RPE cells were established from normal C57BL/6 mice. The target CD4(+) Th22 cells from spleen cells in wild-type control or knockout donors were used. T cell activation was assessed by examining BrdU incorporation (proliferation) and cytokine production. Expression of costimulatory molecules on RPE cells and expression of costimulatory receptors on target Th22 cells were evaluated by flow cytometry. Neutralizing antibodies were used to abolish the suppression function. In addition, human RPE cells and target Th22 cells induced from human CD4(+) cells were also used in similar experiments. RESULTS: Cultured RPE cells significantly suppressed activation of target Th22 cells (e.g., T cell proliferation and IL-22 production). Moreover, human RPE cells suppressed Th22 cell lines and T cell clones established from active uveitis patients. Although cultured RPE cells expressed various costimulatory molecules including programmed cell death 1 ligand 1 (PD-L1), only PD-L1 on the RPE cells was actually delivered to the target Th22 cells. Th22 cells greatly express programmed cell death 1 (PD-1), and RPE cells failed to suppress IL-22 expression by target Th22 cells from PD-1 knockout donors. In addition, if neutralizing antibodies for PD-L1 were cocultured with RPE cells, Th22 suppression was impaired. CONCLUSIONS: RPE cells express PD-L1 costimulatory molecules and suppress bystander Th22-type PD-1(+) bystander T cells through negative costimulatory interactions. PMID- 24065813 TI - Prevalence and risk factors for diabetic retinopathy: the Korea National Health and Nutrition Examination Survey 2008-2011. AB - PURPOSE: We evaluated the prevalence and risk factors for diabetic retinopathy (DR) in a representative Korean population. METHODS: This cross-sectional study involved 16,109 subjects aged >40 years who had participated in the Korean National Health and Nutrition Survey from 2008 to 2011. Seven standard retinal fundus photographs were obtained after pupil dilatation from both eyes. The DR was graded using the modified Airlie House classification system. Risk factors for DR and vision-threatening diabetic retinopathy (VTDR) were evaluated, including age, sex, diabetes duration, glycated hemoglobin (HbA1c), hypertension, lipid profiles, and refractive error. RESULTS: Of the 16,109 eligible individuals participating in the study, 14,595 (90.6%) had fasting blood glucose results available. Of these, 2023 (13.8%) were diagnosed with diabetes mellitus. Among these, gradable photographs were available for 1678 subjects (82.9%), including 1323 subjects with known diabetes mellitus (KDM) and 355 with newly diagnosed diabetes mellitus (NDM). The prevalences of any DR and VTDR were 15.8% (95% confidence interval [CI], 14.1-17.5), and 4.6% (95% CI, 3.6-5.6), respectively. Any DR was associated with a longer duration of diabetes (odds ratio [OR], 1.08; 95% CI, 1.06-1.10), higher HbA1C level (OR, 1.52; 95% CI, 1.28-1.80), higher systolic blood pressure (OR, 1.02; 95% CI, 1.01-1.03), and lower body mass index (OR, 0.91; 95% CI, 0.87-0.96) in a multivariate analysis. CONCLUSIONS: We provide data on the prevalence and risk factors for DR in a representative Korean population. The prevalence of any DR and VTDR in the Korean population was lower than that reported previously. The condition of DR was associated with a longer duration of diabetes, poor glycemic control, and higher systemic blood pressure. PMID- 24065814 TI - MicroRNA signature in wound healing following excimer laser ablation: role of miR 133b on TGFbeta1, CTGF, SMA, and COL1A1 expression levels in rabbit corneal fibroblasts. AB - PURPOSE: The role of microRNA (miRNA) regulation in corneal wound healing and scar formation has yet to be elucidated. This study analyzed the miRNA expression pattern involved in corneal wound healing and focused on the effect of miR-133b on expression of several profibrotic genes. METHODS: Laser-ablated mouse corneas were collected at 0 and 30 minutes and 2 days. Ribonucleic acid was collected from corneas and analyzed using cell differentiation and development miRNA PCR arrays. Luciferase assay was used to determine whether miR-133b targeted the 3' untranslated region (UTR) of transforming growth factor beta1 (TGFbeta1) and connective tissue growth factor (CTGF) in rabbit corneal fibroblasts (RbCF). Quantitative real-time PCR (qRT-PCR) and Western blots were used to determine the effect of miR-133b on CTGF, smooth muscle actin (SMA), and collagen (COL1A1) in RbCF. Migration assay was used to determine the effect of miR-133b on RbCF migration. RESULTS: At day 2, 37 of 86 miRNAs had substantial expression fold changes. miR-133b had the greatest fold decrease at -14.33. Pre-miR-133b targeted the 3' UTR of CTGF and caused a significant decrease of 38% (P < 0.01). Transforming growth factor beta1-treated RbCF had a significant decrease of miR 133b of 49% (P < 0.01), whereas CTGF, SMA, and COL1A1 had significant increases of 20%, 54%, and 37% (P < 0.01), respectively. The RbCF treated with TGFbeta1 and pre-miR133b showed significant decreases in expression of CTGF, SMA, and COL1A1 of 30%, 37%, and 28% (P < 0.01), respectively. Finally, there was significant decrease in migration of miR-133b-treated RbCF. CONCLUSIONS: Significant changes occur in key miRNAs during early corneal wound healing, suggesting novel miRNA targets to reduce scar formation. PMID- 24065815 TI - Choroidal volume variations during childhood. AB - PURPOSE: We analyzed choroidal volume (CV) variations during childhood using enhanced depth imaging optical coherence tomography, and evaluated its association with age, axial length (AXL), sex, weight, and height. METHODS: Imaging studies of the right eyes of 52 healthy children were reviewed and included in this study. Subjects underwent a complete ocular examination and AXL measurement, as well as a raster macular scan using the Heidelberg Spectralis device. The choroid was segmented manually. RESULTS: Subjects included 21 males and 31 females, with mean age of 9 years (range, 2-17 years) and mean AXL of 22.8 +/- 0.98 mm. Mean CV was 0.263 +/- 0.068 mm(3) for the foveal circle and 8.545 +/ 1.822 mm(3) for the total Early Treatment of Diabetic Retinopathy Study (ETDRS) grid. The CV of the nasal quadrant was significantly lower than all others (P < 0.001). Total and foveal CV showed significant negative correlation with AXL after adjustment for age (P < 0.001), and significant positive correlation with age after adjustment for AXL (P < 0.001). Total CV was correlated significantly with sex after adjusting for AXL (P = 0.01), while no correlations were found between total CV and height or weight. The CV increased by 0.214 mm(3) (2.5%) for every year, and decreased by 1.0 mm(3) (11.7%) for every millimeter of axial length. Regression analysis confirmed a trend of higher CV in females than in males (P = 0.056). CONCLUSIONS: The CV increases with age during childhood, but decreases with AXL. This finding supports the hypothesis that the choroid grows progressively during childhood. Intersexual differences of CV also may be present. PMID- 24065816 TI - Variation in the interaction between alleles of HvAPETALA2 and microRNA172 determines the density of grains on the barley inflorescence. AB - Within the cereal grasses, variation in inflorescence architecture results in a conspicuous morphological diversity that in crop species influences the yield of cereal grains. Although significant progress has been made in identifying some of the genes underlying this variation in maize and rice, in the temperate cereals, a group that includes wheat, barley, and rye, only the dosage-dependent and highly pleiotropic Q locus in hexaploid wheat has been molecularly characterized. Here we show that the characteristic variation in the density of grains along the inflorescence, or spike, of modern cultivated barley (Hordeum vulgare) is largely the consequence of a perturbed interaction between microRNA172 and its corresponding binding site in the mRNA of an APELATA2 (AP2)-like transcription factor, HvAP2. We used genome-wide association and biparental mapping to identify HvAP2. By comparing inflorescence development and HvAP2 transcript abundance in an extreme dense-spike mutant and its nearly isogenic WT line, we show that HvAP2 turnover driven by microRNA 172 regulates the length of a critical developmental window that is required for elongation of the inflorescence internodes. Our data indicate that this heterochronic change, an altered timing of developmental events caused by specific temporal variation in the efficiency of HvAP2 turnover, leads to the striking differences in the size and shape of the barley spike. PMID- 24065817 TI - Self-organized optical device driven by motor proteins. AB - Protein molecules produce diverse functions according to their combination and arrangement as is evident in a living cell. Therefore, they have a great potential for application in future devices. However, it is currently very difficult to construct systems in which a large number of different protein molecules work cooperatively. As an approach to this challenge, we arranged protein molecules in artificial microstructures and assembled an optical device inspired by a molecular system of a fish melanophore. We prepared arrays of cell like microchambers, each of which contained a scaffold of microtubule seeds at the center. By polymerizing tubulin from the fixed microtubule seeds, we obtained radially arranged microtubules in the chambers. We subsequently prepared pigment granules associated with dynein motors and attached them to the radial microtubule arrays, which made a melanophore-like system. When ATP was added to the system, the color patterns of the chamber successfully changed, due to active transportation of pigments. Furthermore, as an application of the system, image formation on the array of the optical units was performed. This study demonstrates that a properly designed microstructure facilitates arrangement and self-organization of molecules and enables assembly of functional molecular systems. PMID- 24065818 TI - Crystalline polymorphism induced by charge regulation in ionic membranes. AB - The crystallization of molecules with polar and hydrophobic groups, such as ionic amphiphiles and proteins, is of paramount importance in biology and biotechnology. By coassembling dilysine (+2) and carboxylate (-1) amphiphiles of various tail lengths into bilayer membranes at different pH values, we show that the 2D crystallization process in amphiphile membranes can be controlled by modifying the competition of long-range and short-range interactions among the polar and the hydrophobic groups. The pH and the hydrophobic tail length modify the intermolecular packing and the symmetry of their crystalline phase. For hydrophobic tail lengths of 14 carbons (C14), we observe the coassembly into crystalline bilayers with hexagonal molecular ordering via in situ small- and wide-angle X-ray scattering. As the tail length increases, the hexagonal lattice spacing decreases due to an increase in van der Waals interactions, as demonstrated by atomistic molecular dynamics simulations. For C16 and C18 we observe a reentrant crystalline phase transition sequence, hexagonal-rectangular C-rectangular-P-rectangular-C-hexagonal, as the solution pH is increased from 3 to 10.5. The stability of the rectangular phases, which maximize tail packing, increases with increasing tail length. As a result, for very long tails (C22), the possibility of observing packing symmetries other than rectangular-C phases diminishes. Our work demonstrates that it is possible to systematically exchange chemical and mechanical energy by changing the solution pH value within a range of physiological conditions at room temperature in bilayers of molecules with ionizable groups. PMID- 24065819 TI - Forecasting fisheries collapse. PMID- 24065820 TI - Structural insight on the recognition of surface-bound opsonins by the integrin I domain of complement receptor 3. AB - Complement receptors (CRs), expressed notably on myeloid and lymphoid cells, play an essential function in the elimination of complement-opsonized pathogens and apoptotic/necrotic cells. In addition, these receptors are crucial for the cross talk between the innate and adaptive branches of the immune system. CR3 (also known as Mac-1, integrin alphaMbeta2, or CD11b/CD18) is expressed on all macrophages and recognizes iC3b on complement-opsonized objects, enabling their phagocytosis. We demonstrate that the C3d moiety of iC3b harbors the binding site for the CR3 alphaI domain, and our structure of the C3d:alphaI domain complex rationalizes the CR3 selectivity for iC3b. Based on extensive structural analysis, we suggest that the choice between a ligand glutamate or aspartate for coordination of a receptor metal ion-dependent adhesion site-bound metal ion is governed by the secondary structure of the ligand. Comparison of our structure to the CR2:C3d complex and the in vitro formation of a stable CR3:C3d:CR2 complex suggests a molecular mechanism for the hand-over of CR3-bound immune complexes from macrophages to CR2-presenting cells in lymph nodes. PMID- 24065821 TI - Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients. AB - Circulating tumor cells (CTCs) are promising biomarkers for diagnosis and therapy in systemic cancer. However, their infrequent and unreliable detection, especially in nonmetastatic cancer, currently impedes the clinical use of CTCs. Because leukapheresis (LA) targets peripheral blood mononuclear cells, which have a similar density to CTCs, and usually involves processing the whole circulating blood, we tested whether LA could substantially increase CTC detection in operable cancer patients. Therefore, we screened LA products generated from up to 25 L of blood per patient in two independent studies, and found that CTCs can be detected in more than 90% of nonmetastatic breast cancer patients. Interestingly, complete white blood cell sampling enabled determining an upper level for total CTC numbers of about 100,000 cells (median, 7,500 CTCs) per patient and identified a correlation of CTC numbers with anatomic disease spread. We further show that diagnostic leukapheresis can be easily combined with the US Food and Drug Administration-approved CellSearch system for standardized enumeration of CTCs. Direct comparison with 7.5 mL of blood revealed a significantly higher CTC frequency in matched LA samples. Finally, genomic single-cell profiling disclosed highly aberrant CTCs as therapy-escaping variants in breast cancer. In conclusion, LA is a clinically safe method that enabled a reliable detection of CTCs at high frequency even in nonmetastatic cancer patients, and might facilitate the routine clinical use of CTCs as in the sense of a liquid biopsy. Combined with technologies for single-cell molecular genetics or cell biology, it may significantly improve prediction of therapy response and monitoring of early systemic cancer. PMID- 24065822 TI - Unraveling the role of protein dynamics in dihydrofolate reductase catalysis. AB - Protein dynamics have controversially been proposed to be at the heart of enzyme catalysis, but identification and analysis of dynamical effects in enzyme catalyzed reactions have proved very challenging. Here, we tackle this question by comparing an enzyme with its heavy ((15)N, (13)C, (2)H substituted) counterpart, providing a subtle probe of dynamics. The crucial hydride transfer step of the reaction (the chemical step) occurs more slowly in the heavy enzyme. A combination of experimental results, quantum mechanics/molecular mechanics simulations, and theoretical analyses identify the origins of the observed differences in reactivity. The generally slightly slower reaction in the heavy enzyme reflects differences in environmental coupling to the hydride transfer step. Importantly, the barrier and contribution of quantum tunneling are not affected, indicating no significant role for "promoting motions" in driving tunneling or modulating the barrier. The chemical step is slower in the heavy enzyme because protein motions coupled to the reaction coordinate are slower. The fact that the heavy enzyme is only slightly less active than its light counterpart shows that protein dynamics have a small, but measurable, effect on the chemical reaction rate. PMID- 24065823 TI - Size homeostasis in adherent cells studied by synthetic phase microscopy. AB - The coupling of the rate of cell growth to the rate of cell division determines cell size, a defining characteristic that is central to cell function and, ultimately, to tissue architecture. The physiology of size homeostasis has fascinated generations of biologists, but the mechanism, challenged by experimental limitations, remains largely unknown. In this paper, we propose a unique optical method that can measure the dry mass of thick live cells as accurately as that for thin cells with high computational efficiency. With this technique, we quantify, with unprecedented accuracy, the asymmetry of division in lymphoblasts and epithelial cells. We can then use the Collins-Richmond model of conservation to compute the relationship between growth rate and cell mass. In attached epithelial cells, we find that due to the asymmetry in cell division and size-dependent growth rate, there is active regulation of cell size. Thus, like nonadherent cells, size homeostasis requires feedback control. PMID- 24065824 TI - Multiple origins of pyrethroid insecticide resistance across the species complex of a nontarget aquatic crustacean, Hyalella azteca. AB - Use of pesticides can have substantial nonlethal impacts on nontarget species, including driving evolutionary change, often with unknown consequences for species, ecosystems, and society. Hyalella azteca, a species complex of North American freshwater amphipods, is widely used for toxicity testing of water and sediment and has frequently shown toxicity due to pyrethroid pesticides. We demonstrate that 10 populations, 3 from laboratory cultures and 7 from California water bodies, differed by at least 550-fold in sensitivity to pyrethroids. The populations sorted into four phylogenetic groups consistent with species-level divergence. By sequencing the primary pyrethroid target site, the voltage-gated sodium channel, we show that point mutations and their spread in natural populations were responsible for differences in pyrethroid sensitivity. At least one population had both mutant and WT alleles, suggesting ongoing evolution of resistance. Although nonresistant H. azteca were susceptible to the typical neurotoxic effects of pyrethroids, gene expression analysis suggests the mode of action in resistant H. azteca was not neurotoxicity but was oxidative stress sustained only at considerably higher pyrethroid concentrations. The finding that a nontarget aquatic species has acquired resistance to pesticides used only on terrestrial pests is troubling evidence of the impact of chronic pesticide transport from land-based applications into aquatic systems. Our findings have far-reaching implications for continued uncritical use of H. azteca as a principal species for monitoring and environmental policy decisions. PMID- 24065825 TI - Intraislet SLIT-ROBO signaling is required for beta-cell survival and potentiates insulin secretion. AB - We previously cataloged putative autocrine/paracrine signaling loops in pancreatic islets, including factors best known for their roles in axon guidance. Emerging evidence points to nonneuronal roles for these factors, including the Slit-Roundabout receptor (Robo) family, in cell growth, migration, and survival. We found SLIT1 and SLIT3 in both beta cells and alpha cells, whereas SLIT2 was predominantly expressed in beta cells. ROBO1 and ROBO2 receptors were detected in beta and alpha cells. Remarkably, even modest knockdown of Slit production resulted in significant beta-cell death, demonstrating a critical autocrine/paracrine survival role for this pathway. Indeed, recombinant SLIT1, SLIT2, and SLIT3 decreased serum deprivation, cytokine, and thapsigargin-induced cell death under hyperglycemic conditions. SLIT treatment also induced a gradual release of endoplasmic reticulum luminal Ca(2+), suggesting a unique molecular mechanism capable of protecting beta cells from endoplasmic reticulum stress induced apoptosis. SLIT treatment was also associated with rapid actin remodeling. SLITs potentiated glucose-stimulated insulin secretion and increased the frequency of glucose-induced Ca(2+) oscillations. These observations point to unexpected roles for local Slit secretion in the survival and function of pancreatic beta cells. Because diabetes results from a deficiency in functional beta-cell mass, these studies may contribute to therapeutic approaches for improving beta-cell survival and function. PMID- 24065826 TI - Pax7 is critical for the normal function of satellite cells in adult skeletal muscle. AB - Extensive analyses of mice carrying null mutations in paired box 7 (Pax7) have confirmed the progressive loss of the satellite cell lineage in skeletal muscle, resulting in severe muscle atrophy and death. A recent study using floxed alleles and tamoxifen-induced inactivation concluded that after 3 wk of age, Pax7 was entirely dispensable for satellite cell function. Here, we demonstrate that Pax7 is an absolute requirement for satellite cell function in adult skeletal muscle. Following Pax7 deletion, satellite cells and myoblasts exhibit cell-cycle arrest and dysregulation of myogenic regulatory factors. Maintenance of Pax7 deletion through continuous tamoxifen administration prevented regrowth of Pax7-expressing satellite cells and a profound muscle regeneration deficit that resembles the phenotype of skeletal muscle following genetically engineered ablation of satellite cells. Therefore, we conclude that Pax7 is essential for regulating the expansion and differentiation of satellite cells during both neonatal and adult myogenesis. PMID- 24065827 TI - Irx3 and Pax6 establish differential competence for Shh-mediated induction of GABAergic and glutamatergic neurons of the thalamus. AB - During embryonic development, the presumptive GABAergic rostral thalamus (rTh) and glutamatergic caudal thalamus (cTh) are induced by Sonic hedgehog (Shh) signaling from the zona limitans intrathalamica (ZLI) at the rostral border of the thalamic primordium. We found that these inductions are limited to the neuroepithelium between the ZLI and the forebrain-midbrain boundary, suggesting a prepattern that limits thalamic competence. We hypothesized that this prepattern is established by the overlapping expression of two transcription factors: Iroquois-related homeobox gene 3 (Irx3) posterior to the ZLI, and paired box gene 6 (Pax6) anterior to the forebrain-midbrain boundary. Consistent with this assumption, we show that misexpression of Irx3 in the prethalamus or telencephalon results in ectopic induction of thalamic markers in response to Shh, that it functions as a transcriptional repressor in this context, and that antagonizing its function in the diencephalon attenuates thalamic specification. Similarly, misexpression of Pax6 in the midbrain together with Shh pathway activation results in ectopic induction of cTh markers in clusters of cells that fail to integrate into tectal layers and of atypical long-range projections, whereas antagonizing Pax6 function in the thalamus disrupts cTh formation. However, rTh markers are negatively regulated by Pax6, which itself is down regulated by Shh from the ZLI in this area. Our results demonstrate that the combinatorial expression of Irx3 and Pax6 endows cells with the competence for cTh formation, whereas Shh-mediated down-regulation of Pax6 is required for rTh formation. Thus, thalamus induction and patterning depends both on a prepattern of Irx3 and Pax6 expression that establishes differential cellular competence and on Shh signaling from the ZLI organizer. PMID- 24065828 TI - Sensitivity-enhanced solid-state NMR detection of expansin's target in plant cell walls. AB - Structure determination of protein binding to noncrystalline macromolecular assemblies such as plant cell walls (CWs) poses a significant structural biology challenge. CWs are loosened during growth by expansin proteins, which weaken the noncovalent network formed by cellulose, hemicellulose, and pectins, but the CW target of expansins has remained elusive because of the minute amount of the protein required for activity and the complex nature of the CW. Using solid-state NMR spectroscopy, combined with sensitivity-enhancing dynamic nuclear polarization (DNP) and differential isotopic labeling of expansin and polysaccharides, we have now determined the functional binding target of expansin in the Arabidopsis thaliana CW. By transferring the electron polarization of a biradical dopant to the nuclei, DNP allowed selective detection of (13)C spin diffusion from trace concentrations of (13)C, (15)N-labeled expansin in the CW to nearby polysaccharides. From the spin diffusion data of wild-type and mutant expansins, we conclude that to loosen the CW, expansin binds highly specific cellulose domains enriched in xyloglucan, whereas more abundant binding to pectins is unrelated to activity. Molecular dynamics simulations indicate short (13)C-(13)C distances of 4-6 A between a hydrophobic surface of the cellulose microfibril and an aromatic motif on the expansin surface, consistent with the observed NMR signals. DNP-enhanced 2D (13)C correlation spectra further reveal that the expansin-bound cellulose has altered conformation and is enriched in xyloglucan, thus providing unique insight into the mechanism of CW loosening. DNP enhanced NMR provides a powerful, generalizable approach for investigating protein binding to complex macromolecular targets. PMID- 24065829 TI - Cell-sized liposomes reveal how actomyosin cortical tension drives shape change. AB - Animal cells actively generate contractile stress in the actin cortex, a thin actin network beneath the cell membrane, to facilitate shape changes during processes like cytokinesis and motility. On the microscopic scale, this stress is generated by myosin molecular motors, which bind to actin cytoskeletal filaments and use chemical energy to exert pulling forces. To decipher the physical basis for the regulation of cell shape changes, here, we use a cell-like system with a cortex anchored to the outside or inside of a liposome membrane. This system enables us to dissect the interplay between motor pulling forces, cortex-membrane anchoring, and network connectivity. We show that cortices on the outside of liposomes either spontaneously rupture and relax built-up mechanical stress by peeling away around the liposome or actively compress and crush the liposome. The decision between peeling and crushing depends on the cortical tension determined by the amount of motors and also on the connectivity of the cortex and its attachment to the membrane. Membrane anchoring strongly affects the morphology of cortex contraction inside liposomes: cortices contract inward when weakly attached, whereas they contract toward the membrane when strongly attached. We propose a physical model based on a balance of active tension and mechanical resistance to rupture. Our findings show how membrane attachment and network connectivity are able to regulate actin cortex remodeling and membrane-shape changes for cell polarization. PMID- 24065830 TI - Adult and larval traits as determinants of geographic range size among tropical reef fishes. AB - Most marine organisms disperse via ocean currents as larvae, so it is often assumed that larval-stage duration is the primary determinant of geographic range size. However, empirical tests of this relationship have yielded mixed results, and alternative hypotheses have rarely been considered. Here we assess the relative influence of adult and larval-traits on geographic range size using a global dataset encompassing 590 species of tropical reef fishes in 47 families, the largest compilation of such data to date for any marine group. We analyze this database using linear mixed-effect models to control for phylogeny and geographical limits on range size. Our analysis indicates that three adult traits likely to affect the capacity of new colonizers to survive and establish reproductive populations (body size, schooling behavior, and nocturnal activity) are equal or better predictors of geographic range size than pelagic larval duration. We conclude that adult life-history traits that affect the postdispersal persistence of new populations are primary determinants of successful range extension and, consequently, of geographic range size among tropical reef fishes. PMID- 24065832 TI - Relationship between dynamical entropy and energy dissipation far from thermodynamic equilibrium. AB - Connections between microscopic dynamical observables and macroscopic nonequilibrium (NE) properties have been pursued in statistical physics since Boltzmann, Gibbs, and Maxwell. The simulations we describe here establish a relationship between the Kolmogorov-Sinai entropy and the energy dissipated as heat from a NE system to its environment. First, we show that the Kolmogorov Sinai or dynamical entropy can be separated into system and bath components and that the entropy of the system characterizes the dynamics of energy dissipation. Second, we find that the average change in the system dynamical entropy is linearly related to the average change in the energy dissipated to the bath. The constant energy and time scales of the bath fix the dynamical relationship between these two quantities. These results provide a link between microscopic dynamical variables and the macroscopic energetics of NE processes. PMID- 24065833 TI - A dual host vector for Fab phage display and expression of native IgG in mammalian cells. AB - A significant bottleneck in antibody discovery by phage display is the transfer of immunoglobulin variable regions from phage clones to vectors that express immunoglobulin G (IgG) in mammalian cells for screening. Here, we describe a novel phagemid vector for Fab phage display that allows expression of native IgG in mammalian cells without sub-cloning. The vector uses an optimized mammalian signal sequence that drives robust expression of Fab fragments fused to an M13 phage coat protein in Escherichia coli and IgG expression in mammalian cells. To allow the expression of Fab fragments fused to a phage coat protein in E.coli and full-length IgG in mammalian cells from the same vector without sub-cloning, the sequence encoding the phage coat protein was embedded in an optimized synthetic intron within the immunoglobulin heavy chain gene. This intron is removed from transcripts in mammalian cells by RNA splicing. Using this vector, we constructed a synthetic Fab phage display library with diversity in the heavy chain only and selected for clones binding different antigens. Co-transfection of mammalian cells with DNA from individual phage clones and a plasmid expressing the invariant light chain resulted in the expression of native IgG that was used to assay affinity, ligand blocking activity and specificity. PMID- 24065831 TI - Shear stress triggers insertion of voltage-gated potassium channels from intracellular compartments in atrial myocytes. AB - Atrial myocytes are continuously exposed to mechanical forces including shear stress. However, in atrial myocytes, the effects of shear stress are poorly understood, particularly with respect to its effect on ion channel function. Here, we report that shear stress activated a large outward current from rat atrial myocytes, with a parallel decrease in action potential duration. The main ion channel underlying the increase in current was found to be Kv1.5, the recruitment of which could be directly observed by total internal reflection fluorescence microscopy, in response to shear stress. The effect was primarily attributable to recruitment of intracellular pools of Kv1.5 to the sarcolemma, as the response was prevented by the SNARE protein inhibitor N-ethylmaleimide and the calcium chelator BAPTA. The process required integrin signaling through focal adhesion kinase and relied on an intact microtubule system. Furthermore, in a rat model of chronic hemodynamic overload, myocytes showed an increase in basal current despite a decrease in Kv1.5 protein expression, with a reduced response to shear stress. Additionally, integrin beta1d expression and focal adhesion kinase activation were increased in this model. This data suggests that, under conditions of chronically increased mechanical stress, the integrin signaling pathway is overactivated, leading to increased functional Kv1.5 at the membrane and reducing the capacity of cells to further respond to mechanical challenge. Thus, pools of Kv1.5 may comprise an inducible reservoir that can facilitate the repolarization of the atrium under conditions of excessive mechanical stress. PMID- 24065834 TI - Directed evolution to enhance thermostability of galacto-N-biose/lacto-N-biose I phosphorylase. AB - Galacto-N-biose/lacto-N-biose I phosphorylase (GLNBP) is the key enzyme in the enzymatic production of lacto-N-biose I. For the purpose of industrial use, we improved the thermostability of GLNBP by evolutionary engineering in which five substitutions in the amino acid sequence were selected from a random mutagenesis GLNBP library constructed using error-prone polymerase chain reaction. Among them, C236Y and D576V mutants showed considerably improved thermostability. Structural analysis of C236Y revealed that the hydroxyl group of Tyr236 forms a hydrogen bond with the carboxyl group of E319. The C236Y and D576V mutations together contributed to the thermostability. The C236Y/D576V mutant exhibited 20 degrees C higher thermostability than the wild type. PMID- 24065835 TI - Generalized calcinosis in systemic sclerosis. PMID- 24065836 TI - Is coagulopathy a contraindication for thromboprophylaxis? PMID- 24065837 TI - Complexities of HCV management in the new era of direct-acting antiviral agents. AB - The availability of the direct-acting antiviral agents (DAAs) boceprevir and telaprevir provides improved treatment outcomes for many patients infected with hepatitis C virus (HCV) genotype 1. However, HCV infection must first be identified before a decision on treatment can be made and currently many patients remain unaware that they have the virus. Given the lack of prompt diagnosis, disease severity should be determined as a baseline reference for treatment, and novel non-invasive techniques for evaluating fibrosis are now available. For patients receiving a DAA regimen, response-guided therapy based on the detection, absence or level of HCV RNA at specified time points is required to achieve an optimal treatment outcome. Knowledge of the test used to measure HCV RNA and its analytical sensitivity, as well as how to interpret the results correctly, are therefore required to administer therapy appropriately. Furthermore, effective treatment management includes appropriate handling of side effects. This increased complexity associated with DAA regimens has resulted in confusion over many aspects of care, including treatment monitoring, viral load result interpretation and the optimal duration of therapy. These issues are discussed here in addition to the benefits of referring patients infected with HCV to a specialist centre. PMID- 24065839 TI - Gestational diabetes mellitus: to screen or not to screen?: Is this really still a question? PMID- 24065840 TI - Diagnosing gestational diabetes mellitus: rationed or rationally related to risk? PMID- 24065841 TI - Antidepressant medication as a risk factor for type 2 diabetes and impaired glucose regulation: systematic review. AB - OBJECTIVE: Antidepressant use has risen sharply over recent years. Recent concerns that antidepressants may adversely affect glucose metabolism require investigation. Our aim was to assess the risk of type 2 diabetes associated with antidepressants through a systematic review. RESEARCH DESIGN AND METHODS: Data sources were MEDLINE, Embase, PsycINFO, The Cochrane Library, Web of Science, meeting abstracts of the European Association for the Study of Diabetes, American Diabetes Association, and Diabetes UK, Current Controlled Trials, ClinicalTrials.gov, U.K. Clinical Research Network, scrutiny of bibliographies of retrieved articles, and contact with relevant experts. Relevant studies of antidepressant effects were included. Key outcomes were diabetes incidence and change in blood glucose (fasting and random). RESULTS: Three systemic reviews and 22 studies met the inclusion criteria. Research designs included 1 case series and 21 observational studies comprising 4 cross-sectional, 5 case-control, and 12 cohort studies. There was evidence that antidepressant use is associated with type 2 diabetes. Causality is not established, but rather, the picture is confused, with some antidepressants linked to worsening glucose control, particularly with higher doses and longer duration, others linked with improved control, and yet more with mixed results. The more recent, larger studies, however, suggest a modest effect. Study quality was variable. CONCLUSIONS: Although evidence exists that antidepressant use may be an independent risk factor for type 2 diabetes, long-term prospective studies of the effects of individual antidepressants rather than class effects are required. Heightened alertness to potential risks is necessary until these are complete. PMID- 24065842 TI - Secretion of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes: systematic review and meta-analysis of clinical studies. AB - OBJECTIVE: To investigate glucose-dependent insulinotropic polypeptide (GIP) secretion in patients with type 2 diabetes and nondiabetic control subjects during oral glucose or meal tests. RESEARCH DESIGN AND METHODS: Eligible trials were identified by The Cochrane Library, MEDLINE, Embase, and Web of Science. Data were retrieved and random-effects models for the primary meta-analysis, random-effects meta-regression, and subgroup and regression analyses were applied. RESULTS: Random-effects meta-analysis of GIP responses in 23 trials during 28 different stimulation tests showed that patients with type 2 diabetes (n=363) exhibited no significant differences (P=not significant) in peak plasma GIP, total area under the curve (tAUC), time-corrected tAUC (tAUC*min(-1)), and time-corrected incremental area under the curve (iAUC*min(-1)) in comparison with nondiabetic control subjects (n=325) but had lower GIP responses as evaluated from iAUC (weighted mean difference, -648 pmol/L*min; 95% CI, -1,276 to -21). Fixed-effects models meta-analyses confirmed most of the results of the primary meta-analysis but showed iAUC*min(-1) to be reduced and showed tAUC and tAUC*min( 1) to be higher in diabetic patients. Random-effects meta-regression of the primary meta-analysis showed that age (peak GIP, tAUC, iAUC, and iAUC*min(-1)), BMI (tAUC, iAUC, and iAUC*min(-1)), and HbA1c (iAUC and iAUC*min(-1)) predicted some of the GIP outcomes. Post hoc subgroup analysis showed a negative influence of age and of HbA1c on GIP responses and showed a positive influence of BMI on GIP responses. CONCLUSIONS: Our results suggest that patients with type 2 diabetes are characterized by preserved GIP secretion in response to oral glucose and meal tests. They also suggest that high BMI is associated with increased GIP responses but increasing age and HbA1c are associated with reduced GIP secretion. PMID- 24065843 TI - Sleep-disordered breathing and gestational diabetes mellitus: a meta-analysis of 9,795 participants enrolled in epidemiological observational studies. AB - OBJECTIVE: Recently, sleep-disordered breathing (SDB) has been reported to be associated with the development of gestational diabetes mellitus (GDM). Accordingly, as this is emergent area of research that has significant clinical relevance, the objective of this meta-analysis is to examine the relationship between SDB with GDM. RESEARCH DESIGN AND METHODS: We searched several electronic databases for all of the studies published before January 2013 and reviewed references of published articles. Meta-analytic procedures were used to estimate the unadjusted and BMI-adjusted odds ratios (ORs) using a random effects model. Significant values, weighted effect sizes, and 95% CIs were calculated, and tests of homogeneity of variance were performed. RESULTS: Results from nine independent studies with a total of 9,795 pregnant women showed that SDB was significantly associated with an increased risk of GDM. Women with SDB had a more than threefold increased risk of GDM, with a pooled BMI-adjusted OR 3.06 (95% CI 1.89 4.96). CONCLUSIONS: These findings demonstrate a significant association between SDB and GDM that is evident even after considered confounding by obesity. This meta-analysis indicates a need to evaluate the role of early recognition and treatment of SDB early during pregnancy. PMID- 24065844 TI - Validity of meta-analysis in diabetes: we need to be aware of its limitations. PMID- 24065845 TI - Validity of meta-analysis in diabetes: meta-analysis is an indispensable tool in evidence synthesis. PMID- 24065847 TI - Twizzlers as a cost-effective and equivalent alternative to the glucola beverage in diabetes screening. PMID- 24065848 TI - Coadministration of liraglutide with tacrolimus in kidney transplant recipients: a case series. PMID- 24065849 TI - Pharmacokinetics of insulin aspart in pump-treated subjects with type 1 diabetes: reproducibility and effect of age, weight, and duration of diabetes. PMID- 24065850 TI - Cyclical variation in HbA1c values during the year: clinical and research implications. PMID- 24065851 TI - Blood glucose responses to type, intensity, duration, and timing of exercise. PMID- 24065852 TI - Functional and metabolic imaging of the cardiovascular system in young healthy South Asians and Caucasians unveils early differences. PMID- 24065853 TI - Comment on: the ORIGIN Trial Investigators. Characteristics associated with maintenance of mean A1C<6.5% in people with dysglycemia in the ORIGIN trial. Diabetes Care 2013;36:2915-2922. PMID- 24065854 TI - Response to Comment on: The ORIGIN Trial Investigators. Characteristics Associated With Maintenance of Mean A1C <6.5% in People With Dysglycemia in the ORIGIN Trial. Diabetes Care 2013;36:2915-2922. PMID- 24065855 TI - Comment on: Chakkera et al. Can new-onset diabetes after kidney transplant be prevented? Diabetes Care 2013;36:1406-1412. PMID- 24065856 TI - Response to Comment on: Chakkera et al. Can New-Onset Diabetes After Kidney Transplant Be Prevented? Diabetes Care 2013;36:1406-1412. PMID- 24065857 TI - Comment on: Lin et al. Long-term changes in adiposity and glycemic control are associated with past adenovirus infection. Diabetes Care 2013;36:701-707. PMID- 24065858 TI - Comment on: Tran et al. Early prediction of gestational diabetes mellitus in Vietnam: clinical impact of currently recommended diagnostic criteria. Diabetes Care 2013;36:618-624. PMID- 24065859 TI - Comment on: Tsiakou et al. Arterial stiffness is inversely related to plasma adiponectin levels in young normotensive patients with type 1 diabetes. Diabetes Care 2013;36:734-736. PMID- 24065860 TI - A perspective on the prediction of drug pharmacokinetics and disposition in drug research and development. AB - Prediction of human pharmacokinetics of new drugs, as well as other disposition attributes, has become a routine practice in drug research and development. Prior to the 1990s, drug disposition science was used in a mostly descriptive manner in the drug development phase. With the advent of in vitro methods and availability of human-derived reagents for in vitro studies, drug-disposition scientists became engaged in the compound design phase of drug discovery to optimize and predict human disposition properties prior to nomination of candidate compounds into the drug development phase. This has reaped benefits in that the attrition rate of new drug candidates in drug development for reasons of unacceptable pharmacokinetics has greatly decreased. Attributes that are predicted include clearance, volume of distribution, half-life, absorption, and drug-drug interactions. In this article, we offer our experience-based perspectives on the tools and methods of predicting human drug disposition using in vitro and animal data. PMID- 24065861 TI - Assessment of the roles of P-glycoprotein and cytochrome P450 in triptolide induced liver toxicity in sandwich-cultured rat hepatocyte model. AB - Triptolide (TP), a main bioactive component of Tripterygium wilfordii Hook F., is a promising agent for treatment of autoimmune diseases. However, a high incidence of dose-limiting hepatotoxicity was observed in the clinic. Sandwich-cultured rat hepatocyte model was used in this study to identify the involvement of P glycoprotein (P-gp) in TP disposition and to evaluate TP-induced hepatotoxicity after modulation of P-gp by the known inhibitors, ritonavir and tariquidar, and known inducers, phenobarbital, quercetin, and H(2)O(2). Our data showed that biliary clearance of TP reduced 73.7% and 84.2% upon treatment of ritonavir (25 uM) and tariquidar (5 uM), respectively. In contrast, increases of 346%, 280%, and 273% in biliary clearance of TP were observed with treatment of phenobarbital (1.0 mM), quercetin (20 uM), and H(2)O(2) (0.5 mM), respectively. The TP-induced hepatotoxicity increased by twofold when CYP activity was blocked by 1 aminobenzotriazole, suggesting that CYP and P-gp may both contribute to the detoxification of TP in the SCRH model. In addition, hepatotoxicity and the expression of apoptosis proteins Bax and Bcl-2 were correlated qualitatively with the TP exposure duration and its intracellular concentration, which, in turn, can be modulated by P-gp inhibitors or inducers. Our results for the first time demonstrated that in addition to CYP-mediated metabolism, P-gp also plays an important role in the disposition of TP and TP-induced hepatotoxicity. Thus, the modulation of canalicular P-gp has a potential to cause drug-drug interaction between TP and the coadministered P-gp inhibitors or inducers in the clinic. PMID- 24065862 TI - Perioperative selective serotonin reuptake inhibitor administration is a marker of poor outcomes after surgery. PMID- 24065863 TI - Estimating the cost-effectiveness of modern screening mammography programmes. PMID- 24065864 TI - Structured-illumination photoacoustic Doppler flowmetry of axial flow in homogeneous scattering media. AB - We propose a method for photoacoustic flow measurement based on the Doppler effect from a flowing homogeneous medium. Excited by spatially modulated laser pulses, the flowing medium induces a Doppler frequency shift in the received photoacoustic signals. The frequency shift is proportional to the component of the flow speed projected onto the acoustic beam axis, and the sign of the shift reflects the flow direction. Unlike conventional flowmetry, this method does not rely on particle heterogeneity in the medium; thus, it can tolerate extremely high particle density. A red-ink phantom flowing in a tube immersed in water was used to validate the method in both the frequency and time domains. The phantom flow immersed in an intralipid solution was also measured. PMID- 24065866 TI - Keeping It Short and Sweet: Brief, Ungraded Writing Assignments Facilitate Learning. AB - Can short, ungraded, free-writing assignments promote learning of course material? We randomly assigned introductory psychology recitation sections (N = 978 students) to writing or thinking conditions. For all sections, teaching assistants presented students with a discussion topic based in current coursework. Students either wrote or thought about the topic for 5 min. All sections then discussed the topic for approximately 10 min. Exams included questions related to the discussion topics. Students in the writing condition attended class more often and performed better on factual and conceptual multiple choice exam questions than students in the thinking condition, even after controlling for measures of student quality. The results suggested that brief free writing improved factual and conceptual learning. PMID- 24065865 TI - Effects of First-Grade Number Knowledge Tutoring With Contrasting Forms of Practice. AB - The purpose of this study was to investigate the effects of 1st-grade number knowledge tutoring with contrasting forms of practice. Tutoring occurred 3 times per week for 16 weeks. In each 30-min session, the major emphasis (25 min) was number knowledge; the other 5 min provided practice in 1 of 2 forms. Nonspeeded practice reinforced relations and principles addressed in number knowledge tutoring. Speeded practice promoted quick responding and use of efficient counting procedures to generate many correct responses. At-risk students were randomly assigned to number knowledge tutoring with speeded practice (n = 195), number knowledge tutoring with nonspeeded practice (n = 190), and control (no tutoring, n = 206). Each tutoring condition produced stronger learning than control on all 4 mathematics outcomes. Speeded practice produced stronger learning than nonspeeded practice on arithmetic and 2-digit calculations, but effects were comparable on number knowledge and word problems. Effects of both practice conditions on arithmetic were partially mediated by increased reliance on retrieval, but only speeded practice helped at-risk children compensate for weak reasoning ability. PMID- 24065867 TI - Understanding Children and Adolescents' Victimizations at Multiple Levels: An Ecological Review of the Literature. AB - This article examines children and adolescent exposure to violence in various contexts. A systematic review of the literature was conducted to identify the definitions and types of violence reported in studies on victimization using the ecological systems framework. Sources included research studies and/or reports from scholarly journals (n = 140), books (n = 9), conference/workshops (n = 5), and web sources, such as Uniform Crime Reports (n = 23). The findings indicated that research differed in terminologies, conceptual and operational definitions, sample sizes and age group classification for children and adolescents. Further, studies lacked focus on the co-occurrence and inter-relatedness of victimization, and how these factors might affect the outcomes. Many studies employed a cross sectional design, which limits strong conclusions about the temporal order of victimization experiences and outcomes. Future research efforts need more consistency among researchers in conceptual and operational definitions and the use of more rigorous designs. Increased holistic assessments are critical for effective prevention and intervention strategies for at-risk children and adolescents. PMID- 24065868 TI - Adults show less sensitivity to phonetic detail in unfamiliar words, too. AB - Young word learners fail to discriminate phonetic contrasts in certain situations, an observation that has been used to support arguments that the nature of lexical representation and lexical processing changes over development. An alternative possibility, however, is that these failures arise naturally as a result of how word familiarity affects lexical processing. In the present work, we explored the effects of word familiarity on adults' use of phonetic detail. Participants' eye movements were monitored as they heard single-segment onset mispronunciations of words drawn from a newly learned artificial lexicon. In Experiment 1, single-feature onset mispronunciations were presented; in Experiment 2, participants heard two-feature onset mispronunciations. Word familiarity was manipulated in both experiments by presenting words with various frequencies during training. Both word familiarity and degree of mismatch affected adults' use of phonetic detail: in their looking behavior, participants did not reliably differentiate single-feature mispronunciations and correct pronunciations of low frequency words. For higher frequency words, participants differentiated both 1- and 2-feature mispronunciations from correct pronunciations. However, responses were graded such that 2-feature mispronunciations had a greater effect on looking behavior. These experiments demonstrate that the use of phonetic detail in adults, as in young children, is affected by word familiarity. Parallels between the two populations suggest continuity in the architecture underlying lexical representation and processing throughout development. PMID- 24065869 TI - Consumption, drugs and style: Constructing intra-ethnic boundaries in Asian American youth cultures. AB - Based on 250 qualitative interviews with Asian American young men and women in the dance/club scenes in the San Francisco area, we examine the interplay between consumption, style and taste cultures with issues of ethnic identity, gender and acculturation. We explore the ways that consumption and taste markers (e.g. fashion, cars, music and drugs) are used to establish or negotiate symbolic boundaries between groups in this youth culture. The picture they paint of the dance scene is one less about cohesiveness and unity and more about divisions and boundaries, not only between but also significantly within ethnic groupings. The choice of drugs and ways of exhibiting intoxication are among the types of consumption that the young people drew upon to mark symbolic boundaries and establish identities. The young men and women in this study discuss a number of key boundaries in the scene, e.g. between FOBs and twinkies, between pretty boys and thugs, as they attempt to establish the cultural legitimacy of their own styles of Asian American identities. PMID- 24065870 TI - Removal of Carbamazepine from Water by a Novel TiO2-Coconut Shell Powder/UV Process: Composite Preparation and Photocatalytic Activity. AB - A novel TiO2-coconut shell powder (TCNSP) composite, prepared by the controlled sol-gel method with a subsequent heat treatment, was investigated as an innovative photocatalytic absorbent for the removal of carbamazepine (CBZ). CBZ is used worldwide as an antiepileptic drug, which has recently been recognized as an important organic pollutant increasingly found in wastewaters from urban areas and other aquatic environments. The granulation process was performed by using a semiautomated mass production line to produce sufficient quantities of TCNSP composites, possessing sufficient crush strength for commercialization. Physical properties of the TCNSP composite such as crystallinity, morphology, crush strength, and the Brunauer-Emmett-Teller (BET)-specific surface area were controlled by the mass ratio of titanium dioxide sol and coconut shell powder (CNSP). Calcination at 700 degrees C produced anatase phase TiO2 in the TCNSP composites with a BET high surface area of 454 m2/g. Anatase crystallite size of the TCNSP composite increased from 2.37 to 15.11 nm with increasing calcination temperature from 500 degrees C to 800 degrees C. Calcinated TCNSP composites had higher CBZ removal efficiency (98%) than pure TiO2 (23%) and CNSP (34%) within a 40-min reaction time. Optimization of this innovative adsorption/photocatalytic process was obtained by a response surface methodology and a central composite design model, which indicated that this novel and sustainable technology was successful in removing CBZ from a solution. PMID- 24065871 TI - Evaluation of Anaerobic Biofilm Reactor Kinetic Parameters Using Ant Colony Optimization. AB - Fixed bed reactors with naturally attached biofilms are increasingly used for anaerobic treatment of industry wastewaters due their effective treatment performance. The complex nature of biological reactions in biofilm processes often poses difficulty in analyzing them experimentally, and mathematical models could be very useful for their design and analysis. However, effective application of biofilm reactor models to practical problems suffers due to the lack of knowledge of accurate kinetic models and uncertainty in model parameters. In this work, an inverse modeling approach based on ant colony optimization is proposed and applied to estimate the kinetic and film thickness model parameters of wastewater treatment process in an anaerobic fixed bed biofilm reactor. Experimental data of pharmaceutical industry wastewater treatment process are used to determine the model parameters as a consequence of the solution of the rigorous mathematical models of the process. Results were evaluated for different modeling configurations derived from the combination of mathematical models, kinetic expressions, and optimization algorithms. Analysis of results showed that the two-dimensional mathematical model with Haldane kinetics better represents the pharmaceutical wastewater treatment in the biofilm reactor. The mathematical and kinetic modeling of this work forms a useful basis for the design and optimization of industry wastewater treating biofilm reactors. PMID- 24065872 TI - Predicting Adult Pulmonary Ventilation Volume and Wearing Compliance by On-Board Accelerometry During Personal Level Exposure Assessments. AB - BACKGROUND: Metabolic functions typically increase with human activity, but optimal methods to characterize activity levels for real-time predictions of ventilation volume (l/min) during exposure assessments have not been available. Could tiny, triaxial accelerometers be incorporated into personal level monitors to define periods of acceptable wearing compliance, and allow the exposures (MUg/m3) to be extended to potential doses in MUg/min/kg of body weight? OBJECTIVES: In a pilot effort, we tested: 1) whether appropriately-processed accelerometer data could be utilized to predict compliance and in linear regressions to predict ventilation volumes in real time as an on-board component of personal level exposure sensor systems, and 2) whether locating the exposure monitors on the chest in the breathing zone, provided comparable accelerometric data to other locations more typically utilized (waist, thigh, wrist, etc.). METHODS: Prototype exposure monitors from RTI International and Columbia University were worn on the chest by a pilot cohort of adults while conducting an array of scripted activities (all <10 METS), spanning common recumbent, sedentary, and ambulatory activity categories. Referee Wocket accelerometers that were placed at various body locations allowed comparison with the chest-located exposure sensor accelerometers. An Oxycon Mobile mask was used to measure oral nasal ventilation volumes in-situ. For the subset of participants with complete data (n= 22), linear regressions were constructed (processed accelerometric variable versus ventilation rate) for each participant and exposure monitor type, and Pearson correlations computed to compare across scenarios. RESULTS: Triaxial accelerometer data were demonstrated to be adequately sensitive indicators for predicting exposure monitor wearing compliance. Strong linear correlations (R values from 0.77 to 0.99) were observed for all participants for both exposure sensor accelerometer variables against ventilation volume for recumbent, sedentary, and ambulatory activities with MET values ~<6. The RTI monitors mean R value of 0.91 was slightly higher than the Columbia monitors mean of 0.86 due to utilizing a 20 Hz data rate instead of a slower 1 Hz rate. A nominal mean regression slope was computed for the RTI system across participants and showed a modest RSD of +/-36.6%. Comparison of the correlation values of the exposure monitors with the Wocket accelerometers at various body locations showed statistically identical regressions for all sensors at alternate hip, ankle, upper arm, thigh, and pocket locations, but not for the Wocket accelerometer located at the dominant-side wrist location (R=0.57; p=0.016). CONCLUSIONS: Even with a modest number of adult volunteers, the consistency and linearity of regression slopes for all subjects were very good with excellent within-person Pearson correlations for the accelerometer versus ventilation volume data. Computing accelerometric standard deviations allowed good sensitivity for compliance assessments even for sedentary activities. These pilot findings supported the hypothesis that a common linear regression is likely to be usable for a wider range of adults to predict ventilation volumes from accelerometry data over a range of low to moderate energy level activities. The predicted volumes would then allow real-time estimates of potential dose, enabling more robust panel studies. The poorer correlation in predicting ventilation rate for an accelerometer located on the wrist suggested that this location should not be considered for predictions of ventilation volume. PMID- 24065873 TI - Induction and analysis of the alkaloid mitragynine content of a Mitragyna speciosa suspension culture system upon elicitation and precursor feeding. AB - This study aimed to determine the effects of different concentrations and combinations of the phytohormones 2,4-dichlorophenoxy acetic acid (2,4-D), kinetin, 6-benzylaminopurine (BAP), and 1-naphthaleneacetic acid (NAA) on callus induction and to demonstrate the role of elicitors and exogenous precursors on the production of mitragynine in a Mitragyna speciosa suspension culture. The best callus induction was achieved from petiole explants cultured on WPM that was supplemented with 4 mg L-1 2,4-D (70.83%). Calli were transferred to liquid media and agitated on rotary shakers to establish Mitragyna speciosa cell suspension cultures. The optimum settled cell volume was achieved in the presence of WPM that contained 3 mg L-1 2,4-D and 3% sucrose (9.47 +/- 0.4667 mL). The treatment of cultures with different concentrations of yeast extract and salicylic acid for different inoculation periods revealed that the highest mitragynine content as determined by HPLC was achieved from the culture treated with 250 mg L-1 yeast extract (9.275 +/- 0.082 mg L-1) that was harvested on day 6 of culturing; salicylic acid showed low mitragynine content in all concentrations used. Tryptophan and loganin were used as exogenous precursors; the highest level of mitragynine production was achieved in cultures treated with 3 MUM tryptophan and harvested at 6 days (13.226 +/- 1.98 mg L-1). PMID- 24065874 TI - The ecological response of Carex lasiocarpa community in the Riparian Wetlands to the environmental gradient of water depth in Sanjiang Plain, Northeast China. AB - The response of Carex lasiocarpa in riparian wetlands in Sanjiang Plain to the environmental gradient of water depth was analyzed by using the Gaussian Model based on the biomass and average height data, and the ecological water-depth amplitude of Carex lasiocarpa was derived. The results indicated that the optimum ecological water-depth amplitude of Carex lasiocarpa based on biomass was [13.45 cm, 29.78 cm], while the optimum ecological water-depth amplitude of Carex lasiocarpa based on average height was [2.31 cm, 40.11 cm]. The intersection of the ecological water-depth amplitudes based on biomass and height confirmed that the optimum ecological water-depth amplitude of Carex lasiocarpa was [13.45 cm, 29.78 cm] and the optimist growing water-depth of Carex lasiocarpa was 21.4 cm. The TWINSPAN, a polythetic and divisive classification tool, was used to classify the wetland ecological series into 6 associations. Result of TWINSPAN matrix classification reflected an obvious environmental gradient in these associations: water-depth gradient. The relation of biodiversity of Carex lasiocarpa community and water depth was determined by calculating the diversity index of each association. PMID- 24065875 TI - Does Posttraumatic Stress Disorder (PTSD) Affect Post-Treatment Methamphetamine Use? AB - OBJECTIVE: Although trauma is a well-established risk factor for substance use disorders, little is known about the association between posttraumatic stress disorder (PTSD) and treatment outcomes among methamphetamine users. In the present study, we examine the relationship between PTSD and post-treatment methamphetamine use outcomes, hospitalizations, and overall psychiatric impairment. METHODS: Using data from 526 adults in the largest psychosocial clinical trial of methamphetamine users conducted to date, this study examined: (1) treatment outcomes of methamphetamine users with concomitant PTSD three years after psychosocial treatment for methamphetamine dependence; and (2) PTSD symptom clusters as risk factors for post-treatment relapse to methamphetamine use. RESULTS: PTSD was associated with poorer methamphetamine use outcomes; methamphetamine use frequency throughout the 3-year follow-up was significantly greater among individuals with a PTSD diagnosis, and those with PTSD had more than five times the odds of reporting methamphetamine use in the 30 days prior to the follow-up interview, OR= 5.2, 95% CI [2.0-13.3]. Additionally, higher levels of other Axis I psychopathology were observed among methamphetamine users with PTSD. Avoidance and arousal symptoms predicted post-treatment methamphetamine use. CONCLUSIONS: Addressing these high risk PTSD symptoms and syndromes in methamphetamine users may be helpful as a means of improving treatment outcomes in this population. PMID- 24065876 TI - Non-genomic mechanisms of progesterone action in the brain. AB - Progesterone is a gonadal steroid hormone whose physiological effects extend well beyond the strict confines of reproductive function. In fact, progesterone can have important effects on a variety of tissues, including the bone, the heart and the brain. Mechanistically, progesterone has been thought to exert its effects through the progesterone receptor (PR), a member of the nuclear steroid hormone superfamily, and as such, acts through specific progesterone response elements (PRE) within the promoter region of target genes to regulate transcription of such genes. This has been often described as the "genomic" mechanism of progesterone action. However, just as progesterone has a diverse range of tissue targets, the mechanisms through which progesterone elicits its effects are equally diverse. For example, progesterone can activate alternative receptors, such as membrane-associated PRs (distinct from the classical PR), to elicit the activation of several signaling pathways that in turn, can influence cell function. Here, we review various non-nuclear (i.e., non-genomic) signaling mechanisms that progesterone can recruit to elicit its effects, focusing our discussion primarily on those signaling mechanisms by which progesterone influences cell viability in the brain. PMID- 24065877 TI - Reward-based learning under hardware constraints-using a RISC processor embedded in a neuromorphic substrate. AB - In this study, we propose and analyze in simulations a new, highly flexible method of implementing synaptic plasticity in a wafer-scale, accelerated neuromorphic hardware system. The study focuses on globally modulated STDP, as a special use-case of this method. Flexibility is achieved by embedding a general purpose processor dedicated to plasticity into the wafer. To evaluate the suitability of the proposed system, we use a reward modulated STDP rule in a spike train learning task. A single layer of neurons is trained to fire at specific points in time with only the reward as feedback. This model is simulated to measure its performance, i.e., the increase in received reward after learning. Using this performance as baseline, we then simulate the model with various constraints imposed by the proposed implementation and compare the performance. The simulated constraints include discretized synaptic weights, a restricted interface between analog synapses and embedded processor, and mismatch of analog circuits. We find that probabilistic updates can increase the performance of low resolution weights, a simple interface between analog synapses and processor is sufficient for learning, and performance is insensitive to mismatch. Further, we consider communication latency between wafer and the conventional control computer system that is simulating the environment. This latency increases the delay, with which the reward is sent to the embedded processor. Because of the time continuous operation of the analog synapses, delay can cause a deviation of the updates as compared to the not delayed situation. We find that for highly accelerated systems latency has to be kept to a minimum. This study demonstrates the suitability of the proposed implementation to emulate the selected reward modulated STDP learning rule. It is therefore an ideal candidate for implementation in an upgraded version of the wafer-scale system developed within the BrainScaleS project. PMID- 24065878 TI - Novel progesterone receptors: neural localization and possible functions. AB - Progesterone (P4) regulates a wide range of neural functions and likely acts through multiple receptors. Over the past 30 years, most studies investigating neural effects of P4 focused on genomic and non-genomic actions of the classical progestin receptor (PGR). More recently the focus has widened to include two groups of non-classical P4 signaling molecules. Members of the Class II progestin and adipoQ receptor (PAQR) family are called membrane progestin receptors (mPRs) and include: mPRalpha (PAQR7), mPRbeta (PAQR8), mPRgamma (PAQR5), mPRdelta (PAQR6), and mPRepsilon (PAQR9). Members of the b5-like heme/steroid-binding protein family include progesterone receptor membrane component 1 (PGRMC1), PGRMC2, neudesin, and neuferricin. Results of our recent mapping studies show that members of the PGRMC1/S2R family, but not mPRs, are quite abundant in forebrain structures important for neuroendocrine regulation and other non genomic effects of P4. Herein we describe the structures, neuroanatomical localization, and signaling mechanisms of these molecules. We also discuss possible roles for Pgrmc1/S2R in gonadotropin release, feminine sexual behaviors, fluid balance and neuroprotection, as well as catamenial epilepsy. PMID- 24065879 TI - PGRMC1 and PGRMC2 in uterine physiology and disease. AB - It is clear from studies using progesterone receptor (PGR) mutant mice that not all of the actions of progesterone (P4) are mediated by this receptor. Indeed, many rapid, non-classical P4 actions have been reported throughout the female reproductive tract. Progesterone treatment of Pgr null mice results in behavioral changes and in differential regulation of genes in the endometrium. Progesterone receptor membrane component (PGRMC) 1 and PGRMC2 belong to the heme-binding protein family and may serve as P4 receptors. Evidence to support this derives chiefly from in vitro culture work using primary or transformed cell lines that lack the classical PGR. Endometrial expression of PGRMC1 in menstrual cycling mammals is most abundant during the proliferative phase of the cycle. Because PGRMC2 expression shows the most consistent cross-species expression, with highest levels during the secretory phase, PGRMC2 may serve as a universal non classical P4 receptor in the uterus. While the functional importance of PGRMC1/2 in the uterus remains to be fully explored, accumulating evidence suggests that disruption in PGRMC1/2 expression correlates with uterine disease. In this review we will summarize what is known about PGRMC1/2 in uterine physiology and we will provide examples of disrupted expression of these genes in uterine disease states. PMID- 24065881 TI - Temporal dynamics of a homeostatic pathway controlling neural network activity. AB - Neurons use a variety of mechanisms to homeostatically regulate neural network activity in order to maintain firing in a bounded range. One such process involves the bi-directional modulation of excitatory synaptic drive in response to chronic changes in network activity. Down-scaling of excitatory synapses in response to high activity requires Arc-dependent endocytosis of glutamate receptors. However, the temporal dynamics and signaling pathways regulating Arc during homeostatic plasticity are not well understood. Here we determine the relative contribution of transcriptional and translational control in the regulation of Arc, the signaling pathways responsible for the activity-dependent production of Arc, and the time course of these signaling events as they relate to the homeostatic adjustment of network activity in hippocampal neurons. We find that an ERK1/2-dependent transcriptional pathway active within 1-2 h of up regulated network activity induces Arc leading to a restoration of network spiking rates within 12 h. Under basal and low activity conditions, specialized mechanisms are in place to rapidly degrade Arc mRNA and protein such that they have half-lives of less than 1 h. In addition, we find that while mTOR signaling is regulated by network activity on a similar time scale, mTOR-dependent translational control is not a major regulator of Arc production or degradation suggesting that the signaling pathways underlying homeostatic plasticity are distinct from those mediating synapse-specific forms of synaptic depression. PMID- 24065880 TI - Corticotropin-releasing factor-related peptides, serotonergic systems, and emotional behavior. AB - Corticotropin-releasing factor (CRF) is a 41-amino acid neuropeptide that is involved in stress-related physiology and behavior, including control of the hypothalamic-pituitary-adrenal (HPA) axis. Members of the CRF family of neuropeptides, including urocortin 1 (UCN 1), UCN 2, and UCN 3, bind to the G protein-coupled receptors, CRF type 1 (CRF1) and CRF2 receptors. In addition, CRF binding protein (CRFBP) binds both CRF and UCN 1 and can modulate their activities. There are multiple mechanisms through which CRF-related peptides may influence emotional behavior, one of which is through altering the activity of brainstem neuromodulatory systems, including serotonergic systems. CRF and CRF related peptides act within the dorsal raphe nucleus (DR), the major source for serotonin (5-HT) in the brain, to alter the neuronal activity of specific subsets of serotonergic neurons and to influence stress-related behavior. CRF-containing axonal fibers innervate the DR in a topographically organized manner, which may contribute to the ability of CRF to alter the activity of specific subsets of serotonergic neurons. CRF and CRF-related peptides can either increase or decrease serotonergic neuronal firing rates and serotonin release, depending on their concentrations and on the specific CRF receptor subtype(s) involved. This review aims to describe the interactions between CRF-related peptides and serotonergic systems, the consequences for stress-related behavior, and implications for vulnerability to anxiety and affective disorders. PMID- 24065882 TI - Role of endoplasmic reticulum Ca2+ signaling in the pathogenesis of Alzheimer disease. AB - Alzheimer disease (AD) is a major threat of twenty-first century that is responsible for the majority of dementia in the elderly. Development of effective AD-preventing therapies are the top priority tasks for neuroscience research. Amyloid hypothesis of AD is a dominant idea in the field, but so far all amyloid targeting therapies have failed in clinical trials. In addition to amyloid accumulation, there are consistent reports of abnormal calcium signaling in AD neurons. AD neurons exhibit enhanced intracellular calcium (Ca(2) (+)) liberation from the endoplasmic reticulum (ER) and reduced store-operated Ca(2) (+) entry (SOC). These changes occur primarily as a result of ER Ca(2) (+) overload. We argue that normalization of intracellular Ca(2) (+) homeostasis could be a strategy for development of effective disease-modifying therapies. The current review summarizes recent data about changes in ER Ca(2) (+) signaling in AD. Ca(2) (+) channels that are discussed in the current review include: inositol trisphosphate receptors, ryanodine receptors, presenilins as ER Ca(2) (+) leak channels, and neuronal SOC channels. We discuss how function of these channels is altered in AD and how important are resulting Ca(2) (+) signaling changes for AD pathogenesis. PMID- 24065883 TI - The attenuation of retinal nerve fiber layer thickness and cognitive deterioration. AB - Thinner retinal nerve fiber layer (RNFL) has been reported in Alzheimer's disease (AD) patient. However, whether changes in RNFL thickness can predict the cognitive deterioration remains unknown. We therefore set out a prospective clinical investigation to determine the potential association between the attenuation of RNFL thickness and the deterioration of cognitive function over a period of 25 months. We assessed cognitive function using the Repeatable Battery for the Assessment of Neuropsychological Status and measured RNFL thickness employing optical coherence tomography in 78 participants (mean age 72.31 +/- 3.98 years, 52% men). The participants were categorized as stable participants whose cognitive status remained no change (N = 60) and converted participants whose cognitive status deteriorated (N = 18). We found that there was an association between the attenuation of superior quadrant RNFL thickness and the deterioration of cognitive function in the stable participants. In the converted participants, however, there was an inverse association between the reduction of inferior quadrant RNFL thickness and decline of cognitive functions [scores of list recall (R = -0.670, P = 0.002), adjusted (R = -0.493, P = 0.031)]. These data showed that less reduction in the inferior quadrant of RNFL thickness might indicate a higher risk for the patients to develop cognitive deterioration. These findings have established a system to embark a larger scale study to further test whether changes in RNFL thickness can serve as a biomarker of AD, and would lead to mechanistic studies to determine the cellular mechanisms of cognitive deterioration. PMID- 24065885 TI - cAMP promotes the differentiation of neural progenitor cells in vitro via modulation of voltage-gated calcium channels. AB - The molecular mechanisms underlying the differentiation of neural progenitor cells (NPCs) remain poorly understood. In this study we investigated the role of Ca(2+) and cAMP (cyclic adenosine monophosphate) in the differentiation of NPCs extracted from the subventricular zone of E14.5 rat embryos. Patch clamp recordings revealed that increasing cAMP-signaling with Forskolin or IBMX (3 isobutyl-1-methylxantine) significantly facilitated neuronal functional maturation. A continuous application of IBMX to the differentiation medium substantially increased the functional expression of voltage-gated Na(+) and K(+) channels, as well as neuronal firing frequency. Furthermore, we observed an increase in the frequency of spontaneous synaptic currents and in the amplitude of evoked glutamatergic and GABAergic synaptic currents. The most prominent acute effect of applying IBMX was an increase in L-type Ca(2+)currents. Conversely, blocking L-type channels strongly inhibited dendritic outgrowth and synapse formation even in the presence of IBMX, indicating that voltage-gated Ca(2+) influx plays a major role in neuronal differentiation. Finally, we found that nifedipine completely blocks IBMX-induced CREB phosphorylation (cAMP-response element-binding protein), indicating that the activity of this important transcription factor equally depends on both enhanced cAMP and voltage-gated Ca(2+)-signaling. Taken together, these data indicate that the up-regulation of voltage-gated L-type Ca(2+)-channels and early electrical excitability are critical steps in the cAMP-dependent differentiation of SVZ-derived NPCs into functional neurons. To our knowledge, this is the first demonstration of the acute effects of cAMP on voltage-gated Ca(+2)channels in NPC-derived developing neurons. PMID- 24065884 TI - Age dependency of trauma-induced neocortical epileptogenesis. AB - Trauma and brain infection are the primary sources of acquired epilepsy, which can occur at any age and may account for a high incidence of epilepsy in developing countries. We have explored the hypothesis that penetrating cortical wounds cause deafferentation of the neocortex, which triggers homeostatic plasticity and lead to epileptogenesis (Houweling etal., 2005). In partial deafferentation experiments of adult cats, acute seizures occurred in most preparations and chronic seizures occurred weeks to months after the operation in 65% of the animals (Nita etal., 2006,2007; Nita and Timofeev, 2007). Similar deafferentation of young cats (age 8-12 months) led to some acute seizures, but we never observed chronic seizure activity even though there was enhanced slow wave activity in the partially deafferented hemisphere during quiet wakefulness. This suggests that despite a major trauma, the homeostatic plasticity in young animals was able to restore normal levels of cortical excitability, but in fully adult cats the mechanisms underlying homeostatic plasticity may lead to an unstable cortical state. To test this hypothesis we made an undercut in the cortex of an elderly cat. After several weeks this animal developed seizure activity. These observations may lead to an intervention after brain trauma that prevents epileptogenesis from occurring in adults. PMID- 24065886 TI - Paradoxical proepileptic response to NMDA receptor blockade linked to cortical interneuron defect in stargazer mice. AB - Paradoxical seizure exacerbation by anti-epileptic medication is a well-known clinical phenomenon in epilepsy, but the cellular mechanisms remain unclear. One possibility is enhanced network disinhibition by unintended suppression of inhibitory interneurons. We investigated this hypothesis in the stargazer mouse model of absence epilepsy, which bears a mutation in stargazin, an AMPA receptor trafficking protein. If AMPA signaling onto inhibitory GABAergic neurons is impaired, their activation by glutamate depends critically upon NMDA receptors. Indeed, we find that stargazer seizures are exacerbated by NMDA receptor blockade with CPP (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid) and MK 801, whereas other genetic absence epilepsy models are sensitive to these antagonists. To determine how an AMPA receptor trafficking defect could lead to paradoxical network activation, we analyzed stargazin and AMPA receptor localization and found that stargazin is detected exclusively in parvalbumin positive (PV (+)) fast-spiking interneurons in somatosensory cortex, where it is co-expressed with the AMPA receptor subunit GluA4. PV (+) cortical interneurons in stargazer show a near twofold decrease in the dendrite:soma GluA4 expression ratio compared to wild-type (WT) littermates. We explored the functional consequence of this trafficking defect on network excitability in neocortical slices. Both NMDA receptor antagonists suppressed 0 Mg (2) (+)-induced network discharges in WT but augmented bursting in stargazer cortex. Interneurons mediate this paradoxical response, since the difference between genotypes was masked by GABA receptor blockade. Our findings provide a cellular locus for AMPA receptor dependent signaling defects in stargazer cortex and define an interneuron dependent mechanism for paradoxical seizure exacerbation in absence epilepsy. PMID- 24065887 TI - microRNA function in left-right neuronal asymmetry: perspectives from C. elegans. AB - Left-right asymmetry in anatomical structures and functions of the nervous system is present throughout the animal kingdom. For example, language centers are localized in the left side of the human brain, while spatial recognition functions are found in the right hemisphere in the majority of the population. Disruption of asymmetry in the nervous system is correlated with neurological disorders. Although anatomical and functional asymmetries are observed in mammalian nervous systems, it has been a challenge to identify the molecular basis of these asymmetries. C. elegans has emerged as a prime model organism to investigate molecular asymmetries in the nervous system, as it has been shown to display functional asymmetries clearly correlated to asymmetric distribution and regulation of biologically relevant molecules. Small non-coding RNAs have been recently implicated in various aspects of neural development. Here, we review cases in which microRNAs are crucial for establishing left-right asymmetries in the C. elegans nervous system. These studies may provide insight into how molecular and functional asymmetries are established in the human brain. PMID- 24065888 TI - Combined fluorescent in situ hybridization for detection of microRNAs and immunofluorescent labeling for cell-type markers. AB - Identification of the cell type of origin for normal or aberrant gene expression is critical for many studies, and poses a significant problem for some regulatory RNAs such as microRNAs. MicroRNAs are small non-coding RNAs that regulate cellular function by targeting specific mRNAs and reducing the level of their protein product. Aberrant expression of miRNAs in cell-types where they are not normally expressed occurs in several disease conditions. Therefore, it is important to determine not only the expression level of microRNAs, but also where they are expressed. Here we describe a detailed method for fluorescent in situ hybridization (FISH) combined with immunofluorescent labeling for cell-type markers in formalin fixed paraffin embedded (FFPE) sections along with modifications required to adapt the protocol for primary neurons grown in culture. We have combined the specificity and stability of locked nucleic acid (LNA) probes with tyramide signal amplification. To prevent loss of small RNA species, we performed post-fixation with ethylcarbodiimide (EDC). Additionally by omitting protease digestion and using only high temperature with sodium citrate buffer for FFPE sections, we were able to perform immunolabeling for proteins concurrently with in situ hybridization without compromising efficacy of either procedure. PMID- 24065889 TI - Radixin inhibition decreases adult neural progenitor cell migration and proliferation in vitro and in vivo. AB - Neuronal progenitors capable of long distance migration are produced throughout life in the subventricular zone (SVZ). Migration from the SVZ is carried out along a well-defined pathway called the rostral migratory stream (RMS). Our recent finding of the specific expression of the cytoskeleton linker protein radixin in neuroblasts suggests a functional role for radixin in RMS migration. The ezrin-radixin-moesin (ERM) family of proteins is capable of regulating migration through interaction with the actin cytoskeleton and transmembrane proteins. The ERM proteins are differentially expressed in the RMS with radixin and moesin localized to neuroblasts, and ezrin expression confined to astrocytes of the glial tubes. Here, we inhibited radixin function using the quinocarmycin analog DX52-1 which resulted in reduced neuroblast migration in vitro, while glial migration remained unaltered. Furthermore, the morphology of neuroblasts was distorted resulting in a rounded shape with no or short polysialylated neural cell adhesion molecule positive processes. Intracerebroventricular infusion of the radixin inhibitor resulted in accumulation of neuroblasts in the anterior SVZ. Neuroblast chains were short and intermittently interrupted in the SVZ and considerably disorganized in the RMS. Moreover, we studied the proliferation activity in the RMS after radixin inhibition, since concentrated radixin expression has been demonstrated in the cleavage furrow of dividing cells, which indicates a role of radixin in cell division. Radixin inhibition decreased neuroblast proliferation, whereas the proliferation of other cells in the RMS was not affected. Our results demonstrate a significant role for radixin in neuroblast proliferation and migration. PMID- 24065890 TI - Changes in the expression of GABAA receptor subunit mRNAs in parahippocampal areas after kainic acid induced seizures. AB - The parahippocampal areas including the subiculum, pre- and parasubiculum, and notably the entorhinal cortex (EC) are intimately involved in the generation of limbic seizures in temporal lobe epilepsy. We investigated changes in the expression of 10 major GABAA receptor subunit mRNAs in subfields of the ventral hippocampus, ventral subiculum, EC, and perirhinal cortex (PRC) at different intervals (1, 8, 30, and 90 days) after kainic acid (KA)-induced status epilepticus priming epileptogenesis in the rat. The most pronounced and ubiquitous changes were a transient (24 h after KA only) down-regulation of gamma2 mRNA and lasting decreases in subunit alpha5, beta3, and delta mRNAs that were prominent in all hippocampal and parahippocampal areas. In the subiculum similarly as in sectors CA1 and CA3, levels of subunit alpha1, alpha2, alpha4, and gamma2 mRNAs decreased transiently (1 day after KA-induced status epilepticus). They were followed by increased expression of subunit alpha1 and alpha3 mRNAs in the dentate gyrus (DG) and sectors CA1 and CA3, and subunit alpha1 also in the EC layer II (30 and 90 days after KA). We also observed sustained overexpression of subunits alpha4 and gamma2 in the subiculum and in the Ammon's horn. Subunit gamma2 mRNA was also increased in sector CA1 at the late intervals after KA. Taken together, our results suggest distinct regulation of mRNA expression for individual GABAA receptor subunits. Especially striking was the wide-spread down-regulation of the often peri- or extrasynaptically located subunits alpha5 and delta. These subunits are often associated with tonic inhibition. Their decrease could be related to decreased tonic inhibition or may merely reflect compensatory changes. In contrast, expression of subunit alpha4 that may also mediate tonic inhibition when associated with the delta-subunit was significantly upregulated in the DG and in the proximal subiculum at late intervals. Thus, concomitant up-regulation of subunit gamma2, alpha1 and alpha4 mRNAs (and loss in delta-subunits) ultimately indicates significant rearrangement of GABAA receptor composition after KA-induced seizures. PMID- 24065892 TI - The basal forebrain modulates spontaneous activity of principal cells in the main olfactory bulb of anesthetized mice. AB - Spontaneous activity is an important characteristic of the principal cells in the main olfactory bulb (MOB) for encoding odor information, which is modulated by the basal forebrain. Cholinergic activation has been reported to inhibit all major neuron types in the MOB. In this study, the effect of diagonal band (NDB) stimulation on mitral/tufted (M/T) cell spontaneous activity was examined in anesthetized mice. NDB stimulation increased spontaneous activity in 66 MOB neurons which lasted for 2-35 s before returning to the baseline level. The majority of the effected units showed a decrease of interspike intervals (ISI) at a range of 8-25 ms. Fifty-two percent of NDB stimulation responsive units showed intrinsic rhythmical bursting, which was enhanced temporarily by NDB stimulation, whereas the remaining non-rhythmic units were capable of synchronized bursting. The effect was attenuated by scopolamine in 21 of 27 units tested. Only four NDB units were inhibited by NDB stimulation, an inhibition that lasted less than 10 s. The NDB stimulation responsive neurons appeared to be M/T cells. Our findings demonstrate an NDB excitation effect on M/T neurons that mostly requires muscarinic receptor activation, and is likely due to non-selectivity of electrical stimulation. This suggests that cholinergic and a diverse group of non cholinergic neurons in the basal forebrain co-ordinately modulate the dynamics of M/T cell spontaneous activity, which is fundamental for odor representation and attentional perception. PMID- 24065891 TI - Mushroom body miscellanea: transgenic Drosophila strains expressing anatomical and physiological sensor proteins in Kenyon cells. AB - The fruit fly Drosophila melanogaster represents a key model organism for analyzing how neuronal circuits regulate behavior. The mushroom body in the central brain is a particularly prominent brain region that has been intensely studied in several insect species and been implicated in a variety of behaviors, e.g., associative learning, locomotor activity, and sleep. Drosophila melanogaster offers the advantage that transgenes can be easily expressed in neuronal subpopulations, e.g., in intrinsic mushroom body neurons (Kenyon cells). A number of transgenes has been described and engineered to visualize the anatomy of neurons, to monitor physiological parameters of neuronal activity, and to manipulate neuronal function artificially. To target the expression of these transgenes selectively to specific neurons several sophisticated bi- or even multipartite transcription systems have been invented. However, the number of transgenes that can be combined in the genome of an individual fly is limited in practice. To facilitate the analysis of the mushroom body we provide a compilation of transgenic fruit flies that express transgenes under direct control of the Kenyon-cell specific promoter, mb247. The transgenes expressed are fluorescence reporters to analyze neuroanatomical aspects of the mushroom body, proteins to restrict ectopic gene expression to mushroom bodies, or fluorescent sensors to monitor physiological parameters of neuronal activity of Kenyon cells. Some of the transgenic animals compiled here have been published already, whereas others are novel and characterized here for the first time. Overall, the collection of transgenic flies expressing sensor and reporter genes in Kenyon cells facilitates combinations with binary transcription systems and might, ultimately, advance the physiological analysis of mushroom body function. PMID- 24065893 TI - Motor tics evoked by striatal disinhibition in the rat. AB - Motor tics are sudden, brief, repetitive movements that constitute the main symptom of Tourette syndrome (TS). Multiple lines of evidence suggest the involvement of the cortico-basal ganglia system, and in particular the basal ganglia input structure-the striatum in tic formation. The striatum receives somatotopically organized cortical projections and contains an internal GABAergic network of interneurons and projection neurons' collaterals. Disruption of local striatal GABAergic connectivity has been associated with TS and was found to induce abnormal movements in model animals. We have previously described the behavioral and neurophysiological characteristics of motor tics induced in monkeys by local striatal microinjections of the GABAA antagonist bicuculline. In the current study we explored the abnormal movements induced by a similar manipulation in freely moving rats. We targeted microinjections to different parts of the dorsal striatum, and examined the effects of this manipulation on the induced tic properties, such as latency, duration, and somatic localization. Tics induced by striatal disinhibition in monkeys and rats shared multiple properties: tics began within several minutes after microinjection, were expressed solely in the contralateral side, and waxed and waned around a mean inter-tic interval of 1-4 s. A clear somatotopic organization was observed only in rats, where injections to the anterior or posterior striatum led to tics in the forelimb or hindlimb areas, respectively. These results suggest that striatal disinhibition in the rat may be used to model motor tics such as observed in TS. Establishing this reliable and accessible animal model could facilitate the study of the neural mechanisms underlying motor tics, and the testing of potential therapies for tic disorders. PMID- 24065894 TI - Learning from negative feedback in patients with major depressive disorder is attenuated by SSRI antidepressants. AB - One barrier to interpreting past studies of cognition and major depressive disorder (MDD) has been the failure in many studies to adequately dissociate the effects of MDD from the potential cognitive side effects of selective serotonin reuptake inhibitors (SSRIs) use. To better understand how remediation of depressive symptoms affects cognitive function in MDD, we evaluated three groups of subjects: medication-naive patients with MDD, medicated patients with MDD receiving the SSRI paroxetine, and healthy control (HC) subjects. All were administered a category-learning task that allows for dissociation between learning from positive feedback (reward) vs. learning from negative feedback (punishment). Healthy subjects learned significantly better from positive feedback than medication-naive and medicated MDD groups, whose learning accuracy did not differ significantly. In contrast, medicated patients with MDD learned significantly less from negative feedback than medication-naive patients with MDD and healthy subjects, whose learning accuracy was comparable. A comparison of subject's relative sensitivity to positive vs. negative feedback showed that both the medicated MDD and HC groups conform to Kahneman and Tversky's (1979) Prospect Theory, which expects losses (negative feedback) to loom psychologically slightly larger than gains (positive feedback). However, medicated MDD and HC profiles are not similar, which indicates that the state of medicated MDD is not "normal" when compared to HC, but rather balanced with less learning from both positive and negative feedback. On the other hand, medication-naive patients with MDD violate Prospect Theory by having significantly exaggerated learning from negative feedback. This suggests that SSRI antidepressants impair learning from negative feedback, while having negligible effect on learning from positive feedback. Overall, these findings shed light on the importance of dissociating the cognitive consequences of MDD from those of SSRI treatment, and from cognitive evaluation of MDD subjects in a medication-naive state before the administration of antidepressants. Future research is needed to correlate the mood-elevating effects and the cognitive balance between reward- and punishment-based learning related to SSRIs. PMID- 24065895 TI - Encoding of naturalistic optic flow by motion sensitive neurons of nucleus rotundus in the zebra finch (Taeniopygia guttata). AB - The retinal image changes that occur during locomotion, the optic flow, carry information about self-motion and the three-dimensional structure of the environment. Especially fast moving animals with only little binocular vision depend on these depth cues for maneuvering. They actively control their gaze to facilitate perception of depth based on cues in the optic flow. In the visual system of birds, nucleus rotundus neurons were originally found to respond to object motion but not to background motion. However, when background and object were both moving, responses increased the more the direction and velocity of object and background motion on the retina differed. These properties may play a role in representing depth cues in the optic flow. We therefore investigated, how neurons in nucleus rotundus respond to optic flow that contains depth cues. We presented simplified and naturalistic optic flow on a panoramic LED display while recording from single neurons in nucleus rotundus of anaesthetized zebra finches. Unlike most studies on motion vision in birds, our stimuli included depth information. We found extensive responses of motion selective neurons in nucleus rotundus to optic flow stimuli. Simplified stimuli revealed preferences for optic flow reflecting translational or rotational self-motion. Naturalistic optic flow stimuli elicited complex response modulations, but the presence of objects was signaled by only few neurons. The neurons that did respond to objects in the optic flow, however, show interesting properties. PMID- 24065896 TI - Retrieval of Recent Autobiographical Memories is Associated with Slow-Wave Sleep in Early AD. AB - Autobiographical memory is commonly impaired in Alzheimer's disease (AD). However, little is known about the very recent past which is though highly important in daily life adaptation. In addition, the impact of sleep disturbances, also frequently reported in AD, on the consolidation, and retrieval of autobiographical memories remains to be assessed. Using an adaptation of the TEMPau task, we investigated the neural substrates of autobiographical memory for recent events and the potential relationship with sleep in 14 patients with mild AD. On day 1, autobiographical memory was explored across three periods: remote (18-30 years), the last 2 years and the last month. After testing, sleep was recorded using polysomnography. The next day, AD patients benefited a resting state (18)FDG-PET scan and a second exploration of autobiographical memory, focusing on the very recent past (today and yesterday). Total recall and episodic recall scores were obtained. In addition, for all events recalled, Remember responses justified by specific factual, spatial, and temporal details were measured using the Remember/Know paradigm. Retrieval of autobiographical memories was impaired in AD, but recall of young adulthood and very recent events was relatively better compared to the two intermediate periods. Recall of recent events (experienced the day and the day preceding the assessment) was correlated with brain glucose consumption in the precuneus and retrosplenial cortex, the calcarine region, the angular gyrus, and lateral temporal areas. AD patients also provided more Justified Remember responses for events experienced the previous day than for those experienced the day of the assessment. Moreover, Justified Remember responses obtained for events experienced before sleep were positively correlated with the amount of slow-wave sleep. These data provide the first evidence of an association between the ability to retrieve recent autobiographical memories and sleep in mild AD patients. PMID- 24065897 TI - Neural substrates of figurative language during natural speech perception: an fMRI study. AB - Many figurative expressions are fully conventionalized in everyday speech. Regarding the neural basis of figurative language processing, research has predominantly focused on metaphoric expressions in minimal semantic context. It remains unclear in how far metaphoric expressions during continuous text comprehension activate similar neural networks as isolated metaphors. We therefore investigated the processing of similes (figurative language, e.g., "He smokes like a chimney!") occurring in a short story. Sixteen healthy, male, native German speakers listened to similes that came about naturally in a short story, while blood-oxygenation-level-dependent (BOLD) responses were measured with functional magnetic resonance imaging (fMRI). For the event-related analysis, similes were contrasted with non-figurative control sentences (CS). The stimuli differed with respect to figurativeness, while they were matched for frequency of words, number of syllables, plausibility, and comprehensibility. Similes contrasted with CS resulted in enhanced BOLD responses in the left inferior (IFG) and adjacent middle frontal gyrus. Concrete CS as compared to similes activated the bilateral middle temporal gyri as well as the right precuneus and the left middle frontal gyrus (LMFG). Activation of the left IFG for similes in a short story is consistent with results on single sentence metaphor processing. The findings strengthen the importance of the left inferior frontal region in the processing of abstract figurative speech during continuous, ecologically-valid speech comprehension; the processing of concrete semantic contents goes along with a down-regulation of bilateral temporal regions. PMID- 24065898 TI - Language and cognition-joint acquisition, dual hierarchy, and emotional prosody. PMID- 24065899 TI - Erratum: Targeting the endocannabinoid system to treat haunting traumatic memories. AB - [This corrects the article on p. 100 in vol. 7, PMID: 23340520.]. PMID- 24065900 TI - Discrete sequence production with and without a pause: the role of cortex, basal ganglia, and cerebellum. AB - Our sensorimotor experience unfolds in sequences over time. We hypothesize that the processing of movement sequences with and without a temporal pause will recruit distinct but cooperating neural processes, including cortico-striatal and cortico-cerebellar networks. We thus, compare neural activity during sequence learning in the presence and absence of this pause. Young volunteer participants learned sensorimotor sequences using the discrete sequence production (DSP) task, with Pause, No-Pause, and Control sequences of four elements in an event related fMRI protocol. The No-Pause and Pause sequences involved a more complex sequential structure than the Control sequence, while the Pause sequences involved insertion of a temporal pause, relative to the No-Pause sequence. The Pause vs. No-Pause contrast revealed extensive fronto-parietal, striatal, thalamic and cerebellar activations, preferentially for the Pause sequences. ROI analysis indicated that the cerebellum displays an early activation that was attenuated over successive runs, and a significant preference for Pause sequences when compared with caudate. These data support the hypothesis that a cortico cerebellar circuit plays a specific role in the initial processing of temporal structure, while the basal ganglia play a more general role in acquiring the serial response order of the sequence. PMID- 24065901 TI - The influence of emotions on cognitive control: feelings and beliefs-where do they meet? AB - The influence of emotion on higher-order cognitive functions, such as attention allocation, planning, and decision-making, is a growing area of research with important clinical applications. In this review, we provide a computational framework to conceptualize emotional influences on inhibitory control, an important building block of executive functioning. We first summarize current neuro-cognitive models of inhibitory control and show how Bayesian ideal observer models can help reframe inhibitory control as a dynamic decision-making process. Finally, we propose a Bayesian framework to study emotional influences on inhibitory control, providing several hypotheses that may be useful to conceptualize inhibitory control biases in mental illness such as depression and anxiety. To do so, we consider the neurocognitive literature pertaining to how affective states can bias inhibitory control, with particular attention to how valence and arousal may independently impact inhibitory control by biasing probabilistic representations of information (i.e., beliefs) and valuation processes (e.g., speed-error tradeoffs). PMID- 24065902 TI - Executive control and felt concentrative engagement following intensive meditation training. AB - Various forms of mental training have been shown to improve performance on cognitively demanding tasks. Individuals trained in meditative practices, for example, show generalized improvements on a variety of tasks assessing attentional performance. A central claim of this training, derived from contemplative traditions, posits that improved attentional performance is accompanied by subjective increases in the stability and clarity of concentrative engagement with one's object of focus, as well as reductions in felt cognitive effort as expertise develops. However, despite frequent claims of mental stability following training, the phenomenological correlates of meditation related attentional improvements have yet to be characterized. In a longitudinal study, we assessed changes in executive control (performance on a 32-min response inhibition task) and retrospective reports of task engagement (concentration, motivation, and effort) following one month of intensive, daily Vipassana meditation training. Compared to matched controls, training participants exhibited improvements in response inhibition accuracy and reductions in reaction time variability. The training group also reported increases in concentration, but not effort or motivation, during task performance. Critically, increases in concentration predicted improvements in reaction time variability, suggesting a link between the experience of concentrative engagement and ongoing fluctuations in attentional stability. By incorporating experiential measures of task performance, the present study corroborates phenomenological accounts of stable, clear attentional engagement with the object of meditative focus following extensive training. These results provide initial evidence that meditation related changes in felt experience accompany improvements in adaptive, goal directed behavior, and that such shifts may reflect accurate awareness of measurable changes in performance. PMID- 24065903 TI - Towards the integration of mental practice in rehabilitation programs. A critical review. AB - Many clinical studies have investigated the use of mental practice (MP) through motor imagery (MI) to enhance functional recovery of patients with diverse physical disabilities. Although beneficial effects have been generally reported for training motor functions in persons with chronic stroke (e.g., reaching, writing, walking), attempts to integrate MP within rehabilitation programs have been met with mitigated results. These findings have stirred further questioning about the value of MP in neurological rehabilitation. In fact, despite abundant systematic reviews, which customarily focused on the methodological merits of selected studies, several questions about factors underlying observed effects remain to be addressed. This review discusses these issues in an attempt to identify factors likely to hamper the integration of MP within rehabilitation programs. First, the rationale underlying the use of MP for training motor function is briefly reviewed. Second, three modes of MI delivery are proposed based on the analysis of the research protocols from 27 studies in persons with stroke and Parkinson's disease. Third, for each mode of MI delivery, a general description of MI training is provided. Fourth, the review discusses factors influencing MI training outcomes such as: the adherence to MI training, the amount of training and the interaction between physical and mental rehearsal; the use of relaxation, the selection of reliable, valid and sensitive outcome measures, the heterogeneity of the patient groups, the selection of patients and the mental rehearsal procedures. To conclude, the review proposes a framework for integrating MP in rehabilitation programs and suggests research targets for steering the implementation of MP in the early stages of the rehabilitation process. The challenge has now shifted towards the demonstration that MI training can enhance the effects of regular therapy in persons with subacute stroke during the period of spontaneous recovery. PMID- 24065905 TI - Psychological influences on distance estimation in a virtual reality environment. AB - Studies of embodied perception have revealed that social, psychological, and physiological factors influence space perception. While many of these influences were observed with real or highly realistic stimuli, the present work showed that even the orientation of abstract geometric objects in a non-realistic virtual environment could influence distance perception. Observers wore a head mounted display and watched virtual cones moving within an invisible cube for 5 s with their head movement recorded. Subsequently, the observers estimated the distance to the cones or evaluated their friendliness. The cones either faced the observer, a target behind the cones, or were oriented randomly. The average viewing distance to the cones varied between 1.2 and 2.0 m. At a viewing distance of 1.6 m, the observers perceived the cones facing them as closer than the cones facing a target in the opposite direction, or those oriented randomly. Furthermore, irrespective of the viewing distance, observers moved their head away from the cones more strongly and evaluated the cones as less friendly when the cones faced the observers. Similar distance estimation results were obtained with a 3-dimensional projection onto a large screen, although the effective viewing distances were farther away. These results suggest that factors other than physical distance influenced distance perception even with non-realistic geometric objects in a virtual environment. Furthermore, the distance perception modulation was accompanied by changes in subjective impression and avoidance movement. We propose that cones facing an observer are perceived as socially discomforting or threatening, and potentially violate an observer's personal space, which might influence the perceived distance of cones. PMID- 24065904 TI - Extreme prematurity and attention deficit: epidemiology and prevention. PMID- 24065906 TI - NIRS-measured prefrontal cortex activity in neuroergonomics: strengths and weaknesses. PMID- 24065907 TI - Remaining visual field and preserved subjective visual functioning prevent mental distress in patients with visual field defects. AB - BACKGROUND: Patients with visual field defects after visual pathway lesion may experience reduced vision-related quality of life (vrQoL). It has not been clarified how vrQoL impairments contribute to vision-related mental distress. METHODS: One hundred and eight subjects with visual field defects caused by optic neuropathies (age M = 57.6; SD = 13.7 years) answered the National Eye Institute Visual-Functioning Questionnaire 39 (NEI-VFQ) for vrQoL and the SF-12 Short Form Health Survey for health-related quality of life. A 10 item composite of NEI-VFQ "visual functioning" and 5 items of "mental-health symptoms due to vision problems" were subjected to Rasch analysis. The test battery comprised static and High Resolution Perimetry (HRP). Regression and path analysis were used to investigate associations between QoL, mental distress, and perimetry results. RESULTS: A higher level of "visual functioning" was associated with monocular impairment and a larger remaining visual field compared to binocular impairment. Subjective "visual functioning" but not visual field parameters predicted "mental health symptoms due to vision problems" which was the only variable associated with the SF-12 mental component score. The SF-12 physical component score was less strongly associated with "mental-health symptoms due to vision problems." Here, reaction time in HRP and mean threshold in perimetry were additional significant variables. Path analysis revealed a significant path from remaining visual field via visual functioning on mental health. CONCLUSION: Subjective consequences of visual impairments in everyday life impact mental health rather than "objective" visual function loss as measured by perimetry. Since a higher extent of vrQoL was related to lower levels of mental distress, the maintenance of vrQoL could reduce and prevent mental distress due to vision problems. Patients with persisting visual field defects may benefit from neuropsychological rehabilitation and supportive therapies. PMID- 24065908 TI - Perinatal iron deficiency and neurocognitive development. AB - Iron deficiency is the most common form of nutrient deficiency worldwide. It is highly prevalent due to the limited availability of high quality food in developing countries and poor dietary habits in industrialized countries. According to the World Health Organization, it affects nearly 2 billion people and up to 50% of women who are pregnant. Maternal anemia during pregnancy is especially burdensome to healthy neurodevelopment in the fetus because iron is needed for proper neurogenesis, development, and myelination. Maternal anemia also increases the risk of low birth weight, either due to premature birth or fetal growth restriction, which is associated with delayed neurocognitive development and even psychiatric illness. As rapid neurodevelopment continues after birth infants that received sufficient iron in utero, but that receive a low iron diet after 6 months of age, also show deficits in neurocognitive development, including impairments in learning and memory. Unfortunately, the neurocognitive complications of iron deficiency during critical pre- and postnatal periods of brain development are difficult to remedy, persisting into adulthood. Thus, preventing iron deficiency in the pre- and postnatal periods is critical as is devising new means to recapture cognitive function in individuals who experienced early iron deficiency. This review will discuss the prevalence of pre- and postnatal iron deficiency, the mechanism, and effects of iron deficiency on brain and cognitive development. PMID- 24065909 TI - Tonotopic organization in the depth of human inferior colliculus. AB - Experiments in animal models indicate that inferior colliculus (IC), the primary auditory midbrain structure, represents sound frequency in a particular spatial organization, a tonotopy, that proceeds from dorsal and superficial to ventral and deeper tissue. Experiments are presented that use high-resolution, sparse sampling functional magnetic resonance imaging (fMRI) at 3 T to determine if tonotopic gradients can be reliably measured in human IC using high-resolution fMRI. Stimuli were sequences of bandpass-filtered noise with different center frequencies, presented sequentially while fMRI data were collected. Four subjects performed an adaptive frequency-discrimination task throughout the experiment. Results show statistically significant tonotopic gradients within both ICs of all subjects. Frequency gradients as a function of depth were measured using surface based analysis methods that make virtual penetrations into the IC tissue. This organization was evident over substantial portions of the IC, at locations that are consistent with the expected location of the central nucleus of IC. The results confirm a laminar tonotopy in the human IC at 3 T, but with a heterogeneous, patchy character. The success of these surface-based analysis methods will enable more detailed non-invasive explorations of the functional architecture of other subcortical human auditory structures that have complex, laminar organization. PMID- 24065910 TI - Functional cerebral reorganization: a signature of expertise? Reexamining Guida, Gobet, Tardieu, and Nicolas' (2012) two-stage framework. PMID- 24065911 TI - Concurrent application of TMS and near-infrared optical imaging: methodological considerations and potential artifacts. AB - The simultaneous application of transcranial magnetic stimulation (TMS) with non invasive neuroimaging provides a powerful method for investigating functional connectivity in the human brain and the causal relationships between areas in distributed brain networks. TMS has been combined with numerous neuroimaging techniques including, electroencephalography (EEG), functional magnetic resonance imaging (fMRI), and positron emission tomography (PET). Recent work has also demonstrated the feasibility and utility of combining TMS with non-invasive near infrared optical imaging techniques, functional near-infrared spectroscopy (fNIRS) and the event-related optical signal (EROS). Simultaneous TMS and optical imaging affords a number of advantages over other neuroimaging methods but also involves a unique set of methodological challenges and considerations. This paper describes the methodology of concurrently performing optical imaging during the administration of TMS, focusing on experimental design, potential artifacts, and approaches to controlling for these artifacts. PMID- 24065912 TI - Prospects of functional magnetic resonance imaging as lie detector. AB - Following the demise of the polygraph, supporters of assisted scientific lie detection tools have enthusiastically appropriated neuroimaging technologies "as the savior of scientifically verifiable lie detection in the courtroom" (Gerard, 2008: 5). These proponents believe the future impact of neuroscience "will be inevitable, dramatic, and will fundamentally alter the way the law does business" (Erickson, 2010: 29); however, such enthusiasm may prove premature. For in nearly every article published by independent researchers in peer reviewed journals, the respective authors acknowledge that fMRI research, processes, and technology are insufficiently developed and understood for gatekeepers to even consider introducing these neuroimaging measures into criminal courts as they stand today for the purpose of determining the veracity of statements made. Regardless of how favorable their analyses of fMRI or its future potential, they all acknowledge the presence of issues yet to be resolved. Even assuming a future where these issues are resolved and an appropriate fMRI lie-detection process is developed, its integration into criminal trials is not assured for the very success of such a future system may necessitate its exclusion from courtrooms on the basis of existing legal and ethical prohibitions. In this piece, aimed for a multidisciplinary readership, we seek to highlight and bring together the multitude of hurdles which would need to be successfully overcome before fMRI can (if ever) be a viable applied lie detection system. We argue that the current status of fMRI studies on lie detection meets neither basic legal nor scientific standards. We identify four general classes of hurdles (scientific, legal and ethical, operational, and social) and provide an overview on the stages and operations involved in fMRI studies, as well as the difficulties of translating these laboratory protocols into a practical criminal justice environment. It is our overall conclusion that fMRI is unlikely to constitute a viable lie detector for criminal courts. PMID- 24065913 TI - Do cortical gamma oscillations promote or suppress perception? An under-asked question with an over-assumed answer. AB - Cortical gamma oscillations occur alongside perceptual processes, and in proportion to perceptual salience. They have a number of properties that make them ideal candidates to explain perception, including incorporating synchronized discharges of neural assemblies, and their emergence over a fast timescale consistent with that of perception. These observations have led to widespread assumptions that gamma oscillations' role is to cause or facilitate conscious perception (i.e., a "positive" role). While the majority of the human literature on gamma oscillations is consistent with this interpretation, many or most of these studies could equally be interpreted as showing a suppressive or inhibitory (i.e., "negative") role. For example, presenting a stimulus and recording a response of increased gamma oscillations would only suggest a role for gamma oscillations in the representation of that stimulus, and would not specify what that role were; if gamma oscillations were inhibitory, then they would become selectively activated in response to the stimulus they acted to inhibit. In this review, we consider two classes of gamma oscillations: "broadband" and "narrowband," which have very different properties (and likely roles). We first discuss studies on gamma oscillations that are non-discriminatory, with respect to the role of gamma oscillations, followed by studies that specifically support specifically a positive or negative role. These include work on perception in healthy individuals, and in the pathological contexts of phantom perception and epilepsy. Reference is based as much as possible on magnetoencephalography (MEG) and electroencephalography (EEG) studies, but we also consider evidence from invasive recordings in humans and other animals. Attempts are made to reconcile findings within a common framework. We conclude with a summary of the pertinent questions that remain unanswered, and suggest how future studies might address these. PMID- 24065914 TI - A "bottom-up" approach to aetiological research in autism spectrum disorders. AB - Autism spectrum disorders (ASD) are currently diagnosed in the presence of impairments in social interaction and communication, and a restricted range of activities and interests. However, there is considerable variability in the behaviors of different individuals with an ASD diagnosis. The heterogeneity spans the entire range of IQ and language abilities, as well as other behavioral, communicative, and social functions. While any psychiatric condition is likely to incorporate a degree of heterogeneity, the variability in the nature and severity of behaviors observed in ASD is thought to exceed that of other disorders. The current paper aims to provide a model for future research into ASD subgroups. In doing so, we examined whether two proposed risk factors - low birth weight (LBW), and in utero exposure to selective serotonin reuptake inhibitors (SSRIs) - are associated with greater behavioral homogeneity. Using data from the Western Australian Autism Biological Registry, this study found that LBW and maternal SSRI use during pregnancy were associated with greater sleep disturbances and a greater number of gastrointestinal complaints in children with ASD, respectively. The findings from this "proof of principle" paper provide support for this "bottom-up" approach as a feasible method for creating homogenous groups. PMID- 24065915 TI - From action representation to action execution: exploring the links between cognitive and biomechanical levels of motor control. AB - Along with superior performance, research indicates that expertise is associated with a number of mediating cognitive adaptations. To this extent, extensive practice is associated with the development of general and task-specific mental representations, which play an important role in the organization and control of action. Recently, new experimental methods have been developed, which allow for investigating the organization and structure of these representations, along with the functional structure of the movement kinematics. In the current article, we present a new approach for examining the overlap between skill representations and motor output. In doing so, we first present an architecture model, which addresses links between biomechanical and cognitive levels of motor control. Next, we review the state of the art in assessing memory structures underlying complex action. Following we present a new spatio-temporal decomposition method for illuminating the functional structure of movement kinematics, and finally, we apply these methods to investigate the overlap between the structure of motor representations in memory and their corresponding kinematic structures. Our aim is to understand the extent to which the output at a kinematic level is governed by representations at a cognitive level of motor control. PMID- 24065917 TI - The utility of age-specific cut-offs for visual rating of medial temporal atrophy in classifying Alzheimer's disease, MCI and cognitively normal elderly subjects. AB - BACKGROUND: New research criteria for diagnosing Alzheimer's disease (AD) in the mild cognitive impairment stage (MCI-AD) incorporate biomarkers to assign a level of certainty to the diagnosis. Structural MRI is widely available but greatly under-utilized for assessing atrophy of structures affected in early AD, such as the hippocampus (HP), because the quantification of HP volumes (HP-v) requires special expertise, and normative values have not been established. METHODS: Elderly subjects (n =273) from the Florida ADRC were classified as having no cognitive impairment (cognitively normal, CN), amnestic mild cognitive impairment (aMCI) or AD. Volumes for the hippocampus (HP-v) were measured on structural MRI scans. A validated visual rating system for measuring medial temporal atrophy (VRS-MTA), including hippocampal, entorhinal cortex and perirhinal cortex atrophy was employed. The participants were subdivided into younger (less than or equal to 75 years of age) and older (greater than 75 years of age) subgroups. RESULTS: Volumetric and VRS-MTA measures were equivalent in predicting classification of CN vs. aMCI for older (area under the receiver operator curves [aROC]: 0.652 vs. 0.723) and younger subjects (aROC: 0.764 vs. 0.736). However, for younger AD subjects, aROC values were significantly higher for VRS-MTA measures (0.920) than for volumetric measures (0.847). Relative to HP-v, VRS-MTA score was significantly more correlated to impairment on a range of memory tests and was more associated with progression of aMCI to AD than HP-v. CONCLUSION: Structural MRI with VRS-MTA assessment can serve as a biomarker for supporting the diagnosis of MCI-AD. Age-adjusted VRS-MTA scores are at least as effective as HP-v for distinguishing aMCI and AD from CN and for predicting progression from aMCI to AD. VRS-MTA is convenient for use in the clinic as well as for clinical trials and can readily be incorporated into a standardized radiological report. PMID- 24065916 TI - Growth factors in synaptic function. AB - Synapses are increasingly recognized as key structures that malfunction in disorders like schizophrenia, mental retardation, and neurodegenerative diseases. The importance and complexity of the synapse has fuelled research into the molecular mechanisms underlying synaptogenesis, synaptic transmission, and plasticity. In this regard, neurotrophic factors such as netrin, Wnt, transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF alpha), and others have gained prominence for their ability to regulate synaptic function. Several of these factors were first implicated in neuroprotection, neuronal growth, and axon guidance. However, their roles in synaptic development and function have become increasingly clear, and the downstream signaling pathways employed by these factors have begun to be elucidated. In this review, we will address the role of these factors and their downstream effectors in synaptic function in vivo and in cultured neurons. PMID- 24065919 TI - Prevention of vision loss protects against age-related impairment in learning and memory performance in DBA/2J mice. AB - The DBA/2J mouse is a model of pigmentary glaucoma in humans as it shows age related increases in intraocular pressure (IOP), retinal ganglion cell death and visual impairment. Previously, we showed that visual ability declines from 9 to 12 months of age and visual impairment is correlated with poor learning and memory performance in visuo-spatial tasks but not in tasks that do not depend on visual cues. To test the "sensory impairment" hypothesis of aging, which postulates that sensory impaired individuals are disadvantaged in their performance on psychometric tests as a direct result of difficulties in sensory perception, we treated DBA/2J mice with a conventional glaucoma medication used in humans (Timoptic-XE, 0.00, 0.25, or 0.50%) daily from 9 weeks to 12 months of age to determine whether prevention of vision loss prevented the decline in visuo spatial learning and memory performance. At all ages tested (3, 6, 9, and 12 months of age), mice treated with Timoptic-XE (0.25 and 0.50%) maintained a high level of performance, while 12 month old control mice (0.00%) exhibited impaired performance in visually-dependent, but not non-visual tasks. These results demonstrate that when sensory function is preserved, cognitive performance is normalized. Thus, as in many aging humans, DBA/2J mice show age-related decrements in performance on visually presented cognitive tests, not because of cognitive impairment but as a direct consequence of poor visual ability. Our results demonstrate that age-related impairment in performance in visuo-spatial tasks in DBA/2J mice can be prevented by the preservation of visual ability. PMID- 24065918 TI - A combined electrophysiological and morphological examination of episodic memory decline in amnestic mild cognitive impairment. AB - Early stages of Alzheimer's disease (AD) are characterized by neuropathological changes within the medial temporal lobe cortex (MTLC), which lead to characteristic impairments in episodic memory, i.e., amnestic mild cognitive impairment (aMCI). Here, we tested the neural correlates of this memory impairment using event-related potentials (ERPs) and voxel-based morphometry. Twenty-four participants were instructed to encode lists of words and were tested in a yes/no recognition memory task. The dual-process model of recognition memory dissociates between acontextual familiarity and recollection of contextual details. The early frontal ERP old/new effect, which is thought to represent a neural correlate of familiarity-based memory, was absent in aMCI, whereas the control group showed a significant early old/new effect at frontal electrodes. This effect was positively correlated with behavioral episodic memory performance. Analyses of brain morphology revealed a focused gray matter loss in the inferior and medial temporal lobes in aMCI versus healthy controls. Moreover, the positive correlation between gray matter volume in the MTLC and the familiarity-related early frontal old/new effect supports the notion that this effect relies upon the integrity of the MTLC. Thus, the present findings might provide a further functional marker for prodromal AD. PMID- 24065920 TI - Acute nicotine administration effects on fractional anisotropy of cerebral white matter and associated attention performance. AB - INTRODUCTION: Nicotinic acetylcholine receptors are present in the cerebral white matter (WM). We hypothesized that WM response to nicotine can be detected by diffusion tensor imaging (DTI); and that such responses may be associated with nicotine-led cognitive enhancement in sustained attention. METHODS: A randomized, nicotine-placebo patch, crossover, double-blind clinical trial in two non overlapping cohorts of smokers was used to test the hypothesis. The discovery cohort consisted of 39 subjects (N = 20/19 controls/schizophrenic patients, age = 36.8 +/- 10.1 years) and the replication cohorts consisted of 38 healthy smokers (31.7 +/- 10.5 years). WM integrity was measured by fractional anisotropy (FA) values for the whole brain and nine preselected WM tracts using tract-based spatial-statistics. RESULTS: Nicotine significantly enhanced FA values for the genu of corpus callosum compared with placebo (DeltaFAgenu) (p = 0.01) in smokers with low recent smoking exposure as measured by low average cotinine level. This finding was replicated in the second cohort (p = 0.02). DeltaFAgenu values explained 22% of variance in performance of a sustained attention task during the nicotine session (p = 0.006). However, this effect was limited to schizophrenia patients (r = 0.62 and 0.09; p = 0.003 and 0.7 for patients and controls, respectively). CONCLUSION: Acute pharmacological influence of nicotine patch on WM integrity appeared present, but was dependent on nicotine intake from recent smoking. Change in the WM integrity in the genu of corpus callosum was associated with a significant proportion of variability of nicotine-led changes in sustained attention/working memory of the smokers. Further studies will be necessary to understand biophysical underpinning of the nicotine-related changes in FA. PMID- 24065921 TI - A thermosensitive mutation alters the effects of lacosamide on slow inactivation in neuronal voltage-gated sodium channels, NaV1.2. AB - Epilepsy is a disorder characterized by seizures and convulsions. The basis of epilepsy is an increase in neuronal excitability that, in some cases, may be caused by functional defects in neuronal voltage gated sodium channels (NaVs). The C121W mutation of the beta1 subunit, in particular, gives rise to the thermosensitive generalized epilepsy with febrile seizures plus (GEFS+) phenotype. Lacosamide is used to treat epileptic seizures and is distinct from other anti-seizure drugs by targeting NaV slow-inactivation. We studied the effects of a physiologically relevant concentration of lacosamide on the biophysical properties of NaV1.2 channels associated with either WT-beta1 or the mutant C121W-beta1 subunit. Biophysical parameters were measured at both normal (22 degrees C) and elevated (34 degrees C) temperatures to elicit the differential temperature-sensitivity of C121W. Lacosamide was more effective in NaV1.2 associated with the WT-beta1 than with C121W-beta1 at either temperature. There is also a more potent effect by lacosamide on slow inactivation at elevated temperatures. Our data suggest a modulatory role is imparted by the beta1 subunit in the interaction between the drug and the channel. PMID- 24065922 TI - P2Y2 receptor deficiency aggravates chronic kidney disease progression. AB - Purinergic signaling is involved in a variety of physiological states. P2 receptors are mainly activated by adenosine triphosphate (ATP). Activation of specific P2Y receptor subtypes might influence progression of kidney disease. To investigate the in vivo effect of a particular P2 receptor subtype on chronic kidney disease progression, subtotal nephrectomy was performed on wild type (WT) and P2Y2 receptor knockout (KO) mice. During the observational period of 56 +/- 2 days, survival of KO mice was inferior compared to WT mice after SNX. Subtotal nephrectomy reduced creatinine clearance in both groups of mice, but the decrease was significantly more pronounced in KO compared to WT mice (53.9 +/- 7.7 vs. 84.3 +/- 8.7MUl/min at day 56). The KO mice also sustained a greater increase in systolic blood pressure after SNX compared to WT mice (177 +/- 2 vs. 156 +/- 7 mmHg) and a 2.5-fold increase in albuminuria compared to WT. In addition, WT kidneys showed a significant increase in remnant kidney mass 56 days after SNX, but significant attenuation of hypertrophy in KO mice was observed. In line with the observed hypertrophy in WT SNX mice, a significant dose-dependent increase in DNA synthesis, a marker of proliferation, was present in cultured WT glomerular epithelial cells upon ATP stimulation. Markers for tissue damage (TGF-beta 1, PAI 1) and proinflammatory target genes (MCP1) were significantly upregulated in KO mice after SNX compared to WT SNX mice. In summary, deletion of the P2Y2 receptor leads to greater renal injury after SNX compared to WT mice. Higher systolic blood pressure and inability of compensatory hypertrophy in KO mice are likely causes for the accelerated progression of chronic kidney disease. PMID- 24065923 TI - Renal epithelial cells can release ATP by vesicular fusion. AB - Renal epithelial cells have the ability to release nucleotides as paracrine factors. In the intercalated cells of the collecting duct, ATP is released by connexin30 (cx30), which is selectively expressed in this cell type. However, ATP is released by virtually all renal epithelia and the aim of the present study was to identify possible alternative nucleotide release pathways in a renal epithelial cell model. We used MDCK (type1) cells to screen for various potential ATP release pathways. In these cells, inhibition of the vesicular H(+)-ATPases (bafilomycin) reduced both the spontaneous and hypotonically (80%)-induced nucleotide release. Interference with vesicular fusion using N-ethylamide markedly reduced the spontaneous nucleotide release, as did interference with trafficking from the endoplasmic reticulum to the Golgi apparatus (brefeldin A1) and vesicular transport (nocodazole). These findings were substantiated using a siRNA directed against SNAP-23, which significantly reduced spontaneous ATP release. Inhibition of pannexin and connexins did not affect the spontaneous ATP release in this cell type, which consists of ~90% principal cells. TIRF microscopy of either fluorescently-labeled ATP (MANT-ATP) or quinacrine-loaded vesicles, revealed that spontaneous release of single vesicles could be promoted by either hypoosmolality (50%) or ionomycin. This vesicular release decreased the overall cellular fluorescence by 5.8 and 7.6% respectively. In summary, this study supports the notion that spontaneous and induced ATP release can occur via exocytosis in renal epithelial cells. PMID- 24065924 TI - It's not black or white-on the range of vision and echolocation in echolocating bats. AB - Around 1000 species of bats in the world use echolocation to navigate, orient, and detect insect prey. Many of these bats emerge from their roost at dusk and start foraging when there is still light available. It is however unclear in what way and to which extent navigation, or even prey detection in these bats is aided by vision. Here we compare the echolocation and visual detection ranges of two such species of bats which rely on different foraging strategies (Rhinopoma microphyllum and Pipistrellus kuhlii). We find that echolocation is better than vision for detecting small insects even in intermediate light levels (1-10 lux), while vision is advantageous for monitoring far-away landscape elements in both species. We thus hypothesize that, bats constantly integrate information acquired by the two sensory modalities. We suggest that during evolution, echolocation was refined to detect increasingly small targets in conjunction with using vision. To do so, the ability to hear ultrasonic sound is a prerequisite which was readily available in small mammals, but absent in many other animal groups. The ability to exploit ultrasound to detect very small targets, such as insects, has opened up a large nocturnal niche to bats and may have spurred diversification in both echolocation and foraging tactics. PMID- 24065926 TI - Further steps toward functional systems biology of cancer. PMID- 24065925 TI - Identifying potential functional impact of mutations and polymorphisms: linking heart failure, increased risk of arrhythmias and sudden cardiac death. AB - Researchers and clinicians have discovered several important concepts regarding the mechanisms responsible for increased risk of arrhythmias, heart failure, and sudden cardiac death. One major step in defining the molecular basis of normal and abnormal cardiac electrical behavior has been the identification of single mutations that greatly increase the risk for arrhythmias and sudden cardiac death by changing channel-gating characteristics. Indeed, mutations in several genes encoding ion channels, such as SCN5A, which encodes the major cardiac Na(+) channel, have emerged as the basis for a variety of inherited cardiac arrhythmias such as long QT syndrome, Brugada syndrome, progressive cardiac conduction disorder, sinus node dysfunction, or sudden infant death syndrome. In addition, genes encoding ion channel accessory proteins, like anchoring or chaperone proteins, which modify the expression, the regulation of endocytosis, and the degradation of ion channel a-subunits have also been reported as susceptibility genes for arrhythmic syndromes. The regulation of ion channel protein expression also depends on a fine-tuned balance among different other mechanisms, such as gene transcription, RNA processing, post-transcriptional control of gene expression by miRNA, protein synthesis, assembly and post-translational modification and trafficking. The aim of this review is to inventory, through the description of few representative examples, the role of these different biogenic mechanisms in arrhythmogenesis, HF and SCD in order to help the researcher to identify all the processes that could lead to arrhythmias. Identification of novel targets for drug intervention should result from further understanding of these fundamental mechanisms. PMID- 24065927 TI - Autonomic regulation in muscular dystrophy. PMID- 24065929 TI - Can neurostimulation prevent the risk of Alzheimer's disease in elderly individuals with schizophrenia? PMID- 24065928 TI - Neural Responses during Social and Self-Knowledge Tasks in Bulimia Nervosa. AB - Self-evaluation closely dependent upon body shape and weight is one of the defining criteria for bulimia nervosa (BN). We studied 53 adult women, 17 with BN, 18 with a recent history of anorexia nervosa (AN), and 18 healthy comparison women, using three different fMRI tasks that required thinking about self knowledge and social interactions: the Social Identity task, the Physical Identity task, and the Social Attribution task. Previously, we identified regions of interest (ROI) in the same tasks using whole-brain voxel-wise comparisons of the healthy comparison women and women with a recent history of AN. Here, we report on the neural activations in those ROIs in subjects with BN. In the Social Attribution task, we examined activity in the right temporoparietal junction (RTPJ), an area frequently associated with mentalization. In the Social Identity task, we examined activity in the precuneus (PreC) and dorsal anterior cingulate (dACC). In the Physical Identity task, we examined activity in a ventral region of the dACC. Interestingly, in all tested regions, the average activation in subjects with bulimia was more than the average activation levels seen in the subjects with a history of anorexia but less than that seen in healthy subjects. In three regions, the RTPJ, the PreC, and the dACC, group responses in the subjects with bulimia were significantly different from healthy subjects but not subjects with anorexia. The neural activations of people with BN performing fMRI tasks engaging social processing are more similar to people with AN than healthy people. This suggests biological measures of social processes may be helpful in characterizing individuals with eating disorders. PMID- 24065930 TI - Transcranial direct current stimulation reduces negative affect but not cigarette craving in overnight abstinent smokers. AB - Transcranial direct current stimulation (tDCS) can enhance cognitive control functions including attention and top-down regulation over negative affect and substance craving in both healthy and clinical populations, including early abstinent (~1.5 h) smokers. The aim of this study was to assess whether tDCS modulates negative affect, cigarette craving, and attention of overnight abstinent tobacco dependent smokers. In this study, 24 smokers received a real and a sham session of tDCS after overnight abstinence from smoking on two different days. We applied anode to the left dorsolateral prefrontal cortex and cathode to the right supra-orbital area for 20 min with a current of 2.0 mA. We used self-report questionnaires Profile of Mood States (POMS) to assess negative affect and Urge to Smoke (UTS) Scale to assess craving for cigarette smoking, and a computerized visual target identification task to assess attention immediately before and after each tDCS. Smokers reported significantly greater reductions in POMS scores of total mood disturbance and scores of tension-anxiety, depression dejection, and confusion-bewilderment subscales after real relative to sham tDCS. Furthermore, this reduction in negative affect positively correlated with the level of nicotine dependence as assessed by Fagerstrom scale. However, reductions in cigarette craving after real vs. sham tDCS did not differ, nor were there differences in reaction time or hit rate change on the visual task. Smokers did not report significant side effects of tDCS. This study demonstrates the safety of tDCS and its promising effect in ameliorating negative affect in overnight abstinent smokers. Its efficacy in treating tobacco dependence deserves further investigation. PMID- 24065932 TI - The influence of high-level beliefs on self-regulatory engagement: evidence from thermal pain stimulation. AB - Determinist beliefs have been shown to impact basic motor preparation, prosocial behavior, performance monitoring, and voluntary inhibition, presumably by diminishing the recruitment of cognitive resources for self-regulation. We sought to support and extend previous findings by applying a belief manipulation to a novel inhibition paradigm that requires participants to either execute or suppress a prepotent withdrawal reaction from a strong aversive stimulus (thermal pain). Action and inhibition responses could be determined by either external signals or voluntary choices. Our results suggest that the reduction of free will beliefs corresponds with a reduction in effort investment that influences voluntary action selection and inhibition, most directly indicated by increased time required to initiate a withdrawal response internally (but not externally). It is likely that disbelief in free will encourages participants to be more passive, to exhibit a reduction in intentional engagement, and to be disinclined to adapt their behavior to contextual needs. PMID- 24065931 TI - The CHRNA3 rs578776 Variant is Associated with an Intrinsic Reward Sensitivity Deficit in Smokers. AB - A compromised brain reward system has been postulated as a key feature of drug dependence. We examined whether several polymorphisms of genes found to regulate nicotinic acetylcholine receptor (nAChR) and dopamine expression were related to an intrinsic reward sensitivity (IRS) deficit we previously identified among a subgroup of smokers using event-related potentials (ERPs). We examined genetic polymorphisms within the CHRNA5-A3-B4 gene cluster (CHRNA3 rs578776, CHRNA5 rs16969968, LOC123688 rs8034191, and CHRNA3 rs1051730), the ANKK1 gene (rs1800497), and the D2 dopamine receptor gene (DRD2 rs1079597, DRD2 rs1799732) from 104 smokers of European ancestry in a smoking cessation trial. Prior to treatment, we recorded ERPs evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related pictures. Smokers were assigned to two groups (IRS+/IRS-) based on the amplitude of the late positive potential (LPP) component to the pictures, a neural marker of motivational salience. Smokers (n = 42) with blunted brain responses to intrinsically rewarding (pleasant) pictures and enhanced responses to cigarette pictures were assigned to the IRS- group, while smokers (n = 62) with the opposite pattern of LPP responding were assigned to the IRS+ group. Carriers of the protective minor T allele (T/T, C/T) of the CHRNA3 rs578776 were less likely to be members of the IRS- group than those homozygous for the at-risk C allele (C/C). The CHRNA3 rs578776 polymorphism did not differ on questionnaires of nicotine dependence, depressed mood, or trait affective disposition and did not predict abstinence at 6 months after the quit date. These results suggest that polymorphisms of genes influencing nAChR expression are related to an endophenotype of reward sensitivity in smokers. PMID- 24065933 TI - Everyday attention and lecture retention: the effects of time, fidgeting, and mind wandering. AB - We have all had our thoughts wander from the immediate task at hand. The emerging embodied cognition literature emphasizes the role that the body plays in human thought, and raises the possibility that changes in attentional focus may be associated with changes in body behavior. Recent research has found that when individuals view a lecture, mind wandering increases as a function of time. In the present study we asked whether this decline in attention during lecture viewing was associated with fidgeting. Participants were filmed while they watched a 40-min lecture video, and at regular 5-min intervals provided ratings of their attentiveness. Following the lecture, participant's memory for the material was assessed. Fidgeting behavior was coded from video recordings of each session. Results indicated that attention to, and retention of, lecture material declined as a function of time on task. Critically, and as predicted, fidgeting also increased with time on task. We also found that the relation between fidgeting and retention was significant even when the role of attention was factored into the equation, suggesting that fidgeting makes a unique contribution to retention of lecture material over and above that contributed by an individual's attention. We propose a novel non-attentional stress-based account of fidgeting and how this impacts retention for lecture material over and above changes in levels in mind wandering vis-a-vis changes in attention. PMID- 24065934 TI - Combined visual and motor disorganization in patients with schizophrenia. AB - Cognitive impairments are difficult to relate to clinical symptoms in schizophrenia, partly due to insufficient knowledge on how cognitive impairments interact with one another. Here, we devised a new sequential pointing task requiring both visual organization and motor sequencing. Six circles were presented simultaneously on a touch screen around a fixation point. Participants pointed with the finger each circle one after the other, in synchrony with auditory tones. We used an alternating rhythmic 300/600 ms pattern so that participants performed pairs of taps separated by short intervals of 300 ms. Visual organization was manipulated by using line-segments that grouped the circles two by two, yielding three pairs of connected circles, and three pairs of unconnected circles that belonged to different pairs. This led to three experimental conditions. In the "congruent condition," the pairs of taps had to be executed on circles grouped by connecters. In the "non congruent condition," they were to be executed on the unconnected circles that belonged to different pairs. In a neutral condition, there were no connecters. Twenty two patients with schizophrenia with mild symptoms and 22 control participants performed a series of 30 taps in each condition. Tap pairs were counted as errors when the produced rhythm was inverted (expected rhythm 600/300 = 2; inversed rhythm <1). Error rates in patients with a high level of clinical disorganization were significantly higher in the non-congruent condition than in the two other conditions, contrary to controls and the remaining patients. The tap-tone asynchrony increased in the presence of connecters in both patient groups, but not in the controls. Patients appeared not to integrate the visual organization during the planning phase of action, leading to a large difficulty during motor execution, especially in those patients revealing difficulties in visual organization. Visual motor tapping tasks may help detect those subgroups of patients. PMID- 24065935 TI - Musical training heightens auditory brainstem function during sensitive periods in development. AB - Experience has a profound influence on how sound is processed in the brain. Yet little is known about how enriched experiences interact with developmental processes to shape neural processing of sound. We examine this question as part of a large cross-sectional study of auditory brainstem development involving more than 700 participants, 213 of whom were classified as musicians. We hypothesized that experience-dependent processes piggyback on developmental processes, resulting in a waxing-and-waning effect of experience that tracks with the undulating developmental baseline. This hypothesis led to the prediction that experience-dependent plasticity would be amplified during periods when developmental changes are underway (i.e., early and later in life) and that the peak in experience-dependent plasticity would coincide with the developmental apex for each subcomponent of the auditory brainstem response (ABR). Consistent with our predictions, we reveal that musicians have heightened response features at distinctive times in the life span that coincide with periods of developmental change. The effect of musicianship is also quite specific: we find that only select components of auditory brainstem activity are affected, with musicians having heightened function for onset latency, high-frequency phase-locking, and response consistency, and with little effect observed for other measures, including lower-frequency phase-locking and non-stimulus-related activity. By showing that musicianship imparts a neural signature that is especially evident during childhood and old age, our findings reinforce the idea that the nervous system's response to sound is "chiseled" by how a person interacts with his specific auditory environment, with the effect of the environment wielding its greatest influence during certain privileged windows of development. PMID- 24065936 TI - Ode to positive constructive daydreaming. AB - Nearly 60 years ago, Jerome L. Singer launched a groundbreaking research program into daydreaming (Singer, 1955, 1975, 2009) that presaged and laid the foundation for virtually every major strand of mind wandering research active today (Antrobus, 1999; Klinger, 1999, 2009). Here we review Singer's enormous contribution to the field, which includes insights, methodologies, and tools still in use today, and trace his enduring legacy as revealed in the recent proliferation of mind wandering studies. We then turn to the central theme in Singer's work, the adaptive nature of positive constructive daydreaming, which was a revolutionary idea when Singer began his work in the 1950s and remains underreported today. Last, we propose a new approach to answering the enduring question: Why does mind wandering persist and occupy so much of our time, as much as 50% of our waking time according to some estimates, if it is as costly as most studies suggest? PMID- 24065937 TI - Dual conception of risk in the Iowa Gambling Task: effects of sleep deprivation and test-retest gap. AB - Risk in the Iowa Gambling Task (IGT) is often understood in terms of intertemporal choices, i.e., preference for immediate outcomes in favor of delayed outcomes is considered risky decision making. According to behavioral economics, healthy decision makers are expected to refrain from choosing the short-sighted immediate gain because, over time (10 trials of the IGT), the immediate gains result in a long term loss (net loss). Instead decision makers are expected to maximize their gains by choosing options that, over time (10 trials), result in delayed or long term gains (net gain). However, task choices are sometimes made on the basis of the frequency of reward and punishment such that frequent rewards/infrequent punishments are favored over infrequent rewards/frequent punishments. The presence of these two attributes (intertemporality and frequency of reward) in IGT decision making may correspond to the emotion-cognition dichotomy and reflect a dual conception of risk. Decision making on the basis of the two attributes was tested under two conditions: delay in retest and sleep deprivation. An interaction between sleep deprivation and time delay was expected to attenuate the difference between the two attributes. Participants were 40 male university students. Analysis of the effects of IGT attribute type (intertemporal vs. frequency of reinforcement), sleep deprivation (sleep deprivation vs. no sleep deprivation), and test-retest gap (short vs. long delay) showed a significant within-subjects effect of IGT attribute type thus confirming the difference between the two attributes. Sleep deprivation had no effect on the attributes, but test-retest gap and the three way interaction between attribute type, test-retest gap, and sleep deprivation were significantly different. Post-hoc tests revealed that sleep deprivation and short test-retest gap attenuated the difference between the two attributes. Furthermore, the results showed an expected trend of increase in intertemporal decision making at retest suggesting that intertemporal decision making benefited from repeated task exposure. The present findings add to understanding of the emotion-cognition dichotomy. Further, they show an important time-dependent effect of a universally experienced constraint (sleep deprivation) on decision making. It is concluded that risky decision making in the IGT is contingent on the attribute under consideration and is affected by factors such as time elapsed and constraint experienced before the retest. PMID- 24065938 TI - Grapheme-color synaesthesia is associated with a distinct cognitive style. AB - In this study we investigated whether synaesthesia is associated with a particular cognitive style. Cognitive style refers to preferred modes of information processing, such as a verbal style or a visual style. We reasoned that related to the enriched world of experiences created by synaesthesia, its association with enhanced verbal and visual memory, higher imagery and creativity, synaesthetes might show enhanced preference for a verbal as well as for a visual cognitive style compared to non-synaesthetes. In Study 1 we tested a large convenience sample of 1046 participants, who classified themselves as grapheme-color, sound-color, lexical-gustatory, sequence-space, or as non synaesthetes. To assess cognitive style, we used the revised verbalizer visualizer questionnaire (VVQ), which involves three independent cognitive style dimensions (verbal style, visual-spatial style, and vivid imagery style). The most important result was that those who reported grapheme-color synaesthesia showed higher ratings on the verbal and vivid imagery style dimensions, but not on the visual-spatial style dimension. In Study 2 we replicated this finding in a laboratory study involving 24 grapheme-color synaesthetes with objectively confirmed synaesthesia and a closely matched control group. Our results indicate that grapheme-color synaesthetes prefer both a verbal and a specific visual cognitive style. We suggest that this enhanced preference, probably together with the greater ease to switch between a verbal and a vivid visual imagery style, may be related to cognitive advantages associated with grapheme color synaesthesia such as enhanced memory performance and creativity. PMID- 24065939 TI - Deep generative learning of location-invariant visual word recognition. AB - It is widely believed that orthographic processing implies an approximate, flexible coding of letter position, as shown by relative-position and transposition priming effects in visual word recognition. These findings have inspired alternative proposals about the representation of letter position, ranging from noisy coding across the ordinal positions to relative position coding based on open bigrams. This debate can be cast within the broader problem of learning location-invariant representations of written words, that is, a coding scheme abstracting the identity and position of letters (and combinations of letters) from their eye-centered (i.e., retinal) locations. We asked whether location-invariance would emerge from deep unsupervised learning on letter strings and what type of intermediate coding would emerge in the resulting hierarchical generative model. We trained a deep network with three hidden layers on an artificial dataset of letter strings presented at five possible retinal locations. Though word-level information (i.e., word identity) was never provided to the network during training, linear decoding from the activity of the deepest hidden layer yielded near-perfect accuracy in location-invariant word recognition. Conversely, decoding from lower layers yielded a large number of transposition errors. Analyses of emergent internal representations showed that word selectivity and location invariance increased as a function of layer depth. Word-tuning and location-invariance were found at the level of single neurons, but there was no evidence for bigram coding. Finally, the distributed internal representation of words at the deepest layer showed higher similarity to the representation elicited by the two exterior letters than by other combinations of two contiguous letters, in agreement with the hypothesis that word edges have special status. These results reveal that the efficient coding of written words which was the model's learning objective-is largely based on letter-level information. PMID- 24065940 TI - Dreaming, waking conscious experience, and the resting brain: report of subjective experience as a tool in the cognitive neurosciences. AB - Even when we are ostensibly doing "nothing"-as during states of rest, sleep, and reverie-the brain continues to process information. In resting wakefulness, the mind generates thoughts, plans for the future, and imagines fictitious scenarios. In sleep, when the demands of sensory input are reduced, our experience turns to the thoughts and images we call "dreaming." Far from being a meaningless distraction, the content of these subjective experiences provides an important and unique source of information about the activities of the resting mind and brain. In both wakefulness and sleep, spontaneous experience combines recent and remote memory fragments into novel scenarios. These conscious experiences may reflect the consolidation of recent memory into long-term storage, an adaptive process that functions to extract general knowledge about the world and adaptively respond to future events. Recent examples from psychology and neuroscience demonstrate that the use of subjective report can provide clues to the function(s) of rest and sleep. PMID- 24065941 TI - No learning where to go without first knowing where you're coming from: action discovery is trajectory, not endpoint based. AB - Intrinsic motivations drive an agent to explore, providing essential data for linking behaviors with novel outcomes and so laying the foundation for future flexible action. We present experiments using a new behavioral task which allows us to interrogate the connection between exploration and action learning. Human participants used a joystick to search repeatedly for a target location, only receiving feedback on successful discovery. Feedback delay was manipulated, as was the starting position. Experiment 1 employed stable starting positions, so the task could be learnt with respect to a target location or a target trajectory. Participants were able to learn the correct movement under all delay conditions. Experiment 2 used a variable starting location, so the correct movement could only be learnt in terms of target location. Participants displayed little to no learning in this experiment. These results suggest that movements on this scale are stored as trajectories rather than in terms of target location. Overall the experiments demonstrate the potential of this task for uncovering the native representational substrates of action learning. PMID- 24065942 TI - Age effects on explicit and implicit memory. AB - It is well-documented that explicit memory (e.g., recognition) declines with age. In contrast, many argue that implicit memory (e.g., priming) is preserved in healthy aging. For example, priming on tasks such as perceptual identification is often not statistically different in groups of young and older adults. Such observations are commonly taken as evidence for distinct explicit and implicit learning/memory systems. In this article we discuss several lines of evidence that challenge this view. We describe how patterns of differential age-related decline may arise from differences in the ways in which the two forms of memory are commonly measured, and review recent research suggesting that under improved measurement methods, implicit memory is not age-invariant. Formal computational models are of considerable utility in revealing the nature of underlying systems. We report the results of applying single and multiple-systems models to data on age effects in implicit and explicit memory. Model comparison clearly favors the single-system view. Implications for the memory systems debate are discussed. PMID- 24065943 TI - Charting the role of the number line in mathematical development. AB - Individuals who do well in mathematics and science also often have good spatial skills. However, the predictive direction of links between spatial abilities and mathematical learning has not been firmly established, especially for young children. In the present research, we addressed this issue using a sample from a longitudinal data set that spanned 4 years and which includes measures of mathematical performance and various cognitive skills, including spatial ability. Children were tested once in each of 4 years (Time 1, 2, 3, and 4). At Time 3 and 4, 101 children (in Grades 2, 3, or 4 at Time 3) completed mathematical measures including (a) a number line task (0-1000), (b) arithmetic, and (c) number system knowledge. Measures of spatial ability were collected at Time 1, 2, or 3. As expected, spatial ability was correlated with all of the mathematical measures at Time 3 and 4, and predicted growth in number line performance from Time 3 to Time 4. However, spatial ability did not predict growth in either arithmetic or in number system knowledge. Path analyses were used to test whether number line performance at Time 3 was predictive of arithmetic and number system knowledge at Time 4 or whether the reverse patterns were dominant. Contrary to the prediction that the number line is an important causal construct that facilitates learning arithmetic, no evidence was found that number line performance predicted growth in calculation more than calculation predicted number line growth. However, number system knowledge at Time 3 was predictive of number line performance at Time 4, independently of spatial ability. These results provide useful information about which aspects of growth in mathematical performance are (and are not) related to spatial ability and clarify the relations between number line performance and measures of arithmetic and number system knowledge. PMID- 24065944 TI - Fading red? No evidence that color of trunks influences outcomes in the ultimate fighting championship (UFC). PMID- 24065945 TI - Erratum: Music processing similarities between sleeping newborns and alert adults: cause for celebration or concern? AB - [This corrects the article on p. 492 in vol. 4, PMID: 23966962.]. PMID- 24065946 TI - Enhanced musical rhythmic perception in Turkish early and late learners of German. AB - As language rhythm relies partly on general acoustic properties, such as intensity and duration, mastering two languages with distinct rhythmic properties (i.e., stress position) may enhance musical rhythm perception. We investigated whether competence in a second language (L2) with different rhythmic properties than a L1 affects musical rhythm aptitude. Turkish early (TELG) and late learners (TLLG) of German were compared to German late L2 learners of English (GLE) regarding their musical rhythmic aptitude. While Turkish and German present distinct linguistic rhythm and metric properties, German and English are rather similar in this regard. To account for inter-individual differences, we measured participants' short-term and working memory (WM) capacity, melodic aptitude, and time they spent listening to music. Both groups of Turkish L2 learners of German perceived rhythmic variations significantly better than German L2 learners of English. No differences were found between early and late learners' performance. Our findings suggest that mastering two languages with different rhythmic properties enhances musical rhythm perception, providing further evidence of shared cognitive resources between language and music. PMID- 24065947 TI - Application of the ex-Gaussian function to the effect of the word blindness suggestion on Stroop task performance suggests no word blindness. AB - The aim of the present paper was to apply the ex-Gaussian function to data reported by Parris et al. (2012) given its utility in studies involving the Stroop task. Parris et al. showed an effect of the word blindness suggestion when Response-Stimulus Interval (RSI) was 500 ms but not when it was 3500 ms. Analysis revealed that: (1) The effect of the suggestion on interference is observed in MU, supporting converging evidence indicating the suggestion operates over response competition mechanisms; and, (2) Contrary to Parris et al. an effect of the suggestion was observed in MU when RSI was 3500 ms. The reanalysis of the data from Parris et al. (2012) supports the utility of ex-Gaussian analysis in revealing effects that might otherwise be thought of as absent. We suggest that word reading itself is not suppressed by the suggestion but instead that response conflict is dealt with more effectively. PMID- 24065948 TI - Autonomous visual exploration creates developmental change in familiarity and novelty seeking behaviors. AB - What motivates children to radically transform themselves during early development? We addressed this question in the domain of infant visual exploration. Over the first year, infants' exploration shifts from familiarity to novelty seeking. This shift is delayed in preterm relative to term infants and is stable within individuals over the course of the first year. Laboratory tasks have shed light on the nature of this familiarity-to-novelty shift, but it is not clear what motivates the infant to change her exploratory style. We probed this by letting a Dynamic Neural Field (DNF) model of visual exploration develop itself via accumulating experience in a virtual world. We then situated it in a canonical laboratory task. Much like infants, the model exhibited a familiarity to-novelty shift. When we manipulated the initial conditions of the model, the model's performance was developmentally delayed much like preterm infants. This delay was overcome by enhancing the model's experience during development. We also found that the model's performance was stable at the level of the individual. Our simulations indicate that novelty seeking emerges with no explicit motivational source via the accumulation of visual experience within a complex, dynamical exploratory system. PMID- 24065949 TI - Evolutionary and differential psychology: conceptual conflicts and the path to integration. AB - Evolutionary psychology has seen the majority of its success exploring adaptive features of the mind believed to be ubiquitous across our species. This has given rise to the belief that the adaptationist approach has little to offer the field of differential psychology, which concerns itself exclusively with the ways in which individuals systematically differ. By framing the historical origins of both disciplines, and exploring the means through which they each address the unique challenges of psychological description and explanation, the present article identifies the conceptual and theoretical problems that have kept differential psychology isolated not only from evolutionary psychology, but from explanatory approaches in general. Paying special attention to these conceptual problems, the authors review how these difficulties are being overcome by contemporary evolutionary research, and offer instructive suggestions concerning how differential researchers (and others) can best build upon these innovations. PMID- 24065950 TI - Preattentive processing of emotional musical tones: a multidimensional scaling and ERP study. AB - Musical emotion can be conveyed by subtle variations in timbre. Here, we investigated whether the brain is capable to discriminate tones differing in emotional expression by recording event-related potentials (ERPs) in an oddball paradigm under preattentive listening conditions. First, using multidimensional Fechnerian scaling, pairs of violin tones played with a happy or sad intonation were rated same or different by a group of non-musicians. Three happy and three sad tones were selected for the ERP experiment. The Fechnerian distances between tones within an emotion were in the same range as the distances between tones of different emotions. In two conditions, either 3 happy and 1 sad or 3 sad and 1 happy tone were presented in pseudo-random order. A mismatch negativity for the emotional deviant was observed, indicating that in spite of considerable perceptual differences between the three equiprobable tones of the standard emotion, a template was formed based on timbral cues against which the emotional deviant was compared. Based on Juslin's assumption of redundant code usage, we propose that tones were grouped together, because they were identified as belonging to one emotional category based on different emotion-specific cues. These results indicate that the brain forms an emotional memory trace at a preattentive level and thus, extends previous investigations in which emotional deviance was confounded with physical dissimilarity. Differences between sad and happy tones were observed which might be due to the fact that the happy emotion is mostly communicated by suprasegmental features. PMID- 24065952 TI - Diabetes and technology for increased activity study: the effects of exercise and technology on heart rate variability and metabolic syndrome risk factors. AB - This study tested the hypothesis that an 8-week exercise intervention supported by mobile health (mHealth) technology would improve metabolic syndrome (MetS) risk factors and heart rate variability (HRV) in a population with MetS risk factors. Participants (n = 12; three male; aged 56.9 +/- 7.0 years) reported to the laboratory for assessment of MetS risk factors and fitness (VO2max) at baseline (V 0) and after 8-weeks (V 2) of intervention. Participants received an individualized exercise prescription and a mHealth technology kit for remote monitoring of blood pressure (BP), blood glucose, physical activity, and body weight via smartphone. Participants underwent 24-h ambulatory monitoring of R-R intervals following V 0 and V 2. Low and high frequency powers of HRV were assessed from the recording and the ratio of low-to-high frequency powers and low and high frequency powers in normalized units were calculated. One-way repeated measures analysis of variance showed that waist circumference (V 0: 113.1 +/- 11.0 cm, V 2: 108.1 +/- 14.7 cm; p = 0.004) and diastolic BP (V 0: 81 +/- 6 mmHg, V 2: 76 +/- 11 mmHg; p = 0.04) were reduced and VO2max increased (V 0: 31.3 ml/kg/min, V 2: 34.8 ml/kg/min; p = 0.02) with no changes in other MetS risk factors. Low and high frequency powers in normalized units were reduced (V 0: 75.5 +/- 12.0, V 2: 72.0 +/- 12.1; p = 0.03) and increased (V 0: 24.5 +/- 12.0, V 2: 28.0 +/- 12.1; p = 0.03), respectively, with no other changes in HRV. Over the intervention period, changes in systolic BP were correlated negatively with the changes in R-R interval (r = -0.600; p = 0.04) and positively with the changes in heart rate (r = 0.611; p = 0.03), with no other associations between MetS risk factors and HRV parameters. Thus, this 8-week mHealth supported exercise intervention improved MetS risk factors and HRV parameters, but only changes in systolic BP were associated with improved autonomic function. PMID- 24065951 TI - The Interplay between Circadian System, Cholesterol Synthesis, and Steroidogenesis Affects Various Aspects of Female Reproduction. AB - Circadian aspect of reproduction has gained much attention in recent years. In mammals, it is very important that the timing of greatest sexual motivation is in line with the highest fertility. Peripheral clocks have been found to reside also in reproductive organs, such as the uterus and ovary. The timing signal from the suprachiasmatic nucleus is suggested to be transmitted via hormonal and neural mechanisms, and could thus mediate circadian expression of target genes in these organs. In turn, estrogens from the ovary have been found to signal back to the hypothalamus, completing the feedback loop. In this review we will focus on the interplay between clock and estrogens. Estradiol has been directly linked with expression of Per1 and Per2 in the uterus. CLOCK, on the other hand, has been shown to alter estradiol signaling. We also present the idea that cholesterol could play a vital role in the regulation of reproduction. Cholesterol synthesis itself is circadially regulated and has been found to interfere with steroidogenesis in the ovary on the molecular level. This review presents a systems view on how the interplay between circadian clock, steroidogenesis, and cholesterol synthesis affect various aspects of mammalian reproduction. PMID- 24065953 TI - The functional significance of synaptotagmin diversity in neuroendocrine secretion. AB - Synaptotagmins (syts) are abundant, evolutionarily conserved integral membrane proteins that play essential roles in regulated exocytosis in nervous and endocrine systems. There are at least 17 syt isoforms in mammals, all with tandem C-terminal C2 domains with highly variable capacities for Ca(2+) binding. Many syts play roles in neurotransmitter release or hormone secretion or both, and a growing body of work supports a role for some syts as Ca(2+) sensors of exocytosis. Work in many types of endocrine cells has documented the presence of a number of syt isoforms on dense-core vesicles containing various hormones. Syts can influence the kinetics of exocytotic fusion pores and the choice of release mode between kiss-and-run and full-fusion. Vesicles harboring different syt isoforms can preferentially undergo distinct modes of exocytosis with different forms of stimulation. The diverse properties of syt isoforms enable these proteins to shape Ca(2+) sensing in endocrine cells, thus contributing to the regulation of hormone release and the organization of complex endocrine functions. PMID- 24065954 TI - Dynamin-2 function and dysfunction along the secretory pathway. AB - Dynamin-2 is a ubiquitously expressed mechano-GTPase involved in different stages of the secretory pathway. Its most well-known function relates to the scission of nascent vesicles from the plasma membrane during endocytosis; however, it also participates in the formation of new vesicles from the Golgi network, vesicle trafficking, fusion processes and in the regulation of microtubule, and actin cytoskeleton dynamics. Over the last 8 years, more than 20 mutations in the dynamin-2 gene have been associated to two hereditary neuromuscular disorders: Charcot-Marie-Tooth neuropathy and centronuclear myopathy. Most of these mutations are grouped in the pleckstrin homology domain; however, there are no common mutations associated with both disorders, suggesting that they differently impact on dynamin-2 function in diverse tissues. In this review, we discuss the impact of these disease-related mutations on dynamin-2 function during vesicle trafficking and endocytotic processes. PMID- 24065955 TI - Relaxin-3/RXFP3 Signaling and Neuroendocrine Function - A Perspective on Extrinsic Hypothalamic Control. AB - Complex neural circuits within the hypothalamus that govern essential autonomic processes and associated behaviors signal using amino acid and monoamine transmitters and a variety of neuropeptide (hormone) modulators, often via G protein coupled receptors (GPCRs) and associated cellular pathways. Relaxin-3 is a recently identified neuropeptide that is highly conserved throughout evolution. Neurons expressing relaxin-3 are located in the brainstem, but broadly innervate the entire limbic system including the hypothalamus. Extensive anatomical data in rodents and non-human primate, and recent regulatory and functional data, suggest relaxin-3 signaling via its cognate GPCR, RXFP3, has a broad range of effects on neuroendocrine function associated with stress responses, feeding and metabolism, motivation and reward, and possibly sexual behavior and reproduction. Therefore, this article aims to highlight the growing appreciation of the relaxin-3/RXFP3 system as an important "extrinsic" regulator of the neuroendocrine axis by reviewing its neuroanatomy and its putative roles in arousal-, stress-, and feeding-related behaviors and links to associated neural substrates and signaling networks. Current evidence identifies RXFP3 as a potential therapeutic target for treatment of neuroendocrine disorders and related behavioral dysfunction. PMID- 24065956 TI - Regulated mucin secretion from airway epithelial cells. AB - Secretory epithelial cells of the proximal airways synthesize and secrete gel forming polymeric mucins. The secreted mucins adsorb water to form mucus that is propelled by neighboring ciliated cells, providing a mobile barrier which removes inhaled particles and pathogens from the lungs. Several features of the intracellular trafficking of mucins make the airway secretory cell an interesting comparator for the cell biology of regulated exocytosis. Polymeric mucins are exceedingly large molecules (up to 3 * 10(6) Da per monomer) whose folding and initial polymerization in the ER requires the protein disulfide isomerase Agr2. In the Golgi, mucins further polymerize to form chains and possibly branched networks comprising more than 20 monomers. The large size of mucin polymers imposes constraints on their packaging into transport vesicles along the secretory pathway. Sugar side chains account for >70% of the mass of mucins, and their attachment to the protein core by O-glycosylation occurs in the Golgi. Mature polymeric mucins are stored in large secretory granules ~1 MUm in diameter. These are translocated to the apical membrane to be positioned for exocytosis by cooperative interactions among myristoylated alanine-rich C kinase substrate, cysteine string protein, heat shock protein 70, and the cytoskeleton. Mucin granules undergo exocytic fusion with the plasma membrane at a low basal rate and a high stimulated rate. Both rates are mediated by a regulated exocytic mechanism as indicated by phenotypes in both basal and stimulated secretion in mice lacking Munc13-2, a sensor of the second messengers calcium and diacylglycerol (DAG). Basal secretion is induced by low levels of activation of P2Y2 purinergic and A3 adenosine receptors by extracellular ATP released in paracrine fashion and its metabolite adenosine. Stimulated secretion is induced by high levels of the same ligands, and possibly by inflammatory mediators as well. Activated receptors are coupled to phospholipase C by Gq, resulting in the generation of DAG and of IP3 that releases calcium from apical ER. Stimulated secretion requires activation of the low affinity calcium sensor Synaptotagmin-2, while a corresponding high affinity calcium sensor in basal secretion is not known. The core exocytic machinery is comprised of the SNARE proteins VAMP8, SNAP23, and an unknown Syntaxin protein, together with the scaffolding protein Munc18b. Common and distinct features of this exocytic system in comparison to neuroendocrine cells and neurons are highlighted. PMID- 24065957 TI - Evolution of BRET Biosensors from Live Cell to Tissue-Scale In vivo Imaging. AB - Development of bioluminescence resonance energy transfer (BRET) based genetic sensors for sensing biological functions such as protein-protein interactions (PPIs) in vivo has a special value in measuring such dynamic events at their native environment. Since its inception in the late nineties, BRET related research has gained significant momentum in terms of adding versatility to the assay format and wider applicability where it has been suitably used. Beyond the scope of quantitative measurement of PPIs and protein dimerization, molecular imaging applications based on BRET assays have broadened its scope for screening pharmacologically important compounds by in vivo imaging as well. In this mini review we focus on an in-depth analysis of engineered BRET systems developed and their successful application to cell-based assays as well as in vivo non-invasive imaging in live subjects. PMID- 24065958 TI - Ratiometric Measurements of Adiponectin by Mass Spectrometry in Bottlenose Dolphins (Tursiops truncatus) with Iron Overload Reveal an Association with Insulin Resistance and Glucagon. AB - High molecular weight (HMW) adiponectin levels are reduced in humans with type 2 diabetes and insulin resistance. Similar to humans with insulin resistance, managed bottlenose dolphins (Tursiops truncatus) diagnosed with hemochromatosis (iron overload) have higher levels of 2 h post-prandial plasma insulin than healthy controls. A parallel reaction monitoring assay for dolphin serum adiponectin was developed based on tryptic peptides identified by mass spectrometry. Using identified post-translational modifications, a differential measurement was constructed. Total and unmodified adiponectin levels were measured in sera from dolphins with (n = 4) and without (n = 5) iron overload. This measurement yielded total adiponectin levels as well as site specific percent unmodified adiponectin that may inversely correlate with HMW adiponectin. Differences in insulin levels between iron overload cases and controls were observed 2 h post-prandial, but not during the fasting state. Thus, post-prandial as well as fasting serum adiponectin levels were measured to determine whether adiponectin and insulin would follow similar patterns. There was no difference in total adiponectin or percent unmodified adiponectin from case or control fasting animals. There was no difference in post-prandial total adiponectin levels between case and control dolphins (mean +/- SD) at 763 +/- 298 and 727 +/- 291 pmol/ml, respectively (p = 0.91); however, percent unmodified adiponectin was significantly higher in post-prandial cases compared to controls (30.0 +/- 6.3 versus 17.0 +/- 6.6%, respectively; p = 0.016). Interestingly, both total and percent unmodified adiponectin were correlated with glucagon levels in controls (r = 0.999, p < 0.001), but not in cases, which is possibly a reflection of insulin resistance. Although total adiponectin levels were not significantly different, the elevated percent unmodified adiponectin follows a trend similar to HMW adiponectin reported for humans with metabolic disorders. PMID- 24065960 TI - Genome-enabled studies of anaerobic, nitrate-dependent iron oxidation in the chemolithoautotrophic bacterium Thiobacillus denitrificans. AB - Thiobacillus denitrificans is a chemolithoautotrophic bacterium capable of anaerobic, nitrate-dependent U(IV) and Fe(II) oxidation, both of which can strongly influence the long-term efficacy of in situ reductive immobilization of uranium in contaminated aquifers. We previously identified two c-type cytochromes involved in nitrate-dependent U(IV) oxidation in T. denitrificans and hypothesized that c-type cytochromes would also catalyze Fe(II) oxidation, as they have been found to play this role in anaerobic phototrophic Fe(II)-oxidizing bacteria. Here we report on efforts to identify genes associated with nitrate dependent Fe(II) oxidation, namely (a) whole-genome transcriptional studies [using FeCO3, Fe(2) (+), and U(IV) oxides as electron donors under denitrifying conditions], (b) Fe(II) oxidation assays performed with knockout mutants targeting primarily highly expressed or upregulated c-type cytochromes, and (c) random transposon-mutagenesis studies with screening for Fe(II) oxidation. Assays of mutants for 26 target genes, most of which were c-type cytochromes, indicated that none of the mutants tested were significantly defective in nitrate-dependent Fe(II) oxidation. The non-defective mutants included the c 1-cytochrome subunit of the cytochrome bc 1 complex (complex III), which has relevance to a previously proposed role for this complex in nitrate-dependent Fe(II) oxidation and to current concepts of reverse electron transfer. A transposon mutant with a disrupted gene associated with NADH:ubiquinone oxidoreductase (complex I) was ~35% defective relative to the wild-type strain; this strain was similarly defective in nitrate reduction with thiosulfate as the electron donor. Overall, our results indicate that nitrate-dependent Fe(II) oxidation in T. denitrificans is not catalyzed by the same c-type cytochromes involved in U(IV) oxidation, nor have other c-type cytochromes yet been implicated in the process. PMID- 24065959 TI - Semaphorin signaling in the development and function of the gonadotropin hormone releasing hormone system. AB - The semaphorin proteins are among the best-studied families of guidance cues, contributing to morphogenesis and homeostasis in a wide range of tissue types. The major semaphorin receptors are plexins and neuropilins, however other receptors and co-receptors are capable to mediate signaling by semaphorins. These guidance proteins were originally identified as growth cone "collapsing factors" or as inhibitory signals, crucial for nervous system development. Since those seminal discoveries, the list of functions of semaphorins has rapidly grown. Over the past few years, a growing body of data indicates that semaphorins are involved in the regulation of the immune and vascular systems, in tumor growth/cancer cell metastasis and in neural circuit formation. Recently there has been increasing emphasis on research to determine the potential influence of semaphorins on the development and homeostasis of hormone systems and how circulating reproductive hormones regulate their expression and functions. Here, we focus on the emerging role of semaphorins in the development, differentiation and plasticity of unique neurons that secrete gonadotropin-releasing hormone (GnRH), which are essential for the acquisition and maintenance of reproductive competence in all vertebrates. Genetic evidence is also provided showing that insufficient semaphorin signaling contributes to some forms of reproductive disorders in humans, characterized by the reduction or failure of sexual competence. Finally, we will review some studies with the goal of highlighting how the expression of semaphorins and their receptors might be regulated by gonadal hormones in physiological and pathological conditions. PMID- 24065961 TI - Thalassiosira spp. community composition shifts in response to chemical and physical forcing in the northeast Pacific Ocean. AB - Diatoms are genetically diverse unicellular photosynthetic eukaryotes that are key primary producers in the ocean. Many of the over 100 extant diatom species in the cosmopolitan genus Thalassiosira are difficult to distinguish in mixed populations using light microscopy. Here, we examine shifts in Thalassiosira spp. composition along a coastal to open ocean transect that encountered a 3-month-old Haida eddy in the northeast Pacific Ocean. To quantify shifts in Thalassiosira species composition, we developed a targeted automated ribosomal intergenic spacer analysis (ARISA) method to identify Thalassiosira spp. in environmental samples. As many specific fragment lengths are indicative of individual Thalassiosira spp., the ARISA method is a useful screening tool to identify changes in the relative abundance and distribution of specific species. The method also enabled us to assess changes in Thalassiosira community composition in response to chemical and physical forcing. Thalassiosira spp. community composition in the core of a 3-month-old Haida eddy remained largely (>80%) similar over a 2-week period, despite moving 24 km southwestward. Shifts in Thalassiosira species correlated with changes in dissolved iron (Fe) and temperature throughout the sampling period. Simultaneously tracking community composition and relative abundance of Thalassiosira species within the physical and chemical context they occurred allowed us to identify quantitative linkages between environmental conditions and community response. PMID- 24065963 TI - Erratum: Dangerous liaisons: molecular basis for a syndemic relationship between Kaposi's sarcoma and P. falciparum malaria. AB - [This corrects the article on p. 35 in vol. 4, PMID: 23487416.]. PMID- 24065962 TI - Evidence supporting dissimilatory and assimilatory lignin degradation in Enterobacter lignolyticus SCF1. AB - Lignocellulosic biofuels are promising as sustainable alternative fuels, but lignin inhibits access of enzymes to cellulose, and by-products of lignin degradation can be toxic to cells. The fast growth, high efficiency and specificity of enzymes employed in the anaerobic litter deconstruction carried out by tropical soil bacteria make these organisms useful templates for improving biofuel production. The facultative anaerobe Enterobacter lignolyticus SCF1 was initially cultivated from Cloud Forest soils in the Luquillo Experimental Forest in Puerto Rico, based on anaerobic growth on lignin as sole carbon source. The source of the isolate was tropical forest soils that decompose litter rapidly with low and fluctuating redox potentials, where bacteria using oxygen independent enzymes likely play an important role in decomposition. We have used transcriptomics and proteomics to examine the observed increased growth of SCF1 grown on media amended with lignin compared to unamended growth. Proteomics suggested accelerated xylose uptake and metabolism under lignin-amended growth, with up-regulation of proteins involved in lignin degradation via the 4 hydroxyphenylacetate degradation pathway, catalase/peroxidase enzymes, and the glutathione biosynthesis and glutathione S-transferase (GST) proteins. We also observed increased production of NADH-quinone oxidoreductase, other electron transport chain proteins, and ATP synthase and ATP-binding cassette (ABC) transporters. This suggested the use of lignin as terminal electron acceptor. We detected significant lignin degradation over time by absorbance, and also used metabolomics to demonstrate moderately significant decreased xylose concentrations as well as increased metabolic products acetate and formate in stationary phase in lignin-amended compared to unamended growth conditions. Our data show the advantages of a multi-omics approach toward providing insights as to how lignin may be used in nature by microorganisms coping with poor carbon availability. PMID- 24065964 TI - Chemical synthetic biology: a mini-review. AB - Chemical synthetic biology (CSB) is a branch of synthetic biology (SB) oriented toward the synthesis of chemical structures alternative to those present in nature. Whereas SB combines biology and engineering with the aim of synthesizing biological structures or life forms that do not exist in nature - often based on genome manipulation, CSB uses and assembles biological parts, synthetic or not, to create new and alternative structures. A short epistemological note will introduce the theoretical concepts related to these fields, whereas the text will be largely devoted to introduce and comment two main projects of CSB, carried out in our laboratory in the recent years. The "Never Born Biopolymers" project deals with the construction and the screening of RNA and peptide sequences that are not present in nature, whereas the "Minimal Cell" project focuses on the construction of semi-synthetic compartments (usually liposomes) containing the minimal and sufficient number of components to perform the basic function of a biological cell. These two topics are extremely important for both the general understanding of biology in terms of function, organization, and development, and for applied biotechnology. PMID- 24065965 TI - Differential transforming activity of the retroviral Tax oncoproteins in human T lymphocytes. AB - Human T cell leukemia virus type 1 and type 2 (HTLV-1 and -2) are two closely related retroviruses. HTLV-1 causes adult T cell leukemia and lymphoma, whereas HTLV-2 infection is not etiologically linked to human disease. The viral genomes of HTLV-1 and -2 encode highly homologous transforming proteins, Tax-1 and Tax-2, respectively. Tax-1 is thought to play a central role in transforming CD4+ T lymphocytes. Expression of Tax-1 is crucial for promoting survival and proliferation of virally infected human T lymphocytes and is necessary for initiating HTLV-1-mediated oncogenesis. In transgenic mice and humanized mouse model, Tax-1 has proven to be leukemogenic. Although Tax-1 is able to efficiently transform rodent fibroblasts and to induce lymphoma in mouse model, it rarely transforms primary human CD4+ T lymphocytes. In contrast, Tax-2 efficiently immortalizes human CD4+ T cells though it exhibits a lower transforming activity in rodent cells as compared to Tax-1. We here discuss our recent observation and views on the differential transforming activity of Tax-1 and Tax-2 in human T cells. PMID- 24065966 TI - A mathematical model of T lymphocyte calcium dynamics derived from single transmembrane protein properties. AB - Fate decision processes of T lymphocytes are crucial for health and disease. Whether a T lymphocyte is activated, divides, gets anergic, or initiates apoptosis depends on extracellular triggers and intracellular signaling. Free cytosolic calcium dynamics plays an important role in this context. The relative contributions of store-derived calcium entry and calcium entry from extracellular space to T lymphocyte activation are still a matter of debate. Here we develop a quantitative mathematical model of T lymphocyte calcium dynamics in order to establish a tool which allows to disentangle cause-effect relationships between ion fluxes and observed calcium time courses. The model is based on single transmembrane protein characteristics which have been determined in independent experiments. This reduces the number of unknown parameters in the model to a minimum and ensures the predictive power of the model. Simulation results are subsequently used for an analysis of whole cell calcium dynamics measured under various experimental conditions. The model accounts for a variety of these conditions, which supports the suitability of the modeling approach. The simulation results suggest a model in which calcium dynamics dominantly relies on the opening of channels in calcium stores while calcium entry through calcium release activated channels (CRAC) is more associated with the maintenance of the T lymphocyte calcium levels and prevents the cell from calcium depletion. Our findings indicate that CRAC guarantees a long-term stable calcium level which is required for cell survival and sustained calcium enhancement. PMID- 24065967 TI - Th1/M1 conversion to th2/m2 responses in models of inflammation lacking cell death stimulates maturation of monocyte precursors to fibroblasts. AB - We have demonstrated that cardiac fibrosis arises from the differentiation of monocyte-derived fibroblasts. We present here evidence that this process requires sequential Th1 and Th2 induction promoting analogous M1 (classically activated) and M2 (alternatively activated) macrophage polarity. Our models are: (1) mice subjected to daily repetitive ischemia and reperfusion (I/R) without infarction and (2) the in vitro transmigration of human mononuclear leukocytes through human cardiac microvascular endothelium. In the mouse heart, leukocytes entered after I/R in response to monocyte chemoattractant protein-1 (MCP-1), which is the major cytokine induced by this protocol. Monocytes within the heart then differentiated into fibroblasts making collagen while bearing the markers of M2 macrophages. T cells were seen in these hearts as well as in the human heart with cardiomyopathy. In the in vitro model, transmigration of the leukocytes was likewise induced by MCP-1 and some monocytes matured into fibroblasts bearing M2 markers. In this model, the MCP-1 stimulus induced a transient Th1 and M1 response that developed into a predominantly Th2 and M2 response. An increase in the Th2 product IL-13 was present in both the human and the mouse models, consistent with its known role in fibrosis. In these simplified models, in which there is no cell death to stimulate an anti-inflammatory response, there is nonetheless a resolution of inflammation enabling a profibrotic environment. This induces the maturation of monocyte precursors into fibroblasts. PMID- 24065968 TI - Bioinformatics analysis of the factors controlling type I IFN gene expression in autoimmune disease and virus-induced immunity. AB - Patients with systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS) display increased levels of type I interferon (IFN)-induced genes. Plasmacytoid dendritic cells (PDCs) are natural interferon producing cells and considered to be a primary source of IFN-alpha in these two diseases. Differential expression patterns of type I IFN-inducible transcripts can be found in different immune cell subsets and in patients with both active and inactive autoimmune disease. A type I IFN gene signature generally consists of three groups of IFN-induced genes - those regulated in response to virus-induced type I IFN, those regulated by the IFN-induced mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway, and those by the IFN-induced phosphoinositide-3 kinase (PI 3K) pathway. These three groups of type I IFN-regulated genes control important cellular processes such as apoptosis, survival, adhesion, and chemotaxis, that when dysregulated, contribute to autoimmunity. With the recent generation of large datasets in the public domain from next-generation sequencing and DNA microarray experiments, one can perform detailed analyses of cell-type specific gene signatures as well as identify distinct transcription factors (TFs) that differentially regulate these gene signatures. We have performed bioinformatics analysis of data in the public domain and experimental data from our lab to gain insight into the regulation of type I IFN gene expression. We have found that the genetic landscape of the IFNA and IFNB genes are occupied by TFs, such as insulators CTCF and cohesin, that negatively regulate transcription, as well as interferon regulatory factor (IRF)5 and IRF7, that positively and distinctly regulate IFNA subtypes. A detailed understanding of the factors controlling type I IFN gene transcription will significantly aid in the identification and development of new therapeutic strategies targeting the IFN pathway in autoimmune disease. PMID- 24065969 TI - Proteases: essential actors in processing antigens and intracellular toll-like receptors. AB - MHC class II molecules expressed by professional antigen presenting cells (pAPCs) such as macrophages, B cells, and dendritic cells (DCs) play a fundamental role in presenting peptides to CD4(+) T cells. However, to elicit CD4(+)-T cells immunity, pAPCs need an additional signal, which can be delivered by toll-like receptors (TLRs) molecules. TLRs recognize microbial patterns and are critical in initiating immune responses. Proteases, which provide peptide ligands for the MHC class II antigenic presentation pathway, were recently shown to cleave and activate intracellular TLRs in endosomal compartments. Here, I give an overview on the individual roles of the most well studied proteases in both antigen and TLRs processing. PMID- 24065971 TI - Arbuscular mycorrhizal fungi alter above- and below-ground chemical defense expression differentially among Asclepias species. AB - Below-ground (BG) symbionts of plants can have substantial influence on plant growth and nutrition. Recent work demonstrates that mycorrhizal fungi can affect plant resistance to herbivory and the performance of above- (AG) and BG herbivores. Although these examples emerge from diverse systems, it is unclear if plant species that express similar defensive traits respond similarly to fungal colonization, but comparative work may inform this question. To examine the effects of arbuscular mycorrhizal fungi (AMF) on the expression of chemical resistance, we inoculated 8 species of Asclepias (milkweed)-which all produce toxic cardenolides-with a community of AMF. We quantified plant biomass, foliar and root cardenolide concentration and composition, and assessed evidence for a growth-defense tradeoff in the presence and absence of AMF. As expected, total foliar and root cardenolide concentration varied among milkweed species. Importantly, the effect of mycorrhizal fungi on total foliar cardenolide concentration also varied among milkweed species, with foliar cardenolides increasing or decreasing, depending on the plant species. We detected a phylogenetic signal to this variation; AMF fungi reduced foliar cardenolide concentrations to a greater extent in the clade including A. curassavica than in the clade including A. syriaca. Moreover, AMF inoculation shifted the composition of cardenolides in AG and BG plant tissues in a species-specific fashion. Mycorrhizal inoculation changed the relative distribution of cardenolides between root and shoot tissue in a species-specific fashion, but did not affect cardenolide diversity or polarity. Finally, a tradeoff between plant growth and defense in non-mycorrhizal plants was mitigated completely by AMF inoculation. Overall, we conclude that the effects of AMF inoculation on the expression of chemical resistance can vary among congeneric plant species, and ameliorate tradeoffs between growth and defense. PMID- 24065970 TI - Nitric oxide implication in the control of seed dormancy and germination. AB - Germination ability is regulated by a combination of environmental and endogenous signals with both synergistic and antagonistic effects. Nitric oxide (NO) is a potent dormancy-releasing agent in many species, including Arabidopsis, and has been suggested to behave as an endogenous regulator of this physiological blockage. Distinct reports have also highlighted a positive impact of NO on seed germination under sub-optimal conditions. However, its molecular mode of action in the context of seed biology remains poorly documented. This review aims to focus on the implications of this radical in the control of seed dormancy and germination. The consequences of NO chemistry on the investigations on both its signaling and its targets in seeds are discussed. NO-dependent protein post translational modifications are proposed as a key mechanism underlying NO signaling during early seed germination. PMID- 24065972 TI - Spatio-temporal decoupling of stomatal and mesophyll conductance induced by vein cutting in leaves of Helianthus annuus. AB - Reduction of hydraulic conductance to the canopy has been shown to result in stomatal responses to limit transpiration. To test for similar responses to perturbations of the hydraulic network in leaves, we simultaneously measured leaf gas exchange with spatially explicit chlorophyll-a fluorescence and leaf temperature to examine the effects of cutting a primary leaf vein in Helianthus annuus. We repeated the leaf treatment at each of three different vapor pressure deficits and monitored the short-term dynamics of gas exchange following the treatment. Immediately after treatment, photosynthesis and stomatal conductance (g s) showed a transient "wrong way" response in which photosynthesis declined despite increased g s. Comparisons of fluorescence and temperature across the leaf showed that both photosynthesis and g s were transiently patchy across the measured leaf area, but that the patchiness of the two processes did not correspond in space or time. This suggests that photosynthesis and g s respond to vein cutting-induced cavitation via different mechanisms. Because the stomatal response varied by vapor pressure difference condition but photosynthesis did not, it is likely that g s, but not photosynthesis, responded to a hydraulic signal. In contrast, we hypothesize that photosynthesis declined due to a wound induced electrical signal that has recently been shown to transiently decrease mesophyll conductance to CO2. The interaction of epidermal hydraulics and the electrical signal across the leaf likely created a patchy pattern of chlorophyll fluorescence and leaf temperature that cannot be explained through the action of a single signal. PMID- 24065973 TI - Algal endosymbionts as vectors of horizontal gene transfer in photosynthetic eukaryotes. AB - Photosynthesis in eukaryotes occurs in the plastid, an organelle that is derived from a single cyanobacterial primary endosymbiosis in the common ancestor of the supergroup Plantae (or Archaeplastida) that includes green, red, and glaucophyte algae and plants. However a variety of other phytoplankton such as the chlorophyll c-containing diatoms, dinoflagellates, and haptophytes contain a red alga-derived plastid that traces its origin to secondary or tertiary (eukaryote engulfs eukaryote) endosymbiosis. The hypothesis of Plantae monophyly has only recently been substantiated, however the extent and role of endosymbiotic and horizontal gene transfer (EGT and HGT) in algal genome evolution still remain to be fully understood. What is becoming clear from analysis of complete genome data is that algal gene complements can no longer be considered essentially eukaryotic in provenance; i.e., with the expected addition of several hundred cyanobacterial genes derived from EGT and a similar number derived from the mitochondrial ancestor. For example, we now know that foreign cells such as Chlamydiae and other prokaryotes have made significant contributions to plastid functions in Plantae. Perhaps more surprising is the recent finding of extensive bacterium derived HGT in the nuclear genome of the unicellular red alga Porphyridium purpureum that does not relate to plastid functions. These non-endosymbiont gene transfers not only shaped the evolutionary history of Plantae but also were propagated via secondary endosymbiosis to a multitude of other phytoplankton. Here we discuss the idea that Plantae (in particular red algae) are one of the major players in eukaryote genome evolution by virtue of their ability to act as "sinks" and "sources" of foreign genes through HGT and endosymbiosis, respectively. This hypothesis recognizes the often under-appreciated Rhodophyta as major sources of genetic novelty among photosynthetic eukaryotes. PMID- 24065974 TI - Ceratopteris richardii (C-fern): a model for investigating adaptive modification of vascular plant cell walls. AB - Plant cell walls are essential for most aspects of plant growth, development, and survival, including cell division, expansive cell growth, cell-cell communication, biomechanical properties, and stress responses. Therefore, characterizing cell wall diversity contributes to our overall understanding of plant evolution and development. Recent biochemical analyses, concomitantly with whole genome sequencing of plants located at pivotal points in plant phylogeny, have helped distinguish between homologous characters and those which might be more derived. Most plant lineages now have at least one fully sequenced representative and although genome sequences for fern species are in progress they are not yet available for this group. Ferns offer key advantages for the study of developmental processes leading to vascularisation and complex organs as well as the specific differences between diploid sporophyte tissues and haploid gametophyte tissues and the interplay between them. Ceratopteris richardii has been well investigated building a body of knowledge which combined with the genomic and biochemical information available for other plants will progress our understanding of wall diversity and its impact on evolution and development. PMID- 24065975 TI - Thiol-based redox control of enzymes involved in the tetrapyrrole biosynthesis pathway in plants. AB - The last decades of research brought substantial insights into tetrapyrrole biosynthetic pathway in photosynthetic organisms. Almost all genes have been identified and roles of seemingly all essential proteins, leading to the synthesis of heme, siroheme, phytochromobilin, and chlorophyll (Chl), have been characterized. Detailed studies revealed the existence of a complex network of transcriptional and post-translational control mechanisms for maintaining a well adjusted tetrapyrrole biosynthesis during plant development and adequate responses to environmental changes. Among others one of the known post translational modifications is regulation of enzyme activities by redox modulators. Thioredoxins and NADPH-dependent thioredoxin reductase C (NTRC) adjust the activity of tetrapyrrole synthesis to the redox status of plastids. Excessive excitation energy of Chls in both photosystems and accumulation of light-absorbing unbound tetrapyrrole intermediates generate reactive oxygen species, which interfere with the plastid redox poise. Recent reports highlight ferredoxin-thioredoxin and NTRC-dependent control of key steps in tetrapyrrole biosynthesis in plants. In this review we introduce the regulatory impact of these reductants on the stability and activity of enzymes involved in 5 aminolevulinic acid synthesis as well as in the Mg-branch of the tetrapyrrole biosynthetic pathway and we propose molecular mechanisms behind this redox control. PMID- 24065976 TI - Possible role of glutamine synthetase in the NO signaling response in root nodules by contributing to the antioxidant defenses. AB - Nitric oxide (NO) is emerging as an important regulatory player in the Rhizobium legume symbiosis. The occurrence of NO during several steps of the symbiotic interaction suggests an important, but yet unknown, signaling role of this molecule for root nodule formation and functioning. The identification of the molecular targets of NO is key for the assembly of the signal transduction cascade that will ultimately help to unravel NO function. We have recently shown that the key nitrogen assimilatory enzyme glutamine synthetase (GS) is a molecular target of NO in root nodules of Medicago truncatula, being post translationally regulated by tyrosine nitration in relation to nitrogen fixation. In functional nodules of M. truncatula NO formation has been located in the bacteroid containing cells of the fixation zone, where the ammonium generated by bacterial nitrogenase is released to the plant cytosol and assimilated into the organic pools by plant GS. We propose that the NO-mediated GS post-translational inactivation is connected to nitrogenase inhibition induced by NO and is related to metabolite channeling to boost the nodule antioxidant defenses. Glutamate, a substrate for GS activity is also the precursor for the synthesis of glutathione (GSH), which is highly abundant in root nodules of several plant species and known to play a major role in the antioxidant defense participating in the ascorbate/GSH cycle. Existing evidence suggests that upon NO-mediated GS inhibition, glutamate could be channeled for the synthesis of GSH. According to this hypothesis, GS would be involved in the NO-signaling responses in root nodules and the NO-signaling events would meet the nodule metabolic pathways to provide an adaptive response to the inhibition of symbiotic nitrogen fixation by reactive nitrogen species. PMID- 24065977 TI - Protein S-nitrosylation in plants under abiotic stress: an overview. AB - Abiotic stress is one of the main problems affecting agricultural losses, and understanding the mechanisms behind plant tolerance and stress response will help us to develop new means of strengthening fruitful agronomy. The mechanisms of plant stress response are complex. Data obtained by experimental procedures are sometimes contradictory, depending on the species, strength, and timing applied. In recent years nitric oxide has been identified as a key signaling molecule involved in most plant responses to abiotic stress, either indirectly through gene activation or interaction with reactive oxygen species and hormones; or else directly, as a result of modifying enzyme activities mainly by nitration and S nitrosylation. While the functional relevance of the S-nitrosylation of certain proteins has been assessed in response to biotic stress, it has yet to be characterized under abiotic stress. Here, we review initial works about S nitrosylation in response to abiotic stress to conclude with a brief overview, and discuss further perspectives to obtain a clear outlook of the relevance of S nitrosylation in plant response to abiotic stress. PMID- 24065979 TI - Durum wheat and allelopathy: toward wheat breeding for natural weed management. AB - Wheat-derived foodstuffs represent about one-fifth of the calories consumed by humans worldwide. Bread wheat (Triticum aestivum L.) is one of the most important crops throughout the world, and it has been extensively studied for its allelopathic potential. In contrast, for allelopathy in durum wheat (Triticum turgidum ssp. durum), our knowledge is partial and fragmentary. Through highlighting recent advances in using allelopathy as a crop-breeding tool, we provide an overview of allelopathy in Triticum spp., to stimulate further coordinated breeding-oriented studies, to favor allelopathy exploitation for the sustainable cultivation of wheat, and in particular, to achieve improved biological weed control. PMID- 24065978 TI - Compartmentation and complexation of metals in hyperaccumulator plants. AB - Hyperaccumulators are being intensely investigated. They are not only interesting in scientific context due to their "strange" behavior in terms of dealing with high concentrations of metals, but also because of their use in phytoremediation and phytomining, for which understanding the mechanisms of hyperaccumulation is crucial. Hyperaccumulators naturally use metal accumulation as a defense against herbivores and pathogens, and therefore deal with accumulated metals in very specific ways of complexation and compartmentation, different from non hyperaccumulator plants and also non-hyperaccumulated metals. For example, in contrast to non-hyperaccumulators, in hyperaccumulators even the classical phytochelatin-inducing metal, cadmium, is predominantly not bound by such sulfur ligands, but only by weak oxygen ligands. This applies to all hyperaccumulated metals investigated so far, as well as hyperaccumulation of the metalloid arsenic. Stronger ligands, as they have been shown to complex metals in non hyperaccumulators, are in hyperaccumulators used for transient binding during transport to the storage sites (e.g., nicotianamine) and possibly for export of Cu in Cd/Zn hyperaccumulators [metallothioneins (MTs)]. This confirmed that enhanced active metal transport, and not metal complexation, is the key mechanism of hyperaccumulation. Hyperaccumulators tolerate the high amount of accumulated heavy metals by sequestering them into vacuoles, usually in large storage cells of the epidermis. This is mediated by strongly elevated expression of specific transport proteins in various tissues from metal uptake in the shoots up to the storage sites in the leaf epidermis. However, this mechanism seems to be very metal specific. Non-hyperaccumulated metals in hyperaccumulators seem to be dealt with like in non-hyperaccumulator plants, i.e., detoxified by binding to strong ligands such as MTs. PMID- 24065981 TI - From omics and etics to policy and ethics: regulating evolution. PMID- 24065980 TI - Perspectives on MADS-box expression during orchid flower evolution and development. AB - The diverse morphology of orchid flowers and their complex, often deceptive strategies to become pollinated have fascinated researchers for a long time. However, it was not until the 20th century that the ontogeny of orchid flowers, the genetic basis of their morphology and the complex phylogeny of Orchidaceae were investigated. In parallel, the improvement of techniques for in vitro seed germination and tissue culture, together with studies on biochemistry, physiology, and cytology supported the progress of what is now a highly productive industry of orchid breeding and propagation. In the present century both basic research in orchid flower evo-devo and the interest for generating novel horticultural varieties have driven the characterization of many members of the MADS-box family encoding key regulators of flower development. This perspective summarizes the picture emerging from these studies and discusses the advantages and limitations of the comparative strategy employed so far. I address the growing role of natural and horticultural mutants in these studies and the emergence of several model species in orchid evo-devo and genomics. In this context, I make a plea for an increasingly integrative approach. PMID- 24065982 TI - Imputation of microsatellite alleles from dense SNP genotypes for parentage verification across multiple Bos taurus and Bos indicus breeds. AB - To assist cattle producers transition from microsatellite (MS) to single nucleotide polymorphism (SNP) genotyping for parental verification we previously devised an effective and inexpensive method to impute MS alleles from SNP haplotypes. While the reported method was verified with only a limited data set (N = 479) from Brown Swiss, Guernsey, Holstein, and Jersey cattle, some of the MS SNP haplotype associations were concordant across these phylogenetically diverse breeds. This implied that some haplotypes predate modern breed formation and remain in strong linkage disequilibrium. To expand the utility of MS allele imputation across breeds, MS and SNP data from more than 8000 animals representing 39 breeds (Bos taurus and B. indicus) were used to predict 9410 SNP haplotypes, incorporating an average of 73 SNPs per haplotype, for which alleles from 12 MS markers could be accurately be imputed. Approximately 25% of the MS SNP haplotypes were present in multiple breeds (N = 2 to 36 breeds). These shared haplotypes allowed for MS imputation in breeds that were not represented in the reference population with only a small increase in Mendelian inheritance inconsistancies. Our reported reference haplotypes can be used for any cattle breed and the reported methods can be applied to any species to aid the transition from MS to SNP genetic markers. While ~91% of the animals with imputed alleles for 12 MS markers had <=1 Mendelian inheritance conflicts with their parents' reported MS genotypes, this figure was 96% for our reference animals, indicating potential errors in the reported MS genotypes. The workflow we suggest autocorrects for genotyping errors and rare haplotypes, by MS genotyping animals whose imputed MS alleles fail parentage verification, and then incorporating those animals into the reference dataset. PMID- 24065983 TI - Autoantibodies to neurotransmitter receptors and ion channels: from neuromuscular to neuropsychiatric disorders. AB - Changes of voltage-gated ion channels and ligand-gated receptor channels caused by mutation or autoimmune attack are the cause of so-called channelopathies in the central and peripheral nervous system. We present the pathophysiology of channelopathies of the neuromuscular junction in terms of loss-of-function and gain-of-function principles. Autoantibodies generally have reduced access to the central nervous system, but in some cases this is enough to cause disease. A review is provided of recent findings implicating autoantibodies against ligand activated receptor channels and potassium channels in psychiatric and neurological disorders, including schizophrenia and limbic encephalitis. The emergence of channelopathy-related neuropsychiatric disorders has implications for research and practice. PMID- 24065985 TI - A stochastic inference of de novo CNV detection and association test in multiplex schizophrenia families. AB - The copy number variation (CNV) is a type of genetic variation in the genome. It is measured based on signal intensity measures and can be assessed repeatedly to reduce the uncertainty in PCR-based typing. Studies have shown that CNVs may lead to phenotypic variation and modification of disease expression. Various challenges exist, however, in the exploration of CNV-disease association. Here we construct latent variables to infer the discrete CNV values and to estimate the probability of mutations. In addition, we propose to pool rare variants to increase the statistical power and we conduct family studies to mitigate the computational burden in determining the composition of CNVs on each chromosome. To explore in a stochastic sense the association between the collapsing CNV variants and disease status, we utilize a Bayesian hierarchical model incorporating the mutation parameters. This model assigns integers in a probabilistic sense to the quantitatively measured copy numbers, and is able to test simultaneously the association for all variants of interest in a regression framework. This integrative model can account for the uncertainty in copy number assignment and differentiate if the variation was de novo or inherited on the basis of posterior probabilities. For family studies, this model can accommodate the dependence within family members and among repeated CNV data. Moreover, the Mendelian rule can be assumed under this model and yet the genetic variation, including de novo and inherited variation, can still be included and quantified directly for each individual. Finally, simulation studies show that this model has high true positive and low false positive rates in the detection of de novo mutation. PMID- 24065986 TI - The battle for user-friendly bioinformatics. PMID- 24065984 TI - Metabolic modulation of chromatin: implications for DNA repair and genomic integrity. AB - The maintenance of genomic integrity in response to DNA damage is tightly linked to controlled changes in the damage-proximal chromatin environment. Many of the chromatin modifying enzymes involved in DNA repair depend on metabolic intermediates as cofactors, suggesting that changes in cellular metabolism can have direct consequences for repair efficiency and ultimately, genome stability. Here, we discuss how metabolites may contribute to DNA double-strand break repair, and how alterations in cellular metabolism associated with both aging and tumorigenesis may affect the integrity of our genomes. PMID- 24065988 TI - Etiology and Outcome of Patients with HIV Infection and Respiratory Failure Admitted to the Intensive Care Unit. AB - Background. Although access to HAART has prolonged survival and improved quality of life, HIV-infected patients with severe immunosuppression or comorbidities may develop complications that require critical care support. Our objective is to evaluate the etiology of respiratory failure in patients with HIV infection admitted to the ICU, its relationship with the T-lymphocytes cell count as well as the use of HAART, and its impact on outcome. Methods. A single-center, prospective, and observational study among all patients with HIV-infection and respiratory failure admitted to the ICU from December 1, 2011, to February 28, 2013, was conducted. Results. A total of 42 patients were admitted during the study period. Their median CD4 cell count was 123 cells/ MU L (mean 205.7, range 2.0-694.0), with a median HIV viral load of 203.5 copies/mL (mean 58,676, range <20-367,649). At the time of admission, 23 patients (54.8%) were receiving HAART. Use of antiretroviral therapy at ICU admission was not associated with survival, but it was associated with higher CD4 cell counts and lower HIV viral loads. Twenty-five patients (59.5%) had respiratory failure secondary to non-HIV-related diseases. Mechanical ventilation was required in 36 patients (85.1%). Thirteen patients (31.0%) died. Conclusions. Noninfectious etiologies of respiratory failure account for majority of HIV-infected patients admitted to ICU. Increased mortality was observed among patients with sepsis as etiology of respiratory failure (HIV related and non-AIDS related), in those receiving mechanical ventilation, and in patients with decreased CD4 cell count. Survival was not associated with the use of HAART. Complementary studies are warranted to address the impact of HAART on outcomes of HIV-infected patients with respiratory failure admitted to ICU. PMID- 24065987 TI - Characteristics of the small bowel lesions detected by capsule endoscopy in patients with chronic kidney disease. AB - Obscure gastrointestinal bleeding (OGIB) is one of the common complications in patients with chronic kidney disease (CKD), especially those who are on maintenance hemodialysis (HD). However, little is known about the characteristics of the small-bowel lesions in these patients, or of the factors that could predict the presence of such lesions. Therefore we enrolled a total of 42 CKD patients (including 19 HD patients and 23 non-HD patients), and compared the incidence of the small-bowel lesions among two groups. Furthermore, to identify predictive factors for the presence of small-bowel lesions, we performed multivariate logistic-regression-analyses. The incidence of small-bowel vascular lesions was significantly higher in CKD patients than in age-and-sex matched non CKD patients (P < 0.001). On the other hand, there was any significant difference of the incidence of small-bowel lesions between HD and non-HD patients. In CKD patients, past history of blood transfusion (OR 5.66; 95% CI 1.10-29.1, P = 0.04) was identified as an independent predictor of the presence of vascular lesions, and history of low-dose aspirin use (OR 6.00; 95% CI 1.13-31.9, P = 0.04) was identified as that of erosive/ulcerated lesions. This indicated that proactive CE examination would be clinically meaningful for these patients. PMID- 24065989 TI - Serum 25(OH)D Level and Parathyroid Hormone in Chinese Adult Population: A Cross Sectional Study in Guiyang Urban Community from Southeast of China. AB - Objective. To evaluate vitamin D status and serum parathyroid hormone (IPTH) of healthy adults living in Guiyang. Design and Participants. We conducted a cross sectional evaluation in the General Community in Guiyang by cluster sampling method. The data was a part of 1510 participants (634 men, 876 women) aged 20-79 years median 45.2 years from November 2009 to February 2010 in Guiyang Health Measures Survey. Measurements. Aradioimmunoassay was used to measure the level of 25-hydroxyvitamin D [25(OH)D] and intact parathyroid hormone (iPTH). Results.The mean serum 25(OH)D level was (20.4 +/- 9.0) ng/mL and the highest level among participants aged 40-59 years (22.8 ng/mL). The mean serum PTH level was (32.1 +/ 13.7) pg/mL and the lowest level among participants aged 40-50 years (30.8 ng/mL). Serum 25(OH)D was below 50 nmol/liter in 52.3%, below 75 nmol/liter in 84.6%, and above 75 nmol/liter in 15.4% of the respondents. Secondary hyperparathyroidism was 5.4% (5.4% among men and 4.6% among women). The prevalence of secondary hyperparathyroidism increased (5.8%, 6.5%, and 7.1%, resp.) with decreasing serum 25(OH)D levels among subjects who were 30 to 20, 19.9 to 10, and <10 ng/mL, respectively. Serum 25(OH)D was inversely associated with serum PTH. Conclusions. Vitamin D insufficiency and its complication of secondary hyperparathyroidism are common. PMID- 24065990 TI - Low serum magnesium level is associated with microalbuminuria in chinese diabetic patients. AB - Whether serum magnesium deficiency is independently associated with the prevalence of microalbuminuria is still unclear. The objective of the present study was to elucidate the association between serum magnesium and microalbuminuria in diabetic patients. A cross-sectional study was conducted in 1829 diabetic subjects (aged >= 40 years) from Shanghai, China. Subjects were divided into three groups according to serum magnesium tertiles. A first-voided early-morning spot urine sample was obtained for urinary albumin-creatinine ratio (UACR) measurement. Microalbuminuria was defined as 30 mg/g <= UACR < 300 mg/g. Overall, 208 (11.37%) of the study population had microalbuminuria, with similar proportions in both genders (P = 0.44). The prevalence of microalbuminuria in tertile 1 of serum magnesium was higher than the prevalence in tertile 2 and tertile 3 (15.98%, 9.72%, and 8.46%, resp.; P for trend <0.0001). After adjustment for age, sex, BMI, blood pressure, lipidaemic profile, HbA1c, eGFR, history of cardiovascular disease, HOMA-IR, antihypertensive and antidiabetic medication, and diabetes duration, we found that, compared with the subjects in tertile 3 of serum magnesium, those in tertile 1 had 1.85 times more likeliness to have microalbuminuria. We concluded that low serum magnesium level was significantly associated with the prevalence of microalbuminuria in middle-aged and elderly Chinese. PMID- 24065991 TI - Past Obesity as well as Present Body Weight Status Is a Risk Factor for Diabetic Nephropathy. AB - Aims. We analyzed the prevalence of nephropathy according to past body weight status in Japanese subjects with type 2 diabetes because the influence of past obesity on diabetic complications is not certain. Methods. We examined the prevalence of nephropathy in 2927 subjects with type 2 diabetes mellitus according to current BMI and maximum BMI in the past. We defined "current obesity" as BMI on hospitalization of 25 or more, "previous obesity" as BMI on hospitalization of less than 25 and self-reported maximum BMI in the past of 25 or more, and "continuously lean" as maximum BMI of less than 25. Results. The prevalence of nephropathy was significantly higher in subjects with current obesity (40.6%) or previous obesity (35.6%) than in those who were continuously lean (24.3%) (P < 0.017). In logistic regression analysis, previous obesity, as well as current obesity, was a significant risk factor for nephropathy, independent of sex, age, disease duration, hypertension, dyslipidemia, HbA1c, and diabetic retinopathy. Conclusions. Obesity in the past, as well as the present body weight status, was a risk factor for diabetic nephropathy. PMID- 24065994 TI - Parapharyngeal neck schwannomas with unusual vascular displacement. AB - This case report illustrates two unusual cases of parapharyngeal schwannomas mimicking carotid body tumors in terms of characteristic vascular displacement. Carotid body tumors classically cause splaying of internal and external carotid arteries demonstrating the Lyre sign on imaging. Also interestingly, both of these cases were seen in younger ages and include cervical sympathetic chain schwannoma and vagal schwannoma. However, these schwannomas revealed hypovascularity on imaging studies allowing differentiation from hypervascular carotid body tumors. Preoperative distinction between carotid body tumors and schwannomas is very important. PMID- 24065992 TI - Evaluation of the success criteria for zirconia dental implants: a four-year clinical and radiological study. AB - Objectives. The aim was to evaluate survival and success rates, soft tissue health, and radiographic marginal bone loss (MBL) of zirconia implants placed in the esthetic and posterior areas of the jaws and in association with multiple or single implant restorations after at least 6 months of definitive restoration. Material and Methods. 35 one-piece zirconium implants were utilized for single or partially edentulous ridges rehabilitation. All implants received immediate temporary restorations and six months after surgery were definitively restored. Every 6 months after implant placement, a clinical-radiographic evaluation was performed. For each radiograph, the measurements of MBL were calculated. Results. The results showed that the mean MBL at 48-month followup was 1.631 mm. The mean MBL during the first year of loading was not more significant for implants placed in the first molar regions than for those positioned in other areas. Moreover, no differences in marginal bone level changes were revealed for multiple and single implants, whereas MBL in the first year was observed to be slightly greater for implants placed in the maxilla than for those placed in the mandible. Conclusion. Zirconia showed a good marginal bone preservation that could be correlated with one-piece morphology and characteristics of zirconia implants. PMID- 24065993 TI - Utility of stellate ganglion block in atypical facial pain: a case report and consideration of its possible mechanisms. AB - We present this report of a young patient with chronic severe atypical facial pain who was successfully controlled with stellate ganglion block under ultrasound guidance. The patient had a history of severe disabling, unilateral, facial neuropathic pain with minimal response to analgesic medications. Upon assessment the patient had features suggestive of trigeminal neuralgia, although postherpetic neuralgia could not be ruled out. As a diagnostic test intervention, stellate ganglion block was tried under ultrasound guidance. The patient showed significant improvement in pain control and functional disability lasting beyond 10 weeks. Subsequent blocks reinforced the analgesia. Atypical facial pain has several differential diagnoses. The involvement of sympathetic system in its causation or sustenance is uncertain. Stellate ganglion block achieves sympathetic block of cervicofacial structures, and its blockade has been shown to affect chronic pain conditions. Although its mechanism is not clear, one has to consider its possible role in conditions of stress apart from directly controlling the sympathetic activity. There is certainly a role in exploring the potential benefits of stellate ganglion block in such clinical conditions. The technique of stellate block under ultrasound is also described, as it influences the safety and precision of the block. PMID- 24065995 TI - Langerhans cell histiocytosis presenting as uncontrolled asthma. AB - Langerhans cell histiocytosis (LCH) is an uncommon disorder affecting primarily young adult smokers. It is characterized by abnormal proliferation of Langerhans cells, specialized monocyte-macrophage lineage antigen-presenting cells. LCH can affect the lungs in isolation or as part of a systemic disease. Most commonly, the disease presents in the third or fourth decade without gender predominance. Symptoms typically include dyspnea and cough. Commonly, physical examination is unremarkable but cor pulmonale may be observed in advanced disease. The chest radiograph is typically abnormal with nodular or interstitial infiltrates and cystic changes. High-resolution computed tomography of the chest with these findings in the middle and upper lobes of an adult smoker is virtually diagnostic of LCH. Pulmonary function assessment is variable. Asthma has rarely been reported in association with this disorder. There are only three reported cases of the diagnosis of concomitant asthma which have been made in association with the diagnosis of LCH. We present a case in which our patient presented with signs and symptoms of asthma to include confirmatory findings of airway hyperresponsiveness. The diagnosis of LCH was established after the patient failed to respond to conventional treatment for asthma, and further evaluation was completed. PMID- 24065996 TI - Long-term survival and its related factors in pediatric liver transplant recipients of shiraz transplant center, shiraz, iran in 2012. AB - BACKGROUND: Liver transplantation is considered as the standard treatment for both children and adults with end-stage liver diseases. Using this method, children who have no chance for life can live a much longer life .Shiraz Transplant Center is the major pediatric liver transplant center in Iran. Therefore, determining patients' survival and its effective factors can help clinical programming for increasing such patients' survival after liver transplantation. OBJECTIVES: The present study aimed to investigate the survival of patients below-18-years-old undergoing liver transplantation and the factors affecting their survival. PATIENTS AND METHODS: The present historical cohort study was conducted on 392 patients below-18-year-sold who had undergone liver transplantation for the first time in the Namazi hospital liver transplant center, Shiraz, Iran between 2000 and 2011. In this study, 1-, 3-, 5-, and 10 year survival of the patients was assessed using Kaplan-Meier and life table methods. The effect of factors related to the recipients, donors, and the transplantation process on the patients' survival was also investigated. RESULTS: According to the results, 1, 3, 5 and 10-year survival of patients was 73%, 67%, 66%, and 66%, respectively. Besides, 1 ,3, 5, and 10-year survival of the patients who survived 1 and 3 months after the transplantation was 84%, 78%, 77%, and 77% and 89%, 82%, 81%, and 81%, respectively. In the univariate analysis, age, patients' weight at transplantation, initial diagnosis, PELD/MELD score, existence of post-transplant complications, and year of transplantation were found to be effective factors on the patients' survival. In the multivariate analysis, only the type of graft, PELD/MELD score, and existence of post transplant complications were the prognostic variables. CONCLUSIONS: In this study, the patients' survival rate was 73%, which is quite low compared to the survival rate reported in other studies. Although we only have a 12-year experience with pediatric liver transplantation, the survival rate has increased in our center through the recent years (2008-2011). However, the survival rate of the patients who had survived 3 months after the transplantation was 89% which is comparable to other studies. Overall, cholestatic diseases (biliary atresia was the most prevalent), type of transplantation (split), PELD/MELD score > 20, and existence of post-transplant complications increased the risk of death after the transplantation. PMID- 24065997 TI - The impact of interleukin 28b gene polymorphism on the virological response to combined pegylated interferon and ribavirin therapy in chronic HCV genotype 4 infected egyptian patients using data mining analysis. AB - BACKGROUND: Chronic HCV represents one of the common causes of chronic liver disease worldwide with Egypt having the highest prevalence, namely genotype 4. Interleukin IL-28B gene polymorphism has been shown to relate to HCV treatment response, mainly in genotype1. OBJECTIVES: We aim to evaluate the predictive power of the rs12979860 IL28B SNP and its protein for treatment response in genotype 4 Egyptian patients by regression analysis and decision tree analysis. PATIENTS AND METHODS: The study included 263 chronic HCV Egyptian patients receiving peg-interferon and ribavirin therapy. Patients were classified into 3 groups; non responders (83patients), relapsers (76patients) and sustained virological responders (104 patients). Serum IL 28 B was performed, DNA was extracted and analyzed by direct sequencing of the SNP rs 12979860 of IL28B gene. RESULTS: CT, CC and TT represented 56 %, 25 % and 19% of the patients, respectively. Absence of C allele (TT genotype) was significantly correlated with the early failure of response while CC was associated with sustained virological response. The decision tree showed that baseline alpha fetoprotein (AFP <= 2.68 ng/ml) was the variable of initial split (the strongest predictor of response) confirmed by regression analysis. Patients with TT genotype had the highest probability of failure of response. CONCLUSIONS: Absence of the C allele was significantly associated with failure of response. The presence of C allele was associated with a favorable outcome. AFP is a strong baseline predictor of HCV treatment response. A decision tree model is useful for predicting the probability of response to therapy. PMID- 24065999 TI - Occupational exposure to blood borne viruses among healthcare workers in a tertiary care referral hospital in tehran. PMID- 24065998 TI - Dietary Quality Indices and Biochemical Parameters Among Patients With Non Alcoholic Fatty Liver Disease (NAFLD). AB - BACKGROUND: Dietary intake might have important role in non-alcoholic fatty liver diseases (NAFLD). Although, there are some reports on dietary intake and anthropometrics measurements, few studies have focused on the markers of assessing whole diet like dietary quality indices. OBJECTIVES: Therefore, our aim was to determine the diet quality indices and biochemical parameters among patients with NAFLD and healthy individuals. PATIENTS AND METHODS: This case control study was performed on 100 patients with NAFLD and 100 healthy subjects who were attending to Gastrointestinal Research Center, Baqiyatallah University, Tehran, Iran during the recent years. Usual dietary intake was assessed by three dietary records (one weekend and two week days). Healthy eating index (HEI), dietary diversity score (DDS), dietary energy density (DED), mean adequacy ratio of nutrients (MAR) were assessed according to the standard methods. RESULTS: Patients with NAFLD had higher body mass index, weight and waist circumference compared to the healthy group (P < 0.05). Serum levels of liver enzymes, triglyceride, LDL, BUN, and uric acid were higher in patients with NAFLD (P < 0.05). Although patients with NAFLD had higher energy, carbohydrate and fat intake, their values for antioxidant vitamins, calcium and vitamin D were lower than healthy subjects (P < 0.05). HEI and MAR were higher among healthy group, and DED was lower among them. Nutrient adequacy ratio for calcium, vitamin D, and antioxidant micronutrients were lower in patients with NAFLD (P < 0.05). CONCLUSIONS: It seems that dietary quality indices may be associated with NAFLD. Calcium, vitamin D, and antioxidant micronutrients intake might be lower among patients with NAFLD based on this case-control study. Further prospective studies should be conducted in this regard. PMID- 24066000 TI - HBV Subgenotypes D1, D2, D-del! Are 'Old' Genotyping Methods Interpreted Correctly? PMID- 24066001 TI - Differentially Expressed Proteins in Chronic Active Hepatitis, Cirrhosis, and HCC Related to HCV Infection in Comparison With HBV Infection: A proteomics study. AB - BACKGROUND: Hepatocellular carcinoma is a highly progressive cancer in the case of late diagnosis which is frequently associated with HBV and HCV viral infections. OBJECTIVES: To identify differentially expressed serum proteins among three main stages of HCV infection and healthy individuals, and their comparisons with sera from patients with the same stage of HBV infection. PATIENTS AND METHODS: Two-dimensional polyacrylamide gel electrophoresis combined with liquid chromatography-tandem mass spectrometry was performed on 47 sera from healthy volunteers, those with chronic active hepatitis, cirrhosis and HCC patients associated with HBV and HCV infections. RESULTS: Among these, 62 spots were differentially expressed (>= 1.5 fold; P < 0.05), of which 42 spots that corresponded to 15 proteins were identified by liquid chromatography-tandem mass spectrometry. CD5-like antigen (CD5L) was differentially expressed between cirrhosis and HCC patients with HCV infection. Leucine-rich alpha2-glycoprotein (LRG) and haptoglobin (HP) alpha2 isoforms differed in the HCC that was associated with either HCV or HBV infections. CONCLUSIONS: CD5L might be a useful biomarker for early diagnosis of HCC in HCV cirrhotic patients. LRG and HP alpha2 isoforms could be potential markers for distinguishing viral HCC. Our results also further support the presence of varying molecules involved in hepatocarcinogenesis in HBV when compared with HCV infection. PMID- 24066002 TI - Influencing Factors on the Outcome and Prognosis of Patients With HBV Infction: Seven Years Follow-up. AB - BACKGROUND: Hepatitis B virus (HBV) is one of the most common chronic viral infections in the world. Iran has a low to intermediate HBV prevalence and approximately 1.5 million people are living with HBV infection. The impact of HBV in Iran is unknown and given the very low levels of alcohol consumption, this region provides an opportunity to examine the impact of isolated chronic HBV infection. OBJECTIVES: To examine and evaluate outcome and prognosis of HBV in Iran. PATIENTS AND METHODS: A longitudinal cohort study dating from 2003-2010 was performed. The patients were assessed six months after their first visit and then during periodic visits for the subsequent seven years. The patients' medical history, route of diagnosis of infection, family history, and liver diseases status including: carrier state of HBV, chronic HBV, cirrhosis, and HCC were recorded. Descriptive and analytic statistics were performed, using SPSS software version 18. RESULTS: 275 HBsAg positive patients, who had completed a 7 year follow up period, were selected. The annual incidence rate for chronic hepatitis B in inactive carrier states and cirrhosis were 0.46% and 0.2% respectively. Over seven years, the rate of inactive carriers decreased by eight percent (They turned into chronic HBV or became HBSAg negative). No significant association was found between HBSAg seroclearance, HBeAg seroconversion and the outcome in the end of each year of follow up. Different treatment regimens did not have any statistically significant difference regarding HBeAg seroconversion. There was no significant association between the outcome and different habitual characteristics, especially smoking, as well as family history on HBsAg, HBsAb, HBeAg, and Anti-HBeAg. Values of platelets and ALT showed a significant change during the follow ups. Annual incidence rate of HCC in the present study was in the range of other studies. CONCLUSIONS: These data confirm and extend data from other populations showing a low incidence of significant change in chronic HBV infection in short term with good responses to currently available therapeutics. PMID- 24066003 TI - Ex vivo restimulation of human PBMC expands a CD3+CD4-CD8- gammadelta+ T cell population that can confound the evaluation of CD4 and CD8 T cell responses to vaccination. AB - The measurement of vaccine-induced humoral and CD4(+) and CD8(+) cellular immune responses represents an important correlate of vaccine efficacy. Accurate and reliable assays evaluating such responses are therefore critical during the clinical development phase of vaccines. T cells play a pivotal role both in coordinating the adaptive and innate immune responses and as effectors. During the assessment of cell-mediated immunity (CMI) in subjects participating in a large-scale influenza vaccine trial, we identified the expansion of an IFN-gamma producing CD3(+)CD4(-)CD8(-) gammadelta (+) T cell population in the peripheral blood of 90/610 (15%) healthy subjects. The appearance of CD3(+)CD4(-)CD8(-) gammadelta (+) T cells in the blood of subjects was transient and found to be independent of the study cohort, vaccine group, subject gender and ethnicity, and ex vivo restimulation conditions. Although the function of this population and relevance to vaccination are unclear, their inclusion in the total vaccine specific T-cell response has the potential to confound data interpretation. It is thus recommended that when evaluating the induction of IFN-gamma-producing CD4(+) and CD8(+) immune responses following vaccination, the CD3(+)CD4(-)CD8(-) gammadelta (+) T cells are either excluded or separately enumerated from the overall frequency determination. PMID- 24066004 TI - Decreased PERP expression on peripheral blood mononuclear cells from patient with rheumatoid arthritis negatively correlates with disease activity. AB - BACKGROUND: PERP, p53 apoptosis effector related to PMP-22, is a p53-dependent apoptosis in diverse cell types and has cell type-specific roles in p53-mediated apoptosis. However, its role in PBMCs of RA patients has remained largely unclear. OBJECTIVES: The aim of this study was to detect the expression levels of PERP on PBMCs of RA patients and healthy controls and analyze the role of PERP in the pathogenesis of RA. Methods. The mRNA expression levels of PERP and IL-17 were detected by real-time PCR in PBMCs from patients with RA (n = 40) and healthy controls (n = 40). The correlations of PERP expression levels to IL-17 transcripts and disease activity parameters were analyzed. RESULTS: The PERP and IL-17 expression levels in the PBMCs were significantly decreased and increased in comparison of which in healthy controls. The mRNA expression levels of PERP in PBMCs from patients with RA were negatively correlated with IL-17 and disease activity parameters DAS28, RF, CRP, and ESR rather than Anti-CCP and ANA. CONCLUSIONS: These results demonstrated that PERP might be involved in the pathogenesis and a potential therapeutic target of RA by regulating the expression of IL-17. PMID- 24066005 TI - Neonatal natural killer cell function: relevance to antiviral immune defense. AB - Neonates are particularly susceptible to various pathogens compared to adults, which is attributed in part to their immature innate and adaptive immunity. Natural killer cells provide first-line innate immune reactions against virus infected cells without prior sensitization. This review updates phenotypic and functional deficiencies of neonatal cells compared to their adult counterparts and their clinical implications. PMID- 24066006 TI - Interactions between cytokines, congenital anomalies of kidney and urinary tract and chronic kidney disease. AB - Fetal hydronephrosis is the most common anomaly detected on antenatal ultrasound, affecting 1-5% of pregnancies. Postnatal investigation has the major aim in detecting infants with severe urinary tract obstruction and clinically significant urinary tract anomalies among the heterogeneous universe of patients. Congenital uropathies are frequent causes of pediatric chronic kidney disease (CKD). Imaging techniques clearly contribute to this purpose; however, sometimes, these exams are invasive, very expensive, and not sufficient to precisely define the best approach as well as the prognosis. Recently, biomarkers have become a focus of clinical research as potentially useful diagnostic tools in pediatric urological diseases. In this regard, recent studies suggest a role for cytokines and chemokines in the pathophysiology of CAKUT and for the progression to CKD. Some authors proposed that the evaluation of these inflammatory mediators might help the management of postnatal uropathies and the detection of patients with high risk to developed chronic kidney disease. Therefore, the aim of this paper is to revise general aspects of cytokines and the link between cytokines, CAKUT, and CKD by including experimental and clinical evidence. PMID- 24066007 TI - Identifying core herbal treatments for children with asthma: implication from a chinese herbal medicine database in taiwan. AB - Asthma is one of the most common allergic respiratory diseases around the world and places great burden on medical payment. Chinese herbal medicine (CHM) is commonly used for Taiwanese children to control diseases. The aim of this study is to analyze the CHM prescriptions for asthmatic children by using a nationwide clinical database. The National Health Insurance Research Database (NHIRD) was used to perform this study. Medical records from 1997 to 2009 with diagnosis with asthma made for children aged 6 to 18 were included into the analysis. Association rule mining and social network analysis were used to analyze the prevalence of single CHM and its combinations. Ma-Xing-Gan-Shi-Tang (MXGST) was the most commonly used herbal formula (HF) (20.2% of all prescriptions), followed by Xiao-Qing-Long-Tang (13.1%) and Xing-Su-San (12.8%). Zhe Bei Mu is the most frequently used single herb (SH) (14.6%), followed by Xing Ren (10.7%). MXGST was commonly used with Zhe Bei Mu (3.5%) and other single herbs capable of dispelling phlegm. Besides, MXGST was the core formula to relieve asthma. Further studies about efficacy and drug safety are needed for the CHM commonly used for asthma based on the result of this study. PMID- 24066008 TI - Expression Profiling and Proteomic Analysis of JIN Chinese Herbal Formula in Lung Carcinoma H460 Xenografts. AB - Many traditional Chinese medicine (TCM) formulae have been used in cancer therapy. The JIN formula is an ancient herbal formula recorded in the classic TCM book Jin Kui Yao Lue (Golden Chamber). The JIN formula significantly delayed the growth of subcutaneous human H460 xenografted tumors in vivo compared with the growth of mock controls. Gene array analysis of signal transduction in cancer showed that the JIN formula acted on multiple targets such as the mitogen activated protein kinase, hedgehog, and Wnt signaling pathways. The coformula treatment of JIN and diamminedichloroplatinum (DDP) affected the stress/heat shock pathway. Proteomic analysis showed 36 and 84 differentially expressed proteins between the mock and DDP groups and between the mock and JIN groups, respectively. GoMiner analysis revealed that the differentially expressed proteins between the JIN and mock groups were enriched during cellular metabolic processes, and so forth. The ones between the DDP and mock groups were enriched during protein-DNA complex assembly, and so forth. Most downregulated proteins in the JIN group were heat shock proteins (HSPs) such as HSP90AA1 and HSPA1B, which could be used as markers to monitor responses to the JIN formula therapy. The mechanism of action of the JIN formula on HSP proteins warrants further investigation. PMID- 24066009 TI - The roles of traditional chinese medicine: shen-fu injection on the postresuscitation care bundle. AB - Survival rates following in-hospital and out-of-hospital cardiac arrests remain disappointingly low. Organ injury caused by ischemia and hypoxia during prolonged cardiac arrest is compounded by reperfusion injury that occurs when a spontaneous circulation is restored. A bundle of procedures, which may need to be administered simultaneously, is required. The procedures include prompt identification and treatment of the cause of cardiac arrest, as well as a definitive airway and ventilation together. Additional benefit is possible with appropriate forms of early goal-directed therapy and achieving therapeutic hypothermia within the first few hours, followed by gradual rewarming and ensuring glycaemic control to be within a range of 6 to 10 mmol/L. All these would be important and need to be continued for at least 24 hours. Previous studies have showed that the effects of Shen-Fu injection (SFI) are based on aconitine properties, supplemented by ginsenoside, which can scavenge free radicals, improve energy metabolism, inhibit inflammatory mediators, suppress cell apoptosis, and alleviate mitochondrial damage. SFI, like many other complex prescriptions of traditional Chinese medicine, was also found to be more effective than any of its ingredient used separately in vivo. As the postresuscitation care bundle is known to be, the present paper focuses on the role of SFI played on the postresuscitation care bundle. PMID- 24066010 TI - Chemotherapy-induced peripheral neuropathy in cancer patients: a four-arm randomized trial on the effectiveness of electroacupuncture. AB - Purpose. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose limiting side effect of cytostatic drugs. Since there are no proven therapeutic procedures against CIPN, we were interested to define the role of electroacupuncture (EA) from which preliminary data showed promising results. Methods. In a randomized trial with a group sequential adaptive design in patients with CIPN, we compared EA (LV3, SP9, GB41, GB34, LI4, LI11, SI3, and HT3; n = 14) with hydroelectric baths (HB, n = 14), vitamin B1/B6 capsules (300/300 mg daily; VitB, n = 15), and placebo capsules (n = 17). The statistical power in this trial was primarily calculated for proving EA only, so results of HB and VitB are pilot data. Results. CIPN complaints improved by 0.8 +/- 1.2 (EA), 1.7 +/- 1.7 (HB), 1.6 +/- 2.0 (VitB), and 1.3 +/- 1.3 points (placebo) on a 10-point numeric rating scale without significant difference between treatment groups or placebo. In addition no significant differences in sensory nerve conduction studies or quality of life (EORTC QLQ-C30) were found. Conclusions. The used EA concept, HB, and VitB were not superior to placebo. Since, contrary to our results, studies with different acupuncture concepts showed a positive effect on CIPN, the effect of acupuncture on CIPN remains unclear. Further randomized, placebo controlled studies seem necessary. This trial is registered with DRKS00004448. PMID- 24066011 TI - Differences in Blood Urea and Creatinine Concentrations in Earthed and Unearthed Subjects during Cycling Exercise and Recovery. AB - Contact of humans with the earth, either directly (e.g., with bare feet) or using a metal conductor, changes their biochemical parameters. The effects of earthing during physical exercise are unknown. This study was carried out to evaluate selected biochemical parameters in subjects who were earthed during cycling. In a double-blind, crossover study, 42 participants were divided into two groups and earthed during exercise and recovery. One group was earthed in the first week during 30 minutes of cycling exercise and during recovery, and a second group was earthed in the second week. A double-blind technique was applied. Blood samples were obtained before each training session, after 15 and 30 minutes of exercise, and after 40 minutes of recovery. Significantly lower blood urea levels were observed in subjects earthed during exercise and relaxation. These significant differences were noted in both groups earthed at the beginning of exercise (P < 0.0001), after 15 (P < 0.0001) and 30 minutes (P < 0.0001) of exercise, and after 40 minutes of relaxation (P < 0.0001). Creatinine concentrations in earthed subjects during exercise were unchanged. Conclusions. Earthing during exercise lowers blood urea concentrations and may inhibit hepatic protein catabolism or increase renal urea excretion. Exertion under earthing may result in a positive protein balance. PMID- 24066012 TI - Phytochemical and pharmacological review of da chuanxiong formula: a famous herb pair composed of chuanxiong rhizoma and gastrodiae rhizoma for headache. AB - Chronic headache such as migraine and nervous headache has become one of the most common locations of pain and one of the most difficult diseases to recover due to its numerous causes and inconvenience to keep acesodyne administration for a long time. However, there are a series of treatment theories and herbal formulas for this disease in traditional Chinese medicine (TCM), in which Da Chuanxiong formula (DCXF), a herb pair composed of Chuanxiong Rhizoma (CR), Chuanxiong in Chinese, and Gastrodiae Rhizoma (GR) called as Tianma in China, is a greatly classic representative. This formula has been used for headaches via dispelling wind pathogen and dissipating blood stasis for many years in TCM. In recent years, the efficiency and representativeness of DCXF have garnered many researchers' attention. To reveal the compatibility mechanism and develop innovative Chinese herb, herein ethnopharmacological relevance, chemical characters, and pharmacological actions of DCXF are detailed. It is expected to give a comprehensive interpretation of DCXF, namely, Chuanxiong Tianma herb pair (CTHP), to inherit the essence of herb pair and innovate drug delivery system of this prescription. PMID- 24066013 TI - Analysis of Therapeutic Effect of Ilex hainanensis Merr. Extract on Nonalcoholic Fatty Liver Disease through Urine Metabolite Profiling by Ultraperformance Liquid Chromatography/Quadrupole Time of Flight Mass Spectrometry. AB - Nonalcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease, is increased worldwide in parallel with the obesity epidemic. Our previous studies have showed that the extract of I. hainanensis (EIH) can prevent NAFLD in rat fed with high-fat diet. In this work, we aimed to find biomarkers of NAFLD and investigate the therapeutic effects of EIH. NAFLD model was induced in male Sprague-Dawley rats by high-fat diet. The NAFLD rats were administered EIH orally (250 mg/kg) for two weeks. After the experimental period, samples of 24 h urine were collected and analyzed by ultraperformance liquid chromatography/quadrupole time of flight mass spectrometry (UPLC-Q-TOF). Orthogonal partial least squares analysis (OPLSs) models were built to find biomarkers of NAFLD and investigate the therapeutic effects of EIH. 22 metabolites, which are distributed in several metabolic pathways, were identified as potential biomarkers of NAFLD. Taking these biomarkers as screening indexes, EIH could reverse the pathological process of NAFLD through regulating the disturbed pathway of metabolism. The metabolomic results not only supply a systematic view of the development and progression of NAFLD but also provide a theoretical basis for the prevention or treatment of NAFLD. PMID- 24066015 TI - Needling therapy for myofascial pain control. PMID- 24066014 TI - Grape-Derived Polyphenols Prevent Doxorubicin-Induced Blunted EDH-Mediated Relaxations in the Rat Mesenteric Artery: Role of ROS and Angiotensin II. AB - This study determined whether doxorubicin, an anticancer agent, impairs endothelium-dependent relaxations mediated by nitric oxide (NO) and endothelium derived hyperpolarization (EDH) in the mesenteric artery and, if so, the mechanism underlying the protective effect of red wine polyphenols (RWPs), a rich natural source of antioxidants. Male Wistar rats were assigned into 4 groups: control, RWPs, doxorubicin, and doxorubicin + RWPs. Vascular reactivity was assessed in organ chambers; the vascular formation of reactive oxygen species (ROS) using dihydroethidine and the expression levels of small and intermediate conductance calcium-activated potassium channels (SKCa, IKCa) and connexin 40 (Cx40), which are involved in EDH-type relaxations, endothelial NO synthase (eNOS), angiotensin II, and AT1 receptors by immunofluorescence. The doxorubicin treatment impaired EDH-mediated relaxations, whereas those mediated by NO were minimally affected. This effect was associated with reduced expression levels of SKCa, IKCa, and Cx40, increased expression levels of eNOS, angiotensin II, and AT1 receptors, and formation of ROS in mesenteric arteries. RWPs prevented both the doxorubicin-induced blunted EDH-type relaxations and the increased vascular oxidative stress, and they improved the expression levels of target proteins. These findings suggest that polyphenol-rich natural products might be of interest in the management of doxorubicin-induced vascular injury possibly by improving the vascular angiotensin system. PMID- 24066016 TI - A hybrid method for pancreas extraction from CT image based on level set methods. AB - This paper proposes a novel semiautomatic method to extract the pancreas from abdominal CT images. Traditional level set and region growing methods that request locating initial contour near the final boundary of object have problem of leakage to nearby tissues of pancreas region. The proposed method consists of a customized fast-marching level set method which generates an optimal initial pancreas region to solve the problem that the level set method is sensitive to the initial contour location and a modified distance regularized level set method which extracts accurate pancreas. The novelty in our method is the proper selection and combination of level set methods, furthermore an energy-decrement algorithm and an energy-tune algorithm are proposed to reduce the negative impact of bonding force caused by connected tissue whose intensity is similar with pancreas. As a result, our method overcomes the shortages of oversegmentation at weak boundary and can accurately extract pancreas from CT images. The proposed method is compared to other five state-of-the-art medical image segmentation methods based on a CT image dataset which contains abdominal images from 10 patients. The evaluated results demonstrate that our method outperforms other methods by achieving higher accuracy and making less false segmentation in pancreas extraction. PMID- 24066017 TI - Liver segmentation based on Snakes Model and improved GrowCut algorithm in abdominal CT image. AB - A novel method based on Snakes Model and GrowCut algorithm is proposed to segment liver region in abdominal CT images. First, according to the traditional GrowCut method, a pretreatment process using K-means algorithm is conducted to reduce the running time. Then, the segmentation result of our improved GrowCut approach is used as an initial contour for the future precise segmentation based on Snakes model. At last, several experiments are carried out to demonstrate the performance of our proposed approach and some comparisons are conducted between the traditional GrowCut algorithm. Experimental results show that the improved approach not only has a better robustness and precision but also is more efficient than the traditional GrowCut method. PMID- 24066018 TI - Circulating tumour cells in breast cancer. AB - Evaluation of isolated tumour cells in bone marrow (BM) and peripheral blood has become a major focus of translational cancer research. The presence of disseminated tumour cells in BM is a common phenomenon observed in 30-40% of primary breast cancer patients and independently predicts reduced clinical outcome. The detection of circulating tumour cells (CTCs) in blood might become a desired alternative to the invasive and painful BM biopsy. Recent clinical trials confirmed the feasibility of CTC detection as a robust and reproducible parameter for prognostication in both adjuvant and metastatic setting. The characterisation of CTCs might become an important biomarker for therapy monitoring and help to identify specific targets for novel therapeutic strategies. PMID- 24066019 TI - Sentinel node biopsy in early breast cancer at the Hospital Comarcal La Linea (Spain). AB - OBJECTIVE: Our objective was to determine the identification and the percentage of false negatives in sentinel node biopsies in patients with early breast cancer at the Hospital La Linea (Spain), during the period between November 2007 and September 2010. METHODS: We collected 50 patients with early breast cancer, without clinical and ultrasonographic involvement of axillary nodes, from November 2007 to September 2010. We used the vital dye in the first 20 patients and the combined technique of vital dye and albumin labelled with technetium 99 in the other 30 patients. The site of injection for patients using blue dye was subdermal for palpable tumours and periareolar for non-palpable tumours. The technique of injection with the radioisotope for patients for palpable and most non-palpable tumours was the periareolar technique. We used albumin labelled with technetium 99. In seven patients with non-palpable tumours, we used the sentinel node occult lesion localisation (SNOLL) technique. The sentinel node biopsy was examined during surgery, with the frozen section examination and imprint as follows: the sentinel node was cut in three transversal sections along the axis and five frozen sections of each portion were done at a distance of 60 MUm each; in total, 15-20 frozen sections and three imprints were done for each sentinel node. The axillary dissection was completed in the first 17 patients, and we performed total axillary dissection on the remaining patients if the sentinel node was positive for metastasis. RESULTS: The sentinel nodes were identified in 49 of 50 patients (98%). The patient in whom we did not identify the sentinel node was a patient in the combined technique. The number of nodes identified in the patients with vital dye was one sentinel node, and with the combined technique, it was two sentinel nodes. The false-negative rate was 8% (four patients); the micrometastasis was the principal factor of the false-negative rate (p < 0.05). The cases of false negatives were present at the beginning of the study with the use of the blue dyes; this factor was statistically significant (p < 0.05). The tumour size, the vascular invasion, and the periganglionar adipose tissue invasion were statistically significant for the presentation of axillary metastasis (p < 0.05). CONCLUSION: This study shows that the micrometastasis and the use of vital dye were the principal factors for the presentation of the false-negative rate. The size of the tumour, the vascular invasion, and the periganglionar adipose tissue invasion were statistically significant for the appearance of the axillary metastasis. PMID- 24066020 TI - Electronic discharge summary driving advice: Current practice and future directions. AB - BACKGROUND: Driving is a complex task. Many older drivers are unaware of their obligation to inform authorities of conditions which may impact upon their driving safety. AIMS: This study sought to establish the adequacy of driving advice in electronic discharge summaries from an Australian stroke unit. METHOD: One month of in-patient electronic discharge summaries were reviewed. A predetermined list of items was used to assess each electronic discharge summary: age; gender; diagnosis; relevant co-morbidities; deficit at time of discharge; driving advice; length of stay; and discharge destination. RESULTS: Of 41 participants, the mean age was 72 years. Twenty patients had a discharge diagnosis of stroke, nine of transient ischaemic attack, four of seizure and one of encephalitis. Of these, only eight discharge summaries included driving advice. CONCLUSION: The documentation of driving advice in electronic discharge summaries is poor. This has important public health, ethical and medico-legal implications. Avenues for future research are explored. PMID- 24066021 TI - Evolution of the R2 retrotransposon ribozyme and its self-cleavage site. AB - R2 is a non-long terminal repeat retrotransposon that inserts site-specifically in the tandem 28S rRNA genes of many animals. Previously, R2 RNA from various species of Drosophila was shown to self-cleave from the 28S rRNA/R2 co-transcript by a hepatitis D virus (HDV)-like ribozyme encoded at its 5' end. RNA cleavage was at the precise 5' junction of the element with the 28S gene. Here we report that RNAs encompassing the 5' ends of R2 elements from throughout its species range fold into HDV-like ribozymes. In vitro assays of RNA self-cleavage conducted in many R2 lineages confirmed activity. For many R2s, RNA self-cleavage was not at the 5' end of the element but at 28S rRNA sequences up to 36 nucleotides upstream of the junction. The location of cleavage correlated well with the types of endogenous R2 5' junctions from different species. R2 5' junctions were uniform for most R2s in which RNA cleavage was upstream in the rRNA sequences. The 28S sequences remaining on the first DNA strand synthesized during retrotransposition are postulated to anneal to the target site and uniformly prime second strand DNA synthesis. In species where RNA cleavage occurred at the R2 5' end, the 5' junctions were variable. This junction variation is postulated to result from the priming of second strand DNA synthesis by chance microhomologies between the target site and the first DNA strand. Finally, features of R2 ribozyme evolution, especially changes in cleavage site and convergence on the same active site sequences, are discussed. PMID- 24066022 TI - Popeye domain containing 1 (Popdc1/Bves) is a caveolae-associated protein involved in ischemia tolerance. AB - Popeye domain containing1 (Popdc1), also named Bves, is an evolutionary conserved membrane protein. Despite its high expression level in the heart little is known about its membrane localization and cardiac functions. The study examined the hypothesis that Popdc1 might be associated with the caveolae and play a role in myocardial ischemia tolerance. To address these issues, we analyzed hearts and cardiomyocytes of wild type and Popdc1-null mice. Immunoconfocal microscopy revealed co-localization of Popdc1 with caveolin3 in the sarcolemma, intercalated discs and T-tubules and with costameric vinculin. Popdc1 was co immunoprecipitated with caveolin3 from cardiomyocytes and from transfected COS7 cells and was co-sedimented with caveolin3 in equilibrium density gradients. Caveolae disruption by methyl-beta-cyclodextrin or by ischemia/reperfusion (I/R) abolished the cellular co-localization of Popdc1 with caveolin3 and modified their density co-sedimentation. The caveolin3-rich fractions of Popdc1-null hearts redistributed to fractions of lower buoyant density. Electron microscopy showed a statistically significant 70% reduction in caveolae number and a 12% increase in the average diameter of the remaining caveolae in the mutant hearts. In accordance with these changes, Popdc1-null cardiomyocytes displayed impaired [Ca(+2)]i transients, increased vulnerability to oxidative stress and no pharmacologic preconditioning. In addition, induction of I/R injury to Langendorff-perfused hearts indicated a significantly lower functional recovery in the mutant compared with wild type hearts while their infarct size was larger. No improvement in functional recovery was observed in Popdc1-null hearts following ischemic preconditioning. The results indicate that Popdc1 is a caveolae-associated protein important for the preservation of caveolae structural and functional integrity and for heart protection. PMID- 24066023 TI - Copper bracelets and magnetic wrist straps for rheumatoid arthritis--analgesic and anti-inflammatory effects: a randomised double-blind placebo controlled crossover trial. AB - BACKGROUND: Folklore remedies for pain and inflammation in rheumatoid arthritis include the application of magnets and copper to the skin. Despite the popular use of devices containing magnets or copper for this purpose, little research has been conducted to evaluate the efficacy of such treatments. OBJECTIVE: To investigate whether the practice of wearing magnetic wrists straps, or copper bracelets, offers any specific therapeutic benefit for patients with rheumatoid arthritis. DESIGN: Randomised double-blind placebo-controlled crossover trial. METHODS: 70 patients, aged 33 to 79 years and predominantly female (n = 52), with painful rheumatoid arthritis were recruited from general practices within Yorkshire. Participants were randomly allocated to wear four devices in a different order. Devices tested were: a standard (1502 to 2365 gauss) magnetic wrist strap, a demagnetised (<20 gauss) wrist strap, an attenuated (250 to 350 gauss) magnetic wrist strap, and a copper bracelet. Devices were each worn for five weeks, with treatment phases being separated by one week wash-out periods. The primary outcome measured was pain using a 100 mm visual analogue scale. Secondary pain measures were the McGill Pain Questionnaire and tender joint count. Inflammation was assessed using C-reactive protein and plasma viscosity blood tests and by swollen joint count. Physical function was assessed using the Health Assessment Questionnaire (Disability Index). Disease activity and medication use was also measured. RESULTS: 65 participants provided complete self report outcome data for all devices, four participants provided partial data. Analysis of treatment outcomes did not reveal any statistically significant differences (P>0.05) between the four devices in terms of their effects on pain, inflammation, physical function, disease activity, or medication use. CONCLUSIONS: Wearing a magnetic wrist strap or a copper bracelet did not appear to have any meaningful therapeutic effect, beyond that of a placebo, for alleviating symptoms and combating disease activity in rheumatoid arthritis. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN51459023 ISRCTN51459023. PMID- 24066024 TI - Isolation, purification and characterization of vinblastine and vincristine from endophytic fungus Fusarium oxysporum isolated from Catharanthus roseus. AB - Endophytic fungi reside in a symbiotic fashion inside their host plants, mimic their chemistry and interestingly, produce the same natural products as their hosts and are thus being screened for the production of valuable compounds like taxol, camptothecin, podophyllotoxin, etc. Vinblastine and vincristine are excellent anti-cancer drugs but their current production using plants is non abundant and expensive. In order to make these drugs readily available to the patients at affordable prices, we isolated the endophytic fungi from Catharanthus roseus plant and found a fungus AA-CRL-6 which produces vinblastine and vincristine in appreciable amounts. These drugs were purified by TLC and HPLC and characterized using UV-Vis spectroscopy, ESI-MS, MS/MS and (1)H NMR. One liter of culture filtrate yielded 76 ug and 67 ug of vinblastine and vincristine respectively. This endophytic fungal strain was identified as Fusarium oxysporum based upon its cultural and morphological characteristics and internal transcribed spacer (ITS) sequence analysis. PMID- 24066025 TI - The association of diabetes mellitus with clinical outcomes after coronary stenting: a meta-analysis. AB - BACKGROUND: Previous studies have shown inconsistent results on the association between diabetes mellitus (DM) and some clinical outcomes. We conducted a meta analysis of observational studies to assess effect of DM on clinical outcomes after coronary stenting. METHODS: We searched for studies without language restriction in PubMed, Embase and Cochrane library prior to 2012. The clinical outcomes including in-stent restenosis (ISR), major adverse cardiac events (MACE), stent thrombosis (ST), target lesion revascularization (TLR) and target vessel revascularization (TVR). Adjusted odds ratio (OR), and the corresponding 95% confidence interval (95% CI) was summarized. RESULTS: 55 studies involving 128,084 total patients (38,416 DM patients and 89,668 controls) were eligible for our analysis. Overall, there were significant associations between DM and ISR (OR = 1.70, 95% CI: 1.53-1.89, I(2) = 0.0%), MACE (OR = 1.54, 95% CI: 1.36-1.73, I(2) = 29.0%), ST (OR = 2.01, 95% CI: 1.36-2.97, I(2) = 47.7%), TLR (OR = 1.46, 95% CI: 1.26-1.68, I(2) = 43.3%) as well as TVR (OR = 1.33, 95% CI: 1.17-1.51, I(2) = 48.3). Subgroup analysis showed that the associations were similar between BMS and DES implantation. Moreover, there was no significant association in the ST subgroup after 1-3 years follow-up. CONCLUSIONS: Our meta-analysis suggests that after coronary stent implantation, DM is associated with ISR, MACE, ST, TLR and TVR. DM appears to be a vital risk factor of these clinical outcomes. PMID- 24066027 TI - Mutagenic and cytotoxic properties of oxidation products of 5-methylcytosine revealed by next-generation sequencing. AB - 5-methylcytosine (5-mC) can be sequentially oxidized to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-foC), and finally to 5-carboxylcytosine (5-caC), which is thought to function in active DNA cytosine demethylation in mammals. Although the roles of 5-mC in epigenetic regulation of gene expression are well established, the effects of 5-hmC, 5-foC and 5-caC on DNA replication remain unclear. Here we report a systematic study on how these cytosine derivatives (5 hmC, 5-foC and 5-caC) perturb the efficiency and accuracy of DNA replication using shuttle vector technology in conjugation with next-g sequencing. Our results demonstrated that, in Escherichia coli cells, all the cytosine derivatives could induce CT transition mutation at frequencies of 0.17%-1.12%, though no effect on replication efficiency was observed. These findings provide an important new insight on the potential mutagenic properties of cytosine derivatives occurring as the intermediates of DNA demethylation. PMID- 24066028 TI - Tick paralysis in spectacled flying-foxes (Pteropus conspicillatus) in North Queensland, Australia: impact of a ground-dwelling ectoparasite finding an arboreal host. AB - When a parasite finds a new wildlife host, impacts can be significant. In the late 1980s populations of Spectacled Flying-foxes (SFF) (Pteropus conspicillatus), a species confined, in Australia, to north Queensland became infected by paralysis tick (Ixodes holocyclus), resulting in mortality. This Pteropus-tick relationship was new to Australia. Curiously, the relationship was confined to several camps on the Atherton Tableland, north Queensland. It was hypothesised that an introduced plant, wild tobacco (Solanum mauritianum), had facilitated this new host-tick interaction. This study quantifies the impact of tick paralysis on SFF and investigates the relationship with climate. Retrospective analysis was carried out on records from the Tolga Bat Hospital for 1998-2010. Juvenile mortality rates were correlated to climate data using vector auto-regression. Mortality rates due to tick paralysis ranged between 11.6 per 10,000 bats in 2003 and 102.5 in 2009; more female than male adult bats were affected. Juvenile mortality rates were negatively correlated with the total rainfall in January to March and July to September of the same year while a positive correlation of these quarterly total rainfalls existed with the total population. All tick affected camps of SFF were located in the 80% core range of S. mauritianum. This initial analysis justifies further exploration of how an exotic plant might alter the relationship between a formerly ground-dwelling parasite and an arboreal host. PMID- 24066026 TI - Functional metagenomics reveals novel pathways of prebiotic breakdown by human gut bacteria. AB - The human intestine hosts a complex bacterial community that plays a major role in nutrition and in maintaining human health. A functional metagenomic approach was used to explore the prebiotic breakdown potential of human gut bacteria, including non-cultivated ones. Two metagenomic libraries, constructed from ileum mucosa and fecal microbiota, were screened for hydrolytic activities on the prebiotic carbohydrates inulin, fructo-oligosaccharides, xylo-oligosaccharides, galacto-oligosaccharides and lactulose. The DNA inserts of 17 clones, selected from the 167 hits that were identified, were pyrosequenced in-depth, yielding in total 407, 420 bp of metagenomic DNA. From these sequences, we discovered novel prebiotic degradation pathways containing carbohydrate transporters and hydrolysing enzymes, for which we provided the first experimental proof of function. Twenty of these proteins are encoded by genes that are also present in the gut metagenome of at least 100 subjects, whatever are their ages or their geographical origin. The sequence taxonomic assignment indicated that still unknown bacteria, for which neither culture conditions nor genome sequence are available, possess the enzymatic machinery to hydrolyse the prebiotic carbohydrates tested. The results expand the vision on how prebiotics are metabolized along the intestine, and open new perspectives for the design of functional foods. PMID- 24066029 TI - Convergent RANK- and c-Met-mediated signaling components predict survival of patients with prostate cancer: an interracial comparative study. AB - We reported (PLoS One 6 (12):e28670, 2011) that the activation of c-Met signaling in RANKL-overexpressing bone metastatic LNCaP cell and xenograft models increased expression of RANK, RANKL, c-Met, and phosphorylated c-Met, and mediated downstream signaling. We confirmed the significance of the RANK-mediated signaling network in castration resistant clinical human prostate cancer (PC) tissues. In this report, we used a multispectral quantum dot labeling technique to label six RANK and c-Met convergent signaling pathway mediators simultaneously in formalin fixed paraffin embedded (FFPE) tissue specimens, quantify the intensity of each expression at the sub-cellular level, and investigated their potential utility as predictors of patient survival in Caucasian-American, African-American and Chinese men. We found that RANKL and neuropilin-1 (NRP-1) expression predicts survival of Caucasian-Americans with PC. A Gleason score >= 8 combined with nuclear p-c-Met expression predicts survival in African-American PC patients. Neuropilin-1, p-NF-kappaB p65 and VEGF are predictors for the overall survival of Chinese men with PC. These results collectively support interracial differences in cell signaling networks that can predict the survival of PC patients. PMID- 24066030 TI - CD4+ T cells play a critical role in the generation of primary and memory antitumor immune responses elicited by SA-4-1BBL and TAA-based vaccines in mouse tumor models. AB - The role of CD4(+) T cells in the generation of therapeutic primary and memory immune responses in cancer diverse immunotherapy settings remains ambiguous. We herein investigated this issue using two vaccine formulations containing a novel costimulatory molecule, SA-4-1BBL, as adjuvant and HPV E7 or survivin (SVN) as tumor associated antigens (TAAs) in two mouse transplantable tumor models; the TC 1 cervical cancer expressing xenogeneic HPV E7 and 3LL lung carcinoma overexpressing autologous SVN. Single vaccination with optimized SA-4-1BBL/TAA formulations resulted in the eradication of 6-day established TC-1 and 3LL tumors in >70% of mice in both models. The in vivo depletion of CD4(+) T cells one day before tumor challenge resulted in compromised vaccine efficacy in both TC-1 (25%) and 3LL (12.5%) tumor models. In marked contrast, depletion of CD4(+) T cells 5 days post-tumor challenge and one day prior to vaccination did not significantly alter the therapeutic efficacy of these vaccines. However, long term immunological memory was compromised in the 3LL, but not in TC-1 model as a significant number (85.7%) of tumor free-mice succumbed to tumor growth when rechallenged with 3LL cells 60 days after the initial tumor inoculation. Collectively, these results demonstrate the indispensable role CD4(+) T cells play in the generation of therapeutic primary immune responses elicited by SA-4 1BBL/TAA-based vaccines irrespective of the nature of TAAs and establish the importance of CD4(+) T cells for long-term immune memory against 3LL tumor expressing self-antigen SVN, but not TC-1 expressing xenogeneic viral antigen E7. PMID- 24066031 TI - Clinical applicability and cutoff values for an unstructured neuropsychological assessment protocol for older adults with low formal education. AB - BACKGROUND AND OBJECTIVES: The neuropsychological exam plays a central role in the assessment of elderly patients with cognitive complaints. It is particularly relevant to differentiate patients with mild dementia from those subjects with mild cognitive impairment. Formal education is a critical factor in neuropsychological performance; however, there are few studies that evaluated the psychometric properties, especially criterion related validity, neuropsychological tests for patients with low formal education. The present study aims to investigate the validity of an unstructured neuropsychological assessment protocol for this population and develop cutoff values for clinical use. METHODS AND RESULTS: A protocol composed by the Rey-Auditory Verbal Learning Test, Frontal Assessment Battery, Category and Letter Fluency, Stick Design Test, Clock Drawing Test, Digit Span, Token Test and TN-LIN was administered to 274 older adults (96 normal aging, 85 mild cognitive impairment and 93 mild Alzheimer's disease) with predominantly low formal education. Factor analysis showed a four factor structure related to Executive Functions, Language/Semantic Memory, Episodic Memory and Visuospatial Abilities, accounting for 65% of explained variance. Most of the tests showed a good sensitivity and specificity to differentiate the diagnostic groups. The neuropsychological protocol showed a significant ecological validity as 3 of the cognitive factors explained 31% of the variance on Instrumental Activities of Daily Living. CONCLUSION: The study presents evidence of the construct, criteria and ecological validity for this protocol. The neuropsychological tests and the proposed cutoff values might be used for the clinical assessment of older adults with low formal education. PMID- 24066032 TI - Physiological concentrations of leptin do not affect human neutrophils. AB - Leptin is an adipokine that is thought to be important in many inflammatory diseases, and is known to influence the function of several leukocyte types. However, no clear consensus is present regarding the responsiveness of neutrophils for this adipokine. In this study a 2D DIGE proteomics approach was used as an unbiased approach to identify leptin-induced effects on neutrophils. Additionally chemotaxis and survival experiments were performed to reproduce results from literature showing putative effects of leptin on these neutrophil responses. Leptin did not induce any significant changes in the proteome provided leptin was added at physiologically relevant concentrations (250 ng). Our leptin batches were biologically active as they induced proliferation in LeptinR expressing Ba/F3 cells. At high concentrations (25000 ng) leptin induced a change in neutrophil proteome. Seventeen differently regulated spots were identified of which twelve could be characterized by mass spectrometry. Two of these identified proteins, SerpinB1 and p40 phox, were chosen for further analysis but leptin induced expression analyzed by western blot were highly variable. Additionally leptin also induced neutrophil survival at these high concentrations. No leptin induced chemotaxis of human neutrophils was detected at any concentration. In conclusion, physiological concentrations of leptin do not affect neutrophils. High leptin concentrations induced survival and changes in the neutrophils proteome, but this was most likely mediated by an indirect effect. However, it cannot be ruled out that the effects were mediated by a yet not-identified leptin receptor on human neutrophils. PMID- 24066033 TI - Mutational screening of LCA genes emphasizing RPE65 in South Indian cohort of patients. AB - BACKGROUND: Leber congenital amaurosis (LCA) is the most severe form of inherited retinal visual impairment in children. So far, mutations in more than 20 genes have been known to cause LCA and among them, RPE65 is a suitable candidate for gene therapy. The mutational screenings of RPE65 and other LCA genes are requisite in support of emerging gene specific therapy for LCA. Therefore, we have carried out a comprehensive LCA genes screening using a combined approach of direct sequencing and DNA microarray based Asper chip analysis. METHODOLOGY/PRINCIPAL FINDINGS: Thirty clinically diagnosed index LCA cases from Southern India were screened for coding and flanking intronic regions of RPE65 through direct sequencing. Among thirty, 25 cases excluded from RPE65 mutations were subjected to Asper chip analysis, testing 784 known pathogenic variations in 15 major LCA genes. In RPE65 screening, four different pathogenic variations including two novel (c.361insT & c.939T>A) and two known (c.394G>A & c.361delT) mutations were identified in five index cases. In the chip analysis, seven known pathogenic mutations were identified in six index cases, involving genes GUCY2D, RPGRIP1, AIPL1, CRX and IQCB1. Overall, 11 out of 30 LCA cases (36.6%) revealed pathogenic variations with the involvement of RPE65 (16.6%), GUCY2D (10%), RPGRIP1 (3.3%), AIPL1 (3.3%) and CRX & IQCB1 (3.3%). CONCLUSIONS/SIGNIFICANCE: Our study suggests that such combined screening approach is productive and cost effective for mutation detection and can be applied in Indian LCA cohort for molecular diagnosis and genetic counselling. PMID- 24066035 TI - Trends in and determinants of loss to follow up and early mortality in a rapid expansion of the antiretroviral treatment program in Vietnam: findings from 13 outpatient clinics. AB - BACKGROUND: This study aims to describe the trends in and determinants of six month mortality and loss to follow up (LTFU) during 2005-2009 in 13 outpatient clinics in Vietnam. METHOD: Data were obtained from clinical records of 3,449 Vietnamese HIV/AIDS patients aged 18 years or older who initiated ART between 1 January 2005 and 31 December 2009. Mantel-Haenszel chi-square test, log rank test were conducted to examine the trends of baseline characteristics, six month mortality and LTFU. Cox proportional hazards regression models were performed to compute hazard ratio (HR) and 95% Confidence Interval (CI). RESULTS: Though there was a declining trend, the incidence of six month mortality and LTFU remained as high as 6% and 15%, respectively. Characteristics associated with six month mortality were gender (HR females versus males 0.54, 95%CI: 0.34-0.85), years of initiation (HR 2009 versus 2005 0.54, 95%CI: 0.41-0.80), low baseline CD4 (HR 350 500 cells/mm(3) versus <50 cells/mm(3) 0.26, 95%CI: 0.18-0.52), low baseline BMI (one unit increase: HR 0.96, 95%CI: 0.94-0.97), co-infection with TB (HR 1.61, 95%CI: 1.46-1.95), history of injecting drugs (HR 1.58, 95%CI: 1.31-1.78). Characteristics associated with LTFU were younger age (one year younger: HR 0.97, 95%CI: 0.95-0.98), males (HR females versus males 0.82, 95%CI: 0.63-0.95), and poor adherence (HR 0.55, 95%CI: 0.13-0.87). CONCLUSIONS: To reduce early mortality, special attention is required to ensure timely access to ART services, particularly for patients at higher risk. Patients at risk for LTFU after ART initiation should be targeted through enhancing treatment counselling and improving patient tracing system at ART clinics. PMID- 24066036 TI - VO2max trainability and high intensity interval training in humans: a meta analysis. AB - Endurance exercise training studies frequently show modest changes in VO2max with training and very limited responses in some subjects. By contrast, studies using interval training (IT) or combined IT and continuous training (CT) have reported mean increases in VO2max of up to ~1.0 L . min(-1). This raises questions about the role of exercise intensity and the trainability of VO2max. To address this topic we analyzed IT and IT/CT studies published in English from 1965-2012. Inclusion criteria were: 1)>= 3 healthy sedentary/recreationally active humans <45 yrs old, 2) training duration 6-13 weeks, 3) >= 3 days/week, 4) >= 10 minutes of high intensity work, 5) >= 1:1 work/rest ratio, and 6) results reported as mean +/- SD or SE, ranges of change, or individual data. Due to heterogeneity (I(2) value of 70), statistical synthesis of the data used a random effects model. The summary statistic of interest was the change in VO2max. A total of 334 subjects (120 women) from 37 studies were identified. Participants were grouped into 40 distinct training groups, so the unit of analysis was 40 rather than 37. An increase in VO2max of 0.51 L . min(-1) (95% CI: 0.43 to 0.60 L . min(-1)) was observed. A subset of 9 studies, with 72 subjects, that featured longer intervals showed even larger (~0.8-0.9 L . min(-1)) changes in VO2max with evidence of a marked response in all subjects. These results suggest that ideas about trainability and VO2max should be further evaluated with standardized IT or IT/CT training programs. PMID- 24066034 TI - Identification of male gametogenesis expressed genes from the scallop Nodipecten subnodosus by suppressive subtraction hybridization and pyrosequencing. AB - Despite the great advances in sequencing technologies, genomic and transcriptomic information for marine non-model species with ecological, evolutionary, and economical interest is still scarce. In this work we aimed to identify genes expressed during spermatogenesis in the functional hermaphrodite scallop Nodipecten subnodosus (Mollusca: Bivalvia: Pectinidae), with the purpose of obtaining a panel of genes that would allow for the study of differentially transcribed genes between diploid and triploid scallops in the context of meiotic arrest and reproductive sterility. Because our aim was to isolate genes involved in meiosis and other testis maturation-related processes, we generated suppressive subtractive hybridization libraries of testis vs. inactive gonad. We obtained 352 and 177 ESTs by clone sequencing, and using pyrosequencing (454 Roche) we maximized the identified ESTs to 34,276 reads. A total of 1,153 genes from the testis library had a blastx hit and GO annotation, including genes specific for meiosis, spermatogenesis, sex-differentiation, and transposable elements. Some of the identified meiosis genes function in chromosome pairing (scp2, scp3), recombination and DNA repair (dmc1, rad51, ccnb1ip1/hei10), and meiotic checkpoints (rad1, hormad1, dtl/cdt2). Gene expression analyses in different gametogenic stages in both sexual regions of the gonad of meiosis genes confirmed that the expression was specific or increased towards the maturing testis. Spermatogenesis genes included known testis-specific ones (kelch-10, shippo1, adad1), with some of these known to be associated to sterility. Sex differentiation genes included one of the most conserved genes at the bottom of the sex-determination cascade (dmrt1). Transcript from transposable elements, reverse transcriptase, and transposases in this library evidenced that transposition is an active process during spermatogenesis in N. subnodosus. In relation to the inactive library, we identified 833 transcripts with functional annotation related to activation of the transcription and translation machinery, as well as to germline control and maintenance. PMID- 24066037 TI - Bioactivity of fungal endophytes as a function of endophyte taxonomy and the taxonomy and distribution of their host plants. AB - Fungal endophytes--fungi that grow within plant tissues without causing immediate signs of disease--are abundant and diverse producers of bioactive secondary metabolites. Endophytes associated with leaves of tropical plants are an especially exciting and relatively untapped source of novel compounds. However, one major challenge in drug discovery lies in developing strategies to efficiently recover highly bioactive strains. As part of a 15-year drug discovery project, foliar endophytes were isolated from 3198 plant samples (51 orders, 105 families and at least 232 genera of angiosperms and ferns) collected in nine geographically distinct regions of Panama. Extracts from culture supernatants of >2700 isolates were tested for bioactivity (in vitro percent inhibition of growth, % IG) against a human breast cancer cell line (MCF-7) and the causative agents of malaria, leishmaniasis, and Chagas' disease. Overall, 32.7% of endophyte isolates were highly active in at least one bioassay, including representatives of diverse fungal lineages, host lineages, and collection sites. Up to 17% of isolates tested per assay were highly active. Most bioactive strains were active in only one assay. Fungal lineages differed in the incidence and degree of bioactivity, as did fungi from particular plant taxa, and greater bioactivity was observed in endophytes isolated from plants in cloud forests vs. lowland forests. Our results suggest that using host taxonomy and forest type to tailor plant collections, and selecting endophytes from specific orders or families for cultivation, will markedly increase the efficiency and efficacy of discovering bioactive metabolites for particular pharmaceutical targets. PMID- 24066038 TI - Iron deposition following chronic myocardial infarction as a substrate for cardiac electrical anomalies: initial findings in a canine model. AB - PURPOSE: Iron deposition has been shown to occur following myocardial infarction (MI). We investigated whether such focal iron deposition within chronic MI lead to electrical anomalies. METHODS: Two groups of dogs (ex-vivo (n = 12) and in vivo (n = 10)) were studied at 16 weeks post MI. Hearts of animals from ex-vivo group were explanted and sectioned into infarcted and non-infarcted segments. Impedance spectroscopy was used to derive electrical permittivity ([Formula: see text]) and conductivity ([Formula: see text]). Mass spectrometry was used to classify and characterize tissue sections with (IRON+) and without (IRON-) iron. Animals from in-vivo group underwent cardiac magnetic resonance imaging (CMR) for estimation of scar volume (late-gadolinium enhancement, LGE) and iron deposition (T2*) relative to left-ventricular volume. 24-hour electrocardiogram recordings were obtained and used to examine Heart Rate (HR), QT interval (QT), QT corrected for HR (QTc) and QTc dispersion (QTcd). In a fraction of these animals (n = 5), ultra-high resolution electroanatomical mapping (EAM) was performed, co registered with LGE and T2* CMR and were used to characterize the spatial locations of isolated late potentials (ILPs). RESULTS: Compared to IRON- sections, IRON+ sections had higher[Formula: see text], but no difference in[Formula: see text]. A linear relationship was found between iron content and [Formula: see text] (p<0.001), but not [Formula: see text] (p = 0.34). Among two groups of animals (Iron (<1.5%) and Iron (>1.5%)) with similar scar volumes (7.28% +/- 1.02% (Iron (<1.5%)) vs 8.35% +/- 2.98% (Iron (>1.5%)), p = 0.51) but markedly different iron volumes (1.12% +/- 0.64% (Iron (<1.5%)) vs 2.47% +/- 0.64% (Iron (>1.5%)), p = 0.02), QT and QTc were elevated and QTcd was decreased in the group with the higher iron volume during the day, night and 24-hour period (p<0.05). EAMs co-registered with CMR images showed a greater tendency for ILPs to emerge from scar regions with iron versus without iron. CONCLUSION: The electrical behavior of infarcted hearts with iron appears to be different from those without iron. Iron within infarcted zones may evolve as an arrhythmogenic substrate in the post MI period. PMID- 24066040 TI - Decision makers use norms, not cost-benefit analysis, when choosing to conceal or reveal unfair rewards. AB - We introduce the Conceal or Reveal Dilemma, in which individuals receive unfair benefits, and must decide whether to conceal or to reveal this unfair advantage. This dilemma has two important characteristics: it does not lend itself easily to cost-benefit analysis, neither to the application of any strong universal norm. As a consequence, it is ideally suited to the study of interindividual and intercultural variations in moral-economic norms. In this paper we focus on interindividual variations, and we report four studies showing that individuals cannot be swayed by financial incentives to conceal or to reveal, and follow instead fixed, idiosyncratic strategies. We discuss how this result can be extended to individual and cultural variations in the tendency to display or to hide unfair rewards. PMID- 24066039 TI - Assessment and reconstruction of novel HSP90 genes: duplications, gains and losses in fungal and animal lineages. AB - Hsp90s, members of the Heat Shock Protein class, protect the structure and function of proteins and play a significant task in cellular homeostasis and signal transduction. In order to determine the number of hsp90 gene copies and encoded proteins in fungal and animal lineages and through that key duplication events that this family has undergone, we collected and evaluated Hsp90 protein sequences and corresponding Expressed Sequence Tags and analyzed available genomes from various taxa. We provide evidence for duplication events affecting either single species or wider taxonomic groups. With regard to Fungi, duplicated genes have been detected in several lineages. In invertebrates, we demonstrate key duplication events in certain clades of Arthropoda and Mollusca, and a possible gene loss event in a hymenopteran family. Finally, we infer that the duplication event responsible for the two (a and b) isoforms in vertebrates occurred probably shortly after the split of Hyperoartia and Gnathostomata. PMID- 24066041 TI - A helicopter perspective on TB biomarkers: pathway and process based analysis of gene expression data provides new insight into TB pathogenesis. AB - Biomarker host genetic signatures are considered key tools for improved early diagnosis of tuberculosis (TB) disease (development). The analysis of gene expression changes based on a limited number of genes or single study designs, however, may not be sufficient for the identification of universal diagnostic biomarker profiles. Here we propose that biological pathway and process based analyses from multiple data sets may be more relevant for identification of key pathways in TB pathogenesis, and may reveal novel candidate diagnostic TB biomarkers. A number of independent genome-wide gene expression studies have recently been performed to study expression of biomarkers for TB disease. We have integrated the results from these independent studies and performed pathway- as well as biological process-based analysis on the total data set. Interestingly, IFNalpha/beta signalling is not the single dominant pathway in the analysis of the total dataset, but combined, functional, analysis of biomarkers suggests a strong dominant role for myeloid cell involvement in inflammation. PMID- 24066042 TI - Polymorphisms in SELE gene and risk of coal workers' pneumoconiosis in Chinese: a case-control study. AB - BACKGROUND: Coal workers' pneumoconiosis (CWP) is characterized by chronic pulmonary inflammation and fibrotic nodular lesions that usually lead to progressive fibrosis. Inflammation is the first step in the development of CWP. E selectin, an adhesion molecule, is involved in the development of various inflammatory diseases. METHODS: We investigated the association between the functional polymorphisms in SELE and the risk of CWP in Han Chinese population. Three polymorphisms (T1880C/rs5355, T1559C/rs5368, A16089G/rs4786) in SELE were genotyped and analyzed in a case-control study with 697 CWP cases and 694 controls. The genotyping was based on the TaqMan method with the ABI 7900HT Real Time PCR system. RESULTS: The SELE rs5368 CT genotype was associated with a significantly increased risk of CWP (OR = 1.28, 95% CI = 1.02-1.60, P = 0.03) relative to the CC genotype. The statistical analysis of classification and regression tree (CART) and multifactor dimensionality reduction (MDR) were used to predict the interactions among risk factors of CWP. The MDR analysis found that the best interaction model was the two-factor model that contains pack-years smoked and SELE rs5368 genotypes. For non-smokers, the CART analysis showed an increased risk of CWP for carriers of the SELE rs_5368 variant genotype compared with the common genotype (OR = 1.51; 95% CI = 1.11-2.05, P = 0.0069). CONCLUSION: The results suggest that the T1559C/rs5368 polymorphism and smoking are involved in the susceptibility to CWP. Further studies are warranted to validate these findings. PMID- 24066044 TI - Catch rates, composition and fish size from reefs managed with periodically harvested closures. AB - Periodically-harvested closures are commonly employed within co-management frameworks to help manage small-scale, multi-species fisheries in the Indo Pacific. Despite their widespread use, the benefits of periodic harvesting strategies for multi-species fisheries have, to date, been largely untested. We examine catch and effort data from four periodically-harvested reef areas and 55 continuously-fished reefs in Solomon Islands. We test the hypothesis that fishing in periodically-harvested closures would yield: (a) higher catch rates, (b) proportionally more short lived, fast growing, sedentary taxa, and (c) larger finfish and invertebrates, compared to catches from reefs continuously open to fishing. Our study showed that catch rates were significantly higher from periodically-harvested closures for gleaning of invertebrates, but not for line and spear fishing. The family level composition of catches did not vary significantly between open reefs and periodically-harvested closures. Fish captured from periodically-harvested closures were slightly larger, but Trochus niloticus were significantly smaller than those from continuously open reefs. In one case of intense and prolonged harvesting, gleaning catch rates significantly declined, suggesting invertebrate stocks were substantially depleted in the early stages of the open period. Our study suggests periodically-harvested closures can have some short term benefits via increasing harvesting efficiency. However, we did not find evidence that the strategy had substantially benefited multi-species fin-fisheries. PMID- 24066043 TI - Characterization of a self-sufficient trans-anethole oxygenase from Pseudomonas putida JYR-1. AB - A novel flavoprotein monooxygenase, trans-anethole oxygenase (TAO), from Pseudomonas putida JYR-1, which is capable of catalyzing the oxidation of trans anethole to p-anisaldehyde, was heterologously expressed in E. coli and purified. Enzymatic kinetics of diverse substrates and cofactors revealed that TAO is likely to be a novel self-sufficient flavoprotein monooxygenase. Enzyme assays of GST-TAO demonstrated that TAO catalyzed a trans-anethole oxidation reaction without auxiliary component enzyme-like electron-transfer flavin reductases. The single component TAO had the ability to reduce flavin cofactors and simultaneously oxidize trans-anthole to p-anisaldehyde. In the processes of reduction of flavin and oxidation of trans-anethole, TAO accepted various flavin and NAD(P)H cofactors. TAO also catalyzed oxidation of isoeugenol, O-methyl isoeugenol, and isosafrole, all of which contain the 2-propenyl functional group on the aromatic ring structure with different catalytic efficiency. TAO had the greatest catalytic efficiency (k cat/K m) with the original substrate, trans anethole. Investigation about partially deleted mutants of TAO indicated that reductase active sites appeared to be located near the N terminal. Site directed mutagenesis studies also proved that the proposed flavin binding sites, Trp-38, Thr-43, Tyr-55, were critical for flavin reduction. However, disruption of any portion of TAO eliminated the oxygenase activity. PMID- 24066045 TI - Asymmetric continuous-time neural networks without local traps for solving constraint satisfaction problems. AB - There has been a long history of using neural networks for combinatorial optimization and constraint satisfaction problems. Symmetric Hopfield networks and similar approaches use steepest descent dynamics, and they always converge to the closest local minimum of the energy landscape. For finding global minima additional parameter-sensitive techniques are used, such as classical simulated annealing or the so-called chaotic simulated annealing, which induces chaotic dynamics by addition of extra terms to the energy landscape. Here we show that asymmetric continuous-time neural networks can solve constraint satisfaction problems without getting trapped in non-solution attractors. We concentrate on a model solving Boolean satisfiability (k-SAT), which is a quintessential NP complete problem. There is a one-to-one correspondence between the stable fixed points of the neural network and the k-SAT solutions and we present numerical evidence that limit cycles may also be avoided by appropriately choosing the parameters of the model. This optimal parameter region is fairly independent of the size and hardness of instances, this way parameters can be chosen independently of the properties of problems and no tuning is required during the dynamical process. The model is similar to cellular neural networks already used in CNN computers. On an analog device solving a SAT problem would take a single operation: the connection weights are determined by the k-SAT instance and starting from any initial condition the system searches until finding a solution. In this new approach transient chaotic behavior appears as a natural consequence of optimization hardness and not as an externally induced effect. PMID- 24066046 TI - Comprehensive quantitative analysis on privacy leak behavior. AB - Privacy information is prone to be leaked by illegal software providers with various motivations. Privacy leak behavior has thus become an important research issue of cyber security. However, existing approaches can only qualitatively analyze privacy leak behavior of software applications. No quantitative approach, to the best of our knowledge, has been developed in the open literature. To fill this gap, in this paper we propose for the first time four quantitative metrics, namely, possibility, severity, crypticity, and manipulability, for privacy leak behavior analysis based on Privacy Petri Net (PPN). In order to compare the privacy leak behavior among different software, we further propose a comprehensive metric, namely, overall leak degree, based on these four metrics. Finally, we validate the effectiveness of the proposed approach using real-world software applications. The experimental results demonstrate that our approach can quantitatively analyze the privacy leak behaviors of various software types and reveal their characteristics from different aspects. PMID- 24066047 TI - Salt-dependent chemotaxis of macrophages. AB - Besides their role in immune system host defense, there is growing evidence that macrophages may also be important regulators of salt homeostasis and blood pressure by a TonEBP-VEGF-C dependent buffering mechanism. As macrophages are known to accumulate in the skin of rats fed under high salt diet conditions and are pivotal for removal of high salt storage, the question arose how macrophages sense sites of high sodium storage. Interestingly, we observed that macrophage like RAW264.7 cells, murine bone marrow-derived macrophages and peritoneal macrophages recognize NaCl hypertonicity as a chemotactic stimulus and migrate in the direction of excess salt concentration by using an in vitro transwell migration assay. While RAW264.7 cells migrated toward NaCl in a dose-dependent fashion, no migratory response toward isotonic or hypotonic media controls, or other osmo-active agents, e.g. urea or mannitol, could be detected. Interestingly, we could not establish a specific role of the osmoprotective transcription factor TonEBP in regulating salt-dependent chemotaxis, since the specific migration of bone marrow-derived macrophages following RNAi of TonEBP toward NaCl was not altered. Although the underlying mechanism remains unidentified, these data point to a thus far unappreciated role for NaCl dependent chemotaxis of macrophages in the clearance of excess salt, and suggest the existence of novel NaCl sensor/effector circuits, which are independent of the TonEBP system. PMID- 24066048 TI - First report of circulating microRNAs in tumour necrosis factor receptor associated periodic syndrome (TRAPS). AB - Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder characterized by recurrent episodes of long-lasting fever and inflammation in different regions of the body, such as the musculo-skeletal system, skin, gastrointestinal tract, serosal membranes and eye. Our aims were to evaluate circulating microRNAs (miRNAs) levels in patients with TRAPS, in comparison to controls without inflammatory diseases, and to correlate their levels with parameters of disease activity and/or disease severity. Expression levels of circulating miRNAs were measured by Agilent microarrays in 29 serum samples from 15 TRAPS patients carrying mutations known to be associated with high disease penetrance and from 8 controls without inflammatory diseases. Differentially expressed and clinically relevant miRNAs were detected using GeneSpring GX software. We identified a 6 miRNAs signature able to discriminate TRAPS from controls. Moreover, 4 miRNAs were differentially expressed between patients treated with the interleukin (IL)-1 receptor antagonist, anakinra, and untreated patients. Of these, miR-92a-3p and miR-150-3p expression was found to be significantly reduced in untreated patients, while their expression levels were similar to controls in samples obtained during anakinra treatment. MiR-92b levels were inversely correlated with the number of fever attacks/year during the 1(st) year from the index attack of TRAPS, while miR-377-5p levels were positively correlated with serum amyloid A (SAA) circulating levels. Our data suggest that serum miRNA levels show a baseline pattern in TRAPS, and may serve as potential markers of response to therapeutic intervention. PMID- 24066049 TI - A slow axon antidromic blockade hypothesis for tremor reduction via deep brain stimulation. AB - Parkinsonian and essential tremor can often be effectively treated by deep brain stimulation. We propose a novel explanation for the mechanism by which this technique ameliorates tremor: a reduction of the delay in the relevant motor control loops via preferential antidromic blockade of slow axons. The antidromic blockade is preferential because the pulses more rapidly clear fast axons, and the distribution of axonal diameters, and therefore velocities, in the involved tracts, is sufficiently long-tailed to make this effect quite significant. The preferential blockade of slow axons, combined with gain adaptation, results in a reduction of the mean delay in the motor control loop, which serves to stabilize the feedback system, thus ameliorating tremor. This theory, without any tuning, accounts for several previously perplexing phenomena, and makes a variety of novel predictions. PMID- 24066050 TI - Virtual screening models for prediction of HIV-1 RT associated RNase H inhibition. AB - The increasing resistance to current therapeutic agents for HIV drug regiment remains a major problem for effective acquired immune deficiency syndrome (AIDS) therapy. Many potential inhibitors have today been developed which inhibits key cellular pathways in the HIV cycle. Inhibition of HIV-1 reverse transcriptase associated ribonuclease H (RNase H) function provides a novel target for anti-HIV chemotherapy. Here we report on the applicability of conceptually different in silico approaches as virtual screening (VS) tools in order to efficiently identify RNase H inhibitors from large chemical databases. The methods used here include machine-learning algorithms (e.g. support vector machine, random forest and kappa nearest neighbor), shape similarity (rapid overlay of chemical structures), pharmacophore, molecular interaction fields-based fingerprints for ligands and protein (FLAP) and flexible ligand docking methods. The results show that receptor-based flexible docking experiments provides good enrichment (80 90%) compared to ligand-based approaches such as FLAP (74%), shape similarity (75%) and random forest (72%). Thus, this study suggests that flexible docking experiments is the model of choice in terms of best retrieval of active from inactive compounds and efficiency and efficacy schemes. Moreover, shape similarity, machine learning and FLAP models could also be used for further validation or filtration in virtual screening processes. The best models could potentially be use for identifying structurally diverse and selective RNase H inhibitors from large chemical databases. In addition, pharmacophore models suggest that the inter-distance between hydrogen bond acceptors play a key role in inhibition of the RNase H domain through metal chelation. PMID- 24066051 TI - Microdroplet sandwich real-time rt-PCR for detection of pandemic and seasonal influenza subtypes. AB - As demonstrated by the recent 2012/2013 flu epidemic, the continual emergence of new viral strains highlights the need for accurate medical diagnostics in multiple community settings. If rapid, robust, and sensitive diagnostics for influenza subtyping were available, it would help identify epidemics, facilitate appropriate antiviral usage, decrease inappropriate antibiotic usage, and eliminate the extra cost of unnecessary laboratory testing and treatment. Here, we describe a droplet sandwich platform that can detect influenza subtypes using real-time reverse-transcription polymerase chain reaction (rtRT-PCR). Using clinical samples collected during the 2010/11 season, we effectively differentiate between H1N1p (swine pandemic), H1N1s (seasonal), and H3N2 with an overall assay sensitivity was 96%, with 100% specificity for each subtype. Additionally, we demonstrate the ability to detect viral loads as low as 10(4) copies/mL, which is two orders of magnitude lower than viral loads in typical infected patients. This platform performs diagnostics in a miniaturized format without sacrificing any sensitivity, and can thus be easily developed into devices which are ideal for small clinics and pharmacies. PMID- 24066052 TI - A Bayesian two part model applied to analyze risk factors of adult mortality with application to data from Namibia. AB - Despite remarkable gains in life expectancy and declining mortality in the 21st century, in many places mostly in developing countries, adult mortality has increased in part due to HIV/AIDS or continued abject poverty levels. Moreover many factors including behavioural, socio-economic and demographic variables work simultaneously to impact on risk of mortality. Understanding risk factors of adult mortality is crucial towards designing appropriate public health interventions. In this paper we proposed a structured additive two-part random effects regression model for adult mortality data. Our proposal assumed two processes: (i) whether death occurred in the household (prevalence part), and (ii) number of reported deaths, if death did occur (severity part). The proposed model specification therefore consisted of two generalized linear mixed models (GLMM) with correlated random effects that permitted structured and unstructured spatial components at regional level. Specifically, the first part assumed a GLMM with a logistic link and the second part explored a count model following either a Poisson or negative binomial distribution. The model was used to analyse adult mortality data of 25,793 individuals from the 2006/2007 Namibian DHS data. Inference is based on the Bayesian framework with appropriate priors discussed. PMID- 24066053 TI - Adherence to tuberculosis treatment, sputum smear conversion and mortality: a retrospective cohort study in 48 Rwandan clinics. AB - BACKGROUND: Adherence to treatment and sputum smear conversion after 2 months of treatment are thought to be important for successful outcome of tuberculosis (TB) treatment. METHODS: Retrospective cohort study of new adult TB patients diagnosed in the first quarter of 2007 at 48 clinics in Rwanda. Data were abstracted from TB registers and individual treatment charts. Logistic regression analysis was done to examine associations between baseline demographic and clinical factors and three outcomes adherence, sputum smear conversion at two months, and death. RESULTS: Out of 725 eligible patients the treatment chart was retrieved for 581 (80%). Fifty-six (10%) of these patients took <90% of doses (defined as poor adherence). Baseline demographic characteristics were not associated with adherence to TB treatment, but adherence was lower among HIV patients not taking antiretroviral therapy (ART); p = 0.03). Sputum smear results around 2 months after start of treatment were available for 220 of 311 initially sputum-smear positive pulmonary TB (PTB+) patients (71%); 175 (80%) had achieved sputum smear conversion. In multivariable analysis, baseline sputum smear grade (odds ratio [OR] = 2.7, 95% Confidence interval [CI] 1.1-6.6 comparing smear 3+ against 1+) and HIV infection (OR 3.0, 95%CI 1.3-6.7) were independent predictors for non conversion at 2 months. Sixty-nine of 574 patients (12%) with known TB treatment outcomes had died. Besides other known determinants, poor adherence had an independent, strong effect on mortality (OR 3.4, 95%CI 1.4-7.8). CONCLUSION: HIV infection is an important independent predictor of failure of sputum smear conversion at 2 months among PTB+ patients. Poor adherence to TB treatment is an important independent determinant of mortality. PMID- 24066054 TI - Fast QRS detection with an optimized knowledge-based method: evaluation on 11 standard ECG databases. AB - The current state-of-the-art in automatic QRS detection methods show high robustness and almost negligible error rates. In return, the methods are usually based on machine-learning approaches that require sufficient computational resources. However, simple-fast methods can also achieve high detection rates. There is a need to develop numerically efficient algorithms to accommodate the new trend towards battery-driven ECG devices and to analyze long-term recorded signals in a time-efficient manner. A typical QRS detection method has been reduced to a basic approach consisting of two moving averages that are calibrated by a knowledge base using only two parameters. In contrast to high-accuracy methods, the proposed method can be easily implemented in a digital filter design. PMID- 24066055 TI - Eicosapentaenoic acid enhances heat stress-impaired intestinal epithelial barrier function in Caco-2 cells. AB - OBJECTIVE: Dysfunction of the intestinal epithelial tight junction (TJ) barrier is known to have an important etiologic role in the pathophysiology of heat stroke. N-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), play a role in maintaining and protecting the TJ structure and function. This study is aimed at investigating whether n-3 PUFAs could alleviate heat stress-induced dysfunction of intestinal tight junction. METHODS: Human intestinal epithelial Caco-2 cells were pre-incubated with EPA, DHA or arachidonic acid (AA) and then exposed to heat stress. Transepithelial electrical resistance (TEER) and Horseradish Peroxidase (HRP) permeability were measured to analyze barrier integrity. Levels of TJ proteins, including occludin, ZO-1 and claudin-2, were analyzed by Western blot and localized by immunofluorescence microscopy. Messenger RNA levels were determined by quantitative real time polymerase chain reaction (Q-PCR). TJ morphology was observed by transmission electron microscopy. RESULTS: EPA effectively attenuated the decrease in TEER and impairment of intestinal permeability in HRP flux induced by heat exposure. EPA significantly elevated the expression of occludin and ZO-1, while DHA was less effective and AA was not at all effective. The distortion and redistribution of TJ proteins, and disruption of morphology were also effectively prevented by pretreatment with EPA. CONCLUSION: This study indicates for the first time that EPA is more potent than DHA in protecting against heat-induced permeability dysfunction and epithelial barrier damage of tight junction. PMID- 24066056 TI - Effects of adult exposure to bisphenol a on genes involved in the physiopathology of rat prefrontal cortex. AB - Several neurological and behavioral dysfunctions have been reported in animals exposed to bisphenol A (BPA). However, little is known about the impact of adult exposure to BPA on brain physiopathology. Here, we focused on prefrontal cortex (PFC) of rats, because it is an important area for cognitive control, complex behaviors and is altered in many psychopathologies. Gamma-aminobutyric acid (GABA) and serotonin (5-HT) systems are essential for PFC function. Therefore, we examined the effects of adult exposure to BPA on 5alpha-Reductase (5alpha-R) and cytochrome P450 aromatase (P450arom), enzymes that synthesize GABAA receptor modulators, and tryptophan hydroxylase (Tph), the rate-limiting enzyme in 5-HT biosynthesis. To gain better understanding of BPA's action in the adult PFC, 84 genes involved in neurotoxicity were also analysed. Adult male and female rats were subcutaneously injected for 4 days with 50 ug/kg/day, the current reference safe dose for BPA. mRNA and protein levels of 5alpha-R, P450arom and Tph were quantified by real-time RT-PCR and Western blot. Genes linked to neurotoxicity were analyzed by PCR-Array technology. Adult exposure to BPA increased both P450arom and Tph2 expression in PFC of male and female, but decreased 5alpha-R1 expression in female. Moreover, we identified 17 genes related to PFC functions such as synaptic plasticity and memory, as potential targets of BPA. Our results provided new insights on the molecular mechanisms underlying BPA action in the physiopathology of PFC, but also raise the question about the safety of short term exposure to it in the adulthood. PMID- 24066057 TI - Long-term evolution of brainstem electrical evoked responses to sound after restricted ablation of the auditory cortex. AB - INTRODUCTION: This study aimed to assess the top-down control of sound processing in the auditory brainstem of rats. Short latency evoked responses were analyzed after unilateral or bilateral ablation of auditory cortex. This experimental paradigm was also used towards analyzing the long-term evolution of post-lesion plasticity in the auditory system and its ability to self-repair. METHOD: Auditory cortex lesions were performed in rats by stereotactically guided fine needle aspiration of the cerebrocortical surface. Auditory Brainstem Responses (ABR) were recorded at post-surgery day (PSD) 1, 7, 15 and 30. Recordings were performed under closed-field conditions, using click trains at different sound intensity levels, followed by statistical analysis of threshold values and ABR amplitude and latency variables. Subsequently, brains were sectioned and immunostained for GAD and parvalbumin to assess the location and extent of lesions accurately. RESULTS: Alterations in ABR variables depended on the type of lesion and post-surgery time of ABR recordings. Accordingly, bilateral ablations caused a statistically significant increase in thresholds at PSD1 and 7 and a decrease in waves amplitudes at PSD1 that recover at PSD7. No effects on latency were noted at PSD1 and 7, whilst recordings at PSD15 and 30 showed statistically significant decreases in latency. Conversely, unilateral ablations had no effect on auditory thresholds or latencies, while wave amplitudes only decreased at PSD1 strictly in the ipsilateral ear. CONCLUSION: Post-lesion plasticity in the auditory system acts in two time periods: short-term period of decreased sound sensitivity (until PSD7), most likely resulting from axonal degeneration; and a long-term period (up to PSD7), with changes in latency responses and recovery of thresholds and amplitudes values. The cerebral cortex may have a net positive gain on the auditory pathway response to sound. PMID- 24066058 TI - Aldose reductase is involved in the development of murine diet-induced nonalcoholic steatohepatitis. AB - Hepatic aldose reductase (AR) expression is known to be induced in liver diseases, including hepatitis and hepatocellular carcinoma. However, the role of AR in the development of these diseases remains unclear. We performed this current study to determine whether and how AR might be involved in the development of diet-induced nonalcoholic steatohepatitis. Our results showed that the level of AR protein expression was significantly higher in db/db mice fed the methionine-choline-deficient (MCD) diet than in mice fed the control diet. In parallel with the elevation in AR, steatohepatitis was observed in MCD diet-fed mice, and this diet-induced steatohepatitis was significantly attenuated by lentiviral-mediated knock-down of the AR gene. This suppressive effect of AR knock-down was associated with repressed levels of serum alanine aminotransferase and hepatic lipoperoxides, reduced mRNA and protein expression of hepatic cytochrome P450 2E1 (CYP2E1), and decreased mRNA expression of pro-inflammatory tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Moreover, AR induced elevations on the level of CYP2E1 expression, reactive oxygen species, mRNA expression of TNF-alpha and IL-6 were confirmed in AML12 hepatocytes. Further, lentiviral-mediated knock-down of AR ameliorated MCD diet-induced collagen deposition in the livers of db/db mice. With the improvement in liver fibrosis, the mRNA levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metalloproteinase-2 (MMP-2), two genes involved in hepatic fibrogenesis, were found to be significantly suppressed, while TIMP-2 and MMP-13 were unaffected. Together these data indicate that inhibition of AR alleviates the MCD diet-induced liver inflammation and fibrosis in db/db mice, probably through dampening CYP2E1 mediated-oxidative stress and ameliorating the expression of pro inflammatory cytokines. PMID- 24066059 TI - Impact of climate change effects on contamination of cereal grains with deoxynivalenol. AB - Climate change is expected to aggravate feed and food safety problems of crops; however, quantitative estimates are scarce. This study aimed to estimate impacts of climate change effects on deoxynivalenol contamination of wheat and maize grown in the Netherlands by 2040. Quantitative modelling was applied, considering both direct effects of changing climate on toxin contamination and indirect effects via shifts in crop phenology. Climate change projections for the IPCC A1B emission scenario were used for the scenario period 2031-2050 relative to the baseline period of 1975-1994. Climatic data from two different global and regional climate model combinations were used. A weather generator was applied for downscaling climate data to local conditions. Crop phenology models and prediction models for DON contamination used, each for winter wheat and grain maize. Results showed that flowering and full maturity of both wheat and maize will advance with future climate. Flowering advanced on average 5 and 11 days for wheat, and 7 and 14 days for maize (two climate model combinations). Full maturity was on average 10 and 17 days earlier for wheat, and 19 and 36 days earlier for maize. On the country level, contamination of wheat with deoxynivalenol decreased slightly, but not significantly. Variability between regions was large, and individual regions showed a significant increase in deoxynivalenol concentrations. For maize, an overall decrease in deoxynivalenol contamination was projected, which was significant for one climate model combination, but not significant for the other one. In general, results disagree with previous reported expectations of increased feed and food safety hazards under climate change. This study illustrated the relevance of using quantitative models to estimate the impacts of climate change effects on food safety, and of considering both direct and indirect effects when assessing climate change impacts on crops and related food safety hazards. PMID- 24066062 TI - Recurrence methods for the identification of morphogenetic patterns. AB - This paper addresses the problem of identifying the parameters involved in the formation of spatial patterns in nonlinear two dimensional systems. To this aim, we perform numerical experiments on a prototypical model generating morphogenetic Turing patterns, by changing both the spatial frequency and shape of the patterns. The features of the patterns and their relationship with the model parameters are characterized by means of the Generalized Recurrence Quantification measures. We show that the recurrence measures Determinism and Recurrence Entropy, as well as the distribution of the line lengths, allow for a full characterization of the patterns in terms of power law decay with respect to the parameters involved in the determination of their spatial frequency and shape. A comparison with the standard two dimensional Fourier transform is performed and the results show a better performance of the recurrence indicators in identifying a reliable connection with the spatial frequency of the patterns. Finally, in order to evaluate the robustness of the estimation of the power low decay, extensive simulations have been performed by adding different levels of noise to the patterns. PMID- 24066060 TI - Unique anti-glioblastoma activities of hypericin are at the crossroad of biochemical and epigenetic events and culminate in tumor cell differentiation. AB - Failure of conventional therapies to alleviate glioblastoma (GBM) fosters search for novel therapeutic strategies. These include epigenetic modulators as histone deacetylase inhibitors (HDACi), which relax abnormally compact tumor cell chromatin organization, enabling cells to overcome blockage in differentiation. However, in clinical settings, HDACi efficacy is confined to subsets of hematologic malignancies. We reasoned that molecules targeting multiple epigenetic mechanisms may exhibit superior anti-cancer activities. We focused on the redox perylene-quinone Hypericin (HYP) and showed that HYP targets Hsp90 for polyubiquitination, degradation and inactivation. Hsp90 is implicated in mediating inheritable epigenetic modifications transferable to progeny. We therefore examined if HYP can induce epigenetic alterations in GBM cells and show here that HYP indeed, targets multiple mechanisms in human glioblastoma tumor cell lines via unique manners. These elicit major epigenetic signature changes in key developmentally regulated genes. HYP induces neuroglial tumor cell differentiation modulating the cytoarchitecture, neuroglial differentiation antigen expression and causes exit from cell proliferation cycles. Such activities characterize HDACi however HYP is not an HDAC inhibitor. Instead, HYP effectively down-regulates expression of Class-I HDACs, creating marked deficiencies in HDACs cellular contents, leading to histones H3 and H4 hyperacetylation. Expression of EZH2, the Polycomb repressor complex-2 catalytic subunit, which trimethylates histone H3K27 is also suppressed. The resulting histone hyperacetylation and diminished H3K27-trimethylation relax chromatin structure, activating gene transcription including differentiation-promoting genes. DNMT profiles are also modulated increasing global DNA methylation. HYP induces unique epigenetic down-regulations of HDACs, EZH2 and DNMTs, remodeling chromatin structure and culminating in tumor cell differentiation. These modulations generate clinically significant anti-GBM effects obtained in a clinical trial performed in patients with recurrent, progressive disease. Despite this advanced disease stage, patients responded to HYP, displaying stable disease and partial responses; patients on compassionate therapy survived for up to 34 months. Hypericin may constitute a novel anti-glioblastoma therapeutic paradigm. PMID- 24066061 TI - Association of interleukin-18 gene promoter -607 C>A and -137G>C polymorphisms with cancer risk: a meta-analysis of 26 studies. AB - BACKGROUND: Evidence suggest that IL-18 gene polymorphisms may be risk factors for several cancers. Increasing studies investigating the association between IL 18 gene promoter polymorphisms (-607 C>A and -137G>C) and cancer risk have yielded conflicting results. METHODOLOGY/PRINCIPAL FINDINGS: We performed a meta analysis of 26 studies including 4096 cases and 5222 controls. We assessed the strength of the association of IL-18 gene promoter -607 C>A and -137G>C polymorphisms with cancer risk and performed sub-group analyses by cancer types, ethnicities, source of controls and sample size. The pooled results revealed a significant increased risk of cancer susceptibility for -607 C>A (CA vs. CC: OR = 1.19, 95%CI: 1.04, 1.37, Pheterogeneity = 0.033; CA/AA vs. CC: OR = 1.17, 95% CI: 1.01, 1.34, Pheterogeneity = 0.007), but no significant association for -137 G>C was observed with overall cancer risk. Sub-group analyses revealed that an increased risk of nasopharyngeal carcinoma was both found for -607 C>A (CA/AA vs. CC: OR = 1.32, 95% CI: 1.04, 1.69, Pheterogeneity = 0.823) and -137G>C (GC/CC vs. GG: OR = 1.57, 95%CI: 1.26, 1.96, Pheterogeneity = 0.373). Consistent with the results of the genotyping analyses, the -607A/-137C and -607C/-137C haplotypes were associated with a significantly increased risk of nasopharyngeal carcinoma as compared with the -607C/-137G haplotype (-607A/-137C vs. -607C/-137G: OR = 1.26, 95%CI: 1.13, 1.40; Pheterogeneity = 0.569; -607C/-137C vs. -607C/-137G: OR = 1.14, 95%CI: 1.03, 1.27; Pheterogeneity = 0.775). As for gastrointestinal cancer, we also found that -607 C>A polymorphism was significantly associated with increased cancer risk (CA/AA vs. CC: OR = 1.25, 95% CI: 1.05, 1.50, Pheterogeneity = 0.458). Further sub-group analysis revealed that -137G>C polymorphism contributed to cancer risk in Asians but not in Caucasians (GC/CC vs. GG: OR = 1.31, 95%CI: 1.05, 1.64, Pheterogeneity<0.001). CONCLUSIONS: The meta-analysis results suggest that IL-18 gene promoter -607 C>A polymorphism is significantly associated with overall cancer risk, especially in nasopharyngeal carcinoma and gastrointestinal cancer; and the -137 G>C polymorphism is associated with increased overall cancer risk in Asian populations and also significantly increases the risk of nasopharyngeal carcinoma. PMID- 24066063 TI - Modeling fish egg production and spatial distribution from acoustic data: a step forward into the analysis of recruitment. AB - To date, there are numerous transport simulation studies demonstrating the relevance of the hydrodynamics for the advection, dispersion and recruitment of early stages of marine organisms. However, the lack of data has conditioned the use of realistic locations for the model setup and configuration in transport studies. This work (I) demonstrates the key role played by the use of the realistic initial position of the eggs of small pelagic fishes in the analysis of late-larval recruitment in coastal nursery areas and (II) provides a general solution for deriving future egg positions and abundances from adult biomass obtained from acoustic surveys and available fecundity data. Using European anchovy in the NW Mediterranean as a case study, we first analyzed the impact of the initial location, timing, egg buoyancy and diel vertical migration of larvae on the potential late-larval recruitment to coastal areas. The results suggested that prior knowledge of the initial spawning grounds may substantially affect the estimates of potential recruitment. We then integrated biological and acoustics derived data (the biomass and size structure, sex ratio, a weight-batch fecundity model, mean weight, number of fish and mean spawning) to build a predictive model for interannual egg production. This model was satisfactorily contrasted with field data for two years obtained with the Daily Egg Production Method (DEPM). We discuss our results in the context of the fluctuations of European anchovy egg abundance from 2003 through 2010 in the NW Mediterranean and in terms of the potential applicability of the acoustics-based spatial predictive egg production model. PMID- 24066065 TI - Poliovirus 2A protease triggers a selective nucleo-cytoplasmic redistribution of splicing factors to regulate alternative pre-mRNA splicing. AB - Poliovirus protease 2A (2A(pro)) obstructs host gene expression by reprogramming transcriptional and post-transcriptional regulatory events during infection. Here we demonstrate that expression of 2A(pro) induces a selective nucleo-cytoplasm translocation of several important RNA binding proteins and splicing factors. Subcellular fractionation studies, together with immunofluorescence microscopy revealed an asymmetric distribution of HuR and TIA1/TIAR in 2A(pro) expressing cells, which modulates splicing of the human Fas exon 6. Consistent with this result, knockdown of HuR or overexpression of TIA1/TIAR, leads to Fas exon 6 inclusion in 2A(pro)-expressing cells. Therefore, poliovirus 2A(pro) can target alternative pre-mRNA splicing by regulating protein shuttling between the nucleus and the cytoplasm. PMID- 24066064 TI - The majority of adult pneumococcal invasive infections in Portugal are still potentially vaccine preventable in spite of significant declines of serotypes 1 and 5. AB - In Portugal, pneumococcal conjugate vaccines have been administered to children outside of the national immunization plan since 2001. We determined the serotype and antimicrobial susceptibility of 1265 isolates responsible for adult invasive pneumococcal infections (IPD) between 2009 and 2011 and compared the results with previously published data from 1999 to 2008. Serotypes 3 (12.6%), 7F (10.0%), 19A (9.1%), 14 (8.4%), 1 (6.9%) and 8 (6.2%) were the most frequent and together accounted for 53.2% of adult IPD. Serotypes 1 and 5 declined significantly while serotype 34, not included in any vaccine, increased. Taken together, the serotypes included in the 13-valent conjugate vaccine (PCV13) peaked among adult IPD isolates in 2008 (70.2%) and declined since then reaching 53.5% in 2011. The decline in the serotypes included in the 23-valent polysaccharide vaccine since 2007 was also significant but much more modest with 79.2% of the isolates causing IPD in 2011 expressing these serotypes. Since the changes in serotypes causing IPD in adults coincided with the 10-valent and PCV13 introduction in children, it is unlikely that vaccination triggered these changes although it may have accelerated them. The proportion of IPD caused by serotypes included in the 7 valent conjugate vaccine remained stable (19.0%). Both penicillin non susceptibility and erythromycin resistance increased in the study period, with serotypes 14 and 19A accounting for the majority of resistant isolates. PMID- 24066066 TI - Chronic hypoxia during gestation enhances uterine arterial myogenic tone via heightened oxidative stress. AB - Chronic hypoxia during gestation has profound adverse effects on the adaptation of uteroplacental circulation in pregnancy. Yet, the underlying mechanisms are not fully understood. The present study tested the hypothesis that enhanced production of reactive oxygen species (ROS) in uterine arteries plays a critical role in the maladaptation of uterine circulation associated with chronic hypoxia. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep maintained at sea level (~300 m) or exposed to high-altitude (3801 m) hypoxia for 110 days. Hypoxia significantly increased ROS production in uterine arteries of pregnant, but not nonpregnant, sheep. This was associated with a significant increase in NADPH oxidase (Nox) 2, but not Nox1 or Nox4, protein abundance and total Nox activity in uterine arteries of pregnant animals. Chronic hypoxia significantly increased pressure-dependent uterine arterial myogenic tone in pregnant sheep, which was abrogated by a Nox inhibitor apocynin. Additionally, the hypoxia-induced increase in myogenic reactivity of uterine arteries to phorbol 12,13-dibutyrate in pregnant sheep was blocked by apocynin and tempol. In consistence with the myogenic responses, the hypoxia-mediated down-regulation of BKCa channel activity in uterine arteries of pregnant animals was reversed by apocynin. The findings suggest that heightened oxidative stress in uterine arteries plays a key role in suppressing the BKCa channel activity, resulting in increased myogenic reactivity and maladaptation of uteroplacental circulation caused by chronic hypoxia during gestation. PMID- 24066067 TI - Potential of global cropland phytolith carbon sink from optimization of cropping system and fertilization. AB - The occlusion of carbon (C) by phytoliths, the recalcitrant silicified structures deposited within plant tissues, is an important persistent C sink mechanism for croplands and other grass-dominated ecosystems. By constructing a silica content phytolith content transfer function and calculating the magnitude of phytolith C sink in global croplands with relevant crop production data, this study investigated the present and potential of phytolith C sinks in global croplands and its contribution to the cropland C balance to understand the cropland C cycle and enhance long-term C sequestration in croplands. Our results indicate that the phytolith sink annually sequesters 26.35 +/- 10.22 Tg of carbon dioxide (CO2) and may contribute 40 +/- 18% of the global net cropland soil C sink for 1961-2100. Rice (25%), wheat (19%) and maize (23%) are the dominant contributing crop species to this phytolith C sink. Continentally, the main contributors are Asia (49%), North America (17%) and Europe (16%). The sink has tripled since 1961, mainly due to fertilizer application and irrigation. Cropland phytolith C sinks may be further enhanced by adopting cropland management practices such as optimization of cropping system and fertilization. PMID- 24066068 TI - Effects of sinomenine on the expression of microRNA-155 in 2,4,6 trinitrobenzenesulfonic acid-induced colitis in mice. AB - BACKGROUND: Sinomenine, a pure alkaloid isolated in Chinese medicine from the root of Sinomenium acutum, has been demonstrated to have anti-inflammatory and immunosuppressive effects. MicroRNAs (miRNAs) are gradually being recognized as critical mediators of disease pathogenesis via coordinated regulation of molecular effector pathways. METHODOLOGY/FINDINGS: After colitis was induced in mice by instillation of 5% (w/v) 2,4,6-trinitrobenzenesulfonic acid (TNBS), sinomenine at a dose of 100 or 200 mg/kg was orally administered once daily for 7 days. We evaluated body weight, survival rate, diarrhea score, histological score and myeloperoxidase (MPO) activity. The mRNA and protein expression levels of miR 155, c-Maf, TNF-alpha and IFN-gamma were determined by quantitative RT-PCR and immunohistochemistry, respectively. Sinomenine (100 or 200 mg/kg)-treated mice with TNBS-induced colitis were significantly improved in terms of body weight, survival rate, diarrhea score, histological score and MPO activity compared with untreated mice. Both dosages of sinomenine significantly decreased the mRNA and protein expression levels of c-Maf, TNF-alpha and IFN-gamma, which elevated in TNBS-induced colitis. Furthermore, sinomenine at a dose of 200 mg/kg significantly decreased the level of miR-155 expression by 71% (p = 0.025) compared with untreated TNBS-induced colitis in mice. CONCLUSIONS/SIGNIFICANCE: Our study evaluated the effects and potential mechanisms of sinomenine in the anti-inflammatory response via miRNA-155 in mice with TNBS-induced colitis. Our findings suggest that sinomenine has anti-inflammatory effects on TNBS-induced colitis by down-regulating the levels of miR-155 and several related inflammatory cytokines. PMID- 24066069 TI - Population-level benefits from providing effective HIV prevention means to pregnant women in high prevalence settings. AB - BACKGROUND: HIV prevalence among pregnant women in Southern Africa is extremely high. Epidemiological studies suggest that pregnancy increases the risk of HIV sexual acquisition and that HIV infections acquired during pregnancy carry higher risk of mother-to-child transmission (MTCT). We analyze the potential benefits from extending the availability of effective microbicide to pregnant women (in addition to non-pregnant women) in a wide-scale intervention. METHODS AND FINDINGS: A transmission dynamic model was designed to assess the impact of microbicide use in high HIV prevalence settings and to estimate proportions of new HIV infections, infections acquired during pregnancy, and MTCT prevented over 10 years. Our analysis suggests that consistent use of microbicide with 70% efficacy by 60% of non-pregnant women may prevent approximately 40% and 15% of new infections in women and men respectively over 10 years, assuming no additional increase in HIV risk to either partner during pregnancy (RR(HIV/preg) = 1). It may also prevent 8-15% MTCT depending on the increase in MTCT risk when HIV is acquired during pregnancy compared to before pregnancy (RRMTCT/preg). Extending the microbicides use during pregnancy may improve the effectiveness of the intervention by 10% (RR(HIV/preg) = 1) to 25% (RR(HIV/preg) = 2) and reduce the number of HIV infections acquired during pregnancy by 40% to 70% in different scenarios. It may add between 6% (RR(HIV/preg) = 1, RR(MTCT/preg) = 1) and 25% (RR(HIV/preg) = 2, RR(MTCT/preg) = 4) to the reduction in the residual MTCT. CONCLUSION: Providing safe and effective microbicide to pregnant women in the context of wide-scale interventions would be desirable as it would increase the effectiveness of the intervention and significantly reduce the number of HIV infections acquired during pregnancy. The projected benefits from covering pregnant women by the HIV prevention programs is more substantial in communities in which the sexual risk during pregnancy is elevated. PMID- 24066070 TI - Open defecation and childhood stunting in India: an ecological analysis of new data from 112 districts. AB - Poor sanitation remains a major public health concern linked to several important health outcomes; emerging evidence indicates a link to childhood stunting. In India over half of the population defecates in the open; the prevalence of stunting remains very high. Recently published data on levels of stunting in 112 districts of India provide an opportunity to explore the relationship between levels of open defecation and stunting within this population. We conducted an ecological regression analysis to assess the association between the prevalence of open defecation and stunting after adjustment for potential confounding factors. Data from the 2011 HUNGaMA survey was used for the outcome of interest, stunting; data from the 2011 Indian Census for the same districts was used for the exposure of interest, open defecation. After adjustment for various potential confounding factors--including socio-economic status, maternal education and calorie availability--a 10 percent increase in open defecation was associated with a 0.7 percentage point increase in both stunting and severe stunting. Differences in open defecation can statistically account for 35 to 55 percent of the average difference in stunting between districts identified as low-performing and high-performing in the HUNGaMA data. In addition, using a Monte Carlo simulation, we explored the effect on statistical power of the common practice of dichotomizing continuous height data into binary stunting indicators. Our simulation showed that dichotomization of height sacrifices statistical power, suggesting that our estimate of the association between open defecation and stunting may be a lower bound. Whilst our analysis is ecological and therefore vulnerable to residual confounding, these findings use the most recently collected large-scale data from India to add to a growing body of suggestive evidence for an effect of poor sanitation on human growth. New intervention studies, currently underway, may shed more light on this important issue. PMID- 24066071 TI - MicroRNA and protein profiling of brain metastasis competent cell-derived exosomes. AB - Exosomes are small membrane vesicles released by most cell types including tumor cells. The intercellular exchange of proteins and genetic material via exosomes is a potentially effective approach for cell-to-cell communication and it may perform multiple functions aiding to tumor survival and metastasis. We investigated microRNA and protein profiles of brain metastatic (BM) versus non brain metastatic (non-BM) cell-derived exosomes. We studied the cargo of exosomes isolated from brain-tropic 70W, MDA-MB-231BR, and circulating tumor cell brain metastasis-selected markers (CTC1BMSM) variants, and compared them with parental non-BM MeWo, MDA-MB-231P and CTC1P cells, respectively. By performing microRNA PCR array we identified one up-regulated (miR-210) and two down-regulated miRNAs (miR-19a and miR-29c) in BM versus non-BM exosomes. Second, we analyzed the proteomic content of cells and exosomes isolated from these six cell lines, and detected high expression of proteins implicated in cell communication, cell cycle, and in key cancer invasion and metastasis pathways. Third, we show that BM cell-derived exosomes can be internalized by non-BM cells and that they effectively transport their cargo into cells, resulting in increased cell adhesive and invasive potencies. These results provide a strong rationale for additional investigations of exosomal proteins and miRNAs towards more profound understandings of exosome roles in brain metastasis biogenesis, and for the discovery and application of non-invasive biomarkers for new therapies combating brain metastasis. PMID- 24066072 TI - Contrasting quiescent G0 phase with mitotic cell cycling in the mouse immune system. AB - A transgenic mouse line expressing Fucci (fluorescent ubiquitination-based cell cycle indicator) probes allows us to monitor the cell cycle in the hematopoietic system. Two populations with high and low intensities of Fucci signals for Cdt1(30/120) accumulation were identified by FACS analysis, and these correspond to quiescent G0 and cycling G1 cells, respectively. We observed the transition of immune cells between quiescent and proliferative phases in lymphoid organs during differentiation and immune responses. PMID- 24066074 TI - Neighbourhood society: nesting dynamics, usurpations and social behaviour in solitary bees. AB - Intraspecific cleptoparasitism represents a facultative strategy advantageous for reducing time and energy costs. However, only a few studies about nesting dynamics have described intraspecific cleptoparasitic behaviour in obligate solitary bees. We focused on nesting dynamics with the characterisation of nest owner replacements and frequency of true usurpation in four aggregating species belonging to different phylogenetic lineages--Andrena vaga (Andrenidae), Anthophora plumipes (Apidae), Colletes cunicularius (Colletidae), and Osmia rufa (Megachilidae). Our study, based on the regular observation of individually marked females, shows that nest owner replacement affects 10-45% of nests across all of the studied species and years. However, 39-90% of these nests had been abandoned before owner change and thus true nest usurpations represent only a part of observed nest replacement cases. Females tend to abandon their nests regularly and found new ones when they live long enough, which is in accordance with risk-spreading strategy. We suggest that the original facultative strategy of observed solitary bees during nest founding is not cleptoparasitism per se but rather reuse of any pre-existing nest (similar to "entering" strategy in apoid wasps). This is supported by gradual increase of nests founded by "entering" during the season with an increase in the number of available nests. Although the frequent reuse of conspecific nests results in frequent contact between solitary females, and rarely, in the short-term coexistence of two females in one nest, we detected unexpectedly low level of conflict in these neighbourhood societies. We suggest that nesting dynamics with regular nest switching and reusing reduces long-term and costly intraspecific aggression, a key factor for the origin and evolution of sociality. PMID- 24066073 TI - Molecular characterization of UGT94F2 and UGT86C4, two glycosyltransferases from Picrorhiza kurrooa: comparative structural insight and evaluation of substrate recognition. AB - Uridine diphosphate glycosyltransferases (UGTs) are pivotal in the process of glycosylation for decorating natural products with sugars. It is one of the versatile mechanisms in determining chemical complexity and diversity for the production of suite of pharmacologically active plant natural products. Picrorhiza kurrooa is a highly reputed medicinal herb known for its hepato protective properties which are attributed to a novel group of iridoid glycosides known as picrosides. Although the plant is well studied in terms of its pharmacological properties, very little is known about the biosynthesis of these important secondary metabolites. In this study, we identified two family-1 glucosyltransferases from P. kurrooa. The full length cDNAs of UGT94F4 and UGT86C4 contained open reading frames of 1455 and 1422 nucleotides, encoding polypeptides of 484 and 473 amino acids respectively. UGT94F2 and UGT86C4 showed differential expression pattern in leaves, rhizomes and inflorescence. To elucidate whether the differential expression pattern of the two Picrorhiza UGTs correlate with transcriptional regulation via their promoters and to identify elements that could be recognized by known iridoid-specific transcription factors, upstream regions of each gene were isolated and scanned for putative cis regulatory elements. Interestingly, the presence of cis-regulatory elements within the promoter regions of each gene correlated positively with their expression profiles in response to different phytohormones. HPLC analysis of picrosides extracted from different tissues and elicitor-treated samples showed a significant increase in picroside levels, corroborating well with the expression profile of UGT94F2 possibly indicating its implication in picroside biosynthesis. Using homology modeling and molecular docking studies, we provide an insight into the donor and acceptor specificities of both UGTs identified in this study. UGT94F2 was predicted to be an iridoid-specific glucosyltransferase having maximum binding affinity towards 7-deoxyloganetin while as UGT86C4 was predicted to be a kaempferol-specific glucosyltransferase. These are the first UGTs being reported from P. kurrooa. PMID- 24066075 TI - Controlling seizure-like events by perturbing ion concentration dynamics with periodic stimulation. AB - We investigate the effects of adding periodic stimulation to a generic, conductance-based neuron model that includes ion concentration dynamics of sodium and potassium. Under conditions of high extracellular potassium, the model exhibits repeating, spontaneous, seizure-like bursting events associated with slow modulation of the ion concentrations local to the neuron. We show that for a range of parameter values, depolarizing and hyperpolarizing periodic stimulation pulses (including frequencies lower than 4 Hz) can stop the spontaneous bursting by interacting with the ion concentration dynamics. Stimulation can also control the magnitude of evoked responses to modeled physiological inputs. We develop an understanding of the nonlinear dynamics of this system by a timescale separation procedure that identifies effective nullclines in the ion concentration parameter space. Our results suggest that the manipulation of ion concentration dynamics via external or endogenous stimulation may play an important role in neuronal excitability, seizure dynamics, and control. PMID- 24066076 TI - Patterns of rotavirus vaccine uptake and use in privately-insured US infants, 2006-2010. AB - Rotavirus vaccines are highly effective at preventing gastroenteritis in young children and are now universally recommended for infants in the US. We studied patterns of use of rotavirus vaccines among US infants with commercial insurance. We identified a large cohort of infants in the MarketScan Research Databases, 2006-2010. The analysis was restricted to infants residing in states without state-funded rotavirus vaccination programs. We computed summary statistics and used multivariable regression to assess the association between patient-, provider-, and ecologic-level variables of rotavirus vaccine receipt and series completion. Approximately 69% of 594,117 eligible infants received at least one dose of rotavirus vaccine from 2006-2010. Most infants received the rotavirus vaccines at the recommended ages, but more infants completed the series for monovalent rotavirus vaccine than pentavalent rotavirus vaccine or a mix of the vaccines (87% versus 79% versus 73%, P<0.001). In multivariable analyses, the strongest predictors of rotavirus vaccine series initiation and completion were receipt of the diphtheria, tetanus and acellular pertussis vaccine (Initiation: RR = 7.91, 95% CI = 7.69-8.13; Completion: RR = 1.26, 95% CI = 1.23-1.29), visiting a pediatrician versus family physician (Initiation: RR = 1.51, 95% CI = 1.49-1.52; Completion: RR = 1.13, 95% CI = 1.11-1.14), and living in a large metropolitan versus smaller metropolitan, urban, or rural area. We observed rapid diffusion of the rotavirus vaccine in routine practice; however, approximately one-fifth of infants did not receive at least one dose of vaccine as recently as 2010. Interventions to increase rotavirus vaccine coverage should consider targeting family physicians and encouraging completion of the vaccine series. PMID- 24066077 TI - Higher perceived stress but lower cortisol levels found among young Greek adults living in a stressful social environment in comparison with Swedish young adults. AB - The worldwide financial crisis during recent years has raised concerns of negative public health effects. This is notably evident in southern Europe. In Greece, where the financial austerity has been especially pronounced, the prevalence of mental health problems including depression and suicide has increased, and outbreaks of infectious diseases have risen. The main objective in this study was to investigate whether different indicators of health and stress levels measured by a new biomarker based on cortisol in human hair were different amongst comparable Greek and Swedish young adults, considering that Sweden has been much less affected by the recent economic crises. In this cross-sectional comparative study, young adults from the city of Athens in Greece (n = 124) and from the city of Linkoping in Sweden (n = 112) participated. The data collection comprised answering a questionnaire with different health indicators and hair samples being analyzed for the stress hormone cortisol, a biomarker with the ability to retrospectively measure long-term cortisol exposure. The Greek young adults reported significantly higher perceived stress (p<0.0001), had experienced more serious life events (p = 0.002), had lower hope for the future (p<0.0001), and had significantly more widespread symptoms of depression (p<0.0001) and anxiety (p<0.0001) than the Swedes. But, the Greeks were found to have significantly lower cortisol levels (p<0.0001) than the Swedes, and this difference was still significant in a multivariate regression (p<0.0001), after adjustments for potential intervening variables. A variety of factors related to differences in the physical or socio-cultural environment between the two sites, might possibly explain this finding. However, a potential biological mechanism is that long-term stress exposure could lead to a lowering of the cortisol levels. This study points out a possible hypothesis that the cortisol levels of the Greek young adults might have been suppressed and their HPA-axis down-regulated after living in a stressful environment with economic and social pressure. PMID- 24066078 TI - Physical motif clustering within intrinsically disordered nucleoporin sequences reveals universal functional features. AB - Bioinformatics of disordered proteins is especially challenging given high mutation rates for homologous proteins and that functionality may not be strongly related to sequence. Here we have performed a novel bioinformatic analysis, based on the spatial clustering of physically relevant features such as binding motifs and charges within disordered proteins, on thousands of Nuclear Pore Complex (NPC) FG motif containing proteins (FG nups). The biophysical mechanism by which FG nups regulate nucleocytoplasmic transport has remained elusive. Our analysis revealed a set of highly conserved spatial features in the sequence structure of individual FG nups, such as the separation, localization, and ordering of FG motifs and charged residues along the protein chain. These functionally conserved features provide insight into the particular biophysical mechanisms responsible for regulation of nucleocytoplasmic traffic in the NPC, strongly constraining current models. Additionally this method allows us to identify potentially functionally analogous disordered proteins across distantly related species. PMID- 24066079 TI - Extensive diversity of Streptococcus pyogenes in a remote human population reflects global-scale transmission rather than localised diversification. AB - The Indigenous population of the Northern Territory of Australia (NT) suffers from a very high burden of Streptococcus pyogenes disease, including cardiac and renal sequelae. The aim of this study was to determine if S. pyogenes isolated from this population represent NT endemic strains, or conversely reflect strains with global distribution. emm sequence typing data were used to select 460 S. pyogenes isolates representing NT S. pyogenes diversity from 1987-2008. These isolates were genotyped using either multilocus sequence typing (MLST) or a high resolution melting-based MLST surrogate (Minim typing). These data were combined with MLST data from other studies on NT S. pyogenes to yield a set of 731 MLST or Minim typed isolates for analysis. goeBURST analysis of MLST allelic profiles and neighbour-joining trees of the MLST allele sequences revealed that a large proportion of the known global S. pyogenes MLST-defined diversity has now been found in the NT. Specifically, fully sequence typed NT isolates encompass 19% of known S. pyogenes STs and 43% of known S. pyogenes MLST alleles. These analyses provided no evidence for major NT-endemic strains, with many STs and MLST alleles shared between the NT and the rest of the world. The relationship between the number of known Minim types, and the probability that a Minim type identified in a calendar year would be novel was determined. This revealed that Minim types typically persist in the NT for >1 year, and indicate that the majority of NT Minim types have been identified. This study revealed that many diverse S. pyogenes strains exhibit global scale mobility that extends to isolated populations. The burden of S. pyogenes disease in the NT is unlikely to be due to the nature of NT S. pyogenes strains, but is rather a function of social and living conditions. PMID- 24066081 TI - Anti-wrinkle and anti-inflammatory effects of active garlic components and the inhibition of MMPs via NF-kappaB signaling. AB - Skin aging is a multisystem degenerative process caused by several factors, such as, UV irradiation, stress, and smoke. Furthermore, wrinkle formation is a striking feature of photoaging and is associated with oxidative stress and inflammatory response. In the present study, we investigated whether caffeic acid, S-allyl cysteine, and uracil, which were isolated from garlic, modulate UVB induced wrinkle formation and effect the expression of matrix-metalloproteinase (MMP) and NF-kappaB signaling. The results obtained showed that all three compounds significantly inhibited the degradation of type I procollagen and the expressions of MMPs in vivo and attenuated the histological collagen fiber disorder and oxidative stress in vivo. Furthermore, caffeic acid and S-allyl cysteine were found to decrease oxidative stress and inflammation by modulating the activities of NF-kappaB and AP-1, and uracil exhibited an indirect anti oxidant effect by suppressing cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions levels and downregulating transcriptional factors. These results suggest that the anti-wrinkle effects of caffeic acid, S-allyl cysteine, and uracil are due to anti-oxidant and/or anti-inflammatory effects. Summarizing, caffeic acid, S-allyl cysteine, and uracil inhibited UVB-induced wrinkle formation by modulating MMP via NF-kappaB signaling. PMID- 24066080 TI - Morphological and physiological changes in mature in vitro neuronal networks towards exposure to short-, middle- or long-term simulated microgravity. AB - One of the objectives of the current international space programmes is to investigate the possible effects of the space environment on the crew health. The aim of this work was to assess the particular effects of simulated microgravity on mature primary neuronal networks and specially their plasticity and connectivity. For this purpose, primary mouse neurons were first grown for 10 days as a dense network before being placed in the Random Positioning Machine (RPM), simulating microgravity. These cultures were then used to investigate the impact of short- (1 h), middle- (24 h) and long-term (10 days) exposure to microgravity at the level of neurite network density, cell morphology and motility as well as cytoskeleton properties in established two-dimensional mature neuronal networks. Image processing analysis of dense neuronal networks exposed to simulated microgravity and their subsequent recovery under ground conditions revealed different neuronal responses depending on the duration period of exposure. After short- and middle-term exposures to simulated microgravity, changes in neurite network, neuron morphology and viability were observed with significant alterations followed by fast recovery processes. Long exposure to simulated microgravity revealed a high adaptation of single neurons to the new gravity conditions as well as a partial adaptation of neuronal networks. This latter was concomitant to an increase of apoptosis. However, neurons and neuronal networks exposed for long-term to simulated microgravity required longer recovery time to re-adapt to the ground gravity. In conclusion, a clear modulation in neuronal plasticity was evidenced through morphological and physiological changes in primary neuronal cultures during and after simulated microgravity exposure. These changes were dependent on the duration of exposure to microgravity. PMID- 24066082 TI - Whole body muscle activity during the FIFA 11+ program evaluated by positron emission tomography. AB - PURPOSE: This study investigated the effect of the FIFA 11+ warm-up program on whole body muscle activity using positron emission tomography. METHODS: Ten healthy male volunteers were divided into a control group and a group that performed injury prevention exercises (The 11+). The subjects of the control group were placed in a sitting position for 20 min and 37 MBq of (18)F fluorodeoxyglucose (FDG) was injected intravenously. The subjects then remained seated for 45 min. The subjects of the exercise group performed part 2 of the 11+for 20 min, after which FDG was injected. They then performed part 2 of the 11+for 20 min, and rested for 25 min in a sitting position. Positron emission tomography-computed tomography images were obtained 50 min after FDG injection in each group. Regions of interest were defined within 30 muscles. The standardized uptake value was calculated to examine the FDG uptake of muscle tissue per unit volume. RESULTS: FDG accumulation within the abdominal rectus, gluteus medius and minimus were significantly higher in the exercise group than in the control group (P<0.05). CONCLUSION: The hip abductor muscles and abdominal rectus were active during part 2 of the FIFA 11+ program. PMID- 24066083 TI - Internal-specific morphological analysis of sciatic nerve fibers in a radiofrequency-induced animal neuropathic pain model. AB - This study investigated the reversible effects of pulsed radiofrequency (PRF) treatment at 42 degrees C on the ultrastructural and biological changes in nerve and collagen fibers in the progression of neuropathic pain after rat sciatic nerve injury. Assessments of morphological changes in the extracellular matrices by atomic force microscopy and hematoxylin-eosin, Masson's trichrome and picrosirius-red staining as well as the expressions of two fibril-forming collagens, types-I and -III, and two inflammatory cytokines, TNF-alpha and IL-6, were evaluated on day 30 after RF exposure. There were four groups for different RF thermal treatments: no treatment, no current, PRF, and continuous RF (CRF). An RF procedure similar to that used in human clinical trials was used in this study. The CRF treatment at 82 degrees C led to neural and collagen damage by the permanent blockage of sensory nociceptors. The PRF treatment led to excellent performance and high expandability compared to CRF, with effects including slight damage and swelling of myelinated axons, a slightly decreased amount of collagen fibers, swelling of collagen fibril diameters, decreased immunoreactivity of collagen types-I and -III, presence of newly synthesized collagen, and recovery of inflammatory protein immunoreactivity. These evidence-based findings suggest that PRF-based pain relief is responsible for the temporary blockage of nerve signals as well as the preferential destruction of pain-related principal sensory fibers like the Adelta and C fibers. This suggestion can be supported by the interaction between the PRF-induced electromagnetic field and cell membranes; therefore, PRF treatment provides pain relief while allowing retention of some tactile sensation. PMID- 24066084 TI - Conformational barrier of CheY3 and inability of CheY4 to bind FliM control the flagellar motor action in Vibrio cholerae. AB - Vibrio cholerae contains multiple copies of chemotaxis response regulator (VcCheY1-VcCheY4) whose functions are elusive yet. Although previous studies suggested that only VcCheY3 directly switches the flagellar rotation, the involvement of VcCheY4 in chemotaxis could not be ruled out. None of these studies, however, focused on the structure, mechanism of activation or molecular basis of FliM binding of the VcCheYs. From the crystal structures of Ca(2+) and Mg(2+) bound VcCheY3 we proposed the presence of a conformational barrier composed of the hydrophobic packing of W61, M88 and V106 and a unique hydrogen bond between T90 and Q97 in VcCheY3. Lesser fluorescence quenching and higher Km value of VcCheY3, compared to its mutants VcCheY3-Q97A and VcCheY3-Q97A/E100A supported our proposition. Furthermore, aforesaid biochemical data, in conjunction with the structure of VcCheY3-Q97A, indicated that the coupling of T90 and Q97 restricts the movement of T90 toward the active site reducing the stabilization of the bound phosphate and effectively promoting autodephosphorylation of VcCheY3. The structure of BeF3(-) activated VcCheY3 insisted us to argue that elevated temperature and/or adequacy of phosphate pool might break the barrier of the free-state VcCheY3 and the conformational changes, required for FliM binding, occur upon phosphorylation. Structure of VcCheY4 has been solved in the free and sulfated states. VcCheY4(sulf), containing a bound sulfate at the active site, appears to be more compact and stable with a longer alpha4 helix, shorter beta4alpha4 loop and hydrogen bond between T82 and the sulfate compared to VcCheY4(free). While pull down assay of VcCheYs with VcFliMNM showed that only activated VcCheY3 can interact with VcFliMNM and VcCheY4 cannot, a knowledge based docking explained the molecular mechanism of the interactions between VcCheY3 and VcFliM and identified the limitations of VcCheY4 to interact with VcFliM even in its phosphorylated state. PMID- 24066085 TI - Neonatal pain-related stress and NFKBIA genotype are associated with altered cortisol levels in preterm boys at school age. AB - Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm <= 32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF kappaB, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm. PMID- 24066086 TI - Enhanced cancer metastasis in mice deficient in vasohibin-1 gene. AB - Vasohibin-1 (VASH1) is isolated as an endogenous angiogenesis inhibitor produced by the vascular endothelium. We previously reported that tumor growth and tumor angiogenesis were augmented in VASH1 (-/-) mice. Here we examined whether VASH1 plays any role in cancer metastasis. When Lewis lung carcinoma (LLC) cells were inoculated in the footpad to observe spontaneous metastasis, a significant increase in lung metastasis together with inguinal lymph node metastasis was evident in the VASH1 (-/-) mice. Histological analyses revealed that vessels of the footpad tumor in VASH1 (-/-) mice were more immature, having fewer mural cells. However, when LLC cells were injected into a tail vein, the extent of lung metastasis was unchanged between wild-type mice and VASH1 (-/-) mice. When VASH1 in endothelial cells in culture was knocked-down by siRNA, we observed a decrease in the content of ZO-1, a component of tight junctions, which decrease resulted in increased transmigration of cancer cells across the endothelial cell monolayer. These results indicate that endogenous VASH1 tightens the endothelial barrier and makes tumor vessels resistant to cancer metastasis. PMID- 24066087 TI - In silico modeling of Itk activation kinetics in thymocytes suggests competing positive and negative IP4 mediated feedbacks increase robustness. AB - The inositol-phosphate messenger inositol(1,3,4,5)tetrakisphosphate (IP4) is essential for thymocyte positive selection by regulating plasma-membrane association of the protein tyrosine kinase Itk downstream of the T cell receptor (TCR). IP4 can act as a soluble analog of the phosphoinositide 3-kinase (PI3K) membrane lipid product phosphatidylinositol(3,4,5)trisphosphate (PIP3). PIP3 recruits signaling proteins such as Itk to cellular membranes by binding to PH and other domains. In thymocytes, low-dose IP4 binding to the Itk PH domain surprisingly promoted and high-dose IP4 inhibited PIP3 binding of Itk PH domains. However, the mechanisms that underlie the regulation of membrane recruitment of Itk by IP4 and PIP3 remain unclear. The distinct Itk PH domain ability to oligomerize is consistent with a cooperative-allosteric mode of IP4 action. However, other possibilities cannot be ruled out due to difficulties in quantitatively measuring the interactions between Itk, IP4 and PIP3, and in generating non-oligomerizing Itk PH domain mutants. This has hindered a full mechanistic understanding of how IP4 controls Itk function. By combining experimentally measured kinetics of PLCgamma1 phosphorylation by Itk with in silico modeling of multiple Itk signaling circuits and a maximum entropy (MaxEnt) based computational approach, we show that those in silico models which are most robust against variations of protein and lipid expression levels and kinetic rates at the single cell level share a cooperative-allosteric mode of Itk regulation by IP4 involving oligomeric Itk PH domains at the plasma membrane. This identifies MaxEnt as an excellent tool for quantifying robustness for complex TCR signaling circuits and provides testable predictions to further elucidate a controversial mechanism of PIP3 signaling. PMID- 24066088 TI - On the role of anisotropy of membrane components in formation and stabilization of tubular structures in multicomponent membranes. AB - Influence of isotropic and anisotropic properties of membrane constituents (nanodomains) on formation of tubular membrane structures in two-component vesicle is numerically investigated by minimization of the free energy functional based on the deviatoric-elasticity model of the membrane. It is shown that the lateral redistribution and segregation of membrane components may induce substantial change in membrane curvature resulting in the growth of highly curved tubular structures. PMID- 24066089 TI - Single nucleotide polymorphism array profiling of adrenocortical tumors--evidence for an adenoma carcinoma sequence? AB - Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91% vs 29%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70% of gains frequent in benign were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted "IGF2" locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors. PMID- 24066090 TI - Determining ancestry proportions in complex admixture scenarios in South Africa using a novel proxy ancestry selection method. AB - Admixed populations can make an important contribution to the discovery of disease susceptibility genes if the parental populations exhibit substantial variation in susceptibility. Admixture mapping has been used successfully, but is not designed to cope with populations that have more than two or three ancestral populations. The inference of admixture proportions and local ancestry and the imputation of missing genotypes in admixed populations are crucial in both understanding variation in disease and identifying novel disease loci. These inferences make use of reference populations, and accuracy depends on the choice of ancestral populations. Using an insufficient or inaccurate ancestral panel can result in erroneously inferred ancestry and affect the detection power of GWAS and meta-analysis when using imputation. Current algorithms are inadequate for multi-way admixed populations. To address these challenges we developed PROXYANC, an approach to select the best proxy ancestral populations. From the simulation of a multi-way admixed population we demonstrate the capability and accuracy of PROXYANC and illustrate the importance of the choice of ancestry in both estimating admixture proportions and imputing missing genotypes. We applied this approach to a complex, uniquely admixed South African population. Using genome wide SNP data from over 764 individuals, we accurately estimate the genetic contributions from the best ancestral populations: isiXhosa [Formula: see text], ?Khomani SAN [Formula: see text], European [Formula: see text], Indian [Formula: see text], and Chinese [Formula: see text]. We also demonstrate that the ancestral allele frequency differences correlate with increased linkage disequilibrium in the South African population, which originates from admixture events rather than population bottlenecks. NOMENCLATURE: The collective term for people of mixed ancestry in southern Africa is "Coloured," and this is officially recognized in South Africa as a census term, and for self-classification. Whilst we acknowledge that some cultures may use this term in a derogatory manner, these connotations are not present in South Africa, and are certainly not intended here. PMID- 24066091 TI - The effect of anti-rosetting agents against malaria parasites under physiological flow conditions. AB - Rosetting remains the dominant malaria parasite adhesion phenotype associated with severe disease and pathogenicity in Africa. The formation of rosettes, whereby a Plasmodium falciparum infected erythrocyte (IE) adheres to two or more non-IEs, is thought to facilitate the occlusion of microvascular blood vessels by adhering to host endothelial cells and other bound IEs. Current methods of determining the rosette-disrupting capabilities of antibodies/drugs have focused on static assays. As IEs in vivo are exposed to shear stresses within the microvasculature, the effect of flow conditions on rosetting requires further examination. This study establishes a new rosetting flow assay using a closed perfusion system together with inverted fluorescence microscopy and image analysis, and confirms previous reports that rosettes exist under shear stresses equivalent to those present in the microvasculature (0.5-1.0 dyn/cm(2)). Furthermore, we tested the effectiveness of rosette-disrupting PfEMP1 antibodies, heparin and fucoidan over a range of concentrations on two P. falciparum strains, and found no statistically significant differences between the results of static and flow assays. The new flow assay is a valuable addition to the tools available to study rosetting. However, the static assay has good predictive value and remains useful as the standard screening test for rosette-disrupting interventions. PMID- 24066092 TI - Emotional development in adults with autism and intellectual disabilities: a retrospective, clinical analysis. AB - Individuals with intellectual disability (ID) are at risk for additional autism spectrum disorders (ASD). A large amount of research reveals deficits in emotion related processes that are relevant to social cognition in ASD. However, studies on the structure and level of emotional development (ED) assessing emotional maturity according to the normative trajectory in typically developing children are scares. The level of ED can be evaluated by the 'Scheme of Appraisal of Emotional Development' (SAED), a semi-structured interview with a close caregiver. The SAED assesses the level of emotional developmental based on a five stage system in 10 domains, for example, 'interaction with peers' or 'object permanence', which are conducive to the overall emotional developmental level. This study examined the ED as measured by the SAED in 289 adults (mean age: 36 years) with ID with and without additional ASD. A lower level in ED was observed in ASD/ID combined that corresponded to the ED of typically developing children aged 1.5-3 years versus an ED with a corresponding age of 3-7 years in ID individuals without ASD. Moreover, distinct strengths in 'object permanence', and weaknesses in 'interaction', 'verbal communication', 'experience of self', 'affect differentiation', 'anxiety', and 'handling of material objects' led to a characteristic pattern of ED in ASD. SAED domains with highest discriminative power between ID individuals with and without ASD (5/10) were used to predict ASD group membership. The classification using a selection of SAED domains revealed a sensitivity of 77.5% and a specificity of 76.4%. ASD risk increased 2.7-fold with every SAED level. The recognition of delayed and uneven pattern of ED contributes to our understanding of the emotion-related impairments in adults with ID and ASD these individuals. Assessment of intra-individual ED could add value to the standard diagnostic procedures in ID, a population at risk for underdiagnosed ASD. PMID- 24066093 TI - SMAD7 variant rs4939827 is associated with colorectal cancer risk in Croatian population. AB - BACKGROUND: Twenty common genetic variants have been associated with risk of developing colorectal cancer (CRC) in genome wide association studies to date. Since large differences between populations exist, generalisability of findings to any specific population needs to be confirmed. AIM: The aim of this study was to perform an association study between risk variants: rs10795668, rs16892766, rs3802842 and rs4939827 and CRC risk in Croatian population. METHODS: An association study was performed on 320 colorectal cancer cases and 594 controls recruited in Croatia. We genotyped four variants previously associated with CRC: rs10795668, rs16892766, rs3802842 and rs4939827. RESULTS: SMAD7 variant rs4939827 (18q21.1) was significantly associated with CRC risk in Croatian population. C allele was associated with a decreased risk, odds ratio (OR): 0.70 (95% CI: 0.57 0.85, P=3.5E-04). Compared to TT homozygotes, risk was reduced by 34% in heterozygotes (OR=0.66, 95% CI: 0.47-0.92) and by 52% in CC homozygotes (OR=0.48, 95% CI: 0.33-0.72). CONCLUSION: Our results show association of rs4939827 with colorectal cancer risk in Croatian population. The higher strength of the association in comparison to other studies suggests population-specific environmental or genetic factors may be modifying the association. More studies are needed to further describe role of rs4939827 in CRC. Likely reason for failure of replication for other 3 loci is inadequate study power. PMID- 24066094 TI - Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/B-catenin signaling activator R-spondin 2. AB - Recent developments in molecular programming of mesodiencephalic dopaminergic (mdDA) neurons have led to the identification of many transcription factors playing a role in mdDA specification. LIM homeodomain transcription factor Lmx1a is essential for chick mdDA development, and for the efficient differentiation of ES-cells towards a dopaminergic phenotype. In this study, we aimed towards a more detailed understanding of the subtle phenotype in Lmx1a-deficient (dreher) mice, by means of gene expression profiling. Transcriptome analysis was performed, to elucidate the exact molecular programming underlying the neuronal deficits after loss of Lmx1a. Subsequent expression analysis on brain sections, confirmed that Nurr1 is regulated by Lmx1a, and additional downstream targets were identified, like Pou4f1, Pbx1, Pitx2, C130021l20Rik, Calb2 and Rspo2. In line with a specific, rostral-lateral (prosomer 2/3) loss of expression of most of these genes during development, Nurr1 and C130021l20Rik were affected in the SNc of the mature mdDA system. Interestingly, this deficit was marked by the complete loss of the Wnt/b-catenin signaling activator Rspo2 in this domain. Subsequent analysis of Rspo2-/- embryos revealed affected mdDA neurons, partially phenocopying the Lmx1a mutant. To conclude, our study revealed that Lmx1a is essential for a rostral-lateral subset of the mdDA neuronal field, where it might serve a critical function in modulating proliferation and differentiation of mdDA progenitors through the regulation of the Wnt activator Rspo2. PMID- 24066095 TI - Spatial analysis of "crazy quilts", a class of potentially random aesthetic artefacts. AB - Human artefacts in general are highly structured and often display ordering principles such as translational, reflectional or rotational symmetry. In contrast, human artefacts that are intended to appear random and non symmetrical are very rare. Furthermore, many studies show that humans find it extremely difficult to recognize or reproduce truly random patterns or sequences. Here, we attempt to model two-dimensional decorative spatial patterns produced by humans that show no obvious order. "Crazy quilts" represent a historically important style of quilt making that became popular in the 1870s, and lasted about 50 years. Crazy quilts are unusual because unlike most human artefacts, they are specifically intended to appear haphazard and unstructured. We evaluate the degree to which this intention was achieved by using statistical techniques of spatial point pattern analysis to compare crazy quilts with regular quilts from the same region and era and to evaluate the fit of various random distributions to these two quilt classes. We found that the two quilt categories exhibit fundamentally different spatial characteristics: The patch areas of crazy quilts derive from a continuous random distribution, while area distributions of regular quilts consist of Gaussian mixtures. These Gaussian mixtures derive from regular pattern motifs that are repeated and we suggest that such a mixture is a distinctive signature of human-made visual patterns. In contrast, the distribution found in crazy quilts is shared with many other naturally occurring spatial patterns. Centroids of patches in the two quilt classes are spaced differently and in general, crazy quilts but not regular quilts are well-fitted by a random Strauss process. These results indicate that, within the constraints of the quilt format, Victorian quilters indeed achieved their goal of generating random structures. PMID- 24066096 TI - Duration of anti-tuberculosis therapy and timing of antiretroviral therapy initiation: association with mortality in HIV-related tuberculosis. AB - BACKGROUND: Antiretroviral therapy (ART) decreases mortality risk in HIV-infected tuberculosis patients, but the effect of the duration of anti-tuberculosis therapy and timing of anti-tuberculosis therapy initiation in relation to ART initiation on mortality, is unclear. METHODS: We conducted a retrospective observational multi-center cohort study among HIV-infected persons concomitantly treated with Rifamycin-based anti-tuberculosis therapy and ART in Latin America. The study population included persons for whom 6 months of anti-tuberculosis therapy is recommended. RESULTS: Of 253 patients who met inclusion criteria, median CD4+ lymphocyte count at ART initiation was 64 cells/mm(3), 171 (68%) received >180 days of anti-tuberculosis therapy, 168 (66%) initiated anti tuberculosis therapy before ART, and 43 (17%) died. In a multivariate Cox proportional hazards model that adjusted for CD4+ lymphocytes and HIV-1 RNA, tuberculosis diagnosed after ART initiation was associated with an increased risk of death compared to tuberculosis diagnosis before ART initiation (HR 2.40; 95% CI 1.15, 5.02; P = 0.02). In a separate model among patients surviving >6 months after tuberculosis diagnosis, after adjusting for CD4+ lymphocytes, HIV-1 RNA, and timing of ART initiation relative to tuberculosis diagnosis, receipt of >6 months of anti-tuberculosis therapy was associated with a decreased risk of death (HR 0.23; 95% CI 0.08, 0.66; P=0.007). CONCLUSIONS: The increased risk of death among persons diagnosed with tuberculosis after ART initiation highlights the importance of screening for tuberculosis before ART initiation. The decreased risk of death among persons receiving > 6 months of anti-tuberculosis therapy suggests that current anti-tuberculosis treatment duration guidelines should be re-evaluated. PMID- 24066097 TI - Restriction genes for retroviruses influence the risk of multiple sclerosis. AB - We recently described that the autoimmune, central nervous system disease, multiple sclerosis (MS), is genetically associated with the human endogenous retroviral locus, HERV-Fc1, in Scandinavians. A number of dominant human genes encoding factors that restrict retrovirus replication have been known for a long time. Today human restriction genes for retroviruses include amongst others TRIMs, APOBEC3s, BST2 and TREXs. We have therefore looked for a role of these retroviral restriction genes in MS using genetic epidemiology. We here report that markers in two TRIMs, TRIM5 and TRIM22 and a marker in BST2, associated statistically with the risk of getting MS, while markers in or near APOBEC3s and TREXs showed little or no effect. This indicates that the two TRIMs and BST2 influence the risk of disease and thus supports the hypothesis of a viral involvement. PMID- 24066098 TI - BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality. AB - BACKGROUND/AIMS: Brown adipose tissue (BAT) dissipates energy stored in triglycerides as heat via the uncoupling protein UCP-1 and is a promising target to combat hyperlipidemia and obesity. BAT is densely innervated by the sympathetic nervous system, which increases BAT differentiation and activity upon cold exposure. Recently, Bone Morphogenetic Protein 7 (BMP7) was identified as an inducer of BAT differentiation. We aimed to elucidate the role of sympathetic activation in the effect of BMP7 on BAT by treating mice with BMP7 at varying ambient temperature, and assessed the therapeutic potential of BMP7 in combating obesity. METHODS AND RESULTS: High-fat diet fed lean C57Bl6/J mice were treated with BMP7 via subcutaneous osmotic minipumps for 4 weeks at 21 degrees C or 28 degrees C, the latter being a thermoneutral temperature in which sympathetic activation of BAT is largely diminished. At 21 degrees C, BMP7 increased BAT weight, increased the expression of Ucp1, Cd36 and hormone-sensitive lipase in BAT, and increased total energy expenditure. BMP7 treatment markedly increased food intake without affecting physical activity. Despite that, BMP7 diminished white adipose tissue (WAT) mass, accompanied by increased expression of genes related to intracellular lipolysis in WAT. All these effects were blunted at 28 degrees C. Additionally, BMP7 resulted in extensive 'browning' of WAT, as evidenced by increased expression of BAT markers and the appearance of whole clusters of brown adipocytes via immunohistochemistry, independent of environmental temperature. Treatment of diet-induced obese C57Bl6/J mice with BMP7 led to an improved metabolic phenotype, consisting of a decreased fat mass and liver lipids as well as attenuated dyslipidemia and hyperglycemia. CONCLUSION: Together, these data show that BMP7-mediated recruitment and activation of BAT only occurs at subthermoneutral temperature, and is thus likely dependent on sympathetic activation of BAT, and that BMP7 may be a promising tool to combat obesity and associated disorders. PMID- 24066099 TI - Task-sharing of HIV care and ART initiation: evaluation of a mixed-care non physician provider model for ART delivery in rural Malawi. AB - BACKGROUND: Expanding access to antiretroviral therapy (ART) in sub-Saharan Africa requires implementation of alternative care delivery models to traditional physician-centered approaches. This longitudinal analysis compares outcomes of patients initiated on antiretroviral therapy (ART) by non-physician and physician providers. METHODS: Adults (>=15 years) initiating ART between September 2007 and March 2010, and with >1 follow-up visit were included and classified according to the proportion of clinical visits performed by nurses or by clinical officers (>= 80% of visits). Multivariable Poisson models were used to compare 2-year program attrition (mortality and lost to follow-up) and mortality by type of provider. In sensitivity analyses only patients with less severe disease were included. RESULTS: A total of 10,112 patients contributed 14,012 person-years to the analysis: 3386 (33.5%) in the clinical officer group, 1901 (18.8%) in the nurse care group and 4825 (47.7%) in the mixed care group. Overall 2-year program retention was 81.8%. Attrition was lower in the mixed care and higher in the clinical officer group, compared to the nurse group (adjusted incidence rate ratio [aIRR]=0.54, 95%CI 0.45-0.65; and aIRR=3.03, 95%CI 2.56-3.59, respectively). While patients initiated on ART by clinical officers in the mixed care group had lower attrition (aIRR=0.36, 95%CI 0.29-0.44) than those in the overall nurse care group; no differences in attrition were found between patients initiated on ART by nurses in the mixed care group and those included in the nurse group (aIRR=1.18, 95%CI 0.95-1.47). Two-year mortality estimates were aIRR=0.72, 95%CI 0.49-1.09 and aIRR=5.04, 95%CI 3.56-7.15, respectively. Slightly higher estimates were observed when analyses were restricted to patients with less severe disease. CONCLUSION: The findings of this study support the use of a mixed care model with well trained and regularly supervised nurses and medical assistants to provide HIV care in countries with high HIV prevalence. PMID- 24066100 TI - Effects of constitutive beta-catenin activation on vertebral bone growth and remodeling at different postnatal stages in mice. AB - BACKGROUND AND OBJECTIVE: The Wnt/beta-catenin signaling pathway is essential for controlling bone mass; however, little is known about the variable effects of the constitutive activation of beta-catenin (CA-beta-catenin) on bone growth and remodeling at different postnatal stages. The goal of the present study was to observe the effects of CA-beta-catenin on vertebral bone growth and remodeling in mice at different postnatal stages. In particular, special attention was paid to whether CA-beta-catenin has detrimental effects on these processes. METHODS: Catnblox(ex 3) mice were crossed with mice expressing the TM-inducible Cre fusion protein, which could be activated at designated time points via injection of tamoxifen. beta-catenin was stabilized by tamoxifen injection 3 days, and 2, 4, 5, and 7 months after birth, and the effects lasted for one month. Radiographic imaging, micro-computed tomography, immunohistochemistry, and safranin O and tartrate-resistant acid phosphatase staining were employed to observe the effects of CA-beta-catenin on vertebral bone growth and remodeling. RESULTS: CA-beta catenin in both early (3 days after birth) and late stages (2, 4, 5, and 7 months after birth) increased bone formation and decreased bone resorption, which together increased vertebral bone volume. However, when beta-catenin was stabilized in the early stage, vertebral linear growth was retarded, and the mice demonstrated shorter statures. In addition, the newly formed bone was mainly immature and located close to the growth plate. In contrast, when beta-catenin was stabilized in the late stage, vertebral linear growth was unaffected, and the newly formed bone was mainly mature and evenly distributed throughout the vertebral body. CONCLUSIONS: CA-beta-catenin in both early and late stages of growth can increase vertebral bone volume, but beta-catenin has differential effects on vertebral growth and remodeling when activated at different postnatal stages. PMID- 24066101 TI - Elevated manganese concentrations in drinking water may be beneficial for fetal survival. AB - BACKGROUND: Elevated exposure to the essential element manganese (Mn) can be toxic. Manganese concentrations in ground water vary considerably, and reported associations between Mn and early-life mortality and impaired development have raised concern. We assessed the effects of drinking water Mn exposure during pregnancy upon fetal and infant survival. METHODS: In this population-based cohort study, we identified the outcomes of pregnancies registered between February 2002 and April 2003 in Matlab, Bangladesh. Using inductively coupled plasma mass spectrometry, we measured the concentrations of Mn and other elements in the pregnant women's drinking water. RESULTS: A total of 1,875 women were included in the analysis of spontaneous abortions (n=158) and 1,887 women in the perinatal mortality analysis (n=70). Water Mn ranged from 3.0-6,550 ug/L (median=217 ug/L). The adjusted odds ratio (OR) for spontaneous abortion was 0.65 (95% CI 0.43-0.99) in the highest water Mn tertile (median=1,292 ug/L) as compared to the lowest tertile (median=56 ug/L). The corresponding OR for perinatal mortality was 0.69 (95% CI 0.28-1.71), which increased to 0.78 (95% CI 0.29-2.08) after adjustment for BMI and place of delivery (home/health facility; n=1,648). CONCLUSIONS: Elevated water Mn concentrations during pregnancy appear protective for the fetus, particularly in undernourished women. This effect may be due to the element's role in antioxidant defense. PMID- 24066102 TI - The putative C2H2 transcription factor MtfA is a novel regulator of secondary metabolism and morphogenesis in Aspergillus nidulans. AB - Secondary metabolism in the model fungus Aspergillus nidulans is controlled by the conserved global regulator VeA, which also governs morphological differentiation. Among the secondary metabolites regulated by VeA is the mycotoxin sterigmatocystin (ST). The presence of VeA is necessary for the biosynthesis of this carcinogenic compound. We identified a revertant mutant able to synthesize ST intermediates in the absence of VeA. The point mutation occurred at the coding region of a gene encoding a novel putative C2H2 zinc finger domain transcription factor that we denominated mtfA. The A. nidulans mtfA gene product localizes at nuclei independently of the illumination regime. Deletion of the mtfA gene restores mycotoxin biosynthesis in the absence of veA, but drastically reduced mycotoxin production when mtfA gene expression was altered, by deletion or overexpression, in A. nidulans strains with a veA wild-type allele. Our study revealed that mtfA regulates ST production by affecting the expression of the specific ST gene cluster activator aflR. Importantly, mtfA is also a regulator of other secondary metabolism gene clusters, such as genes responsible for the synthesis of terrequinone and penicillin. As in the case of ST, deletion or overexpression of mtfA was also detrimental for the expression of terrequinone genes. Deletion of mtfA also decreased the expression of the genes in the penicillin gene cluster, reducing penicillin production. However, in this case, over-expression of mtfA enhanced the transcription of penicillin genes, increasing penicillin production more than 5 fold with respect to the control. Importantly, in addition to its effect on secondary metabolism, mtfA also affects asexual and sexual development in A. nidulans. Deletion of mtfA results in a reduction of conidiation and sexual stage. We found mtfA putative orthologs conserved in other fungal species. PMID- 24066103 TI - Bird radar validation in the field by time-referencing line-transect surveys. AB - Track-while-scan bird radars are widely used in ornithological studies, but often the precise detection capabilities of these systems are unknown. Quantification of radar performance is essential to avoid observational biases, which requires practical methods for validating a radar's detection capability in specific field settings. In this study a method to quantify the detection capability of a bird radar is presented, as well a demonstration of this method in a case study. By time-referencing line-transect surveys, visually identified birds were automatically linked to individual tracks using their transect crossing time. Detection probabilities were determined as the fraction of the total set of visual observations that could be linked to radar tracks. To avoid ambiguities in assigning radar tracks to visual observations, the observer's accuracy in determining a bird's transect crossing time was taken into account. The accuracy was determined by examining the effect of a time lag applied to the visual observations on the number of matches found with radar tracks. Effects of flight altitude, distance, surface substrate and species size on the detection probability by the radar were quantified in a marine intertidal study area. Detection probability varied strongly with all these factors, as well as species specific flight behaviour. The effective detection range for single birds flying at low altitude for an X-band marine radar based system was estimated at ~1.5 km. Within this range the fraction of individual flying birds that were detected by the radar was 0.50 +/- 0.06 with a detection bias towards higher flight altitudes, larger birds and high tide situations. Besides radar validation, which we consider essential when quantification of bird numbers is important, our method of linking radar tracks to ground-truthed field observations can facilitate species-specific studies using surveillance radars. The methodology may prove equally useful for optimising tracking algorithms. PMID- 24066104 TI - Multi-modal neuroimaging in premanifest and early Huntington's disease: 18 month longitudinal data from the IMAGE-HD study. AB - IMAGE-HD is an Australian based multi-modal longitudinal magnetic resonance imaging (MRI) study in premanifest and early symptomatic Huntington's disease (pre-HD and symp-HD, respectively). In this investigation we sought to determine the sensitivity of imaging methods to detect macrostructural (volume) and microstructural (diffusivity) longitudinal change in HD. We used a 3T MRI scanner to acquire T1 and diffusion weighted images at baseline and 18 months in 31 pre HD, 31 symp-HD and 29 controls. Volume was measured across the whole brain, and volume and diffusion measures were ascertained for caudate and putamen. We observed a range of significant volumetric and, for the first time, diffusion changes over 18 months in both pre-HD and symp-HD, relative to controls, detectable at the brain-wide level (volume change in grey and white matter) and in caudate and putamen (volume and diffusivity change). Importantly, longitudinal volume change in the caudate was the only measure that discriminated between groups across all stages of disease: far from diagnosis (>15 years), close to diagnosis (<15 years) and after diagnosis. Of the two diffusion metrics (mean diffusivity, MD; fractional anisotropy, FA), only longitudinal FA change was sensitive to group differences, but only after diagnosis. These findings further confirm caudate atrophy as one of the most sensitive and early biomarkers of neurodegeneration in HD. They also highlight that different tissue properties have varying schedules in their ability to discriminate between groups along disease progression and may therefore inform biomarker selection for future therapeutic interventions. PMID- 24066105 TI - Increasing seriousness of plant invasions in croplands of eastern china in relation to changing farming practices: a case study. AB - Arable areas are commonly susceptible to alien plant invasion because they experience dramatic environmental influences and intense anthropogenic activity. However, the limited reports on relevant factors in plant invasion of croplands have addressed single or a few invasive species and environmental factors. To elucidate key factors affecting plant invasions in croplands, we analyzed the relationship between 11 effective factors and changes in composition of alien plants, using field surveys of crop fields in Anhui Province conducted during 1987-1990 (historical dataset) and 2005-2010 (recent dataset), when rapid urbanization was occurring in China. We found that in the past few decades, the dominance and richness of alien plant populations approximately doubled, despite differences among the 4 regions of Anhui Province. Among the 38 alien invasive plant species observed in the sites, the dominance values of 11 species increased significantly, while the dominance of 4 species decreased significantly. The quantity of chemical fertilizer and herbicide applied, population density, agricultural machinery use, traffic frequency, and annual mean temperature were significantly related to increased richness and annual dominance values of alien plant species. Our findings suggest that the increase in alien plant invasions during the past few decades is primarily a result of increased application of chemical fertilizer and herbicides. PMID- 24066106 TI - Generation of Col2a1-EGFP iPS cells for monitoring chondrogenic differentiation. AB - Induced pluripotent stem cells (iPSC) are a promising cell source for cartilage regenerative medicine; however, the methods for chondrocyte induction from iPSC are currently developing and not yet sufficient for clinical application. Here, we report the establishment of a fluorescent indicator system for monitoring chondrogenic differentiation from iPSC to simplify screening for effective factors that induce chondrocytes from iPSC. We generated iPSC from embryonic fibroblasts of Col2a1-EGFP transgenic mice by retroviral transduction of Oct4, Sox2, Klf4, and c-Myc. Among the 30 clones of Col2a1-EGFP iPSC we established, two clones showed high expression levels of embryonic stem cell (ESC) marker genes, similar to control ESC. A teratoma formation assay showed that the two clones were pluripotent and differentiated into cell types from all three germ layers. The fluorescent signal was observed during chondrogenic differentiation of the two clones concomitant with the increase in chondrocyte marker expression. In conclusion, Col2a1-EGFP iPSC are useful for monitoring chondrogenic differentiation and will contribute to research in cartilage regenerative medicine. PMID- 24066107 TI - Inflammatory mediators influence the expression of nociceptin and its receptor in human whole blood cultures. AB - BACKGROUND: Nociceptin/orphanin FQ and its receptor (NOP) are involved in immune responses, inflammation and pain processing. The aim of this study was to investigate the modulation of NOP and prepro-nociceptin (PNoc), the precursor of nociceptin, by inflammatory mediators in human whole blood. METHODS: Peripheral blood from healthy volunteers was cultured for 0, 3, 6 and 24 hrs with or without lipopolysaccharide (LPS), tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, IL-10 or interferon (IFN)-gamma. NOP and PNoc mRNA of peripheral white blood cells were detected by quantitative RT-PCR. Cytokine concentrations in supernatants of whole blood cultures were measured using ELISA. In addition, an intervention experiment using anti-cytokine antibodies was conducted to evaluate possible mechanisms involved in the modulation of NOP and PNoc by LPS. The primary goal was to investigate NOP and PNoc mRNA expression in human peripheral blood under inflammatory conditions. RESULTS: LPS significantly suppressed NOP (median area under the mRNA-expression-time curve (1(st)/3(rd) quartile): 5.4 (4.6/6.6) normalized ratio . hr) and PNoc expression (40.8 (34.4/49.5)) compared to baseline measures (NOP: 22.7 (17.1/25.3); PNoc: 69.9 (58.4/89.2), both p<0.001). LPS incubation induced cytokine concentrations (TNF-alpha, IL-1beta, IL 10 and IFN-gamma) in whole blood cultures. Incubation with TNF-alpha, IL-1beta, IL-10 or IFN-gamma decreased NOP mRNA levels to varying extents (p<0.05 for all). In contrast, PNoc mRNA expression was decreased by IL-10 only (p = 0.018). The LPS effect on NOP expression could be antagonized by anti-TNF-alpha and anti-IL 1beta, whereas anti-IL-10 and anti-INF-gamma had no effect. There was no change of PNoc expression when LPS induced cytokines were antagonized by the respective antibodies. CONCLUSIONS: LPS as well as cytokines suppress mainly NOP and, in part, PNoc mRNA expression in human whole blood cultures. This may represent a negative feedback loop to the previously described upregulation of cytokines by PNoc. PMID- 24066108 TI - Potential role of Hedgehog pathway in liver response to radiation. AB - Radiation-induced fibrosis constitutes a major problem that is commonly observed in the patients undergoing radiotherapy; therefore, understanding its pathophysiological mechanism is important. The Hedgehog (Hh) pathway induces the proliferation of progenitors and myofibroblastic hepatic stellate cells (MF-HSCs) and promotes the epithelial-to-mesenchymal transition (EMT), thereby regulating the repair response in the damaged liver. We examined the response of normal liver to radiation injury. Male mice were sacrificed at 6 weeks and 10 weeks after exposure to a single dose of 6 Gy and the livers were collected for biochemical analysis. Irradiated (IR) and control mice were compared for progenitors, fibrosis, Hh pathway, and EMT at 6 and 10 weeks post irradiation. Fatty hepatocytes were observed and the expressions of Hh ligand, Indian Hh. were greater in the livers at 6 weeks, whereas expression of another Hh ligand, Sonic Hh, increased at 10 weeks post irradiation. Both Smoothened, Hh receptor, and Gli2, Hh-target gene, were up-regulated at 6 and 10 weeks after irradiation. Accumulation of progenitors (CD44, Pan-cytokeratin, and Sox9) was significant in IR livers at 6 and 10 weeks. RNA analysis showed enhanced expression of the EMT stimulating factor, tgf-beta, in the IR livers at 6 weeks and the upregulation of mesenchymal markers (alpha-SMA, collagen, N-cadherin, and s100a4), but down regulation of EMT inhibitors, in IR mouse livers at 6 and 10 weeks. Increased fibrosis was observed in IR mouse livers at 10 weeks. Treatment of mice with Hh inhibitor, GDC-0449, suppressed Hh activity and block the proliferation of hepatic progenitor and expression of EMT-stimulating genes in irradiated mice. Therefore, those results demonstrated that the Hh pathway increased in response to liver injury by radiation and promoted a compensatory proliferation of MF-HSCs and progenitors, thereby regulating liver remodeling. PMID- 24066109 TI - Can REDD+ help the conservation of restricted-range island species? Insights from the endemism hotspot of Sao Tome. AB - REDD+ aims to offset greenhouse gas emissions through "Reduced Emissions from Deforestation and forest Degradation". Some authors suggest that REDD+ can bring additional benefits for biodiversity, namely for the conservation of extinction prone restricted-range species. Here, we assess this claim, using Sao Tome Island (Democratic Republic of Sao Tome and Principe) as a case study. We quantified the abundance of bird and tree species, and calculated the aboveground carbon stocks across a gradient of land-use intensity. We found a strong spatial congruence between carbon and the presence and abundance of endemic species, supporting the potential of REDD+ to protect these taxa. We then assessed if REDD+ could help protect the forests of Sao Tome and Principe. To do so, we used OSIRIS simulations to predict country-level deforestation under two different REDD+ designs. These simulations showed that REDD+ could promote the loss of forests in Sao Tome and Principe through leakage. This happened even when additional payments for biodiversity were included in the simulations, and despite Sao Tome and Principe having the fourth highest carbon stocks per land area and the second highest biodiversity values according to the OSIRIS database. These results show weaknesses of OSIRIS as a planning tool, and demonstrate that the benefits that REDD+ might bring for biodiversity are strongly dependent on its careful implementation. We recommend that payment for ecosystem services programmes such as REDD+ develop safeguards to ensure that biodiversity co-benefits are met and perverse outcomes are avoided across all tropical countries. In particular, we advise specific safeguards regarding the conservation of extinction-prone groups, such as island restricted-range species. PMID- 24066110 TI - Age-related P-glycoprotein expression in the intestine and affecting the pharmacokinetics of orally administered enrofloxacin in broilers. AB - Bioavailability is the most important factor for the efficacy of any drug and it is determined by P- glycoprotein (P-gp) expression. Confirmation of P-gp expression during ontogeny is needed for understanding the differences in therapeutic efficacy of any drug in juvenile and adult animals. In this study, Abcb1 mRNA levels in the liver and intestine of broilers during ontogeny were analysed by RT qPCR. Cellular distribution of P-gp was detected by immunohistochemstry. Age-related differences of enrofloxacin pharmacokinetics were also studied. It was found that broilers aged 4 week-old expressed significantly (P<0.01) higher levels of P-gp mRNA in the liver, jejunum and ileum, than at other ages. However, there was no significant (P>0.05) age-related difference in the duodenum. Furthermore, the highest and lowest levels of Abcb1 mRNA expression were observed in the jejunum, and duodenum, respectively. P-gp immunoreactivity was detected on the apical surface of the enterocytes and in the bile canalicular membranes of the hepatocytes. Pharmacokinetic analysis revealed that the 8 week-old broilers, when orally administrated enrofloxacin, exhibited significantly higher Cmax (1.97 vs. 0.98 MUg * ml(-1), P=0.009), AUC(14.54 vs. 9.35 MUg * ml(-1) * h, P=0.005) and Ka (1.38 vs. 0.43 h(-1), P=0.032), as well as lower Tpeak (1.78 vs. 3.28 h, P=0.048) and T1/2 ka (0.6 vs. 1.64 h, P=0.012) than the 4 week-old broilers. The bioavailability of enrofloxacin in 8 week-old broilers was increased by 15.9%, compared with that in 4 week-old birds. Interestingly, combining verapamil, a P-gp modulator, significantly improved pharmacokinetic behaviour of enrofloxacin in all birds. The results indicate juvenile broilers had a higher expression of P-gp in the intestine, affecting the pharmacokinetics and reducing the bioavailability of oral enrofloxacin in broilers. On the basis of our results, it is recommended that alternative dose regimes are necessary for different ages of broilers for effective therapy. PMID- 24066111 TI - Counting within the subitizing range: the effect of number of distractors on the perception of subset items. AB - When exploring the mechanisms involved in perceiving numbers we must distinguish between two types of numbers: subset numbers (e.g., perceiving "2" when two plates and one cup are displayed on a table) and the total number of items (e.g., perceiving "3" objects in the previous example). Combining feature perception theories with number perception theories, the current paper explores the mechanisms involved in the perception of small numbers in feature-defined subsets. The paper introduces several theories for how subset items can be represented and examines an important prediction of those theories: Will the number of distractors affect the perception of small subset items? In two experiments, we found that the response time (RT) for counting small target items that differ from their distractors by a single feature was faster when there were few distractors compared to many distractors. This was found for different types of distractors: distractors within and outside the subitizing range. Only when distractors were organized in a specific pattern, allowing distractor grouping, the increase in the number of distractors did not affect target counting. The current study suggests that even when performing simple counting of subset targets, the enumeration process can begin only once the locations of the targets have been identified and the targets' shape is bound to these locations. This pre counting procedure depends on the number of individual locations occupied by the distractors. These findings are further discussed within the context of the object file theory. PMID- 24066112 TI - Nuclear survivin and its relationship to DNA damage repair genes in non-small cell lung cancer investigated using tissue array. AB - PURPOSE: To investigate the predictive role and association of nuclear survivin and the DNA double-strand breaks repair genes in non-small cell lung cancer (NSCLC): DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Ku heterodimeric regulatory complex 70-KD subunit (Ku70) and ataxia-telangiectasia mutated (ATM). METHODS: The protein expression of nuclear survivin, DNA-PKcs, Ku70 and ATM were investigated using immunohistochemistry in tumors from 256 patients with surgically resected NSCLC. Furthermore, we analyzed the correlation between the expression of nuclear survivin, DNA-PKcs, Ku70 and ATM. Univariate and multivariate analyses were performed to determine the prognostic factors that inuenced the overall survival and disease-free survival of NSCLC. RESULTS: The expression of nuclear survivin, DNA-PKcs, Ku70 and ATM was significantly higher in tumor tissues than in normal tissues. By dichotomizing the specimens as expressing low or high levels of nuclear survivin, nuclear survivin correlated significantly with the pathologic stage (P = 0.009) and lymph node status (P = 0.004). The nuclear survivin levels were an independent prognostic factor for both the overall survival and the disease-free survival in univariate and multivariate analyses. Patients with low Ku70 and DNA-PKcs expression had a greater benefit from radiotherapy than patients with high expression of Ku70 (P = 0.012) and DNA-PKcs (P = 0.02). Nuclear survivin expression positively correlated with DNA-PKcs (P<0.001) and Ku70 expression (P<0.001). CONCLUSIONS: Nuclear survivin may be a prognostic factor for overall survival in patients with resected stage I-IIIA NSCLC. DNA-PKcs and Ku70 could predict the effect of radiotherapy in patients with NSCLC. Nuclear survivin may also stimulates DNA double-strand breaks repair by its interaction with DNA-PKcs and Ku70. PMID- 24066113 TI - Autophagy defect is associated with low glucose-induced apoptosis in 661W photoreceptor cells. AB - Glucose is an important metabolic substrate of the retina and diabetic patients have to maintain a strict normoglycemia to avoid diabetes secondary effects, including cardiovascular disease, nephropathy, neuropathy and retinopathy. Others and we recently demonstrated the potential role of hypoglycemia in diabetic retinopathy. We showed acute hypoglycemia to induce retinal cell death both in vivo during an hyperinsulinemic/hypoglycemic clamp and in vitro in 661W photoreceptor cells cultured at low glucose concentration. In the present study, we showed low glucose to induce a decrease of BCL2 and BCL-XL anti-apoptotic proteins expression, leading to an increase of free pro-apoptotic BAX. In parallel, we showed that, in retinal cells, low glucose-induced apoptosis is involved in the process of autophagosomes formation through the AMPK/RAPTOR/mTOR pathway. Moreover, the decrease of LAMP2a expression led to a defect in the autophagosome/lysosome fusion process. Specific inhibition of autophagy, either by 3-methyladenine or by down-regulation of ATG5 or ATG7 proteins expression, increased caspase 3 activation and 661W cell death. We show that low glucose modifies the delicate equilibrium between apoptosis and autophagy. Cells struggled against low nutrient condition-induced apoptosis by starting an autophagic process, which led to cell death when inhibited. We conclude that autophagy defect is associated with low glucose-induced 661W cells death that could play a role in diabetic retinopathy. These results could modify the way of addressing negative effects of hypoglycemia. Short-term modulation of autophagy could be envisioned to treat diabetic patients in order to avoid secondary complications of the disease. PMID- 24066114 TI - Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with autism spectrum disorder. AB - Next-generation sequencing (NGS) combined with enrichment of target genes enables highly efficient and low-cost sequencing of multiple genes for genetic diseases. The aim of this study was to validate the accuracy and sensitivity of our method for comprehensive mutation detection in autism spectrum disorder (ASD). We assessed the performance of the bench-top Ion Torrent PGM and Illumina MiSeq platforms as optimized solutions for mutation detection, using microdroplet PCR based enrichment of 62 ASD associated genes. Ten patients with known mutations were sequenced using NGS to validate the sensitivity of our method. The overall read quality was better with MiSeq, largely because of the increased indel related error associated with PGM. The sensitivity of SNV detection was similar between the two platforms, suggesting they are both suitable for SNV detection in the human genome. Next, we used these methods to analyze 28 patients with ASD, and identified 22 novel variants in genes associated with ASD, with one mutation detected by MiSeq only. Thus, our results support the combination of target gene enrichment and NGS as a valuable molecular method for investigating rare variants in ASD. PMID- 24066115 TI - Association between serum ferritin levels and risk of the metabolic syndrome in Chinese adults: a population study. AB - Ferritin is a ubiquitous intracellular protein that can store and release iron and act as a buffer against iron deficiency and iron overload. Ferritin is widely used as a clinical biomarker to evaluate iron status. Increased serum ferritin concentrations have been reported to be associated with metabolic syndrome (MetS) features. However, serum ferritin concentrations differ significantly according to sex and ethnicity, and the data concerning the relationship between serum ferritin concentrations and MetS in Asian men and women are conflicting. This study aimed to explore the relationship between serum ferritin and MetS in Chinese population. Fasting blood samples and anthropometric data collected on 8,441 adults aged 18 and older in 2009 as part of the China Health and Nutrition Survey, a large-scale longitudinal, household-based survey in China. Data was collected by trained physicians and biomarkers were measured with Hitachi Clinical Autoanalyzer 7600 D model and P model. Median levels of serum ferritin were significantly higher in men compared with women (121.9 vs. 51.0 ng/ml, P < 0.001), and significantly lower in non metabolic syndrome population with MetS population (73.2 vs. 106.0 ng/ml, P < 0.001). The difference remained significant after further adjusted for age, nationality, Body mass index (BMI), smoking status, and alcohol consumption. For both men and women, the highest prevalence of MetS occurred in the highest quartile of serum ferritin. The odds ratios increased progressively across the ferritin quartiles (P<0.001 for trend). Increased serum ferritin concentrations are associated with the metabolic syndrome among men and women in China. PMID- 24066116 TI - Roles of Mir-144-ZFX pathway in growth regulation of non-small-cell lung cancer. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung carcinoma (NSCLC) accounts for most of the lung cancer cases and the prognosis of this disease remains poor despite decades of intensive investigation. Thus new insights into underlying mechanisms by which NSCLC develops are avidly needed as the basis for development of new lines of therapeutic strategies. The past decade has witnessed a growing interest on the regulatory roles of micro RNAs on various categories of malignancies. Related data has been well documented in carcinogenesis and pathophysiology of a variety of malignancies. Even so, there is a relative lack of data on roles of mir-144 in tumor biology and there has been no report showing the involvement of mir-144 in NSCLC development. METHODS/PRINCIPAL FINDING: From human NSCLC tumor tissue samples and cell culture samples, we found that the expression of mir-144 is associated with malignant phenotype of NSCLC. Further investigations showed that ectopic mir-144 expression dramatically inhibits NSCLC tumor cell growth and induces apoptosis as manifested by elevated apoptotic protein markers and flowcytometry change. Moreover, we also found that ZFX protein expression is also associated with malignant phenotype of NSCLC and knockdown of ZFX protein results in a similar effect as of ectopic mir-144 expression. Finally, we found that ZFX expression is highly adjustable upon presence of mir-144 and ectopic expression of ZFX dramatically dampens mir-144 action of tumor inhibition. CONCLUSIONS: Our results for the first time showed mir-144-ZFX pathway is involved in the development of NSCLC, which sheds a light for further investigations on underlying mechanisms toward better understanding and management of NSCLC. PMID- 24066117 TI - Expression signature as a biomarker for prenatal diagnosis of trisomy 21. AB - A universal biomarker panel with the potential to predict high-risk pregnancies or adverse pregnancy outcome does not exist. Transcriptome analysis is a powerful tool to capture differentially expressed genes (DEG), which can be used as biomarker-diagnostic-predictive tool for various conditions in prenatal setting. In search of biomarker set for predicting high-risk pregnancies, we performed global expression profiling to find DEG in Ts21. Subsequently, we performed targeted validation and diagnostic performance evaluation on a larger group of case and control samples. Initially, transcriptomic profiles of 10 cultivated amniocyte samples with Ts21 and 9 with normal euploid constitution were determined using expression microarrays. Datasets from Ts21 transcriptomic studies from GEO repository were incorporated. DEG were discovered using linear regression modelling and validated using RT-PCR quantification on an independent sample of 16 cases with Ts21 and 32 controls. The classification performance of Ts21 status based on expression profiling was performed using supervised machine learning algorithm and evaluated using a leave-one-out cross validation approach. Global gene expression profiling has revealed significant expression changes between normal and Ts21 samples, which in combination with data from previously performed Ts21 transcriptomic studies, were used to generate a multi-gene biomarker for Ts21, comprising of 9 gene expression profiles. In addition to biomarker's high performance in discriminating samples from global expression profiling, we were also able to show its discriminatory performance on a larger sample set 2, validated using RT-PCR experiment (AUC=0.97), while its performance on data from previously published studies reached discriminatory AUC values of 1.00. Our results show that transcriptomic changes might potentially be used to discriminate trisomy of chromosome 21 in the prenatal setting. As expressional alterations reflect both, causal and reactive cellular mechanisms, transcriptomic changes may thus have future potential in the diagnosis of a wide array of heterogeneous diseases that result from genetic disturbances. PMID- 24066118 TI - MicroRNA expression profile of mouse lung infected with 2009 pandemic H1N1 influenza virus. AB - MicroRNAs have been implicated in the regulation of gene expression of various biological processes in a post-transcriptional manner under physiological and pathological conditions including host responses to viral infections. The 2009 pandemic H1N1 influenza virus is an emerging reassortant strain of swine, human and bird influenza virus that can cause mild to severe illness and even death. To further understand the molecular pathogenesis of the 2009 pandemic H1N1 influenza virus, we profiled cellular microRNAs of lungs from BALB/c mice infected with wild-type 2009 pandemic influenza virus A/Beijing/501/2009 (H1N1) (hereafter referred to as BJ501) and mouse-adapted influenza virus A/Puerto Rico/8/1934 (H1N1) (hereafter referred to as PR8) for comparison. Microarray analysis showed both the influenza virus BJ501 and PR8 infection induced strain- and temporal specific microRNA expression patterns and that their infection caused a group of common and distinct differentially expressed microRNAs. Characteristically, more differentially expressed microRNAs were aroused on day 5 post infection than on day 2 and more up-regulated differentially expressed microRNAs were provoked than the down-regulated for both strains of influenza virus. Finally, 47 differentially expressed microRNAs were obtained for the infection of both strains of H1N1 influenza virus with 29 for influenza virus BJ501 and 43 for PR8. Among them, 15 microRNAs had no reported function, while 32 including miR-155 and miR-233 are known to play important roles in cancer, immunity and antiviral activity. Pathway enrichment analyses of the predicted targets revealed that the transforming growth factor-beta (TGF-beta) signaling pathway was the key cellular pathway associated with the differentially expressed miRNAs during influenza virus PR8 or BJ501 infection. To our knowledge, this is the first report of microRNA expression profiles of the 2009 pandemic H1N1 influenza virus in a mouse model, and our findings might offer novel therapy targets for influenza virus infection. PMID- 24066119 TI - Characterization of the molecular mechanism of the bone-anabolic activity of carfilzomib in multiple myeloma. AB - Carfilzomib, the next generation of proteasome inhibitor, may increase osteoblast related markers in patients with multiple myeloma, but the molecular mechanism of its effect on mesenchymal stem cell differentiation to osteoblasts remains unknown. Herein, we demonstrated that carfilzomib significantly promoted mesenchymal stem cell differentiation into osteoblasts. In osteoprogenitor cells and primary mesenchymal stem cells from patients with myeloma, carfilzomib induced increases in alkaline phosphatase activity, matrix mineralization, and calcium deposition via Wnt-independent activation of beta-catenin/TCF signaling. Using affinity pull-down assays with immunoblotting analysis and immunofluorescence, we found that carfilzomib induced stabilization of both free and active forms of beta-catenin in a time- and dose-dependent manner that was not associated with beta-catenin transcriptional regulation. Nuclear translocation of beta-catenin protein was associated with TCF transcriptional activity that was independent of the effects of GSK3beta-activation and of signaling induced by 19 Wnt ligands, 10 Frizzled receptors, and LRP5/6 co receptors. Blocking activation of beta-catenin/TCF signaling by dominant negative TCF1 or TCF4 attenuated carfilzomib-induced matrix mineralization. Thus, carfilzomib induced osteoblast differentiation via Wnt-independent activation of the beta-catenin/TCF pathway. These results provide a novel molecular mechanism critical to understanding the anabolic role of carfilzomib on myeloma-induced bone disease. PMID- 24066120 TI - Synergistic effect between amoxicillin and TLR ligands on dendritic cells from amoxicillin-delayed allergic patients. AB - Amoxicillin, a low-molecular-weight compound, is able to interact with dendritic cells inducing semi-maturation in vitro. Specific antigens and TLR ligands can synergistically interact with dendritic cells (DC), leading to complete maturation and more efficient T-cell stimulation. The aim of the study was to evaluate the synergistic effect of amoxicillin and the TLR2, 4 and 7/8 agonists (PAM, LPS and R848, respectively) in TLR expression, DC maturation and specific T cell response in patients with delayed-type hypersensitivity (DTH) reactions to amoxicillin. Monocyte-derived DC from 15 patients with DTH to amoxicillin and 15 controls were cultured with amoxicillin in the presence or absence of TLR2, 4 and 7/8 agonists (PAM, LPS and R848, respectively). We studied TLR1-9 gene expression by RT-qPCR, and DC maturation, lymphocyte proliferation and cytokine production by flow cytometry. DC from both patients and controls expressed all TLRs except TLR9. The amoxicillin plus TLR2/4 or TLR7/8 ligands showed significant differences, mainly in patients: AX+PAM+LPS induced a decrease in TLR2 and AX+R848 in TLR2, 4, 7 and 8 mRNA levels. AX+PAM+LPS significantly increased the percentage of maturation in patients (75%) vs. controls (40%) (p=0.036) and T cell proliferation (80.7% vs. 27.3% of cases; p=0.001). Moreover, the combinations AX+PAM+LPS and AX+R848 produced a significant increase in IL-12p70 during both DC maturation and T-cell proliferation. These results indicate that in amoxicillin-induced maculopapular exanthema, the presence of different TLR agonists could be critical for the induction of the innate and adaptive immune responses and this should be taken into account when evaluating allergic reactions to these drugs. PMID- 24066121 TI - Hydrophobic fluorescent probes introduce artifacts into single molecule tracking experiments due to non-specific binding. AB - Single-molecule techniques are powerful tools to investigate the structure and dynamics of macromolecular complexes; however, data quality can suffer because of weak specific signal, background noise and dye bleaching and blinking. It is less well-known, but equally important, that non-specific binding of probe to substrates results in a large number of immobile fluorescent molecules, introducing significant artifacts in live cell experiments. Following from our previous work in which we investigated glass coating substrates and demonstrated that the main contribution to this non-specific probe adhesion comes from the dye, we carried out a systematic investigation of how different dye chemistries influence the behaviour of spectrally similar fluorescent probes. Single-molecule brightness, bleaching and probe mobility on the surface of live breast cancer cells cultured on a non-adhesive substrate were assessed for anti-EGFR affibody conjugates with 14 different dyes from 5 different manufacturers, belonging to 3 spectrally homogeneous bands (491 nm, 561 nm and 638 nm laser lines excitation). Our results indicate that, as well as influencing their photophysical properties, dye chemistry has a strong influence on the propensity of dye-protein conjugates to adhere non-specifically to the substrate. In particular, hydrophobicity has a strong influence on interactions with the substrate, with hydrophobic dyes showing much greater levels of binding. Crucially, high levels of non-specific substrate binding result in calculated diffusion coefficients significantly lower than the true values. We conclude that the physic-chemical properties of the dyes should be considered carefully when planning single-molecule experiments. Favourable dye characteristics such as photostability and brightness can be offset by the propensity of a conjugate for non-specific adhesion. PMID- 24066122 TI - RNA-Seq analysis of Mycobacterium avium non-coding transcriptome. AB - Deep sequencing was implemented to study the transcriptional landscape of Mycobacterium avium. High-resolution transcriptome analysis identified the transcription start points for 652 genes. One third of these genes represented leaderless transcripts, whereas the rest of the transcripts had 5' UTRs with the mean length of 83 nt. In addition, the 5' UTRs of 6 genes contained SAM-IV and Ykok types of riboswitches. 87 antisense RNAs and 10 intergenic small RNAs were mapped. 6 intergenic small RNAs, including 4.5S RNA and rnpB, were transcribed at extremely high levels. Although several intergenic sRNAs are conserved in M. avium and M. tuberculosis, both of these species have unique intergenic sRNAs. Moreover, we demonstrated that even conserved small RNAs are regulated differently in these species. Different sets of intergenic sRNAs may underlie differences in physiology between conditionally pathogenic M. avium and highly specialized pathogen M. tuberculosis. PMID- 24066123 TI - Spatial and temporal variation in heterophil-to-lymphocyte ratios of nestling passerine birds: comparison of blue tits and great tits. AB - Environmental factors affecting trophic conditions act as stressors on nestling altricial birds. Access of parental birds to a sufficient supply of food in a limited period of the nestling stage differ in time and space, depending on nesting habitat, prey density and weather conditions. Heterophil-to-lymphocyte ratio (H/L) is considered as a reliable indicator of prolonged stress reaction in birds. In this study we examine if variation in H/L shows consistent spatio temporal patterns in nestlings of two parids, blue tit Cyanistes caeruleus and great tit Parus major. We found that blue tit nestlings had on average higher H/L than great tit nestlings, which corresponds with the ecological sensitivity of these species. In both species H/L was higher in a poor parkland habitat than in a high quality forest habitat. In nestling blue tits, higher H/L values occurred in years characterized by more extreme weather conditions and worse caterpillar availability. Such consistent patterns of variation in the H/L ratio of nestling blue tits and great tits suggest that, when age-dependent effects are controlled, the ratio can be used as an indicator of physiological stress that is generated by food-related stressors differing in space and time. In particular, elevated H/L ratios are indicative of human-induced changes in the structure of breeding habitats. PMID- 24066124 TI - Diets based on virgin olive oil or fish oil but not on sunflower oil prevent age related alveolar bone resorption by mitochondrial-related mechanisms. AB - BACKGROUND/OBJECTIVES: Aging enhances frequency of chronic diseases like cardiovascular diseases or periodontitis. Here we reproduced an age-dependent model of the periodontium, a fully physiological approach to periodontal conditions, to evaluate the impact of dietary fat type on gingival tissue of young (6 months old) and old (24 months old) rats. METHODS/FINDINGS: Animals were fed life-long on diets based on monounsaturated fatty acids (MUFA) as virgin olive oil, n-6 polyunsaturated fatty acids (n-6PUFA), as sunflower oil, or n 3PUFA, as fish oil. Age-related alveolar bone loss was higher in n-6PUFA fed rats, probably as a consequence of the ablation of the cell capacity to adapt to aging. Gene expression analysis suggests that MUFA or n-3PUFA allowed mitochondria to maintain an adequate turnover through induction of biogenesis, autophagy and the antioxidant systems, and avoiding mitochondrial electron transport system alterations. CONCLUSIONS: The main finding is that the enhanced alveolar bone loss associated to age may be targeted by an appropriate dietary treatment. The mechanisms involved in this phenomenon are related with an ablation of the cell capacity to adapt to aging. Thus, MUFA or n-3PUFA might allow mitochondrial maintaining turnover through biogenesis or autophagy. They might also be able to induce the corresponding antioxidant systems to counteract age-related oxidative stress, and do not inhibit mitochondrial electron transport chain. From the nutritional and clinical point of view, it is noteworthy that the potential treatments to attenuate alveolar bone loss (a feature of periodontal disease) associated to age could be similar to some of the proposed for the prevention and treatment of cardiovascular diseases, a group of pathologies recently associated with age-related periodontitis. PMID- 24066125 TI - Platelet-derived stromal cell-derived factor-1 is required for the transformation of circulating monocytes into multipotential cells. AB - BACKGROUND: We previously described a primitive cell population derived from human circulating CD14(+) monocytes, named monocyte-derived multipotential cells (MOMCs), which are capable of differentiating into mesenchymal and endothelial lineages. To generate MOMCs in vitro, monocytes are required to bind to fibronectin and be exposed to soluble factor(s) derived from circulating CD14(-) cells. The present study was conducted to identify factors that induce MOMC differentiation. METHODS: We cultured CD14(+) monocytes on fibronectin in the presence or absence of platelets, CD14(-) peripheral blood mononuclear cells, platelet-conditioned medium, or candidate MOMC differentiation factors. The transformation of monocytes into MOMCs was assessed by the presence of spindle shaped adherent cells, CD34 expression, and the potential to differentiate in vitro into mesenchymal and endothelial lineages. RESULTS: The presence of platelets or platelet-conditioned medium was required to generate MOMCs from monocytes. A screening of candidate platelet-derived soluble factors identified stromal cell-derived factor (SDF)-1 as a requirement for generating MOMCs. Blocking an interaction between SDF-1 and its receptor CXCR4 inhibited MOMC generation, further confirming SDF-1's critical role in this process. Finally, circulating MOMC precursors were found to reside in the CD14(+)CXCR4(high) cell population. CONCLUSION: The interaction of SDF-1 with CXCR4 is essential for the transformation of circulating monocytes into MOMCs. PMID- 24066126 TI - SurvExpress: an online biomarker validation tool and database for cancer gene expression data using survival analysis. AB - Validation of multi-gene biomarkers for clinical outcomes is one of the most important issues for cancer prognosis. An important source of information for virtual validation is the high number of available cancer datasets. Nevertheless, assessing the prognostic performance of a gene expression signature along datasets is a difficult task for Biologists and Physicians and also time consuming for Statisticians and Bioinformaticians. Therefore, to facilitate performance comparisons and validations of survival biomarkers for cancer outcomes, we developed SurvExpress, a cancer-wide gene expression database with clinical outcomes and a web-based tool that provides survival analysis and risk assessment of cancer datasets. The main input of SurvExpress is only the biomarker gene list. We generated a cancer database collecting more than 20,000 samples and 130 datasets with censored clinical information covering tumors over 20 tissues. We implemented a web interface to perform biomarker validation and comparisons in this database, where a multivariate survival analysis can be accomplished in about one minute. We show the utility and simplicity of SurvExpress in two biomarker applications for breast and lung cancer. Compared to other tools, SurvExpress is the largest, most versatile, and quickest free tool available. SurvExpress web can be accessed in http://bioinformatica.mty.itesm.mx/SurvExpress (a tutorial is included). The website was implemented in JSP, JavaScript, MySQL, and R. PMID- 24066127 TI - Heterozygous and homozygous JAK2(V617F) states modeled by induced pluripotent stem cells from myeloproliferative neoplasm patients. AB - JAK2(V617F) is the predominant mutation in myeloproliferative neoplasms (MPN). Modeling MPN in a human context might be helpful for the screening of molecules targeting JAK2 and its intracellular signaling. We describe here the derivation of induced pluripotent stem (iPS) cell lines from 2 polycythemia vera patients carrying a heterozygous and a homozygous mutated JAK2(V617F), respectively. In the patient with homozygous JAK2(V617F), additional ASXL1 mutation and chromosome 20 allowed partial delineation of the clonal architecture and assignation of the cellular origin of the derived iPS cell lines. The marked difference in the response to erythropoietin (EPO) between homozygous and heterozygous cell lines correlated with the constitutive activation level of signaling pathways. Strikingly, heterozygous iPS cells showed thrombopoietin (TPO)-independent formation of megakaryocytic colonies, but not EPO-independent erythroid colony formation. JAK2, PI3K and HSP90 inhibitors were able to block spontaneous and EPO induced growth of erythroid colonies from GPA(+)CD41(+) cells derived from iPS cells. Altogether, this study brings the proof of concept that iPS can be used for studying MPN pathogenesis, clonal architecture, and drug efficacy. PMID- 24066128 TI - Identification of the plant compound geraniin as a novel Hsp90 inhibitor. AB - Besides its function in normal cellular growth, the molecular chaperone heat shock protein 90 (Hsp90) binds to a large number of client proteins required for promoting cancer cell growth and/or survival. In an effort to discover new small molecules able to inhibit the Hsp90 ATPase and chaperoning activities, we screened, by a surface plasmon resonance assay, a small library including different plant polyphenols. The ellagitannin geraniin, was identified as the most promising molecule, showing a binding affinity to Hsp90alpha similar to that of 17-(allylamino)-17-demethoxygeldanamycin (17AGG). Geraniin was able to inhibit in vitro the Hsp90alpha ATPase activity in a dose-dependent manner, with an inhibitory efficiency comparable to that measured for 17-AAG. In addition, this compound compromised the chaperone activity of Hsp90alpha, monitored by the citrate synthase thermal induced aggregation assay. Geraniin decreased the viability of HeLa and Jurkat cell lines and caused an arrest in G2/M phase. We also proved that following exposure to different concentrations of geraniin, the level of expression of the client proteins c-Raf, pAkt, and EGFR was strongly down-regulated in both the cell lines. These results, along with the finding that geraniin did not exert any appreciable cytotoxicity on normal cells, encourage further studies on this compound as a promising chemical scaffold for the design of new Hsp90 inhibitors. PMID- 24066129 TI - Genetic structure of Lutzomyia longipalpis populations in Mato Grosso Do Sul, Brazil, based on microsatellite markers. AB - BACKGROUND: Lutzomyialongipalpis (Diptera: Psychodidae) is the major vector of Leishmania (Leishmania) infantum and thus plays a crucial role in the epidemiology of American visceral leishmaniasis (AVL). This vector is the best studied species of sand fly in the Neotropical region. Many studies claim that this vector is in fact a species complex; however there is still no consensus regarding the number of species that belong into this complex or the geographical distribution of sibling species. The aim of the present study was to analyze the genetic relationships within Lu. longipalpis populations in the state of Mato Grosso do Sul (MS), Brazil. METHODOLOGY/PRINCIPAL FINDINGS: We collected 30 Lu. longipalpis (15 females and 15 males) from five localities (Campo Grande, Tres Lagoas, Aquidauana, Miranda and Bonito) and 30 Lu. Cruzi from Corumba, totaling 180 sandflies from MS, and 30 Lu. longipalpis from Estrela de Alagoas, state of Alagoas (AL), Northeast Brazil. We show that eight previously described microsatellite loci were sufficient in distinguishing Lu. longipalpis from Lu. Cruzi, which is a closely related species, and in differentiating between Lu. longipalpis collected in MS versus Estrela de Alagoas. Analyses of the genotypes revealed introgression between sympatric Lu. longipalpis and Lu. Cruzi. CONCLUSIONS/SIGNIFICANCE: Our findings support the hypothesis of cryptic species within the Lu. longipalpis complex. Furthermore, our data revealed introgression between Lu. longipalpis and Lu. cruzi. This phenomenon should be further investigated to determine the level and incidence of hybridization between these two species. We also demonstrated that microsatellite markers are a powerful tool for differentiating sand fly populations and species. The present study has elucidated the population structure of Lu. longipalpis in MS and, by extension, the Neotropical Lu. longipalpis complex itself. PMID- 24066130 TI - Mammographic assessment of a geographically defined population at a mastology referral hospital in Sao Paulo Brazil. AB - OBJECTIVE: To evaluate the results of screening and diagnostic mammography in a geographically defined population attending a regional mastology referral hospital of the State Public Service of Sao Paulo. METHODS: A total of 7508 women, who received screening or diagnostic mammography examinations from 06/2004 to 06/2005, with follow-up until 06/2006, were included in this study. Data corresponding to age, the Breast Imaging-Reporting and Data System (BI-RADS), biopsy, surgery and the stage of breast cancer were collected. Five-year survival of patients with breast cancer was posteriorly calculated during this period. RESULTS: This study included a total of 713 diagnostic and 6795 screening mammograms. The average age of the population was 51.2 years, with a BI-RADS end result of 4 and 5 (abnormal) in 1.9% of the screening and 11.4% of the diagnostic mammograms, respectively. All BI-RADS category zero was complemented. Of the 228 nonsurgical biopsies performed (71 CNB, 94 mammotomy and 63 FNAB), 63 (27.6%) biopsies were malignant findings. Among the 33 surgical biopsies, 10 (30.3%) biopsies were malignant findings, and of the 82 surgeries, 55 (67, 1%) procedures showed malignant findings. Seventy-one (0.9%) breast cancers (25/6795 on screening exams and 46/713 on diagnostics) were diagnosed. A total of 28.6% small cancers (<= 10 mm) were observed, with 27% of the cancers in stages zero and I. Approximately 47.6% of the cases showed nodal invasion, and 4.5% of cases were not staged. Overall detection rate of breast cancer was 8.8/1000 (3.2/1000 screening and 61.7/1000 diagnostic). The overall 5-year survival rate of patients with breast cancer in this population was 79.1%. CONCLUSION: Survival is a key index of the overall effectiveness of health services in the management of patients with cancer. Our results suggest that this approach is feasible and can potentially improve breast cancer outcomes for many women in Sao Paulo. PMID- 24066131 TI - Sinomenine suppresses osteoclast formation and Mycobacterium tuberculosis H37Ra induced bone loss by modulating RANKL signaling pathways. AB - Receptor activator of NF-kappaB ligand (RANKL) is essential for osteoclastogenesis. Targeting RANKL signaling pathways has been an encouraging strategy for treating lytic bone diseases such as osteoporosis and rheumatoid arthritis (RA). Sinomenine (SIN), derived from Chinese medicinal plant Sinomenioumacutum, is an active compound to treat RA, but its effect on osteoclasts has been hitherto unknown. In the present study, SIN was found to ameliorate M. tuberculosis H37Ra (Mt)-induced bone loss in rats with a decreased serum level of TRACP5b and RANKL, and an increased level of osteoprotegerin (OPG). In vitro study also showed that SIN could inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, MMP-9, TRACP were inhibited by SIN in a dose dependent manner. Signal transduction studies showed that SIN could obviously reduce the expression of RANK adaptor molecule TRAF6 and down-regulate RANKL-induced NF kappaB activation. It decreased the RANKL-induced p38, JNK posphorylation but not ERK1/2 posphorylation. SIN could also reduce RANKL-mediated calcium influx which is associated with TRAF6/c-Src complex. Finally, SIN suppressed RANKL induced AP 1 and NFAT transcription, as well as the gene expression of NFATc1 and AP-1 components (Fra-1, Fra-2, c-Fos). The protein expression of c-Fos and TRAF6 were also inhibited by SIN after RANKL stimulation. Taken together, SIN could attenuate osteoclast formation and Mt-induced bone loss by mediating RANKL signaling pathways. PMID- 24066132 TI - Persistence of structural changes at the anterior cornea in bullous keratopathy patients after endothelial keratoplasty. AB - Subepithelial fibrosis (SEF) and the transdifferentiation of keratocytes into fibroblasts or myofibroblasts (Fbs/MFbs) have been detected in the cornea of individuals with bullous keratopathy. We examined the anterior cornea of bullous keratopathy patients for such changes after Descemet's stripping automated endothelial keratoplasty (DSAEK). Twenty-two individuals who underwent unilateral DSAEK at Yamaguchi University Hospital were enrolled in the study. The subjects were divided into groups A (n = 10) and B (n = 12) with a preoperative duration of stromal edema of less than or at least 12 months, respectively. The structure of the anterior stroma was examined by in vivo laser confocal microscopy at various times after surgery. SEF was detected in 1 (10.0%) and 11 (91.7%) cases in groups A and B, respectively, before surgery as well as in 0 (0%) and 7 (58.3%) cases, respectively, at 6 months after DSAEK. Fb/MFb transdifferentiation was detected in 0 (0%) and 8 (66.7%) cases in groups A and B, respectively, before surgery as well as in 0 and 1 (8.3%) case, respectively, at 6 months postsurgery. Anterior stromal scattering (ASS) was detected in 10 (100%) and 12 (100%) cases in groups A and B, respectively, before surgery as well as in 0 (0%) and 6 (50.0%) cases, respectively, at 6 months after DSAEK. Changes in anterior stromal structure apparent before surgery were thus also detected in bullous keratopathy patients after DSAEK. SEF and ASS persisted for more than 6 months in a substantial proportion of individuals with a preoperative duration of stromal edema of at least 12 months. PMID- 24066133 TI - Molecular characterization of RXR (Retinoid X Receptor) gene isoforms from the bivalve species Chlamys farreri. AB - BACKGROUND: Bivalves are among the oldest classes of invertebrates, and they exhibit diverse types of sexual patterning. However, our current understanding of the mechanisms of sex determination and differentiation in bivalves remains very limited. The retinoid X receptors (RXRs), which are members of the nuclear receptor family, are involved in sex differentiation in many organisms. RESULTS: In the present study, four full-length RXR-encoding cDNAs (CfRXRs) named CfRXRa, CfRXRb, CfRXRc and CfRXRd were retrieved from Zhikong scallop (Chlamys farreri). The four RXRs exhibited the conserved five-domain structure of nuclear receptor superfamily members and differed from each other only in the T-box of the C domain. The three variants, designated T (+4), T (+20) and T (+24), contained insertions of 4, 20 and 24 amino acids, respectively. The entire CfRXR gene is composed of eight exons and seven introns, and the four isoforms are generated via alternative mRNA splicing. Expression analysis showed that all four isoforms were expressed in both the testis and the ovary during the differentiation stage, whereas no expression was detected in the growth, mature or resting stages. This result suggests that CfRXRs are involved in germ cell differentiation in both sexes. The expression of the four isoforms was also detected in other tissues examined, including mantle, gill, digestive gland, and adductor muscle of sexually mature male and female Zhikong scallops, implying the multiple biological functions of CfRXRs. CONCLUSION: Our study presents the first report of RXR isoforms in bivalves. Further investigation of the functional roles of different RXR isoforms may provide deep insights into the regulatory mechanism of sex differentiation in C. farreri. PMID- 24066134 TI - Epigenetic induction of EGR-1 expression by the amyloid precursor protein during exposure to novelty. AB - Following transcriptome comparison of primary cultures isolated from brain of mice expressing or not the amyloid precursor protein APP, we found transcription of the EGR-1 gene to be regulated by APP. In primary cultures of cortical neurons, APP significantly down regulated EGR-1 expression at both mRNA and protein levels in a gamma-secretase independent manner. The intracellular domain of APP did not interact with EGR-1 gene promoter, but enrichment of acetylated histone H4 at the EGR-1 promoter region was measured in APP-/- neurons, as well as in brain of APP-/- mice, in which increase in EGR-1 expression was also measured. These results argue for an important function of APP in the epigenetic regulation of EGR-1 gene transcription both in vitro and in vivo. In APP-/- mice, constitutive overexpression of EGR-1 in brain impaired epigenetic induction of this early transcriptional regulator during exposure to novelty. Altogether, these results indicate an important function of APP in the epigenetic regulation of the transcription of EGR-1, known to be important for memory formation. PMID- 24066135 TI - Sox6 up-regulation by macrophage migration inhibitory factor promotes survival and maintenance of mouse neural stem/progenitor cells. AB - Macrophage migration inhibitory factor (MIF) has important roles in supporting the proliferation and/or survival of murine neural stem/progenitor cells (NSPCs), but downstream effectors remain unknown. We show here that MIF robustly increases the expression of Sox6 in NSPCs in vitro. During neural development, Sox6 is expressed in the ventricular zone of the ganglionic eminence (GE) of mouse brains at embryonic day 14.5 (E14.5), cultured NSPCs from E14.5 GE, and NSPCs in the subventricular zone (SVZ) around the lateral ventricle (LV) of the adult mouse forebrain. Retroviral overexpression of Sox6 in NSPCs increases the number of primary and secondary neurospheres and inhibits cell differentiation. This effect is accompanied with increased expression of Hes1 and Bcl-2 and Akt phosphorylation, thus suggesting a role for Sox6 in promoting cell survival and/or self-renewal ability. Constitutive activation of the transcription factor Stat3 results in up-regulation of Sox6 expression and chromatin immunoprecipitation analysis showed that MIF increases Stat3 binding to the Sox6 promoter in NSPCs, indicating that Stat3 stimulates Sox6 expression downstream of MIF. Finally, the ability of MIF to increase the number of primary and secondary neurospheres is inhibited by Sox6 gene silencing. Collectively, our data identify Sox6 as an important downstream effector of MIF signaling in stemness maintenance of NSPCs. PMID- 24066136 TI - Danshen (Salvia miltiorrhiza) injection suppresses kidney injury induced by iron overload in mice. AB - OBJECTIVES: Excessive iron can accumulate in the kidney and induce tissue damage. Danshen (Salvia miltiorrhiza) injection is a traditional Chinese medicinal preparation used for preventing and treating chronic renal failure. The aim of the present study was to evaluate the effects of treatment with Danshen injection on iron overload-induced kidney damage. METHODS: Mice were mock-treated with saline (control group) or given a single dose of iron dextran without treatment (iron overload group, 50 mg/kg/day for 2 weeks) or with daily treatments of low dose Danshen (3 g/kg/day), high-dose Danshen (6 g/kg/day) or deferoxamine (100 mg/kg/day). RESULTS: Treatment of iron-overloaded mice with Danshen injection led to significant improvements of body weight and decreased iron levels in the kidney. Danshen injection treatment also reduced concentrations of blood urea nitrogen, creatinine and malondialdehyde and enhanced glutathione peroxidase and superoxide dismutase activities. Histopathological examinations showed that Danshen injection ameliorated pathological changes and reduced iron deposition in kidneys of iron overloaded mice. Furthermore, the treatment was demonstrated to suppress apoptosis in nephrocytes. CONCLUSIONS: These results indicated that Danshen injection exerted significant renal protective effects in iron-overloaded mice, which were closely associated with the decrease of iron deposition and suppression of lipid peroxidation and apoptosis in the kidney. PMID- 24066137 TI - Age-related characteristics of multipotent human nasal inferior turbinate-derived mesenchymal stem cells. AB - BACKGROUND AND OBJECTIVES: Multipotent mesenchymal stem cells (MSCs) represent a promising cell-based therapy for a number of degenerative conditions. Understanding the effect of aging on MSCs is crucial for both autologous therapy development and allogenic donors in older subjects whom degenerative diseases typically afflict. In this study, we investigated the influence of donor age on the characteristics, proliferation, and differentiation potential of in vitro cultures of multipotent human turbinated mesenchymal stem cells (hTMSCs) from patients of various age groups. SUBJECTS AND METHODS: Twelve patients comprised the four age groups: (I) <20 years, (II) 20-39 years, (III) 40-59 years, and (IV) >60 years. Inferior turbinate tissues were discarded from patients undergoing partial turbinectomy. After isolating hTMSCs, the expression of the hTMSC surface markers CD14, CD19, CD34, CD73, CD90, CD105, and HLA-DR was assessed by FACS analysis, and cell proliferation was assessed using a cell counting kit (CCK)-8. The differentiation potential of hTMSCs was evaluated in osteogenic media by histology and determination of osteoblastic gene expression. RESULTS: FACS analysis revealed that hTMSCs were negative for CD14, CD19, CD34, and HLA-DR, and positive for CD73, CD90, and CD105, representing a characteristic MSC phenotype, and showed no significant differences among the age groups. Cellular proliferation and osteogenic differentiation potential of hTMSCs also showed no significant differences among the age groups. CONCLUSIONS: We conclude that donor age does not affect the characteristics, proliferation, and osteogenic differentiation potential of hTMSCs. Donor age may be excluded as a criterion in the guidelines for clinical use of the autologous or allogenic transplantation of hTMSCs. PMID- 24066138 TI - Disentangling how landscape spatial and temporal heterogeneity affects Savanna birds. AB - In highly seasonal tropical environments, temporal changes in habitat and resources are a significant determinant of the spatial distribution of species. This study disentangles the effects of spatial and mid to long-term temporal heterogeneity in habitat on the diversity and abundance of savanna birds by testing four competing conceptual models of varying complexity. Focussing on sites in northeast Australia over a 20 year time period, we used ground cover and foliage projected cover surfaces derived from a time series of Landsat Thematic Mapper imagery, rainfall data and site-level vegetation surveys to derive measures of habitat structure at local (1-100 ha) and landscape (100-1000s ha) scales. We used generalised linear models and an information theoretic approach to test the independent effects of spatial and temporal influences on savanna bird diversity and the abundance of eight species with different life-history behaviours. Of four competing models defining influences on assemblages of savanna birds, the most parsimonious included temporal and spatial variability in vegetation cover and site-scale vegetation structure, suggesting savanna bird species respond to spatial and temporal habitat heterogeneity at both the broader landscape scale and at the fine-scale. The relative weight, strength and direction of the explanatory variables changed with each of the eight species, reflecting their different ecology and behavioural traits. This study demonstrates that variations in the spatial pattern of savanna vegetation over periods of 10 to 20 years at the local and landscape scale strongly affect bird diversity and abundance. Thus, it is essential to monitor and manage both spatial and temporal variability in avian habitat to achieve long-term biodiversity outcomes. PMID- 24066139 TI - Prolonged glycation of hen egg white lysozyme generates non amyloidal structures. AB - Glycation causes severe damage to protein structure that could lead to amyloid formation in special cases. Here in this report, we have shown for the first time that hen egg white lysozyme (HEWL) does not undergo amyloid formation even after prolonged glycation in the presence of D-glucose, D-fructose and D-ribose. Cross linked oligomers were formed in all the cases and ribose was found to be the most potent among the three sugars. Ribose mediated oligomers, however, exhibit Thioflavin T binding properties although microscopic images clearly show amorphous and globular morphology of the aggregates. Our study demonstrates that the structural damage of hen egg white lysozyme due to glycation generates unstructured aggregates. PMID- 24066140 TI - Common genetic variation near MC4R has a sex-specific impact on human brain structure and eating behavior. AB - Obesity is associated with genetic and environmental factors but the underlying mechanisms remain poorly understood. Recent genome-wide association studies (GWAS) identified obesity- and type 2 diabetes-associated genetic variants located within or near genes that modulate brain activity and development. Among the top hits is rs17782313 near MC4R, encoding for the melanocortin-4-receptor, which is expressed in brain regions that regulate eating. Here, we hypothesized rs17782313-associated changes in human brain regions that regulate eating behavior. Therefore, we examined effects of common variants at rs17782313 near MC4R on brain structure and eating behavior. Only in female homozygous carriers of the risk allele we found significant increases of gray matter volume (GMV) in the right amygdala, a region known to influence eating behavior, and the right hippocampus, a structure crucial for memory formation and learning. Further, we found bilateral increases in medial orbitofrontal cortex, a multimodal brain structure encoding the subjective value of reinforcers, and bilateral prefrontal cortex, a higher order regulation area. There was no association between rs17782313 and brain structure in men. Moreover, among female subjects only, we observed a significant increase of 'disinhibition', and, more specifically, on 'emotional eating' scores of the Three Factor Eating Questionnaire in carriers of the variant rs17782313's risk allele. These findings suggest that rs17782313's effect on eating behavior is mediated by central mechanisms and that these effects are sex-specific. PMID- 24066141 TI - The clinical application of one-stop examination with 640-slice volume CT for Nutcracker syndrome. AB - BACKGROUND: To investigate the relationship between the level of left renal vein (LRV) compression and changes in the perfusion of the left kidney in patients with nutcracker syndrome (NCS) by one-stop whole-organ perfusion imaging of bilateral kidneys using 640-slice volume CT. METHODS: Twelve patients, clinically diagnosed with NCS, were subjected to one-stop examination of kidneys. Angiography and whole-organ perfusion imaging of bilateral kidneys were conducted, and the compression segment of LRV was demonstrated and measured. Information including the results of whole-organ perfusion images of both kidneys in 12 patients was collected. Results of epigastrium dynamic volume scanning by 640-slice volume CT were collected for 12 patients as control group. Left and right renal cortexes were chosen as regions of interest (ROI), and their perfusion values were measured. RESULTS: The perfusion values of the left and right renal cortexes in the control group were 323.8 ml . min(-1) . 100 ml(-1) and 322.9 ml . min(-1) . 100 ml(-1), respectively. The difference was not statistically significant (t = 1.388, P = 0.193). For NCS patients, the perfusion values of the left and right renal cortexes were 350.8 ml . min(-1) . 100 ml(-1) and 391.1 ml . min(-1) . 100 ml(-1), respectively. Significantly decreased value was observed in left renal cortex compared to that of the right renal cortex, with the mean decrease of 40.3 ml . min(-1) . 100 ml(-1), and the difference was statistically significant (t = -4.204, P = 0.001). CONCLUSION: As a non-invasive functional imaging technique, whole-organ perfusion imaging of kidneys can be used to evaluate the organ and tissue perfusion status and to accurately reflect the hemodynamic changes of the left renal cortex in the patients with NCS. Whole organ perfusion imaging may also provide the basis for quantitative diagnosis and clinical interventions of NCS. PMID- 24066142 TI - Another brick in the cell wall: biosynthesis dependent growth model. AB - Expansive growth of plant cell is conditioned by the cell wall ability to extend irreversibly. This process is possible if (i) a tensile stress is developed in the cell wall due to the coupling effect between turgor pressure and the modulation of its mechanical properties through enzymatic and physicochemical reactions and if (ii) new cell wall elements can be synthesized and assembled to the existing wall. In other words, expansive growth is the result of coupling effects between mechanical, thermal and chemical energy. To have a better understanding of this process, models must describe the interplay between physical or mechanical variable with biological events. In this paper we propose a general unified and theoretical framework to model growth in function of energy forms and their coupling. This framework is based on irreversible thermodynamics. It is then applied to model growth of the internodal cell of Chara corallina modulated by changes in pressure and temperature. The results describe accurately cell growth in term of length increment but also in term of cell pectate biosynthesis and incorporation to the expanding wall. Moreover, the classical growth model based on Lockhart's equation such as the one proposed by Ortega, appears as a particular and restrictive case of the more general growth equation developed in this paper. PMID- 24066143 TI - Residential radon and brain tumour incidence in a Danish cohort. AB - BACKGROUND: Increased brain tumour incidence over recent decades may reflect improved diagnostic methods and clinical practice, but remain unexplained. Although estimated doses are low a relationship between radon and brain tumours may exist. OBJECTIVE: To investigate the long-term effect of exposure to residential radon on the risk of primary brain tumour in a prospective Danish cohort. METHODS: During 1993-1997 we recruited 57,053 persons. We followed each cohort member for cancer occurrence from enrolment until 31 December 2009, identifying 121 primary brain tumour cases. We traced residential addresses from 1 January 1971 until 31 December 2009 and calculated radon concentrations at each address using information from central databases regarding geology and house construction. Cox proportional hazards models were used to estimate incidence rate-ratios (IRR) and 95% confidence intervals (CI) for the risk of primary brain tumours associated with residential radon exposure with adjustment for age, sex, occupation, fruit and vegetable consumption and traffic-related air pollution. Effect modification by air pollution was assessed. RESULTS: Median estimated radon was 40.5 Bq/m(3). The adjusted IRR for primary brain tumour associated with each 100 Bq/m(3) increment in average residential radon levels was 1.96 (95% CI: 1.07; 3.58) and this was exposure-dependently higher over the four radon exposure quartiles. This association was not modified by air pollution. CONCLUSIONS: We found significant associations and exposure-response patterns between long-term residential radon exposure radon in a general population and risk of primary brain tumours, adding new knowledge to this field. This finding could be chance and needs to be challenged in future studies. PMID- 24066145 TI - Patient navigation and time to diagnostic resolution: results for a cluster randomized trial evaluating the efficacy of patient navigation among patients with breast cancer screening abnormalities, Tampa, FL. AB - OBJECTIVES: The objective of this study was to evaluate a patient navigation (PN) program that attempts to reduce the time between a breast cancer screening abnormality and definitive diagnosis among medically underserved populations of Tampa Bay, Florida. METHODS: The Moffitt Patient Navigation Research Program conducted a cluster randomized design with 10 primary care clinics. Patients were navigated from time of a breast screening abnormality to diagnostic resolution. This paper examined the length of time between breast abnormality and definitive diagnosis, using a shared frailty Cox proportional hazard model to assess PN program effect. RESULTS: 1,039 patients were eligible for the study because of an abnormal breast cancer screening/clinical abnormality (494 navigated; 545 control). Analysis of PN effect by two time periods of resolution (0-3 months and > 3 months) showed a lagged effect of PN. For patients resolving in the first three months, the adjusted Hazard Ratio (aHR) was 0.85 (95% Confidence Interval [CI]: 0.64-1.13) suggesting that PN had no effect on resolution time during this period. Beyond three months, however, navigated patients resolved more quickly to diagnostic resolution compared with the control group (aHR 2.8, 95%CI: 1.30 6.13). The predicted aHR at 3 months was 1.2, which was not statistically significant, while PN had a significant positive effect beyond 4.7 months. CONCLUSIONS: PN programs may increase the timeliness of diagnostic resolution for patients with a breast cancer-related abnormality. PN did not speed diagnostic resolution during the initial three months of follow up but started to reduce time to diagnostic resolution after three months and showed a significant effect after 4.7 months. TRIAL REGISTRATION: ClinicalTrials.gov NCT00375024. PMID- 24066144 TI - Proteomic amino-termini profiling reveals targeting information for protein import into complex plastids. AB - In organisms with complex plastids acquired by secondary endosymbiosis from a photosynthetic eukaryote, the majority of plastid proteins are nuclear-encoded, translated on cytoplasmic ribosomes, and guided across four membranes by a bipartite targeting sequence. In-depth understanding of this vital import process has been impeded by a lack of information about the transit peptide part of this sequence, which mediates transport across the inner three membranes. We determined the mature N-termini of hundreds of proteins from the model diatom Thalassiosira pseudonana, revealing extensive N-terminal modification by acetylation and proteolytic processing in both cytosol and plastid. We identified 63 mature N-termini of nucleus-encoded plastid proteins, deduced their complete transit peptide sequences, determined a consensus motif for their cleavage by the stromal processing peptidase, and found evidence for subsequent processing by a plastid methionine aminopeptidase. The cleavage motif differs from that of higher plants, but is shared with other eukaryotes with complex plastids. PMID- 24066146 TI - Automatic visual tracking and social behaviour analysis with multiple mice. AB - Social interactions are made of complex behavioural actions that might be found in all mammalians, including humans and rodents. Recently, mouse models are increasingly being used in preclinical research to understand the biological basis of social-related pathologies or abnormalities. However, reliable and flexible automatic systems able to precisely quantify social behavioural interactions of multiple mice are still missing. Here, we present a system built on two components. A module able to accurately track the position of multiple interacting mice from videos, regardless of their fur colour or light settings, and a module that automatically characterise social and non-social behaviours. The behavioural analysis is obtained by deriving a new set of specialised spatio temporal features from the tracker output. These features are further employed by a learning-by-example classifier, which predicts for each frame and for each mouse in the cage one of the behaviours learnt from the examples given by the experimenters. The system is validated on an extensive set of experimental trials involving multiple mice in an open arena. In a first evaluation we compare the classifier output with the independent evaluation of two human graders, obtaining comparable results. Then, we show the applicability of our technique to multiple mice settings, using up to four interacting mice. The system is also compared with a solution recently proposed in the literature that, similarly to us, addresses the problem with a learning-by-examples approach. Finally, we further validated our automatic system to differentiate between C57B/6J (a commonly used reference inbred strain) and BTBR T+tf/J (a mouse model for autism spectrum disorders). Overall, these data demonstrate the validity and effectiveness of this new machine learning system in the detection of social and non-social behaviours in multiple (>2) interacting mice, and its versatility to deal with different experimental settings and scenarios. PMID- 24066147 TI - A novel electronic data collection system for large-scale surveys of neglected tropical diseases. AB - BACKGROUND: Large cross-sectional household surveys are common for measuring indicators of neglected tropical disease control programs. As an alternative to standard paper-based data collection, we utilized novel paperless technology to collect data electronically from over 12,000 households in Ethiopia. METHODOLOGY: We conducted a needs assessment to design an Android-based electronic data collection and management system. We then evaluated the system by reporting results of a pilot trial and from comparisons of two, large-scale surveys; one with traditional paper questionnaires and the other with tablet computers, including accuracy, person-time days, and costs incurred. PRINCIPLE FINDINGS: The electronic data collection system met core functions in household surveys and overcame constraints identified in the needs assessment. Pilot data recorders took 264 (standard deviation (SD) 152 sec) and 260 sec (SD 122 sec) per person registered to complete household surveys using paper and tablets, respectively (P = 0.77). Data recorders felt a lack of connection with the interviewee during the first days using electronic devices, but preferred to collect data electronically in future surveys. Electronic data collection saved time by giving results immediately, obviating the need for double data entry and cross-correcting. The proportion of identified data entry errors in disease classification did not differ between the two data collection methods. Geographic coordinates collected using the tablets were more accurate than coordinates transcribed on a paper form. Costs of the equipment required for electronic data collection was approximately the same cost incurred for data entry of questionnaires, whereas repeated use of the electronic equipment may increase cost savings. CONCLUSIONS/SIGNIFICANCE: Conducting a needs assessment and pilot testing allowed the design to specifically match the functionality required for surveys. Electronic data collection using an Android-based technology was suitable for a large-scale health survey, saved time, provided more accurate geo-coordinates, and was preferred by recorders over standard paper-based questionnaires. PMID- 24066148 TI - Inactivated ORF virus shows antifibrotic activity and inhibits human hepatitis B virus (HBV) and hepatitis C virus (HCV) replication in preclinical models. AB - Inactivated orf virus (iORFV), strain D1701, is a potent immune modulator in various animal species. We recently demonstrated that iORFV induces strong antiviral activity in animal models of acute and chronic viral infections. In addition, we found D1701-mediated antifibrotic effects in different rat models of liver fibrosis. In the present study, we compare iORFV derived from two different strains of ORFV, D1701 and NZ2, respectively, with respect to their antifibrotic potential as well as their potential to induce an antiviral response controlling infections with the hepatotropic pathogens hepatitis C virus (HCV) and hepatitis B virus (HBV). Both strains of ORFV showed anti-viral activity against HCV in vitro and against HBV in a transgenic mouse model without signs of necro inflammation in vivo. Our experiments suggest that the absence of liver damage is potentially mediated by iORFV-induced downregulation of antigen cross presentation in liver sinus endothelial cells. Furthermore, both strains showed significant anti-fibrotic activity in rat models of liver fibrosis. iORFV strain NZ2 appeared more potent compared to strain D1701 with respect to both its antiviral and antifibrotic activity on the basis of dosages estimated by titration of active virus. These results show a potential therapeutic approach against two important human liver pathogens HBV and HCV that independently addresses concomitant liver fibrosis. Further studies are required to characterize the details of the mechanisms involved in this novel therapeutic principle. PMID- 24066149 TI - Regulation of the F11, Klkb1, Cyp4v3 gene cluster in livers of metabolically challenged mice. AB - Single nucleotide polymorphisms (SNPs) in a 4q35.2 locus that harbors the coagulation factor XI (F11), prekallikrein (KLKB1), and a cytochrome P450 family member (CYP4V2) genes are associated with deep venous thrombosis (DVT). These SNPs exert their effect on DVT by modifying the circulating levels of FXI. However, SNPs associated with DVT were not necessarily all in F11, but also in KLKB1 and CYP4V2. Here, we searched for evidence for common regulatory elements within the 4q35.2 locus, outside the F11 gene, that might control FXI plasma levels and/or DVT risk. To this end, we investigated the regulation of the orthologous mouse gene cluster under several metabolic conditions that impact mouse hepatic F11 transcription. In livers of mice in which HNF4alpha, a key transcription factor controlling F11, was ablated, or reduced by siRNA, a strong decrease in hepatic F11 transcript levels was observed that correlated with Cyp4v3 (mouse orthologue of CYP4V2), but not by Klkb1 levels. Estrogens induced hepatic F11 and Cyp4v3, but not Klkb1 transcript levels, whereas thyroid hormone strongly induced hepatic F11 transcript levels, and reduced Cyp4v3, leaving Klkb1 levels unaffected. Mice fed a high-fat diet also had elevated F11 transcription, markedly paralleled by an induction of Klkb1 and Cyp4v3 expression. We conclude that within the mouse F11, Klkb1, Cyp4v3 gene cluster, F11 and Cyp4v3 frequently display striking parallel transcriptional responses suggesting the presence of shared regulatory elements. PMID- 24066150 TI - Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-alpha and chemokine production by human lung parenchyma. AB - BACKGROUND: Roflumilast is the first phosphodiesterase-4 (PDE4) inhibitor to have been approved for the treatment of COPD. The anti-inflammatory profile of PDE4 inhibitors has not yet been explored in human lung tissues. We investigated the effects of roflumilast and its active metabolite roflumilast-N-oxide on the lipopolysaccharide (LPS)-induced release of tumor necrosis factor-alpha (TNF alpha) and chemokines by human lung parenchymal explants. We also investigated roflumilast's interaction with the long-acting beta2-agonist formoterol. METHODS: Explants from 25 patients undergoing surgical lung resection were incubated with Roflumilast, Roflumilast-N-oxide and formoterol and stimulated with LPS. Levels of TNF-alpha, chemokines (in the culture supernatants) and cyclic adenosine monophosphate (in tissue homogenates) were determined with appropriate immunoassays. RESULTS: Roflumilast and Roflumilast-N-oxide concentration dependently reduced the release of TNF-alpha and chemokines CCL2, CCL3, CCL4, CXCL9 and CXCL10 from LPS-stimulated human lung explants, whereas CXCL1, CXCL5 and CXCL8 release was not altered. Formoterol (10 nM) partially decreased the release of the same cytokines and significantly increased the inhibitory effect of roflumilast on the release of the cytokines. CONCLUSIONS: In human lung parenchymal explants, roflumilast and roflumilast-N-oxide reduced the LPS-induced release of TNF-alpha and chemokines involved in the recruitment of monocytes and T-cells but not those involved in the recruitment of neutrophils. Addition of formoterol to roflumilast provided superior in vitro anti-inflammatory activity, which may translate into greater efficacy in COPD. PMID- 24066151 TI - P. brasiliensis virulence is affected by SconC, the negative regulator of inorganic sulfur assimilation. AB - Conidia/mycelium-to-yeast transition of Paracoccidioidesbrasiliensis is a critical step for the establishment of paracoccidioidomycosis, a systemic mycosis endemic in Latin America. Thus, knowledge of the factors that mediate this transition is of major importance for the design of intervention strategies. So far, the only known pre-requisites for the accomplishment of the morphological transition are the temperature shift to 37 degrees C and the availability of organic sulfur compounds. In this study, we investigated the auxotrophic nature to organic sulfur of the yeast phase of Paracoccidioides, with special attention to P. brasiliensis species. For this, we addressed the role of SconCp, the negative regulator of the inorganic sulfur assimilation pathway, in the dimorphism and virulence of this pathogen. We show that down-regulation of SCONC allows initial steps of mycelium-to-yeast transition in the absence of organic sulfur compounds, contrarily to the wild-type fungus that cannot undergo mycelium to-yeast transition under such conditions. However, SCONC down-regulated transformants were unable to sustain yeast growth using inorganic sulfur compounds only. Moreover, pulses with inorganic sulfur in SCONC down-regulated transformants triggered an increase of the inorganic sulfur metabolism, which culminated in a drastic reduction of the ATP and NADPH cellular levels and in higher oxidative stress. Importantly, the down-regulation of SCONC resulted in a decreased virulence of P. brasiliensis, as validated in an in vivo model of infection. Overall, our findings shed light on the inability of P. brasiliensis yeast to rely on inorganic sulfur compounds, correlating its metabolism with cellular energy and redox imbalances. Furthermore, the data herein presented reveal SconCp as a novel virulence determinant of P. brasiliensis. PMID- 24066152 TI - ING3 is essential for asymmetric cell division during mouse oocyte maturation. AB - ING3 (inhibitor of growth family, member 3) is a subunit of the nucleosome acetyltransferase of histone 4 (NuA4) complex, which activates gene expression. ING3, which contains a plant homeodomain (PHD) motif that can bind to trimethylated lysine 4 on histone H3 (H3K4me3), is ubiquitously expressed in mammalian tissues and governs transcriptional regulation, cell cycle control, and apoptosis via p53-mediated transcription or the Fas/caspase-8 pathway. Thus, ING3 plays a number of important roles in various somatic cells. However, the role(s) of ING3 in germ cells remains unknown. Here, we show that loss of ING3 function led to the failure of asymmetric cell division and cortical reorganization in the mouse oocyte. Immunostaining showed that in fully grown germinal vesicle (GV) oocytes, ING3 localized predominantly in the GV. After germinal vesicle breakdown (GVBD), ING3 homogeneously localized in the cytoplasm. In oocytes where Ing3 was targeted by siRNA microinjection, we observed symmetric cell division during mouse oocyte maturation. In those oocytes, oocyte polarization was not established due to the failure to form an actin cap or a cortical granule-free domain (CGFD), the lack of which inhibited spindle migration. These features were among the main causes of abnormal symmetric cell division. Interestingly, an analysis of the mRNA expression levels of genes related to asymmetric cell division revealed that only mTOR was downregulated, and, furthermore, that genes downstream of mTOR (e.g., Cdc42, Rac1, and RhoA) were also downregulated in siIng3-injected oocytes. Therefore, ING3 may regulate asymmetric cell division through the mTOR pathway during mouse oocyte maturation. PMID- 24066153 TI - Application of quantitative MRI for brain tissue segmentation at 1.5 T and 3.0 T field strengths. AB - BACKGROUND: Brain tissue segmentation of white matter (WM), grey matter (GM), and cerebrospinal fluid (CSF) are important in neuroradiological applications. Quantitative Mri (qMRI) allows segmentation based on physical tissue properties, and the dependencies on MR scanner settings are removed. Brain tissue groups into clusters in the three dimensional space formed by the qMRI parameters R1, R2 and PD, and partial volume voxels are intermediate in this space. The qMRI parameters, however, depend on the main magnetic field strength. Therefore, longitudinal studies can be seriously limited by system upgrades. The aim of this work was to apply one recently described brain tissue segmentation method, based on qMRI, at both 1.5 T and 3.0 T field strengths, and to investigate similarities and differences. METHODS: In vivo qMRI measurements were performed on 10 healthy subjects using both 1.5 T and 3.0 T MR scanners. The brain tissue segmentation method was applied for both 1.5 T and 3.0 T and volumes of WM, GM, CSF and brain parenchymal fraction (BPF) were calculated on both field strengths. Repeatability was calculated for each scanner and a General Linear Model was used to examine the effect of field strength. Voxel-wise t-tests were also performed to evaluate regional differences. RESULTS: Statistically significant differences were found between 1.5 T and 3.0 T for WM, GM, CSF and BPF (p<0.001). Analyses of main effects showed that WM was underestimated, while GM and CSF were overestimated on 1.5 T compared to 3.0 T. The mean differences between 1.5 T and 3.0 T were -66 mL WM, 40 mL GM, 29 mL CSF and -1.99% BPF. Voxel-wise t-tests revealed regional differences of WM and GM in deep brain structures, cerebellum and brain stem. CONCLUSIONS: Most of the brain was identically classified at the two field strengths, although some regional differences were observed. PMID- 24066154 TI - A study on the geophylogeny of clinical and environmental Vibrio cholerae in Kenya. AB - Cholera remains a significant public health challenge in many sub-Saharan countries including Kenya. We have performed a combination of phylogenetic and phenotypic analysis based on whole genome DNA sequences derived from 40 environmental and 57 clinical V. cholerae from different regions of Kenya isolated between 2005 and 2010. Some environmental and all clinical isolates mapped back onto wave three of the monophyletic seventh pandemic V. cholerae El Tor phylogeny but other environmental isolates were phylogenetically very distinct. Thus, the genomes of the Kenyan V. cholerae O1 El Tor isolates are clonally related to other El Tor V. cholerae isolated elsewhere in the world and similarly harbour antibiotic resistance-associated STX elements. Further, the Kenyan O1 El Tor isolates fall into two distinct clades that may have entered Kenya independently. PMID- 24066155 TI - A network of HSPG core proteins and HS modifying enzymes regulates netrin dependent guidance of D-type motor neurons in Caenorhabditis elegans. AB - Heparan sulfate proteoglycans (HSPGs) are proteins with long covalently attached sugar side chains of the heparan sulfate (HS) type. Depending on the cellular context HS chains carry multiple structural modifications such as sulfate residues or epimerized sugars allowing them to bind to a wide range of molecules. HSPGs have been found to play extremely diverse roles in animal development and were shown to interact with certain axon guidance molecules. In this study we describe the role of the Caenorhabditis elegans HSPG core proteins Syndecan (SDN 1) and Glypican (LON-2) and the HS modifying enzymes in the dorsal guidance of D type motor axons, a process controlled mainly by the conserved axon guidance molecule UNC-6/Netrin. Our genetic analysis established the specific HS code relevant for this axon guidance event. Using two sensitized genetic backgrounds, we isolated novel components influencing D-type motor axon guidance with a link to HSPGs, as well as new alleles of several previously characterized axon guidance genes. Interestingly, the dorsal axon guidance defects induced by mutations in zfp-1 or lin-35 depended on the transgene oxIs12 used to visualize the D-type motor neurons. oxIs12 is a large multi-copy transgene that enlarges the X chromosome by approximately 20%. In a search for genes with a comparable phenotype we found that a mutation in the known dosage compensation gene dpy-21 showed similar axon guidance defects as zfp-1 or lin-35 mutants. Thus, derepression of genes on X, where many genes relevant for HS dependent axon guidance are located, might also influence axon guidance of D-type motor neurons. PMID- 24066156 TI - Genetic substructure of Kuwaiti population reveals migration history. AB - The State of Kuwait is characterized by settlers from Saudi Arabia, Iran, and other regions of the Arabian Peninsula. The settlements and subsequent admixtures have shaped the genetics of Kuwait. High prevalence of recessive disorders and metabolic syndromes (that increase risk of diabetes) is seen in the peninsula. Understanding the genetic structure of its population will aid studies designed to decipher the underlying causes of these disorders. In this study, we analyzed 572,366 SNP markers from 273 Kuwaiti natives genotyped using the illumina HumanOmniExpress BeadChip. Model-based clustering identified three genetic subgroups with different levels of admixture. A high level of concordance (Mantel test, p=0.0001 for 9999 repeats) was observed between the derived genetic clusters and the surname-based ancestries. Use of Human Genome Diversity Project (HGDP) data to understand admixtures in each group reveals the following: the first group (Kuwait P) is largely of West Asian ancestry, representing Persians with European admixture; the second group (Kuwait S) is predominantly of city dwelling Saudi Arabian tribe ancestry, and the third group (Kuwait B) includes most of the tent-dwelling Bedouin surnames and is characterized by the presence of 17% African ancestry. Identity by Descent and Homozygosity analyses find Kuwait's population to be heterogeneous (placed between populations that have large amount of ROH and the ones with low ROH) with Kuwait S as highly endogamous, and Kuwait B as diverse. Population differentiation FST estimates place Kuwait P near Asian populations, Kuwait S near Negev Bedouin tribes, and Kuwait B near the Mozabite population. FST distances between the groups are in the range of 0.005 to 0.008; distances of this magnitude are known to cause false positives in disease association studies. Results of analysis for genetic features such as linkage disequilibrium decay patterns conform to Kuwait's geographical location at the nexus of Africa, Europe, and Asia. PMID- 24066157 TI - C-di-GMP hydrolysis by Pseudomonas aeruginosa HD-GYP phosphodiesterases: analysis of the reaction mechanism and novel roles for pGpG. AB - In biofilms, the bacterial community optimizes the strategies to sense the environment and to communicate from cell to cell. A key player in the development of a bacterial biofilm is the second messenger c-di-GMP, whose intracellular levels are modulated by the opposite activity of diguanylate cyclases and phosphodiesterases. Given the huge impact of bacterial biofilms on human health, understanding the molecular details of c-di-GMP metabolism represents a critical step in the development of novel therapeutic approaches against biofilms. In this study, we present a detailed biochemical characterization of two c-di-GMP phosphodiesterases of the HD-GYP subtype from the human pathogen Pseudomonas aeruginosa, namely PA4781 and PA4108. Upstream of the catalytic HD-GYP domain, PA4781 contains a REC domain typical of two-component systems, while PA4108 contains an uncharacterized domain of unknown function. Our findings shed light on the activity and catalytic mechanism of these phosphodiesterases. We show that both enzymes hydrolyse c-di-GMP in a two-step reaction via the linear intermediate pGpG and that they produce GMP in vitro at a surprisingly low rate. In addition, our data indicate that the non-phosphorylated REC domain of PA4781 prevents accessibility of c-di-GMP to the active site. Both PA4108 and phosphorylated PA4781 are also capable to use pGpG as an alternative substrate and to hydrolyse it into GMP; the affinity of PA4781 for pGpG is one order of magnitude higher than that for c-di-GMP. These results suggest that these enzymes may not work (primarily) as genuine phosphodiesterases. Moreover, the unexpected affinity of PA4781 for pGpG may indicate that pGpG could also act as a signal molecule in its own right, thus further widening the c-di-GMP-related signalling scenario. PMID- 24066158 TI - Epicardial adipose tissue thickness and ablation outcome of atrial fibrillation. AB - OBJECTIVES: Epicardial fat was closely related to atrial fibrillation (AF). Transthoracic echocardiography (TTE) has been proposed to be a convenient imaging tool in assessing epicardial adipose tissue (EAT). The goal of the present study was to investigate whether the EAT thickness measured on TTE was a useful parameter in predicting procedural outcomes of AF ablations. METHODS AND RESULTS: A total of 227 paroxysmal AF (PAF) and 56 non-paroxysmal AF (non-PAF) patients receiving catheter ablations from 2008-2010 were enrolled. Echocardiography derived regional EAT thickness from parasternal long-axis view was quantified for each patient. Free of recurrence was defined as the absence of atrial arrhythmias without using antiarrhythmic agents after ablations. The mean EAT thickness of the study population was 6.1 +/- 0.8 mm. Non-PAF patients had a thicker EAT than that of PAF patients (7.0 +/- 0.7 mm versus 5.9 +/- 0.7 mm, p value <0.001). During the follow-up of 16 +/- 9 months, there were 95 patients (33.6%) suffering from recurrences of atrial arrhythmias. Non-PAF, chads2 score, left atrial diameter and EAT thickness were independent predictors of recurrence after catheter ablations. At a cutoff value of 6 mm for PAF and 6.9 mm for non-PAF, the measurement of EAT thickness could help us to identify patients at risk of recurrences. CONCLUSIONS: EAT thickness may serve as a useful parameter in predicting recurrences after AF ablations. Compared to other imaging modalities, TTE can be an alternative choice with less cost and time in assessing the effects of EAT on ablation outcomes. PMID- 24066159 TI - Impact of Toll-like receptor 2 deficiency on survival and neurological function after cardiac arrest: a murine model of cardiopulmonary resuscitation. AB - BACKGROUND: Cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) is associated with poor survival rate and neurofunctional outcome. Toll-like receptor 2 (TLR2) plays an important role in conditions of sterile inflammation such as reperfusion injury. Recent data demonstrated beneficial effects of the administration of TLR2-blocking antibodies in ischemia/reperfusion injury. In this study we investigated the role of TLR2 for survival and neurofunctional outcome after CA/CPR in mice. METHODS: Female TLR2-deficient (TLR2(-/-)) and wild type (WT) mice were subjected to CA for eight min induced by intravenous injection of potassium chloride and CPR by external chest compression. Upon the beginning of CPR, n = 15 WT mice received 5 ug/g T2.5 TLR2 inhibiting antibody intravenously while n = 30 TLR2(-/-) and n = 31 WT controls were subjected to injection of normal saline. Survival and neurological outcome were evaluated during a 28-day follow up period. Basic neurological function, balance, coordination and overall motor function as well as spatial learning and memory were investigated, respectively. In a separate set of experiments, six mice per group were analysed for cytokine and corticosterone serum levels eight hours after CA/CPR. RESULTS: TLR2 deficiency and treatment with a TLR2 blocking antibody were associated with increased survival (77% and 80% vs. 51% of WT control; both P < 0.05). Neurofunctional performance was less compromised in TLR2(-/-) and antibody treated mice. Compared to WT and antibody treated mice, TLR2(-/-) mice exhibited reduced IL-6 (both P < 0.05) but not IL-1beta levels and increased corticosterone plasma concentrations (both P < 0.05). CONCLUSION: Deficiency or functional blockade of TLR2 is associated with increased survival and improved neurofunctional outcome in a mouse model of CA/CPR. Thus, TLR2 inhibition could provide a novel therapeutic approach for reducing mortality and morbidity after cardiac arrest and cardiopulmonary resuscitation. PMID- 24066160 TI - Colorectal cancers from distinct ancestral populations show variations in BRAF mutation frequency. AB - It has been demonstrated for some cancers that the frequency of somatic oncogenic mutations may vary in ancestral populations. To determine whether key driver alterations might occur at different frequencies in colorectal cancer, we applied a high-throughput genotyping platform (OncoMap) to query 385 mutations across 33 known cancer genes in colorectal cancer DNA from 83 Asian, 149 Black and 195 White patients. We found that Asian patients had fewer canonical oncogenic mutations in the genes tested (60% vs Black 79% (P = 0.011) and White 77% (P = 0.015)), and that BRAF mutations occurred at a higher frequency in White patients (17% vs Asian 4% (P = 0.004) and Black 7% (P = 0.014)). These results suggest that the use of genomic approaches to elucidate the different ancestral determinants harbored by patient populations may help to more precisely and effectively treat colorectal cancer. PMID- 24066161 TI - Effects of apoE deficiency and occlusal disharmony on amyloid-beta production and spatial memory in rats. AB - Amyloid-beta (Abeta) plays a causative role in Alzheimer's disease. Apolipoprotein E (apoE) is involved in Abeta accumulation, whereas occlusal disharmony increases Abeta production in the rat hippocampus. The purpose of the present study was to investigate the effects of apoE deficiency and occlusal disharmony on Abeta production and spatial memory. Wild-type (WT) (n = 12) and apoE-deficient [ApoE(-/-)] (n = 12) rats (Sprague-Dawley; 8 weeks old) were used. These rats were randomly divided into four groups of six rats each: two control (C) groups: WT (C-WT) and ApoE [C-ApoE(-/-)], and two occlusal disharmony (D) groups: WT (D-WT) and ApoE [D-ApoE(-/-)]. The C group received no treatment for 8 weeks. In the D group, the maxillary molar cusps were cut off for 8 weeks. The spatial memory of rats was assessed according to their behavioral performance in a radial arm maze. In both genotypes of rats, significant differences in the reference memory, Abeta42 production, beta-secretase expression and plasma corticosterone levels were observed between the C and D groups (P < 0.0125). The levels of Abeta42 and glucocorticoid receptor in the C-ApoE(-/-) group were also significantly higher than those in the C-WT group (P < 0.0125). However, no significant differences in these parameters were found between the two genotypes with occlusal disharmony. In conclusion, occlusal disharmony induces cognitive dysfunction and Abeta accumulation in the rat hippocampus, and the effects of occlusal disharmony on Abeta accumulation and cognitive dysfunction were larger than those of apoE deficiency. PMID- 24066162 TI - Threats from climate change to terrestrial vertebrate hotspots in Europe. AB - We identified hotspots of terrestrial vertebrate species diversity in Europe and adjacent islands. Moreover, we assessed the extent to which by the end of the 21(st) century such hotspots will be exposed to average monthly temperature and precipitation patterns which can be regarded as extreme if compared to the climate experienced during 1950-2000. In particular, we considered the entire European sub-continent plus Turkey and a total of 1149 species of terrestrial vertebrates. For each species, we developed species-specific expert-based distribution models (validated against field data) which we used to calculate species richness maps for mammals, breeding birds, amphibians, and reptiles. Considering four global circulation model outputs and three emission scenarios, we generated an index of risk of exposure to extreme climates, and we used a bivariate local Moran's I to identify the areas with a significant association between hotspots of diversity and high risk of exposure to extreme climates. Our results outline that the Mediterranean basin represents both an important hotspot for biodiversity and especially for threatened species for all taxa. In particular, the Iberian and Italian peninsulas host particularly high species richness as measured over all groups, while the eastern Mediterranean basin is particularly rich in amphibians and reptiles; the islands (both Macaronesian and Mediterranean) host the highest richness of threatened species for all taxa occurs. Our results suggest that the main hotspots of biodiversity for terrestrial vertebrates may be extensively influenced by the climate change projected to occur over the coming decades, especially in the Mediterranean bioregion, posing serious concerns for biodiversity conservation. PMID- 24066163 TI - A vertex model of Drosophila ventral furrow formation. AB - Ventral furrow formation in Drosophila is an outstanding model system to study the mechanisms involved in large-scale tissue rearrangements. Ventral cells accumulate myosin at their apical sides and, while being tightly coupled to each other via apical adherens junctions, execute actomyosin contractions that lead to reduction of their apical cell surface. Thereby, a band of constricted cells along the ventral epithelium emerges which will form a tissue indentation along the ventral midline (the ventral furrow). Here we adopt a 2D vertex model to simulate ventral furrow formation in a surface view allowing easy comparison with confocal live-recordings. We show that in order to reproduce furrow morphology seen in vivo, a gradient of contractility must be assumed in the ventral epithelium which renders cells more contractile the closer they lie to the ventral midline. The model predicts previous experimental findings, such as the gain of eccentric morphology of constricting cells and an incremental fashion of apical cell area reduction. Analysis of the model suggests that this incremental area reduction is caused by the dynamical interplay of cell elasticity and stochastic contractility as well as by the opposing forces from contracting neighbour cells. We underpin results from the model through in vivo analysis of ventral furrow formation in wildtype and twi mutant embryos. Our results show that ventral furrow formation can be accomplished as a "tug-of-war" between stochastically contracting, mechanically coupled cells and may require less rigorous regulation than previously thought. SUMMARY: For the developmental biologist it is a fascinating question how cells can coordinate major tissue movements during embryonic development. The so-called ventral furrow of the Drosophila embryo is a well-studied example of such a process when cells from a ventral band, spanning nearly the entire length of the embryo, undergo dramatic shape change by contracting their tips and then fold inwards into the interior of the embryo. Although numerous genes have been identified that are critical for ventral furrow formation, it is an open question how cells work together to elicit this tissue rearrangement. We use a computational model to mimic the physical properties of cells in the ventral epithelium and simulate the formation of the furrow. We find that the ventral furrow can form through stochastic self organisation and that previous experimental observations can be readily explained in our model by considering forces that arise when cells execute contractions while being coupled to each other in a mechanically coherent epithelium. The model highlights the importance of a physical perspective when studying tissue morphogenesis and shows that only a minimal genetic regulation may be required to drive complex processes in embryonic development. PMID- 24066165 TI - Stathmin regulates keratinocyte proliferation and migration during cutaneous regeneration. AB - Cutaneous regeneration utilizes paracrine feedback mechanisms to fine-tune the regulation of epidermal keratinocyte proliferation and migration. However, it is unknown how fibroblast-derived hepatocyte growth factor (HGF) affects these mutually exclusive processes in distinct cell populations. We here show that HGF stimulates the expression and phosphorylation of the microtubule-destabilizing factor stathmin in primary human keratinocytes. Quantitative single cell- and cell population-based analyses revealed that basal stathmin levels are important for the migratory ability of keratinocytes in vitro; however, its expression is moderately induced in the migration tongue of mouse skin or organotypic multi layered keratinocyte 3D cultures after full-thickness wounding. In contrast, clearly elevated stathmin expression is detectable in hyperproliferative epidermal areas. In vitro, stathmin silencing significantly reduced keratinocyte proliferation. Automated quantitative and time-resolved analyses in organotypic cocultures demonstrated a high correlation between Stathmin/phospho-Stathmin and Ki67 positivity in epidermal regions with proliferative activity. Thus, activation of stathmin may stimulate keratinocyte proliferation, while basal stathmin levels are sufficient for keratinocyte migration during cutaneous regeneration. PMID- 24066164 TI - Factors associated with the acceptability of male circumcision among men in Jamaica. AB - OBJECTIVES: To determine the prevalence of male circumcision (MC) among men in the western region of Jamaica, and to identify factors associated with acceptability of MC for self, infants (<1 year) and older sons (1-17 years). METHODS: A cross-sectional, interviewer-administered questionnaire survey of 549 men aged 19-54 years was conducted in the western region of Jamaica. The survey included questions about the acceptance of MC for self, infants, and sons before and after an information session about the benefits of MC in preventing HIV/STI transmission. Logistic regression models were used to identify factors that were associated with acceptability of MC. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) were calculated from the models. RESULTS: Fourteen percent of the men reported that they were circumcised. In the multivariable model, which adjusted for age, education, religion and income, there were increased odds of accepting MC for infants/sons among uncircumcised men who accepted MC for self (AOR=8.1; 95% CI = 4.1-15.9), believed they would experience more pleasure during sex if circumcised (AOR=4.0; 95% CI = 2.0-8.2), and reported having no concerns regarding MC (AOR=3.0; 95% CI = 1.8-4.8). Similarly, uncircumcised men who reported no concerns about MC or who believed that they would experience more pleasure during sex if circumcised were more likely to accept MC for self. CONCLUSION: Providing men with information about MC increased acceptance of MC for self, infants (<17 years) and sons (1-17 years). Since targeted education on the benefits of male circumcision for prevention of HIV/STI can be effective in increasing acceptability of MC, health professionals should be trained, and willing to discuss MC with men in healthcare facilities and in the community. PMID- 24066166 TI - Insight into the intermolecular recognition mechanism between Keap1 and IKKbeta combining homology modelling, protein-protein docking, molecular dynamics simulations and virtual alanine mutation. AB - Degradation of certain proteins through the ubiquitin-proteasome pathway is a common strategy taken by the key modulators responsible for stress responses. Kelch-like ECH-associated protein-1(Keap1), a substrate adaptor component of the Cullin3 (Cul3)-based ubiquitin E3 ligase complex, mediates the ubiquitination of two key modulators, NF-E2-related factor 2 (Nrf2) and IkappaB kinase beta (IKKbeta), which are involved in the redox control of gene transcription. However, compared to the Keap1-Nrf2 protein-protein interaction (PPI), the intermolecular recognition mechanism of Keap1 and IKKbeta has been poorly investigated. In order to explore the binding pattern between Keap1 and IKKbeta, the PPI model of Keap1 and IKKbeta was investigated. The structure of human IKKbeta was constructed by means of the homology modeling method and using reported crystal structure of Xenopus laevis IKKbeta as the template. A protein protein docking method was applied to develop the Keap1-IKKbeta complex model. After the refinement and visual analysis of docked proteins, the chosen pose was further optimized through molecular dynamics simulations. The resulting structure was utilized to conduct the virtual alanine mutation for the exploration of hot spots significant for the intermolecular interaction. Overall, our results provided structural insights into the PPI model of Keap1-IKKbeta and suggest that the substrate specificity of Keap1 depend on the interaction with the key tyrosines, namely Tyr525, Tyr574 and Tyr334. The study presented in the current project may be useful to design molecules that selectively modulate Keap1. The selective recognition mechanism of Keap1 with IKKbeta or Nrf2 will be helpful to further know the crosstalk between NF-kappaB and Nrf2 signaling. PMID- 24066167 TI - Influence of reactive oxygen species on the enzyme stability and activity in the presence of ionic liquids. AB - In this paper, we have examined the effect of ammonium and imidazolium based ionic liquids (ILs) on the stability and activity of proteolytic enzyme alpha chymotrypsin (CT) in the presence of cold atmospheric pressure plasma jet (APPJ). The present work aims to illustrate the state of art implementing the combined action of ILs and APPJ on the enzyme stability and activity. Our circular dichroism (CD), fluorescence and enzyme activity results of CT have revealed that buffer and all studied ILs {triethylammonium hydrogen sulphate (TEAS) from ammonium family and 1-butyl-3-methyl imidazolium chloride ([Bmim][Cl]), 1 methylimidazolium chloride ([Mim][Cl]) from imidazolium family} are notable to act as protective agents against the deleterious action of the APPJ, except triethylammonium dihydrogen phosphate (TEAP) ammonium IL. However, TEAP attenuates strongly the deleterious action of reactive oxygen species (ROS) created by APPJ on native structure of CT. Further, TEAP is able to retain the enzymatic activity after APPJ exposure which is absent in all the other systems.This study provides the first combined effect of APPJ and ILs on biomolecules that may generate many theoretical and experimental opportunities. Through this methodology, we can utilise both enzyme and plasma simultaneously without affecting the enzyme structure and activity on the material surface; which can prove to be applicable in various fields. PMID- 24066168 TI - Turbo FISH: a method for rapid single molecule RNA FISH. AB - Advances in RNA fluorescence in situ hybridization (RNA FISH) have allowed practitioners to detect individual RNA molecules in single cells via fluorescence microscopy, enabling highly accurate and sensitive quantification of gene expression. However, current methods typically employ hybridization times on the order of 2-16 hours, limiting its potential in applications like rapid diagnostics. We present here a set of conditions for RNA FISH (dubbed Turbo RNA FISH) that allow us to make accurate measurements with no more than 5 minutes of hybridization time and 3 minutes of washing, and show that hybridization times can go as low as 30 seconds while still producing quantifiable images. We further show that rapid hybridization is compatible with our recently developed iceFISH and SNP FISH variants of RNA FISH that enable chromosome and single base discrimination, respectively. Our method is simple and cost effective, and has the potential to dramatically increase the throughput and realm of applicability of RNA FISH. PMID- 24066169 TI - Attachment styles and personal growth following romantic breakups: the mediating roles of distress, rumination, and tendency to rebound. AB - The purpose of this research was to examine the associations of attachment anxiety and avoidance with personal growth following relationship dissolution, and to test breakup distress, rumination, and tendency to rebound with new partners as mediators of these associations. Study 1 (N = 411) and Study 2 (N = 465) measured attachment style, breakup distress, and personal growth; Study 2 additionally measured ruminative reflection, brooding, and proclivity to rebound with new partners. Structural equation modelling revealed in both studies that anxiety was indirectly associated with greater personal growth through heightened breakup distress, whereas avoidance was indirectly associated with lower personal growth through inhibited breakup distress. Study 2 further showed that the positive association of breakup distress with personal growth was accounted for by enhanced reflection and brooding, and that anxious individuals' greater personal growth was also explained by their proclivity to rebound. These findings suggest that anxious individuals' hyperactivated breakup distress may act as a catalyst for personal growth by promoting the cognitive processing of breakup related thoughts and emotions, whereas avoidant individuals' deactivated distress may inhibit personal growth by suppressing this cognitive work. PMID- 24066170 TI - Systematic analyses of the cytotoxic effects of compound 11a, a putative synthetic agonist of photoreceptor-specific nuclear receptor (PNR), in cancer cell lines. AB - Photoreceptor cell-specific receptor (PNR/NR2E3) is an orphan nuclear receptor that plays a critical role in retinal development and photoreceptor maintenance. The disease-causing mutations in PNR have a pleiotropic effect resulting in varying retinal diseases. Recently, PNR has been implicated in control of cellular functions in cancer cells. PNR was reported to be a novel regulator of ERalpha expression in breast cancer cells, and high PNR expression correlates with favorable response to tamoxifen treatment. Moreover, PNR was shown to increase p53 stability in HeLa cells, implying that PNR may be a therapeutic target in this and other cancers that retain a wild type p53 gene. To facilitate further understanding of PNR functions in cancer, we characterized compound 11a, a synthetic, putative PNR agonist in several cell-based assays. Interestingly, we showed that 11a failed to activate PNR and its cytotoxicity was independent of PNR expression, excluding PNR as a mediator for 11a cytotoxicity. Systematic analyses of the cytotoxic effects of 11a in NCI-60 cell lines revealed a strong positive correlation of cytotoxicity with p53 status, i.e., p53 wild type cell lines were significantly more sensitive to 11a than p53 mutated or null cell lines. Furthermore, using HCT116 p53+/+ and p53-/- isogenic cell lines we revealed that the mechanism of 11a-induced cytotoxicity occurred through G1/S phase cell cycle arrest rather than apoptosis. In conclusion, we observed a correlation of 11a sensitivity with p53 status but not with PNR expression, suggesting that tumors expressing wild type p53 might be responsive to this compound. PMID- 24066171 TI - Deficiency in repair of the mitochondrial genome sensitizes proliferating myoblasts to oxidative damage. AB - Reactive oxygen species (ROS), generated as a by-product of mitochondrial oxidative phosphorylation, are particularly damaging to the genome of skeletal muscle because of their high oxygen consumption. Proliferating myoblasts play a key role during muscle regeneration by undergoing myogenic differentiation to fuse and restore damaged muscle. This process is severely impaired during aging and in muscular dystrophies. In this study, we investigated the role of oxidatively damaged DNA and its repair in the mitochondrial genome of proliferating skeletal muscle progenitor myoblasts cells and their terminally differentiated product, myotubes. Using the C2C12 cell line as a well-established model for skeletal muscle differentiation, we show that myoblasts are highly sensitive to ROS-mediated DNA damage, particularly in the mitochondrial genome, due to deficiency in 5' end processing at the DNA strand breaks. Ectopic expression of the mitochondrial-specific 5' exonuclease, EXOG, a key DNA base excision/single strand break repair (BER/SSBR) enzyme, in myoblasts but not in myotubes, improves the cell's resistance to oxidative challenge. We linked loss of myoblast viability by activation of apoptosis with deficiency in the repair of the mitochondrial genome. Moreover, the process of myoblast differentiation increases mitochondrial biogenesis and the level of total glutathione. We speculate that our data may provide a mechanistic explanation for depletion of proliferating muscle precursor cells during the development of sarcopenia, and skeletal muscle dystrophies. PMID- 24066172 TI - Comparative analysis of latex transcriptome reveals putative molecular mechanisms underlying super productivity of Hevea brasiliensis. AB - Increasing demand for natural rubber prompts studies into the mechanisms governing the productivity of rubber tree (Heveabrasiliensis). It is very interesting to notice that a rubber tree of clone PR107 in Yunnan, China is reported to yield more than 20 times higher than the average rubber tree. This super-high-yielding (SHY) rubber tree (designated as SY107), produced 4.12 kg of latex (cytoplasm of rubber producing laticifers, containing about 30% of rubber) per tapping, more than 7-fold higher than that of the control. This rubber tree is therefore a good material to study how the rubber production is regulated at a molecular aspect. A comprehensive cDNA-AFLP transcript profiling was performed on the latex of SY107 and its average counterparts by using the 384 selective primer pairs for two restriction enzyme combinations (ApoI/MseI and TaqI/MseI). A total of 746 differentially expressed (DE) transcript-derived fragments (TDFs) were identified, of which the expression patterns of 453 TDFs were further confirmed by RT-PCR. These RT-PCR confirmed TDFs represented 352 non-redundant genes, of which 215 had known or partially known functions and were grouped into 10 functional categories. The top three largest categories were transcription and protein synthesis (representing 24.7% of the total genes), defense and stress (15.3%), and primary and secondary metabolism (14.0%). Detailed analysis of the DE-genes suggests notable characteristics of SHY phenotype in improved sucrose loading capability, rubber biosynthesis-preferred sugar utilization, enhanced general metabolism and timely stress alleviation. However, the SHY phenotype has little correlation with rubber-biosynthesis pathway genes. PMID- 24066173 TI - ULK1 regulates melanin levels in MNT-1 cells independently of mTORC1. AB - Melanosomes are lysosome-related organelles that serve as specialized sites of melanin synthesis and storage in melanocytes. The progression of melanosomes through the different stages of their formation requires trafficking of specific proteins and membrane constituents in a sequential manner, which is likely to deploy ubiquitous cellular machinery along with melanocyte-specific proteins. Recent evidence revealed a connection between melanogenesis and the autophagy machinery, suggesting a novel role for members of the latter in melanocytes. Here we focused on ULK1, a key autophagy protein which is negatively regulated by mTORC1, to assess its potential role in melanogenesis in MNT-1 cells. We found that ULK1 depletion causes an increase in melanin levels, suggesting an inhibitory function for this protein in melanogenesis. Furthermore, this increase was accompanied by increased transcription of MITF (microphthalmia-associated transcription factor) and tyrosinase and by elevated protein levels of tyrosinase, the rate-limiting factor in melanin biogenesis. We also provide evidence to show that ULK1 function in this context is independent of the canonical ULK1 autophagy partners, ATG13 and FIP200. Furthermore we show that regulation of melanogenesis by ULK1 is independent of mTORC1 inhibition. Our data thus provide intriguing insights regarding the involvement of the key regulatory autophagy machinery in melanogenesis. PMID- 24066174 TI - Campylobacter jejuni colonization is associated with a dysbiosis in the cecal microbiota of mice in the absence of prominent inflammation. AB - BACKGROUND: Campylobacter jejuni causes enterocolitis in humans, but does not incite disease in asymptomatic carrier animals. To survive in the intestine, C. jejuni must successfully compete with the microbiota and overcome the host immune defense. Campylobacter jejuni colonization success varies considerably amongst individual mice, and we examined the degree to which the intestinal microbiota was affected in mice (i.e. a model carrier animal) colonized by C. jejuni at high relative to low densities. METHODS: Mice were inoculated with C. jejuni or buffer, and pathogen shedding and intestinal colonization were measured. Histopathologic scoring and quantification of mRNA expression for alpha defensins, toll-like receptors, and cytokine genes were conducted. Mucosa associated bacterial communities were characterized by two approaches: multiplexed barcoded pyrosequencing and terminal restriction fragment length polymorphism analysis. RESULTS: Two C. jejuni treatments were established based on the degree of cecal and colonic colonization; C. jejuni Group A animals were colonized at high cell densities, and C. jejuni Group B animals were colonized at lower cell densities. Histological examination of cecal and colonic tissues indicated that C. jejuni did not incite visible pathologic changes. Although there was no significant difference among treatments in expression of mRNA for alpha-defensins, toll-like receptors, or cytokine genes, a trend for increased expression of toll-like receptors and cytokine genes was observed for C. jejuni Group A. The results of the two methods to characterize bacterial communities indicated that the composition of the cecal microbiota of C. jejuni Group A mice differed significantly from C. jejuni Group B and Control mice. This difference was due to a reduction in load, diversity and richness of bacteria associated with the cecal mucosa of C. jejuni Group A mice. CONCLUSIONS: High density colonization by C. jejuni is associated with a dysbiosis in the cecal microbiota independent of prominent inflammation. PMID- 24066175 TI - The trade-off between accuracy and accessibility of syphilis screening assays. AB - The availability of rapid and sensitive methods to diagnose syphilis facilitates screening of pregnant women, which is one of the most cost-effective health interventions available. We have evaluated two screening methods in Tanzania: an enzyme immunoassay (EIA), and a point-of-care test (POCT). We evaluated the performance of each test against the Treponema pallidum particle agglutination assay (TPPA) as the reference method, and the accessibility of testing in a rural district of Tanzania. The POCT was performed in the clinic on whole blood, while the other assays were performed on plasma in the laboratory. Samples were also tested by the rapid plasma Reagin (RPR) test. With TPPA as reference assay, the sensitivity and specificity of EIA were 95.3% and 97.8%, and of the POCT were 59.6% and 99.4% respectively. The sensitivity of the POCT and EIA for active syphilis cases (TPPA positive and RPR titer >= 1/8) were 82% and 100% respectively. Only 15% of antenatal clinic attenders in this district visited a health facility with a laboratory capable of performing the EIA. Although it is less sensitive than EIA, its greater accessibility, and the fact that treatment can be given on the same day, means that the use of POCT would result in a higher proportion of women with syphilis receiving treatment than with the EIA in this district of Tanzania. PMID- 24066176 TI - Assessing different mechanisms of toxicity in mountaintop removal/valley fill coal mining-affected watershed samples using Caenorhabditis elegans. AB - Mountaintop removal-valley fill coal mining has been associated with a variety of impacts on ecosystem and human health, in particular reductions in the biodiversity of receiving streams. However, effluents emerging from valley fills contain a complex mixture of chemicals including metals, metalloids, and salts, and it is not clear which of these are the most important drivers of toxicity. We found that streamwater and sediment samples collected from mine-impacted streams of the Upper Mud River in West Virginia inhibited the growth of the nematode Caenorhabditis elegans. Next, we took advantage of genetic and transgenic tools available in this model organism to test the hypotheses that the toxicity could be attributed to metals, selenium, oxidative stress, or osmotic stress. Our results indicate that in general, the toxicity of streamwater to C. elegans was attributable to osmotic stress, while the toxicity of sediments resulted mostly from metals or metalloids. PMID- 24066178 TI - Impact of personalised feedback about physical activity on change in objectively measured physical activity (the FAB study): a randomised controlled trial. AB - BACKGROUND: Low levels of physical activity are a major public health concern, and interventions to promote physical activity have had limited success. Whether or not personalised feedback about physical activity following objective measurement motivates behaviour change has yet to be rigorously examined. METHODS: And Findings: In a parallel group, open randomised controlled trial, 466 healthy adults aged 32 to 54 years were recruited from the ongoing population based Fenland Study (Cambridgeshire, UK). Participants were randomised to receive either no feedback until the end of the trial (control group, n=120) or one of three different types of feedback: simple, visual, or contextualised (intervention groups, n=346). The primary outcome was physical activity (physical activity energy expenditure (PAEE) in kJ/kg/day and average body acceleration (ACC) in m/s(2)) measured objectively using a combined heart rate monitor and accelerometer (Actiheart((r))). The main secondary outcomes included self reported physical activity, intention to increase physical activity, and awareness of physical activity (the agreement between self-rated and objectively measured physical activity). At 8 weeks, 391 (83.9%) participants had complete physical activity data. The intervention had no effect on objectively measured physical activity (PAEE: beta=-0.92, 95% CI=-3.50 to 1.66, p=0.48 and ACC: beta=0.01, 95% CI=-0.00 to 0.02, p=0.21), self-reported physical activity (beta= 0.39, 95% CI=-1.59 to 0.81), or intention to increase physical activity (beta= 0.05, 95% CI=-0.22 to 0.11). However, it was associated with an increase in awareness of physical activity (OR=1.74, 95% CI=1.05 to 2.89). Results did not differ according to the type of feedback. CONCLUSIONS: Personalised feedback about physical activity following objective measurement increased awareness but did not result in changes in physical activity in the short term. Measurement and feedback may have a role in promoting behaviour change but are ineffective on their own. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92551397 http://www.controlled-trials.com/ISRCTN92551397. PMID- 24066177 TI - Vascular endothelial growth factor receptor inhibitor SU5416 suppresses lymphocyte generation and immune responses in mice by increasing plasma corticosterone. AB - Inhibitors of vascular endothelial growth factor and its receptors (VEGFRs) are attractive therapeutic candidates for cancer treatment. One such small molecule VEGFR inhibitor, SU5416, limits angiogenesis in vivo and is widely used for investigating VEGFR signaling in tumor pathophysiology. Herein, we describe novel actions of SU5416 on the immune system. Treatment of mice with SU5416 for 3 days induced significant reductions in size and cellularity of peripheral lymph nodes. Interestingly, SU5416 did not affect initial lymphocyte localization to peripheral lymph nodes but did reduce lymphocyte accumulation during long-term migration assays. Treatment with SU5416 also induced severe loss of double positive thymocytes resulting in thymic atrophy and a reduction in peripheral B cells. Furthermore, immune responses following immunization were reduced in mice treated with SU5416. Findings of thymic atrophy and reduced weight gain during SU5416 treatment suggested elevated corticosterone levels. Indeed, a significant 5-fold increase in serum corticosterone was found 4 hours after treatment with SU5416. Importantly, adrenalectomy negated the effects of SU5416 treatment on primary immune tissues, and partial reversal of SU5416-induced changes was observed following blockade of glucocorticoid receptors. SU5416 has been reported to inhibit the activation of latent transforming growth factor (TGF)-beta, a cytokine involved in the regulation of glucocorticoid release by the adrenal glands. Interestingly, treatment with a TGF-beta receptor inhibitor, showed a similar phenotype as SU5416 treatment, including elevated serum corticosterone levels and thymic atrophy. Therefore, these results suggest that SU5416 induces glucocorticoid release directly from the adrenal glands, possibly by inhibition of TGF-beta activation. PMID- 24066179 TI - The effect of instrumental timbre on interval discrimination. AB - We tested non-musicians and musicians in an auditory psychophysical experiment to assess the effects of timbre manipulation on pitch-interval discrimination. Both groups were asked to indicate the larger of two presented intervals, comprised of four sequentially presented pitches; the second or fourth stimulus within a trial was either a sinusoidal (or "pure"), flute, piano, or synthetic voice tone, while the remaining three stimuli were all pure tones. The interval-discrimination tasks were administered parametrically to assess performance across varying pitch distances between intervals ("interval-differences"). Irrespective of timbre, musicians displayed a steady improvement across interval-differences, while non musicians only demonstrated enhanced interval discrimination at an interval difference of 100 cents (one semitone in Western music). Surprisingly, the best discrimination performance across both groups was observed with pure-tone intervals, followed by intervals containing a piano tone. More specifically, we observed that: 1) timbre changes within a trial affect interval discrimination; and 2) the broad spectral characteristics of an instrumental timbre may influence perceived pitch or interval magnitude and make interval discrimination more difficult. PMID- 24066180 TI - AMP deaminase 3 deficiency enhanced 5'-AMP induction of hypometabolism. AB - A hypometabolic state can be induced in mice by 5'-AMP administration. Previously we proposed that an underlying mechanism for this hypometabolism is linked to reduced erythrocyte oxygen transport function due to 5'-AMP uptake altering the cellular adenylate equilibrium. To test this hypothesis, we generated mice deficient in adenosine monophosphate deaminase 3 (AMPD3), the key catabolic enzyme for 5'-AMP in erythrocytes. Mice deficient in AMPD3 maintained AMPD activities in all tissues except erythrocytes. Developmentally and morphologically, the Ampd3(-/-) mice were indistinguishable from their wild type siblings. The levels of ATP, ADP but not 5'-AMP in erythrocytes of Ampd3(-/-) mice were significantly elevated. Fasting blood glucose levels of the Ampd3(-/-) mice were comparable to wild type siblings. In comparison to wild type mice, the Ampd3(-/-) mice displayed a deeper hypometabolism with a significantly delayed average arousal time in response to 5'-AMP administration. Together, these findings demonstrate a central role of AMPD3 in the regulation of 5'-AMP mediated hypometabolism and further implicate erythrocytes in this behavioral response. PMID- 24066181 TI - A novel aromatic carboxylic acid inactivates luciferase by acylation of an enzymatically active regulatory lysine residue. AB - Firefly luciferase (Luc) is widely used as a reporter enzyme in cell-based assays for gene expression. A novel aromatic carboxylic acid, F-53, reported here for the first time, substantially inhibited the enzymatic activity of Luc in a Luc reporter screening. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and tandem mass spectrometry (MS/MS) analyses showed that F-53 modifies Luc at lysine-529 via amidation of the F-53 carboxyl group. The lysine-529 residue of Luc, which plays a regulatory catalytic role, can be acetylated. Luc also has a long-chain fatty acyl-CoA synthase activity. An in vitro assay that involved both recombinant Luc and mouse liver microsomes identified F-53-CoA as the reactive form produced from F-53. However, whereas the inhibitory effect of F-53 is observed in Hela cells that transiently expressed Luc, it is not observed in an in vitro assay that involves recombinant Luc alone. Therefore, insights into the activities of certain mammalian transferases can be translated to better understand the acylation by F-53. The insights from this study about the novel inhibitory modification mechanism might help not only to avoid misinterpretation of the results of Luc-based reporter screening assays but also to explain the pharmacological and toxicological effects of carboxylic acid containing drugs. PMID- 24066182 TI - Internal fixation versus nonoperative treatment for displaced 3-part or 4-part proximal humeral fractures in elderly patients: a meta-analysis of randomized controlled trials. AB - BACKGROUND: A few studies focused on open reduction and internal fixation (ORIF) or nonoperative treatment of displaced 3-part or 4-part proximal humeral fractures in elderly patients have been published, all of whom had a low number of patients. In this meta-analysis of randomized controlled trials (RCTs), we aimed to assess the effect of ORIF or nonoperative treatment of displaced 3-part or 4-part proximal humeral fractures in elderly patients on the clinical outcomes and re-evaluate of the potential benefits of conservative treatment. METHODS: We searched PubMed and the Cochrane Central Register of Controlled Trials databases for randomized controlled trials comparing ORIF and nonoperative treatment of displaced 3-part or 4-part proximal humeral fractures in elderly patients. Our outcome measures were the Constant scores. RESULTS: Three randomized controlled trials with a total of 130 patients were identified and analyzed. The overall results based on fixed-effect model did not support the treatment of open reduction and internal fixation to improve the functional outcome when compared with nonoperative treatment for treating elderly patients with displaced 3-part or 4-part proximal humeral fractures (WMD -0.51, 95% CI: -7.25 to 6.22, P = 0.88, I(2) = 0%). CONCLUSIONS: Although our meta-analysis did not support the treatment of open reduction and internal fixation to improve the functional outcome when compared with nonoperative treatment for treating elderly patients with displaced 3-part or 4-part proximal humeral fractures, this result must be considered in the context of variable patient demographics. Only a limited recommendation can be made based on current data. Considering the limitations of included studies, a large, well designed trial that incorporates the evaluation of clinically relevant outcomes in participants with different underlying risks of shoulder function is required to more adequately assess the role for ORIF or nonoperative treatment. PMID- 24066183 TI - The expression and localization of N-myc downstream-regulated gene 1 in human trophoblasts. AB - The protein N-Myc downstream-regulated gene 1 (NDRG1) is implicated in the regulation of cell proliferation, differentiation, and cellular stress response. NDRG1 is expressed in primary human trophoblasts, where it promotes cell viability and resistance to hypoxic injury. The mechanism of action of NDRG1 remains unknown. To gain further insight into the intracellular action of NDRG1, we analyzed the expression pattern and cellular localization of endogenous NDRG1 and transfected Myc-tagged NDRG1 in human trophoblasts exposed to diverse injuries. In standard conditions, NDRG1 was diffusely expressed in the cytoplasm at a low level. Hypoxia or the hypoxia mimetic cobalt chloride, but not serum deprivation, ultraviolet (UV) light, or ionizing radiation, induced the expression of NDRG1 in human trophoblasts and the redistribution of NDRG1 into the nucleus and cytoplasmic membranes associated with the endoplasmic reticulum (ER) and microtubules. Mutation of the phosphopantetheine attachment site (PPAS) within NDRG1 abrogated this pattern of redistribution. Our results shed new light on the impact of cell injury on NDRG1 expression patterns, and suggest that the PPAS domain plays a key role in NDRG1's subcellular distribution. PMID- 24066184 TI - CD4 T-cell enumeration in a field setting: evaluation of CyFlow counter using the CD4 easy count kit-dry and Pima CD4 systems. AB - BACKGROUND: Flow Cytometry (FCM) is still considered to be the method of choice for accurate CD4 enumeration. However, the use of FCM in developing countries is problematic due to their cost and complexity. Lower-cost technologies have been introduced. We evaluated CyFlow Counter together with its lyophilized reagents, and Pima CD4 in high-temperature area, using FACSCount as reference. MATERIALS AND METHODS: Whole blood samples were consecutively collected by venipuncture from 111 HIV+ patients and 17 HIV-negative donors. CD4 T-cell enumeration was performed on CyFlow Counter, Pima CD4 and FACSCount. RESULTS: CyFlow Counter and Pima CD4 systems showed good correlation with FACSCount (slope of 0.82 and 0.90, and concordance rhoc of 0.94 and 0.98, respectively). CyFlow Counter showed absolute or relative biases (LOA) of -63 cells/mm(3) (-245 to 120) or -9.8% ( 38.1 to 18.4) respectively, and Pima CD4 showed biases (LOA) of -30 cells/mm(3) ( 160 to 101) or -3.5% (-41.0 to 33.9%). CyFlow Counter and Pima CD4 showed respectively 106.7% and 105.9% of similarity with FACSCount. According to WHO 2010 ART initiation threshold of 350 cells/mm(3), CyFlow Counter and Pima CD4 showed respectively sensibility of 100% and 97%, and specificity of 91% and 93%. CyFlow Counter and Pima CD4 were strongly correlated (slope of 1.09 and rhoc of 0.95). These alternative systems showed good agreement with bias of 33 cells/mm(3) (-132 to 203) or 6.3% (-31.2 to 43.8), and similarity of 104.3%. CONCLUSION: CyFlow Counter using CD4 easy count kit-dry and Pima CD4 systems can accurately provide CD4 T-cell counts with acceptable agreement to those of FACSCount. PMID- 24066185 TI - Roles of a novel Crp/Fnr family transcription factor Lmo0753 in soil survival, biofilm production and surface attachment to fresh produce of Listeria monocytogenes. AB - Listeria monocytogenes is a foodborne bacterial pathogen and the causative agent of an infectious disease, listeriosis. L. monocytogenes is ubiquitous in nature and has the ability to persist in food processing environments for extended periods of time by forming biofilms and resisting industrial sanitization. Human listeriosis outbreaks are commonly linked to contaminated dairy products, ready to-eat meats, and in recent years, fresh produce such as lettuce and cantaloupes. We identified a putative Crp/Fnr family transcription factor Lmo0753 that is highly specific to human-associated genetic lineages of L. monocytogenes. Lmo0753 possesses two conserved functional domains similar to the major virulence regulator PrfA in L. monocytogenes. To determine if Lmo0753 is involved in environmental persistence-related mechanisms, we compared lmo0753 deletion mutants with respective wild type and complementation mutants of two fully sequenced L. monocytogenes genetic lineage II strains 10403S and EGDe for the relative ability of growth under different nutrient availability and temperatures, soil survival, biofilm productivity and attachment to select fresh produce surfaces including romaine lettuce leaves and cantaloupe rinds. Our results collectively suggested that Lmo0753 plays an important role in L. monocytogenes biofilm production and attachment to fresh produce, which may contribute to the environmental persistence and recent emergence of this pathogen in human listeriosis outbreaks linked to fresh produce. PMID- 24066186 TI - Type and extent of somatic morbidity before and after the diagnosis of hypothyroidism. a nationwide register study. AB - BACKGROUND: Hypothyroidism has been linked with an increased risk of other morbidities, such as cardiovascular diseases and diabetes mellitus. However, the temporal relationship between these diseases and the diagnosis of hypothyroidism is not well illuminated. Such information may provide insight into causal relationships between hypothyroidism and other morbidities. AIM: To investigate the type and extent of somatic morbidity before and after a diagnosis of hypothyroidism. METHODS: Observational cohort study. From official Danish health registers, 2822 hypothyroid singletons were identified and matched 1:4 with non hypothyroid controls and observed over a mean period of 6 years. Frequency of different morbidities was obtained by person-to-person linking in the registers. Logistic and Cox regression models were used to assess the risk of morbidity before and after the diagnosis of hypothyroidism, respectively. RESULTS: Prior to the diagnosis of hypothyroidism there was a significantly increased risk of being diagnosed with cardiovascular diseases (odds ratio (OR) 1.37; 95% confidence interval (CI): 1.19-1.58), lung diseases (OR 1.25; 95% CI: 1.13-1.39), diabetes mellitus (OR 1.92; 95% CI: 1.61-2.29), as well as malignant diseases (OR 1.24; 95% CI: 1.06-1.45). Following the diagnosis of hypothyroidism there was a significantly increased risk of being diagnosed with cardiovascular diseases (hazard ratio (HR) 1.36; 95% CI: 1.15-1.60); lung diseases (HR 1.51; 95% CI: 1.30 1.75); and diabetes mellitus (HR 1.40; 95% CI: 1.11-1.77). CONCLUSIONS: Prior to the diagnosis of hypothyroidism there is an excess risk of being diagnosed with cardiovascular diseases, lung diseases, diabetes mellitus, and malignant diseases. Following the diagnosis of hypothyroidism we demonstrate an increased frequency of cardiovascular diseases, lung diseases, and diabetes mellitus. PMID- 24066187 TI - High-performance size-based microdevice for the detection of circulating tumor cells from peripheral blood in rectal cancer patients. AB - Since individualized therapy becomes more and more important in the treatment of rectal cancer, an accurate and effective approach should be established in the clinical settings to help physicians to make their decisions. Circulating tumor cells (CTCs), originated from either primary or metastatic cancer, could provide important information for diagnosis and monitoring of cancer. However, the implication and development of CTCs are limited due to the extreme rarity of these tumor cells. In this study we fabricated a simple and high-performance microfluidic device, which exploited numerous filtered microchannels in it to enrich the large-sized target tumor cells from whole blood. A very high CTC capture efficiency (average recovery rate: 94%) was obtained in this device at the optimum flow rate of 0.5 mL/h and channel height of 5 um. Additionally, we used this device for detecting CTCs in 60 patients with rectal cancer. The CTC counts of rectal cancer patients were significantly higher than those in healthy subjects. Furthermore, the CTC counts detected by this device were significantly higher than those by EpCAM bead-based method for rectal cancer patients with various stage. Especially, for localized rectal cancer patients, the positive rates of samples with more than 3 CTCs per 5 mL blood by use of microdevice vs. EpCAM-based ones were 100% vs. 47%, respectively. Thus, this device provides a new and effective tool for accurate identification and measurement of CTCs in patients with rectal cancer, and has broad potential in clinical practice. PMID- 24066188 TI - Organ-specific splice variants of aquaporin water channel AgAQP1 in the malaria vector Anopheles gambiae. AB - BACKGROUND: Aquaporin (AQP) water channels are important for water homeostasis in all organisms. Malaria transmission is dependent on Anopheles mosquitoes. Water balance is a major factor influencing mosquito survival, which may indirectly affect pathogen transmission. METHODOLOGY/PRINCIPAL FINDINGS: We obtained full length mRNA sequences for Anopheles gambiae aquaporin 1 (AgAQP1) and identified two splice variants for the gene. In vitro expression analysis showed that both variants transported water and were inhibited by Hg(2+). One splice variant (AgAQP1A) was exclusively expressed in adult female ovaries indicating a function in mosquito reproduction. The other splice variant (AgAQP1B) was expressed in the midgut, malpighian tubules and the head in adult mosquitoes. Immunolabeling showed that in malpighian tubules, AgAQP1 is expressed in principal cells in the proximal portion and in stellate cells in the distal portion. Moreover, AgAQP1 is expressed in Johnston's organ (the "ear"), which is important for courtship behavior. CONCLUSIONS AND SIGNIFICANCE: These results suggest that AgAQP1 may play roles associated with mating (courtship) and reproduction in addition to water homeostasis in this important African malaria vector. PMID- 24066189 TI - Dynamics of response to asynapsis and meiotic silencing in spermatocytes from Robertsonian translocation carriers. AB - Failure of homologous synapsis during meiotic prophase triggers transcriptional repression. Asynapsis of the X and Y chromosomes and their consequent silencing is essential for spermatogenesis. However, asynapsis of portions of autosomes in heterozygous translocation carriers may be detrimental for meiotic progression. In fact, a wide range of phenotypic outcomes from meiotic arrest to normal spermatogenesis have been described and the causes of such a variation remain elusive. To better understand the consequences of asynapsis in male carriers of Robertsonian translocations, we focused on the dynamics of recruitment of markers of asynapsis and meiotic silencing at unsynapsed autosomal trivalents in the spermatocytes of Robertsonian translocation carrier mice. Here we report that the enrichment of breast cancer 1 (BRCA1) and histone gammaH2AX at unsynapsed trivalents declines during the pachytene stage of meiosis and differs from that observed in the sex body. Furthermore, histone variant H3.3S31, which associates with the sex chromosomes in metaphase I/anaphase I spermatocytes, localizes to autosomes in 12% and 31% of nuclei from carriers of one and three translocations, respectively. These data suggest that the proportion of spermatocytes with markers of meiotic silencing of unsynapsed chromatin (MSUC) at trivalents depends on both, the stage of meiosis and the number of translocations. This may explain some of the variability in phenotypic outcomes associated with Robertsonian translocations. In addition our data suggest that the dynamics of response to asynapsis in Robertsonian translocations differs from the response to sex chromosomal asynapsis in the male germ line. PMID- 24066192 TI - Dipan J. Shah offers editorial oversight for this issue of the Methodist Debakey Cardiovascular Journal. PMID- 24066190 TI - Mitochondrial DNA instability in cells lacking aconitase correlates with iron citrate toxicity. AB - Aconitase, the second enzyme of the tricarboxylic acid cycle encoded by ACO1 in the budding yeast Saccharomyces cerevisiae, catalyzes the conversion of citrate to isocitrate. aco1Delta results in mitochondrial DNA (mtDNA) instability. It has been proposed that Aco1 binds to mtDNA and mediates its maintenance. Here we propose an alternative mechanism to account for mtDNA loss in aco1Delta mutant cells. We found that aco1Delta activated the RTG pathway, resulting in increased expression of genes encoding citrate synthase. By deleting RTG1, RTG3, or genes encoding citrate synthase, mtDNA instability was prevented in aco1Delta mutant cells. Increased activity of citrate synthase leads to iron accumulation in the mitochondria. Mutations in MRS3 and MRS4, encoding two mitochondrial iron transporters, also prevented mtDNA loss due to aco1Delta. Mitochondria are the main source of superoxide radicals, which are converted to H2O2 through two superoxide dismutases, Sod1 and Sod2. H2O2 in turn reacts with Fe(2+) to generate very active hydroxyl radicals. We found that loss of Sod1, but not Sod2, prevents mtDNA loss in aco1Delta mutant cells. We propose that mtDNA loss in aco1Delta mutant cells is caused by the activation of the RTG pathway and subsequent iron citrate accumulation and toxicity. PMID- 24066191 TI - Status of systemic oxidative stress during therapeutic hypothermia in patients with post-cardiac arrest syndrome. AB - Therapeutic hypothermia (TH) is thought to be due to the downregulation of free radical production, although the details of this process remain unclear. Here, we investigate changes in oxidative stress and endogenous biological antioxidant potential during TH in patients with post-cardiac arrest syndrome (PCAS). Nineteen PCAS patients were enrolled in the study. Brain temperature was decreased to the target temperature of 33 degrees C, and it was maintained for 24 h. Patients were rewarmed slowly (0.1 degrees C/h, <1 degrees C/day). The generation of reactive oxygen metabolites (ROMs) was evaluated in plasma samples by d-ROM test. Plasma antioxidant capacity was measured by the biological antioxidant potential (BAP) test. Levels of d-ROMs and BAP levels during the hypothermic stage (33 degrees C) were suppressed significantly compared with pre TH induction levels (P < 0.05), while both d-ROM and BAP levels increased with rewarming (33-36 degrees C) and were correlated with brain temperature. Clinical monitoring of oxidative stress and antioxidant potential is useful for evaluating the redox state of patients undergoing TH after PCAS. Additional therapy to support the antioxidant potential in the rewarming stage following TH may reduce some of the observed side effects associated with the use of TH. PMID- 24066193 TI - Introduction: Cardiovascular magnetic resonance. PMID- 24066194 TI - Cardiac MRI for myocardial ischemia. AB - Proper assessment of the physiologic impact of coronary artery stenosis on the LV myocardium can affect patient prognosis and treatment decisions. Cardiac magnetic resonance imaging (CMR) assesses myocardial perfusion by imaging the myocardium during a first-pass transit of an intravenous gadolinium bolus, with spatial and temporal resolution substantially higher than nuclear myocardial perfusion imaging. Coupled with late gadolinium enhancement (LGE) imaging for infarction during the same imaging session, CMR with vasodilating stress perfusion imaging can qualitatively and quantitatively assess the myocardial extent of hypoperfusion from coronary stenosis independent of infarcted myocardium. This approach has been validated experimentally, and multiple clinical trials have established its diagnostic robustness when compared to stress single-photon emission computed tomography. In specialized centers, dobutamine stress CMR has been shown to have incremental diagnostic value above stress echocardiography due to its high imaging quality and ability to image the heart with no restriction of imaging window. This paper reviews the technical aspects, diagnostic utility, prognostic values, challenges to clinical adaptation, and future developments of stress CMR imaging. PMID- 24066195 TI - Cardiovascular magnetic resonance imaging for assessment of cardiac thrombus. AB - Cardiac thrombus provides a substrate for embolic events and an indication for anticoagulant therapy. Cardiac magnetic resonance (CMR) imaging enables thrombus to be detected based on intrinsic tissue characteristics related to avascular tissue composition. Delayed enhancement CMR tissue characterization has been well validated for thrombus assessment using references of both pathology and clinical thromboembolic outcomes. Comparative studies have demonstrated CMR to yield improved thrombus detection compared to echocardiography, which typically detects thrombus based on anatomic appearance. Experimental studies have demonstrated the feasibility of targeted CMR contrast agents for assessing thrombus composition and chronicity. This review examines established and emerging literature on use of CMR for assessing cardiac thrombus. PMID- 24066196 TI - Safety of MRIs in patients with pacemakers and defibrillators. AB - With a burgeoning population, increases in life expectancy, and expanding indications, the number of patients with cardiac devices such as pacemakers and implantable cardioverter defibrillators continues to increase each year. A majority of these patients will develop an indication for magnetic resonance imaging (MRI) in their lifetime. MRIs have established themselves as one of the most powerful imaging tools for a variety of conditions. However, given the historic safety concerns, many physicians are reluctant to use MRIs in this patient population. In this paper, we discuss the potential adverse effects of MRIs in patients with cardiac devices, review key studies that have addressed strategies to limit adverse effects, and provide our cardiovascular MRI laboratory's protocol for imaging patients with implanted cardiac devices. PMID- 24066197 TI - The role of cardiac magnetic resonance in valvular heart disease. AB - The prevalence of valvular heart disease is increasing as the population ages. In diagnosing individuals with valve disease, echocardiography is the primary imaging modality used by clinicians both for initial assessment and for longitudinal evaluation. However, in some cases cardiovascular magnetic resonance has become a viable alternative in that it can obtain imaging data in any plane prescribed by the scan operator, which makes it ideal for accurate investigation of all cardiac valves: aortic, mitral, pulmonic, and tricuspid. In addition, CMR for valve assessment is noninvasive, free of ionizing radiation, and in most instances does not require contrast administration. The objectives of a comprehensive CMR study for evaluating valvular heart disease are threefold: (1) to provide insight into the mechanism of the valvular lesion (via anatomic assessment), (2) to quantify the severity of the valvular lesion, and (3) to discern the consequences of the valvular lesion. PMID- 24066198 TI - Role of cardiac MRI in the assessment of nonischemic cardiomyopathies. AB - In this review, we will highlight the role of late gadolinium enhancement, along with other strengths available by cardiac MRI, in determining the underlying etiology of various nonischemic cardiomyopathies. Furthermore, we will also emphasize how late gadolinium enhancement may serve as a novel risk stratification tool to further impact patient care. PMID- 24066199 TI - Cardiac magnetic resonance in adults with congenital heart disease. AB - Increasing numbers of adults with congenital heart disease are referred for cardiac magnetic resonance imaging. Knowledge of the congenital heart anatomy, prior surgical interventions, and the development of an imaging focus for each individual patient plays a crucial role when performing a successful cardiac magnetic resonance imaging examination. The following manuscript focuses on cardiac magnetic resonance imaging considerations of three specific conotruncal congenital heart lesions: tetralogy of Fallot, transposition of the great arteries (TGA), and physiologically corrected TGA (c-TGA). PMID- 24066200 TI - Cardiac MR for the assessment of myocardial viability. AB - This article focuses on delayed contrast enhanced MRI (DE-MRI) to assess myocardial viability. We start by discussing previous literature that evaluated the potential importance of myocardial viability testing and follow up with the more recent Surgical Treatment for Heart Disease Trial (STICH) trial results. We then provide an overview of the basic concepts and technical aspects of the current DE-MRI technique and review the initial studies demonstrating that DE-MRI before coronary revascularization can predict functional improvement. Finally, we use DE-MRI as a paradigm to discuss physiological insights into viability assessment and examine common assumptions in the metrics used to evaluate viability techniques. PMID- 24066201 TI - Redefining myocardial infarction: what is new in the ESC/ACCF/AHA/WHF Third Universal Definition of myocardial infarction? AB - Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. Each year, an estimated 785,000 persons will have a new MI in the United States alone, and approximately every minute an American will succumb to one.1 In addition, MI has major psychological and legal implications for patients and the society and is an important outcome measure in research studies. The prevalence of MI provides useful data regarding the burden of coronary artery disease and offers insight into health care planning, policy, and resource allocation. The importance of accurately and reproducibly defining MI is therefore self-evident. The Third Universal Definition of Myocardial Infarction (MI) expert consensus document was published in October 2012 by the global Myocardial Infarction Task Force.2 This landmark document was cosponsored by multiple cardiovascular societies and included both updated definitions and a modified classification of MI that have important clinical, epidemiological, and research implications. We hereby present a critical overview of this important document and summarize its key recommendations. PMID- 24066202 TI - A case of reverse transient ischemic dilatation. PMID- 24066203 TI - Utility of cardiac computed tomography for assessment of prosthetic aortic valve dysfunction with pannus formation. PMID- 24066206 TI - Superior vena cava syndrome associated with metastatic adenocarcinoma to the heart: the diagnostic utility of cardiac resonance imaging. PMID- 24066207 TI - The Texas Medical Center: building blocks for the future. PMID- 24066208 TI - Conducting in chaos. PMID- 24066209 TI - Model of induced leakage of polymethylmethacrilate inside epidural space and prevertebral muscles during vertebroplasty in pigs: clinical, macroscopical, and histological study. AB - STUDY DESIGN: Experimental study in animals. PURPOSE: Study the clinical behavior of animals after an induced leakage of cement during vertebroplasty in pigs. Study the distribution of polymethylmetacrilate inside the epidural space and prevertebral muscle. Study the histological findings of the spinal cord and muscles, which contact with cement. OVERVIEW OF LITERATURE: Although vertebroplasty has a low rate of complication, leakage of cement is highly frequent. There is paucity, in how cement is distributed inside the spinal canal and what occurs when soft tissue comes into contact with polymethylmetacrilate. METHODS: We performed vertebroplasty on six pigs. We performed a leakage of cement into the epidural space and into prevertebral muscles. Two weeks later we performed an anatomic evaluation regarding the spreading of polymethylmetacrilate and a histological analysis of soft tissues that came into contact with it. RESULTS: No clinical alterations were observed. We observed a laminar distribution of the cement surrounding dura mater, and creating a fusiform cavity inside muscles. Spinal cord was normal in all the animals. In dura mater, we observed: synovialmetaplasia, inflammatory reaction, crystal deposits, and giant cell-reaction. In muscles, we observed: inflammatory reaction, crystal deposits, giant-cell-reaction, muscular atrophy, fibrosis, and synovial metaplasia. CONCLUSIONS: The spinal cord was normal; it is likely that dura mater and cerebrospinal fluid are responsible to isolate neural structures from cement. Dura mater and muscle showed similar histological changes than other publications. Synovial metaplasia was observed in dura mater and muscles that came into contact with cement. The pulsatile rubbing between the tissue and cement could be responsible of this phenomenon. PMID- 24066210 TI - Role of intraoperative red cell salvage and autologus transfusion in metastatic spine surgery: a pilot study and review of literature. AB - STUDY DESIGN: Prospective cohort study. PURPOSE: There has been no research examining the use of intraoperative cell salvage during metastatic spinal surgery. The present work is a pilot study investigating the role of cell salvage during metastatic spine surgery. OVERVIEW OF LITERATURE: There is no spinal literature about role of cell salvage and autologus transfusion in metastatic spinal cancer. METHODS: Sixteen spinal metastases patients who received red cell salvage using a leucocyte depletion filter were enrolled. Of these, ten patients who received salvaged blood transfusion were included in the final analysis. Data collection involved looking at the case notes, operating room records and the prospectively updated metastatic spinal cancer database maintained in the spinal department. Cell salvage data was recovered from the central cell salvage database maintained in the anesthetic department. RESULTS: Amount of salvaged blood ranged from 120 to 600 mL (average, 318 mL). The average drop in hemoglobin was 1.65 units (range, 0.4-2.7 units). Three patients (30%) required postoperative allogenic blood transfusion. The average follow up was 9.5 months (range, 6-6 months). One patient developed new lung metastasis, at seven months. No patient developed new liver metastases. Preoperatively, six patients had diffuse skeletal metastases. Of this subgroup, three developed new skeletal metastases. No cases showed any wound related problems in the postoperative period. CONCLUSIONS: In our study transfusion of intraoperatively salvaged blood did not result in disseminated metastatic cancer. We would suggest that red cell salvage might have a role during metastatic spine surgery. PMID- 24066211 TI - Diagnostic usefulness of white blood cell and absolute neutrophil count for postoperative infection after anterior cervical discectomy and fusion using allograft and demineralized bone matrix. AB - STUDY DESIGN: Prospective study. PURPOSE: We investigated normative temporal levels of white blood cell (WBC) and absolute neutrophil count (ANC) in uncomplicated anterior cervical discectomy and fusion (ACDF) using allograft and demineralized bone matrix (DBM). OVERVIEW OF LITERATURE: No study has investigated the diagnostic usefulness of WBC and ANC for postoperative infection following ACDF using allograft and DBM. METHODS: Blood samples of 85 patients, who underwent one or two-level ACDF, were obtained and evaluated before surgery and on the first, third, fifth, seventh, fourteenth, thirtieth, and ninetieth postoperative days. No infection was found in all patients for at least one year follow-up period. RESULTS: Mean WBC and ANC values increased significantly and reached peak levels on the first postoperative day. The peaked levels rapidly decreased but still remained elevated above the preoperative levels on the third postoperative day. The levels returned close to the preoperative levels on the fifth postoperative day. The mean WBC and ANC values did not get out of their normal reference ranges throughout the follow-up periods. One-level and two-level ACDF exhibited a similar course of postoperative changes in WBC and ANC values and no significant difference in mean levels of WBC and ANC throughout the follow up periods. CONCLUSIONS: Uncomplicated ACDF using allograft and DBM showed normal values of WBC and ANC during the early postoperative period. Therefore, significant abnormal values of WBC and ANC at an early postoperative period suggest the possibility of the development of acute postoperative infection after ACDF using allograft and DBM. PMID- 24066212 TI - Validation of the korean version of the neck pain and disability scale. AB - STUDY DESIGN: A prospective study. PURPOSE: To evaluate the reliability and validity of the adapted Korean version of the Neck Pain and Disability Scale (NPDS). OVERVIEW OF LITERATURE: The validity of Korean version of NPDS has not been completely demonstrated yet. METHODS: Translation/retranslation of the English version of NPDS was conducted, and all steps of the cross-cultural adaptation process were performed. The Korean version of the visual analog scale (VAS) measure of pain, NPDS and the previously validated Short Form-36 (SF-36) were mailed to 91 patients, who had been surgically treated for degenerative cervical disease. Eighty-one patients responded to the first mailing of questionnaires and 69 of the first time responder returned their second survey. Factor analysis and reliability assessment by kappa statistics of agreement for each item, the intraclass correlation coefficient and Cronbach's alpha were conducted. Concurrent and construct validity were also evaluated by comparing the responses of NPDS with the results of VAS and responses of SF-36. RESULTS: Factor analysis extracted 3 factors. All items had a kappa statistics of agreement greater than 0.6. The NPDS showed excellent test/re-test reliability. Internal consistency of Cronbach's alpha was found to be very good. The NPDS was correlated with the VAS. The Korean version of NPDS showed good significant correlation with SF-36 total score and with single SF-36 domains scores. CONCLUSIONS: The adapted Korean version of the NPDS was successfully translated and is considered suitable for outcome assessments in the Korean-speaking patients with neck pain. PMID- 24066213 TI - Utility of limited protocol magnetic resonance imaging lumbar spine for nerve root compression in a developing country, is it accurate and cost effective? AB - STUDY DESIGN: Cross sectional study. PURPOSE: To determine the accuracy of the screening magnetic resonance study of the lumbar spine in the diagnosis of nerve root compression in cases of low back pain as compared to the routine magnetic resonance imaging (MRI) study of the lumbar spine. OVERVIEW OF LITERATURE: No local study has been conducted for this purpose. In an international study, the reported sensitivity and specificity of screening MRI lumbar spine protocol in the detection of nerve root compression are 54% and 100% respectively. METHODS: Patients of both genders older than 20 years of age with low back pain of any duration or any severity who were referred to the radiology department of Aga Khan University Hospital for MRI of their lumbar spine were evaluated. Two sets of MRI imaging were recruited for each patient: one labeled as 'screening' and the other labeled as 'routine'. The findings of screening MRI were compared with the findings of the routine MRI study. RESULTS: A total of 109 patients fulfilling the inclusion criteria were included in this study. The diagnostic accuracy, specificity and sensitivity of the screening protocol in our study was 100%, 100% and 100%, respectively in comparison with the routine MRI lumbar spine study for the detection of nerve root compression. CONCLUSIONS: Our data proved that the MRI screening study is a highly accurate tool, and its findings are comparable to the routine study for the detection of nerve root compression especially in cases of lumbar spondylosis. PMID- 24066214 TI - Translaminar microendoscopic herniotomy for cranially migrated lumbar disc herniations encroaching on the exiting nerve root in the preforaminal and foraminal zones. AB - STUDY DESIGN: Case series. PURPOSE: The aim of this study was to describe translaminar microendoscopic herniotomy (TL-MEH) for cranially migrated lumbar disc herniations encroaching on the exiting nerve root in the preforaminal and foraminal zones and to report preliminary results of the procedure. OVERVIEW OF LITERATURE: Conventional interlaminar approaches for preforaminal and foraminal lumbar disc herniations result in extensive removal of the lamina and facet joint to remove disc fragments safely. More destructive approaches increase the risk of postoperative segmental instability. METHODS: TL-MEH is a minimally invasive procedure for herniotomy via the translaminar approach using a microendoscopic technique. TL-MEH was performed in seven patients with a cranially migrated lumbar disc herniation encroaching on the exiting nerve root. The disc fragments were located in the preforaminal zone in four patients, and in the preforaminal and foraminal zones in three. RESULTS: All patients experienced immediate relief from symptoms after surgery and satisfactory results at the final follow-up. Surgical complications, such as a dural tear, nerve injury, and surgical site infection, were not investigated. CONCLUSIONS: TL-MEH seemed to be an effective and safe alternative minimally invasive surgical option for patients with a cranially migrated lumbar disc herniation encroaching the exiting nerve root in the preforaminal and foraminal zones. PMID- 24066215 TI - Prospective randomized study for antibiotic prophylaxis in spine surgery: choice of drug, dosage, and timing. AB - STUDY DESIGN: Prospective randomized study of antibiotic prophylaxis in elective spine surgery. PURPOSE: The aim of this study was to compare the rate of postoperative surgical site infection for a single dose of two different generations of cephalosporin with different dosage and timing of the antibiotics. OVERVIEW OF LITERATURE: Current recommendation for prophylaxis in elective spine surgery is up to 60 minutes prior to incision. No study has investigated between different generation of cephalosporin for prophylaxis in elective spine surgery with respect to choice, dosage and timing. METHODS: This study was a prospective randomized study of 90 patients, assessed for the occurrence of surgical site infection (defined by the Centers for Disease Control and Prevention criteria) and other infections for up to 6 months after surgery. Demographic, surgical and further data were collected on subsequent operations, including hardware removal. RESULTS: Mean age in our group was 47 years (range, 19-71 years). The male to female ratio was 49:41 and the average timing of administration of antibiotics was 77 minutes (range, 30-120 minutes). The average blood loss was 626 mL (range, 150-3,000 mL) with a mean duration of surgery for 3.2 hours (range, 1.5-6 hours). One case of superficial infection and one case of deep infection met the exclusion criteria. CONCLUSIONS: Our results support the use of a single preoperative dose of antibiotics in instrumented and non-instrumented elective spine surgery up to one hour prior to incision. There was no difference in terms of occurrence of surgical site infection with respect to dosage, choice and timing of antibiotics. PMID- 24066216 TI - Effect of correction of the contractured flexed osteoarthritic knee on the sagittal alignment by total replacement. AB - STUDY DESIGN: A prospective analysis of an adaptive change of the spinopelvic alignment after total knee arthroplasty. PURPOSE: To evaluate the effect of correction of the contractured knee in flexion on the spinopelvic alignment by total knee arthroplasty. OVERVIEW OF LITERATURE: Flexion contracture of the knee joint may affect the body posture and precipitate the symptoms in the lumbar spine, which is known as the 'knee-spine syndrome'. METHODS: Fifteen patients who could be followed at least over 12 months were used in this study. Neutral whole spine lateral standing radiograms taken at certain intervals were analyzed. The subjects were divided into two groups (group A, the patients who obtained over 10 degrees correction; group B, the others). The sacral slope, the pelvic tilt and the pelvic incidence were measured preoperatively and at 12 months and thereafter postoperatively in all the patients. Also, the thoracic kyphosis, lumbar lordosis, and lumbosacral angle were measured, including the spinal sagittal balance, S1 overhang and spino-sacral angle. RESULTS: The average correction of the contractured knee in flexion were 13.8 degrees in group A and 2.7 degrees in group B. The median of changes of the sacral slope were 4.2 degrees in group A and -0.4 degrees in group B. These results revealed that there was a significant increase of the sacral slope for group A (p=0.001). However, there were no significant differences between the other parameters. CONCLUSIONS: The sacral slope appears to be affected by the change of the flexion contracture after total knee arthroplasty. PMID- 24066217 TI - No acceleration of intervertebral disc degeneration after a single injection of bupivacaine in young age group with follow-up of 5 years. AB - STUDY DESIGN: Prospective study of changes in intervertebral disc degeneration after injection of bupivacaine. PURPOSE: To examine whether injection of bupivacaine into human intervertebral discs accelerates their degeneration. OVERVIEW OF LITERATURE: Bupivacaine is commonly used for therapy and diagnosis of discogenic low back pain. However, several in vitro studies have reported toxic effects of bupivacaine to disc cells. We sought to evaluate whether this finding is clinically relevant. METHODS: We selected 46 patients with low back pain who showed disc degeneration at only one level (L4-L5 or L5-S1) on magnetic resonance imaging (MRI) (discography group, n=18), discoblock group (injection of bupivacaine, n=18), and a control group, n=10). There were no significant differences in baseline characteristics across the 3 groups. The two experimental groups underwent either discography or anesthetic discoblock, respectively. All three groups were followed up 5 years after the examination. RESULTS: At 5 years follow-up, there was no significant difference in the rate of disc degeneration among the 3 groups (p>0.1). Moreover, X-ray images showed that there was no significant difference in disc height, range of motion, or translation between flex and extension position (p>0.1). CONCLUSIONS: In conclusion, radiologic and MRI findings did not show acceleration of intervertebral disc degeneration at 5 years after a single injection of bupivacaine into human discs. PMID- 24066218 TI - Is kyphoplasty necessary? AB - We describe four cases of delayed union in female patients with severe osteoporotic vertebral fractures, which were treated in a similar but less costly method to kyphoplasty. Due to domestic regulations, inflatable tamps for kyphoplasty are not available to every clinical orthopedists in Japan. In our clinical experience of four cases of delayed lumbar spine union between 2009 and 2010, we performed vertebroplasty using a reduction and spreading prod (Oyamada prod) for fracture reduction and a pediatric uromatic balloon (Medicon Co. Ltd.) to enlarge the pre-existing cavity. Our clinical results were comparable to those of kyphoplasty procedures performed in the USA. Our procedure could be used to overcome the shortage of medical supplies in developing countries or in countries such as Japan, which often prioritize financial concerns over providing optimal health care. Our method could serve as a useful compromise for moribund patients considering its cost efficiency. PMID- 24066219 TI - Tuberculosis affecting multiple vertebral bodies. AB - Spinal tuberculosis usually occurs in a single vertebral body or two to three adjacent vertebrae; it rarely occurs in multiple vertebral bodies. Surgery is indicated in cases that do not improve with conservative therapy, or when paralysis is evident. Two cases regarding patients with spinal tuberculosis in multiple vertebral bodies on whom surgery was performed are reported. Case 1, the patient was a 77-year-old woman with spinal tuberculosis in four vertebral bodies from the lower thoracic to the lumbar spine. As she had pronounced lower back pain, posterolateral fusion with a pedicle screw was performed. Case 2, the patient was a 29-year-old Indonesian man with spinal tuberculosis in 17 vertebral bodies of the spine who was unable to stand due to paralysis of both legs, thus posterolateral fusion with a pedicle screw was performed. Good results were obtained from tuberculostatic drug therapy and surgical instrumentation. PMID- 24066220 TI - Giant invasive sacral schwannoma showing chromosomal numerical aberrations [ 14,+18,+22]. AB - Here, we report on a rare case of a giant invasive sacral schwannoma. The patient was a 58-year-old woman who had a 6-year history of non-specific buttock pain. Histological investigation confirmed the diagnosis of cellular schwannoma. The following numerical aberration was detected using the GTG-banding method for karyotypes: 47,XX,-14,+18,+22. Cytogenetic studies of schwannomas have indicated a complete or partial loss of chromosome 22 as the most common abnormality, but this case is cytogenetically rare because of the recurrence of trisomy 22. PMID- 24066221 TI - Delayed diagnosis of cauda eqina syndrome with perineural cyst after combined spinal-epidural anesthesia in hemodialysis patient. AB - Symptomatic Tarlov (perineural cysts) are uncommon. In the following hemodialysis case, cauda equina syndrome was not detected after combined spinal-epidural anesthesia untilthe patient reported a lack of sensation in the perianal area 14 days postoperatively. She had normal motor function of her extremities. A laminectomy and cyst irrigation was performed. After the operation, her sphincter disturbance subsided gradually and her symptoms had disappeared. PMID- 24066222 TI - Lumbar spinal stenosis due to a large calcified mass in the ligamentum flavum. AB - We describe a rare case of lumbar spinal stenosis due to a large calcified mass in the ligamentum flavum. This patient presented with a 12-month history of severe right leg pain and intermittent claudication. A computed tomography scan was performed, revealing a large calcified mass on the ligamentum flavum at the right-hand side of the lumbar spinal canal. We performed a laminotomy at the L4/5 level with resection of the calcified mass from the ligamentum flavum. The findings of various analyses suggested that the calcified mass consisted mostly of Ca3(PO4)2 and calcium phosphate intermixed with protein and water. The calcified mass in the ligamentum flavum was causing lumbar spinal stenosis. Surgical decompression by resection of the mass was effective in this patient. The calcified material was composed mainly of elements derived from calcium phosphate. Degenerative changes in the ligamentum flavum of the lumbar spine may have been involved in the production of this calcified mass. PMID- 24066223 TI - Gorham's Disease of Spine. AB - Gorham's disease is a rare disorder characterized by clinical and radiological disappearance of bone by proliferation of non-neoplastic vascular tissue. The disease was first reported by Jackson in 1838 in a boneless arm. The disease was then described in detail in 1955 by Gorham and Stout. Since then, about 200 cases have been reported in the literature, with only about 28 cases involving the spine. We report 2 cases of Gorham's disease involving the spine and review related literature to gain more understanding about this rare disease. PMID- 24066224 TI - Vertebroplasty in patients with tumour-related vertebral fractures: is rehabilitation needed? AB - For about 20 years, vertebroplasty has been used to achieve relief from pain and improve function in eligible patients affected by vertebral fractures. The procedure is also performed in patients with tumours of the vertebral body. The aim of this study was to investigate, by means of a literature review, correlations between vertebroplasty and the need for rehabilitation after patients with tumour-related vertebral fractures were operated on. This review was based on literature from the US National Library of Medicine, National Institutes of Health (PubMed), using the following Medical Subject Headings (MeSH) terms: "vertebroplasty," "surgical procedures minimally invasive," "bone neoplasm," "spine," "postoperative care," "rehabilitation," and "exercise." In total, 14 citations were retrieved: potentially relevant studies were identified by searching titles and abstracts, and then the full text of the selected articles was reviewed. From this review, the postoperative course of vertebroplasty today does not strictly indicate the need for rehabilitation. PMID- 24066225 TI - Complete dissection of transcription elongation reveals slow translocation of RNA polymerase II in a linear ratchet mechanism. AB - During transcription elongation, RNA polymerase has been assumed to attain equilibrium between pre- and post-translocated states rapidly relative to the subsequent catalysis. Under this assumption, recent single-molecule studies proposed a branched Brownian ratchet mechanism that necessitates a putative secondary nucleotide binding site on the enzyme. By challenging individual yeast RNA polymerase II with a nucleosomal barrier, we separately measured the forward and reverse translocation rates. Surprisingly, we found that the forward translocation rate is comparable to the catalysis rate. This finding reveals a linear, non-branched ratchet mechanism for the nucleotide addition cycle in which translocation is one of the rate-limiting steps. We further determined all the major on- and off-pathway kinetic parameters in the elongation cycle. The resulting translocation energy landscape shows that the off-pathway states are favored thermodynamically but not kinetically over the on-pathway states, conferring the enzyme its propensity to pause and furnishing the physical basis for transcriptional regulation. DOI:http://dx.doi.org/10.7554/eLife.00971.001. PMID- 24066226 TI - Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway. AB - Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. We identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors. We identified Eiger, the Drosophila tumor necrosis factor (TNF) homolog, as the signal responsible for apoptosis-induced apoptosis (AiA). Eiger is produced in apoptotic cells and, through activation of the c-Jun N-terminal kinase (JNK) pathway, is able to propagate the initial apoptotic stimulus. We also show that during coordinated cell death of hair follicle cells in mice, TNF-alpha is expressed in apoptotic cells and is required for normal cell death. AiA provides a mechanism to explain cohort behavior of dying cells that is seen both in normal development and under pathological conditions. DOI:http://dx.doi.org/10.7554/eLife.01004.001. PMID- 24066228 TI - Role of CD73 in Renal Sympathetic Neurotransmission in the Mouse Kidney. AB - Adenosine formed during renal sympathetic nerve stimulation (RSNS) enhances, by activating A1 receptors, the postjunctional effects of released norepinephrine and participates in renal sympathetic neurotransmission. Because in many cell types CD73 (ecto-5'-nucleotidase) is important for the conversion of 5'-AMP to adenosine, we investigated whether CD73 is necessary for normal renal sympathetic neurotransmission. In isolated kidneys from CD73 wild-type mice (CD73 +/+; n=17) perfused at a constant rate with Tyrode's solution, RSNS increased perfusion pressure by 17+/-4, 36+/-8 and 44+/-10 mm Hg at 3, 5 and 7 Hz, respectively. Similar responses were elicited from kidneys isolated from CD73 knockout mice (CD73 -/-; n=13; 28+/-11, 43+/-10 and 44+/-10 mm Hg at 3, 5 and 7 Hz, respectively); and a high concentration (100 MUmol/L) of alpha,beta methyleneadenosine 5'-diphosphate (CD73 inhibitor) did not alter responses to RSNS in C57BL/6 mouse kidneys (n=5; 21+/-5, 36+/-8 and 43+/-9 at 3, 5 and 7 Hz, respectively). Measurements of renal venous adenosine and inosine (adenosine metabolite) by liquid chromatography-tandem mass spectrometry demonstrated that the metabolism of exogenous 5'-AMP to adenosine and inosine was similar in CD73 /- versus CD73 +/+ kidneys. A1 receptor mRNA expression was increased in CD73 -/- kidneys, and 2-chloro-N6-cyclopentyladenosine (0.1 MUmol/L; A1 receptor agonist) enhanced renovascular responses to norepinephrine more in CD73 -/- versus CD73 +/+ kidneys. We conclude that CD73 is not essential for renal sympathetic neurotransmission because in the absence of renal CD73 other enzymes metabolize 5'-AMP to adenosine and because of compensatory upregulation of postjunctional coincident signaling between norepinephrine and adenosine. PMID- 24066227 TI - Bub3 reads phosphorylated MELT repeats to promote spindle assembly checkpoint signaling. AB - Regulation of macromolecular interactions by phosphorylation is crucial in signaling networks. In the spindle assembly checkpoint (SAC), which enables errorless chromosome segregation, phosphorylation promotes recruitment of SAC proteins to tensionless kinetochores. The SAC kinase Mps1 phosphorylates multiple Met-Glu-Leu-Thr (MELT) motifs on the kinetochore subunit Spc105/Knl1. The phosphorylated MELT motifs (MELT(P)) then promote recruitment of downstream signaling components. How MELT(P) motifs are recognized is unclear. In this study, we report that Bub3, a 7-bladed beta-propeller, is the MELT(P) reader. It contains an exceptionally well-conserved interface that docks the MELT(P) sequence on the side of the beta-propeller in a previously unknown binding mode. Mutations targeting the Bub3 interface prevent kinetochore recruitment of the SAC kinase Bub1. Crucially, they also cause a checkpoint defect, showing that recognition of phosphorylated targets by Bub3 is required for checkpoint signaling. Our data provide the first detailed mechanistic insight into how phosphorylation promotes recruitment of checkpoint proteins to kinetochores. DOI:http://dx.doi.org/10.7554/eLife.01030.001. PMID- 24066229 TI - R-Loop Formation In Trans at an AGGAG Repeat. AB - Formation of RNA-DNA hybrid, or R-loop, was studied in vitro by transcribing an AGGAG repeat with T7 RNA polymerase. When ribonuclease T1 was present, R-loop formation in cis was diminished, indicating that the transcript was separated from the template and reassociated with it. The transcript was found to form an R loop in trans with DNA comprising the AGGAG repeat, when the DNA was supercoiled. Results of chemical modification indicated that the duplex opened at the AGGAG repeat under negative supercoiling. PMID- 24066230 TI - Relevance of hypersexual disorder to family medicine and primary care as a complex multidimensional chronic disease construct. AB - Hypersexual disorder (HD) is not defined in a uniform way in the psychiatric literature. In the absence of solid evidence on prevalence, causes, empirically validated diagnostic criteria, instruments for diagnosis, consistent guidelines on treatment options, medical and psychosocial consequences, and type of caregivers that need to be involved, HD remains a controversial and relatively poorly understood chronic disease construct. The role of family medicine in the detection, treatment, and followup of HD is not well studied. The purpose of this paper is to describe the complexity of HD as a multidimensional chronic disease construct and its relevance to family medicine and primary care. PMID- 24066231 TI - Proteomic Analysis and Label-Free Quantification of the Large Clostridium difficile Toxins. AB - Clostridium difficile is the leading cause of antibiotic-associated diarrhea in hospitals worldwide, due to hypervirulent epidemic strains with the ability to produce increased quantities of the large toxins TcdA and TcdB. Unfortunately, accurate quantification of TcdA and TcdB from different toxinotypes using small samples has not yet been reported. In the present study, we quantify C. difficile toxins in <0.1 mL of culture filtrate by quantitative label-free mass spectrometry (MS) using data-independent analysis (MS(E)). In addition, analyses of both purified TcdA and TcdB as well as a standard culture filtrate were performed using gel-based and gel-independent proteomic platforms. Gel-based proteomic analysis was then used to generate basic information on toxin integrity and provided sequence confirmation. Gel-independent in-solution digestion of both toxins using five different proteolytic enzymes with MS analysis generated broad amino acid sequence coverage (91% for TcdA and 95% for TcdB). Proteomic analysis of a culture filtrate identified a total of 101 proteins, among them TcdA, TcdB, and S-layer proteins. PMID- 24066232 TI - Volume Flow Measurements in Arteriovenous Dialysis Access in Patients with and without Steal Syndrome. AB - Introduction. Dialysis associated steal syndrome (DASS) constitutes a serious risk for patients undergoing vascular access operations. We aim to assess the measured volume flow using ultrasound in patients with clinically suspected steal syndrome and determine differences in flow among types of arteriovenous (AV) access. Methods. Patients with permanent hemodialysis access with and without ischemic steal underwent duplex ultrasound (US) exams for the assessment of volume flow and quantitative evidence of hemodynamic steal. Volume flow was measured in the proximal feeding artery. Results. 118 patients underwent US of which 82 (69.5%) had clinical evidence of steal. Women were more likely to develop steal compared to men (chi-squared test P < 0.04). Mean volume flow in patients with steal was 1542 mL/min compared to 1087 mL/min (P < 0.002) in patients without evidence of steal. A significant difference in flow volumes in patients with and without steal was only seen in patients with a brachial cephalic upper arm AV fistula (AVF) (P < 0.002). When comparing different types of access with steal, brachial-cephalic upper arm AVFs had higher volume flows than the upper extremity AV graft (AVG) group (P = 0.04). Conclusion. In patients with DASS, women were more likely to develop steal syndrome. Significantly higher volume flows were seen with brachial-cephalic upper arm AVF in patients with steal compared to those without. A physiologic basis of this US finding may be present, which warrants further study into the dynamics of flow and its relationship to the underlying peripheral arterial pathology in the development of ischemic steal. PMID- 24066233 TI - Patients with obstructive sleep apnea display increased carotid intima media: a meta-analysis. AB - Background. Obstructive sleep apnea (OSA) is associated with coronary artery disease. Intermittent hypoxia associated with OSA increases sympathetic activity and may cause systemic inflammation, which may contribute to atherosclerosis leading to an increase in the size of carotid intima media thickness (CIMT). Methods. PubMed and Cochrane library were reviewed by utilizing different combinations of key words: sleep apnea, carotid disease, intima media thickness, and carotid atherosclerosis. Inclusion criteria were English articles; studies with adult population with OSA and without OSA; CIMT recorded by ultrasound in mean and standard deviation or median with 95% confidence interval; and OSA defined as apnea hypopnea index of >=5/h. A total of 95 studies were reviewed for inclusion, with 16 studies being pooled for analysis. Results. Ninety-five studies were reviewed, while 16 studies were pooled for analysis; since some studies have more than one data set, there were 25 data sets with 1415 patients being pooled for meta-analysis. All studies used ultrasound to measure CIMT. CIMT standardized difference in means ranged from -0.883 to 8.01. The pooled standardized difference in means was 1.40 (lower limit 0.996 to upper limit 1.803, (P < 0.0001). Conclusion. Patients with OSA appear to have increased CIMT suggestive of an atherosclerotic process. PMID- 24066234 TI - Critical assessment of implantable drug delivery devices in glaucoma management. AB - Glaucoma is a group of heterogeneous disorders involving progressive optic neuropathy that can culminate into visual impairment and irreversible blindness. Effective therapeutic interventions must address underlying vulnerability of retinal ganglion cells (RGCs) to degeneration in conjunction with correcting other associated risk factors (such as elevated intraocular pressure). However, realization of therapeutic outcomes is heavily dependent on suitable delivery system that can overcome myriads of anatomical and physiological barriers to intraocular drug delivery. Development of clinically viable sustained release systems in glaucoma is a widely recognized unmet need. In this regard, implantable delivery systems may relieve the burden of chronic drug administration while potentially ensuring high intraocular drug bioavailability. Presently there are no FDA-approved implantable drug delivery devices for glaucoma even though there are several ongoing clinical studies. The paper critically assessed the prospects of polymeric implantable delivery systems in glaucoma while identifying factors that can dictate (a) patient tolerability and acceptance, (b) drug stability and drug release profiles, (c) therapeutic efficacy, and (d) toxicity and biocompatibility. The information gathered could be useful in future research and development efforts on implantable delivery systems in glaucoma. PMID- 24066236 TI - Antidermatophytic Properties of Ar-Turmerone, Turmeric Oil, and Curcuma longa Preparations. AB - Curcuma longa L. or turmeric of the family Zingiberaceae is widely used in Thai traditional medicines for the treatment of rash, itching, tinea, and ringworm. Previous studies on turmeric oil reported effective antifungal activity against dermatophytes, a group of fungi that causes skin diseases. In this study, turmeric creams containing 6 and 10% w/w turmeric oil were prepared and tested against clinical strains of dermatophytes using broth dilution technique. Minimum fungicidal concentrations of 6 and 10% w/w turmeric creams were found to be 312 MU g/mL. Ar-turmerone, a major compound separated from turmeric oil, promoted more effective antidermatophytic activity with the MICs of 1.56-6.25 MU g/mL, compared to 3.90-7.81 MU g/mL of standard ketoconazole. The results indicated that 6% w/w turmeric oil in the cream was suitable to be formulated as antidermatophytic preparation. Further research should be done on long-term chemical and antifungal stabilities of the preparation. PMID- 24066235 TI - Scientific evaluation of edible fruits and spices used for the treatment of peptic ulcer in traditional Iranian medicine. AB - In traditional Iranian medicine (TIM), several edible fruits and spices are thought to have protective and healing effects on peptic ulcer (PU). The present study was conducted to verify anti-PU activity of these remedies. For this purpose, edible fruits and spices proposed for the management of PU in TIM were collected from TIM sources, and they were searched in modern medical databases to find studies that confirmed their efficacy. Findings from modern investigations support the claims of TIM about the efficacy of many fruits and spices in PU. The fruit of Phyllanthus emblica as a beneficial remedy for PU in TIM has been demonstrated to have antioxidant, wound healing, angiogenic, anti-H. pylori, cytoprotective, antisecretory, and anti-inflammatory properties. The fruit of Vitis vinifera has been found to be anti-H. pylori, anti-inflammatory, wound healing, angiogenic, cytoprotective, and antioxidant. The fruit and aril of seed from Myristica fragrans exert their beneficial effects in PU by increasing prostaglandin, modulation of nitric oxide and inflammatory mediators, wound healing, antisecretory, antacid, antioxidant, and anti-H. pylori activities, and improving angiogenesis. Pharmacological and clinical studies for evaluation of efficacy of all TIM fruits and spices in PU and their possible mechanisms of action are recommended. PMID- 24066237 TI - Impact of neonatal manipulation of androgen receptor function on endocrine metabolic programming in the juvenile female rat. AB - The impact of neonatal androgen receptor (AR) stimulation/blockage, due to testosterone propionate (TP)/AR antagonist treatment, on individual anthropometry and neuroendocrine-metabolic function was evaluated in the juvenile female rat. Pups (age 5 days) were s.c. injected with TP (1.25 mg), flutamide (F; 1.75 mg), and TP + F or vehicle (control, CT) and studied on day 30 of age. Body weight (BW), parametrial adipose tissue (PMAT) mass, food intake, adipoinsular axis, and steroidogenic functions were examined. Opposite to TP-rats, F-treated rats developed hypophagia, grew slowly (BW and PMAT), and displayed heightened peripheral insulin sensitivity. These F effects were abrogated in TP + F animals. Accordingly, TP rats displayed hyperleptinemia, an effect fully prevented by F cotreatment. Finally, androgen-treated animals bore an irreversible ovarian dysfunction (reduced circulating levels of 17HOP4 and ovary 17HOP4 content and P450c17 mRNA abundance). These data indicate that early stimulation of AR enhanced energy store, blockage of AR activity resulted in some beneficial metabolic effects, and neonatally androgenized rats developed a severe ovarian dysfunction. Our study highlights the important role of AR in the early organizational programming of metabolic and neuroendocrine functions. PMID- 24066238 TI - Are both ultrasonography and mammography necessary for cancer investigation of breast lumps in resource-limited countries? AB - Objective. To reevaluate the diagnostic value of breast imaging in the diagnosis of breast cancer in areas where health resources are limited. Methods. Patients were women presenting with breast lumps in two university-affiliated tertiary hospitals, Thailand, during 2006 and 2010. Clinical data were abstracted from the breast cancer registration database and patient records. The diagnostic predictive ability of ultrasonography and mammography was obtained from logistic regression analysis and presented with areas under the receiver operating characteristics (AuROCs) curves. Results. Among 3129 breast lumps (3069 women), 854 were diagnosed with breast cancer by certified pathologists. Age and size of lumps alone already predicted cancer correctly in 77.45% (AuROC = 77.45). Additional ultrasonography increased the prediction to 96.22% (P < 0.001). Additional mammography also increased the prediction to 95.99% (P < 0.001). Performing both imaging modalities did not increase the prediction clinically (0.01%-0.24%). More accurate prediction (2.07%-2.21%) may be added by fine needle aspiration cytology (FNAC). Conclusions. Breast imaging is still valuable in settings where health resources are limited. Single breast imaging (only either ultrasonography or mammography) is adequate for cancer diagnosis. It is therefore unnecessary to perform both imaging modalities. Accuracy of the diagnosis may be improved by FNAC, if available. PMID- 24066239 TI - A new fluorescence-based reporter gene vector as a tool for analyzing and fishing cells with activated wnt signaling pathway. AB - The dysregulated Wnt pathway is a major cause for the activation of cell proliferation and reduced differentiation in tumor cells. Therefore the Wnt signaling pathway is the on-top target in searching for new anticancer drugs or therapeutic strategies. Although the key players of the pathway are known, no specific anti-Wnt drug entered a clinical trial by now. Several screening approaches for potential compounds have been performed with a reporter gene assay using multiple T-cell factor/lymphoid enhancer factor (TCF/LEF) binding motifs as promoters which control luciferase or beta -galactosidase as reporter genes. In our work, we designed a reporter gene construct which anchors the enhanced green fluorescent protein (eGFP) to the plasma membrane. HEK 293T cells, which were stably transfected with this construct, express eGFP on the outer membrane after activation with either LiCl or WNT3A protein. Thus, cells with activated Wnt pathway could be identified and fished out of a heterogeneous cell pool by the use of magnetic-labeled anti-GFP antibodies. In summary, we present a new tool to easily detect, quantify, and sort cells with activated Wnt signaling pathway in a simple, fast, and cost-effective way. PMID- 24066240 TI - Utility of nuclear morphometry in predicting grades of diffusely infiltrating gliomas. AB - Introduction. The ability to reliably differentiate neoplastic from nonneoplastic specimen and ascertain the tumour grade of diffusely infiltrating gliomas (DIGs) is often challenging. Aims and Objective. To evaluate utility of image morphometry in identifying DIG areas and to predict tumour grade. Materials and Methods. Image morphometry was used to analyze the following nuclear features of 30 DIGs and 10 controls (CG): major axis of nucleus (MAJX), minor axis of nucleus (MINX), nuclear area (NA), nuclear perimeter (NP), nuclear roundness (NR), nuclear density (ND), and percentage of total nuclear area (%TNA). Results. Statistically significant differences in all parameters, except NR, were observed between all groups, with strong positive correlation with tumour grade (r > 0.7). The mean values were maximum for HGG and minimum for CG. For NR, the difference between CG/HGG was statistically significant, unlike CG/LGG and LGG/HGG. It was observed that NA distributions for CG were nearly Gaussian type with smaller range, while gliomas displayed erratic pattern with larger range. NA and NP exhibited strong positive correlation with ND. Conclusion. Image morphometry has immense potential in being a powerful tool to distinguish normal from neoplastic tissue and also to differentiate LGG from HGG cases, especially in tiny stereotactic biopsies. PMID- 24066241 TI - Epidemiological and Clinical Aspects and Therapy of Chronic Otitis Media in the "ENT" and Cervicofacial Surgery Ward in the University Hospital of Ouagadougou. AB - Objectives. The aim of this study was to analyze the epidemiological and clinical aspects of chronic otitis media and its therapeutic processes in our context. Patients and Methods. In a prospective study over a period of 1 year (March 2009 February 2010), 79 patients with chronic otitis media have been cared for in the otolaryngology ward of the University Hospital of Ouagadougou. Results. Chronic otitis media (COM) commonly occurs in the age group from 0 to 15 years (40.50%). Otorrhea was the main reason for consultation in 53 cases (67.10%); the most frequently encountered clinicopathological forms were simple COM (71%) followed by otitis media with effusion (24.30%). Intra-auricular instillations of traditional products (46.09%) were the dominant favoring factor. Treatment was essentially through medication in 59 cases with a stabilization of lesions. Endotemporal complications were noticed in 6 cases. Conclusion. The fight against chronic otitis media is carried out through preventive measures of education the of people. PMID- 24066242 TI - Gorham's Disease of the Mandible. AB - Gorham's disease is a rare condition characterized by progressive osteolysis of bone with ultimate total disappearance of bone. The aetiology is undetermined. It may affect any bone of the body, although there is predilection for the pelvis, humerus, axial skeleton, and mandible. Because of the rarity, the disorder goes unrecognized. Various treatment modalities are undertaken with very limited success. We report a case of Gorham's disease of mandible in a 62-year-old man and the literature is reviewed with emphasis on aetiology, diagnosis management. PMID- 24066243 TI - An unusual granular cell tumour of the buttock and a review of granular cell tumours. AB - Granular cell tumours, first described by Abrikossoff in 1926, are known to occur in skin, connective tissue, breast, gastrointestinal and genital tracts. While they are rare, they are more common in people of African descent and show a slight female preponderance, usually presenting as solitary and painless masses. Less than 10% of occurrences are multiple, and fewer than 3% of tumours behave in a malignant fashion. The mean age, at presentation, is 40-60 years. We report a case of granular cell tumour in a young white male presenting with a painful soft tissue tumour in his buttock. The presentation is unusual because of the age, patient demographic, body site, and clinical presentation. The clinical and histological aspects are reviewed in the context of this clinical case and the associated literature. PMID- 24066244 TI - Peripheral T-Cell Lymphoma with Aberrant Expression of CD19, CD20, and CD79a: Case Report and Literature Review. AB - A case of lymphoma of T-cell derivation with aberrant expression of three B-cell lineage markers (CD19, CD20, and CD79a), which was diagnosed on a left axillary excision, is described. Immunohistochemical studies and flow cytometry analysis demonstrated neoplastic cells expressing CD3, CD19, CD20, and CD79a with absence of CD4, CD8, CD10, CD30, CD34, CD56, CD68, TDT, MPO, PAX-5, and surface immunoglobulin. Gene rearrangement studies performed on paraffin blocks demonstrated monoclonal T-cell receptor gamma chain rearrangement with no evidence of clonal heavy chain rearrangement. The neoplastic cells were negative for Epstein-Barr virus (EBV) or Human Herpes Virus 8 (HHV-8). At the time of diagnosis, the PET scan demonstrated hypermetabolic neoplastic cells involving the left axilla, bilateral internal jugular areas, mediastinum, right hilum, bilateral lungs, and spleen. However, bone marrow biopsy performed for hemolytic anemia revealed normocellular bone marrow with trilineage maturation. The patient had no evidence of immunodeficiency or infection with EBV or HHV-8. This is the first reported case of a mature T-cell lymphoma with aberrant expression of three B-cell lineage markers. The current report also highlights the need for molecular gene rearrangement studies to determine the precise lineage of ambiguous neoplastic clones. PMID- 24066245 TI - Daunorubicin, cytarabine, and cladribine regimen plus radiotherapy and donor lymphocyte infusion for extramedullary relapse of acute myeloid leukemia after hematopoietic stem cell transplantation. AB - Myeloid sarcoma is a rare tumor consisting of myeloid blasts that involve anatomic sites outside the bone marrow. Fatal prognosis is inevitable in patients with extramedullary relapse after hematopoietic stem cell transplantation (HSCT), and no standard treatments are available yet. We report the first case of extramedullary relapse after HSCT treated with a combination of daunorubicin, cytarabine, and cladribine (DAC) regimen plus radiotherapy and donor lymphocyte infusion (DLI). This treatment induced a new and durable remission in our patient. The favorable toxicity profile and the reduced cost make this combination worthy of further investigations. PMID- 24066246 TI - Primary breast adenocarcinoma in ectopic breast tissue in the vulva. AB - Introduction. Accessory breast tissue is a rare finding in the general population with an incidence of 1-2%. An even rarer occurrence is accessory breast tissue afflicted with breast carcinoma. We present a brief report discussing diagnosis and management of a patient who presented with primary breast adenocarcinoma in vulval supranumerary tissue. Brief Report. A 60-year-old Caucasian female presented with a lesion in her left vulva that she first identified during adolescence. The lesion began to grow and ulcerate prompting her to receive treatment. Biopsy was inconclusive, and metastatic workup was negative, so her lesion was treated as an isolated breast lump and removed via wide local excision. Conclusion. Primary breast adenocarcinoma of the vulva is exceedingly rare. A paucity of the literature on this topic unfortunately means that strong evidence does not exist detailing the best management of this patient cohort. However, given that histological data confirms these cancers are virtually the same as breast cancers, it logically follows that the best treatment practices for breast cancer may be applied to treat these patients presenting with primary vulva cancers of ectopic breast tissue. PMID- 24066247 TI - Intracystic papillary carcinoma in the male breast: a rare endpoint of a wide spectrum. AB - Introduction. Fibrocystic disease of the male breast is uncommon. The presence of a spectrum of changes ranging from fibrocystic disease to duct papilloma to papillary carcinoma in the same patient renders the case a rarity and therefore reportable. Case Report. A case of intracystic papillary carcinoma of the male breast is presented. Discussion. The pathological, clinical, diagnostic, and therapeutic options are discussed after reviewing the literature. Conclusion. Modified radical mastectomy with axillary clearance is the safest option for established cases. PMID- 24066248 TI - Bilateral breast masses with a rare etiology. AB - Breast masses have a variety of benign and malignant etiologies. We present the case of a 28-year-old woman with bilateral large painful breast masses that developed rapidly in the three weeks before first presentation. Further investigation revealed bilateral ovarian masses. Biopsies of both ovarian masses were taken, and the pathology reported Burkitt's lymphoma. Additional staging with a PET scan was suggestive of bone marrow involvement, but bone marrow biopsy was negative. Examination of the cerebrospinal fluid did not identify malignant cells. The patient underwent CODOX-M/IVAC chemotherapy, and a complete response was demonstrated after one cycle of treatment. Six months after finishing chemotherapy the patient remained in complete remission. To our knowledge this is the first case reporting simultaneous involvement of breast, ovaries, and bones in Burkitt's lymphoma. Gynecologists and oncologists should be aware of this pattern. Polychemotherapy treatment must be initiated rapidly with curative intent. PMID- 24066249 TI - Malignant peripheral nerve sheath tumor of the small bowel: an unusual presentation with fatal outcome. AB - Malignant peripheral nerve sheath tumor of the small bowel is an extremely rare disease. Histologic distinction from other types of soft tissue sarcoma especially fibrosarcoma and leiomyosarcoma requires electron microscopy. Complete surgery remains the only curative treatment. However, late diagnosis makes curative surgery more difficult. The contribution of chemotherapy to incomplete surgery has been proved without controlled studies. We report a case of this type of lesion discovered following a small bowel perforation. PMID- 24066250 TI - Osteoid osteoma of the great toe mimicking osteomyelitis: a case report and review of the literature. AB - Osteoid osteomas are well-known benign tumors, seen generally in long bones. When seen in phalanxes or toes, they can cause a diagnostic dilemma. A young male presented to us with complaints of enlargement of the great toe and severe pain. He had had an ingrown toe-nail operation before, and this situation caused a diagnostic dilemma. In this case report, we emphasize that osteoid osteomas can cause diagnostic dilemmas and it should be kept in mind as a differential diagnosis. PMID- 24066251 TI - An unusual presentation of lupus in a pediatric patient. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease causing inflammatory tissue damage. Multiple organ damage can ensue with renal and neurological involvement carrying the worse prognosis. In this case report we present a 10 year-old African American girl who presented with abnormal choreiform movements, headache, weight loss, and fatigue. Detailed clinical examination with laboratory and imaging studies clinched the diagnosis of SLE. Echocardiogram revealed the presence of Libman-sacks endocarditis. Patient showed rapid resolution of symptoms with steroid therapy. A brief discussion on childhood onset lupus along with the varied clinical presentation is discussed. PMID- 24066252 TI - The differential diagnosis of two cases of chronic periaortitis. AB - The imaging features of chronic periaortitis resemble those of infected aneurysms. Two illustrative cases of chronic periaortitis, in which the etiologies were caused by IgG4-related disease, are presented. The first case involved a 68-year-old man who presented with vague discomfort in his lower abdomen. The second case was a 42-year-old man who presented with a fever of 38 degrees C and persistent, vague chest discomfort. Both cases demonstrated an increased amount of connective tissue around the aorta in computed tomography images and low intensity in the T2-weighed sequence and high intensity in the diffusion-weighed sequence, suggesting the presence of inflammation, in the magnetic resonance imaging. Negative blood cultures, elevated IgG4 levels, and pathological findings confirmed the diagnosis as chronic periaortitis due to IgG4 related disease. This is a newly recognized syndrome of unknown etiology, characterized by a fibroinflammatory condition, tumefactive lesions, and a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells. Both cases were successfully treated with corticosteroids. Infected aneurysms need to be carefully differentiated from this syndrome in view of the similar imaging features. PMID- 24066253 TI - Primary Angioplasty for Cardiac Allograft Vasculopathy Presenting as ST-Elevation Acute Myocardial Infarction during Endomyocardial Biopsy. AB - Cardiac allograft vasculopathy is still a major issue, with significative mortality in heart transplant patients, and the best therapeutic options are not yet established. The progressively higher survival rates after transplantation have made it a major concern. This is a case report about a patient who underwent cardiac transplantation due to chagasic cardiomiopathy. During an endomyocardial biopsy more than 2 years after the transplant, the patient arrested in ventricular fibrillation, with ST-elevation in anterior leads after defibrillation. The angiography showed total occlusion of proximal left anterior descending artery, promptly treated with primary angioplasty, with excellent angiographic and clinical results. PMID- 24066254 TI - Severe necrotizing adenovirus tubulointerstitial nephritis in a kidney transplant recipient. AB - Adenoviruses (AdV) are emerging pathogens with a prevalence of 11% viruria and 6.5% viremia in kidney transplant recipients. Although AdV infection is common, interstitial nephritis (ADVIN) is rare with only 13 biopsy proven cases reported in the literature. We report a case of severe ADVIN with characteristic histological features that includes severe necrotizing granulomatous lesion with widespread tubular basement membrane rupture and hyperchromatic smudgy intranuclear inclusions in the tubular epithelial cells. The patient was asymptomatic at presentation, and the high AdV viral load (quantitative PCR>2,000,000 copies/mL in the urine and 646,642 copies/mL in the serum) confirmed the diagnosis. The patient showed excellent response to a combination of immunosuppression reduction, intravenous cidofovir, and immunoglobulin therapy resulting in complete resolution of infection and recovery of allograft function. Awareness of characteristic biopsy findings may help to clinch the diagnosis early which is essential since the disseminated infection is associated with high mortality of 18% in kidney transplant recipients. Cidofovir is considered the agent of choice for AdV infection in immunocompromised despite lack of randomized trials, and the addition of intravenous immunoglobulin may aid in resolution of infection while help prevention of rejection. PMID- 24066255 TI - Primary malignant melanoma of the genitourinary tract with upper and lower tracts involvement. AB - A 91-year-old female presented with lower extremity swelling and shortness of breath. Laboratory analysis revealed elevations in blood urea nitrogen and creatinine along with microscopic hematuria on urinalysis. Computed tomography imaging showed moderate right hydronephrosis with dilatation of the proximal ureter with a soft tissue density at a transition point. Endoscopic evaluation revealed multiple raised, fleshy, and hemorrhagic masses throughout the bladder which are present in both ureters. Biopsy of these lesions revealed malignant melanoma invading the lamina propria. No dermatologic lesions were identified suggesting a primary malignant melanoma of the genitourinary system. PMID- 24066256 TI - Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold. AB - Palmitoylethanolamide (PEA) is a food component known since 1957. PEA is synthesized and metabolized in animal cells via a number of enzymes and exerts a multitude of physiological functions related to metabolic homeostasis. Research on PEA has been conducted for more than 50 years, and over 350 papers are referenced in PubMed describing the physiological properties of this endogenous modulator and its pharmacological and therapeutical profile. The major focus of PEA research, since the work of the Nobel laureate Levi-Montalcini in 1993, has been neuropathic pain states and mast cell related disorders. However, it is less known that 6 clinical trials in a total of nearly 4000 people were performed and published last century, specifically studying PEA as a therapy for influenza and the common cold. This was done before Levi-Montalcini's clarification of PEA's mechanism of action, analyzing the role of PEA as an anti-inflammatory agent. We will review in depth these studies, as the results support the effectiveness and safety of PEA in flu and respiratory infections. PMID- 24066257 TI - Potential application of cord blood-derived stromal cells in cellular therapy and regenerative medicine. AB - Neonatal stromal cells from umbilical cord blood (CB) are promising alternatives to bone marrow- (BM-) derived multipotent stromal cells (MSCs). In comparison to BM-MSC, the less mature CB-derived stromal cells have been described as a cell population with higher differentiation and proliferation potential that might be of potential interest for clinical application in regenerative medicine. Recently, it has become clear that cord blood contains different stromal cell populations, and as of today, a clear distinction between unrestricted somatic stromal cells (USSCs) and CB-MSC has been established. This classification is based on the expression of DLK-1, HOX, and CD146, as well as functional examination of the adipogenic differentiation potential and the capacity to support haematopoiesis in vitro and in vivo. However, a marker enabling a prospective isolation of the rare cell populations directly out of cord blood is yet to be found. Further analysis may help to reveal even more subpopulations with different properties, which could be useful for the directed application of these cells in preclinical models. PMID- 24066258 TI - High Rates of Hepatitis B and C and HIV Infections among Blood Donors in Cameroon: A Proposed Blood Screening Algorithm for Blood Donors in Resource Limited Settings. AB - Background. Infections with human immunodeficiency virus (HIV), hepatitis B (HBV), and hepatitis C virus (HCV) are currently major public health problems. Methods. A retrospective study was conducted from January to June 2008 at the Blood Bank of the Central Hospital, Yaounde (Cameroon). The objective was to study the prevalence of HIV, HBV, and HCV and their coinfections among blood donors. Results. A total of 4650 donors were identified, and the sex ratio (male/female) was 14/1. The median age of donors was 28 years (range: 16 to 69 years). Among blood donors, HBV, HIV, and HCV infection prevalences were 12.14% (n = 565) , 4.44% (n = 206), and 1.44% (n = 67), respectively. Coinfection with HIV and HBV was observed among 0.77% donors, followed by hepatitis B and C co infection (0.21%) and HIV and HCV coinfection (0.06%). Co-infection with HIV-HBV HCV was encountered in 2 donors. The HIV, HBV, and HCV infections lead to a destruction of one out of six sets of blood collected. Conclusion. There is a need to review policies for blood collection from donors, by modifying the algorithm of blood donors testing. Pretesting potential donors using rapid tests could help to avoid collection and destruction of (infected) blood. PMID- 24066259 TI - Anemia and blood transfusions in critically ill patients. AB - Anemia is common in critically ill patients. As a consequence packed red blood cell (PRBC) transfusions are frequent in the critically ill. Over the past two decades a growing body of literature has emerged, linking PRBC transfusion to infections, immunosuppression, organ dysfunction, and a higher mortality rate. However, despite growing evidence that risk of PRBC transfusion outweighs its benefit, significant numbers of critically ill patients still receive PRBC transfusion during their intensive care unit (ICU) stay. In this paper, we summarize the current literature concerning the impact of anemia on outcomes in critically ill patients and the potential complications of PRBC transfusions. PMID- 24066260 TI - Process improvement by eliminating mixing of whole blood units after an overnight hold prior to component production using the buffy coat method. AB - The elimination of a thorough manual mixing of whole blood (WB) which takes place following the overnight hold, but before the first centrifugation step, during buffy coat component production at Canadian Blood Services (CBS) was investigated. WB was pooled after donation and split. Pairs of platelet, red blood cell (RBC), and plasma components were produced, with half using the standard method and half using a method in which the mixing step was eliminated. Quality assessments included yield, pH, CD62P expression and morphology for platelets, hemoglobin, hematocrit, hemolysis, and supernatant K(+) for RBCs, and volume and factor VIII activity levels for plasma. All components, produced using either method, met CBS quality control criteria. There were no significant differences in platelet yield between components produced with and without mixing. A significant difference was seen for RBC hemolysis at expiry (P = 0.03), but for both groups, levels met quality control requirements. Noninferiority of components produced without mixing was confirmed for all parameters. Manual mixing is laborious and has a risk of repetitive strain for production staff and its significance is unclear. Elimination of this step will improve process efficiencies without compromising quality. PMID- 24066261 TI - An efficient apparatus for rapid deoxygenation of erythrocyte concentrates for alternative banking strategies. AB - Erythrocyte concentrates (ECs) stored for transfusion purposes still represent a lifesaving solution in a wide series of clinically occurring circumstances, especially for traumatized and perioperative patients. However, concerns still arise and persist as to whether current criteria for collection and storage of ECs might actually represent the best case scenario or there might rather be still room for improvement. In particular, the prolonged storage of EC has been associated with the accumulation of a wide series of storage lesions, either reversible (metabolism) or irreversible (protein and morphology). Independent laboratories have contributed to propose alternative strategies, among which is the introduction of oxygen removal treatments to ECs. Convincing biochemical and preliminary clinical evidences have been produced about the benefits derived from the introduction of this practice. We, hereby, propose a rapid, efficient, and time-effective strategy for blood deoxygenation which might fit in current EC production chain. The proposed strategy resulted in the complete deoxygenation of red blood cell hemoglobin (pO2 < 0.0021 mmHg). A preliminary small-scale study about the application of the present method resulted in reduced hemolysis, decreased vesiculation, and limited alterations to the red blood cell morphology, as gleaned from flow cytometry and scanning electron microscopic analyses. Further in-depth and larger-scale investigations are encouraged. PMID- 24066262 TI - Caregiver Asthma Knowledge, Aptitude, and Practice in High Healthcare Utilizing Children: Effect of an Educational Intervention. AB - Factors underlying high healthcare utilization among Hispanic and African American (AA) children with asthma are not well known. We hypothesized that low parental knowledge and suboptimal practices are associated with high healthcare utlization and sought to elucidate these factors and identify ethnicity-specific differences. We also hypothesized that a targeted educational intervention will decrease emergency department (ED) visits and hospitalizations. A 57-item questionnaire investigating asthma knowledge, aptitude, and practice was administered during a hospitalization to 268 caregivers (158 Hispanic and 110 AA) of high healthcare utilizer children. Responses were compared between ethnicities. Participants were randomized into an education group and a control group to investigate the impact of an in-hospital educational intervention on future ED visits and hospitalizations. More than 80% of caregivers knew that asthma is associated with muscle constriction and mucus production. Overall, 66.7%-86.9% of caregivers found preventive steps including allergen avoidance, regular primary care physician (PCP) follow-up, and medication adherence helpful, but only 45.2% reported adherence to controller medications. Similarly, caregivers found management steps, including albuterol use, avoidance of ineffective medications, and need to contact PCP helpful but 33% Hispanic caregivers contacted their child's PCP at the time of the exacerbation leading the current hospitalization, compared with 17% AA caregivers (P=0.006). Moreover, 40% and 30% Hispanic and 27% and 18% AA caregivers felt stressed and helpless, respectively, about their child's asthma. Despite high baseline levels of knowledge, there were fewer ED visits in the education group (1.56+/-1.94) compared with the control group (2.05+/-2.32) (P=0.02) 2 years after the intervention. Although Hispanic and AA caregivers of children with high healthcare utilization were knowledgeable of asthma pathophysiology, and preventive and management steps, they reported being stressed and helpless and were unable to implement the steps at the time of an exacerbation, seeking care at the ED rather than contacting their PCP. The high health utilizers who underwent a targeted educational intervention had fewer ED visits 2 years following the intervention. PMID- 24066263 TI - Racial, Ethnic, and Language Disparities in Children's Exposure to Secondhand Smoke. AB - Race and ethnicity affect children's risk of secondhand smoke exposure. However, little is known about how race and language preference impact parents' self reported smoking and stopping smoking rates. We analyzed data for 16,523 children aged 0-11 years from a pediatric computer decision support system (Child Health Improvement through Computer Automation [CHICA]). CHICA asks families in the waiting room about household smokers. We examined associations between race, insurance, language preference, and household smoking and reported stopping smoking rates using logistic regression. Almost a quarter (23%) of the children's families reported a smoker at home. Hispanic children are least likely (odds ratio [OR]: 0.17, confidence interval [CI]: 0.12-0.24) to have secondhand smoke exposure when compared to African American and white children, as were those with private insurance (OR: 0.52, CI: 0.43-0.64) or no insurance (OR: 0.79, CI: 0.71 0.88) compared to publicly insured. Children from English speaking families were more likely (OR: 1.55, CI: 1.24-1.95) to have secondhand smoke exposure compared to Spanish speaking families. Among smoking families, 30% reported stopping smoking subsequently. Stopping rates were higher in Hispanic (OR: 3.25, CI: 2.06 5.13) and African American (OR: 1.39, CI: 1.01-1.91) families compared to white children's families. Uninsured families were less likely than publicly insured families to report stopping smoking (OR: 0.76, CI: 0.63-0.92). English speaking families were less likely (OR: 0.56, CI: 0.41-0.75) to report stopping smoking compared to Spanish speaking even in a subgroup analyses of Hispanic families (OR: 0.55, CI: 0.39-0.76). In our safety net practices serving children predominantly on public insurance, Spanish speaking families reported the lowest risk of secondhand smoke exposure in children and the highest rate of stopping smoking in the household. Hispanic families may have increasing secondhand exposure and decreasing rates of stopping smoking as they acculturate. PMID- 24066264 TI - Chiral Switch Drugs for Asthma and Allergies: True Benefit or Marketing Hype. AB - Enantiomers are one of several possible molecular configurations present in a drug that has at least 1 chiral center. A drug containing 2 or more enatiomers is called a racemic mixture. Enatiomers are being developed from racemic mixtures as drugs in their own right often to extend patent protection of highly popular drugs. However, the therapeutic advantages of single enantiomer drugs developed for respiratory use such as levalbuterol, arformoterol, and levocetirizine over their racemate has been disappointing. In addition, single enantiomer drugs may be several fold more expensive than the racemic drug. New single enantiomer drugs, which are stable (no interconversion back to the racemate) and have fewer adverse effects and a more predictable pharmacodynamic or pharmacokinetic profile would confer a therapeutic advantage and thus would be beneficial for clinical use. PMID- 24066265 TI - Current Advances in the Use of Therapeutic Hypothermia. PMID- 24066266 TI - Usefulness of Deep Hypothermic Circulatory Arrest and Regional Cerebral Perfusion in Children. AB - To compare the safety and usefulness of deep hypothermic circulatory arrest (DHCA) and regional cerebral perfusion (RCP) during pediatric open heart surgery. Between January 1, 2004 and September 30, 2012, 1250 children with congenital cardiac defect underwent corrective operation with the DHCA or RCP technique in the Shanghai Children's Medical Center. Of them, 947 cases underwent the operation with the aid of DHCA (DHCA group), and 303 cases with RCP (RCP group). The mean DHCA time was 30.64+/-15.81 (7-63) minutes and mean RCP time was 36.18+/ 12.86 (10-82) minutes. The mortality rate was 7.18% (68/947) and 6.60% (20/30) in two groups, respectively. The postoperative incidences of temporary and permanent neurological dysfunction were 6.23% (59/947) in the DHCA group and 2.64% (8/303) in the RCP group (p<0.01). The incidence of other complications such as low cardiac output, renal dysfunction, and lung issues are similar in both groups. RCP is a reliable technique for cerebral protection and it facilitates time consuming corrected procedures for complex congenital cardiac defect repair procedures. PMID- 24066267 TI - Effects of Mild Hypothermia Treatment on Rat Hippocampal beta-Amyloid Expression Following Traumatic Brain Injury. AB - Previous studies have reported that mild induced hypothermia (MIH) treatment has positive effects on traumatic brain injury (TBI) outcomes, which have recently been linked to beta-amyloid (Abeta)-induced secondary brain injury (SBI) extent in hippocampal tissues. We therefore investigate the relationship between MIH treatment and expression of Abeta and related proteins following TBI. Adult Sprague-Dawley rats were randomly divided into three equal groups (S: sham operated, N: normothermia, and H: mild hypothermia). After TBI induced by fluid percussion, group N remained at normal temperature, and group H underwent MIH (32 degrees C) for 6 hours. Behavioral scale scores were then assessed. All rats were sacrificed 24 hours and hippocampal tissues were harvested, stained with hematoxylin and eosin. mRNA and protein expressions of Abeta, beta-amyloid protein precursor (APP), and beta-secretase (BACE) were analyzed. Our results revealed significantly improved behavioral scale scores and the surviving neuron numbers were observed in group H compared to group N (p<0.05). Additionally, group N increased APP, Abeta, and BACE levels compared to group S (all p<0.05). Reduced expression of APP-, Abeta-, and BACE were apparent in group H compared to group N (all p<0.05). However, no statistically significant difference was observed between groups H and S in behavioral scale scores and the expression of APP-, Abeta-, and BACE (p>0.05). In conclusion, MIH treatment significantly improves the survival of neuron and reduced Abeta, BACE, and APP upregulation after TBI, which may provide a better understanding of the mechanisms by which hypothermia reduces SBI in TBI patients. PMID- 24066268 TI - Relative Higher Hematocrit Attenuates the Cerebral Excitatory Amino Acid Elevation Induced by Deep Hypothermic Circulatory Arrest in Rats. AB - Hemodilution is a commonly used technique in cardiopulmonary bypass (CPB) and deep hypothermic circulation arrest (DHCA). Our previous study showed that lower hematocrit aggravated the brain injury after DCHA. Because the excitatory amino acids are critical pathways of ischemic neuronal damage, the purpose of the present study was to investigate the effects of different degrees of hemodilution on the excitatory amino acid content in different brain areas after DHCA Adult Sprague-Dawley rats were randomly divided into four groups: group I hematocrit (Hct) 10% (H1), group II Hct 20% (H2), group III Hct 30% (H3), and control group (C). All animals except those in the control group underwent DHCA at 18 degrees C for 90 minutes. Different degrees of hemodilution were accomplished by changing the composition and volume of the priming solution used in CPB. High-performance liquid chromatography was used to determine the concentration of glutamate (Glu), aspartate (Asp), glycine (Gly), gamma-aminobutyric acid (GABA), and taurine (Tau) in the cerebral cortex, hippocampus, and thalamus. We found that the concentration of these five amino acids in the hippocampus and cortex were all increased after DHCA. Glu, Asp, and Gly in the hippocampus and cortex were significantly lower in the Hct 30% group than in the other two groups (p<0.05). There was no significant difference in the GABA and Tau concentrations among the three groups. In summary, excitatory amino acids increased significantly after DHCA, and relative higher hematocrit attenuates this response. PMID- 24066269 TI - Bullous Lesions After Use of a Commercial Therapeutic Hypothermia Temperature Management System: A Possible Burn Injury? AB - Therapeutic hypothermia (TH) is a novel technique for improving the likelihood of survival with good neurologic outcome after cardiopulmonary arrest. While commercial temperature management systems (TMS) are intended to facilitate cooling of the body during TH, their operation also involves body exposure to heat. We describe the case of a 72-year-old female postarrest patient who underwent TH using a commercial water-circulating TMS and concurrent continuous renal replacement therapy. The patient developed bullous lesions on the thigh and torso suspected to constitute a scald burn injury from the TMS. Clinicians must be aware of this important adverse event when providing TH, especially in the setting of concurrent hemodialysis therapy. PMID- 24066270 TI - Racial and Ethnic Disparities in the Incidence and Trends of Soft Tissue Sarcoma Among Adolescents and Young Adults in the United States, 1995-2008. AB - PURPOSE: The aim of this study was to examine racial/ethnic disparities in the incidence rates and trends of soft tissue sarcoma (STS) by gender, age, and histological type among adolescents and young adults (AYAs) aged 15-29 years. METHODS: The 1995-2008 incidence data from 25 population-based cancer registries, covering 64% of the United States population, were obtained from the North American Association of Central Cancer Registries. The Surveillance, Epidemiology and End Results AYA site recode and International Classification of Diseases for Oncology, 3rd Edition, were adopted to categorize STS histological types and anatomic groups. Age-adjusted incidence rates and average annual percent change (AAPC) were calculated. RESULTS: The incidence of all STSs combined was 34% higher in males than females (95% CI: 1.28, 1.39), 60% higher among blacks than whites (95% CI: 1.52, 1.68), and slightly higher among Hispanics than whites. Compared with whites, blacks had significantly higher incidence of fibromatous neoplasms, and Hispanics had significantly higher incidence of liposarcoma. Whites were more likely to be diagnosed with synovial sarcoma than blacks. Black and Hispanic males had significantly higher Kaposi sarcoma incidence than white males. The AAPC of all STSs combined showed a significant decrease from 1995 to 2008 (AAPC=-2.1%; 95% CI: -3.2%, -1.0%). However, after excluding Kaposi sarcoma, there was no significant trend. CONCLUSION: The incidence rates of STS histological types in AYAs vary among racial/ethnic groups. The declining trends of STS are due mainly to decreasing incidence of Kaposi sarcoma in all races/ethnicities. Research to identify factors associated with racial/ethnic disparities in AYA STS is necessary. PMID- 24066271 TI - A Population-Based Observational Study of First-Course Treatment and Survival for Adolescent and Young Adult Females with Breast Cancer. AB - PURPOSE: Young age at breast cancer diagnosis is associated with poor survival. However, little is known about factors associated with first-course treatment receipt or survival among adolescent and young adult (AYA) females aged 15-39 years. METHODS: Data regarding 19,906 eligible AYA breast cancers diagnosed in California during 1992-2009 were obtained from the population-based California Cancer Registry. Multivariable logistic regression was used to evaluate clinical and sociodemographic differences in treatment receipt. Multivariable Cox proportional hazards regression was used to examine differences in survival by initial treatment, and by patient and tumor characteristics. RESULTS: Black and Hispanic AYAs diagnosed with in situ or stages I-III breast cancer were more likely than White AYAs to receive breast-conserving surgery (BCS) without radiation; Asian and Hispanic AYAs were more likely than Whites to receive mastectomy. Women in lower socioeconomic status (SES) neighborhoods were more likely to omit radiation after BCS, more likely to receive mastectomy, and less likely to receive chemotherapy, compared to those in higher SES neighborhoods. Among patients with invasive disease, survival improved an average of 5% per year during 1992-2009. AYAs who received BCS with radiation experienced better survival than other surgery/radiation options. Black AYAs had poorer survival than Whites. AYAs who resided in higher SES neighborhoods had better survival. CONCLUSIONS: Treatment receipt among AYAs with breast cancer varied by race/ethnicity and neighborhood SES. Poor survival for Black AYAs and AYAs living in low SES neighborhoods in models adjusted for treatment receipt suggests that factors other than treatment may also be important to disease outcome. PMID- 24066272 TI - Accuracy and Concordance in Reporting for Secondhand Smoke Exposure among Adolescents Undergoing Treatment for Cancer and Their Parents. AB - Few studies have examined adolescent reporting accuracy for secondhand smoke exposure (SHSe), and never for youth with cancer. SHSe reporting from adolescents being treated for cancer (Mage=14.92 years, SD=1.67) was examined against parent/guardian reports and urine cotinine among 42 adolescent-parent dyads. Number of days in hospital-based lodgings prior to assessment emerged as the strongest predictor of urine cotinine (beta=-0.46, p=0.003) and adolescent SHSe reporting significantly predicted urine cotinine (beta=0.37, p=0.011) beyond relevant demographic and contextual variables (overall R2=0.40, F(6, 35)=3.90, p=0.004). Findings support adolescents as accurate reporters of discrete SHSe occurrences. PMID- 24066273 TI - Square Pegs, Round Hole? Ensuring Fit in the AYAO Spectrum for Adolescents and Young Adults with Genetic Risk for Cancer. AB - This paper presents a case example of a young woman at genetic risk for future cancer. We discuss psychosocial challenges that adolescents and young adults (AYAs) may share with their cancer survivor peers, and describe an example of psychosocial care. A scientific foundation denoting the needs of AYAs at risk for heritable cancers is lacking, and it is unknown if these AYAs receive adequate support services. This is a call to action for practitioners and researchers to engage in initiatives that assure these AYAs have access to valuable support and more clearly mark their place within the spectrum of AYA oncology. PMID- 24066274 TI - The Technology of Measurement Feedback Systems. AB - Usual care in the community is far from optimal. Sufficient evidence exists that dropout rates are significant, treatment is effective for only a small proportion of clients, and that the translation of evidence-based treatments to the real world is problematic. Technology has been shown to be helpful in health care in improving the effectiveness of treatment. A relatively new technology being used in mental health is measurement feedback systems (MFSs). MFSs are particularly applicable to couple and family psychology (CFP) because of its ability to provide information on the multiple perspectives involved in treatment. The Contextualized Feedback Systemstm (CFS(r)), developed at Vanderbilt University is used as an example of what can be accomplished with an MFS. The advantages and limitations of this technology are described as well as the anticipated reimbursement requirements that mental health services will need. PMID- 24066275 TI - Diet and Neuroimaging Markers of Cerebrovascular Disease. AB - Stroke is one of the leading causes of long-term disability and mortality. Mounting evidence from observational studies suggests that among lifestyle factors, diet may be playing an important role for the prevention of stroke. Neuroimaging markers, particularly white matter hyperintensity (WMH) volume and brain infarcts (BI) are more sensitive measurements of cerebrovascular disease than clinical assessments. We reviewed published observational and clinical studies that evaluate the association between dietary factors and WMH and BI. The few existing studies examined only a handful individual nutrients or foods (dietary intake of alcohol, B vitamins, fish, choline, serum markers of antioxidants, and a few food groups, Mediterranean-style diet, and nutrient biomarker patterns. Findings from these studies are inconclusive either due to conflicting results from different studies or due to lack of replication. Further studies are necessary to replicate the existing findings. Many other foods or nutrients or dietary patterns may worth of investigation and longitudinal studies are needed. PMID- 24066276 TI - Story Immersion in a Health Videogame for Childhood Obesity Prevention. AB - OBJECTIVE: Stories can serve as powerful tools for health interventions. Story immersion refers to the experience of being absorbed in a story. This is among the first studies to analyze story immersion's role in health videogames among children by addressing two main questions: Will children be more immersed when the main characters are similar to them? Do increased levels of immersion relate to more positive health outcomes? SUBJECTS AND METHODS: Eighty-seven 10-12-year old African-American, Caucasian, and Hispanic children from Houston, TX, played a health videogame, "Escape from Diab" (Archimage, Houston, TX), featuring a protagonist with both African-American and Hispanic phenotypic features. Children's demographic information, immersion, and health outcomes (i.e., preference, motivation, and self-efficacy) were recorded and then correlated and analyzed. RESULTS: African-American and Hispanic participants reported higher immersion scores than Caucasian participants (P = 0.01). Story immersion correlated positively (P values < 0.03) with an increase in Fruit and Vegetable Preference (r = 0.27), Intrinsic Motivation for Water (r = 0.29), Vegetable Self Efficacy (r = 0.24), and Physical Activity Self-Efficacy (r = 0.32). CONCLUSION: Ethnic similarity between videogame characters and players enhanced immersion and several health outcomes. Effectively embedding characters with similar phenotypic features to the target population in interactive health videogame narratives may be important when motivating children to adopt obesity prevention behaviors. PMID- 24066277 TI - Cabazitaxel-induced stabilization of microtubules enhances radiosensitivity in ovarian cancer cells. AB - BACKGROUND: Up to 40% of women with ovarian cancer have short disease-free intervals due to molecular mechanisms of chemotherapy resistance. New therapeutic strategies are sought. Ovarian cancers are sensitive to radiochemotherapy. The taxane cabazitaxel (XRP6258, Jevtana) promotes tubulin assembly and stabilizes microtubules against depolymerization in cells, acting similarly in mechanism to paclitaxel. Here, sequences of cabazitaxel-radiation co-administration are tested for drug-alone cytotoxicity and optimal radiosensitization. MATERIALS AND METHODS: SKOV3, OVCAR3, and TOV-112D ovarian cancer cells were administered cabazitaxel 24 h before (first), 18 h before (second), together (third), or 24 h after (fourth) a single radiation dose, and then, investigated by clonogenic assay and flow cytometric assays. Radiation dose-cell survival data were fitted by two-stage multivariate analyses of variance. High-content flow cytometry partitioned cabazitaxel effects into G2-phase versus M-phase events by DNA content, cyclin A2, and phospho-S10-histone H3 (PHH3). Paclitaxel served as a comparator. FINDINGS: Cabazitaxel cytotoxicity and radiosensitization were dose dependent. Cabazitaxel added 24 h before radiation was the most lethal schedule. DNA content measurements by flow cytometry showed that cabazitaxel-treated cells accumulated in the radiosensitive G2/M 4C DNA complement compartment. Cytometry also showed that surviving cabazitaxel-induced cell cycle arrested cells resolve the arrest by entering 4C or by 8C DNA complement cell cycles. INTERPRETATION: The radiosensitizing effect of cabazitaxel was schedule dependent, due to cell cycle redistribution, and best when cabazitaxel was given 24 h before radiation. Clinical trials of administering both cabazitaxel and radiation should be explored in women with chemoresistant ovarian cancer. PMID- 24066278 TI - Selenium Biomarkers in Prostate Cancer Cell Lines and Influence of Selenium on Invasive Potential of PC3 Cells. AB - Dietary selenium intake has been linked to reduced cancer risk, however the underlying mechanisms are yet unknown. We question the commonly used practice of applying selenium concentrations found in human blood to in vitro studies and evaluated the utility of biomarkers, e.g., glutathione peroxidase 1 (GPx1) and thioredoxin reductase 1 (TrxR1), to determine appropriate selenium levels for in vitro work. Furthermore, we investigated the effects of Se-methylselenocysteine (SeMSC) on prostate cancer cell migration and invasion. After excluding cytotoxicity, we demonstrated that prostate cancer cell lines respond differently to selenium treatment as observed through biomarker assessment. We found that the maximum levels of GPx1 activity and TrxR1 expression were reached at lower selenium concentrations in LNCaP compared to PC3 cells, and PC3 compared to DU145 cells. Therefore the use of selenium concentrations extrapolated from human studies for in vitro work may be applicable when further informed using a readout of selenium repletion including use of selenium responsive biomarkers. No effect on PC3 migration or invasion was observed after long term SeMSC treatment; however a slight increase was found when treatment was solely administered during the assay. The opposite could be observed when cells were cultured under low serum conditions, with a significant increase in migration upon long term but not upon acute SeMSC treatment. To conclude, these findings indicate that it is imperative to study the selenium sensitivity of an in vitro model preferably using biomarkers before investigating any effects on biological processes, or before comparing models. PMID- 24066279 TI - More on the Lack of Correlation between Terra Expression and Telomere Length. PMID- 24066280 TI - HERV-K(HML-2), the Best Preserved Family of HERVs: Endogenization, Expression, and Implications in Health and Disease. AB - Retroviruses that have the ability to infect germ line cells can become an integral and inherited part of the host genome. About 8% of the human chromosomal DNA consists of sequences derived from infections by retroviruses that presumably circulated 2-40 millions of years ago, and some elements are actually much older. Post-insertional recombinations, deletions, and mutations have rendered all known human endogenous retroviruses (HERVs) non-infectious. However some, particularly the most recently acquired proviruses of the HERV-K(HML-2) family, can expresses viral proteins and produce viral particles. In this review we will first discuss the major aspects of the endogenization process and peculiarities of the different HERV-K families. We will then focus on the genes and proteins encoded by HERV-K(HML-2) as well as inactivation of these proviruses by postinsertional mutations and their inhibition by antiretroviral factors. After describing the evolutionary interplay between host and endogenous retrovirus we will delve deeper into the currently limited understanding of HERV-K and its possible association with disease, particularly tumorigenesis. PMID- 24066281 TI - Iron metabolism and resistance to infection by invasive bacteria in the social amoeba Dictyostelium discoideum. AB - Dictyostelium cells are forest soil amoebae, which feed on bacteria and proliferate as solitary cells until bacteria are consumed. Starvation triggers a change in life style, forcing cells to gather into aggregates to form multicellular organisms capable of cell differentiation and morphogenesis. As a soil amoeba and a phagocyte that grazes on bacteria as the obligate source of food, Dictyostelium could be a natural host of pathogenic bacteria. Indeed, many pathogens that occasionally infect humans are hosted for most of their time in protozoa or free-living amoebae, where evolution of their virulence traits occurs. Due to these features and its amenability to genetic manipulation, Dictyostelium has become a valuable model organism for studying strategies of both the host to resist infection and the pathogen to escape the defense mechanisms. Similarly to higher eukaryotes, iron homeostasis is crucial for Dictyostelium resistance to invasive bacteria. Iron is essential for Dictyostelium, as both iron deficiency or overload inhibit cell growth. The Dictyostelium genome shares with mammals many genes regulating iron homeostasis. Iron transporters of the Nramp (Slc11A) family are represented with two genes, encoding Nramp1 and Nramp2. Like the mammalian ortholog, Nramp1 is recruited to phagosomes and macropinosomes, whereas Nramp2 is a membrane protein of the contractile vacuole network, which regulates osmolarity. Nramp1 and Nramp2 localization in distinct compartments suggests that both proteins synergistically regulate iron homeostasis. Rather than by absorption via membrane transporters, iron is likely gained by degradation of ingested bacteria and efflux via Nramp1 from phagosomes to the cytosol. Nramp gene disruption increases Dictyostelium sensitivity to infection, enhancing intracellular growth of Legionella or Mycobacteria. Generation of mutants in other "iron genes" will help identify genes essential for iron homeostasis and resistance to pathogens. PMID- 24066282 TI - Immunosuppressive MDSCs induced by TLR signaling during infection and role in resolution of inflammation. AB - Ligand-mediated activation of toll-like receptors (TLRs) not only induces inflammation but also immune suppression, which is an emerging area of investigation. Multiple negative feedback intracellular mechanisms have been described that are brought into play to prevent uncontrolled TLR activation. However, the identification of TLR-induced regulatory myeloid cells is a relatively recent development that has ramifications in pathogen-induced disease state as well as in cancer. Our efforts to understand how a high dose of lipopolysaccharide (LPS), a ligand of TLR4, suppresses allergic airway inflammation led to the identification of myeloid cells that are CD11b(+)Gri(int)(Ly6G(int))F4/80(+) and are phenotypically and morphologically similar to myeloid-derived suppressor cells (MDSCs) which are best studied in the context of cancer. MDSCs have been also detected during infection by various bacteria, parasites and viruses, which can engage different TLRs. These TLR induced myeloid cells produce different types of mediators to influence immune response and inflammation that can be either beneficial or detrimental to the host. One beneficial function of TLR4/MyD88-triggered MDSCs in the lung is to efferocytose apoptotic neutrophils to help resolve inflammation elicited during bacterial pneumonia. A better understanding of the generation and function of these regulatory cells would be helpful to harness their potential or suppress their function for disease-specific immune regulation. PMID- 24066283 TI - Through the dark continent: African trypanosome development in the tsetse fly. AB - African trypanosomes are unicellular flagellated parasites causing trypanosomiases in Africa, a group of severe diseases also known as sleeping sickness in human and nagana in cattle. These parasites are almost exclusively transmitted by the bite of the tsetse fly. In this review, we describe and compare the three developmental programs of the main trypanosome species impacting human and animal health, with focus on the most recent observations. From here, some reflections are made on research issues concerning trypanosome developmental biology in the tsetse fly that are to be addressed in the future. PMID- 24066284 TI - Development of Transgenic Papaya through Agrobacterium-Mediated Transformation. AB - Transgenic papaya plants were regenerated from hypocotyls and immature zygotic embryo after cocultivation with Agrobacterium tumefaciens LBA-4404 carrying a binary plasmid vector system containing neomycin phosphotransferase (nptII) gene as the selectable marker and beta-glucuronidase (GUS) as the reporter gene. The explants were co-cultivated with Agrobacterium tumefaciens on regeneration medium containing 500 mg/L carbenicillin + 200 mg/L cefotaxime for one week. The cocultivated explants were transferred into the final selection medium containing 500 mg/L carbenicillin + 200 mg/L cefotaxime + 50 mg/L kanamycin for callus induction as well as plant regeneration. The callus derived from the hypocotyls of Carica papaya cv. Shahi showed the highest positive GUS activities compared to Carica papaya cv. Ranchi. The transformed callus grew vigorously and formed embryos followed by transgenic plantlets successfully. The result of this study showed that the hypocotyls of C. papaya cv. Shahi and C. papaya cv. Ranchi are better explants for genetic transformation compared to immature embryos. The transformed C. papaya cv. Shahi also showed the maximum number of plant regeneration compared to that of C. papaya cv. Ranchi. PMID- 24066285 TI - Position-specific analysis and prediction of protein pupylation sites based on multiple features. AB - Pupylation is one of the most important posttranslational modifications of proteins; accurate identification of pupylation sites will facilitate the understanding of the molecular mechanism of pupylation. Besides the conventional experimental approaches, computational prediction of pupylation sites is much desirable for their convenience and fast speed. In this study, we developed a novel predictor to predict the pupylation sites. First, the maximum relevance minimum redundancy (mRMR) and incremental feature selection methods were made on five kinds of features to select the optimal feature set. Then the prediction model was built based on the optimal feature set with the assistant of the support vector machine algorithm. As a result, the overall jackknife success rate by the new predictor on a newly constructed benchmark dataset was 0.764, and the Mathews correlation coefficient was 0.522, indicating a good prediction. Feature analysis showed that all features types contributed to the prediction of protein pupylation sites. Further site-specific features analysis revealed that the features of sites surrounding the central lysine contributed more to the determination of pupylation sites than the other sites. PMID- 24066286 TI - Spectrum of bacterial keratitis at a tertiary eye care centre in India. AB - AIM: To report the aetiological spectrum and susceptibility patterns of bacteria isolated from patients with corneal ulceration. METHOD: The microbiological data of all patients with suspected infectious corneal ulceration who presented to the ocular microbiology service at this centre between 2005 and 2012 were reviewed retrospectively. RESULT: Microorganisms were recovered from 1665 (77%) of the 2170 ulcers. Bacterial isolates accounted for 1205 of the organisms isolated. The most common bacterial pathogens isolated were various species of Staphylococcus, representing 777 (64.5%), followed by Staphylococcus spp. (148; 12.3%) and Pseudomonas aeruginosa (117; 9.7%). High percentages of Gram-positive bacteria were susceptible to gatifloxacin (>94%), followed by ofloxacin and moxifloxacin. Almost 90% of Pseudomonas aeruginosa isolates were susceptible to ciprofloxacin and moxifloxacin. Sixty-two (44%) of 140 isolates of Streptococcus pneumoniae, 79 (14.8%) of 534 isolates of Staphylococcus epidermidis, and 33 (14%) of 234 isolates of Staphylococcus aureus were resistant to three or more antibiotics. CONCLUSION: Staphylococcus spp. were the most common bacterial pathogens isolated from patients with keratitis in this setting. High percentages of Gram-positive and Gram-negative bacteria were susceptible to gatifloxacin and moxifloxacin, respectively. Interestingly, a high percentage of Streptococcus pneumoniae isolates were found to be resistant to three or more antibiotics. PMID- 24066287 TI - Initial dose of three monthly intravitreal injections versus PRN intravitreal injections of bevacizumab for macular edema secondary to branch retinal vein occlusion. AB - PURPOSE: To compare visual and anatomic outcomes of intravitreal bevacizumab injections administered as needed (PRN group) and initial treatment with 3 monthly injections followed by as-needed injections (3 monthly initial dose group) in patients with macular edema (ME) secondary to branch retinal vein occlusion (BRVO). METHODS: This retrospective study included 69 and 26 patients in the PRN and 3 monthly initial dose groups, respectively. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were compared between the 2 groups 6 months after initial injection. RESULTS: At month 6, BCVA change from baseline was -0.27 +/- 0.28 (mean +/- standard deviation) logMAR in the PRN group and -0.28 +/- 0.20 logMAR in the 3 monthly initial dose group. Mean CRT changes were -204 +/- 168 in the PRN group and -161 +/- 149 MU m in the 3 monthly initial dose group at month 6. There were no statistically significant differences in BCVA or CRT changes between groups at any time point. The number of intravitreal injections over 6 months was significantly lower in the PRN group (1.8 +/- 0.8 injections) than in the 3 monthly initial dose group (3.4 +/- 0.5 injections; P < 0.001). CONCLUSIONS: Our results suggest that as-needed intravitreal bevacizumab injections are more tolerable for patients with ME secondary to BRVO. PMID- 24066288 TI - Rehabilitation after ACL injury: a fluoroscopic study on the effects of type of exercise on the knee sagittal plane arthrokinematics. AB - A safe rehabilitation exercise for anterior cruciate ligament (ACL) injuries needs to be compatible with the normal knee arthrokinematics to avoid abnormal loading on the joint structures. The objective of this study was to measure the amount of the anterior tibial translation (ATT) of the ACL-deficient knees during selective open and closed kinetic chain exercises. The intact and injured knees of fourteen male subjects with unilateral ACL injury were imaged using uniplanar fluoroscopy, while the subjects performed forward lunge and unloaded/loaded open kinetic knee extension exercises. The ATTs were measured from fluoroscopic images, as the distance between the tibial and femoral reference points, at seven knee flexion angles, from 0 degrees to 90 degrees . No significant differences were found between the ATTs of the ACL-deficient and intact knees at all flexion angles during forward lunge and unloaded open kinetic knee extension (P < 0.05). During loaded open kinetic knee extension, however, the ATTs of the ACL deficient knees were significantly larger than those of the intact knees at 0 degrees (P = 0.002) and 15 degrees (P = 0.012). It was suggested that the forward lunge, as a weight-bearing closed kinetic chain exercise, provides a safer approach for developing muscle strength and functional stability in rehabilitation program of ACL-deficient knees, in comparison with open kinetic knee extension exercise. PMID- 24066289 TI - A new coated nitinol occluder for transcatheter closure of ventricular septal defects in a canine model. AB - AIMS: This study evaluated feasibility and safety of implanting the polyester coated nitinol ventricular septal defect occluder (pcVSDO) in the canine model. METHODS AND RESULTS: VSD models were successfully established by transseptal ventricular septal puncture via the right jugular vein in 15 out of 18 canines. Two types of VSDOs were implanted, either with pcVSDOs (n = 8) as the new type occluder group or with the commercial ventricular septal defect occluders (VSDOs, n = 7, Shanghai Sharp Memory Alloy Co. Ltd.) as the control group. Sheath size was 10 French (10 Fr) in two groups. Then the general state of the canines was observed after implantation. ECG and TTE were performed, respectively, at 7, 30, 90 days of follow-up. The canines were sacrificed at these time points for pathological and scanning electron microscopy examination. The devices were successfully implanted in all 15 canines and were retrievable and repositionable. There was no thrombus formation on the device or occurrence of complete heart block. The pcVSDO surface implanted at day 7 was already covered with neotissue by gross examination, and it completed endothelialization at day 30, while the commercial VSDO was covered with the neotissue in 30th day and the complete endothelialization in 90th day. CONCLUSION: The study shows that pcVSDO is feasible and safe to close canine VSD model and has good biocompatibility and shorter time of endothelialization. PMID- 24066290 TI - Genotypic and antimicrobial characterisation of Propionibacterium acnes isolates from surgically excised lumbar disc herniations. AB - The anaerobic skin commensal Propionibacterium acnes is an underestimated cause of human infections and clinical conditions. Previous studies have suggested a role for the bacterium in lumbar disc herniation and infection. To further investigate this, five biopsy samples were surgically excised from each of 64 patients with lumbar disc herniation. P. acnes and other bacteria were detected by anaerobic culture, followed by biochemical and PCR-based identification. In total, 24/64 (38%) patients had evidence of P. acnes in their excised herniated disc tissue. Using recA and mAb typing methods, 52% of the isolates were type II (50% of culture-positive patients), while type IA strains accounted for 28% of isolates (42% patients). Type III (11% isolates; 21% patients) and type IB strains (9% isolates; 17% patients) were detected less frequently. The MIC values for all isolates were lowest for amoxicillin, ciprofloxacin, erythromycin, rifampicin, tetracycline, and vancomycin (<=1 mg/L). The MIC for fusidic acid was 1-2 mg/L. The MIC for trimethoprim and gentamicin was 2 to >=4 mg/L. The demonstration that type II and III strains, which are not frequently recovered from skin, predominated within our isolate collection (63%) suggests that the role of P. acnes in lumbar disc herniation should not be readily dismissed. PMID- 24066291 TI - Sympathetic innervation induced in engrafted engineered cardiomyocyte sheets by glial cell line derived neurotrophic factor in vivo. AB - The aim of myocardial tissue engineering is to repair or regenerate damaged myocardium with engineered cardiac tissue. However, this strategy has been hampered by lack of functional integration of grafts with native myocardium. Autonomic innervation may be crucial for grafts to function properly with host myocardium. In this study, we explored the feasibility of in vivo induction of autonomic innervation to engineered myocardial tissue using genetic modulation by adenovirus encoding glial cell line derived neurotrophic factor (GDNF). GFP transgene (control group) or GDNF overexpressing (GDNF group) engineered cardiomyocyte sheets were transplanted on cryoinjured hearts in rats. Nerve fibers in the grafts were examined by immunohistochemistry at 1, 2, and 4 weeks postoperatively. Growth associated protein-43 positive growing nerves and tyrosine hydroxylase positive sympathetic nerves were first detected in the grafts at 2 weeks postoperatively in control group and 1 week in GDNF group. The densities of growing nerve and sympathetic nerve in grafts were significantly increased in GDNF group. No choline acetyltransferase immunopositive parasympathetic nerves were observed in grafts. In conclusion, sympathetic innervation could be effectively induced into engrafted engineered cardiomyocyte sheets using GDNF. PMID- 24066292 TI - Candidate genes for proliferative diabetic retinopathy. AB - Several candidate genes have been so far implicated in the pathogenesis of proliferative diabetic retinopathy (PDR) in subjects with type 2 diabetes. Since the principal pathogenetic mechanisms for diabetic retinopathy (DR) and PDR are different, the main pathogenetic mechanism in DR is increased vascular permeability, whereas in PDR the crucial pathogenetic mechanisms are fibrosis and neoangiogenesis. Due to that fact, different candidate genes are expected to be involved in the development of either DR or PDR. None of the candidate genes, however, can be fully and solely responsible for the development of PDR and for DR progression into PDR. Epigenetic mechanisms are expected to be involved in the pathogenesis of PDR as well. Gene polymorphisms responsible for PDR and epigenetic mechanisms responsible for PDR are reviewed in this paper. PMID- 24066293 TI - Phenolic biotransformations during conversion of ferulic acid to vanillin by lactic acid bacteria. AB - Vanillin is widely used as food additive and as a masking agent in various pharmaceutical formulations. Ferulic acid is an important precursor of vanillin that is available in abundance in cell walls of cereals like wheat, corn, and rice. Phenolic biotransformations can occur during growth of lactic acid bacteria (LAB), and their production can be made feasible using specialized LAB strains that have been reported to produce ferulic acid esterases. The present study aimed at screening a panel of LAB isolates for their ability to release phenolics from agrowaste materials like rice bran and their biotransformation to industrially important compounds such as ferulic acid, 4-ethyl phenol, vanillic acid, vanillin, and vanillyl alcohol. Bacterial isolates were evaluated using ferulic acid esterase, ferulic acid decarboxylase, and vanillin dehydrogenase assays. This work highlights the importance of lactic acid bacteria in phenolic biotransformations for the development of food grade flavours and additives. PMID- 24066294 TI - A review on the use of grid-based Boltzmann equation solvers for dose calculation in external photon beam treatment planning. AB - Deterministic linear Boltzmann transport equation (D-LBTE) solvers have recently been developed, and one of the latest available software codes, Acuros XB, has been implemented in a commercial treatment planning system for radiotherapy photon beam dose calculation. One of the major limitations of most commercially available model-based algorithms for photon dose calculation is the ability to account for the effect of electron transport. This induces some errors in patient dose calculations, especially near heterogeneous interfaces between low and high density media such as tissue/lung interfaces. D-LBTE solvers have a high potential of producing accurate dose distributions in and near heterogeneous media in the human body. Extensive previous investigations have proved that D LBTE solvers were able to produce comparable dose calculation accuracy as Monte Carlo methods with a reasonable speed good enough for clinical use. The current paper reviews the dosimetric evaluations of D-LBTE solvers for external beam photon radiotherapy. This content summarizes and discusses dosimetric validations for D-LBTE solvers in both homogeneous and heterogeneous media under different circumstances and also the clinical impact on various diseases due to the conversion of dose calculation from a conventional convolution/superposition algorithm to a recently released D-LBTE solver. PMID- 24066295 TI - Distal airway impairment in obese normoreactive women. AB - BACKGROUND: Asthma-like symptoms are frequent in overweight and obesity, but the mechanism is unclear when airway hyperresponsiveness (AHR) is lacking. In this study, we focused on obese women with a clinical suspicion of asthma but negative methacholine challenge and tested distal airway hyperreactivity, explored by Forced Vital Capacity dose-response slope (FVC DRS). OBJECTIVE: To question AHR at the distal airway level in obese women. METHODS: A total of 293 symptomatic obese and nonobese women free of treatment were investigated. Methacholine challenge tests were undertaken, and patients were divided according to their results to the test. In hyperreactive and nonhyperreactive patients and in our total population, correlations, regression analyses, and analyses of covariance were performed to compare distal airway hyperreactivity in three groups of body mass index (BMI). RESULTS: After adjusting for age and baseline respiratory values, the relationship between FVC and FEV1 (forced expiratory volume in one second) DRS was influenced by BMI, with a lower slope in obese than overweight and normal patients in our total population (P = 0.008) and in our nonhyperreactive one (P = 0.028). CONCLUSION: Distal airway hyperresponsiveness was observed in symptomatic wheezing obese women negative to methacholine challenge. PMID- 24066296 TI - Cryobiopsy: should this be used in place of endobronchial forceps biopsies? AB - Forceps biopsies of airway lesions have variable yields. The yield increases when combining techniques in order to collect more material. With the use of cryotherapy probes (cryobiopsy) larger specimens can be obtained, resulting in an increase in the diagnostic yield. However, the utility and safety of cryobiopsy with all types of lesions, including flat mucosal lesions, is not established. AIMS: Demonstrate the utility/safety of cryobiopsy versus forceps biopsy to sample exophytic and flat airway lesions. SETTINGS AND DESIGN: Teaching hospital based retrospective analysis. METHODS: Retrospective analysis of patients undergoing cryobiopsies (singly or combined with forceps biopsies) from August 2008 through August 2010. Statistical Analysis. Wilcoxon signed-rank test. RESULTS: The comparative analysis of 22 patients with cryobiopsy and forceps biopsy of the same lesion showed the mean volumes of material obtained with cryobiopsy were significantly larger (0.696 cm(3) versus 0.0373 cm(3), P = 0.0014). Of 31 cryobiopsies performed, one had minor bleeding. Cryopbiopsy allowed sampling of exophytic and flat lesions that were located centrally or distally. Cryobiopsies were shown to be safe, free of artifact, and provided a diagnostic yield of 96.77%. CONCLUSIONS: Cryobiopsy allows safe sampling of exophytic and flat airway lesions, with larger specimens, excellent tissue preservation and high diagnostic accuracy. PMID- 24066297 TI - Magnesium coated bioresorbable phosphate glass fibres: investigation of the interface between fibre and polyester matrices. AB - Bioresorbable phosphate glass fibre reinforced polyester composites have been investigated as replacement for some traditional metallic orthopaedic implants, such as bone fracture fixation plates. However, composites tested revealed loss of the interfacial integrity after immersion within aqueous media which resulted in rapid loss of mechanical properties. Physical modification of fibres to change fibre surface morphology has been shown to be an effective method to improve fibre and matrix adhesion in composites. In this study, biodegradable magnesium which would gradually degrade to Mg(2+) in the human body was deposited via magnetron sputtering onto bioresorbable phosphate glass fibres to obtain roughened fibre surfaces. Fibre surface morphology after coating was observed using scanning electron microscope (SEM). The roughness profile and crystalline texture of the coatings were determined via atomic force microscope (AFM) and X ray diffraction (XRD) analysis, respectively. The roughness of the coatings was seen to increase from 40 +/- 1 nm to 80 +/- 1 nm. The mechanical properties (tensile strength and modulus) of fibre with coatings decreased with increased magnesium coating thickness. PMID- 24066298 TI - Oxidative damage and mutagenic potency of fast neutron and UV-B radiation in pollen mother cells and seed yield of Vicia faba L. AB - In recent years, there has been a great deal of attention toward free radicals, reactive oxygen species (ROS) generated by exposure of crop plant cells to physical radiations. Henceforth, the current study was planned to compare oxidative stress and mutagenic potential of different irradiation doses of fast neutron (FN) and UV-B on meiotic-pollen mother cells (PMCs), pollen grains (PGs) and seeds yielded from irradiated faba beans seedlings. On the cytogenetic level, each irradiation type had special interference with DNA of PMC and exhibited wide range of mutagenic action on the frequency and type of chromosomal anomalies, fertility of PGs and seed yield productivity based on the irradiation exposure dose and radiation sensitivity of faba bean plants compared with un-irradiated ones. On the molecular level, SDS-PAGE and RPAD-PCR analyses of seeds yielded from irradiated seedlings exhibited distinctive polymorphisms based on size, intensity, appearance, and disappearance of polypeptides bands compared with un irradiated ones. The total values of protein and DNA polymorphisms reached 88% and 90.80% respectively. The neutron fluency (2.3 * 10(6) n/cm(2)) and UV-B dose for 1 hr were recorded as bio-positive effects. The present study proved that genetic variations revealed by cytogenetic test could be supported by gene expression (alterations in RAPD and protein profiles). PMID- 24066300 TI - Development, disease, and regeneration of tissues in the dental-craniofacial complex. PMID- 24066299 TI - Class A beta-lactamases as versatile scaffolds to create hybrid enzymes: applications from basic research to medicine. AB - Designing hybrid proteins is a major aspect of protein engineering and covers a very wide range of applications from basic research to medical applications. This review focuses on the use of class A beta-lactamases as versatile scaffolds to design hybrid enzymes (referred to as beta-lactamase hybrid proteins, BHPs) in which an exogenous peptide, protein or fragment thereof is inserted at various permissive positions. We discuss how BHPs can be specifically designed to create bifunctional proteins, to produce and to characterize proteins that are otherwise difficult to express, to determine the epitope of specific antibodies, to generate antibodies against nonimmunogenic epitopes, and to better understand the structure/function relationship of proteins. PMID- 24066301 TI - Auditory verbal cues alter the perceived flavor of beverages and ease of swallowing: a psychometric and electrophysiological analysis. AB - We investigated the possible effects of auditory verbal cues on flavor perception and swallow physiology for younger and elder participants. Apple juice, aojiru (grass) juice, and water were ingested with or without auditory verbal cues. Flavor perception and ease of swallowing were measured using a visual analog scale and swallow physiology by surface electromyography and cervical auscultation. The auditory verbal cues had significant positive effects on flavor and ease of swallowing as well as on swallow physiology. The taste score and the ease of swallowing score significantly increased when the participant's anticipation was primed by accurate auditory verbal cues. There was no significant effect of auditory verbal cues on distaste score. Regardless of age, the maximum suprahyoid muscle activity significantly decreased when a beverage was ingested without auditory verbal cues. The interval between the onset of swallowing sounds and the peak timing point of the infrahyoid muscle activity significantly shortened when the anticipation induced by the cue was contradicted in the elderly participant group. These results suggest that auditory verbal cues can improve the perceived flavor of beverages and swallow physiology. PMID- 24066302 TI - Combined treatment of hydroxytyrosol with carbon monoxide-releasing molecule-2 prevents TNF alpha-induced vascular endothelial cell dysfunction through NO production with subsequent NFkappaB inactivation. AB - This study investigated the atheroprotective properties of olive oil polyphenol, hydroxytyrosol (HT), in combination with carbon monoxide-releasing molecule-2 (CORM-2) that acts as a carbon monoxide donor using vascular endothelial cells (VECs). Our results showed that CORM-2 could strengthen the cytoprotective and anti-apoptotic effects of HT against TNFalpha-induced cellular damage by enhancing cell survival and the suppression of caspase-3 activation. While HT alone attenuated NFkappaBp65 phosphorylation and IkappaBalpha degradation triggered by TNFalpha in a dose-dependent manner, combined treatment of HT with CORM-2 but not iCORM-2 nearly completely blocked these TNFalpha effects. Furthermore, combined action of both compounds results in the inhibition of NFkappaB nuclear translocation. Results also indicate that both compounds time dependently increased eNOS phosphorylation levels and the combination of HT with CORM-2 was more effective in enhancing eNOS activation and NO production in VECs. The NOS inhibitor, L-NMMA, significantly suppressed the combined effects of HT and CORM-2 on TNFalpha-triggered NFkappaBp65 and IkappaBalpha phosphorylation as well as decreased cell viability. Together, these data suggest that carbon monoxide-dependent regulation of NO production by the combination of HT with CORM 2 may provide a therapeutic benefit in the treatment of endothelial dysfunction and atherosclerosis. PMID- 24066303 TI - Influence of positive end-expiratory pressure on myocardial strain assessed by speckle tracking echocardiography in mechanically ventilated patients. AB - PURPOSE: The effects of mechanical ventilation (MV) on speckle tracking echocardiography- (STE-)derived variables are not elucidated. The aim of the study was to evaluate the effects of positive end-expiratory pressure (PEEP) ventilation on 4-chamber longitudinal strain (LS) analysis by STE. METHODS: We studied 20 patients admitted to a mixed intensive care unit who required intubation for MV and PEEP titration due to hypoxia. STE was performed at three times: (T1) PEEP = 5 cmH2O; (T2) PEEP = 10 cmH2O; and (T3) PEEP = 15 cmH2O. STE analysis was performed offline using a dedicated software (XStrain MyLab 70 Xvision, Esaote). RESULTS: Left peak atrial-longitudinal strain (LS) was significantly reduced from T1 to T2 and from T2 to T3 (P < 0.05). Right peak atrial-LS and right ventricular-LS showed a significant reduction only at T3 (P < 0.05). Left ventricular-LS did not change significantly during titration of PEEP. Cardiac chambers' volumes showed a significant reduction at higher levels of PEEP (P < 0.05). CONCLUSIONS: We demonstrated for the first time that incremental PEEP affects myocardial strain values obtained with STE in intubated critically ill patients. Whenever performing STE in mechanically ventilated patients, care must be taken when PEEP is higher than 10 cmH2O to avoid misinterpreting data and making erroneous decisions. PMID- 24066304 TI - Green tea polyphenol epigallocatechin-3-gallate enhance glycogen synthesis and inhibit lipogenesis in hepatocytes. AB - The beneficial effects of green tea polyphenols (GTP) against metabolic syndrome and type 2 diabetes by suppressing appetite and nutrient absorption have been well reported. However the direct effects and mechanisms of GTP on glucose and lipid metabolism remain to be elucidated. Since the liver is an important organ involved in glucose and lipid metabolism, we examined the effects and mechanisms of GTP on glycogen synthesis and lipogenesis in HepG2 cells. Concentrations of GTP containing 68% naturally occurring (-)-epigallocatechin-3-gallate (EGCG) were incubated in HepG2 cells with high glucose (30 mM) under 100 nM of insulin stimulation for 24 h. GTP enhanced glycogen synthesis in a dose-dependent manner. 10 MUM of EGCG significantly increased glycogen synthesis by 2fold (P < 0.05) compared with insulin alone. Western blotting revealed that phosphorylation of Ser9 glycogen synthase kinase 3 beta and Ser641 glycogen synthase was significantly increased in GTP-treated HepG2 cells compared with nontreated cells. 10 MUM of EGCG also significantly inhibited lipogenesis (P < 0.01). We further demonstrated that this mechanism involves enhanced expression of phosphorylated AMP-activated protein kinase alpha and acetyl-CoA carboxylase in HepG2 cells. Our results showed that GTP is capable of enhancing insulin-mediated glucose and lipid metabolism by regulating enzymes involved in glycogen synthesis and lipogenesis. PMID- 24066306 TI - An organic solvent and surfactant stable alpha-amylase from soybean seeds. AB - An organic solvent and surfactant stable alpha-amylase was obtained from soybean seeds. The direct and indirect effect of various organic solvents (non-polar, polar protic, and polar aprotic) and surfactants on the activity and stability of free enzyme was determined. The enzyme showed a very high catalytic efficiency and stabilization against most of the organic solvents and surfactants tested, except for few. Those organic solvents and surfactants (like chloroform, dimethyl formamide, n-butanol, and Tween 20), which caused an inhibition in enzyme activity, were used to study their effects on immobilized enzyme. The inhibitory effect was found to be decreased in immobilized enzyme as compared to free enzyme indicating that immobilization imparted stability to the enzyme. Moreover, the possibility of reuse of the enzyme in the presence of the organic solvents and surfactants was increased upon immobilization. The stability of soybean alpha amylase towards organic solvents and surfactants shows that it is a potential candidate for use in organic-solvent biocatalysis as well as in detergent industries. PMID- 24066305 TI - RU28318, an aldosterone antagonist, in combination with an ACE inhibitor and angiotensin receptor blocker attenuates cardiac dysfunction in diabetes. AB - AIMS: We evaluated the effects of RU28318 (RU), a selective mineralocorticoid receptor (MR) antagonist, Captopril (Capt), an angiotensin converting enzyme inhibitor, and Losartan (Los), an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R-) induced cardiac dysfunction in hearts obtained from normal and diabetic rats. METHODS: Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I) followed by a period of 30 min of reperfusion (R). Drugs were administered for 30 min either before or after ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple). Recovery of cardiac hemodynamics was evaluated. RESULTS: Recovery of cardiac function was up to 5 fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly effective as Capt or Los treatment. CONCLUSIONS: RU treatment locally might be considered as an effective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most effective at improving -dP/dt (a measure of diastolic function) when administered to diabetic hearts after ischemia. PMID- 24066308 TI - The effect of systemically administered bisphosphonates on bony healing after tooth extraction and osseointegration of dental implants in the rabbit maxilla. AB - PURPOSE: To evaluate the effects of bisphosphonates on bone healing after tooth extraction and osseointegration of dental implants in a rabbit model. MATERIALS AND METHODS: Twenty-four rabbits were divided into four groups; one control and three experimental. The experimental were treated with intravenous zoledronic acid (ZA, 0.1 mg/kg) twice per week starting 4 (Z4 group) and 8 (Z8 group) weeks before surgery until the end of the experiments. The experimental ZD4 group was treated with intravenous ZA (0.01 mg/kg) and intramuscular dexamethasone (1 mg/kg) twice per week starting 4 weeks before surgery until the end of the experiments. The maxillary first premolar was extracted, and an implant with a diameter of 1.5 mm was placed between the incisor and the premolar of each maxilla. Healing of the extraction socket was evaluated and histomorphometric analysis around the implant was performed, using the bone-to-implant contact ratio (BIC) and bone area ratio (BA) 4 and 8 weeks after the surgery. RESULTS: The control group underwent a normal healing process, but all experimental groups showed necrotic bone with hollow lacunae. BIC and BA in the control group increased from the 4- to 8-week evaluations, but decreased in the experimental groups from 4 to 8 weeks. BIC and BA of the Z8 and ZD4 groups were higher than those of the control group at the 4-week evaluation, but were lower than the control at the the 8-week evaluation. CONCLUSIONS: This study showed that administration of bisphosphonates interferes with normal bone remodeling after tooth extraction. The experimental groups showed good initial stability, but long term healing around the implants was impaired. Within the limits of this study, it may be suggested that patients taking bisphosphonates should be treated with caution when performing tooth extraction or placing dental implants. PMID- 24066309 TI - Comparison of a novel trephine drill with conventional rotary instruments for maxillary sinus floor elevation. AB - PURPOSE: The purpose of this study was to compare a newly designed trephine drill (SLA KIT, Neobiotech) with conventional rotary instruments for maxillary sinus floor elevation based on operative time, postoperative pain, and perforation rates. MATERIALS AND METHODS: Twenty-five patients were treated with a bilateral sinus floor elevation procedure with rotary trephine and conventional instruments. One side was treated with conventional rotary instruments, while the contralateral side was treated with rotary trephine instruments, with a 2-week gap between surgeries. Operative time was measured with a chronometer in seconds as the time from soft tissue incision to primary closure of the incision with the last suture. Pain was scored on a 10-point visual analog scale at 24 hours after surgery. The presence of tears and perforations was determined by direct visualization and the Valsalva maneuver. RESULTS: Twenty-five patients were included in the study. Operative time was shorter when the trephine drill was used (11.1 +/- 2.4 minutes) than with conventional rotary instruments (15.1 +/- 2.9 minutes). Sinus membrane perforation was observed in eight patients when conventional rotary instruments were used, while the trephine drill resulted in two sinus perforations. Mean pain scores were 2.01 +/- 0.11 after using the trephine drill and 2.25 +/- 0.76 when conventional rotary instruments were used. No significant difference was found in postoperative pain scores. CONCLUSION: The trephine drill technique may result in decreased perforation rates and operative time. PMID- 24066310 TI - Marginal and internal adaptation of different superstructure and abutment materials using two different implant systems for five-unit implant-supported fixed partial dentures: an in vitro study. AB - PURPOSE: To evaluate the marginal and internal adaptation of five-unit implant supported fixed partial dentures with different superstructure and abutment materials with two different implant systems. MATERIALS AND METHODS: Two mandibular epoxy resin models (one for each implant system) were fabricated, and implants were inserted in the canine, first premolar, and first molar regions. Thirty impressions of each model were then made. The 30 models of each group were divided into three subgroups: group 1, titanium abutment with metal (nickel chromium) framework; group 2, titanium abutment with zirconium framework; and group 3, zirconium abutment with zirconium framework. The replica technique was used to examine the marginal and internal gap values. For each restoration, 20 measurements were performed, and the data were evaluated statistically using analysis of variance and the least significant difference post hoc test. RESULTS: The highest values for internal adaptation were observed at the occlusal surface in all groups. There were statistically significant differences in marginal measurements between subgroups. The smallest gaps were found in group 1 (79.361 MUm), and the largest gaps were found in group 3 (131.242 MUm). CONCLUSIONS: In this study, marginal and internal gap measurements were 79 to 131 MUm. The marginal discrepancy of the tested materials could be considered clinically acceptable. PMID- 24066311 TI - The effect of static load on dental implant survival: a systematic review. AB - PURPOSE: The purpose of this study was to systematically review the current evidence related to the effects of static loading on the long-term stability of the osseointegrated interface. MATERIALS AND METHODS: The literature search was conducted using Medline supplemented by SCOPUS and the Cochrane databases as well as hand searching from references of reviewed papers. Relevant studies were selected according to predetermined inclusion and exclusion criteria. Key words used in the search included: dental implant passive fit, dental implant misfit, dental implant static load, dental implant overload, orthodontic forces, and dental implants. RESULTS: The initial database search yielded 192 relevant titles. After the subsequent filtering process, 36 studies were finally selected. Twenty-eight articles involved animal studies and eight articles involved human studies. CONCLUSIONS: The results of this systematic review demonstrate that there is no apparent detrimental effect of static loading on osseointegrated dental implants. PMID- 24066312 TI - Effects of oral implant surface roughness on bacterial biofilm formation and treatment efficacy. AB - PURPOSE: The aim of this study was to investigate the influence of oral implant surface roughness on bacterial biofilm formation and antimicrobial treatment efficacy. MATERIALS AND METHODS: Titanium disks with low-roughness pickled surfaces and with moderately rough sandblasted, acid-etched surfaces were used as substrata. Streptococcus mutans biofilms (1 and 3 days old) and Porphyromonas gingivalis biofilms (3 days old) were grown on the two types of substrata and then treated with 0.2% chlorhexidine. Biofilm viability was evaluated by a resazurin metabolism assay and by sonication-colony-forming unit counts. RESULTS: Surface roughness had no influence on the amount of biofilm formation by S mutans or P gingivalis in this in vitro biofilm model. However, it strongly affected the treatment efficacy of chlorhexidine on the biofilms formed by both species. Higher roughness resulted in lower efficacy. Furthermore, treatment efficacy was significantly reduced in older biofilms. CONCLUSION: A moderately roughened surface did not enhance biofilm formation but reduced treatment efficacy of the biofilms. This finding indicates that efforts should be directed toward optimizing implant surface properties for effective antimicrobial treatment without compromising osseointegration. PMID- 24066313 TI - Dental implant survival in irradiated oral cancer patients: a systematic review of the literature. AB - PURPOSE: Oral cancer therapy with surgery and radiation is associated with comorbidities; this affects rehabilitation with osseointegrated dental implants. The aim of this systematic review was to evaluate the effect of radiation therapy on osseointegrated dental implant survival in oral cancer patients. MATERIALS AND METHODS: A review of the literature published between 1990 and June 2012 was conducted. Pertinent studies evaluating the effect of radiation therapy on osseointegration of implants were identified through searches of PubMed, SCIRUS, and Google Scholar. Overall implant survival rates were compared with respect to timing of radiation (prior to or after implantation), site of implant placement (maxilla, mandible, vascularized free flaps, nonvascular bone grafts), radiation dose, time interval between radiation therapy and implant placement, and the effect of hyperbaric oxygen therapy. RESULTS: Thirty-eight articles were eligible for inclusion in the review. Overall implant survival rates with radiation therapy done pre- and postimplantation were 88.9% and 92.2%, respectively. In preimplantation radiation therapy, the implant survival rate was significantly higher for the mandible (93.3%) than for the maxilla (78.9%) or for grafted bone (87.5%). Similarly, the implant survival rate was higher when implants were placed in free flaps (89.3%) than in nonvascularized bone grafts (81.7%). While a radiation dose above 55 Gy significantly decreased implant survival, no significant relationship between increased implant survival and the remaining variables were found. CONCLUSION: There, was no significant difference in dental implant survival rates between preimplantation and postimplantation radiation therapy. The anatomical site of implant placement in preimplantation radiation therapy was the most pertinent variable affecting implant survival, with a better survival rate in the mandible compared to the maxilla and grafted bone. PMID- 24066314 TI - Comparative assessments, meta-analysis, and recommended guidelines for reporting studies on histomorphometric bone-implant contact in humans. AB - PURPOSE: To evaluate factors that have an influence on histomorphometric bone-to implant contact (BIC) of dental implants in humans. MATERIALS AND METHODS: Using inclusion/exclusion criteria, eligible studies were searched in five databases and handsearched in 11 journals. A total of 351 articles were assigned to full text analysis. The extracted data were assigned to comparative statistical assessments and meta-analysis. RESULTS: A total of 55 articles were included in the analysis. The mean BIC found in comparative assessments and meta-analysis of implants in the mandible (70.97 and 69.744 +/- 3.304, respectively) was higher than those in the maxilla (53.24 and 56.692 +/- 3.598; P = .000 and P = .008, respectively). The mean BIC in the anterior mandible (79.42) and maxilla (74.19) were higher than the posterior mandible (69.14) and maxilla (36.68) (P < .05). Differences were detected in BIC of commercially available implants and experimental micro-implants (P < .05). Comparative assessments and meta-analysis showed that conventionally loaded implants (75.70 and 75.786 +/- 4.889, respectively) had higher BIC than unloaded (54.07 and 53.24 +/- 4.971, respectively) and immediately loaded implants (58.53 and 68.831 +/- 4.972; P = .000 and P = .004, respectively). CONCLUSIONS: Based upon a meta-analysis of the literature the following conclusions can be made: The BIC in the mandible is higher than the maxilla. The BIC is higher in the anterior than the posterior regions. The implant design coupled with the anatomical region affects the amount of BIC. Placement of experimental micro-implants with different surfaces in the posterior region always result in low and almost comparable BIC. The loading state and healing period seems to have an influence on BIC. Specific reporting guidelines are required to improve reporting of studies on human BIC. PMID- 24066315 TI - Effect of intraoperative bone quality testing on bone healing and osseointegration of dental implants. AB - PURPOSE: A novel diagnostic device (BoneProbe) for evaluating alveolar bone quality during dental implant surgery has recently been developed. The underlying measurement principle is based on a compressive test of bone, which may subsequently affect bone healing and osseointegration of dental implants. MATERIALS AND METHODS: Six implant sites each were created in the rear left tibia of four sheep and used for bone quality testing with the BoneProbe, while empty osteotomies and implants placed without testing served as controls. Maximum insertion torque and primary implant stability (Osstell) were determined additionally. After 5 and 20 weeks, the animals were sacrificed followed by histomorphometric and microradiographic analysis quantifying bone implant contact (BIC) and bone mineral density (BMD) as parameters. Statistical analysis was conducted applying one-sample t tests, two-sample t tests and Pearson correlation coefficients (alpha = .05). RESULTS: Implants placed following application of the BoneProbe differed from the control treatments only in one case, where BIC was greater (P = .02) at the control implant after 20 weeks of healing. With the exception of the combinations of Osstell/BoneProbe measurement in trabecular bone (0.29) and Osstell/insertion torque (0.34), good correlations of all clinically conducted measurements were found. CONCLUSION: Based on the results obtained, it appears that intraoperative testing of bone quality applying the BoneProbe does not jeopardize bone healing and osseointegration of dental implants. PMID- 24066316 TI - Success rate, healing time, and implant stability of photofunctionalized dental implants. AB - PURPOSE: This is the first study to report the clinical outcomes of photofunctionalized dental implants. MATERIALS AND METHODS: This retrospective study analyzed 95 consecutive patients who received 222 untreated implants and 70 patients who received 168 photofunctionalized implants over a follow-up period of 2.5 years. Photofunctionalization was performed by treating implants with UV light for 15 minutes using a photo device immediately before placement. The generation of superhydrophilicity and hemophilicity along with a substantial reduction in atomic percentage of surface carbon was confirmed after photofunctionalization. In both groups, 90% of the implants were placed in complex cases requiring staged or simultaneous site-development surgery. The implant stability was measured at implant placement and loading using the implant stability quotient (ISQ) values; then, the rate of implant stability development was evaluated by calculating the ISQ increase per month. RESULTS: The healing time before functional loading was 3.2 months in photofunctionalized implants and 6.5 months in untreated implants. The success rate was 97.6% and 96.3% for photofunctionalized and untreated implants, respectively. The ISQ increase per month for photofunctionalized implants ranged from 2.0 to 8.7 depending on the ISQ at placement, and it was considerably higher than that of untreated implants reported in the literature ranging from -1.8 to 2.8. Photofunctionalization resulted in a more frequent use of implants of 10 mm or shorter length and an overall decrease in implant diameter. CONCLUSIONS: Within the limits of this retrospective study, despite the more frequent use of shorter and smaller diameter implants, the use of photofunctionalization allowed for a faster loading protocol without compromising the success rate. The outcome was associated with an increased rate of implant stability development. The results suggest that photofunctionalization may provide a novel and practical avenue to further advance implant therapy. PMID- 24066317 TI - Effect of local application of aminoguanidine on the biomechanical retention of implants in rats with induced diabetes. AB - PURPOSE: To evaluate the effect of surgical placement of an aminoguanidine (AG) loaded chitosan membrane, which allows slow local release of AG, over an endosseous implant on mechanical retention of the implant in nondiabetic and diabetic rats. MATERIALS AND METHODS: Forty-eight male Wistar rats were randomly divided into six groups of eight animals each and subjected to three different treatment modalities: (1) implant placement in the femur, (2) placement of implant + chitosan membrane without AG at the surgical site, or (3) placement of implant + AG-loaded chitosan membrane (AG concentration of 7.35 mmol/kg body weight) at the surgical site. Groups 1, 2, and 3 were nondiabetic (control groups), and groups 4, 5, and 6 had chemically induced type 1 diabetes (test groups). At 4 weeks after implant placement, the animals were sacrificed and the countertorque force (CTF) required to disrupt the bone-implant interface was measured. Analyses of variance were performed, and the mean CTF values were compared between groups by using the Student t test. RESULTS: The mean CTF values were significantly lower in diabetic groups not treated with AG than in the corresponding nondiabetic animals that had received the same treatment modality. In groups that received AG locally, the mean CTF values were not statistically significantly different, regardless of diabetes status. CONCLUSIONS: Induced diabetes (type 1) negatively affected the CTF necessary for disrupting the bone implant interface. Local availability of AG in diabetic animals led to an increase in the CTF values to the same level as that in nondiabetic animals. PMID- 24066318 TI - Prosthetic outcome, patient complaints, and nutritional effects on elderly patients with magnet-retained, implant-supported overdentures--a 1-year report. AB - PURPOSE: To study the changes in treatment outcomes of complete dentures and magnet-retained, implant-supported overdentures in a group of elderly patients. MATERIALS AND METHODS: In this nonrandomized trial, 43 edentulous patients (14 men and 29 women) were fitted with complete dentures followed by implant supported mandibular overdenture in a sequential model. Treatment outcomes used for analysis included objective assessment of denture quality (Woelfel's index), patient satisfaction, nutritional status, body mass index (BMI), and serum albumin level. The McNemar test was used to determine if significant differences in the Woelfel's index and nutritional status existed at different treatment phases. Repeated measures ANOVA and multiple pairwise comparison tests were used to analyze patient satisfaction. BMI status and serum albumin level at different treatment phases were analyzed with one-way ANOVA and Tukey post hoc test. RESULTS: At the 1-year follow-up, significant improvements were recorded for the objective assessment of denture quality and patient complaints (P < .05). No subject was found to be malnourished at pretreatment and in subsequent treatment phases. BMI and serum albumin level were not significantly different at different treatment phases (P > .05) CONCLUSIONS: The present study demonstrated that in elderly patients with stable health and nutritional status, complete dentures made in a university clinic brought about overall improvement in denture quality and reduction in denture complaint score. Insertion of mandibular implant supported overdentures further improved the mandibular denture quality and reduced the mandibular denture complaint score. In this group of patients, no improvement in BMI, serum albumin value, and nutritional status were documented. PMID- 24066319 TI - In vivo evaluation of quantitative percussion diagnostics for determining implant stability. AB - PURPOSE: To test in a rat model whether quantitative percussion diagnostics provide reliable, reproducible indications of osseointegration. MATERIALS AND METHODS: Titanium implants were placed in femurs of 36 Sprague-Dawley rats. Each animal was assigned to one of six groups defined by one of three time points (2, 4, or 8 weeks postplacement) and one of two treatments (matrix metalloproteinase [MMP] inhibitor GM6001 or control). Percussion testing was conducted three times per subject at implant placement and before sacrifice at one of the time points. For each time point, there was an experimental group that received daily intraperitoneal injections of GM6001, and a control group that received no MMP inhibitor. The percussion data consisted of loss coefficient (LC) values that characterize energy dissipation. Statistical analysis was performed on the LC values for the two animal groups using the paired Student t test to assess differences as a function of time, and the independent t test to compare mean LC for the study groups at sacrifice (alpha = .05). Histologic evaluation using the osteogenic CD40 protein marker was also performed. RESULTS: A nearly significant difference in mean LC at the 2-week time point was observed between the two treatments with the GM6001 group having the higher value (P = .053). There was a greater difference between the mean LC values for the 4-week GM6001 and control groups (P = .001). The histologic evidence for subjects in these two groups confirmed reduction of osteogenesis at the implant interface after administration of the MMP inhibitor. CONCLUSIONS: Lower control LC values relative to the GM6001 therapeutic group were observed, consistent with the effect MMP inhibition has on matrix remodeling at the implant bone interface. This finding in conjunction with histologic observations confirms that osseointegration can be monitored using percussion diagnostics. PMID- 24066320 TI - Retrospective results of implants for partially edentulous posterior jaws according to time points of early loading. AB - PURPOSE: This study evaluated the survival and success rates and marginal bone loss conditions of early loaded implants in the posterior maxilla and mandible of partially edentulous patients. MATERIALS AND METHODS: Implants (n = 299) were placed in 105 patients at two research centers. Provisional fixed dental prostheses were provided to the patients between 1 week and 2 months after implant placement. The implants were classified into four groups according to the loading time (1 to 2, 2 to 4, 4 to 6, and 6 to 8 weeks). Periapical radiographs were taken via a parallel imaging technique, and the peri-implant marginal bone level was measured on the radiographic images. RESULTS: Most implants were lost within 1 month, and one implant was removed at 36 days after loading. The cumulative survival rate of the implants was 97.0%. Implants loaded in the maxilla at 1 to 2 weeks after prosthesis insertion had significantly lower survival rates than any other group (P = .013). There were no significant differences in marginal bone levels among the implant groups classified according to loading time. CONCLUSIONS: Early loading is a safe and predictable procedure for implant-supported restoration of posterior partial edentulism. However, care must be taken in early loading within 2 weeks after maxillary implant insertion. PMID- 24066321 TI - Retrospective analysis of prosthetic complications of implant-supported fixed partial dentures after an observation period of 5 to 10 years. AB - PURPOSE: The purpose of this study was to evaluate the incidence of the most common technical problems with implant-supported fixed partial dentures (FPDs) and to assess the survival and success rates (event-free survival) after 5 to 10 years of function. MATERIALS AND METHODS: All of the implants evaluated in this study were from a single manufacturer (Institut Straumann). Follow-up examinations were scheduled 1 week after suprastructure placement, 6 months later, and annually thereafter. Prosthesis-based data on survival/failure rates and technical complications were analyzed. RESULTS: In 95 partially edentulous patients, 231 Straumann implants were placed and restored with 177 implant supported prostheses (125 single crowns, 18 splinted crowns on two adjacent implants, and 34 three-unit FPDs). One hundred thirty one solid abutments and 100 synOcta abutments were inserted. The survival rate of prostheses supported by implants was 97.7%. The prosthetic success rate (event-free survival) was 96.05%. After an observation period of 5 years, the cumulative incidence of screw loosening was 0%. Fracture of the veneering porcelain occurred in 3.95% of all restorations. Fractures of the superstructure framework were not observed. The overall incidence of complications after 5 years was highest for splinted crowns, which showed the lowest success rate (94.4%), followed by three-unit FPDs (96%) and single crowns (98.4%). CONCLUSIONS: Single-unit restorations or short-span FPDs supported by both synOcta and solid abutments on Straumann implants showed low rates of technical complications, the most common being fracture of the veneering porcelain. PMID- 24066322 TI - A pilot study of postoperative pain felt after two implant surgery techniques: a randomized blinded prospective clinical study. AB - PURPOSE: To evaluate postoperative pain after successful implant surgery and compare pain experienced using conventional flap and flapless techniques. MATERIALS AND METHODS: Between January 2007 and September 2012, consecutive patients with bilateral partially edentulous maxillae or mandibles were included in the study. Patients were randomly allocated to receive implants with an atraumatic flapless procedure or with a conventional flap procedure in a split mouth design in a two-stage surgery. This randomized blinded prospective clinical study considered each patient as one unit. The data were analyzed using the Mann Whitney and chi-square tests. RESULTS: One hundred eight implants were placed in 19 patients. Radiographic and clinical examination showed that all implants were successful. Postoperative pain was significantly more intense after surgery with the conventional flap technique than after surgery with the atraumatic flapless technique. Likewise, the inflammatory response was more intense with the flap technique. CONCLUSIONS: Postoperative pain depends on the surgical technique used and is less intense with a flapless technique. PMID- 24066323 TI - Dental implant performance in vertically distracted fibular grafts after mandibular reconstruction: a pilot series of 12 patients. AB - PURPOSE: To clinically and radiographically evaluate the performance of loaded dental implants placed in vertically distracted fibular grafts after mandibular reconstruction, and to evaluate patient satisfaction with implant function and esthetics after oral rehabilitation. MATERIALS AND METHODS: This retrospective study involved patients who received implants in vertically distracted fibular bone after mandibular reconstruction between February 2006 and January 2008. Clinical assessments were performed 6 months after loading and annually thereafter. Patient satisfaction was evaluated with respect to function, phonetics, facial contour esthetics, and oral hygiene practices. The data were evaluated statistically. RESULTS: Thirty-seven dental implants were inserted in 12 patients (mean age, 42.9 +/- 8.0 years). Three patients were completely edentulous and nine were partially edentulous. The low mean plaque score (< 20%) indicated a good level of oral hygiene during the mean follow-up period of 42.1 +/- 4.1 months. Probing depths and modified Sulcus Bleeding Index increased slightly at follow-up, but there was no significant difference in either parameter at years 1 and 3. After 1 year, the average marginal bone loss was 0.8 +/- 0.3 mm (range, 0.2 to 2.1 mm); this increased to 0.9 +/- 0.4 mm (range, 0.5 to 2.4 mm) in year 3, which was not a significant difference. The cumulative survival rate was 100% and the cumulative success rate was 84.8%. Seven of the 12 patients were fully satisfied with the function and esthetics of the restoration. CONCLUSIONS: On the basis of the present study, implant placement in vertically distracted fibulae for mandibular reconstruction may be considered a predictable option in terms of mid- to long-term implant survival and success rates. PMID- 24066324 TI - A 5- to 8-year retrospective study comparing the clinical results of implant supported telescopic crown versus bar overdentures in patients with edentulous maxillae. AB - PURPOSE: The objective of this study was to compare implant survival and success rates, peri-implant parameters, and prosthodontic maintenance efforts for implant supported telescopic crown overdentures and bar overdentures to restore maxillary edentulism. MATERIALS AND METHODS: This retrospective clinical study involved patients with maxillary edentulism who were fitted with implant-supported overdentures from January 2004 to June 2007. During a 5- to 8-year follow-up period, the implant survival and success rates, biologic and mechanical complications, prosthodontic maintenance, and patient satisfaction were retrospectively analyzed. The data were evaluated statistically and P < .05 was considered to be statistically significant. RESULTS: Forty-four patients with maxillary edentulism received implant-supported removable overdentures. Twenty one patients chose telescopic crown overdentures and 23 patients chose bar overdentures. A total of 41 patients and 201 implants were available for follow up. The implant survival and success rates, average bone resorption, and subjective patient satisfaction scores showed no difference between the telescopic crown and the bar overdenture group at follow-up. However, there were higher values for Plaque and Calculus Indexes in the bar group compared with the telescopic crown group, and these values showed a statistically significant difference annually from the 3-year follow-up (P < .05). Each year, the number of prosthodontics maintenance procedures per patient did not significantly differ between the telescopic crown (approximately 0.36 to 0.58) and bar groups (approximately 0.30 to 0.49) (P = .16). CONCLUSIONS: Although there were higher plaque and calculus levels in the bar group and more maintenance was required for the telescopic crown group, overdentures provided a healthy peri-implant structure for implants in both groups. Implant-supported telescopic crown or bar overdentures can provide a good treatment option for patients with edentulous maxillae. PMID- 24066325 TI - Retrospective multicenter study of 230 6-mm SLA-surfaced implants with 1- to 6 year follow-up. AB - PURPOSE: Using short implants poses a challenge in implant surgery. Implant surfaces have evolved, making it possible to improve the success of short implants substantially. However, there is still little information about the long term predictability achieved with short, rough-surfaced implants. The objective of this study was to evaluate the long-term survival rate of 6-mm rough implants. MATERIALS AND METHODS: A retrospective multicenter analysis of the survival of short 6-mm SLA-surfaced implants was conducted. A total of 230 implants placed in 159 patients were included. The follow-up time ranged between 1 and 6 years. RESULTS: Seven of the 230 implants failed, which gives a cumulative survival rate of 96.4%. Two hundred and fourteen implants were placed in the mandible (93.1%), as opposed to 16 placed in the maxilla (6.9%). Five implants failed during the osseointegration period, and two failed after receiving the prosthetic load. No statistically significant differences were found (P < .44). Of the loaded implants, 209 were splinted to other implants, as opposed to 14 that were not. One implant failed in each group, resulting in a 99.5% for the splinted implants and 92.9% for the unsplinted implants. No statistically significant differences were found between the splinted and unsplinted groups (P < .12). CONCLUSIONS: The short implants used in this study displayed high longterm predictability when placed in the mandible and splinted. There is insufficient- information to extrapolate these results to the maxilla and non-splinted implants. PMID- 24066326 TI - Novel technique for the treatment of the severely atrophied posterior mandible. AB - PURPOSE: To present a new technique for the rehabilitation of the severely atrophied mandible that avoids the need for advanced surgical reconstruction. MATERIALS AND METHODS: Severe resorption in the posterior mandible was treated following a conservative approach. A novel drilling technique and vertical implant-guided bone regeneration were performed to insert extra-short implants for maximum use of the bone above the mandibular canal. A progressive loading protocol was followed for the prosthetic rehabilitation with screw-retained prostheses. During the follow-up period, surgical complications, prosthetic failures, marginal bone loss, and implant survival were monitored. RESULTS: The described conservative approach was effective in patients with residual bone height above the mandibular canal that was often less than 6 mm. No signs of sensory disturbances or nerve injury were detected during the observation period. One hundred fourteen extra-short implants were inserted in 72 patients, with a mean follow-up period of 26 months after implant insertion. The implant survival rate was 98.2% (two implants failed). Proximal bone loss was limited to 1 mm, and detailed analysis of factors influencing bone loss indicated that the increase in implant diameter was associated with a tendency toward decreased bone loss. Prosthetic complications (eg, fracture or screw loosening) were not observed in this study. CONCLUSIONS: This minimally invasive approach contributed to successful oral rehabilitation of patients with severely atrophied posterior mandibles. The development of conservative approaches will decrease the risk of surgical morbidity, save money and time, and decrease the complexity of surgery. PMID- 24066327 TI - Clinical accuracy of flapless computer-guided surgery for implant placement in edentulous arches. AB - PURPOSE: Although flapless computer-guided implant placement provides important benefits, deviations from the planned implant placement in the edentulous arch may pose significant risks. This study evaluated the reliability and accuracy of a flapless computer-guided surgical approach. MATERIALS AND METHODS: Computer generated preoperative implant planning was compared to actual placement by cone beam computerized tomography (CBCT) scanning of patients before and after surgery. A well-fitting complete denture or optimized prosthetic tooth arrangement was used and converted to a radiographic template. Prior to scanning, esthetics and functional aspects were checked clinically. The implant positions were virtually determined by the implant planning software relative to the bone structure and prospective tooth position. After implant placement, new CBCT scans were obtained for each subject. Software was used to fuse the images of the planned and placed implants, and the locations and axes were compared. The normality of the data distribution was evaluated by the Kolmogorov-Smirnov test. Mean values were compared between groups based on the upper or lower jaws with the t test for independent samples. The level of significance was fixed at 5%. RESULTS: Sixty-two implants were placed in edentulous arches with stereolithographic surgical guides in 14 patients. Damage due to implant placement was not observed in any critical anatomical structure. Compared to the planned implants, placed implants showed mean and standard deviation linear measurements at the cervical, middle, and apical implant portions of 2.17 (+/- 0.87), 2.32 (+/- 1.52), and 2.86 (+/- 2.17) mm, for the maxilla, and 1.42 (+/- 0.76), 1.42 (+/- 0.76), and 1.42 (+/- 0.76) mm, for the mandible, respectively. The angular deviations were 1.93 (+/- 0.17) and 1.85 (+/- 0.75) degrees for the maxilla and mandible, respectively. The linear deviation differed significantlybetween the upper and lower jaws, but the angular deviation did not. CONCLUSION: Flapless computer-guided surgery may be a viable treatment option for rehabilitating the edentulous arch. PMID- 24066328 TI - The effect of implant surface modifications on survival and bone loss of immediately loaded implants in the edentulous mandible. AB - PURPOSE: To compare the 2-year survival and peri-implant bone loss of implants with and without a fluoride modification under immediate loading conditions in completely edentulous mandibles. MATERIALS AND METHODS: A total of 125 Osseospeed implants (test group) were placed in 25 patients requiring a fixed rehabilitation. Implants were loaded immediately (baseline) with a provisional screw-retained prosthesis. Implant survival and bone level changes were analyzed at 3, 12, and 24 months. Results were compared with the outcome of 25 previously treated patients with immediately loaded TiOblast implants using the same treatment protocol (control group). RESULTS: Implant survival was 100% for both groups. After 3, 12, and 24 months, the mean bone loss for the control group was 0.60, 0.81, and 0.84 mm on the patient level and 0.60, 0.80, and 0.86 mm on the implant level. For the test group, a mean bone loss of 0.14, 0.11, and 0.11 mm was for the patient; and 0.14, 0.11, and 0.11 mm with the implant as statistical unit after 3, 12, and 24 months, respectively. No statistically significant differences were observed comparing peri-implant bone loss at 3 months with 12 and 24 months in both groups, but the control group showed more peri-implant bone loss compared with the test-group (P < .001). Moreover, the control group showed an increasing interquartile range over time, suggesting that not every implant is reaching steady-state bone levels. CONCLUSIONS: Immediate loading of implants placed in the completely edentulous mandible is a successful treatment option with high survival rates and limited bone loss after 2 years. However, initial crestal bone preservation significantly benefits from fluoride modification. PMID- 24066329 TI - Rat bone marrow stromal cell-conditioned medium promotes early osseointegration of titanium implants. AB - PURPOSE: To enhance the stability of titanium (Ti) implants using conditioned medium (CM) derived from rat bone marrow stromal cell (BMSC). MATERIALS AND METHODS: BMSCs were isolated from rat femurs and grown in culture, and the culture medium was used as CM. The CM was immobilized on the surface of Ti implants with calcifying solution. The topology of the Ti implants after immobilization of CM was observed by scanning electron microscopy (SEM). The Ti immobilized CM was analyzed by liquid chromatography with tandem mass spectrometry. The adhesiveness and the osteogenic differentiation of BMSCs grown on CM-coated discs were analyzed by reverse-transcription polymerase chain reaction. Ti implants with specimen-immobilized CM labeled with quantum dots (QDs) were placed into rat femurs. The localization of the CM was detected by in vivo imaging at 1, 7, 14, and 28 days after implantation. The removal torque test and histologic bone implant contact (BIC) were also analyzed. RESULTS: Rat BMSC CM was successfully immobilized on Ti implants. The immobilized CM contained about 2000 proteins, including collagen type I, bone sialoprotein, fibronectin, and vascular endothelial growth factor that are important in new bone formation. CM promoted cell adhesion and osteocalcin gene expression of rat BMSCs. The labeled CM remained associated with the Ti implant at 1, 7, 14, and 28 days postimplantation. The removal torque value and BIC of Ti implants with immobilized CM were higher than those of control implants on days 1, 7, and 14 after implantation. CONCLUSION: Immobilized CM components on the surface of Ti implants promoted integration into bone during an early stage. PMID- 24066330 TI - A comparison of the healing capabilities of various grafting materials in critical-size defects in guinea pig calvaria. AB - PURPOSE: To estimate the efficacy of various bone grafting materials in the healing of 8-mm-diameter critical-size defects (CSD) in guinea pig calvaria. METHODS: In this randomized trial study, critical-size defects were created in the calvaria of 36 guinea pigs 6 months of age. Animals were assigned into three groups and each received one of three experimental protocols. In protocol A, the right-side defect was filled with macroporous biphasic calcium phosphate (MBCP Gel) and the left side was left empty as a control. In protocol B, the right-side defect was filled with demineralized freeze-dried bone allograft (DFDBA) and the left side was filled with Stypro. In protocol C, the right-side defect was filled with Bio-Oss and the left side was filled with autogenous bone. The percentage of new bone formation was evaluated histomorphometrically after 8 weeks. RESULTS: The mean bone formation was 68.19% for autogenous bone, 66.96% for MBCP Gel, 57.28% for Bio-Oss, 50.19% for DFDBA, 18.79% for Stypro, and 10.61% for the empty control. Except for the MBCP Gel and autogenous bone groups (P = .6), the differences between the other groups were statistically significant (P < .05). CONCLUSION: The results of this study indicated that all the testing materials had different capacities to produce new bone in CSD of guinea pig calvaria. MBCP Gel showed promising results in producing new bone proportionate to the autogenous bone graft group. PMID- 24066331 TI - Bone regeneration of tibial defects in rats with enzymatic hydrogelation of gelatin derivative and recombinant human platelet-derived growth factor-BB complex. AB - PURPOSE: To evaluate the capabilities of gelatin derivatives that incorporate phenolic hydroxyl groups (gelatin-Ph) as a delivery carrier with recombinant human platelet-derived growth factor-BB (rhPDGF-BB) for bone regeneration. MATERIALS AND METHODS: The growth factor release profile from gelatin-Ph gel or atelocollagen was analyzed to evaluate the capability of gelatin-Ph as a carrier. The biocompatibility of gelatin-Ph (ie, the survival rates of the cells during gelation, and the morphology and proliferation of the cells) were investigated with rat bone marrow cells (RBMCs) in vitro. To evaluate the effect of the gelatin-Ph-rhPDGF-BB complex on bone formation, the complex was applied to bone defects in rat tibiae and undecalcified specimens were fabricated for histologic analysis. RESULTS: Scarce amounts of rhPDGF-BB from gelatin-Ph gel were detected during 30 days, but the addition of protease induced the release of rhPDGF-BB on day 31. No differences were observed in the survival rates of RBMCs during gelation and in the morphology and proliferation of RBMCs on the gel sheet between groups. Histological analyses demonstrated that the complex enhanced bone formation and mineralization at 2 and 4 weeks. CONCLUSION: These results suggest that gelatin-Ph gel can be an ideal delivery carrier, and the localized delivery of rhPDGF-BB in gelatin-Ph can contribute to bone formation. PMID- 24066332 TI - The response of osteoblast-like SaOS-2 cells to modified titanium surfaces. AB - PURPOSE: To study the effects of different chemically modified titanium surfaces on the proliferation, differentiation, adhesion, and apoptosis of osteoblast-like SaOS-2 cells. MATERIALS AND METHODS: In this work, six different titanium materials were tested and compared to each other: (1) glazed; (2) unglazed; (3) unglazed and alkali-etched; (4) unglazed, sandblasted, acid- and alkali-etched; (5) unglazed and coated with zirconium nitride; and (6) unglazed, sandblasted, and acid-etched. The production of alkaline phosphatase (ALP), tumor necrosis factor alpha (TNF-alpha), matrix metalloproteinase-2, and the expression of adhesion proteins (integrin alpha3beta1, vinculin) were evaluated using ELISA. Finally, the apoptosis of cells was analyzed by flow cytometry. RESULTS: The most significant differences were found for unglazed sandblasted acid- and alkali etched titanium discs compared with unglazed titanium discs. The production of TNF-alpha was decreased after 24 hours, as was the production of ALP after 72 hours. In contrast, the expression of integrin alpha3beta1 was increased after 6 hours. None of the titanium discs showed an apoptotic effect on cells. CONCLUSIONS: This study has shown that physical surface treatments (such as surface roughness) play a more important role than chemical modifications. Generally, chemical modifications such as acid- and alkali-etching can affect the wettability of titanium surfaces, making a surface hydrophilic or hydrophobic according to the modification. The cell attachment is better on hydrophilic surfaces, while hydrophilic surfaces may slightly decrease the expression of ALP activity. PMID- 24066333 TI - Bone regeneration and collagen fiber orientation around calcium phosphate-coated implants with machined or rough surfaces: a short-term histomorphometric study in dog mandibles. AB - PURPOSE: The aim of this study was to compare bone formation and tissue reactions around implants with a calcium phosphate (CaP)-coated machined surface (CPMS) and a CaP-coated rough surface (CPRS) at critical-sized circumferential ridge defects in dogs after 4 and 8 weeks. MATERIALS AND METHODS: All mandibular premolars were extracted bilaterally from five male mongrel dogs. After 8 weeks, circumferential marginal defects (2 mm wide and 5 mm deep) were created unilaterally using a customized drill at sites of CPMS and CPRS implant insertion. Four weeks later, the contralateral side was prepared using the same protocol. The dogs were sacrificed 4 weeks later. Specimens were analyzed histologically and histomorphometrically. RESULTS: Both CPMS and CPRS implants showed successful osseointegration in the apical bone area (without defects) regardless of the observation period (4 or 8 weeks). All circumferential defects were incompletely filled and osseointegration was limited at the apical area of the defect. In the unfilled defect area, collagen fibers were arranged perpendicular or oblique to the exposed implant surfaces, especially on CPRS implants. CONCLUSION: Within the limits of this study, CPMS and CPRS implants showed no statistically significant differences in osseointegration and bone regeneration in circumferential defects, along with the unique feature of collagen fibers arranged perpendicular or oblique to the exposed implant surfaces. PMID- 24066334 TI - Effect of gabapentin-lactam and gamma-aminobutyric acid/lactam analogs on proliferation and phenotype of ovine mesenchymal stem cells. AB - PURPOSE: Classic tissue engineering consists of three components: scaffold, cells, and growth or differentiation factors. Currently, expensive bone morphogenetic proteins are the most common substance used for hard tissue regeneration. An alternative could be gamma-aminobutyric acid/lactam (GABA lactam) analogs. MATERIALS AND METHODS: The effects of gabapentin-lactam, cis- and trans-8-tertbutyl-GABA-pentinlactam (trans-TB-GBP-L), and phenyl-GABA-lactam were tested in this study on ovine mesenchymal stem cell (MSC) proliferation. MSCs were selected from bone marrow aspirate concentrate by plastic adherence and amplified. Aliquots of the cells were incubated in medium, with four different concentrations of the GABA-lactam analogs dissolved in dimethyl sulfoxide. Cells in medium with and without dimethyl sulfoxide served as controls. Cell proliferation was tested with a nonradioactive assay. Before and after GABA lactam analog influence, the MSC character was evaluated by the ability of the cells to differentiate into osteoblasts, chondrocytes, and adipocytes. RESULTS: Proliferation was significantly increased under the influence of the analogs, depending on their concentration. MSCs cultured in 1 nmol/L trans-TB-GBP-L showed the highest proliferation rate. The MSC character was not altered. CONCLUSIONS: GABA-lactam analogs could be suited to stimulate MSC proliferation for tissue engineering applications. Further in vivo studies are necessary to evaluate the possible clinical potential of GABA-lactam analogs for hard tissue regeneration. PMID- 24066335 TI - Closure of 1.5-cm alveolar oral antral fistula with intra-alveolar sinus membrane elevation and bone morphogenetic protein-2/collagen graft followed by dental implant restoration: case report. AB - Closure of a 1.5-cm oral antral fistula was done in combination with sinus floor and extraction socket grafting using recombinant human bone morphogenetic protein 2 within a collagen sponge matrix. The approach to the sinus was transalveolar, with elevation of the sinus membrane done through a molar extraction socket. Following graft placement, soft tissue repair was done with a buccal advancement flap. A dental implant was subsequently placed and restored. Peri-implant bone and implant stability were well maintained at the 1-year follow up examination. PMID- 24066336 TI - Titanium versus zirconia implants supporting maxillary overdentures: three dimensional finite element analysis. AB - PURPOSE: The purpose of this study was to compare the stress and strain occurring in peri-implant bone and implants used to support maxillary overdentures. Three dimensional finite element analysis (3D FEA) was used to compare one-piece zirconia and titanium implants. MATERIALS AND METHODS: Two types of implants were simulated using a 3D FEA model: one-piece zirconia and titanium implants (diameter, 3.8 * 11.5 mm) with 2.25-mm diameter ball abutments. In each simulation four implants were placed bilaterally in the canine/premolar region of an edentulous maxillary model. Static loads were applied axially and 20 degrees buccolingually on the buccal slope of the lingual cusps of posterior teeth of the first quadrant. Von Mises stresses and equivalent strains generated in peri implant bone and first principal stresses in the implants were calculated. RESULTS: Comparable stress and strain values were shown in the peri-implant bone for both types of implants. The maximum equivalent strain produced in the peri implant region was mostly within the range for bone augmentation. Under oblique loading, maximum von Mises stresses and equivalent strain were more evident at the neck of the most distal implant on the loaded side. Under axial load, the stress and strain were transferred to the peri-implant bone around the apex of the implant. Maximum tensile stresses that developed for either material were well below their fracture strength. The highest stresses were mainly located at the distobuccal region of the neck for the two implant materials under both loading conditions. CONCLUSIONS: From a biomechanical point of view, ceramic implants made from yttrium-stabilized tetragonal polycrystalline zirconia may be a potential alternative to conventional titanium implants for the support of overdentures. This is particularly relevant for a select group of patients with a proven allergy to titanium. Prospective clinical studies are still required to confirm these in vitro results. Different simulations presenting various cortical bone thicknesses and implant designs are required to provide a better understanding of the biomechanics of zirconia implants. PMID- 24066337 TI - Torque stability of different abutment screws submitted to mechanical cycling. AB - PURPOSE: To evaluate the torque stability of different UCLA retention screws of single implant-supported crowns submitted to mechanical cycling. MATERIALS AND METHODS: Crowns fabricated from nickel-chromium-molybdenum alloy were attached to external-hexagon implants and grouped by the different retention screws used (n = 10): Ti, titanium screws (BRUNIHT, Biomet 3i); Au, gold-palladium screws with 24 carat gold coating (Gold-Tite, Biomet 3i); TiC, titanium alloy (Ti-6Al-4V) screw with diamondlike carbon coating (Neotorque, Neodent); and TiN, Ti-6Al-4V screw with aluminum-titanium-nitride coating (Ti-Tite, Conexao). Three initial removal torque (RT) values were obtained for each screw after torque insertion using an analog torque gauge. The final RT was measured after mechanical cycling (1 * 106 cycles at 2 Hz under 130 N). Data were submitted to analysis of variance and the Fischer test. RESULTS: Statistically significant differences were observed between the initial RT in groups Ti and TiN, and between TiC and TiN. No statistically significant difference was seen between mean RT obtained before and after mechanical cycling, except for the Ti screws. All groups exhibited similar torque maintenance after mechanical cycling. CONCLUSION: Although no significant difference was observed among groups for the final percentage of torque maintenance, the final RT values of the coated screws were higher than those of the noncoated screws. PMID- 24066338 TI - Inter- and intraobserver variability in resonance frequency analysis of palatal implants--a technical note. AB - PURPOSE: To assess inter- and intraobserver variability in wireless resonance frequency analysis (RFA) stability measurements of palatal implants and to evaluate the influence of age, sex, time after implant insertion, and measurement direction on variability. MATERIALS AND METHODS: Three observers conducted wireless RFA stability measurements of palatal implants from 16 patients. Measurements were taken in anteroposterior and laterolateral directions and were repeated after 1 hour. RESULTS: Data showed a small interobserver variation (1.93) with intraobserver variation (1.77) as its largest component. Time after implantation showed a strong influence (P = .027) on the interobserver variation. CONCLUSIONS: The tested wireless RFA device can be considered a reliable instrument for measuring the stability of palatal implants. Multiple readings and observers could further improve measurement reliability. PMID- 24066339 TI - Prefabricated fibular flaps for reconstruction of defects of the maxillofacial skeleton: planning, technique, and long-term experience. AB - Reconstruction of complex defects involving the maxilla or mandible often requires transfer of free vascularized tissue. In the conventional approach, a flap is transferred to provide vital tissue, and subsequent shaping and debulking are required. The authors present their experience with prefabrication of vascularized fibular flaps. Since 1999, 48 prefabricated flaps have been used to reconstruct 28 maxillary and 20 mandibular defects. The technique involves two surgical steps (prefabrication and flap transfer) and requires accurate planning, done with a solid model of the skull. Correct positioning of the prefabricated flap is accomplished by using the occlusion as a guide. Planning includes fabrication of a provisional prosthesis that is fixed to the flap with implants. Putting the prosthesis into occlusion determines the position of the flap. PMID- 24066340 TI - Commentary: Gabapentin-lactam and gamma-aminobutyric acid/lactam analogs: the enigma of their mechanism of action. PMID- 24066341 TI - rhBMP-2/ACS grafts versus autogenous cancellous marrow grafts in large vertical defects of the maxilla: an unsponsored randomized open-label clinical trial. AB - PURPOSE: This study compared the histologic parameters and outcomes of two types of grafts in large vertical maxillary defects: a composite graft of recombinant human bone morphogenetic protein-2/acellular collagen sponge (rhBMP-2/ACS), crushed cancellous freeze-dried allogeneic bone (CCFDAB), and platelet-rich plasma (PRP); and size-matched 100% autogenous grafts. MATERIALS AND METHODS: Twenty patients each were treated with a composite graft, which contained 1.05 mg rhBMP-2/ACS per two-tooth segment together with CCFDAB and PRP, or a 100% autogenous graft prior to implant placement. Grafting material was contained within a titanium mesh crib. RESULTS: Two grafts in each group were lost as a result of early mesh exposure and infection. Three grafts in each group developed a late exposure of the mesh that did not affect bone regeneration. The remaining 18 autogenous grafts all regenerated sufficient bone for implant restoration (100%), and 17 of 18 (97.4%) of the composite grafts regenerated sufficient bone for implant restoration. The autogenous grafts included 54% +/- 10% of new viable bone but also included residual nonviable graft particles. The composite grafts contained 59% +/- 12% viable new bone and no remaining nonviable bone particles. The composite grafting technique resulted in less blood loss and shorter surgical time but greater and longer-lasting edema. The costs of both grafts were nearly equal. CONCLUSION: A composite graft of rhBMP-2/ACS-CCFDAB-PRP regenerates bone in large vertical ridge augmentations as predictably as 100% autogenous graft with less morbidity, equal cost, and more viable new bone formation without residual nonviable bone particles, but with more edema. This composite graft represents an in situ tissue engineering concept that is able to achieve results equivalent to autogenous grafts in large vertical ridge augmentations without donor bone harvesting. PMID- 24066342 TI - Effects of implant surface on bone healing around titanium screw implants in ovariectomized rats. AB - PURPOSE: The aim of this study was to investigate whether estrogen deficiency interrupts bone healing around titanium implants and to evaluate whether bone healing around implants under a condition of estrogen deficiency is affected by variations in implant surface characteristics. MATERIALS AND METHODS: Forty-eight female rats were divided into two groups: ovariectomized rats (OVX; n = 24) and sham-operated rats (SHAM; n = 24). Each group was further divided into two groups: a machine-polished implants group and a sandblasted implants group. One implant was placed into the left femur of each rat 84 days after OVX or sham surgery. After 28 or 56 days, the rats were killed, and nondecalcified sections were obtained. Bone-to-implant contact (BIC) and bone area (BA) around the implants were assessed for cortical and cancellous bone. Furthermore, bone density (BD) was evaluated in a 500-mm-wide zone of cancellous bone lateral to the implants. RESULTS: At 28 and 56 days after implantation, no significant differences were found between the OVX and SHAM groups for BIC and BA in cortical bone. BIC, BA, and BD with cancellous bone were lower in the OVX group than in the SHAM group. However, BIC and BA tended to increase with the sandblasted implant surface. CONCLUSIONS: Estrogen deficiency affected bone healing and bone density around titanium implants, especially in cancellous bone, but the sandblasted surface has the possibility to improve osseointegration. However, the positive effect of this rough surface is limited at the implant surface. PMID- 24066343 TI - Maxillary full-arch alveolar split osteotomy with island osteoperiosteal flaps and sinus grafting using bone morphogenetic protein-2 and retrofitting for immediate loading with a provisional: surgical and prosthetic procedures and case report. AB - A case report and description of a new technique for bone morphogenetic protein-2 augmentation of the maxilla are provided here. Horizontal maxillary atrophy was treated with a full-arch alveolar split osteotomy combined with sinus floor intrusion. The defect was grafted with bone morphogenetic protein-2 and demineralized freeze-dried bone allograft. Nine months later, a transgingival approach was used to place dental implants and a prefabricated provisional denture. The provisional was attached to several implants and retrofitted into place following gingival sculpting to create a tooth emergence effect. To date, this patient has been followed for 2.5 years with no implant losses or bone level changes. In addition, the gingival profile appeared to be stable. PMID- 24066344 TI - The combined use of rhBMP-2/ACS, autogenous bone graft, a bovine bone mineral biomaterial, platelet-rich plasma, and guided bone regeneration at nonsubmerged implant placement for supracrestal bone augmentation. A case report. AB - This case report presents the clinical application and outcomes of the use of a combined approach to treat a patient with a severe alveolar defect. Recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge carrier, along with autogenous bone graft, bovine bone mineral, platelet-rich plasma, and guided bone regeneration, were used simultaneous with nonsubmerged implant placement. At 1 year postsurgery, healthy peri-implant soft tissues and radiographically stable peri-implant crestal bone levels were observed along with locally increased radiographic bone density. In addition, a cone beam computed tomography (CBCT) scan demonstrated apparent supracrestal peri-implant bone augmentation with the appearance of normal alveolar ridge contours, including the facial bone wall. PMID- 24066345 TI - Effects of self-assembling peptide hydrogel scaffold on bone regeneration with recombinant human bone morphogenetic protein-2. AB - PURPOSE: The objective of this pilot study was to histologically evaluate bone regeneration using a self-assembling peptide hydrogel scaffold with recombinant human bone morphogenetic protein-2 (rhBMP-2) in a rabbit calvaria model. MATERIALS AND METHODS: Five adult New Zealand White rabbits were used for the study. Each received four titanium cylinders, which were placed into perforated slits made in the outer cortical bone of the calvaria. The cylinders were filled with the following test materials: (1) unfilled control; (2) rhBMP-2; (3) PuraMatrix (PM), a synthetic self-assembling peptide (RADA16-I) consisting of a 16-amino acid sequence and with a three-dimensional structure; and (4) PM/rhBMP 2. Each cylinder was covered with a titanium lid. After 8 weeks, the animals were sacrificed, and ground sections were obtained for histomorphometric analysis. RESULTS: Histomorphometric analysis showed that regenerated tissue in the cylinder with PM/rhBMP-2 was significantly increased compared to the empty control. The mean area values of regenerated tissue in the cylinders were 35.80% +/- 10.35% (control), 47.94% +/- 5.65% (rhBMP-2), 48.94% +/- 11.33% (PM), and 58.06% +/- 14.84% (PM/rhBMP-2). The mean area values of newly formed bone in the cylinders were 9.39% +/- 4.34% (control), 14.03% +/- 2.25% (rhBMP-2), 13.99% +/- 2.15% (PM), and 16.61% +/- 3.79% (PM/rhBMP-2). Neither rhBMP-2 nor PM alone significantly enhanced bone regeneration compared to the empty control cylinder. CONCLUSIONS: PM with rhBMP-2 significantly enhanced bone regeneration on the bone augmentation model in a rabbit. PM promises to be a useful alternative synthetic material as a carrier for rhBMP-2 for bone regeneration. PMID- 24066346 TI - A qualitative and quantitative analysis of autologous human multipotent adult stem cells derived from three anatomic areas by marrow aspiration: tibia, anterior ilium, and posterior ilium. AB - PURPOSE: The purpose of this article was to compare the yields of stromal multipotent stem cells (CD34+ and CD105+) and hematopoetic multipotent stem cells (CD44+) obtained from different areas via bone marrow aspiration (BMA). MATERIALS AND METHODS: Sixty 60-mL bone marrow aspirates were taken from the tibial plateau, the anterior ilium, and the posterior ilium using a single point-of-care BMA technique and a single BMA concentration (BMAC) device. A 1-mL portion of each sample was used to determine CD stem cell concentrations and the nucleated cell count. The remaining BMA was centrifuged to separate the more mature red blood cell precursors from the stem cells and then concentrate the latter into a BMAC. The BMAC yield of 10 mL was analyzed with flow cytometry and nucleated cell counts to derive a concentration factor for the BMAC. RESULTS: The yield of total nucleated cells was equal between the anterior and posterior ilium and more than twice that obtained from the tibial plateau. The CD44+ and CD105+ cell yields were also nearly equal between the anterior and posterior ilium but more than twice that of the tibial plateau; however, the ratios between the three different stem cell types in BMAC obtained from the different areas suggest varying potentials for tissue development. CONCLUSIONS: The ilium is the preferred donor site for obtaining autologous stem cells at the point of care. The tibial plateau yielded only half as much bone marrow multipotent/progenitor stem cells as did the anterior and posterior ilium. The composition of the BMAC from each site suggests that the potential for differentiation into various cell types changes depending on the source of bone marrow, but that BMAC represents 6.5 +/- 1.0 concentration factor from BMA. PMID- 24066347 TI - Intraoral grafting of tissue-engineered human oral mucosa. AB - PURPOSE: The primary objective of this study was to evaluate the safety of a tissue-engineered human ex vivo-produced oral mucosa equivalent (EVPOME) in intraoral grafting procedures. The secondary objective was to assess the efficacy of the grafted EVPOME in producing a keratinized mucosal surface epithelium. MATERIALS AND METHODS: Five patients who met the inclusion criteria of having one mucogingival defect or a lack of keratinized gingiva on a nonmolar tooth, along with radiographic evidence of sufficient interdental bone height, were recruited as subjects to increase the width of keratinized gingiva at the defect site. A punch biopsy specimen of the hard palate was taken to acquire oral keratinocytes, which were expanded, seeded, and cultured on an acellular dermal matrix for fabrication of an EVPOME. EVPOME grafts were applied directly over an intact periosteal bed and secured in place. At baseline (biopsy specimen retrieval) and at 7, 14, 30, 90, and 180 days postsurgery, Plaque Index and Gingival Index were recorded for each subject. In addition, probing depths, keratinized gingival width, and keratinized gingival thickness were recorded at baseline, 30, 90, and 180 days. RESULTS: No complications or adverse reactions to EVPOME were observed in any subjects during the study. The mean gain in keratinized gingival width was 3 mm (range, 3 to 4 mm). The mean gain in keratinized gingival thickness was 1 mm (range, 1 to 2 mm). No significant changes in probing depths were observed. CONCLUSION: Based on these findings, it can be concluded that EVPOME is safe for intraoral use and has the ability to augment keratinized tissue around teeth. Future clinical trials are needed to further explore this potential. PMID- 24066348 TI - Biointegration of the osteo-odonto lamina in the modified osteo-odonto keratoprosthesis: engineering of tissue to restore lost vision. AB - The modified osteo-odonto keratoprosthesis (MOOKP) is a biologic keratoprosthesis that is used to treat a severely scarred cornea. The procedure involves multiple stages, including the transplantation of buccal mucosa to the damaged ocular surface and the implantation of an osteo-odonto lamina with a mounted polymethylmethacrylate lens. Among the keratoprostheses currently available, the MOOKP has proven to be the most effective based on the number of patients who have undergone the procedure and the duration of documented follow-up. Upon successful biointegration of the osteo-odonto lamina, the keratoprosthesis is able to resist resorption, provide stability, and prevent bacterial invasion and epithelial ingrowth. The effectiveness of the MOOKP is dependent on the anatomic and physiologic characteristics of the dental tissues and periodontal ligament. PMID- 24066350 TI - Semi-quantification of surface-enhanced Raman scattering using a handheld Raman spectrometer: a feasibility study. AB - The feasibility of utilizing a handheld Raman spectrometer for surface-enhanced Raman scattering detection was evaluated on the pesticide ferbam. A layman's "answer box" was established for semi-quantifying the risk level of ferbam. This study advanced the application of a handheld Raman spectrometer to on-site evaluation of trace amounts of analytes. PMID- 24066351 TI - One-pot facile synthesis of a concentrated Si nanoparticle solution. AB - A silicon nanoparticle solution (size ? 50 nm) with the concentration of 100 mM, which is contamination free, was synthesized using a ball milling method and was stable for 4 months without aggregation. This stability was responsible for large negative zeta potential on the surface of Si-NPs, established by milling in 2 propanol solvent. PMID- 24066349 TI - Bone marrow aspirate concentrate used with bovine bone mineral to reconstruct vertical and horizontal mandibular defects: report of two techniques. AB - PURPOSE: Following initial positive reports of the use of bone marrow aspirate concentrate (BMAC) in combination with bovine bone mineral (BBM) in augmentation procedures, the technique was evaluated in patients with mandibular deficiency. MATERIALS AND METHODS: Two adult patients required surgical correction of a deficient alveolar ridge (one patient showed horizontal deficiency only, and the other patient presented with horizontal and vertical deficiency) prior to dental implant placement. In both patients, the reconstruction was performed with BBM in combination with mononuclear cells concentrated by the BMAC method using different techniques. RESULTS: The patients recovered well from all surgical procedures. Histologically, there was uniform bone formation, which allowed placement of dental implants. CONCLUSION: The results suggest that the use of BMAC in combination with BBM, without autogenous bone, has the potential to restore horizontal and vertical mandibular alveolar defects, providing a functional bone structure and allowing dental implant placement for subsequent prosthetic rehabilitation. PMID- 24066353 TI - A new copper-based metal-organic framework as a promising heterogeneous catalyst for chemo- and regio-selective enamination of beta-ketoesters. AB - Assembly of 5-nitro-1,2,3-benzenetricarboxylic acid (H3nbta) with Cu(II) in the presence of 1,3-bis(1,2,4-triazol-1-yl)propane (1,3-btp) leads to a new metal organic framework, [Cu(Hnbta)(1,3-btp)].2H2O (A1), which is shown to be an efficient and recyclable heterogeneous catalyst for enamination of beta ketoesters with excellent product yields and selectivity. PMID- 24066352 TI - In vivo imaging of tumour bearing near-infrared fluorescence-emitting carbon nanodots derived from tire soot. AB - NIRF imaging of carbon nanodots derived from tire soot was clearly visualized in glioma in vitro and in vivo. PMID- 24066354 TI - Fluorine-doped BP 2000: highly efficient metal-free electrocatalysts for acidic oxygen reduction reaction with superlow H2O2 yield. AB - Fluorine-doped carbon blacks as inexpensive, high performance electrocatalysts for acidic oxygen reduction reaction were synthesized. The performance of the optimal catalyst (BP-18F) is close to the level of other reported best non-Pt electrocatalysts in acid, but with superlow H2O2 yield (<0.1%) ever. Their high performance is confirmed by quantum calculations. PMID- 24066355 TI - Colloidal synthesis of homogeneously alloyed CdSe(x)S(1-x) nanorods with compositionally tunable photoluminescence. AB - Homogenously alloyed CdSe(x)S(1-x) nanorods with controlled aspect ratios are synthesised by a hot-injection colloidal route. The optical absorption and photoluminescence emission are compositionally tunable with chalcogen ratios. The synthetic protocol is sufficiently robust to allow good control of rod aspect ratios, with low polydispersities, suited for their rational assembly into superstructures. PMID- 24066356 TI - Genotypic adaptations associated with prolonged persistence of Lactobacillus plantarum in the murine digestive tract. AB - Probiotic bacteria harbor effector molecules that confer health benefits, but also adaptation factors that enable them to persist in the gastrointestinal tract of the consumer. To study these adaptation factors, an antibiotic-resistant derivative of the probiotic model organism Lactobacillus plantarum WCFS1 was repeatedly exposed to the mouse digestive tract by three consecutive rounds of (re)feeding of the longest persisting colonies. This exposure to the murine intestine allowed the isolation of intestine-adapted derivatives of the original strain that displayed prolonged digestive tract residence time. Re-sequencing of the genomes of these adapted derivatives revealed single nucleotide polymorphisms as well as a single nucleotide insertion in comparison with the genome of the original WCFS1 strain. Detailed in silico analysis of the identified genomic modifications pinpointed that alterations in the coding regions of genes encoding cell envelope associated functions and energy metabolism appeared to be beneficial for the gastrointestinal tract survival of L. plantarum WCFS1. This work demonstrates the feasibility of experimental evolution for the enhancement of the gastrointestinal residence time of probiotic strains, while full-genome resequencing of the adapted isolates provided clues towards the bacterial functions involved. Enhanced gastrointestinal residence is industrially relevant because it enhances the efficacy of the delivery of viable probiotics in situ. PMID- 24066357 TI - Optical, bactericidal and water repellent properties of electrospun nano composite membranes of cellulose acetate and ZnO. AB - In this report, ZnO nanoparticles embedded cellulose acetate (CA) fibrous membrane with multifunctional properties have been prepared through electrospinning method. The morphology of the electrospun composite membrane was analyzed by scanning electron microscope (SEM). It was found that the polymer concentration in the solution has a significant effect on the morphology of the fibers. The optical property of the sample was tested using photo luminescence (PL) spectra. There is no significant change in the emission features of cellulose acetate with the addition of ZnO. The anti-bacterial property of the sample was studied using disk diffusion method. The wettability of the pure and composite fibrous membrane was also studied by measuring the contact angle of water on the membrane. It was observed that the embedded ZnO in the CA was responsible for the hydrophobic nature of the surface. PMID- 24066358 TI - Corrigendum to "Structure of arabinogalactan-protein from Acacia gum: from porous ellipsoids to supramolecular architectures" [Carbohydr. Polym. 90 (2012) 322 332]. PMID- 24066359 TI - VSELs: is ideology overtaking science? PMID- 24066360 TI - Authors' response. PMID- 24066361 TI - The magical mentor I - mole responds: by Caveman. PMID- 24066362 TI - Pressure mounting: HMA braces itself as investor pushes for change, CEO retires. PMID- 24066363 TI - Stamps of greatness. Ambrose Pare (1510-1590). PMID- 24066364 TI - Unique device identification system. Final rule. AB - The Food and Drug Administration (FDA) is issuing a final rule to establish a system to adequately identify devices through distribution and use. This rule requires the label of medical devices to include a unique device identifier (UDI), except where the rule provides for an exception or alternative placement. The labeler must submit product information concerning devices to FDA's Global Unique Device Identification Database (GUDID), unless subject to an exception or alternative. The system established by this rule requires the label and device package of each medical device to include a UDI and requires that each UDI be provided in a plain-text version and in a form that uses automatic identification and data capture (AIDC) technology. The UDI will be required to be directly marked on the device itself if the device is intended to be used more than once and intended to be reprocessed before each use. PMID- 24066365 TI - Regulations implementing the Byrd Amendments to the Black Lung Benefits Act: determining coal miners' and survivors' entitlement to benefits. Final rule. AB - This final rule revises the Black Lung Benefits Act (BLBA or Act) regulations to implement amendments made by the Patient Protection and Affordable Care Act (ACA). The ACA amended the BLBA in two ways. First, it revived a rebuttable presumption of total disability or death due to pneumoconiosis for certain claims. Second, it reinstituted automatic entitlement to benefits for certain eligible survivors of coal miners whose lifetime benefit claims were awarded because they were totally disabled due to pneumoconiosis. These regulations clarify how the statutory presumption may be invoked and rebutted and the application and scope of the survivor-entitlement provision. The rule also eliminates several unnecessary or obsolete provisions. PMID- 24066366 TI - Impact of energy intake on the survival rate of patients with severely ill stroke. AB - INTRODUCTION: Stroke accounts for approximately 10% of all deaths. We examined whether energy intake influences the survival rate of severely ill stroke patients. METHODS: We analyzed 86 consecutive severely ill stroke patients. Patients' background was compared between survivors and non-survivors. Average energy intakes in seven different periods from day one to seven following neurosurgical care unit (NCU) admission were compared between two groups, to examine which period is proper to show an energy difference. Groups were stratified by average total energy intake (group E-I, -II, -III, and -IV; <=.25, 8.25-16.5, 16.5-25, and >25kcal/kg/day, respectively), and cumulative survival rate for 90 days after NCU admission was analyzed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to examine the effect of confounder factors. RESULT: Patients' background did not differ significantly between the two groups. Average daily energy intake for the first seven NCU days of non survivors was significantly lower than that of survivors (p=0.034). The survival rate of group E-II was significantly higher than that of group E-I, which was set as a reference (p=0.030). The adjusted HR of E-II was also significantly lower than that of group E-I (HR=0.19, p=0.047), although E-III did not show significance (HR=0.52, p=0.279). CONCLUSION: Energy intake assessment should be conducted for at least seven days following NCU admission. An average total energy intake ranging from 8.25 to 16.5 kcal/kg/day and enteral feeding increases survival rate in severely ill stroke patients. PMID- 24066367 TI - Dietary intakes consistent with the DASH dietary pattern reduce blood pressure increase with age and risk for stroke in a Chinese population. AB - The Dietary Approaches to Stop Hypertension (DASH) diet has been proven to effectively lower blood pressure(BP), and associate with a lower cardiovascular disease and stroke risk in mainly non-Asians. Further, it is unclear if adhering to the DASH target nutrients has similar BP impact as adhering to the recommended DASH food groups. Associations between adherence to DASH foods or nutrients and BP or stroke risk were assessed in 1420 and 2061 Taiwanese adults from 1989 to 2002, respectively. The DASH food score (p=0.053), dairy(p=0.030) and calcium (p=0.020) intake were significantly and inversely associated with follow up systolic BP change in univariate analyses. Both dairy (p=0.020) and calcium (p=0.001) also showed a consistent inverse association with systolic BP change in multivariate analysis. None of the factors examined was associated with diastolic BP change. Both DASH nutrient score and magnesium intakes were significantly associated with the hazard ratio (HR) for total stroke in an inverse relationship. The HR of total stroke comparing the highest to the lowest tertile was 0.63 (95% CI: 0.41-0.98, p=0.037) for the DASH nutrient score, and 0.62 (95% CI: 0.40-0.97,p=0.030) for magnesium intake. Similar findings were observed for DASH nutrient score (p=0.011) and magnesium intake (p=0.043) with the HR for ischemic stroke. The HR for total and ischemic stroke for calcium intake also showed a borderline trend (p=0.071 and 0.051, respectively). In conclusion, adhering to the DASH diet is beneficial for long term BP control and reduction of stroke risk in this Chinese population. PMID- 24066368 TI - Special report: exome sequencing for clinical diagnosis of patients with suspected genetic disorders. PMID- 24066369 TI - Handheld radiofrequency spectroscopy for intraoperative margin assessment during breast-conserving surgery. PMID- 24066370 TI - Ocriplasmin for symptomatic vitreomacular adhesion. PMID- 24066371 TI - Clinical decision-making for vitamin K-1 and K-2 deficiency and coronary artery calcification with warfarin therapy: are diet, factor Xa inhibitors or both the answer? AB - Coronary artery calcification is a recognised risk factor for ischaemic heart disease and mortality. Evidence is now strong that Monckeberg's arteriosclerosis, a form of vascular calcification, can be attributable to vitamin K deficiency, but that vitamin K-2, especially the MK-4 form from foods like cheese can be protective. Warfarin blocks the recycling of hepatic and peripheral vitamin K leading to secondary vitamin K deficiency with adverse effects on vasculature, bone, kidneys, brain and other tissues and systems (inflammatory, immune function and neoplasia at least). There is individual susceptibility to vitamin K deficiency and warfarin sensitivity, partly explicable in terms of genetic polymorphisms, epigenetics, diet and pharmacotherapy. The emergence of extensive coronary calcification in a man with atrial fibrillation treated for a decade with warfarin is described by way of illustration and to raise the present clinical management conundrums. Finally, a putative set of recommendations is provided. PMID- 24066372 TI - [The need for courses and presentations for graduate and continuing education in medical specialties]. PMID- 24066374 TI - [CIRS-AINS special: particle contamination after drawing drugs - a relevant problem with a solution]. PMID- 24066373 TI - An interview with Ajalmar Maia. Interview by Catia Cardoso Abdo Quintao, Marco Rosa, Guilherme Janson, and Leopoldino Capelozza Filho. PMID- 24066375 TI - [Acute pain - still no clinical routine]. PMID- 24066376 TI - [Quality reports of hospitals. Future annual reports of all sites with additional information]. PMID- 24066377 TI - [Petition of European experts on medical products legislation]. PMID- 24066378 TI - Response. PMID- 24066379 TI - [Cerebral sparganosis]. PMID- 24066380 TI - [Antismoking legislation and prematurity]. PMID- 24066381 TI - [Pacifier restriction and exclusive breastfeeding]. PMID- 24066383 TI - 'Confusing' mortality measures to be replaced. PMID- 24066382 TI - [Rhinovirus wheezing illness and genetic risk of childhood-onset asthma]. PMID- 24066384 TI - Women still lag behind in senior leadership roles. PMID- 24066385 TI - Suppliers to suffer as savings drive extended. PMID- 24066386 TI - FT merger decision reveals policy confusion. PMID- 24066387 TI - An NHS leader is more than 'just a job'. PMID- 24066388 TI - The NHS needs a new leadership style. PMID- 24066389 TI - Mixed picture of female leadership gives hope for future. PMID- 24066390 TI - [The present status and attempts toward the achievement of gender equality in the JAA]. AB - The proportion of female members in The Japanese Association of Anatomists (JAA) is 18% with the proportion of female members higher among the young generation (20-30 Y.O.; 34.8%, 30-40 Y.O.; 26.8%). However, the number of female members in the Board of Directors has been zero or one (0 or 6%) for many years. More than two female members are necessary on the Board to promote the diversity in the management of the JAA. The numbers of female members in other committees has shown gradual increase in recent years. A substantial increase in female faculty members including professors in each university and school will support the future development of the anatomical research field and the association. We have made the first great step by setting up the committee on promotion of gender equality in JAA in March, 2011. In the next year, JAA became a member of Japan Inter-Society Liaison Association Committee for Promoting Equal Participation of Men and Women in Science and Engineering (EPMEWSE). Our committee's activity includes holding workshops and seminars at the annual meetings to promote gender equality in the research field and to encourage mutual support and friendship, not only among women members but also among all members. PMID- 24066391 TI - [How EPMEWSE* worked with supporting programs for female scientists in STEM** fields in Japan]. AB - In gender equality, Japan is still lagging behind other developed nations. The ratio of female to male researchers is only at 14% in 2012, the lowest among developed countries. The Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan has started the programs to support the female researchers and to develop their leadership activities. Our survey revealed that there are too few women in higher positions who can help younger women with career enhancement. Also, male scientists have unconscious bias when they evaluate their female colleagues. At the same time, female scientists often underestimate their ability when seeking leadership roles. The MEXT programs will only exert a long-term effect on the ratio and roles of women in science if the academic climate and leadership changes in Japan. In Japan, a long-term strategy with support by government and universities is essential to overcome the gender gap and maximize the potential of female scientists. PMID- 24066392 TI - [Gender equality activity in the Bioimaging Society]. AB - Gender equality activity in the Bioimaging Society was initiated in 2005 when it joined the Japan Inter-Society Liaison Association Committee for Promoting Equal Participation of Men and Women in Science and Engineering (EPMEWSE). The Gender Equality Committee of the Bioimaging Society is acting on this issue by following the policy of the EPMEWSE, and has also been planning and conducting lectures at annual meetings of the society to gain the understanding, consents, and cooperation of the members of the society to become conscious of gender equality. Women's participation in the society has been promoted through the activities of the Gender Equality Committee, and the number of women officers in the society has since increased from two women out of 40 members in 2005 to five out of 44 in 2013. The activities of the Gender Equality Committee of the Japanese Association of Anatomists (JAA) have just started. There are more than 400 women belonging to the JAA. When these women members join together and collaborate, women's participation in the JAA will increase. PMID- 24066393 TI - [Introduction of Shimane University's outside funded support project for female researchers and healthcare staff]. AB - Shimane University has started to provide facilities and services to female researchers and healthcare staff who have worked for the university or its hospital after 2007. This initiative had been supported by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology until 2010. Over time, it has become clear that these efforts, including a day-and night nursery, day-care for sick children, temporary day-care, after-school programs, and research support system have effectively sustained female researchers and staff in maintaining a balance between private life and work. It is essential that the university devote part of its budget along with outside funding for continued childcare, which has so motivated these female employees. Moreover, it is expected that these efforts will become an effective recruitment tool for excellent young teachers and researchers. PMID- 24066394 TI - [Report of the workshop for gender equality at the annual meeting of the Japanese Association of Anatomists]. PMID- 24066398 TI - Abuse of discretion in benefits denial. PMID- 24066395 TI - [Differences between traditional education and research in clinical anatomy conducted by anatomical departments and surgical training defined by the guidelines for cadaver dissection in education and research of clinical medicine]. PMID- 24066399 TI - Definition of disability. PMID- 24066400 TI - Benefit denial fails ERISA's review requirement. PMID- 24066401 TI - COBRA notice violation. PMID- 24066403 TI - Earnings calculation for disability benefits. PMID- 24066404 TI - Your best shot: With more new choices, there's a flu vaccine for almost everyone. PMID- 24066405 TI - Metabolic syndrome: differences between psychiatric and internal medicine patients. AB - OBJECTIVES: The existence of specific features of Metabolic Syndrome (MetS) in psychiatric population in comparison to not psychiatric patients has not been systematically investigated. The purpose of this study is to evaluate the differences of MetS among a group of psychiatric patients and a group of internal medicine patients in terms of anthropometric measurements, biochemical variables, and cardiovascular risk. METHODS: We enrolled 83 psychiatric inpatients under pharmacological treatment (schizophrenia n = 24, bipolar disorder n = 27, major depression n = 14, other n = 18) and 77 internal medicine patients visited for supposed MetS as affected by overweight or arterial hypertension. RESULTS: Psychiatric patients differed from control subjects by age (yrs) (47 +/- 9 vs. 52 +/- 8.6, p = 0.001), waist circumference (cm) (111.9 +/- 10.9 vs. 106 +/- 12.6, p = 0.02), HDL cholesterol (mg/dl) (36.8 +/- 7 vs. 48 +/- 11.3, p = 0.001), serum insulin (microU/ml) (26 +/- 12.5 vs. 16.4 +/- 8.8, p = 0.001), triglyceride/HDL cholesterol ratio (4.8 +/- 2.7 vs. 3.3 +/- 2.2, p = 0.01). Female psychiatric patients had higher levels of triglycerides (mg) (178 + 86 vs. 115 + 53, p = 0.002) and of HOMA index (7.8 + 5 vs. 3.8 + 3.3, p = 0.005). Triglycerides and triglycerides/HDL ratio levels were higher in Unipolar Depression. A positive association was found between antidepressant drug treatment with triglycerides and triglycerides/HDL ratio levels, neuroleptic treatment with the HOMA index, and antipsychotics drugs with the Framingham index. LIMITATIONS: Psychiatric study population numerosity and duration of psychiatric illness and drug treatment. CONCLUSIONS: Specific features of MetS in psychiatric population are mainly represented by young age of onset, hyperinsulinemia, increased abdominal adiposity, and low HDL cholesterol whose common denominator may be insulin resistance. PMID- 24066407 TI - Delusional disorder and oncology: review of the literature and case report. AB - OBJECTIVE: Delusional disorder is an infrequent diagnosis in outpatient clinical practice. While delusional thought processes are a fairly common part of symptom clusters in chronic psychiatric disorders such as schizophrenia and bipolar disorders, true delusional disorders are believed to be fairly rare. METHOD: In this article, we review scientific data on incidence, diagnosis, and treatment of delusional disorders. This was done by PubMed search utilizing the search terms "delusional disorder," "oncology," "diagnosis," and "treatment." Relevant articles were excluded if they dealt predominantly with schizophrenia instead of primary delusional disorder. RESULTS: We present a case of a patient diagnosed with follicular lymphoma and an apparent longstanding history of persecutory delusions. The patient's symptoms eventually led to intervention in the oncology practice involving the medical center faculty and staff, as well as local police and the court system. CONCLUSIONS: Delusional disorder is an under-researched condition, and limited information is known regarding the treatment of this condition when it impacts upon medical care. Future research directions are proposed. PMID- 24066406 TI - Greater frequency of depression associated with chronic primary headaches than chronic post-traumatic headaches. AB - OBJECTIVE: To compare the prevalence of co-morbid depression between patients with chronic primary headache syndromes and chronic posttraumatic headaches. METHOD: A prospective cross-sectional analysis of all patients presenting sequentially to a community-based general neurology clinic during a 2-year period for evaluation of chronic headache pain was conducted. Headache diagnosis was determined according to the International Headache Society's Headache Classification criteria. Depression was determined through a combination of scores on the clinician administered Hamilton Rating Scale for Depression and patients' self-report. An additional group of patients who suffered traumatic brain injuries (TBI) but did not develop post-traumatic headaches was included for comparison. RESULTS: A total of 83 patients were included in the study: 45 with chronic primary headaches (24 with chronic migraine headaches, 21 with chronic tension headaches), 24 with chronic post-traumatic headaches, and 14 with TBI but no headaches. Depression occurred less frequently among those with chronic post-traumatic headaches (33.3%) compared to those with chronic migraine (66.7%) and chronic tension (52.4%) headaches (Chi-Square = 7.68; df = 3; p = 0.053), and did not significantly differ from TBI patients without headaches. A multivariate logistic regression model using depression as the outcome variable and including headache diagnosis, gender, ethnicity, and alcohol and illicit substance use was statistically significant (Chi-Square = 27.201; df = 10; p < 0.01) and identified primary headache (migraine and tension) diagnoses (Score = 7.349; df = 1; p = 0.04) and female gender (Score = 15.281; df = 1; p < 0.01) as significant predictor variables. The overall model accurately predicted presence of co-morbid depression in 74.7% of the cases. CONCLUSIONS: Co-morbid depression occurs less frequently among patients with chronic post-traumatic headaches and TBI without headaches than among those with chronic primary headaches. PMID- 24066408 TI - Drug therapy versus electroconvulsive therapy for refractory schizophrenia: report of a case with 14 years of follow-up. AB - The long-term efficacy and safety of electroconvulsive therapy (ECT) for refractory schizophrenia is rarely reported. We report the case of a 38-year-old female patient with refractory schizophrenia who was treated with ECT for 14 years (from 24 years of age). Case records of clinical treatment and laboratory tests are described and analyzed. During the first 11 years, the patient was treated with ECT as an adjunct to antipsychotic drugs, but the effectiveness was unstable. For the remaining 3 years she was treated with antipsychotic drugs as an adjunct to ECT and her condition stabilized as she gradually recovered social function. We summarize the clinical characteristics, therapy regimen, long-term effectiveness, and safety of this interesting case. PMID- 24066409 TI - Effects of hospitalization in a psychiatric ward on the body weight of Japanese patients with schizophrenia. AB - OBJECTIVE: In Japan, the prevalence of overweight/obesity in the general population is considerably lower and the mean duration of hospitalization of patients with schizophrenia is much longer than those in Europe and North America. The aim of this study was to investigate whether these differences in ethnics or healthcare systems influence the nutritional status of patients with schizophrenia. METHODS: Body mass index (BMI) and blood biochemistry tests were determined at hospitalization and at discharge for 171 Japanese patients who were hospitalized for the treatment of acute phase schizophrenia. RESULTS: For 56 patients who were overweight/obese at hospitalization, BMI (p < 0.001), fasting plasma glucose (p = 0.039), and low-density lipoprotein (p = 0.027) were significantly lower at discharge than at hospitalization. BMI at hospitalization, duration of hospitalization, and age were associated with a decrease in BMI during hospitalization. Among the 115 patients who were not overweight/obese at hospitalization, there were no changes in BMI and blood biochemistry tests between hospitalization and discharge. CONCLUSIONS: Compared with inpatients, outpatients with schizophrenia may be more likely to be overweight/obese in Japan. PMID- 24066410 TI - Evaluation of the relationship between the ZNF804A single nucleotide polymorphism rs1344706 A/C variant and schizophrenia subtype in Han Chinese patients. AB - OBJECTIVE: Recent genome wide association studies (GWASs) assessing the relationship between schizophrenia (SZ) and the ZNF804A gene, particularly the single nucleotide polymorphism (SNP) rs1344706, have yielded conflicting results. Schizophrenia is a heterogeneous disorder, so it is possible that an association may be restricted to specific SZ subtypes and that population heterogeneity may obscure a contribution of ZNF804A allelic variation to SZ risk. We thus evaluated the association between rs1344706 and different clinical SZ subtypes in a large Han Chinese patient population. METHOD: The rs1344706 genotype was determined in 1,025 SZ patients and 977 healthy controls using polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLPs). The clinical SZ subtypes included paranoid, catatonic, disintegrated, and undifferentiated, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition IV (DSM-IV). RESULTS: No significant differences in genotype and allele frequencies were found between controls and either the total SZ population (A > C, chi2 = 4.339, 2.994; p = 0.227, 0.087, respectively) or paranoid SZ patients (chi2 = 2.053, 0.002; p = 0.562, 0.973, respectively). However, there was a significant association between genotype frequency and SZ subtype (chi2 = 12.632, p = 0.049). CONCLUSIONS: We found no evidence that the ZNF804A SNP rs1344706 is a susceptibility locus for SZ. However, conflicting results from previous association studies may be due to genetic heterogeneity between different patient SZ subtypes. PMID- 24066411 TI - The impact of coercion on treatment outcome: one-year follow-up survey. AB - OBJECTIVE: This study examined whether coercive measures or perceived coercion experienced by mentally disabled patients in the hospitalization process could be justified under paternalism. To find out whether coercion can be justified by paternalism, a year of follow-up research was conducted to examine the impact of coercive measures and perceived coercion experienced during hospitalization on the patients' therapeutic benefit. METHODS: A 6-month period and a 1-year period of follow-up research was conducted with 266 patients to assess whether the coercion they experienced during hospitalization (coercive measures and perceived coercion) had an effect on changing the patients' mental symptoms and insight. RESULTS: The results showed a decrease in both mental symptoms and insight over time. However, it was found that neither coercive measures nor perceived coercion had a significant effect on the change of mental symptoms and that, thus, coercion had little contribution to the declining of symptoms. Coercive measures had no effect on the change of insight but perceived coercion was shown to have a positive effect on a change in insight. Patient insight was shown to improve with increased perceived coercion. CONCLUSIONS: Paternalism provides a partial explanation to serve as a basis for justifying perceived coercion. Limitations and suggestions for further study are discussed. PMID- 24066412 TI - Social-democratic government and health policy in Europe: a quantitative analysis. AB - Although health policy ultimately depends on political decision making, empirical evidence of the impact of politics on implementation of health policies and their population health outcomes is scarce. In this study, we assess the effects of social-democratic government participation on indicators of preventive health policy (tobacco, alcohol, food, mother and child health, infectious diseases, hypertension, cancer screening, road traffic safety, air pollution) in Europe. Cumulative years of social-democratic government differed widely between European countries, as did indicators of current health policy performance, but the latter are not associated with recent social-democratic government. However, there is a positive association with social-democratic government cumulated over five decades. Positive effects of social-democratic government are mainly seen on indicators of tobacco and alcohol control. We conclude that long-term social democratic government participation may have had a positive impact on some areas of preventive health policy, perhaps through the creation of strong public health institutions or a strong public health workforce. PMID- 24066413 TI - A unifying framework of the demand for transnational medical travel. AB - Transnational medical travel has gained attention recently as a strategy for patients to obtain care that is higher quality, costs less, or offers improved access relative to care provided within their home countries. This article examines institutional environments in the European Union and United States that influence transnational medical travel, describes the conceptual model of demand for medical travel, and illustrates individual dimensions in the conceptual model of medical travel using a series of case studies. The conceptual model of medical travel is predicated on Andersen's behavioral model of health services. Transnational medical travel is a heterogeneous phenomenon that is influenced by a number of patient-related factors and by the institutional environment in which the patient resides. While cost, access, and quality are commonly cited factors that influence a patient's decision regarding where to seek care, multiple factors may simultaneously influence the decision about the destination for care, including culture, social factors, and the institutional environment. The conceptual framework addresses the patient-related factors that influence where a patient seeks care. This framework can help researchers and regulatory bodies to evaluate the opportunities and the risks of transnational medical travel and help providers and governments to develop international patient programs. PMID- 24066414 TI - Noncommunicable diseases: global health priority or market opportunity? An illustration of the World Health Organization at its worst and at its best. AB - The promotion of noncommunicable diseases (NCDs) as a global health priority started a decade ago and culminated in a 2011 United Nations high-level meeting. The focus is on four diseases (cardiovascular and chronic respiratory diseases, cancers, and diabetes) and four risk factors (tobacco use, unhealthy diet, physical inactivity, and harmful alcohol use). The message is that disease and death are now globalized, risk factors are overwhelmingly behavioral, and premature NCD deaths, especially in low- and middle-income countries, are the concern. The NCD agenda is promoted by United Nations agencies, foundations, institutes, and organizations in a style that suggests a market opportunity. This "hard sell" of NCDs contrasts with the sober style of the World Health Organization's Global Burden of Disease report, which presents a more nuanced picture of mortality and morbidity and different implications for global health priorities. This report indicates continuing high levels of premature death from infectious disease and from maternal, perinatal, and nutritional conditions in low-income countries and large health inequalities. Comparison of the reports offers an illustration of the World Health Organization at its worst, operating under the influence of the private sector, and at its best, operating according to its constitutional mandate. PMID- 24066415 TI - Primary health care, now and forever? A case study of a paradigm change. AB - The year 2008 marked the 30th anniversary of the Alma Ata Declaration that made Primary Health Care (PHC) the global health policy of member states of the World Health Organization (WHO). Why has PHC remained relevant? In part, this is because of growing evidence that health is a result of social, political, and economic environments, not merely of control of diseases and infirmities through interventions based on biomedical science. Using the conceptual framework developed by Thomas Kuhn, this article traces the emergence of PHC as a new paradigm based on social determinants to address poor health among populations (not individuals), especially those that are low-income. It traces the history of PHC over the last 30 years, focusing on policy developments within WHO. It selects three issues: definitions of PHC; financing and delivery of health services, including lay people's involvement in health care, as examples of the new paradigm; and opposition by those whose concept of health is based on the control of disease and infirmities paradigm. The article concludes by asking whether PHC will continue to be relevant and whether the question mark in the title of this article will be removed in the future. PMID- 24066416 TI - Complementarities or contradictions? Scoping the health dimensions of "flexicurity" labor market policies. AB - Flexicurity, or the integration of labor market flexibility with social security and active labor market policies, has figured prominently in economic and social policy discussions in Europe since the mid-1990s. Such policies are designed to transcend traditional labor-capital conflicts and to form a mutually supportive nexus of flexibility and security within a climate of intensified competition and rapid technological change. International bodies have marketed flexicurity as an innovative win-win strategy for employers and workers alike, commonly citing Denmark and The Netherlands as exemplars of best practice. In this article, we apply a social determinants of health framework to conduct a scoping review of the academic and gray literature to: (a) better understand the empirical associations between flexicurity practices and population health in Denmark and (b) assess the relevance and feasibility of implementing such policies to improve health and reduce health inequalities in Ontario, Canada. Based on 39 studies meeting our full inclusion criteria, preliminary findings suggest that flexicurity is limited as a potential health promotion strategy in Ontario, offers more risks to workers' health than benefits, and requires the strengthening of other social protections before it could be realistically implemented within a Canadian context. PMID- 24066417 TI - Health disparities among wage workers driven by employment instability in the Republic of Korea. AB - Even though labor market flexibility continues to be a source of grave concern in terms of employment instability, as evidenced by temporary employment, only a few longitudinal studies have examined the effects of employment instability on the health status of wage workers. Against this backdrop, this study assesses the manner in which changes in employment type affect the health status of wage workers. The data originate from the Korean Labor and Income Panel Study's health related surveys for the first through fourth years (n = 1,789; 1998 to 2001). This study estimates potential damage to self-rated health through the application of a generalized estimating equation, according to specific levels of employment instability. While controlling for age, socioeconomic position, marital status, health behavior, and access to health care, the study analysis confirms that changes in employment type exert significant and adverse effects on health status for a given year (OR = 1.47; 95% CII 1.10-1.96), to an extent comparable to the marked effects of smoking on human health (OR = 1.47; 95% CI 1.05-2.04). Given the global prevalence of labor flexibility, policy interventions must be implemented if employment instability triggers broad discrepancies not only in social standing, wage, and welfare benefits, but also in health status. PMID- 24066418 TI - Social change and women's health. AB - Over the past five decades, the organization of women's lives has changed dramatically. Throughout the industrialized world, paid work and family biographies have been altered as the once-dominant role of homemaker has given way to the role of secondary, dual, or even primary wage-earner. The attendant changes represent a mix of gains and losses for women, in which not all women have benefited (or suffered) equally. But little is known about the health consequences. This article addresses that gap. It develops a "situated biographies" model to conceptualize how life course change may influence women's health. The model stresses the role of time, both as individual aging and as the anchoring of lives in particular historical periods. "Situating" biographies in this way highlights two key features of social change in women's lives: the ambiguous implications for the health of women as a group, and the probable connections to growing social and economic disparities in health among them. This approach lays the groundwork for more integrated and productive population-based research about how historical transformations may affect women's health. PMID- 24066419 TI - Psychosocial work environment and intention to leave the nursing profession: a cross-national prospective study of eight countries. AB - Many countries throughout the world are facing a serious nursing shortage, and retention of nurses also is a challenge. The aim of this study was to compare the predictive contribution of a broad spectrum of psychosocial work factors, including job strain, effort-reward imbalance, and alternative employment opportunity, to the probability of intention to leave the nursing profession. A total of 7,990 registered female nurses working in hospitals in eight countries (Germany, Italy, France, The Netherlands, Belgium, Poland, Slovakia, and China) were included in the one-year prospective study. A standardized questionnaire on job strain, effort-reward imbalance, employment opportunity, and intention to leave the nursing profession was used in the survey. Multilevel logistic regression modeling was used to analyze the data. Results showed that an imbalance between high effort and low reward (in particular, poor promotion prospects) and good employment opportunity at baseline were independently associated with a new intention to leave the nursing profession at follow-up. However, job strain appeared to have relatively less explanatory power. Findings suggest that interventions to improve the psychosocial work environment, especially the reciprocity experienced between effort and reward, may be effective in improving retention of nurses and tackling the international nursing shortage. PMID- 24066420 TI - Egalitarian policies and social determinants of health in Bolivarian Venezuela. AB - In 1999, newly-elected Venezuelan President Hugo Chavez initiated a far-reaching social movement as part of a political project known as the Bolivarian Revolution. Inspired by the democratic ideologies of Simon Bolivar, this movement was committed to reducing intractable inequalities that defined Venezuela's Fourth Republic (1958-1998). Given the ambitious scope of these reforms, Venezuela serves as an instructive example to understand the political context of social inequalities and population health. In this article, we provide a brief overview of the impact of egalitarian policies in Venezuela, stressing: (a) the socialist reforms and social class changes initiated by the Bolivarian Movement; (b) the impact of these reforms and changes on poverty and social determinants of health; (c) the sustainability of economic growth to continue pro-poor policies; and (d) the implications of egalitarian policies for other Latin American countries. The significance and implications of Chavez's achievements are now further underscored given his recent passing, leading one to ask whether political support for Bolivarianism will continue without its revolutionary leader. PMID- 24066421 TI - Changes in the health care safety net 1992-2003: disparities in access for uninsured persons in Florida. AB - A patchwork of services is available to uninsured in the United States through the health care safety net. During 1996-2003, some safety net hospitals (SNHs) closed or converted their ownership status from public or non-profit to for profit. Meanwhile, the number of community health centers (CHCs) grew as a result of new federal funding. This article examines the impact of these two countervailing events on access to care for the uninsured. Hospital admissions for ambulatory care sensitive conditions relative to marker conditions were used as our access measure. We examined 35,730 discharges for uninsured adults treated in Florida hospitals in the years 1992 or 2003. A generalized estimating equation model was used to assess differential access effects for racial and ethnic groups. We found that in communities with CHC openings but no SNH contractions, uninsured black and white individuals experienced deteriorations in access over time, but the Hispanic uninsured did not. However, in communities where SNHs closed or converted, access deteriorations occurred for all three racial and ethnic groups. Thus, the potentially beneficial effects of CHC expansions on access to primary care for the uninsured Hispanic population in Florida appeared to be offset if contractions in the hospital safety net were present. PMID- 24066422 TI - Needs in health care: what beast is that? AB - Need is a pivotal concept within health systems internationally given its driving force in health care policy, development, and delivery at population and individual levels. Needs assessments are critical activities undertaken to ensure that health services continue to be needed and to identify new target populations that demonstrate unmet need. The concept of need is underpinned by varied theoretical definitions originating from various disciplines. However, when needs are assessed, or health interventions developed based on need, little, if any, detail of the theoretical or conceptual basis of what is being measured is ever articulated. This is potentially problematic and may lead to measurement being invalid and planned health services being ineffective in meeting needs. Seldom are theoretical definitions of need ever compared and contrasted. This critical review is intended to fill this gap in the literature. Interpretations of the concept of need drawing from areas such as psychology, social policy, and health are introduced. The concept and relevance of unmet need for health services are discussed. It is intended that these definitions can be used to operationalize the term "need" in practice, theoretically drive needs assessment, and help guide health care decisions that are based upon need. PMID- 24066423 TI - Revealed: the 100-fold variation in CCG workforce size. PMID- 24066424 TI - NHS England's new vision will be radical. PMID- 24066425 TI - Trusts need their own measures of success. PMID- 24066426 TI - Take the fear out of transformation. PMID- 24066427 TI - Pick up the baton of development. PMID- 24066428 TI - End of life care: Changing the care landscape. PMID- 24066429 TI - Academic health science networks: Dos and don'ts of collaboration. PMID- 24066430 TI - Workforce: Making the case for more nurses. PMID- 24066431 TI - The sequester squeeze: Already-fragile practices brace for its effects. PMID- 24066433 TI - 6 steps you can take to remain independent--for now. PMID- 24066432 TI - You can help set expectations on electronic health records liability. PMID- 24066434 TI - RACs reviewing POS coding for doctor services in an outpatient setting. PMID- 24066435 TI - Circulation education. PMID- 24066436 TI - 3 steps to controlling staff costs. PMID- 24066437 TI - No pain, no gain. PMID- 24066438 TI - Examine your revenue cycle to keep pace with changing economic trends. PMID- 24066440 TI - Doctors: Patients should be able to update but not view full records. PMID- 24066439 TI - Using single HIT vendor has benefits, drawbacks. PMID- 24066441 TI - Meaningful use 2: 2013's interoperability challenge. Connectivity barriers remain as physicians move from EHR implementation to data exchange, communication. PMID- 24066442 TI - Physicians make inroads in EHR use. Significant hurdles remain, however, as operations 'normalize'. PMID- 24066443 TI - Be prepared for breaches of protected patient information. PMID- 24066444 TI - Too many EHR alerts raise patient safety concerns. PMID- 24066445 TI - ACOs redefine relationships with specialists. PMID- 24066446 TI - How to get paid for complex care coordination. PMID- 24066448 TI - Push for wellness continues. PMID- 24066447 TI - Credit line can be lifeline for your practice. PMID- 24066450 TI - Physician groups welcome transparency. PMID- 24066451 TI - Technology, life issues altering what it means to be a physician. Interview by Lois A Bowers. PMID- 24066449 TI - Sunshine Act: 7 things you need to know. PMID- 24066452 TI - The perfect storm in medicine. PMID- 24066453 TI - The PQRS challenge: Will quality metrics improve care or create more reimbursement red tape? PMID- 24066454 TI - Out-of-network payments. PMID- 24066455 TI - The Stark realities your group needs to know. PMID- 24066456 TI - OIG still cracking down on use of modifier 25. PMID- 24066457 TI - COPD: Exploring the value of care. PMID- 24066459 TI - Explore fixes to your EHR system before deciding to replace it. PMID- 24066458 TI - How to master electronic communication with patients. PMID- 24066460 TI - Most provider organizations eyeing MU2 in 2014. PMID- 24066461 TI - How to save $1 trillion in health costs while strengthening primay care. PMID- 24066462 TI - [Progress and new challenges in hepatitis C]. PMID- 24066463 TI - [Reactivation of hepatitis B associated with immunosuppression]. AB - The hepatitis B virus is an important cause of viral reactivation and flares in immunosuppressed patients. Factors associated with viral reactivation include positive HBs antigen, rituximab treatment, onco-haematological pathology and bone marrow transplantation. In situations at high risk of viral reactivation prophylactic antiviral therapy is indicated and reduces morbidity and mortality related to viral hepatitis flares. PMID- 24066464 TI - [Radiofrequency ablation for Barret's esophagus]. AB - Barrett's esophagus consists of the replacement of normal squamous epithelium by a specialised columnar lined epithelium referred to as intestinal metaplasia in the esophagus. It represents a premalignant lesion. The prevalence of Barrett's esophagus is around 1.6%. Esophageal adenocarcinoma results from the development of dysplasia progressing from low to high grade dysplasia and finally adenocarcinoma. Radiofrequency ablation currently represents the treatment of choice in eradicating Barrett's esophagus with associated dysplasia. The technique is based on the application of a radiofrequency current that enables the destruction of the superficial modified epithelium. This new approach presents a good security profile and, compared to other ablative techniques, shows superior results regarding Barrett's eradication. PMID- 24066465 TI - [Management of liver diseases during pregnancy]. AB - Liver tests abnormalities during pregnancy should encourage the clinician to seek liver diseases of pregnancy. The liver diseases of pregnancy are those proper to pregnancy including hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, all the "hypertensive" related diseases and acute fatty liver of pregnancy. These pathologies can involve the vital prognosis of the mother and the child. An adequate management reduces maternal-fetal complications. Close monitoring of pregnancy with sometimes induction of labour and verification of the normalization of liver tests after childbirth are essential. PMID- 24066466 TI - [An update on celiac disease]. AB - Celiac disease is a well-known entity in pediatrics and pediatric gastroenterology that is now also frequently encountered in the adult population. Apart from typical symptoms, celiac disease can present with a wide range of manifestations that are sometimes atypical, scarce or purely extraintestinal. Serologic and genetic testing are useful tools in case of low clinical probability in the early diagnostic algorithm. Upper gastrointestinal endoscopy remains the mainstay to confirm the diagnosis especially in atypical clinical presentations. Complications are rare but can be severe. Although gluten-free diet often leads to complete recovery, compliance is not universal and alternative treatment strategies are under investigation. PMID- 24066467 TI - [Self-expanding metallic stent in malignant colonic obstruction]. AB - About 20% of colorectal cancers are complicated by intestinal obstruction. Self expanding metallic stents (SEMS) permit desobstruction in over 90% of cases. In palliative setting, employing SEMS reduces hospitalisation time and permanent stoma rate with identical mortality rates compared to surgery. When using SEMS as bridge to surgery, higher primary and lower overall stoma rates are obtained with no significant mortality reduction by now. Of concern, procedure-related bowel perforation is frequent, especially among endoscopists lacking sufficient experience in colonic stenting. PMID- 24066468 TI - [An update on hepatitis E]. AB - The hepatitis E virus (HEV) is an RNA virus transmitted via the fecal-oral route or through uncooked animal meat products. Of the 4 known genotypes, genotype 3 is responsible for autochthonous infections in industrialized countries, with a seroprevalence in Switzerland estimated as high as 22%. The majority of infections is asymptomatic but a minority of patients, notably men over 50 or with underlying liver disease, can present with severe acute hepatitis. Chronic hepatitis E with HEV of genotype 3 has been observed in immunosuppressed patients, mostly transplant recipients. Serology is not sufficiently sensitive, especially in immunosuppressed patients, making PCR identification the preferred test for diagnosing active infection. Ribavirin or interferon-alpha can be used to treat chronic hepatitis E if reduction of immunosuppressive treatment does not result in viral elimination. PMID- 24066469 TI - [Stochasticity: the third variable]. PMID- 24066470 TI - [New miracles: let their bodies speak]. PMID- 24066472 TI - [Alzheimer disease: diagnosis before time?]. PMID- 24066473 TI - [Euthanasia: a few Belgian points]. PMID- 24066474 TI - [The privatization (blurred) of the public hospital]. PMID- 24066475 TI - Our mistakes make us better physicians. PMID- 24066476 TI - Coalition: ICD-10 could put many small practices in economic jeopardy. PMID- 24066477 TI - Work-life balance skewed for many PCPs, survey says. PMID- 24066478 TI - Taxes are going up, but you can limit your burden. PMID- 24066479 TI - Understand tax implications of practice buy-ins, buy-outs. PMID- 24066480 TI - Tax writeoffs: what to take, what to avoid. PMID- 24066481 TI - Costs, control, data access remain top EHR concerns. Interview by Lois A Bowers. PMID- 24066482 TI - Take steps to restrict use of personal electronic devices in the office. PMID- 24066483 TI - You will pay the price if you do not meet e-prescribing requirements. PMID- 24066484 TI - As hospital ranks swell, salary pressure could, too. PMID- 24066485 TI - Integration can support clinical quality, technology efforts. Interview by Lois A Bowers. PMID- 24066486 TI - Departing chief urges the NHS to begin a creative new phase. PMID- 24066487 TI - Time to question commissioner-provider split'. PMID- 24066488 TI - Trusts target private patients. PMID- 24066489 TI - Ask questions first, shoot later. PMID- 24066490 TI - Redefining the role of the NHS Chief Executive. PMID- 24066492 TI - Mental health: Piece of my mind. PMID- 24066491 TI - Commissioners need patient data. PMID- 24066493 TI - Law: Put in the hours. PMID- 24066494 TI - Law: case studies. Never again. PMID- 24066495 TI - End of life care: How to find the way home. PMID- 24066496 TI - End of life care: case studies. Where they want to be. PMID- 24066497 TI - Service redesign: Time to go back to the 3Rs. PMID- 24066498 TI - Service redesign: case studies. You're not on your own. PMID- 24066499 TI - Management information: Figure it out. PMID- 24066500 TI - Independent providers: More than just a bed. PMID- 24066501 TI - Independent providers: case studies. Back on their feet. PMID- 24066502 TI - Assurance: Positive peer pressure. PMID- 24066503 TI - Sustainability: Trusts are thinking green to avoid being in the red. PMID- 24066504 TI - Making the shift in frail elderly care. PMID- 24066505 TI - Service redesign: A far cry from child's play. PMID- 24066506 TI - Mental health: A refreshing approach to contracting services. PMID- 24066507 TI - Books: Trust by name, trust by nature. PMID- 24066508 TI - Interview: Building on a strong foundation. Interview by Claire Read. PMID- 24066509 TI - A new flavone from the roots of Milicia excelsa (Moraceae). AB - A new flavonoid identified as 2-(2,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl 4H,8H-pyrano[2,3-f]chromen-4-one (2'-hydroxyatalantoflavone) (1) was obtained from the roots of Milicia excelsa along with five known compounds including atalantoflavone (2), neocyclomorusin (3), 6-geranylnorartocarpetin (4), cudraxanthone I (5), and betulinic acid (6). The structures of the isolates were established on the basis of their spectral data and by comparison with those reported in the literature. PMID- 24066510 TI - Analgesic and anticonvulsant activities of some newly synthesized trisubstituted pyridine derivatives. AB - A series of novel pyridine carbohydrazide derivatives were synthesized from the reaction of 2-chloro-6-hydrazino-isonicotinic acid hydrazide with selected active reagents. All prepared compounds were tested as analgesic and anticonvulsant agents. The pharmacological screening showed that many of these compounds have good activities comparable to those of valdecoxib and carbamazepine as reference drugs. PMID- 24066511 TI - Cytotoxic rocaglamide derivatives from Aglaia duppereana. AB - Phytochemical investigation of Aglaia duppereana flowers led to the isolation of a new rocaglamide derivative and twelve known congeners. The structure of the new compound was unambiguously elucidated by spectroscopic techniques (1D- and 2D NMR, HRESIMS). The isolated compounds exhibited a potent cytotoxic activity against mouse lymphoma (L5178Y) cells with EC50 values ranging from 5.1 to 54.8 nM. PMID- 24066512 TI - Chemical composition of the essential oils of variegated pink-fleshed lemon (Citrus x limon L. Burm. f.) and their anti-inflammatory and antimicrobial activities. AB - The volatile secondary metabolites of essential oils from fruit peel and leaves of variegated pink-fleshed lemon (Citrus x limon) were investigated using GLC and GLC-MS (gas-liquid chromatography-mass spectroscopy). Altogether 141 compounds were identified and quantified, accounting for 99.59% and 96.33% of the total hydrodistilled peel and leaf oil, respectively. Limonene occurred in higher amounts in fruit peel (52.73%) than in leaf oil (29.13%). Neral (12.72%), neryl acetate (8.53%), p-menth-1-en-7-al (4.63%), beta-pinene (6.35%), and nerol (4.42%) were the most abundant constituents in leaf oil, whereas gamma-terpinene (9.88%), beta-pinene (7.67%), geranial (4.44%), and neral (3.64%) dominated in the fruit peel oil. The antioxidant, anti-inflammatory, antitrypanosomal, and antimicrobial activities of the fruit peel essential oil were evaluated. The oil had a low antioxidant activity with an IC50 value of (26.66 +/- 2.07) mg/ml as compared to the efficient antioxidant ascorbic acid [IC50 (16.32 +/- 0.16) microg/ml]. The oil moderately inhibited soybean 5-lipoxygenase (5-LOX) with an IC50 value of (32.05 +/- 3.91) microg/ml and had moderate antitrypanosomal activity [IC50 (60.90 +/- 0.91) microg/ml]. In addition, moderate antimicrobial activities were detected against Gram-positive bacteria (Bacillus subtilis, Staphylococcus capitis, Micrococcus luteus), one Gram-negative bacterium (Pseudomonas fluorescens), and yeasts (Saccharomyces cerevisiae, Candida parapsilosis). PMID- 24066513 TI - Chemical constituents and biological activities of Galinsoga parviflora cav. (Asteraceae) from Egypt. AB - The phytochemical investigation of an aqueous ethanolic extract of Galinsoga parviflora Cav. (Asteraceae) resulted in the isolation and identification of eleven compounds namely: triacontanol, phytol, beta-sitosterol, stigmasterol, 7 hydroxy-beta-sitosterol, 7-hydroxystigmasterol, beta-sitosterol-3-O-beta-D glucoside, 3,4-dimethoxycinnamic acid, protocatechuic acid, fumaric acid, and uracil. Furthermore, 48 volatile constituents were identified in the hydrodistilled oil of the aerial parts. The ethanolic extract at a content of 400 mg/kg body weight (BW) exerted 87% reduction in the alanine aminotransferase enzyme level in cirrhotic rats compared with the standard silymarin (150 mg/kg BW) and also exerted a reduction in the blood glucose level equivalent to that of glibenclamide (5 mg/kg BW) in diabetic rats. The ethanolic extract, light petroleum and ethyl acetate fractions exhibited substantial antimicrobial activity against Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, Aspergillus niger, and Candida albicans. The ethyl acetate fraction showed strong antioxidant activity at a concentration of 150 mg/mL as compared with 0.1 M ascorbic acid. The cytotoxic effect against the MCF-7 cell line was found to be weak. PMID- 24066514 TI - Antitumour and anti-inflammatory effects of palladium(II) complexes on Ehrlich tumour. AB - Palladium(II) complexes are an important class of cyclopalladated compounds that play a pivotal role in various pharmaceutical applications. Here, we investigated the antitumour, anti-inflammatory, and mutagenic effects of two complexes: [Pd(dmba)(Cl)tu] (1) and [Pd(dmba)(N3)tu] (2) (dmba = N,N-dimethylbenzylamine and tu = thiourea), on Ehrlich ascites tumour (EAT) cells and peritoneal exudate cells (PECs) from mice bearing solid Ehrlich tumour. The cytotoxic effects of the complexes on EAT cells and PECs were assessed using the 3-(4,5-dimethylthiazol-3 yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. The effects of the complexes on the immune system were assessed based on the production of nitric oxide (NO) (Griess assay) and tumour necrosis factor-alpha (TNF-alpha), interleukin-12 (IL 12), and interleukin-10 (IL-10) (ELISA). Finally the mutagenic activity was assessed by the Ames test using the Salmonella typhimurium strain TA 98. Cisplatin was used as a standard. The IC50 ranges for the growth inhibition of EAT cells and PECs were found to be (72.8 +/- 3.23) microM and (137.65 +/- 0.22) microM for 1 and (39.7 +/- 0.30) microM and (146.51 +/- 2.67) microM for 2, respectively. The production of NO, IL-12, and TNF-alpha, but not IL-10, was induced by both complexes and cisplatin. The complexes showed no mutagenicity in vitro, unlike cisplatin, which was mutagenic in the strain. These results indicate that the complexes are not mutagenic and have potential immunological and antitumour activities. These properties make them promising alternatives to cisplatin. PMID- 24066515 TI - Antitermite activity of beta-caryophyllene epoxide and episulfide. AB - Caryophyllene-6,7-epoxide and caryophyllene-6,7-episulfide can be easily synthesized from beta-caryophyllene by autoxidation or episulfidation. The bioactivities of beta-caryophyllene and its derivatives were investigated against the subterranean termite Reticulitermes speratus Kolbe. The antifeedant, feeding, and termiticidal activities of each compound were tested using no-choice, dual choice, and non-contact methods. Antitermitic activities were not shown by beta caryophyllene, but were observed for the oxide and sulfide derivatives. Caryophyllene-6,7-episulfide showed especially high antifeedant and termiticidal activities. Thus, naturally abundant, non-bioactive beta-caryophyllene can be easily converted into an antitermite reagent via a non-biological process. PMID- 24066516 TI - Nematicidal activity of the essential oil of Rhododendron anthopogonoides aerial parts and its constituent compounds against Meloidogyne incognita. AB - Hydrodistilled essential oil from Rhododendron anthopogonoides Maxim. (Ericaceae) aerial parts was analysed by gas chromatography-mass spectrometry (GC-MS). A total of 42 compounds, accounting for 95.48% of the total oil, were identified. The main constituents of the essential oil were benzyl acetone (34.41%), nerolidol (10.19%), 1,4-cineole (8.41%), beta-caryophyllene (5.63%), gamma elemene (5.10%), and spathulenol (3.06%). Four constituents were isolated from the essential oil based on fractionation. The essential oil of R. anthopogonoides possessed nematicidal activity against the root knot nematode (Meloidogyne incognita) with an LC50 value of 130.11 microg/ml. The main compound of the essential oil, benzyl acetone, exhibited nematicidal activity against M. incognita with an LC50 value of 74.17 microg/ml while 1,4-cineole, nerolidol, and beta-caryophyllene were not nematicidal at a concentration of 5 mg/ml. The essential oil of R. anthopogonoides and benzyl acetone show potential for their development as possible natural nematicides for the control of the root knot nematode. PMID- 24066517 TI - Identification of volatile compounds emitted by Artemisia ordosica (Artemisia, Asteraceae) and changes due to mechanical damage and weevil infestation. AB - Volatiles emitted by healthy, mechanically damaged, and weevil-infested Artemisia ordosica (Asteraceae) were obtained through a dynamic headspace method and analysed by automatic thermal desorption/gas chromatography/mass spectrometry (ATD/GC/MS). Twenty-eight compounds in all were identified, and the qualitative as well as quantitative differences were compared. The green leaf volatiles 2 hexenal, (Z)-3-hexen-1-ol, 2-hexen-1-ol, 1-hexanol, and (Z)-3-hexen-1-ol acetate were present in all of the damaged plants, but in relatively lower portions when plants were infested by the weevil Adosopius sp., while the terpenoids alpha copaene, beta-cedrene, and (E,E)-alpha-farnesene and the ester methyl salicylate were only present in weevil-damaged plants. The volatiles from healthy and weevil infested leaves were dominated by D-limonene, whereas mechanically damaged leaves emitted beta-pinene as the dominant compound. PMID- 24066518 TI - Evaluation of the biochemical stress response to chlorpyrifos in tissues of the edible crab Barytelphusa guerini: withdrawal of exposure improves the nutritional value. AB - The sublethal stress of the organophosphate insecticide chlorpyrifos was investigated in different tissues of the freshwater crab (Barytelphusa guerini). Crabs were exposed to 1/3 of LC50 concentrations for 7, 14, 21, and 28 days. After 28 days, they were released into fresh water and kept for 18 days for recovery. The study was conducted by estimating total proteins, amino acids, ammonia, urea, and glutamine levels, and protease, transaminases, and phosphatases activities. Total proteins level was decreased whereas amino acids and ammonia were increased. The urea content was decreased in all tissues and glutamine exhibited a mixed response. Protease activities and those of alanine and aspartate aminotransferase, respectively, were elevated. Acid phosphatase activity was reduced in hepatopancreas and brain and induced in gills and muscle. Alkaline phosphatase activity was enhanced in gills and hepatopancreas and reduced in muscle and brain. The crabs recovered from the biochemical stress caused by chlorpyrifos after their release into fresh water. PMID- 24066519 TI - Enterolactone and other lignan metabolites as taxon-specific markers in modern and ancient woodrat middens. AB - Diversely sourced degradation products of higher plant lignans were identified in modern and ancient woodrat (Neotoma) middens. The markers indicate extensive chemical modification by intestinal microbial communities of mammals. The observed defunctionalized phenols represent a group of natural products, and their structural elements reveal information about the plant source. The phenols are derived mainly from two precursor types: (1) enterolactone and derivatives from conifer lignans, and (2) 2,3-bis(3'-hydroxybenzyl)butane and related compounds from lignans such as nordihydroguaiaretic acid common in Larrea sp. (e.g. creosote bush). PMID- 24066520 TI - The influence of resveratrol on the synovial expression of matrix metalloproteinases and receptor activator of NF-kappaB ligand in rheumatoid arthritis fibroblast-like synoviocytes. AB - Medication of rheumatoid arthritis (RA) remains challenging and often controversial concerning side effects or long-term complications. We investigated the effect of resveratrol, a phytoalexin discussed for its chondro-protective and anti-inflammatory qualities, on the synovial expression of matrix-degrading enzymes like matrix metalloproteinases (MMPs) and bone-remodelling proteins in RA fibroblast-like synoviocytes (FLS). Interleukin-1beta-stimulated RA-FLS were treated with 100 microM resveratrol for 24 h. To evaluate the effect of resveratrol on the amount of bound/combined MMPs, a Luminex xMAP multiplexing technology was used. The alteration in expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegrin (OPG) was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Resveratrol reduced the expression of MMP-1 (p = 0.022), MMP-3 (p = 0.021), and MMP-9 (p = 0.047). qRT-PCR showed a significant reduction in the relative abundance of the transcripts of OPG (p = 0.012) and RANKL (p = 0.018). Our in vitro findings indicate that resveratrol could be a new target for further pharmacological studies in the field of RA. In the future it could play a role as a possible substitute or supplement to currently used drugs against RA to prevent cartilage matrix degradation and pathological bone resorption due to inhibition of MMPs and RANKL. PMID- 24066521 TI - Survey finds staffing patterns stable but positions hard to fill. PMID- 24066522 TI - Early action advisable to prepare for new alarm safety standards. PMID- 24066523 TI - OR Manager of the Year embraces golden rule. PMID- 24066524 TI - A steep price to pay: fatigue compromises staff and patient safety. PMID- 24066525 TI - Survey finds continued economic stress for ASCs. PMID- 24066526 TI - Sterile processing questions and answers. PMID- 24066527 TI - High labor expenses? Better staffing and scheduling can cut costs. PMID- 24066528 TI - Turnover rates plummet with patient care intern training program. PMID- 24066529 TI - [Vegetation biomass allocation and its spatial distribution after 20 years ecological restoration in a dry-hot valley in Yuanmou, Yunnan Province of Southwest China]. AB - By using layering harvest method, a comparative study was conducted on the biomass allocation and its spatial distribution of 20-year-old Eucalyptus camaldulensis plantation, Leucaena leucocephala plantation, and E. camaldulensis L. leucocephala plantation in Yuanmou dry-hot valley of Yunnan Province, Southwest China. The stand biomass in the mixed E. camaldulensis-L. leucocephala plantation (82.99 t x hm(-2)) was between that of monoculture E. camaldulensis plantation (60.64 t x hm(-2)) and L. leucocephala plantation (127.79 t x hm(-2)). The individual tree biomass of E. camaldulensis in the mixed plantation (44.32 kg) was 49.8% higher than that in monoculture plantation (29.58 kg). The branch and leaf biomass of L. leucocephala (25.4%) in monoculture plantation was larger than that of E. camaldulensis (8.9%) in monoculture plantation, and the aboveground biomass distribution ratio (78.0%) of L. leucocephala (25.4%) was also higher than that of E. camaldulensis (73.4%). The roots of L. leucocephala in both monoculture and mixed plantations were mainly distributed in 0-40 cm soil layer, while those of E. camaldulensis in monoculture and mixed plantations were mainly found in 0-80 cm and 0-60 cm, respectively. The proportion of biomass allocated to roots including medium roots, small roots, and fine roots of L. leucocephala in mixed plantation was higher than that in monoculture plantation, but it was contrary for E. camaldulensis. It was suggested that introducing L. leucocephala in E. camaldulensis plantation promoted the growth of E. camaldulensis, especially for its aboveground biomass, and increased the amount of lateral roots in 0-20 cm soil layer, which had significance in soil and water conservation in the study area. PMID- 24066530 TI - [Effects of thinning on fine-root morphology, biomass and N concentration of different branch orders of Chinese fir]. AB - Taking a 25-year old Chinese fir (Cunninghamia lanceolata) plantation as the object, this paper studied the effects of thinning on the biomass, morphological traits, and nitrogen concentration of the first five orders roots. With the increase of root order (from the first to the fifth order), there was a significant increase in the fine-root biomass, diameter, and tissue density, and a significantly decrease in the specific root length (SRL), root length density (RLD), and root number (RN). Thinning increased the biomass, RLD, and RN of the first and second orders roots as well as the tissue density of the first, third, fourth, and fifth orders roots significantly, but had no effects on the SRL and nitrogen concentration of each order root. In contrast, thinning decreased the diameter of the first, third, and fourth orders roots significantly. The diameter of the second order roots was obviously smaller in surface (0-10 cm) soil than in subsurface (10-20 cm) soil, while the RLD of the first three orders roots and the RN and nitrogen concentration of the first two orders roots were larger in surface soil than in subsurface soil. The interaction of thinning and soil layer only decreased the diameter of the first two orders roots. It was suggested that the fine-root biomass and morphological traits of Chinese fir were closely related to the vegetation growth and regeneration after thinning. PMID- 24066531 TI - [Effects of thinning intensity on the seed bank and seedling growth of Quercus variabilis on the south slope of Qinling Mountains, Northwest China]. AB - In August-November 2010 and August 2011, and taking the pure Quercus variabilis forests under close-to-natural management of different thinning intensity (30%, 20%, and 10%) in Shangluo district of south slope of Qinling Mountains as the object, an investigation was conducted on the seed amount of seed bank, the survival rate and growth status of seedlings, and their relationships with environmental factors 4-5 years after thinning. As compared with the control, the seed amount in the seed bank of 10%, 20%, and 30% thinning plots increased by 2.0%, 21.1%, and 34.8%, respectively in the fourth year after thinning, and the 1 year-old seedlings amount increased by 28.5%, 99.7%, and 122.2%, respectively in the next year. The survival rate of the seedlings in the 10%, 20%, and 30% thinning plots was increased by 25.5%, 235.7%, and 480.0%, respectively in the fifth year after thinning. Thinning improved the light, temperature, soil moisture, and soil nutrient conditions in the forests, which promoted the height- and new shoot growth and the leaf area index of each age seedlings. The three growth indices also increased with increasing thinning intensity. In the Q. variabilis forest with a canopy density of > or = 0.85, the thinning intensity 30% (canopy density 0.6) was most conducive to the seed germination and seedling growth. PMID- 24066532 TI - [Temperature sensitivity of CO2 fluxes from rhizosphere soil mineralization and root decomposition in Pinus massoniana and Castanopsis sclerophylla forests]. AB - Rhizospheric and non-rhizospheric soils and the absorption, transition, and storage roots were sampled from the mid-subtropical Pinus massoniana and Castanopsis sclerophylla forests to study the CO2 fluxes from soil mineralization and root decomposition in the forests. The samples were incubated in closed jars at 15 degrees C, 25 degrees C, 35 degrees C, and 45 degrees C, respectively, and alkali absorption method was applied to measure the CO2 fluxes during 53 days incubation. For the two forests, the rhizospheric effect (ratio of rhizospheric to non-rhizospheric soil) on the CO2 flux from soil mineralization across all incubation temperature ranged from 1.12 to 3.09, with a decreasing trend along incubation days. There was no significant difference in the CO2 flux from soil mineralization between the two forests at 15 degrees C, but the CO2 flux was significantly higher in P. massoniana forest than in C. sclerophylla forest at 25 degrees C and 35 degrees C, and in an opposite pattern at 45 degrees C. At all incubation temperature, the CO2 release from the absorption root decomposition was higher than that from the transition and storage roots decomposition, and was smaller in P. massoniana than in C. sclerophylla forest for all the root functional types. The Q10 values of the CO2 fluxes from the two forests were higher for soils (1.21-1.83) than for roots (0.96-1.36). No significant differences were observed in the Q10 values of the CO2 flux from soil mineralization between the two forests, but the Q10 value of the CO2 flux from root decomposition was significantly higher in P. massoniana than in C. sclerophylla forest. It was suggested that the increment of CO2 flux from soil mineralization under global warming was far higher than that from root decomposition, and for P. massoniana than for C. sclerophylla forest. In subtropics of China, the adaptability of zonal climax community to global warming would be stronger than that of pioneer community. PMID- 24066533 TI - [Canopy interception of Pinus tabulaeformis plantation on Longzhong Loess Plateau, Northwest China: characteristics and simulation]. AB - Taking the Pinus tabulaeformis plantation in the Anjiagou catchment on Longzhong Loess Plateau as test object, an observation was made on the characteristics of throughfall, stemflow, interception, and canopy structure of P. tabulaeformi during its growth season (from May to September) in 2011. Based on the observed data, the revised Gash analytical model was adopted to simulate the canopy interception, aimed to understand the ecological hydrological processes of Pinus tabulaeformis plantation and related mechanisms. In the observation period, a total of 19 precipitation events were observed, with a total precipitation of 215.80 mm. The throughfall, stemflow, and canopy interception were 165.24 mm, 2.29 mm, and 48.27 mm, occupying 76.7%, 1.1%, and 22.4% of the total precipitation, respectively. The simulated canopy interception was 41.24 mm, being 7.13 mm lower than the observed value and with a relative error of 14.7%. There were 33.8% and 60.0% of interception were evaporated from the canopy during and after precipitation, respectively. The revised Gash analytical model was highly sensitive to the canopy storage capacity, forest coverage, rainfall intensity, and evaporation, but less sensitive to the stemflow rate and stem water holding capacity. PMID- 24066534 TI - [CO2 response process and its simulation of Prunus sibirica photosynthesis under different soil moisture conditions]. AB - Taking the two-year old potted Prunus sibirica seedlings as test materials, and using CIRAS-2 photosynthetic system, this paper studied the CO2 response process of P. sibirica photosynthesis in semi-arid loess hilly region under eight soil moisture conditions. The CO2 response data of P. sibirica were fitted and analyzed by rectangular hyperbola model, exponential equation, and modified rectangular hyperbola model. Meanwhile, the quantitative relationships between the photosynthesis and the soil moisture were discussed. The results showed that the CO2 response process of P. sibirica photosynthesis had obvious response characteristics to the soil moisture threshold. The relative soil water content (RWC) required to maintain the higher photosynthetic rate (P(n)) and carboxylation efficiency (CE) of P. sibirica was in the range of 46.3%-81.9%. In this RWC range, the photosynthesis did not appear obvious CO2 saturated inhibition phenomenon. When the RWC exceeded this range, the photosynthetic capacity (P(n max)), CE, and CO2 saturation point (CSP) decreased evidently. Under different soil moisture conditions, there existed obvious differences among the three models in simulating the CO2 response data of P. sibirica. When the RWC was in the range of 46.3%-81.9%, the CO2 response process and the characteristic parameters such as CE, CO2 compensation point (see symbol), and photorespiration rate (R(p)) could be well fitted by the three models, and the accuracy was in the order of modified rectangular hyperbola model > exponential equation > rectangular hyperbola model. When the RWC was too high or too low, namely, the RWC was > 81.9% or < 46.3%, only the modified rectangular hyperbola model could well fit the CO2 response process and the characteristic parameters. It was suggested that when the RWC was from 46.3% to 81.9%, the photosynthetic efficiency of P. sibirica was higher, and, as compared with rectangular hyperbola model and exponential equation, modified rectangular hyperbola model had more applicability to fit the CO2 response data of P. sibirica photosynthesis under different soil moisture conditions. PMID- 24066535 TI - [Effects nutrients on the seedlings root hair development and root growth of Poncirus trifoliata under hydroponics condition]. AB - Ahydroponics experiment was conducted to study the effects of nutrients (N, P, K, Ca, Mg, Fe, and Mn) deficiency on the length of primary root, the number of lateral roots, and the root hair density, length, and diameter on the primary root and lateral roots of Poncirus trifoliata seedlings. Under the deficiency of each test nutrient, root hair could generate, but was mainly concentrated on the root base and fewer on the root tip. The root hair density on lateral roots was significantly larger than that on primary root, but the root hair length was in adverse. The deficiency of each test nutrient had greater effects on the growth and development of root hairs, with the root hair density on primary root varied from 55.0 to 174.3 mm(-2). As compared with the control, Ca deficiency induced the significant increase of root hair density and length on primary root, P deficiency promoted the root hair density and length on the base and middle part of primary root and on the lateral roots significantly, Fe deficiency increased the root hair density but decreased the root hair length on the tip of primary root significantly, K deficiency significantly decreased the root hair density, length, and diameter on primary root and lateral roots, whereas Mg deficiency increased the root hair length of primary root significantly. In all treatments of nutrient deficiency, the primary root had the similar growth rate, but, with the exceptions of N and Mg deficiency, the lateral roots exhibited shedding and regeneration. PMID- 24066536 TI - [Effects of relative abundance of Quercus mongolica acorns on five tree species seed dispersal in Xiaoxing' an Mountains, Northeast China]. AB - An investigation was conducted in a forest farm in the Xiaoxing' an Mountains in autumn, 2009 and 2010 to study the effects of Quercus mongolica acorn quantity and rodent density on the seed dispersal of five tree species (Juglans mandshurica, Pinus koraiensis, Corylus mandshurica, Corylus heterophylla, and Q. mongolica). In the farm, there was an annual change in rodent density. The total capture rate of small rodents in 2009 (31.0%) was significantly higher than that in 2010 (16.7%). The acorn quantity and relative seed abundance (per capita rodent) of Quercus mongolica in 2009 (6.2 +/- 2.1 acorns x m(-2) and 20.0, respectively) were significantly lower than those in 2010 (26.7 +/- 10.2 acorns x m(-2) and 160.0, respectively). In 2009, all the seeds of the five tree species except J. mandshurica were dispersed or eaten in situ, among which, the acorns of Q. mongolica were scatter-hoarded most, and their average dispersal distance was the furthest. In 2010, the seeds of J. mandshurica were scatter-hoarded most, and their average dispersal distance was the furthest. The relative seed abundance of Q. mongolica could be the key factor determining the seed dispersal of the other tree species in the study area. PMID- 24066537 TI - [Interannual variation patterns of heavy metals concentrations in tree rings of Larix gmelinii near Xilin Lead-zinc Mine, Yichun of Northeast China]. AB - By using dendro-environmental methods, this paper measured and analyzed the variations of five heavy metals (Pb, Cd, Zn, Cu, and Mn) concentrations in the tree rings of Larix gmelinii near Xilin Lead-zinc Mine, Yichun of Northeast China. Among the test heavy metals, the Mn concentration in the tree rings was the highest, while the Cd concentration was the lowest. The Cd, Zn, and Cu concentrations in the tree rings near the ground (0.3 m high from the ground, D0.3) were significantly higher than those at breast height (1.3 m high from the ground, D1.3), while the Pb and Mn concentrations at the two heights had less difference. In 1987-2010, the Pb concentration in the tree rings had a slight increase, but the Cd, Zn, Cu, and Mn concentrations presented a decreasing trend. The Cd concentration decreased most obviously, while the Zn, Cu, and Mn concentrations decreased after an initial increase. With the increase of tree ring width, the Pb concentration decreased, while the Cd, Zn, Cu, and Mn concentrations were in adverse. The relationships between the Pb and other four heavy metals concentrations in the tree rings near the ground and at breast height had definite differences. Near the ground, the Pb concentration showed a significant positive correlation with the other four heavy metals concentrations, but at breast height, less correlation was observed, and even, the Cd concentration decreased significantly with increasing Pb concentration. The variations of the heavy metals concentrations in the L. gmelinii tree rings could be affected by the production and mining activities of Xilin Lead-zinc Mine, an thus, it would be possible to use the Pb concentration in the tree rings to reconstruct the mining his tory of the study area. At present, the Pb concentration in the tailing wastes has polluted the surrounding environments near Xilin Lead-zinc Mine. Therefore, countermeasures should be adopted to manage the heavy metals in tailing wastes if the Mine would be continued to be mined. PMID- 24066538 TI - [Effects of temperature on CH4 emission from subtropical common tree species leaves]. AB - Laboratory incubation test was conducted to study the effects of temperature on the CH4 emission from the leaves of subtropical common tree species Castanopsis carlesii, Schima superb, Cinnamomum chekiangense, Castsanopsis fabri, Cunninghamia lanceolata, and Citrus reticulata. Among the six tree species, only S. superb, C. reticulate, and C. fabri emitted CH4 at 10 degrees C. At above 20 degrees C, all the six species emitted CH4, and the average CH4 emission rate at above 30 degrees C (1.010 ng CH4 x g(-1) DM x h(-1)) was 2.96 times higher than that at 10-30 degrees C (0.255 ng CH4 x g(-1) DM x h(-1)). Moreover, increasing temperature had much more effects on the CH4 emission rate of C. reticulata and C. lanceolata than on that of the other four tree species. Incubation time affected the CH4 emission rate of all test tree species significantly, suggesting that the effects of temperature stress on the CH4 emission could be controlled by plant activity. Dry leaves could not emit CH4 no matter the temperature was very high or low. It was suggested that high temperature stress had important effects on the CH4 emission from subtropical tree leaves, and global warming could increase the CH4 emission from plants. PMID- 24066539 TI - [Quality level assessment of lowly efficient Tamarix chinensis secondary shrubs in Laizhou Bay of Yellow River Delta]. AB - Taking the Tamarix chinensis secondary shrubs in Laizhou Bay of Yellow River Delta as test objects, and by using synthetic factor method, this paper studied the main factors causing the lowly efficiency of T. chinensis secondary shrubs as well as the main parameters for the classification of lowly efficient T. chinensis secondary shrubs. A total of 24 indices including shrubs growth and soil physical and chemical properties were selected to determine the main affecting factors and parameters in evaluating and classifying the lowly efficient shrubs. There were no obvious correlations between the indices reflecting the shrubs growth and soil quality, and thus, only using shrub growth index to reflect the lowly efficiency level of T. chinensis was not enough, and it would be necessary to combine with soil quality factors to make a comprehensive evaluation. The principal factors reflecting the quality level of lowly efficient T. chinensis shrubs included soil salt content and moisture content, stand age, single tree's aboveground stem, leaf biomass, and basal diameter, followed by soil density, porosity, and soil nutrient status. The lowly efficient T. chinensis shrubs in the Bay could be classified into five types, namely, shrub with growth potential, slightly low quality shrub, moderately lowly efficient shrub, moderately low quality and lowly efficient shrub, and seriously low quality and lowly efficient shrub. The main features, low efficiency causes, and management measures of these shrubs were discussed based on the mean cluster value. PMID- 24066540 TI - [Butterfly diversity and faunal characteristics on the south slope of Taibai Mountain, Shaanxi Province of Northwest China]. AB - An investigation was conducted on the butterflies on the south slope of Taibai Mountain from April to October, 2009, with their diversity index, evenness index, dominance index, and species richness calculated and analyzed. A total of 126 species were recorded, belonging to 77 genera and 5 families. Nymphalidae had the highest diversity index (3.3621) and species richness (9.9363), and Pieridae had the highest dominance index (0.0573) and evenness index (0.8352). The genera and species were most abundant in June-August, the diversity index was the highest in July (3.4094), and the species richness was the highest in August (10.7). The bio geographic component analysis of 124 species (other 2 species were not identified) showed that the widely distributed species were most abundant (51 species), occupying 40.5% of the total, followed by Palaearctic species (41 species), occupying 32.5%, and Oriental species were the least (32 species), occupying 25.4%, which suggested that Taibai Mountain could be the transitional area of Palearctic and Oriental regions. The comparative analysis of the butterfly diversity and faunal characteristics on the south and north slopes of Taibai Mountain showed that there were 85 shared species, and the similarity coefficient was 62.0%, indicating that the butterfly fauna had definite difference between the two slopes though they were geographically in proximity. PMID- 24066541 TI - [Prediction models for ground surface fuels moisture content of Larix gmelinii stand in Daxing'anling of China based on one-hour time step]. AB - By using the equilibrium moisture content-time lag methods of Nelson and Simard and the meteorological element regression method, this paper studied the dynamics of the moisture content of ground surface fine dead fuels under a Larix gmelinii stand on the sunny slope in Daxing' anling with a time interval of one hour, established the corresponding prediction models, and analyzed the prediction errors under different understory densities. The results showed that the prediction methods of the fuels moisture content based on one-hour time step were applicable for the typical Larix gmelinii stand in Daxing' anling. The mean absolute error and the mean relative error of Simard method was 1.1% and 8.5%, respectively, being lower than those of Nelson method and meteorological element regression method, and close to those of similar studies. On the same slopes and slope positions, the fuel moisture content varied with different understory densities, and thus, it would be necessary to select the appropriate equilibrium moisture content model for specific regional stand and position, or establish the fuel moisture content model based on specific stand when the dynamics of fuel moisture content would be investigated with a time interval of one hour. PMID- 24066542 TI - [Effects of rice straw returning mode on rice grain yield and soil carbon pool management index in double rice-cropping system]. AB - A 2-year field experiment was conducted to study the effects of different rice straw returning modes on the rice grain yield and soil carbon pool management index (CPMI) in a double rice-cropping system. Four treatments were installed, including balanced mineral fertilization (NPK), NPK plus cut rice straw returning (SNPK), NPK plus incinerated rice straw returning (SINPK), and no fertilization (CK). In treatments SNPK and SINPK, the 2 years average grain yield of early rice and late rice was basically the same, and much higher than that in treatment NPK, with an increment of 5.7%-7.3%. As compared with treatments NPK and SINPK, treatment SNPK increased the grain yield of early rice significantly by 3.8% 8.8%, and enhanced the contents of various soil carbon forms and the soil CPMI, with the soil total organic carbon, active carbon, mineralized carbon contents, and the soil CPMI increased by 1.8%-2.0%, 5.9%-6.5%, 16.0%-41.6%, and 7.3%-7.8%, respectively. There was a significant parabolic correlation between soil CPMI and rice grain yield (r = 0.999 and r = 0.980 in early- and late-rice season, respectively). Treatment SNPK also increased the grain yield, the contents of various soil carbon forms, and the soil CPMI in the next early rice season. PMID- 24066543 TI - [Optimum field observation data for simulating maize leaf area index]. AB - Leaf area index is a key indicator of leaf area change of crop population, and also, an important parameter for studying crop photosynthesis, transpiration, and biomass formation, etc. How to establish an optimum leaf area index (LAI) dynamic model with the minimum field observation data is of great significance for accurately simulating crop growth and yield. Based on the field experiment data of various spring maize varieties from the Jinzhou Agricultural Ecosystem Research Station in Northeast China in 2005-2011, in combination with the universal maize LAI dynamic model, this paper discussed the optimum field observation data for accurately simulating the dynamics of maize LAI. It was suggested that for the accurate simulation of the dynamics of maize LAI, the field observation should be no less than 3 years, with at least 4 times observation during the growth period each year. The proper four observation times during maize growth period were suggested as about 20 d after seedling emergence for the first observation, and monthly thereafter for the other three observations. This study could provide reference for conducting an effective observation on leaf area index and its dynamic modeling. PMID- 24066544 TI - [Effects of drought stress on the root growth and development and physiological characteristics of peanut]. AB - Taking two peanut varieties Huayu 17 and Tangke 8 as test objects, a soil column culture experiment was conducted in a rainproof tank to study the peanut root morphological development and physiological characteristics at late growth stages under moderate drought and well-watered conditions. Tanke 8 had more developed root system and higher yield and drought coefficient, while Huayu 17 had poorer root adaptability to drought stress. For the two varieties, their root length density and root biomass were mainly distributed in 0-40 cm soil layer, whereas their root traits differed in the same soil layer. The total root length, total root surface area, and total root volume of Huayu 17 at each growth stage were smaller under drought stress than under well-balanced water treatment, while these root characteristics of Tangke 8 under drought stress only decreased at flowering-pegging stage. Drought stress increased the root biomass, surface area, and volume of the two varieties in 20-40 cm soil layer, but decreased these root traits in the soil layers below 40 cm. Under drought stress, the root activity of the two varieties in the soil layers below 40 cm at pod filling stage decreased, and the decrement was larger for Huayu 17. The differences in the root system development and physiological characteristics of the two varieties at late growth stages under drought stress suggested that the root system of the two varieties had different water absorption and utilization under drought stress. PMID- 24066545 TI - [Effects of different accumulated temperature on photosynthetic performances of spring maize varieties during grain-filling period]. AB - Taking cold-resistant maize variety Fengdan 3 and cold-sensitive maize variety Zhengdan 958 as test materials, field experiments were conducted in I, II, and III accumulated temperature zones in Heilongjiang Province of Northeast China to study the effects of different accumulated temperature on the photosynthetic performances of different types of cold-resistant spring maize varieties during their grain-filling period. In the three accumulated temperature zones, the tasseling and maturing periods of Fengdan 3 and Zhengdan 958 were prolonged in the order of I > II > and III, and the grain bulk density decreased in the same order. The RuBPCase and PEPCase activities of Fengdan 3 and Zhengdan 958 leaves had different temperature sensitivity. For Fengdan 3, its leaf RuBPCase and PEPCase activities were high in early grain filling period (0-20 days after anthesis), and the variety could ripen in temperature-limited region. For Zhengdan 958, its leaf RuBPCase and PEPCase activities were high within 0-10 days and 40-60 days after anthesis but not sensitive to the active accumulated temperature during 10-40 days after anthesis, and the variety could not ripen in temperature-limited region. The photosynthetic rates of the two varieties were significantly positively correlated with the active accumulated temperature during 0-10 days and 30-40 days after anthesis. The effects of the accumulated temperature in the three zones on the photosynthetic performances were significant at both early and later grain filling stages. For the same varieties, the higher the active accumulated temperature in grain filling period, the higher the grain yield. Zhengdan 958 had higher yield than Fengdan 3. PMID- 24066546 TI - [Change characteristics of soil moisture and nutrients in rain-fed winter wheat field under different fertilization modes in Southern Shanxi of China during summer fallow period]. AB - In 2009-2011, a field experiment was conducted in a rain-fed winter wheat field in Southern Shanxi of China to study the effects of different fertilization modes on the change characteristics of soil moisture and nitrate-N contents in 0-200 cm layer and of soil available phosphorus (Oslen-P) and potassium contents in 0-40 cm layer during summer fallow period (from June to September). Three fertilization modes were installed, i. e., conventional fertilization (CF), recommended fertilization (RF), and ridge film furrow planting (RFFP) combined with straw mulch. The results showed that the rainfall in summer fallow period could complement the consumed water in 0-200 cm soil layer in dryland wheat field throughout the growth season, and more than 94% of the water storage was in 0-140 cm soil layer, with the fallow efficiency ranged from 6% to 27%. The rainfall in summer fallow period caused the soil nitrate-N moving downward. 357-400 mm rainfall could make the soil nitrate-N leaching down to 100 cm soil layer, with the peak in 20-40 cm soil layer. Straw mulching or plastic film with straw mulch in summer fallow period could effectively increase the Oslen-P and available K contents in 0-40 cm soil layer, and the accumulative increment in three summer fallow periods was 16-45% and 36-49%, respectively. Among the three modes, the binary coverage mode of RFFP plus furrow straw mulching had the best effect in maintaining soil water and fertility. The accumulative water storage and mineral N in 0-200 cm soil layer in three summer fallow periods were up to 215 mm and 90 kg x hm(-2), and the accumulative Oslen-P and available K contents in plough layer were increased by 2.7 mg x kg(-1) and 83 mg x kg(-1), respectively, being significantly higher than those in treatments CF and RF. There were no significant differences in the change characteristics in the soil moisture and nutrients between treatments CF and RF. PMID- 24066547 TI - [Relationships of wheat leaf stomatal traits with wheat yield and drought resistance]. AB - Taking the DH population of wheat cultivar Hanxuan10/Lumai14 as test object, and by the methods of correlation analysis and path analysis, this paper studied the relationships of the flag leaf stomatal density (SD), stomatal length and width (SL and SW), stomatal conductance (g(s)), photosynthetic rate (P(n)), and transpiration rate (T(r)) on the 10th and 20th day after anthesis with the yield and the index of drought-resistance under the conditions of drought stress and normal irrigation. Under the two conditions, most of the test leaf traits on the 10th day after anthesis had less correlation with the yield and the index of drought-resistance, whereas the leaf traits on the 20th day after anthesis had significant positive correlations with thousand kernel weight but less correlation with grain number per ear, grain yield per plant, and index of drought-resistance. Path analysis showed that g(s), P(n), and T(r) were the main factors affecting the grain yield per plant (YPP) and the index of drought resistance (IDR), and the effects were stronger both in direct and in indirect ways. The direct and indirect effects of SD, SL, and SW on the YPP and IDR were lesser. Under both drought stress and normal irrigation, and on the 10th and 20th day after anthesis, there were significant correlations between SD and SL, and between SL and SW, g(s), P(n), and Tr, but the correlations of SD and SL with g(s), P(n), and T(r) changed with water condition or growth stage. Therefore, it would be not always a good means to select the leaf stomatal density and size as the targets for breeding to improve the leaf stomatal conductance, photosynthetic rate, and transpiration rate, and further, to promote the yield. PMID- 24066548 TI - [Effects of applying tea seed meal and EDTA on the speciation transformation and phyto-availability of nickel and zinc in soil]. AB - A pot experiment with sugarcane was conducted to study the effects of applying tea seed meal and EDTA on the speciation transformation and phyto-availability of nickel (Ni) and zinc (Zn) in soil. With the increasing application rate of tea seed meal, the biomass of sugarcane root, stem, and leaf increased gradually, but no significant difference was observed in the stem and leaf biomass between EDTA treatments and the control. Applying tea seed meal and EDTA increased the acid soluble Ni and Zn contents in soil, and promoted the bioconcentration and translocation of Ni and Zn in sugarcane. Meanwhile, the strengthening effect increased gradually with the increasing application rate of tea seed meal. As compared with EDTA, tea seed meal was more efficient in improving the accumulation of Ni and Zn in sugarcane, and thus, made the sugarcane remove more Ni and Zn from soil. The Ni and Zn contents in sugarcane stem and leaf had significant positive correlations with the application rate of tea seed meal, while the Ni and Zn contents in sugarcane root were significantly negatively correlated with the application rate of tea seed meal. PMID- 24066549 TI - [Effects of simulated acid rain on seed germination and seedling growth of different type corn Zea mays]. AB - Taking normal corn, waxy corn, pop corn, and sweet corn as test materials, this paper studied their seed germination and seedling growth under effects of simulated acid rain (pH 6.0, 5.0, 4.0, 3.0, 2.0, and 1.0). Simulated acid rain at pH 2.0-5.0 had no significant effects on the seed germination and seedling growth, but at pH 1.0, the germination rate of normal corn, waxy corn, pop corn, and sweet corn was 91.3%, 68.7%, 27.5%, and 11.7%, respectively. As compared with those at pH 6.0 (CK), the germination rate, germination index, vigor index, germination velocity, shoot height, root length, shoot and root dry mass, and the transformation rate of stored substances at pH 1.0 had significant decrease, and the average germination time extended apparently. At pH 1.0, the effects of acid rain were greater at seedling growth stage than at germination stage, and greater on underground part than on aboveground part. Due to the differences in gene type, normal corn and waxy corn had the strongest capability against acid rain, followed by pop corn, and sweet corn. It was suggested that corn could be categorized as an acid rain-tolerant crop, the injury threshold value of acid rain was likely between pH 1.0 and pH 2.0, and normal corn and waxy corn would be prioritized for planting in acid rain-stricken area. PMID- 24066550 TI - [Effects of biological organic fertilizer on microbial community's metabolic activity in a soil planted with chestnut (Castanea mollissima)]. AB - A field experiment was conducted in Zhashui County of Shaanxi Province, Northwest China in 2011 to study the effects of biological organic fertilizer on the microbial community's metabolic activity in a soil planted with chestnut (Castanea mollissima). Three treatments were installed, i. e., control, compound fertilizer, and biological organic fertilizer. Soil samples were collected at harvest, and the metabolic activity was tested by Biolog method. In the treatment of biological organic fertilizer, the average well color development, Shannon evenness, richness, and McIntosh indices of microbial community were all significantly higher than the other two treatments. As compared with the control, applying biological organic fertilizer improved the ability of soil microbes in utilizing the carbon sources of carbohydrates and polymers, while applying compound fertilizer was in opposite. The principal component analysis demonstrated that there was an obvious difference in the soil microbial community among different treatments, mainly depending on the species of carbohydrates and amino acids. PMID- 24066551 TI - [Effects of adding straw carbon source to root knot nematode diseased soil on soil microbial biomass and protozoa abundance]. AB - A field experiment with successive planting of tomato was conducted to study the effects of adding different amounts of winter wheat straw (2.08 g x kg(-1), 1N; 4.16 g x kg(-1), 2N; and 8.32 g x kg(-1), 4N) to the soil seriously suffered from root knot nematode disease on the soil microbial biomass and protozoa abundance. Adding straw carbon source had significant effects on the contents of soil microbial biomass carbon (MBC) and microbial biomass nitrogen (MBN) and the abundance of soil protozoa, which all decreased in the order of 4N > 2N > 1N > CK. The community structure of soil protozoa also changed significantly under straw addition. In the treatments with straw addition, the average proportion of fagellate, amoeba, and ciliates accounted for 36.0%, 59.5%, and 4.5% of the total protozoa, respectively. Under the same adding amounts of wheat straw, there was an increase in the soil MBC and MBN contents, MBC/MBN ratio, and protozoa abundance with increasing cultivation period. PMID- 24066552 TI - [Effects of different vegetation restoration patterns on the diversity of soil nitrogen-fixing microbes in Hulunbeier sandy land, Inner Mongolia of North China]. AB - By using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR DGGE) and sequence analysis, this paper studied the nifH gene diversity and community structure of soil nitrogen-fixing microbes in Hulunbeier sandy land of Inner Mongolia under four years management of five vegetation restoration modes, i. e., mixed-planting of Agropyron cristatum, Hedysarum fruticosum, Caragana korshinskii, and Elymus nutans (ACHE) and of Agropyron cristatum and Hedysarum fruticosum (AC), and mono-planting of Caragana korshinskii (UC), Agropyron cristatum (UA), and Hedysarum fruticosum (UH), taking the bare land as the control (CK). There existed significant differences in the community composition of nitrogen-fixing microbes among the five vegetation restoration patterns. The Shannon index of the nifH gene was the highest under ACHE, followed by under AC, UC, UA, and UH, and the lowest in CK. Except that UH and CK had less difference in the Shannon index, the other four vegetation restoration modes had a significantly higher Shannon index than CK (P < 0.05). The phylogenetic analysis showed that the soil nitrogen-fixing microbes under UA, UH, and UC were mainly of cyanobacteria, but the soil nitrogen-fixing microbes under AC and ACHE changed obviously, mainly of proteobacteria, and also of cyanobacteria. The canonical correlation analysis showed that the soil total phosphorus, available phosphorus, total nitrogen, and nitrate nitrogen contents under the five vegetation restoration modes had significant effects on the nitrogen-fixing microbial communities, and there existed significant correlations among the soil total phosphorus, available phosphorus, total nitrogen, and nitrate nitrogen. It was suggested that the variations of the community composition of soil nitrogen fixing microbes under the five vegetation restoration modes were resulted from the interactive and combined effects of the soil physical and chemical factors. PMID- 24066553 TI - [Exposure degree of important non-target arthropods to Cry2Aa in Bt rice fields]. AB - Based on the principle of "risk = hazard x exposure", the selected representative nontarget organisms in the assessment of the potential effects of insect resistant genetically modified (GM) crops on non-target arthropods in laboratory are generally the arthropod species highly exposed to the insecticidal proteins expressed by the GM crops in farmland ecosystem. In order to understand the exposure degree of the important arthropod species to Cry proteins in Bt rice fields, and to select the appropriate non-target arthropods in the risk assessment of insect-resistant GM crops, the enzyme-linked immunosorbent assay (ELISA) was conducted to measure the Cry2Aa protein concentration in the arthropods collected from the cry2Aa rice fields at different rice growth stages. The results showed that there was a significant difference in the Cry2Aa content protein concentration in different arthropod species. Some species did not contain Cry2Aa protein, while some species contained larger amounts of Cry2Aa protein. Relative to the arthropods colleted after rice anthesis, the arthropods colleted in rice anthesis contained relative higher concentrations of Cry2Aa protein, especially for the predacious arthropods. No Cry proteins were detected in parasitic arthropods. This study provided references for the laboratory assessment of the effects of GM rice on nontarget arthropods. PMID- 24066554 TI - [Land use pattern of Dalian City, Liaoning Province of Northeast China based on CA-Markov model and multi-objective optimization]. AB - Based on the land use/cover maps of 1990, 2000, and 2010, topographic factors, and geographic elements, a CA-Markov model consisting of Markov transition matrix, multi-criteria evaluation, and cellular automata was developed to simulate the change trends of the future land use and landscape patterns of Dalian, Liaoning Province. The future land use pattern of Dalian was optimally allocated by the method of fuzzy multi-objective programming, based on the characters of land use structure, society, economy, and natural environment. The results indicated that in 1990-2010, the rapid development of Dalian showed the characteristics of the continued expansion of urban area and the reduction of cropland and woodland area. With the present speed of urban development, the landscape pattern and land use cover would have a great change, and the landscape fragmentation would be exacerbated. To optimize the land use structure could meet the demand of the future sustainable development of Dalian. PMID- 24066555 TI - [Relationships of wetland landscape fragmentation with climate change in middle reaches of Heihe River, China]. AB - Based on the 1975-2010 multi-temporal remotely sensed TM and ETM images and meteorological data, in combining with wavelet analysis, trend surface simulation, and interpolation method, this paper analyzed the meteorological elements' spatial distribution and change characteristics in the middle reaches of Heihe River, and elucidated the process of wetland landscape fragmentation in the study area by using the landscape indices patch density (PD), mean patch size (MPS), and patch shape fragment index (FS). The relationships between the wetland landscape fragmentation and climate change were also approached through correlation analysis and multiple stepwise regression analysis. In 1975-2010, the overall distribution patterns of precipitation and temperature in the study area were low precipitation in high temperature regions and high precipitation in low temperature regions, and the main characteristics of climate change were the conversion from dry to wet and from cold to warm. In the whole study period, the wetland landscape fragmentation was mainly manifested in the decrease of MPS, with a decrement of 48.95 hm2, and the increase of PD, with an increment of 0.006 ind x hm(-2). PMID- 24066556 TI - [Variation patterns of soil wall temperature and heat flux in sunken solar greenhouse]. AB - From December 2011 to March 2012, a consecutive test was conducted on the temperature and heat flux of different thickness of the soil backwall of sunken solar greenhouse in Shouguang of Shandong Province, East China, aimed to analyze the variation patterns of soil wall temperature and heat flux of the sunken solar greenhouse and to confirm the suitable wall thickness. In winter, the temperature and heat flux of the wall inner surface and outer surface varied over a wide range, which was in accordance with the variation trend of indoor and outdoor air temperature. Overall, the wall temperature decreased from the inner to the outer surface, and the layers of the inner wall with higher variation range of temperature and heat flux were more than those of the outer wall. The variation range of temperature and heat flux decreased gradually from the shallow layers to deep layers of the wall. In successive cloudy days, the temperature of each layer of inner wall decreased to different degrees, and the layers releasing heat to the indoor deepened constantly, whereas the heat in the layers of outer wall was mainly released to the outdoor. According to the variation patterns of temperature and heat flux in the wall, the wall from inside to outside could be divided into heat storage layer, transitional layer, and cold resistant layer, and their thickness was 0.8-1.0 m, 2.2-2.6 m, and 0.4-0.6 m, respectively, under the condition of the outer surface being covered. Without considering the transitional layer, the suitable thickness of the soil wall in Shouguang solar greenhouse would be 1.4-1.6 m. PMID- 24066557 TI - [Relationships between urbanization and water resource utilization in Dongting Lake District of South-central China]. AB - By using analytic hierarchy process and entropy method, the evaluation index system and the response relationship model of comprehensive development level of urbanization and comprehensive development and utilization potential of water resources in Dongting Lake District were constructed, with the key affecting factors, their change characteristics, and response characteristics from 2001 to 2010 analyzed. During the study period, the Dongting Lake District was undergoing a rapid development of urbanization, and at a scale expansion stage. The economic and social development level was lagged behind the population and area increase, and the quality and efficiency of urbanization were still needed to be improved. With the advance of urbanization, the water consumption increased yearly, and the water resources utilization efficiency and management level improved steadily. However, the background condition of water resources and their development and utilization level were more affected by hydrological environment rather than urbanization. To a certain extent, the development of urbanization in 2001, 2002, 2005, 2006, 2007, 2009 was slowed down by the shortage of water resources. At present, Dongting Lake region was confronted with the dual task of improving the level and quality of urbanization, and hence, it would be necessary to reform the traditional epitaxial expansion of urbanization and to enhance the water resource support capability. PMID- 24066558 TI - [Annual changes of phytoplankton's ecological features in Qinzhou Bay of South China]. AB - Four cruise surveys were conducted on the phytoplankton in Qinzhou Bay of South China in different seasons in 2008-2009. A total of 131 phytoplankton species were identified, among which, diatom (101 species) accounted for 30.0% of the total, followed by pyrrophyta (23 species), and other groups (7 species). Most of the phytoplankton was of eurytherm or warm-water species. The total species number and the diatom abundance were the smallest in spring, and increased successively in summer, autumn, and winter, being the highest in winter. The phytoplankton density varied from 232.28 x 10(4) cell x m(-3) to 977.0 x 10(4) cell x m(-3), with an average of about 558.57 x 10(4) cell x m(-3). Temporally, the phytoplankton density was the highest in summer, followed by in spring, and the lowest in winter and autumn. Spatially, the phytoplankton density was increased from the inner bay to the open bay, and decreased from the open bay to outside the bay. In summer, the highest density area switched from the open bay to the bay' s entrance. The average Shannon diversity index was 3.18, and the average evenness index was 0.63, suggesting a high diversity of the phytoplankton community. The correlations of the phytoplankton density with the water temperature, salinity, dissolved inorganic phosphorus, and dissolved inorganic phosphorus varied with seasons. PMID- 24066559 TI - [Active carbon from Thalia dealbata residues: its preparation and adsorption performance to crystal violet]. AB - By using phosphoric acid as activation agent, active carbon was prepared from Thalia dealbata residues. The BET specific surface area of the active carbon was 1174.13 m2 x g(-1), micropore area was 426.99 m2 x g(-1), and average pore diameter was 3.23 nm. An investigation was made on the adsorption performances of the active carbon for crystal violet from aqueous solution under various conditions of pH, initial concentration of crystal violet, contact time, and contact temperature. It was shown that the adsorbed amount of crystal violet was less affected by solution pH, and the adsorption process could be divided into two stages, i. e., fast adsorption and slow adsorption, which followed the pseudo second-order kinetics model. At the temperature 293, 303, and 313 K, the adsorption process was more accordance with Langmuir isotherm model, and the maximum adsorption capacity was 409.83, 425.53, and 438.59 mg x g(-1), respectively. In addition, the adsorption process was spontaneous and endothermic, and the randomness of crystal violet molecules increased. PMID- 24066560 TI - [Distribution characteristics and correlations of phosphorus in sediment and interstitial water of Nansi Lake, Shandong Province of East China in summer and winter]. AB - By using cylindrical sediment sampler and Peeper' s interstitial water sampler, the intact sediment and interstitial water were collected from different zones of Nansi Lake in Shandong Province in summer and winter. The distribution characteristics of the sediment phosphorus forms and of the phosphate (PO4(3-)-P) in interstitial water were analyzed, and their correlations were discussed. In the sediments of Nansi Lake, phosphorus was richer, and had a significant spatial differentiation, with an overall decreasing trend from north to south, which was related to the seriously polluted Northern Nansi Lake near Jining City. Among the phosphorous forms, inorganic phosphorus (IP) had the highest concentration, accounting for 52.3%-87.2% and 60.6%-88.3% of the total phosphorus (TP) in summer and winter, respectively. The TP concentrations in 5 cm surface sediment of four sub-lakes were all higher in summer than in winter, which could be related to the human activities such as exuberant aquaculture, more chemical fertilizers application around lake, and frequent tourism activities, etc. in summer. In vertical direction, the PO4(3-)-P concentration in interstitial water decreased after an initial increase in summer and winter, and was obviously higher in summer than in winter, suggesting that the phosphorous in sediment had a higher potential to release to the overlying water in summer. The organic phosphorus (OP) and IP in sediment had a significant correlation in summer but less correlation in winter, indicating that the transformation between sediment IP and OP was more active in summer than in winter. The iron and aluminum bound phosphorus (Fe/Al-P) and IP in sediment were significantly positively correlated with the PO4(3-)-P in interstitial water. In summer and winter, the average PO4(3 )-P concentration in interstitial water collected by Peeper' s interstitial water sampler was about 20%-50% higher than that collected by the conventional centrifugal method, suggesting that using Peeper' s interstitial water sampler could be more precise. PMID- 24066561 TI - [Fish community structure and its relationships with environmental factors in Haizhou Bay and adjacent waters of East China in winter]. AB - Based on the bottom trawl survey and environmental investigation data in December 2011, and by using species diversity indices and multi-element analysis, this paper studied the species composition, species diversity, and spatial pattern of fish community as well as their relationships with environmental factors in Haizhou Bay and adjacent waters. A total of 60 fish species were captured, belonging to 51 genera, 34 families, and 10 orders, and mainly composed of warm temperature and warm water demersal fishes. The Margalef species richness index, Shannon diversity index, and Pielou evenness index ranged from 1.14 to 2.84, 1.08 to 2.64, and 0.41 to 0.83, respectively. Cluster analysis and non-metric multidimensional scaling (MDS) analysis showed that the fish community could be spatially clustered into three groups. Group I was in the north of 35 N, group II was in the inshore waters near bay-head, and group III was in the south of 35 degrees N. ANOSIM analysis showed that there existed highly significant differences (R = 0.45-0.91) in the fish species composition among the groups. The canonical correspondence analysis (CCA) indicated that the bottom water temperature, water depth, and sea surface salinity were the most important environmental variables affecting the spatial pattern of fish community in Haizhou Bay and adjacent waters in winter. PMID- 24066562 TI - [Influence of 175-m-impoundment in Three Gorges Reservoir area on the food web energy sources of main commercial fishes in backwater area of xiaojiang River]. AB - The impoundment in the Three Gorges Reservoir Area (TGRA) was first reached 175 m in 2010. To approach the influence of this impoundment on the food web energy sources of fishes in the tributaries of TRGA, an analysis was made on the food web energy sources of seven economically important fishes (Carassius auratus, Cyprinus carpio, Silurus asotus, Culter mongolicus mongolicus, Mystus macropterus, Pelteobagrus vachelli, and Pelteobagrus nitidus) in the backwater area of Xiaojiang River by using stable isotope method in combining with IsoSource Model. The results showed that before this impoundment (July 2010), microalgae were the main energy sources for the seven species. After this impoundment (December 2010), the contribution ratio of the microalgae decreased somewhat, while the relative contribution of terrestrial C4 plants had an obvious increase. Especially for crucian carp (C. auratus) and catfish (S. asotus), the contribution rate of the C4 plants reached 38-54% and 32-50%, respectively. After the impoundment, at least 30% of the energy resources of these two fishes were come from terrestrial C4 plants, suggesting that the impoundment in TGRA increased the contribution rate of exogenous terrestrial C4 plants as the energy sources of fishes. PMID- 24066563 TI - [Statistical characteristic analysis of soil PAHs in a coking contaminated site of China]. AB - Statistical characteristic analysis of pollutants in contaminated sites can help identify the origin, generation, and spatial variation of different pollutants, and can reduce the uncertainty of site survey data. Taking a large and abandoned contaminated coking site of China as the object, 114 surface (0-50 cm) soil samples were collected, with the statistical and spatial characteristics of 16 priority PAHs (sigmaPAHs) analyzed. The descriptive statistical analysis indicated that the sigmaPAH levels varied significantly, and the data were severely skewed. The correlation matrix (CM) and principal component analysis (PCA) showed that the extracted first two principal components (PCs) could effectively represent the whole site pollution data. Four pollutants, i. e., Baa, Bbf&Bkf, Bap, and Inp, were selected for trend analysis and spatial local variance analysis. In the east-west and north-south directions of the site, the pollution showed a low-high-low trend. The variation coefficient of pollution for the site was higher in the central, northwest, and southwest regions, while lower in the other regions. PMID- 24066564 TI - [Ecological vulnerability of coal mining area: a case study of Shengli Coalfield in Xilinguole of Inner Mongolia, China]. AB - In this paper, an ecological vulnerability evaluation index system for the Shengli Coalfield in Xilinguole of Inner Mongolia was established, which included 16 factors in ecological sensitivity, natural and social pressure, and ecological recovery capacity, respectively. Based on the expert scoring method and analytic hierarchy process (AHP), an ecological vulnerability model was built for the calculation of the regional ecological vulnerability by means of RS and GIS spatial analysis. An analysis of the relationships between land use and ecological vulnerability was also made, and the results were tested by spatial auto-correlation analysis. Overall, the ecological vulnerability of the study area was at medium-high level. The exploitation of four opencast areas in the Coalfield caused a significant increase of ecological vulnerability. Moreover, due to the effects of mine drained water and human activities, the 300 -2000 m around the opencast areas was turning into higher ecologically fragile area. With further exploitation, the whole Coalfield was evolved into moderate and heavy ecological vulnerability area, and the coal resources mining was a key factor in this process. The cluster analysis showed that the spatial distribution of the ecological vulnerability in the study area had reasonable clustering characteristics. To decrease the population density, control the grazing capacity of grassland, and regulate the ratios of construction land and cultivated land could be the optimal ways for resolving the natural and social pressure, and to increase the investment and improve the vegetation recovery coefficient could be the fundamental measures for decreasing the ecological vulnerability of the study area. PMID- 24066565 TI - [Dark respiration of terrestrial vegetations: a review]. AB - The source and sink effect of terrestrial plants is one of the hotspots in terrestrial ecosystem research under the background of global change. Dark respiration of terrestrial plants accounts for a large fraction of total net carbon balance, playing an important role in the research of carbon cycle under global climate change. However, there is little study on plant dark respiration. This paper summarized the physiological processes of plant dark respiration, measurement methods of the dark respiration, and the effects of plant biology and environmental factors on the dark respiration. The uncertainty of the dark respiration estimation was analyzed, and the future hotspots of related researches were pointed out. PMID- 24066566 TI - [Ecosystem services supply and consumption and their relationships with human well-being]. AB - Sustainable ecosystem services supply is the basis of regional sustainable development, and human beings can satisfy and improve their well-being through ecosystem services consumption. To understand the relationships between ecosystem services supply and consumption and human well-being is of vital importance for coordinating the relationships between the conservation of ecosystem services and the improvement of human well-being. This paper summarized the diversity, complexity, and regionality of ecosystem services supply, the diversity and indispensability of ecosystem services consumption, and the multi-dimension, regionality, and various evaluation indices of human well-being, analyzed the uncertainty and multi-scale correlations between ecosystem services supply and consumption, and elaborated the feedback and asynchronous relationships between ecosystem services and human well-being. Some further research directions for the relationships between ecosystem services supply and consumption and human well being were recommended. PMID- 24066567 TI - [Applications of stable isotope techniques in the studies of soil collembolan: a review]. AB - The development and application of stable isotope techniques is one of the most important progress in ecological methodologies in the 1990s. Many ecological processes are accompanied with the changes of stable isotopes ratio. According to these changes, the material circulation and energy flow of ecosystems can be followed. In recent years, many researchers introduced stable isotope techniques in soil ecology to study the soil carbon cycle and the trophic relationships between soil organisms, which greatly improved our understanding on belowground ecosystem. As for collembolan, one of the most important members of soil animals, its feeding habits and trophic position in soil ecosystem are little known. Stable isotope techniques provide a useful approach to study the food resources, trophic position, and trophic relationships of collembolan. This paper summarized the applications of stable isotope techniques in the studies of the feeding habits and trophic position of collembolan, and discussed the deficiencies and prospects of related researches. PMID- 24066568 TI - [Spatiotemporal distribution of negative air ion concentration in urban area and related affecting factors: a review]. AB - Negative air ion (NAI) concentration is an important indicator comprehensively reflecting air quality, and has significance to human beings living environment. This paper summarized the spatiotemporal distribution features of urban NAI concentration, and discussed the causes of these features based on the characteristics of the environmental factors in urban area and their effects on the physical and chemical processes of NAI. The temporal distribution of NAI concentration is mainly controlled by the periodic variation of solar radiation, while the spatial distribution of NAI concentration along the urban-rural gradient is mainly affected by the urban aerosol distribution, underlying surface characters, and urban heat island effect. The high NAI concentration in urban green area is related to the vegetation life activities and soil radiation, while the higher NAI concentration near the water environment is attributed to the water molecules that participate in the generation of NAI through a variety of ways. The other environmental factors can also affect the generation, life span, component, translocation, and distribution of NAI to some extent. To increase the urban green space and atmospheric humidity and to maintain the soil natural attributes of underlying surface could be the effective ways to increase the urban NAI concentration and improve the urban air quality. PMID- 24066569 TI - [Evidence of long distance migration of diamondback moth (DBM) Plutella xylostella: a review]. AB - As cruciferous plants have been cultivated northwards due to climate warming, diamondback moth (DBM) Plutella xylostella is becoming a major pest in North China. The long distance migration of DBM not only induces its sudden outbreak over extensive areas, but also leads to its insecticide resistance by the spread of resistant genes in large area. To elucidate the long distance migration of DBM is of significance for early warning and decision-making in integrated pest managements. So far, the migration of DBM has not yet been systematically investigated in China. Here, we reviewed the literatures about the long distance migration of DBM at home and abroad, and summarized the related evidence: 1) DBM cannot overwinter in cold regions such as northern Japan, western Canada, and northeast China, where the DBM outbreak is presumed from elsewhere by long distance migration, 2) DBM adults are captured from seas, mountain tops, sea islands, and sky, etc., and the collection of large quantity of DBM presents the powerful direct evidence of DBM long distance migration, 3) the sudden increase of DBM in fields is consistent with the meteorological conditions such as the presence of nocturnal temperature inversion layer and the front passage, suggesting that these meteorological conditions supply suitable backgrounds for the insect migration, 4) the target insect characters identified by vertical insect looking radar is consistent with the measured DBM characters in laboratory and the trapping data from fields, confirming the long distance migration of DBM, 5) the biological characteristics and genetic variations of different DBM populations have no correlations with geographic distance, suggesting the frequent gene flows among the populations in different positions, and 6) the flight test of DBM indicates its long distance flight capacity, and the decreasing fitness of host plants is probably one of the trigger factors for the migration of DBM. Some future research directions are prospected: the construction of track model for DBM long distance migration to clarify the DBM long distance migration pathways in China; the further understanding on the physiological, biochemical, and ecological bases of DBM long distance migration; the strategies for the population insecticide resistance management based on the long distance migration of DBM. PMID- 24066570 TI - [Construction of analytical method for similarity of traditional Chinese medicine components on the basis of biopharmaceutic properties]. AB - Traditional Chinese medicine components are a complex multi-component system. How to characterize and evaluate their diverse properties have long been key scientific problems in the modernization process of traditional Chinese medicines. According to the relevant regulations for biopharmaceutical properties, we made the criteria for evaluating similarity of Chinese medicine components, while establish an analytical method based on cosine and Grubbs to evaluate the dispersion degree of properties of representative components, so as to provide ideas and methods for classifying traditional Chinese medicine sub components and evaluating the integrity of component properties. PMID- 24066571 TI - [Study on pharmaceutical screening of representative components of Salvia miltiorrhiza diterpene quinones]. AB - OBJECTIVE: To screen out the main components with no significant difference with Salvia miltiorrhiza diterpene quinones pharmacological action, in order to determine the compatible form of representative components that can describe the overall property of S. miltiorrhiza diterpene quinones. METHOD: According to the results of the in vitro pharmacological experiment, the myocardial ischemia model of rats was induced through intraperitoneal injection of isoproterenol. The pharmacologic effects of S. miltiorrhiza diterpene quinones, combination with principal component A and combination with principal component B were compared in electrocardiogram (changes in J point), enzymology indicators (SOD, MDA, CK, LDH) and pathology (myocardial histological changes), so as to screen out the compatible form of representative components that can describe the overall property of S. miltiorrhiza diterpene quinones. RESULT: The S. miltiorrhiza diterpenoid quinone high-dose group and the B high-dose group were similar in all pharmacological effects, with equal efficacy but no significant difference. CONCLUSION: The S. miltiorrhiza diterpenoid quinone high-dose group and the B high-dose group showed a certain therapeutic effect on ISO-induced myocardial ischemia. Therefore, the four components in the B high-dose group can be used as representative components of S. miltiorrhiza diterpene quinones. PMID- 24066572 TI - [Experimental study on structure optimization of ginkgolide components]. AB - Having searched a large number of literatures, the author found different concepts of traditional Chinese medicine components among pharmacists. Then, what are traditional Chinese medicine components? The author thinks that traditional Chinese medicine components shall be optimized traditional Chinese medicine components with relatively clear efficient substances, action mechanisms, specific purity and definite internal structure. This experiment preliminarily determined optimized component structures of ginkgolides by comparing the four reported constituents in in vivo and in vitro pharmacodynamic and pharmacological experiments. The experimental design could provide ideas and basis for optimizing traditional Chinese medicine components and determining their matching structures. PMID- 24066573 TI - [Investigation on equilibrium solubility and apparent oil/water partition coefficient of diterpenoid tanshinone component by similarity analysis methods]. AB - OBJECTIVE: To study the equilibrium solubility and apparent oil/water partition coefficient of diterpenoid tanshinone component by similarity analysis methods, so as to lay the foundation for Salvia diterpenoid quinone component of the overall solubility characterization. METHOD: Taking Salvia diterpenoid quinone component as model drug, determined the equilibrium solubility and partition coefficients of the components in different buffer, evaluated the degree of similarity of each component based on the cosine and Grubbs. RESULT: The representative composition of Salvia diterpenoid quinone component, namely dihydrotanshinone I, tanshinone I, cryptotanshinone and tanshinone II(A) had similar properties of equilibrium solubility and partition coefficients in different pH buffer. This similarity was not only manifested in the trends, but also reflected the value. CONCLUSION: This similarity assessment reflected the degree of deviation and dispersion of components, which was applicable to the study of the components; the similarity assessment could increase the science and rationality of component evaluation, and at the same time could optimize the structure of the component. PMID- 24066574 TI - [Study on solubility of ginkgolide components with mass fraction weight coefficient method]. AB - In this study, the HPLC-ELSD method was adopted to detect the equilibrium solubility of B and A in water and different pH buffer solution, as well as their apparent oil-water partition coefficients in the noctanol-water/buffer solution. Furthermore, the mass fraction weight coefficient method was adopted to express the integrated equilibrium solubility and oil-water distribution coefficient of ginkgolide components. The direct addition method and the mass fraction weight coefficient method were compared in calculating the property value of ginkgolide components, showing that the mass fraction weight coefficient method was more scientific and reasonable. The tentative study provided ideas to property characterization of traditional Chinese medicine components, as well as basis for studies on preparations of traditional Chinese medicine components. PMID- 24066575 TI - [Equilibrium solubility of ginkgo flavonoid components in water and PBS of different pHs with mass fraction weight coefficient method]. AB - OBJECTIVE: To descript the equilibrium solubility of ginkgo flavonoid components in water and PBS of different pHs. METHOD: The HPLC method was adopted to determine the concentration of quercetin, kaempferol and isorhamnetin in ginkgo biloba extracts, and the equilibrium solubility of the three components in water and PBS of different pHs. Furthermore, the mass fraction weight coefficient method was adopted to express the integrated equilibrium solubility and oil-water distribution coefficient of ginkgo flavonoid components. RESULT: Ginkgo flavonoid components were well dissoluble in water, with the maximum equilibrium solubility of 408.29 mg x L(-1) at pH 7.8. Therefore, it could be preliminarily predicted that ginkgo flavonoid components had higher application value, and could provide guiding basis for further development of preparations. CONCLUSION: By comparing the results of the direct addition method and the mass fraction weight coefficient method, we found that the mass fraction weight coefficient method was more scientific and reasonable. The tentative study could provide ideas to property characterization of traditional Chinese medicine components. PMID- 24066576 TI - [Advance in studies on effect of traditional Chinese (Tibetan) medicines in prevention and treatment of acute altitude sickness]. AB - Acute altitude reaction is a stress response of organism to special altitude environmental factors such as hypoxia, low pressure, cold, dry and strong ultraviolet. As it is the most incident disease in high altitude areas, its prevention remains a problem to be solved. In China, the traditional Chinese (Tibetan) medicines have been recognized as an effective means of preventing and treating acute altitude sicknesses. Some single-recipe or compound traditional Chinese (Tibetan) medicines have been proved to be effective for acute altitude sicknesses. In this article, we will describe traditional Chinese (Tibetan) medicines of different types with efficacy in prevention and treatment of altitude sicknesses. PMID- 24066577 TI - [Cell membrane chromatography and its application progress in studies of traditional Chinese medicines]. AB - As a novel bioaffinity chromatography technique, cell membrane chromatography (CMC) was first established by Professor He in 1996, with which combined high performance liquid chromatography, cytobiology, and receptor pharmacology. The cell membrane stationary phase (CMSP) consists of porous silica coated with active cell membranes. By immersing silica into a suspension of cell membranes, the whole surface of silica was covered by the cell membranes. In CMC, the interaction of drugs or compounds with the immobilized cell membrane or its receptors is investigated using liquid chromatography. In general, with the aim to provide scientific foundation for further development and application, this paper mainly focuses on the characteristics of the cell membrane stationary phase (CMSP), the CMC analytical system, and its applications in traditional Chinese medicines (TCMs) about CMC. With the development of CMC, the breakthrough progress of it in studying active components of TCMs field is expectant. PMID- 24066578 TI - [Light quality regulation of growth and endogenous IAA metabolism of Ganoderma lucidum mycelium]. AB - To study the effect and mechanism of the light quality acting on Ganoderma lucidum, and provide a theoretical basis for G. lucidum mycelium cultivation, we focused on growth and endogenous IAA metabolism of G. lucidum mycelium under different light-emitting diode (LED) condition. The growth index, endogenous levels of IAA and Enzymes related to IAA metabolism and Polysaccharides content were investigated in different growth periods. Results showed that blue light irradiation was the best from the viewpoint of steady growth and polysaccharides accumulation, red light irradiation improved endogenous IAA level and promoted growth of mycelium in early stage of cultivation, green light irradiation decreased growth rate and fresh weight of mycelium, but increased drying rate. Enzymes related to IAA metabolism also significantly influenced by light quality. The activity of indole acetic acid oxidase (IAAO), peroxidase (POD) and tryptophan synthetase with blue light irradiation were showed high level in early time, but decreased later, and the IAA content was consistently at lower level than that in other treatments, while mycelium irradiated with yellow light showed the highest activity of both IAAO and tryptophan synthetase, and medium level of IAA content. In conclusion, the light quality affects growth and regulation of the level of endogenous IAA of G. lucidum mycelium. PMID- 24066579 TI - [Analysis of endophytic fungi community of Ligusticum chuanxiong using PCR-DGGE]. AB - OBJECTIVE: To research the diversity of endophytic fungal communities among Ligusticum chuanxiong growing at 5 areas in Sichuan province, and illuminate the developing mechanism of geoherbs from the microecological perspective. METHOD: The PCR-DGGE and DNA sequencing techniques were used to analyze the endophytic fungi community of L. chuanxiong. RESULT: The community of endophytic fungi present difference among different growing areas. Though minor difference were found among individuals at the same area, similarity among individuals from the same growing areas were higher significantly than those from different growing areas. Compared with the other 4 growing areas, L. chuanxiong from Shiyang town, Dujiangyan city had more abundant endophytic fungi and low similarity to others, and which probably had special types of fungi. CONCLUSION: The abundant and stable endophytic fungal community is an important factor for the development of geoherb L. chuanxiong at Shiyang town, Dujiangyan city. PMID- 24066580 TI - [Study on human aFGF fusion gene transformation with soybean 24 kDa oleosin and expression in safflower]. AB - OBJECTIVE: To investigate the expression of acidic fibroblast growth factor (aFGF) in transgenic safflower and lay the foundation for the use of the plant bioreactor large-scale production aFGF. METHOD: The haFGF gene was transformed into plant preference of the aFGF sequence as a basis for design of primers, plant preferences aFGF gene sequences was amplified by PCR. The vegetable body expression vector was constructed by using digested connection method and then transferred to Agrobacterium tumefaciens EHA105 by the freeze-thaw method. It transferred to safflowers by agrobacterium-mediated transformation method, and identified by PCR, southern blot and RT-PCR. RESULT: The full-length aFGF gene sequences were amplified through PCR and constructed into plant expression vector with soybean oleosin and promoter, and transformed into safflower. Three independently transformed safflower plant units with point insertion were successfully obtained, which showed the same size of aFGF expression at the transcriptional level. CONCLUSION: The plant oil body expression vectors were successfully constructed, and the optimal condition for genetic transformation was selected. The transgenic safflower plants were obtained. PMID- 24066581 TI - [Dynamic changes of enzyme activities and active component contents in Lonicera japonica during different blossoming stages]. AB - OBJECTIVE: This paper aimed to study the dynamic changes of enzyme activities and active component contents in Lonicera japonica during different blossoming stages. METHOD: The enzyme activities of phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), peroxidase (POD) and the contents of total phenol, total flavonoids, chlorogenic acid, anthocyanins in L. japonica during different blossoming stages were determined. RESULT: The contents of total phenolics, total flavonoids, anthocyanins decreased from the Sanqing stage to Jinhua stage while the content of chlorogenic acid increased slightly in white period, and then decreased gradually. The activities of three enzymes decreased gradually from Sanqing stage, and got to a minimum value in Yinhua stage, then increased slightly until the Jinhua stage. CONCLUSION: The enzyme activities of PPO and POD correlated the content of phenolic substances positively before the Jinhua stage in L. japonica. In the period of maturity, the POD activity was strengthened due to the induction of respiration and became the key enzyme to control active component content during the mature stage. PMID- 24066582 TI - [Separation and molecular identification of fungal contamination on surface of 15 Chinese herbal medicines]. AB - OBJECTIVE: To evaluate fungal contamination on the surface of Chinese herbal medicines and explore an appropriate method for fast and efficient identification of contaminant fungi. METHOD: Chinese herbal medicines were first washed and the washing solution was plated onto potato dextrose agar (PDA) to obtain the pure isolates. For molecular identification, two new pairs of specific primers were designed according to ITS region of fungi genome sequences. The strains were identified through polymerase chain reaction (PCR) and sequence analysis. RESULT: Fifty fungal strains were obtained from the surface of 15 Chinese herbal medicines with the percent of contaminated samples of 93.3%. Twenty-seven strains among them were successfully identified. CONCLUSION: Fungal contamination on the surface of Chinese herbal medicines is quite common. Although different fungal species were isolated, the genus Aspergillus was the predominant. The primer pairs developed in this study are compatible and can be used to identify fungal species from the surface of Chinese herbal medicines. PMID- 24066583 TI - [Correlation analysis between nutritive components of Whitmania pigra and Bellamya purificata]. AB - The dried Whitmania pigra is used for the treatment of cardiovascular and cerebrovascular diseases in traditional Chinese medicine. Bellamya purificata is widely distributed in the Chang Jiang River basin, it is natural diets of W. pigra. Current study was conducted to compare and analyze the nutritional ingredient in W. pigra, body fluid and flesh of B. purificata. Results showed that the contents of protein, crude fat and total sugar in W. pigra, body fluid and flesh of B. purificata were significantly different (P < 0.05). Protein content in W. pigra accounts up to 65.01%. The contents of inorganic elements and amino acid were abundant in W. pigra, body fluid and flesh of B. purificata. The content of essential amino acids in them were 32.6, 221.59, 40.78 mg x g(-1), respectively. The content of flavor amino acid in them were 27.51, 14.5, 32.03 mg x g(-1), while the coresponding content of antioxidant amino acid were 8.81, 5.91, 9.73 mg x g(-1), respectively. The individual amino acids of high content in them were Glu, Asp and Leu. Macro elements Ca, P, Mg and trace elements Zn, Si, Fe were abundant. It could be speculated that W. pigra may be a promising novel food, and the present results provide a foundation to develop artificial feed for W. Pigra. PMID- 24066584 TI - [Determination of amino acids in cornu cervi pantotrichum of different specifications]. AB - OBJECTIVE: To determine the contents of amino acids in Cornu Cervi Pantotrichum of different specifications for controlling the quality. METHOD: The contents of 18 kinds of amino acids were determined by amino acid analyzer. RESULT: The correlation coefficients of 18 kinds of amino acids were all greater than 0.997, the average recovery were all between 99.1%-108.1% with RSDs less than 2.0%. All Cornu Cervi Pantotrichum samples of 29 different specifications contained 17 kinds of amino acids and 7 kinds of essential amino acids. The content of total amino acids in wax slices is relative higher. The content in first born antlers is higher than that in reborn antlers. CONCLUSION: This method is suitable for the determination of amino acids in Cornu Cervi Pantotrichum, it provides good reference for the quality control of Cornu Cervi Pantotrichum. PMID- 24066585 TI - [Preparation and in vitro evaluation of self-assembled beads drug delivery system of berberine hydrochloride]. AB - The purpose of the present work was to investigate the innovative self-assembling system, "beads", prepared by continuously shaking alpha-cyclodextrin and soybean oil without the use of organic solvents and surfactants at room temperature. Berberine hydrochloride previously dissolved in soybean oil was chosen as a model drug to explore the shape, structure, drug loading and in vitro release of beads. The particle size and drug loading of berberine hydrochloride-loaded beads were (2.25 +/- 0.23) mm and (67.02 +/- 0.64) microg x g(-1), respectively. Confocal microscopy showed that the core-shell structure of beads could contain poorly water soluble drugs or lipophilic drugs in the lipid core. The drug release rate and cumulative releases of beads were both higher than those of raw medicine of berberine hydrochloride in simulated intestinal fluid. These results suggested that beads were the novel and potential lipid-based drug delivery system for lipophilic or poorly water soluble traditional Chinese medicine. PMID- 24066586 TI - [UFLC/Q-TOF-MS based analysis on material base of atractylodis macrocephalae rhizoma stir-fried with wheat bran]. AB - To establish a fingerprint spectrum for Atractylodis Macrocephalae Rhizoma stir fried with wheat bran based on UFLC/Q-TOF-MS, and make a principal component analysis (PCA) with Markview software, in order to compare the changes of components between raw and processed Atractylodis Macrocephalae Rhizoma with raw wheat bran as the blank. The results showed that the changed in components raw Atractylodis Macrocephalae Rhizoma and Atractylodis Macrocephalae Rhizoma stir fried with wheat bran were apparently observed by PCA. Six compounds were identified to have significant changes in mass fraction before and after being stir-fried, namely atractylenolide-I, atractylenolide-II, atractylenolide-III, atractylentrid, atractylon and an unknown compound. Among them, atractylenolide-I and atractylenolide-II generated from dehydration and dehydrogenation of atractylenolide-III may be the material base of Atractylodis Macrocephalae Rhizoma stir-fried with wheat bran for strengthening spleen. PMID- 24066587 TI - [Chemical structure of capsicuoside A from fruits of Capsicum annuum]. AB - Five compounds were isolated from Capsicum annuum by means of various chromatographic techniques (silica gel, Sephadex LH-20, MCI GEL CHP-20P and HPLC), and their structures were determined as luteolin-7-O-[2"-O-(5"-O-sinapoyl) beta-D-apiofuranosyl]-beta-D-glucopyranoside (1), uridine (2), adenosine (3), 7 hydroxy-6-methoxy cinnamic acid ethyl ester (4) and 7-hydroxy cinnamic acid ethyl ester (5) by extensive spectroscopic analyses (UV, IR, MS, 1D- and 2D-NMR). Among them, compound 1 is a new flavone glycoside named as capsicuoside A, and cmpounds 2-5 are isolated for the first time from the fruits of C. annuum. PMID- 24066588 TI - [Chemical constituents from seeds of Vigna umbellata]. AB - Phytochemical investigation was carried out on the seeds of Vigna umbellata. The 70% ethanol extract of the seeds of V. umbellata was subjected to silica gel, Sephadex LH-20, ODS column chromatographies and preparative HPLC. The structures of the isolated compounds were elucidated on the basis of NMR and ESI-MS spectroscopic data Eight compounds were obtained and identified as carboxyatractyligenin (1), 2beta-O-beta-D-glucopyranosyl-15alpha-hydroxy-kaur-16 ene-18,19-dicarboxylic acid (2), 2beta-O-(beta-D-glucopyranosyl) atractyligenin (3), 3R-O-[beta-L-arabinopyranosyl-(1-6) -beta-D-glucopyranosyl] oct-1-ene-3-ol (4), (6S, 7E, 9R) -roseoside (5), liriodendrin (6), resveratrol (7) and maltol (8). Compounds 1-7 were isolated from Vigna genus for the first time, and compound 8 was isolated from V. umbellata for the first time. PMID- 24066589 TI - [Flavonoids from leaves of Epimedium pubescens]. AB - Eleven compounds were isolated from the leaves of Epimedium pubescens by means of various chromatographic techniques such as silica gel, MCI, Sephadex LH-20 and preparative HPLC. Their structures were identified as anhydroicaritin (1), icariside II (2), 2'''-O-rhamonosyl-icariside II (3), desmethylanhydroicaritin (4), baohuosaide II (5), epimedokoreanin B (6), acuminatin (7), tricin(8), kaempferol (9), daidzein (10) and 4-hydroxy ethyl benzoate (11) on the basis of physicochemical properties and spectroscopic data analysis. Among them, compound 11 was isolated from Epimedium species for the first time, and other compounds were obtained from this plant for the first time. PMID- 24066590 TI - [Preparation of ferulic acid, senkyunolide I and senkyunolide H from Ligusticum chuanxiong by preparative HPLC]. AB - Preparative HPLC was used to prepare ferulic acid, senkyunolide I and senkyunolide H from Ligusticum chuanxiong. The separation was conducted on a Shim Pack Prep-ODS (20.0 mm x 250 mm, 5 microm) column with the mobile phase of methanol-0.2% glacial acetic acid (50:50)at the flow rate of 5 mL x min(-1). The detection wavelength was 278 nm, and the purity of each compound was detected by HPLC analysis. Spectral data analyses including UV, ESI-MS and NMR were used to identify their structures. This method is simple, fast, which is suitable for preparation of standard reference of ferulic acid, senkyunolide I and senkyunolide H from L. chuanxiong and can meet the requirement of new drug research and development. PMID- 24066591 TI - [Study on HPLC-fingerprint-based identification of dao-di herb and non dao-di herb of scutellariae radix]. AB - OBJECTIVE: To compare the discrepancies between chemical constituents in Dao-di herb and non Dao-di herb of Huangqin (the root of Scutellaria baicalensis), study the impact of habitat and growth pattern (including cultivated and wild Huangqin) on chemical substances of Huangqin, and then provide evidence for the identification of Dao-di herb and quality evaluation of Huangqin. METHOD: The chemical constituents in Huangqin collected from different habitats and under different growth patterns, were analyzed using HPLC fingerprint. The fingerprints obtained were then evaluated by hierarchical clustering analysis, principal component analysis and components peak area pattern. RESULT: The fingerprints' chemical profiles of Dao-di herb and non Dao-di Huangqin had significant disparity. The fingerprints of modem Dao-di herb Huangqin samples originated from Chengde (Hebei Province) were significantly different from those from other habitats, though the fingerprints of the non Dao-di Huangqin collected from Chifeng (Inner Mongolia) and Chengde had high similarity to each other. The chemical characteristics of Huangqin samples collected from the habitats recorded in ancient herbals, such as Qingyang (Gansu Province), Yan'an (Shaanxi Province), Linyi (Shangdong Province), Changzhi and Jinzhong (Shanxi Province) were similar. The fingerprints of modern non Dao-di samples collected from Dingxi and Longnan (Gansu Province) and Shangluo (Shaanxi Province) had high similarity. In addition, the content of acteoside in wild Huangqin was higher than that in cultivated Huangqin. CONCLUSION: Dao-di herb and non Dao-di herb of Huangqin could be distinguished using the developed HPLC fingerprints. The results obtained may provide evidence for the quality control and pharmcodynamical research of Dao-di herb and non Dao-di Huangqin. PMID- 24066592 TI - [Simultaneous determination of eight active components in Chrysanthemum indicum by HPLC]. AB - This study is aimed to establish a high-performance liquid chromatography (HPLC) method for simultaneous determination of chlorogenic acid, caffeic acid, 1,3 dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, luteolin-7-O-beta-D-glucoside, 3,4-dicaffeoylquinic acid, linarin and luteolin in Chrysanthemum indicum. The separation was carried out on a Shim pack VP-ODS (4.6 mm x 250 mm, 5 microm) column eluting with mobile phases of methanol (A) and water containing 0.3% phosphoric acid (B) in gradient mode (0-9 min, 85% -80% B; 9-12 min, 80% -70% B; 12-15 min, 70% -65% B; 15-20 min, 65% -60% B; 20-23 min, 60% -55% B; 23-29 min, 55% -54.4% B; 29-32 min, 54.4% -45% B; 32-37 min, 45% -5% B; 37-45 min, 5% -85% B) at the flow rate of 1.0 mL x min(-1). The column temperature was 35 degrees C and the detection wavelength was set at 326 nm. The good separation of chlorogenic acid, caffeic acid, 1,3-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, luteolin-7-O-beta-D-glucoside, 3,4-dicaffeoylquinic acid, linarin and luteolin was achieved within 40 min. Calibration curves of the eight effective components showed good linear relationship (r > 0.999 5, n = 7). The average recoveries were within 97.03%-102.3% (RSD < 2.0%, n = 6). The method is simple, accurate and repeatable and can be used for the quality control of Ch. indicum. PMID- 24066593 TI - [Study on reducing mechanism of hepatotoxicity induced by ethyl acetate fractions of kansui radix stir-baked with vinegar in mice]. AB - OBJECTIVE: To study the mechanism of the reducing mechanism of hepatotoxicity induced by ethyl acetate fractions of Kansui Radix stir-baked with vinegar in mice. METHOD: Mice with normal ICR were orally administered with ethyl acetate fractions of Kansui Radix and Kansui Radix stir-baked with vinegar. Their blood and liver homogenate were collected to detect the level of AST, ALT, LDH, SOD, activities of Na(+) -K(+) -ATPase and Ca(2+) -Mg(2+) -ATPase, GSH and MDA. Liver tissues were collected for HE staining and morphological observation under light microscope. RESULT: According to the results of pathological sections, compared with the control group, all of Kansui groups showed a significant increase in the hepatic tissues injury (P < 0.01). Compared with Kansui groups, all of vinegar baked groups showed a significant decrease in the hepatic tissues injury (P < 0.01). Compared with the control group, all of Kansui groups showed a significant increase in ALT, AST and LDH (P < 0.05, P < 0.001) in serum and hepatic tissues, and significantly decrease in the activity of SOD (P < 0.001) and the content of GSH. They also showed a significant increase in MDA (P < 0.001) and a significant decrease in the level of Na(+) -K(+) -ATPase and Ca(2+) -Mg(2+) -ATPase (P < 0.01) in hepatic tissues, with a certain dose-effect relationship. Compared with all of Kansui groups, all of vinegar-baked groups showed a significant decrease in ALT, AST and LDH (P < 0.05, P < 0.001), and a notable increase in SOD (P < 0.001) and GSH in serum and hepatic tissues. They also showed a remarkable decrease in MDA (P < 0.001), and a significant increase in the level of Na(+) K(+) -ATPase and Ca(2+) - Mg(2+) -ATPase (P < 0.01) in hepatic tissues, with a certain dose-effect relationship. CONCLUSION: Being stir-baked with vinegar can significantly reduce the hepatotoxicity of Kansui Radix. Its mechanism may be related to the reduction of the effect of Kansui Radix on the permeability of hepatic tissues cell membranes and the oxidative injury. PMID- 24066594 TI - [Investigation of a compound, compatibility of Rhodiola crenulata, Cordyceps militaris, and Rheum palmatum, on metabolic syndrome treatment. V--Mechanisms on improving glucose metabolic disorders]. AB - To investigate the mechanisms of a compound (FF16), compatibility of Rhodiola crenulata, Cordyceps militaris, and Rheum palmatum, on glucose metabolic disorders, the IRF mice charactered with insulin resistance and glucose metabolic disorders induced by high-fat diet in C57BL/6J mice were randomly divided into 3 groups; IRF, rosiglitazone (Rosi) and FF16. The glucose metabolism was evaluated by fasting blood glucose (FBG) levels and intraperitoneal glucose tolerance test (IPGTT). The insulin sensitivity was estimated by insulin tolerance test (ITT), fasting serum insulin levels and the index of HOMA-IR. The expressions of Akt and its phosphorylation levels, GSK3beta and its phosphorylation levels in liver were detected by Western Blot. The results showed that FF16 significantly improved the glucose metabolic disorders through reducing FBG by 15.1%, decreasing AUC values in glucose tolerance tests by 22.3%. FF16 significantly improved the insulin sensitivity through decreasing AUC values in insulin tolerance tests by 22.1%, reducing the levels of serum insulin by 42.9% and of HOMA-IR by 49.5%, comparing with model control, respectively. After the treatment with FF16, the levels of p Akt and p-GSK3beta were increased by 116.4% and 24.9%, respectively, in the liver of IRF mice. In conclusion, compound FF16 could improve glucose metabolic disorders in IRF mice through enhancing the glyconeogenesis. PMID- 24066595 TI - [Effect of pulchinenoside in regulating FLS SFRP2 expression of RA model rats]. AB - OBJECTIVE: To study the effect of pulchinenoside (PULC) in modulating SFRP2 expression in fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA) model rats. METHOD: The effect of PULC in treating RA rats was evaluated by rat arthritis score and paw swelling score. The inhibitory effect of PULC on FLS proliferation was detected by MTT reagent. The effects of PULC gavage treatment in modulating gene expression of FLS SFRP2, critical gene beta-catenin of Wnt pathway and downstream effector genes C-myc of of Wnt pathway were detected by RT PCR and Western blotting. RESULT: PULC had a significant effect in treating RA rats and that SFRP2 expression was down-regulated in FLS. After PULC gavage treatment, FLS SFRP2 expression was obviously up-regulated, whereas beta-catenin and C-myc gene expressions were significantly down-regulated. CONCLUSION: PULC can inhibit abnormal proliferation of synovial membrane by modulating Wnt pathway of RA rats. PMID- 24066596 TI - [Effect of coicis semen oil on renal interstitial fibrosis in rats with unilateral urethral obstruction]. AB - OBJECTIVE: To study the effect and mechanism of Coicis Semen oil (Kanglaite injection, KLT) on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). METHOD: Fifty-four male SD rats were randomly divided into 3 groups, 6 in each group, the sham operated group, the model group, and the KLT group. Renal interstitial fibrosis model was established in rats by UUO. After administration of KLT (15 mL x kg(-1) x d(-1)) for 3, 7 and 14 days, the dynamic histological changes of renal interstitial tissues were observed and renal damage including tubular impairment and interstitial fibrosis were quantified on HE and Masson stained tissue sections. The expression of alpha-smooth muscle actin (alpha-SMA) and transforming growth factor-beta1 (TGF-beta1) were measured by immunohistochemistry staining sections. The protein expression of p-Smad2 and Smad7 were detected by Western blot respectively. RESULT: The degree of tubular damage in KLT group was much lower than that in UUO group (P < 0.05). The expression of alpha-SMA and TGF-beta1 was decreased in both UUO group and KLT group, while it was significantly lower in KLT group at every time point. The protein expression of p-Smad2 was obviously decreased while the protein expressions of Smad7 was obviously increased in KLT group, compared with the UUO group (P < 0.05). CONCLUSION: Coicis Semen oil could attenuate the tubulo interstitial fibrosis, probable by intervening the TGF-beta/Smads signal transduction pathway of UUO rats. PMID- 24066597 TI - [Experimental study on anti-atherosclerotic effect of compatibility of active components of danshen and shanzha]. AB - OBJECTIVE: To investigate the effect of active components of Danshen and Shanzha of different matching proportions on atherosclerosis (AS), in the expectation of obtaining the optimum combination method. METHOD: Atherosclerotic rats were fed with high fat diet, and injected with vitamin D3 and ovalbumin. Aqueous extracts of Danshen (DSA) and Shanzha (SZA) and lipophilic extracts of danshen (DSL) were adopted for a low, medium and high-dose orthogonal experiment, to observe the effect of their different matching proportions on lipid level, oxidative stress, endothelial function and inflammatory reaction. The principal component analysis and cluster analysis were adopted for the multi-objective optimization of experimental results. RESULT: Compared with the model group, all of samples with different proportions of DSA, DSL and SZA showed effect in lowering lipid level, scavenging free radicals, reducing endothelial dysfunction and inhibiting inflammation. According to the variance analysis, DSA2-SZA2-DSL1, DSA3-SZA2-DSL1, DSA3-SZA3 -DSL3 and DSA3-SZA1-DSL1 were the optimal proportions for lowering lipid level, scavenging free radicals, reducing endothelial dysfunction and inhibiting inflammation, respectively. According to the results of the multi objective optimization, DSA2-SZA1-DSL2 was the optimal proportions of anti-AS. CONCLUSION: All of active components of Danshen and Shanzha of different matching proportions show the anti-AS effect in rats to varying degrees, but with different focus in different matching proportions. PMID- 24066598 TI - [Comparative study on effect of 8-prenlynaringenin and narigenin on activity of osteoclasts cultured in vitro]. AB - OBJECTIVE: To compare the effects of 8-prenylnaringenin (PNG) and naringenin (NG) on the activity and apoptosis of osteoclasts cultured in vitro, in order to study physiological activity of 8-prenyl perssad. METHOD: Osteoclasts were separated from long-limb bones of newly born rabbits, cultured in alpha-MEM containing 10% FBS, and then added with PNG and NG with the concentration of 1 x 10(-5) mol x L( 1). They were stained with TRAP and determined for enzymatic activity with TRAP after 4 d, and analyzed by toluidine blue staining after 7 d. The apoptotic osteoclasts were analyzed by Annexin V-FITC staining after 2, 4, 8, 12, 24, 36, and 48 hours, to observe their apoptosis. Their total RNAs were extracted, and analyzed for TRAP and Cathepsin K expressions by Real-time RT-PCR. RESULT: Compared with the control group, both of the PNG group and the NG group showed much less osteoclasts (TRAP positive cells), lower TRAP activity and TRAP and Cathepin K (CTSK) expression, and smaller number of bone resorption pits and areas. The PNG group show lower indexes than the NG group. Additionally, the PNG group reached the apoptotic peak of osteoclasts at 12 h after drug administration, whereas the NG group reached after 24 h. And the former had more apoptotic cells than the latter. CONCLUSION: 8-PNG is much more active than NG in inhibiting the resorption of osteoclasts and inducing apoptosis of osteoclasts. Their only difference lies in 8-prenyl perssad, which is proved to be able to enhance the anti-bone resorption activity of 8-prenylnarigenin. PMID- 24066599 TI - [Protective mechanism of cerebrospinal fluid containing qingxin kaiqiao recipe on PC12 cell injury induced by glutamate]. AB - OBJECTIVE: To study the protective effect of cerebrospinal fluid containing Qingxin Kaiqiao recipe on PC12 cell injury induced by glutamate (Glu), in order to provide basis for the conical application of the recipe. METHOD: SD rats were orally administered with decoction of Qingxin Kaiqiao recipe (7.9 g x kg(-1)) for three and a half days, 2 times a day, in order to prepare cerebrospinal fluid containing Qingxin Kaiqiao recipe. PC cells were divided into the normal group, the model group, the nimodipine group, the 10% normal CSF group, the 10% medicated CSF group, the 20% normal CSF group, the 20% medicated CSF group. Except for the normal group, other groups were cultured with PC12 cells and Glu with the final concentration of 20 mmol x L(-1) to establish the nerve cell injury model. Apart from the model group and the normal group, other groups were intervened with nimodipine, normal cerebrospinal fluid, and 10% and 20% medicated CSF. RT-PCR was used to detect the expression level of Bax mRNA, Bcl-2 mRNA and Caspase-3 mRNA, and MTT method was used to detect the activity of PC12 cells. RESULT: The activity of PC12 cells of all of medicated CSF groups was higher than that of the model group, with the decrease in the expression of Bax mRNA and Caspase-3 mRNA and the increase in the expression of Bcl-2 mRNA. They showed a significant different with the model group (P < 0.01). The 20% medicated CSF group was superior than the 10% medicated CSF group (P < 0.01). CONCLUSION: Qingxin Kaiqiao recipe shows an apparent protective effect on PC12 cells injured by Glu. PMID- 24066600 TI - [Comparative on acute myocardial infarction models in beagle dogs and mongrel dogs]. AB - OBJECTIVE: To compare the acute myocardial infarction models in Beagle dogs and mongrel dogs, and study whether the Beagle dog model is sensitive to drug intervention. METHOD: The acute myocardial infarction model of dog was set up through ligation of anterior descending branch of coronary artery in dogs, in order to observe morphological changes of the heart and determine artery length and heart coefficient of exposed anterior descending branch of coronary artery. The epicardium electrocardiogram (sigmaST, N-ST) was used to measure the degree of myocardial ischemia. The quantitative histological assay (nitroblue tetrazolium, N-BT stain) was adopted to determine the area of myocardial infarction. RESULT: There was no significant difference between Beagle dogs and mongrel dogs in terms of sigmaST, N-ST and ischemia area. The diltiazem group of Beagle dogs showed obvious reduction in the ischemia area (P < 0.05 and P < 0.01), with notable decline in sigmaST and N-ST, however, it had no statistical difference compared with the Beagle dog model group. Beagle dogs had clear coronary branches, longer exposed arteries and less difference in organ coefficient, which were suitable for the preparation of the myocardial infarction model, whereas mongrel dogs had irregular coronary branches and exposed arteries, with greater individual difference. CONCLUSION: Beagle dogs are superior to mongrel dogs in the preparation of the acute myocardial infarction model, which is sensitive to for drug intervention. PMID- 24066601 TI - [Protective effect of yixinshu capsule on myocardial ischemia reperfusion injury in rats]. AB - OBJECTIVE: To observe the protective effect of Yixinshu capsule on myocardial ischemia reperfusion injury (MIRI) in SD rats. METHOD: Sixty healthy SD rats were randomized into six groups: sham group, MIRI model group, Xinsuning capsule group, low, middle or high dose Yixinshu capsule. Acute MIRI rat models were created by reperfusion for 120 min after anterior interventricular branch of the left coronary artery for 30 min. The serum creatine kinase (CK), lactic dehydrogenase (LDH), aspartate aminotransferase (AST) and malondialdehyde(MDA), blood viscosity, and infarction area of myocardium were determined. RESULT: Yixinshu capsule could reduce serum CK, LDH, AST and LDH activity, improve the blood viscosity, and reduced the myocardial infarct size. CONCLUSION: Yixinshu capsule can protect against MIRI in rats. PMID- 24066602 TI - [CYP450 enzyme inhibition of berberine in pooled human liver microsomes by cocktail probe drugs]. AB - OBJECTIVE: To investigate the effect of CYP450 enzyme inhibition of berberine in pooled human liver microsomes by cocktail probe drugs. METHOD: Cocktail probe drugs method has been established, an LC-MS/MS analytical method has been established to determine the five probes of midazolam, phenacetin, dextromethorphan, tolbutamide, chlorzoxazone and the internal standard was benzhydramine to evaluate the effect of CYP450 activity following administration of berberine in pooled human liver microsomes. RESULT: Compared with control group, the pharmacokinetics of midazolam, phenacetin and tolbutamide were no significant differences, but the pharmacokinetics of chlorzoxazone was significantly decreased. There were no significant differences for the pharmacokinetics of dextromethorphan when the concentration of berberine was 50 microg x L(-1). The pharmacokinetics of dextromethorphan was significantly decreased when the concentration of berberine was exceed 200 microg x L(-1). CONCLUSION: Berberine has no influence on the activities of CYP3A4, CYP1A2 and CYP2C19 below 2 000 microg x L(-1), but can inhibit the activity of CYP2E1 and CYP2D6 in concentration-dependent. PMID- 24066603 TI - [Pharmacokinetics of 8-O-acetylharpagide and harpagide after oral administration of Ajuga decumbens extract in beagle dog]. AB - 8-O-acetylharpagide and harpagide are two kinds of effective component of Ajuga decumbens extract. A sensitive LC-MS/MS method has been established for pharmacokinetics of 8-O-acetylharpagide and harpagide in beagle dog after oral administration of from A. decumbens extract. Female beagle dogs received orally 12.9, 25.7 mg x kg(-1) p. o. Concentrations of 8-O-acetylharpagide and harpagide in plasma were determined by LC-MS/MS method at different time points and all pharmacokinetic parameters were estimated by non-compartment analysis. The mobile phase consisted of 0.1% formic acid in water (A) and acetonitrile (B), which was run at a flow rate of 0.3 mL x min(-1). Chromatographic separation was achieved on an Agilent ZORBAX XDB-C18 column (2.1 mm x 50 mm, 3.5 microm) using a gradient elution of 5% B at 0-2 min, 95% B at 2. 1-5 min and 5% B at 5. 1-10 min. All analytes, including the IS, were monitored under positive ionization conditions and quantified in MRM mode with transitions of m/z 429.2-369.2 for 8-O acetylharpagide, m/z 387.2-207.2 for harpagide, and m/z 149.2-103.1 for IS. High purity nitrogen was employed as both the nebulizing and drying gas. Other parameters of the mass spectrometer were optimized as follows: drying gas flow 10.0 L x min(-1); drying gas temperature 300 degrees C; capillary voltage 4 000 V. Results showed that 8-O-acetylharpagide and harpagide showed a dose-dependence profile. T(max) of 8-O-acetylharpagide is 1.7 h, and T(max) of harpagide is 1.57 h, which was higher than T(max) of 8-O-acetylharpagide and harpagide after oral administration of from A. decumbens extract in rats. The different pharmacokinetic parameters may be due to the species differences of rat and beagle dog. PMID- 24066604 TI - [Effects and safety of varying doses of guizhi fuling capsule in patients with primary dysmenorrhea: a multi-center, randomized, double-blind, placebo controlled clinical study]. AB - To evaluate the effects and safety of varying doses of Guizhi Fuling capsule on treating primary dysmenorrhea. From August 2010 to March 2011, 240 subjects (aged 18-30) with primary dysmenorrheal, were enrolled in 8 sites. They were randomized into Guizhi Fuling capsule high dose group, low dose group and placebo control group, 80 cases in each group. These patients were treated for three consecutive menstrual cycles, then were followed up in another three consecutive menstrual cycles. Visual analogue scales (VAS) was used to determine the pain intensity. During the treatment, the high-, low-dose and placebo groups efficiency on pain relief are 68.42%, 67.57% and 47.89% respectively. Guzhi Fuling (included high- and low- dose group) significantly relieves the pain compared to placebo. In follow-up, Guzhi Fuling groups are still superior to the placebo group (73.68%, 72.97% and 53.52%). During the treatment, pain duration reduces 57.88% in high dose group, while 46.17% in low dose group, and 30.40% in placebo group. In follow-up, pain lasting time decrease 67.93%, 53.56%, 47.46%, respectively. Guizhi Fuling significantly reduces the pain duration compared to placebo and high-dose is better than low-dose. The efficacy of Guzhi Fuling (high- and low dose) displays certain dosage-effect relationship. Among these group, no serious adverse event was reported. Guizhi Fuling capsule at high or low dose significantly relieves the pain, improves symptoms, reduces the duration of pain, and has a better overall treatment effect and long-term treatment effect in patients with primary dysmenorrhea. PMID- 24066605 TI - [Preparation and antimicrobial effect of aromatic, natural and bacteriostatic foot wash with skin care]. AB - To prepare the aromatic, natural and bacteriostatic foot wash with skin care and research the inhibition effect on the different bacteria and pathogenic fungus which cause dermatophytosis. It was prepared by using Sophoraflavescens and Dictamnus dasycarpus as materials with the addition of Aloe extract, essential oil, surfactant, etc. The antifungal and antibacterial activity was researched by the levitation liquid quantitative method. The foot wash smelled faintly scent. The use of this product can produce a rich foam. The inhibitory rate were all more than 90%. The preparation process of the foot wash was simple. It has obviously bacteriostatic and fungistatic effect. PMID- 24066606 TI - [Analysis on composition principles of Chinese patent drugs containing ginseng]. AB - Use traditional Chinese medicine inheritance support system (TCMISS) to analyze the composition principles of Chinese patent drugs containing Renshen (Panax ginseng) in national standard for Chinese patent drugs (NSCPD) enacted by Ministry of Public Health of China. Via analyzing the regularity of prescriptions containing Ginseng which are recorded in NSCPD, to identify composition pattern and rule. Tweenty four drugs are used more than 50 times, in which, drugs that tonify qi and nourish flood have the highest frequency, and then medicines of liver and kidney tonifying, yin enriching and yang warming follow. Then 45 commonly used core combinations are analyzed via data mining methods such as association rules, improved mutual information method, etc. Meantime, three diseases, namely, palpitation, amnesia and chest discomfort are chosen from the 24 diseases that Ginseng most frequently used to make deeper analysis, which reflect the composition principle of Chinese patent drugs containing Ginseng. Therefore, TCMISS is an important tool in composition principle exploring of herbal formulae and meanwhile, the comparative analysis method contributes a lot to the exploration as well. PMID- 24066607 TI - [Study on PK/PD model for traditional Chinese medicine biopharmaceutics based on principle of "correspondence of prescriptions and syndromes"]. AB - In the principle of "correspondence of prescription and syndrome", this article focuses on key technical issues of traditional Chinese medicine (TCM) biopharmaceutis by using the integrated pharmacokinetic and pharmacodynamic model: (1) As the prescription formulation and compatibility of TCM compounds could be influential to the in vivo pharmacokinetics of chemical components of TCMs, and closely related to therapeutic and adverse effects, how to describe these actions in a biopharmaceutics model? (2) As there are differences between pharmacokinetic processes in the normal and pathological states, how to express characteristic "syndromes" in an animal model? (3) As prescriptions work to reduce and transform syndromes, how o confirm the type and amount of effective substances in case of physiological and pathological indicators and drug distribution in a dynamic corresponding state. In response to the above key issues, we proposed the TCM biopharmaceutic study model based on PK/PD. (1) The integrity of TCMs was better expressed with the effect at the core, supplemented with the component pharmacokinetics; (2) An integrated pharmacokinetic and pharmacodynamic system was established on the basis of pharmacokinetics and pharmacodynamics of many major effective components; (3) AK/PD mathematical function with the three-phase synchronous characterization of "time-concentration effect" was established by using the data mining techniques, to explore the biopharmaceutic principle of "correspondence of prescriptions and syndromes", in which prescriptions are only required for syndromes, whereas no prescription is required in case of no syndrome. PMID- 24066608 TI - [Understanding of strengthen supervision and administration of herbal extracts]. AB - The article briefly introduces the development history and status of the supervision and administration of herbal extracts, and summarizes the problems existing in the process of supervision and management. Meanwhile provides the countermeasures and suggestions of strengthening the supervision and administration of herbal extracts. PMID- 24066609 TI - Visible-light-responsive photocatalysts toward water oxidation based on NiTi layered double hydroxide/reduced graphene oxide composite materials. AB - A visible-light responsive photocatalyst was fabricated by anchoring NiTi-layered double hydroxide (NiTi-LDH) nanosheets to the surface of reduced graphene oxide sheets (RGO) via an in situ growth method; the resulting NiTi-LDH/RGO composite displays excellent photocatalytic activity toward water splitting into oxygen with a rate of 1.968 mmol g(-1) h(-1) and a quantum efficiency as high as 61.2% at 500 nm, which is among the most effective visible-light photocatalysts. XRD patterns and SEM images indicate that the NiTi-LDH nanosheets (diameter: 100-200 nm) are highly dispersed on the surface of RGO. UV-vis absorption spectroscopy exhibits that the introduction of RGO enhances the visible-light absorption range of photocatalysts, which is further verified by the largely decreased band gap (~1.78 eV) studied by cyclic voltammetry measurements. Moreover, photoluminescence (PL) measurements indicate a more efficient separation of electron-hole pairs; electron spin resonance (ESR) and Raman scattering spectroscopy confirm the electrons transfer from NiTi-LDH nanosheets to RGO, accounting for the largely enhanced carrier mobility and the resulting photocatalytic activity in comparison with pristine NiTi-LDH material. Therefore, this work demonstrates a facile approach for the fabrication of visible-light responsive NiTi-LDH/RGO composite photocatalysts, which can be used as a promising candidate in solar energy conversion and environmental science. PMID- 24066610 TI - Critical study of the charge transfer parameter for the calculation of interaction energy using the local hard-soft acid-base principle. AB - Local hard-soft acid-base (HSAB) principle is semiquantitative in nature due to the presence of an ad hoc charge transfer parameter. The accuracy of HSAB principle significantly depends on the definition of this ad hoc parameter. In this paper, for the first time we have introduced the second-order approximation of DeltaN (DeltaNsecond) as an ad hoc parameter for charge transfer to calculate interaction energies of multiple site based interactions using local hard soft acid base principle. The second-order approximation of DeltaN has been derived from Sanderson's electronegativity equalization principle. To validate our approach, we have studied interaction energies of some prototype molecules. The interaction energies obtained from our approach have been further compared with the interaction energies of those obtained using other charge transfer parameters (DeltaNfirst and lambda) and the conventional methods. We have also discussed the advantages and limitations of the approach. PMID- 24066611 TI - Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis. AB - BACKGROUND: Anti-angiogenesis is a validated strategy to treat cancer, with efficacy in controlling both primary tumor growth and metastasis. The role of the Notch family of proteins in tumor angiogenesis is still emerging, but recent data suggest that Notch signaling may function in the physiologic response to loss of VEGF signaling, and thus participate in tumor adaptation to VEGF inhibitors. METHODS: We asked whether combining Notch and VEGF blockade would enhance suppression of tumor angiogenesis and growth, using the NGP neuroblastoma model. NGP tumors were engineered to express a Notch1 decoy construct, which restricts Notch signaling, and then treated with either the anti-VEGF antibody bevacizumab or vehicle. RESULTS: Combining Notch and VEGF blockade led to blood vessel regression, increasing endothelial cell apoptosis and disrupting pericyte coverage of endothelial cells. Combined Notch and VEGF blockade did not affect tumor weight, but did additively reduce tumor viability. CONCLUSIONS: Our results indicate that Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis, and show that concurrent blockade disrupts primary tumor vasculature and viability further than inhibition of either pathway alone. PMID- 24066612 TI - Establishment of a derivatization method to quantify thiol function in sulfur containing plasma polymer films. AB - Thiol-supported surfaces draw more and more interest in numerous fields of applications from biotechnology to catalysis. Among the various strategies to generate such surfaces, the plasma polymerization of a thiol-containing molecule appears to be one of the ideal candidates. Nevertheless, considering such an approach, a careful characterization of the material surface chemistry is necessary. In this work, an original chemical derivatization method aiming to quantitatively probe the -SH functions in plasma polymers was established using N ethylmaleimide as a labeling molecule. The method was qualitatively and quantitatively validated on self-assembled monolayers of 3 mercaptopropyltrimethoxysilane exhibiting a -SH-terminated group used as "model" surface. For a quantitative determination of the -SH content in propanethiol plasma polymers, the kinetics of the reaction was investigated. The latter is described as a two-step mechanism, namely a fast surface reaction followed by a diffusion-limited one. The density of -SH groups deduced from the derivatization method (~4%) is in good agreement with typical values measured in some other plasma polymer families. The whole set of our data opens up new possibilities for optimizing the -SH content in thiol-based plasma polymer films. PMID- 24066614 TI - Nanotubes complexed with DNA and proteins for resistive-pulse sensing. AB - We use a resistive-pulse technique to analyze molecular hybrids of single-wall carbon nanotubes (SWNTs) wrapped in either single-stranded DNA or protein. Electric fields confined in a glass capillary nanopore allow us to probe the physical size and surface properties of molecular hybrids at the single-molecule level. We find that the translocation duration of a macromolecular hybrid is determined by its hydrodynamic size and solution mobility. The event current reveals the effects of ion exclusion by the rod-shaped hybrids and possible effects due to temporary polarization of the SWNT core. Our results pave the way to direct sensing of small DNA or protein molecules in a large unmodified solid state nanopore by using nanofilaments as carriers. PMID- 24066613 TI - Biochar and microbial signaling: production conditions determine effects on microbial communication. AB - Charcoal has a long soil residence time, which has resulted in its production and use as a carbon sequestration technique (biochar). A range of biological effects can be triggered by soil biochar that can positively and negatively influence carbon storage, such as changing the decomposition rate of organic matter and altering plant biomass production. Sorption of cellular signals has been hypothesized to underlie some of these effects, but it remains unknown whether the binding of biochemical signals occurs, and if so, on time scales relevant to microbial growth and communication. We examined biochar sorption of N-3-oxo dodecanoyl-L-homoserine lactone, an acyl-homoserine lactone (AHL) intercellular signaling molecule used by many gram-negative soil microbes to regulate gene expression. We show that wood biochars disrupt communication within a growing multicellular system that is made up of sender cells that synthesize AHL and receiver cells that express green fluorescent protein in response to an AHL signal. However, biochar inhibition of AHL-mediated cell-cell communication varied, with the biochar prepared at 700 degrees C (surface area of 301 m(2)/g) inhibiting cellular communication 10-fold more than an equivalent mass of biochar prepared at 300 degrees C (surface area of 3 m(2)/g). These findings provide the first direct evidence that biochars elicit a range of effects on gene expression dependent on intercellular signaling, implicating the method of biochar preparation as a parameter that could be tuned to regulate microbial-dependent soil processes, like nitrogen fixation and pest attack of root crops. PMID- 24066615 TI - Metastable interwoven mesoporous metal-organic frameworks. AB - Three isostructural interwoven 3,4-connected mesoporous metal-organic frameworks of pto-a topology (UTSA-28-Cu, UTSA-28-Zn, and UTSA-28-Mn) were synthesized and structurally characterized. Because of their metastable nature, their gas sorption properties are highly dependent on the metal ions and activation profiles. The most stable, UTSA-28a-Cu, exhibits promising gas storage and separation capacities. PMID- 24066616 TI - Importance of matrix effects in LC-MS/MS bioanalysis. PMID- 24066617 TI - Challenges of atypical matrix effects in tissue. PMID- 24066618 TI - New method to identify non-small-cell lung cancer biomarker. PMID- 24066619 TI - Conference report: energized bioanalytical solutions at the 2012 Eastern Analytical Symposium & Exposition. AB - The 51st Eastern Analytical Symposium (EAS) and Exposition was held at the Garden State Exhibit Center in Somerset NJ, USA, from 12-15 November 2012, with a theme of 'Energizing Analytical Solutions'. This conference attracted and energized a diverse group of attendees, presenters, and exhibitors, whose expertise covered the broad topics of analysis in various fields and spanned the frontiers of science through innovation and understanding of nature. The presentations relevant to bioanalysis included: characterization and quantitation of biologics/biomarkers, LC-MS bioanalysis, DBS analysis, microdosing strategy, novel sample preparation techniques, new LC stationary phases, and laboratory management. This conference report highlights some of the lectures and sessions of interest to bioanalysts at the 2012 EAS. PMID- 24066620 TI - HILIC UHPLC-MS/MS for fast and sensitive bioanalysis: accounting for matrix effects in method development. AB - BACKGROUND: Matrix effects are considered to be a main obstacle of quantitative bioanalytical LC-MS/MS methods. Therefore it is often required to minimize them in order to increase method reliability. HILIC has been referenced as one of possible approaches. However, there is a lack of experimental evidence in scientific literature so far. METHODOLOGY: Matrix effects were evaluated using spiked serum samples after SPE and protein precipitation prior to UHPLC-ESI MS/MS. Chromatography was performed in both HILIC and reversed-phase mode. The influence of the matrix effects on the signal response was assessed using a set of 34 compounds of pharmaceutical interest and post-extraction addition approach. RESULTS: The advantages and drawbacks of the HILIC and reversed-phase chromatographic modes were compared and discussed in detail. CONCLUSION: HILIC demonstrated the potential to reduce the occurrence of matrix effects when a more thorough sample pretreatment procedure such as SPE was applied. PMID- 24066621 TI - Impact of organic solvent additive on the integrity of plasma samples in bioanalysis by LC-MS/MS. AB - BACKGROUND: Matrix effects are one of the major drawbacks of ESI-MS/MS. It is majorly caused by lipids in plasma, which can be overcome by using different extraction techniques. RESULTS: In this investigation, a major matrix effect was observed in samples containing a co-administered drug. Unknown compounds appeared over time in the human plasma samples spiked with co-administered drug creating major ion suppression. The changes in matrix integrity were associated with the organic solvent content in the plasma samples. CONCLUSION: The amount and type of organic solvent added to human plasma along with the storage conditions must be carefully determined during method development in order not to impact quantitation. PMID- 24066622 TI - Variability of the IS revealed ionization enhancement by bile acid in mouse plasma. AB - BACKGROUND: Elevated IS response was observed in 22 out of 157 mouse plasma samples in a 3-month toxicity study. This initiated a root cause investigation. RESULTS: Mass spectra revealed that taurocholic acid (TCA) was present in the samples, partially eluted overlapping the analyte peak. An enhanced IS response (> twofold) was reproduced by injecting TCA together with the IS. Tests with five other drug compounds showed compound dependent matrix effects on ESI; enhancement as well as suppression. The matrix effects did not affect the integrity of study results, most likely due to the use of a 13C-labeled IS. CONCLUSION: The variability of TCA levels in plasma as well as the observed instability of the chromatographic retention complicates the evaluation of TCA-induced matrix effects during method development. Thus, monitoring the IS response in incurred samples is a useful tool to evaluate the performance of a validated method. PMID- 24066623 TI - Systematic investigation of orthogonal SPE sample preparation for the LC-MS/MS bioanalysis of a monoclonal antibody after pellet digestion. AB - BACKGROUND: Increasing assay sensitivity is critical for promoting the application of LC-MS/MS quantitative bioanalysis of therapeutic proteins. A sample processing method that can selectively remove the abundant background peptides in the serum tryptic digests and retain the target peptides can greatly improve the assay sensitivity. RESULTS: Mixed-mode strong-cation exchange SPE was systematically investigated as an orthogonal sample separation technique to reversed-phase UHPLC for the analysis of a test monoclonal antibody, BMS-986012, in monkey serum after pellet digestion. Strong cation exchange SPE efficiently removed most of the background peptides and reduced the matrix effect and background level in the monitored mass transition channels. As a result, improved sensitivity was observed for the surrogate peptides VVSV and SLIY. CONCLUSION: This orthogonal approach provides a simple and easy-to-develop sample preparation method that can selectively remove most background peptides and extract the target peptides, therefore, improving the LC-MS/MS assay sensitivity. PMID- 24066624 TI - Aging of biological matrices and its effect on bioanalytical method performance. AB - Apart from the well-known matrix effects that can occur in ESI LC-MS, biological matrices may have other effects influencing the quantitative reliability of bioanalytical methods. In this paper, six case studies are presented that show the effect that aging, that is the change in properties and composition of biological matrices over time, can have on the performance of bioanalytical methods. It is shown that selectivity can be affected due to the formation or disappearance of endogenous compounds. Stability can be influenced because of the decrease (or increase) of enzyme activities and recovery can be impacted if the extractability from binding sites in the matrix is enhanced or decreased. A general discussion on the importance of these matrix effects is provided as well as a perspective on how to properly address them in the method-development and validation stages of regulated bioanalysis. PMID- 24066625 TI - Case studies: the impact of nonanalyte components on LC-MS/MS-based bioanalysis: strategies for identifying and overcoming matrix effects. AB - Achieving sufficient selectivity in bioanalysis is critical to ensure accurate quantitation of drugs and metabolites in biological matrices. Matrix effects most classically refer to modification of ionization efficiency of an analyte in the presence of matrix components. However, nonanalyte or matrix components present in samples can adversely impact the performance of a bioanalytical method and are broadly considered as matrix effects. For the current manuscript, we expand the scope to include matrix elements that contribute to isobaric interference and measurement bias. These three categories of matrix effects are illustrated with real examples encountered. The causes, symptoms, and suggested strategies and resolutions for each form of matrix effects are discussed. Each case is presented in the format of situation/action/result to facilitate reading. PMID- 24066627 TI - Compositional analysis of Chinese water chestnut (Eleocharis dulcis) cell-wall material from parenchyma, epidermis, and subepidermal tissues. AB - Chinese water chestnut (Eleocharis dulcis (Burman f.) Trin ex Henschel) is a corm consumed globally in Oriental-style cuisine. The corm consists of three main tissues, the epidermis, subepidermis, and parenchyma; the cell walls of which were analyzed for sugar, phenolic, and lignin content. Sugar content, measured by gas chromatography, was higher in the parenchyma cell walls (931 MUg/mg) than in the subepidermis (775 MUg/mg) or epidermis (685 MUg/mg). The alkali-extractable phenolic content, measured by high-performance liquid chromatography, was greater in the epidermal (32.4 MUg/mg) and subepidermal cell walls (21.7 MUg/mg) than in the cell walls of the parenchyma (12.3 MUg/mg). The proportion of diferulic acids was higher in the parenchyma. The Klason lignin content of epidermal and subepidermal cell walls was ~15%. Methylation analysis of Chinese water chestnut cell-wall polysaccharides identified xyloglucan as the predominant hemicellulose in the parenchyma for the first time, and also a significant pectin component, similar to other nongraminaceous monocots. PMID- 24066628 TI - Autosomal dominant drusen--a case study. PMID- 24066629 TI - Current issues and future directions in evidence-based child protection practices: a view from Romania. AB - The constantly changing nature of social care practice necessitates continuous development of educational programs to prepare current practitioners. Basing social work practice on methodologically sound research evidence is an appealing prospect for the child protection services. However, Romania, once considered an Eastern European model for child welfare policy and practice, is somehow lagging behind. In this article the author gives a short overview of where the Romanian Child Protection System currently stands in terms of evidence-based practice. PMID- 24066630 TI - Mental health clinicians' experiences of implementing evidence-based treatments. AB - Implementation research has tremendous potential to bridge the research-practice gap; however, we know more about barriers to evidence-based care than the factors that contribute to the adoption and sustainability of evidence-based treatments. In this qualitative study the authors explore the experiences of clinicians (N = 11) who were implementing evidence-based treatments, highlighting the factors that they perceived to be most critical to successful implementation. The clinicians' narratives reveal many leverage points that can inform administrators, clinical supervisors, and clinicians who wish to implement evidence-based treatments, as well as other stakeholders who wish to develop and test strategies for moving evidence-based treatments into routine care. PMID- 24066631 TI - Early childhood attachment and its impact on later life resilience: a comparison of resilient and non-resilient female siblings. AB - Prior research has repeatedly identified early childhood attachment as a primary protective factor. In this study the authors sought to assess if there were significant differences in the attachment levels of resilient females in comparison to their non-resilient female siblings. The authors examine, using standardized attachment scales, the levels of attachment through the use of an intra-family research design. The study consists of a comparative analysis of female inmates from five Midwestern state correctional departments to their resilient female siblings' attachments, in correlation with their subsequent use of alcohol and/or drugs and the completion of high school. This is a replication of Stacy's (2004, 2006) research of the attachment levels of male resilient individuals in comparison to their non-resilient siblings. The conclusions may be utilized by practitioners identifying appropriate interventions for female youth at risk of becoming non-resilient. PMID- 24066632 TI - Stressors, social support, religious practice, and general well-being among Korean adult immigrants. AB - Through this cross-sectional study the authors explore how stressors, social support, and religious practice are associated with the general well-being of 147 Korean adult immigrants through interviews. Hierarchical regression analysis reveals that low English proficiency and financial hardship are significantly related to low general well-being. However, high social support and religious practice are significantly associated with high general well-being. Social service and health care providers need to carefully assess stressors, social support systems, and spiritual issues for providing appropriate services/programs for English, culture, or social activities as well as spiritual intervention to maximize the strengths of Korean immigrants coping with health issues. PMID- 24066633 TI - Concoction of harmful substances in homemade alcoholic beverages in rural areas of Mopani district in Limpopo province-RSA: implications for social work practice. AB - The primary aim of this article is to explore and describe the production and consumption of homemade alcohol and its associated challenges in relation to implications for social work practice. Qualitative, explorative, descriptive, and contextual design was ideal and purposive and snowball sampling methods were used in this research. Data was collected through interviews with brewers and consumers of homemade alcoholic beverages. It was found that foreign substances are put into homemade alcoholic beverages for commercial reasons in an attempt to address social exclusion. PMID- 24066634 TI - The extent of evidence-based information about child maltreatment fatalities in social science textbooks. AB - Previous research has established that child welfare workers lack important information about child maltreatment fatalities and risk factors leading to death. Further, training has not been associated with improvements in knowledge. The authors assessed the presence of evidence-based information about child maltreatment fatalities and risk factors for death in 24 social science textbooks about child abuse and neglect or child welfare. The results indicate that basic information, such as definitions and incidence rates of child maltreatment fatalities are routinely included in social science textbooks, but information about child, parent, and household risk factors are not, and that inaccurate information is often included. Implications of the findings are discussed. PMID- 24066635 TI - Applying inoculation theory to the study of recidivism reduction in criminal prison inmates. AB - The purpose of the authors through this study is to establish inoculation theory as a viable method in the prevention or reduction of recidivism in criminal prison inmate populations in the United States. The authors begin with a detailed literature review on inoculation. They also describe, in detail, recidivism in prisons. In doing so, they provide a series of interconnected topics, such as the total number of inmates in U.S. prisons, statistical displays of repeat offenders or subjects of recidivism, and the types of crimes often times repeated by convicted criminals. What comes afterwards is an explication of how inoculation theory can be applied in the context of reducing prisoner recidivism. The authors conclude this study with a discussion section that offers suggestions for future research. PMID- 24066636 TI - Social workers as "experts" in the family court system: is evidence-based practice a missing link or host-created knowledge? AB - The graduate school curriculum for social workers requires that students learn to critically distinguish between opinion-based knowledge and evidence-based practices, or empirically-supported interventions. Once graduated, licensed social workers are often called upon to offer diagnostic and predictive opinions as experts in a variety of macro-environments. When the family courts are that "host" environment, social workers proffer expert opinions that may categorize and label parents or children for purposes of a judge's allocation of physical or legal custody. In this article, it is suggested that the social work profession, within all three domains of education, practice, and research, should more precisely link the design and fidelity of an evidence-based practice (EBP) with its potential misapplication or warping when proffered as science in "host" environments like family courts. As Foucault and other scholars warn, the failure to verify that an intervention is applied correctly may actually enhance the risk of social injustice by interpreting and translating EBP knowledge in the non empirical form of authority-by-license. This article, therefore, proposes that the social work profession, from the classroom to the field, has an obligation to thoroughly understand and engage interdisciplinary practices that assure respect for the strengths and limits of social work knowledge. PMID- 24066637 TI - Enhancing aging services through evidence-based health promotion: a training for service providers. AB - During the next several decades, increasing numbers of older Americans will suffer chronic illnesses and many will face challenges due to growing racial and economic health disparities. Agencies serving older adults need to respond by creating and promoting evidence-based health promotion (EBHP) practices to address the growing diversity among older adults in urban areas. One such agency, the Detroit Area Agency on Aging recently partnered with the Wayne State University School of Social Work to conduct an EBHP educational program for service providers. The educational program used information from the National Council on Aging Center for Healthy Aging, the reach, effectiveness/efficacy, adoption, implementation, and maintenance (RE-AIM) model, and the National Wellness Institute. Survey respondents found that the interaction with other participants was beneficial and helped them to conceptualize EBHP as a new way of thinking about service delivery. Participants learned practical lessons about implementing a training program on evidence-based practice and additional steps are offered to increase the uptake of EBHP practices by older adult service providers. PMID- 24066638 TI - Learning and change in a community mental health setting. AB - This article offers methodological reflections and lessons learned from a three year university-community partnership that used participatory action research methods to develop and evaluate a model for learning and change. Communities of practice were used to facilitate the translation of recovery-oriented and evidence-based programs into everyday practice at a community mental health agency. Four lessons were drawn from this project. First, the processes of learning and organizational change are complex, slow, and multifaceted. Second, development of leaders and champions is vital to sustained implementation in an era of restricted resources. Third, it is important to have the agency's values, mission, policies, and procedures align with the principles and practices of recovery and integrated treatment. And fourth, effective learning of evidence based practices is influenced by organizational culture and climate. These four lessons are expanded upon and situated within the broader literature and implications for future research are discussed. PMID- 24066639 TI - Mental health management of pathological gamblers by counseling and relaxation practices. AB - The present study examines the mental health management of pathological gamblers by counseling and relaxation practices. Fifty-five treated and 55 non-treated pathological gamblers were evaluated at S. I. Mental and Physical Health Society, Varanasi, India. The two groups were matched by age, ranging 20 to 53 years with a mean age of 36.2 years and mean length of uncontrollable gambling of 7.3 years. The Middlesex Hospital Questionnaire and the Death Anxiety Scale were administered to ascertain mental health and death anxiety on seven selected dimensions, including: anxiety, obsession, phobia, somatization, depression, hysteria, and death anxiety. Mean scores obtained on different variables were analyzed using a t-test of significance. Results indicated that the characteristic associated with treated pathological gamblers was phobia whereas the characteristics associated with non-treated pathological gamblers were anxiety, obsession, somatization, depression, and death anxiety. PMID- 24066640 TI - Social work and online education with all deliberate speed. AB - Imagine a whiteboard, virtual classrooms, instant messaging, chat rooms, Wikis ... and you are visualizing online Web-facilitated education. Is this the direction of social work education or is this a vision of social work that is not quite in focus? In this article the author asserts that online education with its technological innovations is here to stay and that the technological advances are increasing and becoming a driving force in higher education. This force is transforming teaching and learning. To what extent is social work involved in this 21st century transformation and is it enough? PMID- 24066641 TI - Service delivery on rusty health care wheels: implications for visible minority women. AB - The primary purpose of this article is to demonstrate how immigrant/refugee women's access to health services is influenced by both immigration and health policies. The author argues that the wheel of health care must revolve along with the wheel of immigration. The application of health immigration policies that existed preconfederation, as well as health care interventions based on Eurocentric principles, limit minority women's accessibility to health services. An integrated dialogue between all levels of government, health care professionals, policy makers, researchers, and immigrant groups is critical to provide equitable access to health care to foster immigrant settlement in Canada's smaller communities and rural areas. PMID- 24066644 TI - Self-decoupled porphyrin with a tripodal anchor for molecular-scale electroluminescence. AB - A self-decoupled porphyrin with a tripodal anchor has been synthesized and deposited on Au(111) using different wet-chemistry methods. Nanoscale electroluminescence from single porphyrin molecules or aggregates on Au(111) has been realized by tunneling electron excitation. The molecular origin of the luminescence is established by the vibrationally resolved fluorescence spectra observed. The rigid tripodal anchor not only acts as a decoupling spacer but also controls the orientation of the molecule. Intense molecular electroluminescence can be obtained from the emission enhancement provided by a good coupling between the molecular transition dipole and the axial nanocavity plasmon. The unipolar performance of the electroluminescence from the designed tripodal molecule suggests that the porphyrin molecule is likely to be excited by the injection of hot electrons, and then the excited state decays radiatively through Franck Condon pi*-pi transitions. These results open up a new route to generating electrically driven nanoscale light sources. PMID- 24066645 TI - Effect of one-year growth hormone therapy on body composition and cardio metabolic risk in Indian children with growth hormone deficiency. AB - Growth hormone (GH) deficiency in children manifests as short stature but is also associated with metabolic disturbances. Paucity of GH is also likely to be associated with increased intima media thickness. Data on body composition (BC) and carotid intima media thickness (cIMT) in children with growth hormone deficiency (GHD) from developing countries are very scarce. Therefore, objectives of present study were to assess effect of 1 year of rhGH therapy on (i) BC and lipid profile (LP) in a cohort of Indian GHD children and (ii) effect on atherosclerotic markers - cIMT in subsample. Anthropometry, BC [% body fat (BF), % lean body mass (LBM), bone mineral content (BMC)] (DXA) and LP were measured in 49 pre-pubertal GHD-children (9.3 +/- 3.1 years) at baseline and after 1 year of rhGH therapy. On subset of 20 children, cIMT of right common carotid artery was also measured. Baseline BC parameters were compared with age-gender matched healthy controls (n = 49). At baseline % BF was 23 +/- 9 %, LBM was 9 +/- 3 kg and BMC was 0.306 +/- 0.15 kg in GHD- children; BF was comparable, while lean and bone were less than controls (p < 0.05). Post therapy, significant reduction in fat (15%), and cIMT (7%) and increase in LBM and BMC by 40% and 44%, respectively (p < 0.05) was seen. Our cohort of untreated GHD children had abnormal BC and cIMT as compared to controls. rhGH therapy for 1 year had beneficial effect on BC and cardiovascular risk factors. PMID- 24066646 TI - World Health Assembly adopts comprehensive Mental Health Action Plan for 2013 2020. PMID- 24066647 TI - Psychiatric nurses' beliefs, attitudes, and perceived barriers about medical emergency teams. AB - A literature review of nurses' attitudes, beliefs, and barriers regarding the medical emergency team (MET) process is limited to medical hospitals. How psychiatric nurses view the MET process and their prior experiences with METs are important because they are often the ones assessing the need for, and then calling, the MET. This article examines psychiatric nurses' attitudes, beliefs, and barriers toward the MET process in a 310-bed psychiatric hospital that is part of an urban academic medical center. Through the use of key informant interviews, nurses were asked for their feedback and input regarding the current MET practices. The results may be useful in improving the current operating system. PMID- 24066648 TI - Validity and reliability of a Swedish questionnaire for assessing satisfaction with housing and housing support for persons with psychiatric disabilities. AB - The aim of this study was to investigate the reliability and validity of a questionnaire for studying satisfaction with housing and housing support for people with psychiatric disabilities. Most items were gathered from English language questionnaires. These were translated and adapted to a Swedish context and items concerning housing support were added. Two studies were conducted. The first, a test-retest reliability analysis, was performed in a pilot study with 53 participants; in the second study, which had 370 participants, a five factor solution with good internal consistency emerged. Further development of the questionnaire is discussed. PMID- 24066649 TI - Moving toward reclaiming life: lived experiences of being physically active among persons with psychiatric disabilities. AB - There is abundant documentation in research about the significant relationship between physical activity and mental health, but there is still more to be learned about what can enhance motivation to become more physically active. Fourteen persons with psychiatric disabilities were interviewed about their experiences of being physically active, and data was analyzed using a phenomenological-hermeneutic method. Five themes emerged: Capability for Living, Liberation from a Heavy Mind, Companionship in Being in Motion, Longing for Living One's Life, and Struggling with Limitations. The interpreted meaning of being physically active was to be moving toward reclaiming one's life. PMID- 24066650 TI - Social determinants of methadone in pregnancy: violence, social capital, and mental health. AB - Mothering and methadone can occur together with the right resources and support. Methadone mothers need to be seen in the context of their social risks and environment. Societal attitudes, social capital, and other contextual variables can be changed through policy. The purpose of this article is to describe the contextual risks experienced by drug abusing mothers in order to direct further research and policy changes that protect their children. Research has focused on biological or genetic determinants, but now social risks and environmental factors are shaping current literature about substance abuse in pregnancy. Significant risk factors, taken from the literature, are detailed, such as intimate partner violence and mental health co-morbidities. Racial differences and the effect of place on pregnant substance abusers are also discussed. Policy recommendations address the barriers substance abusing women face in their journey toward a healthy pregnancy. PMID- 24066651 TI - Integrating mental health and addictions services to improve client outcomes. AB - Substance use disorders are highly prevalent among adults with mental health disorders. In many health service delivery areas, mental health and addictions services are delivered separately. However, current best practices indicate that integration of mental health and addictions services can lead to better outcomes for clients with co-occurring disorders, including fewer hospitalizations. Service integration in the community can occur in many ways, including full or partial program integration. While the delivery of mental health and addictions services must be responsive to the needs of the local community, fully integrated programs have the strongest evidence base for positive client outcomes. PMID- 24066652 TI - Older persons' lived experiences of depression and self-management. AB - Mental ill-health, such as depression in the elderly, is a complex issue that is influenced by the life-world perspective of older persons. Their self-management ability should be strengthened based on an understanding of their situation, perspectives, and vulnerability. The aim of this study was to explore and increase understanding of old persons' lived experiences of depression and self management using an interpretative explorative design. Understanding was developed by means of hermeneutic interpretation. One theme, Relationships and Togetherness, and four subthemes, A Sense of Carrying a Shoulder Bag, Walking on Eggshells, Holding the Reins, and Estrangement--a Loss of Togetherness, emerged. A collaborative approach can be important for empowering older persons through self-development and management. Although the findings of the present study cannot be considered conclusive or definitive, they nevertheless contribute new knowledge of older persons' lived experiences of depression in everyday life. PMID- 24066653 TI - Iranian nurses' experiences of aggression in psychiatric wards: a qualitative study. AB - Aggression from psychiatric patients is a constant problem for care providers that causes major problems in the therapeutic environment, and may have negative effects on the quality of care. Since recognition of aggression with regard to cultural background leads to better control of aggression in the psychiatric wards, this study has been done to clarify Iranian nurses' experiences of aggression in psychiatric wards. A qualitative content analysis study was conducted to explore experiences of nurses. Data analysis revealed four themes: (1) Damage resulting from aggression, (2) Aggression catalysts, (3) Contagious nature of aggression, and (4) Various control strategies. There are various causes for in-patients' aggression, and nurses use various approaches to control it. These approaches are influenced by personnel, facilities, and ward environment. Identifying these factors and strategies can contribute to better management of aggression and, thus, better quality of care in psychiatric wards. PMID- 24066654 TI - Contextualizing mental health nursing encounters in Australian remote aboriginal communities: Part 2, client encounters and interviews. PMID- 24066655 TI - Collegial cross-cultural relations for health academics: concepts and considerations. PMID- 24066656 TI - Paliperidone palmitate injection site. PMID- 24066658 TI - Quantum-chemical and molecular dynamics study of M+ [TOTO]- (M = Li, Na, K) ionic liquids. AB - Quantum-chemical calculations and classical molecular dynamics simulations with the Optimized Potentials for Liquid Simulations-All Atom (OPLS-AA) force field are presented for ionic liquids based on 2,5,8,11-tetraoxatridecan-13-oate anion (TOTO) and alkali cations (Li, Na, K). Complexation energies decrease with increasing cation radius from Li to K. Cation interactions with carboxylate oxygen atoms are preferred over complexation to ether oxygens. Cross-linking occurs in the structure of the liquid because of interactions of multiple metal ions with carboxylate oxygen atoms from multiple TOTO anions. Anticorrelated motion of ions of the same charge is an important factor decreasing conductivity of the liquid. Results of modeling agree with available experimental data for Na TOTO. PMID- 24066659 TI - Multifocal infections of the musculoskeletal system: description of a safe one step procedure for eradication of associated spinal infections. AB - BACKGROUND: The aim of this study was to evaluate the clinical outcome after radical surgical treatment of multifocal infections involving the spine. METHODS: The study demonstrates a retrospective chart review of seven patients who had more than three different abscesses in the musculoskeletal system and at least one of them in the area of the spinal column. All patients had a sepsis. RESULTS: Beside different musculoskeletal abscesses four patients had a spondylodiscitis in the cervical spine segments C4/5 or C5/6. Six patients had inflammatory processes in the lumbar spine with epidural abscesses, diffuse thoracolumbar paravertebral abscesses and a spondylodiscitis in different segments. In all cases we performed a radical surgical treatment of all related inflammatory focuses. Prompt radical surgical treatment of the spine included decompression, debridement and in the cases of spondylodiscitis a fusion of the involved segments. For more than one focus at the spine, a surgical one-step procedure was performed. An antibiotic therapy was administered for six to eight weeks. In follow up examinations no signs of ongoing inflammatory processes were seen in imaging studies or laboratory tests. CONCLUSIONS: In the event of multiple abscesses of the musculoskeletal system involving the spine an early correct diagnosis and radical surgical treatment is recommended. We strongly favor a surgical single-stage procedure for treatment of multiple infections of the spine. In addition to a radical debridement and a sufficient decompression, the segmental fusion of affected areas in spondylodiscitis is essential. At the same time a surgical therapy of all other infected sites should be performed. PMID- 24066660 TI - Comparison of clinical and dental panoramic findings: a practice-based crossover study. AB - BACKGROUND: Aim was to compare clinical findings with x-ray findings using dental panoramic radiography (DPR). In addition, type and frequency of secondary findings in x-rays were investigated. METHODS: Patients were selected on the basis of available DPRs (not older than 12 months). No therapeutic measures were permitted between the DPR and the clinical findings. The clinical findings were carried out by several investigators who had no knowledge of the purpose of the study. A calibrated investigator established the x-ray findings, independently and without prior knowledge of the clinical findings. The evaluation parameters for each tooth were: missing, healthy, carious, restorative or prosthetically sufficient or insufficient treatment. Type and frequency of additional findings in the DPR were documented, e.g. quality of a root canal filling and apical changes. RESULTS: Findings of 275 patients were available. Comparison showed a correspondence between clinical and radiographic finding in 93.6% of all teeth (n = 7,789). The differences were not significant (p > 0.05). Regarding carious as well as insufficiently restored or prosthetically treated teeth, respectively there were significant differences between the two methods (p < 0.05). The DPRs showed additional findings: root fillings in 259 teeth and 145 teeth with periapical changes. CONCLUSIONS: With reference to the assessment of teeth, there was no difference between the two methods. However, in the evaluation of carious as well as teeth with insufficiently restorative or prosthetic treatment, there was a clear discrepancy between the two methods. Therefore, it would have been possible to have dispensed with x-rays. Nevertheless, additional x-ray findings were found. PMID- 24066661 TI - Hormone variations associated with quantitative fat measures in the menopausal transition. AB - OBJECTIVE: Reproductive hormone levels are associated with body size, and the association between estradiol and body size varies over the menopausal transition. This study aims to delineate these relationships using quantitative measures of visceral and subcutaneous fat. METHODS: Early follicular hormones (follicle stimulating hormone (FSH), estradiol, luteinizing hormone, dehydroepiandrosterone sulfate, testosterone) and T-1 weighted abdominal MRI images were obtained in a cross-sectional assessment of 77 women in the Penn Ovarian Aging Study. Fat volume (cm(3)) was quantified using validated software (Amira) and divided into tertiles of visceral and subcutaneous fat volume for analysis. Multivariable linear regression models compared hormone values between tertiles adjusting for race, age, and menopausal status. RESULTS: In adjusted models, estradiol was positively associated with visceral fat tertiles (geometric mean (GM) estradiol (pg/ml): Low 13.0, Mid 17.5, High 26.7, p = 0.006) while FSH was inversely associated with visceral fat tertiles (GM FSH (mIU/ml): Low 42.8, Mid 43.2, High 30.8, p = 0.03). The association of estradiol with visceral and subcutaneous fat tertiles varied by menopausal status (p < 0.001). In the early transition, estradiol was similar across tertiles of fat; postmenopause, estradiol was positively associated with visceral fat. Other hormones were not associated with fat measures. CONCLUSIONS: Estradiol was associated with quantitative measures of visceral fat and varies by menopausal status. This finding suggests that visceral fat may be an important mediator in hormone changes over the menopausal transition. PMID- 24066662 TI - An independent construct for conditional expression of atonal homolog-1. AB - The mammalian homolog of the basic helix-loop-helix transcription factor atonal-1 (Atoh1 or Math1) is required for development of cochlear hair cells that function as the mechanosensory cells required for audition. Forced expression of Atoh1 in cochlear-supporting cells may provide a way to regenerate hair cells and provide for a therapy for hearing loss. Additionally, Atoh1 is an inhibitor of proliferation and has further clinical applications in anticancer therapies. The goal of these experiments was to improve the method for Atoh1 expression by engineering a genetic construct that may be used in future translational applications. To address the poor control of Atoh1 expression in standard gene expression systems where Atoh1 is expressed constitutively at abnormally elevated levels, our aim was to engineer an inducible system whereby Atoh1 was upregulated by an inducer and downregulated once the inducer was removed. A further aim was to engineer a single genetic construct that allowed for conditional expression of Atoh1 independent of secondary regulatory elements. Here we describe a stand alone genetic construct that utilizes the tamoxifen sensitivity of a mutated estrogen receptor (ER) ligand-binding domain for the conditional expression of Atoh1. The Atoh1-ER-DsRed construct is translated into an ATOH1-ER-DSRED fusion protein that remains sequestered in the cytoplasm and therefore rendered inactive because it cannot enter the nucleus to activate Atoh1 signaling pathways. However, application of 4-hydroxytamoxifen results in translocation of the fusion protein to the nucleus, where it binds to the Atoh1 enhancer, upregulates transcription and translation of endogenous ATOH1 and activates downstream Atoh1 signaling such as upregulation of the hair cell protein MYOSIN 7A. Removal of tamoxifen reverses the upregulation of endogenous Atoh1 signaling. This construct serves as an independent genetic construct that allows for the conditional upregulation and downregulation of Atoh1, and may prove useful for manipulating Atoh1 expression in vivo. PMID- 24066663 TI - Single nucleotide polymorphisms and haplotypes associated with feed efficiency in beef cattle. AB - BACKGROUND: General, breed- and diet-dependent associations between feed efficiency in beef cattle and single nucleotide polymorphisms (SNPs) or haplotypes were identified on a population of 1321 steers using a 50 K SNP panel. Genomic associations with traditional two-step indicators of feed efficiency - residual feed intake (RFI), residual average daily gain (RADG), and residual intake gain (RIG) - were compared to associations with two complementary one-step indicators of feed efficiency: efficiency of intake (EI) and efficiency of gain (EG). Associations uncovered in a training data set were evaluated on independent validation data set. A multi-SNP model was developed to predict feed efficiency. Functional analysis of genes harboring SNPs significantly associated with feed efficiency and network visualization aided in the interpretation of the results. RESULTS: For the five feed efficiency indicators, the numbers of general, breed dependent, and diet-dependent associations with SNPs (P-value < 0.0001) were 31, 40, and 25, and with haplotypes were six, ten, and nine, respectively. Of these, 20 SNP and six haplotype associations overlapped between RFI and EI, and five SNP and one haplotype associations overlapped between RADG and EG. This result confirms the complementary value of the one and two-step indicators. The multi SNP models included 89 SNPs and offered a precise prediction of the five feed efficiency indicators. The associations of 17 SNPs and 7 haplotypes with feed efficiency were confirmed on the validation data set. Nine clusters of Gene Ontology and KEGG pathway categories (mean P-value < 0.001) including, 9nucleotide binding; ion transport, phosphorous metabolic process, and the MAPK signaling pathway were overrepresented among the genes harboring the SNPs associated with feed efficiency. CONCLUSIONS: The general SNP associations suggest that a single panel of genomic variants can be used regardless of breed and diet. The breed- and diet-dependent associations between SNPs and feed efficiency suggest that further refinement of variant panels require the consideration of the breed and management practices. The unique genomic variants associated with the one- and two-step indicators suggest that both types of indicators offer complementary description of feed efficiency that can be exploited for genome-enabled selection purposes. PMID- 24066664 TI - Methodological developments in searching for studies for systematic reviews: past, present and future? AB - The Cochrane Collaboration was established in 1993, following the opening of the UK Cochrane Centre in 1992, at a time when searching for studies for inclusion in systematic reviews was not well-developed. Review authors largely conducted their own searches or depended on medical librarians, who often possessed limited awareness and experience of systematic reviews. Guidance on the conduct and reporting of searches was limited. When work began to identify reports of randomized controlled trials (RCTs) for inclusion in Cochrane Reviews in 1992, there were only approximately 20,000 reports indexed as RCTs in MEDLINE and none indexed as RCTs in Embase. No search filters had been developed with the aim of identifying all RCTs in MEDLINE or other major databases. This presented The Cochrane Collaboration with a considerable challenge in identifying relevant studies.Over time, the number of studies indexed as RCTs in the major databases has grown considerably and the Cochrane Central Register of Controlled Trials (CENTRAL) has become the best single source of published controlled trials, with approximately 700,000 records, including records identified by the Collaboration from Embase and MEDLINE. Search filters for various study types, including systematic reviews and the Cochrane Highly Sensitive Search Strategies for RCTs, have been developed. There have been considerable advances in the evidence base for methodological aspects of information retrieval. The Cochrane Handbook for Systematic Reviews of Interventions now provides detailed guidance on the conduct and reporting of searches. Initiatives across The Cochrane Collaboration to improve the quality inter alia of information retrieval include: the recently introduced Methodological Expectations for Cochrane Intervention Reviews (MECIR) programme, which stipulates 'mandatory' and 'highly desirable' standards for various aspects of review conduct and reporting including searching, the development of Standard Training Materials for Cochrane Reviews and work on peer review of electronic search strategies. Almost all Cochrane Review Groups and some Cochrane Centres and Fields now have a Trials Search Co-ordinator responsible for study identification and medical librarians and other information specialists are increasingly experienced in searching for studies for systematic reviews.Prospective registration of clinical trials is increasing and searching trials registers is now mandatory for Cochrane Reviews, where relevant. Portals such as the WHO International Clinical Trials Registry Platform (ICTRP) are likely to become increasingly attractive, given concerns about the number of trials which may not be registered and/or published. The importance of access to information from regulatory and reimbursement agencies is likely to increase. Cross-database searching, gateways or portals and improved access to full-text databases will impact on how searches are conducted and reported, as will services such as Google Scholar, Scopus and Web of Science. Technologies such as textual analysis, semantic analysis, text mining and data linkage will have a major impact on the search process but efficient and effective updating of reviews may remain a challenge.In twenty years' time, we envisage that the impact of universal social networking, as well as national and international legislation, will mean that all trials involving humans will be registered at inception and detailed trial results will be routinely available to all. Challenges will remain, however, to ensure the discoverability of relevant information in diverse and often complex sources and the availability of metadata to provide the most efficient access to information. We envisage an ongoing role for information professionals as experts in identifying new resources, researching efficient ways to link or mine them for relevant data and managing their content for the efficient production of systematic reviews. PMID- 24066665 TI - Surveillance during pregnancy: methods and response rates from a hospital based pilot study of the Pregnancy Risk Assessment Monitoring System in Ireland. AB - BACKGROUND: Many European countries including Ireland lack high quality, on going, population based estimates of maternal behaviours and experiences during pregnancy. PRAMS is a CDC surveillance program which was established in the United States in 1987 to generate high quality, population based data to reduce infant mortality rates and improve maternal and infant health. PRAMS is the only on-going population based surveillance system of maternal behaviours and experiences that occur before, during and after pregnancy worldwide. METHODS: The objective of this study was to adapt, test and evaluate a modified CDC PRAMS methodology in Ireland. The birth certificate file which is the standard approach to sampling for PRAMS in the United States was not available for the PRAMS Ireland study. Consequently, delivery record books for the period between 3 and 5 months before the study start date at a large urban obstetric hospital [8,900 births per year] were used to randomly sample 124 women. Name, address, maternal age, infant sex, gestational age at delivery, delivery method, APGAR score and birth weight were manually extracted from records. Stillbirths and early neonatal deaths were excluded using APGAR scores and hospital records. Women were sent a letter of invitation to participate including option to opt out, followed by a modified PRAMS survey, a reminder letter and a final survey. RESULTS: The response rate for the pilot was 67%. Two per cent of women refused the survey, 7% opted out of the study and 24% did not respond. Survey items were at least 88% complete for all 82 respondents. Prevalence estimates of socially undesirable behaviours such as alcohol consumption during pregnancy were high [>50%] and comparable with international estimates. CONCLUSION: PRAMS is a feasible and valid method of collecting information on maternal experiences and behaviours during pregnancy in Ireland. PRAMS may offer a potential solution to data deficits in maternal health behaviour indicators in Ireland with further work. This study is important to researchers in Europe and elsewhere who may be interested in new ways of tailoring an established CDC methodology to their unique settings to resolve data deficits in maternal health. PMID- 24066671 TI - Scandium triflate-catalyzed nucleophilic additions to indolylmethyl Meldrum's acid derivatives via a gramine-type fragmentation: synthesis of substituted indolemethanes. AB - Treatment of indolylmethyl Meldrum's acids with catalytic scandium triflate and a variety of nucleophiles results in the nucleophilic displacement of the Meldrum's acid moiety via a gramine-type fragmentation. The reaction is useful for the generation of heterocyclic compounds of significant molecular complexity. PMID- 24066670 TI - Head and neck irradiation modulates pharmacokinetics of 5-fluorouracil and cisplatin. AB - BACKGROUND: 5-fluorouracil (5-FU) and cisplatin (CDDP) are used to enhance radiotherapy (RT) effect for head and neck (HN) cancers. However, the effect of local RT on systemic chemotherapeutics remains unclear. Here, we evaluated the influence of HN irradiation on the pharmacokinetics (PK) of 5-FU and CDDP in rats as experimental model. METHODS: The radiation dose distributions of HN cancer patients were determined for the low dose areas, which are generously deposited around the target volume. Two Gy and 0.5 Gy RT were selected. Single-fraction radiation was delivered to the HN of Sprague-Dawley rats. 5-FU at 100 mg/kg or CDDP at 5 mg/kg was intravenously infused 24 hours after radiation. RESULTS: Radiation at 2 Gy reduced the area under the plasma concentration vs. time curve (AUC) of 5-FU and CDDP by 16% and 29% compared to non-irradiated controls, respectively. This was accompanied by incremental total plasma clearance values. Intriguingly, low dose radiation at 0.5 Gy resulted in a similar pharmacokinetic profile, with a 17% and 33% reduction in the AUC of 5-FU and CDDP, respectively. The changes in AUC of bile, which increases with RT, were opposite to AUC of plasma for both drugs. CONCLUSIONS: The local HN RT could modulate systemic PK of 5-FU and CDDP in rats. This unexpected RT-PK phenomena may provide a reference for adjustment of drug administration and is worthy of further investigation. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01755585 and NCT01609114. PMID- 24066672 TI - Effect of beraprost sodium on arterial stiffness in patients with type 2 diabetic nephropathy. AB - BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). Cardiovascular (CV) complications are the most common cause of death among ESRD patients. Beraprost sodium (BPS) is a prostacyclin analog with vasodilatory and antiplatelet effects. METHODS: This is a multicenter prospective, randomized, double-blind, placebo-controlled trial to determine whether treatment with BPS improves arterial stiffness in patients with type 2 diabetic nephropathy. A total of 102 participants with type 2 diabetic nephropathy will be screened, enrolled, and randomly assigned to receive either 80 MUg BPS or placebo daily for 12 weeks. The primary outcome is the change in brachial-ankle pulse wave velocity between baseline and after 12 weeks of medication use. The secondary outcomes will include changes in the ankle-brachial index, the urine albumin to creatinine ratio, the estimated glomerular filtration rate, lipid profiles, and blood pressure from baseline to after treatment. DISCUSSION: This clinical trial is the first to investigate the effects of BPS on changes in CV biomarkers, albuminuria, renal function, and lipid profiles in patients with diabetic nephropathy. TRIAL REGISTRATION: ClinicalTrials.gov number NCT01796418. PMID- 24066674 TI - Tanespimycin and tipifarnib exhibit synergism in inducing apoptosis in melanoma cell lines from later stages of tumor progression. AB - Many anticancer strategies rely on efficient induction of apoptosis. The need for development of drug combinations with a strong pro-apoptotic activity is of particular interest in melanoma resistant to currently available chemotherapeutic regimes. We studied the pro-apoptotic properties of combination of tanespimycin+tipifarnib in five melanoma cell lines representing various stages of tumor progression. Our results show that in cells derived from vertical- and metastatic-phase the combination of tested drugs is strongly cytotoxic and efficient in inducing apoptosis, as evidenced by activation of caspase-9 and caspase-3 and enhanced fragmentation of DNA. PMID- 24066673 TI - FGF2-induced effects on transcriptome associated with regeneration competence in adult human fibroblasts. AB - BACKGROUND: Adult human fibroblasts grown in low oxygen and with FGF2 supplementation have the capacity to tip the healing outcome of skeletal muscle injury - by favoring regeneration response in vivo over scar formation. Here, we compare the transcriptomes of control adult human dermal fibroblasts and induced regeneration-competent (iRC) fibroblasts to identify transcriptional changes that may be related to their regeneration competence. RESULTS: We identified a unique gene-expression profile that characterizes FGF2-induced iRC fibroblast phenotype. Significantly differentially expressed genes due to FGF2 treatment were identified and analyzed to determine overrepresented Gene Ontology terms. Genes belonging to extracellular matrix components, adhesion molecules, matrix remodelling, cytoskeleton, and cytokines were determined to be affected by FGF2 treatment. CONCLUSIONS: Transcriptome analysis comparing control adult human fibroblasts with FGF2-treated fibroblasts identified functional groups of genes that reflect transcriptional changes potentially contributing to their regeneration competence. This comparative transcriptome analysis should contribute new insights into genes that characterize cells with greater regenerative potential. PMID- 24066675 TI - Dialysis initiation: what's the rush? AB - The recent trend to early initiation of dialysis (at eGFR >10 ml/min/1.73 m(2) ) appears to have been based on conventional wisdoms that are not supported by evidence. Observational studies using administrative databases report worse comorbidity-adjusted dialysis survival with early dialysis initiation. Although some have concluded that the IDEAL randomized controlled trial of dialysis start provided evidence that patients become symptomatic with late dialysis start, there is no definitive support for this view. The potential harms of early start of dialysis, including the loss of residual renal function (RRF), have been well documented. The rate of RRF loss (renal function trajectory) is an important consideration for the timing of the dialysis initiation decision. Patients with low glomerular filtration rate (GFR) may have sufficient RRF to be maintained off dialysis for years. Delay of dialysis start until a working arterio-venous access is in place seems prudent in light of the lack of harm and possible benefit of late dialysis initiation. Prescribing frequent hemodialysis is not recommended when dialysis is initiated early. The benefits of early initiation of chronic dialysis after episodes of congestive heart failure or acute kidney injury require further study. There are no data to show that early start benefits diabetics or other patient groups. Preemptive start of dialysis in noncompliant patients may be necessary to avoid complications. The decision to initiate dialysis requires informed patient consent and a joint decision by the patient and dialysis provider. Possible talking points for obtaining informed consent are provided. PMID- 24066677 TI - Violet emission in ZnO nanorods treated with high-energy hydrogen plasma. AB - Violet photoluminescence was observed in high-energy hydrogen-plasma-treated ZnO nanorods at 13 K. The photoluminescence spectrum is dominated by a strong violet emission and a shoulder attributed to excitonic emission. The violet emission shows normal thermal behavior with an average lifetime of about 1 MUs at 13 K. According to the time-resolved and excitation density-dependent photoluminescence, it was found that the violet emission is determined by at least two emitting channels, which was confirmed by annealing experiments. Evidence was also given that the violet emission is related to hydrogen. We suggested that the hydrogen-related complex defects formed under high-energy hydrogen plasma treatment are responsible for this violet emission. PMID- 24066676 TI - Indoor pollutant exposures modify the effect of airborne endotoxin on asthma in urban children. AB - RATIONALE: The effect of endotoxin on asthma morbidity in urban populations is unclear. OBJECTIVES: To determine if indoor pollutant exposure modifies the relationships between indoor airborne endotoxin and asthma health and morbidity. METHODS: One hundred forty-six children and adolescents with persistent asthma underwent repeated clinical assessments at 0, 3, 6, 9, and 12 months. Home visits were conducted at the same time points for assessment of airborne nicotine, endotoxin, and nitrogen dioxide (NO2) concentrations. The effect of concomitant pollutant exposure on relationships between endotoxin and asthma outcomes were examined in stratified analyses and statistical models with interaction terms. MEASUREMENTS AND MAIN RESULTS: Both air nicotine and NO2 concentrations modified the relationships between airborne endotoxin and asthma outcomes. Among children living in homes with no detectable air nicotine, higher endotoxin was inversely associated with acute visits and oral corticosteroid bursts, whereas among those in homes with detectable air nicotine, endotoxin was positively associated with these outcomes (interaction P value = 0.004 and 0.07, respectively). Among children living in homes with lower NO2 concentrations (<20 ppb), higher endotoxin was positively associated with acute visits, whereas among those living in homes with higher NO2 concentrations, endotoxin was negatively associated with acute visit (interaction P value = 0.05). NO2 also modified the effect of endotoxin on asthma symptom outcomes in a similar manner. CONCLUSIONS: The effects of household airborne endotoxin exposure on asthma are modified by coexposure to air nicotine and NO2, and these pollutants have opposite effects on the relationships between endotoxin and asthma-related outcomes. PMID- 24066683 TI - Radiation-induced opticochiasmatic glioblastoma multiforme following conventional radiotherapy for Cushing's disease. AB - We report the rare occurrence of an opticochiasmatic glioblastoma multiforme 6 years following conventional radiotherapy for Cushing's disease. This article highlights the risks of collateral damage to the optic apparatus when irradiating the sellar region. PMID- 24066684 TI - Reorganization of left primary (face) motor cortex due to a low-grade glioma. AB - We present a patient with a low-grade glioma restricted to the 'face area' of the left primary motor cortex. Little is known about functional consequences of surgery within this specific part of the brain. After surgery there were only mild and transient deficits. We suggest that original functions had already reorganized to direct perilesional areas. PMID- 24066685 TI - Foramen magnum decompression for Chiari I malformation: a procedure not to be underestimated. AB - OBJECTIVE: Chiari I malformation may be treated with foramen magnum decompression (FMD). We aim to describe the symptoms with which patients initially present, and to determine the number and type of complications occurring after FMD for Chiari I malformation. METHODS: Retrospective review of medical records for patients who had FMD performed for Chiari I malformation between January 2009 and December 2011. Post-operative outcomes were recorded and analysed. Patient demographic details and other relevant medical conditions were also noted. RESULTS: Between January 2009 and December 2011, 54 FMDs were performed for Chiari I malformation. Among them, 40(74%) patients were female and 14 patients (26%) were male. The majority of patients (42.6%) were aged 16-39 years and 24.07% of patients were children aged < 16 years. A total of 30(55.6%) patients had documented evidence of a syrinx pre-operatively. 18(33.3%) patients developed complications. Nine of these developed multiple complications while nine had a single problem. One mortality was reported. Ten (18.5%) patients developed hydrocephalus requiring shunting. Two patients developed subdural collections requiring evacuation associated with hydrocephalus. Six (11.1%) patients developed post-operative infections: two CNS infections; one wound infection; and three other infections. CONCLUSIONS: FMD for Chiari I malformation is a procedure which carries risk. In particular, the risk of developing post-operative hydrocephalus requiring permanent shunting is relatively high. ICP monitoring prior to FMD may be required to definitively rule out raised intracranial pressure. PMID- 24066686 TI - A case of cauda equina cavernous angioma coexisting with multiple cerebral cavernous angiomas. AB - The simultaneous presence of cavernous angiomas in both the brain and spinal cord is a very rare finding, as is the location of a cavernous angioma in the cauda equina. We reported a unique case of coexisting with multiple cerebral cavernous angiomas in the brain and cauda equina. PMID- 24066687 TI - Management of malignant middle cerebral artery infarction following a cardiac stab wound--the role of early decompressive craniectomy. AB - We report the presentation, investigation and management of a 22-year-old male who developed a right malignant middle cerebral artery infarct following a cardiac stab wound. This case exemplifies that early identification and timely decompression of young patients with embolic infarcts as a result of penetrating trauma can lead to a favourable clinical outcome. PMID- 24066688 TI - Pb(II)-promoted amide cleavage: mechanistic comparison to a Zn(II) analogue. AB - Two new Pb(II) complexes of the amide-appended nitrogen/sulfur epppa (N-((2 ethylthio)ethyl)-N-((6-pivaloylamido-2-pyridyl)methyl)-N-((2 pyridyl)methyl)amine) chelate ligand, [(epppa)Pb(NO3)2] (4-NO3) and [(epppa)Pb(ClO4)2] (4-ClO4), were prepared and characterized. In the solid state, 4-NO3 exhibits kappa(5)-epppa chelate ligand coordination as well as the coordination of two bidentate nitrate ions. In acetonitrile, 4-NO3 is a 1:1 electrolyte with a coordinated NO3(-), whereas 4-ClO4 is a 1:2 electrolyte. Treatment of 4-ClO4 with 1 equiv Me4NOH.5H2O in CH3CN:CH3OH (3:5) results in amide methanolysis in a reaction that is akin to that previously reported for the Zn(II) analogue [(epppa)Zn](ClO4)2 (3-ClO4). (1)H NMR kinetic studies of the amide methanolysis reactions of 4-ClO4 and 3-ClO4 as a function of temperature revealed free energies of activation of 21.3 and 24.5 kcal/mol, respectively. The amide methanolysis reactions of 4-ClO4 and 3-ClO4 differ in terms of the effect of the concentration of methanol (saturation kinetics for 4-ClO4; second-order behavior for 3-ClO4), the observation of a small solvent kinetic isotope effect (SKIE) only for the reaction of the Zn(II)-containing 3-ClO4, and the properties of an initial intermediate isolated from each reaction upon treatment with Me4NOH.5H2O. These experimental results, combined with computational studies of the amide methanolysis reaction pathways of 4-ClO4 and 3-ClO4, indicate that the Zn(II)-containing 3-ClO4 initially undergoes amide deprotonation upon treatment with Me4NOH.5H2O. Subsequent amide protonation from coordinated methanol yields a structure containing a coordinated neutral amide and methoxide anion from which amide cleavage can then proceed. The rate-determining step in this pathway is either amide protonation or protonation of the leaving group. The Pb(II) containing 4-ClO4 instead directly forms a neutral amide-containing, epppa ligated Pb(II)-OH/Pb(II)-OCH3 equilibrium mixture upon treatment with Me4NOH.5H2O in methanol. The rate-determining step in the amide methanolysis pathway of 4 ClO4 is nucleophilic attack of the Pb(II)-OCH3 moiety on the coordinated amide. Overall, it is the larger size of the Pb(II) center and the availability of coordination positions that enable direct formation of a Pb(II)-OH/Pb(II)-OCH3 mixture versus the initial amide deprotonation identified in the reaction of the Zn(II)-containing 3-ClO4. PMID- 24066689 TI - Enzymatic synthesis of novel phenol acid rutinosides using rutinase and their antiviral activity in vitro. AB - Novel rutinosides of vanillic acid, sinapic acid, ferulic acid, and caffeic acid were prepared via a rutinase-catalyzed transglycosylation reaction. Reaction mixtures containing rutin, phenolic acid, and rutinase derived from tartary buckwheat ( Fagopyrum tataricum ) seeds were incubated in 20 mM acetate buffer (pH 5.0) at 40 degrees C. The resulting rutinoside of each phenolic acid was purified by HPLC, and the structure was determined by NMR and FAB-MS analysis. Antiviral activity was determined using feline calicivirus (FCV) strain F9, which is a typical norovirus surrogate. It was found that rutinosylation of the phenolic acids increased their antiviral activity against FCV, with the sinapic acid rutinoside being the most effective. These results will contribute to the development of antiviral agents against noroviruses. PMID- 24066693 TI - Tumor necrosis factor-alpha attenuates starvation-induced apoptosis through upregulation of ferritin heavy chain in hepatocellular carcinoma cells. AB - BACKGROUND: Tumor microenviroment is characteristic of inflammation, ischemia and starvation of nutrient. TNF-alpha, which is an extraordinarily pleiotropic cytokine, could be an endogenous tumor promoter in some tumor types. The basic objective of this study was to investigate the effects of TNF-alpha on the cell viability and apoptosis of hepatocellular carcinoma cells under serum starvation, and to identify the molecular mechanisms involved. METHODS: For this purpose, five different concentrations of TNF-alpha and two different serum settings (serum-cultured and serum-deprived) were used to investigate the effects of TNF alpha on the cell viability and apoptosis of Hep3B and SMMC-7721 cells. RESULTS: TNF-alpha (10 ng/ml) attenuated serum starvation-induced apoptosis of hepatocellular carcinoma cells, and autophagy conferred this process. BAY11-7082, a specific inhibitor of NF-kappaB, reversed the suppression of serum starvation induced apoptosis by TNF-alpha. Moreover, TNF-alpha-induced NF-kappaB transactivation was suppressed by autophagy inhibitor 3-MA. In addition, TNF alpha up-regulated Ferritin heavy chain (FHC) transiently by NF-kappaB activation and FHC levels were correlated with the TNF-alpha-induced protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells. Furthermore, FHC-mediated inhibition of apoptosis depended on suppressing ROS accumulation. CONCLUSIONS: Our findings suggested that autophagy conferred the TNF-alpha protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells, the mechanism involved with the activation of the TNF-alpha/ NF-kappaB /FHC signaling pathway. PMID- 24066694 TI - The human hepatic cell line HepaRG as a possible cell source for the generation of humanized liver TK-NOG mice. AB - 1. Humanized-liver mice, in which the liver has been repopulated with human hepatocytes, have been used to study aspects of human liver physiology such as drug metabolism, toxicology and hepatitis infection. However, the procurement of human hepatocytes is a major problem in producing humanized-liver mice because of the finite nature of the patient-derived resource. 2. In order to overcome this limitation, the human hepatic cell line HepaRG(r) were evaluated as promising donor cells for liver reconstitution in the TK-NOG mouse model. 3. We demonstrate that, in vivo, transplanted confluent culture or differentiated HepaRG(r) cells proliferated and differentiated toward both hepatocyte-like and biliary-like cells within the recipient liver. In contrast, proliferative HepaRG(r) cells could engraft TK-NOG mouse liver but could differentiate only toward biliary-like cells. The differentiation to hepatocyte-like cells was characterized by the detection of human albumin in the recipient mouse serum and was confirmed by immunohistochemical staining for human leukocyte antigen, human albumin, cytochrome P450 3A4, and multidrug resistance-associated protein 2. Biliary-like cells were characterized by positive staining for cytokeratin-19. 4. These results indicated that the differentiated HepaRG(r) cells are a possible cell source for generating humanized-liver mice, which are a useful model for in vivo studies of liver physiology. PMID- 24066695 TI - Structure and dynamics of full-length HIV-1 capsid protein in solution. AB - The HIV-1 capsid protein plays a crucial role in viral infectivity, assembling into a cone that encloses the viral RNA. In the mature virion, the N-terminal domain of the capsid protein forms hexameric and pentameric rings, while C terminal domain homodimers connect adjacent N-terminal domain rings to one another. Structures of disulfide-linked hexamer and pentamer assemblies, as well as structures of the isolated domains, have been solved previously. The dimer configuration in C-terminal domain constructs differs in solution (residues 144 231) and crystal (residues 146-231) structures by ~30 degrees , and it has been postulated that the former connects the hexamers while the latter links pentamers to hexamers. Here we study the structure and dynamics of full-length capsid protein in solution, comprising a mixture of monomeric and dimeric forms in dynamic equilibrium, using ensemble simulated annealing driven by experimental NMR residual dipolar couplings and X-ray scattering data. The complexity of the system necessitated the development of a novel computational framework that should be generally applicable to many other challenging systems that currently escape structural characterization by standard application of mainstream techniques of structural biology. We show that the orientation of the C-terminal domains in dimeric full-length capsid and isolated C-terminal domain constructs is the same in solution, and we obtain a quantitative description of the conformational space sampled by the N-terminal domain relative to the C-terminal domain on the nano- to millisecond time scale. The positional distribution of the N-terminal domain relative to the C-terminal domain is large and modulated by the oligomerization state of the C-terminal domain. We also show that a model of the hexamer/pentamer assembly can be readily generated with a single configuration of the C-terminal domain dimer, and that capsid assembly likely proceeds via conformational selection of sparsely populated configurations of the N-terminal domain within the capsid protein dimer. PMID- 24066696 TI - Vibration response imaging: protocol for a systematic review. AB - BACKGROUND: The concept of lung sounds conveying information regarding lung physiology has been used extensively in clinical practice, particularly with physical auscultation using a stethoscope. Advances in computer technology have facilitated the construction of dynamic visual images derived from recorded lung sounds. Arguably, the most significant progress in this field was the development of the commercially available vibration response imaging (VRI) (Deep Breeze Ltd, Or-Akiva, Israel). This device provides a non-invasive, dynamic image of both lungs constructed from sounds detected from the lungs using surface sensors. In the literature, VRI has been utilized in a multitude of clinical and research settings. This systematic review aims to address three study questions relating to whether VRI can be used as an evaluative device, whether the images generated can be characterized, and which tools and measures have been used to assess these images. METHODS/DESIGN: This systematic review will involve implementing search strategies in five online journal databases in order to extract articles relating to the application of VRI. Appropriate articles will be identified against a set of pre-determined eligibility criteria and assessed for methodological quality using a standardized scale. Included articles will have data extracted by the reviewers using a standardized evidence table. A narrative synthesis based on a standardized framework will be conducted, clustering evidence into three main groups; one for each of the study questions. A meta-analysis will be conducted if two or more research articles meet pre-determined criteria that allow quantitative synthesis to take place. DISCUSSION: This systematic review aims to provide a complete overview of the scope of VRI in the clinical and research settings, as well as to discuss methods to interpret the data obtained from VRI. The systematic review intends to help clinicians to make informed decisions on the clinical applicability of the device, to allow researchers to identify further potential avenues of investigation, and to provide methods for the evaluation and interpretation of dynamic and static images. The publication and registration of this review with PROSPERO provides transparency and accountability, and facilitates the appraisal of the proposed systematic review against the original design. TRIAL REGISTRATION: PROSPERO registration number: CRD42013003751. PMID- 24066697 TI - Sex therapy for female sexual dysfunction. AB - INTRODUCTION: About 45% of women suffer from some form of sexual dysfunction. Despite its high prevalence, there are few studies that have systematically evaluated sex therapy in comparison with other interventions. OBJECTIVE: Review randomized clinical trials that present psychotherapeutic interventions for female sexual dysfunctions. METHOD: Through a search in three databases (Medline, Web of Science and PsycInfo), 1419 references were found. After an analysis of the abstracts, twenty-seven articles met the inclusion criteria and composed this review. RESULTS: Sex therapy, as proposed by Masters and Johnson and Heiman and LoPiccolo, is still the most commonly used form of therapy for sexual dysfunctions; although it has shown results, the results do not consistently support that this is the best alternative in the treatment of sexual dysfunctions. CONCLUSION: There is a lack of systematic study of many female sexual dysfunctions. Orgasmic disorder and sexual pain (vaginismus and dyspaurenia) are the most extensively studied disorders and those in which sex therapy seems to have better outcomes. PMID- 24066698 TI - They live in the land down under: thyroid function and basal metabolic rate in the Blind Mole Rat, Spalax. AB - The Israeli blind subterranean mole rat (Spalax ehrenbergi superspecies) lives in sealed underground burrows under extreme, hypoxic conditions. The four Israeli Spalax allospecies have adapted to different climates, the cool-humid (Spalax galili, 2 n = 52 chromosomes), semihumid (S. golani, 2 n = 54) north regions, warm-humid (S. carmeli, 2 n = 58) central region and the warm-dry S. judaei, 2 n = 60) southern regions. A dramatic interspecies decline in basal metabolic rate (BMR) from north to south, even after years of captivity, indicates a genetic basis for this BMR trait. We examined the possibility that the genetically conditioned interspecies BMR difference was expressed via circulating thyroid hormone. An unexpected north to south increase in serum free thyroxine (FT4) and total 3, 5, 3'-triiodo-L-thyronine (T3) (p < 0.02) correlated negatively with previously published BMR measurements. The increases in serum FT4 and T3 were symmetrical, so that the T3:FT4 ratio - interpretable as an index of conversion of T4 to T3 in nonthyroidal tissues - did not support relative decrease in production of T3 as a contributor to BMR. Increased north-to-south serum FT4 and T3 levels also correlated negatively with hemoglobin/hematocrit. North-to-south adaptations in spalacids include decreased BMR and hematocrit/hemoglobin in the face of increasing thyroid hormone levels, arguing for independent control of hormone secretion and BMR/hematocrit/hemoglobin. But the significant inverse relationship between thyroid hormone levels and BMR/hematocrit/hemoglobin is also consistent with a degree of cellular resistance to thyroid hormone action that protects against hormone-induced increase in oxygen consumption in a hostile, hypoxic environment. PMID- 24066700 TI - Looming animate and inanimate threats: the response of the amygdala and periaqueductal gray. AB - Looming stimuli are processed as threatening and activate basic neural defense systems. However, it is unclear how animacy information modulates this response. Participants (N = 25) viewed threatening or neutral images that were either animate (animals) or inanimate (objects) and which either approached (loomed) or receded from the participant. The amygdala was responsive to emotional, animacy, and looming information (particularly to looming threats and looming animate stimuli). Periaqueductal gray was also sensitive to emotional information and particularly responsive to looming threats. The data are interpreted within category-specific models of the amygdala and temporal cortex. PMID- 24066701 TI - Achieving micelle control through core crystallinity. AB - We have designed a pathway for controlling the critical micelle concentration and micelle size of polyester-based systems. This was achieved by creating an array of different copolymers with semicrystalline or amorphous hydrophobic blocks. The hydrophobic block was constructed through ring-opening polymerization of epsilon caprolactone, L-lactide, and epsilon-decalactone, either as homopolymers or random copolymers, using PEG as both the initiator and the hydrophilic block. Micelles formed with amorphous cores exhibited considerably higher critical micelle concentrations than those with semicrystalline cores. Micelles with amorphous cores also became larger in size with an increased molecular weight of the hydrophobic bock, in contrast to micelles with semicrystalline cores, which displayed the opposite behavior. Hence, core crystallinity was found to be a potent tool for tailoring micelle properties and thereby facilitating the optimization of drug delivery systems. The introduction of PEG-PepsilonDL also proved to be a valuable asset in the tuning of micelle properties. PMID- 24066702 TI - Beta-asarone, a major component of Acorus tatarinowii Schott, attenuates focal cerebral ischemia induced by middle cerebral artery occlusion in rats. AB - BACKGROUND: Ischemic hypoxic brain injury often causes irreversible brain damage. The lack of effective and widely applicable pharmacological treatments for ischemic stroke patients may explain a growing interest in traditional medicines. beta-Asarone, which has significant pharmacological effects on the central nervous system (CNS), was used in the prevention of cerebral ischemia in this paper. METHODS: The right middle cerebral artery occlusion model was used in the study. The effects of beta-Asarone on mortality rate, neurobehavior, grip strength, lactate dehydrogenase, glutathione content, Lipid peroxidation, glutathione peroxidase activity, glutathione reductase activity, catalase activity, Na+-K+-ATPase activity and glutathione S transferase activity in a rat model were studied respectively. RESULTS: beta-Asarone significantly improved the neurological outcome after cerebral ischemia and reperfusion in terms of neurobehavioral function in rats. Meanwhile, supplementation of beta-Asarone significantly boosted the defense mechanism against cerebral ischemia via increasing antioxidants activity related to lesion pathogenesis. Restoration of the antioxidant homeostasis in the brain after reperfusion may help the brain recover from ischemic injury. CONCLUSIONS: These experimental results suggest that complement beta-Asarone is protective against cerebral ischemia in specific way. The administration of beta-Asarone could reduce focal cerebral ischemic/reperfusion injury. The Mechanism of beta-Asarone in protection of cerebral ischemia was via increasing antioxidants activity related to lesion pathogenesis. PMID- 24066703 TI - Pulmonary blood volume indexed to lung volume is reduced in newly diagnosed systemic sclerosis compared to normals--a prospective clinical cardiovascular magnetic resonance study addressing pulmonary vascular changes. AB - BACKGROUND: Pulmonary involvement, manifested as pulmonary arterial hypertension or pulmonary fibrosis, is the most common cause of death in systemic sclerosis (SSc). We aimed to explore the feasibility of detecting early pulmonary involvement in SSc using recently developed non-invasive quantitative measures of pulmonary physiology using cardiovascular magnetic resonance (CMR). METHODS: Twenty-seven SSc patients (9 men, 57 +/- 13 years) and 10 healthy controls (3 men, 54 +/- 9 years) underwent CMR to determine the pulmonary blood volume (PBV) and the PBV variation (PBVV) throughout the cardiac cycle. Patients underwent Doppler echocardiography, high-resolution computed tomography (HRCT), and pulmonary function testing by spirometry. Comparisons were performed using the unpaired t-test and linear regression analysis was performed with Pearson's correlation coefficient (r). RESULTS: Compared to healthy controls, the PBV indexed to lung volume (PBVI) was lower in patients (16 +/- 4 vs 20 +/- 5%, p < 0.05). There was no difference in PBV (466 +/- 87 vs 471 +/- 122 mL, p = 0.91) or PBVV/stroke volume (45 +/- 10 vs 40 +/- 6%, p = 0.09). There were no significant correlations between PBVI and pulmonary artery pressure estimated by Doppler (p = 0.08) the lung's diffusion capacity for carbon monoxide (DLCO) (p = 0.09), vital capacity (p = 0.45), or pulmonary fibrosis by HRCT (p = 0.74). CONCLUSIONS: This study is the first to measure the PBV in humans using CMR. Compared to healthy controls, newly diagnosed SSc patients have a reduced amount of blood in the pulmonary vasculature (PBVI) but unchanged pulmonary vascular distensibility (PBVV/stroke volume). PBVI is unrelated to DLCO, pulmonary artery pressure, vital capacity, and the presence of pulmonary fibrosis. PBVI may be a novel parameter reflecting vascular lung involvement in early-stage SSc, and these findings may be consistent with pathophysiological changes of the pulmonary vasculature. PMID- 24066705 TI - Pd-catalyzed cyclization and carbene migratory insertion: new approach to 3 vinylindoles and 3-vinylbenzofurans. AB - A Pd-catalyzed stereoselective synthesis of 3-vinylindoles and 3-vinylbenzofurans has been developed. The reaction merges the alkyne-based Pd-catalyzed cyclization and Pd carbene migratory insertion in a single catalytic cycle, generating a C-C single bond and a C?C double bond in one operation. PMID- 24066704 TI - Cognitive-behavioral therapy for binge eating disorder in adolescents: study protocol for a randomized controlled trial. AB - BACKGROUND: Binge eating disorder is a prevalent adolescent disorder, associated with increased eating disorder and general psychopathology as well as an increased risk for overweight and obesity. As opposed to binge eating disorder in adults, there is a lack of validated psychological treatments for this condition in adolescents. The goal of this research project is therefore to determine the efficacy of age-adapted cognitive-behavioral therapy in adolescents with binge eating disorder - the gold standard treatment for adults with binge eating disorder. METHODS/DESIGN: In a single-center efficacy trial, 60 12- to 20-year old adolescents meeting diagnostic criteria of binge eating disorder (full syndrome or subthreshold) according to the Diagnostic and Statistical Manual of Mental Disorders 4th or 5th Edition, will be centrally randomized to 4 months of cognitive-behavioral therapy (n = 30) or a waiting-list control condition (n = 30). Using an observer-blind design, patients are assessed at baseline, mid treatment, post-treatment, and at 6- and 12-month follow-ups after the end of treatment. In 20 individual outpatient sessions, cognitive-behavioral therapy for adolescents focuses on eating behavior, body image, and stress; parents receive psychoeducation on these topics. Primary endpoint is the number of episodes with binge eating over the previous 28 days at post-treatment using a state-of-the art clinical interview. Secondary outcome measures address the specific eating disorder psychopathology, general psychopathology, mental comorbidity, self esteem, quality of life, and body weight. DISCUSSION: This trial will allow us to determine the short- and long-term efficacy of cognitive-behavioral therapy in adolescent binge eating disorder, to determine cost-effectiveness, and to identify predictors of treatment outcome. Evidence will be gathered regarding whether this treatment will help to prevent excessive weight gain. If efficacy can be demonstrated, the results from this trial will enhance availability of evidence-based treatment of adolescent binge eating disorder. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00000542. PMID- 24066706 TI - Direct preparation of nitriles from carboxylic acids in continuous flow. AB - A continuous-flow protocol for the preparation of organic nitriles from carboxylic acids has been developed. The method is based on the acid-nitrile exchange reaction with acetonitrile, used as the solvent, and takes place without any catalyst or additives under the high-temperature/high-pressure conditions employed. At 350 degrees C and 65 bar, where acetonitrile is in its supercritical state, the transformation of benzoic acid to benzonitrile requires 25 min. The protocol has been tested for a variety of nitriles, including aromatic and aliphatic substrates. PMID- 24066707 TI - Construction of a genetic linkage map and QTL analysis of erucic acid content and glucosinolate components in yellow mustard (Sinapis alba L.). AB - BACKGROUND: Yellow mustard (Sinapis alba L.) is an important condiment crop for the spice trade in the world. It has lagged behind oilseed Brassica species in molecular marker development and application. Intron length polymorphism (ILP) markers are highly polymorphic, co-dominant and cost-effective. The cross-species applicability of ILP markers from Brassica species and Arabidopsis makes them possible to be used for genetic linkage mapping and further QTL analysis of agronomic traits in yellow mustard. RESULTS: A total of 250 ILP and 14 SSR markers were mapped on 12 linkage groups and designated as Sal01-12 in yellow mustard. The constructed map covered a total genetic length of 890.4 cM with an average marker interval of 3.3 cM. The QTL for erucic content co-localized with the fatty acid elongase 1 (FAE1) gene on Sal03. The self-(in)compatibility gene was assigned to Sal08. The 4-hydroxybenzyl, 3-indolylmethyl and 4-hydroxy-3 indolylmethyl glucosinolate contents were each controlled by one major QTL, all of which were located on Sal02. Two QTLs, accounting for the respective 20.4% and 19.2% of the total variation of 2-hydroxy-3-butenyl glucosinolate content, were identified and mapped to Sal02 and Sal11. Comparative synteny analysis revealed that yellow mustard was phylogenetically related to Arabidopsis thaliana and had undergone extensive chromosomal rearrangements during speciation. CONCLUSION: The linkage map based on ILP and SSR markers was constructed and used for QTL analysis of seed quality traits in yellow mustard. The markers tightly linked with the genes for different glucosinolate components will be used for marker assisted selection and map-based cloning. The ILP markers and linkage map provide useful molecular tools for yellow mustard breeding. PMID- 24066708 TI - Impact of lactose starvation on the physiology of Lactobacillus casei GCRL163 in the presence or absence of tween 80. AB - The global proteomic response of the nonstarter lactic acid bacteria Lactobacillus casei strain GCRL163 under carbohydrate depletion was investigated to understand aspects of its survival following cessation of fermentation. The proteome of L. casei GCRL163 was analyzed quantitatively after growth in modified MRS (with and without Tween 80) with different levels of lactose (0% lactose, starvation; 0.2% lactose, growth limiting; 1% lactose, non-growth-limited control) using gel-free proteomics. Results revealed that carbohydrate starvation lead to suppression of lactose and galactose catabolic pathways as well as pathways for nucleotide and protein synthesis. Enzymes of the glycolysis/gluconeogenesis pathway, amino acid synthesis, and pyruvate and citrate metabolism become more abundant as well as other carbohydrate catabolic pathways, suggesting increased optimization of intermediary metabolism and scavenging. Tween 80 did not affect growth yield; however, proteins related to fatty acid biosynthesis were repressed in the presence of Tween 80. The data suggest that L. casei adeptly switches to a scavenging mode, using both citrate and Tween 80, and efficiently adjusts energetic requirements when carbohydrate starved and thus can sustain survival for weeks to months. Explaining the adaptation of L. casei during lactose starvation will assist efforts to maintain viability of L. casei and extend its utility as a beneficial dietary adjunct and fermentation processing aid. PMID- 24066709 TI - Fine Mapping of 6q23.1 Identifies TULP4 as Contributing to Clefts. AB - Objective : The aim of this work was to fine-map the region 6q23.1, which obtained suggestive linkage signal (logarithm of the odds [LOD] score = 2.22 under a recessive model) to cleft lip with or without cleft palate (CL+/-P) in our previous genome-wide linkage scan to identify possible genetic variants that may contribute to CL+/-P. Design : We used densely spaced markers spanning the entire 6q23.1 region to test for association with CL+/-P in a family cohort sample. Setting : Clinical information and DNA samples were obtained from families in the Philippines at their homes or primary health care clinics. Participants : The study sample consisted of 477 subjects (224 females and 253 males), segregating isolated CL+/-P, from 72 living in the same area in the Philippines. Main Outcome Measure : Overtransmission of alleles to persons born with CL+/-P. Results : We found statistical evidence of association between a marker of TULP4 (rs651333) with CL+/-P (P = .00007). Conclusions : Our results further support the linkage results for the chromosome 6q region and reveal a novel candidate gene for CL+/-P. PMID- 24066710 TI - Congenital trilobe tongue associated with cleft palate: a rare anomaly. AB - Cleft of the palate and congenital anomaly of the tongue is a rare occurrence. A child with the tongue in three segments is being presented for the first time in the literature. This child also had partial cleft palate. The cleft palate was repaired at 7 months of age, and the tongue was reconstructed at 15 months. The tongue reconstruction was done utilizing the three segments of the tongue by an innovative method. This child has been followed up for 6 months with satisfactory results. Congenital abnormalities of the tongue associated with cleft palate may be considered as evidence of close interrelation of embryogenesis of the tongue and palate. PMID- 24066711 TI - Fabrication of a novel polymer-free nanostructured drug-eluting coating for cardiovascular stents. AB - Angioplasty with stents is the most important method for the treatment of coronary artery disease (CAD). However, the drug-eluting stents (DES) that are widely used have the increased risks of inflammatory reactions and late stent thrombosis (LST) because of the persistence of the polymer coatings. To improve the biosafety, a novel polymer-free-composite drug-eluting coating composed of magnetic mesoporous silica nanoparticles (MMSNs) and carbon nanotubes (CNTs) was constructed using the electrophoretic deposition (EPD) method in this study. A crack-free two-layered coating with impressive network nanotopologies was successfully obtained by regulating the composition and structures. This nanostructured coating exhibits excellent mechanical flexibility and blood compatibility in vitro, and the drug-loading and release performance is satisfactory as well. The in vivo study shows that this composite coating has the obvious advantage of rapid endothelialization because of its unique 3D nanostructured topology in comparison with the commercial polymer-coated DES. This study aims to provide new ideas and reliable data to design novel functional coatings that could accelerate the re-endothelialization process and avoid inflammatory reactions, thus improving the in vivo biosafety of DES. PMID- 24066713 TI - Michigan's approach to Medicaid expansion and reform. PMID- 24066712 TI - Predicting response to intensive multimodal inpatient treatment: a comparison of single- and multiple-class growth modeling approaches. AB - In a modest body of research, personality functioning assessed via performance based instruments has been found to validly predict treatment outcome and, to some extent, differential response to treatment. However, state-of-the-science longitudinal and mixture modeling techniques, which are common in many areas of clinical psychology, have rarely been used. In this article, we compare multilevel growth curve modeling (MLM) and latent class growth modeling (LCGM) approaches with the same data set to illustrate the different research questions that can be addressed by each method. Global Assessment of Functioning (GAF) scores collected at 6 points during the course of a long-term multimodal inpatient treatment of 58 severely and persistently mentally ill adults were used to model the trajectory of treatment outcome. Pretreatment Rorschach-based markers of personality functioning and other markers of psychiatric severity were examined as covariates in each modeling approach. The results of both modeling approaches generally indicated that more psychologically impaired clients responded less favorably to treatment. The LCGM approach revealed 2 unique trajectories of improvement (a persistently low group and a higher starting, improving group). Personality functioning and baseline psychiatric variables significantly predicted group membership and the rate of change within the groups. A side-by-side examination of these 2 methods was found to be useful in predicting differential treatment response with personality functioning variables. PMID- 24066714 TI - Variation in contents of main active components and antioxidant activity in leaves of different pigeon pea cultivars during growth. AB - Pigeon pea is an important and multiuse grain legume crop, and its leaves are a very valuable natural resource. To obtain a high-quality biological resource, it is necessary to choose the excellent cultivar and determine the appropriate harvest time. In this study, the variation in contents of main active components and antioxidant activity in leaves of six pigeon pea cultivars during growth were investigated. The level of each individual active component significantly varied during growth, but with a different pattern, and this variation was different among cultivars. Flavonoid glycosides orientin, vitexin, and apigenin-6,8-di-C alpha-L-arabinopyranoside showed two peak values at mid-late and final stages of growth in most cases. Pinostrobin chalcone, longistyline C, and cajaninstilbene acid showed remarkablely higher values at the mid-late stage of growth than at other stages. Pinostrobin had an extremely different variation pattern compared to other active components. Its content was the highest at the earlier stage of growth. Principal component analysis (PCA) revealed that vitexin and apigenin-6,8 di-C-alpha-L-arabinopyranoside were mainly responsible for distinguishing cultivars analyzed. In a comprehensive consideration, the leaves should preferentially be harvested at the 135th day after sowing when the level of active components and antioxidant activity reached higher values. Cultivars ICP 13092, ICPL 87091, and ICPL 96053 were considered to be excellent cultivars with high antioxidant activity. Our findings can provide valuable information for producing a high-quality pigeon pea resource. PMID- 24066715 TI - Heart rate variability on antihypertensive drugs in black patients living in sub Saharan Africa. AB - BACKGROUND: Compared with Caucasians, African Americans have lower heart rate variability (HRV) in the high-frequency domain, but there are no studies in blacks born and living in Africa. METHODS: In the Newer versus Older Antihypertensive agents in African Hypertensive patients trial (NCT01030458), patients (30-69 years) with uncomplicated hypertension (140-179/90-109 mmHg) were randomized to single-pill combinations of bisoprolol/hydrochlorothiazide (R) or amlodipine/valsartan (E). 72 R and 84 E patients underwent 5-min ECG recordings at randomization and 8, 16 and 24 weeks. HRV was determined by fast Fourier transform and autoregressive modelling. RESULTS: Heart rate decreased by 9.5 beats/min in R patients with no change in E patients (- 2.2 beats/min). R patients had reduced total (- 0.13 ms2; p = 0.0038) and low-frequency power (- 3.6 nu; p = 0.057), higher high-frequency (+ 3.3 nu; p = 0.050) and a reduced low to high-frequency ratio (- 0.08; p = 0.040). With adjustment for heart rate, these differences disappeared, except for the reduced low-frequency power in the R group (- 4.67 nu; p = 0.02). Analyses confined to 39 R and 47 E patients with HRV measurements at all visits or based on autoregressive modelling were confirmatory. CONCLUSION: In native black African patients, antihypertensive drugs modulate HRV, an index of autonomous nervous tone. However, these effects were mediated by changes in heart rate except for low-frequency variability, which was reduced on beta blockade independent of heart rate. PMID- 24066719 TI - Understanding success and failure in multimorbidity: protocol for using realist synthesis to identify how social learning and workplace practices can be optimised. AB - BACKGROUND: Multimorbidity is increasingly prevalent but, aside from epidemiological work, the impact on associated provision of healthcare and/or education is little understood. For example, it is unclear how or why healthcare interventions meet (or do not meet) people's multiple needs. Professionals working in primary care training sites must reconcile two goals: provision of appropriate individualised healthcare and provision of constructive workplace based learning for future professionals. Given that professionals, learners and patients may have differing priorities and conceptualisations of success and failure in the absence of cure, achievement of both goals depends on social and cultural mechanisms. This review aims to make sense of how healthcare delivery for, and education about, multimorbidity can be concurrently delivered in primary care through identification of relevant theoretical frameworks. METHODS/DESIGN: Realist synthesis identifies and makes sense of variable outcomes caused by interaction between mechanisms and contexts. This review will produce a synthesis of social science, education and primary care literature. Our objective is to understand interactivity between models of workplace-based education and models of patient-centred/integrated care with a focus on perceptions of 'success' and 'failure' in multimorbidity. We intend to build a conceptual map and a realist programme theory, populated with evidence from the literature, as the first step towards answering our review question: what is known about how and why concurrent health service delivery and professional medical education interact together to generate outcomes valued by professionals, learners and patients for patients with multimorbidity in primary care? To answer this we are focusing on relationship-based negotiation of needs-based learning and needs-based care as our primary outcome of interest. In this protocol we outline our search strategy and proposed methods of analysis and synthesis of credible and trustworthy data judged to be relevant to our research question. DISCUSSION: Findings will be submitted for peer-reviewed publication. Identification of how mechanisms of social learning and workplace practices could be optimised to improve quality and utility of patient care in multimorbidity is important. This can inform the future research regarding interventions that will produce a sustainable medical workforce equipped to provide healthcare, when the possibility of cure is absent. PMID- 24066720 TI - Tristability in a light-actuated single-molecule magnet. AB - Molecules exhibiting bistability have been proposed as elementary binary units (bits) for information storage, potentially enabling fast and efficient computing. In particular, transition metal complexes can display magnetic bistability via either spin-crossover or single-molecule magnet behavior. We now show that the octahedral iron(II) complexes in the molecular salt [Fe(1 propyltetrazole)6](BF4)2, when placed in its high-symmetry form, can combine both types of behavior. Light irradiation under an applied magnetic field enables fully reversible switching between an S = 0 state and an S = 2 state with either up (M(S) = +2) or down (M(S) = -2) polarities. The resulting tristability suggests the possibility of using molecules for ternary information storage in direct analogy to current binary systems that employ magnetic switching and the magneto-optical Kerr effect as write and read mechanisms. PMID- 24066721 TI - Sensing Hg(II) in vitro and in vivo using a benzimidazole substituted BODIPY. AB - A multisignaling Hg(II) sensor based on a benzimidazole substituted BODIPY framework was designed, which displays excellent selectively toward Hg(II) in vitro and in vivo. Optical and fluorogenic measurements in solution reveal that the sensor can detect mercury ions at submicromolar concentrations, with high specificity. The detection of Hg(II) is associated with a blue-shift in optical spectra and a simultaneous increase in the fluorescence quantum yield of the sensor, which is attributed to a decrease in charge delocalization and inhibition of photoinduced electron transfer upon binding to Hg(II). Using several spectroscopic measurements, it is shown that the binding mechanism involves two sensor molecules, where lone pairs of the benzimidazole nitrogen coordinate to a single mercury ion. The utility of this BODIPY sensor to detect Hg(II) in vivo was demonstrated by fluorescence imaging and spectroscopy of labeled human breast adenocarcinoma cells. While average emission intensity of the sensor over a large number of cells increases with incubated mercury concentrations, spatially resolved fluorescence spectroscopy performed on individual cells reveals clear spectral blue-shifts from a subensemble of sensors, corroborating the detection of Hg(II). Interestingly, the emission spectra at various submicrometer locations within cells exhibited considerable inhomogeneity in the extent of blue-shift, which demonstrates the potential of this sensor to monitor the local (effective) concentration of mercury ions within various subcellular environments. PMID- 24066722 TI - Detection of autoantibodies against heat shock proteins and collapsin response mediator proteins in autoimmune retinopathy. AB - BACKGROUND: Autoimmune retinopathy (AR) and Cancer-Associated Retinopathy (CAR) are associated with a diverse repertoire of anti-retinal autoantibodies (AAbs) but not all antigenic targets have been characterized. Identification of new AAbs may help with clinical diagnosis and prognosis of retinal dysfunction in AR. The goal was to identify frequently targeted retinal autoantigens within the 60-70 kDa molecular weight range. METHODS: Human retinal proteins were separated by SDS PAGE and 2D gel electrophoresis (2-DE) and sera from AR patients with and without cancer were used to identify immunoreactive proteins by Western blotting. Proteins were identified following separation by electrophoresis, Coomassie staining using in-gel trypsin digestion and mass spectrometric analysis. Circulating serum hsp60 and anti-hsp60 antibody levels were determined by quantitative ELISA. RESULTS: Retrospective evaluation of 819 patients with anti retinal AAbs showed that 29% patients had AAbs targeted proteins between 60-70 kDa. Shotgun mass spectrometry of human retinal proteins present in 1D-gel found 66 species within this range. To identify the immunoreactive proteins, we performed Western blots of 2-DE gels and showed a group of heat shock proteins (hsps), including hsp60 and CRMP proteins that were frequently recognized by AR patient AAbs, irrespective of cancer status. These results were validated by immunostaining of purified hsp60 and CRMP2 proteins. ELISA results revealed that patients with AR and CAR had significantly increased levels of serum anti-hsp60 antibodies compared to control healthy subjects (p < 0.0001). However, circulating hsp60 protein was not significantly elevated in sera of either patient group. CONCLUSIONS: Different anti-retinal antibodies frequently co-exist in a single patient, creating antibody-arrays related to the syndrome. Hsps and CRMP-2 are newly identified autoantigens in AR. A frequent co-association of anti hsp antibodies with other anti-retinal AAbs may augment pathogenic processes, leading to retinal degeneration. PMID- 24066723 TI - Selectivity for inhibition of nilotinib on the catalytic activity of human UDP glucuronosyltransferases. AB - 1. Nilotinib, a tyrosine kinase inhibitor, could potently inhibit SN-38 glucuronidation mainly catalyzed by UDP-glucuronosyltransferase (UGT) 1A1. This study was designed to investigate whether nilotinib can be used as a selective inhibitor of UGT1A1 in human liver. 2. Assays with recombinant UGTs indicated that nilotinib could strongly inhibit the activity of UGT1A1 and decreased the activity of extra-hepatic UGT1A7 to a much lesser extent. The inhibition on 4 methylumbelliferone (4Mu) glucuronidation by recombinant UGT1A1 obeyed competitive inhibition mechanism, with a kinetic constants (Ki) value of 0.17 MUM. Assays with human liver microsomes (HLM) demonstrated that nilotinib could selectively inhibit estradiol-3-O-glucuronidation (E2-3-O-glucuronidation), a probe reaction of UGT1A1. Kinetic studies displayed that the inhibition on E2-3-O glucuronidation followed non-competitive inhibition model, different from the inhibition on 4Mu glucuronidation. The Ki values were calculated to be 0.14 and 0.53 MUM, depending on the enzyme sources of recombinant UGT1A1 or HLM, respectively. 3. Given that UGT1A7 is an extra-hepatic enzyme, this study indicates that nilotinib can be used as a selective inhibitor of UGT1A1 in human liver. PMID- 24066724 TI - Identification of three particular morphological phenotypes in sporadic thoracic aortic aneurysm: phenotype III as sporadic thoracic aortic aneurysm biomarker in aged individuals. AB - Aging has a striking impact on the heart and the vascular system, and particularly on the large elastic arteries (i.e., aorta), resulting in a multitude of changes at different structural and functional levels. As result, medial degeneration (MD) occurs. A characteristic example of MD is sporadic thoracic aortic aneurysm (S-TAA), whose patho-physiological mechanisms remain unclear. In this study, typical MD morphological phenotypes were researched in S TAA cases and control aorta specimens using histopathological and mainly immunohistochemical analyses. Three phenotypes (I, II, and III) were detected, but the phenotype III was observed. Elevated cystic MD, plurifocal medial apoptosis, and increased metalloproteinase-9 amount characterize it. In addition, it was significantly correlated with the severity of elastic fragmentation, hypertension, and smoking, and particularly with advancing age. Thus, phenotype III might represent the typical MD phenotype associated with S-TAA in old people that have a major risk of aorta rupture and dissection independently on aneurysm diameter. This might permit the assumption that phenotype III with its typical histological abnormalities is an optimal biomarker of rupture and/or dissection in aged individuals and is useful both for applying different surgical approaches and providing appropriate surgical indications. PMID- 24066726 TI - Quantitative prediction of renal transporter-mediated clinical drug-drug interactions. AB - Kidney plays a critical role in the elimination of xenobiotics. Drug-drug interactions (DDIs) via inhibition of renal organic anion (OAT) and organic cation (OCT) transporters have been observed in the clinic. This study examined the quantitative predictability of renal transporter-mediated clinical DDIs based on basic and mechanistic models. In vitro transport and clinical pharmacokinetics parameters were used to quantitatively predict DDIs of victim drugs when coadministrated with OAT or OCT inhibitors, probenecid and cimetidine, respectively. The predicted changes in renal clearance (CLr) and area under the plasma concentration-time curve (AUC) were comparable to that observed in clinical studies. With probenecid, basic modeling predicted 61% cases within 25% and 94% cases within 50% of the observed CLr changes in clinic. With cimetidine, basic modeling predicted 61% cases within 25% and 92% cases within 50% of the observed CLr changes in clinic. Additionally, the mechanistic model predicted 54% cases within 25% and 92% cases within 50% of the observed AUC changes with probenecid. Notably, the magnitude of AUC changes attributable to the renal DDIs is generally less than 2-fold, unlike the DDIs associated with inhibition of CYPs and/or hepatic uptake transporters. The models were further used to evaluate the renal DDIs of Pfizer clinical candidates/drugs, and the overall predictability demonstrates their utility in the drug discovery and development settings. PMID- 24066725 TI - A survey of cancer patients' unmet information and coordination needs in handovers--a cross-sectional study. AB - BACKGROUND: The care responsibilities for cancer patients are frequently handed over from one healthcare professional to another. These handovers are known to pose a threat to the safety of patients and the efficiency of the healthcare system. Little is known about specific needs of cancer patients in handovers. The objectives of this study were to examine cancer patients' unmet needs for information and coordination in handovers and to analyse the association between patients' demographic and clinical characteristics and unmet information and coordination needs. METHODS: Cancer patients treated in an oncology and a surgery outpatient setting completed a questionnaire developed to examine unmet information and coordination needs of cancer patients in handovers. Associations between unmet needs and comorbidity, treatment type, time since diagnosis, gender, age, and education in various handover situations were analysed. RESULTS: Of 250 eligible patients 131 participated (response rate of 52%). Overall, 18% of patients had unmet coordination needs and 18% had unmet information needs.Hospital discharge was the type of handover where patients most frequently reported unmet information needs (18%). Unmet coordination needs were most frequently reported in handovers between different hospitals (19%) and in handovers between hospital and general practice (18%). In general, age and education were statistically significantly associated with reporting unmet needs, where patients younger than 60 years and patients with a higher education were more likely to express unmet needs. CONCLUSIONS: The findings indicate room for improvements regarding exchange of information and coordination between healthcare professionals, and between healthcare professionals and patients. PMID- 24066727 TI - Safety profile of the yellow fever vaccine Stamaril(r): a 17-year review. AB - Since the creation by the manufacturer in 1993, of an electronic pharmacovigilance database for all spontaneous, voluntary reports of adverse events (AEs) after vaccination, 276 million doses of Stamaril(r) have been distributed worldwide. We review this database for the safety of Stamaril with emphasis on yellow fever (YF) vaccine associated acute viscerotropic and neurotropic diseases, anaphylaxis and on specific at risk groups: elderly adults, pregnant and lactating women and the immunosuppressed. Findings confirm that the vaccine's safety profile in routine practice is favorable and consistent with the summary of product characteristics. Estimated reporting rates of serious adverse events associated after Stamaril vaccination are lower than the previously published and widely cited estimates of the worldwide reporting rate for YF vaccines in general. These data provide important additional information for the prescribers in assessing the risks and benefits associated with the use of Stamaril in individuals exposed to YF virus. PMID- 24066729 TI - Regular three-dimensional presentations improve in the identification of surgical liver anatomy - a randomized study. AB - BACKGROUND: Three-dimensional (3D) presentations enhance the understanding of complex anatomical structures. However, it has been shown that two dimensional (2D) "key views" of anatomical structures may suffice in order to improve spatial understanding. The impact of real 3D images (3Dr) visible only with 3D glasses has not been examined yet. Contrary to 3Dr, regular 3D images apply techniques such as shadows and different grades of transparency to create the impression of 3D.This randomized study aimed to define the impact of both the addition of key views to CT images (2D+) and the use of 3Dr on the identification of liver anatomy in comparison with regular 3D presentations (3D). METHODS: A computer based teaching module (TM) was used. Medical students were randomized to three groups (2D+ or 3Dr or 3D) and asked to answer 11 anatomical questions and 4 evaluative questions. Both 3D groups had animated models of the human liver available to them which could be moved in all directions. RESULTS: 156 medical students (57.7% female) participated in this randomized trial. Students exposed to 3Dr and 3D performed significantly better than those exposed to 2D+ (p < 0.01, ANOVA). There were no significant differences between 3D and 3Dr and no significant gender differences (p > 0.1, t-test). Students randomized to 3D and 3Dr not only had significantly better results, but they also were significantly faster in answering the 11 anatomical questions when compared to students randomized to 2D+ (p < 0.03, ANOVA). Whether or not "key views" were used had no significant impact on the number of correct answers (p > 0.3, t-test). CONCLUSION: This randomized trial confirms that regular 3D visualization improve the identification of liver anatomy. PMID- 24066730 TI - Delivering enhanced cardiovascular (hypertension) disease care through private health facilities in Pakistan. AB - BACKGROUND: Cardiovascular diseases (CVDs) are one of the leading causes of death and disability in the world. Over 80% of CVD deaths take place in low-and middle income countries. One-third of the population aged above 40 years suffers from Hypertension (HTN) and this is largely unreported as there is no registry for CVDs. No guidelines are available for use in health care facilities, especially private health facilities where practice among GPs varies considerably. We aim to conduct a Cluster Randomized Controlled trial delivering a quality HTN-CVD care package at strengthened private health facilities as compared to current practice at private health facilities. METHODS/DESIGN: A pragmatic cluster randomized trial, with qualitative and economic studies, will be conducted in Sargodha district of Punjab, Pakistan, from January 2012 to December 2016. At least 912 hypertensives will be registered in the two arms, six clusters per arm. The proposed cluster randomized controlled trial will evaluate the effects of delivering quality HTN-CVD care, through enabled private health care facilities, to achieve better case registration, adherence and hypertension control also blood glucose and serum cholesterol control. The trial will be conducted through the doctors and paramedics at private health facilities. Main outcomes are mean difference in Systolic blood pressure among the two arms. Secondary outcomes are mean change in total serum cholesterol levels and mean change in glycaemic control achieved in the adult hypertensive patients. Individual and Cluster level analysis will be done according to intention-to-treat. DISCUSSION: Due to the high burden of disease where 1 in 3 individuals aged above 45 suffers from hypertension, topped with the fact that there is a dearth of a set of available, standardised guidelines for management, the disease is constantly on a hike in Pakistan. The government has made no effort to issue a set of guidelines adapted specifically for our population and this becomes more of a problem when managing CVD in urban population through private practitioners whose practices vary widely.If our set of context sensitive guidelines show an effectiveness in the proposed intervention districts it will be replicated in other such settings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34381594. PMID- 24066731 TI - Effect of carbohydrate mouth rinsing on multiple sprint performance. AB - BACKGROUND: Research suggests that carbohydrate mouth rinsing (CMR) improves endurance performance; yet, little is known regarding the effect of CMR on multiple sprint efforts. As many sports involve multiple sprinting efforts, followed by periods of recovery, the aim of our current study was to investigate the influence of CMR on multiple sprint performance. METHODS: We recruited eight active males (Age; 22 +/- 1 y; 75.0 +/- 8.8 kg; estimated VO2max 52.0 +/- 3.0 ml/kg/min) to participate in a randomly assigned, double-blind, counterbalanced study administering a CMR (6.4% Maltodextrin) or similarly flavoured placebo solution. Primary outcomes for our study included: (a) time for three repeated sprint ability tests (RSA) and (b) the Loughborough Intermittent Shuttle Test (LIST). Time was expressed in seconds (sec). Secondary outcomes included ratings of perceived exertion (RPE) and blood glucose concentration. Tertiary outcomes included two psychological assessments designed to determine perceived activation (i.e., arousal) and pleasure-displeasure after each section of the LIST. We analysed our data using a two-way analysis of variance (ANOVA) for repeated measures, a Bonferroni adjusted post hoc t-test to determine significant differences in treatment, and a liberal 90% confidence interval between treatment conditions. Effect sizes were calculated between trials and interpreted as <= 0.2 trivial, > 0.2 small, > 0.6 moderate, > 1.2 large, > 2 very large and > 4 extremely large. Data are means +/- SD. Overall statistical significance was set as P < 0.05; yet, modified accordingly when Bonferroni adjustments were made. RESULTS: Overall, we observed no significant difference in average (3.46 +/- 0.2 vs. 3.44 +/- 0.17; P = 0.11) or fastest time (3.38 +/- 0.2 vs. 3.37 +/- 0.2; P = 0.39) in the RSA test for the placebo vs. CMR conditions, respectively. Similar findings were also noted for the placebo vs. CMR, respectively, during the LIST test (3.52 +/- 0.2 vs. 3.54 +/- 0.2 sec; P = 0.63). Despite a significantly higher within group RPE during the 3rd and 4th sections of the LIST (< 0.05), no between group differences were otherwise noted. No differences were noted for blood glucose concentrations throughout the testing protocol. Lastly, from a psychological perspective, we observed no differences in pleasure-displeasure or perceived activation. CONCLUSIONS: The results of our current study suggest that CMR does not improve exercise performance, RPE or perceived pleasure-displeasure during high intensity activity requiring repeated, intermittent, sprint efforts. PMID- 24066732 TI - Late, new-onset thrombocytopenia in a rattlesnake envenomation treated with a Fab antivenom. PMID- 24066733 TI - Performance of clinical scoring systems in acute organophosphate poisoning. AB - INTRODUCTION: Clinical scoring systems are used to predict mortality rate in hospitalized patients. Their utility in organophosphate (OP) poisoning has not been well studied. METHODS: In this retrospective study of 396 patients, we evaluated the performance of the Acute Physiology and Chronic Health Evaluation (APACHE) II score, the Simplified Acute Physiology Score (SAPS) II, Mortality Prediction Model (MPM) II, and the Poisoning Severity Score (PSS). Demographic, laboratory, and survival data were recorded. Receiver operating characteristic (ROC) curves were generated, and the area under the curve (AUC) was calculated to study the relationship between individual scores and mortality rate. RESULTS: The mean (standard deviation) age of the patients was 31.4 (12.7) years, and at admission, their pseudocholinesterase (median, interquartile) level was 317 (222 635) U/L. Mechanical ventilation was required in 65.7% of the patients and the overall mortality rate was 13.1%. The mean (95% confidence interval) scores were as follows: APACHE-II score, 16.4 (15.5-17.3); SAPS-II, 34.4 (32.5-36.2); MPM-II score, 28.6 (25.7-31.5); and PSS, 2.4 (2.3-2.5). Overall, the AUC for mortality was significantly higher for APACHE-II (0.77) and SAPS-II (0.77) than the PSS (0.67). When patients were categorized, the AUCs were better for WHO Class II (0.71-0.82) than that for Class I compounds (0.60-0.66). For individual compounds, the AUC for APACHE-II was highest in quinalphos (0.93, n = 46) and chlorpyrifos (0.86, n = 38) and lowest in monocrotophos (0.60, n = 63). AUCs for SAPS-II and MPM-II were marginally but not significantly lower than those for APACHE-II. The PSS was generally a poorer discriminator compared to the other scoring systems across all categories. CONCLUSIONS: In acute OP poisoning, the generic scoring systems APACHE-II and SAPS-II outperform the PSS. These tools may be used to predict the mortality rate in OP poisoning. PMID- 24066734 TI - Characterizing risk factors for pediatric lamp oil product exposures. AB - Poisonings from lamp oil ingestion continue to occur worldwide among the pediatric population despite preventive measures such as restricted sale of colored and scented lamp oils. This suggests that optimal prevention practices for unintentional pediatric exposures to lamp oil have yet to be identified and/or properly implemented. OBJECTIVE: To characterize demographic, health data, and potential risk factors associated with reported exposures to lamp oil by callers to poison centers (PCs) in the US and discuss their public health implications. STUDY DESIGN: This was a two part study in which the first part included characterizing all exposures to a lamp oil product reported to the National Poison Data System (NPDS) with regard to demographics, exposure, health, and outcome data from 1/1/2000 to 12/31/2010. Regional penetrance was calculated using NPDS data by grouping states into four regions and dividing the number of exposure calls by pediatric population per region (from the 2000 US census). Temporal analyses were performed on NPDS data by comparing number of exposures by season and around the July 4th holiday. Poisson regression was used to model the count of exposures for these analyses. In the second part of this project, in order to identify risk factors we conducted a telephone-based survey to the parents of children from five PCs in five different states. The 10 most recent lamp oil product exposure calls for each poison center were systematically selected for inclusion. Calls in which a parent or guardian witnessed a pediatric lamp oil product ingestion were eligible for inclusion. Data on demographics, exposure information, behavioral traits, and health were collected. A descriptive analysis was performed and Fisher's exact test was used to evaluate associations between variables. All analyses were conducted using SAS v9.3. RESULTS: Among NPDS data, 2 years was the most common patient age reported and states in the Midwestern region had the highest numbers of exposure calls compared to other regions. Exposure calls differed by season (p < 0.0001) and were higher around the July 4th holiday compared to the rest of the days in July (2.09 vs. 1.89 calls/day, p < 0.002). Most exposures occurred inside a house, were managed on site and also had a "no effect" medical outcome. Of the 50 PC-administered surveys to parents or guardians, 39 (78%) met inclusion criteria for analysis. The majority of ingestions occurred in children that were 2 years of age, that were not alone, involved tiki torch fuel products located on a table or shelf, and occurred inside the home. The amount of lamp oil ingested did not appear to be associated with either the smell (p = 0.19) or the color of the oil (p = 1.00) in this small sample. Approximately half were asymptomatic (n = 18; 46%), and of those that reported symptoms, cough was the most common (n = 20, 95%) complaint. CONCLUSIONS: Lamp oil product exposures are most common among young children (around 2 years of age) while at home, not alone and likely as a result of the product being in a child-accessible location. Increasing parental awareness about potential health risks to children from these products and teaching safe storage and handling practices may help prevent both exposures and associated illness. These activities may be of greater benefit in Midwestern states and during summer months (including the period around the July 4th holiday). PMID- 24066736 TI - Total synthesis of (+)-gregatin B and E. AB - The first total synthesis of (+)-gregatin E and a new total synthesis of (+) gregatin B are described. Key features of our synthetic approach involve a palladium-catalyzed cyclization-methoxycarbonylation of optically active propargylic acetate and a Suzuki-Miyaura coupling or CuTC-mediated coupling reaction. The absolute configuration of (+)-gregatin E (5R,5'S) is proposed. PMID- 24066735 TI - A randomized blinded controlled trial of mobile phone reminders on the follow-up medical care of HIV-exposed and HIV-infected children in Cameroon: study protocol (MORE CARE). AB - BACKGROUND: In Cameroon, only two-thirds of children with HIV exposure or infection receive appropriate HIV-directed medical care. Mortality, antiretroviral therapy resistance and suboptimal virological response are strongly related to missed opportunities for treatment, and, more specifically, to skipped scheduled medical appointments. The present trial, MORE CARE (Mobile Reminders for Cameroonian Children Requiring HIV Care) seeks to determine if reminders sent by text message (SMS), phone call, or concomitant SMS and phone calls most increase the presence at medical appointments of HIV-infected or exposed children (efficacy), and which is the most efficient related to working time and financial cost (efficiency). METHODS/DESIGN: We will carry out a multicenter single-blind, randomized, factorial controlled trial. A randomization list will be electronically generated using random block sizes. Central allocation will be determined by sequentially numbered. A total of 224 subjects will be randomized into four groups (SMS, Call, SMS + Call, and Control) with an allocation ratio of 1:1:1:1. SMS and calls will be sent between 48 and 72 hours before the scheduled appointment. A medical assistant will send out text messages and will call participants. Our primary outcome is appointment measured by efficacy and efficiency of interventions. We hypothesize that two reminders (concomitant use of SMS and phone calls) as an appointment reminder is more effective to improve appointment compared to one reminder (only SMS or only call), and that the most efficient is use of only SMS. The analysis will be intention to treat. DISCUSSION: This trial investigates the potential of SMS and phone calls as motivational reminders to improve children's adherence to medical appointments for HIV-related care in Cameroon. The intervention will act to end missed appointment due to forgetfulness. TRIAL REGISTRATION: Pan African Clinical Trials Registry: PACTR201304000528276. PMID- 24066738 TI - Synthesis of amorphous FeOOH/reduced graphene oxide composite by infrared irradiation and its superior lithium storage performance. AB - A new hybrid nanostructure composed of mildly reduced graphene oxide (mRGO) nanosheets and homogeneous loading of amorphous FeOOH with ultrafine particles (~2 nm) is successfully synthesized via a facile infrared irradiation approach. Surprisingly, the as-prepared FeOOH/mRGO hybrid exhibits high reversible capacity, long-term stability, and excellent rate performance, when used as an anode material for lithium-ion batteries. A high reversible capacity of 767 mA h g(-1), with a coulombic efficiency of ~100%, can be achieved at a high current density of 1000 mA g(-1) even after 600 discharge/charge cycles. The superior electrochemical performances are attributed to the synergistic effects of the small particle size, amorphous structure, and conductive mRGO. PMID- 24066737 TI - Acute lung injury and fibrosis in a baboon model of Escherichia coli sepsis. AB - Sepsis-induced inflammation of the lung leads to acute respiratory distress syndrome (ARDS), which may trigger persistent fibrosis. The pathology of ARDS is complex and poorly understood, and the therapeutic approaches are limited. We used a baboon model of Escherichia coli sepsis that mimics the complexity of human disease to study the pathophysiology of ARDS. We performed extensive biochemical, histological, and functional analyses to characterize the disease progression and the long-term effects of sepsis on the lung structure and function. Similar to humans, sepsis-induced ARDS in baboons displays an early inflammatory exudative phase, with extensive necrosis. This is followed by a regenerative phase dominated by proliferation of type 2 epithelial cells, expression of epithelial-to-mesenchymal transition markers, myofibroblast migration and proliferation, and collagen synthesis. Baboons that survived sepsis showed persistent inflammation and collagen deposition 6-27 months after the acute episodes. Long-term survivors had almost double the amount of collagen in the lung as compared with age-matched control animals. Immunostaining for procollagens showed persistent active collagen synthesis within the fibroblastic foci and interalveolar septa. Fibroblasts expressed markers of transforming growth factor-beta and platelet-derived growth factor signaling, suggesting their potential role as mediators of myofibroblast migration and proliferation, and collagen deposition. In parallel, up-regulation of the inhibitors of extracellular proteases supports a deregulated matrix remodeling that may contribute to fibrosis. The primate model of sepsis-induced ARDS mimics the disease progression in humans, including chronic inflammation and long-lasting fibrosis. This model helps our understanding of the pathophysiology of fibrosis and the testing of new therapies. PMID- 24066739 TI - Higher order structure of personality and mental health: does general affectivity matter? AB - The higher order personality model, namely the Big Two, was tested in 2 studies (Ns = 878 and 467, respectively) by controlling for the effects of both general affectivity and common method variance. Study 2 also examined the associations of the metatraits with different mental health indicators through regression analyses. The results consistently provided support for the validity of the Big Two model in the latent space, with and without the effects of general affectivity and the common method variance. Moreover, in both studies, the high correlation between stability and plasticity decreased when these 2 method effects were controlled statistically. The regression analyses also showed that the associations of plasticity and stability with the indicators of both subjective and psychological well-being, as well as psychopathology, were consistent with the theoretical arguments behind the Big Two. PMID- 24066740 TI - Pectic oligosacharides from lemon peel wastes: production, purification, and chemical characterization. AB - Lemon peel wastes were extracted with water to remove free sugars and other soluble compounds, and the insoluble solid was employed as a substrate for the manufacture of pectin-derived oligosaccharides by processing with hot, compressed water. When water-extracted lemon peel wastes were treated with water at 160 degrees C, the oligomer concentration reached the maximum value (31 g/L). Autohydrolysis liquors were subjected to two membrane filtration stages (diafiltration followed by concentration), yielding a refined product containing about 98 wt % of oligomers at a global yield of 14 kg/100 kg oven-dry lemon peel. The concentrate contained oligogalacturonides (with DP in the range of 2-18) and arabinooligosaccharides (with DP in the range of 2-8). PMID- 24066741 TI - Diverse sources of C. difficile infection identified on whole-genome sequencing. AB - BACKGROUND: It has been thought that Clostridium difficile infection is transmitted predominantly within health care settings. However, endemic spread has hampered identification of precise sources of infection and the assessment of the efficacy of interventions. METHODS: From September 2007 through March 2011, we performed whole-genome sequencing on isolates obtained from all symptomatic patients with C. difficile infection identified in health care settings or in the community in Oxfordshire, United Kingdom. We compared single-nucleotide variants (SNVs) between the isolates, using C. difficile evolution rates estimated on the basis of the first and last samples obtained from each of 145 patients, with 0 to 2 SNVs expected between transmitted isolates obtained less than 124 days apart, on the basis of a 95% prediction interval. We then identified plausible epidemiologic links among genetically related cases from data on hospital admissions and community location. RESULTS: Of 1250 C. difficile cases that were evaluated, 1223 (98%) were successfully sequenced. In a comparison of 957 samples obtained from April 2008 through March 2011 with those obtained from September 2007 onward, a total of 333 isolates (35%) had no more than 2 SNVs from at least 1 earlier case, and 428 isolates (45%) had more than 10 SNVs from all previous cases. Reductions in incidence over time were similar in the two groups, a finding that suggests an effect of interventions targeting the transition from exposure to disease. Of the 333 patients with no more than 2 SNVs (consistent with transmission), 126 patients (38%) had close hospital contact with another patient, and 120 patients (36%) had no hospital or community contact with another patient. Distinct subtypes of infection continued to be identified throughout the study, which suggests a considerable reservoir of C. difficile. CONCLUSIONS: Over a 3-year period, 45% of C. difficile cases in Oxfordshire were genetically distinct from all previous cases. Genetically diverse sources, in addition to symptomatic patients, play a major part in C. difficile transmission. (Funded by the U.K. Clinical Research Collaboration Translational Infection Research Initiative and others.). PMID- 24066742 TI - Complement-binding anti-HLA antibodies and kidney-allograft survival. AB - BACKGROUND: Anti-HLA antibodies hamper successful transplantation, and activation of the complement cascade is involved in antibody-mediated rejection. We investigated whether the complement-binding capacity of anti-HLA antibodies plays a role in kidney-allograft failure. METHODS: We enrolled patients who received kidney allografts at two transplantation centers in Paris between January 1, 2005, and January 1, 2011, in a population-based study. Patients were screened for the presence of circulating donor-specific anti-HLA antibodies and their complement-binding capacity. Graft injury phenotype and the time to kidney allograft loss were assessed. RESULTS: The primary analysis included 1016 patients. Patients with complement-binding donor-specific anti-HLA antibodies after transplantation had the lowest 5-year rate of graft survival (54%), as compared with patients with non-complement-binding donor-specific anti-HLA antibodies (93%) and patients without donor-specific anti-HLA antibodies (94%) (P<0.001 for both comparisons). The presence of complement-binding donor-specific anti-HLA antibodies after transplantation was associated with a risk of graft loss that was more than quadrupled (hazard ratio, 4.78; 95% confidence interval [CI], 2.69 to 8.49) when adjusted for clinical, functional, histologic, and immunologic factors. These antibodies were also associated with an increased rate of antibody-mediated rejection, a more severe graft injury phenotype with more extensive microvascular inflammation, and increased deposition of complement fraction C4d within graft capillaries. Adding complement-binding donor-specific anti-HLA antibodies to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 0.75; 95% CI, 0.54 to 0.97). CONCLUSIONS: Assessment of the complement-binding capacity of donor-specific anti-HLA antibodies appears to be useful in identifying patients at high risk for kidney-allograft loss. PMID- 24066743 TI - CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. AB - BACKGROUND: The use of available antiviral agents for the prevention of cytomegalovirus (CMV) disease is limited by frequent toxic effects and the emergence of resistance. CMX001 has potent in vitro activity against CMV and other double-stranded DNA viruses. We evaluated the safety and anti-CMV activity of CMX001 in patients who had undergone allogeneic hematopoietic-cell transplantation. METHODS: From December 2009 through June 2011, a total of 230 patients with data that could be evaluated were enrolled in the study. We randomly assigned these adult CMV-seropositive transplant recipients from 27 centers to oral administration of CMX001 or placebo. Patients were assigned in a 3:1 ratio to five sequential study cohorts according to a dose-escalating, double blind design. Randomization was stratified according to the presence or absence of acute graft-versus-host disease and CMV DNA in plasma. Patients received the study drug after engraftment for 9 to 11 weeks, until week 13 after transplantation. Polymerase-chain-reaction analysis of CMV DNA in plasma was performed weekly. Patients in whom CMV DNA was detected at a level that required treatment discontinued the study drug and received preemptive treatment against CMV infection. The primary end point was a CMV event, defined as CMV disease or a plasma CMV DNA level greater than 200 copies per milliliter when the study drug was discontinued. The analysis was conducted in the intention-to-treat population. RESULTS: The incidence of CMV events was significantly lower among patients who received CMX001 at a dose of 100 mg twice weekly than among patients who received placebo (10% vs. 37%; risk difference, -27 percentage points; 95% confidence interval, -42 to -12; P=0.002). Diarrhea was the most common adverse event in patients receiving CMX001 at doses of 200 mg weekly or higher and was dose-limiting at 200 mg twice weekly. Myelosuppression and nephrotoxicity were not observed. CONCLUSIONS: Treatment with oral CMX001 at a dose of 100 mg twice weekly significantly reduced the incidence of CMV events in recipients of hematopoietic-cell transplants. Diarrhea was dose-limiting in this population at a dose of 200 mg twice weekly. (Funded by Chimerix; CMX001-201 ClinicalTrials.gov number, NCT00942305.). PMID- 24066744 TI - Robotic leg control with EMG decoding in an amputee with nerve transfers. AB - The clinical application of robotic technology to powered prosthetic knees and ankles is limited by the lack of a robust control strategy. We found that the use of electromyographic (EMG) signals from natively innervated and surgically reinnervated residual thigh muscles in a patient who had undergone knee amputation improved control of a robotic leg prosthesis. EMG signals were decoded with a pattern-recognition algorithm and combined with data from sensors on the prosthesis to interpret the patient's intended movements. This provided robust and intuitive control of ambulation--with seamless transitions between walking on level ground, stairs, and ramps--and of the ability to reposition the leg while the patient was seated. PMID- 24066745 TI - Resuscitation fluids. PMID- 24066746 TI - Images in clinical medicine. Extramedullary hematopoiesis in thalassemia. PMID- 24066747 TI - Case records of the Massachusetts General Hospital. Case 30-2013. A 19-year-old man with otalgia, slurred speech, and ataxia. PMID- 24066748 TI - Clostridium difficile--beyond the usual suspects. PMID- 24066749 TI - C1q-binding antibodies in kidney transplantation. PMID- 24066750 TI - Performance anxiety--what can health care learn from K-12 education? PMID- 24066751 TI - Blood-pressure lowering in acute intracerebral hemorrhage. PMID- 24066752 TI - Blood-pressure lowering in acute intracerebral hemorrhage. PMID- 24066753 TI - Blood-pressure lowering in acute intracerebral hemorrhage. PMID- 24066754 TI - Blood-pressure lowering in acute intracerebral hemorrhage. PMID- 24066755 TI - Dupilumab in persistent asthma. PMID- 24066756 TI - Dupilumab in persistent asthma. PMID- 24066757 TI - Dupilumab in persistent asthma. PMID- 24066758 TI - Ibrutinib in relapsed chronic lymphocytic leukemia. PMID- 24066759 TI - Ibrutinib in relapsed chronic lymphocytic leukemia. PMID- 24066760 TI - Ibrutinib in relapsed chronic lymphocytic leukemia. PMID- 24066761 TI - More on JC viremia in natalizumab-treated patients with multiple sclerosis. PMID- 24066762 TI - More on JC viremia in natalizumab-treated patients with multiple sclerosis. PMID- 24066763 TI - Ivacaftor in a G551D homozygote with cystic fibrosis. PMID- 24066764 TI - Images in clinical medicine. Uremic pericarditis. PMID- 24066766 TI - Extracellular metalloproteinases in neural crest development and craniofacial morphogenesis. AB - The neural crest (NC) is a population of migratory stem/progenitor cells that is found in early vertebrate embryos. NC cells are induced during gastrulation, and later migrate to multiple destinations and contribute to many types of cells and tissues, such as craniofacial structures, cardiac tissues, pigment cells and the peripheral nervous system. Recently, accumulating evidence suggests that many extracellular metalloproteinases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin motifs (ADAMTSs), play important roles in various stages of NC development. Interference with metalloproteinase functions often causes defects in craniofacial structures, as well as in other cells and tissues that are contributed by NC cells, in humans and other vertebrates. In this review, we summarize the current state of the field concerning the roles of these three families of metalloproteinases in NC development and related tissue morphogenesis, with a special emphasis on craniofacial morphogenesis. PMID- 24066781 TI - GMOs in animal agriculture: time to consider both costs and benefits in regulatory evaluations. AB - In 2012, genetically engineered (GE) crops were grown by 17.3 million farmers on over 170 million hectares. Over 70% of harvested GE biomass is fed to food producing animals, making them the major consumers of GE crops for the past 15 plus years. Prior to commercialization, GE crops go through an extensive regulatory evaluation. Over one hundred regulatory submissions have shown compositional equivalence, and comparable levels of safety, between GE crops and their conventional counterparts. One component of regulatory compliance is whole GE food/feed animal feeding studies. Both regulatory studies and independent peer reviewed studies have shown that GE crops can be safely used in animal feed, and rDNA fragments have never been detected in products (e.g. milk, meat, eggs) derived from animals that consumed GE feed. Despite the fact that the scientific weight of evidence from these hundreds of studies have not revealed unique risks associated with GE feed, some groups are calling for more animal feeding studies, including long-term rodent studies and studies in target livestock species for the approval of GE crops. It is an opportune time to review the results of such studies as have been done to date to evaluate the value of the additional information obtained. Requiring long-term and target animal feeding studies would sharply increase regulatory compliance costs and prolong the regulatory process associated with the commercialization of GE crops. Such costs may impede the development of feed crops with enhanced nutritional characteristics and durability, particularly in the local varieties in small and poor developing countries. More generally it is time for regulatory evaluations to more explicitly consider both the reasonable and unique risks and benefits associated with the use of both GE plants and animals in agricultural systems, and weigh them against those associated with existing systems, and those of regulatory inaction. This would represent a shift away from a GE evaluation process that currently focuses only on risk assessment and identifying ever diminishing marginal hazards, to a regulatory approach that more objectively evaluates and communicates the likely impact of approving a new GE plant or animal on agricultural production systems. PMID- 24066782 TI - Deamidation of asparagine to aspartate destabilizes Cu, Zn superoxide dismutase, accelerates fibrillization, and mirrors ALS-linked mutations. AB - The reactivity of asparagine residues in Cu, Zn superoxide dismutase (SOD1) to deamidate to aspartate remains uncharacterized; its occurrence in SOD1 has not been investigated, and the biophysical effects of deamidation on SOD1 are unknown. Deamidation is, nonetheless, chemically equivalent to Asn-to-Asp missense mutations in SOD1 that cause amyotrophic lateral sclerosis (ALS). This study utilized computational methods to identify three asparagine residues in wild-type (WT) SOD1 (i.e., N26, N131, and N139) that are predicted to undergo significant deamidation (i.e., to >20%) on time scales comparable to the long lifetime (>1 year) of SOD1 in large motor neurons. Site-directed mutagenesis was used to successively substitute these asparagines with aspartate (to mimic deamidation) according to their predicted deamidation rate, yielding: N26D, N26D/N131D, and N26D/N131D/N139D SOD1. Differential scanning calorimetry demonstrated that the thermostability of N26D/N131D/N139D SOD1 is lower than WT SOD1 by ~2-8 degrees C (depending upon the state of metalation) and <3 degrees C lower than the ALS mutant N139D SOD1. The triply deamidated analog also aggregated into amyloid fibrils faster than WT SOD1 by ~2-fold (p < 0.008**) and at a rate identical to ALS mutant N139D SOD1 (p > 0.2). A total of 534 separate amyloid assays were performed to generate statistically significant comparisons of aggregation rates among WT and N/D SOD1 proteins. Capillary electrophoresis and mass spectrometry demonstrated that ~23% of N26 is deamidated to aspartate (iso-aspartate was undetectable) in a preparation of WT human SOD1 (isolated from erythrocytes) that has been used for decades by researchers as an analytical standard. The deamidation of asparagine--an analytically elusive, sub-Dalton modification--represents a plausible and overlooked mechanism by which WT SOD1 is converted to a neurotoxic isoform that has a similar structure, instability, and aggregation propensity as ALS mutant N139D SOD1. PMID- 24066765 TI - Molecular mechanisms of ETS transcription factor-mediated tumorigenesis. AB - The E26 transformation-specific (ETS) family of transcription factors is critical for development, differentiation, proliferation and also has a role in apoptosis and tissue remodeling. Changes in expression of ETS proteins therefore have a significant impact on normal physiology of the cell. Transcriptional consequences of ETS protein deregulation by overexpression, gene fusion, and modulation by RAS/MAPK signaling are linked to alterations in normal cell functions, and lead to unlimited increased proliferation, sustained angiogenesis, invasion and metastasis. Existing data show that ETS proteins control pathways in epithelial cells as well as stromal compartments, and the crosstalk between the two is essential for normal development and cancer. In this review, we have focused on ETS factors with a known contribution in cancer development. Instead of focusing on a prototype, we address cancer associated ETS proteins and have highlighted the diverse mechanisms by which they affect carcinogenesis. Finally, we discuss strategies for ETS factor targeting as a potential means for cancer therapeutics. PMID- 24066783 TI - Sexuality and chronic illness. AB - Sexual function is often affected in individuals living with chronic illness and their partners, and multiple comorbidities increase the likelihood of sexual dysfunction. This review focuses on the areas of cardiovascular disease, respiratory conditions, and cancer, all areas for which there are practical, evidence-based strategies to guide sexual counseling. Although nurses have been reluctant to address the topic of sexuality in practice, a growing number of studies suggest that patients want nurses to address their concerns and provide resources to them. Thus, nurses must be proactive in initiating conversations on sexual issues to fill this gap in practice. PMID- 24066784 TI - The invisible elderly: lesbian, gay, bisexual, and transgender older adults. AB - More than 2 million older adults identify as lesbian, gay, bisexual, or transgender (LGBT). The purpose of this article is to present an overview of the physical and mental health needs of LGBT older adults to sensitize nurses to the specific needs of this group. Nurses are in a prominent position to create health care environments that will meet the needs of this invisible, and often misunderstood, group of people. PMID- 24066785 TI - Validity and reliability of the geriatric sexuality inventory. AB - Effective health care for older adults requires that providers assess and manage sexual health needs with high priority. This assessment begins with an effective sexuality assessment tool. A two-step, research approach was undertaken to develop and test the Geriatric Sexuality Inventory (GSI). Literature and expert review resulted in a 34-item instrument that was initially completed by 34 older adults ages 60 to 91 (mean age = 75). The testing was repeated in 19 of the original participants. The sample was 75% women, and 88% Caucasian with 9% single, 27% married, 18% divorced, and 46% widowed participants. Internal consistency reliability was run on all 53 responses and revealed adequate reliability (alpha = 0.74). Test-retest analysis also revealed good initial instrument reliability (r = 0.78; p < 0.001). Responses to open-ended questions regarding sexual information and care needs supported evidence gathered from the literature. Initial testing of the GSI revealed content validity and good internal consistency and test-retest reliability. PMID- 24066786 TI - Influence of cognitive decline on sexuality in individuals with dementia and their caregivers. AB - Sexuality is an important element of human life that is strongly influenced by the social environment. People assess themselves and relate their roles to one another in terms of sexuality. More attention must be directed at the sexual needs of individuals with dementia and their caregivers. A myth believed by society is that individuals with dementia are asexual and that sexual desires and needs for connection will wane over time; whereas in reality many couples living with dementia remain sexually active as the disease progresses. The sexual needs of individuals with dementia are similar to those of younger people but might vary in occurrence and expression. An increase or decline in sexual desire is dependent on the level of cognitive impairment. Sexuality in individuals with dementia may be expressed as inappropriate or hypersexual behavior due to disinhibition and forgetting social cues. Although hypersexuality is often less common than other challenging behaviors that can occur in dementia, it affects both the health of the individual with dementia and the health of his or her caregiver. PMID- 24066787 TI - Therapeutic interactions to enhance the mental health and wellness of dementia caregivers and patients. AB - Individuals with dementia and their family caregivers have higher rates of stress and mental health concerns than the general population. Gerontological nurses have unique and valuable opportunities to conduct therapeutic interactions that support the mental health and well-being of patients and family members. Information regarding dementia patient and family caregiver stressors are presented, followed by engaging strategies for opening therapeutic conversations about these topics. Ways in which gerontological nurses can facilitate coping skills and strengths identification are also outlined. PMID- 24066788 TI - Supporting conversations between individuals with dementia and their family members. AB - Remembrance of recent events is a major problem for individuals with dementia. Consequently, this article explores the process of acceptance and integration of a digital photograph diary (DPD) as a tool for remembrance of and conversations about daily life events. A design for multiple case studies was used. Seven couples, in which one individual in the couple had Alzheimer's disease, tested the DPD for 6 months. Data were collected in three sequences with interviews, observations, and screening instruments. In the analysis, all data were integrated to find common patterns of content. Some couples became regular users, while others used the DPD more sporadically. Factors contributing to regular use were how the DPD matched expectations, actual use, support, experienced usefulness, and reactions from family and friends. For those couples who became regular users, the DPD facilitated their conversation about recent daily activities. PMID- 24066789 TI - Sexually transmitted infections and older adults. AB - Older adults continue to be sexually active in their later years. A range of sexually transmitted infections (STIs) such as chlamydia, gonorrhea, syphilis, and HIV have been reported among older adults. Risk factors for STIs in older populations include (a) normal sexual changes associated with aging (e.g., increased time to attain an erection, decreased vaginal lubrication, decreases in sexual hormones); (b) psychosocial changes (e.g., loss of partner or spouse and re-entering the dating scene); and (c) risky sexual behaviors, including no or infrequent use of condoms. Screening of adults for STIs should occur regardless of age based on guidelines such as those from the Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force. As discussed in this article, nurses can use assessment guides and engage in interventions such as counseling and education with older adults to reduce STI risk or refer for treatment. Numerous online resources exist for both nurses and older adults to increase knowledge of STIs. PMID- 24066790 TI - Highly luminescent dinuclear platinum(II) complexes incorporating bis cyclometallating pyrazine-based ligands: a versatile approach to efficient red phosphors. AB - A series of luminescent dinuclear platinum(II) complexes incorporating diphenylpyrazine-based bridging ligands (L(n)H2) has been prepared. Both 2,5 diphenylpyrazine (L(2)H2) and 2,3-diphenylpyrazine (L(3)H2) are able to undergo cyclometalation of the two phenyl rings, with each metal ion binding to the two nitrogen atoms of the central heterocycle, giving, after treatment with the anion of dipivaloyl methane (dpm), complexes of formula {Pt(dpm)}2L(n). These compounds are isomers of the analogous complex of 4,6-diphenylpyrimidine (L(1)H2). Related complexes of dibenzo(f,h)quinoxaline (L(4)H2), 2,3-diphenyl-quinoxaline (L(5)H2), and dibenzo[3,2-a:2',3'-c]phenazine (L(6)H2) have also been prepared, allowing the effects of strapping together the phenyl rings (L(4)H2 and L(6)H2) and/or extension of the conjugation from pyrazine to quinoxaline (L(5)H2 and L(6)H2) to be investigated. In all cases, the corresponding mononuclear complexes, Pt(dpm)L(n)H, have been isolated too. All 12 complexes are phosphorescent in solution at ambient temperature. Emission spectra of the dinuclear complexes are consistently red shifted compared to their mononuclear analogues, as are the lowest energy absorption bands. Electrochemical data and TD-DFT calculations suggest that this effect arises primarily from stabilization of the LUMO. Introduction of the second metal ion also has the effect of substantially increasing the molar absorptivity and, in most cases, the radiative rate constants. Meanwhile, extension of conjugation in the heterocycle of L(5)H2 and L(6)H2 and planarization of the aromatic system favored by interannular bond formation in L(4)H2 and L(6)H2 leads to further red shifts of the absorption and emission spectra to wavelengths that are unusually long for cyclometalated platinum(II) complexes. The results may offer a versatile design strategy for tuning and optimizing the optical properties of d-block metal complexes for contemporary applications. PMID- 24066792 TI - The perspectives of Iranian physicians and patients towards patient decision aids: a qualitative study. AB - BACKGROUND: Patient preference is one of the main components of clinical decision making, therefore leading to the development of patient decision aids. The goal of this study was to describe physicians' and patients' viewpoints on the barriers and limitations of using patient decision aids in Iran, their proposed solutions, and, the benefits of using these tools. METHODS: This qualitative study was conducted in 2011 in Iran by holding in-depth interviews with 14 physicians and 8 arthritis patient. Interviewees were selected through purposeful and maximum variation sampling. As an example, a patient decision aid on the treatment of knee arthritis was developed upon literature reviews and gathering expert opinion, and was presented at the time of interview. Thematic analysis was conducted to analyze the data by using the OpenCode software. RESULTS: The results were summarized into three categories and ten codes. The extracted categories were the perceived benefits of using the tools, as well as the patient related and physician-related barriers in using decision aids. The following barriers in using patient decision aids were identified in this study: lack of patients and physicians' trainings in shared decision making, lack of specialist per capita, low treatment tariffs and lack of an exact evaluation system for patient participation in decision making. CONCLUSIONS: No doubt these barriers demand the health authorities' special attention. Hence, despite patients and physicians' inclination toward using patient decision aids, these problems have hindered the practical usage of these tools in Iran--as a developing country. PMID- 24066793 TI - Predictors of premarital sexual activity among unmarried youth in Vientiane, Lao PDR: the role of parent-youth interactions and peer influence. AB - Research indicates that adolescents in low-income countries have an early sexual debut and engage in risky sexual behaviours. Few studies in low-income countries however, have explored the factors that influence young people's sexual behaviours. This study examined individual, family and peer-level factors associated with premarital sexual behaviours in the Lao People's Democratic Republic (PDR). A cross-sectional survey was undertaken with unmarried youth aged 18 to 24 years (N = 1200) in Vientiane Capital City. Logistic regression models, controlling for confounding variables, were employed to test for the contribution of factors influencing premarital sexual activity. Most respondents held positive attitudes towards premarital sex, with males having more liberal attitudes than females (mean score of 2.68 vs. 2.32, p < 0.001). Prevalence of premarital sexual activity was higher among males than females (44.7% and 19.2%, respectively). Predictors of premarital sex for males were age, sexual attitudes, perceived parental expectations regarding sex, dating and peer influence. For females, predictors were father's level of education, parent-youth sexual communication, peer influence and liberal sexual attitudes. The results highlight the role of parent-youth interaction and peer influence. The results suggest the need for a range of strategies at the individual, peer and family level, as well as a gender specific focus. PMID- 24066795 TI - Poly(aminoether)-gold nanorod assemblies for shRNA plasmid-induced gene silencing. AB - Gold nanorods (GNRs) have emerged as promising nanomaterials for biosensing, imaging, photothermal hyperthermia treatments, and therapeutic delivery for several diseases. We generated poly(aminoether)-GNR nanoassemblies using a layer by-layer deposition approach based on the 1,4C-1,4Bis polymer from a library recently synthesized in our laboratory. Subtoxic concentrations of 1,4C-1,4Bis GNR nanoassemblies were employed to deliver expression vectors that express shRNA ("shRNA plasmid") against firefly luciferase gene to knock down expression of the protein constitutively expressed in prostate cancer cells. The role of hydrodynamic size and zeta potential in determining nanoassembly mediated luciferase silencing was investigated. Finally, the theranostic potential of 1,4C 1,4Bis-GNR nanoassemblies was demonstrated using live cell two-photon induced luminescence bioimaging. Our results indicate that poly(aminoether)-GNR nanoassemblies are a promising theranostic platform for delivery of therapeutic payloads capable of simultaneous gene silencing and bioimaging. PMID- 24066791 TI - Factors associated with physical growth of children during the first two years of life in rural and urban areas of Vietnam. AB - BACKGROUND: Differences between urban and rural settings can be seen as a very important example of gaps between groups in a population. The aim of this paper is to compare an urban and a rural area regarding child growth during the first two years of life as related to mother's use of antenatal care (ANC), breastfeeding and reported symptoms of illness. METHODS: The studies were conducted in two Health and Demographic Surveillance Sites, one rural and one urban in Hanoi, Vietnam. RESULTS: We found that children in the urban area grow faster than those in the rural area. There were statistical associations between growth and the education of the mother as well as household resources. There were positive correlations between the number of ANC visits and child growth. We also saw a positive association between growth and early initiation (first hour of life) of breastfeeding but the reported duration of exclusive breastfeeding was not statistically significantly related to growth. Reporting symptoms of illness was negatively correlated to growth, i.e. morbidity is hampering growth. CONCLUSIONS: All predictors of growth discussed in this article, ANC, breastfeeding and illness, are associated with social and economic conditions. To improve and maintain good conditions for child growth it is important to strengthen education of mothers and household resources particularly in the rural areas. Globalization and urbanization means obvious risks for increasing gaps not least between urban and rural areas. Improvement of the quality of programs for antenatal care, breastfeeding and integrated management of childhood illness are also needed in Vietnam. PMID- 24066796 TI - Cancer vaccination by electro-gene-transfer. AB - Therapeutic vaccination could become an important modality to fight cancer. Efficacious immune responses against cancer cells have to be directed simultaneously against multiple epitopes belonging to tumor-associated antigens and will require the involvement of both CD4(+) and CD8(+) cells as well as antibodies. The inoculation of a nucleic acid coding for a protein antigen by means of intradermal or intramuscular injection is a simple and cheap approach to induce an immune response against a target antigen. For long time, however, clinical translation of this concept has suffered from the poor immunogenicity of plasmid DNA vaccines in larger species. An emerging technology potentially capable of overcoming these limitations is in vivo electroporation. In this review, we report recent data showing initial evidence of immunogenicity by gene electro-transfer in the clinic and discuss how new vector development combined with in vivo electroporation will allow nucleic acid vaccination to become a robust approach to fight cancer. PMID- 24066797 TI - Phytochemical and biological activities of an anticancer plant medicine: Brucea javanica. AB - In this review, the literature data on recent advances of the medicinal plant Brucea javanica (L.) Merr. (Simaroubaceae), both phytochemical and biological investigations, are compiled. Brucea javanica is an evergreen shrub distributed widely in Southeast Asia and northern Australia. In China, the seeds of Brucea javanica have been used as traditional herbal medicine due to its multifaceted activities. To date, 153 compounds have been reported from the seeds and aerial parts of Brucea javanica. Quassinoids are the main constituents of this species. The extract of Brucea javanica and the isolated compounds especially quassinoids exhibited various biological properties, such as antitumor and antimalarial effects. PMID- 24066798 TI - Modeling study of phenylsulfonylfuroxan derivatives as P-gp inhibitors: a combined approach of CoMFA, CoMSIA and HQSAR. AB - Multidrug resistance (MDR) is a phenomenon whereby cancer cells experience intrinsic or acquired resistance to a broad spectrum of structurally and functionally distinct chemotherapeutic agents. Permeability glycoprotein (P-gp) is the key protein responsible for the development of MDR in cancer cells, as it exports chemotherapeutic agents from cells. In the present study, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram quantitative structure activity relationship (HQSAR) techniques were used to derive predictive models for phenylsulfonylfuroxan derivatives as P-gp inhibitors. Cross-validated correlation coefficients (q(2)) of 0.811, 0.855, and 0.907 and non-cross-validated correlation coefficients (r(2)) of 0.87, 0.985, and 0.973 were obtained for CoMFA, CoMSIA, and HQSAR derived models, respectively. The predictive power of the models were assessed using an external test set of five compounds and showed reasonable external predictabilities (r(2) pred) of 0.704, 0.517, and 0.713, respectively. Contour and atomic contribution maps were generated to investigate physicochemical requirements of ligands for better receptor binding affinity. 3D Contour maps suggested molecular interactions such as steric and electrostatic effects and hydrogen bond formation. However, atomic contribution maps indicated that ortho and para positions of the R(1) phenylsulfonyl ring are the most desirable regions to modulate P-gp antagonism. The 3(rd) and 4(th) positions of the central five-membered ring were also found to be important. Our results are in line with previous reports. Information obtained from the contour and atomic contribution maps were utilized to design more potent compounds containing different R(1) fragments. In addition, the activities of these more potent compounds were predicted using derived models. PMID- 24066801 TI - Practicing nurses perspectives of clinical scholarship: a qualitative study. AB - BACKGROUND: There is a scarcity of research published on clinical scholarship. Much of the conceptualisation has been conducted in the academy. Nurse academics espouse that the practice of nursing must be built within a framework of clinical scholarship. A key concept of clinical scholarship emerging from discussions in the literature is that it is an essential component of enabling evidence-based nursing and the development of best practice standards to provide for the needs of patients/clients. However, there is no comprehensive definition of clinical scholarship from the practicing nurses. The aim of this study was to contribute to this definitional discussion on the nature of clinical scholarship in nursing. METHODS: Naturalistic inquiry informed the method. Using an interpretative approach 18 practicing nurses from Australia, Canada and England were interviewed using a semi-structured format. The audio-taped interviews were transcribed and the text coded for emerging themes. The themes were sorted into categories and the components of clinical scholarship described by the participants compared to the scholarship framework of Boyer [JHEOE 7:5-18, 2010]. RESULTS: Clinical scholarship is difficult to conceptualise. Two of the essential elements of clinical scholarship are vision and passion. The other components of clinical scholarship were building and disseminating nursing knowledge, sharing knowledge, linking academic research to practice and doing practice-based research. CONCLUSION: Academic scholarship dominated the discourse in nursing. However, in order for nursing to develop and to impact on health care, clinical scholarship needs to be explored and theorised. Nurse educators, hospital-based researchers and health organisations need to work together with academics to achieve this goal.Frameworks of scholarship conceptualised by nurse academics are reflected in the findings of this study with their emphasis on reading and doing research and translating it into nursing practice. This needs to be done in a nonthreatening environment. PMID- 24066799 TI - Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines. AB - Rho GTPases play a key role in the regulation of multiple essential cellular processes, including actin dynamics, gene transcription and cell cycle progression. Aberrant activation of Rac1, a member of Rho family of small GTPases, is associated with tumorigenesis, cancer progression, invasion and metastasis. Particularly, Rac1 is overexpressed and hyperactivated in highly aggressive breast cancer. Thus, Rac1 appears to be a promising and relevant target for the development of novel anticancer drugs. We identified the novel Rac1 inhibitor ZINC69391 through a docking-based virtual library screening targeting Rac1 activation by GEFs. This compound was able to block Rac1 interaction with its GEF Tiam1, prevented EGF-induced Rac1 activation and inhibited cell proliferation, cell migration and cell cycle progression in highly aggressive breast cancer cell lines. Moreover, ZINC69391 showed an in vivo antimetastatic effect in a syngeneic animal model. We further developed the novel analog 1A-116 by rational design and showed to be specific and more potent than the parental compound in vitro and interfered Rac1-P-Rex1 interaction. We also showed an enhanced in vivo potency of 1A-116 analog. These results show that we have developed novel Rac1 inhibitors that may be used as a novel anticancer therapy. PMID- 24066803 TI - Effect of select organic compounds on perchlorate formation at boron-doped diamond film anodes. AB - Rates of ClO4(-) formation from ClO3(-) oxidation were investigated in batch experiments as a function of organic compounds (p-nitrophenol, p-benzoquinone, p methoxyphenol, and oxalic acid) and current density using boron-doped diamond film anodes. Excluding organics, ClO4(-) formation rates ranged from 359 to 687 MUmoles m(-2) min(-1) for current densities of 1-10 mA cm(-2). The presence of p substituted phenols inhibited ClO4(-) formation rates between 13.0 and 99.6%. Results from a reactive-transport model of the diffuse layer adjacent to the anode surface indicate that competition between organics and ClO3(*) for OH(*) within a reaction zone (0.02-0.96 MUm) adjacent to the anode controls ClO4(-) formation. Under kinetic-limited conditions (1.0 mA cm(-2)), organics reach the anode surface and substrates with higher OH(*) reaction rates demonstrate greater inhibition of perchlorate formation (IPF). At higher current densities (10 mA cm( 2)), organic compound oxidation becomes mass transfer-limited and compounds degrade a small distance from the anode surface (~ 0.26 MUm for p-methoxyphenol). Therefore, OH(*) scavenging does not occur at the anode surface and IPF values decrease. Results provide evidence for the existence of desorbed OH(*) near the anode surface and highlight the importance of controlling reactor operating conditions to limit ClO4(-) production during anodic treatment of organic compounds. PMID- 24066802 TI - The views of mothers and GPs about postpartum care in Australian general practice. AB - BACKGROUND: The postpartum period is a time of increased morbidity for mothers and infants under 12 months, yet is an under-researched area of primary care. Despite a relatively clear framework for involving general practitioners (GPs) in antenatal care, the structure of maternity service provision in some Australian jurisdictions has resulted in highly variable roles of general practice in routine postpartum care. This study aimed to investigate the views and experiences of mothers and GPs about postpartum care in general practice. METHODS: This was a qualitative study of mothers and GPs in rural, regional and metropolitan areas of Queensland, Australia. Semi-structured interviews were conducted with 88 mothers and six general practitioners between September 2010 and February 2012. Interviews were recorded and transcribed verbatim. Data were analysed thematically and compared across groups. RESULTS: Three main themes emerged: The relationship between the mother and GP; practice management; and GP visits. This paper focuses on the theme GP visits and its subthemes: recommendations for GP visits; scope of practice; and content of a routine visit. Recommendations about GP visits given to mothers varied by birthing sector, obstetric provider and model of maternity care resulting in confusion amongst mothers about the timing and role of GPs in routine postpartum care. Similarly, GPs voiced concerns about a lack of consistent guidelines for their involvement in routine postpartum care. Although ideally placed to provide primary care to mothers and their infants in the postpartum period, the lack of consistent guidelines for the role of GPs is of concern to both the GPs and early parenting women. CONCLUSION: General practice is an important source of postpartum care for mothers and provides a basis for ongoing support for the family. More consistent guidelines and better coordination with other care providers would benefit both mothers and GPs. PMID- 24066804 TI - Solvent-induced alpha- to 3(10)-helix transition of an amphiphilic peptide. AB - The amphiphilic peptide of the triacylglycerol lipase derived from Pseudomonas aeruginosa plays a critical role in guarding the gate for ligand access. Conformations of this peptide at several water-oil interfaces and in protein environments were compared using atomistic simulations with explicit solvents. In oil-containing solvents, this peptide is able to retain a folded structure. Interestingly, when the peptide is immersed in a low-polarity solvent environment, it exhibits a "coalesced" helix structure, which has both alpha- and 3(10)-helix components. The observation that the 3(10)-helical conformation is populated in a highly nonpolar environment is consistent with a previous report on polymethylalanine. Frequent interconversions of the secondary structure (between alpha-helix and 3(10)-helix) of the peptide are also observed. We further studied how this solvent-induced structural transition may be connected to the trigger mechanism of lipase gating and how the lipase senses the hydrophobic-hydrophilic interface. PMID- 24066806 TI - Is carbohydrate needed to further stimulate muscle protein synthesis/hypertrophy following resistance exercise? AB - It is now well established that protein supplementation after resistance exercise promotes increased muscle protein synthesis, which ultimately results in greater net muscle accretion, relative to exercise alone or exercise with supplementary carbohydrate ingestion. However, it is not known whether combining carbohydrate with protein produces a greater anabolic response than protein alone. Recent recommendations have been made that the composition of the ideal supplement post exercise would be a combination of a protein source with a high glycemic index carbohydrate. This is based on the hypothesis that insulin promotes protein synthesis, thus maximising insulin secretion will maximally potentiate this action. However, it is still controversial as to whether raising insulin level, within the physiological range, has any effect to further stimulate muscle protein synthesis. The present commentary will review the evidence underpinning the recommendation to consume carbohydrates in addition to a protein supplementation after resistance exercise for the specific purpose of increasing muscle mass. The paucity of data will be discussed, thus our conclusions are that further studies are necessary prior to any conclusions that enable evidence-based recommendations to be made. PMID- 24066805 TI - Psychodynamic Motivation and Training program (PMT) for the secondary prevention in patients with stable coronary heart disease: study protocol for a randomized controlled trial of feasibility and effects. AB - BACKGROUND: Nonpharmacological secondary prevention of coronary heart disease is considered a safe and effective measure to substantially reduce mortality. Despite the effectiveness of lifestyle changes, the compliance rate of patients is very low mainly due to psychosocial barriers. Psychotherapeutic approaches that address how persons think about themselves and their behaviors appear to have a significant potential for improving health behavior. METHODS/DESIGN: Against this background, our study aims to examine the feasibility and effects of a Psychodynamic Motivation and Training program (PMT) as compared to one session of advice in exercise training (EX) and treatment as usual (TAU). For that purpose, 90 patients with stable coronary heart disease and a physically inactive lifestyle will be randomly assigned to the three groups (each with n = 30). The primary outcome is the change in the individual anaerobic threshold as determined by spiroergometry from baseline to six month follow-up. Secondary endpoints include change in endothelial function, biomarkers of inflammation and oxidative stress, quality of life, symptoms of fatigue, illness perception and feasibility of the treatment approach. We hypothesize that physical fitness will improve more in PMT than in EX and TAU, with PMT and EX more than TAU, and that the effects will be more pronounced for participants with current mental or psychosocial distress. DISCUSSION: The results of the study will help to determine the effectiveness of a psychodynamic lifestyle change approach and to identify measures for designing specifically tailored interventions to improve compliance with cardiovascular prevention. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01445808. PMID- 24066807 TI - Synthesis of (+/-)-amathaspiramide F and discovery of an unusual stereocontrolling element for the [2,3]-Stevens rearrangement. AB - A formal total synthesis of (+/-)-amathaspiramide F through a tandem palladium catalyzed allylic amination/[2,3]-Stevens rearrangement is reported. The unexpected diastereoselectivity of the [2,3]-Stevens rearrangement was controlled by the substitution patterns of an aromatic ring. This discovery represents a new stereocontrolling element for [2,3]-sigmatropic rearrangements in complex molecular settings. PMID- 24066809 TI - Rambutan-like FeCO3 hollow microspheres: facile preparation and superior lithium storage performances. AB - Rambutan-like FeCO3 hollow microspheres were prepared via a facile and economic one-step hydrothermal method. The structure and morphology evolution mechanism was disclosed through time-dependent experiments. After undergoing the symmetric inside-out Ostwald ripening, the resultants formed microporous/nanoporous constructions composed of numerous one-dimensional (1D) nanofiber building blocks. Tested as anode materials of Li-ion batteries, FeCO3 hollow microspheres presented attractive electrochemical performances. The capacities were over 1000 mAh g(-1) for initial charge, ~880 mAh g(-1) after 100 cycles at 50 mA g(-1), and ~710 mAh g(-1) after 200 cycles at 200 mA g(-1). The 1D nanofiber assembly and hollow interior endow this material efficient contact with electrolyte, short Li(+) diffusion paths, and sufficient void spaces to accommodate large volume variation. The cost-efficient FeCO3 with rationally designed nanostructures is a promising anode candidate for Li-ion batteries. PMID- 24066808 TI - IkappaBbeta-mediated NF-kappaB activation confers protection against hyperoxic lung injury. AB - Supplemental oxygen is frequently used in an attempt to improve oxygen delivery; however, prolonged exposure results in damage to the pulmonary endothelium and epithelium. Although NF-kappaB has been identified as a redox-responsive transcription factor, whether NF-kappaB activation exacerbates or attenuates hyperoxic lung injury is unclear. We determined that sustained NF-kappaB activity mediated by IkappaBbeta attenuates lung injury and prevents mortality in adult mice exposed to greater than 95% O2. Adult wild-type mice demonstrated evidence of alveolar protein leak and 100% mortality by 6 days of hyperoxic exposure, and showed NF-kappaB nuclear translocation that terminated after 48 hours. Furthermore, these mice showed increased expression of NF-kappaB-regulated proinflammatory and proapoptotic cytokines. In contrast, mice overexpressing the NF-kappaB inhibitory protein, IkappaBbeta (AKBI), demonstrated significant resistance to hyperoxic lung injury, with 50% surviving through 8 days of exposure. This was associated with NF-kappaB nuclear translocation that persisted through 96 hours of exposure. Although induction of NF-kappaB-regulated proinflammatory cytokines was not different between wild-type and AKBI mice, significant up-regulation of antiapoptotic proteins (BCL-2, BCL-XL) was found exclusively in AKBI mice. We conclude that sustained NF-kappaB activity mediated by IkappaBbeta protects against hyperoxic lung injury through increased expression of antiapoptotic genes. PMID- 24066810 TI - Psychoanalytic interpretation of superego functioning following CS readministration procedures: case illustration. AB - The Comprehensive System (CS; Exner, 2003) has specific procedures to address brief Rorschach protocols when the first administration yields fewer than 14 responses. These procedures involve the assessor's asking the client to retake the test by providing more responses on the second administration than the first administration. The request carries with it an implicit criticism of the client's initial effort and a mandate to improve performance on retake. The retake request, with its ambiguously worded demand for improved performance, engages the client's superego (i.e., the client feels judged) and makes it possible to study superego manifestations (e.g., guilt, shame) on the Rorschach test, using a model of (a) brief first record, (b) retake directive, and (c) second administration. We present a case that illustrates a clinical strategy, modeled on a psychoanalytic understanding of the CS retake procedure, for studying the client's superego functioning under retest conditions. PMID- 24066811 TI - Analysis of 2-alkylcyclobutanones in cashew nut, nutmeg, apricot kernel, and pine nut samples: re-evaluating the uniqueness of 2-alkylcyclobutanones for irradiated food identification. AB - 2-Alkylcyclobutanones (2-ACBs) have long been considered as unique radiolytic products that can be used as indicators for irradiated food identification. A recent report on the natural existence of 2-ACB in non-irradiated nutmeg and cashew nut samples aroused worldwide concern because it contradicts the general belief that 2-ACBs are specific to irradiated food. The goal of this study is to test the natural existence of 2-ACBs in nut samples using our newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with enhanced analytical sensitivity and selectivity ( Ye , Y. ; Liu , H. ; Horvatovich , P. ; Chan , W. Liquid chromatography-electrospray ionization tandem mass spectrometric analysis of 2-alkylcyclobutanones in irradiated chicken by precolumn derivatization with hydroxylamine . J. Agric. Food Chem. 2013 , 61 , 5758 - 5763 ). The validated method was applied to identify 2-dodecylcyclobutanone (2-DCB) and 2-tetradecylcyclobutanone (2-TCB) in nutmeg, cashew nut, pine nut, and apricot kernel samples (n = 22) of different origins. Our study reveals that 2 DCB and 2-TCB either do not exist naturally or exist at concentrations below the detection limit of the existing method. Thus, 2-DCB and 2-TCB are still valid to be used as biomarkers for identifying irradiated food. PMID- 24066812 TI - The correlation between pre-operative serum tumor markers and lymph node metastasis in gastric cancer patients undergoing curative treatment. AB - BACKGROUND: There was few study concentrated on the correlation between the evaluated tumor markers and lymph node metastasis. In this study, we aimed to evaluate the correlation between the CA724, CA242, CA199, CEA and the lymph node metastasis of gastric cancer and assess the prognostic value of them in different N stage patients. METHODS: We analyzed the correlation between serum level of CA724, CA242, CA199, CEA and lymph node metastasis in 1501 gastric cancer patients. RESULTS: Lymph node metastasis of gastric cancer was related with tumor location, Bormann type, tumor size, histological type, depth of invasion and TNM stage (p < 0.05). The values of CA724, CA242, CA199 and CEA were positively correlated with the metastatic lymph node counts and the N stage (p < 0.05). The later the N stage was, the levels of CA724, CA242 and CA199 were higher. The later the N stage was, the positive rates of tumor markers were higher (p < 0.05). In comparing with single tumor markers, the positive rates of tumor markers combination were higher. The combination of CA724 + CA242 + CA199 + CEA had highest positive rate. The higher CEA level related to N1 stage patients while higher CA199 was related with poor prognosis for N1 stage patients. For N0 and N2 stage patients, evaluation of CA724 indicated poorer prognosis. For N1 and N2 stage gastric patients, the patients with increased CA242 inclined to have shorter survival time. CONCLUSIONS: The tumor makers CA724, CA242, CA199 and CEA were evaluated significantly in the gastric patients with later N stage. The combination of these four tumor markers maybe prefer diagnostic index of gastric cancer and its lymph node metastasis. These tumor markers can be a possible indicator of poorer prognosis in different N stage patients. PMID- 24066830 TI - The correlationship between the metabolizable energy content, chemical composition and color score in different sources of corn DDGS. AB - BACKGROUND: This study was conducted to evaluate the apparent metabolizable energy (AME) and true metabolizable energy (TME) contents in 30 sources of corn distillers dried grains with solubles (DDGS) in adult roosters, and establish the prediction equations to estimate the AME and TME value based on its chemical composition and color score. METHODS: Twenty-eight sources of corn DDGS made from several processing plants in 11 provinces of China and others imported from the United States. DDGS were analyzed for their metabolizable energy (ME) contents, measured for color score and chemical composition (crude protein, crude fat, ash, neutral detergent fiber, acid detergent fiber), to predict the equation of ME in DDGS. A precision-fed rooster assay was used, each DDGS sample was tube fed (50 g) to adult roosters. The experiment was conducted as a randomized incomplete block design with 3 periods. Ninety-five adult roosters were used in each period, with 90 being fed the DDGS samples and 5 being fasted to estimate basal endogenous energy losses. RESULTS: Results showed that the AME ranged from 5.93 to 12.19 MJ/kg, TME ranged from 7.28 to 13.54 MJ/kg. Correlations were found between ME and ash content (-0.64, P < 0.01) and between ME and yellowness score (0.39, P < 0.05) of the DDGS samples. Furthermore, the best-fit regression equation for AME content of DDGS based on chemical composition and color score was AME = 6.57111 + 0.51475 GE - 0.10003 NDF + 0.13380 ADF + 0.07057 fat - 0.57029 ash - 0.02437 L (R2 = 0.70). The best-fit regression equation for TME content of DDGS was TME = 7.92283 + 0.51475 GE - 0.10003 NDF + 0.13380 ADF + 0.07057 fat - 0.57029 ash - 0.02437 L (R2 = 0.70). CONCLUSIONS: This experiment suggested that measuring the chemical composition and color score of a corn DDGS sample may provide a quality parameter for identifying corn DDGS sources energy digestibility and metabolizable energy content. PMID- 24066831 TI - DNA catalysts with tyrosine kinase activity. AB - We show that DNA catalysts (deoxyribozymes, DNA enzymes) can phosphorylate tyrosine residues of peptides. Using in vitro selection, we identified deoxyribozymes that transfer the gamma-phosphoryl group from a 5' triphosphorylated donor (a pppRNA oligonucleotide or GTP) to the tyrosine hydroxyl acceptor of a tethered hexapeptide. Tyrosine kinase deoxyribozymes that use pppRNA were identified from each of N30, N40, and N50 random-sequence pools. Each deoxyribozyme requires Zn(2+), and most additionally require Mn(2+). The deoxyribozymes have little or no selectivity for the amino acid identities near the tyrosine, but they are highly selective for phosphorylating tyrosine rather than serine. Analogous GTP-dependent DNA catalysts were identified and found to have apparent Km(GTP) as low as ~20 MUM. These findings establish that DNA has the fundamental catalytic ability to phosphorylate the tyrosine side chain of a peptide substrate. PMID- 24066833 TI - THF exchange and molecular dynamics in the series (BDI)MgX(THF), where X = Bu(n), NEt2, and OBu(t) and BDI = 2-[(2,6-diisopropylphenyl)amino]-4-[(2,6 diisopropylphenyl)imino]pent-2-ene. AB - The complexes (BDI)MgX(THF), where X = Bu(n), NEt2, and OBu(t), are shown to undergo THF exchange at low added concentrations of THF by a dissociative mechanism: X = Bu(n), DeltaH(#) (kcal mol(-1)) = 13.4 +/- 0.4 and DeltaS(#) (cal mol(-1) K(-1)) = 6.3 +/- 1.6; X = NEt2, DeltaH(#) (kcal mol(-1)) = 15.2 +/- 0.5 and DeltaS(#) (cal mol(-1) K(-1)) = 11.4 +/- 2.3; X = OBu(t), DeltaH(#) (kcal mol(-1)) = 16.4 +/- 0.3 and DeltaS(#) (cal mol(-1) K(-1)) = 9.5 +/- 1.3. The apparent aryl group rotations involving the BDI ligands have, within experimental error, the same activation parameters as the THF dissociation, which suggests that the two are correlated involving a three coordinate reactive intermediate akin to what is well-known for related (BDI)ZnR compounds involving three coordinate trigonal planar Zn(2+). At higher concentrations of THF for X = Bu(n) and OBu(t), but not for X = NEt2, the coalescence temperatures for apparent aryl group rotation are depressed from those of the pure compounds in toluene-d8, and evidence is presented that this correlates with an associative interchange process which becomes dominant in neat THF. We estimate the Ia mechanism to have activation parameters: DeltaH(#) (kcal mol(-1)) = 5.4 +/- 0.1 and DeltaS(#) (cal mol(-1) K(-1)) = -20.9 +/- 0.3 for X = Bu(n) and DeltaH(#) (kcal mol(-1)) = 8.3 +/- 0.8 and DeltaS(#) (cal mol(-1) K(-1)) = -19.8 +/- 3.0 for X = OBu(t). For the complex (BDI)MgBu(n)(2-MeTHF), the dissociative exchange with added 2-MeTHF occurs more readily than for its THF analogue, as expected for the more sterically demanding Lewis base O-donor: DeltaH(#) (kcal mol(-1)) = 12.8 +/- 0.5 and DeltaS(#) (cal mol(-1) K(-1)) = 8.6 +/- 1.8. At very low temperatures in toluene-d8, restricted rotation about the Mg-O(THF) bond is observed for the complexes where X = NEt2 and OBu(t) but not for the complex where X = Bu(n). These observations, which have been determined from dynamic NMR studies, are correlated with the reactivities of these complexes in solution. PMID- 24066832 TI - Mental health recovery and voting: why being treated as a citizen matters and how we can do it. AB - It helps people with mental illnesses to recover if they are not deprived of their rights of citizenship. The right to vote is an important marker of citizenship. Ensuring citizenship through the right to vote is especially important when someone is committed under mental health legislation, yet it is unclear how and whether this occurs in practice. This paper discusses what occurs for this population in Australia and overseas and reviews the role of capacity and supported decision making in the context of the right to vote. Solutions are offered for how mental health practice can protect the interest that Australians with mental illnesses have in voting. A central feature of recovery-based practice for people with mental illness is that they are able to exercise rights and experience membership of a community. This notion of citizenship is especially important when someone has had rights removed after being committed under mental health legislation. The right to vote is a central marker of citizenship. Supporting a person's right to vote is important for recovery-based practice. In this paper, we review the issue of voting for people who have been committed under mental health legislation, why it matters for recovery, and what occurs from the Australian and international perspective. We briefly review the concepts of capacity and supported decision making in the context of the right to vote. We also consider the usefulness of the American 'Doe Standard', which has been used with the Competency Assessment Tool (CAT-V), to determine capacity to vote. Some solutions are offered that would protect the interest that Australians with mental illnesses have in voting. PMID- 24066834 TI - Predictive properties of the A-TAC inventory when screening for childhood-onset neurodevelopmental problems in a population-based sample. AB - BACKGROUND: Identifying children with childhood-onset neurodevelopmental problems (NDPs, defined here as autism spectrum disorders [ASDs], attention deficit/hyperactivity disorder [AD/HD], tic disorders [TDs], learning disorders [LDs] and development coordination disorder), using easily administered screening instruments, is a prerequisite for epidemiological research. Such instruments are also clinically useful to prioritize children for comprehensive assessments, to screen risk groups, and to follow controls.Autism-Tics, ADHD, and other Co morbidities inventory (A-TAC) was developed to meet these requirements; here the A-TAC's prospective and psychometric properties are examined, when used in a population-based, epidemiological setting. METHODS: Since 2004, parents of all Swedish twins have been asked to take part in an ongoing, nation-wide twin study (The Child and Adolescent Twin Study in Sweden). The study includes the A-TAC, carried out as a telephone interview with parents of twins aged 9 or 12. In the present study, screen-positive twins from three birth year cohorts (1993-1995) were invited to a comprehensive clinical follow-up (blinded for previous screening results) together with their co-twins and randomly selected, healthy controls at age 15 (Total N = 452). RESULTS: Sensitivity and specificity of A-TAC scores for predicting later clinical diagnoses were good to excellent overall, with values of the area under the receiver operating characteristics curves ranging from 0.77 (AD/HD) to 0.91 (ASDs). Among children who were screen-positive for an ASD, 48% received a clinical diagnosis of ASDs. For AD/HD, the corresponding figure was also 48%, for LDs 16%, and for TDs 60%. Between 4% and 35% of screen-positive children did not receive any diagnosis at the clinical follow-up three years later. Among screen-negative controls, prevalence of ASDs, AD/HD, LDs, and TDs was 0%, 7%, 4%, and 2%, respectively. CONCLUSIONS: The A-TAC appeared to be a valid instrument to assess NDPs in this population-based, longitudinal study. It has good-to-excellent psychometric properties, with an excellent ability to distinguish NDPs (mainly ASDs) from non-NDPs at least three years after the screening evaluations, although specific diagnoses did not correspond closely to actual clinical diagnoses. PMID- 24066835 TI - A novel blood collection device stabilizes cell-free RNA in blood during sample shipping and storage. AB - BACKGROUND: Cell-free RNA (cfRNA) naturally occurs in blood and has clinical significance. Accurate quantification of these extracellular RNAs in whole blood is hindered by the simultaneous unintended release of cellular RNA and degradation of cfRNA after blood draw. An appropriate blood collection device is needed to stabilize cfRNA during blood processing, transportation and storage, which will ensure cfRNA test reliability. In this study we compared a novel blood collection device against traditional K3EDTA tubes for its ability to stabilize cfRNA in blood when subjected to conditions that can occur during sample storage and shipping. FINDINGS: Shipping blood samples drawn into K3EDTA tubes showed a significant increase in mRNA copy numbers for beta-actin, c-fos, and 18S rRNA in plasma. In contrast, shipping blood drawn into Cell-Free RNA BCTTMs (BCTs) showed only a slight change in mRNA copy numbers for circulating beta-actin, c-fos, and 18S rRNA. Moreover, blood stored in K3EDTA tubes at 6 degrees C, 22 degrees C and 30 degrees C for 3 days showed a significant increase in mRNA copy numbers for c fos and beta-actin, whereas samples stored in BCTs only showed a slight increase. CONCLUSION: Our results show that BCTs minimize increases in background RNA levels caused by temperature fluctuations or agitation that can occur during blood sample storage and shipping. This novel blood collection tube could provide a method for obtaining high quality stabilized cfRNA samples for rare RNA target detection and determining accurate cfRNA concentrations. PMID- 24066837 TI - Evolution of supersaturation of amorphous pharmaceuticals: the effect of rate of supersaturation generation. AB - The combination of a rapidly dissolving and supersaturating "spring" with a precipitation retarding "parachute" has often been pursued as an effective formulation strategy for amorphous solid dispersions (ASDs) to enhance the rate and extent of oral absorption. However, the interplay between these two rate processes in achieving and maintaining supersaturation remains inadequately understood, and the effect of rate of supersaturation buildup on the overall time evolution of supersaturation during the dissolution of amorphous solids has not been explored. The objective of this study is to investigate the effect of supersaturation generation rate on the resulting kinetic solubility profiles of amorphous pharmaceuticals and to delineate the evolution of supersaturation from a mechanistic viewpoint. Experimental concentration-time curves under varying rates of supersaturation generation and recrystallization for model drugs, indomethacin (IND), naproxen (NAP) and piroxicam (PIR), were generated from infusing dissolved drug (e.g., in ethanol) into the dissolution medium and compared with that predicted from a comprehensive mechanistic model based on the classical nucleation theory taking into account both the particle growth and ripening processes. In the absence of any dissolved polymer to inhibit drug precipitation, both our experimental and predicted results show that the maximum achievable supersaturation (i.e., kinetic solubility) of the amorphous solids increases, the time to reach maximum decreases, and the rate of concentration decline in the de-supersaturation phase increases, with increasing rate of supersaturation generation (i.e., dissolution rate). Our mechanistic model also predicts the existence of an optimal supersaturation rate which maximizes the area under the curve (AUC) of the kinetic solubility concentration-time profile, which agrees well with experimental data. In the presence of a dissolved polymer from ASD dissolution, these observed trends also hold true except the de supersaturation phase is more extended due to the crystallization inhibition effect. Since the observed kinetic solubility of nonequilibrium amorphous solids depends on the rate of supersaturation generation, our results also highlight the underlying difficulty in determining a reproducible solubility advantage for amorphous solids. PMID- 24066836 TI - Role of aldehydes in the toxic and mutagenic effects of nitrosamines. AB - alpha-Hydroxynitrosamine metabolites of nitrosamines decompose to a reactive diazohydroxide and an aldehyde. To test the hypothesis that the aldehydes contribute to the harmful effects of nitrosamines, the toxic and mutagenic activities of three model methylating agents were compared in Chinese hamster ovary cells expressing or not expressing human O6-alkylguanine DNA alkyltransferase (AGT). N-Nitrosomethylurethane (NMUr), acetoxymethylmethylnitrosamine (AMMN), and 4-(methylnitrosamino)-4-acetoxy-1-(3 pyridyl)-1-butanone (NNK-4-OAc) are all activated by ester hydrolysis to methanediazohydroxide. NMUr does not form an aldehyde, whereas AMMN generates formaldehyde, and NNK-4-OAc produces 4-oxo-1-(3-pyridyl)-1-butanone (OPB). Since these compounds were likely to alkylate DNA to different extents, the toxic and mutagenic activities of these compounds were normalized to the levels of the most cytotoxic and mutagenic DNA adduct, O6-mG, to assess if the aldehydes contributed to the toxicological properties of these methylating agents. Levels of 7-mG indicated that the differences in cytotoxic and mutagenic effects of these compounds resulted from differences in their ability to methylate DNA. When normalized against the levels of O6-mG, there was no difference between these three compounds in cells that lacked AGT. However, AMMN and NNK-4-OAc were more toxic than NMUr in cells expressing AGT when normalized against O6-mG levels. In addition, AMMN was more mutagenic than NNK-4-OAc and MNUr in these cells. These findings demonstrate that the aldehyde decomposition products of nitrosamines can contribute to the cytotoxic and/or mutagenic activity of methylating nitrosamines. PMID- 24066838 TI - Therapeutic and cosmetic applications of mangiferin: a patent review. AB - INTRODUCTION: Mangiferin, a natural C-glucoside xanthone [2-C-beta-D glucopyranosyl-1, 3, 6, 7-tetrahydroxyxanthone], is abundantly present in young leaves and stem bark of the mango tree. The xanthonoid structure of mangiferin with C-glycosyl linkage and polyhydroxy components contributes to its free radical-scavenging ability, leading to a potent antioxidant effect as well as multiple biological activities. AREAS COVERED: An extensive search was carried out to collect patent information on mangiferin and its derivatives using various patent databases spanning all priority years to date. The patents claiming therapeutic and cosmetic applications of mangiferin and its derivatives were analyzed in detail. The technology areas covered in this article include metabolic disorders, cosmeceuticals, multiple uses of the same compound, miscellaneous uses, infectious diseases, inflammation, cancer and autoimmune disorders, and neurological disorders. EXPERT OPINION: Mangiferin has the potential to modulate multiple molecular targets including nuclear factor-kappa B (NF-kappaB) signaling and cyclooxygenase-2 (COX-2) protein expression. Mangiferin exhibits antioxidant, antidiabetic, antihyperuricemic, antiviral, anticancer and antiinflammatory activities. The molecular structure of mangiferin fulfils the four Lipinski's requisites reported to favor high bioavailability by oral administration. There is no evidence of adverse side effects of mangiferin so far. Mangiferin could thus be a promising candidate for development of a multipotent drug. PMID- 24066839 TI - The burden of preserved ejection fraction heart failure in a real-world Swedish patient population. AB - OBJECTIVES: To evaluate resource use and associated costs in patients with a diagnosis of heart failure with preserved ejection fraction (HF-PEF) in Sweden. METHODS: This retrospective study identified real-world patients with an ICD-10 diagnosis code for heart failure (I50) for the period between July 1, 2005 and December 31, 2006 from electronic medical records of primary care centers in Uppsala County Council, and in the Swedish patient registry data. Patients were categorized as having HF-PEF (left ventricle ejection fraction [LVEF] > 50%) during the index period. The study assessed medication utilization, outpatient visits, hospitalizations, and associated healthcare costs, as well as the incidence rates and time to all-cause and heart failure mortality following the index period. RESULTS: The study included 137 HF-PEF patients with a mean age of 77.1 (SD = 9.1) years. Over 50% of HF-PEF patients were female and hypertensive. Nearly all patients received >= 1 medication post-index. Patients had an average of 1.5 heart failure related hospitalizations per follow-up year. The average annual per patient cost for the management of a HF-PEF patient was found in Sweden to be Swedish Krona (SEK) 108,246 (EURO [EUR] 11,344). Hospitalizations contributed to more than 80% of the total cost. All-cause mortality over the 18 month study period was 25.5%, and more than 50% of these deaths occurred within 1 year of index. LIMITATIONS: Due to the limitations of registry data, it is not possible to confirm the HF diagnosis, and therefore the accuracy of registry records must be assumed. Other factors such as short follow-up time, the study mandated LVEF assessment, and a lack of drug duration data may also have an impact on the study results. CONCLUSIONS: All-cause mortality was high in the HF PEF population, with more than half of patients dying within 1 year of study follow-up. Study results also indicate that 60% of HF-PEF patients have >= 1 hospitalization during follow-up. Hospitalizations, especially heart failure related admissions, represent a substantial proportion of the total healthcare burden of patients with HF-PEF in Sweden. PMID- 24066840 TI - Work-aged stroke survivors' psychosocial challenges narrated during and after participating in a dialogue-based psychosocial intervention: a feasibility study. AB - BACKGROUND: Studies point to the lack of psychosocial support and rehabilitation services that are adjusted to the work-aged stroke survivors' specific needs in order to promote psychosocial well-being. The aim of the study was to illuminate the psychosocial challenges work-aged participants (i.e. aged 18-67 years) thematised during and after participating a dialogue-based psychosocial intervention during the first year following a stroke. METHODS: The study was a feasibility study guided by the UK Medical Research Council Framework for developing and evaluating complex interventions. Qualitative data from in-depth interviews with fourteen stroke-survivors aged 33-66 years, researcher field notes and log notes written during the intervention were analysed applying a hermeneutic-phenomenological approach. RESULTS: The stroke and its consequences had a substantial impact on family and work life. Their experiences were summarised in the two themes The threat of becoming marginalised in family life and The threat of becoming marginalised in work life. CONCLUSION: Life as a work aged stroke survivor was experienced as challenging and created a threat of becoming marginalised in family and work life. The study highlights the need to understand the specific psychosocial challenges and needs facing work-aged stroke survivors' in order to promote their psychosocial well-being. More research is needed concerning specific life-span challenges amongst work-aged stroke survivors in order to further develop appropriate interventions that helps address this issue. PMID- 24066841 TI - Assessment of two-dimensional separative systems using nearest-neighbor distances approach. Part 1: orthogonality aspects. AB - We propose here a new approach to the evaluation of two-dimensional and, more generally, multidimensional separations based on topological methods. We consider the apex plot as a graph, which could further be treated using a topological tool: the measure of distances between the nearest neighbors (NND). Orthogonality can be thus defined as the quality of peak dispersion in normalized separation space, which is characterized by two factors describing the population of distances between nearest neighbors: the lengths (di(o)) of distances and the degree of similarity of all lengths. Orthogonality grows with the increase of both factors. The NND values were used to calculate a number of new descriptors. They inform about the extent of peak distribution, like the arithmetic mean (A(o)) of NNDs, as well as about the homogeneity of peak distribution, like the geometric mean (G(o)) and the harmonic mean (H(o)). Our new, NND-based approach was compared with another recently published method of orthogonality evaluation: the fractal dimensionality (DF). The comparison shows that the geometric mean (G(o)) is the descriptor behaving in the most similar way to dimensionality (DF) and the harmonic mean (H(o)) displays superior sensitivity to the shortest, critical distances between peaks. The latter descriptor (H(o)) can be considered as sufficient to describe the degree of orthogonality based on NND. The method developed is precise, simple, easy to implement, and possible to use for the description of separations in a true or virtual system of any number of dimensions. PMID- 24066842 TI - The safety netting behaviour of first contact clinicians: a qualitative study. AB - BACKGROUND: Acute illness is common in childhood, and it is difficult for healthcare professionals to distinguish seriously ill children from the vast majority with minor or self-limiting illnesses. Safety netting provides parents with advice on when and where to return if their child deteriorates, and it is widely recommended that parents of acutely sick young children should be given safety netting advice. Yet little is known about how and when this is given. We aimed to understand what safety netting advice first contact clinicians give parents of acutely sick young children, how, when, and why. METHODS: This was a qualitative study. Interviews and focus groups were held with doctors and nurses in a general practice surgery, a District General Hospital emergency department, a paediatric emergency department, and an out-of-hours service. Data were analysed using the method of constant comparison. RESULTS: Sixteen clinicians participated. They described that safety netting advice includes advising parents what to look for, when and where to seek help. How safety netting was delivered and whether it was verbal or written was inconsistent, and no participants described being trained in this area. Safety netting appeared to be rarely documented, and was left to individual preference. Limitations of written materials, and structural barriers to the provision of safety netting, were perceived. Participants described that safety netting was influenced by clinicians' experience, confidence, time and knowledge; and perceived parental anxiety, experience, and competence. Participants noted several limitations to safety netting including not knowing if it has been understood by parents or been effective; parental difficulty interpreting information and desire for face-to face reassurance; and potential over-reassurance. CONCLUSION: First contact clinicians employ a range of safety netting techniques, with inconsistencies within and between organisations. Structural changes, clinician training, and documentation in patient notes may improve safety netting provision. Research is needed into the optimal components of safety netting advice so that clinicians can consistently deliver the most effective advice for parents. PMID- 24066843 TI - Steroidal cardiac Na+/K+ ATPase inhibitors exhibit strong anti-cancer potential in vitro and in prostate and lung cancer xenografts in vivo. AB - Sodium potassium pump (Na(+)/K(+)ATPase) is a validated pharmacological target for the treatment of congestive heart failure. Recent data with inotropic drugs such as digoxin & digitoxin (digitalis) suggest a potent anti-cancer action of these drugs and promote Na(+)/K(+)ATPase as a novel therapeutic target in cancer. However, digitalis have narrow therapeutic indices, are pro-arrhythmic and are considered non-developable drugs by the pharmaceutical industry. On the contrary, a series of recently-developed steroidal inhibitors showed better pharmacological properties and clinical activities in cardiac patients. Their anti-cancer activity however, remained unknown. In this study, we synthesized seventeen steroidal cardiac inhibitors and explored for the first time their anti-cancer activity in vitro and in vivo. Our results indicate potent anti-cancer actions of steroidal cardiac inhibitors in multiple cell lines from different tumor panels including multi-drug resistant cells. Furthermore, the most potent compound identified in our studies, the 3-[(R)-3- pyrrolidinyl]oxime derivative 3, showed outstanding potencies (as measured by GI50, TGI and LC50 values) in most cells in vitro, was selectively cytotoxic in cancer versus normal cells showing a therapeutic index of 31.7 and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo. Collectively, our results suggest that previously described cardiac Na(+)/K(+)ATPase inhibitors have potent anti-cancer actions and may thus constitute strong re-purposing candidates for further cancer drug development. PMID- 24066845 TI - Water consumption footprint and land requirements of large-scale alternative diesel and jet fuel production. AB - Middle distillate (MD) transportation fuels, including diesel and jet fuel, make up almost 30% of liquid fuel consumption in the United States. Alternative drop in MD and biodiesel could potentially reduce dependence on crude oil and the greenhouse gas intensity of transportation. However, the water and land resource requirements of these novel fuel production technologies must be better understood. This analysis quantifies the lifecycle green and blue water consumption footprints of producing: MD from conventional crude oil; Fischer Tropsch MD from natural gas and coal; fermentation and advanced fermentation MD from biomass; and hydroprocessed esters and fatty acids MD and biodiesel from oilseed crops, throughout the contiguous United States. We find that FT MD and alternative MD derived from rainfed biomass have lifecycle blue water consumption footprints of 1.6 to 20.1 Lwater/LMD, comparable to conventional MD, which ranges between 4.1 and 7.4 Lwater/LMD. Alternative MD derived from irrigated biomass has a lifecycle blue water consumption footprint potentially several orders of magnitude larger, between 2.7 and 22 600 Lwater/LMD. Alternative MD derived from biomass has a lifecycle green water consumption footprint between 1.1 and 19 200 Lwater/LMD. Results are disaggregated to characterize the relationship between geo-spatial location and lifecycle water consumption footprint. We also quantify the trade-offs between blue water consumption footprint and areal MD productivity, which ranges from 490 to 4200 LMD/ha, under assumptions of rainfed and irrigated biomass cultivation. Finally, we show that if biomass cultivation for alternative MD is irrigated, the ratio of the increase in areal MD productivity to the increase in blue water consumption footprint is a function of geo-spatial location and feedstock-to-fuel production pathway. PMID- 24066844 TI - Glucose-6-phosphate dehydrogenase: a biomarker and potential therapeutic target for cancer. AB - Re-programming of metabolic pathways is a hallmark of pathological changes in cancer cells. The expression of certain genes that directly control the rate of key metabolic pathways including glycolysis, lipogenesis and nucleotide synthesis is dysregulated for the adaptation and progression of tumor cells to become more aggressive phenotypes. The pentose phosphate pathway controlled by glucose- 6 phosphate dehydrogenase (G6PD) has been appreciated largely to its role as a provider of reducing power and ribose phosphate to the cell for maintenance of redox balance and biosynthesis of nucleotides and lipids. Recently, G6PD has been revealed to be involved in apoptosis, angiogenesis, and the efficacy to anti cancer therapy, making it as a promising target in cancer therapy. This review summarizes the information about the latest progress relating the activity of the G6PD to cell proliferation, angiogenesis, and resistance to therapy in cancer cells, and discusses the possibility of G6PD as a diagnostic biomarker of cancer and the therapeutic potentials of G6PD inhibitors in cancer treatment. The available data show that G6PD plays a critical role in survival, proliferation, and metastasis of cancer cells. Development of potent and selective G6PD inhibitors would provide novel opportunity for cancer therapy. PMID- 24066846 TI - Phosphatidylcholine attenuates aggregation of nonsteroidal anti-inflammatory drugs with bile acid. AB - Prolonged usage of nonsteroidal anti-inflammatory drugs (NSAIDs) causes gastrointestinal injury. Bile acids and phospholipids have been shown to exasperate and attenuate NSAIDs' toxicity, respectively. However, the molecular mechanisms underlying these effects remain undetermined. We have investigated the molecular interactions in various mixtures of indomethacin (Indo), a commonly used NSAID, and cholic acid (CA), a bile acid, in the presence and absence of palmitoyloleylphosphatidylcholine (POPC) lipids. We found that CA and Indo spontaneously form mixed micelles, with the hydrophobic face of CA and hydrophobic region of Indo forming the core. Increasing the Indo concentration resulted in more stable and larger aggregates that contain a progressively larger number of Indo molecules. More dynamic aggregates with a maximum size of 15 were obtained when the relative concentration of CA was higher. The mixture of CA, Indo, and POPC also led to ternary mixed micelles in which CA and Indo distribute almost uniformly on the surface such that intra-CA, intra-Indo, and CA/Indo interactions are minimized. A number of previous reports have shown that Indo perforates the cell membrane in the presence of bile acids (e.g., Petruzzelli et al., (2006) Dig. Dis. Sci., 51, 766-774). We propose that this may be related to the stable, highly charged, large CA/Indo binary micelles observed in our simulations. Similarly, the diminished ability of the CA/Indo mixture to aggregate in the presence of POPC may partly explain the lower toxicity of PC conjugated NSAIDs. PMID- 24066847 TI - The effects of a medical hypnotherapy on clothing industry employees suffering from chronic pain. AB - BACKGROUND: Problems associated with pain in several body regions due to work related musculoskeletal disorders (WRMDs), repetitive movement and negative stress at work are quite common in many manufacturing industries of Latvia, int.al. clothing industry. The aim of this study was to evaluate efficiency of the psychotherapeutic intervention using medical hypnotherapy (MH) program for mind-body relaxation with pain-blocking imagery, cognitive restructuring of unpleasant physical and emotional experience. METHODS: 300 sewers and 50 cutters with chronic pain were involved in the study. Self-rated WRMDs symptoms, pain intensity and interference were assessed using the extended version of Nordic Musculoskeletal Questionnaire and Brief Pain Inventory Scale. Assessment of the functional state of muscles was carried out using myotonometric (MYO) measurements. Work heaviness degree was estimated via heart rate monitoring (HRM). The MH program was composed of cognitive hypnotherapy and self-hypnosis training. Sunnen Trance Scale was used to determine person's hypnotic susceptibility. Life quality assessment before and after MH program was carried out using Quality of Life Scale. RESULTS: At the beginning of MH program sessions both sewers and cutters reported on pain interference with general activities, mood, sleep, normal work, etc., but after MH the interference of pain significantly decreased. HRM data confirmed that work heaviness degree of sewers and cutters can be referred to as light and moderate work (energy expenditure for their tasks varies from 3.4 till 4.7 kcal/min). Using MYO measurements it was stated that before MH 22% of workers involved in the study fell under III MYO category indices, consequently, their muscle tone was increased, which is associated with muscular fatigue. After MH muscle tone remained within the normal range meaning that they were able to adapt to the existing workload (II MYO category) or fully relax (I MYO category). CONCLUSIONS: MH program including exercises-workouts, cognitive hypnotherapy and self-hypnosis training sessions is an effective method to decrease composite chronic pain intensity for sewers and cutters, as well as to decrease psychogenic tension and muscle fatigue (proved by objective measurements of muscles tone) and to increase the life quality. PMID- 24066848 TI - The role of physical activity and diet on bone mineral indices in young men: a cross-sectional study. AB - BACKGROUND: Osteoporotic fractures are a significant cause of morbidity and mortality, particularly in developed countries. Increasing peak bone mass in young people may be the most important primary prevention strategy to reduce the risk of osteoporosis. This study aimed to examine the relationship between dietary factors and physical activity on bone mineralization in young men. METHODS: Thirty-five healthy men aged 18-25 y had anthropometric measures, body composition, resting metabolic rate, blood pressure, blood lipids, food intake, physical activity and cardiorespiratory fitness assessed. RESULTS: Participants who consumed more than 1000 mg/d of calcium were taller and had higher levels of whole body mineral content than participants who consumed less than 1000 mg/d of calcium. Similarly, participants who expended more than 20% of total daily energy engaged in moderate- to vigorous-intensity physical activity had higher cardiorespiratory fitness and higher levels of body mass adjusted bone mineral content than participants who did not meet this level of energy expenditure. There were no differences in blood pressure or blood lipids between participants in calcium or in physical activity energy expenditure categories. CONCLUSIONS: A high intake of dietary calcium and high daily energy expenditure engaged in moderate- to vigorous-intensity physical activity were positively associated with bone mineralization in young men, particularly in the lumbar region. PMID- 24066849 TI - Effect of multi-sensory balance training for unsteady elderly people: pilot study of the "Reykjavik model". AB - PURPOSE: To evaluate effects of combined mechano- and proprioceptive, vestibular and fall-prevention training on postural control, functional ability, confidence in activities of daily living (ADL) and frequency of falls among unsteady elderly people. METHOD: Subjects were 37 elderly outpatients attending physiotherapy because of instability. Treatment consisted of 18 multisensory balance training sessions. RESULTS from Sensory Organization Test, Five-Times-Sit-to-Stand Test, 30-m normal and fast walk with a turn, Ascending-Descending 11 steps and Activities-specific Balance Confidence Scale were compared before and after training. Information was gathered about number of falls 1 year prior to training, during training period and for 6 months after completion of training. RESULTS: Significant improvement was observed in all measured parameters (p < 0.001). The subjects aged between 70 and 92 years (mean age 80.8 years), had considerable medical history. Thirty four of them reported 159 falls in the year prior to the study. Six subjects reported seven falls during the training period and seven subjects reported 17 falls in the 6 months follow-up period. CONCLUSIONS: Combined vestibular, proprioceptive and fall-prevention training improve postural control, functional ability, confidence in ADL and might even decrease the risk of falling among elderly people. PMID- 24066850 TI - Facile and economical synthesis of large hollow ferrites and their applications in adsorption for As(V) and Cr(VI). AB - Unlike the previous ferrites (MFe2O4; M=Fe, Co, Zn, and Mn) solid nanospheres/nanoparticles, which were prepared by polluted solvothermal (glycol) approaches, here controllable monodisperse porous ferrites hollow nanospheres are promptly synthesized by a nontemplate hydrothermal method which has introduced an addition agent, polyacrylamide. The hollow nanospheres with different size can be prepared by varying the synthetic compositions. Scanning/transmission micros graphs show the outside diameters of ferrite nanospheres are 180-380 nm and the shell thicknesses of that are only 20-45 nm, which could be adjusted by controlling CH3COONa concentration. X-ray diffraction (XRD) and X-ray photoelectron (XPS) spectroscopy, scanning electron (SEM) and transmission electron (TEM) microscopy, energy-dispersive spectrometer (EDS), the measurement of N2 adsorption-desorption isotherms and Brunauer-Emmett-Teller (BET) surface area, and superconducting quantum interference device (SQID) magnetometer were adopted to analyze their phase composition, morphology, porosity, and magnetic properties, respectively. The results of controlled experiments show that citrate and polyacrylamide are vital for the phase purities and morphology of ferrites. In particular, the as-obtained samples exhibit a large adsorption capacity for the toxic solution containing As(V) and Cr(VI) ions, and the calculated result of the maximum adsorption capacity is 340 mg/g based on Langmuir model, which shows excellent As(V) and Cr(VI) ions uptake capacity in contrast to other solid nanosphere materials. PMID- 24066852 TI - Rhodium(III)-catalyzed intermolecular N-chelator-directed aromatic C-H amidation with amides. AB - Rh(III)-catalyzed intermolecular direct aromatic C-H bond amidation with amides has been accomplished under mild reaction conditions. This protocol is applicable to a broad range of N-chelator-containing arenes amidated with aromatic and aliphatic sulfonamides. A possible mechanism is proposed according to the experimental results. PMID- 24066851 TI - Differential diagnosis of amyotrophic lateral sclerosis from Guillain-Barre syndrome by quantitative determination of TDP-43 in cerebrospinal fluid. AB - The aim of this study was to investigate whether an increased level of TAR DNA binding protein 43 (TDP-43) in the cerebrospinal fluid (CSF) could be a biomarker for amyotrophic lateral sclerosis (ALS) and facilitate differential diagnosis of ALS from peripheral motor neuropathy. TDP-43 is the major constituent of neuronal and glial inclusions that neuropathologically characterize both ALS and tau negative frontotemporal lobar degeneration. Recent discoveries of various missense mutations in the TDP-43 gene in familial ALS indicate a pivotal role of the aberrant accumulation of TDP-43 in neurodegeneration. Increased TDP-43 in the CSF could be a hallmark of ALS and other TDP-43 proteinopathy. Sandwich enzyme linked immunosorbent assay (ELISA) was established to measure the concentration of TDP-43 in biological fluids. Culture supernatants of cells transfected with various TDP-43 constructs were used to confirm that the ELISA detected TDP-43. TDP-43 in the culture supernatant of TDP-43 transfected cells was detected by immunoprecipitation with subsequent immunoblotting and concentrations were successfully measured by sandwich ELISA. We then measured TDP-43 concentrations in the CSF of patients with ALS and Guillain-Barre syndrome (GBS). TDP-43 concentrations in CSF were significantly higher in ALS than in GBS (p = 0.016). The sensitivity of the diagnostic test was 71.4% and the specificity was 84.6%. Quantitative determination of TDP-43 concentrations in the CSF by sandwich ELISA is a potential laboratory test for differentiating ALS from peripheral motor neuropathies such as GBS. PMID- 24066853 TI - The antimalarial drug artesunate inhibits primary human cultured airway smooth muscle cell proliferation. AB - Airway smooth muscle (ASM) cell hyperplasia contributes to airway wall remodeling (AWR) in asthma. Glucocorticoids, which are used as first-line therapy for the treatment of inflammation in asthma, have limited impact on AWR, and protracted usage of high doses of glucocorticoids is associated with an increased risk of side effects. Moreover, patients with severe asthma often show reduced sensitivity to glucocorticoids. Artesunate, a semisynthetic artemisinin derivative used to treat malaria with minimal toxicity, attenuates allergic airway inflammation in mice, but its impact on AWR is not known. We examined the effects of artesunate on ASM proliferation in vitro and in vivo. Primary human ASM cells derived from nonasthmatic donors were treated with artesunate before mitogen stimulation. Artesunate reduced mitogen-stimulated increases in cell number and cyclin D1 protein abundance but had no significant effect on ERK1/2 phosphorylation. Artesunate, but not dexamethasone, inhibited phospho-Akt and phospho-p70(S6K) protein abundance. Artesunate, but not dexamethasone, inhibited mitogen-stimulated increases in cell number, cyclin D1, and phospho-Akt protein abundance on ASM cells derived from asthmatic donors. In a murine model of allergic asthma, artesunate reduced the area of alpha-smooth muscle actin positive cells and decreased cyclin D1 protein abundance. Our study provides a basis for the future development of artesunate as a novel anti-AWR agent that targets ASM hyperplasia via the PI3K/Akt/p70(S6K) pathway and suggests that artesunate may be used as combination therapy with glucocorticoids. PMID- 24066854 TI - Measuring four perspectives of justice sensitivity with two items each. AB - People differ systematically in their vulnerability to injustice. We present two item scales for the efficient measurement of justice sensitivity from 4 perspectives (victim, observer, beneficiary, perpetrator). In Study 1 using a quota-based sample of German adults, a latent state-trait analysis revealed the factorial validity and high reliabilities of the scales. In Study 2 employing a large random sample, we tested for measurement invariance of the items within the context of our short 2-item scales compared to the original 10-item scales. Multigroup confirmatory factor analyses confirmed that the validity of the indicators and the internal structure of the assessed constructs did not change across item contexts. In both studies, correlations with personality dimensions and life satisfaction provide evidence for the validity of our scales. With the presented instrument, future research can extend scientific knowledge regarding the role of individual differences in reactions to injustice for the explanation of well-being and physical health. PMID- 24066855 TI - Leptin, ghrelin and calprotectin: inflammatory markers in childhood asthma? AB - BACKGROUND: Appetite-modulating hormones ghrelin and leptin might be relevant to asthma with their pro-inflammatory effects, and calprotectin has been recognized as a promising marker of inflammation. The purpose of this study was to explore whether asthma, atopy and lung functions has a relation with serum levels of leptin, ghrelin and calprotectin as inflammatory markers in children. METHODS: A cross-sectional study was performed by searching the doctor diagnosed asthma through questionnaires filled in by parents who were phoned, and children were invited to supply fasting blood samples in order to measure serum levels of leptin, ghrelin and calprotectin, and to perform skin prick test and spirometry. Participants were divided into Group 1, children with previous diagnosis of asthma, and Group 2, children without previous diagnosis of asthma. RESULTS: One thousand and two hundred questionnaires were distributed and 589 of them were returned filled in. Out of 74 children whose parents accepted to participate in the study, 23 were in Group 1 and 51 were in Group 2. There was no statistical difference in serum levels of leptin, ghrelin, calprotectin, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF) , forced expiratory flow between 25 and 75% of vital capacity (FEF25-75) values , and skin prick test results between the two groups (p values are 0.39, 0.72, 0.5, 0.17, 0.5, 0.27, 0.18, and 0.81 respectively). CONCLUSION: In this study the inflammation in asthmatic children could not be shown by using serum leptin, ghrelin and calprotectin levels and this is possibly due to the low number of children with ever asthma and equal skin prick test positivity in both groups. This study is the first study aimed to show the relation between serum calprotectin levels and inflammation in asthma. As this study was a cross sectional study, further prospectively designed randomized controlled studies are necessary to show the association of these markers and inflammation in asthma. PMID- 24066856 TI - Psychometric properties of the Mastery Scale-Chinese version: applying classical test theory and Rasch analysis. AB - AIMS: This study examines the reliability and validity of the Mastery Scale Chinese version (MS-C) when applied to three groups diagnosed with major depression, schizophrenia, or HIV/AIDS. METHODS: The individuals participating in the study were recruited from outpatient units of a medical center and a municipal hospital in northern Taiwan. The study sample (n = 2009) included 237 patients with depressive disorders, 160 with schizophrenia, and 1612 with HIV/AIDS. The reliability and construct validity of the MS-C was evaluated by confirmatory factor analysis (CFA) and Rasch analysis. RESULTS: The results of the CFA showed that the MS-C has adequate construct validity with all indices meeting the criteria, except for chi-square values. The Rasch analysis supported the four-point rating scale structure and a unidimensional construct of the MS-C. The DIF analysis showed that all items demonstrated stable measurement properties among the different diagnosis groups (major depression, schizophrenia, HIV/AIDS). CONCLUSION: This study found that MS-C has acceptable psychometric qualities in terms of reliability, construct validity, rating scale performance, and item characteristics when applied to patients with depression, schizophrenia, and HIV/AIDS in Taiwan. PMID- 24066859 TI - Molecular dynamics simulations of human serum albumin and role of disulfide bonds. AB - Atomistic molecular dynamics simulations of human serum albumin in the presence and absence of disulfide bonds are presented. Simulations of 70 ns duration provide information on the relevance of disulfide bonds in the dynamics and structural conformation of HSA. Significant conformational changes are observed in the absence of disulfide bonds after 35 ns that could impact the functionality and stability of the protein. Changes in the secondary structure, hydrogen bonds, B factors, and cross-correlations reveal which disulfide bonds are important for keeping the secondary and tertiary structure and dynamics of the protein (e.g., Cys168-Cys177, Cys278-Cys289) and which have little effect on the local structure and dynamics (e.g., Cys200-Cys246, Cys461-Cys477). Removing all disulfide bonds in the protein appears to be a practical prescreening tool for identifying disulfide bonds relevant to structure and dynamics. In the absence of disulfide bonds, certain hydrogen bonds and correlated motions vanish, affecting the structure of neighboring residues. The structure of the primary binding sites of HSA is partially affected when disulfide bonds are removed. For the native structure, simulations clearly reveal the conformational changes that allow the only free cysteine to be exposed on the protein surface to form intermolecular disulfide bonds; this information could not be resolved from the static crystal structure alone. The absence of specific disulfide bonds could lead to partially unfolded structures; such structures are known to be prone to protein aggregation. Removing disulfide bonds could have similar consequences in other proteins of interest, such as immunoglobulin G. PMID- 24066858 TI - Temporal comparison of PBDEs, OH-PBDEs, PCBs, and OH-PCBs in the serum of second trimester pregnant women recruited from San Francisco General Hospital, California. AB - Prenatal exposures to polybrominated diphenyl ethers (PBDEs) can harm neurodevelopment in humans and animals. In 2003-2004, PentaBDE and OctaBDE were banned in California and phased-out of US production; resulting impacts on human exposures are unknown. We previously reported that median serum concentrations of PBDEs and their metabolites (OH-PBDEs) among second trimester pregnant women recruited from San Francisco General Hospital (2008-2009; n = 25) were the highest among pregnant women worldwide. We recruited another cohort from the same clinic in 2011-2012 (n = 36) and now compare serum concentrations of PBDEs, OH PBDEs, polychlorinated biphenyl ethers (PCBs) (structurally similar compounds banned in 1979), and OH-PCBs between two demographically similar cohorts. Between 2008-2009 and 2011-2012, adjusted least-squares geometric mean (LSGM) concentrations of ?PBDEs decreased 65% (95% CI: 18, 130) from 90.0 ng/g lipid (95% CI: 64.7, 125.2) to 54.6 ng/g lipid (95% CI: 39.2, 76.2) (p = 0.004); ?OH PBDEs decreased 6-fold (p < 0.0001); and BDE-47, -99, and -100 declined more than BDE-153. There was a modest, nonsignificant (p = 0.13) decline in LSGM concentrations of ?PCBs and minimal differences in ?OH-PCBs between 2008-2009 and 2011-2012. PBDE exposures are likely declining due to regulatory action, but the relative stability in PCB exposures suggests PBDE exposures may eventually plateau and persist for decades. PMID- 24066857 TI - Circular dichroism, magnetic circular dichroism, and variable temperature variable field magnetic circular dichroism studies of biferrous and mixed-valent myo-inositol oxygenase: insights into substrate activation of O2 reactivity. AB - myo-Inositol oxygenase (MIOX) catalyzes the 4e(-) oxidation of myo-inositol (MI) to D-glucuronate using a substrate activated Fe(II)Fe(III) site. The biferrous and Fe(II)Fe(III) forms of MIOX were studied with circular dichroism (CD), magnetic circular dichroism (MCD), and variable temperature variable field (VTVH) MCD spectroscopies. The MCD spectrum of biferrous MIOX shows two ligand field (LF) transitions near 10000 cm(-1), split by ~2000 cm(-1), characteristic of six coordinate (6C) Fe(II) sites, indicating that the modest reactivity of the biferrous form toward O2 can be attributed to the saturated coordination of both irons. Upon oxidation to the Fe(II)Fe(III) state, MIOX shows two LF transitions in the ~10000 cm(-1) region, again implying a coordinatively saturated Fe(II) site. Upon MI binding, these split in energy to 5200 and 11200 cm(-1), showing that MI binding causes the Fe(II) to become coordinatively unsaturated. VTVH MCD magnetization curves of unbound and MI-bound Fe(II)Fe(III) forms show that upon substrate binding, the isotherms become more nested, requiring that the exchange coupling and ferrous zero-field splitting (ZFS) both decrease in magnitude. These results imply that MI binds to the ferric site, weakening the Fe(III)-MU-OH bond and strengthening the Fe(II)-MU-OH bond. This perturbation results in the release of a coordinated water from the Fe(II) that enables its O2 activation. PMID- 24066860 TI - Teratogenic risk and contraceptive counselling in psychiatric practice: analysis of anticonvulsant therapy. AB - BACKGROUND: Anticonvulsants have been used to manage psychiatric conditions for over 50 years. It is recognised that some, particularly valproate, carbamazepine and lamotrigine, are human teratogens, while others including topiramate require further investigation. We aimed to appraise the documentation of this risk by psychiatrists and review discussion around contraceptive issues. METHODS: A retrospective review of prescribing patterns of four anticonvulsants (valproate, carbamazepine, lamotrigine and topiramate) in women of child bearing age was undertaken. Documented evidence of discussion surrounding teratogenicity and contraceptive issues was sought. RESULTS: Valproate was most commonly prescribed (n=67). Evidence of teratogenic risk counselling at medication initiation was sub optimal--40% of individuals prescribed carbamazepine and 22% of valproate. Documentation surrounding contraceptive issues was also low- 17% of individuals prescribed carbamazepine and 13% of valproate. CONCLUSION: We found both low rates of teratogenic risk counselling and low rates of contraception advice in our cohort. Given the high rates of unplanned pregnancies combined with the relatively high risk of major congenital malformations, it is essential that a detailed appraisal of the risks and benefits associated with anticonvulsant medication occurs and is documented within patients' psychiatric notes. PMID- 24066861 TI - Binding region of alanopine dehydrogenase predicted by unbiased molecular dynamics simulations of ligand diffusion. AB - Opine dehydrogenases catalyze the reductive condensation of pyruvate with L-amino acids. Biochemical characterization of alanopine dehydrogenase from Arenicola marina revealed that this enzyme is highly specific for L-alanine. Unbiased molecular dynamics simulations with a homology model of alanopine dehydrogenase captured the binding of L-alanine diffusing from solvent to a putative binding region near a distinct helix-kink-helix motif. These results and sequence comparisons reveal how mutations and insertions within this motif dictate the L amino acid specificity. PMID- 24066863 TI - Improved lentiviral transduction of ALS motoneurons in vivo via dual targeting. AB - Treatment of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, is hampered by its complex etiology and lack of efficient means for targeted transfer of therapeutics into motoneurons. The objective of this research was engineering of a versatile motoneuron targeting adapter--a full length atoxic tetanus toxin fused to core-streptavidin (CS-TeTIM)--for retro axonal transduction of viral vectors; validation of the targeting efficiency of CS-TeTIM in vivo, by expression of green fluorescence protein (GFP) reporter in motoneurons of presymptomatic and symptomatic ALS-like SOD1(G93A) mice, and comparison with age-matched controls; and appraisal of lentiviral transduction with CS-TeTIM relative to (1) a HC binding fragment of tetanus toxin CS-TeTx(HC), (2) rabies glycoprotein (RG), and (3) a CS-TeTIM-RG dual targeting approach. CS TeTIM and CS-TeTx(HC) were engineered using recombinant technology and site directed mutagenesis. Biotinylated vectors, pseudotyped with vesicular stomatitis virus glycoprotein (VSV-G) or RG, were linked to these adaptors and injected intraperitoneally (ip) into presymptomatic (12 weeks old), symptomatic SOD1(G93A) (22 weeks old) or wild type control mice, followed by monitoring of GFP expression in the spinal cord and supraspinal motor structures with quantitative PCR and immuno-histochemistry. Transcripts were detected in the spinal cord and supraspinal motor structures of all mice 2 weeks after receiving a single ip injection, although in symptomatic SOD1(G93A) animals reporter RNA levels were lower compared to presymptomatic and wild-type controls irrespective of the targeting approach. GFP transduction with CS-TeTIM proved more efficient than CS TeTx(HC) across all groups while CS-TeTIM-RG dual-targeted vectors yielded the highest transcript numbers. Importantly, in both wild-type and presymptomatic SOD1(G93A) mice strong colabeling of choline-acetyltransferase (ChAT) and GFP was visualized in neurons of the brain stem and spinal cord. CS-TeTIM, a versatile adaptor protein for targeted lentiviral transduction of motoneurons, has been engineered and its competence assessed relative to CS-TeTx(HC) and RG. Evidence has been provided that highlights the potential usefulness of this novel recombinant tool for basic research with implications for improved transfer of therapeutic candidates into motoneurons for the amelioration of ALS and related diseases. PMID- 24066864 TI - Variations in ncRNA gene LOC284889 and MIF-794CATT repeats are associated with malaria susceptibility in Indian populations. AB - BACKGROUND: There are increasing evidences on the role of non-coding RNA (ncRNA) as key regulator of cellular homeostasis. LOC284889 is an uncharacterized ncRNA gene on reverse strand to MIF mapped to 22q11.23. MIF, a lymphokine, regulates innate immune response by up-regulating the expression of TLR4, suppressing the p53 activity and has been shown to be involved in malaria pathogenesis. METHODS: In this study, the possible effect of MIF variations on malaria susceptibility was investigated by re-sequencing the complete MIF gene along with 1 kb each of 5' and 3' region in 425 individuals from malaria endemic regions of the Orissa and Chhattisgarh states of India. The subjects comprised of 160 cases of severe malaria, 101 of mild malaria and 164 ethnically matched asymptomatic controls. Data were statistically compared between cases and controls for their possible association with Plasmodium falciparum malarial outcome. RESULTS: It is the first study, which shows that the allele A (rs34383331T > A) in ncRNA is significantly associated with increased risk to P. falciparum malaria [severe: OR = 2.08, p = 0.002 and mild: OR = 2.09, P = 0.005]. In addition, it has been observed that the higher MIF-794CATT repeats (>5) increases malaria risk (OR = 1.61, p = 0.01). Further, diplotype (MIF-794CATT and rs34383331T > A) 5 T confers protection to severe malaria (OR = 0.55, p = 0.002) while 6A (OR = 3.07, p = 0.001) increases malaria risk. CONCLUSIONS: These findings support the involvement of ncRNA in malarial pathogenesis and further emphasize the complex genetic regulation of malaria outcome. In addition, the study shows that the higher MIF-794CATT repeats (>5) is a risk factor for severe malaria. The study would help in identifying people who are at higher risk to malaria and adapt strategies for prevention and treatment. PMID- 24066866 TI - Response to comment on "Evolution of the macondo well blowout: simulating the effects of the circulation and synthetic dispersants on the subsea oil transport". PMID- 24066865 TI - Incubation periods of viral gastroenteritis: a systematic review. AB - BACKGROUND: Accurate knowledge of incubation period is important to investigate and to control infectious diseases and their transmission, however statements of incubation period in the literature are often uncited, inconsistent, and/or not evidence based. METHODS: In a systematic review of the literature on five enteric viruses of public health importance, we found 256 articles with incubation period estimates, including 33 with data for pooled analysis. RESULTS: We fit a log normal distribution to pooled data and found the median incubation period to be 4.5 days (95% CI 3.9-5.2 days) for astrovirus, 1.2 days (95% CI 1.1-1.2 days) for norovirus genogroups I and II, 1.7 days (95% CI 1.5-1.8 days) for sapovirus, and 2.0 days (95% CI 1.4-2.4 days) for rotavirus. CONCLUSIONS: Our estimates combine published data and provide sufficient quantitative detail to allow for these estimates to be used in a wide range of clinical and modeling applications. This can translate into improved prevention and control efforts in settings with transmission or the risk of transmission. PMID- 24066867 TI - Induced furoeudesmanes: a defense mechanism against stress in Laggera pterodonta, a Chinese herbal plant. AB - Laggera pterodonta displays different phenotypes in its natural habitat but expresses a uniform phenotype with large, broad leaves and fewer secondary metabolites when grown under optimal conditions. The production of six furoeudesmanes is only induced when L. pterodonta encounters stresses, conferring host resistance against a broad spectrum of plant invaders. PMID- 24066869 TI - A novel in vitro model to study alveologenesis. AB - Many pediatric pulmonary diseases are associated with significant morbidity and mortality due to impairment of alveolar development. The lack of an appropriate in vitro model system limits the identification of therapies aimed at improving alveolarization. Herein, we characterize an ex vivo lung culture model that facilitates investigation of signaling pathways that influence alveolar septation. Postnatal Day 4 (P4) mouse pup lungs were inflated with 0.4% agarose, sliced, and cultured within a collagen matrix in medium that was optimized to support cell proliferation and promote septation. Lung slices were grown with and without 1D11, an active transforming growth factor-beta-neutralizing antibody. After 4 days, the lung sections (designated P4 + 4) and noncultured lung sections were examined using quantitative morphometry to assess alveolar septation and immunohistochemistry to evaluate cell proliferation and differentiation. We observed that the P4 + 4 lung sections exhibited ex vivo alveolarization, as evidenced by an increase in septal density, thinning of septal walls, and a decrease in mean linear intercept comparable to P8, age-matched, uncultured lungs. Moreover, immunostaining showed ongoing cell proliferation and differentiation in cultured lungs that were similar to P8 controls. Cultured lungs exposed to 1D11 had a distinct phenotype of decreased septal density when compared with untreated P4 + 4 lungs, indicating the utility of investigating signaling in these lung slices. These results indicate that this novel lung culture system is optimized to permit the investigation of pathways involved in septation, and potentially the identification of therapeutic targets that enhance alveolarization. PMID- 24066870 TI - Case report: Papillary mesothelioma of the peritoneum with foamy cell lining. AB - A 34-year-old female, with a history of continued asbestos exposure, presented with a papillary peritoneal mesothelioma with a diffuse, prominent clear foamy cell change, with microvacuolation in its papillary lining, that expressed cytokeratins 7, 5/6 and calretinin as well as nuclear WT-1 and apical membrane staining for thrombomodulin, podoplanin D2-40 and HBME-1. In contrast, lining cells were CD68 negative. Foamy cell change has been reported in isolated cases as solid cords but not as a diffuse change in the mesothelial papillary lining. This phenomenon prompts differential diagnoses with abdominal and renal papillary clear cell tumours, which were discarded after a characteristic mesothelial immunophenotype was demonstrated. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4679576081031834. PMID- 24066871 TI - Short-range spin-phonon coupling in in-plane CuO nanowires: a low-temperature Raman investigation. AB - We report an application of low-temperature Raman scattering on in-plane CuO nanowires, in which an overview of the characteristic parameter of spin-phonon coefficient, the interaction of incident light with the spin degrees of freedom, and size effects will be given. The appearance of spin-phonon coefficient decrease reflects the existence of finite size effect. PMID- 24066872 TI - Phosphine-free synthesis from 1D Pb(OH)Cl nanowires to 0D and 1D PbSe nanocrystals. AB - In this paper, we report a new phosphine-free, low-cost, low-temperature colloidal method of controlled synthesis of PbSe nanocrystals in both zero dimension (0D) and one-dimension (1D). Different from the widely used "hot injection" method and "nonprecursor injection" method, the novelty of this new method is that it does not require a nucleation process. Instead, high-quality presynthesized 1D Pb(OH)Cl nanowires (~80 to ~160 nm in diameter) can be directly used as a Pb precursor and reacted with a Se precursor to form monodisperse dot shaped 0D cubic PbSe and 1D orthorhombic PbSe nanowires. 0D cubic PbSe nanocrystals begin to form at elevated temperatures after the Se precursor is added to react with Pb(OH)Cl nanowires. By prolonging the reaction time for 3 h, good self-assembled 0D cubic PbSe nanocrystals can be synthesized with an average diameter of about 15 nm. Furthermore, such method has been demonstrated to synthsize high-quality 1D PbSe nanowires successfully with temperature as low as 110 degrees C. 1D PbSe nanowires possess a mean diameter of 15-24 nm with the shortest and longest length from 600 nm to 5 MUm. The only sharp and strong peak, which is consistent with characteristic peaks of orthorhombic PbSe, indicates that the nanowires' elongation axis is in the [111] direction, and 0D cubic PbSe nanocrystals change to 1D orthorhombic PbSe nanowires completely. PMID- 24066880 TI - Morphology-based plasmonic nanoparticle sensors: controlling etching kinetics with target-responsive permeability gate. AB - We present a sensing platform based on the morphological changes of plasmonic nanoparticles. Detection is achieved by using a stimulus-responsive polyelectrolyte-aptamer thin film to control the rate of diffusion of etchants that alter the shape and size of the nanoparticles. We show that the extent of morphological change and the colorimetric response depends on the amount of analyte bound. Contrary to conventional plasmonic sensors, our detection scheme does not rely on any interparticle interaction and is completely label-free, both in terms of the analyte and the capture probe. It presents new opportunities for designing facile, low-cost, and portable chip-based sensors for biodiagnostic and field analysis. PMID- 24066881 TI - Nanofiber for cardiovascular tissue engineering. AB - INTRODUCTION: Organ/tissue replacement therapy is inherently difficult for application in the tissue engineering field due to immune rejection that limits the long-term efficacy of implanted devices. As the application of tissue engineering in the biomedical field has steadily expanded, stem cells have emerged as a viable option to promote the immune acceptance of implantable devices and to expedite alleviation of the pathological conditions. With various novel scaffolds being introduced, nanofibers which have a three-dimensional architecture can be considered as an efficient carrier for stem cells. AREAS COVERED: This article reviews the novel tissue engineering processes involved with nanofiber and stem cells. Topics such as the fabrication of nanofiber via electrospinning techniques, the interaction between nanofiber scaffold and specific cell and advanced techniques to enhance the stability of stem cells are delineated in detail. In addition, cardiovascular applications of nanofiber scaffolds loaded with stem cells are examined from a clinical perspective. EXPERT OPINION: Electrospun nanofibers have been intensively explored as a tool for the architecture control of cardiovascular tissue engineering due to their tunable physicochemical properties. The modification of nanofiber with biological cues, which provide rapid differentiation of stem cells into a specific lineage and protect stem cells under the harsh conditions (i.e., hypoxia), will significantly enhance therapeutic efficacies of transplanted cells. A combination of nanofiber carriers and stem cell therapy for tissue regeneration seems to pose enormous potential for the treatment of cardiac diseases including atherosclerosis and myocardial infarction. PMID- 24066882 TI - Discrepancy between body surface area and body composition in cancer. AB - Calculation of cytostatic dose is typically based on body surface area (BSA) regardless of body composition. The aim of this study was to assess the discrepancy between BSA and low fat-free mass (FFM) by investigating the prevalence of low FFM with regard to BSA in 630 cancer patients. First, BSA was calculated according to DuBois and DuBois. Patients were divided into 6 categories with respect to their BSA. Each BSA category was further divided into 3 groups according to FFM: low (<-1 SD of mean FFM), normal (-0.99 and 0.99 SD of mean FFM) or high (>1 SD of mean FFM), which was derived through bioelectric impedance analysis. FFM was reduced in 15.7% of patients, 69% had normal and 15.2% had high FFM. In patients with low FFM (i.e., more than-1 SD lower than the mean FFM within their BSA group), body mass index and fatigue were higher whereas functional status was reduced. Moreover, in the subcohort of patients receiving chemotherapy, absolute FFM [Hazard ratio (HR) = 0.970, P = 0.026] as well as the allocation to the low FFM group (HR = 1.644, P = 0.025) emerged as predictors of increased 1-yr mortality. In conclusion, there was a large discrepancy between FFM and BSA. Particularly women were affected by low FFM. PMID- 24066884 TI - Oestrogens and androgen receptors in oral squamous cell carcinoma. AB - OBJECTIVE: To investigate the gender-related expressions of androgen (AR), estrogen alpha (ERalpha) and beta (ERbeta) receptors and aromatase enzyme in oral squamous cell carcinomas (OSCC). MATERIALS AND METHODS: A total of 60 cases of OSCC (30 from males and 30 from females) were retrieved and submitted to immunohistochemistry. Also, steroid expression was studied in two OSCC cell lines using Western blotting and immunofluorescence. RESULTS: Immunohistochemistry demonstrated that ERbeta was expressed in almost 40% of the cases and AR in 26%. Aromatase enzyme and ERalpha were less commonly expressed. Only AR presented statistically significant differences between genders. Western blotting and immunofluorescence analysis demonstrated that ERbeta was abundantly expressed in the nuclei of both cell lines and aromatase enzyme presented a cytoplasmic expression. CONCLUSION: The detection of steroid hormones, especially ERbeta, can indicate a role of these proteins in the process of carcinogenesis of some OSCC. Further studies of the mechanisms involved may provide important biological information regarding therapeutic approaches. PMID- 24066883 TI - alpha-Synuclein misfolding assessed with single molecule AFM force spectroscopy: effect of pathogenic mutations. AB - Misfolding and subsequent aggregation of alpha-synuclein (alpha-Syn) protein are critically involved in the development of several neurodegenerative diseases, including Parkinson's disease (PD). Three familial single point mutations, A30P, E46K, and A53T, correlate with early onset PD; however, the molecular mechanism of the effects of these mutations on the structural properties of alpha-Syn and its propensity to misfold remains unclear. Here, we address this issue utilizing a single molecule AFM force spectroscopy approach in which structural details of dimers formed by all four variants of alpha-Syn are characterized. Analysis of the force spectroscopy data reflecting contour length distribution for alpha-Syn dimer dissociation suggests that multiple segments are involved in the assembly of the dimer. The interactions are not limited to the central nonamyloid-beta component (NAC) of the protein but rather expand beyond this segment. All three mutations alter the protein's folding and interaction patterns affecting interactions far beyond their immediate locations. Implementation of these findings to our understanding of alpha-Syn aggregation pathways is discussed. PMID- 24066885 TI - Pertussis vaccines: state-of-the-art and future trends. AB - Bordetella pertussis is the causative agent of whooping cough (pertussis) which is a worldwide vaccine preventable acute respiratory illness that predominantly involves infants. The reactogenicity of whole-cell (Pw) vaccines and the difficulty of their consistent production have led to the development of acellular pertussis (Pa) vaccines. However, despite high vaccination coverage using either Pw or Pa and introduction of adolescent and adult vaccines with reduced antigen content, there are still reports about the circulation of the microorganism in populations, morbidity in infants and increasing incidence of pertussis among adolescent and adults who transmit the infection to yet unimmunized infants. Waning vaccine-induced immunity and antigenic divergence in circulating strains seem to be the major problems accounting for resurgence of pertussis. Considering the need for new vaccination strategies, improvement of current Pa vaccines by including new virulence factors would probably be the most rationale strategy. Recent advances in B. pertussis proteomics, subproteomics and immunoproteomics greatly aided in identifying novel antigens of the pathogen. Future studies involving quantitative transcriptomic and proteomic profiling of host-B. pertussis interactions, studying gene expression in vivo and reverse vaccinology will also be very promising approaches and tools to develop pertussis vaccines inducing long term immunity. PMID- 24066887 TI - Antibacterial vaccine research in 21st century: from inoculation to genomics approaches. AB - Vaccination is one of the safest and most cost-effective public health interventions, which save millions of lives annually. Thanks to all the genius pioneers of the field, we have already developed many effective vaccines. On the other hand, there are still many pathogens for which we do not yet have an effective or optimal vaccine, including malaria, HIV, and tuberculosis. In the 21(st) century, biological sciences are at the edge of a growing and fruitful genomics era, which provide many opportunities for vaccine research to have a better understanding of host-pathogen interactions, immune responses, targets and thus allow the scientists to design better vaccines. After the publication of the first bacterial genome of a pathogen, Haemophilus influenza, genomics technology revolutionized the field and created novel vaccine discovery approaches like reverse vaccinology, antigenome technology, surfome analysis, immunoproteomics, and genetics vaccinology to discover novel immunogenic antigens. This review is an attempt to briefly explain these methodologies and the history of their development since the beginning of the century. PMID- 24066886 TI - Challenges and opportunities for cancer vaccines in the current NSCLC clinical scenario. AB - This review is aimed to focus on NSCLC as an emerging and promising model for active immunotherapy and the challenges for its inclusion in the current clinical scenario. Cancer vaccines for NSCLC have been focused as a therapeutic option based on the identification of a tumor hallmark and the active immunization with the related molecules that triggers cellular and/or humoral responses that consequently destroy or delay the rate of malignant progression. This therapeutic intervention in an established disease state has been aimed to impact into prolonging patient's survival with ethically accepted quality of life. Understanding of relationship between structure and function in cancer vaccines is essential to interpret their opportunities to impact into prolonging survival and increasing quality of life in cancer patients. It is widely accepted that the failure of the cancer vaccines in the NSCLC scenario is related with its introduction in the advanced disease stages and poor performance status of the patients due to the combination of the tumor induced immunosuppression with the immune senescence. Despite first, second and emerging third line of onco-specific treatments the life expectancy for NSCLC patients diagnosed at advanced stages is surrounding the 12 months of median survival and in facts the today real circumstances are extremely demanding for the success inclusion of cancer vaccines as therapeutic choice in the clinical scenario. The kinetics of the active immunizations encompasses a sequential cascade of clinical endpoints: starting by the activation of the immune system, followed by the antitumor response and finalizing with the consequential impact on patients' overall survival. Today this cascade of clinical endpoints is the backbone for active immunization assessment and moreover the concept of cancer vaccines, applied in the NSCLC setting, is just evolving as a complex therapeutic strategy, in which the opportunities for cancer vaccines start from the selection of the target cancer hallmark, followed by the vaccine formulation and its platforms for immune potentiating, also cover the successful insertion in the standard of care, the chronic administration beyond progression disease, the personalization based on predictors of response and the potential combination with other targeted therapies. PMID- 24066888 TI - Structural vaccinology: a three-dimensional view for vaccine development. AB - The Structural Vaccinology (SV) approach is the logical evolution of Reverse Vaccinology: a genome-based approach combined with structural biology, with the idea that protective determinants can be used to selectively engineer the antigens that can be re-designed and simplified for inclusion in vaccine combinations. The final objectives of the rational structure-based antigen optimization are the facilitation of industrial-scale production of the antigens combination, obtain a greater immunogenicity and a greater safety profile and finally expand the breadth of protection. Structural Vaccinology is particularly powerful in case of antigenic variation between closely related strains and species. Several examples are available in literature of how SV has already been applied successfully to several bacterial and viral projects. The examples of structure-based antigens optimization reviewed here describe different template procedures that can be followed to develop improved vaccines against other pathogens and potentially help resolve challenges in manufacturing or efficacy. PMID- 24066889 TI - Mucosal vaccines: where do we stand? AB - Mucosal vaccinology is a relatively young but rapidly expanding discipline. At present the vast majority of vaccines are administered by injection, including vaccines that protect against mucosally acquired pathogens such as influenza virus and human papilloma virus. However, mucosal immune responses are most efficiently induced by the administration of vaccines onto mucosal surfaces. The small number of currently licensed mucosal vaccines have reduced the burden of disease and mortality caused by enteric pathogens including rotavirus, V. cholerae and S. typhi, or those that spread to affect distal organs such as poliovirus. Expanding knowledge about the special features of the mucosal immune system promises to accelerate development of mucosal vaccines that could contribute significantly to protection against pathogens that colonize or invade via mucosal surfaces including HIV, Shigella, ETEC, Campylobacter jejuni, Helicobacter pylori and many others. PMID- 24066890 TI - Innate immunity and vaccines. AB - The use of vaccines has led to tremendous decreases in disease burdens across the world. Many challenges remain in expanding vaccine coverage to new pathogens, however, a struggle further hampered by a lack of understanding into many of the fundamental processes through which vaccines elicit robust immunity. In this review we cover recent advances in the field of innate immunity and vaccinology that offer new insights into the reasons some vaccines may succeed or fail. We begin with the secreted cytokines that can influence the nature of the adaptive immune response, and how these may be tuned with the use of particular adjuvants. From there we cover dendritic cells, perhaps the key cell at the interface between innate and adaptive immunity. We discuss mechanisms for targeting specific subsets of dendritic cells, and the effects of this targeting. We further discuss additional modifications of the vaccine formulation to enhance interactions with innate immunity, including phagocytocis and antigen presentation. Finally, we step back to review recent advances in systems biology, and the ability of these new tools to provide deeper understanding of innate immune functions. We hope that this review will provide researchers with access to a breadth and depth of recent work that will allow for the rational design of novel vaccines to combat the most serious infectious diseases of today and tomorrow. PMID- 24066891 TI - Vaccine adjuvants: key tools for innovative vaccine design. AB - Vaccines represent the most efficient tool for preventing diseases caused by infectious pathogens. During the last century significant progress has been made in vaccine development, resulting in the eradication or control of several diseases. However, the emergence of new pathogens and the inadequate protection conferred by some existing vaccines render necessary new vaccination strategies. Newly arising immunization approaches, such as subunit vaccines and mucosal administration, make the use of novel adjuvants essential. However, only a limited number of adjuvants are available on the market. The present review is focused on vaccine adjuvants approved for human vaccines and promising candidates which are currently under development. In this regard, emerging immune stimulators and combinations are discussed, together with their strengths, limitations and regulatory framework. PMID- 24066892 TI - Immune senescence and vaccination in the elderly. AB - Vaccines are powerful public health tools that have been of tremendous benefit in protecting vulnerable populations worldwide from many pathogens. However, vaccine preventable diseases still remain a considerable burden and this is particularly true among aging and aged populations in industrialized countries. The predicted demographic shift in the population landscape towards an ever-increasing aging population and the evidence suggesting that older individuals mount less-than optimal immune response to vaccination have raised the question of improving vaccine responses in older individuals. This review presents recent progress in the understanding at the cellular and molecular levels of age related immune decline and strategies to translate current knowledge into the development of immunization strategies to promote healthy aging, keeping older members of our society autonomous and independent. PMID- 24066893 TI - Novel strategies for development of next-generation glycoconjugate vaccines. AB - Most bacterial pathogens are decorated with surface glycans called capsular polysaccharides (CPSs). Each CPS has a unique structure that is distinctively recognized by our immune cells. These polysaccharides are important vaccine candidates given that they are located on the surface of pathogens, are easily accessible by the immune system, and often result in formation of protective antibodies. To induce CPS specific adaptive immune response (i.e., T cell mediated B cell response), CPSs are conjugated with carrier proteins, and the conjugation products are called glycoconjugate vaccines. Immunization with glycoconjugate vaccines has had significant health benefits in controlling infections caused by Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis. However, owing to insufficient understanding of their immune activation mechanisms, glycoconjugate vaccines have been designed and synthesized empirically. In recent years, we have witnessed important advancements in the glycoconjugate vaccine field: the discovery of the mechanism of action for glycoconjugate vaccines, a novel in vivo conjugation strategy, and progress in the use of novel carriers. These studies will be reviewed in detail herein. PMID- 24066894 TI - Vaccinology in the 21st century. PMID- 24066895 TI - Chicken astrovirus capsid proteins produced by recombinant baculoviruses: potential use for diagnosis and vaccination. AB - Chicken astroviruses (CAstVs) have been characterized recently. Due to their relatively poor growth in cell culture, virus-specific antigens are not readily available for the development of diagnostic reagents and vaccines. For this purpose two capsid protein antigens, specified by the 11672 isolate of CAstV, were produced in insect cells following infection with recombinant baculoviruses. The GST-11672 capsid protein, a fusion protein comprising the capsid protein and glutathione-S-transferase (GST) as an N-terminal affinity tag, and the 11672 capsid protein alone were detected by western blotting as proteins of ~100 and 70 kDa, respectively. Immunization with the affinity-purified GST-11672 capsid protein produced a polyclonal rabbit antiserum, which reacted by indirect immunofluorescence with Group B CAstVs but which showed no reactivity with the Group A CAstV isolate, 612. When used as part of an immunoperoxidase-based immunohistochemical procedure, this rabbit antiserum facilitated the detection of CAstV antigen in formalin-fixed, paraffin-embedded kidney tissue at the sites of histopathology characteristic of nephritis. Although further evaluation with sera from commercial chickens is required, a prototype indirect antibody-detecting enzyme-linked immunosorbent assay (ELISA) based on affinity-purified GST-11672 capsid protein as coating antigen demonstrated considerable potential with low ELISA absorbance values being generated with sera from specific pathogen free (SPF) chickens, and high absorbance values being generated with serum samples from experimentally infected chickens. Immunization experiments of SPF chickens showed that, when administered as mixtures with oil adjuvant, crude cell lysates containing the GST-11672 capsid protein or the 11672 capsid protein elicited virus-specific antibody responses that were detectable by indirect immunofluorescence and by virus neutralization assays. PMID- 24066896 TI - The occurrence of enteric viruses in Light Turkey Syndrome. AB - Two studies were conducted to determine the role of enteric viruses in Light Turkey Syndrome (LTS), which is characterized by lower weight in market age turkeys than their standard breed character. In the surveillance study, we selected four LTS and two non-LTS turkey flocks in Minnesota and collected faecal samples at 2, 3, 5 and 8-weeks of age. Astrovirus, rotavirus, and reovirus were detected alone or in various combinations in both LTS and non-LTS flocks. No coronavirus was detected in LTS flocks and no corona- or reovirus was detected in non-LTS flocks. In the second study, 2-week-old turkey poults were divided into two groups; Group A (challenged) was inoculated orally with 10% pooled faecal suspension from LTS flocks and group B (control) was inoculated with phosphate buffered saline (PBS). Clinical signs of depression, huddling, and lack of uniform size were observed in the challenged group but not in the control group. diarrhoea was observed in both groups but was more severe in the challenged group than in the control group. Birds in the challenged group shed astrovirus, rotavirus and reovirus, while the control group shed only astrovirus. Virus shedding in both groups was observed for up to nine weeks of age. Significantly lower body weights were seen in the challenged group starting at seven weeks of age and lasting until 20 weeks of age. These findings suggest that viral enteritis at an early age may set up conditions for the development of LTS in adult turkeys. PMID- 24066897 TI - Prevalence of IgY antibodies against Erysipelothrix rhusiopathiae in a critically endangered parrot (kakapo, Strigops habroptilus) and associated responses to vaccination. AB - An enzyme-linked immunosorbent assay (ELISA) was developed to estimate levels of IgY antibody against the bacterium Erysipelothrix rhusiopathiae in serum samples collected from the critically endangered kakapo (Strigops habroptilus, Psittaciformes, Aves) before and after vaccination against this bacterium. Relative IgY antibody titres in pre-vaccination serum samples (n = 71 individual kakapo) were normally distributed with the exception of four outliers which displayed low IgY levels. Notably all four low IgY samples were collected from fledglings 3 - 6 months old. Pre-vaccination serum samples from nine nestlings <3 months old, seven of which were hatched in incubators and had no contact with either adult kakapo or their natural environment (e.g. soil), were found to have relatively high IgY levels, suggesting transfer of maternal IgY molecules to fledglings via the yolk. IgY levels in pre-vaccination serum samples from seven kakapo aged 25 - 30 months were also relatively high, suggesting that most kakapo naturally acquire anti- E.rhusiopathiae IgYs within their first 2 years. There was no evidence that vaccination increased the kakapo population's mean anti E.rhusiopathiae IgY levels. However, there was a significant negative relationship between an individual bird's pre-vaccination IgY level and any subsequent increase following vaccination, suggesting that vaccination may only raise the IgY levels of birds with relatively low pre-vaccination IgY levels. A statistical model of the relationship between 'death from erysipelas' and sex, age and transfer from one to island sanctuary to another found that only transfer was significantly associated with death from erysipelas. PMID- 24066899 TI - Implantation of in vitro tissue engineered muscle repair constructs and bladder acellular matrices partially restore in vivo skeletal muscle function in a rat model of volumetric muscle loss injury. AB - The frank loss of a large volume of skeletal muscle (i.e., volumetric muscle loss [VML]) can lead to functional debilitation and presents a significant problem to civilian and military medicine. Current clinical treatment for VML involves the use of free muscle flaps and physical rehabilitation; however, neither are effective in promoting regeneration of skeletal muscle to replace the tissue that was lost. Toward this end, skeletal muscle tissue engineering therapies have recently shown great promise in offering an unprecedented treatment option for VML. In the current study, we further extend our recent progress (Machingal et al., 2011, Tissue Eng; Corona et al., 2012, Tissue Eng) in the development of tissue engineered muscle repair (TEMR) constructs (i.e., muscle-derived cells [MDCs] seeded on a bladder acellular matrix (BAM) preconditioned with uniaxial mechanical strain) for the treatment of VML. TEMR constructs were implanted into a VML defect in a tibialis anterior (TA) muscle of Lewis rats and observed up to 12 weeks postinjury. The salient findings of the study were (1) TEMR constructs exhibited a highly variable capacity to restore in vivo function of injured TA muscles, wherein TEMR-positive responders (n=6) promoted an ~61% improvement, but negative responders (n=7) resulted in no improvement compared to nonrepaired controls, (2) TEMR-positive and -negative responders exhibited differential immune responses that may underlie these variant responses, (3) BAM scaffolds (n=7) without cells promoted an ~26% functional improvement compared to uninjured muscles, (4) TEMR-positive responders promoted muscle fiber regeneration within the initial defect area, while BAM scaffolds did so only sparingly. These findings indicate that TEMR constructs can improve the in vivo functional capacity of the injured musculature at least, in part, by promoting generation of functional skeletal muscle fibers. In short, the degree of functional recovery observed following TEMR implantation (BAM+MDCs) was 2.3*-fold greater than that observed following implantation of BAM alone. As such, this finding further underscores the potential benefits of including a cellular component in the tissue engineering strategy for VML injury. PMID- 24066900 TI - Active targeting of block copolymer micelles with trastuzumab Fab fragments and nuclear localization signal leads to increased tumor uptake and nuclear localization in HER2-overexpressing xenografts. AB - Block copolymer micelles (BCMs) have been employed as effective drug delivery systems to solid tumors by virtue of their capacity to transport large therapeutic payloads and passively target tumor sites. Active targeting of nanoparticles (NPs) has been exploited as a means to increase the therapeutic efficacy of NP-based drugs by promoting their delivery to cellular sites of action. Effective whole tumor accumulation and cellular uptake constitute key objectives in the success of preclinical drug formulations, although they have seldom been investigated concurrently in vivo. The current study aims to elucidate the in vivo fate of 31-nm-sized block copolymer micelles (BCMs) targeted to the nucleus of HER2-overexpressing breast cancer cells. Pharmacokinetics, biodistribution, tumor uptake, and intratumoral distribution of BCMs were investigated in mice bearing subcutaneous BT-474 and MDA-MB-231 xenografts expressing high and low levels of HER2, respectively. Radiolabeling with (111)indium enabled quantitative assessment of BCM distribution at the whole body, tissue, and cellular levels. Surface-grafted trastuzumab Fab fragments (TmAb-Fab) facilitated binding and internalization of BCMs by HER2-positive breast cancer cells, while synthetic 13-mer nuclear localization signal (NLS) peptides conjugated to the TmAb-Fab conferred nuclear translocation capability. Active targeting of BCMs led to a 5-fold increase in tumor uptake in HER2 overexpressing BT-474 tumors, alongside a correspondingly greater level of cellular uptake and nuclear localization, relative to the nontargeted formulations. This study distinctively highlights the quantitative evaluation of active targeting on tumor, cellular and subcellular uptake of BCMs and presents a promising platform for the effective delivery of chemo- and/or radiotherapy in vivo. PMID- 24066901 TI - Defining the contribution of SNPs identified in asthma GWAS to clinical variables in asthmatic children. AB - BACKGROUND: Asthma genome-wide association studies (GWAS) have identified several asthma susceptibility genes with confidence; however the relative contribution of these genetic variants or single nucleotide polymorphisms (SNPs) to clinical endpoints (as opposed to disease diagnosis) remains largely unknown. Thus the aim of this study was to firstly bridge this gap in knowledge and secondly investigate whether these SNPs or those that are in linkage disequilibrium are likely to be functional candidates with respect to regulation of gene expression, using reported data from the ENCODE project. METHODS: Eleven of the key SNPs identified in eight loci from recent asthma GWAS were evaluated for association with asthma and clinical outcomes, including percent predicted FEV1, bronchial hyperresponsiveness (BHR) to methacholine, severity defined by British Thoracic Society steps and positive response to skin prick test, using the family based association test additive model in a well characterised UK cohort consisting of 370 families with at least two asthmatic children. RESULTS: GSDMB SNP rs2305480 (Ser311Pro) was associated with asthma diagnosis (p = 8.9*10-4), BHR (p = 8.2*10 4) and severity (p = 1.5*10-4) with supporting evidence from a second GSDMB SNP rs11078927 (intronic). SNPs evaluated in IL33, IL18R1, IL1RL1, SMAD3, IL2RB, PDE4D, CRB1 and RAD50 did not show association with any phenotype tested when corrected for multiple testing. Analysis using ENCODE data provides further insight into the functional relevance of these SNPs. CONCLUSIONS: Our results provide further support for the role of GSDMB SNPs in determining multiple asthma related phenotypes in childhood asthma including associations with lung function and disease severity. PMID- 24066902 TI - In situ surface chemical modification of thin-film composite forward osmosis membranes for enhanced organic fouling resistance. AB - Forward osmosis (FO) is an emerging membrane-based water separation process with potential applications in a host of environmental and industrial processes. Nevertheless, membrane fouling remains a technical obstacle affecting this technology, increasing operating costs and decreasing membrane life. This work presents the first fabrication of an antifouling thin-film composite (TFC) FO membrane by an in situ technique without postfabrication treatment. The membrane was fabricated and modified in situ, grafting Jeffamine, an amine-terminated poly(ethylene glycol) derivative, to dangling acyl chloride surface groups on the nascent polyamide active layer. Surface characterization by contact angle, Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), zeta potential, atomic force microscopy (AFM), and fluorescence microscopy, confirms the presence of Jeffamine on the membrane surface. We demonstrate the improved fouling resistance of the in situ modified membranes through accelerated dynamic fouling FO experiments using a synthetic wastewater feed solution at high concentration (250 mg/L) of alginate, a model macromolecule for the hydrophilic fraction of wastewater effluent organic matter. Our results show a significantly lower flux decline for the in situ modified membranes compared to pristine polyamide (14.3 +/- 2.7% vs 2.8 +/- 1.4%, respectively). AFM adhesion force measurements between the membrane and a carboxylate-modified latex particle, a surrogate for the organic (alginate) foulant, show weaker foulant-membrane interactions, further confirming the enhanced fouling resistance of the in situ modified membranes. PMID- 24066903 TI - Behavior of Arcobacter butzleri and Arcobacter cryaerophilus in ultrahigh temperature, pasteurized, and raw cow's milk under different temperature conditions. AB - The growth and survival of Arcobacter butzleri and Arcobacter cryaerophilus in milk were investigated at different storage temperatures. Three strains of each Arcobacter species were inoculated into ultrahigh-temperature (UHT), pasteurized, and raw cow's milk and stored at 4, 10, and 20 degrees C for 6 days. The survival of Arcobacter spp. during storage was evaluated by a culture method. Results clearly showed that A. butzleri and A. cryaerophilus remained viable in milk when stored at 4 degrees C and 10 degrees C for a period of 6 days. When UHT and pasteurized milk were stored at 20 degrees C, the A. butzleri count increased, with a longer lag-phase in pasteurized milk, whereas the A. cryaerophilus count increased in the first 48 h and then rapidly decreased to below the detection limit on the sixth storage day. When raw milk was stored at 20 degrees C, the A. butzleri and A. cryaerophilus counts decreased from the first day of storage and no viable bacteria were recovered on the last day of storage. Generally, A. butzleri displayed a significantly better growth and survival capacity than A. cryaerophilus in milk. The present study is the first to assess the survival and/or growth of A. butzleri and A. cryaerophilus in milk. The evidence suggests that in case of primary contamination of milk or secondary contamination due to postprocessing contamination, milk can act as a potential source of Arcobacter infection in humans and could have public health implications, especially for raw milk consumption. PMID- 24066904 TI - Development of a novel hexa-plex PCR method for identification and serotyping of Salmonella species. AB - Salmonella is one of the most important foodborne pathogens, which causes a huge economic burden worldwide. To detect Salmonella rapidly is very meaningful in preventing salmonellosis and decreasing economic losses. Currently, isolation of Salmonella is confirmed by biochemical and serobased serotyping methods, which are time consuming, labor intensive, and complicated. To solve this problem, a hexa-plex polymerase chain reaction (PCR) method was developed using comparative genomics analysis and multiplex PCR technology to detect Salmonella and Salmonella Typhimurium, Salmonella Enteritidis, Salmonella Agona, Salmonella Choleraesuis, and Salmonella Pullorum simultaneously. The accuracy of this method was tested by a collection of 142 Salmonella. Furthermore, the strategy described in this article to mine serovar-specific fragments for Salmonella could be used to find specific fragments for other Salmonella serotypes and bacteria. The combination of this strategy and multiplex PCR is promising in the rapid identification of foodborne pathogens. PMID- 24066905 TI - In vitro antibacterial activity of Tabernaemontana alternifolia (Roxb) stem bark aqueous extracts against clinical isolates of methicillin resistant Staphylococcus aureus. AB - BACKGROUND: The rise of antibiotic resistance among methicillin resistant Staphylococcus aureus (MRSA), have caused concerns for the treatment of MRSA infections. Hence, search for an alternative therapy for these infections is inevitable. Folk Indian medicine refers to the use of leaf and stem bark powder of Tabernaemontana alternifolia (Roxb) in treatment of skin infections, but no scientific report establishes its antibacterial activity. METHODS: Direct aqueous extracts and sequential aqueous extracts of the stem bark of T. alternifolia (using petroleum ether and ethyl acetate as other solvents) were prepared by soxhlet extraction. The antibiotic sensitivity profiles of the clinical isolates were determined against 18 antibiotics using disc diffusion method. The isolates were identified by 16S rRNA gene sequencing. The methicillin resistance among S. aureus (MRSA) was confirmed by PCR amplification of mecA gene. The disc diffusion method was used to determine the antibacterial activity of the extracts. The micro-dilution method was used to determine the minimum inhibitory concentration (MIC) of the extract against the test organism. To further evaluate the therapeutic potential of the extract, cell cytotoxicity was checked on Vero cells by MTT assay. Chemical profiling of the extract was done by HPTLC method. RESULTS: The aqueous extracts of T. alternifolia stem bark exhibited antibacterial activity against Gram-positive microorganisms, particularly against clinical isolates of MRSA and vancomycin resistant S. aureus (VRSA). The minimum inhibitory concentration (MIC) of extract against the isolates ranged from 600 800 MUg/ml. The extract did not exhibit cytotoxic activity against Vero cells even at the concentration of 4 mg/ml. The chemical profiling revealed presence of alkaloids, flavonoids, coumarins, saponins and steroids. Petroleum ether and ethyl acetate extracts did not exhibit antibacterial activity. CONCLUSION: Our results offer a scientific basis for the traditional use of T. alternifolia in the treatment of skin infections, showing that the plant extract has an enormous potential as a prospective alternative therapy against MRSA skin infections. The present study lays the basis for future studies, to validate the possible use of T. alternifolia as a candidate in the treatment of MRSA infections. PMID- 24066907 TI - Et3B-mediated radical-polar crossover reaction for single-step coupling of O,Te acetal, alpha,beta-unsaturated ketones, and aldehydes/ketones. AB - Et3B-mediated three-component coupling reactions between O,Te-acetal, alpha,beta unsaturated ketones, and aldehydes/ketones were developed. Et3B promoted the generation of the potently reactive bridgehead radical from the O,Te-acetal of the trioxaadamantane structure and converted the alpha-carbonyl radical of the resultant two-component adduct to the boron enolate, which then underwent a stereoselective aldol reaction with the aldehyde/ketone. This powerful, yet mild, radical-polar crossover reaction efficiently connected the hindered linkages between the three units and selectively introduced three new stereocenters. PMID- 24066906 TI - Cardiovascular disease risk factors and socioeconomic variables in a nation undergoing epidemiologic transition. AB - BACKGROUND: Cardiovascular disease (CVD) related deaths is not only the prime cause of mortality in the world, it has also continued to increase in the low and middle income countries. Hence, this study examines the relationship between CVD risk factors and socioeconomic variables in Malaysia, which is a rapidly growing middle income nation undergoing epidemiologic transition. METHODS: Using data from 11,959 adults aged 30 years and above, and living in urban and rural areas between 2007 and 2010, this study attempts to examine the prevalence of CVD risk factors, and the association between these factors, and socioeconomic and demographic variables in Malaysia. The socioeconomic and demographic, and anthropometric data was obtained with blood pressure and fasting venous blood for glucose and lipids through a community-based survey. RESULTS: The association between CVD risk factors, and education and income was mixed. There was a negative association between smoking and hypertension, and education and income. The association between diabetes, hypercholesterolemia and being overweight with education and income was not clear. More men than women smoked in all education and income groups. The remaining consistent results show that the relationship between smoking, and education and income was obvious and inverse among Malays, others, rural women, Western Peninsular Malaysia (WPM) and Eastern Peninsular Malaysia (EPM). Urban men showed higher prevalence of being overweight than rural men in all education and income categories. Except for those with no education more rural men smoked than urban men. Also, Malay men in all education and income categories showed the highest prevalence of smoking among the ethnic groups. CONCLUSIONS: The association between CVD risk factors and socioeconomic variables should be considered when formulating programmes to reduce morbidity and mortality rates in low and middle income countries. While general awareness programmes should be targeted at all, specific ones should be focused on vulnerable groups, such as, men and rural inhabitants for smoking, Malays for hypertension and hypercholesterolemia, and Indians and Malays, and respondents from EPM for diabetes. PMID- 24066910 TI - Effects of carprofen and meloxicam on C-reactive protein, ceruloplasmin, and fibrinogen concentrations in dogs undergoing ovariohysterectomy. AB - OBJECTIVE: To evaluate the effects of perioperative oral administration of carprofen and meloxicam on concentrations of 3 acute-phase proteins in dogs undergoing elective ovariohysterectomy (OVH). ANIMALS: 18 healthy adult anestrous female dogs undergoing elective OVH. PROCEDURES: Dogs were allocated to 3 groups (6 dogs/group). A placebo treatment, carprofen (2.0 mg/kg), or meloxicam (0.2 mg/kg) was orally administered to the dogs of the respective groups. The initial doses were administered 30 minutes before premedication prior to OVH; additional doses were administered once daily for 4 days after surgery. Blood samples were collected 45 minutes before premedication and 4, 8, 12, 24, 36, 48, 72, 96, and 120 hours after the end of OVH; samples were used for measurement of total WBC and neutrophil counts and concentrations of C-reactive protein (CRP), ceruloplasmin, and fibrinogen. RESULTS: Values did not differ significantly among groups for WBC and neutrophil counts, serum concentrations of CRP and ceruloplasmin, and plasma concentrations of fibrinogen. Concentrations of all inflammatory markers, except serum ceruloplasmin, increased significantly following OVH, but in a similar manner for each group. No significant changes were detected in serum ceruloplasmin concentrations over time. CONCLUSIONS AND CLINICAL RELEVANCE: Perioperative administration of both carprofen and meloxicam did not significantly affect the concentrations of CRP, ceruloplasmin, and fibrinogen in dogs undergoing OVH. Thus, use of carprofen or meloxicam should not affect clinical interpretation of results for these 3 acute-phase proteins. PMID- 24066911 TI - Cardiopulmonary effects of three concentrations of isoflurane with or without mechanical ventilation and supramaximal noxious stimulation in New Zealand white rabbits. AB - OBJECTIVE: To determine the cardiopulmonary effects of 3 doses of isoflurane, with and without controlled mechanical ventilation and noxious stimulation, in healthy adult New Zealand white rabbits. ANIMALS: 6 adult female rabbits. PROCEDURES: Each rabbit was administered isoflurane in oxygen at each of 3 anesthetic doses (1.0, 1.5, or 2.0 times the published minimum alveolar concentration of 2.07%). At each anesthetic dose, blood gas and cardiopulmonary measurements were obtained before and during application of a supramaximal noxious stimulus. Effects of spontaneous and mechanical ventilation were assessed during separate anesthetic episodes. RESULTS: Mean +/- SEM isoflurane concentrations used were 2.11 +/- 0.04%, 3.14 +/- 0.07%, and 4.15 +/- 0.06%. During spontaneous ventilation, the rabbits' Paco2 and mixed venous Pco2 significantly increased with concomitant reductions in both arterial and mixed venous pH as isoflurane concentration increased. Cardiac output and vascular resistance did not change significantly. Noxious stimulation minimally affected measured cardiopulmonary variables. During mechanical ventilation, significant reductions in arterial blood pressures and cardiac output occurred with increasing isoflurane dose. Systemic vascular resistance index at the highest anesthetic dose was significantly lower than the value at the lowest anesthetic dose. During noxious stimulation, systolic arterial blood pressure and cardiac output significantly increased at the 2 lower isoflurane concentrations, but not at the highest concentration. CONCLUSIONS AND CLINICAL RELEVANCE: In rabbits, isoflurane-induced dose-dependent cardiopulmonary depression was attributable to vasodilation and negative inotropy. At an isoflurane concentration of 4.15% with mechanical ventilation, cardiovascular depression was severe; use of unnecessarily high isoflurane concentrations in this species should be avoided. PMID- 24066912 TI - Effect of large colon ischemia and reperfusion on concentrations of calprotectin and other clinicopathologic variables in jugular and colonic venous blood in horses. AB - OBJECTIVE: To determine the effect of large colon ischemia and reperfusion on concentrations of the inflammatory neutrophilic protein calprotectin and other clinicopathologic variables in jugular and colonic venous blood in horses. ANIMALS: 6 healthy horses. PROCEDURES: Horses were anesthetized, and ischemia was induced for 1 hour followed by 4 hours of reperfusion in a segment of the pelvic flexure of the large colon. Blood samples were obtained before anesthesia, before induction of ischemia, 1 hour after the start of ischemia, and 1, 2, and 4 hours after the start of reperfusion from jugular veins and veins of the segment of the large colon that underwent ischemia and reperfusion. A sandwich ELISA was developed for detection of equine calprotectin. Serum calprotectin concentrations and values of blood gas, hematologic, and biochemical analysis variables were determined. RESULTS: Large colon ischemia caused metabolic acidosis, a significant increase in lactate and potassium concentrations and creatine kinase activities, and a nonsignificant decrease in glucose concentrations in colonic venous blood samples. Values of these variables after reperfusion were similar to values before ischemia. Ischemia and reperfusion induced activation of an inflammatory response characterized by an increase in neutrophil cell turnover rate in jugular and colonic venous blood samples and calprotectin concentrations in colonic venous blood samples. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study suggested that large colon ischemia and reperfusion caused local and systemic inflammation in horses. Serum calprotectin concentration may be useful as a marker of this inflammatory response. PMID- 24066913 TI - Relative metabolite concentrations and ratios determined by use of 3-T region specific proton magnetic resonance spectroscopy of the brain of healthy Beagles. AB - OBJECTIVE: To determine relative concentrations of selected major brain tissue metabolites and their ratios and lobar variations by use of 3-T proton (hydrogen 1 [(1)H]) magnetic resonance spectroscopy (MRS) of the brain of healthy dogs. ANIMALS: 10 healthy Beagles. PROCEDURES: 3-T (1)H MRS at echo times of 144 and 35 milliseconds was performed on 5 transverse slices and 1 sagittal slice of representative brain lobe regions. Intravoxel parenchyma was classified as white matter, gray matter, or mixed (gray and white) and analyzed for relative concentrations (in arbitrary units) of N-acetylaspartate (NAA), choline, and creatine (ie, height at position of peak on MRS graph) as well as their ratios (NAA-to-choline, NAA-to-creatine, and choline-to-creatine ratios). Peak heights for metabolites were compared between echo times. Peak heights for metabolites and their ratios were correlated and evaluated among matter types. Yield was calculated as interpretable voxels divided by available lobar voxels. RESULTS: Reference ranges of the metabolite concentration ratios were determined at an echo time of 35 milliseconds (NAA-to-choline ratio, 1.055 to 2.224; NAA-to creatine ratio, 1.103 to 2.161; choline-to-creatine ratio, 0.759 to 1.332) and 144 milliseconds (NAA-to-choline ratio, 0.687 to 1.788; NAA-to-creatine ratio, 0.984 to 2.044; choline-to-creatine ratio, 0.828 to 1.853). Metabolite concentration ratios were greater in white matter than in gray matter. Voxel yields ranged from 43% for the temporal lobe to 100% for the thalamus. CONCLUSIONS AND CLINICAL RELEVANCE: Metabolite concentrations and concentration ratios determined with 3-T (1)H MRS were not identical to those in humans and were determined for clinical and research investigations of canine brain disease. PMID- 24066914 TI - Effect of delayed exposure of cattle to Mycobacterium avium subsp paratuberculosis on the development of subclinical and clinical Johne's disease. AB - OBJECTIVE: To evaluate the effect of delayed exposure of dairy cattle to Mycobacterium avium subsp paratuberculosis (MAP) on the incidence of those cows testing positive for MAP and developing clinical Johne's disease (CJD). ANIMALS: 79 cows not exposed to MAP as calves (unexposed cohort) and 260 cows exposed to MAP as calves (exposed cohort). PROCEDURES: Cows in the unexposed cohort were born into 5 MAP-uninfected herds and introduced at various ages into 5 MAP infected herds where the exposed cohort cows were born and raised. Beginning when each cow was 24 months old, fecal and serum samples were collected annually from 2003 through 2006. Feces were cultured for MAP, and an ELISA was used to analyze serum samples for antibodies against MAP. Date and reason for culling were obtained from herd records. Incidence of positive culture and ELISA results and CJD was compared between unexposed and exposed cohort cows with Cox regression. RESULTS: Compared with exposed cohort cows, the hazard ratios for unexposed cohort cows having positive culture results, having positive ELISA results, and developing CJD were 0.12, 0.03, and 0.001, respectively, and those ratios increased by 2%, 6%, and 17%, respectively, for each month spent in an MAP infected herd. CONCLUSIONS AND CLINICAL RELEVANCE: Delayed exposure of cows to MAP resulted in lower incidences of positive culture and ELISA results and CJD in those cows, compared with incidences of cows exposed to MAP since birth. The hazard of testing positive for MAP or developing CJD increased with time, regardless of cohort. PMID- 24066915 TI - Evaluation of mRNA expression levels and electrophysiological function of neuron like cells derived from canine bone marrow stromal cells. AB - OBJECTIVE: To investigate the in vitro differentiation of canine bone marrow stromal cells (BMSCs) into functional, mature neurons. SAMPLE: Bone marrow from 6 adult dogs. PROCEDURES: BMSCs were isolated from bone marrow and chemically induced to develop into neurons. The morphology of the BMSCs during neuronal induction was monitored, and immunocytochemical analyses for neuron markers were performed after the induction. Real-time PCR methods were used to evaluate the mRNA expression levels of markers for neural stem or progenitor cells, neurons, and ion channels, and western blotting was used to assess the expression of neuronal proteins before and after neuronal induction. The electrophysiological properties of the neuron-like cells induced from canine BMSCs were evaluated with fluorescent dye to monitor Ca(2)+ influx. RESULTS: Canine BMSCs developed a neuron-like morphology after neuronal induction. Immunocytochemical analysis revealed that these neuron-like cells were positive for neuron markers. After induction, the cells' mRNA expression levels of almost all neuron and ion channel markers increased, and the protein expression levels of nestin and neurofilament L increased significantly. However, the neuron-like cells derived from canine BMSCs did not have the Ca(2)+ influx characteristic of spiking neurons. CONCLUSIONS AND CLINICAL RELEVANCE: Although canine BMSCs had neuron-like morphological and biochemical properties after induction, they did not develop the electrophysiological characteristics of neurons. Thus, these results have suggested that canine BMSCs could have the capacity to differentiate into a neuronal lineage, but the differentiation protocol used may have been insufficient to induce development into functional neurons. PMID- 24066916 TI - Degree and duration of corneal anesthesia after topical application of 0.4% oxybuprocaine hydrochloride ophthalmic solution in ophthalmically normal dogs. AB - OBJECTIVE: To assess the anesthetic efficacy and local tolerance of topically applied 0.4% oxybuprocaine ophthalmic solution to in dogs and compare its effects with those of 1% tetracaine solution. ANIMALS: 34 ophthalmically normal Beagles. PROCEDURES: Dogs were assigned to 2 groups, and baseline corneal touch threshold (CTT) was measured bilaterally with a Cochet-Bonnet aesthesiometer. Dogs of group 1 (n = 22) received a single drop of 0.4% oxybuprocaine ophthalmic solution in one eye and saline (0.9% NaCl) solution (control treatment) in the contralateral eye. Dogs of group 2 (n = 12) received a single drop of 0.4% oxybuprocaine ophthalmic solution in one eye and 1% tetracaine ophthalmic solution in the contralateral eye. The CTT of each eye was measured 1 and 5 minutes after topical application and then at 5-minute intervals until 75 minutes after topical application. RESULTS: CTT changes over time differed significantly between oxybuprocaine-treated and control eyes. After instillation of oxybuprocaine, maximal corneal anesthesia (CTT = 0) was achieved within 1 minute, and CTT was significantly decreased from 1 to 45 minutes, compared with the baseline value. No significant difference in onset, depth, and duration of corneal anesthesia was found between oxybuprocaine-treated and tetracaine-treated eyes. Conjunctival hyperemia and chemosis were detected more frequently in tetracaine-treated eyes than in oxybuprocaine-treated eyes. CONCLUSIONS AND CLINICAL RELEVANCE: Topical application of oxybuprocaine and tetracaine similarly reduced corneal sensitivity in dogs, but oxybuprocaine was less irritating to the conjunctiva than was tetracaine. PMID- 24066917 TI - Pharmacokinetics and safety of silibinin in horses. AB - OBJECTIVE: To determine the oral bioavailability, single and multidose pharmacokinetics, and safety of silibinin, a milk thistle derivative, in healthy horses. ANIMALS: 9 healthy horses. PROCEDURES: Horses were initially administered silibinin IV and silibinin phospholipid orally in feed and via nasogastric tube. Five horses then consumed increasing orally administered doses of silibinin phospholipid during 4 nonconsecutive weeks (0 mg/kg, 6.5 mg/kg, 13 mg/kg, and 26 mg/kg of body weight, twice daily for 7 days each week). RESULTS: Bioavailability of orally administered silibinin phospholipid was 0.6% PO in feed and 2.9% via nasogastric tube. During the multidose phase, silibinin had nonlinear pharmacokinetics. Despite this, silibinin did not accumulate when given twice daily for 7 days at the evaluated doses. Dose-limiting toxicosis was not observed. CONCLUSIONS AND CLINICAL RELEVANCE: Silibinin phospholipid was safe, although poorly bio-available, in horses. Further study is indicated in horses with hepatic disease. PMID- 24066918 TI - Evaluation of antioxidant capacity and inflammatory cytokine gene expression in horses fed silibinin complexed with phospholipid. AB - OBJECTIVE: To evaluate antioxidant capacity and inflammatory cytokine gene expression in horses fed silibinin complexed with phospholipid. ANIMALS: 5 healthy horses. PROCEDURES: Horses consumed increasing orally administered doses of silibinin phospholipid during 4 nonconsecutive weeks (0 mg/kg, 6.5 mg/kg, 13 mg/kg, and 26 mg/kg of body weight, twice daily for 7 days each week). Dose related changes in plasma antioxidant capacity, peripheral blood cell glutathione concentration and antioxidant enzyme activities, and blood cytokine gene expression were evaluated. RESULTS: Plasma antioxidant capacity increased throughout the study period with increasing dose. Red blood cell nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase I activity decreased significantly with increasing doses of silibinin phospholipid. No significant differences were identified in glutathione peroxidase activity, reduced glutathione or oxidized glutathione concentrations, or expression of tumor necrosis factor alpha, interleukin-1, or interleukin-2. CONCLUSIONS AND CLINICAL RELEVANCE: Minor alterations in antioxidant capacity of healthy horses that consumed silibinin phospholipid occurred and suggest that further study in horses with liver disease is indicated. PMID- 24066919 TI - Effects of pneumoperitoneum induced at various pressures on cardiorespiratory function and working space during laparoscopy in cats. AB - OBJECTIVE: To evaluate the effect of pneumoperitoneum on cardiorespiratory variables and working space during experimental induction of 3 intra-abdominal pressures (IAPs) in cats. ANIMALS: 6 healthy young adult neutered male domestic shorthair cats. PROCEDURES: All cats were anesthetized through use of a standardized protocol. A catheter was placed in the right femoral artery for blood pressure and blood gas monitoring. A thermodilution catheter was placed in the right jugular vein via fluoroscopic guidance. Cardiopulmonary variables were measured before (baseline) and 2 and 30 minutes after initiation of pneumoperitoneum at IAPs of 4, 8, and 15 mm Hg; these were created through the use of a mechanical insufflator. At each IAP, abdominal dimensions (height, width, and circumference) were measured at a standardized location. RESULTS: At 4 mm Hg and 8 mm Hg IAP, no clinically important changes were identified in cardiorespiratory values. Heart rate, cardiac index, and stroke volume index remained unchanged throughout the study at all IAPs. Mean arterial blood pressure began to increase at 8 mm Hg and was significantly higher, compared with baseline, at both time points at 15 mm Hg. At 15 mm Hg, Paco2 was significantly higher and cats were more acidotic than at baseline. Working space was subjectively greater at 8 mm Hg than at 4 mm Hg IAP; however, at 15 mm Hg, no clinically important enlargement of the working space was identified, compared with at 8 mm Hg. CONCLUSIONS AND CLINICAL RELEVANCE: Values of cardiopulmonary variables were largely unchanged by induction of pneumoperitoneum in healthy cats up to an IAP of 8 mm Hg, and no clinically important increases in working space were evident at an IAP of 15 versus 8 mm Hg. These findings provide little justification for use of IAPs > 8 mm Hg in healthy cats undergoing laparoscopic procedures; however, whether the situation is similar in diseased or elderly cats remains to be determined. PMID- 24066920 TI - Influence of acidifying or alkalinizing diets on bone mineral density and urine relative supersaturation with calcium oxalate and struvite in healthy cats. AB - OBJECTIVE: To evaluate the influence of acidifying or alkalinizing diets on bone mineral density and urine relative supersaturation (URSS) with calcium oxalate and struvite in healthy cats. ANIMALS: 6 castrated male and 6 spayed female cats. PROCEDURES: 3 groups of 4 cats each were fed diets for 12 months that differed only in acidifying or alkalinizing properties (alkalinizing, neutral, and acidifying). Body composition was estimated by use of dual energy x-ray absorptiometry, and 48-hour urine samples were collected for URSS determination. RESULTS: Urine pH differed significantly among diet groups, with the lowest urine pH values in the acidifying diet group and the highest values in the alkalinizing diet group. Differences were not observed in other variables except urinary ammonia excretion, which was significantly higher in the neutral diet group. Calcium oxalate URSS was highest in the acidifying diet group and lowest in the alkalinizing diet group; struvite URSS was not different among groups. Diet was not significantly associated with bone mineral content or density. CONCLUSIONS AND CLINICAL RELEVANCE: Urinary undersaturation with calcium oxalate was achieved by inducing alkaluria. Feeding an alkalinizing diet was not associated with URSS with struvite. Bone mineral density and calcium content were not adversely affected by diet; therefore, release of calcium from bone caused by feeding an acidifying diet may not occur in healthy cats. PMID- 24066921 TI - Effects of dietary vitamin A content on antibody responses of feedlot calves inoculated intramuscularly with an inactivated bovine coronavirus vaccine. AB - OBJECTIVE: To investigate effects of low dietary vitamin A content on antibody responses in feedlot calves inoculated with an inactivated bovine coronavirus (BCoV) vaccine. ANIMALS: 40 feedlot calves. PROCEDURES: Calves were fed diets containing high (3,300 U/kg) or low (1,100 U/kg) amounts of vitamin A beginning on the day of arrival at a feedlot (day 0) and continuing daily until the end of the study (day 140). Serum retinol concentrations were evaluated in blood samples obtained throughout the study. Calves were inoculated IM with an inactivated BCoV vaccine on days 112 and 126. Blood samples obtained on days 112 and 140 were used for assessment of BCoV-specific serum IgG1, IgG2, IgM, and IgA titers via an ELISA. RESULTS: The low vitamin A diet reduced serum retinol concentrations between days 112 and 140. After the BCoV inoculation and booster injections, predominantly serum IgG1 antibodies were induced in calves fed the high vitamin A diet; however, IgG1 titers were compromised at day 140 in calves fed the low vitamin A diet. Other isotype antibodies specific for BCoV were not affected by the low vitamin A diet. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary vitamin A restriction increases marbling in feedlot cattle; however, its effect on antibody responses to vaccines is unknown. A low vitamin A diet compromised the serum IgG1 responses against inactivated BCoV vaccine, which suggested suppressed T-helper 2 associated antibody (IgG1) responses. Thus, low vitamin A diets may compromise the effectiveness of viral vaccines and render calves more susceptible to infectious disease. PMID- 24066922 TI - Aptamer-modified magnetic nanoprobe for molecular MR imaging of VEGFR2 on angiogenic vasculature. AB - Nucleic acid-based aptamers have been developed for the specific delivery of diagnostic nanoprobes. Here, we introduce a new class of smart imaging nanoprobe, which is based on hybridization of a magnetic nanocrystal with a specific aptamer for specific detection of the angiogenic vasculature of glioblastoma via magnetic resonance (MR) imaging. The magnetic nanocrystal imaging core was synthesized using the thermal decomposition method and enveloped by carboxyl polysorbate 80 for water solubilization and conjugation of the targeting moiety. Subsequently, the surface of the carboxylated magnetic nanocrystal was modified with amine functionalized aptamers that specifically bind to the vascular growth factor receptor 2 (VEGFR2) that is overexpressed on angiogenic vessels. To assess the targeted imaging potential of the aptamer-conjugated magnetic nanocrystal for VEGFR2 markers, the magnetic properties and MR imaging sensitivity were investigated using the orthotopic glioblastoma mouse model. In in vivo tests, the aptamer-conjugated magnetic nanocrystal effectively targeted VEGFR2 and demonstrated excellent MR imaging sensitivity with no cytotoxicity. PMID- 24066923 TI - Impact of hemodialysis on exhaled volatile organic compounds in end-stage renal disease: a pilot study. AB - AIM: To demonstrate the feasibility of nanomaterial-based sensors for identifying patterns of exhaled volatile organic compound of end-stage renal disease (ESRD) and study the impact of hemodialysis (HD) on these patterns. PATIENTS & METHODS: Exhaled breath samples were collected from a group of 37 volunteers (26 ESRD HD patients; 11 healthy controls); a third of the samples were randomly blinded for determining the sensitivity/specificity of the method. Discriminant function analysis was used to build a model for discriminating ESRD patients and healthy controls (classification accuracy for blind samples: 80%), based on the signals of the nanomaterial sensors. RESULTS & CONCLUSION: The breath pattern of the ESRD patients approached the healthy pattern during the HD treatment, without reaching it completely. Gas chromatography/mass spectrometry identified four volatile organic compounds as potential ESRD biomarkers. Although this pilot study has yielded encouraging results, additional large-scale clinical studies are required to develop a fast, noninvasive breath test for monitoring HD adequacy in real time. PMID- 24066924 TI - Reactions of a chromium(III)-superoxo complex and nitric oxide that lead to the formation of chromium(IV)-oxo and chromium(III)-nitrito complexes. AB - The reaction of an end-on Cr(III)-superoxo complex bearing a 14-membered tetraazamacrocyclic TMC ligand, [Cr(III)(14-TMC)(O2)(Cl)](+), with nitric oxide (NO) resulted in the generation of a stable Cr(IV)-oxo species, [Cr(IV)(14 TMC)(O)(Cl)](+), via the formation of a Cr(III)-peroxynitrite intermediate and homolytic O-O bond cleavage of the peroxynitrite ligand. Evidence for the latter comes from electron paramagnetic resonance spectroscopy, computational chemistry and the observation of phenol nitration chemistry. The Cr(IV)-oxo complex does not react with nitrogen dioxide (NO2), but reacts with NO to afford a Cr(III) nitrito complex, [Cr(III)(14-TMC)(NO2)(Cl)](+). The Cr(IV)-oxo and Cr(III) nitrito complexes were also characterized spectroscopically and/or structurally. PMID- 24066925 TI - Prediction of electron energies in metal oxides. AB - The ability to predict energy levels in metal oxides is paramount to developinguseful materials, such as in the development of water photolysis catalysts and efficient photovoltaic cells. The binding energy of electrons in materials encompasses a wealth of information concerning their physicochemistry. The energies control the optical and electrical properties, dictating for which kinds of chemistry and physics a particular material is useful. Scientists have developed theories and models for electron energies in a variety of chemical systems over the past century. However, the prediction of quantitative energy levels in new materials remains a major challenge. This issue is of particular importance in metal oxide research, where novel chemistries have opened the possibility of a wide range of tailored systems with applications in important fields including light-emitting diodes, energy efficient glasses, and solar cells. In this Account, we discuss the application of atomistic modeling techniques, covering the spectrum from classical to quantum descriptions, to explore the alignment of electron energies between materials. We present a number of paradigmatic examples, including a series of oxides (ZnO, In2O3, and Cu2O). Such calculations allow the determination of a "band alignment diagram" between different materials and can facilitate the prediction of the optimal chemical composition of an oxide for use in a given application. Throughout this Account, we consider direct computational solutions in the context of heuristic models, which are used to relate the fundamental theory to experimental observations. We review a number of techniques that have been commonly applied in the study of electron energies in solids. These models have arisen from different answers to the same basic question, coming from solid-state chemistry and physics perspectives. We highlight common factors, as well as providing a critical appraisal of the strengths and weaknesses of each, emphasizing the difficulties in translating concepts from molecular to solid-state systems. Finally, we stress the need for a universal description of the alignment of band energies for materials design from first-principles. By demonstrating the applicability and challenges of using theory to calculate the relevant quantities, as well as impressing the necessity of a clarification and unification of the descriptions, we hope to provide a stimulus for the continued development of this field. PMID- 24066927 TI - High-mobility n-type conjugated polymers based on electron-deficient tetraazabenzodifluoranthene diimide for organic electronics. AB - High-mobility p-type and ambipolar conjugated polymers have been widely reported. However, high-mobility n-type conjugated polymers are still rare. Herein we present poly(tetraazabenzodifluoranthene diimide)s, PBFI-T and PBFI-BT, which exhibit a novel two-dimensional (2D) pi-conjugation along the main chain and in the lateral direction, leading to high-mobility unipolar n-channel transport in field-effect transistors. The n-type polymers exhibit electron mobilities of up to 0.30 cm(2)/(V s), which is among the highest values for unipolar n-type conjugated polymers. Complementary inverters incorporating n-channel PBFI-T transistors produced nearly perfect switching characteristics with a high gain of 107. PMID- 24066926 TI - Hypofractionated stereotactic radiation therapy for recurrent glioblastoma: single institutional experience. AB - BACKGROUND: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Tumor control and survival have improved with the use of radiotherapy (RT) plus concomitant and adjuvant chemotherapy, but the prognosis remain poor. In most cases the recurrence occurs within 7-9 months after primary treatment. Currently, many approaches are available for the salvage treatment of patients with recurrent GBM, including resection, re-irradiation or systemic agents, but no standard of care exists. METHODS: We analysed a cohort of patients with recurrent GBM treated with frame-less hypofractionated stereotactic radiation therapy with a total dose of 25 Gy in 5 fractions. RESULTS: Of 91 consecutive patients with newly diagnosed GBM treated between 2007 and 2012 with conventional adjuvant chemo-radiation therapy, 15 underwent salvage RT at recurrence. The median time interval between primary RT and salvage RT was 10.8 months (range, 6 54 months). Overall, patients undergoing salvage RT showed a longer survival, with a median survival of 33 vs. 9.9 months (p= 0.00149). Median overall survival (OS) from salvage RT was 9.5 months. No patients demonstrated clinically significant acute morbidity, and all patients were able to complete the prescribed radiation therapy without interruption. CONCLUSION: Our results suggest that hypofractionated stereotactic radiation therapy is effective and safe in recurrent GBM. However, until prospective randomized trials will confirm these results, the decision for salvage treatment should remain individual and based on a multidisciplinary evaluation of each patient. PMID- 24066928 TI - Diagnosis of skeletal muscle channelopathies. AB - INTRODUCTION: Skeletal muscle channelopathies are rare disorders of muscle membrane excitability. Their episodic nature may result in diagnostic difficulty and delays in diagnosis. Advances in diagnostic clinical electrophysiology combined with DNA-based diagnosis have improved diagnostic accuracy and efficiency. Ascribing pathogenic status to identified genetic variants in muscle channel genes may be complex and functional analysis, including molecular expression, may help with this. Accurate clinical and genetic diagnosis enables genetic counselling, advice regarding prognosis and aids treatment selection. AREAS COVERED: An approach to accurate and efficient diagnosis is outlined. The importance of detailed clinical evaluation including careful history, examination and family history is emphasised. The role of specialised electrodiagnostics combined with DNA testing and molecular expression is considered. New potential biomarkers including muscle MRI using MRC Centre protocols are discussed. EXPERT OPINION: A combined diagnostic approach using careful clinical assessment, specialised neurophysiology and DNA testing will now achieve a clear diagnosis in most patients with muscle channelopathies. An accurate diagnosis enables genetic counselling and provides information regarding prognosis and treatment selection. Genetic analysis often identifies new variants of uncertain significance. In this situation, functional expression studies as part of a diagnostic service will enable determination of pathogenic status of novel genetic variants. PMID- 24066929 TI - Is dairy intake associated to breast cancer? A case control study of Iranian women. AB - Current epidemiologic data lack consistent evidence for an association between consumption of dairy products and breast cancer risk. In this study we assessed the relationship between consumption of dairy products and the odds of breast cancer. This case-control study was conducted on 275 women (100 cases and 175 controls). Data regarding sociodemographic factors, medical history, medications, and anthropometric measurements were collected. Dietary data were assessed using a validated food frequency questionnaire. The odds [95% confidence interval (CI)] of breast cancer were estimated across quartile categories of energy-adjusted dairy intake using multiple logistic regression models with adjustment for confounders. We observed that higher consumption of total dairy intake was accompanied with reduced breast cancer risk [odds ratio (OR) = 0.14, 95% CI = 0.04-0.38]. A similar inverse association was also observed for higher intakes of low-fat and fermented dairy products (P for trend <0.05). Lower intake of high fat dairy was associated with reduced odds of breast cancer, and no significant association was found between nonfermented dairy and breast cancer risk. Our study demonstrates the protective effects of high intakes of total dairy, low-fat and fermented dairy, as well as low intakes of high-fat dairy products against breast cancer risk and shows no association with nonfermented dairy. PMID- 24066930 TI - Commentary on the special issue on the impact of myogenic tone in health and disease. AB - Autoregulation is a vital homeostatic mechanism that helps maintain constant delivery of oxygen to organs despite fluctuations in arteriolar pressure. Autoregulation of blood flow to elevations in pressure is largely mediated by the myogenic response of small arteries and arterioles which constrict in response to elevations in distending pressure. There is now general agreement that the myogenic response is an intrinsic property of vascular smooth muscle cells in the vessel wall that involves depolarization and calcium influx through L-type voltage-gated calcium channels (VGCC), calcium/ calmodulin-dependent phosphorylation of myosin light chain kinase and actin myosin-based contraction. Despite intensive investigation, however, the mechanotransduction events that initiate the myogenic response and the signaling pathways involved remain uncertain. This special issue on the Impact of Myogenic Tone in Health and Disease includes 9 papers that address current thought regarding the molecular mechanisms underlying myogenic control of vascular tone in the renal, cerebral and coronary circulations and the evidence that impairments in the myogenic response contribute to the development of vascular and end organ damage associated with hypertension, diabetes and aging. PMID- 24066931 TI - Mechanisms of renal microvascular dysfunction in type 1 diabetes: potential contribution to end organ damage. AB - The mechanisms underlying initiation and progression of diabetic nephropathy are not well understood, despite the fact that diabetes represents the chief underlying cause of end-stage renal disease. The onset of diabetic hyperglycemia is now known to evoke functional alterations in the renal microvasculature, glomeruli and tubular epithelium. Although the scope of these effects is not yet fully recognized, the renal vascular dysfunction evident early after onset of T1D likely encompasses impaired electromechanical coupling in preglomerular vascular smooth muscle and altered interactions between tubular transport and vascular function. These changes, which arise in environment conducive to oxidative stress and inflammation, are thought to either initiate or facilitate the eventual development of diabetic nephropathy in susceptible individuals. PMID- 24066932 TI - Myogenic tone as a therapeutic target for ischemic stroke. AB - Ischemic stroke causes vascular paralysis and impaired autoregulation in the brain, the degree of which is dependent on the depth and duration of ischemia and reperfusion (I/R). Ischemic stroke also impairs the myogenic response of middle cerebral arteries (MCA) that may be an underlying mechanism by which autoregulation is impaired. Myogenic responses are affected by I/R through several mechanisms, including production of peroxynitrite, depolymerization of F actin in vascular smooth muscle, and circulating vasoactive factors. The vascular endothelium is also significantly affected during focal ischemia that has a particularly large influence on vascular tone in the cerebral circulation. Endothelial nitric oxide (NO) and endothelin-1 (ET-1) are important endothelium dependent vasoactive substances that can influence the level of myogenic tone in cerebral arteries and arterioles that are significantly affected during ischemic stroke. Unlike MCA, brain penetrating arterioles have considerable myogenic tone that appears less affected by focal ischemia. The persistent tone of brain parenchymal arterioles during focal ischemia could contribute to perfusion deficit and infarct expansion. These arterioles within the cerebral cortex are also unique from MCA in that they constrict to small- and intermediate- conductance calcium-activated potassium channel (SKCa and IKCa, respectively) inhibition, suggesting basal endothelium-derived hyperpolarizing factor (EDHF) is preserved during focal ischemia. This review will highlight our current understanding of the effects of I/R on myogenic response in both MCA and parenchymal arterioles and discuss underlying mechanisms by which focal ischemia affects myogenic tone in these different vascular segments. PMID- 24066933 TI - Renal blood flow dynamics in inbred rat strains provides insight into autoregulation. AB - Renal autoregulation maintains stable renal blood flow in the face of constantly fluctuating blood pressure. Autoregulation is also the only mechanism that protects the delicate glomerular capillaries when blood pressure increases. In order to understand autoregulation, the renal blood flow response to changing blood pressure is studied. The steadystate response of blood flow is informative, but limits investigation of the individual mechanisms of autoregulation. The dynamics of autoregulation can be probed with transfer function analysis. The frequency-domain analysis of autoregulation allows investigators to probe the relative activity of each mechanism of autoregulation. We discuss the methodology and interpretation of transfer function analysis. Autoregulation is routinely studied in the rat, of which there are many inbred strains. There are multiple strains of rat that are either selected or inbred as models of human pathology. We discuss relevant characteristics of Brown Norway, Spontaneously hypertensive, Dahl, and Fawn-Hooded hypertensive rats and explore differences among these strains in blood pressure, dynamic autoregulation, and susceptibility to hypertensive renal injury. Finally we show that the use of transfer function analysis in these rat strains has contributed to our understanding of the physiology and pathophysiology of autoregulation and hypertensive renal disease.Interestingly all these strains demonstrate effective tubuloglomerular feedback suggesting that this mechanism is not sufficient for effective autoregulation. In contrast, obligatory or conditional failure of the myogenic mechanism suggests that this component is both necessary and sufficient for autoregulation. PMID- 24066934 TI - Endogenous events modulating myogenic regulation of cerebrovascular function. AB - The existence of arterial myogenic tone was first described by Bayliss in 1902, however, its association with pressure-dependent membrane depolarization was not observed until 1984. The factors that mediate myogenic arterial constriction remain unknown. One possible clue was a finding by our laboratory that cerebral arterial muscle cells express CYP 4A omega-hydroxylase enzyme that catalyzes the formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid (AA), the production of which increased by elevations of intravascular pressure. 20-HETE activates protein kinase C (PKC), inhibits Ca(2+) activated K(+) (KCa) channels, depolarizes arterial muscle cell membrane, activates L-type Ca(2+) channels, increases intracellular Ca(2+) ([Ca(2+)]i) and mediates autoregulation of cerebral blood flow. Emerging evidence indicates that 20-HETE level increases in ischemia/reperfusion injury and stimulates production of reactive oxygen species (ROS) resulting in oxidative stress induced ischemic stroke injury, which can be prevented by inhibition of 20-HETE synthesis or action. The brain also expresses CYP epoxygenases that convert AA to the vasodilator epoxyeicosatrienoic acids (EETs), the production of which increases in ischemia and provide protection against ischemia-induced tissue damage. Basal or stimulus released ROS act to modify cerebral myogenic tone. Similar to other enzymes CYP epoxygenase and omega-hydroxylase also generate ROS that modify myogenic cerebral reactivity. Hypoxia per se or adenosine released during hypoxia induces increased production of ROS that alter cerebrovascular function. The capacity of the brain to express CYP enzymes that produce bioactive EETs and 20 HETE and generate ROS has a significant bearing in regulating the dynamics of cerebral blood flow and serve as potential therapeutic targets for the management of pathologic disorders of the cerebral circulation. PMID- 24066936 TI - Myogenic properties of brain and cardiac vessels and their relation to disease. AB - Intrinsic arterial myogenic function comprises the degree of constriction (myogenic tone), the arterial constriction to an increase in intraluminal pressure and vice versa (myogenic response), and forced dilation at high intraluminal pressure. Although the development of myogenic tone at 40-60 mmHg involves the influx of calcium (Ca(2+)) through voltage- dependent Ca(2+) channels and an elevation in arterial intracellular Ca(2+) (Ca(2+) i), myogenic responses between 60-140 mmHg involves predominantly Rho kinase (ROK)-mediated changes in Ca(2+) sensitivity. In the cerebral circulation an impaired myogenic response results in impaired cerebral autoregulation and susceptibility hypertension-induced cerebral haemorrhage. An impaired cerebral artery myogenic response, due to blunted ROK mediated changes in Ca(2+) sensitivity, may be a consequence of defective mechanotransduction of the intraluminal pressure stimulus; this may be a result of abnormalities in the extracellular matrix. In the coronary circulation distinctions between the mechanisms involved in the development of myogenic tone and the myogenic response have not been clearly defined. However, coronary artery myogenic tone is dependent on both Ca(2+) entry through voltage -dependent Ca(2+) channels and protein kinase C (PKC) activity. Impaired coronary myogenic tone has been observed in animal models of disease but the implications of these findings are currently uncertain. PMID- 24066935 TI - P2 receptors in renal autoregulation. AB - Autoregulation of renal blood flow and glomerular filtration rate is an essential function of the renal microcirculation. While the existence of this phenomenon has been known for many years, the exact mechanisms that underlie this regulatory system remain poorly understood. The work of many investigators has provided insights into many aspects of the autoregulatory mechanism, but many critical components remain elusive. This review is intended to update the reader on the role of P2 purinoceptors as a postulated mechanism responsible for renal autoregulatory resistance adjustments. It will summarize recent advances in normal function and it will touch on more recent ideas regarding autoregulatory insufficiency in hypertension and inflammation. Current thoughts on the nature of the mechanosensor responsible for myogenic behavior will be also be discussed as well as current thoughts on the mechanisms involved in ATP release to the extracellular fluid space. PMID- 24066937 TI - Vildagliptin restores renal myogenic function and attenuates renal sclerosis independently of effects on blood glucose or proteinuria in zucker diabetic fatty rat. AB - Type 2 diabetes mellitus (T2DM) is associated with risk for chronic kidney disease (CKD), which is associated with a decrease in renal myogenic tone - part of renal autoregulatory mechanisms. Novel class of drugs used for the treatment of T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitors, have protective effects on the cardiovascular system. A Zucker Diabetic Fatty (ZDF) rat is an animal model of T2DM that displays progressive nephropathy in which inflammation leads to initiation of renal fibrosis and CKD. We hypothesized that CKD in the ZDF rat is related to decrease in myogenic constriction (MC) of intrarenal arteries and that treatment with the DPP-4 inhibitor, vildagliptin, prevents such changes. Renal arteries isolated from 25 weeks old lean, ZDF and ZDF treated with vildagliptin (n=7 in each group) were transferred to an arteriograph to assess agonist and pressure induced contractile responses. Furthermore, blood glucose, proteinuria, focal glomerulosclerosis (FGS) and p22phox mRNA expression of renal tissue were measured. Compared to lean controls, ZDF had significantly increased plasma glucose and cholesterol levels, focal glomerulosclerosis and interstitial alpha SMA expression, and urinary protein excretion. ZDF rats also had impaired MC of renal arteries and increased renal p22phox expression. Vildagliptin did not affect plasma glucose levels or proteinuria, but effectively decreased glomerulosclerosis and restored MC and p22phox expression to the levels found in lean rats. Based on these data, it can be suggested that vildagliptin treatment protects diabetic rats from the loss of renal vascular reactivity and the development of glomerulosclerosis perhaps secondary to a reduction in oxidative stress. PMID- 24066939 TI - Impaired renal autoregulation in susceptible models of renal disease. AB - One of the major functions of the kidney is to maintain constant renal blood flow and glomerular filtration rate in response to increases in renal perfusion pressure. This phenomenon is referred to autoregulation and involves two independent mechanisms: tubular glomerular feedback and myogenic response. The latter, the renal myogenic response, involves constriction of the preglomerular vasculature to increases in transmural pressure. Over the last three decades, there has been substantial evidence that demonstrates that the myogenic response plays an important role in protecting the kidney from hypertension-induced renal injury. Furthermore, impairment of the renal myogenic response allows the transmission of systemic pressures to the glomerular capillaries leading to the development of glomerular injury and progressive proteinuria during hypertension. This review article discusses the role of the myogenic response in the pathogenesis of renal disease in various genetic and experimental rodent models that develop hypertension-induced renal injury. PMID- 24066940 TI - Pulsed-field gel electrophoresis proficiency testing trials: toward European harmonization of the typing of food and clinical strains of Listeria monocytogenes. AB - The European Union Reference Laboratory for Listeria monocytogenes (EURL for Lm) coordinates a European network of 35 National Reference Laboratories (NRLs), most of which perform food, environmental, and veterinary Lm strain surveillance in their respective countries. The EURL activities resulted in the recent creation of a database (EURL Lm DB). Typing and related epidemiological data submitted to the EURL Lm DB will be collected and shared by all the NRLs. For a given NRL, the only criterion required in order to submit pulsed-field gel electrophoresis (PFGE) profiles to the database was the successful participation with at least one EURL PFGE and PFGE profile interpretation Proficiency Testing (PT) trial. In this context, the EURL organized a PT trial in 2012 to evaluate the NRL's ability to perform PFGE and profile interpretation. A total of 18 NRLs took part in this study. Upon request from the Food- and Waterborne Diseases and Zoonoses Programme of the European Centre for Disease Prevention and Control, 10 National Public Health Reference Laboratories (NPHLs) also took part in this PT trial. Of the 28 participating laboratories, 16 obtained results classified as "good" or "satisfactory." These 16 laboratories included 10 NRLs (56%) and 6 NPHLs (60%). Of the 22 NRLs and NHPLs that participated in the part of the PT trial related to PFGE profile interpretation, 11 laboratories obtained good results. These 11 laboratories included eight NRLs, which therefore can now submit profiles to the EURL Lm DB. This PT trial provided a valuable opportunity to facilitate and to stimulate the sharing of reproducible PFGE profiles between human and food reference laboratories. PMID- 24066942 TI - Sericin removal from raw Bombyx mori silk scaffolds of high hierarchical order. AB - Silk fibroin has previously been described as a promising candidate for ligament tissue engineering (TE) approaches. For biocompatibility reasons, silkworm silk requires removal of sericin, which can elicit adverse immune responses in the human body. One disadvantage of the required degumming process is the alteration of the silk fiber structural properties, which can hinder textile engineering of high order hierarchical structures. Therefore, the aim of this study was to find a way to remove sericin from a compact and highly ordered raw silk fiber matrix. The wire rope design of the test model scaffold comprises several levels of geometric hierarchy. Commonly used degumming solutions fail in removing sericin in this wire rope design. Weight loss measurements, picric acid and carmine staining as well as scanning electron microscopy demonstrated that the removal of sericin from the model scaffold of a wire rope design can be achieved through a borate buffer-based system. Furthermore, the borate buffer degummed silks were shown to be nontoxic and did not alter cell proliferation behavior. The possibility to remove sericin after the textile engineering process has taken place eases the production of highly ordered scaffold structures and may expand the use of silk as scaffold material in further TE and regenerative medicine applications. PMID- 24066938 TI - Molecular mechanisms of renal blood flow autoregulation. AB - Diabetes and hypertension are the leading causes of chronic kidney disease and their incidence is increasing at an alarming rate. Both are associated with impairments in the autoregulation of renal blood flow (RBF) and greater transmission of fluctuations in arterial pressure to the glomerular capillaries. The ability of the kidney to maintain relatively constant blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure is mediated by the myogenic response of afferent arterioles working in concert with tubuloglomerular feedback that adjusts the tone of the afferent arteriole in response to changes in the delivery of sodium chloride to the macula densa. Despite intensive investigation, the factors initiating the myogenic response and the signaling pathways involved in the myogenic response and tubuloglomerular feedback remain uncertain. This review focuses on current thought regarding the molecular mechanisms underlying myogenic control of renal vascular tone, the interrelationships between the myogenic response and tubuloglomerular feedback, the evidence that alterations in autoregulation of RBF contributes to hypertension and diabetes-induced nephropathy and the identification of vascular therapeutic targets for improved renoprotection in hypertensive and diabetic patients. PMID- 24066941 TI - Assessing tumor contrast in radiographically dense breast tissue using Diffuse Optical Spectroscopic Imaging (DOSI). AB - INTRODUCTION: Radiographic density adversely affects the performance of X-ray mammography and can be particularly problematic in younger and high-risk women. Because of this limitation, there is significant ongoing effort to develop alternative cancer screening and detection strategies for this population. This pilot study evaluates the potential of Diffuse Optical Spectroscopic Imaging (DOSI) to image known tumors in dense breast tissue. METHODS: We performed a retrospective analysis on 24 radiographically dense breast cancer subjects measured with DOSI over a four-year period (Breast Imaging Reporting and Data System - BI-RADS, category 3 and 4, average age = 39 +/- 7.6, average maximum size 31 +/- 1 7 mm). Two previously-described DOSI contrast functions, the tissue optical index (TOI) and the specific tumor component (STC), which are based upon the concentrations and spectral signatures of hemoglobin, water and lipids, respectively, were used to form 2D optical images of breast tumors. RESULTS: Using TOI and STC, 21 out of 24 breast tumors were found to be statistically different from the surrounding highly vascularized dense tissue and to be distinguishable from the areolar region. For these patients, the tumor to normal contrast was 2.6 +/- 1.2 (range 1.3 to 5.5) and 10.0 +/- 7.5 (range 3.3 to 26.4) for TOI and STC, respectively. STC images were particularly useful in eliminating metabolic background from the retroareolar region which led to identification of two out of four retroareolar tumors. CONCLUSIONS: Using both the abundance and the disposition of the tissue chromophores recovered from the DOSI measurements, we were able to observe tumor contrast relative to dense breast tissue. These preliminary results suggest that DOSI spectral characterization strategies may provide new information content that could help imaging breast tumors in radiographically dense tissue and in particular in the areolar complex. PMID- 24066943 TI - Phytochemicals from Kigelia pinnata leaves show antioxidant and anticancer potential on human cancer cell line. AB - Studies suggest that the traditional applications of Kigelia pinnata leaves have beneficial effects against oxidative stress-mediated diseases and cancers. The pulverized dried leaves of K. pinnata were extracted with hexane, ethyl acetate, and methanol sequentially, and the crude extracts were fractionated by silica gel column chromatography with solvent gradient of increasing polarity. 3-hydro-4,8 phytene, trans-phytol, (9Z,12Z)-methyl octadeca-9,12-dienoate, and two oil fractions were obtained. The chemical compositions of chromatographic fractions were determined using gas chromatography-mass spectroscopy. The structure elucidations of the isolated compounds were based on FTIR, MS, and NMR spectral data analyses. These along with the crude extracts were examined for their antioxidant activities using ferric reducing antioxidant power (FRAP), 2,2 diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, and 2,2-azinobis(3-ethyl benzothiazoline-6-sulfonic acid) (ABTS) assays. Total phenolic contents were also determined. The crude extracts and purified compounds were evaluated on the rhabdomyosarcoma human cancer cell for their cytotoxicity using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assays. The methanol extract was richer in phenolics and was most potent as antioxidant and cytotoxic agent among all the substances tested. Among the fractions and pure compounds, the two oil fractions showed more cytotoxicity potency, with IC50s of 143.4+/-0.5 and 147.9+/-1.3 ng/mL, which is more significant than the reference standard, cyclophosphamide (165.6+/-1.0 ng/mL). 3 hydro-4,8-phytene showed lower antioxidant and cytotoxicity potential (IC50=1818+/-5.2 MUg/mL and 171.7+/-0.8 ng/mL, respectively). Trans-phytol did not show a high cytotoxic power (IC50=769.8+/-4.3 ng/mL). The comparatively high cytotoxicity index of (9Z, 12Z)-methyl octadeca-9,12-dienoate (IC50=153.3+/-0.1 ng/mL) indicated that it may be one of the principal cytotoxic agent in the ethyl acetate extract. These results suggest that the leaves of K. pinnata possess tumor cytotoxic potential and could be part of a drug combination for future cancer chemotherapy. PMID- 24066944 TI - Chlorophyll-related compounds inhibit cell adhesion and inflammation in human aortic cells. AB - The objectives of this study were to investigate the effects of chlorophyll related compounds (CRCs) and chlorophyll (Chl) a+b on inflammation in human aortic endothelial cells. Adhesion molecule expression and interleukin (IL)-8, nuclear factor (NF)-kappaB p65 protein, and NF-kappaB and activator protein (AP) 1 DNA binding were assessed. The effects of CRCs on inflammatory signaling pathways of signal transducers and activators of transcription 3 (STAT3) and mothers against decapentaplegic homolog 4, respectively induced by IL-6 and transforming growth factor (TGF)-beta, in human aortic smooth muscle cells cultured in vitro were also investigated. HAECs were pretreated with 10 MUM of CRCs, Chl a+b, and aspirin (Asp) for 18 h followed by tumor necrosis factor (TNF) alpha (2 ng/mL) for 6 h, and U937 cell adhesion was determined. TNF-alpha-induced monocyte-endothelial cell adhesion was significantly inhibited by CRCs. Moreover, CRCs and Chl a+b significantly attenuated vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and IL-8 expressions. Treatments also significantly decreased in NF-kappaB expression, DNA binding, and AP-1 DNA binding by CRCs and Asp. Thus, CRCs exert anti-inflammatory effects through modulation of NF-kappaB and AP-1 signaling. Ten micromoles of CRCs and Asp upregulated the expression of mothers against decapentaplegic homolog 4 (Drosophila) (SMAD4) in the TGF-beta receptor signaling pathway, and SMAD3/4 transcription activity was also increased. Ten micromoles of CRCs were able to potently inhibit STAT3-binding activity by repressing IL-6-induced STAT3 expression. Our results provide a potential mechanism that explains the anti inflammatory activities of these CRCs. PMID- 24066946 TI - Vitamin D supplementation and mortality risk in chronic kidney disease: a meta analysis of 20 observational studies. AB - BACKGROUND: Vitamin D insufficiency correlates with mortality risk among patients with chronic kidney disease (CKD). The survival benefits of active vitamin D treatment have been assessed in patients with CKD not requiring dialysis and in patients with end stage renal disease (ESRD) requiring dialysis. METHODS: MEDLINE, Embase, the Cochrance Library, and article reference lists were searched for relevant observational trials. The quality of the studies was evaluated using the Newcastle-Ottawa Scale (NOS) checklist. Pooled effects were calculated as hazard ratios (HR) using random-effects models. RESULTS: Twenty studies (11 prospective cohorts, 6 historical cohorts and 3 retrospective cohorts) were included in the meta-analysis., Participants receiving vitamin D had lower mortality compared to those with no treatment (adjusted case mixed baseline model: HR, 0.74; 95% confidence interval [95% CI], 0.67-0.82; P <0.001; time dependent Cox model: HR, 0.71; 95% CI, 0.57-0.89; P <0.001). Participants that received calcitriol (HR, 0.63; 95% CI, 0.50-0.79; P <0.001) and paricalcitol (HR, 0.43 95% CI, 0.29-0.63; P <0.001) had a lower cardiovascular mortality. Patients receiving paricalcitol had a survival advantage over those that received calcitriol (HR, 0.95; 95% CI, 0.91-0.99; P <0.001). CONCLUSIONS: Vitamin D treatment was associated with decreased risk of all-cause and cardiovascular mortality in patients with CKD not requiring dialysis and patients with end stage renal disease (ESRD) requiring dialysis. There was a slight difference in survival depending on the type of vitamin D analogue. Well-designed randomized controlled trials are necessary to assess the survival benefits of vitamin D. PMID- 24066947 TI - GIS-aided planning of insecticide spraying to control dengue transmission. AB - BACKGROUND: The purpose of this paper is to integrate a multi-objective integer programming formulation and geographic information system (GIS) into dynamically planning the insecticide spraying area for preventing the transmission of dengue fever. METHODS: The optimal spraying area to combat dengue infections is calculated by the multi-objective integer programming model using the dengue epidemic in 2007 in Tainan City of southern Taiwan and is compared with the areas actually sprayed by the local health department. The dynamic epidemic indicators (i.e. frequency, intensity and duration) that identify major temporal characteristics of the dynamic process of an epidemic are all incorporated into the model. RESULTS: The results indicate that the model can design the spraying area effectively when the trade-off between the coverage of dengue epidemics risk and area compactness is considered. CONCLUSIONS: The model provides an alternative way to obtain a cost-effective spraying area in controlling future dengue epidemics. The proposed model in this study will be beneficial for strategically allocating dengue control resources. PMID- 24066948 TI - Sensor-based monitoring of the prevalence and severity of foot pad dermatitis in broiler chickens. AB - 1. The aim of this study was to assess the suitability of a dielectric measurement to evaluate the prevalence and severity of foot pad dermatitis (FPD) in broiler chickens. 2. The study focussed on surveying the occurrence of FPD during the growing period of one broiler chicken flock. A scoring system consisting of 5 categories was used to assess the prevalence and severity of FPD macroscopically. Additionally, the dielectric constant (DC) of both foot pads of 50 chickens was measured in a triple iteration with the MoistureMeter D (Delfin Technologies, Kuopio, Finland) on three different dates. 3. On all measurement days, DC and FPD score were negatively correlated. The severity of FPD increased during the growing period, and severe lesions occurred at an early stage. 4. Further research is necessary to develop an effective early warning system for FPD in poultry houses. However, the non-invasive measurement of DC provides a reliable method for the objective assessment of occurrence and severity of FPD. PMID- 24066945 TI - FSH in vitro versus LH in vivo: similar genomic effects on the cumulus. AB - The use of gonadotropins to trigger oocyte maturation both in vivo and in vitro has provided precious and powerful knowledge that has significantly increased our understanding of the ovarian function. Moreover, the efficacy of most assisted reproductive technologies (ART) used in both humans and livestock species relies on gonadotropin input, mainly FSH and LH. Despite the significant progress achieved and the huge impact of gonadotropins, the exact molecular pathways of the two pituitary hormones, FSH and LH, still remain poorly understood. Moreover, these pathways may not be the same when moving from the in vivo to the in vitro context. This misunderstanding of the intricate synergy between these two hormones leads to a lack of consensus about their use mainly in vitro or in ovulation induction schedules in vivo. In order to optimize their use, additional work is thus required with a special focus on comparing the in vitro versus the in vivo effects. In this context, this overview will briefly summarize the downstream gene expression pathways induced by both FSH in vitro and LH in vivo in the cumulus compartment. Based on recent microarray comparative analysis, we are reporting that in vitro FSH stimulation on cumulus cells appears to achieve at least part of the gene expression activity after in vivo LH stimulation. We are then proposing that the in vitro FSH-response of cumulus cells have similitudes with the in vivo LH-response. PMID- 24066949 TI - Toxoplasmosis, leptospirosis and brucellosis in stray dogs housed at the shelter in Umuarama municipality, Parana, Brazil. AB - BACKGROUND: Leptospirosis, toxoplasmosis and brucellosis are diseases with worldwide distribution. Among stray dogs, these zoonoses are facilitated by direct contact with other animal species, by the habit of scavenging garbage and hunting in search of food, drinking standing water, smelling other animals' urine, licking female genitalia and the sexual act itself. The objective of this study was to detect antibodies anti-Toxoplasma gondii, anti-Leptospira spp., anti Brucella canis and anti-Brucella abortus in stray dogs housed in shelters at Umuarama city, Parana, Brazil. In order to detect toxoplasmosis, indirect immunofluorescence assay (IFA) was performed, agglutination microscopic (MAT) test for leptospirosis and agar gel immunodiffusion (AGID) and buffered acidified antigen (BAA) tests for brucellosis. RESULTS: Of the 175 serum samples analyzed, 70.85% were considered positive for toxoplasmosis by IFA, 20% by MAT for leptospirosis and 2.85% by AGID for Brucella canis. CONCLUSIONS: The serological results of this study showed that stray dogs housed at the private shelter are potential carriers of these three different zoonoses and contribute to the spread and maintenance of these etiologic agents in the urban area of Umuarama (PR), Brazil. PMID- 24066950 TI - The prognostic value of percentage of positive biopsy cores, percentage of cancer volume, and maximum involvement of biopsy cores in prostate cancer patients receiving proton and photon beam therapy. AB - The purpose of this study was to compare the prognostic value of the percentage of positive biopsy cores (PPBC), the percentage of cancer volume (PCV), and the maximum involvement of biopsy cores (MIBC) as a prognostic factor in low- and intermediate-risk patients with clinically localized prostate cancer who received proton or photon beam therapy. Four hundred and fifty-nine patients with clinically localized prostate carcinoma who were treated with proton or photon beam therapy at Loma Linda University Medical Center were used for this analysis. Patients were treated with a median dose of 74.0 Gy (range 70.2-79.2) proton or combined proton/photon beam radiotherapy. Pathology reports were reviewed and PPBC, PCV, and MIBC were recorded. Analysis of biochemical no evidence of disease (bNED) outcome was assessed using Kaplan-Meier analyses. Cox regression multivariate analyses were performed to assess the impact of the biopsy factors on survival. RESULTS: 285, 291, and 291 patients had biopsy information available for analysis, respectively. Survival analysis showed that a higher PPBC, PCV, and MIBC were each individually associated with an increased risk of biochemical failure on univariate analysis (p < 0.01). Only PPBC and PCV were associated with an increased risk of biochemical failure on multivariate analysis, adjusting for age, NCCN risk group, and dose (p < 0.01). When isolating the intermediate-risk group, only PPBC and PCV were statistically significant on multivariate analysis. Multivariate analysis of the intermediate-risk group comparing PPBC and PCV showed that PPBC was not a significant predictor of biochemical failure, while PCV was a significant predictor of biochemical failure (p = 0.37 and p = 0.03, respectively). CONCLUSION: PPBC and PCV can potentially be used for additional risk stratification of intermediate-risk patients with PCV potentially being the most clinically relevant predictor bNED survival. MIBC was not found to have utility in the prognosis of low- and intermediate-risk patients. PMID- 24066951 TI - Tomotherapy: implications on daily workload and scheduling patients based on three years' institutional experience. AB - Helical tomotherapy (HT) was introduced at the Greater Poland Cancer Centre (GPCC) in April 2009. Retrospective analysis included data from the treatments performed for the first 656 patients treated with HT between May 2009 and May 2012 at the GPCC. In order to evaluate the implications on daily workload and scheduling of patients, stepwise regression and time analysis for each component of the overall treatment time, such as positioning, imaging, registration, and irradiation were performed. A detailed analysis included: (1) learning curves and optimized time needed for positioning and registration; (2) relation between irradiation time and parameters used for plan creation; and (3) average time of daily imaging. The irradiation component has the highest influence on the overall treatment time (R = 0.911). The lowest influence was observed for the imaging (R = 0.670). The learning curve for positioning was 7 months while the reduction of the average daily time needed for registration was observed even after two years. The irradiation time strongly depends on the planning parameters. Changing the pitch from 0.215 to 0.287 for pelvic cancer cases decreased the average daily beam-on time per patient by about 2 minutes. Similar changes for head and neck reduced this time by 1.3 minutes. The limitation in the usage of 1 cm field width only for complex cases, lower than 10 cm in the cranio-caudal direction, reduced the beam-on time per patient by 2 minutes. The average overall treatment time decreased from 21.5 minutes per patient in the first year of the HT usage to 13.8 minutes per patient in current practice. Our current practice shows that for a group of patients including mainly those with pelvis and head and neck cancers, the HT treatment takes approximately 15 minutes per patient allowing 40 patients to be treated within 10 hours. PMID- 24066952 TI - Sequential chemoradiotherapy with accelerated hypofractionated radiotherapy compared to concurrent chemoradiotherapy with standard radiotherapy for locally advanced non-small cell lung cancer. AB - To compare the outcomes and treatment-related toxicities of two chemoradiotherapy schedules given to the patients with unresectable locally advanced non-small cell lung cancer (NSCLC): sequential chemotherapy with accelerated hypofractionated radiotherapy (SCRT), and concurrent chemotherapy with standard radiotherapy (CCRT), 68 patients from two prospective clinical trials were included. Thirty four patients were treated with SCRT using an accelerated hypofractionated radiation schedule, 34 patients received CCRT with standard radiation. Between the two treatment groups there were no significant differences in terms of overall survival, progression-free survival (PFS), locoregional-PFS or distant metastasis-PFS. For the SCRT group, the median survival time and 2- and 4-year overall survival rates were 19 months, 38.2%, and 23.5%, respectively, and for the CCRT group these were 19 months, 44.1%, and 19.6%. Esophageal and constitutional toxicities were more pronounced in the CCRT group, while there was no significant difference in pulmonary toxicities. The results suggest that for unresectable stage III NSCLC, the outcomes of SCRT with accelerated hypofractionated radiotherapy and CCRT with standard radiotherapy are similar, but the toxicities associated with treatment are less in the SCRT group. PMID- 24066953 TI - Immobilization considerations for proton radiation therapy. AB - Proton therapy is rapidly developing as a mainstream modality for external beam radiation therapy. This development is largely due to the ability of protons to deposit much of their energy in a region known as the Bragg peak, minimizing the number of treatment fields and hence integral dose delivered to the patient. Immobilization in radiation therapy is a key component in the treatment process allowing for precise delivery of dose to the target volume and this is certainly true in proton therapy. In proton therapy immobilization needs to not only immobilize the patient, placing them in a stable and reproducible position for each treatment, but its impact on the depth dose distribution and range uncertainty must also be considered. The impact of immobilization on range is not a primary factor in X-ray radiation therapy, but it is a governing factor in proton therapy. This contribution describes the immobilization considerations in proton therapy which have been developed at Loma Linda over twenty plus years of clinical operation as a hospital based proton center. PMID- 24066954 TI - MicroRNAs in body fluids as biomarkers for non-small cell lung cancer: a systematic review. AB - Non-small cell lung cancer (NSCLC) is one of the most common life-threatening malignant tumors. A test for early diagnosis of NSCLC needs to be not too invasive and not too heavy a burden for weakened patients. A series of studies reported various microRNAs (miRNAs) could be novel serum biomarkers for NSCLC. However, the diagnostic ability of different miRNA biomarkers varies among the reports. The goal of this study was to perform a systematic review to examine the effect of miRNAs on NSCLC-related outcomes. We systematically searched The Cochrane Central Register of Controlled Trials, MEDLINE, Pub Med, EMBASE, the Chinese Biomedical Literature Database, the China Academic Journals Full-text Database, and the Chinese Scientific Journals Database for potential studies. Studies were included if they were related to miRNAs, NSCLC, and reported diagnostic outcomes. Diagnostic values analysis was used to summarize the overall test performance of miRNAs. 13 studies were included in this systematic review. The ranges of sensitivity (SEN) and specificity (SPE) of diagnosis model with miRNAs as identifying NSCLC were 0.69~1.00 and 0.66~1.00, respectively. The overall area under the curve (AUC) value of summary receiver operating characteristic (SROC) curve was 0.9151. The ranges of positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.33~24.75 and 0.010.40, respectively. The range of diagnostic odds ratio (DOR) was 6.52~983.38. The current evidence indicates that miRNAs in body fluids show high accuracy in identifying NSCLC, and could be a useful screening tool for diagnosing NSCLC patients. PMID- 24066955 TI - Implanting metal fiducials to guide stereotactic liver radiation: McGill experience and review of current devices, techniques and complications. AB - In this work we report our technique and outcomes placing percutaneous liver fiducials, summarize the literature on the risks of this procedure and present the various fiducials available today. Thirty-nine subjects, 27 males and 12 females who had received liver fiducial implants between November 2006 and September 2010 were retrospectively studied. Eighty-five gold cylinders (15%) and platinum coils (85%) were inserted under computed tomography (CT) guidance. All fiducials placed proved adequate to proceed with radiation image guidance. With one notable exception of gross migration, fiducials were inserted without serious complications. Although fiducial implantation in the liver has proven successful, the procedure does carry a variety of risks. PMID- 24066956 TI - Developing an instrument-independent algorithm for Raman spectroscopy: a case of cancer detection. AB - One of the problems in the use of Raman spectroscopy for cancer detection in clinical application is the variety of Raman instruments, producing different spectra for the same sample, due to the nature of the measurement system. This prevents the measured spectra from different systems to be compared against one another without appropriate tools and techniques. Therefore, for each instrument one needs to spend considerable amount of time to prepare a set of reference data based on which the future measurements to be interpreted. For early diagnosis of cancer by Raman spectroscopy, there is a need for an algorithm by which such diagnosis can be made by any type of Raman instrument giving rise to the same findings. In the present study we have investigated the detection of breast cancer in three classes of breast samples (normal, benign and cancer) using three different Raman instruments (Almega, Bruker and R3000) to develop an algorithm that, irrespective of the type of Raman instrument, can be applied to the spectra to extract the features necessary to arrive at the same diagnosis. In doing so, we employed different pre-processing methods to eliminate the instrument dependent effects on the spectra enabling us to fuse such spectra obtained from different instruments. Then, we classified the data using support vector machine (SVM) and multi-layer perception (MLP) to assess the degree to which the employed methods have been able to detect cancer. The results of the study showed that the range and resolution matching using spline interpolation, and noise and fluorescence elimination using wavelet and SNV normalizations were the most sensitive and accurate procedures for eliminating the instrumental specification based effects and fusing the data from different instruments. PMID- 24066958 TI - Mechanism of glutathione transferase P1-1-catalyzed activation of the prodrug canfosfamide (TLK286, TELCYTA). AB - Canfosfamide (TLK286, TELCYTA) is a prodrug that upon activation by glutathione transferase P1-1 (GST P1-1) yields an anticancer alkylating agent and a glutathione derivative. The rationale underlying the use of TLK286 in chemotherapy is that tumor cells overexpressing GST P1-1 will be locally exposed to the released alkylating agent with limited collateral toxicity to the surrounding normal tissues. TLK286 has demonstrated clinical effects in phase II and III clinical trials for the treatment of malignancies, such as ovarian cancer, nonsmall cell lung cancer, and breast cancer, as a single agent and in combination with other chemotherapeutic agents. In spite of these promising results, the detailed mechanism of GST P1-1 activation of the prodrug has not been elucidated. Here, we propose a mechanism for the TLK286 activation by GST P1 1 on the basis of density functional theory (DFT) and on potential of mean force (PMF) calculations. A catalytic water molecule is instrumental to the activation by forming a network of intermolecular interactions between the active-site Tyr7 hydroxyl and the sulfone and COO(-) groups of TLK286. The results obtained are consistent with the available experimental kinetic data and provide an atomistic understanding of the TLK286 activation mechanism. PMID- 24066957 TI - Copper complexes relevant to the catalytic cycle of copper nitrite reductase: electrochemical detection of NO(g) evolution and flipping of NO2 binding mode upon Cu(II) -> Cu(I) reduction. AB - Copper complexes of the deprotonated tridentate ligand, N-2-methylthiophenyl-2' pyridinecarboxamide (HL1), were synthesized and characterized as part of our investigation into the reduction of copper(II) o-nitrito complexes into the related copper nitric oxide complexes and subsequent evolution of NO(g) such as occurs in the enzyme copper nitrite reductase. Our studies afforded the complexes [(L1)Cu(II)Cl]n (1), [(L1)Cu(II)(ONO)] (2), [(L1)Cu(II)(H2O)](ClO4).H2O (3.H2O), [(L1)Cu(II)(CH3OH)](ClO4) (4), [(L1)Cu(II)(CH3CO2)].H2O (5.H2O), and [Co(Cp)2][(L1)Cu(I)(NO2)(CH3CN)] (6). X-ray crystal structure determinations revealed distorted square-pyramidal coordination geometry around Cu(II) ion in 1 5. Substitution of the H2O of 3 by nitrite quantitatively forms 2, featuring the kappa(2)-O,O binding mode of NO2(-) to Cu(II). Reduction of 2 generates two Cu(I) species, one with kappa(1)-O and other with the kappa(1)-N bonded NO2(-) group. The Cu(I) analogue of 2, compound 6, was synthesized. The FTIR spectrum of 6 reveals the presence of kappa(1)-N bonded NO2(-). Constant potential electrolysis corresponding to Cu(II) -> Cu(I) reduction of a CH3CN solution of 2 followed by reaction with acids, CH3CO2H or HClO4 generates 5 or 3, and NO(g), identified electrochemically. The isolated Cu(I) complex 6 independently evolves one equivalent of NO(g) upon reaction with acids. Production of NO(g) was confirmed by forming [Co(TPP)NO] in CH2Cl2 (lambda(max) in CH2Cl2: 414 and 536 nm, nu(NO) = 1693 cm(-1)). PMID- 24066959 TI - Dipalladium(I) terphenyl diphosphine complexes as models for two-site adsorption and activation of organic molecules. AB - A para-terphenyl diphosphine was employed to support a dipalladium(I) moiety. Unlike previously reported dipalladium(I) species, the present system provides a single molecular hemisphere for binding of ligands across two metal centers, enabling the characterization and comparison of the binding of a wide variety of saturated and unsaturated organic molecules. The dipalladium(I) terphenyl diphosphine toluene-capped complex was synthesized from a dipalladium(I) hexaacetonitrile precursor in the presence of toluene. The palladium centers display interactions with the pi-systems of the central ring of the terphenyl unit and that of the toluene. Exchange of toluene for anisole, 1,3-butadiene, 1,3 cyclohexadiene, thiophenes, pyrroles, or furans resulted in well-defined pi-bound complexes which were studied by crystallography, nuclear magnetic resonance (NMR) spectroscopy, and density functional theory. Structural characterization shows that the interactions of the dipalladium unit with the central arene of the diphosphine does not vary significantly in this series allowing for a systematic comparison of the binding of the incoming ligands to the dipalladium moiety. Several of the complexes exhibit rare MU-eta(2):eta(2) or MU-eta(2):eta(1)(O or S) bridging motifs. Hydrogenation of the thiophene and benzothiophene adducts was demonstrated to proceed at room temperature. The relative binding strength of the neutral ligands was determined by competition experiments monitored by NMR spectroscopy. The relative equilibrium constants for ligand substitution span over 13 orders of magnitude. This represents the most comprehensive analysis to date of the relative binding of heterocycles and unsaturated ligands to bimetallic sites. Binding interactions were computationally studied with electrostatic potentials and molecular orbital analysis. Anionic ligands were also demonstrated to form pi-bound complexes. PMID- 24066960 TI - Increasing the complexity: new genes and new types of albinism. AB - Albinism is a rare genetic condition globally characterized by a number of specific deficits in the visual system, resulting in poor vision, in association with a variable hypopigmentation phenotype. This lack or reduction in pigment might affect the eyes, skin, and hair (oculocutaneous albinism, OCA), or only the eyes (ocular albinism, OA). In addition, there are several syndromic forms of albinism (e.g. Hermansky-Pudlak and Chediak-Higashi syndromes, HPS and CHS, respectively) in which the described hypopigmented and visual phenotypes coexist with more severe pathological alterations. Recently, a locus has been mapped to the 4q24 human chromosomal region and thus represents an additional genetic cause of OCA, termed OCA5, while the gene is eventually identified. In addition, two new genes have been identified as causing OCA when mutated: SLC24A5 and C10orf11, and hence designated as OCA6 and OCA7, respectively. This consensus review, involving all laboratories that have reported these new genes, aims to update and agree upon the current gene nomenclature and types of albinism, while providing additional insights from the function of these new genes in pigment cells. PMID- 24066966 TI - Study protocol: evaluation of a parenting and stress management programme: a randomised controlled trial of Triple P Discussion Groups and Stress Control. AB - BACKGROUND: Children displaying psychosocial problems are at an increased risk of negative developmental outcomes. Parenting practices are closely linked with child development and behaviour, and parenting programmes have been recommended in the treatment of child psychosocial problems. However, parental mental health also needs to be addressed when delivering parenting programmes as it is linked with parenting practices, child outcomes, and treatment outcomes of parenting programmes. This paper describes the protocol of a study examining the effects of a combined intervention of a parenting programme and a cognitive behavioural intervention for mental health problems. METHODS/DESIGN: The effects of a combined intervention of Triple P Discussion Groups and Stress Control will be examined using a randomised controlled trial design. Parents with a child aged 3 8 years will be recruited to take part in the study. After obtaining informed consent and pre-intervention measures, participants will be randomly assigned to either an intervention or a waitlist condition. The two primary outcomes for this study are change in dysfunctional/ineffective parenting practices and change in symptoms of depression, anxiety, and stress. Secondary outcomes are child behaviour problems, parenting experiences, parental self-efficacy, family relationships, and positive parental mental health. Demographic information, participant satisfaction with the intervention, and treatment fidelity data will also be collected. Data will be collected at pre-intervention, mid-intervention, post-intervention, and 3-month follow-up. DISCUSSION: The aim of this paper is to describe the study protocol of a randomised controlled trial evaluating the effects of a combined intervention of Triple P Discussion Groups and Stress Control in comparison to a waitlist condition. This study is important because it will provide evidence about the effects of this combined intervention for parents with 3-8 year old children. The results of the study could be used to inform policy about parenting support and support for parents with mental health problems. TRIAL REGISTRATION: ClinicalTrial.gov: NCT01777724, UTN: U1111-1137 1053. PMID- 24066968 TI - The liver-targeting study of the N-galactosylated chitosan in vivo and in vitro. AB - In order to study the liver targeting of the N-galactosylated chitosan (GC) polymer in liver, we first conjugated the lactobionic acid with chitosan (CS) to obtain the carrier of GC with different degree of substitution of lactosyl group. Western blot was performed to detect the expression levels of the asialoglycoprotein receptors (ASGPR) in the cell lines of HepG2, SMMC-7721, and HL-7702. The protein level of ASGPR was lower in HepG2 compared to HL-7702 and SMMC-7721. Although all treated by CS, viabilities of HL-7702 and HepG2 did not experience any significant drop, while viability of SMMC-7721 decreased 15% on average from control. It was the first data about the inhibitory effect of GC on the liver cells. Fluorescein isothiocyanate (FITC) labeled GC (GC-FITC) was injected intravenously into mice at a dose of 0.02 MUmol/mouse. GC-FITC showed maximum liver localization at 5 min and even detectable at 48 h after injection. Further, the accumulation of GC in liver was about 5.4-fold higher than that of CS. In conclusion, GC demonstrated its higher efficacy in drug liver targeting and thus could be a more promising drug or gene carrier in future therapies. PMID- 24066969 TI - Emerging therapies for the treatment of chronic Philadelphia chromosome-negative myeloproliferative neoplasm-associated myelofibrosis. AB - INTRODUCTION: Chronic Philadelphia chromosome-negative myeloproliferative neoplasm-associated myelofibrosis significantly impacts afflicted patients with cytopenia, splenomegaly, debilitating constitutional symptoms and decreased survival. Approval of the first Janus kinase 2 (JAK2) inhibitor therapy, ruxolitinib, has improved splenomegaly, symptomatic burden, survival and perhaps fibrosis in some treated patients; however, other patients remain symptomatic and are in need of alternate therapeutic strategies. AREAS COVERED: A review of recent literature via PubMed and meeting abstracts has revealed many studies investigating new treatment approaches for chronic Philadelphia chromosome negative myeloproliferative neoplasms. Multiple additional JAK2 inhibitors (fedratinib, pacritinib and momelotinib) are well into single agent development, as well as multiple combination approaches with ruxolitinib. Efforts to combine JAK2 inhibition with agents to improve cytopenia, marrow fibrosis, additional pathway inhibitors and even allogeneic transplant are planned or ongoing. Additionally, Phase III trials of immunomodulation with pomalidomide are ongoing. EXPERT OPINION: This article discusses investigational therapies for the treatment of Philadelphia chromosome-negative myeloproliferative neoplasms, particularly those in Phase II clinical trials, employing new JAK2 inhibitors, novel multi-agent therapeutic approaches and innovative new drug targets. Additionally, the future era of Philadelphia chromosome-negative myeloproliferative neoplasms is addressed with potentially expanded niches for JAK2 inhibition. PMID- 24066967 TI - New insights into the synergism of nucleoside analogs with radiotherapy. AB - Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells. PMID- 24066970 TI - Magnolol suppresses vascular endothelial growth factor-induced angiogenesis by inhibiting Ras-dependent mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways. AB - Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, has been reported to possess anticancer activity. Recent studies have also demonstrated that magnolol inhibits cell growth and induces the apoptosis of cancer cells. However, the effects of magnolol on vascular endothelial growth factor (VEGF)-induced angiogenesis in endothelial cells have not been studied. In the present study, we have used human umbilical vein endothelial cells (HUVECs) to investigate the antiangiogenic effect and molecular mechanism of magnolol. Magnolol inhibited the VEGF-induced proliferation, chemotactic motility and tube formation of HUVECs in vitro as well as the vessel sprouting of the aorta ex vivo. Furthermore, magnolol inhibited VEGF-induced Ras activation and subsequently suppressed extracellular signal-regulated kinase (ERK), phosphatidylinositol-3-kinase (PI3K)/Akt and p38, but not Src and focal adhesion kinase (FAK). Interestingly, the knockdown of Ras by short interfering RNA produced inhibitory effects that were similar to the effects of magnolol on VEGF induced angiogenic signaling events, such as ERK and Akt/eNOS activation, and resulted in the inhibition of proliferation, migration, and vessel sprouting in HUVECs. In combination, these results demonstrate that magnolol is an inhibitor of angiogenesis and suggest that this compound could be a potential candidate in the treatment of angiogenesis-related diseases. PMID- 24066971 TI - Microfluidic fabrication of stable gas-filled microcapsules for acoustic contrast enhancement. AB - We introduce a facile approach for the production of gas-filled microcapsules designed to withstand high pressures. We exploit microfluidics to fabricate water filled microcapsules that are then externally triggered to become gas-filled, thus making them more echogenic. In addition, the gas-filled microcapsules have a solid polymer shell making them resistant to pressure-induced buckling, which makes them more mechanically robust than traditional prestabilized microbubbles; this should increase the potential of their utility for acoustic imaging of porous media with high hydrostatic pressures such as oil reservoirs. PMID- 24066972 TI - Causes of missed synchronous gastric epithelial neoplasms with endoscopic submucosal dissection: a multicenter study. AB - OBJECTIVE: Unlike surgery, endoscopic submucosal dissection (ESD) removes gastric epithelial neoplasms within a tight margin, leaving most normal tissue around the neoplasm intact, thus resulting in a high risk for missed synchronous gastric epithelial neoplasms (mSGENs). The purpose of this study was to evaluate the characteristics and risk factors of mSGENs (mSGENs) compared to simultaneously identified SGENs (siSGENs) in patients who underwent ESD. MATERIALS AND METHODS: The authors have retrospectively examined 312 SGENs from 275 patients treated with ESD at three hospitals in Korea between January 2004 and May 2011. The incidence and clinicopathological features of SGENs, mSGENs, and siSGENs were investigated. Any second epithelial neoplasm found within 1 year of the first ESD procedure was defined as an mSGEN and any neoplasm detected simultaneously with the first neoplasm was defined as a siSGEN. RESULTS: The overall incidence of ESD patients with SGENs was 9.1% (275 of 3018 patients). Of the SGENs, 45.2% were siSGENs and 54.8% were mSGENs. Independent risk factors for mSGENs were adenoma as the first gastric lesion (Exp (B) = 2.154, 95% CI: 1.282-3.262) and duration of endoscopic examination before the first ESD (Exp (B) = 1.074, 95% CI: 1.001 1.141). The results suggest that 33% of mSGENs could have been identified during the endoscopic examination prior to ESD. CONCLUSION: Additional effort needs to be expended in identifying siSGENs, particularly prior to ESD for less serious adenomas. This should include sufficient time for endoscopic examination, prior to ESD, to ensure a thorough examination for siSGENs. PMID- 24066974 TI - Method for characterization of PEGylated bioproducts in biological matrixes. AB - PEGylation of peptides and proteins has been widely used to enhance stability and reduce immunogenicity of biotherapeutics. Characterizing the degradation of these PEGylated products in biological fluids can yield essential information to support pharmacokinetic evaluations and provide clues about their in vivo properties useful for further molecular optimization. In this paper, we describe a novel and uncomplicated approach to characterize PEGylated peptides or proteins and their related degradation products in biological matrixes. The method involves direct liquid chromatography/mass spectrometry (LC/MS) analysis of animal sera containing low nanograms to low micrograms per milliliter of PEGylated product with or without an acetonitrile precipitation sample treatment. Applying the methodology to analyze the model PEGylated peptides, 20K PEGylated Pancreatic Polypeptide analogue (PPA) and 20K PEGylated-glucagon, we elucidated the decomposition pathways occurring in animal sera. The data provided direct evidence of cleavages within the peptide backbone. The identified degradation products were unambiguously confirmed by tandem mass spectrometry with high energy C-trap dissociation (HCD) analysis, followed with in-source fragmentation. Additional spiking studies demonstrated nearly full recovery of PEGylated products, linear detection when the spiked concentration of PEGylated product was <=1000 ng/mL, and a low ng/mL limit of quantitation (LOQ). PMID- 24066975 TI - The volumetric change and dose-response relationship following hypofractionated proton therapy for chordomas. PMID- 24066976 TI - In situ study of hydrogenation of graphene and new phases of localization between metal-insulator transitions. AB - Monolayer graphene synthesized by chemical vapor deposition was subjected to controlled and sequential hydrogenation using RF plasma while monitoring its electrical properties in situ. Low-temperature transport properties, namely, electrical resistance (R), thermopower (S), Hall mobility (MU), and magnetoresistance (MR), were measured for each sample and correlated with ex situ Raman scattering and X-ray photoemission (XPS) characteristics. For weak hydrogenation, the transport is seen to be governed by electron diffusion, and low-temperature transport properties show metallic behavior (conductance G remains nonzero as T -> 0). For strong hydrogenation, the transport is found to be describable by variable range hopping (VRH) and the low T conductance shows insulating behavior (G -> 0 as T -> 0). Weak localization (WL) behavior is seen with a negative MR for weakly hydrogenated graphene, and these WL effects are seen to diminish as the hydrogenation progresses. A clear transition to strong localization (SL) is evident with the emergence of pronounced negative MR for strongly hydrogenated graphene. PMID- 24066973 TI - The interplay between lipids and dopamine on alpha-synuclein oligomerization and membrane binding. AB - The deposition of alpha-syn (alpha-synuclein) as amyloid fibrils and the selective loss of DA (dopamine) containing neurons in the substantia nigra are two key features of PD (Parkinson's disease). alpha-syn is a natively unfolded protein and adopts an alpha-helical conformation upon binding to lipid membrane. Oligomeric species of alpha-syn have been proposed to be the pathogenic species associated with PD because they can bind lipid membranes and disrupt membrane integrity. DA is readily oxidized to generate reactive intermediates and ROS (reactive oxygen species) and in the presence of DA, alpha-syn form of SDS resistant soluble oligomers. It is postulated that the formation of the alpha syn:DA oligomers involves the cross-linking of DA-melanin with alpha-syn, via covalent linkage, hydrogen and hydrophobic interactions. We investigate the effect of lipids on DA-induced alpha-syn oligomerization and studied the ability of alpha-syn:DA oligomers to interact with lipids vesicles. Our results show that the interaction of alpha-syn with lipids inhibits the formation of DA-induced alpha-syn oligomers. Moreover, the alpha-syn:DA oligomer cannot interact with lipid vesicles or cause membrane permeability. Thus, the formation of alpha syn:DA oligomers may alter the actions of alpha-syn which require membrane association, leading to disruption of its normal cellular function. PMID- 24066977 TI - Angiogenic biomarkers for prediction of early preeclampsia onset in high-risk women. AB - OBJECTIVE: Chronic hypertension, pregestational diabetes mellitus, history of prior preeclampsia and obese nulliparity are maternal conditions associated with increased preeclampsia risk. Whether altered maternal angiogenic factor levels allow for prediction of pending disease is unclear. Our objective was to evaluate angiogenic factors for early preeclampsia prediction in high-risk women. METHODS: Serial serum specimens were collected from 157 women at high preeclampsia risk and 50 low-risk controls between 23 and 36 weeks gestation in 3 windows (23-27.6, 28-31.6, and 32-35.6 weeks) in a two-center observational cohort. Soluble fms like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) were measured by ELISA. RESULTS: Multivariate parsimonious logistic regression analyses using backward elimination for prediction of early preeclampsia (diagnosed < 34 weeks) found the best-fitting model included the predictors (1) sFlt1 measured in the second window (28-31.6 weeks) with AUC 0.85, sensitivity 67% and specificity 96% and (2) sFlt1 measured in the first window (23-27.6 weeks) and sEng change between first and second window with AUC 0.91, sensitivity 86% and specificity 96%. CONCLUSIONS: Two-stage sampling screening protocol utilizing sFlt1 and sEng is promising for prediction of preeclampsia diagnosed before 34 weeks. Larger studies are needed to confirm these findings. PMID- 24066978 TI - Erythropoiesis-stimulating agent resistance and mortality in hemodialysis and peritoneal dialysis patients. AB - BACKGROUND: Responsiveness to erythropoiesis-stimulating agents (ESAs) varies widely among dialysis patients. ESA resistance has been associated with mortality in hemodialysis (HD) patients, but in peritoneal dialysis (PD) patients data is limited. Therefore we assessed the relation between ESA resistance in both HD and PD patients. METHODS: NECOSAD is a Dutch multi-center prospective cohort study of incident dialysis patients who started dialysis between January 1997 and January 2007. ESA resistance was defined as hemoglobin level < 11 g/dL with an above median ESA dose (i.e. 8,000 units/week in HD and 4,000 units/week in PD patients). Unadjusted and adjusted Cox regression analysis for all-cause 5-year mortality was performed for HD and PD patients separately. RESULTS: 1013 HD and 461 PD patients were included in the analysis. ESA resistant HD patients had an adjusted hazard ratio of 1.37 (95% CI 1.04-1.80) and ESA resistant PD patients had an adjusted hazard ratio of 2.41 (1.27-4.57) as compared to patients with a good response. CONCLUSIONS: ESA resistance, as defined by categories of ESA and Hb, is associated with increased mortality in both HD and PD patients. The effect of ESA resistance, ESA dose and hemoglobin are closely related and the exact mechanism remains unclear. Our results strengthen the need to investigate and treat causes of ESA resistance not only in HD, but also in PD patients. PMID- 24066979 TI - Prevalence of selected clinical problems in older adults with autism and intellectual disability. AB - BACKGROUND: Originally described as a disorder of childhood, evidence now demonstrates the lifelong nature of autism spectrum disorder (ASD). Despite the increase of the population over age 65, older adults with ASD remain a scarcely explored subpopulation. This study set out to investigate the prevalence of clinically relevant behaviors and medical problems in a sample of US adults aged 30 to 59 with ASD and intellectual disability (ID), in comparison to those with ID only. METHODS: A cross-sectional study, with both an exploratory and replication analysis, was conducted using National Core Indicators (NCI) multi state surveys from 2009 to 2010 and 2010 to 2011. There were 4,989 and 4,261 adults aged 30-59 with ID examined from the 2009 to 2010 and 2010 to 2011 samples, respectively. The two consecutive annual samples consisted of 438 (9%) and 298 (7%) individuals with ASD and ID. Variables were chosen from the NCI data as outcomes, including medication use for behavior problems, severe or aggressive behavior problems and selected medical conditions. RESULTS: No age-associated disparities were observed between adults with ASD and ID versus adults with ID only in either sample. For the 2009 to 2010 sample, the prevalence of support needed to manage self-injurious, disruptive and destructive behavior in subjects with ASD and ID ranged from 40 to 60%. Similarly, the prevalence estimates of self-injurious, disruptive and destructive behavior were each almost double in adults with ASD and ID relative to those with ID only. These results were replicated in the 2010 to 2011 sample. CONCLUSIONS: The findings of this study highlight the urgent need for research on the nature and treatment of severe behavior problems in the rapidly increasing population of older adults with ASD. They also suggest the importance of developing policies that expand our capacity to care for these individuals. PMID- 24066980 TI - A popliteal giant synovial osteochondroma mimicking a parosteal osteosarcoma. AB - Both giant synovial osteochondroma and parosteal osteosarcoma are rare musculo skeletal tumors, often localized in the vicinity of the knee. Misdiagnosis of a malignant bone tumor can entail fatal consequences. Etiology of giant synovial osteochondroma is widely unsolved but is believed to originate from synovial chondromatosis, a mostly benign metaplasia of the synovial membrane. Parosteal osteosarcoma is a low-grade surface osteosarcoma with a propensity of local recurrence and the potential of distant metastasis and therefore requiring a different therapeutical approach. We report the case of a popliteal giant osteochondroma mimicking a parosteal osteosarcoma. Relevant facts of this rare entity regarding pathogenesis, treatment, and differential diagnoses will be discussed. PMID- 24066981 TI - Diminished gene expression of cardiac heat shock proteins in pulmonary hypertensive chickens. AB - 1. The relative expression of heat shock protein (HSP) genes (HSP60, HSP70 and HSP90) was performed using quantitative real-time PCR on tissue from the heart ventricles to investigate the effect of 3,5,3'-l-triiodothyronine (T3)-induced pulmonary hypertension in broiler chickens. 2. The ratio of the right ventricle to total ventricle (index of pulmonary hypertension) was increased in the treated groups at 12 and 42 d of age compared to controls but was significant only at 42 d. 3. The HSP genes were expressed in the right and left ventricles of control but T3-treated broilers at 12 and 42 d of age. The relative amounts of HSP60 and HSP90 gene expression in the right ventricle of treated groups were significantly increased at 12 d and decreased at 42 d of age compared to controls. 4. Variations of HSP60 and HSP90 mRNAs in the left ventricle were not significant. The relative amount of HSP70 mRNA expression in the right and left ventricles of treated groups was significantly decreased at 42 d of age compared to controls. HSP70 mRNA expression did not differ between the right and left ventricles at 12 d of age. 5. It is concluded that gene expression of HSPs (i.e. HSP60 and HSP90) was upregulated in the heart of chickens developing pulmonary hypertension syndrome, probably to delay the pathological process of disease. The right ventricle from hearts of pulmonary hypertensive chickens showed considerable reductions of HSP60, HSP70 and HSP90, which is evidence of a loss of compensatory responsiveness in dilated heart. PMID- 24066982 TI - Vasoconstrictor effect of Africanized honeybee (Apis mellifera L.) venom on rat aorta. AB - BACKGROUND: Apis mellifera stings are a problem for public health worldwide, particularly in Latin America due to the aggressiveness of its Africanized honeybees. Massive poisoning by A. mellifera venom (AmV) affects mainly the cardiovascular system, and several works have described its actions on heart muscle. Nevertheless, no work on the pharmacological action mechanisms of the AmV in isolated aorta has been reported. Thus, the present work aimed to investigate the actions of AmV and its main fractions, phospholipase A2 (PLA2) and melittin, on isolated aorta rings and a probable action mechanism. RESULTS: AmV and the complex PLA2 + melittin (0.1-50 MUg/mL) caused contraction in endothelium containing aorta rings, but neither isolated PLA2 nor melittin were able to reproduce the effect. Endothelium removal did not change the maximum vasoconstrictor effect elicited by AmV. Ca2+-free medium, as well as treatment with phentolamine (5 MUM), verapamil (10 MUM), losartan (100 MUM), and U-73122 (10 MUM, a phospholipase C inhibitor), eliminated the AmV-induced contractile effects. CONCLUSIONS: In conclusion, AmV caused contractile effect in aorta rings probably through the involvement of voltage-operated calcium channels, AT1 and alpha-adrenergic receptors via the downstream activation of phospholipase C. The protein complex, PLA2 + melittin, was also able to induce vasoconstriction, whereas the isolated proteins were not. PMID- 24066983 TI - The sulfur shift: an activation mechanism for periplasmic nitrate reductase and formate dehydrogenase. AB - A structural rearrangement known as sulfur shift occurs in some Mo-containing enzymes of the DMSO reductase family. This mechanism is characterized by the displacement of a coordinating cysteine thiol (or SeCys in Fdh) from the first to the second shell of the Mo-coordination sphere metal. The hexa-coordinated Mo ion found in the as-isolated state cannot bind directly any exogenous ligand (substrate or inhibitors), while the penta-coordinated ion, attained upon sulfur shift, has a free binding site for direct coordination of the substrate. This rearrangement provides an efficient mechanism to keep a constant coordination number throughout an entire catalytic pathway. This mechanism is very similar to the carboxylate shift observed in Zn-dependent enzymes, and it has been recently detected by experimental means. In the present paper, we calculated the geometries and energies involved in the sulfur-shift mechanism using QM-methods (M06/(6-311++G(3df,2pd),SDD)//B3LYP/(6-31G(d),SDD)). The results indicated that the sulfur-shift mechanism provides an efficient way to enable the metal ion for substrate coordination. PMID- 24066984 TI - Screening for type 2 diabetes: does the ADDITION--Cambridge trial distract from the real policy challenge? PMID- 24066985 TI - The Atlas trial: Tamoxifen for a longer duration for early breast cancer. PMID- 24066986 TI - Allogeneic haematopoietic stem cell transplantation: the Army hospital experience. AB - BACKGROUND: We analysed the results of allogeneic haematopoietic stem cell transplantation (HSCT) in various genetic disorders, bone marrow failures and haematological malignancies done from 2002 to 2010 at the Army Hospital, Research and Referral, Delhi. METHODS: A total of 119 matched-related allogeneic- HSCTs (allo-HSCTs) were done in 114 patients (men 76, women 38) aged between 2 and 60 years. Peripheral blood stem cells (n=75) and bone marrow (n=43) were used as the source of stem cells. RESULTS: The overall survival was 62.3% (71/114) at a median follow-up of 34 months. Graft versus host disease (GVHD) was seen in 42 (36.8%) patients; grade III/IV acute GVHD in 17 (15%) and chronic GVHD in 24 (21%) patients. There were 4 (3.5%) graft rejections and one nonengraftment. The overall mortality was 37.7% (n=43) and the main causes of death were GVHD (32%), infections (26%), relapse (23%) and regimen-related toxicity (11%). CONCLUSION: Our results are comparable to published data in most disease conditions. With improvements in GVHD prophylaxis and better supportive care, we need to further reduce our mortality and morbidity. PMID- 24066987 TI - Community-based physical activity intervention using principles of social marketing: a demonstration project in Southern India. AB - BACKGROUND: We aimed to study the development and implementation of promotion of physical activity in a rural community by applying the principles of social marketing and to determine participation behaviour in a physical activity programme in a community setting. METHODS: The intervention targeted 485 people, 20-49 years of age, residents of Periakattupalayam and Rangareddipalayam villages, Tamil Nadu. This community-based participatory research was based on the principles of 'social marketing'. Health education by one-to-one counselling, written materials and community events were used to popularize moderate intensity physical activity (brisk walking for 30 minutes on 4 days/week). We formed 30 walking groups under four coordinators, in a home-based setting with professional supervision and guidance. A log of physical activity sessions for the 10-week intervention period was maintained in the form of group attendance record. Village leaders, self-help groups and youth clubs were involved in promoting physical activity. RESULTS: Of the 485 subjects, 265 people (54.6%) engaged in brisk walking >4 days a week, while 156 subjects (32.2%) performed walking on 1-4 days per week during the intervention. The drop-out rate was 13.2% (64 subjects). Age, occupation and educational status were important determinants of participation and adherence to the physical activity programme. CONCLUSION: Application of social marketing techniques in an intervention to promote physical activity was successful in a rural Indian community. Studying the determinants of adoption of a physical activity programme and addressing the barriers to behaviour change are essential for designing relevant policies and effective programmes. PMID- 24066988 TI - Assessing the readiness to integrate tobacco control in medical curriculum: experiences from five medical colleges in Southern India. AB - BACKGROUND: Making tobacco cessation a normative part of all clinical practice is the only way to substantially reduce tobacco-related deaths and the burden of tobacco-related morbidity in the short term. This study was undertaken because information on receptivity to integrate tobacco control education in the medical curriculum is extremely limited in low- and middle-income countries. METHODS: From five medical colleges (two government) in southern India, 713 (men 59%) faculty and 2585 (men 48%) students participated in our cross-sectional survey. Information on self-reported tobacco use and readiness to integrate tobacco control education in the medical curriculum was collected from both the faculty and students using a pretested structured questionnaire. Multiple logistic regression analysis was done to find the associated factors. RESULTS: Current smoking was reported by 9.0% (95% CI 6.6-12.1) of men faculty and 13.7% (CI 11.8 15.9) by men students. Faculty who were teaching tobacco-related topics [odds ratio (OR) 2.29; 95% CI 1.65-3.20] compared to those who were not, faculty in government colleges (OR 1.69; CI 1.22-2.35) compared to those in private colleges and medical pecialists (OR 1.79; CI 1.23-2.59) compared to surgical and non clinical specialists were more likely to be ready to integrate tobacco control education in the medical curriculum. Non-smoking students (OR 2.58; CI 2.01-3.33) compared to smokers, and women students (OR 1.80; CI 1.50-2.17) compared to men were more likely to be ready to integrate a tobacco control education in the curriculum. CONCLUSION: Faculty and students are receptive to introduce tobacco control in the medical curriculum. Government faculty, medical specialists and faculty who already teach tobacco-related topics are likely to be early introducers of this new curriculum. PMID- 24066989 TI - Are surgeons spunkier than non-surgeons? AB - BACKGROUND: Surgeons are known to be bolder than other members of the medical profession. Testosterone levels are known to be higher in aggressive men. We wondered whether the above two statements indicated that the spunkiness of surgeons was related to higher testosterone levels. METHODS: Sixteen surgeons and 16 non-surgeons, all men, aged 32-59 years took part in a prospective study that assessed their testosterone levels. RESULTS: There was no statistical difference between the testosterone levels of the two groups. CONCLUSION: The reason for the gutsy behaviour of surgeons is not linked to their testosterone levels. Surgeons were disappointed to know this while non-surgeons were amused and a bit relieved. PMID- 24066991 TI - Biotinidase deficiency: an atypical presentation. AB - Biotinidase deficiency is a rare metabolic disorder which can cause dermatological manifestations and lead to severe neurological sequelae if untreated. Holocarboxylase synthetase deficiency also has similar manifestations and needs to be differentiated. We present a neonate who had atypical early onset symptoms and was diagnosed to have biotinidase deficiency. PMID- 24066990 TI - Emergence of decreased susceptibility to extended-spectrum cephalosporins in Neisseria gonorrhoeae in India. AB - BACKGROUND: In the past, Neisseria gonorrhoeae has developed resistance to antimicrobial agents used for its treatment. Consequently, extended-spectrum cephalosporins form the mainstay of treatment for gonorrhoea. METHODS: Samples from 88 patients attending the sexually transmitted diseases clinics from December 2009 to January 2011 in two referral hospitals in New Delhi were studied. Antimicrobial susceptibility testing was done using the disc diffusion method as per the calibrated dichotomous sensitivity technique against the following antibiotics: penicillin (0.5 i.u.), tetracycline (10 MUg), nalidixic acid (30 MUg), ciprofloxacin (1 MUg), spectinomycin (100 MUg), ceftriaxone (0.5 MUg) and cefpodoxime (10 MUg) (Oxoid UK). Azithromycin (15 MUg) (Oxoid, UK) was tested as per the guidelines of the Clinical and Laboratory Standards Institute. Minimum inhibitory concentrations were determined using the Etest for penicillin, tetracycline, ciprofloxacin, ceftriaxone, spectinomycin and azithromycin as per the manufacturer's instruction (Biomerieux, France). RESULTS: Eighteen isolates of Neisseria gonorrhoeae were obtained. Three of these had decreased susceptibility to ceftriaxone and cefpodoxime by the disc diffusion method. The minimum inhibitory concentrations of ceftriaxone for two isolates were 0.064 MUg/ml and for one isolate it was 0.125 MUg/ml. CONCLUSION: Higher minimum inhibitory concentrations to extended-spectrum cephalosporins is of concern as it has been shown to precede treatment failure. This may warrant its use in increased/multiple dosages alone or possibly in combination (dual therapy), thereby complicating effective disease control. Our report is in accordance with earlier reports from different parts of the world. Therefore, a continuous surveillance of antimicrobial resistance is crucial to tailor treatment schedules for Neisseria gonorrhoeae in a particular geographical region. PMID- 24066992 TI - A hospital-based epidemiological study of corrosive alimentary injuries with particular reference to the Indian experience. AB - Corrosive alimentary tract injuries are a source of considerable morbidity all over the world. Despite this, actual data on the epidemiology of this problem are scarce mainly due to the lack of a well-established reporting system for poisoning in most countries. The burden of the disease is naturally more in countries such as India where the condition is common because of poor regulation of sale of corrosive substances. We analyse the available data on epidemiology of corrosive injuries, as well as patterns of involvement of the alimentary tract, with special reference to Indian data, and also provide an overview of the management options and long-term sequelae of this condition. PMID- 24066993 TI - Can intermittent preventive treatment for malaria reduce child mortality? PMID- 24066994 TI - An effective dengue vaccine: a glass half full or half empty? PMID- 24066995 TI - Road traffic noise: a risk factor for myocardial infarction? PMID- 24066996 TI - Workplace-based assessment: measuring and shaping clinical learning. AB - Assessment of clinical competence is a challenge. It should not only help us in measuring performance but also in improving performance. Traditional assessment has many flaws, mainly related to snapshot observations, artificial settings and lack of opportunity to improve performance. Workplace-based assessment (WPBA) refers to direct observation of performance at the workplace. It builds on the ways people learn at the workplace. The key feature of all tools used for WPBA is direct observation of trainee performance at the workplace followed by provision of feedback based on that observation. This makes such an assessment valid. Though most of the tools use subjective observations, the assessment is reliable due to use of multiple encounters being assessed by multiple assessors in multiple settings. In addition, WPBA has high utility in terms of its educational impact. WPBA involves sampling of the clinical work using logbooks or encounter cards and direct observation of performance of clinical competence and procedural skills. These are supplemented by assessment by various people who can provide authentic information about a trainee's work habits. The encounters and ratings are documented in a portfolio, which allows a longitudinal record of trainees' progress. Experience suggests that WPBA has the potential to shape clinical learning and steer it towards desirable learning outcomes. Most of the tools used for WPBA can be applied in the Indian context. PMID- 24066998 TI - Letter from Chennai. PMID- 24066999 TI - Letter from Glasgow. PMID- 24067007 TI - Validation of the female sexual function index in Southern India. PMID- 24067008 TI - Leprosy elimination: battle won, but the war remains. PMID- 24067009 TI - Pyrethroid ingestion-induced status epilepticus in a young woman. PMID- 24067010 TI - Are sustainable development goals a replacement for the Millennium Development Goals post-2015? PMID- 24067011 TI - Knowledge, attitude and practice towards infection control among healthcare professionals. PMID- 24067012 TI - Camphor poisoning in a child. PMID- 24067018 TI - Malaria funds drying up: World Malaria Report 2012. PMID- 24067021 TI - A substrate-assisted mechanism of nucleophile activation in a Ser-His-Asp containing C-C bond hydrolase. AB - The meta-cleavage product (MCP) hydrolases utilize a Ser-His-Asp triad to hydrolyze a carbon-carbon bond. Hydrolysis of the MCP substrate has been proposed to proceed via an enol-to-keto tautomerization followed by a nucleophilic mechanism of catalysis. Ketonization involves an intermediate, ES(red), which possesses a remarkable bathochromically shifted absorption spectrum. We investigated the catalytic mechanism of the MCP hydrolases using DxnB2 from Sphingomonas wittichii RW1. Pre-steady-state kinetic and LC ESI/MS evaluation of the DxnB2-mediated hydrolysis of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid to 2-hydroxy-2,4-pentadienoic acid and benzoate support a nucleophilic mechanism catalysis. In DxnB2, the rate of ES(red) decay and product formation showed a solvent kinetic isotope effect of 2.5, indicating that a proton transfer reaction, assigned here to substrate ketonization, limits the rate of acylation. For a series of substituted MCPs, this rate was linearly dependent on MCP pKa2 (betanuc ~ 1). Structural characterization of DxnB2 S105A:MCP complexes revealed that the catalytic histidine is displaced upon substrate-binding. The results provide evidence for enzyme-catalyzed ketonization in which the catalytic His-Asp pair does not play an essential role. The data further suggest that ES(red) represents a dianionic intermediate that acts as a general base to activate the serine nucleophile. This substrate-assisted mechanism of nucleophilic catalysis distinguishes MCP hydrolases from other serine hydrolases. PMID- 24067022 TI - Phosphorus removal in an enhanced biological phosphorus removal process: roles of extracellular polymeric substances. AB - Phosphorus-accumulating organisms are considered to be the key microorganisms in the enhanced biological phosphorus removal (EBPR) process. A large amount of phosphorus is found in the extracellular polymeric substances (EPS) matrix of these microorganisms. However, the roles of EPS in phosphorus removal have not been fully understood. In this study, the phosphorus in the EBPR sludge was fractionated and further analyzed using quantitative (31)P nuclear magnetic resonance spectroscopy. The amounts and forms of phosphorus in EPS as well as their changes in an anaerobic-aerobic process were also investigated. EPS could act as a reservoir for phosphorus in the anaerobic-aerobic process. About 5-9% of phosphorus in sludge was reserved in the EPS at the end of the aerobic phase and might further contribute to the phosphorus removal. The chain length of the intracellular long-chain polyphosphate (polyP) decreased in the anaerobic phase and then recovered under aerobic conditions. However, the polyP in the EPS had a much shorter chain length than the intracellular polyP in the whole cycle. The migration and transformation of various forms of phosphorus among microbial cells, EPS, and bulk liquid were also explored. On the basis of these results, a model with a consideration of the roles of EPS was proposed, which is beneficial to elucidate the mechanism of phosphorus removal in the EBPR system. PMID- 24067023 TI - C-H activation by a diselenido dinickel(II) complex. AB - Addition of selenium to the nickel(I) complex, [Ni(Me4[12]aneN4)(CO)]PF6, effects a redox reaction leading to the diselenido dinickel(II) complex, {[(Ni(Me4[12]aneN4)]2(Se2)}(PF6)2, in 70% crystalline yield. The product's structure features a MU-eta(2):eta(2)-Se2 ligand with Se-Se bond length of 2.379(13) A. Upon mild heating, {[(Ni(Me4[12]aneN4)]2(MU-eta(2):eta(2) Se2)}(PF6)2 oxidizes 9,10-dihydroanthracene or 1,4-cyclohexadiene forming the terminal hydroselenide, [Ni(Me4[12]aneN4)(SeH)]PF6, and anthracene or benzene, respectively. [Ni(Me4[12]aneN4)(SeH)]PF6 cleanly converts back to the diselenido dinickel(II) adduct upon addition of a phenoxy radical. PMID- 24067025 TI - Unanimous on dementia. PMID- 24067024 TI - Proteomic analysis of differentially expressed proteins in vitamin C-treated AGS cells. AB - BACKGROUND: Vitamin C (ascorbic acid) is an essential nutrient of most living tissues that readily acts as a strong reducing agent, which is abundant in fruits and vegetables. Although, it inhibits cell growth in many human cancer cells in vitro, treatment in cancer is still controversial. Hence, the purpose of this study was to investigate the molecular mechanism of the inhibitory effect of vitamin C on AGS cell growth, and protein profiles in AGS cells after exposure to vitamin C treatment, by using proteomic tools. RESULTS: Vitamin C showed a cytotoxic effect on AGS cells (IC50 300 MUg/mL) and, 20 differentially expressed proteins (spot intensities which show >=2 fold change and statistically significant, p<0.05 between the control and vitamin-C treated group) were successfully identified by assisted laser desorption/ ionization-time of flight/mass spectrometry (MALDI-TOF/MS). Of the 20 proteins, six were up regulated and fourteen were down-regulated. Specifically, 14-3-3sigma, 14-3 3epsilon, 14-3-3delta, tropomyosin alpha-3 chain and tropomyosin alpha-4 chain were down-regulated and peroxiredoxin-4 and thioredoxin domain-containing proteins 5 were up-regulated. The identified proteins are mainly involved in cell mobility, antioxidant and detoxification, signal transduction and protein metabolism. Further, the expressions of 14-3-3 isoforms were verified with immuno blotting analysis. CONCLUSIONS: Our proteome results suggest that the apoptosis related proteins were involved in promoting and regulating cell death of AGS cells, and might be helpful to understand the molecular mechanism of vitamin C on AGS cell growth inhibition. PMID- 24067030 TI - Therapeutic lying should be avoided. PMID- 24067033 TI - Charity calls for communities to be more dementia friendly. PMID- 24067034 TI - Earlier diagnosis of constipation would cut emergency admissions. PMID- 24067038 TI - Wise words for a new system. PMID- 24067042 TI - Practice question: how can I manage patients with acute illness in their own homes? PMID- 24067043 TI - The effect of visual impairment on patients' falls risk. AB - When older people fall it can result in injuries and adversely affect quality of life. People with visual impairment are at greater risk of falling. This article explores the risk of falling and preventive assessment in patients with visual impairment, whether they are in long-term care settings or living in their own homes. Five types of visual impairment common to older people are discussed. The importance of assessment for falls prevention and suggestions for practice are highlighted. PMID- 24067044 TI - How nurses can help ease patient transitions to end of life care. AB - Moving from curative to palliative care is often difficult for patients, families and healthcare providers, because hospice or end of life care can be seen as a failure of healthcare teams or as patients having given up. Nurses' role in this transition is to provide care, educate and advocate for patients, and encourage reflection on the implications of end of life. Providers face challenges in identifying when end of life begins, impaired communication in healthcare teams and feelings of guilt. Patients and families must come to terms with the idea of death while maintaining dignity. Ensuring older patients are included in discussions can improve their quality of life and sense of dignity. Nurses can help by enabling conversations about the end of life to take place early on, improving communication between staff, and encouraging reflection by healthcare providers. PMID- 24067045 TI - Factors affecting residents' sleep in care homes. AB - AIM: The aim of this study was to undertake a detailed exploration of sleep in the context of 24 hours in a care home environment, exploring the subjective experience of residents and the perceptions of staff. METHOD: Qualitative research in four care homes for older people consisting of semi-structured interviews and ethnographic observations. Interviews were conducted with 38 residents and 39 staff, and were analysed using a grounded theory approach. FINDINGS: The findings have highlighted some challenges and opportunities for developing practice in care homes to improve residents' sleep. In addition to pain and physical disabilities, the physical environment and practices in care homes can affect residents' sleep and night-time experience. CONCLUSION: Improving our understanding of residents' and staff's experiences at night in care homes can inform the development of good practice in night-time care and contribute to a positive culture of person-centred care. PMID- 24067046 TI - Prevention and treatment of acute ischaemic stroke. AB - When someone has a stroke it can cause death or severe disability. However, advances in treatment have changed the way professionals need to respond. Nurses must recognise the signs of stroke and understand why prompt action can save more of the brain. They also need to recognise and respond appropriately to transient ischaemic attacks, which can warn of impending stroke, and to support people in reducing their individual risk. PMID- 24067047 TI - Driving force. PMID- 24067048 TI - Age-period-cohort analysis for trends in body mass index in Ireland. AB - BACKGROUND: Obesity is a growing problem worldwide and can often result in a variety of negative health outcomes. In this study we aim to apply partial least squares (PLS) methodology to estimate the separate effects of age, period and cohort on the trends in obesity as measured by body mass index (BMI). METHODS: Using PLS we will obtain gender specific linear effects of age, period and cohort on obesity. We also explore and model nonlinear relationships of BMI with age, period and cohort. We analysed the results from 7,796 men and 10,220 women collected through the SLAN (Surveys of Lifestyle, attitudes and Nutrition) in Ireland in the years 1998, 2002 and 2007. RESULTS: PLS analysis revealed a positive period effect over the years. Additionally, men born later tended to have lower BMI (-0.026 kg . m(-2) yr(-1), 95% CI: -0.030 to -0.024) and older men had in general higher BMI (0.029 kg . m(-2) yr(-1), 95% CI: 0.026 to 0.033). Similarly for women, those born later had lower BMI (-0.025 kg . m(-2) yr(-1), 95% CI: -0.029 to -0.022) and older women in general had higher BMI (0.029 kg . m(-2) yr(-1), 95% CI: 0.025 to 0.033). Nonlinear analyses revealed that BMI has a substantial curvilinear relationship with age, though less so with birth cohort. CONCLUSION: We notice a generally positive age and period effect but a slightly negative cohort effect. Knowing this, we have a better understanding of the different risk groups which allows for effective public intervention measures to be designed and targeted for these specific population subgroups. PMID- 24067049 TI - Surgical pathology and the diagnosis of invasive visceral yeast infection: two case reports and literature review. AB - Invasive mycoses are life-threatening opportunistic infections that have recently emerged as a cause of morbidity and mortality following general and gastrointestinal surgery.Candida species are the main fungal strains of gut flora. Gastrointestinal tract surgery might lead to mucosal disruption and cause Candida spp. to disseminate in the bloodstream.Here we report and discuss the peculiar clinical and morphological presentation of two cases of gastrointestinal Candida albicans lesions in patients who underwent abdominal surgery.Although in the majority of cases reported in the literature, diagnosis was made on the basis of microbiological criteria, we suggest that morphological features of fungi in histological sections of appropriate surgical specimens could help to detect the degree of yeast colonization and identify patients at risk of developing severe abdominal Candida infection.Better prevention and early antifungal treatments are highlighted, and relevant scientific literature is reviewed. PMID- 24067050 TI - Influence of bracket-slot design on the forces released by superelastic nickel titanium alignment wires in different deflection configurations. AB - OBJECTIVE: To evaluate how different bracket-slot design characteristics affect the forces released by superelastic nickel-titanium (NiTi) alignment wires at different amounts of wire deflection. MATERIALS AND METHODS: A three-bracket bending and a classic-three point bending testing apparatus were used to investigate the load-deflection properties of one superelastic 0.014-inch NiTi alignment wire in different experimental conditions. The selected NiTi archwire was tested in association with three bracket systems: (1) conventional twin brackets with a 0.018-inch slot, (2) a self-ligating bracket with a 0.018-inch slot, and (3) a self-ligating bracket with a 0.022-inch slot. Wire specimens were deflected at 2 mm and 4 mm. RESULTS: Use of a 0.018-inch slot bracket system, in comparison with use of a 0.022-inch system, increases the force exerted by the superelastic NiTi wires at a 2-mm deflection. Use of a self-ligating bracket system increases the force released by NiTi wires in comparison with the conventional ligated bracket system. NiTi wires deflected to a different maximum deflection (2 mm and 4 mm) release different forces at the same unloading data point (1.5 mm). CONCLUSION: Bracket design, type of experimental test, and amount of wire deflection significantly affected the amount of forces released by superelastic NiTi wires (P<.05). This phenomenon offers clinicians the possibility to manipulate the wire's load during alignment. PMID- 24067051 TI - A patient with protrusion and multiple missing teeth treated with autotransplantation and space closure. AB - OBJECTIVE: To present a patient treated with submerging autotransplantation (SA) of an immature premolar and subsequent orthodontic space closure (OSC) and to report a 10-year follow-up result. CASE AND METHOD: A 10-year-old boy had multiple missing premolars with an asymmetric pattern (maxillary right first and second premolars, teeth 14 and 15; maxillary left second premolar, tooth 25; and mandibular right second premolar, tooth 45). After considering several treatment options, tooth 35 with immature root development underwent SA into the missing site of tooth 15 at a depth 5 mm below the occlusal plane and was stabilized with sutures to create a symmetric missing condition of the premolars in the four quadrants. RESULTS: Three months after autotransplantation, spontaneous eruption of the transplanted tooth was observed. Nine months after autotransplantation, presence of the lamina dura of the transplanted tooth was confirmed with a periapical radiograph. Active orthodontic treatment was initiated to reduce lip protrusion by closing the missing spaces of teeth 14, 25, 35, and 45 and to correct dental midline deviation. After 33 months of active orthodontic treatment, Class I canine and molar relationships were obtained. During the 10 year follow-up, the pulp vitality of the transplanted tooth was maintained without any pathologic findings, including root resorption or pulp canal obliteration. CONCLUSIONS: In a patient with lip protrusion and multiple congenitally missing premolars with an asymmetric pattern, SA of one premolar from the normal quadrant into the quadrant missing two premolars with subsequent OSC of the missing sites of the other premolars can be an effective treatment modality. PMID- 24067052 TI - Severe unilateral scissor bite and bimaxillary protrusion treated by horseshoe Le Fort I osteotomy combined with mid-alveolar osteotomy. AB - This report describes an orthognathic surgical case employing horseshoe Le Fort I osteotomy (HLFO) combined with mid-alveolar osteotomy and bilateral sagittal split ramus osteotomy (BSSRO) for a patient with severe unilateral scissor bite and bimaxillary protrusion. A female patient (aged 26 years, 2 months) presented with a chief complaint of dysmasesis caused by scissor bite on the right side. The clinical examination revealed difficulty in lip closure and a convex profile. Overerupted right maxillary premolars and molars and lingual tipping of the right mandibular premolars and molars were indicated before treatment. After 3 months of presurgical orthodontic treatment, two-jaw surgery involving a combination of HLFO with mid-alveolar osteotomy and BSSRO was performed. A good interdigitation in the right side was established by superior-posterior-medial movement of the dento-alveolar segment of the maxilla. Next, both the maxilla and mandible were moved superiorly and posteriorly to correct the improper lip protrusion, thereby improving the patient's profile. Our results suggest that this new orthognathic surgery technique-achieved by combining HLFO with mid-alveolar osteotomy and BSSRO-is effective for adult patients exhibiting severe unilateral scissor bite and bimaxillary protrusion. PMID- 24067053 TI - Psoriatic arthritis: advances in pharmacotherapy based on molecular target. AB - The progress on the improved understanding of disease pathogenesis and molecular biology has changed the understanding of disease profiles, emphasizing aspects that simple clinical observation could not identify, and demarcating differences between clinical pictures that seemed to overlap. An example of this spectacular evolution is represented by psoriatic arthritis (PsA). This increase of knowledge on pathogenesis has led to an important impact on therapeutic approach. Therapies are now taken into account because their precise target is known. The authors describe treatment guidelines and revisit traditional therapies as well as innovative therapies in PsA. PMID- 24067054 TI - A seven-year storage report of good manufacturing practice-grade naked plasmid DNA: stability, topology, and in vitro/in vivo functional analysis. AB - The great interest for naked plasmid DNA in gene therapy studies is reflected by the fact that it is currently used in 18% of all gene therapy trials. Therefore, validation of topology and functionality of DNA resulting from its long-term stability is an essential requirement for safe and effective gene transfer. To this aim, we analyzed the stability of good manufacturing practice-grade pCMVbeta reporter plasmid DNA by capillary gel electrophoresis, agarose gel electrophoresis, and atomic force microscopy. The plasmid DNA was produced for a clinical gene transfer study started in 2005 and was stored for meanwhile 7 years under continuously monitored conditions at -20 degrees C. The stability of plasmid DNA was monitored by LacZ transgene expression functional assays performed in vitro and in vivo on the 7-year-old plasmid DNA samples compared with plasmid batches newly produced in similar experimental conditions and quality standards. The analyses revealed that during the overall storage time and conditions, the proportion of open circular and supercoiled or covalently closed circular forms is conserved without linearization or degradation of the plasmid. The in vitro transfection and the in vivo jet-injection of DNA showed unaltered functionality of the long-stored plasmid. In summary, the 7-year-old and the newly produced plasmid samples showed similar topology and expression performance. Therefore, our stable storage conditions are effective to preserve the integrity of the DNA to be used in clinical studies. This is an important prerequisite for the long-term performance of gene transfer materials used in trials of long duration as well as of the reference material used in standardization procedures and assays. PMID- 24067055 TI - Evolution of environmental exposure science: using breath-borne biomarkers for "discovery" of the human exposome. AB - According to recent research, 70-90% of long-term latency and chronic human disease incidence is attributable to environmental (human exposome) factors through the gene-environment interaction. Environmental exposure science is now embarking on a new "discovery" path for decoding the human exposome using biomarkers in breath and other biological media. PMID- 24067056 TI - Selective plasmon enhancement of the 1.08 MUm Nd3+ laser Stark transition by tailoring Ag nanoparticles chains on a PPLN Y-cut. AB - Selective photoluminescence enhancement of the specific Nd(3+) Stark transition for which laser gain has been obtained in Nd(3+)/LiNbO3 is demonstrated by means of plasmonic resonances with the appropriate symmetry configuration. By using the nonpolar Y-cut of a periodically poled LiNbO3 crystal as platform for photoreduction of metallic nanostructures, periodically distributed chains of Ag nanoparticles oriented parallel to the ferroelectric c-axis are obtained. This alternative metallic nanostructure configuration supports the resonance between the localized surface plasmon and exclusively the pi-polarized Stark laser line of Nd(3+) ions at 1.08 MUm, while maintaining the remaining crystal field transitions unchanged. The work provides the experimental proof on how plasmonic based optical antennas can be used to influence selectively rare earth optical Stark transitions to improve the performance of solid state laser gain media. PMID- 24067057 TI - NSAID is inversely associated with asymptomatic gastric ulcer: local health examination data from the Korean National Health Insurance Corporation. AB - BACKGROUND. Silent peptic ulcer has been considered to be associated with nonsteroidal anti-inflammatory drug (NSAID). The recent studies have reported no relationship between them. AIM. We attempted to investigate an association between asymptomatic peptic ulcer and NSAID in Korean adults. METHODS. The subjects were enrolled from participants visiting Myongji Hospital for health examination program of the Korean National Health Insurance Corporation. The questionnaires were designed to investigate individual medical information and gastroduodenal symptoms. RESULTS. From May 2005 to March 2009, 5459 participants were enrolled and 299 participants were excluded. Of 5160 participants, 3144 (60.9%) participants were asymptomatic and 424 (8.2%) participants had peptic ulcer. Among 3144 asymptomatic participants, NSAID-taking participants had the odds ratio of 1.4 [95% confidence interval (CI): 0.7-2.6, p = 0.339] for the risk of peptic ulcer. Among 424 peptic ulcer patients, 247 (58.3%) were asymptomatic. They had lower prevalence of NSAID use (4.9% vs. 14.7%). The asymptomatic gastric ulcer patients had smaller size and more frequent healing stage than the symptomatic gastric ulcer patients. In multivariable analysis of 424 peptic ulcer patients, NSAID patients had the odds ratio of 0.249 (95%CI: 0.115-0.536, p < 0.05) for asymptomatic peptic ulcer. In subgroup analysis of 284 gastric ulcer patients, NSAID-taking patients had the odds ratio of 0.263 (95% CI: 0.105-0.657, p = 0.004) for asymptomatic peptic ulcer. CONCLUSION. NSAID has an inverse association with asymptomatic patients with gastric peptic ulcer, but has no association with gastroduodenal symptoms in duodenal ulcer patients. These suggest that NSAID may be associated with gastroduodenal symptoms rather than masking symptoms, at least in gastric ulcer patients. PMID- 24067058 TI - Primary angiosarcoma of the small intestine with metastasis to the liver: a case report and review of the literature. AB - Angiosarcoma is a rare disease with a poor prognosis; significantly, patients with intestinal angiosarcomas who survive over 1 year after diagnosis are extraordinarily rare. This article describes the case of a 33-year-old gentleman who presented with abdominal pain of 4 months duration, which had increased in severity 2 weeks prior to presentation. After a complicated diagnostic and therapeutic process, the diagnosis of primary angiosarcoma of the small intestine with metastasis to the liver was made by pathological and immunohistochemical examinations. We reviewed previous cases of angiosarcoma described in the English literature to determine their risk factors, diagnosis and treatment, and we found that angiosarcoma is extremely rare, especially in the small intestine. To the best of our knowledge, this may be the youngest case of primary angiosarcoma of the small intestine with metastasis to the liver reported in the English literature. PMID- 24067059 TI - Induced pluripotent stem cell-derived neural stem cells: new hope for stroke? AB - Human induced pluripotent stem cells (iPSCs) have attracted increasing interest in the field of ischemic stroke therapy, due to the lack of ethical concerns and reduced risk of immune rejection. However, the safety and efficiency of the donor iPSC derivates in the ischemic brain challenged the therapeutic efficacy of iPSC transplantation. Studies have focused on improving the methods to induce neural derivates from iPSCs and on trying to determine how these cells and the host ischemic environment influence each other. A recent study by Yuan and colleagues reported that neural stem cells induced from human iPSCs using retinoic acid and serum-free medium showed stable neural phenotype. After acute transplantation into the ischemic stroke model, these cells survived, migrated into the ischemic penumbra, differentiated into mature neural cells and showed beneficial effects on functional recovery. Their findings take a clear step towards the clinical application of human iPSCs for ischemic stroke. A wide range of careful studies may be raised from their work, from basic research to preclinic, to develop the best therapy for ischemic stroke. PMID- 24067060 TI - Molecular simulations of polycation-DNA binding exploring the effect of peptide chemistry and sequence in nuclear localization sequence based polycations. AB - Gene therapy relies on the delivery of DNA into cells, and polycations are one class of vectors enabling efficient DNA delivery. Nuclear localization sequences (NLS), cationic oligopeptides that target molecules for nuclear entry, can be incorporated into polycations to improve their gene delivery efficiency. We use simulations to study the effect of peptide chemistry and sequence on the DNA binding behavior of NLS-grafted polycations by systematically mutating the residues in the grafts, which are based on the SV40 NLS (peptide sequence PKKKRKV). Replacing arginine (R) with lysine (K) reduces binding strength by eliminating arginine-DNA interactions, but placing R in a less hindered location (e.g., farther from the grafting point to the polycation backbone) has surprisingly little effect on polycation-DNA binding strength. Changing the positions of the hydrophobic proline (P) and valine (V) residues relative to the polycation backbone changes hydrophobic aggregation within the polycation and, consequently, changes the conformational entropy loss that occurs upon polycation DNA binding. Since conformational entropy loss affects the free energy of binding, the positions of P and V in the grafts affect DNA binding affinity. The insight from this work guides synthesis of polycations with tailored DNA binding affinity and, in turn, efficient DNA delivery. PMID- 24067061 TI - Acute endophthalmitis after intravitreal injection and preventive effect of preoperative topical antibiotics. AB - PURPOSE: To evaluate the incidence, causative organism, clinical features, and visual outcome of acute endophthalmitis following intravitreal injection and to report the clinical outcome of patients receiving preinjection antibiotics for the prevention of endophthalmitis. METHODS: For all intravitreal triamcinolone acetonide, bevacizumab, ranibizumab, and C3F8 gas injections performed in our outpatient clinic between June 2008 and November 2012, the number of injections, indications, types of administered drugs, and methods of injection were investigated. A retrospective chart review was performed comparing patients with self-administration of antibiotic eye drops for 3 days before injection (n=8649 injections), and patients those who received no pretreatment with antibiotics (n=8683 injections). Cases of suspected endophthalmitis after intravitreal injection during this period were identified and reviewed retrospectively. RESULTS: The total number of intravitreal injections was 17,332. The incidence of acute endophthalmitis for all intravitreal injections was 0.000% (0/849) for triamcinolone acetonide, 0.022% (2/9,125) for bevacizumab, 0.000% (0/7,061) for ranibizumab, and 0.337% (1/297) for C3F8 gas injections. The overall rate of intravitreal injection-related endophthalmitis with the use of topical antibiotics given 3 days before injection was no less statistically significant compared with that of no antibiotics. Staphylococcus species was confirmed in the bacterial culture of one eye with acute endophthalmitis. After early vitrectomy and intravitreal antibiotic injection, one eye maintained vision, but the other eye developed phthisis. CONCLUSIONS: All 3 endophthalmitis patients had not taken prophylactic preinjection topical antibiotics, but the difference in the rates of endophthalmitis between those who received a multiday course of preinjection antibiotics and those who did not was not statistically significant. The rate of endophthalmitis after intravitreal injection using aseptic techniques in the clinical practice setting is similar with or without the use of preinjection antibiotics. Preinjection antibiotic use confers no additional benefit in the treatment of endophthalmitis compared to without preinjection antibiotics. PMID- 24067062 TI - Difference in blood pressure response to ACE-Inhibitor monotherapy between black and white adults with arterial hypertension: a meta-analysis of 13 clinical trials. AB - BACKGROUND: Among African-Americans adults, arterial hypertension is both more prevalent and associated with more complications than among white adults. Hypertension is also epidemic among black adults in sub-Saharan Africa. The treatment of hypertension among black adults may be complicated by lesser response to certain classes of anti-hypertensive agents. METHODS: We systematically searched literature for clinical trials of ACE-inhibitors among hypertensive adults comparing blood pressure response between whites and blacks. Meta-analysis was performed to determine the difference in systolic and diastolic blood pressure response. Further analysis including meta-regressions, funnel plots, and one-study-removed analyses were performed to investigate possible sources of heterogeneity or bias. RESULTS: In a meta-analysis of 13 trials providing 17 different patient groups for evaluation, black race was associated with a lesser reduction in systolic (mean difference: 4.6 mmHg (95% CI 3.5-5.7)) and diastolic (mean difference: 2.8 mmHg (95% CI 2.2-3.5)) blood pressure response to ACE-inhibitors, with little heterogeneity. Meta-regression revealed only ACE-inhibitor dosage as a significant source of heterogeneity. There was little evidence of publication bias. CONCLUSIONS: Black race is consistently associated with a clinically significant lesser reduction in both systolic and diastolic blood pressure to ACE-inhibitor therapy in clinical trials in the USA and Europe. In black adults requiring monotherapy for uncomplicated hypertension, drugs other than ACE-inhibitors may be preferred, though the proven benefits of ACE-inhibitors in some sub-groups and the large overlap of response between blacks and whites must be remembered. These data are particularly important for interpretation of clinical drug trials for hypertensive black adults in sub Saharan Africa and for the development of treatment recommendations in this population. PMID- 24067063 TI - Household preferences for cataract surgery in rural India: a population-based stated preference survey. AB - PURPOSE: Cataract surgery is provided both by the private and public sector in India. Free cataract surgery (with minimal amenities) funded through subsidies/reimbursements by government and non-governmental organizations is provided for underprivileged and poor patients, especially in rural areas. However, no evidence exists whether this free surgery is used by those who could afford to pay and are willing to pay for cataract surgery. So, understanding willingness to pay and preferences for cataract surgery in the population can have important policy implications. METHODS: A cross-sectional survey of 1272 households from four randomly drawn rural household clusters in Theni district, Tamilnadu state, India was conducted. Respondents from households were presented with scenarios (with and without free surgery availability) to elicit their willingness to pay and preferences for cataract surgery. RESULTS: Of those willing to undergo surgery; 696 (57%) were willing to undergo paid surgery, 148 (12%) only free surgery, and 378 (31%) paid surgery if no free surgery was available. In a multinomial logit model, household wealth measures, income variables and family history of cataract surgery largely distinguished the preferences. Good understanding of cataract and its intervention only marginally influenced preference for paid surgery. CONCLUSION: A larger number of people were willing to pay when free surgery was not available. Free surgery may be crowding out surgery for which costs can be recovered. With non-cataract causes of blindness in the Indian population also requiring attention, this has implications for allocation of scarce resources. PMID- 24067064 TI - Application of computed tomography to assess the effect of egg yolk ratio on body composition in chickens of different genotype and gender at hatch and during the rearing period. AB - 1. Computed tomography was used for the in vivo determination of yolk ratio in 7000 domestic hen eggs, originated from two markedly different genotypes, in order to examine the effect of egg yolk ratio, gender and genotype on the development of hatched chicks. 2. Eggs with extremely low, average and extremely high yolk ratio were chosen for further investigation (n = 350 in each group in both genotypes). After incubating the selected eggs, hatched birds were reared and slaughtered at 11 weeks of age. 3. The yolk ratio of eggs significantly affected the body composition of the chickens at hatching and during rearing to 8 9 weeks of age. 4. Chickens of a genotype selected partly for weight gain had significantly higher live weight from hatching to the end of the rearing period and had better slaughter characteristics than those of the dual purpose TETRA-H genotype. 5. At hatching, only the dry matter content of the body was affected by the gender of the birds. The effect of gender on the live weight and body composition of chickens was evident from the 5th week of age to the time of slaughter. 6. It was concluded that eggs with a low yolk ratio were most beneficial for broiler production, because chickens hatched from these eggs had the highest slaughter weight and muscle index and the lowest fat index for their body mass. PMID- 24067065 TI - Validity of ultrasound muscle thickness measurements for predicting leg skeletal muscle mass in healthy Japanese middle-aged and older individuals. AB - BACKGROUND: The skeletal muscle mass of the lower limb plays a role in its mobility during daily life. From the perspective of physical resources, leg muscle mass dominantly decreases after the end of the fifth decade. Therefore, an accurate estimate of the muscle mass is important for the middle-aged and older population. The present study aimed to clarify the validity of ultrasound muscle thickness (MT) measurements for predicting leg skeletal muscle mass (SM) in the healthy Japanese middle-aged and older population. FINDINGS: MTs at four sites of the lower limb and the bone-free lean tissue mass (LTM) of the right leg were determined using brightness-mode ultrasonography and dual-energy X-ray absorptiometry (DXA), respectively, in 44 women and 33 men, 52- to 78-years old. LTM was used as a representative variable of leg skeletal muscle mass. In the model-development group (30 women and 22 men), regression analysis produced an equation with R2 and standard error of the estimate (SEE) of 0.958 and 0.3 kg, respectively: LTM (kg) = 0.01464 * (MTSUM*L) (cm2) - 2.767, where MTSUM is the sum of the product of MTs at four sites, and L is length of segment where MT is determined. The estimated LTM (7.0 +/- 1.7 kg) did not significantly differ from the measured LTM (7.0 +/- 1.7 kg), without a significant systematic error on a Bland-Altman plot. The application of this equation for the cross-validation group (14 women and 11 men) did not yield a significant difference between the measured (7.2 +/- 1.6 kg) or estimated (7.2 +/- 1.6 kg) LTM and systematic error. CONCLUSION: The developed prediction equation may be useful for estimating the lean tissue mass of the lower extremity for the healthy Japanese middle-aged and older population. PMID- 24067067 TI - Photoactivity of mono- and dicarbonyl complexes of ruthenium(II) bearing an N,N,S donor ligand: role of ancillary ligands on the capacity of CO photorelease. AB - One monocarbonyl and one dicarbonyl complex of ruthenium(II), namely, [Ru(Cl)(CO)(qmtpm)(PPh3)]BF4 (2) and [Ru(Cl)(CO)2(qmtpm)]ClO4 (3), derived from the tridentate ligand 2-quinoline-N-(2'-methylthiophenyl)methyleneimine (qmtpm) have been synthesized and structurally characterized. The qmtpm ligand binds in a meridional fashion in these carbonyl complexes, and in 3, the two carbon monoxide (CO) ligands are cis to each other. Solutions of 2 in ethanol, chloroform, or acetonitrile rapidly release CO upon illumination with low-power (3-15 mW) light in the 300-450 nm range. Loss of CO from 2 brings about a dramatic color change from yellow to magenta because of the formation of [Ru(Cl)(MeCN)(qmtpm)(PPh3)]BF4 (4). In acetonitrile, photorelease of CO from 3 under 360 nm light occurs in two steps, and the violet photoproduct [Ru(Cl)(MeCN)2(qmtpm)](+) upon reaction with Ag(+) and PPh3 affords red [Ru(MeCN)2(qmtpm)(PPh3)](ClO4)2 (5). The structure of 5 has also been determined by X-ray crystallography. Reduced myoglobin assay confirms that 2 and 3 act as photoactive CO-releasing molecules (photoCORMs) that deliver 1 and 2 equiv of CO, respectively. The results of density functional theory (DFT) and time-dependent DFT studies confirm that electronic transitions from molecular orbitals with predominantly Ru-CO character to ligand-based pi* orbitals facilitate CO release from these two photoCORMs. Complexes 2-5 have provided an additional opportunity to analyze the roles of the ancillary ligands, namely, PPh3, Cl(-), and MeCN, in shifting the positions of the metal-to-ligand charge-transfer bands and the associated sensitivity of the two photoCORMs to different wavelengths of light. Collectively, the results provide helpful hints toward the future design of photoCORMs that release CO upon exposure to visible light. PMID- 24067066 TI - Physical characterization of the manganese-sensing pneumococcal surface antigen repressor from Streptococcus pneumoniae. AB - Transition metals, including manganese, are required for the proper virulence and persistence of many pathogenic bacteria. In Streptococcus pneumoniae (Spn), manganese homeostasis is controlled by a high-affinity Mn(II) uptake complex, PsaBCA, and a constitutively expressed efflux transporter, MntE. psaBCA expression is transcriptionally regulated by the DtxR/MntR family metalloregulatory protein pneumococcal surface antigen repressor (PsaR) in Spn. Here, we present a comprehensive analysis of the metal and DNA binding properties of PsaR. PsaR is a homodimer in the absence and presence of metals and binds two manganese or zinc atoms per protomer (four per dimer) in two pairs of structurally distinct sites, termed site 1 and site 2. Site 1 is likely filled with Zn(II) in vivo (K(Zn1) >= 1013 M-1; K(Mn1) ~ 108 M-1). The Zn(II)-site 1 complex adopts a pentacoordinate geometry as determined by X-ray absorption spectroscopy containing a single cysteine and appears to be analogous to the Cd(II) site observed in Streptococcus gordonii ScaR. Site 1 is necessary but not sufficient for full positive allosteric activation of DNA operator binding by metals as measured by DeltaGc, the allosteric coupling free energy, because site 1 mutants show an intermediate DeltaGc. Site 2 is the primary regulatory site and governs specificity for Mn(II) over Zn(II) in PsaR, where DeltaGc(Zn,Mn) >> DeltaGc(Zn,Zn) despite the fact that Zn(II) binds site 2 with an affinity 40-fold higher than that of Mn(II); i.e., K(Zn2) > K(Mn2). Mutational studies reveal that Asp7 in site 2 is a critical ligand for Mn(II)-dependent allosteric activation of DNA binding. These findings are discussed in the context of other well-studied DtxR/MntR Mn(II)/Fe(II) metallorepressors. PMID- 24067069 TI - Large-scale multiple testing in genome-wide association studies via region specific hidden Markov models. AB - BACKGROUND: Identifying genetic variants associated with complex human diseases is a great challenge in genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNPs) arising from genetic background are often dependent. The existing methods, i.e., local index of significance (LIS) and pooled local index of significance (PLIS), were both proposed for modeling SNP dependence and assumed that the whole chromosome follows a hidden Markov model (HMM). However, the fact that SNP data are often collected from separate heterogeneous regions of a single chromosome encourages different chromosomal regions to follow different HMMs. In this research, we developed a data-driven penalized criterion combined with a dynamic programming algorithm to find change points that divide the whole chromosome into more homogeneous regions. Furthermore, we extended PLIS to analyze the dependent tests obtained from multiple chromosomes with different regions for GWAS. RESULTS: The simulation results show that our new criterion can improve the performance of the model selection procedure and that our region specific PLIS (RSPLIS) method is better than PLIS at detecting disease-associated SNPs when there are multiple change points along a chromosome. Our method has been used to analyze the Daly study, and compared with PLIS, RSPLIS yielded results that more accurately detected disease-associated SNPs. CONCLUSIONS: The genomic rankings based on our method differ from the rankings based on PLIS. Specifically, for the detection of genetic variants with weak effect sizes, the RSPLIS method was able to rank them more efficiently and with greater power. PMID- 24067071 TI - A flow visualization model of duodenogastric reflux after esophagectomy with gastric interposition. AB - BACKGROUND: Our goal was to verify surgical factors that affect duodenogastric reflux (DGR) after esophagectomy through the use of a flow visualization model that would mimic an intrathoracic gastric tube. METHODS: Transparent gastric tube models for different routes (retrosternal space [RS] and posterior mediastinum [PM]) were fabricated. Various distal pressures were applied to the experimental model filled with water, and the flow was recorded with a high-speed camera. The volume and maximum height of the refluxate through the pylori of two different sizes (7.5 mm, 15 mm) in two different postures (upright, semi-Fowler) was measured by analyzing the video clips. RESULTS: For the large pylorus setting, when the pressures of 20, 30, and 40 mmHg were applied in the upright position, the volumes of the refluxate in the RS/PM tubes were 87.7 +/- 1.1/96.4 +/- 1.7 mL, 150.8 +/- 1.1/158.0 +/- 3.2 mL, and 156.8 +/- 3.3/198.0 +/- 4.7 mL (p < 0.05), and the maximum heights were 101.6 +/- 4.8/113.4 +/- 2.9 mm, 151.4 +/- 2.2/165.4 +/- 1.5 mm, and 166.1 +/- 1.7/193.7 +/- 6.6 mm (p < 0.05). The data for the small pylorus setting or in the semi-Fowler position showed similar tendencies. For any given route, posture or pressure setting, DGR in the large pylorus model was definitively higher than that for small one. CONCLUSIONS: This fluid mechanics study demonstrates posterior mediastinal gastric interposition or pyloric drainage procedure, or both, is associated with high reflux of duodenal contents. PMID- 24067070 TI - Dysregulation of the complement cascade in the hSOD1G93A transgenic mouse model of amyotrophic lateral sclerosis. AB - BACKGROUND: Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS); however, a comprehensive examination of complement expression in this disease has not been performed. This study therefore aimed to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5 and CD88) and regulators (CD55 and CD59a) in the lumbar spinal cord of hSOD1(G93A) mice during defined disease stages. METHODS: hSOD1(G93A) and wild-type mice were examined at four different ages of disease progression. mRNA and protein expression of complement components and regulators were examined using quantitative PCR, western blotting and ELISA. Localisation of complement components within lumbar spinal cord was investigated using immunohistochemistry. Statistical differences between hSOD1(G93A) and wild type mice were analysed using a two-tailed t-test at each stage of disease progression. RESULTS: We found several early complement factors increased as disease progressed, whilst complement regulators decreased; suggesting overall increased complement activation through the classical or alternative pathways in hSOD1(G93A) mice. CD88 was also increased during disease progression, with immunolocalisation demonstrating expression on motor neurons and increasing expression on microglia surrounding the regions of motor neuron death. CONCLUSIONS: These results indicate that local complement activation and increased expression of CD88 may contribute to motor neuron death and ALS pathology in the hSOD1(G93A) mouse. Hence, reducing complement-induced inflammation could be an important therapeutic strategy to treat ALS. PMID- 24067072 TI - Somatic and reproductive development in pre-pubertal mice treated with cyclophosphamide and subsequent estrogen replacement. AB - We tested the hypothesis that chemotherapy would prevent the expected pubertal development of uterus, ovaries, and long bones, and that estrogen replacement subsequent to treatment with chemotherapy would restore uterine and bone development to expected sizes. Pre-pubertal female C57BL/6J mice (n = 78) were assigned to receive placebo (controls), 200 mg/kg (group A), or 120 mg/kg (group B) of cyclophosphamide (CTX) on postnatal day 18. Mice were subsequently randomized to receive estradiol placebo or long-release estradiol pellet insertion on day 22 (early estradiol dose), day 45 (mid estradiol dose), or day 67 (late estradiol dose) of life. Body weight and length, uterine and ovarian weight, and right femur length and weight were measured. Mice treated with CTX had shorter and lighter femurs and lighter ovaries than controls (13.46 cm +/- 1.51 cm vs. 15.00 cm +/- 1.10 cm, 57.70 mg +/- 9.71 mg vs. 65.30 mg +/- 3.68 mg, and 5.16 mg +/- 3.00 mg vs. 10.05 mg +/- 2.31 mg, respectively; p < 0.05). Mice receiving estrogen replacement had a larger average body weight, BMI, and uterine weight than those that received placebo estrogen (19.56 g +/- 1.82 g vs. 18.10 g +/- 2.08 g, 26.53 g/cm(2) +/- 2.91 g/cm(2) vs. 23.47 g/cm(2) +/- 3.06 g/cm(2), 101.19 mg +/- 41.69 mg vs. 50.00 mg +/- 9.49 mg, respectively; p < 0.05). Cyclophosphamide treatment in pre-pubertal mice negatively affected femur and reproductive development. Estrogen treatment restored expected uterine development by maturity, regardless of the timing of administration. However, there was no similar recovery of femur length and bone mass was only partially recovered. PMID- 24067073 TI - The devil's in the biorepository details. PMID- 24067074 TI - Tramadol and acetaminophen combination for chronic non-cancer pain. AB - INTRODUCTION: There is some evidence to support the use of tramadol in chronic non-cancer pain, especially osteoarthritis pain, but modest analgesic activity is tempered by adverse effects. Combination of a lower dose of tramadol and acetaminophen is postulated to act synergistically, potentially reducing adverse effects without reduction in analgesic efficacy. AREAS COVERED: This review discusses use of tramadol in chronic non-cancer pain and the pharmacokinetics/pharmacodynamics of tramadol and acetaminophen and when combined. Existing published controlled trial data for the effectiveness (efficacy and adverse effects) of tramadol/acetaminophen combination therapy in chronic non-cancer pain is critically appraised. EXPERT OPINION: Combination therapy with tramadol and acetaminophen reduces pain outcomes in several types of chronic non-cancer pains. However, the effect is limited and is based on short duration trials and is associated with a significant adverse effect profile. There are few data comparing other pharmacological options and also sparse evidence to confirm benefits of the putative synergism of tramadol with acetaminophen. Nevertheless, other medications used for these chronic pains also have appreciable side effects and the combination may have a role to play. Increasing incidence of tramadol-associated deaths may lead to legislative changes that could alter prescription trends of tramadol-based medication. PMID- 24067075 TI - Differentiated effects of social participation components on suicidal ideation across age groups in South Korea. AB - BACKGROUND: Suicide among adults in the Korean population merits study to improve the understanding of the salient risk and protective factors because suicide rates in Korea have increased dramatically over the past 20 years. However, the association between social participation and suicidal ideation is poorly understood. Thus, this study aimed to identify the components of social participation in Korean society and to examine the processes through which the components of social participation influence the degree of suicidal ideation people experience across age groups. METHODS: This study used survey data from the 2010 Seoul Welfare Panel Study. The sample population was restricted to adults aged 20 or older and was categorised into three groups by respondents' ages. The groups were defined as 'young adults' (aged 20-39), 'middle-aged adults' (aged 40-64) and 'the elderly' (age 65 or more). Three dimensions of social participation were identified by factor analysis--friendship network and hobby group, religious involvement, and instrumental social participation. RESULTS: In the young adult group, only instrumental participation was statistically significant (-0.10, p = 0.06). In the middle-aged adult group, only friendship network and hobby group had a strong association with suicidal ideation (-0.11, p = 0.01). Interestingly, for the elderly, religious involvement was related to suicidal ideation, but in a positive way (0.26, p = 0.02). CONCLUSION: The study results supported the theory that different components of social participation are associated with a lower risk of suicidal ideation in different stages of adulthood. PMID- 24067076 TI - Kinetic pathway of palladium nanoparticle sulfidation process at high temperatures. AB - A significant issue related to Palladium (Pd) based catalysts is that sulfur containing species, such as alkanethiols, can form a PdSx underlayer on nanoparticle surface and subsequently poison the catalysts. Understanding the exact reaction pathway, the degree of sulfidation, the chemical stoichiometry, and the temperature dependence of this process is critically important. Combining energy-filtered transmission electron microscopy (EFTEM), X-ray diffraction (XRD), and X-ray absorption spectroscopy experiments at the S K-, Pd K-, and L2,3 edges, we show the kinetic pathway of Pd nanoparticle sulfidation process with the addition of excess amount of octadecanethiol at different temperatures, up to 250 degrees C. We demonstrate that the initial polycrystalline Pd-oleylamine nanoparticles gradually become amorphous PdSx nanoparticles, with the sulfur atomic concentration eventually saturating at Pd/S = 66:34 at 200 degrees C. This final chemical stoichiometry of the sulfurized nanoparticles closely matches that of the crystalline P16S7 phase (30.4% S), albeit being structurally amorphous. Sulfur diffusion into the nanoparticle depends strongly on the temperature. At 90 degrees C, sulfidation remains limited at the surface of nanoparticles even with extended heating time; whereas at higher temperatures beyond 125 degrees C, sulfidation occurs rapidly in the interior of the particles, far beyond what can be described as a core-shell model. This indicates sulfur diffusion from the surface to the interior of the particle is subject to a diffusion barrier and likely first go through the grain boundaries of the nanoparticle. PMID- 24067077 TI - Biosensor based on ultrasmall MoS2 nanoparticles for electrochemical detection of H2O2 released by cells at the nanomolar level. AB - Monodispersed surfactant-free MoS2 nanoparticles with sizes of less than 2 nm were prepared from bulk MoS2 by simple ultrasonication and gradient centrifugation. The ultrasmall MoS2 nanoparticles expose a large fraction of edge sites, along with their high surface area, which lead to attractive electrocatalytic activity for reduction of H2O2. An extremely sensitive H2O2 biosensor based on MoS2 nanoparticles with a real determination limit as low as 2.5 nM and wide linear range of 5 orders of magnitude was constructed. On the basis of this biosensor, the trace amount of H2O2 released from Raw 264.7 cells was successfully recorded, and an efficient glucose biosensor was also fabricated. Since H2O2 is a byproduct of many oxidative biological reactions, this work serves as a pathway for the application of MoS2 in the fields of electrochemical sensing and bioanalysis. PMID- 24067078 TI - Testing a self-determination theory model of children's physical activity motivation: a cross-sectional study. AB - BACKGROUND: Understanding children's physical activity motivation, its antecedents and associations with behavior is important and can be advanced by using self-determination theory. However, research among youth is largely restricted to adolescents and studies of motivation within certain contexts (e.g., physical education). There are no measures of self-determination theory constructs (physical activity motivation or psychological need satisfaction) for use among children and no previous studies have tested a self-determination theory-based model of children's physical activity motivation. The purpose of this study was to test the reliability and validity of scores derived from scales adapted to measure self-determination theory constructs among children and test a motivational model predicting accelerometer-derived physical activity. METHODS: Cross-sectional data from 462 children aged 7 to 11 years from 20 primary schools in Bristol, UK were analysed. Confirmatory factor analysis was used to examine the construct validity of adapted behavioral regulation and psychological need satisfaction scales. Structural equation modelling was used to test cross sectional associations between psychological need satisfaction, motivation types and physical activity assessed by accelerometer. RESULTS: The construct validity and reliability of the motivation and psychological need satisfaction measures were supported. Structural equation modelling provided evidence for a motivational model in which psychological need satisfaction was positively associated with intrinsic and identified motivation types and intrinsic motivation was positively associated with children's minutes in moderate-to vigorous physical activity. CONCLUSIONS: The study provides evidence for the psychometric properties of measures of motivation aligned with self-determination theory among children. Children's motivation that is based on enjoyment and inherent satisfaction of physical activity is associated with their objectively assessed physical activity and such motivation is positively associated with perceptions of psychological need satisfaction. These psychological factors represent potential malleable targets for interventions to increase children's physical activity. PMID- 24067080 TI - Is empirical radioactive iodine therapy still a valid approach to patients with thyroid cancer and elevated thyroglobulin? AB - BACKGROUND: At present, empirical radioactive iodine therapy is recommended for patients with thyroid cancer and elevated thyroglobulin (Tg) after initial therapy when neck ultrasonography (US), chest computed tomography (CT), and 18 fluorodeoxyglucose positron emission tomography (FDG-PET) do not reveal metastases. The objective of this study was to determine whether empirical (131)I therapy is indeed useful in these patients. METHODS: Patients with papillary thyroid cancer submitted to total thyroidectomy followed by remnant ablation with (131)I in whom whole-body scanning at the time of ablation (WBS-ablation) did not reveal metastases and who had elevated Tg after initial therapy were selected. Included in the study were patients with basal Tg >2 ng/mL or Tg >5 ng/mL after stimulation with recombinant human thyrotropin or Tg >10 ng/mL after levothyroxine withdrawal for 4 weeks. All patients were first investigated by neck US and chest CT. FDG-PET/CT was performed in patients with negative US and CT. The final sample of this study consisted of patients with negative US, CT, and FDG-PET/CT. These patients received an activity of 100 mCi (131)I and were submitted to posttherapy WBS (RxWBS). RESULTS: Among the 24 patients receiving empirical (131)I therapy, no ectopic uptake was seen in 23 and mild uptake in the thyroid bed (<0.5%) in 15. Only one patient presented pulmonary metastases detected by RxWBS. Disease was observed in two other patients during short-term follow-up (mean 22 months), one with lymph node metastases diagnosed by a repeat US and one with bone metastases diagnosed by CT and FDG-PET scans. CONCLUSIONS: We conclude that RxWBS rarely reveals disease in patients with elevated Tg after ablation, but with negative findings on WBS-ablation, US, CT, and FDG-PET. In this situation, empirical (131)I therapy should be restricted to patients with documented progression of serum Tg. PMID- 24067079 TI - Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy. AB - Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5-58) with large deletions in the red/green opsin gene array. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed the existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM. PMID- 24067081 TI - Effect of volume expansion with hypertonic- and isotonic saline and isotonic glucose on sodium and water transport in the principal cells in the kidney. AB - BACKGROUND: The renal distal nephron plays an important role in the maintenance of sodium balance, extra cellular volume and blood pressure. The degree of water transport, via aquaporin2 water channels (AQP2), and sodium transport, via epithelial sodium channels (ENaC) in renal collecting duct principal cells are reflected by the level of urinary excretion of AQP2 (u-AQP2) and the gamma fraction of ENaC (u-ENaCgamma). The effects of an acute intravenous volume load with isotonic saline, hypertonic saline and glucose on u-AQP2, u-ENaCgamma and underlying mechanisms have never been studied in a randomized, placebo-controlled trial in healthy humans. METHODS: We studied the effects of 0.9% saline (23 ml/kg), 3% saline (7 ml/kg) and 5% glucose (23 ml/kg) on u-AQP2 and u-ENaCgamma, fractional sodium excretion (FENa), free water clearance (CH2O), and plasma concentrations of vasopressin (AVP), renin (PRC), angiotensin II (ANG II) and aldosterone (Aldo) in a randomized, crossover study of 23 healthy subjects, who consumed a standardized diet, regarding calories, sodium and fluid for 4 days before each examination day. RESULTS: After isotonic saline infusion, u-AQP2 increased (27%). CH2O and u-ENaCgamma were unchanged, whereas FENa increased (123%). After hypertonic saline infusion, there was an increase in u-AQP2 (25%), u-ENaCgamma (19%) and FENa (96%), whereas CH2O decreased (-153%). After isotonic glucose infusion, there was a decrease in u-AQP2 (-16%), ENaCgamma (-10%) and FENa (-44%) whereas CH2O increased (164%). AVP remained unchanged after isotonic saline and glucose, but increased after hypertonic saline (139%). PRC, AngII and p-Aldo decreased after isotonic and hypertonic saline infusion, but not after glucose infusion. CONCLUSIONS: Volume expansion with 3% and 0.9% saline increased u-AQP2, while isotonic glucose decreased u-AQP2. Infusion of hypertonic saline increased u-ENaCgamma, whereas u-ENaCgamma was not significantly changed after isotonic saline and tended to decrease after glucose. Thus, the transport of water and sodium is changed both via the aquaporin 2 water channels and the epithelial sodium channels during all three types of volume expansion to regulate and maintain water- and sodium homeostasis in the body. TRIAL REGISTRATION: Clinical Trial no: NCT01414088. PMID- 24067082 TI - Diverse plant extracts and trans-resveratrol inhibit biofilm formation and swarming of Escherichia coli O157:H7. AB - Infection with enterohemorrhagic Escherichia coli O157:H7 (EHEC) is a worldwide problem. Of the 498 plant extracts screened against EHEC, 16 inhibited the formation of biofilm of EHEC by >85% without inhibiting the growth of planktonic cells, and 14 plant extracts reduced the swarming motility of EHEC. The most active extract, Carex dimorpholepis, decreased swimming and swarming motilities and curli formation. Transcriptional analyses showed that the extract of C. dimorpholepis repressed curli genes, various motility genes, and AI-2 quorum sensing genes, which was corroborated by reduction in the production of fimbria, motility, and biofilm by EHEC. Trans-resveratrol at 10 MUg ml(-1) in the extract of C. dimorpholepis was found to be a new anti-biofilm compound against EHEC, but importantly, the extract of C. dimorpholepis and trans-resveratrol did not inhibit the fomation of biofilm in four commensal E. coli strains. Furthermore, the extract of C. dimorpholepis decreased the adhesion of EHEC cells to human epithelial cells without affecting the viability of these cells. PMID- 24067083 TI - Geographical variation and factors influencing modern contraceptive use among married women in Ethiopia: evidence from a national population based survey. AB - BACKGROUND: Modern contraceptive use persists to be low in most African countries where fertility, population growth, and unmet need for family planning are high. Though there is an evidence of increased overall contraceptive prevalence, a substantial effort remains behind in Ethiopia. This study aimed to identify factors associated with modern contraceptive use and to examine its geographical variations among 15-49 married women in Ethiopia. METHODS: We conducted secondary analysis of 10,204 reproductive age women included in the 2011 Ethiopia Demographic and Health Survey (DHS). The survey sample was designed to provide national, urban/rural, and regional representative estimates for key health and demographic indicators. The sample was selected using a two-stage stratified sampling process. Bivariate and multivariate logistic regressions were applied to determine the prevalence of modern contraceptive use and associated factors in Ethiopia. RESULTS: Being wealthy, more educated, being employed, higher number of living children, being in a monogamous relationship, attending community conversation, being visited by health worker at home strongly predicted use of modern contraception. While living in rural areas, older age, being in polygamous relationship, and witnessing one's own child's death were found negatively influence modern contraceptive use. The spatial analysis of contraceptive use revealed that the central and southwestern parts of the country had higher prevalence of modern contraceptive use than that of the eastern and western parts. CONCLUSION: The findings indicate significant socio-economic, urban-rural and regional variation in modern contraceptive use among reproductive age women in Ethiopia. Strengthening community conversation programs and female education should be given top priority. PMID- 24067087 TI - BGFit: management and automated fitting of biological growth curves. AB - BACKGROUND: Existing tools to model cell growth curves do not offer a flexible integrative approach to manage large datasets and automatically estimate parameters. Due to the increase of experimental time-series from microbiology and oncology, the need for a software that allows researchers to easily organize experimental data and simultaneously extract relevant parameters in an efficient way is crucial. RESULTS: BGFit provides a web-based unified platform, where a rich set of dynamic models can be fitted to experimental time-series data, further allowing to efficiently manage the results in a structured and hierarchical way. The data managing system allows to organize projects, experiments and measurements data and also to define teams with different editing and viewing permission. Several dynamic and algebraic models are already implemented, such as polynomial regression, Gompertz, Baranyi, Logistic and Live Cell Fraction models and the user can add easily new models thus expanding current ones. CONCLUSIONS: BGFit allows users to easily manage their data and models in an integrated way, even if they are not familiar with databases or existing computational tools for parameter estimation. BGFit is designed with a flexible architecture that focus on extensibility and leverages free software with existing tools and methods, allowing to compare and evaluate different data modeling techniques. The application is described in the context of bacterial and tumor cells growth data fitting, but it is also applicable to any type of two dimensional data, e.g. physical chemistry and macroeconomic time series, being fully scalable to high number of projects, data and model complexity. PMID- 24067088 TI - On the intersection of phonetic detail and the organization of interaction: clinical connections. AB - The analysis of language use in real-world contexts poses particular methodological challenges. We codify responses to these challenges as a series of methodological imperatives. To demonstrate the relevance of these imperatives to clinical investigation, we present analyses of single episodes of interaction where one participant has a speech and/or language impairment: atypical prosody, echolalia and dysarthria. We demonstrate there is considerable heuristic and analytic value in taking this approach to analysing the organization of interaction involving individuals with a speech and/or language impairment. PMID- 24067089 TI - Higher levels of depression are associated with reduced global bias in visual processing. AB - Negative moods have been associated with a tendency to prioritise local details in visual processing. The current study investigated the relation between depression and visual processing using the Navon task, a standard task of local and global processing. In the Navon task, global stimuli are presented that are made up of many local parts, and the participants are instructed to report the identity of either a global or a local target shape. Participants with a low self reported level of depression showed evidence of the expected global processing bias, and were significantly faster at responding to the global, compared with the local level. By contrast, no such difference was observed in participants with high levels of depression. The reduction of the global bias associated with high levels of depression was only observed in the overall speed of responses to global (versus local) targets, and not in the level of interference produced by the global (versus local) distractors. These results are in line with recent findings of a dissociation between local/global processing bias and interference from local/global distractors, and support the claim that depression is associated with a reduction in the tendency to prioritise global-level processing. PMID- 24067086 TI - Development of RNA aptamers targeting Ebola virus VP35. AB - Viral protein 35 (VP35), encoded by filoviruses, is a multifunctional dsRNA binding protein that plays important roles in viral replication, innate immune evasion, and pathogenesis. The multifunctional nature of these proteins also presents opportunities to develop countermeasures that target distinct functional regions. However, functional validation and the establishment of therapeutic approaches toward such multifunctional proteins, particularly for nonenzymatic targets, are often challenging. Our previous work on filoviral VP35 proteins defined conserved basic residues located within its C-terminal dsRNA binding interferon (IFN) inhibitory domain (IID) as important for VP35 mediated IFN antagonism and viral polymerase cofactor functions. In the current study, we used a combination of structural and functional data to determine regions of Ebola virus (EBOV) VP35 (eVP35) to target for aptamer selection using SELEX. Select aptamers, representing, two distinct classes, were further characterized based on their interaction properties to eVP35 IID. These results revealed that these aptamers bind to distinct regions of eVP35 IID with high affinity (10-50 nM) and specificity. These aptamers can compete with dsRNA for binding to eVP35 and disrupt the eVP35-nucleoprotein (NP) interaction. Consistent with the ability to antagonize the eVP35-NP interaction, select aptamers can inhibit the function of the EBOV polymerase complex reconstituted by the expression of select viral proteins. Taken together, our results support the identification of two aptamers that bind filoviral VP35 proteins with high affinity and specificity and have the capacity to potentially function as filoviral VP35 protein inhibitors. PMID- 24067090 TI - The ventral habenulae of zebrafish develop in prosomere 2 dependent on Tcf7l2 function. AB - BACKGROUND: The conserved habenular neural circuit relays cognitive information from the forebrain into the ventral mid- and hindbrain. In zebrafish, the bilaterally formed habenulae in the dorsal diencephalon are made up of the asymmetric dorsal and symmetric ventral habenular nuclei, which are homologous to the medial and lateral nuclei respectively, in mammals. These structures have been implicated in various behaviors related to the serotonergic/dopaminergic neurotransmitter system. The dorsal habenulae develop adjacent to the medially positioned pineal complex. Their precursors differentiate into two main neuronal subpopulations which differ in size across brain hemispheres as signals from left sided parapineal cells influence their differentiation program. Unlike the dorsal habenulae and despite their importance, the ventral habenulae have been poorly studied. It is not known which genetic programs underlie their development and why they are formed symmetrically, unlike the dorsal habenulae. A main reason for this lack of knowledge is that the vHb origin has remained elusive to date. RESULTS: To address these questions, we applied long-term 2-photon microscopy time-lapse analysis of habenular neural circuit development combined with depth color coding in a transgenic line, labeling all main components of the network. Additional laser ablations and cell tracking experiments using the photoconvertible PSmOrange system in GFP transgenic fish show that the ventral habenulae develop in prosomere 2, posterior and lateral to the dorsal habenulae in the dorsal thalamus. Mutant analysis demonstrates that the ventral habenular nuclei only develop in the presence of functional Tcf7l2, a downstream modulator of the Wnt signaling cascade. Consistently, photoconverted thalamic tcf7l2exl/exl mutant cells do not contribute to habenula formation. CONCLUSIONS: We show in vivo that dorsal and ventral habenulae develop in different regions of prosomere 2. In the process of ventral habenula formation, functional tcf7l2 gene activity is required and in its absence, ventral habenular neurons do not develop. Influenced by signals from parapineal cells, dorsal habenular neurons differentiate at a time at which ventral habenular cells are still on their way towards their final destination. Thus, our finding may provide a simple explanation as to why only neuronal populations of the dorsal habenulae differ in size across brain hemispheres. PMID- 24067091 TI - A master course on "Methodologies for bio-medical research in diabetes". AB - The Master Course on "Methodologies for Bio-Medical Research in Diabetes" was organized jointly by the University of Bari Aldo Moro, Bari, Italy, and the Italian Society of Diabetology (SID, Societa Italiana di Diabetologia). This Course Program has been active throughout the academic year 2011-2012, and engaged selected students in lectures on diabetes research, training in laboratory work, and personal study on selected review articles and original papers. Lecturing activities involved 26 Italian and international experts in the field of diabetes and metabolism and were highly interactive also involving discussion of experimental data sets. The lectures addressed several aspects of diabetes aetiology, pathophysiology, and management, as well methodological and biotechnology topics. At the end of the Course, students were requested to write a review article on a research topic of their choice. PMID- 24067092 TI - Composition- and size-controlled cyclic self-assembly by solvent- and C60 responsive self-sorting. AB - Synthesis, solvent-, and guest-controlled self-assembly, and self-sorting of new hydrogen-bonded chiral cavity receptors are reported. The design of the cavity is based on the cyclic self-aggregation of monomers containing the 4H-bonding ureidopyrimidinone motif fused with the bicylo[3.3.1]nonane framework. Selective formation of kinetically inert cyclic tetramers is observed in chloroform, while in toluene an equilibrium between tetrameric and pentameric forms exists. The high affinity of the tetrameric aggregates toward C60 and C70 is observed in aromatic solvents. The host-guest interaction of unconventional pi-acidic supramolecular receptors for fullerenes is turned off and on by changing the solvent, whereas the selection of size and the very composition of the cavity aggregate is controlled by either the change of solvent or the addition of fullerene guest, making our systems a new type of self-sorting device. PMID- 24067093 TI - Two-dimensional coordination polymers constructed by [Ni(II)Ln(III)] nodes and [W(IV)(bpy)(CN)6]2- spacers: a network of [Ni(II)Dy(III)] single molecule magnets. AB - Three isomorphous two-dimensional (2D) coordination polymers of general formula {[Ni(II)(valpn)Ln(III)(NO3)(H2O)(MU-NC)4W(IV)(bipy)(CN)2].xH2O.yCH3CN}n have been synthesized by reacting Ph4P[W(V)(CN)6(bipy)] with the heterodinuclear [Ni(II)Ln(III)(valpn)(O2NO)3] complexes [H2valpn = 1,3-propanediyl-bis(2 iminomethylene-6-methoxyphenol), bipy = 2,2'-bipyridine, and Ln = Gd (1), Dy (2), and Tb (3) with x = 2 (1), 3.9 (2), and 3.35 (3) and y = 2.50 (1), 2 (2), and 1.8 (3)]. Their crystal structures consist of [Ni(II)Ln(III)] 3d-4f nodes which are connected by [W(IV)(bipy)(CN)6](2-) diamagnetic linkers resulting from the reduction of W(V) to W(IV) during the reaction process. The Ni(II) and Ln(III) ions occupy the inner and outer coordination sites of the dideprotonated valpn ligand, respectively, and they are doubly bridged by the phenoxo oxygen atoms of such a ligand. The value of Ni(II)...Ln(III) separation through this bridge is 3.4919(10) (1), 3.4760(10) (2), and 3.4799(9) (3) A, and those of the angles at the bridgehead phenoxo atoms are 106.6(2) and 107.3(2) (1), 106.9(2), and 107.8(2) (2) and 106.5(2)-106.8(2) degrees (3). Each W(IV) is eight-coordinated with a bidentate bipy molecule and six cyanide-carbon atoms building a somewhat distorted square antiprism environment. The rare-earth cations are nine coordinated, the donor atoms describing a monocapped square antiprism for 1 and 3 and a tricapped trigonal prism for 2. Magnetic susceptibility measurements in the temperature range 1.9-300 K show the occurrence of ferromagnetic interactions between the Ni(II) and Ln(III) ions in 1-3. Frequency-dependent alternating susceptibility signals were observed for the Dy(III) derivative below 8.0 K under an applied dc field of 2500 G indicating the presence of slow magnetic relaxation with values of the pre-exponential factor (tau0) and energy barrier (E(#)) of ca. 5.7 * 10(-8) s and 15.9 cm(-1), respectively. Complex 2 constitutes the first example of a 2D 3d-4f heterobimetallic single molecule magnet (SMM). PMID- 24067094 TI - Association of interleukin-1beta C + 3953T gene polymorphism with human male infertility. AB - Cytokines are involved in the regulation of spermatogenesis likely mediating the crosstalk among Sertoli and germ cells to facilitate germ cell movement across the seminiferous epithelium during cellular events such as germ cell differentiation. Members of the Interleukin-1 (IL-1) family are pleiotropic cytokines that are involved in inflammation, immunoregulation, and other homeostatic functions. Interleukin-1 alpha (IL-1alpha), IL-1beta, and the IL-1 antagonistic molecule (IL-1 Ra) are present in the testis under normal homeostasis and they further increase upon infection/inflammation. In the present study we have examined the association of C + 3953T polymorphism of the human IL 1B gene with human male infertility. The case control study comprised of two groups: 222 infertile patients and 230 fertile healthy control men. Genotyping for SNP C + 3953T IL-1B was carried out by polymerase chain reaction followed by analysis with specific endonucleases (PCR-RFLP). DNA sequencing was used to validate the PCR-RFLP results. The genotype frequencies of the IL-1B Taq C/T polymorphism were compared between infertile men and controls. The frequency was significantly higher in asthenozoospermic patients compared to fertile control men (odds ratio = 10.4, CI: 2.50- 43.96, p = 0.001). The C + 3953T of the IL-1B gene is associated with male infertility risk in the asthenozoospermic patients from an Indian population. PMID- 24067095 TI - Technological characterisation, antibiotic susceptibility and antimicrobial activity of wild-type Leuconostoc strains isolated from North Italian traditional cheeses. AB - Genotypic and technological properties, antibiotic susceptibility and antimicrobial activity of 35 Leuconostoc strains, isolated from different Italian raw milk cheeses, were investigated. RAPD-PCR was used to study genetic variability and to distinguish closely related strains. The results showed a high degree of heterogeneity among isolates. All the strains had weak acidifying activity and showed low proteolytic and lipolytic activities. Reduction activity, was generally low. All the Leuconostoc were susceptible to ampicillin, mupirocin, erythromycin, quinupristin/dalfopristin and tetracycline. Many strains were classified as resistant to oxacillin, ciprofloxacin and nitrofurantonin, while all isolates were found resistant to vancomycin. PCR-based detection did not identify any of the common genetic determinants for vancomycin (vanA, vanB, vanC1, vanC2, vanC3, vanD, vanE, vanG) or erythromycin (ermB and ermC). Tetracycline resistance genes were detected in 25 tetracycline susceptible strains, the most frequent one being tetM. One strain, belonging to Ln. pseudomesenteroides species, was positive for the presence of the int gene of the Tn916/Tn1545 trasposon family. This is the first time the conjugative transposon Tn916 has been detected inside the Leuconostoc species. All strains showed antimicrobial activity against Enterococcus faecalis and Ent. faecium. The presence of genes encoding amino-acid decarboxylases (hdc and tdc) was not detected. Some strains are interesting in view of their use in cheese production as starter and non starter cultures. PMID- 24067096 TI - Patient's access to healthcare and treatment in rheumatoid arthritis: the views of stakeholders in Portugal. AB - BACKGROUND: The access to healthcare and treatment by rheumatoid arthritis (RA) patients, particularly to biologics, differs significantly among European countries.We aimed to explore the views and experiences of Portuguese healthcare stakeholders on key barriers which limit the access to treatment, and ultimately to biologics, by RA patients and to find potential solutions (leverage points) to overcome the identified barriers. METHODS: This was a qualitative research consisting of semi-structured face-to-face interviews with key stakeholders in RA framework. Thirty four individuals from eight groups of stakeholders were interviewed: rural and urban general practitioners (GPs), rheumatologists, hospital managers, hospital pharmacists, budget holders, representatives from the Portuguese Rheumatology Society and the RA Patient Association. Interviews were conducted between May and June 2011. Conventional content analysis with research triangulation was used. RESULTS: The key barriers identified were related to the accessibility to primary healthcare services, difficulties in RA diagnosis among GPs, inefficient referral to secondary healthcare and controlled process of biologics prescription in public hospitals. The leverage points identified included the improvement of epidemiological and clinical knowledge about RA in Portugal, a better understanding of the disease among patients and GPs, the clarification of biologics benefits among budget holders and a raised awareness of the current treatment guidelines. In order to further address the leverage points, the following key initiatives were proposed: optimization of RA national registry; dissemination of information on rheumatic symptoms in primary care facilities and among the general public; increase interaction between rheumatologists and GPs through clinical discussions of successfully treated patients or workshops; broader utilization of disease diagnosis and monitoring tools, such as DAS28, and implementation of hospital-based research to collect real-world data. CONCLUSIONS: Most of the key barriers limiting the access to treatment, including biologics, in RA in Portugal are upstream of rheumatology practice. Our findings suggest that future actions should be focused on the primary care level to improve referral to rheumatologists. In addition, the collection of real-world data seems essential to characterise the RA population, to improve disease management and to increase compliance with current treatment guidelines. PMID- 24067097 TI - The reference intervals of thyroid stimulating hormone in healthy individuals with normal levels of serum free thyroxine and without sonographic pathologies. AB - INTRODUCTION: The aim of the present study was to investigate the reference intervals for thyroid stimulating hormone (TSH) in healthy individuals with normal levels of serum free thyroxine (fT4) and without sonographic pathologies, and determine the effects of age, gender, and residence on the TSH reference intervals. SUBJECTS AND METHODS: This research was a population-based study conducted in 70 regions. The random sampling method was used to select the 1095 subjects of the study among inhabitants aged 18 and above. Patients who had a previous history of thyroid disease and had been taking medication were excluded from the study as this may have affected their fT4 or TSH levels. In addition, subjects who had serum fT4 without a reference range and abnormal ultrasonography findings were also excluded. A total of 408 subjects were used for establishing the reference intervals for TSH. RESULTS: The data for TSH in the study group were not normally distributed according to the Kolmogorov-Smirnov index. The geometric mean was 1.62 mIU/L, the median was 1.40 mIU/L, and the 95% reference intervals were 0.38-4.22 mIU/L. The median TSH level was higher in females compared to males (p < 0.05). In the female subjects 2.5th percentile of TSH was lower and 97.5th percentile was higher than those of males. The reference intervals of TSH were of lower values in subjects over 50 years old (p < 0.001). DISCUSSION: Studies suggest that determination of the TSH reference intervals may differ due to environmental influences or due to age, gender, and race. It is suggested that the lower limit of normal TSH for the adult Turkish population would be 0.38 mIU/L and the upper limit similar to the traditional value of 4.2 mIU/L. If each clinician uses their population-specific reference interval for TSH, thyroid function abnormalities can be accurately estimated. PMID- 24067098 TI - Organocatalytic enantioselective gamma-aminoalkylation of unsaturated ester: access to pipecolic acid derivatives. AB - The direct gamma-carbon functionalization of alpha,beta-unsaturated esters via N Heterocyclic Carbene (NHC) catalysis is disclosed. This catalytically generated nucleophilic gamma-carbon undergoes highly enantioselective additions to hydrazones. The resulting delta-lactam products can be readily transformed to optically enriched pipecolic acid derivatives. PMID- 24067099 TI - Fabrication of submicrometer pores with an outer shell using modified poly(vinyl alcohol) and the molecular or particle collection effect. AB - Pores with an outer shell (POS) are fabricated on the submicrometer scale using modified poly(vinyl alcohol) (PVA). An aqueous solution is mixed with cationic PVA and a water-based colloidal suspension of polystyrene (PS) spheres of submicrometer diameter. The mixture is then spin-coated onto a substrate. The resultant structure is immersed in toluene, which dissolves the PS spheres. As a result, POS are formed by PVA on the substrate. By using PS spheres with 500 nm diameter, the pore openings have a diameter of about 300 nm and are surrounded by the outer shell. This structure exhibits beneficial molecular and particle collection effects, which are attributed to the peripheral shell rising from the surface. In addition, POS can be formed using a photo-cross-linkable PVA that is often used for enzyme-immobilized hydrogel matrices. PMID- 24067100 TI - Amperometric nitric oxide sensors with enhanced selectivity over carbon monoxide via platinum oxide formation under alkaline conditions. AB - An improved planar amperometric nitric oxide (NO) sensor with enhanced selectivity over carbon monoxide (CO), which represents a volatile interfering species for NO sensors that has been largely overlooked until recently, is described. Formation of an oxide film on the inner platinum working electrode via anodic polarization using an inner alkaline electrolyte solution provides the basis for improved selectivity. Cyclic voltammetry reveals that formation of an oxidized Pt film inhibits adsorption of CO to the electrode surface, which is a necessary initial step in the electrocatalytic oxidation of CO on Pt. Previous NO gas sensors that employ internal electrolyte solutions have been assembled using acidic internal solutions that inhibit the formation of a dense platinum oxide film on the working electrode surface. It is demonstrated herein that increasing the internal electrolyte pH promotes oxidized platinum film formation, resulting in improved selectivity over CO. Selectivity coefficients (log KNO,j) for sensors assembled with internal solutions at various pH values range from -0.08 at pH 2.0 to -2.06 at pH 11.7, with average NO sensitivities of 1.24 nA/MUM and a limit of detection (LOD) of <1 nM. PMID- 24067102 TI - DaGO-Fun: tool for Gene Ontology-based functional analysis using term information content measures. AB - BACKGROUND: The use of Gene Ontology (GO) data in protein analyses have largely contributed to the improved outcomes of these analyses. Several GO semantic similarity measures have been proposed in recent years and provide tools that allow the integration of biological knowledge embedded in the GO structure into different biological analyses. There is a need for a unified tool that provides the scientific community with the opportunity to explore these different GO similarity measure approaches and their biological applications. RESULTS: We have developed DaGO-Fun, an online tool available at http://web.cbio.uct.ac.za/ITGOM, which incorporates many different GO similarity measures for exploring, analyzing and comparing GO terms and proteins within the context of GO. It uses GO data and UniProt proteins with their GO annotations as provided by the Gene Ontology Annotation (GOA) project to precompute GO term information content (IC), enabling rapid response to user queries. CONCLUSIONS: The DaGO-Fun online tool presents the advantage of integrating all the relevant IC-based GO similarity measures, including topology- and annotation-based approaches to facilitate effective exploration of these measures, thus enabling users to choose the most relevant approach for their application. Furthermore, this tool includes several biological applications related to GO semantic similarity scores, including the retrieval of genes based on their GO annotations, the clustering of functionally related genes within a set, and term enrichment analysis. PMID- 24067103 TI - Combined rod and cone transduction by adeno-associated virus 2/8. AB - Gene transfer to both cone and rod photoreceptors (PRs) is essential for gene therapy of inherited retinal degenerations that are caused by mutations in genes expressed in both PR types. Vectors based on the adeno-associated virus (AAV) efficiently transduce PRs of different species. However, these are predominantly rods and little is known about the ability of the AAV to transduce cones in combination with rods. Here we show that AAV2/8 transduces pig cones to levels that are similar to AAV2/9, and the outer nuclear layer (mainly rods) to levels that are on average higher, although not statistically significant, than both AAV2/5 and AAV2/9. We additionally found that the ubiquitous cytomegalovirus (CMV), but not the PR-specific GRK1 promoter, transduced pig cones efficiently, presumably because GRK1 is not expressed in pig cones as observed in mice and humans. Indeed, the GRK1 and CMV promoters transduce a similar percentage of murine cones with the CMV reaching the highest expression levels. Consistent with this, the AAV2/8 vectors with either the CMV or the GRK1 promoter restore cone function in a mouse model of Leber congenital amaurosis type 1 (LCA1), supporting the use of AAV2/8 for gene therapy of LCA1 as well as of other retinal diseases requiring gene transfer to both PR types. PMID- 24067104 TI - Study of the activity of quaternary ammonium compounds in the mitigation of biofouling in heat exchangers-condensers cooled by seawater. AB - The effectiveness of two quaternary ammonium compounds (QACs) (non-oxidising biocides) to reduce the growth of biofilm adhering to the tubes of a heat exchanger-condenser cooled by seawater was evaluated. Their effectiveness was compared to that of a conventional oxidising biocide (sodium hypochlorite [NaOCl]) under the same testing conditions. Each biocide was applied intermittently (6 h on, 6 h off) in a first shock stage (1.5 ppm over 8 days) and a second stabilising stage (0.5 ppm over 20 days). The results showed that the antifouling effectiveness of the first of the QACs (fifth generation) was comparable to that shown by the oxidising power of NaOCl. Although the reaction time was longer than that of NaOCl, both the compounds removed the biofilm, and the tube was practically restored to its clean condition. Treatment with the second of the QACs (fourth generation) allowed for the stabilisation of biofilm growth, but not for its removal. Ecotoxicology studies classified the QACs as environmentally harmless under the testing conditions. PMID- 24067108 TI - CD68 tumor-associated macrophage marker is not prognostic of clinical outcome in classical Hodgkin lymphoma. AB - Abstract A novel biomarker, CD68, which marks tumor-associated macrophages (TAMs) in the microenvironment, has recently been reported to affect the prognosis of Hodgkin lymphoma (HL). We aimed to evaluate its role in our patient cohort (n = 100) by utilizing a routine immunohistochemistry method on whole tissue sections and a semiquantitative method for CD68 scoring. Clinical data were taken from medical records. Correlation with baseline characteristics, attainment of complete remission (CR), progression-free survival (PFS) and disease-specific survival (DSS) was done by categorical analysis using different cut-offs of CD68 score and also by taking absolute CD68 score as a continuous variable. There was no significant association between levels of CD68 expression and baseline characteristics or CR after primary therapy. CD68 score (neither categorical nor absolute continuous values) also did not predict for any difference in PFS or DSS. We conclude that CD68 TAM marker does not have prognostic value in HL. PMID- 24067107 TI - Evidence for the interaction of the human metapneumovirus G and F proteins during virus-like particle formation. AB - BACKGROUND: Human metapneumovirus (HMPV) is now a major cause of lower respiratory infection in children. Although primary isolation of HMPV has been achieved in several different cell lines, the low level of virus replication and the subsequent recovery of low levels of infectious HMPV have hampered biochemical studies on the virus. These experimental methodologies usually require higher levels of biological material that can be achieved following HMPV infection. In this study we demonstrate that expression of the HMPV F, G and M proteins in mammalian cells leads to HMPV virus-like particles (VLP) formation. This experimental strategy will serve as a model system to allow the process of HMPV virus assembly to be examined. METHODS: The HMPV F, G and M proteins were expressed in mammalian cell lines. Protein cross-linking studies, sucrose gradient centrifugation and in situ imaging was used to examine interactions between the virus proteins. VLP formation was examined using sucrose density gradient centrifugation and electron microscopy analysis. RESULTS: Analysis of cells co-expressing the F, G and M proteins demonstrated that these proteins interacted. Furthermore, in cells co-expression the three HMPV proteins the formation VLPs was observed. Image analysis revealed the VLPs had a similar morphology to the filamentous virus morphology that we observed on HMPV-infected cells. The capacity of each protein to initiate VLP formation was examined using a VLP formation assay. Individual expression of each virus protein showed that the G protein was able to form VLPs in the absence of the other virus proteins. Furthermore, co-expression of the G protein with either the M or F proteins facilitated their incorporation into the VLP fraction. CONCLUSION: Co-expression of the F, G and M proteins leads to the formation of VLPs, and that incorporation of the F and M proteins into VLPs is facilitated by their interaction with the G protein. Our data suggests that the G protein plays a central role in VLP formation, and further suggests that the G protein may also play a role in the recruitment of the F and M proteins to sites of virus particle formation during HMPV infection. PMID- 24067109 TI - MicroRNA let-7f is down-regulated in patients with refractory acute myeloid leukemia and is involved in chemotherapy resistance of adriamycin-resistant leukemic cells. PMID- 24067110 TI - Evolutionary mechanisms for loneliness. AB - Robert Weiss (1973) conceptualised loneliness as perceived social isolation, which he described as a gnawing, chronic disease without redeeming features. On the scale of everyday life, it is understandable how something as personally aversive as loneliness could be regarded as a blight on human existence. However, evolutionary time and evolutionary forces operate at such a different scale of organisation than we experience in everyday life that personal experience is not sufficient to understand the role of loneliness in human existence. Research over the past decade suggests a very different view of loneliness than suggested by personal experience, one in which loneliness serves a variety of adaptive functions in specific habitats. We review evidence on the heritability of loneliness and outline an evolutionary theory of loneliness, with an emphasis on its potential adaptive value in an evolutionary timescale. PMID- 24067111 TI - Maintaining endotracheal tube cuff pressure at 20 mm Hg to prevent dysphagia after anterior cervical spine surgery; protocol of a double-blind randomised controlled trial. AB - BACKGROUND: In anterior cervical spine surgery a retractor is obligatory to approach the spine. Previous studies showed an increase of endotracheal tube cuff pressure after placement of a retractor. It is known that high endotracheal tube cuff pressure increases the incidence of postoperative dysphagia, hoarseness, and sore throat. However, until now no evidence supports the fact whether adjusting the endotracheal tube cuff pressure during anterior cervical spine surgery will prevent this comorbidity. We present the design of a randomized controlled trial to determine whether adjusting endotracheal tube cuff pressure after placement of a retractor during anterior cervical spine surgery will prevent postoperative dysphagia. METHODS/DESIGN: 177 patients (aged 18-90 years) scheduled for anterior cervical spine surgery on 1 or more levels will be included. After intubation, endotracheal tube cuff pressure is manually inflated to 20 mm Hg in all patients. Patients will be randomized into two groups. In the control group endotracheal tube cuff pressure is not adjusted after retractor placement. In the intervention group endotracheal tube cuff pressure after retractor placement is maintained at 20 mm Hg and air is withdrawn when cuff pressure exceeds 20 mm Hg. Endotracheal tube cuff pressure is measured after intubation, before and after placement and removal of the retractor. Again air is inflated if cuff pressure sets below 20 mmHg after removal of the retractor. The primary outcome measure is postoperative dysphagia. Other outcome measures are postoperative hoarseness, postoperative sore throat, degree of dysphagia, length of hospital stay, and pneumonia. The study is a single centre double blind randomized trial in which patients and research nurses will be kept blinded for the allocated treatment during the follow-up period of 2 months. DISCUSSION: Postoperative dysphagia occurs frequently after anterior cervical spine surgery. This may be related to high endotracheal tube cuff pressure. Whether adaptation and maintaining the pressure after placement of the retractor will decrease the incidence of dysphagia, has to be determined by this trial. TRIAL REGISTRATION: Netherlands Trial Register (NTR) 3542: http://www.trialregister.nl. PMID- 24067112 TI - Post-transplantation encapsulating peritoneal sclerosis without inflammation or radiological abnormalities. AB - BACKGROUND: Post-transplantation encapsulating peritoneal sclerosis (EPS) causing bowel obstruction has been identified as a serious complication after kidney transplantation in patients previously treated with peritoneal dialysis. Systemic inflammation and abnormalities on an abdominal computed tomography (CT) scan are important hallmarks of EPS. To our knowledge, this is the first report of a case being diagnosed with late-onset post-transplantation EPS without systemic inflammation or abnormalities on a CT scan which could only be diagnosed by laparotomy. CASE PRESENTATION: A 59-year old female presented because of symptoms of bowel obstruction 33 months after kidney transplantation. The patient had a 26 month history of peritoneal dialysis before her first kidney transplantation and was treated with peritoneal dialysis for 4 years before undergoing a second kidney transplantation. Physical examination was unremarkable and laboratory tests showed no signs of systemic inflammation (C-reactive protein <1 mg/L). An abdominal CT scan did not reveal any abnormalities fitting the diagnosis of EPS, except a "feces sign". Given the severity of the progressive symptoms, a diagnostic laparotomy was performed, visualizing a classical EPS. Total peritonectomy and enterolysis were performed, leading to restoration of peristalsis. CONCLUSION: EPS may occur several years after kidney transplantation in the absence of inflammation and typical radiological abnormalities. Obtaining a diagnosis of post-transplantation EPS is challenging, however, a low threshold for surgical exploration in case of high clinical suspicion and negative findings on the CT scan is mandatory. PMID- 24067114 TI - Self-consistent colloidal energy and diffusivity landscapes in macromolecular solutions. AB - We report a dynamic analysis to simultaneously measure colloidal forces and hydrodynamic interactions in the presence of both adsorbed and unadsorbed macromolecules. A Bayesian inference method is used to self-consistently obtain the position-dependent potential energy (i.e., energy landscape) and diffusivity (i.e., diffusivity landscape) from measured colloidal trajectories normal to a wall. Measurements are performed for particles and surfaces with adsorbed polyethylene oxide (PEO) copolymer as a function of unadsorbed PEO homopolymer concentration. Energy landscapes are well described by a steric repulsion between adsorbed brushes and depletion attraction due to unadsorbed macromolecules. Diffusivity landscapes show agreement with predicted short-range permeable brush models and long-range mobilities determined by the bulk solution viscosity. Lower than expected mobilities in the vicinity of overlapping depletion layers are attributed to interactions of adsorbed and unadsorbed macromolecules altering nonconservative lubrication forces. PMID- 24067113 TI - Horizontally acquired divergent O-antigen contributes to escape from cross immunity in the classical bordetellae. AB - BACKGROUND: Horizontal gene transfer (HGT) allows for rapid spread of genetic material between species, increasing genetic and phenotypic diversity. Although HGT contributes to adaptation and is widespread in many bacteria, others show little HGT. This study builds on previous work to analyze the evolutionary mechanisms contributing to variation within the locus encoding a prominent antigen of the classical bordetellae. RESULTS: We observed amongst classical bordetellae discrete regions of the lipopolysaccharide O-antigen locus with higher sequence diversity than the genome average. Regions of this locus had less than 50% sequence similarity, low dN/dS ratios and lower GC content compared to the genome average. Additionally, phylogenetic tree topologies based on genome wide SNPs were incongruent with those based on genes within these variable regions, suggesting portions of the O-antigen locus may have been horizontally transferred. Furthermore, several predicted recombination breakpoints correspond with the ends of these variable regions. To examine the evolutionary forces that might have selected for this rare example of HGT in bordetellae, we compared in vitro and in vivo phenotypes associated with different O-antigen types. Antibodies against O1- and O2-serotypes were poorly cross-reactive, and did not efficiently kill or mediate clearance of alternative O-type bacteria, while a distinct and poorly immunogenic O-antigen offered no protection against colonization. CONCLUSIONS: This study suggests that O-antigen variation was introduced to the classical bordetellae via HGT through recombination. Additionally, genetic variation may be maintained within the O-antigen locus because it can provide escape from immunity to different O-antigen types, potentially allowing for the circulation of different Bordetella strains within the same host population. PMID- 24067116 TI - Exercise order influences number of repetitions and lactate levels but not perceived exertion during resistance exercise in adolescents. AB - The purpose of this study was to analyze the effects of resistance training (RT) order on number of repetitions, total training volume, ratings of perceived exertion (RPE), and the lactate response in male adolescents. Twelve adolescents (age: 15.7 +/- 1.4 yrs) completed two RT sessions in a counterbalanced crossover design: one with exercises for smaller muscle groups followed by larger muscle groups (SM-LM), whereas the other session was performed in the opposite sequence (LM-SM). The exercise order for SM-LM was standing triceps extension (TE), dumbbell biceps curl (BC), bench press (BP), and seated row machine (RM), while the order for LM-SM was the opposite. Subjects performed three sets of a predetermined 10 repetition maximum for each exercise. Total repetitions completed for each exercise and RPE were assessed after each set, and blood lactate (BL) was measured before RT, 1 m after the first exercise, 1 m after the third exercise, and 10 m after each RT session. Blood lactate (BL) was higher for the LM-SG compared with SM-LM 10 m after exercise (7.4 +/- 1.8 versus 6.5 +/- 2.1 mmol/L; p < 0.05). More repetitions were completed on the TE and BC in the SM-LM compared with LM-SG (24.9 +/- 3.4 and 16.2 +/- 3.2 versus 16.3 +/- 4.2 and 14.6 +/- 3.0, respectively; p < 0.02), while more repetitions were completed on the BP and RM following the LM-SM (14.3 +/- 2.3 and 23.4 +/- 4.5 versus 12.4 +/- 4.2 and 13.6 +/- 5.1, respectively; p < 0.02). No differences were found for RPE. It may be appropriate to perform multijoint exercises first to improve general coordination and force, while the use of smaller muscle groups first may be interesting to target specific muscle weaknesses. PMID- 24067115 TI - Functional effect of Saffron supplementation and risk genotypes in early age related macular degeneration: a preliminary report. AB - BACKGROUND: To determine whether the functional effects of oral supplementation with Saffron, a natural compound that proved to be neuroprotective in early age related macular degeneration, are influenced by complement factor H (CFH) and age related maculopathy susceptibility 2 (ARMS2) risk genotypes. METHODS: Thirty three early AMD patients, screened for CFH (rs1061170) and ARMS2 (rs10490924) polymorphisms and receiving Saffron oral supplementation (20 mg/day) over an average period of treatment of 11 months (range, 6-12), were longitudinally evaluated by clinical examination and focal electroretinogram (fERG)-derived macular (18 degrees ) flicker sensitivity estimate. fERG amplitude and macular sensitivity, the reciprocal value of the estimated fERG amplitude threshold, were the main outcome measures. RESULTS: After three months of supplementation, mean fERG amplitude and fERG sensitivity improved significantly when compared to baseline values (p < 0.01). These changes were stable throughout the follow-up period. No significant differences in clinical and fERG improvements were observed across different CFH or ARMS2 genotypes. CONCLUSIONS: The present results indicate that the functional effect of Saffron supplementation in individual AMD patients is not related to the major risk genotypes of disease. PMID- 24067117 TI - A comparison of hyperhydration versus ad libitum fluid intake strategies on measures of oxidative stress, thermoregulation, and performance. AB - Dehydration has been shown to augment cellular stress. Glycerol hyperhydration can delay dehydration, which may decrease the level of pre- and post-exercise oxidative stress. This study aimed to compare the effects of glycerol (G) or water (W) hyperhydration with no hyperhydration (C) on oxidative stress, thermoregulation, and cycle performance. Seven trained males consumed 1.2 g of glycerol.kg-1 body mass (BM) in 26 ml.kg-1 BM water or equal volume water to achieve hyperhydration followed by a 90 min time trial. Total glutathione increased post exercise (PE) in all trials (p < 0.01), while oxidized glutathione (p < 0.05) and protein carbonyl concentrations (p < 0.001) were increased PE for the C trial only. Mean body temperature and heart rate increased with exercise but were not different between interventions. Total distance covered and power outputs were not different between interventions. Fluid intake attenuated oxidative stress but did not enhance thermoregulation or performance. PMID- 24067118 TI - Traumatic upper limb injuries during the Men's Field Hockey Junior World Cup 2009. AB - This study was a prospective epidemiological investigation of upper limb injuries during the Men's Field Hockey Junior World Cup 2009. Three hundred twenty-four players were observed in 58 matches of the tournament. Twenty-eight upper limb related injuries were documented. The injury incidence was 0.48 per match and 19 per 1,000 match hours. Most injuries were due to contact with the ball, and the left hand was the most commonly injured part. Contusion was the most common type of injury. The odds ratio for hand and wrist injuries in players not wearing gloves was 4.01 (95% CI, 0.52-30.62), and the relative risk of hand and wrist injuries in players wearing gloves was 0.26 (95% CI, 0.03-1.92). Male youth hockey players are at a high risk of upper limb, especially hand and wrist, injuries during major international tournaments and that use of protective gloves can provide significant protection against hand and wrist injuries in the sport. PMID- 24067119 TI - The effects of three jump landing tasks on kinetic and kinematic measures: implications for ACL injury research. AB - This study compared the biomechanics of jump landing tasks used in ACL research. Twenty-seven female subjects performed a drop landing (DL), a drop landing with a vertical jump (DVJ), and a forward jump landing with a vertical jump (FVJ). We hypothesized that as one progressed from the drop landing through the forward vertical jump that the kinematic and kinetic demands would increase, with progressively increasing knee and hip forces, moments, and angles on landing. Separate repeated-measures ANOVAs were performed. The FVJ had the highest peak anterior tibial shear force (p < 0.001), hip flexion angle (p < 0.001), knee flexion moment (p < 0.001), and knee valgus moment (p < 0.001). The DL had the smallest knee flexion angle (p = 0.001) and hip flexion angle (p < 0.001), while the DVJ had the lowest knee valgus moment (p < 0.001). These results indicate that seemingly minor variations between jump landing tasks may influence landing biomechanics. Caution should be used when comparing studies using different tasks. PMID- 24067120 TI - Does chronic exercise attenuate age-related physiological decline in males? AB - Alteration in body composition, physical function, and substrate metabolism occur with advancing age. These changes can be attenuated by exercise. This study evaluated whether master athletes (MA [n = 20]) would have improved exercise capabilities, anthropometry, and hormone profiles when compared with age-matched sedentary counterparts (S [n = 28]). The MA group was predominantly aerobically trained with some resistance exercise incorporated in their routine. The VO(2max), peak power output, and salivary testosterone was significantly higher (p < 0.05) in the MA group, while diastolic blood pressure, systolic blood pressure, and body fat percentage were lower (p < 0.05). Cortisol, fat free mass, (FFM) and total body mass were not significantly different between groups. Salivary testosterone correlated positively with VO(2max) (r2 = .320), suggesting that increased aerobic capacity is linked with higher concentrations of testosterone. These results suggest that life-long exercise is associated with favorable body composition and attenuation of the age related decline in testosterone. PMID- 24067121 TI - Influence of exercise order on repetition performance among all possible combinations on resistance training. AB - The purposes of this study were to compare the repetition performance and rating of perceived exertion (RPE) in different exercises order of three resistance training (RT) exercises: bench press (BP), shoulder press (SP), and triceps extension (TE). Twelve trained men participated in this study (26.75 +/- 2.49 years; 177 +/- 4.66 cm; 77.7 +/- 6.20 kg; 12.61 +/- 2.01% body fat; RT experience 3.58 +/- 1.24 years). Data were collected in two phases: (1) 10 RM test for BP, SP, and TE and (2) performance of six RT sequences. The sequences were: SEQA (BP, SP, TE), SEQB (BP, TE, SP), SEQC (SP, BP, TE), SEQD (SP, TE, BP), SEQE (TE, BP, SP), and SEQF (TE, SP, BP). The repetition performance on SEQD was significantly smaller than SEQE and SEQF. No significant differences were found for repetition performance and RPE among other sequences. These data indicate that priority might be given to exercises performed in the beginning of the RT session. PMID- 24067122 TI - A comparison of coping responses among high school and college athletes with concussion, orthopedic injuries, and healthy controls. AB - This study compared the coping responses of concussed athletes with those with an orthopedic injury and healthy controls and explored sex differences in coping behaviors following sport injury. Sixty-eight athletes with a concussion (CONCUSS), 42 with an orthopedic injury (ORTHO), and 33 healthy controls (CONTROL) completed the Brief COPE approximately 1 week following sport injury. The CONCUSS group reported lower active, planning, acceptance, religion, self distraction, venting, and self-blame coping than the ORTHO group. The ORTHO group reported lower acceptance, venting, and substance use coping than CONTROLS. Females reported higher levels of planning, humor, instrumental support, and venting than males. Females reported more venting than males in the ORTHO and CONTROL groups, but not in the CONCUSS group. In conclusion, concussed athletes may not engage in coping to the same extent as athletes with other injuries. PMID- 24067123 TI - The biomechanics of vertical hopping: a review. AB - Repetitive vertical hopping is a simple and relatively controlled task useful for studying basic neuromuscular properties and tissue mechanics. However, several biomechanical and physiological factors are involved. This article provides an overview of muscle and tendon properties and how these interact during vertical hopping. Muscle properties discussed are force-velocity and force-length relationships, electromechanical delay, muscle fiber type, stretch induced contraction amplification, and muscle spindle afferent feedback. Tendon properties include storage and reuse of elastic energy, tendon stiffness, afferent information from Golgi tendon organs, and failure points. These muscle and tendon properties interact to generate vertical hopping force and power. In addition to these basic properties, there are other more complicated factors to consider when analyzing vertical hopping such as balance and coordination. A wealth of information can be gathered by studying vertical hopping. Caution should be taken, however, to prevent inappropriate conclusions being drawn about hop performance due to oversimplification. PMID- 24067124 TI - Influence of backpack load and gait speed on plantar forces during walking. AB - The purpose of this study is to examine the differences in plantar force associated with changes in backpack load and gait speed during walking. The F scan tethered system was used to collect plantar pressure data. Subjects were asked to walk on a treadmill with varied levels of backpack load (0%, 10%, 20%, and 30% of body mass) and gait speed (4, 5, and 6 km/h). We found that an increase in gait speed and backpack load lead to increase in the magnitude of the first vertical ground reaction force (vGRF) peak. Greater magnitudes of the second vGRF peak were only associated with an increase when gait speeds were 4 km/h and 5 km/h. There was no speed-related change in the magnitudes of the second vGRF peak at the speed of 6 km/h. The results of this study may be important for the purpose of constituting a load-bearing walking program for protecting against osteoporosis. PMID- 24067126 TI - Comparative study of flexible nasoendoscopic and rigid endoscopic examination for patients with upper aerodigestive tract symptoms. AB - INTRODUCTION: The objective of the current study was to compare the outcomes of rigid endoscopic procedures with those of pre-operative flexible nasoendoscopy. METHODS: A total of 253 patients who had undergone rigid endoscopic examination under anaesthesia between 6 January 2010 and 31 August 2011 were identified. Their clinical, surgical and histological records were evaluated. RESULTS: A total of 213 patients had a flexible nasoendoscopic procedure performed and recorded pre-operatively, and 82 in this cohort had a specific lesion or area of concern identified. There were 21 confirmed malignant biopsy results, the majority of which were squamous cell carcinoma. No patient with a negative pre operative endoscopy had a malignant lesion discovered on endoscopic biopsy. The sensitivity and specificity of pre-operative nasoendoscopy were 100 per cent and 66.3 per cent, respectively. CONCLUSION: Diagnostic rigid endoscopic examination of the upper aerodigestive tract remains an important tool for excluding malignancy in high-risk patients, but is an unnecessary procedure in those low risk patients with normal pre-operative findings. PMID- 24067128 TI - Strong overtones modes in inelastic electron tunneling spectroscopy with cross conjugated molecules: a prediction from theory. AB - Cross-conjugated molecules are known to exhibit destructive quantum interference, a property that has recently received considerable attention in single-molecule electronics. Destructive quantum interference can be understood as an antiresonance in the elastic transmission near the Fermi energy and leading to suppressed levels of elastic current. In most theoretical studies, only the elastic contributions to the current are taken into account. In this paper, we study the inelastic contributions to the current in cross-conjugated molecules and find that while the inelastic contribution to the current is larger than for molecules without interference, the overall behavior of the molecule is still dominated by the quantum interference feature. Second, an ongoing challenge for single molecule electronics is understanding and controlling the local geometry at the molecule-surface interface. With this in mind, we investigate a spectroscopic method capable of providing insight into these junctions for cross conjugated molecules: inelastic electron tunneling spectroscopy (IETS). IETS has the advantage that the molecule interface is probed directly by the tunneling current. Previously, it has been thought that overtones are not observable in IETS. Here, overtones are predicted to be strong and, in some cases, the dominant spectroscopic features. We study the origin of the overtones and find that the interference features in these molecules are the key ingredient. The interference feature is a property of the transmission channels of the pi system only, and consequently, in the vicinity of the interference feature, the transmission channels of the sigma system and the pi system become equally transmissive. This allows for scattering between the different transmission channels, which serves as a pathway to bypass the interference feature. A simple model calculation is able to reproduce the results obtained from atomistic calculations, and we use this to interpret these findings. PMID- 24067127 TI - Dominant optic atrophy, OPA1, and mitochondrial quality control: understanding mitochondrial network dynamics. AB - Mitochondrial quality control is fundamental to all neurodegenerative diseases, including the most prominent ones, Alzheimer's Disease and Parkinsonism. It is accomplished by mitochondrial network dynamics - continuous fission and fusion of mitochondria. Mitochondrial fission is facilitated by DRP1, while MFN1 and MFN2 on the mitochondrial outer membrane and OPA1 on the mitochondrial inner membrane are essential for mitochondrial fusion. Mitochondrial network dynamics are regulated in highly sophisticated ways by various different posttranslational modifications, such as phosphorylation, ubiquitination, and proteolytic processing of their key-proteins. By this, mitochondria process a wide range of different intracellular and extracellular parameters in order to adapt mitochondrial function to actual energetic and metabolic demands of the host cell, attenuate mitochondrial damage, recycle dysfunctional mitochondria via the mitochondrial autophagy pathway, or arrange for the recycling of the complete host cell by apoptosis. Most of the genes coding for proteins involved in this process have been associated with neurodegenerative diseases. Mutations in one of these genes are associated with a neurodegenerative disease that originally was described to affect retinal ganglion cells only. Since more and more evidence shows that other cell types are affected as well, we would like to discuss the pathology of dominant optic atrophy, which is caused by heterozygous sequence variants in OPA1, in the light of the current view on OPA1 protein function in mitochondrial quality control, in particular on its function in mitochondrial fusion and cytochrome C release. We think OPA1 is a good example to understand the molecular basis for mitochondrial network dynamics. PMID- 24067129 TI - Training tomorrow's laryngologists - head and neck training alone is not sufficient. AB - BACKGROUND: Diagnostic ability is essential in laryngology. The UK Higher Surgical Training syllabus includes competencies specific to laryngology. This study aimed to identify the factors in training that lead to a consultant level of laryngology-related diagnostic ability. METHOD: An online test of training experience was constructed using laryngoscopy videos obtained from a specialist UK voice clinic. Participation was aimed at both trainees and trainers via invitation through national ENT forums. RESULTS: There were 51 complete responses. Trainees with six months of laryngology experience scored significantly higher than those without this experience (p < 0.001). There was no improvement in score demonstrated for those with head and neck specialty experience without laryngology experience. Trainees who had completed 12 months of laryngology, or 6 months of laryngology coupled with 12 months of head and neck training, scored similarly to their consultant trainers. CONCLUSION: It is recommended that all trainees have at least six months of experience in a specialist voice or laryngology placement prior to gaining the Certificate of Completion of Training. PMID- 24067131 TI - Evaluation of HbA1c criteria for diagnosis of diabetes mellitus: a retrospective study of 12 785 type 2 Saudi male patients. AB - Recently, American Diabetic Association has recommended glycated hemoglobin (HbA1c >=6.5%) as an alternate to fasting plasma glucose (FPG >=7.0 mmol/L) for diagnosis of diabetes. However, studies from different groups showed inconsistent results with the use of HbA1c criteria. We examined the validity of HbA1c cut point of 6.5% for diagnosis of diabetes. A total of 12 785 male diabetic patients (FGP >=7.0 mmol/L), aged 56.27 +/- 13.32 years were included. The average values of FPG and HbA1c of all the 12 785 patients were 10.127 +/- 0.026 mmol/L and 8.729 +/- 0.013%, respectively. Sub-grouping of patients into different age categories showed significantly high levels of FPG (10.934 +/- 0.123 mmol/L) in the youngest group (age, >=20-35 years) as compared to FPG (ranged from 10.021 +/ 0.052 to 10.190 +/- 0.050 mmol/L) in patients with other age categories. The level of HbA1c was highest in the youngest group (8.809 +/- 0.056%) and lowest in the oldest group (8.653 +/- 0.082%). There was a significant correlation between FPG and HbA1c (R = 0.571, p < 0.001). There were 484 patients below the diagnostic threshold (HbA1c <6.5%), resulting in 3.78% false negative predictions. Majority of the false negative patients were in the age group of 40 75 years and had borderline FPG (7.0-8.0 mmol/L) and HbA1c (6.0-6.5%). These findings suggest that Saudi individuals with HbA1c between 6.0% and 6.5% may be considered as "probable diabetic" and their status should be verified by combined FPG and HbA1c criteria. PMID- 24067132 TI - Are the children and adolescents with congenital heart disease living in Southwestern Ontario really overweight and obese? AB - OBJECTIVE: To assess the prevalence of overweight and obesity in children with congenital heart disease and compare them with age-matched healthy children in Southwestern Ontario, Canada. METHODS: We compared the Center of Disease Control weight and body mass index z-scores of 1080 children, aged 2 to 18 years, who presented to our paediatric cardiology outpatient clinic from 2008 to 2010 for congenital heart disease with 1083 healthy controls. RESULTS: In all, 18.2% of the children with congenital heart disease and 20.8% of healthy children were identified to be either overweight or obese. Overall, the weight category distribution had been similar between the congenital heart disease and healthy control groups, as well as between the congenital heart disease subgroups. There was no difference in normal weight and overweight/obese categories between children with congenital heart disease and healthy children. The underweight category, however, showed a significantly higher prevalence in congenital heart disease compared with healthy children (6.8 and 4.5%, respectively, p = 0.03). CONCLUSION: The prevalence of overweight/obesity did not differ in children with congenital heart disease compared with age-matched healthy children; however, it is still high (18.2%). Obesity may represent an additional risk factor for the long-term cardiovascular health of congenital heart disease patients aside from the underlying heart defect. PMID- 24067133 TI - Parts-per-million of polyethylene glycol as a non-interfering blocking agent for homogeneous biosensor development. AB - Many homogeneous assays are complicated by the adsorption of probe molecules by the surface of reaction vessels, which are often made of polypropylene or polystyrene-based plastics. To solve this problem, many protein and surfactant based blocking agents are used. However, these blockers may interfere with intended assays by sequestering transition-metal ions, inducing protein denaturing, generating air bubbles or making pores in membranes. Coating surfaces with polyethylene glycol (PEG) through covalent linkages has been proven to be an effective method to minimize protein adsorption. However, this method is more difficult to apply on plastic surfaces and is quite expensive. While unmodified PEG is often considered as a nonadsorbing polymer, in this Technical Note, we report that PEG at very low concentration (ppm level) can still effectively block plastic surfaces. This method works for DNA, protein, and liposome-based assays as long as the molecular weight of PEG is greater than 2000. PEG works because of multivalent hydrophobic interaction from its repeating methylene units. This Technical Note will not only facilitate biosensor development, but also enhance our understanding of the interaction between various molecules and plastic surfaces. PMID- 24067134 TI - Four coordination polymers based on identical eight-connected heptanuclear clusters: spin canting, spin glass, antiferromagnetism, and gas adsorption. AB - Four 3D coordination polymers, [Co7(OH)4(H2O)2(ina)4(ip)3].10H2O (1.10H2O, ina = isonicotinate, ip = isophthalate), [Ni7(OH)4(H2O)2(ina)4(ip)3].10H2O (2.10H2O), [Co7(OH)4(H2O)2(ina)4(pip)3].5H2O (3.5H2O, pip = 5-phenyl-isophthalate), and [Ni7(OH)4(H2O)2(ina)4(pip)3].5H2O (4.5H2O), respectively, were hydrothermally synthesized. They crystallized in the orthorhombic space group Pba2 for 1.10H2O and 2.10H2O and monoclinic space group P2/n for 3.5H2O and 4.5H2O, respectively, and were constructed with the identical 8-connected heptanuclear {M7(OH)4} (M = Co(II) or Ni(II)) clusters, possessing uninodal hexagonal primitive net with the point symbol {3(6).4(18).5(3).6}. The four coordination polymers showed dominant antiferromangetic properties, in which 1.10H2O shows spin-canted behavior and 2.10H2O exhibits the coexistence of spin canting and spin glass. Meanwhile, the activated polymers 1 and 2 possessed permanent porosity, displaying relatively large H2 uptake capacity (77 K, 1 atm) of 114 and 133 cm(3) g(-1), and CO2 uptake capacity (273 K, 1 atm) of 65.8 and 73.3 cm(3) g(-1), for 1 and 2, respectively. PMID- 24067135 TI - Disparate survival and risk of secondary non-Hodgkin lymphoma in histologic subtypes of Hodgkin lymphoma: a population-based study. AB - We compared survival outcomes and rates of secondary non-Hodgkin lymphoma (NHL) in 28 323 patients with nodular lymphocyte predominant (NLPHL) and classical Hodgkin lymphoma (HL) from the Surveillance, Epidemiology and End Results database, diagnosed between 1995 and 2010. In a multivariate analysis NLPHL demonstrated a significantly better relative survival (5-year risk of lymphoma related death 5.7%, hazard ratio [HR] 0.46, p < 0.0001) than the reference nodular sclerosis (NSHL) subtype (5-year risk 12.7%). Lymphocyte-rich classical HL had outcomes comparable to NSHL (5-year risk 14.3%, HR 0.84, p = 0.11). Exceptionally poor outcomes were observed in lymphocyte depleted HL (5-year risk 48.8%, HR 2.26, p < 0.0001). The risk of secondary NHL was increased in NLPHL (HR 2.81, p < 0.001) and lymphocyte-rich classical HL (HR 2.27, p = 0.002), but not in other subtypes compared with NSHL. In conclusion, the histologic classification retains a significant prognostic value in HL and the disparities between the subtypes warrant customized treatment and surveillance strategies. PMID- 24067136 TI - Plerixafor to the rescue: boosting peripheral blood stem cell mobilization in patients previously treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone/methotrexate, cytarabine (Hyper-CVAD) chemotherapy. AB - Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone/methotrexate, cytarabine (Hyper-CVAD) chemotherapy exerts deleterious effects on peripheral blood stem cell (PBSC) mobilization. We retrospectively reviewed the use of plerixafor to salvage mobilization in 18 Hyper-CVAD treated patients who initially mobilized poorly with chemotherapy and granulocyte colony stimulating factor (G-CSF). After plerixafor administration the median peripheral blood (PB) CD34 + count rose from 3.74/MUL (0-17/MUL) to 6.85/MUL (0-47.2/MUL). The patients collected a median of 1.64 (0.21-5.56) * 10(6) CD34 + cells/kg with a median number of 3 (1-4) doses in the same collection cycle, and 11 patients reached the 2.0 * 10(6) CD34 + cells/kg minimum required for transplant. Six patients were remobilized later with G-CSF and plerixafor, and three additional patients reached this goal. For these 14 patients the median number of doses of plerixafor required to reach 2.0 * 10(6) CD34 + cells/kg was 3 (range 1-4). In conclusion, plerixafor can be utilized successfully in many cases to overcome the effects of Hyper-CVAD on PBSC mobilization. PMID- 24067137 TI - Impact of mutations in FLT3, PTPN11 and RAS genes on the overall survival of pediatric B cell precursor acute lymphoblastic leukemia in Brazil. AB - We analyzed mutations in four genes (FLT3, KRAS/NRAS and PTPN11) that might disrupt the RAS/mitogen activated protein kinase (MAPKinase) signaling pathway, to evaluate their prognostic value in children younger than 16 years old with B cell precursor acute lymphoblastic leukemia (Bcp-ALL). The overall survival (OS) was determined with the Kaplan-Meier method. MAPKinase genes were mutated in 25.4% and 20.1% of childhood and infant Bcp-ALL, respectively. Children with hyperdiploidy were more prone to harboring a MAPKinase gene mutation (odds ratio [OR] 3.18; 95% confidence interval [CI] 1.07-9.49). The mean OS of all cases was 54.0 months. FLT3 and PTPN11 mutations had no impact on OS. K/NRAS mutations were strongly associated with MLL-AFF1 (OR 5.78; 95% CI 1.00-33.24), and conferred poorer OS (p = 0.034) in univariate analysis. PMID- 24067138 TI - Bortezomib and lenalidomide as front-line therapy for multiple myeloma. AB - The objective of the study was to investigate the effects and safety of novel agents such as bortezomib and lenalidomide in the treatment of newly diagnosed patients with multiple myeloma. We performed a comprehensive meta-analysis of randomized controlled trials (RCTs). An initial search yielded 627 citations, of which 10 RCTs enrolling 4534 patients met the inclusion criteria. The addition of bortezomib to first-line therapy significantly prolonged overall survival (OS) (hazard ratio [HR], 0.75 [0.65, 0.87], p < 0.001). On the other hand, the addition of lenalidomide had no impact on survival (HR, 0.88 [0.65, 1.20], p = 0.42). Both lenalidomide and bortezomib consistently improved progression-free survival (PFS) compared with conventional therapy alone. The corresponding HRs were 0.65, 95% confidence interval (CI) [0.55, 0.77] (p < 0.001) for bortezomib and 0.48, 95% CI [0.42, 0.55]; (p < 0.001) for lenalidomide, respectively. Some of the increased adverse events reported were herpes zoster (relative risk [RR], 3.64 [2.23, 5.94], p < 0.001), peripheral neuropathy (RR, 3.59 [1.89, 6.83], p < 0.001) and gastrointestinal effects (RR, 2.19 [1.37, 3.50], p = 0.001) among patients receiving bortezomib, and gastrointestinal effects (RR, 2.36 [1.33, 4.17], p = 0.003) and thromboembolic events (RR, 2.55 [1.48, 4.38], p < 0.001) among patients receiving lenalidomide. Interestingly, treatment with bortezomib seemed to be associated with a lower rate of treatment related mortality (RR, 0.39 [0.18, 0.85], p = 0.02). An increased incidence of second primary cancers was observed in the lenalidomide group (RR 2.61 [1.60, 4.27], p < 0.001). In summary, bortezomib improved OS, and both lenalidomide and bortezomib consistently improved PFS of patients with newly diagnosed myeloma when it was added to standard therapy. PMID- 24067139 TI - Expression of KLF4 is a predictive marker for survival in pediatric Burkitt lymphoma. AB - Kruppel-like factor 4 (KLF4) is expressed in a variety of tissues with diverse physiological functions and activities. KLF4 can also function as a tumor suppressor or an oncogene, depending on the cellular context. Its role in hematological malignancies is controversial. This study examined the expression levels of KLF4 by immunohistochemistry in 73 pediatric non-Hodgkin lymphomas (NHLs) in a tissue microarray and also on several B-NHL cell lines. Elevated levels of KLF4 expression were detected in 66% of lymphoma cases and were more frequent in the Burkitt lymphoma (p = 0.05) subtype. There was a significant predictive power for outcome with low KLF4 expression, predicting a favorable overall survival compared to high levels. Multivariate analyses confirmed the association of KLF4 expression with unfavorable overall survival (p < 0.005). These findings were consistent with analyses in existing NHL microarray datasets. The present findings revealed that KLF4 is overexpressed in Burkitt pediatric lymphoma and is a potential biomarker for inferior overall survival. PMID- 24067140 TI - Hodgkin lymphoma, allogeneic transplant and the graft-versus-tumor effect: size does matter. PMID- 24067141 TI - IFN-gamma alters the human sperm membrane permeability to Ca(2+). AB - Inflammation in the male genitourinary tract has been associated with the release of pro-inflammatory cytokines such as interferon-gamma (IFN-gamma) and elevated reactive oxygen species, which affects spermatozoa capacitation, motility, and the acrosome reaction, along with functions regulated by the concentration of cytoplasmic Ca(2+) ([Ca(2+)]cyto). Though Ca(2+) signaling is of particular significance in sperm, the effect of IFN-gamma intracellular calcium on these cells is still unknown. The present study evaluated the effect of IFN-gamma on the [Ca(2+)]cyto and Ca(2+) permeability on human sperm. A cell suspension loaded with fura-2 was incubated with or without IFN-gamma (from 0 to 2000 pg/ml) for 0, 30, 60, and 120 minutes, and the [Ca(2+)]cyto was measured. The permeability to Ca(2+) was evaluated by the change of the intracellular concentration following an extracellular Ca(2+) pulse. IFN-gamma at low concentrations (<= 500 pg/ml) did not affect the [Ca(2+)]cyto and Ca(2+) permeability of sperm. At a high concentration (2000 pg/ml), IFN-gamma did not alter the [Ca(2+)](cyto), but significantly decreased the magnitude and velocity of Ca(2+) entry into the cell. This effect was dependent on incubation time and IFN-gamma concentration. This alteration induced by IFN-gamma was prevented by the simultaneous incubation of sperm with the antioxidant butylhydroxytoluene (BHT). In conclusion, in vitro, IFN-gamma modifies Ca(2+) sperm membrane permeability, probably via lipid peroxidation. IFN-gamma in high concentration, as observed in inflammation/infection, can affect [Ca(2+)](cyto) regulation and alter sperm fertilizing capacity. PMID- 24067142 TI - The case for multimodal analysis of atypical interaction: questions, answers and gaze in play involving a child with autism. AB - Conversation analysis (CA) continues to accrue interest within clinical linguistics as a methodology that can enable elucidation of structural and sequential orderliness in interactions involving participants who produce ostensibly disordered communication behaviours. However, it can be challenging to apply CA to re-examine clinical phenomena that have initially been defined in terms of linguistics, as a logical starting point for analysis may be to focus primarily on the organisation of language ("talk") in such interactions. In this article, we argue that CA's methodological power can only be fully exploited in this research context when a multimodal analytic orientation is adopted, where due consideration is given to participants' co-ordinated use of multiple semiotic resources including, but not limited to, talk (e.g., gaze, embodied action, object use and so forth). To evidence this argument, a two-layered analysis of unusual question-answer sequences in a play episode involving a child with autism is presented. It is thereby demonstrated that only when the scope of enquiry is broadened to include gaze and other embodied action can an account be generated of orderliness within these sequences. This finding has important implications for CA's application as a research methodology within clinical linguistics. PMID- 24067143 TI - A facile approach for the asymmetric synthesis of oxindoles with a 3-sulfenyl substituted quaternary stereocenter. AB - With the employment of a threonine-incorporating multifunctional catalyst 9, Michael addition of 3-sulfenyloxindoles to nitroolefins proceeded stereoselectively, leading to the formation of oxindoles with a 3-sulfenyl substituted quaternary center in excellent yields, and with high diastereoselectivities and excellent enantioselectivities. PMID- 24067144 TI - Korean red ginseng for allergic rhinitis. PMID- 24067146 TI - The role of social relationships and culture in the cognitive representation of emotions. AB - There are individual and cultural differences in how memories of our emotions are cognitively represented. This article examines the cognitive representation of emotions in different cultures, as a result of emotional (in)consistency in different cultures. Using a continuous semantic priming task, we showed in two studies that individuals who were less emotionally consistent across relationships have stronger associations of their emotions within those relationships. Further, we found (in Study 2) that in a culture characterised by higher levels of emotional inconsistency across relationships (Singapore), stronger associations between emotions within relationships were found than in a culture characterised by emotional consistency (USA). This cultural difference in cognitive representation was fully mediated by individual differences in cross situational consistency levels. PMID- 24067145 TI - Transcriptional mechanisms underlying sensitization of peripheral sensory neurons by granulocyte-/granulocyte-macrophage colony stimulating factors. AB - BACKGROUND: Cancer-associated pain is a major cause of poor quality of life in cancer patients and is frequently resistant to conventional therapy. Recent studies indicate that some hematopoietic growth factors, namely granulocyte macrophage colony stimulating factor (GMCSF) and granulocyte colony stimulating factor (GCSF), are abundantly released in the tumor microenvironment and play a key role in regulating tumor-nerve interactions and tumor-associated pain by activating receptors on dorsal root ganglion (DRG) neurons. Moreover, these hematopoietic factors have been highly implicated in postsurgical pain, inflammatory pain and osteoarthritic pain. However, the molecular mechanisms via which G-/GMCSF bring about nociceptive sensitization and elicit pain are not known. RESULTS: In order to elucidate G-/GMCSF mediated transcriptional changes in the sensory neurons, we performed a comprehensive, genome-wide analysis of changes in the transcriptome of DRG neurons brought about by exposure to GMCSF or GCSF. We present complete information on regulated genes and validated profiling analyses and report novel regulatory networks and interaction maps revealed by detailed bioinformatics analyses. Amongst these, we validate calpain 2, matrix metalloproteinase 9 (MMP9) and a RhoGTPase Rac1 as well as Tumor necrosis factor alpha (TNFalpha) as transcriptional targets of G-/GMCSF and demonstrate the importance of MMP9 and Rac1 in GMCSF-induced nociceptor sensitization. CONCLUSION: With integrative approach of bioinformatics, in vivo pharmacology and behavioral analyses, our results not only indicate that transcriptional control by G-/GMCSF signaling regulates a variety of established pain modulators, but also uncover a large number of novel targets, paving the way for translational analyses in the context of pain disorders. PMID- 24067147 TI - Phylogeny and biogeography of a shallow water fish clade (Teleostei: Blenniiformes). AB - BACKGROUND: The Blenniiformes comprises six families, 151 genera and nearly 900 species of small teleost fishes closely associated with coastal benthic habitats. They provide an unparalleled opportunity for studying marine biogeography because they include the globally distributed families Tripterygiidae (triplefin blennies) and Blenniidae (combtooth blennies), the temperate Clinidae (kelp blennies), and three largely Neotropical families (Labrisomidae, Chaenopsidae, and Dactyloscopidae). However, interpretation of these distributional patterns has been hindered by largely unresolved inter-familial relationships and the lack of evidence of monophyly of the Labrisomidae. RESULTS: We explored the phylogenetic relationships of the Blenniiformes based on one mitochondrial (COI) and four nuclear (TMO-4C4, RAG1, Rhodopsin, and Histone H3) loci for 150 blenniiform species, and representative outgroups (Gobiesocidae, Opistognathidae and Grammatidae). According to the consensus of Bayesian Inference, Maximum Likelihood, and Maximum Parsimony analyses, the monophyly of the Blenniiformes and the Tripterygiidae, Blenniidae, Clinidae, and Dactyloscopidae is supported. The Tripterygiidae is the sister group of all other blennies, and the Blenniidae is the sister group of the remaining blennies. The monophyly of the Labrisomidae is supported with the exclusion of the Cryptotremini and inclusion of Stathmonotus, and we elevate two subgenera of Labrisomus to establish a monophyletic classification within the family. The monophyly of the Chaenopsidae is supported with the exclusion of Stathmonotus (placed in the Stathmonotini) and Neoclinus and Mccoskerichthys (placed in the Neoclinini). The origin of the Blenniiformes was estimated in the present-day IndoPacific region, corresponding to the Tethys Sea approximately 60.3 mya. A largely Neotropical lineage including the Labrisomidae, Chaenopsidae and Dactyloscopidae (node IV) evolved around 37.6 mya when the Neotropics were increasingly separated from the IndoPacific, but well before the closure of the Tethys Sea. CONCLUSIONS: Relationships recovered in this study are similar to those of earlier analyses within the Clinidae and Chaenopsidae, and partially similar within the Blenniidae, but tripterygiid relationships remain poorly resolved. We present the first comprehensive phylogenetic hypothesis for a monophyletic Labrisomidae with five tribes (Labrisomini, Mnierpini, Paraclinini, Stathmonotini and Starksiini). Global distributions of blenny genera included in our analysis support the evolution of a largely Neotropical clade whose closest relatives (clinids and cryptotremines) are temperate in distribution. PMID- 24067148 TI - Gastric outlet obstruction at Bugando Medical Centre in Northwestern Tanzania: a prospective review of 184 cases. AB - BACKGROUND: Gastric outlet obstruction poses diagnostic and therapeutic challenges to general surgeons practicing in resource-limited countries. There is a paucity of published data on this subject in our setting. This study was undertaken to highlight the etiological spectrum and treatment outcome of gastric outlet obstruction in our setting and to identify prognostic factors for morbidity and mortality. METHODS: This was a descriptive prospective study which was conducted at Bugando Medical Centre between March 2009 and February 2013. All patients with a clinical diagnosis of gastric outlet obstruction were, after informed consent for the study, consecutively enrolled into the study. Statistical data analysis was done using SPSS computer software version 17.0. RESULTS: A total of 184 patients were studied. More than two-third of patients were males. Patients with malignant gastric outlet obstruction were older than those of benign type. This difference was statistically significant (p < 0.001). Gastric cancer was the commonest malignant cause of gastric outlet obstruction where as peptic ulcer disease was the commonest benign cause. In children, the commonest cause of gastric outlet obstruction was congenital pyloric stenosis (13.0%). Non-bilious vomiting (100%) and weight loss (93.5%) were the most frequent symptoms. Eighteen (9.8%) patients were HIV positive with the median CD 4+ count of 282 cells/MUl. A total of 168 (91.3%) patients underwent surgery. Of these, gastro-jejunostomy (61.9%) was the most common surgical procedure performed. The complication rate was 32.1 % mainly surgical site infections (38.2%). The median hospital stay and mortality rate were 14 days and 18.5% respectively. The presence of postoperative complication was the main predictor of hospital stay (p = 0.002), whereas the age > 60 years, co-existing medical illness, malignant cause, HIV positivity, low CD 4 count (<200 cells/MUl), high ASA class and presence of surgical site infection significantly predicted mortality ( p< 0.001). The follow up of patients was generally poor as more than 60% of patients were lost to follow up. CONCLUSION: Gastric outlet obstruction in our setting is more prevalent in males and the cause is mostly malignant. The majority of patients present late with poor general condition. Early recognition of the diagnosis, aggressive resuscitation and early institution of surgical management is of paramount importance if morbidity and mortality associated with gastric outlet obstruction are to be avoided. PMID- 24067149 TI - Changes in plantar loading based on shoe type and sex during a jump-landing task. AB - CONTEXT: Metatarsal stress fractures are common in cleated-sport athletes. Previous authors have shown that plantar loading varies with footwear, sex, and the athletic task. OBJECTIVE: To examine the effects of shoe type and sex on plantar loading in the medial midfoot (MMF), lateral midfoot (LMF), medial forefoot (MFF), middle forefoot (MidFF), and lateral forefoot (LFF) during a jump landing task. DESIGN: Crossover study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty-seven recreational athletes (14 men, 13 women) with no history of lower extremity injury in the last 6 months and no history of foot or ankle surgery. MAIN OUTCOME MEASURE(S): The athletes completed 7 jumping trials while wearing bladed-cleat, turf-cleat, and running shoes. Maximum force, contact area, contact time, and the force-time integral were analyzed in each foot region. We calculated 2 * 3 analyses of variance (alpha = .05) to identify shoe condition and sex differences. RESULTS: We found no shoe * sex interactions, but the MMF, LMF, MFF, and LFF force-time integrals were greater in men (P < .03). The MMF maximum force was less with the bladed-cleat shoes (P = .02). Total foot and MidFF maximum force was less with the running shoes (P < .01). The MFF and LFF maximum forces were different among all shoe conditions (P < .01). Total foot contact area was less in the bladed-cleat shoes (P = .01). The MMF contact area was greatest in the running shoes (P < .01). The LFF contact area was less in the running shoes (P = .03). The MFF and LFF force-time integrals were greater with the bladed-cleat shoes (P < .01). The MidFF force-time integral was less in the running shoes (P < .01). CONCLUSIONS: Independent of shoe, men and women loaded the foot differently during a jump landing. The bladed cleat increased forefoot loading, which may increase the risk for forefoot injury. The type of shoe should be considered when choosing footwear for athletes returning to activity after metatarsal stress fractures. PMID- 24067150 TI - Lower extremity muscle strength after anterior cruciate ligament injury and reconstruction. AB - CONTEXT: Quadriceps and hamstrings weakness occurs frequently after anterior cruciate ligament (ACL) injury and reconstruction. Evidence suggests that knee injury may precipitate hip and ankle muscle weakness, but few data support this contention after ACL injury and reconstruction. OBJECTIVE: To determine if hip, knee, and ankle muscle weakness present after ACL injury and after rehabilitation for ACL reconstruction. DESIGN: Case-control study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Fifteen individuals with ACL injury (8 males, 7 females; age = 20.27 +/- 5.38 years, height = 1.75 +/- 0.10 m, mass = 74.39 +/- 13.26 kg) and 15 control individuals (7 men, 8 women; age = 24.73 +/- 3.37 years, height = 1.75 +/- 0.09 m, mass = 73.25 +/- 13.48 kg). INTERVENTION(S): Bilateral concentric strength was assessed at 60 degrees /s on an isokinetic dynamometer. The participants with ACL injury were tested preoperatively and 6 months postoperatively. Control participants were tested on 1 occasion. MAIN OUTCOME MEASURES: Hip-flexor, -extensor, -abductor, and adductor; knee-extensor and -flexor; and ankle-plantar-flexor and -dorsiflexor strength (Nm/kg). RESULTS: The ACL-injured participants demonstrated greater hip extensor (percentage difference = 19.7, F1,14 = 7.28, P = .02) and -adductor (percentage difference = 16.3, F1,14 = 6.15, P = .03) weakness preoperatively than postoperatively, regardless of limb, and greater postoperative hip-adductor strength (percentage difference = 29.0, F1,28 = 10.66, P = .003) than control participants. Knee-extensor and -flexor strength were lower in the injured than in the uninjured limb preoperatively and postoperatively (extensor percentage difference = 34.6 preoperatively and 32.6 postoperatively, t14 range = -4.59 to 4.23, P <= .001; flexor percentage difference = 30.6 preoperatively and 10.6 postoperatively, t14 range = -6.05 to -3.24, P < .05) with greater knee-flexor (percentage difference = 25.3, t14 = -4.65, P < .001) weakness preoperatively in the injured limb of ACL-injured participants. The ACL-injured participants had less injured limb knee-extensor (percentage difference = 32.0, t28 = -2.84, P = .008) and -flexor (percentage difference = 24.0, t28 = -2.44, P = .02) strength preoperatively but not postoperatively (extensor: t28 = -1.79, P = .08; flexor: t28 = 0.57, P = .58) than control participants. Ankle-plantar-flexor weakness was greater preoperatively than postoperatively in the ACL-injured limb (percentage difference = 31.9, t14 = -3.20, P = .006). CONCLUSIONS: The ACL-injured participants presented with hip-extensor, -adductor, and ankle-plantar-flexor weakness that appeared to be countered during postoperative rehabilitation. Our results confirmed previous findings suggesting greater knee-extensor and -flexor weakness postoperatively in the injured limb than the uninjured limb. The knee extensors and flexors are important dynamic stabilizers; weakness in these muscles could impair knee joint stability. Improving rehabilitation strategies to better target this lingering weakness seems imperative. PMID- 24067151 TI - Interrater reliability of the star excursion balance test. AB - CONTEXT: Dynamic postural control has gained popularity as a more useful assessment of function than static postural control. One measurement of dynamic postural control that has increased in frequency of use is the Star Excursion Balance Test (SEBT). Although the intrarater reliability of the SEBT is excellent, few authors have determined interrater reliability. Preliminary evidence has shown poor reliability between assessors. OBJECTIVE: To determine interrater reliability using a group of investigators at 2 testing sites. A corollary purpose was to examine the interrater reliability when using normalized and nonnormalized performance scores on the SEBT. DESIGN: Descriptive laboratory study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 29 healthy participants between 18 and 50 years of age. INTERVENTION(S): Participants were evaluated by 5 raters at 2 testing sites. After participants performed 4 practice trials, each rater assessed 3 test trials in the anterior, posteromedial, and posterolateral reaching directions of the SEBT. MAIN OUTCOME MEASURE(S): Normalized and nonnormalized (leg-length) reaching distances were analyzed. Additionally, the mean and maximum values from the 3 test trials were analyzed, producing a total of 16 variables. RESULTS: For all 16 measures, the interrater reliability was excellent. For the normalized maximum excursion distances, the intraclass correlation coefficients (1,1) ranged from 0.86 to 0.92. Reliability for the nonnormalized measurements was stronger, ranging from 0.89 to 0.94. CONCLUSIONS: When the raters have been trained by an experienced rater, the SEBT is a test with excellent reliability when used across multiple raters in different settings. This information adds to the body of knowledge that exists regarding the usefulness of the SEBT as an assessment tool in clinical and research practice. Establishing excellent interrater reliability with normalized and nonnormalized scores strengthens the evidence for using the SEBT, especially at multiple sites. PMID- 24067152 TI - Fulfillment of work-life balance from the organizational perspective: a case study. AB - CONTEXT: Researchers studying work-life balance have examined policy development and implementation to create a family-friendly work environment from an individualistic perspective rather than from a cohort of employees working under the same supervisor. OBJECTIVE: To investigate what factors influence work-life balance within the National Collegiate Athletic Association (NCAA) Division I clinical setting from the perspective of an athletic training staff. DESIGN: Qualitative study. SETTING: Web-based management system. PATIENTS OR OTHER PARTICIPANTS: Eight athletic trainers (5 men, 3 women; age = 38 +/- 7 years) in the NCAA Division I setting. DATA COLLECTION AND ANALYSIS: Participants responded to a series of questions by journaling their thoughts and experiences. We included data-source triangulation, multiple-analyst triangulation, and peer review to establish data credibility. We analyzed the data via a grounded theory approach. RESULTS: Three themes emerged from the data. Family-oriented and supportive work environment was described as a workplace that fosters and encourages work-life balance through professionally and personally shared goals. Nonwork outlets included activities, such as exercise and personal hobbies, that provide time away from the role of the athletic trainer. Individualistic strategies reflected that although the athletic training staff must work together and support one another, each staff member must have his or her own personal strategies to manage personal and professional responsibilities. CONCLUSIONS: The foundation for a successful work environment in the NCAA Division I clinical setting potentially can center on the management style of the supervisor, especially one who promotes teamwork among his or her staff members. Although a family-friendly work environment is necessary for work-life balance, each member of the athletic training staff must have personal strategies in place to fully achieve a balance. PMID- 24067153 TI - Different modes of feedback and peak vertical ground reaction force during jump landing: a systematic review. AB - CONTEXT: Excessive ground reaction force when landing from a jump may result in lower extremity injuries. It is important to better understand how feedback can influence ground reaction force (GRF) and potentially reduce injury risk. OBJECTIVE: To determine the effect of expert-provided (EP), self-analysis (SA), and combination EP and SA (combo) feedback on reducing peak vertical GRF during a jump-landing task. DATA SOURCES: We searched the Web of Science database on July 1, 2011; using the search terms ground reaction force, landing biomechanics, and feedback elicited 731 initial hits. STUDY SELECTION: Of the 731 initial hits, our final analysis included 7 studies that incorporated 32 separate data comparisons. DATA EXTRACTION: Standardized effect sizes and 95% confidence intervals (CIs) were calculated between pretest and posttest scores for each feedback condition. DATA SYNTHESIS: We found a homogeneous beneficial effect for combo feedback, indicating a reduction in GRF with no CIs crossing zero. We also found a homogeneous beneficial effect for EP feedback, but the CIs from 4 of the 10 data comparisons crossed zero. The SA feedback showed strong, definitive effects when the intervention included a videotape SA, with no CIs crossing zero. CONCLUSIONS: Of the 7 studies reviewed, combo feedback seemed to produce the greatest decrease in peak vertical GRF during a jump-landing task. PMID- 24067154 TI - Inter-association recommendations for developing a plan to recognize and refer student-athletes with psychological concerns at the collegiate level: an executive summary of a consensus statement. PMID- 24067155 TI - Partial sublimation of enantioenriched amino acids at low temperature. Is it coming from the formation of a euatmotic composition of the gaseous phase? AB - The partial sublimation of enantioenriched amino acids was performed slowly at low temperature with the aim to determine the rules of sublimation of these compounds. Although the formation of a euatmotic composition of the gaseous phase starting from DL + L mixtures of Leu, Pro, and Phe can be deduced from the enantiomeric excess of sublimates, the behavior of the kinetic conglomerate explains the results for D + L mixtures of Ala, Leu, Val, and Pro. Consequently, the enantiomeric excess of the partial sublimate is dependent not only on the studied compound but also on the composition of the starting mixture. PMID- 24067156 TI - Unusual epileptic deterioration and extensive white matter lesion during treatment in Wilson's disease. AB - BACKGROUND: Wilson's disease (WD) is a genetic disorder which can be controlled fairly well with decupuration therapy. However, symptoms, on rare occasions, can worsen even when WD is being treated. Herein, we report a case involving unusual neurological deterioration during decupuration therapy for WD. CASE PRESENTATION: A 28-year-old man was diagnosed with WD 13 years prior to his clinical visit; however, his drug compliance has been poor over the years. He was treated with trientine because tremors and dysarthria have presented in recent years. However, dysarthria and dystonia developed in his limbs, which were worse on the right side and had been aggravated for several weeks despite good drug compliance. His symptoms were fluctuating. It was initially misdiagnosed as dystonia; although, it turned out to be a seizure due to cortical degeneration. These symptoms were completely resolved with antiepileptic drugs. Moreover, the cortical enhancement of bifrontal degeneration has disappeared on the MRI. CONCLUSION: This case showed unusual epileptic neurologic deterioration due to cortical degeneration during decupuration therapy. Seizures in WD can easily be mistaken as part of dystonia. However, the fluctuating symptoms suggest a seizure. PMID- 24067157 TI - Creative Speech Technology: editorial introduction to this special issue. AB - CreST is the Creative Speech Technology Network, a research network which brought together people from a wide variety of backgrounds spanning arts technology and beyond. The papers in this volume represent some of the outcomes of that collaboration. This editorial introduces the background of the network and each of the papers. In conclusion we demonstrate that this work helped to realize many of the objectives of the network. PMID- 24067158 TI - Fog-harvesting potential of lubricant-impregnated electrospun nanomats. AB - Hydrophobic PVDF-HFP nanowebs were fabricated by a facile electrospinning method and proposed for harvesting fog from the atmosphere. A strong adhesive force between the surface and a water droplet has been observed, which resists the water being shed from the surface. The water droplets on the inhomogeneous nanomats showed high contact angle hysteresis. The impregnation of nanomats with lubricants (total quartz oil and Krytox 1506) decreased the contact angle hysteresis and hence improved the roll off of water droplets on the nanomat surface. It was found that water droplets of 5 MUL size (diameter = 2.1 mm) and larger roll down on an oil-impregnated surface, held vertically, compared to 38 MUL (diameter = 4.2 mm) on a plain nanoweb. The contact angle hysteresis decreased from ~95 to ~23 degrees with the Krytox 1506 impregnation. PMID- 24067159 TI - Assessment of P-wave dispersion in children with atrial septal aneurysm. AB - BACKGROUND: This was a prospective controlled study to determine the P-wave duration and P-wave dispersion in patients with atrial septal aneurysm. METHODS: A total of 41 children with atrial septal aneurysm, including 21 boys and 20 girls (mean age 11.85 +/- 3.8 years), and 32 controls, including 17 boys and 15 girls (mean age 12.3 +/- 2.9 years), were included. P-wave dispersion was calculated from the 12-lead electrocardiogram. Cardiac functions, morphology of the aneurysm, and left atrial diameter were measured using conventional echocardiography. The diagnosis of atrial septal aneurysm was made when the base of the aneurysms with an excursion ratio >=25% was found on echocardiography. RESULTS: There was no significant difference between the patient and control groups in demographic, clinical findings, and M-mode echocardiographic parameters. The P-wave dispersion in patients with atrial septal aneurysm was significantly longer compared with the control group (64.4 +/- 13.4 ms; p < 0.0001). Similarly, the the maximum duration of the P wave in the patient group was significantly longer compared with the control group (106.1 +/- 13.3 ms; p < 0.001). The P-wave duration and dispersion were not correlated with age, gender, systolic and diastolic blood pressure, or m-mode echocardiographic parameters. CONCLUSIONS: This study shows that P-wave dispersion is delayed in atrial septal aneurysm patients. Prolonged P-wave dispersion was determined to indicate electrical disturbance, and therefore it has an increased electrocardiographic risk of atrial arrhythmia in children with atrial septal aneurysm. PMID- 24067161 TI - Lewis base mediated beta-elimination and Lewis acid mediated insertion reactions of disilazido zirconium compounds. AB - The reactivity of a series of disilazido zirconocene complexes is dominated by the migration of anionic groups (hydrogen, alkyl, halide, OTf) between the zirconium and silicon centers. The direction of these migrations is controlled by the addition of two-electron donors (Lewis bases) or two-electron acceptors (Lewis acids). The cationic nonclassical [Cp2ZrN(SiHMe2)2](+) ([2](+)) is prepared from Cp2Zr{N(SiHMe2)2}H (1) and B(C6F5)3 or [Ph3C][B(C6F5)4], while reactions of B(C6F5)3 and Cp2Zr{N(SiHMe2)2}R (R = Me (3), Et (5), n-C3H7 (7), CH?CHSiMe3 (9)) provide a mixture of [2](+) and [Cp2ZrN(SiHMe2)(SiRMe2)](+). The latter products are formed through B(C6F5)3 abstraction of a beta-H and R group migration from Zr to the beta-Si center. Related beta-hydrogen abstraction and X group migration reactions are observed for Cp2Zr{N(SiHMe2)2}X (X = OTf (11), Cl (13), OMe (15), O-i-C3H7 (16)). Alternatively, addition of DMAP (DMAP = 4 (dimethylamino)pyridine) to [2](+) results in coordination to a Si center and hydrogen migration to zirconium, giving the cationic complex [Cp2Zr{N(SiHMe2)(SiMe2DMAP)}H](+) ([19](+)). Related hydrogen migration occurs from [Cp2ZrN(SiHMe2)(SiMe2OCHMe2)](+) ([18](+)) to give [Cp2Zr{N(SiMe2DMAP)(SiMe2OCHMe2)}H](+) ([22](+)), whereas X group migration is observed upon addition of DMAP to [Cp2ZrN(SiHMe2)(SiMe2X)](+) (X = OTf ([12](+)), Cl ([14](+))) to give [Cp2Zr{N(SiHMe2)(SiMe2DMAP)}X](+) (X = OTf ([26](+)), Cl ([20](+))). The species involved in these transformations are described by resonance structures that suggest beta-elimination. Notably, such pathways are previously unknown in early metal amide chemistry. Finally, these migrations facilitate direct Si-H addition to carbonyls, which is proposed to occur through a pathway that previously had been reserved for later transition metal compounds. PMID- 24067160 TI - Probing nanoscale self-assembly of nonfluorescent small molecules inside live mammalian cells. AB - Like cellular proteins that form fibrillar nanostructures, small hydrogelator molecules self-assemble in water to generate molecular nanofibers. In contrast to the well-defined (dys)functions of endogenous protein filaments, the fate of intracellular assembly of small molecules remains largely unknown. Here we demonstrate the imaging of enzyme-triggered self-assembly of nonfluorescent small molecules by doping the molecular assemblies with a fluorescent hydrogelator. The cell fractionation experiments, fluorescent imaging, and electron microscopy indicate that the hydrogelators self-assemble and localize to the endoplasmic reticulum (ER) and are likely processed via the cellular secretory pathway (i.e., ER-Golgi-lysosomes/secretion). This work, as the first example of the use of correlative light and electron microscopy for probing the self-assembly of nonfluorescent small molecules inside live mammalian cells, not only establishes a general strategy to provide the spatiotemporal profile of the assemblies of small molecules inside cells but may lead to a new paradigm for regulating cellular functions based on the interactions between the assemblies of small molecules (e.g., molecular nanofibers) and subcellular organelles. PMID- 24067163 TI - Progress toward the total synthesis of bielschowskysin. AB - Progress toward the total synthesis of bielschowskysin is described including introduction of the quaternary C12 and neighboring C13 stereocenters. PMID- 24067162 TI - Telmisartan increases lipoprotein lipase expression via peroxisome proliferator activated receptor-alpha in HepG2 cells. AB - In addition to their hypotensive properties, angiotensin receptor blockers (ARBs) have been shown to exert clinical antidyslipidemic effects. The mechanism underlying these ARB lipid metabolic effects remains unclear. Some ARBs, for example, telmisartan, activate peroxisome proliferator-activated activated receptor-gamma (PPAR-gamma). We hypothesized that PPAR-gamma-activating ARBs might exert antidyslipidemic effects via PPAR-alpha. In this study, we assessed the effect of telmisartan on the expression of PPAR-alpha and lipoprotein lipase (LPL). PPAR-alpha expression was detected by reverse-transcription polymerase chain reaction and Western blot in HepG2 hepatocytes as well as differentiated C2C12 myocytes treated with increasing concentrations of telmisartan (0.1-10 MUmol/L) for 48 h. Results showed that 1 MUmol/L and 10 MUmol/L telmisartan significantly increased the expression of PPAR-alpha mRNA and protein in HepG2 cells (p < 0.01). No effect was shown in differentiated C2C12 cells. Similarly, 1 umol/L and 10 MUmol/L telmisartan significantly increased the expression of LPL mRNA and protein in HepG2 cells (p < 0.01), and this increase was significantly (p < 0.01) inhibited by the PPAR-alpha-specific antagonist MK886. These results indicate that certain of the antidyslipidemic effects of telmisartan might be mediated via increased PPAR-alpha-dependent induction of LPL expression. PMID- 24067164 TI - Does active psychosis cause neurobiological pathology? A critical review of the neurotoxicity hypothesis. AB - BACKGROUND: Since the neurotoxicity hypothesis was launched in 1991, it has generated a great deal of interest and given rise to several studies investigating the validity of the hypothesis that being psychotic has a toxic effect on the brain. The toxicity argument is used to justify early treatment. This review attempts to assess the studies that have addressed the question: Does an active psychosis, indexed by the duration of untreated psychosis (DUP), cause neurobiological pathology? METHOD: The validity of the hypothesis has been studied primarily by correlation analyses that assess whether there are significant correlations between DUP and changes in neurocognitive functioning or brain structure. In this review, relevant reports were identified by a literature survey. RESULTS: Of the 35 studies (33 papers) evaluated, six neurocognitive studies supported the hypothesis and 16 did not. Eight morphology studies supported the hypothesis and five did not. In general, the studies that did not support the neurotoxicity hypothesis were larger in size and had more adequate designs (longitudinal) than those that supported the hypothesis. CONCLUSIONS: Overall, there is limited empirical evidence for the neurotoxicity hypothesis in the studies reviewed. However, it is possible that there is a threshold value for a toxic effect of psychosis, rather than a linear relationship between DUP and a neurotoxic effect, and that several of the studies evaluated did not have a long enough DUP to detect a toxic effect of active psychosis. PMID- 24067166 TI - Theory and practice in action: the contributions of Michael Perkins to clinical linguistics. AB - This article reviews the scholarly contributions of Michael R. Perkins in the discipline of clinical linguistics and provides some indication of the reasons that he has been so successful. Three primary attributes were described through an analysis of his publications. PMID- 24067165 TI - Noise propagation through extracellular signaling leads to fluctuations in gene expression. AB - BACKGROUND: Cell-to-cell variability in mRNA and proteins has been observed in many biological systems, including the human innate immune response to viral infection. Most of these studies have focused on variability that arises from (a) intrinsic stochastic fluctuations in gene expression and (b) extrinsic sources (e.g. fluctuations in transcription factors). The main focus of our study is the effect of extracellular signaling on enhancing intrinsic stochastic fluctuations. As a new source of noise, the communication between cells with fluctuating numbers of components has received little attention. We use agent-based modeling to study this contribution to noise in a system of human dendritic cells responding to viral infection. RESULTS: Our results, validated by single-cell experiments, show that in the transient state cell-to-cell variability in an interferon-stimulated gene (DDX58) arises from the interplay between the spatial randomness of the cellular sources of the interferon and the temporal stochasticity of its own production. The numerical simulations give insight into the time scales on which autocrine and paracrine signaling act in a heterogeneous population of dendritic cells upon viral infection. We study the effect of different factors that influence the magnitude of the cell-to-cell-variability of the induced gene, including the cell density, multiplicity of infection, and the time scale over which the cellular sources begin producing the cytokine. CONCLUSIONS: We propose a mechanism of noise propagation through extracellular communication and establish conditions under which the mechanism is operative. The cellular stochasticity of gene induction, which we investigate, is not limited to the specific interferon-induced gene we have studied; a broad distribution of copy numbers across cells is to be expected for other interferon stimulated genes. This can lead to functional consequences for the system-level response to a viral challenge. PMID- 24067167 TI - Recognizing short coding sequences of prokaryotic genome using a novel iteratively adaptive sparse partial least squares algorithm. AB - BACKGROUND: Significant efforts have been made to address the problem of identifying short genes in prokaryotic genomes. However, most known methods are not effective in detecting short genes. Because of the limited information contained in short DNA sequences, it is very difficult to accurately distinguish between protein coding and non-coding sequences in prokaryotic genomes. We have developed a new Iteratively Adaptive Sparse Partial Least Squares (IASPLS) algorithm as the classifier to improve the accuracy of the identification process. RESULTS: For testing, we chose the short coding and non-coding sequences from seven prokaryotic organisms. We used seven feature sets (including GC content, Z-curve, etc.) of short genes.In comparison with GeneMarkS, Metagene, Orphelia, and Heuristic Approachs methods, our model achieved the best prediction performance in identification of short prokaryotic genes. Even when we focused on the very short length group ([60-100 nt)), our model provided sensitivity as high as 83.44% and specificity as high as 92.8%. These values are two or three times higher than three of the other methods while Metagene fails to recognize genes in this length range.The experiments also proved that the IASPLS can improve the identification accuracy in comparison with other widely used classifiers, i.e. Logistic, Random Forest (RF) and K nearest neighbors (KNN). The accuracy in using IASPLS was improved 5.90% or more in comparison with the other methods. In addition to the improvements in accuracy, IASPLS required ten times less computer time than using KNN or RF. CONCLUSIONS: It is conclusive that our method is preferable for application as an automated method of short gene classification. Its linearity and easily optimized parameters make it practicable for predicting short genes of newly-sequenced or under-studied species. PMID- 24067168 TI - Survival in ALS with home mechanical ventilation non-invasively and invasively: a 15-year cohort study in west Denmark. AB - Our objective was to describe patient characteristics, survival and long-term outcome in amyotrophic lateral sclerosis (ALS) patients treated with non-invasive and invasive home mechanical ventilation (HMV). A single-centre cohort study over a 15-years period (1998-2012) was performed. All ALS patients admitted to the centre were enrolled in the study. All patients were offered treatment with non invasive and/or invasive HMV. The patients were divided into four groups: 1) no treatment; 2) treatment with non-invasive HMV; 3) treatment with non-invasive HMV followed by invasive HMV by tracheostomy; and 4) treatment with invasive HMV by tracheostomy. Patient characteristics and effects on survival were studied. Four hundred and thirty-one patients with ALS were admitted to a referral respiratory care unit (RCU) in the period January 1998 to June 2012. The average treatment time in the groups was: 1) 22.9 months (range 1-164); 2) 25.8 months (range 1 145); 3) 56.8 months (range 14-207); and 4) 33.8 months (range 6-88). Non invasive HMV followed by invasive HMV is a possible treatment of respiratory symptoms in ALS and has a significant effect on survival. PMID- 24067169 TI - How many bytes does it take? A content analysis of cyber issues in couple and family therapy journals. AB - In the fifteen years since the explosion of the Internet, using cyber technology for work and social functions has exponentially increased. Yet, questions around how to manage such changes remain elusive in family therapy literature. In this investigation, we conducted a content analysis to determine to what extent marriage/couple and family therapy (M/CFT) journals have responded to the integration of the Internet in couple and family life. We found 79 of 13,274 articles across seventeen journals focused on the Internet in some capacity. Implications for clinical practice, training, and future research are discussed. PMID- 24067170 TI - Highly sensitive and selective rhodamine-based "off-on" reversible chemosensor for tin (Sn4+) and imaging in living cells. AB - A structurally characterized new oxo-chromene functionalized rhodamine derivative L1 exhibits high selectivity toward Sn(4+) by forming a 1:1 complex, among other biologically important metal ions, as studied by fluorescence, absorption, and HRMS spectroscopy. Complexing with Sn(4+) triggers the formation of a highly fluorescent ring-open form which is pink in color. The sensor shows extremely high fluorescence enhancement upon complexation with Sn(4+), and it can be used as a "naked-eye" sensor. DFT computational studies carried out in mimicking the formation of a 1:1 complex between L1 and Sn(4+) resulted in a nearly planar pentacoordinate Sn(IV) complex. Studies reveal that the in situ prepared L1-Sn complex is selectively and fully reversible in presence of sulfide anions. Further, confocal microscopic studies confirmed that the receptor shows in vitro detection of Sn(4+) ions in RAW cells. PMID- 24067171 TI - "All dwellers at high altitude are persons of impaired physical and mental powers". PMID- 24067174 TI - The practical aspects of insulin at high altitude. AB - With the increasing prevalence of diabetes and current social philosophy of enablement, many more diabetics are travelling to high altitude where the rate of AMS in Type 1 diabetic mountaineers is no different than nondiabetics. Numerous effects of exercise, both degree and duration, dietary change, illness, stress, mountain sickness, counter-regulatory hormones, and altitude increased sympathetic output, and catecholamines have led to conflicting accounts of insulin requirement increasing or decreasing at altitude. Overall, it would appear that the effects of diet and exercise outweigh those of altitude. Good control requires continual insulin dose adjustment with frequent feedback from blood sugar testing, but glucometers can over- or under-read at altitude. Additionally, heat or cold exposure can degrade insulin efficacy; strategies for storing insulin are described. PMID- 24067175 TI - Pro: All dwellers at high altitude are persons of impaired physical and mental powers. PMID- 24067176 TI - Pro: All dwellers at high altitude are persons of impaired physical and mental powers. PMID- 24067177 TI - Con: All dwellers at high altitude are persons of impaired physical and mental powers: the view from the Andes. PMID- 24067178 TI - Con: All dwellers at high altitude are persons of impaired physical and mental powers: the view from the Himalayas. PMID- 24067179 TI - Rebuttal to con statements. PMID- 24067180 TI - Rebuttal to con statements. PMID- 24067181 TI - Rebuttal to pro statements. PMID- 24067182 TI - Rebuttal to pro statements. PMID- 24067183 TI - Epidemiological study of chronic mountain sickness in natives of Spiti Valley in the Greater Himalayas. AB - AIMS: This study determined the prevalence of chronic mountain sickness (CMS) and its predisposing factors among natives of Spiti Valley in the northern state of Indian Himalayas. A cross-sectional survey study was conducted in natives of Spiti Valley aged >= 20 years residing at altitudes of 3000 to 4200 meters. CMS was diagnosed using Qinghai criteria. Demographics, behavioral characteristics, specified symptoms of CMS were recorded, including BP, anthropometrics, evidence of RHF, PAH, and severe cyanosis. ECG, echocardiography, PFT, and Sao2 were recorded, and Hb level was estimated with the cyanmethhemoglobin method. RESULTS: 694 subjects free of cardiorespiratory diseases were analyzed. Prevalence of CMS was 28.7%, (95% C.I. of 25.9%-32.8%) and was higher in women than in men (36.6% vs. 15.7%, p<0.001). Erythrocythemia and hypoxemia were recorded in 10.5% and 7.5%, respectively. Age, truncal obesity, female gender, altitude of residence, and physical activity index were independent predictors of CMS with z statistics of 4.2, 2.29, -3.7, 2.8, and -2.8, respectively, and were statistically significant p<0.001. 6.2% of the surveyed population had HAPH. CONCLUSION: 28.7% (95% C.I. of 25.9%-32.8%) of the natives of the Spiti Valley in the Indian Himalayas are affected with CMS. Higher prevalence of CMS amongst women needs further studies. Westernized lifestyle appears to have predisposition to CMS. PMID- 24067184 TI - Continuous positive airway pressure treatment for acute mountain sickness at 4240 m in the Nepal Himalaya. AB - Acute mountain sickness (AMS) is very common at altitudes above 2500 m. There are few treatment options in the field where electricity availability is limited, and medical assistance or oxygen is unavailable or difficult to access. Positive airway pressure has been used to treat AMS at 3800 m. We hypothesized that continuous positive airway pressure (CPAP) could be used under field conditions powered by small rechargeable batteries. Methods Part 1. 5 subjects trekked to 3500 m from 2800 m in one day and slept there for one night, ascending in the late afternoon to 3840 m, where they slept using CPAP 6-7 cm via mask. The next morning they descended to 3500 m, spent the day there, ascended in late afternoon to 3840 m, and slept the night without CPAP. Continuous overnight oximetry was recorded and the Lake Louise questionnaire for AMS administered both mornings. Methods Part 2. 14 trekkers with symptoms of AMS were recruited at 4240 m. All took acetazolamide. The Lake Louise questionnaire was administered, oximetry recorded, and CPAP 6-7 cm was applied for 10-15 min. CPAP was used overnight and oximetry recorded continuously. In the morning the Lake Louise questionnaire was administered, and oximetry recorded for 10-15 min. The equipment used in both parts was heated, humidified Respironics RemStar(r) machines powered by NovuscellTM rechargeable lithium ion batteries. Oximetry was recorded using EmblettaTM PDS. Results Part 1. CPAP improved overnight Sao2 and eliminated AMS symptoms in the one subject who developed AMS. CPAP was used for 7-9 h and the machines operated for >8 h using the battery. Results Part 2. CPAP use improved Sao2 when used for 10-15 min at the time of recruitment and overnight CPAP use resulted in significantly reduced AMS symptoms. Conclusion. CPAP with rechargeable battery may be a useful treatment option for trekkers and climbers who develop AMS. PMID- 24067185 TI - Reduced insulin sensitivity as a marker for acute mountain sickness? AB - Reduced insulin sensitivity might increase the susceptibility to acute mountain sickness (AMS). The diabetogenic side effects of dexamethasone should therefore be considered for AMS treatment. To examine whether reduced insulin sensitivity is predictive of AMS and how it is affected by dexamethasone at high altitude, we analyzed endocrine and metabolic parameters obtained from healthy mountaineers in Zurich (LA; 490 m), and 2 and 4 days after fast ascent to the Capanna Regina Margherita (HA2, HA4; 4559 m). 14 of 25 participants developed AMS and were treated with dexamethasone starting in the evening of HA2. Before and after ingestion of an 1800 kJ meal, plasma was analyzed for erythropoietin (EPO) and cholecystokinin (CCK). Insulin sensitivity (HOMA-S) and beta cell activity were calculated. HOMA-S (p<0.01) and EPO levels (p<0.05) were lower in Zurich in the group developing AMS and given dexamethasone, i.e., before treatment and exposure to hypoxia. CCK was lower (p<0.01) and glucose and insulin were higher on HA4 in the dexamethasone group compared to the untreated group. Individuals with low baseline insulin sensitivity and low baseline EPO levels were more susceptible to AMS. Reduced CCK may contribute to the beneficial effect of dexamethasone on high altitude anorexia. However, reduced insulin sensitivity questions the widespread use of dexamethasone to prevent/treat AMS. PMID- 24067186 TI - The use of skeletal muscle near infrared spectroscopy and a vascular occlusion test at high altitude. AB - Microcirculatory function, central to tissue regulation of oxygen flux, may be altered by the chronic hypoxemia experienced at high altitude. We hypothesized that at high altitude, adaptations within skeletal muscle would result in reduced oxygen consumption and reduced microcirculatory responsiveness, detectable by near infrared spectroscopy (NIRS) during a vascular occlusion test (VOT). The VOT comprised 3 min of noninvasive arterial occlusion; thenar eminence tissue oxygenation (Sto2) was measured by NIRS during the VOT at sea level, 4900 m and 5600 m (after 7 and 17 days at altitude, respectively) in 12 healthy volunteers. Data were derived from Sto2 time-curves using specifically designed computer software. Mean (+/-SD) resting Sto2 was reduced at 4900 m and 5600 m (69.3 (+/- 8.2)% (p=0.001) and 64.2 (+/- 6.1)% (p<0.001) respectively) when compared to sea level (84.4 (+/- 6.0)%. The rate of Sto2 recovery after vascular occlusion (Sto2 upslope) was significantly reduced at 4900 m (2.4 (+/- 0.4)%/sec) and 5600 m (2.4 (+/- 0.8)%/sec) compared to sea level (3.7 (+/- 1.3)%/sec) (p=0.021 and p=0.032, respectively). There was no change from sea level in the rate of desaturation during occlusion (Sto2 downslope) at either altitude. The findings suggest that in resting skeletal muscle of acclimatizing healthy volunteers at high altitude, microvascular reactivity is reduced (Sto2 upslope after a short period of ischemia) but that oxygen consumption remains unchanged (Sto2 downslope). PMID- 24067187 TI - Oxidative stress in hypobaric hypoxia and influence on vessel-tone modifying mediators. AB - Increased pulmonary artery pressure is a well-known phenomenon of hypoxia and is seen in patients with chronic pulmonary diseases, and also in mountaineers on high altitude expedition. Different mediators are known to regulate pulmonary artery vessel tone. However, exact mechanisms are not fully understood and a multimodal process consisting of a whole panel of mediators is supposed to cause pulmonary artery vasoconstriction. We hypothesized that increased hypoxemia is associated with an increase in vasoconstrictive mediators and decrease of vasodilatators leading to a vasoconstrictive net effect. Furthermore, we suggested oxidative stress being partly involved in changement of these parameters. Oxygen saturation (Sao2) and clinical parameters were assessed in 34 volunteers before and during a Swiss research expedition to Mount Muztagh Ata (7549 m) in Western China. Blood samples were taken at four different sites up to an altitude of 6865 m. A mass spectrometry-based targeted metabolomic platform was used to detect multiple parameters, and revealed functional impairment of enzymes that require oxidation-sensitive cofactors. Specifically, the tetrahydrobiopterin (BH4)-dependent enzyme nitric oxide synthase (NOS) showed significantly lower activities (citrulline-to-arginine ratio decreased from baseline median 0.21 to 0.14 at 6265 m), indicating lower NO availability resulting in less vasodilatative activity. Correspondingly, an increase in systemic oxidative stress was found with a significant increase of the percentage of methionine sulfoxide from a median 6% under normoxic condition to a median level of 30% (p<0.001) in camp 1 at 5533 m. Furthermore, significant increase in vasoconstrictive mediators (e.g., tryptophan, serotonin, and peroxidation sensitive lipids) were found. During ascent up to 6865 m, significant altitude dependent changes in multiple vessel-tone modifying mediators with excess in vasoconstrictive metabolites could be demonstrated. These changes, as well as highly significant increase in systemic oxidative stress, may be predictive for increase in acute mountain sickness score and changes in Sao2. PMID- 24067189 TI - The Kilimanjaro score for assessing fitness to fly paragliders at high altitude. AB - Extreme sports such as paragliding are increasing in popularity, providing continued challenges for the development of safe practice techniques. In January and February 2013, the Wings of Kilimanjaro expedition aimed to launch 95 paragliders from the summit of Mount Kilimanjaro, 5790 m above sea level. A safe launch was paramount but risked being impaired by adverse environmental conditions, in particular the pathophysiological effects of high altitude. There are no existing scores to assess fitness for high-altitude paraglider launches present in the literature. A novel scoring system, the Kilimanjaro Score, was therefore developed to rapidly assess pilots pre-flight. The Kilimanjaro Score aimed to assess cognition, memory, and visual-spatial skill within the context of standard pre-flight checks. Further testing, including the Lake Louise Score, was to be performed if the pilot's Kilimanjaro Score was deemed unsatisfactory. We present the Kilimanjaro Score here for comment and refinement, and we invite other parties to consider its use in the field for high altitude paragliding activities. PMID- 24067188 TI - Abundance of plasma antioxidant proteins confers tolerance to acute hypobaric hypoxia exposure. AB - Systematic identification of molecular signatures for hypobaric hypoxia can aid in better understanding of human adaptation to high altitude. In an attempt to identify proteins promoting hypoxia tolerance during acute exposure to high altitude, we screened and identified hypoxia tolerant and susceptible rats based on hyperventilation time to a simulated altitude of 32,000 ft (9754 m). The hypoxia tolerance was further validated by estimating 8-isoprotane levels and protein carbonyls, which revealed that hypoxia tolerant rats possessed significant lower plasma levels as compared to susceptible rats. We used a comparative plasma proteome profiling approach using 2-dimensional gel electrophoresis (2-DGE) combined with MALDI TOF/TOF for both groups, along with an hypoxic control group. This resulted in the identification of 19 differentially expressed proteins. Seven proteins (TTR, GPx-3, PON1, Rab-3D, CLC11, CRP, and Hp) were upregulated in hypoxia tolerant rats, while apolipoprotein A-I (APOA1) was upregulated in hypoxia susceptible rats. We further confirmed the consistent higher expression levels of three antioxidant proteins (PON1, TTR, and GPx-3) in hypoxia-tolerant animals using ELISA and immunoblotting. Collectively, these proteomics-based results highlight the role of antioxidant enzymes in conferring hypoxia tolerance during acute hypobaric hypoxia. The expression of these antioxidant enzymes could be used as putative biomarkers for screening altitude adaptation as well as aiding in better management of altered oxygen pathophysiologies. PMID- 24067190 TI - Cardiac protective effects of irbesartan via the PPAR-gamma signaling pathway in angiotensin-converting enzyme 2-deficient mice. AB - BACKGROUND: Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase which metabolizes angiotensin II (Ang II) to generate Ang-(1-7), has been shown to prevent cardiac hypertrophy and injury but the mechanism remains elusive. Irbesartan has the dual actions of angiotensin receptor blockade and peroxisome proliferator-activated receptor-gamma (PPARgamma) activation. We hypothesized that irbesartan would exert its protective effects on ACE2 deficiency-mediated myocardial fibrosis and cardiac injury via the PPARgamma signaling. METHODS: 10 week-old ACE2 knockout (ACE2KO; Ace2(-/y)) mice received daily with irbesartan (50 mg/kg) or saline for 2 weeks. The wild-type mice (Ace2(+/y)) were used to the normal controls. We examined changes in myocardial ultrastructure, fibrosis related genes and pathological signaling by real-time PCR gene array, Western blotting, Masson trichrome staining and transmission electron microscope analyses, respectively. RESULTS: Compared with the Ace2(+/y) mice, cardiac expression of PPARalpha and PPARgamma were reduced in Ace2(-/y) mice and the myocardial collagen volume fraction (CVF) and expression of fibrosis-related genes were increased, including transforming growth factor-beta1 (TGFbeta1), connective tissue growth factor (CTGF), collagen I and collagen III. Moreover, ACE2 deficiency triggered cardiac hypertrophy, increased myocardial fibrosis and adverse ultrastructure injury in ACE2KO hearts with higher levels of atrial natriuretic factor (ANF) and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), without affecting cardiac systolic function. Intriguingly, treatment with irbesartan significantly reversed ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in Ace2(-/y) mice linked with enhancement of plasma Ang-(1-7) level and downregulation of AT1 receptor in heart. Consistent with attenuation of myocardial fibrosis and ultrastructure injury, the myocardial CVF and levels of ANF, TGFbeta1, CTGF, collagen I, collagen III and phosphorylated ERK1/2 were lower, and expression of PPARgamma was higher in ACE2KO mice in response to irbesartan treatment, without affecting cardiac expression of PPARalpha, PPARdelta, beta-myosin heavy chain, TGFbeta2 and fibronectin. CONCLUSIONS: We conclude that irbesartan prevents ACE2 deficiency mediated pathological hypertrophy and myocardial fibrosis in ACE2 mutant mice via activation of the PPARgamma signaling and suppression of the TGFbeta-CTGF-ERK signaling, resulting in attenuation of myocardial injury. Drugs targeting ACE2 and PPARgamma represent potential candidates to prevent and treat myocardial injury and related cardiac disorders. PMID- 24067193 TI - Domino Knoevenagel condensation/intramolecular aldol cyclization route to diverse indolizines with densely functionalized pyridine units. AB - A highly efficient [4 + 2] annulation route to polysubstituted indolizines is described employing a domino Knoevenagel condensation/intramolecular aldol cyclization process as a key step. Construction of pyridine rings in indolizine skeleton was rapidly achieved from several pyrrole-2-carboxaldehydes in good to excellent yields, leading to indolizines with various substituents at the 5, 6, and 7 positions depending on the reacting active methylene partners. PMID- 24067192 TI - Sexual functioning in patients with major depressive disorder in randomized placebo-controlled studies of extended release quetiapine fumarate. AB - OBJECTIVE: We evaluated sexual functioning from 6 acute, randomized, placebo controlled studies (6-10 weeks) of once-daily extended release quetiapine fumarate (quetiapine XR) 50, 150, or 300 mg/day as monotherapy (Studies 1-4) or adjunct therapy (Studies 6-7) in major depressive disorder (MDD). METHODS: We present a pre-planned, non-inferiority analysis of quetiapine XR monotherapy versus placebo using Changes in Sexual Functioning Questionnaire (CSFQ) total score change (Studies 1-4). Post hoc analyses evaluated CSFQ total and domain scores for fixed-dose monotherapy (Studies 1-2), modified fixed-dose (Studies 3 4), and adjunct therapy studies (Studies 6-7). CSFQ data for active comparators (duloxetine [Study 2], escitalopram [Study 4]) are reported. RESULTS: Quetiapine XR monotherapy was non-inferior to placebo for sexual functioning (least squares mean [LSM] difference in CSFQ score change versus placebo, 0.16 [95% confidence interval: -0.59, 0.92]); LSM change in CSFQ score: 1.90, quetiapine XR (all doses) and 1.73, placebo. LSM differences versus placebo (95% confidence interval): 0.18 (-1.40, 1.75), duloxetine (Study 2); 0.16 (-1.77, 2.10), escitalopram (Study 4). LSM differences with adjunct quetiapine XR 150 mg/day (0.52; p = 0.338) or 300 mg/day (0.22; p = 0.679) were comparable with placebo plus antidepressants. Post hoc all-patient and gender-specific analyses were comparable for CSFQ total scores versus placebo with quetiapine XR 50, 150, or 300 mg/day, duloxetine, and escitalopram. Discussion Lack of negative effects on sexual functioning in patients with MDD may improve treatment acceptability. CONCLUSION: Quetiapine XR (monotherapy or adjunct therapy) had an impact on sexual function that was comparable with placebo. PMID- 24067191 TI - A new locus on chromosome 22q13.31 linked to recessive genetic epilepsy with febrile seizures plus (GEFS+) in a Tunisian consanguineous family. AB - BACKGROUND: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with extremely variable expressivity. The aim of our study was to identify the responsible locus for GEFS+ syndrome in a consanguineous Tunisian family showing three affected members, by carrying out a genome-wide single nucleotide polymorphisms (SNPs) genotyping followed by a whole-exome sequencing. We hypothesized an autosomal recessive (AR) mode of inheritance. RESULTS: Parametric linkage analysis and haplotype reconstruction identified a new unique identical by descent (IBD) interval of 527 kb, flanking by two microsatellite markers, 18GTchr22 and 15ACchr22b, on human chromosome 22q13.31 with a maximum multipoint LOD score of 2.51. Our analysis was refined by the use of a set of microsatellite markers. We showed that one of them was homozygous for the same allele in all affected individuals and heterozygous in healthy members of this family. This microsatellite marker, we called 17ACchr22, is located in an intronic region of TBC1D22A gene, which encodes a GTPase activator activity. Whole-exome sequencing did not reveal any mutation on chromosome 22q13.31 at the genome wide level. CONCLUSIONS: Our findings suggest that TBC1D22A is a new locus for GEFS+. PMID- 24067194 TI - To surrender in dependence of another: the relationship with the ambulance clinicians as experienced by patients. AB - Historically, the ambulance care has focused on acute transports and medical treatment, although ambulance care has also been reported as complex, encompassing more than just medical treatment and transports. Previous studies, on ambulance clinicians, have pointed out the importance of interpersonal caring activities complementary to the medical treatment. Those activities can be understood as taking part in the relationship between patients and ambulance clinicians, earlier described as essential and a core component of care. The aim of this study was to elucidate the meaning of the relationship with the ambulance clinicians as experienced by patients. Twenty ambulance patients were interviewed in the study. The interviews were transcribed verbatim and analysed with a phenomenological hermeneutical method to grasp meanings in the patients' experiences. The regional ethical committee approved the study. In the result emerged one main theme: To surrender in dependence of another. The main theme includes four themes: Being in the hands of another, Being in a caring temporary presence, Being important while involved and Being powerless while insignificant, and the themes comprise eleven subthemes. The main theme meant to have no other option than to surrender and to put their life into the hand of another. This surrender also meant to adapt to the clinicians' views even if not shared. This is experienced as excessive care. Summarised, the patients' experiences were both positive and negative and the findings provide a complex understanding of the relationship between the patient and the ambulance clinicians. Overall, the relationship embraces the whole person without reducing the patient to be a recipient of an objectified ambulance care. PMID- 24067196 TI - Loss of a close family member the year before or during pregnancy and the risk of placental abruption: a cohort study from Denmark and Sweden. AB - BACKGROUND: Maternal stress during pregnancy is associated with a modestly increased risk of fetal growth restriction and pre-eclampsia. Since placental abruption shares similar pathophysiological mechanisms and risk factors with fetal growth restriction and pre-eclampsia, we hypothesized that maternal stress may be implicated in abruption risk. We investigated the association between maternal bereavement during pregnancy and placental abruption. METHOD: We studied singleton births in Denmark (1978-2008) and Sweden (1973-2006) (n = 5,103,272). In nationwide registries, we obtained data on death of women's close family members (older children, siblings, parents, and partners), abruption and potential confounders. RESULTS: A total of 30,312 (6/1000) pregnancies in the cohort were diagnosed with placental abruption. Among normotensive women, death of a child the year before or during pregnancy was associated with a 54% increased odds of abruption [95% confidence interval (CI) 1.30-1.82]; the increased odds were restricted to women who lost a child the year before or during the first trimester in pregnancy. In the group with chronic hypertension, death of a child the year before or in the first trimester of pregnancy was associated with eight-fold increased odds of abruption (odds ratio 8.17, 95% CI 3.17-21.10). Death of other relatives was not associated with abruption risk. CONCLUSIONS: Loss of a child the year before or in the first trimester of pregnancy was associated with an increased risk of abruption, especially among women with chronic hypertension. Studies are needed to investigate the effect of less severe, but more frequent, sources of stress on placental abruption risk. PMID- 24067197 TI - An Iranian family with azoospermia and premature ovarian insufficiency segregating NR5A1 mutation. AB - In brief, we report an Iranian family with a history of both azoospermia and premature ovarian insufficiency with the same heterozygote mutation in the NR5A1 gene that can be transmitted. As far as we know, this is the first observation that a common mutation in NR5A1 can cause these above-mentioned phenotypes in a family. PMID- 24067198 TI - Hydrogen bond cooperativity in water hexamers: atomic energy perspective of local stabilities. AB - Atomic energies are used to describe local stability in eight low-lying water hexamers: prism, cage, boat 1, boat 2, bag, chair, book 1, and book 2. The energies are evaluated using the quantum theory of atoms in molecules (QTAIM) at MP2/aug-cc-pVTZ geometries. It is found that the simple, stabilizing cooperativity observed in linear hydrogen-bonded water systems is diminished as clusters move from nearly planar to three-dimensional structures. The prism, cage, and bag clusters can have local water stabilities differing up to 5 kcal mol(-1) as a result of mixed cooperative and anticooperative interactions. At the atomic level, in many cases a water may have a largely stabilized oxygen atom but the net water stability will be diminished due to strong destabilization of the water's hydrogen atoms. Analysis of bond critical point (BCP) electron densities shows that the reduced cooperativity results in a decrease in hydrogen bond strength and an increase in covalent bond strength, most evident in the prism. The chair, with the greatest cooperativity, has the largest average electron density at the BCP per hydrogen bond, whereas the cage has the largest total value for BCP density at all hydrogen bonds. The cage also has the second largest value (after the prism) for covalent bond critical point densities and an oxygen oxygen BCP which may factor into the experimentally observed stability of the structure. PMID- 24067199 TI - Cisplatin induces cell cycle arrest and senescence via upregulating P53 and P21 expression in HepG2 cells. AB - OBJECTIVE: Cellular senescence as one of the important steps against tumor is observed in many cancer patients receiving chemotherapy and is related to chemotherapeutic response. To investigate the effect of cisplatin on hepatocellular carcinoma, we treated HepG2 cells exhibiting wild-type TP53 with gradient concentrations of cisplatin. METHODS: The inhibitory effects of cisplatin on human hepatoma HepG2 cells were detected by MTT assay and colony formation test. The changes in cell cycle were analyzed by flow cytometry, and cellular senescence was detected with senescence associated beta-galactosidase (SA beta-gal) staining. The relative mRNA expression levels of TP53, P21 and P19 was estimated using semi-quantitative real-time RT-PCR, and the protein expressions of P53 and P21 were detected using Western blotting. RESULTS: Cisplatin induced irreversible proliferation inhibition and G1 phase arrest of HepG2 cells. Elevated levels of senescence-associated beta-galactosidase was observed in HepG2 cells exposed to low doses of cisplatin. P19 expression immediately increased following cisplatin exposure and reached the maximum level at 48 h, followed then by a rapid decrease to the baseline level, whereas the expressions levels of TP53 and P21 mRNA increased continuously. Western blotting confirmed P53 and P21 expression changes similar to their mRNA expressions during cisplatin-induced cellular senescence in HepG2 cells. CONCLUSION: Our results revealed a functional link between cisplatin and hepatocellular senescence. Cellular senescence induced by cisplatin as a stabile senescent cellular model can be used for further research. PMID- 24067200 TI - Mid- and long-term clinical effects of trochanteric flip osteotomy for treatment of Pipkin I and II femoral head fractures. AB - OBJECTIVE: To investigate the mid- and long-term clinical results of trochanteric flip osteotomy for treating Pipkin type I and II femoral head fractures. METHODS: We retrospectively reviewed twenty-three patients (aged 23-72 years with a mean of 44.1 years, including 15 male and 8 female patients) with femoral head fractures and posterior hip dislocation. The fracture was classified according to Pipkin classification based radiographic findings, and 9 patients were found to have type I and 14 had type II fractures. Trochanteric flip osteotomy was performed in all patients for surgical open reduction and internal fixation of the fractures. The clinical and radiographic outcomes of the patients were measured using Thompson-Epstein scoring scale and Merle d' Aubigne-Postel score. RESULTS: One patient with follow-up period less than 12 months was excluded from analysis. Of the 22 patients (95.7%) followed up for more than 12 months (mean 23.5 months), the average Merle d' Aubigne Postel score was 13.77 at the final follow-up. According to the Thompson-Epstein criteria, 8 (36.4%) patients had excellent, 9 (40.9%) had good, 3 (13.6%) had fair, and two (9.1%) had poor outcomes; the total rate of excellent and good outcomes was 77.3% in these 22 patients. None of the patients developed habitual dislocation of the femoral head after the operation. Heterotopic ossification occurred in 2 patients. Partial neurapraxia of the sciatic nerve occurred in one patient and recovered completely within 6 months. Three patients developed post-traumatic arthritis, and one of them had avascular necrosis of the femoral head one year after surgery and received subsequently total hip arthroplasty. CONCLUSION: The follow-up data demonstrate that trochanteric flip osteotomy is an effective and reliable option for treating Pipkin type I and type II femoral head fractures. PMID- 24067201 TI - [Volume changes of cortical and subcortical reward circuitry in the brain of patients with type 2 diabetes mellitus]. AB - OBJECTIVE: To elucidate the volume changes of cortical and subcortical reward circuitry in patients with type 2 diabetes mellitus. METHODS: High-resolution three-dimensional T1-weighted fast spoiled gradient recalled echo MRI images were obtained from 16 patients with type 2 diabetes mellitus and 16 normal controls, and 11 type 2 diabetic patients also received the same MRI scans after insulin therapy for 1 year. Volumetric analysis was performed and analysis of covariance and paired t test were applied. RESULTS: A decreased volume was found in the left insular lobe, left nucleus accumbens area, right hippocampus, putamen and amygdala in type 2 diabetic patients compared with normal controls (P<0.05). After insulin therapy for 1 year, an increased volume of bilateral cortical reward structures was observed (left, 33.65?3.66 ml; right, 33.35?4.25 ml) compared the baseline level (left, 31.45?2.90 ml; right, 31.12?2.97 ml) in diabetic patients (P<0.05). No significant volume change in the bilateral basal ganglia structures was found after insulin therapy for 1 year (P>0.05), and bilateral ventral diencephalon area showed an increased volume after the treatment (left, 3.26?0.68 ml; right, 3.20?0.78 ml) compared with the baseline (left, 2.96?0.76 ml; right, 2.82?0.90 ml)(P<0.05). CONCLUSION: Type 2 diabetic patients have a decreased volume of the cortical and subcortical reward circuitry, and insulin therapy can reverse such changes and improve the damage of reward circuitry. PMID- 24067202 TI - [Construction of a recombinant adenovirus co-expressing bone morphogenic proteins 9 and 6 and its effect on osteogenesis in C3H10 cells]. AB - OBJECTIVE: To construct a recombinant adenovirus co-expressing bone morphogenic protein (BMP) 9 and BMP6 and observe its effect on the osteogenesis in C3H10 cells. METHOD: The full-length sequences of BMP9 and BMP6 were amplified from AdEasy vector by PCR and cloned into the shuttle plasmid pASG2 vector to construct the co-expression shuttle plasmid pASG2-BMP9, 6 followed by homologous recombination with plasmid pAdeasy-1 in BJ5183. After confirmation by restriction endonuclease digestion, the recombinant vector was transfected into HEK293 cells, and high-titer recombinant adenovirus (Ad-BMP9, 6) was collected after amplification. Ad-BMP9, 6 was then transduced into C3H10 cells in vitro, and the mRNA expression of BMP9 and BMP6 was detected by RT-PCR. The osteogenic capability of the transfected cells was observed by alkaline phosphatase staining and calcium-alizarin red staining. RESULTS: AdBMP9,6 was constructed successfully and effectively infected in C3H10 cells, in which high expressions of BMP6 and BMP9 were detected. C3H10 cells infected with Ad-BMP9,6 showed stronger alkaline phosphatase and calcium-alizarin red staining than the cells transfected by either BMP9 or BMP6 alone. CONCLUSION: The recombinant adenovirus co-expressing BMP9 and BMP6 we constructed shows a more potent effect than the adenoviruses expressing either BMP9 or BMP6 alone in inducing the osteogenic differentiation of C3H10 cells into osteoblasts. PMID- 24067203 TI - [Evaluation of rapid teeth movement through reducing resistance and distraction in Beagle dogs with cone-beam computed tomography]. AB - OBJECTIVE: To evaluate the effect of rapid teeth movement through reducing resistance and distraction using cone-beam computed tomography (CBCT). METHODS: The left or right side of the mandible of 10 beagles (5 males and 5 females) was randomly selected as the control side (for the conventional distraction with a force of about 85 g) and the other side as the experimental side (subjected to reducing resistance and distraction). CBCT images were taken at 5, 10, and 15 days and also after retaining for 10 and 90 days after distraction for 15 days. The distance of teeth transportation, degree of inclination, alveolar bone density of the compressive area and root resorption were evaluated based on the CBCT images and Ez3D2009 visualization software. RESULTS: No significant difference was found between CBCT-based measurement and direct measurement of teeth transportation distance within the mouths (P>0.05). Teeth inclination on the experimental side was slightly greater than that on the control side (P<0.05). The root resorption on the experimental side was minimal, and the bone density increased gradually along with the teeth migration. The experimental side showed a comparable newly formed alveolar bone density and similar X-ray features of the compressive area with the control side. CONCLUSIONS: CBCT three dimensional imaging can resolve the problems of overlapping and deformation of the two-dimensional images and is especially useful for measurement of teeth inclination and alveolar bone density in the process of reducing resistance and distraction. PMID- 24067204 TI - [Effect of the C-terminal truncated human apoptosis-inducing factor delta1-480 on biological behaviors of MCF-7 cells]. AB - OBJECTIVE: To observe the expression of the C-terminal truncated human apoptosis inducing factor (AIF) and its biological effect on MCF-7 cells. METHODS: PcDNA3.0 FDT-AIFdelta1-480 was transfected into human breast carcinoma MCF-7 cells with lipofectamine. The expression of the truncated AIF gene was detected by Western blotting, and its effects on the biological behaviors of MCF-7 cells and on the expression of cytochrome c (cytC) were evaluated using flow cytometry, MTT assay, colony-forming assay, and mitochondrial membrane potential measurement. RESULTS: PcDNA3.0-FDT-AIFdelta1-480 enhanced AIF expression in MCF-7 cells, obviously inhibited the cell proliferation, and significantly reduced the mitochondrial membrane potentials (P<0.05). Transfection of the cells with PcDNA3.0-FDT AIFdelta1-480 promoted the expression of cytC and resulted in significantly increased apoptosis of MCF-7 cells (P<0.05). CONCLUSION: The expression of C terminal truncated human AIF gene can induce apoptosis of human MCF-7 cells by promoting cytC release from mitochondria. PMID- 24067205 TI - [Monitoring radiofrequency ablation by ultrasound temperature imaging and elastography under different power intensities]. AB - OBJECTIVE: To evaluate the reliability of diagnostic ultrasound-based temperature and elasticity imaging during radiofrequency ablation (RFA) through ex vivo experiments. METHODS: Procine liver samples (n=7) were employed for RFA experiments with exposures of different power intensities (10 and 50w). The RFA process was monitored by a diagnostic ultrasound imager and the information were postoperatively captured for further temperature and elasticity image analysis. Infrared thermometry was concurrently applied to provide temperature change calibration during the RFA process. RESULTS: Results from this study demonstrated that temperature imaging was valid under 10 W RF exposure (r=0.95), but the ablation zone was no longer consistent with the reference infrared temperature distribution under high RF exposures. The elasticity change could well reflect the ablation zone under a 50 W exposure, whereas under low exposures, the thermal lesion could not be well detected due to the limited range of temperature elevation and incomplete tissue necrosis. CONCLUSION: Diagnostic ultrasound-based temperature and elastography is valid for monitoring thr RFA process. Temperature estimation can well reflect mild-power RF ablation dynamics, whereas the elastic change estimation can can well predict the tissue necrosis. This study provide advances toward using diagnostic ultrasound to monitor RFA or other thermal-based interventions. PMID- 24067206 TI - [Preparation and identification of polyclonal antibody against methyl-accepting chemotaxis signal transduction protein of Helicobacter hepaticus]. AB - OBJECTIVE: To prepare the polyclonal antibody against methyl-accepting chemotaxis signal transduction protein (MCP) of Helicobacter hepaticus (H.hepaticus). METHODS: The recombinant plasmid pET22b+/MCP was transformed into E.coli BL2l(DE3) to express the fusion protein His-rhMCP under the induction of IPTG. The fusion protein was purified and the antibody was obtained by immunizing rabbits. The titer of the polyclonal antibody was tested by indirect ELISA, and the specificity of the antibody was identified based on Western blotting using the prepared cell surface proteins (CSPs) of the bacteria. RESULTS: The fusion protein was successfully expressed, and the titer of the antibody reached 1:32 000. Western blotting indicated that the antibody could specifically bind to CSPs and His-rhMCP. CONCLUSION: The antibody with a high titer and specificity was prepared to facilitate further study of the pathogenicity and epidemiology of H.hepaticus in human. PMID- 24067207 TI - [Low-dose CT angiography image restoration using normal dose scan-induced non local means algorithm]. AB - OBJECTIVE: To minimize of the radiation dose of cardiovascular CT angiography (CTA) imaging while preserving the image quality. METHODS: To reduce the radiation dose in CTA imaging, the normal-dose scan induced non-local means (ndiNLM) algorithm was adapted for low-mAs scanned CTA image restoration by using the previous scanned high-quality image. RESULTS: Qualitative and quantitative evaluations were carried out on both simulated phantom and clinical CTA scans in terms of accuracy and resolution properties. Compared to the original NLM algorithm, the ndiNLM method could achieve noticeable gains in terms of noise induced artifacts suppression and enhanced structure preservation. CONCLUSION: The ndiNLM algorithm is a potential useful technique to reduce the radiation dose in CTA imaging. PMID- 24067208 TI - [Effect of 3-bromopyruvate on mitochondrial membrane potential and apoptosis of human breast carcinoma SK-BR-3 cells]. AB - OBJECTIVE: To study the effect of glycolysis inhibitor 3-bromopyruvate (3-BrPA) in inducing apoptosis of human breast carcinoma cells SK-BR-3 and the possible mechanism. METHODS: MTT assay was used to detect the growth inhibition induced by 3-BrPA in breast cancer cells SK-BR-3. The apoptotic cells were detected by flow cytometry with propidium iodide (PI). ATP levels in the cells were detected by ATP assay kit, and DHE fluorescent probe technique was used to determine superoxide anion levels; the mitochondrial membrane potential was assessed using JC-1 staining assay. RESULTS: MTT assay showed that the proliferation of SK-BR-3 cells was inhibited by 3-BrPA in a time- and concentration-dependent manner. Exposure to 80, 160, and 320 umol.L(-1) 3-BrPA for 24 h resulted in cell apoptosis rates of 6.7%, 22.3%, and 79.6%, respectively, and the intracellular ATP levels of SK-BR-3 cells treated with 80, 160, 320 umol.L(-1) 3-BrPA for 5 h were 87.7%, 60.6%, and 23.7% of the control levels. 3-BrPA at 160 umol.L(-1) increased reactive oxygen levels and lowered mitochondrial membrane potential of SK-BR-3 cells. CONCLUSION: 3-BrPA can inhibit cell proliferation, reduce the mitochondrial membrane potential and induce apoptosis in SK-BR-3 cells, the mechanism of which may involve a reduced ATP level by inhibiting glycolysis and increasing the reactive oxygen level in the cells. PMID- 24067209 TI - [Detection of binding capability of targeted KDR ultrasound contrast agent in vitro for evaluating endometrial receptivity]. AB - OBJECTIVE: To prepare a new targeted liposome ultrasonic contrast agent with anti KDR antibody that binds specifically with KDR as the main receptor of VEGF and evaluate its physical characteristics, biological activity and specific binding capability in vitro. METHODS: A sonicator was used to prepare the biotinylated lipid micro-bubbles (MB-B), and biotin-avidin-mediated technique was used for attachment of anti-mouse KDR monoclonal antibody to the micro-bubble shell to generate MB-BAB-KDR. MB-BAB-KDR was incubated with fluorescent second antibody to assess the link condition, and the control groups were the MB-B and micro-bubbles with the antibody alone (MB-B-KDR). A parallel plate flow chamber system was used to characterize micro-bubbles attachment efficiency to KDR Fc. RESULTS: The surface of the micro-bubbles could carry KDR antibody through the biotin-avidin bridge and MB-BAB-KDR were spherical and well-distributed. After incubation with the second antibody, MB-BAB-KDR could be observed to emit bright green fluorescence (Grade II) as compared with little or weak fluorescence in the control MB-B group (Grade 0) and MB-B-KDR group (Grade I). Targeted micro-bubbles bound to KDR Fc increased as the KDR Fc concentration increased (P<0.05). CONCLUSION: The targeted liposome contrast agent linked with KDR antibody by biotin-avidin bridge we prepared shows an increased binding number as the KDR Fc concentration increases, which provides a novel approach to molecular imaging study of endometrial receptivity. PMID- 24067210 TI - [Effect of exercise combined with encouragement on quality of life of patients with chronic obstructive pulmonary disease]. AB - OBJECTIVE: To explore the effect of rehabilitation exercise combined with encouragement on the quality of life of patients with chronic obstructive pulmonary disease (COPD). METHODS: A total of 120 inpatients with moderate or severe COPD in stable conditions were randomized equally into experimental and control groups. The patients in both groups received routine treatment for 1 year, and those in the experimental group had additional respiratory muscle and limb exercises with encouragement. The quality of life, 6-min walking distance, lung function, anxiety and depression levels were compared between the two groups before and after the treatments. RESULTS: The quality of life was improved significantly in the experimental group after the treatments (P<0.01) with obviously increased 6-min walking distance and lowered levels of anxiety and depression in comparison with those in the control group (P<0.05). Compared with the control group, the patients in the experimental group showed also significantly improved lung functions. CONCLUSION: Comprehensive pulmonary rehabilitation training program with exercise combined with encouragement can improve the physical and emotional state, social adapt ability and the quality of life of patients with COPD. PMID- 24067211 TI - [Effect of propofol on thrombospondin-1 expression in cultured newborn rat cortical astrocytes]. AB - OBJECTIVE: To investigate the effect of propofol on the expression of thrombospondin-1 (THBS-1) mRNA and protein in purified newborn rat cortical astrocytes in vitro. METHODS: Astrocytes were isolated from newborn rat cortex and grown in culture before exposure to propofol at 3, 10, 30, 100 or 300 umol/L for 6 h, 12, or 24 h. The mRNA level of THBS-1 was detected by RT-PCR, and the protein level of THBS-1 was detected by immunofluorescence cytochemistry and Western blotting. RESULTS: Propofol exposure caused significantly upregulated THBS-1 level in cultured astrocytes (P<0.05) to a level about 1.3 times higher than that in control cells. The mRNA and protein levels of THBS-1 in cultured rat cortical astrocytes were upregulated by exposures to 10, 30 and 100 umol/L propofol (P<0.01). High expression of THBS-1 mRNA and protein was detected in the cells with exposures for different durations (P<0.05), especially in the 12 h group (P<0.01). CONCLUSION: Propofol at clinically relevant concentrations can modulate the level of THBS-1 secreted by astrocytes of rat cerebral cortex in vitro. PMID- 24067212 TI - [Effect of folic acid for treatment of acute cerebral infarction in rats]. AB - OBJECTIVE: To test whether folic acid offers protection of the brain tissue against acute cerebral infarction in rats. METHODS: Sprague-Dawley rats were divided into control (n=8), pre-treatment (n=12) and treatment (n=16) groups, all having routine feed for 7 days. The rats in the control and treatment groups were given normal saline daily, and those in the pre-treatment group received folic acid suspension daily. All the rats were then subject to middle cerebral artery occlusion (MCAO) for 24 h followed by reperfusion. On and after the operation day, the rats in the control group were given normal saline and those in the other two groups were given folic acid suspension daily. Neural function deficiency was evaluated on a daily basis after the operation, and on day 6 after the operation, brain biopsy was performed for examination with TTC staining. Monocyte chemokine -1 (MCP-1) in both normal and infarct tissues was measured by ELISA. RESULTS: On day 6 after the operation, the neural function deficiency scores of the control, pre-treatment and treatment groups were 4.56?3.63, 2.94?2.94 and 1.00?1.00, and the percentages of the infarct area (to the whole brain area) were (44.23?10.06)%, (20.64?6.78)% and (14.61?13.51)%, respectively. The contents of MCP-1 in the infarct area of the brain tissues were 168.58?107.21 ng/L, 152.91?64.78 ng/L, and 97.74?46.19 ng/L in the 3 groups, respectively. CONCLUSION: Folic acid can protect brain tissue against acute cerebral infarction in rats. PMID- 24067213 TI - [Role of miR-19a in ulcerative colitis in mice]. AB - OBJECTIVE: To study the role of miR-19a in ulcerative colitis (UC) in mice. METHODS: The target gene of miR-19a was predicted by bioinformatics analysis. The expression of the target protein in UC colon was detected by immunohistochemistry and Western blotting. The target gene was further identified by enhanced green fluorescent protein (EGFP) report vector system. RESULTS: The target gene of miR 19a was TNF-alpha as predicted by bioinformatics analysis. TNF-alpha expression was highly expressed in the colonic tissue of UC mice. MiR-19a could inhibit the report gene activity of TNF-alpha-3'UTR-WT but no that of TNF-alpha-3'UTR-Mut. CONCLUSION: The target gene of miR-19a is TNF-alpha, and the binding site is TNF alpha 3'UTR. The possible role of miR-19a in UC pathogenesis involves regulation of TNF-alpha expression in the colon. PMID- 24067214 TI - [Expression of aquaporin-4 protein in the brain of preeclampsia model rats]. AB - OBJECTIVE: To study the expression of aquaporin-4 (AQP4) protein in preeclampsia(PE) model rats. METHODS: Adult SD rats were divided into PE model group (n=7) induced by endotoxin, normal pregnancy group (n=6) and non-pregnancy group (n=12) treated with an equal volume of saline. AQP4 protein expression in the brain of the rats was detected with immunohistochemical staining and Western blotting. RESULTS: The blood pressure in PE model rats (135?9 mmHg) was significantly higher than that in normal pregnancy rats (116?8 mmHg) and non pregnancy rats (112?6 mmHg) (P<0.02). The rats in PE model group showed obvious proteinuria compared with the other two groups (3.8?0.5 vs 2.6?0.6 and 2.3?0.4, P<0.05). Immunohistochemistry showed that AQP4 protein was localized primarily around the brain parenchymal blood vessels. Western analysis revealed a significantly elevated AQP4 protein expression in PE model group (39.6?4.9) compared with that in normal pregnancy group (26.5?4.3) and non-pregnancy group (9.7?2.1) (P<0.01). CONCLUSION: The up-regulation of AQP4 protein around the intraparenchymal blood vessels of the brain may play a role in the development of eclampsia. PMID- 24067215 TI - [Effect of erythropoietin on activities of antioxidant enzymes in the brain tissue of aged rats]. AB - OBJECTIVE: To study the effect of erythropoietin (EPO) on the activities of antioxidant enzymes, namely catalase (CAT) and glutathione peroxidase (GSH-Px) in the brain tissues of aged rats. METHODS: Thirty SD rats were randomly divided into normal control, aging model, and recombinant human erythropoietin (rhEPO) treatment groups (n=10). Morris water maze was used to compare the behavioral indexes. The rats were then sacrificed to observe Nissl bodies in the hippocampal neurons with Nissl staining and test the activities of CAT and GSH-Px in the brain tissues. RESULTS: Compared with the control group, the aging rats showed significantly deteriorated learning and memory abilities (P<0.05), which were improved obviously by rhEPO treatment (P<0.05). The number of Nissl bodies in the neurons was reduced in the aging rats compared with that in the control group, and rhEPO treatment increased the number of Nissle bodies but failed to restore the control level. The aging rats also showed significantly lowered activities of CAT and GSH-Px in the brain tissue (P<0.05), which were increased significantly after rhEPO treatment (P<0.05). CONCLUSION: EPO can enhance the activities of the antioxidant enzymes in the brain tissues of aged rats to increase the antioxidant capacity and produces an anti-aging effect. PMID- 24067216 TI - [Expressions of CD133 and CD82/KAI1 in bladder urothelial carcinoma and their correlation with vasculogenic mimicry]. AB - OBJECTIVE: To explore the expressions of CD133 and CD82/KAI1 in bladder urothelial carcinoma, their association with the clinicopathological factors and their roles in vasculogenic mimicry (VM) in the tumor. METHODS: The expressions of CD133 and CD82/KAI1 and VM were detected by immunohistochemistry and histochemistry in 90 specimens of bladder urothelial carcinoma and 20 specimens of normal bladder epithelium tissue. RESULTS: The positivity rates of CD133, CD82/KAI1 and VM in normal bladder epithelium tissue were 0, 90% and 0, showing significant differences from the rates of 65.6%, 31.1% and 31.1% in urothelial carcinoma, respectively (P<0.01). Positive expressions of CD133, CD82/KAI1 and VM were significantly correlated with pTNM stage and tumor relapse (P<0.01) but not with gender, age, or tumor numbers (P>0.05). CD133 expression was positively correlated with VM (P=0.487, P<0.05), and CD82/KAI1 expression was negatively correlated with VM (r=-0.452, P<0.01) and CD133 (r=-0.776, P<0.05). CONCLUSION: The expressions of CD133 and CD82/KAI1 proteins are involved in the occurrence of VM in bladder urothelial carcinoma to contribute to the invasion and relapse of bladder carcinoma. PMID- 24067217 TI - [Establishment of a chronic obstructive pulmonary disease model by passive cigarette smoking and intratracheal LPS instillation in spontaneously hypertensive rats]. AB - OBJECTIVE: To establish a chronic obstructive pulmonary disease (COPD) model by passive cigarette smoking and (or) intratracheal instillation of lipopolysaccharide (LPS) in spontaneously hypertensive (SH) rats. METHODS: Fifteen male SH rats were randomly divided into control group, cigarette smoking exposure (CS) group and CS+LPS (cigarette smoking exposure plus intratracheal instillation of LPS) group. After 8 weeks' treatment, the COPD model was validated by inspecting the general condition and examining lung function and pulmonary pathological changes. The expressions of surfactant-associated protein A (SP-A), NF-kappaB, histone, p-Ikappa-Kalpha/beta, Ikappa-Kalpha/beta, and IkappaB-alpha were determined with Western blotting, and the expression of TNF alpha and IL-6 mRNA were measured using qRT-PCR. RESULTS: The rats in both CS and CS+LPS groups were marantic with intermittent cough and tachypnea. Lung function test showed increased RI and lowered peak expiratory flow in CS group, which were more prominent in CS+LPS group (P<0.05). HE staining demonstrated typical chronic bronchitic inflammation and emphysema in the lungs of the two model groups with significantly decreased mean alveolar number and significantly increased mean lining intermittent and destruction index. The emphysema level was more serious in CS+LPS group than in CS group. Western blotting showed markedly decreased expressions of SP-A and IkappaB-alpha in CS group and CS+LPS , especially the latter group. The protein levels of NF-kappaB, Ikappa-K phosphorylation and mRNA expressions of TNF-alpha and IL-6 increased obviously in the two model groups. CONCLUSION: COPD model can be established by passive smoking and (or) intratracheal instillation of LPS in SH rats, and the model induced by combined exposures is optimal. PMID- 24067218 TI - [Comparison of two equations for calculating glomerular filtration rate in evaluation of the prevalence of chronic kidney disease in healthy population]. AB - OBJECTIVE: To compare two equations for calculating glomerular filtration rate (GFR) in the evaluation of the prevalence of chronic kidney disease (CKD) and the risk factors of CKD in urban healthy population. METHODS: A total of 40377 subjects (24164 males and 16213 females) participated in this study. Body height, weight and blood pressure were measured, and morning urine and venous blood samples were collected for routine urine and blood tests with measurements of blood glucose, total cholesterol, high density lipoprotein (HDL), low-density lipoprotein (LDL), creatinine and uric acid. RESULTS AND CONCLUSION: Using Japanese CKD Epidemiology Collaboration (J-EPI) equation and Chinese modified Modification of Diet in Renal Disease (C-MDRD) equation, the prevalence of CKD calculated was 3.9% and 6.3% in this population, respectively. The independent risk factors of CKD included an age over 60 years, high uric acid, and high blood glucose. PMID- 24067219 TI - [A new method for measuring pulmonary function parameters]. AB - OBJECTIVE: To propose a new method for acquiring pulmonary function parameters based on measurement of volume changes of thoracic impedance. METHODS: We studied the relationship between the volume changes of thoracic impedance and pulmonary function parameters during forced breathing based on bioimpedance measurement, and developed an instrument for measuring thoracic impedance. Using this instrument and a MRI spirolab III lung function test instrument, both based on flowmeter measurement, we measured such pulmonary function parameters including forced vital capacity (FVC), forced expiratory volume in one second/FVC (FEV1/FVC), and peak expiratory flow in 10 healthy volunteers and compared the measurement results. RESULTS: The differences in the parameters measured using the two instruments were all within two folds of the positive and negative standard deviations of the average values, demonstrating good consistency in the measurement between the two methods. CONCLUSIONS: The measurement results of the bioimpedance-based instrument we developed show good consistency with those by the commercially available pulmonary function test instrument. PMID- 24067220 TI - [Relationship between heroin spongiform leucoencephalopathy and respiratory chain complex I deficiency]. AB - OBJECTIVE: To investigate the relationship between heroin spongiform leucoencephalopathy and respiratory chain complex I deficiency. METHODS: The activity of respiratory chain complex I in peripheral white blood cell mitochondria was compared between 36 cases of heroin spongiform leucoencephalopathy and 36 healthy subjects using enzyme-linked immunosorbent assay (ELISA). RESULTS: The activity of respiratory chain complex I was 5.6?2.4 U/ml in patients with heroin spongiform leucoencephalopathy, significantly higher than that in the normal subjects (4.2?2.1 U/ml, t=2.634, P<0.05). CONCLUSION: In patients with heroin spongiform leucoencephalopathy, mitochondrial dysfunction results in energy metabolism disorder to cause extensive demyelination of the cerebral white matter. Respiratory chain complex I deficiency of the mitochondria plays a significant role in the pathogenesis of heroin spongiform leucoencephalopathy. PMID- 24067221 TI - [Surgical techniques and perioperative management for improving the success rate of orthotopic liver transplantation in rats]. AB - OBJECTIVE: To investigate the surgical techniques and appropriate perioperative management for ensuring successful orthotopic liver transplantation (ROLT) in rats. METHODS: Based on the double-cuff technique of Kamada, we modified the surgical techniques of separation, perfusion and cold preservation of the donor liver, shearing and anastomosis of the suprahepatic vena cava with optimized postoperative infusion protocols and animal care. RESULTS: Two hundred and seventy rats underwent ROLT and a learning curve of the success rate was built to reflect the improvement of techniques. The learning curve showed steep improvements over the exploration stage, breakthrough stage and maturation stage, and the success rates increased sharply over time (0%, 71.1%, and 94.5%, respectively) until finally reaching over 90%. The shearing and anastomosis of the suprahepatic vena cava remained the most critical and difficult techniques in ROLT modeling. CONCLUSION: Proficient microsurgical techniques and meticulous nursing can reduce postoperative complications, enhance operational success rate and extend the survival time after ROLT. PMID- 24067222 TI - [The synthetic peptide RGDSY-CTTHWGFTLC inhibits metastasis and proliferation of breast cancer cells in vitro]. AB - OBJECTIVE: To study the effect of the synthetic peptide RGDSY-CTTHWGFTLC on the biological behavior of breast cancer MCF-7 cells in vitro. METHODS: MCF-7 cells were incubated with different concentrations of the synthesized peptide RGDSY CTTHWGFTLC (RGDSY-CTT), the positive control peptide CTTHWGFTLC (CTT), or the negative control peptide STTHWGFTLS (STT) in fibronectin-coated 96-well plates for different time lengths, and the changes in cell adhesion, invasiveness, proliferation, apoptosis and cell cycle were detected using Transwell chamber assay, MTT assay, and flow cytometry. RESULTS: Incubation of the cells with 50, 100 and 200 ug/ml of RGDSY-CTT caused a significant concentration- dependent inhibition of the cell adhesion (cell adhesion rates of 85.1%, 74.1% and 63.8%, respectively) with stronger effects than CTT (P<0.05). At 100 and 200 ug/ml, RGDSY-CTT significantly inhibited the invasion (with inhibition rate of 41.8% and 63.9%, respectively) of MCF-7 cells with an effect similar to that by CTT (P>0.05). At 50, 100 and 200 ug/ml, RGDSY-CTT concentration-dependently suppressed MCF-7 cell proliferation (with cell proliferation rates of 98.8%, 82.4% and 63.0%, respectively), and this inhibitory effect was stronger than that of CTT at 100 and 200 ug/ml (P<0.05). The results of flow cytometry also demonstrated a stronger apoptosis-inducing effect of RGDSY-CTT (76.7%) than that in CTT, STT and the blank control groups (P<0.05). CONCLUSIONS: RGDSY-CTT can inhibit cell invasion, suppress adhesion and proliferation, and induce apoptosis in MCF-7 cells. PMID- 24067223 TI - [Expression of Engrailed-2 and beta-catenin in bladder urothelial carcinoma and their significance]. AB - OBJECTIVE: To investigate the expressions of Engrailed-2 (EN2) and beta-catenin in bladder urothelial carcinoma and explore their significance. METHODS: Sixty bladder urothelial carcinoma samples of different grades and stages and 10 normal bladder mucosal tissues were examined for expressions of EN2 and beta-catenin proteins and mRNA using immunochemistry, Western blotting and RT-PCR. RESULTS Compared to normal bladder mucosa, bladder urothelial carcinoma tissues showed significantly increased expressions of EN2 and beta-catenin proteins (P<0.05), and the high-grade carcinoma tissues exhibited significantly stronger expressions than the low-grade ones (P<0.05); the expressions of the proteins increased also significantly with advanced pathological stages of bladder urothelial carcinoma (P<0.05). The expressions of EN2 and beta-catenin mRNAs showed a consistent pattern of changes with their protein expressions. CONCLUSION: The expressions of EN2 and beta-catenin are significantly increased in bladder urothelial carcinoma. EN2 may contribute to the development and progression of bladder urothelial carcinoma by activating Wnt/beta-catenin signal pathway. PMID- 24067224 TI - [Optimization of acoustic parameters of microbubble-enhanced ultrasound sonoporation for augmenting tumor cell permeability in vivo]. AB - OBJECTIVE: To explore the appropriate acoustic parameters for augmenting the permeability of tumor cells using microbubble-enhanced ultrasound. METHODS: Ninety intramuscular VX2 tumors grown in New Zealand white rabbits were randomly divided into 4 parts by 4 factors, namely sound intensity, pulse width, insonation time and microbubble dose, each at different levels. Therapeutic ultrasound was delivered directly to the tumor surface during intravenous infusion of microbubbles. The tumor was excised after the treatment and sliced to investigate the change in tumor cell permeability using lanthanum nitrate electron microscopy. The appropriate acoustic parameters of the 4 factors were investigated. RESULTS: Sonoporation induced by microbubble-enhanced ultrasound augmented the permeability of the tumor cells, and the appropriate sound intensity, pulse width, insonation time and microbubble dose were 0.43 W/cm(2), 2.42 ms, 10 min, and 0.50 ml/kg, respectively. CONCLUSION: Sonoporation induced by microbubble-enhanced ultrasound can induce pores in tumor cell membrane, which may potential increase the efficacy of tumor chemotherapy. PMID- 24067225 TI - [Efficacy of intramedullary and extramedullary decompression on cervical ossification of the posterior longitudinal ligament with spinal cord signal change]. AB - OBJECTIVE: To evaluate the clinical effect of different surgical approaches for treating cervical ossification of the posterior longitudinal ligament (OPLL) with spinal cord signal change. METHODS: Thirty-eight patients with OPLL with spinal cord signal change were treated from January 2005 to January 2011. Surgical removal via an anterior approach or partial decompression was performed in 10 cases (group A), posterior approach open-door laminoplasty with decompression, bone grafting and internal fixation was performed in 12 cases (group B), and opening the cervical spinal meninges to relieve the pressure was performed in 16 cases (group C) on the basis of the procedures in group B. All the patients were followed up and the pre- and postoperative JOA scores, improvement ratio and inter-body implant fusion were evaluated. Imaging examinations including X-rays, CT and MRI were also performed pre- and postoperatively, and the surgical complications were recorded. RESULTS: At 12 months postoperatively, the mean improvement rates in groups A, B, and C were 52.39%, 55.15%, and 60.32%, respectively, with the mean JOA scores of 13.54?0.56, 13.56?1.26, and 14.70?1.41, respectively. The JOA scores and improvement rates significantly increased after the surgeries. One patient in group A became paraplegic after the operation with cerebrospinal fluid leakage, and one patient in group B and one in group C reported numbness of the upper limb. Group C showed a shorter postoperative recovery time without severe complications. CONCLUSION: Posterior open-door laminoplasty, decompression, bone grafting and internal fixation can be an effective approach for treatment of cervical OPLL with spinal cord signal change and requires shorter rehabilitation time after the operation. PMID- 24067226 TI - [Value of serum cystatin C level in assessing renal damage in preeclamptic patients]. AB - OBJECTIVE: To evaluate the significance of the serum cystatin C (Cys-C) in assessing renal dysfunction in preeclamptic women. METHODS: Ninety-six women with normal pregnancies and 48 with severe preeclampsia were examined for 24-hour creatinine clearance (CrCl), serum creatinine (Scr), Cys-C, uric acid (UA) and beta microglobulin (MG) concentrations during the second and third trimesters and postpartum in severe preeclamptic patients. These indexes were analyzed to estimate the glomerular filtration rate. RESULTS: The concentrations of Scr, UA and MG were significantly higher in the third trimester than in the second trimester in women with normal pregnancies, where serum Cys-C levels showed no significant variations. Severe preeclamptic patients exhibited significantly higher serum Cys-C levels in the third than in the second trimester. Correlation analyses demonstrated significant negative correlations between Cys-C and 24-hour CrCl in the second and third trimesters in all the 144 pregnant women and in the postpartum period in severe preeclamptic patients. CONCLUSION: Serum Cys-C can serve as a good indicator for assessing renal function in severe preeclamptic women from antepartum to postpartum periods. PMID- 24067227 TI - [Value of X-ray combined with ultrasound in the diagnosis and treatment of solitary osteochondroma]. AB - OBJECTIVE: To explore the most appropriate imaging examinations for solitary osteochondroma in primary hospitals. METHODS: A retrospective evaluation was performed to analyze the imaging examinations (including X-ray, CT, and ultrasound) of 62 patients undergoing surgeries for solitary osteochondroma in terms of the diagnostic results and preoperative expenditure of the patients. RESULTS: X-ray and CT have a high diagnostic value for solitary osteochondroma, but X-ray cannot display cartilage and lesions in surrounding soft tissues. Ultrasound is limited in diagnosis of solitary osteochondroma, but performed well as CT in displaying cartilage and lesions in surrounding soft tissues. There was no statistical difference between combined X-ray and ultrasound and CT in diagnosis of solitary osteochondroma (P>0.05), but the former had a lower cost (P<0.05). CONCLUSION: X-ray combined with ultrasound has almost comparable value with CT in the diagnosis of solitary osteochondroma and is more practical for application in primary hospitals. PMID- 24067228 TI - [Expression of NLRP3 inflammasome in BALB/c mice with imiquimod-induced psoriasis like inflammation and therapeutic effect of mustard seed (Sinapis Alba Linn)]. AB - OBJECTIVE: To investigate the role of NLRP3 inflammasome in imiquimod-induced psoriasis-like inflammation in mice and the therapeutic effects of mustard seed (Sinapis Alba Linn). METHODS: Thirty BALB/c mice were randomized equally into blank control group (fed with normal forage and treated with vehicle), model group (fed with normal forage and treated with 5% imiquimod cream), and experimental group (fed with 5% mustard seed forage and treated with 5% imiquimod cream). RT-PCR was used to detect the mRNA expression of NLRP3, ASC, caspase-1, and caspase-11. Immunohistochemistry was performed to determine the expression and distribution of ASC and caspase-1. ELISA was used to test the serum levels of interleukin-1beta (IL-1beta) and IL-18. RESULTS: Compared with the blank control group, the mice with imiquimod-induced psoriasis-like inflammation showed significantly increased NLRP3, ASC, caspase-1, and caspase-11 mRNA expressions, ASC and caspase-1 protein expressions , and serum levels of IL-1beta and IL-18 (P<0.05). These changes were obviously attenuated by feeding the mice with mustard seed. CONCLUSION: NLRP3 inflammasome is involved in imiquimod-induced psoriasis-like inflammation in mice, and mustard seed may suppress the inflammation induced by IL-1beta and IL-18 through down-regulating the expression of NLRP3 inflammasome. PMID- 24067229 TI - [Comparison of peroral endoscopic myotomy with transverse entry incision versus longitudinal entry incision for achalasia]. AB - OBJECTIVE: To compare the safety and efficiency of transverse-incision peroral endoscopic myotomy (POEM) with longitudinal-incision POEM. METHODS: POEM, with a transverse or longitudinal entry incision, was performed in 53 consecutive patients with confirmed achalasia (AC) between December 2010 and September 2012. Data of those patients was collected including the time spent for different procedures and complications. RESULTS: All the 53 patients underwent POEM successfully, among whom 41 patients had a transverse entry incision and 12 had a longitudinal incision. Treatment success (Eckardt score<=3) with a follow-up for 3-24 months (median 5 month) was achieved in 96.2% of the cases (mean score pre treatment vs. post-treatment: 7.5 vs 0.6, P<0.001). The whole operation time of transverse-incision group was slightly shorter than that of longitudinal-incision group (65.0?18.0 min vs 74.1?18.2 min, P=0.142), but it took much less time in tunnel built-up and muscle dissection in the transverse-incision group (36.3?9.0 min vs 45.4?10.5 min; 10.2?4.6 min vs 15.5?5.5 min, P<0.05). In addition, patients in transverse incision group were much less likely to develop pneumatosis- related complications [9.8% (4/41) vs 41.7% (5/12), P<0.05). No serious complications occurred in these two groups such as pleural effusion, mediastinitis or digestive tract fistula. CONCLUSIONS: POEM with a transverse entry incision can significantly decrease the operation time and reduce the incidence of pneumatosis-related complications while obviously relieving the symptoms. PMID- 24067230 TI - [Expression of pin1 in endometrial carcinoma and its relation with PR]. AB - OBJECTIVE: To investigate the clinicopathologic significance of pin1 and PR in patients with endometrial adenocarcinoma. METHODS: The expression of pin1 and PR were investigated by immunohistochemistry in a total of 50 endometrial adenocarcinoma specimens. RESULTS: Pin1 was over expressed in 66% (33/50) of the cases. The expression rate decreased gradually with tumor differentiation(P<0.05). In addition, pin1 expression was negatively correlated with lymph node metastasis and invasive depth of myometrium. Moreover, pin1 was positively correlated with PR expression. CONCLUSION: Our results suggest that pin1 may play important roles in the tumorigenesis and migration of endometrial cancer. Pin1 expression may be considered as a prognostic marker as PR in patients with endometrial cancer. PMID- 24067231 TI - [Hypophosphatemia and chest pain related to adefovir dipivoxil treatment for chronic hepatitis B: report of two cases]. AB - Adefovir dipivoxil (ADV) is an acyclic nucleotide phosphate analogue, currently used for anti-HBV therapy. A few cases of hypophosphatemia related to ADV were reviewed. We report two cases of chronic hepatitis B patients with the chief complaints of chest pain due to hypophosphatemia associated with ADV treatment. PMID- 24067233 TI - Family of mixed 3d-4f dimeric 14-metallacrown-5 compounds: syntheses, structures, and magnetic properties. AB - An isomorphous family of mixed 3d-4f dodenuclear aggregates, {[Mn(III)8Ln4(Clshi)8(OAc)6(MU3-OCH3)2(MU3-O)2(CH3OH)12(H2O)2].4CH3OH.xH2O)} (where Ln = Eu(III) (1), Gd(III) (2), Tb(III) (3), and Dy(III) (4); ClshiH3 = 5 chlorosalicylhydroxamic acid; x = 5 for 1 and 3; x = 6 for 2; x = 2 for 4), were synthesized and characterized. They were obtained from the reaction of ClshiH3 with Mn(OAc)2.4H2O and Ln(NO3)3.6H2O. These isomorphous mixed 3d-4f compounds represent a family of novel structures with lanthanide ions in the metallacrown (MC) ring. Each dodecanuclear aggregate contains two offset stacked 14-MC-5 units with M-N-O-M-N-O-Ln-O-N-M-O-N-M connectivity to capture one Ln(III) ion in the core of each MC. Two 14-MC-5 units are connected through O ions with four Mn ions and six O atoms arranged in a double Mn4O6 cubane. Magnetic measurement indicates that antiferromagnetic interactions are present between the metal ions. The Dy(III) analogue with high anisotropy and large spin shows slow magnetization relaxation at a direct-current field of 2 kOe. PMID- 24067232 TI - Interferon-induced transmembrane protein 3 is a type II transmembrane protein. AB - The interferon-induced transmembrane (IFITM) proteins are a family of small membrane proteins that inhibit the cellular entry of several genera of viruses. These proteins had been predicted to adopt a two-pass, type III transmembrane topology with an intracellular loop, two transmembrane helices (TM1 and TM2), and extracellular N and C termini. Recent work, however, supports an intramembrane topology for the helices with cytosolic orientation of both termini. Here we determined the topology of murine Ifitm3. We found that the N terminus of Ifitm3 could be stained by antibodies at the cell surface but that this conformation was cell type-dependent and represented a minority of the total plasma membrane pool. In contrast, the C terminus was readily accessible to antibodies at the cell surface and extracellular C termini comprised most or all of those present at the plasma membrane. The addition of a C-terminal KDEL endoplasmic reticulum retention motif to Ifitm3 resulted in sequestration of Ifitm3 in the ER, demonstrating an ER-luminal orientation of the C terminus. C-terminal, but not N terminal, epitope tags were also degraded within lysosomes, consistent with their luminal orientation. Furthermore, epitope-tagged Ifitm3 TM2 functioned as a signal anchor sequence when expressed in isolation. Collectively, our results demonstrate a type II transmembrane topology for Ifitm3 and will provide insight into its interaction with potential targets and cofactors. PMID- 24067234 TI - Intersubunit communication via changes in hemoglobin quaternary structures revealed by time-resolved resonance Raman spectroscopy: direct observation of the Perutz mechanism. AB - Time-resolved resonance Raman spectroscopy was used to investigate intersubunit communication of hemoglobin using hybrid hemoglobin in which nickel was substituted for the heme iron in the beta subunits. Changes in the resonance Raman spectra of the alpha heme and the beta Ni-heme groups in the hybrid hemoglobin were observed upon CO photolysis in the alpha subunit using a probe pulse of 436 and 418 nm, respectively. Temporal evolution of the frequencies of the nu(Fe-His) and the gamma7 band of alpha heme was similar to that of unsubstituted hemoglobin, suggesting that substitution with Ni-heme did not perturb the allosteric dynamics of the hemoglobin. In the beta subunits, no structural change in the Ni-heme was observed until 1 MUs. In the microsecond regime, temporal evolution of the frequencies of the nu(Ni-His) and the gamma7 band of beta Ni-heme was observed concomitant with an R -> T quaternary change at about 20 MUs. The changes in the nu(Fe-His) and nu(Ni-His) frequencies of the alpha and beta subunits with the common time constant of ~20 MUs indicated that the proximal tension imposed on the bond between the heme and the proximal histidine strengthened upon the quaternary changes in both the alpha and the beta subunits concertedly. This observation is consistent with the Perutz mechanism for allosteric control of oxygen binding in hemoglobin and, thus, is the first real-time observation of the mechanism. Protein dynamics and allostery based on the observed time-resolved spectra also are discussed. PMID- 24067235 TI - Oxidative damage and myofiber degeneration in the gastrocnemius of patients with peripheral arterial disease. AB - Peripheral arterial disease (PAD), a manifestation of systemic atherosclerosis that produces blockages in arteries supplying the legs, affects an estimated 27 million people in Europe and North America. Increased production of reactive oxygen species by dysfunctional mitochondria in leg muscles of PAD patients is viewed as a key mechanism of initiation and progression of the disease. Previous studies demonstrated increased oxidative damage in homogenates of biopsy specimens from PAD gastrocnemius compared to controls, but did not address myofiber-specific damage. In this study, we investigated oxidative damage to myofibers as a possible cause of the myopathy of PAD. To achieve this, we developed and validated fluorescence microscopy procedures for quantitative analysis of carbonyl groups and 4-hydroxy-2-nonenal (HNE) adducts in myofibers of biopsy specimens from human gastrocnemius. PAD and control specimens were evaluated for differences in 1) myofiber content of these two forms of oxidative damage and 2) myofiber cross-sectional area. Furthermore, oxidative damage to PAD myofibers was tested for associations with clinical stage of disease, degree of ischemia in the affected leg, and myofiber cross-sectional area. Carbonyl groups and HNE adducts were increased 30% (p < 0.0001) and 40% (p < 0.0001), respectively, in the myofibers of PAD (N = 34) compared to control (N = 21) patients. Mean cross-sectional area of PAD myofibers was reduced 29.3% compared to controls (p < 0.0003). Both forms of oxidative damage increased with clinical stage of disease, blood flow limitation in the ischemic leg, and reduced myofiber cross-sectional area. The data establish oxidative damage to myofibers as a possible cause of PAD myopathy. PMID- 24067236 TI - A comparison of state and national Australian data on external cause of injury due to falls. AB - Falls are the leading cause of hospital-treated injuries in Australia. Injury surveillance data are analysed to identify common causes and types of fall injuries, risk factors for particular activities, location of injury occurrence, and age groups at risk of injury. External cause of injury data include cause of injury, place of occurrence, and activity when injured. These are collected in hospitals, where ICD-10-AM codes are assigned by Health Information Managers and clinical coders, based on medical record documentation. The current study examined the extent and quality of Victorian coded data on external cause of injury due to a fall, assessed its usefulness for injury prevention, and compared the Victorian and Australia-wide data. This involved an analysis, using the Victorian Admitted Episode Dataset, of 38,153 hospital separations in 2007-08 for fall injuries and a comparison with the 2003-04 national data. This showed similar usage of External cause codes in Victoria and Australia-wide. There was overuse of residual categories such as Other and Unspecified, these being assigned in 73.8% of separations in Victoria and 71.6% nationally. The problem of overuse of Unspecified external cause codes for hospitalised fall injuries is arguably multifactorial. Inevitably, this overuse reduces the value of the coded data for injury surveillance and prevention, and for monitoring of the public health. PMID- 24067237 TI - Methodological processes in validating and analysing the quality of population based data: a case study using the Victorian Perinatal Data Collection. AB - This paper describes methods used and results obtained from a study that measured the accuracy of a routinely collected population-based data set. Data on a random sample of births were extracted from the 2003 Victorian Perinatal Data Collection (VPDC) and compared with information in the original medical record. Accuracy was calculated for 111 items related to diverse aspects of maternity and neonatal health and care. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for dichotomous items. Seventynine items were accurate in at least 97% of cases, 45 of them in at least 99% of cases, and accuracy was below 90% for five items. Very high specificities demonstrate that conditions were rarely reported in error. Lower sensitivities indicate that some events that occurred went unreported on the perinatal form. The excellent results for specifi city indicated that the dataset is appropriate for a conservative analysis of relationships between factors. The lower sensitivities could result in true relationships between factors remaining unidentified. Reasons for discrepancies between the VPDC and the original medical record are described. PMID- 24067238 TI - Assessing the reliability of causes of death reported by the Vital Registration System in Sri Lanka: medical records review in Colombo. AB - Information on causes of death is critical for informed decision making in the health sector. This paper reports findings from a study that measured the accuracy of registered causes of death and quality of medical records for a sample of deaths occurring in hospitals in Colombo, Sri Lanka. Five physicians, trained in medical certification of cause of death, reconstructed death certificates for hospital deaths from medical records and assessed the quality of medical records for this purpose. The majority of medical records were found to be of average quality. Concordance between the underlying cause of death in the vital registration data and that from the 'gold standard' (medical records review) diagnosis was 41.4% (n=249). The sensitivity of all leading causes of death and positive predictive value were below 67%. Major misclassification errors were found in identifying deaths due to vascular diseases and diabetes mellitus. Certified causes of death in Sri Lanka are frequently incorrect, thus limiting their value for health policy and for monitoring progress towards development goals. Sri Lanka, and other countries at a similar level of statistical development, should consider periodically conducting research to evaluate the quality of cause of death reporting at both local and national levels. PMID- 24067239 TI - The application of data mining to explore association rules between metabolic syndrome and lifestyles. AB - This study used an efficient data mining algorithm, called DCIP (the data cutting and inner product method), to explore association rules between the lifestyles of factory workers in Taiwan and the metabolic syndrome. A total of 1,216 workers in four companies completed a lifestyle questionnaire. Results of the questionnaire survey were integrated into the workers' health examination reports to form an attribute database of the metabolic syndrome. Among the association rules derived by DCIP, 80% of those on the list of the top 15 highest support counts are corroborated by medical literature or by healthcare professionals. These findings prove that data mining is a valid and effective research method, and that larger sample sizes will likely produce more accurate associations connecting the metabolic syndrome to specific lifestyles. The rules already verified can serve as a reference guide for the health management of factory workers. The remaining 20%, while still lacking hard evidence, provide fertile ground for future research. PMID- 24067241 TI - Longitudinal cohort studies of the prognosis of epilepsy: contribution of the National General Practice Study of Epilepsy and other studies. AB - Longitudinal cohort studies of prognosis in epilepsy have been carried out since the late 1970s and these have transformed our understanding of prognosis in epilepsy. This paper reviews the contribution of such studies and focuses particularly on the National General Practice Study of Epilepsy, a prospective population-based cohort study of 1195 patients that was initiated in 1983. The National General Practice Study of Epilepsy and other studies have shown that: (i) epilepsy has an often good prognosis with 65-85% of cases eventually entering long-term remission, and an even higher proportion of cases entering a short-term remission; (ii) the likelihood of long-term remission of seizures is much better in newly diagnosed cases than in patients with chronic epilepsy; (iii) the early response to treatment is a good guide to longer term prognosis (although not inevitably so, as in a minority of cases seizure remission can develop after prolonged activity); (iv) the longer is the remission (and follow-up), the less likely is subsequent recurrence; (v) the longer an epilepsy is active, the poorer is the longer term outlook; (vi) that delaying treatment, even for many years, does not worsen long-term prognosis; (vii) the 'continuous' and 'burst' patterns are more common than the 'intermittent' seizure pattern; (viii) epilepsy has a mortality that is highest in the early years after diagnosis, and in the early years is largely due to the underlying cause, however, higher mortality rates than expected are observed throughout the course of an epilepsy; (ix) the prognosis of febrile seizures is generally good, with ~6-7% developing later epilepsy; and (x) clinical factors associated with outcome have been well studied, and those consistently found to predict a worse outcome include: the presence of neurodeficit, high frequency of seizures before therapy (seizure density), poor response to initial therapy, some epilepsy syndromes. PMID- 24067240 TI - Capturing cooperative interactions with the PSI-MI format. AB - The complex biological processes that control cellular function are mediated by intricate networks of molecular interactions. Accumulating evidence indicates that these interactions are often interdependent, thus acting cooperatively. Cooperative interactions are prevalent in and indispensible for reliable and robust control of cell regulation, as they underlie the conditional decision making capability of large regulatory complexes. Despite an increased focus on experimental elucidation of the molecular details of cooperative binding events, as evidenced by their growing occurrence in literature, they are currently lacking from the main bioinformatics resources. One of the contributing factors to this deficiency is the lack of a computer-readable standard representation and exchange format for cooperative interaction data. To tackle this shortcoming, we added functionality to the widely used PSI-MI interchange format for molecular interaction data by defining new controlled vocabulary terms that allow annotation of different aspects of cooperativity without making structural changes to the underlying XML schema. As a result, we are able to capture cooperative interaction data in a structured format that is backward compatible with PSI-MI-based data and applications. This will facilitate the storage, exchange and analysis of cooperative interaction data, which in turn will advance experimental research on this fundamental principle in biology. PMID- 24067242 TI - Racial differences in motor neuron disease. AB - Our objective was to compare and contrast clinical features of black and white patients seen in the UAMS ALS/Motor Neuron Disease (MND) clinic from January 2001 to December 2010. Death certificate information was reviewed to determine race of Arkansans who died of ALS/MND between 1999 and 2006. We used a retrospective chart review of patients with ALS/MND seen at least once in our clinic and reviewed state death certificate data. Results showed that from 1999 to 2006, 466 Arkansas deaths were attributed (immediate or contributory) to ALS/MND; 17 (3.6%) were black, four (0.9%) other, and 445 (95.5%) white. During this period, the proportion of black Arkansans was 17%. From 2001 to 2010, we saw 330 patients with ALS/MND: 30 (9.1%) black, six (1.8%) other, 294 (89.1%) white. Average onset age for whites was 58.1 + 12.4 years, for blacks 52.8 + 13.0 (p = 0.038). Gender, onset site, time from symptom onset to first clinic visit and initial vital capacity were similar between the groups. Initial ALSFRS-R was 37.5 + 7.2 for whites and 30.8 + 8.5 (p = 0.004) for blacks. A first or second degree relative with ALS/MND was reported by 8.1% of whites and by none of the black patients (p = 0.15). Riluzole, PEG and non-invasive ventilation use was similar between the groups. Median tracheostomy-free survival was 36 months for white and 40 months for black patients (p = 0.475). In conclusion, although blacks appear relatively spared from ALS/MND, they present at an earlier age and are functionally worse at their first visit. Investigating the genetic make-up of blacks with the disease may help identify genes that modify risk of developing ALS/MND. PMID- 24067243 TI - Patient-centered assessment of cognitive symptoms of depression. AB - OBJECTIVE: To identify and explore concepts important to patients with cognitive symptoms of major depressive disorder (MDD) and adapt an existing patient reported outcome (PRO) measure to assess these symptoms. METHODS: Four focus groups were conducted with MDD patients (n = 33) to elicit relevant concepts and determine whether one of several PRO scales could be used to assess cognitive symptoms of depression. Following selection and minor modification of the Perceived Deficits Questionnaire (PDQ), cognitive debriefing interviews were conducted with additional patients (n = 17) to further refine and adapt this measure for use in MDD. Minor revisions based on patient input yielded the PDQ for Depression (PDQ-D). RESULTS: Focus group participants reported a variety of cognitive symptoms that were classified into 7 general categories: lack of focus and clear thought, memory problems, difficulty with lexical access, difficulty with divided attention, difficulty with decision making, difficulty thinking quickly, and difficulty learning new things. Limitations in work productivity were the most commonly reported impacts of cognitive symptoms. While suggesting a few modifications, focus group participants reacted positively to the PDQ based on the breadth, specificity, and relevance of the items. Cognitive debriefing participants indicated that the modified PDQ items were generally easy to understand and relevant to their experiences with MDD. CONCLUSION: Because cognitive symptoms are burdensome to patients with MDD, their assessment is important to optimize treatment outcomes. The PDQ-D has the potential to supplement existing assessment methods, providing unique information important for both comprehensive evaluation of individuals with MDD and evaluation of new treatments. PMID- 24067244 TI - Review of porous silicon preparation and its application for lithium-ion battery anodes. AB - Silicon is of great interest for use as the anode material in lithium-ion batteries due to its high capacity. However, certain properties of silicon, such as a large volume expansion during the lithiation process and the low diffusion rate of lithium in silicon, result in fast capacity degradation in limited charge/discharge cycles, especially at high current rate. Therefore, the use of silicon in real battery applications is limited. The idea of using porous silicon, to a large extent, addresses the above-mentioned issues simultaneously. In this review, we discuss the merits of using porous silicon for anodes through both theoretical and experimental study. Recent progress in the preparation of porous silicon through the template-assisted approach and the non-template approach have been highlighted. The battery performance in terms of capacity and cyclability of each structure is evaluated. PMID- 24067245 TI - A method for the rapid generation of nonsequential light-response curves of chlorophyll fluorescence. AB - Light-response curves (LCs) of chlorophyll fluorescence are widely used in plant physiology. Most commonly, LCs are generated sequentially, exposing the same sample to a sequence of distinct actinic light intensities. These measurements are not independent, as the response to each new light level is affected by the light exposure history experienced during previous steps of the LC, an issue particularly relevant in the case of the popular rapid light curves. In this work, we demonstrate the proof of concept of a new method for the rapid generation of LCs from nonsequential, temporally independent fluorescence measurements. The method is based on the combined use of sample illumination with digitally controlled, spatially separated beams of actinic light and a fluorescence imaging system. It allows the generation of a whole LC, including a large number of actinic light steps and adequate replication, within the time required for a single measurement (and therefore named "single-pulse light curve"). This method is illustrated for the generation of LCs of photosystem II quantum yield, relative electron transport rate, and nonphotochemical quenching on intact plant leaves exhibiting distinct light responses. This approach makes it also possible to easily characterize the integrated dynamic light response of a sample by combining the measurement of LCs (actinic light intensity is varied while measuring time is fixed) with induction/relaxation kinetics (actinic light intensity is fixed and the response is followed over time), describing both how the response to light varies with time and how the response kinetics varies with light intensity. PMID- 24067246 TI - Quality of life and mental health related to timing, frequency and dose of hemodialysis. AB - The perceived quality of life (QOL) and mental health of dialysis patients can have a significant impact on clinical outcomes in the end-stage renal disease (ESRD) population. There is growing interest in increasing dialysis frequency, dose and duration to achieve more adequate dialysis clearance, particularly of middle molecules. Over the past decade, there has been an interest in earlier initiation of dialysis; however, the results of the IDEAL study call this practice into question, and showed no difference in QOL scores between the early start and later start dialysis patients. There are inconsistent results regarding the impact of increased dialysis frequency and dose on patients' perceived health related QOL (HRQOL). Some studies of daily nocturnal dialysis patients show a positive impact on QOL, while others show no significant difference. The disparate outcomes may be partly related to differences in the demographic characteristics of the study populations and the specific questionnaires used to measure HRQOL. Additional research is necessary to determine whether changes in dialysis frequency, timing, and dose can positively or negatively impact patients' perceptions of their QOL and mental health. PMID- 24067247 TI - Depression, delinquency, and suicidal behaviors among college students. AB - BACKGROUND: Liu (2004) investigated the interaction between delinquency and depression among adolescents and found that delinquency moderated the relationship between depression and suicidal behaviors. AIMS: This study also explored the relationship between depression, delinquency, and suicidal behaviors, although delinquency was expected to mediate, as opposed to moderate, the relationship between depression and suicidal behaviors. METHOD: The participants comprised 354 college students. The students completed a series of questionnaires measuring delinquent behavior, depressive symptoms, and suicidal thoughts and behaviors. RESULTS: Contrary to Liu's (2004) findings, delinquency was found not to moderate but rather to partially mediate the relationship between depression and suicidal behaviors. CONCLUSION: The findings suggest that for some college students, depression is associated with delinquent behaviors, which, in turn, are associated with suicidal behaviors. PMID- 24067248 TI - Witnessing suicide-related behavior in prison: a qualitative study of young male prisoners in England. AB - BACKGROUND: Rates of suicide and suicide-related behavior (SRB) are high in prison. Those witnessing such behavior may develop psychological morbidity. Most previous studies have been quantitative. Little has been written about the witnesses' qualitative experience. AIMS: The aim of the study was to explore, through interview and then thematic analysis, the core concerns of those witnessing another's SRB in prison. METHOD: We interviewed 70 detained young men about their experience of another's SRB in prison. RESULTS: Three main themes were identified: their experience of another's SRB; their thoughts of why the victim died by/attempted suicide; and the physical, emotional, and cognitive effects of another's SRB on them. Responses to questions about the witnesses' experience of support from others, unmet needs, and peers' responses are also described. Two categories within the theme "thoughts of why the victim died by/attempted suicide" were associated with being in prison, all others could be experienced in the community. Over half of the sample reported negative reactions to witnessing another's SRB. CONCLUSION: Most themes were unrelated to prison. Though many reported negative reactions to their experience, suggesting a need for support, many denied that need. The implication of this study is that prison discipline and health-care staff need to consider how to provide needed support and care in an acceptable form to young men in prison. PMID- 24067249 TI - What do the bereaved by suicide communicate in online support groups? A content analysis. AB - BACKGROUND: Every year, more than six million people lose a loved one through suicide. These bereaved by suicide are at relatively high risk for mental illnesses including suicide. The social stigma attached to suicide often makes it difficult to talk about grief. Participating in online forums may be beneficial for the bereaved by suicide, but it is unknown what they communicate in these forums. AIMS: What do the bereaved by suicide communicate in online forums? We examined which self-help mechanisms, grief reactions, and experiences with health care services they shared online. METHOD: We conducted a content analysis of 1,250 messages from 165 members of two Dutch language forums for the bereaved by suicide. RESULTS: We found that sharing personal experiences featured most prominently in the messages, often with emotional expressions of grief. Other frequently used self-help mechanisms were expressions of support or empathy, providing advice, and universality (recognition), while experiences with health care services featured only occasionally. Compared with previous studies about online forums for somatic illnesses, the bereaved by suicide communicated more personal experiences and engaged much less in chitchat. CONCLUSION: Online forums appear to have relevant additional value as a platform for talking about grief and finding support. PMID- 24067251 TI - An investigation of the pattern of kidney injury in HIV-positive persons exposed to tenofovir disoproxil fumarate: an examination of a large population database (MHRA database). AB - The potential for tenofovir to cause a range of kidney syndromes has been established from mechanistic and randomised clinical trials. However, the exact pattern of kidney involvement is still uncertain. We undertook a descriptive analysis of Yellow Card records of 407 HIV-positive persons taking tenofovir disoproxil fumarate (TDF) as part of their antiretroviral therapy regimen and submitted to the Medicines and Healthcare Products Regulatory Agency (MHRA) with suspected kidney adverse effects. Reports that satisfy defined criteria were classified as acute kidney injury, kidney tubular dysfunction and Fanconi syndrome. Of the 407 Yellow Card records analysed, 106 satisfied criteria for TDF related kidney disease, of which 53 (50%) had features of kidney tubular dysfunction, 35 (33%) were found to have features of glomerular dysfunction and 18 (17%) had Fanconi syndrome. The median TDF exposure was 316 days (interquartile range 120-740). The incidence of hospitalisation for TDF kidney adverse effects was high, particularly amongst patients with features of Fanconi syndrome. The pattern of kidney syndromes in this population series mirrors that reported in randomised clinical trials. Cessation of TDF was associated with complete restoration of kidney function in up half of the patients in this report. PMID- 24067250 TI - Suicides in urban and rural counties in the United States, 2006-2008. AB - BACKGROUND: Suicide rates are higher in rural areas. It has been hypothesized that inadequate access to care may play a role, but studies examining individual decedent characteristics are lacking. AIMS: We sought to characterize the demographic, socioeconomic, and mental health features of individual suicide decedents by urban-rural residence status. METHOD: We analyzed suicides in 16 states using 2006-2008 data from the National Violent Death Reporting System and examined associations between decedent residence type and suicide variables with separate logistic regressions adjusted for age, sex, race, and ethnicity. RESULTS: Of 17,504 analyzed suicides, 78% were in urban, 15% in rural adjacent, and 8% in rural nonadjacent locations. Rural decedents were less likely than urban decedents to have a mental health diagnosis or mental health care, although the prevalence of depressed moods appeared similar. Most suicides were by firearm, and rural decedents were more likely than urban decedents to have used a firearm. CONCLUSION: Rural decedents were less likely to be receiving mental health care and more likely to use firearms to commit suicide. A better understanding of geographic patterns of suicide may aid prevention efforts. PMID- 24067252 TI - Three-year longitudinal population-based volumetric MRI study in first-episode schizophrenia spectrum patients. AB - BACKGROUND: Schizophrenia is a chronic brain disorder associated with structural brain abnormalities already present at the onset of the illness. Whether these brain abnormalities might progress over time is still under debate. METHOD: The aim of this study was to investigate likely progressive brain volume changes in schizophrenia during the first 3 years after initiating antipsychotic treatment. The study included 109 patients with a schizophrenia spectrum disorder and a control group of 76 healthy subjects. Subjects received detailed clinical and cognitive assessment and structural magnetic resonance imaging (MRI) at regular time points during a 3-year follow-up period. The effects of brain changes on cognitive and clinical variables were examined along with the impact of potential confounding factors. RESULTS: Overall, patients and healthy controls exhibited a similar pattern of brain volume changes. However, patients showed a significant lower progressive decrease in the volume of the caudate nucleus than control subjects (F 1,307.2 = 2.12, p = 0.035), with healthy subjects showing a greater reduction than patients during the follow-up period. Clinical and cognitive outcomes were not associated with progressive brain volume changes during the early years of the illness. CONCLUSIONS: Brain volume abnormalities that have been consistently observed at the onset of non-affective psychosis may not inevitably progress, at least over the first years of the illness. Taking together with clinical and cognitive longitudinal data, our findings, showing a lack of brain deterioration in a substantial number of individuals, suggest a less pessimistic and more reassuring perception of the illness. PMID- 24067255 TI - Photodynamic therapy with methyl-aminolevulinate can be useful in the management of Scytalidium infections. PMID- 24067256 TI - Acquired epidermodysplasia verruciformis in a patient with congenital HIV infection. PMID- 24067257 TI - Microbial expression profiles in the rhizosphere of willows depend on soil contamination. AB - The goal of phytoremediation is to use plants to immobilize, extract or degrade organic and inorganic pollutants. In the case of organic contaminants, plants essentially act indirectly through the stimulation of rhizosphere microorganisms. A detailed understanding of the effect plants have on the activities of rhizosphere microorganisms could help optimize phytoremediation systems and enhance their use. In this study, willows were planted in contaminated and non contaminated soils in a greenhouse, and the active microbial communities and the expression of functional genes in the rhizosphere and bulk soil were compared. Ion Torrent sequencing of 16S rRNA and Illumina sequencing of mRNA were performed. Genes related to carbon and amino-acid uptake and utilization were upregulated in the willow rhizosphere, providing indirect evidence of the compositional content of the root exudates. Related to this increased nutrient input, several microbial taxa showed a significant increase in activity in the rhizosphere. The extent of the rhizosphere stimulation varied markedly with soil contamination levels. The combined selective pressure of contaminants and rhizosphere resulted in higher expression of genes related to competition (antibiotic resistance and biofilm formation) in the contaminated rhizosphere. Genes related to hydrocarbon degradation were generally more expressed in contaminated soils, but the exact complement of genes induced was different for bulk and rhizosphere soils. Together, these results provide an unprecedented view of microbial gene expression in the plant rhizosphere during phytoremediation. PMID- 24067258 TI - Linking N2O emissions from biochar-amended soil to the structure and function of the N-cycling microbial community. AB - Nitrous oxide (N2O) contributes 8% to global greenhouse gas emissions. Agricultural sources represent about 60% of anthropogenic N2O emissions. Most agricultural N2O emissions are due to increased fertilizer application. A considerable fraction of nitrogen fertilizers are converted to N2O by microbiological processes (that is, nitrification and denitrification). Soil amended with biochar (charcoal created by pyrolysis of biomass) has been demonstrated to increase crop yield, improve soil quality and affect greenhouse gas emissions, for example, reduce N2O emissions. Despite several studies on variations in the general microbial community structure due to soil biochar amendment, hitherto the specific role of the nitrogen cycling microbial community in mitigating soil N2O emissions has not been subject of systematic investigation. We performed a microcosm study with a water-saturated soil amended with different amounts (0%, 2% and 10% (w/w)) of high-temperature biochar. By quantifying the abundance and activity of functional marker genes of microbial nitrogen fixation (nifH), nitrification (amoA) and denitrification (nirK, nirS and nosZ) using quantitative PCR we found that biochar addition enhanced microbial nitrous oxide reduction and increased the abundance of microorganisms capable of N2-fixation. Soil biochar amendment increased the relative gene and transcript copy numbers of the nosZ-encoded bacterial N2O reductase, suggesting a mechanistic link to the observed reduction in N2O emissions. Our findings contribute to a better understanding of the impact of biochar on the nitrogen cycling microbial community and the consequences of soil biochar amendment for microbial nitrogen transformation processes and N2O emissions from soil. PMID- 24067259 TI - Ultra performance liquid chromatography PDA method for determination of tigecycline in human plasma. AB - : A simple ultra performance liquid chromatography with photodiode array method for the quantification of human plasma concentrations of tigecycline was developed and validated. Quinaxoline, used as an internal standard, was added to 500 MUL of plasma before adding 1 mL of protein precipitation solution. The extracts were dried in a vacuum centrifuge system at 60 degrees C and reconstituted with 60 MUL of water and acetonitrile (95:5, vol/vol), and 5 MUL was injected onto an ACQUITY UPLC H-Class system. Chromatographic separation was performed on a C18 ACQUITY UPLC HSS T3 column using a gradient of potassium phosphate buffer (pH 3.2) and acetonitrile. Detection was performed using a photodiode array detector at 350 nm. Relative error at 3 quality control concentrations ranged from -2.49% to -8.74%. Intraday and interday (percent relative standard error) precision ranged from 3.93% to 12.27% and from 9.53% to 13.32%, respectively. Limit of quantification and limit of detection were 0.024 and 0.006 MUg/mL, respectively. Mean recovery was 95%. The calibration curve was linear up to 6 MUg/mL. This concentration range proved to be adequate to measure tigecycline concentrations in patients treated with the drug, therefore this method would be suitable for therapeutic drug monitoring. PMID- 24067260 TI - Plasma cannabinoid concentrations during dronabinol pharmacotherapy for cannabis dependence. AB - BACKGROUND: Recently, high-dose oral synthetic delta-9-tetrahydrocannabinol (THC) was shown to alleviate cannabis withdrawal symptoms. The present data describe cannabinoid pharmacokinetics in chronic, daily cannabis smokers who received high dose oral THC pharmacotherapy and later a smoked cannabis challenge. METHODS: Eleven daily cannabis smokers received 0, 30, 60, or 120 mg/d THC for four 5-day medication sessions, each separated by 9 days of ad libitum cannabis smoking. On the fifth day, participants were challenged with smoking one 5.9% THC cigarette. Plasma collected on the first and fifth days was quantified by two-dimensional gas chromatography mass spectrometer for THC, 11-hydroxy-THC (11-OH-THC), and 11 nor-9-carboxy-THC (THCCOOH). Linear ranges (ng/mL) were 0.5-100 for THC, 1-50 for 11-OH-THC, and 0.5-200 for THCCOOH. RESULTS: During placebo dosing, THC, 11-OH THC, and THCCOOH concentrations consistently decreased, whereas all cannabinoids increased dose dependently during active dronabinol administration. THC increase over time was not significant after any dose, 11-OH-THC increased significantly during the 60- and 120-mg/d doses, and THCCOOH increased significantly only during the 120-mg/d dose. THC, 11-OH-THC, and THCCOOH concentrations peaked within 0.25 hours after cannabis smoking, except after 120 mg/d THC when THCCOOH peaked 0.5 hours before smoking. CONCLUSIONS: The significant withdrawal effects noted during placebo dronabinol administration were supported by significant plasma THC and 11-OH-THC concentration decreases. During active dronabinol dosing, significant dose-dependent increases in THC and 11-OH-THC concentrations support withdrawal symptom suppression. THC concentrations after cannabis smoking were only distinguishable from oral THC doses for 1 hour, too short a period to feasibly identify cannabis relapse. THCCOOH/THC ratios were higher 14 hours after overnight oral dronabinol abstinence but cannot distinguish oral THC dosing from the smoked cannabis intake. PMID- 24067261 TI - Incidence, time trends, laterality, indications, and pathological findings of unilateral oophorectomy before menopause. AB - OBJECTIVE: Unilateral oophorectomy (UO) is a common surgical practice, yet it remains understudied. We investigated trends in incidence rates, indications, and pathological differences in the right and left ovaries in women younger than 50 years. METHODS: The Rochester Epidemiology Project medical records linkage system was used to identify all women in Olmsted County, MN, who underwent UO between 1950 and 2007 (n = 1,838). We studied the incidence rates, indications, and pathologies of UO by laterality, and investigated trends across time. RESULTS: Pooling all oophorectomies across a 58-year period, we found that the incidence of UO was higher than the incidence of bilateral oophorectomy through the age of 39 years; however, bilateral oophorectomy surpassed UO thereafter. The incidence of UO increased from 1950 to 1974 but decreased thereafter and was surpassed by the rate of bilateral oophorectomy after 1979. Before 1985, left ovaries were removed more frequently than right ovaries with or without a medical indication for UO. Ovaries removed with a medical indication showed pathological differences between the right ovary and the left ovary, with endometriosis being more common in the left ovary. Ovaries removed without a medical indication did not differ in pathology by side. CONCLUSIONS: There have been major changes in incidence rates of UO across six decades. Medically indicated UO has been more common on the left side due, in part, to the higher prevalence of endometriosis. However, UO without a medical indication has also been more common on the left side because of surgical preferences and traditions. The long-term consequences of right or left UO on timing of menopause, morbidity, and mortality need further study. PMID- 24067262 TI - Adipocytokines and cytokeratin-18 in patients with nonalcoholic fatty liver disease: Introduction of CHA index. AB - BACKGROUND AND RATIONALE: Insulin resistance (IR), adipocytokines, oxidative stress and hepatic apoptosis play a pathogenetic role in nonalcoholic fatty liver disease (NAFLD). AIMS: The evaluation of specific adipocytokines and markers of IR, oxidative stress and apoptosis in NAFLD patients; the introduction of a combined non-invasive index for nonalcoholic steatohepatitis (NASH). MATERIAL AND METHODS: Thirty patients with biopsy-proven NAFLD (15 with simple nonalcoholic fatty liver [NAFL], 15 with NASH) and 24 controls were recruited. Blood samples for total and high molecular weight (HMW) adiponectin, visfatin and tumor necrosis factor (TNF)-alpha, the apoptotic by-product cytokeratin (CK)-18, the reactive oxygen metabolites (ROMs) and standard biochemical tests were measured. Homeostatic model of assessment - insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were calculated. MAIN RESULTS: Total and HMW adiponectin were significantly lower and TNF-alpha higher in either NAFL or NASH group compared to control group; CK-18 was significantly higher in NASH compared to either NAFL or control group. CHAI (an acronym of CK-18, HOMA-IR, AST Index) was calculated as the product of parameters being significantly different between NAFL and NASH groups. CHAI was significantly higher in NASH (24.2 [15.1 214.0]) compared to either NAFL (15.7 [6.8-22.7]) or control (5.1 [2.4-7.6]) group (p < 0.001) and significantly higher as the severity of steatosis, fibrosis, ballooning, lobular and portal inflammation advanced. CONCLUSION: CHAI was escalating from controls to NAFL and NASH and was higher by increasing the severity of all the main histological lesions. However, a validation study is needed before introducing CHAI in clinical practice. PMID- 24067263 TI - Mechanical response of dental cements as determined by nanoindentation and scanning electron microscopy. AB - This study evaluated the effects of nanoindentation on the surface of white mineral trioxide aggregate (WMTA), Bioaggregate and Nano WMTA cements. Cements were mixed according to the manufacturer directions, condensed inside glass tubes, and randomly divided into three groups (n = 8). Specimens were soaked in synthetic tissue fluid (pH = 7.4) and incubated for 3 days. Cement pellets were subjected to nanoindentation tests and observed by scanning electron microscopy. Then, the images were processed and the number of cracks and total surface area of defects on the surface were calculated and analyzed using ImageJ. Data were submitted to one-way analysis of variance and a post hoc Tukey's test. The lowest number of cracks and total surface of defects were detected in Nano WMTA samples; however, it was not significantly different from WMTA samples (p = 0.588), while the highest values were noticed in Bioaggregate specimens that were significantly different from Nano WMTA and WMTA (p = 0.0001). The surface of WMTA and Nano WMTA showed more resistance after exposure to nano-compressive forces which indicated a better surface tolerance against these forces and crack formation. This suggests these substances are more tolerant cement materials which can predictably withstand loaded situations in a clinical scenario. PMID- 24067264 TI - Size-dependent giant-magnetoresistance in millimeter scale GaAs/AlGaAs 2D electron devices. AB - Large changes in the electrical resistance induced by the application of a small magnetic field are potentially useful for device-applications. Such Giant Magneto Resistance (GMR) effects also provide new insights into the physical phenomena involved in the associated electronic transport. This study examines a "bell shape" negative GMR that grows in magnitude with decreasing temperatures in mm wide devices fabricated from the high-mobility GaAs/AlGaAs 2-Dimensional Electron System (2DES). Experiments show that the span of this magnetoresistance on the magnetic-field-axis increases with decreasing device width, W, while there is no concurrent Hall resistance, Rxy, correction. A multi-conduction model, including negative diagonal-conductivity, and non-vanishing off-diagonal conductivity, reproduces experimental observations. The results suggest that a size effect in the mm-wide 2DES with mm-scale electron mean-free-paths is responsible for the observed "non-ohmic" size-dependent negative GMR. PMID- 24067265 TI - Direct visualization of a guest-triggered crystal deformation based on a flexible ultramicroporous framework. AB - Host-guest composites may exhibit abnormal and/or controllable physical properties that are unavailable for traditional solids. However, it is still very difficult to control or visualize the occupancy and motion of the guest. Here we report a flexible ultramicroporous coordination polymer showing exceptional guest responsive thermal-expansion properties. The vacant crystal exhibits constant and huge thermal expansion over a wide temperature range not only in vacuum but also in air, as its ultramicroporous channel excludes air adsorption even at 77 K. More interestingly, as demonstrated by single-crystal X-ray crystallography, molecular dynamic simulations and solid-state nuclear magnetic resonance, it selectively responds to the molecular rearrangement of N,N-dimethylformamide, leading to conformation reversion of the flexible ligand, which transfers these actions to deform the whole crystal lattice. These results illustrate that combination of ultramicroporous channel and flexible pore surface could be an effective strategy for the utilization of external physical and chemical stimuli. PMID- 24067266 TI - Stable cycling and excess capacity of a nanostructured Sn electrode based on Sn(CH3COO)2 confined within a nanoporous carbon scaffold. AB - A high capacity, electrochemically stable, nanostructured Sn electrode for Li ion battery anodes is described. This electrode utilizes a rigid, electrically conductive, nanoporous carbon aerogel scaffold by incorporating tin acetate, Sn(CH3COO)2, into the scaffold pore volume through melt infusion. Incorporation of the Sn(CH3COO)2 by melt infusion ensures a chemically stable contact with the scaffold. The mechanical rigidity of the pore volume confines the Sn to nanometer dimensions without sintering, leading to stable cycling. Separation of the synthesis of the scaffold from the loading with Sn(CH3COO)2 permits optimized division of the scaffold pore volume for expansion and electrolyte access during reaction with Li. Using this design, an electrode based on an aerogel with a 5 nm mode pore size was cycled over 300 times without degradation. In addition, after subtracting the contribution from the carbon scaffold, the capacity exceeded the theoretical capacity for Sn, due to an oxidation reaction occurring at 1.2 V. This excess capacity may be related to the solid-solid or solid-electrolyte interfaces in the electrode, possibly representing a new reversible Li ion reaction. PMID- 24067268 TI - Hydrogen-induced change in core structures of {110}[111] edge and {110}[111] screw dislocations in iron. AB - Employing the empirical embedded-atom method potentials, the evolution of edge and screw dislocation core structure is calculated at different hydrogen concentrations. With hydrogen, the core energy and Peierls potential are reduced for all dislocations. A broaden-core and a quasi-split core structure are observed for edge and screw dislocation respectively. The screw dislocation and hydrogen interaction in body-centred cubic iron is found to be not mainly due to the change of elastic modulus, but the variation of dislocation core structure. PMID- 24067269 TI - Lung cancer: needs assessment, treatment and therapies. AB - Lung cancer is the most common cancer in the world. Globally, the annual diagnosis rate of new cases is approximately 1.6 million. The latest figures for the UK show that there are approximately 39000 cases each year and that lung cancer accounts for about 22% of all cancer deaths (Cancer Research UK, 2013a). This article will look at the latest national recommendations for managing and treating non-small cell lung cancer, which accounts for about 80% of lung cancers, as well as emerging therapies. It is not within the scope of this article to discuss each type and aspect of lung cancer in detail and further reading is encouraged. PMID- 24067267 TI - Effects of an individually tailored Web-based chronic pain management program on pain severity, psychological health, and functioning. AB - BACKGROUND: It is estimated that 30% of adults in the United States experience daily chronic pain. This results in a significant burden on the health care system, in particular primary care, and on the workplace. Chronic pain management with cognitive-behavioral psychological treatment is effective in reducing pain intensity and interference, health-related quality of life, mood, and return to work. However, the population of individuals with chronic pain far exceeds the population of therapists that can provide this care face-to-face. The use of tailored, Web-based interventions for the management of chronic pain could address limitations to access by virtue of its unlimited scalability. OBJECTIVE: To examine the effects of a tailored Web-based chronic pain management program on subjective pain, activity and work interference, quality of life and health, and stress. METHODS: Eligible participants accessed the online pain management program and informed consent via participating employer or health care benefit systems; program participants who completed baseline, 1-, and 6-month assessments were included in the study. Of the 645 participants, the mean age was 56.16 years (SD 12.83), most were female (447/645, 69.3%), and white (505/641, 78.8%). Frequent pain complaints were joint (249/645, 38.6%), back (218/645, 33.8%), and osteoarthritis (174/654, 27.0%). The online pain management program used evidence based theories of cognitive behavioral intervention, motivational enhancement, and health behavior change to address self-management, coping, medical adherence, social support, comorbidities, and productivity. The program content was individually tailored on several relevant participant variables. RESULTS: Both pain intensity (mean 5.30, SD 2.46), and unpleasantness (mean 5.43, SD 2.52) decreased significantly from baseline to 1-month (mean 4.16, SD 2.69 and mean 4.24, 2.81, respectively) and 6-month (mean 3.78, SD 2.79 and mean 3.78, SD 2.79, respectively) assessments (P<.001). The magnitude of the 6-month effects were large. Trends for decreases in pain interference (36.8% reported moderate or enormous interference) reached significance at 6 months (28.9%, P<.001). The percentage of the sample reporting fair or poor quality of life decreased significantly from 20.6% at baseline to 16.5% at 6 months (P=.006). CONCLUSIONS: Results suggest that the tailored online chronic pain management program showed promising effects on pain at 1 and 6 months posttreatment and quality of life at 6 months posttreatment in this naturalistic study. Further research is warranted to determine the significance and magnitude of the intervention's effects in a randomized controlled trial. PMID- 24067270 TI - Ovarian cancer: risk factors, treatment and management. AB - Ovarian cancer is the fifth most common cancer affecting women in the UK today, with associated statistics illustrating a steadily increasing rate, particularly in women aged 65 and over (Cancer Research UK, 2013). There are no recognised preventative measures and no effective screening tool. Although evidence suggests that the majority of women experience a variety of non-specific symptoms in the year before diagnosis, the disease it is not commonly recognised until an advanced stage, leading to increased mortality and morbidity. This highlights the need to raise awareness among health professionals and women as a whole, as early recognition undoubtedly improves ovarian cancer survival. Best clinical practice in the UK for the recognition and initial management of ovarian cancer is provided by the National Institute for Health and Care Excellence (NICE). Clinical guideline CG 122 (NICE, 2011) and quality standard QS 18 (NICE, 2012) use relevant clinical evidence to define high-quality care standards for ovarian cancer management. Accurate staging of ovarian cancer is essential to the provision of individualised care and management. However, there is currently no single test that provides a reliable indicator of ovarian malignancy. At present, risk-of-malignancy scores are calculated by serum cancer antigen 125 (CA 125) levels, ultrasound score and menopausal status. These are widely used to identify women who are at high risk and require referral to a specialised gynaecological oncology service. Women diagnosed with ovarian cancer require information and support. The clinical nurse specialist acts as a key worker, providing communication, support and holistic care throughout a woman's cancer journey. The value of this role cannot be underestimated. Surgery followed by platinum-based chemotherapy is the usual standard treatment pathway, although individualised assessment and management may deviate from it. Early disease may be successfully treated with surgery alone; advanced disease may require complex management and treatment. New treatments such as bevacizumab show promise of improving ovarian cancer outcomes. PMID- 24067271 TI - Improving care at local and national levels. PMID- 24067272 TI - Infusion pumps in palliative care are vital, but many need updating. PMID- 24067273 TI - Dexrazoxane: a management option for anthracycline extravasations. AB - AIMS: This article reviews the efficacy and place in therapy of dexrazoxane (Savene(r)) for the treatment of anthracycline extravasation, highlighting the lack of inclusion of Savene in most UK cancer network and organisational treatment guidelines. Here we offer advice to nurses on making a case to ensure the availability of Savene. KEY FINDINGS: In 2010, the UK National Extravasation Information Service (NEXIS) green card scheme reported that anthracyclines were the second most common agent involved in extravasations, but they carry the greatest risk to the patient because of their potentially serious consequences. Anthracycline extravasations therefore require prompt and effective treatment. Due to the infrequent occurrence of anthracycline extravasations, their accidental nature and ethical considerations, conducting randomised controlled clinical trials in this therapy area is not possible. As treatment decisions should always be made on patient-specific factors, health professionals need to demonstrate the rationale for choosing a particular course of action when presented with an anthracycline extravasation, especially when we are moving into an era of increased medical litigation. There are several possible treatment options, some of which require demonstrable local core competencies in order to be considered for a particular patient. Based on the available evidence, Savene the only licensed antidote-is recommended as an effective management strategy for anthracycline extravasation and should be made available in all settings where chemotherapy is administered. However, a high percentage of nurses administering chemotherapy still do not have access to Savene, as it has not been included in their local guidelines for the management of extravasations. Thus, in a large part of the UK, this important treatment option is not available, leaving a significant unmet need (Figure 1). CONCLUSIONS: As nurses play a key role in the prevention, detection, and management of extravasations, they should also assume a key role in ensuring that their local protocols include all appropriate management strategies. Where appropriate, if Savene is not included in the treatment guidelines, nurses should feel empowered to encourage their trust and Specialist Commissioning Groups (SCGs) to make it available, and thus minimise the serious risks associated with anthracycline extravasations. PMID- 24067274 TI - Epidemiology of arrhythmias and sudden cardiac death in Asia. AB - Cardiac arrhythmias are cardiac rhythm disorders that comprise an important epidemiological and public health problem. Cardiac arrhythmias are significantly associated with increased risks of cardiovascular complications and sudden death, consequently leading to decreased quality of life, disability, high mortality, and healthcare expense. Atrial fibrillation (AF) is the most common sustained arrhythmia, and has been further increasing with the aging of society. Although the prevalence is relatively lower in Asians than in Westerners, the prognostic impacts on stroke and mortality in Asians are comparable. Sudden cardiac death (SCD) occurs in approximately 40 cases per 100,000 persons annually in each country of Asia. Most cases are caused by myocardial infarction and ventricular fibrillation in out-of-hospital cardiac arrest cases, but the proportion of myocardial infarction is lower in Asia than in Western countries. The primary electrophysiological disorders related to channelopathies, such as long QT syndrome, short QT syndrome, Brugada syndrome, early repolarization syndrome, and catecholaminergic polymorphic ventricular tachycardia, are estimated to be responsible for 10% of SCDs. Implantable cardioverter-defibrillator implantation has become established as an effective secondary prevention for SCD, and numbers have been increasing annually worldwide. New insights into arrhythmic diseases have been emerging from epidemiological, clinical, and genetic research, and contribute to improvements in diagnosis and prognosis. PMID- 24067275 TI - High-density lipoproteins. Multifunctional but vulnerable protections from atherosclerosis. AB - Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary artery disease (CAD). HDL particles exert many effects in vitro and in vivo that may protect arteries from chemical or biological harm or facilitate repair of injuries. Nevertheless, HDL has not yet been successfully exploited for therapy. One potential reason for this shortfall is the structural and functional complexity of HDL particles, which carry more than 80 different proteins and more than 200 lipid species as well as several microRNAs and other potentially bioactive molecules. This physiological heterogeneity is further increased in several inflammatory conditions that increase cardiovascular risk, including CAD itself but also diabetes mellitus, chronic kidney disease, and rheumatic diseases. The quantitative and qualitative modifications of the proteome and lipidome, as well as the resulting loss of functions or gain of dysfunctions, are not recovered by the biomarker HDL cholesterol. As yet the relative importance of the many physiological and pathological activities of normal and dysfunctional HDL, respectively, for the pathogenesis of atherosclerosis is unknown. The answer to this question, as well as detailed knowledge of structure-function-relationships of HDL-associated molecules, is a prerequisite to exploit HDL for the development of anti atherogenic drugs as well as of diagnostic biomarkers for the identification, personalized treatment stratification, and monitoring of patients at increased cardiovascular risk. PMID- 24067279 TI - Slippery liquid-infused porous surfaces showing marine antibiofouling properties. AB - Marine biofouling is a longstanding problem because of the constant challenges placed by various fouling species and increasingly restricted environmental regulations for antifouling coatings. Novel nonbiocidal strategies to control biofouling will necessitate a multifunctional approach to coating design. Here we show that slippery liquid-infused porous surfaces (SLIPSs) provide another possible strategy to obtaining promising antifouling coatings. Microporous butyl methacrylate-ethylene dimethacrylate (BMA-EDMA) surfaces are prepared via UV initiated free-radical polymerization. Subsequent infusion of fluorocarbon lubricants (Krytox103, Krytox100, and Fluorinert FC-70) into the porous microtexture results in liquid-repellent slippery surfaces. To study the interaction with marine fouling organisms, settlement of zoospores of the alga Ulva linza and cypris larvae of the barnacle Balanus amphitrite is tested in laboratory assays. BMA-EDMA surfaces infused with Krytox103 and Krytox100 exhibit remarkable inhibition of settlement (attachment) of both spores and cyprids to a level comparable to that of a poly(ethylene glycol) (PEG)-terminated self assembled monolayer. In addition, the adhesion strength of sporelings (young plants) of U. linza is reduced for BMA-EDMA surfaces infused with Krytox103 and Krytox100 compared to pristine (noninfused) BMA-EDMA and BMA-EDMA infused with Fluorinert FC-70. Immersion tests suggest a correlation between the stability of slippery coatings in artificial seawater and fouling resistance efficacy. The results indicate great potential for the application of this concept in fouling resistant marine coatings. PMID- 24067278 TI - SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. AB - DESIGN: Pharmacokinetic and pharmacodynamic parameters of cremophor-paclitaxel, nab-paclitaxel (human-albumin-bound paclitaxel, Abraxane) and a novel mouse albumin-bound paclitaxel (m-nab-paclitaxel) were evaluated in genetically engineered mouse models (GEMMs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS), histological and biochemical analysis. Preclinical evaluation of m nab-paclitaxel included assessment by three-dimensional high-resolution ultrasound and molecular analysis in a novel secreted protein acidic and rich in cysteine (SPARC)-deficient GEMM of pancreatic ductal adenocarcinoma (PDA). RESULTS: nab-Paclitaxel exerted its antitumoural effects in a dose-dependent manner and was associated with less toxicity compared with cremophor-paclitaxel. SPARC nullizygosity in a GEMM of PDA, Kras(G12D);p53(flox/-);p48Cre (KPfC), resulted in desmoplastic ductal pancreas tumours with impaired collagen maturation. Paclitaxel concentrations were significantly decreased in SPARC null plasma samples and tissues when administered as low-dose m-nab-paclitaxel. At the maximally tolerated dose, SPARC deficiency did not affect the intratumoural paclitaxel concentration, stromal deposition and the immediate therapeutic response. CONCLUSIONS: nab-Paclitaxel accumulates and acts in a dose-dependent manner. The interaction of plasma SPARC and albumin-bound drugs is observed at low doses of nab-paclitaxel but is saturated at therapeutic doses in murine tumours. Thus, this study provides important information for future preclinical and clinical trials in PDA using nab-paclitaxel in combination with novel experimental and targeted agents. PMID- 24067280 TI - Genetic aspects of vitamin D receptor and metabolism in relation to the risk of multiple sclerosis. AB - Recent findings suggest that polymorphisms in vitamin D pathway genes are candidates for association with multiple sclerosis susceptibility. It has been now well demonstrated that vitamin D has immunomodulatory functions that may be favorable for reduction of multiple sclerosis risk. Current research has been focused on identification of new variants of genes involved in vitamin D pathway, namely in vitamin D receptor and enzymes of vitamin D metabolism. These variants have been intensively studied as possible genetic predictors of both vitamin D levels and the risk of multiple sclerosis. Considering the findings available up to-date, we may recognize two groups of genetic variants. The first group of genes was found to predict vitamin D levels but not the risk of multiple sclerosis. The second group of genetic variants is represented by promising genes predicting vitamin D levels as well as the risk of multiple sclerosis. A strong association with increased risk of the disease has been observed for a rare variant in the CYP27B1 gene encoding a vitamin D-activating enzyme. Observed interaction between genetic and epidemiological findings brings the rationale for supplementation trials of vitamin D. Although promising effects of vitamin D supplementation have emerged, the results obtained so far are inconclusive and the real therapeutic significance of vitamin D supplementation remains to be elucidated. PMID- 24067281 TI - Nuclear receptors - target molecules for isoflavones in cancer chemoprevention. AB - Breast cancer is the most occurring type of cancer among women. In Slovakia, there are yearly diagnosed about 1900 new cases of this disease. Breast cancer treatment is very expensive, psychic stressful and in some cases ineffective. Therefore, it is essential to search for new and/or alternative methods for breast cancer treatment, since nuclear receptors are considered to be a central goal for maximizing treatment opportunities in breast cancer. Among natural ligands for estrogen receptors (ERalpha and ERbeta), which are member of nuclear receptors superfamily, belongs also isoflavones. These natural compounds have similar structure to main female hormon-17beta estradiol. A rich source of isoflavones is soy and its products. Three aglycones form of isoflavones (genistein, daidzein, glycitein) are predominantly found in soybean and red clover. Among other important isoflavones belongs also biochanin A and formononetin. PMID- 24067282 TI - Effects of the blood components on the AMPA and NMDA synaptic responses in brain slices in the onset of hemorrhagic stroke. AB - Blood-borne events play a major role in post bleeding disturbances of the neuronal network. However, very little is known about the early effects of blood plasma, leucocytes, and the red blood cells on the AMPA and NMDA-mediated synaptic responses in the onset of experimental intracranial hemorrhage (ICH). In this study, we used the technique of on-line monitoring of electrophysiological parameters referred to synaptic activity in piriform cortex of SHR rat slice. We exposed the olfactory cortex slices to diluted autologous blood or its components and compared with effects of ferric chloride. Whole blood exerted a total inhibition of synaptic activity in piriform cortex within first 5 min. Dilution of blood induced prolonged epileptic synaptic activation of NMDA receptors. Blood plasma and fraction of leucocytes induced hyperactivation of neurons transforming to epileptiform discharges. Fraction of red blood cells acted biphasic, an initial sharp activity of AMPA- and NMDA-mediated receptors replaced by a following total depression. Our slice-based models of experimental stroke revealed the mechanism of the earliest pathophysiologic events occur in brain tissue during bleeding that may be relevant to the human ICH. PMID- 24067283 TI - Quercetin attenuates oxidative stress in the blood plasma of rats bearing DMBA induced mammary cancer and treated with a combination of doxorubicin and docetaxel. AB - The development of side-effects during doxorubicin-docetaxel (DOX-DTX) chemotherapy is considered as related to generation of oxidative stress by DOX. The addition of docetaxel potentiates this effect. Thus, antioxidants are assumed as a promising remedy for neutralizing deteriorating effects of reactive oxygen species (ROS) in pathological conditions and polyphenolic antioxidants are suitable candidates for such a therapeutic approach. We evaluated the ability of quercetin to attenuate oxidative stress developed during the process of DMBA carcinogenesis and DOX-DTX chemotherapy in the blood plasma of rats bearing mammary tumors. We have found that quercetin significantly improved the plasma nonenzymatic antioxidant capacity (NEAC) and reduced lipid peroxidation, which suggest the beneficial effect of flavonoid. The inclusion of quercetin to the DOX DTX chemotherapy was also advantageous. A considerable decrease of carbonyls and lipid peroxidation products (TBARS) and improvement of the endogenous antioxidant defense system (an increase of NEAC, thiols and SOD activity) were observed compared to rats treated with DOX-DTX chemotherapy. These results suggest that quercetin could protect blood plasma constituents against oxidative damage evoked by DOX and DTX. PMID- 24067284 TI - Should I buy this book? How we construct prospective value. PMID- 24067285 TI - Starvation favors glioma stem cells. PMID- 24067286 TI - Synaptic uSIRPation: the active neuron reigns over presynaptic partners. PMID- 24067287 TI - Spermidine cures flies of senior moments. PMID- 24067288 TI - Slicing a pie is no piece of cake. PMID- 24067289 TI - Context-dependent plasticity in a sensory circuit. PMID- 24067290 TI - Biopsychosocial risk factors for driving cessation: findings from the Health and Retirement Study. AB - OBJECTIVE: This study aims to identify social, psychological, and biomedical risk factors for current and future driving cessation in older adults. METHOD: Data from six waves (1998-2008) of the Health and Retirement Study (HRS) were pooled. Participants aged 65 and above were included in the study (N = 17,349). RESULTS: Multivariate logistic regression models to identify risk factors for current and future driving cessation were consistent (age, gender, education, race, marital status, income, cognitive function, limits in activities of daily living and instrumental activities of daily living, vision, health, diabetes, stroke, arthritis, and hip fracture). Only one variable, falls, was associated with future driving cessation (odds ratio [OR] = 0.92; confidence interval [CI] = [0.85, 1.0]), but not current driving cessation. DISCUSSION: Older age, female gender, and minority race were risk factors for current and future cessation. Adults with arthritis were more likely to keep driving compared with those without arthritis. PMID- 24067291 TI - Polypharmacy and bipolar disorder: what's personality got to do with it? AB - The majority of patients treated for bipolar disorder receive multiple psychotropic medications concurrently (polypharmacy), despite a lack of empirical evidence for any combination of three or more medications. Some patients benefit from the skillful management of a complex medication regimen, but iterative additions to a treatment regimen often do not lead to clinical improvement, are expensive, and can confound assessment of the underlying mood disorder. Given these potential problems of polypharmacy, this paper reviews the evidence supporting the use of multiple medications and seeks to identify patient personality traits that may put patients at a greater risk for ineffective complex chronic care. Patients with bipolar disorder (n = 89), ages 18 and older, were assessed on the Montgomery Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), and the NEO Five Factor Inventory (NEO-FFI), and completed a treatment history questionnaire to report psychotropic medication use. We found that patients with lower scores on openness had significantly more current psychotropic medications than patients with higher scores on openness (3.7 +/- 1.9 vs. 2.8 +/- 1.8, p < 0.05). Patients with the highest lifetime medication use had significantly lower extraversion (21.8 +/- 8.9 vs. 25.4 +/- 7.6, p < 0.05) and lower conscientiousness (21.9 +/- 8.2 vs. 27.9 +/- 8.2, p < 0.01) than those reporting lower lifetime medication use. Low levels of openness, extraversion, and conscientiousness may be associated with increased psychotropic medication use. Investigating the role of individual differences, such as patient personality traits, in moderating effective polypharmacy warrants future research. PMID- 24067292 TI - A rare cause of septic arthritis: melioidosis. AB - Melioidosis is a pyogenic infection with high mortality caused by the bacterium Burkholderia pseudomallei. As the clinical presentation is not distinctive, a high index of clinical suspicion is required for diagnosis. We present a case of a 50-year-old farmer who was diabetic and a chronic alcoholic, who presented to us with pneumonia, followed by septic arthritis. He was ultimately diagnosed as having melioidosis. PMID- 24067293 TI - Systematic evaluation of personal genome services for Japanese individuals. AB - Disease risk prediction (DRP) is one of the most important challenges in personal genome research. Although many direct-to-consumer genetic test (DTC) companies have begun to offer personal genome services for DRP, there is still no consensus on what constitutes a gold-standard service. Here, we systematically evaluated the distributions of DRPs from three DTC companies, that is, 23andMe, Navigenics and deCODEme, for 22 diseases using three Japanese samples. We systematically quantified and analyzed the differences between each DTC company's DRPs. Our independency test showed that the overall prediction results were correlated with each other, but not perfectly matched; less than onethird mismatching of the opposite direction occurred in eight diseases. Moreover, we found that the differences could mainly be attributed to four factors: (1) single nucleotide polymorphism (SNP) selection, (2) average risk estimation, (3) the disease risk calculation algorithm and (4) ethnicity adjustment. In particular, only 7.1% of SNPs over 22 diseases were reviewed by all three companies. Therefore, development of a universal core SNPs list for non-Caucasian samples will be important for achieving better prediction capacity for Japanese samples. This systematic methodology provides useful insights for improving the capacity of DRPs in future personal genome services. PMID- 24067294 TI - Clinical features and management of organic acidemias in Japan. AB - Organic acidemias (OAs) are rare inborn errors of metabolism. The clinical presentations of methylmalonic acidemia (MMA) and propionic acidemia (PA) in Japan have not yet been examined in detail. We aimed to investigate the clinical presentations of OAs in Japan and evaluate current therapies for improving long term outcomes, especially in MMA and PA cases. Questionnaires were sent to 928 institutions in 2009 inquiring about OAs, and secondary questionnaires were sent to those who confirmed that they had diagnosed and/or treated such cases; 119 cases were eventually included for analysis. In Japan, the majority of OAs was MMA, which was associated with a high mortality rate. The survival rates at 20 years of age in vitamin B12-unresponsive MMA, vitamin B12-responsive MMA and PA patients were 69.8%, 94.4% and 95.8%, respectively. Factors associated with mortality in MMA were failure to thrive, hypoglycemia and pancreatitis. Factors associated with mental retardation in vitamin B12-unresponsive MMA, vitamin B12 responsive MMA, and PA were seizure and liver dysfunction, seizure and failure to thrive, and failure to thrive, respectively. We advocated that avoiding failure to thrive due to too restricted protein diet, hypoglycemia and pancreatitis associated with mortality lead to improve outcome, especially in vitamin B12 unresponsive MMA patients. PMID- 24067295 TI - Predicting ethnic minority children's vocabulary from socioeconomic status, maternal language and home reading input: different pathways for host and ethnic language. AB - When bilingual children enter formal reading education, host language proficiency becomes increasingly important. This study investigated the relation between socioeconomic status (SES), maternal language use, reading input, and vocabulary in a sample of 111 six-year-old children of first- and second-generation Turkish immigrant parents in the Netherlands. Mothers reported on their language use with the child, frequency of reading by both parents, and availability of children's books in the ethnic and the host language. Children's Dutch and Turkish vocabulary were tested during a home visit. SES was related to maternal language use and to host language reading input. Reading input mediated the relation between SES and host language vocabulary and between maternal language use and host language vocabulary, whereas only maternal language use was related to ethnic language vocabulary. During transition to formal reading education, one should be aware that children from low-SES families receive less host language reading input. PMID- 24067296 TI - Digoxin and 30-day all-cause hospital admission in older patients with chronic diastolic heart failure. AB - BACKGROUND: In the main Digitalis Investigation Group (DIG) trial, digoxin reduced the risk of 30-day all-cause hospitalization in older systolic heart failure patients. However, this effect has not been studied in older diastolic heart failure patients. METHODS: In the ancillary DIG trial, of the 988 patients with chronic heart failure and preserved (> 45%) ejection fraction, 631 were age >= 65 years (mean age 73 years, 45% women, 12% non-whites), of whom 311 received digoxin. RESULTS: All-cause hospitalization 30-day post randomization occurred in 4% of patients in the placebo group and 9% each among those in the digoxin group receiving 0.125 mg and >= 0.25 mg a day dosage (P = .026). Hazard ratios (HR) and 95% confidence intervals (CI) for digoxin use overall for 30-day, 3-month, and 12 month all-cause hospitalizations were 2.46 (1.25-4.83), 1.45 (0.96-2.20) and 1.14 (0.89-1.46), respectively. There was one 30-day death in the placebo group. Digoxin-associated HRs (95% CIs) for 30-day hospitalizations due to cardiovascular, heart failure, and unstable angina causes were 2.82 (1.18-6.69), 0.51 (0.09-2.79), and 6.21 (0.75-51.62), respectively. Digoxin had no significant association with 30-day all-cause hospitalization among younger patients (6% vs 7% for placebo; HR 0.80; 95% CI, 0.36-1.79). CONCLUSIONS: In older patients with chronic diastolic heart failure, digoxin increased the risk of 30-day all-cause hospital admission, but not during longer follow-up. Although chance finding due to small sample size is possible, these data suggest that unlike in systolic heart failure, digoxin may not reduce 30-day all-cause hospitalization in older diastolic heart failure patients. PMID- 24067297 TI - In silico identification and characterization of conserved miRNAs and their target genes in sweet potato (Ipomoea batatas L.) expressed sequence tags (ESTs). AB - The endogenous small non-coding micro RNAs (miRNAs), which are typically ~21-24 nt nucleotides, play a crucial role in regulating the intrinsic normal growth of cells and development of the plants as well as in maintaining the integrity of genomes. These small non-coding RNAs function as the universal specificity factors in post-transcriptional gene silencing. Discovering miRNAs, identifying their targets, and further inferring miRNA functions is a routine process to understand normal biological processes of miRNAs and their roles in the development of plants. Comparative genomics based approach using expressed sequence tags (EST) and genome survey sequences (GSS) offer a cost-effective platform for identification and characterization of miRNAs and their target genes in plants. Despite the fact that sweet potato (Ipomoea batatas L.) is an important staple food source for poor small farmers throughout the world, the role of miRNA in various developmental processes remains largely unknown. In this paper, we report the computational identification of miRNAs and their target genes in sweet potato from their ESTs. Using comparative genomics-based approach, 8 potential miRNA candidates belonging to miR168, miR2911, and miR156 families were identified from 23 406 ESTs in sweet potato. A total of 42 target genes were predicted and their probable functions were illustrated. Most of the newly identified miRNAs target transcription factors as well as genes involved in plant growth and development, signal transduction, metabolism, defense, and stress response. The identification of miRNAs and their targets is expected to accelerate the pace of miRNA discovery, leading to an improved understanding of the role of miRNA in development and physiology of sweet potato, as well as stress response. PMID- 24067298 TI - Monitoring dietary intake and physical activity electronically: feasibility, usability, and ecological validity of a mobile-based Ecological Momentary Assessment tool. AB - BACKGROUND: Despite the growing body of research on complex lifestyle behaviors (eg, Dietary Intake [DI] and Physical Activity [PA]), monitoring of these behaviors has been hampered by a lack of suitable methods. A possible solution to this deficiency is mobile-based Ecological Momentary Assessment (mEMA), which enables researchers to collect data on participants' states in real-time by means of a smartphone application. However, feasibility, usability, and ecological validity need to be anticipated and managed in order to enhance the validity of mEMA. OBJECTIVE: To examine the feasibility, usability, and ecological validity of a mEMA application (app) with regard to DI and PA among Dutch vocational education students. METHODS: The students (n=30) participated in the mEMA study for seven consecutive days. They downloaded the mEMA app on their smartphone. Feasibility and usability of the mEMA app were evaluated by completing an online evaluation after seven days of participation. Ecological validity was measured by assessing the degree to which the content of the mEMA app approximated the real world setting that was being examined, through several multiple-choice questions. RESULTS: Compliance rates, as registered by the mEMA app, declined 46% over a seven-day period, while self-reported compliance, as measured with an online evaluation questionnaire afterwards, indicated a smaller decrease in compliance (29%). The students evaluated the mEMA app as feasible and usable. Ecological validity analyses showed that all DI and almost all PA multiple-choice options were covered with the compound response categories. CONCLUSIONS: The mEMA app offers the opportunity to assess complex health behaviors (eg, DI and PA) in real time settings, in which specifically routinized behaviors are involved. However, the mEMA app faced several challenges that needed to be overcome in order to improve its validity. Overall, the present study showed that the mEMA app is a usable and ecologically valid tool to measure DI and PA behaviors among vocational education students, but compliance is still limited. PMID- 24067299 TI - DeltaFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes. AB - DeltaFosB, a FosB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to several stimuli including antipsychotic drugs such as haloperidol. However, the functional consequences of increased DeltaFosB expression following antipsychotic treatment have not been explored. Here, we assessed whether DeltaFosB induction by haloperidol mediates the positive or negative consequences or clinical-related actions of antipsychotic treatment. We show that individuals with schizophrenia who were medicated with antipsychotic drugs at their time of death display increased DeltaFosB levels in the PFC, an effect that is replicated in rats treated chronically with haloperidol. In contrast, individuals with schizophrenia who were medication-free did not exhibit this effect. Viral-mediated overexpression of DeltaFosB in the PFC of rodents induced cognitive deficits as measured by inhibitory avoidance, increased startle responses in prepulse inhibition tasks, and increased MK-801-induced anxiety-like behaviors. Together, these results suggest that DeltaFosB induction in the PFC by antipsychotic treatment contributes to the deleterious effects of these drugs and not to their therapeutic actions. PMID- 24067302 TI - Relationship between arousal response in newborn infants before micturition and bed-wetting from 5 to 7 years of age. AB - We evaluated the relationship between arousal response in newborn infants before micturition and the occurrence of bed-wetting from 5 to 7 years of age. This study found that neonates without an arousal response before micturition showed a high probability of bed-wetting in early childhood. PMID- 24067300 TI - Increased extracellular glutamate in the nucleus accumbens promotes excessive ethanol drinking in ethanol dependent mice. AB - Using a well-established model of ethanol dependence and relapse, this study examined adaptations in glutamatergic transmission in the nucleus accumbens (NAc) and their role in regulating voluntary ethanol drinking. Mice were first trained to drink ethanol in a free-choice, limited access (2 h/day) paradigm. One group (EtOH mice) received repeated weekly cycles of chronic intermittent ethanol (CIE) exposure with intervening weeks of test drinking sessions, whereas the remaining mice (CTL mice) were similarly treated but did not receive CIE treatment. Over repeated cycles of CIE exposure, EtOH mice exhibited significant escalation in drinking (up to ~3.5 g/kg), whereas drinking remained relatively stable at baseline levels (2-2.5 g/kg) in CTL mice. Using in vivo microdialysis procedures, extracellular glutamate (GLUEX) levels in the NAc were increased approximately twofold in EtOH mice compared with CTL mice, and this difference was observed 7 days after final CIE exposure, indicating that this hyperglutamatergic state persisted beyond acute withdrawal. This finding prompted additional studies examining the effects of pharmacologically manipulating GLUEX in the NAc on ethanol drinking in the CIE model. The non-selective glutamate reuptake antagonist, threo-beta-benzyloxyaspartate (TBOA), was bilaterally microinjected into the NAc and found to dose-dependently increase drinking in nondependent (CTL) mice to levels attained by dependent (EtOH) mice. TBOA also further increased drinking in EtOH mice. In contrast, reducing glutamatergic transmission in the NAc via bilateral injections of the metabotropic glutamate receptor-2/3 agonist LY379268 reduced drinking in dependent (EtOH) mice to nondependent (CTL) levels, whereas having a more modest effect in decreasing ethanol consumption in CTL mice. Taken together, these data support an important role of glutamatergic transmission in the NAc in regulating ethanol drinking. Additionally, these results indicate that ethanol dependence produces adaptations that favor elevated glutamate activity in the NAc which, in turn, promote excessive levels of ethanol consumption associated with dependence. PMID- 24067301 TI - Oxytocin promotes facial emotion recognition and amygdala reactivity in adults with asperger syndrome. AB - The neuropeptide oxytocin has recently been shown to enhance eye gaze and emotion recognition in healthy men. Here, we report a randomized double-blind, placebo controlled trial that examined the neural and behavioral effects of a single dose of intranasal oxytocin on emotion recognition in individuals with Asperger syndrome (AS), a clinical condition characterized by impaired eye gaze and facial emotion recognition. Using functional magnetic resonance imaging, we examined whether oxytocin would enhance emotion recognition from facial sections of the eye vs the mouth region and modulate regional activity in brain areas associated with face perception in both adults with AS, and a neurotypical control group. Intranasal administration of the neuropeptide oxytocin improved performance in a facial emotion recognition task in individuals with AS. This was linked to increased left amygdala reactivity in response to facial stimuli and increased activity in the neural network involved in social cognition. Our data suggest that the amygdala, together with functionally associated cortical areas mediate the positive effect of oxytocin on social cognitive functioning in AS. PMID- 24067303 TI - Assignment of the Q-bands of the chlorophylls: coherence loss via Qx - Qy mixing. AB - We provide a new and definitive spectral assignment for the absorption, emission, high-resolution fluorescence excitation, linear dichroism, and/or magnetic circular dichroism spectra of 32 chlorophyllides in various environments. This encompases all data used to justify previous assignments and provides a simple interpretation of unexplained complex decoherence phenomena associated with Qx -> Qy relaxation. Whilst most chlorophylls conform to the Gouterman model and display two independent transitions Qx (S2) and Qy (S1), strong vibronic coupling inseparably mixes these states in chlorophyll-a. This spreads x-polarized absorption intensity over the entire Q-band system to influence all exciton transport, relaxation and coherence properties of chlorophyll-based photosystems. The fraction of the total absorption intensity attributed to Qx ranges between 7% and 33%, depending on chlorophyllide and coordination, and is between 10% and 25% for chlorophyll-a. CAM-B3LYP density-functional-theory calculations of the band origins, relative intensities, vibrational Huang-Rhys factors, and vibronic coupling strengths fully support this new assignment. PMID- 24067305 TI - The Berwick Report: let's hear it for the NHS. PMID- 24067304 TI - Understanding state variation in health insurance dynamics can help tailor enrollment strategies for ACA expansion. AB - The number and types of people who become eligible for and enroll in the Affordable Care Act's (ACA's) health insurance expansions will depend in part on the factors that cause people to become uninsured for different lengths of time. We used a small-area estimation approach to estimate differences across states in percentages of adults losing health insurance and in lengths of their uninsured spells. We found that nearly 50 percent of the nonelderly adult population in Florida, Nevada, New Mexico, and Texas--but only 18 percent in Massachusetts and 22 percent in Vermont--experienced an uninsured spell between 2009 and 2012. Compared to people who lost private coverage, those with public insurance were more likely to experience an uninsured spell, but their spells of uninsurance were shorter. We categorized states based on estimated incidence of uninsured spells and the spells' duration. States should tailor their enrollment outreach and retention efforts for the ACA's coverage expansions to address their own mix of types of coverage lost and durations of uninsured spells. PMID- 24067306 TI - Advanced breast cancer: 'here and now'. PMID- 24067307 TI - Diabetes: increasing the knowledge base of mental health nurses. AB - Physical health assessment for people with a serious mental illness (SMI) has been a neglected issue, with all the evidence showing that mental health nurses (MHNs) and associated practitioners need to develop such skills. The University of Huddersfield and South West Yorkshire Partnership Foundation Trust collaborated in a Physical Skills Project with the aim of facilitating knowledge and skills for MHNs. The development of the education and training workshop is presented. The results of a pre- and post-test evaluation of diabetes, evaluation of the workshop and, finally, implications for practice with regard to transferable knowledge and skill, are discussed. PMID- 24067308 TI - FIT4Safety: recommendations in the diabetes care setting. AB - Sharps injuries pose a serious threat to health professionals, patients, and downstream workers. FIT4Safety is an initiative that seeks to promote safety and best practice in the diabetes setting. An Introduction to FIT4Safety and its Recommendations for the Safety of Sharps in the Diabetes Care Setting explains how and why the FIT4Safety initiative was formed, what it aims to achieve, and the importance of ensuring safety in the diabetes care setting. Outputs from FIT4Safety include Injection Safety in UK and Ireland: Safety of Sharps in Diabetes Recommendations. These recommendations were developed to provide a resource for all those directly involved in, or overseeing, diabetes care. The main topics and guidance detailed within the recommendations are discussed, as well as EU Directive 2010/32 on sharps injury prevention and the UK's Health and Safety (Sharp Instruments in Healthcare) Regulations 2013. PMID- 24067309 TI - Teaching patient safety and human factors in undergraduate nursing curricula in England: a pilot survey. AB - Patient safety is a key priority for all healthcare systems, and there is growing recognition for the need to educate tomorrow's nurses about the role of human factors in reducing avoidable harm to patients. A pilot survey was sent to 20 schools of nursing in England to explore the teaching of patient safety and human factors. All 13 schools that responded (65% response rate) stated that patient safety was covered in their curricula and was allocated more than 4 hours; all the classes included human factors. Only two respondents indicated their teaching to be multi-professional. Awareness of the World Health Organization's multiprofessional patient safety curriculum guide was poor. Faculties also seemed unaware that the Institute for Healthcare Improvement provides free online patient safety modules for students and that there is a global network of student patient safety chapters. PMID- 24067310 TI - Clinical competency assessment in intravenous therapy and vascular access: part 2. AB - This article explores and critically evaluates clinical practice competencies as a form of assessment within post-registration nurse education, specifically relating to competence assessment of intravenous (IV) therapy. In the first article in this two-part series, 'Competency assessment in intravenous therapy and vascular access: part 1' (BJN, 22(16)), an in-depth literature review was carried out and applied to current competency assessment design. Clinical staff opinion was sought to evaluate users' opinions of this assessment method against recommended literature. The aim of both articles is to describe critically and analyse existing practice using this form of assessment, and relate other forms of assessment to IV therapy and vascular access clinical competence. A small scale study was performed to evaluate whether clinical competency assessment is the most appropriate form of assessment of IV therapy and vascular access skills. A questionnaire was designed to assess nurse opinion in relation to advantages (positives) and disadvantages (negatives) of clinical practice competency assessment; 35 randomly selected post-registered nurses were included in the sample. Findings illustrated that clinical competency assessment is the most appropriate form for the assessment of clinical skills in IV therapy. However, recommendations were made for the possible use of Objective Structured Clinical Examination (OSCE) assessment. Furthermore, this report recommends the assessment of theory and knowledge through written exams or multiple-choice questions (MCQs) as an addition to clinical practice competence assessment for IV therapy. PMID- 24067311 TI - Early psoriatic arthritis: facing the challenge. AB - Early diagnosis and initiation of therapy has become a primary objective in clinical rheumatology. As psoriatic arthritis causes deformities and joint damage leading to impaired quality of life and function as well as increased mortality risk, there was an urgent call for action aiming at inducing remission of the active inflammatory process. Until the year 2000 there were no treatments that led to a reduction in progression of joint damage. However, with the advent of anti-tumour necrosis factor agents, it is now possible to arrest the progression of damage in these patients. Therefore, the concept of window of opportunity, that is early assessment and management in specialist clinics, has been extended to psoriatic arthritis with successful outcomes among psoriatic arthritis patients similar to those with rheumatoid arthritis. Although all this sounds plausible, early psoriatic arthritis assessment remains limited to research as setting up this type of service in standard clinical practice faces several challenges that would need tackling. The objective of this article is to provide an overview of these challenges and suggest a paradigm for use in standard clinical practice to identify early psoriatic arthritis patients. PMID- 24067312 TI - Factors influencing participation in breast cancer screening. AB - Despite the efficacy of mammography and the widespread promotion of screening programmes, a significant number of eligible women still do not attend for regular breast screening. An integrative review methodology was considered the most appropriate means to critically analyse the available literature pertaining to factors which influence participation in breast cancer screening. From the extensive literature search, 12 selected core research papers met the inclusion criteria and were incorporated in the literature review. Four themes emerged from the literature which impact on participation in mammography screening: psychological and practical issues, ethnicity issues, influence of socioeconomic status and issues related to screening programmes. The recent Independent Review Panel on Breast Cancer Screening endorsed the importance of access to information which clearly communicates the harms and benefits of breast screening to enable women to make informed decisions about their health. The recommendations from the panel and others have been included in this review. PMID- 24067313 TI - What sort of nurses do we need for integrated care? PMID- 24067314 TI - Making caring a career: the role of the healthcare assistant. PMID- 24067315 TI - Instilling a patient safety culture in the NHS. PMID- 24067316 TI - Advancing practice: from staff nurse to nurse consultant. Part 5: planning a session. PMID- 24067317 TI - Nursing in a changing landscape. PMID- 24067318 TI - Rapid fabrication of self-ordered porous alumina with 10-/sub-10-nm-scale nanostructures by selenic acid anodizing. AB - Anodic porous alumina has been widely investigated and used as a nanostructure template in various nanoapplications. The porous structure consists of numerous hexagonal cells perpendicular to the aluminum substrate and each cell has several tens or hundreds of nanoscale pores at its center. Because the nanomorphology of anodic porous alumina is limited by the electrolyte during anodizing, the discovery of additional electrolytes would expand the applicability of porous alumina. In this study, we report a new self-ordered nanoporous alumina formed by selenic acid (H2SeO4) anodizing. By optimizing the anodizing conditions, anodic alumina possessing 10-nm-scale pores was rapidly assembled (within 1 h) during selenic acid anodizing without any special electrochemical equipment. Novel sub 10-nm-scale spacing can also be achieved by selenic acid anodizing and metal sputter deposition. Our new nanoporous alumina can be used as a nanotemplate for various nanostructures in 10-/sub-10-nm-scale manufacturing. PMID- 24067319 TI - Health care for our aging population. PMID- 24067320 TI - The impact of modulated, colored light on the autonomic nervous system. AB - CONTEXT: Scientists are now finding that light acts on individuals through multiple pathways, most notably the optic nerve that links to the brain's visual cortex, providing a pathway for the visual effects of light. The optic nerve also links to the more recently discovered retinohypothalamic tract, providing a pathway for the nonvisual effects of light. However, specific effects have not yet been widely evaluated clinically, especially in relationship to chromotherapy (ie, therapy based on colored light). OBJECTIVE: The purpose of this study was to evaluate the impact of modulated-light projections, perceived through the eyes, on the autonomic nervous system (ANS). DESIGN: The research team designed a randomized, controlled, partially blinded study with three intervention groups and one control group. SETTING: The study took place in two locations: (1) Midwestern State University, Wichita Falls, Texas, USA (40 participants) and Centre de Sante Satori, Quebec, Canada (77 participants). PARTICIPANTS: The research team recruited 117 individuals, 89 women and 28 men, to participate in the study. Participants were normal healthy individuals who were 19 to 72 y old (average age = 43 y). INTERVENTION: Three types of light projections, each containing both specific colors and specific modulations in the frequency range of brainwaves, were tested, in addition to a placebo projection consisting of nonmodulated white light. OUTCOME MEASURES: Evaluation was done using a combination of physiological measures-heart rate (HR), heart rate variability (HRV), and skin conductance (SC)- and psychological tests: the Profile of Mood States (POMS) and a subjective evaluation questionnaire. RESULTS: The research team observed significant differences in the effects of light-modulation projections from baseline to postsession as compared with an equivalent intensity of white light, including decreased HR, increased HRV standard deviations of normalized NN (beat-to-beat) intervals (SDNN), very low (VLF) and low frequency (LF) levels, and decreased POMS total mood disturbance (TMD). Also, the different colors of modulated light were found to result in different ANS effects. CONCLUSIONS: Interest is growing in the therapeutic potential of light. The effects demonstrated in the current study indicate that colored light could significantly enrich the therapeutic potential of light, and further research into chromotherapy is warranted. PMID- 24067321 TI - Yoga therapy for anxiety: a case report. AB - Yoga therapy is a mind-body intervention that can be an important solution in the treatment of anxiety. Yoga therapy alleviates the hyperarousal of the sympathetic nervous system (SNS) and the hypervigilance of the hypothalamic-pituitary-adrenal (HPA) axis that occurs in anxiety. Yoga therapy activates the parasympathetic branch of the nervous system, replacing SNS overdrive, or the flight-or-fight response, with the relaxation response and balancing the nervous system. Yoga therapy increases positive coping skills and builds self-esteem without harmful side effects. The results of this case study have demonstrated the clinical efficacy of yoga therapy in the treatment of anxiety and panic disorder (PD) in an adolescent female. Treatment consisted of 4 wks of individual sessions (60-min session/wk) and 6 wks of group sessions (90-min session/wk) with daily home practice. The results of the case study are significant because growing numbers of youth in the United States are presenting with anxiety and seeking nonpharmacological options. PMID- 24067322 TI - The Saratoga WarHorse project: a case study of the treatment of psychological distress in a veteran of Operation Iraqi Freedom. AB - OBJECTIVE: We theorized that ability to direct and control a horse will lead to a sense of empowerment, facilitate a relationship between horse and veteran, lead to a decrease in anxiety, and improve physical and social functioning. METHODS: This case study utilizes the Connection methodology: nonverbal language of the horse in a predictable, sequential, and repeatable method. Psychological testing occurred immediately pre- and post-Connection with follow-up occurring at 2, 4, 6, and 12 wks post-Connection. PARTICIPANT: Twice-deployed combat medic who served in Operation Iraqi Freedom (OIF). SETTING: Saratoga Springs, New York. PRIMARY OUTCOME MEASURES: Beck Depression Inventory-II (BDI-II); Posttraumatic Stress Disorder Checklist (PCL-C); the Response to Stressful Experiences Scale (RSES); the Quality of Life Inventory (QOLI); and the Modified Social Support Survey (MSSS). RESULTS: The participant demonstrated significant improvement in measures of psychological functioning (eg, over 12 wks); both PCL-C and RSES scores decreased 58% and 44%, respectively. Participant further reported an increase in sleep quality. CONCLUSION: The results of this case study strongly support the potential for the intervention and indicate the need for a controlled, randomized study that might more stringently investigate the impact of the intervention. PMID- 24067323 TI - Daniel Amen, MD: healing brain injury and damage from environmental toxins. Interviewed by Karen Burnett. PMID- 24067324 TI - Atomic layer deposition of amorphous TiO2 on graphene as an anode for Li-ion batteries. AB - Atomic layer deposition (ALD) was used to deposit TiO2 anode material on high surface area graphene (reduced graphene oxide) sheets for Li-ion batteries. An Al2O3 ALD ultrathin layer was used as an adhesion layer for conformal deposition of the TiO2 ALD films at 120 degrees C onto the conducting graphene sheets. The TiO2 ALD films on the Al2O3 ALD adhesion layer were nearly amorphous and conformal to the graphene sheets. These nanoscale TiO2 coatings minimized the effect of the low diffusion coefficient of lithium ions in bulk TiO2. The TiO2 ALD films exhibited stable capacities of ~120 mAh g(-1) and ~100 mAh g(-1) at high cycling rates of 1 A g(-1) and 2 A g(-1), respectively. The TiO2 ALD films also displayed excellent cycling stability with ~95% of the initial capacity remaining after 500 cycles. These results illustrate that ALD can provide a useful method to deposit electrode materials on high surface area substrates for Li-ion batteries. PMID- 24067325 TI - Temporal trends in hospitalization for acute myocardial infarction between 2004 and 2011 in Kumamoto, Japan. AB - BACKGROUND: The Kumamoto Acute Coronary Events Study explored trends for acute myocardial infarction (AMI). METHODS AND RESULTS: The number of people of advanced age in Kumamoto Prefecture has gradually increased. In 2004-2011, 8,131 AMI patients were registered. Although the age-adjusted AMI incidence in men decreased from 93.1 in 2004 to 70.7 in 2011 (P=0.0294), the age-adjusted in hospital cardiac death rate was maintained at ~7%; however, the all-cause mortality and noncardiac death rate increased and appeared to be related. CONCLUSIONS: A steady trend of decreasing AMI incidence was observed. Urgent measures should be established against non-cardiac mortality in this era of an aging population. PMID- 24067326 TI - A protein structural classes prediction method based on predicted secondary structure and PSI-BLAST profile. AB - Knowledge of protein secondary structural classes plays an important role in understanding protein folding patterns. In this paper, 25 features based on position-specific scoring matrices are selected to reflect evolutionary information. In combination with other 11 rational features based on predicted protein secondary structure sequences proposed by the previous researchers, a 36 dimensional representation feature vector is presented to predict protein secondary structural classes for low-similarity sequences. ASTRALtraining dataset is used to train and design our method, other three low-similarity datasets ASTRALtest, 25PDB and 1189 are used to test the proposed method. Comparisons with other methods show that our method is effective to predict protein secondary structural classes. Stand alone version of the proposed method (PSSS-PSSM) is written in MATLAB language and it can be downloaded from http://letsgob.com/bioinfo_PSSS_PSSM/. PMID- 24067327 TI - Increase in brain-derived neurotrophic factor expression in early crack cocaine withdrawal. AB - Recent reports suggest that brain-derived neurotrophic factor (BDNF) could be a biomarker for relapse, drug craving and withdrawal severity. In particular, elevated BDNF levels among former cocaine users have been associated with higher rates of relapse in 90 d. However, no data are available on BDNF levels at baseline and during crack cocaine withdrawal. This study evaluated BDNF among crack cocaine users during inpatient treatment, before and after withdrawal, vs. healthy controls. Clinical correlates with changes in BDNF levels were also assessed. Serum BDNF was evaluated in 49 male crack users on the first and last days of hospitalization and in 97 healthy controls. Serum BDNF was assayed using a sandwich ELISA kit. BDNF levels were significantly lower upon admission when compared to controls, even after adjustment for age, length of inpatient treatment, number of crack rocks used in the last 30 d, years of crack use and interaction between the latter two variables. At discharge, BDNF levels between patients and controls were similar. Number of crack rocks used in the last 30 d and years of crack use were inversely correlated with the outcome. Our findings show that BDNF levels increase during early crack cocaine withdrawal, at an inverse correlation with number of crack rocks used in the last 30 d and years of crack use. PMID- 24067328 TI - Valuing psychiatric patients' stories: belief in and use of the supernatural in the Jamaican psychiatric setting. AB - The aim of this study was to examine illness presentation and understand how psychiatric patients make meaning of the causes of their mental illnesses. Six Jamaican psychiatric patients were interviewed using the McGill Illness Narrative Interview Schedule. Of the 6, 3 representative case studies were chosen. The hermeneutic phenomenological approach and the common sense model were used in the formulation of patients' explanatory models. Results indicate that psychiatric patients actively conceptualized the causes and resultant treatment of their mental illnesses. Patients' satisfaction and compliance with treatment were dependent on the extent to which practitioners' conceptualization matched their own, as well as practitioners' acknowledgement of patients' concerns about causation, prognosis, and treatment. PMID- 24067329 TI - Share2Quit: Web-Based Peer-Driven Referrals for Smoking Cessation. AB - BACKGROUND: Smoking is the number one preventable cause of death in the United States. Effective Web-assisted tobacco interventions are often underutilized and require new and innovative engagement approaches. Web-based peer-driven chain referrals successfully used outside health care have the potential for increasing the reach of Internet interventions. OBJECTIVE: The objective of our study was to describe the protocol for the development and testing of proactive Web-based chain-referral tools for increasing the access to Decide2Quit.org, a Web-assisted tobacco intervention system. METHODS: We will build and refine proactive chain referral tools, including email and Facebook referrals. In addition, we will implement respondent-driven sampling (RDS), a controlled chain-referral sampling technique designed to remove inherent biases in chain referrals and obtain a representative sample. We will begin our chain referrals with an initial recruitment of former and current smokers as seeds (initial participants) who will be trained to refer current smokers from their social network using the developed tools. In turn, these newly referred smokers will also be provided the tools to refer other smokers from their social networks. We will model predictors of referral success using sample weights from the RDS to estimate the success of the system in the targeted population. RESULTS: This protocol describes the evaluation of proactive Web-based chain-referral tools, which can be used in tobacco interventions to increase the access to hard-to-reach populations, for promoting smoking cessation. CONCLUSIONS: Share2Quit represents an innovative advancement by capitalizing on naturally occurring technology trends to recruit smokers to Web-assisted tobacco interventions. PMID- 24067330 TI - Evaluation of the physiological properties of ventilatory ratio in a computational cardiopulmonary model and its clinical application in an acute respiratory distress syndrome population. AB - BACKGROUND: Owing to complexities of measuring dead space, ventilatory failure is difficult to quantify in critical care. A simple, novel index called ventilatory ratio (VR) can quantify ventilatory efficiency at the bedside. The study objectives were to evaluate physiological properties of VR and examine its clinical applicability in acute respiratory distress syndrome (ARDS) patients. METHODS: A validated computational model of cardiopulmonary physiology [Nottingham Physiology Simulator (NPS)] was used to evaluate VR ex vivo in three virtual patients with varying degrees of gas exchange defects. Arterial P(CO2) and mixed expired P(CO2) were obtained from the simulator while either dead space or CO2 production was altered in isolation. VR and deadspace fraction was calculated using these values. A retrospective analysis of a previously presented prospective ARDS database was then used to evaluate the clinical utility of VR. Basic characteristics of VR and its association with mortality were examined. RESULTS: The NPS showed that VR behaved in an intuitive manner as would be predicted by its physiological properties. When CO2 production was constant, there was strong positive correlation between dead space and VR (modified Pearson's r 0.98, P<0.01). The ARDS database had a mean VR of 1.47 (standard deviation 0.58). Non-survivors had a significantly higher VR compared with survivors [1.70 vs 1.34, mean difference 0.35, 95% confidence interval (CI) 0.16 0.56, P<0.01]. VR was an independent predictor of mortality (odds ratio 3.05, CI 1.35-6.91, P<0.01). CONCLUSIONS: VR is influenced by dead space and CO2 production. In ARDS, high VR was associated with increased mortality. PMID- 24067331 TI - Liver function test abnormalities after traumatic brain injury: is hepato-biliary ultrasound a sensitive diagnostic tool? AB - BACKGROUND: This study was to evaluate the usefulness of hepato-biliary ultrasound (HBUS) for the investigation of isolated liver function tests (LFTs) abnormalities. METHODS: We retrospectively reviewed HBUS reports in traumatic brain injury (TBI) patients admitted to our tertiary neuro-critical care unit (NCCU; January 2005-June 2011). We included patients receiving an HBUS for isolated LFTs derangement, excluding pre-existing hepato-biliary diseases or trauma. We assessed the temporal profile of alanine aminotransferase (ALT), bilirubin (Bil), and alkaline phosphatase (ALP). RESULTS: Of 511 patients, 58 received an HBUS. Of these, 47 were investigated for isolated LFTs derangement; HBUS always failed to identify a cause for these abnormalities. The HBUS was performed on day 18 (range 6-51) with the following mean values: 246 IU litre(-1) [ALT, 95% confidence interval (CI) 183-308], 24 MUmol litre(-1) (Bil, 95% CI 8 40), and 329 IU litre(-1) (ALP, 95% CI 267-390); only ALT (72, 95% CI 36-107) and ALP (73, 95% CI 65-81) were deranged from admission values (both P<0.01). At NCCU discharge, both ALT (160, 95% CI 118-202) and ALP (300, 95% CI 240-360) were higher than at admission (P<0.01). Compared with HBUS-day value, only ALT improved by NCCU discharge (P<0.05), while both were recovering by hospital discharge (ALT 83, 95% CI 59-107; ALP 216, 95% CI 181-251; P<0.01). At hospital discharge, ALP remained higher than at admission (P<0.01). CONCLUSIONS: In TBI patients, HBUS did not appear sensitive in detecting causes for isolated LFT abnormalities. Both ALT and ALP worsened and gradually recovered. Their abnormalities did not prevent NCCU discharge. ALP recovered more slowly than ALT. TBI and its complications, critical illness, and pharmacological strategies may explain the LFTs derangement. PMID- 24067332 TI - Vecuronium pharmacokinetics in patients with major burns. AB - BACKGROUND: Burn patients develop resistance to non-depolarizing neuromuscular blocking agents (NDNMBAs) and require a significantly large dose to produce a desired clinical response. Pathophysiological changes related to burn injury may alter pharmacokinetics (PK) and pharmacodynamics of NDNMBAs. The purpose of this study was to compare vecuronium PK in burns vs non-burns. METHODS: Twenty adults, aged 23-58 yr, with 27-81% total body surface area (TBSA) burn, were studied at 4 57 post-burn days and compared with age- and sex-matched, non-burn controls. Vecuronium 0.12 mg kg(-1) was given i.v. as a single bolus within 10 s. Blood samples (n=20) were collected over 12 h at predetermined time points. NONMEM was used to describe plasma drug concentration-time profiles for burns and non-burns. RESULTS: A three-compartment model best described vecuronium concentration-time profiles. Burn patients showed enhanced distributional clearance at the terminal phase (0.12 vs 0.095 litre min(-1), P<0.0001), which yielded shorter elimination half-life for vecuronium (5.5 vs 6.6 h, P<0.001). BURN was the single most significant covariate that explained the altered vecuronium disposition in burns. CONCLUSIONS: The altered drug distribution between tissues may partially explain the known resistance to vecuronium in patients with major burns. PMID- 24067333 TI - Dual intervention to improve pathologic staging of resectable lung cancer. AB - BACKGROUND: Detection of lymph node metastasis is of immense prognostic value in patients with resectable non-small cell lung cancer (NSCLC), but routine pathologic nodal staging is suboptimal. To determine the impact on the rate of detection of nodal metastasis, we tested dual intervention with a prelabeled lymph node specimen collection kit to improve intraoperative node dissection and a fastidious gross dissection of the lung resection specimen for intrapulmonary lymph nodes. METHODS: We matched dual-intervention cases with controls staged using standard surgical specimen collection and pathologic examination protocols. Controls were hierarchically matched for extent of resection, laterality, surgeon, pathologist, and T stage. All statistical comparisons were made with exact conditional logistic regression, to account for the matched case-control design. RESULTS: One hundred dual-intervention cases were matched with 100 controls. The dual interventions resulted in approximately a 3-fold increase in the number of lymph nodes examined and the number of lymph nodes with metastasis detected; they also increased the proportion of patients with lymph node metastasis from 21% to 35% (p = 0.02). There were strong trends toward higher aggregate stage distribution, and eligibility for postoperative adjuvant chemotherapy in the dual-intervention cases. CONCLUSIONS: The combination of interventions improved the thoroughness and accuracy of pathologic nodal staging. A prospective randomized trial to test the survival impact of the dual interventions is warranted. PMID- 24067334 TI - The natural and surgically modified history of anomalous pulmonary veins from the left lung. AB - BACKGROUND: Reconstruction of anomalous left pulmonary veins (ALPV) requires an anastomosis at a nonanatomic position, posing the potential risk of pulmonary vein obstruction (PVO). METHODS: The 514 patients who were diagnosed with a pulmonary vein abnormality from 1990 to 2010 were reviewed. Thirty-eight patients (7.4%; median age, 1.4 years; interquartile range, 0.1 to 5.7 years) were identified. ALPV was diagnosed as an isolated anomaly in 23 (61%) or as part of mixed total anomalous pulmonary venous drainage in 15 (39%). Patients were divided into 3 groups (group 1: partial ALPV, treated; group 2: total ALPV, treated; or group 3: partial ALPV, untreated). Freedom from poor clinical (death/reoperation) and functional (any PVO, mean pressure gradient > 3 mm Hg) outcomes were analyzed. RESULTS: Repair in 30 ALPV patients (79%) was performed with direct anastomosis to the left atrium (n = 26 [68%]) or by sutureless repair (n = 4 [11%]). Two deaths occurred in group 2 (heart failure and PVO). The 4 reoperations in group 2 were prompted by PVO and occurred within 6 months of the initial repair. There was a nonsignificant trend of lower freedom from poor outcomes in group 2 (74.6%) vs group 1 (100%) at 10 years (p = 0.105). There was no difference in the incidence of any left PVO among the groups (p = 0.381). Severe left PVO did not develop in group 3 (n = 8 [21%]). CONCLUSIONS: Total ALPV carries a high risk of early PVO. Thus, the optimal surgical approach remains elusive. Untreated partial ALPV remained unobstructed during midterm follow-up. Therefore, surgical treatment may not be necessary in patients with partial ALPV. PMID- 24067335 TI - Current spectrum of surgical procedures performed for Ebstein's malformation: an analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. AB - BACKGROUND: Ebstein's malformation is a rare congenital cardiac anomaly. Available data are limited to individual reports demonstrating highly variable approaches. We sought to understand the spectrum of surgical treatment of Ebstein's anomaly across institutions. METHODS: A retrospective review of surgical procedures performed on patients with primary diagnosis of Ebstein's malformation (2002 through 2009) in The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) was conducted. RESULTS: A total of 595 operations on 498 patients with Ebstein's anomaly were included: 116 on neonates (19%), 122 on infants (21%), 264 on children (44%), and 93 on adults (16%). Average annual institutional case volumes were low (median, 1 per year; range, 0 to 8 per year). Neonates had a high rate of palliative procedures: systemic-to pulmonary artery shunts with or without tricuspid valve closure (43; 37.1%) and tricuspid valve closure (10; 8.6%); Ebstein's repair or tricuspid valvuloplasty was performed in 32%. The most common procedures among infants were superior cavopulmonary connections (62; 50.8%) and systemic-to-pulmonary shunt (10; 8.2%). Among older patients, procedures were primarily in three categories: tricuspid valve surgery (children, 54.5%; adults, 68.8%), arrhythmia procedures (children, 8.7%; adults, 17.3%), and Fontan (children, 14.8%). In-hospital mortality was high in neonatal patients (23.4%) in comparison with infants (4.1%), children (0.7%), and adults (1.1%). CONCLUSIONS: Surgery for Ebstein's anomaly consists of a wide range of procedures, with low individual institutional volumes. Mortality is highest among neonates. A prospective multicenter inception cohort study would be valuable to better define indications for specific strategies of surgical management. PMID- 24067336 TI - Depth of origin of magma in eruptions. AB - Many volcanic hazard factors--such as the likelihood and duration of an eruption, the eruption style, and the probability of its triggering large landslides or caldera collapses--relate to the depth of the magma source. Yet, the magma source depths are commonly poorly known, even in frequently erupting volcanoes such as Hekla in Iceland and Etna in Italy. Here we show how the length-thickness ratios of feeder dykes can be used to estimate the depth to the source magma chamber. Using this method, accurately measured volcanic fissures/feeder-dykes in El Hierro (Canary Islands) indicate a source depth of 11-15 km, which coincides with the main cloud of earthquake foci surrounding the magma chamber associated with the 2011-2012 eruption of El Hierro. The method can be used on widely available GPS and InSAR data to calculate the depths to the source magma chambers of active volcanoes worldwide. PMID- 24067337 TI - Methacholine bronchial challenge effects on nasal symptoms and function in patients with allergic rhinitis. AB - BACKGROUND: Allergic rhinitis and asthma may be associated, bronchial hyperreactivity (BHR) is quite common in AR patients. It has been reported that allergen bronchial challenge induces nasal inflammation. Methacholine (MCH) is a stimulus able to elicit BHR. There is no study that investigated the effect of MCH bronchial challenge on the nose. OBJECTIVE: The aim of this study was to evaluate whether MCH bronchial challenge is able to induce changes in nasal symptom perception and nasal function in patients with AR. METHODS: 122 patients (117 males, median age 28 years) suffering from AR were evaluated. Values for bronchial function (FVC, FEV1, FEF25-75, and FEV1/FVC ratio), MCH bronchial challenge, VAS for nasal and bronchial symptoms, and nasal airflow and resistance were assessed. RESULTS: 23 patients (18.9%) had BHR. MCH bronchial challenge induced a significant reduction of nasal obstruction perception (p<0.001), but did not affect the nasal function. Most of patients (91) did not perceive impairment of respiration. The perception of nasal obstruction was strongly related to the AR duration (r=0.65). The highest values of both baseline rhinoVAS and Delta bronchial VAS predicted BHR (OR 1.7 and 2.9 respectively). CONCLUSIONS: The present study demonstrates that in AR patients MCH bronchial challenge does not substantially affect nasal symptoms and function, also in subjects with an acute bronchospasm, such as in BHR patients. However, severity of nasal obstruction perception might predict BHR. PMID- 24067338 TI - Mugwort-fennel-allergy-syndrome associated with sensitization to an allergen homologous to Api g 5. AB - BACKGROUND: The cross-reactive allergen responsible for the so called "mugwort celery-spice-syndrome", a pollen-food allergy that occurs in a minority of mugwort pollen-allergic patients, is still undefined. OBJECTIVE: To identify the allergen responsible for the cross-reactivity between mugwort pollen and plant derived foods. METHODS: The serum from one index patient with both fennel and mugwort pollen allergy was used to identify IgE-reactive allergens by direct ELISA and Immunoblot analysis. Cross-reactivity between mugwort pollen and fennel was checked by cross-inhibition experiments. Fennel and mugwort allergens selected on the basis of IgE reactivity and inhibition tests were excised from SDS-PAGE gels and microsequenced. The amino acid sequences obtained were used to screen the NCBI database using the protein BLAST software. RESULTS: On ELISA inhibition experiments, serum absorption with fennel extract completely inhibited the IgE response to mugwort. On immmunoblot analysis periodate treatment caused the disappearance of all bands of IgE reactivity except one at about 60 kDa. The 60 kDa bands from both mugwort and fennel PAGE-SDS gels revealed the presence of distinct proteins. The N-terminal amino acid sequencing gave the same major amino acid sequence corresponding to an Api g 5-like allergen. The MS/MS spectra were analyzed and a provided evidence of a fennel-specific protein with sequence similarity to phosphoglyceromutase from Apium graveolens. CONCLUSION: A 60 kDa allergen, highly homologous to Api g 5, was recognized in fennel by patient's IgE. Inhibition experiments showed a high degree of cross-reactivity between this fennel allergen and the homologous mugwort pollen allergen. This allergen might be responsible for the mugwort-celery-spice syndrome. PMID- 24067339 TI - Ultra short pre-seasonal subcutaneous immunotherapy and pre-coseasonal sublingual immunotherapy for pollen allergy: an evaluation of patient's preference in real life. AB - BACKGROUND: Specific immunotherapy (SIT) efficacy and safety by subcutaneous (SCIT) and sublingual (SLIT) route is supported by literature data. Pre coseasonal treatment is currently the more accepted option for pollen immunotherapy in terms of costs and patient's compliance. This retrospective study evaluated the patient's preference concerning subcutaneous or sublingual route in pre-coseasonal treatment. MATERIALS AND METHODS: We evaluated 145 patients (79 males, 66 females, age ranging from 14 to 69 years), suffering from moderate-severe rhino-conjunctivitis or mild bronchial asthma and with homogeneous characteristic according to allergic disease severity. We proposed either SLIT, with extracts by different producers, or SCIT with Pollinex 4 (Allergy Therapeutics, Worthing, UK), a product designed for ultra-short administration in 4 injections, highlighting for each kind of SIT the major practical advantages or burdens. RESULTS: Of 145 patients, 72 chose Pollinex 4 SCIT and 73 chose SLIT. SCIT-treated patients received a total of 90 vaccines (18 patients had double course of SCIT). SLIT-treated patients received a total of 87 vaccines (14 patients had double course of SLIT). In the SCIT group, there were 49 males and 23 females; in the SLIT group, there were 30 males and 43 females. Mean age was 36.5 years in SCIT group and 28.5 years in SLIT group. Males preferred SCIT (49 of 72 patients) and females preferred SLIT (43 of 73 patients). No severe reaction was observed either in SCIT or SLIT group. CONCLUSION: Patients are active subjects in decisional process. Trying to apply in real life the indications coming from guidelines about patient's preference is an important matter. In our patients SCIT with ultra short schedule and SLIT are similarly preferred. PMID- 24067341 TI - Anaphylaxis only to a home-made rose wine from a variety of grape. AB - This study reports a case of anaphylaxis to a home-made wine and tolerance to other wines. PMID- 24067340 TI - Bovine Serum Albumin: a double allergy risk. AB - We analyse two cases of Bovine Serum Albumin (BSA) allergy. The first regards a female laboratory technician with a history of bronchial asthma due to cat allergy, who developed an exacerbation of bronchial symptoms as a consequence of BSA powder inhalation at work. To date, sensitization to BSA as a cause of occupational asthma has rarely been reported in the scientific literature. The second case concerns a woman with a similar cat sensitivity, who presented an oral allergy syndrome-type clinical reaction, gastric pain and diarrhoea immediately after eating cooked pork meat. Subsequently, she developed the same reaction after eating goat meat and goat cheese, and then also after eating beef. Both patients resulted specifically sensitized to BSA and to other mammalian serum albumins which play a role as panallergens in animals. The two cases show that BSA, a well known cause of food allergy in childhood, may also provoke symptoms of food allergy in adulthood, though in case of powder inhalation, it may provoke respiratory symptoms. Prior animal sensitization appears to represent a risk factor. PMID- 24067342 TI - The role of nasal endoscopy in the prescription of allergen immunotherapy. PMID- 24067343 TI - MMP20 modulates cadherin expression in ameloblasts as enamel develops. AB - Matrix metalloproteinase-20 (enamelysin, MMP20) is essential for dental enamel development. Seven different MMP20 mutations in humans cause non-syndromic enamel malformations, termed amelogenesis imperfecta, and ablation of Mmp20 in mice results in thin brittle enamel with a dysplastic rod pattern. Healthy enamel formation requires the sliding movement of ameloblasts in rows during the secretory stage of development. This is essential for formation of the characteristic decussating enamel rod pattern observed in rodents, and this is also when MMP20 is secreted into the enamel matrix. Therefore, we propose that MMP20 facilitates ameloblast movement by cleaving ameloblast cell-cell contacts. Here we show that MMP20 cleaves the extracellular domains of the E- and N cadherin adherens junction proteins, that both E- and N-cadherin transcripts are expressed at significantly higher levels in Mmp20 null vs. wild-type (WT) mice, and that in Mmp20 ablated mice, high-level ameloblast N-cadherin expression persists during the maturation stage of development. Furthermore, we show that E cadherin gene expression is down-regulated from the pre-secretory to the secretory stage, while N-cadherin levels are up-regulated. This E- to N-cadherin switch supports epithelial migration in other tissues and may be an important event necessary for the ameloblasts to start moving in rows that slide by one another. PMID- 24067344 TI - Enhancement of superconductivity near the pressure-induced semiconductor-metal transition in the BiS2-based superconductors LnO0.5F0.5BiS2 (Ln = La, Ce, Pr, Nd). AB - Measurements of electrical resistivity were performed between 3 and 300 K at various pressures up to 2.8 GPa on the BiS2-based superconductors LnO0.5F0.5BiS2 (Ln=Pr, Nd). At lower pressures, PrO0.5F0.5BiS2 and NdO0.5F0.5BiS2 exhibit superconductivity with critical temperatures Tc of 3.5 and 3.9 K, respectively. As pressure is increased, both compounds undergo a transition at a pressure Pt from a low Tc superconducting phase to a high Tc superconducting phase in which Tc reaches maximum values of 7.6 and 6.4 K for PrO0.5F0.5BiS2 and NdO0.5F0.5BiS2, respectively. The pressure-induced transition is characterized by a rapid increase in Tc within a small range in pressure of ~0.3 GPa for both compounds. In the normal state of PrO0.5F0.5BiS2, the transition pressure Pt correlates with the pressure where the suppression of semiconducting behaviour saturates. In the normal state of NdO0.5F0.5BiS2, Pt is coincident with a semiconductor-metal transition. This behaviour is similar to the results recently reported for the LnO0.5F0.5BiS2 (Ln=La, Ce) compounds. We observe that Pt and the size of the jump in Tc between the two superconducting phases both scale with the lanthanide element in LnO0.5F0.5BiS2 (Ln=La, Ce, Pr, Nd). PMID- 24067346 TI - Malignant hypertension and interferon-beta: a case report. PMID- 24067345 TI - Blood pressure changes after renal denervation at 10 European expert centers. AB - We did a subject-level meta-analysis of the changes (Delta) in blood pressure (BP) observed 3 and 6 months after renal denervation (RDN) at 10 European centers. Recruited patients (n=109; 46.8% women; mean age 58.2 years) had essential hypertension confirmed by ambulatory BP. From baseline to 6 months, treatment score declined slightly from 4.7 to 4.4 drugs per day. Systolic/diastolic BP fell by 17.6/7.1 mm Hg for office BP, and by 5.9/3.5, 6.2/3.4, and 4.4/2.5 mm Hg for 24-h, daytime and nighttime BP (P?0.03 for all). In 47 patients with 3- and 6-month ambulatory measurements, systolic BP did not change between these two time points (P?0.08). Normalization was a systolic BP of <140 mm Hg on office measurement or <130 mm Hg on 24-h monitoring and improvement was a fall of ?10 mm Hg, irrespective of measurement technique. For office BP, at 6 months, normalization, improvement or no decrease occurred in 22.9, 59.6 and 22.9% of patients, respectively; for 24-h BP, these proportions were 14.7, 31.2 and 34.9%, respectively. Higher baseline BP predicted greater BP fall at follow up; higher baseline serum creatinine was associated with lower probability of improvement of 24-h BP (odds ratio for 20-MUmol l(-1) increase, 0.60; P=0.05) and higher probability of experiencing no BP decrease (OR, 1.66; P=0.01). In conclusion, BP responses to RDN include regression-to-the-mean and remain to be consolidated in randomized trials based on ambulatory BP monitoring. For now, RDN should remain the last resort in patients in whom all other ways to control BP failed, and it must be cautiously used in patients with renal impairment. PMID- 24067347 TI - Aldehyde dehydrogenase 2 as a potential protective factor for renal insufficiency in Japanese subjects with heart failure: a pilot study. AB - The association between the aldehyde dehydrogenase 2 (ALDH2, rs671) genotypes and the estimated glomerular filtration rate (eGFR) was investigated in Japanese hypertensive patients with/without coronary artery disease or with ischemic heart failure (HF), and age/sex-matched normotensive healthy controls. The eGFRs were significantly lower in the HF subjects with the ALDH2 *2/*2 genotype than in those with the other genotypes. Multiple regression analyses adjusted by the potentially confounding factors showed the *2/*2 genotype to be significantly associated with the decreased eGFR, compared to the *1/*1 genotype (beta = 31.99 ml min1 per 1.73 m2, P < 0.01). PMID- 24067348 TI - Effects of the DASH diet on blood pressure in patients with and without metabolic syndrome: results from the DASH trial. AB - In the Dietary Approach to Stop Hypertension (DASH) trial, the DASH diet reduced blood pressure (BP) in a diverse sample of US adults. Subsequent analyses of this trial documented the efficacy of the DASH diet in several subgroups. Although subgroup analyses in individuals with metabolic syndrome (MS) have not been performed, the DASH diet has been recommended in MS patients. This paper is a subgroup analysis of the DASH trial, in which we examined the effect of study diets on BP in participants with and without MS. Participants were stratified according to MS status (99 with MS, 311 without MS (Non-MS)). The trial was a dietary intervention study in which participants were randomized to receive a control diet, a diet rich in fruits and vegetables, or the DASH diet. Outcomes were (i) the difference in BP between the end and the beginning of intervention and (ii) control of hypertension. We found no significant interaction between MS status and diet assignment on BP (each P-interaction >0.05). In the MS subgroup, the DASH diet compared with the control diet reduced systolic BP by 4.9 mm Hg (P=0.006) and diastolic BP by 1.9 mm Hg (P=0.15). In the Non-MS subgroup, corresponding net BP reductions were 5.2 mm Hg (P<0.001) and 2.9 mm Hg (P<0.001), respectively. The DASH diet controlled hypertension in 75% of hypertensive participants with MS (adjusted odds ratio=9.5 vs the control diet, P=0.05). In conclusion, the DASH diet similarly reduces BP in those with and without MS. Our findings provide direct evidence for existing recommendations. PMID- 24067349 TI - Percentile distribution of blood pressure readings in 35683 men and women aged 18 to 99 years. AB - The percentile distribution of blood pressure (BP) with regard to age, sex and cardiovascular risk factors is unknown. We aimed to provide epidemiological data for a comprehensive description of the BP distribution across a wide age-range. We used data from the German Metabolic and Cardiovascular Risk Project (GEMCAS), a cross-sectional study with 35 683 participants aged 18-99 years, conducted during October 2005 in 1511 randomly selected general practices in Germany. BP and waist circumference were measured, data on lifestyle, cardiovascular disease (CVD) risk factors and medication assessed. In men, we found even in the lowest percentile (5th) a gradual increase of the systolic BP from the lowest to the highest age group of 10 mm Hg, all other percentile groups an increase of 20 mm Hg. In women, this increase ranged from 15 mm Hg (5th percentile) to 40 mm Hg (95th percentile). In a subgroup of participants with no antihypertensive usage (n=22 550) and no CVD/CVD risk factors (n=13 297), we still observed a distinct age-related increase of BP readings. Our study provides detailed information on the population distribution of BP readings in both sexes and also among very old individuals. The results are useful in a public health context to plan gender- and age-specific prevention strategies. PMID- 24067351 TI - Switching cell fates in the developing Drosophila eye. AB - The developing Drosophila ommatidium is characterized by two distinct waves of pattern formation. In the first wave, a precluster of five cells is formed by a complex cellular interaction mechanism. In the second wave, cells are systematically recruited to the cluster and directed to their fates by developmental cues presented by differentiating precluster cells. These developmental cues are mediated through the receptor tyrosine kinase (RTK) and Notch (N) signaling pathways and their combined activities are crucial in specifying cell type. The transcription factor Lozenge (Lz) is expressed exclusively in second wave cells. Here, we ectopically supply Lz to precluster cells and concomitantly supply the various RTK/N codes that specify each of three second wave cell fates. We thereby reproduce molecular markers of each of the second wave cell types in precluster cells and draw three inferences. First, we confirm that Lz provides key intrinsic information to second wave cells. We can now combine this with the RTK/N signaling to provide a cell fate specification code that entails both extrinsic and intrinsic information. Second, the reproduction of each second wave cell type in the precluster confirms the accuracy of the RTK/N signaling code. Third, RTK/N signaling and Lz need only be presented to the cells for a short period of time in order to specify their fate. PMID- 24067352 TI - Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene. AB - Morphogenesis of the semicircular canal ducts in the vertebrate inner ear is a dramatic example of epithelial remodelling in the embryo, and failure of normal canal development results in vestibular dysfunction. In zebrafish and Xenopus, semicircular canal ducts develop when projections of epithelium, driven by extracellular matrix production, push into the otic vesicle and fuse to form pillars. We show that in the zebrafish, extracellular matrix gene expression is high during projection outgrowth and then rapidly downregulated after fusion. Enzymatic disruption of hyaluronan in the projections leads to their collapse and a failure to form pillars: as a result, the ears swell. We have cloned a zebrafish mutant, lauscher (lau), identified by its swollen ear phenotype. The primary defect in the ear is abnormal projection outgrowth and a failure of fusion to form the semicircular canal pillars. Otic expression of extracellular matrix components is highly disrupted: several genes fail to become downregulated and remain expressed at abnormally high levels into late larval stages. The lau mutations disrupt gpr126, an adhesion class G protein-coupled receptor gene. Expression of gpr126 is similar to that of sox10, an ear and neural crest marker, and is partially dependent on sox10 activity. Fusion of canal projections and downregulation of otic versican expression in a hypomorphic lau allele can be restored by cAMP agonists. We propose that Gpr126 acts through a cAMP-mediated pathway to control the outgrowth and adhesion of canal projections in the zebrafish ear via the regulation of extracellular matrix gene expression. PMID- 24067353 TI - FGF signaling sustains the odontogenic fate of dental mesenchyme by suppressing beta-catenin signaling. AB - Odontoblasts and osteoblasts develop from multipotent craniofacial neural crest cells during tooth and jawbone development, but the mechanisms that specify and sustain their respective fates remain largely unknown. In this study we used early mouse molar and incisor tooth germs that possess distinct tooth-forming capability after dissociation and reaggregation in vitro to investigate the mechanism that sustains odontogenic fate of dental mesenchyme during tooth development. We found that after dissociation and reaggregation, incisor, but not molar, mesenchyme exhibits a strong osteogenic potency associated with robustly elevated beta-catenin signaling activity in a cell-autonomous manner, leading to failed tooth formation in the reaggregates. Application of FGF3 to incisor reaggregates inhibits beta-catenin signaling activity and rescues tooth formation. The lack of FGF retention on the cell surface of incisor mesenchyme appears to account for the differential osteogenic potency between incisor and molar, which can be further attributed to the differential expression of syndecan 1 and NDST genes. We further demonstrate that FGF signaling inhibits intracellular beta-catenin signaling by activating the PI3K/Akt pathway to regulate the subcellular localization of active GSK3beta in dental mesenchymal cells. Our results reveal a novel function for FGF signaling in ensuring the proper fate of dental mesenchyme by regulating beta-catenin signaling activity during tooth development. PMID- 24067354 TI - Atypical protein kinase C couples cell sorting with primitive endoderm maturation in the mouse blastocyst. AB - During mouse pre-implantation development, extra-embryonic primitive endoderm (PrE) and pluripotent epiblast precursors are specified in the inner cell mass (ICM) of the early blastocyst in a 'salt and pepper' manner, and are subsequently sorted into two distinct layers. Positional cues provided by the blastocyst cavity are thought to be instrumental for cell sorting; however, the sequence of events and the mechanisms that control this segregation remain unknown. Here, we show that atypical protein kinase C (aPKC), a protein associated with apicobasal polarity, is specifically enriched in PrE precursors in the ICM prior to cell sorting and prior to overt signs of cell polarisation. aPKC adopts a polarised localisation in PrE cells only after they reach the blastocyst cavity and form a mature epithelium, in a process that is dependent on FGF signalling. To assess the role of aPKC in PrE formation, we interfered with its activity using either chemical inhibition or RNAi knockdown. We show that inhibition of aPKC from the mid blastocyst stage not only prevents sorting of PrE precursors into a polarised monolayer but concomitantly affects the maturation of PrE precursors. Our results suggest that the processes of PrE and epiblast segregation, and cell fate progression are interdependent, and place aPKC as a central player in the segregation of epiblast and PrE progenitors in the mouse blastocyst. PMID- 24067355 TI - Mouse Hoxa2 mutations provide a model for microtia and auricle duplication. AB - External ear abnormalities are frequent in newborns ranging from microtia to partial auricle duplication. Little is known about the molecular mechanisms orchestrating external ear morphogenesis. In humans, HOXA2 partial loss of function induces a bilateral microtia associated with an abnormal shape of the auricle. In mice, Hoxa2 inactivation at early gestational stages results in external auditory canal (EAC) duplication and absence of the auricle, whereas its late inactivation results in a hypomorphic auricle, mimicking the human HOXA2 mutant condition. By genetic fate mapping we found that the mouse auricle (or pinna) derives from the Hoxa2-expressing neural crest-derived mesenchyme of the second pharyngeal arch, and not from a composite of first and second arch mesenchyme as previously proposed based on morphological observation of human embryos. Moreover, the mouse EAC is entirely lined by Hoxa2-negative first arch mesenchyme and does not develop at the first pharyngeal cleft, as previously assumed. Conditional ectopic Hoxa2 expression in first arch neural crest is sufficient to induce a complete duplication of the pinna and a loss of the EAC, suggesting transformation of the first arch neural crest-derived mesenchyme lining the EAC into an ectopic pinna. Hoxa2 partly controls the morphogenesis of the pinna through the BMP signalling pathway and expression of Eya1, which in humans is involved in branchio-oto-renal syndrome. Thus, Hoxa2 loss- and gain-of function approaches in mice provide a suitable model to investigate the molecular aetiology of microtia and auricle duplication. PMID- 24067356 TI - p120RasGAP mediates ephrin/Eph-dependent attenuation of FGF/ERK signals during cell fate specification in ascidian embryos. AB - ERK1/2 MAP kinase exhibits a highly dynamic activation pattern in developing embryos, which largely depends on fibroblast growth factor (FGF) signals. In ascidian embryos, FGF-dependent activation of ERK1/2 occurs differentially between sister cells during marginal zone and neural lineage patterning. Selective attenuation of FGF signals by localised ephrin/Eph signals accounts for this differential ERK activation, which controls the binary fate choice of each sibling cell pair. Here, we show that p120 Ras GTPase-activating protein (p120RasGAP) is a crucial mediator of these ephrin/Eph signals. First, inhibition of p120RasGAP has a similar effect to inhibition of ephrin/Eph function during marginal zone and neural patterning. Second, p120RasGAP acts epistatically to ephrin/Eph signals. Third, p120RasGAP physically associates with Eph3 in an ephrin-dependent manner. This study provides the first in vivo evidence that the functional association between Eph and RasGAP controls the spatial extent of FGF activated ERK. PMID- 24067357 TI - Impact of an incentive-based mobility program, "Motivated and Moving," on physiologic and quality of life outcomes in a stem cell transplant population. AB - BACKGROUND: Research suggests that patients experience increased fatigue, reduced physical activity, and diminished quality of life (QOL) after hematopoietic stem cell transplantation (HSCT). Structured exercise during hospitalization has been shown to maintain or improve fatigue. Incentive-based interventions have not been tested to encourage physical activity maintenance. OBJECTIVES: The study's aim was to evaluate the effect of participation in an incentive-based mobility program on fatigue, physical conditioning, performance status, and QOL in individuals undergoing allogeneic HSCT. We hypothesized that program participation would affect these variables and that time spent engaged in physical activity would correlate with improved outcomes. METHODS: A 1-group repeated-measures design used the Brief Fatigue Inventory, 6-minute walk test, and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale to assess study variables. Repeated-measures models assessed the effect of participation time on these variables. RESULTS: Individuals with higher participation (minutes) significantly increased 6-minute walk test scores throughout hospitalization but had no significant changes in Brief Fatigue Inventory and Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale scores. Fatigue and QOL decreased over hospitalization but improved by discharge. Subjects who demonstrated higher participation averaged fewer hospital days (R = 1.65; P = .005). CONCLUSIONS: This study is unique in examining the impact of an incentive-based mobility program, participation in which may decrease length of hospital stay for HSCT patients. Randomized trials are needed to further validate these findings and assess additional variables that can influence outcomes. IMPLICATIONS FOR PRACTICE: An incentive-based mobility program during hospitalization for HSCT has the potential to minimize fatigue and stabilize, if not improve, QOL. PMID- 24067358 TI - Green tea extract containing a highly absorbent catechin prevents diet-induced lipid metabolism disorder. AB - We investigated the effects of extracts of Benifuuki (a tea cultivar that contains methylated catechins such as epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3"Me)) in mice fed a high-fat/high-sucrose (HF/HS) diet. This tea cultivar was then compared with an extract of Yabukita (a popular tea cultivar that lacks methylated catechins). For 6 weeks, C57BL/6J mice were fed either HF/HS diet with or without tea extracts from tea cultivars, which contained almost identical ingredients except for methylated catechins (i.e., Yabukita (0.2% and 1%) or Benifuuki (0.2% and 1%) extract powders). Supplementation with Benifuuki 0.2% markedly lowered plasma levels of TG and NEFAs compared with mice supplemented with Yabukita 0.2%. The diet containing Benifuuki 1% decreased adipose tissue weights, liver TG, and expression of lipogenic genes in the liver. These results suggested that Benifuuki had much greater lipid-lowering effects than Yabukita. Taken together, these data suggest that methylated catechins direct the strong lipid-lowering activity of Benifuuki. PMID- 24067360 TI - Void where prohibited. PMID- 24067359 TI - Dysregulation of Npas2 leads to altered metabolic pathways in a murine knockout model. AB - In our primate model of maternal high fat diet exposure, we have described that fetal epigenomic modifications to the peripheral circadian Npas2 are associated with persistent alterations in fetal hepatic metabolism and non-alcoholic fatty liver. As the interaction of circadian response with metabolism is not well understood, we employed a murine knockout model to characterize the molecular mechanisms with which Npas2 reprograms the fetal hepatic metabolic response. cDNA was generated from Npas2-/- and +/+ (wild type) livers at day 2 (newborn) and at 25 weeks (adult) of life. Newborn samples were analyzed by exon array (n = 3/cohort). Independent pathway analysis software determined that the primary dysregulated pathway(s) in the Npas2-/- animals uniformly converged on lipid metabolism. Of particular interest, Ppargc1a, which integrates circadian and metabolism pathways, was significantly (p < .01) over expressed in newborn (1.7 fold) and adult (1.8 fold) Npas2-/- animals. These findings are consistent with an essential role for Npas2 in programming the peripheral circadian response and hepatic metabolism, which has not been previously described. PMID- 24067361 TI - Activation of mGluR2/3 receptors in the ventro-rostral prefrontal cortex reverses sensorimotor gating deficits induced by systemic NMDA receptor antagonists. AB - Prepulse inhibition (PPI) of acoustic startle is an operational measure of sensorimotor gating, which is disrupted in schizophrenia. NMDA receptor (NMDAR) antagonist induced PPI disruption has become an important pharmacological model for schizophrenia; however, knowledge of the underlying mechanism remains incomplete. This study examines the role of NMDAR in the caudal pontine reticular nucleus (PnC) and the medial prefrontal cortex (mPFC) in NMDARs antagonist induced PPI deficits, as well as the NMDA receptor subtypes involved. We administered the NMDA antagonist MK-801 locally into the caudal pontine reticular formation (PnC), where the PPI mediating pathway converges with the primary startle pathway, and into the mPFC prior to behavioural testing. PnC microinjections had no effect on startle and PPI, whereas injections into the ventro-rostral part, but not into the dorso-caudal part of the mPFC, disrupted PPI. These effects could be mimicked by local injection of the NR2B subunit specific antagonist ifenprodil, whereas co-application of MK-801 and the mGluR2/3 agonist LY354740 had no effect on PPI. Moreover, PPI disruptions by systemically administered MK-801 could be reversed by local injections of LY354740 into the ventro-rostral mPFC, but not into the dorso-caudal mPFC. Our results indicate that NR2B subunit containing NMDARs in a specific subregion of the mPFC play a major role in PPI disruptions by systemic NMDAR antagonism. Our results further support the hypothesis that glutamate hyper-function in the mPFC is a main mechanism involved in sensory gating deficits induced by systemic MK-801, supporting the notion that this is an important mechanism in schizophrenia pathology. PMID- 24067362 TI - Oncolytic vesicular stomatitis virus and bortezomib are antagonistic against myeloma cells in vitro but have additive anti-myeloma activity in vivo. AB - Multiple myeloma cells are highly sensitive to the oncolytic effects of vesicular stomatitis virus (VSV), which specifically targets and kills cancer cells. Myeloma cells are also exquisitely sensitive to the cytotoxic effects of the clinically approved proteasome inhibitor bortezomib. Therefore, we sought to determine whether the combination of VSV and bortezomib would enhance tumor cell killing. However, as shown here, combining these two agents in vitro results in antagonism. We show that bortezomib inhibits VSV replication and spread. We found that bortezomib inhibits VSV-induced NF-kappaB activation and, using the NF kappaB-specific inhibitor BMS-345541, that VSV requires NF-kappaB activity to spread efficiently in myeloma cells. In contrast to other cancer cell lines, viral titer is not recovered by BMS-345541 when myeloma cells are pretreated with interferon beta. Thus, inhibiting NF-kappaB activity, either with bortezomib or BMS-345541, results in reduced VSV titers in myeloma cells in vitro. However, when VSV and bortezomib are combined in vivo in two syngeneic, immunocompetent myeloma models, the combination reduces tumor burden to a greater degree than VSV does as a single agent. Intratumoral VSV viral load is unchanged when mice are treated concomitantly with bortezomib compared to VSV treatment alone. To our knowledge, this report is the first to analyze the combination of VSV and bortezomib in vivo. Although antagonism between VSV and bortezomib is seen in vitro, analyzing these cells in the context of their host environment shows that bortezomib enhances VSV response, suggesting that this combination will also enhance response in myeloma patients. PMID- 24067363 TI - Resilient and resourceful: genome maintenance strategies in hematopoietic stem cells. AB - Blood homeostasis is maintained by a rare population of quiescent hematopoietic stem cells (HSCs) that self-renew and differentiate to give rise to all lineages of mature blood cells. In contrast to most other blood cells, HSCs are preserved throughout life, and the maintenance of their genomic integrity is therefore paramount to ensure normal blood production and to prevent leukemic transformation. HSCs are also one of the few blood cells that truly age and exhibit severe functional decline in old organisms, resulting in impaired blood homeostasis and increased risk for hematologic malignancies. In this review, we present the strategies used by HSCs to cope with the many genotoxic insults that they commonly encounter. We briefly describe the DNA-damaging insults that can affect HSC function and the mechanisms that are used by HSCs to prevent, survive, and repair DNA lesions. We also discuss an apparent paradox in HSC biology, in which the genome maintenance strategies used by HSCs to protect their function in fact render them vulnerable to the acquisition of damaging genetic aberrations. PMID- 24067364 TI - Tumor suppressor function of miR-483-3p on squamous cell carcinomas due to its pro-apoptotic properties. AB - The frequent alteration of miRNA expression in many cancers, together with our recent reports showing a robust accumulation of miR-483-3p at the final stage of skin wound healing, and targeting of CDC25A leading to an arrest of keratinocyte proliferation, led us to hypothesize that miR-483-3p could also be endowed with antitumoral properties. We tested that hypothesis by documenting the in vitro and in vivo impacts of miR-483-3p in squamous cell carcinoma (SCC) cells. miR-483-3p sensitized SCC cells to serum deprivation- and drug-induced apoptosis, thus exerting potent tumor suppressor activities. Its pro-apoptotic activity was mediated by a direct targeting of several anti-apoptotic genes, such as API5, BIRC5, and RAN. Interestingly, an in vivo delivery of miR-483-3p into subcutaneous SCC xenografts significantly hampered tumor growth. This effect was explained by an inhibition of cell proliferation and an increase of apoptosis. This argues for its further use as an adjuvant in the many instances of cancers characterized by a downregulation of miR-483-3p. PMID- 24067365 TI - Co-regulation of senescence-associated genes by oncogenic homeobox proteins and polycomb repressive complexes. AB - Cellular senescence is a stable cell cycle arrest that can be induced by stresses such as telomere shortening, oncogene activation or DNA damage. Senescence is a potent anticancer barrier that needs to be circumvented during tumorigenesis. The cell cycle regulator p16(INK4a) is a key effector upregulated during senescence. Polycomb repressive complexes (PRCs) play a crucial role in silencing the INK4/ARF locus, which encodes for p16(INK4a), but the mechanisms by which PRCs are recruited to this locus as well as to other targets remain poorly understood. Recently we discovered the ability of the homeobox proteins HLX1 (H2.0-like homeobox 1) and HOXA9 (Homeobox A9) to bypass senescence. We showed that HLX1 and HOXA9 recruit PRCs to repress INK4a, which constitutes a key mechanism explaining their effects on senescence. Here we provide evidence for the regulation of additional senescence-associated PRC target genes by HLX1 and HOXA9. As both HLX1 and HOXA9 are oncogenes implicated in leukemogenesis, we discuss the implications that the collaboration between Homeobox proteins and PRCs has for senescence and cancer. PMID- 24067366 TI - Identifying new small molecule anti-invasive compounds for glioma treatment. AB - Glioblastoma is a disease with poor survival rates after diagnosis. Treatment of the disease involves debulking of the tumor, which is limited by the degree of invasiveness of the disease. Therefore, a treatment to halt the invasion of glioma is desirable for clinical implementation. There have been several candidate compounds targeting specific aspects of invasion, including cell adhesions, matrix degradation, and cytoskeletal rearrangement, but they have failed clinically for a variety of reasons. New targets against glioma invasion include upstream mediators of these classical targets in an effort to better inhibit invasion with more specificity for cancer. Included in these treatments is a new class of compounds inhibiting the generation of reactive oxygen species by targeting the NADPH oxidases. These compounds stand to inhibit multiple pathways, including nuclear factor kappa B and Akt. By conducting a screen of compounds thought to inhibit these pathways, a new compound to halt invasion was found that may have a beneficial effect against glioma, based on recent publications. Further, there are still limitations to the treatment of glioblastoma regardless of the discovery of new targets and compounds that should be addressed to better the therapies against this deadly cancer. PMID- 24067367 TI - Genetic ablation of caveolin-2 sensitizes mice to bleomycin-induced injury. AB - Caveolar domains act as platforms for the organization of molecular complexes involved in signal transduction. Caveolin proteins, the principal structural components of caveolae, have been involved in many cellular processes. Caveolin-1 (Cav-1) and caveolin-2 (Cav-2) are highly expressed in the lung. Cav-1-deficient mice (Cav-1(-/-)) and Cav-2-deficient mice (Cav-2(-/-)) exhibit severe lung dysfunction attributed to a lack of Cav-2 expression. Recently, Cav-1 has been shown to regulate lung fibrosis in different models. Here, we show that Cav-2 is also involved in modulation of the fibrotic response, but through distinct mechanisms. Treatment of wild-type mice with the pulmonary fibrosis-inducer bleomycin reduced the expression of Cav-2 and its phosphorylation at tyrosine 19. Importantly, Cav-2(-/-) mice, but not Cav-1(-/-) mice, were more sensitive to bleomycin-induced lung injury in comparison to wild-type mice. Bleomycin-induced lung injury was characterized by alveolar thickening, increase in cell density, and extracellular matrix deposition. The lung injury observed in bleomycin treated Cav-2(-/-) mice was not associated with alterations in the TGF-beta signaling pathway and/or in the ability to produce collagen. However, apoptosis and proliferation were more prominent in lungs of bleomycin-treated Cav-2(-/-) mice. Since Cav-1(-/-) mice also lack Cav-2 expression and show a different outcome after bleomycin treatment, we conclude that Cav-1 and Cav-2 have distinct roles in bleomycin induced-lung fibrosis, and that the balance of both proteins determines the development of the fibrotic process. PMID- 24067368 TI - BRCA1 downregulates the kinase activity of Polo-like kinase 1 in response to replication stress. AB - In response to DNA damage or replication stress, proliferating cells are arrested at different cell cycle stages for DNA repair by downregulating the activity of both the cyclin-dependent kinases (CDKs) and other important cell cycle kinases, including Polo-like kinase 1 (PLK1) . The signaling pathway to inhibit CDKs is relatively well understood, and breast cancer gene 1 (BRCA1) and other DNA damage response (DDR) factors play a key role in this process. However, the DNA damage induced inhibition of PLK1 is still largely a mystery. Here we show that DNA damage and replication stress stimulate the association between BRCA1 and PLK1. Most importantly, we demonstrate that BRCA1 downregulates the kinase activity of PLK1 by modulating the dynamic interactions of Aurora A, hBora, and PLK1. Together with previous findings, we propose that in response to replication stress and DNA damage, BRCA1 plays a critical role in downregulating the kinase activity of both CDKs and PLK1. PMID- 24067369 TI - HIC1 interacts with and modulates the activity of STAT3. AB - HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene, expression of which is frequently suppressed in human cancers. Very little is known about the molecular basis of HIC1 in antagonizing oncogenic pathways. Here, we report that HIC1 forms complexes with the signal transducers and activators of transcription 3 (STAT3) and attenuates STAT3-mediated transcription. STAT3 was identified as a HIC1-interacting protein by affinity capture and followed by mass spectrometry analysis. Overexpression or depletion of HIC1 resulted in decreased or increased levels of interleukin-6 (IL-6)/oncostatin M (OSM)-induced STAT3-mediated reporter activity and expression of target genes such as VEGF and c-Myc, respectively. Furthermore, HIC1 suppressing the VEGF and c-Myc promoter activity and the colony formation of MDA-MB 231 cells were STAT3-dependent. Further studies showed that HIC1 interacts with the DNA binding domain of STAT3 and suppresses the binding of STAT3 to its target gene promoters. Domain mapping study revealed that HIC1 C terminal domain binds to STAT3. HIC1 mutant defective in STAT3 interaction reduced its repressive effect on STAT3 DNA binding activity, the reporter activity and gene expression of the VEGF and c-Myc genes, and cell growth in MDA MB 231 cells. Altogether, our findings not only provide a novel role of HIC1 in antagonizing STAT3-mediated activation of VEGF and c-Myc gene expression and cell growth, but also elucidate a molecular basis underlying the inhibitory effect of HIC1 on STAT3 transcriptional potential. PMID- 24067370 TI - Loss of VHL promotes progerin expression, leading to impaired p14/ARF function and suppression of p53 activity. AB - Renal cell carcinomas (RCCs) are frequently occurring genitourinary malignancies in the aged population. A morphological characteristic of RCCs is an irregular nuclear shape, which is used to index cancer grades. Other features of RCCs include the genetic inactivation of the von Hippel-Lindau gene, VHL, and p53 genetic-independent inactivation. An aberrant nuclear shape or p53 suppression has not yet been demonstrated. We examined the effect of progerin (an altered splicing product of the LMNA gene linked to Hutchinson Gilford progeria syndrome; HGPS) on the nuclear deformation of RCCs in comparison to that of HGPS cells. In this study, we showed that progerin was suppressed by pVHL and was responsible for nuclear irregularities as well as p53 inactivation. Thus, progerin suppression can ameliorate nuclear abnormalities and reactivate p53 in response to genotoxic addition. Furthermore, we found that progerin was a target of pVHL E3 ligase and suppressed p53 activity by p14/ARF inhibition. Our findings indicate that the elevated expression of progerin in RCCs results from the loss of pVHL and leads to p53 inactivation through p14/ARF suppression. Interestingly, we showed that progerin was expressed in human leukemia and primary cell lines, raising the possibility that the expression of this LMNA variant may be a common event in age-related cancer progression. PMID- 24067371 TI - CUL3 and protein kinases: insights from PLK1/KLHL22 interaction. AB - Posttranslational mechanisms drive fidelity of cellular processes. Phosphorylation and ubiquitination of substrates represent very common, covalent, posttranslational modifications and are often co-regulated. Phosphorylation may play a critical role both by directly regulating E3-ubiquitin ligases and/or by ensuring specificity of the ubiquitination substrate. Importantly, many kinases are not only critical regulatory components of these pathways but also represent themselves the direct ubiquitination substrates. Recent data suggest the role of CUL3-based ligases in both proteolytic and non-proteolytic regulation of protein kinases. Our own recent study identified the mitotic kinase PLK1 as a direct target of the CUL3 E3-ligase complex containing BTB-KELCH adaptor protein KLHL22. (1) In this study, we aim at gaining mechanistic insights into CUL3-mediated regulation of the substrates, in particular protein kinases, by analyzing mechanisms of interaction between KLHL22 and PLK1. We find that kinase activity of PLK1 is redundant for its targeting for CUL3-ubiquitination. Moreover, CUL3/KLHL22 may contact 2 distinct motifs within PLK1 protein, consistent with the bivalent mode of substrate targeting found in other CUL3-based complexes. We discuss these findings in the context of the existing knowledge on other protein kinases and substrates targeted by CUL3-based E3-ligases. PMID- 24067372 TI - SEPT9_i1 is required for the association between HIF-1alpha and importin-alpha to promote efficient nuclear translocation. AB - Septin 9 isoform 1 (SEPT9_i1) protein associates with hypoxia-inducible factor (HIF)-1alpha to augment HIF-1 transcriptional activity. The first 25 amino acids of SEPT9_i1 (N 25) are unique compared with other members of the mammalian septin family. This N 25 domain is critical for HIF-1 activation by SEPT9_i1 but not essential for the protein-protein interaction. Here, we show that expression of N 25 induces a significant dose-dependent inhibition of HIF-1 transcriptional activity under normoxia and hypoxia without influencing cellular HIF-1alpha protein levels. In vivo, N 25 expression inhibits proliferation, tumor growth and angiogenesis concomitant with decreased expression levels of intratumoral HIF-1 downstream genes. Depletion of endogenous SEPT9_i1 or the exogenous expression of N 25 fragment reduces nuclear HIF-1alpha levels accompanied by reciprocal accumulation of HIF-1alpha in the cytoplasm. Mechanistically, SEPT9_i1 binds to importin-alpha through N 25 depending on its bipartite nuclear localization signal, to scaffold the association between HIF-1alpha and importin-alpha, which leads to facilitating HIF-1alpha nuclear translocation. Our data explore a new and a previously unrecognized role of a septin protein in the cytoplasmic-nuclear translocation process. This new level in the regulation of HIF-1alpha translocation is critical for efficient HIF-1 transcriptional activation that could be targeted for cancer therapeutics. PMID- 24067373 TI - Activation of miR200 by c-Myb depends on ZEB1 expression and miR200 promoter methylation. AB - Tumor progression to metastasis is a complex, sequential process that requires proliferation, resistance to apoptosis, motility and invasion to colonize at distant sites. The acquisition of these features implies a phenotypic plasticity by tumor cells that must adapt to different conditions by modulating several signaling pathways (1) during the journey to the final site of metastasis. Several transcription factors and microRNA play a role in tumor progression, but less is known about the control of their expression during this process. Here, we demonstrate by ectopic expression and gene silencing that the proto-oncogene c Myb activates the expression of the 5 members of miR200 family (miR200b, miR200a, miR429, miR200c and miR141) that are involved in the control of epithelial mesenchymal transition (EMT) and metastasis in many types of cancers. Transcriptional activation of miR200 by c-Myb occurs through binding to myb binding sites located in the promoter regions of miR200 genes on human chromosomes 1 and 12. Furthermore, when c-Myb and the transcriptional repressor ZEB1 are co-expressed, as at the onset EMT, the repression by ZEB1 prevails over the activation by c-Myb, and the expression of miR200 is inhibited. We also demonstrate that during EMT induced by TGF-beta, the promoters of miR200 genes are methylated, and their transcription is repressed regardless of the presence of repressors such as ZEB1 and activators such as c-Myb. Finally, we find a correlation between the expression of c-Myb and that of four out of 5 miR200 in a data set of 207 breast cancer patients. PMID- 24067375 TI - Is p38gamma MAPK a metastasis-promoting gene or an oncogenic property-maintaining gene? PMID- 24067374 TI - Tumor protein translationally controlled 1 is a p53 target gene that promotes cell survival. AB - Tumor suppressor p53 maintains genome stability by differentially activating target genes that control diverse cellular responses, such as the antioxidant response, cell cycle arrest and apoptosis. Despite the fact that many p53 downstream genes have been well characterized, novel p53 target genes are continuously being identified. Here, we report that Tpt1 is a direct target gene of p53. We found that p53 upregulates the transcription of Tpt1 and identified a p53-responsive element in the promoter of the mouse Tpt1 gene. Furthermore, p53 dependent induction of Tpt1 was able to reduce oxidative stress, minimize apoptosis, and promote cell survival in response to H 2O2 challenge. In addition, a positive correlation between the expression of p53 and Tpt1 only existed in normal lung tissues, not in lung tumors. Such positive correlation was also found in lung cell lines that contain wild-type p53, but not mutated p53. Based on the important role of Tpt1 in cancer development, chemoresistance, and cancer reversion, identification of Tpt1 as a direct target gene of p53 not only adds to the complexity of the p53 network, but may also open up a new avenue for cancer prevention and intervention. PMID- 24067376 TI - Association of human leukocyte antigen E polymorphism with human cytomegalovirus reactivation in Chinese burn patients. PMID- 24067377 TI - Photoluminescence from amino-containing polymer in the presence of CO2: carbamato anion formed as a fluorophore. AB - Organic photoluminescent materials are important to many applications especially for diagnosis and detection, and most of organic photoluminescent materials contain fluorophores with extended conjugated structures. Recently some of amino containing polymers without fluorophores with extended conjugated structure are observed to be photoluminescent, and one possible cause of the photoluminescence is oxidation of the amines. Here we show that photoluminescence can be produced by exposing a typical amino-containing polymer, polyethylenimine, to carbon dioxide. We demonstrate that carbamato anion formed via the reaction between the amine and carbon dioxide is a fluorophore; and the loosely-bound protonated water molecule can increase UV absorption but reduce the photoluminescence emission. Also carbamato anion shows solvent- and excitation wavelength-dependent emission of photoluminescence. The photoluminescence profile of carbamoto anion was discussed. These results will facilitate the understanding of photoluminescence observed from amino-containing materials and the design of new fluorophores. PMID- 24067378 TI - Psychosocial aspects of systemic sclerosis. AB - PURPOSE OF REVIEW: In 2010, an international consortium of researchers published a consensus agenda for research on psychosocial aspects of systemic sclerosis (SSc; scleroderma). The present review summarizes recent research on SSc-related depression and anxiety, fatigue and sleep, pain, pruritus, body image distress, sexual function, work disability, healthcare needs, psychosocial interventions, and psychoneuroimmunology. RECENT FINDINGS: Researchers have used structured interviews to establish prevalence rates for clinical mood disorders in SSc, although anxiety remains understudied and distress may be a useful outcome to consider. Longitudinal research has identified predictors of fatigue. Research on body image distress suggests the importance of changes in the facial skin and hands. Studies have identified sexual function problems in women and men with SSc. A prospective study found that breathing problems and fatigue predicted workplace disability. A randomized controlled trial evaluating multidisciplinary care showed benefits for health-related quality of life. SUMMARY: There has been a recent expansion in studies of psychosocial aspects of SSc, and in the validation of psychosocial measures that can be used in clinics to identify problems and track outcomes; however, prospective studies remain scarce. To better address the psychosocial needs of persons with SSc, interventions need to be developed and tested via randomized controlled trials with power to detect clinically meaningful changes. PMID- 24067379 TI - Entering a new phase of immunogenetics in the idiopathic inflammatory myopathies. AB - PURPOSE OF REVIEW: To review the progress that has been made in understanding the genetics of the idiopathic inflammatory myopathies (IIMs) in the past 2 years, with particular focus on polymyositis, dermatomyositis and inclusion body myositis. RECENT FINDINGS: Candidate gene studies in the Japanese population have implicated signal transducer and activator of transcription 4 as a risk locus for IIM, and HLA-DRB1 as a risk locus for anti-melanoma differentiation-associated gene 5-positive dermatomyositis. Evidence for gene-environment interactions has been found between HLA-DRB1*03 and smoking as a risk factor for the development of anti-histidyl tRNA synthetase antibodies, and HLA-DRB1*11:01 and statins for the development of anti-hydroxymethyl glutaryl-coenzyme A reductase-positive statin-induced myopathy. The HLA-DRB1*03:01/*01:01 genotype confers the highest disease risk in inclusion body myositis. A recent genome-wide association study has been performed in dermatomyositis. The most significant signals were in the major histocompatibility complex region, with other loci suggesting evidence of genetic overlap with different autoimmune diseases. SUMMARY: Recent association and gene-environment interaction studies have increased our knowledge of genetic risk factors for the IIMs. Ongoing international collaborations will facilitate larger and more meaningful genetic studies revealing much about the genetic architecture of these complex diseases. PMID- 24067380 TI - Biomarkers of inclusion body myositis. AB - PURPOSE OF REVIEW: Inclusion body myositis (IBM) is a poorly understood autoimmune and degenerative disorder of skeletal muscle. Here, pathophysiological and diagnostic biomarkers of IBM are reviewed. RECENT FINDINGS: Muscle histopathological biomarkers have been successful in stimulating the study of IBM pathophysiology for over three decades. Their use as diagnostic biomarkers, in contrast, has significant limitations. A blood biomarker, autoantibodies against a 43-kDa muscle protein reported in 2011, has now been identified as targeting cytoplasmic 5' nucleotidase (cN1A; NT5C1A), a protein involved in nucleic acid metabolism. Diagnostic testing for these autoantibodies is of high diagnostic performance for IBM. SUMMARY: Muscle biomarkers have suggested that IBM pathophysiology is linked to myonuclear degeneration and disordered nucleic acid metabolism. A blood biomarker has high diagnostic performance for IBM, and through identification of its target links, IBM autoimmunity and degeneration together, supporting the view that IBM pathophysiology includes abnormal nucleic acid metabolism. PMID- 24067381 TI - Update in inclusion body myositis. AB - PURPOSE OF REVIEW: The purpose of this study is to review recent scientific advances relating to the natural history, cause, treatment and serum and imaging biomarkers of inclusion body myositis (IBM). RECENT FINDINGS: Several theories regarding the aetiopathogenesis of IBM are being explored and new therapeutic approaches are being investigated. New diagnostic criteria have been proposed, reflecting the knowledge that the diagnostic pathological findings may be absent in patients with clinically typical IBM. The role of MRI in IBM is expanding and knowledge about pathological biomarkers is increasing. The recent description of autoantibodies to cytosolic 5' nucleotidase 1A in patients with IBM is a potentially important advance that may aid early diagnosis and provides new evidence regarding the role of autoimmunity in IBM. SUMMARY: IBM remains an enigmatic and often misdiagnosed disease. The pathogenesis of the disease is still not fully understood. To date, pharmacological treatment trials have failed to show clear efficacy. Future research should continue to focus on improving understanding of the pathophysiological mechanisms of the disease and on the identification of reliable and sensitive outcome measures for clinical trials. IBM is a rare disease and international multicentre collaboration for trials is important to translate research advances into improved patient outcomes. PMID- 24067383 TI - Synthesis and characterization of fluorinated carbon nanotubes for lithium primary batteries with high power density. AB - The synthesis and characterization of fluorinated carbon nanotubes have been carried out under an inert gas containing fluorine. All of the samples have been characterized by x-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), solid-state nuclear magnetic resonance ((13)C and (19)F ss-NMR) and transmission electron microscopy (TEM) techniques. The comparison of the effects of various experimental parameters on the structure of fluorinated materials allows the disclosure of the fluorination mechanism. It is shown that fluorine was intercalated into the outer part of the carbon nanotubes initially where graphene layers were coaxial within a distance of 0.60 nm. In contrast, the inner part of the carbon nanotubes was not intercalated. The electrochemical performance such as discharge capacity as a cathode for a primary lithium battery has also been investigated. The samples with a F/C ratio of 0.75 exhibited the best performance, namely high energy and power densities. The highest specific energy density and specific power density were 1147 Wh kg(-1) and 8998 W kg(-1), respectively, at a current density of 4 A g(-1). PMID- 24067382 TI - IL-6 regulates neutrophil microabscess formation in IL-17A-driven psoriasiform lesions. AB - The lack of a generally accepted animal model for human psoriasis has hindered progress with respect to understanding the pathogenesis of the disease. Here we present a model in which transgenic IL-17A expression is targeted to the skin in mice, achievable after crossing our IL-17A(ind) allele to the K14-Cre strain. K14 IL-17A(ind/+) mice invariably develop an overt skin inflammation bearing many hallmark characteristics of human psoriasis including dermal infiltration of effector T cells, formation of neutrophil microabscesses, and hyperkeratosis. IL 17A expression in the skin results in upregulated granulopoiesis and migration of IL-6R-expressing neutrophils into the skin. Neutralization of IL-6 signaling efficiently reduces the observed pathogenesis in skin of IL-17A-overexpressing mice, with marked reductions in epidermal neutrophil abscess formation and epidermal thickening. Thus, IL-6 functions downstream of IL-17A to exacerbate neutrophil microabscess development in psoriasiform lesions. PMID- 24067384 TI - Complex effects of vitamin E and vitamin C supplementation on in vitro neonatal mononuclear cell responses to allergens. AB - Low maternal dietary vitamin E (but not vitamin C) intake during pregnancy has been associated with increased in vitro cord blood mononuclear cell (CBMC) proliferative responses, childhood wheezing and asthma. We investigated whether these associations reflect direct effects of vitamin E by investigating the effects of supplementing CBMC cultures with physiological concentrations of vitamin E. CBMC from seventy neonates were cultured supplemented with either nothing, alpha-tocopherol or ascorbic acid. Proliferative, IFN-gamma, IL-4, IL-10 and TGF-beta responses were measured. In general, vitamin E supplementation was associated with a trend for reduced proliferative responses after stimulation with antigens and house dust mite, and with increased proliferation after stimulation with timothy grass allergen. There was a trend for CBMC cultures to exhibit decreased secretion of IFN-gamma, IL-10 and IL-4. Supplementation with vitamin C had no effect on CBMC proliferation, but increased IFN-gamma and IL-4 production, and decreased IL-10 production. In conclusion, in vitro vitamin E and C supplementation of CBMC modifies neonatal immune function, but not in a manner predicted by observational epidemiological studies. The observed associations between vitamin E and childhood respiratory disease are complex, and the nature and form of nutritional intervention need to be carefully considered before inclusion in trials. PMID- 24067385 TI - Association between subcutaneous white adipose tissue and serum 25-hydroxyvitamin D in overweight and obese adults. AB - Cholecalciferol is known to be deposited in human adipose tissue, but it is not known whether 25-hydroxyvitamin D (25(OH)D) is found in detectable concentrations. Therefore, our objective was to determine whether 25(OH)D is detectable in subcutaneous white adipose tissue (SWAT) in overweight and obese persons enrolled in a twelve week energy restricted diet. Baseline and post intervention gluteal SWAT biopsies were collected from 20 subjects participating in a larger clinical weight loss intervention. LC-MS/MS was utilized to determine SWAT 25(OH)D concentrations. Serum 25(OH)D and 1,25(OH)2D were measured by RIA. Body composition was assessed by dual energy x-ray absorptiometry. SWAT 25(OH)D concentrations were 5.8 +/- 2.6 nmol/kg tissue and 6.2 +/- 2.7 nmol/kg tissue pre and post-intervention SWAT, respectively. There was a significant positive association between SWAT 25(OH)D concentration and serum 25(OH)D concentration (r = 0.52, P < 0.01). Both SWAT and serum 25(OH)D concentrations did not significantly change after a twelve-week period of energy restriction with approximately 5 kg of fat loss. In conclusion, we have demonstrated our LC-MS/MS method can detect 25(OH)D3 in human subcutaneous fat tissue from overweight and obese individuals and is consistent with previously reported concentrations in swine. Additionally, our findings of no significant changes in SWAT 25(OH)D3 or serum 25(OH)D after a 6% loss of total body weight and 13% reduction in total fat provides the first human evidence that adipose 25(OH)D does not likely contribute to serum 25(OH)D with moderate weight loss; whether this is also the case with larger amounts of weight loss is unknown. Weight loss alone is not sufficient to increase serum 25(OH)D and increases in dietary or dermal biosynthesis of vitamin D appear to be the most critical contributors to in vitamin D status. PMID- 24067386 TI - Is early enteral nutrition better for postoperative course in esophageal cancer patients? AB - We retrospectively examined esophageal cancer patients who received enteral nutrition (EN) to clarify the validity of early EN compared with delayed EN. A total of 103 patients who underwent transthoracic esophagectomy with three-field lymphadenectomy for esophageal cancer were entered. Patients were divided into two groups; Group E received EN within postoperative day 3, and Group L received EN after postoperative day 3. The clinical factors such as days for first fecal passage, the dose of postoperative albumin infusion, differences of serum albumin value between pre- and postoperation, duration of systematic inflammatory response syndrome (SIRS), incidence of postoperative infectious complication, and use of total parenteral nutrition (TPN) were compared between the groups. The statistical analyses were performed using Mann-Whitney U test and Chi square test. The statistical significance was defined as p < 0.05. Group E showed fewer days for the first fecal passage (p < 0.01), lesser dose of postoperative albumin infusion (p < 0.01), less use of TPN (p < 0.01), and shorter duration of SIRS (p < 0.01). However, there was no significant difference in postoperative complications between the two groups. Early EN started within 3 days after esophagectomy. It is safe and valid for reduction of albumin infusion and TPN, for promoting early recovery of intestinal movement, and for early recovery from systemic inflammation. PMID- 24067387 TI - Acute effects of different multivitamin mineral preparations with and without Guarana on mood, cognitive performance and functional brain activation. AB - Previous work has identified the positive effects of the acute administration of a multivitamin-guarana preparation during an effortful executive/working memory task. Here, we aimed to differentiate the effects of multivitamins with and without guarana and to examine the neural substrates of such effects using functional magnetic resonance imaging (fMRI). Following a double-blind, placebo controlled, randomised, balanced crossover design, 20 participants (mean age 29 +/- 5.54 years) consumed multivitamin preparations with or without guarana (Berocca(r) Performance and Boost, respectively) and a placebo. Thirty minutes post-treatment, they underwent neurocognitive assessment, consisting of a 10 min Cognitive Demand Battery, with mood ratings taken immediately before and after the battery. Five additional participants underwent post-treatment fMRI scanning during Rapid Visual Information Processing and Inspection Time activation tasks. The multivitamin with guarana treatment was associated with significantly enhanced Serial Threes performance and self-rated contentment. fMRI revealed that both multivitamin treatments increased activation in areas associated with working memory and attentional processing, with the effect being greater in the multivitamin with guarana condition. These data confirm the acute benefits of multivitamins with guarana on mood and cognitive performance. Furthermore, they demonstrate for the first time increased brain activation from multivitamin preparations both with and without guarana, as measured using fMRI. PMID- 24067388 TI - Vitamin D: deficiency, sufficiency and toxicity. AB - The plethora of vitamin D studies over the recent years highlight the pleomorphic effects of vitamin D outside its conventional role in calcium and bone homeostasis. Vitamin D deficiency, though common and known, still faces several challenges among the medical community in terms of proper diagnosis and correction. In this review, the different levels of vitamin D and its clinical implications are highlighted. Recommendations and consensuses for the appropriate dose and duration for each vitamin D status are also emphasized. PMID- 24067389 TI - Fatty acid and phytosterol content of commercial saw palmetto supplements. AB - Saw palmetto supplements are one of the most commonly consumed supplements by men with prostate cancer and/or benign prostatic hyperplasia (BPH). Some studies have found significant improvements in BPH and lower urinary tract symptoms (LUTS) with saw palmetto supplementation, whereas others found no benefits. The variation in the efficacy in these trials may be a result of differences in the putative active components, fatty acids and phytosterols, of the saw palmetto supplements. To this end, we quantified the major fatty acids (laurate, myristate, palmitate, stearate, oleate, linoleate) and phytosterols (campesterol, stigmasterol, beta-sitosterol) in 20 commercially available saw palmetto supplements using GC-FID and GC-MS, respectively. Samples were classified into liquids, powders, dried berries, and tinctures. Liquid saw palmetto supplements contained significantly higher (p < 0.05) concentrations of total fatty acids (908.5 mg/g), individual fatty acids, total phytosterols (2.04 mg/g), and individual phytosterols, than the other supplement categories. Powders contained significantly higher (p < 0.05) concentrations of total fatty acids than tinctures, which contain negligible amounts of fatty acids (46.3 mg/g) and phytosterols (0.10 mg/g). Our findings suggest that liquid saw palmetto supplements may be the best choice for individuals who want to take a saw palmetto supplement with the highest concentrations of both fatty acids and phytosterols. PMID- 24067390 TI - Biological variability and impact of oral contraceptives on vitamins B(6), B(12) and folate status in women of reproductive age. AB - Vitamins B(6), B(12) and folate play crucial metabolic roles especially during the reproductive years for women. There is limited reporting of within-subject variability of these vitamins. This study aimed to determine the within and between subject variability in serum vitamins B(6), B(12), folate and erythrocyte folate concentrations in young women; identify factors that contribute to variability; and determine dietary intakes and sources of these vitamins. Data were obtained from the control group of a trial aimed at investigating the effect of iron on the nutritional status of young women (age 25.2 +/- 4.2 year; BMI 21.9 +/- 2.2 kg/m2). The coefficients of variability within-subject (CVI) and between subject (CVG) for serum vitamins B(6), B(12)and folate, and erythrocyte folate were calculated. Food frequency questionnaires provided dietary data. CVI and CVG were in the range 16.1%-25.7% and 31.7%-62.2%, respectively. Oral contraceptive pill (OCP) use was associated (P = 0.042) with lower serum vitamin B12 concentrations. Initial values were 172 +/- 16 pmol/L and 318 +/- 51 pmol/L for OCP and non-OCP users, respectively; with differences maintained at four time points over 12 weeks. BMI, age, physical activity, alcohol intake and haematological variables did not affect serum or erythrocyte vitamin concentrations. Vitamin B12 intakes were derived from traditional and unexpected sources including commercial energy drinks. Young women using OCP had significantly lower serum vitamin B12 concentrations. This should be considered in clinical decision making and requires further investigation. PMID- 24067392 TI - A randomized steady-state bioavailability study of synthetic versus natural (kiwifruit-derived) vitamin C. AB - Whether vitamin C from wholefoods has equivalent bioavailability to a purified supplement remains unclear. We have previously showed that kiwifruit provided significantly higher serum and tissue ascorbate levels than synthetic vitamin C in a genetically vitamin C-deficient mouse model, suggesting a synergistic activity of the whole fruit. To determine if these results are translatable to humans, we carried out a randomized human study comparing the bioavailability of vitamin C from kiwifruit with that of a vitamin C tablet of equivalent dosage. Thirty-six young non-smoking adult males were randomized to receive either half a gold kiwifruit (Actinidia Chinensis var. Hort 16A) per day or a comparable vitamin C dose (50 mg) in a chewable tablet for six weeks. Ascorbate was monitored weekly in fasting venous blood and in urine, semen, leukocytes, and skeletal muscle (vastus lateralis) pre- and post-intervention. Dietary intake of vitamin C was monitored using seven day food and beverage records. Participant ascorbate levels increased in plasma (P < 0.001), urine (P < 0.05), mononuclear cells (P < 0.01), neutrophils (P < 0.01) and muscle tissue (P < 0.001) post intervention. There were no significant differences in vitamin C bioavailability between the two intervention groups in any of the fluid, cell or tissue samples tested. Overall, our study showed comparable bioavailability of synthetic and kiwifruit-derived vitamin C. PMID- 24067391 TI - Nutritional recommendations for cardiovascular disease prevention. AB - Lifestyle factors, including nutrition, play an important role in the etiology of Cardiovascular Disease (CVD). This position paper, written by collaboration between the Israel Heart Association and the Israel Dietetic Association, summarizes the current, preferably latest, literature on the association of nutrition and CVD with emphasis on the level of evidence and practical recommendations. The nutritional information is divided into three main sections: dietary patterns, individual food items, and nutritional supplements. The dietary patterns reviewed include low carbohydrate diet, low-fat diet, Mediterranean diet, and the DASH diet. Foods reviewed in the second section include: whole grains and dietary fiber, vegetables and fruits, nuts, soy, dairy products, alcoholic drinks, coffee and caffeine, tea, chocolate, garlic, and eggs. Supplements reviewed in the third section include salt and sodium, omega-3 and fish oil, phytosterols, antioxidants, vitamin D, magnesium, homocysteine-reducing agents, and coenzyme Q10. PMID- 24067393 TI - Decrease in the incidence of culture-positive meningitis and cerebral tuberculomas in France from 1990 to 2007. AB - We evaluated the incidence rate of culture-positive central nervous system tuberculosis (CNS TB) in France in 2007 and its time trend between 1990 and 2007. We used a capture-recapture analysis by using data recorded in 2007 by the mandatory notification system and the national network of the National Reference Centre (NRC). The 2007 sensitivity of the NRC was 79.4%. The previous sensitivity for 2000 (75.6%) and that for 2007 yielded a pooled estimate of 77.4% (95% confidence interval 64.8-88.0), which was used to extrapolate the number of culture-positive CNS TB cases from those reported in four surveys (1990, 1995, 2000, 2007). The extrapolated number of culture-positive CNS TB cases fell from 90 to 35 between 1990 and 2007, and the extrapolated incidence rates fell from 1.6 to 0.55 cases/million (P < 0.001). This favourable trend should be closely monitored following the change of the BCG vaccination policy in 2007. PMID- 24067394 TI - American Pediatric Society 2013 presidential address: 125th anniversary of the American Pediatric Society--lessons from the past to guide the future. AB - This year is the 125th anniversary of the American Pediatric Society (APS), a time to reflect on the past 125 years of child health and child health research, a time to consider the health of America's children in a social and global context, and a time to consider the future. This paper is a combination of pediatric and APS history and personal story. PMID- 24067396 TI - Locking of iridium magnetic moments to the correlated rotation of oxygen octahedra in Sr2IrO4 revealed by x-ray resonant scattering. AB - Sr2IrO4 is a prototype of the class of Mott insulators in the strong spin-orbit interaction (SOI) limit described by a Jeff = 1/2 ground state. In Sr2IrO4, the strong SOI is predicted to manifest itself in the locking of the canting of the magnetic moments to the correlated rotation by 11.8(1) degrees of the oxygen octahedra that characterizes its distorted layered perovskite structure. Using x ray resonant scattering at the Ir L3 edge we have measured accurately the intensities of Bragg peaks arising from different components of the magnetic structure. From a careful comparison of integrated intensities of peaks due to basal-plane antiferromagnetism, with those due to b-axis ferromagnetism, we deduce a canting of the magnetic moments of 12.2(8) degrees . We thus confirm that in Sr2IrO4 the magnetic moments rigidly follow the rotation of the oxygen octahedra, indicating that, even in the presence of significant non-cubic structural distortions, it is a close realization of the Jeff = 1/2 state. PMID- 24067397 TI - Complexity and diversity of eyes in early Cambrian ecosystems. AB - Here we report exceptionally preserved non-biomineralized compound eyes of a non trilobite arthropod Cindarella eucalla from the lower Cambrian Chengjiang Lagerstatte, China. The specimen represents the oldest microanatomical evidence confirming the occurrence of highly developed vision in the early Cambrian, over 2,000 ommatidia in each eye. Moreover, a quantitative analysis of the distribution of eyes related to life habit, feeding types, and phyla respectively, from the Chengjiang biota indicates that specimens with eyes mostly belong to the arthropods, and they usually were actively mobile epifaunal and nektonic forms as hunters or scavengers. Arthropods took the lead in evolution of 'good vision' and domination in Cambrian communities, which supports the hypothesis that the origin and evolution of 'good vision' was a key trait that promoted preferential diversification and formed the foundation of modern benthic ecosystems in the early Cambrian ocean. PMID- 24067395 TI - Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk. AB - BACKGROUND: Myo-inositol given to preterm infants with respiratory distress has reduced death, increased survival without bronchopulmonary dysplasia, and reduced severe retinopathy of prematurity in two randomized trials. Pharmacokinetic (PK) studies in extremely preterm infants are needed before efficacy trials. METHODS: Infants born in 23-29 wk of gestation were randomized to a single intravenous (i.v.) dose of inositol at 60 or 120 mg/kg or placebo. Over 96 h, serum levels (sparse sampling population PK) and urine inositol excretion were determined. Population PK models were fit using a nonlinear mixed-effects approach. Safety outcomes were recorded. RESULTS: A single-compartment model that included factors for endogenous inositol production, allometric size based on weight, gestational age strata, and creatinine clearance fit the data best. The central volume of distribution was 0.5115 l/kg, the clearance was 0.0679 l/kg/h, endogenous production was 2.67 mg/kg/h, and the half-life was 5.22 h when modeled without the covariates. During the first 12 h, renal inositol excretion quadrupled in the 120 mg/kg group, returning to near-baseline value after 48 h. There was no diuretic side effect. No significant differences in adverse events occurred among the three groups (P > 0.05). CONCLUSION: A single-compartment model accounting for endogenous production satisfactorily described the PK of i.v. inositol. PMID- 24067399 TI - The murky path to drug discovery in ALS becomes clearer. PMID- 24067400 TI - Estimation of anaerobic threshold, a classical index drawing renewed attention, by new methods without respiratory gas measurements. PMID- 24067398 TI - Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. AB - BACKGROUND: In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease. METHODS: In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18-80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice-interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12-18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov, number NCT01281189. FINDINGS: Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441.76, 95% CI 415.43-468.08) and those in the placebo group (438.84, 412.81-464.88; p=0.86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (-13.34 in the dexpramipexole group vs -13.42 in the placebo group; p=0.90) or time to death (74 [16%] vs 79 [17%]; hazard ratio 1.03 [0.75-1.43]; p=0.84). 37 (8%) participants in the dexpramipexole group developed neutropenia compared with eight (2%) participants in the placebo group, and incidence of other adverse events was similar between groups. INTERPRETATION: Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis. FUNDING: Biogen Idec. PMID- 24067401 TI - A peculiar presentation of a large retrocardiac mass. PMID- 24067402 TI - From headache to heartache: ergotamine-induced aortic and mitral valvulopathy. PMID- 24067403 TI - How do statins work?: changing paradigms with implications for statin allocation. PMID- 24067404 TI - Interdependent networks: the fragility of control. AB - Recent work in the area of interdependent networks has focused on interactions between two systems of the same type. However, an important and ubiquitous class of systems are those involving monitoring and control, an example of interdependence between processes that are very different. In this Article, we introduce a framework for modelling 'distributed supervisory control' in the guise of an electrical network supervised by a distributed system of control devices. The system is characterised by degrees of freedom salient to real-world systems- namely, the number of control devices, their inherent reliability, and the topology of the control network. Surprisingly, the behavior of the system depends crucially on the reliability of control devices. When devices are completely reliable, cascade sizes are percolation controlled; the number of devices being the relevant parameter. For unreliable devices, the topology of the control network is important and can dramatically reduce the resilience of the system. PMID- 24067405 TI - Antidepressant-like activity of magnesium in the chronic mild stress model in rats: alterations in the NMDA receptor subunits. AB - Recent data suggests that the glutamatergic system is involved in the pathophysiology and treatment of major depressive disorder (MDD) and that the N methyl-D-aspartate (NMDA) receptor is a potential target for antidepressant drugs. The magnesium ion blocks the ion channel of the NMDA receptor and prevents its excessive activation. Some preclinical and clinical evidence suggests also that magnesium may be useful in the treatment of depression. The present study investigated the effect of magnesium treatment (10, 15 and 20 mg/kg, given as magnesium hydroaspartate) in the chronic mild stress (CMS) model of depression in rats. Moreover, the effect of CMS and magnesium (with an effective dose) on the level of the proteins related to the glutamatergic system (GluN1, GluN2A, GluN2B and PSD-95) in the hippocampus, prefrontal cortex (PFC) and amygdala were examined. A significant reduction in the sucrose intake induced by CMS was increased by magnesium treatment at a dose of 15 mg/kg, beginning from the third week of administration. Magnesium did not affect this behavioural parameter in the control animals. CMS significantly increased the level of the GluN1 subunit in the amygdala (by 174%) and GluN2A in the hippocampus (by 191%), both of which were significantly attenuated by magnesium treatment. Moreover, magnesium treatment in CMS animals increased the level of GluN2B (by 116%) and PSD-95 (by 150%) in the PFC. The present results for the first time demonstrate the antidepressant-like activity of magnesium in the animal model of anhedonia (CMS), thus indicating the possible involvement of the NMDA/glutamatergic receptors in this activity. PMID- 24067406 TI - Characterization of hepatitis C infection in tuberculosis patients in an urban city in the USA. AB - The impact of hepatitis C virus infection (HCI), the most common bloodborne virus infection in the USA, on outcome of active tuberculosis (TB) treatment is largely unknown. We aimed to describe characteristics of TB patients with hepatitis C virus infection (TB-HCI) in King County, Washington, including TB treatment duration and outcome. We reviewed 1510 records of patients treated for active TB at the Public Health - Seattle & King County Tuberculosis Control Program between 2000 and 2010, and identified 53 with HCI. Advanced age, being born in the USA, HIV infection, homelessness and injection drug use were independently associated with HCI in TB cases. Independent factors associated with increased treatment duration included HIV infection, excess alcohol use, extrapulmonary TB, and any drug-resistant TB disease. Our findings suggest that TB-HCI patients can be successfully treated for active TB without extending treatment duration. PMID- 24067407 TI - The relation between blinking and conjunctival folds and dry eye symptoms. AB - PURPOSE: To investigate the relationship between blink action, dry eye symptoms, and lid-parallel conjunctival folds (LIPCOF). METHODS: In 30 subjects (14 were women; mean [standard deviation {SD}] age, 42.4 [+/-12.3] years), spontaneous blinks were recorded from a temporal-inferior view (high-speed video), and the blink extent (incomplete [IC], almost complete [AC], and complete [CC]) was evaluated. Dry eye symptoms were evaluated using the Ocular Surface Disease Index (OSDI), and nasal and temporal LIPCOF grades were noted. Correlations between groups were calculated with Pearson correlation (or Spearman rank in nonparametric data), and differences between groups were calculated with an unpaired t-test (or U-test Mann-Whitney in nonparametric data). RESULTS: Blink rate was significantly higher in females (22.0% [+/-16.8]) than in males (8.6% [+/-7.2]; unpaired t-test: p = 0.007). The percentage of AC of all blinks (AC%) was significantly correlated to LIPCOF sum (nasal + temporal) and OSDI scores (r > 0.570, p < 0.001). The percentage of IC was significantly correlated to LIPCOF sum (r = -0.541, p < 0.001) but not to OSDI. CONCLUSIONS: The frequency and type of blinking may have an effect on dry eye symptoms and LIPCOF severity since almost all complete blinks were significantly related to both factors. PMID- 24067408 TI - With an eye to low vision: optic flow enables perception despite image blur. AB - PURPOSE: From static blurry images, it is difficult to perceive objects because high spatial frequency details are filtered out. However, in the context of events (defined as objects in motion), motion generates optic flow, which provides a depth map of 3D layout and allows good event perception. Visual motion measurement uses low spatial frequencies that remain available in blurry images, making events perceivable. Optic flow and image structure are intrinsically related in vision because optic flow takes one image to the next. Optic flow is powerful in specifying depth structures and it calibrates the degraded image structure; image structure is persistent and it preserves events perceived with ongoing motion, after it stops. Might optic flow and image structures interact and allow events to be perceived despite poor quality images? The answer to this question has implications for event perception with low vision. METHODS: Twenty blurry images depicting each of eight daily events were used as stimuli. Ten normally sighted participants perceived the stimuli and described the events in five ordered conditions: (1) when single frames were presented, (2) when all frames were presented with motion masks, (3) when all frames were presented without motion masks, (4) when single frames were presented, and (5) when single frames were presented 5 days later. RESULTS: With blurry static images alone, participants were unable to identify events. Events were perceptible when the blurred images were played in sequence, making motion-generated information available. Subsequently, when given the original blurry static images again, post motion performance was vastly superior to the pre-motion performance. Furthermore, the high rate of recognition persisted after 5 days. CONCLUSIONS: Optic flow calibrates low-quality image structure to allow accurate event perception during and after motion. This implies that low-vision observers should perform much better than allowed by weakened image structure information alone. PMID- 24067410 TI - Hierarchically structured materials for lithium batteries. AB - The lithium-ion battery (LIB) is one of the most promising power sources to be deployed in electric vehicles, including solely battery powered vehicles, plug-in hybrid electric vehicles, and hybrid electric vehicles. With the increasing demand for devices of high-energy densities (>500 Wh kg(-1)), new energy storage systems, such as lithium-oxygen (Li-O2) batteries and other emerging systems beyond the conventional LIB, have attracted worldwide interest for both transportation and grid energy storage applications in recent years. It is well known that the electrochemical performance of these energy storage systems depends not only on the composition of the materials, but also on the structure of the electrode materials used in the batteries. Although the desired performance characteristics of batteries often have conflicting requirements with the micro/nano-structure of electrodes, hierarchically designed electrodes can be tailored to satisfy these conflicting requirements. This work will review hierarchically structured materials that have been successfully used in LIB and Li-O2 batteries. Our goal is to elucidate (1) how to realize the full potential of energy materials through the manipulation of morphologies, and (2) how the hierarchical structure benefits the charge transport, promotes the interfacial properties and prolongs the electrode stability and battery lifetime. PMID- 24067411 TI - Guest editorial. Computational systems biology. PMID- 24067412 TI - Functional tunability of biological circuits from additional toggle switches. AB - In many complex regulatory networks with interlinked feedback loops, the simple core circuits are sufficient to achieve the specific biological functions of the whole networks, naturally raising a question: what is the role of the additional feedback loops. By investigating the effect of an additional toggle switch on the auto-activation circuit responsible for competent switch in Bacillus subtilits and on the activator-repressor circuit responsible for cell cycle in Xenopus embryonic, the authors show that the additional toggle switch can elaborate the dynamical behaviour of both circuits. Specifically, the additional toggle switch in B. subtilits does not significantly affect the saturation level of the competent state but can tune the activation threshold (i.e. the minimal stimulus required to switch the system from the non-competent state to the competent state). For the activator-repressor circuit in X. embryonic cell cycle, the additional toggle switch can tune the oscillation frequency but does not change the oscillation amplitude. The proposed detailed results not only provide guidelines to the engineering of synthetic genetic circuits, but also imply a significant fact that additional toggle switches in a complex network are not really redundant but play a role of tuning network functions. PMID- 24067413 TI - Gene expression rate comparison for multiple high-throughput datasets. AB - Microarray provides genome-wide transcript profiles, whereas RNA-seq is an alternative approach applied for transcript discovery and genome annotation. Both high-throughput techniques show quantitative measurement of gene expression. To explore differential gene expression rates and understand biological functions, the authors designed a system which utilises annotations from Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathways and Gene Ontology (GO) associations for integrating multiple RNA-seq or microarray datasets. The developed system is initiated by either estimating gene expression levels from mapping next generation sequencing short reads onto reference genomes or performing intensity analysis from microarray raw images. Normalisation procedures on expression levels are evaluated and compared through different approaches including Reads Per Kilobase per Million mapped reads (RPKM) and housekeeping gene selection. Such gene expression levels are shown in different colour shades and graphically displayed in designed temporal pathways. To enhance importance of functional relationships of clustered genes, representative GO terms associated with differentially expressed gene cluster are visually illustrated in a tag cloud representation. PMID- 24067414 TI - Gaussian graphical model for identifying significantly responsive regulatory networks from time course high-throughput data. AB - With rapid accumulation of functional relationships between biological molecules, knowledge-based networks have been constructed and stocked in many databases. These networks provide curated and comprehensive information for functional linkages among genes and proteins, whereas their activities are highly related with specific phenotypes and conditions. To evaluate a knowledge-based network in a specific condition, the consistency between its structure and conditionally specific gene expression profiling data are an important criterion. In this study, the authors propose a Gaussian graphical model to evaluate the documented regulatory networks by the consistency between network architectures and time course gene expression profiles. They derive a dynamic Bayesian network model to evaluate gene regulatory networks in both simulated and true time course microarray data. The regulatory networks are evaluated by matching network structure with gene expression to achieve consistency measurement. To demonstrate the effectiveness of the authors method, they identify significant regulatory networks in response to the time course of circadian rhythm. The knowledge-based networks are screened and ranked by their structural consistencies with dynamic gene expression profiling. PMID- 24067415 TI - Wright-Fisher dynamics on adaptive landscape. AB - Adaptive landscape, proposed by Sewall Wright, has provided a conceptual framework to describe dynamical behaviours. However, it is still a challenge to explicitly construct such a landscape, and apply it to quantify interesting evolutionary processes. This is particularly true for neutral evolution. In this work, the authors study one-dimensional Wright Fisher process, and analytically obtain an adaptive landscape as a potential function. They provide the complete characterisation for dynamical behaviours of all possible mutation rates under the influence of mutation and random drift. This same analysis has been applied to situations with additive selection and random drift for all possible selection rates. The critical state dividing the basins of two stable states is directly obtained by the landscape. In addition, the landscape is able to handle situations with pure random drift, which would be non-normalisable for its stationary distribution. The nature of non-normalisation is from the singularity of adaptive landscape. In addition, they propose a new type of neutral evolution. It has the same probability for all possible states. The new type of neutral evolution describes the non-neutral alleles with 0%. They take the equal effect of mutation and random drift as an example. PMID- 24067416 TI - Latent factor analysis facilitates modelling of oncogenic genes for colon adenocarcinoma. AB - Identification of oncogenic genes from a large sample number of genomic data is a challenge. In this study, a well-established latent factor model, Bayesian factor and regression model, are applied to predict unknown colon cancer related genes from colon adenocarcinoma genomic data. Four important latent factors were addressed by the latent factor model, focusing on characterisation of heterogeneity of expression patterns of specific oncogenic genes by using microarray data of 174 colon cancer patients. Based on the fact that variables included in the same latent factor have some common characteristics and known cancer related genes in Online Mendelian Inheritance in Man, the authors found that the four latent factors can be employed to predict unknown colon cancer related genes that were never reported in the literature. The authors validated 15 identified genes by checking their somatic mutations of the same patients from DNA sequencing data. PMID- 24067417 TI - Construction and analysis of single nucleotide polymorphism-single nucleotide polymorphism interaction networks. AB - The study of gene regulatory network and protein-protein interaction network is believed to be fundamental to the understanding of molecular processes and functions in systems biology. In this study, the authors are interested in single nucleotide polymorphism (SNP) level and construct SNP-SNP interaction network to understand genetic characters and pathogenetic mechanisms of complex diseases. The authors employ existing methods to mine, model and evaluate a SNP sub-network from SNP-SNP interactions. In the study, the authors employ the two SNP datasets: Parkinson disease and coronary artery disease to demonstrate the procedure of construction and analysis of SNP-SNP interaction networks. Experimental results are reported to demonstrate the procedure of construction and analysis of such SNP-SNP interaction networks can recover some existing biological results and related disease genes. PMID- 24067418 TI - Small RNA-mediated switch-like regulation in bacterial quorum sensing. AB - Quorum sensing (QS) is a signalling mechanism by which bacteria produce, release and then detect and respond to changes in their density and biosignals called autoinducers (AIs). There are multiple feedback loops in the QS system of Vibrio harveyi. However, how these feedback loops function to control signal processing remains unclear. In this study, the authors present a computational model for the switch-like regulation of signal transduction by small regulatory RNA-mediated QS based on intertwined network involving AIs, LuxO, LuxU, Qrr sRNAs and LuxR. In agreement with experimental observations, the model suggests that different feedbacks play critical roles in the switch-like regulation. The authors results reveal that V. harveyi uses multiple feedbacks to precisely control signal transduction. PMID- 24067419 TI - Drug repositioning framework by incorporating functional information. AB - As a shortcut for drug development, drug repositioning draws more and more attention in pharmaceutical industry to identify new indications for marketed drugs or drugs failed in late clinical trial phase. At the same time, the abundant high-throughput data pushes the computationally repositioning drugs a hot topic in the area of systems biology. Here, the authors propose a general framework for repositioning drug by incorporating various functional information. The framework starts with the identification of differentially expressed gene sets under disease state and drug treatment. Then the disease and drug are associated by the overlap of these two gene sets via biological function. The authors provide two strategies to assess the functional overlap. In the first strategy, functional relevance are evaluated by leveraging genes' lethality information to reveal drug's potential of curing diseases. In the second strategy, biological process perturbation profiles are identified by mapping differentially expressed genes into pathways and gene ontology (GO) terms. Their associations are assessed and used to rank drugs' potential of curing diseases. The preliminary results on prostate cancer demonstrate that our new framework improves the drug repositioning efficiency and various function information could complement each other. Importantly, the new framework will enhance the biological interpretation and rationale of drug repositioning and provide insights into drug action mechanisms. PMID- 24067420 TI - Gene regulatory network discovery using pairwise Granger causality. AB - Discovery of gene regulatory network from gene expression data can yield a useful insight to drug development. Among the methods applied to time-series data, Granger causality (GC) has emerged as a powerful tool with several merits. Since gene expression data usually have a much larger number of genes than time points therefore a full model cannot be applied in a straightforward manner, GC is often applied to genes pair wisely. In this study, the authors first investigate with synthetic data how spurious causalities (false discoveries) may arise because of the use of pairwise rather than full-model GC detection. Furthermore, spurious causalities may also arise if the order of the vector autoregressive model is not high enough. As a remedy, the authors demonstrate that model validation techniques can effectively reduce the number of false discoveries. Then, they apply pairwise GC with model validation to the real human HeLa cell-cycle dataset. They find that Akaike information criterion is generally most suitable for determining model order, but precaution should be taken for extremely short time series. With the authors proposed implementation, degree distributions and network hubs are obtained and compared with existing results, giving a new observation that the hubs tend to act as sources rather than receivers of interactions. PMID- 24067421 TI - Analysis and simulation of an Adefovir anti-hepatitis B virus infection therapy immune model with alanine aminotransferase. AB - Hepatitis B virus (HBV) infection models and anti-HBV infection therapy models have been set up to understand and explain clinical phenomena. Many of these models have been proposed based on Zeuzem et al. and Nowak et al.'s basic virus infection model (BVIM). Some references have pointed out that the basic infection reproductive number of the BVIM is biologically questionable and gave the modified models with standard mass action incidences. This study describes one anti-HBV therapy immune model with alanine aminotransferase (ALT) based on standard mass action incidences. There are two basic infection reproductive numbers R0 and R1 in the model. It is proved that if R0 < 1 and R1 < 1, the disease free equilibrium is locally and globally asymptotically stable, respectively. For the endemic equilibrium, simulation shows that if R1 > 1, it may be also globally asymptotically stable. Simulations based on clinical data of HBV DNA and ALT can explain some clinical phenomena. Simulations of the correlation between liver cells, HBV DNA, cytotoxic T lymphocytes and ALT are also given. PMID- 24067422 TI - M-matrix-based stability conditions for genetic regulatory networks with time varying delays and noise perturbations. AB - Stability is essential for designing and controlling any dynamic systems. Recently, the stability of genetic regulatory networks has been widely studied by employing linear matrix inequality (LMI) approach, which results in checking the existence of feasible solutions to high-dimensional LMIs. In the previous study, the authors present several stability conditions for genetic regulatory networks with time-varying delays, based on M-matrix theory and using the non-smooth Lyapunov function, which results in determining whether a low-dimensional matrix is a non-singular M-matrix. However, the previous approach cannot be applied to analyse the stability of genetic regulatory networks with noise perturbations. Here, the authors design a smooth Lyapunov function quadratic in state variables and employ M-matrix theory to derive new stability conditions for genetic regulatory networks with time-varying delays. Theoretically, these conditions are less conservative than existing ones in some genetic regulatory networks. Then the results are extended to genetic regulatory networks with time-varying delays and noise perturbations. For genetic regulatory networks with n genes and n proteins, the derived conditions are to check if an n * n matrix is a non singular M-matrix. To further present the new theories proposed in this study, three example regulatory networks are analysed. PMID- 24067423 TI - Clustering based on multiple biological information: approach for predicting protein complexes. AB - Protein complexes are a cornerstone of many biological processes. Protein-protein interaction (PPI) data enable a number of computational methods for predicting protein complexes. However, the insufficiency of the PPI data significantly lowers the accuracy of computational methods. In the current work, the authors develop a novel method named clustering based on multiple biological information (CMBI) to discover protein complexes via the integration of multiple biological resources including gene expression profiles, essential protein information and PPI data. First, CMBI defines the functional similarity of each pair of interacting proteins based on the edge-clustering coefficient and the Pearson correlation coefficient. Second, CMBI selects essential proteins as seeds to build the protein complexes. A redundancy-filtering procedure is performed to eliminate redundant complexes. In addition to the essential proteins, CMBI also uses other proteins as seeds to expand protein complexes. To check the performance of CMBI, the authors compare the complexes discovered by CMBI with the ones found by other techniques by matching the predicted complexes against the reference complexes. The authors use subsequently GO::TermFinder to analyse the complexes predicted by various methods. Finally, the effect of parameters T and R is investigated. The results from GO functional enrichment and matching analyses show that CMBI performs significantly better than the state-of-the-art methods. PMID- 24067424 TI - Concordant effects of aromatase inhibitors on gene expression in ER+ Rat and human mammary cancers and modulation of the proteins coded by these genes. AB - Aromatase inhibitors are effective in therapy/prevention of estrogen receptor positive (ER+) breast cancers. Rats bearing methylnitrosourea (MNU)-induced ER+ mammary cancers were treated with the aromatase inhibitor vorozole (1.25 mg/kg BW/day) for five days. RNA expression showed 162 downregulated and 180 upregulated (P < 0.05 and fold change >1.5) genes. Genes modulated by vorozole were compared with published data from four clinical neoadjuvant trials using aromatase inhibitors (anastrozole or letrozole). More than 30 genes and multiple pathways exhibited synchronous changes in animal and human datasets. Cell-cycle genes related to chromosome condensation in prometaphase [anaphase-prometaphase complex (APC) pathway, including Aurora-A kinase, BUBR1B, TOP2, cyclin A, cyclin B CDC2, and TPX-2)] were downregulated in animal and human studies reflecting the strong antiproliferative effects of aromatase inhibitors. Comparisons of rat arrays with a cell culture study where estrogen was removed from MCF-7 cells showed decreased expression of E2F1-modulated genes as a major altered pathway. Alterations of the cell cycle and E2F-related genes were confirmed in a large independent set of human samples (81 pairs baseline and two weeks anastrozole treatment). Decreases in proliferation-related genes were confirmed at the protein level for cyclin A2, BuRB1, cdc2, Pttg, and TPX-2. Interestingly, the proteins downregulated in tumors were similarly downregulated in vorozole-treated normal rat mammary epithelium. Finally, decreased expression of known estrogen responsive genes (including TFF, 1,3, progesterone receptor, etc.) were decreased in the animal model. These studies demonstrate that gene expression changes (pathways and individual genes) are similar in humans and the rat model. PMID- 24067428 TI - Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock. AB - Multiple experimental and human trials have shown that microcirculatory alterations are frequent in sepsis. In this review, we discuss the various mechanisms that are potentially involved in their development and the implications of these alterations. Endothelial dysfunction, impaired inter-cell communication, altered glycocalyx, adhesion and rolling of white blood cells and platelets, and altered red blood cell deformability are the main mechanisms involved in the development of these alterations. Microcirculatory alterations increase the diffusion distance for oxygen and, due to the heterogeneity of microcirculatory perfusion in sepsis, may promote development of areas of tissue hypoxia in close vicinity to well-oxygenated zones. The severity of microvascular alterations is associated with organ dysfunction and mortality. At this stage, therapies to specifically target the microcirculation are still being investigated. PMID- 24067429 TI - Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir. AB - Plasma concentrations of orally administered methadone are reduced by the human immunodeficiency virus protease inhibitor combination ritonavir and lopinavir, but the mechanism is unknown. Methadone metabolism, clearance, and drug interactions have been attributed to CYP3A4, but this remains controversial. This investigation assessed the effects of acute (2 days) and steady-state (2 weeks) ritonavir-lopinavir on intravenous and oral methadone metabolism and clearance, hepatic and intestinal CYP3A4/5 activity (using the probe substrate intravenous and oral alfentanil), and intestinal transporter activity (using oral fexofenadine) in healthy volunteers. Plasma and urine concentrations of methadone and metabolite enantiomers, and other analytes, were determined by mass spectrometry. Acute and chronic ritonavir-lopinavir reduced plasma methadone enantiomer concentrations in half, with an average 2.6- and 1.5-fold induction of systemic and apparent oral methadone clearances. Induction was attributable to stereoselectively increased hepatic methadone N-demethylation, hepatic extraction, and hepatic clearance, and there was a strong correlation between methadone N-demethylation and clearance. Methadone renal clearance was unchanged. Alfentanil's systemic clearance and hepatic extraction, apparent oral clearance, and intestinal extraction were reduced to 25%, 16%, and 35% of control, indicating strong inhibition of hepatic and intestinal CYP3A activities. Ritonavir-lopinavir (acute > chronic) increased fexofenadine exposure, suggesting intestinal P-glycoprotein inhibition. No correlation was found between methadone clearance and CYP3A activity. Acute and steady-state ritonavir-lopinavir stereoselectively induced methadone N-demethylation and clearance, despite significant inhibition of hepatic and intestinal CYP3A activity. Ritonavir lopinavir inhibited intestinal transporters activity but had no effect on methadone bioavailability. These results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose methadone disposition. PMID- 24067430 TI - Toward a working definition of C3 glomerulopathy by immunofluorescence. AB - Precise immunofluorescence criteria for C3 glomerulopathy remain to be defined. Here we tested hierarchical immunofluorescence criteria with varying stringency for C3 glomerulopathy in a cohort with dense deposit disease as the gold standard and then applied these criteria to analyze the incidence of C3 glomerulopathy in membranoproliferative glomerulonephritis (MPGN) types 1 and 3. Among 319 archived cases of primary MPGN types 1-3, immunofluorescence reports were retrospectively coded as glomerular deposits of the following: C3 only; C3 dominant with trace or 1+ immunoglobulin (Ig)M only; and C3 dominant and at least two orders of intensity stronger than any combination of IgG, IgM, IgA, and C1q. The most restrictive criteria of 'C3 only' captured only half of the cases with dense deposit disease (compared with 8% of type 1 and 10% of type 3). Adding the most liberal definition identified 88% of those with dense deposit disease (compared with 31% of type 1 and 39% of type 3). The unaccounted 12% had stronger intensity of Ig staining, but it never exceeded the intensity of C3. Among MPGN type 3, 90% of C3 glomerulopathy cases were the Strife and Anders variant. Repeat biopsies in C3 glomerulopathy revealed a change in immunofluorescence pattern in 10 of 23 biopsies. The prevalence of low serum C3 and/or low C4 did not significantly differ among the three immunofluorescence criteria. Thus, 'C3 only' is an impractical definition of C3 glomerulopathy, and we propose a definition of C3 dominant and at least two orders of magnitude more intense than any other immune reactant, which requires validation by alternative pathway evaluation. These criteria provide a framework for identifying patients most likely to benefit from investigations of alternative complement pathway dysregulation. PMID- 24067431 TI - Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. AB - In patients with diabetes, glycemic improvement by sodium-glucose cotransporter-2 inhibition depends on the kidney's ability to filter glucose. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces hyperglycemia in patients with diabetes and normal or mildly impaired renal function. In this randomized, double blind, placebo-controlled study we assessed daily treatment with dapagliflozin in 252 patients with inadequately controlled type 2 diabetes and moderate renal impairment. The primary endpoint, the mean change in HbA1c, was not statistically different from placebo after 24 weeks (-0.41% and -0.44% for 5- and 10-mg doses, respectively, and -0.32% for placebo). The mean weight change from baseline was 1.54 and -1.89 kg for the 5- and 10-mg doses, respectively, and +0.21 kg for placebo. The mean systolic and diastolic blood pressure decreased in the dapagliflozin groups compared to placebo. Through 104 weeks, 13 patients receiving dapagliflozin and no patients receiving placebo experienced bone fracture. At 1 week, the mean serum creatinine increased with dapagliflozin 5 mg (+0.13 mg/dl) and 10 mg (+0.18 mg/dl) and did not change further after 104 weeks. Mean serum electrolytes did not change in any group, and there were fewer episodes of hyperkalemia with dapagliflozin than placebo. Thus, in patients with moderate renal impairment, dapagliflozin did not improve glycemic control, but reduced weight and blood pressure. PMID- 24067432 TI - Comparison of fluid volume estimates in chronic hemodialysis patients by bioimpedance, direct isotopic, and dilution methods. AB - Bioimpedance analysis (BIA) is accepted for the assessment of total-body water (TBW), intracellular fluid (ICF) and extracellular fluid (ECF). We aimed to compare precision and accuracy of single and multi-frequency-BIA to direct estimation methods (DEMs) of TBW, ECF, and ICF in hemodialysis patients. Linear regression analysis of volume estimates in 49 patients by single- and multi frequency-BIA correlated significantly with DEMs. Bland-Altman analysis (BAA) found systemic bias for ECF single-frequency-BIA vs. ECF-DEMs. No other systematic biases were found. Proportional errors were found by BAA of ICF and ECF assessments with single- and multi-frequency bioimpedance spectroscopy compared to the DEMs. Comparisons of indirect methods (IEMs) to DEMs showed no significant differences and proportional errors. Root mean-squared-error analysis suggested slightly better accuracy and precision of ICF single-frequency-BIA vs. DEMs over ICF multi-frequency-BIA and IEMs to DEMs, and slightly better performance for ECF multi-frequency-BIA over both respective other methods. Compared to DEMs, there is slightly better accuracy for ECF multi- over single frequency-BIA and ICF single- over multi-frequency-BIA. However the margin of differences between direct and indirect methods suggests that none of the analyzed methods served as a true "gold standard", because indirect methods are almost equally precise compared to DEMs. PMID- 24067434 TI - A novel CFHR5 fusion protein causes C3 glomerulopathy in a family without Cypriot ancestry. AB - C3 glomerulopathy describes glomerular pathology associated with predominant deposition of complement C3 including dense deposit disease and C3 glomerulonephritis. Familial C3 glomerulonephritis has been associated with rearrangements affecting the complement factor H-related (CFHR) genes. These include a hybrid CFHR3-1 gene and an internal duplication within the CFHR5 gene. CFHR5 nephropathy, to date, occurred exclusively in patients with Cypriot ancestry, and is associated with a heterozygous internal duplication of the CFHR5 gene resulting in duplication of the exons encoding the first two domains of the CFHR5 protein. Affected individuals possess both the wild-type nine-domain CFHR5 protein (CFHR5(12-9)) and an abnormally large mutant CFHR5 protein in which the initial two protein domains are duplicated (CFHR5(1212-9)). We found CFHR5(1212 9) in association with familial C3 glomerulonephritis in a family without Cypriot ancestry. The genomic rearrangement was distinct from that seen in Cypriot CFHR5 nephropathy. Our findings strengthen the association between CFHR5(1212-9) and familial C3 glomerulonephritis and recommend screening for CFHR5(1212-9) in patients with C3 glomerulopathy irrespective of ethnicity. Since CFHR5(1212-9) can result from at least two genomic rearrangements, screening is most readily achieved through analysis of CFHR5 protein. PMID- 24067433 TI - New magnetic resonance imaging methods in nephrology. AB - Established as a method to study anatomic changes, such as renal tumors or atherosclerotic vascular disease, magnetic resonance imaging (MRI) to interrogate renal function has only recently begun to come of age. In this review, we briefly introduce some of the most important MRI techniques for renal functional imaging, and then review current findings on their use for diagnosis and monitoring of major kidney diseases. Specific applications include renovascular disease, diabetic nephropathy, renal transplants, renal masses, acute kidney injury, and pediatric anomalies. With this review, we hope to encourage more collaboration between nephrologists and radiologists to accelerate the development and application of modern MRI tools in nephrology clinics. PMID- 24067435 TI - Educational programs improve the preparation for dialysis and survival of patients with chronic kidney disease. AB - Preparation for end-stage renal disease (ESRD) is widely acknowledged to be suboptimal in the United States. We sought to determine whether participation in a kidney disease screening and education program resulted in improved ESRD preparation and survival in 595 adults who developed ESRD after participating in the National Kidney Foundation Kidney Early Evaluation Program (KEEP), a community-based screening and education program. Non-KEEP patients were selected from a national ESRD registry and matched to KEEP participants based on demographic and clinical characteristics. The main outcomes were pre-ESRD nephrologist care, placement of permanent vascular access, use of peritoneal dialysis, pre-emptive transplant wait listing, transplantation, and mortality after ESRD. Participation in KEEP was associated with significantly higher rates of pre-ESRD nephrologist care (76.0% vs. 69.3%), peritoneal dialysis (10.3% vs. 6.4%), pre-emptive transplant wait listing (24.2% vs. 17.1%), and transplantation (9.7% vs. 6.4%) but not with higher rates of permanent vascular access (23.4% vs. 20.1%). Participation in KEEP was associated with a lower risk for mortality (hazard ratio 0.80), but this was not statistically significant after adjusting for ESRD preparation. Thus, participation in a voluntary community kidney disease screening and education program was associated with higher rates of ESRD preparation and survival. PMID- 24067436 TI - Reading between the (guide)lines--the KDIGO practice guideline on acute kidney injury in the individual patient. AB - The KDIGO guidelines for acute kidney injury (AKI) are designed to assist health care providers around the world in managing patients with AKI. Clinical guidelines are intended to help the clinician make an informed decision based on review of the currently available evidence. Due to the generic nature of guidelines, it is sometimes difficult to translate a guideline for a particular individual patient who may have specific clinical circumstances. To illustrate this point, we have discussed the interpretation of the KDIGO guideline in patients who have subtleties in their clinical presentation, which may make treatment decisions less than straightforward. PMID- 24067437 TI - Age, kidney function, and risk factors associate differently with cortical and medullary volumes of the kidney. AB - The kidney atrophies in patients with advanced chronic kidney disease (CKD) but factors influencing kidney size in normal adults are less clear. To help define this, we measured kidney volumes on contrast-enhanced computed tomographic images from 1344 potential kidney donors (aged 18-75 years). Cortical volume per body surface area progressively declined in both genders with increased age. Statistically, this was primarily dependent on the age-related decline in glomerular filtration rate (GFR). Independent predictors of increased cortical volume per body surface area were male gender, increased GFR, increased 24-h urine albumin, current smoker, and decreased high-density lipid cholesterol. Medullary volume per body surface area increased with age in men, while it increased with age in women until the age of 50 years followed by a subsequent decline. Independent predictors of increased medullary volume per body surface area were older age, male gender, increased GFR, increased 24-h urine albumin, increased serum glucose, and decreased serum uric acid. Thus, while cortical volume declines with age along the same biological pathway as the age-related decline in GFR, albuminuria and some risk factors are actually associated with increased cortical or medullary volume among relatively healthy adults. Underlying hypertrophy or atrophy of different nephron regions may explain these findings. PMID- 24067438 TI - Identification of IGFBP-7 by urinary proteomics as a novel prognostic marker in early acute kidney injury. AB - Early diagnosis of acute kidney injury (AKI) and accurate prognostic stratification is a prerequisite for optimal medical management. To identify novel prognostic markers of AKI, urine was collected on the first day of AKI in critically ill patients. Twelve patients with early recovery and 12 matching patients with late/non-recovery were selected and their proteome analyzed by gel electrophoresis and mass spectrometry. We identified eight prognostic candidates including alpha-1 microglobulin, alpha-1 antitrypsin, apolipoprotein D, calreticulin, cathepsin D, CD59, insulin-like growth factor-binding protein 7 (IGFBP-7), and neutrophil gelatinase-associated lipocalin (NGAL). Subsequent quantification by ELISA showed that IGFBP-7 was the most potent predictor of renal recovery. IGFBP-7 and NGAL were then chosen for further analyses in an independent verification group of 28 patients with and 12 control patients without AKI. IGFBP-7 and NGAL discriminated between early and late/non-recovery patients and patients with and without AKI. Significant upregulation of the urinary markers predicted mortality (IGFBP-7: AUC 0.68; NGAL: AUC 0.81), recovery (IGFBP-7: AUC 0.74; NGAL: AUC 0.70), and severity of AKI (IGFBP-7: AUC 0.77; NGAL: AUC 0.69), and were associated with the duration of AKI. IGFBP-7 was a more accurate predictor of renal outcome than NGAL. Thus, IGFBP-7 is a novel prognostic urinary marker that warrants further investigation. PMID- 24067439 TI - Expression patterns of RelA and c-mip are associated with different glomerular diseases following anti-VEGF therapy. AB - Renal toxicity constitutes a dose-limiting side effect of anticancer therapies targeting vascular endothelial growth factor (VEGF). In order to study this further, we followed up 29 patients receiving this treatment, who experienced proteinuria, hypertension, and/or renal insufficiency. Eight developed minimal change nephropathy/focal segmental glomerulopathy (MCN/FSG)-like lesions and 13 developed thrombotic microangiopathy (TMA). Patients receiving receptor tyrosine kinase inhibitors (RTKIs) mainly developed MCN/FSG-like lesions, whereas TMA complicated anti-VEGF therapy. There were no mutations in factor H, factor I, or membrane cofactor protein of the complement alternative pathway, while plasma ADAMTS13 activity persisted and anti-ADAMTS13 antibodies were undetectable in patients with TMA. Glomerular VEGF expression was undetectable in TMA and decreased in MCN/FSG. Glomeruli from patients with TMA displayed a high abundance of RelA in endothelial cells and in the podocyte nuclei, but c-mip was not detected. Conversely, MCN/FSG-like lesions exhibited a high abundance of c-mip, whereas RelA was scarcely detected. RelA binds in vivo to the c-mip promoter and prevents its transcriptional activation, whereas RelA knockdown releases c-mip activation. The RTKI sorafenib inhibited RelA activity, which then promoted c-mip expression. Thus, our results suggest that c-mip and RelA define two distinct types of renal damage associated with VEGF-targeted therapies. PMID- 24067440 TI - Capturing drug responses by quantitative promoter activity profiling. AB - Quantitative analysis of cellular responses to drugs is of major interest in pharmaceutical research. Microarray technologies have been widely used for monitoring genome-wide expression changes. However, this approach has several limitations in terms of coverage of targeted RNAs, sensitivity, and quantitativeness, which are crucial for accurate monitoring of cellular responses. In this article, we report an application of genome-wide and quantitative profiling of cellular responses to drugs. We monitored promoter activities in MCF-7 cells by Cap Analysis of Gene Expression using a single molecule sequencer. We identified a distinct set of promoters affected even by subtle inhibition of the Ras-ERK and phosphatidylinositol-3-kinase-Akt signal transduction pathways. Furthermore, we succeeded in explaining the majority of promoter responses to inhibition of the upstream epidermal growth factor receptor kinase quantitatively based on the promoter profiles upon inhibition of the two individual downstream signaling pathways. Our results demonstrate unexplored utility of highly quantitative promoter activity profiling in drug research.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e77; doi:10.1038/psp.2013.53; published online 25 September 2013. PMID- 24067441 TI - Temporal and farm-management-associated variation in faecal-pat prevalence of Campylobacter fetus in sheep and cattle. AB - SUMMARY: The faecal-pat prevalence (as estimated by culture) of Campylobacter fetus from cattle and sheep on 19 farms in rural Lancashire was investigated using standard Campylobacter culture techniques and PCR during a 2-year longitudinal study. C. fetus was isolated from 9.48% [95% confidence interval (CI) 8.48-10.48] of cattle faecal pats and 7.29% (95% CI 6.21-9.62) of sheep faecal pats. There was evidence of significant differences in shedding prevalence between geographical regions; cows in geographical zone 3 had an increased risk of shedding C. fetus compared to cows in geographical zones 1 and 2 (OR 6.64, 95% CI 1.67-26.5, P = 0.007), as did cows at pasture (OR 1.66, 95% CI 1.01-2.73, P = 0.046) compared to when housed. Multiple logistic regression modelling demonstrated underlying seasonal periodicity in both species. PMID- 24067442 TI - Post-mesozoic rapid increase of seawater Mg/Ca due to enhanced mantle-seawater interaction. AB - The seawater Mg/Ca ratio increased significantly from ~ 80 Ma to present, as suggested by studies of carbonate veins in oceanic basalts and of fluid inclusions in halite. We show here that reactions of mantle-derived peridotites with seawater along slow spreading mid-ocean ridges contributed to the post Cretaceous Mg/Ca increase. These reactions can release to modern seawater up to 20% of the yearly Mg river input. However, no significant peridotite-seawater interaction and Mg-release to the ocean occur in fast spreading, East Pacific Rise-type ridges. The Mesozoic Pangean superocean implies a hot fast spreading ridge system. This prevented peridotite-seawater interaction and Mg release to the Mesozoic ocean, but favored hydrothermal Mg capture and Ca release by the basaltic crust, resulting in a low seawater Mg/Ca ratio. Continent dispersal and development of slow spreading ridges allowed Mg release to the ocean by peridotite-seawater reactions, contributing to the increase of the Mg/Ca ratio of post-Mesozoic seawater. PMID- 24067443 TI - The effect of antiphase boundaries on the elastic properties of Ni-Mn-Ga austenite and premartensite. AB - The evolution of elastic properties with temperature and magnetic field was studied in two differently heat-treated single crystals of the Ni-Mn-Ga magnetic shape memory alloy using resonant ultrasound spectroscopy. Quenching and slow furnace cooling were used to obtain different densities of antiphase boundaries. We found that the crystals exhibited pronounced differences in the c' elastic coefficient and related shear damping in high-temperature ferromagnetic phases (austenite and premartensite). The difference can be ascribed to the formation of fine magnetic domain patterns and pinning of the magnetic domain walls on antiphase boundaries in the material with a high density of antiphase boundaries due to quenching. The fine domain pattern arising from mutual interactions between antiphase boundaries and ferromagnetic domain walls effectively reduces the magnetocrystalline anisotropy and amplifies the contribution of magnetostriction to the elastic response of the material. As a result, the anomalous elastic softening prior to martensite transformation is significantly enhanced in the quenched sample. Thus, for any comparison of experimental data and theoretical calculations the microstructural changes induced by specific heat treatment must be taken into account. PMID- 24067445 TI - Is expert opinion enough? A critical assessment of the evidence for potential impacts of climate change on tick-borne diseases. AB - Before attributing cause and consequence to climate change, the precise patterns of change must be known. Ground records across much of Europe show a 1-2 degrees C rise in temperatures in 1989 with no significant rise since then. The timing and spatial uniformity of this pattern, relative to changes in the distribution and incidence of many vector-borne diseases, are sufficient to falsify most simple claims that climate change is the principal cause of disease emergence. Furthermore, age-specific increases in incidence indicate causes other than, or in addition to, climate change. Unfortunately, many public health professionals repeat the received wisdom that climate change is worsening the burden of indirectly transmitted infections; this 'expert opinion' soon becomes consensus dogma divorced from quantitative evidence. The pressing need is to gather appropriate data to test the simple concept that the composition and relative importance of disparate multifactorial factors, commonly integrated within a causal nexus, will inevitably vary with the geographical, cultural, socio economical, wildlife, etc. context. The greatest impact of warming occurs at the geographical limits of current distributions, where low temperatures limit the hazard of infected vectors. Within core endemic regions, changing exposure of humans to this hazard, through changing socio-economic factors is evidently more important amongst both the poor and the wealthy. PMID- 24067446 TI - The CCHamide 1 receptor modulates sensory perception and olfactory behavior in starved Drosophila. AB - The olfactory response of the vinegar fly Drosophila melanogaster to food odor is modulated by starvation. Here we show that this modulation is not restricted to food odors and their detecting sensory neurons but rather increases the behavioral response to odors as different as food odors, repellents and pheromones. The increased behavioral responsiveness is paralleled by an increased physiological sensitivity of sensory neurons regardless whether they express olfactory or ionotropic receptors and regardless whether they are housed in basiconic, coeloconic, or trichoid sensilla. Silencing several genes that become up-regulated under starvation confirmed the involvement of the short neuropeptide f receptor in the starvation effect. In addition it revealed that the CCHamide-1 receptor is another important factor governing starvation-induced olfactory modifications. PMID- 24067447 TI - Microbiological and abiotic processes in modelling longer-term marine corrosion of steel. AB - Longer term exposure of mild steel in natural (biotic) waters progresses as a bimodal function of time, both for corrosion mass loss and for pit depth. Recent test results, however, found this also for immersion in clean fresh, almost pure and triply distilled waters. This shows chlorides or microbiological activity is not essential for the electrochemical processes producing bimodal behaviour. It is proposed that the first mode is aerobic corrosion that eventually produces a non-homogeneous corroded surface and rust coverage sufficient to allow formation of anoxic niches. Within these, aggressive autocatalytic reduction then occurs under anoxic abiotic conditions, caused by sulfide species originating from the MnS inclusions typical in steels. This is consistent with Wranglen's model for abiotic anoxic crevice and pitting corrosion without external aggressive ions. In biotic conditions, metabolites from anaerobic bacterial activity within and near the anoxic niches provides additional (sulfide) species to contribute to the severity of corrosion. Limited observational evidence that supports this hypothesis is given but further investigation is required to determine all contributor(s) to the cathodic current for the electrochemical reaction. The results are important for estimating the contribution of microbiological corrosion in infrastructure applications. PMID- 24067448 TI - Synthesis of nano-scale fast ion conducting cubic Li7La3Zr2O12. AB - A solution-based process was investigated for synthesizing cubic Li7La3Zr2O12 (LLZO), which is known to exhibit the unprecedented combination of fast ionic conductivity, and stability in air and against Li. Sol-gel chemistry was developed to prepare solid metal-oxide networks consisting of 10 nm cross-links that formed the cubic LLZO phase at 600 degrees C. Sol-gel LLZO powders were sintered into 96% dense pellets using an induction hot press that applied pressure while heating. After sintering, the average LLZO grain size was 260 nm, which is 13 times smaller compared to LLZO prepared using a solid-state technique. The total ionic conductivity was 0.4 mS cm(-1) at 298 K, which is the same as solid-state synthesized LLZO. Interestingly, despite the same room temperature conductivity, the sol-gel LLZO total activation energy is 0.41 eV, which 1.6 times higher than that observed in solid-state LLZO (0.26 eV). We believe the nano-scale grain boundaries give rise to unique transport phenomena that are more sensitive to temperature when compared to the conventional solid state LLZO. PMID- 24067444 TI - Can biowarfare agents be defeated with light? AB - Biological warfare and bioterrorism is an unpleasant fact of 21st century life. Highly infectious and profoundly virulent diseases may be caused in combat personnel or in civilian populations by the appropriate dissemination of viruses, bacteria, spores, fungi, or toxins. Dissemination may be airborne, waterborne, or by contamination of food or surfaces. Countermeasures may be directed toward destroying or neutralizing the agents outside the body before infection has taken place, by destroying the agents once they have entered the body before the disease has fully developed, or by immunizing susceptible populations against the effects. A range of light-based technologies may have a role to play in biodefense countermeasures. Germicidal UV (UVC) is exceptionally active in destroying a wide range of viruses and microbial cells, and recent data suggests that UVC has high selectivity over host mammalian cells and tissues. Two UVA mediated approaches may also have roles to play; one where UVA is combined with titanium dioxide nanoparticles in a process called photocatalysis, and a second where UVA is combined with psoralens (PUVA) to produce "killed but metabolically active" microbial cells that may be particularly suitable for vaccines. Many microbial cells are surprisingly sensitive to blue light alone, and blue light can effectively destroy bacteria, fungi, and Bacillus spores and can treat wound infections. The combination of photosensitizing dyes such as porphyrins or phenothiaziniums and red light is called photodynamic therapy (PDT) or photoinactivation, and this approach cannot only kill bacteria, spores, and fungi, but also inactivate viruses and toxins. Many reports have highlighted the ability of PDT to treat infections and stimulate the host immune system. Finally pulsed (femtosecond) high power lasers have been used to inactivate pathogens with some degree of selectivity. We have pointed to some of the ways light-based technology may be used to defeat biological warfare in the future. PMID- 24067449 TI - Challenges facing human rabies control: the Lebanese experience. AB - Rabies is one of the most important zoonotic infections worldwide. The burden of the disease continues to be significant in countries in the Middle East where the most important vector is stray dogs. Control efforts are hindered by lack of awareness and incomplete post-exposure prophylaxis. The aim of this article is to re-assess the situation of rabies in Lebanon and compare it to other Middle Eastern countries. Eight cases of rabies and 5280 incidents of animal bites to humans were reported to the Lebanese Ministry of Public Health between 2001 and 2012. Dogs were the only vector of infection and were responsible for most reported animal bites to humans. An average of 3.2 doses of vaccine per bite was administered as post-exposure prophylaxis. The status of human and canine rabies control, the risks associated with children's behaviour and the hazards of secondary wild reservoirs are discussed. Our data illustrates the importance of prevention through vector control, public awareness and education, and timely administration of active and passive immunization, as well as the significance of regional cooperation and monitoring the circulation of viral variants in wild animals. PMID- 24067450 TI - Effect of freezing treatment on colostrum to prevent the transmission of bovine leukemia virus. AB - Here, we used a sheep bioassay to determine the effect of freezing colostrum to prevent the transmission of bovine leukemia virus (BLV) among neonatal calves. Leukocytes were isolated from the colostrum of a BLV-infected Holstein cow and were then either left untreated (control) or freeze-thawed. A sheep inoculated intraperitoneally with the untreated leukocytes was infected with BLV at 3 weeks after inoculation, whereas the sheep inoculated with treated leukocytes did not become infected. The uninfected sheep was inoculated again with leukocytes isolated from the colostrum of another BLV-infected Holstein cow after freezing treatment, and again it did not become infected with BLV. Finally, this sheep was inoculated with the leukocytes isolated from the colostrum of another virus infected cow without freezing treatment, and it became infected with BLV at 4 weeks after inoculation. The results indicate that colostrum should be frozen as a useful means of inactivating the infectivity of BLV-infected lymphocytes. PMID- 24067451 TI - Iron acquisition by Mycobacterium tuberculosis residing within myeloid dendritic cells. AB - The pathophysiology of Mycobacterium tuberculosis (M.tb) infection is linked to the ability of the organism to grow within macrophages. Lung myeloid dendritic cells are a newly recognized reservoir of M.tb during infection. Iron (Fe) acquisition is critical for M.tb growth. In vivo, extracellular Fe is chelated to transferrin (TF) and lactoferrin (LF). We previously reported that M.tb replicating in human monocyte-dervied macrophages (MDM) can acquire Fe bound to TF, LF, and citrate, as well as from the MDM cytoplasm. Access of M.tb to Fe may influence its growth in macrophages and dendritic cells. In the present work we confirmed the ability of different strains of M.tb to grow in human myeloid dendritic cells in vitro. Fe acquired by M.tb replicating within dendritic cells from externally added Fe chelates varied with the Fe chelate present in the external media: Fe-citrate > Fe-LF > Fe-TF. Fe acquisition rates from each chelate did not vary over 7 days. M.tb within dendritic cells also acquired Fe from the dendritic cell cytoplasm, with the efficiency of Fe acquisition greater from cytoplasmic Fe sources, regardless of the initial Fe chelate from which that cytoplasmic Fe was derived. Growth and Fe acquisition results with human MDM were similar to those with dendritic cells. M.tb grow and replicate within myeloid dendritic cells in vitro. Fe metabolism of M.tb growing in either MDM or dendritic cells in vitro is influenced by the nature of Fe available and the organism appears to preferentially access cytoplasmic rather than extracellular Fe sources. Whether these in vitro data extend to in vivo conditions should be examined in future studies. PMID- 24067452 TI - Bacillus anthracis, virulence factors, PCR, and interpretation of results. PMID- 24067453 TI - Probing quantum discord in a Heisenberg dimer compound. AB - A quantitative estimation of quantum discord is performed for a Heisenberg spin 1/2 dimer compound (NH4CuPO4, H2O) by means of experimental magnetic and thermal measurements. Magnetic susceptibility and specific heat data were collected for NH4CuPO4, H2O and analyzed within the framework of the Heisenberg isolated dimer model. Internal energy as a function of temperature is obtained by integrating the specific heat versus temperature data. Subsequently, quantum discord, total correlations and spin-spin correlation function are quantified from susceptibility and internal energy and plotted as a function of temperature. Violation of Bell's inequality is also tested for NH4CuPO4, H2O via both experimental susceptibility and specific heat data signifying the presence of entanglement. PMID- 24067454 TI - Immunological treatments for occupational allergy. AB - Although avoidance of occupational triggers remains the primary step in the management of work-related allergies, immunological treatments (including biological agents and specific immunotherapy) can be regarded as potential therapeutic options for IgE-mediated diseases; for example, many studies with allergen-specific immunotherapy have been carried out on latex allergy, showing overall favorable results, at least with sublingual immunotherapy. On the other hand, only few case reports have suggested the efficacy of immunotherapy in baker's asthma as well as in laboratory animal-induced asthma. The new technologies, including component-resolved diagnosis and recombinant allergens, are expected to improve the quality and efficacy of specific immunotherapy in the future. Also the use of omalizumab may represent a suitable therapeutic choice in very selected cases of occupational allergy, as well as an approach to reduce side effects of venom immunotherapy in subjects with previous severe reactions to the treatment. PMID- 24067455 TI - Systemic lupus erythematosus: immunopathogenesis and novel therapeutic targets. AB - Systemic lupus erythematosus (SLE) is the prototype of autoimmune diseases with multiorgan involvement. SLE presents many genetic and epigenetic associations and the pathogenesis is characterized by a complex network of alterations affecting both adaptative and innate immunity. The disclosure of novel mechanisms of SLE pathogenesis suggested new therapeutic targets, based on interference with the cytokine pathways or on depletion of the immune cells. PMID- 24067456 TI - Impact of capsaicin on mast cell inflammation. AB - Mast cells are inflammatory cells, and they are prominent in inflammatory diseases such as allergy and asthma. Mast cells possess high-affinity receptors for IgE (FcERI) and the cross-linking of these receptors is essential to trigger the secretion of granules containing arachidonic acid metabolism (such as prostaglandin (PG) D2, leukotriene (LT) B4, and LTC4), histamine, cytokines, chemokines, and proteases, including mast cell-specific chymases and tryptases. Activation of mast cells provokes the secretion of cytokines and mediators that are responsible for the pathologic reaction of immediate hypersensitivity. Sensory nerve stimulation by irritants and other inflammatory mediators provokes the release of neuropeptides, causing an increase in vascular permeability, plasma extravasation and edema. Trigeminal nerve stimulation actives dura mast cells and increases vascular permeability, effects inhibited by capsaicin. Capsaicin causes release of sensory neuropeptide, catecholamines and vasodilation. Several studies have reported that capsaicin is effective in relief and prevention of migraine headaches, improves digestion, helps to prevent heart disease, and lowers blood cholesterol and blood pressure levels. The findings reported in these studies may have implications for the pathophysiology and possible therapy of neuroinflammatory disorders. PMID- 24067457 TI - SHH-dependent knockout of HIF-1 alpha accelerates the degenerative process in mouse intervertebral disc. AB - Hypoxia-inducible factor-1alpha (HIF-1 alpha) has been reported to have an important role in the metabolism and synthesis of extracellular matrix of the nucleus pulposus cells (NPCs) and was assumed to be involved in the process of intervertebral disc degeneration. The objective of this study was to investigate the role of HIF-1alpha in disc degeneration in vivo using a conditional HIF 1alpha knockout (KO) mouse model. ShhCre transgenic mice were mated with HIF-1 alpha fl/fl mice to generate conditional HIF-1alpha KO mice (HIF-1alpha fl/fl ShhCre+). Three mice of each genotype (Wide-type and HIF-1alpha KO) at the age of 3 days, 6, and 12 weeks were sacrificed after genotyping. Five lumbar disc samples were harvested from each mouse, with a total of 45 disc samples for each genotype. In situ hybridization and immunohistochemical analysis were used to check the efficacy of HIF-1alpha knockout. Histological grading of the disc degeneration was performed according to the classification system proposed by Boos et al. Picro-sirius red staining, Safranine O/fast green staining and immunohistochemical study were used to evaluate the expression of aggrecan, type II collagen and vascular endothelial growth factor (VEGF). Histologic analysis revealed more NPC deaths and signs of degeneration in HIF-1alpha KO mice and the degeneration scores of HIF-1alpha KO mice were significantly higher than those of the Wide-type mice at the age of 6 weeks and 12 weeks. There were less expressions of aggrecan, type-II collagen and VEGF in the intervertebral discs of HIF1-alpha KO mice than in those of wild-type mice. Taken together, the results of our study indicated that HIF-1alpha is a pivotal contributor to NPC survival and the homeotasis of extracellular matrix through the HIF-1alpha/VEGF signaling pathway, and plays an important role in the development of disc degeneration. PMID- 24067458 TI - P16INK4A immunohistochemistry for detection of human papilloma virus-associated penile squamous cell carcinoma is superior to in-situ hybridization. AB - We evaluated p16INK4A as a reliable option to detect human papilloma virus (HPV) DNA in penile tumor specimens. Formalin-fixed paraffin embedded samples of 26 patients with penile cancer and another 18 cases with non-tumorigenic lesions were stained by three different widely used commercially available chromogenic in situ hybridization assays high-risk HPV CISH Y1443 (Genpoint, DAKO), pan HPV CISH Y1404 (Genpoint, DAKO), INFORM HPV III (Ventana, Tucson, Arizona) and p16INK4A immunohistochemistry, then compared to the known gold standard polymerase chain reaction detecting HPV 16, 18, 31, and 33. Immunoreactivity for p16INK4A was evaluated by using a 4-tiered (0, 1, 2, and 3) pattern based system. 19 cases were positive for p16INK4A, 13 of which showed a continuous transepithelial staining (pattern 3). Pan HPV ISH showed positivity in 9 cases, high-risk HPV ISH in 7 cases and INFORM HPVIII ISH in 7 cases. p16INK4A IHC pattern 3 versus pattern 0, 1 and 2 exhibited a specificity and positive predictive value of 100 percent, with a sensitivity and negative predictive value of 72 and 62 percent, respectively, which was much better than all HPV in-situ hybridization methods referred to polymerase chain reaction. p16INK4A seems to be a superior marker for the detection of HPV-associated penile squamous cell carcinoma compared to CISH tests, but is not recommend for the detection of non-tumorigenic lesions, where PCR should be used for the initial assessment. PMID- 24067459 TI - Growth factors, their receptor expression and markers for proliferation of endothelial and neoplastic cells in human osteosarcoma. AB - Osteosarcoma is the most common primary malignant tumour of the bone. Although new therapies continue to be reported, osteosarcoma-related morbidity and mortality remain high. Modern medicine has greatly increased knowledge of the physiopathology of this neoplasm. Novel targets for drug development may be identified through an understanding of the normal molecular processes that are deeply modified in pathological conditions. The aim of the present study is to investigate, by immunohistochemistry, the localisation of different growth factors and of the proliferative marker Ki-67 in order to determine whether these factors are involved in the transformation of osteogenic cells and in the development of human osteosarcoma. We observed a general positivity for NGF - TrKA - NT3 - TrKC - VEGF in the cytoplasm of neoplastic cells and a strong expression for NT4 in the nuclear compartment. TGF-beta was strongly expressed in the extracellular matrix and vascular endothelium. BDNF and TrKB showed a strong immunolabeling in the extracellular matrix. Ki-67/MIB-1 was moderately expressed in the nucleus of neoplastic cells. We believe that these growth factors may be considered potential therapeutic targets in the treatment of osteosarcoma, although proof of this hypothesis requires further investigation. PMID- 24067460 TI - Sulphurous thermal water increases the release of the anti-inflammatory cytokine IL-10 and modulates antioxidant enzyme activity. AB - The beneficial effects of hot springs have been known for centuries and treatments with sulphurous thermal waters are recommended in a number of chronic pathologies as well as acute recurrent infections. However, the positive effects of the therapy are often evaluated in terms of subjective sense of wellbeing and symptomatic clinical improvements. Here, the effects of an S-based compound (NaSH) and of a specific sulphurous thermal water characterized by additional ions such as sodium chloride, bromine and iodine (STW) were investigated in terms of cytokine release and anti-oxidant enzyme activity in primary human monocytes and in saliva from 50 airway disease patients subjected to thermal treatments. In vitro, NaSH efficiently blocked the induction of pro-inflammatory cytokines and counterbalanced the formation of ROS. Despite STW not recapitulating these results, possibly due to the low concentration of S-based compounds reached at the minimum non-toxic dilution, we found that it enhanced the release of IL-10, a potent anti-inflammatory cytokine. Notably, higher levels of IL-10 were also observed in patients' saliva following STW treatment and this increase correlated positively with salivary catalase activity (r2 = 0.19, *p less than 0.01). To our knowledge, these results represent the first evidence suggesting that S-based compounds and STW may prove useful in facing chronic inflammatory and age-related illness due to combined anti-inflammatory and anti-oxidant properties. PMID- 24067461 TI - Helicobacter pylori HP(2-20) induces eosinophil activation and accumulation in superficial gastric mucosa and stimulates VEGF-alpha and TGF-beta release by interacting with formyl-peptide receptors. AB - Eosinophils participate in the immune response against Helicobacter pylori, but little is known about their role in the gastritis associated to the infection. We recently demonstrated that the Hp(2-20) peptide derived from H. pylori accelerates wound healing of gastric mucosa by interacting with N-formyl peptide receptors (FPRs) expressed on gastric epithelial cells. The aim of the present study was to investigate whether eosinophils play a role in the repair of gastric mucosa tissue during H. pylori infection. Immuno-histochemistry and transmission electron microscopy were used to detect eosinophils in gastric mucosal biopsies. Eosinophil re-distribution occurred in the gastric mucosa of H. pylori-infected patients: their density did not change in the deep mucosal layer, whereas it increased in the superficial lamina propria just below the foveolar epithelium; eosinophils entered the epithelium itself as well as the lumen of foveolae located close to the area harboring bacteria, which in turn were also engulfed by eosinophils. The H. pylori-derived peptide Hp(2-20) stimulated eosinophil migration through the engagement of FPR2 and FPR3, and also induced production of VEGF-A and TGF-beta, two key mediators of tissue remodelling. We also demonstrate that Hp(2-20) in vivo induced eosinophil infiltration in rat gastric mucosa after injury brought about by indomethacin. This study suggests that eosinophil infiltrate could modulate the capacity of gastric mucosa to maintain or recover its integrity thereby shedding light on the role of eosinophils in H. pylori infection. PMID- 24067462 TI - Assessment of host defence mechanisms induced by Candida species. AB - Some species of Candida are opportunistic pathogens that can cause disease in a host immunocompromised by underlying local or systemic pathological processes. C. albicans is the species most often associated with oral lesions, but other species of Candida, including C. glabrata, C. tropicalis and C. parapsilosis, have also been isolated in the saliva of subjects with and without candidiasis. In the present study we evaluated the host defence mechanisms induced by Candida albicans and other Candida species in monocytes and oral epithelial cells in order to establish the existence of a species-specific cellular response. Our results indicated that, during Candida species infection, the epithelial cells actively participate in the host defence by producing antimicrobial peptides and proinflammatory cytokines. Moreover, in infections caused by Candida tropicalis and Candida glabrata, the host defence may be strengthened by the release of perforin and granzyme by polymorphonuclear leukocytes recruited at the site of infection. PMID- 24067463 TI - Acute exposure to essential amino acids (EAA) activates MTOR/p70 signaling in soleus muscle of chronically EAA-treated aged rats. AB - Using an in vitro assay we assessed whether the acute exposure of soleus muscle of adult and aged rats to essential amino acid enriched mixture (EAAem) activates mTOR signaling pathway (mTOR and p70S6K) even after prolonged supplementation with the same mixture. A total of 20 adult (9 months of age at the end of treatment) and 20 aged (18 months of age at the end of treatment) male Wistar rats were used. Ten of each group were treated with EAAem (1.5 gr/kg/day in tap water) for 6 months. At the end of treatment the rats were grouped (n = 5 each group) as follows: adult (AD) and aged (AG) untreated controls; adult (AD_EAAem) and aged (AG_EAAem) chronically supplemented with EAAem; adult (AD+EAAem) and aged (AG+EAAem) acutely incubated with EAAem (soleus in 1 percent EAAem for 30 min); AD_EAAem+ and AG_EAAem+ acutely incubated with EAAem. Following treatment the activation level of mTOR and p70S6K was measured by Western blot. The basal level of mTOR and p70S6K activation appeared to be higher in AD compared with AG. In AG+EAAem a significant change in the level of p70S6K activation, unlike mTOR, was observed whereas no change was observed in AD+EAAem. In AD_EAAem muscles the basal level of p70S6K activation, unlike mTOR, was significantly lower than in AD and the acute exposure to EAAem produced a significant reduction of mTOR activation. Contrarily to AG, in AG_EAAem+ the acute exposure to EAAem produced a significant activation of mTOR, unlike p70S6K. Results in the adults indicated a higher basal level of activation and a lower responsiveness of the pathway to acute and chronic exposure to EAA-enriched mixture. On the contrary, in the aged, a lower basal level of activation was associated with a higher responsiveness to EAAem. In particular, although with a different timing, acute exposure to EAAem activated mTOR signaling even following prolonged supplementation. PMID- 24067464 TI - Association of the RANTES gene promoter polymorphisms -28C/G and -403G/A with pneumonia in Greek children. AB - Pneumonia is an inflammation of the lung caused by microbial or viral infection. It is an important factor of morbidity for children in the developed world, as well as a frequent cause of death of children in the developing world. Chemokines are a very important part of the immune system. The purpose of this study was to investigate the role of polymorphisms of chemokine RANTES (-28C/G and-403G/A) in the development of pneumonia in children. The study included two groups of children, the patient group and the control group. The patient group consisted of 60 children, who were hospitalized with the diagnosis of pneumonia from November 2009 until May 2010. The control group consisted of 135 healthy children who had no previous history of lower respiratory tract infections. According to the results, polymorphism of chemokine RANTES -28C/G was associated to the development of pneumonia in the studied population. Polymorphism of chemokine RANTES -403G/A was not associated to the development of pneumonia in the same population. Serum levels of chemokine RANTES were lower in children who were carriers of the polymorphism -28C/G compared to children who had the normal gene type. Also, serum levels of chemokine RANTES were higher in children with pneumococcal pneumonia compared to children with pneumonia caused by other pathogens. PMID- 24067465 TI - Use of Oral ChromaTM in the assessment of volatile sulfur compounds in patients with fixed protheses. AB - Prosthetic rehabilitation improves the patient's quality of life and oral health. The purpose of the present study was to assess the production of volatile sulfur compounds (VSCs) using Oral Chroma? in patients wearing provisional and permanent fixed prosthesis, who were treated or not, with supportive non-surgical periodontal therapy. A total of 10 healthy patients not affected by periodontal disease and who needed the restoration of at least two edentulous single sites were included in the present study. Registrations of VSCs were carried out with a Gas Chromatograph OralChromaTM (Oral ChromaTM, Abimedical, Abilit Corp., Osaka, Japan) one month after placement of the provisional restoration (group 1) and one month after placement of the final restoration (group 3). After each measurement, professional oral hygiene was carried out both on patients with provisional (group 2) and permanent prostheses (group 4) and VSC values were registered. The results showed that there were no statistical significant differences in the VSC quantity between groups with temporary or permanent prostheses. Meanwhile, statistically significant differences were found in VCS values between groups before and after the professional health care session (p less than 0.05). Also it was observed that dimethyl sulphide (CH3)2S was present in all the study groups. The present preliminary study suggests that OralChromaTM produce a comprehensive assessment of VSC in the clinical diagnosis of halitosis and that professional oral hygiene seems to influence VSC production. However, further clinical long term studies with a larger sample size are necessary for a better understanding of halitosis manifestation in patients wearing provisional and permanent fixed prosthesis. PMID- 24067466 TI - Bradykinin-forming components in Kuwaiti patients with type 2 diabetes. AB - Diabetes is the most common risk factor in inducing hypertension, nephropathy and retinopathy. The bradykinin (BK)-forming system has been proposed to protect cardiovascular and renal functions. We therefore evaluated urinary active and proactive kallikrein, total kininogen, plasma tissue kallikrein, plasma creatinine, plasma glucose and plasma HbA1c in newly diagnosed untreated type 2 diabetic patients and healthy subjects. In diabetic patients, urinary and plasma tissue kallikrein concentrations were significantly increased. In addition, plasma prekallikrein levels were also significantly higher. However, urinary kininogen values were significantly reduced in diabetic patients when compared with healthy subjects. This is the first investigation among Kuwaiti Arab patients with type 2 diabetes showing abnormal activities in the BK-forming system. High levels of plasma prekallikrein may be a risk factor for developing high blood pressure as well as nephropathy. The urinary and plasma tissue kallikrein concentrations were higher in diabetic patients, which could indicate the hyperactivities of these components, and may result in increased levels of plasma glucose to induce diabetes. Furthermore, the urinary kininogen levels were reduced in diabetic patients. These alterations might reflect the utilization of urinary kininogen to form BK, a potent inflammatory agent. However, this hypothesis needs further investigation. PMID- 24067467 TI - Systemic nickel allergy syndrome: nosologic framework and usefulness of diet regimen for diagnosis. AB - Systemic (gastrointestinal and skin) reactions to ingestion of nickel rich foods in patients with nickel allergic contact dermatitis characterize Systemic Nickel Allergy Syndrome (SNAS). The objective of the study was to describe the nosologic framework of the syndrome and to compare sensibility and specificity for SNAS diagnosis between two different low nickel diets - BraMa-Ni and the usually prescribed list of forbidden foods - along with patient adherence to diet. One hundred forty-five patients with suspected SNAS (by history and benefit from nickel dietary restrictions) were selected and orally challenged with nickel for a definite diagnosis. Specificity and sensibility of the diets were calculated in relation to the results of nickel challenges. The nosologic framework of SNAS was deduced from the clinical pictures of 98 patients with positive nickel challenge and characterized essentially by skin and gastrointestinal symptoms, whereas all other symptoms (dizziness, headache etc.) were never elicited by the oral nickel challenge. The specificity and sensibility of BraMa-Ni in detecting SNAS were significantly higher than the forbidden food list diet, with an excellent patient adherence. Therefore, BraMa-Ni diet can be prescribed for the treatment of the syndrome other than for the diagnosis, the gold standard of which remains the oral nickel challenge. PMID- 24067468 TI - HIV impairs CD34+-derived monocytic precursor differentiation into functional dendritic cells. AB - Dendritic cells (DCs) perform a basic role in the immune system by allowing the initiation of the primary T-cell-dependent immune response. Given previous indirect evidence that DC maturation and function are impaired by HIV, we have developed an in vitro culture system in order to verify the effect of HIV infection on DC function during the development from hematopoietic progenitors. Considering that monocytic (Mo) differentiating cells efficiently replicate monocytotropic HIV, we examined whether HIV-infected monocytic precursors (MoP) were able to generate functional DCs. CD34+ hematopoietic progenitor cells (HPCs) were induced along Mo differentiative pathway in liquid cultures and at an early stage of culture, MoP were infected with M-tropic BaL HIV strain, and after 2 days they were switched to DC differentiation with GM-CSF and IL-4. Derived DCs were actively infected, as detected by HIV-p24 production. HIV did not significantly affect cell viability, but induced a reduction in cell proliferation and an inefficient functional activity in terms of uptake capability and stimulation of allogenic T cells. These results indicate that HIV infected MoP lost the capacity to generate functional DCs, and this may represent one of the many mechanisms of immunosuppression exploited by HIV. PMID- 24067469 TI - The role of transforming growth factor-beta1 in airway inflammation of childhood asthma. AB - TGF-beta-targeting structural and inflammatory cells has been implicated in the mechanisms leading to the inflammatory and restructuring processes in asthma, suggesting an impact of TGF-beta1 signaling on the development and persistency of this disease. We investigated the potential early involvement of TGF-beta1 activity in the immunological and molecular mechanisms underlying progression of inflammation in childhood asthma. We evaluated the levels of TGF-beta1 in induced sputum supernatants (ISSs) and the expression of small mother cell against decapentaplegic (Smad) 2 and Smad7 proteins in induced sputum cells (ISCs) from children with intermittent asthma (IA), moderate asthma (MA) and control subjects (C). Furthermore, we investigated the regulatory role of TGF-beta1 activity on eosinophil and neutrophil adhesion to epithelial cells using adhesion assay, and on the granulocyte expression of adhesion molecule CD11b/CD18 Macrophage-1 antigen (MAC-1), by flow cytometry. We found that the levels of TGF-beta1 are increased in ISSs of IA and MA in comparison to C, concomitantly to the activation of intracellular signaling TGFbeta/Smads pathway in ISCs. In MA, TGF beta1 levels correlated with the number of sputum eosinophils and neutrophils. Furthermore, we showed the ability of sputum TGF-beta1 to promote eosinophil and neutrophil adhesion to epithelial cells, and to increase the expression of MAC-1 on the granulocyte surface. This study shows the activation of TGFbeta/Smad signaling pathway in the airways of children with IA and, despite the regular ICS treatment, in children with MA, and provides evidence for the contribution of TGF beta1 in the regulation of granulocyte activation and trafficking. PMID- 24067470 TI - In vitro effects of nicotine on sperm motility and bio-functional flow cytometry sperm parameters. AB - The aim of this experimental study was to evaluate the effects of nicotine on sperm motility and on non-conventional sperm parameters in vitro. Capacitated spermatozoa isolated from 10 normozoospermic, healthy, non-smoker men were evaluated. Spermatozoa were exposed to increasing concentrations of nicotine (0, 1, 10, and 100 ng/ml) for 3 and 24 hours. Progressive motility and the following non-conventional sperm parameters, evaluated by flow cytometry, were assessed: mitochondrial membrane potential, viability, phosphatidylserine externalization, late apoptosis, degree of chromatin compactness, and DNA fragmentation. Nicotine suppressed, in a concentration-dependent manner, sperm progressive motility starting from the lowest concentration used (1 ng/ml). Similarly, it reduced the percentage of viable spermatozoa and increased the number of spermatozoa in late apoptosis, with altered chromatin compactness, or DNA fragmentation already after 3 hours of incubation. These effects were observed at a concentration similar (100 ng/ml) to that found in the seminal plasma of smokers (70 ng/ml), with the exception of the effects on sperm DNA fragmentation whose significant effect was detected also at a lower concentration (10 ng/ml). Nicotine may be regarded as a noxious component of cigarette smoke on the male reproductive function. PMID- 24067472 TI - Sarcoidosis, cancer and molecular mimicry. AB - Molecular mimicry seems to be the most important factor for the heterogeneous clinical presentation and the immunopathogenesis of sarcoidosis. Molecular mimicry may occur as a result of altered activity of oncogenes. This can lead to crossed-type mediated body reactions targeting structurally similar sections or regions from the tissue homeostasis. Available data suggest that structural analogy between tissue and foreign or de novo-appearing peptides is not always reliable. Nevertheless, lack of amino acid identity between the tissue and the de novo-generated tumour antigens does not exclude the phenomenon of molecular mimicry as the major generator of sarcoidosis. There is growing evidence of the mimicry phenomena, caused not only by the similarity between the amino acids but also between the elements which connect segments in the immunological cascade and which may also be affected by external factors. Molecular mimicry may occur between two identified peptides having similar antigenic surfaces (transitory or not), in the absence of a primary homology in amino acid sequence. As far as tumour antigens are concerned, a structural analogy to the de novo-appearing tumour antigens is more likely than transitory imitation resulting from the additional interference of other physical forces. Further research should be performed to confirm, or reject, the transitory imitation thesis or hypothesis. PMID- 24067471 TI - Association of HLA-DQB1*0501 with scleroderma and its clinical features in Chinese population. AB - Specific human leukocyte antigen (HLA) DQB1 alleles confer strong susceptibility to systemic sclerosis (SSc). However, the frequencies of specific DQB1 alleles and their associations with SSc vary according to ethnicity and clinical features of SSc. The aim of this study was to profile DQB1 alleles in a Chinese population and to identify specific DQB1 alleles in association with SSc of Han Chinese. A cohort containing 213 patients with SSc and 239 gender-matched and unrelated controls was examined in the study. The HLA-DQB1 genotyping was performed with sequence-based typing (SBT) method. Exact p-values were obtained (Fisher's test) from 2x2 tables of allele counts or allele carriers and disease status. Seventeen DQB1 alleles were found in the cohort. DQB1*03:03 was the most common allele in this cohort. DQB1*05:01 was significantly increased in SSc, and was strongly associated with anti-centromere autoantibodies (ACA). Compared with SSc in other ethnic populations, SSc patients of Han Chinese are distinct in association with DQB1*06:11, common in association with DQB1*05:01, but lack association with DQB1*03:01. In addition, DQB1*06:01 appeared more common in ATA-positive Chinese SSc, and marginally associated with pulmonary fibrosis, and an increased frequency of DQB1*03:03 was observed in anti-U1RNP-positive Chinese SSc patients. PMID- 24067473 TI - Huperzine A inhibits CCL2 production in experimental autoimmune encephalomyelitis mice and in cultured astrocyte. AB - The active role of chemokines and inflammatory cytokines in the central nervous system (CNS) during the pathogenesis of experimental autoimmune encephalomyelitis (EAE) has been clearly established. Recent studies from our laboratory reported that Huperzine A (HupA) can attenuate the disease process in EAE by the inhibition of inflammation, demyelination, and axonal injury in the spinal cord as well as encephalomyelitic T-cell proliferation. In this study, the effects of low dose HupA on CCL2, TNF-alpha, IL-6, and IL-1beta expression were evaluated in EAE. The effect of HupA on lipopolysachharide (LPS)-induced inflammatory molecule secretion was investigated in cultured-astrocytes in vitro. In MOG35-55-induced EAE mice, intraperitoneal injections of HupA (0.1 mg/kg?d-1) significantly suppressed the expression of CCL2, IL-6, TNF-alpha, and IL-1beta in the spinal cord. HupA also repressed LPS-induced CCL2 production, but with little influence on pro-inflammatory cytokines in primary cultured astrocytes. The inhibition effect of HupA on CCL2 is PPARgamma-dependent and nicotine receptor-independent. Conditioned culture media from HupA-treated astrocyte decreased PBMC migration in vitro. Collectively, these results suggest that HupA can ameliorate EAE by inhibiting CCL2 production in astrocyte, which may consequently decrease inflammatory cell infiltration in the spinal cord. HupA may have a potential therapeutic value for the treatment of MS and other neuroinflammatory diseases. PMID- 24067474 TI - Intravitreal infliximab for choroidal neovascularization in patients refractory to conventional treatments. AB - The aim of the study is to evaluate the effectiveness and safety of intravitreal infliximab in the course of compassionate use in patients affected by choroidal neovascularization. This prospective interventional case series includes four eligible patients, affected by exudative age-related macular degeneration (2/4), retinal angiomatous proliferation (1/4) and central retinal vein occlusion (1/4), who were refractory to conventional treatments. The patients received a single intravitreal injection of 0.05 ml of reconstituted infliximab solution (20mg/ml). The main outcomes measure were changes in best-corrected visual acuity and central retinal thickness. Patients were evaluated at baseline, every week for the first month, then every two weeks, and on demand. Morphologic parameters improved after a single infliximab intravitreal injection. However, all patients developed acute uveitis in a period ranging from 4 to 7 weeks after treatment. Control of the intraocular inflammation was achieved with topical and systemic steroids in 3 patients, whereas in one case pars plana vitrectomy was needed. A single intravitreal injection of infliximab does not seem to improve the natural history of CNV from different aetiologies. However, all patients in our series developed a serious inflammatory response that required surgical management in one case. The intravitreal administration of infliximab is hence not safe and not recommended in clinical practice. PMID- 24067475 TI - Nephrotic syndrome and stroke. AB - The hypercoagulability of patients with nephrotic syndrome could be an important trigger for arterial and venous thrombotic events. Arterial thromboses are less frequent than venous thromboses and the most common locations are femoral arteries. The association of stroke and nephrotic syndrome is extremely rare. Here we report the case of a patient with stroke as first manifestation of nephrotic syndrome. Ischemic stroke can be the first manifestation of nephrotic syndrome and should be considered as a possible complication of the syndrome, when the commonest causes of ischemic stroke are excluded and especially in presence of pre-existing glomerular disease. PMID- 24067476 TI - First-line chemotherapy with liposomal doxorubicin plus cyclofosfamide in metastatic breast cancer: a case report of early and prolonged response. AB - The treatment choice for metastatic breast cancer should consider the appropriate balance between efficacy and toxicity of the therapy. We discuss a clinical case with an early response and prolonged to liposomal anthracyclines-based chemotherapy, without cardiotoxicity, enhancing the evidence of safety of liposomal formulation to prevent heart damage. Moreover, the case seems to be of interest for the role of 18F-FDG-PET in clinical response assessment: an early decrease of the standardized uptake value value, even before conventional imaging evaluation, is highly predictive for prolonged clinical response. PMID- 24067477 TI - Comparison of manual methods of extracting genomic DNA from dried blood spots collected on different cards: implications for clinical practice. AB - Isolating genomic DNA from blood samples is essential when studying the associations between genetic variants and susceptibility to a given clinical condition, or its severity. This study of three extraction techniques and two types of commercially available cards involved 219 children attending our outpatient pediatric clinic for follow-up laboratory tests after they had been hospitalised. An aliquot of venous blood was drawn into plastic tubes without additives and, after several inversions, 80 microL were put on circles of common paper cards and Whatman FTA-treated cards. Three extraction methods were compared: the Qiagen Investigator, Gensolve, and Masterpure. The best method in terms of final DNA yield was Masterpure, which led to a significantly higher yield regardless of the type of card (p less than 0.001), followed by Qiagen Investigator and Gensolve. Masterpure was also the best in terms of price, seemed to be simple and reliable, and required less hands-on time than other techniques. These conclusions support the use of Masterpure in studies that evaluate the associations between genetic variants and the severity or prevalence of infectious diseases. PMID- 24067478 TI - Microbiological and molecular characterization of extreme drug-resistant carbapenemase-producing Klebsiella pneumoniae isolates. AB - Fifteen Klebsiella pneumoniae clinical isolates showing non-susceptibility to carbapenems and resistant to colistin were collected in an Italian hospital. All isolates resulted negative to AmpC, MBL and ESBL production but positive to modified Hodge test, therefore were evaluated as KPC producers. The presence of blaKPC genes was verified by polymerase chain reaction (PCR) and sequencing. Furthermore, molecular typing was performed by multilocus sequence typing (MLST). PCR analysis and nucleotide sequencing revealed that all 15 isolates carried the blaKPC-3 gene. MLST analysis attributed the isolates from all patients to belong to the sequence type ST512. All isolates showed extensively drug-resistant (XDR) phenotype. The emergence of colistin-resistant K. pneumoniae underscores the implementation of strict control measures to prevent the dissemination of these organisms in hospitals. PMID- 24067479 TI - Lichen sclerosus et atrophicus induced by carbamazepine: a case report. AB - We report a case of Lichen Sclerosus in a 73-year-old man who had been treated for epilepsy with carbamazepine. Lichen sclerosus et atrophicus (LSA), also called lichen sclerosus (LS), is a chronic inflammatory cutaneous condition characterized by white plaques with epidermal atrophy and scarring. To date no cases of LSA has been linked to carbamazepine, although in a few cases lichenoid eruptions but without sclero-atrophy have been described after exposure to this drug. Therefore, to our knowledge, this is the first report of a Lichen sclerosus et atrophicus induced by carbamazepine. PMID- 24067480 TI - Usefulness of Atopy Patch Test on a child with milk protein-induced enterocolitis syndrome: a case report. AB - We describe the case of a child affected by milk-protein induced enterocolitis, in which oral challenge with corn was performed without symptoms after a negative specific Atopy Patch Test. Food protein-induced enterocolitis syndrome (FPIES) is an uncommon nonIgE-mediated gastrointestinal food hypersensitivity of infancy, characterized by severe vomiting and diarrhea arising within 1 to 3 hours after ingestion of the causative food. Little is known about the pathophysiology of FPIES. The absence of food-specific IgE as demonstrated by negative skin prick tests suggests that the disease is not caused by an early onset IgE-mediated reaction. Atopy Patch Test has been described as sensitive and predictive in this syndrome. The hypothesis on the immunological pathogenesis has been discussed on the basis of literature data. PMID- 24067481 TI - Italian study on buckwheat allergy: prevalence and clinical features of buckwheat sensitized patients in Italy. AB - Buckwheat allergy is considered a rare food allergy outside of Asia. In Europe, buckwheat has been described mainly as a hidden allergen. Data on the prevalence of buckwheat hypersensitivity in non-Asian countries is very poor. The aim of this multicenter study was to evaluate the prevalence of buckwheat sensitization and its association with other sensitizations among patients referred to allergy clinics in different geographic areas of Italy. All patients referred to 18 Italian allergy clinics from February through April 2011 were included in the study and evaluated for sensitization to buckwheat and other allergens depending on their clinical history. A total of 1,954 patients were included in the study and 61.3 percent of them were atopic. Mean prevalence of buckwheat sensitization was 3.6 percent with significant difference between Northern (4.5 percent), Central (2.2 percent) and Southern (2.8 percent) regions. This is, to our knowledge, the largest epidemiological survey on buckwheat allergy reported outside of Asia. Buckwheat is an emerging allergen in Italy, being more frequently associated to sensitization in Northern regions. PMID- 24067482 TI - Improvement of a rapid screening test for chronic granulomatous disease. AB - Diagnosis of CGD is made by demonstrating absent or markedly reduced oxidase activity in stimulated neutrophils. The screening test proposed is based upon the naked eye evaluation of the reduction of NBT on a solid surface. It seems to be a useful tool for rapid and inexpensive detection of CGD patients, especially for large-scale screening purposes. The test was carried out on forty-five subjects: two males affected by CGD, three female carriers and forty healthy donors. The test confirmed the results obtained with flow cytometric and NBT assays. PMID- 24067483 TI - Different subsets of circulating angiogenic cells do not predict bronchopulmonary dysplasia or other diseases of prematurity in preterm infants. AB - Bronchopulmonary dysplasia (BPD) is a chronic lung disease occurring in very and extremely preterm infants undergoing mechanical ventilation. Given the altered lung vascular growth characterizing BPD, circulating angiogenic cells could be useful biomarkers to predict the risk. The objective of the study was to determine whether the percentages of circulating angiogenic cells (CD34+VEGFR-2+, CD34+CD133+VEGFR-2+, and CD45-CD34+CD133+VEGFR-2+ cells), assessed in the peripheral blood at birth by flow cytometry, could be used as markers for the risk of BPD. In one-hundred and forty-two preterm neonates (gestational age less than 32 weeks and/or birth weight less than 1500 g) admitted to our tertiary care Neonatal Intensive Care Unit between 2006 and 2009, we evaluated the percentages of circulating angiogenic cells at birth, at 7 days, and, in a subset of infants (n=40), at 28 days of life. The main outcome was the correlation between cell counts at birth and the subsequent risk of developing BPD. In our study, all the three cell populations failed to predict the development of BPD or other diseases of prematurity. We suggest that these cells cannot be used as biomarkers in preterm infants, and that research is needed to find other early predictors of BPD. PMID- 24067484 TI - Expression of gelatinases (MMP-2, MMP-9) in human articular cartilage. AB - Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by destruction of the articular cartilage, subchondral bone alterations and synovitis. Matrix metalloproteinases (MMPs) are expressed in joint tissues of patients with osteoarthritis (OA). The objective of this study was to define the steady state levels of two different MMPs to provide more insight into the role of MMPs in cartilage destruction in OA. We investigated the expression of gelatinases through immunohistochemistry Our results show that high levels of MMP 2 and MMP-9 are present in OA and suggest that once these MMPs are fully activated they may contribute to the cartilage destruction in OA. PMID- 24067485 TI - Combination therapy including serratiopeptidase improves outcomes of mechanical antibiotic treatment of periimplantitis. AB - This study was designed as a retrospective analysis of clinical outcomes of cases of periimplantitis treated by mechanical debridement and the administration of antibiotics combined or not with the administration of either the proteolytic enzyme serratiopeptidase (SPEP) or non-steroidal anti-inflammatory drugs (NSAIDs). Clinical charts of 544 partially edentulous patients treated for periimplantitis between June 1996 and December 2010 were analyzed to obtain clinical data of the affected implants just before the beginning of treatment and 12 months later to evaluate the outcomes of combined mechanical antibiotic treatment alone or in combination with the co-administration of the anti inflammatory SPEP or NSAIDs. The comparative analysis revealed that therapeutic outcomes were significantly different in the three groups. Failure rate in the group that received SPEP (6 percent) was significantly lower compared to the group that received NSAIDS (16.9 percent; P less than 0.01) and to the group that received no anti-inflammatory therapy (18.9 percent; P less than 0.01). Treatment including SPEP was associated with significantly better healing also when successful treatments alone were considered. The data reported in this paper strongly support the hypothesis that SPEP is a valid addition to protocols for the combined therapy of peri-implantitis. In fact, it allows to enhance success rates significantly and also favors better tissue repair around successfully treated implants as compared to other regimens. PMID- 24067486 TI - Remission of psoriatic arthritis after etanercept discontinuation: analysis of patients' clinical characteristics leading to disease relapse. AB - Psoriatic arthritis is a chronic, inflammatory, disabling arthritis affecting up to 30 percent of psoriatic patients. Recently, it has been demonstrated that tumor necrosis factor alpha (TNF-alpha) plays a pivotal role in inducing and maintaining joint damage and that molecules that block this cytokine are effective in the treatment of psoriatic arthritis. Etanercept is a recombinant fusion protein acting as a competitive inhibitor of TNF-alpha, and numerous clinical trials have demonstrated its efficacy in determining psoriatic arthritis remission. However, specific criteria defining psoriatic arthritis remission have not been delineated and few data describing the length of the remission after etanercept discontinuation are available. The aim of this observational, retrospective study was to assess post-remission efficacy maintenance and relapse characteristics after etanercept interruption in patients with moderate-to-severe peripheral psoriatic arthritis (PsA) and cutaneous involvement. PMID- 24067487 TI - Solar forcing of the Indian summer monsoon variability during the Allerod period. AB - Rapid climatic shifts across the last glacial to Holocene transition are pervasive feature of the North Atlantic as well as low latitude proxy archives. Our decadal to centennial scale record of summer monsoon proxy Globigerina bulloides from rapidly accumulating sediments from Hole 723A, Arabian Sea shows two distinct intervals of weak summer monsoon wind coinciding with cold periods within Allerod inerstadial of the North Atlantic named here as IACP-A1 and IACP A2 and dated (within dating uncertainties) at 13.5 and 13.3 calibrated kilo years before the present (cal kyr BP), respectively. Spectral analysis of the Globigerina bulloides time series for the segment 13.6-13.1 kyr (Allerod period) reveals a strong solar 208-year cycle also known as de Vries or Suess cycle, suggesting that the centennial scale variability in Indian summer monsoon winds during the Allerod inerstadial was driven by changes in the solar irradiance through stratospheric-tropospheric interactions. PMID- 24067488 TI - Algorithm-based management of patients with gastrointestinal symptoms in patients after pelvic radiation treatment (ORBIT): a randomised controlled trial. AB - BACKGROUND: Chronic gastrointestinal symptoms after pelvic radiotherapy are common, multifactorial in cause, and affect patients' quality of life. We assessed whether such patients could be helped if a practitioner followed an investigative and management algorithm, and whether outcomes differed by whether a nurse or a gastroenterologist led this algorithm-based care. METHODS: For this three-arm randomised controlled trial we recruited patients (aged >=18 years) from clinics in London, UK, with new-onset gastrointestinal symptoms persisting 6 months after pelvic radiotherapy. Using a computer-generated randomisation sequence, we randomly allocated patients to one of three groups (1:1:1; stratified by tumour site [urological, gynaecological, or gastrointestinal], and degree of bowel dysfunction [IBDQ-B score <60 vs 60-70]): usual care (a detailed self-help booklet), gastroenterologist-led algorithm-based treatment, or nurse led algorithm-based treatment. The primary endpoint was change in Inflammatory Bowel Disease Questionnaire-Bowel subset score (IBDQ-B) at 6 months, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00737230. FINDINGS: Between Nov 26, 2007, and Dec 12, 2011, we enrolled and randomly allocated 218 patients to treatment: 80 to the nurse group, 70 to the gastroenterologist group, and 68 to the booklet group (figure). Most had a baseline IBDQ-B score indicating moderate-to-severe symptoms. We recorded the following pair-wise mean difference in change in IBDQ-B score between groups: nurse versus booklet 4.12 (95% CI 0.04-8.19; p=0.04), gastroenterologist versus booklet 5.47 (1.14-9.81; p=0.01). Outcomes in the nurse group were not inferior to outcomes in the gastroenterologist group (mean difference 1.36, one sided 95% CI -1.48). INTERPRETATION: Patients given targeted intervention following a detailed clinical algorithm had better improvements in radiotherapy-induced gastrointestinal symptoms than did patients given usual care. Our findings suggest that, for most patients, this algorithm-based care can be given by a trained nurse. FUNDING: The National Institute for Health Research. PMID- 24067489 TI - Radiation induced bowel injury: a neglected problem. PMID- 24067490 TI - Optimal multi-photon phase sensing with a single interference fringe. AB - Quantum entanglement can help to increase the precision of optical phase measurements beyond the shot noise limit (SNL) to the ultimate Heisenberg limit. However, the N-photon parity measurements required to achieve this optimal sensitivity are extremely difficult to realize with current photon detection technologies, requiring high-fidelity resolution of N + 1 different photon distributions between the output ports. Recent experimental demonstrations of precision beyond the SNL have therefore used only one or two photon-number detection patterns instead of parity measurements. Here we investigate the achievable phase sensitivity of the simple and efficient single interference fringe detection technique. We show that the maximally-entangled "NOON" state does not achieve optimal phase sensitivity when N > 4, rather, we show that the Holland-Burnett state is optimal. We experimentally demonstrate this enhanced sensitivity using a single photon-counted fringe of the six-photon Holland Burnett state. Specifically, our single-fringe six-photon measurement achieves a phase variance three times below the SNL. PMID- 24067491 TI - Leukemic evolution of donor-derived cells harboring IDH2 and DNMT3A mutations after allogeneic stem cell transplantation. PMID- 24067493 TI - Using eye temperature and heart rate for stress assessment in young horses competing in jumping competitions and its possible influence on sport performance. AB - The aims of this study were, first, to evaluate eye temperature (ET) with infrared thermography and heart rate (HR) to measure stress in horses during show jumping competitions and their relationship with competition results, and second, to evaluate the influence of different extrinsic and intrinsic factors of the horse on the stress measurements analysed. One hundred and seventy-three Spanish Sport Horses were analysed for ET and HR, and these measurements were taken 3 h before the competition, just after and 3 h after it. Two interval measurements were also assessed for each parameter. Positive significant correlations were found between ET and HR, measured before (r=0.23), just after competition (r=0.28) and for the later interval (r=0.26), whereas negative correlations with competition results were found only for ET when measured just after competing (r= 0.25). Two intrinsic factors (genetic line and age) and no extrinsic factors showed significant differences for ET, whereas one intrinsic factor (age) and two extrinsic factors (journey duration and number of training hours) showed significant differences for HR. The marginal means showed significantly higher ET values for the Anglo-Arab genetic line and for 5-year-old animals. HR values were significantly higher for 4-year-old animals, for horses which had travelled 4 to 6 h and for horses that had 3 to 6 h of daily training. This study suggests that, although ET and HR seemed to share a similar physiological basis, the factors that most influenced each parameter were different. Finally, ET seems to be a suitable tool for assessing stress during show jumping competitions in horses. PMID- 24067492 TI - CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. AB - Multiple myeloma (MM) is an incurable hematological malignancy. Chimeric antigen receptor (CAR)-expressing T cells have been demonstrated successfully in the clinic to treat B-lymphoid malignancies. However, the potential utility of antigen-specific CAR-engineered natural-killer (NK) cells to treat MM has not been explored. In this study, we determined whether CS1, a surface protein that is highly expressed on MM cells, can be targeted by CAR NK cells to treat MM. We successfully generated a viral construct of a CS1-specific CAR and expressed it in human NK cells. In vitro, CS1-CAR NK cells displayed enhanced MM cytolysis and interferon-gamma (IFN-gamma) production, and showed a specific CS1-dependent recognition of MM cells. Ex vivo, CS1-CAR NK cells also showed similarly enhanced activities when responding to primary MM tumor cells. More importantly, in an aggressive orthotopic MM xenograft mouse model, adoptive transfer of NK-92 cells expressing CS1-CAR efficiently suppressed the growth of human IM9 MM cells and also significantly prolonged mouse survival. Thus, CS1 represents a viable target for CAR-expressing immune cells, and autologous or allogeneic transplantation of CS1-specific CAR NK cells may be a promising strategy to treat MM. PMID- 24067494 TI - High prevalence of low skeletal muscle mass associated with male gender in midlife and older HIV-infected persons despite CD4 cell reconstitution and viral suppression. AB - Therapeutic goals for HIV-infected patients receiving antiretroviral therapy include minimizing risk of future physical disability. Presarcopenia and sarcopenia precede age-associated physical disability. We investigated their prevalence and the predictive value of patient mid-upper arm circumference (MUAC) for them. Eighty community-dwelling patients >=45 years old demonstrating durable viral suppression were evaluated. Sarcopenia was defined as low skeletal muscle index (SMI, skeletal muscle kg/height m(2)) and either low strength or poor performance by handgrip dynamometry and gait speed, respectively. Presarcopenia was defined as low SMI only. MUAC was interpreted according to National Health Statistics percentile. Prevalence of sarcopenia and presarcopenia was 5.0% and 20.0%, respectively. Male gender (odds ratio [OR] 10.72; P < .026), recreational psychoactive substance use (OR 5.13; P < .037), and intravenous drug use transmission category (OR 6.94; P <.0327) were associated with presarcopenia. Higher body mass index (OR 0.80; P < .0007), MUAC (OR 0.83; P < .024), and large skeletal frame (OR 0.09; P < .003) were negatively associated with presarcopenia. Finding that a participant did not have a MUAC <25th percentile on physical examination had a 90.4% negative predictive value for presarcopenia. Although sarcopenia was uncommon, presarcopenia was highly prevalent in midlife and older HIV-infected males. Determination of MUAC percentile may identify those least likely to demonstrate skeletal muscle deficit and improve patient selection for mass and function testing. PMID- 24067495 TI - Blood Transfusion-Associated HIV Infection in Children in Ibadan, Nigeria. AB - INTRODUCTION: This study describes the epidemiologic features and clinical course of children with blood transfusion-associated HIV infection (TAHI) in Ibadan, Nigeria. METHODOLOGY: All children diagnosed to have TAHI at the University College Hospital, Ibadan, were studied and compared with children who acquired HIV vertically using the pediatric HIV database in the hospital. RESULTS: Transfusion-associated HIV infection accounted for 14 (2.3%) of the 597 children diagnosed to have HIV infection between January 2004 and December 2011. The mean age at diagnosis of TAHI was 10.2 years and that of vertically acquired HIV infection was 3.9 years ( P < .001). In 9 cases, blood transfusion took place in private hospitals and in 5 cases in public hospitals. Median interval between infection and diagnosis of AIDS was 84 months in cases with TAHI and 48 months in vertically acquired cases ( P = .542). CONCLUSION: Optimal blood safety practices are advocated for prevention of TAHI in Nigeria. PMID- 24067496 TI - Excess lithium storage and charge compensation in nanoscale Li(4+x)Ti5O12. AB - Lithium titanate spinel (Li4Ti5O12; LTO) is a promising candidate for anodes in lithium-ion batteries due to its excellent cyclability and safety performance, and has been known as a 'zero-strain' material that allows reversible lithium insertion-deinsertion with little change in the lattice parameters. For a better understanding of lithium reaction mechanisms in this material, it has been of great interest to identify where lithium is inserted and how it migrates during charge and discharge, which is often difficult with x-ray and electron scattering techniques due to the low scattering power of lithium. In this study, we employed atomic-resolution annular bright-field imaging to directly image the lithium on interstitial sites in nanoscale LTO, and electron energy-loss spectroscopy to measure local lithium occupancy and electronic structure at different states of charge. During lithiation, charge compensation occurs primarily at O sites, rather than at Ti sites, and no significant change was found in the projected density of states (Ti 3d) until the voltage was lowered to ~50 mV or below. The Li K-edge spectra were simulated via ab initio calculations, providing a direct correlation between the near-edge fine structure and the local lithium coordination. During the initial states of discharge, lithium ions on 8a sites migrate to 16c sites (above 740 mV). Further lithiation causes the partial re occupation of 8a sites, initially in the near-surface region at ~600 mV, and then in the bulk at lower voltages (~50 mV). We attribute the enhanced capacity in nanostructured LTO to extra storage of lithium in the near-surface region, primarily at {111} facets. PMID- 24067497 TI - The mitochondrial Na+-Ca2+ exchanger, NCLX, regulates automaticity of HL-1 cardiomyocytes. AB - Mitochondrial Ca(2+) is known to change dynamically, regulating mitochondrial as well as cellular functions such as energy metabolism and apoptosis. The NCLX gene encodes the mitochondrial Na(+)-Ca(2+) exchanger (NCXmit), a Ca(2+) extrusion system in mitochondria. Here we report that the NCLX regulates automaticity of the HL-1 cardiomyocytes. NCLX knockdown using siRNA resulted in the marked prolongation of the cycle length of spontaneous Ca(2+) oscillation and action potential generation. The upstrokes of action potential and Ca(2+) transient were markedly slower, and sarcoplasmic reticulum (SR) Ca(2+) handling were compromised in the NCLX knockdown cells. Analyses using a mathematical model of HL-1 cardiomyocytes demonstrated that blocking NCXmit reduced the SR Ca(2+) content to slow spontaneous SR Ca(2+) leak, which is a trigger of automaticity. We propose that NCLX is a novel molecule to regulate automaticity of cardiomyocytes via modulating SR Ca(2+) handling. PMID- 24067498 TI - Neurovascular interactions in the retina: physiological and pathological roles. AB - Increasing evidence suggests that the complex interactions among multiple cell types including neuronal, glial, and vascular cells, are critical for maintaining adequate cerebral blood flow that is necessary for normal brain function and survival. The disturbance of these interactions contributes to the pathogenesis of central nervous system disorders such as stroke and Alzheimer's disease. The retina is part of the central nervous system, and the properties of vasculature in the retina are similar to those in the brain. The interactions among multiple cell types in the retina also play an important role in the maintenance of tissue homeostasis, and the impairment of interactions can contribute to the onset and/or progression of retinal diseases. In this review, we describe the neurovascular interactions in the retina and alternations of interactions in pathological conditions such as diabetic retinopathy and glaucoma. PMID- 24067499 TI - Secular changes in at-risk drinking in Sweden: birth cohort comparisons in 75 year-old men and women 1976-2006. AB - BACKGROUND: little is known about the prevalence of at-risk drinking in older adults. OBJECTIVE: to compare rates of at-risk drinking in 75-year-olds examined in 1976-77 and in 2005-06. DESIGN: cross-sectional survey. SETTING: two samples representative of the general population in Gothenburg, Sweden. PARTICIPANTS: 75 year-olds born in 1901-02 (n = 303) and in 1930 (n = 753). METHODS: participants took part in a multidisciplinary study on health and ageing. Protocols regarding alcohol consumption were identical for both cohorts. Total weekly alcohol intake was estimated and at-risk drinking was defined as >=100 g alcohol/week. RESULTS: the proportion abstaining differed significantly between birth cohorts (18% in 1976-77 versus 9% in 2005, P < 0.001). Frequencies of drinking beer and liquor were similar in the two cohorts for men, but were lower for women in the later born cohort. Proportions drinking wine were higher in the later-born cohort for both sexes. Total weekly alcohol intake was higher for both men and women. At risk drinking was observed in 19.3% of the men in the earlier-born cohort, and in 27.4% in the later-born cohort (P = 0.117). Corresponding figures for women were 0.6 and 10.4% (P < 0.001). At-risk drinking was significantly associated with birth cohort in women (OR: 13.77, CI: 1.82-104.0, P = 0.011) and the occupational group in men (OR: 1.60, CI: 1.13-2.26, P = 0.008). CONCLUSIONS: alcohol consumption in 75-year-olds has changed markedly, especially in women. Studies need to be carried out in varied settings in order to evaluate the clinical and public health implications of changing trends in alcohol consumption. PMID- 24067500 TI - New horizons in the pathogenesis, assessment and management of delirium. AB - Delirium is one of the foremost unmet medical needs in healthcare. It affects one in eight hospitalised patients and is associated with multiple adverse outcomes including increased length of stay, new institutionalisation, and considerable patient distress. Recent studies also show that delirium strongly predicts future new-onset dementia, as well as accelerating existing dementia. The importance of delirium is now increasingly being recognised, with a growing research base, new professional international organisations, increased interest from policymakers, and greater prominence of delirium in educational and audit programmes. Nevertheless, the field faces several complex research and clinical challenges. In this article we focus on selected areas of recent progress and/or uncertainty in delirium research and practice. (i) PATHOGENESIS: recent studies in animal models using peripheral inflammatory stimuli have begun to suggest mechanisms underlying the delirium syndrome as well as its link with dementia. A growing body of blood and cerebrospinal fluid studies in humans have implicated inflammatory and stress mediators. (ii) PREVENTION: delirium prevention is effective in the context of research studies, but there are several unresolved issues, including what components should be included, the role of prophylactic drugs, and the overlap with general best care for hospitalised older people. (iii) ASSESSMENT: though there are several instruments for delirium screening and assessment, detection rates remain dismal. There are no clear solutions but routine screening embedded into clinical practice, and the development of new rapid screening instruments, offer potential. (iv) MANAGEMENT: studies are difficult given the heterogeneity of delirium and currently expert and comprehensive clinical care remains the main recommendation. Future studies may address the role of drugs for specific elements of delirium. In summary, though facing many challenges, the field continues to make progress, with several promising lines of enquiry and an expanding base of interest among researchers, clinicians and policymakers. PMID- 24067501 TI - Mitigation of informational masking in individuals with single-sided deafness by integrated bone conduction hearing aids. AB - OBJECTIVES: To confirm an increased susceptibility to informational masking among individuals with single-sided deafness (SSD). To demonstrate a reduction in informational masking when SSD is treated with an integrated bone conduction hearing aid (IBC). To identify the acoustic cues that contribute to IBC-aided masking release. To determine the effects of device experience on the IBC advantage. DESIGN: Informational masking was evaluated with the coordinate response measure. Participants performed the task by reporting color and number coordinates that changed randomly within target sentences. The target sentences were presented in free field accompanied by zero to three distracting sentences. Target and distracting sentences were spoken by different talkers and originated from different source locations, creating two sources of information for auditory streaming. Susceptibility to informational masking was inferred from the error rates of unaided SSD patients relative to normal controls. These baseline measures were derived by testing inexperienced IBC users without the device on the day of their initial fitting. The benefits of IBC-aided listening were assessed by measuring the aided performance of users who had at least 3 months' device experience. The acoustic basis of the listening advantage was isolated by correlating response errors with the voice pitch and location of distracting sentences. The effects of learning on cue effectiveness were evaluated by comparing the error rates of experienced and inexperienced users. RESULTS: Unaided SSD participants (inexperienced users) performed as well as normal controls when tested without distracting sentences but produced significantly higher error rates when tested with distracting sentences. Most errors involved responding with coordinates that were contained in distracting sentences. This increased susceptibility to informational masking was significantly reduced when experienced IBC users were tested with the device. The listening advantage was most strongly correlated with the availability of voice pitch cues, although performance was also influenced by the location of distracting sentences. Directional asymmetries appear to be dictated by location-dependent cues that are derived from the distinctive transmission characteristics of IBC stimulation. Experienced users made better use of these cues than inexperienced users. CONCLUSIONS: These results suggest that informational masking is a significant source of communication impairment among individuals with SSD. Despite the lateralization of auditory function, unaided SSD subjects experience informational masking when distractors occur in either the deaf or normal spatial hemifield. Restoration of aural sensitivity in the deaf hemifield with an IBC enhances speech intelligibility under complex listening conditions, presumably by providing additional sound-segregation cues that are derived from voice pitch and spatial location. The optimal use of these cues is not immediate, but a significant listening advantage is observed after 3 months of unstructured use. PMID- 24067502 TI - An epidemiological investigation of Campylobacter in pig and poultry farms in the Mekong delta of Vietnam. AB - Campylobacter are zoonotic pathogens commonly associated with gastroenteritis. To assess the relevance of Campylobacter in Vietnam, an economically transitioning country in SE Asia, we conducted a survey of 343 pig and poultry farms in the Mekong delta, a region characterized by mixed species farming with limited biosecurity. The animal-level prevalence of Campylobacter was 31.9%, 23.9% and 53.7% for chickens, ducks and pigs, respectively. C. jejuni was predominant in all three host species, with the highest prevalence in pigs in high-density production areas. Campylobacter isolates demonstrated high levels of antimicrobial resistance (21% and 100% resistance against ciprofloxacin and erythromycin, respectively). Multilocus sequence type genotyping showed a high level of genetic diversity within C. jejuni, and predicted C. coli inter-species transmission. We suggest that on-going intensification of animal production systems, limited biosecurity, and increased urbanization in Vietnam is likely to result in Campylobacter becoming an increasingly significant cause of human diarrhoeal infections in coming years. PMID- 24067503 TI - Immune-modulating drugs and hypomethylating agents to prevent or treat relapse after allogeneic stem cell transplantation. AB - Allogeneic stem cell transplantation is a curative treatment option for many hematological diseases, and the numbers of transplantations are steadily increasing worldwide. Major progress has been made in lowering treatment-related mortality by reducing intensity of the conditioning regimen and by improving supportive care (eg, for infectious complications). Accordingly, relapse after allogeneic stem cell transplantation has become the major cause for treatment failure. Major efforts to prevent or treat relapse are focused on cellular- (T cell, natural killer cell), cytokine-, or antibody-based strategies to enhance the graft-versus-tumor effect or circumvent immunoescape. In the more recent years, new classes of agents have shown activity in several hematological malignancies, and besides their immediate antitumor activity, most of them also possess immune-modulatory qualities that may be useful alone or in combination with adoptive immunotherapy after allogeneic stem cell transplantation to enhance graft-versus-tumor effects. Here, we summarize the current knowledge and potential use of 2 of these compounds in preventing or treating relapse after allogeneic stem cell transplantation, namely immune-modulating drugs and hypomethylating agents. PMID- 24067504 TI - Transplantation of umbilical cord blood-derived cells for novel indications in regenerative therapy or immune modulation: a scoping review of clinical studies. AB - Although used mainly for transplantation of hematopoietic stem cells in the treatment of blood disorders, umbilical cord blood (UCB)-based therapies are now being used increasingly for novel applications in nonhematopoietic diseases and as a form of cellular regenerative therapy or immune modulation. We performed a systematic scoping review by searching Medline, EMBASE, and the Cochrane Library for published articles, and we searched www.clinicaltrials.com and the World Health Organization International Clinical Trials Registry Platform to describe the breadth of published studies and ongoing clinical activity in umbilical cord based cellular therapy for regenerative therapy and immune modulation. The most commonly published area of expertise in the use of UCB-derived cellular transplantation for novel indications is for neurological disorders and this remains the most active area of study in ongoing registered trials. An increasingly broad range of disorders, however, are reflected in ongoing registered trials, which suggests greater activity, interest, and investment in UCB-derived cellular therapy. Interestingly, adult patients compose the majority of patients reported in published reports and registered ongoing clinical studies continue to enroll predominantly adult subjects. Geographically, Asian countries appear most active in UCB-derived cellular therapy and our analysis of ongoing studies suggests this trend will likely continue. Regular assessment of published and ongoing activity in UCB transplantation for emerging novel indications will be critical for informing UCB banking establishments and funding agencies to guide changes in banking practices related to emerging trends in cell therapy. PMID- 24067505 TI - A nanoparticle-coated chemiresistor array as a microscale gas chromatograph detector for explosive marker compounds: flow rate and temperature effects. AB - The effects of flow rate and temperature on the performance of a microscale gas chromatographic (MUGC) detector consisting of a chemiresistor (CR) array coated with different thiolate-monolayer-protected gold nanoparticles (MPNs) are described with respect to the analysis of three gas-phase markers of the explosive trinitrotoluene (TNT): 2,4-dinitrotoluene (2,4-DNT), 2,6-dinitrotoluene (2,6-DNT), and 2,3-dimethyl-2,3-dinitrobutane (DMNB). In chamber tests, sensors were stable at 70 degrees C for several days in air, with <2% sensitivity drift per day and virtually no change in the array response patterns. In tests with a conventional upstream GC column, increasing the array temperature from 55-80 degrees C (1.2 mL min(-1)) led to similar (i.e., 4-6.6-fold) decreases in sensitivity, increases in the limits of detection (LODs), and increases in (estimated) chromatographic resolution. Increasing the flow rate from 1.1-3.7 mL min(-1) (70 degrees C) led to ~1.3-2-fold decreases in sensitivity and LOD for 2,4-DNT and 2,6-DNT, a ~2-fold net increase in LOD for DMNB (passes through a maximum), and a <2-fold increase in resolution. Results indicate that the rates of desorption of the marker vapors out of the MPN films are important determinants of observed trends. With Si-micromachined focuser/injector and separation column devices placed upstream of a CR array held at 70 degrees C, a mixture of the two primary markers, 2,4-DNT and DMNB, and four similarly volatile alkane interferents was separated in 1.5 min at 3 mL min(-1). PMID- 24067506 TI - Targeting sonic hedgehog-associated medulloblastoma through inhibition of Aurora and Polo-like kinases. AB - Medulloblastoma is the most common malignant brain tumor in children. Although aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated medulloblastomas do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated medulloblastoma. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor propagating cells (TPC). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent medulloblastoma. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2-M phases of the cell cycle. Here, we show that CD15(+) cells progress more rapidly through the cell cycle than CD15(-) cells and contain an increased proportion of cells in G2-M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora kinase (Aurk) and Polo-like kinases (Plk), key regulators of G2-M, induces cell-cycle arrest, apoptosis, and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived medulloblastoma xenografts are also sensitive to Aurk and Plk inhibitors. Our findings suggest that targeting G2-M regulators may represent a novel approach for treatment of human medulloblastoma. PMID- 24067508 TI - Prognostic value of coronary computed tomography angiography during 5 years of follow-up in patients with suspected coronary artery disease. AB - AIMS: Coronary computed tomography angiography (CCTA) has a high accuracy for detection of obstructive coronary artery disease (CAD). Several studies also showed a good predictive value for subsequent cardiac events. However, the follow up period of these studies was limited to ~2 years and long-term follow-up data on prognosis out to 5 years are very limited. METHODS AND RESULTS: This study is based on 1584 patients with suspected CAD undergoing CCTA between December 2003 and November 2006. Among other CCTA parameters, the total plaque score defined as number of abnormal segments (having either a non-obstructive plaque or a stenosis) and the most severe stenosis were recorded. The primary endpoint was a composite of death and non-fatal myocardial infarction. Revascularization procedures later than 90 days after the CT study were assessed as secondary endpoints. During a median follow-up of 5.6 years (IQR: 5.1-6.3 years) 61 patients suffered death or myocardial infarction and 52 underwent late revascularization. The severity of CAD and the total plaque score were the best predictors of death and non-fatal myocardial infarction, both significantly improving prediction over standard clinical risk scores (multivariate c-index 0.60 and 0.66, respectively, P = 0.002 and <0.0001, respectively). The annual event rate ranged from 0.24% for patients with no CAD to 1.1% for patients with obstructive CAD and 1.5% for patients with CAD and extensive plaque load (>5 segments). Both parameters also improved prediction of need for subsequent revascularization (c-index 0.72 and 0.63, respectively, P < 0.0001 and P = 0.0013, respectively). CONCLUSION: Data from CCTA predict both death and myocardial infarction as well as need for subsequent revascularizations out to 5 years. CCTA imaging may be a valuable tool in the assessment of long-term prognosis in patients with suspected CAD. PMID- 24067507 TI - The complex pathogenesis of bacteremia: from antimicrobial clearance mechanisms to the genetic background of the host. AB - Bacteremia develops when bacteria manage to escape the host immune mechanisms or when the otherwise well-orchestrated immune response fails to control bacterial spread due to inherent or acquired immune defects that are associated with susceptibility to infection. The pathogenesis of bacteremia has some characteristic features that are influenced by the genetic signature of the host. In this review, the host defense mechanisms that help prevent bacteremia will be described and the populations who are at risk because of congenital or acquired deficiencies in such mechanisms will be defined. A special mention will be made to novel insights regarding host immune defense against the most commonly isolated organisms from patients with community-acquired bloodstream infections. PMID- 24067510 TI - Time-reversal-symmetry-broken state in the BCS formalism for a multi-band superconductor. AB - In three-band BCS superconductors with repulsive inter-band interactions, frustration between the bands can lead to an inherently complex gap function, arising out of a phase difference between the bands in the range 0 and pi. Since the complex conjugate of this state is also a solution, the ground state is degenerate, and there appears a time-reversal-symmetry-broken state. In this paper we investigate the existence of this state as a function of inter-band coupling strength and show how a new phase transition appears between the TRSB and conventional BCS states. PMID- 24067509 TI - Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. PMID- 24067511 TI - Resident work conditions under the microscope. PMID- 24067513 TI - A new era for resident duty hours in surgery calls for greater emphasis on resident wellness. PMID- 24067514 TI - Laparoscopic versus open surgery for the treatment of colorectal cancer: a literature review and recommendations from the Comite de l'evolution des pratiques en oncologie. AB - BACKGROUND: Adoption of the laparoscopic approach for colorectal cancer treatment has been slow owing to initial case study results suggesting high recurrence rates at port sites. The use of laparoscopic surgery for colorectal cancer still raises a number of concerns, particularly with the technique's complexity, learning curve and longer duration. After exploring the scientific literature comparing open and laparoscopic surgery for the treatment of colorectal cancer with respect to oncologic efficacy and shortterm outcomes, the Comite de l'evolution des pratiques en oncologie (CEPO) made recommendations for surgical practice in Quebec. METHODS: Scientific literature published from January 1995 to April 2012 was reviewed. Phase III clinical trials and meta-analyses were included. RESULTS: Sixteen randomized trials and 10 meta-analyses were retrieved. Analysis of the literature confirmed that for curative treatment of colorectal cancer, laparoscopy is not inferior to open surgery with respect to survival and recurrence rates. Moreover, laparoscopic surgery provides short-term advantages, including a shorter hospital stay, reduced analgesic use and faster recovery of intestinal function. However, this approach does require a longer operative time. CONCLUSION: Considering the evidence, the CEPO recommends that laparoscopic resection be considered an option for the curative treatment of colon and rectal cancer; that decisions regarding surgical approach take into consideration surgeon experience, tumour stage, potential contraindications and patient expectations; and that laparoscopic resection for rectal cancer be performed only by appropriately trained surgeons who perform a sufficient volume annually to maintain competence. PMID- 24067515 TI - Comparison of the major intraoperative and postoperative complications between unilateral and sequential bilateral total knee arthroplasty in a high-volume community hospital. AB - BACKGROUND: Total knee arthroplasty (TKA) is a common surgical treatment for arthritis. In the event of bilateral knee symptoms, a patient may elect for bilateral TKA (BTKA) under 1 anesthetic or 2 separate unilateral TKAs (UTKA). Controversy exists in the literature regarding the safety of BTKA versus UTKA. We compared the rate of major intraoperative and postoperative complications for BTKA versus UTKA at a high-volume community hospital. METHODS: We compared 373 patients who underwent BTKA with 966 who underwent UTKA between May 2008 and May 2011. Health records were used to determine patient characteristics and major intraoperative and postoperative complications. The BTKA and UTKA cohorts were matched for demographic characteristics and comorbidities with the exception of previous transient ischemic attack and previous knee surgery (UTKA > BTKA). RESULTS: Rates of intraoperative and postoperative complications, including cardiovascular, thromboembolic and neurologic complications; deep wound infections; and mortality, did not differ significantly between groups. Bilateral TKA was associated with a greater proportion of patients requiring blood transfusion than UTKA (29.8% v. 8.9%, p < 0.001). Among those transfused, there was no significant difference between the groups in the mean number of units required (1.72 +/- 0.77 v. 1.53 +/- 0.85 units, p = 0.68). CONCLUSION: Bilateral TKA was not associated with statistically greater rates of intraoperative and postoperative complications than UTKA, barring the proportion of patients requiring transfusion. Our results support the use of BTKA to treat bilateral knee arthritis in a high-volume community hospital setting. PMID- 24067516 TI - Impact of a regional acute care surgery model on patient access and outcomes. AB - BACKGROUND: The consolidation of acute care surgery (ACS) services at 3 of 6 hospitals in a Canadian health region sought to alleviate a relative shortage of surgeons able to take emergency call. We examined how this affected patient access and outcomes. METHODS: Using the generalized linear model and statistical process control, we analyzed ACS-related episodes that occurred between 39 months prior to and 17 months after the model's implementation (n = 14,713). RESULTS: Time to surgery increased after the consolidation. Wait times increased primarily for patients presenting at nonreferral hospitals who were likely to require transfer to a referral hospital. Although ACS teams enabled referral hospitals to handle a much higher volume of patients without increasing within-hospital wait times, overall system wait times were lengthened by the growing frequency of patient transfers. Wait times for inpatient admission were difficult to interpret because there was a trend toward admitting patients directly to the ACS service, bypassing the emergency department (ED). For patients who did go through the ED, wait times for inpatient admission increased after the consolidation; however, this trend was cancelled out by the apparently zero waits of patients who bypassed the ED. Regionalization showed no impact on length of stay, readmissions, mortality or complications. CONCLUSION: Consolidation enabled the region to ensure adequate surgical coverage without harming patients. The need to transfer patients who presented at nonreferral hospitals led to longer waits. PMID- 24067517 TI - Incremental value and clinical impact of neck sonography for primary hyperparathyroidism: a risk-adjusted analysis. AB - BACKGROUND: Despite the different preoperative imaging modalities available for parathyroid adenoma localization, there is currently no uniform consensus on the most appropriate preoperative imaging algorithm that should be routinely followed prior to the surgical management of primary hyperparathyroidism (PHPT). We sought to determine the incremental value of adding neck ultrasonography to scintigraphy based imaging tests. METHODS: In a single institution, surgically naive patients with PHPT underwent the following localization studies before parathyroidectomy: 1) Tc-99m sestamibi imaging with single photon emission computed tomography/computed tomography (SPECT/CT) or Tc-99m sestamibi imaging with SPECT alone, or 2) ultrasonography in addition to those tests. We retrospectively collected data and performed a multivariate analysis comparing group I (single study) to group II (addition of ultrasonography) and risk of bilateral (BNE) compared with unilateral (UNE) neck exploration. RESULTS: Our study included 208 patients. Group II had 0.45 times the odds of BNE versus UNE compared with group I (unadjusted odds ratio [OR] 0.45, 95% confidence interval [CI] 0.25-0.81, p = 0.008). When adjusting for patient age, sex, preoperative calcium level, use of intraoperative PTH monitoring, preoperative PTH level, adenoma size, and number of abnormal parathyroid glands, Group II had 0.48 times the odds of BNE versus UNE compared with group I (adjusted OR 0.48, 95% CI 0.23-1.03, p = 0.06). In a subgroup analysis, only the addition of ultrasonography to SPECT decreased the risk of undergoing BNE compared with SPECT alone (unadjusted OR 0.40, 95% CI 0.19 0.84, p = 0.015; adjusted OR 0.38, 95% CI 0.15-0.96, p = 0.043). CONCLUSION: The addition of ultrasonography to SPECT, but not to SPECT/CT, has incremental value in decreasing the extent of surgery during parathyroidectomy, even after adjusting for multiple confounding factors. PMID- 24067518 TI - Total hip arthroplasty using a combined anterior and posterior approach via a lateral incision in patients with ankylosed hips. AB - BACKGROUND: For most patients with severely ankylosed hips, traditional surgical approaches do not provide sufficient exposure during THAs. We report our experience with a combined anterior and posterior approach using a lateral incision for total hip arthroplasty (THA) in patients with severe, spontaneous bony hip ankylosis. METHODS: Between January 2004 and December 2008, patients with severe, spontaneous bony hip ankylosis underwent THA via a combined anterior and posterior approach using a lateral incision. RESULTS: We included 47 patients (76 hips) with a mean age of 53 (range 22-72) years in our study. All surgeries were successful, and no significant postoperative complications occurred. The mean operative duration was 1.5 (range 1.3-1.7) hours, and mean blood loss was 490 (range 450-580) mL. The mean duration of follow-up was 5.5 (range 2-11) years. Harris hip score improved from 53 to 88 points postoperatively, and the outcome was good to excellent in 88.37% of cases. Heterotopic ossification occurred in 6 hips, and infection, which resolved with antibiotics, occurred in 1 patient. CONCLUSION: This combined anterior and posterior approach to THA using a lateral incision in patients with severe, spontaneous ankylosis provides very good exposure, protects the abduction unit and results in good to excellent postoperative recovery. PMID- 24067519 TI - Clinical outcomes compared between laparoscopic and open appendectomy in pregnant women. AB - BACKGROUND: Despite the initial absolute or relative contraindication of laparoscopic surgery during pregnancy, in the last decade, laparoscopic appendectomy (LA) has been performed in pregnant women. But few studies compare the outcomes of LA compared with open appendectomy (OA). We investigated clinical outcomes to evaluate the safety and efficacy of LA compared with OA in pregnant women. METHODS: We recruited consecutive pregnant patients with a diagnosis of acute appendicitis who were undergoing LA or OA between May 2007 and August 2011 into the study. RESULTS: Sixty-one patients (22 LA and 39 OA) enrolled in our study. There were no significant differences in duration of surgery, postoperative complication rate and obstetric and fetal outcomes, including incidence of preterm labour, delivery type, gestation age at delivery, birth weight and APGAR scores between the 2 groups. However, the LA group had shorter time to first flatus (2.4 +/- 0.4 d v. 4.0 +/- 1.7 d, p = 0.034), earlier time to oral intake (2.3 +/- 1.6 d v. 4.1 +/- 1.9 d, p = 0.023) and shorter postoperative hospital stay (4.2 +/- 2.9 d v. 6.9 +/- 3.7 d, p = 0.043) than the OA group. CONCLUSION: Laparoscopic appendectomy is a clinically safe and effective procedure in all trimesters of pregnancy and should be considered as a standard treatment alternative to OA. Further evaluation including prospective randomized clinical trials comparing LA with OA are needed to confirm our results. PMID- 24067520 TI - Complications associated with laparoscopic sleeve gastrectomy for morbid obesity: a surgeon's guide. AB - Obesity is a common disease affecting adults and children. The incidence of obesity in Canada is increasing. Laparoscopic sleeve gastrectomy (LSG) is a relatively new and effective procedure for weight loss. Owing to an increase in the number of bariatric surgical procedures, general surgeons should have an understanding of the complications associated with LSG and an approach for dealing with them. Early postoperative complications following LSG that need to be identified urgently include bleeding, staple line leak and development of an abscess. Delayed complications include strictures, nutritional deficiencies and gastresophageal reflux disease. We discuss the principles involved in the management of each complication. PMID- 24067521 TI - Cost-effectiveness of bariatric surgery for severely obese adults with diabetes. PMID- 24067522 TI - Identification and use of operating room efficiency indicators: the problem of not performing the right search within PubMed. PMID- 24067523 TI - Comment on "Identification and use of operating room efficiency indicators: the problem of definition". PMID- 24067524 TI - Comment on "Identification and use of operating room efficiency indicators: the problem of definition". PMID- 24067525 TI - Adding an endovascular aortic surgery program to a rural regional medical centre. AB - BACKGROUND: Abdominal aortic aneurysms requiring surgical intervention are generally treated by endovascular means. Such procedures are not always offered in rural hospitals, possibly leaving patients underserved. We reviewed our experience initiating an endoaortic surgery program. METHODS: A surgeon in a rural centre was credentialed to perform endovascular aortic aneurysm repair through collaboration with a university centre and was proctored locally for the first 5 abdominal aneurysm repairs. Web-based image storage was used to review complex cases as part of an ongoing partnership. Referred patients were screened for multiple aneurysms and underwent long-term monitoring. RESULTS: In all, 160 patients were evaluated for 176 aortic pathologies. Twenty-five patients (17 men) aged 55-89 years underwent 26 endovascular abdominal (n = 23) or thoracic (n = 3) aortic procedures. Emergent endovascular procedures were not performed. There were no operative deaths, requirements for dialysis or conversions to open repair. Two endoleaks required early reintervention. The median length of stay in hospital for endovascular procedures was 2.5 days. Chronic endoleaks were observed in 7 patients. An additional 8 patients underwent open abdominal aneurysm repair locally and 15 patients were referred to the university program. CONCLUSION: Creation of an endovascular aortic surgery program in a rural hospital is feasible through collaboration with a high-volume centre. Patient safety is enhanced by obtaining second opinions using web-based image review. Most interventions are for abdominal aortic aneurysms, but planning for a comprehensive aortic clinic is preferable. PMID- 24067526 TI - Development and preliminary validation of a Function IndeX for Trauma (FIX-IT). AB - BACKGROUND: Assessing fracture healing in clinical trials is subjective. The new Function IndeX for Trauma (FIX-IT) score provides a simple, standardized approach to assess weight-bearing and pain in patients with lower extremity fractures. We conducted an initial validation of the FIX-IT score. METHODS: We conducted a cross-sectional study involving 50 patients with lower extremity fractures across different stages of healing to evaluate the reliability and preliminary validity of the FIX-IT score. Patients were independently examined by 2 orthopedic surgeons, 1 orthopedic fellow, 2 orthopedic residents and 2 research coordinators. Patients also completed the Short Form-36 version 2 (SF-36v2) questionnaire, and convergent validity was tested with the SF-36v2. RESULTS: For interrater reliability, the intraclass correlation coefficients ranged from 0.637 to 0.915. The overall interrater reliability for the total FIX-IT score was 0.879 (95% confidence interval 0.828-0.921). The correlations between the FIX-IT score and the SF-36 ranged from 0.682 to 0.770 for the physical component summary score, from 0.681 to 0.758 for the physical function subscale, and from 0.677 to 0.786 for the role-physical subscale. CONCLUSION: The FIX-IT score had high interrater agreement across multiple examiners. Moreover, FIX-IT scores correlate with the physical scores of the SF-36. Although additional research is needed to fully validate FIX-IT, our results suggest the potential for FIX-IT to be a reliable adjunctive clinician measure to evaluate healing in lower extremity fractures. LEVEL OF EVIDENCE: Diagnostic Study Level I. PMID- 24067527 TI - Quality of narrative operative reports in pancreatic surgery. AB - BACKGROUND: Quality in health care can be evaluated using quality indicators (QIs). Elements contained in the surgical operative report are potential sources for QI data, but little is known about the completeness of the narrative operative report (NR). We evaluated the completeness of the NR for patients undergoing a pancreaticoduodenectomy. METHODS: We reviewed NRs for patients undergoing a pancreaticoduodenectomy over a 1-year period. We extracted 79 variables related to patient and narrator characteristics, process of care measures, surgical technique and oncology-related outcomes by document analysis. Data were coded and evaluated for completeness. RESULTS: We analyzed 74 NRs. The median number of variables reported was 43.5 (range 13-54). Variables related to surgical technique were most complete. Process of care and oncology-related variables were often omitted. Completeness of the NR was associated with longer operative duration. CONCLUSION: The NRs were often incomplete and of poor quality. Important elements, including process of care and oncology-related data, were frequently missing. Thus, the NR is an inadequate data source for QI. Development and use of alternative reporting methods, including standardized synoptic operative reports, should be encouraged to improve documentation of care and serve as a measure of quality of surgical care. PMID- 24067528 TI - The impact of a massive transfusion protocol (1:1:1) on major hepatic injuries: does it increase abdominal wall closure rates? AB - BACKGROUND: Massive transfusion protocols (MTPs) using high plasma and platelet ratios for exsanguinating trauma patients are increasingly popular. Major liver injuries often require massive resuscitations and immediate hemorrhage control. Current published literature describes outcomes among patients with mixed patterns of injury. We sought to identify the effects of an MTP on patients with major liver trauma. METHODS: Patients with grade 3, 4 or 5 liver injuries who required a massive blood component transfusion were analyzed. We compared patients with high plasma:red blood cell:platelet ratio (1:1:1) transfusions (2007-2009) with patients injured before the creation of an institutional MTP (2005-2007). RESULTS: Among 60 patients with major hepatic injuries, 35 (58%) underwent resuscitation after the implementation of an MTP. Patient and injury characteristics were similar between cohorts. Implementation of the MTP significantly improved plasma: red blood cell:platelet ratios and decreased crystalloid fluid resuscitation (p = 0.026). Rapid improvement in early acidosis and coagulopathy was superior with an MTP (p = 0.009). More patients in the MTP group also underwent primary abdominal fascial closure during their hospital stay (p = 0.021). This was most evident with grade 4 injuries (89% vs. 14%). The mean time to fascial closure was 4.2 days. The overall survival rate for all major liver injuries was not affected by an MTP (p = 0.61). CONCLUSION: The implementation of a formal MTP using high plasma and platelet ratios resulted in a substantial increase in abdominal wall approximation. This occurred concurrently to a decrease in the delivered volume of crystalloid fluid. PMID- 24067530 TI - The coiled-coil domain containing protein CCDC151 is required for the function of IFT-dependent motile cilia in animals. AB - Cilia are evolutionarily conserved organelles endowed with essential physiological and developmental functions. In humans, disruption of cilia motility or signaling leads to complex pleiotropic genetic disorders called ciliopathies. Cilia motility requires the assembly of multi-subunit motile components such as dynein arms, but mechanisms underlying their assembly pathway and transport into the axoneme are still largely unknown. We identified a previously uncharacterized coiled-coil domain containing protein CCDC151, which is evolutionarily conserved in motile ciliated species and shares ancient features with the outer dynein arm-docking complex 2 of Chlamydomonas. In Drosophila, we show that CG14127/CCDC151 is associated with motile intraflagellar transport (IFT)-dependent cilia and required for geotaxis behavior of adult flies. In zebrafish, Ccdc151 is expressed in tissues with motile cilia, and morpholino-induced depletion of Ccdc151 leads to left-right asymmetry defects and kidney cysts. We demonstrate that Ccdc151 is required for proper motile function of cilia in the Kupffer's vesicle and in the pronephros by controlling dynein arm assembly, showing that Ccdc151 is a novel player in the control of IFT-dependent dynein arm assembly in animals. However, we observed that CCDC151 is also implicated in other cellular functions in vertebrates. In zebrafish, ccdc151 is involved in proper orientation of cell divisions in the pronephros and genetically interacts with prickle1 in this process. Furthermore, knockdown experiments in mammalian cells demonstrate that CCDC151 is implicated in the regulation of primary cilium length. Hence, CCDC151 is required for motile cilia function in animals but has acquired additional non-motile functions in vertebrates. PMID- 24067529 TI - Differences between referred and nonreferred patients in cancer research. AB - BACKGROUND: In Canada, provincial cancer registries have been established to provide rigorous population-based data for patients with colorectal cancer. Databases maintained by regional cancer agencies contain a broader scope of information and have been used as a surrogate source of information for colorectal cancer research. It is unclear whether these data can be reliably extrapolated to all patients affected by colorectal cancer. We sought to determine whether patients included in a referral-based database are systematically different from patients who are not included. METHODS: We conducted a retrospective cohort study to compare patients referred to the British Columbia Cancer Agency with those who were not referred. Comparison was based on age, sex and geographic location. We used univariate and logistic regression analysis to identify significant differences between the cohorts. RESULTS: Univariate analysis demonstrated that the referral and nonreferral cohorts differed in sex, age and geographic location. For patients with rectal cancer, the referral and nonreferral cohorts varied in age and geographic location. Multivariate analysis demonstrated significant differences in age and geographic location but not sex for patients with colon and rectal cancer. CONCLUSION: Patients included in the referral database differed in age and geographic location from those included only in the provincial database. Studies using large data sets from referral centres must be interpreted with caution and may not be representative of the entire patient population. PMID- 24067531 TI - Tumor-derived exosomes are enriched in DeltaNp73, which promotes oncogenic potential in acceptor cells and correlates with patient survival. AB - Tumor-derived exosomes are emerging as local and systemic cell-to-cell mediators of oncogenic information through the horizontal transfer of mRNAs, microRNAs and proteins during tumorigenesis. The exosomal content has been described as biologically active when taken up by the recipient cell. Identifying the specific molecular cargo of exosomes will help to determine their function in specific steps of the tumorigenic process. Here we evaluate whether DeltaNp73 is selectively packaged in tumor-derived exosomes, its function in the acceptor cells in vitro and in vivo and its prognosis potential in cancer. DeltaNp73 messenger is enriched in tumor-derived exosomes, suggesting its active sorting in these microvesicles. We observed the transmission of this exosome cargo to different cell types and how it confers proliferation potential and chemoresistance to the acceptor cells in vitro and in animal models. Finally, our data support the potential prognostic value of exosomal DeltaNp73 in colon cancer patients. PMID- 24067532 TI - Chondrolectin affects cell survival and neuronal outgrowth in in vitro and in vivo models of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is characterized by the selective loss of spinal motor neurons owing to reduced levels of survival motor neuron (Smn) protein. In addition to its well-established role in assembling constituents of the spliceosome, diverse cellular functions have been proposed for Smn, but the reason why low levels of this widely expressed protein result in selective motor neuron pathology is still debated. In longitudinal studies of exon-level changes in SMA mouse model tissues, designed to determine the contribution of splicing dysfunction to the disease, we have previously shown that a generalized defect in splicing is unlikely to play a causative role in SMA. Nevertheless, we identified a small subset of genes that were alternatively spliced in the spinal cord compared with control mice before symptom onset, indicating a possible mechanistic role in disease. Here, we have performed functional studies of one of these genes, chondrolectin (Chodl), known to be highly expressed in motor neurons and important for correct motor axon outgrowth in zebrafish. Using in vitro and in vivo models of SMA, we demonstrate altered expression of Chodl in SMA mouse spinal motor neurons, show that Chodl has distinct effects on cell survival and neurite outgrowth and that increasing the expression of chodl can rescue motor neuron outgrowth defects in Smn-depleted zebrafish. Our findings thus link the dysregulation of Chodl to the pathophysiology of motor neuron degeneration in SMA. PMID- 24067534 TI - Vedolizumab, a monoclonal antibody to the gut homing alpha4beta7 integrin, does not affect cerebrospinal fluid T-lymphocyte immunophenotype. AB - Vedolizumab, a gut-homing alpha4beta7 integrin antagonist, has demonstrated efficacy in ulcerative colitis and Crohn's disease. Development of progressive multifocal leukoencephalopathy, a serious brain infection associated with natalizumab (an alpha4beta7 and alpha4beta1 integrin antagonist), has raised concern that vedolizumab may convey a similar risk. Natalizumab is believed to impair central nervous system immune surveillance by affecting cerebrospinal fluid (CSF) lymphocyte counts and the CD4:CD8 ratio. To determine if vedolizumab elicits similar effects, we examined CSF of healthy volunteers by flow cytometry for T-lymphocyte surface markers 5 weeks after administration of intravenous vedolizumab 450 mg. No significant changes were observed in CSF T-lymphocyte populations. PMID- 24067533 TI - Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms. AB - Using a Drosophila model of Alzheimer's disease (AD), we systematically evaluated 67 candidate genes based on AD-associated genomic loci (P < 10(-4)) from published human genome-wide association studies (GWAS). Genetic manipulation of 87 homologous fly genes was tested for modulation of neurotoxicity caused by human Tau, which forms neurofibrillary tangle pathology in AD. RNA interference (RNAi) targeting 9 genes enhanced Tau neurotoxicity, and in most cases reciprocal activation of gene expression suppressed Tau toxicity. Our screen implicates cindr, the fly ortholog of the human CD2AP AD susceptibility gene, as a modulator of Tau-mediated disease mechanisms. Importantly, we also identify the fly orthologs of FERMT2 and CELF1 as Tau modifiers, and these loci have been independently validated as AD susceptibility loci in the latest GWAS meta analysis. Both CD2AP and FERMT2 have been previously implicated with roles in cell adhesion, and our screen additionally identifies a fly homolog of the human integrin adhesion receptors, ITGAM and ITGA9, as a modifier of Tau neurotoxicity. Our results highlight cell adhesion pathways as important in Tau toxicity and AD susceptibility and demonstrate the power of model organism genetic screens for the functional follow-up of human GWAS. PMID- 24067535 TI - First-principles study of the nano-scaling effect on the electrochemical behavior in LiNi(0.5)Mn(1.5)O4. AB - Nano-scaling of electrode materials is often used in battery applications to enhance performance, particularly relating to rate capability. However, for the high-voltage spinel LiNi0.5Mn1.5O4 conflicting results have been reported on the benefits of nano-scaling. In this study, we present first-principles calculations to investigate the effect of nano-scaling on LiNi0.5Mn1.5O4, specifically focusing on the roles and coupling between surface stability, cation ordering and phase behavior. We calculate and compare the surface energy for the low index facets (100), (110), and (111), and find that the most stable facet is dependent on the cation ordering at the surface layer. In this context, we predict a spontaneous surface reconstruction in the cation-ordered structure which leads to a deviation from the perfect surface cation ordering and results in an enhanced accessibility to solid solution behavior as a function of Li content. Our results imply that nano-scaling will be more beneficial for the cation-ordered structure, as compared to the disordered structure where the solid solution region is already intrinsically accessible for a broad range of Li concentrations. PMID- 24067536 TI - How can we best predict acute kidney injury following cardiac surgery?: a prospective observational study. AB - BACKGROUND: Several models for predicting acute kidney injury following cardiac surgery have been published, and various end-point definitions have been used. OBJECTIVES: Our aim was to investigate how acute kidney injury following cardiac surgery could be most accurately predicted. DESIGN: Single-centre prospective observational study. SETTING: St Olav's University Hospital, Trondheim, Norway, from 2000 to 2007. PATIENTS: All 5029 adult patients undergoing cardiac surgery were considered eligible for participation. Patients who required preoperative dialysis and patients with missing information on preoperative or maximum postoperative serum creatinine concentration were excluded (n=51). A total of 4978 patients were entered into the statistical analyses. MAIN OUTCOME MEASURES: Logistic regression with bootstrapping methods was applied for model development and validation, together with the area under the receiver operating characteristic curve and Hosmer-Lemeshow test. We tested different end-points, exchanged serum creatinine concentration with creatinine clearance or estimated glomerular filtration rate and added intraoperative variables. The main end-point was at least 50% increase in serum creatinine concentration, an increase in concentration by at least 26.4 MUmol l(-1) (0.3 mg dl(-1)) or a new requirement for dialysis after surgery. RESULTS: The final model consisted of 11 preoperative predictors of acute kidney injury: age, BMI, lipid-lowering treatment, hypertension, peripheral vascular disease, chronic pulmonary disease, haemoglobin concentration, serum creatinine concentration, previous cardiac surgery, emergency operation and operation type. The area under the receiver operating characteristic curve was 0.819 (95% confidence interval 0.801 to 0.837), and the Hosmer-Lemeshow test P value was 0.17. Exchanging serum creatinine concentration with glomerular filtration rate or creatinine clearance slightly reduced model discrimination and the addition of intraoperative variables improved discrimination somewhat. Slight end-point definition changes had little impact. CONCLUSION: The risk of acute kidney injury can be accurately predicted using preoperative variables. Serum creatinine concentration was more accurate than estimated glomerular filtration rate or creatinine clearance. Intraoperative variables slightly improved the model, but did not seem to outweigh the advantages of a preoperative model. PMID- 24067537 TI - Association of serum resistin with peripheral arterial disease. AB - INTRODUCTION: Resistin is an inflammatory mediator and a potential biomarker in cardiovascular diseases. OBJECTIVES: We sought to examine its association with peripheral arterial disease (PAD). PATIENTS AND METHODS: We recruited 200 patients with PAD and 100 healthy controls. Patients were divided into 4 subgroups according to the Fontaine classification for PAD, that is, from Stage I to Stage IV. Serum resistin levels were compared between the PAD group and the control group and among 4 PAD subgroups adjusted for selected factors. RESULTS: Serum resistin (Ln-resistin - log scale) levels and high-sensitivity C-reactive protein (hsCRP) levels in patients with PAD were higher than in healthy controls (P <0.05). Moreover, among the 4 PAD subgroups, the value of Ln-resistin in Stage I subgroup was the lowest, and Stage II subgroup had lower Ln-resistin than Stage III subgroup or Stage IV subgroup (P <0.05). There was also a significant difference in hsCRP levels among those 4 subgroups (P <0.05). In PAD patients, Ln resistin levels correlated inversely with the ankle-brachial pressure index (r = 0.301, P <0.05), and positively with total cholesterol levels (r = 0.228, P <0.01). Moreover, a multivariate analysis showed Ln-resistin levels to be an independent risk factor for PAD (odds ratio, 1.237; 95% confidence interval, 1.086-1.396; P <0.01). CONCLUSIONS: Ln-resistin levels and hsCRP are elevated in PAD patients, and they rise as the severity of PAD increases. A multivariate analysis suggests that Ln-resistin could be a prognostic biomarker for the presence of PAD. PMID- 24067538 TI - Morphology and diversity of the forcipules in Strigamia centipedes (Chilopoda, Geophilomorpha). AB - The morphology of the venomous limbs (forcipules) of 13 species of Strigamia and of six other geophilomorphs was studied with light microscopy, scanning electron microscopy, and, for a subsample, with confocal laser scanning microscopy. In all Strigamia species a well-distinct denticle is present invariantly on the inner side of the terminal article (tarsungulum), in sub-basal position, just proximal to a faint transverse sulcus and a cuticular introflexion that corresponds to the insertion point of a tendon. Strigamia species differ mainly in size and shape of the denticle and thickness of the distal part of the tarsungulum, suggesting some functional diversity in piercing and handling prey. Anatomical evidence supports the hypothesis that the tarsungulum corresponds to two ancestral articles and a denticle at the basis of the tarsungulum originated multiple times within geophilomorphs, however in different positions corresponding to either the ancestral sub-terminal article (in Strigamia, other Geophiloidea and some Schendylidae) or the ancestral terminal article (in the himantariid Thracophilus). PMID- 24067539 TI - A developmental study of serotonin-immunoreactive neurons in the embryonic brain of the marbled crayfish and the migratory locust: evidence for a homologous protocerebral group of neurons. AB - It is well established that the brains of adult malacostracan crustaceans and winged insects display distinct homologies down to the level of single neuropils such as the central complex and the optic neuropils. We wanted to know if developing insect and crustacean brains also share similarities and therefore have explored how neurotransmitter systems arise during arthropod embryogenesis. Previously, Sintoni et al. (2007) had already reported a homology of an individually identified cluster of neurons in the embryonic crayfish and insect brain, the secondary head spot cells that express the Engrailed protein. In the present study, we have documented the ontogeny of the serotonergic system in embryonic brains of the Marbled Crayfish in comparison to Migratory Locust embryos using immunohistochemical methods combined with confocal laser-scan microscopy. In both species, we found a cluster of early emerging serotonin immunoreactive neurons in the protocerebrum with neurites that cross to the contralateral brain hemisphere in a characteristic commissure suggesting a homology of this cell cluster. Our study is a first step towards a phylogenetic analysis of neurotransmitter system development and shows that, as for the ventral nerve cord, traits related to neurogenesis in the brain can provide valuable hints for resolving the much debated question of arthropod phylogeny. PMID- 24067540 TI - Strategies for assessing mental health in Haiti: local instrument development and transcultural translation. AB - The lack of culturally appropriate mental health assessment instruments is a major barrier to screening and evaluating efficacy of interventions. Simple translation of questionnaires produces misleading and inaccurate conclusions. Multiple alternate approaches have been proposed, and this study compared two approaches tested in rural Haiti. First, an established transcultural translation process was used to develop Haitian Kreyol versions of the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). This entailed focus group discussions evaluating comprehensibility, acceptability, relevance, and completeness. Second, qualitative data collection was employed to develop new instruments: the Kreyol Distress Idioms (KDI) and Kreyol Function Assessment (KFA) scales. For the BDI and BAI, some items were found to be nonequivalent due to lack of specificity, interpersonal interpretation, or conceptual nonequivalence. For all screening tools, items were adjusted if they were difficult to endorse or severely stigmatizing, represented somatic experiences of physical illness, or were difficult to understand. After the qualitative development phases, the BDI and BAI were piloted with 31 and 27 adults, respectively, and achieved good reliability. Without these efforts to develop appropriate tools, attempts at screening would have captured a combination of atypical suffering, everyday phenomena, and potential psychotic symptoms. Ultimately, a combination of transculturally adapted and locally developed instruments appropriately identified those in need of care through accounting for locally salient symptoms of distress and their negative sequelae. PMID- 24067543 TI - Therapeutic strategy for low-risk thyroid cancer in Kanaji Thyroid Hospital. AB - It is well-known that differentiated thyroid carcinoma (DTC) has a generally indolent character and shows a favorable prognosis in comparison with many other carcinomas. The therapeutic strategy for patients with DTC in Japan has differed from that in Western countries. Total thyroidectomy followed by radioactive iodine (RAI) ablation has been standard in Western countries, whereas limited hemi-thyroidectomy and subtotal thyroidectomy has been extensively accepted in Japan. Papillary thyroid carcinoma (PTC) accounts for over 90% of all thyroid cancers in Japan. The majority of patients with PTC are categorized into a low risk group on the basis of the recent risk-group classification schemes, and they show excellent outcomes. Several management guidelines for thyroid cancers have been published in Western countries. However, the optimal therapeutic options for PTC remain controversial, and high-level clinical evidence aimed at resolving these issues is lacking. Moreover, as socioeconomic differences in medical care exist, conventional policies for the treatment of PTC have differed between Japan and other countries. This review focuses on the special features of treatment in Japan for patients with low-risk DTC involving subtotal thyroidectomy without adjuvant therapies, rather than total thyroidectomy with RAI, with the aim of preserving quality of life. At our institution in Japan, we have had extensive experience with RAI treatment for high-risk DTC patients, and this represents a very rare situation. Here we introduce the therapeutic strategy for low-risk thyroid cancer in Japan, including the measures adopted at our institution. PMID- 24067544 TI - Association between osteoprotegerin genetic variants and osteoporosis in Chinese postmenopausal women. AB - The objective of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) of osteoprotegerin gene (OPG) with bone mineral density (BMD) and osteoporosis. A total of 338 Chinese postmenopausal women with primary osteoporosis and 367 healthy controls were enrolled. The lumbar spine (L2-4), total hip and femoral neck hip of BMD were assessed by dual-energy X-ray absorptiometry (DEXA). OPG genetic variants were genotyped through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), created restriction site-PCR (CRS-PCR) and DNA sequencing methods. In this study, the g.18861A>G and g.25548C>T SNPs were detected and our data suggested that the significant differences of spine BMD, femoral neck hip BMD and total hip BMD were found among different g.18861A>G genotype, subjects with the AA genotype were significantly higher than those of AG and GG genotypes (p < 0.05). The g.25548C>T variant was not significantly associated with spine BMD, femoral neck hip BMD and total hip BMD (p > 0.05), while almost reached at the significant level in total hip BMD (p = 0.061). These findings suggeste that OPG gene variants are related to BMD and osteoporosis in Chinese postmenopausal women. PMID- 24067542 TI - Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue. AB - Myocardial ischemia, while causing cardiomyocyte injury, can activate innate protective processes, enhancing myocardial tolerance to ischemia. Such processes are present in not only the heart, but also remote organs. In this investigation, we demonstrated a cardioprotective process involving FGF21 from the liver and adipose tissue. In response to myocardial ischemia/reperfusion injury in the mouse, FGF21 was upregulated and released from the hepatic cells and adipocytes into the circulation and interacted with FGFR1 in cardiomyocytes under the mediation of the cell membrane protein beta-Klotho, inducing FGFR1 phosphorylation. This action caused phosphorylation of the signaling molecules PI3K p85, Akt1, and BAD, thereby reducing caspase 3 activity, cell death, and myocardial infarction in association with improvement of myocardial function. These observations suggest that FGF21 is upregulated and released from the liver and adipose tissue in myocardial injury, contributing to myocardial protection by the mediation of the FGFR1/beta-Klotho-PI3K-Akt1-BAD signaling network. PMID- 24067545 TI - Serial transplantation and long-term engraftment of intra-arterially delivered clonally derived mesenchymal stem cells to injured bone marrow. AB - It has been hypothesized that mesenchymal stem cells (MSCs) home to sites of injury. Nevertheless, efficient delivery of MSCs to target organs and description of their ultimate fate remain major challenges. We provide evidence that intra arterially (IA) injected MSCs selectively engraft from the circulation as perivascular cells in the bone marrow (BM) after a localized radiation injury. Luciferase-expressing MSCs, derived from a conditionally immortalized clone (BMC 9) representing a pure population of cells, were arterially delivered into mice irradiated in one leg. Cell distribution was measured by bioluminescent imaging and final destination assessed by luciferase immunolocalization. IA injections resulted in engraftment only in the irradiated leg where cells localize and proliferate abluminal to the BM vasculature, a phenomenon not replicated with intravenous injections or with IA injections of kidney cells harvested from the same donor used for MSCs. Furthermore, MSCs harvested from the engrafted marrow and serially transplanted retain the ability to selectively engraft at sites of injury. This study demonstrates that MSCs can serially engraft at sites of injury from the circulation, that they reside in the perivascular space, and that arterial delivery is more efficient than venous delivery for cell engraftment. PMID- 24067546 TI - The effect of flow trigger on rapid shallow breathing index measured through the ventilator. AB - BACKGROUND: The rapid shallow breathing index (RSBI) has the best predictive value to assess readiness for weaning from mechanical ventilation. At many institutions, this index is conveniently measured without disconnecting the patient from the ventilator, but this method may be inaccurate. Because modern ventilators have a base flow in the flow trigger mode that may provide a substantial help to the patient, we hypothesized that the RSBI is significantly decreased when measured through the ventilator with flow trigger even without continuous positive airway pressure (CPAP) and pressure support (PS). METHODS: The RSBI was calculated using the values of minute ventilation and respiratory rate obtained either through the digital display of the ventilator or from a digital ventilometer. The RSBI was measured using 3 different methods: method 1, CPAP and PS both 0 cm H2O with flow trigger; method 2, CPAP and PS both 0 cm H2O without flow trigger; and method 3, using digital ventilometer. RESULTS: A total of 165 measurements per method were obtained in 80 adult patients in the medical intensive care unit (MICU). The RSBI (breaths/min/L) values were 70.2 +/- 26.5 with method 1, 85.4 +/- 30.3 with method 2, and 80.1 +/- 30.3 with method 3. The RSBI was significantly decreased using mechanical ventilation with flow trigger as compared with mechanical ventilation without flow trigger (P < .0001) or digital ventilometer (P < .0001). When method 1 was compared with methods 2 and 3, the RSBI decreased by 17% and 12%, respectively. CONCLUSIONS: The RSBI measurement is significantly decreased by the base flow delivered through modern ventilators in the flow trigger mode. If RSBI is measured through the ventilator in the flow trigger mode, the difference should be considered when using RSBI to assess readiness for weaning from mechanical ventilation. PMID- 24067547 TI - Amiodarone-induced thyroid dysfunction. AB - Amiodarone is an effective medication for the treatment of cardiac arrhythmias. Originally developed for the treatment of angina, it is now the most frequently prescribed antiarrhythmia drug despite the fact that its use is limited because of potential serious side effects including adverse effects on the thyroid gland and thyroid hormones. Although the mechanisms of action of amiodarone on the thyroid gland and thyroid hormone metabolism are poorly understood, the structural similarity of amiodarone to thyroid hormones, including the presence of iodine moieties on the inner benzene ring, may play a role in causing thyroid dysfunction. Amiodarone-induced thyroid dysfunction includes amiodarone-induced thyrotoxicosis (AIT) and amiodarone-induced hypothyroidism (AIH). The AIT develops more commonly in iodine-deficient areas and AIH in iodine-sufficient areas. The AIT type 1 usually occurs in patients with known or previously undiagnosed thyroid dysfunction or goiter. The AIT type 2 usually occurs in normal thyroid glands and results in destruction of thyroid tissue caused by thyroiditis. This is the result of an intrinsic drug effect from the amiodarone itself. Mixed types are not uncommon. Patients with cardiac disease receiving amiodarone treatment should be monitored for signs of thyroid dysfunction, which often manifest as a reappearance of the underlying cardiac disease state. When monitoring patients, initial tests should include the full battery of thyroid function tests, thyroid-stimulating hormone, thyroxine, triiodothyronine, and antithyroid antibodies. Mixed types of AIT can be challenging both to diagnose and treat and therapy differs depending on the type of AIT. Treatment can include thionamides and/or glucocorticoids. The AIH responds favorably to thyroid hormone replacement therapy. Amiodarone is lipophilic and has a long half-life in the body. Therefore, stopping the amiodarone therapy usually has little short-term benefit. PMID- 24067548 TI - Test of mutually unbiased bases for six-dimensional photonic quantum systems. AB - In quantum information, complementarity of quantum mechanical observables plays a key role. The eigenstates of two complementary observables form a pair of mutually unbiased bases (MUBs). More generally, a set of MUBs consists of bases that are all pairwise unbiased. Except for specific dimensions of the Hilbert space, the maximal sets of MUBs are unknown in general. Even for a dimension as low as six, the identification of a maximal set of MUBs remains an open problem, although there is strong numerical evidence that no more than three simultaneous MUBs do exist. Here, by exploiting a newly developed holographic technique, we implement and test different sets of three MUBs for a single photon six dimensional quantum state (a "qusix"), encoded exploiting polarization and orbital angular momentum of photons. A close agreement is observed between theory and experiments. Our results can find applications in state tomography, quantitative wave-particle duality, quantum key distribution. PMID- 24067549 TI - Efficient spectral hole-burning and atomic frequency comb storage in Nd(3+):YLiF4. AB - We present spectral hole-burning measurements of the (4)I9/2 -> (4)F3/2 transition in Nd(3+):YLiF4. The isotope shifts of Nd(3+) can be directly resolved in the optical absorption spectrum. We report atomic frequency comb storage with an echo efficiency of up to 35% and a memory bandwidth of 60 MHz in this material. The interesting properties show the potential of this material for use in both quantum and classical information processing. PMID- 24067550 TI - Pulmonary pathology: new updates. PMID- 24067551 TI - Diagnosis of Streptococcus pneumoniae-associated hemolytic uremic syndrome. AB - BACKGROUND: Hemolytic uremic syndrome related to pneumococcal infection (P+HUS) can be difficult to diagnose due to the lack of a specific test and the absence of a consensus for definite diagnostic criteria. METHODS: A retrospective study was conducted on the cases that have been considered as P+HUS in the participating centers during the past 10 years. Diagnostic strategy and criteria used for the diagnosis of P+HUS were evaluated and compared with a review of literature data. RESULTS: A total of 17 children were studied. Tests ruling out other causes of HUS were performed in 94% of cases. Direct confirmatory tests for P+HUS were done in a minority of cases as Thomsen-Friedenreich antigen testing using lectin assay were done in only 2 patients (11%). Retrospectively, the diagnosis of P+HUS was confirmed in 28% to 89% of cases depending on the already published criteria used. A literature review focused on the last 15 years confirmed these diagnostic difficulties due to variable definition criteria and bring a new light on the potential usefulness of tests used to reveal T activation in this setting. CONCLUSION: To date, in a context of suspicion of P+HUS, no precise, practical and consensual strategy exists for T-antigen exposure diagnosis. The T-antigen activation test using peanut lectin might be the most appropriate test for a direct diagnosis of P+HUS. A large prospective study is required to confirm this hypothesis. However, before such data are available, its use could be of help when a suspicion of P+HUS is present given the therapeutic impact of such a diagnosis. PMID- 24067553 TI - Safety and immunogenicity of a recombinant tetravalent dengue vaccine in 9-16 year olds: a randomized, controlled, phase II trial in Latin America. AB - BACKGROUND: The dengue virus is a member of the Flavivirus (FV) genus, which also includes the yellow fever virus. Dengue disease is caused by any 1 of 4 dengue virus serotypes and is a serious public health concern in Latin America. This study evaluated the safety and immunogenicity of a candidate recombinant, live attenuated, tetravalent dengue vaccine (CYD-TDV) in 9-16 year olds in Latin America. METHODS: In this randomized, blinded, controlled study, volunteers received either 3 doses of CYD-TDV (n = 401) or placebo as first and second injection and tetanus/diphtheria/acellular pertussis vaccine as third injection (n = 199) at 0, 6 and 12 months. Adverse events were documented. Plaque reduction neutralization test antibody titers against the 4 CYD-TDV parental strains were measured before and 28 days after each dose. Seropositivity was defined as antibody titers >=10 1/dil. RESULTS: The number of adverse reactions decreased after each successive CYD-TDV dose. After each CYD-TDV dose, antibody titers against all 4 serotypes were higher than baseline and respective predose titers. After the third dose of CYD-TDV, 100%, 98.6% and 93.4% of participants were seropositive for at least 2, at least 3 or all 4 serotypes, respectively. Higher antibody titers were observed in participants in the CYD-TDV group who were FV seropositive at baseline compared with those who were FV-seronegative. CONCLUSIONS: CYD-TDV had a favorable safety profile and elicited antibody responses against all 4 dengue virus serotypes in 9-16 year olds in Latin America. These findings support the continued development of CYD-TDV. PMID- 24067554 TI - Sleep and infection: no snooze, you lose? PMID- 24067555 TI - Fatal outcome of rhino-orbital-cerebral mucormycosis due to bilateral internal carotid occlusion in a child after hematopoietic stem cell transplantation. AB - Rhino-orbito-cerebral mucormycosis is a rare fulminant opportunistic fungal infection that particularly occurs in immunocompromised patients. We present a case of fatal invasive rhino-orbito-cerebral mucormycosis complicated by bilateral thrombotic occlusion of the internal carotid artery with consequent cerebral infarction in a 5-year-old boy after hematopoietic stem cell transplantation for acute pre-B-cell lymphoblastic leukemia. PMID- 24067552 TI - Incidence of opportunistic illness before and after initiation of highly active antiretroviral therapy in children. AB - BACKGROUND: Little is known about immune reconstitution inflammatory syndrome in children in the United States. METHODS: LEGACY is a longitudinal cohort study of HIV-infected participants 0-24 years at enrollment during 2005 to 2007 from 22 US clinics. For this analysis, we included participants with complete medical record abstraction from birth or time of HIV diagnosis through 2006. Opportunistic illness (OI) included AIDS-defining conditions and selected HIV-related diagnoses. We calculated the incidence (#/100 patient-years) of OI diagnosed in the months pre- and postinitiation of the first highly active antiretroviral therapy (HAART) regimen which was followed by >=1 log reduction in HIV viral load. We defined OI as immune reconstitution inflammatory syndrome if an OI incidence increased after HAART initiation. "Responders" were defined as experiencing >=1 log decline in viral load within 6 months after HAART initiation. RESULTS: Among 575 patients with complete chart abstraction, 524 received HAART. Of these 524 patients, 343 were responders, 181 were nonresponders and 86 experienced OI. Responders accounted for 98 of 124 (79%) of OI. Pre-HAART and post-HAART OI incidences were 43.7 and 24.4 (P = 0.003), respectively, among responders and 15.9 and 9.1 (P = 0.2), respectively, among nonresponders. Overall, OI incidences among responders and nonresponders were 33.8 and 12.3, respectively (P = 0.002). Responders were more likely than nonresponders to experience herpes simplex and herpes zoster before HAART initiation (all, P < 0.002). CONCLUSIONS: The lack of immune reconstitution inflammatory syndrome in participants initiating HAART may be due to low overall OI rates. The unexpectedly higher OI prevalence comprised mainly of herpes simplex and zoster, before HAART initiation among responders, may have motivated them to better adhere to HAART. PMID- 24067556 TI - Severe pertussis in newborns and young vulnerable infants. AB - A retrospective chart review of 18 nonvaccinated newborns and infants admitted to 6 intensive care units in the north of Portugal between 2007 and 2012 revealed a high rate of admissions in 2012 along with significant rates of severe pulmonary hypertension and mortality. Hyperleukocytosis was significantly associated with a more severe clinical picture and mortality. PMID- 24067557 TI - Role of intercellular adhesion molecule-1 and polymeric immunoglobulin receptor in co-colonization of airways with Streptococcus pneumoniae and haemophilus influenzae. PMID- 24067558 TI - Group A streptococcal primary ileitis: a novel presentation of a common pathogen. PMID- 24067559 TI - Mumps vaccines: do we need a new one? PMID- 24067560 TI - Emphysematous pyelonephritis in an infant. PMID- 24067561 TI - HIV-1 phenotypic drug resistance testing among highly treatment experienced and poorly adherent youth. PMID- 24067562 TI - Tenofovir-induced renal tubular dysfunction in vertically HIV-infected patients associated with polymorphisms in ABCC2, ABCC4 and ABCC10 genes. AB - Tenofovir disoproxyl fumarate is a known cause of kidney tubular dysfunction in HIV-infected patients. Recent studies reported significant association between specific allelic variants in ABCC2, ABCC4 and/or ABCC10 genes and the development of kidney tubular dysfunction in HIV-infected adults. We describe the first 2 cases of vertically HIV-infected patients affected by kidney tubular dysfunction associated with polymorphisms in the ABCC genes. PMID- 24067564 TI - Large negative thermal expansion of the Co subnetwork measured by EXAFS in highly disordered Nd1-xCox thin films with perpendicular magnetic anisotropy. AB - We have measured a negative thermal expansion (NTE) of the Co subnetwork in amorphous Nd1-xCox (0.78 < x < 0.84) thin films of the order of 1% in volume using linearly polarized EXAFS spectroscopy at RT and 10 K. The expansion, which is anisotropic, is uncorrelated with the perpendicular magnetic anisotropy (PMA) observed in all the films, but correlated with the method used to deposit them. The atomic environments of the Nd atoms resulted in such a strong disorder that Nd-Nd and Nd-Co environments were invisible to EXAFS, and only Co-Co atomic environments were detected. The information on the Nd subnetwork was obtained through its magnetic moment measured by XMCD. These measurements demonstrate an increasing interaction of neodymium atoms with their particular local crystal field as the temperature decreased, suggesting possible structural modifications at their sites. Since the magnetic moment of the cobalt subnetwork remains essentially constant with the temperature, it is proposed that its detected NTE may be caused by the mechanical response of the amorphous network to structural transformations at the Nd sites. These results support that the PMA in RE-TM alloys is localized at the RE sites. The complete absence of EXAFS oscillations in the Nd L3 EXAFS spectra is remarkable: it means that the coherence length of the photoemitted electrons in disordered matter can be strongly reduced from that expected by atomic calculations to the point of being less than first neighbor distances, which is contrary to the common belief that first neighbors are always visible by EXAFS. PMID- 24067563 TI - Evaluation of risk for late language emergence after in utero antiretroviral drug exposure in HIV-exposed uninfected infants. AB - BACKGROUND: Combination antiretroviral (cARV) regimens are recommended for pregnant women with HIV to prevent perinatal HIV transmission. Safety is a concern for infants who were HIV-exposed but uninfected, particularly for neurodevelopmental problems, such as language delays. METHODS: We studied late language emergence (LLE) in HIV-exposed but uninfected children enrolled in a US based prospective cohort study. LLE was defined as a caregiver-reported score <=10th percentile in any of 4 domains of the MacArthur-Bates Communicative Development Inventory for 1-year olds and as >=1 standard deviation below age specific norms for the Ages and Stages Questionnaire for 2-year olds. Logistic regression models were used to evaluate associations of in utero cARV exposure with LLE, adjusting for infant, maternal and environmental characteristics. RESULTS: 1129 language assessments were conducted among 792 1- and 2-year-old children (50% male, 62% black and 37% Hispanic). Overall, 86% had in utero exposure to cARV and 83% to protease inhibitors. LLE was identified in 26% of 1 year olds and 23% of 2-year olds, with higher rates among boys. In adjusted models, LLE was not associated with maternal cARV or ARV drug classes in either age group. Among cARV-exposed 1-year olds, increased odds of LLE was observed for those exposed to atazanavir (adjusted odds ratio = 1.83, 95% confidence interval: 1.10-3.04), particularly after the first trimester (adjusted odds ratio = 3.56, P = 0.001), compared with atazanavir-unexposed infants. No associations of individual ARV drugs with LLE were observed among 2-year olds. CONCLUSIONS: In utero cARV exposure showed little association with LLE, except for a higher risk of language delay observed in 1-year-old infants with atazanavir exposure. PMID- 24067567 TI - Pulsed-laser time-resolved thermal mirror technique in low-absorbance homogeneous linear elastic materials. AB - A theoretical model for a time-resolved photothermal mirror technique using pulsed-laser excitation was developed for low absorption samples. Analytical solutions to the temperature and thermoelastic deformation equations are found for three characteristic pulse profiles and are compared to finite element analysis methods results for finite samples. An analytical expression for the intensity of the center of a continuous probe laser at the detector plane is derived using the Fresnel diffraction theory, which allows modeling of experimental results. Experiments are performed in optical glasses, and the models are fitted to the data. The parameters of the fit are in good agreement with previous literature data for absorption, thermal diffusion, and thermal expansion of the materials tested. The combined modeling and experimental techniques are shown to be useful for quantitative determination of the physical properties of low absorption homogeneous linear elastic material samples. PMID- 24067566 TI - Simple enrichment and analysis of plasma lysophosphatidic acids. AB - A simple and highly efficient technique for the analysis of lysophosphatidic acid (LPA) subspecies in human plasma is described. The streamlined sample preparation protocol furnishes the five major LPA subspecies with excellent recoveries. Extensive analysis of the enriched sample reveals only trace levels of other phospholipids. This level of purity not only improves MS analyses, but enables HPLC post-column detection in the visible region with a commercially available fluorescent phospholipids probe. Human plasma samples from different donors were analyzed using the above method and validated by LC-ESI/MS/MS. PMID- 24067568 TI - Real-time feedback control using online attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy for continuous flow optimization and process knowledge. AB - The use of automated continuous flow reactors is described, with real-time online Fourier transform infrared spectroscopy (FT-IR) analysis to enable rapid optimization of reaction yield using a self-optimizing feedback algorithm. This technique has been applied to the solvent-free methylation of 1-pentanol with dimethyl carbonate using a gamma-alumina catalyst. Calibration of the FT-IR signal was performed using gas chromatography to enable quantification of yield over a wide variety of flow rates and temperatures. The use of FT-IR as a real time analytical technique resulted in an order of magnitude reduction in the time and materials required compared to previous studies. This permitted a wide exploration of the parameter space to provide process understanding and validation of the optimization algorithms. PMID- 24067565 TI - The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer? AB - Sepsis remains the leading cause of death in most intensive care units. Advances in understanding the immune response to sepsis provide the opportunity to develop more effective therapies. The immune response in sepsis can be characterized by a cytokine-mediated hyper-inflammatory phase, which most patients survive, and a subsequent immune-suppressive phase. Patients fail to eradicate invading pathogens and are susceptible to opportunistic organisms in the hypo-inflammatory phase. Many mechanisms are responsible for sepsis-induced immuno-suppression, including apoptotic depletion of immune cells, increased T regulatory and myeloid derived suppressor cells, and cellular exhaustion. Currently in clinical trial for sepsis are granulocyte macrophage colony stimulating factor and interferon gamma, immune-therapeutic agents that boost patient immunity. Immuno-adjuvants with promise in clinically relevant animal models of sepsis include anti programmed cell death-1 and interleukin-7. The future of immune therapy in sepsis will necessitate identification of the immunologic phase using clinical and laboratory parameters as well as biomarkers of innate and adaptive immunity. PMID- 24067569 TI - Structural analysis of mold temperature dependence of polycarbonate by mid infrared spectroscopy. AB - The mold temperature dependence of bisphenol A polycarbonate (BPAPC) in the view of changing the "flexed state" was investigated by mid-infrared spectroscopy combined with a previously developed thin sample preparation system. The differences in the samples of different mold temperatures were clearly detected. The structural changes in the flexed state of each mold temperature were analyzed by comparing the results using dielectric function analysis of different cutting procedures. Some structure parameters were associated with the contact angle of liquids on polymer plate. The evidence suggests that mold temperature and surface wettability affects the cohesive or entanglement state of polymers at the chemical structure level. PMID- 24067570 TI - In-line near-infrared (NIR) and Raman spectroscopy coupled with principal component analysis (PCA) for in situ evaluation of the transesterification reaction. AB - Biodiesel was synthesized from different commercially available oils while in line Raman and near-infrared (NIR) spectra were obtained simultaneously, and the spectral changes that occurred during the reaction were evaluated with principal component analysis (PCA). Raman and NIR spectra were acquired every 30 s with fiber optic probes inserted into the reaction vessel. The reaction was performed at 60-70 degrees C using magnetic stirring. The time of reaction was 90 min, and during this time, 180 Raman and NIR spectra were collected. NIR spectra were collected using a transflectance probe and an optical path length of 1 mm at 8 cm(-1) spectral resolution and averaging 32 scans; for Raman spectra a 3 s exposure time and three accumulations were adequate for the analysis. Raman spectroscopy showed the ester conversion as evidenced by the displacement of the C=O band from 1747 to 1744 cm(-1) and the decrease in the intensity of the 1000 1050 cm(-1) band and the 1405 cm(-1) band as methanol was consumed in the reaction. NIR spectra also showed the decrease in methanol concentration with the band in the 4750-5000 cm(-1) region; this signal is present in the spectra of the transesterification reaction but not in the neat oils. The variations in the intensity of the methanol band were a main factor in the in-line monitoring of the transesterification reaction using Raman and NIR spectroscopy. The score plot of the first principal component showed the progress of the reaction. The final product was analyzed using (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy and using mid-infrared spectroscopy, confirming the conversion of the oils to biodiesel. PMID- 24067571 TI - Application of Raman spectroscopy, surface-enhanced Raman scattering (SERS), and density functional theory for the identification of phenethylamines. AB - We evaluated the normal Raman (NR) and the surface-enhanced Raman scattering (SERS) of three sympathomimetic amines: phenethylamine, ephedrine, and 3,4 methylenedioxymethamphetamine (MDMA). In addition, quantum mechanical calculations-geometry optimization and calculations of the harmonic vibrational frequencies-were performed using the density functional theory (DFT) approach. Vibrational assignments were made by comparing the experimental and calculated spectra. The study found that both NR and SERS provided excellent spectra for the drugs tested. Certain conditions, such as response to various laser wavelengths and background fluorescence of the analyte, could be easily managed using SERS techniques. The DFT-calculated spectra could be correlated with the experimental spectra without the aid of a scaling factor. We also present a set of discriminant bands, useful for distinguishing the three compounds, despite their structural similarities. PMID- 24067572 TI - Advancing energy cane cell wall digestibility screening by near-infrared spectroscopy. AB - Breeding energy cane for cellulosic biofuel production involves manipulating various traits. An important trait to optimize is cell wall degradability as defined by enzymatic hydrolysis. We investigated the feasibility of using near infrared spectroscopy (NIRS) combined with multivariate calibration to predict energy cane cell wall digestibility based upon fiber samples from a range of sugarcane genotypes and related species. These samples produced digestibility values ranging between 6 and 31%. To preserve the practicality of the technique, spectra obtained from crudely prepared samples were used. Various spectral pre processing methods were tested, with the best NIRS calibration obtained from second derivative, orthogonal signal-corrected spectra. Model performance was evaluated by cross-validation and independent validation. Large differences between the performance results from the two validation approaches indicated that the model was sensitive to the choice of test data. This may be remedied by using a larger calibration training set containing diverse sample types. The best result was obtained through independent validation which produced a R(2) value of 0.86, a root mean squared error of prediction (RMSEP) of 1.59, and a ratio of prediction to deviation (RPD) of 2.7. This study has demonstrated that it is feasible and practical to use NIRS to predict energy cane cell wall digestibility. PMID- 24067573 TI - Determination of phosphorus fertilizer soil reactions by Raman and synchrotron infrared microspectroscopy. AB - The reaction mechanisms of phosphate-bearing mineral phases from sewage sludge ash-based fertilizers in soil were determined by Raman and synchrotron infrared microspectroscopy. Different reaction mechanisms in wet soil were found for calcium and magnesium (pyro-) phosphates. Calcium orthophosphates were converted over time to hydroxyapatite. Conversely, different magnesium phosphates were transformed to trimagnesium phosphate. Since the magnesium phosphates are unable to form an apatite structure, the plant-available phosphorus remains in the soil, leading to better growth results observed in agricultural pot experiments. The pyrophosphates also reacted very differently. Calcium pyrophosphate is unreactive in soil. In contrast, magnesium pyrophosphate quickly formed plant-available dimagnesium phosphate. PMID- 24067574 TI - Accurate Fourier transform infrared (FT-IR) spectroscopy measurements of nitrogen dioxide (NO2) and nitric acid (HNO3) calibrated with synthetic spectra. AB - A novel method for determining the accuracy of laboratory-based measurements of nitrogen dioxide (NO2) and nitric acid (HNO3) mole fractions using Fourier transform infrared (FT-IR) spectroscopy 1 cm(-1) resolution instruments calibrated with synthetic spectra has been developed. The traceability of these measurement results is to the reference line strength data contained within the high-resolution transmission molecular absorption (HITRAN) database. Incorporating a proper estimate of the uncertainty of this data into the measurement results will ensure that the SI traceable values are encompassed within the uncertainty of the measurement results. The major contributors to the uncertainties of the results are, in descending order of importance, the uncertainty in the line strength values (HITRAN 2004), the uncertainty attributed to the generation of reference spectra (including knowledge of the optical path length of the FT-IR gas cell), and temperature measurements of the gas. The stability of the FT-IR instrument itself is only a minor contributor to the overall uncertainty of the measurements. FT-IR measurements of NO2 mole fractions at nominal values of 10 MUmol mol(-1) calibrated with synthetic spectra lead to standard uncertainties of 0.34 MUmol mol(-1) (3.4% relative). In contrast, calibration of the FT-IR instrument with SI traceable gas standards generated by a dynamic weighing system resulted in measurements results with standard uncertainties of 0.04 MUmol mol(-1) (0.4% relative). When comparing the consistency of measurement results based on the synthetic calibration method against those obtained by calibrations with SI traceable gas standards, the existence of a potential bias of ~5% was observed, although this was within the stated uncertainties of the results. The FT-IR measurements of HNO3 mole fractions at nominal values of 200 nmol mol(-1) calibrated with synthetic spectra resulted in values with standard uncertainties of 23 nmol mol(-1) (11% relative) with the dominating uncertainty in this case arising from the stabilization of the mole fraction value within the FT-IR gas cell. PMID- 24067575 TI - Ultraviolet (UVB and UVA) photoprotector activity and percutaneous penetration of extracts obtained from Arrabidaea chica. AB - The aim of this work is to investigate the photoprotection activity and toxicity level of formulations containing the extract and its fractions obtained from leaves of Arrabidaea chica. The ex vivo percutaneous penetration of the extract was evaluated using the photoacoustic spectroscopy technique. The formulation presented optical absorption in the ultraviolet region, including UVA and UVB. This formulation was obtained without adding inorganic UV filters, as is frequently used in commercial sunscreens. The results showed a penetration rate similar to those of commercial sunscreens with its presence on the skin surface at least 180 min after the application. This formulation presented no toxic effects evaluated using hematological, biochemical, and histological assays. The results suggest that the formulation from the leaves of A. chica provides substantial protection against UVA + UVB radiation with a possible advantage of being natural and free of inorganic compounds compared with the majority of available commercial sunscreens. PMID- 24067576 TI - Improved intact soil-core carbon determination applying regression shrinkage and variable selection techniques to complete spectrum laser-induced breakdown spectroscopy (LIBS). AB - Laser-induced breakdown spectroscopy (LIBS) provides a potential method for rapid, in situ soil C measurement. In previous research on the application of LIBS to intact soil cores, we hypothesized that ultraviolet (UV) spectrum LIBS (200-300 nm) might not provide sufficient elemental information to reliably discriminate between soil organic C (SOC) and inorganic C (IC). In this study, using a custom complete spectrum (245-925 nm) core-scanning LIBS instrument, we analyzed 60 intact soil cores from six wheat fields. Predictive multi-response partial least squares (PLS2) models using full and reduced spectrum LIBS were compared for directly determining soil total C (TC), IC, and SOC. Two regression shrinkage and variable selection approaches, the least absolute shrinkage and selection operator (LASSO) and sparse multivariate regression with covariance estimation (MRCE), were tested for soil C predictions and the identification of wavelengths important for soil C prediction. Using complete spectrum LIBS for PLS2 modeling reduced the calibration standard error of prediction (SEP) 15 and 19% for TC and IC, respectively, compared to UV spectrum LIBS. The LASSO and MRCE approaches provided significantly improved calibration accuracy and reduced SEP 32-55% over UV spectrum PLS2 models. We conclude that (1) complete spectrum LIBS is superior to UV spectrum LIBS for predicting soil C for intact soil cores without pretreatment; (2) LASSO and MRCE approaches provide improved calibration prediction accuracy over PLS2 but require additional testing with increased soil and target analyte diversity; and (3) measurement errors associated with analyzing intact cores (e.g., sample density and surface roughness) require further study and quantification. PMID- 24067577 TI - Modeling, characterizing, and accommodating static birefringence in circular and linear dichroism spectroscopy. AB - Nearly all circular dichroism (CD) and linear dichroism (LD) spectrometers use a photoelastic modulator (PEM) in which an optical element is stressed using a high tension voltage (HT) signal to induce birefringence. The birefringence consequently produces a phase difference between perpendicular polarization states of light passing through the PEM that is appropriate to CD or LD measurements. However, even without external stress (i.e., at zero HT) the PEM exhibits an inherent static birefringence. This article discusses the characterization of the static birefringence inherent to a PEM and its effect on the measurement of CD and LD, as well as the development and implementation of a novel model that accommodates for the presence of static birefringence. The model is validated with CD and LD experiments using purely chiral or linearly structured molecules (camphorsulfonic acid and chrysazin). PMID- 24067578 TI - Spectroscopic characterization of urea aqueous solutions: experimental phase diagram of the urea-water binary system. AB - Raman spectroscopy was used to analyze mixtures of urea and water in order to identify the influence of the urea concentration on the solution's freezing point. Our approach consisted in the analysis of urea aqueous solutions and the determination of their phase transitions at low temperatures. Hence, Raman spectra of these solutions were acquired in a -30 to 10 degrees C temperature range. This enabled us to build the experimental phase diagram of the urea-water binary system. PMID- 24067579 TI - A new method for separating configurational and constitutional chiralities using diffuse reflectance circular dichroism (DRCD). AB - Solid-state chiral chemistry has attracted significant scientific interest because of its application in the chiral-selective production, chiral recognition, resolution, and detection of enantiomers of a chiral compound. Combining a novel diffuse reflectance circular dichroism (DRCD) technique with powder X-ray crystallographic analysis, we investigated the origin of chiral properties from the molecular and supramolecular chiralities and the possibility of separating independent CD signals from the superimposed CD signal resulting from different chiral origins. PMID- 24067580 TI - Suicidal ideation in elderly Korean population: a two-year longitudinal study. AB - BACKGROUND: This study aimed to assess the prevalence, incidence, and persistence of suicidal ideation (SI), and to investigate the psychosocial factors associated with these. METHODS: A total of 1,204 community dwelling elderly adults aged 65 years or older were evaluated at baseline, 909 (75%) of whom were followed two years later. The presence of SI was identified using the questions from the community version of the Geriatric Mental State (GMS) diagnostic schedule (GMS B3) at both baseline and follow-up interviews. Baseline measures included demographic status, years of education, rural/urban residence, accommodation, past and current occupation, monthly income, marital status, stressful life events, social support deficits, number of physical illnesses, severity of pain, physical activity, disability, depressive symptoms, anxiety, insomnia, cognitive function, alcohol consumption, and smoking. RESULTS: Baseline SI prevalence, follow-up incidence (SI rate at follow-up of 805 elderly subjects who did not have SI at baseline), and persistence (SI rate at follow-up of 104 elderly subjects who had SI at baseline) were 11.5%, 9.6%, and 36.5%, respectively. Baseline SI was independently associated with no current employment, lower monthly income, stressful life events, more severe pain, presence of disability, depressive symptoms, and smoking. Incident SI was independently predicted by baseline unmarried status, social support deficit, severe pain, presence of depressive symptoms, and smoking. Persistent SI was independently predicted by baseline stressful life events and depressive symptoms. CONCLUSIONS: Depressive symptoms were independently associated with prevalent, incident, and persistent SI, but other predictors varied according to incidence and persistence outcomes. PMID- 24067581 TI - Deaths and severe adverse events associated with anesthesia-assisted rapid opioid detoxification--New York City, 2012. AB - During August-September 2012, the New York City Department of Health and Mental Hygiene (DOHMH) was notified by the New York City Poison Control Center regarding three patients who experienced serious adverse events after anesthesia-assisted rapid opiate detoxification (AAROD) at a local outpatient clinic. All three patients required hospitalization, and one subsequently died. DOHMH issued an order requiring that the clinic cease performing AAROD pending an investigation and searched for additional cases of AAROD-related serious adverse events at the clinic and elsewhere in New York City for the period September 2011 to September 2012. That search found no serious adverse events at clinics other than the one implicated. Of the 75 patients who underwent AAROD at the implicated clinic during January-September 2012, two died, and five others experienced serious adverse events requiring hospitalization. As a result of the findings, the New York State Department of Health, the New York Office of Alcoholism and Substance Abuse Services, and DOHMH jointly issued a Health Alert informing New York health care providers of AAROD-associated serious adverse events and recommending that they avoid use of AAROD in favor of evidence-based options for opioid dependence treatment. PMID- 24067582 TI - Influenza vaccination coverage among health-care personnel--United States, 2012 13 influenza season. AB - Routine influenza vaccination of health-care personnel (HCP) every influenza season can reduce influenza-related illness and its potentially serious consequences among HCP and their patients. To protect HCP and their patients, the Advisory Committee on Immunization Practices (ACIP) recommends that all HCP be vaccinated against influenza during each influenza season. To estimate influenza vaccination coverage among HCP during the 2012-13 season, CDC conducted an opt-in Internet panel survey of 1,944 self-selected HCP during April 1-16, 2013. This report summarizes the results of that survey, which found that, overall, 72.0% of HCP reported having had an influenza vaccination for the 2012-13 season, an increase from 66.9% vaccination coverage during the 2011-12 season. By occupation type, coverage was 92.3% among physicians, 89.1% among pharmacists, 88.5% among nurse practitioners/physician assistants, and 84.8% among nurses. By occupational setting, vaccination coverage was highest among hospital-based HCP (83.1%) and was lowest among HCP at long-term care facilities (LTCF) (58.9%). Vaccination coverage was higher for HCP in occupational settings offering vaccination on-site at no cost for one (75.7%) or multiple (86.2%) days compared with HCP in occupational settings not offering vaccination on-site at no cost (55.3%). Widespread implementation of comprehensive influenza vaccination strategies that focus on improving access to vaccination services is needed to improve HCP vaccination coverage. Influenza vaccination of HCP in all health-care settings might be increased by providing 1) HCP with information on vaccination benefits and risks for themselves and their patients, 2) vaccinations in the workplace at convenient locations and times, and 3) influenza vaccinations at no cost. PMID- 24067583 TI - Influenza vaccination coverage among pregnant women--United States, 2012-13 influenza season. AB - Pregnant women and infants aged <6 months are at increased risk for influenza related severe illness and hospitalization. Influenza vaccination of pregnant women has been shown to reduce the risk for illness in both mother and infant. To help protect pregnant women, the Advisory Committee on Immunization Practices (ACIP) and the American College of Obstetricians and Gynecologists recommend influenza vaccination for all women who are or will be pregnant during the influenza season, regardless of trimester. To estimate influenza vaccination coverage among pregnant women during the 2012-13 influenza season, CDC analyzed data from an Internet panel survey conducted April 1-12, 2013. Among 1,702 self selected survey respondents pregnant at any time during the 4-month period of October 2012-January 2013, 50.5% reported they received influenza vaccination before or during their pregnancy. Influenza vaccination coverage was higher among women reporting both a health-care provider recommendation and offer of influenza vaccination (70.5%) compared with women who received a recommendation but no offer of vaccination (46.3%) and women who received no recommendation (16.1%). Vaccination coverage of women who will be or are pregnant during an influenza season might be improved by implementing a combination of community-based interventions, including enhanced access to low-cost vaccination services, provider recommendation and offer of influenza vaccination, and education of pregnant women about influenza vaccination safety and efficacy during pregnancy to increase demand. PMID- 24067584 TI - Updated information on the epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV) infection and guidance for the public, clinicians, and public health authorities, 2012-2013. AB - The Middle East respiratory syndrome coronavirus (MERS-CoV) was first reported to cause human infection in September 2012. In July 2013, the World Health Organization (WHO) International Health Regulations Emergency Committee determined that MERS-CoV did not meet criteria for a "public health emergency of international concern," but was nevertheless of "serious and great concern". This report summarizes epidemiologic information and provides updates to CDC guidance about patient evaluation, case definitions, travel, and infection control as of September 20, 2013. PMID- 24067585 TI - Progress in increasing electronic reporting of laboratory results to public health agencies--United States, 2013. AB - Electronic reporting of laboratory results to public health agencies can improve public health surveillance for reportable diseases and conditions by making reporting more timely and complete. Since 2010, CDC has provided funding to 57 state, local, and territorial health departments through the Epidemiology and Laboratory Capacity for Infectious Diseases cooperative agreement to assist with improving electronic laboratory reporting (ELR) from clinical and public health laboratories to public health agencies. As part of this agreement, CDC and state and large local health departments are collaborating to monitor ELR implementation in the United States by developing data from each jurisdiction regarding total reporting laboratories, laboratories sending ELR by disease category and message format, and the number of ELR laboratory reports compared with the total number of laboratory reports. At the end of July 2013, 54 of the 57 jurisdictions were receiving at least some laboratory reports through ELR, and approximately 62% of 20 million laboratory reports were being received electronically, compared with 54% in 2012. Continued progress will require collaboration between clinical laboratories, laboratory information management system (LIMS) vendors, and public health agencies. PMID- 24067586 TI - Notes from the field: Department of Defense response to a multistate outbreak of fungal meningitis--United States, October 2012. AB - On October 1, 2012, the Department of Defense (DoD) learned of a multistate outbreak of fungal meningitis in persons who received injections of methylprednisolone acetate (MPA) from a single compounding pharmacy. Ten patients with fungal meningitis after epidural steroid injection (ESI) were initially identified in Tennessee and North Carolina. No military treatment facilities had received MPA from this pharmacy. However, clinics receiving implicated MPA lots were located throughout the United States, and active duty military service members and other DoD health-care beneficiaries could have been exposed through health-care services purchased outside of the DoD health-care system. Therefore, a timely method was needed to determine whether exposure to implicated MPA had occurred among DoD personnel who used purchased care. PMID- 24067588 TI - [Effect of high altitude on birth weight and adverse perinatal outcomes in two Argentine populations]. AB - INTRODUCTION: Depending on the geographical altitude the purpose of this work was to analyze in two argentine populations the variation of birth weight (BW) and adverse perinatal outcomes, adjusting for maternal and obstetric factors. MATERIAL AND METHODS: Data from 4000 births in the provinces of Jujuy and 4000 in Buenos Aires (Sarda Maternity Hospital) (1996-2000) recruited and randomized from the Perinatal Information System was used. The data were grouped according to an altitudinal gradient composed by Sarda Maternity (20 masl) and the geographic regions of Jujuy province: Ramal (500 masl), Valle (1200 masl), Quebrada (2500 masl) and Puna (3500 masl). Outcome variables were BW > 3000 g, BW <2500 g, ponderal index (PI), prematurity, small for gestational age (SGA) and intrauterine growth restriction (FGR), while potentially confounding variables were: age, type of partner, education, overweight, obesity, smoking, hypertension, preeclampsia, urinary infection, growth restriction and cesarean section. RESULTS: An increasing altitudinal gradient for adolescent mothers (<19 years) and decreasing for the rest of the maternal obstetric variables was observed. The BW, BW>3000 g, BW<2500 g and PI were negatively associated with altitude (p <0.001). Prematurity, SGA and FGR showed an opposite trend (p <0.001). Adjusted for confounding variables BW <3000 g, SGA, FGR<0.90 and PI <2.53 showed an increased risk with geographical altitude (p <0.05). CONCLUSIONS: Altitude was independently associated with BW restriction and adverse perinatal outcomes. Given the impact of BW reduction in the risk of chronic no communicable diseases this relationship in other populations, regardless of their location altitude, should be assess. PMID- 24067589 TI - [Pertussis predictors in hospitalized infants with acute lower respiratory tract infection]. AB - BACKGROUND: Pertussis, or whooping cough, caused by Bordetella pertussis (BP) is a re-emerging problem in our environment. Although generally considered that the disease is relatively easy to identify infections respiratory syncytial virus (RSV) can present with similar symptoms in infants remains difficult discrimination. OBJECTIVE: Compare clinical symptoms at admission and complementary studies in infants hospitalized with acute respiratory infection (ARI) and RSV by BP to establish markers that enable their early clinical prediction. MATERIALS AND METHODS: Observational, analytical, case-crossover cross comparing younger than 6 months hospitalized with suspected IRA and pertussis (2007-2012) in which BP identified (PCR and culture) and / or VRS (immunofluorescence in nasal secretions). Coinfections were excluded. Bivariate analysis was performed by calculating OR with 95% CI. Were considered significant at p <0.05. The variables studied were age, sex, hits cough, cyanosis, vomiting, apnea, wheezing and CBC with differential RESULTS: We included 174 infants, 72 (41%) BP and 102 (59%) VRS. Age 2 +/- 1 months (range :1-6). In both groups was documented cough and wheeze (OR: 1.2 (0.9 to 1.5) p: 0.1 and OR = 0.9 (0.8 to 1.06) p: 0.2, respectively ). Cyanosis (87% vs. 6%, OR: 14.8 p <0.01), apnea (38% vs. 3%, OR: 13.4 p <0.01) and vomiting (26% vs. 5% , OR: 3.4 p <0.01) were more frequent in infants with BP. The absolute lymphocyte count was significantly higher in children with BP (9387 +/- 6317 vs. 5127 +/- 2766, p <0.01). By ROC curve was identified at 9000 cells / ml as the best point to differentiate VSR BP (AUC = 0.73, 95% CI :0,64-0, 81). CONCLUSIONS: In infants under 6 months with IRA income presence of apnea, cyanosis and lymphocytosis allowing predict significantly differentiate between pertussis those with RSV infections. PMID- 24067590 TI - [Adverse event reporting in an intensive care unit at Tunja, Colombia]. AB - INTRODUCTION: Patient safety in critical areas has been subject of several studies. In Colombia, there is a growing conscience about adverse events management. This study explores the first phase of this management: report in a typical private intensive care unit. OBJECTIVE: To assess adverse event report at a Colombian tertiary level institution, through frequency and report category assessment. METHODS: A descriptive study regarding adverse event report rates during 2011 period in Clinica de los Andes de Tunja, was carried out, through frequency and report category assessment. Adverse event report rate was defined as the number of reports per 1000 patient bed. We reported major and minor categories of events. RESULTS: A total of 383 admissions (2374 patient days) were recorded. 54 adverse events were reported (rate of 22,74 per 1000 patient days). The most frequent events were related to intravenous route (55%)(CI 95% 50,1 58,3) followed by process deviation (22%)(CI 95% 18,2-26,1). CONCLUSIONS: An adverse event report rate close to the upper limit of literature reports numbers was found. Probably, there is still non quantified under-report of adverse events, likely due to cultural factors. PMID- 24067591 TI - [Cultural adaptation and Argentine validation of the Northwick Park Neck Pain Questionnaire in the hospitals of the Autonomous City of Buenos Aires]. AB - OBJECTIVE: [corrected] To make cultural adaptation and validation of the Northwick Park Neck Pain Questionnaire (NPQ) in Argentina, determining its psychometric properties in patients with neck pain of mechanical origin referred to the physiotherapy Service at D. F. Santojanni Hospital. MATERIALS AND METHODS: autorization of original author of the NPQ was requested. Then we make the linguistic adaptation and pilot study. Psychometric analyses included test-retest reliability (intraclass correlation coefficient), validity (Pearson correlation coefficient NPQ-Visual Analog Scale, VAS), internal consistency (Cronbach Coefficient Alpha) and sensibility to change (paired t test). Sixty patients were inclueed from September 2007 to February 2009 with mechanical neck pain. The variables percentage of disability (NPQ) and pain (VAS) were measured on the day of admission, 24 hours later and when the patient was discharged. RESULTS: Twenty six patients completed the study, 4 were eliminated and 30 did not complete the 3rd measurement. We get a good test-retest reliability (CCI 0,8979) and a high internal consistency (Cronbach Coefficient Alpha 0,86). Validity obtained a good correlation (r=0,678). Sensitivity to change was good (r=0,661). CONCLUSION: The NPQ is a valid, reliable and sensitive instrument to assess disability associated with neck pain of mechanical origin in patients treated at the hospitals of the Autonomous City of Buenos Aires. PMID- 24067592 TI - [Arterial hypertension in patients with type 2 diabetes mellitus]. AB - Hypertension, diabetes and that cluster of metabolic alterations often referred to as the metabolic syndrome are highly prevalent in Argentina and Latin America and occur frequently as associated conditions (65%). The development of diagnostic and therapeutic recommendations prepared through the joint work of experts in different areas of medicine is desirable, considering the low rates of control achieved in the real world, and the benefits that can be expected when reasonable objectives are met. Health care resources and priorities, the socio economic status of the population, and the prevalence of hypertension, diabetes mellitus, and other related diseases vary considerably in different regions of the world and also in different countries within each region, and even in different areas of individual countries. Recommendations to be usefully translated into practice should consider the particular medical and social features of the region where they should be applied and be cost-effective in terms of local needs and possibilities Effectively treatment of hypertension in general and particularly in diabetic patients is one of the major objectives to prevent target organ damage. Unfortunately, in our countries only 25% of the patients are in target. In this document a rationale therapeutic approach is analyzed for hypertension in diabetic patients. Life style changes and pharmacologic treatment combinations is extensively reporte. PMID- 24067593 TI - [Multiple embolisms by atrial myxoma]. PMID- 24067594 TI - [Lung malformation, intralobar pulmonary sequestration]. PMID- 24067595 TI - [Silence is golden]. PMID- 24067596 TI - Porous silicon nanowires for lithium rechargeable batteries. AB - Porous silicon nanowire is fabricated by a simple electrospinning process combined with a magnesium reduction; this material is investigated for use as an anode material for lithium rechargeable batteries. We find that the porous silicon nanowire electrode from the simple and scalable method can deliver a high reversible capacity with an excellent cycle stability. The enhanced performance in terms of cycling stability is attributed to the facile accommodation of the volume change by the pores in the interconnect and the increased electronic conductivity due to a multi-level carbon coating during the fabrication process. PMID- 24067597 TI - Exceptional preservation of Palaeozoic steroids in a diagenetic continuum. AB - The occurrence of intact sterols has been restricted to immature Cretaceous (~125 Ma) sediments with one report from the Late Jurassic (~165 Ma). Here we report the oldest occurrence of intact sterols in a Crustacean fossil preserved for ca. 380 Ma within a Devonian concretion. The exceptional preservation of the biomass is attributed to microbially induced carbonate encapsulation, preventing full decomposition and transformation thus extending sterol occurrences in the geosphere by 250 Ma. A suite of diagenetic transformation products of sterols was also identified in the concretion, demonstrating the remarkable coexistence of biomolecules and geomolecules in the same sample. Most importantly the original biolipids were found to be the most abundant steroids in the sample. We attribute the coexistence of steroids in a diagenetic continuum -ranging from stenols to triaromatic steroids- to microbially mediated eogenetic processes. PMID- 24067598 TI - Myocardial protection by co-administration of L-arginine and tetrahydrobiopterin during ischemia and reperfusion. AB - BACKGROUND: Reduced bioavailability of nitric oxide (NO) is a key factor contributing to myocardial ischemia and reperfusion injury. The mechanism behind the reduction of NO is related to deficiency of the NO synthase (NOS) substrate L arginine and cofactor tetrahydrobiopterin (BH4) resulting in NOS uncoupling. The aim of the study was to investigate if the combination of L-arginine and BH4 given iv or intracoronary before reperfusion protects from reperfusion injury. METHODS: Sprague-Dawley rats and pigs were subjected to myocardial ischemia and reperfusion. Rats received vehicle, L-arginine, BH4, L-arginine+BH4 with or without the NOS-inhibitor L-NMMA iv 5 min before reperfusion. Pigs received infusion of vehicle, L-arginine, BH4 or L-arginine+BH4 into the left main coronary artery for 30 min starting 10 min before reperfusion. RESULTS: Infarct size was significantly smaller in the rats (50 +/- 2%) and pigs (54 +/- 5%) given L-arginine+BH4 in comparison with the vehicle groups (rats 65 +/- 3% and pigs 86 +/- 5%, P<0.05). Neither L-arginine nor BH4 alone significantly reduced infarct size. Administration of L-NMMA abrogated the cardioprotective effect of L arginine+BH4. Myocardial BH4 levels were 3.5- to 5-fold higher in pigs given L arginine+BH4 and BH4 alone. The generation of superoxide in the ischemic reperfused myocardium was reduced in pigs treated with intracoronary L arginine+BH4 versus the vehicle group (P<0.05). CONCLUSION: Administration of L arginine+BH4 before reperfusion protects the heart from ischemia-reperfusion injury. The cardioprotective effect is mediated via NOS-dependent pathway resulting in diminished superoxide generation. PMID- 24067599 TI - A simple method for measuring baroreflex sensitivity holds prognostic value in heart failure. PMID- 24067600 TI - A cornerstone of heart failure treatment is not effective in experimental right ventricular failure. AB - BACKGROUND: Right ventricular (RV) failure due to increased pressure load causes significant morbidity and mortality in patients with congenital heart diseases and pulmonary arterial hypertension. It is unknown whether renin-angiotensin aldosterone-system (RAAS) inhibition (the cornerstone of left ventricular failure treatment) is effective in RV failure. We investigated the effects of combination treatment of aldosterone-blocker eplerenone+angiotensin II receptor blocker losartan (Ep/Lo) on RV remodeling and function in a model of RV failure due to increased pressure load. METHODS AND RESULTS: Rats (n=48) were randomized for pulmonary artery banding (PAB) or sham surgery and for losartan (20 mg/kg/d)+eplerenone (100 mg/kg/d) treatment (Ep/Lo) or vehicle (VEH). RV function was assessed by echocardiography and pressure-volume analysis at 5 and 11 weeks, or at the occurrence of clinical RV failure symptoms necessitating termination. PAB resulted in RV failure in all rats, as defined by reduced cardiac output, RV stroke volume, increased RV end diastolic pressure and liver congestion as well as RV fibrosis, hypertrophy and reduced capillary density. Clinical RV failure necessitated termination in 5/12 PAB-VEH rats. Angiotensin II type 1-receptor expression in the RV was reduced in PAB rats indicating local RAAS activation. Treatment of PAB rats with Ep/Lo significantly lowered arterial pressures, but had no significant effect on RV function, remodeling or survival compared to PAB VEH rats. CONCLUSIONS: RAAS inhibition does not beneficially affect experimental RV failure due to chronic pressure load. This is of high clinical relevance, because it indicates that the RV response to RAAS inhibition might fundamentally differ from that of the LV. PMID- 24067602 TI - Fertility sparing treatment of recurrent stage I serous borderline ovarian tumours. AB - Here we report the outcomes of 26 patients who relapsed following conservative surgical treatment of stage I serous borderline ovarian tumours treated initially with fertility-sparing surgery. All recurrences were diagnosed by systematic ultrasonography during follow-up. Eleven patients relapsed at least twice after such management. Twenty-one pregnancies were observed in 13 patients. Eleven of these patients became pregnant after the treatment of their first recurrence. All patients had a borderline ovarian tumour and/or non-invasive peritoneal implants at the time of the first recurrence but two of them had invasive ovarian and peritoneal disease at the time of the second or third recurrence (one of them died of disease). Fertility-preserving surgery remains a valuable alternative (if technically feasible), in young patients with recurrent SBOT, in the form of a non-invasive ovarian lesion, who wish to start a pregnancy. However, it should be associated with meticulous follow-up because the risk of progression to carcinoma exists, albeit small. PMID- 24067601 TI - p,p'-DDE activates CatSper and compromises human sperm function at environmentally relevant concentrations. AB - STUDY QUESTION: Is the environmental endocrine disruptor p,p' dichlorodiphenyldichloroethylene (p,p'-DDE) able to induce non-genomic changes in human sperm and consequently affect functional sperm parameters? SUMMARY ANSWER: p,p'-DDE promoted Ca(2+) flux into human sperm by activating CatSper channels even at doses found in human reproductive fluids, ultimately compromising sperm parameters important for fertilization. WHAT IS KNOWN ALREADY: p,p'-DDE may promote non-genomic actions and interact directly with pre-existing signaling pathways, as already observed in other cell types. However, although often found in both male and female reproductive fluids, its effects on human spermatozoa function are not known. STUDY DESIGN, SIZE, DURATION: Normozoospermic sperm samples from healthy individuals were included in this study. Samples were exposed to several p,p'-DDE concentrations for 3 days at 37 degrees C and 5% CO2 in vitro to mimic the putative continuous exposure to this toxicant in the female reproductive tract in vivo. Shorter p,p'-DDE incubation periods were also performed in order to monitor sperm rapid Ca(2+) responses. All experiments were repeated on a minimum of five sperm samples from different individuals. PARTICIPANTS/MATERIALS, SETTING, METHODS: All healthy individuals were recruited at the Biosciences School, University of Birmingham, the Medical Research Institute, University of Dundee and in the Human Reproduction Service at University Hospitals of Coimbra. Intracellular Ca(2+) concentration ([Ca(2+)]i) was monitored by imaging single spermatozoa loaded with Oregon Green BAPTA-1AM and further whole-cell patch-clamp recordings were performed to validate our results. Sperm viability and acrosomal integrity were assessed using the LIVE/DEAD sperm vitality kit and the acrosomal content marker PSA-FITC, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: p,p'-DDE rapidly increased [Ca(2+)]i (P < 0.05) even at extremely low doses (1 pM and 1 nM), with magnitudes of response up to 200%, without affecting sperm viability, except after 3 days of continuous exposure to the highest concentration tested (P < 0.05). Furthermore, experiments performed in a low Ca(2+) medium demonstrated that extracellular Ca(2+) influx was responsible for this Ca(2+) increase (P < 0.01). Mibefradil and NNC 55-0396, both inhibitors of the sperm-specific CatSper channel, reversed the p,p'-DDE-induced [Ca(2+)]i rise, suggesting the participation of CatSper in this process (P < 0.05). In fact, whole-cell patch-clamp recordings confirmed CatSper as a target of p,p'-DDE action by monitoring an increase in CatSper currents of >100% (P < 0.01). Finally, acrosomal integrity was adversely affected after 2 days of exposure to p,p'-DDE concentrations, suggesting that [Ca(2+)]i rise may cause premature acrosome reaction (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: This is an in vitro study, and caution must be taken when extrapolating the results. WIDER IMPLICATIONS OF THE FINDINGS: A novel non-genomic p,p'-DDE mechanism specific to sperm is shown in this study. p,p'-DDE was able to induce [Ca(2+)]i rise in human sperm through the opening of CatSper consequently compromising male fertility. The promiscuous nature of CatSper activation may predispose human sperm to the action of some persistent endocrine disruptors. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by both the Portuguese National Science Foundation (FCT; PEst-C/SAU/LA0001/2011) and the UK Wellcome Trust (Grant #86470). SM was supported by the Infertility Research Trust. RST is a recipient of a PhD fellowship from FCT (SFRH/BD/46002/2008). None of the authors has any conflict of interest to declare. PMID- 24067603 TI - Carbamylated-oxidized LDL: proatherosclerotic effects on endothelial cells and macrophages. AB - AIM: Both oxidized LDL and carbamylated LDL are considered important for initiating atherosclerosis in patients with end-stage kidney disease through vascular endothelial cell dysfunction or injury. However their effects on each other and their relationship related to pro-atherosclerotic effects on endothelial cells and macrophages have not been investigated. In this study, we analyzed the competition between LDL carbamylation and oxidation, tested biological effects of carbamylated-oxidized LDL (coxLDL) toward the endothelial cells, assessed its ability to cause foam cell development, and determined the roles of scavenger receptors in this process. METHODS: Cross-competition between carbamylation and oxidation of LDL particles was tested using cell-free fluorescent ligand-receptor assay. Pro-atherogenic properties (cell proliferation, cytotoxicity, and foam cell formation) of all LDL isoforms were tested in vitro and ex vivo using endothelial cells and peritoneal macrophages. In addition, coxLDL was assessed in human sera and in vivo atherosclerotic plaques which were developed in mouse model of uremia-induced atherosclerosis. RESULTS: Our data suggest that there is potential competition between carbamylation and oxidation of LDL, and that oxidation is a much stronger inhibitor of carbamylation than vice versa. coxLDL is highly cytotoxic to endothelial cells and strongly induce their proliferation measured by DNA synthesis. All three tested LDL isoforms demonstrated strong ability for transformation of primary mouse peritoneal macrophages to foam cells using predominantly CD36 scavenger receptor. coxLDL was the most potent inducer of foam cell development and macrophages/foam cell injury assessed by cell count and TUNEL, respectively. Finally, LDL particles modified by oxidation and carbamylation were detected in blood and shown to co-localize in atherosclerotic plaques in mice. CONCLUSION: Our study demonstrated that LDL particles can be simultaneously carbamylated and oxidized and modifications are likely coexisting in the same LDL particle. We also demonstrated proatherosclerotic properties of coxLDL and proposed its role in atherosclerosis. PMID- 24067604 TI - Prevalence and factors related to hepatitis B and C infection in inflammatory bowel disease patients in China: a retrospective study. AB - OBJECTIVES: The objectives of this retrospective study were to assess the prevalence of HBV and HCV infection in Chinese IBD patients, identify potential risk factors of the infection in this population, and discuss the prevalence of HBV and HCV in the general Chinese population. METHODS: A total of 714 IBD patients who had been investigated for HBV and/or HCV infection were consecutively enrolled in the study. Clinical and laboratory data on IBD and hepatitis infection were collected. A control group of 22,373 healthy individuals was also included in the study. RESULTS: Present and past HBV infection was found in 40.62% of IBD patients (ulcerative colitis: HBsAg+, 5.68%; anti-HBc+, 41.64%; Crohn's disease: HBsAg+, 5.29%; anti-HBc+, 39.80%;), and 27.58% of the non-IBD group (HBsAg+, 5.52%; anti-HBc+, 27.58% [P = 0.00]). HCV infection was found in 0.42% of IBD patients and 0.36% of the non-IBD group (P=0.80). One hundred and fifty-four of the IBD patients (21.57%) had been effectively vaccinated for HBV. In a multivariate analysis, age, family history of hepatitis B, and IBD-related admission were significantly related to HBV infection in IBD patients. Potential risk factors for HCV were not analyzed due to the limited number of HCV-positive patients in the study. CONCLUSIONS: Prevalence of HBV infection in IBD patients was higher than that in the non-IBD patients, whereas prevalence of HCV infection was similar to that of the non-IBD group. Effective vaccination for HBV was present in only a small proportion of IBD patients. PMID- 24067606 TI - Hot electron attenuation of direct and scattered carriers across an epitaxial Schottky interface. AB - Hot electron transport of direct and scattered carriers across an epitaxial NiSi2/n-Si(111) interface, for different NiSi2 thickness, is studied using ballistic electron emission microscopy (BEEM). We find the BEEM transmission for the scattered hot electrons in NiSi2 to be significantly lower than that for the direct hot electrons, for all thicknesses. Interestingly, the attenuation length of the scattered hot electrons is found to be twice as large as that of the direct hot electrons. The lower BEEM transmission for the scattered hot electrons is due to inelastic scattering of the injected hot holes while the larger attenuation length of the scattered hot electrons is a consequence of the differences in the energy distribution of the injected and scattered hot electrons and the increasing attenuation length, at lower energies, of the direct hot electrons in NiSi2. PMID- 24067605 TI - Changes in symptoms and lifestyle factors in patients seeking healthcare for gastrointestinal symptoms: an 18-year follow-up study. AB - BACKGROUND: Gastrointestinal symptoms and lifestyle change over time. The data from this 18-year longitudinal study are intended to further elucidate the long term natural course of functional gastrointestinal (GI) symptoms and possible influencing factors. AIM: The aim of this study was to evaluate the correlation between lifestyle factors over time by reassessing symptom profiles in patients who presented with GI symptoms in 1990. METHOD: The study population comprises a subset of individuals enrolled in the Swedish Dyspepsia Study, which commenced in 1990. In 1990, each participant in the Swedish Dyspepsia Study underwent physical assessment and completed a computer-based questionnaire on eight GI symptoms and lifestyle factors. An identical questionnaire was completed in 2008. RESULTS: In total, 137 participants, 85 women and 52 men, were included in the follow-up study. None of the symptoms increased in frequency. Four of the symptoms decreased in frequency: abdominal pain [odds ratio (OR) 2.70], flatulence (OR 4.09), nausea (OR 3.05), and acid regurgitation (OR 1.59). Significant lifestyle changes included increased BMI (P<0.0001), decreased tobacco smoking (P<0.0001), and milk drinking (P=0.0080). Increased exercise was correlated with a decrease in acid regurgitation (OR 3.05) and vomiting (OR 7.38), but an increase in diarrhea (OR 0.23) and nausea (OR 0.33). Decreased smoking was correlated with a decrease in acid regurgitation (OR 3.45) and heartburn (OR 2.91). CONCLUSION: The results indicated that the lifestyle changes in the studied population followed the same pattern as seen in the general population, and changes in lifestyle factors may have an impact on GI symptoms and may guide symptom management in the patient, all in order to reduce personal suffering and healthcare costs in the form of fewer visits to the doctor and lower numbers of drug prescriptions. PMID- 24067607 TI - Biological techniques: Chromosomes captured one by one. PMID- 24067608 TI - Microscopic observation of magnon bound states and their dynamics. AB - The existence of bound states of elementary spin waves (magnons) in one dimensional quantum magnets was predicted almost 80 years ago. Identifying signatures of magnon bound states has so far remained the subject of intense theoretical research, and their detection has proved challenging for experiments. Ultracold atoms offer an ideal setting in which to find such bound states by tracking the spin dynamics with single-spin and single-site resolution following a local excitation. Here we use in situ correlation measurements to observe two magnon bound states directly in a one-dimensional Heisenberg spin chain comprising ultracold bosonic atoms in an optical lattice. We observe the quantum dynamics of free and bound magnon states through time-resolved measurements of two spin impurities. The increased effective mass of the compound magnon state results in slower spin dynamics as compared to single-magnon excitations. We also determine the decay time of bound magnons, which is probably limited by scattering on thermal fluctuations in the system. Our results provide a new way of studying fundamental properties of quantum magnets and, more generally, properties of interacting impurities in quantum many-body systems. PMID- 24067609 TI - Directional tissue migration through a self-generated chemokine gradient. AB - The directed migration of cell collectives is a driving force of embryogenesis. The predominant view in the field is that cells in embryos navigate along pre patterned chemoattractant gradients. One hypothetical way to free migrating collectives from the requirement of long-range gradients would be through the self-generation of local gradients that travel with them, a strategy that potentially allows self-determined directionality. However, a lack of tools for the visualization of endogenous guidance cues has prevented the demonstration of such self-generated gradients in vivo. Here we define the in vivo dynamics of one key guidance molecule, the chemokine Cxcl12a, by applying a fluorescent timer approach to measure ligand-triggered receptor turnover in living animals. Using the zebrafish lateral line primordium as a model, we show that migrating cell collectives can self-generate gradients of chemokine activity across their length via polarized receptor-mediated internalization. Finally, by engineering an external source of the atypical receptor Cxcr7 that moves with the primordium, we show that a self-generated gradient mechanism is sufficient to direct robust collective migration. This study thus provides, to our knowledge, the first in vivo proof for self-directed tissue migration through local shaping of an extracellular cue and provides a framework for investigating self-directed migration in many other contexts including cancer invasion. PMID- 24067610 TI - Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. AB - Large-scale chromosome structure and spatial nuclear arrangement have been linked to control of gene expression and DNA replication and repair. Genomic techniques based on chromosome conformation capture (3C) assess contacts for millions of loci simultaneously, but do so by averaging chromosome conformations from millions of nuclei. Here we introduce single-cell Hi-C, combined with genome-wide statistical analysis and structural modelling of single-copy X chromosomes, to show that individual chromosomes maintain domain organization at the megabase scale, but show variable cell-to-cell chromosome structures at larger scales. Despite this structural stochasticity, localization of active gene domains to boundaries of chromosome territories is a hallmark of chromosomal conformation. Single-cell Hi-C data bridge current gaps between genomics and microscopy studies of chromosomes, demonstrating how modular organization underlies dynamic chromosome structure, and how this structure is probabilistically linked with genome activity patterns. PMID- 24067611 TI - A Silurian placoderm with osteichthyan-like marginal jaw bones. AB - The gnathostome (jawed vertebrate) crown group comprises two extant clades with contrasting character complements. Notably, Chondrichthyes (cartilaginous fish) lack the large dermal bones that characterize Osteichthyes (bony fish and tetrapods). The polarities of these differences, and the morphology of the last common ancestor of crown gnathostomes, are the subject of continuing debate. Here we describe a three-dimensionally preserved 419-million-year-old placoderm fish from the Silurian of China that represents the first stem gnathostome with dermal marginal jaw bones (premaxilla, maxilla and dentary), features previously restricted to Osteichthyes. A phylogenetic analysis places the new form near the top of the gnathostome stem group but does not fully resolve its relationships to other placoderms. The analysis also assigns all acanthodians to the chondrichthyan stem group. These results suggest that the last common ancestor of Chondrichthyes and Osteichthyes had a macromeric dermal skeleton, and provide a new framework for studying crown gnathostome divergence. PMID- 24067612 TI - Temperature-dependent regulation of flowering by antagonistic FLM variants. AB - The appropriate timing of flowering is crucial for plant reproductive success. It is therefore not surprising that intricate genetic networks have evolved to perceive and integrate both endogenous and environmental signals, such as carbohydrate and hormonal status, photoperiod and temperature. In contrast to our detailed understanding of the vernalization pathway, little is known about how flowering time is controlled in response to changes in the ambient growth temperature. In Arabidopsis thaliana, the MADS-box transcription factor genes FLOWERING LOCUS M (FLM) and SHORT VEGETATIVE PHASE (SVP) have key roles in this process. FLM is subject to temperature-dependent alternative splicing. Here we report that the two main FLM protein splice variants, FLM-beta and FLM-delta, compete for interaction with the floral repressor SVP. The SVP-FLM-beta complex is predominately formed at low temperatures and prevents precocious flowering. By contrast, the competing SVP-FLM-delta complex is impaired in DNA binding and acts as a dominant-negative activator of flowering at higher temperatures. Our results show a new mechanism that controls the timing of the floral transition in response to changes in ambient temperature. A better understanding of how temperature controls the molecular mechanisms of flowering will be important to cope with current changes in global climate. PMID- 24067613 TI - Attractive photons in a quantum nonlinear medium. AB - The fundamental properties of light derive from its constituent particles- massless quanta (photons) that do not interact with one another. However, it has long been known that the realization of coherent interactions between individual photons, akin to those associated with conventional massive particles, could enable a wide variety of novel scientific and engineering applications. Here we demonstrate a quantum nonlinear medium inside which individual photons travel as massive particles with strong mutual attraction, such that the propagation of photon pairs is dominated by a two-photon bound state. We achieve this through dispersive coupling of light to strongly interacting atoms in highly excited Rydberg states. We measure the dynamical evolution of the two-photon wavefunction using time-resolved quantum state tomography, and demonstrate a conditional phase shift exceeding one radian, resulting in polarization-entangled photon pairs. Particular applications of this technique include all-optical switching, deterministic photonic quantum logic and the generation of strongly correlated states of light. PMID- 24067614 TI - Temperature triggers immune evasion by Neisseria meningitidis. AB - Neisseria meningitidis has several strategies to evade complement-mediated killing, and these contribute to its ability to cause septicaemic disease and meningitis. However, the meningococcus is primarily an obligate commensal of the human nasopharynx, and it is unclear why the bacterium has evolved exquisite mechanisms to avoid host immunity. Here we demonstrate that mechanisms of meningococcal immune evasion and resistance against complement increase in response to an increase in ambient temperature. We have identified three independent RNA thermosensors located in the 5' untranslated regions of genes necessary for capsule biosynthesis, the expression of factor H binding protein, and sialylation of lipopolysaccharide, which are essential for meningococcal resistance against immune killing. Therefore increased temperature (which occurs during inflammation) acts as a 'danger signal' for the meningococcus, enhancing its defence against human immune killing. Infection with viral pathogens, such as influenza, leads to inflammation in the nasopharynx with an increased temperature and recruitment of immune effectors. Thermoregulation of immune defence could offer an adaptive advantage to the meningococcus during co-infection with other pathogens, and promote the emergence of virulence in an otherwise commensal bacterium. PMID- 24067615 TI - Palaeontology: A jaw-dropping fossil fish. PMID- 24067616 TI - Microbiology: RNAs at fever pitch. PMID- 24067617 TI - Condensed-matter physics: Quantum togetherness. PMID- 24067618 TI - Advancements in biomedical micro/nano tools and technology. PMID- 24067619 TI - Mitro-aortic aneurysms in children: single-centre experience and review of the literature. AB - OBJECTIVES: This publication aims to report the cases of four children with pseudoaneurysm of the mitral-aortic intervalvular fibrosa and carry out a review of the literature. BACKGROUND: Pseudoaneurysm of the mitral-aortic intervalvular fibrosa is a very rare anomaly in children. It can be either congenital or acquired, namely, after bacterial endocarditis or cardiac trauma. This pathology does not usually cause specific symptoms but its outcome may be potentially fatal. METHODS: We report the cases of four patients presenting with pseudoaneurysm of the mitral-aortic intervalvular fibrosa, referred for treatment in a paediatric cardiology clinic. Patient clinical notes were retrospectively reviewed for aetiology, clinical presentation, diagnostic work-up, surgical treatment, and follow-up. Literature on the subject was extensively reviewed. RESULTS: In three patients, pseudoaneurysm of the mitral-aortic intervalvular fibrosa was acquired, being secondary to bacterial endocarditis in two cases and establishing after mitral surgery in another case. The remaining patient had a "congenital" aetiology - no other cause could be traced. The diagnosis was achieved by transthoracic echocardiography for all patients, and confirmed in all by trans-oesophageal echocardiography, to better define morphological details and to access flow into the aneurysmal formation. All patients were submitted to corrective cardiac surgery. Of the patients, three survived and were cured by surgery, staying asymptomatic, and one died after repeated interventions, for persistent endocarditis. CONCLUSIONS: Pseudoaneurysm of the mitral-aortic intervalvular fibrosa is a rare but potentially fatal anomaly. In our experience, surgical cure was achieved for the majority of the cases, except for a case for which infection could not be locally eradicated, leading to multiple reinterventions. PMID- 24067620 TI - Sexually transmitted infections screening at HIV treatment centers for MSM can be cost-effective. AB - OBJECTIVE: To estimate the cost-effectiveness of anorectal chlamydia screening among men who have sex with men (MSM) in care at HIV treatment centers. DESIGN: Transmission model combined with economic analysis over a 20-year period. SETTING AND PARTICIPANTS: MSM in care at HIV treatment centers. INTERVENTION: Once-yearly or twice-yearly screening for anorectal chlamydia among MSM in care at HIV treatment centers. MAIN OUTCOME MEASURES: Averted HIV and chlamydia infections; discounted quality-adjusted life-years and costs; incremental cost-effectiveness ratio (ICER). RESULTS: Costs will be saved by routine chlamydia screening of MSM in care at HIV treatment centers if these patients seek little or no screening elsewhere. Nonroutine screening is considerably more expensive than routine screening offered within a scheduled visit. Adding once-yearly chlamydia screening for MSM in care at HIV treatment centers is cost saving when 30% or fewer of those men seek once-yearly screening elsewhere (1.5 to 8.1 million euro saved). Twice-yearly routine screening at HIV treatment centers is cost-effective only when routine screening takes place without additional nonroutine screening (1.9 million euro saved). CONCLUSIONS: Adding annual chlamydia screening to the HIV consultation will be cost saving as long as only a limited proportion of men are nonroutinely screened. The ICER was most sensitive to the percentage of MSM that continue to be screened elsewhere. PMID- 24067622 TI - Prediction stability in a data-based, mechanistic model of sigmaF regulation during sporulation in Bacillus subtilis. AB - Mathematical modeling of biological networks can help to integrate a large body of information into a consistent framework, which can then be used to arrive at novel mechanistic insight and predictions. We have previously developed a detailed, mechanistic model for the regulation of sigma(F) during sporulation in Bacillus subtilis. The model was based on a wide range of quantitative data, and once fitted to the data, the model made predictions that could be confirmed in experiments. However, the analysis was based on a single optimal parameter set. We wondered whether the predictions of the model would be stable for all optimal parameter sets. To that end we conducted a global parameter screen within the physiological parameter ranges. The screening approach allowed us to identify sensitive and sloppy parameters, and highlighted further required datasets during the optimization. Eventually, all parameter sets that reproduced all available data predicted the physiological situation correctly. PMID- 24067621 TI - Role of hysteroscopy prior to assisted reproduction techniques. AB - STUDY OBJECTIVE: To determine whether diagnostic hysteroscopy before assisted reproduction techniques (AlphaRT) in women without known disease of the uterine cavity is necessary. DESIGN: Prospective cohort clinical study. SETTING: Reproductive medicine clinic. PATIENTS: The study group consisted of 217 infertile women attending the Reproductive Clinic for examination before undergoing ART, either in vitro fertilization or intracytoplasmic sperm injection. INTERVENTIONS: Patients underwent transvaginal sonography (TVS) and hysterosalpingography (HSG) for initial evaluation. If there were no abnormal intrauterine findings, diagnostic hysteroscopy was additionally performed. MEASUREMENTS AND MAIN RESULTS: The safety and diagnostic value of hysteroscopy before ART was examined. Diagnostic hysteroscopy was performed successfully, without complications, in all 217 women. Ninety-five (43.7%) had a history of ART failures (group 1), and 122 (56.3%) had undergone no previous ART attempts (group 2). In 148 women (68.2%), findings at hysteroscopy were normal, whereas in 69 (31.8%), hysteroscopy revealed intrauterine lesions (polyps, septa, submucosal leiomyomas, or synechiae) that led to operative hysteroscopy. The most common intrauterine abnormality was the presence of endometrial polyps in 26 patients (12%). The total percentage of abnormal intrauterine findings was higher in women with a history of repeated ART failures in comparison with those with no history of ART attempts. No statistically significant difference in the outcome of in vitro fertilization or intracytoplasmic sperm injection was observed between women with normal hysteroscopic findings and patients with hysteroscopically corrected endometrial disease. CONCLUSION: Sensitivity of diagnostic hysteroscopy is significantly higher than TVS and HSG in the diagnosis of intrauterine lesions. Diagnostic hysteroscopy should be performed before ART in all patients, including women with normal TVS and/or HSG findings, because a significant percentage of them have undiagnosed uterine disease that may impair the success of fertility treatment. PMID- 24067623 TI - Determination of aerosol oxidative activity using silver nanoparticle aggregation on paper-based analytical devices. AB - Airborne particulate matter (PM) pollution significantly impacts human health, but the cellular mechanisms of PM-induced toxicity remain poorly understood. A leading hypothesis on the effects of inhaled PM involves the generation of cellular oxidative stress. To investigate PM-induced oxidative stress, analytical methods have been developed to study the chemical oxidation of dithiothreitol (DTT) in the presence of PM. Although DTT readily reacts with several forms of reactive oxygen species, this molecule is not endogenously produced in biological systems. Glutathione (GSH), on the other hand, is an endogenous antioxidant that is produced throughout the body and is directly involved in combating oxidative stress in the lungs and other tissues. We report here a new method for measuring aerosol oxidative activity that uses silver nanoparticle (AgNP) aggregation coupled to glutathione (GSH) oxidation in a paper-based analytical device. In this assay, the residual reduced GSH from the oxidation of reduced GSH to its disulfide induces the aggregation of AgNPs on a paper-based analytical device, which produces a reddish-brown product. Two methods for aerosol oxidative reactivity are presented: one based on change in color intensity using a traditional paper-based techniques and one based on the length of the color product formed using a distance-based device. These methods were validated against traditional spectroscopic assays for DTT and GSH that employ Elman's reagent. No significant difference was found between the levels measured by all three GSH methods (our two paper-based devices and the traditional method) at the 95% confidence level. PM reactivity towards GSH was less than towards DTT most likely due to the difference in the oxidation potential between the two molecules. PMID- 24067624 TI - Metabolic profiling framework for discovery of candidate diagnostic markers of malaria. AB - Despite immense efforts to combat malaria in tropical and sub-tropical regions, the potency of this vector-borne disease and its status as a major driver of morbidity and mortality remain undisputed. We develop an analytical pipeline for characterizing Plasmodium infection in a mouse model and identify candidate urinary biomarkers that may present alternatives to immune-based diagnostic tools. We employ (1)H nuclear magnetic resonance (NMR) profiling followed by multivariate modeling to discover diagnostic spectral regions. Identification of chemical structures is then made on the basis of statistical spectroscopy, multinuclear NMR, and entrapment of candidates by iterative liquid chromatography (LC) and mass spectrometry (MS). We identify two urinary metabolites (i) 4-amino 1-[3-hydroxy-5-(hydroxymethyl)-2,3-dihydrofuran-2-yl]pyrimidin-2(1H)-one, (ii) 2 amino-4-({[5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4-hydroxy-4,5-dihydrofuran-2 yl]methyl}sulfanyl)butanoic acid that were detected only in Plasmodium berghei infected mice. These metabolites have not been described in the mammalian or parasite metabolism to date. This analytical pipeline could be employed in prospecting for infection biomarkers in human populations. PMID- 24067625 TI - In situ Raman spectroscopy of LiFePO4: size and morphology dependence during charge and self-discharge. AB - Previous studies of the size dependent properties of LiFePO4 have focused on the diffusion rate or phase transformation pathways by bulk analysis techniques such as x-ray diffraction (XRD), neutron diffraction and electrochemistry. In this work, in situ Raman spectroscopy was used to study the surface phase change during charge and self-discharge on a more localized scale for three morphologies of LiFePO4: (1) 25 +/- 6 nm width nanorods, (2) 225 +/- 6 nm width nanorods and (3) ~2 MUm porous microspheres. Both the large nanorod and microsphere geometries showed incomplete delithiation at the end of charge, which was most likely caused by anti-site defects along the 1D diffusion channels in the bulk of the larger particles. Based on the in situ Raman measurements, all of the morphologies studied exhibited self-discharge with time. Among them, the smallest FePO4 particles self-discharged (lithiated) the fastest. While nanostructuring LiFePO4 can offer advantages in terms of lowering anti-site defects within particles, it also creates new problems due to high surface energies that allow self-discharge. The in situ Raman spectroscopy also showed that carbon coating did not provide significant improvement to the stability of the lithiated particles. PMID- 24067628 TI - Guest editorial: Eastern Analytical Symposium and Exhibition 2012. PMID- 24067626 TI - Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness. AB - BACKGROUND: Small abdominal aortic aneurysms (AAAs; 3.0-5.4 cm in diameter) are usually asymptomatic and managed by regular ultrasound surveillance until they grow to a diameter threshold (commonly 5.5 cm) at which surgical intervention is considered. The choice of appropriate surveillance intervals is governed by the growth and rupture rates of small AAAs, as well as their relative cost effectiveness. OBJECTIVES: The aim of this series of studies was to inform the evidence base for small AAA surveillance strategies. This was achieved by literature review, collation and analysis of individual patient data, a focus group and health economic modelling. DATA SOURCES: We undertook systematic literature reviews of growth rates and rupture rates of small AAAs. The databases MEDLINE, EMBASE on OvidSP, Cochrane Central Register of Controlled Trials 2009 Issue 4, ClinicalTrials.gov, and controlled-trials.com were searched from inception up until the end of 2009. We also obtained individual data on 15,475 patients from 18 surveillance studies. REVIEW METHODS: Systematic reviews of publications identified 15 studies providing small AAA growth rates, and 14 studies with small AAA rupture rates, up to December 2009 (later updated to September 2012). We developed statistical methods to analyse individual surveillance data, including the effects of patient characteristics, to inform the choice of surveillance intervals and provide inputs for health economic modelling. We updated an existing health economic model of AAA screening to address the cost-effectiveness of different surveillance intervals. RESULTS: In the literature reviews, the mean growth rate was 2.3 mm/year and the reported rupture rates varied between 0 and 1.6 ruptures per 100 person-years. Growth rates increased markedly with aneurysm diameter, but insufficient detail was available to guide surveillance intervals. Based on individual surveillance data, for each 0.5-cm increase in AAA diameter, growth rates increased by about 0.5 mm/year and rupture rates doubled. To control the risk of exceeding 5.5 cm to below 10% in men, on average a 7-year surveillance interval is sufficient for a 3.0-cm aneurysm, whereas an 8-month interval is necessary for a 5.0-cm aneurysm. To control the risk of rupture to below 1%, the corresponding estimated surveillance intervals are 9 years and 17 months. Average growth rates were higher in smokers (by 0.35 mm/year) and lower in patients with diabetes (by 0.51 mm/year). Rupture rates were almost fourfold higher in women than men, doubled in current smokers and increased with higher blood pressure. Increasing the surveillance interval from 1 to 2 years for the smallest aneurysms (3.0-4.4 cm) decreased costs and led to a positive net benefit. For the larger aneurysms (4.5 5.4 cm), increasing surveillance intervals from 3 to 6 months led to equivalent cost-effectiveness. LIMITATIONS: There were no clear reasons why the growth rates varied substantially between studies. Uniform diagnostic criteria for rupture were not available. The long-term cost-effectiveness results may be susceptible to the modelling assumptions made. CONCLUSIONS: Surveillance intervals of several years are clinically acceptable for men with AAAs in the range 3.0-4.0 cm. Intervals of around 1 year are suitable for 4.0-4.9-cm AAAs, whereas intervals of 6 months would be acceptable for 5.0-5.4-cm AAAs. These intervals are longer than those currently employed in the UK AAA screening programmes. Lengthening surveillance intervals for the smallest aneurysms was also shown to be cost effective. Future work should focus on optimising surveillance intervals for women, studying whether or not the threshold for surgery should depend on patient characteristics, evaluating the usefulness of surveillance for those with aortic diameters of 2.5-2.9 cm, and developing interventions that may reduce the growth or rupture rates of small AAAs. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 24067629 TI - Thermo-optical characterization of cadmium selenide/zinc sulfide (CdSe/ZnS) quantum dots embedded in biocompatible materials. AB - Cadmium selenide/zinc sulfide (CdSe/ZnS) core-shell quantum dots (QDs) embedded in biocompatible materials were thermally and optically characterized with a thermal lens (TL) technique. Transient TL measurements were performed with a mode mismatched, dual-beam (excitation and probe) configuration. A thermo-optical study of the CdSe/ZnS QDs was performed for different core diameters (3.5, 4.0, 5.2, and 6.6 nm) in aqueous solution and synthetic saliva, and three different core diameters (2.4, 2.9, and 4.1 nm) embedded in restorative dental resin (0.025% by mass). The thermal diffusivity results are characteristic of the biocompatible matrices. The radiative quantum efficiencies for aqueous solution and biofluid materials are dependent on the core size of the CdSe/ZnS core-shell QDs. The results obtained from the fluorescence spectral measurements for the biocompatible materials support the TL results. PMID- 24067630 TI - Time-resolved surface infrared spectroscopy during atomic layer deposition. AB - This work presents a novel method for obtaining surface infrared spectra with sub second time resolution during atomic layer deposition (ALD). Using a rapid-scan Fourier transform infrared (FT-IR) spectrometer, we obtain a series of synchronized interferograms (120 ms) during multiple ALD cycles to observe the dynamics of an average ALD cycle. We use a buried metal layer (BML) substrate to enhance absorption by the surface species. The surface selection rules of the BML allow us to determine the contribution from the substrate surface as opposed to that from gas-phase molecules and species adsorbed at the windows. In addition, we use simulation to examine the origins of increased reflectivity associated with phonon absorption by the oxide layers. The simulations are also used to determine the decay in enhancement by the buried metal layer substrate as the oxide layer grows during the experiment. These calculations are used to estimate the optimal number of ALD cycles for our experimental method. PMID- 24067631 TI - Photothermal lens spectrometry measurements in highly turbid media. AB - We measured the photothermal lens signal in samples exhibiting high turbidity using a pump-probe scheme. We show that the photothermal lens signal properties remain nearly unchanged up to values of turbidity of 6 cm(-1) despite the signal reduction due to the decrease of excitation power associated to turbidity losses. The signal starts decreasing abruptly for values of turbidity larger than 6 cm( 1). Multiple light scattering yields a reduction of the temperature gradients, which results in a decrease of the effective signal. However, the signal-to-noise ratio remains above 50 for turbidity values of 9 cm(-1), which corresponds to a reduction of light transmission by more than four orders of magnitude. We report on the detection of the photothermal lens signal through a 2 mm layer of organic tissue with a signal-to-noise ratio of about 500. This technique appears promising for imaging applications in organic samples, which usually exhibit high turbidity for visible and near-infrared light. PMID- 24067632 TI - Continuous online Fourier transform infrared (FT-IR) spectrometry analysis of hydrogen chloride (HCl), carbon dioxide (CO2), and water (H2O) in nitrogen-rich and ethylene-rich streams. AB - The prevalence of optical spectroscopy techniques being applied to the online analysis of continuous processes has increased in the past couple of decades. The ability to continuously "watch" changing stream compositions as operating conditions change has proven invaluable to pilot and world-scale manufacturing in the chemical and petrochemical industries. Presented here is an application requiring continuous monitoring of parts per million (ppm) by weight levels of hydrogen chloride (HCl), water (H2O), and carbon dioxide (CO2) in two gas-phase streams, one nitrogen-rich and one ethylene-rich. Because ethylene has strong mid infrared (IR) absorption, building an IR method capable of quantifying HCl, H2O, and CO2 posed some challenges. A long-path (5.11m) Fourier transform infrared (FT IR) spectrometer was used in the mid-infrared region between 1800 and 5000 cm( 1), with a 1 cm(-1) resolution and a 10 s spectral update time. Sample cell temperature and pressure were controlled and measured to minimize measurement variability. Models using a modified classical least squares method were developed and validated first in the laboratory and then using the process stream. Analytical models and process sampling conditions were adjusted to minimize interference of ethylene in the ethylene-rich stream. The predictive capabilities of the measurements were +/-0.5 ppm for CO2 in either stream; +/-1.1 and +/-1.3 ppm for H2O in the nitrogen-rich and ethylene-rich streams, respectively; and +/-1.0 and +/-2.4 ppm for HCl in the nitrogen-rich and ethylene rich streams, respectively. Continuous operation of the instrument in the process stream was demonstrated using an automated stream switching sample system set to 10 min intervals. Response time for all components of interest was sufficient to acquire representative stream composition data. This setup provides useful insight into the process for troubleshooting and optimizing plant operating conditions. PMID- 24067633 TI - Development of a spectrofluorimetric method for the determination of ofloxacin in urine. AB - A simple, accurate, rapid, and sensitive spectrofluorimetric method for the determination of ofloxacin in urine was developed by means of first derivative matrix isopotential synchronous fluorescence spectrometry (MISF). The calibration curve was found to be linear in the concentration range 40-320 ng/mL. The method allows the determination of compound in samples with unknown background fluorescence without the need for tedious pre-separation. Synchronous scans are performed along a trajectory that connects points of identical intensity in a three-dimensional fluorescence spectrum. The unknown analytical signal of the urine is suppressed from the MISF spectrum by calculating its first derivative at lambdaex = 319.2 and lambdaem = 465 nm. In order to ensure maximum sensitivity and adequate selectivity, the experimental variables affecting fluorescence intensity were studied in the ofloxacin band centered at lambdaex = 333 and lambdaem = 460 nm. As result, the determination was performed in a water medium at pH 7.2, adjusted by using sodium dihydrogen phosphate as a buffer solution. Calibration graphs were subjected to a comprehensive statistical analysis. The detection limit according to Long and Winefordner was 8.4 ng/mL, and the detection limit proposed by Clayton was 13.9 ng/mL. PMID- 24067634 TI - Studies on the optogalvanic effect and isotope-selective excitation of ytterbium in a hollow cathode discharge lamp using a pulsed dye laser. AB - This paper presents studies on the pulsed optogalvanic effect and isotope selective excitation of Yb 555.648 nm (0 cm(-1) -> 17 992.007 cm(-1)) and 581.067 nm (17 992.007 cm(-1) -> 35 196.98 cm(-1)) transitions, in a Yb/Ne hollow cathode lamp. The Yb atoms were excited by narrow linewidth (500-1000 MHz) Rh110 and Rh6G dye based pulsed lasers. Optogalvanic signal inversion for ground state transition at 555.648 nm was observed beyond a hollow cathode discharge current of 8.5 mA, in contrast to normal optogalvanic signal at 581.067 nm up to maximum current of 14 mA. The isotope-selective excitation studies of Yb were carried out by recording Doppler limited optogalvanic signals as a function of dye laser wavelength. For the 581.067 nm transition, three even isotopes, (172)Yb, (174)Yb, and (176)Yb, and one odd isotope, (171)Yb, were clearly resolved. These data were compared with selective isotope excitation by 10 MHz linewidth continuous-wave dye laser. For 555.648 nm transition, isotopes were not clearly resolved, although isotope peaks of low modulation were observed. PMID- 24067635 TI - Phenylhydrazones of piperidin-4-ones as AND, OR, NOR, NAND, and INH molecular logic gates. AB - Phenylhydrazone derivatives of 2,6-diarylpiperidin-4-ones viz., 3-methyl-2,6 diphenylpiperidin-4-one (PMP-PH) and 3-methyl-2,6-di-(9H-fluorenyl)piperidin-4 one (FMP-PH) when illuminated and protonated perform the functions of AND, OR, NOR, NAND Boolean logic gates with all optical outputs. The functions of the AND and the NAND gates rely on changes in absorption and emission of the phenylhydrazone upon isomerization of the photochromic unit. We report novel heterocyclic compounds where setting up of threshold absorption or emission can be made as a logic device. PMID- 24067636 TI - Application of visible/near-infrared reflectance spectroscopy to uranium ore concentrates for nuclear forensic analysis and attribution. AB - Uranium ore concentrates (UOCs) are produced at mining facilities from the various types of uranium-bearing ores using several processes that can include different reagents, separation procedures, and drying conditions. The final UOC products can consist of different uranium species, which are important to identify to trace interdicted samples back to their origins. Color has been used as a simple indicator; however, visual determination is subjective and no chemical information is provided. In this work, we report the application of near infrared (NIR) spectroscopy as a non-contact, non-destructive method to rapidly analyze UOC materials for species and/or process information. Diffuse reflectance spectra from 350 to 2500 nm were measured from a number UOC samples that were also characterized by X-ray diffraction. Combination and overtone bands were used to identify the amine and hydroxyl-containing species, such as ammonium uranates or ammonium uranyl carbonate, while other uranium oxide species (e.g., uranium trioxide [UO3] and triuranium octoxide [U3O8]) exhibit absorption bands arising from crystal field effects and electronic transitions. Principal component analysis was used to classify the different UOC materials. PMID- 24067637 TI - Mid-infrared planar silver halide waveguides with integrated grating couplers. AB - Grating couplers for planar silver halide waveguides were designed and fabricated by using focused ion beam (FIB) milling technology, facilitating coupling of mid infrared radiation from quantum cascade lasers into thin-film waveguide structures. An optimized rectangular grating structure for an emitted wavelength of 10.4 MUm, with a grating constant of 16.4 MUm was integrated into a silver halide waveguide substrate via an optimized FIB fabrication procedure. Efficient incoupling and radiation propagation through the waveguide was confirmed by analyzing droplets of acetic acid at different concentrations, deposited at the waveguide surface via evanescent field absorption spectroscopy. PMID- 24067638 TI - Application of laser-induced breakdown spectroscopy (LIBS) and neural networks to olive oils analysis. AB - The adulteration and traceability of olive oils are serious problems in the olive oil industry. In this work, a method based on laser-induced breakdown spectroscopy (LIBS) and neural networks (NNs) has been developed and applied to the identification, quality control, traceability, and adulteration detection of extra virgin olive oils. Instant identification of the samples is achieved using a spectral library, which was obtained by analysis of representative samples using a single laser pulse and treatment by NNs. The samples used in this study belong to four countries. The study also included different regions of each country. The results obtained allow the identification of the oils tested with a certainty of more than 95%. Single-shot measurements were enough for clear identification of the samples. The method can be developed for automatic real time, fast, reliable, and robust measurements, and the system can be packed into portable form for non-specialist users. PMID- 24067639 TI - Raman chemical mapping of magnesium stearate delivered by a punch-face lubrication system on the surface of placebo and active tablets. AB - Raman chemical mapping was used to determine the distribution of magnesium stearate, a lubricant, on the surface of tablets. The lubrication was carried out via a punch-face lubrication system with different spraying rates applied on placebo and active-containing tablets. Principal component analysis was used for decomposing the matrix of Raman mapping spectra. Some of the loadings associated with minuscule variation in the data significantly overlap with the Raman spectrum of magnesium stearate in placebo tablets and allow for imaging the domains of magnesium stearate via corresponding scores. Despite the negligible variation accounted for by respective principal components, the score images seem reliable as demonstrated through thresholding the one-dimensional representation and the spectra of the hot pixels that show a weak but perceivable magnesium stearate band at 1295 cm(-1). The same approach was applied on the active formulation, but no magnesium stearate was identified, presumably due to overwhelming concentration and spectral contribution of the active pharmaceutical ingredient. PMID- 24067640 TI - High-pressure far-infrared spectroscopic studies of hydrogen bonding in formic acid. AB - Simple molecules such as HCOOH, or formic acid, are suggested to have played important roles in planetary physics due to their possibility for high pressure and temperature chemistry under impact conditions. In this study, we have investigated the effect of pressure (up to 50 GPa) on H-bonding and reactivity of formic acid using synchrotron far infrared spectroscopy. Based on the pressure induced changes to H-bond nu(O-H...O) stretching and gamma(O-H...O) deformations, we observe significant reorganization of H-bonding network beginning at ~20 GPa. This is in good agreement with reports of symmetrization of H-bonds reported at 16-21 GPa from X-ray diffraction and Raman spectroscopy studies as well as molecular dynamics simulations. With further increase in pressure, beyond 35 GPa, formic acid undergoes a polymerization process that is complete beyond 45 GPa. Remarkably, upon decompression, the polymeric phase reverts to the crystalline high-pressure phase at 8 GPa. PMID- 24067641 TI - A method for resolving overlapped peaks in laser-induced breakdown spectroscopy (LIBS). AB - Spectral peak overlapping is a basic problem in analytical data processing of laser-induced breakdown spectroscopy (LIBS). Curve fitting is the typical method of resolving overlapped peaks. For preventing ambiguous fitting, appropriate initial values must be known. The aim of this work was to present a method that could be used to determine appropriate initial values of the curve-fitting method by using fractional differential theory. According to the variation of characteristic points of Lorentzian peaks at different fractional differential orders, parameter estimators were obtained that were used to calculate the initial values of the curve-fitting method. As it is a widely used optimization method, the Levenberg-Marquardt method was used in curve fitting. Simulation and LIBS experimental results proved that the proposed method of the initial value estimation can effectively resolve the overlapped peaks in LIBS data processing. PMID- 24067642 TI - Broadband two-color laser-induced incandescence pyrometry approach for nanoparticle characterization with improved sensitivity. AB - A spectral filtering approach for improving the sensitivity of two-color laser induced incandescence measurements is proposed. The commonly used bandpass filters providing wavelength selection, and hence temperature sensitivity, are replaced by shortpass and longpass filters, respectively, allowing significantly higher signal intensities to be detected. This modification is of particular interest when nanoparticles with low emissivity, for instance, metal and metal oxide particles, are investigated. An example case in which the conventional optical components are compared with the new approach reveals an improvement by more than one order of magnitude. PMID- 24067643 TI - Determination of phosphate phases in sewage sludge ash-based fertilizers by Raman microspectroscopy. AB - The chemical form of phosphate phases in sewage sludge ash (SSA)-based fertilizers was determined by Raman microspectroscopy. Raman mapping with a lateral resolution of 5 * 5 MUm(2) easily detected different compounds present in the fertilizers with the help of recorded reference spectra of pure substances. Quartz and aluminosilicates showed Raman bands in the range of 450-520 cm(-1). Phosphates with apatite structure and magnesium triphosphate were determined at around 960 and 980 cm(-1), respectively. Furthermore, calcium/magnesium pyrophosphates were detected in some samples. PMID- 24067644 TI - Real-time sensing of soil nitrate concentration in the parts per million range while the soil is in motion. AB - Reactive nitrogen (Nr) is a term used to describe non-nitrogen gas (non-N2) forms of nitrogen (N) in the biosphere. It causes major pollution problems when it occurs in excess, and it has many sources, including fertilizers used in production agriculture. Currently there is no on-the-go soil nitrate sensor that could guide the application of the optimal amount of fertilizer, which often varies significantly within a field. We report for the first time nitrate-in-soil measurements performed on moving soil samples at concentration levels relevant for fertilizer application. An infrared emission technique called transient infrared spectroscopy (TIRS) was tested on soil samples spiked with different nitrate concentrations in the parts-per-million range and moving at a velocity of 2.6 m/s (5.8 miles per hour) in the laboratory. The TIRS Fourier transform infrared (FT-IR) spectra were modeled by partial least squares and produced a standard error of cross-validation (SECV) of 6.3 parts per million (ppm) N and an R(2) of 0.938 for 512-scan spectra. These results are compared to those using fewer TIRS scans and to those from photoacoustic spectroscopy (PAS) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) measurements on stationary samples. TIRS 128-, 32-, and 8-scan spectra yielded SECVs of 11.2, 11.4, and 18.4 ppm N and R(2) values of 0.800, 0.831, and 0.583, respectively. The PAS and DRIFTS measurements produced SECVs of 12.4 and 9.0 ppm N and R(2) values of 0.766 and 0.876, respectively. PMID- 24067645 TI - Role of orthopyroxene in rheological weakening of the lithosphere via dynamic recrystallization. AB - For plate tectonics to operate on a terrestrial planet, the surface layer (the lithosphere) must have a modest strength (Earth, <= 200 MPa), but a standard strength profile based on olivine far exceeds this threshold value. Consequently, it is essential to identify mechanisms that reduce the strength of the lithosphere on Earth. Here we report results of high-strain laboratory deformation experiments on a representative olivine-orthopyroxene composition that show the addition of orthopyroxene substantially reduces the strength in the ductile regime within a certain temperature window. The reduction in strength is associated with the formation of small orthopyroxene and olivine grains. Our samples show heterogeneous microstructures similar to those observed in natural peridotites in shear zones: fine-grained regions containing both orthopyroxene and olivine that form interconnected bands where a large fraction of strain is accommodated. A model is developed to apply these results to geological conditions. Such a model, combined with our experimental observations, suggests that orthopyroxene may play a key role in the plastic deformation of the lithosphere in a critical temperature range, leading to long-term weakening associated with strain localization in the lithosphere. PMID- 24067646 TI - Mechanism of E-cadherin dimerization probed by NMR relaxation dispersion. AB - Epithelial cadherin (E-cadherin), a member of the classical cadherin family, mediates calcium-dependent homophilic cell-cell adhesion. Crystal structures of classical cadherins reveal an adhesive dimer interface featuring reciprocal exchange of N-terminal beta-strands between two protomers. Previous work has identified a putative intermediate (called the "X-dimer") in the dimerization pathway of wild-type E-cadherin EC1-EC2 domains, based on crystal structures of mutants not capable of strand swapping and on deceleration of binding kinetics by mutations at the X-dimer interface. In the present work, NMR relaxation dispersion spectroscopy is used to directly observe and characterize intermediate states without the need to disrupt the strand-swapped binding interface by mutagenesis. The results indicate that E-cadherin forms strand-swapped dimers predominantly by a mechanism in which formation of a weak and short-lived X-dimer like state precedes the conformational changes required for formation of the mature strand-swapped dimeric structure. Disruption of this intermediate state through mutation reduces both association and dissociation rates by factors of ~10(4), while minimally perturbing affinity. The X-dimer interface lowers the energy barrier associated with strand swapping and enables E-cadherins to form strand-swapped dimers at a rate consistent with residence times in adherens junctions. PMID- 24067647 TI - Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina. AB - Accumulating evidence suggests that photoreceptor cells play a previously unappreciated role in the development of early stages of diabetic retinopathy, but the mechanism by which this occurs is not clear. Inhibition of oxidative stress is known to inhibit the vascular lesions of early diabetic retinopathy, and we investigated whether the diabetes-induced oxidative stress in the retina emanates from photoreceptors. Superoxide generation was assessed in retinas of male C57BL/6J mice made diabetic for 2 mo (4 mo of age when killed) using histochemical (dichlorofluorescein and dihydroethidine) and bioluminescence (lucigenin) methods. Photoreceptors were eliminated in vivo by genetic (opsin(-/ )) and chemical (iodoacetic acid) techniques. Immunoblots were used to measure expression of intercellular adhesion molecule 1 and the inducible form of nitric oxide synthase. Diabetes increased the generation of superoxide by diabetic mouse retina more at night than during the day. Photoreceptors were the major source of reactive oxygen species in the retina, and their deletion (either genetically in opsin(-/-) mice or acutely with iodoacetic acid) inhibited the expected diabetes induced increase in superoxide and inflammatory proteins in the remaining retina. Both mitochondria and NADPH oxidase contributed to the observed retinal superoxide generation, which could be inhibited in vivo with either methylene blue or apocynin. Photoreceptors are the major source of superoxide generated by retinas of diabetic mice. Pharmaceuticals targeting photoreceptor oxidative stress could offer a unique therapy for diabetic retinopathy. PMID- 24067648 TI - Reversible DNA methylation regulates seasonal photoperiodic time measurement. AB - In seasonally breeding vertebrates, changes in day length induce categorically distinct behavioral and reproductive phenotypes via thyroid hormone-dependent mechanisms. Winter photoperiods inhibit reproductive neuroendocrine function but cannot sustain this inhibition beyond 6 mo, ensuring vernal reproductive recrudescence. This genomic plasticity suggests a role for epigenetics in the establishment of seasonal reproductive phenotypes. Here, we report that DNA methylation of the proximal promoter for the type III deiodinase (dio3) gene in the hamster hypothalamus is reversible and critical for photoperiodic time measurement. Short photoperiods and winter-like melatonin inhibited hypothalamic DNA methyltransferase expression and reduced dio3 promoter DNA methylation, which up-regulated dio3 expression and induced gonadal regression. Hypermethylation attenuated reproductive responses to short photoperiods. Vernal refractoriness to short photoperiods reestablished summer-like methylation of the dio3 promoter, dio3 expression, and reproductive competence, revealing a dynamic and reversible mechanism of DNA methylation in the mammalian brain that plays a central role in physiological orientation in time. PMID- 24067649 TI - 14-3-3sigma stabilizes a complex of soluble actin and intermediate filament to enable breast tumor invasion. AB - The protein 14-3-3sigma (stratifin) is frequently described as a tumor suppressor silenced in about 80% of breast tumors. Intriguingly, we show that 14-3-3sigma expression, which in normal breast is localized to the myoepithelial cells, tracks with malignant phenotype in two models of basal-like breast cancer progression, and in patients, it is associated with basal-like subtype and poor clinical outcome. We characterized a mechanism by which 14-3-3sigma guides breast tumor invasion by integrating cytoskeletal dynamics: it stabilizes a complex of solubilized actin and intermediate filaments to maintain a pool of "bioavailable" complexes for polarized assembly during migration. We show that formation of the actin/cytokeratin/14-3-3sigma complex and cellular migration are regulated by PKCzeta-dependent phosphorylation, a finding that could form the basis for intervention in aggressive breast carcinomas expressing 14-3-3sigma. Our data suggest that the biology of this protein is important in cellular movement and is contingent on breast cancer subtype. PMID- 24067650 TI - Optimizing water permeability through the hourglass shape of aquaporins. AB - The ubiquitous aquaporin channels are able to conduct water across cell membranes, combining the seemingly antagonist functions of a very high selectivity with a remarkable permeability. Whereas molecular details are obvious keys to perform these tasks, the overall efficiency of transport in such nanopores is also strongly limited by viscous dissipation arising at the connection between the nanoconstriction and the nearby bulk reservoirs. In this contribution, we focus on these so-called entrance effects and specifically examine whether the characteristic hourglass shape of aquaporins may arise from a geometrical optimum for such hydrodynamic dissipation. Using a combination of finite-element calculations and analytical modeling, we show that conical entrances with suitable opening angle can indeed provide a large increase of the overall channel permeability. Moreover, the optimal opening angles that maximize the permeability are found to compare well with the angles measured in a large variety of aquaporins. This suggests that the hourglass shape of aquaporins could be the result of a natural selection process toward optimal hydrodynamic transport. Finally, in a biomimetic perspective, these results provide guidelines to design artificial nanopores with optimal performances. PMID- 24067651 TI - A functional sequence-specific interaction between influenza A virus genomic RNA segments. AB - Influenza A viruses cause annual influenza epidemics and occasional severe pandemics. Their genome is segmented into eight fragments, which offers evolutionary advantages but complicates genomic packaging. The existence of a selective packaging mechanism, in which one copy of each viral RNA is specifically packaged into each virion, is suspected, but its molecular details remain unknown. Here, we identified a direct intermolecular interaction between two viral genomic RNA segments of an avian influenza A virus using in vitro experiments. Using silent trans-complementary mutants, we then demonstrated that this interaction takes place in infected cells and is required for optimal viral replication. Disruption of this interaction did not affect the HA titer of the mutant viruses, suggesting that the same amount of viral particles was produced. However, it nonspecifically decreased the amount of viral RNA in the viral particles, resulting in an eightfold increase in empty viral particles. Competition experiments indicated that this interaction favored copackaging of the interacting viral RNA segments. The interaction we identified involves regions not previously designated as packaging signals and is not widely conserved among influenza A virus. Combined with previous studies, our experiments indicate that viral RNA segments can promote the selective packaging of the influenza A virus genome by forming a sequence-dependent supramolecular network of interactions. The lack of conservation of these interactions might limit genetic reassortment between divergent influenza A viruses. PMID- 24067652 TI - Tudor domain containing 12 (TDRD12) is essential for secondary PIWI interacting RNA biogenesis in mice. AB - Piwi-interacting RNAs (piRNAs) are gonad-specific small RNAs that provide defense against transposable genetic elements called transposons. Our knowledge of piRNA biogenesis is sketchy, partly due to an incomplete inventory of the factors involved. Here, we identify Tudor domain-containing 12 (TDRD12; also known as ECAT8) as a unique piRNA biogenesis factor in mice. TDRD12 is detected in complexes containing Piwi protein MILI (PIWIL2), its associated primary piRNAs, and TDRD1, all of which are already implicated in secondary piRNA biogenesis. Male mice carrying either a nonsense point mutation (reproductive mutant 23 or repro23 mice) or a targeted deletion in the Tdrd12 locus are infertile and derepress retrotransposons. We find that TDRD12 is dispensable for primary piRNA biogenesis but essential for production of secondary piRNAs that enter Piwi protein MIWI2 (PIWIL4). Cell-culture studies with the insect ortholog of TDRD12 suggest a role for the multidomain protein in mediating complex formation with other participants during secondary piRNA biogenesis. PMID- 24067653 TI - Node-by-node disassembly of a mutualistic interaction web driven by species introductions. AB - Interaction webs summarize the diverse interactions among species in communities. The addition or loss of particular species and the alteration of key interactions can lead to the disassembly of the entire interaction web, although the nontrophic effects of species loss on interaction webs are poorly understood. We took advantage of ongoing invasions by a suite of exotic species to examine their impact in terms of the disassembly of an interaction web in Patagonia, Argentina. We found that the reduction of one species (a host of a keystone mistletoe species) resulted in diverse indirect effects that led to the disassembly of an interaction web through the loss of the mistletoe, two key seed-dispersers (a marsupial and a bird), and a pollinator (hummingbird). Our results demonstrate that the gains and losses of species are both consequences and drivers of global change that can lead to underappreciated cascading coextinctions through the disruption of mutualisms. PMID- 24067654 TI - Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer's APP CTF for terminal degradation via autophagy. AB - The hallmarks of Alzheimer's disease (AD) are the aggregates of amyloid-beta (Abeta) peptides and tau protein. Autophagy is a major cellular pathway leading to the removal of aggregated proteins. We have reported recently that autophagy was responsible for amyloid precursor protein cleaved C-terminal fragment (APP CTF) degradation and amyloid beta clearance in an Atg5-dependent manner. Here we aimed to elucidate the molecular mechanism by which autophagy mediates the degradation of APP-CTF and the clearance of amyloid beta. Through affinity purification followed by mass spectrum analysis, we identified adaptor protein (AP) 2 together with phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) as binding proteins of microtubule-associated protein 1 light chain 3 (LC3). Further analysis showed that AP2 regulated the cellular levels of APP-CTF. Knockdown of AP2 reduced autophagy-mediated APP-CTF degradation. Immunoprecipitation and live imaging analysis demonstrated that AP2 and PICALM cross-link LC3 with APP-CTF. These data suggest that the AP-2/PICALM complex functions as an autophagic cargo receptor for the recognition and shipment of APP CTF from the endocytic pathway to the LC3-marked autophagic degradation pathway. This molecular mechanism linking AP2/PICALM and AD is consistent with genetic evidence indicating a role for PICALM as a risk factor for AD. PMID- 24067655 TI - Core small nuclear ribonucleoprotein particle splicing factor SmD1 modulates RNA interference in Drosophila. AB - RNAi is an evolutionarily conserved gene regulatory process that operates in a wide variety of organisms. During RNAi, long double-stranded RNA precursors are processed by Dicer proteins into ~21-nt siRNAs. Subsequently, siRNAs are incorporated into the RNA-induced silencing complexes (RISCs) that contain Argonaute-family proteins and guide RISC to target RNAs via complementary base pairing, leading to posttranscriptional gene silencing. Select pre-mRNA splicing factors have been implicated in RNAi in fission yeast, worms, and flies, but the underlying molecular mechanisms are not well understood. Here, we show that SmD1, a core component of the Drosophila small nuclear ribonucleoprotein particle implicated in splicing, is required for RNAi and antiviral immunity in cultured cells and in vivo. SmD1 interacts with both Dicer-2 and dsRNA precursors and is indispensable for optimal siRNA biogenesis. Depletion of SmD1 impairs the assembly and function of the small interfering RISC without significantly affecting the expression of major canonical siRNA pathway components. Moreover, SmD1 physically and functionally associates with components of the small interfering RISC, including Argonaute 2, both in flies and in humans. Notably, RNAi defects resulting from SmD1 silencing can be uncoupled from defects in pre mRNA splicing, and the RNAi and splicing machineries are physically and functionally distinct entities. Our results suggest that Drosophila SmD1 plays a direct role in RNAi-mediated gene silencing independently of its pre-mRNA splicing activity and indicate that the dual roles of splicing factors in posttranscriptional gene regulation may be evolutionarily widespread. PMID- 24067656 TI - Phonon-interface scattering in multilayer graphene on an amorphous support. AB - The recent studies of thermal transport in suspended, supported, and encased graphene just began to uncover the richness of two-dimensional phonon physics, which is relevant to the performance and reliability of graphene-based functional materials and devices. Among the outstanding questions are the exact causes of the suppressed basal-plane thermal conductivity measured in graphene in contact with an amorphous material, and the layer thickness needed for supported or embedded multilayer graphene (MLG) to recover the high thermal conductivity of graphite. Here we use sensitive in-plane thermal transport measurements of graphene samples on amorphous silicon dioxide to show that full recovery to the thermal conductivity of the natural graphite source has yet to occur even after the MLG thickness is increased to 34 layers, considerably thicker than previously thought. This seemingly surprising finding is explained by long intrinsic scattering mean free paths of phonons in graphite along both basal-plane and cross-plane directions, as well as partially diffuse scattering of MLG phonons by the MLG-amorphous support interface, which is treated by an interface scattering model developed for highly anisotropic materials. Based on the phonon transmission coefficient calculated from reported experimental thermal interface conductance results, phonons emerging from the interface consist of a large component that is scattered across the interface, making rational choice of the support materials a potential approach to increasing the thermal conductivity of supported MLG. PMID- 24067657 TI - Leaf-galling phylloxera on grapes reprograms host metabolism and morphology. AB - Endoparasitism by gall-forming insects dramatically alters the plant phenotype by altering growth patterns and modifying plant organs in ways that appear to directly benefit the gall former. Because these morphological and physiological changes are linked to the presence of the insect, the induced phenotype is said to function as an extension of the parasite, albeit by unknown mechanisms. Here we report the gall-forming aphid-like parasite phylloxera, Daktulosphaira vitifoliae, induces stomata on the adaxial surface of grape leaves where stomata typically do not occur. We characterized the function of the phylloxera-induced stomata by tracing transport of assimilated carbon. Because induction of stomata suggests a significant manipulation of primary metabolism, we also characterized the gall transcriptome to infer the level of global reconfiguration of primary metabolism and the subsequent changes in downstream secondary metabolism. Phylloxera feeding induced stomata formation in proximity to the insect and promoted the assimilation and importation of carbon into the gall. Gene expression related to water, nutrient, and mineral transport; glycolysis; and fermentation increased in leaf-gall tissues. This shift from an autotrophic to a heterotrophic profile occurred concurrently with decreased gene expression for nonmevalonate and terpenoid synthesis and increased gene expression in shikimate and phenylpropanoid biosynthesis, secondary metabolite systems that alter defense status in grapes. These functional insect-induced stomata thus comprise part of an extended phenotype, whereby D. vitifoliae globally reprograms grape leaf development to alter patterns of primary metabolism, nutrient mobilization, and defense investment in favor of the galling habit. PMID- 24067658 TI - Conversion from CUL4-based COP1-SPA E3 apparatus to UVR8-COP1-SPA complexes underlies a distinct biochemical function of COP1 under UV-B. AB - The evolutionarily conserved constitutive photomorphogenesis 1 (COP1) is a RING and WD40 protein that functions as a substrate receptor of CULLIN4-damaged DNA binding protein 1 (CUL4-DDB1)-based E3 ubiquitin ligases in both plants and animals. In Arabidopsis, COP1 is a central repressor of photomorphogenesis in the form of COP1-suppressor of PHYA (SPA) complex(es). CUL4-DDB1-COP1-SPA suppresses the photomorphogenic program by targeting the transcription factor elongated hypocotyl 5 for degradation. Intriguingly, under photomorphogenic UV-B light, COP1 reverses its repressive role and promotes photomorphogenesis. However, the mechanism by which COP1 is functionally switched is still obscure. Here, we demonstrate that UV-B triggers the physical and functional disassociation of the COP1-SPA core complex(es) from CUL4-DDB1 and the formation of a unique complex(es) containing the UV-B receptor UV resistance locus 8 (UVR8). The establishment of this UV-B-dependent COP1 complex(es) is associated with its positive modulation of elongated hypocotyl 5 stability and activity, which sheds light on the mechanism of COP1's promotive action in UV-B-induced photomorphogenesis. PMID- 24067659 TI - Properties of Slo1 K+ channels with and without the gating ring. AB - High-conductance Ca(2+)- and voltage-activated K(+) (Slo1 or BK) channels (KCNMA1) play key roles in many physiological processes. The structure of the Slo1 channel has two functional domains, a core consisting of four voltage sensors controlling an ion-conducting pore, and a larger tail that forms an intracellular gating ring thought to confer Ca(2+) and Mg(2+) sensitivity as well as sensitivity to a host of other intracellular factors. Although the modular structure of the Slo1 channel is known, the functional properties of the core and the allosteric interactions between core and tail are poorly understood because it has not been possible to study the core in the absence of the gating ring. To address these questions, we developed constructs that allow functional cores of Slo1 channels to be expressed by replacing the 827-amino acid gating ring with short tails of either 74 or 11 amino acids. Recorded currents from these constructs reveals that the gating ring is not required for either expression or gating of the core. Voltage activation is retained after the gating ring is replaced, but all Ca(2+)- and Mg(2+)-dependent gating is lost. Replacing the gating ring also right-shifts the conductance-voltage relation, decreases mean open-channel and burst duration by about sixfold, and reduces apparent mean single-channel conductance by about 30%. These results show that the gating ring is not required for voltage activation but is required for Ca(2+) and Mg(2+) activation. They also suggest possible actions of the unliganded (passive) gating ring or added short tails on the core. PMID- 24067660 TI - QnAs with William Bialek. PMID- 24067661 TI - Amyloid and inflammation. PMID- 24067662 TI - Calcium amendment may increase hydraulic efficiency and forest evapotranspiration. PMID- 24067663 TI - Investigating suspected cancer clusters and responding to community concerns: guidelines from CDC and the Council of State and Territorial Epidemiologists. AB - This report augments guidelines published in 1990 for investigating clusters of health events (CDC. Guidelines for investigating clusters of health events. MMWR 1990;39[No. RR-11]). The 1990 Guidelines considered any noninfectious disease cluster, injuries, birth defects, and previously unrecognized syndromes or illnesses. These new guidelines focus on cancer clusters. State and local health departments can use these guidelines to develop a systematic approach to responding to community concerns regarding cancer clusters. The guidelines are intended to apply to situations in which a health department responds to an inquiry about a suspected cancer cluster in a residential or community setting only. Occupational or medical treatment-related clusters are not included in this report. Since 1990, many improvements have occurred in data resources, investigative techniques, and analytic/statistical methods, and much has been learned from both large- and small-scale cancer cluster investigations. These improvements and lessons have informed these updated guidelines. These guidelines utilize a four-step approach (initial response, assessment, major feasibility study, and etiologic investigation) as a tool for managing a reported cluster. Even if a cancer cluster is identified, there is no guarantee that a common cause or an environmental contaminant will be implicated. Identification of a common cause or an implicated contaminant might be an expected outcome for the concerned community. Therefore, during all parts of an inquiry, responders should be transparent, communicate clearly, and explain their decisions to the community. PMID- 24067664 TI - Concrete embedded dye-synthesized photovoltaic solar cell. AB - This work presents the concept of a monolithic concrete-integrated dye synthesized photovoltaic solar cell for optical-to-electrical energy conversion and on-site power generation. The transport measurements carried out in the dark revealed the presence of VOC of ~190 mV and ISC of ~9 MUA, induced by the electrochemical conversion of concrete-supplied ionic impurities at the electrodes. The current-voltage measurements performed under illumination at incident optical powers of ~46 mW confirmed the generation of electrical power of ~0.64 MUW with almost half generated via battery effect. This work presents a first step towards realizing the additional pathways to low-cost electrical power production in urban environments based on a combined use of organic dyes, nanotitania and concrete technology. PMID- 24067666 TI - Integrated program achieves good survival but moderate recovery rates among children with severe acute malnutrition in India. AB - BACKGROUND: At any point in time, an average 8 million Indian children suffer from severe acute malnutrition (SAM). OBJECTIVE: This article assesses the effectiveness of an integrated model for the management of SAM (IM-SAM) in India comprising facility- and community-based care and using locally adapted protocols. DESIGN: Children (n = 2740) were randomly sampled from the 44,017 children aged 6-59 mo admitted to 199 Nutrition Rehabilitation Centers in the state of Madhya Pradesh (1 January to 31 December 2010). RESULTS: On admission, 2.2% of children had edema, 23.4% had medical complications, 56% were girls, 79% were in the age group 6-23 mo, and 64% belonged to scheduled tribe or scheduled caste families. Fifty-six children (2.0%) with severe congenital or pathological conditions were transferred to the district hospital. Of the 2684 program exits, 10 children (0.4%) died, 860 (32.0%) did not complete treatment (defaulted), and 1814 (67.6%) were discharged after a mean (+/-SD) stay of 75.8 +/- 9.4 d. The mean weight gain among discharged children was 2.7 +/- 1.9 g . kg body wt(-1) . d(-1); on discharge, 1179 (65%) of the children had recovered (weight gain >=15% of initial weight). CONCLUSIONS: The survival rates in the IM-SAM program were very high. However, the moderate recovery rates documented seem to indicate that the protocols currently in use need to be improved. This trial was registered at clinicaltrials.gov as NCT01917734. PMID- 24067665 TI - Postinfancy growth, schooling, and cognitive achievement: Young Lives. AB - BACKGROUND: Early life growth failure and resulting cognitive deficits are often assumed to be very difficult to reverse after infancy. OBJECTIVE: We used data from Young Lives, which is an observational cohort of 8062 children in Ethiopia, India, Peru, and Vietnam, to determine whether changes in growth after infancy are associated with schooling and cognitive achievement at age 8 y. DESIGN: We represented the growth by height-for-age z score at 1 y [HAZ(1)] and height-for age z score at 8 y that was not predicted by the HAZ(1). We also characterized growth as recovered (stunted at age 1 y and not at age 8 y), faltered (not stunted at age 1 y and stunted at age 8 y), persistently stunted (stunted at ages 1 and 8 y), or never stunted (not stunted at ages 1 and 8 y). Outcome measures were assessed at age 8 y. RESULTS: The HAZ(1) was inversely associated with overage for grade and positively associated with mathematics achievement, reading comprehension, and receptive vocabulary. Unpredicted growth from 1 to 8 y of age was also inversely associated with overage for grade (OR range across countries: 0.80-0.84) and positively associated with mathematics achievement (effect-size range: 0.05-0.10), reading comprehension (0.02-0.10), and receptive vocabulary (0.04-0.08). Children who recovered in linear growth had better outcomes than did children who were persistently stunted but were not generally different from children who experienced growth faltering. CONCLUSIONS: Improvements in child growth after early faltering might have significant benefits on schooling and cognitive achievement. Hence, although early interventions remain critical, interventions to improve the nutrition of preprimary and early primary school-age children also merit consideration. PMID- 24067667 TI - Obesity research in adolescence: moving object--hard to target. PMID- 24067668 TI - Cobalamin supplements for infants: a shot in the cradle? PMID- 24067670 TI - Filling and wetting transitions at grooved substrates. AB - The wetting and filling properties of a fluid adsorbed on a solid grooved substrate are studied by means of a microscopic density functional theory. The grooved substrates are modelled using a solid slab, interacting with the fluid particles via long-range dispersion forces, to which a one-dimensional array of infinitely long rectangular grooves is sculpted. By investigating the effect of the groove periodicity and the width of the grooves and the ridges, a rich variety of different wetting morphologies is found. In particular, we show that for a saturated ambient gas, the adsorbent can occur in one of four wetting states characterized by (i) empty grooves, (ii) filled grooves, (iii) a formation of mesoscopic hemispherical caps (iv) a macroscopically wet surface. The character of the transition between particular regimes, that also extend off coexistence, sensitively depends on the model geometry. The temperature at which the system becomes completely wet is considerably higher than that for a flat wall. PMID- 24067669 TI - Maternal fatty acids in pregnancy, FADS polymorphisms, and child intelligence quotient at 8 y of age. AB - BACKGROUND: Brain tissue is selectively enriched with highly unsaturated fatty acids (FAs). Altering the maternal FA status in pregnancy may improve fetal neural development with lasting consequences for child development. OBJECTIVE: We explored whether maternal FAs in erythrocytes, either measured directly or indirectly by maternal FADS genetic variants, are associated with child intelligence quotient (IQ). DESIGN: Linear regression analyses, adjusted for 18 confounders, were used to investigate the associations in 2839 mother-child pairs from the population-based Avon Longitudinal Study of Parents and Children cohort. RESULTS: Low levels of arachidonic acid (20:4n-6) were associated with lower performance IQ (-2.0 points; 95% CI: -3.5, -0.6 points; P = 0.007, increased R2 = 0.27%), high levels of osbond acid (22:5n-6) were associated with verbal IQ (-1.8 points; 95% CI: -3.2, -0.4 points; P = 0.014, R2 = 0.20%), and high levels of adrenic acid (22:4n-6) were associated with verbal IQ (-1.7 points; 95% CI:-3.1, 0.3 points; P = 0.016, R2 = 0.19%). There was some evidence to support a negative association of low docosahexaenoic acid (DHA; 22:6n-3) with full-scale IQ (R2 = 0.15%). Novel weak associations were also observed for low levels of osbond acid (R2 <= 0.29%) and FADS variants with opposite effects for intron variants and variants in the promoter region such as rs3834458 (R2 <= 0.38%). CONCLUSIONS: These results support the positive role of maternal arachidonic acid and DHA on fetal neural development, although the effects on child IQ by 8 y of age were small (0.1 SD), with other factors contributing more substantially. The endogenous synthesis of these FAs by FADS genes, especially FADS2, may also be important. The replication of these results is recommended. PMID- 24067671 TI - HIV treatment and associated mitochondrial pathology: review of 25 years of in vitro, animal, and human studies. AB - Antiretroviral therapy has dramatically reduced mortality in human immunodeficiency virus (HIV) infection. In 1988, the suggestion that the first antiretroviral drug, zidovudine, was the potential cause of muscle pathology in HIV-infected persons resulted in structural and biochemical patient studies demonstrating acquired mitochondrial dysfunction. Assessment of subsequent nucleoside analog reverse transcriptase inhibitor (NRTI) antiretroviral drugs has indicated that mitochondria are a common target of NRTI toxicity in multiple tissues, leading to a wide variety of pathology ranging from lipodystrophy to neuropathy. Overwhelmingly, these complications have emerged during post licensing human studies. Subsequent animal and in vitro studies have then elucidated the potential pathological mechanisms, suggesting that NRTI-associated mitochondrial toxicity arises principally from inhibition of the sole mitochondrial DNA (mtDNA) polymerase gamma, leading to a reduction in mtDNA content (depletion). Millions of patients have been treated with mitochondrially toxic NRTIs and these drugs remain the backbone of antiretroviral rollout in much of sub-Saharan Africa. Here we describe the 25-year history of antiretroviral associated mitochondrial pathology and critically review the strength of evidence linking clinical, histopathological, and molecular data. We discuss recently described novel mechanisms of NRTI-associated mitochondrial damage and whether or not recently licensed NRTIs may be considered free from mitochondrial toxicity. PMID- 24067672 TI - Carbaryl-induced histopathologic alterations in the digestive tract of the Levantine frog, Pelophylax bedriagae (Anura: Ranidae). AB - In this study, histopathologic changes following carbaryl exposure for 96 hr were investigated in the digestive tract of Levantine frog, Pelophylax bedriagae. Adult frogs were exposed to carbaryl once by oral gavage in concentrations of 0.05, 0.1, and 0.2 mg/g. Histopathological changes were more prominent in medium- (0.1 mg/g) and high-dose (0.2 mg/g) groups than in the low-dose (0.05 mg/g) group. Esophageal cells showed vacuolization, cellular swelling, nuclear pyknosis, karyolysis, and necrosis. Additionally, esophageal glandular atrophy and infiltration of inflammatory cells around esophageal glands were observed at medium and high doses. In the stomach, there were prominent histopathologic defects such as cellular swelling and necrosis in gastric glands, necrotic cells within the interstitial spaces, separation of epithelial cell layer, congested vessels, and hemorrhage at medium and high doses. In the intestine, detachment of epithelial layer, epithelial cell disorganization, inflammation, and necrosis were detected at medium and high doses. The results of this study showed that carbaryl caused adverse effects on the digestive tract of the Levantine frog, P. bedriagae. PMID- 24067673 TI - Toxicities associated with 1-month treatment with propylthiouracil (PTU) and methimazole (MMI) in male rats. AB - Thionamides such as propylthiouracil (PTU) and methimazole (MMI) have been used for more than 50 years to treat the more common causes of thyrotoxicosis/hyperthyroidism such as Graves' disease. Serious adverse effects associated with thionamides in humans include idiosyncratic liver damage, agranulocytosis, aplastic anemia, and vasculitis. Both prospective and retrospective clinical studies with these drugs have failed to identify predictive biomarker for these adverse effects. To assess whether rat is a good model for predicting drug-related adverse events in the liver and in the bone marrow, we conducted a comprehensive study in male rats with multiple doses of PTU and MMI. As expected, euthyroid animals became hypothyroid along with several secondary changes associated with hypothyroidism. There were slight reductions in red blood cell parameters along with some marginal effects on the bone marrow elements. However, there was no evidence of significant neutropenia and liver injury in both PTU-treated and MMI-treated cohorts. MMI-related effects were noted in the seminiferous tubules of the testes. Overall, 1-month daily treatment of euthyroid rats with PTU or MMI resulted in hypothyroidism, minor bone marrow effects, and several secondary effects associated with hypothyroidism, but without any evidence of adverse effects reported in humans including liver injury and agranulocytosis. PMID- 24067674 TI - Effects of in utero exposure to di(n-butyl) phthalate for estrogen receptors alpha, beta, and androgen receptor of Leydig cell on rats. AB - Estrogens and androgens affect male and female reproductive systems. Recently, we reported that prenatal di(n-butyl) phthalate (DBP) exposure induced atypical Leydig cells (LCs) hyperplasia during adulthood. The present study investigated the expression of estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), and androgen receptor (AR) in LCs of 5-, 7-, 9-, 14-, and 17-week-old Sprague-Dawley (srl) rats whose dams had been administered DBP intragastrically at 100 mg/kg/day or the vehicle (corn oil) from days 12 to 21 postconception. Immunohistochemical, Western blotting, and reverse transcription polymerase chain reaction analyses revealed that the expressions of ERalpha, ERbeta, and AR proteins and mRNAs in the DBP group were similar to those of the vehicle group at 5 and 7 weeks, but significantly higher ERalpha and lower ERbeta and AR levels were observed in the DBP group at 9 to 17 weeks. The rats prenatally exposed to DBP had seminiferous tubule degeneration and atypical hyperplasia of LCs during adulthood, which was associated with an increase in expression of ERalpha and a decrease of ERbeta and AR in the testis. PMID- 24067675 TI - Behavioural insights are vital to policy-making. PMID- 24067687 TI - Drilling hit by budget woes. PMID- 24067688 TI - Mystery over obesity 'fraud'. PMID- 24067689 TI - Universities struggle to make patents pay. PMID- 24067690 TI - Mozilla plan seeks to debug scientific code. PMID- 24067691 TI - Regulation stacks up for e-cigarettes. PMID- 24067692 TI - Interface superconductivity found in single crystal. PMID- 24067694 TI - Biotechnology: The start-up engine. PMID- 24067695 TI - Marine science: Oceanography's billion-dollar baby. PMID- 24067701 TI - Citations: Ethical ways to grow impact. PMID- 24067702 TI - Alternative careers: Once a scientist, always a scientist. PMID- 24067703 TI - Citations: In defence of Brazilian journals. PMID- 24067704 TI - Citations: Overcome the language barrier. PMID- 24067705 TI - Global hunger: Food crisis spurs aid for poverty. PMID- 24067706 TI - Biodiversity: Temperate hotspots. PMID- 24067707 TI - Electronics: The carbon-nanotube computer has arrived. PMID- 24067708 TI - Earth science: A resolution of the Archaean paradox. PMID- 24067709 TI - Heat-pipe Earth. AB - The heat transport and lithospheric dynamics of early Earth are currently explained by plate tectonic and vertical tectonic models, but these do not offer a global synthesis consistent with the geologic record. Here we use numerical simulations and comparison with the geologic record to explore a heat-pipe model in which volcanism dominates surface heat transport. These simulations indicate that a cold and thick lithosphere developed as a result of frequent volcanic eruptions that advected surface materials downwards. Declining heat sources over time led to an abrupt transition to plate tectonics. Consistent with model predictions, the geologic record shows rapid volcanic resurfacing, contractional deformation, a low geothermal gradient across the bulk of the lithosphere and a rapid decrease in heat-pipe volcanism after initiation of plate tectonics. The heat-pipe Earth model therefore offers a coherent geodynamic framework in which to explore the evolution of our planet before the onset of plate tectonics. PMID- 24067710 TI - Swings between rotation and accretion power in a binary millisecond pulsar. AB - It is thought that neutron stars in low-mass binary systems can accrete matter and angular momentum from the companion star and be spun-up to millisecond rotational periods. During the accretion stage, the system is called a low-mass X ray binary, and bright X-ray emission is observed. When the rate of mass transfer decreases in the later evolutionary stages, these binaries host a radio millisecond pulsar whose emission is powered by the neutron star's rotating magnetic field. This evolutionary model is supported by the detection of millisecond X-ray pulsations from several accreting neutron stars and also by the evidence for a past accretion disc in a rotation-powered millisecond pulsar. It has been proposed that a rotation-powered pulsar may temporarily switch on during periods of low mass inflow in some such systems. Only indirect evidence for this transition has hitherto been observed. Here we report observations of accretion powered, millisecond X-ray pulsations from a neutron star previously seen as a rotation-powered radio pulsar. Within a few days after a month-long X-ray outburst, radio pulses were again detected. This not only shows the evolutionary link between accretion and rotation-powered millisecond pulsars, but also that some systems can swing between the two states on very short timescales. PMID- 24067711 TI - Carbon nanotube computer. AB - The miniaturization of electronic devices has been the principal driving force behind the semiconductor industry, and has brought about major improvements in computational power and energy efficiency. Although advances with silicon-based electronics continue to be made, alternative technologies are being explored. Digital circuits based on transistors fabricated from carbon nanotubes (CNTs) have the potential to outperform silicon by improving the energy-delay product, a metric of energy efficiency, by more than an order of magnitude. Hence, CNTs are an exciting complement to existing semiconductor technologies. Owing to substantial fundamental imperfections inherent in CNTs, however, only very basic circuit blocks have been demonstrated. Here we show how these imperfections can be overcome, and demonstrate the first computer built entirely using CNT-based transistors. The CNT computer runs an operating system that is capable of multitasking: as a demonstration, we perform counting and integer-sorting simultaneously. In addition, we implement 20 different instructions from the commercial MIPS instruction set to demonstrate the generality of our CNT computer. This experimental demonstration is the most complex carbon-based electronic system yet realized. It is a considerable advance because CNTs are prominent among a variety of emerging technologies that are being considered for the next generation of highly energy-efficient electronic systems. PMID- 24067712 TI - Alkane desaturation by concerted double hydrogen atom transfer to benzyne. AB - The removal of two vicinal hydrogen atoms from an alkane to produce an alkene is a challenge for synthetic chemists. In nature, desaturases and acetylenases are adept at achieving this essential oxidative functionalization reaction, for example during the biosynthesis of unsaturated fatty acids, eicosanoids, gibberellins and carotenoids. Alkane-to-alkene conversion almost always involves one or more chemical intermediates in a multistep reaction pathway; these may be either isolable species (such as alcohols or alkyl halides) or reactive intermediates (such as carbocations, alkyl radicals, or sigma-alkyl-metal species). Here we report a desaturation reaction of simple, unactivated alkanes that is mechanistically unique. We show that benzynes are capable of the concerted removal of two vicinal hydrogen atoms from a hydrocarbon. The discovery of this exothermic, net redox process was enabled by the simple thermal generation of reactive benzyne intermediates through the hexadehydro-Diels-Alder cycloisomerization reaction of triyne substrates. We are not aware of any single step, bimolecular reaction in which two hydrogen atoms are simultaneously transferred from a saturated alkane. Computational studies indicate a preferred geometry with eclipsed vicinal C-H bonds in the alkane donor. PMID- 24067713 TI - Atmospheric oxygenation three billion years ago. AB - It is widely assumed that atmospheric oxygen concentrations remained persistently low (less than 10(-5) times present levels) for about the first 2 billion years of Earth's history. The first long-term oxygenation of the atmosphere is thought to have taken place around 2.3 billion years ago, during the Great Oxidation Event. Geochemical indications of transient atmospheric oxygenation, however, date back to 2.6-2.7 billion years ago. Here we examine the distribution of chromium isotopes and redox-sensitive metals in the approximately 3-billion-year old Nsuze palaeosol and in the near-contemporaneous Ijzermyn iron formation from the Pongola Supergroup, South Africa. We find extensive mobilization of redox sensitive elements through oxidative weathering. Furthermore, using our data we compute a best minimum estimate for atmospheric oxygen concentrations at that time of 3 * 10(-4) times present levels. Overall, our findings suggest that there were appreciable levels of atmospheric oxygen about 3 billion years ago, more than 600 million years before the Great Oxidation Event and some 300-400 million years earlier than previous indications for Earth surface oxygenation. PMID- 24067714 TI - Integrating abundance and functional traits reveals new global hotspots of fish diversity. AB - Species richness has dominated our view of global biodiversity patterns for centuries. The dominance of this paradigm is reflected in the focus by ecologists and conservation managers on richness and associated occurrence-based measures for understanding drivers of broad-scale diversity patterns and as a biological basis for management. However, this is changing rapidly, as it is now recognized that not only the number of species but the species present, their phenotypes and the number of individuals of each species are critical in determining the nature and strength of the relationships between species diversity and a range of ecological functions (such as biomass production and nutrient cycling). Integrating these measures should provide a more relevant representation of global biodiversity patterns in terms of ecological functions than that provided by simple species counts. Here we provide comparisons of a traditional global biodiversity distribution measure based on richness with metrics that incorporate species abundances and functional traits. We use data from standardized quantitative surveys of 2,473 marine reef fish species at 1,844 sites, spanning 133 degrees of latitude from all ocean basins, to identify new diversity hotspots in some temperate regions and the tropical eastern Pacific Ocean. These relate to high diversity of functional traits amongst individuals in the community (calculated using Rao's Q), and differ from previously reported patterns in functional diversity and richness for terrestrial animals, which emphasize species-rich tropical regions only. There is a global trend for greater evenness in the number of individuals of each species, across the reef fish species observed at sites ('community evenness'), at higher latitudes. This contributes to the distribution of functional diversity hotspots and contrasts with well known latitudinal gradients in richness. Our findings suggest that the contribution of species diversity to a range of ecosystem functions varies over large scales, and imply that in tropical regions, which have higher numbers of species, each species contributes proportionally less to community-level ecological processes on average than species in temperate regions. Metrics of ecological function usefully complement metrics of species diversity in conservation management, including when identifying planning priorities and when tracking changes to biodiversity values. PMID- 24067717 TI - Zhang et al. reply. PMID- 24067718 TI - Low-voltage magnetoresistance in silicon. PMID- 24067719 TI - Efficacy and safety of ipilimumab in patients with pre-treated, uveal melanoma. AB - BACKGROUND: Patients with advanced uveal melanoma have a poor prognosis and limited treatment options. Ipilimumab is approved for pre-treated adult patients with advanced melanoma. However, because previous clinical trials with ipilimumab have excluded patients with uveal melanoma, data in this patient population are limited. PATIENTS AND METHODS: Pre-treated patients with advanced uveal melanoma received ipilimumab 3 mg/kg through an expanded access programme, every 3 weeks for four doses. Tumour assessments were conducted at baseline and after completion of treatment and patients were monitored throughout for adverse events. RESULTS: Among 82 assessable patients, 4 (5%) had an immune-related objective response and 24 (29%) had immune-related stable disease lasting >=3 months for an immune-related disease control rate of 34%. With a median follow-up of 5.6 months, median overall survival (OS) was 6.0 months and median progression free survival (PFS) was 3.6 months. The 1-year rates of OS and PFS were 31% and 11%, respectively. The safety profile of ipilimumab was similar to that in patients with cutaneous melanoma. CONCLUSIONS: These data suggest ipilimumab 3 mg/kg is a feasible option in pre-treated patients with metastatic uveal melanoma. Evidence of disease control and a 1-year survival rate of 31% indicate the need for further investigation in randomised, controlled trials to determine the optimal timing and use of ipilimumab in this patient population. PMID- 24067720 TI - Discharge planning for the patient with chronic pancreatitis. AB - For patients with chronic pancreatitis, there are many ramifications of failing to plan for the patient's discharge appropriately. The chronicity of the disease often makes discharge planning more complex. In addition, patient needs may include complicated home regimens, psychosocial interventions, or both. Patients with chronic pancreatitis have disease-specific needs and issues that should be assessed to implement an appropriate plan. Resources need to be identified, implemented, and evaluated to ensure positive outcomes, adequate patient satisfaction, and lower readmission rates. This article presents the impact of chronic pancreatitis on the healthcare system, recommendations for appropriate discharge planning for this population, and a case study demonstrating the discharge planning process for a patient with chronic pancreatitis. PMID- 24067721 TI - Nonylphenol disrupts the cardio-protective effects of 17beta-estradiol on ischemia/reperfusion injury in isolated hearts of guinea pig. AB - Nonylphenol (NP), a widely distributed, toxic, endocrine-disrupting chemical, has estrogenic properties. However, its cardiac effects remain unclear. In this study, the effects of NP on isolated guinea pig hearts were studied in three separate experiments. First, hearts were perfused with 10-7 M NP or 10-5 M NP to determine whether NP was toxic to isolated healthy hearts. Next, hearts were subjected to 50 min of ischemia and 60 min of reperfusion (I50R60) with 10-7 M NP or 10-5 M NP to determine whether NP could aggravate ischemia/reperfusion (I/R) injury. Finally, the interaction of the cardio-protective agent 17beta-estradiol (E2) with NP was studied using 10-7 M E2, 10-7 M E2 plus 10-7 M NP, and 10-7 M E2 plus 10-5 M NP. Heart rate (HR) and coronary flow (CF) were significantly decreased and the leakage of lactate dehydrogenase (LDH) in effluent was increased in the 10-5 M NP group. However, there were no obvious changes in HR, CF, the leakage of LDH or creatine kinase (CK), or the activity of superoxide dismutase in either of the NP treatments in the I50R60 model. Treatment with 10-7 M E2 attenuated I/R injury by increasing HR, decreasing the leakage of LDH and CK, and decreasing infarct size. However, these effects were reversed by both concentrations of NP. These data demonstrate that NP had direct toxic effects on normal hearts and NP might disrupt the cardio-protective effects of E2 on I/R injury. PMID- 24067722 TI - Differential responses of human hepatocytes to the non-nucleoside HIV-1 reverse transcriptase inhibitor nevirapine. AB - Nevirapine is a non-nucleoside reverse transcriptase (RT) inhibitor used for the treatment of AIDS and the prevention of mother-to-child transmission of HIV-1. Despite its therapeutic benefits, treatment with nevirapine has been associated with significant incidences of liver and dermal toxicity. The present study examined the effects of nevirapine on cell growth and death in human hepatocyte HepG2 cells and THLE2 cells and the possible pathways involved in these effects. The concentrations of nevirapine inhibiting 50% cell growth were similar for both cell lines. Nevirapine (0-250 uM) treatment caused a slight increase in the amount of lactate dehydrogenase released into the medium. Apoptotic cell death did not contribute to the decrease in viable cells. Exposing of HepG2 cells to nevirapine caused G2/M phase arrest, and the activity of senescence-associated beta-galactosidase was not altered. In THLE2 cells, the percentage of cells in G1/G0 phase was increased and cellular senescence was induced in a concentration dependent manner. Endogenous non-telomeric RT activity was not detected in either cell line. Western blot analysis indicated lower levels of p53 and phospho-p53 (ser15) in HepG2 cells as compared to THLE2 cells; no significant changes in p53 or phospho-p53 (ser15) were noted with nevirapine treatment. These data demonstrate that nevirapine inhibits cell growth, induces cell cycle arrest at different phases, and has different effects on cellular senescence in HepG2 cells and THLE2 cells. The differential responses appear to be related to differences in the basal levels of p53 in the HepG2 cells and THLE2 cells. PMID- 24067723 TI - Down-regulation of S100A9 and S100A10 in manganese-resistant RBL-2H3 cells. AB - Exposure to excess amounts of manganese causes toxic effects, including neurological symptoms such as Parkinsonism. However, endogenous factors involved in the protection against manganese toxicity remain unclear. Previously, we showed that rat basophilic leukemia RBL-2H3 cells are highly sensitive to MnCl2 compared with other rat cell lines. To identify the genes involved in resistance to manganese toxicity, two lines of Mn-resistant cells showing resistance to 300 uM MnCl2 (RBL-Mnr300) and 1200 uM MnCl2 (RBL-Mnr1200) were developed from RBL-2H3 cells by a stepwise increase in MnCl2 concentration in the medium. Microarray analyses were carried out to compare gene expression between parental RBL-2H3 cells and RBL-Mnr300 or RBL-Mnr1200 cells. Five genes exhibited more than 10-fold up-regulation in both RBL-Mnr300 and RBL-Mnr1200 cells, and 24 genes exhibited less than 0.1-fold down-regulation in both Mn-resistant cell lines. The S100a9 and S100a10 genes, encoding the calcium-binding S100A9 and S100A10 proteins, respectively, were found among the three most down-regulated genes in both Mn resistant cell lines. The marked decreases in mRNA levels of S100a9 and S100a10 were confirmed by real-time RT-PCR analyses. Further characterization and comparison of these Mn-resistant cells may enable the identification of novel genes that play important roles in the modification of manganese toxicity. PMID- 24067724 TI - Combined repeated-dose and reproductive/developmental toxicity screening test of 3-amino-5-mercapto-1,2,4-triazole in rats. AB - The substance 3-amino-5-mercapto-1,2,4-triazole (AMT, CAS No. 16691-43-3) was daily administered by gavage to Crl:CD (SD)IGS rats at doses of 0 (control), 10, 50, and 250 mg/kg bw/day. Males (12/group) were treated for a total of 42 days beginning 14 days before mating. Females (12/group) were treated beginning 14 days before mating to day 4 of lactation throughout the mating and gestation periods. No deaths occurred in males but three females died on day 23 of gestation at 250 mg/kg/day. Only temporary decreases in body weight and food intake were found in both sexes at 250 mg/kg/day. There were no considerable changes in general appearance, the functional battery tests, biochemical analysis or urinalysis. Anemia was observed in both sexes at 250 mg/kg/day. The relative weight of thyroid glands was significantly increased in both sexes at 250 mg/kg/day and hypertrophy of thyroid follicular cells was observed in 50 and 250 mg/kg/day males and 250 mg/kg/day females. As this effect on thyroid glands was considered to be the major toxicity, the possible mechanism was discussed comparing with the toxicity of structural similar analogs. Other histopathological changes in males were hypertrophy of centrilobular hepatocytes at 250 mg/kg/day, and anterior pituitary glands at 50 mg/kg/day and more. Vacuolization in renal tubular epithelium of females was observed at 50 and 250 mg/kg/day. For reproduction, the gestation period was prolonged and the delivery index was decreased at 250 mg/kg/day. The number of pups born and the birth index were also reduced. It was thus concluded that the NOAEL for repeated-dose toxicity was 10 mg/kg/day based on the thyrotoxicity and renal toxicity, and that the NOAEL for reproductive/developmental toxicity was 50 mg/kg/day based on the reduced number of offspring, etc. PMID- 24067725 TI - p,p'-DDT induces microcytic anemia in rats. AB - Emerging evidence suggests that chronic exposure to DDT and its derivatives is associated with a variety of human disorders such as anemia. The present study demonstrated that p,p'-DDT caused microcystic anemia in a dose-dependent manner (0, 5, 50, and 500 ppm) in the long-term study up to 2 years. To elucidate the mechanism(s) by which p,p'-DDT induces anemia, certain hematological parameters were assessed in rats fed specific doses of p,p'-DDT for 2 weeks, and the effect of lipopolysaccharide on anemia of inflammation was also examined in p,p'-DDT treated rats. The parameters included the content of hemoglobin per reticulocyte, mean corpuscular volume of reticulocytes and mature erythrocytes, corpuscular hemoglobin concentration mean of mature erythrocytes, and saturation levels of transferrin and iron. During the 2-week treatment period, hypochromic microcytic reticulocytes and hypochromic normocytic mature erythrocytes were observed in p,p'-DDT-treated rats, with no evidence of alteration in plasma iron levels. p,p' DDT enhanced microcytosis of reticulocytes, as well as mature erythrocytes, which occurred due to severe hypoferremia resulting from anemia of inflammation; however, plasma iron levels were attenuated probably through the inhibition of interleukin-6. Our data suggests that long-term treatment with p,p'-DDT induces microcytic anemia, possibly because of the impairment of iron utility in erythrocytes. PMID- 24067726 TI - Di-(2-ethylhexyl)-phthalate reduces MyoD and myogenin expression and inhibits myogenic differentiation in C2C12 cells. AB - The purpose of this study was to investigate the effects of di-(2-ethylhexyl) phthalate (DEHP) treatment on MyoD and myogenin expression and myotube formation in the murine C2C12 cells. Myogenic differentiation is principally regulated by activities of myogenic regulatory factors, such as MyoD and myogenin, leading the elongation and fusion of mononucleated myoblasts into multinucleated myotubes. In the present study, myogenic differentiation of C2C12 cells was induced by serum deprivation with medium containing vehicle or DEHP (10, 100, 1,000 MUg/ml) for 5 days. Using 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay clearly demonstrated cell viability was not affected by DEHP at any given dose. At the dose of 1,000 MUg/ml DEHP, the elongation of multinucleated myotubes, and the percent of nuclei incorporated into myosin heavy chain (MyHC) stained myotubes were markedly reduced. In addition, immunoblotting revealed expression of muscle specific marker MyHC, as well as myogenic regulatory factors MyoD and myogenin, were reduced in DEHP-treated myotubes during myogenic differentiation. Taken together, the results showed that DEHP may impair myogenic differentiation through repression of myogenic regulatory factors, such as MyoD and myogenin, resulting in a reduction of MyHC expression. This in vitro study suggests that DEHP may be an environmental risk factor for myogenesis. PMID- 24067727 TI - Activation of EGFR/MEK/ERK/AP-1 signaling mediated by 1,2-naphthoquinone, an atmospheric electrophile, in human pulmonary A549 cells. AB - 1,2-Naphthoquinone (1,2-NQ) is found to be an electrophile contaminated in the atmosphere. Although we found that 1,2-NQ activates epidermal growth factor receptor (EGFR) coupled to inhibition of protein tyrosine phosphatase 1B (PTP1B) activity through covalent modification of Cys121 in human epithelial A431 cells, modulation of its downstream signal transduction pathway caused by 1,2-NQ remains to be elucidated. In the present study, we examined whether 1,2-NQ could affect such cellular signaling in human pulmonary A549 cells. Exposure of A549 cells to 1,2-NQ increased EGFR phosphorylation, resulting in activation of MEK/ERK signaling that was blocked by either PD15035 or PD98059. As a result, DNA binding activity of transcription factor AP-1 was enhanced during exposure to 1,2-NQ in the cells. These results suggest that the atmospheric electrophile phosphorylates EGFR, thereby activating the MEK/ERK/AP-1 signal transduction pathway in A549 cells. PMID- 24067728 TI - DNA microarray expression analysis of mouse kidney following cadmium exposure for 12 months. AB - Cadmium (Cd) is a toxic heavy metal and chronic exposure causes kidney injury. This study used DNA microarray analysis to examine gene expression in the kidney of mice chronically exposed to Cd. Female C57BL/6J mice were fed a 300 ppm Cd containing diet or a control diet for 12 months. In comparison with control mice, the expression levels of 32 genes, including Hmox1 and Mt2, were elevated more than 2.0-fold, whereas 113 genes, including transport- and ubiquitination-related genes, were reduced less than 0.5-fold. PMID- 24067729 TI - Cerebral cortex and hippocampus respond differently after post-natal exposure to uranium. AB - The central nervous system (CNS) is known to be sensitive to pollutants during its development. Uranium (U) is a heavy metal that occurs naturally in the environment as a component of the earth's crust, and populations may therefore be chronically exposed to U through drinking water and food. Previous studies have shown that the CNS is a target of U in rats exposed in adulthood. We assessed the effects of U on behavior and cholinergic system of rats exposed from birth for 10 weeks at 10 mg.L-1 or 40 mg.L-1. For behavioral analysis, the sleep/wake cycle (recorded by telemetry), the object recognition memory and the spatial working memory (Y-maze) were evaluated. Acetylcholine (ACh) and acetylcholinesterase (AChE) levels were evaluated in the entorhinal cortex and hippocampus. At 40 mg.L 1, U exposure impaired object recognition memory (-20%), but neither spatial working memory nor the sleep/wake cycle was impaired. A significant decrease was observed in both the ACh concentration (-14%) and AChE activity (-14%) in the entorhinal cortex, but not in the hippocampus. Any significant effect on behaviour and cholinergic system was observed at 10 mg U.L-1. These results demonstrate that early exposure to U during postnatal life induces a structure cerebral-dependant cholinergic response and modifies such memory process in rats. This exposure to U early in life could have potential delayed effects in adulthood. PMID- 24067730 TI - Lactococcus formosensis sp. nov., a lactic acid bacterium isolated from yan-tsai shin (fermented broccoli stems). AB - A coccal-shaped organism, designated 516(T), was isolated from yan-tsai-shin (fermented broccoli stems), a traditional fermented food in Taiwan. 16S rRNA gene sequencing results showed that strain 516(T) had 98.9 % sequence similarity to that of the type strain Lactococcus garvieae NBRC 100934(T). Comparison of three housekeeping genes, rpoA, rpoB and pheS, revealed that strain 516(T) was well separated from Lactococcus garvieae NBRC 100934(T). DNA-DNA hybridization studies indicated that strain 516(T) had low DNA relatedness with Lactococcus garvieae NBRC 100934(T) (46.1 %). The DNA G+C content of strain 516(T) was 38.1 mol% and the major fatty acids were C16 : 0 (22.7 %), C19 : 0 cyclo omega8c (17.9 %) and summed feature 7 (29.0 %). Based on the evidence, strain 516(T) represents a novel species of the genus Lactococcus, for which the name Lactococcus formosensis sp. nov. is proposed. The type strain is 516(T) ( = NBRC 109475(T) = BCRC 80576(T)). PMID- 24067731 TI - Rhizobium laguerreae sp. nov. nodulates Vicia faba on several continents. AB - Several fast-growing strains nodulating Vicia faba in Peru, Spain and Tunisia formed a cluster related to Rhizobium leguminosarum. The 16S rRNA gene sequences were identical to that of R. leguminosarum USDA 2370(T), whereas rpoB, recA and atpD gene sequences were phylogenetically distant, with sequence similarities of less than 96 %, 97 % and 94 %, respectively. DNA-DNA hybridization analysis showed a mean relatedness value of 43 % between strain FB206(T) and R. leguminosarum USDA 2370(T). Phenotypic characteristics of the novel strains also differed from those of the closest related species of the genus Rhizobium. Therefore, based on genotypic and phenotypic data obtained in this study, we propose to classify this group of strains nodulating Vicia faba as a novel species of the genus Rhizobium named Rhizobium laguerreae sp. nov. The type strain is FB206(T) ( = LMG 27434(T) = CECT 8280(T)). PMID- 24067733 TI - Frequent floods in the European Alps coincide with cooler periods of the past 2500 years. AB - Severe floods triggered by intense precipitation are among the most destructive natural hazards in Alpine environments, frequently causing large financial and societal damage. Potential enhanced flood occurrence due to global climate change would thus increase threat to settlements, infrastructure, and human lives in the affected regions. Yet, projections of intense precipitation exhibit major uncertainties and robust reconstructions of Alpine floods are limited to the instrumental and historical period. Here we present a 2500-year long flood reconstruction for the European Alps, based on dated sedimentary flood deposits from ten lakes in Switzerland. We show that periods with high flood frequency coincide with cool summer temperatures. This wet-cold synchronism suggests enhanced flood occurrence to be triggered by latitudinal shifts of Atlantic and Mediterranean storm tracks. This paleoclimatic perspective reveals natural analogues for varying climate conditions, and thus can contribute to a better understanding and improved projections of weather extremes under climate change. PMID- 24067734 TI - Technical efficiency of public district hospitals in Madhya Pradesh, India: a data envelopment analysis. AB - BACKGROUND: Scarcity of resources for healthcare is a well-acknowledged problem. In this context, efficient utilization of existing financial and human resources becomes crucial for strengthening the healthcare delivery. The assessment of efficiency of health facilities can guide decision makers in ensuring the optimum utilization of available resources. OBJECTIVE: The objective of this study was to evaluate the technical efficiency (TE) of the public district hospitals in Madhya Pradesh, India, with special emphasis on maternal healthcare services, using data envelopment analysis (DEA). METHODS: Data from 40 district hospitals from January to December 2010 were collected from the health management information system and other records of the department of health and family welfare of the state. DEA was performed with input orientation and variable returns to scale assumption. RESULTS: TE and scale efficiency scores of the district hospitals were 0.90 (SD = 0.14) and 0.88 (SD = 0.15), respectively. Of the total district hospitals in the study, 20 (50%) were technically efficient constituting the 'best practice frontier'. The other half were technically inefficient, with an average TE score of 0.79 (SD = 0.12) meaning that these hospitals could produce the same outputs by using 21% less inputs from current input levels. Twenty-six (65%) district hospitals were found to be scale inefficient, manifesting a mean score of 0.81 (SD = 0.16). CONCLUSIONS: Half of the district hospitals in the study were operating inefficiently. Decision makers and administrators in the state should identify the causes of the observed inefficiencies and take appropriate measures to increase efficiency of these hospitals. PMID- 24067735 TI - A reduced graphene oxide/Cu6Sn5 nanocomposite with enhanced cycling stability for lithium storage. AB - We report a reduced graphene oxide (RGO)/Cu6Sn5 composite with enhanced lithium storage capability in which the nano-sized Cu6Sn5 is anchored on multi-layer graphene sheet using a soft chemical process. Being different from previous carbon modification technology, which usually loses the electronic path between the alloy particle and the supporting carbon medium after cycling, the graphene sheets provide a very useful buffer matrix for the volume change during lithiation and provide unique electronic conductivity. As a result, the RGO/Cu6Sn5 composite delivers a reversible capacity of 450 mAh g(-1) at a constant current density of 100 mA g(-1) between 0.0 and 2.0 V (versus Li(+)/Li), and exhibits excellent cycling stability with a capacity retention of 88% over 250 cycles. PMID- 24067737 TI - Constantin N. Arseni: a leader of Romanian neurosurgery. PMID- 24067736 TI - Results of immunohistochemical staining of cell-cycle regulators: the prediction of recurrence of functioning pituitary adenoma. AB - OBJECTIVE: This study was undertaken primarily to investigate the possible prognostic values of several cell-cycle regulators for the prediction of functioning pituitary adenoma (FPA) recurrence after surgical resection by immunohistochemically analyzing tumor samples obtained by surgical resection. METHODS: The medical records of the patients with FPA diagnosed from January 2000 to December 2009 at the Department of Neurosurgery at Samsung Changwon Hospital and Dong-A University Medical Center were selected. Immunohistochemical staining was performed on archived paraffin-embedded tissues obtained by surgical resection for adenohypophysial cells, cell-cycle regulatory proteins (p16, p15, p21, cyclin-dependent kinase [CDK] 4 and 6, phosphorylated retinoblastoma [pRB] protein, and cyclin D1), MIB-1 antigen, and p53. RESULTS: Of the 174 FPAs, 62 (35.6%) recurred during follow-up period (mean duration 62.4 months, range 24.2 118.9 months). Immunohistochemically, overstaining for p16 in 89 samples (51.1%), p15 in 27 samples (15.5%), p21 in 20 samples (11.5%), CDK4 in 54 samples (31.0%), CDK6 in 18 samples (10.3%), pRB protein in 69 samples (39.7%), and cyclin D1 in 87 samples (50.0%). Multivariate analysis using the Cox proportional hazard regression model showed that invasion into cavernous sinus (hazard ratio [HR] of 4.02; P < 0.001), immunohistochemical normostaining for p16 (HR of 3.16; P < 0.001), immunohistochemical overstaining for pRB protein (HR of 2.45; P = 0.008), cyclin D1 (HR of 2.13; P = 0.029), MIB-1 antigen (HR of 2.74; P = 0.002), and p53 (HR of 2.21; P = 0.002), predicted the recurrence of FPA after surgical resection. CONCLUSIONS: Our findings indicate that p16, pRB protein, and cyclin D1 are associated with recurrence FPA after surgical resection. PMID- 24067738 TI - Radiologic advantages of potential use of polymer plastic clips in neurosurgery. AB - BACKGROUND: Plastic clips are made of diamagnetic material and may result in fewer computed tomography (CT) and magnetic resonance artifacts than titanium clips. Considering that polymer plastic clips are increasingly being used in endoscopic surgery, our study examined the CT and magnetic resonance imaging (MRI) characteristics of plastic clips after application in the neurocranium and compared them with titanium clips. METHODS: Craniotomy was performed on the heads of domestic pigs (Sus scrofa domestica), and, at an angle of 90 degrees , a permanent Yasargil FT 746 T clip was placed in a frontobasal, interhemispheric position. A plastic polymer medium-large Hem-o-lok clip was placed in the same position into another animal. After this procedure, CT of the brain was performed using Siemens 16 slice, followed by an MRI scan, on Philips MRI, 1.5 Tesla. The CT and magnetic resonance scans were analyzed. RESULTS: On axial CT sections through the site of placement of titanium clips, dotted hyperdensity with a high value of Hounsfield units (HUI) of about 2800-3000 could be clearly seen. At the site where the plastic polymer clips were placed, discrete hyperdensity was observed, measuring 130-140 HUI. MRI of the brain in which titanium clips were used revealed a hypointensive T1W signal in the interhemispheric fissure, with a hypointensive T2W signal. On the other hand, upon examination of the MRI of the brain in which plastic clips were used, the T1W signal described above did not occur, and there was also no T2W signal, and no artifacts observed. CONCLUSIONS: The plastic clips are made of a diamagnetic, nonconductive material that results in fewer CT and MRI artifacts than titanium clips. PMID- 24067739 TI - Computational fluid dynamic simulation of a giant basilar tip aneurysm with eventual rupture after Hunterian ligation. AB - BACKGROUND: Hunterian ligation is performed to reduce and to change the flow of an aneurysm; it is a surgical option for a complex aneurysm that cannot be managed by either clipping or coiling. However, it may be associated with adverse effects. This study was carried out to analyze how Hunterian ligation changed the flow dynamics of a particular cerebral aneurysm. METHODS: A case of giant basilar tip aneurysm, in which Hunterian ligation resulted in rupture 6 months later, was subjected to computational fluid dynamic simulation. Among the simulations with various boundary conditions, the flow dynamic parameters of streamlines, velocities, and wall shear stresses were compared and analyzed qualitatively and quantitatively. RESULTS: Hunterian ligation switched the parent artery from the basilar artery to the left posterior communicating artery. The changes in the direction and the diameter of the parent arteries resulted in the focal elevation of the shear magnitude and the high shear gradient on the posterior wall of the aneurysm after the ligation. These hemodynamic changes might have been associated with the eventual rupture of the aneurysm. CONCLUSIONS: Hunterian ligation is a useful flow diversion surgery, but it might worsen the flow dynamics in specific cases. PMID- 24067740 TI - Incidence and mortality of spontaneous subarachnoid hemorrhage in Hong Kong from 2002 to 2010: a Hong Kong hospital authority clinical management system database analysis. AB - BACKGROUND: Ninety-five percent of the Hong Kong population is Chinese, and no previous epidemiological study has focused on spontaneous subarachnoid hemorrhage (SAH) in Hong Kong. These data would have significant public health implications and can guide future resource allocations and service development in Hong Kong. The aim of this study was to investigate the local incidences of spontaneous SAH and 1-year mortality rates in Hong Kong, with the respective time trends in recent years. METHODS: Data from the Clinical Management System database of the Hong Kong Hospital Authority were used to examine the incidence of SAH and 1-year mortality rates among the Hong Kong population for the 2002-2010 period. Age standardized incidence rates were calculated by the direct method using the standard population given in World Health Organization World Standard Population 2000-2025. RESULTS: Crude SAH incidences increased from 5.5 per 100,000 person years in 2002 to 7.5 in 2010. Standardized SAH incidences increased from 4.1 per 100,000 person-years in 2002 to 5.6 in 2010. Crude 1-year mortality rates decreased from 43% in 2002 to 19% in 2010, and the standardized 1-year mortality rate decreased from 38% in 2002 to 19% in 2010. CONCLUSION: The Hong Kong SAH incidence was 7.5 per 100,000 person-years in 2010, and an increasing trend over time was noted. The 1-year mortality rates decreased from 43% in 2002 to 19% in 2010, in accordance with the worldwide trend. PMID- 24067741 TI - Challenges and changes in the endovascular treatment of very small intracranial aneurysms. PMID- 24067742 TI - Nanoparticle-based signal generation and amplification in microfluidic devices for bioanalysis. AB - Signal generation and amplification based on nanomaterials and microfluidic techniques have both attracted considerable attention separately due to the demands for ultrasensitive and high-throughput detection of biomolecules. This article reviews the latest development of signal amplification strategies based on nanoparticles for bioanalysis and their integration and applications in microfluidic systems. The applications of nanoparticles in bioanalysis were categorized based on the different approaches of signal amplification, and the microfluidic techniques were summarized based on cell analysis and biomolecule detection with a focus on the integration of nanoparticle-based amplification in microfluidic devices for ultrasensitive bioanalysis. The advantages and limitations of the combination of nanoparticles-based amplification with microfluidic techniques were evaluated, and the possible developments for future research were discussed. PMID- 24067743 TI - Anisotropic vanadium dioxide sculptured thin films with superior thermochromic properties. AB - VO2 (M) STF through reduction of V2O5 STF was prepared. The results illustrate that V2O5 STF can be successfully obtained by oblique angle thermal evaporation technique. After annealing at 550 degrees C/3 min, the V2O5 STF deposited at 85 degrees can be easily transformed into VO2 STF with slanted columnar structure and superior thermochromic properties. After deposition SiO2 antireflective layer, Tlum of VO2 STF is enhanced 26% and DeltaTsol increases 60% compared with that of normal VO2 thin films. Due to the anisotropic microstructure of VO2 STF, angular selectivity transmission of VO2 STF is observed and the solar modulation ability is further improved from 7.2% to 8.7% when light is along columnar direction. Moreover, the phase transition temperature of VO2 STF can be depressed into 54.5 degrees C without doping. Considering the oblique incidence of sunlight on windows, VO2 STF is more beneficial for practical application as smart windows compared with normal homogenous VO2 thin films. PMID- 24067744 TI - The importance of short-term off-target effects in estimating the long-term renal and cardiovascular protection of angiotensin receptor blockers. AB - Angiotensin receptor blockers (ARBs) have multiple effects that may contribute to their efficacy on renal/cardiovascular outcomes. We developed and validated a risk score that incorporated short-term changes in multiple risk markers to predict the ARB effect on renal/cardiovascular outcomes. The score was used to predict renal/cardiovascular risk at baseline and at month 6 in the ARB treatment arm of the Reduction of Endpoints in NIDDM (noninsulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial. The net risk difference at these time points indicated the estimated long-term renal/cardiovascular treatment effect. Predicted relative risk reductions (RRRs) based on multiple markers were close to observed RRRs for renal (RRR(predicted): 30.1% vs. RRR(observed): 21.8%; P = 0.44) and cardiovascular outcomes (RRR(predicted): 9.4% vs. RRR(observed): 9.2%; P = 0.98), in addition to being markedly more accurate than predicted RRRs based on changes in single markers. The score was validated in an independent ARB trial. Predictions of long-term renal/cardiovascular ARB effects are more accurate when considering short-term changes in multiple risk markers, challenging the use of single markers to establish drug efficacy. PMID- 24067745 TI - Grapefruit juice inhibits the metabolic activation of clopidogrel. AB - Cytochrome P450 (CYP) enzymes, including CYP2C19 and CYP3A4, participate in the bioactivation of clopidogrel. Grapefruit juice constituents potently inactivate intestinal CYP3A4 and have been shown to inhibit CYP2C19 as well. In a randomized crossover study, 14 healthy volunteers ingested 200 ml of grapefruit juice or water three times daily for 3 days. On day 3, they ingested a single 600-mg dose of clopidogrel. Grapefruit juice reduced the peak plasma concentration (Cmax) of the active metabolite of clopidogrel to 13% of the control (range 11-17%, P < 0.001) and the area under the plasma concentration-time curve from 0 to 3 h to 14% (range 12-17%, P < 0.001) of the control, but it had no significant effect on the parent clopidogrel. Moreover, grapefruit juice markedly decreased the platelet-inhibitory effect of clopidogrel, as assessed with the VerifyNow P2Y12 test in two of the participants. In conclusion, concomitant use of grapefruit juice may impair the efficacy of clopidogrel. Therefore, the use of grapefruit juice is best avoided during clopidogrel therapy. PMID- 24067746 TI - Cost-effectiveness of pharmacogenetics-guided warfarin therapy vs. alternative anticoagulation in atrial fibrillation. AB - Pharmacogenetics-guided warfarin dosing is an alternative to standard clinical algorithms and new oral anticoagulants for patients with nonvalvular atrial fibrillation. However, clinical evidence for pharmacogenetics-guided warfarin dosing is limited to intermediary outcomes, and consequently, there is a lack of information on the cost-effectiveness of anticoagulation treatment options. A clinical trial simulation of S-warfarin was used to predict times within therapeutic range for different dosing algorithms. Relative risks of clinical events, obtained from a meta-analysis of trials linking times within therapeutic range with outcomes, served as inputs to an economic analysis. Neither dabigatran nor rivaroxaban were cost-effective options. Along the cost-effectiveness frontier, in relation to clinically dosed warfarin, pharmacogenetics-guided warfarin and apixaban had incremental cost-effectiveness ratios of L13,226 and L20,671 per quality-adjusted life year gained, respectively. On the basis of our simulations, apixaban appears to be the most cost-effective treatment. PMID- 24067747 TI - Erythrocyte osmotic resistance recovery after lung volume reduction surgery. AB - OBJECTIVES: Alteration of erythrocyte osmotic resistance, with increment of reticulocytes, is common in emphysema. This fragility is probably due to an altered fatty acid membrane composition from lipid peroxidation, a reaction triggered by the disease-related increment of reactive oxidative species. We analysed the effects of lung volume reduction surgery (LVRS) on this anomaly compared with respiratory rehabilitation (RR) therapy. METHODS: We retrospectively compared 58 male patients with moderate-to-severe emphysema who underwent LVRS with 56 similar patients who underwent standardized RR. Respiratory function parameters, erythrocyte osmotic resistance and antioxidant enzymes levels were evaluated before and 6 months after treatments. RESULTS: Significant improvements in respiratory function, exercise capacity, unsaturated fatty acid content (+10.0%, P = 0.035), erythrocyte osmotic resistance (hyperosmolar resistance -21.0%, P = 0.001; hyposmolar resistance -18.0%, P = 0.007) and erythrocyte antioxidant enzymes [superoxide dismutase (SOD) +60.0%, P < 0.001; glutathione peroxidase +39.0%, P = 0.004 and glutathione reductase +24.5%, P = 0.008] were observed after surgery. In the RR group, we did not find any significant improvements in osmotic resistance, although respiratory and functional parameters were significantly improved. Correlation analysis in the surgical group showed that the reduction in residual volume (RV) significantly correlated the normalization of hyperosmotic (P = 0.019) and hyposmotic resistances (P = 0.006), the decrease in the absolute number of reticulocytes (P = 0.037) and increase in SOD (P < 0.001). CONCLUSIONS: LVRS improved unsaturated fatty acid content, erythrocyte osmotic resistance and levels of erythrocyte antioxidant enzymes compared with RR. Correlations between erythrocyte osmotic resistance and antioxidant intracellular enzymes with RV suggest that reduction in lung hyperinflation with the elimination of inflammatory emphysematous tissue may explain such improvements after surgery. PMID- 24067748 TI - The right internal thoracic artery: how much do we know? PMID- 24067749 TI - Trends in mortality (1975-2011) after one- and two-stage Fontan surgery, including bidirectional Glenn through Fontan completion. AB - OBJECTIVES: Techniques and strategies in the Fontan procedure have evolved over the years, including the evolution from a one- to two-stage procedure. With such adjustments made, attention should shift towards survival analysis, including bidirectional cavopulmonary shunt (BCPS) and interstage mortality. The purpose of this study was to investigate the trends in the overall mortality of all patients who underwent a BCPS or one-stage Fontan procedure at our institution in the period of 1975-2011. METHODS: Using a single-institution, retrospective design, we reviewed the patient records of 203 patients from the University Medical Center Groningen, Netherlands, who underwent a Fontan procedure or a BCPS (with the intention to complete cavopulmonary connection at a second later stage) between 1975 and 2011. Trends in mortality were investigated by comparing survival rates during four consecutive decades (1975-84; 1985-94; 1995-2004; 2005 11), and predictors for mortality were identified. RESULTS: During a mean follow up of 12 years, survival was 69%. Overall mortality declined significantly during the past decades (P = 0.017). This was driven by a decrease in early mortality (P = 0.016), whereas no changes in late mortality could be demonstrated. Multivariate analyses identified a diagnosis of heterotaxy (P = 0.049) and an atriopulmonary connection type of Fontan circulation (P = 0.015) as independent risk factors for overall mortality. CONCLUSIONS: We demonstrate that, with the inclusion of first-stage and interstage mortality also, overall survival after Fontan procedures improved over time. This improvement, however, is mainly caused by a decline in early mortality. Improvement in long-term survival of patients operated on over the past four decades could not (yet) be demonstrated in this series. PMID- 24067750 TI - Can maximal inspiratory and expiratory pressures during exercise predict complications in patients submitted to major lung resections? A prospective cohort study. AB - OBJECTIVES: The measurement of maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax) generated at the mouth is an accepted non-invasive clinical method for evaluating the strength of respiratory muscles. The aim of our study was to verify whether PImax and PEmax measured before and after a symptom-limited stair-climbing test are associated with complications in patients submitted to major lung resections. METHODS: In a prospective cohort study of 283 consecutive patients submitted to lobectomy (231) or pneumonectomy (52) with a preoperative symptom-limited stair-climbing test, PImax and PEmax were measured before and immediately after the exercise. PImax and PEmax values were expressed as percentages of predicted values. DeltaPImax and DeltaPEmax were defined as the percentage difference between the pre- and postexercise values. Logistic regression analysis and the bootstrap resampling technique were performed to identify predictors of cardiopulmonary complications. RESULTS: On average, PImax dropped by 3.6% and PEmax increased by 0.8% after the exercise. In total, 173 patients (61%) experienced a reduction in their PImax after exercise, while 150 (53%) had their PEmax reduced. Postoperative cardiopulmonary complications occurred in 74 patients (26%). Complicated patients had a greater reduction in their PImax compared with non-complicated patients (8.7% vs 2.1%, P = 0.03), whereas DeltaPEmax was similar in complicated and non-complicated patients (0.7% vs 1.3%, P = 0.5). Receiver operating characteristic analysis indicated that the best cut-off for predicting complications was a DeltaPImax of 10%. Stepwise logistic regression analysis and bootstrap confirmed that DeltaPImax of >10 was associated with cardiopulmonary complications after adjusting for baseline and surgical factors (DeltaPImax regression coefficient -0.02, P = 0.09, bootstrap frequency 51%). A progressive increase in complications was observed in patients with greater reduction in DeltaPImax after exercise, particularly for values >10% reduction. CONCLUSION: The measurement of PImax at the mouth during exercise represents an additional parameter that can be used to refine risk stratification of lung resection candidates and to identify patients who may benefit from inspiratory muscle training. PMID- 24067751 TI - Exercise improvement after pectus excavatum repair is not related to chest wall function. AB - OBJECTIVES: In patients undergoing corrective surgery for pectus excavatum, there is evidence of improvement in cardiopulmonary function. It is unclear how much of this improvement is attributable to improved chest wall function. Thus, we observed changes in chest wall function in response to an incremental load exercise pre- and postoperatively. METHODS: Using optoelectronic plethysmography, total and regional chest wall volumes were measured in 7 male patients with severe pectus excavatum who underwent a Nuss correction. Rib cage and abdominal volumes were recorded at rest and during exercise (incremental cycle ergometry), pre- and postoperatively in conjunction with spirometry. RESULTS: Tidal volume increases during exercise are blunted compared with baseline measurements at 6 days (-36 +/- 7%) partially recovering at 6 months postoperatively (-18 +/- 22%). This is mirrored by changes in spirometry. Tidal volume decreased during exercise initially in all compartments, but persisted in the rib cage compartment. An increase of 44% (P = 0.009) in exercise tolerance was found 6 months after surgical correction. CONCLUSIONS: Six months after Nuss correction in pectus patients, there was a decrease in rib cage mobility. Despite reduction, patients had a significant improvement in exercise tolerance. Therefore, we conclude that early postoperative improvement in exercise capacity is not due to changes in chest wall function. The longer term effects on chest wall function are yet to be defined. PMID- 24067752 TI - A rationale for managing rare complications: evidence from the European Registry of Endovascular Aortic Repair Complications about aorto-oesophageal fistula. PMID- 24067753 TI - Left main bronchial obstruction caused by a mediastinal bronchogenic cyst. PMID- 24067754 TI - Renewable hydrogen and carbon nanotubes from biodiesel waste glycerol. AB - In this report, we introduce a novel and commercially viable method to recover renewable hydrogen and carbon nanotubes from waste glycerol produced in the biodiesel process. Gas-phase catalytic reforming converts glycerol to clean hydrogen fuel and by replacing the problematical coke formed on the catalyst with high value carbon nanotubes, added value can be realised. Additional benefits of around 2.8 kg CNTs from the reforming of 1 tonne of glycerol and the production of 500 Nm(3) H2 could have a considerable impact on the economics of glycerol utilization. Thereby, the contribution of this research will be a significant step forward in solving a current major technical and economic challenge faced by the biofuels industry. PMID- 24067755 TI - The Surviving Sepsis Campaign guidelines 2012: update for emergency physicians. AB - The Surviving Sepsis Campaign recently developed and published an updated version in 2012 of the international guidelines for the assessment and management of severe sepsis and septic shock. These guidelines reflect literature published in the last 5 years, and many of the recommendations have direct implications for emergency physicians. In this review, we present a concise summary of these recommendations, with a particular focus on those that have changed and those that have direct relevance to the clinical practice of emergency medicine. PMID- 24067757 TI - Agriculture and drought. PMID- 24067758 TI - Modelling: Predictive yield. PMID- 24067759 TI - Perspectives: Legislating change. PMID- 24067760 TI - Crop pests: Under attack. PMID- 24067761 TI - Microbiome: Soil science comes to life. PMID- 24067762 TI - The dry facts. PMID- 24067763 TI - Water: The flow of technology. PMID- 24067764 TI - Plant breeding: Discovery in a dry spell. PMID- 24067765 TI - Differentiation of microbial species and strains in coculture biofilms by multivariate analysis of laser desorption postionization mass spectra. AB - 7.87 to 10.5 eV vacuum ultraviolet (VUV) photon energies were used in laser desorption postionization mass spectrometry (LDPI-MS) to analyze biofilms comprised of binary cultures of interacting microorganisms. The effect of photon energy was examined using both tunable synchrotron and laser sources of VUV radiation. Principal components analysis (PCA) was applied to the MS data to differentiate species in Escherichia coli-Saccharomyces cerevisiae coculture biofilms. PCA of LDPI-MS also differentiated individual E. coli strains in a biofilm comprised of two interacting gene deletion strains, even though these strains differed from the wild type K-12 strain by no more than four gene deletions each out of approximately 2000 genes. PCA treatment of 7.87 eV LDPI-MS data separated the E. coli strains into three distinct groups, two "pure" groups, and a mixed region. Furthermore, the "pure" regions of the E. coli cocultures showed greater variance by PCA at 7.87 eV photon energies compared to 10.5 eV radiation. This is consistent with the expectation that the 7.87 eV photoionization selects a subset of low ionization energy analytes while 10.5 eV is more inclusive, detecting a wider range of analytes. These two VUV photon energies therefore give different spreads via PCA and their respective use in LDPI-MS constitute an additional experimental parameter to differentiate strains and species. PMID- 24067766 TI - Traumatic cerebrovascular injury following severe head injury: proper diagnostic timetable and examination methods. AB - Traumatic cerebrovascular injury (TCVI) is a serious complication of severe head injury, with a high mortality rate. To establish a proper treatment strategy for TCVI, we investigated patients with a high risk of TCVI according to the Guidelines for the Management of Severe Head Injury (hereafter "the Guidelines") to elucidate the validity of the criteria for TCVI in the Guidelines and the appropriate screening timing and methods. Of those transported to our facility between December 2008 and June 2012, 67 individuals with a high risk of TCVI were evaluated to reveal the proper timing and methods of vascular evaluation. Of the 67 patients, 21 had a diagnosis of TCVI based on cerebral angiography, three dimensional computed tomography angiography (3DCTA), or magnetic resonance imaging (MRI), accounting for 6.4% of all patients with severe head injury and as high as 31.3% of patients with a high risk of TCVI according to the Guidelines. In addition, according to the Glasgow Outcome Scale (GOS), outcomes were three deaths due to primary brain injury, six cases of persistent vegetative state, five cases of severe disability, three cases of moderate disability, and four cases of good recovery. Although 3DCTA is a simple and convenient diagnostic method, cerebral angiography is necessary to evaluate dissecting lesions. If patients have any signs or symptoms of TCVI, as described in the Guidelines, cerebral angiography or 3DCTA should be performed as an initial screening method within 72 hours of admission, followed by cerebral angiography on postadmission Day 14 +/- 2 to prevent failed diagnosis. PMID- 24067767 TI - Simple strategy to prevent severe head trauma in Judo. AB - To determine whether the use of an under-mat has an effect on impact forces to the head in Judo, a Judo expert threw an anthropomorphic test device using the Osoto-gari and Ouchi-gari techniques onto a tatami (judo mat) with and without an under-mat. Head acceleration was measured and the head injury criterion (HIC) values with or without under-mat were compared. The use of an under-mat significantly decreased (p = 0.021) the HIC values from 1174.7 +/- 246.7 (without under-mat) to 539.3 +/- 43.5 in Ouchi-gari and from 330.0 +/- 78.3 (without under mat) to 156.1 +/- 30.4 in Osoto-gari. The use of an under-mat simply reduces impact forces to the head in Judo. Rule changes are not necessary and the enjoyment and health benefits of Judo are maintained. PMID- 24067768 TI - Computed tomography evaluation of the brain and upper cervical spine in patients with traumatic cardiac arrest who achieved return of spontaneous circulation. AB - The outcomes of patients with traumatic cardiac arrest (TCA) have been dismal. However, imaging modalities are improving rapidly and are expected to play a role in treatment of patients with TCA. In this retrospective study, whether obtaining computed tomography (CT) immediately after resuscitation had any clinical value was evaluated. Among 145 patients with TCA admitted to our institution during 4 years, hemodynamically stable return of spontaneous circulation (ROSC) was achieved in 38 (26%). Brain and cervical spine CT was obtained prospectively, and the frequency and type of traumatic brain injury (TBI)/upper cervical spine injury (UCSI) were investigated. CT was performed uneventfully in all patients with an average door-to-CT time of 51.5 +/- 18.6 min. Twenty (53%) had CT evidence of TBI. However, no patients underwent brain surgery because of lack of return of brainstem functions. Among the 18 patients without TBI, CT signs of hypoxia were present in 15 patients (39%), and CT was considered intact in 3 patients (8%). None of the 35 patients with abnormal CT findings survived, and the presence of such findings predicted fatality with high sensitivity and specificity. While 13 of the 38 patients (34%) had CT evidence of UCSI, concomitant TBI and USCI were uncommon. None of the 13 patients with UCSI underwent spine surgery because of lack of return of brainstem functions, and the presence of USCI might also be associated with fatality. Although obtaining CT was useful in the prognostication of TCA patients with ROSC, it did not have much impact in therapeutic decision making. PMID- 24067769 TI - Autologous vascularized dural wrapping for temporalis muscle preservation and reconstruction after decompressive craniectomy: report of twenty-five cases. AB - Temporalis muscle reconstruction is a necessary step during frontotemporal cranioplasty ensuing decompressive craniectomy (DC). During this procedure, scarring between the temporalis muscle and the dural layer may lead to complicated muscle dissection, which carries an increased risk of dura and muscle damage. At time of DC, temporalis muscle wrapping by an autologous vascularized dural flap can later on facilitate dissection and rebuilding during the subsequent cranioplasty. In a span of 2 years, we performed 57 DCs for different etiologies. In 30 cases, the temporalis muscle was isolated by wrapping its inner surface using the autologous dura. At cranioplasty, the muscle could easily be dissected from the duraplasty. The inner surface was easily freed from the autologous dural envelope, and reconstruction achieved in an almost physiological position. Follow-up examinations were held at regular intervals to disclose signs of temporalis muscle depletion. Twenty-five patients survived to undergo cranioplasty. Muscle dissection could always be performed with no injury to the dural layer. No complications related to temporalis muscle wrapping were recorded. Face asymmetry developed in four cases but it was always with bone resorption. None of the patients with a good neurological recovery reported functional or aesthetic complaints. In our experience, temporalis muscle wrapping by vascularized autologous dura proved to be effective in preserving its bulk and reducing its adhesion to duraplasty, thereby improving muscle dissection and reconstruction during cranioplasty. Functional and aesthetic results were satisfying, except in cases of bone resorption. PMID- 24067770 TI - Potential risk of artificial cerebrospinal fluid solution without magnesium ion for cerebral irrigation and perfusion in neurosurgical practice. AB - The effect of irrigation with artificial cerebrospinal fluid (CSF) containing various magnesium ion (Mg(2+)) concentrations on vasospastic arteries was investigated in the dog. Cerebral vasospasm was induced by the experimental subarachnoid hemorrhage model in 15 beagle dogs. Cisternal irrigation was performed for 1 hour via a microcatheter placed in the cisterna magna with commercially available artificial CSF (ARTCEREB(r)) with physiological concentration of Mg(2+) (2.2 mEq/l) (ACM group, n = 5), ARTCEREB solution without Mg(2+) (ACR group, n = 5), and ARTCEREB solution with higher Mg(2+) concentration (5 mEq/l) (ACMM group, n = 5). CSF electrolyte concentrations and the diameters of the basilar and vertebral arteries were measured. In the ACM group, no changes were detected in either CSF Mg(2+) concentration or arterial diameters. In the ACR group, the CSF Mg(2+) decreased significantly to 0.8 +/- 0.07 mEq/l from the baseline value of 1.4 +/- 0.03 mEq/l, and both basilar and vertebral artery diameters were significantly decreased to 0.61 +/- 0.18 mm and 0.57 +/- 0.23 mm from their baseline values of 0.74 +/- 0.22 mm and 0.68 +/- 0.17 mm, respectively. In the ACMM group, the CSF Mg(2+) significantly increased to 2.4 +/ 0.15 mEq/l from the baseline value of 1.4 +/- 0.05 mEq/l, and both basilar and vertebral artery diameters were significantly increased to 0.84 +/- 0.19 mm and 0.90 +/- 0.22 mm from their baseline values of 0.71 +/- 0.21 mm and 0.69 +/- 0.24 mm, respectively. Irrigation with artificial CSF solution without Mg(2+) causes vasoconstriction of the cerebral artery. Irrigation with artificial CSF with appropriate Mg(2+) concentration is essential, especially in patients with subarachnoid hemorrhage. PMID- 24067771 TI - White matter characteristics of idiopathic normal pressure hydrocephalus: a diffusion tensor tract-based spatial statistic study. AB - Using magnetic resonance-diffusion tensor imaging (DTI), we examined white matter changes within the brains of patients diagnosed with idiopathic normal pressure hydrocephalus (INPH). We analyzed data for 24 INPH patients who were presented with typical clinical symptoms (gait disturbance, dementia, and/or urinary incontinence) and Evans index > 0.3, and compared these with the control data from 21 elderly persons (>= 60 years). DTI brain images were obtained with a 3T scanner. Fractional anisotropy (FA) brain maps were generated using a computer automated method, and tract-based spatial statistics (TBSS) were then applied to compare the FA brain maps of the INPH and control groups in standard space. The TBSS data were further investigated using region-of-interest (ROI) analyses. ROIs were set within the corpus callosum, the posterior limb of the internal capsule (PLIC), and the cerebral peduncle in reference to a standard brain template. Compared with the control group, FA values in the INPH group were significantly lower in the corpus callosum and just significantly higher in the PLIC, but no significant differences were evident in the cerebral peduncle. The much lower FA values in the corpus callosum, but not the slightly higher FA values in the PLIC, were associated with more severe clinical symptoms such as gait disturbance. The lower FA values in the corpus callosum may offer a clue to solve the pathophysiology of INPH. PMID- 24067772 TI - Delayed progression of edema formation around a hematoma expressing high levels of VEGF and mmp-9 in a patient with traumatic brain injury: case report. AB - The mechanisms accounting for the development of tissue damage following traumatic brain injury (TBI) have been studied for several decades. A variety of mediators, such as vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), which play a crucial role in edema formation after TBI, have been identified. We experienced a case of brain edema that progressed continuously at least until 13 days after head injury. The brain edema occurred around the hemorrhage from an intracerebral contusion. The evacuated hematoma was investigated based on the inference that the unexpected expansion of edema was induced by the mediators within the hematoma itself. A 64-year-old woman was admitted to our hospital following a traffic injury. Left brain contusion was revealed by head computed tomography (CT) on admission. Three hours later, formation of an intracerebral hematoma became evident. Serial CT examination revealed that brain edema had developed progressively till 13 days after the injury. A hematoma removal operation was performed on Day 13. The hematoma was centrifuged and the supernatant was analyzed for the expression of VEGF and MMP 9. The values of both (4400 pg/ml and 920 ng/ml, respectively) were extremely high compared with values reported previously in serum and cerebrospinal fluid collected from patients with intracranial infection or injury. This case suggested that the delayed exacerbation of edema following traumatic intracranial hemorrhage was possibly induced by secretory factors such as VEGF and MMP-9 released from within and around the hematoma. PMID- 24067773 TI - Translucent three-dimensional CT is useful in considering the treatment strategy for the penetrating skull base injury with a metal rod: case report. AB - An 18-year-old male suffered a penetrating skull base injury caused by a metal rod. We made translucent three-dimensional (3D) computed tomography (CT) for clearing the injury site. This method has revealed that right carotid artery was compressed directly by the foreign body, and internal carotid artery trapping was carried out based on hemodynamics as revealed by angiography. This patient achieved modified Rankin scale score of 1 at discharge. Cases of trauma involve a variety of circumstances and therefore require a case-by-case evaluation that depends on the patient's condition. Translucent 3D CT was useful in considering the treatment strategy of the penetrating skull base injury. PMID- 24067774 TI - Unilateral oculomotor nerve palsy as an initial presentation of bilateral chronic subdural hematoma: case report. AB - Isolated oculomotor nerve palsy is well known as a symptom of microvascular infarction and intracranial aneurysm, but unilateral oculomotor nerve palsy as an initial manifestation of chronic subdural hematoma (CSDH) is a rare clinical condition. We report a rare case of an 84-year-old woman with bilateral CSDH who presented with unilateral oculomotor nerve palsy as the initial symptom. The patient, who had a medical history of minor head injury 3 weeks prior, presented with left ptosis, diplopia, and vomiting. She had taken an antiplatelet drug for lacunar cerebral infarction. Computed tomography (CT) of the head showed bilateral CSDH with a slight midline shift to the left side. She underwent an urgent evacuation through bilateral frontal burr holes. Magnetic resonance angiography (MRA) after evacuation revealed no intracranial aneurysms, but constructive interference in steady-state (CISS) magnetic resonance imaging (MRI) revealed that the left posterior cerebral artery (PCA) ran much more anteriorly and inferiorly compared with the right PCA and the left oculomotor nerve passed very closely between the left PCA and the left superior cerebellar artery (SCA). There is the possibility that the strong compression to the left uncus, the left PCA, and the left SCA due to the bilateral CSDH resulted in left oculomotor nerve palsy with an initial manifestation without unconsciousness. Unilateral oculomotor nerve palsy as an initial presentation caused by bilateral CSDH without unconsciousness is a rare clinical condition, but this situation is very important as a differential diagnosis of unilateral oculomotor nerve palsy. PMID- 24067775 TI - Subarachnoid hematoma of the craniocervical junction and upper cervical spine after traumatic cerebral contusion: case report. AB - Spinal subarachnoid hematoma (SSH) is a rare condition, more commonly occurring after lumbar puncture for diagnostic or anesthesiological procedures. It has also been observed after traumatic events, in patients under anticoagulation therapy or in case of arteriovenous malformation rupture. In a very small number of cases no causative agent can be identified and a diagnosis of spontaneous SSH is established. The lumbar and thoracic spine are the most frequently involved segments and only seven cases of cervical spine SSH have been described until now. Differential diagnosis between subdural and subarachnoid hematoma is complex because the common neuroradiological investigations, including a magnetic resonance imaging (MRI), are not enough sensitive to exactly define clot location. Actually, confirmation of the subarachnoid location of bleeding is obtained at surgery, which is necessary to resolve the fast and sometimes dramatic evolution of clinical symptoms. Nonetheless, there are occasional reports on successful conservative treatment of these lesions. We present a peculiar case of subarachnoid hematoma of the craniocervical junction, developing after the rupture of a right temporal lobe contusion within the adjacent arachnoidal spaces and the following clot migration along the right lateral aspect of the foramen magnum and the upper cervical spine, causing severe neurological impairment. After surgical removal of the hematoma, significant symptom improvement was observed. PMID- 24067776 TI - Endoscopic surgery for hemorrhagic pineal cyst following antiplatelet therapy: case report. AB - Pineal cysts of the third ventricle presenting with acute obstructive hydrocephalus due to internal cystic hemorrhage are a rare clinical entity. The authors report a case of a 61-year-old man taking antiplatelet medication who suffered from a hemorrhagic pineal cyst and was treated with endoscopic surgery. One month prior to treatment, the patient was diagnosed with a brainstem infarction and received clopidogrel in addition to aspirin. A small incidental pineal cyst was concurrently diagnosed using magnetic resonance (MR) imaging which was intended to be followed conservatively. The patient presented with a sudden onset of headache and diplopia. On admission, the neurological examination revealed clouding of consciousness and Parinaud syndrome. Computerized tomography (CT) scans demonstrated a hemorrhagic mass lesion in the posterior third ventricle. The patient underwent emergency external ventricular drainage with staged endoscopic biopsy and third ventriculostomy using a flexible videoscope. Histological examination revealed pineal tissue with necrotic change and no evidence of tumor cells. One year later MR imaging demonstrated no evidence of cystic lesion and a flow void between third ventricle and prepontine cistern. In patients with asymptomatic pineal cysts who are treated with antiplatelet therapy, it is important to be aware of the risk of pineal apoplexy. Endoscopic management can be effective for treatment of hemorrhagic pineal cyst with obstructive hydrocephalus. PMID- 24067777 TI - Post-traumatic malignant glioma in a pregnant woman: case report and review of the literature. AB - To add a further contribution to the literature supporting the relationship between previous head trauma and the development of glioma. We present the first case of pregnancy-related post-traumatic malignant glioma in a 29-year-old female who was admitted because of left sided hemiplegia and epilepsy due to a malignant glial tumor. She had been operated for a right frontal hematoma caused by a motorbike accident 9 years before. Neuroimaging showed a large neoplasia in the right frontal region beneath the material used for cranialplasty, and postoperative pathological revealed a glioblastoma multiforme (GBM) in continuity with the scar resulting from the trauma. While epidemiologic studies may not be conclusive, a pathologic basis has been suggested which show that trauma act as a cocarcinogen in the presence of an initiating carcinogen. Our case fulfilled the widely established criteria for brain tumors of traumatic origin. We believe that in specific cases it is reasonable to acknowledge an etiological association between head trauma and glioma. And additional factors such as pregnancy may promote the manifestation of the clinical symptoms. PMID- 24067778 TI - Cosmetic frontotemporal craniotomy using an osteotome: technical note. AB - A frontotemporal craniotomy is usually performed using a "keyhole," made at the union of the zygomatic arch and frontal bone. Consequently, skull depression may occur postoperatively, leading to temporal area deformities and poor cosmetic results. To prevent these complications, we describe our technique for frontotemporal craniotomy using an osteotome to prevent cosmetic deformities. After the temporal muscle is dissected and reflected with the scalp flap, a total of 3 burr holes are made in the frontal and temporal bones. In the lateral greater wing of the sphenoid, where a keyhole is usually made, a bone incision is made anteriorly-posteriorly with an osteotome. The bone flap is lifted upward, and the osteotome is inserted from behind to continue the incision. At craniotomy closure, the bone flap is fixed using a cranial bone flap fixation clamp. This procedure involves almost no removal of frontal or inferior temporal bone, resulting in virtually no bone defect. The absence of skull depression or deformity in the temples postoperatively leads to excellent cosmetic results. Our technique for frontotemporal craniotomy using an osteotome does not create bone defects, and use of titanium clamps for bone flap fixation provides normal skull bone alignment. This procedure provides excellent postoperative cosmetic results. PMID- 24067779 TI - Lumbosubarachnoid-lumboepidural shunting in patients with idiopathic normal pressure hydrocephalus: surgical procedures and follow-up study of five cases. AB - The objective of the study is to introduce the surgical procedure of the lumbosubarachnoid-lumboepidural (L-L) shunting performed as treatment for idiopathic normal-pressure hydrocephalus (iNPH) and its follow-up. The subjects were five patients with probable iNPH (aged 78-85 years; mean age 81 years; four males and one female) who were judged to be at high risk from general or lumbar anesthesia due to their systemic complications and age. The L-L shunt operation was performed for all the patients under local anesthesia using Codman-Hakim Programmable Valve((r)) (Codman & Shurtleff, Inc., Raynham, Massachusetts, USA). The initial pressure for all patients was set at 8 cmH2O. The evaluation of shunt efficacy and the lumbar epidural space cerebrospinal fluid (CSF) absorption test (injection of contrast media into epidural space) were performed both on the operation day and during follow-up period (9-12 months). The shunt operation was judged to be effective in four out of five patients (regarded as shunt responders), whereas no improvement in symptoms was seen in one patient (regarded as shunt nonresponder) where the shunting had no effect after the initial pressure was changed to 4 cmH2O. The lumbar epidural space CSF absorption test both on the operation day and during the follow-up period confirmed absorption in all patients. The L-L shunting is useful for patients with probable iNPH who are at high risk from general or lumbar anesthesia due to their systemic complications and age. CSF was continuously absorbed in the lumbar epidural space during postoperative follow-up period. A longer follow-up is required to establish this surgical procedure. PMID- 24067781 TI - Electrochemical performances and volume variation of nano-textured silicon thin films as anodes for lithium-ion batteries. AB - Electrochemical behaviors of nano-textured silicon thin film (NTSTF) coated with Al2O3 or Cu layers as anodes for lithium-ion batteries have been investigated. The cyclic performance of NTSTF electrodes is superior to dense Si thin films. The NTSTF with a 5 nm thick Cu coating layer shows superior cyclic performance and rate performance to other NTSTF samples. The volume changes of NTSTF electrodes after the first cycle and the tenth cycle have been investigated. This series of electrodes shows an anisotropic volume variation: the height does not change but the diameter does expand. This finding shows the feasibility of dealing with the vertical expansion and contraction of Si-based powder electrodes in Li-ion batteries. PMID- 24067782 TI - Manageable N-doped graphene for high performance oxygen reduction reaction. AB - Catalysts for oxygen reduction reaction (ORR) are at the heart of key green energy fuel cell technology. N-doped graphene is a potential metal-free electrode with much better electrocatalytic activity, long-term stability, and tolerance to crossover effect than expensive platinum-based electrocatalysts. Here, we report a feasible direct-synthesis method in preparing N-graphene with manageable N contents in a large scale. The resultant N-graphene used as electrocatalysts exhibits similar catalytic activity but superior stability compared to commercial Pt/C for ORR in an alkaline solution. It was found that their electrocatalytic activities were demonstrated to depend largely on N-doping content. When nitrogen content reaches a high value at about 24-25%, ORR reaction exhibits a favorable formation of water via a four-electron pathway. Furthermore, the effect of pyrolysis temperature and precursor on the activity of N-graphene is systematically analyzed, and may shed some light on the principle of choosing appropriate way for preparing N-graphene. PMID- 24067783 TI - Origin of easy magnetization switching in magnetic tunnel junctions with voltage controlled interfacial anisotropy. AB - Spin-polarized currents represent an efficient tool for manipulating ferromagnetic nanostructures but the critical current density necessary for the magnetization switching is usually too high for applications. Here we show theoretically that, in magnetic tunnel junctions having electric-field-dependent interfacial anisotropy, the critical density may reduce down to a very low level (~10(4) A cm(-2)) when the junction combines small conductance with the proximity of free layer to a size-driven spin reorientation transition. The theory explains easy magnetization switching recently discovered in CoFeB/MgO/CoFeB tunnel junctions, surprisingly showing that it happens when the spin-transfer torque is relatively small, and provides a recipe for the fabrication of magnetic tunnel junctions suitable for industrial memory applications. PMID- 24067784 TI - Knowledge of palliative care: an online survey. AB - BACKGROUND: The main purpose of palliative care is to manage symptoms among patients, reduce their burden of pain, and improve their quality of life. Nurses are an essential part of the palliative care team in providing high standards of care since they spend the longest time with patients. However, lack of adequate knowledge of palliative care is considered as one of the main barriers to palliative care development and practise. OBJECTIVE: To evaluate Jordanian nursing students' knowledge about palliative care. METHODS: Design A quantitative research method and descriptive online-survey design were used. Settings and Participants The sample consisted of 220 students enrolled in five nursing schools (four governmental and one private) in Jordan. The Palliative Care Quiz for Nursing was used to measure students' knowledge. RESULTS: The sample consisted of 220 nursing students; the mean age was 20.5, SD 2.5, and most of the students were female (67), 74 (34%) were fourth-year students and 58 (26%) were in their third year. The total mean score was low, at 8.0 (SD 3.1), ranging from 0 to 18 and the number of correctly answered statements ranged from 60 (27%, statement no. 3) to 145 (66%, statement no. 2). It was found that there were no significant impacts (H (3)=5.69, p=0.137) for place of study. However, students' knowledge was strongly affected by their academic level (H (3)=12.60, p=0.005). CONCLUSIONS: Integrating palliative care education is required as the mainstay to improve students' knowledge and therefore practise. This education needs to be comprehensive in covering the basic principles of palliative care and symptom management and it should be distributed throughout the different courses to discuss palliative care within different contexts, such as elderly, paediatric and adult settings. PMID- 24067785 TI - Treatment of diffuse systemic sclerosis with hyperimmune caprine serum (AIMSPRO): a phase II double-blind placebo-controlled trial. AB - OBJECTIVE: The primary objective of the study was to explore safety and tolerability of hyperimmune caprine serum (AIMSPRO) in established diffuse cutaneous systemic sclerosis (SSc). Secondary objectives included assessment of potential efficacy and biological activity and exploration of candidate biomarkers. METHODS: This was a double-blind parallel group randomised placebo controlled clinical trial. After informed consent 20 patients with established diffuse cutaneous SSc of greater than 3 years duration not receiving immunosuppressive therapy were randomised to receive either active (n=10) or placebo formulation (n=10) by subcutaneous twice weekly injection over 26 weeks. Clinical assessments were evaluated over 26 weeks. RESULTS: There were no safety concerns during this study. Frequency of adverse events was not different between active and placebo groups. Mean modified Rodnan Skin Score (mRSS) fell by 1.4+/ 4.7 units with active treatment but increased by 2.1+/-6.4 units on placebo when baseline values were compared with 26 weeks and responder analysis showed clinically meaningful improvement in mRSS at 26 weeks in 5 (50%) of actively treated patients compared with 1 (10%) in the control group (p=0.062). PIIINP (ug/L) showed a comparatively larger increase in the treatment group compared with the placebo group, (p=0.0118). CONCLUSIONS: These results confirm tolerability and safety of this novel biological agent in established diffuse SSc. The value of a placebo treated control group in small clinical trials evaluating skin disease in SSc is confirmed. Potential improvement in mRSS and changes in PIIINP in cases receiving active therapy suggest that this intervention may be of clinical benefit and warrants further evaluation. PMID- 24067786 TI - Lab on a Biomembrane: rapid prototyping and manipulation of 2D fluidic lipid bilayers circuits. AB - Lipid bilayer membranes are among the most ubiquitous structures in the living world, with intricate structural features and a multitude of biological functions. It is attractive to recreate these structures in the laboratory, as this allows mimicking and studying the properties of biomembranes and their constituents, and to specifically exploit the intrinsic two-dimensional fluidity. Even though diverse strategies for membrane fabrication have been reported, the development of related applications and technologies has been hindered by the unavailability of both versatile and simple methods. Here we report a rapid prototyping technology for two-dimensional fluidic devices, based on in-situ generated circuits of phospholipid films. In this "lab on a molecularly thin membrane", various chemical and physical operations, such as writing, erasing, functionalization, and molecular transport, can be applied to user-defined regions of a membrane circuit. This concept is an enabling technology for research on molecular membranes and their technological use. PMID- 24067787 TI - Severity of injury can be assessed on a number of dimensions. PMID- 24067788 TI - Genetic linkage analysis identifies Pas1 as the common locus modulating lung tumorigenesis and acute inflammatory response in mice. AB - Selective breeding for the acute inflammatory response (AIR) generated two mouse lines characterized by maximum (AIRmax) and minimum (AIRmin) responses, explained by the additive effect of alleles differentially fixed in quantitative trait loci (QTLs). These mice also differ in their susceptibility to lung tumorigenesis, raising the possibility that the same loci are involved in the control of both phenotypes. To map the QTLs responsible for the different phenotypes, we carried out a genome-wide linkage analysis using single-nucleotide polymorphism arrays in a pedigree consisting of 802 mice, including 693 (AIRmax * AIRmin)F2 intercross mice treated with urethane and phenotyped for AIR and lung tumor multiplicity. We mapped five loci on chromosomes 4, 6, 7, 11 and 13 linked to AIR (logarithm of odds (LOD)=3.56, 3.52, 15.74, 7.74 and 3.34, respectively) and two loci linked to lung tumor multiplicity, on chromosomes 6 and 18 (LOD=12.18 and 4.69, respectively). The known pulmonary adenoma susceptibility 1 (Pas1) locus on chromosome 6 was the only locus linked to both phenotypes, suggesting that alleles of this locus were differentially fixed during breeding and selection of AIR mice. These results represent a step toward understanding the link between inflammation and cancer. PMID- 24067789 TI - The MyD88 rs6853 and TIRAP rs8177374 polymorphic sites are associated with resistance to human pulmonary tuberculosis. AB - Toll-like receptors recognize several components of Mycobacterium tuberculosis, the main causative agent of tuberculosis. The signaling pathways leading to activation of the immune response require the MyD88 and TIRAP genes. The hypothesis that polymorphic variants of these genes influenced resistance to pulmonary tuberculosis was tested by a case-control study (400 cases and 400 controls). Heterozygosity at the polymorphic sites MyD88 rs6853 (alleles: A, G) or TIRAP rs8177374 (S180L) (alleles: C, T) is associated with resistance to pulmonary tuberculosis (P: 7.8 * 10(-8) and 2 * 10(-6), respectively). Double heterozygosity confers higher protection levels (P: 10(-14) to 2 * 10(-16)). The logistic regression model displayed that the double homozygous genotype GG/TT predisposes to the disease (odds ratio (OR): 5.78) and the AG/TT genotype combination neutralizes the protective activity exerted by AG (OR: 3.05). The same model showed that the risk of developing the disease increases with age from 31-40 years to 71-80 years (OR: 1.32-13.59). PMID- 24067790 TI - The origins of '5-HT and mechanisms of defence' by Deakin and Graeff: a personal perspective. AB - In this brief reflection I outline how Fred Graeff and I came to integrate our ideas and findings concerning the behavioural functions of serotonin (5-HT) over 20 years ago in '5-HT and mechanisms of defence', reproduced in this volume (pp. 000-000). The principal insight was that different 5-HT pathways mediate distinct adaptive responses to aversive events of different types. It emerged from a number of strands in neuropsychopharmacology: the functional implications of the still-fresh images of monoamine neuroanatomy of the 1970s; the ethological differentiation of behavioural responses to proximal and distal threats; and the seemingly contradictory effects of 5-HT drugs in unconditioned, Pavlovian and instrumental paradigms of reward and aversion. The article has been cited over 600 times and continues to be cited. The evidence was mainly from the animal literature but included some experimental psychopharmacological tests in humans. Some more recent and notable human corroborations are highlighted in this perspective. PMID- 24067791 TI - Benzodiazepines: risks and benefits. A reconsideration. AB - Over the last decade there have been further developments in our knowledge of the risks and benefits of benzodiazepines, and of the risks and benefits of alternatives to benzodiazepines. Representatives drawn from the Psychopharmacology Special Interest Group of the Royal College of Psychiatrists and the British Association for Psychopharmacology together examined these developments, and have provided this joint statement with recommendations for clinical practice. The working group was mindful of widespread concerns about benzodiazepines and related anxiolytic and hypnotic drugs. The group believes that whenever benzodiazepines are prescribed, the potential for dependence or other harmful effects must be considered. However, the group also believes that the risks of dependence associated with long-term use should be balanced against the benefits that in many cases follow from the short or intermittent use of benzodiazepines and the risk of the underlying conditions for which treatment is being provided. PMID- 24067792 TI - Visual mnemonics for serum protein electrophoresis. PMID- 24067793 TI - Different serum levels of interleukin-23 in patients affected by peripheral arterial disease. PMID- 24067794 TI - Is Rickettsia the key to solving the puzzle of Buerger's disease? PMID- 24067798 TI - Thermally driven metastable solid-solution Li(0.5)FePO4 in nanosized particles and its phase separation behaviors. AB - Nanosized LiFePO4 particles easily show a fast electrochemical response that can be achieved via a non-equilibrium pathway. To understand this intriguing phase transition behavior in nanosized LiFePO4 particles, the metastable solid-solution phase was prepared by thermal treatment with a chemically delithiated nanosized Li0.5FePO4 sample. Thermal treatment makes all the nanosized particles transform easily to the metastable solid-solution phase because of the large thermal energy while an electrochemical reaction does not. The phase separation behavior of the metastable solid-solution sample (Li0.5FePO4) was investigated under various kinetic conditions to understand critical factors affecting the phase separation behavior of nanosized LiFePO4 particles. The main findings in this study are as follows. The first finding is that the depressed phase separation behavior of the metastable phase may originate from the nanoparticle effect, in which the formation of a second phase inside a nanosized particle is not energetically favored because of the large interfacial energy. Therefore, phase separation in nanosized particles occurs between particles rather than inside a particle. If there was no over-potential, such as in the relaxed pellet experiment or in the relaxed electrode experiment in the electrolyte, the metastable phase was quite stable showing no phase separation behavior even though efficient pathways for lithium ions and electrons were well developed. The second finding is that the phase separation behavior of the metastable phase actually depends on the over potential. Under open circuit voltage (OCV) conditions, the metastable phase started to exhibit a slight structural change during a long relaxation time, about ten days. The slow change of the metastable phase may be due to the low driving force, less than 10 mV, which comes from the energetic difference between the two-phase state and the metastable phase. This indicates that the phase separation behavior may require a large over-potential. When a large over potential was applied using an external current, phase separation of the metastable phase was achieved, indicating that the phase separation behavior may be related to activation processes. Furthermore, the requirement for a large over potential indirectly shows that the spinodal decomposition is depressed in nanosized particles. Considering that phase separation in nanosized particles occurs between particles, the surface charge transfer reaction can be a limited reaction for achieving phase separation because it is an activated process and governed by the over-potential. Considering the understanding obtained from the phase separation behavior of the metastable phase, the phase transition behavior of nanosized LiFePO4 particles during charging/discharging can proceed via the metastable phase because there is no spinodal decomposition behavior in nanosized particles and the metastable phase is quite stable. PMID- 24067797 TI - Eicosapentaenoic acid improves glycemic control in elderly bedridden patients with type 2 diabetes. AB - Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega3 polyunsaturated fatty acids mainly contained in the blue-backed fish oil, and are effective in decreasing the lipids disorder and the cardiovascular incidence among diabetic patients. Moreover, it has been suggested that EPA and DHA may improve the insulin resistance and glucose metabolism. However, the clinical effects of EPA and DHA on glucose metabolism remain unclear. We aimed to clarify the effects of EPA/DHA treatment on glycemic control in type 2 diabetes mellitus. This study was a multicenter prospective randomized controlled trial involving 30 elderly type 2 diabetic patients on a liquid diet. Their exercises were almost zero and the content of their meals was strictly managed and understood well. Therefore, the difference by the individual's life was a minimum. The subjects were divided into two groups: those receiving EPA/DHA-rich liquid diet [EPA/DHA (+)] or liquid diet lacking EPA/DHA [EPA/DHA (-)]. Changes in factors related to glucose and lipid metabolism were assessed after the three-month study. Serum concentrations of EPA rose in EPA/DHA (+), although the levels of DHA and fasting C-peptide remained unchanged in EPA/DHA (+). In addition, there was a significant decline in the fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), fasting remnant-like particles and apolipoprotein (apo) B in EPA/DHA (+), compared with the values in EPA/DHA (-). EPA/DHA-rich diet might improve glucose metabolism in elderly type 2 diabetic patients on a liquid diet. This phenomenon may be due to the improved insulin resistance mediated by the rise in serum EPA concentrations. PMID- 24067799 TI - Giant bronchial artery aneurysm treated by coil embolization and Amplatzer placement. PMID- 24067800 TI - Assessment of vascularity in common blue nevi, small/medium congenital nevocellular, common and dysplastic acquired melanocytic nevi and melanomas: a comparative study. AB - Angiogenesis and vascularity are researched in melanocytic tumors for their importance in carcinogenesis. For the first time, to the best of our knowledge, the authors compared the microvascular characteristics between small/medium congenital nevocellular nevi (CN), common blue nevi (BN), common and dysplastic acquired melanocytic nevi (AMN), and melanomas. The authors collected 31 BN, 48 CN (<=5 cm), 35 AMN (14 common, 21 dysplastic), and 26 melanomas. Vessels were stained with factor VIII. Microvascular density (MVD) and total vascular area (TVA), where evaluated in high capillary density areas. Student t and Mann Whitney tests were used. MVD (mean +/- SD) was low in BN (3.52 +/- 1.21) and significantly higher in CN (7.56 +/- 2.47) (P < 0.001). TVA was low in BN and significantly higher in CN (Mann-Whitney U = 141, n1 = 48, n2 = 31, P < 0.001, 2 tailed). MVD was not significantly different between common and dysplastic AMN (20.64 +/- 7.87 and 20.38 +/- 9.54, respectively) (P > 0.05). TVA was not significantly different between common and dysplastic AMN (Mann-Whitney U = 164, n1 = 14, n2 = 21, P > 0.05, 2-tailed). MVD was significantly lower in CN (7.56 +/ 2.47) compared with AMN (20.49 +/- 8.79) (P < 0.001). TVA was significantly lower in CN compared with AMN (Mann-Whitney U = 1486, n1 = 48, n2 = 35, P < 0.001, 2-tailed). MVD was significantly lower in AMN (20.49 +/- 8.79) compared with melanomas (33.77 +/- 14.32) (P < 0.001). TVA (mean +/- SD) was significantly smaller in AMN (18473.94 +/- 7050.61) compared with melanomas (29308.50 +/- 11307.22) (P < 0.001). Vascularity increased from BN to CN to AMN with melanomas being the most vascular. Common and dysplastic AMN had comparable vascularity. The implications of our results regarding melanoma transformation risk are considered. PMID- 24067801 TI - Angiomatous kaposi sarcoma: a variant that mimics hemangiomas. AB - We describe 14 cases of angiomatous Kaposi sarcoma (KS), a distinct histological variant of KS first mentioned by Gottlieb and Ackerman in 1988 that can easily be mistaken for a hemangioma. Intriguingly, this variant of KS has not attracted much attention and has not been studied in detail. Immunohistochemistry showed prominent staining of podoplanin (D2-40) of the neoplastic vasculature but not the preexisting vessels, suggesting lymphatic differentiation, despite the erythrocyte-filled round lumens. To test whether D2-40 staining of round vessels with erythrocytes was distinctive, we stained sinusoidal hemangiomas and cellular angiolipomas, both of which have these structures. In contrast to angiomatous KS, the vessels in both entities were podoplanin (D2-40) negative. The finding of round erythrocyte-filled vessels with podoplanin (D2-40) positivity may be distinctive for this form of KS. PMID- 24067802 TI - Fatal case of metastatic cellular fibrous histiocytoma: case report and review of literature. AB - BACKGROUND: Cellular fibrous histiocytoma was first described in 1994 as a distinct variant of fibrous histiocytoma. Since then, at least 21 cases of cellular fibrous histiocytomas metastasizing to regional lymph nodes and/or lungs have been described, though not all fatal. CASE: We report the case of a 68-year old male patient who presented with a large ulcerated skin tumor on the left thigh. The lesion was urgently excised. Histopathological examination led to the diagnosis of cellular fibrous histiocytoma. Nine months later, the patient presented with progressive dyspnea. A thoracoabdominal computed tomography revealed diffusely spread nodular lung lesions. A lung biopsy confirmed them to be metastases of the cellular fibrous histiocytoma. The condition of the patient quickly deteriorated, and he deceased 2 months later. CONCLUSIONS: Given the possible aggressive nature of cellular type of fibrous histiocytoma, we advice complete excision and clinical follow-up. Chest x-rays and ultrasound examination of regional lymph nodes should be performed in atypical lesions. PMID- 24067804 TI - Subcutaneous infiltrative nodule at the injection site of low-molecular weight heparin simulating malignancy. AB - Low-molecular weight heparins (LMWHs) are the standard agents used for the prevention and treatment of thromboembolic disorders. Despite their widespread use, reports on adverse effects from LMWHs are uncommon. The present report describes a 23-year-old woman with a 3.8-cm solitary, fibrofatty, poorly demarcated nodule involving the subcutaneous tissue of the infraumbilical abdominal wall that appeared 4 years after iterative local administration of LMWH. Microscopically, the nodule showed atypical cells, with bizarre nuclei in the septa of cellular fibrous tissue dissecting the adipose lobules, in the absence of any other malignant changes. To the best of our knowledge, this kind of LMWH-related lesion has not been previously reported. The lesion may result from the combination of an idiosyncratic reaction to the LMWH with local trauma being a probable promoting factor. Alternatively, this reactive proliferation may be entirely due to the trauma represented by repeated injections. This rare process could easily be confused with liposarcoma. As the clinical history of injections is often not provided in the requisition form, pathologists should be aware of this adverse effect from LMWH to avoid misdiagnosis and excessive treatment. PMID- 24067805 TI - Investigation of the open-circuit voltage in solar cells doped with quantum dots. AB - Quantum dots (QDs) have attracted much attention for use in photovoltaic applications because of their potential for overcoming the limits of conventional single-junction devices. One problem associated with solar cells using QDs is that the open-circuit voltage (V(oc)) always decreases with the addition of QDs with respect to the reference cell without QDs. Here, we report the investigation of current-voltage characteristics in Ge/Si QD solar cells in the temperature range from 100 to 300 K. We show that even though V(oc) decreases with increasing temperature, it depends on the nominal Ge thickness, indicating that V(oc) reduction is primarily caused by a decrease in the bandgap energy of the cell. From photoluminescence decay measurements, we found that rapid carrier extraction from QDs occurred in the solar cells; this process eliminates the quasi-Fermi energy splitting between the QDs and the host semiconductor and causes V(oc )reduction in QD solar cells. PMID- 24067806 TI - Late diagnosis of a congenital apical ventricular septal defect with complete closure by right ventricular trabeculations. PMID- 24067807 TI - Coronary flow velocity reserve in three major coronary arteries by transthoracic echocardiography for the functional assessment of coronary artery disease: a comparison with fractional flow reserve. AB - AIMS: Coronary flow velocity reserve (CFVR) measurement in three major coronary arteries by transthoracic echocardiography is a promising and non-invasive method for detecting myocardial ischaemia. Its value when compared with fractional flow reserve (FFR) is unknown. Our aim was to determine the diagnostic accuracy of CFVR in three major coronary arteries for detecting ischaemia compared with FFR. METHODS: This is a prospective study in 172 vessels of 140 patients with at least one >=50% stenosis in a major epicardial artery as determined by visual assessment on computed tomography coronary angiography. We performed CFVR measurement by transthoracic echocardiography within 48 h before coronary angiography and FFR measurement. The cut-off value of CFVR was estimated by the receiver operating characteristic (ROC) curve based on that of FFR <=0.75. RESULTS: The CFVR was 1.86 +/- 0.36 in coronary arteries with FFR <=0.75 (n = 79) and 2.54 +/- 0.48 in those with FFR >0.75 (n = 93, P < 0.0001). CFVR with cut-off of 2.2, determined by the ROC curve, was 85% sensitive and 79% specific in predicting the stenotic condition of the coronary artery with FFR <=0.75 in three major vessels. In each vessel, the sensitivity and specificity were 85 and 78% (left anterior descending coronary artery), 94 and 83% (right coronary artery), and 88 and 88% (left circumflex coronary artery). CFVR was indirect proportional to FFR (r = 0.56, P < 0.0001) and to per cent diameter stenosis (r = 0.26, P = 0.0008). CONCLUSIONS: The non-invasive CFVR measurement could be a reliable stenosis-specific method for determining the haemodynamic significance of three major coronary arteries. PMID- 24067808 TI - Impact insensitive dinitromethanide salts. AB - Several stable guanidinium, triazolium, and tetrazolium dinitromethanide salts with high nitrogen content, good detonation properties, and concomitant low impact sensitivities are potential energetic materials. PMID- 24067809 TI - Countless ways to make a difference. PMID- 24067810 TI - The old becomes new. PMID- 24067811 TI - Functional hemodynamic indicators. PMID- 24067812 TI - Positive deviance. PMID- 24067813 TI - Positive deviance. PMID- 24067814 TI - Horse therapy. PMID- 24067815 TI - Nurses sue for wrongful termination after tuberculosis outbreak. PMID- 24067819 TI - New worldwide nursing group. PMID- 24067825 TI - Helping transgender children and teens. PMID- 24067832 TI - Nursing staff innovations result in improved patient satisfaction. PMID- 24067834 TI - Bedbugs: what nurses need to know. PMID- 24067833 TI - Opioid-induced neurotoxicity. PMID- 24067835 TI - Podcasts for the uninitiated. PMID- 24067840 TI - What price glory? PMID- 24067841 TI - The grief train. PMID- 24067842 TI - Oligothiophenes on CVD graphene grown on multi-crystalline copper foil: supramolecular assembly and impact of morphology. AB - On graphene grown on copper foil, oligothiophenes form identical supramolecular assemblies on different copper facets. Most importantly, we found that the graphene ripple structures, even with a height as small as ~0.5 nm, can significantly alter the molecule-substrate interaction, which has never been observed previously. PMID- 24067843 TI - Creation of a caspase-3 sensing system using a combination of split-GFP and split intein. AB - A genetically encodable caspase-3 sensing system has been created using self assembling split-GFP, in which a C-terminal fragment is "covalently" cyclized via a caspase-3 substrate sequence mediated by split-intein. The specific cleavage of the cyclic C-terminal fragment by caspase-3 induces the GFP reassembly and fluorescence recovery. PMID- 24067844 TI - A change of heart, not so fast: tattoo removal in 2013. PMID- 24067846 TI - Prevalence of psoriasis and rosacea comorbidities in the outpatient setting. PMID- 24067847 TI - Comparative trial of oral ivermectin versus sulfur 8% ointment for the treatment of scabies. PMID- 24067848 TI - Laser therapy for onychomycosis. AB - BACKGROUND: Laser therapy is a rapidly expanding new treatment modality for onychomycosis. OBJECTIVE: To review current and prospective laser systems for the treatment of onychomycosis. METHOD: We searched the PubMed database, the Food and Drug Administration 510(k) database, ClinicalTrials.gov, and Google Scholar for in vitro studies, peer-reviewed clinical trials, manufacturers' white papers, and registered clinical trials of laser systems indicated for the treatment of onychomycosis. All published clinical trials were assessed on a 20-point methodological quality scale. RESULTS: We identified three basic science articles, five peer-reviewed articles, three white papers, and four pending clinical trials, as well as numerous gray literature documents. The overall methodological score for the clinical trials was 9.1 +/- 1.1, with peer-reviewed studies showing a higher score (9.8 +/- 1.5) than white papers (7.5 +/- 0.7). We also identified 11 commercial laser device systems of varying global availability. CONCLUSION: Laser therapy has been tested and approved as a cosmetic treatment only for onychomycosis. It cannot be recommended as a therapeutic intervention to eradicate fungal infection at this time as more rigorous randomized, controlled trials are required to determine if laser therapy is efficacious on par with oral and topical interventions. PMID- 24067849 TI - Compact fluorescent lamps and risk of skin cancer. AB - BACKGROUND: Previously considered safe for typical use, concerns have recently been expressed regarding the potential effect of compact fluorescent lamps (CFLs) on human skin and, in particular, on skin cancer risk. OBJECTIVE: We sought to address this concern by reviewing the current literature on CFLs, ultraviolet (UV) radiation, and photocarcinogenic exposure. RESULTS: On average, the UV radiation from CFLs and subsequent carcinogenic exposure is lower than that from incandescent bulbs. However, defective bulbs can emit higher levels of UV radiation, which may cause significant damage. CONCLUSION: Our review calls for further investigation to determine how frequently these bulbs are sufficiently defective to lead to adverse effects. PMID- 24067850 TI - Intralesional Candida antigen for common warts in people with HIV. AB - BACKGROUND: Intralesional Candida antigen has been used as immunotherapy to treat refractory warts in the immunocompetent pediatric and adult populations but has not been reported in individuals with human immunodeficiency virus (HIV). PURPOSE: To examine if Candida antigen resulted in clearance of medically refractory, long-standing common warts in a series of HIV patients. METHOD: At a hospital-based, adult, outpatient dermatology clinic, seven patients with HIV with common warts of the hands and feet were treated with intralesional Candida antigen. The warts had been resistant to standard patient- and physician-applied modalities. RESULTS: Clearance was achieved in three of seven patients, whereas four of seven did not respond due to a lack of effectiveness or an inability to tolerate treatment. Adverse events included injection-site redness, pruritus, and pain. CONCLUSION: This is the first reported case series using Candida antigen for warts in individuals with HIV. The use of Candida antigen represents a simple and novel approach to the management of treatment-refractory warts in those with HIV. This case series provides a foundation for future larger, randomized trials. PMID- 24067851 TI - The Children's Dermatology Life Quality Index (CDLQI): linguistic and cultural validation in Serbian. AB - BACKGROUND: The Children's Dermatology Life Quality Index (CDLQI) evaluates the impact of skin diseases on the patient's quality of life. OBJECTIVE: The purpose of the study was to translate and to validate the CDLQI into Serbian. METHODS: The CDLQI was translated into Serbian following international recommendations for translation and cultural adaptation. The validation study was carried out on a large cohort of secondary schoolchildren who self-reported acne. RESULTS: Translating the CDLQI consisted of forward translation, reconciliation, back translation, back-translation review, and cognitive debriefing. The good internal consistency of the scale was demonstrated with a Cronbach alpha coefficient of 0.87. A Spearman correlation coefficient of 0.66 between the CDLQI and the Cardiff Acne Disability Index (CADI) was deemed satisfactory to demonstrate concurrent validity. CONCLUSION: The translation, cross-cultural adaptation, and psychometric qualities of the CDLQI were satisfactory, enabling its application in clinical practice and future studies. PMID- 24067852 TI - Clinical and immunologic characterization in 26 Indian pemphigus patients. AB - BACKGROUND: Pemphigus shows geographically variable characteristics. OBJECTIVE: To study the clinical and immunologic characteristics of Indian pemphigus patients before and after treatment. METHODS: Twenty-six Indian pemphigus patients were analyzed with regard to age, gender, clinical features, treatments and response, the results of histopathology, direct and indirect immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and immunoblot analyses. RESULTS: There were 22 pemphigus vulgaris (PV) and 4 pemphigus foliaceus (PF) patients. Direct and indirect IF was positive in 95.8% and 56% of patients, respectively. Indices of ELISA were lower in our study. Immunoblot assays detected the 130 kDa desmoglein-3 in 10 PV patients and the 160 kDa desmoglein-1 in 1 PV patient; 190 kDa periplakin was unexpectedly detected in 8 patients. CONCLUSION: Indian pemphigus patients showed several unique characteristics, including younger population, predominance of PV, low ELISA indices, lower sensitivity of indirect IF and immunoblotting, and the presence of the 190 kDa periplakin in nearly one-third of patients. PMID- 24067853 TI - Mycophenolic acid for lymphomatoid papulosis. AB - BACKGROUND: Lymphomatoid papulosis is a rare CD30+ lymphoproliferative T-cell disorder with limited effective treatments. OBJECTIVE: We describe the case of a 50-year-old woman diagnosed with lymphomatoid papulosis who was unable to access phototherapy and who failed to clear while on systemic treatment with methotrexate. METHODS: The patient was initiated on mycophenolate mofetil (MMF), a prodrug of mycophenolic acid, at a dose of 2 g divided twice daily. RESULTS: MMF produced a rapid response with complete clearing within 8 weeks, and the patient has been successfully maintained for 2 years at the same dose with no noted side effects. Other patients in our clinic have had similar success. CONCLUSIONS: Mycophenolic acid is a safe and well-tolerated therapy for lymphomatoid papulosis. PMID- 24067854 TI - Nevus lipomatosus superficialis unseen or unrecognized: a report of eight cases. AB - BACKGROUND: Nevus lipomatosus superficialis (NLS) is a unique developmental anomaly or nevoid form of lipoma characterized by the ectopic presence of mature adipocytes in reticular dermis. The condition is rare; apart frrom isolated case reports, there are no large case series dealing with the clinicoepidemiologic characteristics and posttreatment long-term follow-up in patients with NLS and little published information on treatment outcome. OBJECTIVE: To study the clinicoepidemiologic characteristics and long-term posttreatment follow-up in patients with NLS. METHODS: This was an 11-year retrospective study analyzing disease characteristics and treatment outcome in eight patients with NLS. RESULTS: There were eight (six males, two females) patients with NLS, of whom three were children. The classic variant of NLS was the predominant presentation. One patient demonstrated a combination of both classic and solitary variants. Most patients, especially those with solitary variants, were commonly misdiagnosed before presenting to us. Four patients, including two with the solitary variant, one each with the classic and the combined type, underwent surgical resection without any recurrence over 8 years of follow-up. CONCLUSIONS: The rare nature of the disorder, which is commonly misdiagnosed, and the absence of long-term follow-up data prompted us to share our experience about NLS to increase its awareness among health care providers. PMID- 24067855 TI - Preparing for subsequent entry biologics in dermatology and rheumatology in Canada. AB - BACKGROUND: Patents on several biologics will expire in Canada in the coming years. As they expire, applications to market subsequent entry biologics (SEBs) may be filed in Canada. OBJECTIVE: To provide an understanding of the regulatory pathway and types of trials used for SEB authorization in Canada. METHODS: Health Canada's draft guidance on SEBs was reviewed in regards to key issues and challenges in the development and authorization of SEBs. RESULTS: Health Canada states that SEBs are not "generic biologics" and their authorization is not a declaration of pharmaceutical or therapeutic equivalence to the originator. The agency recommends that physicians make well-informed decisions regarding therapeutic interchange. CONCLUSIONS: Decisions on how to determine the place of SEBs in clinical practice for biologic-naive patients and those already receiving biologics should be made on a case-by-case basis, considering the patient's needs, the characteristics of the biologic required, and the clinical development programs of the applicable SEB. PMID- 24067856 TI - Successful treatment of necrobiotic xanthogranuloma with intravenous immunoglobulin. AB - BACKGROUND: Necrobiotic xanthogranuloma (NXG) is a rare chronic disorder characterized by firm yellow to red-orange nodules and plaques affecting the face, abdomen, and extremities with the potential for systemic involvement. NXG has a close association with monoclonal gammopathies, and there is a predilection for the development of multiple myeloma. Treatment options are varied due to inconsistent results seen with the use of corticosteroids, immunomodulators, chemotherapeutic agents, and antibiotics. OBJECTIVE: We describe a patient with smoldering multiple myeloma associated with progressive NXG successfully treated with high-dose intravenous immunoglobulin (IVIG). CONCLUSION: Our case adds to the single previous report of two cases of NXG with significant improvement from treatment with IVIG and confirms the efficacy of this treatment modality. PMID- 24067857 TI - Giant Merkel cell carcinoma of the lower limb: case report and review of the literature. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine malignancy that usually grows rapidly at the head and neck. Giant forms at the lower limbs are rarely reported and usually affect patients in the eighth decade or older. METHODS: We report the case of a 60-year-old man who presented with a giant MCC on his right thigh. We managed this case by applying the 2012 updated guidelines and reviewed all cases of giant MCC of the lower limbs reported in the literature. RESULTS: At the 4-month follow-up, the patient showed complete remission. CONCLUSION: Giant forms of MCC are still treated as typical cases of MCC, when these patients show a very poor prognosis. In young and adult people, such as our case, wide surgical excisions, sentinel lymph node biopsy in clinically negative node cases, radiotherapy of the regional drain area, and a strict follow-up should be routinely performed to improve patients' survival. PMID- 24067858 TI - Familial classic Kaposi sarcoma in two siblings: case report and literature review. AB - BACKGROUND: Kaposi sarcoma (KS) is a cutaneous endothelial vascular proliferation with four subtypes: iatrogenic, acquired immune deficiency syndrome (AIDS) related, African, and classic. Familial cases of KS are rare, with 72 cases reported to date, and all were described with the classic variant. The occurrence of classic KS in the Jewish population is well documented, and most of the familial classic KS cases were also reported in Jewish families. OBJECTIVE: We briefly present the history, biopsies, laboratory data, diagnosis, and treatment of localized lower limb classic KS in two siblings of Jewish Eastern European ethnic descent with their response to different therapy modalities. One of our cases had the second longest reported period of follow-up for familial classic KS of 40 years. PMID- 24067859 TI - Dermabrasion and staged excision of facial lesions in a neurofibromatosis case for improvement of facial appearance. AB - BACKGROUND: Neurofibromatosis may present with different skin lesions. Disfiguring lesions on the face might be challenging for the surgeon or clinician to correct and may have adverse effects on patients' social lives, especially in young women. OBJECTIVE: To present the dermabrasion technique combined with serial excisions of a deeper accompanying lesion to treat superficial facial lesions in a young neurofibromatosis patient. METHODS: Dermabrasion was applied to superficial lesions on the face, and staged excision was applied to the deeper lesion located on the forehead. RESULTS: We obtained high patient satisfaction with the result. The deep lesion was excised totally, and superficial lesions were decreased with dermabrasion. CONCLUSION: Dermabrasion may become a good alternative in cases of neurofibromatosis with superficial facial lesions. PMID- 24067860 TI - Unprecedented stacking of MV2+ dications and MV+ radical cations in the mixed valence viologen salt (MV)2(BF4)3 (MV = methylviologen). AB - Using a slow liquid-gas diffusion method, the mixed-valence viologen salt (MV)2(BF4)3 (1) and the radical cation salt (MV)(BF4) (2) are crystallized. Both structures contain regular stacks of MV(+) radical cations (2) or alternating MV(+) and MV(2+) entities (1). A short intrastack intermolecular separation (3.23 A) unprecedently reveals strong interactions between MV(2+) and MV(+) in 1. PMID- 24067863 TI - Use of blood tests to predict upper gastrointestinal lesions in patients with chronic kidney disease. AB - OBJECTIVE: Anemia and iron deficiency are common complications in patients with chronic kidney disease (CKD). However, information about the diagnostic indicators of bleeding-related upper gastrointestinal (GI) tract lesions is sparse and few studies have investigated anemic upper GI tract lesions. METHODS: We included 165 anemic patients with non-dialysis-dependent CKD stages 3 to 5 (44 patients at stage 3, 52 patients at stage 4, and 69 patients at stage 5). Transferrin saturation (TSAT), serum ferritin, mean corpuscular volume, and corrected reticulocyte count data were collected to evaluate their diagnostic use for bleeding-related upper GI tract lesions, which were identified by esophagogastroduodenoscopy. RESULTS: Bleeding-related GI tract lesions were found in 57 patients (34.5%). The area under the receiver-operating characteristic curve used to predict bleeding-related lesions was 0.63 for TSAT (P = 0.007), and the best cutoff value was 19.7% (sensitivity, 0.53; specificity, 0.76). The combination of cutoffs TSAT less than 20% or serum ferritin less than 100 ng/mL produced a 17% increment in sensitivity compared with that of TSAT less than 20% alone. The corrected reticulocyte levels and mean corpuscular volume had no significant diagnostic use. In patients with CKD stage 5, the sensitivity of TSAT or its combination with serum ferritin less than 100 ng/mL was significantly lower than in patients with CKD stage 3 (all P < 0.05). CONCLUSIONS: Transferrin saturation is a significant predictor of anemic lesions in the upper GI tract, and serum ferritin can increase the sensitivity of TSAT. However, these indicators should be used with caution in patients with CKD stage 5 because their sensitivity is poor in this context. PMID- 24067865 TI - Effects of intensive whole-body vibration training on muscle strength and balance in adults with chronic stroke: a randomized controlled pilot study. AB - OBJECTIVES: To investigate the effects of a 6-week whole body vibration (WBV) training program in patients with chronic stroke. DESIGN: Randomized controlled pilot trial with 6 weeks' follow-up. SETTING: University hospital. PARTICIPANTS: Adults with chronic stroke (N=15) were randomly assigned to an intervention (n=7) or a control group (n=8). INTERVENTIONS: Supervised, intensive WBV training. The vibration group performed a variety of static and dynamic squat exercises on a vibration platform with vibration amplitudes of 1.7 and 2.5mm and frequencies of 35 and 40Hz. The vibration lasted 30 to 60 seconds, with 5 to 17 repetitions per exercise 3 times weekly for 6 weeks. Participants in the control group continued their usual activities and were not involved in any additional training program. MAIN OUTCOME MEASURES: The primary outcome variable was the isometric and isokinetic muscle strength of the quadriceps (isokinetic dynamometer). Additionally, hamstrings muscle strength, static and dynamic postural control (dynamic posturography), and muscle spasticity (Ashworth Scale) were assessed. RESULTS: Compliance with the vibration intervention was excellent, and the participants completed all 18 training sessions. Vibration frequencies of both 35 and 40Hz were well tolerated by the patients, and no adverse effects resulting from the vibration were noted. Overall, the effect of intensive WBV intervention resulted in significant between-group differences in favor of the vibration group only in isometric knee extension strength (knee angle, 60 degrees ) (P=.022) after 6 weeks of intervention and in isokinetic knee extension strength (velocity, 240 degrees /s) after a 6-week follow-up period (P=.005), both for the paretic leg. Postural control improved after 6 weeks of vibration in the intervention group when the patients had normal vision and a sway-referenced support surface (P<.05). Muscle spasticity was not affected by vibration (P>.05). CONCLUSIONS: These preliminary results suggest that intensive WBV might potentially be a safe and feasible way to increase some aspect of lower limb muscle strength and postural control in adults with chronic stroke. Further studies should focus on evaluating how the training protocol should be administered to achieve the best possible outcome, as well as comparing this training protocol to other interventions. PMID- 24067866 TI - Improved therapeutic effect on malignant glioma with adenoviral suicide gene therapy combined with temozolomide. AB - Malignant gliomas (MGs) are cancers with poor prognosis and limited therapeutic options. Herpes Simplex virus-1 thymidine kinase expressed from adenoviruses with prodrug ganciclovir (TK/GCV) is the best-characterized suicide gene therapy, whereas temozolomide (TMZ) is the first-line chemotherapy for MG. However, the potential of their combination has not been studied thoroughly. The aim of this study was to evaluate the therapeutic response of this combination and to study whether addition of valproic acid (VPA) could benefit the treatment outcome. Efficacies of different treatments were first studied in vitro in BT4C rat MG cells. Therapeutic assessment in vivo was done in an immunocompetent rat MG model for treatment efficacy and toxicity. In vitro, VPA was able to significantly enhance cytotoxicity and increase adenovirus-mediated transduction efficiency up to sevenfold. In vivo, rats receiving TK/GCV+TMZ had notably smaller tumors and enhanced survival (P<0.001) in comparison with control rats. However, VPA was not able to further enhance the treatment response in vivo. Leukocytopenia and thrombocytopenia were the major side effects. We conclude that careful optimization of the treatment schedules and doses of individual therapies are necessary to achieve an optimal therapeutic effect with TK/GCV+TMZ combination. No further in vivo benefit with VPA was observed. PMID- 24067867 TI - Adeno-associated virus type 6 is retrogradely transported in the non-human primate brain. AB - We recently demonstrated that axonal transport of adeno-associated virus (AAV) is serotype-dependent. Thus, AAV serotype 2 (AAV2) is anterogradely transported (e.g., from cell bodies to nerve terminals) in both rat and non-human primate (NHP) brain. In contrast, AAV serotype 6 (AAV6) is retrogradely transported from terminals to neuronal cell bodies in the rat brain. However, the directionality of axonal transport of AAV6 in the NHP brain has not been determined. In this study, two Cynomolgus macaques received an infusion of AAV6 harboring green fluorescent protein (GFP) into the striatum (caudate and putamen) by magnetic resonance (MR)-guided convection-enhanced delivery. One month after infusion, immunohistochemical staining of brain sections revealed a striatal GFP expression that corresponded well with MR signal observed during gene delivery. As shown previously in rats, GFP expression was detected throughout the prefrontal, frontal and parietal cortex, as well as the substantia nigra pars compacta and thalamus, indicating retrograde transport of the vector in NHP. AAV6-GFP preferentially transduced neurons, although a few astrocytes were also transduced. Transduction of non-neuronal cells in the brain was associated with the upregulation of the major histocompatibility complex-II and lymphocytic infiltration as previously observed with AAV1 and AAV9. This contrasts with highly specific neuronal transduction in the rat brain. Retrograde axonal transport of AAV6 from a single striatal infusion permits efficient transduction of cortical neurons in significant tissue volumes that otherwise would be difficult to achieve. PMID- 24067870 TI - Control of the spin geometric phase in semiconductor quantum rings. AB - Since the formulation of the geometric phase by Berry, its relevance has been demonstrated in a large variety of physical systems. However, a geometric phase of the most fundamental spin-1/2 system, the electron spin, has not been observed directly and controlled independently from dynamical phases. Here we report experimental evidence on the manipulation of an electron spin through a purely geometric effect in an InGaAs-based quantum ring with Rashba spin-orbit coupling. By applying an in-plane magnetic field, a phase shift of the Aharonov-Casher interference pattern towards the small spin-orbit-coupling regions is observed. A perturbation theory for a one-dimensional Rashba ring under small in-plane fields reveals that the phase shift originates exclusively from the modulation of a pure geometric-phase component of the electron spin beyond the adiabatic limit, independently from dynamical phases. The phase shift is well reproduced by implementing two independent approaches, that is, perturbation theory and non perturbative transport simulations. PMID- 24067868 TI - The intrinsic microglial molecular clock controls synaptic strength via the circadian expression of cathepsin S. AB - Microglia are thought to play important roles in the maintenance of neuronal circuitry and the regulation of behavior. We found that the cortical microglia contain an intrinsic molecular clock and exhibit a circadian expression of cathepsin S (CatS), a microglia-specific lysosomal cysteine protease in the brain. The genetic deletion of CatS causes mice to exhibit hyperlocomotor activity and removes diurnal variations in the synaptic activity and spine density of the cortical neurons, which are significantly higher during the dark (waking) phase than the light (sleeping) phase. Furthermore, incubation with recombinant CatS significantly reduced the synaptic activity of the cortical neurons. These results suggest that CatS secreted by microglia during the dark phase decreases the spine density of the cortical neurons by modifying the perisynaptic environment, leading to downscaling of the synaptic strength during the subsequent light-phase. Disruption of CatS therefore induces hyperlocomotor activity due to failure to downscale the synaptic strength. PMID- 24067871 TI - Natural versus anthropogenic subsidence of Venice. AB - We detected land displacements of Venice by Persistent Scatterer Interferometry using ERS and ENVISAT C-band and TerraSAR-X and COSMO-SkyMed X-band acquisitions over the periods 1992-2010 and 2008-2011, respectively. By reason of the larger observation period, the C-band sensors was used to quantify the long-term movements, i.e. the subsidence component primarily ascribed to natural processes. The high resolution X-band satellites reveal a high effectiveness to monitor short-time movements as those induced by human activities. Interpolation of the two datasets and removal of the C-band from the X-band map allows discriminating between the natural and anthropogenic components of the subsidence. A certain variability characterizes the natural subsidence (0.9 +/- 0.7 mm/yr), mainly because of the heterogeneous nature and age of the lagoon subsoil. The 2008 displacements show that man interventions are responsible for movements ranging from -10 to 2 mm/yr. These displacements are generally local and distributed along the margins of the city islands. PMID- 24067872 TI - Purinergic signalling: pathophysiology and therapeutic potential. AB - The article begins with a review of the main conceptual steps involved in the development of our understanding of purinergic signalling, including non adrenergic, non-cholinergic (NANC) neurotransmission; identification of ATP as a NANC transmitter; purinergic cotransmission; recognition of two families of purinoceptors [P1 (adenosine) and P2 (ATP/ADP)]; and, later, cloning and characterisation of P1 (G protein-coupled), P2X (ion channel) and P2Y (G protein coupled) receptor subtypes. Further studies have established the involvement of ATP in synaptic neurotransmission in both ganglia and in the central nervous system; long-term (trophic) purinergic signalling in cell proliferation, differentiation and death occurring in development and regeneration; and short term purinergic signalling in neurotransmission, neuromodulation and secretion. ATP is released from most cell types in response to gentle mechanical stimulation and is rapidly degraded to adenosine by ecto-nucleotidases. This review then focuses on the pathophysiology of purinergic signalling in a wide variety of systems, including urinogenital, cardiovascular, airway, musculoskeletal and gastrointestinal. Consideration is also given to the involvement of purinoceptors in pain, cancer and diseases of the central nervous system. Purinergic therapeutic approaches for the treatment of some of these diseases are discussed. PMID- 24067873 TI - Biomechanical properties of the glenohumeral joint capsule in hemiplegic shoulder pain. AB - BACKGROUND: Although many hemiplegic shoulder patients have been suffering from limited range of motion, it is not fully established whether the pathologic biomechanics are same in hemiplegic shoulder pain and adhesive capsulitis. Therefore we aimed to investigate biomechanical properties of glenohumeral joint capsules of hemiplegic shoulder pain with limited range of motions. METHODS: Participants were 14 patients with hemiplegic shoulder pain, 10 controls, and 42 adhesive capsulitis patients matched with the hemiplegic shoulder pain group for sex, age, and range of motion. Demographic data, clinical variables, and sonographic findings were comparable between hemiplegic shoulder pain and adhesive capsulitis groups. We compared capsular capacity, maximal pressure, and capsular stiffness of glenohumeral joint capsule among the 3 groups. FINDINGS: Hemiplegic shoulder pain and adhesive capsulitis groups had smaller capsular capacity and higher maximal pressure than controls. The capsular stiffness of hemiplegic shoulder pain group was higher than that of controls (P=0.001) but lower than that of adhesive capsulitis group (P<0.001). INTERPRETATION: The stiffness of glenohumeral joint capsules in hemiplegic shoulder pain and adhesive capsulitis patients was substantially higher than that in controls, suggesting that hemiplegic shoulder pain patients had stiffer capsules as adhesive capsulitis patients did although the severities were different. This finding implicates that hemiplegic shoulder pain may share common pathologic properties of tighter capsules with adhesive capsulitis. However, there may be additional mechanisms contributing to range of motion limitation in hemiplegic shoulder pain because capsular stiffness in those patients was not as severe as that in adhesive capsulitis patients with similar range of motion limitation. PMID- 24067874 TI - Do people with recurrent back pain constrain spinal motion during seated horizontal and downward reaching? AB - BACKGROUND: Although the effect of symptomatic back pain on functional movement has been investigated, changes to spinal movement patterns in essentially pain free people with a history of recurrent back pain are largely unreported. Reaching activities, important for everyday and occupational function, often present problems to such people, but have not been considered in this population. The purpose of this study was to compare the amplitude and timing of spinal and hip motions during two, seated reaching activities in people with and without a history of recurrent low back pain (RLBP). METHODS: Spinal and hip motions during reaching downward and across the body, in both directions, were tracked using electromagnetic sensors. Analyses were conducted to explore the amplitudes, velocities and timings of 3D segmental movements and to compare controls with subjects with recurrent, but asymptomatic lumbar or lumbosacral pain. FINDINGS: We detected significant differences in the amplitude and timing of movement in the lower thoracic region, with the RLBP group restricting movement and demonstrating compensatory increased motion at the hip. The lumbar region displayed no significant between-group differences. The order in which the spinal segments achieved peak velocity in cross-reaching was reversed in RLBP compared to controls, with lumbar motion leading in controls and lagging in RLBP. INTERPRETATION: Subjects with a history of RLBP show a number of altered kinematic features during reaching activities which are not related to the presence or intensity of pain, but which suggest adaptive changes to movement control. PMID- 24067875 TI - Ipilimumab granulomatous interstitial nephritis. AB - Drug-induced interstitial nephritis is a recognized cause of acute and chronic renal failure. Some of them lead to the formation of granulomata. T-cell-mediated immune response is implicated in the pathogenesis. Here, we describe the case of a 74-year-old male patient with metastatic melanoma who was referred to our clinic with a history of rash and worsening renal function. Because of subacute onset, progressively worsening renal function in the presence of skin rash, elevated liver enzymes, and in the background of exposure, medication-induced interstitial nephritis was suspected. He received 3 doses of ipilimumab, a novel drug used in the treatment of metastatic melanoma within 3 months before the onset of renal failure. A renal biopsy was done, which showed granulomatous interstitial nephritis. Renal biopsy findings, temporal relation between renal failure and exposure to medication, and review of the literature supported a diagnosis of ipilimumab-induced renal failure. He was started on steroids, and renal function recovered in the next 1 month. Immune-related adverse reaction is one of the common side effects of ipilimumab. Ipilimumab-induced hepatitis and colitis has been previously reported in the literature. This is the first ever case report of ipilimumab-induced granulomatous interstitial nephritis. PMID- 24067876 TI - Levofloxacin-induced hepatotoxicity and death. AB - Drug-induced hepatotoxicity is a major cause of hepatocellular injury in patients admitting to emergency services with acute liver failure. Hepatic necrosis may be at varying degrees from mild elevations in transaminases to fulminant hepatitis, and even death. The case of a 53-year-old female patient with toxic hepatitis due to levofloxacin and multiple organ failure secondary to toxic hepatitis is presented. Patient suffered itching, redness, and rash after receiving a single dose of 750 mg of levofloxacin tablets for pulmonary infection 10 days ago. Skin lesions had regressed within 3 days, but desquamation formed all over the body. After the fifth day of drug intake, complaints of abdominal pain, vomiting, and yellowing in skin color had started. The patient was referred to our emergency department with these complaints 10 days after drug intake. Patient was thought as a candidate for liver transplant, but cardiopulmonary arrest occurred, and the patient died before she could be referred to a transplant center. This case is important because hepatotoxicity and death due to levofloxacin is uncommon in the literature. PMID- 24067877 TI - Activating Ag by even more inert Au: a peculiar effect on electrocatalysis toward oxygen reduction in alkaline media. AB - Combined computational and experimental studies reveal a noble, non-d-band effect on Ag activation and electrocatalysis: upon coating Ag onto the even more inert Au surface, the catalytic activity toward the oxygen reduction reaction in alkaline media can be improved by about half an order of magnitude in comparison to the usual Ag surface. PMID- 24067878 TI - Postoperative ileus involves interleukin-1 receptor signaling in enteric glia. AB - BACKGROUND & AIMS: Postoperative ileus (POI) is a common consequence of abdominal surgery that increases the risk of postoperative complications and morbidity. We investigated the cellular mechanisms and immune responses involved in the pathogenesis of POI. METHODS: We studied a mouse model of POI in which intestinal manipulation leads to inflammation of the muscularis externa and disrupts motility. We used C57BL/6 (control) mice as well as mice deficient in Toll-like receptors (TLRs) and cytokine signaling components (TLR-2(-/-), TLR-4(-/-), TLR 2/4(-/-), MyD88(-/-), MyD88/TLR adaptor molecule 1(-/-), interleukin-1 receptor [IL-1R1](-/-), and interleukin (IL)-18(-/-) mice). Bone marrow transplantation experiments were performed to determine which cytokine receptors and cell types are involved in the pathogenesis of POI. RESULTS: Development of POI did not require TLRs 2, 4, or 9 or MyD88/TLR adaptor molecule 2 but did require MyD88, indicating a role for IL-1R1. IL-1R1(-/-) mice did not develop POI; however, mice deficient in IL-18, which also signals via MyD88, developed POI. Mice given injections of an IL-1 receptor antagonist (anakinra) or antibodies to deplete IL 1alpha and IL-1beta before intestinal manipulation were protected from POI. Induction of POI activated the inflammasome in muscularis externa tissues of C57BL6 mice, and IL-1alpha and IL-1beta were released in ex vivo organ bath cultures. In bone marrow transplantation experiments, the development of POI required activation of IL-1 receptor in nonhematopoietic cells. IL-1R1 was expressed by enteric glial cells in the myenteric plexus layer, and cultured primary enteric glia cells expressed IL-6 and the chemokine monocyte chemotactic protein 1 in response to IL-1beta stimulation. Immunohistochemical analysis of human small bowel tissue samples confirmed expression of IL-1R1 in the ganglia of the myenteric plexus. CONCLUSIONS: IL-1 signaling, via IL-1R1 and MyD88, is required for development of POI after intestinal manipulation in mice. Agents that interfere with the IL-1 signaling pathway are likely to be effective in the treatment of POI. PMID- 24067879 TI - Telbivudine improves renal function in patients with chronic hepatitis B. AB - BACKGROUND & AIMS: There is a close relationship between chronic hepatitis B virus infection and chronic renal disease. We analyzed changes in renal function using different markers of glomerular filtration rate (GFR) in multiple studies of telbivudine treatment of patients with chronic hepatitis B virus infection. METHODS: We used serum creatinine-based equations (ie, Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration) to estimate GFR (eGFR) in adults with chronic hepatitis B virus infection and compensated liver disease who participated in a phase III, randomized, double-blind study comparing the efficacy and safety of telbivudine (600 mg/d) and lamivudine (100 mg/d) for 2 years (the GLOBE study) and in long term extension studies (4-6 years), as well as in patients with decompensated cirrhosis (2 years). RESULTS: eGFRs calculated using the Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations were concordant, indicating improved renal function in telbivudine-treated patients during the 2-year GLOBE study (there was an 8.5% increase in mean eGFR, based on the Modification of Diet in Renal Disease equation). Improved renal function was maintained for 4-6 years. Increased eGFR with telbivudine treatment was also observed in patients at increased risk for renal impairment: patients with baseline eGFRs of 60-89 mL/min/1.73 m(2) (+17.2%), older than 50 years (+11.4%), and with liver fibrosis/cirrhosis (+7.2% for patients with Ishak fibrosis score at 5-6). In decompensated patients with high renal risk, eGFR was also improved on telbivudine (+2.0%). CONCLUSIONS: In global trials of patients with compensated and decompensated cirrhosis, long-term telbivudine therapy was associated with a sustained improvement of renal function particularly among patients with increased risk of renal impairment. The mechanisms of this renal protective effect remain to be determined. PMID- 24067882 TI - Capture of iodine in highly stable metal-organic frameworks: a systematic study. AB - A series of aluminum-based metal-organic frameworks were investigated for sorption of iodine (I2) in cyclohexane. The best sorption uptake was obtained with solids decorated by electro-donor groups attached either to the organic ligand (-NH2) or the inorganic sub-network (-OH). PMID- 24067881 TI - Adalimumab therapy is associated with reduced risk of hospitalization in patients with ulcerative colitis. AB - BACKGROUND & AIMS: Adalimumab is effective for induction and maintenance of remission in patients with moderate to severe ulcerative colitis (UC). We assessed whether adalimumab, in addition to standard UC therapy, reduced the risk for hospitalization (from all causes, from complications of UC, or from complications of UC or the drugs used to treat it) and colectomy in patients with moderate to severe UC compared with placebo. METHODS: Data were combined from patients that received induction therapy (a 160-mg dose followed by an 80-mg dose of adalimumab) or placebo in 2 trials (ULTRA 1 and ULTRA 2; n = 963). The risks of hospitalization and colectomy were compared between groups using unadjusted rates during the 8-week induction period, and patient-year-adjusted rates during 52 weeks. Statistical differences between groups were determined using the chi(2) method and Z score normal approximations. Numbers of hospitalizations were compared using Poisson regression with time offset. RESULTS: Significant reductions in risk of all-cause, UC-related, and UC- or drug-related hospitalizations (by 40%, 50%, and 47%, respectively; P < .05 for all comparisons) were observed within the first 8 weeks of adalimumab therapy compared with placebo. Significantly lower incidence rates for all-cause (0.18 vs 0.26; P = .03), UC-related (0.12 vs 0.22; P = .002), and UC- or drug-related (0.14 vs 0.24; P = .005) hospitalizations were observed during 52 weeks of adalimumab therapy compared with placebo. Rates of colectomy did not differ significantly between patients given adalimumab vs placebo. CONCLUSIONS: In patients with moderate to severe UC, the addition of adalimumab to standard of care treatment reduced the number of hospitalizations for any cause, as well as for UC-related and UC- or drug-related complications, compared with placebo. ClinicalTrials.gov numbers, NCT00385736 and NCT00408629. PMID- 24067883 TI - Meeting the needs of young people in hospital. PMID- 24067880 TI - Activated wnt signaling in stroma contributes to development of pancreatic mucinous cystic neoplasms. AB - BACKGROUND & AIMS: Pancreatic mucinous cystic neoplasm (MCN), a cystic tumor of the pancreas that develops most frequently in women, is a potential precursor to pancreatic ductal adenocarcinoma. MCNs develop primarily in the body and tail of the pancreas and are characterized by the presence of a mucinous epithelium and ovarian-like subepithelial stroma. We investigated the involvement of Wnt signaling in KRAS-mediated pancreatic tumorigenesis and development of MCN in mice, and Wnt activation in human MCN samples. METHODS: LSL-Kras(G12D), Ptf1a-cre mice were crossed with elastase-tva mice to allow for introduction of genes encoded by the replication-competent avian sarcoma-leukosis virus long-terminal repeat with splice acceptor viruses to pancreatic acinar cells and acinar cell progenitors, postnatally and sporadically. Repeat with splice acceptor viruses that expressed Wnt1 were delivered to the pancreatic epithelium of these mice; pancreatic lesions were analyzed by histopathology and immunohistochemical analyses. We analyzed levels of factors in Wnt signaling pathways in 19 MCN samples from patients. RESULTS: Expression of Wnt1 in the pancreatic acinar cells and acinar cell progenitors of female mice led to development of unilocular or multilocular epithelial cysts in the pancreas body and tail, similar to MCN. The cystic lesions resembled the estrogen receptor- and progesterone receptor positive ovarian-like stroma of MCN, but lacked the typical mucinous epithelium. Activated Wnt signaling, based on nuclear localization of beta-catenin, was detected in the stroma but not cyst epithelium. Wnt signaling to beta-catenin was found to be activated in MCN samples from patients, within the ovarian-like stroma, consistent with the findings in mice. CONCLUSIONS: Based on studies of mice and pancreatic MCN samples from patients, the canonical Wnt signaling pathway becomes activated and promotes development of the ovarian-like stroma to contribute to formation of MCNs. PMID- 24067884 TI - Gout in Maori. PMID- 24067885 TI - Identification of clinical predictors of flare in systemic lupus erythematosus patients: a 24-month prospective cohort study. AB - OBJECTIVE: SLE has a relapsing-remitting course with disease activity flares over time. This study aims to identify clinical predictors of SLE flares. METHODS: This prospective cohort study over 24 months included all SLE patients on follow up at one academic lupus clinic. Flare was defined as an increase in SLEDAI-2K score >=4 points. Baseline clinical and demographic parameters were compared using survival analysis for time-to-flare outcome with univariate log-rank tests. Variables with significant differences were further evaluated as predictors with multivariate Cox regression models adjusting for potential confounding or contributing factors and hazard ratio (HR) calculation. RESULTS: A total of 202 SLE patients were included. Over the follow-up period, 1083 visits were documented and 16.8% of patients presented with flares. In multivariate analysis, the following parameters emerged as flare predictors: SLE diagnosis up to 25 years of age (HR = 2.14, P = 0.03), lupus nephritis previous to baseline visit (HR = 4.78, P < 0.0001) and immunosuppressor treatment for severe SLE (HR = 3.22, P < 0.001). Baseline disease activity, disease duration and treatment with prednisone or HCQ were not predictive factors. CONCLUSION: Patients with an SLE diagnosis before age 25 years, lupus nephritis or immunosuppressor treatment for severe SLE present greater HRs for flares, suggesting the need for tighter clinical monitoring. Current immunosuppressive strategies seem to be inefficient in providing flare prevention. PMID- 24067886 TI - Urinary free light chains: a potential biomarker in lupus nephritis. PMID- 24067887 TI - The bacterial skin microbiome in psoriatic arthritis, an unexplored link in pathogenesis: challenges and opportunities offered by recent technological advances. AB - The resident microbial community, harboured by humans in sites such as the skin and gastrointestinal tract, is enormous, representing a candidate environmental factor affecting susceptibility to complex diseases, where both genetic and environmental risk factors are important. The potential of microorganisms to influence the human immune system is considerable, given their ubiquity. The impact of the host-gene-microbe interaction on the maintenance of health and the development of disease has not yet been assessed robustly in chronic inflammatory conditions. PsA represents a model inflammatory disease to explore the role of the microbiome because skin involvement and overlap with IBD implicates both the skin and gastrointestinal tract as sources of microbial triggers for PsA. In parallel with genetic studies, characterization of the host microbiota may benefit our understanding of the microbial contribution to disease pathogenesis knowledge that may eventually inform the development of novel therapeutics. PMID- 24067888 TI - Bisphosphonates vs infliximab in ankylosing spondylitis treatment. AB - OBJECTIVE: The objective of this study was to evaluate if the anti-inflammatory properties of bisphosphonates and their effect on bone turnover could be useful in the treatment of AS. METHODS: Sixty patients were consecutively assigned in a 1:1 ratio in a 6-month open-label, single-centre study on active AS to receive monthly i.v. neridronate (100 mg) or standard infliximab (5 mg/kg) therapy. RESULTS: A significant reduction in the mean BASDAI was observed over 6 months of either neridronate (-1.72) or infliximab (-1.62) administration. The BASFI decreased significantly at 3 and 6 months in the neridronate arm, while in the infliximab group a significant reduction at 3 months but not 6 months was observed. The 10-cm visual analogue scale for axial pain decreased significantly and comparably at 3 and 6 months in both groups. No significant differences between treatment arms for all these changes were observed at both 3 months and the final assessment. The BASMI was not significantly modified in the neridronate or infliximab group. No significant variations of BMD were observed in the infliximab group, while in patients treated with neridronate a significant increase was observed at the lumbar spine. CONCLUSION: High i.v. doses of the amino-bisphosphonate neridronate are as effective as infliximab therapy in reducing disease activity in AS patients, with additional benefits on BMD changes. Further studies to confirm these results over a longer time frame are warranted together with the possibility to explore the long-term efficacy of a combination of lower anti-TNF doses with bisphosphonates. PMID- 24067889 TI - [Impact of depressive disorders on adherence to oral anti-cancer treatment]. AB - The improper adherence to therapy is an emerging medical and economic issue in oncology which raised with the increasing use of oral anti-cancer treatment. Currently, the average rate of non-adherence to oral anti-cancer therapy is estimated at around 21%. In this study, we use the examples of the imatinib treatment against chronic lymphocytic leukemia and the tamoxifene treatment against breast cancer to assess the negative consequences of the non-adherence to therapy in terms of medical outcome and health care cost. One of the main causes of non-adherence to these oral cancer treatments is depression. Surprisingly, this aspect is still relatively unknown to oncologists, while depression has been taken into account for the treatment of other chronic diseases (e.g. diabetes...). We therefore propose that cancer patients should be screened for depression throughout their treatment to improve the adherence to therapy. Cancer patients should have the opportunity to explain their own perception of their disease and their treatment that are key parameters in the onset of depression. The recent use of oral therapy in cancer treatment should thus be accompanied by the establishment of a global management of cancer patient on a case-by-case basis. PMID- 24067890 TI - Quantitative analysis of the evolution of novelty in cinema through crowdsourced keywords. AB - The generation of novelty is central to any creative endeavor. Novelty generation and the relationship between novelty and individual hedonic value have long been subjects of study in social psychology. However, few studies have utilized large scale datasets to quantitatively investigate these issues. Here we consider the domain of American cinema and explore these questions using a database of films spanning a 70 year period. We use crowdsourced keywords from the Internet Movie Database as a window into the contents of films, and prescribe novelty scores for each film based on occurrence probabilities of individual keywords and keyword pairs. These scores provide revealing insights into the dynamics of novelty in cinema. We investigate how novelty influences the revenue generated by a film, and find a relationship that resembles the Wundt-Berlyne curve. We also study the statistics of keyword occurrence and the aggregate distribution of keywords over a 100 year period. PMID- 24067891 TI - Response to Wang et al.: Mechanisms for catheter-based renal denervation to lower blood pressure: personal speculation. PMID- 24067893 TI - The relative roles of electrostatics and dispersion in the stabilization of halogen bonds. AB - In this work we highlight recent work aimed at the characterization of halogen bonds. Here we discuss the origins of the sigma-hole, the modulation of halogen bond strength by changing of neighboring chemical groups (i.e. halogen bond tuning), the performance of various computational methods in treating halogen bonds, and the strength and character of the halogen bond, the dihalogen bond, and two hydrogen bonds in bromomethanol dimers (which serve as model complexes) are compared. Symmetry adapted perturbation theory analysis of halogen bonding complexes indicates that halogen bonds strongly depend on both dispersion and electrostatics. The electrostatic interaction that occurs between the halogen sigma-hole and the electronegative halogen bond donor is responsible for the high degree of directionality exhibited by halogen bonds. Because these noncovalent interactions have a strong dispersion component, it is important that the computational method used to treat a halogen bonding system be chosen very carefully, with correlated methods (such as CCSD(T)) being optimal. It is also noted here that most forcefield-based molecular mechanics methods do not describe the halogen sigma-hole, and thus are not suitable for treating systems with halogen bonds. Recent attempts to improve the molecular mechanics description of halogen bonds are also discussed. PMID- 24067892 TI - Differences in vascular reactivity between pregnant women with chronic hypertension and preeclampsia. AB - The purpose of this study was to evaluate the distinct pathogenic mechanisms underlying chronic hypertension in pregnancy and preeclampsia in terms of oxidative stress and vascular reactivity. A total of 17 women with uncomplicated pregnancies, 30 women with preeclampsia and 17 women with chronic hypertension were evaluated. We measured serum derivatives of reactive oxygen metabolites (d ROMs; marker of oxygen free radicals), flow-mediated vasodilation (FMD; marker of endothelial function) and intima-media thickness in the carotid artery (IMT; marker of atherogenesis) during pregnancy and 1 month after delivery. Serum d-ROM concentrations were significantly higher in women with chronic hypertension and severe preeclampsia than in the control group during pregnancy. d-ROM concentrations in all groups significantly decreased to similar levels 1 month after delivery. FMD was significantly lower during pregnancy in preeclamptic and chronic hypertension groups compared with the control group. FMD in preeclamptic groups significantly increased and normalized to control levels after delivery. Similarly, FMD in the chronic hypertension group significantly increased after delivery but was still lower. IMT in the chronic hypertension group was significantly higher than that in control and preeclamptic groups. These findings suggest that endothelial dysfunction induced by enhanced oxidative stress is reversible in women with preeclampsia, whereas impaired vascular reactivity may be associated with atherosclerotic changes in women with chronic hypertension. PMID- 24067895 TI - Exploring energy landscapes: from molecular to mesoscopic systems. AB - We review a comprehensive computational framework to survey the potential energy landscape for systems composed of rigid or partially rigid molecules. Illustrative case studies relevant to a wide range of molecular clusters and soft and condensed matter systems are discussed. PMID- 24067894 TI - Direct visualization and quantitative analysis of water diffusion in complex biological tissues using CARS microscopy. AB - To date, it has not been possible to measure microscopic diffusive water movements in epithelia and in the interstitial space of complex tissues and organs. Diffusive water movements are essential for life because they convey physiologically important small molecules, e.g. nutrients and signaling ligands throughout the extracellular space of complex tissues. Here we report the development of a novel method for the direct observation and quantitative analysis of water diffusion dynamics in a biologically organized tissue using Coherent Anti-Stokes Raman Scattering (CARS) microscopy. Using a computer simulation model to analyze the CARS O-H bond vibration data during H2O/D2O exchange in a 3D epithelial cyst, we succeeded in measuring the diffusive water permeability of the individual luminal and basolateral water pathways and also their response to hormonal stimulation. Our technique will be applicable to the measurement of diffusive water movements in other structurally complex and medically important tissues and organs. PMID- 24067896 TI - Reductions in neuronal peroxisomes in multiple sclerosis grey matter. AB - BACKGROUND: Peroxisomes are organelles in eukaryotic cells with multiple functions including the detoxification of reactive oxygen species, plasmalogen synthesis and beta-oxidation of fatty acids. Recent evidence has implicated peroxisomal dysfunction in models of multiple sclerosis (MS) disease progression. OBJECTIVES: Our aims were to determine whether there are changes in peroxisomes in MS grey matter (GM) compared to control GM. METHODS: We analysed cases of MS and control GM immunocytochemically to assess peroxisomal membrane protein (PMP70) and neuronal proteins. We examined the expression of ABCD3 (the gene that encodes PMP70) in MS and control GM. Analyses of very long chain fatty acid (VLCFA) levels in GM were performed. RESULTS: PMP70 immunolabelling of neuronal somata was significantly lower in MS GM compared to control. Calibration of ABCD3 gene expression with reference to glyceraldehyde 3-phsophate dehydrogenase (GAPDH) revealed overall decreases in expression in MS compared to controls. Mean PMP70 counts in involved MS GM negatively correlated to disease duration. Elevations in C26:0 (hexacosanoic acid) were found in MS GM. CONCLUSIONS: Collectively, these observations provide evidence that there is an overall reduction in peroxisomal gene expression and peroxisomal proteins in GM neurons in MS. Changes in peroxisomal function may contribute to neuronal dysfunction and degeneration in MS. PMID- 24067897 TI - Patterns and predictors of naturally occurring change in depressive symptoms over a 30-month period in multiple sclerosis. AB - BACKGROUND: Depressive symptoms are common in multiple sclerosis (MS), yet there is little information about the pattern and predictors of changes in depressive symptoms over time. OBJECTIVE: We examined changes in depressive symptoms over a 30-month period and the demographic, clinical and behavioral predictors of such changes in relapsing-remitting MS (RRMS). METHODS: 269 persons with RRMS completed the Hospital Anxiety and Depression Scale (HADS) and a demographic/clinical scale, Godin Leisure-Time Exercise Questionnaire (GLTEQ) and Patient Determined Disease Steps (PDDS) scale every 6 months over a 30-month period. Data were analyzed using latent class growth modeling (LCGM). RESULTS: LCGM identified a two-class model for changes in HADS depression scores over time. Class 1 involved lower initial status (i.e. fewer depressive symptoms) and linear decreases in depressive symptoms over time (i.e. improving HADS scores), whereas Class 2 involved higher initial status (i.e. more depressive symptoms) and linear increases in depressive symptoms over time (i.e. worsening HADS scores). LCGM further indicated that being older (OR = 2.46; p < .05), married (OR = 2.62; p < .05), employed (OR = 4.29; p < .005) and physically active (OR = 2.71; p < .05) predicted a greater likelihood of belonging to C1 than C2. CONCLUSIONS: Depressive symptoms change over time in persons with RRMS, and the pattern of change can be predicted by modifiable and non-modifiable factors. PMID- 24067898 TI - Tpl2 knockout keratinocytes have increased biomarkers for invasion and metastasis. AB - Skin cancer is the most common form of cancer in the USA, with an estimated two million cases diagnosed annually. Tumor progression locus 2 (Tpl2), also known as MAP3K8, is a serine/threonine protein kinase in the mitogen-activated protein kinase signal transduction cascade. Tpl2 was identified by our laboratory as having a tumor suppressor function in skin carcinogenesis, with the absence of this gene contributing to heightened inflammation and increased skin carcinogenesis. In this study, we used gene expression profiling to compare expression levels between Tpl2 (+/+) and Tpl2 (-) (/-) keratinocytes. We identified over 2000 genes as being differentially expressed between genotypes. Functional annotation analysis identified cancer, cell growth/proliferation, cell death, cell development, cell movement and cell signaling as the top biological processes to be differentially regulated between genotypes. Further microarray analysis identified several candidate genes, including Mmp1b, Mmp2, Mmp9 and Mmp13, involved in migration and invasion to be upregulated in Tpl2 (-) (/-) keratinocytes. Moreover, Tpl2 (-/-) keratinocytes had a significant downregulation in the matrix metalloproteinase (MMP) inhibitor Timp3. Real-time PCR validated the upregulation of the MMPs in Tpl2 (-/-) keratinocytes and zymography confirmed that MMP2 and MMP9 activity was higher in conditioned media from Tpl2 (-/-) keratinocytes. Immunohistochemistry confirmed higher MMP9 staining in 12-O-tetradecanoylphorbol-13-acetate-treated skin from Tpl2 (-/-) mice and grafted tumors formed from v-ras(Ha) retrovirus-infected Tpl2 (-/-) keratinocytes. Additionally, Tpl2 (-/-) keratinocytes had significantly higher invasion, malignant conversion rates and increased endothelial cell tube formation when compared with Tpl2 (+/+) keratinocytes. In summary, our studies reveal that keratinocytes from Tpl2 (-/-) mice demonstrate a higher potential to be invasive and metastatic. PMID- 24067899 TI - RECQL4 and p53 potentiate the activity of polymerase gamma and maintain the integrity of the human mitochondrial genome. AB - Germline mutations in RECQL4 and p53 lead to cancer predisposition syndromes, Rothmund-Thomson syndrome (RTS) and Li-Fraumeni syndrome (LFS), respectively. RECQL4 is essential for the transport of p53 to the mitochondria under unstressed conditions. Here, we show that both RECQL4 and p53 interact with mitochondrial polymerase (PolgammaA/B2) and regulate its binding to the mitochondrial DNA (mtDNA) control region (D-loop). Both RECQL4 and p53 bind to the exonuclease and polymerase domains of PolgammaA. Kinetic constants for interactions between PolgammaA-RECQL4, PolgammaA-p53 and PolgammaB-p53 indicate that RECQL4 and p53 are accessory factors for PolgammaA-PolgammaB and PolgammaA-DNA interactions. RECQL4 enhances the binding of PolgammaA to DNA, thereby potentiating the exonuclease and polymerization activities of PolgammaA/B2. To investigate whether lack of RECQL4 and p53 results in increased mitochondrial genome instability, resequencing of the entire mitochondrial genome was undertaken from multiple RTS and LFS patient fibroblasts. We found multiple somatic mutations and polymorphisms in both RTS and LFS patient cells. A significant number of mutations and polymorphisms were common between RTS and LFS patients. These changes are associated with either aging and/or cancer, thereby indicating that the phenotypes associated with these syndromes may be due to deregulation of mitochondrial genome stability caused by the lack of RECQL4 and p53. SUMMARY: The biochemical mechanisms by which RECQL4 and p53 affect mtDNA replication have been elucidated. Resequencing of RTS and LFS patients' mitochondrial genome reveals common mutations indicating similar mechanisms of regulation by RECQL4 and p53. PMID- 24067900 TI - The neurotrophic factor neurturin contributes toward an aggressive cancer cell phenotype, neuropathic pain and neuronal plasticity in pancreatic cancer. AB - Neurotrophic factors possess an emerging role in the pathophysiology of several gastrointestinal disorders, regulating innervation, pain sensation and disease associated neuroplasticity. Here, we aimed at characterizing the role of the neurotrophic factor neurturin (NRTN) and its receptor glial-cell-line-derived neurotrophic factor receptor alpha-2 (GFRalpha-2) in pancreatic cancer (PCa) and pancreatic neuropathy. For this purpose, NRTN and GFRalpha-2 were studied in normal human pancreas and PCa tissues via immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, immunoblotting and correlated to abdominal pain. The impact of NRTN/GFRalpha-2 on PCa cell (PCC) biology was investigated via exposure to hypoxia, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide viability and matrigel invasion assays in native and specific small interfering RNA-silenced PCCs. To assess the influence of NRTN on pancreatic neuroplasticity and neural invasion (NI), its impact was explored via an in vitro 'neuroplasticity assay' and a 3D neural migration assay. NRTN and GFRalpha-2 demonstrated a site-specific upregulation in PCa, predominantly in nerves, PCCs and extracellular matrix. Patients with severe pain demonstrated higher intraneural GFRalpha-2 immunoreactivity than patients with no pain. PCa tissue and PCCs contained increased amounts of NRTN, which was suppressed under hypoxia. NRTN promoted PCC invasiveness, and silencing of NRTN limited both PCC proliferation and invasion. Depletion of NRTN from PCa tissue extracts and PCC supernatants decreased axonal sprouting in neuronal cultures but did not influence glial density. Silencing of NRTN in PCCs boosted NI. We conclude that increased NRTN/GFRalpha-2 in PCa seems to promote an aggressive PCC phenotype and neuroplasticity in PCa. Accelerated NI following NRTN suppression constitutes a novel explanation for the attraction of PCC to nerves in the hypoxic PCa tumor microenvironment. SUMMARY: PCa is characterized by intrapancreatic neuroplasticity and NI. Here, we show that PCC produce the neurotrophic factor NRTN, which reinforces their biological properties, triggers neuroplastic alterations, NI and influences pain sensation via the GFRalpha-2 receptor. PMID- 24067901 TI - Dietary black raspberries modulate DNA methylation in dextran sodium sulfate (DSS)-induced ulcerative colitis. AB - Ulcerative colitis (UC) is characterized by chronic inflammation of the colon. During inflammation, NF-kappaB is increased in colonic epithelial cells and in immune cells, leading to increases in proinflammatory cytokines. These events then increase DNA methyltransferases (DNMTs), which silence a subset of tumor suppressor genes by promoter methylation. Negative regulators of the Wnt pathway are frequently methylated in UC, leading to dysregulation of the pathway and, potentially, to colorectal cancer. We determined if black raspberries (BRBs) influence promoter methylation of suppressors in the Wnt pathway in dextran sodium sulfate (DSS)-induced UC. C57BL/6J mice received 1% DSS and were fed either control or 5% BRB diets. Mice were euthanized on days 7, 14 and 28, and their colons, spleen and bone marrow were collected. Berries reduced ulceration at day 28. This was accompanied by decreased staining of macrophages and neutrophils and decreased NF-kappaB p65 nuclear localization in the colon at all time points. At day 7, BRBs demethylated the promoter of dkk3, leading to its increased messenger RNA (mRNA) expression in colon, spleen and bone marrow. beta Catenin nuclear localization, c-Myc staining as well as protein expression of DNMT3B, histone deacetylases 1 and 2 (HDAC1 and HDAC2) and methyl-binding domain 2 (MBD2) were all decreased in colon; mRNA expression of these four proteins was decreased in bone marrow cells by BRBs. These results suggest that BRBs suppress colonic ulceration by correcting promoter hypermethylation of suppressor genes in the colon, as well as in the spleen and bone marrow that systematically regulate inflammation. SUMMARY: Our results suggest that dietary BRBs suppress colonic ulceration by correcting promoter hypermethylation of suppressor genes in the colon, as well as in the spleen and bone marrow that systematically regulate inflammation in DSS-induced UC. PMID- 24067902 TI - Telbivudine treatment corrects HBV-induced epigenetic alterations in liver cells of patients with chronic hepatitis B. AB - Hepatitis B virus (HBV) alters the expression of host cellular genes to support its replication and survival and to promote the liver cell injury. However, the underlying mechanism remained incompletely understood. In this study, we investigated HBV-induced epigenetic changes in HepG2 cells by profiling the landscapes of the active histone modification mark H3K4me3 and repressive mark H3K27me3 using chromatin immunoprecipitation-sequencing. HBV caused the altered histone modifications at thousands of genomic loci, which are critically involved in HBV entry, inflammation, fibrosis and carcinogenesis of host cells. Interestingly, treatment of the HBV-transformed HepG2 cells with the anti-HBV drug Telbivudine substantially restored the H3K4me3 level to that of untransformed HepG2 cells. More importantly, our analysis of liver samples from control and chronic hepatitis B patients revealed that treatment of the patients with Telbivudine not only corrected the target gene expression but also the epigenetic modification of critical genes. In addition, the expression of the histone methyltransferases SMYD3 and EZH2 that regulate histone H3-specific methylation showed no difference in HepG2 cell with or without HBV existence. Thus, our data suggest that abnormal histone modifications might critically involved in HBV-mediated liver pathogenesis and Telbivudine therapy might benefit patients with HBV-related chronic infection, liver cirrhosis and even hepatic carcinoma. SUMMARY: Telbivudine substantially restores in vitro and in vivo HBV caused abnormal expressions and histone H3K4me3 and H3K27me3 modifications at thousands of genomic loci that are involved in the pathogenesis of liver cells, revealing a novel mechanism for HBV-mediated liver damage. PMID- 24067905 TI - [Information monitoring and communication an USCDC visit report]. PMID- 24067906 TI - [Effects of self-selection of dietary sessions on weight loss, dropouts during the intervention, and weight maintenance after 1 year]. AB - OBJECTIVES: To compare the effects of weekly or bi-weekly dietary sessions with the same number of total lecture hours, periods, and lecture contents on weight loss, dropouts during the intervention, and the weight loss maintenance after 1 year. METHODS: The study included 52 middle-aged women with at least 1 risk factor for cardiovascular disease (i.e., obesity, hypertension, dyslipidemia, and hyperglycemia) who were encouraged to lose weight. Thirty-seven women were assigned to the weekly class (self-selected weekly class group: n=26) or the bi weekly class (self-selected bi-weekly class group: n=11) based on their preference. Fifteen women were assigned to the bi-weekly class against their will (bi-weekly class group). All groups participated in the same number of sessions (total, 26 h), and were instructed to reduce their dietary intakes to 1200 kcal/day for 13 weeks. The self-selected weekly class group attended a 2-h instructional session every week, whereas both the bi-weekly class groups received 1-h sessions twice a week. Data on the body weight of the participants was collected 1 year after the intervention using a self-administered questionnaire via mail. RESULTS: The self-selected bi-weekly class group had significantly fewer dropouts (self-selected weekly class group: 5 persons, 19.2%; self-selected bi-weekly class group: 1 person, 9.0%; bi-weekly class group: 8 persons, 53.3%; P<0.05). There was a significant decrease in weight (P<0.05) in all 3 groups during the intervention (self-selected weekly class group: -4.3+/ 2.7 kg, self-selected bi-weekly class group: -6.7+/-3.0 kg, bi-weekly class group: -6.0+/-3.4 kg). However, weight loss in the self-selected bi-weekly class group was significantly greater than that in the other 2 groups. A significant change in body weight at the 1-year follow-up was not observed in any group (self selected weekly class group: +0.4+/-1.3 kg, self-selected bi-weekly class group: 0.1+/-2.3 kg, bi-weekly class group: +0.5+/-0.6 kg). Repeated-measures ANOVA (time*group) revealed no significant interactions in weight loss. CONCLUSION: These results suggest that a greater frequency of dietary sessions contributes to weight loss, while a lesser frequency of dietary sessions contributed to a decrease in questionnaire recovery rates. The dropout rate in the self-selected weekly and bi-weekly class groups was lesser than that in the bi-weekly class group. Therefore, dietary sessions tailored to the needs of the participants might decrease the dropout rate. PMID- 24067903 TI - Apigenin inhibits prostate cancer progression in TRAMP mice via targeting PI3K/Akt/FoxO pathway. AB - Forkhead box O (FoxO) transcription factors play an important role as tumor suppressor in several human malignancies. Disruption of FoxO activity due to loss of phosphatase and tensin homolog and activation of phosphatidylinositol-3 kinase (PI3K)/Akt are frequently observed in prostate cancer. Apigenin, a naturally occurring plant flavone, exhibits antiproliferative and anticarcinogenic activities through mechanisms, which are not fully defined. In the present study, we show that apigenin suppressed prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice through the PI3K/Akt/FoxO signaling pathway. Apigenin-treated TRAMP mice (20 and 50 MUg/mouse/day, 6 days/week for 20 weeks) exhibited significant decrease in tumor volumes of the prostate as well as completely abolished distant organ metastasis. Apigenin treatment resulted in significant decrease in the weight of genitourinary apparatus (P < 0.0001), dorsolateral (P < 0.0001) and ventral prostate (P < 0.028), compared with the control group. Apigenin-treated mice showed reduced phosphorylation of Akt (Ser473) and FoxO3a (Ser253), which correlated with its increased nuclear retention and decreased binding of FoxO3a with 14-3-3. These events lead to reduced proliferation as assessed by Ki-67 and cyclin D1, along with upregulation of FoxO-responsive proteins BIM and p27/Kip1. Complementing in vivo results, similar observations were noted in human prostate cancer LNCaP and PC-3 cells after apigenin treatment. Furthermore, binding of FoxO3a with p27/Kip1 was markedly increased after 10 and 20 MUM apigenin treatment resulting in G0/G1 phase cell cycle arrest, which was consistent with the effects elicited by PI3K/Akt inhibitor, LY294002. These results provide convincing evidence that apigenin effectively suppressed prostate cancer progression, at least in part, by targeting the PI3K/Akt/FoxO-signaling pathway. PMID- 24067907 TI - [The effects of age, period, and birth cohorts on the rates of overweight and underweight students in 1977-2006 and a prediction of the rates in 2007-2016]. AB - OBJECTIVES: The increase in the overweight or underweight student population in Japanese schools is an important health issue. To assess the independent effects of age, period, and birth cohorts, we analyzed trends in the rates of overweight and underweight students from 1977 to 2006 using a Bayesian age-period-cohort (APC) analysis. Additionally, we predicted the rates overweight and underweight students in 2007-2016. METHODS: We created a data set of the rates of overweight and underweight students aged 6-14 years using the annual school health survey report data. We then analyzed a cohort table that plotted age against calendar time using a Bayesian APC model. We also made a prediction of the rates of overweight and underweight students in 2007-2016. RESULTS: For overweight students, the age effect increased from 6 to 11 years of age for male students and from 6 to 12 years of age for female students; thereafter, the effects decreased. The period effects consistently increased until late 1990, and decreased thereafter for both male and female students. The cohort effects increased for male students born between 1963 and 1969, and later decreased for those born in 1981. However, this trend for male students later increased. For female students, the cohort effects decreased for those born between 1963 and 1975, and later increased for those born in 1990, indicating a plateau or slight increase in the trend. For underweight students, the age effect in male students increased from 7 to 10 years of age, and then plateaued; whereas, the age effect increased from 7 to 12 years of age for female students before reaching a plateau. The period effects increased consistently by 2000 and decreased slightly in both male and female students. The birth cohort effect in male students increased for those born after the mid-1980s, and then plateaued in the early 1990s. The cohort effect increased for female students born after 1984, and then plateaued in 1993. The projections for the rates of overweight and underweight student population indicated a steady trend until 2016. CONCLUSION: The rate of overweight and underweight students was strongly influenced by age; however, period and birth cohort also played a role. The projections for the rates of overweight and underweight students indicated a steady trend until 2016. These results suggest that strategies based on age-, period-, and cohort-specific measures may be required for future interventions for preventing overweight and underweight among students. PMID- 24067908 TI - [The prevalence and characteristics of long term care insurance clients who are judged to need frequent home visiting service by their care managers]. PMID- 24067910 TI - Synthesis of gamma-AlOOH nanocrystals with different morphologies due to the effect of sulfate ions and the corresponding formation mechanism study. AB - The investigation of the metal oxide/inorganic ion interface at the atomic level represents a fundamental issue for the understanding of chemical and physical processes involved in several fields such as catalysis, adsorption, directed synthesis and the mechanistic study of crystal growth. In this paper, a combined hydrothermal synthesis and computational approach based on DFT theory is adopted to investigate the effects of sulfate ions on the final morphology of gamma AlOOH. The quantum mechanical calculations reveal that the sulfate ions interact with gamma-AlOOH facets through surface hydroxyls and act as a morphology directing agent. The adsorption type and chemical bonds between the sulfate ion and gamma-AlOOH are discussed. The formation of nanosheets and nanorods of gamma AlOOH is controlled by thermodynamic factors. Moreover, the HR-TEM images reveal the growth directions and exposed planes of boehmite, indicating an oriented aggregation process which is consistent with the DFT calculations. Overall, all the morphologies of boehmite suggested by the calculations are confirmed by experimental results. PMID- 24067909 TI - Plant immune response to pathogens differs with changing temperatures. AB - Temperature fluctuation is a key determinant for microbial invasion and host evasion. In contrast to mammals that maintain constant body temperature, plant temperature oscillates on a daily basis. It remains elusive how plants operate inducible defenses in response to temperature fluctuation. Here we report that ambient temperature changes lead to pronounced shifts of the following two distinct plant immune responses: pattern-triggered immunity (PTI) and effector triggered immunity (ETI). Plants preferentially activate ETI signaling at relatively low temperatures (10-23 degrees C), whereas they switch to PTI signaling at moderately elevated temperatures (23-32 degrees C). The Arabidopsis arp6 and hta9hta11 mutants, phenocopying plants grown at elevated temperatures, exhibit enhanced PTI and yet reduced ETI responses. As the secretion of bacterial effectors favours low temperatures, whereas bacteria multiply vigorously at elevated temperatures accompanied with increased microbe-associated molecular pattern production, our findings suggest that temperature oscillation might have driven dynamic co-evolution of distinct plant immune signaling responding to pathogen physiological changes. PMID- 24067913 TI - Default cascades in complex networks: topology and systemic risk. AB - The recent crisis has brought to the fore a crucial question that remains still open: what would be the optimal architecture of financial systems? We investigate the stability of several benchmark topologies in a simple default cascading dynamics in bank networks. We analyze the interplay of several crucial drivers, i.e., network topology, banks' capital ratios, market illiquidity, and random vs targeted shocks. We find that, in general, topology matters only--but substantially--when the market is illiquid. No single topology is always superior to others. In particular, scale-free networks can be both more robust and more fragile than homogeneous architectures. This finding has important policy implications. We also apply our methodology to a comprehensive dataset of an interbank market from 1999 to 2011. PMID- 24067914 TI - Evolution and cell physiology. 3. Using Dictyostelium discoideum to investigate mechanisms of epithelial polarity. AB - In Metazoa, a polarized epithelium forms a single-cell-layered barrier that separates the outside from the inside of the organism. In tubular epithelia, the apical side of the cell is constricted relative to the basal side, forming a wedge-shaped cell that can pack into a tube. Apical constriction is mediated by actomyosin activity. In higher animals, apical actomyosin is connected between cells by specialized cell-cell junctions that contain a classical cadherin, the Wnt signaling protein beta-catenin, and the actin-binding protein alpha-catenin. The molecular mechanisms that lead to selective accumulation of myosin at the apical surface of cells are poorly understood. We found that the nonmetazoan Dictyostelium discoideum forms a polarized epithelium that surrounds the stalk tube at the tip of the multicellular fruiting body. Although D. discoideum lacks a cadherin homolog, it expresses homologs of beta- and alpha-catenin. Both catenins are essential for formation of the tip epithelium, polarized protein secretion, and proper multicellular morphogenesis. Myosin localizes apically in tip epithelial cells, and it appears that constriction of this epithelial tube is required for proper morphogenesis. Localization of myosin II is controlled by the protein IQGAP1 and its binding partners cortexillins I and II, which function downstream of alpha- and beta-catenin to exclude myosin from the basolateral cortex and promote apical accumulation of myosin. These studies show that the function of catenins in cell polarity predates the evolution of Wnt signaling and classical cadherins, and that apical localization of myosin is a morphogenetic mechanism conserved from nonmetazoans to vertebrates. PMID- 24067915 TI - Time-dependent modulation of GABA(A)-ergic synaptic transmission by allopregnanolone in locus coeruleus neurons of Mecp2-null mice. AB - Rett syndrome (RTT) is a neurodevelopmental disorder with symptoms starting 6-18 mo after birth, while what underlies the delayed onset is unclear. Allopregnanolone (Allop) is a metabolite of progesterone and a potent modulator of GABAA-ergic currents whose defects are seen in RTT. Allop changes its concentration during the perinatal period, which may affect central neurons via the GABAA-ergic synaptic transmission, contributing to the onset of the disease. To determine whether Mecp2 disruption affects Allop modulation, we performed studies in brain slices obtained from wild-type (WT) and Mecp2(-/Y) mice. Allop dose dependently suppressed locus coeruleus (LC) neuronal excitability in WT mice, while Mecp2-null neurons showed significant defects. Using optogenetic approaches, channelrhodopsin was specifically expressed in GABA-ergic neurons in which optical stimulation evoked action potentials. In LC neurons of WT mice, Allop exposure increased the amplitude of GABAA-ergic inhibitory postsynaptic currents (IPSCs) evoked by optical stimulation and prolonged the IPSC decay time. Consistently, Allop augmented both frequency and amplitude of GABAA-ergic spontaneous IPSCs (sIPSCs) and extended the decay time of sIPSCs. The Allop induced potentiation of sIPSCs was deficient in Mecp2(-/Y) mice. Surprisingly, the impairment occurred at 3 wk postnatal age, while no significant difference in Allop modulation was observed in 1-2 wk between WT and Mecp2(-/Y) mice. These results indicate that the modulation of GABAA-ergic synaptic transmission by Allop is impaired in LC neurons of Mecp2-null mice at a time when RTT-like symptoms manifest, suggesting a potential mechanism for the delayed onset of the disease. PMID- 24067917 TI - A theme series on physical biology in cancer in AJP-Cell. PMID- 24067916 TI - Type-1 pericytes participate in fibrous tissue deposition in aged skeletal muscle. AB - In older adults, changes in skeletal muscle composition are associated with increased fibrosis, loss of mass, and decreased force, which can lead to dependency, morbidity, and mortality. Understanding the biological mechanisms responsible is essential to sustaining and improving their quality of life. Compared with young mice, aged mice take longer to recover from muscle injury; their tissue fibrosis is more extensive, and regenerated myofibers are smaller. Strong evidence indicates that cells called pericytes, embedded in the basement membrane of capillaries, contribute to the satellite-cell pool and muscle growth. In addition to their role in skeletal muscle repair, after tissue damage, they detach from capillaries and migrate to the interstitial space to participate in fibrosis formation. Here we distinguish two bona fide pericyte subtypes in the skeletal muscle interstitium, type-1 (Nestin-GFP(-)/NG2-DsRed(+)) and type-2 (Nestin-GFP(+)/NG2-DsRed(+)), and characterize their heretofore unknown specific roles in the aging environment. Our in vitro results show that type-1 and type-2 pericytes are either fibrogenic or myogenic, respectively. Transplantation studies in young animals indicate that type-2 pericytes are myogenic, while type 1 pericytes remain in the interstitial space. In older mice, however, the muscular regenerative capacity of type-2 pericytes is limited, and type-1 pericytes produce collagen, contributing to fibrous tissue deposition. We conclude that in injured muscles from aging mice, the pericytes involved in skeletal muscle repair differ from those associated with scar formation. PMID- 24067918 TI - Cell surface F1/FO ATP synthase contributes to interstitial flow-mediated development of the acidic microenvironment in tumor tissues. AB - To address pivotal roles of cell surface F1/FO ATP synthase in the development of acidic microenvironment in tumor tissues, we investigated effects of shear stress stimulation on the cultured human breast cancer cells, MDA-MB-231 and MDA-MB-157, or human melanoma cells, SK-Mel-1. Shear stress stimulation (0.5-5.0 dyn/cm(2)), the levels of which are similar to those produced by the interstitial flow, induced strength-dependent corelease of ATP and H(+) from the cells, which triggered CO2 gas excretion. In contrast, the same level of shear stress stimulation did not induce significant ATP release and CO2 gas excretion from the control human mammary epithelial cells (HMEC). Marked immunocytochemical and mRNA expression of cell surface F1/FO ATP synthase, vacuolar-ATPase (V-ATPase), carbonic anhydrase type IX, and ectonucleoside triphosphate diphosphohydrolase (ENTPDase) 3 were detected in MDA-MB-231 cells, but little or no expression on the HMEC. Pretreatment with cell surface F1/FO ATP synthase inhibitors, but not cell surface V-ATPase inhibitors, caused a significant reduction of the shear stress stimulation-mediated ATP release and CO2 gas excretion from MDA-MB-231 cells. The ENTPDase activity in the shear stress-loaded MDA-MB-231 cell culture medium supernatant increased significantly in a time-dependent manner. In addition, MDA-MB-231 cells displayed strong staining for purinergic 2Y1 (P2Y1) receptors on their surfaces, and the receptors partially colocalized with ENTPDase 3. These findings suggest that cell surface F1/FO ATP synthase, but not V-ATPase, may play key roles in the development of interstitial flow-mediated acidic microenvironment in tumor tissues through the shear stress stimulation induced ATP and H(+) corelease and CO2 gas production. PMID- 24067919 TI - Biomechanical properties and mechanobiology of the articular chondrocyte. AB - To withstand physiological loading over a lifetime, human synovial joints are covered and protected by articular cartilage, a layer of low-friction, load bearing tissue. The unique mechanical function of articular cartilage largely depends on the composition and structural integrity of the cartilage matrix. The matrix is produced by highly specialized resident cells called chondrocytes. Under physiological loading, chondrocytes maintain the balance between degradation and synthesis of matrix macromolecules. Under excessive loading or injury, however, degradation exceeds synthesis, causing joint degeneration and, eventually, osteoarthritis (OA). Hence, the mechanoresponses of chondrocytes play an important role in the development of OA. Despite its clear importance, the mechanobiology of articular chondrocytes is not well understood. To summarize our current understanding, here we review studies of the effect of mechanical forces on mechanical and biological properties of articular chondrocytes. First, we present the viscoelastic properties of the cell nucleus, chondrocyte, pericellular matrix, and chondron. Then we discuss how these properties change in OA. Finally, we discuss the responses of normal and osteoarthritic chondrocytes to a variety of mechanical stimuli. Studies reviewed here may provide novel insights into the pathogenesis of OA and may help in development of effective biophysical treatment. PMID- 24067920 TI - Control of decoherence with no control. AB - A common philosophy in control theory is the control of disorder by order. Control of decoherence is no exception; strategies aimed at suppressing quantum decoherence adopt this point of view. Here we predict an anomalous phenomenon in open quantum systems-control of disorder by (even more) disorder. It is shown that suppression of decoherence can be achieved using the most disordered white noise field, specifically a white Poissonian noise field. This phenomenon seems to be another anomaly in quantum mechanics and may offer a new strategy in quantum control practices. PMID- 24067921 TI - Primary chylous reflux syndrome I presenting with vaginal chylous discharge and vulvar vesicles. PMID- 24067922 TI - Potent and long-lasting inhibition of human P2X2 receptors by copper. AB - P2X receptors are ion channels gated by ATP. In rodents these channels are modulated by zinc and copper. Zinc is co-released with neurotransmitter at some synapses and can modulate neuronal activity, but the role of copper in the brain is unclear. Rat P2X2 receptors show potentiation by 2-100 MUM zinc or copper in the presence of a submaximal concentration of ATP but are inhibited by zinc or copper at concentrations above 100 MUM. In contrast, human P2X2 (hP2X2) receptors show no potentiation and are strongly inhibited by zinc over the range of 2-100 MUM. The effect of copper on hP2X2 is of interest because there are human brain disorders in which copper concentration is altered. We found that hP2X2 receptors are potently inhibited by copper (IC50 = 40 nM). ATP responsiveness recovered extremely slowly after copper washout, with full recovery requiring over 1 h. ATP binding facilitated copper binding but not unbinding from this inhibitory site. A mutant receptor in which the first six extracellular cysteines were deleted, C(1 6)S, showed normal copper inhibition, however reducing agents dramatically accelerated recovery from copper inhibition in wild type hP2X2 and the C(1-6)S mutant, indicating that the final two disulfide bonds are required to maintain the high affinity copper binding site. Three histidine residues required for normal zinc inhibition were also required for normal copper inhibition. Humans with untreated Wilson's disease have excess amounts of copper in the brain. The high copper sensitivity of hP2X2 receptors suggests that they are non-functional in these patients. PMID- 24067923 TI - Tegaserod mimics the neurostimulatory glycan polysialic acid and promotes nervous system repair. AB - Glycans attached to the cell surface via proteins or lipids or exposed in the extracellular matrix affect many cellular processes, including neuritogenesis, cell survival and migration, as well as synaptic activity and plasticity. These functions make glycans attractive molecules for stimulating repair of the injured nervous system. Yet, glycans are often difficult to synthesize or isolate and have the disadvantage to be unstable in a complex tissue environment. To circumvent these issues, we have screened a library of small organic compounds to search for structural and functional mimetics of the neurostimulatory glycan polysialic acid (PSA) and identified the 5-HT4 receptor agonist tegaserod as a PSA mimetic. The PSA mimicking activity of tegaserod was shown in cultures of central and peripheral nervous system cells of the mouse and found to be independent of its described function as a serotonin (5-HT4) receptor agonist. In an in vivo model for peripheral nerve regeneration, mice receiving tegaserod at the site of injury showed enhanced recovery compared to control mice receiving vehicle control as evidenced by functional measurements and histology. These data indicate that tegaserod could be repurposed for treatment of nervous system injuries and underscores the potential of using small molecules as mimetics of neurostimulatory glycans. PMID- 24067925 TI - Antidepressant-like and anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa). AB - It has been demonstrated that the translocator protein (18 kDa) (TSPO) plays an important role in stress-response and stress-related disorders, such as anxiety and depression, by affecting the production of neurosteroids, supporting the potential use of selective TSPO ligands as antidepressant or anxiolytic drugs. N ethyl-N-(2-pyridinylmethyl)- 2-(3,4-ichlorophenyl)- 7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride (YL-IPA08), a novel TSPO ligand that has been synthesized at our institute, exerted a high affinity for TSPO in a crude mitochondrial fraction prepared from rat cerebellum but exhibited only a negligible affinity for the central benzodiazepine receptor. As expected, YL IPA08 incubation with the cultured rat astrocyte cells increased the pregnenolone and progesterone concentration from the cultured medium. Moreover, YL-IPA08 produced significant antidepressant-like and anxiolytic-like effects in a series of mouse and rat behavior models. In addition, the antidepressant-like behavior of YL-IPA08 was totally blocked by the TSPO antagonist PK11195 in a tail suspension test, and the anxiolytic effect was blocked by PK11195 but not by a CBR antagonist in the elevated plus-maze test. Furthermore, compared with the CBR agonist diazepam, YL-IPA08 had no myorelaxant effects and did not affect the motor coordination, memory or hexobarbitone-induced sleep in mice. Overall, these results indicate that YL-IPA08 is a more potent and selective TSPO ligand, which exerts antidepressant-like and anxiolytic-like effects on behaviors that are mediated by TSPO but does not cause the side effects that are typically associated with conventional benzodiazepines. PMID- 24067924 TI - Effects of prolonged selective serotonin reuptake inhibition on the development and expression of L-DOPA-induced dyskinesia in hemi-parkinsonian rats. AB - Dopamine (DA) replacement therapy with l-DOPA is the standard treatment for Parkinson's disease (PD). Unfortunately chronic treatment often leads to the development of abnormal involuntary movements (AIMs) referred to as L-DOPA induced dyskinesia (LID). Accumulating evidence has shown that compensatory plasticity in serotonin (5-HT) neurons contributes to LID and recent work has indicated that acute 5-HT transporter (SERT) blockade provides anti-dyskinetic protection. However neither the persistence nor the mechanism(s) of these effects have been investigated. Therefore the current endeavor sought to mimic a prolonged regimen of SERT inhibition in L-DOPA-primed and -naive hemi parkinsonian rats. Rats received 3 weeks of daily co-treatment of the selective 5 HT reuptake inhibitors (SSRIs) citalopram (0, 3, or 5 mg/kg) or paroxetine (0, 0.5, or 1.25 mg/kg) with L-DOPA (6 mg/kg) during which AIMs and motor performance were monitored. In order to investigate potential mechanisms of action, tissue levels of striatal monoamines were monitored and the 5-HT(1A) receptor antagonist WAY100635 (0.5 mg/kg) was used. Results revealed that prolonged SSRIs attenuated AIMs expression and development in L-DOPA-primed and -naive subjects, respectively, without interfering with motor performance. Neurochemical analysis of striatal tissue indicated that a 3 week SERT blockade increased DA levels in L DOPA-treated rats. Pharmacologically, anti-dyskinetic effects were partially reversed with WAY100635 signifying involvement of the 5-HT1A receptor. Collectively, these findings demonstrate that prolonged SERT inhibition provides enduring anti-dyskinetic effects in part via 5-HT(1A) receptors while maintaining L-DOPA's anti-parkinsonian efficacy by enhancing striatal DA levels. PMID- 24067926 TI - Congenital brain serotonin deficiency leads to reduced ethanol sensitivity and increased ethanol consumption in mice. AB - Serotonergic dysfunction has been hypothesized to play an important role in the pathophysiology of alcoholism. However, whether congenital serotonin (5-HT) deficiency leads to increased alcohol consumption or affects ethanol-related behaviors has not been established. Here, we use a transgenic mouse line that expresses a hypofunctional variant of the 5-HT synthesis enzyme, tryptophan hydroxylase 2, to examine the impact of 5-HT deficiency on responses to alcohol. We demonstrate that these 5-HT-deficient transgenic animals (Tph2KI mice) recover their righting reflex more rapidly than wild-type controls following a high dose of ethanol and exhibit blunted locomotor retardation in response to repeated ethanol administration. In addition, compared to WT controls, 5-HT-deficient animals consume significantly more ethanol and exhibit increased preference for ethanol in two-bottle choice tests. Our data also suggest that 5-HT plays a critical role in mediating the effects of ethanol on Akt/GSK3beta signaling in the nucleus accumbens. Overall, our results corroborate previous theories regarding the importance of brain 5-HT levels in mediating responsiveness to alcohol and demonstrate, for the first time, that congenital 5-HT deficiency leads to increased ethanol consumption and decreased sensitivity to the sedative like effects of ethanol, perhaps in part through modulating Akt/GSK3beta signaling. PMID- 24067927 TI - Staurosporine induces dopaminergic neurite outgrowth through AMP-activated protein kinase/mammalian target of rapamycin signaling pathway. AB - Axonal degeneration of dopaminergic neurons is one of the pathological features in the early stages of Parkinson disease. Promotion of axonal outgrowth of the remaining dopaminergic neurons leads to the recovery of the nigrostriatal pathway. Staurosporine (STS), a wide-spectrum kinase inhibitor, induces neurite outgrowth in various cell types, although its mechanism of action remains elusive. In this study, we analyzed which protein kinase is involved in STS induced neurite outgrowth. We have previously established the method to measure the length of dopaminergic neurites that extend from a mesencephalic cell region, which is formed on a coverslip by an isolation wall. By means of this method, we clarified that STS treatment causes dopaminergic axonal outgrowth in mesencephalic primary cultures. Among the specific protein kinase inhibitors we tested, compound C (C.C), an AMP-activated protein kinase (AMPK) inhibitor, promoted dopaminergic neurite outgrowth. STS as well as C.C elevated the phosphorylation level of 70-kDa ribosomal protein S6 kinase, a downstream target of mammalian target of rapamycin (mTOR) signaling pathway. The STS- and C.C induced dopaminergic neurite outgrowth was suppressed by rapamycin, an mTOR inhibitor. Furthermore, the application of C.C rescued 1-methyl-4 phenylpyridinium ion (MPP(+))-induced dopaminergic neurite degeneration. These results suggest that STS induces dopaminergic axonal outgrowth through mTOR signaling pathway activation as a consequence of AMPK inhibition. PMID- 24067929 TI - Reversible bone marrow aplasia induced by pegylated interferon-alpha-2a therapy in a patient with primary myelofibrosis. AB - Interferon has been widely used in the management of patients with hematological malignancies such as polycythemia vera, myelofibrosis, chronic myeloid leukemia and viral infections such as chronic hepatitis C. Hematological adverse effects such as cytopenias have been observed, particularly in patients who receive a combination of interferon-alpha-2a and ribavirin for hepatitis C. Mild myelosuppression can be seen with pegylated interferon; however, bone marrow aplasia in patients with myelofibrosis has not been reported. It is important to be aware of such a serious complication since persistent bone marrow aplasia can be fatal. We describe a case of pegylated interferon-induced reversible bone marrow aplasia in a patient with primary myelofibrosis. PMID- 24067928 TI - Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D. AB - Phosphodiesterase type 4 inhibitors (PDE4-Is) have received increasing attention as cognition-enhancers and putative treatment strategies for Alzheimer's disease (AD). By preventing cAMP breakdown, PDE4-Is can enhance intracellular signal transduction and increase the phosphorylation of cAMP response element-binding protein (CREB) and transcription of proteins related to synaptic plasticity and associated memory formation. Unfortunately, clinical development of PDE4-Is has been seriously hampered by emetic side effects. The new isoform-specific PDE4D-I, GEBR-7b, has shown to have beneficial effects on memory at non-emetic doses. The aim of the current study was to investigate chronic cognition-enhancing effects of GEBR-7b in a mouse model of AD. To this extent, 5-month-old (5M) APPswe/PS1dE9 mice received daily subcutaneous injections with GEBR-7b (0.001 mg/kg) or vehicle for a period of 3 weeks, and were tested on affective and cognitive behavior at 7M. We demonstrated a cognition-enhancing potential in APPswe/PS1dE9 mice as their spatial memory function at 7M in the object location test was improved by prior GEBR-7b treatment. APPswe/PS1dE9 mice displayed lower levels of CREB phosphorylation, which remained unaltered after chronic GEBR-7b treatment, and higher levels of tau in the hippocampus. Hippocampal brain-derived neurotrophic factor levels and synaptic densities were not different between experimental groups and no effects were observed on hippocampal GSK3beta and tau phosphorylation or Abeta levels. In conclusion, GEBR-7b can enhance spatial memory function in the APPswe/PS1dE9 mouse model of AD. Although the underlying mechanisms of its cognition-enhancing potential remain to be elucidated, PDE4D inhibition appears an interesting novel therapeutic option for cognitive deficits in AD. PMID- 24067930 TI - Mobility transition from ballistic to diffusive transport in non-Hermitian lattices. AB - Within all physical disciplines, it is accepted that wave transport is predetermined by the existence of disorder. In this vein, it is known that ballistic transport is possible only when a structure is ordered, and that disorder is crucial for diffusion or (Anderson-)localization to occur. As this commonly accepted picture is based on the very foundations of quantum mechanics where Hermiticity of the Hamiltonian is naturally assumed, the question arises whether these concepts of transport hold true within the more general context of non-Hermitian systems. Here we demonstrate theoretically and experimentally that in ordered time-independent -symmetric systems, which are symmetric under space time reflection, wave transport can undergo a sudden change from ballistic to diffusive after a specific point in time. This transition as well as the diffusive transport in general is impossible in Hermitian systems in the absence of disorder. In contrast, we find that this transition depends only on the degree of dissipation. PMID- 24067931 TI - Three-stage quality control strategies for DNA re-sequencing data. AB - Advances in next-generation sequencing (NGS) technologies have greatly improved our ability to detect genomic variants for biomedical research. In particular, NGS technologies have been recently applied with great success to the discovery of mutations associated with the growth of various tumours and in rare Mendelian diseases. The advance in NGS technologies has also created significant challenges in bioinformatics. One of the major challenges is quality control of the sequencing data. In this review, we discuss the proper quality control procedures and parameters for Illumina technology-based human DNA re-sequencing at three different stages of sequencing: raw data, alignment and variant calling. Monitoring quality control metrics at each of the three stages of NGS data provides unique and independent evaluations of data quality from differing perspectives. Properly conducting quality control protocols at all three stages and correctly interpreting the quality control results are crucial to ensure a successful and meaningful study. PMID- 24067932 TI - Modern bioinformatics meets traditional Chinese medicine. AB - MOTIVATION: Traditional Chinese medicine (TCM) is gaining increasing attention with the emergence of integrative medicine and personalized medicine, characterized by pattern differentiation on individual variance and treatments based on natural herbal synergism. Investigating the effectiveness and safety of the potential mechanisms of TCM and the combination principles of drug therapies will bridge the cultural gap with Western medicine and improve the development of integrative medicine. Dealing with rapidly growing amounts of biomedical data and their heterogeneous nature are two important tasks among modern biomedical communities. Bioinformatics, as an emerging interdisciplinary field of computer science and biology, has become a useful tool for easing the data deluge pressure by automating the computation processes with informatics methods. Using these methods to retrieve, store and analyze the biomedical data can effectively reveal the associated knowledge hidden in the data, and thus promote the discovery of integrated information. Recently, these techniques of bioinformatics have been used for facilitating the interactional effects of both Western medicine and TCM. The analysis of TCM data using computational technologies provides biological evidence for the basic understanding of TCM mechanisms, safety and efficacy of TCM treatments. At the same time, the carrier and targets associated with TCM remedies can inspire the rethinking of modern drug development. This review summarizes the significant achievements of applying bioinformatics techniques to many aspects of the research in TCM, such as analysis of TCM-related '-omics' data and techniques for analyzing biological processes and pharmaceutical mechanisms of TCM, which have shown certain potential of bringing new thoughts to both sides. PMID- 24067933 TI - Monolacunary Keggin polyoxometalates connected to ten 4d or 4f metal atoms. AB - The rational self-assembly of mono-lacunary Keggin clusters with 4d and 4f metal salts via a conventional method has yielded two novel polyoxometalate-based 4d-4f heterometallic compounds containing lacunary Keggin anions connected to ten metal atoms: {[Ag{Ag2(H2O)4}{Ln(H2O)6}2H ? {SiW11Ln(H2O)4O39}2].nH2O (Ln = Ce and n = 7 for 1, Ln = Pr and n = 3 for 2). Their structures were determined by single crystal X-ray diffraction analyses and further characterized by elemental analyses, IR spectra, and thermogravimetric (TG) analyses. A structural feature in 1 and 2 is that each [SiW11O39](8-) cluster (SiW11) is connected to ten metals (five Ag(+) and five Ln(3+) cations), representing the highest number of connected metal atoms to any mono-lacunary Keggin anion to date. This large connectivity leads to a structure with a purely inorganic 3D framework with two kinds of channels along the [100] and [010] directions. The magnetic properties of both compounds show the expected magnetic moments (0.8 and 1.6 amu K mol(-1) per Ce(3+) and Pr(3+) ion, respectively) and confirm the presence of isolated Ce(3+) and Pr(3+) ions. PMID- 24067934 TI - 3D structures of liquid-phase GaIn alloy embedded in PDMS with freeze casting. AB - Liquid phase electronic circuits are created by freeze casting gallium-indium (GaIn) alloys, such as eutectic gallium-indium (EGaIn), and encapsulating these frozen components within an elastomer. These metal alloys are liquid at room temperature, and can be cast using either injection or a vacuum to fill a PDMS mold and placing the mold in a freezer. Once solidified, a GaIn alloy segment can be manipulated, altered, or bonded to other circuit elements. A stretchable circuit can be fabricated by placing frozen components onto an elastomer substrate, which can be either patterned or flat, and sealing with an additional layer of elastomer. Circuits produced in this fashion are soft, stretchable, and can have complex 3D channel geometries. In contrast, current fabrication techniques, including needle injection, mask deposition, and microcontact printing, are limited to 2D planar designs. Additionally, freeze casting fabrication can create closed loops, multi-terminal circuits with branching features, and large area geometries. PMID- 24067935 TI - ADAR1 regulates ARHGAP26 gene expression through RNA editing by disrupting miR 30b-3p and miR-573 binding. AB - Rho GTPase activating protein 26 (ARHGAP26) is a negative regulator of the Rho family that converts the small G proteins RhoA and Cdc42 to their inactive GDP bound forms. It is essential for the CLIC/GEEC endocytic pathway, cell spreading, and muscle development. The present study shows that ARHGAP26 mRNA undergoes extensive A-to-I RNA editing in the 3' UTR that is specifically catalyzed by ADAR1. Furthermore, the mRNA and protein levels of ARHGAP26 were decreased in cells in which ADAR1 was knocked down. Conversely, ADAR1 overexpression increased the abundance of ARHGAP26 mRNA and protein. In addition, we found that both miR 30b-3p and miR-573 target the ARHGAP26 gene and that RNA editing of ARHGAP26 mediated by ADAR1 abolished the repression of its expression by miR-30b-3p or miR 573. When ADAR1 was overexpressed, the reduced abundance of ARHGAP26 protein mediated by miR-30b-3p or miR-573 was rescued. Importantly, we also found that knocking down ADAR1 elevated RhoA activity, which was consistent with the reduced level of ARHGAP26. Conversely, when ADAR1 was overexpressed, the amount of RhoA GTP decreased. The similar expression patterns of ARHGAP26 and ADAR1 in human tissue samples further confirmed our findings. Taken together, our results suggest that ADAR1 regulates the expression of ARHGAP26 through A-to-I RNA editing by disrupting the binding of miR-30b-3p and miR-573 within the 3' UTR of ARHGAP26. This study provides a novel insight into the mechanism by which ADAR1 and its RNA editing function regulate microRNA-mediated modulation of target genes. PMID- 24067937 TI - Glycosylation of autoantibodies: insights into the mechanisms of immune thrombocytopenia. AB - Immune thrombocytopenia (ITP) is a bleeding disorder caused by IgG autoantibodies (AAbs) directed against platelets (PLTs). IgG effector functions depend on their Fc-constant region which undergoes posttranslational glycosylation. We investigated the role of Asn279-linked N-glycan of AAbs in vitro and in vivo. AAbs were purified from ITP patients (n=15) and N-glycans were enzymatically cleaved by endoglycosidase F. The effects of native AAbs and deglycosylated AAbs were compared in vitro on enhancement of phagocytosis of platelets by monocytes and complement fixation and activation applying flow cytometry, laser scanning microscopy, and a complement consumption assay. AAb-induced platelet phagocytosis was inhibited by N-glycan cleavage (median phagocytic activity: 8% vs 0.8%, p=0.004). Seven out of 15 native AAbs bound C1q and activated complement. N glycan cleavage significantly reduced both effects. In vivo survival of human PLTs was assessed after co-transfusion with native or N-glycan cleaved AAbs in a NOD/SCID mouse model. Injection of AAbs resulted in rapid clearance of human platelets compared to control (platelet clearance after 5h (CL(5h))75% vs 30%, p<0.001). AAbs that were able to activate complement induced more pronounced platelet clearance in the presence of complement compared to the clearance in the absence of complement (CL(5h) 82% vs 62%, p=0.003). AAbs lost their ability to destroy platelets in vivo after deglycosylation (CL(5h) 42%, p<0.001). N glycosylation of human ITP AAbs appears to be required for platelet phagocytosis and complement activation, reducing platelet survival in vivo. Posttranslational modification of AAbs may constitute an important determinant for the clinical manifestation of ITP. PMID- 24067938 TI - A cap-type Schiff base acting as a fluorescence sensor for zinc(II) and a colorimetric sensor for iron(II), copper(II), and zinc(II) in aqueous media. AB - A simple and low cost chemosensor is described. This sensor could simultaneously detect three biologically important metal ions through fluorogenic (Zn(2+)) and chromogenic (Fe(2+), Cu(2+), and Zn(2+)) methods in aqueous solution. The sensor could function as a "turn-on" fluorescence receptor only to Zn(2+) ions. In addition, the sensor could be successfully applied to the detection of intracellular Zn(2+). Meanwhile, the sensor displayed an obvious red color upon selective binding with Fe(2+). Therefore, the sensor could serve as a useful tool for the discrimination of Fe(2+) from Fe(3+) in aqueous media. Moreover, the sensor also showed color changes from yellow to colorless upon selective binding with Zn(2+) and Cu(2+), respectively. The detection limit of the sensor for Cu(2+) (1.5 MUM) is far below the guidelines of the World Health Organization (30 MUM) as the maximum allowable copper concentration in drinking water, and therefore it is capable of being a practical system for the monitoring of Cu(2+) concentrations in aqueous samples. These results provide a new approach for selectively recognizing the most important three trace elements in the human body simultaneously, for Zn(2+) by emission spectra and Fe(2+), Cu(2+), and Zn(2+) by the naked eye. PMID- 24067939 TI - A vascular growth following radiation therapy for breast carcinoma treatment. Atypical vascular lesion (AVL) (lymphatic type). PMID- 24067940 TI - A novel human recombinant antibody fragment capable of neutralizing Mexican scorpion toxins. AB - Using phage display and directed evolution, our group has progressed in the construction of a second family of human single chain variable fragments (scFv) which bind to scorpion toxins dangerous to mammals. It was observed that scFv C1 only bound initially to toxin Cn2, which constitutes 6.8% of whole venom from the scorpion Centruroides noxius Hoffman. Only a few amino acid changes were necessary to extend its recognition to other similar toxins and without affecting the recognition for its primary antigen (Cn2 toxin). One variant of scFv C1 (scFv 202F) was selected after two cycles of directed evolution against Cll1 toxin, the second major toxic component from the venom of the Mexican scorpion Centruroides limpidus limpidus Karsh (0.5% of the whole venom). scFv 202F is also capable of recognizing Cn2 toxin. Despite not having the highest affinity for toxins Cll1 (KD = 25.1 * 10(-9) M) or Cn2 (KD = 8.1 * 10(-9) M), this antibody fragment neutralized one LD50 of each one of these toxins. Additionally, scFv 202F moderately recognized Cll2 toxin which constitutes 1.5% of the venom from C. limpidus. Based on our previous experience, we consider that these results are promising; consequently, we continue working on generating new optimized variants from scFv C1 that could be part of a recombinant scorpion anti-venom from human origin, that might reach the market in the near future. PMID- 24067942 TI - Reaction of Sn4(4-) in liquid ammonia: the formation of Rb6[(eta2-Sn4)Zn(eta3 Sn4)].5NH3. AB - The reaction of Rb4Sn4 with ZnPh2 in liquid ammonia in the presence of [2.2.2] cryptand yielded crystals of Rb6[(eta(2)-Sn4)Zn(eta(3)-Sn4)].5NH3, which could be characterized by single crystal X-ray diffraction. This is the first example of a successful solution reaction of the highly charged tetrahedral Sn4(4-) anions. The homoleptic [E4ZnE4](6-) complex (E = tetrel element) was previously known only for E=Ge and Si/Ge. PMID- 24067943 TI - Differential telomerase expression in idiopathic pulmonary fibrosis and non-small cell lung cancer. AB - Telomerase is a reverse transcriptase ribonucleo-protein (h-TERT) that synthesizes telomeric repeats using its RNA component (h-TERC) as a template. Telomerase dysfunction has been associated with both fibrogenesis and carcinogenesis. In this study, we aimed to evaluate the telomerase mRNA expression levels of both subunits (h-TERT and h-TERC) in lung tissue and bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) and non-small cell lung cancer (NSCLC), since there are indications of common pathogenetic pathways in these diseases. We prospectively examined lung tissue samples from 29 patients with IPF, 10 patients with NSCLC and 21 controls. Furthermore, we examined BALF samples from 31 patients with NSCLC, 23 patients with IPF and 12 control subjects. The mRNA expression for both h-TERT and h-TERC was measured by real-time RT-PCR. In the lung tissue samples, both h-TERT and h-TERC mRNA expression levels varied among the 3 groups (p=0.036 and p=0.002, respectively). h-TERT mRNA levels in the patients with IPF were lower compared with those in the controls (p=0.009) and patients with NSCLC (p=0.004). h-TERC mRNA levels in the patients with IPF were lower compared with those in the controls (p=0.0005) and patients with NSCLC (p=0.0004). In the BALF samples, h-TERT mRNA expression levels varied among the groups (p=0.012). More specifically, h-TERT mRNA levels in the patients with IPF were higher compared with those in the controls (p=0.03) and patients with NSCLC (p=0.007). The attenuation of telomerase gene expression in IPF in comparison to lung cancer suggests a differential role of this regulatory gene in fibrogenesis and carcinogenesis. Further functional studies are required in order to further elucidate the role of telomerase in these devastating diseases. PMID- 24067944 TI - Co-stimulation with LPS or Poly I:C markedly enhances the anti-platelet immune response and severity of fetal and neonatal alloimmune thrombocytopenia. AB - Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal antibodies against fetal/neonatal platelets. FNAIT is also linked with miscarriages, although the incidence and mechanisms of fetal death have not been well studied. IntegrinalphaIIbbeta3 (GPIIbIIIa) and the GPIbalpha complex are major glycoproteins expressed on platelets and are also major antigens targeted in autoimmune thrombocytopenia (ITP), but reported cases of anti-GPIb-mediated FNAIT are rare. Bacterial and viral infections have been causally linked with the pathogenesis of immune-mediated thrombocytopenia (ITP); however, it is unknown whether these infections contribute to the severity of FNAIT. Here, immune responses against platelet antigens were examined by transfusing wild-type (WT) mouse platelets into beta3-/- or GPIbalpha-/- mice. To mimic bacterial or viral infections, lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly I:C) were injected intraperitoneally following platelet transfusions. The FNAIT model was established by breeding the immunised female mice with WT male mice. We demonstrated for the first time that the platelet GPIbalpha has lower immunogenicity compared to beta3 integrin. Interestingly, co-stimulation with LPS or Poly I:C markedly enhanced the immune response against platelet GPIbalpha and caused severe pathology of FNAIT (i.e. miscarriages). LPS or Poly I:C also enhanced the immune response against platelet beta3 integrin. Our data suggest that bacterial and viral infections facilitate the anti-platelet GPIbalpha response, which may lead to a severe non-classical FNAIT (i.e. miscarriage but not neonatal bleeding) that has not been adequately reported in humans. PMID- 24067945 TI - Non-OO blood type influences the risk of recurrent venous thromboembolism. A cohort study. AB - The role of ABO blood type as a risk factor for recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who complete oral anticoagulation therapy is unknown. The aim of this study was to determine if non-OO blood type is a risk factor for recurrent VTE in patients with a first unprovoked VTE who completed 5-7 months of anticoagulant therapy. In an ongoing cohort study of patients with unprovoked VTE who discontinued oral anticoagulation after 5-7 months of therapy, six single nucleotide polymorphisms sites were tested to determine ABO blood type using banked DNA. The main outcome was objectively proven recurrent VTE. Mean follow-up for the cohort was 4.19 years (SD 2.16). During 1,553 patient-years of follow-up, 101 events occurred in 380 non-OO patients (6.5 events per 100 patient years; 95% CI 5.3-7.7) compared to 14 events during 560 patient years of follow-up in 129 OO patients (2.5 per 100 patient years; 95% CI 1.2-3.7), the adjusted hazard ratio was 1.98 (1.2-3.8). In conclusion, non-OO blood type is associated with a statistically significant and clinically relevant increased risk of recurrent VTE following discontinuation of anticoagulant therapy for a first episode of unprovoked VTE. PMID- 24067946 TI - A prospective cohort study investigating an exposure-response relationship among vibration-exposed male workers with numbness of the hands. AB - OBJECTIVE: The aim of this study was to investigate the exposure-response relationship of hand-arm vibration exposure to neurological symptoms (numbness) of the hand in a cohort of vibration-exposed workers. METHODS: The baseline cohort comprised 241 office and manual workers with and without exposure to hand arm vibration. Numbness (the symptom or event) in the hand was assessed for all subjects at baseline and follow-ups after 5, 10, and 16 years. The workers were stratified into quartiles with no exposure in the first quartile and increasing intensity of exposure in quartiles 2-4 (groups 1-3). Data analysis was performed using survival analysis (time to event). Information on cumulative exposure and years of exposure to event was collected via questionnaires. Measurements were performed in accordance with the International Organization for Standardization (ISO) 5349-1. RESULTS: The hazard ratio (HR) of risk of event (numbness) differed statistically significantly between the non-exposed group (group 0) and the two higher exposure groups (groups 2 and 3). There was also a significant ratio difference between the lowest exposure group (group 1) and the two higher groups. The ratio for group 1 was 1.77 [95% confidence interval (95% CI) 0.96-3.26] compared with 3.78 (95% CI 2.15-6.62) and 5.31 (95% CI 3.06-9.20) for groups 2 and 3, respectively. CONCLUSION: The results suggest a dose-response relationship between vibration exposure and numbness of the hands. This underlines the importance of keeping vibration levels low to prevent neurological injury to the hands. PMID- 24067948 TI - Mobile applications in dermatology. AB - IMPORTANCE: With advancements in mobile technology, cellular phone-based mobile applications (apps) may be used in the practice and delivery of dermatologic care. OBJECTIVE: To identify and categorize the variety of current mobile apps available in dermatology for patients and providers. DESIGN, SETTING, AND PARTICIPANTS: Dermatology-related search terms were queried in the online app stores of the most commonly used mobile platforms developed by Apple, Android, Blackberry, Nokia, and Windows. Applications were assigned to categories based on description. Popularity, price, and reviews were recorded and target audiences were determined through websites offering online mobile apps. MAIN OUTCOMES AND MEASURES: Number, type, and price of mobile apps in dermatology. RESULTS: A total of 229 dermatology-related apps were identified in the following categories: general dermatology reference (61 [26.6%]), self-surveillance/diagnosis (41 [17.9%]), disease guide (39 [17.0%]), educational aid (20 [8.7%]), sunscreen/UV recommendation (19 [8.3%]), calculator (12 [5.2%]), teledermatology (8 [3.5%]), conference (6 [2.6%]), journal (6 [2.6%]), photograph storage/sharing (5 [2.2%]), dermoscopy (2 [0.9%]), pathology (2 [0.9%]), and other (8 [3.5%]). The most reviewed apps included Ultraviolet ~ UV Index (355 reviews), VisualDx (306), SPF (128), iSore (61), and SpotMole (50). There were 209 unique apps, with 17 apps existing on more than 1 operating system. More than half of the apps were offered free of charge (117 [51.1%]). Paid apps (112 [48.9%]) ranged from $0.99 to $139.99 (median, $2.99). Target audiences included patient (117 [51.1%]), health care provider (94 [41.0%]), and both (18 [7.9%]). CONCLUSIONS AND RELEVANCE: The widespread variety and popularity of mobile apps demonstrate a great potential to expand the practice and delivery of dermatologic care. PMID- 24067949 TI - Idiopathic sudden sensorineural hearing loss: vascular or viral? AB - OBJECTIVE: To demonstrate that sudden sensorineural hearing loss is possibly of viral origin rather than vascular. STUDY DESIGN: The histopathologic morphology in 7 temporal bones with known vascular impairment due to surgical interventions was compared with that of 11 bones with a history of idiopathic sudden sensorineural hearing loss (ISSNHL). Attention was paid to the spiral ligament, stria vascularis, organ of Corti hair cells, tectorial membrane, ganglion cell population, and degree of perilymph fibrosis and the auditory nerve. SETTING: A temporal bone laboratory that has been in operation for more than 50 years and includes a database consisting of clinical and histopathological information that facilitates quantitative and qualitative analysis. SUBJECTS: Eight hundred forty nine individuals who pledged their temporal bones for scientific study, of which 18 were selected for this study by means of the database criteria of sudden sensorineural hearing loss and postmiddle fossa and retro sigmoid sinus tumor removal or vestibular nerve section. RESULTS: Sudden sensorineural hearing loss bones exhibited no perilymph fibrosis compared with 6 of 7 vascular cases with fibrosis (P <= .001), exhibited less loss of ganglion cells (P <= .026), exhibited greater survival of spiral ligament (P <= .029), and averaged twice the survival of hair cells and more widespread tectorial membrane abnormalities. CONCLUSION: Analysis of human temporal bones from patients with a sudden sensorineural hearing loss does not support a vascular insufficiency but is more suggestive of a viral etiology. PMID- 24067950 TI - Hairy polyp of the anterior nasal cavity. PMID- 24067951 TI - Surface glycoproteins of an African henipavirus induce syncytium formation in a cell line derived from an African fruit bat, Hypsignathus monstrosus. AB - Serological screening and detection of genomic RNA indicates that members of the genus Henipavirus are present not only in Southeast Asia but also in African fruit bats. We demonstrate that the surface glycoproteins F and G of an African henipavirus (M74) induce syncytium formation in a kidney cell line derived from an African fruit bat, Hypsignathus monstrosus. Despite a less broad cell tropism, the M74 glycoproteins show functional similarities to glycoproteins of Nipah virus. PMID- 24067952 TI - Configuration of viral ribonucleoprotein complexes within the influenza A virion. AB - The influenza A virus possesses an eight-segmented, negative-sense, single stranded RNA genome (vRNA). Each vRNA segment binds to multiple copies of viral nucleoproteins and a small number of heterotrimeric polymerase complexes to form a rod-like ribonucleoprotein complex (RNP), which is essential for the transcription and replication of the vRNAs. However, how the RNPs are organized within the progeny virion is not fully understood. Here, by focusing on polymerase complexes, we analyzed the fine structure of purified RNPs and their configuration within virions by using various electron microscopies (EM). We confirmed that the individual RNPs possess a single polymerase complex at one end of the rod-like structure and that, as determined using immune EM, some RNPs are incorporated into budding virions with their polymerase-binding ends at the budding tip, whereas others align with their polymerase-binding ends at the bottom of the virion. These data further our understanding of influenza virus virion morphogenesis. PMID- 24067953 TI - Comprehensive mapping and analysis of Kaposi's sarcoma-associated herpesvirus 3' UTRs identify differential posttranscriptional control of gene expression in lytic versus latent infection. AB - 3' untranslated regions (UTRs) are known to play an important role in posttranscriptional regulation of gene expression. Here we map the 3' UTRs of Kaposi's sarcoma-associated herpesvirus (KSHV) using next-generation RNA sequencing, 3' rapid amplification of cDNA ends (RACE), and tiled microarray analyses. Chimeric reporters containing the KSHV 3' UTRs show a general trend toward reduced gene expression under conditions of latent infection. Those 3' UTRs with a higher GC content are more likely to be associated with reduced gene expression. KSHV transcripts display an extensive use of shared polyadenylation sites allowing for partially overlapping 3' UTRs and regulatory activities. In addition, a subset of KSHV 3' UTRs is sufficient to convey increased gene expression under conditions of lytic infection. These results suggest a role for viral 3' UTRs in contributing to differential gene expression during latent versus lytic infection. PMID- 24067955 TI - Chicken interferon-inducible transmembrane protein 3 restricts influenza viruses and lyssaviruses in vitro. AB - Interferon-inducible transmembrane protein 3 (IFITM3) is an effector protein of the innate immune system. It confers potent, cell-intrinsic resistance to infection by diverse enveloped viruses both in vitro and in vivo, including influenza viruses, West Nile virus, and dengue virus. IFITM3 prevents cytosolic entry of these viruses by blocking complete virus envelope fusion with cell endosome membranes. Although the IFITM locus, which includes IFITM1, -2, -3, and 5, is present in mammalian species, this locus has not been unambiguously identified or functionally characterized in avian species. Here, we show that the IFITM locus exists in chickens and is syntenic with the IFITM locus in mammals. The chicken IFITM3 protein restricts cell infection by influenza A viruses and lyssaviruses to a similar level as its human orthologue. Furthermore, we show that chicken IFITM3 is functional in chicken cells and that knockdown of constitutive expression in chicken fibroblasts results in enhanced infection by influenza A virus. Chicken IFITM2 and -3 are constitutively expressed in all tissues examined, whereas IFITM1 is only expressed in the bursa of Fabricius, gastrointestinal tract, cecal tonsil, and trachea. Despite being highly divergent at the amino acid level, IFITM3 proteins of birds and mammals can restrict replication of viruses that are able to infect different host species, suggesting IFITM proteins may provide a crucial barrier for zoonotic infections. PMID- 24067954 TI - Discovery of a unique novel clade of mosquito-associated bunyaviruses. AB - Bunyaviruses are the largest known family of RNA viruses, infecting vertebrates, insects, and plants. Here we isolated three novel bunyaviruses from mosquitoes sampled in Cote d'Ivoire, Ghana, and Uganda. The viruses define a highly diversified monophyletic sister clade to all members of the genus Orthobunyavirus and are virtually equidistant to orthobunyaviruses and tospoviruses. Maximal amino acid identities between homologous putative proteins of the novel group and orthobunyaviruses ranged between 12 and 25%. The type isolates, tentatively named Herbert virus (HEBV), Tai virus (TAIV), and Kibale virus (KIBV), comprised genomes with L, M, and S segments of about 7.4 kb, 2.7 kb, and 1.1 kb, respectively. HEBV, TAIV, and KIBV encode the shortest bunyavirus M segments known and did not seem to encode NSs and NSm proteins but contained an elongated L segment with an ~500-nucleotide (nt) insertion that shows no identity to other bunyaviruses. The viruses replicated to high titers in insect cells but did not replicate in vertebrate cells. The enveloped virions were 90 to 110 nm in diameter and budded at cellular membranes with morphological features typical of the Golgi complex. Viral RNA recovered from infected cells showed 5'-terminal nontemplated sequences of 9 to 22 nt, suggestive of cap snatching during mRNA synthesis, as described for other bunyaviruses. Northern blotting identified RNA species of full and reduced lengths, suggested upon analogy with other bunyaviruses to constitute antigenomic-sense cRNA and transcript mRNAs, respectively. Functional studies will be necessary to determine if this group of viruses constitutes a novel genus in the bunyavirus family. PMID- 24067956 TI - The L gene of J paramyxovirus plays a critical role in viral pathogenesis. AB - J paramyxovirus (JPV) was first isolated from moribund mice with hemorrhagic lung lesions in Australia in the 1970s. Recent sequencing of JPV (JPV-LW) confirms that JPV is a paramyxovirus with several unique features. However, neither JPV-LW nor a recombinant JPV based on its sequence (rJPV-LW) caused obvious illness in mice. In this work, we analyzed a different JPV isolate (JPV-BH), which behaved differently from JPV-LW; JPV-BH grew more slowly in Vero cells and had less of a cytopathic effect on tissue culture cells but caused severe disease in mice. We have determined the whole genome sequence of JPV-BH. There were several nucleotide sequence differences between JPV-BH and JPV-LW, one in the leader sequence, one in the GX gene, and three in the L gene. The high sequence identity between JPV-BH and JPV-LW suggests that JPV-BH and JPV-LW are the same virus strain but were obtained at different passages from different laboratories. To understand the roles of these nucleotide sequence differences in pathogenicity in mice, we generated a recombinant JPV-BH strain (rJPV-BH) and hybrid rJPV-BH strains with sequences from the leader sequence (rJPV-BH-Le-LW), the GX gene (rJPV-BH-GX-LW), and the L gene (rJPV-BH-L-LW) of JPV-LW and compared their pathogenicities in mice. We have found that rJPV-BH-L-LW was attenuated in mice, indicating that nucleotide sequence differences in the L gene play a critical role in pathogenesis. PMID- 24067957 TI - Local blockade of epithelial PDL-1 in the airways enhances T cell function and viral clearance during influenza virus infection. AB - In order to maintain the gas exchange function of the lung following influenza virus infection, a delicate orchestration of positive and negative regulatory pathways must be maintained to attain viral eradication while minimizing local inflammation. The programmed death receptor 1 ligand/programmed death receptor 1 (PDL-1/PD-1) pathway plays an important immunoregulatory role, particularly in the context of T cell function. Here, we have shown that influenza virus infection of primary airway epithelial cells strongly enhances PDL-1 expression and does so in an alpha interferon receptor (IFNAR) signaling-dependent manner. PD-1 is expressed primarily on effector T cells in the lung, compared to effector memory and central memory cells, and shortly after influenza virus infection, an increased number of PD-1(+) T cells are recruited to the airways. Using in vitro cocultures of airway epithelial cells and T cells and in vivo models of influenza virus infection, we have demonstrated that blockade of airway epithelial PDL-1 improves CD8 T cell function, defined by increased production of gamma interferon (IFN-gamma) and granzyme B and expression of CD107ab. Furthermore, PDL-1 blockade in the airways served to accelerate influenza virus clearance and enhance infection recovery. Our findings suggest that local manipulation of the PDL-1/PD 1 axis in the airways may represent a therapeutic alternative during acute influenza virus infection. PMID- 24067958 TI - Phylogenomic network and comparative genomics reveal a diverged member of the PhiKZ-related group, marine vibrio phage PhiJM-2012. AB - Bacteriophages are the largest reservoir of genetic diversity. Here we describe the novel phage PhiJM-2012. This natural isolate from marine Vibrio cyclitrophicus possesses very few gene contents relevant to other well-studied marine Vibrio phages. To better understand its evolutionary history, we built a mathematical model of pairwise relationships among 1,221 phage genomes, in which the genomes (nodes) are linked by edges representing the normalized number of shared orthologous protein families. This weighted network revealed that PhiJM 2012 was connected to only five members of the Pseudomonas PhiKZ-like phage family in an isolated network, strongly indicating that it belongs to this phage group. However, comparative genomic analyses highlighted an almost complete loss of colinearity with the PhiKZ-related genomes and little conservation of gene order, probably reflecting the action of distinct evolutionary forces on the genome of PhiJM-2012. In this phage, typical conserved core genes, including six RNA polymerase genes, were frequently displaced and the hyperplastic regions were rich in both unique genes and predicted unidirectional promoters with highly correlated orientations. Further, analysis of the PhiJM-2012 genome showed that segments of the conserved N-terminal parts of PhiKZ tail fiber paralogs exhibited evidence of combinatorial assortment, having switched transcriptional orientation, and there was recruitment and/or structural changes among phage endolysins and tail spike protein. Thus, this naturally occurring phage appears to have branched from a common ancestor of the PhiKZ-related groups, showing a distinct genomic architecture and unique genes that most likely reflect adaptation to its chosen host and environment. PMID- 24067959 TI - Nonstructural protein sigma1s mediates reovirus-induced cell cycle arrest and apoptosis. AB - Reovirus nonstructural protein sigma1s is implicated in cell cycle arrest at the G2/M boundary and induction of apoptosis. However, the contribution of sigma1s to these effects in an otherwise isogenic viral background has not been defined. To evaluate the role of sigma1s in cell cycle arrest and apoptosis, we used reverse genetics to generate a sigma1s-null reovirus. Following infection with wild-type virus, we observed an increase in the percentage of cells in G2/M, whereas the proportion of cells in G2/M following infection with the sigma1s-null mutant was unaffected. Similarly, we found that the wild-type virus induced substantially greater levels of apoptosis than the sigma1s-null mutant. These data indicate that sigma1s is required for both reovirus-induced cell cycle arrest and apoptosis. To define sequences in sigma1s that mediate these effects, we engineered viruses encoding C-terminal sigma1s truncations by introducing stop codons in the sigma1s open reading frame. We also generated viruses in which charged residues near the sigma1s amino terminus were replaced individually or as a cluster with nonpolar residues. Analysis of these mutants revealed that amino acids 1 to 59 and the amino-terminal basic cluster are required for induction of both cell cycle arrest and apoptosis. Remarkably, viruses that fail to induce cell cycle arrest and apoptosis also are attenuated in vivo. Thus, identical sequences in sigma1s are required for reovirus-induced cell cycle arrest, apoptosis, and pathogenesis. Collectively, these findings provide evidence that the sigma1s-mediated properties are genetically linked and suggest that these effects are mechanistically related. PMID- 24067960 TI - Apoptosis induction influences reovirus replication and virulence in newborn mice. AB - Apoptosis is a type of controlled cell death that is essential for development and tissue homeostasis. It also serves as a robust host response against infection by many viruses. The capacity of neurotropic viruses to induce apoptosis strongly correlates with virulence. However, the precise function of apoptosis in viral infection is not well understood. Reovirus is a neurotropic virus that induces apoptosis in a variety of cell types, including central nervous system neurons, leading to fatal encephalitis in newborn mice. To determine the effect of apoptosis on reovirus replication in the host, we generated two otherwise isogenic viruses that differ in a single amino acid in viral capsid protein MU1 that segregates with apoptotic capacity. Apoptosis proficient and apoptosis-deficient viruses were compared for replication, dissemination, tropism, and tissue injury in newborn mice and for the capacity to spread to uninfected littermates. Our results indicate that apoptotic capacity enhances reovirus replication in the brain and consequent neurovirulence but reduces transmission efficiency. The replication advantage of the apoptosis proficient strain is limited to the brain and correlates with enhanced infectivity of neurons. These studies reveal a new cell type-specific determinant of reovirus virulence. PMID- 24067961 TI - Novel apoptosis suppressor Apsup from the baculovirus Lymantria dispar multiple nucleopolyhedrovirus precludes apoptosis by preventing proteolytic processing of initiator caspase Dronc. AB - We previously identified a novel baculovirus-encoded apoptosis suppressor, Apsup, from the baculovirus Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV). Apsup inhibits the apoptosis of L. dispar Ld652Y cells triggered by infection with p35-defective Autographa californica MNPV (vAcDeltap35) and exposure to actinomycin D or UV light. Here, we examined the functional role of Apsup in apoptosis regulation in insect cells. Apsup prevented apoptosis and the proteolytic processing of L. dispar initiator caspase Dronc (Ld-Dronc) in Ld652Y cells triggered by overexpression of Ld-Dronc, LdMNPV inhibitor-of-apoptosis 3 (IAP3), or Hyphantria cunea MNPV IAP1. In vAcDeltap35-infected apoptotic Ld652Y cells, Apsup restricted apoptosis induction and prevented processing of endogenous Ld-Dronc. Conversely, upon RNA interference (RNAi)-mediated silencing of apsup, LdMNPV-infected Ld652Y cells, which typically support high-titer virus replication, underwent apoptosis, accompanied by the processing of endogenous Ld Dronc. Furthermore, endogenous Ld-Dronc coimmunoprecipitated with transiently expressed Apsup, indicating that Apsup physically interacts with Ld-Dronc. Apsup prevented the apoptosis of Sf9 cells triggered by vAcDeltap35 infection but did not inhibit apoptosis or activation of caspase-3-like protease in vAcDeltap35 infected Drosophila melanogaster S2 cells. Apsup also inhibited the proteolytic processing of L. dispar effector caspase Ld-caspase-1 in the transient expression assay but did not physically interact with Ld-caspase-1. These results demonstrate that Apsup inhibits apoptosis in Ld652Y cells by preventing the proteolytic processing of Ld-Dronc. Together with our previous findings showing that Apsup prevents the processing of both overexpressed Ld-Dronc and Bombyx mori Dronc, these results also demonstrate that Apsup functions as an effective apoptotic suppressor in various lepidopteran, but not dipteran, insect cells. PMID- 24067962 TI - Herpes simplex virus 1 E3 ubiquitin ligase ICP0 protein inhibits tumor necrosis factor alpha-induced NF-kappaB activation by interacting with p65/RelA and p50/NF kappaB1. AB - NF-kappaB plays central roles in regulation of diverse biological processes, including innate and adaptive immunity and inflammation. HSV-1 is the archetypal member of the alphaherpesviruses, with a large genome encoding over 80 viral proteins, many of which are involved in virus-host interactions and show immune modulatory capabilities. In this study, we demonstrated that the HSV-1 ICP0 protein, a viral E3 ubiquitin ligase, was shown to significantly suppress tumor necrosis factor alpha (TNF-alpha)-mediated NF-kappaB activation. ICP0 was demonstrated to bind to the NF-kappaB subunits p65 and p50 by coimmunoprecipitation analysis. ICP0 bound to the Rel homology domain (RHD) of p65. Fluorescence microscopy demonstrated that ICP0 abolished nuclear translocation of p65 upon TNF-alpha stimulation. Also, ICP0 degraded p50 via its E3 ubiquitin ligase activity. The RING finger (RF) domain mutant ICP0 (ICP0-RF) lost its ability to inhibit TNF-alpha-mediated NF-kappaB activation and p65 nuclear translocation and degrade p50. Notably, the RF domain of ICP0 was sufficient to interact with p50 and abolish NF-kappaB reporter gene activity. Here, it is for the first time shown that HSV-1 ICP0 interacts with p65 and p50, degrades p50 through the ubiquitin-proteasome pathway, and prevents NF-kappaB dependent gene expression, which may contribute to immune evasion and pathogenesis of HSV-1. PMID- 24067963 TI - SAMHD1 restricts herpes simplex virus 1 in macrophages by limiting DNA replication. AB - Macrophages play important roles in host immune defense against virus infection. During infection by herpes simplex virus 1 (HSV-1), macrophages acquire enhanced antiviral potential. Restriction of HSV-1 replication and progeny production is important to prevent viral spread, but the cellular mechanisms that inhibit the DNA virus in macrophages are unknown. SAMHD1 was recently identified as a retrovirus restriction factor highly expressed in macrophages. The SAMHD1 protein is expressed in both undifferentiated monocytes and differentiated macrophages, but retroviral restriction is limited to differentiated cells by modulation of SAMHD1 phosphorylation. It is proposed to block reverse transcription of retroviral RNA into DNA by depleting cellular deoxynucleotide triphosphates (dNTPs). Viruses with DNA genomes do not employ reverse transcription during infection, but replication of their viral genomes is also dependent on intracellular dNTP concentrations. Here, we demonstrate that SAMHD1 restricts replication of the HSV-1 DNA genome in differentiated macrophage cell lines. Depleting SAMHD1 in THP-1 cells enhanced HSV-1 replication, while ectopic overexpression of SAMHD1 in U937 cells repressed HSV-1 replication. SAMHD1 did not impact viral gene expression from incoming HSV-1 viral genomes. HSV-1 restriction involved the dNTP triphosphohydrolase activity of SAMHD1 and was partially overcome by addition of exogenous deoxynucleosides. Unlike retroviruses, restriction of HSV-1 was not affected by SAMHD1 phosphorylation status. Our results suggest that SAMHD1 functions broadly to inhibit replication of DNA viruses in nondividing macrophages. PMID- 24067964 TI - Viroplasm protein P9-1 of Rice black-streaked dwarf virus preferentially binds to single-stranded RNA in its octamer form, and the central interior structure formed by this octamer constitutes the major RNA binding site. AB - The P9-1 protein of Rice black-streaked dwarf virus (RBSDV) is an essential part of the viroplasm. However, little is known about its nature or biological function in the viroplasm. In this study, the structure and function of P9-1 were analyzed for in vitro binding to nucleic acids. We found that the P9-1 protein preferentially bound to single-stranded versus double-stranded nucleic acids; however, the protein displayed no preference for RBSDV versus non-RBSDV single stranded ssRNA (ssRNA). A gel mobility shift assay revealed that the RNA gradually shifted as increasing amounts of P9-1 were added, suggesting that multiple subunits of P9-1 bind to ssRNA. By using discontinuous blue native gel and chromatography analysis, we found that the P9-1 protein was capable of forming dimers, tetramers, and octamers. Strikingly, we demonstrated that P9-1 preferentially bound to ssRNA in the octamer, rather than the dimer, form. Deletion of the C-terminal arm resulted in P9-1 no longer forming octamers; consequently, the deletion mutant protein bound to ssRNA with significantly lower affinity and with fewer copies bound per ssRNA. Alanine substitution analysis revealed that electropositive amino acids among residues 25 to 44 are important for RNA binding and map to the central interior structure that was formed only by P9-1 octamers. Collectively, our findings provide novel insights into the structure and function of RBSDV viroplasm protein P9-1 binding to RNA. PMID- 24067965 TI - The T antigen locus of Merkel cell polyomavirus downregulates human Toll-like receptor 9 expression. AB - Establishment of a chronic infection is a key event in virus-mediated carcinogenesis. Several cancer-associated, double-stranded DNA (dsDNA) viruses act via their oncoproteins to downregulate Toll-like receptor 9 (TLR9), a key receptor in the host innate immune response that senses viral or bacterial dsDNA. A novel oncogenic virus, Merkel cell polyomavirus (MCPyV), has been recently identified that causes up to 80% of Merkel cell carcinomas (MCCs). However, it is not yet known whether this oncogenic virus also disrupts immune-related pathways. We find that MCPyV large T antigen (LT) expression downregulates TLR9 expression in epithelial and MCC-derived cells. Accordingly, silencing of LT expression results in upregulation of mRNA TLR9 levels. In addition, small T antigen (sT) also appears to inhibit TLR9 expression, since inhibition of its expression also resulted in an increase of TLR9 mRNA levels. LT inhibits TLR9 expression by decreasing the mRNA levels of the C/EBPbeta transactivator, a positive regulator of the TLR9 promoter. Chromatin immunoprecipitation reveals that C/EBPbeta binding at a C/EBPbeta response element (RE) in the TLR9 promoter is strongly inhibited by expression of MCPyV early genes and that mutation of the C/EBP RE prevents MCPyV downregulation of TLR9. A survey of BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), KI polyomavirus (KIPyV), MCPyV, simian virus 40 (SV40), and WU polyomavirus (WUPyV) early genes revealed that only BKPyV and MCPyV are potent inhibitors of TLR9 gene expression. MCPyV LT targeting of C/EBP transactivators is likely to play an important role in viral persistence and potentially inhibit host cell immune responses during MCPyV tumorigenesis. PMID- 24067966 TI - Genome scale evolution of myxoma virus reveals host-pathogen adaptation and rapid geographic spread. AB - The evolutionary interplay between myxoma virus (MYXV) and the European rabbit (Oryctolagus cuniculus) following release of the virus in Australia in 1950 as a biological control is a classic example of host-pathogen coevolution. We present a detailed genomic and phylogeographic analysis of 30 strains of MYXV, including the Australian progenitor strain Standard Laboratory Strain (SLS), 24 Australian viruses isolated from 1951 to 1999, and three isolates from the early radiation in Britain from 1954 and 1955. We show that in Australia MYXV has spread rapidly on a spatial scale, with multiple lineages cocirculating within individual localities, and that both highly virulent and attenuated viruses were still present in the field through the 1990s. In addition, the detection of closely related virus lineages at sites 1,000 km apart suggests that MYXV moves freely in geographic space, with mosquitoes, fleas, and rabbit migration all providing means of transport. Strikingly, despite multiple introductions, all modern viruses appear to be ultimately derived from the original introductions of SLS. The rapidity of MYXV evolution was also apparent at the genomic scale, with gene duplications documented in a number of viruses. Duplication of potential virulence genes may be important in increasing the expression of virulence proteins and provides the basis for the evolution of novel functions. Mutations leading to loss of open reading frames were surprisingly frequent and in some cases may explain attenuation, but no common mutations that correlated with virulence or attenuation were identified. PMID- 24067967 TI - Suppression of PACT-induced type I interferon production by herpes simplex virus 1 Us11 protein. AB - Herpes simplex virus 1 (HSV-1) Us11 protein is a double-stranded RNA-binding protein that suppresses type I interferon production through the inhibition of the cytoplasmic RNA sensor RIG-I. Whether additional cellular mediators are involved in this suppression remains to be determined. In this study, we report on the requirement of cellular double-stranded RNA-binding protein PACT for Us11 mediated perturbation of type I interferon production. Us11 associates with PACT tightly to prevent it from binding with and activating RIG-I. The Us11-deficient HSV-1 was indistinguishable from the Us11-proficient virus in the suppression of interferon production when PACT was compromised. More importantly, HSV-1-induced activation of interferon production was abrogated in PACT knockout murine embryonic fibroblasts. Our findings suggest a new mechanism for viral evasion of innate immunity through which a viral double-stranded RNA-binding protein interacts with PACT to circumvent type I interferon production. This mechanism might also be used by other PACT-binding viral interferon-antagonizing proteins such as Ebola virus VP35 and influenza A virus NS1. PMID- 24067968 TI - Polycomb repressive complex 2 silences human cytomegalovirus transcription in quiescent infection models. AB - Chromatin-based regulation of herpesviral transcriptional programs is increasingly appreciated as a mechanism for modulating infection outcomes. Transcriptionally permissive euchromatin predominates during lytic infection, whereas heterochromatin domains refractory to transcription are enriched at lytic genes during latency. Reversibly silenced facultative heterochromatin domains are often enriched for histone H3 trimethylated on lysine 27 (H3K27me3), a modification catalyzed by Polycomb repressive complex 2 (PRC2). The requirement for PRC2 in suppressing the human cytomegalovirus (HCMV) lytic transcriptional program during latency has not been thoroughly evaluated. Therefore, we disrupted PRC2 activity in the highly tractable THP1 and NT2D1 quiescent-infection models by treating cells with small-molecule inhibitors of PRC2 activity. Compared to control cells, disruption of PRC2 in HCMV-infected THP1 or NT2D1 cells resulted in significant increases in viral transcript levels and the detection of viral protein. Using chromatin immunoprecipitation, we demonstrated that enrichment of H3K27me3, deposited by PRC2, correlates inversely with lytic transcriptional output, suggesting that PRC2 catalytic activity at viral chromatin directly represses lytic transcription. Together, our data suggest that PRC2-mediated repression of viral transcription is a key step in the establishment and maintenance of HCMV latency. PMID- 24067969 TI - Efficient replication of Epstein-Barr virus-derived plasmids requires tethering by EBNA1 to host chromosomes. AB - The EBNA1 protein of Epstein-Barr virus enables plasmids carrying oriP both to duplicate and to segregate efficiently in proliferating cells. EBNA1 recruits the origin recognition complex (ORC) to establish a replication origin at one element of oriP, DS (dyad symmetry); at another element, FR (family of repeats), EBNA1 binds to an array of sites from which it tethers plasmids to host chromosomes for mitotic stability. We report experiments leading to the conclusion that tethering by EBNA1 to host chromosomes is also needed within interphase nuclei in order for plasmids to be replicated efficiently from oriP. The DNA-binding domain of EBNA1, which lacks chromosome-binding ability, was found to support weak, DS-specific replication in HEK293 cells after transient transfection, being 17% as active as wild-type EBNA1. The low efficiency of replication was not due to the failure of the DNA-binding domain to retain plasmids within nuclei, because plasmids were recovered in similar amounts and entirely from the nuclear fraction of these transiently transfected cells. A derivative of EBNA1 with its chromosome tethering domains replaced by a 22-amino-acid nucleosome-binding domain was fully active in supporting oriP functions. The implication is that EBNA1's DNA-binding domain is able to recruit ORC to DS, but either this step or subsequent replication is only efficient if the plasmid is tethered to a host chromosome. Finally, with some cell lines, DS can hardly support even transient plasmid replication without FR. A loss of plasmids lacking FR from nuclei cannot account for this requirement, suggesting that the stronger tethering to chromosomes by FR is needed for plasmid replication within the nuclei of such cells. PMID- 24067970 TI - Inhibition of Middle East respiratory syndrome coronavirus infection by anti-CD26 monoclonal antibody. AB - We identified the domains of CD26 involved in the binding of Middle East respiratory syndrome coronavirus (MERS-CoV) using distinct clones of anti-CD26 monoclonal antibodies (MAbs). One clone, named 2F9, almost completely inhibited viral entry. The humanized anti-CD26 MAb YS110 also significantly inhibited infection. These findings indicate that both 2F9 and YS110 are potential therapeutic agents for MERS-CoV infection. YS110, in particular, is a good candidate for immediate testing as a therapeutic modality for MERS. PMID- 24067971 TI - Parvovirus B19 uptake is a highly selective process controlled by VP1u, a novel determinant of viral tropism. AB - The VP1 unique region (VP1u) of human parvovirus B19 (B19V) is the immunodominant part of the viral capsid. Originally inaccessible, the VP1u becomes exposed upon primary attachment to the globoside receptor. To study the function of the exposed VP1u in B19V uptake, we expressed this region as a recombinant protein. Here, we report that purified recombinant VP1u binds and is internalized in UT7/Epo cells. By means of truncations and specific antibodies, we identified the most N-terminal amino acid residues of VP1u as the essential region for binding and internalization. Furthermore, the recombinant VP1u was able to block B19V uptake, suggesting that the protein and the virus undertake the same internalization pathway. Assays with different erythroid and nonerythroid cell lines showed that the N-terminal VP1u binding was restricted to a few cell lines of the erythroid lineage, which were also the only cells that allowed B19V internalization and infection. These results together indicate that the N terminal region of VP1u is responsible for the internalization of the virus and that the interacting receptor is restricted to B19V-susceptible cells. The highly selective uptake mechanism represents a novel determinant of the tropism and pathogenesis of B19V. PMID- 24067972 TI - Replication stress and mitotic dysfunction in cells expressing simian virus 40 large T antigen. AB - We previously demonstrated that simian virus 40 (SV40) large T antigen (LT) binds to the Bub1 kinase, a key regulator of the spindle checkpoint and chromosome segregation. Bub1 mutations or altered expression patterns are linked to chromosome missegregation and are considered to be a driving force in some human cancers. Here we report that LT, dependent on Bub1 binding, causes micronuclei, lagging chromatin, and anaphase bridges, which are hallmarks of chromosomal instability (CIN) and Bub1 insufficiency. Using time-lapse microscopy, we demonstrate that LT imposes a Bub1 binding-dependent delay in the metaphase-to anaphase transition. Kinetochore fibers reveal that LT, via Bub1 binding, causes aberrant kinetochore (KT)-microtubule (MT) attachments and a shortened interkinetochore distance, consistent with a lack of tension. Previously, we showed that LT also induces the DNA damage response (DDR) via Bub1 binding. Using inducible LT cell lines, we show that an activated DDR was observed before the appearance of anaphase bridges and micronuclei. Furthermore, LT induction in serum-starved cells demonstrated gamma-H2AX accumulation in cells that had not yet entered mitosis. Thus, DDR activation can occur independently of chromosome segregation defects. Replication stress pathways may be responsible, because signatures of replication stress were observed, which were attenuated by exogenous supplementation with nucleosides. Our observations allow us to propose a model that explains and integrates the diverse manifestations of genomic instability induced by LT. PMID- 24067974 TI - Multiple roles for sialylated glycans in determining the cardiopulmonary tropism of adeno-associated virus 4. AB - Adeno-associated virus 4 (AAV4) is one of the most divergent serotypes among known AAV isolates. Mucins or O-linked sialoglycans have been identified as the primary attachment receptors for AAV4 in vitro. However, little is known about the role(s) played by sialic acid interactions in determining AAV4 tissue tropism in vivo. In the current study, we first characterized two loss-of-function mutants obtained by screening a randomly mutated AAV4 capsid library. Both mutants harbored several amino acid residue changes localized to the 3-fold icosahedral symmetry axes on the AAV4 capsid and displayed low transduction efficiency in vitro. This defect was attributed to decreased cell surface binding as well as uptake of mutant virions. These results were further corroborated by low transgene expression and recovery of mutant viral genomes in cardiac and lung tissue following intravenous administration in mice. Pharmacokinetic analysis revealed rapid clearance of AAV4 mutants from the blood circulation in conjunction with low hemagglutination potential ex vivo. These results were recapitulated with mice pretreated intravenously with sialidase, directly confirming the role of sialic acids in determining AAV4 tissue tropism. Taken together, our results support the notion that blood-borne AAV4 particles interact sequentially with O-linked sialoglycans expressed abundantly on erythrocytes followed by cardiopulmonary tissues and subsequently for viral cell entry. PMID- 24067973 TI - Hypoxia induces permeability and giant cell responses of Andes virus-infected pulmonary endothelial cells by activating the mTOR-S6K signaling pathway. AB - Andes virus (ANDV) is a South American hantavirus that causes a highly lethal hantavirus pulmonary syndrome (HPS) characterized by hypoxia, thrombocytopenia, and vascular leakage leading to acute pulmonary edema. ANDV infects human pulmonary microvascular and lymphatic endothelial cells (MECs and LECs, respectively) and nonlytically enhances the permeability of interendothelial cell adherence junctions in response to vascular endothelial growth factor (VEGF). Recent findings also indicate that ANDV causes the formation of giant endothelial cells. Here, we demonstrate that hypoxic conditions alone enhance permeability and giant cell responses of ANDV-infected MECs and LECs through activation of the mTOR signaling pathway. In contrast to infection of cells with nonpathogenic Tula virus (TULV), we observed that exposure of ANDV-infected MECs and LECs to hypoxic conditions resulted in a 3- to 6-fold increase in monolayer permeability and the formation of giant cells 3* to 5* normal size. ANDV infection in combination with hypoxic conditions resulted in the enhancement of hypoxia-inducible factor 1alpha (HIF1alpha)-directed VEGF A, angiopoietin 4, and EGLN3 transcriptional responses. Constitutive mTOR signaling induces the formation of giant cells via phosphorylation of S6K, and mTOR regulates hypoxia and VEGF A-induced cellular responses. We found that S6K was hyperphosphorylated in ANDV-infected, hypoxia treated MECs and LECs and that rapamycin treatment for 1 h inhibited mTOR signaling responses and blocked permeability and giant cell formation in ANDV infected monolayers. These findings indicate that ANDV infection and hypoxic conditions enhance mTOR signaling responses, resulting in enhanced endothelial cell permeability and suggest a role for rapamycin in therapeutically stabilizing the endothelium of microvascular and lymphatic vessels during ANDV infection. PMID- 24067975 TI - Tetherin restricts herpes simplex virus 1 and is antagonized by glycoprotein M. AB - Tetherin is a broadly active antiviral effector that works by tethering nascent enveloped virions to a host cell membrane, thus preventing their release. In this study, we demonstrate that herpes simplex virus 1 (HSV-1) is targeted by tetherin. We identify the viral envelope glycoprotein M (gM) as having moderate anti-tetherin activity. We show that gM but not gB or gD efficiently removes tetherin from the plasma membrane and can functionally substitute for the human immunodeficiency virus type 1 (HIV-1) Vpu protein, the prototypic viral tetherin antagonist, in rescuing HIV-1 release from tetherin-expressing cells. Our data emphasize that tetherin is a broadly active antiviral effector and contribute to the emerging hypothesis that viruses must suppress or evade an array of host cell countermeasures in order to establish a productive infection. PMID- 24067976 TI - Comparative analysis of adeno-associated virus capsid stability and dynamics. AB - Icosahedral viral capsids are obligated to perform a thermodynamic balancing act. Capsids must be stable enough to protect the genome until a suitable host cell is encountered yet be poised to bind receptor, initiate cell entry, navigate the cellular milieu, and release their genome in the appropriate replication compartment. In this study, serotypes of adeno-associated virus (AAV), AAV1, AAV2, AAV5, and AAV8, were compared with respect to the physical properties of their capsids that influence thermodynamic stability. Thermal stability measurements using differential scanning fluorimetry, differential scanning calorimetry, and electron microscopy showed that capsid melting temperatures differed by more than 20 degrees C between the least and most stable serotypes, AAV2 and AAV5, respectively. Limited proteolysis and peptide mass mapping of intact particles were used to investigate capsid protein dynamics. Active hot spots mapped to the region surrounding the 3-fold axis of symmetry for all serotypes. Cleavages also mapped to the unique region of VP1 which contains a phospholipase domain, indicating transient exposure on the surface of the capsid. Data on the biophysical properties of the different AAV serotypes are important for understanding cellular trafficking and is critical to their production, storage, and use for gene therapy. The distinct differences reported here provide direction for future studies on entry and vector production. PMID- 24067977 TI - Herpes simplex virus 1 counteracts tetherin restriction via its virion host shutoff activity. AB - The interferon-inducible membrane protein tetherin (Bst-2, or CD317) is an antiviral factor that inhibits enveloped virus release by cross-linking newly formed virus particles to the producing cell. The majority of viruses that are sensitive to tetherin restriction appear to be those that acquire their envelopes at the plasma membrane, although many viruses, including herpesviruses, envelope at intracellular membranes, and the effect of tetherin on such viruses has been less well studied. We investigated the tetherin sensitivity and possible countermeasures of herpes simplex virus 1 (HSV-1). We found that overexpression of tetherin inhibits HSV-1 release and that HSV-1 efficiently depletes tetherin from infected cells. We further show that the virion host shutoff protein (Vhs) is important for depletion of tetherin mRNA and protein and that removal of tetherin compensates for defects in replication and release of a Vhs-null virus. Vhs is known to be important for HSV-1 to evade the innate immune response in vivo. Taken together, our data suggest that tetherin has antiviral activity toward HSV-1 and that the removal of tetherin by Vhs is important for the efficient replication and dissemination of HSV-1. PMID- 24067978 TI - Adenovirus E4orf4 protein-induced death of p53-/- H1299 human cancer cells follows a G1 arrest of both tetraploid and diploid cells due to a failure to initiate DNA synthesis. AB - The adenovirus E4orf4 protein selectively kills human cancer cells independently of p53 and thus represents a potentially promising tool for the development of novel antitumor therapies. Previous studies suggested that E4orf4 induces an arrest or a delay in mitosis and that both this effect and subsequent cell death rely largely on an interaction with the B55 regulatory subunit of protein phosphatase 2A. In the present report, we show that the death of human H1299 lung carcinoma cells induced by expression of E4orf4 is typified not by an accumulation of cells arrested in mitosis but rather by the presence of both tetraploid and diploid cells that are arrested in G1 because they are unable to initiate DNA synthesis. We believe that these E4orf4-expressing cells eventually die by various processes, including those resulting from mitotic catastrophe. PMID- 24067979 TI - Increased Escherichia coli-induced interleukin-23 production by CD16+ monocytes correlates with systemic immune activation in untreated HIV-1-infected individuals. AB - The level of microbial translocation from the intestine is increased in HIV-1 infection. Proinflammatory cytokine production by peripheral antigen-presenting cells in response to translocated microbes or microbial products may contribute to systemic immune activation, a hallmark of HIV-1 infection. We investigated the cytokine responses of peripheral blood myeloid dendritic cells (mDCs) and monocytes to in vitro stimulation with commensal enteric Escherichia coli in peripheral blood mononuclear cells (PBMC) from untreated HIV-1-infected subjects and from uninfected controls. Levels of interleukin 23 (IL-23) produced by PBMC from HIV-1-infected subjects in response to E. coli stimulation were significantly higher than those produced by PBMC from uninfected subjects. IL-23 was produced primarily by CD16(+) monocytes. This subset of monocytes was increased in frequency and expressed higher levels of Toll-like receptor 4 (TLR4) in HIV-1-infected individuals than in controls. Blocking TLR4 on total CD14(+) monocytes reduced IL-23 production in response to E. coli stimulation. Levels of soluble CD27, an indicator of systemic immune activation, were elevated in HIV-1 infected subjects and were associated with the percentage of CD16(+) monocytes and the induction of IL-23 by E. coli, providing a link between these parameters and systemic inflammation. Taken together, these results suggest that IL-23 produced by CD16(+) monocytes in response to microbial stimulation may contribute to systemic immune activation in HIV-1-infected individuals. PMID- 24067980 TI - Robust neutralizing antibodies elicited by HIV-1 JRFL envelope glycoprotein trimers in nonhuman primates. AB - Host cell-mediated proteolytic cleavage of the human immunodeficiency virus type 1 (HIV-1) gp160 precursor glycoprotein into gp120 and gp41 subunits is required to generate fusion-competent envelope glycoprotein (Env) spikes. The gp120 directed broadly neutralizing monoclonal antibodies (bNabs) isolated from HIV infected individuals efficiently recognize fully cleaved JRFL Env spikes; however, nonneutralizing gp120-directed monoclonal antibodies isolated from infected or vaccinated subjects recognize only uncleaved JRFL spikes. Therefore, as an immunogen, cleaved spikes that selectively present desired neutralizing epitopes to B cells may elicit cross-reactive neutralizing antibodies. Accordingly, we inoculated nonhuman primates (NHPs) with plasmid DNA encoding transmembrane-anchored, cleaved JRFL Env or by electroporation (EP). Priming with DNA expressing soluble, uncleaved gp140 trimers was included as a comparative experimental group of NHPs. DNA inoculation was followed by boosts with soluble JRFL gp140 trimers, and control NHPs were inoculated with soluble JRFL protein trimers without DNA priming. In the TZM-bl assay, elicitation of neutralizing antibodies against HIV-1 tier 1 isolates was robust following the protein boost. Neutralization of tier 2 isolates was detected, but only in animals primed with plasmid DNA and boosted with trimeric protein. Using the more sensitive A3R5 assay, consistent neutralization of both clade B and C tier 2 isolates was detected from all regimens assessed in the current study, exceeding levels achieved by our previous vaccine regimens in primates. Together, these data suggest a potential advantage of B cell priming followed by a rest interval and protein boosting to present JRFL Env spikes to the immune system to better generate HIV-1 cross-clade neutralizing antibodies. PMID- 24067981 TI - Characterization of Mus musculus papillomavirus 1 infection in situ reveals an unusual pattern of late gene expression and capsid protein localization. AB - Full-length genomic DNA of the recently identified laboratory mouse papillomavirus 1 (MusPV1) was synthesized in vitro and was used to establish and characterize a mouse model of papillomavirus pathobiology. MusPV1 DNA, whether naked or encapsidated by MusPV1 or human papillomavirus 16 (HPV 16) capsids, efficiently induced the outgrowth of papillomas as early as 3 weeks after application to abraded skin on the muzzles and tails of athymic NCr nude mice. High concentrations of virions were extracted from homogenized papillomatous tissues and were serially passaged for >10 generations. Neutralization by L1 antisera confirmed that infectious transmission was capsid mediated. Unexpectedly, the skin of the murine back was much less susceptible to virion induced papillomas than the muzzle or tail. Although reporter pseudovirions readily transduced the skin of the back, infection with native MusPV1 resulted in less viral genome amplification and gene expression on the back, including reduced expression of the L1 protein and very low expression of the L2 protein, results that imply skin region-specific control of postentry aspects of the viral life cycle. Unexpectedly, L1 protein on the back was predominantly cytoplasmic, while on the tail the abundant L1 was cytoplasmic in the lower epithelial layers and nuclear in the upper layers. Nuclear localization of L1 occurred only in cells that coexpressed the minor capsid protein, L2. The pattern of L1 protein staining in the infected epithelium suggests that L1 expression occurs earlier in the MusPV1 life cycle than in the life cycle of high-risk HPV and that virion assembly is regulated by a previously undescribed mechanism. PMID- 24067982 TI - Structure of the fusion core and inhibition of fusion by a heptad repeat peptide derived from the S protein of Middle East respiratory syndrome coronavirus. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) recently emerged as a severe worldwide public health concern. The virus is highly pathogenic, manifesting in infected patients with an approximately 50% fatality rate. It is known that the surface spike (S) proteins of coronaviruses mediate receptor recognition and membrane fusion, thereby playing an indispensable role in initiating infection. In this process, heptad repeats 1 and 2 (HR1 and HR2) of the S protein assemble into a complex called the fusion core, which represents a key membrane fusion architecture. To date, however, the MERS-CoV fusion core remains uncharacterized. In this study, we performed a series of biochemical and biophysical analyses characterizing the HR1/HR2 complexes of this novel virus. The HR sequences were variably truncated and then connected with a flexible amino acid linker. In each case, the recombinant protein automatically assembled into a trimer in solution, displaying a typical alpha-helical structure. One of these trimers was successfully crystallized, and its structure was solved at a resolution of 1.9 A. A canonical 6-helix bundle, like those reported for other coronaviruses, was revealed, with three HR1 helices forming the central coiled coil core and three HR2 chains surrounding the core in the HR1 side grooves. This demonstrates that MERS-CoV utilizes a mechanism similar to those of other class I enveloped viruses for membrane fusion. With this notion, we further identified an HR2-based peptide that could potently inhibit MERS-CoV fusion and entry by using a pseudotyped-virus system. These results lay the groundwork for future inhibitory peptidic drug design. PMID- 24067983 TI - Recombination can lead to spurious results in retroviral transduction with dually fluorescent reporter genes. AB - Fluorescent proteins are routinely employed as reporters in retroviral vectors. Here, we demonstrate that transduction with retroviral vectors carrying a tandem dimer Tomato (TdTom) reporter produces two distinct fluorescent cell populations following template jumping due to a single nucleotide polymorphism between the first and second Tomato genes. Template jumping also occurs between repeated sequences in the Tomato and green fluorescent protein (GFP) genes. Thus, proper interpretation of the fluorescence intensity of transduced cells requires caution. PMID- 24067986 TI - Silver-catalyzed oxidative coupling/cyclization of acrylamides with 1,3 dicarbonyl compounds. AB - An efficient silver-catalyzed oxidative cyclization of acrylamides with 1,3 dicarbonyl compounds is described. It proceeds through a tandem radical addition/cyclization process, in which two new C-C bonds were formed. Furthermore, the same concept can also be extended to the reaction of easily available ketones and acrylamides. PMID- 24067984 TI - Kaposi's sarcoma-associated herpesvirus transactivator Rta induces cell cycle arrest in G0/G1 phase by stabilizing and promoting nuclear localization of p27kip. AB - The Kaposi's sarcoma-associated herpesvirus (KSHV) immediate-early gene, replication, and transcription activator (K-Rta) is a key viral protein that serves as the master regulator for viral lytic replication. In this study, we investigated the role of K-Rta in cell cycle regulation and found that the expression of K-Rta in doxycycline (Dox)-inducible BJAB cells induced cell cycle arrest in G0/G1 phase. Western blot analysis of key cell cycle regulators revealed that K-Rta-mediated cell cycle arrest was associated with a decrease in cyclin A and phosphorylated Rb (pS807/pS811) protein levels, both markers of S phase progression, and an increase in protein levels for p27, a cyclin-dependent kinase inhibitor. Further, we found that K-Rta does not affect the transcription of p27 but regulates p27 at the posttranslational level by inhibiting its proteosomal degradation. Immunofluorescence staining and cell fractionation experiments revealed largely nuclear compartmentalization of p27 in K-Rta expressing cells, demonstrating that K-Rta not only stabilizes p27 but also modulates its cellular localization. Finally, short hairpin RNA knockdown of p27 significantly abrogates cell cycle arrest in K-Rta-expressing cells, supporting its key role in K-Rta-mediated cell cycle arrest. Our findings are consistent with previous studies which showed that expression of immediate-early genes of several herpesviruses, including herpes simplex virus, Epstein-Barr virus, and cytomegalovirus, results in cell cycle arrest at the G0/G1 phase, possibly to avoid competition for resources needed for host cell replication during the S phase. PMID- 24067987 TI - A highly photocatalytic polyoxomolybdate compound constructed from novel-type triple helix {Mo4O12}n chains and copper(I)-organic nets. AB - A novel-type 3D polyoxomolybdate-organic framework, {[Cu3(H3tpb)2(tpb)(Mo4O12)].4H2O}n (1, H3tpb = 1,3,5-tri(1H-pyrazol-3 yl)benzene), was prepared and characterized by elemental analysis, IR spectroscopy, and luminescence analysis. Single-crystal X-ray diffraction analysis reveals that novel neutral triple helix {Mo4O12}n chains are encased in bowl-like 2D [Cu3(H3tpb)2(tpb)]n intervals via bond interactions between terminal oxygen atoms and cations of Cu(I), leaving an unprecedented (3,3,5,8)-connected (3.4.6(8))3(3(6).4(6).8(6).9(6).10(4))(4(3))2(6(3)) topology. Moreover, compound 1 exhibits remarkable photocatalytic activities for decomposition of methylene orange (MO), methylene red (MR), methylene blue (MB), methylene violet (MV), and rhodamine B (RhB) under UV light. PMID- 24067988 TI - Prevention of graft-versus-host-disease with preserved graft-versus-leukemia effect by ex vivo and in vivo modulation of CD4(+) T-cells. AB - This is the first report showing that an epitope-specific ex vivo modulation of an allogeneic hematopoietic stem cell graft by the anti-human CD4 antibody MAX.16H5 IgG1 simultaneously facilitates the anti-tumor capacity of the graft (Graft-versus-leukemia effect, GvL) and the long-term suppression of the deleterious side effect Graft-versus-host-disease (GvHD). To distinguish and consolidate GvL from GvHD, the anti-human CD4 antibody MAX16.H5 IgG1 was tested in murine GvHD and tumor models. The survival rate was significantly increased in recipients receiving a MAX.16H5 IgG1 short-term (2 h) pre-incubated graft even when tumor cells were co-transplanted or when recipient mice were treated by MAX.16H5 IgG1 before transplantation. After engraftment, regulatory T-cells are generated only supporting the GvL effect. It was also possible to transfer the immune tolerance from GvHD-free recipient chimeras into third party recipient mice without the need of reapplication of MAX.16H5 IgG1 anti-human CD4 antibodies. These findings are also benefical for patients with leukemia when no matched related or unrelated donor is available and provides a safer allogeneic HSCT, which is more effective against leukemia. It also facilitates allogeneic (stem) cell transplantations for other indications (e.g., autoimmune-disorders). PMID- 24067989 TI - A painful squat test provides limited diagnostic utility in CAM-type femoroacetabular impingement. AB - PURPOSE: The purpose of this study is to determine the relationship between a symptomatic maximal squat and the presence of radiographic CAM-type femoroacetabular impingement (FAI) on magnetic resonance imaging (MRI) and to determine the sensitivity and specificity of a maximal squat test for the presence of radiographic CAM-type femoral deformity in an adult population. METHODS: In this pilot study, 76 consecutive patients were recruited from an outpatient clinic at McMaster University. All patients presented with pre arthritic hip pain and were asked to perform a maximal squat. The results of this test were compared to magnetic resonance imaging and magnetic resonance angiographic (MRI and MRA) findings evaluating and characterizing CAM-type FAI deformity. RESULTS: The sensitivity and specificity of the maximal squat test were 75 % (56.6-88.5 %) and 41 % (27.0-56.8 %), respectively, for CAM-type FAI deformity. The positive and negative likelihood ratios were modest at 1.3 (0.9 1.7) and 0.6 (0.3-1.2), respectively. This means that a 30 % pre-test probability is improved to 36 % following a positive squat test and reduced to 20 % with a negative squat test. CONCLUSION: The maximal squat test was found to have marginal incremental diagnostic ability for CAM-type FAI. Its utility in the diagnostic evaluation of FAI remains limited. This survey elucidates areas of research for future studies relevant to the clinical diagnosis of FAI. PMID- 24067990 TI - An orthopaedic conquest: the first inter-human tissue transplantation. AB - Nineteenth century Scottish surgeon William Macewen performed, in 1879, the first inter-human living donor transplantation in medical history. It was a bone allograft performed on a 3-year-old boy affected by a huge humeral bone loss. This paper analyses the historical context around Macewen, briefly introducing his life and the discoveries made by Lister and by the pioneers of anaesthesia. It focuses on the details of the bone allograft procedure invented by Macewen. He was both a basic researcher and a skilled surgeon, a combination that is rare nowadays. The paper includes a description of the surgical procedure and is also enriched by the reproduction of the original image used by Macewen in his 1881 article to explain the clinical evolution. William Macewen was one of the greatest pioneers in musculoskeletal medicine whose brilliant intuition led to the origin and development of bone grafting, one of the most common orthopaedic procedures in the world today. LEVEL OF EVIDENCE: V. PMID- 24067991 TI - Unicondylar knee arthroplasty: what's new? PMID- 24067992 TI - New method of diagnosis for chronic ankle instability: comparison of manual anterior drawer test, stress radiography and stress ultrasound. AB - PURPOSE: To diagnose chronic ankle instability, clinicians frequently use manual anterior drawer test and stress radiography. However, both exams can yield incorrect results and do not reveal the extent of ankle instability. The use of stress ultrasound during a manual anterior drawer stress procedure might enable the diagnosis of chronic ankle instability. METHODS: Seventy-three patients with chronic ankle pain or laxity after remote ankle sprain were included. The study population included 41 males and 32 females. The mean age of the patients at the time of the operation was 29 years. A standardized physical examination (manual anterior drawer test), stress radiography and stress ultrasonography were performed to assess the anterior talofibular ligament (ATFL). Ultrasound images were taken in the resting position and the maximal anterior drawer position. The statistical significance of stress ultrasound among the three groups according to manual anterior drawer test and a specific degree (5 mm) of anterior translation of stress radiography were analysed. Correlation coefficients between stress ultrasound, stress radiography and manual anterior drawer test were calculated. RESULTS: There was a significant difference for ATFL length (ATFL stress) and ATFL ratio (ATFL stress/ATFL resting) among the three groups (both p < 0.001). However, there was no significant difference for anterior translation of stress radiography among three groups according to manual anterior drawer test (p = 0.159). There was a significant difference for ATFL length (ATFL stress) and ATFL ratio between two groups with 5-mm anterior translation of stress radiography (p = 0.002 and p = 0.011, respectively). The mean value of grade of manual anterior drawer test between the two groups also differed (p = 0.021). There was a moderately positive linear relationship between stress ultrasound and manual anterior drawer test. Also, there was a positive linear relationship between stress ultrasound and stress radiography. CONCLUSION: The results suggest that the value of ATFL length (ATFL stress) and ATFL ratio of stress ultrasound could be used for diagnosis of chronic ankle instability in addition to manual anterior drawer test and stress radiography. PMID- 24067993 TI - Ultrasound-assisted calcaneoplasty. AB - PURPOSE: The endoscopic technique for resection of a postero-superior part of calcaneus served as a golden standard during the last 10 years, and it has mostly replaced the open techniques. In an effort to reduce the morbidity and the recovery time, we had introduced the ultrasound-assisted technique. METHODS: In the period of 1 year, 15 patients with the prominent postero-superior part of calcaneus and retrocalcaneal bursitis were operated through the single skin incision using the ultrasound-assisted technique. The prominent part of calcaneus was resected with a bone abrader under the ultrasound control to the point when there was no impingement between Achilles tendon and calcaneus in maximal dorsal flexion. The patients were evaluated preoperatively and postoperatively with the AOFAS score and Ogilvie-Harris score. The strength test of the muscle triceps surae, as well as the proprioceptive test, was also undertaken. RESULTS: Initially, the follow-up was meant to last 6 months, but there were no differences in results between 6 weeks and 3 months postoperatively, so it was concluded that the 3-month follow-up is sufficient and relevant. All 15 patients were available for follow-up. All measured variables significantly improved (AOFAS, Ogilvie-Harris), and all the patients were satisfied with the postoperative result. Only one minor complication occurred: superficial infection. CONCLUSION: The ultrasound-assisted calcaneoplasty enables a precise resection of the postero-superior part of calcaneus and removal of the retrocalcaneal impingement. This method could become clinically relevant as it enables effective treatment of Haglund deformity, and results of this study presented rapid functional recovery. LEVEL OF EVIDENCE: Case series with no comparison group, Level IV. PMID- 24067994 TI - Medial hamstring muscle activation patterns are affected 1-6 years after ACL reconstruction using hamstring autograft. AB - PURPOSE: Although changes in hamstring muscle morphology after anterior cruciate ligament reconstruction (ACLR) using a semitendinosus autograft hamstrings gracilis (HG) of the ipsilateral limb are recognized, alterations in muscle activation patterns have not been extensively studied. The purpose of this controlled laboratory trial was therefore to monitor muscle activation levels of the medial (MH) and lateral (LH) hamstring muscles in athletes who had undergone ACLR using a HG autograft and to contrast these to activation levels demonstrated by healthy controls. METHODS: Surface electromyography (EMG) was sampled from bilateral hamstring muscles of 18 athletes 1-6 years after ACLR and 18 matched controls (CTRL) during the performance of two dissimilar exercises, both involving eccentric knee flexor activity. Peak normalized muscle activation levels were identified for MH and LH of both limbs during the performance of the Nordic Hamstring (NH) exercise and TRX) hamstring curl (TRX) exercise. RESULTS: A statistically significant limb by exercise interaction was found for peak activation levels of LH, due to significant interlimb differences in activation during the performance of the TRX exercise compared to more symmetrical activation during the NH (p < 0.001). A three-way interaction was found for peak activation levels of MH, due to group differences in peak muscle activation between limbs and exercise type (p = 0.025). Whereas CTRL group participants consistently favoured one limb over the other during the performance of both exercises, ACLR participants demonstrated dissimilar peak MH activation patterns between limbs during the performance of the NH exercise compared to the TRX. CONCLUSIONS: In light of these results and considering the surgical procedure, patients who undergo ACLR using a HG autograft from the ipsilateral limb may benefit from post-operative rehabilitation that involves muscle activation and strengthening specifically targeting the MH component. PMID- 24067995 TI - MiR-223 is dispensable for platelet production and function in mice. AB - MicroRNAs (miRNAs) are key physiological regulators in multiple cell types. Here, we assessed platelet production and function in mice deficient in miR-223, one of the most abundantly expressed miRNAs in platelets and megakaryocytes. We found platelet number, size, life-span as well as surface expression of platelet adhesion receptors to be unchanged in miR-223-deficient mice. Likewise, loss of miR-223 did not affect platelet activation, adhesion and aggregation and also had no effect on bleeding times. Moreover, miR-223 null megakaryocytes developed normally and were capable to form pro-platelets. However, we detected a transient delay in the recovery of platelet numbers following antibody-induced platelet depletion in miR-223-deficient animals. This delay was not observed after transplantation of bone marrow from miR-223-deficient animals into wild-type recipients, indicating a non-cell-autonomous role of miR-223 for thrombopoiesis. Overall, our data indicate a surprisingly modest role of miR-223 in platelet production, while the function of platelets does not seem to depend on miR-223. PMID- 24067997 TI - A clinicopathologic analysis of 177 acral melanomas in Koreans: relevance of spreading pattern and physical stress. AB - IMPORTANCE: The pathogenesis of acral melanoma remains unclear, even though trauma may be a predisposing factor. A study about the association of long-term physical stress with the incidence and spreading patterns through detailed anatomic mapping may be important to understand the unique features of acral melanoma. OBJECTIVES: To analyze the epidemiologic and clinicopathologic characteristics of acral melanoma and evaluate how long-term physical stress or pressure strength influences acral melanoma based on the analysis of differences in incidence, prognosis of the distinct site (weight or non-weight-bearing portion of sole, volar, or subungual location), and the spreading pattern of melanoma on the soles. DESIGN, SETTING, AND PATIENTS: Cross-sectional, retrospective study of 177 Korean patients with acral melanoma from January 1, 1994, through October 31, 2012. MAIN OUTCOMES AND MEASURES: Anatomic mapping and histopathologic examination of acral melanoma. RESULTS The male to female ratio was 1:1.03, and the mean age at first admission was 55.3 years. Acral lentiginous melanoma was the most common histopathologic subtype (85.9%), followed by nodular melanoma (12.8%). There was a high incidence of acral melanoma at more physically stressed sites, such as the center of the heels and inner forefoot. In addition, a peculiar spreading pattern with the long axis of melanoma, typically along naturally occurring creases due to long-term pressure on the soles, was often observed. The prognostic index and survival rate showed no significant difference between volar and subungual locations or between weight and non-weight-bearing portions of the soles. CONCLUSIONS AND RELEVANCE: Clinicopathologic characteristics of acral melanoma diagnosed at an advanced stage and resulting in a low survival rate are not significantly different between Koreans and other Asians. Interestingly, based on our study, long-term physical stress or pressure strength can influence the incidence and spreading pattern of acral melanoma in a particular manner. Acral melanoma occurs on more physically stressed sites with the long axis along natural creases on the sole. A further prospective investigation, especially of in situ lesions, regarding location-based differences in incidence, progress, and survival is necessary to better understand the pathophysiologic characteristics of acral melanoma. PMID- 24067998 TI - Expression of thymidylate synthase predicts clinical outcomes of pemetrexed containing chemotherapy for non-small-cell lung cancer: a systemic review and meta-analysis. AB - PURPOSE: Observational and preclinical studies suggested an association between the expression of thymidylate synthase (TS) and clinical effects of pemetrexed based chemotherapy in non-small-cell lung cancer (NSCLC) patients. However, the predictive value of TS for pemetrexed-containing chemotherapy regimen remained controversial. The aim of the study was to further appraise the association between the expression of TS and clinical efficacy pemetrexed-based chemotherapy in NSCLC patients. METHODS: We searched in MEDLINE (PubMed), EMBASE, and Cochrane Library from January 1945 to May 2013. Two authors independently extracted information from the characteristics of study participants. Primary outcomes included therapeutic response (TR; i.e., complete response + partial response vs. stable disease + progressive disease), progression-free survival (PFS), and overall survival (OS). Relative risk (RR) and hazard ratio (HR) were used for evaluating the risk or hazard. RESULTS: Eight studies were included in the meta analysis. Better response usually appeared in NSCLC patients with a lower expression of TS [RR = 2.06 95 % confidence intervals (CI) 1.44, 2.96]. There was a significant association between TS expression and outcomes of pemetrexed-based chemotherapy for NSCLC (PFS: HR = 0.63 95 % CI 0.52, 0.76; OS: HR = 0.74, 95 % CI: 0.63, 0.88). In addition, no evidence of publication bias was observed. CONCLUSIONS: This meta-analysis evaluated the predictive value of TS and provided evidence that NSCLC patients with lower TS expression could significantly benefit from pemetrexed-based chemotherapy. This increased level of TS was probably an independent risk factor of potential resistance against pemetrexed. PMID- 24068000 TI - Activation of mTOR modulates SREBP-2 to induce foam cell formation through increased retinoblastoma protein phosphorylation. AB - AIMS: Our previous studies demonstrated that inflammation contributes to atherosclerosis through disruption of the low density lipoprotein receptor (LDLr) pathway. However, this effect is overridden by rapamycin, which is an inhibitor of mammalian target of rapamycin (mTOR). This study investigated the role of the mTOR pathway in atherosclerosis in vivo and in vitro. METHODS AND RESULTS: To induce inflammation, we used subcutaneous injection of 10% casein in apolipoprotein E knockout (ApoE KO) mice and lipopolysaccharide stimulation in rat vascular smooth muscle cells (VSMCs). Results showed that inflammation increased lipid accumulation in aortas of ApoE KO mice and in VSMCs, which were correlated with increased expressions of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), and SREBP-2 as well as with enhanced translocation of SCAP/SREBP-2 complex from the endoplasmic reticulum (ER) to the Golgi. Furthermore, inflammation increased both the percentage of cells in the S phase of cell cycle and protein expressions of the phosphorylated forms of retinoblastoma tumour suppressor protein (Rb), mTOR, eukaryotic initiation factor 4E-binding protein 1 (4EBP1), and P70 S6 kinase. After treatment with rapamycin or mTOR siRNA, the activity of the mTOR pathway was blocked. Interestingly, the expression levels of LDLr, SCAP, and SREBP-2 and the translocation of SCAP/SREBP-2 complex from the ER to the Golgi in treated VSMCs were decreased even in the presence of inflammatory stress. CONCLUSION: Our findings demonstrate for the first time that inflammation disrupts LDLr feedback regulation through the activation of the mTOR pathway. Increased mTORC1 activity was found to up-regulate SREBP-2-mediated cholesterol uptake through Rb phosphorylation. PMID- 24068002 TI - A facile method for synthesis of N-doped ZnO mesoporous nanospheres and enhanced photocatalytic activity. AB - A facile synthesis route is reported for preparation of N-doped mesoporous ZnO nanospheres by a solvothermal treatment of Zn(NO3)2.6H2O which provides a source of both zinc and nitrogen. A variety of different spectroscopic and analytical techniques, such as powder X-ray diffraction (XRD), transmission electron microscopy (TEM), UV-vis and X-ray photoelectron (XPS) spectroscopies were used to characterize the physicochemical properties of catalysts. The photocatalytic activities of the composites were evaluated by the degree of degradation of rhodamine B in aqueous solutions at room temperature with near-UV light irradiation. These nanocomposites exhibit higher photocatalytic activity compared with pure ZnO nanoparticles. The enhancement of photocatalytic activity of N doped ZnO nanoparticles is mainly attributed to their absorption of more photons and reduced electron-hole pair recombination. Our one-step, environmentally friendly synthetic method may provide a new means of designing and synthesizing series of N-doped metal oxide semiconductors for use in photo-assisted catalytic reactions. PMID- 24067999 TI - Cardiac stem cells with electrical stimulation improve ischaemic heart function through regulation of connective tissue growth factor and miR-378. AB - AIMS: In this study, we investigated whether pre-conditioning (PC) by electrical stimulation (EleS) induces cytoprotective effect on cardiac stem cells (CSCs) and determined its underlying molecular mechanisms. METHODS AND RESULTS: Sca-1(+) CSCs were isolated from male C57BL6 mice (12 weeks) hearts. PC of CSCs with EleS ((EleS)CSCs) was carried out for 3 h at 1.5 V followed by exposure to 300 uM H2O2 for 5 h. Cytoprotective effects and cell adhesion ability were significantly increased by EleS as evaluated by transferase-mediated dUTP nick-end labelling (TUNEL), lactate dehydrogenase (LDH) release assay, and adhesion assay. EleS increased phosphorylation of AKT, focal adhesion kinase (FAK), and glycogen synthase kinase (GSK3beta), as well as decreased caspase-3 cleavage. Interestingly, inhibition of AKT or FAK abolished the pro-survival effects of EleS. We found that connective tissue growth factor (Ctgf) was responsible for EleS-induced CSC survival and adhesion.The survival rate of (EleS)CSCs after transplantation in the infarcted myocardium was significantly increased together with improvement in cardiac function. Importantly, knockdown of Ctgf abolished EleS-induced cytoprotective effects and recovery of cardiac function. Furthermore, we identified miR-378 as a potential Ctgf regulator in (EleS)CSCs. CONCLUSION: EleS enhanced CSC survival in vitro and in vivo as well as functional recovery of the ischaemic heart through an AKT/FAK/CTGF signalling pathway. It is suggested that Ctgf and miR-378 are novel therapeutic targets for stem cell-based therapy. PMID- 24068004 TI - Performance monitoring of mycobacterium tuberculosis dried culture spots for use with the GeneXpert system within a national program in South Africa. AB - The use of dried culture spots (DCSs) has been reported in the verification of GeneXpert instruments as being "fit for purpose" for the South African National implementation program. We investigated and compared the performance of the DCSs for verification across different bulk batches, testing the settings and cadre of staff, and the Xpert MTB/RIF assay version. Four bulk batches (V005 to V008) were used to prepare (i) 619 DCS panels for laboratory testing on G3 or G4 cartridges by a technologist, (ii) 13 DCS panels (batch V005) used for clinic verification on G3 cartridges by a nurse or lay counselor, and (iii) 20 DCS panels (batch V005) used for the verification of 10 GeneXpert 16 module instruments in mobile vehicles on the G3 cartridge performed by a scientist. The stabilities of the DCSs over 6 months at 4 degrees C, room temperature, and 37 degrees C were investigated. The mean cycle threshold (CT) and standard deviation (SD) for probe A were calculated. The proportions of variability in the CT values across bulk batches, assay versions, and settings and cadre of staff were determined using regression analysis. Overall, the DCSs demonstrated SDs of 3.3 (n = 660) for the G3 cartridges and 3.8 (n = 1,888) for the G4 cartridges, with an overall error rate of 1.5% and false rifampin resistance rate of 0.1%. The proportions of variability (R(2)) in the CT values explained by batch were 14%, by setting and cadre of staff, 5.6%, and by assay version, 4.2%. The most stable temperature in a period of up to 6 months was 37 degrees C (SD, 2.7). The DCS is a robust product suitable for storage, transport, and use at room temperature for the verification of the GeneXpert instrument, and the testing can be performed by non laboratory-trained personnel in nonlaboratory settings. PMID- 24068005 TI - Rifampin heteroresistance in Mycobacterium tuberculosis cultures as detected by phenotypic and genotypic drug susceptibility test methods. AB - Tuberculosis patients may harbor both drug-susceptible and -resistant bacteria, i.e., heteroresistance. We used mixtures of rifampin-resistant and -susceptible Mycobacterium tuberculosis strains to simulate heteroresistance in patient samples. Molecular tests can be used for earlier discovery of multidrug resistance (MDR), but the sensitivity to detect heteroresistance is unknown. Conventional phenotypic drug susceptibility testing was the most sensitive, whereas two line probe assays and sequencing were unable to detect the clinically important 1% resistant bacteria. PMID- 24068006 TI - Stewardship approach for optimizing antimicrobial therapy through use of a rapid microarray assay on blood cultures positive for Enterococcus species. AB - Enterococci are a major cause of bloodstream infections in hospitalized patients and have limited antimicrobial treatment options due to their many resistance mechanisms. Molecular technologies have significantly shortened the time to enterococcal isolate identification compared with conventional methods. We evaluated the impact of rapid organism identification and resistance detection with the Verigene Gram-positive blood culture microarray assay on clinical and economic outcomes for patients with enterococcal bacteremia. A single-center preintervention/postintervention quasiexperimental study compared inpatients with enterococcal bacteremia from 1 February 2012 to 9 September 2012 (preintervention period) and 10 September 2012 to 28 February 2013 (postintervention period). An infectious disease and/or critical care pharmacist was contacted with the microarray assay results, and effective antibiotics were recommended. The clinical and economic outcomes for 74 patients were assessed. The mean time to appropriate antimicrobial therapy was 23.4 h longer in the preintervention group than in the postintervention group (P = 0.0054). A nonsignificant decrease in the mean time to appropriate antimicrobial therapy was seen for patients infected with vancomycin-susceptible Enterococcus isolates (P = 0.1145). For patients with vancomycin-resistant Enterococcus bacteremia, the mean time to appropriate antimicrobial therapy was 31.1 h longer in the preintervention group than in the postintervention group (P < 0.0001). In the postintervention group, the hospital length of stay was significantly 21.7 days shorter (P = 0.0484) and mean hospital costs were $60,729 lower (P = 0.02) than in the preintervention group. The rates of attributed deaths in the two groups were not statistically different. Microarray technology, supported by pharmacy and microbiology departments, can decrease the time to appropriate antimicrobial therapy, the hospital length of stay, and health care costs. PMID- 24068007 TI - Evaluation and implementation of FilmArray version 1.7 for improved detection of adenovirus respiratory tract infection. AB - The BioFire FilmArray respiratory panel is a multiplex PCR technology capable of detecting a number of bacteria and viruses that cause respiratory tract infection. The assay is technically simple to perform and provides rapid results, making it an appealing option for physicians and laboratorians. The initial product released by BioFire (version 1.6) was reported to have poor sensitivity for adenovirus detection and was therefore of concern when testing immunocompromised patients. This study evaluates the redesigned FilmArray assay (version 1.7) for detection of adenovirus. In this evaluation, we performed both retrospective and prospective verification studies, as well as a detailed serotype analysis. We found that version 1.7 demonstrated improved adenovirus sensitivity. In retrospective studies, sensitivity improved from 66.6% to 90.5%, and in prospective studies, it improved from 42.7% to 83.3%. In addition, when 39 clinically relevant serotypes were tested, 8 were not detected by version 1.6 and only 1 was not detected by version 1.7. The limit of detection remained the same when tested against serotype 4 but improved by 2 log units for serotype 7. Lastly, turnaround time analyses showed that the FilmArray assay was completed 3 h and 9 min after collection, which was more than a 37-h improvement over the previous multiplex PCR assay performed in our laboratory. PMID- 24068008 TI - Mycobacterium tuberculosis outbreak strain of Danish origin spreading at worrying rates among greenland-born persons in Denmark and Greenland. AB - Transmission of Mycobacterium tuberculosis continues at high rates among Greenland-born persons in Greenland and Denmark, with 203 and 450 notified cases per 10(5) population, respectively, in the year 2010. Here, we document that the predominant M. tuberculosis outbreak strain C2/1112-15 of Danish origin has been transmitted to Greenland-born persons in Denmark and subsequently to Greenland, where it is spreading at worrying rates and adding to the already heavy tuberculosis burden in this population group. It is now clear that the C2/1112-15 strain is able to gain new territories using a new population group as the "vehicle." Thus, it might have the ability to spread even further, considering the potential clinical consequences of strain diversity such as that seen in the widely spread Beijing genotype. The introduction of the predominant M. tuberculosis outbreak strain C2/1112-15 into the Arctic circumpolar region is a worrying tendency which deserves attention. We need to monitor whether this strain already has, or will, spread to other countries. PMID- 24068009 TI - Genetic marker suitable for identification and genotyping of Plasmodium ovale curtisi and Plasmodium ovale wallikeri. AB - We present a seminested PCR method that specifically discriminates between Plasmodium ovale curtisi and P. ovale wallikeri with high sensitivity. The test is based on species-specific amplification of a size-polymorphic fragment of the tryptophan-rich antigen gene, potra, which also permits discrimination of intraspecific sequence variants at this locus. PMID- 24068010 TI - Comparative cost-effectiveness of two-tiered testing strategies for serodiagnosis of lyme disease with noncutaneous manifestations. AB - The mainstay of laboratory diagnosis for Lyme disease is two-tiered serological testing, in which a reactive first-tier enzyme-linked immunosorbent assay (ELISA) or an immunofluorescence assay is supplemented by separate IgM and IgG immunoblots. Recent data suggest that the C6 ELISA can be substituted for immunoblots without a reduction in either sensitivity or specificity. In this study, the costs of 4 different two-tiered testing strategies for Lyme disease were compared using the median charges for these tests at 6 commercial diagnostic laboratories in 2012. The study found that a whole-cell sonicate ELISA followed by the C6 ELISA was the most cost-effective two-tiered testing strategy for Lyme disease with acute-phase serum samples. We conclude that the C6 ELISA can substitute for immunoblots in the two-tiered testing protocol for Lyme disease without a loss of sensitivity or specificity and is less expensive. PMID- 24068011 TI - Hepatitis C virus genotype 2 may not be detected by the Cobas AmpliPrep/Cobas TaqMan HCV Test, Version 1.0. PMID- 24068012 TI - Evaluation of the betaLacta test, a rapid test detecting resistance to third generation cephalosporins in clinical strains of Enterobacteriaceae. AB - For decades, third-generation cephalosporins (3GC) have been major drugs used to treat infections due to Enterobacteriaceae; growing resistance to these antibiotics makes the rapid detection of such resistance important. The betaLacta test is a chromogenic test developed for detecting 3GC-resistant isolates from cultures on solid media within 15 min. A multicenter prospective study conducted in 5 French and Belgian hospitals evaluated the performance of this test on clinical isolates. Based on antibiotic susceptibility testing, strains resistant or intermediate to cefotaxime or ceftazidime were classified as 3GC resistant, and molecular characterization of this resistance was performed. The rates of 3GC resistance were 13.9% (332/2,387) globally, 9.4% in Escherichia coli (132/1,403), 25.6% in Klebsiella pneumoniae (84/328), 30.3% in species naturally producing inducible AmpC beta-lactamases (109/360), and 5.6% in Klebsiella oxytoca and Citrobacter koseri (7/124). The sensitivities and specificities of the betaLacta test were, respectively, 87.7% and 99.6% overall, 96% and 100% for E. coli and K. pneumoniae, and 67.4% and 99.6% for species naturally producing inducible AmpC beta-lactamase. False-negative results were mainly related to 3GC-resistant strains producing AmpC beta-lactamase. Interestingly, the test was positive for all 3GC-resistant extended-spectrum beta-lactamase-producing isolates (n = 241). The positive predictive value was 97% and remained at >=96% for prevalences of 3GC resistance ranging between 10 and 30%. The negative predictive values were 99% for E. coli and K. pneumoniae and 89% for the species producing inducible AmpC beta-lactamase. In conclusion, the betaLacta test was found to be easy to use and efficient for the prediction of resistance to third-generation cephalosporins, particularly in extended-spectrum beta-lactamase-producing strains. PMID- 24068013 TI - Comparison of heat inactivation and cell disruption protocols for identification of mycobacteria from solid culture media by use of vitek matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - Two novel protocols for inactivation and extraction were developed and used to identify 107 Mycobacterium clinical isolates, including Mycobacterium tuberculosis complex, from solid cultures using Vitek matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. The protocol using heat inactivation with sonication and cell disruption with glass beads resulted in 82.2% and 88.8% species and genus level identifications, respectively. PMID- 24068014 TI - High-throughput matrix-assisted laser desorption ionization-time of flight mass spectrometry as an alternative approach to monitoring drug resistance of hepatitis B virus. AB - Long-term antiviral therapy of chronic hepatitis B virus (HBV) infection can lead to the selection of drug-resistant HBV variants and treatment failure. Moreover, these HBV strains are possibly present in treatment-naive patients. Currently available assays for the detection of HBV drug resistance can identify mutants that constitute >=5% of the viral population. Furthermore, drug-resistant HBV variants can be detected when a viral load is >10(4) copies/ml (1,718 IU/ml). The aim of this study was to compare matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and multitemperature single-strand conformation polymorphism (MSSCP) with commercially available assays for the detection of drug-resistant HBV strains. HBV DNA was extracted from 87 serum samples acquired from 45 chronic hepatitis B (CHB) patients. The 37 selected HBV variants were analyzed in 4 separate primer extension reactions on the MALDI-TOF MS. Moreover, MSSCP for identifying drug-resistant HBV YMDD variants was developed and turned out to be more sensitive than INNOLiPA HBV DR and direct sequencing. MALDI-TOF MS had the capability to detect mutant strains within a mixed viral population occurring with an allelic frequency of approximately 1% (with a specific value of >=10(2) copies/ml, also expressed as >=17.18 IU/ml). In our study, MSSCP detected 98% of the HBV YMDD variants among strains detected by the MALDI-TOF MS assay. The routine tests revealed results of 40% and 11%, respectively, for INNOLiPA and direct sequencing. The commonly available HBV tests are less sensitive than MALDI-TOF MS in the detection of HBV-resistant variants, including quasispecies. PMID- 24068015 TI - Improved sensitivity of the novel Xpert flu test for detection of influenza B virus. PMID- 24068016 TI - Molecular characterization of Staphylococcus aureus and influenza virus coinfections in patients with fatal Pneumonia. AB - Molecular techniques were used to characterize genetic features of Staphylococcus aureus in 66 fatal cases of pneumonia caused by S. aureus and influenza A or B viruses. Nucleic acids were extracted from formalin-fixed, paraffin-embedded tissues. The majority of cases revealed genetic markers for Panton-Valentine leukocidin, mecA, and spa type t008. PMID- 24068017 TI - Comparative evaluation of PCR and imprint smear microscopy analyses of skin biopsy specimens in diagnosis of macular, papular, and mixed papulo-nodular lesions of post-kala-azar dermal leishmaniasis. AB - Diagnosis of post-kala-azar dermal leishmaniasis (PKDL), particularly the macular form, is difficult when based on microscopy. This study compared the results of nested PCR (91.9% positive samples) with imprint smear microscopy (70.9% positive samples) for 62 PKDL samples. We found that nested PCR, which indicated 87.5% positivity for the macular lesions, compared to 41.6% positivity by imprint smear microscopy, is an efficient method for early diagnosis of PKDL. PMID- 24068018 TI - Virulence gene profiles and population genetic analysis for exploration of pathogenic serogroups of Shiga toxin-producing Escherichia coli. AB - Infection with Shiga toxin (Stx)-producing Escherichia coli (STEC) is a serious public health concern, causing severe diarrhea and hemolytic-uremic syndrome. Patient symptoms are varied among STEC strains, possibly implying the presence of markers for STEC virulence other than Stx. To reveal the genotypic traits responsible for STEC virulence, we investigated 282 strains of various serogroups for the presence of 17 major virulence genes, i.e., stx1, stx2a, stx2c, stx2d, stx2e, stx2f, eae, tir, espB, espD, iha, saa, subA, ehxA, espP, katP, and stcE. Next, we examined the prevalence of virulence genes according to the seropathotypes in which serotypes were classified (seropathotypes A through E) based on the reported frequencies in human illness, as well as known associations with outbreaks and with severe disease. Our results demonstrate that the presence of both katP and stcE in STEC, in addition to the genes located in the locus of enterocyte effacement (LEE), including eae, tir, espB, and espD, may indicate the most pathogenic genotype of STEC. A population structure analysis of the profiles of virulence genes statistically supported the pathogenic genotype and, furthermore, revealed that there are serogroups with potentially higher pathogenicity than previously thought. Some strains in serogroups O26, O145, and O165 may have high virulence equivalent to that of serogroup O157. Several serogroups, including O14, O16, O45, O63, O74, 119, O128, and O untypeable, also may be potentially pathogenic, although rarely in humans. PMID- 24068019 TI - Complexity, temporal stability, and clinical correlates of airway bacterial community composition in primary ciliary dyskinesia. AB - Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary function, leading to compromised airway clearance and chronic bacterial infection of the upper and lower airways. The compositions of these infections and the relationships between their characteristics and disease presentation are poorly defined. We describe here the first systematic culture independent evaluation of lower airway bacteriology in PCD. Thirty-three airway samples (26 from sputum, 7 from bronchoalveolar lavage [BAL] fluid) were collected from 24 PCD patients aged 4 to 73 years. 16S rRNA quantitative PCR and pyrosequencing were used to determine the bacterial loads and community compositions of the samples. Bacterial loads, which ranged from 1.3 * 10(4) to 5.2 * 10(9) CFU/ml, were positively correlated with age (P = 0.002) but not lung function. An analysis of ~7,000 16S rRNA sequences per sample identified bacterial species belonging to 128 genera. The concurrently collected paired samples showed high bacterial community similarity. The mean relative abundance of the dominant genera was 64.5% (standard deviation [SD], 24.5), including taxa reported through standard diagnostic microbiology (members of the genera Pseudomonas, Haemophilus, and Streptococcus) and those requiring specific ex vivo growth conditions (members of the genera Prevotella and Porphyromonas). The significant correlations observed included a positive relationship between Pseudomonas aeruginosa relative abundance and age and a negative relationship between P. aeruginosa relative abundance and lung function. Members of the genus Ralstonia were also found to contribute substantially to the bacterial communities in a number of patients. Follow-up samples from a subset of patients revealed high levels of bacterial community temporal stability. The detailed microbiological characterization presented here provides a basis for the reassessment of the clinical management of PCD airway infections. PMID- 24068020 TI - Open-ended song learning in a hummingbird. AB - Vocal learning in birds is typically restricted to a sensitive period early in life, with the few exceptions reported in songbirds and parrots. Here, we present evidence of open-ended vocal learning in a hummingbird, the third avian group with vocal learning. We studied vocalizations at four leks of the long-billed hermit Phaethornis longirostris during a four-year period. Individuals produce a single song repertoire, although several song-types can coexist at a single lek. We found that nine of 49 birds recorded on multiple days (18%) changed their song type between consecutive recordings. Three of these birds replaced song-types twice. Moreover, the earliest estimated age when song replacement occurred ranged from 186 to 547 days (mean = 307 days) and all nine birds who replaced song-types produced a crystallized song before replacement. The findings indicate that song type replacement is distinct from an initial early learning sensitive period. As half of lekking males do not survive past the first year of life in this species, song learning may well extend throughout the lifespan. This behaviour would be convergent to vocal learning programmes found in parrots and songbirds. PMID- 24068021 TI - Humble origins for a successful strategy: complete enrolment in early Cambrian olenellid trilobites. AB - Trilobites are typified by the behavioural and morphological ability to enrol their bodies, most probably as a defence mechanism against adverse environmental conditions or predators. Although most trilobites could enrol at least partially, there is uncertainty about whether olenellids-among the most phylogenetically and stratigraphically basal representatives-could perform this behaviour because of their poorly caudalized trunk and scarcity of coaptative devices. Here, we report complete-but not encapsulating-enrolment for the olenellid genus Mummaspis from the early Cambrian Mural Formation in Alberta, the earliest direct evidence of this strategy in the fossil record of polymerid trilobites. Complete enrolment in olenellids was achieved through a combination of ancestral morphological features, and thus provides new information on the character polarity associated with this key trilobite adaptation. PMID- 24068023 TI - Aortic valve sclerosis in acute coronary syndrome patients : potential value in predicting coronary artery lesion complexity. AB - OBJECTIVE: The purpose of the present study was to investigate the relation between aortic valve sclerosis (AVS) and coronary artery lesion complexity as assessed using the SYNTAX score (SxScore) in acute coronary syndrome (ACS) patients. PATIENTS AND METHODS: A total of 164 patients with a first time diagnosis of acute coronary syndrome were consecutively enrolled. AVS was defined by echocardiography as thickening and calcification of the normal trileaflet aortic valve without obstruction to the left ventricular outflow. The SxScore was calculated using dedicated computer software. RESULTS: There were significantly higher SxScores in subjects with AVS than those without AVS (18 +/- 6 vs 12 +/- 5, p = 0.02). In the univariate analysis, age (p = 0.03) and presence of AVS (p = 0.007) were significantly associated with higher SxScores. Logistic regression analysis demonstrated AVS [95 % confidence interval (CI) 0.17-0.86, p = 0.017] and age (95 % CI 1.01-1.21, p = 0.028) as independent determinants of higher SxScores. CONCLUSION: Aortic valve sclerosis was significantly and independently associated with a high SxScore in acute coronary syndrome patients. PMID- 24068024 TI - [Management of acute myocardial infarction with ST-segment elevation: Update 2013]. AB - This article gives an update on the management of ST-segment elevation myocardial infarction (STEMI) according to guidelines released in 2012 by the European Society of Cardiology. To ensure a reliable diagnosis the updated universal definition of myocardial infarction will also be covered which is defined by myocardial necrosis. Criteria for diagnosis are a rise or fall of cardiac biomarkers, preferably troponin, in conjunction with symptoms of myocardial ischemia, new repolarisation disorders or left bundle branch block, development of pathological Q-waves, new hypokinesia/akinesia or loss in viability or the detection of intracoronary thrombi during cardiac catheterization or autopsy. The current recommendations for primary diagnosis and treatment by the first medical contact will also be discussed and contains decision-making for the optimal reperfusion strategy. Primary percutaneous coronary intervention remains the preferred reperfusion strategy; however, specifications with respect to time for diagnosis and reperfusion have been introduced. Furthermore, establishing a STEMI network has been emphasized in more detail. Special attention is paid to the new antiplatelet agents and anticoagulation therapy where prasugrel and ticagrelor are currently preferred over clopidogrel. PMID- 24068025 TI - Thrombin activatable fibrinolysis inhibitor : its role in slow coronary flow. AB - BACKGROUND: The slow coronary flow (SCF) phenomenon is characterized by slow progression of angiographic contrast medium in the coronary arteries in the absence of stenosis in the epicardial vessels. The pathophysiological mechanisms of SCF phenomenon remain uncertain. Several hypotheses, however, have been suggested for SCF phenomenon, including an early form of atherosclerosis, small vessel dysfunction, dilatation of coronary vessels, imbalance between vasoconstrictor and vasodilatory factors, platelet function disorder, and inflammation. Atherosclerosis and inflammation are the most accepted mechanisms for the pathogenesis of SCF. Thrombin activatable fibrinolysis inhibitor (TAFI) was described as a new inhibitor of fibrinolysis recently and plays an important role in coagulation and fibrinolysis. In previous studies, the role of TAFI was associated with inflammation and evolution of atherosclerosis in coronary artery disease. There are no data available about TAFI levels in patients with SCF phenomenon investigated by angiography. Our goal was to evaluate TAFI antigen (Ag) levels in patients with SCF and to determine the association of the TAFI Ag level with traditional cardiovascular risk factors in our study. METHODS: The study group constituted 41 patients with angiographically confirmed SCF and 46 patients with normal coronary flow as the control group. The TAFI Ag levels of each patient were determined. RESULTS: Between the control and study group, a statistical difference in the levels of TAFI Ag (p < 0.05) was observed. The TAFI Ag level was significantly higher in the SCF group than the control group (132.21 +/- 21.14 versus 122.15 +/- 21.59). CONCLUSION: We have demonstrated that TAFI might be a risk factor for the development of SCF independently of conventional cardiovascular risk factors. In addition, TAFI Ag levels were positively correlated with C-reactive protein (CRP) known as an acute phase reactant. Our findings support the reports of previous studies that increased TAFI levels may be associated with inflammation. Further large studies are required to evaluate the importance of TAFI antigen levels in relation to the development of SCF. PMID- 24068026 TI - Mitochondrial tRNA glutamine variant in hypertrophic cardiomyopathy. AB - BACKGROUND: Mitochondria play critical roles in both the life and death of cardiac myocytes. Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause cardiomyopathies (CMPs). Our aim was to investigate the underlying mitochondrial defect in a patient with hypertrophic cardiomyopathy (hCMP). A detailed clinical and molecular genetic analysis was performed. PATIENTS AND METHODS: Total DNA was extracted from lymphocytes in a 14 year-old index male patient with hCMP, preexcitation syndrome, and severe ventricular arrhythmias. Direct sequencing of the PCR fragments was performed. To distinguish deleterious from functionally neutral variants, the ClustalW program, RNAfold software, and PolyPhen algorithm were applied, which predict the pathogenicity of a particular variant by using a set of empirical rules based on the nature of the mutation, the phylogenetic conservation of the variant, and the physicochemical property of the amino acid. RESULTS: The mutational analysis of mtDNA genes revealed four variants. The m.4395A>G transition (C6G) in the MT-TQ gene, which altered an evolutionary conserved nucleotide, with a conservation index of 85.7 % and affected a highly conserved U.G base pair in the secondary structure of MT-TQ. Additionally, the previously reported polymorphisms m.14757T>A, m.15236A>G, and m.15314G>A resulting in the replacement of amino acid residues in the MT-CYB gene were detected. CONCLUSION: The m.4395A>G variant was scored as possibly pathogenic and may exert a negative effect on heart function to generate hCMP. PMID- 24068027 TI - Cardiomyopathy due to pheochromocytoma. AB - Alpha 33-year-old woman was admitted to our clinic with electrocardiographic (ECG) manifestations of anterior ST-elevation myocardial infarction, dizziness, weakness, and feeling of oncoming collapse. She underwent coronary angiography that showed normal coronary arteries and an echocardiography study that showed reduced left ventricular contractility with diffuse hypokinesis and an estimated ejection fraction of (EF) 35-40 %. The biochemical testing showed enzymatic activity typical of myocardial necrosis. The patient had hypertensive peaks on a 24-h recording of blood pressure, while immunological and virological test results were negative. Magnetic resonance imaging showed partial epicardial enhancement. A tumor in the right adrenal medulla was detected with computed tomography, and biochemical testing showed increased levels of urinary vanillylmandelic acid as well as serum metanephrines. The diagnosis of pheochromocytoma was made and confirmed by histological findings after surgical resection of the tumor. The left ventricular systolic dysfunction gradually reversed, the EF returned to normal, and the ECG findings were normalized, indicating cardiomyopathy due to pheochromocytoma. PMID- 24068028 TI - Unexpected occurrence of cardiac tamponade following temporary pacemaker lead extraction. PMID- 24068029 TI - Pseudoaneurysm of the radial artery following coronary angiography. PMID- 24068030 TI - [Carotid artery stenting technique]. AB - Over the past 25 years carotid artery stenting (CAS) has emerged as an alternative to carotid endarterectomy (CEA). Most of all younger patients and symptomatic patients with contralateral carotid artery occlusion particularly benefit from CAS. To achieve an optimal result with CAS, patient selection and even more important, knowledge and experience of the interventionist is crucial. The periprocedural complication rate of CAS in large experienced centers is lower (2-3%) than those in randomized trials. Several different devices are now available which allow the procedure to be tailored according to patient anatomy and lesion complexity. Complications like hyperperfusion syndrome and intracerebral bleeding, rupture of side branches of the external or internal carotid artery as well as problems caused by slow flow can be widely avoided by adequate experience. PMID- 24068031 TI - [GeCAS registry. Sense and purpose of a carotid percutaneous transluminal angioplasty register in the era of obligatory quality assurance]. AB - Clinical registries have become increasingly more important tools for scientists as well as for medical admission boards worldwide during recent years due to the ability to investigate the safety and efficacy of a therapeutic method in the general population under real world conditions. The clinical benefit of current registry data seems to be particularly high in a treatment method, such as carotid artery stenting (CAS) where safety and efficacy, especially in daily clinical practice, could not be totally clarified by several randomized clinical trials (RCT). For this reason the new multidisciplinary, multicenter and prospective German Carotid Artery Registry (GeCAS) was founded in January 2011 for continuing quality control in CAS in clinical practice in Germany. The GeCAS registry is a fusion of two large German CAS registries, the ALKK-CAS registry and the PROCAS registry, which were conducted by cardiologists, angiologists and radiologists and operated from 1996 until December 2010. However, a general duty of documentation (BQS) of every CAS procedure exists throughout Germany since January 2012. In contrast to optional documentation of CAS within the GeCAS registry, the nationwide and obligatory documentation is strictly focused on the main issues, such as indications and between hospital comparisons of outcome of patients. In the GeCAS registry data collection is generally more extensive and also includes a 30-day and 10-year follow-up. Compared to the BQS institute, benchmarking reports of GeCAS are more detailed and are made available to every participating hospital on a biannual basis. This generates an image of the current reality of CAS in Germany in addition to the nationwide obligatory documentation. Furthermore, data of the GeCAS registry is the basis for research work (e.g. publications and presentations), for generating new hypotheses and for technical development in CAS in Germany. Consequently, the existence of a multicenter and multidisciplinary CAS registry, such as the GeCAS registry, is considered necessary and medically useful. PMID- 24068032 TI - [Carotid interventions: pro and contra]. PMID- 24068033 TI - Proteome modulation in H9c2 cardiac cells by microRNAs miR-378 and miR-378. AB - MicroRNAs are a novel class of powerful endogenous regulators of gene expression. MiR-378 and miR-378* are localized in the first intron of the Ppargc1b gene that codes the transcriptional co-activator PGC-1beta. The latter regulates energy expenditure as well as mitochondrial biogenesis. The miR-378:miR-378* hairpin is highly expressed in cardiac cells. To better assess their role in cardiomyocytes, we identified miR-378 and miR-378* targets via a proteomic screen. We established H9c2 cellular models of overexpression of miR-378 and miR-378* and identified a total of 86 down-regulated proteins in the presence of either one of these miRs. Functional annotation clustering showed that miR-378 and miR-378* regulate related pathways in cardiomyocytes, including energy metabolism, notably glycolysis, cytoskeleton, notably actin filaments and muscle contraction. Using bioinformatics algorithms we found that 20 proteins were predicted as direct targets of the miRs. We validated eight of these targets by quantitative RT-PCR and luciferase reporter assay. We found that miR-378 targets lactate dehydrogenase A and impacts on cell proliferation and survival whereas miR-378* targets cytoskeleton proteins actin and vimentin. Proteins involved in endoplasmic reticulum stress response such as chaperone and/or calcium buffering proteins GRP78, PPIA (cyclophilin A), calumenin, and GMMPA involved in glycosylation are repressed by these miRs. Our results show that the miR-378/378* hairpin establishes a connection among energy metabolism, cytoskeleton remodeling, and endoplasmic reticulum function through post-transcriptional regulation of key proteins involved in theses pathways. PMID- 24068034 TI - FPSAC: fast phylogenetic scaffolding of ancient contigs. AB - MOTIVATIONS: Recent progress in ancient DNA sequencing technologies and protocols has lead to the sequencing of whole ancient bacterial genomes, as illustrated by the recent sequence of the Yersinia pestis strain that caused the Black Death pandemic. However, sequencing ancient genomes raises specific problems, because of the decay and fragmentation of ancient DNA among others, making the scaffolding of ancient contigs challenging. RESULTS: We show that computational paleogenomics methods aimed at reconstructing the organization of ancestral genomes from the comparison of extant genomes can be adapted to correct, order and orient ancient bacterial contigs. We describe the method FPSAC (fast phylogenetic scaffolding of ancient contigs) and apply it on a set of 2134 ancient contigs assembled from the recently sequenced Black Death agent genome. We obtain a unique scaffold for the whole chromosome of this ancient genome that allows to gain precise insights into the structural evolution of the Yersinia clade. PMID- 24068035 TI - BlastGraph: a comparative genomics tool based on BLAST and graph algorithms. AB - BlastGraph is an interactive Java program for comparative genome analysis based on Basic Local Alignment Search Tool (BLAST), graph clustering and data visualization. The software generates clusters of sequences of multiple genomes from all-to-all BLAST results and visualizes the results in graph plots together with related information such as sequence features, gene conservation and similarity relationships. Pruning algorithms are used to reduce results to more meaningful subclusters. Subsequent analyses can then be conducted based on the predicted clusters, including gene content, genome phylogenetics and gene gain and loss. AVAILABILITY AND IMPLEMENTATION: https://github.com/bigwiv/BlastGraph. PMID- 24068036 TI - Influence of surgical and minimally invasive facial cosmetic procedures on psychosocial outcomes: a systematic review. AB - IMPORTANCE: Millions of surgical and minimally invasive cosmetic procedures of the face are performed each year, but objective clinical measures that evaluate surgical procedures, such as complication rates, have limited utility when applied to cosmetic procedures. While there may be subjective improvements in appearance, it is important to determine if these interventions have an impact on patients in other realms such as psychosocial functioning. This is particularly important in light of the Patient Protection and Affordable Care Act and its emphasis on patient-centered outcomes and effectiveness. OBJECTIVES: To review the literature investigating the impact of facial cosmetic surgery and minimally invasive procedures on relevant psychological variables to guide clinical practice and set norms for clinical performance. EVIDENCE REVIEW: English language randomized clinical trials and prospective cohort studies that preoperatively and postoperatively assessed psychological variables in at least 10 patients seeking surgical or minimally invasive cosmetic procedures of the face. FINDINGS: Only 1 study investigating minimally invasive procedures was identified. Most studies reported modest improvement in psychosocial functioning, which included quality of life, self-esteem, and body image. Unfortunately, the overall quality of evidence is limited owing to an absence of control groups, short follow-up periods, or loss to follow-up. CONCLUSIONS AND RELEVANCE: The current literature suggests that a number of psychosocial domains may improve following facial cosmetic surgery, although the quality of this evidence is limited (grade of recommendation 2A). Despite the dramatic rise in nonsurgical cosmetic procedures, there is a paucity of information regarding the impact of chemodenervation and soft-tissue augmentation on psychosocial functioning. PMID- 24068037 TI - Genotoxic and carcinogenic potential of engineered nanoparticles: an update. AB - Nanoscience and nanotechnology have seen an exponential growth over the past decade largely due to the unique properties of engineered nanoparticles (ENPs), advances in ENP synthesis, and imaging or analysis tools. The unique properties such as high surface area to volume ratio, abundant reactive sites on the surface, large fraction of atoms located on the exterior face have made these novel materials the most sought after for consumer and industrial applications. This significant increase in the ENP containing consumer products has also enhanced the chances of human and environmental exposure. Humans get exposed to ENPs at various steps of its synthesis (laboratory), manufacture (industry), use (consumer products, devices, medicines, etc.) and through the environment (contaminated water, aerosolized particles, and disposal). Such exposures to ENPs are known to induce genotoxicity, cytotoxicity, and carcinogenicity in biological system. This is attributed to several factors, such as direct interaction of ENPs with the genetic material, indirect damage due to reactive oxygen species generation, release of toxic ions from soluble ENPs, interaction with cytoplasmic/nuclear proteins, binding with mitotic spindle or its components, increased oxidative stress, disturbance of cell cycle checkpoint functions, inhibition of antioxidant defense, and many others. The present review describes an overview of in vitro and in vivo genotoxicity studies with ENPs, advantages and potential problems associated with the methods used in genotoxicity assessment, and the need for appropriate method and approach for risk assessment of ENPs. PMID- 24068038 TI - Arsenic-induced cancer cell phenotype in human breast epithelia is estrogen receptor-independent but involves aromatase activation. AB - Accumulating data suggest arsenic may be an endocrine disruptor and tentatively linked to breast cancer by some studies. Therefore, we tested the effects of chronic inorganic arsenic exposure on the normal estrogen receptor (ER)-negative breast epithelial cell line, MCF-10A. Cells were chronically exposed to a low level arsenite (500 nM) for up to 24 weeks. Markers of cancer cell phenotype and the expression of critical genes relevant to breast cancer or stem cells (SCs) were examined. After 24 weeks, chronic arsenic-exposed breast epithelial (CABE) cells showed increases in secreted MMP activity, colony formation, invasion, and proliferation rate, indicating an acquired cancer cell phenotype. These CABE cells presented with basal-like breast cancer characteristics, including ER alpha, HER-2, and progesterone receptor negativity, and overexpression of K5 and p63. Putative CD44(+)/CD24(-/low) breast SCs were increased to 80 % over control in CABE cells. CABE cells also formed multilayer cell mounds, indicative of loss of contact inhibition. These mounds showed high levels of K5 and p63, indicating the potential presence of cancer stem cells (CSCs). Epithelial-to-mesenchymal transition occurred during arsenic exposure. Overexpression of aromatase, a key rate-limiting enzyme in estrogen synthesis, occurred with arsenic starting early on in exposure. Levels of 17beta-estradiol increased in CABE cells and their conditioned medium. The aromatase inhibitor letrozole abolished arsenic-induced increases in 17beta-estradiol production and reversed cancer cell phenotype. Thus, chronic arsenic exposure drives human breast epithelia into a cancer cell phenotype with an apparent overabundance of putative CSCs. Arsenic appears to transform breast epithelia through overexpression of aromatase, thereby activating oncogenic processes independent of ER. PMID- 24068039 TI - ERK pathway is activated in bare-FeNPs-induced autophagy. AB - Iron oxide nanoparticles (FeNPs) are known to be one of the most biocompatible and safe nanoparticles. However, their long-term persistence remains a problem, and macrophages play as an important mediator in continuous stimulation of the immune system due to biopersistence of nanoparticles. In the present study, we identified the mechanisms underlying the uptake and toxicity of bare-FeNPs using RAW264.7 cells, a mouse peritoneal macrophage cell line. The bare-FeNPs penetrated the cell membrane through electrostatic interactions together with the general phagocytic pathway. At 24 h after exposure, they distributed freely in the cytosol or within autophagosome-like vacuoles. Bare-FeNPs induced decrease in the cell viability along with the cell cycle arrest in G1 phase. In addition, they increased the generation of ROS and the secretion of NO and TNF alpha as well as the expression of SOD-1 and SOD-2 proteins, which are an antioxidant. While the mitochondrial calcium level, the intensity of labeled mitochondria, and ATP production decreased, the levels of autophagy-related proteins such as p62, beclin 1, ATG5, and LC3B increased in a dose-dependent manner together with the levels of ATF 3, p-EGFR, and p-ERK proteins. However, the level of p-JNK protein clearly decreased. TEM images also showed that damaged organelle exist within autophagosome-like vacuoles with bare-FeNPs. On the basis of these results, we suggest that bare-FeNPs induce autophagy by initiating oxidative stress in RAW264.7 cells. Furthermore, ERK, but not JNK, pathway is activated in bare-FeNPs induced autophagy. PMID- 24068040 TI - Commentary to Gebel 2012: A quantitative review should apply meta-analytical methods-and this applies also to quantitative toxicological reviews. AB - Gebel (In Arch Toxicol 87(5):923-924, 2013) replied to my Letter to the Editor (Morfeld in Arch Toxicol 87(5):921, 2013) in which I criticized the quantitative review of inhalation rat studies on the association of granular biopersistent dust exposures and lung cancer risk (Gebel in Arch Toxicol 86(7):995-1007, 2012). My methodological comments were not understood. The Editors of the Archives invited me to detail and substantiate my criticism. The main issues are as follows: (1) A quantitative summary of the study results was performed without weighting for precision of the single studies (the published unweighted synthesis is potentially biased). (2) No heterogeneity assessment was performed before combining the findings (it is unclear whether overall summaries are sensible). (3) Correlation coefficients were used (correlations are distorted estimates of exposure-response and misleading). (4) An incomplete input data table was published (no transparent reporting, no replication possible for the reader). The quantitative synthesis by Gebel (In Arch Toxicol 86(7):995-1007, 2012) does not fulfil the usual requirements of a scientific quantitative review and should be replaced by an appropriate meta-analysis. PMID- 24068041 TI - Tryblionella persuadens comb. nov. (Bacillariaceae, Diatomeae): new observations on frustule morphology of a seldom recorded diatom. AB - The species originally described from brackish waters of the Venetian Lagoon as Nitzschia persuadens is a diatom rarely cited in the literature since its proposition and it is here recorded for the first time in a freshwater environment in South America. Morphological features of this species, such valve slightly panduriform, with a longitudinal straight fold of the valve face, poroidal areolae, and strongly eccentric raphe system clearly assign this species to Tryblionella, and the transfer was made. Here we present new observations on the frustule morphology and comparisons with related species. Light and scanning electron microscopy data of Tryblionella persuadens comb. nov. from Cachoeira River, Northeastern Brazil are documented. PMID- 24068042 TI - Morphology and anatomy of the diaspores and seedling of Paspalum (Poaceae, Poales). AB - The knowledge regarding of the diaspore and post-seminal development of Paspalum L. is important for grassland biodiversity conservation, based on their representativeness and genetic improvement of forage. The morphology of the diaspore and the post-seminal development of Paspalum dilatatum Poir. (rhizomatous), P. mandiocanum Trin. var. subaequiglume Barreto (stoloniferous), P. pumilum Nees. (decumbent caespitose) and P. urvillei Steud. (erect caespitose) was described to distinguish species with different growth forms and to survey the characters useful for taxonomy. P. dilatatum differs by presenting oval diaspores larger than the others, with five prominent nerves and trichomes; P. urvillei presents diaspores with one central nerve that is more developed than the two lateral nerves and trichomes; P. mandiocanum var. subaequiglume presents diaspores with trichomes only in the margin; and P. pumilum differs by presenting glabrous diaspores. The caryopsis involves the seed that presents the differentiated embryo and disposed laterally, an elliptical hilum in all of the studied species and a rostellum in P. dilatatum and P. mandiocanum var. subaequiglume. The post-seminal development is similar in the four species and begins with germination that is marked by the emergence of the coleorhiza, followed by the coleoptile. These characteristics are common to other Poaceae previously studied, indicating a pattern to the family and do not distinguish the growth forms. PMID- 24068043 TI - Straightforward synthesis of novel cyclic metallasiloxanes supported by an N,C,N chelating ligand. AB - The reaction of an N,C,N-intramolecularly coordinated tin(IV) carbonate LSn(Ph)(CO3) (1) and antimony(III) and bismuth(III) oxides (LMO)2 (where M = Sb (2), Bi (3) and L = C6H3-2,6-(CH2NMe2)2) with (HO)SiPh2(O)SiPh2(OH) in 1 : 1 (in the case of 1) or 1 : 2 molar ratio (in the cases of 2 and 3) gave the metallasiloxanes cyclo-LSn(Ph)(OSiPh2)2O (4) and cyclo-LM(OSiPh2)2O (where M = Sb (6) and Bi (7)) containing six-membered MSi2O3 rings. Alternatively, the compounds 4, 6 and 7 can be also prepared reacting Ph2Si(OH)2 and compounds 1, 2 and 3, respectively, in the molar ratio of either 2 : 1 (for 4) or 4 : 1 (for 6 and 7). The reaction of Ph2Si(OH)2 with 1 in 1 : 1 molar ratio gave cyclo Ph2Si(OSnL(Ph)O)2SiPh2 (5) containing an eight-membered Sn2Si2O4 stannasiloxane ring. The analogous eight-membered stibasiloxane derivative cyclo Ph2Si(OSbLO)2SiPh2 (8) was obtained as well, while attempts to synthesize the bismuth analogue failed. Compounds 1-3 react with the siloxane cyclo-(Me2SiO)3 providing either eight-membered metallasiloxanes cyclo-LSn(Ph)(OSiMe2O)2SiMe2 (9) and cyclo-LSb(OSiMe2O)2SiMe2 (10) or the six-membered bismutasiloxane cyclo LBi(OSiMe2)2O (11). All compounds were characterized with the help of elemental analysis, (1)H, (13)C, (29)Si and (119)Sn NMR spectroscopy, and single crystal X ray diffraction analyses (except 9 and 10). PMID- 24068044 TI - Aquaporins in avian kidneys: function and perspectives. AB - For terrestrial vertebrates, water economy is a prerequisite for survival, and the kidney is their major osmoregulatory organ. Birds are the only vertebrates other than mammals that can concentrate urine in adaptation to terrestrial environments. Aquaporin (AQP) and glyceroporin (GLP) are phylogenetically old molecules and have been found in plants, microbial organisms, invertebrates, and vertebrates. Currently, 13 AQPs/aquaGLPs and isoforms are known to be present in mammals. AQPs 1, 2, 3, 4, 6, 7, 8, and 11 are expressed in the kidney; of these, AQPs 1, 2, 3, 4, and 7 are shown to be involved in fluid homeostasis. In avian kidneys, AQPs 1, 2, 3, and 4 have been identified and characterized. Also, gene and/or amino acid sequences of AQP5, AQP7, AQP8, AQP9, AQP11, and AQP12 have been reported in birds. AQPs 2 and 3 are expressed along cortical and medullary collecting ducts (CDs) and are responsible, respectively, for the water inflow and outflow of CD epithelial cells. While AQP4 plays an important role in water exit in the CD of mammalian kidneys, it is unlikely to participate in water outflow in avian CDs. This review summarizes current knowledge on structure and function of avian AQPs and compares them to those in mammalian and nonmammalian vertebrates. Also, we aim to provide input into, and perspectives on, the role of renal AQPs in body water homeostasis during ontogenic and phylogenetic advancement. PMID- 24068046 TI - Postnatal shifts in ischemic tolerance and cell survival signaling in murine myocardium. AB - The immature heart is known to be resistant to ischemia-reperfusion (I/R) injury; however, key proteins engaged in phospho-dependent signaling pathways crucial to cell survival are not yet defined. Our goal was to determine the postnatal changes in myocardial tolerance to I/R, including baseline expression of key proteins governing I/R tolerance and their phosphorylation during I/R. Hearts from male C57Bl/6 mice (neonates, 2, 4, 8, and 12 wk of age, n = 6/group) were assayed for survival signaling/effectors [Akt, p38MAPK, glycogen synthase kinase 3beta (GSK-3beta), heat shock protein 27 (HSP27), connexin-43, hypoxia-inducible factor-1alpha (HIF-1alpha), and caveolin-3] and regulators of apoptosis (Bax and Bcl-2) and autophagy (LC3B, Parkin, and Beclin1). The effect of I/R on ventricular function was measured in isolated perfused hearts from immature (4 wk) and adult (12 wk) mice. The neonatal myocardium exhibits a large pool of inactive Akt; high phospho-activation of p38MAPK, HSP27 and connexin-43; phospho inhibition of GSK-3beta; and high expression of caveolin-3, HIF-1alpha, LC3B, Beclin1, Bax, and Bcl-2. Immature hearts sustained less dysfunction and infarction following I/R than adults. Emergence of I/R intolerance in adult vs. immature hearts was associated with complex proteomic changes: decreased expression of Akt, Bax, and Bcl-2; increased GSK-3beta, connexin-43, HIF-1alpha, LC3B, and Bax:Bcl-2; enhanced postischemic HIF-1alpha, caveolin-3, Bax, and Bcl 2; and greater postischemic GSK-3beta and HSP27 phosphorylation. Neonatal myocardial stress resistance reflects high expression of prosurvival and autophagy proteins and apoptotic regulators. Notably, there is high phosphorylation of GSK-3beta, p38MAPK, and HSP27 and low phosphorylation of Akt (high Akt "reserve"). Subsequent maturation-related reductions in I/R tolerance are associated with reductions in Akt, Bcl-2, LC3B, and Beclin1, despite increased expression and reduced phospho-inhibition of GSK-3beta. PMID- 24068045 TI - Loss of neurotrophin-3 from smooth muscle disrupts vagal gastrointestinal afferent signaling and satiation. AB - A large proportion of vagal afferents are dependent on neurotrophin-3 (NT-3) for survival. NT-3 is expressed in developing gastrointestinal (GI) smooth muscle, a tissue densely innervated by vagal mechanoreceptors, and thus could regulate their survival. We genetically ablated NT-3 from developing GI smooth muscle and examined the pattern of loss of NT-3 expression in the GI tract and whether this loss altered vagal afferent signaling or feeding behavior. Meal-induced c-Fos activation was reduced in the solitary tract nucleus and area postrema in mice with a smooth muscle-specific NT-3 knockout (SM-NT-3(KO)) compared with controls, suggesting a decrease in vagal afferent signaling. Daily food intake and body weight of SM-NT-3(KO) mice and controls were similar. Meal pattern analysis revealed that mutants, however, had increases in average and total daily meal duration compared with controls. Mutants maintained normal meal size by decreasing eating rate compared with controls. Although microstructural analysis did not reveal a decrease in the rate of decay of eating in SM-NT-3(KO) mice, they ate continuously during the 30-min meal, whereas controls terminated feeding after 22 min. This led to a 74% increase in first daily meal size of SM-NT-3(KO) mice compared with controls. The increases in meal duration and first meal size of SM-NT-3(KO) mice are consistent with reduced satiation signaling by vagal afferents. This is the first demonstration of a role for GI NT-3 in short-term controls of feeding, most likely involving effects on development of vagal GI afferents that regulate satiation. PMID- 24068047 TI - Norepinephrine increases NADPH oxidase-derived superoxide in human peripheral blood mononuclear cells via alpha-adrenergic receptors. AB - Many diseases associated with sympathoexcitation also exhibit elevated reactive oxygen species (ROS). A recent animal study indicated that exogenous administration of the sympathetic neurotransmitter norepinephrine (NE) increased systemic ROS via circulating leukocytes. The mechanisms contributing to this effect of NE and whether these findings can be translated to humans is unknown. Thus we tested the hypothesis that NE increases superoxide production in human peripheral blood mononuclear cells (PBMCs) via NADPH oxidase. Primary human PBMCs were freshly isolated from healthy young men and placed in culture. After NE (50 pg/ml, 50 ng/ml, and 50 MUg/ml concentrations) or control treatments, NADPH oxidase mRNA expression (gp91(phox), p22(phox), and p67(phox)) was assessed using real-time RT-PCR, and intracellular superoxide production was measured using dihydroethidium fluorescence. PBMCs were also treated with selective adrenergic agonists-antagonists to determine the receptor population involved. In addition, CD14(+) monocyte-endothelial cell adhesion was determined using a fluorescent based assay. NE significantly increased NADPH oxidase gene expression and intracellular superoxide production in a time-dependent manner (superoxide: 0.9 +/- 0.2 fold, 6 h vs. 3.0 +/- 0.3 fold, 36 h; NE, 50 MUg/ml; P < 0.05). The sustained increase in NE-induced superoxide production was primarily mediated via alpha-adrenergic receptors, preferentially alpha2-receptors. The NADPH oxidase blocker diphenylene iodonium and protein kinase C inhibitor Staurosporine significantly attenuated NE-induced increases in superoxide production. Importantly, NE treatment increased CD14(+) monocyte-endothelial cell adhesion. These findings indicate for the first time that NE increases superoxide production in freshly isolated primary human PBMCs via NADPH oxidase through alpha-adrenergic receptors, an effect facilitating monocyte adhesion to the endothelium. PMID- 24068048 TI - Muscle metabolic responses during high-intensity intermittent exercise measured by (31)P-MRS: relationship to the critical power concept. AB - We investigated the responses of intramuscular phosphate-linked metabolites and pH (as assessed by (31)P-MRS) during intermittent high-intensity exercise protocols performed with different recovery-interval durations. Following estimation of the parameters of the power-duration relationship, i.e., the critical power (CP) and curvature constant (W'), for severe-intensity constant power exercise, nine male subjects completed three intermittent exercise protocols to exhaustion where periods of high-intensity constant-power exercise (60 s) were separated by different durations of passive recovery (18 s, 30 s and 48 s). The tolerable duration of exercise was 304 +/- 68 s, 516 +/- 142 s, and 847 +/- 240 s for the 18-s, 30-s, and 48-s recovery protocols, respectively (P < 0.05). The work done >CP (W>CP) was significantly greater for all intermittent protocols compared with the subjects' W', and this difference became progressively greater as recovery-interval duration was increased. The restoration of intramuscular phosphocreatine concentration during recovery was greatest, intermediate, and least for 48 s, 30 s, and 18 s of recovery, respectively (P < 0.05). The W>CP in excess of W' increased with greater durations of recovery, and this was correlated with the mean magnitude of muscle phosphocreatine reconstitution between work intervals (r = 0.61; P < 0.01). The results of this study show that during intermittent high-intensity exercise, recovery intervals allow intramuscular homeostasis to be restored, with the degree of restoration being related to the duration of the recovery interval. Consequently, and consistent with the intermittent CP model, the ability to perform W>CP during intermittent high-intensity exercise and, therefore, exercise tolerance, increases when recovery-interval duration is extended. PMID- 24068049 TI - Chronic vasodilation increases renal medullary PDE5A and alpha-ENaC through independent renin-angiotensin-aldosterone system pathways. AB - We have previously observed that many of the renal and hemodynamic adaptations seen in normal pregnancy can be induced in virgin female rats by chronic systemic vasodilation. Fourteen-day vasodilation with sodium nitrite or nifedipine (NIF) produced plasma volume expansion (PVE), hemodilution, and increased renal medullary phosphodiesterase 5A (PDE5A) protein. The present study examined the role of the renin-angiotensin-aldosterone system (RAAS) in this mechanism. Virgin females were treated for 14 days with NIF (10 mg.kg(-1).day(-1) via diet), NIF with spironolactone [SPR; mineralocorticoid receptor (MR) blocker, 200-300 mg.kg( 1).day(-1) via diet], NIF with losartan [LOS; angiotensin type 1 (AT1) receptor blocker, 20 mg.kg(-1).day(-1) via diet], enalapril (ENAL; angiotensin-converting enzyme inhibitor, 62.5 mg/l via water), or vehicle (CON). Mean arterial pressure (MAP) was reduced 7.4 +/- 0.5% with NIF, 6.33 +/- 0.5% with NIF + SPR, 13.3 +/- 0.9% with NIF + LOS, and 12.0 +/- 0.4% with ENAL vs. baseline MAP. Compared with CON (3.6 +/- 0.3%), plasma volume factored for body weight was increased by NIF (5.2 +/- 0.4%) treatment but not by NIF + SPR (4.3 +/- 0.3%), NIF + LOS (3.6 +/- 0.1%), or ENAL (4.0 +/- 0.3%). NIF increased PDE5A protein abundance in the renal inner medulla, and SPR did not prevent this increase (188 +/- 16 and 204 +/- 22% of CON, respectively). NIF increased the alpha-subunit of the epithelial sodium channel (alpha-ENaC) protein in renal outer (365 +/- 44%) and inner (526 +/- 83%) medulla, and SPR prevented these changes. There was no change in either PDE5A or alpha-ENaC abundance vs. CON in rats treated with NIF + LOS or ENAL. These data indicate that the PVE and renal medullary adaptations in response to chronic vasodilation result from RAAS signaling, with increases in PDE5A mediated through AT1 receptor and alpha-ENaC through the MR. PMID- 24068050 TI - Protection of signal processing at low temperature in baroreceptive neurons in the nucleus tractus solitarius of Syrian hamsters, a hibernating species. AB - We previously described synaptic currents between baroreceptor fibers and second order neurons in the nucleus tractus solitarius (NTS) that were larger in Syrian hamsters than in rats. This suggested that although electrical activity throughout the hamster brain decreased as brain temperature declined, the greater synaptic input to its NTS would support continued operation of cardiorespiratory reflexes at low body temperatures. Here, we focused on properties that would protect these neurons against potential damage from the larger synaptic inputs, testing the hypotheses that hamster NTS neurons exhibit: 1) intrinsic N-methyl-D aspartate receptor (NMDAR) properties that limit Ca(2+) influx to a greater degree than do rat NTS neurons and 2) properties that reduce gating signals to NMDARs to a greater degree than in rat NTS neurons. Whole cell patch-clamp recordings on anatomically identified second-order NTS baroreceptive neurons showed that NMDAR-mediated synaptic currents between sensory fibers and second order NTS neurons were larger in hamsters than in rats at 33 degrees C and 15 degrees C, with no difference in their permeability to Ca(2+). However, at 15 degrees C, but not at 33 degrees C, non-NMDAR currents evoked by glutamate released from baroreceptor fibers had significantly shorter durations in hamsters than in rats. Thus, hamster NMDARs did not exhibit lower Ca(2+) influx than did rats (negating hypothesis 1), but they did exhibit significant differences in non NMDAR neuronal properties at low temperature (consistent with hypothesis 2). The latter (shorter duration of non-NMDAR currents) would likely limit NMDAR coincidence gating and may help protect hamster NTS neurons, enabling them to contribute to signal processing at low body temperatures. PMID- 24068052 TI - Jules Bordet (1870-1961): pioneer of immunology. PMID- 24068051 TI - Ascorbate infusion increases skeletal muscle fatigue resistance in patients with chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is associated with systemic oxidative stress and skeletal muscle dysfunction. The purpose of this study was to examine the impact of intravenous ascorbate administration (AO) on biological markers of antioxidant capacity and oxidative stress, and subsequently skeletal muscle function during dynamic, small muscle mass exercise in patients with COPD. Ten patients with spirometric evidence of COPD performed single-leg knee extensor (KE) trials matched for intensity and time (isotime) following intravenous ascorbate (2 g) or saline infusion (PL). Quadriceps fatigue was quantified by changes in force elicited by maximal voluntary contraction (MVC) and magnetic femoral nerve stimulation (Qtw,pot). AO administration significantly increased antioxidant capacity, as measured by the ferric-reducing ability of plasma (PL: 1 +/- 0.1 vs. AO: 5 +/- 0.2 mM), and significantly reduced malondialdehyde levels (PL: 1.16 +/- 0.1 vs. AO: 0.97 +/- 0.1 mmol). Additionally, resting blood pressure was significantly reduced (PL: 104 +/- 4 vs. AO: 93 +/- 6 mmHg) and resting femoral vascular conductance was significantly elevated after AO (PL: 2.4 +/- 0.2 vs. AO: 3.6 +/- 0.4 ml.min(-1).mmHg(-1)). During isotime exercise, the AO significantly attenuated both the ventilatory and metabolic responses, and patients accumulated significantly less peripheral quadriceps fatigue, as illustrated by less of a fall in MVC (PL: -11 +/- 2% vs. AO: -5 +/- 1%) and Qtw,pot (PL: -37 +/- 1% vs. AO: -30 +/- 2%). These data demonstrate a beneficial role of AO administration on skeletal muscle fatigue in patients with COPD and further implicate systemic oxidative stress as a causative factor in the skeletal muscle dysfunction observed in this population. PMID- 24068053 TI - Postnatal depression: a family medicine perspective. AB - The prevalence of postnatal depression (PND) was reported to be 6.8% in an obstetric setting in Singapore. Since primary care physicians are the healthcare clinicians most likely to interact with postnatal mothers in Singapore, they are in the best position to screen for PND and help new mothers. PND affects the well being of the mother, her baby and those around her. If left untreated, depression can result in lasting adverse outcomes such as unfavourable parenting practices, impaired mother-infant bonding, impaired intellectual and emotional development of the infant, maternal suicide, and even infanticide. The Edinburgh Postnatal Depression Scale and the Patient Health Questionnaire-2 are effective screening tools that can be easily used in primary care settings for screening at-risk mothers. Herein, we discuss the management options available in primary care settings, as well as share some local resources available to mothers and the benefits of timely intervention. PMID- 24068054 TI - Diagnosis of prostate adenoma and the relationship between the site of prostate adenoma and bladder outlet obstruction. AB - INTRODUCTION: The objective of this study was to evaluate the accuracy of using intravesical prostatic protrusion (IPP) as a parameter for the diagnosis of prostate adenoma (PA), as well as to determine the relationship between the site of PA and bladder outlet obstruction. IPP was determined with the use of transabdominal ultrasonography (TAUS). METHODS: A total of 77 consecutive adult men aged 30-85 years with haematuria or undergoing checkup for bladder tumour were enrolled. International Prostate Symptom Score (IPSS), and the results of uroflowmetry, TAUS and cystourethroscopy were assessed. All cases of IPP were classified into grades 0 (no IPP), 1 (1-5 mm), 2 (6-10 mm) or 3 (> 10 mm). PA diagnosis was confirmed using flexible cystourethroscopy. The sites of PA were classified as U0 (no adenoma), U1 (lateral lobes), U2 (middle lobe) or U3 (lateral and middle lobes). RESULTS: Of the 77 patients, 11 (14.3%) had no IPP. PA was confirmed using cystourethroscopy for all patients with IPP and for 7 of the 11 patients without IPP. Of the 37 patients with prostate volume < 20 g, 29 (78.4%) had IPP. Sensitivity, specificity, as well as positive and negative predictive values for diagnosing PA using only IPP were 90.4%, 100.0%, 100.0% and 36.4%, respectively. Higher sensitivity (95.9%) and negative predictive value (50.0%) were obtained when PA was used together with peak urinary flow rate (Qmax) < 20.0 mL/s. The mean Qmax of patients classified as U1 (n = 39) was 16.0 mL/s, while the mean Qmax in those classified as U2 (n = 12) and U3 (n = 22) was 11.9 mL/s and 8.9 mL/s, respectively. CONCLUSION: All patients with IPP had PA, and PA in the middle lobe was more obstructive than those in lateral lobes. Patients without IPP may still have PA. PMID- 24068055 TI - Nonimmune hydrops fetalis in a children's hospital: a six-year series. AB - INTRODUCTION: We aimed to study the profile of nonimmune hydrops fetalis (NIHF) in the local population and identify its outcomes and causes. METHODS: We carried out a retrospective review of the medical records in KK Women's and Children's hospital, a single tertiary referral centre, for pregnancies with an antenatal diagnosis of NIHF in the six-year period from 1 January 2005 to 31 December 2010. RESULTS: A total of 29 cases of NIHF were identified; 19 (66%) cases underwent karyotype evaluation, 17 (59%) underwent intrauterine infection screening, and all underwent antenatal thalassaemia screening. The median gestational age at diagnosis was 27 (range 12-37) weeks, median gestational age at birth was 33 (range 27-37) weeks, and median birth weight of live births was 2,480 (range 1,230-3,900) g. The aetiologies for NIHF were identified in 20 (69%) cases, which included cardiac anomalies (n = 5), haematological problems (n = 4), congenital tumours (n = 4), genetic/metabolic disorders (n = 4) and cystic hygromas (n = 3). The cause of NIHF was not identified in the remaining 9 (31%) cases. There were 19 live births - 8 (42%) survived and 11 (58%) died in the neonatal period - and one stillbirth. Nine women opted for medical termination of pregnancy following the diagnosis of NIHF. CONCLUSION: It is important to thoroughly investigate all cases of NIHF and identify its causes in order to provide appropriate antenatal and postnatal counselling. In our series, almost one-third of NIHF cases had no identified aetiology. The neonatal mortality rate was approximately 58%. PMID- 24068056 TI - Deliberate self-harm in adolescent psychiatric outpatients in Singapore: prevalence and associated risk factors. AB - INTRODUCTION: Deliberate self-harm (DSH) is frequently seen in adolescents with a range of mental health problems. The prevalence and features of DSH vary among different countries and settings. This study examines the prevalence of self-harm in a sample of adolescents seen at a psychiatric outpatient clinic in Singapore. METHODS: Information regarding self-harm, as well as its associated demographic and clinical risk factors, was extracted from the clinical records of 542 consecutive, new patients, aged 12-19 years, who presented between 2006 and 2010. RESULTS: DSH was reported in 23.6% of patients, and was positively associated with the female gender (odds ratio [OR] 4.54), mood disorders (OR 4.58), adjustment disorders (OR 3.41) and regular alcohol use (OR 4.80). However, there was no association with parental marital status, anxiety disorder, habitual smoking or family history of psychiatric illness. CONCLUSION: DSH is a significant clinical problem that may be influenced by biological and clinical factors. Adolescents presenting with DSH should be examined for mood and alcohol use disorders. PMID- 24068057 TI - Incidence of needlestick injuries among medical students after implementation of preventive training. AB - INTRODUCTION: Structured training for the prevention of needlestick injuries (NSIs) among medical students was implemented in Singapore in 1998. In this study, we determined the incidence of NSIs and the knowledge and practice of managing and reporting NSIs among first-year clinical students in a medical school in Singapore, as well as the adequacy of the training provided for these students, 14 years after preventive training was instituted. METHODS: All third year medical students (n = 257) from the Yong Loo Lin School of Medicine, National University of Singapore, Singapore, who had completed their first clinical year posting were enrolled in this cross-sectional study. A self administered questionnaire was answered by the students one month after completion of their last clinical posting. Students who repeated their first clinical year were excluded from the study. RESULTS: 237 students completed the questionnaire. However, 9 of these students were excluded because they repeated their first clinical year. The response rate was 91.9%. Although 8 (3.5%) students reported one NSI each, only 2 (25.0%) of these 8 students reported the incident to the relevant authority. Among the students surveyed, 65.8% reported using gloves at all times during venepuncture procedures, 48.7% felt that improvements could be made to the current reporting system and procedures, and 53.2% felt that the training provided before commencement of clinical posting could be enhanced. CONCLUSION: There was a decrease in the incidence of NSIs among medical undergraduates in their first clinical year when compared to the incidences reported in earlier studies conducted in the same centre (35.1% in 1993 and 5.3% in 2004). The current reporting system could use a more user friendly platform, and training on NSIs could be improved to focus more on real life procedures and incident reporting. PMID- 24068058 TI - Patient safety culture among medical students in Singapore and Hong Kong. AB - INTRODUCTION: Undergraduate education in medical schools plays an important role in promoting patient safety. Medical students from different backgrounds may have different perceptions and attitudes toward issues concerning safety. This study aimed to investigate whether patient safety cultures differed between students from two Asian countries, and if they did, to find out how they differed. This study also aimed to identify the educational needs of these students. METHODS: A voluntary, cross-sectional and self-administered questionnaire survey was conducted on 259 students from two medical schools - one in Hong Kong and the other in Singapore. None of the students had received any formal teaching on patient safety. We used a validated survey instrument, the Attitudes to Patient Safety Questionnaire III (APSQ-III), which was designed specifically for students and covered nine key factors of patient safety culture. RESULTS: Of the 259 students, 81 (31.3%) were from Hong Kong and 178 (68.7%) were from Singapore. The overall response rate was 66.4%. Significant differences between the two groups of students were found for two key factors - 'patient safety training', with Hong Kong students being more likely to report having received more of such training (p = 0.007); and 'error reporting confidence', which Singapore students reported having less of (p < 0.001). Both groups considered medical errors as inevitable, and that long working hours and professional incompetence were important causes of medical errors. The importance of patient involvement and team functioning were ranked relatively lower by the students. CONCLUSION: Students from different countries with no prior teaching on patient safety may differ in their baseline patient safety cultures and educational needs. Our findings serve as a reference for future longitudinal studies on the effects of different teaching and healthcare development programmes. PMID- 24068059 TI - Use of strong opioids for chronic non-cancer pain: a retrospective analysis at a pain centre in Singapore. AB - INTRODUCTION: The use of opioids in chronic non-cancer pain (CNCP) is controversial, as it presents both benefits and risks. There is currently no available data on the incidence, prescription pattern, functional outcomes and adverse effects of opioids in patients with CNCP in Singapore. This study aimed to address the aforementioned deficit. METHODS: All records of patients who were prescribed strong opioids (for > 3 months per year) for the management of CNCP over a two-year period were retrospectively analysed. Factors including type of opioid, indications for opioid prescription, uncontrolled side effects, functional status, coexisting psychological issues and suspicion of aberrant drug seeking behaviour were studied. RESULTS: Out of the 1,389 new patients who visited the centre, 42 (3.0%) with CNCP received strong opioids for more than three months a year. The most commonly prescribed opioid was methadone (42.9%). The principal diagnosis for opioid prescription was spinal pain (38.1%). Ten patients had severe side effects. 15 patients saw improvement in activities of daily living scores. Although ten patients returned to work, one stopped following the commencement of opioids. Aberrancy was seen in 5 (11.9%) patients, while 19 (45.2%) had psychological issues and 10 (23.8%) required psychiatric co management. CONCLUSION: Opioids are not a panacea for chronic pain. Therefore, functional outcomes should be considered more important end points than mere reductions in pain scores. A multidisciplinary team approach is essential for the effective management of patients with CNCP who are on opioids. PMID- 24068060 TI - Evaluation of serum interleukin 6 and tumour necrosis factor alpha levels, and their association with various non-immunological parameters in renal transplant recipients. AB - INTRODUCTION: Renal transplant rejection involves both immunological and non immunological factors. The objective of the present study was to investigate the association between immunological factors, such as serum interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha), and non-immunological parameters, such as age, serum creatinine (SCr), creatinine clearance (CrCl) and dyslipidaemia, in renal transplant recipients (RTRs). METHODS: This study included 90 RTRs and 90 healthy controls. Biochemical parameters, including serum IL-6 and TNF-alpha, were estimated using standard protocols. CrCl was calculated using the Cockroft Gault equation, and the type of rejection was confirmed on biopsy. Student's t test and univariate and multivariate analyses were performed using the Statistical Package for the Social Sciences for Windows version 15. RESULTS: The mean levels of serum IL-6 and TNF-alphawere significantly higher in RTRs than in the control group (p < 0.001). These parameters were also found to be significantly different between the transplant rejection (TR) and transplant stable (TS) groups (p < 0.001). CrCl was significantly decreased in the TR group when compared to the TS group (p < 0.001). The two cytokines, IL-6 and TNF-alpha, correlated significantly with all metabolic parameters, such as SCr, CrCl and dyslipidaemia. Multiple regression analysis showed that TNF-alpha and CrCl were the strongest predictors of IL-6. CONCLUSION: We conclude that immunological factors, as well as non-immunological factors such as CrCl, SCr and dyslipidaemia, play important roles in the pathogenesis of graft rejection and renal graft dysfunction. PMID- 24068061 TI - Multiple regression analysis of anthropometric measurements influencing the cephalic index of male Japanese university students. AB - INTRODUCTION: Cephalic index (CI), the ratio of head breadth to head length, is widely used to categorise human populations. The aim of this study was to access the impact of anthropometric measurements on the CI of male Japanese university students. METHODS: This study included 1,215 male university students from Tokyo and Kyoto, selected using convenient sampling. Multiple regression analysis was used to determine the effect of anthropometric measurements on CI. RESULTS: The variance inflation factor (VIF) showed no evidence of a multicollinearity problem among independent variables. The coefficients of the regression line demonstrated a significant positive relationship between CI and minimum frontal breadth (p < 0.01), bizygomatic breadth (p < 0.01) and head height (p < 0.05), and a negative relationship between CI and morphological facial height (p < 0.01) and head circumference (p < 0.01). Moreover, the coefficient and odds ratio of logistic regression analysis showed a greater likelihood for minimum frontal breadth (p < 0.01) and bizygomatic breadth (p < 0.01) to predict round-headedness, and morphological facial height (p < 0.05) and head circumference (p < 0.01) to predict long-headedness. Stepwise regression analysis revealed bizygomatic breadth, head circumference, minimum frontal breadth, head height and morphological facial height to be the best predictor craniofacial measurements with respect to CI. CONCLUSION: The results suggest that most of the variables considered in this study appear to influence the CI of adult male Japanese students. PMID- 24068062 TI - Clinics in diagnostic imaging. 148. Bursal-sided partial-thickness supraspinatus tendon tear. AB - Rotator cuff injury comprises a continual spectrum of lesions ranging from tendinopathy, which may progress to partial- or full-thickness tear. This progression may be influenced by the interplay of extrinsic and intrinsic factors. We describe the case of a 29-year-man who presented with right shoulder pain for one year. His initial magnetic resonance (MR) arthrogram showed supraspinatus tendinopathy. Subsequent MR arthrogram, obtained after a road traffic accident, showed a bursal-sided partial-thickness tear of the supraspinatus tendon. In view of his worsening clinical symptoms, surgery was performed ten months later, revealing a full-thickness rotator cuff tear near the tendon insertion, with a tight subacromial space and bony protuberance of the humeral head. The pathogenesis of rotator cuff injuries, the roles of different imaging modalities in the diagnosis of rotator cuff injuries, as well as the advantages and limitations of various radiological modalities, are discussed. PMID- 24068063 TI - Interstitial incisional hernia following appendectomy. PMID- 24068064 TI - Isolated deletion of the long arm of chromosome 20 [del(20q12)] in myelodysplastic syndrome: a case report and literature review. AB - Isolated deletion of the long arm of chromosome 20 [del(20q12)] is a rare abnormality in patients with de novo myelodysplastic syndrome. It is characterised by refractory thrombocytopenia, minimal haematological dysplasia and a lower risk for progression to acute myeloid leukaemia. Its distinction from chronic autoimmune thrombocytopenia, although clinically and morphologically difficult, is critical. We report a case of refractory cytopenia and unilineage dysplasia in an elderly woman with isolated del(20q12), identified via fluorescence in situ hybridisation analysis of her bone marrow. In order to avoid a misdiagnosis, we suggest that cytogenetic analysis be performed on all patients suspected to have myelodysplastic syndrome with predominant thrombocytopenic presentation. PMID- 24068065 TI - Retropharyngeal lipoma with parapharyngeal extension: is transoral excision possible? AB - Retropharyngeal lipomas are rare tumours that are usually asymptomatic until they reach a large size. The definitive treatment is surgical excision. Since the tumours are typically large at the time of presentation, extensive surgery for complete clearance of the lipoma from the retropharyngeal and parapharyngeal regions is to be expected. Transoral excision is typically indicated for small retropharyngeal tumours, as this approach does not give good access to the parapharyngeal area laterally. Herein, we present the case of a patient who underwent transoral excision of a huge retropharyngeal lipoma, which extended into the right parapharyngeal space. The surgical technique used and the insights gained are described in this report. Even with parapharyngeal extension, transoral resection of a huge retropharyngeal lipoma can be performed. More invasive surgery, which may involve a neck incision, mandibulotomy or pharyngotomy, is not necessary. While huge retropharyngeal lipomas are usually symptomatic and require surgical intervention, transoral resection can be adequate and safe for treatment. PMID- 24068066 TI - A rare case of primary muscular non-Hodgkin's lymphoma and a review of how imaging can assist in its diagnosis. AB - Primary malignant non-Hodgkin's lymphoma of the muscle is rare. Currently, imaging tools are necessary to enable its diagnosis. Herein, we report the case of a patient who presented with swelling and pain in the right thigh and pelvis. Computed tomography findings revealed isodense masses in the patient's right thigh and left iliacus muscle, leading to the initial diagnosis of either primary muscular lymphoma or soft tissue sarcoma. Further investigation with magnetic resonance imaging was done, and a biopsy was performed. The ensuing histological diagnosis was that of diffuse large B-cell lymphoma. PMID- 24068067 TI - Pleomorphic adenoma of the minor salivary gland of the cheek. AB - Pleomorphic adenoma is the most common tumour of the salivary gland. While the majority arises from the parotid gland, only a small percentage arises from the minor salivary glands. The cheek, however, is a rarely affected site with respect to pleomorphic adenomas of the minor salivary glands. Herein, we report a case of pleomorphic adenoma of the cheek, which presented with intraoral swelling, and conclude that complete surgical excision can be a curative treatment for this benign tumour. PMID- 24068068 TI - Delayed diagnosis of impacted partial denture in a patient with mental retardation. AB - Foreign body ingestion is a common problem. To minimise any complications arising from an ingested foreign body, early diagnosis and proper treatment are essential. However, this may be a diagnostic challenge, especially in patients who have psychiatric disorders or are mentally challenged. We report a case of delayed diagnosis of an impacted partial denture in the pharynx of a man with mental retardation. PMID- 24068069 TI - Posterior reversible encephalopathy syndrome: an acute manifestation of systemic lupus erythematous. AB - Stroke mimickers are common, and they represent a diagnostic dilemma for clinicians. Many, like posterior reversible encephalopathy syndrome (PRES), are easily reversible. The manifestation of PRES is characterised by headaches, convulsions, altered mental functioning and blindness. In most cases, computed tomography of the brain will show hypodense lesions in the parieto-occpitial lobe, which only further confounds the physician. Although this syndrome is uncommon, prompt and accurate recognition allows early treatment, which has been shown to produce favourable outcomes. Herein, we report the case of a 54-year-old woman, who presented with PRES, as an acute manifestation of systemic lupus erythematous (SLE) and lupus nephritis. The patient was initially thought to be experiencing an ischaemic stroke, but the diagnosis was later changed. On management of her underlying condition, her symptoms resolved. PRES should be recognised as an acute emergency manifestation of SLE. It should not be mistaken for an ischaemic stroke as inappropriate treatment could have adverse outcomes. PMID- 24068070 TI - Parotid gland involvement as a presenting feature of Wegener's granulomatosis. AB - Salivary gland involvement is a rare presenting clinical feature of Wegener's granulomatosis (WG). Early recognition and identification of any unusual presentations of WG may enable the early commencement of appropriate treatment. We report a case in which the initial manifestation of the disease was parotid gland swelling, and discuss the management of the patient. WG should be considered in the differential diagnosis when salivary gland enlargement occurs with other otolaryngological symptoms. PMID- 24068071 TI - Abdominal distension in a middle-aged woman. PMID- 24068072 TI - Ti diffusion in (001) SrTiO3-CoFe2O4 epitaxial heterostructures: blocking role of a MgAl2O4 buffer. AB - Titanium diffusion from (001) SrTiO3 (STO) substrates into CoFe2O4 (CFO) films grown using pulsed laser deposition is reported. To elucidate the reasons for Ti interdiffusion, a comparative study of CFO films grown on MgAl2O4 (MAO) and STO substrates, buffered by thin STO and MAO layers, has been made. It is shown that whereas bottom STO layers always result in Ti migration, a thin MAO layer, only 8 nm thick, is effective in blocking it. We argue that this success relies on the lower mobility of Ti ions in the MAO lattice compared to that of CFO. This result should contribute to the development of high quality epitaxial heterostructures of dissimilar complex oxides. PMID- 24068073 TI - Meta-analysis of surgical safety checklist effects on teamwork, communication, morbidity, mortality, and safety. AB - The purpose of this study is to examine the effectiveness of surgical safety checklists on teamwork, communication, morbidity, mortality, and compliance with safety measures through meta-analysis. Four meta-analyses were conducted on 19 studies that met the inclusion criteria. The effect size of checklists on teamwork and communication was 1.180 (p = .003), on morbidity and mortality was 0.123 (p = .003) and 0.088 (p = .001), respectively, and on compliance with safety measures was 0.268 (p < .001). The results indicate that surgical safety checklists improve teamwork and communication, reduce morbidity and mortality, and improve compliance with safety measures. This meta-analysis is limited in its generalizability based on the limited number of studies and the inclusion of only published research. Future research is needed to examine possible moderating variables for the effects of surgical safety checklists. PMID- 24068074 TI - Origin of highly stable conductivity of H plasma exposed ZnO films. AB - H was intentionally incorporated into as-deposited ZnO films by plasma exposure treatment. The resistivity of ZnO films was reduced to the order of 10(-3) Omega cm after H plasma treatment, and high conductive stability was identified using a post-annealing process. To find an explanation for the stable conductivity, first principle calculation was performed. Results predicted that H atoms trapped in oxygen vacancies (V(O)) have the lowest formation energy. By reducing oxygen vacancies in as-deposited films by adding O2 into the working atmosphere, we further testified that H in V(O) is the origin of highly stable conductivity of ZnO films. Our study provided a solution to the problem of how to incorporate H into the V(O) position to produce highly stable H doped ZnO films. PMID- 24068075 TI - Identification of the crystallographic sites of Eu(2+) in Ca9NaMg(PO4)7: structure and luminescence properties study. AB - The substituted activator ions Eu(2+) in the beta-Ca3(PO4)2-type structure, Ca9NaMg(PO4)7 compound, have been studied as emission centers, as well as structural probes. The crystal structure and crystallographic sites of Eu(2+) in Ca9NaMg(PO4)7 have been identified by Rietveld refinements, electron paramagnetic resonance (EPR) spectroscopy analysis and combined photoluminescence spectral analysis, respectively. Ca9NaMg(PO4)7:Eu(2+) phosphor exhibits a broad emission band in the visible light region with three distinguished peaks centered at 415, 458, and 615 nm, which are ascribed to different Eu(2+) emission centers occupied in three different Ca crystallographic sites. The concentration quenching behavior, variation in lifetimes and the temperature dependent luminescence properties have been investigated as a function of different emission centers, 415, 458, and 625 nm for Ca9NaMg(PO4)7:Eu(2+) phosphor. Accordingly, the relationship among three different Eu(2+) luminescence centers originating from three different Ca(2+) crystallographic sites has been found and verified. PMID- 24068076 TI - Genetic modification of characteristic masculine traits: enhancement or deformity? PMID- 24068077 TI - A closer look at the Impact Factor (JCR 2012): problems, concerns and actions needed. PMID- 24068079 TI - Chemical constituents of Distictella elongata (Vahl) Urb. (Bignoniaceae). AB - Pectolinarin, a flavone heteroside, was isolated from Distictella elongata (Vahl) Urb. leaves ethanol extract, along with a mixture of ursolic, pomolic and oleanolic acids, besides beta-sitosterol. Their structures were established on the basis of spectral analysis (1H and 13C NMR, 1D and 2D) and they were compared with literature. This is the first report on the occurrence of this flavonoid in a species of the Bignoniaceae family. PMID- 24068080 TI - Flavonoids from leaves of Derris urucu: assessment of potential effects on seed germination and development of weeds. AB - In some previous studies, we described the isolation of nine compounds from leaves of Derris urucu, a species found widely in the Amazon rainforest, identified as five stilbenes and four dihydroflavonols. In this work, three of these dihydroflavonols [urucuol A (1), urucuol B (2) and isotirumalin (3)] were evaluated to identify their potential as allelochemicals, and we are also reporting the isolation and structural determination of a new flavonoid [5,3' dihydroxy-4'-methoxy-(7,6:5",6")-2",2"-dimethylpyranoflavanone (4)]. We investigated the effects of the dihydroflavonols 1-3 on seed germination and radicle and hypocotyl growth of the weed Mimosa pudica, using solutions at 150 mg.L-1. Urucuol B, alone, was the substance with the greatest potential to inhibit seed germination (26%), while isotirumalin showed greater ability to reduce the development of the hypocotyl (25%), but none of the three substances showed the potential to inhibit radicle. When combined in pairs, the substances showed synergism for the development of root and hypocotyl and effects on seed germination that could be attributed to antagonism. When tested separately, the trend has become more intense effects on seed germination, while for the substances tested in pairs, the intensity of the effect was greater on development of weed. PMID- 24068081 TI - Multivariate optimization of an ultrasound-assisted extraction procedure for Cu, Mn, Ni and Zn determination in ration to chickens. AB - In this work, multivariate optimization techniques were used to develop a method based on the ultrasound-assisted extraction for copper, manganese, nickel and zinc determination from rations for chicken nutrition using flame atomic absorption spectrometry. The proportions of extracting components (2.0 mol.L-1 nitric, hydrochloric and acetic acid solutions) were optimized using centroid simplex mixture design. The optimum proportions of this mixture taken as percentage of each component were respectively 20%, 37% and 43%. Variables of method (sample mass, sonication time and final acid concentration) were optimized using Doehlert design. The optimum values found for these variables were respectively 0.24 g, 18s and 3.6 mol.L-1. The developed method allows copper, manganese, nickel and zinc determination with quantification limits of 2.82; 4.52; 10.7; e 9.69 ug.g-1, and precision expressed as relative standard deviation (%RSD, 25 ug.g-1, N = 5) of 5.30; 2.13; 0.88; and 0.83%, respectively. This method was applied in the analytes determination from chicken rations collected from specialized commerce in Jequie city (Bahia State/Brazil). Application of paired t-test at the obtained results, in a confidence level of 95%, does not show significant difference between the proposed method and the microwave assisted digestion. PMID- 24068083 TI - A study of structural lineaments in Pantanal (Brazil) using remote sensing data. AB - This paper presents a study of the structural lineaments of the Pantanal extracted visually from satellite images (CBERS-2B satellite, Wide Field Imager sensor, a free image available in INTERNET) and a comparison with the structural lineaments of Precambrian and Paleozoic rocks surrounding the Cenozoic Pantanal Basin. Using a free software for satellite image analysis, the photointerpretation showed that the NS, NE and NW directions observed on the Pantanal satellite images are the same recorded in the older rocks surrounding the basin, suggesting reactivation of these basement structural directions during the Quaternary. So the Pantanal Basin has an active tectonics and its evolution seems to be linked to changes that occurred during the Andean subduction. PMID- 24068082 TI - In vitro trypanocidal activity of solamargine and extracts from Solanum palinacanthum and Solanum lycocarpum of Brazilian cerrado. AB - The present investigation was to evaluate the potential trypanocidal activity of crude ethanolic extract of the fruits of Solanum palinacanthum, Solanum lycocarpum and the glycoalcaloid, solamargine. S. palinacanthum and S. lycocarpum fruit powders were submitted to exhaustively extraction with 96% ethanol and solamargine were isolated from the extract of S. palinacanthum. Both extracts and solamargine were analysed for trypanocidal activity by using MTT colorimetric assay. Extracts of S. palinacanthum showed to be more active (IC50 = 175.9 ug.ml 1) than S. lycocarpum (IC50 = 194.7 ug.ml-1). Solamargine presented a strong activity (IC50 = 15.3 ug.ml-1), which can explain the better activity of the both extracts. Benznidazol (IC50 = 9.0 ug.ml-1) is the only drug used to treat Chagas' disease. These findings demonstrate for the first time that ethanol extracts obtained from both fruits of S. palinacanthum and S. lycocarpum and also solamargine have a potential anti-trypanosomal activity. PMID- 24068084 TI - The Brazilian research contribution to knowledge of the plant communities from Antarctic ice free areas. AB - This work aims to summarize the results of research carried out by Brazilian researchers on the plant communities of Antarctic ice free areas during the last twenty five years. Since 1988 field work has been carried out in Elephant Island, King George Island, Nelson Island and Deception Island. During this period six papers were published on the chemistry of lichens, seven papers on plant taxonomy, five papers on plant biology, two studies on UVB photoprotection, three studies about the relationships between plant communities and bird colonies and eleven papers on plant communities from ice free areas. At the present, Brazilian botanists are researching the plant communities of Antarctic ice free areas in order to understand their relationships to soil microbial communities, the biodiversity, the distribution of the plants populations and their relationship with birds colonies. In addition to these activities, a group of Brazilian researchers are undertaking studies related to Antarctic plant genetic diversity, plant chemistry and their biotechnological applications. PMID- 24068085 TI - Assessment of the cytotoxic, genotoxic, and antigenotoxic activities of Celtis iguanaea (Jacq.) in mice. AB - Ethnobotanical surveys of Cerrado native plants show that leaves of Celtis iguanaea (Jacq.) Sargent (Cannabaceae), popularly known in Brazil as "esporao de galo", are used in folk medicine for body pain, asthma, cramps, poor digestion, urinary infection, kidney dysfunctions, as well as a stimulant and diuretic. This work aimed at evaluating possible C. iguanaea aqueous leaf extract (CALE) cytotoxicity, genotoxicity, and antigenotoxicity using the mouse bone marrow micronucleous test. To assess CALE genotoxicity, Swiss mice were orally treated with three different extract concentrations (100, 300, and 500 mgkg-1). To evaluate its antigenotoxicity, the same doses were used simultaneously with a single i.p. dose of mitomycin C (MMC, 4mg.kg-1). The frequencies of micronucleated polychromatic erythrocytes (MNPCE) were evaluated 24 h and 48 h after administration except for the negative control (24 h). Genotoxicity was evaluated using the frequency of micronucleated polychromatic erythrocytes (MNPCE), whereas cytotoxicity was assessed by the polychromatic and normochromatic erythrocytes ratio (PCE/NCE). The results showed that CALE did not exhibit a significant reduction in the PCE/NCE ratio, neither a considerable increase in the frequency of MNPCE. Nonetheless, CALE reduced bone marrow toxicity (increased PCE/NCE ratio) and decreased the micronuclei frequency induced by MMC. We can conclude that CALE presented no cytotoxic and genotoxic effects, but showed antigenotoxic and anticytotoxic actions under the experimental conditions applied in this study. PMID- 24068086 TI - Expression of manganese peroxidase by Lentinula edodes and Lentinula boryana in solid state and submerged system fermentation. AB - The production of ethanol from lignocellulosic biomass is referred as a second generation biofuel, whose processing is one of the most promising technologies under development. There are few available studies on the use of enzymes produced by fungi as active for the biodegradation of lignocellulosic biomass. However, the manganese peroxidase (MnP) enzyme presents high potential to degrade lignin and the basidiomycetes are the major producers of this oxidase. Thus, this study aimed at evaluating the ability of fungi Lentinula edodes and Lentinula boryana to produce this enzyme when cultivated in submerged fermentation system (SS) and also in solid-state fermentation system (SSF) containing Eucalyptus benthamii sawdust with or without corn cob meal. In the SS the greatest MnP expression occurred on the 25th day, being of 70 UI.L-1 for L. boryana and of 20 UI.L-1 for L. edodes. In the SSF, the best results were obtained on the 10th day for L. edodes, while for L. boryana it happened between the 20th and the 25th days, despite both species presented values close to 110 UI.L-1. Therefore, the results indicated that the studied fungi express the enzyme of interest and that its production is enhanced when cultivated in solid system. PMID- 24068087 TI - Chironomidae (Insecta: Diptera) of different habitats and microhabitats of the Vacacai-Mirim River microbasin, Southern Brazil. AB - The Chironomidae family is one of the main groups of aquatic insects present in streams. This work aimed to investigate the influences of anthropogenic pressures and substrate types on chironomid community composition and structure. Chironomid larvae were collected during the summer of 2007 at four sites along the Vacacai Mirim River microbasin, chosen based on the different available benthic substrates. The organisms were identified in the laboratory at the genus level, and the density, the rarefied taxonomic richness and the Shannon diversity index were calculated. The faunal structure was subjected to an ANOVA to compare the metrics among sites and substrates. The community composition of the sites was subjected to a multivariate statistical analysis. Differences in the composition, richness, density, and diversity were observed among the sites due to differences in the levels of nutrients and solids generated by the presence of crops close to water bodies. Samples collected from sandy substrates exhibited a lower density and taxonomic richness because sand is a poorer substrate than the others that were sampled. In organic or mixed substrates with higher energy availability and better shelter conditions, the observed densities were higher. The physical and chemical conditions and the morphometric characteristics of the sites were more influential than the substrates. PMID- 24068088 TI - Evaluation of analgesic and anti-inflammatory activities of Hydrocotyle umbellata L., Araliaceae (acaricoba) in mice. AB - The Hydrocotyle umbellata L. is a specimen of the Araliaceae family popularly known as acaricoba. Its indications in folk medicine include treatment of skin ulcers, and rheumatism. The aim of this study was to evaluate the antinociceptive and anti-inflammatory activities of the ethanolic extract from acaricoba's underground parts (EEA). EEA reduced the nociceptive response of the animals as evaluated in the acetic acid-induced writhing test and in both phases of formalin test. EEA also presented a supraspinal analgesic activity by increasing the pain latency in the hot plate test. Moreover, EEA reduced the leukocytes migration and plasma extravasation to pleural cavity in the carrageenan-induced pleurisy, besides reducing the edema induced by carrageenan until the second hour and also the edema induced by dextran. In conclusion our results showed that EEA of H. umbellata L. presents analgesic and anti-inflammatory activities, and that a blockade of activity or reduction in the release of different mediators, such as histamine and serotonin, could be involved in these pharmacologic effects. PMID- 24068089 TI - Impacts of hydroelectric dams on alluvial riparian plant communities in Eastern Brazilian Amazonian. AB - The major rivers of the Amazon River basin and their biota are threatened by the planned construction of large hydroelectric dams that are expected to have strong impacts on floodplain plant communities. The present study presents forest inventories from three floodplain sites colonized by alluvial riparian vegetation in the Tapajos, Xingu and Tocantins River basins in eastern Amazonian. Results indicate that tree species of the highly specialized alluvial riparian vegetation are clearly distinct among the three river basins, although they are not very distinct from each other and environmental constraints are very similar. With only 6 of 74 species occurring in all three inventories, most tree and shrub species are restricted to only one of the rivers, indicating a high degree of local distribution. Different species occupy similar environmental niches, making these fragile riparian formations highly valuable. Conservation plans must consider species complementarily when decisions are made on where to place floodplain forest conservation units to avoid the irreversible loss of unique alluvial riparian vegetation biodiversity. PMID- 24068090 TI - Germination responses of the invasive Calotropis procera (Ait.) R. Br. (Apocynaceae): comparisons with seeds from two ecosystems in Northeastern Brazil. AB - Life history traits are considered key indicators of plant invasibility. Among them, the germination behavior of seeds is of major relevance because it is influenced by environmental factors of invaded ecosystem. Here, we investigated how seed traits and seed tolerance to environmental factors on seed germination of Calotropis procera vary depending on the invaded ecosystems in northeastern Brazil. We have tested seeds from two vegetation types - Caatinga and Restinga - to different levels of light intensity, salinity, and water stress. Previous to those experiments, seed-set and morphometric analysis were carried out for both studied populations. We have observed a higher seed-set in Caatinga. Seeds produced in this ecosystem had lower seed moisture content. Seeds from Restinga showed lower germination time when light intensity decreased. We observed a reduction in both the germinability and the synchronization index with decreasing osmotic potential and increasing salinity. Nevertheless, both populations exhibited changes in photoblastism when seeds were submitted to water and saline stress. In conclusion, C. procera seeds are tolerant to environmental factors assessed. That characteristic ensures the colonization success and wide distribution of this plant species in the studied ecosystems. PMID- 24068091 TI - Are leaf physiological traits related to leaf water isotopic enrichment in restinga woody species? AB - During plant-transpiration, water molecules having the lighter stable isotopes of oxygen and hydrogen evaporate and diffuse at a faster rate through the stomata than molecules having the heavier isotopes, which cause isotopic enrichment of leaf water. Although previous models have assumed that leaf water is well-mixed and isotopically uniform, non-uniform stomatal closure, promoting different enrichments between cells, and different pools of water within leaves, due to morpho-physiological traits, might lead to inaccuracies in isotopic models predicting leaf water enrichment. We evaluate the role of leaf morpho physiological traits on leaf water isotopic enrichment in woody species occurring in a coastal vegetation of Brazil known as restinga. Hydrogen and oxygen stable isotope values of soil, plant stem and leaf water and leaf traits were measured in six species from restinga vegetation during a drought and a wet period. Leaf water isotopic enrichment relative to stem water was more homogeneous among species during the drought in contrast to the wet period suggesting convergent responses to deal to temporal heterogeneity in water availability. Average leaf water isotopic enrichment relative to stem water during the drought period was highly correlated with relative apoplastic water content. We discuss this observation in the context of current models of leaf water isotopic enrichment as a function of the Peclet effect. We suggest that future studies should include relative apoplastic water content in isotopic models. PMID- 24068092 TI - Regional movements of the tiger shark, Galeocerdo cuvier, off Northeastern Brazil: inferences regarding shark attack hazard. AB - An abnormally high shark attack rate verified off Recife could be related to migratory behavior of tiger sharks. This situation started after the construction of the Suape port to the south of Recife. A previous study suggested that attacking sharks could be following northward currents and that they were being attracted shoreward by approaching vessels. In this scenario, such northward movement pattern could imply a higher probability of sharks accessing the littoral area of Recife after leaving Suape. Pop-up satellite archival tags were deployed on five tiger sharks caught off Recife to assess their movement patterns off northeastern Brazil. All tags transmitted from northward latitudes after 7-74 days of freedom. The shorter, soak distance between deployment and pop-up locations ranged between 33-209 km and implied minimum average speeds of 0.02 0.98 km.h-1. Both pop-up locations and depth data suggest that tiger shark movements were conducted mostly over the continental shelf. The smaller sharks moved to deeper waters within 24 hours after releasing, but they assumed a shallower (< 50 m) vertical distribution for most of the monitoring period. While presenting the first data on tiger shark movements in the South Atlantic, this study also adds new information for the reasoning of the high shark attack rate verified in this region. PMID- 24068093 TI - Anurans in a forest remnant in the transition zone between cerrado and Atlantic Rain Forest domains in Southeastern Brazil. AB - This study presents the species richness, temporal distribution and reproductive activity of anurans from the Uaimii State Forest (Floresta Estadual do Uaimii - FLOE Uaimii), situated in the Quadrilatero Ferrifero region, municipality of Ouro Preto, Minas Gerais state, Brazil. Field activities were performed monthly from September 2009 to August 2010. We recorded 36 anurans species, distributed in 10 families. The greatest richness of the sampled sites corresponds to a permanent rivulet in a secondary forest. The majority of anuran species presented seasonal vocalization activity pattern, mainly in the rainy season. The anuran species composition of FLOE Uaimii is similar to others studied areas from the Quadrilatero Ferrifero region. PMID- 24068094 TI - Ecological features of titica vine (Heteropsis flexuosa (Kunth) GS Bunting) in Rondonia State, Northwest Brazilian Amazon. AB - The aim of this study was to characterize the forest structure with H. flexuosa in Rondonia State, as a first step in developing sustainable harvest and conservation guidelines for the species. Crown attributes, total height (m) and diameter at breast height >= 10 (cm) of trees and palms with H. flexuosa were evaluated in three permanent plots (100 m x 150 m each) randomized in 219 ha. A total of 22 botanical families hosted H. flexuosa. It was not observed any specific preference for the species standing up itself. Nevertheless it was frequently associated to Burseraceae, Leguminosae, Sapotaceae, Annonaceae, Chrysobalanaceae, Apocynaceae, Moraceae and Myristicaceae and species with thick bark like Schweilera coriacea, Protium sp. and Licania membranaceae. The species was less frequent with taller and broader trees and tended to develop in understory light condition. Trunks or branches were the main position for the attaching of H. flexuosa (90.83%) and a low frequency of other lianas was observed on the same host trees. These highlight the need to promote appropriate management practices for root harvesting and species conservation in order to maintain the species in open ombrophylus forest habitat. PMID- 24068095 TI - Pouteria ramiflora extract inhibits salivary amylolytic activity and decreases glycemic level in mice. AB - In this study, extracts of plant species from the Cerrado biome were assessed in order to find potential inhibitors of human salivary alpha-amylase. The plants were collected and extracts were obtained from leaves, bark, and roots. We performed a preliminary phytochemical analysis and a screening for salivar alpha amylase inhibitory activity. Only three botanical families (Sapotaceae, Sapindaceae and Flacourtiaceae) and 16 extracts showed a substantial inhibition (>75%) of alpha-amylase. The ethanolic extracts of Pouteria ramiflora obtained from stem barks and root barks decreased amylolytic activity above 95% at a final concentration of 20 ug/mL. Thus, adult male Swiss mice were treated orally with P. ramiflora in acute toxicity and glycemic control studies. Daily administration with 25, 50 and 100 mg/kg of aqueous extract of P. ramiflora for eight days can reduce significantly body weight and blood glucose level in mice. These data suggest that the crude polar extract of P. ramiflora decreases salivary amylolytic activity while lowering the blood levels of glucose. PMID- 24068096 TI - Effect of l-glutamine on myenteric neuron and of the mucous of the ileum of diabetic rats. AB - The objective of this work was to investigate the effect of the L-glutamine supplementation to prevent - diabetes induced changes in myenteric neurons and also to verify the effect on the mucosa of the ileum of Wistar rats. The animals were divided in five groups (n = 5): untreated normoglycaemic (UN), normoglycaemic treated with L-glutamine (NG), untreated diabetics (UD), diabetics treated with L-glutamine, starting on the 4th (DG4) or 45th day following diabetes induction (DG45). The amino acid was added to the diet at 1%. The density and size of neurons, the metaphasic index in the crypt, the height of the villus, the depth of the crypt and the number of globet cells were determined. There was no difference in the neuronal density and in the cellular body area of the myosin-stained myenteric neurons of groups DG4 and DG45 when compared to group D. The metaphase index and the number of goblet cells showed no significant differences when all groups were compared (P > 0.05). The villi height of groups DG4 and DG45 were 45.5% (P < 0.05) and 32.4% (P > 0.05) higher than those in group UD, respectively. The analyzed crypts showed similar depth for all studied groups. PMID- 24068097 TI - Hawkmoth fauna (Sphingidae, Lepidoptera) in a semi-deciduous rainforest remnant: composition, temporal fluctuations, and new records for Northeastern Brazil. AB - We carried out a qualitative and quantitative inventory of the hawkmoth fauna (Sphingidae) of an area of semi-deciduous seasonal rainforest in the state of Pernambuco (Tapacura Ecological Station), northeastern Brazil. Hawkmoths were sampled monthly from October 2004 to February 2007 (27 months). We recorded 31 species from 16 genera, three tribes, and three families. Macroglossinae was the most abundant subfamily and represented ca. 71% of all species. Out of the 277 individuals collected, 88.4% were males. Five new records were made for northeastern Brazil: Enyo gorgon (Cramer, 1777), Perigonia stulta (Herrich Schaffer, [1854]), Eupyrrhoglossum sagra (Poey, 1832), Nyceryx coffaeae (Walker, 1856) and Xylophanes chiron (Drury, 1773). Eight further species were recorded for the first time for the Pernambuco Endemism Center, showing the important role played by Tapacura Station in preserving the biodiversity of this insect group. Species richness and abundance were directly related to rainfall: about 70% of all individuals were captured during the rainy season. Changes in Sphingidae populations may, however, be caused by other factors that directly affect either larvae and adults of those insects, such as matrix effect and forest fragment size, which influence migration processes and the presence of predators. PMID- 24068098 TI - Handling sticky resin by Stingless Bees: adhesive properties of surface structures. AB - Many Stingless Bees (Hymenoptera: Meliponini) like Tetragonisca angustula collect resin to defend their nests against intruders like ants or Robber Bees. Small portions of resin are attached to intruders bodies and extremities causing their immobilization. It has been observed that resin is removed easily from the bee's mandible but adheres strongly to the intruder's cuticle. We tested the hypothesis that resin sticks lesser to the mandibles of Stingless Bees than to the surface of intruders due to special surface structures or adhesive properties of these structures. The surface structures of the mandible of T. angustula and the trochanter of Camponotus sericeiventris were studied by scanning electron microscopy. To measure adhesion properties, selected surfaces were fixed on a fine glass pin and withdrawn from a glass tip covered with resin. The deformation of the glass pin indicates adhesion forces operating between the resin and the selective surface. The absolute value of the forces is computed from the glass pin's stiffness. It has been shown that resin sticks more to the smooth mandible of the bee than to the structured trochanter of the ant. A new hypothesis to be tested says that the bees might lubricate their mandibles with nectar or honey to reduce the resin's adhesion temporarily. PMID- 24068099 TI - Predictive factors of subjective sleep quality and insomnia complaint in patients with stroke: implications for clinical practice. AB - The complaints regarding sleep problems have not been well identified after a stroke. The aim of this study was to investigate the predictive factors of sleep quality and insomnia complaints in patients with stroke. A total of 70 subjects, 40 patients (57 +/- 7 years) and 30 healthy controls (52 +/- 6 years) assessed by the Pittsburgh Sleep Quality Index (PSQI) and the Sleep Habits Questionnaire took part in the study. The data were analyzed using the chi-square test, the Student's t-test and logistic regression analysis. On average, the patients showed poor sleep quality (patients: 6.3 +/- 3.5; controls: 3.9 +/- 2.2; p= 0.002) and insomnia complaint was the most prevalent (patients: 37.5%; controls: 6.7%; p= 0.007). The absence of insomnia complaint (OR= 0.120; 95%CI= 0.017 0.873; p= 0.036) and the decreased latency of sleep (OR= 0.120; 95%CI= 0.017 0.873; p= 0.036) were the protective factors of sleep quality. Female sex (OR= 11.098; 95%CI= 1.167-105.559; p= 0.036) and fragmented sleep (OR= 32.040; 95%CI= 3.236-317.261; p= 0.003) were the risk factors for insomnia complaint. We suggest that complaints of poor sleep quality and insomnia should be given priority assessment during clinical diagnosis of sleep disorders in stroke. PMID- 24068100 TI - Biochemical and hematological analysis in acute intermittent porphyria (AIP): a case report. AB - Acute intermittent porphyria is the most common acute porphyria caused by a decrease in hepatic porphobilinogen deaminase activity, resulting in an accumulation of delta-aminolevulinic acid and porphobilinogen. This disease shows nonspecific signs and symptoms that can be confused with other diseases, thereby making the diagnosis difficult. We report a case of acute intermittent porphyria, reviewing clinical and laboratory aspects, highlighting the hematological and biochemical parameters during and after the crisis. A female patient, aged 28 years, suffered two crises, both presenting gastrointestinal disorders. The second presented neuropsychiatric symptoms. The analysis of hematological and biochemical parameters during the second crisis showed anemia, leukocytosis, hyponatremia, mild hypokalemia, uremia and elevated C-reactive protein. The initial treatment included glucose infusion, a diet rich in carbohydrates and interruption of porphyrinogenic drugs. Subsequently, treatment was maintained with oral contraceptive use. According to the observed data, signs and symptoms of gastrointestinal, neurological and psychiatric disorders, associated with laboratory results presented in this paper can be applied to screen acute porphyria, contributing to early diagnosis. PMID- 24068102 TI - A Case Report of CLIPPERS (Chronic Lymphocytic Inflammation with Pontocerebellar Perivascular Enhancement Responsive to Steroids) Syndrome. PMID- 24068104 TI - Discarding the haystack to examine the needles: the potential role of urinary exosome analysis. PMID- 24068103 TI - Hydrogen sulfide protects endothelial nitric oxide function under conditions of acute oxidative stress in vitro. AB - The aim of this study was to examine the ability of H2S, released from NaHS to protect vascular endothelial function under conditions of acute oxidative stress by scavenging superoxide anions (O2(-)) and suppressing vascular superoxide anion production. O2(-) was generated in Krebs' solution by reacting hypoxanthine with xanthine oxidase (Hx-XO) or with the O2(-) generator pyrogallol to model acute oxidative stress in vitro. O2(-) generation was measured by lucigenin-enhanced chemiluminescence. Functional responses in mouse aortic rings were assessed using a small vessel myograph. NaHS scavenged O2(-) in a concentration-dependent manner. Isolated aortic rings exposed to either Hx-XO or pyrogallol displayed significantly attenuated maximum vasorelaxation responses to the endothelium dependent vasodilator acetylcholine, and significantly reduced NO bioavailability, which was completely reversed if vessels were pre-incubated with NaHS (100 MUM). NADPH-stimulated aortic O2(-) production was significantly attenuated by the NADPH oxidase inhibitor diphenyl iodonium. Prior treatment of vessels with NaHS (100 nM-100 MUM; 30 min) inhibited NADPH-stimulated aortic O2( ) production in a concentration-dependent manner. This effect persisted when NaHS was washed out prior to measuring NADPH-stimulated O2(-) production. These data show for the first time that NaHS directly scavenges O2(-) and suppresses vascular NADPH oxidase-derived O2(-) production in vitro. Furthermore, these properties protect endothelial function and NO bioavailability in an in vitro model of acute oxidative stress. These results suggest that H2S can elicit vasoprotection by both scavenging O2(-) and by reducing vascular NADPH oxidase derived O2(-) production. PMID- 24068105 TI - Peering beneath the surface: novel imaging techniques to noninvasively select gametes and embryos for ART. AB - Embryo imaging has long been a critical tool for in vitro fertilization laboratories, aiding in morphological assessment of embryos, which remains the primary tool for embryo selection. With the recent emergence of clinically applicable real-time imaging systems to assess embryo morphokinetics, a renewed interest has emerged regarding noninvasive methods to assess gamete and embryo development as a means of inferring quality. Several studies exist that utilize novel imaging techniques to visualize or quantify intracellular components of gametes and embryos with the intent of correlating localization of organelles or molecular constitution with quality or outcome. However, the safety of these approaches varies due to the potential detrimental impact of light exposure or other variables. Along with complexity of equipment and cost, these drawbacks currently limit clinical application of these novel microscopes and imaging techniques. However, as evidenced by clinical incorporation of some real-time imaging devices as well as use of polarized microscopy, some of these imaging approaches may prove to be useful. This review summarizes the existing literature on novel imaging approaches utilized to examine gametes and embryos. Refinement of some of these imaging systems may permit clinical application and serve as a means to offer new, noninvasive selection tools to improve outcomes for various assisted reproductive technology procedures. PMID- 24068107 TI - Growth of a ZIF-8 membrane on the inner-surface of a ceramic hollow fiber via cycling precursors. AB - For the first time, a ZIF-8 membrane was grown on the inner surface of a ceramic hollow fiber via cycling precursors. The inner-side hollow fiber ZIF-8 membrane exhibits good performance for recovering hydrogen. PMID- 24068108 TI - Cooperative hydration of carboxylate groups with alkali cations. AB - We study the orientational dynamics of water molecules in solutions of formate salts using femtosecond mid-infrared spectroscopy. We observe that combining the formate ion with small cations like Na(+) or Li(+) leads to a cooperative effect on the water dynamics. This observation points at the formation of solvent separated ion pairs. PMID- 24068106 TI - Estrogen responsiveness of the TFIID subunit TAF4B in the normal mouse ovary and in ovarian tumors. AB - Estrogen signaling in the ovary is a fundamental component of normal ovarian function, and evidence also indicates that excessive estrogen is a risk factor for ovarian cancer. We have previously demonstrated that the gonadally enriched TFIID subunit TAF4B, a paralog of the general transcription factor TAF4A, is required for fertility in mice and for the proliferation of ovarian granulosa cells following hormonal stimulation. However, the relationship between TAF4B and estrogen signaling in the normal ovary or during ovarian tumor initiation and progression has yet to be defined. Herein, we show that Taf4b mRNA and TAF4B protein, but not Taf4a mRNA or TAF4A protein, are increased in whole ovaries and granulosa cells of the ovary after exposure to 17beta-estradiol or the synthetic estrogen diethylstilbestrol and that this response occurs within hours after stimulation. Furthermore, this increase occurs via nuclear estrogen receptors both in vivo and in a mouse granulosa cancer cell line, NT-1. We observe a significant increase in Taf4b mRNA in estrogen-supplemented mouse ovarian tumors, which correlates with diminished survival of these mice. These data highlight the novel response of the general transcription factor TAF4B to estrogen in the normal ovary and during ovarian tumor progression in the mouse, suggesting its potential role in regulating actions downstream of estrogen stimulation. PMID- 24068109 TI - Single bubble perturbation in cavitation proximity of solid glass: hot spot versus distance. AB - A systematic study of the energy loss of a cavitation bubble in a close proximity of a glass surface is introduced for the first time in a low acoustic field (1.2 2.4 bar). Single bubble sonoluminescence (SBSL) is used as a tool to predict the temperature and pressure decrease of bubble (MUm) versus surface distance. A glass as a model system is used to imitate the boundary conditions relevant for nano- or micromaterials. SBSL preequilibrated with 5% argon is perturbed by a glass rod with the tip (Z-perturbation) and with the long axis (X-perturbation) at a defined distance. From 2 mm to 500 MUm argon-SBSL lines monotonically narrow and the effective emission temperature decreases from 9000 K to 6800 K comparable to multiple bubbles. The electron density decreases by two orders of magnitude in Z-perturbation and is by a factor of two higher in X-perturbation than the unperturbed cavitating bubble. The perturbed single bubble sonoluminescence pressure decreases from 2700 atm to 1200 atm at 2.4 bar. In water new non-SBSL SiO molecular emission lines are observed and OH emission disappears. PMID- 24068110 TI - Electrical impact of MoSe2 on CIGS thin-film solar cells. AB - The CIGS solar cell is one of the most promising photovoltaic devices due to the achievement of the highest conversion efficiency (>20%) among all thin-film solar cells. The CIGS cell has a glass/Mo/CIGS/CdS/TCO configuration, and the CIGS-Mo interface is a Schottky barrier to holes. During the sulfurization-after selenization (SAS) CIGS formation process with H2Se gas, the Mo surface transforms naturally into MoSe2 at the CIGS-Mo interface. In this work, the electrical impact of MoSe2 on CIGS solar cells was investigated. Different CIGS Mo interfaces were prepared with two CIGS processes. One is SAS, and the other is the sequential-sputtering-selenization CIGS process with Se gas. Formation of MoSe2 is hardly observed in the latter process. Samples were characterized by XRD, the van der Pauw method, reflectance, and visual inspection. Besides, Schottky barrier heights of cells were extracted from J-V-T measurements. For the first time, it was experimentally shown that the existence of thin MoSe2 film can decrease the apparent Schottky barrier height of CIGS solar cells. In addition, 1 dimensional numerical simulation showed that a larger barrier height affects both the fill factor and open-circuit voltage. Therefore, the formation of MoSe2 during the CIGS process should minimize the negative effect of Schottky barrier on solar-cell performances, especially with large Schottky barrier. PMID- 24068111 TI - Enhanced activity of Rhizomucor miehei lipase by deglycosylation of its propeptide in Pichia pastoris. AB - Many studies have demonstrated that the properties of enzymes expressed in eukaryotes can be affected by the position and extent of glycosylation on enzyme. In this study, two potential glycosylation sites (the 8th and the 58th asparagine) were identified and the effect of propeptide glycosylation on Rhizomucor miehei lipase (RML) expressed in Pichia pastoris was investigated. To better understand the effect of glycosylation on the activity of RML, three mutants (M1, generated by N8A; M2, generated by N58A; and M3, generated by N8A and N58A) were designed to generate deglycosylated enzymes. The results showed that deglycosylated RML exhibited a twofold higher activity compared to the wild type. However, it was also found that glycosylation on the propeptide was important for the removal of the propeptide by Kex2 protease and secretion of the enzyme. Thus, our study provided a further understanding into the role of glycosylation on enzyme function. PMID- 24068112 TI - More questions than answers in 6 cases. PMID- 24068113 TI - The ergonomics of dishonesty: the effect of incidental posture on stealing, cheating, and traffic violations. AB - Research in environmental sciences has found that the ergonomic design of human made environments influences thought, feeling, and action. In the research reported here, we examined the impact of physical environments on dishonest behavior. In four studies, we tested whether certain bodily configurations-or postures-incidentally imposed by the environment led to increases in dishonest behavior. The first three experiments showed that individuals who assumed expansive postures (either consciously or inadvertently) were more likely to steal money, cheat on a test, and commit traffic violations in a driving simulation. Results suggested that participants' self-reported sense of power mediated the link between postural expansiveness and dishonesty. Study 4 revealed that automobiles with more expansive driver's seats were more likely to be illegally parked on New York City streets. Taken together, the results suggest that, first, environments that expand the body can inadvertently lead people to feel more powerful, and second, these feelings of power can cause dishonest behavior. PMID- 24068114 TI - In the eye of the beholder: eye contact increases resistance to persuasion. AB - Popular belief holds that eye contact increases the success of persuasive communication, and prior research suggests that speakers who direct their gaze more toward their listeners are perceived as more persuasive. In contrast, we demonstrate that more eye contact between the listener and speaker during persuasive communication predicts less attitude change in the direction advocated. In Study 1, participants freely watched videos of speakers expressing various views on controversial sociopolitical issues. Greater direct gaze at the speaker's eyes was associated with less attitude change in the direction advocated by the speaker. In Study 2, we instructed participants to look at either the eyes or the mouths of speakers presenting arguments counter to participants' own attitudes. Intentionally maintaining direct eye contact led to less persuasion than did gazing at the mouth. These findings suggest that efforts at increasing eye contact may be counterproductive across a variety of persuasion contexts. PMID- 24068115 TI - Unaware person recognition from the body when face identification fails. AB - How does one recognize a person when face identification fails? Here, we show that people rely on the body but are unaware of doing so. State-of-the-art face recognition algorithms were used to select images of people with almost no useful identity information in the face. Recognition of the face alone in these cases was near chance level, but recognition of the person was accurate. Accuracy in identifying the person without the face was identical to that in identifying the whole person. Paradoxically, people reported relying heavily on facial features over noninternal face and body features in making their identity decisions. Eye movements indicated otherwise, with gaze duration and fixations shifting adaptively toward the body and away from the face when the body was a better indicator of identity than the face. This shift occurred with no cost to accuracy or response time. Human identity processing may be partially inaccessible to conscious awareness. PMID- 24068116 TI - Social status moderates the relationship between facial structure and aggression. AB - A growing body of evidence has linked individual differences in facial structure in particular, the facial width-to-height ratio (FWHR)-to social behaviors, including aggression, cheating, and nonreciprocation of trust. In the research reported here, we extended this work by demonstrating that the association between FWHR and aggression is moderated by subjective and objective measures of social status. In Study 1 (N = 237 college students), FWHR was positively correlated with aggressive behavior, but only among men reporting relatively low social status. In Study 2 (N = 891 professional hockey players), FWHR was positively correlated with penalty minutes, but only among players who earned relatively low salaries. Collectively, these studies provide compelling evidence for the role of social status in moderating the relationship between facial structure and aggression, indicating that FWHR is a robust predictor of aggressive behavior, but only in the context of relatively low social status. PMID- 24068117 TI - Adaptation to faces and voices: unimodal, cross-modal, and sex-specific effects. AB - Exposure, or adaptation, to faces or voices biases perceptions of subsequent stimuli, for example, causing faces to appear more normal than they would be otherwise if they are similar to the previously presented stimuli. Studies also suggest that there may be cross-modal adaptation between sound and vision, although the evidence is inconsistent. We examined adaptation effects within and across voices and faces and also tested whether adaptation crosses between male and female stimuli. We exposed participants to sex-typical or sex-atypical stimuli and measured the perceived normality of subsequent stimuli. Exposure to female faces or voices altered perceptions of subsequent female stimuli, and these adaptation effects crossed modality; exposure to voices influenced judgments of faces, and vice versa. We also found that exposure to female stimuli did not influence perception of subsequent male stimuli. Our data demonstrate that recent experience of faces and voices changes subsequent perception and that mental representations of faces and voices may not be modality dependent. Both unimodal and cross-modal adaptation effects appear to be relatively sex-specific. PMID- 24068118 TI - Theoretical studies on concerted versus two steps hydrogen atom transfer reaction by non-heme Mn(IV/III)=O complexes: how important is the oxo ligand basicity in the C-H activation step? AB - High-valent metal-oxo complexes have been extensively studied over the years due to their intriguing properties and their abundant catalytic potential. The majority of the catalytic reactions performed by these metal-oxo complexes involves a C-H activation step and extensive efforts over the years have been undertaken to understand the mechanistic aspects of this step. The C-H activation by metal-oxo complexes proceeds via a hydrogen atom transfer reaction and this could happen by multiple pathways, (i) via a proton-transfer followed by an electron transfer (PT-ET), (ii) via an electron-transfer followed by a proton transfer (ET-PT), (iii) via a concerted proton-coupled electron transfer (PCET) mechanism. Identifying the right mechanism is a surging topic in this area and here using [Mn(III)H3buea(O)](2-) (1) and [Mn(IV)H3buea(O)](-) (2) species (where H3buea = tris[(N'-tert-butylureaylato)-N-ethylene]aminato) and its C-H activation reaction with dihydroanthracene (DHA), we have explored the mechanism of hydrogen atom transfer reactions. The experimental kinetic data reported earlier (T. H. Parsell, M.-Y. Yang and A. S. Borovik, J. Am. Chem. Soc., 2009, 131, 2762) suggests that the mechanism between 1 and 2 is drastically different. By computing the transition states, reaction energies and by analyzing the wavefunction of the reactant and transitions states, we authenticate the proposal that the Mn(III)=O undergoes a step wise PT-ET mechanism where as the Mn(IV)=O species undergo a concerted PCET mechanism. Both the species pass through a [Mn(III)-OH] intermediate and the stability of this species hold the key to the difference in the reactivity. The electronic origin for the difference in reactivity is routed back to the strength and basicity of the Mn-oxo bond and the computed results are in excellent agreement with the experimental results. PMID- 24068119 TI - Environmental dermatology: skin manifestations of injuries caused by invertebrate aquatic animals. AB - Contact between humans and coastal areas has increased in recent decades, which has led to an increase in injuries from aquatic animals. The majority of these present dermatological manifestations, and some of them show typical lesions. The highest percentages of injuries that occur in marine environments are associated with invertebrates such as sea urchins, jellyfish and Portuguese men-of-war (echinoderms and cnidarians). In this review, we discuss the clinical, therapeutic and preventive aspects of injuries caused by marine and freshwater invertebrates, focusing on first aid measures and diagnosis for dermatologists and professionals in coastal areas. PMID- 24068120 TI - Cutaneous mosaicisms: concepts, patterns and classifications. AB - A mosaic is an organism composed of two or more genetically distinct cell populations derived from a genetically homogeneous zygote. Cutaneous mosaicisms are the clinical expressions of these disorders. The main event which allows the existence of mosaicism is a genetic mutation, either structural or functional. Cutaneous mosaicisms usually manifest by specific patterns on the skin and the archetypic pattern is the system of Blaschko lines, but others include checkerboard, phylloid, large patches without midline separation and lateralization. Since 1901, when Blaschko lines were first described, the study of mosasicism has helped to elucidate the behavior of numerous genetic diseases, generating therapeutic perspectives for these pathologies, including the promising gene therapy. PMID- 24068121 TI - Colonization by S. aureus increases the EASI and the number of appointments by patients with atopic dermatitis: cohort with 93 patients. AB - BACKGROUND: Atopic dermatitis leads to epidermal barrier dysfunction and bacteria colonization. The relationship of the last factor with the severity of the disease and the frequency of exacerbation is not fully known. OBJECTIVES: Verify the severity of the atopic dermatitis and the number of appointments generated by dermatosis, comparing patients colonized with patients not colonized by S. aureus. Verify the frequency of colonization by methicillin resistant Staphylococcus aureus acquired in the community. METHODS: Cohort study with a 12 months follow-up, in a sample of patients from Porto Alegre, RS public network. Cultures in active injuries and nasal cavities were carried out as well as methicillin sensitivity tests to S. aureus. The severity of atopic dermatitis was defined by Eczema Area and Severity Index (EASI). RESULTS: We included 93 patients, 43% female and 56% male, 26 colonized by S. aureus in the nasal orifices, 56 in the skin damage. The mean of initial Eczema Area and Severity Index was 5.5 and final 3.9. The initial Eczema Area and Severity Index of patients colonized by S. aureus in the skin and nasal cavity was larger than the number of patients without colonization(p< 0.05). During the period of one year, in average, there were six appointments/patient. There was linear correlation between the number of appointments during one year and the inicial Eczema Area and Severity Index (r = 0,78). There were no patients with methicillin resistant Staphylococcus aureus acquired in the community. CONCLUSION: There is a relevant influence of staphylococcal colonization on the severity of atopic dermatitis and the number of appointments required by its exacerbation. Methicillin resistance among those affected by S. aureus does not seem to be an emergent problem, in this Brazilian sample. PMID- 24068122 TI - Sexually transmitted diseases in a specialized STD healthcare center: epidemiology and demographic profile from January 1999 to December 2009. AB - BACKGROUND: Sexually Transmitted Diseases are still considered a serious public health problem in Brazil and worldwide. OBJECTIVE: To examine Sexually Transmitted Diseases prevalence and the sickness impact profile of STDs in a reference health center specializing in the treatment of Sexually Transmitted Diseases. METHOD: We collected epidemiological, demographic, clinical and laboratory data from the medical records and interviews of 4,128 patients who had attended the center from January 1999 to December 2009. RESULTS: Male patients outnumbered (76%) females (24%), Caucasians outnumbered (74.3%) those of mixed race (14.8%), blacks (10.8%) and Asians (0.1%). STD occurrence was higher in the 20-29 age group (46.2%) This population included 34.7% high school graduates, 8.7% college graduates and 0.8% illiterates. As for affective-sexual orientation, 86.5% were heterosexual, 7.8% homosexual and 5.5% bisexual. Regarding patients' sexual practices over the previous 30 days, 67.7% reported sexual intercourse with one person, 8.6% had had sex with two persons and 3.9%, with three or more people. The highest incidence of STD was condyloma acuminata, affecting 29.4% of all the patients, genital candidiasis 14.2%, and genital herpes 10.6%. Of the 44.3% who submitted to serologic testing for HIV detection 5% were positive, with a ratio of 6.8 males to 1 female. CONCLUSIONS: STD prevalence remains high in Brazil and it is necessary to invest in early detection, prevention and treatment. PMID- 24068124 TI - Cutaneous metastasis from internal carcinomas: a review of 45 years. AB - BACKGROUND: cutaneous metastases are not so frequent and in the medical literature there are several communications of isolated cases, thereby we decided to continue our study initiated in 1981 (45 years). OBJECTIVE: our objective is to present the research and review of cutaneous metastases of 45 years through our archives at Hospital do Servidor Publico Estadual de Sao Paulo. METHODS: the data were collected from clinical cases registered in our archives at anatomopathology department. RESULTS: since 1963 we have registered 209 patients with cutaneous metastases being the anterior thorax region the most affected area and in second place the abdominal region. Breast cancer was responsible for most of the cases in women and the lung in men. CONCLUSION: this study represents a significant number of cases in medical practice because skin metastases of internal carcinomas rarely are observed and the great predominance, mainly due of his origin were represented by adenocarcinomas. PMID- 24068123 TI - Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients. AB - BACKGROUND: Porphyria cutanea tarda is the most common form of porphyria, characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with porphyria cutanea tarda worldwide, although up to date only one study has been conducted in Brazil. OBJECTIVES: Investigation of porphyria cutanea tarda association with C282Y and H63D mutations in the HFE gene. Identification of precipitating factors (hepatitis C, HIV, alcoholism and estrogen) and their link with HFE mutations. METHODS: An ambispective study of 60 patients with PCT was conducted during the period from 2003 to 2012. Serological tests for hepatitis C and HIV were performed and histories of alcohol abuse and estrogen intake were investigated. HFE mutations were identified with real-time PCR. RESULTS: Porphyria cutanea tarda predominated in males and alcohol abuse was the main precipitating factor. Estrogen intake was the sole precipitating factor present in 25% of female patients. Hepatitis C was present in 41.7%. All HIV positive patients (15.3%) had a history of alcohol abuse. Allele frequency for HFE mutations, i.e., C282Y (p = 0.0001) and H63D (p = 0.0004), were significantly higher in porphyria cutanea tarda patients, compared to control group. HFE mutations had no association with the other precipitating factors. CONCLUSIONS: Alcohol abuse, hepatitis C and estrogen intake are prevalent precipitating factors in our porphyria cutanea tarda population; however, hemochromatosis in itself can also contribute to the outbreak of porphyria cutanea tarda, which makes the research for HFE mutations necessary in these patients. PMID- 24068125 TI - Epidemiological and histopathological profile of cutaneous melanoma at a center in northeastern Brazil from 2000 to 2010. AB - BACKGROUND: While representing only 3-4% of malignant skin tumors, cutaneous melanoma is the most aggressive and lethal. Statistical knowledge about the biological behavior of this tumor is essential for guiding daily outpatient practice and aiding public health policies. OBJECTIVES: To analyze the profile of patients with cutaneous melanoma attending a pathology department in Teresina (state of Piaui) between 2000 and 2010. METHODS: Retrospective study of melanoma patients diagnosed between 2000 and 2010 in the Sao Marcos Hospital in the city of Teresina. The pathology laboratory reports were studied and all the statistical analyses performed using SPSS 19.0. RESULTS: A total of 25 in situ, 199 invasive and 89 metastatic melanomas of unknown primary site were observed. Histological types found were nodular (52.8%), superficial spreading melanoma (18.6%), acral (10.6%) and lentigo maligna (9.5%). In 144 (73.4%) cases the Breslow thickness was >1 mm. Metastasis was found in 28.6% of invasive melanomas and nodular melanoma, Clark IV/ V, Breslow > 1 mm, mitotic index > 6 and ulcerated lesions were more likely to metastasize. CONCLUSION: Most melanomas presented Breslow> 1mm. The main factors associated with metastasis were nodular type, Clark IV / V, Breslow > 1mm, mitotic index > 6 and ulcerated lesions. PMID- 24068126 TI - Prevalence of sun exposure and its associated factors in southern Brazil: a population-based study. AB - BACKGROUND: Sunlight exposure is responsible for a large number of dermatological diseases. OBJECTIVE: We estimated the prevalence of sunlight exposure and its associated factors in adults from southern Brazil in a cross-sectional, population-based study. METHODS: We investigated a representative sample of individuals aged >= 20 years (n=3,136). Sunlight exposure and its associated factors were evaluated in two distinct situations: at leisure time and at work. The time period investigated ranged from December 2004 to March 2005, comprising 120 days of the highest ultraviolet index in the urban area of the city of Pelotas, in southern Brazil. The participants were asked about sunlight exposure for at least 20 minutes between 10 A.M. and 4 P.M. The analysis was stratified by sex, and sunlight exposure was grouped into five categories. RESULTS: Among the 3,136 participants, prevalence of sunlight exposure at the beach was 32.8% (95% CI, 30.3 - 35.2) and 26.3% (95% CI, 24.2 28.3) among men and women, respectively. The prevalence at work was 39.8% (95% CI, 37.2 - 42.4) among men and 10.5% (95% CI, 9.1 - 12.0) among women. Age was inversely associated with sunlight exposure. Family income and achieved schooling were positively associated with sunlight exposure at leisure time and inversely associated with sunglight exposure at work. Self-reported skin color was not associated. Knowledge of any friend or relative who has been affected by skin cancer was positively associated with sunlight exposure among men at work. CONCLUSION: Despite the media campaigns on the harmful effects of excessive sunlight exposure, we found a high prevalence of sunlight exposure during a period of high ultraviolet index. PMID- 24068127 TI - Time needed to schedule dermatological consultations in Brazil. AB - BACKGROUND: It is not clear what the population's demand for dermatologists is, nor how many professionals are needed in order to provide adequate care in this area of expertise. Knowledge of the flow of patients at dermatological clinics throughout the country allows for the formation of expansion and distribution policies regarding professionals, and provides backing for the decision to increase medical residency places. OBJECTIVES: To evaluate the time it takes to schedule a private dermatological consultation in Brazil, and other factors concerning consultations. METHODS: Survey with a random sample of 14% of Brazilian dermatologists, simulating the scheduling of emergency clinical and cosmetic consultations, and botulinum toxin procedures. Also, details relating to cost and professionals, were studied. Data were adjusted for each region of the country. RESULTS: A total of 873 dermatologists were evaluated. Full SBD members represented 85%, and 66% were women. The median time to schedule a consultation ranged from 6 (out-of-pocket payment) to 7 (medical insurance) consecutive working days. Times varied depending on the region. A multivariate analysis showed that out-of-pocket consultations and procedures were scheduled sooner than with medical insurance, regardless of whether they were clinical or cosmetic. CONCLUSION: The characteristics of dermatologists are varied throughout regions of the country. Private consultations and procedures are scheduled sooner than with insurance companies. PMID- 24068128 TI - Treatment of HIV-associated facial lipoatrophy: impact on infection progression assessed by viral load and CD4 count. AB - BACKGROUND: HIV/AIDS-Associated Lipodystrophy Syndrome includes changes in body fat distribution, with or without metabolic changes. The loss of fat from the face, called facial lipoatrophy, is one of the most stigmatizing signs of the syndrome. OBJECTIVES: To evaluate the effect of FL treatment using polymethylmethacrylate (PMMA) implants on disease progression, assessed by viral load and CD4 cell count. METHODS: This was a prospective study of 44 patients treated from July 2009 to December 2010. Male and female patients, aged over 18 years, with clinically detectable FL and who had never been treated were included in the study. PMMA implantation was done to fill atrophic areas. Laboratory tests were conducted to measure viral load and CD4 count before and after treatment. RESULTS: Of the 44 patients, 72.72% were male and 27.27% female, mean age of 44.38 years. Before treatment, 82% of patients had undetectable viral load, which increased to 88.6% after treatment, but without statistical significance (p = 0.67). CD4 count before treatment ranged from 209 to 1293, averaging 493.97. After treatment, the average increased to 548.61. The increase in CD4 count after treatment was statistically significant with p = 0.02. CONCLUSION: The treatment of FL with PMMA implants showed a statistically significant increase in CD4 count after treatment, revealing the impact of FL treatment on disease progression. Viral load before and after treatment did not vary significantly. PMID- 24068129 TI - Hereditary angioedema type III (estrogen-dependent) report of three cases and literature review. AB - In this article, three cases of hereditary angioedema (HAE) type III (estrogen dependent or with normal C1 inhibitor) are reported. The HAE was initially described in women of the same family in association with high-leveled estrogenic conditions such as the use of oral contraceptives and pregnancy. There is no change in the C1 inhibitor as happens in other types of hereditary angioedema, and mutations are observed in the encoding gene of the XII factor of coagulation in several patients. The current diagnosis is mainly clinical and treatment consists in the suspension of the triggering factors and control of acute symptoms. A brief review of physiopathology, clinical features, genetic alterations and treatment are also presented. PMID- 24068130 TI - Retinoids for prevention and treatment of actinic keratosis. AB - Actinic keratosis is a common cause of dermatological consultations and it presents a strong association with squamous cell carcinoma. Many substances are used for treatment and prevention, such as retinoids. Nevertheless, many studies on retinoids emphasize their application in treating and preventing non melanoma skin cancers. In this article, we reviewed studies about systemic and topical retinoids used with immunocompetent patients and organ transplant recipients with actinic keratosis, as primary or secondary outcomes. The majority of these papers pointed to a reduction in actinic keratosis count after treatment with retinoids. However, studies need to be better-defined in order to address the lack of a standardized dose, the absence of control groups, the low number of patients and short follow-up periods. Blind, randomized and controlled clinical trials with adequate sample sizes, specifically focused on actinic keratosis, are needed to clarify the real benefit of topical and/or oral retinoids. Comparison of efficacy and safety between oral and topical retinoids in the prevention and treatment of non-melanoma skin cancers and actinic keratosis is an essential pre requisite to establish new strategies to control these conditions. PMID- 24068131 TI - Review: dermatitis herpetiformis. AB - Dermatitis herpetiformis (DH) or Duhring-Brocq disease is a chronic bullous disease characterized by intense itching and burning sensation in the erythematous papules and urticarial plaques, grouped vesicles with centrifuge growth, and tense blisters. There is an association with the genotypes HLA DR3, HLA DQw2, found in 80-90% of cases. It is an IgA-mediated cutaneous disease, with immunoglobulin A deposits appearing in a granular pattern at the top of the dermal papilla in the sublamina densa area of the basement membrane, which is present both in affected skin and healthy skin. The same protein IgA1 with J chain is found in the small intestinal mucosa in patients with adult celiac disease, suggesting a strong association with DH. Specific antibodies such as antiendomysium, antireticulina, antigliadin and, recently identified, the epidermal and tissue transglutaminase subtypes, as well as increased zonulin production, are common to both conditions, along with gluten-sensitive enteropathy and DH. Autoimmune diseases present higher levels of prevalence, such as thyroid (5-11%), pernicious anemia (1-3%), type 1 diabetes (1-2%) and collagen tissue disease. The chosen treatment is dapsone and a gluten-free diet. PMID- 24068132 TI - Linear IgA dermatosis associated with ulcerative colitis: complete and sustained remission after total colectomy. AB - Linear IgA dermatosis has been increasingly associated with inflammatory bowel diseases, particularly ulcerative colitis. A 13-year-old male patient with an 11 month history of ulcerative colitis developed vesicles, pustules and erosions on the skin of the face, trunk and buttocks and in the oral mucosa. The work-up revealed a neutrophil-rich sub-epidermal bullous disease and linear deposition of IgA along the dermoepidermal junction, establishing the diagnosis of linear IgA dermatosis. The patient experienced unsatisfactory partial control of skin and intestinal symptoms despite the use of adalimumab, mesalazine, prednisone and dapsone for some months. After total colectomy, he presented complete remission of skin lesions, with no need of medications during two years of follow-up. A review of previously reported cases of the association is provided here and the role of ulcerative colitis in triggering linear IgA dermatosis is discussed. PMID- 24068133 TI - Involucrin in the differential diagnosis between linear psoriasis and inflammatory linear verrucous epidermal nevus: a report of one case. AB - Inflammatory linear verrucous epidermal nevus is a variant of verrucous epidermal nevus, characterized by recurrent inflammatory phenomena. Despite well established clinical manifestations, the differential diagnosis between inflammatory linear verrucous epidermal nevus and linear psoriasis remains difficult. Clinical history, physical examination and histopathology analysis may not be sufficient to confirm the diagnosis. We report the case of a 4-year-old girl in which the involucrin immunostaining was helpful in the diagnosis of inflammatory linear verrucous epidermal nevus. Our findings confirm that involucrin immunohistochemistry is a useful tool in such cases. PMID- 24068134 TI - Breast carcinoma en Cuirasse--case report. AB - Cutaneous metastasis is a phenomenon that results from a tumor spreading via lymphatic or vascular embolization, direct implant during surgery or skin involvement by contiguity. The primary malignant tumor that most commonly metastasizes to the skin in women is breast cancer, which can be manifested through papulonodular lesions, erysipeloid or sclerodermiform infiltration, en cuirasse. We report the case of a female patient, 78 years old, with papular, scaly and confluent lesions in the right breast for one year, progressing to edema and skin infiltration, reduction of breast volume and plaque en cuirasse, and similar lesions in the contralateral breast and abdomen for four months. The pathological diagnosis was invasive ductal breast carcinoma with Paget-like foci, epidermal skin metastases and lymphatic embolization. PMID- 24068135 TI - Protein contact dermatitis--case report. AB - Protein contact dermatitis is a skin condition not well known and underdiagnosed by dermatologists, resulting from an IgE-mediated allergic reaction. Clinically it presents as a chronic hand and/or forearms eczema of occupational origin, especially in professionals who work as food handlers. Epicutaneous tests are negative, and to diagnose this condition it is necessary to perform immediate type allergy tests. The most sensitive and practical is the prick-by-prick test with food that the patient refers to cause intense itching after immediate skin contact. Treatment is symptomatic, and it is mandatory to avoid the responsible allergen, wearing plastic gloves and even sometimes leaving the workplace for symptom resolution. PMID- 24068136 TI - Dermatofibroma in a black tattoo: report of a case. AB - Tattooing has been associated with a variety of complications including inflammatory and granulomatous reactions, transmission of infections, and neoplasms. We report a case of a 24-year-old male who presented with a 2-month history of an erythematous nodule involving a newly made tattoo on the right leg. An excisional biopsy was performed and the histopathological evaluation was consistent with dermatofibroma. Only three cases of dermatofibroma associated with tatooing were reported in literature. We report an additional case and review the literature regarding cutaneous reactions to tattoos. PMID- 24068137 TI - Fixed drug eruption caused by tadalafil--case report. AB - Fixed drug eruptions (FDE) are commonly reported type of mucocutaneous drug eruption. The aim of this paper is to present a patient with multiple mucocutaneous erythema fixum type lesions caused by oral tadalafil use. A short course of topical corticosteroid therapy resulted in complete resolution of all lesions leaving residual hyperpigmentation of the involved skin sites. Mucosal oral lesions were effectively treated with gingival hyaluronic acid 0.2% gel. CONCLUSION: when assessing a patient of any age with drug eruptions, a thorough personal history should be obtained, in particular data on regular or recreational use of phospodiesterase type 5 inhibitors. PMID- 24068138 TI - Extensive hydroa vacciniforme. AB - Hydroa Vaciniforme is a very rare photodermatosis that is mainly seen in childhood. An 18 year old female student reported that since the age of 5 she has been suffering necrotic lesions and vesicles lesions in exposed areas, leaving asymptomatic varioliform scars, which worsened in summer. Light microscopy showed epidermal necrosis with lymphocytic infiltration . Sunscreens were prescribed with light improvement. PMID- 24068139 TI - Circumscribed palmoplantar hypokeratosis: report of two Brazilian cases. AB - Circumscribed palmoplantar hypokeratosis is a recently recognized dermatosis and rarely reported. It was first described in 2002 and is characterized by localized loss of the horny layer in the palmoplantar area. This dermatosis is clinically presented with a sharply circumscribed, reddish and asymptomatic plaque with slightly depressed surface localized on the palms or the soles. The clinical differential diagnosis includes mainly porokeratosis and Bowen's disease. Its pathogenesis remains unknown, but studies have proposed a human papillomavirus induced disease or a localized keratinization disorder in the palmoplantar area. We report herein two cases of patients with lesions clinically and microscopically compatible with the diagnosis of circumscribed palmoplantar hypokeratosis. We also present a brief literature review of the etiopathogenic hyphoteses of this dermatosis. PMID- 24068140 TI - Ichthyosis associated with widespread tinea corporis: report of three cases. AB - Ichthyoses are a common group of keratinization disorders. A non-inflammatory generalized persistent skin desquamation is observed. It is characterized by increased cell turnover, thickening of the stratum corneum and functional changes of sebaceous and sweat glands. All of these favor fungal proliferation. Dermatophytes may infect skin, hair and nails causing ringworm or tinea. They have the ability to obtain nutrients from keratinized material. One of its most prevalent genera is Trichophyton rubrum. Although tineas and ichthyoses are quite common, the association of the two entities is rarely reported in the literature. Three cases of ichthyosis associated with widespread infection by T. rubrum are presented. Resistance to several antifungal treatments was responsible for worsening of ichthyosis signs and symptoms. PMID- 24068141 TI - Soft-tissue masses as presentation of non-Hodgkin's lymphoma in AIDS patients. AB - Primary soft tissue Non-Hodgkin lymphomas are very rare and account only for 0.1 % of the cases. Generally, Non-Hodgkin lymphomas of the soft tissue present as large subcutaneous masses without evidence of nodal or skin involvement. We describe four cases of primary Non-Hodgkin lymphomas of the soft tissue in patients infected with the human immunodeficiency virus. The most common site of involvement was the chest wall in all the patients; histopathological and immunophenotypic examination of the biopsy smears revealed two cases of plasmablastic lymphomas, one Burkitt and one diffuse large B-cell lymphoma. Non Hodgkin lymphomas should be included in the differential diagnosis of soft tissue masses in human immunodeficiency virus - seropositive patients. PMID- 24068142 TI - Cutaneous mucinosis in mixed connective tissue disease. AB - Cutaneous mucinosis is a group of conditions involving an accumulation of mucin or glycosaminoglycan in the skin and its annexes. It is described in some connective tissue diseases but never in association with mixed connective tissue disease. This report concerns two cases of cutaneous mucinosis in patients with mixed connective tissue disease in remission; one patient presented the papular form, and the other reticular erythematous mucinosis. These are the first cases of mucinosis described in mixed connective tissue disease. Both cases had skin lesions with no other clinical or laboratorial manifestations, with clinical response to azathioprine in one, and to an association of chloroquine and prednisone in the other. PMID- 24068143 TI - Severe multi-resistant pemphigus vulgaris: prolonged remission with a single cycle of rituximab. AB - Pemphigus vulgaris is an autoimmune bullous disease whose therapy is based on systemic corticosteroids, with or without immunosuppressants. Rituximab is a chimeric monoclonal antibody of the IgG class, directed at a specific CD20 B cell surface antigen, used in pemphigus vulgaris empirically since 2002, with success in 90% of the cases and long periods of remission. Male patient, 33 years old, diagnosed with pemphigus vulgaris, confirmed by histopathology and direct immunofluorescence. He was treated for seven months with numerous treatments, including immunosuppressive drugs, with an unsatisfactory response, until he had complete remission with the use of rituximab. During a 34-month follow-up period, the patient presented a slight clinical relapse, which was successfully controlled with prednisone in a daily dose of 120 mg, soon reduced to 20mg. PMID- 24068144 TI - Dermatoscopic findings in telangiectasia macularis eruptiva perstans. AB - Telangiectasia macularis eruptiva perstans is a rare form of cutaneous mastocytosis, characterized by the presence of erythematous or yellowish-brown macules with telangiectasias, preferably located on the trunk and upper limbs. We have described a case of telangiectasia macularis eruptiva perstans focusing on the dermoscopic characteristics of this disease. PMID- 24068145 TI - Parallel ridge pattern on dermoscopy: observation in non-melanoma cases. AB - The acral melanoma is the most prevalent type of melanoma in the non-Caucasian population, and dermoscopy is a useful tool for earlier diagnosis and differentiation from benign lesions. The dermoscopic pattern often associated with melanoma on the volar skin is the parallel ridge, with 99% specificity according to the literature. However, this pattern can also occur in several benign acral lesions, so it is important to make a good interpretation of this pattern, along with the clinical history and evolution. PMID- 24068146 TI - Tungiasis under dermoscopy: in vivo and ex vivo examination of the cutaneous infestation due to Tunga penetrans. AB - The female flea Tunga penetrans is responsible for a cutaneous parasitosis known as Tungiasis. We report the clinical case of a 12 year-old Caucasian boy who sought treatment in a dermatological private office due to a painful lesion in the plantar area and whose dermoscopic examination, without skin contact, allowed the visualization of parasite's movement inside the skin. The diagnosis of tungiasis is clinical, but it can be aided by in vivo and ex vivo dermoscopic examination of the lesion. PMID- 24068147 TI - Case for diagnosis: bullosis diabeticorum. AB - We present a case of bullosis diabeticorum. It is a rare disorder, probably underdiagnosed, associated with long-term diabetes mellitus. Its etiology remains unclear. It is characterized by tense blisters, with serous content, recurrent and spontaneous on normal skin especially in the acral regions. Displays self limiting course. No specific laboratory tests for diagnosis of this bullous disease exist. Clinical and conservative management to prevent secondary infection reduces morbidity in diabetic patients. PMID- 24068148 TI - Case for diagnosis: Linear Darier. AB - Linear Darier is a rare variant of Darier's Disease. The keratotic papules follow Blaschko's lines, characterizing the cutaneous mosaicism. We report the case of a 42-year-old woman who presented with small, linearly distributed, reddish-brown papules on the left mammary region, from the left flank to the hypogastrium and on the pretibial area of the left leg. Histologically, suprabasal acantholysis and dyskeratotic cells were seen, confirming the diagnosis. PMID- 24068149 TI - Case for diagnosis: childhood granulomatous periorificial dermatitis. AB - Childhood Granulomatous Periorificial Dermatitis is an acneiform facial rash that affects the periorificial area in children. The clinical aspectare asymptomatic 1 3 mm papules of, monomorphic, erythematous or hypopigmented in periorificial areas - mouth, nose and eyes. It's a benign and self-limited disease that heals spontaneously without scarring and specific therapy. Differential diagnoses include perioral dermatitis, granulomatous-rosacea, sarcoidosis, and lupus miliaris disseminatus faciei. We present the case of a 4-year-old boy, presenting papules in periorificials areas. Due to its low incidence and low number of publications we report the present case. PMID- 24068150 TI - Do you know this syndrome? Noonan syndrome. AB - Noonan Syndrome is one of the most common genetic syndromes and also an important differential diagnosis in children presenting with syndromic facies similar to Turner's syndrome phenotype. This syndrome is characterized by facial dysmorphism, congenital heart defects, short stature and also a wide phenotypic variation. This article discusses the case of a 10 year-old patient with Noonan syndrome that presented typical facies, cardiac defects (pulmonary dilatation and mitral regurgitation), dental malocclusion, micrognatism, short stature and a certain degree of learning disability. PMID- 24068151 TI - Evaluation of renal function in patients with psoriasis using immunobiologicals. AB - The aim of this study was to evaluate renal function in patients with psoriasis using immunobiologicals. A prospective study was conducted with 15 patients with confirmed diagnosis of psoriasis who were starting to use immunobiologicals. The mean age was 41 +/- 11 years, with 60% females. The mean time of disease was 11 +/- 6.6 years. Significant changes in creatinine and creatinine clearance were not observed in the course of the study. There was an increase in transaminases and a decrease in magnesium levels. PMID- 24068152 TI - Occupational and non-occupational allergic contact dermatitis and quality of life: a prospective study. AB - Attempted to evaluate and compare the impact on quality of life of occupational and non-occupational ACD and to identify the most frequently involved allergens. A quality of life questionnaire was applied. We noted moderate impact on the quality of life of both groups, without a statistical difference. Our study corroborates previous general data on the prevalence of nickel sulphate and paraphenylenediamine as the most common allergens. Potassium bichromate was shown to be one of the main occupational allergens and thimerosal as the main non occupational allergen in our sample. PMID- 24068153 TI - Pulse therapy in pemphigus: report of 11 cases. AB - In this study, five cases of pemphigus vulgaris and two cases of pemphigus foliaceus were treated with cyclophosphamide pulse therapy associated with prednisone, resulting in the need for a smaller maintenance dose of prednisone. In three cases of pemphigus vulgaris and one case of pemphigus foliaceus, dexamethasone and cyclophosphamide pulse therapy associated with prednisone helped the lesions to heal more rapidly. Neither treatment however prevented the recurrence of the disease. Amenorrhea, myelotoxicity and Stevens-Johnson syndrome were among the cyclophosphamide side effects. All the patients treated with prednisone experienced known side effects. PMID- 24068154 TI - Off-label use of rituximab in dermatology: pemphigus treatment. AB - Since its approval in 1997 by the FDA (United States Food and Drug Administration), rituximab has been used for certain B-cell lymphomas and treatment-resistant rheumatoid arthritis. Nevertheless, over the past 14 years, many case reports have demonstrated the efficacy of off-label rituximab in several dermatological inflammatory conditions. This study describes two cases of pemphigus vulgaris and two cases of pemphigus foliaceous that were treated with rituximab at 375 mg/m2 once a week for 4 weeks, and that responded well to treatment. PMID- 24068155 TI - Diagnostic challenges of CD4+/CD56+/CD123+ hematological neoplasms. PMID- 24068156 TI - Highly enantioselective hydrogenation and transfer hydrogenation of cycloalkyl and heterocyclic ketones catalysed by an iridium complex of a tridentate phosphine-diamine ligand. AB - Ir complexes of chiral phosphine-diamine ligands catalyse the hydrogenation and transfer hydrogenation of aryl-piperidin-4-yl methanones, and ketones bearing both an aryl group and secondary alkyl substituent with up to 98% e.e., and with substrate to catalyst ratios of up to 4000. PMID- 24068158 TI - Consequences of radial artery harvest: results of a prospective, randomized, multicenter trial. AB - IMPORTANCE: To date, no study has defined the consequences of radial artery harvest based on a large number of patients in a prospective randomized trial. OBJECTIVE: To compare pain at the harvest site and functional changes associated with harvesting the radial artery vs saphenous vein for coronary artery bypass grafting. DESIGN, SETTING, AND PARTICIPANTS: This study compares the consequences of radial artery harvest with saphenous vein harvest in patients undergoing elective coronary artery bypass grafting procedures in Veterans Affairs hospitals. MAIN OUTCOMES AND MEASURES: Eleven hospitals screened 6148 patients, of whom 751 were included in this trial. We analyzed 2 variables: pain at the harvest site as measured on a scale of 0 to 100 (least to most painful) and hand performance testing. Patients included in this analysis had radial artery only (n = 80) or saphenous vein only (n = 337) harvest. Pain score, grip strength, and dexterity were measured before surgery and at 3 and 12 months after surgery. We adjusted for pain scores of the nonharvested extremity, age, whether the patient underwent endoscopic vein harvesting, and comorbid health conditions (smoking history, type 2 diabetes mellitus, hypertension, and heart failure). RESULTS: There was a significant difference in change of pain score at 3 months from the preoperative baseline between radial artery and saphenous vein groups after adjusting for covariates (P < .001) but not at 12 months (P = .07). No significant changes occurred in grip strength or dexterity from preoperative baseline to 3 and 12 months after surgery (P > .05). CONCLUSIONS AND RELEVANCE: The radial artery group reported significantly more pain than the saphenous vein group 3 months after surgery; however, similar levels of pain were observed in both groups at 12 months after surgery. Grip strength and manual dexterity were not changed by radial artery harvesting at 3 and 12 months. PMID- 24068157 TI - Seizures during antidepressant treatment in psychiatric inpatients--results from the transnational pharmacovigilance project "Arzneimittelsicherheit in der Psychiatrie" (AMSP) 1993-2008. AB - RATIONALE: There is little clinical data available about seizure rates in psychiatric inpatients, and there are no studies with reference data to the frequencies of antidepressant (AD) use for this important clinical population. OBJECTIVE: This study investigates seizure rates during AD treatment in psychiatric inpatient settings, drawn from the transnational pharmacovigilance programme Arzneimittelsicherheit in der Psychiatrie (AMSP) in relation to the known frequencies of ADs used in the participating clinics. Comparisons are made to former publications and their limitations. RESULTS: Seventy-seven cases were identified with grand mal seizures (GMS) during AD treatment between 1993 and 2008, with a total number of 142,090 inpatients under surveillance treated with ADs in the participating hospitals. The calculated overall rate of reported seizures of patients during AD treatment in this collective is 0.05 % for ADs imputed alone or in combination with other psychotropic drug groups and 0.02 % when only ADs were given and held responsible for GMS. The patients receiving tri or tetracyclic ADs (TCAs) had a 2-fold risk to develop a seizure as compared to the overall average rate in this sample. In 11 cases, there was only one AD imputed--the majority of these cases (9/11) were TCA. Monotherapy with selective serotonin reuptake inhibitors (SSRI) or dual serotonin and noradrenaline reuptake inhibitors (SNRI) were never imputed alone in this sample. CONCLUSIONS: The results of the study favour the assumption that SSRIs, noradrenergic and specific serotonergic antidepressants (NaSSA) and dual SNRI might be more appropriate than TCAs for the treatment of psychiatric patients with an enhanced seizure risk. PMID- 24068159 TI - Metallothionein polymorphisms in pathological processes. AB - Metallothioneins (MTs) are a class of metal-binding proteins characterized by a high cysteine content and low molecular weight. MTs play an important role in metal metabolism and protect cells against the toxic effects of radiation, alkylating agents and oxygen free radicals. The evidence that individual genetic characteristics of MTs play an important role in physiological and pathological processes associated with antioxidant defense and detoxification inspired targeted studies of genetic polymorphisms in a clinical context. In recent years, common MT polymorphisms were identified and associated with, particularly, western lifestyle diseases such as cancer, complications of atherosclerosis, and type 2 diabetes mellitus along with related complications. This review summarizes all evidence regarding MT polymorphisms of major human MTs (MT1, MT2, MT3 and MT4), their relation to pathological processes, and outlines specific applications of MTs as a set of genetic markers for certain pathologies. PMID- 24068160 TI - Silver oxide nanocrystals anchored on titanate nanotubes and nanofibers: promising candidates for entrapment of radioactive iodine anions. AB - Iodine radioisotopes are released into the environment by the nuclear industry and medical research institutions using radioactive materials. The (129)I(-) anion is one of the more mobile radioactive species due to a long half-life, and it is a great challenge to design long-term management solutions for such radioactive waste. In this study, a new adsorbent structure with the potential to efficiently remove radioactive iodine anions (I(-)) from water is devised: silver oxide (Ag2O) nanocrystals firmly anchored on the surface of titanate nanotubes and nanofibers via coherent interfaces between Ag2O and titanate phases. I(-) anions in fluids can easily access the Ag2O nanocrystals and be efficiently trapped by forming AgI precipitate that firmly attaches to the adsorbent. Due to their one-dimensional morphology, the new adsorbents can be readily dispersed in liquids and easily separated after purification; and the adsorption beds loaded with the adsorbents can permit high flux. This significantly enhances the adsorption efficiency and reduces the separation costs. The proposed structure reveals a new direction in developing efficient adsorbents for the removal of radioactive anions from wastewater. PMID- 24068161 TI - Tautomeric effect of hydrazone Schiff bases in tetranuclear Cu(II) complexes: magnetism and catalytic activity towards mild hydrocarboxylation of alkanes. AB - Three new tetranuclear copper(II) complexes [Cu(HL(1))]4.4EtOH (1.4EtOH), [Cu(HL(2))]4 (2) and [Cu(H2L(3))]4(NO3)4.2H2O (3.2H2O) have been synthesized using three different hydrazone Schiff base ligands derived from the condensation of the aromatic acid hydrazides 2-hydroxybenzo-, 2-aminobenzo- or benzo hydrazide, with 2,3-dihydroxybenzaldehyde. Complexes 1 and 3 have been characterized by single crystal X-ray diffraction analysis. The coordinating behaviour of the ligand depends on the nature of the ortho substituent present in the hydrazide moiety. The ligands bearing a strong electron donating group (by resonance) in the ortho position undergo complexation via enolization and deprotonation, whereas the absence of such an effect leads to complexation via the keto form, and two different types of tetranuclear Cu(II) clusters, viz. open cubane and cubane, are obtained. Variable temperature magnetic susceptibility measurements of complexes 1 and 3 have been carried out to examine the nature of magnetic interaction between the Cu(II) centres. All the three complexes (1-3) act as good catalyst precursors towards mild hydrocarboxylation of linear and cyclic alkanes into carboxylic acids in water-acetonitrile medium. PMID- 24068162 TI - Effective shell layer thickness of platinum for oxygen reduction reaction alloy catalysts. AB - Effects of surface Pt monolayer thickness on electrochemical oxygen reduction reaction of molecular-beam-epitaxially-prepared Pt/Ni/Pt(111) were investigated. The effective thickness of Pt for stabilizing the topmost surface can be deduced to be three monolayers. PMID- 24068163 TI - The in vitro and in vivo treatment effects of overexpressed lentiviral vector mediated human BMP2 gene in the femoral bone marrow stromal cells of osteoporotic rats. AB - This study aimed to compare the treatment effects of lentiviral vector-mediated hBMP2 which was overexpressed in the femoral bone marrow stromal cells of osteoporotic rats through genetic infection in vitro and in vivo. Comparison of the two transgenic effects may be crucial to determining the lentivirus infection method to be used. Following a comparison of the rat bone marrow stromal cells (rBMSCs) in osteoporotic (MSCs OVX) and normal (MSCs CON) groups, the lentiviral vector-mediated human bone morphogenetic protein 2 (hBMP2), which overexpressed the BMSCs of osteoporotic rats in vitro (rBMSCs in OE group), was constructed. The osteogenic ability in the overexpressed (OE) group was then compared to that of the MSCs CON. The rBMSCs in the OE group (transplants of genetic infection in vitro) and the lentivirus-containing solution (injected material of genetic infection in vivo) were injected into the femurs. The treatment effect of each group was compared via bone mineral density (BMD) and bone histomorphometry. The hBMP2-modified osteoporosis rBMSCs formed by genetic infection in vitro (n=7) had an ameliorated treatment effect on the femur as compared to that of the in vivo (n=7) (BMD: 0.315 vs. 0.19 g/cm2, P<0.01; bone histomorphometry: For bone trabeculars (Tb.Ar/T.Ar): 0.301 vs. 0.114, P<0.01; for trabecular thickness (Tb.Th): 43.54 vs. 21.39 um, P<0.01; for trabecular separation (Tb.Sp): 115.7 vs. 304.87 um, P<0.01). The results showed that the treatment effects of osteoporotic rBMSCs on local osteoporosis performed by genetic infection were improved in vitro as compared to those in vivo. PMID- 24068164 TI - Dyspnea perception in cystic fibrosis patients. AB - We evaluated dyspnea perception in cystic fibrosis patients compared with normal subjects, during an inspiratory resistive loading test and 6-min walk test. We also evaluated the correlation between dyspnea scores induced by resistive loads and by the 6-min walk test. In this prospective, cross-sectional study, 31 patients with cystic fibrosis (>=15 years of age) and 31 age-, gender-, and ethnicity-matched healthy volunteers (20 females and 11 males per group) underwent inspiratory resistive loading, spirometry, and the 6-min walk test. As the magnitude of the inspiratory loads increased, dyspnea scores increased (P<0.001), but there was no difference between groups in dyspnea score (P=0.654). Twenty-six (84%) normal subjects completed all the resistive loads, compared with only 12 (39%) cystic fibrosis patients (P<0.001). Dyspnea scores were higher after the 6-min walk test than at rest (P<0.001), but did not differ between groups (P=0.080). Post-6-min walk test dyspnea scores correlated significantly with dyspnea scores induced by resistive loads. We conclude that dyspnea perception induced in cystic fibrosis patients by inspiratory resistive loading and by 6-min walk test did not differ from that induced in normal subjects. However, cystic fibrosis patients discontinued inspiratory resistive loading more frequently. There were significant correlations between dyspnea perception scores induced by inspiratory resistance loading and by the 6-min walk test. This study should alert clinicians to the fact that some cystic fibrosis patients fail to discriminate dyspnea perception and could be at risk for delay in seeking medical care. PMID- 24068165 TI - Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway. AB - Quercetin (Que), a plant-derived flavonoid, has multiple benefical actions on the cardiovascular system. The current study investigated whether Que postconditioning has any protective effects on myocardial ischemia/reperfusion (I/R) injury in vivo and its potential cardioprotective mechanisms. Male Sprague Dawley rats were randomly allocated to 5 groups (20 animals/group): sham, I/R, Que postconditioning, Que+LY294002 [a phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway inhibitor], and LY294002+I/R. I/R was produced by 30-min coronary occlusion followed by 2-h reperfusion. At the end of reperfusion, myocardial infarct size and biochemical changes were compared. Apoptosis was evaluated by both TUNEL staining and measurement of activated caspase-3 immunoreactivity. The phosphorylation of Akt and protein expression of Bcl-2 and Bax were determined by Western blotting. Que postconditioning significantly reduced infarct size and serum levels of creatine kinase and lactate dehydrogenase compared with the I/R group (all P<0.05). Apoptotic cardiomyocytes and caspase-3 immunoreactivity were also suppressed in the Que postconditioning group compared with the I/R group (both P<0.05). Akt phosphorylation and Bcl-2 expression increased after Que postconditioning, but Bax expression decreased. These effects were inhibited by LY294002. The data indicate that Que postconditioning can induce cardioprotection by activating the PI3K/Akt signaling pathway and modulating the expression of Bcl-2 and Bax proteins. PMID- 24068168 TI - FTIR spectro-imaging of collagen scaffold formation during glioma tumor development. AB - Evidence has recently emerged that solid and diffuse tumors produce a specific extracellular matrix (ECM) for division and diffusion, also developing a specific interface with microvasculature. This ECM is mainly composed of collagens and their scaffolding appears to drive tumor growth. Although collagens are not easily analyzable by UV-fluorescence means, FTIR imaging has appeared as a valuable tool to characterize collagen contents in tissues, specially the brain, where ECM is normally devoid of collagen proteins. Here, we used FTIR imaging to characterize collagen content changes in growing glioma tumors. We could determine that C6-derived solid tumors presented high content of triple helix after 8-11 days of growth (typical of collagen fibrils formation; 8/8 tumor samples; 91 % of total variance), and further turned to larger alpha-helix (days 12-15; 9/10 of tumors; 94 % of variance) and beta-turns (day 18-21; 7/8 tumors; 97 % of variance) contents, which suggest the incorporation of non-fibrillar collagen types in ECM, a sign of more and more organized collagen scaffold along tumor progression. The growth of tumors was also associated to the level of collagen produced (P < 0.05). This study thus confirms that collagen scaffolding is a major event accompanying the angiogenic shift and faster tumor growth in solid glioma phenotypes. PMID- 24068166 TI - Surveying the Down syndrome mouse model resource identifies critical regions responsible for chronic otitis media. AB - Chronic otitis media (OM) is common in Down syndrome (DS), but underlying aetiology is unclear. We analysed the entire available mouse resource of partial trisomy models of DS looking for histological evidence of chronic middle-ear inflammation. We found a highly penetrant OM in the Dp(16)1Yey mouse, which carries a complete trisomy of MMU16. No OM was found in the Dp(17)1Yey mouse or the Dp(10)1Yey mouse, suggesting disease loci are located only on MMU16. The Ts1Cje, Ts1RhR, Ts2Yah, and Ts65Dn trisomies and the transchomosomic Tc1 mouse did not develop OM. On the basis of these findings, we propose a two-locus model for chronic middle-ear inflammation in DS, based upon epistasis of the regions of HSA21 not in trisomy in the Tc1 mouse. We also conclude that environmental factors likely play an important role in disease onset. PMID- 24068167 TI - Glucagonlike peptide 2 analogue teduglutide: stimulation of proliferation but reduction of differentiation in human Caco-2 intestinal epithelial cells. AB - IMPORTANCE: Short bowel syndrome occurs when a shortened intestine cannot absorb sufficient nutrients or fluids. Teduglutide is a recombinant analogue of human glucagonlike peptide 2 that reduces dependence on parenteral nutrition in patients with short bowel syndrome by promoting enterocytic proliferation, increasing the absorptive surface area. However, enterocyte function depends not only on the number of cells that are present but also on differentiated features that facilitate nutrient absorption and digestion. OBJECTIVE: To test the hypothesis that teduglutide impairs human intestinal epithelial differentiation. DESIGN AND SETTING: We investigated the effects of teduglutide in the modulation of proliferation and differentiation in human Caco-2 intestinal epithelial cells at a basic science laboratory. This was an in vitro study using Caco-2 cells, a human-derived intestinal epithelial cell line commonly used to model enterocytic biology. EXPOSURE: Cells were exposed to teduglutide or vehicle control. MAIN OUTCOMES AND MEASURES: We analyzed the cell cycle by bromodeoxyuridine incorporation or propidium iodide staining and flow cytometry and measured cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium (MTS) assay. We used quantitative reverse transcription-polymerase chain reaction to assay the expression of the enterocytic differentiation markers villin, sucrase-isomaltase, glucose transporter 2 (GLUT2), and dipeptidyl peptidase 4 (DPP-4), as well as that of the putative differentiation signals schlafen 12 (SLFN12) and caudal-related homeobox intestine-specific transcription factor (Cdx2). Villin promoter activity was measured by a luciferase-based assay. RESULTS: The MTS assay demonstrated that teduglutide increased cell numbers by a mean (SD) of 10% (2%) over untreated controls at a maximal 500 nM (n = 6, P < .05). Teduglutide increased bromodeoxyuridine-positive cells vs untreated controls by a mean (SD) of 19.4% (2.3%) vs 12.0% (0.8%) (n = 6, P < .05) and increased the S-phase fraction by flow cytometric analysis. Teduglutide reduced the mean (SD) expression of villin by 29% (6%), Cdx2 by 31% (10%), DPP-4 by 15% (6%), GLUT2 by 40% (11%), SLFN12 by 61% (14%), and sucrase-isomaltase by 28% (8%) (n = 6, P < .05 for all). CONCLUSIONS AND RELEVANCE: Teduglutide increased Caco-2 proliferation but tended to inhibit intestinal epithelial differentiation. The effects of mitogenic stimulation with teduglutide in patients with short bowel syndrome might be greater if the more numerous teduglutide-treated cells could be stimulated toward a more fully differentiated phenotype. PMID- 24068169 TI - Parallel electromembrane extraction in a multiwell plate. AB - This paper describes the concept of parallel electromembrane extraction (Pa-EME) with flat membranes in a multiwell format for the first time. The setup is based on a multiwell plate and provided simultaneous and selective isolation, cleanup, and enrichment of several human plasma samples as well as LC-MS-compatible extracts within 8 min of extraction. Undiluted human plasma samples spiked with four antidepressant drugs were added to separate wells in the donor plate. Subsequently, the samples were extracted with Pa-EME. The four drugs migrated electrokinetically from undiluted human plasma through a flat polypropylene membrane impregnated with 2-nitrophenyl octyl ether, and were isolated into formic acid. Extraction time, extraction voltage, agitation rate, sample volume, and acceptor solution volume were all optimized with an experimental design. The optimal conditions were as follows: The agitation rate was 1,040 rpm, and an extraction voltage of 200 V was applied. The sample volume and acceptor solution volume was 240 and 70 MUL, respectively. The extraction was continued for 8 min. Eventually, the extracts were analyzed by LC-MS/MS. The combination of Pa-EME with LC-MS/MS provided quantitation limits below the therapeutic level and reported relative standard deviations in the range 5-13 %. Linear calibration curves were obtained for all analytes, and the correlation coefficients were above 0.9974 in the range 1-400 ng mL(-1). The drug concentrations from two subjects treated with quetiapine and sertraline were successfully determined with Pa-EME combined with LC-MS/MS. Post-column infusion experiments demonstrated that Pa-EME provided extracts free from interfering matrix components. PMID- 24068170 TI - Optimization of flow field-flow fractionation for the characterization of natural colloids. AB - The methodological approach used to robustly optimize the characterization of the polydisperse colloidal phase of drain water samples is presented. The approach is based on asymmetric flow field-flow fractionation coupled to online ultraviolet/visible spectrophotometry, multi-angle light scattering, and inductively coupled plasma mass spectrometry. Operating factors such as the amount of sample injected and the ratio between main-flow and cross-flow rates were considered. The evaluation of the injection and fractionation steps was performed considering the polydispersity index and the contribution to the polydispersity of the plate height, the recovery, the retention ratio and the size range of the fractionated colloids. This approach allows the polydispersity of natural colloid samples to be taken into consideration to achieve the most efficient and representative fractionation. In addition to the size characterization, elemental analysis was also evaluated using the recovery, precision, and limits of detection and quantification relative to a trace element of interest (copper) in drain water. To complete this investigation, the potential application of the methodology was assessed using several independent drain water samples from different soils. The contribution of the polydispersity to the plate height ranges from 4.8 to 8.9 cm with a mean precision of 6%. The mean colloidal recovery was 81 +/- 3 %, and the mean retention ratio was 0.043 0.062. The limits of detection and quantification for copper were 0.6 and 1.8 MUg L(-1), respectively. PMID- 24068171 TI - Developing new materials for paper-based diagnostics using electrospun nanofibers. AB - The use of electrospun nanofibers as functional material in paper-based lateral flow assays (LFAs) was studied. Specific chemical features of the nanofibers were achieved by doping the base polymer, poly(lactic acid) (PLA), with poly(ethylene glycol) (PEG) and polystyrene8K-block-poly(ethylene-ran-butylene)25K-block polyisoprene10K-Brij76 (K3-Brij76) (KB). The LFAs were assembled such that the sample flowed through the nanofiber mat via capillary action. Initial investigations focused on the sustainable spinning and assembly of different polymer structures to allow the LFA format. Here, it was found that the base polymer poly(vinyl alcohol) (PVA), which was shown to function well in microfluidic biosensors, did not work in the LFA format. In contrast, PLA-based nanofibers enabled easy assembly. Three relevant features were chosen to study nanofiber-based functionalities in the LFA format: adsorption of antibodies, quantification of results, and nonspecific binding. In particular, streptavidin conjugated sulforhodamine B (SRB)-encapsulating liposomes were captured by anti streptavidin antibodies adsorbed on the nanofibers. Varying the functional polymer concentration within the PLA base enabled the creation of distinct capture zones. Also, a sandwich assay for the detection of Escherichia coli O157:H7 was developed using anti-E. coli antibodies as capture and reporter species with horseradish peroxidase for signal generation. A dose-response curve for E. coli with a detection limit of 1.9 * 10(4) cells was achieved. Finally, functional polymers were used to demonstrate that nonspecific binding could be eliminated using antifouling block copolymers. The enhancement of paper-based devices using functionalized nanofibers provides the opportunity to develop a broad spectrum of sensitive and specific bioassays with significant advantages over their traditional counterparts. PMID- 24068172 TI - A novel surface imaging system for patient positioning and surveillance during radiotherapy. A phantom study and clinical evaluation. AB - BACKGROUND: The use of optical surface positioning to support or replace X-ray based image-guided radiotherapy (IGRT) may reduce patient exposure to extra dose. In specifically designed phantom tests, we analyzed the potential of a new scanning device preclinically. The system's clinical performance was evaluated in comparison to cone-beam computed tomography (CBCT) in a prospective study. MATERIALS AND METHODS: We first evaluated the scanning performance in terms of accuracy and reproducibility using phantom tests. An institutional review board (IRB)-approved clinical evaluation encompassing 224 fractions in 13 patients treated in three different regions (head and neck, thorax, pelvis) was then performed. Patients were first positioned using CBCT and then scanned with the Catalyst(TM) (C-RAD, Uppsala, Sweden) optical system to define the resulting difference vector. RESULTS: Individual system settings are necessary for different scanning conditions. Reproducibility tests with phantoms showed a mean difference of 0.25 +/- 0.21 cm. Accuracy tests showed a mean difference of less than 0.52 +/- 0.41 cm. Considering all patients, clinical data showed residual target position differences between Catalyst(TM) (surface-driven) and CBCT (target-driven) systems within 0.07 +/- 0.28 cm/- 0.13 +/- 0.40 cm/0.15 +/- 0.36 cm/0.11 +/- 1.57 degrees /- 0.43 +/- 1.68/- 0.10 +/- 1.67 degrees (lateral/longitudinal/vertical/rotation/roll/pitch). CONCLUSION: Scanning quality depends on the color and shape of the scanned surface. Upon prospective clinical evaluation, excellent agreement between target- and contour driven positioning was observed. Catalyst(TM) may reduce CBCT scan frequency in patients where tumor location is fixed relative to the surface. PMID- 24068173 TI - Interaction rules underlying group decisions in homing pigeons. AB - Travelling in groups gives animals opportunities to share route information by following cues from each other's movement. The outcome of group navigation will depend on how individuals respond to each other within a flock, school, swarm or herd. Despite the abundance of modelling studies, only recently have researchers developed techniques to determine the interaction rules among real animals. Here, we use high-resolution GPS (global positioning system) tracking to study these interactions in pairs of pigeons flying home from a familiar site. Momentary changes in velocity indicate alignment with the neighbour's direction, as well as attraction or avoidance depending on distance. Responses were stronger when the neighbour was in front. From the flocking behaviour, we develop a model to predict features of group navigation. Specifically, we show that the interactions between pigeons stabilize a side-by-side configuration, promoting bidirectional information transfer and reducing the risk of separation. However, if one bird gets in front it will lead directional choices. Our model further predicts, and observations confirm, that a faster bird (as measured from solo flights) will fly slightly in front and thus dominate the choice of homing route. Our results explain how group decisions emerge from individual differences in homing flight behaviour. PMID- 24068174 TI - Density-functional theory study of gramicidin A ion channel geometry and electronic properties. AB - Understanding the mechanisms underlying ion channel function from the atomic scale requires accurate ab initio modelling as well as careful experiments. Here, we present a density functional theory (DFT) study of the ion channel gramicidin A (gA), whose inner pore conducts only monovalent cations and whose conductance has been shown to depend on the side chains of the amino acids in the channel. We investigate the ground state geometry and electronic properties of the channel in vacuum, focusing on their dependence on the side chains of the amino acids. We find that the side chains affect the ground state geometry, while the electrostatic potential of the pore is independent of the side chains. This study is also in preparation for a full, linear scaling DFT study of gA in a lipid bilayer with surrounding water. We demonstrate that linear scaling DFT methods can accurately model the system with reasonable computational cost. Linear scaling DFT allows ab initio calculations with 10,000-100,000 atoms and beyond, and will be an important new tool for biomolecular simulations. PMID- 24068175 TI - Photons and particles emitted from cold atmospheric-pressure plasma inactivate bacteria and biomolecules independently and synergistically. AB - Cold atmospheric-pressure plasmas are currently in use in medicine as surgical tools and are being evaluated for new applications, including wound treatment and cosmetic care. The disinfecting properties of plasmas are of particular interest, given the threat of antibiotic resistance to modern medicine. Plasma effluents comprise (V)UV photons and various reactive particles, such as accelerated ions and radicals, that modify biomolecules; however, a full understanding of the molecular mechanisms that underlie plasma-based disinfection has been lacking. Here, we investigate the antibacterial mechanisms of plasma, including the separate, additive and synergistic effects of plasma-generated (V)UV photons and particles at the cellular and molecular levels. Using scanning electron microscopy, we show that plasma-emitted particles cause physical damage to the cell envelope, whereas UV radiation does not. The lethal effects of the plasma effluent exceed the zone of physical damage. We demonstrate that both plasma generated particles and (V)UV photons modify DNA nucleobases. The particles also induce breaks in the DNA backbone. The plasma effluent, and particularly the plasma-generated particles, also rapidly inactivate proteins in the cellular milieu. Thus, in addition to physical damage to the cellular envelope, modifications to DNA and proteins contribute to the bactericidal properties of cold atmospheric-pressure plasma. PMID- 24068176 TI - The quest for stiff, strong and tough hybrid materials: an exhaustive exploration. AB - How to arrange soft materials with strong but brittle reinforcements to achieve attractive combinations of stiffness, strength and toughness is an ongoing and fascinating question in engineering and biological materials science. Recent advances in topology optimization and bioinspiration have brought interesting answers to this question, but they provide only small windows into the vast design space associated with this problem. Here, we take a more global approach in which we assess the mechanical performance of thousands of possible microstructures. This exhaustive exploration gives a global picture of structure property relationships and guarantees that global optima can be found. Landscapes of optimum solutions for different combinations of desired properties can also be created, revealing the robustness of each of the solutions. Interestingly, while some of the major hybrid designs used in engineering are absent from the set of solutions, the microstructures emerging from this process are reminiscent of materials, such as bone, nacre or spider silk. PMID- 24068177 TI - Complexity of physiological responses decreases in high-stress musical performance. AB - For musicians, performing in front of an audience can cause considerable apprehension; indeed, performance anxiety is felt throughout the profession, with wide ranging symptoms arising irrespective of age, skill level and amount of practice. A key indicator of stress is frequency-specific fluctuations in the dynamics of heart rate known as heart rate variability (HRV). Recent developments in sensor technology have made possible the measurement of physiological parameters reflecting HRV non-invasively and outside of the laboratory, opening research avenues for real-time performer feedback to help improve stress management. However, the study of stress using standard algorithms has led to conflicting and inconsistent results. Here, we present an innovative and rigorous approach which combines: (i) a controlled and repeatable experiment in which the physiological response of an expert musician was evaluated in a low-stress performance and a high-stress recital for an audience of 400 people, (ii) a piece of music with varying physical and cognitive demands, and (iii) dynamic stress level assessment with standard and state-of-the-art HRV analysis algorithms such as those within the domain of complexity science which account for higher order stress signatures. We show that this offers new scope for interpreting the autonomic nervous system response to stress in real-world scenarios, with the evolution of stress levels being consistent with the difficulty of the music being played, superimposed on the stress caused by performing in front of an audience. For an emerging class of algorithms that can analyse HRV independent of absolute data scaling, it is shown that complexity science performs a more accurate assessment of average stress levels, thus providing greater insight into the degree of physiological change experienced by musicians when performing in public. PMID- 24068178 TI - Effective viscosity of puller-like microswimmers: a renormalization approach. AB - Effective viscosity (EV) of suspensions of puller-like microswimmers (pullers), for example Chlamydamonas algae, is difficult to measure or simulate for all swimmer concentrations. Although there are good reasons to expect that the EV of pullers is similar to that of passive suspensions, analytical determination of the passive EV for all concentrations remains unsatisfactory. At the same time, the EV of bacterial suspensions is closely linked to collective motion in these systems and is biologically significant. We develop an approach for determining analytical EV estimates at all concentrations for suspensions of pullers as well as for passive suspensions. The proposed methods are based on the ideas of renormalization group (RG) theory and construct the EV formula based on the known asymptotics for small concentrations and near the critical point (i.e. approaching dense packing). For passive suspensions, the method is verified by comparison against known theoretical results. We find that the method performs much better than an earlier RG-based technique. For pullers, the validation is done by comparing them to experiments conducted on Chlamydamonas suspensions. PMID- 24068179 TI - Glassy dynamics in three-dimensional embryonic tissues. AB - Many biological tissues are viscoelastic, behaving as elastic solids on short timescales and fluids on long timescales. This collective mechanical behaviour enables and helps to guide pattern formation and tissue layering. Here, we investigate the mechanical properties of three-dimensional tissue explants from zebrafish embryos by analysing individual cell tracks and macroscopic mechanical response. We find that the cell dynamics inside the tissue exhibit features of supercooled fluids, including subdiffusive trajectories and signatures of caging behaviour. We develop a minimal, three-parameter mechanical model for these dynamics, which we calibrate using only information about cell tracks. This model generates predictions about the macroscopic bulk response of the tissue (with no fit parameters) that are verified experimentally, providing a strong validation of the model. The best-fit model parameters indicate that although the tissue is fluid-like, it is close to a glass transition, suggesting that small changes to single-cell parameters could generate a significant change in the viscoelastic properties of the tissue. These results provide a robust framework for quantifying and modelling mechanically driven pattern formation in tissues. PMID- 24068180 TI - An encapsulated drug delivery system for recalcitrant urinary tract infection. AB - One of the hallmarks of urinary tract infection, a serious global disease, is its tendency to recur. Uropathogenic bacteria can invade cells lining the bladder, where they form longer-term intracellular reservoirs shielded from antibiotics, re-emerging at a later date to initiate flare-ups. In these cases, only lengthy systemic antibiotic treatment can eradicate all the reservoirs. Yet, long courses of antibiotics are not ideal, as they can lead to side effects and an increase in antibiotic resistance. Moreover, most antibiotics lose some potency by the time they reach the bladder, and many cannot permeate cells, so they cannot access intracellular reservoirs. Here, using coaxial electrohydrodynamic forming, we developed novel core-shell capsules containing antibiotics as a prototype for a future product that could be infused directly into the bladder. Gentamicin was encapsulated in a polymeric carrier (polymethylsilsesquioxane) and these capsules killed Enterococcus faecalis, a common chronic uropathogen, in vitro in a dose responsive, slow-release manner. Capsules containing a fluorescent tracer dye in place of gentamicin penetrated human bladder cells and released their dye cargo with no apparent toxicity, confirming their ability to successfully permeate cells. These results suggest that such antibiotic capsules could prove useful in the treatment of recalcitrant UTI. PMID- 24068181 TI - Graphene oxide assisted synthesis of GaN nanostructures for reducing cell adhesion. AB - We report a general approach for the synthesis of large-scale gallium nitride (GaN) nanostructures by the graphene oxide (GO) assisted chemical vapor deposition (CVD) method. A modulation effect of GaN nanostructures on cell adhesion has been observed. The morphology of the GaN surface can be controlled by GO concentrations. This approach, which is based on the predictable choice of the ratio of GO to catalysts, can be readily extended to the synthesis of other materials with controllable nanostructures. Cell studies show that GaN nanostructures reduced cell adhesion significantly compared to GaN flat surfaces. The cell-repelling property is related to the nanostructure and surface wettability. These observations of the modulation effect on cell behaviors suggest new opportunities for novel GaN nanomaterial-based biomedical devices. We believe that potential applications will emerge in the biomedical and biotechnological fields. PMID- 24068182 TI - Public understanding of local lead contamination. AB - Residents of Herculaneum, Missouri have been influential in shaping the management of contamination challenges resulting from the community's proximity to the last primary lead processing plant in the United States. This paper provides a nuanced examination of two perspectives of resident activist groups involved in lead-related controversy in Herculaneum. Ethnographic data collection and storyline analysis were used to trace the evolution in local views from resembling an industrialist-environmentalist dichotomy to more compromising positions associated with ecological modernization. Implications for characterizing public environmental perspectives in the US as beginning to entertain certain aspects of the ecological modernist paradigm are discussed. PMID- 24068183 TI - Evaluating the 2008 consensus conference on genetically modified foods in Taiwan. AB - Genetically modified foods have become one of the most popular topics for deliberative exercises involving ordinary citizens worldwide. This paper examines the Taiwanese consensus conference on GM foods held in June 2008, and the implications and limitations of the public deliberations. The consensus conference facilitated multiparty dialogues and enhanced citizens' knowledge, and affected their attitudes. This study demonstrates the ways contextual factors have influenced the outcome of the citizens' deliberative practices, including the government's conventional technocratic decision-making style, the strong influence of the U.S. government, the political and technological culture, the government's framing of economic development concerns, and a lack of pressure from civil society to compel the government to formally respond to their concerns. The consensus conference had a limited effect on policy decision making, and seemed to serve as a socio-political experiment. PMID- 24068184 TI - Probing the interface of doped isotopically mixed helium droplets by the directional anisotropy of interatomic Coulombic decay. AB - Interatomic Coulombic decay (ICD) represents an efficient electronic relaxation mechanism of an ionized or an excited system embedded in an environment. The type of this environment and its size have a great impact on the ICD performance. It is stressed that ICD is sensitive to the arrangement of neighboring atoms when the initially created vacancy has a polarization direction. This is demonstrated in the present paper for the case of a 3p-ionized Ca surrounded by He atoms. Useful explicit expressions are derived for the ICD widths which show that the neighbors located along the polarization direction of the ionized orbital have the largest contribution to the ICD rate. By comparison with ab initio results for small clusters, we also show that in a helium environment, the pairwise approximation represents a reliable approach for computing ICD widths. Using this approximation and the density distribution of the helium atoms obtained within density functional theory, we explore ICD in large isotopically mixed helium droplets doped with Ca. A special emphasis is given to the difference between the ICD widths for the Ca3p orbitals directed perpendicular and parallel to the droplet surface. Depending on the size and isotopic composition of the droplet, Ca resides in the interfacial layer between the (4)He core and the (3)He outer shell. Hence, ICD studies in these droplets may provide valuable information on the properties of this interface. PMID- 24068185 TI - Ionizing radiation regulates cardiac Ca handling via increased ROS and activated CaMKII. AB - Ionizing radiation (IR) is an integral part of modern multimodal anti-cancer therapies. IR involves the formation of reactive oxygen species (ROS) in targeted tissues. This is associated with subsequent cardiac dysfunction when applied during chest radiotherapy. We hypothesized that IR (i.e., ROS)-dependently impaired cardiac myocytes' Ca handling might contribute to IR-dependent cardiocellular dysfunction. Isolated ventricular mouse myocytes and the mediastinal area of anaesthetized mice (that included the heart) were exposed to graded doses of irradiation (sham 4 and 20 Gy) and investigated acutely (after ~1 h) as well as chronically (after ~1 week). IR induced a dose-dependent effect on myocytes' systolic function with acutely increased, but chronically decreased Ca transient amplitudes, which was associated with an acutely unaltered but chronically decreased sarcoplasmic reticulum (SR) Ca load. Likewise, in vivo echocardiography of anaesthetized mice revealed acutely enhanced left ventricular contractility (strain analysis) that declined after 1 week. Irradiated myocytes showed persistently increased diastolic SR Ca leakage, which was acutely compensated by an increase in SR Ca reuptake. This was reversed in the chronic setting in the face of slowed relaxation kinetics. As underlying cause, acutely increased ROS levels were identified to activate Ca/calmodulin-dependent protein kinase II (CaMKII). Accordingly, CaMKII-, but not PKA-dependent phosphorylation sites of the SR Ca release channels (RyR2, at Ser-2814) and phospholamban (at Thr 17) were found to be hyperphosphorylated following IR. Conversely, ROS-scavenging as well as CaMKII-inhibition significantly attenuated CaMKII-activation, disturbed Ca handling, and subsequent cellular dysfunction upon irradiation. Targeted cardiac irradiation induces a biphasic effect on cardiac myocytes Ca handling that is associated with chronic cardiocellular dysfunction. This appears to be mediated by increased oxidative stress and persistently activated CaMKII. Our findings suggest impaired cardiac myocytes Ca handling as a so far unknown mediator of IR-dependent cardiac damage that might be of relevance for radiation induced cardiac dysfunction. PMID- 24068186 TI - Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease. AB - Conventionally, ischemic heart disease (IHD) is equated with large vessel coronary disease. However, recent evidence has suggested a role of compromised microvascular regulation in the etiology of IHD. Because regulation of coronary blood flow likely involves activity of specific ion channels, and key factors involved in endothelium-dependent dilation, we proposed that genetic anomalies of ion channels or specific endothelial regulators may underlie coronary microvascular disease. We aimed to evaluate the clinical impact of single nucleotide polymorphisms in genes encoding for ion channels expressed in the coronary vasculature and the possible correlation with IHD resulting from microvascular dysfunction. 242 consecutive patients who were candidates for coronary angiography were enrolled. A prospective, observational, single-center study was conducted, analyzing genetic polymorphisms relative to (1) NOS3 encoding for endothelial nitric oxide synthase (eNOS); (2) ATP2A2 encoding for the Ca2+/H+-ATPase pump (SERCA); (3) SCN5A encoding for the voltage-dependent Na+ channel (Nav1.5); (4) KCNJ8 and KCNJ11 encoding for the Kir6.1 and Kir6.2 subunits of K-ATP channels, respectively; and (5) KCN5A encoding for the voltage gated K+ channel (Kv1.5). No significant associations between clinical IHD manifestations and polymorphisms for SERCA, Kir6.1, and Kv1.5 were observed (p > 0.05), whereas specific polymorphisms detected in eNOS, as well as in Kir6.2 and Nav1.5 were found to be correlated with IHD and microvascular dysfunction. Interestingly, genetic polymorphisms for ion channels seem to have an important clinical impact influencing the susceptibility for microvascular dysfunction and IHD, independent of the presence of classic cardiovascular risk factors. PMID- 24068187 TI - Evidence for the involvement of peripheral beta-adrenoceptors in delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats. AB - Dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At) delay liquid gastric emptying (GE) in rats. We evaluated adrenergic participation in this phenomenon in a study in male Wistar rats (250-300 g) pretreated subcutaneously with guanethidine (GUA), 100 mg.kg-1.day-1, or vehicle (V) for 2 days before experimental treatments. Other groups of animals were pretreated intravenously (iv) 15 min before treatment with V, prazosin (PRA; 1 mg/kg), yohimbine (YOH; 3 mg/kg), or propranolol (PRO; 4 mg/kg), or with intracerebroventricular (icv) administration of 25 ug PRO or V. The groups were treated iv with saline or with 240 umol/kg Dp, AA, or At. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. %GR (mean +/- SE, n=8) indicated that GUA abolished the effect of Dp (GUA vs V=31.7 +/- 1.6 vs 47.1 +/- 2.3%) and of At (33.2 +/- 2.3 vs 54.7 +/- 3.6%) on GE and significantly reduced the effect of AA (48.1 +/- 3.2 vs 67.2 +/- 3.1%). PRA and YOH did not modify the effect of the drugs. %GR (mean +/- SE, n=8) indicated that iv, but not icv, PRO abolished the effect of Dp (PRO vs V=29.1 +/- 1.7 vs 46.9 +/- 2.7%) and At (30.5 +/- 1.7 vs 49 +/- 3.2%) and significantly reduced the effect of AA (48.4 +/- 2.6 vs 59.5 +/- 3.1%). These data suggest activation of peripheral beta-adrenoceptors in the delayed GE induced by phenylpyrazolone derivatives. PMID- 24068188 TI - Nitro-fatty acids: novel anti-inflammatory lipid mediators. AB - Nitro-fatty acids are formed and detected in human plasma, cell membranes, and tissue, modulating metabolic as well as inflammatory signaling pathways. Here we discuss the mechanisms of nitro-fatty acid formation as well as their key chemical and biochemical properties. The electrophilic properties of nitro-fatty acids to activate anti-inflammatory signaling pathways are discussed in detail. A critical issue is the influence of nitroarachidonic acid on prostaglandin endoperoxide H synthases, redirecting arachidonic acid metabolism and signaling. We also analyze in vivo data supporting nitro-fatty acids as promising pharmacological tools to prevent inflammatory diseases. PMID- 24068189 TI - Histone demethylase retinoblastoma binding protein 2 regulates the expression of alpha-smooth muscle actin and vimentin in cirrhotic livers. AB - Liver cirrhosis is one of the most common diseases of Chinese patients. Herein, we report the high expression of a newly identified histone 3 lysine 4 demethylase, retinoblastoma binding protein 2 (RBP2), and its role in liver cirrhosis in humans. The siRNA knockdown of RBP2 expression in hepatic stellate cells (HSCs) reduced levels of alpha-smooth muscle actin (alpha-SMA) and vimentin and decreased the proliferation of HSCs; and overexpression of RBP2 increased alpha-SMA and vimentin levels. Treatment with transforming growth factor beta (TGF-beta) upregulated the expression of RBP2, alpha-SMA, and vimentin, and the siRNA knockdown of RBP2 expression attenuated TGF-beta-mediated upregulation of alpha-SMA and vimentin expression and HSC proliferation. Furthermore, RBP2 was highly expressed in cirrhotic rat livers. Therefore, RBP2 may participate in the pathogenesis of liver cirrhosis by regulating the expression of alpha-SMA and vimentin. RBP2 may be a useful marker for the diagnosis and treatment of liver cirrhosis. PMID- 24068190 TI - A detailed description of an economical setup for electroporation of chick embryos in ovo. AB - One of the challenges of the postgenomic era is characterizing the function and regulation of specific genes. For various reasons, the early chick embryo can easily be adopted as an in vivo assay of gene function and regulation. The embryos are robust, accessible, easily manipulated, and maintained in the laboratory. Genomic resources centered on vertebrate organisms increase daily. As a consequence of optimization of gene transfer protocols by electroporation, the chick embryo will probably become increasingly popular for reverse genetic analysis. The challenge of establishing chick embryonic electroporation might seem insurmountable to those who are unfamiliar with experimental embryological methods. To minimize the cost, time, and effort required to establish a chick electroporation assay method, we describe and illustrate in great detail the procedures involved in building a low-cost electroporation setup and the basic steps of electroporation. PMID- 24068191 TI - Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion. AB - To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitro and the possible mechanism involved, ADSCs were cocultured with pancreatic cancer cells, and a cell counting kit (CCK-8) was used to detect the proliferation of pancreatic cancer cells. ELISA was used to determine the concentration of stromal cell derived factor-1 (SDF-1) in the supernatants. RT-PCR was performed to detect the expression of the chemokine receptor CXCR4 in pancreatic cancer cells and ADSCs. An in vitro invasion assay was used to measure invasion of pancreatic cancer cells. SDF-1 was detected in the supernatants of ADSCs, but not in pancreatic cancer cells. Higher CXCR4 mRNA levels were detected in the pancreatic cancer cell lines compared with ADSCs (109.3 +/- 10.7 and 97.6 +/- 7.6 vs 18.3 +/- 1.7, respectively; P<0.01). In addition, conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells, and AMD3100, a CXCR4 antagonist, significantly downregulated these growth-promoting effects. We conclude that ADSCs can promote the proliferation and invasion of pancreatic cancer cells, which may involve the SDF-1/CXCR4 axis. PMID- 24068192 TI - Ox-LDL increases OX40L in endothelial cells through a LOX-1-dependent mechanism. AB - Oxidative low-density lipoprotein (Ox-LDL) is a key risk factor for the development of atherosclerosis, and it can stimulate the expression of a variety of inflammatory signals. As a new and highly sensitive inflammation index, OX40L may be a key to understanding the mechanisms that regulate interactions between cells within the vessel wall and inflammatory mediators during the development of atherosclerosis. To investigate whether Ox-LDL regulates OX40L expression through an oxidized LDL-1 receptor (LOX-1)-mediated mechanism, we investigated the effect of different concentrations of Ox-LDL (50, 100, 150 ug/mL) on endothelial cell proliferation and apoptosis. Stimulation with Ox-LDL increased OX40L protein 1.44 fold and mRNA 4.0-fold in endothelial cells, and these effects were inhibited by blocking LOX-1. These results indicate that LOX-1 plays an important role in the chronic inflammatory process in blood vessel walls. Inhibiting LOX-1 may reduce blood vessel inflammation and provide a therapeutic option to limit atherosclerosis progression. PMID- 24068193 TI - Sedative and anesthetic activities of the essential oils of Hyptis mutabilis (Rich.) Briq. and their isolated components in silver catfish (Rhamdia quelen). AB - This study evaluated the sedative and anesthetic effects of the essential oils (EO) of Hyptis mutabilis (Rich.) Briq. and their isolated components on silver catfish (Rhamdia quelen). Quantitative chemical differences between the EOs obtained from leaves and inflorescences were verified, and a new chemotype rich in globulol was described. Although there were no significant differences in the time of induction for sedation and anesthesia between the EOs, only the leaf EO at 344 mg/L anesthetized all fish without side effects. Fractionation of the leaf EO was carried out by column chromatography. The isolated compounds [(+)-1 terpinen-4-ol and (-)-globulol] showed different activity from that detected for the leaf EO in proportional concentrations and similar sedation to a eugenol control at 10 mg/L. However, fish exposed to 1-terpinen-4-ol (3 and 10 mg/L) did not remain sedated for 30 min. Anesthesia was obtained with 83-190 mg/L globulol, but animals showed loss of mucus during induction and mortality at these concentrations. Synergism of the depressor effects was detected with the association of globulol and benzodiazepine (BDZ), compared with either drug alone. Fish exposed to BDZ or globulol+BDZ association showed faster recovery from anesthesia in water containing flumazenil, but the same did not occur with globulol. In conclusion, the use of globulol in aquaculture procedures should be considered only at sedative concentrations of 10 and 20 mg/L, and its mechanism of action seems not to involve the GABAA-BDZ system. PMID- 24068194 TI - Antioxidant effect of 4-nerolidylcatechol and alpha-tocopherol in erythrocyte ghost membranes and phospholipid bilayers. AB - 4-Nerolidylcatechol (4-NC) is found in Pothomorphe umbellata root extracts and is reported to have a topical protective effect against UVB radiation-induced skin damage, toxicity in melanoma cell lines, and antimalarial activity. We report a comparative study of the antioxidant activity of 4-NC and alpha-tocopherol against lipid peroxidation initiated by two free radical-generating systems: 2,2' azobis(2-aminopropane) hydrochloride (AAPH) and FeSO4/H2O2, in red blood cell ghost membranes and in egg phosphatidylcholine (PC) vesicles. Lipid peroxidation was monitored by membrane fluidity changes assessed by electron paramagnetic resonance spectroscopy of a spin-labeled lipid and by the formation of thiobarbituric acid-reactive substances. When lipoperoxidation was initiated by the hydroxyl radical in erythrocyte ghost membranes, both 4-NC and alpha tocopherol acted in a very efficient manner. However, lower activities were observed when lipoperoxidation was initiated by the peroxyl radical; and, in this case, the protective effect of alpha-tocopherol was lower than that of 4-NC. In egg PC vesicles, malondialdehyde formation indicated that 4-NC was effective against lipoperoxidation initiated by both AAPH and FeSO4/H2O2, whereas alpha tocopherol was less efficient in protecting against lipoperoxidation by AAPH, and behaved as a pro-oxidant for FeSO4/H2O2. The DPPH (2,2-diphenyl-1-picrylhydrazyl) free-radical assay indicated that two free radicals were scavenged per 4-NC molecule, and one free radical was scavenged per alpha-tocopherol molecule. These data provide new insights into the antioxidant capacity of 4-NC, which may have therapeutic applications for formulations designed to protect the skin from sunlight irradiation. PMID- 24068195 TI - Osteogenesis induced in goat bone marrow progenitor cells by recombinant adenovirus coexpressing bone morphogenetic protein 2 and basic fibroblast growth factor. AB - Bone morphogenetic protein 2 (BMP2) and basic fibroblast growth factor (bFGF) have been shown to exhibit a synergistic effect to promote bone repair and healing. In this study, we constructed a novel adenovirus with high coexpression of BMP2 and bFGF and evaluated its effect on osteogenic differentiation of goat bone marrow progenitor cells (BMPCs). Recombinant adenovirus Ad-BMP2-bFGF was constructed by using the T2A sequence. BMPCs were isolated from goats by density gradient centrifugation and adherent cell culture, and were then infected with Ad BMP2-bFGF or Ad-BMP2. Expression of BMP2 and bFGF was detected by ELISA, and alkaline phosphatase (ALP) activity was detected by an ALP assay kit. In addition, von Kossa staining and immunocytochemical staining of collagen II were performed on BMPCs 21 days after infection. There was a high coexpression of BMP2 and bFGF in BMPCs infected with Ad-BMP2-bFGF. Twenty-one days after infection, ALP activity was significantly higher in BMPCs infected with Ad-BMP2-bFGF than in those infected with Ad-BMP2. Larger and more mineralized calcium nodules, as well as stronger collagen II staining, were observed in BMPCs infected with Ad-BMP2 bFGF than in those infected with Ad-BMP2. In summary, we developed a novel adenovirus vector Ad-BMP2-bFGF for simultaneous high coexpression of BMP2 and bFGF, which could induce BMPCs to differentiate efficiently into osteoblasts. PMID- 24068196 TI - Metformin decreases high-fat diet-induced renal injury by regulating the expression of adipokines and the renal AMP-activated protein kinase/acetyl-CoA carboxylase pathway in mice. AB - Metabolic syndrome is characterized by insulin resistance, dyslipidemia and hypertension. These metabolic changes contribute to the development of obesity induced kidney injury. AMP-activated protein kinase (AMPK) is a ubiquitous enzyme that is involved in the cellular metabolic response to metabolic stress. Metformin, an AMPK activator, has been reported to exert a protective effect against non-alcoholic steatohepatitis. However, little is known about its role in the pathogenesis of obesity-induced renal injury. The aim of this study was to investigate the effects of metformin on high-fat diet (HFD)-induced kidney injury. Obesity was induced by HFD (60% of total calories from fat, 20% protein and 20% carbohydrates) in 6-week-old C57BL/6 mice. Mice were fed HFD plus 0.5% metformin. The effects of metformin on HFD-induced renal injury were evaluated by determining metabolic parameters, serum adipokine levels and renal AMPK/acetyl CoA carboxylase (ACC) activities, as well as a histological examination. HFD induced metabolic derangement, systemic insulin resistance and glomerular mesangial matrix expansion. The administration of metformin reduced HFD-induced metabolic derangement and renal injury. The administration of metformin reduced the HFD-induced increase in adipokine expression and macrophage infiltration. Moreover, renal AMPK activity, which was decreased by HFD, was recovered following the administration of metformin; in addition, fatty acid oxidation was increased by the inhibition of ACC. These results indicate that metformin exerts beneficial effects on obesity-induced renal injury by regulating systemic inflammation, insulin resistance and the renal AMPK/ACC pathway. The clinical application of metformin to obese or early diabetic patients may be helpful in preventing obesity- or diabetes-related kidney disease. PMID- 24068197 TI - Real-time observation of Cu2ZnSn(S,Se)4 solar cell absorber layer formation from nanoparticle precursors. AB - The selenization of Cu-Zn-Sn-S nanocrystals is a promising route for the fabrication of low-cost thin film solar cells. However, the reaction pathway of this process is not completely understood. Here, the evolution of phase formation, grain size, and elemental distributions is investigated during the selenization of Cu-Zn-Sn-S nanoparticle precursor thin films by synchrotron-based in situ energy-dispersive X-ray diffraction and fluorescence analysis as well as by ex situ electron microscopy. The precursor films are heated in a closed volume inside a vacuum chamber in the presence of selenium vapor while diffraction and fluorescence signals are recorded. The presented results reveal that during the selenization the cations diffuse to the surface to form large grains on top of the nanoparticle layer and the selenization of the film takes place through two simultaneous reactions: (1) a direct and fast formation of large grained selenides, starting with copper selenide which is subsequently transformed into Cu2ZnSnSe4; and (2) a slower selenization of the remaining nanoparticles. As a consequence of the initial formation of copper selenides at the surface, the subsequent formation of CZTSe starts under Cu-rich conditions despite an overall Cu-poor composition of the film. The implications of this process path for the film quality are discussed. Additionally, the proposed growth model provides an explanation for the previously observed accumulation of carbon from the nanoparticle precursor beneath the large grained layer. PMID- 24068198 TI - Levels of cotinine in dried blood specimens from newborns as a biomarker of maternal smoking close to the time of delivery. AB - The precise quantitation of smoking during pregnancy is difficult in retrospective studies. Routinely collected blood specimens from newborns, stored as dried blood spots, may provide a low-cost method to objectively measure maternal smoking close to the time of delivery. This article compares cotinine levels in dried blood spots to those in umbilical cord blood to assess cotinine in dried blood spots as a biomarker of maternal smoking close to the time of delivery. The California Genetic Disease Screening Program provided dried blood spots from 428 newborns delivered in 2001-2003 with known umbilical cord blood cotinine levels. Cotinine in dried blood spots was measured in 6.35--mm punches by using liquid chromatography--tandem mass spectrometry (quantitation limit, 3.1 ng/mL). Repeated measures of cotinine in dried blood spots were highly correlated (R(2) = 0.99, P < 0.001) among 100 dried blood spots with cotinine quantitated in 2 separate punches. Linear regression revealed that cotinine levels in dried blood spots were slightly lower than those in umbilical cord blood and predicted umbilical cord blood cotinine levels well (beta = 0.95, R(2) = 0.80, and P < 0.001 for both cotinine levels in log10 scale). When defining active smoking as a cotinine level of 10 ng/mL or more and using umbilical cord blood cotinine as the criterion standard, we found that measurements of cotinine in dried blood spots had high sensitivity (92.3%) and specificity (99.7%) in the prediction of maternal active smoking. Cotinine levels in dried blood spots are an accurate biomarker of maternal smoking close to the time of delivery. PMID- 24068199 TI - Fine particulate matter and risk of preterm birth in Connecticut in 2000-2006: a longitudinal study. AB - Several studies have examined associations between particulate matter with aerodynamic diameter of 2.5 um or less (PM2.5) and preterm birth, but it is uncertain whether results were affected by individual predispositions (e.g., genetic factors, social conditions) that might vary considerably between women. We tested the hypothesis that a woman is at greater risk of preterm delivery when she has had elevated exposure to ambient PM2.5 during a pregnancy than when she has not by comparing pregnancies in the same woman. From 271,204 births, we selected 29,175 women who had vaginal singleton livebirths at least twice in Connecticut in 2000-2006 (n = 61,688 births). Analyses matched pregnancies to the same woman. Adjusted odds ratios per interquartile range (2.33-ug/m(3)) increase in PM2.5 in the first trimester, second trimester, third trimester, and whole pregnancy were 1.07 (95% confidence interval (CI): 1.00, 1.15), 0.96 (95% CI: 0.90, 1.03), 1.03 (95% CI: 0.97, 1.08), and 1.13 (95% CI: 1.01, 1.28), respectively. Among Hispanic women, the odds ratio per interquartile range increase in whole-pregnancy exposure was 1.31 (95% CI: 1.00, 1.73). Pregnancies with elevated PM2.5 exposure were more likely to result in preterm birth than were other pregnancies to the same woman at lower exposure. Associations were most pronounced in the first trimester and among Hispanic women. PMID- 24068201 TI - [Reconstruction after pancreatoduodenectomy. Pancreatojejunostomy or pancreatogastrostomy?]. PMID- 24068200 TI - Lung cancer risk among hairdressers: a pooled analysis of case-control studies conducted between 1985 and 2010. AB - Increased lung cancer risks among hairdressers were observed in large registry based cohort studies from Scandinavia, but these studies could not adjust for smoking. Our objective was to evaluate the lung cancer risk among hairdressers while adjusting for smoking and other confounders in a pooled database of 16 case control studies conducted in Europe, Canada, China, and New Zealand between 1985 and 2010 (the Pooled Analysis of Case-Control Studies on the Joint Effects of Occupational Carcinogens in the Development of Lung Cancer). Lifetime occupational and smoking information was collected through interviews with 19,369 cases of lung cancer and 23,674 matched population or hospital controls. Overall, 170 cases and 167 controls had ever worked as hairdresser or barber. The odds ratios for lung cancer in women were 1.65 (95% confidence interval (CI): 1.16, 2.35) without adjustment for smoking and 1.12 (95% CI: 0.75, 1.68) with adjustment for smoking; however, women employed before 1954 also experienced an increased lung cancer risk after adjustment for smoking (odds ratio = 2.66, 95% CI: 1.09, 6.47). The odds ratios in male hairdressers/barbers were generally not elevated, except for an increased odds ratio for adenocarcinoma in long-term barbers (odds ratio = 2.20, 95% CI: 1.02, 4.77). Our results suggest that the increased lung cancer risks among hairdressers are due to their smoking behavior; single elevated risk estimates should be interpreted with caution and need replication in other studies. PMID- 24068202 TI - [Osteomyelitis: treatment concepts from the plastic surgeon's point of view]. AB - Despite promising advances in antibiotic and surgical therapy osteomyelitis remians a severe disease with a high morbidity. Nowadays it occurs mainly after traumata. Typical clinical manifestations are signs of local infection, non healing wounds, pathological fractures or loosening of orthopedic implants. Besides the clinical judgement the diagnosis is consolidated by imaging procedures, histopathological and microbiological examinations. Ideally, the treatment plan is based on an interdisciplinary approach. Besides the radical surgical debridement a test appropriate antibiotic therapy is essential. Defect reconstruction after surgical debridement and optimization of local microcirculation is essential to preserve limbs and to obtain a good functional result. Microsurgical free tissue transfer is often necessary to achieve healing. An optimal therapeutic management with stable long-term clinical results can be achieved by the interaction of different surgical and medical disciplines. PMID- 24068203 TI - [Physical prophylaxis for thromboembolism. Current state of knowledge on use of medical thromboprophylaxis stockings]. AB - BACKGROUND: Thromboprophylaxis in surgery patients is a combination of physical and medical thromboprophylaxis. The established mode of physical thromboprophylaxis in Germany is graduated compression stockings. Recent publications from various authors generally scrutinized the additional benefits of physical prophylaxis in patients who received medical thromboprophylaxis. MATERIAL AND METHODS: A thorough search was carried out in PubMed and Medline. The focus of the search was on studies which investigated the advantages of physical thromboprophylaxis in surgery patients. RESULTS: The low amount of evidence available for prophylaxis of thromboembolism in surgery patients was mainly deduced from trials that had a combination of medical and physical thromboprophylaxis as part of the study protocol. The results of experimental investigations were able to show a statistically highly significant reduction of the diameter of lower extremity veins. CONCLUSION: There is no current evidence to support refraining from routine use of graduated compression stockings in surgery patients. This is also the case for the new oral anti-Xa and anti-IIa inhibitors. PMID- 24068204 TI - Proteomic analysis of aqueous humor from patients with branch retinal vein occlusion-induced macular edema. AB - The mechanisms responsible for macular edema with branch retinal vein occlusion (BRVO) remain to be elucidated. It is known that the expression profile of certain proteins in the aqueous humor (AH) changes in some diseases. Accordingly, determining the expression of these AH proteins may aid in the understanding of their potential role in this pathogenesis. The aim of this study was to identify the possible mechanisms involved in the development of BRVO-induced macular edema. A proteomic analysis of the AH composition in the eyes of patients with BRVO was performed and compared with that in the eyes of patients with cataract (non-BRVO; controls). AH from 6 patients with macular edema due to BRVO and 6 patients with cataract (non-BRVO) was collected. A proteomic approach which included 2-dimensional electrophoresis (2-DE) coupled with mass spectrometry (MS) and bioinformatics analysis were used to identify AH proteins with altered expression in patients with macular edema due to BRVO compared with the controls. An enzyme-linked immunosorbent assay was used to validate the proteomic results. The total protein concentration in the AH of patients with BRVO-induced macular edema was significantly greater than that of the controls. In the patients with BRVO, a total of 56 protein spots were significantly altered on the 2D gels. A total of 49 protein spots were identified by MS; many of these proteins have been implicated in angiogenesis, oxidative stress and collagen synthesis. In conclusion, the protein composition in AH differed significantly between the patients with BRVO and the controls. The identified proteins may be potential biomarkers for the development of macular edema due to BRVO and may play a role in the mechanisms responsible for it. PMID- 24068206 TI - Management of inadvertent carotid artery sheath insertion during central venous catheter placement. AB - IMPORTANCE: Inadvertent carotid sheath insertion during central venous catheter placement could lead to serious complications. OBJECTIVE: To describe management of inadvertent carotid artery sheath insertion placed intraoperatively during attempted jugular venous cannulation for pulmonary artery catheter placement. DESIGN, SETTING, AND PARTICIPANTS: In a retrospective medical record review of patients from hospitals affiliated with Baylor College of Medicine, Houston, Texas, a total of 12 patients over 11 years who sustained intraoperative carotid artery introducer sheath placement during attempted jugular vein cannulation were identified. Six patients underwent immediate carotid artery exploration with sheath removal and primary repair. The remaining 6 patients underwent percutaneous closure using a suture-mediated closure device. Treatment outcomes of these 2 groups were analyzed. MAIN OUTCOMES AND MEASURES: Technical success, duration of treatment, stroke, return to the operating room, and long-term outcomes. RESULTS: Technical success was achieved in all patients in both groups. The intended operations were aborted in all patients following catheter removal and carotid artery closure. The mean (SD) durations of treatment for the operative and endovascular groups were 32 (12) minutes and 6 (3) minutes, respectively (P = .03). No neurological deficit occurred in either group. The intended operations were all subsequently performed, and the mean delays of operation in the operative and endovascular groups were 5 and 3 days, respectively (P = .20). Follow-up carotid duplex showed no injury of the repaired artery in either group. During a mean follow-up of 42 months, no complications or neurological deficits were noted in either patient cohort. CONCLUSIONS AND RELEVANCE: Inadvertent carotid artery sheath placement during attempted central venous cannulation for pulmonary artery catheter insertion mandates catheter removal and repair of the carotid artery puncture site. The closure device permits percutaneous repair of the carotid artery expeditiously. Our experience showed this treatment modality to be as safe and effective as operative repair. PMID- 24068205 TI - Molecular diagnostics of pancreatic cysts. AB - INTRODUCTION: Due to an extensive use of modern imaging, incidental pancreatic cysts are increasingly diagnosed these days. Fortunately, comprehensive research over the past years has remarkably improved our pathogenetic and clinical understanding of pancreatic cysts that, as we know, are in majority harmless. However, mucinous cysts including intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, as well as solid pseudopapillary neoplasms harbor relevant potential for developing into a lethal invasive cancer and may therefore require immediate surgical resection or at least close surveillance. In order to allow an optimized clinical management, it is crucial to gather reliable information about entity as well as biologic behavior of every cyst detected. Unfortunately, in the absence of reliable biomarkers and by just applying currently available diagnostic means such as clinical and radiologic criteria or cyst fluid cytology, there is still a risk for incorrect preoperative diagnoses. This may be followed by inappropriate treatment possibly resulting in severe morbidity or even mortality. OBJECTIVE: In this review article, we summarize some of the salient recent advances in molecular diagnostics of pancreatic cysts. Herein, we put particular focus on the emerging field of biomarker research in pancreatic cyst fluid based on protein, DNA, and microRNA analyses. PMID- 24068207 TI - A well-written paper. PMID- 24068208 TI - Secular state, conscientious objection and public health policies. PMID- 24068209 TI - [Scientific output: quality assessment or an accountant's tale?]. AB - Quality assessment of scientific output is based extensively (if not exclusively) on quantitative bibliometric indicators, despite mounting criticism. The reaction by the academic community has increased in recent years. After presenting a critical evaluation of this model, the article presents an alternative qualitative model oriented towards removing the excessive stimulus for the unbridled production of articles that make a dubious contribution to science. Criticism of the proposed model is presented and discussed. PMID- 24068210 TI - [To measure or to classify the researchers scientific output?]. PMID- 24068211 TI - [For a new game]. PMID- 24068212 TI - [Many doubts, few certainties, as for this . . ]. PMID- 24068213 TI - [Evaluation of the quality of the scientific output and its unforeseen and undesirable consequences: a self-evident concept?]. PMID- 24068214 TI - [The challenge of the evaluation of the scientific output]. PMID- 24068215 TI - [How to evaluate the sciences with a deficient science of scientific evaluation?]. PMID- 24068216 TI - [Debate]. PMID- 24068217 TI - [Excessive evaluation]. PMID- 24068218 TI - [What are we evaluating?]. PMID- 24068219 TI - [Lets go ahead?]. PMID- 24068220 TI - [Effectiveness of ferrous sulfate supplementation in the prevention of anemia in children: a systematic literature review and meta-analysis]. AB - This was a systematic review and meta-analysis of studies evaluating the effectiveness of ferrous sulfate supplementation in the prevention of anemia in children under five. The database search included PubMed, Scopus, LILACS, and SciELO. Articles published between 1980 and 2011 in Spanish, English, or Portuguese were included, using the keywords child, preschool, infant, anemia, prevention, and iron supplementation. The authors selected 13 studies, which showed that regardless of dose and duration of supplementation, daily regimen was more consistently related to improvement in hemoglobin levels (pooled effect 0.56mg/dL, 95%CI: 0.31; 0.81, p < 0.001) as compared to weekly intervention (pooled effect 0.28mg/dL, 95%CI: -0.22; 0.78, p = 0.273). Iron supplementation was not associated with decreased prevalence of anemia, even with daily doses, and administration with other micronutrients did not bring additional benefits compared to the exclusive administration of iron supplement. Daily supplementation of ferrous sulfate was more effective than weekly doses in improving hemoglobin levels. PMID- 24068221 TI - [Social thinking in health in Latin America: revisiting Juan Cesar Garcia]. AB - The article reconstitutes the social thinking in health by Argentine physician and sociologist Juan Cesar Garcia (1932-1984), analyzing the main publications approaching his work and activities. The article situates his thinking in the two fields that marked his production: social medicine and the social sciences from the 1960s to the late 1980s. The article highlights his work with the Pan American Health Organization and his perspective of analyzing social medicine and the social sciences by relating them not only to the Latin American historical, social, economic, and political context, but also to historical materialism: linking medicine to the social structure; the influence of the social structure on the production and distribution of diseases; internal analysis of the production of medical services; and the relationship between training of health personnel and the medical field. As demonstrated, even today his work can be a reference for the discussion of such themes as medical education, health personnel training, the role of science and technology, the social sciences in medical education, and historical aspects of public health. PMID- 24068222 TI - ["Where there's a woman, there's a Pap smear": the meanings assigned to cervical cancer prevention among women in Salvador, Bahia State, Brazil]. AB - This study focuses on the meanings assigned to practices for cervical cancer prevention among women from low-income neighborhoods in Salvador, Bahia State, Brazil. This was a qualitative study based on content analysis of semi-structured interviews with 15 women 24 to 68 years of age. The results showed high appreciation of the Pap smear test, performed as part of routine gynecological examination (but without the patient necessarily having biomedical knowledge of its role). Besides accessibility and quality of health services, other factors influence the way the women assign meaning to cervical cancer prevention. Moral values associated with sexuality and gender influence risk perception, adoption of preventive practices, and interpretation of cervical cytology results. The ongoing practice of the Pap smear test is part of the construction of femininity, which is associated with maturity and personal responsibility for self care in a context of medicalization of the female body. PMID- 24068223 TI - [Chronic diseases and quality of life in primary health care]. AB - The aim of this cross-sectional study was to evaluate quality of life in chronic patients treated at primary care services associated with the Catholic University of Pelotas, Rio Grande do Sul State, Brazil. Quality of life was assessed by WHOQOL-Bref, and data on chronic diseases were obtained from patients' medical records and categorized as cardiovascular diseases, respiratory diseases, endocrine diseases, mental illness, and other musculoskeletal diseases. A total of 920 subjects were interviewed. Low self-rated quality of life was associated with female gender, older age, low socioeconomic status, single conjugal status, and chronic disease. In all domains of quality of life, mean levels were lower in patients with diseases of the nervous system, except in the environmental domains, which were lower in patients with mental illness. The results corroborate that quality of life in patients with chronic diseases is a priority for public health policies. PMID- 24068224 TI - Reproducibility, relative validity and calibration of a food frequency questionnaire for adults. AB - The purpose of the present study was to evaluate the reproducibility and relative validity and calibrate the dietary intake assessment of a food frequency questionnaire (FFQ) using a random sample of 195 adults aged 20 to 50 years from the Central-West Region of Brazil. The reference method used by the study was two 24-hour recalls (24hR) that provided energy-adjusted deattenuated food intake data for comparison purposes. With respect to reproducibility, the average weighted kappa was 0.43 and exact agreement was 41.5%. With regard to relative validity, correlation coefficients ranged from 0.32 (thiamin) to 0.51 (carbohydrates), with a mean of 0.41. Deattenuation and adjustment for energy intake decreased most correlation coefficients in relation to crude values. The food frequency questionnaire showed good reliability and moderate validity for most nutrients based on classification into quartiles of energy and nutrient intake. The calibrated means of the FFQ were more similar to the means estimated from the 24hR and showed lower standard deviation. PMID- 24068225 TI - Validity and reproducibility of a food frequency questionnaire to assess food group intake in adolescents. AB - The objective of this study was to assess the validity and reproducibility of a food frequency questionnaire to assess intake of the food groups included in the food guide pyramid for adolescents (FFQ-FP). The final version of the FFQ-FP consisted of 50 food items. The study was carried out with a sample of 109 adolescents over a period of four months. A 24hr recall (24hr) was conducted four times and the FFQ-FP was conducted twice. Validity was determined by comparing the second FFQ-FP and the mean of the four 24hrs, while reproducibility was verified by comparing the results of the two FFQ-FPs. Statistical analysis was carried out using medians, standard deviations, Pearson and intraclass correlations and Kappa statistics to assess concordance. Best results were achieved for the rice (including bread, grains and starches), meats and sugars groups. Weakest correlation was observed for the variable vitamin C. The validity and reproducibility of the FFQ-FP was satisfactory for most variables. PMID- 24068226 TI - [Primary healthcare and underreporting and (in)visibility of violence against women]. AB - This study aimed to map indicators of violence against women as recorded by primary healthcare services in Belo Horizonte, Minas Gerais State, Brazil, and to identify difficulties experienced by health professionals in reporting such violence. Epidemiological data on this type of notification were collected in the information system of the Municipal Health Department. Data were produced with a semi-structured questionnaire and three focus group sessions with participation by 270 primary care professionals. The data were submitted to content analysis and were coded, categorized, and discussed in light of a literature review. A central analytical axis was called (in)visibility of violence against women. The data revealed both the recognition of violence as a public health problem and the invisibility that prevents dealing with it properly. Notification of such violence is often viewed as a fuss or commotion, which hampers progress in discussing and acting on the problem. PMID- 24068228 TI - [Use of health services by quilombo communities in southwest Bahia State, Brazil]. AB - Use of health services is increasing in Brazil as a whole, but geographic and social inequalities persist, especially among minority groups. The aim of this study was to analyze the use of health services by members of quilombos (slavedescendant African-Brazilian communities) in Vitoria da Conquista, Bahia State, Brazil. This cross-sectional health survey in 2011 focused on 797 adults (>= 18 years old) belonging to quilombos. The magnitude of the associations between explanatory variables and use of services was estimated by the prevalence ratio obtained from Poisson regression with 95% confidence interval. Of the total sample, 455 (57.1%) reported having used health services in the 12 months prior to the interview. Higher rates of health services utilization were associated with female gender, non-single conjugal status, fair, poor, or very poor self rated health, enrolment in the Family Health Program, and referral to a health facility for regular or on-going care. The results showed underutilization of health services by members of quilombos, thus demonstrating the need to improve health services provision for this population group. PMID- 24068227 TI - [Prevalence of wheezing and associated factors in children under 5 years of age in Cuiaba, Mato Grosso State, Brazil]. AB - Wheezing is highly prevalent in Brazil, with variations in rates and risk factors between the regions of the country. This cross-sectional study aimed to analyze the prevalence of wheezing in children under 5 years of age (n = 733) in Cuiaba, Mato Grosso State, Brazil. The study used a brief version of the standardized instrument from the International Study of Wheezing in Infants (EISL). Analysis of factors associated used logistic regression with a hierarchical approach. Prevalence of wheezing in the previous 12 months was 43.2%. Factors associated with wheezing were: lack of at least 6 months of breastfeeding (adjusted OR = 1.91; 95%CI: 1.18-3.06), diagnosis of asthma in the family (adjusted OR = 2.02; 95%CI: 1.06-3.87), current respiratory infection (adjusted OR = 1.81; 95%CI: 1.05 3.14), and male gender (adjusted OR = 1.50; 95%CI: 1.07-2.11). The study concludes that prevalence of wheezing is high among children in this age bracket in Cuiaba and is associated with factors related to allergy, current respiratory infection, and male gender. PMID- 24068229 TI - [Spatial distribution of scorpion stings in Ponta Grossa, Parana State, Brazil]. AB - Among all bites and stings by venomous animals, scorpion stings have increased significantly in urban areas all over Brazil. Considering that Ponta Grossa is the city in Parana State with the highest incidence of reported scorpion stings, the current study aimed to assess trends in scorpion stings based on notification records and complaints from January 2008 to December 2010. The geographic coordinates of addresses with reported scorpion stings were collected, digitized, and spatialized, resulting in a cartogram of the georeferenced scorpion stings in the city. The incidence coefficients for this period showed that Ponta Grossa had 113.3 cases per 100,000 inhabitants, and that Colonia Dona Luiza, Neves, and Chapada were the neighborhoods with the highest rates. Investigation of determinants of scorpion stings used visual and statistical analysis, indicating wooded or green areas, water mains, and the sewer system as the main correlated variables. PMID- 24068230 TI - [Can teenage obesity affect mental health?]. AB - This study evaluated the association between obesity and emotional and behavioral difficulties in adolescents. We studied 4,325 individuals 11 to 15 years of age who were members of the 1993 birth cohort in Pelotas, Rio Grande do Sul State, Brazil. Information on body mass index (BMI), maternal assessment of the adolescents' emotional and behavioral health (Strengths and Difficulties Questionnaire - SDQ), and sociodemographic and behavioral characteristics were used. Gender-stratified analyses were conducted with simple and multivariate linear regression. In the adjusted analysis, obesity only correlated with total SDQ scores in boys. Among the latter, teenage obesity was associated with higher scores on the subscale of relational problems with peers. Given current knowledge on the future implications of obesity and mental health and in dealing with adolescents, studies on gender differences in adolescence may contribute to understanding such associations. PMID- 24068231 TI - [Air pollution and respiratory and cardiovascular diseases: a time series study in Cubatao, Sao Paulo State, Brazil]. AB - This study evaluated the association between air pollution and hospital admissions due to respiratory and cardiovascular diseases in Cubatao, Sao Paulo State, Brazil. Generalized additive Poisson regression models were used to model daily concentrations of particulate matter (PM10), sulfur dioxide (SO2), and ozone (O3) and daily hospital admissions counts. Explanatory variables were temperature, relative humidity, day of the week, and holidays. For each increment of 10ug/m3 in PM10, we found an excess of 4.25 % (95%CI: 2.82; 71), 5.74% (95%CI: 3.80; 7.71), and 2.29% (95%CI: 0.86; 3.73) in admissions due to respiratory diseases for all ages, respiratory diseases in children under 5 years old, and cardiovascular diseases in adults over 39 years of age, respectively. For SO2, the increase was 3.51% (IC95%: 1.24; 5.83) for cardiovascular diseases in adults more than 39 years. For O3, the increase was 2.85% (IC95%: 0.77; 4.98) for cardiovascular diseases in adults more than 39 years of age and 3.91% (IC95%: 1.37; 6.51) for respiratory diseases in children under 5 years old. Air pollution has serious impacts on health in Cubatao, thus emphasizing the need for air quality control policies. PMID- 24068232 TI - [Adolescent health: a population-based study in Campinas, Sao Paulo State, Brazil]. AB - We estimated the prevalence of chronic diseases and other health problems reported by adolescents in relation to social and demographic variables and nutritional status. This cross-sectional population-based survey analyzed data from the Health Survey in Campinas, Sao Paulo State, Brazil, 2008. We used descriptive statistics and associations between variables with the chisquare test. Prevalence of chronic diseases among adolescents was 19.17%, with asthma showing the highest prevalence (7.59%), followed by heart disease (1.96%), hypertension (1.07%), and diabetes 0.21%. Prevalence rates were 61.53% for health problems, 40.39% for allergy, and 24.83% for frequent headache or migraine. After multivariate analysis using Poisson regression, the factors associated with chronic disease were age 15 to 19 years (PR = 1.38), not attending school (PR = 1.46), having children (PR = 1.84), and obesity (PR = 1.54). Female gender (PR = 1.12) was statistically associated with health problems. The study illustrates that adolescence is a life stage in which chronic disease and health problems can occur. PMID- 24068233 TI - [Quilombo communities in Vitoria da Conquista, Bahia State, Brazil: hypertension and associated factors]. AB - The study aimed to estimate the prevalence of hypertension in members of quilombos (slavedescendant African-Brazilian communities) and to evaluate possible associated factors. A population-based survey included 797 individuals 18 years or older. Hypertension was defined as systolic blood pressure >= 140mmHg or diastolic blood pressure >= 90mmHg or reported use of antihypertensive medication. We used Poisson regression with robust variance and hierarchical entry of variables. Prevalence of hypertension was 45.4% (95%CI: 41.89-48.85). Factors associated with hypertension were: neighborhood security (distal), age, economic class, education, and physical inactivity (intermediate), and body mass index (proximal). Health promotion is needed in the quilombo communities through action at the individual and population levels. The high prevalence of hypertension highlights the need for broad access to health services for prevention, early diagnosis, and guidelines for adequate management. PMID- 24068235 TI - Transportation and physical activity in Sao Paulo, Brazil. PMID- 24068234 TI - [Persistent amphetamine consumption by truck drivers in Sao Paulo State, Brazil, despite the ban on production, prescription, and use]. AB - Amphetamine use by truck drivers for occupational purposes is widely known. The production and consumption of amphetamines was banned by the Brazilian National Health Surveillance Agency (ANVISA) in October 2011. This study analyzes persistent amphetamine use by truck drivers since the ban was implemented. A convenience sample of 427 truck drivers was taken along highways in Sao Paulo State in 2012. Participants were asked to answer a structured questionnaire and provide a urine sample to screen for recent amphetamine consumption through toxicological analysis. Among the interviewed drivers, 7% had used some illicit drug recently and 2.7% had used amphetamines. Amphetamines are still consumed by truck drivers despite the risks and the recent ban. The authorities should thus monitor the possession and use of amphetamines by drivers in order to effectively enforce the ban. PMID- 24068238 TI - Bacterial adaptation to cold. AB - Micro-organisms react to a rapid temperature downshift by triggering a physiological response to ensure survival in unfavourable conditions. Adaptation includes changes in membrane composition and in the translation and transcription machineries. The cold shock response leads to a growth block and overall repression of translation; however, there is the induction of a set of specific proteins that help to tune cell metabolism and readjust it to the new conditions. For a mesophile like E. coli, the adaptation process takes about 4 h. Although the bacterial cold shock response was discovered over two decades ago we are still far from understanding this process. In this review, we aim to describe current knowledge, focusing on the functions of RNA-interacting proteins and RNases involved in cold shock adaptation. PMID- 24068239 TI - Functional analysis of TetR-family regulator AmtRsav in Streptomyces avermitilis. AB - In actinomycetes, two main regulators, the OmpR-like GlnR and the TetR-type AmtR, have been identified as the central regulators for nitrogen metabolism. GlnR mediated regulation was previously identified in different actinomycetes except for members of the genus Corynebacterium, in which AmtR plays a predominant role in nitrogen metabolism. Interestingly, some actinomycetes (e.g. Streptomyces avermitilis) harbour both glnR- and amtR-homologous genes in the chromosome. Thus, it will be interesting to determine how these two different types of regulators function together in nitrogen regulation of these strains. In this study, AmtRsav (sav_6701) in S. avermitilis, the homologue of AmtR from Corynebacterium glutamicum, was functionally characterized. We showed, by real time reverse transcription (RT)-PCR (qPCR) in combination with electrophoretic mobility shift assays (EMSAs), that gene cluster sav_6697-6700 encoding a putative amidase, a urea carboxylase and two hypothetical proteins, respectively, and sav_6709 encoding a probable amino acid permease are under the direct control of AmtRsav. Using approaches of comparative analysis combined with site-directed DNA mutagenesis, the AmtRsav binding sites in the respective intergenic regions of sav_6700/6701 and sav_6709/6710 were defined. By genome screening coupled with EMSAs, two novel AmtRsav binding sites were identified. Taken together, AmtRsav seems to play a marginal role in regulation of nitrogen metabolism of S. avermitilis. PMID- 24068240 TI - Comparative phenotypic analysis and genome sequence of Clostridium beijerinckii SA-1, an offspring of NCIMB 8052. AB - Production of butanol by solventogenic clostridia is controlled through metabolic regulation of the carbon flow and limited by its toxic effects. To overcome cell sensitivity to solvents, stress-directed evolution methodology was used three decades ago on Clostridium beijerinckii NCIMB 8052 that spawned the SA-1 strain. Here, we evaluated SA-1 solventogenic capabilities when growing on a previously validated medium containing, as carbon- and energy-limiting substrates, sucrose and the products of its hydrolysis d-glucose and d-fructose and only d-fructose. Comparative small-scale batch fermentations with controlled pH (pH 6.5) showed that SA-1 is a solvent hyper-producing strain capable of generating up to 16.1 g l(-1) of butanol and 26.3 g l(-1) of total solvents, 62.3 % and 63 % more than NCIMB 8052, respectively. This corresponds to butanol and solvent yields of 0.3 and 0.49 g g(-1), respectively (63 % and 65 % increase compared with NCIMB 8052). SA-1 showed a deficiency in d-fructose transport as suggested by its 7 h generation time compared with 1 h for NCIMB 8052. To potentially correlate physiological behaviour with genetic mutations, the whole genome of SA-1 was sequenced using the Illumina GA IIx platform. PCR and Sanger sequencing were performed to analyse the putative variations. As a result, four errors were confirmed and validated in the reference genome of NCIMB 8052 and a total of 10 genetic polymorphisms in SA-1. The genetic polymorphisms included eight single nucleotide variants, one small deletion and one large insertion that it is an additional copy of the insertion sequence ISCb1. Two of the genetic polymorphisms, the serine threonine phosphatase cbs_4400 and the solute binding protein cbs_0769, may possibly explain some of the observed physiological behaviour, such as rerouting of the metabolic carbon flow, deregulation of the d fructose phosphotransferase transport system and delayed sporulation. PMID- 24068241 TI - Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP. AB - Isoprenoid lipid carriers are essential in protein glycosylation and bacterial cell envelope biosynthesis. The enzymes involved in their metabolism (synthases, kinases and phosphatases) are therefore critical to cell viability. In this review, we focus on two broad groups of isoprenoid pyrophosphate phosphatases. One group, containing phosphatidic acid phosphatase motifs, includes the eukaryotic dolichyl pyrophosphate phosphatases and proposed recycling bacterial undecaprenol pyrophosphate phosphatases, PgpB, YbjB and YeiU/LpxT. The second group comprises the bacterial undecaprenol pyrophosphate phosphatase, BacA/UppP, responsible for initial formation of undecaprenyl phosphate, which we predict contains a tyrosine phosphate phosphatase motif resembling that of the tumour suppressor, phosphatase and tensin homologue (PTEN). Based on protein sequence alignments across species and 2D structure predictions, we propose catalytic and lipid recognition motifs unique to BacA/UppP enzymes. The verification of our proposed active-site residues would provide new strategies for the development of substrate-specific inhibitors which mimic both the lipid and pyrophosphate moieties, leading to the development of novel antimicrobial agents. PMID- 24068242 TI - Trust in the health-care provider-patient relationship: a systematic mapping review of the evidence base. AB - PURPOSE: Trust is important for patients and may be used as an indicator and potential 'marker' for how patients evaluate the quality of health care. The review aimed to classify the current evidence base on trust in the patient provider relationship in order to identify strengths and weaknesses and to point towards areas for future research. DATA SOURCES: Nine electronic databases were searched from 2004 onwards using text and subject heading keywords relating to 'trust' and 'health care' and 'relationships'. STUDY SELECTION: Abstracts were identified for empirical studies carried out in health-care settings that explicitly examined trust or reported trust-related findings as a secondary outcome. Data extraction Two review authors assessed the relevance of abstracts and extracted data relating to year published, country of study, clinical speciality, STUDY DESIGN: and participants. RESULTS OF DATA SYNTHESIS: Five hundred and ninety-six abstracts were included. Most reported on patients' trust in providers; were carried out in the USA; collected data in family care or oncology/palliative care settings; used questionnaires and interviews and elicited patients' perspectives. Only one study explicitly set out to examine providers' trust in patients and <5% of included studies reported on providers' trust in patients. CONCLUSION: Providers' trust in patients remains a neglected area on the trust research agenda. Empirical studies examining the factors that influence providers' trust in patients and how this might affect the quality of care and patient health-related behaviours are urgently needed to readdress this imbalance. Further exploration of this area using observational methods is recommended. PMID- 24068243 TI - Fabrication of molecular nanopatterns at aluminium oxide surfaces by nanoshaving of self-assembled monolayers of alkylphosphonates. AB - Nanoshaving, by tracing an atomic force microscope probe across a surface at elevated load, has been used to fabricate nanostructures in self-assembled monolayers of alkylphosphonates adsorbed at aluminium oxide surfaces. The simple process is implemented under ambient conditions. Because of the strong bond between the alkylphosphonates and the oxide surface, loads in excess of 400 nN are required to pattern the monolayer. Following patterning of octadecylphosphonate SAMs, adsorption of aminobutyl phosphonate yielded features as small as 39 nm. Shaving of monolayers of aryl azide-terminated alkylphosphonates, followed by attachment of polyethylene glycol to unmodified regions in a photochemical coupling reaction, yielded 102 nm trenches into which NeutrAvidin coated, dye-labelled, polymer nanospheres could be deposited, yielding bright fluorescence with little evidence of non-specific adsorption to other regions of the surface. Structures formed in alkylphosphonate films by nanoshaving were used to etch structures into the underlying metal. Because of the isotropic nature of the etch process, and the large grain size, some broadening was observed, but features 25-35 nm deep and 180 nm wide were fabricated. PMID- 24068244 TI - Electroencephalography (EEG)-based neurofeedback training for brain-computer interface (BCI). AB - Electroencephalography has become a popular tool in basic brain research, but in recent years, several practical limitations have been highlighted. Some of the drawbacks pertain to the offline analyses of the neural signal that prevent the subjects from engaging in real-time error correction during learning. Other limitations include the complex nature of the visual stimuli, often inducing fatigue and introducing considerable delays, possibly interfering with spontaneous performance. By replacing the complex external visual input with internally driven motor imagery, we can overcome some delay problems, at the expense of losing the ability to precisely parameterize features of the input stimulus. To address these issues, we here introduce a nontrivial modification to brain-computer Interfaces (BCI). We combine the fast signal processing of motor imagery with the ability to parameterize external visual feedback in the context of a very simple control task: attempting to intentionally control the direction of an external cursor on command. By engaging the subject in motor imagery while providing real-time visual feedback on their instantaneous performance, we can take advantage of positive features present in both externally- and internally driven learning. We further use a classifier that automatically selects the cortical activation features that most likely maximize the performance accuracy. Under this closed loop coadaptation system, we saw a progression of the cortical activation that started in sensorymotor areas, when at chance performance motor imagery was explicitly used, migrated to BA6 under deliberate control and ended in the more frontal regions of prefrontal cortex, when at maximal performance accuracy, the subjects reportedly developed spontaneous mental control of the instructed direction. We discuss our results in light of possible applications of this simple BCI paradigm to study various cognitive phenomena involving the deliberate control of a directional signal in decision making tasks performed with intent. PMID- 24068246 TI - An estimate of the science-wise false discovery rate and application to the top medical literature. AB - The accuracy of published medical research is critical for scientists, physicians and patients who rely on these results. However, the fundamental belief in the medical literature was called into serious question by a paper suggesting that most published medical research is false. Here we adapt estimation methods from the genomics community to the problem of estimating the rate of false discoveries in the medical literature using reported $P$-values as the data. We then collect $P$-values from the abstracts of all 77 430 papers published in The Lancet, The Journal of the American Medical Association, The New England Journal of Medicine, The British Medical Journal, and The American Journal of Epidemiology between 2000 and 2010. Among these papers, we found 5322 reported $P$-values. We estimate that the overall rate of false discoveries among reported results is 14% (s.d. 1%), contrary to previous claims. We also found that there is no a significant increase in the estimated rate of reported false discovery results over time (0.5% more false positives (FP) per year, $P = 0.18$) or with respect to journal submissions (0.5% more FP per 100 submissions, $P = 0.12$). Statistical analysis must allow for false discoveries in order to make claims on the basis of noisy data. But our analysis suggests that the medical literature remains a reliable record of scientific progress. PMID- 24068245 TI - A nationwide study of the association between celiac disease and the risk of autistic spectrum disorders. AB - IMPORTANCE: Most case reports suggest an association between autistic spectrum disorders (ASDs) and celiac disease (CD) or positive CD serologic test results, but larger studies are contradictory. OBJECTIVE: To examine the association between ASDs and CD according to small intestinal histopathologic findings. DESIGN AND SETTING: Nationwide case-control study in Sweden. MAIN OUTCOMES AND MEASURES: Through 28 Swedish biopsy registers, we collected data about 26,995 individuals with CD (equal to villous atrophy, Marsh stage 3), 12,304 individuals with inflammation (Marsh stages 1-2), and 3719 individuals with normal mucosa (Marsh stage 0) but positive CD serologic test results (IgA/IgG gliadin, endomysium, or tissue transglutaminase) and compared them with 213,208 age- and sex-matched controls. Conditional logistic regression estimated odds ratios (ORs) for having a prior diagnosis of an ASD according to the Swedish National Patient Register. In another analysis, we used the Cox proportional hazards regression model to estimate hazard ratios (HRs) for future ASDs in individuals undergoing small intestinal biopsy. RESULTS: A prior ASD was not associated with CD (OR, 0.93; 95% CI, 0.51-1.68) or inflammation (OR 1.03; 95% CI, 0.40-2.64) but was associated with a markedly increased risk of having a normal mucosa but a positive CD serologic test result (OR, 4.57; 95% CI, 1.58-13.22). Restricting our data to individuals without a diagnosis of an ASD at the time of biopsy, CD (HR, 1.39; 95% CI, 1.13-1.71) and inflammation (HR, 2.01; 95% CI, 1.29-3.13) were both associated with moderate excess risks of later ASDs, whereas the HR for later ASDs in individuals with normal mucosa but positive CD serologic test results was 3.09 (95% CI, 1.99-4.80). CONCLUSIONS AND RELEVANCE: Although this study found no association between CD or inflammation and earlier ASDs, there was a markedly increased risk of ASDs in individuals with normal mucosa but a positive CD serologic test result. PMID- 24068247 TI - Discussion: An estimate of the science-wise false discovery rate and applications to top medical journals by Jager and Leek. PMID- 24068248 TI - Discussion: Comment on a paper by Jager and Leek. PMID- 24068249 TI - Discussion: Difficulties in making inferences about scientific truth from distributions of published p-values. PMID- 24068250 TI - Discussion: An estimate of the science-wise false discovery rate and application to the top medical literature. PMID- 24068251 TI - Discussion: Why "An estimate of the science-wise false discovery rate and application to the top medical literature" is false. AB - Jager and Leek have tried to estimate a false-discovery rate (FDR) in abstracts of articles published in five medical journals during 2000-2010. Their approach is flawed in sampling, calculations, and conclusions. It uses a tiny portion of select papers in highly select journals. Randomized controlled trials and systematic reviews (designs with the lowest anticipated false-positive rates) are 52% of the analyzed papers, while these designs account for only 4% in PubMed in the same period. The FDR calculations consider the entire published literature as equivalent to a single genomic experiment where all performed analyses are reported without selection or distortion. However, the data used are the P-values reported in the abstracts of published papers; these P-values are a highly distorted, highly select sample. Besides selective reporting biases, all other biases, in particular confounding in observational studies, are also ignored, while these are often the main drivers for high false-positive rates in the biomedical literature. A reproducibility check of the raw data shows that much of the data Jager and Leek used are either wrong or make no sense: most of the usable data were missed by their script, 94% of the abstracts that reported >=2 P values had high correlation/overlap between reported outcomes, and only a minority of P-values corresponded to relevant primary outcomes. The Jager and Leek paper exemplifies the dreadful combination of using automated scripts with wrong methods and unreliable data. Sadly, this combination is common in the medical literature. PMID- 24068252 TI - Discussion: An estimate of the science-wise false discovery rate and application to the top medical literature. PMID- 24068253 TI - Regulation of estrogen receptor beta1 expression in breast cancer by epigenetic modification of the 5' regulatory region. AB - ERbeta1 is often down-regulated in breast cancer compared to normal breast but mechanisms surrounding this are unclear. We examined whether loss of heterozygosity (LOH) or methylation at ERbeta promoters (0N, 0K) and/or untranslated exon 0N were involved in ERbeta down-regulation in breast cancer tissues and cell lines and if treatment with the de-methylating agent 5-aza deoxycytidine and/or the histone deacetylase inhibitor Trichostatin A could influence expression in vitro. We found no evidence of correlation between LOH at 14q22-24 (genomic locus containing ERbeta/ESR2), and ERbeta1 expression in primary breast cancers. A negative correlation between ERbeta1 mRNA expression and methylation status was observed for promoter 0N in BT-20, MDA-MB-453 and T47D cells. Promoter 0K was consistently unmethylated. In primary breast tumours, methylation of the untranslated exon 0N, downstream of promoter 0N, but not of promoter 0N itself, correlated with down-regulation of ERbeta. In MDA-MB-453 cells, treatment with 5-aza-deoxycytidine was sufficient to induce ERbeta1 expression from the 0N promoter while in BT-20 both agents were required. Examination of various sites on ESR2 highlighted epigenetic but not genetic regulation of ERbeta1. In particular methylation adjacent to promoter 0N was a key regulatory event for ERbeta1 silencing. A combination of de-methylating agents and histone deacetylase inhibitors fully restored ERbeta1 expression which may offer a novel therapeutic angle for breast cancer management. PMID- 24068254 TI - Insulin suppresses IKs (KCNQ1/KCNE1) currents, which require beta-subunit KCNE1. AB - Abnormal QT prolongation in diabetic patients has become a clinical problem because it increases the risk of lethal ventricular arrhythmia. In an animal model of type 1 diabetes mellitus, several ion currents, including the slowly activating delayed rectifier potassium current (IKs), are altered. The IKs channel is composed of KCNQ1 and KCNE1 subunits, whose genetic mutations are well known to cause long QT syndrome. Although insulin is known to affect many physiological and pathophysiological events in the heart, acute effects of insulin on cardiac ion channels are poorly understood at present. This study was designed to investigate direct electrophysiological effects of insulin on IKs (KCNQ1/KCNE1) currents. KCNQ1 and KCNE1 were co-expressed in Xenopus oocytes, and whole cell currents were measured by a two-microelectrode voltage-clamp method. Acute application of insulin suppressed the KCNQ1/KCNE1 currents and phosphorylated Akt and extracellular signal-regulated kinase (ERK), the two major downstream effectors, in a concentration-dependent manner. Wortmannin (10(-6) M), a phosphoinositide 3-kinase (PI3K) inhibitor, attenuated the suppression of the currents and phosphorylation of Akt by insulin, whereas U0126 (10(-5) M), a mitogen-activated protein kinase kinase (MEK) inhibitor, had no effect on insulin induced suppression of the currents. In addition, insulin had little effect on KCNQ1 currents without KCNE1, which indicated an essential role of KCNE1 in the acute suppressive effects of insulin. Mutagenesis studies revealed amino acid residues 111-118 within the distal third C-terminus of KCNE1 as an important region. Insulin has direct electrophysiological effects on IKs currents, which may affect cardiac excitability. PMID- 24068255 TI - FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway. AB - Cholangiocytes, bile duct lining cells, actively adjust the amount of cholesterol and bile acids in bile through expression of enzymes and channels involved in transportation and metabolism of the cholesterol and bile acids. Herein, we report molecular mechanisms regulating bile acid biosynthesis in cholangiocytes. Among the cytochrome p450 (Cyp) enzymes involved in bile acid biosynthesis, sterol 27-hydroxylase (Cyp27) that is the rate-limiting enzyme for the acidic pathway of bile acid biosynthesis expressed in cholangiocytes. Expression of other Cyp enzymes for the basic bile acid biosynthesis was hardly detected. The Cyp27 expression was negatively regulated by a hydrophobic bile acid through farnesoid X receptor (FXR), a nuclear receptor activated by bile acid ligands. Activated FXR exerted the negative effects by inducing an expression of fibroblast growth factor 15/19 (FGF15/19). Similar to its repressive function against cholesterol 7alpha-hydroxylase (Cyp7a1) expression in hepatocytes, secreted FGF15/19 triggered Cyp27 repression in cholangiocytes through interaction with its cognate receptor fibroblast growth factor receptor 4 (FGFR4). The involvements of FXR and FGFR4 for the bile acid-induced Cyp27 repression were confirmed in vivo using knockout mouse models. Different from the signaling in hepatocytes, wherein the FGF15/19-induced repression signaling is mediated by c-Jun N-terminal kinase (JNK), FGF15/19-induced Cyp27 repression in cholangiocytes was mediated by p38 kinase. Thus, the results collectively suggest that cholangiocytes may be able to actively regulate bile acid biosynthesis in cholangiocytes and even hepatocyte by secreting FGF15/19. We suggest the presence of cholangiocyte-mediated intrahepatic feedback loop in addition to the enterohepatic feedback loop against bile acid biosynthesis in the liver. PMID- 24068257 TI - Ab initio non-adiabatic molecular dynamics. AB - Adiabatic nuclear potential energy surfaces (PESs) defined via the Born Oppenheimer (BO) approximation are a fundamental concept underlying chemical reactivity theory. For a wide range of excited-state phenomena such as radiationless decay, energy and charge transfer, and photochemical reactions, the BO approximation breaks down due to strong couplings between two or more BO PESs. Non-adiabatic molecular dynamics (NAMD) is the method of choice to model these processes. We review new developments in quantum-classical dynamics, analytical derivative methods, and time-dependent density functional theory (TDDFT) which have lead to a dramatic expansion of the scope of ab initio NAMD simulations for molecular systems in recent years. We focus on atom-centered Gaussian basis sets allowing highly efficient simulations for molecules and clusters, especially in conjunction with hybrid density functionals. Using analytical derivative techniques, forces and derivative couplings can be obtained with machine precision in a given basis set, which is crucial for accurate and stable dynamics. We illustrate the performance of surface-hopping TDDFT for photochemical reactions of the lowest singlet excited states of cyclohexadiene, several vitamin D derivatives, and a bicyclic cyclobutene. With few exceptions, the calculated quantum yields and excited state lifetimes agree qualitatively with experiment. For systems with ~50 atoms, the present Turbomole implementation allows NAMD simulations with 0.2-0.4 ns total simulation time using hybrid density functionals and polarized double zeta valence basis sets on medium-size compute clusters. We close by discussing open problems and future directions. PMID- 24068258 TI - Rehabilitation after posterior cruciate ligament reconstruction: a review of the literature and theoretical support. AB - INTRODUCTION: The purpose of this study was to conduct a literature review of studies that have addressed rehabilitation after posterior cruciate ligament (PCL) reconstruction. In particular, we intended to perform categorical analysis and discuss some critical points. MATERIALS AND METHODS: A literature review of English language articles was performed using the PubMed databases. Our literature search was performed using the following text words: [posterior cruciate ligament OR PCL] AND [reconstruction] AND [rehabilitation]. A total of 34 articles met our criteria and were included in the final systematic review. Rehabilitation protocols were reviewed and tabulated according to main rehabilitation protocol categories [range of motion (ROM), weight bearing, bracing, and strengthening]. RESULTS: Ranges of motion of 90 degrees and 120 degrees were allowed at 4-8 and 6-12 weeks postoperatively in 70 % of studies. Full weight bearing was delayed until 6 weeks postoperatively in 60 % of studies. Most studies (73 % of studies) used a brace for 6-8 weeks and active hamstring exercise was not allowed for 6-24 weeks postoperatively. CONCLUSIONS: The review showed that flexion of 90 degrees was allowed at around 6 weeks and prone passive flexion exercise or supine passive ROM exercise with posterior support was used to prevent a posteriorly directed force. Most authors used non-weight bearing or partial weight bearing in their rehabilitation programs, however it may be possible to perform active weight bearing in full extension or early flexion grades as soon as the soft tissue situation allows. Co-strengthening exercises could be recommended because these exercises produce co-contraction between the quadriceps and hamstring muscles with little posterior shear force. PMID- 24068256 TI - Function of matrix IGF-1 in coupling bone resorption and formation. AB - Balancing bone resorption and formation is the quintessential component for the prevention of osteoporosis. Signals that determine the recruitment, replication, differentiation, function, and apoptosis of osteoblasts and osteoclasts direct bone remodeling and determine whether bone tissue is gained, lost, or balanced. Therefore, understanding the signaling pathways involved in the coupling process will help develop further targets for osteoporosis therapy, by blocking bone resorption or enhancing bone formation in a space- and time-dependent manner. Insulin-like growth factor type 1 (IGF-1) has long been known to play a role in bone strength. It is one of the most abundant substances in the bone matrix, circulates systemically and is secreted locally, and has a direct relationship with bone mineral density. Recent data has helped further our understanding of the direct role of IGF-1 signaling in coupling bone remodeling which will be discussed in this review. The bone marrow microenvironment plays a critical role in the fate of mesenchymal stem cells and hematopoietic stem cells and thus how IGF-1 interacts with other factors in the microenvironment are equally important. While previous clinical trials with IGF-1 administration have been unsuccessful at enhancing bone formation, advances in basic science studies have provided insight into further mechanisms that should be considered for future trials. Additional basic science studies dissecting the regulation and the function of matrix IGF-1 in modeling and remodeling will continue to provide further insight for future directions for anabolic therapies for osteoporosis. PMID- 24068259 TI - COPD Assessment Test: rapid and easily applied test that promotes patient self management. PMID- 24068260 TI - Portuguese-language version of the COPD Assessment Test: validation for use in Brazil. AB - OBJECTIVE: To validate a Portuguese-language version of the COPD assessment test (CAT) for use in Brazil and to assess the reproducibility of this version. METHODS: This was multicenter study involving patients with stable COPD at two teaching hospitals in the city of Fortaleza, Brazil. Two independent observers (twice in one day) administered the Portuguese-language version of the CAT to 50 patients with COPD. One of those observers again administered the scale to the same patients one week later. At baseline, the patients were submitted to pulmonary function testing and the six-minute walk test (6MWT), as well as completing the previously validated Portuguese-language versions of the Saint George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (MMRC) dyspnea scale, and hospital anxiety and depression scale (HADS). RESULTS: Inter-rater and intra-rater reliability was excellent (intraclass correlation coefficient [ICC] = 0.96; 95% CI: 0.93-0.97; p < 0.001; and ICC = 0.98; 95% CI: 0.96-0.98; p < 0.001, respectively). Bland Altman plots showed good test-retest reliability. The CAT total score correlated significantly with spirometry results, 6MWT distance, SGRQ scores, MMRC dyspnea scale scores, and HADS depression scores. CONCLUSIONS: The Portuguese-language version of the CAT is a valid, reproducible, and reliable instrument for evaluating patients with COPD in Brazil. PMID- 24068261 TI - Local adverse effects associated with the use of inhaled corticosteroids in patients with moderate or severe asthma. AB - OBJECTIVE: To describe and characterize local adverse effects (in the oral cavity, pharynx, and larynx) associated with the use of inhaled corticosteroids (ICSs) in patients with moderate or severe asthma. METHODS: This was a cross sectional study involving a convenience sample of 200 asthma patients followed in the Department of Pharmaceutical Care of the Bahia State Asthma and Allergic Rhinitis Control Program Referral Center, located in the city of Salvador, Brazil. The patients were >= 18 years of age and had been using ICSs regularly for at least 6 months. Local adverse effects (irritation, pain, dry throat, throat clearing, hoarseness, reduced vocal intensity, loss of voice, sensation of thirst, cough during ICS use, altered sense of taste, and presence of oral candidiasis) were assessed using a 30-day recall questionnaire. RESULTS: Of the 200 patients studied, 159 (79.5%) were women. The mean age was 50.7 +/- 14.4 years. In this sample, 55 patients (27.5%) were using high doses of ICS, with a median treatment duration of 38 months. Regarding the symptoms, 163 patients (81.5%) reported at least one adverse effect, and 131 (65.5%) had a daily perception of at least one symptom. Vocal and pharyngeal symptoms were identified in 57 (28.5%) and 154 (77.0%) of the patients, respectively. The most commonly reported adverse effects were dry throat, throat clearing, sensation of thirst, and hoarseness. CONCLUSIONS: Self-reported adverse effects related to ICS use were common among the asthma patients evaluated here. PMID- 24068262 TI - Congenital lobar emphysema: 30-year case series in two university hospitals. AB - OBJECTIVE: To review the cases of patients with congenital lobar emphysema (CLE) submitted to surgical treatment at two university hospitals over a 30-year period. METHODS: We reviewed the medical records of children with CLE undergoing surgical treatment between 1979 and 2009 at the Botucatu School of Medicine Hospital das Clinicas or the Mogi das Cruzes University Hospital. We analyzed data regarding symptoms, physical examination, radiographic findings, diagnosis, surgical treatment, and postoperative follow-up. RESULTS: During the period studied, 20 children with CLE underwent surgery. The mean age at the time of surgery was 6.9 months (range, 9 days to 4 years). All of the cases presented with symptoms at birth or during the first months of life. In all cases, chest X rays were useful in defining the diagnosis. In cases of moderate respiratory distress, chest CT facilitated the diagnosis. One patient with severe respiratory distress was misdiagnosed with hypertensive pneumothorax and underwent chest tube drainage. Only patients with moderate respiratory distress were submitted to bronchoscopy, which revealed no tracheobronchial abnormalities. The surgical approach was lateral muscle-sparing thoracotomy. The left upper and middle lobes were the most often affected, followed by the right upper lobe. Lobectomy was performed in 18 cases, whereas bilobectomy was performed in 2 (together with bronchogenic cyst resection in 1 of those). No postoperative complications were observed. Postoperative follow-up time was at least 24 months (mean, 60 months), and no late complications were observed. CONCLUSIONS: Although CLE is an uncommon, still neglected disease of uncertain etiology, the radiological diagnosis is easily made and surgical treatment is effective. PMID- 24068263 TI - Reliability of the Brazilian Portuguese version of the fatigue severity scale and its correlation with pulmonary function, dyspnea, and functional capacity in patients with COPD. AB - OBJECTIVE: To describe the intra-rater and inter-rater reliability of the Brazilian Portuguese version of the fatigue severity scale (FSS) in patients with COPD and to identify the presence of its association with parameters of pulmonary function, dyspnea, and functional capacity. METHODS: This was an observational cross-sectional study involving 50 patients with COPD, who completed the FSS in interviews with two researchers in two visits. The FSS scores were correlated with those of the Medical Research Council (MRC) scale, as well as with FEV1, FVC, and six-minute walk distance (6MWD). RESULTS: The mean age of the patients was 69.4 +/- 8.23 years, whereas the mean FEV1 was 46.5 +/- 20.4% of the predicted value. The scale was reliable, with an intraclass correlation coefficient of 0.90 (95% CI, 0.81-0.94; p < 0.01). The FSS scores showed significant correlations with those of MRC scale (r = 0.70; p < 0.01), as well as with 6MWD (r = -0.77; p < 0.01), FEV1 (r = -0.38; p < 0.01), FVC (r = -0.35; p < 0.01), and stage of the disease in accordance with the Global Initiative for Chronic Obstructive Lung Disease criteria (r = 0.37; p < 0.01). CONCLUSIONS: The Brazilian Portuguese version of the FSS proved reliable for use in COPD patients in Brazil and showed significant correlations with sensation of dyspnea, functional capacity, pulmonary function, and stage of the disease. PMID- 24068264 TI - Effect of tramadol on lung injury induced by skeletal muscle ischemia reperfusion: an experimental study. AB - OBJECTIVE: To determine whether tramadol has a protective effect against lung injury induced by skeletal muscle ischemia-reperfusion. METHODS: Twenty Wistar male rats were allocated to one of two groups: ischemia-reperfusion (IR) and ischemia-reperfusion + tramadol (IR+T). The animals were anesthetized with intramuscular injections of ketamine and xylazine (50 mg/kg and 10 mg/kg, respectively). All of the animals underwent 2-h ischemia by occlusion of the femoral artery and 24-h reperfusion. Prior to the occlusion of the femoral artery, 250 IU heparin were administered via the jugular vein in order to prevent clotting. The rats in the IR+T group were treated with tramadol (20 mg/kg i.v.) immediately before reperfusion. After the reperfusion period, the animals were euthanized with pentobarbital (300 mg/kg i.p.), the lungs were carefully removed, and specimens were properly prepared for histopathological and biochemical studies. RESULTS: Myeloperoxidase activity and nitric oxide levels were significantly higher in the IR group than in the IR+T group (p = 0.001 for both). Histological abnormalities, such as intra-alveolar edema, intra-alveolar hemorrhage, and neutrophil infiltration, were significantly more common in the IR group than in the IR+T group. CONCLUSIONS: On the basis of our histological and biochemical findings, we conclude that tramadol prevents lung tissue injury after skeletal muscle ischemia-reperfusion. PMID- 24068265 TI - Oxygen desaturation in healthy subjects undergoing the incremental shuttle walk test. AB - OBJECTIVE: To determine the probability of oxygen desaturation in healthy individuals undergoing the incremental shuttle walk test (ISWT). METHODS: We enrolled 83 healthy subjects: 55 males (including 1 smoker) and 28 females. We determined pre-ISWT FEV1, FEV6, HR and SpO2, as well as post-ISWT HR and SpO2. RESULTS: Mean values overall were as follows: age, 35.05 +/- 12.53 years; body mass index, 24.30 +/- 3.47 kg/m2; resting HR, 75.12 +/- 12.48 bpm; resting SpO2, 97.96 +/- 1.02%; FEV1, 3.75 +/- 0.81 L; FEV6, 4.45 +/- 0.87 L; FEV1/FEV6 ratio, 0.83 +/- 0.08 (no restriction or obstruction); incremental shuttle walk distance, 958.30 +/- 146.32 m; post-ISWT HR, 162.41 +/- 18.24 bpm; and post-ISWT SpO2, 96.27 +/- 2.21%. In 11 subjects, post-ISWT SpO2 was higher than was pre-ISWT SpO2. In 17 subjects, there was a 4% decrease in SpO2 after the ISWT. There were no statistically significant differences between the groups with and without post ISWT oxygen desaturation in terms of age, gender, FEV1, FEV6, FEV1/FEV6, pre-ISWT SpO2, incremental shuttle walk distance, HR, or percentage of maximal HR. In the individuals with post-ISWT oxygen desaturation, the body mass index was higher (p = 0.01) and post-ISWT SpO2 was lower (p = 0.0001). CONCLUSIONS: Healthy individuals can present oxygen desaturation after the ISWT. Using the ISWT to predict subtle respiratory abnormalities can be misleading. In healthy subjects, oxygen desaturation is common after the ISWT, as it is during any intense physical activity. PMID- 24068266 TI - Contribution of flow-volume curves to the detection of central airway obstruction. AB - OBJECTIVE: To assess the sensitivity and specificity of flow-volume curves in detecting central airway obstruction (CAO), and to determine whether their quantitative and qualitative criteria are associated with the location, type and degree of obstruction. METHODS: Over a four-month period, we consecutively evaluated patients with bronchoscopy indicated. Over a one-week period, all patients underwent clinical evaluation, flow-volume curve, bronchoscopy, and completed a dyspnea scale. Four reviewers, blinded to quantitative and clinical data, and bronchoscopy results, classified the morphology of the curves. A fifth reviewer determined the morphological criteria, as well as the quantitative criteria. RESULTS: We studied 82 patients, 36 (44%) of whom had CAO. The sensitivity and specificity of the flow-volume curves in detecting CAO were, respectively, 88.9% and 91.3% (quantitative criteria) and 30.6% and 93.5% (qualitative criteria). The most prevalent quantitative criteria in our sample were FEF50%/FIF50% >= 1, in 83% of patients, and FEV1/PEF >= 8 mL . L(-1) . min( 1), in 36%, both being associated with the type, location, and degree of obstruction (p < 0.05). There was concordance among the reviewers as to the presence of CAO. There is a relationship between the degree of obstruction and dyspnea. CONCLUSIONS: The quantitative criteria should always be calculated for flow-volume curves in order to detect CAO, because of the low sensitivity of the qualitative criteria. Both FEF50%/FIF50% >= 1 and FEV1/PEF >= 8 mL . L(-1) . min( 1) were associated with the location, type and degree of obstruction. PMID- 24068267 TI - Lung function in post-poliomyelitis syndrome: a cross-sectional study. AB - OBJECTIVE: To compare lung function between patients with post-poliomyelitis syndrome and those with sequelae of paralytic poliomyelitis (without any signs or symptoms of post-poliomyelitis syndrome), as well as between patients with post poliomyelitis syndrome and healthy controls. METHODS: Twenty-nine male participants were assigned to one of three groups: control; poliomyelitis (comprising patients who had had paralytic poliomyelitis but had not developed post-poliomyelitis syndrome); and post-poliomyelitis syndrome. Volunteers underwent lung function measurements (spirometry and respiratory muscle strength assessment). RESULTS: The results of the spirometric assessment revealed no significant differences among the groups except for an approximately 27% lower mean maximal voluntary ventilation in the post-poliomyelitis syndrome group when compared with the control group (p = 0.0127). Nevertheless, the maximal voluntary ventilation values for the post-poliomyelitis group were compared with those for the Brazilian population and were found to be normal. No significant differences were observed in respiratory muscle strength among the groups. CONCLUSIONS: With the exception of lower maximal voluntary ventilation, there was no significant lung function impairment in outpatients diagnosed with post-poliomyelitis syndrome when compared with healthy subjects and with patients with sequelae of poliomyelitis without post-poliomyelitis syndrome. This is an important clinical finding because it shows that patients with post-poliomyelitis syndrome can have preserved lung function. PMID- 24068268 TI - Psychological morbidity as a moderator of intention to quit smoking: a study of smokers and former smokers. AB - OBJECTIVE: To analyze psychological morbidity as a moderator of the relationship between smoking representations and quality of life in smokers and former smokers, as well as to determine which psychological variables discriminate between smokers with and without the intention to quit smoking. METHODS: This was a quantitative, correlational cross-sectional study involving a convenience sample of 224 smokers and 169 former smokers. RESULTS: In smokers and former smokers, psychological morbidity had a moderating effect on the relationship between mental/physical quality of life and smoking representations (cognitive representations, emotional representations, and comprehensibility). Smokers with the intention to quit smoking more often presented with low comprehensibility, threatening emotional representations, behavioral beliefs, and perceived behavioral control, as well as with normative/control beliefs, than did those without the intention to quit. CONCLUSIONS: The results of this study underscore the importance of the moderating effect exerted by psychological morbidity, as well as that of sociocognitive variables, among smokers who have the intention to quit smoking. PMID- 24068269 TI - Adaptation to different noninvasive ventilation masks in critically ill patients. AB - OBJECTIVE: To identify which noninvasive ventilation (NIV) masks are most commonly used and the problems related to the adaptation to such masks in critically ill patients admitted to a hospital in the city of Sao Paulo, Brazil. METHODS: An observational study involving patients >= 18 years of age admitted to intensive care units and submitted to NIV. The reason for NIV use, type of mask, NIV regimen, adaptation to the mask, and reasons for non-adaptation to the mask were investigated. RESULTS: We evaluated 245 patients, with a median age of 82 years. Acute respiratory failure was the most common reason for NIV use (in 71.3%). Total face masks were the most commonly used (in 74.7%), followed by full face masks and near-total face masks (in 24.5% and 0.8%, respectively). Intermittent NIV was used in 82.4% of the patients. Adequate adaptation to the mask was found in 76% of the patients. Masks had to be replaced by another type of mask in 24% of the patients. Adequate adaptation to total face masks and full face masks was found in 75.5% and 80.0% of the patients, respectively. Non adaptation occurred in the 2 patients using near-total facial masks. The most common reason for non-adaptation was the shape of the face, in 30.5% of the patients. CONCLUSIONS: In our sample, acute respiratory failure was the most common reason for NIV use, and total face masks were the most commonly used. The most common reason for non-adaptation to the mask was the shape of the face, which was resolved by changing the type of mask employed. PMID- 24068270 TI - Prevalence of nutritional deficiency in patients with pulmonary tuberculosis. AB - OBJECTIVE: To determine the prevalence of nutritional deficiency among patients with pulmonary tuberculosis. METHODS: This was a cross-sectional study using data obtained from the Brazilian Case Registry Database and from the medical records of patients diagnosed with pulmonary tuberculosis (15-59 years of age) residing in one of the municipalities that make up the 16th Regional Health District of the state of Bahia. We calculated the incidence, lethality, and mortality rates, as well as the prevalence of nutritional deficiency, as evaluated by body mass index. Demographic, social, clinical, and epidemiological data were collected. RESULTS: Of the 72 confirmed cases of tuberculosis, 59 (81.9%) were in males, and 21 (29.2%) of the patients were in the 40-49 year age bracket. The majority (85.3%) described themselves as Mulatto or Black; 55.2% reported using alcohol; and approximately 90% were treated as outpatients. In the district and age bracket studied, the incidence of pulmonary tuberculosis was 30.6/100,000 population. Among the 72 patients, data regarding nutritional status was available for 34. Of those, 50% and 25%, respectively, presented nutritional deficiency at the beginning and at the end of treatment. No statistically significant differences were found between normal-weight and malnourished patients regarding the characteristics studied. CONCLUSIONS: The prevalence of nutritional deficiency was high among our sample of patients with pulmonary tuberculosis. This underscores the importance of nutritional follow-up for the assessment of tuberculosis treatment in the decision-making process regarding therapeutic interventions. PMID- 24068271 TI - Pulmonary tuberculosis and lung cancer: simultaneous and sequential occurrence. AB - OBJECTIVE: Lung cancer (LC) is the leading cause of cancer-related death and represents a major public health problem worldwide. Another major cause of morbidity and mortality, especially in developing countries, is tuberculosis. The simultaneous or sequential occurrence of pulmonary tuberculosis and LC in the same patient has been reported in various case series and case-control studies. The objective of this study was to describe the characteristics of patients developing tuberculosis and LC, either simultaneously or sequentially. METHODS: This was a cross-sectional study based on the review of medical charts. RESULTS: The study involved 24 patients diagnosed with tuberculosis and LC between 2009 and 2012. The diagnoses of tuberculosis and LC occurred simultaneously in 10 patients, whereas tuberculosis was diagnosed prior to LC in 14. The median time between the two diagnoses was 5 years (interquartile range: 1-30 years). Fourteen patients (58.3%) were male, 20 (83.3%) were White, and 22 (91.7%) were smokers or former smokers. The most common histological type was adenocarcinoma, identified in 14 cases (58.3%), followed by epidermoid carcinoma, identified in 6 (25.0%). Seven patients (29.2%) presented with distant metastases at diagnosis; of those 7 patients, 5 (71%) were diagnosed with LC and tuberculosis simultaneously. CONCLUSIONS: In the present study, most of the patients with tuberculosis and LC were smokers or former smokers, and tuberculosis was diagnosed either before or simultaneously with LC. Non-small cell lung cancer, especially adenocarcinoma, was the most common histological type. PMID- 24068272 TI - Effectiveness of diaphragmatic stimulation with single-channel electrodes in rabbits. AB - Every year, a large number of individuals become dependent on mechanical ventilation because of a loss of diaphragm function. The most common causes are cervical spinal trauma and neuromuscular diseases. We have developed an experimental model to evaluate the performance of electrical stimulation of the diaphragm in rabbits using single-channel electrodes implanted directly into the muscle. Various current intensities (10, 16, 20, and 26 mA) produced tidal volumes above the baseline value, showing that this model is effective for the study of diaphragm performance at different levels of electrical stimulation. PMID- 24068274 TI - Transdiaphragmatic intercostal hernia: imaging aspects in three cases. AB - Transdiaphragmatic intercostal hernia is uncommon and mostly related to blunt or penetrating trauma. We report three similar cases of cough-induced transdiaphragmatic intercostal hernia, highlighting the anatomic findings obtained with different imaging modalities (radiography, ultrasonography, CT, and magnetic resonance) in each of the cases. PMID- 24068273 TI - Pseudomonas aeruginosa infection in patients with cystic fibrosis: scientific evidence regarding clinical impact, diagnosis, and treatment. AB - Evidence-based techniques have been increasingly used in the creation of clinical guidelines and the development of recommendations for medical practice. The use of levels of evidence allows the reader to identify the quality of scientific information that supports the recommendations made by experts. The objective of this review was to address current concepts related to the clinical impact, diagnosis, and treatment of Pseudomonas aeruginosa infections in patients with cystic fibrosis. For the preparation of this review, the authors defined a group of questions that would be answered in accordance with the principles of PICO-an acronym based on questions regarding the Patients of interest, Intervention being studied, Comparison of the intervention, and Outcome of interest. For each question, a structured review of the literature was performed using the Medline database in order to identify the studies with the methodological design most appropriate to answering the question. The questions were designed so that each of the authors could write a response. A first draft was prepared and discussed by the group. Recommendations were then made on the basis of the level of scientific evidence, in accordance with the classification system devised by the Oxford Centre for Evidence-Based Medicine, as well as the level of agreement among the members of the group. PMID- 24068275 TI - Not all that wheezes is asthma! PMID- 24068276 TI - Visual scale for the quantification of hyperhidrosis. PMID- 24068277 TI - Pulmonary histoplasmosis presenting with a halo sign on CT in an immunocompetent patient. PMID- 24068279 TI - Development of bis-unsaturated ester aldehydes as amino-glue probes: sequential double azaelectrocyclization as a promising strategy for bioconjugation. AB - The unsaturated ester aldehyde, (E)-3-alkoxycarbonyl-5-phenyl-2,4-dienal, was efficiently dimerized by applying the strain-promoted double-click reaction with sym-dibenzo-1,5-cyclooctadiene-3,7-diyne. The resulting dimerized probe was sequentially reacted first with one peptide molecule and then with a protein or the amino groups on the surface of a live cell through double azaelectrocyclization to achieve highly efficient bioconjugation. PMID- 24068278 TI - Stress cardiomyopathy following acute ischemic stroke during flexible bronchoscopy: a rare sequence of complications. PMID- 24068280 TI - Emerging clinical role of pivmecillinam in the treatment of urinary tract infection in the context of multidrug-resistant bacteria. AB - The continuing spread of resistant Gram-negative bacteria is a therapeutic challenge and prudent use of antimicrobials is therefore essential. Urinary tract infections (UTIs), usually due to Gram-negative bacteria, are among the most common infections seen in the community. Moreover, bacterial strains producing extended-spectrum beta-lactamases (ESBLs) that are resistant not only to cephalosporins and penicillins, but also to fluoroquinolones and trimethoprim, are becoming more prevalent in the community. This means that oral antibiotic options to treat these infections are limited. The discovery of new drugs to tackle these problems has been difficult and slow paced; it is therefore timely to 'rediscover' the current antibiotics we have available in our clinical formulary, to determine how best they can be used. Pivmecillinam is an oral antibiotic with excellent clinical efficacy in the treatment of uncomplicated UTIs. It has been used extensively in Nordic countries with few problems, but, despite this, it is not widely used in other countries. There is emerging in vitro and in vivo evidence of its activity against ESBL-producing organisms and its synergistic potential with beta-lactamase inhibitors. Pivmecillinam is well tolerated with a low side-effect profile. Pivmecillinam also has a minimal effect on the intestinal and vaginal flora of the host; thus, there is a lower rate of selection of resistant bacteria, vaginal candidiasis and, of note, Clostridium difficile. PMID- 24068281 TI - Crosstalk between monocytes and renal mesangial cells via interaction of metalloproteinases and fractalkine in diabetic nephropathy. AB - An increasing number of studies suggest that the activation of innate immunity with the development of a chronic low-grade inflammatory response is a factor in the pathogenesis of diabetic nephropathy (DN). Advanced glycation end products (AGEs), chemokines and matrix metalloproteinases (MMPs) are known to be important in inflammatory reactions in DN. In the present study, the inter-regulation of MMP2 and fractalkine was observed between monocytes (U937) and human renal mesangial cells (HRMCs) and its potential pathophysiological role in DN. The expression of fractalkine and MMP2 was analyzed by RT-PCR, western blot analysis and enzyme-linked immunosorbent assay. The chemotaxis and adhesiveness of HRMCs to U937 cells was detected with a transwell system, co-culture and fluorescent staining, respectively. The results showed a decreased expression of MMP2 and an increased expression of fractalkine by AGEs in HRMCs. Fractalkine downregulated the mRNA expression and activity of MMP2, and the reduced MMP2 activity was reversed with an anti-fractalkine antibody. Conversely, MMP2 upregulated fractalkine mRNA and protein expression in HRMCs, which led to an increase in chemotaxis and a decrease in monocytic adhesion to HRMCs. In conclusion, these observations suggest a crosstalk between monocytes and HRMCs via the interaction of MMP2 and fractalkine, which may represent a therapeutic target to impede the inflammatory process associated with DN. PMID- 24068282 TI - FGF23 affects the lineage fate determination of mesenchymal stem cells. AB - FGF23 is a bone-derived hormone that regulates mineral metabolism by inhibiting renal tubular phosphate reabsorption and suppressing circulating 1,25(OH)2D and PTH levels. These effects are mediated by FGF-receptor binding and activation in the presence of its coreceptor Klotho, which is expressed in the distal tubules of the kidney. Recently, expression of Klotho in skeletal tissues has been reported, indicating a direct, yet unclear, extrarenal effect of FGF23 on cells involved with bone development and remodeling. In the present study, we found that bone marrow stromal cells harvested from Klotho null mice developed fewer osteoblastic but more adipocytic colonies than cells from wild-type mice. The underlying mechanism was explored by experiments on mouse C3H10T1/2 cells. We found that Klotho was weakly expressed and that FGF23 dose-dependently affected the lineage fate determination. The effects of FGF23 on cell differentiation can be diminished by SU 5402, a specific tyrosine kinase inhibitor for FGF receptors. Our results indicate that FGF23 directly affects the differentiation of bone marrow stromal cells. PMID- 24068284 TI - Characterization of fluoride-tolerant halophilic Bacillus flexus NM25 (HQ875778) isolated from fluoride-affected soil in Birbhum District, West Bengal, India. AB - A new Gram-positive, nonpigmented, rod-shaped fluoride-tolerant bacterial strain, NM25, was isolated from waterlogged muddy field soil collected from the fluoride endemic area of Rampurhat II block (average fluoride in water, 4.7 mg/l, and in soil, 1.5 mg/kg) in Birbhum District, West Bengal, India. The study was undertaken to characterize the fluoride-tolerant bacterial isolate, to determine its role in bioaccumulation of fluoride, and to analyze the water and soil quality of the bacterial environment. The isolate was positive for catalase, lipase, urease, protease, oxidase, and H2S production, but negative for indole production, nitrate reduction, and Vogues-Proskauer test. The organisms were sensitive to recommended doses of ofloxacin, kanamycin, rifampicin, levofloxacin, vancomycin, gatifloxacin, gentamicin, doxycycline, streptomycin, and nalidixic acid but resistant to ampicillin. Based on the phenotypic characteristics, 16S rRNA gene sequence, and phylogenetic analysis, the bacterial isolate NM25 was identified as Bacillus flexus. The G+C content of the 16S rDNA was 53.14 mol%. This strain tolerated up to 20% (w/v) NaCl in nutrient agar medium and was grown at the pH range 4-12. It reduced fluoride concentration up to 67.45% and tolerated more than 1,500 ppm of fluoride in brain-heart infusion agar medium. PMID- 24068283 TI - Evaluation of different wastewater treatment techniques in three WWTPs in Istanbul for the removal of selected EDCs in liquid phase. AB - Endocrine-disrupting compounds (EDCs) are exogenous substances that cause adverse health effects in an intact organism, or its progeny, subsequent to the changes in endocrine function. Recent studies have shown that wastewater treatment plant effluents play an important role in the release of EDCs into aquatic environments. Therefore, in this study, influent and effluent samples from three different wastewater treatment plants (WWTPs) in Istanbul were analysed for the presence of the principal EDCs. These chemicals include steroids and synthetic organic chemicals. Thus, the occurrence and fate of EDCs of great health concern were monitored at three WWTPs in Istanbul. Furthermore, these WWTPs are employing different treatment processes. Therefore, the EDC removal performances of different treatment regimes were also evaluated. Phytosterol was the most abundant EDC in the influent samples. Second group of compounds at high influent levels were alkyl phenols. Pesticide levels of all three WWTP influent samples were low. Pasakoy Advanced WWTP is more effective at eliminating EDCs. Kadikoy Primary WWTP exhibits the lowest EDC elimination efficiencies. To the best of our knowledge, this work comprises the first detailed report on the occurrence and behaviour of both natural and synthetic EDCs in WWTPs of Istanbul and Turkey. The steroid estrogen levels of this study are higher than the previously documented values, except the levels given for Gaobeidian WWTP in Beijing, China. This is attributed to higher population densities of Beijing and Istanbul and as well as to lower individual water consumption rates in the two cities. PMID- 24068285 TI - The effectiveness and risk comparison of EDTA with EGTA in enhancing Cd phytoextraction by Mirabilis jalapa L. AB - In the previous study, Mirabilis jalapa L. had revealed the basic Cd hyperaccumulator characteristics, but the accumulation ability was not as strong as that of other known Cd hyperaccumulators. In order to improve the accumulation ability of this ornamental plant, the chelants were used to activate the Cd in soil. As a substitute, ethylene glycol bis(2-aminoethyl) tetraacetic acid (EGTA) was selected to testify whether it has better effectiveness and can bring lesser metal leaching risk than EDTA. The data showed that the growth of M. jalapa was inhibited, while the Cd concentration of the plant was significantly increased under the treatments containing EDTA or EGTA. The Cd translocation ability under the EGTA treatments was higher than that under the EDTA treatments. The available Cd resulted from the application of chelant EGTA to the contaminated soils can be limited to the top 5 cm, while the application of chelant EDTA to the contaminated soils can be limited to the top 10 cm. In a word, EGTA showed better effectiveness than EDTA in enhancing Cd phytoextraction of M. jalapa. As an ornamental plant, M. jalapa has the potential to be used for phytoextraction of Cd-contaminated soils and it can beautify the environment at the same time. PMID- 24068286 TI - Validation of the prosthetic esthetic index. AB - OBJECTIVES: In order to diagnose impaired esthetics and evaluate treatments for these, it is crucial to evaluate all aspects of oral and prosthetic esthetics. No professionally administered index currently exists that sufficiently encompasses comprehensive prosthetic esthetics. This study aimed to validate a new comprehensive index, the Prosthetic Esthetic Index (PEI), for professional evaluation of esthetics in prosthodontic patients. MATERIAL AND METHODS: The content, criterion, and construct validity; the test-retest, inter-rater, and internal consistency reliability; and the sensitivity of the index were evaluated in 95 patients in need of oral rehabilitation. RESULTS: The content validity was sufficient: Most correlations between aspects of the PEI were low (R > 0.5). The PEI was significantly correlated to the Dental Aesthetic Index (R = 0.52) and could distinguish between subgroups of patients indicating sufficient criterion and construct validity. The test-retest reliability showed an Interclass Correlation Coefficient (ICC) of 0.80, the internal consistency reliability showed a Cronbach's alpha of 0.7; and the inter-rater reliability was excellent, with an ICC of 0.94. The PEI could furthermore distinguish between participants and controls, indicating sufficient sensitivity. CONCLUSION: The PEI is considered a valid and reliable instrument involving sufficient aspects for assessment of the professionally evaluated esthetics in prosthodontic patients. CLINICAL RELEVANCE: With the validated PEI available, the clinician can directly assess and document the comprehensive esthetics of prosthodontic patients in a structured manner. PMID- 24068287 TI - Skeletal and dental considerations in orthodontic treatment mechanics: a contemporary view. AB - Orthodontics has undergone a paradigm shift in the last 40 years. There have been both technical and philosophical changes ushered by the development of new appliances, techniques, and by the explosion in the amount of research being conducted all around the world. However, the application of any new concept requires a firm understanding of the fundamentals of orthodontics. This paper presents a broad review of some fundamental concepts of treatment mechanics that enable us to bring about skeletal and dental correction of the presenting malocclusion. The basic concepts of facemask therapy, mechanics, and biology of tooth movement will be discussed with an insight into the challenges facing us in the future. PMID- 24068290 TI - Metal-free, hydroacylation of C=C and N=N bonds via aerobic C-H activation of aldehydes, and reaction of the products thereof. AB - In this report, a thorough evaluation of the use of aerobically initiated, metal free hydroacylation of various C=C and N=N acceptor molecules with a wide range of aldehydes is presented. The aerobic-activation conditions that have been developed are in sharp contrast to previous conditions for hydroacylation, which tend to use transition metals, peroxides that require thermal or photochemical degradation, or N-heterocyclic carbenes. The mildness of the conditions enables a number of reactions involving sensitive reaction partners and, perhaps most significantly, allows for alpha-functionalised chiral aldehydes to undergo radical-based hydroacylation with complete retention of optical purity. We also demonstrate how the resulting hydroacylation products can be transformed into other useful intermediates, such as gamma-keto-sulfonamides, sultams, sultones, cyclic N-sulfonyl imines and amides. PMID- 24068291 TI - [Cardiac valve diseases]. PMID- 24068292 TI - [Imaging monitors--requirements and pitfalls]. AB - When applying the standard DIN V 6868-57 rule "acceptance testing for image display devices" it always comes to misunderstandings in the practical implementation. In a brief summary the most important requirements are presented. With the pending replacement of DIN V 6868-57 by DIN 6868-157 "acceptance and constancy tests of image display systems in their environment" there will be fundamental changes. Future requirements are presented as examples. Besides the introduction of a classroom concept and new test images, the focus of the standard is aligned with the image display system. This change places new demands on the management concept of picture archiving and communication system (PACS) workstations. For testing the unit, consisting of a computer system, video card, operating system and image display equipment only one organizational unit should be responsible. PMID- 24068293 TI - [Bilateral parotid gland swelling caused by...?: when the diagnosis is written in the stars!]. PMID- 24068294 TI - [Magnetic resonance imaging of the shoulder: impingement and instability related abnormalities--update 2013]. AB - Magnetic resonance imaging (MRI) plays an important role in the diagnosis and differentiation of numerous shoulder abnormalities and chronic shoulder pain. Important indications for MRI are assessment of the rotator cuff and the labrocapsular complex. The assessment of the rotator cuff muscles is crucial. The value of MR arthrography is discussed. The potential benefit of MR arthrography is the accurate evaluation of subtle rotator cuff abnormalities, shoulder instability-related lesions and the assessment of pathological conditions of the long biceps tendon. The following article describes the most common pathological findings of the shoulder joint and gives a description of the relevant findings for the orthopedic shoulder surgeon. The current article represents an update of an article previously published in 2006 with the same title (Zanetti and Saupe, Radiologe 46:79-89, 2006). PMID- 24068295 TI - The rs266729 single-nucleotide polymorphism in the adiponectin gene shows association with gestational diabetes. AB - AIM: Gestational diabetes mellitus (GDM) is a condition of impaired glucose tolerance during pregnancy in women without previous diagnosis of diabetes. It is associated with serious complications for both mother and child in the pre- and postnatal period. Moreover, women with GDM are at an increased risk of developing type 2 diabetes. Adiponectin is an important factor involved in the regulation of both carbohydrate and lipid metabolism. Polymorphisms in its gene (ADIPOQ) are known to affect the individual's predisposition to metabolic syndrome and type 2 diabetes. The aim of the current study was to investigate the possible association between three common single-nucleotide polymorphisms in ADIPOQ and gestational diabetes. METHODS: A total of 394 individuals were recruited to the study-130 pregnant women with GDM, 130 pregnant women without glucose intolerance and 134 female population controls. All subjects were genotyped for rs266729, rs2241766 and rs1501299 in the ADIPOQ gene. RESULTS: A significant association with the disease was observed for rs266729 (p = 0.0037). The rare G allele was found to be over-represented among controls (pregnant, population and pooled). While no association was found for rs2241766 and rs1501299, a GTG haplotype formed by the three polymorphisms was found to be more common among controls (0.004). CONCLUSION: The adiponectin promoter polymorphism rs266729 is associated with gestational diabetes. The minor G allele appears to confer protection against pregnancy-related diabetes mellitus. This effect is probably due to the influence of the variant on the adiponectin transcription regulation during gestation. PMID- 24068296 TI - In vitro maturation (IVM) of human oocytes. AB - In vitro maturation is a technique of assisted reproduction which in contrast to standard IVF or ICSI almost fully avoids hormonal stimulation. Immature oocytes will be fully matured in vitro within 24 h after oocyte collection. The method was introduced in the early nineties and is indicated in patients at high risk for ovarian hyperstimulation. Results are almost comparable to standard techniques. Up to now no elevated risk for fetal malformations has been described. IVM is a suitable alternative in IVF for an exactly defined subgroup of patients, in particular patients with PCOS, but still does not replace standard techniques. PMID- 24068297 TI - Preterm birth and mortality and morbidity: a population-based quasi-experimental study. AB - IMPORTANCE: Preterm birth is associated with increased mortality and morbidity. However, previous studies have been unable to rigorously examine whether confounding factors cause these associations rather than the harmful effects of being born preterm. OBJECTIVE: To estimate the extent to which the associations between early gestational age and offspring mortality and morbidity are the result of confounding factors by using a quasi-experimental design, the sibling comparison approach, and by controlling for statistical covariates that varied within families. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study, combining Swedish registries to identify all individuals born in Sweden from 1973 to 2008 (3,300,708 offspring of 1,736,735 mothers) and link them with multiple outcomes. MAIN OUTCOMES AND MEASURES: Offspring mortality (during infancy and throughout young adulthood) and psychiatric (psychotic or bipolar disorder, autism, attention-deficit/hyperactivity disorder, suicide attempts, substance use, and criminality), academic (failing grades and educational attainment), and social (partnering, parenthood, low income, and social welfare benefits) outcomes through 2009. RESULTS: In the population, there was a dose response relationship between early gestation and the outcome measures. For example, extreme preterm birth (23-27 weeks of gestation) was associated with infant mortality (odds ratio, 288.1; 95% CI, 271.7-305.5), autism (hazard ratio [HR], 3.2; 95% CI, 2.6-4.0), low educational attainment (HR, 1.7; 1.5-2.0), and social welfare benefits (HR, 1.3; 1.2-1.5) compared with offspring born at term. The associations between early gestation and mortality and psychiatric morbidity generally were robust when comparing differentially exposed siblings and controlling for statistical covariates, whereas the associations with academic and some social problems were greatly or completely attenuated in the fixed effects models. CONCLUSIONS AND RELEVANCE: The mechanisms responsible for the associations between preterm birth and mortality and morbidity are outcome specific. Associations between preterm birth and mortality and psychiatric morbidity are largely independent of shared familial confounds and measured covariates, consistent with a causal inference. However, some associations, particularly predicting suicide attempt, educational attainment, and social welfare benefits, are the result of confounding factors. The findings emphasize the importance of both reducing preterm birth and providing wraparound services to all siblings in families with an offspring born preterm. PMID- 24068298 TI - Can items used in 4-year-old well-child visits predict children's health and school outcomes? AB - To examine whether items comprising a preschool well-child check for use by family doctors in Australia with 4-5-year old children predicts health and academic outcomes at 6-7 years. The well-child check includes mandatory (anthropometry, eye/vision, ear/hearing, dental, toileting, allergy problems) and non-mandatory (processed food consumption, low physical activity, motor, behaviour/mood problems) items. The predictive validity of mandatory and non mandatory items measured at 4-5 years was examined using data from the Longitudinal Study of Australian Children. Outcomes at 6-7 years included overweight/obesity, asthma, health care/medication needs, general health, mental health problems, quality of life, teacher-reported mathematics and literacy ability (n = 2,280-2,787). Weight or height >90th centile at 4-5 years predicted overweight/obesity at 6-7 years with 60% sensitivity, 79% specificity and 40% positive predictive value (PPV). Mood/behaviour problems at 4-5 predicted mental health problems at 6-7 years with 86% sensitivity, 40% specificity and 8% PPV. Non-mandatory items improved the discrimination between children with and without mental health problems at 6-7 years (area under the receiver operating characteristic curve 0.75 compared with 0.69 for mandatory items only), but was weak for most outcomes. Items used in a well-child health check were moderate predictors of overweight/obesity and mental health problems at 6-7 years, but poor predictors of other health and academic outcomes. PMID- 24068299 TI - Systemic regulation of sulfur homeostasis in Medicago truncatula. AB - Sulfur (S) is an essential macronutrient for plants, and deficiency in soil S availability limits plant growth. Adaptive strategies have been evolved by plants to respond to S deficiency by coordinating systemic regulatory mechanism. A split root experiment using legume model plant Medicago truncatula Gaertn. was conducted to investigate the systemic response to S deficiency. Plant growth, root morphology and S contents under varying conditions of S supply were determined, and the expression of genes encoding sulfate transporter (MtSULTRs) and MtAPR1 encoding an enzyme involved in S assimilation was monitored. Our results demonstrated that there was an apparent systemic response of M. truncatula to heterogeneous S supply in terms of root length, S contents, and S uptake and assimilation at the transcriptional level. When exposed to heterogeneous S supply, M. truncatula plants showed proliferation of lateral roots in S-rich medium and reduction in investment to S-depleted roots. Growth was stimulated with half-part of roots exposed to S-deficient medium. There were different expression patterns of MtSULTRs and MtAPR1 in response to heterogeneous S supply both in roots and shoots of M. truncatula. Expression of MtSULTR1.1 and MtSULTR1.3 was systemically responsive to S deficiency, leading to an enhancement of S uptake in roots exposed to S-sufficient medium. In addition, the response of S-deprived seedlings to re-supply of sulfate and Cys was also analyzed. It was shown that sulfate, but not Cys, may serve as a systemic signal to regulate the expression of genes associated with S absorption and assimilation in M. truncatula. These findings provide a comprehensive picture of systemic responses to S deficiency in leguminous species. PMID- 24068300 TI - Molecular cloning and characterization of CrNCED1, a gene encoding 9-cis epoxycarotenoid dioxygenase in Citrus reshni, with functions in tolerance to multiple abiotic stresses. AB - Abscisic acid (ABA) is an important stress phytohormone that plays an essential role in mediating the signaling networks associated with plant responses to various abiotic stresses. In the present study, we isolated a gene CrNCED1 encoding the rate-limiting enzyme of ABA synthesis, 9-cis-epoxycarotenoid dioxygenase (NCED), from Citrus reshni. Expression patterns of CrNCED1 varied among different tissues, in which higher levels were measured in the leaves than in the roots. The steady-state mRNA levels of CrNCED1 were progressively elevated by dehydration and ABA, only transiently induced by cold, but not affected by salt. To examine its function in stress tolerance, transgenic tobacco (Nicotiana nudicaulis) plants constitutively overexpressing CrNCED1 were generated, which contained higher ABA levels than the wild type (WT) under both normal growth conditions and drought stress. The transgenic lines displayed enhanced tolerance to dehydration, drought, salt and oxidative stresses when compared with the WT. Lower levels of reactive oxygen species (H2O2 and O2-) were detected in the transgenic plants than in the WT under dehydration and salt stress. On the contrary, transcript levels of several genes associated with ROS scavenging, osmoticum adjustment, and water maintenance, and activities of two antioxidant enzymes were higher in the transgenic plants relative to the WT under the dehydration stress. Taken together, CrNCED1 overexpression confers enhanced tolerance to multiple abiotic stresses, which may be, at least in part, ascribed to the positive activation of the stress-responsive genes. PMID- 24068301 TI - Polydrug use among college students in Brazil: a nationwide survey. AB - OBJECTIVE: To estimate the frequency of polydrug use (alcohol and illicit drugs) among college students and its associations with gender and age group. METHODS: A nationwide sample of 12,544 college students was asked to complete a questionnaire on their use of drugs according to three time parameters (lifetime, past 12 months, and last 30 days). The co-use of drugs was investigated as concurrent polydrug use (CPU) and simultaneous polydrug use (SPU), a subcategory of CPU that involves the use of drugs at the same time or in close temporal proximity. RESULTS: Almost 26% of college students reported having engaged in CPU in the past 12 months. Among these students, 37% had engaged in SPU. In the past 30 days, 17% college students had engaged in CPU. Among these, 35% had engaged in SPU. Marijuana was the illicit drug mostly frequently used with alcohol (either as CPU or SPU), especially among males. Among females, the most commonly reported combination was alcohol and prescribed medications. CONCLUSIONS: A high proportion of Brazilian college students may be engaging in polydrug use. College administrators should keep themselves informed to be able to identify such use and to develop educational interventions to prevent such behavior. PMID- 24068302 TI - Inverted repeats and genome architecture conversions of terrestrial isopods mitochondrial DNA. AB - Mitochondrial DNA (mtDNA) is usually depicted as a circular molecule, however, there is increasing evidence that linearization of mtDNA evolved independently many times in organisms such as fungi, unicellular eukaryotes, and animals. Recent observations in various models with linear mtDNA revealed the presence of conserved inverted repeats (IR) at both ends that, when they become single stranded, may be able to fold on themselves to create telomeric-hairpins involved in genome architecture conversions. The atypical mtDNA of terrestrial isopods (Crustacea: Oniscidea) composed of linear monomers and circular dimers is an interesting model to study genome architecture conversions. Here, we present the mtDNA control region sequences of two species of the genus Armadillidium: A. vulgare and A. pelagicum. All features of arthropods mtDNA control regions are present (origin of replication, poly-T stretch, GA and TA-rich blocks and one variable domain), plus a conserved IR. This IR can potentially fold into a hairpin structure and is present in two different orientations among the A. vulgare populations: either in one sense or in its reverse complement. This polymorphism, also observed in a single individual (heteroplasmy), might be a signature of genome architecture conversions from linear to circular monomeric mtDNA via successive opening and closing of the molecules. PMID- 24068303 TI - A novel four-step system for screening angiogenesis inhibitors. AB - Angiogenesis exhibits a significant effect on tumor progression. Inhibiting angiogenesis may provide significant advantages over currently available therapeutics for cancer therapies thus, the development of a system of screening angiogenesis is essential. In the present study, a novel available system of screening angiogenesis inhibitors by four steps was developed. The chorioallantoic membrane (CAM), yolk sac membrane and early chick embryo blood island assay were initially performed to obtain possible antitumor compounds. The MMTV-PyMT transgenic breast cancer mouse model was used for final screening and to confirm potential antitumor effects. Four angiogenesis inhibitors were isolated from 480 compounds, which were obtained from ICCB known bioactives library, by a combination of the CAM, yolk sac membrane and early chick embryo blood island assay. The MMTV-PyMT mouse was treated with one of four agents and it was demonstrated that the tumor volume was significantly inhibited. These results demonstrate that the four-step screening system is feasible. PMID- 24068304 TI - Cycles, spirals and linear flows. PMID- 24068305 TI - Data availability and the need for research to localize, quantify and recycle critical metals in information technology, telecommunication and consumer equipment. AB - The supply of critical metals like gallium, germanium, indium and rare earths elements (REE) is of technological, economic and strategic relevance in the manufacturing of electrical and electronic equipment (EEE). Recycling is one of the key strategies to secure the long-term supply of these metals. The dissipation of the metals related to the low concentrations in the products and to the configuration of the life cycle (short use time, insufficient collection, treatment focusing on the recovery of other materials) creates challenges to achieve efficient recycling. This article assesses the available data and sets priorities for further research aimed at developing solutions to improve the recycling of seven critical metals or metal families (antimony, cobalt, gallium, germanium, indium, REE and tantalum). Twenty-six metal applications were identified for those six metals and the REE family. The criteria used for the assessment are (i) the metal criticality related to strategic and economic issues; (ii) the share of the worldwide mine or refinery production going to EEE manufacturing; (iii) rough estimates of the concentration and the content of the metals in the products; (iv) the accuracy of the data already available; and (v) the occurrence of the application in specific WEEE groups. Eight applications were classified as relevant for further research, including the use of antimony as a flame retardant, gallium and germanium in integrated circuits, rare earths in phosphors and permanent magnets, cobalt in batteries, tantalum capacitors and indium as an indium-tin-oxide transparent conductive layer in flat displays. PMID- 24068306 TI - Waste management and recycling in the former Soviet Union: the City of Bishkek, Kyrgyz Republic (Kyrgyzstan). AB - The UN-Habitat Integrated Sustainable Waste Management (ISWM) benchmarking methodology was applied to profile the physical and governance features of municipal solid waste (MSW) management in the former Soviet Union city of Bishkek, capital of the Kyrgyz Republic. Most of the ISWM indicators were in the expected range for a low-income city when compared with 20 reference cities. Approximately 240,000 t yr(-1) of MSW is generated in Bishkek (equivalent to 200 kg capita(-1) yr(-1)); collection coverage is over 80% and 90% of waste disposed goes to semi-controlled sites operating with minimal environmental standards. The waste composition was a distinctive feature, with relatively high paper content (20-27% wt.) and intermediate organic content (30-40% wt.). The study provides the first quantitative estimates of informal sector recycling, which is currently unrecognised by the city authorities. Approximately 18% wt. of generated MSW is recycled, representing an estimated annual saving to the city authorities of US$0.7-1.1 million in avoided collection/disposal costs. The waste management system is controlled by a centralised municipal waste enterprise (Tazalyk); therefore, institutional coherence is high relative to lower-middle and low income cities. However, performance on other governance factors, such as inclusivity and financial sustainability, is variable. Future priorities in Bishkek include extending collection to unserved communities; improving landfill standards; increasing recycling rates through informal sector cooperation; improving data availability; and engaging all stakeholders in waste management strategy decisions. Extending the scope and flexibility of the ISWM protocol is recommended to better represent the variation in conditions that occur in waste management systems in practice. PMID- 24068307 TI - Armchair BN nanotubes--levothyroxine interactions: a molecular study. AB - The density functional theory has been applied to investigate the structural and electronic properties of single-wall boron nitride nanotubes (SW-BNNT) of (5,5) chirality, with surface and ends functionalized by the drug levothyroxine (C15H11NI4O4). The exchange-correlation energies have been modeled according to the Hamprecht-Cohen-Tozer-Handy functional within the generalized gradient approximation (HCTH-GGA) and a base function with double polarization has been used. The (5,5) BNNT-Levothyroxine structural optimization has been done considering the minimum energy criterion in nine possible atomic structures. Simulation results indicate that the preferential adsorption site (chemical adsorption) of the levothyroxine fragment is at the nanotube ends. The BNNT Levothyroxine system polarity increases which indicates the possible dispersion and solubility both non-solvated and solvated in water. The BNNT-Levothyroxine solvated in water modifies its chemical reactivity which may allow the drug delivery within the biological systems. On the other hand, the decrease in the work function is important for the optoelectronic device design, which also makes these materials suitable to improve the field emission properties. PMID- 24068308 TI - The competition of C-X?O=P halogen bond and pi-hole?O=P bond between halopentafluorobenzenes C6F5X (X=F, Cl, Br, I) and triethylphosphine oxide. AB - Calculation predicted the interacting forms of halopentafluorobenzene C6F5X (X=F, Cl, Br, I) with triethylphosphine oxide which is biologically interested and easily detected by (31)P NMR. The interaction energy and geometric parameters of resultant halogen or pi-hole bonding complexes were estimated and compared. Moreover, the bonding constants were determined by (31)P NMR. Both theory and experiments indicated the C6F6 and C6F5Cl interact with triethylphosphine oxide by pi-hole bonding pattern, while C6F5I by halogen/sigma-hole bonding form. For C6F5Br, two interactions are comparative and should coexist competitively. The calculated interaction energies of sigma-hole bonding complexes, -5.07 kcal mol( 1) for C6F5Br?O=P and -8.25 kcal mol(-1) for C6F5I?O=P, and pi-hole bonding complexes, -7.29 kcal mol(-1) for C6F6?O=P and -7.24 kcal mol(-1) for C6F5Cl?O=P, are consistent with the changing tendency of bonding constants measured by (31)P NMR, 4.37, 19.7, 2.42 and 2.23 M(-1), respectively. PMID- 24068309 TI - The study of interactions between DNA and PcrA DNA helicase by using targeted molecular dynamic simulations. AB - DNA helicases are important enzymes involved in all aspects of nucleic acid metabolism, ranging from DNA replication and repair to recombination, rescue of stalled replication and translation. DNA helicases are molecular motors. Through conformational changes caused by ATP hydrolysis and binding, they move along the template double helix, break the hydrogen bonds between the two strands and separate the template chains, so that the genetic information can be accessed. In this paper, targeted molecular dynamic simulations were performed to study the important interactions between DNA and PcrA DNA helicase, which can not be observed from the crystal structures. The key residues on PcrA DNA helicase that have strong interactions with both double stranded DNA (ds-DNA) and single stranded DNA (ss-DNA) have been identified, and it was found that such interactions mostly exist between the protein and DNA backbone, which indicates that the translocation of PcrA is independent of the DNA sequence. The simulations indicate that the ds-DNA is separated upon ATP rebinding, rather than ATP hydrolysis, which suggests that the two strokes in the mechanism have two different major roles. Firstly, in the power stroke (ATP hydrolysis), most of the translocations of the bases from one pocket to the next occur. In the relaxation stroke (ATP binding), most of the 'work' is being done to 'melt' the DNA at the separation fork. Therefore, we propose a mechanism whereby the translocation of the ss-DNA is powered by ATP hydrolysis and the separation of the ds-DNA is powered by ATP binding. PMID- 24068316 TI - Diversity of the clinical presentation of the MMR gene biallelic mutations. AB - Constitutional mismatch repair-deficiency, due to biallelic mutations of MMR genes, results in a tumour spectrum characterized by leukaemias, lymphomas, brain tumours and adenocarcinomas of the gastro-intestinal tract, occurring mostly in childhood. We report here two families illustrating the phenotypic diversity associated with biallelic MMR mutations. In the first family, two siblings developed six malignancies including glioblastoma, lymphoblastic T cell lymphoma, rectal and small bowel adenocarcinoma with onset as early as 6 years of age. We showed that this dramatic clinical presentation was due to the presence of two complex genomic PMS2 deletions in each patient predicted to result into complete PMS2 inactivation. In the second family, the index case presented with an early form of Lynch syndrome with colorectal adenocarcinomas at ages 17 and 20 years, and urinary tract tumours at the age of 25 years. We identified in this patient two MSH6 mutations corresponding to a frameshift deletion and an in frame deletion. The latter was not predicted to result into complete inactivation of MSH6. These reports show that the clinical expression of biallelic MMR mutations depends on the biological impact of the second MMR mutation and that, in clinical practice, the presence of a second MMR mutation located in trans should also be considered in patients suspected to present a Lynch syndrome with an unusual early-onset of tumours. PMID- 24068318 TI - Introduction of hydrophilic groups onto the ortho-position of benzoate anions induced phase separation of the corresponding ionic liquids with water. AB - Ionic liquids (ILs) composed of tetrabutylphosphonium cations and benzoate anion derivatives with hydrophilic hydroxyl or carboxyl groups introduced onto the ortho-position were found to be less hydrophilic and showed phase separation with water, whereas unmodified benzoate-type IL was freely miscible with water. PMID- 24068317 TI - More breast cancer patients prefer BRCA-mutation testing without prior face-to face genetic counseling. AB - Currently, most breast cancer (BC) patients receive face-to-face genetic counseling (DNA-intake) prior to BRCA-mutation testing, with generic information regarding hereditary BC and BRCA-mutation testing. This prospective study evaluated a novel format: replacing the intake consultation with telephone, written and digital information sent home, and face-to-face contact following BRCA-mutation testing (DNA-direct). From August 2011 to February 2012, 161 of 233 eligible BC patients referred to our Human Genetics department chose between DNA direct (intervention) or DNA-intake (control). Exclusion criteria were psychological problems (n = 33), difficulty with Dutch text (n = 5), known BRCA family (n = 3), non-BRCA-referral (n = 1). 30 declined genetic counseling or study participation. Participants received questionnaires including satisfaction and psychological distress. 59 % chose DNA-direct (p = 0.03), of whom 90 % were satisfied and would choose DNA-direct again (including 6/8 BRCA-mutation carriers); although 27 % hesitated to recommend DNA-direct to other patients. General distress (GHQ-12, p = 0.001) and heredity-specific distress (IES, p = 0.02) scored lower in DNA-direct than DNA-intake, both at baseline and follow-up 2 weeks after BRCA-result disclosure; all scores remained below clinical relevance. DNA-direct participants reported higher website use (53 vs. 32 %, p = 0.01), more referrer information about personal consequences (41 vs. 20 %, p = 0.004) and lower decisional conflict (median 20 [0-88] vs. 25 [0-50], p = 0.01). Processing time in DNA-direct was reduced by 1 month. Mutation detection rate was 8 % in both groups. All BRCA-mutation carriers fulfilled current testing criteria. In conclusion, more BC patients preferred DNA-direct over intake consultation prior to BRCA-mutation testing, the majority being strongly to moderately satisfied with the procedure followed, without increased distress. PMID- 24068319 TI - One-pot synthesis of 4-methylisoquinolines via a sequential Pd-catalyzed Heck reaction and intramolecular cyclization. AB - An efficient, one-pot synthesis of 4-methylisoquinolines via a cascade Pd catalyzed Heck reaction, intramolecular cyclization and isomerization has been developed. This reaction has a wide range of substrates with various functional groups, and the corresponding products have been obtained in good yields. PMID- 24068321 TI - [Diseases of the external genitalia]. PMID- 24068320 TI - Human CLOCK gene-associated attention deficit hyperactivity disorder-related features in healthy adults: quantitative association study using Wender Utah Rating Scale. AB - Circadian rhythm disturbance is highly prevalent in attention deficit hyperactivity disorder (ADHD). Recently, the association between the CLOCK gene and ADHD has been demonstrated in clinical samples, and the CLOCK gene's role was thought to be mediated by rhythm dysregulation. Meanwhile, ADHD has been suggested as the extreme end of a continuously distributed trait that can be found in the general population. Therefore, we examined two possibilities: (1) an ADHD-related continuous trait may be associated with the CLOCK gene, and (2) this association may be mediated by the degree of individuals' evening preference. To explore these possibilities, we performed a quantitative trait locus association study with a sample of 1,289 healthy adults. The Wender Utah Rating Scale (WURS) and the Composite Scale of Morningness (CSM) were utilized to measure the quantitative traits. Quantitative association analysis was performed using PLINK software. We found that rs1801260 (=T3111C) was associated with WURS scores in both allele-wise (p = 0.018) and haplotype-wise analyses (range of p values: 0.0155-0.0171) in male participants only. After controlling for the CSM total score as a covariate, the strength of the association did not change at all, suggesting that the association was not mediated by evening preference. Despite the very weak association signal, our results provide evidence that the CLOCK gene's association with ADHD in clinical samples may be generalizable to traits measured in the normal population. However, as our results failed to show a mediating role of evening preference, ongoing efforts are needed to identify the mechanisms by which the CLOCK gene determines ADHD-related traits. PMID- 24068322 TI - [Urological dermatosis]. AB - Urologists are often confronted with venereal and dermatological diseases during clinical evaluation of the external genitals. Dermatosis of the male genitalia ranges from infectious (viral and bacterial) lesions and inflammatory conditions to neoplastic alterations. There are also more general skin diseases (e.g. psoriasis) which occur as genital manifestations. In this case they often show unusual characteristics or the genitalia might be involved only incidentally. This review highlights the clinical diagnosis and therapy of the most common genital skin disorders and demonstrates the medical features. PMID- 24068323 TI - A deubiquitinase negatively regulates retro-translocation of nonubiquitinated substrates. AB - Endoplasmic reticulum (ER) membrane-bound E3 ubiquitin ligases promote ER associated degradation (ERAD) by ubiquitinating a retro-translocated substrate that reaches the cytosol from the ER, targeting it to the proteasome for destruction. Recent findings implicate ERAD-associated deubiquitinases (DUBs) as positive and negative regulators during ERAD, reflecting the different consequences of deubiquitinating a substrate prior to proteasomal degradation. These observations raise the question of whether a DUB can control the fate of a nonubiquitinated ERAD substrate. In this study, we probed the role of the ERAD associated DUB, YOD1, during retro-translocation of the nonubiquitinated cholera toxin A1 (CTA1) peptide, a critical intoxication step. Through combining knockdown, overexpression, and binding studies, we demonstrated that YOD1 negatively controls CTA1 retro-translocation, likely by deubiquitinating and inactivating ubiquitinated ERAD components that normally promote toxin retro translocation. YOD1 also antagonizes the proteasomal degradation of nonglycosylated pro-alpha factor, a postulated nonubiquitinated yeast ERAD substrate, in mammalian cells. Our findings reveal that a cytosolic DUB exerts a negative function during retro-translocation of nonubiquitinated substrates, potentially by acting on elements of the ERAD machinery. PMID- 24068325 TI - Smyd1b is required for skeletal and cardiac muscle function in zebrafish. AB - Smyd1b is a member of the Smyd family that is specifically expressed in skeletal and cardiac muscles. Smyd1b plays a key role in thick filament assembly during myofibrillogenesis in skeletal muscles of zebrafish embryos. To better characterize Smyd1b function and its mechanism of action in myofibrillogenesis, we analyzed the effects of smyd1b knockdown on myofibrillogenesis in skeletal and cardiac muscles of zebrafish embryos. The results show that knockdown of smyd1b causes significant disruption of myofibril organization in both skeletal and cardiac muscles of zebrafish embryos. Microarray and quantitative reverse transcription-PCR analyses show that knockdown of smyd1b up-regulates heat shock protein 90 (hsp90) and unc45b gene expression. Biochemical analysis reveals that Smyd1b can be coimmunoprecipitated with heat shock protein 90 alpha-1 and Unc45b, two myosin chaperones expressed in muscle cells. Consistent with its potential function in myosin folding and assembly, knockdown of smyd1b significantly reduces myosin protein accumulation without affecting mRNA expression. This likely results from increased myosin degradation involving unc45b overexpression. Together these data support the idea that Smyd1b may work together with myosin chaperones to control myosin folding, degradation, and assembly into sarcomeres during myofibrillogenesis. PMID- 24068324 TI - alphaE-catenin actin-binding domain alters actin filament conformation and regulates binding of nucleation and disassembly factors. AB - The actin-binding protein alphaE-catenin may contribute to transitions between cell migration and cell-cell adhesion that depend on remodeling the actin cytoskeleton, but the underlying mechanisms are unknown. We show that the alphaE catenin actin-binding domain (ABD) binds cooperatively to individual actin filaments and that binding is accompanied by a conformational change in the actin protomer that affects filament structure. alphaE-catenin ABD binding limits barbed-end growth, especially in actin filament bundles. alphaE-catenin ABD inhibits actin filament branching by the Arp2/3 complex and severing by cofilin, both of which contact regions of the actin protomer that are structurally altered by alphaE-catenin ABD binding. In epithelial cells, there is little correlation between the distribution of alphaE-catenin and the Arp2/3 complex at developing cell-cell contacts. Our results indicate that alphaE-catenin binding to filamentous actin favors assembly of unbranched filament bundles that are protected from severing over more dynamic, branched filament arrays. PMID- 24068326 TI - Distinct amino acid-sensing mTOR pathways regulate skeletal myogenesis. AB - Signaling through the mammalian target of rapamycin (mTOR) in response to amino acid availability controls many cellular and developmental processes. mTOR is a master regulator of myogenic differentiation, but the pathways mediating amino acid signals in this process are not known. Here we examine the Rag GTPases and the class III phosphoinositide 3-kinase (PI3K) Vps34, two mediators of amino acid signals upstream of mTOR complex 1 (mTORC1) in cell growth regulation, for their potential involvement in myogenesis. We find that, although both Rag and Vps34 mediate amino acid activation of mTORC1 in C2C12 myoblasts, they have opposing functions in myogenic differentiation. Knockdown of RagA/B enhances, whereas overexpression of active RagB/C mutants impairs, differentiation, and this inhibitory function of Rag is mediated by mTORC1 suppression of the IRS1-PI3K-Akt pathway. On the other hand, Vps34 is required for myogenic differentiation. Amino acids activate a Vps34-phospholipase D1 (PLD1) pathway that controls the production of insulin-like growth factor II, an autocrine inducer of differentiation, through the Igf2 muscle enhancer. The product of PLD, phosphatidic acid, activates the enhancer in a rapamycin-sensitive but mTOR kinase-independent manner. Our results uncover amino acid-sensing mechanisms controlling the homeostasis of myogenesis and underline the versatility and context dependence of mTOR signaling. PMID- 24068327 TI - NFkappaB1 (p50) suppresses SOD2 expression by inhibiting FoxO3a transactivation in a miR190/PHLPP1/Akt-dependent axis. AB - The biological functions of nuclear factor kappaB1 (NFkappaB1; p50) have not been studied as often as those of other members of the NFkappaB family due to its lack of a transcriptional domain. Our recent studies showed that p50 functions as an apoptotic mediator via its inhibition of GADD45alpha protein degradation and increase in p53 protein translation. Here we report a novel function of p50 in its regulation of superoxide dismutase 2 (SOD2) transcription via an NFkappaB independent pathway. We find that deletion of p50 in mouse embryonic fibroblasts (MEFs; p50(-/-)) up-regulates SOD2 expression at both protein and mRNA levels. SOD2 promoter-driven luciferase is also up-regulated in p50(-/-) cells compared with wild-type (WT) MEF (p50(+/+)) cells, suggesting p50 regulation of SOD2 at the transcriptional level. Our results also show that p50 deficiency specifically results in down-regulation of phosphorylation and increased transactivation of FoxO3a compared with WT cells. Further studies indicate that p50-down-regulated FoxO3a phosphorylation is mediated by activated Akt via up-regulation of microRNA 190 (miR190), in turn inhibiting PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) translation. Together our studies identify a novel p50 function in the regulation of SOD2 transcription by modulating the miR190/PHLPP1/Akt-FoxO3a pathway, which provides significant insight into the physiological function of p50. PMID- 24068328 TI - LAMP2 as a marker of EBV-mediated B lymphocyte transformation in the study of lysosomal storage diseases. AB - Following the degradative pathway, vesicles loaded with extracellular material, eventually, dock and fuse with lysosomes, acquiring specific membrane markers of these organelles and acid hydrolases responsible for digest their content. The lysosomal-associated membrane protein 2 (LAMP-2), the best characterized lysosomal membrane protein, is found in late stages of endosome maturation and may be used as a marker of lysosome-associated membranes. Lysosomal storage disorders (LSDs) are described by the absence or deficiency in hydrolase activity leading to substrate accumulation within lysosomal components and to the onset of several diseases. It is known that lymphocytes infected by Epstein-Barr virus (EBV) are able to form cytoplasmic vacuoles, which work as a storage compartment for lysosomal acidic hydrolases. At the present study, we validate the EBV as a transforming agent of B lymphocytes in stability studies of long-term stored samples, since the methods used to keep samples in liquid nitrogen and thaw them have all proven to be efficient in samples frozen for up to 2 years. To confirm and investigate some of the most prevalent LSDs in the South of Brazil-Pompe, Fabry and Gaucher diseases-we first measured the enzymatic activity of alpha glicosidase, alpha-galactosidase, and beta-glicosidase in those cytoplasmic formed vacuoles and then looked to LAMP-2 immunoreactivity by employing confocal microscopy techniques. PMID- 24068329 TI - Peroxisome proliferator-activated receptor-alpha activation protects against endoplasmic reticulum stress-induced HepG2 cell apoptosis. AB - Live ischemia-reperfusion injury is associated with endoplasmic reticulum (ER) stress-induced apoptosis. Activation of peroxisome proliferator-activated receptor-alpha (PPARalpha) may inhibit hepatocyte apoptosis induced by oxidative stress and protect against liver injury. This study aimed to investigate the effects of PPARalpha activation, through a specific agonist, on ER stress-induced apoptosis in human liver hepatocellular carcinoma (HepG2) cells. HepG2 cells were challenged with H2O2 and treated with WY14643, a selective PPARalpha agonist, in the presence or absence of the PPARalpha antagonist of MK886. Cell viable assay (MTT) and immunostaining were used to evaluate cell viability. The level of apoptotic cell death was quantified through Annexin V/PI staining. Alanine aminotransferase, asparatate aminotransferase, and malondialdehyde levels were measured to determine the presence of cellular injury and oxidative stress. RT PCR and Western blot analysis were used to detect mRNA and protein expression of PPARalpha, BiP, and CHOP. Immunofluorescence was utilized to determine the intracellular localization of CHOP. H2O2 and MK886 both reduced the viability of HepG2 cells, increased oxidative stress and apoptosis, up-regulated the BiP and CHOP expression, and induced CHOP translocation from the cytoplasm to the nucleus. Compared with cells treated with H2O2 alone, pre-administration of WY14643 increased cell viability, attenuated apoptosis, improved cell function, down-regulated BiP and CHOP expression and inhibited CHOP translocation. The effects of WY14643 were completely abolished using the MK886 antagonist. PPARalpha activation protects against H2O2-induced HepG2 cell apoptosis. The underlying mechanisms may be associated with its activation to suppress excessive ER stress. PMID- 24068331 TI - Acral melanoma: a unique disease in Asia. PMID- 24068330 TI - Identifying large-scale brain networks in fragile X syndrome. AB - IMPORTANCE: Fragile X syndrome (FXS) is an X-linked neurogenetic disorder characterized by a cognitive and behavioral phenotype resembling features of autism spectrum disorder. Until now, research has focused largely on identifying regional differences in brain structure and function between individuals with FXS and various control groups. Very little is known about the large-scale brain networks that may underlie the cognitive and behavioral symptoms of FXS. OBJECTIVE: To identify large-scale, resting-state networks in FXS that differ from control individuals matched on age, IQ, and severity of behavioral and cognitive symptoms. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional, in vivo neuroimaging study conducted in an academic medical center. Participants (aged 10 23 years) included 17 males and females with FXS and 16 males and females serving as controls. MAIN OUTCOMES AND MEASURES: Univariate voxel-based morphometric analyses, fractional amplitude of low-frequency fluctuations (fALFF) analysis, and group-independent component analysis with dual regression. RESULTS: Patients with FXS showed decreased functional connectivity in the salience, precuneus, left executive control, language, and visuospatial networks compared with controls. Decreased fALFF in the bilateral insular, precuneus, and anterior cingulate cortices also was found in patients with FXS compared with control participants. Furthermore, fALFF in the left insular cortex was significantly positively correlated with IQ in patients with FXS. Decreased gray matter density, resting-state connectivity, and fALFF converged in the left insular cortex in patients with FXS. CONCLUSIONS AND RELEVANCE: Fragile X syndrome results in widespread reductions in functional connectivity across multiple cognitive and affective brain networks. Converging structural and functional abnormalities in the left insular cortex, a region also implicated in individuals diagnosed with autism spectrum disorder, suggests that insula integrity and connectivity may be compromised in FXS. This method could prove useful in establishing an imaging biomarker for FXS. PMID- 24068332 TI - Oral health and impact on performance of athletes participating in the London 2012 Olympic Games: a cross-sectional study. AB - BACKGROUND: Oral health is important both for well-being and successful elite sporting performance. Reports from Olympic Games have found significant treatment needs; however, few studies have examined oral health directly. The aim of this study was to evaluate oral health, the determinants of oral health and the effect of oral health on well-being, training and performance of athletes participating in the London 2012 Games. METHODS: Cross-sectional study at the dental clinic within the Polyclinic in the athletes' village. Following informed consent, a standardised history, clinical examination and brief questionnaire were conducted. RESULTS: 302 athletes from 25 sports were recruited with data available for 278. The majority of athletes were from Africa, the Americas and Europe. Overall, the results demonstrated high levels of poor oral health including dental caries (55% athletes), dental erosion (45% athletes) and periodontal disease (gingivitis 76% athletes, periodontitis 15% athletes). More than 40% of athletes were 'bothered' by their oral health with 28% reporting an impact on quality of life and 18% on training and performance. Nearly half of the participants had not undergone a dental examination or hygiene care in the previous year. CONCLUSIONS: The oral health of athletes attending the dental clinic of the London 2012 Games was poor with a resulting substantial negative impact on well-being, training and performance. As oral health is an important element of overall health and well-being, health promotion and disease prevention interventions are urgently required to optimise athletic performance. PMID- 24068333 TI - Bacterial communities in manures of piglets and adult pigs bred with different feeds revealed by 16S rDNA 454 pyrosequencing. AB - Pyrosequencing-based analysis was used to characterize and compare bacterial communities in manure samples of piglets (GSPM) and adult pigs (GBPM) bred with green feeds without additives, and piglets (ASPM) and adult pigs (ABPM) bred with synthetic feeds containing additives. For each sample, 5,010 effective sequences were selected and utilized to do the bacterial composition analysis, respectively. In total, 1,489, 1,327, 941, and 883 operational taxonomic units were obtained at 5 % distance cutoff in GBPM, GSPM, ABPM, and ASPM, respectively. Bacterial phylotype richness in GBPM was higher than the other samples, and ASPM had the least richness. The most dominant class in the four samples is Bacteroidia. Approximately 41 % sequences in GBPM were affiliated with the Clostridiales order. Campylobacter, Clostridium and Streptococcus genera containing pathogenic bacteria were detected in the four samples. Bacterial diversity and abundance in swine manures varied with piglets, adult pigs, and feeds. In the four samples, higher bacterial diversity but less potentially pathogenic bacterial genera in manures of adult pigs bred with green feeds were found, which indicated that those manures were more suitable for resource utilization. This study also provides evidence for the reasonableness of pig farming with green feeds. PMID- 24068334 TI - Substrates and enzyme activities related to biotransformation of resveratrol from phenylalanine by Alternaria sp. MG1. AB - To identify the substrates and enzymes related to resveratrol biosynthesis in Alternaria sp. MG1, different substrates were used to produce resveratrol, and their influence on resveratrol production was analyzed using high performance liquid chromatography (HPLC). Formation of resveratrol and related intermediates was identified using mass spectrum. During the biotransformation, activities of related enzymes, including phenylalanine ammonia-lyase (PAL), trans-cinnamate 4 hydroxylase (C4H), and 4-coumarate-CoA ligase (4CL), were analyzed and tracked. The reaction system contained 100 mL 0.2 mol/L phosphate buffer (pH 6.5), 120 g/L Alternaria sp. MG1 cells, 0.1 g/L MgSO4, and 0.2 g/L CaSO4 and different substrates according to the experimental design. The biotransformation was carried out for 21 h at 28 degrees C and 120 rpm. Resveratrol formation was identified when phenylalanine, tyrosine, cinnamic acid, and p-coumaric acid were separately used as the only substrate. Accumulation of cinnamic acid, p-coumaric acid, and resveratrol and the activities of PAL, C4H, and 4CL were identified and changed in different trends during transformation with phenylalanine as the only substrate. The addition of carbohydrates and the increase of phenylalanine concentration promoted resveratrol production and yielded the highest value (4.57 MUg/L) when 2 g/L glucose, 1 g/L cyclodextrin, and phenylalanine (4.7 mmol/L) were used simultaneously. PMID- 24068335 TI - Bacteriology of drinking water distribution systems: an integral and multidimensional review. AB - A drinking water distribution system (DWDS) is the final and essential step to supply safe and high-quality drinking water to customers. Biological processes, such as biofilm formation and detachment, microbial growth in bulk water, and the formation of loose deposits, may occur. These processes will lead to deterioration of the water quality during distribution. In extreme conditions, pathogens and opportunistic pathogens may proliferate and pose a health risk to consumers. It is, therefore, necessary to understand the bacteriology of DWDSs to develop effective strategies that can ensure the water quality at consumers' taps. The bacteriology of DWDSs, both the quantitative growth and the qualitative bacterial community, has attracted considerable research attention. However, the researchers have focused mainly on the pipe wall biofilm. In this review, DWDS bacteriology has been reviewed multidimensionally, including both the bacterial quantification and identification. For the first time, the available literature was reviewed with an emphasis on the subdivision of DWDS into four phases: bulk water, suspended solids, loose deposits, and pipe wall biofilm. Special concentration has been given to potential contribution of particulate matter: suspended particles and loose deposits. Two highlighted questions were reviewed and discussed: (1) where does most of the growth occur? And (2) what is the contribution of particle-associated bacteria to DWDS bacteriology and ecology? At the end of this review, recommendations were given based on the conclusion of this review to better understand the integral DWDS bacteriology. PMID- 24068336 TI - Transcriptional characterisation of the negative effect exerted by a deficiency in type II signal peptidase on extracellular protein secretion in Streptomyces lividans. AB - Bacterial lipoproteins are a specialised class of membrane proteins that represent a small percentage of the proteome of Gram-positive bacteria, yet these lipoproteins have been reported to play important roles in nutrient scavenging, cell envelope assembly, protein folding, environmental signalling, host cell adhesion and virulence. Upon translocation of lipoproteins, the type II signal peptidase (Lsp) cleaves the signal peptide, leaving the lipoproteins bound to the outer face of the cytoplasmic membrane by means of linking lipid molecule to their +1 cysteine residue. We have studied the role played by Lsp in Streptomyces lividans cellular metabolism, particularly, in secretory protein production, and found that the absence of functional Lsp, apparently produces a translocase blockage, diminishes the synthesis of secretory proteins and triggers a stringent response. These findings could be particularly relevant when optimising S. lividans for the overproduction of secretory proteins of industrial application. PMID- 24068337 TI - Recent advances in recombinant protein expression by Corynebacterium, Brevibacterium, and Streptomyces: from transcription and translation regulation to secretion pathway selection. AB - Gram-positive bacteria are widely used to produce recombinant proteins, amino acids, organic acids, higher alcohols, and polymers. Many proteins have been expressed in Gram-positive hosts such as Corynebacterium, Brevibacterium, and Streptomyces. The favorable and advantageous characteristics (e.g., high secretion capacity and efficient production of metabolic products) of these species have increased the biotechnological applications of bacteria. However, owing to multiplicity from genes encoding the proteins and expression hosts, the expression of recombinant proteins is limited in Gram-positive bacteria. Because there is a very recent review about protein expression in Bacillus subtilis, here we summarize recent strategies for efficient expression of recombinant proteins in the other three typical Gram-positive bacteria (Corynebacterium, Brevibacterium, and Streptomyces) and discuss future prospects. We hope that this review will contribute to the development of recombinant protein expression in Corynebacterium, Brevibacterium, and Streptomyces. PMID- 24068338 TI - Dietary considerations in migraine management: does a consistent diet improve migraine? AB - The clinical expression of migraine is significantly impacted by dietary and gastrointestinal issues. This includes gut dysfunction during and between attacks, food triggers, increase in migraine with obesity, comorbid GI and systemic inflammation influenced by diet, and specific food allergies such as dairy and gluten. Practitioners often encourage migraineurs to seek consistency in their lifestyle behaviors, and environmental exposures, as a way of avoiding sudden changes that may precipitate attacks. However, rigorous evidence linking consistency of diet with improvement in migraine is very limited and is, at best, indirect, being based mainly on the consistency of avoiding suspected food triggers. A review of current data surrounding the issue of dietary consistency is presented from the perspective of migraine as an illness (vulnerable state), as a disease (symptom expression traits), and with a view toward the role of local and systemic inflammation in its genesis. Firm recommendations await further investigation. PMID- 24068340 TI - Cortical lateralization in stroke patients measured by event-related potentials during motor imagery. AB - Stroke is a leading cause of impairment and disability worldwide, and motor imagery (MI) has been used in stroke rehabilitation. Electroencephalography (EEG) has been used to study MI. However, the characteristic features of EEG during MI in stroke patients have not been established. The purpose of this study was to investigate the difference in event-related potentials (ERPs) during MI between healthy controls and stroke patients. This study included nine stroke patients and nine healthy age-matched controls, who performed tasks involving MI, passive movement without MI and passive movement with MI. One hundred and twenty-eight channel ERPs were recorded to capture cerebral activation. Electrodes E44 and E120 (corresponding to the inferior precentral area) were selected to analyze the lateralization effects of ERPs. Lateralization was calculated as the ratio of the potential at 500 ms at electrode E120 to that at electrode E44. In the controls, the different ERPs exhibited differential direction between the 0-300 and the 300 700 ms interval. ERPs were evoked by passive movement with MI and MI alone, but not passive movement without MI. In addition, a lateralization effect in control patients as shown by the observation that the lateralization ratio in passive movement with MI and MI alone was significantly different from that in passive movement without MI (P<0.05). The amplitudes of the different ERPs were significantly smaller in stroke patients compared with those in the controls (P<0.05). The lateralization ratio in the stroke patients was opposite and significantly different from that of the controls (P<0.05). The results suggested that the MI-induced lateralization effect in ERPs may be used as a measure for evaluating the MI impairment and recovery in stroke patients. PMID- 24068339 TI - Calcitonin gene-related peptide receptor antagonists: beyond migraine pain--a possible analgesic strategy for osteoarthritis? AB - Osteoarthritis (OA) pain is poorly understood and managed, as current analgesics have only limited efficacy and unwanted side effect profiles. A broader understanding of the pathological mechanisms driving OA joint pain is vital for the development of improved analgesics. Both clinical and preclinical data suggest an association between joint levels of the sensory neuropeptide calcitonin gene-related peptide (CGRP) and pain during OA. Whether a direct causative link exists remains an important unanswered question. Given the recent development of small molecule CGRP receptor antagonists with clinical efficacy against migraine pain, the interrogation of the role of CGRP in OA pain mechanisms is extremely timely. In this article, we provide the background to the importance of CGRP in pain mechanisms and review the emerging clinical and preclinical evidence implicating a role for CGRP in OA pain. We suggest that the CGRP receptor antagonists developed for migraine pain warrant further investigation in OA. PMID- 24068341 TI - Internal hernia through the falciform ligament. PMID- 24068342 TI - Dendritic cells regulate angiogenesis associated with liver fibrogenesis. AB - During liver fibrogenesis the immune response and angiogenesis process are fine tuned resulting in activation of hepatic stellate cells that produce an excess of extracellular matrix proteins. Dendritic cells (DC) play a central role modulating the liver immunity and have recently been implicated to favour fibrosis regression; although their ability to influence the development of fibrogenesis is unknown. Therefore, we explored whether the depletion of DC during early stages of liver injury has an impact in the development of fibrogenesis. Using the CD11c.DTR transgenic mice, DC were depleted in two experimental models of fibrosis in vivo. The effect of anti-angiogenic therapy was tested during early stages of liver fibrogenesis. DC depletion accelerates the development of fibrosis and as a consequence, the angiogenesis process is boosted. We observed up-regulation of pro-angiogenic factors together with an enhanced vascular endothelial growth factor (VEGF) bioavailability, mainly evidenced by the decrease of anti-angiogenic VEGF receptor 1 (also known as sFlt 1) levels. Interestingly, fibrogenesis process enhanced the expression of Flt-1 on hepatic DC and administration of sFlt-1 was sufficient to abrogate the acceleration of fibrogenesis upon DC depletion. Thus, DC emerge as novel players during the development of liver fibrosis regulating the angiogenesis process and thereby influencing fibrogenesis. PMID- 24068345 TI - Multifaceted catalysis approach to nitrile activation: direct synthesis of halogenated allyl amides from allylic alcohols. AB - Allyl amides were synthesised from the reaction of allyl alcohols and halogenated nitriles using a platinum multifaceted catalysis approach in which both the nucleophilic addition and subsequent [3,3]-sigmatropic rearrangement steps of the process were catalysed by the same complex. Additionally, (1)H/(13)C{(1)H} NMR and GC studies provided the first insights into the mechanism of this transformation. PMID- 24068343 TI - Fine mapping of the Rrs1 resistance locus against scald in two large populations derived from Spanish barley landraces. AB - KEY MESSAGE: In two Spanish barley landraces with outstanding resistance to scald, the Rrs1 Rh4 locus was fine mapped including all known markers used in previous studies and closely linked markers were developed. Scald, caused by Rhynchosporium commune, is one of the most prevalent barley diseases worldwide. A search for new resistance sources revealed that Spanish landrace-derived lines SBCC145 and SBCC154 showed outstanding resistance to scald. They were crossed to susceptible cultivar Beatrix to create large DH-mapping populations of 522 and 416 DH lines that were scored for disease resistance in the greenhouse using two R. commune isolates. To ascertain the pattern of resistance, parents and reference barley lines with known scald resistance were phenotyped with a panel of differential R. commune isolates. Subpopulations were genotyped with the Illumina GoldenGate 1,536 SNP Assay and a large QTL in the centromeric region of chromosome 3H, known to harbour several scald resistance genes and/or alleles, was found in both populations. Five SNP markers closest to the QTL were converted into CAPS markers. These CAPS markers, together with informative SSR markers used in other scald studies, confirmed the presence of the Rrs1 locus. The panel of differential scald isolates indicated that the allele carried by both donors was Rrs1 Rh4 . The genetic distance between Rrs1 and its flanking markers was 1.2 cM (11_0010) proximally and 0.9 cM (11_0823) distally, which corresponds to a distance of just below 9 Mbp. The number and nature of scald resistance genes on chromosome 3H are discussed. The effective Rrs1 allele found and the closely linked markers developed are already useful tools for molecular breeding programs and provide a good step towards the identification of candidate genes. PMID- 24068347 TI - JEB is 90! PMID- 24068346 TI - TLR2, TLR3, and TLR4 activation specifically alters the oxidative status of intestinal epithelial cells. AB - Intestinal inflammatory diseases are the result of multiple processes, including mucosal oxidative stress and perturbed homeostasis between commensal bacteria and mucosal immunity. Toll-like receptors (TLRs) recognize molecular-associated microorganisms' patterns and trigger innate immunity responses contributing to intestinal homeostasis and inflammatory responses. However, TLRs effects on redox balance in intestinal mucosa remain unknown. Therefore, the present study analyzes the effect of TLR2, TLR3, and TLR4 on both oxidative damage of lipids and proteins, and the activity of antioxidant enzymes in enterocyte-like Caco-2 cells. The results show that the activation of these TLRs increased lipid and protein oxidation levels; however, the effect on the antioxidant enzymes activity is different depending on the TLR activated. These results suggest that the activation of TLR2, TLR3, and TLR4 might affect intestinal inflammation by not only their inherent innate immunity responses, but also their pro-oxidative effects on intestinal epithelial cells. PMID- 24068348 TI - Indefatigable: an erect coralline alga is highly resistant to fatigue. AB - Intertidal organisms are subjected to intense hydrodynamic forces as waves break on the shore. These repeated insults can cause a plant or animal's structural materials to fatigue and fail, even though no single force would be sufficient to break the organism. Indeed, the survivorship and maximum size of at least one species of seaweed is set by the accumulated effects of small forces rather than the catastrophic imposition of a single lethal force. One might suppose that fatigue would be especially potent in articulated coralline algae, in which the strain of the entire structure is concentrated in localized joints, the genicula. However, previous studies of joint morphology suggest an alternative hypothesis. Each geniculum is composed of a single tier of cells, which are attached at their ends to the calcified segments of the plant (the intergenicula) but have minimal connection to each other along their lengths. This lack of neighborly attachment potentially allows the weak interfaces between cells to act as 'crack stoppers', inhibiting the growth of fatigue cracks. We tested this possibility by repeatedly loading fronds of Calliarthron cheilosporioides, a coralline alga common on wave washed shores in California. When repeatedly loaded to 50-80% of its breaking strength, C. cheilosporioides commonly survives more than a million stress cycles, with a record of 51 million. We show how this extraordinary fatigue resistance interacts with the distribution of wave-induced water velocities to set the limits to size in this species. PMID- 24068349 TI - Nonshivering thermogenesis in the African lesser bushbaby, Galago moholi. AB - The capacity for nonshivering thermogenesis (NST) plays an important role during arousal from torpid states. Recent data on heterotherms inhabiting warmer regions, however, suggest that passive rewarming reduces the need of metabolic heat production during arousal significantly, leading to the question: to what extent do subtropical or tropical heterotherms depend on NST? The African lesser bushbaby, Galago moholi, enters torpid states as an emergency response only, but otherwise stays normothermic throughout the cold and dry winter season. In addition, this species shows unusual rewarming difficulties during arousal from torpor on cold days. We therefore examined the seasonal adjustments of the capacity for NST of naturally acclimatized G. moholi by stimulation with noradrenaline (NA) injection. Dissection of two adult female bushbabies revealed that G. moholi possesses brown adipose tissue, and NA treatment (0.5 mg kg(-1), s.c.) induced a significant elevation in oxygen consumption compared with control (saline) injection. However, the increase in oxygen consumption following injection of NA was not significantly different between winter and summer. Our results show that the ability to produce heat via NST seems to be available throughout the year and that G. moholi is able to change NST capacity within a very short time frame in response to cold spells. Together with results from studies on other (Afro-)tropical heterotherms, which also indicate low or even absent seasonal difference in NST capacity, this raises the question of whether the definition of NST needs to be refined for (Afro-)tropical mammals. PMID- 24068350 TI - GABA(B) receptors play an essential role in maintaining sleep during the second half of the night in Drosophila melanogaster. AB - GABAergic signalling is important for normal sleep in humans and flies. Here we advance the current understanding of GABAergic modulation of daily sleep patterns by focusing on the role of slow metabotropic GABAB receptors in the fruit fly Drosophila melanogaster. We asked whether GABAB-R2 receptors are regulatory elements in sleep regulation in addition to the already identified fast ionotropic Rdl GABAA receptors. By immunocytochemical and reporter-based techniques we show that the pigment dispersing factor (PDF)-positive ventrolateral clock neurons (LNv) express GABAB-R2 receptors. Downregulation of GABAB-R2 receptors in the large PDF neurons (l-LNv) by RNAi reduced sleep maintenance in the second half of the night, whereas sleep latency at the beginning of the night that was previously shown to depend on ionotropic Rdl GABAA receptors remained unaltered. Our results confirm the role of the l-LNv neurons as an important part of the sleep circuit in D. melanogaster and also identify the GABAB-R2 receptors as the thus far missing component in GABA signalling that is essential for sleep maintenance. Despite the significant effects on sleep, we did not observe any changes in circadian behaviour in flies with downregulated GABAB-R2 receptors, indicating that the regulation of sleep maintenance via l-LNv neurons is independent of their function in the circadian clock circuit. PMID- 24068351 TI - Environmental and hormonal factors controlling reversible colour change in crab spiders. AB - Habitat heterogeneity that occurs within an individual's lifetime may favour the evolution of reversible plasticity. Colour reversibility has many different functions in animals, such as thermoregulation, crypsis through background matching and social interactions. However, the mechanisms underlying reversible colour changes are yet to be thoroughly investigated. This study aims to determine the environmental and hormonal factors underlying morphological colour changes in Thomisus onustus crab spiders and the biochemical metabolites produced during these changes. We quantified the dynamics of colour changes over time: spiders were kept in yellow and white containers under natural light conditions and their colour was measured over 15 days using a spectrophotometer. We also characterised the chemical metabolites of spiders changing to a yellow colour using HPLC. Hormonal control of colour change was investigated by injecting 20 hydroxyecdysone (20E) into spiders. We found that background colouration was a major environmental factor responsible for colour change in crab spiders: individuals presented with white and yellow backgrounds changed to white and yellow colours, respectively. An ommochrome precursor, 3-OH-kynurenine, was the main pigment responsible for yellow colour. Spiders injected with 20E displayed a similar rate of change towards yellow colouration as spiders kept in yellow containers and exposed to natural sunlight. This study demonstrates novel hormonal manipulations that are capable of inducing reversible colour change. PMID- 24068353 TI - Fungal metabolic plasticity and sexual development mediate induced resistance to arthropod fungivory. AB - Prey organisms do not tolerate predator attack passively but react with a multitude of inducible defensive strategies. Although inducible defence strategies are well known in plants attacked by herbivorous insects, induced resistance of fungi against fungivorous animals is largely unknown. Resistance to fungivory is thought to be mediated by chemical properties of fungal tissue, i.e. by production of toxic secondary metabolites. However, whether fungi change their secondary metabolite composition to increase resistance against arthropod fungivory is unknown. We demonstrate that grazing by a soil arthropod, Folsomia candida, on the filamentous fungus Aspergillus nidulans induces a phenotype that repels future fungivores and retards fungivore growth. Arthropod-exposed colonies produced significantly higher amounts of toxic secondary metabolites and invested more in sexual reproduction relative to unchallenged fungi. Compared with vegetative tissue and asexual conidiospores, sexual fruiting bodies turned out to be highly resistant against fungivory in facultative sexual A. nidulans. This indicates that fungivore grazing triggers co-regulated allocation of resources to sexual reproduction and chemical defence in A. nidulans. Plastic investment in facultative sex and chemical defence may have evolved as a fungal strategy to escape from predation. PMID- 24068354 TI - Signal verification can promote reliable signalling. AB - The central question in communication theory is whether communication is reliable, and if so, which mechanisms select for reliability. The primary approach in the past has been to attribute reliability to strategic costs associated with signalling as predicted by the handicap principle. Yet, reliability can arise through other mechanisms, such as signal verification; but the theoretical understanding of such mechanisms has received relatively little attention. Here, we model whether verification can lead to reliability in repeated interactions that typically characterize mutualisms. Specifically, we model whether fruit consumers that discriminate among poor- and good-quality fruits within a population can select for reliable fruit signals. In our model, plants either signal or they do not; costs associated with signalling are fixed and independent of plant quality. We find parameter combinations where discriminating fruit consumers can select for signal reliability by abandoning unprofitable plants more quickly. This self-serving behaviour imposes costs upon plants as a by-product, rendering it unprofitable for unrewarding plants to signal. Thus, strategic costs to signalling are not a prerequisite for reliable communication. We expect verification to more generally explain signal reliability in repeated consumer-resource interactions that typify mutualisms but also in antagonistic interactions such as mimicry and aposematism. PMID- 24068355 TI - Sex-specific responses to sexual familiarity, and the role of olfaction in Drosophila. AB - Studies of mating preferences have largely neglected the potential effects of individuals encountering their previous mates ('directly sexually familiar'), or new mates that share similarities to previous mates, e.g. from the same family and/or environment ('phenotypically sexually familiar'). Here, we show that male and female Drosophila melanogaster respond to the direct and phenotypic sexual familiarity of potential mates in fundamentally different ways. We exposed a single focal male or female to two potential partners. In the first experiment, one potential partner was novel (not previously encountered) and one was directly familiar (their previous mate); in the second experiment, one potential partner was novel (unrelated, and from a different environment from the previous mate) and one was phenotypically familiar (from the same family and rearing environment as the previous mate). We found that males preferentially courted novel females over directly or phenotypically familiar females. By contrast, females displayed a weak preference for directly and phenotypically familiar males over novel males. Sex-specific responses to the familiarity of potential mates were significantly weaker or absent in Orco(1) mutants, which lack a co-receptor essential for olfaction, indicating a role for olfactory cues in mate choice over novelty. Collectively, our results show that direct and phenotypic sexual familiarity is detected through olfactory cues and play an important role in sex specific sexual behaviour. PMID- 24068356 TI - Species loss on spatial patterns and composition of zoonotic parasites. AB - Species loss can result in the subsequent loss of affiliate species. Though largely ignored to date, these coextinctions can pose threats to human health by altering the composition, quantity and distribution of zoonotic parasites. We simulated host extinctions from more than 1300 host-parasite associations for 29 North American carnivores to investigate changes in parasite composition and species richness. We also explored the geography of zoonotic parasite richness under three carnivore composition scenarios and examined corresponding levels of human exposure. We found that changes in parasite assemblages differed among parasite groups. Because viruses tend to be generalists, the proportion of parasites that are viruses increased as more carnivores went extinct. Coextinction of carnivore parasites is unlikely to be common, given that few specialist parasites exploit hosts of conservation concern. However, local extirpations of widespread carnivore hosts can reduce overall zoonotic richness and shift distributions of parasite-rich areas. How biodiversity influences disease risks remains the subject of debate. Our results make clear that hosts vary in their contribution to human health risks. As a consequence, so too does the loss (or gain) of particular hosts. Anticipating changes in host composition in future environments may help inform parasite conservation and disease mitigation efforts. PMID- 24068357 TI - A heuristic model on the role of plasticity in adaptive evolution: plasticity increases adaptation, population viability and genetic variation. AB - An ongoing new synthesis in evolutionary theory is expanding our view of the sources of heritable variation beyond point mutations of fixed phenotypic effects to include environmentally sensitive changes in gene regulation. This expansion of the paradigm is necessary given ample evidence for a heritable ability to alter gene expression in response to environmental cues. In consequence, single genotypes are often capable of adaptively expressing different phenotypes in different environments, i.e. are adaptively plastic. We present an individual based heuristic model to compare the adaptive dynamics of populations composed of plastic or non-plastic genotypes under a wide range of scenarios where we modify environmental variation, mutation rate and costs of plasticity. The model shows that adaptive plasticity contributes to the maintenance of genetic variation within populations, reduces bottlenecks when facing rapid environmental changes and confers an overall faster rate of adaptation. In fluctuating environments, plasticity is favoured by selection and maintained in the population. However, if the environment stabilizes and costs of plasticity are high, plasticity is reduced by selection, leading to genetic assimilation, which could result in species diversification. More broadly, our model shows that adaptive plasticity is a common consequence of selection under environmental heterogeneity, and hence a potentially common phenomenon in nature. Thus, taking adaptive plasticity into account substantially extends our view of adaptive evolution. PMID- 24068358 TI - Drifting behaviour as an alternative reproductive strategy for social insect workers. AB - Restricted reproduction is traditionally posited as the defining feature of eusocial insect workers. The discovery of worker reproduction in foreign colonies challenges this view and suggests that workers' potential to pursue selfish interests may be higher than previously believed. However, whether such reproductive behaviour truly relies on a reproductive decision is still unknown. Workers' reproductive decisions thus need to be investigated to assess the extent of workers' reproductive options. Here, we show in the bumblebee Bombus terrestris that drifting is a distinct strategy by which fertile workers circumvent competition in their nest and reproduce in foreign colonies. By monitoring workers' movements between colonies, we show that drifting is a remarkably dynamic behaviour, widely expressed by both fertile and infertile workers. We demonstrate that a high fertility is, however, central in determining the propensity of workers to enter foreign colonies as well as their subsequent reproduction in host colonies. Moreover, our study shows that the drifting of fertile workers reflects complex decision-making processes associated with in nest reproductive competition. This novel finding therefore adds to our modern conception of cooperation by showing the previously overlooked importance of alternative strategies which enable workers to assert their reproductive interests. PMID- 24068359 TI - Genetic composition of social groups influences male aggressive behaviour and fitness in natural genotypes of Drosophila melanogaster. AB - Indirect genetic effects (IGEs) describe how an individual's behaviour-which is influenced by his or her genotype-can affect the behaviours of interacting individuals. IGE research has focused on dyads. However, insights from social networks research, and other studies of group behaviour, suggest that dyadic interactions are affected by the behaviour of other individuals in the group. To extend IGE inferences to groups of three or more, IGEs must be considered from a group perspective. Here, I introduce the 'focal interaction' approach to study IGEs in groups. I illustrate the utility of this approach by studying aggression among natural genotypes of Drosophila melanogaster. I chose two natural genotypes as 'focal interactants': the behavioural interaction between them was the 'focal interaction'. One male from each focal interactant genotype was present in every group, and I varied the genotype of the third male-the 'treatment male'. Genetic variation in the treatment male's aggressive behaviour influenced the focal interaction, demonstrating that IGEs in groups are not a straightforward extension of IGEs measured in dyads. Further, the focal interaction influenced male mating success, illustrating the role of IGEs in behavioural evolution. These results represent the first manipulative evidence for IGEs at the group level. PMID- 24068360 TI - Evolution of recombination in eutherian mammals: insights into mechanisms that affect recombination rates and crossover interference. AB - Recombination allows faithful chromosomal segregation during meiosis and contributes to the production of new heritable allelic variants that are essential for the maintenance of genetic diversity. Therefore, an appreciation of how this variation is created and maintained is of critical importance to our understanding of biodiversity and evolutionary change. Here, we analysed the recombination features from species representing the major eutherian taxonomic groups Afrotheria, Rodentia, Primates and Carnivora to better understand the dynamics of mammalian recombination. Our results suggest a phylogenetic component in recombination rates (RRs), which appears to be directional, strongly punctuated and subject to selection. Species that diversified earlier in the evolutionary tree have lower RRs than those from more derived phylogenetic branches. Furthermore, chromosome-specific recombination maps in distantly related taxa show that crossover interference is especially weak in the species with highest RRs detected thus far, the tiger. This is the first example of a mammalian species exhibiting such low levels of crossover interference, highlighting the uniqueness of this species and its relevance for the study of the mechanisms controlling crossover formation, distribution and resolution. PMID- 24068361 TI - Evidence for a receiver bias underlying female preference for a male mating pheromone in sea lamprey. AB - Receiver bias models suggest that a male sexual signal became exaggerated to match a pre-existing sensory, perceptual or cognitive disposition of the female. Accordingly, these models predict that females of related taxa possessing the ancestral state of signalling evolved preference for the male trait in a non sexual context. We postulated that female preference for the male-released bile alcohol mating pheromone, 3 keto petromyzonol sulfate (3kPZS), of the sea lamprey (Petromyzon marinus) evolved as a result of a receiver bias. In particular, we propose that migratory silver lamprey (Ichthyomyzon unicuspis), a basal member of the Petromyzontidae, evolved a preference for 3kPZS released by stream-resident larvae as a means of identifying productive habitat for offspring. Larval silver lamprey released 3kPZS at rates sufficient to be detected by migratory lampreys. Females responded to 3kPZS by exhibiting upstream movement behaviours relevant in a migratory context, but did not exhibit proximate behaviours important to mate search and spawning. Male silver lamprey did not release 3kPZS at rates sufficient to be detected by females in natural high-volume stream environments. We infer that female silver lamprey cue onto 3kPZS excreted by stream-resident larvae as a mechanism to locate habitat conducive to offspring survival and that males do not signal with 3kPZS. We suggest that this female preference for a male signal in a non-sexual context represents a bias leading to the sexual signalling observed in sea lamprey. PMID- 24068362 TI - Sustainable, efficient livestock production with high biodiversity and good welfare for animals. AB - What is the future for livestock agriculture in the world? Consumers have concerns about sustainability but many widely used livestock production methods do not satisfy consumers' requirements for a sustainable system. However, production can be sustainable, occurring in environments that: supply the needs of the animals resulting in good welfare, allow coexistence with a wide diversity of organisms native to the area, minimize carbon footprint and provide a fair lifestyle for the people working there. Conservation need not just involve tiny islands of natural vegetation in a barren world of agriculture, as there can be great increases in biodiversity in farmed areas. Herbivores, especially ruminants that consume materials inedible by humans, are important for human food in the future. However, their diet should not be just ground-level plants. Silvopastoral systems, pastures with shrubs and trees as well as herbage, are described which are normally more productive than pasture alone. When compared with widely used livestock production systems, silvopastoral systems can provide efficient feed conversion, higher biodiversity, enhanced connectivity between habitat patches and better animal welfare, so they can replace existing systems in many parts of the world and should be further developed. PMID- 24068364 TI - In pursuit of human dignity. PMID- 24068363 TI - Generation of reactive oxygen species by leukocytes of Prochilodus lineatus. AB - Prochilodus lineatus (curimbata), from the Procholodontidae family, is a Brazilian freshwater fish, which is important commercially, nutritionally and ecologically. It is encountered in the Rio da Prata Bay in Southern South America. Studies on the immune system of this fish are scarce, but the physiological mechanisms of the species are analogous to those of other vertebrates. Thus, this work discusses the present study, which correlates P. lineatus leukocytes and the generation of reactive oxygen species after modulatory stimuli. Leukocytes were characterized by light and electron transmission microscopy and investigated by the generation of H2O2 and O2 (-), using phenol red, flow-cytometry and electron transmission histochemistry. The study determined that monocytes and neutrophils are the main cells responsible for generating O2 after stimulation with phorbol myristate acetate. Superoxide dismutase successfully inhibited the generation of reactive oxygen species in neutrophils and monocytes, but stimulated generation when in association with phorbol myristate acetate. Fish leukocyte samples from P. lineatus showed cross reactivity with antibodies directed against human NADPH-oxidase antibody subunits (p47(phox) and p67(phox)). Thus, catalase enhanced the presence of p47(phox). Neutrophil mitochondria were shown to be generators of H2O2 (charged by cerium precipitate), being enlarged and changing their format. The present study contributes to a better understanding of the respiratory burst pathways in this species and suggests mitochondria as the organelle responsible for generation of reactive oxygen species. PMID- 24068365 TI - Metal-free, polyether-mediated H2-release from ammonia borane: roles of hydrogen bonding interactions in promoting dehydrogenation. AB - Polyetheral additives were found to be efficient promoters to enhance the rate of H2-release from ammonia borane (AB) at various temperatures. In particular, tetraethylene glycol dimethyl ether (T4EGDE, 29 wt% relative to AB + T4EGDE) exhibited significantly improved activities for AB dehydrogenation, with the material-based hydrogen storage capacity of 10.3 wt% at 125 degrees C within 40 min. In situ FT-IR spectroscopy indicated the formation of B (cyclodiborazanyl)amino-borohydride (BCDB), borazine, and MU-aminodiborane as gaseous byproducts. In addition, (11)B nuclear magnetic resonance (NMR) spectroscopy further revealed that diammoniate of diborane (DADB) was initially formed to give polyaminoborane as liquid and/or solid spent-fuel, consistent with previous reports. Density Functional Theory (DFT) calculations suggested that hydrogen bonding interactions between AB and a polyetheral promoter initially played an important role in increasing the reactivity of B-H bonds of AB by transferring electron density from oxygen atoms of the promoter into B-H bonds of AB. These partially activated, hydridic B-H bonds were proposed to help promote the formation of diammoniate of diborane (DADB), which is considered as a reactive intermediate, eventually enhancing the rate of H2-release from AB. In addition, our in situ solid state (11)B magic angle spinning (MAS) NMR measurements further confirmed that the rate of DADB formation from AB with a small quantity of T4EGDE was found to be much faster than that of pristine AB even at 50 degrees C. This metal-free method for H2-release from AB with an added, small quantity of polyethers would be helpful to develop feasible hydrogen storage systems for long-term fuel cell applications. PMID- 24068366 TI - Bus therapy: a problematic practice in psychiatry. PMID- 24068367 TI - It's right there in your hand: underuse of mobile applications in dermatology. PMID- 24068368 TI - Combined oestrogen and progesterone for preventing miscarriage. AB - BACKGROUND: Historically, oestrogen and progesterone were each commonly used to save threatened pregnancies. In the 1940s it was postulated that their combined use would be synergistic and thereby led to the rationale of combined therapy for women who risked miscarriage. OBJECTIVES: To determine the efficacy and safety of combined oestrogen and progesterone therapy to prevent miscarriage. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (23 June 2013) CENTRAL (OVID) (The Cochrane Library 2013, Issue 6 of 12), MEDLINE (OVID) (1946 to June Week 2 2013), OLDMEDLINE (1946 to 1965), Embase (1974 to Week 25 2013), Embase Classic (1947 to 1973), CINAHL (1994 to 23 June 2013) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials that assessed the effectiveness of combined oestrogen and progesterone for preventing miscarriage. We included one stratified randomised trial and one quasi-randomised trials. Cluster-randomised trials were eligible for inclusion but none were identified. We excluded studies published only as abstracts.We included studies that compared oestrogen and progesterone versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed trial quality. Two review authors extracted data. Data were checked for accuracy. MAIN RESULTS: Two trials (281 pregnancies and 282 fetuses) met our inclusion criteria. However, the two trials had significant clinical and methodological heterogeneity such that a meta-analysis combining trial data was considered inappropriate.One trial (involving 161 pregnancies) was based on women with a history of diabetes. It showed no statistically significant difference between using combined oestrogen and progestogen and using placebo for all our proposed primary outcomes, namely, miscarriage (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.32 to 2.80), perinatal death (RR 0.94, 95% CI 0.53 to 1.69) and preterm birth (less than 34 weeks of gestation) (RR 0.91, 95% CI 0.80 to 1.04). In terms of this review's secondary outcomes, use of combined oestrogen and progestogen was associated with an increased risk of maternal cancer in the reproductive system (RR 6.65, 95% CI 1.56 to 28.29). However, for the outcome of cancer other than that of the reproductive system in mothers, there was no difference between groups. Similarly, there were no differences between the combined oestrogen and progestogen group versus placebo for other secondary outcomes reported: low birthweight of less than 2500 g, genital abnormalities in the offspring, abnormalities other than genital tract in the offspring, cancer in the reproductive system in the offspring, or cancer other than of the reproductive system in the offspring.The second study was based on pregnant women who had undergone in-vitro fertilisation (IVF). This study showed no difference in the rate of miscarriage between the combined oestrogen and progesterone group and the no treatment group (RR 0.66, 95% CI 0.23 to 1.85). The study did not report on this review's other primary outcomes (perinatal death or rates of preterm birth), nor on any of our proposed secondary outcomes. AUTHORS' CONCLUSIONS: There is an insufficient evidence from randomised controlled trials to assess the use of combined oestrogen and progesterone for preventing miscarriages. We strongly recommend further research in this area. PMID- 24068369 TI - Optic neuropathy in Behcet's syndrome. AB - This paper presents the clinical features, investigation results and response to treatment of four cases of primary optic neuropathy in Behcet's syndrome, with a comprehensive literature search for all other published cases. A total of 20 cases has been identified; the clinical syndrome is a unilateral or bilateral optic neuropathy of inflammatory type in which pain arises in 20 % and optic disc swelling seen in 45 % of cases. The condition was relapsing in four cases, and a progressive optic neuropathy was seen in one case. All but the progressive case responded to steroids with or without additional immunosuppression. The nadir visual acuity was the only determinant of visual outcome. 67 % of cases reported a return to normal acuity following treatment. PMID- 24068370 TI - Neuro-ophthalmology update. AB - This review summarizes the most relevant articles from the field of neuro ophthalmology published in the Journal of Neurology from January 2012 to July 2013. With the advent of video-oculography, several articles describe new applications for eye movement recordings as a diagnostic tool for a wide range of disorders. In myasthenia gravis, anti-Kv1.4 and anti-Lrp4 have been characterized as promising novel autoantibodies for the diagnosis of hitherto 'seronegative' myasthenia gravis. Several articles address new diagnostic and therapeutic approaches to neuromyelitis optica, which further sharpen its profile as a distinct entity. Additionally, 4-aminopyridine has become a standard therapeutic for patients with cerebellar downbeat nystagmus. Finally, revised diagnostic criteria have been proposed for chronic relapsing inflammatory optic neuropathy based on a careful literature review over the last decade. PMID- 24068371 TI - Glucose metabolism in nine patients with probable sporadic Creutzfeldt-Jakob disease: FDG-PET study using SPM and individual patient analysis. AB - Only one large series using statistical parametric mapping (SPM) reports on FDG PET in sporadic (Heidenhain and non-Heidenhain variant) Creutzfeldt-Jakob disease (sCJD), describing hypometabolism in bilateral parietal, frontal, and occipital cortices. Our aim was to study FDG-PET in non-Heidenhain probable sCJD patients in order to assess the most pertinent FDG-PET pattern, and to compare FDG-PET and MRI data. We used both SPM and NeuroGam((r)) software analysis, compared with healthy controls, to describe the FDG-PET abnormalities. Individual FDG-PET and MRI-DWI data were compared. SPM group analysis showed lateralized hypometabolism in the medial parietal cortex, the lateral and medial frontal (sparing Brodmann's area 4 and 6 and the anterior cingulate cortex), and lateral parietal cortex, in the absence of basal ganglia or cerebellar hypometabolism. The most severe hypometabolism was seen in Brodmann's area 31, and to a lesser degree area 23 (both areas correspond to the posterior cingulate cortex) and the precuneus. On individual analysis using NeuroGam((r)) software, additional variable temporal cortex and frequent basal ganglia (with caudate nucleus as the most frequently involved structure) hypometabolism was seen, in the absence of cerebellar hypometabolism. The cerebral lobe cortex was more frequently and more severely hypometabolic than basal ganglia structures. Concordance between FDG-PET and MRI abnormalities was most often present for both the cerebral lobe cortex and the basal ganglia. In the case of discordance, FDG-PET was more sensitive than MRI for the cortex, whereas MRI was more sensitive than FDG-PET for the basal ganglia. When pathological, both cortical lobe cortex and basal ganglia involvement were slightly more often lateralized on FDG-PET than on MRI. Despite the presence of overlapping features with other diseases presenting with rapidly progressive dementia, the FDG-PET pattern we found in our non-Heidenhain sCJD patients may help in the differential diagnosis of rapidly progressive dementia. PMID- 24068372 TI - Outcome of patients with atrial fibrillation after intravenous thrombolysis for cerebral ischaemia. AB - The question of whether i.v. rt-PA is beneficial in patients with ischaemic stroke and atrial fibrillation (AF) remains unresolved. Our objective was to evaluate the outcome of patients with AF who received i.v. rt-PA for stroke in the registries of Lille (France) and Belgrade (Serbia). End-points were poor outcome [modified Rankin Scale (mRS) 3-6], and symptomatic haemorrhagic transformation (sHT) according to ECASS3. Of 734 consecutive patients, 155 (21.2 %) had AF. The unadjusted comparison found patients with AF to be 12 years older, more likely to be women, to have hypertension, and baseline INR > 1.2, and less likely to be smokers. They had higher baseline NIHSS scores, diastolic blood pressure, and serum glucose concentrations, and lower platelet counts. They did not differ for sHT (5.8 vs. 5.5 %; p = 0.893), but they more frequently had poor outcomes (52.3 vs. 35.2 %; p < 0.001) and death (21.9 vs. 9.0 %; p < 0.001). The only independent predictor of sHT was baseline NIHSS (adjOR 1.05 per 1 point increase; 95 % CI 1.01-1.10). Independent variables associated with poor outcome were age (adjOR 1.04 for 1 year increase; 95 % CI 1.03-1.06), baseline NIHSS (adjOR 1.17 per 1 point increase; 95 % CI 1.13-1.21), and sHT (adjOR 47.6; 95 % CI 10.2-250) but not AF. In patients treated with i.v. rt-PA for cerebral ischaemia, those with AF have worse outcomes because they are older and have more severe strokes at admission. This result suggests that we should focus on prevention and research of more aggressive strategies at the acute stage. PMID- 24068373 TI - Cryptic FUS-ERG fusion identified by RNA-sequencing in childhood acute myeloid leukemia. AB - Sequential combination of cytogenetics and RNA-sequencing (RNA-Seq) has been shown to be an efficient approach to detect pathogenetically important fusion genes in neoplasms carrying only one or a few chromosomal rearrangements. We performed RNA-Seq on an acute myeloid leukemia in a 2-year-old girl with the karyotype 46,XX,add(1)(p36), der(2)t(2;3)(q21;q21),del(3)(q21),der(10)t(1;10)(q32;q24),der(16)(2qter- >2q21::16p11-->16q24::16p11-->16pter)[13]/46,XX[2] and identified a cryptic FUS/ERG fusion gene. PCR and direct sequencing verified the presence of the FUS ERG chimeric transcript in which exon 7 of FUS from 16p11 (nt 904 in sequence with accession number NM_004960 version 3) was fused in frame to exon 8 of ERG from sub-band 21q22.2 (nt 967 in NM_004449 version 4). The FUS-ERG transcript found here has been reported in only two other cases of childhood leukemia, in a 1-year-old boy and an 8-month-old boy, both diagnosed with precursor B cell ALL. The fusion transcript codes for a 497 amino acid residues FUS-ERG protein and, similar to other AML-related FUS-ERG fusion proteins, contains both functional domains (TR1 and TR2) of the transactivation domain of FUS and the ETS domain of ERG. The clinical significance, if any, of the amino acid residues which are coded by the exons 8, 9 and 10 of ERG in the fusion FUS-ERG proteins, remains unclear. PMID- 24068374 TI - Atypical carcinoid presenting as dumb-bell-shaped tumour in the normal kidney. AB - Carcinoid tumours are low-grade malignant neoplasms with neuroendocrine differentiation and occur frequently in the gastrointestinal and respiratory tracts. Primary carcinoid tumours of the kidney are rare and a majority of these tumours occur in anomalous kidney and exhibit typical renal carcinoid morphology. We reported a middle-aged man with primary atypical carcinoid tumour occurring in a normal kidney. The patient was diagnosed as having renal cell carcinoma owing to a lack of neuroendocrinal clinical features. Immunohistochemical staining of the nephrectomy specimen helped in the diagnosis of atypical renal carcinoid. PMID- 24068375 TI - Unusual presentation of two Chinese phenylketonuria sisters who were misdiagnosed for years. AB - Significant developmental delay was first noticed when both sisters were in their third year of life. However, no biochemical disorders were found through the routine biochemical tests, including liver and kidney function, lipoprotein, urine and blood cell count analysis. Progressively, both sisters exhibited odd behaviour, accompanied by personality changes and altered sleep rhythm and then were diagnosed as attention deficit hyperactivity disorder. In the eighth year, the younger sister began to take risperidone due to a presumed psychiatric disorder. Four months before attending our hospital, both sisters were diagnosed by MRI as having hereditary leukodystrophy. Nerve-nurturing treatment was tried, but without good outcome. They were then referred to our hospital for further consultation. After systematic examinations, it was confirmed that both the sisters were suffering from phenylketonuria. The symptoms were alleviated after dietary restriction of phenylalanine and symptomatic treatment. PMID- 24068376 TI - Pauses...what pauses? PMID- 24068377 TI - Large anterior urethral calculus presented as scrotal mass with urethrocutaneous fistula. PMID- 24068378 TI - Refractures of the paediatric forearm with the intramedullary nail in situ. AB - Forearm fractures in children are common. When conservative treatment fails, internal fixation with Elastic Stable Intramedullary Nailing (ESIN) become the first choice in the operative treatment of diaphyseal forearm shaft fractures. Refractures with the intramedullary nail in situ are known to occur but formal guidelines to guide management in such fractures are lacking. We present a well documented case of a radius midshaft refracture in a 12-year-old boy with the intramedullary nail in situ, managed by closed reduction. Literature is reviewed for this type of complication, the treatment of 30 similar cases is discussed and a treatment strategy is defined. The refracture of the paediatric forearm fracture with the intramedullary nail in situ is a rare, but probably under recognised complication which is observed in approximately 2.3% of the study population. Closed reduction may be considered in these cases. PMID- 24068379 TI - Small bowel carcinoid: a rare cause of bowel obstruction. AB - Carcinoid tumours though commonly affect the appendix, are a rare cause of small bowel obstruction, causing a diagnostic dilemma. We presented a 70-year-old man with small bowel obstruction, not responding to conservative management, which required an emergency laparotomy and was found to have a mass encasing the mid jejunal loops and mesentery that was resected and reported to be a carcinoid tumour. PMID- 24068380 TI - Spinal ependymoma complicated by superficial siderosis. PMID- 24068382 TI - Two interesting cases of tracheobronchial foreign bodies. PMID- 24068381 TI - Therapeutic pulmonary artery stenting for metastatic bronchial carcinoid. AB - We present a case of a middle-aged man with a 3-month history of progressive shortness of breath and peripheral oedema. Ten years prior to this, he had undergone a left pneumonectomy for metastatic bronchial carcinoid. Clinical examination revealed significant right heart failure, supported by transthoracic echocardiography. CT pulmonary angiogram revealed the cause to be marked progression of the bronchial carcinoid causing severe external compression of right pulmonary artery (RPA). In view of the distressing symptoms, a palliative endovascular intervention to the RPA was attempted to relieve obstruction, improve blood flow through the right lung and offload the right ventricle. This was performed under general anaesthesia involving interventional cardiology and radiology specialists together with a specialist anaesthetic team with extensive experience of managing carcinoid patients. The result was a marked improvement in symptoms and right heart function and the patient was discharged 2 days later. PMID- 24068383 TI - Epidermolysis bullosa and congenital pyloric atresia. AB - The association between epidermolysis bullosa (EB) and pyloric atresia (PA) is rare but well documented. Herein, we report a case of EB associated with congenital PA. A female baby, weighing 1480 g, was born vaginally to a 31-year old gravida 7 lady at 33 weeks of gestation. Polyhydramnios was detected on antenatal assessment. The parents were non-consanguineous Saudis with no family history of significant illness. At birth, well-demarcated areas of peeled skin were present over knees, left leg and periumbilical region. Systemic examination revealed no other abnormality. On second day, the patient developed recurrent vomiting and abdominal distension. An abdominal X-ray revealed a single gastric gas bubble suggesting pyloric obstruction. Following gastroduodenostomy, the baby developed severe sepsis with multiorgan dysfunction and expired on 25th day of life. Skin biopsy showed cleavage within lamina lucida. PMID- 24068384 TI - Beware of what you eat: small bowel obstruction caused by freekeh bezoars. PMID- 24068385 TI - Assessment of global disease activity in RA patients monitored in the METEOR database: the patient's versus the rheumatologist's opinion. AB - The objectives of this study were to compare the patient's (PtGDA) and physician's (PhGDA) assessment of global disease activity and to identify factors that might influence these differences as well as factors that may influence the patient's and the physician's scores separately. Anonymous data were used from 2,117 Dutch patients included in the Measurement of efficacy of Treatment in the Era of Rheumatology database. PtGDA and PhGDA were scored independently on a 100 mm visual analog scale (VAS) with 0 and 100 as extremes. The agreement, intraclass correlation coefficients (ICC), was calculated and a Bland-Altman plot was created to visualize the differences between PtGDA and PhGDA. Linear mixed model analysis was used to model PtGDA and PhGDA. Logistic repeated measurements were used to model the difference in PtGDA and PhGDA (PtGDA > PhGDA versus PtGDA <= PhGDA). Gender patient, gender physician, age, swollen joint count (SJC), tender joint count, VAS pain, disease duration, and erythrocyte sedimentation rate (ESR) were considered as possible determinants in both models. Mean (standard deviation) age was 57 (15) years and 67 % of the patients were female. Agreement between PtGDA and PhGDA was moderate (ICC, 0.57). Patients scored on average 11 units higher (worse) than rheumatologists (95 % limits of agreement, 25.2 to 47.6). Patient's perception of pain (VAS) was positively associated with a PtGDA being higher than PhGDA. Similarly, ESR and swollen joint counts were positively associated with a PtGDA being lower or equal to the PhGDA. Patients rate global disease activity consistently higher than their rheumatologists. Patients base their judgment primarily on the level of pain, physicians on the level of SJC and ESR. PMID- 24068386 TI - SMAD2 disruption in mouse pancreatic beta cells leads to islet hyperplasia and impaired insulin secretion due to the attenuation of ATP-sensitive K+ channel activity. AB - AIMS/HYPOTHESIS: The TGF-beta superfamily of ligands provides important signals for the development of pancreas islets. However, it is not yet known whether the TGF-beta family signalling pathway is required for essential islet functions in the adult pancreas. METHODS: To identify distinct roles for the downstream components of the canonical TGF-beta signalling pathway, a Cre-loxP system was used to disrupt SMAD2, an intracellular transducer of TGF-beta signals, in pancreatic beta cells (i.e. Smad2beta knockout [KO] mice). The activity of ATP sensitive K(+) channels (KATP channels) was recorded in mutant beta cells using patch-clamp techniques. RESULTS: The Smad2betaKO mice exhibited defective insulin secretion in response to glucose and overt diabetes. Interestingly, disruption of SMAD2 in beta cells was associated with a striking islet hyperplasia and increased pancreatic insulin content, together with defective glucose-responsive insulin secretion. The activity of KATP channels was decreased in mutant beta cells. CONCLUSIONS/INTERPRETATION: These results suggest that in the adult pancreas, TGF-beta signalling through SMAD2 is crucial for not only the determination of beta cell mass but also the maintenance of defining features of mature pancreatic beta cells, and that this involves modulation of KATP channel activity. PMID- 24068387 TI - Functional analysis of limb enhancers in the developing fin. AB - Despite diverging ~365 million years ago, tetrapod limbs and pectoral fins express similar genes that could be regulated by shared regulatory elements. In this study, we set out to analyze the ability of enhancers to maintain tissue specificity in these two divergent structures. We tested 22 human sequences that were previously reported as mouse limb enhancers for their enhancer activity in zebrafish (Danio rerio). Using a zebrafish enhancer assay, we found that 10/22 (45 %) were positive for pectoral fin activity. Analysis of the various criteria that correlated with positive fin activity found that both spatial limb activity and evolutionary conservation are not good predictors of fin enhancer activity. These results suggest that zebrafish enhancer assays may be limited in detecting human limb enhancers, and this limitation does not improve by the use of limb spatial expression or evolutionary conservation. PMID- 24068388 TI - Characterization of y-type high-molecular-weight glutenins in tetraploid species of Leymus. AB - Three y-type high-molecular-weight (HMW) glutenin gene open reading frames (ORFs), Chiy1, Chiy2, and Racy, were isolated and characterized from Leymus chinensis PI499516 and Leymus racemosus ssp. racemosus W623305. They shared an extra glutamine in the N-terminal and LAAQLPAMCRL peptides in the C-terminal with x-type HMW glutenins but had different N-terminal lengths. Like other y-type HMW glutenins, Chiy2 and Racy had 104 (or 105) amino acid (aa) residues at the N terminal and started with EGEASR, whereas Chiy1 had 99 aa in this domain and started with QLQCER because of the deletion of EGEASR. Five other y-type glutenins, including those from Elymus ciliaris, Pseudoroegneria libanotica, and Leymus mollis, were similar to Chiy1. The ORF of Chiy2 was probably not expressed. The ORFs of both Chiy1 and Racy were expressed in bacteria. The maximum likelihood phylogenic tree based on the signal peptide and N-terminal and C-terminal aa residues revealed two clades of y-type HMW glutenins in Triticeae; the first contained Ay, By, Cy, Dy, Eey, Gy, Ky, Ry, Tay, and Uy, while the second clade contained the remaining y types, including those from Leymus. Within the second clade, HMW glutenins lacking the EGEASR peptide formed a subclade. These y-type HMW glutenins in Leymus could not be targeted to the Xm or Ns genome. PMID- 24068390 TI - Molybdenum and tungsten oxygen transferases--and functional diversity within a common active site motif. AB - Molybdenum and tungsten are the only second and third-row transition elements with a known function in living organisms. The molybdenum and tungsten enzymes show common structural features, with the metal being bound by a pyranopterin dithiolene cofactor called molybdopterin. They catalyze a variety of oxygen transferase reactions coupled with two-electron redox chemistry in which the metal cycles between the +6 and +4 oxidation states usually with water, either product or substrate, providing the oxygen. The functional roles filled by the molybdenum and tungsten enzymes are diverse; for example, they play essential roles in microbial respiration, in the uptake of nitrogen in green plants, and in human health. Together, the enzymes form a superfamily which is among the most prevalent known, being found in all kingdoms of life. This review discusses what is known of the active site structures and the mechanisms, together with some recent insights into the evolution of these important enzyme systems. PMID- 24068389 TI - Incentivizing HIV/STI testing: a systematic review of the literature. AB - Suboptimal HIV/STI testing uptake has a profound impact on morbidity and mortality. Incentives have been effective in other areas of medicine and may improve HIV/STI testing uptake rates. This study reviewed the effects of incentives on HIV/STI testing uptake. A systematic search of seven databases was undertaken. Testing uptake was defined as test implementation and/or test result retrieval. Incentives were defined as monetary or non-monetary rewards or free-of charge testing vouchers. Seven studies were included. All seven studies demonstrated higher rates of uptake in an incentivized group. Incentives offered at a non-clinical setting demonstrated more significant differences in uptake rates compared to incentives offered at a clinical setting. Incentivizing HIV/STI testing uptake, especially testing at a non-clinical setting, may be a useful tool to modify health behavior. Further research is needed to understand how incentives could be an effective component within a comprehensive HIV/STI control strategy. PMID- 24068391 TI - Significant but weak spousal concordance of metabolic syndrome components in Japanese couples. AB - OBJECTIVE: This study was initiated to investigate if spousal concordance in metabolic syndrome (MS) components exist in Japan. METHODS: In all, 756 couples (mean age: 48.9 and 47.3 years for husbands and wives, respectively) were identified. Each subject was classified as an MS, MS reserves (MSRES) or no risk of MS (NonMS) case after Japanese Ministry of Health, Labour and Welfare (JMHLW) criteria. Criteria of the National Cholesterol Education Program and of the Joint Interim Statement were also applied. RESULTS: With Japanese Ministry of Health, Labor and Welfare (JMHLW) criteria, MS, MSRES and NonMS cases accounted for 11.9, 14.7 and 73.4 % in husbands and 1.6, 3.7 and 94.7 % in wives. Waist circumference (WC), body mass index (BMI), systolic blood pressure (SBP) and hemoglobin A1c (HbA1c) showed significant correlation (p < 0.01). Correlation was also significant (p < 0.05) for mean blood pressure (MBP) and fasting plasma glucose (FPG). When adjusted for age, correlations were significant only for WC, BMI and HbA1c. Furthermore, none of the correlation coefficients were greater than 0.2. Logistic regression analyses did not suggest significant mutual influence in MS status between the couples. CONCLUSIONS: Spousal concordance in MS components was detected for WC, BMI, SBP, MBP, FPG and HbA1c, but the correlation was generally weak and modest in Japanese couples. PMID- 24068392 TI - Microglia: first responders in the central nervous system. AB - Microglia has emerged not only as an essential inflammatory cell but also as a major player in the development of the adult brain. Microglia phagocytize extra numerical synapses during postnatal development, maintain and strengthen the remaining subset of synapses, remodel synaptic circuits and clearing apoptotic newborn neurons. Thereby, microglia plays a crucial role for the establishment, plasticity and function of adult neural circuits. In addition to the key role in normal brain function, any imbalance in microglia activity has been associated with neurodegenerative diseases. Microglial cells respond rapidly to smallest pathological changes, this being a vital aspect in many tissue scaring and the local confinement of focal lesions. It is assumed that the high motility of microglial cells represents an important requirement to fulfill the numerous functions. In this review will highlight the role of microglial motility in the healthy and the injured brain, and discuss how impairment of microglia motility can affect normal brain function. PMID- 24068393 TI - Dental pulp as a stem cell reservoir. AB - Currently, much information is provided regarding the presence and the roles in tissue regeneration of stem cell niches residing in post-natal dental pulp. So far, three types of adult stem cells have been isolated from dental pulp. Correct evaluation of these cells is important in order to determine their potential use in clinical fields. The present study aims to review the origins and immunophenotype of these cells. The particularities of interstitial cells of the stem cell niches are also debated. PMID- 24068394 TI - High variability in MMP2/TIMP2 and MMP9/TIMP1 expression in secondary liver tumors. AB - The assessment of MMPs/TIMPs expression in various primary tumors has potential prognostic values. Considering the paucity of studies in secondary liver tumors, our aim was to study the expression of MMP2, MMP9, TIMP1, and TIMP2 in secondary hepatic cancer, focusing on their variability in the malignant cells. The study group included 25 cases of liver metastases of colorectal cancer, diagnosed and surgically treated at "Sf. Spiridon" University Hospital of Iassy, Romania. Immunohistochemistry for MMP2, MMP9, TIMP1, and TIMP2 has been performed, followed by the semi-quantitative assessment of the markers using a scoring system based on the positive tumoral cells percentage and the staining intensity. The expression of investigated markers revealed an increased staining variability. The scores showed that MMP2/TIMP2 and MMP9/TIMP1 immunoreactivity was extremely heterogeneous within the analyzed group, with a dominant weak expression for MMP2 and MMP9, in contrast to strong TIMP2 and TIMP1 expression. Ten different patterns of expression of the investigated markers have been identified. No major differences between the expression of MMP2 (14 positive cases) and MMP9 (16 positive cases) could be detected. Our results sustain the inverse correlation between MMP and the correspondent TIMP expression, supporting the hypothesis that MMPs/TIMPs balance has mainly an inhibitory effect on invasiveness. Our study demonstrated that tumoral cells are adapted to MMPs:TIMPs production in the liver microenvironment. The lack of significant differences between MMP2 and MMP9 expression shows that the activity of both MMPs is independent, without reciprocal influences. PMID- 24068395 TI - Study of the diagnosis and treatment of cancer located in the head and neck and correlation with expression of prognostic markers. AB - A prospective study made by authors was initiated in 2000 in order to analyze differences in terms of response rate, overall survival and progression free survival for patients with advanced head and neck carcinoma treated with radiotherapy vs. radiochemotherapy, respectively and to analyze the role of modern molecular biomarkers in the prognosis of these patients (p53, EGFR and Ki67). It was detected one significant difference appeared between the two groups for response rate (p<0.0001) and median overall survival [18.8 months in Group A and 17.2 months in Group B, with a hazard ratio for survival of 0.88 (95% CI, 0.75-1.12, p<0.0001]. Progression free survival was not significant different between these two groups [6.9 months for Group A and 7.2 months for Group B, p=0.3179]. Multivariate analysis by sex, age, TNM stage, site of disease, revealed TNM stage and site of disease as clinical phenotypes with predictive value. Also, the molecular biomarkers p53, EGFR and Ki67 have a prognostic significance in head and neck cancer in addition to the established clinical prognostic factors such as the stage, site of the tumor and the type of treatment. Because of material reasons, we decided to carry out the immunohistochemical marking in the group of patients who were radiochemotherapy treated and the results of multivariate analysis reached statistical significance threshold in terms of response rate to treatment, overall survival and disease free interval. Furthermore, immunohistochemical examination was not performed for patients with rhinopharyngeal carcinoma with marked radiochemosensibility and reduced tumor aggressiveness reflected in significantly better therapeutic outcomes by treatment response rate, overall survival and disease free interval. In the present study of the 93 cases that underwent immunohistochemical staining for EGFR, the majority (66 cases) showed a positive reaction for this marker, in 36 cases are highly immunohistochemical staining, and in 30 cases were weakly positive. In addition, cell proliferation was intense in 26 cases in which Ki67 index was greater than 45%, p53 protein expression was positive in 18 cases, but the majority (22) of cases showed a positive reaction for this marker; index was greater than 55%, and in the most (22) cases p53 protein was not expressed. Radio/chemoradiotherapy regimen associated with molecular anti-EGFR target therapy is standard therapy in advanced squamous head and neck carcinoma. PMID- 24068396 TI - Immunohistochemical expression of RBP2 and LSD1 in papillary thyroid carcinoma. AB - PURPOSE: To investigate the prognostic significance of LSD1 and RBP2 expression in patients with papillary thyroid carcinoma. MATERIALS AND METHODS: LSD1 and RBP2 expressions were detected by immunohistochemistry in surgically resected samples from thyroid adenoma, papillary thyroid carcinoma and paracancerous tissues. RESULTS: To be members of histone demethylases, LSD1 and RBP2 were both localized mainly to the thyroid cell nucleus. Despite the fact that both RBP2 and LSD1 expressions were higher in papillary thyroid carcinoma than in paracancerous tissues (U=-3.855, p=0.000; U=-5.575, p=0.000) and thyroid adenoma (U=-1.972, p=0.049; U=-3.190, p=0.001), they did not show us statistical correlation (r= 0.149, p=0.270). Like LSD1 (U=-2.286, p=0.022), RBP2 expression was less frequently in paracancerous tissues than in thyroid adenoma (U=-1.985, p=0.047). Neither LSD1 nor RBP2 expression was significantly associated with age, gender, stage status, tumor size, and lymph node metastases (p>0.05). CONCLUSIONS: Both LSD1 and RBP2 are well related with the occurrence and malignant transformation of papillary thyroid carcinoma. Though the positive expression of both LSD1 and RBP2 can be used to estimate the potentiality of thyroid carcinoma and help for the adjuvant treatment, LSD1 is a more sensitive molecular marker than RBP2 on thyroid cancer diagnosis. PMID- 24068397 TI - Comparative study of placenta acute fetal distress and diabetes associated with pregnancy. AB - The authors analyze the main histopathological changes of placentas from pregnancies ended with fetal distress at birth and the tasks associated with diabetes. The parallel between the two types of placentas not trying to prove the existence of pathognomonic lesions. Are set out both the similarities between the two titles of placentas lesions (such as changes in microcirculation and so on) as well as particular aspects. The authors analyze a group of 19 pregnant women hospitalized in Obstetrics and Gynecology Clinics of Emergency County Hospital of Craiova, Romania, in September 2010-September 2011, who were born and who were diagnosed with diabetes. In the same period, were studied 21 pregnant women whose pregnancy ended with the birth of a child with fetal distress. Such were identified as placental lesions suggestive of fetal distress as diverse etiology of placental vascular changes and the placenta in pregnancy associated diabetes as immaturity and vascular edema and fibrinoid changes and glycogen stores. The authors have proposed to highlight some lesions suggestive of two groups of diseases but independent groups were analyzed and conclusions were drawn after discussing results. This study is justified by insufficient knowledge of the causes that lead to fetal distress regardless of its etiology. In conclusion, the authors mention both placenta's common changes as specifically changes of the placenta for each type of disorder. PMID- 24068398 TI - Morphological expression of the anterior spinal artery and the intracranial segment of the vertebral artery: a direct anatomic study. AB - Given its importance for clinical diagnosis and management, the purpose of this study was to determine the morphological expression of the intracranial segment of both vertebral and spinal arteries. Ninety-five fresh cadaveric specimens autopsied at the Instituto de Medicina Legal of Bucaramanga (Colombia) were perfused with polyester resins at the vertebrobasilar vascular bed, by canalizing the proximal segment of the internal carotids and vertebral arteries. The intracranial segment of the vertebral arteries (VA) had a length of 33.2+/-5.2 mm and a caliber of 3.03+/-0.81 mm. The left vertebral artery had a caliber of 3.12+/-0.85 mm, this being greater than the caliber of the right artery in 59.6% of the cases. The VA junction was seen at the level of the ponto-medullary sulcus in 44.2%, above this level in 30.5%, and below it in 25.3%. The distance from the origin of the anterior spinal branches (ASBs) to the VA junction was 7.34+/-2.71 mm, with a greater distance corresponding to the right ASBs, a difference that did not reach statistical significance (p=0.32). The anterior spinal arteries (ASA) had a bilateral origin in 65.3% of the cases, with the caliber being balanced in 37 (39%) and dominant at the right side in 15.8%. A right unilateral origin of the ASA was observed in 13.7% and a left unilateral origin in 9.5% of the specimens. There is disagreement in the literature as to the level of the junction of the two vertebral arteries. The unilateral origin of the spinal arteries is more frequent than most prior studies have indicated. PMID- 24068399 TI - CD105 microvessels density, VEGF, EGFR-1 and c-erbB-2 and their prognostic correlation in different subtypes of cervical adenocarcinoma. AB - In this study, we have investigated the immunohistochemical expression of endoglin (CD105), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR-1) and epidermal growth factor receptor 2 (c-erbB-2) and their prognostic correlation in 13 cases of cervical adenocarcinomas with mucinous, endometrioid and serous type differentiation. Our study revealed that for uterine cervix adenocarcinoma the most intense angiogenic activity occurs at the invasion front of these tumors. In addition, we noticed a trend towards increased CD105 MVD values in those cases in which were recorded the highest VEGF and c-erbB-2 reactivity. Thus, we concluded that in cervical adenocarcinomas occurs an intense process of angiogenesis, mainly at the invasion front, controlled by interrelations between VEGF and EGFR family members, especially the c-erbB-2 receptor. Further studies are needed to elucidate whether specific angiogenic molecular profiles exist in different histopathological subtypes of uterine adenocarcinomas and which is their impact on prognosis and therapeutic outcomes for these patients. PMID- 24068400 TI - Childhood rhabdomyosarcoma. Anatomo-clinical and therapeutic study on 25 cases. Surgical implications. AB - Rhabdomyosarcomas (RMS) are the most frequent soft tissue sarcomas of childhood. Despite advances in knowledge about biological pathways of tumorigenesis, risk stratification and multimodal treatment, the immediate and long-term prognosis of these lesions in many countries with limited resources is still poor. PATIENTS AND METHODS: Twenty-five histologically confirmed pediatric RMS were recorded during the period of study. Demography, clinical presentation, diagnostic means, pretreatment staging and post-surgical grouping, histological type, therapy and outcome were evaluated. RESULTS: The mean age was 6.7 years; the group included 12 boys and 13 girls. Twelve lesions were localized in the genitourinary tract, eight in the trunk and extremities, two cases each in head and neck and retroperitoneum and one case in biliary tract. Primary surgical attempt was performed in 15 patients but only in nine of them underwent complete resection (three with free margins) other six cases achieving removal with residual disease. In 10 cases, solely biopsy was possible. Twenty-four patients received chemotherapy but only four cases performed radiation therapy. Overall survival rate was only 36% (nine cases). CONCLUSIONS: As mean feature children from our series had late presentation with locally extended (bulky and node positive) lesions and unfavorable sites. Improved multimodal management of RMS in recent years will probably lead to better survival curves in an increasing number of cases and an outstanding outcome in children with locally advanced disease. PMID- 24068401 TI - Oral treatment of metabolic acidosis in hemodialyzed patients and the implications on the hemodynamic status. AB - Metabolic acidosis slowly develops during renal impairment natural evolution towards ESRD and represents an important contributing factor of CKD progression. Although, several clinical and experimental trials reported the major impact of metabolic acidosis on CKD evolution, the pathophysiology mechanism remains a matter of debate. Furthermore, international guidelines do not impose a specific treatment scheme for metabolic acidosis in CKD patients, and metabolic acidosis is not fully compensated once hemodialysis starts. Therefore, the aim of our study was to determine an adequate follow-up of metabolic acidosis therapy benefits and risks in HD patients. PATIENTS AND METHODS: 164 HD patients were evaluated according to the following protocol: bioumoral laboratory tests, the measure of different important parameters (residual diuresis, UF, BP, LVMI, volemia status). The assessed data were statistic analyzed using non-paired Student's t-test for continuous variables and chi-square (chi2) test for qualitative parameters (p-value <0.05 was considered statistically significant). RESULTS: HD individuals were followed-up depending on their predialysis-alkaline reserve value. After therapy started, predialysis-alkaline reserve mean level increased from 19.4 mEq/L to 22.6 mEq/L (p<0.001). Furthermore, we observed a significant decrease of nitrogenous waste products values (T=10.87<1.66) and intradialytic hypotension events (p<0.001). CONCLUSIONS: Our findings emphasize the beneficial effects of correcting metabolic acidosis using the proposed treatment scheme with direct impact on hemodynamic status improvement. PMID- 24068402 TI - Immunohistochemical expression of EGF, c-erbB-2 and EGFR in intestinal variant of gastric adenocarcinomas. AB - In this study, we aimed to determine EGF, c-erbB-2 and EGFR expression in 25 specimens of intestinal gastric adenocarcinomas by standardized immunohistochemistry and to establish correlations with the major clinico morphological parameters of these patients. We observed EGF reactivity in 22 (88%) cases, a c-erbB-2 protein expression in eight (32%) cases and an EGFR reactivity in 13 (46.42%) cases. The EGF expression was significantly correlated with the tumor degree of differentiation, but not with other investigated clinico morphological parameters and nor with c-erbB-2 and EGFR1 expression. However, we noticed the existence of a dependence between c-erbB-2 and EGFR1 expression in the main tumor mass. Such immunoprofile suggests the possible intervention of autocrine and paracrine loops in the developing of intestinal variant of gastric adenocarcinomas. PMID- 24068403 TI - Histological diagnosis and risk of renal vein thrombosis, and other thrombotic complications in primitive nephrotic syndrome. AB - BACKGROUND: The risk of thromboembolic events is increased in patients with nephrotic syndrome (NS) as compared with other medical conditions and is a severe complication associated with significant morbidity and mortality. We aimed to assess the risk of renal vein thrombosis, and other venous thromboembolic events (VTE) in a large cohort of patients with NS and to identify the disease-specific risk for VTE. PATIENTS AND METHODS: We performed a prospective observational study including consecutive adult patients with primitive NS admitted to our department. Clinical and biological data were obtained every six months during follow-up. Occurrence of VTE confirmed by imaging techniques was the primary study outcome. RESULTS: We enrolled 191 patients (47+/-15 years, 53% men) with a median follow-up of 24 [IQR:12,36] months. During follow-up, 23 VTE occurred, of which 65.2% in the first six months. The disease-specific risk of VTE during the follow-up period was different across the histological groups, with the lowest risk in minimal change disease and IgA nephropathy and the highest in membranous nephropathy and membranoproliferative glomerulonephritis patients. In the subgroup of membranous, the severity of the subepithelial electron dense deposits did not correlate with the risk for VTE (p=0.5). CONCLUSIONS: In this prospective study, the risk of VTE was higher in the first six months of follow-up in NS patients. The histological pattern seems to influence the risk of VTE in this setting. PMID- 24068404 TI - Microanatomic aspects of arterial blood supply in rectal carcinomas--predictive models. AB - Rectum is divided into three distinctive regions (pelvic peritoneal, pelvic subperitoneal and perineal) regarding the regions where it is crossing through. Those three parts are individually not only due to their relation but due to their blood supply, also. The differences occur among them when one of them is involved into a neoplastic process. Both types of pelvic rectal tumors behave quite in the same way but those involving perineal rectum are much different. This is because they purchase a smaller number of anastomosis; when a tumor monopolizes a wide vessel the possibility to grow and become a metastasis is much more likely. These two processes (growth and metastasis) are directly related to the size of its supplying artery. On the other hand, a pelvic rectal tumor is more likely to metastasis by blood flow then a perineal rectal one. The last one will rather send clone cells by lymphatic drainage or will disseminate into the soft tissues around it. In this study, we want to propose an anatomical mathematical model for each of the rectal tumors, depending on their stages also. We used specimens from 24 patients and analyzed them using arteriography; we connected the results of mathematical counting of micro vessels density in a specific area with already known medical aspects regarding their diagnosis, treatment and evolution. The goal of the study concerns the prognosis of the patients (with or without surgical treatment) and the example is useful in rectal tumors staging. PMID- 24068405 TI - K-ras gene mutation status in colorectal cancer: comparative analysis of pyrosequencing and PCR-RFLP. AB - BACKGROUND: In patients with high-stage colorectal carcinomas (CRC), anti-EGFR therapy is known to be effective only in cases with a wild-type K-ras gene status. Different procedures have been proposed for such evaluation. MATERIALS AND METHODS: The mutation status of K-ras gene, codons 12, 13 and 61 was determined in 250 CRC cases using the pyrosequencing assay. In addition, we compared the performance of the pyrosequencing procedure with that of PCR-RFLP in a subset (n=100) of the CRC samples the latter only in codons 12 and 13. RESULTS: Using pyrosequencing, 46.4% of the 250 CRC cases were found mutated. Most mutations were located in codon 12 (36.4% from all cases) and several were located in codon 61 (3.2%). All mutation identified by PCR-RFLP were confirmed by pyrosequencing and, in addition, one more mutated sample was identified in the subset of 100 samples. CONCLUSIONS: Both methods are highly specific and can profitably be used in the molecular diagnosis of colorectal cancer in order to establish the adequate therapy. PMID- 24068406 TI - Hairy cell leukemia--a rare type of leukemia. A retrospective study on 39 patients. AB - Hairy cell leukemia (HCL) is a chronic B-cell lymphoid leukemia characterized by pancytopenia, splenomegaly, myelofibrosis and the presence in peripheral blood, bone marrow and spleen of atypical lymphoid cells with a hairy aspect. This is a retrospective analysis of 39 patients hospitalized in the Clinic of Hematology, "Filantropia" Municipal Hospital, Craiova, Romania, between 1997-2012, devised by age, sex, and HCL type. Characteristic features of diagnosis (including clinical features, laboratory data: complete blood cell count, differential count, peripheral blood and bone marrow infiltration with atypical lymphoid cells with cytoplasm fine prolongations, immunophenotyping of peripheral blood, bone marrow, spleen or lymph node biopsies with histopathological exams and immunohistochemistry), types of therapy (focused on IFN-alpha), complications (infections, hemorrhage, autoimmune, second malignancies) and survival rate were monitored. Conclusions of the study revealed the importance of histopathology and immunohistochemistry for diagnosis, of the therapeutic options in the absence of purine nucleoside analogues, the most frequent complications and the decrease of their incidence correlated with therapy and increased count of neutrophils. PMID- 24068407 TI - Anatomical description of the deep venous channel from the anterior vestibular wall of the right atrium. AB - The deep venous channels in the walls of the right atrium are not routinely described in medical treatises although their existence has been remarked from some time. Our study demonstrates that the right atrium is opened for some of the anterior veins of the heart through a venous channel located deep in the myocardium of the vestibule of the right atrium. We suggest that no Thebesian veins drain into this channel. We achieved anatomical dissection in 14 adult human cadaveric hearts, which had been fixed in formalin solution, and we found the channel in 75% of cases. These channels were measured, photographed and presented in detail. We highlighted the importance of the proximity with the tricuspid annulus in order to avoid incidents during tricuspid annuloplasty. The authors intend that through a qualitative study to draw attention to such a structure often ignored. This vascular structure and its role in cardiac physiology and pathology have not been investigated yet. Although not constant, specialists in cardiology and cardiac surgery should be informed about this basic detail on the endocardium morphology. PMID- 24068408 TI - Masticatory tensile developed in upper anterior teeth with chronic apical periodontitis. A finite-element analysis study. AB - Commonly is accepted that a non-vital tooth has a higher risk of root fracture but there is a relatively little knowledge about the specific biomechanical behavior of non-vital frontal teeth with chronic apical periodontitis. The aim of our study was to evaluate the deformation and tensile generated in these teeth while vertically loading them because it is crucial to assess the moment when the absorbed occlusal forces exceed the elasticity of root dentine. Using the method of finite-element analysis, we highlighted the distribution patterns of the compressive and tension tensile, as well as their concentration areas. The vertical forces of 100 N generate deformations of no clinical risk in teeth with chronic apical periodontitis. The tensile developed in these teeth are higher than those in the vital teeth are but do not exceed the value of the elastic modulus of the radicular dentin. By increasing the force to 300 N occur elastic deformations, which cannot be neglected anymore. Even so, the 300 N forces do not generate deformations of the alveolar bone. The highest tensile at loading with 300 N was generated in vertical direction but in the cervical area of the tooth also developed tensile in lingual and mesiodistal direction that must be taken into consideration because they are near the risk limit of the elasticity modulus. The crack lines or fractures can appear both in case of excessive or even usual but accumulative occlusal forces that gradually alter the mechanical resistance of the tooth. PMID- 24068409 TI - A complex assessment of patients with knee osteoarthritis and Baker's cyst: observational study. AB - In our observational study, we performed the clinical and functional examination, analyzed imagistic and histological findings and evaluated the correlation between previous aspects in patients with primary knee osteoarthritis (PKOA) and Baker's cyst (BC). The correlations were made to better understanding of BC in patients with PKOA and optimal choosing for treatment. Seventy patients with painful PKOA (ACR criteria) and BC were assessed. We evaluated knee pain using a 100 mm VAS and functional status using the pain, stiffness and functional subscales of WOMAC index. All patients were imagistic examined (ultrasonography and MRI). Thirty-eight patients with PKOA and simple BC respond to conservative treatments. Thirty-two patients with PKOA and complex BC need surgical removal (arthroscopic decompression +/- open excision in larger cysts). For these patients, it is performed histological assessment. Any medical team that manages a PKOA patient with BC may develop the treatment plan based upon not only the size of BC, symptoms and other associated conditions but also on the WOMAC scoring and complex anatomic and histological data about BC. PMID- 24068410 TI - Histopathological examination in evaluation of long-term results after osteocartilaginous transplantation. AB - OBJECTIVE: To assess long-term outcomes of osteocartilaginous transplantation for non-degenerative lesions of hyaline articular cartilage in the knee, by performing minibiopsies from the transplanted area and examining them histopathologically. PATIENTS AND METHODS: Forty-four patients with post traumatic cartilage injuries of the bearing surfaces of the knee were enrolled in a prospective study, that included treatment with autologous osteocartilaginous grafts at the level of the lesion, "second look" arthroscopy and targeted minibiopsies at one year and five years postoperatively (six minibiopsies per patient). The collected tissue fragments were examined by optic microscopy. In order to integrate the histopathological findings in the clinical context, the function of the knee was also quantified by calculation of the International Cartilage Repair Society Score preoperatively, at one year and at five years postoperatively. RESULTS: Five years post-transplant the outcomes for 36 patients were available. One year post-transplant, the histopathological examination revealed the presence of hyaline cartilage in 165 of the 216 (76.39%) tissue samples collected and fibrocartilage in 51 (23.61%) respectively. Five years after surgery, the proportions of these findings were 159/216 (73.61%) for hyaline cartilage and 57/216 (26.39%) for fibrocartilage. The difference was not statistically significant (p>0.1).The evolution of the ICRS clinical score was from 38.57+/-3.42 preoperatively to 80.31+/-3.85 (p<0.0001) after one year and to 81.35+/-4.57, respectively at five years after surgery. CONCLUSIONS: Autologous osteocartilaginous transplantation brings hyaline articular cartilage at the level of the injured area. Approximately three quarters of the surface lesion remains covered by high quality hyaline cartilage that maintains its macroscopic structure and architecture for a long period of time. PMID- 24068411 TI - Anatomo-clinical aspects of the basal cell carcinoma at the level of the cephalic end. AB - More than one third of all diagnosed cancer cases from all over the world are skin cancers, and the majorities are basal cell carcinomas. The incidence of skin tumors around the world is growing, the main concern being the increased frequency of skin tumors among young persons. Therefore, an early detection is required, starting with the general practitioner, dermatologist, oncologist, plastic surgeon and not least, the pathologist. We studied a sample consisting of 149 patients diagnosed with basal cell carcinoma at the level of the cephalic end and neck, all of them undergoing surgery--surgery individualized for each case. Some cellular and molecular modifications also resulted from infecting the cells with high carcinogenic risk HPV, considered by some scientists as responsible for the developing and progression of some neoplasias, including melanocytes and non melanocytes skin tumors. PMID- 24068412 TI - Morphometric analysis of bone vascular channels during the biointegration of autologous bone grafts. AB - Vascularization of the transplanted bone tissue is a key factor for success and precedes the formation of bone tissue. Vascularized bone grafts have been widely used in bone transplantation for their efficiency. Maturation of the bone tissue at the place of the transplant involves the change in the vascular patterning, from plexiform irregular vascular networks, to regular, polygonal networks following the structure of osteons. Seven dogs were performed bone transplantation and intravenous injection with China ink in order to highlight the network of blood vessels during bone formation at the place of the transplant. The area occupied by blood vessels increased during osteogenesis, and their length decreased in evolution, suggesting a maturation of the vascular pattern. PMID- 24068413 TI - The effect of chronic toxicity of pethidine on the spinal cord: an experimental model in rabbits. AB - The aim of this study was to evaluate the toxicity of chronic spinal analgesia with pethidine in a rabbit model. We introduced epidural catheters in twenty New Zealand white rabbits, divided into two groups, and we administered 0.5 mg/kg pethidine or the same volume of normal saline through the catheters, for three consecutive days. Throughout the experiment, the animals were evaluated in terms of neurological status using the Tarlov score. After the rabbit's euthanasia, 4 MUm sections of spinal cord stained with Hematoxylin-Eosin were analyzed by a pathologist blinded to the study for neurohistopathological changes. The results were statistically analyzed with Prism 5 software for Windows. No significant differences were noticed between the two groups in as far as body temperature (p=0.295) and weight (p=0.139) were concerned. In the group of animals, which received epidural pethidine, nine rabbits showed histological changes suggestive for neurotoxicity at the lumbar level of the spinal cord. These findings were significantly different compared with the control group which received only saline (no microscopic lesions revealed; p=0.0006). When combining the data from both groups or using the pethidine group alone, there was a significant correlation between the presence of neurological injury (Tarlov score) and the presence of the histopathological lesions in the spinal cord (r=-0.709, p=0.0002 and r=-0.635, p=0.013, respectively). Based on our findings, the chronic epidural administration of pethidine in rabbits induces moderate to severe histological changes on the spinal cord, but further investigations are needed to make a definitive statement about the histological effect of pethidine on the neurological tissue. PMID- 24068414 TI - Microscopic aspects of angiogenesis and lymphangiogenesis in oral squamous cell carcinoma. AB - Despite various great scientific and financial efforts, head and neck carcinomas represent a public health problem, being the eighth cause of cancer death worldwidely. The rate of tumor growth, its local expansion, as well as the metastasis of cancerous cells depend on the tumor vascularization, on the ability of blood vessels to provide a constant supply of nourishing substances and oxygen and to eliminate the residual products resulted from tumor growth. That is why angiogenesis and lymphogenesis are considered to be essential processes within the neoplastic process. The assessment of tumoral neoformed blood vessels in oral squamous carcinomas, using the CD34 antibody, showed a significant growth of the microvascular density, the average number being 504.66+/-177.65 vessels/mm2. The diameter of angiogenesis vessels varied between 3.42 and 121.27 MUm. The density of lymphogenesis vessels was 508.78+/-235.93 vessels/mm2, while the diameter varied from 2.82 to 165.28 MUm. Both angiogenesis and lymphogenesis vessels were more numerous in the areas where the inflammatory infiltrate was more abundant, which suggests that chronic inflammation plays the part of a promoter factor of neoplastic lesions. PMID- 24068415 TI - Synchronous diagnosis of signet ring cell colon carcinoma and transitional carcinoma of the left distal ureter. AB - The presence of synchronous multiple primary carcinomas, although recognized, remains very uncommon. Their etiopathogeny is unclear. The wide spread of imaging techniques currently facilitates diagnosis of simultaneous tumors. We present the rare case of a signet ring cell colon carcinoma coexisting with a transitional cell carcinoma (TCC) of the ureter, which debuted with symptoms of intestinal obstruction in a 75-year-old male patient, with no prior relevant history. Computed tomography showed signs of a tumor mass on the transverse colon, as well as left hydronephrosis with a tumor in the lower third of the ureter, which prompted for immediate emergency surgery. After the appropriate surgical maneuvers, tissue collected from both tumors underwent usual histological preparation and Hematoxylin-Eosin staining, as well as multiple immunostaining with a complex panel of markers. The patient had a favorable postoperative course and during a six-month follow-up, we did not detect any signs of illness. PMID- 24068416 TI - Abnormalities in embryological development in total anomalous pulmonary venous connection. A case report. AB - Pulmonary venous system development starts early in embryonic life. Abnormalities in the development of pulmonary venous system occur either by the absence of common pulmonary vein communication to the splanchnic plexus or by the absence of its incorporation into the dorsal wall of the left atrium. We present the case of a 10-day-old male newborn, diagnosed with TAPVC, operated, with long recovery and, who died by pneumonia, heart failure, and obstructive pulmonary disease (one pulmonary vein obstructed and another one with severe stenosis). Total anomalous pulmonary venous connection (TAPVC) reflects one of the most severe forms of congenital heart disease, with important clinical consequences. PMID- 24068417 TI - Bilateral extensor medii proprius with split tendon of extensor indicis proprius, a rare anatomical variant. AB - The extensor medii proprius (EMP) is anomalous extensor muscle of the hand. During the routine dissection of a 78-year-old Chinese male cadaver, bilateral EMP and extensor indicis proprius (EIP) were observed in the upper limbs. The EMP originated from the distal third of the ulna and its tendon was inserted into the dorsal aponeurosis of the middle finger on both hands. The tendon of EIP was split into two slips on the dorsum of hand and inserted to the radial and ulnar side of the extensor digitorium communis (EDC)-index, respectively. Awareness of such anatomical variations in the extensor compartment of the forearm could help in the identification and repair of these structures. PMID- 24068418 TI - MRI diagnosis of perivascular epithelioid cell tumor (PEComa) of the liver. AB - INTRODUCTION: Perivascular epithelioid cell tumor (PEComa) has been rarely reported in the liver. PATIENT, METHODS AND RESULTS: We present a liver PEComa case diagnosed by magnetic resonance imaging (MRI) findings. The patient was incidentally found to have an abnormal mass in the liver. MRI revealed early and strikingly homogeneous enhancement of the lesion. Partial hepatectomy was performed, and a pathological examination revealed signs of typical of PEComa. The patient was closely monitored for 12 months after the surgery, with no clinical or radiographic evidence of recurrence or metastatic disease. CONCLUSION: MRI diagnosis is applicable for PEComa. PMID- 24068419 TI - Malignant pleural mesothelioma presenting with symptomatic brain metastases: report of a case. AB - We describe a unique case of brain metastases presenting as first symptom of a malignant mesothelioma (MM). MM is a highly aggressive tumor of the serous membrane that is generally believed to be rarely metastasizing. Recently, the reports of long surviving cases and larger literature reviews have suggested that cerebral metastases are not so uncommon. An extensive histochemical and immunohistochemical panel is needed to achieve a correct differential diagnosis, especially in the epithelioid type. Pathologists should be aware that brain metastases could have a mesothelial origin. PMID- 24068420 TI - Myxoid/round cell conjunctival liposarcoma. A case report. AB - PURPOSE: To present a rare case of conjunctival myxoid liposarcoma, subtype round cells, that had a seven years follow up. CLINICAL OBSERVATION: A 61-year-old female patient presents with a palpable, non-painful tumor, on the superior temporal bulbar conjunctiva of the right eye. The initial examination detects a fleshy tumor, orange in color, under the superior temporal bulbar conjunctiva, as well as two oval-shaped hyperpigmented conjunctival lesions, near the limbus at 10 o'clock, causing moderate blepharoptosis. Vision was normal, there was no diplopia, proptosis, afferent pupillary defect or lymphadenopathy; there was no orbital involvement in MRI. An isolated 15/15 mm tumor, with no connections with the eye socket, was excised. Histopathology revealed a poorly differentiated myxoid liposarcoma. Five recurrences occurred, of which four were treated by local excision and the last required exenteration. Repeat histopathology detects lipoblasts, small round cells, with immunohistochemistry positive for CD34, S100 and vimentin. The last two rapidly evolving and large recurrences, as well as pulmonary metastasis and finally death of the patient, underlined the aggressive character of round cell conjunctival liposarcoma. CONCLUSIONS: Conjunctival myxoid liposarcoma is characterized by numerous local recurrences, but the speed of the succession and volume of the recurrences may suggest a change in the underlying histopathological aspect, that is definitory for the therapeutical and prognostic approach of the case. PMID- 24068421 TI - Progressive intraparenchymal lung nodules dissemination in a heavy smoker and seropositive rheumatoid arthritis suspected of tuberculosis relapse. AB - Anthony Caplan first described rheumatoid lung nodules associated with pneumoconiosis in coal-miners (Caplan, 1953). Intraparenchymal lung nodules were later described in rheumatoid arthritis (RA) patients who were never exposed to coal dust and/or without pneumoconiosis. Rheumatoid lung nodules are usually detected in unselected patients: 0.2% in chest radiography and 4% in high resolution computed tomography (Nannini et al., 2008). Patients could be reluctant to perform surgical lung biopsy for an accurate histopathological diagnosis. We present a peculiar association between a seropositive RA and a presumptive active tuberculosis (TB) disease in a 59-year-old male patient, ex smoker with a previously healed pulmonary TB disease. The purpose of this report is to describe an unusual case of a presumptive relapse of the nodular TB disease, which progressed to an extensive nodular bilateral dissemination under anti-tuberculosis therapy, mimicking a metastatic carcinoma. The diagnosis of rheumatoid necrobiotic lung nodules was confirmed after open biopsy left pulmonary was performed. Formalin-fixed paraffin-embedded pulmonary rheumatoid nodules were processed for histology and stained with Masson's trichrome. Central structure of the removed pulmonary nodules is typical of a rheumatoid nodule with central necrosis surrounded by a palisade of macrophages. The accumulation of anthracotic pigment was noticed inside the pulmonary nodules in a RA patient without professional exposure to coal or mineral dust. This rare entity is an appearance of the rheumatoid nodules lung syndrome and anthracosis in a heavy tobacco former smoker. PMID- 24068422 TI - Sebaceous carcinoma of the eyelid: anatomoclinical data. AB - Sebaceous gland carcinoma of the eyelid is a rare slow-growing tumor and is one of the most aggressive malignancies of the eyelid. Diagnosis is often delayed because it can be confused with other periocular lesions. We report the case of a 78-year-old female who presented for the anesthetic aspect of a nodular tumor on the right upper eyelid occurring one year earlier. The patient was treated for three months for recurrent chalazion. Ophthalmologic examination revealed a nodular ulcerated tumor of 1 cm in size adherent to adjacent tissues. Surgical excision was performed with a safety margin of 4 mm. The diagnosis of moderately differentiated sebaceous carcinoma was made by routine morphological methods and immunohistochemical reactions (EMA and Ki-67). Being a rare tumor with considerable morbidity and mortality, early diagnosis and proper treatment are essential for a favorable prognosis and preservation of visual function. PMID- 24068423 TI - Atypical debut manifestations in juvenile idiopathic arthritis. AB - Considering that destructive articular lesions may occur in the first stages of the illness, it is difficult but necessary to establish a diagnosis of Juvenile Idiopathic Arthritis (JIA) in due time. The authors present the case of a 9-year old girl admitted to the Pediatrics Clinic of the "Filantropia" Municipal Hospital in Craiova, Romania, on November 26, 2002, for bilateral pain in the tarsometatarsal and carpometatarsal joints that had begun approximately four weeks before. After the clinical examination and paraclinical investigations, a diagnosis of unspecified arthritis is established and the adequate treatment is begun. Two months later, the patient returns to the clinic with bilateral knee pain and swelling. The results of laboratory tests indicate the persistence of anemia and of the inflammatory syndrome. The diagnosis of JIA is established. The evolution of the patient is unfavorable, both from a clinical point of view (a large number of articulations affected, a persistent rash, hepatomegaly) and a paraclinical one (increased acute phase reactants and radiological changes occurring two years after the onset of the illness). PMID- 24068424 TI - Does "signet-ring stromal tumor" exist? PMID- 24068425 TI - XX/XO, a rare sex chromosome system in Potamotrygon freshwater stingray from the Amazon Basin, Brazil. AB - Potamotrygonidae is a representative family of South American freshwater elasmobranchs. Cytogenetic studies were performed in a Potamotrygon species from the middle Negro River, Amazonas, Brazil, here named as Potamotrygon sp. C. Mitotic and meiotic chromosomes were analyzed using conventional staining techniques, C-banding, and detection of the nucleolus organizing regions (NOR) with Silver nitrate (Ag-NOR). The diploid number was distinct between sexes, with males having 2n = 67 chromosomes, karyotype formula 19m + 8sm + 10st + 30a, and fundamental number (FN) = 104, and females having 2n = 68 chromosomes, karyotype formula 20m + 8sm + 10st + 30a, and FN = 106. A large chromosome, corresponding to pair number two in the female karyotype, was missing in the male complement. Male meiotic cells had 33 bivalents plus a large univalent chromosome in metaphase I, and n = 33 and n = 34 chromosomes in metaphase II. These characteristics are consistent with a sex chromosome system of the XX/XO type. Several Ag-NOR sites were identified in both male and female karyotypes. Positive C-banding was located only in the centromeric regions of the chromosomes. This sex chromosome system, which rarely occurs in fish, is now being described for the first time among the freshwater rays of the Amazon basin. PMID- 24068426 TI - Seasonal variation in genetic population structure of sabalo (Prochilodus lineatus) in the Lower Uruguay River. AB - Prochilodus lineatus is a highly migratory fish species that sustains the most important commercial fishery of Parana-Paraguay basin. Migratory patterns are poorly known and only few population genetic studies are available for this species in the Upper Parana. To assess genetic population structure, we genotyped a sample of 93 individuals from the Lower Uruguay River close to Gualeguaychu city (Entre Rios, Argentina) at three different times, July 2008 (Winter), September 2008 (Spring) and May 2009 (Fall). All individuals were genotyped for 12 microsatellite loci previously found to be informative to assess populations of P. lineatus. Our results show seasonal variation of the genetic sub structuring at this locality that may be related to the presence of different migratory stocks throughout the year. The Fall sample includes an additional genetic cluster of individuals not detected in Winter and Spring, suggesting that this species should be considered a mixed stock fishery. PMID- 24068427 TI - Orexin-A activates hypothalamic AMP-activated protein kinase signaling through a Ca2+-dependent mechanism involving voltage-gated L-type calcium channel. AB - Hypothalamic AMP-activated protein kinase (AMPK) and orexins/hypocretins are both involved in the control of feeding behavior, but little is known about the interaction between these two signaling systems. Here, we demonstrated that orexin-A elicited significant activation of AMPK in the arcuate nucleus (ARC) of the hypothalamus by elevating cytosolic free Ca2+ involving extracellular calcium influx. Electrophysiological results revealed that orexin-A increased the L-type calcium current via the orexin receptor-phospholipase C-protein kinase C signaling pathway in ARC neurons that produce neuropeptide Y, an important downstream effector of orexin-A's orexigenic effect. Furthermore, the L-type calcium channel inhibitor nifedipine attenuated orexin-A-induced AMPK activation in vitro and in vivo. We found that inhibition of AMPK by either compound C (6-[4 [2-(1-piperidinyl)ethoxy]phenyl]-3-(4-pyridinyl)-pyrazolo[1,5-a]pyrimidine) or the ATP-mimetic 9-beta-D-arabinofuranoside prevented the appetite-stimulating effect of orexin-A. This action can be mimicked by nifedipine, the blocker of the L-type calcium channel. Our results indicated that orexin-A activates hypothalamic AMPK signaling through a Ca2+-dependent mechanism involving the voltage-gated L-type calcium channel, which may serve as a potential target for regulating feeding behavior. PMID- 24068428 TI - Mycoplasma hyorhinis-encoded purine nucleoside phosphorylase: kinetic properties and its effect on the cytostatic potential of purine-based anticancer drugs. AB - A mycoplasma-encoded purine nucleoside phosphorylase (designated PNPHyor) has been cloned and characterized for the first time. Efficient phosphorolysis of natural 6-oxopurine and 6-aminopurine nucleosides was observed, with adenosine the preferred natural substrate (Km = 61 uM). Several cytostatic purine nucleoside analogs proved to be susceptible to PNPHyor-mediated phosphorolysis, and a markedly decreased or increased cytostatic activity was observed in Mycoplasma hyorhinis-infected human breast carcinoma MCF-7 cell cultures (MCF 7.Hyor), depending on the properties of the released purine base. We demonstrated an ~10-fold loss of cytostatic activity of cladribine in MCF-7.Hyor cells and observed a rapid and complete phosphorolysis of this drug when it was exposed to the supernatant of mycoplasma-infected cells. This conversion (inactivation) could be prevented by a specific PNP inhibitor. These findings correlated well with the high efficiency of PNPHyor-catalyzed phosphorolysis of cladribine to its less toxic base 2-chloroadenine (Km = 80 uM). In contrast, the cytostatic activity of nucleoside analogs carrying a highly toxic purine base and being a substrate for PNPHyor, but not human PNP, was substantially increased in MCF 7.Hyor cells (~130-fold for fludarabine and ~45-fold for 6-methylpurine-2' deoxyriboside). Elimination of the mycoplasma from the tumor cell cultures or selective inhibition of PNPHyor by a PNP inhibitor restored the cytostatic activity of the purine-based nucleoside drugs. Since several studies suggest a high and preferential colonization or association of tumor tissue in cancer patients with different prokaryotes (including mycoplasmas), the data presented here may be of relevance for the optimization of purine nucleoside-based anticancer drug treatment. PMID- 24068429 TI - Transcriptome profiling and digital gene expression analysis of Nile tilapia (Oreochromis niloticus) infected by Streptococcus agalactiae. AB - Tilapia is an important freshwater aquaculture species worldwide. In recent years, streptococcal diseases have severely threatened development of tilapia aquaculture, while effective prevention and control methods have not yet been established. In order to understand the immunological response of tilapia to infection by Streptococcus agalactiae (S. agalactiae), this study employed Solexa/Illumina RNA-seq and digital gene expression (DGE) technology to investigate changes in the tilapia transcriptome before and after S. agalactiae infection. We obtained 82,799 unigenes (mean size: 618 bp) using de novo assembly. Unigenes were annotated by comparing against databases including Nr, Swissprot, cluster of orthologous groups of proteins, Kyoto encyclopedia of genes and genomes, and gene ontology. Combined with DGE technology, transcriptomic changes in tilapia before and after bacteria challenging were examined. A total of 774 significantly up-regulated and 625 significantly down-regulated unigenes were identified, among which 293 were mapped to 181 signaling pathways including 17 immune-related pathways involving 65 differentially expressed genes. We observed a change in the expression of six genes in the Toll-like receptor signaling pathway, and this was subsequently confirmed via quantitative real-time PCR. This comparative study of the tilapia transcriptome before and after S. agalactiae infection identified important differentially-expressed immune-related genes and signaling pathways that will provide useful insights for further analysis of the mechanisms of tilapia defense against S. agalactiae infection. PMID- 24068430 TI - Systematic investigation of interactions between papain and MPA-capped CdTe quantum dots. AB - Fluorescent quantum dots (QDs) have been widely applied in biological and biomedical areas, but relatively little is known about the interaction of QDs with some natural enzymes. Herein, the interactions between 3-mercaptopropionic acid-capped CdTe QDs (MPA-QDs) and papain were systematically investigated by UV Vis absorption spectra, fluorescence spectra and circular dichroism (CD) spectra under the physiological conditions. The fluorescence spectra results indicated that MPA-QDs quenched the fluorescence intensity of papain. The modified Stern Volmer quenching constant K a at different temperatures and the corresponding thermodynamic parameters DeltaH, DeltaG and DeltaS were also calculated. The binding of MPA-QDs and papain is a result of the formation of QDs-papain complex and the electrostatic interactions play a major role in stabilizing the complex. The CD technique was further used to analyze the conformational changes of papain induced by MPA-QDs and the results indicated that the biological activity of papain was affected by MPA-QDs dramatically. PMID- 24068431 TI - Plasma-free amino acid profiling of cervical cancer and cervical intraepithelial neoplasia patients and its application for early detection. AB - In this study, plasma-free amino acid profiles were used to investigate pre cancerous cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma (CSCC) metabolic signatures in plasma. Additionally, the diagnostic potential of these profiles was assessed, as well as their ability to provide novel insight into CSCC metabolism and systemic effects. Plasma samples from CIN patients (n = 26), CSCC patients (n = 22), and a control healthy group (n = 35) were analyzed by high-performance liquid chromatography, and their spectral profiles were subjected to the t test for statistical significance. Potential metabolic biomarkers were identified using database comparisons that examine the significance of metabolites. Compared with healthy controls, patients with CIN and CSCC demonstrated lower levels of plasma amino acids; plasma levels of arginine and threonine were increased in CIN patients but were decreased in cervical cancer patients. Additionally, the levels of a larger group of amino acids (aspartate, glutamate, asparagine, serine, glycine, histidine, taurine, tyrosine, valine, methionine, lysine, isoleucine, leucine, and phenylalanine) were gradually reduced from CIN to invasive cancer. These findings suggest that plasma-free amino acid profiling has great potential for improving cancer screening and diagnosis and for understanding disease pathogenesis. Plasma-free amino acid profiles may have the potential be used to determine cancer diagnoses in the early stage from a single blood sample and may enhance our understanding of its mechanisms. PMID- 24068432 TI - Molecular phylogeny of Indian horse breeds with special reference to Manipuri pony based on mitochondrial D-loop. AB - Manipuri pony is the geographically distant breed of horse from the five recognized horse breeds found in the Indian subcontinent. The phylogenetic relationship of Manipuri pony with the other breeds is unknown. The diversity in the mitochondrial (mt) DNA D-loop region is employed as an important tool to understand the origin and genetic diversification of domestic horses and to examine genetic relationships among breeds around the world. This study was carried out to understand the maternal lineages of Manipuri pony using the 247 bp region of the mtDNA D-loop. The dataset comprised of eleven numbers of self developed sequences of Manipuri pony, 59 and 35 number of retrieved sequences of Indian horse breeds and other worldwide breeds respectively. A total of 35 haplotypes was identified with a high level of genetic diversity in the Indian breeds. A total of seven major mtDNA haplogroups (A-G) was identified in the Indian horse breeds that indicated the abundance of mtDNA diversity and multiple origins of maternal lineages in them. The majority of the studied sequences of Indian breeds (33.3 %) were grouped into haplogroup D and least (3.9 %) in haplogroup E. The Manipuri breed showed the least FST distance (0.03866) with the most diverged Indian breeds and with Thoroughbred horse among the worldwide. This study indicated a close association between Manipuri pony and Thoroughbred. PMID- 24068433 TI - CYP1A1, GCLC, AGT, AGTR1 gene-gene interactions in community-acquired pneumonia pulmonary complications. AB - This study was conducted to establish the possible contribution of functional gene polymorphisms in detoxification/oxidative stress and vascular remodeling pathways to community-acquired pneumonia (CAP) susceptibility in the case-control study (350 CAP patients, 432 control subjects) and to predisposition to the development of CAP complications in the prospective study. All subjects were genotyped for 16 polymorphic variants in the 14 genes of xenobiotics detoxification CYP1A1, AhR, GSTM1, GSTT1, ABCB1, redox-status SOD2, CAT, GCLC, and vascular homeostasis ACE, AGT, AGTR1, NOS3, MTHFR, VEGFalpha. Risk of pulmonary complications (PC) in the single locus analysis was associated with CYP1A1, GCLC and AGTR1 genes. Extra PC (toxic shock syndrome and myocarditis) were not associated with these genes. We evaluated gene-gene interactions using multi-factor dimensionality reduction, and cumulative gene risk score approaches. The final model which included >5 risk alleles in the CYP1A1 (rs2606345, rs4646903, rs1048943), GCLC, AGT, and AGTR1 genes was associated with pleuritis, empyema, acute respiratory distress syndrome, all PC and acute respiratory failure (ARF). We considered CYP1A1, GCLC, AGT, AGTR1 gene set using Set Distiller mode implemented in GeneDecks for discovering gene-set relations via the degree of sharing descriptors within a given gene set. N-acetylcysteine and oxygen were defined by Set Distiller as the best descriptors for the gene set associated in the present study with PC and ARF. Results of the study are in line with literature data and suggest that genetically determined oxidative stress exacerbation may contribute to the progression of lung inflammation. PMID- 24068434 TI - GP73 is a potential marker for evaluating AIDS progression and antiretroviral therapy efficacy. AB - Golgi protein-73 (GP73) is upregulated in cancers and viral infections; however, its role in human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) remains undetermined. GP73 was evaluated as a biomarker of HIV progression and AIDS treatment efficacy. Forty-eight HIV patients (<= 350 CD4 + T cells/MUL) undergoing highly active antiretroviral therapy (HAART group) and 18 HIV patients expected to undergo HAART within 9 months (>350 CD4 + T cells/MUL) (control group) were enrolled in a prospective, single center, cohort study from May 2009 to Jun 2012. Blood aspartate aminotransferase, alanine aminotransferase (ALT), cholesterol, triglycerides, and total bilirubin were assessed at baseline, 2 weeks, and 1, 3, 6, 9, and 12 months (HAART group) or 3 month intervals (control group). Serum HIV RNA level (viral load) was determined by reverse transcriptase polymerase chain reaction (RT-PCR), and serum and peripheral blood mononuclear cell (PBMC) GP73 concentration were determined by chemiluminescent immunoassay kit and western blot, respectively. Significant positive and negative correlations in baseline serum GP73 concentration and HIV viral load (r = 0.39, P < 0.001) and CD4 + T cell count (r = -0.501, P < 0.001) were observed, respectively. In receiver operator characteristic (ROC) analysis, area under the curve (AUC) was 0.79 (95 % CI 0.66-0.92). The sensitivity and specificity of GP73 for correct identification of patients with <=350 CD4 + T cells/MUL were 76.09 and 75.0 %, respectively, with an ROC-derived cut-off of 100.6 ng/mL. For HIV patients undergoing antiretroviral therapy, GP73 may be a potential biomarker treatment efficacy useful in AIDS management. PMID- 24068435 TI - Molecular evolution of plant P5CS gene involved in proline biosynthesis. AB - The P5CS ({Delta} 1-Pyrroline-5-Carboxylate Synthetase) gene encodes for a bifunctional enzyme that catalyzes the rate limiting reaction in proline biosynthesis in living organisms. A wide range of multifunctional roles of proline have now been shown in stress defense. The proline biosynthetic genes, especially, P5CS is commonly used in metabolic engineering for proline overproduction conferring stress tolerance in plants. The gene is functionally well characterized at the molecular level, but there is more to learn about its evolutionary path in the plant kingdom, particularly the drive behind functional (osmoprotective and developmental) divergence of duplication of P5CS genes. In this review, we present the current understanding of the evolutionary trail of plant P5CS gene which plays a key role in stress tolerance. PMID- 24068436 TI - Selection of suitable reference genes for mRNA quantification studies using common marmoset tissues. AB - The common marmoset (Callithrix jacchus) is increasingly being used as a non human primate animal model in biomedical research. To perform accurate quantitative analysis of gene expression by quantitative reverse transcription polymerase chain reaction, reliable reference genes should be selected. In this study, we evaluated the expressions of 11 widely used reference genes: ACTB, ATP5F1, B2M, GAPDH, HPRT1, PGK1, PPIA, RN18S1, RPLP0, TBP and UBC in 12 tissues and five brain areas of healthy common marmosets. NormFinder and geNorm indicated that the most suitable reference genes for cross-sectional studies of the 17 tissues were RN18S1 and RPLP0. Conversely, ACTB and PPIA were the most suitable for analyzing brain samples; however, the expression of PGK1 fluctuated among brain areas. These results indicate that suitable reference genes differ between the tissues examined. This study provides fundamental information for gene expression studies of the common marmoset and highlights the importance of validating reference genes before quantification of target mRNAs. PMID- 24068437 TI - Genetic attributions and mental illness diagnosis: effects on perceptions of danger, social distance, and real helping decisions. AB - Genetic essentialism suggests that beliefs in genetic causes of mental illness will inflate a desire for social distance from affected individuals, regardless of specific disorder. However, genetic contingency theory predicts that genetic attributions will lead to an increased desire for social distance only from persons with disorders who are perceived as dangerous. PURPOSE: To assess the interactive effect of diagnosis and attribution on social distance and actual helping decisions across disorders. METHODS: Undergraduate students (n = 149) were randomly assigned to read one of the six vignettes depicting a person affected by one of the three disorders (i.e., schizophrenia, bipolar disorder, or major depression) with either a genetic or environmental causal attribution for disorder. Participants completed measures of perceived dangerousness, social distance, empathic concern, familiarity with mental illness, and actual helping decisions. RESULTS: When provided with genetic attributions, participants' desire for social distance was greater for targets with schizophrenia relative to targets with depression or bipolar disorder. This effect was mediated by perceived dangerousness. The indirect effect of diagnosis on helping decisions, through social distance, was significant within the genetic attribution condition. CONCLUSION: Consistent with genetic contingency theory, genetic attributions for schizophrenia, but not affective disorders, lead to greater desire for social distance via greater perceived dangerousness. Further, results suggest that genetic attributions decrease the likelihood of helping people with schizophrenia, but have no effect on the likelihood of helping people with affective disorders. These effects are partially accounted for by desired social distance from people with schizophrenia. PMID- 24068438 TI - Visual outcomes of Femto-LASIK for correction of residual refractive error after corneal graft. AB - PURPOSE: To evaluate the outcomes of the Femto-LASIK method in the treatment of refractive errors following penetrating keratoplasty (PK) at the Persian Eye Clinic, Isfahan, Iran METHODS: In a prospective, non-comparative case series, 34 consecutive symptomatic eyes of 34 patients after corneal graft, were operated on. Tissue-saving (TS) Femto-LASIK (n = 16), and Zyoptix Personalized Treatment Advanced (PTA) Femto-LASIK (n = 18) were performed using the Bausch & Lomb Technolas 217z excimer laser and Zyoptic algorithm. Uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), manifest refraction, contrast sensitivity, and HOAs were evaluated preoperatively and 12 months after enhancement treatment. RESULTS: At 12 months, the mean preoperative myopic spherical equivalent refraction (SE) decreased from -6.50 +/- 2.8 D to -1.6 +/- 1.8 D, and mean hyperopic SE from +3.2 +/- 2.20 D to 0.37 +/- 1.2 D. The safety index was 1.42 (1.2 in the TS group and 1.5 in the PTA group). In the TS group, 100% of eyes achieved 20/80 or better UCVA and 50%, 20/40 or better and in the PTA group, 100% of eyes achieved 20/80 or better UCVA and 77.7%, 20/40 or better. The efficacy index was 1.08 (0.9 in TS group and 1.21 in the PTA group). Patients obtained statistically significant lower values of root mean square (RMS) of HOAs with spherical aberrations (p < 0.05). CONCLUSIONS: Femto-LASIK method with Zyoptic programs after PK was safe, effective, and predictable for correction of spherical and cylindrical components of the refractive error. PMID- 24068439 TI - Global rates of glaucoma surgery. AB - PURPOSE: To estimate global rates of glaucoma surgery. METHODS: National glaucoma and national ophthalmology societies were contacted to obtain rates of glaucoma surgery for the preceding 5 years. In countries without a professional society, leading ophthalmologists or non-governmental organizations (NGO) were approached. When available, published literature was used for the estimates. Three levels of evidence were assigned: published data from central government or insurance registries (level I), estimates provided by a national professional society based on survey of members (level II), and estimates based on data from individual glaucoma surgeons (level III). Glaucoma surgical rate (GSR) was defined as the annual number of total glaucoma surgeries performed per million population. Linear regression analysis was performed between GSR and the following parameters: population per ophthalmologist, per capita gross domestic product (GDP), and per capita health expenditures. RESULTS: Seventy-three glaucoma societies, 35 ophthalmology societies, as well as six NGOs and 37 leading ophthalmologists (11 other countries) were contacted. Data were obtained from 38 countries (10 level I, 23 level II, and 5 lev el III) with a total population of 1.723 billion. The average GSR was 139.2 +/- 113.1 (range, 2.9-500.0). There was a positive correlation between GSR and GDP (r(2) = 0.309, P = 0.0004) and GSR and the number of ophthalmologists (r(2) = 0.476, P < 0.0001). CONCLUSION: There is a paucity of data on rates of glaucoma surgery, particularly from developing countries. The new metric GSR may be useful for the allocation of healthcare resources, as well as for planning and monitoring public health interventions in glaucoma. PMID- 24068440 TI - Promoter hypermethylation of the tumor-suppressor genes RASSF1A, GSTP1 and CDH1 in endometrial cancer. AB - Endometrial cancer is a common gynecological malignancy with a good prognosis in early stages of the disease. The CpG island in the promoter region of tumor suppressor genes are frequently methylated in various types of human cancers. In the present study, we examined the methylation status of the GSTP1, CDH1 and RASSF1A genes in endometrioid endometrial cancer (EEC), endometrial complex hyperplasia (EHP) and healthy endometrium with the aim to identify correlations between promoter hypermethylation, disease risk and clinicopathological parameters. A nested two-stage methylation-specific PCR (MSP) was performed to analyze the promoter CpG methylation status of GSTP1, CDH1 and RASSF1A genes in the population studied. A total of 92 subjects were initially included in the study of which 41 EEC, 19 EHP and 20 controls were processed for final analyses. A significant difference was found between the study groups and the presence of promoter CpG hypermethylation status in the GSTP1 (p<0.05) and RASSF1A (p<0.0001) genes. RASSF1A, GSTP1 and CDH1 gene promoter methylation was present in 85.4, 68.3 and 31.4% of EEC samples when compared to that in the controls with 30.0, 35.0 and 20.0%, respectively. CpG methylation of all three investigated tumor suppressor genes was found in 12.2% of EEC patients, in 4.2% of EHP patients and in 3.7% of the controls, respectively. Positive findings for the promoter methylation of two investigated genes were found in 48.7% of EEC patients, 26.0% of EHP patients and in 18.5% of the controls. With regard to histopathological variables and CpG methylation, we found significant correlations between the RASSF1A and GSTP1 genes and higher tumor grade, deeper myometrial invasion and positive metastatic involvement of pelvic lymph nodes. No associations were noted between promoter hypermethylation of the CDH1 gene and biological features of the endometrial cancer cases. The results indicate that aberrant CpG methylation of the promoter region in the GSTP1 and RASSF1A tumor-suppressor genes is an important event in carcinogenesis of endometrial cancer and may have an impact on tumor aggressiveness. Finally, the present study suggests that epigenetic alterations may be of diagnostic value for the better clinical management of premalignant endometrial lesions. PMID- 24068442 TI - Comparative clinical study on deformity correction accuracy of different external fixators. AB - PURPOSE: In this study, the correction accuracy of Smart Correction spatial fixators and of Ilizarov-type external fixators are compared in terms of deformity complexity. METHODS: Seventy-seven (40 male, 37 female) bone segments of 57 patients treated with a Smart Correction device were compared with 94 (51 male, 43 female) segments of 68 patients treated with an Ilizarov fixator. Mean age of the Smart Correction group was 20.69 +/- 12.94 years, and or the Ilizarov group 22.45 +/- 12.18 years. Patients were categorised according to limb lengthening and the number of deformity planes. RESULTS: A longer correction period was found with Ilizarov (66.53 +/- 47.7 days) compared with Smart Correction (49.05 +/- 35.6 days) devices. The bone healing index of the Ilizarov group was significantly better compared with the spatial group. Residual deformity after treatment was significantly lower with the Smart Correction device; however, this relationship could not be shown between subgroups. Although there was no significant difference between subgroups, mean residual deformity was higher with the increasing number of planes of the deformity. CONCLUSIONS: The Smart Correction fixator is an accurate device that allows ease of application and planning. It demonstrates higher accuracy for correcting deformities compared with an Ilizarov external fixator. With an increasing number of planes, the difference between the two devices becomes even more pronounced. The relationship between the complexity of the deformity and residual deformity may possibly be significantly greater in favour of the Smart Correction fixator in a study with a larger sample size. PMID- 24068441 TI - Does the surgical approach in one stage bilateral total hip arthroplasty affect blood loss? AB - PURPOSE: It is not clear whether type of surgical approach affects the amount of blood loss in one-stage bilateral total hip arthroplasty (THA). This study therefore aims to examine if type of surgical approach can affect peri-operative blood loss and allogeneic blood transfusion in patients undergoing one-stage bilateral THA. METHODS: Records of 319 patients who underwent one-stage bilateral THA from January 2004 to June 2011 were retrospectively reviewed. Patients were divided into two groups: direct anterior (DA) approach (75 patients) and direct lateral (DL) approach (244 patients). Blood loss was calculated using a previously validated formula. Blood loss and need for allogeneic blood transfusion were compared between the two groups. Additionally, the effects of using cell saver and surgical approach were evaluated in a multivariate analysis. RESULTS: Compared to the DL approach, calculated blood loss was significantly lower in the DA group (2,813.90 +/- 804.13 ml vs 3,617.03 +/- 1,148.47 ml) and a significantly lower per cent of patients needed allogeneic blood transfusion in the DA group (26.6 vs 52.4%). Intra-operative cell saver was used in 36 patients. Compared to the non-cell saver group, mean blood loss was significantly higher in the cell saver group (4,061.0 +/- 1,285.55 ml vs 3,347.71 +/- 1,083.85 ml), whereas the difference between the two groups regarding allogeneic blood transfusion was not statistically significant. The DA approach was an independent predictor of lower peri-operative blood loss and allogeneic blood transfusion while using cell saver was not. CONCLUSIONS: Our results may be explained by the lower extent of muscular dissection performed in the DA approach. Our findings also indicate that intra-operative cell salvage might not be justified in bilateral THA performed expeditiously. PMID- 24068443 TI - Deep venous structures distortion in spontaneous intracranial hypotension as an explanation for altered level of consciousness. AB - Spontaneous intracranial hypotension (SIH) is a syndrome of low pressure headache associated with low CSF pressure. The condition is generally considered benign but extreme cases of SIH can lead to changes in the level of consciousness. We describe a case in which alteration in the level of consciousness was prolonged and severe, and could not be explained solely by the presence of subdural collections. MRI of the brain showed evidence of impaired venous flow secondary to brain sagging causing distortion of deep venous structures. PMID- 24068444 TI - Correlation of intracardiac electrogram with surface electrocardiogram in Brugada syndrome patients. AB - AIMS: The objective of this study was to correlate the electrocardiogram (ECG) modification during an Ajmaline challenge in patients affected by the Brugada syndrome and implanted with an implantable cardioverter-defibrillator (ICD) with the morphological changes of their ICD's intracardiac electrogram (IEGM). METHODS AND RESULTS: Sixteen type 1 Brugada syndrome patients implanted with a St Jude Medical AnalyST((r)) ICD were enrolled and underwent ajmaline challenge. Intracardiac electrograms and 12 lead ECG signals were collected over the duration of the study and analysed off-line. The right precordial ECG leads were in both the third and fourth intercostal space by putting V5 and V6 in V1 and V2 at the third intercostal space. Two patients were excluded from the analysis due to signal noise issues. Of the remaining 14 patients, 12 and 2 patients were adjudicated to have positive and negative ajmaline challenges, respectively, based on standard ECG criteria. In the ajmaline positive patients, the IEGM T wave amplitude changes were more prominent than those of the IEGM ST segment ( 898 +/- 463 vs. -55 +/- 381 uV, P < 0.05). Furthermore, all of these T wave amplitude changes were in the negative polarity, whereas the change in polarity of the ST segment was mixed. The changes in the IEGM T wave amplitude and ST segment were significantly smaller in the ajmaline negative patients compared with those in the ajmaline positive patients [211 +/- 158 (P < 0.05) and 107 +/- 54 (P < 0.05) uV, respectively). Over all 14 analysable patients, the change in the ECG ST segment over the timecourse of the ajmaline challenge correlated better with the IEGM T wave amplitude change (R = 0.72 +/- 0.33) than the IEGM ST segment change (R = 0.63 +/- 0.33). Applying an IEGM T wave amplitude change cut off of 400 uV for predicting the outcome of the ajmaline challenge yielded 92% sensitivity (11/12) and 100% specificity (2/2). CONCLUSION: In Brugada patients, ajmaline challenge elicits significant T wave amplitude changes within the ICD IEGM, greater than those of the IEGM ST segment. This study is the first step to provide new tools able to continuously monitor the type I Brugada aspect in patients affected by the Brugada syndrome. PMID- 24068445 TI - Applicability of the iterative technique for cardiac resynchronization therapy optimization: full-disclosure, 50-sequential-patient dataset of transmitral Doppler traces, with implications for future research design and guidelines. AB - AIMS: Full-disclosure study describing Doppler patterns during iterative atrioventricular delay (AVD) optimization of biventricular pacemakers (cardiac resynchronization therapy, CRT). METHOD AND RESULTS: Doppler traces of the first 50 eligible patients undergoing iterative Doppler AVD optimization in the BRAVO trial were examined. Three experienced observers classified conformity to guideline-described patterns. Each observer then selected the optimum AVD on two separate occasions: blinded and unblinded to AVD. Four Doppler E-A patterns occurred: A (always merged, 18% of patients), B (incrementally less fusion at short AVDs, 12%), C (full separation at short AVDs, as described by the guidelines, 28%), and D (always separated, 42%). In Groups A and D (60%), the iterative guidelines therefore cannot specify one single AVD. On the kappa scale (0 = chance alone; 1 = perfect agreement), observer agreement for the ideal AVD in Classes B and C was poor (0.32) and appeared worse in Groups A and D (0.22). Blinding caused the scattering of the AVD selected as optimal to widen (standard deviation rising from 37 to 49 ms, P < 0.001). By blinding 28% of the selected optimum AVDs were <=60 or >=200 ms. All 50 Doppler datasets are presented, to support future methodological testing. CONCLUSION: In most patients, the iterative method does not clearly specify one AVD. In all the patients, agreement on the ideal AVD between skilled observers viewing identical images is poor. The iterative protocol may successfully exclude some extremely unsuitable AVDs, but so might simply accepting factory default. Irreproducibility of the gold standard also prevents alternative physiological optimization methods from being validated honestly. PMID- 24068446 TI - Acute respiratory distress syndrome following straightforward pulmonary vein isolation. PMID- 24068447 TI - How 'cool' is cryoablation in the vicinity of the atrioventricular node? PMID- 24068448 TI - Ventricular tachycardia ablation in a patient with a parachute device: a decent word of warning. PMID- 24068449 TI - Electrocautery-induced ventricular fibrillation during routine implantable cardioverter-defibrillator generator replacement. PMID- 24068450 TI - Long-term follow-up of asymptomatic Brugada patients with inducible ventricular fibrillation under hydroquinidine. AB - AIMS: To evaluate the long-term efficacy and safety of an electrophysiologically guided therapy, based on a strategy of treatment using hydroquinidine (HQ) among asymptomatic Brugada patients with inducible ventricular fibrillation (VF). METHODS AND RESULTS: In two French reference centres, consecutive asymptomatic type 1 Brugada patients with inducible VF were treated with HQ (600 mg/day, targeting a therapeutic range between 3 and 6 umol/L) and enroled in a specific follow-up (mean 6.6 +/- 3 years), including a second programmed ventricular stimulation (PVS) under HQ. An implantable cardioverter defibrillator (ICD) was eventually implanted in patients inducible under HQ, or during follow-up in case of HQ intolerance, as well as occurrence of arrhythmic events. From a total of 397 Brugada patients, 44 were enroled (47 +/- 10 years, 95% male). Of these, 34 (77%) were no more inducible (Group PVS-), and were maintained under HQ alone during a mean follow-up of 6.2 +/- 3 years. In this group, an ICD was eventually implanted in four patients (12%), with occurrence of appropriate ICD therapies in one. Among the 10 other patients (22%), who remained inducible and received ICD (Group PVS+), none of them received appropriate therapy during a mean follow-up of 7.7 +/- 2 years. The overall annual rate of arrhythmic events was 1.04% (95% confidence interval 0.00-2.21), without any significant difference according to the result of PVS under HQ. One-third of patients experienced device-related complications. CONCLUSION: Our long-term follow-up results emphasize that the rate of arrhythmic events among asymptomatic Brugada patients with inducible VF remains low over time. Our results also suggest that residual inducibility under HQ is of limited value to predict events during follow-up. PMID- 24068451 TI - Binding of CD14 to Mycoplasma genitalium-derived lipid-associated membrane proteins upregulates TNF-alpha. AB - Lipid-associated membrane proteins (LAMPs) are a mixture of mycoplasmal lipoproteins expressed on the surface, and they are the main structures for interaction with the host cells. The objective of this study was to explore the role of CD14 in immune recognition of Mycoplasma genitalium-derived LAMPs and investigate whether the binding of CD14 to LAMPs affects the inflammatory response. Enzyme-linked immunosorbent assay (ELISA), transient co-transfection, dual-luciferase reporter assay, specific inhibition assay, and competitive inhibition ELISA (CI-ELISA) were used. CD14 was involved in LAMP-stimulated production of tumor necrosis factor (TNF)-alpha by blocking CD14 antibody in THP 1 cells. Co-transfection experiments in HeLa cells provide evidence that CD14 facilitates LAMP-induced TNF-alpha release via toll-like receptor 2 (TLR2). In addition, LAMP-induced TNF-alpha release was increased by soluble CD14 but decreased by soluble TLR2. Lipid moieties of LAMPs pre-treated with lipoprotein lipase were responsible for TNF-alpha production. The binding of CD14 to LAMPs was supported by binding assay and CI-ELISA. Thus, we provide evidences that CD14 is not only able to recognize LAMPs but also its binding to LAMPs upregulates TNF alpha release. These findings provide insight into the function of CD14 and the pathogenesis of mycoplasmal infections. PMID- 24068452 TI - Flavobacterium kyungheensis sp. nov., isolated from soil of a ginseng field. AB - A Gram-staining negative, strictly aerobic, motile by gliding, non-spore-forming, pale yellow pigmented and rod-shaped bacterium designated strain THG-107(T) was isolated from soil of a ginseng field on Ganghwa Island in the Republic of Korea and its taxonomic position was investigated by using a polyphasic study. Growth of strain THG-107(T) was found to occur at 4-37 degrees C (optimum, 20-30 degrees C), at pH 5.5-10 (optimum, pH 7.0) and in the presence of 0-1 % (w/v) NaCl (optimum, absence) on R2A agar. On the basis of 16S rRNA gene sequence similarity, strain THG-107(T) was shown to belong to the family Flavobacteriaceae and was related to Flavobacterium denitrificans ED5(T) (99.1 % similarity). The G+C content of the genomic DNA was determined to be 34.2 mol%. These results are consistent with characteristics of members of the genus Flavobacterium. The only isoprenoid quinone detected in strain THG-107(T) was menaquinone-6 (MK-6) and the major polyamine was identified as homospermidine (82.9 %). The major polar lipid detected was phosphatidylethanolamine and the major cellular fatty acids were identified as iso-C15:0 (26.3 %), iso-C17:0 3OH (12.6 %) and summed feature 3 (comprising C16:1 omega7c and/or C16:1 omega6c; 11.6 %). Flexirubin-type pigments were found to be present. Strain THG-107(T) has beta-glucosidase activity to convert ginsenosides Rb1 and Rd into Gyp17 and F2. DNA-DNA hybridization with F. denitrificans ED5(T) was 52 %. Strain THG-107(T) could be distinguished from F. denitrificans ED5(T) and the other species of the genus Flavobacterium by its phylogenetic and genetic distinctiveness and by several phenotypic properties. Therefore, strain THG-107(T) is considered to represent a novel species in the genus Flavobacterium, for which the name Flavobacterium kyungheensis sp. nov. is proposed (type strain THG-107(T) = KACC 16219(T) = LMG 26575(T)). PMID- 24068453 TI - White rot Basidiomycetes isolated from Chiloe National Park in Los Lagos region, Chile. AB - Wood decomposition is an important component in forest ecosystems but information about the diversity of fungi causing decay is lacking. This is especially true for the temperate rain forests in Chile. These investigations show results of a biodiversity study of white-rot fungi in wood obtained from Chiloe National Park in Los Lagos region, Chile. Culturing from white-rotted wood followed by sequencing of the complete internal transcribed spacer region of the ribosomal DNA (rDNA) or partial large subunit region of the rDNA, identified 12 different species in the Basidiomycota. All of these fungi were characterized as white rot fungi and were identified with a BLAST match of 97 % or greater to sequences in the GenBank database. Fungi obtained were species of Phlebia, Mycoacia, Hyphodontia, Bjerkandera, Phanerochaete, Stereum, Trametes, and Ceriporiopsis. This report identifies for the first time in Chile the species Ceriporiopsis subvermispora, Hyphodontia radula, Phlebia radiata, Phanerochaete affinis, Peniophora cinerea, Stereum gausapatum, Phlebia setulosa and Phanerochaete sordida. Scanning electron microscopy was used to characterize the type of decay caused by the fungi that were isolated and a combination of selective lignin degraders and simultaneous white rot fungi were found. Fungi that cause a selective degradation of lignin are of interest for bioprocessing technologies that require modification or degradation of lignin without cellulose removal. PMID- 24068454 TI - Intracranial internal carotid artery changes in acromegaly: a quantitative magnetic resonance angiography study. AB - PURPOSE: Although cerebrovascular mortality is increased up to eightfold in acromegaly, intracranial internal carotid artery (ICA) changes have not been well investigated. This is a magnetic resonance angiography (MRA) quantitative cross sectional study of ICA tortuosity, ectasia and intercarotid distance in acromegalic patients with subsequent analysis of concomitant clinical, laboratory and neuroimaging findings. METHODS: One hundred seventy six acromegalic patients (mean-age 55 +/- 14 years, age range 21-88, 92 females) and 104 subjects with headache or transient neurological deficits underwent MRA with the same 1.5 T scanner. Clinical data, laboratory and pituitary adenoma imaging findings were recorded. Using a commercially available software, we measured the tortuosity index [(curved/linear ICA length from C3-midpoint to intracranial bifurcation) - 1], ICA ectasia index (intracavernous/petrous ICA diameter) and intercarotid distance at C3 and C4 levels. RESULTS: Mean ICA tortuosity and ectasia indices were increased in acromegalic patients compared with controls (1.06 +/- 0.29 vs 0.93 +/- 0.26, p < 0.001; 1.02 +/- 0.10 vs 0.92 +/- 0.09, p < 0.001). Mean intercarotid distance was reduced at C3 and increased at C4 in acromegalic patients (16.7 +/- 3.4 vs 17.9 +/- 2.5 mm, p < 0.001; 16.7 +/- 4.6 vs 15.4 +/- 4.1 mm, p < 0.05; t test). ICA tortuosity and ectasia correlated neither with laboratory findings nor with previous or current treatment. On multivariate analysis, C3 intercarotid distance was reduced in patients on dopamine agonist treatment (p < 0.01) and increased in patients with GH-deficit (p = 0.01), while C4 intercarotid distance was increased with macroadenoma (p = 0.01) and reduced in patients under dopamine agonist (p < 0.01) or somatostatin analogue (p < 0.05) treatment. CONCLUSIONS: Intracranial ICA changes are common findings in acromegaly, and further studies focused on their possible clinical impact are needed. PMID- 24068455 TI - Reversible pituitary insufficiency due to bexarotene therapy in a patient with mycosis fungoides. PMID- 24068456 TI - Prevalence of obstructive sleep apnea in patients with prolactinoma before and after treatment with dopamine agonists. AB - OBJECTIVES: Obesity is the main risk factor for the development of obstructive sleep apnea (OSA). Hyperprolactinemia has also been related to obesity. To determine the OSA prevalence in patients with prolactinoma before and after dopamine agonist (DA) and to evaluate the correlation between the apnea-hypopnea index (AHI) and prolactin levels, body mass index (BMI), waist circumference (WC), visceral fat volume (VFV), subcutaneous fat volume, and other metabolic parameters. METHODS: Thirty-five patients with prolactinoma at baseline and twenty-one who completed the 6-month DA treatment were submitted to clinical/laboratorial evaluations, polysomnography and abdominal imaging. RESULTS: Before treatment, the prevalence of obesity/overweight and OSA were, respectively, 68.5 and 34.2 %. We found a positive correlation between AHI and weight (r = 0.57; p < 0.001), BMI (r = 0.56; p < 0.001), WC (r = 0.61; p < 0.001), VFV (r = 0.55; p = 0.002), insulin levels (r = 0.57; p < 0.001), and HOMA IR index (r = 0.57; p < 0.001); and a negative correlation between AHI and HDL cholesterol (r = -0.47; p = 0.005). After multivariate analysis, VFV and insulin levels were the most important predictors for AHI (p = 0.001 and p = 0.02, respectively). After DA, the obesity/overweight and OSA prevalence did not change. CONCLUSIONS: The OSA prevalence in patients with prolactinoma is similar to the obese subjects and did not change after treatment. Higher BMI and visceral obesity, but not prolactin levels, seem to be the major factor involved in the occurrence of OSA in these patients. PMID- 24068458 TI - Synthesis of novel 3-allylseleno-6-alkylthiopyridazines: their anticancer activity against MCF-7 cells. AB - A new series of 3-allylseleno-6-alkylthiopyridazines 6a-6g was synthesized by two synthetic routes from 3,6-dichloropyridazine to develop new anticancer agents. These new compounds showed antiproliferative activities against breast cancer (MCF-7) cells in CCK-8 assays, and could be promising candidates for chemotherapy of carcinomas. Compound 6e (3-allylseleno-6-pentylthiopyridazine) showed higher potency than 5FU for inhibiting the growth of these cell lines. This suggests the potential anticancer activity of compound 6e. PMID- 24068457 TI - Bereavement and complicated grief. AB - Bereavement is a common experience in adults aged 60 and older. Loss of a loved one usually leads to acute grief characterized by yearning and longing, decreased interest in ongoing activities, and frequent thoughts of the deceased. For most, acute grief naturally evolves into a state of integrated grief, where the bereaved is able to reengage with everyday activities and find interest or pleasure. About 7 % of bereaved older adults, however, will develop the mental health condition of Complicated Grief (CG). In CG, the movement from acute to integrated grief is derailed, and grief symptoms remain severe and impairing. This article reviews recent publications on the diagnosis of CG, risk factors for the condition and evidenced-based treatments for CG. Greater attention to CG detection and treatment in older adults is needed. PMID- 24068459 TI - Pediatric non-alcoholic fatty liver disease: an increasing public health issue. AB - Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition that encompasses a wide spectrum of liver abnormalities ranging from simple liver steatosis to steatohepatitis (non-alcoholic steatohepatitis), which may be associated with fibrosis and progress to cirrhosis and end-stage liver disease. NAFLD has recently become the most common cause of chronic liver disease in children and adolescents. NAFLD prevalence, alongside obesity, continues to increase among pediatric patients. Obesity is believed to represent a major risk factor for NAFLD, which is considered to be the liver presentation of the metabolic syndrome. Although the pathogenesis of NAFLD is not fully understood, the notion that multiple factors affect disease development and progression is widely accepted. Both genetic background and environmental factors contribute to NAFLD development. A more complete understanding of the pathogenesis may aid in developing non-invasive diagnostic tools and identifying new therapeutic targets. Liver biopsy currently remains the gold standard for NAFLD diagnosis and staging. Although lifestyle and diet modifications are key in NAFLD treatment, the development of new pharmacological therapies is crucial for patients who are unresponsive to first-line therapy. CONCLUSION: Pediatric NAFLD is an increasing public health issue that remains underdiagnosed. A large-scale screening in the high-risk population, especially among the overweight pediatric patients, should be considered, including measurement of serum transaminases and liver ultrasound. It is crucial to treat this condition as soon as possible in order to avoid the progression to end-stage liver disease. PMID- 24068460 TI - Maternal gene polymorphisms involved in folate metabolism and the risk of having a Down syndrome offspring: a meta-analysis. AB - Down syndrome (DS) is the most common chromosomal abnormality. Many studies have assessed the association between maternal gene polymorphisms involved in folate metabolism and the risk of having a DS offspring, but data are conflicting. Our study aimed to arrive at a more accurate estimation. Therefore, we carried out a meta-analysis of 26, 17, 9, 15, 9 and 6 case-control studies on the relationship between maternal methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, methionine synthase reductase (MTRR) A66G, reduced folate carrier 1 A80G and cystathionine beta-synthase 844ins68 polymorphisms and the risk of having a DS offspring. The allele contrast and model-free approach were used. Results showed marginal significant associations for MTHFR C677T, overall [odds ratio (OR) = 1.28 (1.22, 1.46) and generalised odds ratio (ORG) = 1.35 (1.16, 1.57)] and in Caucasian [OR = 1.15 (1.03, 1.29) and ORG = 1.20 (1.04, 1.38)], Asian [OR = 1.68 (1.08, 2.63) and ORG = 1.74 (1.08, 2.80)] and Brazilian [OR = 1.22 (1.04, 1.43) and ORG = 1.28 (1.06, 1.55)] populations; for MTRR A66G, overall [OR = 1.22 (1.02, 1.46) and ORG = 1.31 (1.06, 1.62)]; and for RFC1 A80G, overall [OR = 1.16 (1.02, 1.31) and ORG = 1.18 (1.01, 1.37)]. MTHFR A1298C, MTR 12756G and CBS 844ins68 polymorphisms produced non significant results. Since potential confounders could not be ruled out completely in this meta-analysis, further studies are needed to confirm these results. PMID- 24068461 TI - Golgi's way: a long path toward the new paradigm of the intra-Golgi transport. AB - The transport of proteins and lipids is one of the main cellular functions. The vesicular model, compartment (or cisterna) maturation model, and the diffusion model compete with each other for the right to be the paradigm within the field of the intra-Golgi transport. These models have significant difficulties explaining the existing experimental data. Recently, we proposed the kiss-and-run (KAR) model of intra-Golgi transport (Mironov and Beznoussenko in Int J Mol Sci 13(6):6800-6819, 2012), which can be symmetric, when fusion and fission occur in the same location, and asymmetric, when fusion and fission take place at different sites. Here, we compare the ability of main models of the intra-Golgi transport to explain the existing results examining the evidence in favor and against each model. We propose that the KAR model has the highest potential for the explanation of the majority of experimental observations existing within the field of intracellular transport. PMID- 24068462 TI - Breast milk lead concentrations of mothers living near tin smelters. AB - We compared Pb concentration in human milk from 37 mothers living in a neighborhood of tin-ore smelters to that from 45 mothers living in a fishing community. The median breast-milk-Pb (BM-Pb) concentration was significantly (p = 0.0000001) higher (11.3 MUg L(-1); <=0.96-29.4 MUg L(-1)) in mothers living in the vicinity of smelters than that of rural mothers (1.9 MUg L(-1); <=0.96-20.0 MUg L(-1)). These mothers also showed a statistically significant correlation between length of residence and BM-Pb concentration (Spearman r = 0.6864; p < 0.0001). The estimated median exposure (for infants <6 months) was 3.0 MUg kg(-1) b.w. for rural infants compared to 7.5 MUg kg(-1) b.w. for infants in the vicinity of metal smelters. Overall, most BM-Pb concentrations (79 %) in the metal smelter area were above the critical limit of 5.0 MUg L(-1) set by the WHO. PMID- 24068463 TI - Spatial-based assessment of heavy metal contamination in agricultural soils surrounding a non-ferrous metal smelting zone. AB - This work aimed to assess the degree of anthropogenic influence and severity of heavy metal from a non-ferrous metal smelting industrial zone. The results suggested that anthropogenic inputs played a dominant role in the enrichment of Cu, Zn, Pb, Sb and Cd. These metals showed similar spatial distribution patterns. Multivariate analysis showed strongly significant relationships between Cu-Zn,Cd Zn, Cd-Sb, Sb, Sb, Cu, Zn, and Pb. Strong relationship was found between Cr, Ni, Cu, Zn, Sb and organic matter in soil. Risk evaluation results within the soil investigated profile was in the following order: Cd > Sb > Cu > Zn > Pb. Nemerow's synthetical contamination index revealed that there is substantial ecotoxicological risk among the sampling sites with 8 of 9 of these locations exceeding the Nemerow criteria for seriously impacted sites and another site was close to moderately polluted domain. PMID- 24068464 TI - Effect of perfluorooctane sulfonate on the conformation of wheat germ acid phosphatase. AB - Fluorescence spectroscopy was used to study the quenching mechanism, the type of force and the binding sites of perfluorooctane sulfonate (PFOS) on wheat germ acid phosphatase (ACPase). The results showed that the quenching effect of PFOS on ACPase was mainly due to a static quenching mechanism that occurred via the formation of hydrogen bonds and van der Waals forces. The results from synchronous fluorescence spectroscopy demonstrated that PFOS interacts with ACPase close to the tryptophan residues. In addition, synchronous fluorescence spectroscopy also showed that PFOS increases the hydrophobicity of the microenvironment of the tyrosine residues, hence decreasing the local polarity. PMID- 24068465 TI - Surface water-borne multidrug and heavy metal-resistant Staphylococcus isolates characterized by 16S rDNA sequencing. AB - Four Staphylococcus isolates having both multidrug- and multimetal-resistant ability were isolated from surface water. Further identification of the isolates was obtained through biochemical tests and 16S rDNA gene sequencing. One methicillin-resistant and two methicillin-sensitive isolates were determined as Staphylococcus aureus. The other isolate was identified as Staphylococcus warneri. The antibiotic and heavy metal resistance profiles of the Staphylococcus isolates were determined by using 26 antibiotics and 17 heavy metals. S. aureus isolates displayed resistance to most of the beta-lactam antibiotics tested. All Staphylococcus isolates were resistant to heavy metals including silver, lithium, and barium. Due to a possible health risk of these pathogenic bacteria, a need exists for an accurate assessment of their acquired resistance to multiple drugs and metals. PMID- 24068466 TI - Effects of sublethal copper concentrations on gills of white shrimp (Litopenaeus vannamei, Boone 1931). AB - The objective of this study was to measure the copper (Cu) concentration in gills of juveniles Litopenaeus vannamei after exposure to Cu at sublethal concentrations, and to evaluate its effect upon the structure of gill tissue. The Cu concentration in gills of control shrimp was 0.075 mg/kg. Copper concentrations increased significantly by 147 %, 180 % and 205 % in gills of shrimp exposed to 0.675, 1.325 and 2.010 mg Cu/L, respectively. After exposure to 0.675 mg Cu/L for 15 days, gill tissue hyperplasia was observed, with a narrowing of the hemolymphatic lacunae. Necrosis and loss of hemolymphatic lacunae were observed at exposures of 1.325 and 2.010 mg Cu/L. PMID- 24068467 TI - Determination of copper pollution and associated ecological risk in coastal sediments of southeastern Black Sea region, Turkey. AB - In this study, the natural and anthropogenic copper (Cu) pollution in coastal sediments near the city Trabzon which exhibits an increasing population and industrial activity in the Southeastern Black Sea Region, were investigated spatially and temporally. The sediment along the coast of Trabzon is influenced by three rivers called Degirmendere, Yanbolu and Solakli resulting in a spatial separation. The highest Cu sediment concentration was measured in the section influenced by Solakli (88.07 MUg g(-1)) and the lowest at the sites affected by Yanbolu (56.86 MUg g(-1)). Also a strong temporal trend was observed displaying the highest Cu concentration in autumn (107.06 MUg g(-1)) and the lowest in spring (52.06 MUg g(-1)). Based upon the results of this study and; according to the Sediment Quality Guideline, Cu is the major contributor to toxicity in the coastal zones of all regions. PMID- 24068468 TI - Mouthparts of southern leopard frog, Lithobates sphenocephalus, tadpoles not affected by exposure to a formulation of glyphosate. AB - This study evaluated the impacts of Roundup(r) on tadpole mouthpart damage as a mechanism for reduced growth and developmental rates in Lithobates sphenocephalus (Southern leopard frog) tadpoles. We did not find evidence that Roundup((r)) damages larval mouthparts, nor was there a significant relationship between mouthpart damage and either body condition or developmental rate. However, the highest concentration of Roundup(r) significantly stunted development compared to all other treatments. Although we observed a significant effect of Roundup(r) on developmental rate, we conclude that mouthpart damage is likely not a mechanism for this life history response. PMID- 24068469 TI - Lemurs and macaques show similar numerical sensitivity. AB - We investigated the precision of the approximate number system (ANS) in three lemur species (Lemur catta, Eulemur mongoz, and Eulemur macaco flavifrons), one Old World monkey species (Macaca mulatta) and humans (Homo sapiens). In Experiment 1, four individuals of each nonhuman primate species were trained to select the numerically larger of two visual arrays on a touchscreen. We estimated numerical acuity by modeling Weber fractions (w) and found quantitatively equivalent performance among all four nonhuman primate species. In Experiment 2, we tested adult humans in a similar procedure, and they outperformed the four nonhuman species but showed qualitatively similar performance. These results indicate that the ANS is conserved over the primate order. PMID- 24068470 TI - Regulated medical fee schedule of the Japanese health care system. AB - This study presents a theoretical framework for examining the effect of the Japanese government-regulated medical price schedule, 'Shinryo-Houshu-Seido,' on the behavior of medical providers. In particular, we discuss the optimal rule of this price schedule for the regulator, taking into account information asymmetry between the regulator and providers. Our simple model predicts that heterogeneous providers either under-provide or over-provide medical inputs in comparison with the socially optimal outcome. Moreover, our results show that when the allocated budget is reduced to a certain level, even the second-best outcome becomes unachievable, no matter how the price schedule is regulated. While the limited budget size is shown to have a clear negative effect on social welfare, we suggest that the prospect of obtaining the second-best outcome is left to negotiation between the regulator and the budget allocator. PMID- 24068472 TI - Prenatal origins of bronchiolitis: protective effect of optimised asthma management during pregnancy. AB - OBJECTIVE: Maternal asthma is the most common chronic disease complicating pregnancy and is a risk factor for bronchiolitis in infancy. Recurrent episodes of bronchiolitis are strongly associated with the development of childhood asthma. METHODS: We conducted a follow-up study of infants born to women with asthma who completed a double-blind randomised controlled trial during pregnancy. In this trial, pregnant women with asthma were assigned to treatment adjustment by an algorithm using clinical symptoms (clinical group) or the fraction of exhaled nitric oxide (FeNO group) and we showed that the FeNO group had significantly lower asthma exacerbation rates in pregnancy. RESULTS: 146 infants attended the 12-month follow-up visit. Infants born to mothers from the FeNO group were significantly less likely to have recurrent episodes of bronchiolitis in the first year of life (OR 0.08, 95% CI 0.01 to 0.62; p=0.016) as compared with the clinical group. CONCLUSIONS: Optimised management of asthma during pregnancy may reduce recurrent episodes of bronchiolitis in infancy, which could potentially modulate the risk to develop or the severity of emerging childhood asthma. PMID- 24068473 TI - DNA-binding studies and antitumor evaluation of novel water soluble organic pip and hpip analogs. AB - Two new water-soluble pip and hpip analogs, 1 and 2 pip = 2-phenylimidazo[4,5 f][1, 10]phenanthroline; hpip = 2-(2-hydroxyphenyl)imidazo[4,5-f][1, 10]phenanthroline, have been synthesized and fully characterized by CHN analysis, MALDI-TOF MS, (1)H-NMR, IR (ATR), and UV-Vis methods. The DNA-binding behaviors of both compounds have been studied by viscosity measurements, spectroscopic methods, and gel electrophoresis studies, and potential for antitumor activity was evaluated by measuring their ability to inhibit DNA transcription. The results indicate that both compounds show some strong binding to DNA in a mixture of electrostatic and intercalative mode resulting in the intrinsic binding constants Kb of (4.0 +/- 0.5) * 10(5) M(-1) and (7.5 +/- 0.5) * 10(5) M(-1) for 1 and 2, respectively. These strong binding affinities for DNA are comparable for that seen for many transition metal-based intercalators. Comparatively, observed difference in the DNA-binding affinities of two complexes can be reasonably explained by the presence of an intra-molecular hydrogen-bonding between the ortho-phenolic group and the nitrogen atom of the imidazole ring. The extended co planarity of 2 due to the intramolecular hydrogen bonding may lead to an enhancement of DNA binding affinity of 2. In addition, 2 can promote cleavage of pBR322 DNA upon irradiation, it inhibits DNA transcription and it is more cytotoxic at lower concentrations in comparison to 1, as revealed by the spectroscopic measurements. PMID- 24068474 TI - Suramin is a novel activator of PP5 and biphasically modulates S100-activated PP5 activity. AB - Suramin is an activator of ryanodine receptors and competitively binds to the calmodulin-binding site. In addition, S100A1 and calmodulin compete for the same binding site on ryanodine receptors. We therefore studied the effects of suramin on protein phosphatase 5 (PP5) and S100-activated PP5. In the absence of S100 proteins, suramin bound to the tetratricopeptide repeat (TPR) domain of PP5 and activated the enzyme in a dose-dependent manner. In the presence of S100A2/Ca(2+), lower concentrations of suramin dose-dependently inhibited PP5 activity as an S100 antagonist, whereas higher concentrations of suramin reactivated PP5. Although the C-terminal fragment of heat shock protein 90 (HspC90) also weakly activated PP5, the binding site of suramin and HspC90 may be different, and addition of suramin showed no clear effect on the phosphatase activity of PP5. Similar biphasic effects of suramin were observed with S100A1-, S100B- or S100P-activated PP5. However, the inhibitory effects of lower concentrations of suramin on S100A6-activated PP5 are weak and high concentrations of suramin further activated PP5. SPR and the cross-linking study showed inhibition of the interaction between S100 protein and PP5 by suramin. Our results revealed that suramin is a novel PP5 activator and modulates S100 activated PP5 activity by competitively binding to the TPR domain. PMID- 24068475 TI - Susceptibility against grey blight disease-causing fungus Pestalotiopsis sp. in tea (Camellia sinensis (L.) O. Kuntze) cultivars is influenced by anti-oxidative enzymes. AB - Reactive oxygen species (ROS) production is the first level of response by a host during stress. Even though the ROS are toxic to cell, when present in a limited amount, they act as a signalling molecule for the expression of defence-related genes and later are scavenged by either enzymatic or non-enzymatic mechanisms of the host. The different anti-oxidative enzymes like glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APO), peroxidase (POD) and polyphenol oxidase (PPO) were estimated, and their activities were compared between infected and healthy leaves of the tolerant and susceptible cultivars of tea. The infected leaves of the susceptible cultivars registered higher amount of enzyme activity when compared with the tolerant cultivars. The study reveals that the more anti-oxidative enzymes, the more susceptible the cultivar will be. PMID- 24068476 TI - Effect of operating conditions in production of diagnostic Salmonella Enteritidis O-antigen-specific monoclonal antibody in different bioreactor systems. AB - In this study, different cultivation systems such as roller bottles (RB), 5-L stirred-tank bioreactor (STR), and disposable bioreactors were used to cultivate hybridoma for lab-scale production of Salmonella Enteritidis O-antigen-specific monoclonal antibody (MAb). Hybridoma cell line was cultivated in either serum containing or serum-free medium (SFM) culture conditions. In STR, MAb production scaled up to 4 L, and production capabilities of the cells were also evaluated in different featured production systems. Moreover, the growth parameters of the cells in all production systems such as glucose consumption, lactate and ammonia production, and also MAb productivities were determined. Collected supernatants from the reactors were concentrated by a cross-flow filtration system. In conclusion, cells were not adapted to SFM in RB and STR. Therefore, less MAb titer in both STR and RB systems with SFM was observed compared to the cultures containing fetal bovine serum-supplemented medium. A higher MAb titer was gained in the membrane-aerated system compared to those in STR and RB. Although the highest MAb titer was obtained in the static membrane bioreactor system, the highest productivity was obtained in STR operated in semicontinuous mode with overlay aeration. PMID- 24068477 TI - Reversible immobilization of urease by using bacterial cellulose nanofibers. AB - In this work, bacterial cellulose nanofibers were produced by using the Gluconacetobacter hansenii HE1 strain. These nanofibers were derivatized with dye affinity ligand Reactive Green 5, and these newly synthesized dye-attached nanofibers were used for affinity adsorption of urease. Reactive Green 5-attached nanofibers were characterized by Fourier transform infrared spectroscopy, SEM, and energy-dispersive x-ray spectroscopy analysis. Some adsorption conditions which significantly affect the adsorption efficiency were investigated. The maximum urease adsorption capacity was found to be 240 mg/g nanofiber in pH 6.0 and at room temperature. Dye-free plain nanofibers also used for studying nonspecific urease adsorption onto plain nanofibers and nonspecific adsorption were found to be negligible (3.5 mg/g nanofiber). Prepared dye-attached nanofibers can be used in five successive adsorption/desorption steps without any decrease in their urease adsorption capacity. The desorption rate of the adsorbed urease was found to be 98.9 %. The activity of the urease was also investigated, and it was found that free and desorbed urease from the dye-attached nanofibers showed similar specific activity. PMID- 24068478 TI - Identification of site-specific degradation in bacterially expressed human fibroblast growth factor 4 and generation of an aminoterminally truncated, stable form. AB - Fibroblast growth factor 4 (FGF4) is considered as a crucial gene for tumorigenesis in humans and the development of mammalian embryos. The secreted, mature form of human FGF4 is thought to be comprised of 175 amino acid residues (proline(32) to leucine(206), Pro(32)-Leu(206)). Here, we found that bacterially expressed, 6* histidine (His)-tagged human FGF4 (Pro(32)-Leu(206)) protein, referred to as HishFGF4, was unstable such as in phosphate-buffered saline. In these conditions, site-specific cleavage, including between Ser(54) and Leu(55), in HishFGF4 was identified. In order to generate stable human FGF4 derivatives, a 6* His-tagged human FGF4 (Leu(55)-Leu(206)), termed HishFGF4L, was expressed in Escherichia coli. HishFGF4L could be purified from the supernatant of cell lysates by heparin column chromatography. In phosphate-buffered saline, HishFGF4L was considered as sufficiently stable. HishFGF4L exerted significant mitogenic activities in mouse embryonic fibroblast Balb/c 3T3 cells. In the presence of PD173074, an FGF receptor inhibitor, the growth-stimulating activity of HishFGF4L disappeared. Taken together, we suggest that HishFGF4L is capable of promoting cell growth via an authentic FGF signaling pathway. Our study provides a simple method for the production of a bioactive human FGF4 derivative in E. coli. PMID- 24068479 TI - Reliability of therapist self-report on treatment targets and focus in family based intervention. AB - Reliable therapist-report methods appear to be an essential component of quality assurance procedures to support adoption of evidence-based practices in usual care, but studies have found weak correspondence between therapist and observer ratings of treatment techniques. This study examined therapist reliability and accuracy in rating intervention target (i.e., session participants) and focus (i.e., session content) in a manual-guided, family-based preventive intervention implemented with 50 inner-city adolescents at risk for substance use. A total of 106 sessions selected from three phases of treatment were rated via post-session self-report by the participating therapist and also via videotape by nonparticipant coders. Both groups estimated the amount of session time devoted to model-prescribed treatment targets (adolescent, parent, conjoint) and foci (family, school, peer, prosocial, drugs). Therapists demonstrated excellent reliability with coders for treatment targets and moderate to high reliability for treatment foci across the sample and within each phase. Also, therapists did not consistently overestimate their degree of activity with targets or foci. Implications of study findings for fidelity assessment in routine settings are discussed. PMID- 24068480 TI - Analysis of the expression of p53 during the morphogenesis of the gastroesophageal mucosa of Gallus gallus domesticus (Linnaeus, 1758). AB - Ontogenesis comprises a series of events including cell proliferation and apoptosis and resulting in the normal development of the embryo. Protein p53 has been described as being involved in the development of several animal species. The aim of this study was to analyze the expression of protein p53 during the morphogenesis of the gastroesophageal mucosa of Gallus gallus domesticus and to correlate it with the histogenesis of structures present in this tissue. We used 24 embryos (at 12-20 days of incubation) and the thymus of two chickens. Immunohistochemical analysis was performed with the ABC indirect method. The expression of p53 in the gastroesophageal mucosa increased during the formation of the organ, mainly at the stages during which tissue remodeling and cell differentiation began. In the esophagus at stages 42 and 45, we observed immunoreactive (IR) cells in the surface epithelium and in early esophageal glands. In the proventriculus at stages 39-45, IR cells were present in the epithelial mucosa and rarely in the proventricular glands. In the gizzard after stage 42, we found IR cells mainly in the medial and basal epithelial layers of the mucosa and especially within the intercellular spaces that appeared at this phase and formed the tubular gland ducts. Thus, protein p53 occurs at key stages of development: in the esophagus during the remodeling of esophageal glands, in the proventriculus during the differentiation of the epithelium of the mucosa and in the gizzard during the formation of tubular glands. PMID- 24068481 TI - Epidemiology and clinical characteristics of chronic daily headache in a clinic based cohort of Iranian population. AB - Although CDH is a major health care problem encountered in headache clinics, our knowledge about the epidemiological features of CDH is limited in developing countries. The objective of this study was to survey the frequency and clinical features of chronic daily headache (CDH) and its subtypes among Iranian population presenting to a referral tertiary Headache clinic in a University Hospital. This cross-sectional survey was carried out between September 2011 and March 2012. Data of patients with CDH including their age, sex, educational level, and marital status were recorded using structured face-to-face interview. Subtypes of the CDH were determined by history, physical examination and appropriated laboratory or imaging findings. A total number of 177 cases (32.71%) fulfilled the CDH criteria. The frequency of CDH was higher in 40-49 age groups (n = 54) and among women with a female to male ratio of 2.12/1. Chronic migraine was the most common subtype of CDH in 75 cases (44.4%). Chronic tension-type headache and secondary causes were second and third frequent subtypes of CDH in 27.8 and 20.1% of cases, respectively. Cervicogenic headaches (10.7%) and medication overuse headache (4.1%) were the most common causes of secondary headaches. The present study confirmed previous findings which showed a high prevalence of CDH and chronic migraine in clinic setting, with preponderance for women. In addition, we found the highest prevalence of cervicogenic headaches among secondary causes of CDH. PMID- 24068482 TI - Scientific research of Italian neurologists from 2008 to 2011. AB - Quantifying the number of publications is the easiest way to estimate the scientific production of a country in any scientific field. The aim of this article is to provide information about the scientific production from 2008 to 2011 of Italian neurologists and to compare it with scientific production data of other countries. The analysis regarded the research in Web of Science, in the Subject Category Clinical Neurology, of the publications published from 2008 to 2011, with at least one Italian author belonging to a scientific Italian institution. The overall data, their quality and scientific impact were compared with those of the first 15 world countries for scientific production. We observed that even if the Gross National Product of Italy registered a slight and gradual reduction from 2008 to 2011, the neurological scientific production of Italian neurologists showed an increase in the number of papers, maintaining the fifth position in these four years after USA, Germany, England and Japan. Moreover, dividing the neurological journals in quartiles according to the impact factor, we observed constant increase of the numbers of Italian publications in the highest quartile journals during the considered period. These data suggest that from 2008 to 2011 Italian neurologists have increased the number of publications, also improving the quality of works. PMID- 24068483 TI - Vertebral artery dissection during Kung-Fu training. PMID- 24068484 TI - Bilateral sequential audiovestibular loss as an initial manifestation of chronic myelogenous leukemia. PMID- 24068486 TI - Video feedforward for rapid learning of a picture-based communication system. AB - This study examined the efficacy of video self modeling (VSM) using feedforward, to teach various goals of a picture exchange communication system (PECS). The participants were two boys with autism and one man with Down syndrome. All three participants were non-verbal with no current functional system of communication; the two children had long histories of PECS failure. A series of replications, with different length baselines, was used to examine whether video self modeling could replace the PECS method of teaching to achieve the same goals. All three participants showed rapid learning of their target behavior when introduced to their self modeling videos, and effects generalized without the need for further intervention. We conclude that VSM, using feedforward, can provide a fast, simple way of teaching the use of a picture-based communication system without the need for prompts or intensive operant conditioning. VSM may provide an accessible, easy-to-use alternative to common methods of teaching augmentative and alternative communication systems. PMID- 24068485 TI - Leukoencephalopathy due to oral methotrexate. AB - Methotrexate (MTX) is considered the main agent for the treatment of rheumatoid arthritis (RA). Neurotoxicity is often mild, but severe encephalopathy can develop, especially with intrathecal or intravenous administration. In rare cases, this syndrome has been observed in patients on long-term low-dose oral administration. A 68-year-old male was diagnosed with RA and on treatment with oral MTX 25 mg weekly for 4 years. The patient started with progressive dysarthria, ataxia and cognitive dysfunction. Complementary tests were normal. Magnetic resonance imaging (MRI) showed hyperintense lesions in both cerebellar hemispheres on T2-weighted and FLAIR images with a diffusion restriction on diffusion-weighted imaging (DWI) and on the apparent diffusion coefficient map (ADC). On postgadolinium T1-weighted images, there were mild enhancements. Spectroscopy showed a demyelinating pattern. A pharmacogenetics determination was made, showing a heterozygous genotype in the MTHFR and ABCB1 genes. Medication with antirheumatic drug was stopped immediately on admission, and the patient gradually improved. MTX-induced leukoencephalopathy can occur even with low-dose administration. The exact pathogenic mechanism is still unknown, but it is hypothesised that it could be the result of a cumulative toxic effect on the blood-brain barrier. The nature of the relationship between the polymorphism and CNS toxicity is still unclear, and thus, further studies are warranted. Often located in the occipital lobes, the involvement of the cerebellum is quite rare. Early recognition of the condition and withdrawal of the drug lead to a better prognosis. PMID- 24068487 TI - A single bout of downhill running transiently increases HOMA-IR without altering adipokine response in healthy adult women. AB - PURPOSE: Eccentric exercise-induced muscle damage may cause marked alterations in insulin sensitivity. However, it is not entirely known whether such alterations are also related to changes in adipokine levels. The aim of this study was to investigate the effects of muscle damage due to downhill running on inflammation, insulin sensitivity and selected adipokines related to insulin regulation (adiponectin, visfatin, resistin). METHODS: Data were collected from 12 healthy adult women. Each subject participated in two trials, 4 weeks apart. The first trial was reserved for resting measurements only (control trial), while the second trial involved a 45-min exercise (-15 % slope, ~60 % of VO2max) intervention (exercise trial). Insulin sensitivity (HOMA), creatine kinase activity (CK), delayed onset muscle soreness (DOMS), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), glucose, insulin, adiponectin, resistin, and visfatin were assessed pre-exercise and 1, 2, 3, and 4 days post-exercise and during the same time points in the control trial. RESULTS: Analyses revealed that CK, DOMS, TNF-alpha, IL-6, insulin and HOMA significantly increased (p < 0.05) throughout recovery (days 1-4). Adiponectin and visfatin remained unchanged, while resistin significantly increased (p < 0.05) only 2 days post-exercise. Visfatin was negatively correlated with HOMA at days 1 and 4 of recovery. CONCLUSION: Although muscle damage due to downhill running caused a decline of insulin sensitivity, this response was not associated with the changes in adipokine levels. PMID- 24068488 TI - NAA-SLR and ICP-AES application in the assessment of mass fraction of 19 chemical elements in pediatric and young adult prostate glands. AB - The effect of age on the mass fraction of 19 chemical elements in the intact prostate of 50 apparently healthy 0-30-year-old males was investigated by neutron activation analysis with high-resolution spectrometry of short-lived radionuclides and inductively coupled plasma atomic emission spectrometry. Mean values (M +/- standard error of the mean) for mass fraction (in milligrams per kilogram, on dry weight basis) of chemical elements were as follows: Al, 77 +/- 17; B, 1.31 +/- 0.29; Ba, 4.0 +/- 1.2; Br, 37.7 +/- 4.3; Ca, 1,536 +/- 189; Cl, 13,414 +/- 949; Cu, 12.3 +/- 2.1; Fe, 132 +/- 11; K, 11,547 +/- 468; Li, 0.064 +/ 0.009; Mg, 922 +/- 89; Mn, 1.88 +/- 0.16; Na, 9,834 +/- 411; P, 6,741 +/- 335; S, 8,034 +/- 251; Si, 199 +/- 34; Sr, 1.40 +/- 0.19; and Zn, 277 +/- 33. The upper limit of mean mass fraction of V was <=0.24. This work revealed that there is significant tendency for the mass fractions of Ca, K, Mg, and Zn in the prostate tissue of healthy individuals to increase with age from the time of birth up to 30 years. It means that Ca, K, Mg, and Zn mass fractions in prostate tissue are the androgen-dependent parameters. Our finding of a positive correlation between the prostatic Zn and Ca, K, Mg, P, and S mass fractions indicates that there is a special relationship of Zn with some main electrolytes (Ca, K, and Mg) and with P- and S-containing compounds in the prostate. It was shown also that high levels of Al, B, Ba, Br, Cl, Li, Na, and Sr mass fraction in prostate tissue do not indicate a direct involvement of these elements in the reproductive function of the prostate. PMID- 24068490 TI - Effect of various remineralising agents on human eroded enamel of primary teeth. AB - AIM: To determine the effect of three remineralising agents on human primary anterior teeth, i.e. CPP-ACP, CPP-ACPF, fluoridated toothpaste and artificial saliva as control. STUDY DESIGN: Forty primary maxillary anterior teeth were divided into four groups: Group I: CPP-ACP, Group II: CPP-ACPF and Group III: fluoridated toothpaste as experimental and Group IV: artificial saliva as control. The samples were immersed in cola soft drink and artificial saliva for 10 cycles of 5 s each. After erosive procedure, a thin layer of CPP-ACP, CPP-ACPF or fluoridated toothpaste were applied to the tooth surfaces for 3 min, and kept in artificial saliva for 8 h. Samples in the control group were directly kept in artificial saliva without any treatment. The Knoop microhardness of the labial surface of enamel was measured at baseline, after erosion and after the remineralisation procedures. RESULTS: No significant differences were observed among the different groups at pre-erosion and post-erosion intervals. However, after remineralisation, mean microhardness in different groups was significantly higher in Group II as compared to all the other groups (p < 0.001). Group IV had significantly lower mean microhardness as compared to all the other groups (p < 0.001). STATISTICS: The collected data were statistically analysed using ANOVA test followed by Tukey's HSD test as the post-hoc tests to compare the differences in mean microhardness at different time intervals. Paired t test was used to assess the change in mean microhardness within a group. CONCLUSION: CPP ACPF showed the best remineralisation potential. PMID- 24068489 TI - Aetiology of supernumerary teeth: a literature review. AB - BACKGROUND: Supernumerary teeth are teeth, or tooth-like structures that have either erupted or remain unerupted in addition to the 20 primary and 32 permanent teeth. AIMS: This paper attempts to (a) provide an overview of the proposed hypotheses and the current understanding of the aetiology of supernumerary teeth, and (b) review the published cases of supernumerary teeth occurring in families. REVIEW: No studies have been able to distinguish between different aetiologies for the different locations of supernumerary teeth, while, from a developmental or molecular perspective, the proposed hypotheses may be plausible and explains the origin of different types of supernumerary teeth. CONCLUSION: The only clearly evident feature, based on the existing published reports, is that it is logical to state that supernumerary teeth have a genetic component in their aetiology. PMID- 24068491 TI - Oral health care in children with haemophilia in Helsinki, Finland. AB - BACKGROUND: The bleeding tendency and fear of bleeds may have a negative effect on preventive dental care of patients with haemophilia both at home and at dental appointments. AIM: To describe the clinical practice of dental care in children with haemophilia in Helsinki, Finland. METHODS: This study evaluated retrospectively the medical records of 28 paediatric patients with haemophilia (aged 5.3-17.4 years) from dental visits during 2009-2010. Decayed, missing and filled teeth in the primary (dmft) and permanent dentition (DMFT), Community Periodontal Index (CPI), signs of developmental dental defects in enamel and the number of preventive and restorative procedures were gathered. Dmft + DMFT scores were compared with those of 17,079 non-haemophiliac boys. The Mann-Whitney U-test was used to compare the data between the groups of different severity of haemophilia. RESULTS: The median number of dental visits per patient was three (range 1-11). Twenty-two patients (79 %) had dmft + DMFT-scores within the 95 % reference range for age. None of the children had a CPI >2. Twelve (43 %) patients had developmental enamel defects. Half had received restorative dental care and three out of four preventive procedures. CONCLUSIONS: Dental care during hospital visits in children with haemophilia may enhance confidence in the preventive dental care and help minimise bleeding during dental procedures. PMID- 24068492 TI - JAK2 p.V617F detection and allele burden measurement in peripheral blood and bone marrow aspirates in patients with myeloproliferative neoplasms. AB - Detection of the JAK2 p.V617F mutation and measurement of its allele burden can be performed using both peripheral blood (PB) and bone marrow (BM) samples from patients with myeloproliferative neoplasms (MPNs). However, the diagnostic accuracy of detecting the JAK2 p.V617F mutation and quantifying its allele burden in PB and BM samples has not been systematically compared. We retrospectively analyzed 388 patients with MPN who had been tested for JAK2 p.V617F allele burden using both PB and BM samples within 3 months of each other. The sensitivity and specificity of detecting JAK2 p.V617F in PB when compared with BM were both 100%. Furthermore, the JAK2 p.V617F allele burden measured in PB and BM were equivalent by linear regression analysis (R(2) = 0.991; P < .0001). We therefore conclude that PB is a reliable source for testing for the JAK2 p.V617F mutation and quantifying its allele burden in patients with MPN. PMID- 24068493 TI - CD49d is overexpressed by trisomy 12 chronic lymphocytic leukemia cells: evidence for a methylation-dependent regulation mechanism. AB - CD49d is a negative prognosticator in chronic lymphocytic leukemia (CLL), expressed by ~40% of CLL cases and associated with aggressive, accelerated clinical courses. In this study, analyzing CD49d expression in a wide CLL cohort (n = 1200) belonging to different cytogenetic groups, we report that trisomy 12 CLL almost universally expressed CD49d and were characterized by the highest CD49d expression levels among all CD49d(+) CLL. Through bisulfite genomic sequencing, we demonstrated that, although CD49d(+)/trisomy 12 CLL almost completely lacked methylation of the CD49d gene, CD49d(-)/no trisomy 12 CLL were overall methylated, the methylation levels correlating inversely to CD49d expression (P = .0001). Consistently, CD49d expression was recovered in CD49d(-) hypermethylated CLL cells upon in vitro treatment with the hypomethylating agent 5-aza-2'-deoxycytidine. This may help explain the clinicobiological features of trisomy 12 CLL, including the high rates of cell proliferation and disease progression, lymph node involvement, and predisposition to Richter syndrome transformation. PMID- 24068495 TI - Full genome sequences and preliminary molecular characterization of three tick borne encephalitis virus strains isolated from ticks and a bank vole in Slovak Republic. AB - The full genome sequences of three tick-borne encephalitis virus strains, two isolated from Ixodes ricinus ticks and one from the brain of a bank vole, Myodes glareolus, originating from the Slovak Republic were determined. Nucleotide sequences were found to be very similar (>99.5 % nt-identity) with only one distinct amino acid (aa) difference to each other. They all shared 30 aa-changes when compared to type strain Neudoerfl, isolated in neighboring Austria. An internal poly(A)-stretch similar to that of strain Neudoerfl was found only in TBEV strain 114 from a tick. Despite this heterogeneity in the 3'-NCR, the high level of sequence identity was striking, indicating a low rate of nucleotide substitutions of TBEV strains in Slovakia and no obvious relation to the host species. PMID- 24068494 TI - Regulatory T cells and natural killer T cells for modulation of GVHD following allogeneic hematopoietic cell transplantation. AB - Alloreactivity of donor lymphocytes leads to graft-versus-host disease (GVHD) contributing to significant morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Within the past decade, significant progress has been made in elucidating the mechanisms underlying the immunologic dysregulation characteristic of GVHD. The recent discoveries of different cell subpopulations with immune regulatory function has led to a number of studies aimed at understanding their role in allogeneic HCT and possible application for the prevention and treatment of GVHD and a host of other immune-mediated diseases. Preclinical animal modeling has helped define the potential roles of distinct populations of regulatory cells that have progressed to clinical translation with promising early results. PMID- 24068496 TI - Biochemical characterization and high-level production of oxidized polyvinyl alcohol hydrolase from Sphingopyxis sp. 113P3 expressed in methylotrophic Pichia pastoris. AB - The Sphingopyxis sp. 113P3 gene oph, encoding oxidized polyvinyl alcohol hydrolase (OPH), was optimized with the preferred codons of Pichia pastoris and ligated into the pPIC9K vector behind the alpha-factor signal sequence. The vector was then transfected into P. pastoris GS115 and genomic integration was confirmed. Large-scale production of recombinant protein was performed by induction with 14.4 g/L methanol at 22 degrees C in a 3-L bioreactor. The maximal OPH activity obtained was 68.4 U/mL, which is the highest activity reported. The optimal pH and temperature of recombinant OPH were 8.0 and 45 degrees C, respectively. OPH activity was stable over a pH range of 5.0-8.5, and at a maximal temperature of 45 degrees C. The K cat /K m of recombinant OPH was 598 mM(-1) s(-1), which was 4.27-fold higher than that of recombinant OPH derived from Escherichia coli. The improved catalytic efficiency of OPH expressed in recombinant P. pastoris makes it favorable for industrial applications. PMID- 24068497 TI - Population dynamics of methanogens and methane formation associated with different loading rates of organic acids along with ammonia: redundancy analysis. AB - In anaerobic processes, the population dynamics of methanogens in the methanogenic stage were monitored along with hydraulic retention times (HRTs) shift. Decreasing HRTs increased the loading rates of volatile fatty acids (VFAs) and ammonia. Methanomicrobiales (MMB) began to be dominant at longer than 12.5 days HRT, Methanosarcinales (MSL) were dominant at 8, 10, and 12.5 days HRT, and Methanobacteriales (MBT) were dominant at shorter than 6 days HRT. Increased loading rates of VFAs and ammonia increased MBT, decreased MMB, and had no significant effect on MSL. Maximal daily methane production was observed at 1.57 L/L when MSL copy numbers also reached 3.60 * 10(7) copy/mL as a peak, which were expressed as positive correlation between DMA and MSL. No sooner had methane yield (MY) increased from 1.15 to 1.32 L/g VSremoved along with HRT reduction from 25 to 22.5 days, then MY gradually decreased from 1.32 to 0.04 L/g VSremoved. PMID- 24068498 TI - Sequence characterization and computational analysis of the non-ribosomal peptide synthetases controlling biosynthesis of lipopeptides, fengycins and bacillomycin D, from Bacillus amyloliquefaciens Q-426. AB - Lipopeptides secreted by bacteria attract interest because of their uses in biomedicine, biotechnology and food technology; however, harnessing their megasynthases (non-ribosomal peptide synthetases, NRPSs) has met with some difficulties in heterologous expression and crystallization. Here, we used similarity and phylogenetic analysis of NRPS sequences, including the fengycin and iturin family synthetases from Bacillus spp., and have developed a novel approach for delineating the length and boundaries of NRPS domains from Bacillus amyloliquefaciens strain Q-426. The sequences were further characterized (including specific residues and conserved motifs) that gave insight into the basis of the substrate specificity. Data from the prediction of the NRPS domains, obtained by the self-optimized prediction method with Alignment program, showed they are all structurally unstable, making it difficult to determine their crystal structures. PMID- 24068499 TI - Transmembrane routes of cationic liposome-mediated gene delivery using human throat epidermis cancer cells. AB - For studying the mechanism of cationic liposome-mediated transmembrane routes for gene delivery, various inhibitors of endocytosis were used to treat human throat epidermis cancer cells, Hep-2, before transfection with Lipofectamine 2000/pGFP N2 or Lipofectamine 2000/pGL3. To eliminate the effect of inhibitor toxicity on transfection, the RLU/survival rate was used to represent the transfection efficiency. Chlorpromazine and wortmannin, clathrin inhibitors, decreased transfection efficiency by 44 % (100 MUM) and 31 % (100 nM), respectively. At the same time, genistein, a caveolin inhibitor, decreased it by 30 % (200 MUM). Thus combined transmembrane routes through the clathrin and caveolae-mediated pathways were major mechanisms of cell uptake for the cationic liposome-mediated gene delivery. After entering the cells, microtubules played an important role on gene delivery as vinblastine, a microtubulin inhibitor, could reduce transfection efficiency by 41 % (200 nM). PMID- 24068500 TI - Generation of Rm21LG transgenic mice: a powerful tool to generate conditional overexpression of miR-21 that is involved in oncogenesis. AB - miR-21 is highly expressed in a variety of cancers, suggesting that it might play a role in the process of oncogenesis, as supported by it directly causing pre-B cell lymphomas in transgenic mice. Rm21LG transgenic mice for the conditional co expression of miR-21 and luciferase (Luc) mediated by Cre/lox P system were generated. The homozygous Rm21LG transgenic mice were visually and readily characterized immediately after birth by whole-body fluorescence imaging. More importantly, miR-21 and Luc were successfully activated in the liver of Rm21LG/Alb-Cre double-transgenic mice, demonstrating that Rm21LG conditional transgenic system could work in a Cre-dependent manner. The combined use of this conditional miR-21 transgenic mouse line, various cell/tissue-specific Cre mouse lines and bioluminescence imaging will be a valuable tool in vivo to uncover the functions of miR-21 as oncomiR in initiating tumors. PMID- 24068501 TI - An example of enzymatic promiscuity: the Baylis-Hillman reaction catalyzed by a biotin esterase (BioH) from Escherichia coli. AB - Ten lipases and esterases have been examined to catalyse the reaction between p nitrobenzaldehyde and methyl vinyl ketone, the Baylis-Hillman reaction, to form 3 [hydroxyl-(4-nitrophenyl)-methyl]-but-3-en-2-one. Among these enzymes, Escherichia coli BioH esterase had the best activity. Optimal conditions for this reaction were: 0.1 mmol aldehyde, 0.1 mmol activated alkene, 30 mg E. coli BioH, 1 ml acetonitrile at 30 degrees C for 96 h. In addition to the named substrates, four other aldehydes and three activated alkenes were also investigated to determine the substrate range of the enzyme. The structures of nine products were confirmed by NMR and yields of the corresponding products ranged from 21 to 46 %. PMID- 24068502 TI - Construction and characterization of the interdomain chimeras using Cry11Aa and Cry11Ba from Bacillus thuringiensis and identification of a possible novel toxic chimera. AB - Three structural domains of mosquitocidal Cry11Aa and Cry11Ba from Bacillus thuringiensis were exchanged to produce interdomain chimeras [BAA (11Ba/11Aa/11Aa), ABA (11Aa/11Ba/11Aa), AAB (11Aa/11Aa/11Ba), ABB (11Aa/11Ba/11Ba), BAB (11Ba/11Aa/11Ba), BBA (11Ba/11Ba/11Aa]. Chimeras BAB, BAA, BBA, and AAB formed inclusion bodies in the crystal-negative B. thuringiensis host and produced expected protein bands on SDS-PAGE gel. However, no inclusion body or target protein could be found for chimeras ABA and ABB. In bioassays using the fourth-instar larvae of Culex quinquefasciatus and Aedes aegypti, AAB had ~50 % lethal concentrations of 4.8 and 2.2 MUg ml(-1), respectively; however, the rest of chimeras were not toxic. This study thus helps to understand the domain-function relationships of the Cry11Aa and Cry11Ba toxins. The toxic chimera, AAB, might be a candidate for mosquito control as its amino acid sequence is different from the two parental toxins. PMID- 24068503 TI - Enzymatic transformation of nitro-aromatic compounds by a flavin-free NADH azoreductase from Lysinibacillus sphaericus. AB - Azo dyes and nitro-aromatic compounds are the largest group of pollutants released in the environment as industrial wastes. They create serious health and environmental problems. Azoreductases catalyze the reduction of azo dyes and nitro compounds to their respective amines. AN azoreductase was purified up to 12 fold from Lysinibacillus sphaericus using ion-exchange and size exclusion chromatography. It was optimally active at pH 7.4 and 75 degrees C. It was stable at 70 degrees C for 30 min. The purified enzyme utilized NADH rather than NADPH as an electron donor to reduce substrates. The molecular weight of the purified enzyme was ~29 kDa. The enzyme also acted as nitroreductase and could selectively reduce the nitro group of 2-nitrophenol, 4-nitrobenzoic acid, 2-nitro benzaldehyde and 3-nitrophenol. Reduction products of these compounds were identified by IR and NMR. PMID- 24068504 TI - Oxidation of methane by Methylomicrobium album and Methylocystis sp. in the presence of H2S and NH 3. AB - Oxidation of methane by methanotrophs, Methylomicrobium album and Methylocystis sp., was measured at several initial concentrations of H2S and NH3 in the headspace of stoppered flasks, at the same initial concentration of methane as sole carbon and energy source: 15 % (v/v). No effect was observed at 0.01 % (v/v) H2S and 0.025 % (v/v) NH3 in gas phase but over 0.05 and 0.025 % (v/v), respectively, they inhibited the oxidation of methane. The effect of H2S was stronger in Methylocystis sp. and both microorganisms were similarly affected by NH3. Depending on their concentrations in gas phase, H2S and NH3 can thus affect the rate of oxidation of methane and biomass growth of both methanotrophs. PMID- 24068505 TI - A novel VHH nanobody against the active site (the CA domain) of tumor-associated, carbonic anhydrase isoform IX and its usefulness for cancer diagnosis. AB - Expression of carbonic anhydrase IX (CAIX) significantly increases under hypoxic conditions in tumor cells. CAIX activity is executed by the catalytic domain (CA) located on the extracellular part of the enzyme. Neutralization of CAIX enzymatic activity reduces malignancy and survival of tumor cells. To inhibit the enzymatic activity, a VHH nanobody was developed against the CA domain of CAIX using phage display technology. Following immunization of a camel with the recombinant CAIX, VHH fragments were isolated by nested PCR on lymphocyte cDNA. Binding affinity of isolated nanobodies was tested by ELISA. A clone (K24) with the highest binding affinity was expressed in a soluble form. Affinity of K24 nanobody was determined to be approx. 2.3 * 10(-5). K24 nanobody recognized the expressed CAIX in the HeLa cell lines with high selectivity and specificity. These findings thus have usefulness for the diagnosis and treatment of cancers. PMID- 24068506 TI - Cloning, expression and stress-respondent transcription of long-chain acyl coenzyme A synthetase cDNA gene of Nannochloropsis gaditana and its involvement in the biosynthesis of eicosapentaenoic and decosahexaenoic acids. AB - A novel cDNA gene, NgLACS, that encodes a long-chain acyl-CoA sythetase (LACS), was cloned from Nannochloropsis gaditana and characterized. The cDNA was 2,360 bp in length, consisting of an ORF of 1,950 bp, a 5'-untranslated region of 88 bp and a 3'-untranslated region of 322 bp. The deduced amino acid sequence of LACS was 649 amino acid residues in length with a predicted molecular weight of 71 kDa and an isoelectric point of pH 7.8. When the alga was treated with excessive nitrogen and iron, and at 15 degrees C, the proportion of long-chain polyunsaturated acyl-CoAs in the total acyl-CoAs and the abundance of NgLACS cDNA gene transcript were up-regulated. Over-expression of NgLACS in Saccharomyces cerevisiae caused the accumulation of eicosapentaenoic acid and docosahexaenoic acid. PMID- 24068508 TI - Design of riboregulators for control of cyanobacterial (Synechocystis) protein expression. AB - Cyanobacteria are attractive host bacteria for biofuel production because they can covert CO2 to biofuel lipids using only sunlight, water, and inorganic ions. For genetically engineering an ideal cyanobacterium, a synthetic biological approach is promising but few genetic components have been characterized in cyanobacteria. Here for controlling cyanobacterial protein expression, we constructed riboregulators, that one of the post-transcriptional regulators composed of RNAs. Riboregulators harboring a ribosome-binding site suitable for Synechocystis sp. were designed by trial and error using Escherichia coli as host bacteria. The designed riboregulators were effective in Synechocystis sp. as well as E. coli with slight interference on growth only observed in E. coli. They will therefore be useful tools for controlling target gene expression. PMID- 24068507 TI - Production of volatile phenols by Lactobacillus plantarum in wine conditions. AB - Some lactic acid bacteria produce volatile phenols in culture medium but this activity has not been extensively studied in wine conditions. Red and white wines were mixed with MRS medium at different ratios to study the influence of wine on the metabolism of p-coumaric and ferulic acids by Lactobacillus plantarum. In MRS broth supplemented with these precursors at 10 mg l(-1), only 4-ethylphenol was produced (1 mg l(-1)) while, in the presence of wine, 4-vinylphenol was also obtained. Both volatile phenols are produced in nearly equal amounts (1 mg l(-1)) or almost only 4-vinylphenol depending on the MRS:wine ratio. Thus, wine favours the accumulation of 4-vinylphenol. Ferulic acid was not or was weakly metabolized in the conditions studied. PMID- 24068509 TI - Crystallization and structural analysis of 2-hydroxyacid dehydrogenase from Ketogulonicigenium vulgare. AB - L-2-Hydroxyacid dehydrogenase (HDH) from Ketogulonicigenium vulgare Y25 was cloned and overexpressed in Escherichia coli. The protein was purified and crystallized by the sitting-drop vapour-diffusion method with polyethylene glycol 3350 as precipitant. The crystal structure of HDH was determined at 1.64 A resolution using the molecular replacement method with the crystal structure of hydroxyl (phenyl) pyruvate reductase from Coleus blumei Benth as the search model. The overall structure of HDH was similar to that of hydroxyl(phenyl)pyruvate reductase, consisting of two compact domains separated by a deep active cleft. The most significant structural divergence is located around the pocket gate comprising residues A210, T211 and R212, which is located on top of the catalytic triad. PMID- 24068510 TI - Risk factors for choledocholithiasis in a south Indian population: a case-control study. AB - AIM: To identify risk factors for common bile duct (CBD) stones in a south Indian population. METHODS: Demographic characteristics and diet details were obtained from patients with isolated CBD stones (Gp I) and those with combined CBD and gallstones (Gp II) and age- and sex-matched controls. The risk factors were compared between the two groups. RESULTS: The demographic characteristics were similar between the two groups and matched controls. The significant risk factors for Gp I were infrequent consumption of green vegetable (odds ratio (OR), 2.3; p < 0.05), intake of tea/coffee (OR 3.3; p < 0.01) and less consumption of sugar (p < 0.01). For Gp II, the risk factors were frequent intake (>3 times per week) of spices (OR, 2.8; p < 0.05), fried foods (OR, 2.7; p < 0.05), tamarind (OR, 2.8; p < 0.01), and quantum of oil (p < 0.01) per month. Green vegetables (OR, 8.5; p < 0.00001) and sugar (9.5 + 4.2 vs. 13.8 + 11.2 g; p < 0.00001) were protective. Between the two groups, the risk factors for Gp II were less frequent green vegetable intake (OR: 6.4; p < 0.00001), more frequent spicy food (0-3 times per week) (OR, 7.0; p < 0.05), and higher monthly oil intake (251 + 105 vs. 292 + 89 mL; p < 0.05). CONCLUSION: CBD stones in both groups were associated with reduced intake of sugar and green vegetables. Our findings need to be validated in larger studies. PMID- 24068513 TI - Tubercular thyroiditis with multinodular goitre with adenomatous hyperplasia: a rare coexistence. AB - A 32-year-old Indian woman presented with swelling in the anterior part of the neck for the last 3 years. Clinical and radiological examination and fine needle aspiration cytology suggested the diagnosis of multinodular goitre. A subtotal thyroidectomy was performed by the surgeon and the specimen was submitted for the final diagnosis. Histological examination of the specimen revealed multiple caseating tubercular granulomas coexistent with multinodular goitre and adenomatous hyperplasia. The sections demonstrated acid-fast tubercle bacteria, confirming the diagnosis of tubercular thyroiditis. This case emphasises that tubercular thyroiditis should always be considered in patients with thyroid swelling or nodule, in countries where the prevalence of tuberculosis is high. PMID- 24068514 TI - Ameloblastoma: unusual cause of chest wall mass and effusion. PMID- 24068511 TI - Sperm DNA and chromatin integrity in semen samples used for intrauterine insemination. AB - BACKGROUND: Sperm DNA damage is associated with male infertility but whether normozoospermic infertile men also have DNA damage is unknown. OBJECTIVE: To evaluate sperm DNA and chromatin integrity in men with mild male factor infertility. DESIGN, SETTING AND PARTICIPANTS: Prospective study of 102 consecutive men (78 normozoospermic, 15 asthenozoospermic, 9 oligozoospermic) enrolled for intrauterine insemination (IUI) and 15 fertile controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Standard semen parameters and sperm chromatin and DNA integrity were assessed and compared between groups. Sperm chromatin quality was assessed by (1) aniline blue staining (AB is specific to histone lysines), (2) iodoacetamide fluorescein fluorescence (IAF targets free protamine sulfhydryl groups) and (3) sperm chromatin structure assay (SCSA) with the results expressed as % DNA fragmentation index (%DFI). RESULTS AND LIMITATIONS: The mean (+/-SD) percentage of spermatozoa with positive IAF fluorescence was significantly higher in the IUI population compared to fertile controls (17 % +/- 10 % vs. 8 % +/- 6 %, P = 0.0011) and also in the normozoospermic subset (n = 78) compared to controls (16 % +/- 9 % vs. 8 % +/- 6 %, P < 0.0001, ANOVA). We also observed a trend toward lower %progressive motility, and higher %AB staining and %DFI in the IUI group compared to controls. We observed significant relationships between sperm %DFI and progressive motility (r = -0.40, P < 0.0001) and between positive AB staining and IAF fluorescence (r = 0.58, P < 0.0001). CONCLUSIONS: The data indicate that sperm chromatin integrity may be abnormal in men enrolled in IUI treatment cycles, despite the fact that most of these men are normozoospermic. PMID- 24068515 TI - Evidence for cytomegalovirus-induced haemophagocytic syndrome in a young patient with AIDS. AB - A 29-year-old man with HIV infection was referred to our department because of a 1-month history of low-grade fever and fatigue. Bone marrow aspiration and biopsy showed findings consistent with haemophagocytic syndrome (HPS), and immunohistochemical assessment showed cytomegalovirus (CMV) infection. HIV associated HPS can occur at any stages of HIV disease and requires diverse differential diagnosis. CMV-associated HPS (CMV-HPS) in patients with HIV infection is relatively rare, but the present case showed that the clinicians should consider the possibility of CMV-HPS as a clinical feature of CMV infection. PMID- 24068516 TI - ROS scavenging system, osmotic maintenance, pigment and growth status of Panicum sumatrense roth. Under drought stress. AB - Drought stress is one of the abiotic stresses and it may alter plant growth, metabolism and yield. The present study aims to analyze the growth, chlorophyll pigments, osmotic adjustment and antioxidative enzymes activity in Panicum sumatrense under drought stress. The control was irrigated daily and treated plants were irrigated at 4-, 7-, 10-, 13-day intervals. Later, they were irrigated at 3-day interval up to 70 DAS. The root and leaf samples were collected on 30 DAS, 50 DAS and 70 DAS and used for analysis. The root length increased gradually in all drought treatments at all growth stages of P. sumatrense. The chlorophyll pigments and plant height showed a reduction in 13 DID treatment when compared to all treatment. Compatible solutes like proline, glycine betaine and free amino acid increased in all drought treatment when compared to control at 70 DAS. Furthermore, stress treatment caused an increase in activity of antioxidant enzymes like superoxide dismutase, catalase and peroxidase. Panicum sumatrense possess many growth and physiological drought tolerance characters which can be used in future breeding program. PMID- 24068517 TI - The role of protein conformational switches in pharmacology: its implications in metabolic reprogramming and protein evolution. AB - Besides pharmacogenomics and drug dynamics, pharmacological properties of a drug could also arise from protein conformational switches. These switches would arise from the following mechanisms: (a) slight shifts away from a protein's native conformation induced by mutation, (b) changes in the protein's environment allowing for structural rearrangements to form hitherto unknown conformations, (c) parsing the protein into foldable polypeptide fragment(s) by either proteolysis of the native structure or (d) perturbation of the native conformation to generate polypeptide fragment(s). These switches are modulated by changes in the protein's matrix properties such as pH, temperature, ligands-their nature, concentration and complexes; micronutrients, oxidant/antioxidant status and metabolic products within the functional environment of the protein. The pharmacological implications of these are discussed in light of polypharmacology arising from protein isomerism, cross-pharmacology, possible decreases in both the expressible and expressed protein population and metabolic reprogramming-and ultimately, how these factors relate to diseases. Further implications include variational drug toxicity and drug response idiosyncrasies. Another important consequence is that the "whole life" history of the individual would play an active role in that individual's response to disease severity and drug response up to that very moment and is prone to variations with changes in pre-disposing factors. PMID- 24068518 TI - Citric acid cycle and role of its intermediates in metabolism. AB - The citric acid cycle is the final common oxidative pathway for carbohydrates, fats and amino acids. It is the most important metabolic pathway for the energy supply to the body. TCA is the most important central pathway connecting almost all the individual metabolic pathways. In this review article, introduction, regulation and energetics of TCA cycle have been discussed. The present study was carried out to review literature on TCA cycle. PMID- 24068519 TI - 5-HTT SS genotype is associated with the pro-nociceptive sensation by alcoholic sting. AB - The purpose of this study was to examine the relationship between the genetic polymorphism in the promoter of the SLC6A4 gene encoding the serotonin transporter (5-HTT) and the sensitivity to noxious stimulation from a clinical perspective. The genotyping of the 217 outpatients with mild epidermal abrasion in lateral crural region was performed by a combination of polymerase chain reaction and digestion. The intensity of pain to medical alcohol treatment was rated on a visual analog scale (VAS). The results suggest that the human triallelic 5-HTT genotypes are related to individual differences in sensitivity to alcoholic sting. According to the VAS ratings, the subjects with the 5-HTT low expression genotype reported more pain than those with 5-HTT medium- and high expression genotypes following test stimuli. There is no significant difference between sexes in the same SLC6A4 genotype and between medium and high expressions of 5-HTT subjects. Taken together, our study supports the hypothesis that the transcription rate of the 5-HTT transporter may play an important role in the pain sensitivity and central sensitization. PMID- 24068520 TI - Combined hepatocellular-cholangiocarcinoma with fever of unknown origin: a case report and review of literature. AB - Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is a rare form of primary liver cancer (PLC). It is difficult to make a correct preoperative diagnosis of cHCC-CC because of the lack of special features of the disease. We here present a case of a 68-year-old man who presented with fluctuant fever, chills, and sweating and was eventually diagnosed as cHCC-CC after surgery. The tumor was 6.0 cm in diameter with distinct borders and no satellite lesions or lymph nodes were observed during macroscopic examination of the resection specimen. The fever resolved in the postoperative period till the 28th day after surgery, when the patient developed extensive abdominal metastases and died shortly after. More attention should be paid to the patient with PLC showing abnormal features such as FUO, normal range of tumor markers, atypical imaging, and less cirrhosis. Hepatic resection is the treatment of choice although with short-term outcomes. PMID- 24068521 TI - Hispidulin induces apoptosis through mitochondrial dysfunction and inhibition of P13k/Akt signalling pathway in HepG2 cancer cells. AB - Hispidulin is a flavonoid compound which is an active ingredient in a number of traditional Chinese medicinal herbs. However, it's therapeutic activity remains poorly understood. The present study investigated the pro-apoptotic effects and mechanism by which Hispidulin induces apoptosis in human hepatoblastoma cancer (HepG2) cells. The results showed that Hispidulin induced cell death in a dose- and time-dependent manner in HepG2 cells whereas no toxic reaction was observed in normal human liver cells at indicated concentration. This study also demonstrated that Hispidulin induces apoptosis through mitochondrial dysfunction, which is characterized by decreased Bcl-2/Bax ratio, disrupted mitochondrial membrane potential and increased release of cytochrome C and activated capase-3. Our results also showed that mitochondrial dysfunction was triggered by Hispidulin-induced excessive ROS generation. Hispidulin also significantly inhibited Akt activation. ROS inhibitor NAC abrogated the inhibitory effect of Hispidulin on P13k/Akt signalling pathway and the proapoptotic effect in HepG2 cells. Our results demonstrate for the first time that Hispidulin induces apoptosis in HepG2 cells and suggested that the pro-apoptotic effect of Hispidulin was mediated through mitochondrial dysfunction and inhibition of P13k/Akt signalling pathway. Since no toxic effect was observed when normal liver cells were treated with Hispidulin, Hispidulin may have the potential to be used as therapeutic for liver cancer. PMID- 24068522 TI - The time-dependent manner of sinusoidal electromagnetic fields on rat bone marrow mesenchymal stem cells proliferation, differentiation, and mineralization. AB - Electromagnetic fields (EMFs) are used clinically to promote fracture healing and slow down osteoporosis without knowledge of optimal parameters and underlying principles. In the present study, we investigate the effects of irritation for different durations with 15 Hz 1 mT sinusoidal EMFs (SEMFs) on rat bone marrow mesenchymal stem cells (BMSCs) proliferation, differentiation, and mineralization potentials. Our results show that SEMFs irritation promote rat BMSCs proliferation in a time-dependent manner, and the expression of osteogenic gen [Cbfa 1/RUNX2, bone sialoprotein (BSP), osteopontin (OPN)], alkaline phosphatase activity, and calcium deposition were enhanced after SEMFs treatment depending on the time duration of treatment. To determine the role of MEK/ERK signaling pathway, U0126, a MEK/ERK inhibitor was used. It can suppress rat BMSCs' proliferation with or without SEMF exposure, and partly attenuate the expression of osteogenesis related proteins (RUNX2, BSP, OPN) which were improved by SEMF. This finding suggests that the effects of SEMF on rat BMSCs' proliferation differentiation and mineralization are time duration dependent and MEK/ERK signaling pathway plays important role. PMID- 24068523 TI - Oxidized low density lipoprotein and inflammation in gout patients. AB - To analyze the levels of oxidized low density lipoprotein (ox-LDL) and inflammatory cytokines in the plasma of gout patients. The levels of ox-LDL, hypersensitive C-reactive protein (hs-CRP), interleukin-1beta, interleukin-6 (IL 6) and tumor necrosis factor-alpha (TNF-alpha) were measured in the plasma of 41 gout patients [28 in acute phase episode, 13 in intermittent phase (IP)], and in 40 healthy controls. The relationship between ox-LDL and inflammation was also explored by measuring the levels of several pro-inflammatory cytokines in the plasma. The plasma levels of ox-LDL, hs-CRP, IL-6 and TNF-alpha were significantly increased in patients with gout in the acute phase compared to those in the IP group and healthy controls (P < 0.05), but the levels of TGF-beta were significantly lower in the acute phase group than in the IP group and healthy controls (P < 0.01). The levels of ox-LDL in the gout patients in the IP were significantly higher than those in healthy controls (P < 0.05). Correlation analysis indicated that the levels of ox-LDL were positively correlated with hs CRP, IL-6 and TNF-alpha (r = 0.343, r = 0.386, r = 0.659, P < 0.01, respectively), but negatively correlated with TGF-beta levels in patients in the acute phase (r = -0.240, P < 0.05). The levels of ox-LDL in gout patients were significantly higher than those in healthy controls. The changes in ox-LDL levels may be associated with enhanced inflammation in gout patients. PMID- 24068524 TI - The report of sustained low-efficiency dialysis (SLED) treatment in fifteen patients of severe snakebite. AB - To investigate the therapeutic efficacy of sustained low-efficiency dialysis (SLED) in severe snakebite patients. Fifteen patients of severe snakebite was treated with SLED from July 2005 to August 2009 were included in the study. Central venous access was established in all patients. SLED was administered using Dialog(+) dialyzer (B. Braun, Germany). SLED sessions were 6-12 h in duration at a blood flow rate of 200 ml/min and a dialysate flow rate of 300 ml/min. Heparin or low molecular weight heparin was used as anticoagulant. Biochemical indicators, APACHE II scores before and after SLED, and clinical outcomes were evaluated. The levels of serum creatinine, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, creatine kinase isozyme MB, and creatine kinase were significantly lower than the level before SLED (P < 0.05); the level of cholinesterase was significantly higher after SLED (P < 0.01); the APACHE II score before SLED was 14.1 +/- 3.8, but decreased significantly to 7.9 +/- 1.4, 6.2 +/- 1.1, and 4.2 +/- 0.8 on days 1, 2, and 7 after SLED, respectively (P < 0.01). Three patients died on days 1, 3, and 4 after SLED, respectively. The remaining twelve patients were either cured or showed improvement at the time of discharge. The survival rate was 80 % where as mortality was 20 %. SLED may be an effective treatment option in severe snakebite patients. It can reduce mortality, thereby, resulting in increased survival rates. PMID- 24068525 TI - I'm in a virtual body: a locked allocentric memory may impair the experience of the body in both obesity and anorexia nervosa. PMID- 24068526 TI - C3 nephritic factor associated with C3 glomerulopathy in children. AB - BACKGROUND: C3 glomerulopathy (C3G) is characterized by predominant C3 deposits in glomeruli and dysregulation of the alternative pathway of complement. Half of C3G patients have a C3 nephritic factor (C3NeF). C3G incorporated entities with a range of features on microscopy including dense deposit diseases (DDD) and C3 glomerulonephritis (C3GN). The aim of this work was to study children cases of C3G associated with C3NeF. METHODS: We reviewed 18 cases of C3G with a childhood onset associated with C3NeF without identified mutations in CFH, CFI, and MCP genes. RESULTS: Clinical histories started with recurrent hematuria for seven patients, nephrotic syndrome for four, acute post-infectious glomerulonephritis for three and acute renal failure for four. Twelve patients had a low C3 at first investigation. Kidney biopsy showed ten C3GN and eight DDD. Twenty-three percent of the patients tested presented elevated sC5b9. Seven patients relapsed 3 to 6 years after the onset. At the end of follow-up, two patients were under dialysis, 11 had a persistent proteinuria, five had none; four patients did not follow any treatment. Steroids were first used in 80 % of cases. CONCLUSIONS: C3NeF associated C3G has a heterogeneous presentation and outcome. Anti-proteinuric agents may control the disease during follow-up, even after nephrotic syndrome at the onset. The efficiency of immunosuppressive therapy remains questionable. PMID- 24068528 TI - Two-year outcome of the self-expandable stent for chronic total occlusion of the iliac artery. AB - To evaluate the 2-year results obtained with self-expandable stent for chronic total occlusion (CTO) of the iliac artery, a retrospective study was performed of patients who underwent endovascular therapy (EVT) for chronic iliac artery CTO who presented from April 2007 to September 2012. 82 patients with 86 occluded iliac arteries underwent successful recanalization and stenting with a self expandable stent. The primary equivalence end point was a composite of restenosis, mortality, target vessel revascularization, and limb salvage rates. Patients were followed up with the presence of a palpable femoral artery pulse, resolution of symptoms, and noninvasive vascular laboratory testing reviewed at 1, 3, and 6 months after EVT and then were evaluated at 6-month intervals. In patients who gave consent, repeat angiography was done in sixty-one of 86 lesions (70.1 %) for follow-up. The mean follow-up was at 27.6 +/- 17.8 months (range 3 60 months). All stents were placed in the true lumen under intravascular ultrasound (IVUS) guidance. There were no cases of peripheral embolization or iliac artery rupture after the procedure. The ankle-brachial index increased significantly from 0.55 +/- 0.19 to 0.88 +/- 0.17 (P < 0.001). The primary patency rate was 96.5 % at 2 years. The MLD immediately after the procedure was 5.10 +/- 0.26 mm and increased significantly to 5.40 +/- 0.28 mm at the period of follow-up angiography. The 2-year outcome of endovascular therapy with self expandable stents for CTO of the iliac artery had an acceptable result. PMID- 24068527 TI - Neural stem and progenitor cells in health and disease. AB - Neural stem/progenitor cells (NSPCs) have the potential to differentiate into neurons, astrocytes, and/or oligodendrocytes. Because these cells can be expanded in culture, they represent a vast source of neural cells. With the recent discovery that patient fibroblasts can be reprogrammed directly into induced NSPCs, the regulation of NSPC fate and function, in the context of cell-based disease models and patient-specific cell-replacement therapies, warrants review. PMID- 24068529 TI - Current management of choroid plexus carcinomas. AB - Choroid plexus carcinoma (CPC) is a World Health Organization (WHO) grade III brain tumor with a poor prognosis that occurs mainly in children. Gross total resection of CPC is highly recommended and is associated with improved overall survival, although it is often associated with increased morbidity. The use of adjuvant therapies has yet to be standardized, although evidence suggests that for patients with incompletely resected CPCs, a combination of chemotherapy and radiation therapy may be beneficial. The use of radiation therapy for younger children (<3 years old) with CPC, however, is not recommended, due to the potential negative neurological sequelae associated with radiation to the developing brain. Given that the majority of CPC patients are young children, questions regarding optimal radiation dose, chemotherapy agents, and how to combine these two adjuvant treatment modalities to achieve the best outcomes remain unanswered. In this paper we summarize the current management of CPC in the literature. Further studies are needed to standardize the treatment paradigm for this malignant brain tumor. PMID- 24068530 TI - Extracellular biosynthesis of silver nanoparticles using a novel and non pathogenic fungus, Neurospora intermedia: controlled synthesis and antibacterial activity. AB - In the present study, the biosynthesis of silver nanoparticles (AgNPs) using Neurospora intermedia, as a new non-pathogenic fungus was investigated. For determination of biomass harvesting time, the effect of fungal incubation period on nanoparticle formation was investigated using UV-visible spectroscopy. Then, AgNPs were synthesized using both culture supernatant and cell-free filtrate of the fungus. Two different volume ratios (1:100 and 1:1) of the culture supernatant to the silver nitrate were employed for AgNP synthesis. In addition, cell-free filtrate and silver nitrate were mixed in presence and absence of light. Smallest average size and highest productivity were obtained when using equal volumes of the culture supernatant and silver nitrate solution as confirmed by UV-visible spectra of colloidal AgNPs. Comparing the UV-visible spectra revealed that using cell-free filtrate for AgNP synthesis resulted in the formation of particles with higher stability and monodispersity than using culture supernatant. The absence of light in cell-free filtrate mediated synthesis led to the formation of nanoparticles with the lowest rate and the highest monodispersity. The presence of elemental silver in all prepared samples was confirmed using EDX, while the crystalline nature of synthesized particles was verified by XRD. FTIR results showed the presence of functional groups which reduce Ag(+) and stabilize AgNPs. The presence of nitrate reductase was confirmed in the cell-free filtrate of the fungus suggesting the potential role of this enzyme in AgNP synthesis. Synthesized particles showed significant antibacterial activity against E. coli as confirmed by examining the growth curve of bacterial cells exposed to AgNPs. PMID- 24068532 TI - Impact of subacute ruminal acidosis on the diversity of liquid and solid associated bacteria in the rumen of goats. AB - This study was aimed to investigate the impact of subacute ruminal acidosis (SARA) on the diversity of liquid (LAB) and solid-associated bacteria (SAB) following high-grain feeding. Six ruminally cannulated goats were divided into two groups: one group was fed a hay diet (COD), and the other group was fed a high grain diet (SAID). Rumen liquids and rumen solids were sampled after 2 weeks adaption. SARA was diagnosed with a pH below 5.8 for 8 h. SAID decreased ruminal pH (P < 0.001) and increased the acetate (P = 0.017), propionate (P = 0.001), butyrate (P < 0.001) and total volatile fatty acid (P < 0.001) concentration in rumen compared with the COD. Denaturing gradient gel electrophoresis fingerprints analysis revealed a clear separation between both the diet and the fraction of rumen digesta in bacterial communities. Pyrosequencing analysis showed that the proportion of phylum Bacteroidetes in the SAID-LAB and SAID-SAB communities was less than in the COD group, whereas the SAID group had a greater percentage of Firmicutes in both the LAB and SAB libraries. UniFrac analyses and a Venn diagram revealed a large difference between the two diets in the diversity of rumen bacterial communities. Overall, our findings revealed that SARA feeding did alter the community structure of rumen liquids and rumen solids. Thus, manipulation of dietary factors, such as ratio of forage to concentrate may have the potential to alter the microbial composition of rumen liquid and rumen solid. PMID- 24068533 TI - Enhanced riboflavin production by recombinant Bacillus subtilis RF1 through the optimization of agitation speed. AB - Dissolved oxygen is one of the most important bioprocess parameters that could affect cell growth and product formation, and it is easy to control by changing agitation speed. In this work, the effects of agitation speed on the performance of riboflavin production by recombinant Bacillus subtilis RF1 was investigated in fed-batch fermentation. The lower agitation speed (600 rpm) was beneficial for cell growth and riboflavin biosynthesis in the initial phase of fermentation process. While, during the later phase, higher agitation speed (900 rpm) was favor for cell growth and riboflavin biosynthesis. Thus, a two-stage agitation speed control strategy was proposed based on kinetic analysis, in which the agitation speed was controlled at 600 rpm in the first 26 h and then switched to 900 rpm to maintain high MU for cell growth and high q(p) for riboflavin production during the entire fermentation process. However, it was observed that a sharp increase of agitation speed resulted in an adverse effect on cell growth and riboflavin synthesis within a short time. To avoid this phenomenon, a multi stage agitation speed control strategy was set up based on the two-stage control strategy, the maximum concentration of riboflavin reached 9.4 g l(-1) in 48 h with the yield of 0.051 g g(-1) by applying this strategy, which were 20.5 and 21.4% over the best results controlled by constant agitation speeds. PMID- 24068534 TI - Antibiotic resistance and molecular typing among cockle (Anadara granosa) strains of Vibrio parahaemolyticus by polymerase chain reaction (PCR)-based analysis. AB - Genomic DNA of Vibrio parahaemolyticus were characterized by antibiotic resistance, enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) and random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR) analysis. These isolates originated from 3 distantly locations of Selangor, Negeri Sembilan and Melaka (East coastal areas), Malaysia. A total of 44 (n = 44) of tentatively V. parahaemolyticus were also examined for the presence of toxR, tdh and trh gene. Of 44 isolates, 37 were positive towards toxR gene; while, none were positive to tdh and trh gene. Antibiotic resistance analysis showed the V. parahaemolyticus isolates were highly resistant to bacitracin (92%, 34/37) and penicillin (89%, 33/37) followed by resistance towards ampicillin (68%, 25/37), cefuroxime (38%, 14/37), amikacin (6%, 2/37) and ceftazidime (14%, 5/37). None of the V. parahaemolyticus isolates were resistant towards chloramphenicol, ciprofloxacin, ceftriaxone, enrofloxacin, norfloxacin, streptomycin and vancomycin. Antibiogram patterns exhibited, 9 patterns and phenotypically less heterogenous when compared to PCR-based techniques using ERIC and RAPD-PCR. The results of the ERIC- and RAPD-PCR were analyzed using GelCompare software. ERIC-PCR with primers ERIC1R and ERIC2 discriminated the V. parahaemolyticus isolates into 6 clusters and 21 single isolates at a similarity level of 80%. While, RAPD-PCR with primer Gen8 discriminated the V. parahaemolyticus isolates into 11 clusters and 10 single isolates and Gen9 into 8 clusters and 16 single isolates at the same similarity level examined. Results in the presence study demonstrated combination of phenotypically and genotypically methods show a wide heterogeneity among cockle isolates of V. parahaemolyticus. PMID- 24068535 TI - Identification and characterization of ethanol utilizing fungal flora of oil refinery contaminated soil. AB - The indigenous fungal flora of three oil refinery contaminated sites (Bharuch, Valsad and Vadodara) of India has been documented in the present investigation. A total seventy-five fungal morphotypes were isolated from these sites and out of them, only fifteen isolates were capable of utilizing ethanol (0-8%; v:v) as a sole source of carbon and energy for growth. Ten percent ethanol was completely lethal for the growth of all the isolated fungus. Biochemical characterization of the potent ethanol utilizing fungal isolates was studied based on substrate utilization profiles using BIOLOG phenotype microarray plates. Based on the morphological characters and Internal Transcribed Spacer region of ribosomal DNA, the fungal isolates were identified as Fusarium brachygibbosum, Fusarium equiseti, Fusarium acuminatum, Pencillium citrinum, Alternaria tenuissima, Septogloeum mori, Hypocrea lixii, Aureobasidium sp., Penicillium sp., and Fusarium sp. Intra-species genetic diversity among Fusarium sp. was evaluated by whole genome analysis with repetitive DNA sequences (ERIC, REP and BOX) based DNA fingerprinting. It was found that these fungus use alcohol dehydrogenase and acetaldehyde dehydrogenase enzymes based metabolism pathway to utilize ethanol for their growth and colonization. PMID- 24068538 TI - The expression of redox proteins in phyllodes tumor. AB - This study aimed to investigate the associations between the expression of redox related proteins which regulate reactive oxygen species (ROS) production and the histologic factors in phyllodes tumor (PT). We used tissue microarrays to analyze 193 PTs and performed immunohistochemical staining against five redox-related proteins including catalase, thioredoxin reductase (TxNR), glutathione S transferase pi (GST pi), thioredoxin interacting protein (TxNIP), and manganese superoxide dismutase (MnSOD). We then compared the immunohistochemical results and histologic parameters. The 193 PTs were classified as benign (n = 145, 75.1 %), borderline (n = 33, 17.1 %), and malignant (n = 15, 7.8 %). With worsening histologic grade, the expression of catalase, TxNR, TxNIP, and MnSOD in the stromal component increased (P < 0.001), and GST pi and MnSOD expression in the epithelial component increased (P = 0.014, and 0.038). Significant associations were found between the expression of catalse-TxNR, catalase-TxNIP, catalase MnSOD, TxNR-TxNIP, TxNR-MnSOD, and TxNIP-MnSOD in both the epithelial and stromal components (P < 0.05). This study confirmed that the stromal expression of catalase, TxNR, TxNIP, and MnSOD increased with worsening histologic grade in PT, reflecting the change in ROS production during the malignant transformation of PT. PMID- 24068537 TI - Effects of temperature, growth phase and luxO-disruption on regulation systems of toxin production in Vibrio vulnificus strain L-180, a human clinical isolate. AB - Vibrio vulnificus is a halophilic estuarine bacterium while it causes fatal septicemia or necrotizing wound infections in humans. This pathogen secretes the metalloprotease (V. vulnificus protease: VVP) and the cytolysin (V. vulnificus hemolysin: VVH) as protein toxins; however, their production was coordinated in response to the bacterial cell density. This regulation is termed quorum sensing (QS) and is mediated by the small diffusible molecule called autoinducer 2 (AI 2). In the present study, we investigated effects of disruption of luxO encoding a central response regulator of the QS circuit, as well as effects of temperature and growth phase, on the toxin production by V. vulnificus. Disruption of luxO was found to increase VVP production and expression of its gene vvpE. The expression of smcR, crp and rpoS, of which products positively regulate vvpE expression, and luxS encoding the AI-2 synthetase were also significantly increased. On the other hand, the luxO disruption resulted in reduction of VVH production and expression of its gene vvhA. Expression of other two genes affecting the QS circuit, luxT and rpoN, were also significantly decreased. The regulation systems of VVP production were found to exert their action during the stationary phase of the bacterial growth and to be operated strongly at 26 degrees C. By contrast, those of VVH production apparently started at the log phase and were operated more effectively at 37 degrees C. PMID- 24068539 TI - Phase I-II study of the farnesyl transferase inhibitor tipifarnib plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in HER2/neu-negative inflammatory carcinoma and non-inflammatory estrogen receptor-positive breast carcinoma. AB - Tipifarnib (T) is a farnesyl transferase inhibitor (FTI) that enhances the antineoplastic effects of cytotoxic therapy in vitro, has activity in metastatic breast cancer, and enhances the pathologic complete response (pCR) rate to neoadjuvant doxorubicin-cyclophosphamide (AC) chemotherapy. We, therefore, performed a phase I-II trial of T plus neoadjuvant sequential weekly paclitaxel and 2-week AC chemotherapy in locally advanced breast cancer. Eligible patients with HER2-negative clinical stage IIB-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m(2)) followed by AC (60/600 mg/m(2) every 2 weeks and filgrastim), plus T (100 or 200 mg PO on days 1-3 of each P dose, and 200 mg PO on days 2-7 of each AC cycle). The trial was powered to detect an improvement in breast pCR rate from 15 to 35 % (alpha = 0.10, beta = 0.10) in two strata, including ER and/or PR-positive, non-inflammatory (stratum A) and inflammatory carcinoma (stratum B). Of the 60 patients accrued, there were no dose-limiting toxicities among the first six patients treated at the first T dose level (100 mg BID; N = 3) or second T dose level (200 mg BID; N = 3) plus paclitaxel. Breast pCR occurred in 6/33 patients (18 %, 95 % confidence intervals (CI) 7-36 %) and 1/22 patients (4 %, 95 % CI 0-8 %) in stratum B. Combination of the FTI T with weekly paclitaxel-AC is unlikely to be associated with a breast pCR rate of 35 % or higher in patients with locally advanced HER2/neu-negative inflammatory or non inflammatory ER- and/or PR-positive breast carcinoma. PMID- 24068540 TI - Diagnostics and treatment of cryoglobulinaemia: it takes two to tango. AB - Cryoglobulins are immunoglobulins that reversibly precipitate in the cold. They come in different flavours and, as such, are differentially associated with lymphoproliferative diseases (type I), or systemic autoimmune diseases, and/or infectious diseases (type II/III). The clinical manifestations of cryoglobulinaemia result from either hyper-viscosity or small vessel vasculitis. Hepatitis C virus (HCV) is a well-known factor in the aetiology of cryoglobulinaemia, but substantial geographical differences exist in the association between cryoglobulins and HCV. In the absence of any underlying disease, cryoglobulinaemia is referred to as 'idiopathic' or 'essential'. Detection of cryoglobulins in the laboratory is hampered by several pitfalls, in particular in the pre-analytical stage as well as in the quantification. In addition, our personal experience reveals that the detection of rheumatoid factor, most often present in high concentrations in patients with mixed cryoglobulinaemia, relies on the choice of the test system. Hence, interpretation of the laboratory results in relation to the clinical manifestations requires a partnership between the clinician and the laboratory specialist in order to make a correct diagnosis. Treatment options are primarily directed by identification of underlying diseases, i.e. infections or systemic autoimmune diseases. Idiopathic cryoglobulinaemia is treated with corticosteroids and immunosuppression, or B cell depleting anti-CD20 biologicals. In this overview, the recent literature on current laboratory and clinical practice of cryoglobulinaemia is discussed from a personal perspective. PMID- 24068536 TI - A potential role of probiotics in colorectal cancer prevention: review of possible mechanisms of action. AB - A number of investigations, mainly using in vitro and animal models, have demonstrated a wide range of possible mechanisms, by which probiotics may play a role in colorectal cancer (CRC) prevention. In this context, the most well studied probiotics are certain strains from the genera of lactobacilli and bifidobacteria. The reported anti-CRC mechanisms of probiotics encompass intraluminal, systemic, and direct effects on intestinal mucosa. Intraluminal effects detailed in this review include competitive exclusion of pathogenic intestinal flora, alteration of intestinal microflora enzyme activity, reduction of carcinogenic secondary bile acids, binding of carcinogens and mutagens, and increasing short chain fatty acids production. Reduction of DNA damage and suppression of aberrant crypt foci formation have been well demonstrated as direct anti-CRC effects of probiotics on intestinal mucosa. Existing evidence clearly support a multifaceted immunomodulatory role of probiotics in CRC, particularly its ability to modulate intestinal inflammation, a well known risk factor for CRC. The effectiveness of probiotics in CRC prevention is dependent on the strain of the microorganism, while viability may not be a prerequisite for certain probiotic anticancer mechanisms, as indicated by several studies. Emerging data suggest synbiotic as a more effective approach than either prebiotics or probiotics alone. More in vivo especially human studies are warranted to further elucidate and confirm the potential role of probiotics (viable and non-viable), prebiotics and synbiotics in CRC chemoprevention. PMID- 24068541 TI - Elevated cytokine expression of different PEEK wear particles compared to UHMWPE in vivo. AB - Due to their mechanical properties, there has been growing interest in poly-ether ether-ketone (PEEK) and its composites as bearing material in total and unicompartmental knee arthroplasty. The aim of this study was to analyze the biological activity of wear particles of two different (pitch and PAN) carbon fiber-reinforced- (CFR-) PEEK varieties in comparison to ultra-high-molecular weight-polyethylene (UHMWPE) in vivo. The authors hypothesized no difference between the used biomaterials. Wear particle suspensions of the particulate biomaterials were injected into knee joints of Balb/c mice, which were sacrificed after seven days. The cytokine expression (IL-1beta, IL-6, TNF-alpha) was analyzed immunohistochemically in the synovial layer, the adjacent bone marrow and the articular cartilage. Especially in the bone marrow of the two CFR-PEEK varieties there were increased cytokine expressions compared to the control and UHMWPE group. Furthermore, in the articular cartilage the CFR-PEEK pitch group showed an enhanced cytokine expression, which could be a negative predictor for the use in unicondylar knee systems. As these data suggest an increased proinflammatory potential of CFR-PEEK and its composites in vivo, the initial hypothesis had to be refuted. Summarizing these results, CFR-PEEK seems not to be an attractive alternative to UHMWPE as a bearing material, especially in unicompartmental knee arthroplasty. PMID- 24068542 TI - PMMA brush-containing two-solution bone cement: preparation, characterization, and influence of composition on cement properties. AB - Two-solution bone cement consisting of poly (methyl methacrylate) (PMMA) brushes in methyl methacrylate has been developed as an alternative to the traditional two-solution (TSBC) and powder-liquid cements. It was hypothesized that the substitution of brushes, for the entire pre-polymer phase of the cement, would permit a decrease in solution viscosity at higher polymer fractions, and allow for physical entanglements with the cement matrix. Consequently, improved cement exothermal and mechanical properties could be expected with brush addition. PMMA brushes were grafted on the surface of cross-linked PMMA nanospheres following a multi-stage synthetic strategy. Brushes exhibiting optimal molecular weight for preparation of TSBC were used for characterization of cement viscosity, flexural and compressive mechanical properties, exothermal properties and residual monomer content. Interactions between grafts and free polymer formed during free radical polymerization of the cement were evaluated based on molecular weight measurements of the cement matrix and brushes. Brush-containing cements exhibited lower viscosity at significantly higher polymer fractions in comparison to TSBC. Cements with PMMA brushes had significantly lower polymerization temperatures and residual monomer content. Measurements of molecular weight revealed the existence of a dry brush regime when using the brush compositions selected in this study, which led to a reduction in the mechanical properties of some of the compositions tested. The optimal cement viscosity and maintenance of other important cement properties achieved with addition of PMMA brushes is expected to expand the use of the two-solution cements in a range of applications. PMID- 24068543 TI - Glucose-sensitive polyelectrolyte nanocapsules based on layer-by-layer technique for protein drug delivery. AB - The glucose-responsive nanocapsules [CS-NAC/p(GAMA-r-AAPBA)] were readily fabricated with modified chitosan (CS-NAC) and random glycopolymer poly(D gluconamidoethyl methacrylate-r-3-acrylamidophenylboronic acid) p(GAMA-r-AAPBA) as the alternant multilayered polyelectrolyte hybrid shell via layer-by-layer self-assembly after etching the amino functionalized SiO2 spheres by NH4F/HF. The spherical and hollow structure of nanocapsules was confirmed by TEM analysis and there was no clear collapse found after removal of the sacrificial cores. The reversible zeta potential changes of the nanocapsule materials evaluated the reversible glucose sensitivity. Besides, this system demonstrated a good capacity for encapsulation and loading insulin entrapped in nanocapsules as model protein drug. A good biocompatibility of the material was confirmed by the cell viability. In vitro release of insulin experiments revealed that no obvious release was found in acidic condition and the release could be normally conducted at physiological pH. These results implied that it was feasible for nanocapsules to be used in controlled release drug delivery system. PMID- 24068544 TI - Evaluation of MAGE-D4 expression in hepatocellular carcinoma in Japanese patients. AB - BACKGROUND AND OBJECTIVES: Though Melanoma-associated antigen (MAGE) family genes have received lots of attention as cancer-related genes and targets for immunotherapy, MAGE-D4 expression in hepatocellular carcinoma (HCC) has not yet been evaluated. METHODS: MAGE-D4 mRNA expression was assayed in nine HCC cell lines and 94 HCC surgical specimens obtained from Japanese patients by quantitative real-time reverse transcription polymerase chain reaction, and the correlations between MAGE-D4 mRNA expression and clinicopathological factors were evaluated. The expression and distribution of MAGE-D4b protein were evaluated immunohistochemically. RESULTS: MAGE-D4 mRNA was overexpressed in five of nine HCC cell lines and 34 of 94 primary HCCs (36.2%). Median overall survival (14.8 vs. 118 months, P < 0.001) and relapse-free survival (2.7 vs. 18.3 months, P < 0.001) were significantly shorter in patients with high than with low-moderate MAGE-D4 expression. Multivariate analysis for overall survival showed that MAGE D4 overexpression was independently prognostic for survival (hazard ratio 2.88, P = 0.009) and significantly associated with high alpha-fetoprotein concentration (P < 0.001), poor tumor differentiation (P = 0.003) and vascular invasion (P = 0.021). MAGE-D4b protein expression patterns were consistent with those of MAGE D4 mRNA. CONCLUSIONS: Overexpression of MAGE-D4 may be a predictive marker of early recurrence and mortality in patients with HCC. PMID- 24068545 TI - Public attitudes towards preventive genomics and personal interest in genetic testing to prevent disease: a survey study. AB - BACKGROUND: Genetic testing and family history assessment can be used as an aid in the prevention of common chronic diseases. The aim of this study was to determine public attitudes and interests towards offering genetic testing and family history-based risk assessment for common chronic disease prevention. METHODS: Cross-sectional questionnaire survey of a consumer panel representative for the Dutch population. The questionnaire was sent to 1399 panel members, aged >= 18 years. RESULTS: The response was 70% (978/1399). About half of the respondents expressed an interest in genetic testing to prevent specific diseases (cancer, cardiovascular disease, diabetes or dementia), with lower-educated respondents showing more interest than higher-educated respondents. Few respondents (24%) agreed that people should be preventively tested for all kinds of diseases. According to the respondents, genetic testing should be performed in the hospital (66%) and be directed to curable (57%) or preventable diseases (69%). Half of the respondents believed that family history assessment could help prevent disease, but only 21% thought it should be offered to everyone, as this could cause people to be worried. A minority (12%) reported that their family history had been assessed, whereas 59% did not have it assessed and did not think this would be necessary. Respondents have differentiated interests in preventive genomics, which varies depending on sex, age and level of education. CONCLUSIONS: Members of the public are interested in genetic testing for preventable and curable diseases, but they are ambivalent about family history risk assessment to prevent disease. PMID- 24068546 TI - Deprivation and health risk indicators in full-time permanent workers. AB - BACKGROUND: Association between deprivation and health is well established, particularly among unemployed or fixed-term contract or temporary contract subjects. This study aimed to assess if this relationship existed as well in full time permanent workers. METHODS: Biometrical, biological, behavioural and psychosocial health risk indicators and an individual deprivation score, the Evaluation of Precarity and Inequalities in Health Examination Centres score, were recorded from January 2007 to June 2008, in 34 905 full-time permanent workers aged 18-70 years, all volunteers for a free health examination. Comparisons of the behavioural, metabolic, cardiovascular and health risk indicators between quintiles of the deprivation score with adjustments on age and socioeconomic categories were made by covariance analysis or logistic regression. RESULTS: For both genders, degradation of nutritional behaviours, metabolic and cardiovascular indicators and health appeared gradually with deprivation, even for deprivation score usually considered as an insignificant value. The absence of only one social support or one social network was associated with a degradation of health. Full-time permanent workers with the poorest health risk indicators had more frequent social exclusion signs. These results were independent of socioeconomic categories and age. CONCLUSION: Understanding how deprivation influences health status may lead to more effective interventions to reduce social inequalities in health. The deprivation Evaluation of Precarity and Inequalities in Health Examination Centres score is a relevant tool to detect subjects who could benefit from preventive interventions. Our findings suggest that this deprivation score should be used as a health risk indicator even in full-time permanent workers. Assessing deprivation is useful to design and evaluate specific intervention programmes. PMID- 24068547 TI - Socio-economic inequalities in all-cause mortality in Europe: an exploration of the role of heightened social mobility. AB - The larger than expected socio-economic inequalities in health in more egalitarian countries might be explained by a heightened social mobility in these countries. Therefore, the aim of this explorative study was to examine the associations between country-level social mobility, income inequality and socio economic differences in all-cause mortality, using country-level secondary data from 12 European countries. Both income equality and social mobility were found to be associated with larger socio-economic differences in mortality, particularly in women. These findings suggest that social mobility and income equality, beside their shiny side of improving population health, might have a shady side of increasing socio-economic health inequalities. PMID- 24068548 TI - Health-related quality of life and risk factor control: the importance of educational level in prevention of cardiovascular diseases. AB - BACKGROUND: This study aimed to describe and to analyse the importance of educational level for controlled risk factors and health-related quality of life (HRQoL). METHODS: This observational study was conducted in nine European countries (5632 patients in 249 practices). We compared patients with a low level of education (up to 9 years) with patients with a high level of education (>9 years), with regard to controlled cardiovascular disease risk factors and HRQoL. A multilevel approach was used for statistical analysis. RESULTS: Patients with a low level of education were older (P < 0.001), more often female (P < 0.001), more often single (P < 0.001) and had a higher number of other conditions (e.g. heart failure) (P < 0.001). Significant differences in terms of controlled risk factors were revealed for blood pressure (RR) <= 140/90 mmHg (P = 0.039) and the sum of controlled risk factors (P = 0.027). Higher age, lower education, female gender, living as single, patient group (coronary heart disease patients) and the number of other conditions were negatively associated with HRQoL. A higher sum of controlled risk factors were positively associated with higher HRQoL in the whole sample (r = 0.0086, P < 0.001) as well as in both educational-level groups (r = 0.0075, P = 0.038 in the low-level group and r = 0.0082, P = 0.001 in the high level group). CONCLUSION: Patients with a lower educational level were more often females, singles, had a higher number of other conditions, a higher number of uncontrolled risk factors and a lower HRQoL. However, the higher the control of risk factors was, the higher the HRQoL was overall as well as in both educational level groups. PMID- 24068549 TI - Fast-track surgery improves postoperative clinical recovery and reduces postoperative insulin resistance after esophagectomy for esophageal cancer. AB - PURPOSE: This study aims to investigate the influence of fast-track surgery (FTS) on insulin resistance indicators in a prospective randomized, controlled clinical trial in esophageal cancer patients. METHODS: Between November 2009 and March 2011, 34 patients underwent the FTS pathway, and 34 patients underwent the conventional pathway after esophagectomy in our department. The times to postoperative flatus and defecation, duration of postoperative hospital stay, hospitalization expenditures, and postoperative complications were recorded. Insulin resistance indicators were measured before operation as well as on the 1st, 3rd, and 7th postoperative days (PODs), including serum levels of fasting blood glucose (FBG), fasting insulin (FINS), interleukin-6 (IL-6), and C-reactive protein (CRP) in patients of both groups. The insulin resistance index (homeostasis model assessment of insulin resistance (HOMA-IR)) was calculated at each time point. RESULTS: We found a significantly shorter postoperative hospital stay and faster return of gastrointestinal function in patients who underwent FTS (P < 0.01). In addition, the total hospitalization expenditure was significantly lower in the FTS group (P < 0.01). The preoperative insulin resistance indicators showed no significant differences between the two groups. On PODs 1 and 3, the levels of log-HOMA-IR, FINS, IL-6, and CRP in the FTS group were significantly lower than those in the control group (all P < 0.05). On POD 7, the CRP level in the FTS group was significantly lower than that in the control group (P < 0.05). CONCLUSIONS: FTS promotes early recovery of gastrointestinal function and reduces stress reaction and postoperative insulin resistance after esophagectomy for esophageal cancer. PMID- 24068550 TI - The Knowledge Exchange-Decision Support Model: application to cancer navigation programs. AB - PURPOSE: The Knowledge Exchange-Decision Support (KE-DS) Model provides a framework outlining essential components of knowledge generation and exchange. The purpose of this research was to illustrate how the Model makes explicit the different contextual aspects implicit in the planning and implementation of two cancer navigation programs in Canada. METHODS: The KE-DS Model guided the collection and analysis of interviews with program personnel and narrative data. A qualitative thematic analysis was conducted wherein we compared and contrasted the planning and implementation of these two navigation programs. RESULTS: The planning and implementation of these two programs was conceptualized differently and adapted to meet local contingencies. The KE-DS Model highlighted three factors that influenced program delivery. First, the structure of health services was shaped by the interaction of professionals and services operating in the region, and the existing health services influenced the program's approach to navigation. Second, while there were similarities in the professional roles and responsibilities of the navigators, these roles and responsibilities also reflected local context in their approaches to patient assessment, referral, education, coordination of services, and advocacy. Third, these two distinct approaches to navigation have responded to the needs of diverse populations being served by improving access to care. CONCLUSIONS: Evidence generated using the KE DS Model could ensure a more robust and structured approach to the planning and implementation of future navigation programs. The Model prompts users to make explicit the different types of evidence utilized during program planning and implementation. The systematic collection of new information on program implementation using the KE-DS Model in future initiatives will contribute to an improved understanding of the science of knowledge exchange. PMID- 24068552 TI - Projections from caudal ventrolateral prefrontal areas to brainstem preoculomotor structures and to Basal Ganglia and cerebellar oculomotor loops in the macaque. AB - The caudal part of the macaque ventrolateral prefrontal (VLPF) cortex hosts several distinct areas or fields--45B, 45A, 8r, caudal 46vc, and caudal 12r- connected to the frontal eye field (area 8/FEF). To assess whether these areas/fields also display subcortical projections possibly mediating a role in controlling oculomotor behavior, we examined their descending projections, based on anterograde tracer injections in each area/field, and compared them with those of area 8/FEF. All the studied areas/fields displayed projections to brainstem preoculomotor structures, precerebellar centers, and striatal sectors that are also targets of projections originating from area 8/FEF. Specifically, these projections involved: (1) the intermediate and superficial layers of the superior colliculus; (2) the mesencephalic and pontine reticular formation; (3) the dorsomedial and lateral pontine nuclei and the reticularis tegmenti pontis; and (4) the body of the caudate nucleus. Furthermore, area 45B projected also to the regions around the trochlear nucleus and to the raphe interpositus. The present data provide evidence for a role of the caudal VLPF areas/fields in controlling oculomotor behavior not only through their connections to area 8/FEF, but also in parallel through a direct access to preoculomotor brainstem structures and to the cerebellar and basal ganglia oculomotor loops. PMID- 24068551 TI - Large-scale brain networks of the human left temporal pole: a functional connectivity MRI study. AB - The most rostral portion of the human temporal cortex, the temporal pole (TP), has been described as "enigmatic" because its functional neuroanatomy remains unclear. Comparative anatomy studies are only partially helpful, because the human TP is larger and cytoarchitectonically more complex than in nonhuman primates. Considered by Brodmann as a single area (BA 38), the human TP has been recently parceled into an array of cytoarchitectonic subfields. In order to clarify the functional connectivity of subregions of the TP, we undertook a study of 172 healthy adults using resting-state functional connectivity MRI. Remarkably, a hierarchical cluster analysis performed to group the seeds into distinct subsystems according to their large-scale functional connectivity grouped 87.5% of the seeds according to the recently described cytoarchitectonic subregions of the TP. Based on large-scale functional connectivity, there appear to be 4 major subregions of the TP: (1) dorsal, with predominant connectivity to auditory/somatosensory and language networks; (2) ventromedial, predominantly connected to visual networks; (3) medial, connected to paralimbic structures; and (4) anterolateral, connected to the default-semantic network. The functional connectivity of the human TP, far more complex than its known anatomic connectivity in monkey, is concordant with its hypothesized role as a cortical convergence zone. PMID- 24068553 TI - Miravirsen (SPC3649) can inhibit the biogenesis of miR-122. AB - MicroRNAs (miRNAs) are short noncoding RNAs, which bind to messenger RNAs and regulate protein expression. The biosynthesis of miRNAs includes two precursors, a primary miRNA transcript (pri-miRNA) and a shorter pre-miRNA, both of which carry a common stem-loop bearing the mature miRNA. MiR-122 is a liver-specific miRNA with an important role in the life cycle of hepatitis C virus (HCV). It is the target of miravirsen (SPC3649), an antimiR drug candidate currently in clinical testing for treatment of HCV infections. Miravirsen is composed of locked nucleic acid (LNAs) ribonucleotides interspaced throughout a DNA phosphorothioate sequence complementary to mature miR-122. The LNA modifications endow the drug with high affinity for its target and provide resistance to nuclease degradation. While miravirsen is thought to work mainly by hybridizing to mature miR-122 and blocking its interaction with HCV RNA, its target sequence is also present in pri- and pre-miR-122. Using new in vitro and cellular assays specifically developed to discover ligands that suppress biogenesis of miR-122, we show that miravirsen binds to the stem-loop structure of pri- and pre-miR-122 with nanomolar affinity, and inhibits both Dicer- and Drosha-mediated processing of miR-122 precursors. This inhibition may contribute to the pharmacological activity of the drug in man. PMID- 24068555 TI - Transcription factor binding to Caenorhabditis elegans first introns reveals lack of redundancy with gene promoters. AB - Gene expression is controlled through the binding of transcription factors (TFs) to regulatory genomic regions. First introns are longer than other introns in multiple eukaryotic species and are under selective constraint. Here we explore the importance of first introns in TF binding in the nematode Caenorhabditis elegans by combining computational predictions and experimentally derived TF-DNA interaction data. We found that first introns of C. elegans genes, particularly those for families enriched in long first introns, are more conserved in length, have more conserved predicted TF interactions and are bound by more TFs than other introns. We detected a significant positive correlation between first intron size and the number of TF interactions obtained from chromatin immunoprecipitation assays or determined by yeast one-hybrid assays. TFs that bind first introns are largely different from those binding promoters, suggesting that the different interactions are complementary rather than redundant. By combining first intron and promoter interactions, we found that genes that share a large fraction of TF interactions are more likely to be co-expressed than when only TF interactions with promoters are considered. Altogether, our data suggest that C. elegans gene regulation may be additive through the combined effects of multiple regulatory regions. PMID- 24068556 TI - Nucleosome positioning and kinetics near transcription-start-site barriers are controlled by interplay between active remodeling and DNA sequence. AB - We investigate how DNA sequence, ATP-dependent chromatin remodeling and nucleosome-depleted 'barriers' co-operate to determine the kinetics of nucleosome organization, in a stochastic model of nucleosome positioning and dynamics. We find that 'statistical' positioning of nucleosomes against 'barriers', hypothesized to control chromatin structure near transcription start sites, requires active remodeling and therefore cannot be described using equilibrium statistical mechanics. We show that, unlike steady-state occupancy, DNA site exposure kinetics near a barrier is dominated by DNA sequence rather than by proximity to the barrier itself. The timescale for formation of positioning patterns near barriers is proportional to the timescale for active nucleosome eviction. We also show that there are strong gene-to-gene variations in nucleosome positioning near barriers, which are eliminated by averaging over many genes. Our results suggest that measurement of nucleosome kinetics can reveal information about sequence-dependent regulation that is not apparent in steady state nucleosome occupancy. PMID- 24068558 TI - Follicular thyroid carcinoma with signet ring cell morphology: fine-needle aspiration cytology, histopathology, and immunohistochemistry. AB - Thyroid follicular neoplasms with signet ring cell morphology represent a challenging cytological and histopathologic diagnosis. The low frequency of these neoplasms and their broad differential diagnosis contribute to this difficult scenario. Here, we present an exceptionally rare case of thyroid follicular carcinoma with signet ring cell morphology in a 62-year-old female. We analyze the characteristics in fine-needle aspiration cytology, histopathology, and immunohistochemistry and compare our results in a discussion with previous literature reports. PMID- 24068559 TI - Aging voice: presbyphonia. AB - Presbyphonia is a physiological process of aging voice that includes morphological changes in the coverage mucosa, muscle, and cartilage. We revised the morphological, endoscopic, and vocal acoustic changes that occur in presbyphonia and discussed some treatments proposed to minimize glottal incompetence and improve vocal performance of the elderly. PMID- 24068557 TI - Association of prediagnostic physical activity with survival following breast cancer diagnosis: influence of TP53 mutation status. AB - PURPOSE: Physical activity both before and after breast cancer diagnosis has been associated with improved survival. However, it is not clear whether this association differs by molecular features of the tumor or by recency of the physical activity to the time of diagnosis. METHODS: We examined the association of prediagnostic physical activity with survival in a cohort of 1,170 women with primary, incident, and histologically confirmed breast cancer, examining tumor molecular subtypes. Cox regression models were used to estimate hazard ratios (HR) and 95 % confidence intervals (95 % CI). RESULTS: Mean follow-up time was 87.4 months after breast cancer diagnosis; there were 170 deaths identified. Compared with inactive patients (<3 h/week), women with higher average lifetime physical activity (>6 h/week) had reduced risk of all-cause mortality (adjusted HR = 0.61, 95 % CI 0.40-0.95; p trend =0.04). There were no clear differences in the associations for lifetime and more recent physical activity. Lifetime physical activity was also weakly associated with decreased risk of breast cancer specific mortality. Higher lifetime physical activity was associated with reduced risk of all-cause mortality among women with ER-positive tumors (HR = 0.52, 95 % CI 0.29-0.93) and mutant TP53 tumors (HR = 0.22, 95 % CI 0.06-0.72); however, no statistically significant interactions were observed for ER or TP53 status. CONCLUSIONS: Our study further supports that prediagnostic physical activity improves overall survival following breast cancer and suggests that the associations of prediagnostic physical activity with survival following breast cancer may vary by molecular features of the tumor, particularly ER and TP53 status. PMID- 24068554 TI - Type I restriction enzymes and their relatives. AB - Type I restriction enzymes (REases) are large pentameric proteins with separate restriction (R), methylation (M) and DNA sequence-recognition (S) subunits. They were the first REases to be discovered and purified, but unlike the enormously useful Type II REases, they have yet to find a place in the enzymatic toolbox of molecular biologists. Type I enzymes have been difficult to characterize, but this is changing as genome analysis reveals their genes, and methylome analysis reveals their recognition sequences. Several Type I REases have been studied in detail and what has been learned about them invites greater attention. In this article, we discuss aspects of the biochemistry, biology and regulation of Type I REases, and of the mechanisms that bacteriophages and plasmids have evolved to evade them. Type I REases have a remarkable ability to change sequence specificity by domain shuffling and rearrangements. We summarize the classic experiments and observations that led to this discovery, and we discuss how this ability depends on the modular organizations of the enzymes and of their S subunits. Finally, we describe examples of Type II restriction-modification systems that have features in common with Type I enzymes, with emphasis on the varied Type IIG enzymes. PMID- 24068560 TI - Characteristics and determinants of survival in oldest old nursing home residents admitted to hospital with an acute illness compared to their younger counterparts. AB - BACKGROUND AND OBJECTIVES: The clinical problems and needs of our oldest old (>=85 years) are often substantially different from those of younger patients, and are arguably different from younger elderly patients (age 65-84). With the increasing number of frail oldest olds residing in Nursing Homes (NH), we aim to identify differences in prognostic indicators and outcomes in this age group compared to younger NH residents. METHODS: We retrospectively identified all consecutive admissions from NHs to an Acute Medical Assessment Unit between January 2005 and December 2007. Admission prognostic indicators and outcomes at follow-up were compared between younger (<85) and older (>=85) age groups. Using multiple regression methods controlling for potential confounders, we compared in hospital mortality and long-term survival after discharge between the groups. RESULTS: Three hundred and sixteen patients (mean age 84.3, SD 8.34 years) were included (68 % females). Admission characteristics were mostly similar between age groups. In-hospital mortality rates were not significantly different between groups, even after adjusting for possible confounders. Oldest old patients had a significantly greater hazard of dying after discharge (HR 1.37; 1.03-1.83) compared to the younger group after removing explanatory variables with more than 5 % missing data. CONCLUSION: Whilst the admission characteristics are similar between younger and older patients from NHs, there is evidence to suggest worse long-term survival prospects for oldest old patients. PMID- 24068561 TI - Valorization of solid waste products from olive oil industry as potential adsorbents for water pollution control--a review. AB - The global olive oil production for 2010 is estimated to be 2,881,500 metric tons. The European Union countries produce 78.5% of the total olive oil, which stands for an average production of 2,136,000 tons. The worldwide consumption of olive oil increased of 78% between 1990 and 2010. The increase in olive oil production implies a proportional increase in olive mill wastes. As a consequence of such increasing trend, olive mills are facing severe environmental problems due to lack of feasible and/or cost-effective solutions to olive-mill waste management. Therefore, immediate attention is required to find a proper way of management to deal with olive mill waste materials in order to minimize environmental pollution and associated health risks. One of the interesting uses of solid wastes generated from olive mills is to convert them as inexpensive adsorbents for water pollution control. In this review paper, an extensive list of adsorbents (prepared by utilizing different types of olive mill solid waste materials) from vast literature has been compiled, and their adsorption capacities for various aquatic pollutants removal are presented. Different physicochemical methods that have been used to convert olive mill solid wastes into efficient adsorbents have also been discussed. Characterization of olive based adsorbents and adsorption mechanisms of various aquatic pollutants on these developed olive-based adsorbents have also been discussed in detail. Conclusions have been drawn from the literature reviewed, and suggestions for future research are proposed. PMID- 24068562 TI - Detection of veterinary drug residues in surface waters collected nearby farming areas in Galicia, North of Spain. AB - The occurrence of pharmaceuticals in the aquatic environment has become a matter of concern in the last decade due to potential risks posed to non-target organisms and the potential for unintended human exposure via food chain. This concern has been driven by a high detection frequency for drugs in environmental samples; these substances are produced in large quantities and are used in both veterinary and human medicine, leading to deposition and potential effects in the environment. However, few studies have focused on the presence of pharmaceuticals in rural areas associated with farming activities in comparison to urban areas. The aim of this study is to investigate the occurrence of pharmaceutically active compounds in surface waters collected from urban and rural areas in northwestern Spain. A monitoring study was conducted with 312 river water samples analysed by high-performance liquid chromatography coupled to tandem mass spectrometry. Positive detection of pharmaceuticals was made for 51 % of the samples. Decoquinate, sulfamethazine, sulfamethoxypyridazine and trimethoprim were the drugs most frequently detected, being present in more than 10 % of the samples. The sampling sites located downstream of the discharge points for wastewater treatment plants yielded the highest number of positive samples, 13 % of the positive samples were detected in these sites and 38 % of the samples collected near the collection point of a drinking water treatment plant were positive. PMID- 24068563 TI - Quality of life and predictors of long-term outcome after severe burn injury. AB - The aim of this study was to identify the long-term quality of life after severe burn injury. In a prospective longitudinal design, N = 265 burn patients were examined 6, 12, 24, and 36 months after burn injury. A multilevel approach was used to measure stability and change in self-reported health status. Besides injury-related variables, self-report instruments included measures of quality of life, psychological distress, personality, and specific burn outcome measures. Fitting of unconditional growth models indicated that there was significant intra and inter-individual variation in self-reported physical and mental health short form-12. Over the course of 3 years, participants reported on average a slight improvement of physical quality of life. Physical health was mainly predicted by mobility and level of burn severity. Variance in mental health status was mainly predicted by gender, mobility, neuroticism, level of depression and posttraumatic stress disorder (PTSD)-related avoidance. Thus mobility (i.e., simple abilities) seems a crucial variable for overall quality of life. An early identification and treatment of patients with high levels of depression and PTSD-related avoidance may contribute to better mental health. PMID- 24068564 TI - Prognostic value of regulatory T cells in newly diagnosed chronic myeloid leukemia patients. AB - BACKGROUND: Chronic myeloid leukemia (CML) is a clonal disease, characterized by a reciprocal t(9, 22) that results in a chimeric BCR/ABL fusion gene. Regulatory T cells (Tregs) constitute the main cell population that enables cancer cells to evade immune surveillance. OBJECTIVE: The purpose of our study was to investigate the level of Tregs in newly diagnosed CML patients and to correlate it with the patients' clinical, laboratory and molecular data. We also aimed to assess the effect of treatment using tyrosine kinase inhibitor (TKI) on Treg levels. METHODS: Tregs were characterized and quantified by flow cytometry in 63 newly diagnosed CML patients and 40 healthy controls. TKI was used in 45 patients with chronic phase CML, and the response to therapy was correlated with baseline Treg levels. RESULTS: The percentages of Tregs were significantly increased in CML patients compared to the controls. Treg numbers were significantly lower in patients with chronic phase CML versus the accelerated and blast phases, and were significantly lower in patients with complete molecular remission (CMR) compared to those patients without CMR. CONCLUSION: Tregs may play a role in the maintenance of CML. Moreover, the decrease of their levels in patients with CMR suggests that Tregs might have a clinical value in evaluating the effects of therapy. PMID- 24068565 TI - miR-34a regulates cisplatin-induce gastric cancer cell death by modulating PI3K/AKT/survivin pathway. AB - The purposes of this study were to determine the expression profiles of microRNA 34a (miR-34a) in human gastric cancer cell line (SGC-7901) and cisplatin resistant cell lines (SGC-7901/DDP), and to establish the correlation between miR 34a expression profile and the sensitivity of human gastric cancer cell to cisplatin-based pattern, thereby providing new methods and strategies for treating gastric cancer. Gastric cancer cell line (SGC-7901) and cisplatin resistant cell line (SGC-7901/DDP) were cultivated in vitro, respectively. Quantitative real-time PCR (qRT-PCR) and Western blot were utilized to determine the expression profiles of miR-34a and survivin in both gastric cancer cell lines. With miR-34a mimic and miR-34a inhibitor transfected into SGC-7901 and SGC 7901/DDP for 48 h, post-transfection changes of miR-34a expression was determined; the effects of miR-34a ectopic expression on the viability of cisplatin-induce gastric cancer cell were assayed by the MTT method. The effects of miR-34a ectopic expression on apoptosis of cisplatin-induce gastric cancer cell were determined by Annexin V/propidium iodide (PI) double staining method and flow cytometry. The effects of miR-34a ectopic expression on the AKT and p AKT expression of cisplatin-induce gastric cancer cells were determined by Western blot and flow cytometry with the PI3K pathway inhibitor Wortmannin. As shown by qRT-PCR and Western blot analyses, the expression of miR-34a in cisplatin-resistant cell lines decreased significantly in comparison to that of SGC-7901 cell line (p < 0.05), while significant up-regulation of survivin expression was also observed (p < 0.05). Compared with the control group, the expression of miR-34a increased significantly in SGC-7901 cells transfected with miR-34a mimic for 48 h (p < 0.01). After miR-34a inhibitor transfection, the expression of miR-34a decreased significantly (p < 0.05). The viability of cisplatin-induce gastric cancer cells increased significantly (p < 0.05) with significant decrease of apoptosis after miR-34a expression inhibition, as demonstrated by MTT and flow cytometry with miR-34a over-expression, the viability of cisplatin-induce gastric cancer cells decreased significantly (p < 0.05), with significant apoptosis increase (p < 0.05). As shown by Western blot and flow cytometry, in comparison to the control group, Wortmannin could inhibit miR-34a inhibitor and DDP induced up-regulation of p-AKT significantly (p < 0.05) and stimulated apoptosis. In conclusion, miR-34a expression was down-regulated in cisplatin-resistant cell lines. miR-34a over-expression could improve the sensitivity of gastric cancer cells against cisplatin-based chemotherapies, with PI3K/AKT/survivin signaling pathway possibly involved in the mechanism. PMID- 24068566 TI - Polymorphisms in the vitamin D receptor gene and the lung cancer risk. AB - The relationship between the vitamin D receptor (VDR) polymorphisms and the susceptibility to lung cancer remains unclear. The present meta-analysis was performed to estimate the polymorphisms of VDR and lung cancer risk. The pooled odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) were calculated. Subgroup analysis by smoking status was carried out for further elucidation. The VDR BsmI polymorphism seemed to be negatively associated with the lung cancer risk (A vs. G, OR = 0.71, 95 % CI, 0.52-0.96; GA vs. GG, OR = 0.54, 95 % CI, 0.35-0.83; AA + GA vs. GG, OR = 0.55, 95 % CI, 0.36-0.84), particularly among the smokers (AA + GA vs. GG, OR = 0.39, 95 % CI, 0.21-0.72). The VDR ApaI variant genotypes did not alter the risk of lung cancer under all gene models in overall analysis. However, smokers carrying the variant G allele were more susceptible to lung cancer (G vs. T, OR = 1.60, 95 % CI, 1.14-2.25). The polymorphism of VDR TaqI was related to a decreased risk of lung cancer (C vs. T, OR = 0.62, 95 % CI, 0.26-1.46; CC vs. TT, OR = 0.44, 95 % CI, 0.21-0.91; TC vs. TT, OR = 0.58, 95 % CI, 0.38-0.90; CC + TC vs. TT, OR = 0.55, 95 % CI, 0.36-0.84). Besides, the CC + TC carriers in the smokers were at a significantly reduced risk of lung cancer (CC + TC vs. TT, OR = 0.48, 95 % CI, 0.16-1.44). The study supports that the polymorphisms of VDR BsmI and TaqI play protective roles in the lung carcinogenesis, particularly among the smokers. The association of VDR ApaI polymorphism with the lung cancer risk needs to be further elucidated. PMID- 24068567 TI - A critical review on HE4 performance in endometrial cancer: where are we now? AB - To date, no good marker for endometrial cancer (EC) that may be routinely used in clinical practice for diagnosis, prognosis and monitoring is available; besides the use of tumour markers is not recommended by international guidelines. However, during the last years, an increasing interest in literature has been growing on human epididymis protein 4 (HE4) that demonstrated to be a useful clinical marker with high sensitivity and specificity even at early stage. However, published studies differ for some variables such as HE4 cut-off and sample size. Therefore, we assess this comprehensive review to gather all the evidence reported in literature on HE4 potential value in diagnosis, prognosis, and recurrence of EC. A systematic literature search was performed using PubMed/PubMed Central/MEDLINE predefined keywords from January 1952 to June 2013. We divided all the relevant studies into three different clinical issues: "Diagnosis", "Prognosis" and "Disease monitoring". The analysis of published data suggests that HE4 is the most accurate and sensitive EC marker identified to date. In particular, this new marker seems to have a good performance in diagnosis. The best cut-off of HE4 in diagnosis ranges between 50 and 70 pmol/L, resulting at least in 78.8 % of sensitivity and 100 % of specificity in all stages. Another important aspect to consider is HE4 capacity in predicting the stage of disease and myometrial involvement, which can help scheduling the appropriate timing of imaging and surgery in a more individualised fashion and as indicator of patients prognosis. PMID- 24068568 TI - The tumor suppressor microRNA, miR-124a, is regulated by epigenetic silencing and by the transcriptional factor, REST in glioblastoma. AB - Reduced levels of specific microRNA in cancer are frequently reported and associated with attenuated cancer genes and associated pathways. We previously reported a loss of miR-124a in glioblastoma (GBM) patient specimens; however, the upstream causes of this loss are largely unknown. Loss of miR-124a has been attributed to hypermethylation while other studies have shown miR-124a to be regulated by the repressor-element-1-silencing transcription factor (REST, also known as neuron-restrictive silencing factor). This current study looked at both epigenetic and transcription factor regulation as potential mechanisms resulting in the loss of miR-124a expression in GBM patient specimens and cell lines. Hypermethylation of miR-124a was observed in 82 % of GBM patient specimens (n = 56). In vitro miR-124a expression levels also increased after treatment of several patient-derived cell lines with 5-aza-2'-deoxycytidine. Additionally, we also demonstrated a positive interaction between REST activity and miR-124a using a luciferase-binding assay and we correlated the reciprocal expression of REST and miR-124a in our clinical cohort. This result indicates that miR-124a expression may also be modulated through the upstream targeting of REST. Preclinical studies involving inhibitors of REST and treatment with demethylating agents with the intent to increase miR-124a levels could be interesting. PMID- 24068569 TI - Comment on Zhou et al. entitled "High plasma D-dimer level is associated with decreased survival in patients with lung cancer: a meta-analysis based on current evidence". PMID- 24068570 TI - Candidate epitopes for measurement of hCG and related molecules: the second ISOBM TD-7 workshop. AB - Participants of the Second International Workshop (WS) on human chorionic gonadotropin (hCG) of the International Society of Oncology and Biomarkers Tissue Differentiation 7 (ISOBM TD-7) have characterized in detail a panel of 69 antibodies (Abs) directed against hCG and hCG-related variants that were submitted by eight companies and research groups. Specificities of the Abs were determined using the First WHO International Reference Reagents for six hCG variants, i.e., hCG, hCGn, hCGbeta, hCGbetan, hCGbetacf, and hCGalpha, which are calibrated in SI units, and hLH. Molecular epitope localizations were assigned to the ISOBM-mAbs by comparing ISOBM-Ab specificity, sandwich compatibility, and mutual inhibition profiles, to those of 17 reference monoclonal (m)Abs of known molecular epitope specificities. It appeared that 48 Abs recognized hCGbeta-, 8 hCGalpha-, and 13 alphabeta-heterodimer-specific epitopes. Twenty-seven mAbs were of pan hCG specificity, two thereof with no (<0.1%; epitope beta1), 12 with low (<1.0%; epitopes beta2/4), and 13 with high (>>1%; epitopes beta3/5) hLH cross reactivity. The majority of hCGbeta epitopes recognized were located in two major antigenic domains, one on the peptide chain of the tips of beta-sheet loops 1 and 3 (epitopes beta2-6; 27 mAbs) and the second around the cystine knot (e.g., epitopes beta1, beta7, and beta10; 9 mAbs). Four mAbs recognized epitopes on hCGbetacf-only (e.g., epitopes beta11 and beta13) and six mAbs epitopes on the remote hCGbeta-carboxyl-terminal peptide (epitopes beta8 and beta9 corresponding to amino acids 135-144 and 111-116, respectively). For routine diagnostic measurements, methods are used that either detect hCG-only, hCGbeta-only, or hCG together with hCGbeta or hCG together with hCGbeta and hCGbetacf. Sandwich assays that measure hCG plus hCGbeta and eventually hCGbetacf should recognize the protein backbone of the analytes preferably on an equimolar basis, should not cross-react with hLH and not be susceptible to blunting of signal by nonmeasured variants like hCGbetacf. Such assays can be constructed using pairs of mAbs directed against the cystine knot-associated epitope beta1 (Asp10, Asp60, and Gln89) in combination with epitopes beta2 or beta4 located at the top of beta sheet loops 1 + 3 of hCGbeta involving aa hCGbeta20-25 + 68-77. In summary, the results of the First and Second ISOBM TD-7 WSs on hCG provide the basis for harmonization of specificities and epitopes of mAbs to be used in multifunctional and selective diagnostic hCG methods for different clinical purposes. PMID- 24068571 TI - Incidence of postoperative delirium is high even in a population without known risk factors. AB - PURPOSE: Postoperative delirium is a recognized complication in populations at risk. The aim of this study is to assess the prevalence of early postoperative delirium in a population without known risk factors admitted to the ICU for postoperative monitoring after elective major surgery. The secondary outcome investigated is to identify eventual independent risk factors among demographic data and anesthetic drugs used. METHODS: An observational, prospective study was conducted on a consecutive cohort of patients admitted to our ICU within and for at least 24 h after major surgical procedures. Exclusion criteria were any preexisting predisposing factor for delirium or other potentially confounding neurological dysfunctions. Patients were assessed daily using the confusion assessment method for the ICU scale for 3 days after the surgical procedure. Early postoperative delirium incidence risk factors were then assessed through three different multiple regression models. RESULTS: According to the confusion assessment method for the ICU scale, 28 % of patients were diagnosed with early postoperative delirium. The use of thiopentone was significantly associated with an eight-fold-higher risk for delirium compared to propofol (57.1% vs. 7.1%, RR = 8.0, chi2 = 4.256; df = 1; 0.05 < p < 0.02). CONCLUSION: In this study early postoperative delirium was found to be a very common complication after major surgery, even in a population without known risk factors. Thiopentone was independently associated with an increase in its relative risk. PMID- 24068572 TI - Do intrauterine device/intrauterine system users check their threads? AB - BACKGROUND: Expulsion of an intrauterine device (IUD) occurs in about 1 in 20 women and expulsion may not be noticed by the user. Current guidance recommends that users are instructed to check regularly for their threads. This is the first study to explore the reality of how women feel about checking their threads and the details surrounding how frequently checks are done. METHODS: One hundred consecutive IUD users were interviewed regarding their type of device, duration of use, frequency of thread checking, prompts for checking and reasons for not checking. RESULTS: Only 23% checked their threads regularly and 51% had never done so. The most common reason for not checking was forgetting about it. CONCLUSIONS: Despite being advised to do so, the majority of users do not check their threads at all and fewer than one-quarter of them check regularly. We propose that advice offered about thread checking should be given less emphasis and suggested more for user reassurance. PMID- 24068573 TI - Novel insights into M3 muscarinic acetylcholine receptor physiology and structure. AB - Recent studies with M3 muscarinic acetylcholine receptor (M3R) mutant mice suggest that drugs selectively targeting this receptor subtype may prove useful for the treatment of various pathophysiological conditions. Moreover, the use of M3R-based designer G protein-coupled receptors (GPCRs) has provided novel insights into how Gq-coupled GPCRs can modulate whole-body glucose homeostasis by acting on specific peripheral cell types. More recently, we succeeded in using X ray crystallography to determine the structure of the M3R bound to the bronchodilating drug tiotropium, a muscarinic antagonist (inverse agonist). This new structural information should facilitate the development of orthosteric or allosteric M3R-selective drugs that are predicted to have considerable therapeutic potential. PMID- 24068574 TI - Assessment of microembolization associated with revascularization in acute myocardial infarction: MDCT cardiac perfusion and function study. AB - To use multi-detector computed tomography (MDCT) for assessing the effects of coronary microemboli on pre-existing acute myocardial infarct (AMI) and to compare this pathology to LAD microembolization and occlusion/reperfusion. An angioplasty balloon catheter was placed in the LAD coronary artery of pigs under X-ray guidance. Four animals served as controls without intervention (group A) and an additional 24 animals (8/group) were subjected to microembolization (group B), occlusion/reperfusion (group C) or combination of the two insults (group D). MDCT was used to assess perfusion, LV function and viability. At postmortem, the LV sections were stained with hematoxylin/eosin and triphenyltetrazolium chloride (TTC). Dynamic perfusion and helical cine MDCT demonstrated decline in regional LV perfusion and function, respectively, after all interventions. MDCT showed significant differences in ejection fraction between groups: A = 57.5 +/- 4.7%, B = 40.3 +/- 0.5% P < 0.05, C = 34.9 +/- 1.3% P < 0.05 and D = 30.7 +/- 1.2% P < 0.05, while viability MDCT demonstrated differences in enhancement patterns and extents of damage between the groups (B = 9.1 +/- 0.4% LV mass, C = 11.9 +/- 0.7% and D = 16.2 +/- 1.2%, P < 0.05) and extent of microvascular obstruction (MVO) (group C = 3.2 +/- 1.0% LV mass versus D = 5.2 +/- 0.7%, P < 0.01). DE-MDCT overestimated all types of myocardial damage compared with TTC, but showed a close correlation (r > 0.7). Microscopic examination confirmed the presence of patchy and contiguous necrosis, MVO, edema and calcium deposits. Dynamic and helical cine MDCT imaging can grade LV dysfunction and perfusion deficit, respectively. DE-MDCT demonstrated a large and persistent MVO zone after microembolization of pre-existing AMI. Furthermore, it has the potential to visualize patchy microinfarct, detect perfusion deficits and dysfunction at the border zone after microembolization of pre-existing AMI. PMID- 24068575 TI - Coronary artery angiography and myocardial viability imaging: a 3.0-T contrast enhanced magnetic resonance coronary artery angiography with Gd-BOPTA. AB - With improving MR sequence, phase-array coil and image quality, cardiac magnetic resonance imaging is becoming a promising method for a comprehensive non-invasive evaluation of coronary artery and myocardial viability. The study aimed to evaluate contrast-enhanced whole-heart coronary MR angiography (CE WH-CMRA) at 3.0-Tesla for the diagnosis of significant stenosis (>=50%) and detection of myocardial infarction (MI) in patients with suspected coronary artery disease (CAD). CE WH-CMRA was performed in consecutive 70 patients with suspected CAD by using a 3.0-T MR system. A respiratory-gated, electrocardiography-triggered, inversion-recovery, segmented fast low angle shot sequence (TI = 200 ms) was used. Data acquisition began 60 s after the slow injection of Gd-BOPTA (0.2 mmol/kg body weight, at an injection rate 0.3 ml/s). At last, breath-hold 2D-PSIR SSFP sequence was performed. Diagnostic accuracy of CE WH-CMRA in detecting significant stenosis (>=50%) was evaluated using invasive coronary angiography as the referenced standard. The MI region appearing as high signal intensity visualized on CEWH-CMRA and 2D-PSIR-SSFP images were compared and analyzed. CE WH CMRA correctly identified 42 of 44 patients with significant CAD. The overall sensitivity, specificity, negative predictive value, positive predictive value and accuracy for diagnosing significant CAD was 83.6, 95.8, 96.0, 82.8 and 93.4% respectively. The MI region detected by WH-CMRA and 2D-PSIR-SSFP were consistent in 10 patients and these segments manifested with transmural or subendocardial enhancement patterns. Only one MI patient was judged inconsistent between WH-CMRA and 2D-PSIR-SSFP, who was confirmed by clinical and electrocardiogram results. The enhancement pattern in this patient was spotted and focal in 2D-PSIR-SSFP, but was dismissed by WH-CMRA. It is feasible to obtain information about coronary artery stenosis and myocardial viability in a single CE WH-CMRA with administration of Gd-BOPTA. PMID- 24068576 TI - Improved spatial resolution and electrogram wave direction independence with the use of an orthogonal electrode configuration. AB - To improve spatial resolution in recordings of intra-cardiac electrograms we characterized the utility of a novel configuration of two recording electrodes arranged perpendicularly to the endocardial surface. We hypothesized that this configuration denoted as orthogonal close unipolar (OCU) would combine advantages of conventional unipolar and contact bipolar (CBP) configurations. Electrical excitation was simulated in a computational model as arising from dipole current or from multi-wavelet reentry sources. Recordings were calculated for electrode tips 1 mm above the plane of the heart. Analogous recordings were obtained from swine hearts. Electrograms recorded with CBP showed strong dependence on orientation of the electrode pair with respect to the direction of spread of tissue excitation. By contrast, OCU recordings exhibited no directional dependence. OCU was significantly superior to CBP with respect to avoidance of far-field confounding of local tissue activity; the average far-field/near-field ratios for CBP and OCU were 0.09 and 0.05, respectively, for the simulated dipole current sources. In the swine hearts the ratios of ventricular to atrial signals for CBP and OCU were 0.15 +/- 0.07 and 0.08 +/- 0.09, respectively (p < 0.001). The difference between the actual dominant frequency in the tissue and that recorded by the electrodes was 0.44 +/- 0.33 Hz for OCU, 0.58 +/- 0.40 Hz for unipolar, and 0.62 +/- 0.46 Hz for CBP. OCU confers improved spatial resolution compared with both unipolar and CBP electrode configurations. Unlike the case with CBP, OCU recordings are independent of excitation wave-front direction. PMID- 24068577 TI - High fat diet exacerbates neuroinflammation in an animal model of multiple sclerosis by activation of the Renin Angiotensin system. AB - Epidemiological studies suggest a positive correlation between the incidence and severity of multiple sclerosis (MS) and the intake of fatty acids. It remains to be clarified whether high fat diet (HFD) indeed can exacerbate the disease pathology associated with MS and what the underlying mechanisms are. In this study, we determined the influence of HFD on the severity and pathology of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Mice were fed either normal diet (ND) or HFD and subsequently induced with EAE. Immunohistochemical staining and real-time PCR were used to determine immune cell infiltration and inflammatory mediators in the central nervous system (CNS). Our data show that HFD increases immune cell infiltration and inflammatory mediator production in the CNS and thereby aggravates EAE. Moreover, our data demonstrate that activation of the renin angiotensin system (RAS) is associated with the HFD mediated effects on EAE severity. These results show that HFD exacerbates an autoreactive immune response within the CNS. This indicates that diets containing excess fat have a significant influence on neuroinflammation in EAE, which may have important implications for the treatment and prevention of neuroinflammatory disorders. PMID- 24068578 TI - The Asia Pacific meeting on vasculitis and ANCA 2012 workshop on Takayasu arteritis: advances in diagnosis and medical treatment. AB - Takayasu arteritis is a rare disease affecting especially young females. Nonspecific symptoms make the diagnosis difficult; cases in which a diagnosis has not been made for a long period are not rare. However, recent progress in imaging modalities including magnetic resonance angiography, computed tomography angiography, and positron emission tomography have allowed making specific diagnoses in the early stage. Although specific serological markers of this disease are not known, many biomarkers specific to arterial inflammation are being developed and applied for diagnosing this disease. Also, advances in immunosuppressive treatment including new biological agents could alter the clinical outcome of the disease. According to these changes in diagnosis and treatment, the prognosis of Takayasu arteritis has been improving. PMID- 24068579 TI - A novel, cell-free PCR-based assay for evaluating the inhibitory activity of antiretroviral compounds against HIV reverse transcriptase. AB - This study describes a novel, PCR-based assay that evaluates the ability of compounds to inhibit cDNA generation by HIV reverse transcriptase (RT), of both commercial and viral lysate origin, from a known RNA template. The template consisted of RNA from stable transfectants ectopically expressing the US6 gene of herpes simplex virus-1, coding for glycoprotein D. Controls were carried out to demonstrate that no residual DNA polymerase activity or DNA contamination was responsible for the amplified DNA in the tested, control samples. In this assay, 0.1 MUM nevirapine totally inhibited the RT activity of 0.5 U commercial HIV RT, while 10 nM inhibited it by only 10%. Conversely, 10 pM efavirenz completely inhibited 0.5 U HIV RT. Similar results were obtained when a self-prepared viral lysate was used as a source of HIV RT. A reference commercial kit directly measuring HIV RT activity, without amplification, was less sensitive than the new assay. As a consequence, the HIV RT 50% inhibitory concentration of nevirapine and efavirenz in the newly described assay was 8 and 5 * 10(3) times lower, respectively, than in the commercial assay. In conclusion, this novel method was sensitive, reproducible, and sufficiently rapid for screening in vitro the functional activity of known or potential antiretroviral compounds against HIV RT. PMID- 24068581 TI - Contamination of live attenuated vaccines with an infectious feline endogenous retrovirus (RD-114 virus). AB - Retroviruses are classified as exogenous and endogenous retroviruses according to the mode of transmission. Endogenous retroviruses (ERVs) are retroviruses which have been integrated into germ-line cells and inherited from parents to offspring. Most ERVs are inactivated by deletions and mutations; however, certain ERVs maintain their infectivity and infect the same host and new hosts as exogenous retroviruses. All domestic cats have infectious ERVs, termed RD-114 virus. Several canine and feline attenuated vaccines are manufactured using RD 114 virus-producing cell lines such as Crandell-Rees feline kidney cells; therefore, it is possible that infectious RD-114 virus contaminates live attenuated vaccines. Recently, Japanese and UK research groups found that several feline and canine vaccines were indeed contaminated with infectious RD-114 virus. This was the first incidence of contamination of 'infectious' ERVs in live attenuated vaccines. RD-114 virus replicates efficiently in canine cell lines and primary cells. Therefore, it is possible that RD-114 virus infects dogs following inoculation with contaminated vaccines and induces proliferative diseases and immune suppression, if it adapts to grow efficiently in dogs. In this review, we summarize the incidence of contamination of RD-114 virus in live attenuated vaccines and potential risks of infection with RD-114 virus in dogs. PMID- 24068580 TI - Molecular characterization of human respiratory syncytial virus, 2010-2011: identification of genotype ON1 and a new subgroup B genotype in Thailand. AB - This study reports the molecular epidemiology and genetic characterization of human respiratory syncytial virus (RSV) samples collected in Thailand from January 2010 to December 2011. In total, 1,315 clinical samples were collected from Bangkok and Khon Kaen provinces and were screened by semi-nested PCR for RSV infection. We found 74 samples (27.7 %) and 71 samples (6.8 %) to be RSV positive for Bangkok and Khon Kaen, respectively, and we sequenced 122 of these samples. Phylogenetic analysis revealed that 100 of the RSV-A-positive samples clustered into either genotype NA1 or the recently discovered genotype ON1 strain, which has a 72-nucleotide duplication in the second variable region of its G protein. Moreover, 22 of the RSV-B-positive samples clustered into four genotypes; BA4, BA9, BA10 and genotype THB, first described here. The NA1 genotype was found to be the predominant strain in 2010 and 2011. The ON1 strain detected in this study first emerged in 2011 and is genetically similar to ON1 strains characterized in other counties. We also describe the THB genotype, which was first identified in 2005 and is genetically similar to the GB2 genotype. In conclusion, this study indicates the importance of molecular epidemiology and characterization of RSV in Thailand in order to better understand this virus. Further studies should be conducted to bolster the development of antiviral agents and a vaccine. PMID- 24068582 TI - Phylogenetic relationships, recombination analysis, and genetic variability among diverse variants of tomato yellow leaf curl virus in Iran and the Arabian Peninsula: further support for a TYLCV center of diversity. AB - The discovery of five strains of TYLCV in Iran, including the most well-known and widespread, TYLCV-IL, spurred a detailed study of the full-length genomes of additional TYLCV field isolates and an in-depth analysis of phylogenetic relationships, extent of recombination, and genetic variability of TYLCV isolates within Iran and throughout the Arabian Peninsula. Phylogenetic analysis of complete genome sequences of TYLCV isolates from Iran and other countries revealed four monophyletic clusters could be differentiated based on geographical origin, indicating that recent dispersal of these populations (by the vector or by humans) from these four regions has occurred minimally, or not at all. Genetic analysis revealed that TYLCV-IL isolates from southern Iran possessed greater genetic variability than the northeastern isolates, a pattern that may be reflective of evolution driven by geographically dependent isolation. Similarly, isolates of TYLCV-OM originating from Oman showed greater genetic variability than TYLCV-OM variants from Iran. Major recombination events, which were detected in all strains of TYLCV had breakpoints initiating in the C1, C1/C4, C2/C3 and V1 open reading frames (ORFs) and ending at the non-coding region and the C1, C1/C2 and C3 ORFs. Hence, these regions have consistently served as hot spots for recombination worldwide during the evolution of all currently recognized isolates and strains of TYLCV. PMID- 24068584 TI - The impact of personality disorders on legally supervised community treatment: a systematic literature review. AB - Mental health needs are common among community corrections offenders and many are enrolled in some form of supervised or mandated treatment. One category of mental health problem which may be germane to both treatment completion and recidivism among those in legally supervised treatment is the diagnosis of Personality Disorder (PD). This systematic review reports on sixteen studies comprised of full or mixed legally-supervised samples of offender in community-based treatment and examines the impact of PDs on treatment completion. These studies were difficult to compare because of the differences in program setting, definition of treatment completion, definition of PD, method of PD assessment and type of treatment, among other variables. The impact of antisocial personality disorder in treatment was a common focus, and other PDs were rarely assessed. The relevance of DSM PD categories to offender management in community corrections as well as the limitations of the current PD diagnostic categories is discussed. PMID- 24068583 TI - Epigenetics and ncRNAs in brain function and disease: mechanisms and prospects for therapy. AB - The most fundamental roles of non-coding RNAs (ncRNAs) and epigenetic mechanisms are the guidance of cellular differentiation in development and the regulation of gene expression in adult tissues. In brain, both ncRNAs and the various epigenetic gene regulatory mechanisms play a fundamental role in neurogenesis and normal neuronal function. Thus, epigenetic chromatin remodelling can render coding sites transcriptionally inactive by DNA methylation, histone modifications or antisense RNA interactions. On the other hand, microRNAs (miRNAs) are ncRNA molecules that can regulate the expression of hundreds of genes post transcriptionally, typically recognising binding sites in the 3' untranslated region (UTR) of mRNA transcripts. Furthermore, there are a myriad of interactions in the interface of miRNAs and epigenetics. For example, epigenetic mechanisms can silence miRNA coding sites, and miRNAs can be the effectors of transcriptional gene silencing, targeting complementary promoters or silencing the expression of epigenetic modifier genes like MECP2 and EZH2 leading to global changes in the epigenome. Alterations in this regulatory machinery play a key role in the pathology of complex disorders including cancer and neurological diseases. For example, miRNA genes are frequently inactivated by epimutations in gliomas. Here we describe the interactions between epigenetic and ncRNA regulatory systems and discuss therapeutic potential, with an emphasis on tumors, cognitive disorders and neurodegenerative diseases. PMID- 24068585 TI - MR signal changes on hepatobiliary imaging after oral ingestion of manganese chloride tetrahydrate: preliminary examination. AB - PURPOSE: To clarify magnetic resonance (MR) signal changes during hepatobiliary imaging after oral ingestion of manganese chloride tetrahydrate (Bothdel Oral Solution 10) (MCT). MATERIALS AND METHODS: Subjects were an MCT phantom, 10 healthy volunteers and 155 consecutive patients. The phantom study evaluated the relationship between MCT concentration and MR signal intensity. The volunteer study qualitatively and quantitatively analyzed the time course of hepatobiliary imaging immediately and 30, 60, 120 and 180 min after oral ingestion of MCT. The clinical study analyzed the incidence and factors affecting signal changes on additional MRCP with MCT as a final scan during routine clinical MRCP. RESULTS: In the phantom study, a significant and excellent positive linear correlation was found between MCT concentration and R2* measurement (r(2) = 0.996, p < 0.01). In the volunteer study, biliary imaging and hepatic R2* values changed significantly after oral ingestion of MCT (p < 0.05). In the clinical study, a signal drop on MRCP with MCT was visually confirmed in 14.8 % of cases. Multivariate logistic regression found no factors significantly affecting signal drop. CONCLUSION: We recommend performing MRCP early after oral ingestion of MCT, because signal changes occur even during routine MRCP. PMID- 24068586 TI - Expression and role of grainyhead-like 2 in gastric cancer. AB - The aim of this study was to evaluate the expression and role of Grhl2 in gastric cancer. Immunohistochemistry was performed to explore the expression of Grhl2 in gastric cancer and surrounding non-tumor tissues. Moreover, the mRNA and protein expression level of Grhl2 in human immortalized gastric epithelial cell line GES 1 and four gastric cancer cell lines (MGC803, SGC7901, MKN45, HGC27) were detected by qRT-PCR and Western blotting, respectively. To further investigate the role of Grhl2 in gastric cancer as well as the potential mechanisms, SGC7901 cells were transfected with lentiviral constructs expressing Grhl2 or empty vector, and then proliferation and apoptosis of SGC7901 cells were evaluated by MTT assay and flow cytometry, respectively. Finally, the protein expression level of c-Myc and Bcl-2 was detected by Western blotting. Both mRNA and protein expression level of Grhl2 were significantly downregulated in gastric cancer. Exogenous Grhl2 transduced into SGC7901 cells significantly inhibited the proliferation and promoted apoptosis. Meanwhile, over-expression of Grhl2 decreased c-Myc and Bcl-2 protein expression level. Taken together, our results demonstrated that Grhl2 downregulated in gastric cancer and may function as a tumor suppressor and play an important role in the development and progression of gastric cancer. These results may provide a new clue for treatment for gastric cancer. PMID- 24068587 TI - Endoscopic ultrasound elastography in diagnosing chronic pancreatitis: has the strain ratio found its region of interest? PMID- 24068588 TI - Feasibility and efficiency of a new 22G core needle: a prospective comparison study. AB - BACKGROUND AND STUDY AIMS: Histological examination of core tissue samples may have advantages over cytology in endoscopic ultrasound (EUS)-guided sampling. We aimed to evaluate the feasibility and efficiency of a new 22G core biopsy needle. PATIENTS AND METHODS: Consecutive patients with a pancreatic mass lesion or peri intestinal lymphadenopathy sequentially underwent fine needle biopsy with both a newly developed 22G core needle (the FNB needle) and a standard 22G fine needle aspiration (FNA) needle, in randomized order. RESULTS: In 144 patients, mean age 48 years (+/- standard deviation [SD] 14; range 18 - 82), with 145 lesions (mean lesion size 39 +/- 15 mm, range 15 - 99), EUS-guided sampling was technically feasible with both needles in all patients. Mean number of passes to obtain sufficient tissue was 1.2 +/- 0.5 with the core needle vs. 2.5 +/- 0.9 with the standard needle (P < 0.001). FNB specimens were adequate for evaluation in 125 (86.2 %) vs. 127 (87.6 %) with FNA (P = 0.72). Among 139 patients available for follow-up, FNB provided a correct diagnosis in 110 (79.1 %) and FNA in 112 (80.6 %) (P = 0.73). Sensitivity, specificity, positive and negative predictive values, and accuracy for diagnosis of malignancy were 90 %, 100 %, 100 %, 93 %, 96 % for FNB and 77 %, 100 %, 100 %, 85 %, 92 % for FNA, respectively (P > 0.05). CONCLUSION: FNB with the new 22G core needle was technically feasible, efficient and comparable to FNA with a standard needle. The core needle required fewer passes to provide an adequate sample, offering potentially shorter procedure time. PMID- 24068589 TI - The German colonoscopy screening program: the quality of a quality register. PMID- 24068590 TI - Endoscopic submucosal dissection of gastric lesions using the "yo-yo technique". PMID- 24068591 TI - The benefit of celiac ganglion injection remains unclear. PMID- 24068592 TI - Reply to Dr. Sahai. PMID- 24068593 TI - Endoloop/clip technique for gastrointestinal hemorrhage: rescue or first-line line therapy? PMID- 24068594 TI - Reply to Curcio et al. PMID- 24068596 TI - State and local law enforcement agency efforts to prevent sales to obviously intoxicated patrons. AB - Alcohol sales to intoxicated patrons are illegal and may lead to public health issues such as traffic crashes and violence. Over the past several decades, considerable effort has been made to reduce alcohol sales to underage persons but less attention has been given to the issue of sales to obviously intoxicated patrons. Studies have found a high likelihood of sales to obviously intoxicated patrons (i.e., overservice), but little is known about efforts by enforcement agencies to reduce these sales. We conducted a survey of statewide alcohol enforcement agencies and local law enforcement agencies across the US to assess their strategies for enforcing laws prohibiting alcohol sales to intoxicated patrons at licensed alcohol establishments. We randomly sampled 1,631 local agencies (1,082 participated), and surveyed all 49 statewide agencies that conduct alcohol enforcement. Sales to obviously intoxicated patrons were reported to be somewhat or very common in their jurisdiction by 55 % of local agencies and 90 % of state agencies. Twenty percent of local and 60 % of state agencies reported conducting enforcement efforts to reduce sales to obviously intoxicated patrons in the past year. Among these agencies, fewer than half used specific enforcement strategies on at least a monthly basis to prevent overservice of alcohol. Among local agencies, enforcement efforts were more common among agencies that had a full-time officer specifically assigned to carry out alcohol enforcement efforts. Enforcement of laws prohibiting alcohol sales to obviously intoxicated patrons is an underutilized strategy to reduce alcohol-related problems, especially among local law enforcement agencies. PMID- 24068597 TI - Attitudes affecting the potential use of human papillomavirus vaccination: a survey of health promotion students in Mexico City. AB - Our aim was to explore the knowledge and attitudes of Mexican college students towards human papillomavirus (HPV) vaccination. We conducted a written questionnaire survey of a group of male and female undergraduate students in Health Promotion at the Autonomous University of Mexico City. A total of 163 subjects (40 males and 123 females, median age 24 years) took part. Only 13 % identified the risks factors of cervical cancer and 32 % knew the diseases caused by HPV. Females had a better knowledge than males on matters related to HPV vaccine. Seventy percent (110 of 157) of the respondents completely agreed on the importance of including protection against genital warts in the vaccine. Eighty eight percent (141/161) of subjects would have accepted receiving the vaccine, but 8 % (13/161) were ambivalent. There was a strong desire in this group of young adults who are not yet included in the current vaccination programs to receive the HPV vaccine, preferably the quadrivalent one. In conclusion, attitudes towards vaccination could be complex and opposed. PMID- 24068598 TI - Semi-stochastic cell-level computational modeling of the immune system response to bacterial infections and the effects of antibiotics. AB - A mathematical model for the immune system response to bacterial infections is proposed. The formalism is based on modeling the chemokine-determined transmigration of leukocytes from a venule through the venule walls and the subsequent in-tissue migration and engulfment of the pathogens that are responsible for the infection. The model is based on basic principles, such as Poiseuille blood flow through the venule, fundamental solutions of the diffusion reaction equation for the concentration field of pathogen-released chemokines, linear chemotaxis of the leukocytes, random walk of pathogens, and stochastic processes for the death and division of pathogens. Thereby, a computationally tractable and, as far as we know, original framework has been obtained, which is used to incorporate the interaction of a substantial number of leukocytes and thereby to unravel the significance of biological processes and parameters regarding the immune system response. The developed model provides a neat way for visualization of the biophysical mechanism of the immune system response. The simulations indicate a weak correlation between the immune system response in terms of bacterial clearing time and the leukocyte stiffness, and a significant decrease in the clearing time with increasing in-blood leukocyte density, decreasing pathogen motility, and increasing venule wall transmissivity. Finally, the increase in the pathogen death rate and decrease in pathogen motility induce a decrease in the clearing time of the infection. The adjustment of the latter two quantities mimic the administration of antibiotics. PMID- 24068599 TI - Obesity and asymptomatic hypertension among children aged 6-13 years living in Bursa, Turkey. AB - INTRODUCTION: Hypertension is an independent risk factor for cardiovascular disease. It is known that essential hypertension begins at a very early age. Recently, there have been reports of an increase in childhood hypertension, which has been attributed to an increase in the prevalence of childhood obesity. Obesity-dependent or independent asymptomatic hypertension can only be determined by random blood pressure measurements in children. OBJECTIVE: In this study, we aimed to investigate the prevalence of obesity and asymptomatic hypertension among children living in Bursa, Turkey. METHODS: One thousand children living in Nilufer district and being served by the Fethiye Bulvar Family Health Care Center were enrolled in this study. All seven family physicians working at the centre participated in the study. RESULTS: Eighty-five children (8.5%) were determined to be hypertensive. One hundred and twelve children (11.2%) were obese. Blood pressure and body mass index (BMI) increased with age, with peak prevalence of hypertension at age 12 and of obesity at age 10. CONCLUSIONS: The prevalence of obesity and hypertension is high among school-age children in Turkey. Family physicians should consistently perform blood pressure and BMI measurements as a part of well child visits through late childhood. PMID- 24068604 TI - Advanced Materials 25 years on. PMID- 24068600 TI - Application of dedifferentiated fat cells for periodontal tissue regeneration. AB - Periodontal diseases result from inflammation by bacterial infection in plaques, leading to tooth loss. However, regenerative approaches with periodontal tissue regeneration by guided tissue regeneration and enamel matrix derivative are not yet well established. Tissue regeneration requires three factors: cells, scaffold, and growth factors. Dedifferentiated fat cells (DFATs) are pluripotent with the same differentiation capacities as mesenchymal stem cells (MSCs). Access to MSCs is limited, whereas donor cells for DFATs are abundant in adipose tissues and can be non-invasively obtained. Therefore, we tested DFATs as a new source for periodontal tissue regeneration in an experimental periodontal tissue loss model in rats by transplanting DFATs on an atelocollagen scaffold using DFATs isolated from Sprague-Dawley (SD) rats expressing green fluorescent protein (GFP). GFP-DFAT cells were transplanted on the palatal side of the upper left first molar in SD rats and detected by H&E staining, GFP, and proliferating cell nuclear antigen (PCNA) expression. DFAT differentiation was also evaluated in three-dimensional cultures. GFP positive cells were detected in the regenerated tissue by the DFATs/scaffold mixture at 4 weeks after transplantation, and PCNA positive cells were significantly increased in the periodontal ligament along the new bone in the DFATs/scaffold group more than in the scaffold-only group, suggesting that DFATs differentiate in the same manner as MSCs and regenerate in the defective areas. Consistent with previous reports, DFATs differentiation was slower than that with stem cells. The present study demonstrates that DFATs are pluripotent and an effective new source of cells for periodontal tissue regeneration. PMID- 24068608 TI - Manometric abnormalities in the postural orthostatic tachycardia syndrome: a case series. AB - BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a rare disease that is believed to be mediated by dysautonomia. Gastrointestinal complaints in POTS patients are common and disturbing but not well characterized. AIMS: We hypothesized that gastrointestinal dysmotility may be contributory to these symptoms. METHODS: We studied 12 POTS patients who presented with gastrointestinal symptoms to a tertiary referral center. Gastrointestinal symptoms were quantified using a previously validated symptom questionnaire. All patients underwent gastroduodenal manometry (GDM); select patients also underwent further testing including esophageal manometry (EM), anorectal manometry (ARM), plain abdominal radiography (AXR), abdominal computed tomography (CT), gastric emptying studies (GES), and colonic transit time (CTT) studies. RESULTS: The four most common symptoms were bloating, constipation, abdominal pain, and nausea/vomiting, all experienced by greater than 70 % of patients. On GDM testing, 93 % of patients demonstrated signs of neuropathy, and the most common abnormalities observed included bursts of uncoordinated phasic activity in both fasting (59 %) and post-prandial (42 %) states, low contractility in the post prandial state (67 %), and lack of post-prandial pattern (42 %). A total of 67 % of patients undergoing EM and 86 % of those undergoing ARM demonstrated abnormalities consistent with dysmotility. On AXR or CT, 58 % demonstrated either dilated intestinal loops or air-fluid levels. On CTT 80 % demonstrated delayed colonic transit, while on GES 60 % demonstrated delayed gastric emptying. CONCLUSIONS: In this cohort of POTS patients with gastrointestinal symptoms, there is a high prevalence of abnormal manometric and radiographic findings suggestive of dysmotility. PMID- 24068609 TI - Chronic insulin exposure does not cause insulin resistance but is associated with chemo-resistance in colon cancer cells. AB - Insulin resistance is an adaptive process in insulin-sensitive tissues characterised by reduced insulin receptor (IR) and insulin-receptor substrate (IRS)-1 expression, increased IRS-1 serine phosphorylation and attenuated downstream signalling. We tested whether this molecular phenotype prevails in cancer cells after long-term exposure to insulin. We characterised expression of IR-related molecules, IRS-1 phosphorylation and downstream signalling in a panel of 5 colon cancer cell lines at different insulin exposures: 15 min (100 nM), approximating to acute stimulation; 48 h (100 nM), used to demonstrate adaptive changes; and 12 weeks (20 nM; chronic insulin exposure, CIE), approximating to chronic hyperinsulinaemia. To assess clinical relevance, we determined IC50 values (increased indicating chemo-resistance) in the CIE-treated cells using oxaliplatin, SN38 (irinotecan) and 5-fluorouracil (5-FU). All colon cancer cell lines (HCT 116, HT-29, C32, CaCo2, LoVo) were sensitive to 15 min insulin exposure with increased phosphorylation of Akt, PRAS40 and p70-S6K. At 48 h, there was incomplete or absent features of insulin resistance. In CIE-treated cells, there was reduced IR expression, incomplete IRS-1 adaptation, lack of signalling pathway attenuation and contra-adaptive increases in IRS-1 tyrosine phosphorylation in several cell types. In CIE cells, there were multiple examples of increased IC50 values (2- to 100-fold) following 24-h treatment with oxaliplatin and SN38, but not with 5-FU. We concluded that CIE in colon cancer cells does not completely induce an insulin resistance molecular phenotype but is associated with chemo-resistance. Adaptive changes seen in insulin-sensitive non neoplastic cells in response to long-term insulin may not extrapolate to neoplastic cells. PMID- 24068610 TI - Role of secretin peptide family and their receptors in the hypothalamic control of energy homeostasis. AB - Secretin family of peptide hormones is a group of structurally related brain-gut peptides that exert their functions via interactions with the class B1 G protein coupled receptors (GPCRs). Recent researches of these peptides and receptors in metabolism have been an area of intense focus for the development of promising drug targets as therapeutic potentials for metabolic disorders. The fact that agonists of GLP-1, a member in the family, have already started being used as therapeutics clearly indicates the importance and relevance of further research on the clinical applications of these peptides. This review aims to provide an overview of the current understanding regarding the importance of this family of peptides as well as their receptors in metabolism with special focus on their actions in the hypothalamus. PMID- 24068611 TI - Smoking topography in Korean American and white men: preliminary findings. AB - This is the first study of Korean Americans' smoking behavior using a topography device. Korean American men smoke at higher rates than the general U.S. POPULATION: Korean American and White men were compared based on standard tobacco assessment and smoking topography measures. They smoked their preferred brand of cigarettes ad libitum with a portable smoking topography device for 24 h. Compared to White men (N = 26), Korean American men (N = 27) were more likely to smoke low nicotine-yield cigarettes (p < 0.001) and have lower Fagerstrom nicotine dependence scores (p = 0.04). Koreans smoked fewer cigarettes with the device (p = 0.01) than Whites. Controlling for the number of cigarettes smoked, Koreans smoked with higher average puff flows (p = 0.05), greater peak puff flows (p = 0.02), and shorter interpuff intervals (p < 0.001) than Whites. Puff counts, puff volumes, and puff durations did not differ between the two groups. This study offers preliminary insight into unique smoking patterns among Korean American men who are likely to smoke low nicotine-yield cigarettes. We found that Korean American men compensated their lower number and low nicotine-yield cigarettes by smoking with greater puff flows and shorter interpuff intervals than White men, which may suggest exposures to similar amounts of nicotine and harmful tobacco toxins by both groups. Clinicians will need to consider in identifying and treating smokers in a mutually aggressive manner, irrespective of cigarette type and number of cigarette smoked per day. PMID- 24068612 TI - Clinical practice guidelines for the prevention and treatment of osteoporosis in Taiwan: summary. AB - Osteoporosis is recognized as a major public health problem worldwide and in Taiwan. However, many patients with osteoporotic fractures do not receive appropriate assessments or treatments. This guideline, proposed by the Taiwanese Osteoporosis Association, is to serve as a quick reference for healthcare providers to improve the assessment of osteoporosis and development of optimal strategies for osteoporotic management in Taiwan. To review and update osteoporosis management, the guideline is constituted with Taiwan-specific osteoporosis epidemiological data, medication protocols, and the 10-year FRAX((r)). The guideline is based on evidence-based medicine and public health considerations. Recommendations are not limited to the reimbursement regulations permitted by the National Health Insurance of Taiwan. PMID- 24068613 TI - Alterations in the peripheral blood B cell subpopulations of multidrug-resistant tuberculosis patients. AB - The function of B cells in the immune response against Mycobacterium tuberculosis (Mtb) is still regarded as secondary, although major findings in mouse models of tuberculosis (TB) support their participation as regulators and antibody producers. However, studies in cohorts of TB or multidrug-resistant TB (MDR-TB) patients have failed to clearly identify changes in the circulating B cell pool. Therefore, in the present study we aimed at identifying alterations in the different B cell subpopulations in peripheral blood samples of HIV-negative pulmonary MDR-TB patients when compared to healthy donors. The data show, for the first time, that MDR-TB patients, similarly to what has been observed in other chronic inflammatory diseases, have a much lower frequency of peripheral blood unswitched IgD(+)CD27(+) memory B cells. Equally novel are the findings that in MDR-TB patients there is a reduction in the circulating plasma cell pool and that in MDR-TB there is an increased frequency of circulating type 1 transitional IgD(+)CD38(++), CD69(+) and TLR9(+) B cells. These results document disease related shifts in peripheral blood B cell subsets in MDR-TB and suggest that such changes should be taken into account when designing new strategies to boost the cellular and humoral immune response against Mtb. PMID- 24068614 TI - Detection and evaluation of immunofunction of patients with severe fever with thrombocytopenia syndrome. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by SFTS virus (SFTSV) with a high fatality rate. But the immunofunction was still unclear. The objective of our study was to assess the immunofunction in SFTS patients. Immunofunction test with flow cytometry which contains CD3+, CD4+ and CD8+ T lymphocytes, B cells and NK cells would be used for detecting serum samples collected from 34 SFTS cases and 20 healthy donors. We found that CD3+ and CD4+ T lymphocytes were significantly diminished in SFTS compared to normal control. In contrast, the percentage of NK cells was elevated. Further analysis revealed that the number of CD3+ and CD4+ T lymphocytes showed that there was a more robust pattern of depression in acute phase and severe SFTS infection compared to the patients in recovery phase and mild SFTS infection. But NK cells were significantly increased in acute phase and severe SFTS. They reverted to the near normal levels in convalescent phase. Additionally, the levels of CD3+ and CD4+ T lymphocytes progressively decreased in death group when compared with the survival group, but the level of B cells was higher. The damages of immune system were obvious, and the immune dysfunction might be partly responsible for disease progression of patients with SFTSV infection. PMID- 24068615 TI - Laforin-malin complex degrades polyglucosan bodies in concert with glycogen debranching enzyme and brain isoform glycogen phosphorylase. AB - In Lafora disease (LD), the deficiency of either EPM2A or NHLRC1, the genes encoding the phosphatase laforin and E3 ligase, respectively, causes massive accumulation of less-branched glycogen inclusions, known as Lafora bodies, also called polyglucosan bodies (PBs), in several types of cells including neurons. The biochemical mechanism underlying the PB accumulation, however, remains undefined. We recently demonstrated that laforin is a phosphatase of muscle glycogen synthase (GS1) in PBs, and that laforin recruits malin, together reducing PBs. We show here that accomplishment of PB degradation requires a protein assembly consisting of at least four key enzymes: laforin and malin in a complex, and the glycogenolytic enzymes, glycogen debranching enzyme 1 (AGL1) and brain isoform glycogen phosphorylase (GPBB). Once GS1-synthesized polyglucosan accumulates into PBs, laforin recruits malin to the PBs where laforin dephosphorylates, and malin degrades the GS1 in concert with GPBB and AGL1, resulting in a breakdown of polyglucosan. Without fountional laforin-malin complex assembled on PBs, GPBB and AGL1 together are unable to efficiently breakdown polyglucosan. All these events take place on PBs and in cytoplasm. Deficiency of each of the four enzymes causes PB accumulation in the cytoplasm of affected cells. Demonstration of the molecular mechanisms underlying PB degradation lays a substantial biochemical foundation that may lead to understanding how PB metabolizes and why mutations of either EPM2A or NHLRC1 in humans cause LD. Mutations in AGL1 or GPBB may cause diseases related to PB accumulation. PMID- 24068617 TI - Laparoscopic gastric banding outcomes do not depend on device or technique. long term results of a prospective randomized study comparing the Lapband(r) and the SAGB(r). AB - BACKGROUND: Gastric banding still represents one of the most widely used bariatric procedures. It provides acceptable weight loss in many patients, but has frequent long-term complications. Because different types of bands may lead to different results, we designed a randomized study to compare the Lapband(r) with the SAGB(r). We hereby report on the long-term results. METHODS: Between December 1998 and June 2002, 180 morbidly obese patients were randomized between Lapband(r) or SAGB(r). Weight loss, long-term morbidity, and need for reoperation were evaluated. RESULTS: Long-term weight loss did not differ between the two bands. Patients who maintained their band had an acceptable long-term weight loss of between 50 and 60 % EBMIL. In both groups, about half the patients developed long-term complications, with about 50 % requiring major redo surgery. There was no difference in the overall rates of long-term complications or failures between the two groups, but patients who had a Lapband(r) were significantly more prone to develop band slippage/pouch dilatation (13.3 versus 0 %, p < 0,001). CONCLUSIONS: Although in the absence of complication, gastric banding leads to acceptable weight loss; the long-term complication and major reoperation rates are very high independently from the type of band used or on the operative technique. Gastric banding leads to relatively poor overall long-term results and therefore should not be considered the procedure of choice for the treatment of morbid obesity. Patients should be informed of the limited overall weight loss and the very high complication rates. PMID- 24068618 TI - Synthesis, antimicrobial evaluation and QSAR studies of stearic acid derivatives. AB - A series of Schiff bases (1-17) and esters (18-28) of stearic acid was synthesized and characterized by physicochemical as well as spectral means. The synthesized compounds were evaluated in vitro for their antimicrobial activity by tube dilution method. The antimicrobial screening results indicated that the compounds having electron releasing groups on benzylidene nucleus were found to be more active against bacterial strains and compounds having electron withdrawing groups on benzylidene nucleus were found to be more active against fungal strains. QSAR studies demonstrated that electronic parameters dipole moment (u) and total energy (Te) were the most important descriptors in describing the antimicrobial activity of synthesized stearic acid derivatives. PMID- 24068619 TI - [Between faith and delusion]. AB - Religious beliefs can lead to difficulties in psychiatric diagnosis, when it comes to distinguishing between faith and delusion. Delusion is defined as a false assessment of reality combined with subjective certainty, which is in contrast with the reality of the social environment. The problem with this definition is that reality cannot be examined with scientific methods/criteria and that the assessment of reality itself underlies historical and cultural fluctuations. The current diagnostic manuals for psychiatric disorders DSM 5 and ICD-10 require, that the content of the belief has to be inadequate even in the subculture of the patient (ICD-10) and that the cultural and socioeconomic background of the patient has to be taken into account (DSM 5). On the basis of this case-report and of selected publications on this topic we want to discuss this diagnostic problem. After that we present a diagnostic model for delusion, which is easy to handle in the daily routine of psychiatrists. PMID- 24068616 TI - The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs). AB - The World Health Organization classifies myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) as a nervous system disease. Together with other diseases under the G93 heading, ME/cfs shares a triad of abnormalities involving elevated oxidative and nitrosative stress (O&NS), activation of immuno inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also abundant evidence that many patients with ME/cfs (up to around 60 %) may suffer from autoimmune responses. A wide range of reported abnormalities in ME/cfs are highly pertinent to the generation of autoimmunity. Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-alpha, and increased levels of nuclear factor-kappaB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability to produce antibodies. The chronic or recurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host's immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA. Here we also outline options for treatment involving rituximab and endotherapia. PMID- 24068622 TI - hypertensive intracranial bleed due to mid aortic syndrome. AB - The authors describe an 11-y-old child with intracranial bleed due to malignant hypertension. Child presented with hypertension, right hemiparesis, feeble femoral pulses and lower limb blood pressure less than the upper limb. CT angiogram revealed narrowing of the abdominal aorta with thinned out left renal artery and hypoplasia of the left kidney. A diagnosis of Mid aortic syndrome was arrived at. CT brain revealed left ganglio capsular bleed. Child was treated with antihypertensives and steriods in view of suspected Takayasu arteritis. Child recovered with minimal hemiparesis and is being followed up. PMID- 24068621 TI - Metallothioneins and trace elements dyshomeostasis induced by exposure to gasoline vapor in mice. AB - To investigate the effects of air pollution related with the gasoline/petrochemical industry the expression of metallothionein I (MT-I) mRNA and tissue metals were analyzed in organs of mice, exposed to gasoline (G) vapor in laboratory conditions. Control groups consisted of intact mice and of those exposed in the metabolic chamber to fresh air. The data obtained by RT-PCR and inductively coupled plasma spectrometry have shown that exposure to G vapor leads to upregulation of MT-I mRNA in organs that receive a strong respiratory and olfactory input or participate in gasoline degradation and elimination (lungs, brain, kidney and liver). Besides, in the brain and in the lungs, kidney and liver a decreased tissue content of Zn2+ or Cu2+ and Mg2+ was found (p<0.001). Some of these changes were obtained also in mice closed in the metabolic chamber, pointing to the involvement of stress-induced mechanisms in the transcriptional regulation of MTs. PMID- 24068623 TI - Myocarditis in children. AB - Myocarditis, a masquerader of common illnesses, presents with non-specific symptoms which are often missed by clinicians. The diagnosis is made based on clinical presentation and echocardiography findings and requires a high degree of clinical suspicion. The authors report seven children with myocarditis with review of spectrum of clinical presentation and management. PMID- 24068620 TI - Dual inhibition of MEK1/2 and EGFR synergistically induces caspase-3-dependent apoptosis in EGFR inhibitor-resistant lung cancer cells via BIM upregulation. AB - Epidermal growth factor receptor (EGFR) gene mutations activate the KRAS-RAF-MEK ERK pathway in lung cancer cells. EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib induce apoptosis of cancer cells, but prolonged treatment is often associated with acquired resistance. Here, we identified a novel MEK1/2 inhibitor, CZ0775, and compared its cytotoxic effects to those of AZD6244 (selumetinib) in non-small cell lung cancer (NSCLC) cell lines harboring EGFR mutations. The lapatinib-sensitive HCC827 and PC9 and lapatinib-resistant H1650 and H1975 cell lines showed poor responses to CZ0775 and AZD6244 monotherapy with an IC50 > 10 MUM. By contrast, combination treatment with lapatinib and CZ0775 inhibited cell proliferation and produced a 2-fold higher number of annexin V labeled cells than lapatinib alone in H1975 cells. Furthermore, combination treatment decreased phosphorylated extracellular signal related kinase (p-ERK) and survivin levels and upregulated the expression of the pro-apoptotic protein BIM. siRNA-mediated BIM depletion reduced caspase-3 activity (~40%) in lapatinib and CZ0775 treated H1975 cells. An in vitro ERK activity assay showed that p-ERK levels were approximately a 3-fold lower in H1975 cells treated with CZ0775 and lapatinib combination than in cells treated with lapatinib alone. CZ0775 was more cytotoxic than AZD6244 when used in combination with lapatinib. Our results suggest that combination treatment with CZ0774 and EGFR inhibitors is a promising therapeutic approach for the treatment of EGFR-TKI-resistant lung cancers and its effect is mediated by the inhibition of ERK and the induction of BIM. PMID- 24068624 TI - Inguinal swelling in a child - is it always hernia? PMID- 24068625 TI - Baygon (Propoxur) poisoning leading to acute respiratory distress syndrome (ARDS). PMID- 24068626 TI - An infant with primary autoimmune neutropenia and infection by Chlamydia pneumonia: an unusual association. PMID- 24068627 TI - Unsuspected right lobe liver infarction in Byler's disease--identified by hepatobiliary scintigraphy. PMID- 24068628 TI - Hiding the word: examining the relationship between a new measure of religiosity and sexual behavior. AB - The relationship between religiosity and sexual behavior has been previously investigated, but researchers have not examined the relationship between the intellectual dimension of religiosity and sexual behavior. In this study, we developed an intellectual measure of religiosity, Hiding the Word (HTW), and examined whether it accounted for variation in the sexual behavior of college students, beyond that for which age and a generic measure of religiosity could account. Results showed, after accounting for age and generic religiosity, HTW made a significant contribution to distinguishing between students who had, and those who had not, engaged in various sexual behaviors. For females, this was the case in three of the five behaviors examined (all except receiving oral sex and participating in unprotected penile-vaginal intercourse at most recent sexual encounter), and for males, two of the four behaviors (sexual intercourse and anal intercourse). HTW was less of a factor in accounting for variation in the frequency of participation. For males, HTW was significant for the frequency of participation in penile-vaginal intercourse, receiving oral sex, and the number of sexual partners in the last month. For females, HTW was significant only for the number of sexual partners in the last month. Thus, religiosity, and specifically HTW, seems to play more of a role in determining whether or not a person has participated in behavior, rather than in the frequency of participation. PMID- 24068629 TI - Intracranial arachnoid cysts in a chimpanzee (Pan troglodytes). AB - An intracranial arachnoid cyst was detected in a 32-year-old, 44.6-kg, female chimpanzee at the Primate Research Institute, Kyoto University. Magnetic resonance imaging (MRI) and computed tomography (CT) were performed and the cognitive studies in which she participated were reviewed. MRI revealed that the cyst was present in the chimpanzee's right occipital convexity, and was located in close proximity to the posterior horn of the right lateral ventricle without ventriculomegaly. CT confirmed the presence of the cyst and no apparent signs indicating previous skull fractures were found. The thickness of the mandible was asymmetrical, whereas the temporomandibular joints and dentition were symmetrical. She showed no abnormalities in various cognitive studies since she was 3 years old, except a different behavioural pattern during a recent study, indicating a possible visual field defect. Detailed cognitive studies, long-term observation of her physical condition and follow-up MRI will be continued. PMID- 24068630 TI - The effect of active vitamin D administration on muscle mass in hemodialysis patients. AB - BACKGROUND: Muscle wasting is common and insidious in end-stage renal disease (ESRD). Loss of muscle quantity and quality reduces quality of life and increases mortality in ESRD patients. Additionally, secondary hyperparathyroidism (SHPT) causes muscle atrophy. Meanwhile, vitamin D, which is used for SHPT treatment, plays an essential role in muscle growth. OBJECTIVES: We prospectively investigated the effect of active vitamin D administration on muscle mass. METHODS: We measured muscle mass based on bioelectrical impedance analysis in 68 hemodialysis patients. Patients were divided into a control group (without active vitamin D administration) and a VitD group (with active vitamin D administration). We compared muscle mass at the beginning of treatment and 1 year later. We also investigated health-related quality of life (HR-QOL) using the Medical Outcome Study Short Form-36 (SF-36). RESULTS: The VitD group experienced a significant increase in the amount of change in total muscle mass and muscle mass percentage in men (p = 0.025) but not in women (p = 0.945). By multivariable logistic regression analysis, active vitamin D administration was independently associated with increased muscle mass percentage in men only. In the SF-36, the physical functioning (PF) scores were significantly decreased at the end of the study in the patients without active vitamin D treatment, especially in women. CONCLUSION: Our results suggested that active vitamin D treatment was associated with increased muscle mass in men, and it might have a favorable effect on maintaining PF in HR-QOL in hemodialysis patients. PMID- 24068632 TI - The second issue of Nuclear Medicine Review for 2013. PMID- 24068631 TI - Xanthophylls, phytosterols and pre-beta1-HDL are differentially affected by fenofibrate and niacin HDL-raising in a cross-over study. AB - Fenofibrate and extended-release (ER) niacin similarly raise high-density lipoprotein cholesterol (HDL-C) concentration but their effects on levels of potent plasma antioxidant xanthophylls (lutein and zeaxanthin) and phytosterols obtained from dietary sources, and any relationship with plasma lipoproteins and pre-beta1-HDL levels, have not been investigated. We studied these parameters in 66 dyslipidemic patients treated for 6 week with fenofibrate (160 mg/day) or ER niacin (0.5 g/day for 3 week, then 1 g/day) in a cross-over study. Both treatments increased HDL-C (16 %) and apolipoprotein (apo) A-I (7 %) but only fenofibrate increased apoA-II (28 %). Lutein and zeaxanthin levels were unaffected by fenofibrate but inversely correlated with percentage change in apoB and low-density lipoprotein cholesterol and positively correlated with end of treatment apoA-II. ApoA-II in isolated HDL in vitro bound more lutein than apoA I. Xanthophylls were increased by ER-niacin (each ~30 %) without any correlation to lipoprotein or apo levels. Only fenofibrate markedly decreased plasma markers of cholesterol absorption; pre-beta1-HDL was significantly decreased by fenofibrate (-19 %, p < 0.0001), with little change (3.4 %) for ER-niacin. Although fenofibrate and ER-niacin similarly increased plasma HDL-C and apoA-I, effects on plasma xanthophylls, phytosterols and pre-beta1-HDL differed markedly, suggesting differences in intestinal lipidation of HDL. In addition, the in vitro investigations suggest an important role of plasma apoA-II in xanthophyll metabolism. PMID- 24068633 TI - 18F-FDGPET/CT: diabetes and hyperglycaemia. AB - BACKGROUND: Some patients who undergo 18F-FDG PET/CTfor neoplastic or benign disease are also affected by diabetes or hyperglycaemia. We propose different preparation procedures inpatients (pts) with hyperglycaemia (acute, temporary or chronic)or diabetes (type 1 or 2) at the time of the 18F-FDG injection, in order to improve the diagnostic scheduling of 18F-FDG PET/CT. MATERIAL AND METHODS: We evaluated a sample of 13,063 pts, examined in two different PET/CT centres, one with a stationary scanner (94.4%) and the other with a mobile device (5.6%). High blood sugar was present in 1,698 patients (13%) at the time of the 18F-FDG injection (hyperglycaemia was defined as fasting blood glucose > 11.1 mmol/l). We considered all 18F-FDG PET/CT tests performed over a period of 4 years (2006 2009). In the first 2 years (6,236 tests), scheduling was done directly by the administrative secretary. In the next two years, 6,827 pts underwent a preliminary visit to assess the test indications, medical history, and therapy as well as pre-test preparation. We evaluated different preparation protocols for hyperglycaemic or diabetic pts, especially those recommended in the guidelines of the European Association of Nuclear Medicine (EANM) and Society of Nuclear Medicine (SNM). RESULTS: In the four-year period, 713/13,063 patients (5.45%)were rescheduled; of these, 78.8% were rescheduled in the two years before the implementation of our preparation protocols and 21.2% in the next two years.Before the implementation of our preparation protocols, 562 patients (9%) presented occasional, acute or chronic hyperglycaemia (56.7%), or diabetes (43.3%), requiring postponement of the test to a later date. The test was not performed in 17 of 6,236 pts (0.27%) because of blood glucose levels above 11.1 mmol/l for several days, while in 16/6236 pts (0.26%) the18F-FDG injection was performed despite high blood glucose levels, in view of the clinical urgency.After the implementation of the preparation protocols, 2.2% of pts were rescheduled because of occasional, acute or chronic hyperglycaemia (79%), or diabetes (21%); 0.1% of pts did not undergo the test because of chronic high blood glucose levels. Although the administration of insulin is recommended in theEANM and SNM guidelines, in our new preparation procedures experience it was not necessary, because we reduced the numbers of hyperglycaemic pts thanks to screening at the preliminary visit and a subsequent good preparation of the patient before scheduling. CONCLUSIONS: The application of our preparation protocols improves the on-time performance and diagnostic accuracy,and increases patients' compliance. PMID- 24068634 TI - Individual dose monitoring of the nuclear medicine departments staff controlled by Central Laboratory for Radiological Protection. AB - Presented paper describes the results of the individual doses measurements for ionizing radiation, carried out by the Laboratory of Individual and Environmental Doses Monitoring (PDIS) of the Central Laboratory for Radiological Protection in Warsaw (CLOR) for the medical staff employees in several nuclear medicine (NM) departments across Poland. In total there are48 NM departments in operation in Poland [1] (consultation in Nuclear Atomic Agency). Presented results were collected over the period from January 2011 to December 2011 at eight NM departments located in Krakow, Warszawa (two departments), Rzeszow (two departments), Opole, Przemysl and Gorzow Wielkopolski. For radiation monitoring three kinds of thermo luminescence dosimeters (TLD) were used. The first TLD h collected information about whole body (C) effective dose, the second dosimeter was mounted in the ring (P) meanwhile the third on the wrist (N) of the tested person. Reading of TLDs was performed in quarterly periods. As a good approximation of effective and equivalent dose assessment of operational quantities both the individual dose equivalent Hp(10) and the Hp(0.07) were used. The analysis of the data was performed using two methods The first method was based on quarterly estimations of Hp(10)q and Hp(0.07)q while the second measured cumulative annual doses Hp(10)a and Hp(0.07)a. The highest recorded value of the radiation dose for quarterly assessments reached 24.4 mSv and was recorded by the wrist type dosimeter worn by a worker involved in source preparation procedure. The mean values of Hp(10)q(C type dosimeter) and Hp(0.07)q (P and N type dosimeter) for all monitored departments were respectively 0.46 mSv and 3.29 mSv. There was a strong correlation between the performed job and the value of the received dose. The highest doses always were absorbed by those staff members who were involved in sources preparation. The highest annual cumulative dose for a particular worker in the considered time period was 4.22 mSv for Hp(10)a and 67.7 mSv for Hp(0.07)a. In 2011 no case of exceeding the allowed dose limits was noted. PMID- 24068635 TI - Pattern and distribution of bone metastases in common malignant tumors. AB - BACKGROUND: Bone scan is a sensitive but not specific method for evaluation of bone metastases. However, the clinical data and the pattern of bone scan findings help the physician to narrow the diagnostic differentials. We tried to investigate the distribution of bone metastases in common cancers using bone scintigraphy. MATERIAL AND METHODS: 160 consecutive patients with malignancy (prostate cancer: 32, breast cancer: 107, lung cancer:8, and gastrointestinal cancers: 13) underwent bone scan. RESULTS: From the 160 patients, 58 patients (36.3%) had abnormal bone scans attributable to metastatic tumor. Bone metastases were found in 32.7%, 40.6%, 38.5% and 62.5% of patients with breast, prostate, GI and lung cancers, respectively (P = 0.35). The most frequently involved area was the spine, followed by ribs and pelvic bones. Spine was the most frequent site of bone metastases in breast and GI cancers. Except for the spine, common locations of bone metastases from breast cancer were ribs and sternum. In prostate cancer, the most frequent site were spine and pelvis, with similar incidences. In lung cancer, ribs followed by spine were most frequent sites of bone metastases. 97 (60.6%) of the cancer patients studied had symptoms of bone pain. The highest incidence was associated with metastatic lesions in bone scan (P = 0.004). Significant correlation between location of bone pain and evidence of bone metastasis in the same region was noticed in the pelvis (P =0.001), skull (P = 0.04), sternum (P = 0.01), spine (P = 0.003) and femur (P < 0.001). CONCLUSIONS: Our results indicate that the spine and pelvis in prostate carcinoma and the spine, ribs and sternum in breast carcinoma as well as ribs and spine in lung cancer are most frequently invaded. Bone pain in the skull, sternum, lumbar vertebrae, pelvis and proximal portion of femurs are more important to keep in mind for metastatic bone involvement. PMID- 24068636 TI - Different technical possibilities of post-therapeutic tandem 90Y/ /177Lu-DOTATATE imaging. AB - BACKGROUND: Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms derived from endocrine stem cells.These tumors are characterized by overexpression of somatostatin receptors (SSTR), which is utilized for imaging using SSTR analogs. Peptide receptor radionuclide therapy (PRRT) somatostatin analogs labeled with 90Y and 177Lu in neuroendocrine tumors (NETs) results in symptomatic improvement, prolonged survival,and enhanced quality of life. The post-therapeutic imaging leadsto possibility of biodistribution of therapy. The aim of our study was to describe different possibilities of post-therapeutic imaging in patients underwent tandem therapy 90Y/177Lu-DOTATATE with preliminary results of 90Y PET imaging. MATERIAL AND METHODS: Thirty patients (11 men, 19 women; the mean age 55 +/- 10.9 y) with histological confirmation of metastatic neuroendocrine tumors (G1 and G2) were treated with tandem therapy 90Y/177Lu DOTATATE. WHBA scan and SPECT acquisition of the abdomen were performed 24 hours post therapy injection, on the dual-head Varicam camera (ELSCINT) using 177Lu photopeak and 90Y bremsstrahlung. PET imaging of 90Y component was done on Siemens Biograph Truepoint PET/CT (window 511 keV +/- 15%)4 hours after 90Y/177Lu DOTATATE. Additionally phantom studies were performer to analyze the spatial resolution of different protocols. RESULTS: Out of all the patients, median OS was 49.8 months and median EFS time 24.3 months. Spatial resolution achieved for 90Y, 177 Lu and PET imaging of 90Y component measured using the phantom of the torso filled up with water was 20 mm, 8 mm and 4-5 mm FWHM, respectively. Spatial resolution in human body in our study was about 30 mm for 90Y, 15 mm for 177Lu and 25-30 mm for PET imaging of 90Y component. CONCLUSIONS: The theoretically best spatial resolution offers PET scanner, however it is important to keep in mind that 90Y-imaging PET is not used for diagnosis purposes (small activities)but rather to present new possibility of post-therapeutic imaging (substantially higher activities). For post-therapeutic imaging after intravenous radiopharmaceutical administration the best spatial resolution offers standard scintigraphic camera for 90Y/177Lu DOTATATE imaging, with using 177Lu photopeaks. The worst spatial resolution offers standard scintigraphic camera for 90Y/177Lu DOTATATE imaging, with using 90Y bremsstrahlung gammas. PMID- 24068637 TI - Imaging patterns of liver uptakes on PET scan: pearls and pitfalls. AB - OBJECTIVE: PET imaging is becoming increasingly universal, and therefore increased liver uptake is frequently encountered. The purpose of this article is to describe and illustrate the various morphological patterns of increased metabolic activity within the liver with an emphasis on the diagnostic pitfalls and potential limitations. CONCLUSION: Knowing the pitfalls of PET imaging, correlation with clinical background and findings from other imaging modalities are all important in the correct interpretation of increased hepatic activity on PET imaging. PMID- 24068638 TI - Extraosseous myocardial uptake incidentally detected during bone scan: report of three cases and a systematic literature review of extraosseous uptake. AB - Bone scintigraphy is widely considered as an important technique able to investigate various pathological conditions of the skeletal system. Many unexpected extraosseous uptakes have been reported in literature. We present here three cases of unexpected 99mTc-oxidronate (HDP) myocardial extraosseous uptakes in patients undergoing bone scan for staging purposes. In particular, we present the first reported case ofa myocardial uptake in a patient with IgM-related amyloidosis. Subsequently, we perform a review of the existing literature about extraosseous uptakes. PMID- 24068639 TI - Repetition of FDG PET study in the same day after appropriate patient preparation revealed two new cancer localizations: a case report. AB - A positron emission tomography scan with fluorodeoxyglucose can be affected by several factors. Skeletal muscle activation and physiological presence of radioactivity in urine frequently cause difficulties in images interpretation. We report a case of a patient with a non-operable left lung cancer, who was scheduled for FDG PET examination for radiotherapy planning purposes. In the first scan performed in the morning both elevated muscular and urinary uptake were present. For this reason another examination was performed on the same day. A new dose of radiopharmaceutical was given five hours after the first FDG injection and the patient was instructed to drink a large quantity of water in the meantime. The second PET scan clearly revealed two new lesions not visible at the time of the first examination: a synchronous bladder cancer, previously not known, and a mediastinal metastasis of the primary lung cancer. This case emphasizes the importance of correct patient preparation and shows the possibility to repeat PET examination on the same day. PMID- 24068640 TI - The association of increased stomach wall radiotracer uptake with prolonged use of omeprazole capsules on myocardial perfusion imaging (MPI) using 99mTc sestamibi SPECT. AB - Myocardial perfusion imaging (MPI) is widely used in routine practice for diagnosis and risk stratification of coronary artery disease (CAD). Intense curvilinear activity in the stomach wall of a patient was seen on MPI raw data. This phenomenon was completely dissimilar to the familiar intraluminal gastric reflux of sestamibi. This observed activity could have resulted in false-positive or false-negative artifacts - and inaccurate diagnosis - of the inferior wall of the left ventricle after MPI processing. On further exploration, the current researchers found that the patient had a history of 10-year Omeprazole capsule consumption. The authors present this infrequent case of intense stomach uptake to stress the related clinical and diagnostic implications with the aim to stimulate acute awareness of possible, unexpected infringements on image quality that could potentially interfere with accurate interpretation of the data. PMID- 24068641 TI - Imaging struma ovarii by means of 124I-Na PET/CT. AB - Struma ovarii is a rare form of ovary tumour defined as the presence of ectopic thyroid tissue in the ovarian structures. It usually presents with a benign course, although in some cases carcinoma or other malignant tumours can be found in the context of the ectopic tissue. Herein we report the case of a young patient affected by struma ovarii visualized by means of 124I-NaPET/CT. Thanks to the excellent target-to-background ratio of the tracer and the high resolution of the method, we could well identify the presence of some minimal tumour at the level of the left ovary. To our knowledge, this is the first report of its kind. PMID- 24068642 TI - An incidental detection of aortic aneurysm on Tc-99m MAG3 renal scintigraphy. AB - A 71-year-old man with newly diagnosed hypertension was referred for Technetium 99m mercaptoacetyltriglycine (Tc-99m MAG3) renal scintigraphy to evaluate the recent onset of impairment in renal functions. Dynamic imaging revealed activity flow which was suspicious for aortic aneurysm (AA) with a concurrent decrease in left renal blood flow. CT angiography of the thoracoabdominal aorta confirmed that this area corresponded to AA. The purpose of this report was to present the first case of incidental detection of AA on Tc-99m MAG3 scintigraphy and highlight the importance of correlative imaging for the diagnosis of abnormal radioactivity accumulation in the region of vascular structures. PMID- 24068645 TI - Calculations in nuclear medicine--application of free online software. PMID- 24068649 TI - Measuring brain perfusion with intravoxel incoherent motion (IVIM): initial clinical experience. AB - PURPOSE: To evaluate the feasibility of intravoxel incoherent motion (IVIM) perfusion measurements in the brain with currently available imaging systems. MATERIALS AND METHODS: We acquired high in-plane resolution (1.2*1.2 mm2) diffusion-weighted images with 16 different values of b ranging from 0 to 900 s/mm2, in three orthogonal directions, on 3T systems with a 32-multichannel receiver head coil. IVIM perfusion maps were extracted by fitting a double exponential model of signal amplitude decay. Regions of interest were drawn in pathological and control regions, where IVIM perfusion parameters were compared to the corresponding dynamic susceptibility contrast (DSC) parameters. RESULTS: Hyperperfusion was found in the nonnecrotic or cystic part of two histologically proven glioblastoma multiforme and in two histologically proven glioma WHO grade III, as well as in a brain metastasis of lung adenocarcinoma, in a large meningioma, and in a case of ictal hyperperfusion. A monoexponential decay was found in a territory of acute ischemia, as well as in the necrotic part of a glioblastoma. The IVIM perfusion fraction f correlated well with DSC CBV. CONCLUSION: Our initial report suggests that high-resolution brain perfusion imaging is feasible with IVIM in the current clinical setting. PMID- 24068650 TI - Toxicity of endosulfan to tadpoles of Fejervarya spp. (Anura: Dicroglossidae): mortality and morphological deformities. AB - The acute toxicity of endosulfan to the tadpoles of three coexisting species of the anuran genus Fejervarya revealed 96 h LC50 values of 46.715, 6.596, and 3.015 MUg l(-1) for Fejervarya sp.1, F. teraiensis and Fejervarya sp.2, respectively. Toxicity of endosulfan was also tested at the sublethal concentrations of 5 and 0.5, and 0.3 and 0.03 MUg l(-1) (c 10 and 1% of their respective 96 h LC50 values) in Fejervarya sp.1 and Fejervarya sp.2, and 0.35 and 0.18 MUg l(-1) (c 5 and 2.5% of 96 h LC50) in F. teraiensis. Endosulfan was observed to cause mortality at concentrations as low as c 1, 2.5 and 10% of their respective 96 h LC50 values in Fejervarya sp.2, F. teraiensis, and Fejervarya sp.1. Such vulnerabilities are likely to have implications for the survival of natural populations of these co-existing species as well as other anurans present in the study area where pesticide use is relatively high in the tea plantations. Morphological deformities caused by endosulfan comprised failure to develop one or both forelimb in Fejervarya sp.1 and F. teraiensis, stunted hindlimb growth in Fejervarya sp.1, and axial malformation in Fejervarya sp.1 and Fejervarya sp.2. Fore- and hind-limb deformities were likely to have occurred due to the impairment of thyroid metabolism by endosulfan. These effects illustrate the threat that continued endosulfan use poses to natural populations of anuran amphibians. PMID- 24068651 TI - Effect of Hg, As and Pb on biomass production, photosynthetic rate, nutrients uptake and phytochelatin induction in Pfaffia glomerata. AB - Plantlets of Pfaffia glomerata (Spreng.) were exposed for 28 days to three different metal/metalloid (Hg, Pb and As) with different levels (Hg 1; As 25, 50, 100 and Pb 100 and 400 MUM) to analyze the possible phytochelatin initiation and affects on growth and photosynthetic pigments vis-a-vis metal accumulation potential of plants. The plantlets showed significant Hg, As and Pb accumulation in roots (150, 1267.67 and 2129 MUg g(-1) DW respectively); however, a low root to shoot metal translocation was observed. It was interesting to note that all tested macronutrient (Mg, K, Ca) was higher in shoots and just opposite in case of micronutrients (Cu, Fe, Zn), was recorded highest in roots. The growth of plantlets (analyzed in terms of length and dry weight) was negatively affected by various metal treatments. In addition, the level of photosynthetic pigments alters significantly in response to all metal/metalloid treatment. In response to all tested metal/metalloids in plants only As induced phytochelatins (PC2, PC3 and PC4) in roots, and in shoots, GSH was observed in all tested metal/metalloids. In conclusion, P. glomerata plantlets could not cooperatively induce phytochelatins under any of Hg and Pb levels. PMID- 24068653 TI - Female and male gamete mitochondria are distinct and complementary in transcription, structure, and genome function. AB - Respiratory electron transport in mitochondria is coupled to ATP synthesis while generating mutagenic oxygen free radicals. Mitochondrial DNA mutation then accumulates with age, and may set a limit to the lifespan of individual, multicellular organisms. Why is this mutation not inherited? Here we demonstrate that female gametes-oocytes-have unusually small and simple mitochondria that are suppressed for DNA transcription, electron transport, and free radical production. By contrast, male gametes-sperm-and somatic cells of both sexes transcribe mitochondrial genes for respiratory electron carriers and produce oxygen free radicals. This germ-line division between mitochondria of sperm and egg is observed in both the vinegar fruitfly and the zebrafish-species spanning a major evolutionary divide within the animal kingdom. We interpret these findings as an evidence that oocyte mitochondria serve primarily as genetic templates, giving rise, irreversibly and in each new generation, to the familiar energy transducing mitochondria of somatic cells and male gametes. Suppressed mitochondrial metabolism in the female germ line may therefore constitute a mechanism for increasing the fidelity of mitochondrial DNA inheritance. PMID- 24068652 TI - Birth of three stowaway-like MITE families via microhomology-mediated miniaturization of a Tc1/Mariner element in the yellow fever mosquito. AB - Eukaryotic genomes contain numerous DNA transposons that move by a cut-and-paste mechanism. The majority of these elements are self-insufficient and dependent on their autonomous relatives to transpose. Miniature inverted repeat transposable elements (MITEs) are often the most numerous nonautonomous DNA elements in a higher eukaryotic genome. Little is known about the origin of these MITE families as few of them are accompanied by their direct ancestral elements in a genome. Analyses of MITEs in the yellow fever mosquito identified its youngest MITE family, designated as Gnome, that contains at least 116 identical copies. Genome wide search for direct ancestral autonomous elements of Gnome revealed an elusive single copy Tc1/Mariner-like element, named as Ozma, that encodes a transposase with a DD37E triad motif. Strikingly, Ozma also gave rise to two additional MITE families, designated as Elf and Goblin. These three MITE families were derived at different times during evolution and bear internal sequences originated from different regions of Ozma. Upon close inspection of the sequence junctions, the internal deletions during the formation of these three MITE families always occurred between two microhomologous sites (6-8 bp). These results suggest that multiple MITE families may originate from a single ancestral autonomous element, and formation of MITEs can be mediated by sequence microhomology. Ozma and its related MITEs are exceptional candidates for the long sought-after endogenous active transposon tool in genetic control of mosquitoes. PMID- 24068655 TI - Appropriate dose reduction in induction therapy is essential for the treatment of infants with acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group. AB - Infants (<1 year old) with acute myeloid leukemia (AML) are particularly vulnerable to intensive cytotoxic therapy. Indeed, the mortality rate was high among infants enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study, which prompted us to temporarily suspend patient enrollment and amend the protocol. Forty-five infants with AML were enrolled. For patients aged <2 years, drug doses were adjusted for body weight. Following the protocol amendments, doses for infants were reduced by a further 33 % in the initial induction course. Six infants died during the induction phase (including five early deaths), mainly due to pulmonary complications. The 3-year probability of overall survival (pOS) in all 45 infants [55.9 %, 95 % confidence interval (CI) 37.9-70.6 %] was significantly lower than that of patients aged 1 to <2 years (77.0 %, 95 % CI 62.7-86.3 %) and those aged >=2 years (74.7 %, 95 % CI 69.2-79.4 %) (P = 0.037), mainly due to the higher non-relapse mortality rate in infants. No early deaths occurred after the protocol amendments, and the 3-year pOS of the 17 infants enrolled thereafter was 76.4 % (95 % CI 48.8-90.4 %). In conclusion, appropriate dose reduction is essential to avoid early deaths when treating infants with AML. PMID- 24068654 TI - The effect of St John's wort on the pharmacokinetics of docetaxel. AB - BACKGROUND AND OBJECTIVE: St John's wort (SJW), a herbal antidepressant, is commonly used by cancer patients, and its component hyperforin is a known inducer of the cytochrome P450 (CYP) isoenzyme 3A4. Here, the potential pharmacokinetic interaction between SJW and the sensitive CYP3A4 substrate docetaxel was investigated. METHODS: In ten evaluable cancer patients, the pharmacokinetics of docetaxel (135 mg administered intravenously over 60 min) were compared before and after 14 days of supplementation with SJW (300 mg extract [Hyperiplant((r))] three times daily). RESULTS: SJW supplementation resulted in a statistically significant decrease in the mean area under the docetaxel plasma concentration time curve extrapolated to infinity (AUCinfinity) from 3,035 +/- 756 to 2,682 +/- 717 ng . h/mL (P = 0.045). Furthermore, docetaxel clearance significantly increased from 47.2 to 53.7 L/h (P = 0.045) after SJW intake. The maximum plasma concentration and elimination half-life of docetaxel were (non-significantly) decreased after SJW supplementation. In addition, the incidence of docetaxel related toxicities was lower after SJW supplementation. CONCLUSION: These results suggest that concomitant use of docetaxel and the applied SJW product should be avoided to prevent potential undertreatment of cancer patients. PMID- 24068656 TI - Romiplostim as early treatment for refractory primary immune thrombocytopenia. AB - Romiplostim is a thrombopoietin-receptor agonist approved to treat chronic immune thrombocytopenia (ITP). We treated eight patients with acute or persistent primary ITP, severe clinical bleeding, and resistance to corticosteroids and/or intravenous immunoglobulins (IVIg). Romiplostim, initially administered at 2 or 3 MUg/kg/week, was subsequently increased to achieve and maintain platelet-count responses and control bleeding. Seven patients' platelet counts rose above 30 G/L, representing >=twofold increases, within a median of 14 days after 1-5 infusions. The weekly dose reached 9 MUg/kg at week 5 for three patients; the other patients' ITPs were controlled with <=6 MUg/kg/week. No thromboembolic events occurred. Five patients received rituximab concomitantly with romiplostim, four of whom could stop romiplostim within 2 months, thereby demonstrating rituximab efficacy. All three patients treated with romiplostim alone required maintenance therapy. Thus, romiplostim represents an alternative for patients with severe acute or persistent ITP refractory to conventional therapy. PMID- 24068657 TI - Phase II study of ifosfamide, etoposide, and oxaliplatin (IFETOx) chemotherapy for relapsed or refractory non-Hodgkin's lymphoma. AB - As part of an effort to develop a more effective and safe treatment for relapsed or refractory non-Hodgkin's lymphoma (NHL), we conducted a phase II study of the oxaliplatin, etoposide, and ifosfamide (IFETOx) regimen. Patients with relapsed or refractory NHL and a performance status of 0-2 were eligible. The IFETOx consisted of etoposide at 100 mg/m(2) on days 1-3, oxaliplatin at 130 mg/m(2) on day 2, and ifosfamide 5,000 mg/m(2) on day 2, every 21 days. The primary endpoint was the overall response rate (ORR) for IFETOx regimen. A total of 23 eligible patients were enrolled. The median age was 58 years (range 19-76 years), and the male-to-female ratio was 15:8. The disease status was as follows: 15 patients had relapsed and 8 patients were refractory to treatment. The ORR for IFETOx chemotherapy was 65.2 %. In the 15 patients who responded to the protocol treatment, five underwent hematopoietic stem cell transplantation. The 2-year probability of progression-free survival and overall survival rates were 51.4 and 56.1 %, respectively. Grade 3/4 neutropenia was observed in 73.9 % of the patients. No significant renal impairment was observed. In conclusion, IFETOx chemotherapy shows a tolerable toxicity profile and efficacy as a salvage treatment regimen for relapsed or refractory NHL. PMID- 24068658 TI - Loop technique for mitral valve repair. AB - A new artificial chordal reconstruction technique has been developed using several expanded polytetrafluoroethylene (ePTFE) loops. This technique differs from conventional artificial chordal reconstruction in the use of premeasured ePTFE loops. The loop technique involves several steps: (1) assessment of the corresponding papillary muscle; (2) measurement of the required ePTFE loop length; (3) making a loop set of the premeasured length; (4) anchoring the loop set to the papillary muscle; (5) fixing the ePTFE loops to the prolapsing leaflet; (6) adjusting the loop length if necessary; and (7) ring implantation. Favorable early and mid-term results of this loop technique have been reported in patients undergoing mitral valve repair through mini-thoracotomy and via median sternotomy, with 3-year survival and re-operation-free rates of 94.8 and 97.4 %, respectively. The loop technique using ePTFE chordal reconstruction with premeasured loops thus appears to be a safe, reliable, and reproducible technique for mitral valve repair. In addition, it is suitable for both minimally invasive and conventional sternotomy approaches, and represents a useful technique for treating posterior, anterior, and especially bi-leaflet prolapses. PMID- 24068659 TI - Recent advances of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension including Japanese experiences. AB - Pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) remains challenging with some difficulties, although it has been a well established procedure. Its current situation including indications, surgical techniques with perioperative management, early and late outcome, and risk factors for mortality and poor hemodynamic improvement are reviewed. With the recent advancement of PEA including perioperative management and the accumulation of experiences, early outcome has been improved with low mortality rates, which are 5-10 % in most or <5 % in experienced centers. The risk factors for mortality were high pulmonary vascular resistance before and immediately after surgery, poor preoperative exercise capacity (NYHA-class IV), and advanced age. Reperfusion lung injury and residual pulmonary hypertension remain problematic as the most serious complications. The latter occurs in cases with surgically inaccessible distal lesions. For them, more careful perioperative management using pharmacological agents in conjunction with skillful PEA is required, occasionally with prompt use of percutaneous cardiopulmonary support. Although there have been a few reports on the long-term outcome, it is also favorable with good survival and event-free rates, which are affected by residual pulmonary hypertension. The recurrence of CTEPH after PEA is extremely rare. Consequently, as the first-line treatment for CTEPH, PEA can be performed safely with hemodynamic improvement and favorable early and long-term outcomes, except for potentially high-risk patients with distal lesions, elevated pulmonary vascular resistance, poor exercise capacity, and advanced age. Recently advanced balloon pulmonary angioplasty might be a promising alternative for such difficult patients. PMID- 24068662 TI - Neuraminidase reprograms lung tissue and potentiates lipopolysaccharide-induced acute lung injury in mice. AB - We previously reported that removal of sialyl residues primed PBMCs to respond to bacterial LPS stimulation in vitro. Therefore, we speculated that prior desialylation can sensitize the host to generate an enhanced inflammatory response upon exposure to a TLR ligand, such as LPS, in a murine model of acute lung injury. Intratracheal instillation of neuraminidase (NA) 30 min prior to intratracheal administration of LPS increased polymorphonuclear leukocytes (PMNs) in the bronchoalveolar lavage fluid and the wet-to-dry lung weight ratio, a measure of pulmonary edema, compared with mice that received LPS alone. Administration of NA alone resulted in desialylation of bronchiolar and alveolar surfaces and induction of TNF-alpha, IL-1beta, and chemokines in lung homogenates and bronchoalveolar lavage fluid; however, PMN recruitment in mice treated with NA alone did not differ from that of PBS-administered controls. NA pretreatment alone induced apoptosis and markedly enhanced LPS-induced endothelial apoptosis. Administration of recombinant Bcl-2, an antiapoptotic molecule, abolished the effect of NA treatment on LPS-induced PMN recruitment and pulmonary edema formation. We conclude that NA pretreatment potentiates LPS-induced lung injury through enhanced PMN recruitment, pulmonary edema formation, and endothelial and myeloid cell apoptosis. A similar "reprogramming" of immune responses with desialylation may occur during respiratory infection with NA-expressing microbes and contribute to severe lung injury. PMID- 24068663 TI - alpha3/4 Fucosyltransferase 3-dependent synthesis of Sialyl Lewis A on CD44 variant containing exon 6 mediates polymorphonuclear leukocyte detachment from intestinal epithelium during transepithelial migration. AB - Polymorphonuclear leukocyte (PMN) migration across the intestinal epithelium closely parallels disease symptoms in patients with inflammatory bowel disease. PMN transepithelial migration (TEM) is a multistep process that terminates with PMN detachment from the apical epithelium into the lumen. Using a unique mAb (GM35), we have previously demonstrated that engagement of the CD44 variant containing exon 6 (CD44v6) blocks both PMN detachment and cleavage of CD44v6. In this article, we report that PMN binding to CD44v6 is mediated by protein specific O-glycosylation with sialyl Lewis A (sLe(a)). Analyses of glycosyltransferase expression identified fucosyltransferase 3 (Fut3) as the key enzyme driving sLe(a) biosynthesis in human intestinal epithelial cells (IECs). Fut3 transfection of sLe(a)-deficient IECs resulted in robust expression of sLe(a). However, this glycan was not expressed on CD44v6 in these transfected IECs; therefore, engagement of sLe(a) had no effect on PMN TEM across these cells. Analyses of sLe(a) in human colonic mucosa revealed minimal expression in noninflamed areas, with striking upregulation under colitic conditions that correlated with increased expression of CD44v6. Importantly, intraluminal administration of mAb GM35 blocked PMN TEM and attenuated associated increases in intestinal permeability in a murine intestinal model of inflammation. These findings identify a unique role for protein-specific O-glycosylation in regulating PMN-epithelial interactions at the luminal surface of the intestine. PMID- 24068664 TI - Human memory Helios- FOXP3+ regulatory T cells (Tregs) encompass induced Tregs that express Aiolos and respond to IL-1beta by downregulating their suppressor functions. AB - FOXP3(+) regulatory T cells (Tregs) are critical regulators of self-tolerance and immune homeostasis. In mice and humans, two subsets of FOXP3(+) Tregs have been defined based on their differential expression of Helios, a transcription factor of the Ikaros family. Whereas the origin, specificity, and differential function of the two subsets are as yet a source of controversy, their characterization thus far has been limited by the absence of surface markers to distinguish them. In this article, we show that human memory Helios(+) and Helios(-) Tregs are phenotypically distinct and can be separated ex vivo based on their differential expression of IL-1RI, which is restricted to Helios(-) Tregs, in combination with CCR7. The two populations isolated using this strategy are distinct with respect to the expression of other Ikaros family members. Namely, whereas Eos, which has been reported to mediate FOXP3-dependent gene silencing, is expressed in Helios(+) Tregs, Aiolos, which is involved in the differentiation of TH17 and induced Tregs, is instead expressed in Helios(-) Tregs. In addition, whereas both subsets are suppressive ex vivo, Helios(-) Tregs display increased suppressive capacity in comparison to Helios(+) Tregs, but respond to IL-1beta by downregulating their suppressive activity. Together, these data support the concept that human Helios(-) memory Tregs encompass induced Tregs that can readily respond to changes in the environment by modulating their suppressive capacity. PMID- 24068665 TI - Identification of TLR4 as the receptor that recognizes Shiga toxins in human neutrophils. AB - Hemolytic uremic syndrome (HUS) caused by intestinal Shiga toxin-producing Escherichia coli infections is a worldwide health problem, as dramatically exemplified by the German outbreak occurred in summer 2011 and by a constant burden of cases in children. Shiga toxins (Stx) play a pivotal role in HUS by triggering endothelial damage in kidney and brain through globotriaosylceramide (Gb3Cer) receptor targeting. Moreover, Stx interact with human neutrophils, as experimentally demonstrated in vitro and as observed in patients with HUS. A neutrophil-protective role on endothelial damage (sequestration of circulating toxins) and a causative role in toxin delivery from the gut to the kidney (piggyback transport) have been suggested in different studies. However, the receptor that recognizes Stx in human neutrophils, which do not express Gb3Cer, has not been identified. In this study, by competition and functional experiments with appropriate agonists and antagonists (LPS, anti-TLR4 Abs, respectively), we have identified TLR4 as the receptor that specifically recognizes Stx1 and Stx2 in human neutrophils. Accordingly, these treatments displaced both toxin variants from neutrophils and, upon challenge with Stx1 or Stx2, neutrophils displayed the same pattern of cytokine expression as in response to LPS (assessed by quantitative RT-PCR, ELISA, or multiplexed Luminex-based immunoassays). Moreover, data were supported by adequate controls excluding any potential interference of contaminating LPS in Stx-binding and activation of neutrophils. The identification of the Stx-receptor on neutrophils provides additional elements to foster the understanding of the pathophysiology of HUS and could have an important effect on the development of therapeutic strategies. PMID- 24068666 TI - Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis. AB - Autoantibody production and immune complex deposition within the kidney promote renal disease in patients with lupus nephritis. Thus, therapeutics that inhibit these pathways may be efficacious in the treatment of systemic lupus erythematosus. Bruton's tyrosine kinase (BTK) is a critical signaling component of both BCR and FcR signaling. We sought to assess the efficacy of inhibiting BTK in the development of lupus-like disease, and in this article describe (R)-5 amino-1-(1-cyanopiperidin-3-yl)-3-(4-[2,4-difluorophenoxy]phenyl)-1H-pyrazole-4 carboxamide (PF-06250112), a novel highly selective and potent BTK inhibitor. We demonstrate in vitro that PF-06250112 inhibits both BCR-mediated signaling and proliferation, as well as FcR-mediated activation. To assess the therapeutic impact of BTK inhibition, we treated aged NZBxW_F1 mice with PF-06250112 and demonstrate that PF-06250112 significantly limits the spontaneous accumulation of splenic germinal center B cells and plasma cells. Correspondingly, anti-dsDNA and autoantibody levels were reduced in a dose-dependent manner. Moreover, administration of PF-06250112 prevented the development of proteinuria and improved glomerular pathology scores in all treatment groups. Strikingly, this therapeutic effect could occur with only a modest reduction observed in anti dsDNA titers, implying a critical role for BTK signaling in disease pathogenesis beyond inhibition of autoantibody production. We subsequently demonstrate that PF 06250112 prevents proteinuria in an FcR-dependent, Ab-mediated model of glomerulonephritis. Importantly, these results highlight that BTK inhibition potently limits the development of glomerulonephritis by impacting both cell- and effector molecule-mediated pathways. These data provide support for evaluating the efficacy of BTK inhibition in systemic lupus erythematosus patients. PMID- 24068667 TI - TIM-4 has dual function in the induction and effector phases of murine arthritis. AB - T cell Ig and mucin domain (TIM)-4 is involved in immune regulation. However, the pathological function of TIM-4 has not been understood and remains to be clarified in various disease models. In this study, DBA/1 mice were treated with anti-TIM-4 mAb during the induction or effector phase of collagen-induced arthritis (CIA). Anti-TIM-4 treatment in the induction phase exacerbated the development of CIA. In vitro experiments suggest that CD4 T cells bind to TIM-4 on APCs, which induces inhibitory effect to CD4 T cells. In contrast, therapeutic treatment with anti-TIM-4 mAb just before or after the onset or even at later stage of CIA significantly suppressed the development and progression by reducing proinflammatory cytokines in the ankle joints without affecting T or B cell responses. Consistently, clinical arthritis scores of collagen Ab-induced arthritis, which is not mediated by T or B cells, were significantly reduced in anti-TIM-4-treated mice with a concomitant decrease of proinflammatory cytokines in the joints. In vitro, macrophages secreted proinflammatory cytokines in response to TIM-4-Ig protein and LPS, which were reduced by the anti-TIM-4 mAb. The anti-TIM-4 mAb also inhibited the differentiation and bone-resorbing activity of osteoclasts. These results indicate that TIM-4 has two distinct functions depending on the stage of arthritis. The therapeutic effect of anti-TIM-4 mAb on arthritis is mediated by the inhibition of proinflammatory cytokine production by inflammatory cells, osteoclast differentiation, and bone resorption, suggesting that TIM-4 might be an appropriate target for the therapeutic treatment of arthritis. PMID- 24068668 TI - Multiparametric analysis of host response to murine cytomegalovirus in MHC class I-disparate mice reveals primacy of Dk-licensed Ly49G2+ NK cells in viral control. AB - MHC class I D(k) and Ly49G2 (G2) inhibitory receptor-expressing NK cells are essential to murine CMV (MCMV) resistance in MA/My mice. Without D(k), G2(+) NK cells in C57L mice fail to protect against MCMV infection. As a cognate ligand of G2, D(k) licenses G2(+) NK cells for effector activity. These data suggested that D(k)-licensed G2(+) NK cells might recognize and control MCMV infection. However, a role for licensed NK cells in viral immunity is uncertain. We combined classical genetics with flow cytometry to visualize the host response to MCMV. Immune cells collected from individuals of a diverse cohort of MA/My * C57L offspring segregating D(k) were examined before infection and postinfection, including Ly49(+) NK subsets, receptor expression features, and other phenotypic traits. To identify critical NK cell features, automated analysis of 110 traits was performed in R using the Pearson correlation, followed with a Bonferroni correction for multiple tests. Hierarchical clustering of trait associations and principal component analyses were used to discern shared immune response and genetic relationships. The results demonstrate that G2 expression on naive blood NK cells was predictive of MCMV resistance. However, rapid G2(+) NK cell expansion following viral exposure occurred selectively in D(k) offspring; this response was more highly correlated with MCMV control than all other immune cell features. We infer that D(k)-licensed G2(+) NK cells efficiently detected missing self MHC cues on viral targets, which elicited cellular expansion and target cell killing. Therefore, MHC polymorphism regulates licensing and detection of viral targets by distinct subsets of NK cells required in innate viral control. PMID- 24068669 TI - Ebf1 and c-Myb repress rag transcription downstream of Stat5 during early B cell development. AB - The temporal control of RAG (Rag) expression in developing lymphocytes prevents DNA breaks during periods of proliferation that could threaten genomic integrity. In developing B cells, the IL-7R and precursor B cell Ag receptor (pre-BCR) synergize to induce proliferation and the repression of Rag at the protein and mRNA levels for a brief period following successful Ig H chain gene rearrangement. Whereas the mechanism of RAG2 protein downregulation is well defined, little is known about the pathways and transcription factors that mediate transcriptional repression of Rag. Using Abelson murine leukemia virus transformed B cells to model this stage of development, we identified early B cell factor 1 (Ebf1) as a strong repressor of Rag transcription. Short hairpin RNA-mediated knockdown of either Ebf1 or its downstream target c-Myb was sufficient to induce Rag transcription in these highly proliferative cells. Ebf1 and c-Myb antagonize Rag transcription by negatively regulating the binding of Foxo1 to the Rag locus. Ebf1 accomplishes this through both direct negative regulation of Foxo1 expression and direct positive regulation of Gfi1b expression. Ebf1 expression is driven by the IL-7R downstream effector Stat5, providing a link between the negative regulation of Rag transcription by IL-7 and a novel repressive pathway involving Ebf1 and c-Myb. PMID- 24068670 TI - Inhibition of NF-kappaB by opioids in T cells. AB - Opioids potently inhibit a number of physiological and pathophysiological effects such as pain and inflammation in the brain and the periphery. One of the targets of opioids mediating such effects is the proinflammatory transcription factor NF kappaB. In neuronal cells, opioids inhibit this factor by inducing I-kappaB independently on calcium, involving the opioid-mediated activation of the transcription factor AP-1. However, when and how precisely NF-kappaB is modulated by opioids in T cells are unknown. By using the TNF-triggered, NF-kappaB-mediated induction of IL-8 mRNA in primary human T cells and Jurkat T cells, in this study we show that opioids inhibit NF-kappaB in T cells as well, but that the underlying mechanisms are different from those observed in neuronal cells. We found that stimulation of the T cells with opioids resulted in a significant inhibition of the TNF-triggered ubiquitination and degradation of I-kappaB. Additionally, an opioid-mediated induction of the deubiquitinating enzyme ubiquitin-specific protease 15 was observed, which is known to inhibit the NF kappaB pathway by stabilizing I-kappaB. The induction of ubiquitin-specific protease 15 was dependent on calcium and the transcription factor NFAT. Activation of AP-1 and induction of I-kappaB in response to the opioids were not observed in the T cells. These results indicate that MU opioid receptors, which mediate the effects in both cell types, might be coupled to different effector cascades in the different cell types, which may then result in cell type-specific effects of the drugs. PMID- 24068672 TI - AID-expressing germinal center B cells cluster normally within lymph node follicles in the absence of FDC-M1+ CD35+ follicular dendritic cells but dissipate prematurely. AB - Upon activation with T-dependent Ag, B cells enter germinal centers (GC) and upregulate activation-induced deaminase (AID). AID(+) GC B cells then undergo class-switch recombination and somatic hypermutation. Follicular dendritic cells (FDC) are stromal cells that underpin GC and require constitutive signaling through the lymphotoxin (LT) beta receptor to be maintained in a fully mature, differentiated state. Although it was shown that FDC can be dispensable for the generation of affinity-matured Ab, in the absence of FDC it is unclear where AID expression occurs. In a mouse model that lacks mature FDC, as well as other LT sensitive cells, we show that clusters of AID(+)PNA(+)GL7(+) Ag-specific GC B cells form within the B cell follicles of draining lymph nodes, suggesting that FDC are not strictly required for GC formation. However, later in the primary response, FDC-less GC dissipated prematurely, correlating with impaired affinity maturation. We examined whether GC dissipation was due to a lack of FDC or other LTbeta receptor-dependent accessory cells and found that, in response to nonreplicating protein Ag, FDC proved to be more critical for long-term GC maintenance. Our study provides a spatial-temporal analysis of Ag-specific B cell activation and AID expression in the context of a peripheral lymph node that lacks FDC-M1(+) CD35(+) FDC and other LT-sensitive cell types, and reveals that FDC are not strictly required for the induction of AID within an organized GC like environment. PMID- 24068674 TI - Chemoinformatics profiling of ionic liquids--automatic and chemically interpretable cytotoxicity profiling, virtual screening, and cytotoxicophore identification. AB - Ionic liquids (ILs) possess a unique physicochemical profile providing a wide range of applications. Their almost limitless structural possibilities allow the design of task-specific ILs. However, their "greenness," specifically their claimed relative nontoxicity has been frequently questioned, hindering their REACH registration processes and, so, their final application. Because the vast majority of ILs is yet to be synthesized, the development of chemoinformatics tools efficiently profiling their hazardous potential becomes essential. In this work, we introduce a reliable, predictive, simple, and chemically interpretable Classification and Regression Trees (CART) classifier, enabling the prioritization of ILs with a favorable cytotoxicity profile. Besides a good predictive capability (81% or 75% or 83% of accuracy or sensitivity or specificity in an external evaluation set), the other salient feature of the proposed cytotoxicity CART classifier is their simplicity and transparent chemical interpretation based on structural molecular fragments. The essentials of the current structure-cytotoxicity relationships of ILs are faithfully reproduced by this model, supporting its biophysical relevance and the reliability of the resultant predictions. By inspecting the structure of the CART, several moieties that can be regarded as "cytotoxicophores" were identified and used to establish a set of SAR trends specifically aimed to prioritize low cytotoxicity ILs. Finally, we demonstrated the suitability of the joint use of the CART classifier and a group fusion similarity search as a virtual screening strategy for the automatic prioritization of safe ILs disperse in a data set of ILs of moderate to very high cytotoxicity. PMID- 24068671 TI - Genotype-dependent effects of TGF-beta1 on mast cell function: targeting the Stat5 pathway. AB - We previously demonstrated that TGF-beta1 suppresses IgE-mediated signaling in human and mouse mast cells in vitro, an effect that correlated with decreased expression of the high-affinity IgE receptor, FcepsilonRI. The in vivo effects of TGF-beta1 and the means by which it suppresses mast cells have been less clear. This study shows that TGF-beta1 suppresses FcepsilonRI and c-Kit expression in vivo. By examining changes in cytokine production concurrent with FcepsilonRI expression, we found that TGF-beta1 suppresses TNF production independent of FcepsilonRI levels. Rather, IgE-mediated signaling was altered. TGF-beta1 significantly reduced expression of Fyn and Stat5, proteins critical for cytokine induction. These changes may partly explain the effects of TGF-beta1, because Stat5B overexpression blocked TGF-mediated suppression of IgE-induced cytokine production. We also found that Stat5B is required for mast cell migration toward stem cell factor, and that TGF-beta1 reduced this migration. We found evidence that genetic background may alter TGF responses. TGF-beta1 greatly reduced mast cell numbers in Th1-prone C57BL/6, but not Th2-prone 129/Sv mice. Furthermore, TGF-beta1 did not suppress IgE-induced cytokine release and did increase c-Kit mediated migration in 129/Sv mast cells. These data correlated with high basal Fyn and Stat5 expression in 129/Sv cells, which was not reduced by TGF-beta1 treatment. Finally, primary human mast cell populations also showed variable sensitivity to TGF-beta1-mediated changes in Stat5 and IgE-mediated IL-6 secretion. We propose that TGF-beta1 regulates mast cell homeostasis, and that this feedback suppression may be dependent on genetic context, predisposing some individuals to atopic disease. PMID- 24068673 TI - Interruption of the OX40-OX40 ligand pathway in LDL receptor-deficient mice causes regression of atherosclerosis. AB - Patients suffering from cardiovascular disease have well-established atherosclerotic lesions, rendering lesion regression of therapeutic interest. The OX40 (TNFRSF4)-OX40 ligand (OX40L; TNFSF4) pathway is important for the proliferation and survival of T cells, stimulates B cells, and is associated with cardiovascular disease. We hypothesized that interference with the OX40-OX40L pathway, in combination with decreases in cholesterol, may induce regression of atherosclerosis. LDLr(-/-) mice were fed a Western-type diet for 10 wk, after which they received chow diet and were treated with anti-OX40L or PBS for 10 wk. A significant regression of lesions was observed in the aorta and aortic arch of anti-OX40L-treated mice compared with control mice. Interference of the OX40 OX40L pathway reduced Th2 responses, as shown by decreases in GATA-3 and IL-4 levels. Also, IgE levels were decreased, as demonstrated by reduced mast cell presence and activation. Notably, IL-5 production by T and B1 cells was increased, thus enhancing atheroprotective oxidized low-density lipoprotein specific IgM production. The increase in IL-5 production and IgM was mediated by IL-33 production by APCs upon OX40L blockade. We conclude that interruption of the OX40-OX40L signaling pathway, combined with decreases in dietary cholesterol, induces the regression of atherosclerosis through induction of IL-5-producing T cells and oxidized low-density lipoprotein-specific IgM and reductions in Th2 and mast cells. PMID- 24068675 TI - Oral propylparaben administration to juvenile male Wistar rats did not induce toxicity in reproductive organs. AB - Parabens are in widespread use as preservatives in drugs. In the late 1990 s, concerns were raised about their capacity to disrupt endocrine function based on in vitro data and in vivo uterotrophic tests. Studies in juvenile male rats provided conflicting results on pospubertal sperm production. In an exploratory pharmacokinetic study, Wistar male rats received a single dose of propylparaben (PP) at 3, 10, 100, or 1000 mg/kg, orally on postnatal day (PND) 31. Plasma PP concentrations were quantifiable up 8h after dosing with a mean T max value of 15 min. Distribution was 4.8 l/kg, the plasma elimination half-life was 47 min, and clearance was 4.20 (l/h)/kg at 10mg/kg. A sulfoconjugated metabolite was detected. In the juvenile toxicology study, PP was orally administered by gavage to 20 Wistar male rats at doses of 3, 10, 100, or 1000 mg/kg/day in 1% hydroxyethylcellulose for 8 weeks starting on PND21. A first subgroup of 10 males/dose was necropsied immediately after the 8-week exposure period; a second subgroup of 10 males/dose was necropsied after a 26-week washout period. Blood samples were taken from additional satellite animals after dosing on PND21 and PND77 for toxicokinetic analysis. There was no evidence of an effect of PP on the weight of the male reproductive organs, epididymal sperm parameters, hormone levels, or histopathology. The dose of 1000 mg/kg/day was the no-observed adverse effect level, corresponding to a maximum plasma concentration of 12,030 ng/ml and exposure to 47 760 ng . h/ml (AUC0-8 h) at the end of the treatment. PMID- 24068676 TI - Ethylene oxide in blood of ethylene-exposed B6C3F1 mice, Fischer 344 rats, and humans. AB - The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largest volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain, and only limited data are available on the EO burden in ET-exposed rodents. Therefore, EO was quantified in blood of mice, rats, or 4 volunteers that were exposed once to constant atmospheric ET concentrations of between 1 and 10 000 ppm (rodents) or 5 and 50 ppm (humans). Both the compounds were determined by gas chromatography. At ET concentrations of between 1 and 10 000 ppm, areas under the concentration-time curves of EO in blood (umol * h/l) ranged from 0.039 to 3.62 in mice and from 0.086 to 11.6 in rats. At ET concentrations <= 30 ppm, EO concentrations in blood were 8.7-fold higher in rats and 3.9-fold higher in mice than that in the volunteer with the highest EO burdens. Based on measured EO concentrations, levels of EO adducts to hemoglobin and lymphocyte DNA were calculated for diverse ET concentrations and compared with published adduct levels. For given ET exposure concentrations, there were good agreements between calculated and measured levels of adducts to hemoglobin in rats and humans and to DNA in rats and mice. Reported hemoglobin adduct levels in mice were higher than calculated ones. Furthermore, information is given on species-specific background adduct levels. In summary, the study provides most relevant data for an improved assessment of the human health risk from exposure to ET. PMID- 24068677 TI - Uptake, p53 pathway activation, and cytotoxic responses for Co(II) and Ni(II) in human lung cells: implications for carcinogenicity. AB - Cobalt(II) and nickel(II) ions display similar chemical properties and act as hypoxia mimics in cells. However, only soluble Co(II) but not soluble Ni(II) is carcinogenic by inhalation. To explore potential reasons for these differences, we examined responses of human lung cells to both metals. We found that Co(II) showed almost 8 times higher accumulation than Ni(II) in H460 cells but caused a less efficient activation of the transcriptional factor p53 as measured by its accumulation, Ser15 phosphorylation, and target gene expression. Unlike Ni(II), Co(II) was ineffective in downregulating the p53 inhibitor MDM4 (HDMX). Co(II) treated cells continued DNA replication at internal doses that caused massive apoptosis by Ni(II). Apoptosis and the overall cell death by Co(II) were delayed and weaker than by Ni(II). Inhibition of caspases but not programmed necrosis pathways suppressed Co(II)-induced cell death. Knockdown of p53 produced 50%-60% decreases in activation of caspases 3/7 and expression of 2 most highly upregulated proapoptotic genes PUMA and NOXA by Co(II). Overall, p53-mediated apoptosis accounted for 55% cell death by Co(II), p53-independent apoptosis for 20%, and p53/caspase-independent mechanisms for 25%. Similar to H460, normal human lung fibroblasts and primary human bronchial epithelial cells had several times higher accumulation of Co(II) than Ni(II) and showed a delayed and weaker caspase activation by Co(II). Thus, carcinogenicity of soluble Co(II) could be related to high survival of metal-loaded cells, which permits accumulation of genetic and epigenetic abnormalities. High cytotoxicity of soluble Ni(II) causes early elimination of damaged cells and is expected to be cancer suppressive. PMID- 24068678 TI - Formation of synovial joints and articular cartilage. AB - Chondrocytes differentiate from mesenchymal progenitors and produce templates(anlagen) for the developing bones. Chondrocyte differentiation is controlled by Sox transcription factors. Templates for the neighbour bones are subsequently separated by conversion of differentiated chondrocytes into non chondrogenic cells and emergence of interzone in which joints cavitation occurs. A central role in initiating synovial joint formation plays Wnt-14/beta-catenin signalling pathway.Moreover, bone morphogenetic proteins and growth and differentiation factors are expressed at the site of joint formation. Joint cavitation is associated with increased hyaluronic acid synthesis. Hyaluronic acid facilitates tissue separation and creation of a functional joint cavity. According to the traditional view articular cartilage represents part of cartilage anlage that is not replaced by bone through endochondral ossification. Recent studies indicate, however, that peri-joint mesenchymal cells take part in interzone formation and that these interzone cells subsequently differentiate into articular chondrocytes and synovial cells. Thus,anlage chondrocytes have a transient character and disappear after cessation of growth plate function while articular chondrocytes have stable and permanent phenotype and function throughout life. PMID- 24068680 TI - The impact of left main coronary artery morphology on the distribution of atherosclerotic lesions in its branches. AB - BACKGROUND: Atherosclerotic occlusion of a coronary vessel is the commonest cause of ischaemic heart disease. The distribution of atherosclerotic lesions is not random,with stenoses preferentially situated at branch ostia, bifurcation points, and the proximal segments of daughter vessels. The aim of this study was to determine the effect of the intrinsic anatomical properties of the left main coronary artery(LMCA) on the distribution of atherosclerotic lesions in its branches. MATERIALS AND METHODS: A retrospective review of 170 consecutive coronary angiograms obtained from the cardiac catheterisation laboratories of private hospitals in the eThekwini Municipality area of KwaZulu-Natal, South Africa was performed. The LMCA was absent in 19/170 (11.2%). The remaining angiograms(n = 151) were divided into two groups: normal 63/151 (41.7%) and those with coronary artery disease (CAD) 88/151 (58.3%). The CAD group was sub-divided into proximal 42/88 (47.7%), mixed (proximal and distal) 26/88 (29.6%) and distal20/88 (22.7%) sub-groups based on the location of atherosclerotic lesions in the branches of the LMCA. RESULTS AND CONCLUSIONS: The mean length, diameter and angle of division of the LMCA were as follows: Total angiograms: 10.4 mm, 3.8 mm and 86.2o; normal group:10.5 mm, 3.9 mm and 85.7o, CAD group: 10.2 mm, 3.7 mm and 86.3o; proximal sub-group: 10.9 mm, 3.7 mm and 91.6o, mixed sub-group - 9.8 mm, 3.7 mm and 85o and distal sub-group - 9.1 mm, 3.8 mm and 79.4o, respectively. The vessels with proximally located lesions were recorded to have longer lengths and wider angles of division than vessels with distal lesions. Coronary angiographic delineation of the LMCA anatomy may be predictive of a coronary arterial arrangement that may favour the progression of proximally located lesions. PMID- 24068679 TI - The utility of multidetector computed tomography for evaluation of congenital heart disease. AB - BACKGROUND: Congenital heart diseases (CHD) are the leading cause of birth defect related deaths. Multi detector computed tomography (MDCT) plays an important role for imaging CHD in addition to echocardiography and provides a comprehensive evaluation of complex heart malformations for the referring cardiologist. The aim of the study was to evaluate the utility of MDCT in the assessment of CHD. MATERIALS AND METHODS: A 102 patients with CHD were investigated after initial assessment by echocardiography. The information obtained by MDCT and findings of echocardiography were reviewed together by paediatric cardiologists and cardiac radiologists. Perioperative anatomic descriptions, wherever available(n = 34) formed the gold standard for the comparison. RESULTS: The clinical consensus diagnosis defined 154 cardiovascular lesions in the patients. The results were classified in groups. We present the appearance of various congenital cardiac lesions seen in clinical practice. CONCLUSIONS: MDCT provides important information about anatomic details of CHD for the referring cardiologist. The evaluation of different anatomic structures such as heart, great vessels, lungs and abdomen is possible in one acquisition with this technique. PMID- 24068681 TI - Septomarginal trabecula and anterior papillary muscle in primate hearts: developmental issues. AB - The septomarginal trabecula is present in all human hearts as well as in the hearts of other primates. It usually connects the interventricular septum with the anterior papillary muscle, although there are many variations in how this is achieved. The object of the analyses was to estimate the bilateral topography of the septomarginal trabecula and the anterior papillary muscle in the context of the ontogeny and phylogeny of primates. A total of 138 hearts were examined from number of different non-human primates. The presence of the septomarginal trabecula was confirmed in 94.9% of cases, although not in the hearts of Lemur varius. Four configurations could be distinguished by defining the location of the septomarginal trabecula and its relation to the anterior papillary muscle.For the hearts of the Strepsirrhini and the majority of Platyrrhini neither structure was related, whereas in all examined representatives of Homino idea they had fused and created morphologically varying forms. On the basis of these results,a concept was developed for the sequence of changes which the topography of the septomarginal trabecula and the anterior papillary muscle undergo during ontogeny and phylogeny. PMID- 24068682 TI - Structure and immunohistochemistry of the human lenticulostriate arteries. AB - BACKGROUND: Data about the structure and immunohistochemistry of the lenticulostriate arteries (LSAs), although very important for medical research and clinical practice, have been rarely reported in literature. MATERIALS AND METHODS: Fourty serially sectioned LSAs were stained with hematoxilin and eosin, and prepared for immunohistochemistry. RESULTS: Our examination revealed a typical endothelial lining and a narrow subendothelial space with subintimal smooth muscle cells occasionally. The internal elastic lamina was fragmented or absent in the smallest LSAs branches. The mediacoat, with a mean diameter of 148.5 MUm, contained typical smooth muscle cells which formed 14.2 layers on average and showed a positive immune reactions for alfa-actin, desmine, laminin and collagen IV. The thin adventitial coat contained fibroblasts, collagen fibers, and nerve bundles, with the strongest immunopositivity to thyrosin hydroxilase. The immune reactions against CD31 and CD34 proteins,endothelial nitric oxide synthase, S 100 protein, neurofilament protein and synaptophysin,seem to be performed in the LSAs wall for the first time. Similarly,the thickness of the LSAs wall and its coats have never been reported, nor the number of the smooth muscle cell layers. CONCLUSIONS: Our results related to the structure and immunohistochemistry of the LSAs could be important in cerebrovascular pathology, neurology and neurosurgery. PMID- 24068683 TI - The morphology of lumbar sympathetic trunk in humans: a cadaveric study. AB - The vasospastic diseases and chronic pain related to lower limb have been successfully treated by surgical ablation of lumbar sympathetic trunk for last 80 years.Precise knowledge of anatomy of lumbar sympathetic trunk and its adjoining structures is mandatory for safe and uncomplicated lumbar and spinal surgeries.We aim to study the detailed anatomy of entry and exit of lumbar sympathetic trunk, the number, dimensions and location of lumbar ganglia in relation to lumbar vertebra. Thorough dissection was carried out in 30 formalin embalmed cadavers available in the Department of Anatomy, Pravara Institute of Medical Sciences (PIMS), Rural Medical College (RMC), Loni, Maharashtra. A total of 238 ganglia were observed in 60 lumbar sympathetic trunks. The sympathetic trunk traversed dorsal to the crus of diaphragm in 72.6% and in 13.3% it entered dorsal to the medial arcuate ligament. The most common site of the location of lumbar ganglia was in relation to the second lumbar vertebra, sometimes extending up to the L2 L3 vertebral disc. There was a medial shift of sympathetic trunk in lumbar region and it coursed over sacral promontory to reach the pelvic region in 96% of specimens. These variations should be kept in mind in order to prevent hazardous complications like accidental avulsion of first lumbar ganglia and genitofemoral neuritis. PMID- 24068684 TI - Morphometric analysis of muscularis proper and myenteric plexus of the normal human oesophagus. Age related changes. AB - BACKGROUND: Oesophagus is a muscular tube that transports food and liquids by coordinated contraction of its muscular lining led by stimuli from the nerve plexus. Its muscularis proper layer consists of muscle cells, connective tissue and myenteric plexus. The aim of our histomorphometric study was to reveal detailed characteristics of this layer, cell number, volume, orientation, properties of myenteric plexus as well as changes related to aging. MATERIALS AND METHODS: Oesophagus tissue samples from 17 male cadavers were taken from the cranial and thoracic parts. Samples were divided in 2 groups: younger(ages 21-45) and older (ages 66-78). The tissue was routinely processed,embedded and serially sectioned. Sections were stained with Masson-Goldner and Cresyl-violet dyes. Digital images were analysed with the image analysis software.Statistics were performed with SPSS software. RESULTS: The average thickness of the cranial part of the oesophageal wall and muscularis proper was 2590 MUm and 1197 MUm, respectively in the younger and 2453 MUm and 1144 MUm in the older group. Overall volume of the muscle tissue was slightly larger in the thoracic part, and in the younger group compared to the cranial part and the older group. The average number of the striated muscle cells per 100 MUm in the cranial part was 771.5 and 749.7 in the younger and the older group, respectively. Striated cells were significantly less present only in the lower thoracic part of the oesophagus. In the older group,smaller striated muscle cells dominated over the larger ones. In the younger group, majority of the striated muscle cells were mid-sized. The thickness of the circular layer of muscularis proper was more affected by aging than the longitudinal one. Ganglion cells number was lower in the older group, but plexus area was unchanged. CONCLUSIONS: Aging affects muscularis proper and myenteric plexus of the oesophagus.Major differences can be observed in the striated muscle cells size, volume of the circular layer and number of the ganglionic cells in the myenteric plexus. PMID- 24068685 TI - Ossification of the vertebral column in human foetuses: histological and computed tomography studies. AB - There is no agreement in the literature as to the time of the onset and progress of the vertebral column ossification. The aim of the present study was to determine the precise sequence of ossification of the neural arches and vertebral centra.Histological and radiographic studies were performed on 27 human foetuses aged from 9 to 21 weeks. It was found that the ossification of vertebrae commences in foetuses aged 10 and 11 weeks. Ossification centres appear first for neuralarches in the cervical and upper thoracic vertebrae and by the end of 11th week they are present in all thoracic and lumbar neural arches. In the vertebral centrain foetus of 10 weeks ossification was found in the lower 7 thoracic and first lumbar vertebrae. By the end of 11th week ossification is present in the lower 4 cervical, all thoracic, all lumbar and 4 sacral vertebral centra. The study indicates that ossification of the neural arches proceeds in the craniocaudal direction,whereas in the vertebral centra it progresses from the lower thoracic vertebrae into both directions. Different shapes of ossification centres were also described. PMID- 24068686 TI - Histomorphometric, fractal and lacunarity comparative analysis of sheep (Ovis aries), goat (Capra hircus) and roe deer (Capreolus capreolus) compact bone samples. AB - Quantitative and qualitative studies dealing with histomorphometry of the bone tissue play a new role in modern legal medicine/forensic medicine and archaeozoology nowadays. This study deals with the differences found in case of humerus and metapodial bones of recent sheep (Ovis aries), goat (Capra hircus) and roedeer (Capreolus capreolus) specimens, both from a qualitative point of view, but mainly from a quantitative perspective. A novel perspective given by the fractal analysis performed on the digital histological images is approached. This study shows that the qualitative assessment may not be a reliable one due to the close resemblance of the structures. From the quantitative perspective (several measurements performed on osteonal units and statistical processing of data),some of the elements measured show significant differences among 3 species(the primary osteonal diameter, etc.). The fractal analysis and the lacunarity of the images show a great deal of potential, proving that this type of analysis can be of great help in the separation of the material from this perspective. PMID- 24068687 TI - Anatomical variations of the hand extensors. AB - This study was performed to investigate the anatomy and variations of the human extensor tendons of the fingers and their intertendinous connections. Ninetyfive upper limbs of adult cadavers were dissected. The variations in the extensor tendons of the fingers, both proximal and distal to the extensor retinaculum, and their mode of insertion were observed. Also, the intertendinous connections were explored and the obtained data were analysed. The extensor pollicis longus and brevis tendons were found to be single, doubled or, rarely, absent. Their insertion could be traced to either the proximal phalanx, or through the extensor expansion to both phalanges, or rarely to the distal phalanx of thumb. The extensor indicis had a single tendon in all specimens. In the majority of specimens, extensor digitorum had no independent slip to the little finger; it gave off a single tendon to the index, double tendons to the middle finger and triple tendons to the ring finger. Extensor digiti minimi muscle often had double or triple tendons distal to the extensor retinaculum. Three types of juncturae tendinum (JT) were identified between the tendons of extensor digitorum in the 2nd, 3rd and 4th intermetacarpal spaces (IMS) of hands. Types 1 and 2 JT were seen in the three IMS. Type 3 JT was the most frequently identified of all juncturae and was always absent in the 2nd IMS. The percentages of the present data were compared with other researchers'data. PMID- 24068688 TI - Subgross and macroscopic investigation of the coeliac artery in the chinchilla (chinchilla lanigera). AB - The knowledge of branching and variations of the coeliac artery is clinically important, especially in the surgical operations and non-surgical treatments.Moreover, the chinchillas abdominal region have been used as a model in some surgical experimental researches. In this frame, we have aimed to explain the branching of this artery in the chinchillas detailedly. A total of 10 adult, healthy,male chinchillas (chinchilla lanigera) were used to investigate the origin and the course of the coeliac artery and its branches. Coloured latex was injected into the carotid arteries, following conventional anatomical applications. The results indicated that the coeliac artery was divided into 4 branches such as left gastricartery, hepatic artery, splenic artery and gastrolienal artery. The left gastric artery was a continuity of the coeliac artery and the main vessel of the stomach. The hepatic artery was divided into the left lateral branch, the left medial branch and the right branch. The splenic artery was covered by the pancreas tissue and sent branches to the pancreas. The gastrolienal artery was supplying the fundus of the stomach and the dorsal extremity of the spleen. We believe that the findings will be of help to the researchers interested in the anatomical area, surgeons and experimental researches. PMID- 24068689 TI - Woven coronary artery: a case report and literature review. AB - Woven coronary artery is extremely rare. It is characterised by thin channels arising from the coronary artery and reanastamosis at the distal portion. A 62 year-oldman was diagnosed of coronary artery disease. Coronary angiography showed 3-vessel coronary artery disease. The distal right coronary artery derived 3 twisting thin channels, and the inferior thin channel sprouted second-class thin channels,which then reanstomosed distally. He received off-pump coronary artery bypass.The present patient had woven coronary artery with a more complex configuration of thin channels different from the previously reported cases. PMID- 24068690 TI - Anatomic variability of groin innervation. AB - Inguinal hernia repairs are very common yet fairly complex surgical procedures.Variations in the anatomical course of the inguinal nerves require that diligence is taken in their proper recognition. Inadvertent surgical injury to these nerves is associated with long term postoperative pain and complications. The aim of the present study was to highlight the complexity and variation in the innervation of the inguinal region in order to increase proper nerve identification during surgical interventions. Bilateral dissection of the inguinal and posterior abdominal regions in one human male cadaver revealed an atypical anatomic topography of the groin innervation. This unusual case was observed at the Jagiellonian University Anatomy Department during routine cadaveric preparations. The left ilioinguinal nerve was absent. The left genital branch of the genitofemoral nerve arose higher than expected from the lumbar plexus and supplied the groin region, which is typically innervated by the ilioinguinal nerve. Furthermore, the left lateral cutaneous femoral nerve and the right genital branch of the genitofemoral nerve also followed uncharacteristic courses. Awareness of topographical nerve variations during inguinal hernia repair will help surgeons identify and preserve important nerves, thus decreasing the incidence of chronic postoperative pain. PMID- 24068691 TI - Persistent left superior vena cava with an absent right superior vena cava in a 72-year-old male with multivessel coronary artery disease. AB - Congenital anomalies of systemic veins are usually asymptomatic and found incidentally during ultrasonography, computed tomography (CT) or magnetic resonance examinations performed for other clinical indications. Persistent left superior vena cava (PLSVC) with absent right superior vena cava (RSVC) is the congenital aberration in the thoracic venous system which occurs in only 0.09%to 0.13% of patients who have congenital heart defects. In this paper, we present the extremely rare case of a 72-year-old male with PLSVC associated with an absence of RSVC, referred for coronary CT angiography. Multidetector CT angiography is a powerful tool for the detection of venous anomalies, which is essential before invasive procedures such as the implantation of pacemakers. PMID- 24068692 TI - Multidetector computed tomography findings of an asymptomatic levoatrial cardinal vein with an interatrial course. AB - A 57-year-old female patient with a family history of coronary artery disease admitted to our hospital for the coronary check-up. A coronary angiography was performed with ECG-gated 128 slice dual source computed tomography.Multidetector computed tomography (MDCT) showed, in addition to the normal coronary arteries, a persistent levoatrial cardinal vein (LCV) draining into vena cava superior. ECG gated cardiac MDCT is a useful tool showing the origin, course, and drainage site of LCV. PMID- 24068693 TI - Jugular phlebectasia presenting as globus pharyngeus. AB - Even though much has been written on the aetiology of globus pharyngeus, it still remains elusive and multifactorial. We present a case of a 54-year-old woman who was referred by an orthopedist to the radiology department with a 6-day history of an intense feeling of "pressure" and "tightness" in the jugular notch.After performing a contrast-enhanced computed tomography scan, a phlebectasia of the right anterior jugular vein was discovered. When trying to determine the cause of the globus sensation one has to consider the possible existence ofa phlebectasia of one of the jugular veins. PMID- 24068694 TI - In situ monitoring of laser-assisted hydrothermal growth of ZnO nanowires: thermally deactivating growth kinetics. AB - The laser-assisted hydrothermal growth kinetics of a cluster of ZnO nanowires are studied based on optical in situ growth monitoring. The growth yields are orders of magnitude higher than those of conventional hydrothermal methods that use bulk heating. This remarkable improvement is attributed to suppression of precursor depletion occurring by homogeneous growth reactions, as well as to enhanced mass transport. The obtained in situ data show gradually decaying growth kinetics even with negligible precursor consumption. It is revealed that the growth deceleration is caused by thermal deactivation resulting from heat dissipation through the growing nanowires. Finally, it is demonstrated that the tailored temporal modulation of the input power enables sustained growth to extended dimensions. These results provide a key to highly efficient use of growth precursors that has been pursued for industrial use of this functional metal oxide semiconductor. PMID- 24068696 TI - Atypical form of sporadic bovine leukosis (SBL) in the Netherlands. PMID- 24068695 TI - Autologous tenocyte injection for the treatment of severe, chronic resistant lateral epicondylitis: a pilot study. AB - BACKGROUND: Severe chronic lateral epicondylitis (LE) is associated with degenerative tendon changes, extracellular matrix breakdown, and tendon cell loss. On the basis of positive outcomes from preclinical studies, this study is the first clinical trial of autologous tenocyte injection (ATI) on severe tendinopathy associated with chronic LE. HYPOTHESIS: Autologous tenocyte injection is a safe and effective procedure that enables a reduction in pain and improvement in function in resistant LE. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients with severe refractory LE underwent clinical evaluation and magnetic resonance imaging (MRI) before intervention. A patellar tendon needle biopsy was performed under local anesthetic, and tendon cells were expanded by in vitro culture. Tenocytes used for the injection were characterized by flow cytometry and real-time polymerase chain reaction. Autologous tenocytes were injected into the site of tendinopathy identified at the origin of the extensor carpi radialis brevis tendon under ultrasound guidance on a single occasion. Patients underwent serial clinical evaluations and repeat MRI at 12 months after intervention. RESULTS: A total of 20 consecutive patients were included in the study. Three patients withdrew consent after enrollment and before ATI. No adverse event was reported at either biopsy or injection sites. Furthermore, no infection or excessive fibroblastic reaction was found in any patient at the injection site. Clinical evaluation revealed an improvement in mean visual analog scale scores, for a maximum pain score from 5.94 at the initial assessment to 0.76 at 12 months (P < .001). Mean quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) and grip strength scores also significantly improved over the 12-month follow-up (QuickDASH score, 45.88 [baseline] to 3.84; grip strength, 20.17 kg [baseline] to 37.38 kg; P < .001). With use of a validated MRI scoring system, the grade of tendinopathy at the common extensor origin improved significantly by 12 months (P < .001). One patient elected to proceed to surgery 3 months after ATI following a reinjury at work. CONCLUSION: In this study, patients with chronic LE who had previously undergone an unsuccessful full course of nonoperative treatment showed significantly improved clinical function and structural repair at the origin of the common extensor tendon after ATI. This novel treatment is encouraging for the treatment of tendinopathy and warrants further evaluation. PMID- 24068697 TI - The effects of UV light on calcium metabolism in ball pythons (Python regius). AB - Despite the popularity of keeping snakes in captivity, there has been limited investigation into the effects of UV radiation on vitamin D levels in snakes. The aim of this study was to investigate the effects of UV-b radiation on plasma 25 hydroxyvitamin D3 levels and ionised calcium concentrations in ball pythons (Python regius). Blood samples were taken from 14 ball pythons, which had never been exposed to UV-b light, to obtain baseline 25-hydroxyvitamin D3 levels and ionised calcium concentrations. Blood samples were then taken again from the same snakes 70 days later after one group (Group 1, n=6 females) were exposed to UV-b radiation daily, and the other group (Group 2, n=5 males and 3 females) were exposed to no UV-b radiation. Mean+/-sd 25-hydroxyvitamin D3 levels on day 0 in Group 1 were 197+/-35 nmol/l, and on day 70 were 203.5+/-13.8 nmol/l. Mean+/-sd 25-hydroxyvitamin D3 levels in Group 2 on day 0 were 77.7+/-41.5 nmol/l, and on day 70 were 83.0+/-41.9 nmol/l. Mean+/-sd ionised calcium levels at day 0 were 1.84+/-0.05 mmol/l for Group 1, and on day 70 were 1.78+/-0.07 mmol/l. Mean+/-sd ionised calcium levels at day 0 were 1.79+/-0.07 mmol/l for Group 2, and on day 70 were 1.81+/-0.05 mmol/l. No association was demonstrated between exposure to UV-b radiation and plasma 25-hydroxyvitamin D3 and ionised calcium concentrations. These results may provide baseline parameters for future studies in this and other snake species to determine ability to utilise UV-b light for vitamin D production. PMID- 24068698 TI - A cost comparison of faecal egg count-directed anthelmintic delivery versus interval programme treatments in horses. PMID- 24068699 TI - Factors influencing antibiotic prescribing habits and use of sensitivity testing amongst veterinarians in Europe. AB - The Heads of Medicines Agencies and the Federation of Veterinarians of Europe undertook a survey to gain a better insight into the decision-making process of veterinarians in Europe when deciding which antibiotics to prescribe. The survey was completed by 3004 practitioners from 25 European countries. Analysis was to the level of different types of practitioner (food producing (FP) animals, companion animals, equines) and country for Belgium, Czech Republic, France, Germany, Spain, Sweden and the UK. Responses indicate no single information source is universally considered critical, though training, published literature and experience were the most important. Factors recorded which most strongly influenced prescribing behaviour were sensitivity tests, own experience, the risk for antibiotic resistance developing and ease of administration. Most practitioners usually take into account responsible use warnings. Antibiotic sensitivity testing is usually performed where a treatment failure has occurred. Significant differences were observed in the frequency of sensitivity testing at the level of types of practitioners and country. The responses indicate a need to improve sensitivity tests and services, with the availability of rapid and cheaper testing being key factors. PMID- 24068701 TI - Protection against hepatitis C and other enveloped viruses? Another reason why "breast is best". PMID- 24068702 TI - Seroprevalence and demographic determinants of human T-lymphotropic virus type 1 and 2 infections among first-time blood donors--United States, 2000-2009. AB - BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) and HTLV-2 are prevalent at low levels among US blood donors, but recent data on their prevalence is lacking. METHODS. Data on all first-time blood donors in a large network of US blood centers were examined during 2000-2009. HTLV-1 and HTLV-2 antibodies were measured by enzyme immunoassay (EIA) with confirmation by immunofluorescence or recombinant immunoblot. Prevalence rates were calculated, and odds ratios were assessed using multivariable logistic regression. RESULTS: Among 2 047 740 first time donors, 104 were seropositive for HTLV-1 (prevalence, 5.1 cases/per 100 000; 95% confidence interval [CI], 4.1-6.1), and 300 were seropositive for HTLV-2 (prevalence, 14.7 cases/per 100 000; 95% CI, 13.0-16.3). The prevalence was lower than reported in the 1990s but stable from 2000 to 2009. HTLV-1 seropositivity was associated with female sex, older age, and black and Asian race/ethnicity. HTLV-2 seropositivity was associated with female sex, older age, nonwhite race/ethnicity, lower educational level, and residence in the western and southwestern United States. CONCLUSIONS: The HTLV-1 and HTLV-2 prevalences among US blood donors has declined since the early 1990s. A higher prevalence of HTLV-2 in the west and southwest may be attributed to endemic foci among Amerindians. PMID- 24068703 TI - Inactivation of hepatitis C virus infectivity by human breast milk. AB - BACKGROUND: Hepatitis C virus (HCV) is spread through direct contact with blood, although alternative routes of transmission may contribute to the global burden. Perinatal infection occurs in up to 5% of HCV-infected mothers, and presence of HCV RNA in breast milk has been reported. We investigated the influence of breast milk on HCV infectiousness. METHODS/RESULTS: Human breast milk reduced HCV infectivity in a dose-dependent manner. This effect was species-specific because milk from various animals did not inhibit HCV infection. Treatment of HCV with human breast milk did not compromise integrity of viral RNA or capsids but destroyed the lipid envelope. Fractionation of breast milk revealed that the antiviral activity is present in the cream fraction containing the fat. Proteolytic digestion of milk proteins had no influence on its antiviral activity, whereas prolonged storage at 4 degrees C increased antiviral activity. Notably, pretreatment with a lipase inhibitor ablated the antiviral activity and specific free fatty acids of breast milk were antiviral. CONCLUSIONS: The antiviral activity of breast milk is linked to endogenous lipase-dependent generation of free fatty acids, which destroy the viral lipid envelope. Therefore, nursing by HCV-positive mothers is unlikely to play a major role in vertical transmission. PMID- 24068705 TI - Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B cell immortalization. AB - Altered DNA methylation occurs ubiquitously in human cancer from the earliest measurable stages. A cogent approach to understanding the mechanism and timing of altered DNA methylation is to analyze it in the context of carcinogenesis by a defined agent. Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associated with lymphoma and nasopharyngeal carcinoma, but also used commonly in the laboratory to immortalize human B-cells in culture. Here we have performed whole-genome bisulfite sequencing of normal B-cells, activated B-cells, and EBV immortalized B-cells from the same three individuals, in order to identify the impact of transformation on the methylome. Surprisingly, large-scale hypomethylated blocks comprising two-thirds of the genome were induced by EBV immortalization but not by B-cell activation per se. These regions largely corresponded to hypomethylated blocks that we have observed in human cancer, and they were associated with gene-expression hypervariability, similar to human cancer, and consistent with a model of epigenomic change promoting tumor cell heterogeneity. We also describe small-scale changes in DNA methylation near CpG islands. These results suggest that methylation disruption is an early and critical step in malignant transformation. PMID- 24068704 TI - Comparative analysis of disease pathogenesis and molecular mechanisms of New World and Old World arenavirus infections. AB - Arenaviruses can cause fatal human haemorrhagic fever (HF) diseases for which vaccines and therapies are extremely limited. Both the New World (NW) and Old World (OW) groups of arenaviruses contain HF-causing pathogens. Although these two groups share many similarities, important differences with regard to pathogenicity and molecular mechanisms of virus infection exist. These closely related pathogens share many characteristics, including genome structure, viral assembly, natural host selection and the ability to interfere with innate immune signalling. However, members of the NW and OW viruses appear to use different receptors for cellular entry, as well as different mechanisms of virus internalization. General differences in disease signs and symptoms and pathological lesions in patients infected with either NW or OW arenaviruses are also noted and discussed herein. Whilst both the OW Lassa virus (LASV) and the NW Junin virus (JUNV) can cause disruption of the vascular endothelium, which is an important pathological feature of HF, the immune responses to these related pathogens seem to be quite distinct. Whereas LASV infection results in an overall generalized immune suppression, patients infected with JUNV seem to develop a cytokine storm. Additionally, the type of immune response required for recovery and clearance of the virus is different between NW and OW infections. These differences may be important to allow the viruses to evade host immune detection. Understanding these differences will aid the development of new vaccines and treatment strategies against deadly HF viral infections. PMID- 24068706 TI - Solution small angle X-ray scattering (SAXS) studies of RecQ from Deinococcus radiodurans and its complexes with junction DNA substrates. AB - RecQ helicases, essential enzymes for maintaining genome integrity, possess the capability to participate in a wide variety of DNA metabolisms. They can initiate the homologous recombination repair pathway by unwinding damaged dsDNA and suppress hyper-recombination by promoting Holliday junction (HJ) migration. To learn how DrRecQ participates in the homologous recombination repair pathway, solution structures of Deinococcus radiodurans RecQ (DrRecQ) and its complexes with DNA substrates were investigated by small angle x-ray scattering. We found that the catalytic core and the most N-terminal HRDC (helicase and RNase D C terminal) domain (HRDC1) undergo a conformational change to a compact state upon binding to a junction DNA. Furthermore, models of DrRecQ in complexes with two kinds of junction DNA (fork junction and HJ) were built based on the small angle x-ray scattering data, and together with the EMSA results, possible binding sites were proposed. It is demonstrated that two DrRecQ molecules bind to the opposite arms of HJ. This architecture is similar to the RuvAB complex and is hypothesized to be highly conserved in the other HJ migration proteins. This work provides us new clues to understand the roles DrRecQ plays in the RecFOR pathway. PMID- 24068709 TI - Shrinkage of prostate volume in sunitinib-treated patients with renal cell carcinoma. AB - Sunitinib is widely used to treat patients with advanced renal cell carcinoma; however, its influences on the prostate volume and lower urinary tract symptoms remain unclear. To investigate the influence of sunitinib on clinical findings of urinary tract, we recruited a total of 20 male patients with advanced renal cell carcinoma who are treated with sunitinib. We evaluated clinical findings during clinical visits over 24 weeks: International Prostate Symptom Score, urine flow rate, residual urine volume, serum prostate-specific antigen level and prostate volume. Residual urine and prostate volumes were significantly decreased at Week 24. The residual urine volume was especially decreased in patients with a high residual volume at baseline. No differences were observed in the International Prostate Symptom Score total score, International Prostate Symptom Score quality of life score, maximal urinary flow rate or prostate-specific antigen level. We observed a reduction in prostate volume and an improvement in urinary symptoms through relief from urinary tract obstruction during sunitinib treatment. Careful attention to urinary functions and drug dose adjustment seems to be necessary in patients with comorbid benign prostatic hyperplasia or dysuria. PMID- 24068708 TI - The allosteric mechanism of activation of antithrombin as an inhibitor of factor IXa and factor Xa: heparin-independent full activation through mutations adjacent to helix D. AB - Allosteric conformational changes in antithrombin induced by binding a specific heparin pentasaccharide result in very large increases in the rates of inhibition of factors IXa and Xa but not of thrombin. These are accompanied by CD, fluorescence, and NMR spectroscopic changes. X-ray structures show that heparin binding results in extension of helix D in the region 131-136 with coincident, and possibly coupled, expulsion of the hinge of the reactive center loop. To examine the importance of helix D extension, we have introduced strong helix promoting mutations in the 131-136 region of antithrombin (YRKAQK to LEEAAE). The resulting variant has endogenous fluorescence indistinguishable from WT antithrombin yet, in the absence of heparin, shows massive enhancements in rates of inhibition of factors IXa and Xa (114- and 110-fold, respectively), but not of thrombin, together with changes in near- and far-UV CD and (1)H NMR spectra. Heparin binding gives only ~3-4-fold further rate enhancement but increases tryptophan fluorescence by ~23% without major additional CD or NMR changes. Variants with subsets of these mutations show intermediate activation in the absence of heparin, again with basal fluorescence similar to WT and large increases upon heparin binding. These findings suggest that in WT antithrombin there are two major complementary sources of conformational activation of antithrombin, probably involving altered contacts of side chains of Tyr-131 and Ala-134 with core hydrophobic residues, whereas the reactive center loop hinge expulsion plays only a minor additional role. PMID- 24068707 TI - Artificial sweeteners stimulate adipogenesis and suppress lipolysis independently of sweet taste receptors. AB - G protein-coupled receptors mediate responses to a myriad of ligands, some of which regulate adipocyte differentiation and metabolism. The sweet taste receptors T1R2 and T1R3 are G protein-coupled receptors that function as carbohydrate sensors in taste buds, gut, and pancreas. Here we report that sweet taste receptors T1R2 and T1R3 are expressed throughout adipogenesis and in adipose tissues. Treatment of mouse and human precursor cells with artificial sweeteners, saccharin and acesulfame potassium, enhanced adipogenesis. Saccharin treatment of 3T3-L1 cells and primary mesenchymal stem cells rapidly stimulated phosphorylation of Akt and downstream targets with functions in adipogenesis such as cAMP-response element-binding protein and FOXO1; however, increased expression of peroxisome proliferator-activated receptor gamma and CCAAT/enhancer-binding protein alpha was not observed until relatively late in differentiation. Saccharin-stimulated Akt phosphorylation at Thr-308 occurred within 5 min, was phosphatidylinositol 3-kinase-dependent, and occurred in the presence of high concentrations of insulin and dexamethasone; phosphorylation of Ser-473 occurred more gradually. Surprisingly, neither saccharin-stimulated adipogenesis nor Thr 308 phosphorylation was dependent on expression of T1R2 and/or T1R3, although Ser 473 phosphorylation was impaired in T1R2/T1R3 double knock-out precursors. In mature adipocytes, artificial sweetener treatment suppressed lipolysis even in the presence of forskolin, and lipolytic responses were correlated with phosphorylation of hormone-sensitive lipase. Suppression of lipolysis by saccharin in adipocytes was also independent of T1R2 and T1R3. These results suggest that some artificial sweeteners have previously uncharacterized metabolic effects on adipocyte differentiation and metabolism and that effects of artificial sweeteners on adipose tissue biology may be largely independent of the classical sweet taste receptors, T1R2 and T1R3. PMID- 24068710 TI - A newly introduced comprehensive consultation fee in the national health insurance system in Japan: a promotive effect of multidisciplinary medical care in the field of radiation oncology--results from a questionnaire survey. AB - OBJECTIVE: The consultation fee for outpatient radiotherapy was newly introduced in the national health insurance system in Japan in April 2012. We conducted a survey on the use of this consultation fee and its effect on clinical practices. METHODS: The health insurance committee of the Japanese Society of Therapeutic Radiology and Oncology conducted a questionnaire survey. The questionnaire form was mailed to 160 councilors of the Society, the target questionees. A total of 94 answers (58% of the target questionees) sent back were used for analyses. RESULTS: The analyses revealed that 75% of the hospitals charged most of the patients who receive radiotherapy in an outpatient setting a consultation fee. The introduction of the consultation fee led to some changes in radiation oncology clinics, as evidenced by the response of 'more careful observations by medical staff' in 37% of questionees and a 12% increase in the number of full time radiation oncology nurses. It was also shown that the vast majority (92%) of radiation oncologists expected a positive influence of the consultation fee on radiation oncology clinics in Japan. CONCLUSIONS: Our questionnaire survey revealed the present status of the use of a newly introduced consultation fee for outpatient radiotherapy, and the results suggested its possible effect on promoting a multidisciplinary medical care system in radiation oncology departments in Japan. PMID- 24068711 TI - Involvement of anticancer drugs in the relief system for adverse drug reactions in Japan. AB - OBJECTIVE: The compensation scheme for adverse drug reactions in Japan was implemented more than three decades ago as relief system by regulatory agencies. Because of the high frequency of adverse drug reactions, anticancer drugs have been excluded from coverage by the relief system since its implementation. Requests have recently been made by some patient advocates for the expansion of relief coverage to include anticancer drugs. In response to these requests, the Ministry of Health, Labor and Welfare of Japan established a committee to discuss relief from anticancer drug-induced health damages in June 2011. METHODS: We conducted comprehensive research into the compensation scheme for adverse drug reactions in the world. We also investigated the situation of compensation and the committee for discussing inclusion of anticancer drugs into the relief system in Japan. RESULTS: Many countries including the United States and UK do not have relief or compensation schemes for no-fault compensation. We investigated whether a no-fault compensation system exists in Nordic countries (Sweden, Denmark, Norway and Finland), France, Germany, New Zealand and Taiwan in the world, although they offer different services from Japan. We also reviewed current situation and the fundamental difficulties associated with including anticancer drugs in the systems in Japan. CONCLUSIONS: The present study investigated the current situation and the fundamental difficulties associated with including anticancer drugs in the systems in Japan and pointed out part of the reason why the committee could not conclude involvement of anticancer drugs in the relief system. PMID- 24068712 TI - Pathological and oncological outcomes of elderly men with clinically localized prostate cancer. AB - OBJECTIVE: The aim of the study was to characterize pathological and oncological outcomes of elderly men with clinically localized prostate cancer treated with radical prostatectomy. METHODS: Data from 1268 patients undergoing radical prostatectomy between 2000 and 2009 were retrospectively reviewed. Patients were classified according to whether they were of age <70 or >=70 years at radical prostatectomy. Patient characteristics, pathological and oncological outcomes were compared among the groups. RESULTS: Of the total population, 31.4% (398 of 1268) of patients were >=70 years of age. The median age in patients <70 and >=70 years of age was 64 (45-69) and 72 (70-83) years. The proportion of low-risk disease was significantly lower among those >=70 years of age than in those <70 years, while the proportion of high-risk disease was significantly higher among those >=70 years of age than in those <70 years (P < 0.001). The proportions of pathological high-risk disease (>=T3b, GS >=8, positive surgical margin or lymph node invasion) in patients <70 and >=70 years of age were 42.0 and 50.0%, respectively (P = 0.008). The proportions of organ-confined disease in patients <70 and >=70 years of age were 69.9 and 65.1%, respectively (P = 0.09). With a median follow-up of 50 months, 5-year biochemical recurrence-free and cancer specific survival rates were not significantly different among the groups. CONCLUSIONS: Radical prostatectomy was more likely to be performed in those with higher-risk disease among patients >=70 years of age. About half of the patients >=70 years of age had pathological, high-risk disease. Radical prostatectomy could be considered for patients with expected long-term life expectancy, even in the setting of advanced age. PMID- 24068713 TI - Kicking clinical commissioning groups into the long grass. PMID- 24068714 TI - An unusual case of quadriparesis. PMID- 24068715 TI - People want to learn as much as possible from the PACE trial for chronic fatigue syndrome. PMID- 24068716 TI - Do low grade thyroid cancers really require thyroidectomy? PMID- 24068717 TI - The case for licensing cytosine now for smoking cessation is overwhelming. PMID- 24068718 TI - What's the problem with sharing research committee's discussions? PMID- 24068719 TI - Thyroid nodules: time to stop over-reporting normal findings and update consensus guidelines. PMID- 24068721 TI - Patients are not friends. PMID- 24068720 TI - Misunderstanding the value of troponin testing. PMID- 24068722 TI - The importance of establishing a rapport with patients. PMID- 24068723 TI - Listening is paramount when discussing sensitive topics with patients. PMID- 24068724 TI - How to get out of hospital. PMID- 24068725 TI - Adding acupuncture or counselling to usual care hastens improvement in persistent depression. PMID- 24068726 TI - Tetanus vaccination during pregnancy reduces risk of neonatal mortality in India, study finds. PMID- 24068727 TI - Gaza is running out of medicines as Egypt limits movement through the Rafah crossing [corrected]. PMID- 24068728 TI - Strong government accountability is crucial to meeting millennium development goals, UN assembly is told. PMID- 24068729 TI - The patient's perspective: we all want private hospital rooms. PMID- 24068732 TI - Vaccine economics: what price human life? PMID- 24068730 TI - Targeted STAT3 disruption in myeloid cells alters immunosuppressor cell abundance in a murine model of spontaneous medulloblastoma. AB - Although the immune system may provide early protection against cancer, tumors may exploit the healing arm of the immune system to enhance their growth and metastasis. For example, myeloid derived suppressor cells (MDSCs) are thought to promote tumor growth by several mechanisms, including the suppression of T cell activity. It has been suggested that STAT3 activation in myeloid cells modulates multiple aspects of MDSC physiology, including their expansion and activity. Whereas most animal studies investigating tumor immunology have used tumor implants, we used transgenic mice (Smo*) that spontaneously develop medulloblastoma brain tumors to investigate the temporal accumulation of MDSCs within tumors and how myeloid STAT3 disruption affects MDSC and other immune cell types. We found distinct populations of MDSC in medulloblastoma tumors, with a high prevalence of CD11b(+)Ly6G(+)Ly6C(low/-) cells, described previously by others as G-MDSCs. These were found early in tumor development, in premalignant lesions located on the surface of the cerebellum of 28-day-old mice. In fully developed tumors, pSTAT3 was found in the majority of these cells. Conditional STAT3 gene disruption in myeloid cells resulted in an enhanced proinflammatory phenotype of macrophages in Smo* mice. Moreover, a significant reduction in the abundance of G-MDSCs and Tregs was observed within tumors along with an increased presence of CD4(+) and CD8(+) cells. Despite these alterations in immune cells induced by myeloid STAT3 disruption, we found no effect on tumor incidence in Smo* mice with this deletion. PMID- 24068733 TI - Comment on "Community-wide isoniazid preventive therapy drives drug-resistant tuberculosis: a model-based analysis". AB - Mills et al. recently used mathematical modeling to show that community-wide isoniazid preventative therapy may lead to a long-term increase in resistance at the population level. Although community-wide isoniazid preventive therapy may be useful in preventing tuberculosis (TB) in low-TB/HIV settings, isoniazid resistance is especially of concern in high TB/HIV populations. PMID- 24068731 TI - STAT5 polarization promotes iTregs and suppresses human T-cell alloresponses while preserving CTL capacity. AB - Alloreactivity negatively influences outcomes of organ transplantation or HCT from allogeneic donors. Standard pharmacologic immune suppression impairs T-cell function and jeopardizes the beneficial reconstitution of Tregs. Murine transplantation models have shown that STAT3 is highly expressed in alloreactive T cells and may be therapeutically targeted. The influence and effects of STAT3 neutralization in human alloreactivity, however, remain to be elucidated. In this study, S3I-201, a selective small-molecule inhibitor of STAT3, suppressed human DC-allosensitized T-cell proliferation and abrogated Th17 responses. STAT3 blockade significantly enhanced the expansion of potent iTregs and permitted CD8(+) cytolytic effector function. Mechanistically, S3I-201 polarized the ratio of STAT phosphorylation in favor of STAT5 over STAT3 and also achieved a significant degree of Foxp3 demethylation among the iTregs. Conversely, selective impairment of STAT5 phosphorylation with CAS 285986-31-4 markedly reduced iTregs. STAT3 represents a relevant target for achieving control over human alloresponses, where its suppression facilitates STAT5-mediated iTreg growth and function. PMID- 24068734 TI - Response to comment on "Community-wide isoniazid preventive therapy drives drug resistant tuberculosis: a model-based analysis". AB - Our modeling work suggests that isoniazid preventive therapy (IPT) can be effective in reducing drug-sensitive tuberculosis (TB) and that the risk of IPT driving resistance can be reduced by improving the detection and rapid treatment of individuals with drug-resistant disease and by limiting IPT to those in whom the intervention will have the largest benefit. PMID- 24068735 TI - Human skin in the game. AB - Clinical and experimental observations in atopic dermatitis and psoriasis reveal new mechanisms of antiviral immunity and inflammation (Wolk et al., this issue; Kim et al., previous issue). PMID- 24068736 TI - IL-29 is produced by T(H)17 cells and mediates the cutaneous antiviral competence in psoriasis. AB - Psoriasis and atopic dermatitis (AD) are the most common chronic inflammatory skin diseases. Although both patient groups show strongly impaired skin barrier function, only AD patients frequently suffer from cutaneous viral infections. The mechanisms underlying the distinct susceptibilities to these pathogenetic and often life-threatening infections are unknown. We show that antiviral proteins (AVPs) such as MX1, BST2, ISG15, and OAS2 were strongly elevated in psoriatic compared to AD lesions and healthy skin. Of 30 individually quantified cytokines in psoriatic lesions, interleukin-29 (IL-29) was the only mediator whose expression correlated with the AVP levels. IL-29 was absent in AD lesions, and neutralization of IL-29 in psoriatic skin reduced AVP expression. Accordingly, IL 29 raised AVP levels in isolated keratinocytes, epidermis models, and human skin explants, but did not influence antibacterial protein production. AVP induction correlated with increased antiviral defense of IL-29-treated keratinocytes. Furthermore, IL-29 elevated the expression of signaling elements, resulting in increased sensitivity of keratinocytes toward its own action. We identified T helper 17 (T(H)17) cells as IL-29 producers and demonstrated their ability to increase the antiviral competence of keratinocytes in an IL-29-dependent manner. Transforming growth factor-beta and the activity of RORgammat/RORalpha were most critical for the development of IL-29-producing T(H)17 cells. IL-29 secretion by these cells was dependent on NFAT and c-Jun N-terminal kinase and was inhibited by IL-4. These data suggest that T(H)17 cell-derived IL-29, which is absent in AD, mediates the robust antiviral state on psoriatic skin, and demonstrate a new function of T(H)17 cells. PMID- 24068737 TI - Generation of effector memory T cell-based mucosal and systemic immunity with pulmonary nanoparticle vaccination. AB - Many pathogens infiltrate the body and initiate infection via mucosal surfaces. Hence, eliciting cellular immune responses at mucosal portals of entry is of great interest for vaccine development against mucosal pathogens. We describe a pulmonary vaccination strategy combining Toll-like receptor (TLR) agonists with antigen-carrying lipid nanocapsules [interbilayer-crosslinked multilamellar vesicles (ICMVs)], which elicit high-frequency, long-lived, antigen-specific effector memory T cell responses at multiple mucosal sites. Pulmonary immunization using protein- or peptide-loaded ICMVs combined with two TLR agonists, polyinosinic-polycytidylic acid (polyI:C) and monophosphoryl lipid A, was safe and well tolerated in mice, and led to increased antigen transport to draining lymph nodes compared to equivalent subcutaneous vaccination. This response was mediated by the vast number of antigen-presenting cells (APCs) in the lungs. Nanocapsules primed 13-fold more T cells than did equivalent soluble vaccines, elicited increased expression of mucosal homing integrin alpha4beta7+, and generated long-lived T cells in both the lungs and distal (for example, vaginal) mucosa strongly biased toward an effector memory (T(EM)) phenotype. These T(EM) responses were highly protective in both therapeutic tumor and prophylactic viral vaccine settings. Together, these data suggest that targeting cross-presentation-promoting particulate vaccines to the APC-rich pulmonary mucosa can promote robust T cell responses for protection of mucosal surfaces. PMID- 24068739 TI - Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development. AB - New drug deployment strategies are imperative to address the problem of drug resistance, which is limiting the management of infectious diseases and cancers. We evolved resistance in Escherichia coli toward 23 drugs used clinically for treating bacterial infections and mapped the resulting collateral sensitivity and resistance profiles, revealing a complex collateral sensitivity network. On the basis of these data, we propose a new treatment framework--collateral sensitivity cycling--in which drugs with compatible collateral sensitivity profiles are used sequentially to treat infection and select against drug resistance development. We identified hundreds of such drug sets and demonstrated that the antibiotics gentamicin and cefuroxime can be deployed cyclically such that the treatment regimen selected against resistance to either drug. We then validated our findings with related bacterial pathogens. These results provide proof of principle for collateral sensitivity cycling as a sustainable treatment paradigm that may be generally applicable to infectious diseases and cancer. PMID- 24068738 TI - siRNA screen for genes that affect Junin virus entry uncovers voltage-gated calcium channels as a therapeutic target. AB - New World hemorrhagic fever arenavirus infection results in 15 to 30% mortality in humans. We performed a high-throughput small interfering RNA screen with Junin virus glycoprotein-pseudotyped viruses to find potential host therapeutic targets. Voltage-gated calcium channel (VGCC) subunits, for which there are Food and Drug Administration (FDA)-approved drugs, were identified in the screen. Knockdown of VGCC subunits or treatment with channel blockers diminished Junin virus-cell fusion and entry into cells and thereby decreased infection. Gabapentin, an FDA-approved drug used to treat neuropathic pain that targets the alpha2delta2 subunit, inhibited infection of mice by the Candid 1 vaccine strain of the virus. These findings demonstrate that VGCCs play a role in virus infection and have the potential to lead to therapeutic intervention of New World arenavirus infection. PMID- 24068740 TI - A role for paralog-specific sumoylation in histone deacetylase 1 stability. AB - Histone deacetylase 1 (HDAC1) is an essential epigenetic regulator belonging to a highly conserved family of deacetylases. Increased HDAC1 activity and expression often correlates with neoplastic transformation. Here we show how specific modification of HDAC1 by SUMO1, but not by SUMO2, facilitates HDAC1 degradation. Our findings reveal that SUMO1, but not SUMO2, conjugation to HDAC1 promotes HDAC1 ubiquitination and degradation. This is suggested by the observation that in non-tumorigenic mammary epithelial cells HDAC1 is preferentially conjugated to SUMO1 leading to HDAC1 proteolysis, whereas in breast cancer cells HDAC1 is more conjugated to SUMO2, promoting HDAC1 protein stability. SUMO E3 ligases play an important role in paralog-specific conjugation; in particular, the SUMO E3 ligase PIASy, which is overexpressed in breast cancer cells, selectively promotes the conjugation of HDAC1 to SUMO2. Therefore, cell environment affects paralog specific sumoylation of HDAC1, whose conjugation to SUMO1 but not to SUMO2 facilitates its protein turnover. Our findings uncover a role for paralog specific sumoylation of HDAC1 whose significance is emphasized by the use of HDAC inhibitors as anticancer drugs. PMID- 24068743 TI - Concussion and sport. PMID- 24068744 TI - Health Research Authority's great leap forward on UK trial registration. PMID- 24068745 TI - Supporting poorly performing NHS hospitals to improve. PMID- 24068742 TI - Repeated autologous bone marrow-derived mesenchymal stem cell injections improve radiation-induced proctitis in pigs. AB - The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high dose radiation-induced proctitis. Irradiated pigs received repeated intravenous administrations of autologous bone marrow-derived MSCs. Immunostaining and real time polymerase chain reaction analysis were used to assess the MSCs' effect on inflammation, extracellular matrix remodeling, and angiogenesis, in radiation induced anorectal and colon damages. In humans, as in pigs, rectal overexposure induces mucosal damage (crypt depletion, macrophage infiltration, and fibrosis). In a pig model, repeated administrations of MSCs controlled systemic inflammation, reduced in situ both expression of inflammatory cytokines and macrophage recruitment, and augmented interleukin-10 expression in rectal mucosa. MSC injections limited radiation-induced fibrosis by reducing collagen deposition and expression of col1a2/col3a1 and transforming growth factor-beta/connective tissue growth factor, and by modifying the matrix metalloproteinase/TIMP balance. In a pig model of proctitis, repeated injections of MSCs effectively reduced inflammation and fibrosis. This treatment represents a promising therapy for radiation-induced severe rectal damage. PMID- 24068741 TI - Nestin expression in end-stage disease in dystrophin-deficient heart: implications for regeneration from endogenous cardiac stem cells. AB - Nestin(+) cardiac stem cells differentiate into striated cells following myocardial infarct. Transplantation of exogenous stem cells into myocardium of a murine model for Duchenne muscular dystrophy (DMD) increased proliferation of endogenous nestin(+) stem cells and resulted in the appearance of nestin(+) striated cells. This correlated with, and may be responsible for, prevention of dilated cardiomyopathy. We examined nestin(+) stem cells in the myocardium of dystrophin/utrophin-deficient (mdx/utrn(-/-)) mice, a model for DMD. We found that 92% of nestin(+) interstitial cells expressed Flk-1, a marker present on cardiac progenitor cells that differentiate into the cardiac lineage, and that a subset expressed Sca-1, present on adult cardiac cells that become cardiomyocytes. Nestin(+) interstitial cells maintained expression of Flk-1 but lost Sca-1 expression with age and were present in lower numbers in dystrophin deficient heart than in wild-type heart. Unexpectedly, large clusters of nestin(+) striated cells ranging in size from 20 to 250 cells and extending up to 500 MUm were present in mdx/utrn(-/-) heart near the end stage of disease. These cells were also present in dystrophin-deficient mdx/utrn(+/-) and mdx heart but not wild-type heart. Nestin(+) striated cells expressed cardiac troponin I, desmin, and Connexin 43 and correlated with proinflammatory CD68(+) macrophages. Elongated nestin(+) interstitial cells with striations were observed that did not express Flk-1 or the late cardiac marker cardiac troponin I but strongly expressed the early cardiac marker desmin. Nestin was also detected in endothelial and smooth muscle cells. These data indicate that new cardiomyocytes form in dystrophic heart, and nestin(+) interstitial cells may generate them in addition to other cells of the cardiac lineage. PMID- 24068746 TI - Judge quashes GMC's decision to pursue old allegations against a consultant. PMID- 24068747 TI - The hardness test is key to diagnosis of factitious calcium carbonate stones. PMID- 24068748 TI - A study of clinical complications and risk factors in 1,001 native and transplant kidney biopsies in Sweden. AB - BACKGROUND: In Sweden, native and transplant kidney biopsies are usually performed in major renal medical centers. PURPOSE: To clarify risk factors in native and transplant kidney biopsies to improve patient safety. MATERIAL AND METHODS: A total of 1001 biopsies (in 352 women and 565 men) were included. The median age was 54 years (range, 16-90 years). Data were derived from 826 native kidney biopsies (640 prospective and 186 retrospective) and 175 transplant kidney biopsies (170 prospective and 5 retrospective). Various factors and complications were registered while performing native and transplant kidney biopsies, focusing on major (e.g. blood transfusions, invasive procedures) and minor complications. The prospective protocol was used at six centers and at one center data were obtained retrospectively. RESULTS: Women were at greater risk of overall complications than men (12.2% vs. 6.5%; P = 0.003; odds ratio [OR], 2.0; confidence interval [CI], 1.3-3.1) as well as of major complications (9.6% vs. 4.5%; P = 0.002; OR, 2.2, CI 1.3-3.7). Major complications occurred more commonly after biopsies from the right kidney, in women than in men (10.8% vs. 3.1%; P = 0.005; OR, 3.7; CI, 1.5-9.5), and in patients with lower BMI (25.5 vs. 27.3, P = 0.016) and of younger age (45 years vs. 52.5 years; P = 0.001). Lower mean arterial pressure in transplant kidney biopsies indicated a risk of major complications (90 mmHg vs. 98 mmHg; P = 0.039). Factors such as needle size, number of passes, serum creatinine, and eGFR did not influence complication rates. CONCLUSION: The present findings motivate greater attention being paid to the risk of major side-effects after right-side biopsies from women's kidneys, as well as after biopsies from younger patients and patients with lower BMI. PMID- 24068749 TI - Superior vena cava (SVC) filters placed over central lines - analysis of line trapping and difficulties with line retrieval: an in-vitro experimental study. AB - BACKGROUND: Placement of superior vena cava (SVC) filters has been shown to be both safe and effective in preventing symptomatic pulmonary embolism in patients with upper extremity deep venous thrombosis that have contraindications to anticoagulation therapy. In many patients, existing central lines pose a challenge to SVC filter placement due to the theoretical risk of line displacement and/or entrapment. PURPOSE: To assess the risk of catheter entrapment by filter legs during SVC filter deployment and the risk of subsequent filter migration during catheter removal. MATERIAL AND METHODS: A model was created by placing a 22 mm vascular graft inside a plastic tube and submerged in a warm saline bath. Five types of filters were deployed under fluoroscopic guidance over different types of central lines of varying calibers (5-14 Fr). Each filter was deployed five times over each type of central line. The positioning of the legs of the filters in relationship to the central lines was studied by fluoroscopic and direct inspection. The lines were then removed under fluoroscopic guidance noting any line trapping, migration, and/or tilting of the filters. RESULTS: Movement of the lines during filter expansion was commonly seen after deployment of all filters with varying frequencies. During line removal slight resistance was encountered with the Celect filter (10%) and the Option filter (5%), while significant resistance was only encountered when using the OptEase filter (20%). Filter migration was only observed when the OptEase filter was deployed over large (>10 Fr) caliber lines (10%). CONCLUSION: When SVC filters are placed over existing central lines, the risk of catheter entrapment is very low in this in-vitro model. Filter migration during line retrieval was only observed when the OptEase filter was placed over >10 Fr caliber lines. PMID- 24068750 TI - The effect of a combined versus a conventional cognitive-behavioral therapy on quality of life for comorbid panic disorder with agoraphobia and generalized anxiety disorder: preliminary results. AB - Concurrent panic disorder with agoraphobia (PDA) and generalized anxiety disorder (GAD) are the most common diagnostic occurrences among anxiety disorders. This particular comorbidity is associated with significant impairments in quality of life (QOL). The current study sought to investigate the efficacy of a combined cognitive-behavioral psychotherapy that addressed both conditions compared with a conventional psychotherapy, which attends solely to the primary disorder. The hypotheses postulated firstly, that both treatment conditions would lead to improvements in participants' QOL and secondly, that the combined therapy would lead to greater QOL ameliorations. Twenty-five participants with comorbid PDA/GAD diagnoses were evaluated with a number of clinical interviews and self-report questionnaires, and were provided with either conventional or combined cognitive behavioral psychotherapy, which consisted of 14 one-hour weekly sessions. Participants were once again evaluated in the same fashion 2-weeks after the completion of the psychotherapy. The results revealed that both conditions led to significant improvements in participants' QOL, but that the two groups did not significantly differ in terms of the effect on QOL. The results also reveal that the two conditions did not significantly differ in terms of their effect on PDA and GAD symptomatology or psychiatric comorbidity. The results demonstrate that the combined psychotherapy, which addresses both conditions simultaneously, is similar to the conventional psychotherapy employed for the primary disorder in terms of QOL enhancement, symptom severity, and comorbidity reduction. PMID- 24068751 TI - Consequences of 9/11 and the war on terror on children's and young adult's mental health: a systematic review of the past 10 years. AB - This mixed method systematic review appraises the individual, familial and systemic effect of 9/11 and the war on terror for majority and minority children and youth in North America. The results highlight the broad social consequences of the socio-political transformations associated with the terror context, which cannot be understood only through a trauma focus analysis. The social stereotypes transformed youth experiences of belonging and exclusion. The difference between the consequences for majority and minority youth suggests the need for a broader appraisal of this societal context to support the development of prevention and intervention intersectorial programs. PMID- 24068752 TI - Separate evaluation of target facilitation and distractor suppression in the activity of macaque lateral intraparietal neurons during visual search. AB - During visual search, neurons in the lateral intraparietal area (LIP) discriminate the target from distractors by exhibiting stronger activation when the target appears within the receptive field than when it appears outside the receptive field. It is generally thought that such target-discriminative activity is produced by the combination of target-related facilitation and distractor related suppression. However, little is known about how the target-discriminative activity is constituted by these two types of neural modulation. To address this issue, we recorded activity from LIP of monkeys performing a visual search task that consisted of target-present and target-absent trials. Monkeys had to make a saccade to a target in the target-present trials, whereas they had to maintain fixation in the target-absent trials, in which only distractors were presented. By introducing the activity from the latter trials as neutral activity, we were able to separate the target-discriminative activity into target-related elevation and distractor-related reduction components. We found that the target discriminative activity of most LIP neurons consisted of the combination of target-related elevation and distractor-related reduction or only target-related elevation. In contrast, target-discriminative activity composed of only distractor-related reduction was observed for very few neurons. We also found that, on average, target-related elevation was stronger and occurred earlier compared with distractor-related reduction. Finally, we consider possible underlying mechanisms, including lateral inhibitory interactions, responsible for target-discriminative activity in visual search. The present findings provide insight into how neuronal modulations shape target-discriminative activity during visual search. PMID- 24068755 TI - Altered cortical spectrotemporal processing with age-related hearing loss. AB - Presbycusis (age-related hearing loss) is a prevalent disability associated with aging that impairs spectrotemporal processing, but the mechanisms of such changes remain unclear. The goal of this study was to quantify cortical responses to frequency-modulated (FM) sweeps in a mouse model of presbycusis. Previous studies showed that cortical neurons in young mice are selective for the rate of frequency change in FM sweeps. Here single-unit data on cortical selectivity and response variability to FM sweeps of either direction and different rates (0.08 20 kHz/ms) were compared across young (1-3 mo), middle-aged (6-8 mo), and old (14 20 mo) groups. Three main findings are reported. First, there is a reduction in FM rate selectivity in the old group. Second, there is a slowing of the sweep rates at which neurons likely provide best detection and discrimination of sweep rates. Third, there is an increase in trial-to-trial variability in the magnitude and timing of spikes in response to sweeps. These changes were only observed in neurons that were selective for the fast or intermediate range of sweep rates and not in neurons that preferred slow sweeps or were nonselective. Increased variability of response magnitude, but not changes in temporal fidelity or selectivity, was seen even in the middle-aged group. The results show that spectrotemporal processing becomes slow and noisy with presbycusis in specific types of neurons, suggesting receptive field mechanisms that are altered. These data suggest neural correlates of presbycusis-related reduction in the ability of humans to process rapid spectrotemporal changes. PMID- 24068753 TI - Activation properties of trigeminal motoneurons in participants with and without bruxism. AB - In animals, sodium- and calcium-mediated persistent inward currents (PICs), which produce long-lasting periods of depolarization under conditions of low synaptic drive, can be activated in trigeminal motoneurons following the application of the monoamine serotonin. Here we examined if PICs are activated in human trigeminal motoneurons during voluntary contractions and under physiological levels of monoaminergic drive (e.g., serotonin and norepinephrine) using a paired motor unit analysis technique. We also examined if PICs activated during voluntary contractions are larger in participants who demonstrate involuntary chewing during sleep (bruxism), which is accompanied by periods of high monoaminergic drive. In control participants, during a slowly increasing and then decreasing isometric contraction, the firing rate of an earlier-recruited masseter motor unit, which served as a measure of synaptic input to a later recruited test unit, was consistently lower during derecruitment of the test unit compared with at recruitment (DeltaF = 4.6 +/- 1.5 imp/s). The DeltaF, therefore, is a measure of the reduction in synaptic input needed to counteract the depolarization from the PIC to provide an indirect estimate of PIC amplitude. The range of DeltaF values measured in the bruxer participants during similar voluntary contractions was the same as in controls, suggesting that abnormally high levels of monoaminergic drive are not continually present in the absence of involuntary motor activity. We also observed a consistent "onion skin effect" during the moderately sized contractions (<20% of maximal), whereby the firing rate of higher threshold motor units discharged at slower rates (by 4-7 imp/s) compared with motor units with relatively lower thresholds. The presence of lower firing rates in the more fatigue-prone, higher threshold trigeminal motoneurons, in addition to the activation of PICs, likely facilitates the activation of the masseter muscle during motor activities such as eating, nonnutritive chewing, clenching, and yawning. PMID- 24068754 TI - Whole body motion-detection tasks can yield much lower thresholds than direction recognition tasks: implications for the role of vibration. AB - Earlier spatial orientation studies used both motion-detection (e.g., did I move?) and direction-recognition (e.g., did I move left/right?) paradigms. The purpose of our study was to compare thresholds measured with motion-detection and direction-recognition tasks on a standard Moog motion platform to see whether a substantial fraction of the reported threshold variation might be explained by the use of different discrimination tasks in the presence of vibrations that vary with motion. Thresholds for the perception of yaw rotation about an earth vertical axis and for interaural translation in an earth-horizontal plane were determined for four healthy subjects with standard detection and recognition paradigms. For yaw rotation two-interval detection thresholds were, on average, 56 times smaller than two-interval recognition thresholds, and for interaural translation two-interval detection thresholds were, on average, 31 times smaller than two-interval recognition thresholds. This substantive difference between recognition thresholds and detection thresholds is one of our primary findings. For motions near our measured detection threshold, we measured vibrations that matched previously established vibration thresholds. This suggests that vibrations contribute to whole body motion detection. We also recorded yaw rotation thresholds on a second motion device with lower vibration and found direction-recognition and motion-detection thresholds that were not significantly different from one another or from the direction-recognition thresholds recorded on our Moog platform. Taken together, these various findings show that yaw rotation recognition thresholds are relatively unaffected by vibration when moderate (up to ~ 0.08 m/s(2)) vibration cues are present. PMID- 24068756 TI - Midfrontal conflict-related theta-band power reflects neural oscillations that predict behavior. AB - Action monitoring and conflict resolution require the rapid and flexible coordination of activity in multiple brain regions. Oscillatory neural population activity may be a key physiological mechanism underlying such rapid and flexible network coordination. EEG power modulations of theta-band (4-8 Hz) activity over the human midfrontal cortex during response conflict have been proposed to reflect neural oscillations that support conflict detection and resolution processes. However, it has remained unclear whether this frequency-band-specific activity reflects neural oscillations or nonoscillatory responses (i.e., event related potentials). Here, we show that removing the phase-locked component of the EEG did not reduce the strength of the conflict-related modulation of the residual (i.e., non-phase-locked) theta power over midfrontal cortex. Furthermore, within-subject regression analyses revealed that the non-phase locked theta power was a significantly better predictor of the conflict condition than was the time-domain phase-locked EEG component. Finally, non-phase-locked theta power showed robust and condition-specific (high- vs. low-conflict) cross trial correlations with reaction time, whereas the phase-locked component did not. Taken together, our results indicate that most of the conflict-related and behaviorally relevant midfrontal EEG signal reflects a modulation of ongoing theta-band oscillations that occurs during the decision process but is not phase locked to the stimulus or to the response. PMID- 24068757 TI - Retinal NMDA receptor function and expression are altered in a mouse lacking D amino acid oxidase. AB - D-serine is present in the vertebrate retina and serves as a coagonist for the N methyl-D-aspartate (NMDA) receptors of ganglion cells. Although the enzyme D amino acid oxidase (DAO) has been implicated as a pathway for d-serine degradation, its role in the retina has not been established. In this study, we investigated the role of DAO in regulating D-serine levels using a mutant mouse line deficient in DAO (ddY/DAO(-)) and compared these results with their wild type counterparts (ddY/DAO(+)). Our results show that DAO is functionally present in the mouse retina and normally serves to reduce the background levels of D serine. The enzymatic activity of DAO was restricted to the inner plexiform layer as determined by histochemical analysis. Using capillary electrophoresis, we showed that mutant mice had much higher levels of D-serine. Whole cell recordings from identified retinal ganglion cells demonstrated that DAO-deficient animals had light-evoked synaptic activity strongly biased toward a high NMDA-to-AMPA receptor ratio. In contrast, recordings from wild-type ganglion cells showed a more balanced ratio between the two receptor subclasses. Immunostaining for AMPA and NMDA receptors was carried out to compare the two receptor ratios by quantitative immunofluorescence. These studies revealed that the mutant mouse had a significantly higher representation of NMDA receptors compared with the wild type controls. We conclude that 1) DAO is an important regulatory enzyme and normally functions to reduce D-serine levels in the retina, and 2) D-serine levels play a role in the expression of NMDA receptors and the NMDA-to-AMPA receptor ratio. PMID- 24068758 TI - In vivo electrophysiology of nigral and thalamic neurons in alpha-synuclein overexpressing mice highlights differences from toxin-based models of parkinsonism. AB - Numerous studies have suggested that alpha-synuclein plays a prominent role in both familial and idiopathic Parkinson's disease (PD). Mice in which human alpha synuclein is overexpressed (ASO) display progressive motor deficits and many nonmotor features of PD. However, it is unclear what in vivo pathophysiological mechanisms drive these motor deficits. It is also unknown whether previously proposed pathophysiological features (i.e., increased beta oscillations, bursting, and synchronization) described in toxin-based, nigrostriatal dopamine depletion models are also present in ASO mice. To address these issues, we first confirmed that 5- to 6-mo-old ASO mice have robust motor dysfunction, despite the absence of significant nigrostriatal dopamine degeneration. In the same animals, we then recorded simultaneous single units and local field potentials (LFPs) in the substantia nigra pars reticulata (SNpr), the main basal ganglia output nucleus, and one of its main thalamic targets, the ventromedial nucleus, as well as LFPs in the primary motor cortex in anesthetized ASO mice and their age matched, wild-type littermates. Neural activity was examined during slow wave activity and desynchronized cortical states, as previously described in 6 hydroxydopamine-lesioned rats. In contrast to toxin-based models, we found a small decrease, rather than an increase, in beta oscillations in the desynchronized state. Similarly, synchronized burst firing of nigral neurons observed in toxin-based models was not observed in ASO mice. Instead, we found more subtle changes in pauses of SNpr firing compared with wild-type control mice. Our results suggest that the pathophysiology underlying motor dysfunction in ASO mice is distinctly different from striatal dopamine-depletion models of parkinsonism. PMID- 24068760 TI - The dynamics of sensorimotor calibration in reaching-to-grasp movements. AB - Reach-to-grasp movements require information about the distance and size of target objects. Calibration of this information could be achieved via feedback information (visual and/or haptic) regarding terminal accuracy when target objects are grasped. A number of reports suggest that the nervous system alters reach-to-grasp behavior following either a visual or haptic error signal indicating inaccurate reaching. Nevertheless, the reported modification is generally partial (reaching is changed less than predicted by the feedback error), a finding that has been ascribed to slow adaptation rates. It is possible, however, that the modified reaching reflects the system's weighting of the visual and haptic information in the presence of noise rather than calibration per se. We modeled the dynamics of calibration and showed that the discrepancy between reaching behavior and the feedback error results from an incomplete calibration process. Our results provide evidence for calibration being an intrinsic feature of reach-to-grasp behavior. PMID- 24068759 TI - Synthesis, transport, and metabolism of serotonin formed from exogenously applied 5-HTP after spinal cord injury in rats. AB - Spinal cord transection leads to elimination of brain stem-derived monoamine fibers that normally synthesize most of the monoamines in the spinal cord, including serotonin (5-hydroxytryptamine, 5-HT) synthesized from tryptophan by enzymes tryptophan hydroxylase (TPH, synthesizing 5-hydroxytryptophan, 5-HTP) and aromatic l-amino acid decarboxylase (AADC, synthesizing 5-HT from 5-HTP). Here we examine whether spinal cord caudal to transection remains able to manufacture and metabolize 5-HT. Immunolabeling for AADC reveals that, while most AADC is confined to brain stem-derived monoamine fibers in spinal cords from normal rats, caudal to transection AADC is primarily found in blood vessel endothelial cells and pericytes as well as a novel group of neurons (NeuN positive and GFAP negative), all of which strongly upregulate AADC with injury. However, immunolabeling for 5-HT reveals that there is no detectable endogenous 5-HT synthesis in any structure in the spinal cord caudal to a chronic transection, including in AADC-containing vessels and neurons, consistent with a lack of TPH. In contrast, when we applied exogenous 5-HTP (in vitro or in vivo), AADC containing vessels and neurons synthesized 5-HT, which contributed to increased motoneuron activity and muscle spasms (long-lasting reflexes, LLRs), by acting on 5-HT2 receptors (SB206553 sensitive) located on motoneurons (TTX resistant). Blocking monoamine oxidase (MAO) markedly increased the sensitivity of the motoneurons (LLR) to 5-HTP, more than it increased the sensitivity of motoneurons to 5-HT, suggesting that 5-HT synthesized from AADC is largely metabolized in AADC-containing neurons and vessels. In summary, after spinal cord injury AADC is upregulated in vessels, pericytes, and neurons but does not endogenously produce 5-HT, whereas when exogenous 5-HTP is provided AADC does produce functional amounts of 5-HT, some of which is able to escape metabolism by MAO, diffuse out of these AADC-containing cells, and ultimately act on 5-HT receptors on motoneurons. PMID- 24068761 TI - Strengths and weaknesses of working with the Global Trigger Tool method for retrospective record review: focus group interviews with team members. AB - OBJECTIVES: The aim was to describe the strengths and weaknesses, from team member perspectives, of working with the Global Trigger Tool (GTT) method of retrospective record review to identify adverse events causing patient harm. DESIGN: A qualitative, descriptive approach with focus group interviews using content analysis. SETTING: 5 Swedish hospitals in 2011. PARTICIPANTS: 5 GTT teams, with 5 physicians and 11 registered nurses. INTERVENTION: 5 focus group interviews were carried out with the five teams. Interviews were taped and transcribed verbatim. RESULTS: 8 categories emerged relating to the strengths and weaknesses of the GTT method. The categories found were: Usefulness of the GTT, Application of the GTT, Triggers, Preventability of harm, Team composition, Team tasks, Team members' knowledge development and Documentation. Gradually, changes in the methodology were made by the teams, for example, the teams reported how the registered nurses divided up the charts into two sets, each being read respectively. The teams described the method as important and well functioning. Not only the most important, but also the most difficult, was the task of bringing the results back to the clinic. The teams found it easier to discuss findings at their own clinics. CONCLUSIONS: The GTT method functions well for identifying adverse events and is strengthened by its adaptability to different specialties. However, small, gradual methodological changes together with continuingly developed expertise and adaption to looking at harm from a patient's perspective may contribute to large differences in assessment over time. PMID- 24068762 TI - Pharmacist intervention for glycaemic control in the community (the RxING study). AB - OBJECTIVE: To determine the effect of a community pharmacist prescribing intervention on glycaemic control in patients with poorly controlled type 2 diabetes. DESIGN: Pragmatic, before-after design. SETTING: 12 community pharmacies in Alberta, Canada. PARTICIPANTS: Type 2 diabetes receiving oral hypoglycaemic medications and with glycated haemoglobin (HbA1c) of 7.5-11%. INTERVENTION: Pharmacists systematically identified potential candidates by inviting patients with type 2 diabetes to test their HbA1c using validated point of-care technology. Pharmacists prescribed 10 units of insulin glargine at bedtime, adjusted by increments of 1 unit daily to achieve a morning fasting glucose of <=5.5 mmol/L. The patients were followed up at 2, 4, 8, 14, 20 and 26 weeks. PRIMARY OUTCOME: Change in HbA1c from baseline to week 26. SECONDARY OUTCOMES: Proportion of patients achieving target HbA1c, changes in oral hypoglycaemic agents, quality of life and patient satisfaction, persistence on insulin glargine, number of insulin dosage adjustments per patient and number of hypoglycaemic episodes. RESULTS: We screened 365 patients of whom 111 were eligible. Of those, 100 (90%) were enrolled in the study; all 11 patients who did not consent refused to use insulin. Average age was 64 years (SD 10.4), while average diabetes duration was 10.2 years (SD 7). HbA1c was reduced from 9.1% (SD 1) at baseline to 7.3% (SD 0.9); a change of 1.8% (95% CI 1.4 to 2, p<0.001). Fasting plasma glucose was reduced from 11 (SD 3.3) to 6.9 mmol/L (SD 1.8); a change of 4.1 mmol/L (95% CI of 3.3 to 5, p=0.007). Fifty-one per cent of the patients achieved the target HbA1c of <=7% at the end of the study. CONCLUSIONS: This is the first completed study of independent prescribing by pharmacists. Our results showed similar improvements in glycaemic control as previous physician led studies. RxING provides further evidence for the benefit of pharmacist care in diabetes. TRIAL REGISTRATION: clinicaltrials.gov; Identifier: NCT01335763. PMID- 24068763 TI - Dentists' practice patterns regarding caries prevention: results from a dental practice-based research network. AB - OBJECTIVE: The purposes of this study were to (1) quantify dentists' practice patterns regarding caries prevention and (2) test the hypothesis that certain dentists' characteristics are associated with these practice patterns. DESIGN: The study used a cross-sectional study design consisting of a questionnaire survey. PARTICIPANTS: The study queried dentists who worked in outpatient dental practices who were affiliated with the Dental Practice-Based Research Network Japan, which seeks to engage dentists in investigating research questions and sharing experiences and expertise (n=282). MEASUREMENT: Dentists were asked about their practice patterns regarding caries preventive dentistry. Background data on patients, practice and dentist were also collected. RESULTS: 38% of dentists (n=72) provided individualised caries prevention to more than 50% of their patients. Overall, 10% of the time in daily practice was spent on caries preventive dentistry. Dentists who provided individualised caries prevention to more than 50% of their patients spent significantly more time on preventive care and less time on removable prosthetics treatment, compared to dentists who did not provide individualised caries prevention. Additionally, they provided oral hygiene instruction, patient education, fluoride recommendations, intraoral photographs taken and diet counselling to their patients significantly more often than dentists who did not provide individualised caries prevention. Multiple logistic regression analysis suggested that the percentage of patients interested in caries prevention and the percentage of patients who received hygiene instruction, were both associated with the percentage of patients who receive individualised caries prevention. CONCLUSIONS: We identified substantial variation in dentists' practice patterns regarding preventive dentistry. Individualised caries prevention was significantly related to provision of other preventive services and to having a higher percentage of patients interested in caries prevention, but not to the dentist's belief about the effectiveness of caries risk assessment. (Clinicaltrials.gov registration number NCT01 680 848). PMID- 24068764 TI - Visual analogue scales in stroke: what can they tell us about health-related quality of life? AB - OBJECTIVES: Contrasting accounts exist on whether people with stroke are able to self-report on outcomes using visual analogue scales (VASs). We explored correlations between multi-item scale-rated health-related quality of life (HRQL) and VAS-rated HRQL after stroke, and compared those with versus without aphasia. DESIGN: Cross-sectional survey. SETTING: Community dwelling stroke patients living in London. PARTICIPANTS: People with first stroke were recruited during their hospital stay and were assessed 3 months later. MEASURES: The Frenchay Aphasia Screening Test, the Stroke and Aphasia Quality of Life Scale (SAQOL-39g) and a single vertical VAS. RESULTS: 73 people took part, 14 with aphasia. VAS scores were significantly correlated with the overall SAQOL-39g (r=0.69, p<0.01). SAQOL-39g subdomain scores were also correlated with VAS scores, with the psychosocial domain most highly correlated (r=0.67, p<0.01) and the communication least correlated (rho=0.30, p<0.05). SAQOL-39g-VAS difference scores were higher for people with aphasia and the difference was significant (t (71)=2.02, p<0.05). CONCLUSIONS: Despite the significant correlation of the overall SAQOL-39g and the VAS-rated HRQL, subdomain results suggested that people considered mostly psychosocial aspects when rating their HRQL on a single VAS. Agreement was poorer for people with aphasia, raising issues for the use of VASs with people with aphasia. PMID- 24068765 TI - Impact of corticofugal fibre involvement in subcortical stroke. AB - OBJECTIVE: To correlate motor deficit with involvement of corticofugal fibres in patients with subcortical stroke. The descending motor corticofugal fibres originate from the primary motor cortex (M1), dorsal and ventral premotor area (PMdv) and supplementary motor area (SMA). DESIGN: Retrospective study. SETTING: Single tertiary teaching hospital. PARTICIPANTS: 57 patients (57% men) with subcortical infarcts on MRI (2009-2011) were included. The mean age was 64.3+/ 14.4 years. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOME MEASURES: National Institute of Health Stroke Scale subscores for arm and leg motor deficit at 90 days. RESULTS: An area under the receiver operating characteristics curve (AUC) for the volume of overlap with infarct (and M1/PMdv/SMA fibres) and motor outcome was calculated. The AUC for the association with arm motor deficit from M1 fibres involvement was 0.80 (95% CI 0.66 to 0.94), PMdv was 0.76 (95% CI 0.61 to 0.91) and SMA was 0.73 (95% CI 0.58 to 0.88). The AUC for leg motor deficit from M1 fibres involvement was 0.69 (95% CI 0.52 to 0.85), PMdv was 0.67 (95% CI 0.50 to 0.85), SMA was 0.66 (95% CI 0.48 to 0.84). CONCLUSIONS: Following subcortical stroke, the correlations between involvement of the corticofugal fibres for upper and lower limbs motor deficit were variable. A poor motor outcome was not universal following subcortical stroke. PMID- 24068766 TI - Rosiglitazone use and post-discontinuation glycaemic control in two European countries, 2000-2010. AB - OBJECTIVES: To evaluate the impact of risk minimisation policies on the use of rosiglitazone-containing products and on glycaemic control among patients in Denmark and the UK. DESIGN, SETTING AND PARTICIPANTS: We used population-based data from the Aarhus University Prescription Database (AUPD) in northern Denmark and from the General Practice Research Database (GPRD) in the UK. MAIN OUTCOME MEASURES: We examined the use of rosiglitazone during its entire period of availability on the European market (2000-2010) and evaluated changes in the glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels among patients discontinuing this drug. RESULTS: During 2000-2010, 2321 patients with records in AUPD used rosiglitazone in northern Denmark and 25 428 patients with records in GPRD used it in the UK. The proportion of rosiglitazone users among all users of oral hypoglycaemic agents peaked at 4% in AUPD and at 15% in GPRD in May 2007, the month of publication of a meta-analysis showing increased cardiovascular morbidity associated with rosiglitazone use. 12 months after discontinuation of rosiglitazone-containing products, the mean change in HbA1c was -0.16% (95% CI -3.4% to 3.1%) in northern Denmark and -0.17% (95% CI -0.21% to 0.13%) in the UK. The corresponding mean changes in FPG were 0.01 mmol/L (95% CI -7.3 to 7.3 mmol/L) and 0.03 mmol/L (95% CI -0.22 to 0.28 mmol/L). CONCLUSIONS: Publication of evidence concerning the potential cardiovascular risks of rosiglitazone was associated with an irreversible decline in the use of rosiglitazone-containing products in Denmark and the UK. The mean changes in HbA1c and FPG after drug discontinuation were slight. PMID- 24068768 TI - The association between patients' beliefs about medicines and adherence to drug treatment after stroke: a cross-sectional questionnaire survey. AB - OBJECTIVES: Adherence to preventive drug treatment is a clinical problem and we hypothesised that patients' beliefs about medicines and stroke are associated with adherence. The objective was to examine associations between beliefs of patients with stroke about stroke and drug treatment and their adherence to drug treatment. DESIGN: Cross-sectional questionnaire survey. SETTING: Patients with stroke from 25 Swedish hospitals were included. MEASUREMENTS: Questionnaires were sent to 989 patients to assess their perceptions about stroke (Brief Illness Perception Questionnaire, Brief IPQ), beliefs about medicines (Beliefs about Medicines Questionnaires, BMQ) and adherence to treatment (Medication Adherence Report Scale, MARS) 3 months after stroke onset. Only patients living at home were included in the analysis. The primary outcome was self-reported adherence as measured on MARS. MARS scores were dichotomised into adherent/non-adherent. Background and clinical data from the Swedish Stroke register were included. RESULTS: 811 patients were still living at home and 595 answered the questionnaire. Complete MARS data were available for 578 patients and 72 (12.5%) of these were classified as non-adherent. Non-adherent patients scored lower on positive beliefs as measured on BMQ-necessity (OR = 0.90, 95% CI 0.83 to 0.98) and BMQ-benefit (OR=0.77, 95% CI 0.68 to 0.87), and higher on negative beliefs as measured on BMQ-concern (OR=1.12, 95% CI 1.05 to 1.21), BMQ-overuse (OR=1.29, 95% CI 1.14 to 1.45), and BMQ-harm (OR=1.12, 95% CI 1.01 to 1.24). The Brief IPQ showed that non-adherent patients believed their current treatment to be less useful (p=0.001). CONCLUSIONS: This study showed associations between beliefs of Swedish patients with stroke about medicines and adherence. Positive beliefs were less common and negative more common among non-adherent. To improve adherence, patients' beliefs about medicines should be considered. PMID- 24068767 TI - Rehabilitation impact indices and their independent predictors: a systematic review. AB - OBJECTIVES: To (1) identify all available rehabilitation impact indices (RIIs) based on their mathematical formula, (2) assess the evidence for independent predictors of each RII and (3) propose a nomenclature system to harmonise the names of RIIs. DESIGN: Systematic review. DATA SOURCES: PubMed and references in primary articles. STUDY SELECTION: First, we identified all available RII through preliminary literature review. Then, various names of the same formula were used to identify studies, limited to articles in English and up to 31 December 2011, including case-control and cohort studies, and controlled interventional trials where RIIs were outcome variable and matching or multivariate analysis was performed. RESULTS: The five RIIs identified were (1) absolute functional gain (AFG)/absolute efficacy/total gain, (2) rehabilitation effectiveness (REs)/Montebello Rehabilitation Factor Score (MRFS)/relative functional gain (RFG), (3) rehabilitation efficiency (REy)/length of stay-efficiency (LOS EFF)/efficiency, (4) relative functional efficiency (RFE)/MRFS efficiency and (5) revised MRFS (MRFS-R). REy/LOS-EFF/efficiency had the most number of supporting studies, followed by REs and AFG. Although evidence for different predictors of RIIs varied according to the RII and study population, there is good evidence that older age, lower prerehabilitation functional status and cognitive impairment are predictive of poorer AFG, REs and REy. CONCLUSIONS: 5 RIIs have been developed in the past two decades as composite rehabilitation outcome measures controlling premorbid and prerehabilitation functional status, rate of functional improvement, each with varying levels of evidence for its predictors. To address the issue of multiple names for the same RII, a new nomenclature system is proposed to harmonise the names based on common mathematical formula and a first-named basis. PMID- 24068769 TI - Treatment of ductal carcinoma in situ after excision: would a prophylactic paradigm be more appropriate? AB - Corresponding to the increased use of mammography, the incidence of ductal carcinoma in situ (DCIS) has risen dramatically in the past 30 years. Despite its growing incidence, the treatment of DCIS remains highly variable and controversial. Although DCIS itself does not metastasize and is never lethal, it may be a precursor of invasive breast cancer and is a marker of increased breast cancer risk. Confusing a precursor lesion with cancer, many clinicians apply an invasive breast cancer treatment paradigm to DCIS patients, offering adjuvant radiation therapy and tamoxifen after diagnosis. In this commentary, we outline the issues associated with DCIS management--is DCIS a cancer, a precursor of cancer, or a marker of invasive carcinoma risk? Specifically, we argue that consideration be given to removing the term "carcinoma" from DCIS, using cancer "occurrence" to mean the diagnosis of invasive cancer after DCIS instead of "recurrence," and make the argument that a prophylactic paradigm of treatment after excision may be more appropriate. PMID- 24068770 TI - Ductal carcinoma in situ: a rose by any other name. PMID- 24068772 TI - Pustular skin lesions in a patient with advanced HIV infection and pneumonia. PMID- 24068774 TI - Prognostic value of preoperative right ventricular geometry and tricuspid valve tethering area in patients undergoing tricuspid annuloplasty. AB - BACKGROUND: Patients who undergo tricuspid annuloplasty during left-side heart valve surgery have a poor postoperative clinical outcome. However, preoperative right ventricular (RV) echocardiography parameters that predict adverse events in these patients are poorly understood. METHODS AND RESULTS: We studied 74 patients (age, 58+/-10 years; men, 27%) with significant tricuspid regurgitation who consequently underwent tricuspid annuloplasty during left-side heart valve surgery. A total of 26 adverse events (22 heart failures and 4 cardiovascular deaths) occurred during a median follow-up of 26 months. RV midcavity diameter (hazard ratio=2.44; 95% confidence interval=1.48-4.02; P<0.01), RV longitudinal dimension (hazard ratio=1.64; 95% confidence interval=1.10-2.45; P=0.02), and tricuspid valve tethering area (hazard ratio=3.25; 95% confidence interval=1.71 6.19; P<0.01) were independently associated with adverse events after adjustment for age and New York Heart Association class III/IV. Receiver-operator characteristic curve analysis demonstrated that RV midcavity diameter (area under the curve=0.74; P<0.01) and tricuspid valve tethering area (area under the curve=0.70; P=0.04) were most associated with adverse events at the 1-year follow up. The presence of either a large RV midcavity diameter or tricuspid valve tethering area was predictive of adverse outcome at 1 year after tricuspid annuloplasty. CONCLUSIONS: The present study demonstrates that RV geometry dimensions, namely RV midcavity diameter and tricuspid valve tethering area, are important preoperative measures associated with adverse events in patients undergoing tricuspid annuloplasty. PMID- 24068775 TI - Postconditioning during percutaneous coronary intervention in acute myocardial infarction: continued difficulty in translation. PMID- 24068776 TI - Ischemic postconditioning during primary percutaneous coronary intervention: the effects of postconditioning on myocardial reperfusion in patients with ST-segment elevation myocardial infarction (POST) randomized trial. AB - BACKGROUND: Ischemic postconditioning has been reported to reduce infarct size in patients with ST-segment-elevation myocardial infarction. However, cardioprotective effects of postconditioning have not been demonstrated in a large-scale trial. METHODS AND RESULTS: We performed a multicenter, prospective, randomized, open-label, blinded end-point trial. A total of 700 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction within 12 hours after symptom onset were randomly assigned to the postconditioning group or to the conventional primary PCI group in a 1:1 ratio. Postconditioning was performed immediately after restoration of coronary flow as follows: The angioplasty balloon was positioned at the culprit lesion and inflated 4 times for 1 minute with low-pressure (<6 atm) inflations, each separated by 1 minute of deflation. The primary end point was complete ST segment resolution (percentage resolution of ST-segment elevation >70%) measured at 30 minutes after PCI. Complete ST-segment resolution occurred in 40.5% of patients in the postconditioning group and 41.5% of patients in the conventional PCI group (absolute difference, -1.0%; 95% confidence interval, -8.4 to 6.4; P=0.79). The rate of myocardial blush grade of 0 or 1 and the rate of major adverse cardiac events (a composite of death, myocardial infarction, severe heart failure, or stent thrombosis) at 30 days did not differ significantly between the postconditioning group and the conventional PCI group (17.2% versus 22.4% [P=0.20] and 4.3% versus 3.7% [P=0.70], respectively). CONCLUSION: Ischemic postconditioning did not improve myocardial reperfusion in patients with ST segment-elevation myocardial infarction undergoing primary PCI with current standard practice. PMID- 24068777 TI - How safe is renal replacement therapy? A national study of mortality and adverse events contributing to the death of renal replacement therapy recipients. AB - BACKGROUND: Patients receiving treatment with renal replacement therapy (RRT) have high mortality, and ensuring patient safety in this population is difficult. We aimed to estimate the incidence and nature of medical adverse events contributing to the death of patients being treated with RRT. METHODS: This population registry-based retrospective case review study included all patients being treated with RRT for established renal failure in Scotland and who died between 1 January 2008 and 30 June 2011. Deaths were reviewed by consultant nephrologists using a structured questionnaire to identify factors contributing to death occurring in both the inpatient and outpatient setting. Reviewers were able to use any information source deemed relevant, including paper and electronic clinical records, mortality and morbidity meetings and procurator fiscal (Scottish coroner) investigations. Deaths occurring in 2008 and 2009 where avoidable factors were identified that may have or did lead to death of a patient were subject to further review and root cause analysis, in order to identify recurrent themes. RESULTS: Of 1551 deaths in the study period, 1357 were reviewed (87.5%). Cumulative RRT exposure in the cohort was 2.78 million person-days. RRT complications were the primary cause of death in 28 (2.1%). Health-care associated infection had contributed to 9.6% of all deaths. In 3.5% of deaths, factors were identified which may have or did contribute to death. These were both organizational and human error related and were largely due to five main causes: management of hyperkalaemia, prescribing, out of hours care, infection and haemodialysis vascular access. CONCLUSIONS: Adverse events contributing to death in RRT recipients mainly relate to the everyday management of common medical problems and not the technical aspects of RRT. Efforts to avoid harm in this population should address these ubiquitous causes of harm. PMID- 24068778 TI - Overweight, obesity, hypertension and albuminuria in Polish adolescents--results of the Sopkard 15 study. AB - BACKGROUND: Obesity is a well-known risk factor of many pathologies, including cardiovascular and renal diseases. The prevalence of overweight and obesity has increased markedly in an epidemic way over the past three decades, including a dramatic increase in overweight and obesity among adolescents. METHODS: This study is part of the Sopkard 15 programme-a comprehensive analysis of the overall health of middle school students in the age range between 14 and 15 years with particular emphasis on the risk factors of lifestyle diseases, including metabolic syndrome, chronic kidney disease (CKD) and hypertension. Between 2006 and 2010, we examined 889 students (428 girls, 461 boys) 14 years old, and 26% of them attended classes with an extended sports curriculum. From the three separate blood pressure (BP) measurements a mean value of systolic and diastolic BP from the second and third measurements was taken into analysis. Body mass index (BMI), waist-to-height ratio (WHtR) and body fat mass calculated using bioelectrical impedance analysis (BIA), albuminuria and urine albumin-to-creatinine ratio, estimated glomerular filtration rate (eGFR) estimated on the basis of serum creatinine according to Schwartz and abbreviated Modification of Diet in Renal Disease (MDRD) formula were explored. RESULTS: In the examined homogeneous population of adolescents, we found 8% of participants to be overweight and a further 8% of participants to be obese. An abnormal BMI was statistically significant and was more often present in girls compared with boys. WHtR values typical for abdominal obesity were reported in 17% of the population, significantly more often in girls 19.8 versus 12.4% in boys, P < 0.02. Albuminuria was detected in 16% of adolescents according to urinary albumin excretion (UAE) compared with 11% by an urine albumin-to-creatinine ratio (UACR) method. A higher number of participants with elevated BP were observed to be statistically significant more often in subpopulations with overweight and obesity compared with adolescents with normal weight. The relationship between obesity and hypertension was also confirmed in participants with an increased WHtR. However, no significant relationship between weight disturbances (BMI), as well as abdominal obesity (WHtR), and albuminuria was identified. CONCLUSIONS: Overweight and obesity are present in a significant proportion of adolescents from a general, healthy population of middle school students in the age of 14 years. This phenomenon is strictly connected to the presence of hypertension. PMID- 24068779 TI - Obesity as an effect modifier of the risk of death in chronic kidney disease. AB - In the general population, obesity is associated with increased risk of end-stage renal disease (ESRD), especially if obesity occurs during young adulthood. Obesity is also associated with increased cardiovascular risk and mortality in the general population. However, observational studies which focused on populations with ESRD have demonstrated a more indirect association between body mass index and mortality, and this association has been termed paradoxical. Some have questioned whether the association between obesity and mortality is modified by ESRD. In this review, we discuss effect modification and interaction and factors that may lead to an assumption of effect modification when we observe decreased mortality among obese adults with ESRD. We show that assumptions of the existence of effect modification may be incorrect when the analysis is conditioned on a particular disease state that is influenced by obesity. PMID- 24068780 TI - Reactive tissue proliferation and damage of elastic lamina caused by hydrogel coated coils in experimental rat aneurysms. AB - BACKGROUND AND OBJECTIVE: The HydroCoil Endovascular Aneurysm Occlusion and Packing Study clinical trial, comparing HydroCoil with platinum coils, reported an 8.6% reduction in significant recurrence following cerebral aneurysm coil embolization. We sought to better understand the mechanism of aneurysmal healing following HydroCoil implantation using the rat external carotid artery (ECA) sidewall aneurysm model. METHODS: We ligated the proximal ECA, creating a blind pouch in our rat model. HydroCoil or bare platinum coil segments (5 mm) were inserted into aneurysms. Sham operated rats underwent identical procedures without coil insertion. 14 days after coil embolization, animals were sacrificed and the common carotid artery/internal carotid artery/ECA complex removed. Sac and surrounding vasculature underwent microscopic and histopathologic evaluation. Cellular and fibrotic components within the sac were defined as the organized area. Percentage of organized area and residual length of internal elastic lamina were calculated. RESULTS: Organized tissue area in ECA sac 2 weeks following coil embolization was significantly greater in the HydroCoil group than the bare coil (60.42+/-22.58% vs 15.62+/-19.24%; p=0.01) and sham (60.42+/-22.58% vs 4.61+/ 3.86%; p=0.002) groups. Elastic lamina was significantly reduced in the HydroCoil group compared with the sham and bare coil groups (21.67+/-16.50% vs 100% and 96.06+/-8.78%; both p<0.001). No significant difference was found between the bare coil and sham groups for organized tissue formation or reduction in elastic lamina. Greater numbers of B cells, T cells, and neutrophils were present within HydroCoil induced organized tissue compared with the platinum group; this difference was not statistically significant. CONCLUSIONS: In the rat ECA sidewall aneurysm model, hydrogel coated coils cause more tissue reaction and organization compared with bare platinum coils, possibly attributed to observed elastic lamina damage and vascular smooth muscle cell proliferation. PMID- 24068781 TI - Culture-negative Candida meningitis diagnosed by detection of Candida mannan antigen in CSF. PMID- 24068782 TI - Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. AB - OBJECTIVE: We examined whether copy number variants (CNVs) were more common in those with a combination of intellectual disability (ID) and genetic generalized epilepsy (GGE) than in those with either phenotype alone via a case-control study. METHODS: CNVs contribute to the genetics of multiple neurodevelopmental disorders with complex inheritance, including GGE and ID. Three hundred fifty nine probands with GGE and 60 probands with ID-GGE were screened for GGE associated recurrent microdeletions at 15q13.3, 15q11.2, and 16p13.11 via quantitative PCR or loss of heterozygosity. Deletions were confirmed by comparative genomic hybridization (CGH). ID-GGE probands also had genome-wide CGH. RESULTS: ID-GGE probands showed a significantly higher rate of CNVs compared with probands with GGE alone, with 17 of 60 (28%) ID-GGE probands having one or more potentially causative CNVs. The patients with ID-GGE had a 3-fold-higher rate of the 3 GGE-associated recurrent microdeletions than probands with GGE alone (10% vs 3%, p = 0.02). They also showed a high rate (13/60, 22%) of rare CNVs identified using genome-wide CGH. CONCLUSIONS: This study shows that CNVs are common in those with ID-GGE with recurrent deletions at 15q13.3, 15q11.2, and 16p13.11, particularly enriched compared with individuals with GGE or ID alone. Recurrent CNVs are likely to act as risk factors for multiple phenotypes not just at the population level, but also in any given individual. Testing for CNVs in ID GGE will have a high diagnostic yield in a clinical setting and will inform genetic counseling. PMID- 24068783 TI - omega-3 fatty acids and domain-specific cognitive aging: secondary analyses of data from WHISCA. AB - OBJECTIVE: To test the hypothesis that higher levels of red blood cell (RBC) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have a protective association with domain-specific cognitive function in women aged 65 years and older. METHODS: A total of 2,157 women with normal cognition enrolled in a clinical trial of postmenopausal hormone therapy were followed with annual cognitive testing for a median of 5.9 years. In this retrospective cohort study, we assessed the relationship between prerandomization RBC DHA + EPA levels and a) cognitive measures at baseline, and b) cognitive change over time. Endpoints were composite cognitive function and performance in 7 cognitive domains: fine motor speed, verbal memory, visual memory, spatial ability, verbal knowledge, verbal fluency, and working memory. RESULTS: After adjustment for demographic, clinical, and behavioral characteristics, no significant (p < 0.01) cross-sectional cognitive differences were found between women in the high and low DHA + EPA tertiles at the time of the first annual cognitive battery. In addition, no significant (p < 0.01) differences were found between the high and low DHA + EPA tertiles in the rate of cognitive change over time. CONCLUSIONS: We did not find an association between RBC DHA + EPA levels and age-associated cognitive decline in a cohort of older, dementia-free women. PMID- 24068785 TI - Autoimmune encephalopathies: expanding spectrum of GABAB receptor antibody disorders. PMID- 24068784 TI - Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. AB - OBJECTIVE: To report the clinical features of 20 newly diagnosed patients with GABAB receptor (GABABR) antibodies and determine the frequency of associated tumors and concurrent neuronal autoantibodies. METHODS: Clinical data were retrospectively obtained and evaluated. Serum and CSF samples were examined for additional antibodies using methods previously reported. RESULTS: Seventeen patients presented with seizures, memory loss, and confusion, compatible with limbic encephalitis (LE), one patient presented with ataxia, one patient presented with status epilepticus, and one patient presented with opsoclonus myoclonus syndrome (OMS). Nineteen (95%) patients eventually developed LE during the course of the disease. Small-cell lung cancer (SCLC) was identified in 10 (50%) patients, all with LE. Treatment and outcome was available from 19 patients: 15 showed complete (n = 7) or partial (n = 8) neurologic improvement after steroids, IV immunoglobulins, or plasma exchange and oncologic treatment when indicated; 1 patient died of tumor progression shortly after the first cycle of immunotherapy, and 3 were not treated. Five patients with SCLC had additional onconeuronal antibodies (Ri, amphiphysin, or SOX1), and 2 without tumor had GAD65 and NMDAR antibodies, respectively. GABABR antibodies were not detected in serum of 116 patients with SCLC without neurologic symptoms. CONCLUSION: Our study confirms GABABR as an autoantigen of paraneoplastic and nonparaneoplastic LE and expands the phenotype of GABABR antibodies to ataxia, OMS, and status epilepticus. The long-term prognosis is dictated by the presence of a tumor. Recognition of syndromes associated with GABABR antibodies is important because they usually respond to treatment. PMID- 24068786 TI - Quality improvement in neurology: dementia management quality measures. PMID- 24068787 TI - Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Biomarker Study. AB - OBJECTIVE: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD). METHODS: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 +/- 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study. RESULTS: Plasma levels of 25 hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson's Disease Rating Scale scores at baseline and during follow-up. CONCLUSIONS: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D-deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association. PMID- 24068789 TI - Lack of association between autism and anti-GM1 ganglioside antibody. PMID- 24068788 TI - Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. AB - OBJECTIVE: To explore whether the isocitrate dehydrogenase 1 (IDH1) or 1p/19q status determines the prognostic vs predictive role of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in the Neuro-Oncology Working Group of the German Cancer Society (NOA)-04 trial anaplastic glioma biomarker cohort. METHODS: Patients (n = 183) of the NOA-04 trial with known MGMT and IDH1 status were analyzed for interdependency of the prognostic vs predictive role of MGMT promoter methylation from IDH1 or 1p/19q status and treatment, using progression free survival (PFS) as an endpoint. An independent validation cohort of the German Glioma Network (n = 75) and the NOA-08 trial (n = 34) served as a confirmation cohort. RESULTS: In tumors with IDH1 mutation, MGMT promoter methylation was associated with prolonged PFS with chemotherapy +/- radiotherapy (RT) or RT-only groups, and is thus prognostic. In tumors without IDH1 mutation, MGMT promoter methylation was associated with increased PFS in patients treated with chemotherapy, but not in those who received RT alone as the first-line treatment, and is thus chemotherapy-predictive. In contrast, 1p/19q codeletions showed no such association with the prognostic vs predictive value of MGMT. CONCLUSIONS: MGMT promoter methylation is a predictive biomarker for benefit from alkylating agent chemotherapy in patients with IDH1-wild-type, but not IDH1 mutant, malignant gliomas of World Health Organization grades III/IV. Combined IDH1/MGMT assessment may help to individualize clinical decision-making in neuro oncology. PMID- 24068790 TI - A program impact pathway analysis identifies critical steps in the implementation and utilization of a behavior change communication intervention promoting infant and child feeding practices in Bangladesh. AB - Mapping pathways of how interventions are implemented and utilized enables contextually grounded interpretation of results, differentiates poor design from poor implementation, and identifies factors that might influence the utilization of interventions. Few studies in nutrition have comprehensively examined the steps of implementation and utilization in behavior change communication (BCC) interventions, thus limiting the interpretation of variable impacts of BCC interventions. A program impact pathway (PIP) analysis was used to study a BCC intervention implemented in Bangladesh to improve infant and young child feeding (IYCF) practices. The PIP was developed through an iterative process with the program implementation team; the PIP then guided the choice of methods and tools. Using mixed methods, we reviewed the content of training materials for implementation staff, measured their IYCF knowledge (n = 100), observed their communication with mothers (n = 37), and examined factors influencing promotion of IYCF practices and their trial and adoption by mothers (n = 64). Implementation staff demonstrated good knowledge and maintained fidelity to the intervention to a large extent. Mothers identified them as their primary sources of information, and a majority of mothers tried recommended IYCF practices. Key facilitators included family support and availability of resources, whereas lack of time, maternal and family perceptions of age-appropriate feeding, and lack of resources were salient barriers to adopting recommended practices. Using a PIP analysis identified critical issues pertaining to implementation (e.g., the role of paid and volunteer staff) and utilization (e.g., resource and time constraints that require complementary interventions) and the need for further research and programmatic attention. PMID- 24068791 TI - Infant macronutrient composition is associated with differences in cardiovascular structures and function in childhood. AB - Early-life nutrition may influence cardiovascular development. Not much is known about the associations between dietary composition and cardiovascular risk factors in childhood. We examined the associations of infant macronutrient intake with cardiovascular structures and function in 2882 children participating in a prospective, population-based cohort study. Information on macronutrient intake at the age of 14 mo was obtained from food-frequency questionnaires completed by a parent. Systolic and diastolic blood pressure, carotid-femoral pulse wave velocity (PWV), fractional shortening, and left cardiac structures (left atrial diameter, aortic root diameter, and left ventricular mass) were measured at the age of 6 y. Linear regression analyses were performed by using energy-adjusted macronutrient intakes, adjusted for maternal, child, and other dietary factors. Higher total fat intake was associated with higher carotid-femoral PWV (P-trend = 0.03), whereas higher intakes of total carbohydrate and mono- and disaccharides were associated with lower carotid-femoral PWV. No consistent associations were observed for macronutrient intake with systolic blood pressure, diastolic blood pressure, fractional shortening, and aortic root diameter. Higher intakes of total, saturated, monounsaturated, and polyunsaturated fat were associated with lower left atrial diameter (all P-trend <= 0.01), and higher total carbohydrate and mono- and disaccharide intakes were associated with higher left atrial diameter (P-trend < 0.01 and 0.02, respectively). Furthermore, the third tertile of mono- and disaccharide intake was associated with a higher left ventricular mass (difference: 1.01 g; 95% CI: 0.18, 1.85 g; P = 0.02). Dietary macronutrient composition in infancy may lead to developmental differences in cardiovascular structures and function in childhood. Further studies are needed to investigate whether these differences have consequences for the risk of future cardiovascular disease. PMID- 24068792 TI - Systematic development and validation of a theory-based questionnaire to assess toddler feeding. AB - This paper describes the development and validation of a 27-item caregiver reported questionnaire on toddler feeding. The development of the Toddler Feeding Behavior Questionnaire was based on a theory of interactive feeding that incorporates caregivers' responses to concerns about their children's dietary intake, appetite, size, and behaviors rather than relying exclusively on caregiver actions. Content validity included review by an expert panel (n = 7) and testing in a pilot sample (n = 105) of low-income mothers of toddlers. Construct validity and reliability were assessed among a second sample of low income mothers of predominately African-American (70%) toddlers aged 12-32 mo (n = 297) participating in the baseline evaluation of a toddler overweight prevention study. Internal consistency (Cronbach's alpha: 0.64-0.87) and test retest (0.57-0.88) reliability were acceptable for most constructs. Exploratory and confirmatory factor analyses revealed 5 theoretically derived constructs of feeding: responsive, forceful/pressuring, restrictive, indulgent, and uninvolved (root mean square error of approximation = 0.047, comparative fit index = 0.90, standardized root mean square residual = 0.06). Statistically significant (P < 0.05) convergent validity results further validated the scale, confirming established relations between feeding behaviors, toddler overweight status, perceived toddler fussiness, and maternal mental health. The Toddler Feeding Behavior Questionnaire adds to the field by providing a brief instrument that can be administered in 5 min to examine how caregiver-reported feeding behaviors relate to toddler health and behavior. PMID- 24068793 TI - S-adenosylmethionine is associated with fat mass and truncal adiposity in older adults. AB - S-adenosylmethionine (SAM) is synthesized from methionine, which is abundant in animal-derived protein, in an energy-consuming reaction. SAM and S adenosylhomocysteine (SAH) correlate with body mass index (BMI). Plasma total concentration of the SAM-associated product cysteine (tCys) correlates with fat mass in humans and cysteine promotes adiposity in animals. In a cross-sectional study of 610 participants, we investigated whether SAM and SAH are associated with BMI via lean mass or fat mass and dietary protein sources as determinants of SAM and tCys concentrations. Plasma SAM was not associated with lean mass, but mean adjusted fat mass increased from 24 kg (95% CI: 22.6, 25.1) to 30 kg (95% CI: 28.7, 31.3) across SAM quartiles (P < 0.001) and trunk fat:total fat ratio increased from 0.48 to 0.52 (P < 0.001). Erythrocyte SAM was also positively associated with fat mass and trunk fat:total fat ratio. The association of SAM with fat mass was not weakened by adjustment for serum tCys, lipids, creatinine, or dietary or lifestyle confounders. Concentrations of the SAM precursor, methionine, and the SAM product, SAH, were not independently associated with adiposity. Intake of animal-derived protein was not related to serum methionine but was positively associated with plasma SAM (partial r = 0.11) and serum tCys (partial r = 0.13; P < 0.05 for both after adjustment for age, gender, and total energy intake). In conclusion, plasma SAM, but not methionine, is independently associated with fat mass and truncal adiposity, suggesting increased conversion of methionine to SAM in obese individuals. Prospective studies are needed to investigate the interactions among dietary energy and animal protein content, SAM concentrations, and change in body weight and cardiometabolic risk. PMID- 24068794 TI - Maternal knowledge after nutrition behavior change communication is conditional on both health workers' knowledge and knowledge-sharing efficacy in rural Haiti. AB - In the context of a food assistance program in rural Haiti, we developed measures of the effectiveness of community health worker (CHW)-delivered behavior change communication (BCC). We administered knowledge tests to 954 mothers and 38 CHWs to define 4 measures: CHW knowledge, maternal knowledge, knowledge-sharing efficacy (proportion of CHW knowledge shared), and shared correct knowledge between the CHWs and the mothers with whom they interacted. On the basis of the tests, CHWs had high knowledge (93% correct), mothers scored 72% on maternal knowledge, the proportion of CHW knowledge shared was 75%, and shared correct knowledge between CHWs and mothers was 70%. Factors affecting maternal knowledge included CHW characteristics (unmarried: beta = -0.070, P < 0.05), long duration (19-45 mo) of program participation (beta = 0.034, P < 0.05), and having multiple sources of health and nutrition information (beta = 0.072, P < 0.01). Shared correct knowledge and CHW knowledge-sharing efficacy were positively associated with CHW (age, education) and program participation characteristics. We parsed the relative contributions of CHW characteristics to total and proportion of shared CHW knowledge. We observed a positive association between CHW education and shared correct knowledge between the CHWs and mothers (beta = 0.328, P < 0.01), not because of more knowledge (beta = -0.012, P > 0.05) but rather because of greater knowledge-sharing efficacy (beta = 0.340, P < 0.01). These measures provide a means of examining features of program delivery and interpreting impact evaluation results. They show that BCC outcomes are conditional on both frontline workers' knowledge and knowledge-sharing efficacy. Whereas most programs focus on content training to improve CHWs' knowledge, it is also important to strengthen process training and support to foster knowledge-sharing efficacy. PMID- 24068795 TI - Roles of pollen-specific boron efflux transporter, OsBOR4, in the rice fertilization process. AB - Arabidopsis thaliana BOR1 was the first boron (B) transporter identified in living systems. There are four AtBOR1-like genes, OsBOR1, 2, 3 and 4, present in the rice genome. We characterized the activity, expression and physiological function of OsBOR4. OsBOR4 is an active efflux transporter of B. Quantitative PCR analysis and OsBOR4 promoter-green fluorescent protein (GFP) fusion revealed that OsBOR4 was both highly and specifically expressed in pollen. We obtained five Tos17 insertion mutants of osbor4. The pollen grains were viable and development of floral organs was normal in the homozygous osbor4 mutants. We observed that in all Tos17 insertion lines tested, the frequency of osbor4 homozygous plants was lower than expected in the progeny of self-fertilized heterozygous plants. These results establish that OsBOR4 is essential for normal reproductive processes. Pollen from osbor4 homozygous plants elongated fewer tubes on wild-type stigmas, and tube elongation of mutant pollen was less efficient compared with the wild type pollen, suggesting reduced competence of osbor4 mutant pollen. The reduced competence of mutant pollen was further supported by the crosses of independent Tos17-inserted alleles of OsBOR4. Our results suggest that OsBOR4, a boron efflux transporter, is required for normal pollen germination and/or tube elongation. PMID- 24068796 TI - Enhanced cell expansion in a KRP2 overexpressor is mediated by increased V-ATPase activity. AB - Decreased cell numbers during leaf development often trigger increased cell size, a phenomenon called compensation. In compensation-exhibiting mutants, the unusually high cell expansion activity occurs through two different mechanisms during the post-mitotic stage of leaf development, except in the KIP-RELATED PROTEIN 2-overexpressing line (KRP2 o/e), whose cell sizes are 2-fold greater during proliferative growth. However, the molecular basis of compensated cell expansion (CCE) has not been characterized. The det3-1 mutant has a mutation in the C-subunit of the vacuolar-type H(+)-ATPase (V-ATPase) complex that causes a 50% decrease in its activity and cell size. To determine the contribution of V ATPase activity to CCE, the cellular phenotypes of double mutants between det3-1 and compensation-exhibiting fugu5-1, an3-4, fas1-5 and KRP2 o/e were analyzed in detail. Interestingly, while decreased V-ATPase activity caused by det3-1 did not suppress CCE in fugu5-1, fas1-5 and an3-4, CCE in KRP2 o/e was totally suppressed. Furthermore, measurements revealed that the activity and quantity of the A-subunit of the V-ATPase complex were significantly increased in the shoots of KRP2 o/e plants. Importantly, the unusually increased size of actively dividing KRP2 o/e cells was restored to normal in the det3-1 background. Taken together, our data strongly suggest that CCE in KRP2 o/e, but not in other compensation-exhibiting mutants, occurs exclusively through the increase of V ATPase activity. PMID- 24068797 TI - Representations of distinct salience signals in the nucleus accumbens. PMID- 24068798 TI - Individual predisposition for learning and neuroplasticity. PMID- 24068800 TI - Synaptic mechanisms underlying strong reciprocal connectivity between the medial prefrontal cortex and basolateral amygdala. AB - The medial prefrontal cortex (mPFC) plays a critical role in the control of cognition and emotion. Reciprocal circuits between the mPFC and basolateral amygdala (BLA) are particularly important for emotional control. However, the neurons and synapses that link these brain regions remain largely unknown. Here we examine long-range connections between the mouse mPFC and BLA, using whole cell recordings, optogenetics, and two-photon microscopy. We first identify two non-overlapping populations of layer 2 pyramidal neurons that directly project to either the BLA or contralateral mPFC. We then show that pyramidal neurons projecting to the BLA receive much stronger excitatory inputs from this same brain region. We next assess the contributions of both presynaptic and postsynaptic mechanisms to this cell-type and input-specific connectivity. We use two-photon mapping to reveal differences in both the synaptic density and subcellular targeting of BLA inputs. Finally, we simulate and experimentally validate how the number, volume, and location of active spines all contribute to preferential synaptic drive. Together, our findings reveal a novel and strong reciprocal circuit that is likely to be important for how the mPFC controls cognition and emotion. PMID- 24068799 TI - When the sense of smell meets emotion: anxiety-state-dependent olfactory processing and neural circuitry adaptation. AB - Phylogenetically the most ancient sense, olfaction is characterized by a unique intimacy with the emotion system. However, mechanisms underlying olfaction emotion interaction remain unclear, especially in an ever-changing environment and dynamic internal milieu. Perturbing the internal state with anxiety induction in human subjects, we interrogated emotion-state-dependent olfactory processing in a functional magnetic resonance imaging (fMRI) study. Following anxiety induction, initially neutral odors become unpleasant and take longer to detect, accompanied by augmented response to these odors in the olfactory (anterior piriform and orbitofrontal) cortices and emotion-relevant pregenual anterior cingulate cortex. In parallel, the olfactory sensory relay adapts with increased anxiety, incorporating amygdala as an integral step via strengthened (afferent or efferent) connections between amygdala and all levels of the olfactory cortical hierarchy. This anxiety-state-dependent neural circuitry thus enables cumulative infusion of limbic affective information throughout the olfactory sensory progression, thereby driving affectively charged olfactory perception. These findings could constitute an olfactory etiology model of emotional disorders, as exaggerated emotion-olfaction interaction in negative mood states turns innocuous odors aversive, fueling anxiety and depression with rising ambient sensory stress. PMID- 24068801 TI - Decrease of gray matter volume in the midbrain is associated with treatment response in medication-overuse headache: possible influence of orbitofrontal cortex. AB - Patients with chronic daily headache and overuse of analgesics, triptans, or other acute headache compounds, are considered to suffer from medication-overuse headache (MOH). This implies that medication overuse is the cause of headache chronification. It remains a key question why only two-thirds of patients with chronic migraine-like headache and overuse of pain medication improve after detoxification, whereas the remainder continue to have chronic headache. In the present longitudinal MRI study, we used voxel-based morphometry to investigate gray matter changes related to medication withdrawal in a group of humans with MOH. As a main result, we found that only patients with significant clinical improvement showed a significant decrease of previously increased gray matter in the midbrain including periaqueductal gray matter and nucleus cuneiformis, whereas patients without improvement did not. Patients without treatment response had less gray matter in the orbitofrontal cortex. Another striking result is the correlation of treatment response with the amount of orbitofrontal gray matter. Thus, we demonstrate adaptive gray matter changes within the pain modulatory system in patients with MOH who responded to detoxification, probably reflecting neuronal plasticity. Decreased gray matter in the orbitofrontal cortex at baseline may be predictive of poor response to treatment. PMID- 24068802 TI - Short hairpin RNA against PTEN enhances regenerative growth of corticospinal tract axons after spinal cord injury. AB - Developing approaches to promote the regeneration of descending supraspinal axons represents an ideal strategy for rebuilding neuronal circuits to improve functional recovery after spinal cord injury (SCI). Our previous studies demonstrated that genetic deletion of phosphatase and tensin homolog (PTEN) in mouse corticospinal neurons reactivates their regenerative capacity, resulting in significant regeneration of corticospinal tract (CST) axons after SCI. However, it is unknown whether nongenetic methods of suppressing PTEN have similar effects and how regenerating axons interact with the extrinsic environment. Herein, we show that suppressing PTEN expression with short-hairpin RNA (shRNA) promotes the regeneration of injured CST axons, and these axons form anatomical synapses in appropriate areas of the cord caudal to the lesion. Importantly, this model of increased CST regrowth enables the analysis of extrinsic regulators of CST regeneration in vivo. We find that regenerating axons avoid dense clusters of fibroblasts and macrophages in the lesion, suggesting that these cell types might be key inhibitors of axon regeneration. Furthermore, most regenerating axons cross the lesion in association with astrocytes, indicating that these cells might be important for providing a permissive bridge for axon regeneration. Lineage analysis reveals that these bridge-forming astrocytes are not derived from ependymal stem cells within the spinal cord, suggesting that they are more likely derived from a subset of mature astrocytes. Overall, this study reveals insights into the critical extrinsic and intrinsic regulators of axon regeneration and establishes shRNA as a viable means to manipulate these regulators and translate findings into other mammalian models. PMID- 24068803 TI - Fast vesicle transport is required for the slow axonal transport of synapsin. AB - Although it is known that cytosolic/soluble proteins synthesized in cell bodies are transported at much lower overall velocities than vesicles in fast axonal transport, the fundamental basis for this slow movement is unknown. Recently, we found that cytosolic proteins in axons of mouse cultured neurons are conveyed in a manner that superficially resembles diffusion, but with a slow anterograde bias that is energy- and motor-dependent (Scott et al., 2011). Here we show that slow axonal transport of synapsin, a prototypical member of this rate class, is dependent upon fast vesicle transport. Despite the distinct overall dynamics of slow and fast transport, experimentally induced and intrinsic variations in vesicle transport have analogous effects on slow transport of synapsin as well. Dynamic cotransport of vesicles and synapsin particles is also seen in axons, consistent with a model where higher-order assemblies of synapsin are conveyed by transient and probabilistic associations with vesicles moving in fast axonal transport. We posit that such dynamic associations generate the slow overall anterogradely biased flow of the population ("dynamic-recruitment model"). Our studies uncover the underlying kinetic basis for a classic cytosolic/soluble protein moving in slow axonal transport and reveal previously unknown links between slow and fast transport, offering a clearer conceptual picture of this curious phenomenon. PMID- 24068804 TI - The role of sleep spindles and slow-wave activity in integrating new information in semantic memory. AB - Assimilating new information into existing knowledge is a fundamental part of consolidating new memories and allowing them to guide behavior optimally and is vital for conceptual knowledge (semantic memory), which is accrued over many years. Sleep is important for memory consolidation, but its impact upon assimilation of new information into existing semantic knowledge has received minimal examination. Here, we examined the integration process by training human participants on novel words with meanings that fell into densely or sparsely populated areas of semantic memory in two separate sessions. Overnight sleep was polysomnographically monitored after each training session and recall was tested immediately after training, after a night of sleep, and 1 week later. Results showed that participants learned equal numbers of both word types, thus equating amount and difficulty of learning across the conditions. Measures of word recognition speed showed a disadvantage for novel words in dense semantic neighborhoods, presumably due to interference from many semantically related concepts, suggesting that the novel words had been successfully integrated into semantic memory. Most critically, semantic neighborhood density influenced sleep architecture, with participants exhibiting more sleep spindles and slow-wave activity after learning the sparse compared with the dense neighborhood words. These findings provide the first evidence that spindles and slow-wave activity mediate integration of new information into existing semantic networks. PMID- 24068805 TI - Protein synthesis-dependent associative long-term memory in larval zebrafish. AB - The larval zebrafish is a model organism to study the neural circuitry underlying behavior. There exist, however, few examples of robust long-term memory. Here we describe a simple, unrestrained associative place-conditioning paradigm. We show that visual access to a group of conspecifics has rewarding properties for 6- to 8-day-old larval zebrafish. We use this social reward as an unconditioned stimulus and pair it with a distinct visual environment. After training, larvae exhibited spatial preference for the location previously paired with the social reward for up to 36 h, indicating that zebrafish larvae can exhibit long-term associative memory. Furthermore, incubation with a protein synthesis inhibitor or an NMDAR-antagonist impaired memory. In future experiments, this learning paradigm could be used to study the social interactions of larval zebrafish or paired with cell-specific metabolic labeling to visualize circuits underlying memory formation. PMID- 24068806 TI - The stimulation of adenosine A2A receptors ameliorates the pathological phenotype of fibroblasts from Niemann-Pick type C patients. AB - Niemann-Pick type C1 (NPC1) disease is a rare neurovisceral disorder characterized by intracellular accumulation of unesterified cholesterol, sphingolipids, and other lipids in the lysosomal compartment. A deregulation of lysosomal calcium has been identified as one of the earliest steps of the degenerative process. Since adenosine A2A receptors (A2ARs) control lysosome trafficking and pH, which closely regulates lysosomal calcium, we hypothesized a role for these receptors in NPC1. The aim of this study was to evaluate the effects of the A2AR agonist CGS21680 on human control and NPC1 fibroblasts. We show that CGS21680 raises lysosomal calcium levels and rescues mitochondrial functionality (mitochondrial inner membrane potential and expression of the complex IV of the mitochondrial respiratory chain), which is compromised in NPC1 cells. These effects are prevented by the selective blockade of A2ARs by the antagonist ZM241385. The effects of A2AR activation on lysosomal calcium are not mediated by the cAMP/PKA pathway but they appear to involve the phosphorylation of ERK1/2. Finally, CGS21680 reduces cholesterol accumulation (Filipin III staining), which is the main criterion currently used for identification of a compound or pathway that would be beneficial for NPC disease, and such an effect is prevented by the Ca(2+) chelator BAPTA-AM. Our findings strongly support the hypothesis that A2AR agonists may represent a therapeutic option for NPC1 and provide insights on their mechanisms of action. PMID- 24068807 TI - Opposite adaptive processing of stimulus intensity in two major nuclei of the somatosensory brainstem. AB - Tactile information ascends from the brainstem to the somatosensory cortex via two major parallel pathways, lemniscal and paralemniscal. In both pathways, and throughout all processing stations, adaptation effects are evident. Although parallel processing of sensory information is not unique to this system, the distinct information carried by these adaptive pathways remains unclear. Using in vivo intracellular recordings at their divergence point (brainstem trigeminal complex) in rats, we found opposite adaptation effects in the corresponding nuclei of these two pathways. Increasing the intensity of vibrissa stimulation entailed more adaption in paralemniscal neurons, whereas it caused less adaptation in lemniscal cells. Furthermore, increasing the intensity sharpens lemniscal receptive field profile as adaptation progresses. We hypothesize that these pathways evolved to operate optimally at different dynamic ranges of sustained sensory stimulation. Accordingly, the two pathways are likely to serve different functional roles in the transmission of weak and strong inputs. Hence, our results suggest that due to the disparity in the adaptation properties of two major parallel pathways in this system, high and reliable throughput of information can be achieved at a wider range of stimulation intensities than by each pathway alone. PMID- 24068808 TI - DHHC8-dependent PICK1 palmitoylation is required for induction of cerebellar long term synaptic depression. AB - The palmitoyl acyltransferase (PAT) DHHC8 is implicated in synaptic regulation but few DHHC8 substrates are known. Here we report that DHHC8 binds and palmitoylates the PDZ domain-containing protein PICK1 at a cysteine residue that is essential for long-term synaptic depression (LTD) in cultured mouse cerebellar Purkinje neurons. Cerebellar LTD is palmitoylation-dependent and induction of LTD requires DHHC8. Furthermore, PICK1 is a critical DHHC8 substrate whose palmitoylation is necessary for LTD. These results identify the first DHHC8 substrate required for a specific form of synaptic plasticity and provide new insights into synaptic roles of palmitoylation. PMID- 24068809 TI - Size does not always matter: Ts65Dn Down syndrome mice show cerebellum-dependent motor learning deficits that cannot be rescued by postnatal SAG treatment. AB - Humans with Down syndrome (DS) and Ts65Dn mice both show a reduced volume of the cerebellum due to a significant reduction in the density of granule neurons. Recently, cerebellar hypoplasia in Ts65Dn mice was rescued by a single treatment with SAG, an agonist of the Sonic hedgehog pathway, administered on the day of birth. In addition to normalizing cerebellar morphology, this treatment restored the ability to learn a spatial navigation task, which is associated with hippocampal function. It is not clear to what extent this improved performance results from restoration of the cerebellar architecture or a yet undefined role of Sonic hedgehog (Shh) in perinatal hippocampal development. The absence of a clearly demonstrated deficit in cerebellar function in trisomic mice exacerbates the problem of discerning how SAG acts to improve learning and memory. Here we show that phase reversal adaptation and consolidation of the vestibulo-ocular reflex is significantly impaired in Ts65Dn mice, providing for the first time a precise characterization of cerebellar functional deficits in this murine model of DS. However, these deficits do not benefit from the normalization of cerebellar morphology following treatment with SAG. Together with the previous observation that the synaptic properties of Purkinje cells are also unchanged by SAG treatment, this lack of improvement in a region-specific behavioral assay supports the possibility that a direct effect of Shh pathway stimulation on the hippocampus might explain the benefits of this potential approach to the improvement of cognition in DS. PMID- 24068811 TI - Presynaptic control of corticostriatal synapses by endogenous GABA. AB - Corticostriatal terminals have presynaptic GABA(B) receptors that limit glutamate release, but how these receptors are activated by endogenous GABA released by different types of striatal neurons is still unknown. To address this issue, we used single and paired whole-cell recordings combined with stimulation of corticostriatal fibers in rats and mice. In the presence of opioid, GABA(A), and NK1 receptor antagonists, antidromic stimulation of a population of striatal projection neurons caused suppression of subsequently evoked EPSPs in projection neurons. These effects were larger at intervals of 500 ms than 1 or 2 s, and were fully blocked by the selective GABA(B) receptor antagonist CGP 52432. Bursts of spikes in individual projection neurons were not able to inhibit evoked EPSPs. Similarly, spikes in fast spiking interneurons and low-threshold spike interneurons failed to elicit detectable effects mediated by GABA(B) receptors. Conversely, spikes in individual neurogliaform interneurons suppressed evoked EPSPs, and these effects were blocked by CGP 52432. These results provide the first demonstration of how GABA(B) receptors are activated by endogenous GABA released by striatal neuronal types. PMID- 24068810 TI - Neural dynamics of phonological processing in the dorsal auditory stream. AB - Neuroanatomical models hypothesize a role for the dorsal auditory pathway in phonological processing as a feedforward efferent system (Davis and Johnsrude, 2007; Rauschecker and Scott, 2009; Hickok et al., 2011). But the functional organization of the pathway, in terms of time course of interactions between auditory, somatosensory, and motor regions, and the hemispheric lateralization pattern is largely unknown. Here, ambiguous duplex syllables, with elements presented dichotically at varying interaural asynchronies, were used to parametrically modulate phonological processing and associated neural activity in the human dorsal auditory stream. Subjects performed syllable and chirp identification tasks, while event-related potentials and functional magnetic resonance images were concurrently collected. Joint independent component analysis was applied to fuse the neuroimaging data and study the neural dynamics of brain regions involved in phonological processing with high spatiotemporal resolution. Results revealed a highly interactive neural network associated with phonological processing, composed of functional fields in posterior temporal gyrus (pSTG), inferior parietal lobule (IPL), and ventral central sulcus (vCS) that were engaged early and almost simultaneously (at 80-100 ms), consistent with a direct influence of articulatory somatomotor areas on phonemic perception. Left hemispheric lateralization was observed 250 ms earlier in IPL and vCS than pSTG, suggesting that functional specialization of somatomotor (and not auditory) areas determined lateralization in the dorsal auditory pathway. The temporal dynamics of the dorsal auditory pathway described here offer a new understanding of its functional organization and demonstrate that temporal information is essential to resolve neural circuits underlying complex behaviors. PMID- 24068812 TI - Temporally specific sensory signals for the detection of stimulus omission in the primate deep cerebellar nuclei. AB - The cerebellum is implicated in sensory prediction in the subsecond range. To explore how neurons in the cerebellum encode temporal information for the prediction of sensory events, we trained monkeys to make a saccade in response to either a single omission or deviation of isochronous repetitive stimuli. We found that neurons in the cerebellar dentate nucleus exhibited a gradual elevation of the baseline firing rate as the repetition progressed. Most neurons showed a transient suppression for each stimulus, and this firing modulation also increased gradually, opposed to the sensory adaptation. The magnitude of the enhanced sensory response positively correlated with interstimulus interval. Furthermore, when stimuli appeared unexpectedly earlier than the regular timing, the neuronal modulation became smaller, suggesting that the sensory response depended on the time elapsed since the previous stimulus. The enhancement of neuronal modulation was context dependent and was reduced or even absent when monkeys were unmotivated to detect stimulus omission. A significant negative correlation between neuronal activity at stimulus omission and saccade latency suggested that the timing of each stimulus was predicted by the amount of recovery from the transient response. Because inactivation of the recording sites delayed the detection of stimulus omission but only slightly altered the detection of stimulus deviation, these signals might be necessary for the prediction of stimulus timing but may not be involved only in the generation of saccades. Our results demonstrate a novel mechanism for temporal prediction of upcoming stimuli that accompanies the time-dependent modification of sensory gain in the cerebellum. PMID- 24068813 TI - Distinct regions of right temporal cortex are associated with biological and human-agent motion: functional magnetic resonance imaging and neuropsychological evidence. AB - In human lateral temporal cortex, some regions show specific sensitivity to human motion. Here we examine whether such effects reflect a general biological nonbiological organizational principle or a process specific to human-agent processing by comparing processing of human, animal, and tool motion in a functional magnetic resonance imaging (fMRI) experiment with healthy participants and a voxel-based lesion-symptom mapping (VLSM) study of patients with brain damage (77 stroke patients). The fMRI experiment revealed that in the lateral temporal cortex, the posterior superior temporal sulcus shows a preference for human and animal motion, whereas the middle part of the right superior temporal sulcus/gyrus (mSTS/STG) shows a preference for human and functional tool motion. VLSM analyses also revealed that damage to this right mSTS/STG region led to more severe impairment in the recognition of human and functional tool motion relative to animal motion, indicating the causal role of this brain area in human-agent motion processing. The findings for the right mSTS/STG cannot be reduced to a preference for articulated motion or processing of social variables since neither factor is involved in functional tool motion recognition. We conclude that a unidimensional biological-nonbiological distinction cannot fully explain the visual motion effects in lateral temporal cortex. Instead, the results suggest the existence of distinct components in right posterior temporal cortex and mSTS/STG that are associated, respectively, with biological motion and human agent motion processing. PMID- 24068815 TI - Right supramarginal gyrus is crucial to overcome emotional egocentricity bias in social judgments. AB - Humans tend to use the self as a reference point to perceive the world and gain information about other people's mental states. However, applying such a self referential projection mechanism in situations where it is inappropriate can result in egocentrically biased judgments. To assess egocentricity bias in the emotional domain (EEB), we developed a novel visuo-tactile paradigm assessing the degree to which empathic judgments are biased by one's own emotions if they are incongruent to those of the person we empathize with. A first behavioral experiment confirmed the existence of such EEB, and two independent fMRI experiments revealed that overcoming biased empathic judgments is associated with increased activation in the right supramarginal gyrus (rSMG), in a location distinct from activations in right temporoparietal junction reported in previous social cognition studies. Using temporary disruption of rSMG with repetitive transcranial magnetic stimulation resulted in a substantial increase of EEB, and so did reducing visuo-tactile stimulation time as shown in an additional behavioral experiment. Our findings provide converging evidence from multiple methods and experiments that rSMG is crucial for overcoming emotional egocentricity. Effective connectivity analyses suggest that this may be achieved by early perceptual regulation processes disambiguating proprioceptive first person information (touch) from exteroceptive third-person information (vision) during incongruency between self- and other-related affective states. Our study extends previous models of social cognition. It shows that although shared neural networks may underlie emotional understanding in some situations, an additional mechanism subserved by rSMG is needed to avoid biased social judgments in other situations. PMID- 24068814 TI - Categorical clustering of the neural representation of color. AB - Cortical activity was measured with functional magnetic resonance imaging (fMRI) while human subjects viewed 12 stimulus colors and performed either a color naming or diverted attention task. A forward model was used to extract lower dimensional neural color spaces from the high-dimensional fMRI responses. The neural color spaces in two visual areas, human ventral V4 (V4v) and VO1, exhibited clustering (greater similarity between activity patterns evoked by stimulus colors within a perceptual category, compared to between-category colors) for the color-naming task, but not for the diverted attention task. Response amplitudes and signal-to-noise ratios were higher in most visual cortical areas for color naming compared to diverted attention. But only in V4v and VO1 did the cortical representation of color change to a categorical color space. A model is presented that induces such a categorical representation by changing the response gains of subpopulations of color-selective neurons. PMID- 24068816 TI - Activation of presynaptic GABA(B(1a,2)) receptors inhibits synaptic transmission at mammalian inhibitory cholinergic olivocochlear-hair cell synapses. AB - The synapse between olivocochlear (OC) neurons and cochlear mechanosensory hair cells is cholinergic, fast, and inhibitory. The inhibitory sign of this cholinergic synapse is accounted for by the activation of Ca(2+)-permeable postsynaptic alpha9alpha10 nicotinic receptors coupled to the opening of hyperpolarizing Ca(2+)-activated small-conductance type 2 (SK2)K(+) channels. Acetylcholine (ACh) release at this synapse is supported by both P/Q- and N-type voltage-gated calcium channels (VGCCs). Although the OC synapse is cholinergic, an abundant OC GABA innervation is present along the mammalian cochlea. The role of this neurotransmitter at the OC efferent innervation, however, is for the most part unknown. We show that GABA fails to evoke fast postsynaptic inhibitory currents in apical developing inner and outer hair cells. However, electrical stimulation of OC efferent fibers activates presynaptic GABA(B(1a,2)) receptors [GABA(B(1a,2))Rs] that downregulate the amount of ACh released at the OC-hair cell synapse, by inhibiting P/Q-type VGCCs. We confirmed the expression of GABA(B)Rs at OC terminals contacting the hair cells by coimmunostaining for GFP and synaptophysin in transgenic mice expressing GABA(B1)-GFP fusion proteins. Moreover, coimmunostaining with antibodies against the GABA synthetic enzyme glutamic acid decarboxylase and synaptophysin support the idea that GABA is directly synthesized at OC terminals contacting the hair cells during development. Thus, we demonstrate for the first time a physiological role for GABA in cochlear synaptic function. In addition, our data suggest that the GABA(B1a) isoform selectively inhibits release at efferent cholinergic synapses. PMID- 24068817 TI - Activity-dependent regulation of the K/Cl transporter KCC2 membrane diffusion, clustering, and function in hippocampal neurons. AB - The neuronal K/Cl transporter KCC2 exports chloride ions and thereby influences the efficacy and polarity of GABA signaling in the brain. KCC2 is also critical for dendritic spine morphogenesis and the maintenance of glutamatergic transmission in cortical neurons. Because KCC2 plays a pivotal role in the function of central synapses, it is of particular importance to understand the cellular and molecular mechanisms underlying its regulation. Here, we studied the impact of membrane diffusion and clustering on KCC2 function. KCC2 forms clusters in the vicinity of both excitatory and inhibitory synapses. Using quantum-dot based single-particle tracking on rat primary hippocampal neurons, we show that KCC2 is slowed down and confined at excitatory and inhibitory synapses compared with extrasynaptic regions. However, KCC2 escapes inhibitory synapses faster than excitatory synapses, reflecting stronger molecular constraints at the latter. Interfering with KCC2-actin interactions or inhibiting F-actin polymerization releases diffusion constraints on KCC2 at excitatory but not inhibitory synapses. Thus, F-actin constrains KCC2 diffusion at excitatory synapses, whereas KCC2 is confined at inhibitory synapses by a distinct mechanism. Finally, increased neuronal activity rapidly increases the diffusion coefficient and decreases the dwell time of KCC2 at excitatory synapses. This effect involves NMDAR activation, Ca(2+) influx, KCC2 S940 dephosphorylation and calpain protease cleavage of KCC2 and is accompanied by reduced KCC2 clustering and ion transport function. Thus, activity-dependent regulation of KCC2 lateral diffusion and clustering allows for a rapid regulation of chloride homeostasis in neurons. PMID- 24068819 TI - Cytoarchitectonic and dynamic origins of giant positive local field potentials in the dentate gyrus. AB - To determine why some pathways but not others produce sizable local field potentials (LFPs) and how far from the source can these be recorded, complementary experimental analyses and realistic modeling of specific brain structures are required. In the present study, we combined multiple in vivo linear recordings in rats and a tridimensional finite element model of the dentate gyrus, a curved structure displaying abnormally large positive LFPs. We demonstrate that the polarized dendritic arbour of granule cells (GCs), combined with the curved layered configuration of the population promote the spatial clustering of GC currents in the interposed hilus and project them through the open side at a distance from cell domains. LFPs grow up to 20 times larger than observed in synaptic sites. The dominant positive polarity of hilar LFPs was only produced by the synchronous activation of GCs in both blades by either somatic inhibition or dendritic excitation. Moreover, the corresponding anatomical pathways must project to both blades of the dentate gyrus as even a mild decrease in the spatial synchronization resulted in a dramatic reduction in LFP power in distant sites, yet not in the GC domains. It is concluded that the activation of layered structures may establish sharply delimited spatial domains where synaptic currents from one or another input appear to be segregated according to the topology of afferent pathways and the cytoarchitectonic features of the target population. These also determine preferred directions for volume conduction in the brain, of relevance for interpretation of surface EEG recordings. PMID- 24068818 TI - Differential roles of postsynaptic density-93 isoforms in regulating synaptic transmission. AB - In the postsynaptic density of glutamatergic synapses, the discs large (DLG) membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins coordinates a multiplicity of signaling pathways to maintain and regulate synaptic transmission. Postsynaptic density-93 (PSD-93) is the most variable paralog in this family; it exists in six different N-terminal isoforms. Probably because of the structural and functional variability of these isoforms, the synaptic role of PSD-93 remains controversial. To accurately characterize the synaptic role of PSD-93, we quantified the expression of all six isoforms in the mouse hippocampus and examined them individually in hippocampal synapses. Using molecular manipulations, including overexpression, gene knockdown, PSD-93 knock out mice combined with biochemical assays, and slice electrophysiology both in rat and mice, we demonstrate that PSD-93 is required at different developmental synaptic states to maintain the strength of excitatory synaptic transmission. This strength is differentially regulated by the six isoforms of PSD-93, including regulations of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-active and inactive synapses, and activity-dependent modulations. Collectively, these results demonstrate that alternative combinations of N-terminal PSD-93 isoforms and DLG-MAGUK paralogs can fine-tune signaling scaffolds to adjust synaptic needs to regulate synaptic transmission. PMID- 24068820 TI - Two-dimensional representation of action and arm-use sequences in the presupplementary and supplementary motor areas. AB - The medial frontal cortex has been thought to be crucially involved in temporal structuring of behavior in monkeys and humans. We examined neuronal activity in the supplementary and presupplementary motor areas of monkeys to investigate how the nervous system deals with the coding of 16 motor sequences resulting from multiple actions involving bilateral use of the arms. We first found in both areas that this behavioral demand resulted in attribute-based representation of individual motor acts, reflecting functional (action) or anatomical (right/left arm) attributes. Actions were frequently represented according to a body-axis centered reference frame (supination or pronation) regardless of the arm to be used. Moreover, behavioral sequences were primarily represented with respect to the action- or arm-use sequence rather than the sequence of individual movements. We propose that the two-dimensional attribute-based sequence representation provides a robust and efficient means of processing multiple behavioral sequences. PMID- 24068821 TI - Drosophila neuroligin 4 regulates sleep through modulating GABA transmission. AB - Sleep is an essential and evolutionarily conserved behavior that is closely related to synaptic function. However, whether neuroligins (Nlgs), which are cell adhesion molecules involved in synapse formation and synaptic transmission, are involved in sleep is not clear. Here, we show that Drosophila Nlg4 (DNlg4) is highly expressed in large ventral lateral clock neurons (l-LNvs) and that l-LNv derived DNlg4 is essential for sleep regulation. GABA transmission is impaired in mutant l-LNv, and sleep defects in dnlg4 mutant flies can be rescued by genetic manipulation of GABA transmission. Furthermore, dnlg4 mutant flies exhibit a severe reduction in GABAA receptor RDL clustering, and DNlg4 associates with RDLs in vivo. These results demonstrate that DNlg4 regulates sleep through modulating GABA transmission in l-LNvs, which provides the first known link between a synaptic adhesion molecule and sleep in Drosophila. PMID- 24068822 TI - GABA(A) receptor agonist and antagonist alter vestibular compensation and different steps of reactive neurogenesis in deafferented vestibular nuclei of adult cats. AB - Strong reactive cell proliferation occurs in the vestibular nuclei after unilateral vestibular neurectomy (UVN). Most of the newborn cells survive, differentiate into glial cells and neurons with GABAergic phenotype, and have been reported to contribute to recovery of the posturo-locomotor functions in adult cats. Because the GABAergic system modulates vestibular function recovery and the different steps of neurogenesis in mammals, we aimed to examine in our UVN animal model the effect of chronic infusion of GABA(A) receptor (R) agonist and antagonist in the vestibular nuclei. After UVN and one-month intracerebroventricular infusions of saline, GABA(A)R agonist (muscimol) or antagonist (gabazine), cell proliferation and differentiation into astrocytes, microglial cells, and neurons were revealed using immunohistochemical methods. We also determined the effects of these drug infusions on the recovery of posturo locomotor and oculomotor functions through behavioral tests. Our results showed that surprisingly, one month after UVN, newborn cells did not survive in the UVN muscimol group whereas the number of GABAergic pre-existent neurons increased, and the long-term behavioral recovery of the animals was drastically impaired. Conversely, a significant number of newborn cells survived up to 1 month in the UVN-gabazine group whereas the astroglial population increased, and these animals showed the fastest recovery in behavioral functions. This study reports for the first time that GABA plays multiple roles, ranging from beneficial to detrimental on the different steps of a functional postlesion neurogenesis and further, strongly influences the time course of vestibular function recovery. PMID- 24068823 TI - The ability of BDNF to modify neurogenesis and depressive-like behaviors is dependent upon phosphorylation of tyrosine residues 365/367 in the GABA(A) receptor gamma2 subunit. AB - Brain-derived neurotrophic factor (BDNF) is a potent regulator of neuronal activity, neurogenesis, and depressive-like behaviors; however, downstream effectors by which BDNF exerts these varying actions remain to be determined. Here we reveal that BDNF induces long-lasting enhancements in the efficacy of synaptic inhibition by stabilizing gamma2 subunit-containing GABA(A) receptors (GABA(A)Rs) at the cell surface, leading to persistent reductions in neuronal excitability. This effect is dependent upon enhanced phosphorylation of tyrosines 365 and 367 (Y365/7) in the GABA(A)R gamma2 subunit as revealed using mice in which these residues have been mutated to phenyalanines (Y365/7F). Heterozygotes for this mutation exhibit an antidepressant-like phenotype, as shown using behavioral-despair models of depression. In addition, heterozygous Y365/7F mice show increased levels of hippocampal neurogenesis, which has been strongly connected with antidepressant action. Both the antidepressant phenotype and the increased neurogenesis seen in these mice are insensitive to further modulation by BDNF, which produces robust antidepressant-like activity and neurogenesis in wild-type mice. Collectively, our results suggest a critical role for GABA(A)R gamma2 subunit Y365/7 phosphorylation and function in regulating the effects of BDNF. PMID- 24068824 TI - Spared and impaired spoken discourse processing in schizophrenia: effects of local and global language context. AB - Individuals with schizophrenia are impaired in a broad range of cognitive functions, including impairments in the controlled maintenance of context relevant information. In this study, we used ERPs in human subjects to examine whether impairments in the controlled maintenance of spoken discourse context in schizophrenia lead to overreliance on local associations among the meanings of individual words. Healthy controls (n = 22) and patients (n = 22) listened to short stories in which we manipulated global discourse congruence and local priming. The target word in the last sentence of each story was globally congruent or incongruent and locally associated or unassociated. ERP local association effects did not significantly differ between control participants and schizophrenia patients. However, in contrast to controls, patients only showed effects of discourse congruence when targets were primed by a word in the local context. When patients had to use discourse context in the absence of local priming, they showed impaired brain responses to the target. Our findings indicate that schizophrenia patients are impaired during discourse comprehension when demands on controlled maintenance of context are high. We further found that ERP measures of increased reliance on local priming predicted reduced social functioning, suggesting that alterations in the neural mechanisms underlying discourse comprehension have functional consequences in the illness. PMID- 24068825 TI - Short-term quetiapine treatment alters the use of reinforcement signals during risky decision-making and promotes the choice of negative expected values in healthy adult males. AB - Effective decision-making can involve using environmental signals about the possible good and bad outcomes, and their probabilities, to select optimal actions. Problematic decision-making in psychiatric disorders, and particularly bipolar illness, may result from disrupted use of these reinforcement cues, leading to actions that reflect or precipitate pathological changes in mood. Previous experiments indicate that the processing of reinforcement cues while selecting between risky actions can be influenced by dopamine and serotonin activity. Quetiapine is an atypical antipsychotic agent with a complex pharmacology, including antagonist actions at 5-HT2A and, to a lesser extent, D2 receptors. Here, we investigated the effects of (short-term) treatment with quetiapine on the risky decision-making of healthy human adults. Twenty participants received 150 mg of quetiapine XL for 7 d, whereas 20 age- and IQ matched participants received a placebo. On the eighth day, all participants completed a risky decision-making task that involved making a series of choices between two simultaneously presented gambles that differed in the magnitudes of their possible gains and losses, and the probabilities with which these outcomes were delivered. Quetiapine treatment was associated with a marked tendency to choose options with negative expected values compared with placebo treatment in male but not female participants. Our results demonstrate that antagonism of serotonin and dopamine receptor activity can alter the way individuals use information about gains and losses when selecting between risky actions, possibly reflecting gender-specific differences in risk attitudes. These effects may be beneficial by correcting decision-making biases that feature in mood disorders. PMID- 24068826 TI - Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice. AB - Brain-derived neurotrophic factor (BDNF) improves molecular, cellular, and behavioral measures of neural dysfunction in genetic models of Alzheimer's disease (Blurton-Jones et al., 2009; Nagahara et al., 2009). However, BDNF treatment after disease onset has not been reported to improve neuronal survival in these models. We now report prevention of neuronal loss with early life BDNF treatment in mutant mice expressing two amyloid precursor protein (APP) mutations associated with early-onset familial Alzheimer's disease. APP transgenic mice underwent lentiviral BDNF gene delivery into the entorhinal cortices at age 2 months and were examined 5 months later. BDNF-treated mice exhibited significant improvements in hippocampal-dependent contextual fear conditioning compared with control-treated APP mice (p < 0.05). Stereological analysis of entorhinal cortical cell number demonstrated ~20% reductions in neuronal number in layers II VI of the entorhinal cortex in untreated APP mutant mice compared with wild-type mice (p < 0.0001), and significant amelioration of cell loss by BDNF (p < 0.001). Moreover, BDNF gene delivery improved synaptophysin immunoreactivity in the entorhinal cortex and, through anterograde BDNF transport, in the hippocampus (p < 0.01). Notably, BDNF did not affect amyloid plaque numbers, indicating that direct amyloid reduction is not necessary to achieve significant neuroprotective benefits in mutant amyloid models of Alzheimer's disease. PMID- 24068827 TI - Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment. AB - Glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor that contributes to this poor prognosis is the highly invasive character of the tumor. GBM is characterized by microscopic infiltration of tumor cells throughout the brain, whereas non-neural metastases, as well as select lower grade gliomas, develop as self-contained and clearly delineated lesions. Illustrated by rodent xenograft tumor models as well as pathological human patient specimens, we present evidence that one fundamental switch between these two distinct pathologies--invasion and noninvasion--is mediated through the tumor extracellular matrix. Specifically, noninvasive lesions are associated with a rich matrix containing substantial amounts of glycosylated chondroitin sulfate proteoglycans (CSPGs), whereas glycosylated CSPGs are essentially absent from diffusely infiltrating tumors. CSPGs, acting as central organizers of the tumor microenvironment, dramatically influence resident reactive astrocytes, inducing their exodus from the tumor mass and the resultant encapsulation of noninvasive lesions. Additionally, CSPGs induce activation of tumor-associated microglia. We demonstrate that the astrogliotic capsule can directly inhibit tumor invasion, and its absence from GBM presents an environment favorable to diffuse infiltration. We also identify the leukocyte common antigen-related phosphatase receptor (PTPRF) as a putative intermediary between extracellular glycosylated CSPGs and noninvasive tumor cells. In all, we present CSPGs as critical regulators of brain tumor histopathology and help to clarify the role of the tumor microenvironment in brain tumor invasion. PMID- 24068828 TI - Sulcal depth-position profile is a genetically mediated neuroscientific trait: description and characterization in the central sulcus. AB - Genetic and environmental influences on brain morphology were assessed in an extended-pedigree design by extracting depth-position profiles (DPP) of the central sulcus (CS). T1-weighted magnetic resonance images were used to measure CS length and depth in 467 human subjects from 35 extended families. Three primary forms of DPPs were observed. The most prevalent form, present in 70% of subjects, was bimodal, with peaks near hand and mouth regions. Trimodal and unimodal configurations accounted for 15 and 8%, respectively. Genetic control accounted for 56 and 66% of between-subject variance in average CS depth and length, respectively, and was not significantly influenced by environmental factors. Genetic control over CS depth ranged from 1 to 50% across the DPP. Areas of peak heritability occurred at locations corresponding to hand and mouth areas. Left and right analogous CS depth measurements were strongly pleiotropic. Shared genetic influence lessened as the distance between depth measurements was increased. We argue that DPPs are powerful phenotypes that should inform genetic influence of more complex brain regions and contribute to gene discovery efforts. PMID- 24068829 TI - Sodium-mediated plateau potentials in lumbar motoneurons of neonatal rats. AB - The development and the ionic nature of bistable behavior in lumbar motoneurons were investigated in rats. One week after birth, almost all (~80%) ankle extensor motoneurons recorded in whole-cell configuration displayed self-sustained spiking in response to a brief depolarization that emerged when the temperature was raised >30 degrees C. The effect of L-type Ca(2+) channel blockers on self sustained spiking was variable, whereas blockade of the persistent sodium current (I(NaP)) abolished them. When hyperpolarized, bistable motoneurons displayed a characteristic slow afterdepolarization (sADP). The sADPs generated by repeated depolarizing pulses summed to promote a plateau potential. The sADP was tightly associated with the emergence of Ca(2+) spikes. Substitution of extracellular Na(+) or chelation of intracellular Ca(2+) abolished both sADP and the plateau potential without affecting Ca(2+) spikes. These data suggest a key role of a Ca(2+)-activated nonselective cation conductance ((CaN)) in generating the plateau potential. In line with this, the blockade of (CaN) by flufenamate abolished both sADP and plateau potentials. Furthermore, 2-aminoethoxydiphenyl borate (2-APB), a common activator of thermo-sensitive vanilloid transient receptor potential (TRPV) cation channels, promoted the sADP. Among TRPV channels, only the selective activation of TRPV2 channels by probenecid promoted the sADP to generate a plateau potential. To conclude, bistable behaviors are, to a large extent, determined by the interplay between three currents: L-type I(Ca), I(NaP), and a Na(+)-mediated I(CaN) flowing through putative TRPV2 channels. PMID- 24068830 TI - Cannabinoid transmission in the prelimbic cortex bidirectionally controls opiate reward and aversion signaling through dissociable kappa versus MU-opiate receptor dependent mechanisms. AB - Cannabinoid, dopamine (DA), and opiate receptor pathways play integrative roles in emotional learning, associative memory, and sensory perception. Modulation of cannabinoid CB1 receptor transmission within the medial prefrontal cortex (mPFC) regulates the emotional valence of both rewarding and aversive experiences. Furthermore, CB1 receptor substrates functionally interact with opiate-related motivational processing circuits, particularly in the context of reward-related learning and memory. Considerable evidence demonstrates functional interactions between CB1 and DA signaling pathways during the processing of motivationally salient information. However, the role of mPFC CB1 receptor transmission in the modulation of behavioral opiate-reward processing is not currently known. Using an unbiased conditioned place preference paradigm with rats, we examined the role of intra-mPFC CB1 transmission during opiate reward learning. We report that activation or inhibition of CB1 transmission within the prelimbic cortical (PLC) division of the mPFC bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission as systemic blockade of DAergic transmission prevented CB1-dependent modulation of morphine reward and aversion behaviors. We further report that CB1-mediated intra-PLC opiate motivational signaling is mediated through a MU-opiate receptor-dependent reward pathway, or a kappa-opiate receptor-dependent aversion pathway, directly within the ventral tegmental area. Our results provide evidence for a novel CB1-mediated motivational valence switching mechanism within the PLC, controlling dissociable subcortical reward and aversion pathways. PMID- 24068831 TI - Dab1 is required for synaptic plasticity and associative learning. AB - Disabled-1 (Dab1) is an adaptor protein that is an obligate effector of the Reelin signaling pathway, and is critical for neuronal migration and dendrite outgrowth during development. Components of the Reelin pathway are highly expressed during development, but also continue to be expressed in the adult brain. Here we investigated in detail the expression pattern of Dab1 in the postnatal and adult forebrain, and determined that it is expressed in excitatory as well as inhibitory neurons. Dab1 was found to be localized in different cellular compartments, including the soma, dendrites, presynaptic and postsynaptic structures. Mice that are deficient in Dab1, Reelin, or the Reelin receptors ApoER2 and VLDLR exhibit severely perturbed brain cytoarchitecture, limiting the utility of these mice for investigating the role of this signaling pathway in the adult brain. In this study, we developed an adult forebrain specific and excitatory neuron-specific conditional knock-out mouse line, and demonstrated that Dab1 is a critical regulator of synaptic function and hippocampal-dependent associative and spatial learning. These dramatic abnormalities were accompanied by a reduction in dendritic spine size, and defects in basal and plasticity-induced Akt and ERK1/2 signaling. Deletion of Dab1 led to no obvious changes in neuronal positioning, dendrite morphology, spine density, or synaptic composition. Collectively, these data conclusively demonstrate an important role for Reelin-Dab1 signaling in the adult forebrain, and underscore the importance of this pathway in learning and memory. PMID- 24068832 TI - Dopamine beta-hydroxylase inhibitors enhance the discriminative stimulus effects of cocaine in rats. AB - Inhibitors of dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic cells, have shown promise for the treatment of cocaine abuse disorders. However, the mechanisms underlying the beneficial effects of these compounds have not been fully elucidated. We used the drug discrimination paradigm to determine the impact of DBH inhibitors on the interoceptive stimulus properties of cocaine. Sprague-Dawley rats were trained to discriminate cocaine (5.6 mg/kg) from saline using a multicomponent, food reinforced discrimination procedure. On test days, subjects were pretreated with the nonselective DBH inhibitor disulfiram (0-100.0 mg/kg i.p.) or the selective DBH inhibitor nepicastat (0-56.0 mg/kg i.p.) 2 hours prior to a test session either alone or in combination with cumulatively administered cocaine (0-5.6 mg/kg i.p.). Neither disulfiram nor nepicastat substituted for the cocaine stimulus when tested up to doses that nonspecifically reduced responding. However, in combination studies, pretreatment with either disulfiram or nepicastat produced leftward shifts in the cocaine dose-response function and also conferred cocaine-like stimulus effects to the selective NE transporter inhibitor, reboxetine (0.3-5.6 mg/kg i.p.). These results indicate that pharmacological inhibition of DBH does not produce cocaine-like interoceptive stimulus effects alone, but functionally enhances the interoceptive stimulus effects of cocaine, possibly due to facilitated increases in DA released from noradrenergic terminals. These findings suggest that DBH inhibitors have low abuse liability and provide support to clinical reports that some subjective effects produced by cocaine, particularly aversive effects, are enhanced after DBH inhibition. PMID- 24068833 TI - Pharmacologic profiling of phosphoinositide 3-kinase inhibitors as mitigators of ionizing radiation-induced cell death. AB - Ionizing radiation (IR) induces genotoxic stress that triggers adaptive cellular responses, such as activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling cascade. Pluripotent cells are the most important population affected by IR because they are required for cellular replenishment. Despite the clear danger to large population centers, we still lack safe and effective therapies to abrogate the life-threatening effects of any accidental or intentional IR exposure. Therefore, we computationally analyzed the chemical structural similarity of previously published small molecules that, when given after IR, mitigate cell death and found a chemical cluster that was populated with PI3K inhibitors. Subsequently, we evaluated structurally diverse PI3K inhibitors. It is remarkable that 9 of 14 PI3K inhibitors mitigated gammaIR-induced death in pluripotent NCCIT cells as measured by caspase 3/7 activation. A single intraperitoneal dose of LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4 one], administered to mice at 4 or 24 hours, or PX-867 [(4S,4aR,5R,6aS,9aR,Z)-11 hydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,7,10-trioxo-1-(pyrrolidin-1 ylmethylene)-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydroindeno[4,5-H]isochromen-5-yl acetate (CID24798773)], administered 4 hours after a lethal dose of gammaIR, statistically significantly (P < 0.02) enhanced in vivo survival. Because cell cycle checkpoints are important regulators of cell survival after IR, we examined cell cycle distribution in NCCIT cells after gammaIR and PI3K inhibitor treatment. LY294002 and PX-867 treatment of nonirradiated cells produced a marked decrease in S phase cells with a concomitant increase in the G1 population. In irradiated cells, LY294002 and PX-867 treatment also decreased S phase and increased the G1 and G2 populations. Treatment with LY294002 or PX-867 decreased gammaIR-induced DNA damage as measured by gammaH2AX, suggesting reduced DNA damage. These results indicate pharmacologic inhibition of PI3K after IR abrogated cell death. PMID- 24068834 TI - Quo Vadis medycyno regeneracyjna?: Quo Vadis Regenerative Medicine? AB - There are presented the most important sources of pluripotent stem cells for potential application in the regenerative medicine. This review summarizes also advantages and disadvantages for potential application of these cells in clinical medicine. PMID- 24068835 TI - Fractal tiles associated with shift radix systems. AB - Shift radix systems form a collection of dynamical systems depending on a parameter r which varies in the d-dimensional real vector space. They generalize well-known numeration systems such as beta-expansions, expansions with respect to rational bases, and canonical number systems. Beta-numeration and canonical number systems are known to be intimately related to fractal shapes, such as the classical Rauzy fractal and the twin dragon. These fractals turned out to be important for studying properties of expansions in several settings. In the present paper we associate a collection of fractal tiles with shift radix systems. We show that for certain classes of parameters r these tiles coincide with affine copies of the well-known tiles associated with beta-expansions and canonical number systems. On the other hand, these tiles provide natural families of tiles for beta-expansions with (non-unit) Pisot numbers as well as canonical number systems with (non-monic) expanding polynomials. We also prove basic properties for tiles associated with shift radix systems. Indeed, we prove that under some algebraic conditions on the parameter r of the shift radix system, these tiles provide multiple tilings and even tilings of the d-dimensional real vector space. These tilings turn out to have a more complicated structure than the tilings arising from the known number systems mentioned above. Such a tiling may consist of tiles having infinitely many different shapes. Moreover, the tiles need not be self-affine (or graph directed self-affine). PMID- 24068836 TI - Challenge in Understanding Size and Shape Dependent Toxicity of Gold Nanomaterials in Human Skin Keratinocytes. AB - As the nanotechnology field continues to develop, assessing nanoparticle toxicity is very important for advancing nanoparticles for biomedical application. Here we report cytotoxicity of gold nanomaterial of different size and shape using MTT test, absorption spectroscopy and TEM. Spherical gold nanoparticles with different sizes are not inherently toxic to human skin cells, but gold nanorods are highly toxic due to the presence of CTAB as coating material. Due to CTAB toxicity, and aggregation of gold nanomaterials in the presence of cell media, it is a real challenge to study the cytotoxicity of gold nanomaterials individually. PMID- 24068837 TI - THE CODE OF THE STREET AND INMATE VIOLENCE: INVESTIGATING THE SALIENCE OF IMPORTED BELIEF SYSTEMS. AB - Scholars have long argued that inmate behaviors stem in part from cultural belief systems that they "import" with them into incarcerative settings. Even so, few empirical assessments have tested this argument directly. Drawing on theoretical accounts of one such set of beliefs-the code of the street-and on importation theory, we hypothesize that individuals who adhere more strongly to the street code will be more likely, once incarcerated, to engage in violent behavior and that this effect will be amplified by such incarceration experiences as disciplinary sanctions and gang involvement, as well as the lack of educational programming, religious programming, and family support. We test these hypotheses using unique data that include measures of the street code belief system and incarceration experiences. The results support the argument that the code of the street belief system affects inmate violence and that the effect is more pronounced among inmates who lack family support, experience disciplinary sanctions, and are gang involved. Implications of these findings are discussed. PMID- 24068840 TI - Complete elliptical ring geometry provides energy and instrument calibration for synchrotron-based two-dimensional X-ray diffraction. AB - A complete calibration method to characterize a static planar two-dimensional detector for use in X-ray diffraction at an arbitrary wavelength is described. This method is based upon geometry describing the point of intersection between a cone's axis and its elliptical conic section. This point of intersection is neither the ellipse centre nor one of the ellipse focal points, but some other point which lies in between. The presented solution is closed form, algebraic and non-iterative in its application, and gives values for the X-ray beam energy, the sample-to-detector distance, the location of the beam centre on the detector surface and the detector tilt relative to the incident beam. Previous techniques have tended to require prior knowledge of either the X-ray beam energy or the sample-to-detector distance, whilst other techniques have been iterative. The new calibration procedure is performed by collecting diffraction data, in the form of diffraction rings from a powder standard, at known displacements of the detector along the beam path. PMID- 24068838 TI - Evaluating health and disease in Sub-Saharan Africa: minimally invasive collection of plasma in the Malawi Longitudinal Study of Families and Health (MLSFH). PMID- 24068839 TI - Synthesis, structure and luminescence studies of Eu(III), Tb(III), Sm(III), Dy(III) cationic complexes with acetylacetone and bis(5-(pyridine-2-yl)-1,2,4 triazol-3-yl)propane. AB - Studies concerning synthesis, structure and luminescence of eight-coordinate Eu, Tb, Sm and Dy complexes of the type [Ln(acac)2(L)]Cl (Hacac = pentanedione-2,4 and L = bis(5-(pyridine-2-yl)-1,2,4-triazol-3-yl)propane) are reported in detail. The obtained complexes were investigated by various means including elemental- and thermogravimetric analysis, IR- and electron transition spectroscopy. The structure of the Tb complex was determined by single-crystal X-ray crystallography: Tb is eight-coordinate, and L acting only as a tetradentate chelate together with two bidentate acac ligands. Photophysical studies of the complexes were carried out. The Tb(III) and Eu(III) complexes show strong emissions both in solid state and solution. The intensity of the luminescence of Dy(III) and Sm(III) are relatively weak. The factors determining the intensity of the photoluminescence are discussed. PMID- 24068841 TI - Strain distribution in an Si single crystal measured by interference fringes of X ray mirage diffraction. AB - In X-ray interference fringes accompanied by mirage diffraction, variations have been observed in the spacing and position of the fringes from a plane-parallel Si single crystal fixed at one end as a function of distance from the incident plane of the X-rays to the free crystal end. The variations can be explained by distortion of the sample crystal due to gravity. From the variations and positions of the fringes, the strain gradient of the crystal has been determined. The distribution of the observed strain agrees with that expected from rod theory except for residual strain. When the distortion is large, the observed strain distribution does not agree with that expected from rod theory. PMID- 24068842 TI - X-ray analysis of residual stress gradients in TiN coatings by a Laplace space approach and cross-sectional nanodiffraction: a critical comparison. AB - Novel scanning synchrotron cross-sectional nanobeam and conventional laboratory as well as synchrotron Laplace X-ray diffraction methods are used to characterize residual stresses in exemplary 11.5 um-thick TiN coatings. Both real and Laplace space approaches reveal a homogeneous tensile stress state and a very pronounced compressive stress gradient in as-deposited and blasted coatings, respectively. The unique capabilities of the cross-sectional approach operating with a beam size of 100 nm in diameter allow the analysis of stress variation with sub micrometre resolution at arbitrary depths and the correlation of the stress evolution with the local coating microstructure. Finally, advantages and disadvantages of both approaches are extensively discussed. PMID- 24068843 TI - Graphene as a protein crystal mounting material to reduce background scatter. AB - The overall signal-to-noise ratio per unit dose for X-ray diffraction data from protein crystals can be improved by reducing the mass and density of all material surrounding the crystals. This article demonstrates a path towards the practical ultimate in background reduction by use of atomically thin graphene sheets as a crystal mounting platform for protein crystals. The results show the potential for graphene in protein crystallography and other cases where X-ray scatter from the mounting material must be reduced and specimen dehydration prevented, such as in coherent X-ray diffraction imaging of microscopic objects. PMID- 24068844 TI - Interactive visualization tools for the structural biologist. AB - In structural biology, management of a large number of Protein Data Bank (PDB) files and raw X-ray diffraction images often presents a major organizational problem. Existing software packages that manipulate these file types were not designed for these kinds of file-management tasks. This is typically encountered when browsing through a folder of hundreds of X-ray images, with the aim of rapidly inspecting the diffraction quality of a data set. To solve this problem, a useful functionality of the Macintosh operating system (OSX) has been exploited that allows custom visualization plugins to be attached to certain file types. Software plugins have been developed for diffraction images and PDB files, which in many scenarios can save considerable time and effort. The direct visualization of diffraction images and PDB structures in the file browser can be used to identify key files of interest simply by scrolling through a list of files. PMID- 24068845 TI - Erratum: A novel small-angle neutron scattering detector geometry. Corrigendum. AB - Errors in the paper by Kanaki, Jackson, Hall-Wilton, Piscitelli, Kirstein & Andersen [J. Appl. Cryst. (2013), 46, 1031-1037] are corrected.[This corrects the article DOI: 10.1107/S0021889813011862.]. PMID- 24068846 TI - Does Child Care Quality Mediate Associations Between Type of Care and Development? AB - Studies document that, on average, children cared for in centers, as compared to homes, have higher cognitive test scores but worse socioemotional and health outcomes. The authors assessed whether the quality of care received explains these associations. They considered multiple domains of child development cognitive, socioemotional, and health-and examined whether mediation is greater when quality measures are better aligned with outcome domains. Using the Early Childhood Longitudinal Study Birth Cohort, they found that children in centers have better cognitive skills and behavioral regulation than children in homes, but worse social competence and generally equivalent health (N = 1,550). They found little evidence that quality of child care, as measured by standard instruments (e.g., the Early Childhood Environment Rating Scale-Revised), accounts for associations between type of care and child developmental outcomes. PMID- 24068847 TI - Hispanic Familism Reconsidered: Ethnic Differences in Perceived Value of Children and Fertility Intentions. AB - Familism has been described as a cultural trait that might explain why the fertility of Hispanic women remains higher than non-Hispanic White women. Still, few studies have analyzed group differences in childbearing attitudes. This paper focuses on two dimensions of childbearing orientation: social value of children and fertility intentions. Using the National Survey of Family Growth we find limited support for the idea that familism undergirds differentials in fertility between native-born Hispanics and Whites. However, for foreign-born Hispanics, there are some differences in the perceived value of children compared with Whites, and these differences could contribute to fertility differentials. PMID- 24068848 TI - Enantiodivergent hydroboration reactions of a racemic allenylsilane with diisopinocampheylborane and Curtin-Hammett controlled double asymmetric crotylboration reactions of (S)-E-alphaphenyldimethylsilyl( d diisopinocampheyl) crotylborane. AB - The enantiodivergent hydroboration reactions of racemic allenylsilane (+/-)-4 with ( d Ipc)2BH and subsequent crotylboration of achiral aldehydes with the product crotylborane (S)-E-5 at -78 degrees C provide (E)-delta-silyl-anti homoallylic alcohols 6 in 71-89% yield and with 93-96% ee. Intriguingly, mismatched double asymmetric crotylboration reactions of enantioenriched chiral aldehydes 20 with (S)-E-5 proceed under Curtin-Hammett control to give anti-beta hydroxylcrotylsilanes 24 as the only products. PMID- 24068849 TI - Straight to the Source: Detecting Aggregate Objects in Astronomical Images with Proper Error Control. AB - The next generation of telescopes, coming on-line in the next decade, will acquire terabytes of image data each night. Collectively, these large images will contain billions of interesting objects, which astronomers call sources. One critical task for astronomers is to construct from the image data a detailed source catalog that gives the sky coordinates and other properties of all detected sources. The source catalog is the primary data product produced by most telescopes and serves as an important input for studies that build and test new astrophysical theories. To construct an accurate catalog, the sources must first be detected in the image. A variety of effective source detection algorithms exist in the astronomical literature, but few if any provide rigorous statistical control of error rates. A variety of multiple testing procedures exist in the statistical literature that can provide rigorous error control over pixelwise errors, but these do not provide control over errors at the level of sources, which is what astronomers need. In this paper, we propose a technique that is effective at source detection while providing rigorous control on source-wise error rates. We demonstrate our approach with data from the Chandra X-ray Observatory Satellite. Our method is competitive with existing astronomical methods, even finding two new sources that were missed by previous studies, while providing stronger performance guarantees and without requiring costly follow up studies that are commonly required with current techniques. PMID- 24068850 TI - Joint Modeling and Estimation for Recurrent Event Processes and Failure Time Data. AB - Recurrent event data are commonly encountered in longitudinal follow-up studies related to biomedical science, econometrics, reliability, and demography. In many studies, recurrent events serve as important measurements for evaluating disease progression, health deterioration, or insurance risk. When analyzing recurrent event data, an independent censoring condition is typically required for the construction of statistical methods. In some situations, however, the terminating time for observing recurrent events could be correlated with the recurrent event process, thus violating the assumption of independent censoring. In this article, we consider joint modeling of a recurrent event process and a failure time in which a common subject-specific latent variable is used to model the association between the intensity of the recurrent event process and the hazard of the failure time. The proposed joint model is flexible in that no parametric assumptions on the distributions of censoring times and latent variables are made, and under the model, informative censoring is allowed for observing both the recurrent events and failure times. We propose a "borrow-strength estimation procedure" by first estimating the value of the latent variable from recurrent event data, then using the estimated value in the failure time model. Some interesting implications and trajectories of the proposed model are presented. Properties of the regression parameter estimates and the estimated baseline cumulative hazard functions are also studied. PMID- 24068851 TI - Measuring the influence of aerosols and albedo on sky polarization. AB - All-sky distributions of the polarized radiance are measured using an automated fish-eye camera system with a rotating polarizer. For a large range of aerosol and surface albedo situations, the influence on the degree of polarization and sky radiance is investigated. The range of aerosol optical depth and albedo is 0.05-0.5 and 0.1-0.75, respectively. For this range of parameters, a reduction of the degree of polarization from about 0.7 to 0.4 was observed. The analysis is done for 90 degrees scattering angle in the principal plane under clear sky conditions for a broadband channel of 450 +/- 25 nm and solar zenith angles between 55 degrees and 60 degrees . Radiative transfer calculations considering three different aerosol mixtures are performed and and agree with the measurements within the statistical error. PMID- 24068853 TI - Self-esteem and academic achievement: a comparative study of adolescent students in England and the United States. AB - Utilizing mixed methodology, this paper investigates the relationship between self-esteem and academic achievement for young adolescents within two Western cultural contexts: the United States and England. Quantitative and qualitative data from 86 North American and 86 British adolescents were utilized to examine the links between self-esteem and academic achievement from the beginning to the end of their academic year during their 11th-12th year of age. For both samples, quantitative results demonstrated that fall self-esteem was related to multiple indicators of later year academic achievement. While country differences emerge by the end of the year, math appears to have a consistent relationship with self esteem in both country contexts. Qualitative analyses found some support for British students' self-perceptions as more accurately reflecting their academic experience than the students from the United States. PMID- 24068852 TI - Temporal genetic variation of the red fox, Vulpes vulpes, across western Europe and the British Isles. AB - Quaternary climatic fluctuations have had profound effects on the phylogeographic structure of many species. Classically, species were thought to have become isolated in peninsular refugia, but there is limited evidence that large, non polar species survived outside traditional refugial areas. We examined the phylogeographic structure of the red fox (Vulpes vulpes), a species that shows high ecological adaptability in the western Palaearctic region. We compared mitochondrial DNA sequences (cytochrome b and control region) from 399 modern and 31 ancient individuals from across Europe. Our objective was to test whether red foxes colonised the British Isles from mainland Europe in the late Pleistocene, or whether there is evidence that they persisted in the region through the Last Glacial Maximum. We found red foxes to show a high degree of phylogeographic structuring across Europe and, consistent with palaeontological and ancient DNA evidence, confirmed via phylogenetic indicators that red foxes were persistent in areas outside peninsular refugia during the last ice age. Bayesian analyses and tests of neutrality indicated population expansion. We conclude that there is evidence that red foxes from the British Isles derived from central European populations that became isolated after the closure of the landbridge with Europe. PMID- 24068854 TI - Strong-interaction shifts and widths of kaonic helium isotopes. AB - The kaonic 3He and 4He [Formula: see text] transitions in gaseous targets were observed by the SIDDHARTA experiment. The X-ray energies of these transitions were measured with large-area silicon-drift detectors using the timing information of the [Formula: see text] pairs produced by the DAPhiNE [Formula: see text] collider. The strong-interaction shifts and widths both of the kaonic 3He and 4He 2p states were determined, which are much smaller than the results obtained by the previous experiments. The "kaonic helium puzzle" (a discrepancy between theory and experiment) was now resolved. PMID- 24068855 TI - Cell-Based Microscale Isolation of Glycoaminoglycans for Glycomics Study. AB - Glycomics research requires the isolation of glycans from cells for structural characterization and functional studies of the glycans. A method for cell-based microscale isolation and quantification of highly sulfated, moderately sulfated, and nonsulfated glycosaminoglycans (GAGs) was developed using Chinese hamster ovary (CHO) cells. This microscale isolation relies on a mini-strong anion exchange spin column eluted stepwise with different concentrations of sodium chloride solution. Hyaluronic acid, chondroitin sulfate, and heparin were used to optimize the isolation of the endogenous glycosaminoglycans in CHO cells. This method can also be used to determine the presence of nonsulfated GAGs including heparosan, hyaluronic acid, and nonsulfated chondroitin. PMID- 24068856 TI - Schooling effects on preschoolers' self-regulation, early literacy, and language growth. AB - The present study examined the influence of schooling during children's first and second years of preschool for children who experienced different amounts of preschool (i.e., one or two years), but who were essentially the same chronological age. Children (n = 76) were tested in the fall and spring of the school year using measures of self-regulation, decoding, letter knowledge, and vocabulary. Using hierarchical linear modeling (HLM), preschool was not associated with children's development of self-regulation in either year. For decoding and letter knowledge, children finishing their second year of preschool had higher scores, although both groups of children grew similarly during the school year. Thus, our results suggest that the first and second years of preschool are both systematically associated with decoding and letter knowledge gains, and the effects are cumulative (two years predicted greater gains overall than did one year of preschool). Finally, children's chronological age, and not whether they experienced one versus two years of preschool, predicted children's vocabulary and self-regulation outcomes. Implications for preschool curricula and instruction are discussed, including the increasing emphasis on literacy learning prior to kindergarten entry and the need to address self-regulation development along with academic learning. PMID- 24068859 TI - Retraction: Agrobacterium tumefaciens-mediated transformation and efficient regeneration of a timber yielding plant Dalbergia sissoo Roxb. PMID- 24068858 TI - Tumor necrosis factor- alpha and interleukin-6: potential interorgan inflammatory mediators contributing to destructive periodontal disease in obesity or metabolic syndrome. AB - Obesity has become a worldwide health burden in the last two decades. Obesity has been associated with increased comorbidities, such as coronary artery disease, diabetes, and destructive periodontal disease. Obesity is also part of a group of risk factors occurring together in an individual, which is referred to as metabolic syndrome. Clinical studies have shown higher risk for destructive periodontal disease in obesity and metabolic syndrome. However, the role of obesity and metabolic syndrome in the onset and development of destructive periodontal disease has not yet been fully understood. In this review, we discuss a working model, which focuses on interorgan inflammation as a common etiological factor for destructive periodontal disease associated with obesity and metabolic syndrome. Specifically, we suggest that elevated levels of tumor necrosis factor- alpha (TNF- alpha ) or interleukin 6 (IL-6)--both adipokines and known risk factors for destructive periodontal disease--in obesity and metabolic syndrome contribute to the onset and development of destructive periodontal disease. The connections between destructive periodontal disease and systemic conditions, such as obesity or metabolic syndrome, are complex and potentially multidirectional. This review largely focuses on TNF- alpha and IL-6, inflammatory mediators, as potential common risk factors and does not exclude other biological mechanisms. PMID- 24068860 TI - Dynamic Social Networks and Physical Aggression: The Moderating Role of Gender and Social Status Among Peers. AB - We examined three interrelated questions: (1) Who selects physically aggressive friends?; (2) Are physically aggressive adolescents influential?; and (3) Who is susceptible to influence from these friends? Using stochastic actor-based modeling, we tested our hypotheses using a sample of 480 adolescents (ages 11-13) who were followed across four assessments (fall and spring of 6th and 7th grade). After controlling for other factors that drive network and behavioral dynamics, we found that physically aggressive adolescents were attractive as friends, physically aggressive adolescents and girls were more likely to select physically aggressive friends, and peer-rejected adolescents were less likely to select physically aggressive friends. There was an overall peer influence effect, but gender and social status were not significant moderators of influence. PMID- 24068861 TI - The T allele of lysyl oxidase-like 1 rs41435250 is a novel risk factor for pseudoexfoliation syndrome and pseudoexfoliation glaucoma independently and through intragenic epistatic interaction. AB - PURPOSE: Two coding single nucleotide polymorphisms (SNPs) in lysyl oxidase-like 1 (LOXL1) are major genetic risk factors for pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG) in diverse populations. However, recent conflicting results suggest that the currently known disease-associated missense variants R141L and G153D are not causal and that they may be proxies for other unknown functional LOXL1 variants. The purpose of this study was to investigate the possible association of XFS/XFG with a novel LOXL1 exonic variant. METHODS: Genotypes of the synonymous coding LOXL1 SNP rs41435250 (p.A310A) were identified with direct sequencing. A case-control study was conducted with 115 unrelated Mexican patients with XFS/XFG (43 XFS/72 XFG) as well as 130 control subjects. Allele frequencies, genotype frequencies, and Hardy-Weinberg equilibrium were assessed with the HaploView software. A probable intragenic epistasis effect was assessed by comparing the frequencies of the rs41435250 alleles among a subset of 51 patients with XFS/XFG without the high-risk TT genotype at LOXL1 intronic rs2165241 and the control group. RESULTS: The T allele of the exonic SNP rs41435250 was more frequent in patients with XFS/XFG than in controls (odds ratios [95% confidence intervals] = 2.0 [1.1-3.6]; p = 0.01). Interestingly, the strength of association with the rs41435250 T allele was strongly increased (odds ratio [95% confidence intervals] = 4.9 [2.7-9.1]; p = 0.00000005) in the subgroup of subjects without the risk genotype at rs2165241. CONCLUSIONS: Our results indicate that allele T of rs41435250 is a novel risk genetic factor for XFS/XFG development in our population and points toward the possibility of a LOXL1 intragenic epistatic effect between rs41435250 and rs2165241. Functional studies are needed to investigate if the synonymous p.A310A mutation could affect messenger ribonucleic acid stability and thus LOXL1 enzymatic activity. PMID- 24068857 TI - Nanoparticles for Improving Cancer Diagnosis. AB - Despite the progress in developing new therapeutic modalities, cancer remains one of the leading diseases causing human mortality. This is mainly attributed to the inability to diagnose tumors in their early stage. By the time the tumor is confirmed, the cancer may have already metastasized, thereby making therapies challenging or even impossible. It is therefore crucial to develop new or to improve existing diagnostic tools to enable diagnosis of cancer in its early or even pre-syndrome stage. The emergence of nanotechnology has provided such a possibility. Unique physical and physiochemical properties allow nanoparticles to be utilized as tags with excellent sensitivity. When coupled with the appropriate targeting molecules, nanoparticle-based probes can interact with a biological system and sense biological changes on the molecular level with unprecedented accuracy. In the past several years, much progress has been made in applying nanotechnology to clinical imaging and diagnostics, and interdisciplinary efforts have made an impact on clinical cancer management. This article aims to review the progress in this exciting area with emphases on the preparation and engineering techniques that have been developed to assemble "smart" nanoprobes. PMID- 24068862 TI - Decrease in hyperosmotic stress-induced corneal epithelial cell apoptosis by L carnitine. AB - PURPOSE: To characterize the osmoprotective properties of L-carnitine on human corneal epithelial cell volume and apoptosis during hyperosmotic stress. METHODS: Human corneal limbal epithelial (HCLE) cells were exposed to culture medium at 300 mOsm (isotonic) or 500 mOsm (hyperosmotic) with or without L-carnitine (10 mM). Induction of apoptosis was detected by quantifying the proteolytic activity of caspase-8, caspase-9, and caspase-3/7 using caspase activity assays, the expression of tumor necrosis factor (TNF)-alpha with enzyme-linked immunosorbent assay, and annexin V/propidium iodide staining of HCLE cells evaluated with confocal microscopy and flow cytometry. Cell volume changes in response to hyperosmotic stress were analyzed using flow cytometry. RESULTS: After the HCLE cells were exposed to hyperosmotic medium (500 mOsm), the percentage of shrunken cells and damaged/dead cells (stained positively for annexin V and/or propidium iodide) was six- and three-fold, respectively, higher than that under isotonic conditions (300 mOsm). This was paralleled by an increase in TNF-alpha concentration in media and caspase-8, -9, and -3/7 activities (six-, four-, ten-, and twelve-fold, respectively; all showing p < 0.001). Addition of L-carnitine during hyperosmotic stress partly restored cell volume and significantly reduced the concentration of TNF-alpha released (p = 0.005) and caspase-9 activity (p = 0.0125). Addition of L-carnitine reduced the percentage of hyperosmolarity induced damaged/dead cells to levels observed under isotonic conditions. CONCLUSIONS: L-carnitine can regulate human corneal epithelial cell volume under hyperosmotic stress and ameliorate hyperosmotic stress-induced apoptosis. PMID- 24068863 TI - Topical administration of interleukin-1 receptor antagonist as a therapy for aqueous-deficient dry eye in autoimmune disease. AB - PURPOSE: Dry eye is commonly associated with autoimmune diseases such as Sjogren's syndrome (SS), in which exocrinopathy of the lacrimal gland leads to aqueous tear deficiency and keratoconjunctivitis sicca (KCS). KCS is among the most common and debilitating clinical manifestations of SS that is often recalcitrant to therapy. We established mice deficient in the autoimmune regulator (Aire) gene as a model for autoimmune-mediated aqueous-deficient dry eye. In Aire-deficient mice, CD4+ T cells represent the main effector cells and local signaling via the interleukin-1 (IL-1/IL-1R1) pathway provides an essential link between autoreactive CD4+ T cells and ocular surface disease. In the current study, we evaluated the efficacy of topical administration of IL-1R1 antagonist (IL-1RA) anakinra in alleviating ocular surface damage resulting from aqueous deficient dry eye in the setting of autoimmune disease. METHODS: We compared the effect of commercially available IL-1R1 antagonist, anakinra (50 MUg/mL concentration) to that of carboxymethylcellulose (CMC) vehicle control as a treatment for dry eye. Age-matched, Aire-deficient mice were treated three times daily with anakinra or CMC vehicle for 14 days using side-by-side (n = 4 mice/group) and paired-eye (n = 5) comparisons. We assessed (1) ocular surface damage with lissamine green staining; (2) tear secretion with wetting of phenol red threads; (3) goblet cell (GC) mucin glycosylation with lectin histochemistry; (4) immune cell infiltration using anti-F4/80, CD11c, and CD4 T cell antibodies; and (5) gene expression of cornified envelope protein, Small Proline-Rich Protein 1B (SPRR1B) with real-time quantitative polymerase chain reaction. RESULTS: Aire deficient mice treated with anakinra experienced significant improvements in ocular surface integrity and tear secretion. After 7 days of treatment, lissamine green staining decreased in eyes treated with anakinra compared to an equivalent increase in staining following treatment with CMC vehicle alone. By day 14, lissamine green staining in anakinra-treated eyes remained stable while eyes treated with CMC vehicle continued to worsen. Accordingly, there was a progressive decline in tear secretion in eyes treated with the CMC vehicle compared to a progressive increase in the anakinra-treated eyes over the 2-week treatment period. Aberrant acidification of GC mucins and pathological keratinization of the ocular surface were significantly reduced in anakinra treated eyes. Significantly fewer Maackia amurensis leukoagglutinin positive goblet cells were noted in the conjunctiva of anakinra-treated eyes with a corresponding decrease in the expression of the pathological keratinization marker, SPRR1B. Finally, there was a downward trend in the infiltration of each immune cell type following anakinra treatment, but the cell counts compared to eyes treated with the vehicle alone were not significantly different. CONCLUSIONS: IL-1R antagonist, anakinra, demonstrates therapeutic benefits as a topical treatment for aqueous-deficient dry eye in a spontaneous mouse model of autoimmune KCS that mimics the clinical characteristics of SS. Targeting the IL 1/IL-1R1 signaling pathway through topical administration of IL-1RA may provide a novel option to improve ocular surface integrity, increase tear secretion, and restore the normal glycosylation pattern of GC mucins in patients with SS. PMID- 24068864 TI - Sphingolipids and ceramides in human aqueous humor. AB - PURPOSE: To determine the differential profiles of sphingomyelin, sphingoid base, sphingoid base-1-phosphate and ceramide lipid species and their quantitative differences between control and glaucomatous aqueous humor (AQH) derived from human donors. METHODS: AQH from control and primary open-angle glaucoma donors was collected and subjected to lipid extraction using suitable modifications of the Bligh and Dyer method. Proteins were estimated using Bradford's method. Lipids were identified and ratiometrically quantified in a two-step process using precursor ion scan or neutral loss scan (NLS) with appropriate class-specific lipid standards on a TSQ Quantum Access Max mass spectrometer following established procedures. Primary human trabecular meshwork cells and video microscopic imaging were used to assess changes in cell shape and motility upon exposure to 20 pmol of Cer(d18:0/18:1(9Z)) in 10% dimethyl sulfoxide (vehicle). RESULTS: We identified several species of sphingomyelin, sphingoid base, sphingoid base-1-phosphate, and ceramides that were common between control and glaucomatous AQH. Some unique lipid species in these classes were also identified in controls but not in glaucoma and vice versa. We found exposure to 20 pmol of Cer(d18:0/18:1(9Z)) resulted in changes in the trabecular meshwork cell shape and observed motility changes compared to vehicle-only control. CONCLUSIONS: Most lipids belonging to the sphingomyelin, sphingoid base, sphingoid base-1 phosphate, and ceramide species were common between control and primary open angle glaucoma donors. However, some sphingolipids and ceramides were found to be uniquely present in control but absent in the glaucomatous AQH and vice versa. Identification of unique lipid species present or absent in the pathophysiological context may contribute further insight into glaucoma pathology. PMID- 24068865 TI - Review: retinal degeneration: focus on the unfolded protein response. AB - Recently published literature has provided evidence that the unfolded protein response (UPR) is involved in the development of retinal degeneration. The scope of these studies encompassed diabetic retinopathy, retinopathy of prematurity, glaucoma, retinal detachment, light-induced retinal degeneration, age-related macular degeneration, and inherited retinal degeneration. Subsequent studies investigating the role of individual UPR markers in retinal pathogenesis and examining the therapeutic potential of reprogramming the UPR as a method for modulating the rate of retinal degeneration have been initiated. Manipulation of UPR markers has been made possible by the use of knockout mice, pharmacological agents, and viral vector-mediated augmentation of gene expression. Future research will aim at identifying specific inhibitors and/or inducers of UPR regulatory markers as well as expand the list of UPR-related animal models. Additionally, adeno-associated virus-mediated gene delivery is a safe and effective method for modulating gene expression, and thus is a useful research tool for manipulating individual UPR markers in affected retinas and a promising delivery vector for gene therapy in retinal degenerative disorders. PMID- 24068866 TI - Prevention of venous thromboembolism in hospitalized acutely ill medical patients: focus on the clinical utility of (low-dose) fondaparinux. AB - Venous thromboembolism (VTE) is a frequent complication among acutely ill medical patients hospitalized for congestive heart failure, acute respiratory insufficiency, rheumatologic disorders, and acute infectious and/or inflammatory diseases. Based on robust data from randomized controlled studies and meta analyses showing a reduced incidence of VTE by 40% to about 60% with pharmacologic thromboprophylaxis, prevention of VTE with low molecular weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux is currently recommended in all at-risk hospitalized acutely ill medical patients. In patients who are bleeding or are at high risk for major bleeding, mechanical prophylaxis with graduated compression stockings or intermittent pneumatic compression may be suggested. Thromboprophylaxis is generally continued for 6 to 14 days or for the duration of hospitalization. Selected cases could benefit from extended thromboprophylaxis beyond this period, although the risk of major bleeding remains a concern, and additional studies are needed to identify patients who may benefit from prolonged prophylaxis. For hospitalized acutely ill medical patients with renal insufficiency, a low dose (1.5 mg once daily) of fondaparinux or prophylactic LMWH subcutaneously appears to have a safe profile, although proper evaluation in randomized studies is lacking. The evidence on the use of prophylaxis for VTE in this latter group of patients, as well as in those at higher risk of bleeding complications, such as patients with thrombocytopenia, remains scarce. For critically ill patients hospitalized in intensive care units with no contraindications, LMWH or UFH are recommended, with frequent and careful assessment of the risk of bleeding. In this review, we discuss the evidence for use of thromboprophylaxis for VTE in acutely ill hospitalized medical patients, with a focus on (low-dose) fondaparinux. PMID- 24068867 TI - Unexpected effects of peripherally administered kynurenic acid on cortical spreading depression and related blood-brain barrier permeability. AB - Cortical spreading depression (CSD) involves a slowly-propagating depolarization wave in the cortex, which can appear in numerous pathophysiological conditions, such as migraine with aura, stroke, and traumatic brain injury. Neurons and glial cells are also depolarized transiently during the phenomena. CSD is followed by a massive increase in glutamate release and by changes in the brain microcirculation. The aim of this study was to investigate the effects of two N methyl-D-aspartate receptor antagonists, endogenous kynurenic acid (KYNA) and dizocilpine, on CSD and the related blood-brain barrier (BBB) permeability in rats. In intact animals, KYNA hardly crosses the BBB but has some positive features as compared with its precursor L-Kynurenine, which is frequently used in animal studies (KYNA cannot be metabolized to excitotoxic agents such as 3 hydroxy-L-kynurenine and quinolinic acid). We therefore investigated the possible effects of peripherally administered KYNA. Repetitive CSD waves were elicited by the application of 1 M KCl solution to the cortex. Direct current electrocorticograms were measured for 1 hour. Four parameters of the waves were compared. Evans blue dye and fluorescent microscopy were used to study the possible changes in the permeability of the BBB. The results demonstrated that N methyl-D-aspartate receptor antagonists can reduce the number of CSD waves and decrease the permeability of the BBB during CSD. These results suggest that KYNA itself or its derivatives may offer a new approach in the therapy of migraines. PMID- 24068869 TI - Economic burden of inpatient and outpatient antibiotic treatment for methicillin resistant Staphylococcus aureus complicated skin and soft-tissue infections: a comparison of linezolid, vancomycin, and daptomycin. AB - BACKGROUND: Previous economic analyses evaluating treatment of methicillin resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infections (cSSTI) failed to include all direct treatment costs such as outpatient parenteral antibiotic therapy (OPAT). Our objective was to develop an economic model from a US payer perspective that includes all direct inpatient and outpatient costs incurred by patients with MRSA cSSTI receiving linezolid, vancomycin, or daptomycin. METHODS: A 4-week decision model was developed for this economic analysis. Published literature and database analyses with validation by experts provided clinical, resource use, and cost inputs on data such as efficacy rate, length of stay, adverse events, and OPAT services. Base case analysis assumed equal efficacy and equal length of stay for treatments. We conducted several sensitivity analyses where assumptions on resource use or efficacy were varied. Costs were reported in year-end 2011 US dollars. RESULTS: Total treatment costs in the base-case were lower for linezolid ($10,571) than vancomycin ($11,096), and daptomycin ($13,612). Inpatient treatment costs were $740 more, but outpatient costs, $1,266 less with linezolid than vancomycin therapy due to a switch to oral linezolid when the patient was discharged. Compared with daptomycin, both inpatient and outpatient treatment costs were lower with linezolid by $87 and $2,954 respectively. In sensitivity analyses, linezolid had lower costs compared with vancomycin and daptomycin when using differential length of stay data from a clinical trial, and using success rates from a meta-analysis. In a scenario without peripherally inserted central catheter line costs, linezolid became slightly more expensive than vancomycin (by $285), but remained less costly than daptomycin (by $2,316). CONCLUSION: Outpatient costs of managing MRSA cSSTI may be reduced by 30%-50% with oral linezolid compared with vancomycin or daptomycin. Results from this analysis support potential economic benefit and cost savings of using linezolid versus traditional OPAT when total inpatient and outpatient medical costs are evaluated. PMID- 24068870 TI - Alteration of liver function due to H1N1 infection: a case report. AB - H1N1 virus is known to affect the respiratory tract. The majority of healthcare providers focus on the respiratory complications attributed to H1N1 infection, overlooking possible multi-organ involvement. We present a rare case of abnormal liver function in a child who was admitted for respiratory illness due to the H1N1 virus. There was a marked elevation in liver function tests concurrent with the respiratory disease. Our patient was treated with oseltamavir for the H1N1 infection, and the liver function levels decreased dramatically in 72 hours. PMID- 24068868 TI - Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy--focus on alogliptin. AB - Type 2 diabetes mellitus is a complex and progressive disease that is showing an apparently unstoppable increase worldwide. Although there is general agreement on the first-line use of metformin in most patients with type 2 diabetes, the ideal drug sequence after metformin failure is an area of increasing uncertainty. New treatment strategies target pancreatic islet dysfunction, in particular gut derived incretin hormones. Inhibition of the enzyme dipeptidyl peptidase-4 (DPP 4) slows degradation of endogenous glucagon-like peptide-1 (GLP-1) and thereby enhances and prolongs the action of the endogenous incretin hormones. The five available DPP-4 inhibitors, also known as 'gliptins' (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin), are small molecules used orally with similar overall clinical efficacy and safety profiles in patients with type 2 diabetes. The main differences between the five gliptins on the market include: potency, target selectivity, oral bioavailability, long or short half-life, high or low binding to plasma proteins, metabolism, presence of active or inactive metabolites, excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. On average, treatment with gliptins is expected to produce a mean glycated hemoglobin (HbA1c) decrease of 0.5%-0.8%, with about 40% of diabetic subjects at target for the HbA1c goal <7%. There are very few studies comparing DPP-4 inhibitors. Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose, or insulin therapy significantly improves glycemic control compared with placebo in adult or elderly patients with inadequately controlled type 2 diabetes. In the EXAMINE trial, alogliptin is being compared with placebo on cardiovascular outcomes in approximately 5,400 patients with type 2 diabetes. In clinical studies, DPP-4 inhibitors were generally safe and well tolerated. However, there are limited data on their tolerability, due to their relatively recent marketing approval. Alogliptin will be used most when avoidance of hypoglycemic events is paramount, such as in patients with congestive heart failure, renal failure, and liver disease, and in the elderly. PMID- 24068871 TI - A clinical case-based hypothesis: secretory IgA operates as an electronic transistor controlling the selection or rejection of molecules in the absorption process in the lumen of gastrointestinal tract. AB - There is a clinical correlation between (1) an allergic patient's ability to resist the development of symptoms that would have resulted from an allergenic challenge, (2) the magnitude of geomagnetism at a geographic site, and (3) the amount of solar energy falling on that site. It is suggested that the digestive membrane has an electronic gatekeeper that "decides" electronically which molecules to allow or not allow to pass on to the absorptive surface. The unique bipolar structure of secretory immunoglobulin A (IgA), having a central secretory piece and the resultant unique electronic function of this polarized molecule, allows it to function as an electronic transistor, producing an electronic gatekeeper in the form of an electronic sieve. PMID- 24068872 TI - Application of colon capsule endoscopy (CCE) to evaluate the whole gastrointestinal tract: a comparative study of single-camera and dual-camera analysis. AB - BACKGROUND AND STUDY AIMS: Colon capsule endoscopy (CCE) was developed for the evaluation of colorectal pathology. In this study, our aim was to assess if a dual-camera analysis using CCE allows better evaluation of the whole gastrointestinal (GI) tract compared to a single-camera analysis. PATIENTS AND METHODS: We included 21 patients (12 males, mean age 56.20 years) submitted for a CCE examination. After standard colon preparation, the colon capsule endoscope (PillCam ColonTM) was swallowed after reinitiation from its "sleep" mode. Four physicians performed the analysis: two reviewed both video streams at the same time (dual-camera analysis); one analyzed images from one side of the device ("camera 1"); and the other reviewed the opposite side ("camera 2"). We compared numbers of findings from different parts of the entire GI tract and level of agreement among reviewers. RESULTS: A complete evaluation of the GI tract was possible in all patients. Dual-camera analysis provided 16% and 5% more findings compared to camera 1 and camera 2 analysis, respectively. Overall agreement was 62.7% (kappa = 0.44, 95% CI: 0.373-0.510). Esophageal (kappa = 0.611) and colorectal (kappa = 0.595) findings had a good level of agreement, while small bowel (kappa = 0.405) showed moderate agreement. CONCLUSION: The use of dual camera analysis with CCE for the evaluation of the GI tract is feasible and detects more abnormalities when compared with single-camera analysis. PMID- 24068873 TI - The long-term outcomes of a cohort of Sri Lankan patients with ulcerative colitis: a retrospective study at two national referral centers and review of literature. AB - BACKGROUND: Inflammatory bowel disease, especially ulcerative colitis, is increasing in many "non-Western" countries, including Sri Lanka. The aim was to evaluate long-term outcomes of ulcerative colitis in a Sri Lankan population. METHODS: A retrospective cohort study was conducted at the gastroenterology clinics of the Colombo North Teaching Hospital, Ragama and the National Hospital of Sri Lanka, Colombo; the two major referral centers for ulcerative colitis. All cases had histological confirmation of ulcerative colitis. Three outcomes: colectomy, development of colorectal carcinoma, and death were assessed. Patients not attending the clinic during the previous 4 weeks, or their families, were contacted to obtain clinical details and survival status. In those who had died, the cause of death was confirmed from clinical records and death certificates. RESULTS: Details of 348/425 (81.9%) patients with ulcerative colitis (mean age 45.6 [standard deviation {SD} 14.3] years, male/female ratio = 1.00:1.03) were available. The mean follow-up was 6.8 (SD 6.5) years. The cumulative colectomy rates at 1, 5, 10, and 15 years were 1.5%, 4.0%, 5.5%, and 9.3% respectively. The cumulative probability of colorectal cancer in this cohort after 10 and 15 years was 0.47% and 2.36% respectively. The cumulative survival rate after 1, 5, 10, and 15 years was 99.7%, 98.9%, 98.1%, and 94.5% respectively. Patients with pancolitis were more likely to have disease-related death (P = 0.05). Multivariate analysis (Cox proportional hazards model) showed that an older age at diagnosis was associated with long-term mortality (hazard ratio, 1.11; P = 0.001). CONCLUSION: In this cohort, colectomy, colorectal carcinoma, and death rates were low, suggesting a relatively benign disease course for ulcerative colitis. PMID- 24068874 TI - Event detection using population-based health care databases in randomized clinical trials: a novel research tool in interventional cardiology. AB - AIM: To describe a new research tool, designed to reflect routine clinical practice and relying on population-based health care databases to detect clinical events in randomized clinical trials. BACKGROUND: Randomized clinical trials often focus on short-term efficacy and safety in a controlled environment. Trial follow-up may be linked with study-related investigations and differ from routine clinical practice. Because treatment and control in randomized trials differ from daily practice, trial results may have reduced general applicability and may be of limited value in clinical decision-making. Further, it is economically very costly to conduct randomized clinical trials. METHODS AND RESULTS: Population based health care databases collect data continuously and prospectively, and make it possible to monitor lifelong outcomes of cardiac interventions in large numbers of patients. This strengthens external validity by eliminating the effects of study-related monitoring or diagnostic tests. Further, follow-up data can be obtained at low expense. Importantly, data sources encompassing a complete population are likely to reflect clinical practice. Because population-based health care databases collect data for quality-control and administrative purposes unrelated to scientific investigations, certain biases, such as nonresponse bias, recall bias, and bias from losses to follow-up, can be avoided. CONCLUSION: Event detection using population-based health care databases is a new research tool in interventional cardiology that may allow large, low-cost, randomized clinical trials to reflect daily clinical practice, covering a broad range of patients and end points with complete lifelong follow-up. PMID- 24068876 TI - Erratum: Monitoring human papillomavirus prevalence in urine samples: a review [Corrigendum]. AB - [This corrects the article on p. 67 in vol. 5, PMID: 23516174.]. PMID- 24068875 TI - Screening for severe combined immunodeficiency in neonates. AB - Severe combined immunodeficiency (SCID) is a rare disease that severely affects the cellular and humoral immune systems. Patients with SCID present with recurrent or severe infections and often with chronic diarrhea and failure to thrive. The disease is uniformly fatal, making early diagnosis essential. Definitive treatment is hematopoietic stem cell transplantation, with best outcomes prior to 3.5 months of age. Newborn screening for SCID using the T-cell receptor excision circle assay has revolutionized early identification of infants with SCID or severe T-cell lymphopenia. PMID- 24068877 TI - An update on clinical utility of rilpivirine in the management of HIV infection in treatment-naive patients. AB - Non-nucleoside analog reverse transcriptase inhibitors (NNRTIs) are an important component of combination antiretroviral regimens. Amongst the NNRTIs, efavirenz is commonly recommended for initial regimens in treatment-naive HIV patients, but its use in some settings is limited by adverse effects, particularly those affecting the central nervous system and lipid metabolism. Rilpivirine is a new second-generation NNRTI that is recommended as an alternative to efavirenz in treatment-naive HIV patients. Evidence of the clinical efficacy of rilpivirine versus efavirenz, in combination with two nucleoside or nucleotide analog reverse transcriptase inhibitors in treatment-naive patients, is derived from the THRIVE and ECHO studies. These studies demonstrated that rilpivirine 25 mg once daily was potent and noninferior to efavirenz 600 mg once daily using an intention-to treat time-to-loss-of-virologic-response (ITT-TLOVR) endpoint. Although virologic failure was higher in subjects treated with rilpivirine, study discontinuations due to adverse effects were more common in subjects treated with efavirenz. In addition, the virologic response to rilpivirine was suboptimal in patients with a baseline viral load >100,000 copies/mL. The overall incidence of adverse events and grade 2-4 adverse events was lower in the rilpivirine than in the efavirenz groups. Patients with rilpivirine failure were more likely to have resistance mutations that confer cross-resistance to other NNRTIs, including etravirine. Rilpivirine is currently available as a fixed-dose combination that allows for once-daily administration as a single pill, and is approved for use in treatment naive patients. This drug is contraindicated when co-administered with rifamycins or proton-pump inhibitors. PMID- 24068879 TI - Synthesis and Characterization of Thiolate-Oxo Ligated Zinc Alkyl Derivatives for Production of Zn-Based Nanoparticles. AB - A series of mercapto-oxo containing reagents [3-mercaptopropionic acid (H2-3MPA), 4-mercaptophenol (H2-4MP), 2-mercaptopyridine-N-oxide (H-2MPO)] was reacted with diethyl zinc (ZnEt2) in hexanes/pyridine (py) to yield {(MU4 3MPA)[Zn(Et)(py)]4}infinity (1), [(py)2(Et)Zn(MU3-4MP)Zn(Et)(py)]2 (2), and (2MPO)Zn(Et)py (3). For polymeric 1, each of the functional sites of the 3MPA was bound to four tetrahedral (Td) coordinated Zn(Et)(py) subunits. The sulfur of the 3MPA bridges two of the 'Zn(Et)(py)' subunits, which are also bridged by the two carboxylate oxygens of another 3MPA to propagate the chain. In contrast, 2 forms a discrete tetranuclear species consisting of two Zn(Et)(py) moieties bridged by the oxygens of two 4MP ligands with the thiolate sites of each terminated by Zn(Et)(py)2 moieties. Compound 3 adopts a monomeric species using a chelating 2MPO, a terminal Et, and a bound py to fill the Td coordination of the Zn metal center. Compounds 1 - 3 were then used to generate nanoparticles via solution precipitation and solvothermal routes to determine the effect these precursors have on the morphology and composition of the final materials produced. Compounds 1 - 3 were found to form zincite, zinc metal, or mixed zincite/wurtzite phases from solution precipitation or solvothermal routes; however, no routes yielded the mixed anion (i.e., ZnO x S y ) materials. PMID- 24068878 TI - A review of cardiovascular and renal function monitoring: a consideration of older adults with HIV. AB - The prevalence of human immunodeficiency virus (HIV) infection in older and elderly adults is significant worldwide. This population poses new challenges and opportunities in the management of HIV. In addition to the risks affecting HIV patients of all ages, including risk of opportunistic infection and medication resistance, age-related changes in physiology, higher comorbidity burdens, increased use of medications, and potential adverse drug reactions to HIV medications all factor into the care of older adults with HIV. The risk and progression of cardiovascular and renal comorbidities may be higher in the older adult HIV population and in patients taking specific HIV medications. Understanding these risks is essential when managing a new type of patient: the older adult with HIV. PMID- 24068880 TI - Neonatal euthanasia: A claim for an immoral law. AB - Active ending of the life of a newborn baby is a crime. Yet its clandestine practise is a reality in several European countries. In this paper, we defend the necessity to institute a proper legal frame for what we define as active neonatal euthanasia. The only legal attempt so far, the Dutch Groningen protocol, is not satisfactory. We critically analyse this protocol, as well as several other clinical practises and philosophical stances. Furthermore, we have tried to integrate our opinions as clinicians into a law project, with the purpose of pinpointing several issues, specific of perinatality that should be addressed by such a law. In conclusion, we argue that the legalisation of neonatal euthanasia under exceptional circumstances is the only way to avoid all the "well intentioned" malpractices associated with ending life at the very dawn of it. PMID- 24068881 TI - Associations Between Temperament and Social Responsiveness in Young Children. AB - Recent research has demonstrated that social responsiveness (comprised of social awareness, social information processing, reciprocal social communication, social motivation, and repetitive/restricted interests) is continuously distributed within the general population. In the present study, we consider temperament as a co-occurring source of individual differences in social responsiveness in young children. The sample consisted of 62 infants assessed at 2-, 3-, and 4-years-old. Measures of temperament were obtained at each age (Early Childhood Behavior Questionnaire, Children's Behavior Questionnaire) and social responsiveness was measured at 4-years-old (Social Responsiveness Scale; SRS). Multivariate patterns of association between components of temperament and social responsiveness were observed at each age, with overall findings in line with the broader literature examining temperament and socio-development associations. Importantly, these results provide support for the usefulness of temperament as a relevant source of variability in social responsiveness, as measured by the SRS, in typically developing young children. PMID- 24068882 TI - Chelating ligand-mediated hydrothermal synthesis of samarium orthovanadate with decavanadate as vanadium source. AB - A new ethylenediaminetetraacetic acid- (EDTA-) mediated hydrothermal route to prepare chrysanthemum-shaped samarium orthovanadate (SmVO4) nanocrystals with decavanadate (K6V10O28.9H2O) as vanadium source has been developed. The present hydrothermal approach is simple and reproducible and employs a relatively mild reaction temperature. The EDTA, pH value, and temperature of the reaction systems play important roles in determining the morphologies and growth process of the SmVO4 products. The products have been characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT IR), photoluminescence spectra (PL), and UV-Vis spectroscopy. PMID- 24068883 TI - Integration of seismic and petrophysics to characterize reservoirs in "ALA" oil field, Niger Delta. AB - In the exploration and production business, by far the largest component of geophysical spending is driven by the need to characterize (potential) reservoirs. The simple reason is that better reservoir characterization means higher success rates and fewer wells for reservoir exploitation. In this research work, seismic and well log data were integrated in characterizing the reservoirs on "ALA" field in Niger Delta. Three-dimensional seismic data was used to identify the faults and map the horizons. Petrophysical parameters and time-depth structure maps were obtained. Seismic attributes was also employed in characterizing the reservoirs. Seven hydrocarbon-bearing reservoirs with thickness ranging from 9.9 to 71.6 m were delineated. Structural maps of horizons in six wells containing hydrocarbon-bearing zones with tops and bottoms at range of -2,453 to -3,950 m were generated; this portrayed the trapping mechanism to be mainly fault-assisted anticlinal closures. The identified prospective zones have good porosity, permeability, and hydrocarbon saturation. The environments of deposition were identified from log shapes which indicate a transitional-to deltaic depositional environment. In this research work, new prospects have been recommended for drilling and further research work. Geochemical and biostratigraphic studies should be done to better characterize the reservoirs and reliably interpret the depositional environments. PMID- 24068885 TI - Response of rice nitrogen physiology to high nighttime temperature during vegetative stage. AB - The effects of night temperature on plant morphology and nitrogen accumulation were examined in rice (Oryza sativa L.) during vegetative growth. The results showed that the shoot biomass of the plants was greater at 27 degrees C (high nighttime temperature, HNT) than at 22 degrees C (CK). However, the increase in both shoot and root biomasses was not significant under 10 mg N/L. The shoot nitrogen concentrations were 16.1% and 16.7% higher in HNT than in CK under 160 and 40 mg N/L. These results suggest that plant N uptake was enhanced under HNT; however, the positive effect might be limited by the N status of the plants. In addition, leaf area, plant height, root maximum length, root and shoot nitrogen concentrations, soluble leaf protein content, and soluble leaf carbohydrate content were greater in HNT than in CK under 40 and 160 mg N/L, while fresh root volume, root number, and the content of free amino acid in leaf were not significantly different between HNT and CK regardless of nitrogen levels. Moreover, leaf GS activity under HNT was increased at 160 mg N/L compared with that under CK, which might partly explain the positive effect of HNT on soluble protein and carbohydrate content. PMID- 24068886 TI - Isotretinoin oil-based capsule formulation optimization. AB - The purpose of this study was to develop and optimize an isotretinoin oil-based capsule with specific dissolution pattern. A three-factor-constrained mixture design was used to prepare the systemic model formulations. The independent factors were the components of oil-based capsule including beeswax (X1), hydrogenated coconut oil (X2), and soybean oil (X3). The drug release percentages at 10, 30, 60, and 90 min were selected as responses. The effect of formulation factors including that on responses was inspected by using response surface methodology (RSM). Multiple-response optimization was performed to search for the appropriate formulation with specific release pattern. It was found that the interaction effect of these formulation factors (X1X2, X1X3, and X2X3) showed more potential influence than that of the main factors (X1, X2, and X3). An optimal predicted formulation with Y(10 min), Y(30 min), Y(60 min), and Y(90 min) release values of 12.3%, 36.7%, 73.6%, and 92.7% at X1, X2, and X3 of 5.75, 15.37, and 78.88, respectively, was developed. The new formulation was prepared and performed by the dissolution test. The similarity factor f2 was 54.8, indicating that the dissolution pattern of the new optimized formulation showed equivalence to the predicted profile. PMID- 24068884 TI - Hypoxic culture conditions as a solution for mesenchymal stem cell based regenerative therapy. AB - Cell-based regenerative therapies, based on in vitro propagation of stem cells, offer tremendous hope to many individuals suffering from degenerative diseases that were previously deemed untreatable. Due to the self-renewal capacity, multilineage potential, and immunosuppressive property, mesenchymal stem cells (MSCs) are considered as an attractive source of stem cells for regenerative therapies. However, poor growth kinetics, early senescence, and genetic instability during in vitro expansion and poor engraftment after transplantation are considered to be among the major disadvantages of MSC-based regenerative therapies. A number of complex inter- and intracellular interactive signaling systems control growth, multiplication, and differentiation of MSCs in their niche. Common laboratory conditions for stem cell culture involve ambient O2 concentration (20%) in contrast to their niche where they usually reside in 2-9% O2. Notably, O2 plays an important role in maintaining stem cell fate in terms of proliferation and differentiation, by regulating hypoxia-inducible factor-1 (HIF 1) mediated expression of different genes. This paper aims to describe and compare the role of normoxia (20% O2) and hypoxia (2-9% O2) on the biology of MSCs. Finally it is concluded that a hypoxic environment can greatly improve growth kinetics, genetic stability, and expression of chemokine receptors during in vitro expansion and eventually can increase efficiency of MSC-based regenerative therapies. PMID- 24068887 TI - The psychometric properties of the persian migraine-specific quality of life questionnaire version 2.1 in episodic and chronic migraines. AB - BACKGROUND: Migraine-specific quality of life (MSQ) is a valid and reliable questionnaire. Linguistic validation of Persian MSQ questionnaire, analysis of psychometric properties between chronic and episodic migraine patients, and capability of MSQ to differentiate between chronic and episodic migraines were the aims of this study. METHOD: Participants were selected from four different neurology clinics that were diagnosed as chronic or episodic migraine patients. Baseline data included information from MSQ v. 2.1, MIGSEV, SF-36, and symptoms questionnaire. At the third week from the baseline, participants filled out MSQ and MIGSEV. Internal consistency (Cronbach alpha) and test-retest reproducibility (intraclass correlation coefficients) were used to assess reliability. Convergent and discriminant validities were also assessed. RESULTS: A total of 106 participants were enrolled. Internal consistencies of MSQ among all patients, chronic and episodic migraines, were 0.92, 0.91, and 0.92, respectively. Test retest correlation of MSQ dimensions between visits 1 and 2 varied from 0.41 to 0.50. Convergent, item discriminant, and discriminant validities were approved. In all visits MSQ scores were lower in chronic migraine than episodic migraine; however, the difference was not statistically significant. CONCLUSION: Persian translation of MSQ is consistent with original version of MSQ in terms of psychometric properties in both chronic and episodic migraine patients. PMID- 24068888 TI - Knee point search using cascading top-k sorting with minimized time complexity. AB - Anomaly detection systems and many other applications are frequently confronted with the problem of finding the largest knee point in the sorted curve for a set of unsorted points. This paper proposes an efficient knee point search algorithm with minimized time complexity using the cascading top-k sorting when a priori probability distribution of the knee point is known. First, a top-k sort algorithm is proposed based on a quicksort variation. We divide the knee point search problem into multiple steps. And in each step an optimization problem of the selection number k is solved, where the objective function is defined as the expected time cost. Because the expected time cost in one step is dependent on that of the afterwards steps, we simplify the optimization problem by minimizing the maximum expected time cost. The posterior probability of the largest knee point distribution and the other parameters are updated before solving the optimization problem in each step. An example of source detection of DNS DoS flooding attacks is provided to illustrate the applications of the proposed algorithm. PMID- 24068889 TI - Adult Personality Development: Dynamics and Processes. AB - The focus of this special issue of Research in Human Development is on adult personality and how personality may contribute to and be involved in adult development. Specifically, the contributions in this issue focus on the links between personality structures (e.g., traits) and personality processes (e.g., goal pursuit, self--regulation) and emphasize the contributions that intensive repeated measurement approaches can make to the understanding of personality and development across the adult life span. PMID- 24068890 TI - A Cullin1-based SCF E3 ubiquitin ligase targets the InR/PI3K/TOR pathway to regulate neuronal pruning. AB - Pruning that selectively eliminates unnecessary axons/dendrites is crucial for sculpting the nervous system during development. During Drosophila metamorphosis, dendrite arborization neurons, ddaCs, selectively prune their larval dendrites in response to the steroid hormone ecdysone, whereas mushroom body gamma neurons specifically eliminate their axon branches within dorsal and medial lobes. However, it is unknown which E3 ligase directs these two modes of pruning. Here, we identified a conserved SCF E3 ubiquitin ligase that plays a critical role in pruning of both ddaC dendrites and mushroom body gamma axons. The SCF E3 ligase consists of four core components Cullin1/Roc1a/SkpA/Slimb and promotes ddaC dendrite pruning downstream of EcR-B1 and Sox14, but independently of Mical. Moreover, we demonstrate that the Cullin1-based E3 ligase facilitates ddaC dendrite pruning primarily through inactivation of the InR/PI3K/TOR pathway. We show that the F-box protein Slimb forms a complex with Akt, an activator of the InR/PI3K/TOR pathway, and promotes Akt ubiquitination. Activation of the InR/PI3K/TOR pathway is sufficient to inhibit ddaC dendrite pruning. Thus, our findings provide a novel link between the E3 ligase and the InR/PI3K/TOR pathway during dendrite pruning. PMID- 24068892 TI - Deep genealogy and the dilution of risk. PMID- 24068891 TI - Dectin-1 is essential for reverse transcytosis of glycosylated SIgA-antigen complexes by intestinal M cells. AB - Intestinal microfold (M) cells possess a high transcytosis capacity and are able to transport a broad range of materials including particulate antigens, soluble macromolecules, and pathogens from the intestinal lumen to inductive sites of the mucosal immune system. M cells are also the primary pathway for delivery of secretory IgA (SIgA) to the gut-associated lymphoid tissue. However, although the consequences of SIgA uptake by M cells are now well known and described, the mechanisms whereby SIgA is selectively bound and taken up remain poorly understood. Here we first demonstrate that both the Calpha1 region and glycosylation, more particularly sialic acid residues, are involved in M cell mediated reverse transcytosis. Second, we found that SIgA is taken up by M cells via the Dectin-1 receptor, with the possible involvement of Siglec-5 acting as a co-receptor. Third, we establish that transcytosed SIgA is taken up by mucosal CX3CR1+ dendritic cells (DCs) via the DC-SIGN receptor. Fourth, we show that mucosal and systemic antibody responses against the HIV p24-SIgA complexes administered orally is strictly dependent on the expression of Dectin-1. Having deciphered the mechanisms leading to specific targeting of SIgA-based Ag complexes paves the way to the use of such a vehicle for mucosal vaccination against various infectious diseases. PMID- 24068894 TI - Physician emigration from sub-Saharan Africa to the United States: analysis of the 2011 AMA physician masterfile. AB - BACKGROUND: The large-scale emigration of physicians from sub-Saharan Africa (SSA) to high-income nations is a serious development concern. Our objective was to determine current emigration trends of SSA physicians found in the physician workforce of the United States. METHODS AND FINDINGS: We analyzed physician data from the World Health Organization (WHO) Global Health Workforce Statistics along with graduation and residency data from the 2011 American Medical Association Physician Masterfile (AMA-PM) on physicians trained or born in SSA countries who currently practice in the US. We estimated emigration proportions, year of US entry, years of practice before emigration, and length of time in the US. According to the 2011 AMA-PM, 10,819 physicians were born or trained in 28 SSA countries. Sixty-eight percent (n = 7,370) were SSA-trained, 20% (n = 2,126) were US-trained, and 12% (n = 1,323) were trained outside both SSA and the US. We estimated active physicians (age <= 70 years) to represent 96% (n = 10,377) of the total. Migration trends among SSA-trained physicians increased from 2002 to 2011 for all but one principal source country; the exception was South Africa whose physician migration to the US decreased by 8% (-156). The increase in last decade migration was >50% in Nigeria (+1,113) and Ghana (+243), >100% in Ethiopia (+274), and >200% (+244) in Sudan. Liberia was the most affected by migration to the US with 77% (n = 175) of its estimated physicians in the 2011 AMA-PM. On average, SSA-trained physicians have been in the US for 18 years. They practiced for 6.5 years before US entry, and nearly half emigrated during the implementation years (1984-1999) of the structural adjustment programs. CONCLUSION: Physician emigration from SSA to the US is increasing for most SSA source countries. Unless far-reaching policies are implemented by the US and SSA countries, the current emigration trends will persist, and the US will remain a leading destination for SSA physicians emigrating from the continent of greatest need. Please see later in the article for the Editors' Summary. PMID- 24068895 TI - Health workforce brain drain: from denouncing the challenge to solving the problem. PMID- 24068893 TI - Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. AB - The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging. PMID- 24068897 TI - Translating Cochrane reviews to ensure that healthcare decision-making is informed by high-quality research evidence. PMID- 24068896 TI - Current and former smoking and risk for venous thromboembolism: a systematic review and meta-analysis. AB - BACKGROUND: Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose-response relationship exists. METHODS AND FINDINGS: We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09-1.25) for ever smokers, 1.23 (95% CI 1.14-1.33) for current smokers, and 1.10 (95% CI 1.03 1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6% 11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8% 8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24-1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%-12.3%) for ever smoking, 5.8% (95% CI 3.6%-8.2%) for current smoking, and 2.7% (95% CI 0.8%-4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4-26.7) cases per 100,000 person-years. CONCLUSIONS: Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE. Please see later in the article for the Editors' Summary. PMID- 24068898 TI - Learning contrast-invariant cancellation of redundant signals in neural systems. AB - Cancellation of redundant information is a highly desirable feature of sensory systems, since it would potentially lead to a more efficient detection of novel information. However, biologically plausible mechanisms responsible for such selective cancellation, and especially those robust to realistic variations in the intensity of the redundant signals, are mostly unknown. In this work, we study, via in vivo experimental recordings and computational models, the behavior of a cerebellar-like circuit in the weakly electric fish which is known to perform cancellation of redundant stimuli. We experimentally observe contrast invariance in the cancellation of spatially and temporally redundant stimuli in such a system. Our model, which incorporates heterogeneously-delayed feedback, bursting dynamics and burst-induced STDP, is in agreement with our in vivo observations. In addition, the model gives insight on the activity of granule cells and parallel fibers involved in the feedback pathway, and provides a strong prediction on the parallel fiber potentiation time scale. Finally, our model predicts the existence of an optimal learning contrast around 15% contrast levels, which are commonly experienced by interacting fish. PMID- 24068899 TI - Predicting odor perceptual similarity from odor structure. AB - To understand the brain mechanisms of olfaction we must understand the rules that govern the link between odorant structure and odorant perception. Natural odors are in fact mixtures made of many molecules, and there is currently no method to look at the molecular structure of such odorant-mixtures and predict their smell. In three separate experiments, we asked 139 subjects to rate the pairwise perceptual similarity of 64 odorant-mixtures ranging in size from 4 to 43 mono molecular components. We then tested alternative models to link odorant-mixture structure to odorant-mixture perceptual similarity. Whereas a model that considered each mono-molecular component of a mixture separately provided a poor prediction of mixture similarity, a model that represented the mixture as a single structural vector provided consistent correlations between predicted and actual perceptual similarity (r>=0.49, p<0.001). An optimized version of this model yielded a correlation of r = 0.85 (p<0.001) between predicted and actual mixture similarity. In other words, we developed an algorithm that can look at the molecular structure of two novel odorant-mixtures, and predict their ensuing perceptual similarity. That this goal was attained using a model that considers the mixtures as a single vector is consistent with a synthetic rather than analytical brain processing mechanism in olfaction. PMID- 24068900 TI - Specialization of gene expression during mouse brain development. AB - The transcriptome of the brain changes during development, reflecting processes that determine functional specialization of brain regions. We analyzed gene expression, measured using in situ hybridization across the full developing mouse brain, to quantify functional specialization of brain regions. Surprisingly, we found that during the time that the brain becomes anatomically regionalized in early development, transcription specialization actually decreases reaching a low, "neurotypic", point around birth. This decrease of specialization is brain wide, and mainly due to biological processes involved in constructing brain circuitry. Regional specialization rises again during post-natal development. This effect is largely due to specialization of plasticity and neural activity processes. Post-natal specialization is particularly significant in the cerebellum, whose expression signature becomes increasingly different from other brain regions. When comparing mouse and human expression patterns, the cerebellar post-natal specialization is also observed in human, but the regionalization of expression in the human Thalamus and Cortex follows a strikingly different profile than in mouse. PMID- 24068901 TI - Using biological pathway data with paxtools. AB - A rapidly growing corpus of formal, computable pathway information can be used to answer important biological questions including finding non-trivial connections between cellular processes, identifying significantly altered portions of the cellular network in a disease state and building predictive models that can be used for precision medicine. Due to its complexity and fragmented nature, however, working with pathway data is still difficult. We present Paxtools, a Java library that contains algorithms, software components and converters for biological pathways represented in the standard BioPAX language. Paxtools allows scientists to focus on their scientific problem by removing technical barriers to access and analyse pathway information. Paxtools can run on any platform that has a Java Runtime Environment and was tested on most modern operating systems. Paxtools is open source and is available under the Lesser GNU public license (LGPL), which allows users to freely use the code in their software systems with a requirement for attribution. Source code for the current release (4.2.0) can be found in Software S1. A detailed manual for obtaining and using Paxtools can be found in Protocol S1. The latest sources and release bundles can be obtained from biopax.org/paxtools. PMID- 24068902 TI - From birdsong to human speech recognition: bayesian inference on a hierarchy of nonlinear dynamical systems. AB - Our knowledge about the computational mechanisms underlying human learning and recognition of sound sequences, especially speech, is still very limited. One difficulty in deciphering the exact means by which humans recognize speech is that there are scarce experimental findings at a neuronal, microscopic level. Here, we show that our neuronal-computational understanding of speech learning and recognition may be vastly improved by looking at an animal model, i.e., the songbird, which faces the same challenge as humans: to learn and decode complex auditory input, in an online fashion. Motivated by striking similarities between the human and songbird neural recognition systems at the macroscopic level, we assumed that the human brain uses the same computational principles at a microscopic level and translated a birdsong model into a novel human sound learning and recognition model with an emphasis on speech. We show that the resulting Bayesian model with a hierarchy of nonlinear dynamical systems can learn speech samples such as words rapidly and recognize them robustly, even in adverse conditions. In addition, we show that recognition can be performed even when words are spoken by different speakers and with different accents-an everyday situation in which current state-of-the-art speech recognition models often fail. The model can also be used to qualitatively explain behavioral data on human speech learning and derive predictions for future experiments. PMID- 24068904 TI - Potential role of a bistable histidine kinase switch in the asymmetric division cycle of Caulobacter crescentus. AB - The free-living aquatic bacterium, Caulobacter crescentus, exhibits two different morphologies during its life cycle. The morphological change from swarmer cell to stalked cell is a result of changes of function of two bi-functional histidine kinases, PleC and CckA. Here, we describe a detailed molecular mechanism by which the function of PleC changes between phosphatase and kinase state. By mathematical modeling of our proposed molecular interactions, we derive conditions under which PleC, CckA and its response regulators exhibit bistable behavior, thus providing a scenario for robust switching between swarmer and stalked states. Our simulations are in reasonable agreement with in vitro and in vivo experimental observations of wild type and mutant phenotypes. According to our model, the kinase form of PleC is essential for the swarmer-to-stalked transition and to prevent premature development of the swarmer pole. Based on our results, we reconcile some published experimental observations and suggest novel mutants to test our predictions. PMID- 24068903 TI - Computational optogenetics: empirically-derived voltage- and light-sensitive channelrhodopsin-2 model. AB - Channelrhodospin-2 (ChR2), a light-sensitive ion channel, and its variants have emerged as new excitatory optogenetic tools not only in neuroscience, but also in other areas, including cardiac electrophysiology. An accurate quantitative model of ChR2 is necessary for in silico prediction of the response to optical stimulation in realistic tissue/organ settings. Such a model can guide the rational design of new ion channel functionality tailored to different cell types/tissues. Focusing on one of the most widely used ChR2 mutants (H134R) with enhanced current, we collected a comprehensive experimental data set of the response of this ion channel to different irradiances and voltages, and used these data to develop a model of ChR2 with empirically-derived voltage- and irradiance- dependence, where parameters were fine-tuned via simulated annealing optimization. This ChR2 model offers: 1) accurate inward rectification in the current-voltage response across irradiances; 2) empirically-derived voltage- and light-dependent kinetics (activation, deactivation and recovery from inactivation); and 3) accurate amplitude and morphology of the response across voltage and irradiance settings. Temperature-scaling factors (Q10) were derived and model kinetics was adjusted to physiological temperatures. Using optical action potential clamp, we experimentally validated model-predicted ChR2 behavior in guinea pig ventricular myocytes. The model was then incorporated in a variety of cardiac myocytes, including human ventricular, atrial and Purkinje cell models. We demonstrate the ability of ChR2 to trigger action potentials in human cardiomyocytes at relatively low light levels, as well as the differential response of these cells to light, with the Purkinje cells being most easily excitable and ventricular cells requiring the highest irradiance at all pulse durations. This new experimentally-validated ChR2 model will facilitate virtual experimentation in neural and cardiac optogenetics at the cell and organ level and provide guidance for the development of in vivo tools. PMID- 24068905 TI - Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation. AB - Natural killer (NK) cells are innate lymphocytes that provide early host defense against intracellular pathogens, such as viruses. Although NK cell development, homeostasis, and proliferation are regulated by IL-15, the influence of IL-15 receptor (IL-15R)-mediated signaling at the cellular level has not been quantitatively characterized. We developed a mathematical model to analyze the kinetic interactions that control the formation and localization of IL-15/IL-15R complexes. Our computational results demonstrated that IL-15/IL-15R complexes on the cell surface were a key determinant of the magnitude of the IL-15 proliferative signal and that IL-15R occupancy functioned as an effective surrogate measure of receptor signaling. Ligand binding and receptor internalization modulated IL-15R occupancy. Our work supports the hypothesis that the total number and duration of IL-15/IL-15R complexes on the cell surface crosses a quantitative threshold prior to the initiation of NK cell division. Furthermore, our model predicted that the upregulation of IL-15Ralpha on NK cells substantially increased IL-15R complex formation and accelerated the expansion of dividing NK cells with the greatest impact at low IL-15 concentrations. Model predictions of the threshold requirement for NK cell recruitment to the cell cycle and the subsequent exponential proliferation correlated well with experimental data. In summary, our modeling analysis provides quantitative insight into the regulation of NK cell proliferation at the receptor level and provides a framework for the development of IL-15 based immunotherapies to modulate NK cell proliferation. PMID- 24068906 TI - Trial-type dependent frames of reference for value comparison. AB - A central question in cognitive neuroscience regards the means by which options are compared and decisions are resolved during value-guided choice. It is clear that several component processes are needed; these include identifying options, a value-based comparison, and implementation of actions to execute the decision. What is less clear is the temporal precedence and functional organisation of these component processes in the brain. Competing models of decision making have proposed that value comparison may occur in the space of alternative actions, or in the space of abstract goods. We hypothesized that the signals observed might in fact depend upon the framing of the decision. We recorded magnetoencephalographic data from humans performing value-guided choices in which two closely related trial types were interleaved. In the first trial type, each option was revealed separately, potentially causing subjects to estimate each action's value as it was revealed and perform comparison in action-space. In the second trial type, both options were presented simultaneously, potentially leading to comparison in abstract goods-space prior to commitment to a specific action. Distinct activity patterns (in distinct brain regions) on the two trial types demonstrated that the observed frame of reference used for decision making indeed differed, despite the information presented being formally identical, between the two trial types. This provides a potential reconciliation of conflicting accounts of value-guided choice. PMID- 24068907 TI - Target inhibition networks: predicting selective combinations of druggable targets to block cancer survival pathways. AB - A recent trend in drug development is to identify drug combinations or multi target agents that effectively modify multiple nodes of disease-associated networks. Such polypharmacological effects may reduce the risk of emerging drug resistance by means of attacking the disease networks through synergistic and synthetic lethal interactions. However, due to the exponentially increasing number of potential drug and target combinations, systematic approaches are needed for prioritizing the most potent multi-target alternatives on a global network level. We took a functional systems pharmacology approach toward the identification of selective target combinations for specific cancer cells by combining large-scale screening data on drug treatment efficacies and drug-target binding affinities. Our model-based prediction approach, named TIMMA, takes advantage of the polypharmacological effects of drugs and infers combinatorial drug efficacies through system-level target inhibition networks. Case studies in MCF-7 and MDA-MB-231 breast cancer and BxPC-3 pancreatic cancer cells demonstrated how the target inhibition modeling allows systematic exploration of functional interactions between drugs and their targets to maximally inhibit multiple survival pathways in a given cancer type. The TIMMA prediction results were experimentally validated by means of systematic siRNA-mediated silencing of the selected targets and their pairwise combinations, showing increased ability to identify not only such druggable kinase targets that are essential for cancer survival either individually or in combination, but also synergistic interactions indicative of non-additive drug efficacies. These system-level analyses were enabled by a novel model construction method utilizing maximization and minimization rules, as well as a model selection algorithm based on sequential forward floating search. Compared with an existing computational solution, TIMMA showed both enhanced prediction accuracies in cross validation as well as significant reduction in computation times. Such cost-effective computational experimental design strategies have the potential to greatly speed-up the drug testing efforts by prioritizing those interventions and interactions warranting further study in individual cancer cases. PMID- 24068908 TI - Adaptation dynamics in densely clustered chemoreceptors. AB - In many sensory systems, transmembrane receptors are spatially organized in large clusters. Such arrangement may facilitate signal amplification and the integration of multiple stimuli. However, this organization likely also affects the kinetics of signaling since the cytoplasmic enzymes that modulate the activity of the receptors must localize to the cluster prior to receptor modification. Here we examine how these spatial considerations shape signaling dynamics at rest and in response to stimuli. As a model system, we use the chemotaxis pathway of Escherichia coli, a canonical system for the study of how organisms sense, respond, and adapt to environmental stimuli. In bacterial chemotaxis, adaptation is mediated by two enzymes that localize to the clustered receptors and modulate their activity through methylation-demethylation. Using a novel stochastic simulation, we show that distributive receptor methylation is necessary for successful adaptation to stimulus and also leads to large fluctuations in receptor activity in the steady state. These fluctuations arise from noise in the number of localized enzymes combined with saturated modification kinetics between the localized enzymes and the receptor substrate. An analytical model explains how saturated enzyme kinetics and large fluctuations can coexist with an adapted state robust to variation in the expression levels of the pathway constituents, a key requirement to ensure the functionality of individual cells within a population. This contrasts with the well-mixed covalent modification system studied by Goldbeter and Koshland in which mean activity becomes ultrasensitive to protein abundances when the enzymes operate at saturation. Large fluctuations in receptor activity have been quantified experimentally and may benefit the cell by enhancing its ability to explore empty environments and track shallow nutrient gradients. Here we clarify the mechanistic relationship of these large fluctuations to well-studied aspects of the chemotaxis system, precise adaptation and functional robustness. PMID- 24068909 TI - Predictive modeling of in vivo response to gemcitabine in pancreatic cancer. AB - A clear contradiction exists between cytotoxic in-vitro studies demonstrating effectiveness of Gemcitabine to curtail pancreatic cancer and in-vivo studies failing to show Gemcitabine as an effective treatment. The outcome of chemotherapy in metastatic stages, where surgery is no longer viable, shows a 5 year survival <5%. It is apparent that in-vitro experiments, no matter how well designed, may fail to adequately represent the complex in-vivo microenvironmental and phenotypic characteristics of the cancer, including cell proliferation and apoptosis. We evaluate in-vitro cytotoxic data as an indicator of in-vivo treatment success using a mathematical model of tumor growth based on a dimensionless formulation describing tumor biology. Inputs to the model are obtained under optimal drug exposure conditions in-vitro. The model incorporates heterogeneous cell proliferation and death caused by spatial diffusion gradients of oxygen/nutrients due to inefficient vascularization and abundant stroma, and thus is able to simulate the effect of the microenvironment as a barrier to effective nutrient and drug delivery. Analysis of the mathematical model indicates the pancreatic tumors to be mostly resistant to Gemcitabine treatment in-vivo. The model results are confirmed with experiments in live mice, which indicate uninhibited tumor proliferation and metastasis with Gemcitabine treatment. By extracting mathematical model parameter values for proliferation and death from monolayer in-vitro cytotoxicity experiments with pancreatic cancer cells, and simulating the effects of spatial diffusion, we use the model to predict the drug response in-vivo, beyond what would have been expected from sole consideration of the cancer intrinsic resistance. We conclude that this integrated experimental/computational approach may enhance understanding of pancreatic cancer behavior and its response to various chemotherapies, and, further, that such an approach could predict resistance based on pharmacokinetic measurements with the goal to maximize effective treatment strategies. PMID- 24068910 TI - Collective dynamics underlying allosteric transitions in hemoglobin. AB - Hemoglobin is the prototypic allosteric protein. Still, its molecular allosteric mechanism is not fully understood. To elucidate the mechanism of cooperativity on an atomistic level, we developed a novel computational technique to analyse the coupling of tertiary and quaternary motions. From Molecular Dynamics simulations showing spontaneous quaternary transitions, we separated the transition trajectories into two orthogonal sets of motions: one consisting of intra-chain motions only (referred to as tertiary-only) and one consisting of global inter chain motions only (referred to as quaternary-only). The two underlying subspaces are orthogonal by construction and their direct sum is the space of full motions. Using Functional Mode Analysis, we were able to identify a collective coordinate within the tertiary-only subspace that is correlated to the most dominant motion within the quaternary-only motions, hence providing direct insight into the allosteric coupling mechanism between tertiary and quaternary conformation changes. This coupling-motion is substantially different from tertiary structure changes between the crystallographic structures of the T- and R-state. We found that hemoglobin's allosteric mechanism of communication between subunits is equally based on hydrogen bonds and steric interactions. In addition, we were able to affect the T-to-R transition rates by choosing different histidine protonation states, thereby providing a possible atomistic explanation for the Bohr effect. PMID- 24068911 TI - Limited agreement of independent RNAi screens for virus-required host genes owes more to false-negative than false-positive factors. AB - Systematic, genome-wide RNA interference (RNAi) analysis is a powerful approach to identify gene functions that support or modulate selected biological processes. An emerging challenge shared with some other genome-wide approaches is that independent RNAi studies often show limited agreement in their lists of implicated genes. To better understand this, we analyzed four genome-wide RNAi studies that identified host genes involved in influenza virus replication. These studies collectively identified and validated the roles of 614 cell genes, but pair-wise overlap among the four gene lists was only 3% to 15% (average 6.7%). However, a number of functional categories were overrepresented in multiple studies. The pair-wise overlap of these enriched-category lists was high, ~19%, implying more agreement among studies than apparent at the gene level. Probing this further, we found that the gene lists implicated by independent studies were highly connected in interacting networks by independent functional measures such as protein-protein interactions, at rates significantly higher than predicted by chance. We also developed a general, model-based approach to gauge the effects of false-positive and false-negative factors and to estimate, from a limited number of studies, the total number of genes involved in a process. For influenza virus replication, this novel statistical approach estimates the total number of cell genes involved to be ~2,800. This and multiple other aspects of our experimental and computational results imply that, when following good quality control practices, the low overlap between studies is primarily due to false negatives rather than false-positive gene identifications. These results and methods have implications for and applications to multiple forms of genome-wide analysis. PMID- 24068912 TI - Network signatures of survival in glioblastoma multiforme. AB - To determine a molecular basis for prognostic differences in glioblastoma multiforme (GBM), we employed a combinatorial network analysis framework to exhaustively search for molecular patterns in protein-protein interaction (PPI) networks. We identified a dysregulated molecular signature distinguishing short term (survival<225 days) from long-term (survival>635 days) survivors of GBM using whole genome expression data from The Cancer Genome Atlas (TCGA). A 50-gene subnetwork signature achieved 80% prediction accuracy when tested against an independent gene expression dataset. Functional annotations for the subnetwork signature included "protein kinase cascade," "IkappaB kinase/NFkappaB cascade," and "regulation of programmed cell death" - all of which were not significant in signatures of existing subtypes. Finally, we used label-free proteomics to examine how our subnetwork signature predicted protein level expression differences in an independent GBM cohort of 16 patients. We found that the genes discovered using network biology had a higher probability of dysregulated protein expression than either genes exhibiting individual differential expression or genes derived from known GBM subtypes. In particular, the long-term survivor subtype was characterized by increased protein expression of DNM1 and MAPK1 and decreased expression of HSPA9, PSMD3, and CANX. Overall, we demonstrate that the combinatorial analysis of gene expression data constrained by PPIs outlines an approach for the discovery of robust and translatable molecular signatures in GBM. PMID- 24068913 TI - ISCB computational biology Wikipedia competition. PMID- 24068916 TI - Lymph node colonization dynamics after oral Salmonella Typhimurium infection in mice. AB - An understanding of how pathogens colonize their hosts is crucial for the rational design of vaccines or therapy. While the molecular factors facilitating the invasion and systemic infection by pathogens are a central focus of research in microbiology, the population biological aspects of colonization are still poorly understood. Here, we investigated the early colonization dynamics of Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm) in the streptomycin mouse model for diarrhea. We focused on the first step on the way to systemic infection -- the colonization of the cecal lymph node (cLN) from the gut -- and studied roles of inflammation, dendritic cells and innate immune effectors in the colonization process. To this end, we inoculated mice with mixtures of seven wild type isogenic tagged strains (WITS) of S. Tm. The experimental data were analyzed with a newly developed mathematical model describing the stochastic immigration, replication and clearance of bacteria in the cLN. We estimated that in the beginning of infection only 300 bacterial cells arrive in the cLN per day. We further found that inflammation decreases the net replication rate in the cLN by 23%. In ccr7(-/-) mice, in which dendritic cell movement is impaired, the bacterial migration rate was reduced 10-fold. In contrast, cybb(-/-) mice that cannot generate toxic reactive oxygen species displayed a 4-fold higher migration rate from gut to cLN than wild type mice. Thus, combining infections with mixed inocula of barcoded strains and mathematical analysis represents a powerful method for disentangling immigration into the cLN from replication in this compartment. The estimated parameters provide an important baseline to assess and predict the efficacy of interventions. PMID- 24068917 TI - Cross-seeding of misfolded proteins: implications for etiology and pathogenesis of protein misfolding diseases. PMID- 24068918 TI - Self and non-self discrimination of intracellular membranes by the innate immune system. PMID- 24068919 TI - Innate immune sensing of flaviviruses. PMID- 24068920 TI - Death be not proud--cell death control in plant fungal interactions. PMID- 24068921 TI - Acute neonatal infections 'lock-in' a suboptimal CD8+ T cell repertoire with impaired recall responses. AB - Microbial infection during various stages of human development produces widely different clinical outcomes, yet the links between age-related changes in the immune compartment and functional immunity remain unclear. The ability of the immune system to respond to specific antigens and mediate protection in early life is closely correlated with the level of diversification of lymphocyte antigen receptors. We have previously shown that the neonatal primary CD8+ T cell response to replication competent virus is significantly constricted compared to the adult response. In the present study, we have analyzed the subsequent formation of neonatal memory CD8+ T cells and their response to secondary infectious challenge. In particular, we asked whether the less diverse CD8+ T cell clonotypes that are elicited by neonatal vaccination with replication competent virus are 'locked-in' to the adult memory T cell, and thus may compromise the strength of adult immunity. Here we report that neonatal memory CD8+ T cells mediate poor recall responses compared to adults and are comprised of a repertoire of lower avidity T cells. During a later infectious challenge the neonatal memory CD8+ T cells compete poorly with the fully diverse repertoire of naive adult CD8+ T cells and are outgrown by the adult primary response. This has important implications for the timing of vaccination in early life. PMID- 24068922 TI - Aggressive chemotherapy and the selection of drug resistant pathogens. AB - Drug resistant pathogens are one of the key public health challenges of the 21st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by >150-fold), without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible. PMID- 24068923 TI - Phosphoproteomic analyses reveal signaling pathways that facilitate lytic gammaherpesvirus replication. AB - Lytic gammaherpesvirus (GHV) replication facilitates the establishment of lifelong latent infection, which places the infected host at risk for numerous cancers. As obligate intracellular parasites, GHVs must control and usurp cellular signaling pathways in order to successfully replicate, disseminate to stable latency reservoirs in the host, and prevent immune-mediated clearance. To facilitate a systems-level understanding of phosphorylation-dependent signaling events directed by GHVs during lytic replication, we utilized label-free quantitative mass spectrometry to interrogate the lytic replication cycle of murine gammaherpesvirus-68 (MHV68). Compared to controls, MHV68 infection regulated by 2-fold or greater ca. 86% of identified phosphopeptides - a regulatory scale not previously observed in phosphoproteomic evaluations of discrete signal-inducing stimuli. Network analyses demonstrated that the infection-associated induction or repression of specific cellular proteins globally altered the flow of information through the host phosphoprotein network, yielding major changes to functional protein clusters and ontologically associated proteins. A series of orthogonal bioinformatics analyses revealed that MAPK and CDK-related signaling events were overrepresented in the infection associated phosphoproteome and identified 155 host proteins, such as the transcription factor c-Jun, as putative downstream targets. Importantly, functional tests of bioinformatics-based predictions confirmed ERK1/2 and CDK1/2 as kinases that facilitate MHV68 replication and also demonstrated the importance of c-Jun. Finally, a transposon-mutant virus screen identified the MHV68 cyclin D ortholog as a viral protein that contributes to the prominent MAPK/CDK signature of the infection-associated phosphoproteome. Together, these analyses enhance an understanding of how GHVs reorganize and usurp intracellular signaling networks to facilitate infection and replication. PMID- 24068924 TI - Activation of Ran GTPase by a Legionella effector promotes microtubule polymerization, pathogen vacuole motility and infection. AB - The causative agent of Legionnaires' disease, Legionella pneumophila, uses the Icm/Dot type IV secretion system (T4SS) to form in phagocytes a distinct "Legionella-containing vacuole" (LCV), which intercepts endosomal and secretory vesicle trafficking. Proteomics revealed the presence of the small GTPase Ran and its effector RanBP1 on purified LCVs. Here we validate that Ran and RanBP1 localize to LCVs and promote intracellular growth of L. pneumophila. Moreover, the L. pneumophila protein LegG1, which contains putative RCC1 Ran guanine nucleotide exchange factor (GEF) domains, accumulates on LCVs in an Icm/Dot dependent manner. L. pneumophila wild-type bacteria, but not strains lacking LegG1 or a functional Icm/Dot T4SS, activate Ran on LCVs, while purified LegG1 produces active Ran(GTP) in cell lysates. L. pneumophila lacking legG1 is compromised for intracellular growth in macrophages and amoebae, yet is as cytotoxic as the wild-type strain. A downstream effect of LegG1 is to stabilize microtubules, as revealed by conventional and stimulated emission depletion (STED) fluorescence microscopy, subcellular fractionation and Western blot, or by microbial microinjection through the T3SS of a Yersinia strain lacking endogenous effectors. Real-time fluorescence imaging indicates that LCVs harboring wild-type L. pneumophila rapidly move along microtubules, while LCVs harboring DeltalegG1 mutant bacteria are stalled. Together, our results demonstrate that Ran activation and RanBP1 promote LCV formation, and the Icm/Dot substrate LegG1 functions as a bacterial Ran activator, which localizes to LCVs and promotes microtubule stabilization, LCV motility as well as intracellular replication of L. pneumophila. PMID- 24068925 TI - Vesicular transport of progeny parvovirus particles through ER and Golgi regulates maturation and cytolysis. AB - Progeny particles of non-enveloped lytic parvoviruses were previously shown to be actively transported to the cell periphery through vesicles in a gelsolin dependent manner. This process involves rearrangement and destruction of actin filaments, while microtubules become protected throughout the infection. Here the focus is on the intracellular egress pathway, as well as its impact on the properties and release of progeny virions. By colocalization with cellular marker proteins and specific modulation of the pathways through over-expression of variant effector genes transduced by recombinant adeno-associated virus vectors, we show that progeny PV particles become engulfed into COPII-vesicles in the endoplasmic reticulum (ER) and are transported through the Golgi to the plasma membrane. Besides known factors like sar1, sec24, rab1, the ERM family proteins, radixin and moesin play (an) essential role(s) in the formation/loading and targeting of virus-containing COPII-vesicles. These proteins also contribute to the transport through ER and Golgi of the well described analogue of cellular proteins, the secreted Gaussia luciferase in absence of virus infection. It is therefore likely that radixin and moesin also serve for a more general function in cellular exocytosis. Finally, parvovirus egress via ER and Golgi appears to be necessary for virions to gain full infectivity through post-assembly modifications (e.g. phosphorylation). While not being absolutely required for cytolysis and progeny virus release, vesicular transport of parvoviruses through ER and Golgi significantly accelerates these processes pointing to a regulatory role of this transport pathway. PMID- 24068926 TI - Methionine biosynthesis in Staphylococcus aureus is tightly controlled by a hierarchical network involving an initiator tRNA-specific T-box riboswitch. AB - In line with the key role of methionine in protein biosynthesis initiation and many cellular processes most microorganisms have evolved mechanisms to synthesize methionine de novo. Here we demonstrate that, in the bacterial pathogen Staphylococcus aureus, a rare combination of stringent response-controlled CodY activity, T-box riboswitch and mRNA decay mechanisms regulate the synthesis and stability of methionine biosynthesis metICFE-mdh mRNA. In contrast to other Bacillales which employ S-box riboswitches to control methionine biosynthesis, the S. aureus metICFE-mdh mRNA is preceded by a 5'-untranslated met leader RNA harboring a T-box riboswitch. Interestingly, this T-box riboswitch is revealed to specifically interact with uncharged initiator formylmethionyl-tRNA (tRNAi(fMet)) while binding of elongator tRNA(Met) proved to be weak, suggesting a putative additional function of the system in translation initiation control. met leader RNA/metICFE-mdh operon expression is under the control of the repressor CodY which binds upstream of the met leader RNA promoter. As part of the metabolic emergency circuit of the stringent response, methionine depletion activates RelA dependent (p)ppGpp alarmone synthesis, releasing CodY from its binding site and thereby activating the met leader promoter. Our data further suggest that subsequent steps in metICFE-mdh transcription are tightly controlled by the 5' met leader-associated T-box riboswitch which mediates premature transcription termination when methionine is present. If methionine supply is limited, and hence tRNAi(fMet) becomes uncharged, full-length met leader/metICFE-mdh mRNA is transcribed which is rapidly degraded by nucleases involving RNase J2. Together, the data demonstrate that staphylococci have evolved special mechanisms to prevent the accumulation of excess methionine. We hypothesize that this strict control might reflect the limited metabolic capacities of staphylococci to reuse methionine as, other than Bacillus, staphylococci lack both the methionine salvage and polyamine synthesis pathways. Thus, methionine metabolism might represent a metabolic Achilles' heel making the pathway an interesting target for future anti-staphylococcal drug development. PMID- 24068927 TI - Rapid sequential spread of two Wolbachia variants in Drosophila simulans. AB - The maternally inherited intracellular bacteria Wolbachia can manipulate host reproduction in various ways that foster frequency increases within and among host populations. Manipulations involving cytoplasmic incompatibility (CI), where matings between infected males and uninfected females produce non-viable embryos, are common in arthropods and produce a reproductive advantage for infected females. CI was associated with the spread of Wolbachia variant wRi in Californian populations of Drosophila simulans, which was interpreted as a bistable wave, in which local infection frequencies tend to increase only once the infection becomes sufficiently common to offset imperfect maternal transmission and infection costs. However, maternally inherited Wolbachia are expected to evolve towards mutualism, and they are known to increase host fitness by protecting against infectious microbes or increasing fecundity. We describe the sequential spread over approximately 20 years in natural populations of D. simulans on the east coast of Australia of two Wolbachia variants (wAu and wRi), only one of which causes significant CI, with wRi displacing wAu since 2004. Wolbachia and mtDNA frequency data and analyses suggest that these dynamics, as well as the earlier spread in California, are best understood as Fisherian waves of favourable variants, in which local spread tends to occur from arbitrarily low frequencies. We discuss implications for Wolbachia-host dynamics and coevolution and for applications of Wolbachia to disease control. PMID- 24068928 TI - Human cytomegalovirus gene UL76 induces IL-8 expression through activation of the DNA damage response. AB - Human cytomegalovirus (HCMV), a beta-herpesvirus, has evolved many strategies to subvert both innate and adaptive host immunity in order to ensure its survival and propagation within the host. Induction of IL-8 is particularly important during HCMV infection as neutrophils, primarily attracted by IL-8, play a key role in virus dissemination. Moreover, IL-8 has a positive effect in the replication of HCMV. This work has identified an HCMV gene (UL76), with the relevant property of inducing IL-8 expression at both transcriptional and protein levels. Up-regulation of IL-8 by UL76 results from activation of the NF-kB pathway as inhibition of both IKK-beta activity or degradation of Ikbetaalpha abolishes the IL-8 induction and, concomitantly, expression of UL76 is associated with the translocation of p65 to the nucleus where it binds to the IL-8 promoter. Furthermore, the UL76-mediated induction of IL-8 requires ATM and is correlated with the phosphorylation of NEMO on serine 85, indicating that UL76 activates NF kB pathway by the DNA Damage response, similar to the impact of genotoxic drugs. More importantly, a UL76 deletion mutant virus was significantly less efficient in stimulating IL-8 production than the wild type virus. In addition, there was a significant reduction of IL-8 secretion when ATM -/- cells were infected with wild type HCMV, thus, indicating that ATM is also involved in the induction of IL 8 by HCMV. In conclusion, we demonstrate that expression of UL76 gene induces IL 8 expression as a result of the DNA damage response and that both UL76 and ATM have a role in the mechanism of IL-8 induction during HCMV infection. Hence, this work characterizes a new role of the activation of DNA Damage response in the context of host-pathogen interactions. PMID- 24068929 TI - Alpha-interferon suppresses hepadnavirus transcription by altering epigenetic modification of cccDNA minichromosomes. AB - Covalently closed circular DNA (cccDNA) of hepadnaviruses exists as an episomal minichromosome in the nucleus of infected hepatocyte and serves as the transcriptional template for viral mRNA synthesis. Elimination of cccDNA is the prerequisite for either a therapeutic cure or immunological resolution of HBV infection. Although accumulating evidence suggests that inflammatory cytokines mediated cure of virally infected hepatocytes does occur and plays an essential role in the resolution of an acute HBV infection, the molecular mechanism by which the cytokines eliminate cccDNA and/or suppress its transcription remains elusive. This is largely due to the lack of convenient cell culture systems supporting efficient HBV infection and cccDNA formation to allow detailed molecular analyses. In this study, we took the advantage of a chicken hepatoma cell line that supports tetracycline-inducible duck hepatitis B virus (DHBV) replication and established an experimental condition mimicking the virally infected hepatocytes in which DHBV pregenomic (pg) RNA transcription and DNA replication are solely dependent on cccDNA. This cell culture system allowed us to demonstrate that cccDNA transcription required histone deacetylase activity and IFN-alpha induced a profound and long-lasting suppression of cccDNA transcription, which required protein synthesis and was associated with the reduction of acetylated histone H3 lysine 9 (H3K9) and 27 (H3K27) in cccDNA minichromosomes. Moreover, IFN-alpha treatment also induced a delayed response that appeared to accelerate the decay of cccDNA. Our studies have thus shed light on the molecular mechanism by which IFN-alpha noncytolytically controls hepadnavirus infection. PMID- 24068930 TI - Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection. AB - Respiratory virus infections, such as influenza, typically induce a robust type I (pro-inflammatory cytokine) immune response, however, the production of type 2 cytokines has been observed. Type 2 cytokine production during respiratory virus infection is linked to asthma exacerbation; however, type 2 cytokines may also be tissue protective. Interleukin (IL)-5 is a prototypical type 2 cytokine that is essential for eosinophil maturation and egress out of the bone marrow. However, little is known about the cellular source and underlying cellular and molecular basis for the regulation of IL-5 production during respiratory virus infection. Using a mouse model of influenza virus infection, we found a robust transient release of IL-5 into infected airways along with a significant and progressive accumulation of eosinophils into the lungs, particularly during the recovery phase of infection, i.e. following virus clearance. The cellular source of the IL 5 was group 2 innate lymphoid cells (ILC2) infiltrating the infected lungs. Interestingly, the progressive accumulation of eosinophils following virus clearance is reflected in the rapid expansion of c-kit+ IL-5 producing ILC2. We further demonstrate that the enhanced capacity for IL-5 production by ILC2 during recovery is concomitant with the enhanced expression of the IL-33 receptor subunit, ST2, by ILC2. Lastly, we show that NKT cells, as well as alveolar macrophages (AM), are endogenous sources of IL-33 that enhance IL-5 production from ILC2. Collectively, these results reveal that c-kit+ ILC2 interaction with IL-33 producing NKT and AM leads to abundant production of IL-5 by ILC2 and accounts for the accumulation of eosinophils observed during the recovery phase of influenza infection. PMID- 24068931 TI - A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies. AB - A desirable but as yet unachieved property of a human immunodeficiency virus type 1 (HIV-1) vaccine candidate is the ability to induce broadly neutralizing antibodies (bNAbs). One approach to the problem is to create trimeric mimics of the native envelope glycoprotein (Env) spike that expose as many bNAb epitopes as possible, while occluding those for non-neutralizing antibodies (non-NAbs). Here, we describe the design and properties of soluble, cleaved SOSIP.664 gp140 trimers based on the subtype A transmitted/founder strain, BG505. These trimers are highly stable, more so even than the corresponding gp120 monomer, as judged by differential scanning calorimetry. They are also homogenous and closely resemble native virus spikes when visualized by negative stain electron microscopy (EM). We used several techniques, including ELISA and surface plasmon resonance (SPR), to determine the relationship between the ability of monoclonal antibodies (MAbs) to bind the soluble trimers and neutralize the corresponding virus. In general, the concordance was excellent, in that virtually all bNAbs against multiple neutralizing epitopes on HIV-1 Env were highly reactive with the BG505 SOSIP.664 gp140 trimers, including quaternary epitopes (CH01, PG9, PG16 and PGT145). Conversely, non-NAbs to the CD4-binding site, CD4-induced epitopes or gp41ECTO did not react with the trimers, even when their epitopes were present on simpler forms of Env (e.g. gp120 monomers or dissociated gp41 subunits). Three non neutralizing MAbs to V3 epitopes did, however, react strongly with the trimers but only by ELISA, and not at all by SPR and to only a limited extent by EM. These new soluble trimers are useful for structural studies and are being assessed for their performance as immunogens. PMID- 24068932 TI - The crystal structure and RNA-binding of an orthomyxovirus nucleoprotein. AB - Genome packaging for viruses with segmented genomes is often a complex problem. This is particularly true for influenza viruses and other orthomyxoviruses, whose genome consists of multiple negative-sense RNAs encapsidated as ribonucleoprotein (RNP) complexes. To better understand the structural features of orthomyxovirus RNPs that allow them to be packaged, we determined the crystal structure of the nucleoprotein (NP) of a fish orthomyxovirus, the infectious salmon anemia virus (ISAV) (genus Isavirus). As the major protein component of the RNPs, ISAV-NP possesses a bi-lobular structure similar to the influenza virus NP. Because both RNA-free and RNA-bound ISAV NP forms stable dimers in solution, we were able to measure the NP RNA binding affinity as well as the stoichiometry using recombinant proteins and synthetic oligos. Our RNA binding analysis revealed that each ISAV-NP binds ~12 nts of RNA, shorter than the 24-28 nts originally estimated for the influenza A virus NP based on population average. The 12-nt stoichiometry was further confirmed by results from electron microscopy and dynamic light scattering. Considering that RNPs of ISAV and the influenza viruses have similar morphologies and dimensions, our findings suggest that NP-free RNA may exist on orthomyxovirus RNPs, and selective RNP packaging may be accomplished through direct RNA-RNA interactions. PMID- 24068933 TI - Small RNA sX13: a multifaceted regulator of virulence in the plant pathogen Xanthomonas. AB - Small noncoding RNAs (sRNAs) are ubiquitous posttranscriptional regulators of gene expression. Using the model plant-pathogenic bacterium Xanthomonas campestris pv. vesicatoria (Xcv), we investigated the highly expressed and conserved sRNA sX13 in detail. Deletion of sX13 impinged on Xcv virulence and the expression of genes encoding components and substrates of the Hrp type III secretion (T3S) system. qRT-PCR analyses revealed that sX13 promotes mRNA accumulation of HrpX, a key regulator of the T3S system, whereas the mRNA level of the master regulator HrpG was unaffected. Complementation studies suggest that sX13 acts upstream of HrpG. Microarray analyses identified 63 sX13-regulated genes, which are involved in signal transduction, motility, transcriptional and posttranscriptional regulation and virulence. Structure analyses of in vitro transcribed sX13 revealed a structure with three stable stems and three apical C rich loops. A computational search for putative regulatory motifs revealed that sX13-repressed mRNAs predominantly harbor G-rich motifs in proximity of translation start sites. Mutation of sX13 loops differentially affected Xcv virulence and the mRNA abundance of putative targets. Using a GFP-based reporter system, we demonstrated that sX13-mediated repression of protein synthesis requires both the C-rich motifs in sX13 and G-rich motifs in potential target mRNAs. Although the RNA-binding protein Hfq was dispensable for sX13 activity, the hfq mRNA and Hfq::GFP abundance were negatively regulated by sX13. In addition, we found that G-rich motifs in sX13-repressed mRNAs can serve as translational enhancers and are located at the ribosome-binding site in 5% of all protein-coding Xcv genes. Our study revealed that sX13 represents a novel class of virulence regulators and provides insights into sRNA-mediated modulation of adaptive processes in the plant pathogen Xanthomonas. PMID- 24068934 TI - Porphyromonas gingivalis facilitates the development and progression of destructive arthritis through its unique bacterial peptidylarginine deiminase (PAD). AB - Rheumatoid arthritis and periodontitis are two prevalent chronic inflammatory diseases in humans and are associated with each other both clinically and epidemiologically. Recent findings suggest a causative link between periodontal infection and rheumatoid arthritis via bacteria-dependent induction of a pathogenic autoimmune response to citrullinated epitopes. Here we showed that infection with viable periodontal pathogen Porphyromonas gingivalis strain W83 exacerbated collagen-induced arthritis (CIA) in a mouse model, as manifested by earlier onset, accelerated progression and enhanced severity of the disease, including significantly increased bone and cartilage destruction. The ability of P. gingivalis to augment CIA was dependent on the expression of a unique P. gingivalis peptidylarginine deiminase (PPAD), which converts arginine residues in proteins to citrulline. Infection with wild type P. gingivalis was responsible for significantly increased levels of autoantibodies to collagen type II and citrullinated epitopes as a PPAD-null mutant did not elicit similar host response. High level of citrullinated proteins was also detected at the site of infection with wild-type P. gingivalis. Together, these results suggest bacterial PAD as the mechanistic link between P. gingivalis periodontal infection and rheumatoid arthritis. PMID- 24068935 TI - Epstein Barr virus-induced 3 (EBI3) together with IL-12 negatively regulates T helper 17-mediated immunity to Listeria monocytogenes infection. AB - Although the protective functions by T helper 17 (Th17) cytokines against extracellular bacterial and fungal infection have been well documented, their importance against intracellular bacterial infection remains unclear. Here, we investigated the contribution of Th17 responses to host defense against intracellular bacteria Listeria monocytogenes and found that Th17 cell generation was suppressed in this model. Unexpectedly, mice lacking both p35 and EBI3 cleared L. monocytogenes as efficiently as wild-type mice, whereas p35-deficient mice failed to do so. Furthermore, both innate cells and pathogen-specific T cells from double-deficient mice produced significantly higher IL-17 and IL-22 compared to wild-type mice. The bacterial burden in the liver of double-deficient mice treated with anti-IL-17 was significantly increased compared to those receiving a control Ab. Transfer of Th17 cells specific for listeriolysin O as well as administration of IL-17 and IL-22 significantly suppressed bacterial growth in p35-deficient mice, indicating the critical contribution of Th17 responses to host defense against the intracellular pathogen in the absence of IL 12 and proper Th1 responses. Our findings unveil a novel immune evasion mechanism whereby the intracellular bacteria exploit IL-27EBI3 to suppress Th17-mediated protective immunity. PMID- 24068936 TI - HTLV-1 bZIP factor induces inflammation through labile Foxp3 expression. AB - Human T-cell leukemia virus type 1 (HTLV-1) causes both a neoplastic disease and inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 basic leucine zipper factor (HBZ) gene is encoded in the minus strand of the proviral DNA and is constitutively expressed in infected cells and ATL cells. HBZ increases the number of regulatory T (Treg) cells by inducing the Foxp3 gene transcription. Recent studies have revealed that some CD4+Foxp3+ T cells are not terminally differentiated but have a plasticity to convert to other T-cell subsets. Induced Treg (iTreg) cells tend to lose Foxp3 expression, and may acquire an effector phenotype accompanied by the production of inflammatory cytokines, such as interferon-gamma (IFN-gamma). In this study, we analyzed a pathogenic mechanism of chronic inflammation related with HTLV-1 infection via focusing on HBZ and Foxp3. Infiltration of lymphocytes was observed in the skin, lung and intestine of HBZ-Tg mice. As mechanisms, adhesion and migration of HBZ-expressing CD4+ T cells were enhanced in these mice. Foxp3-CD4+ T cells produced higher amounts of IFN-gamma compared to those from non-Tg mice. Expression of Helios was reduced in Treg cells from HBZ-Tg mice and HAM/TSP patients, indicating that iTreg cells are predominant. Consistent with this finding, the conserved non-coding sequence 2 region of the Foxp3 gene was hypermethylated in Treg cells of HBZ-Tg mice, which is a characteristic of iTreg cells. Furthermore, Treg cells in the spleen of HBZ-transgenic mice tended to lose Foxp3 expression and produced an excessive amount of IFN-gamma, while Foxp3 expression was stable in natural Treg cells of the thymus. HBZ enhances the generation of iTreg cells, which likely convert to Foxp3-T cells producing IFN gamma. The HBZ-mediated proinflammatory phenotype of CD4+ T cells is implicated in the pathogenesis of HTLV-1-associated inflammation. PMID- 24068937 TI - Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming. AB - Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors. PMID- 24068938 TI - Genome-wide mouse mutagenesis reveals CD45-mediated T cell function as critical in protective immunity to HSV-1. AB - Herpes simplex encephalitis (HSE) is a lethal neurological disease resulting from infection with Herpes Simplex Virus 1 (HSV-1). Loss-of-function mutations in the UNC93B1, TLR3, TRIF, TRAF3, and TBK1 genes have been associated with a human genetic predisposition to HSE, demonstrating the UNC93B-TLR3-type I IFN pathway as critical in protective immunity to HSV-1. However, the TLR3, UNC93B1, and TRIF mutations exhibit incomplete penetrance and represent only a minority of HSE cases, perhaps reflecting the effects of additional host genetic factors. In order to identify new host genes, proteins and signaling pathways involved in HSV 1 and HSE susceptibility, we have implemented the first genome-wide mutagenesis screen in an in vivo HSV-1 infectious model. One pedigree (named P43) segregated a susceptible trait with a fully penetrant phenotype. Genetic mapping and whole exome sequencing led to the identification of the causative nonsense mutation L3X in the Receptor-type tyrosine-protein phosphatase C gene (Ptprc(L3X)), which encodes for the tyrosine phosphatase CD45. Expression of MCP1, IL-6, MMP3, MMP8, and the ICP4 viral gene were significantly increased in the brain stems of infected Ptprc(L3X) mice accounting for hyper-inflammation and pathological damages caused by viral replication. Ptprc(L3X) mutation drastically affects the early stages of thymocytes development but also the final stage of B cell maturation. Transfer of total splenocytes from heterozygous littermates into Ptprc(L3X) mice resulted in a complete HSV-1 protective effect. Furthermore, T cells were the only cell population to fully restore resistance to HSV-1 in the mutants, an effect that required both the CD4+ and CD8+ T cells and could be attributed to function of CD4+ T helper 1 (Th1) cells in CD8+ T cell recruitment to the site of infection. Altogether, these results revealed the CD45-mediated T cell function as potentially critical for infection and viral spread to the brain, and also for subsequent HSE development. PMID- 24068939 TI - Inactivation of intergenic enhancers by EBNA3A initiates and maintains polycomb signatures across a chromatin domain encoding CXCL10 and CXCL9. AB - Epstein-Barr virus (EBV) causes a persistent infection in human B cells by establishing specific transcription programs to control B cell activation and differentiation. Transcriptional reprogramming of EBV infected B cells is predominantly driven by the action of EBV nuclear antigens, among them the transcriptional repressor EBNA3A. By comparing gene expression profiles of wt and EBNA3A negative EBV infected B cells, we have previously identified a broad array of cellular genes controlled by EBNA3A. We now find that genes repressed by EBNA3A in these cells are significantly enriched for the repressive histone mark H3K27me3, which is installed by Polycomb group (PcG) proteins. This PcG controlled subset of genes also carries H3K27me3 marks in a variety of other tissues, suggesting that the commitment to PcG silencing is an intrinsic feature of these gene loci that can be used by EBNA3A. In addition, EBNA3A targets frequently reside in co-regulated gene clusters. To study the mechanism of gene repression by EBNA3A and to evaluate the relative contribution of PcG proteins during this process, we have selected the genomic neighbors CXCL10 and CXCL9 as a model for co-repressed and PcG-controlled genes. We show that EBNA3A binds to CBF1 occupied intergenic enhancers located between CXCL10 and CXCL9 and displaces the transactivator EBNA2. This impairs enhancer activity, resulting in a rapid transcriptional shut-down of both genes in a CBF1-dependent manner and initiation of a delayed gain of H3K27me3 marks covering an extended chromatin domain. H3K27me3 marks increase gradually and are maintained by EBNA3A. Our study provides direct evidence that repression by EBNA3A requires CBF1 and that EBNA3A and EBNA2 compete for access to CBF1 at identical genomic sites. Most importantly, our results demonstrate that transcriptional silencing by EBNA3A precedes the appearance of repressive PcG marks and indicate that both events are triggered by loss of enhancer activity. PMID- 24068941 TI - Drosophila fatty acid taste signals through the PLC pathway in sugar-sensing neurons. AB - Taste is the primary sensory system for detecting food quality and palatability. Drosophila detects five distinct taste modalities that include sweet, bitter, salt, water, and the taste of carbonation. Of these, sweet-sensing neurons appear to have utility for the detection of nutritionally rich food while bitter-sensing neurons signal toxicity and confer repulsion. Growing evidence in mammals suggests that taste for fatty acids (FAs) signals the presence of dietary lipids and promotes feeding. While flies appear to be attracted to fatty acids, the neural basis for fatty acid detection and attraction are unclear. Here, we demonstrate that a range of FAs are detected by the fly gustatory system and elicit a robust feeding response. Flies lacking olfactory organs respond robustly to FAs, confirming that FA attraction is mediated through the gustatory system. Furthermore, flies detect FAs independent of pH, suggesting the molecular basis for FA taste is not due to acidity. We show that low and medium concentrations of FAs serve as an appetitive signal and they are detected exclusively through the same subset of neurons that sense appetitive sweet substances, including most sugars. In mammals, taste perception of sweet and bitter substances is dependent on phospholipase C (PLC) signaling in specialized taste buds. We find that flies mutant for norpA, a Drosophila ortholog of PLC, fail to respond to FAs. Intriguingly, norpA mutants respond normally to other tastants, including sucrose and yeast. The defect of norpA mutants can be rescued by selectively restoring norpA expression in sweet-sensing neurons, corroborating that FAs signal through sweet-sensing neurons, and suggesting PLC signaling in the gustatory system is specifically involved in FA taste. Taken together, these findings reveal that PLC function in Drosophila sweet-sensing neurons is a conserved molecular signaling pathway that confers attraction to fatty acids. PMID- 24068940 TI - Integration of the unfolded protein and oxidative stress responses through SKN 1/Nrf. AB - The Unfolded Protein Response (UPR) maintains homeostasis in the endoplasmic reticulum (ER) and defends against ER stress, an underlying factor in various human diseases. During the UPR, numerous genes are activated that sustain and protect the ER. These responses are known to involve the canonical UPR transcription factors XBP1, ATF4, and ATF6. Here, we show in C. elegans that the conserved stress defense factor SKN-1/Nrf plays a central and essential role in the transcriptional UPR. While SKN-1/Nrf has a well-established function in protection against oxidative and xenobiotic stress, we find that it also mobilizes an overlapping but distinct response to ER stress. SKN-1/Nrf is regulated by the UPR, directly controls UPR signaling and transcription factor genes, binds to common downstream targets with XBP-1 and ATF-6, and is present at the ER. SKN-1/Nrf is also essential for resistance to ER stress, including reductive stress. Remarkably, SKN-1/Nrf-mediated responses to oxidative stress depend upon signaling from the ER. We conclude that SKN-1/Nrf plays a critical role in the UPR, but orchestrates a distinct oxidative stress response that is licensed by ER signaling. Regulatory integration through SKN-1/Nrf may coordinate ER and cytoplasmic homeostasis. PMID- 24068942 TI - Growth factor independent-1 maintains Notch1-dependent transcriptional programming of lymphoid precursors. AB - Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a gene activated in T-cell leukemias induced by Moloney-murine leukemia virus infection. Notch1 is a transmembrane receptor that is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL). Gfi1 is an important factor in the initiation and maintenance of lymphoid leukemias and its deficiency significantly impedes Notch dependent initiation of T-ALL in animal models. Here, we show that immature hematopoietic cells require Gfi1 to competently integrate Notch-activated signaling. Notch1 activation coupled with Gfi1 deficiency early in T-lineage specification leads to a dramatic loss of T cells, whereas activation in later stages leaves development unaffected. In Gfi1 deficient multipotent precursors, Notch activation induces lethality and is cell autonomous. Further, without Gfi1, multipotent progenitors do not maintain Notch1 activated global expression profiles typical for T-lineage precursors. In agreement with this, we find that both lymphoid-primed multipotent progenitors (LMPP) and early T lineage progenitors (ETP) do not properly form or function in Gfi1(-/-) mice. These defects correlate with an inability of Gfi1(-/-) progenitors to activate lymphoid genes, including IL7R, Rag1, Flt3 and Notch1. Our data indicate that Gfi1 is required for hematopoietic precursors to withstand Notch1 activation and to maintain Notch1 dependent transcriptional programming to determine early T-lymphoid lineage identity. PMID- 24068943 TI - A shift to organismal stress resistance in programmed cell death mutants. AB - Animals have many ways of protecting themselves against stress; for example, they can induce animal-wide, stress-protective pathways and they can kill damaged cells via apoptosis. We have discovered an unexpected regulatory relationship between these two types of stress responses. We find that C. elegans mutations blocking the normal course of programmed cell death and clearance confer animal wide resistance to a specific set of environmental stressors; namely, ER, heat and osmotic stress. Remarkably, this pattern of stress resistance is induced by mutations that affect cell death in different ways, including ced-3 (cell death defective) mutations, which block programmed cell death, ced-1 and ced-2 mutations, which prevent the engulfment of dying cells, and progranulin (pgrn-1) mutations, which accelerate the clearance of apoptotic cells. Stress resistance conferred by ced and pgrn-1 mutations is not additive and these mutants share altered patterns of gene expression, suggesting that they may act within the same pathway to achieve stress resistance. Together, our findings demonstrate that programmed cell death effectors influence the degree to which C. elegans tolerates environmental stress. While the mechanism is not entirely clear, it is intriguing that animals lacking the ability to efficiently and correctly remove dying cells should switch to a more global animal-wide system of stress resistance. PMID- 24068944 TI - The hedgehog pathway gene shifted functions together with the hmgcr-dependent isoprenoid biosynthetic pathway to orchestrate germ cell migration. AB - The Drosophila embryonic gonad is assembled from two distinct cell types, the Primordial Germ Cells (PGCs) and the Somatic Gonadal Precursor cells (SGPs). The PGCs form at the posterior of blastoderm stage embryos and are subsequently carried inside the embryo during gastrulation. To reach the SGPs, the PGCs must traverse the midgut wall and then migrate through the mesoderm. A combination of local repulsive cues and attractive signals emanating from the SGPs guide migration. We have investigated the role of the hedgehog (hh) pathway gene shifted (shf) in directing PGC migration. shf encodes a secreted protein that facilitates the long distance transmission of Hh through the proteoglycan matrix after it is released from basolateral membranes of Hh expressing cells in the wing imaginal disc. shf is expressed in the gonadal mesoderm, and loss- and gain of-function experiments demonstrate that it is required for PGC migration. Previous studies have established that the hmgcr-dependent isoprenoid biosynthetic pathway plays a pivotal role in generating the PGC attractant both by the SGPs and by other tissues when hmgcr is ectopically expressed. We show that production of this PGC attractant depends upon shf as well as a second hh pathway gene ggamma1. Further linking the PGC attractant to Hh, we present evidence indicating that ectopic expression of hmgcr in the nervous system promotes the release/transmission of the Hh ligand from these cells into and through the underlying mesodermal cell layer, where Hh can contact migrating PGCs. Finally, potentiation of Hh by hmgcr appears to depend upon cholesterol modification. PMID- 24068946 TI - Extensive divergence of transcription factor binding in Drosophila embryos with highly conserved gene expression. AB - To better characterize how variation in regulatory sequences drives divergence in gene expression, we undertook a systematic study of transcription factor binding and gene expression in blastoderm embryos of four species, which sample much of the diversity in the 40 million-year old genus Drosophila: D. melanogaster, D. yakuba, D. pseudoobscura and D. virilis. We compared gene expression, measured by mRNA-seq, to the genome-wide binding, measured by ChIP-seq, of four transcription factors involved in early anterior-posterior patterning. We found that mRNA levels are much better conserved than individual transcription factor binding events, and that changes in a gene's expression were poorly explained by changes in adjacent transcription factor binding. However, highly bound sites, sites in regions bound by multiple factors and sites near genes are conserved more frequently than other binding, suggesting that a considerable amount of transcription factor binding is weakly or non-functional and not subject to purifying selection. PMID- 24068945 TI - Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. AB - Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. PMID- 24068947 TI - Common variants in left/right asymmetry genes and pathways are associated with relative hand skill. AB - Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68 * 10(-9)), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR <= 5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR <= 5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development. PMID- 24068948 TI - Genomic identification of founding haplotypes reveals the history of the selfing species Capsella rubella. AB - The shift from outcrossing to self-fertilization is among the most common evolutionary transitions in flowering plants. Until recently, however, a genome wide view of this transition has been obscured by both a dearth of appropriate data and the lack of appropriate population genomic methods to interpret such data. Here, we present a novel population genomic analysis detailing the origin of the selfing species, Capsella rubella, which recently split from its outcrossing sister, Capsella grandiflora. Due to the recency of the split, much of the variation within C. rubella is also found within C. grandiflora. We can therefore identify genomic regions where two C. rubella individuals have inherited the same or different segments of ancestral diversity (i.e. founding haplotypes) present in C. rubella's founder(s). Based on this analysis, we show that C. rubella was founded by multiple individuals drawn from a diverse ancestral population closely related to extant C. grandiflora, that drift and selection have rapidly homogenized most of this ancestral variation since C. rubella's founding, and that little novel variation has accumulated within this time. Despite the extensive loss of ancestral variation, the approximately 25% of the genome for which two C. rubella individuals have inherited different founding haplotypes makes up roughly 90% of the genetic variation between them. To extend these findings, we develop a coalescent model that utilizes the inferred frequency of founding haplotypes and variation within founding haplotypes to estimate that C. rubella was founded by a potentially large number of individuals between 50 and 100 kya, and has subsequently experienced a twenty-fold reduction in its effective population size. As population genomic data from an increasing number of outcrossing/selfing pairs are generated, analyses like the one developed here will facilitate a fine-scaled view of the evolutionary and demographic impact of the transition to self-fertilization. PMID- 24068949 TI - An atypical kinase under balancing selection confers broad-spectrum disease resistance in Arabidopsis. AB - The failure of gene-for-gene resistance traits to provide durable and broad spectrum resistance in an agricultural context has led to the search for genes underlying quantitative resistance in plants. Such genes have been identified in only a few cases, all for fungal or nematode resistance, and encode diverse molecular functions. However, an understanding of the molecular mechanisms of quantitative resistance variation to other enemies and the associated evolutionary forces shaping this variation remain largely unknown. We report the identification, map-based cloning and functional validation of QRX3 (RKS1, Resistance related KinaSe 1), conferring broad-spectrum resistance to Xanthomonas campestris (Xc), a devastating worldwide bacterial vascular pathogen of crucifers. RKS1 encodes an atypical kinase that mediates a quantitative resistance mechanism in plants by restricting bacterial spread from the infection site. Nested Genome-Wide Association mapping revealed a major locus corresponding to an allelic series at RKS1 at the species level. An association between variation in resistance and RKS1 transcription was found using various transgenic lines as well as in natural accessions, suggesting that regulation of RKS1 expression is a major component of quantitative resistance to Xc. The co existence of long lived RKS1 haplotypes in A. thaliana is shared with a variety of genes involved in pathogen recognition, suggesting common selective pressures. The identification of RKS1 constitutes a starting point for deciphering the mechanisms underlying broad spectrum quantitative disease resistance that is effective against a devastating and vascular crop pathogen. Because putative RKS1 orthologous have been found in other Brassica species, RKS1 provides an exciting opportunity for plant breeders to improve resistance to black rot in crops. PMID- 24068950 TI - Recent acquisition of Helicobacter pylori by Baka pygmies. AB - Both anatomically modern humans and the gastric pathogen Helicobacter pylori originated in Africa, and both species have been associated for at least 100,000 years. Seven geographically distinct H. pylori populations exist, three of which are indigenous to Africa: hpAfrica1, hpAfrica2, and hpNEAfrica. The oldest and most divergent population, hpAfrica2, evolved within San hunter-gatherers, who represent one of the deepest branches of the human population tree. Anticipating the presence of ancient H. pylori lineages within all hunter-gatherer populations, we investigated the prevalence and population structure of H. pylori within Baka Pygmies in Cameroon. Gastric biopsies were obtained by esophagogastroduodenoscopy from 77 Baka from two geographically separated populations, and from 101 non-Baka individuals from neighboring agriculturalist populations, and subsequently cultured for H. pylori. Unexpectedly, Baka Pygmies showed a significantly lower H. pylori infection rate (20.8%) than non-Baka (80.2%). We generated multilocus haplotypes for each H. pylori isolate by DNA sequencing, but were not able to identify Baka-specific lineages, and most isolates in our sample were assigned to hpNEAfrica or hpAfrica1. The population hpNEAfrica, a marker for the expansion of the Nilo-Saharan language family, was divided into East African and Central West African subpopulations. Similarly, a new hpAfrica1 subpopulation, identified mainly among Cameroonians, supports eastern and western expansions of Bantu languages. An age-structured transmission model shows that the low H. pylori prevalence among Baka Pygmies is achievable within the timeframe of a few hundred years and suggests that demographic factors such as small population size and unusually low life expectancy can lead to the eradication of H. pylori from individual human populations. The Baka were thus either H. pylori-free or lost their ancient lineages during past demographic fluctuations. Using coalescent simulations and phylogenetic inference, we show that Baka almost certainly acquired their extant H. pylori through secondary contact with their agriculturalist neighbors. PMID- 24068951 TI - The prefoldin complex regulates chromatin dynamics during transcription elongation. AB - Transcriptional elongation requires the concerted action of several factors that allow RNA polymerase II to advance through chromatin in a highly processive manner. In order to identify novel elongation factors, we performed systematic yeast genetic screening based on the GLAM (Gene Length-dependent Accumulation of mRNA) assay, which is used to detect defects in the expression of long transcription units. Apart from well-known transcription elongation factors, we identified mutants in the prefoldin complex subunits, which were among those that caused the most dramatic phenotype. We found that prefoldin, so far involved in the cytoplasmic co-translational assembly of protein complexes, is also present in the nucleus and that a subset of its subunits are recruited to chromatin in a transcription-dependent manner. Prefoldin influences RNA polymerase II the elongation rate in vivo and plays an especially important role in the transcription elongation of long genes and those whose promoter regions contain a canonical TATA box. Finally, we found a specific functional link between prefoldin and histone dynamics after nucleosome remodeling, which is consistent with the extensive network of genetic interactions between this factor and the machinery regulating chromatin function. This study establishes the involvement of prefoldin in transcription elongation, and supports a role for this complex in cotranscriptional histone eviction. PMID- 24068952 TI - Regulation of the boundaries of accessible chromatin. AB - Regulatory regions maintain nucleosome-depleted, open chromatin status but simultaneously require the presence of nucleosomes for specific histone modifications. It remains unclear how these can be achieved for proper regulatory function. Here we demonstrate that nucleosomes positioned within accessible chromatin regions near the boundaries provide platforms for histone modifications while preventing the occlusion of regulatory elements. These boundary nucleosomes were particularly enriched for active or poised regulatory marks in human, such as histone acetylations, H3K4 methylations, H3K9me3, H3K79me2, and H4K20me1. Additionally, we found that based on a genome-wide profiling of ~100 recombinant yeast strains, the location of open chromatin borders tends to vary mostly within 150 bp upon genetic perturbation whereas this positional variation increases in proportion to the sequence preferences of the underlying DNA for nucleosome formation. More than 40% of the local boundary shifts were associated with genetic variation in cis- or trans-acting factors. A sizeable fraction of the identified genetic factors was also associated with nearby gene expression, which was correlated with the distance between the transcription start site (tss) and the boundary that faces the tss. Taken together, the variation in the width of accessible chromatin regions may arise in conjunction with the modulation of the boundary nucleosomes by post-translational modifications or by chromatin regulators and in association with the activity of nearby gene transcription. PMID- 24068953 TI - A Pre-mRNA-splicing factor is required for RNA-directed DNA methylation in Arabidopsis. AB - Cytosine DNA methylation is a stable epigenetic mark that is frequently associated with the silencing of genes and transposable elements (TEs). In Arabidopsis, the establishment of DNA methylation is through the RNA-directed DNA methylation (RdDM) pathway. Here, we report the identification and characterization of RDM16, a new factor in the RdDM pathway. Mutation of RDM16 reduced the DNA methylation levels and partially released the silencing of a reporter gene as well as some endogenous genomic loci in the DNA demethylase ros1 1 mutant background. The rdm16 mutant had morphological defects and was hypersensitive to salt stress and abscisic acid (ABA). Map-based cloning and complementation test led to the identification of RDM16, which encodes a pre-mRNA splicing factor 3, a component of the U4/U6 snRNP. RNA-seq analysis showed that 308 intron retention events occurred in rdm16, confirming that RDM16 is involved in pre-mRNA splicing in planta. RNA-seq and mRNA expression analysis also revealed that the RDM16 mutation did not affect the pre-mRNA splicing of known RdDM genes, suggesting that RDM16 might be directly involved in RdDM. Small RNA expression analysis on loci showing RDM16-dependent DNA methylation suggested that unlike the previously reported putative splicing factor mutants, rdm16 did not affect small RNA levels; instead, the rdm16 mutation caused a decrease in the levels of Pol V transcripts. ChIP assays revealed that RDM16 was enriched at some Pol V target loci. Our results suggest that RDM16 regulates DNA methylation through influencing Pol V transcript levels. Finally, our genome-wide DNA methylation analysis indicated that RDM16 regulates the overall methylation of TEs and gene-surrounding regions, and preferentially targets Pol IV-dependent DNA methylation loci and the ROS1 target loci. Our work thus contributes to the understanding of RdDM and its interactions with active DNA demethylation. PMID- 24068954 TI - Maternal depletion of Piwi, a component of the RNAi system, impacts heterochromatin formation in Drosophila. AB - A persistent question in epigenetics is how heterochromatin is targeted for assembly at specific domains, and how that chromatin state is faithfully transmitted. Stable heterochromatin is necessary to silence transposable elements (TEs) and maintain genome integrity. Both the RNAi system and heterochromatin components HP1 (Swi6) and H3K9me2/3 are required for initial establishment of heterochromatin structures in S. pombe. Here we utilize both loss of function alleles and the newly developed Drosophila melanogaster transgenic shRNA lines to deplete proteins of interest at specific development stages to dissect their roles in heterochromatin assembly in early zygotes and in maintenance of the silencing chromatin state during development. Using reporters subject to Position Effect Variegation (PEV), we find that depletion of key proteins in the early embryo can lead to loss of silencing assayed at adult stages. The piRNA component Piwi is required in the early embryo for reporter silencing in non-gonadal somatic cells, but knock-down during larval stages has no impact. This implies that Piwi is involved in targeting HP1a when heterochromatin is established at the late blastoderm stage and possibly also during embryogenesis, but that the silent chromatin state created is transmitted through cell division independent of the piRNA system. In contrast, heterochromatin structural protein HP1a is required for both initial heterochromatin assembly and the following mitotic inheritance. HP1a profiles in piwi mutant animals confirm that Piwi depletion leads to decreased HP1a levels in pericentric heterochromatin, particularly in TEs. The results suggest that the major role of the piRNA system in assembly of heterochromatin in non-gonadal somatic cells occurs in the early embryo during heterochromatin formation, and further demonstrate that failure of heterochromatin formation in the early embryo impacts the phenotype of the adult. PMID- 24068955 TI - MYB64 and MYB119 are required for cellularization and differentiation during female gametogenesis in Arabidopsis thaliana. AB - In angiosperms, the egg cell forms within the multicellular, haploid female gametophyte. Female gametophyte and egg cell development occurs through a unique process in which a haploid spore initially undergoes several rounds of synchronous nuclear divisions without cytokinesis, resulting in a single cell containing multiple nuclei. The developing gametophyte then forms cell walls (cellularization) and the resulting cells differentiate to generate the egg cell and several accessory cells. The switch between free nuclear divisions and cellularization-differentiation occurs during developmental stage FG5 in Arabidopsis, and we refer to it as the FG5 transition. The molecular regulators that initiate the FG5 transition during female gametophyte development are unknown. In this study, we show using mutant analysis that two closely related MYB transcription factors, MYB64 and MYB119, act redundantly to promote this transition. MYB64 and MYB119 are expressed during the FG5 transition, and most myb64 myb119 double mutant gametophytes fail to initiate the FG5 transition, resulting in uncellularized gametophytes with supernumerary nuclei. Analysis of cell-specific markers in myb64 myb119 gametophytes that do cellularize suggests that gametophytic polarity and differentiation are also affected. We also show using multiple-mutant analysis that MYB119 expression is regulated by the histidine kinase CKI1, the primary activator of two-component signaling (TCS) during female gametophyte development. Our data establish a molecular pathway regulating the FG5 transition and implicates CKI1-dependent TCS in the promotion of cellularization, differentiation, and gamete specification during female gametogenesis. PMID- 24068956 TI - MEIOB targets single-strand DNA and is necessary for meiotic recombination. AB - Meiotic recombination is a mandatory process for sexual reproduction. We identified a protein specifically implicated in meiotic homologous recombination that we named: meiosis specific with OB domain (MEIOB). This protein is conserved among metazoan species and contains single-strand DNA binding sites similar to those of RPA1. Our studies in vitro revealed that both recombinant and endogenous MEIOB can be retained on single-strand DNA. Those in vivo demonstrated the specific expression of Meiob in early meiotic germ cells and the co-localization of MEIOB protein with RPA on chromosome axes. MEIOB localization in Dmc1 (-/-) spermatocytes indicated that it accumulates on resected DNA. Homologous Meiob deletion in mice caused infertility in both sexes, due to a meiotic arrest at a zygotene/pachytene-like stage. DNA double strand break repair and homologous chromosome synapsis were impaired in Meiob (-/-) meiocytes. Interestingly MEIOB appeared to be dispensable for the initial loading of recombinases but was required to maintain a proper number of RAD51 and DMC1 foci beyond the zygotene stage. In light of these findings, we propose that RPA and this new single-strand DNA binding protein MEIOB, are essential to ensure the proper stabilization of recombinases which is required for successful homology search and meiotic recombination. PMID- 24068958 TI - Chromatin-specific regulation of mammalian rDNA transcription by clustered TTF-I binding sites. AB - Enhancers and promoters often contain multiple binding sites for the same transcription factor, suggesting that homotypic clustering of binding sites may serve a role in transcription regulation. Here we show that clustering of binding sites for the transcription termination factor TTF-I downstream of the pre-rRNA coding region specifies transcription termination, increases the efficiency of transcription initiation and affects the three-dimensional structure of rRNA genes. On chromatin templates, but not on free rDNA, clustered binding sites promote cooperative binding of TTF-I, loading TTF-I to the downstream terminators before it binds to the rDNA promoter. Interaction of TTF-I with target sites upstream and downstream of the rDNA transcription unit connects these distal DNA elements by forming a chromatin loop between the rDNA promoter and the terminators. The results imply that clustered binding sites increase the binding affinity of transcription factors in chromatin, thus influencing the timing and strength of DNA-dependent processes. PMID- 24068957 TI - MicroRNA-17-92, a direct Ap-2alpha transcriptional target, modulates T-box factor activity in orofacial clefting. AB - Among the most common human congenital anomalies, cleft lip and palate (CL/P) affects up to 1 in 700 live births. MicroRNA (miR)s are small, non-coding RNAs that repress gene expression post-transcriptionally. The miR-17-92 cluster encodes six miRs that have been implicated in human cancers and heart development. We discovered that miR-17-92 mutant embryos had severe craniofacial phenotypes, including incompletely penetrant CL/P and mandibular hypoplasia. Embryos that were compound mutant for miR-17-92 and the related miR-106b-25 cluster had completely penetrant CL/P. Expression of Tbx1 and Tbx3, the DiGeorge/velo-cardio-facial (DGS) and Ulnar-mammary syndrome (UMS) disease genes, was expanded in miR-17-92 mutant craniofacial structures. Both Tbx1 and Tbx3 had functional miR seed sequences that mediated gene repression. Analysis of miR-17 92 regulatory regions uncovered conserved and functional AP-2alpha recognition elements that directed miR-17-92 expression. Together, our data indicate that miR 17-92 modulates expression of critical T-box transcriptional regulators during midface development and is itself a target of Bmp-signaling and the craniofacial pioneer factor AP-2alpha. Our data are the first genetic evidence that an individual miR or miR cluster is functionally important in mammalian CL/P. PMID- 24068959 TI - System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity. AB - Many fibroblast-secreted proteins promote tumorigenicity, and several factors secreted by cancer cells have in turn been proposed to induce these proteins. It is not clear whether there are single dominant pathways underlying these interactions or whether they involve multiple pathways acting in parallel. Here, we identified 42 fibroblast-secreted factors induced by breast cancer cells using comparative genomic analysis. To determine what fraction was active in promoting tumorigenicity, we chose five representative fibroblast-secreted factors for in vivo analysis. We found that the majority (three out of five) played equally major roles in promoting tumorigenicity, and intriguingly, each one had distinct effects on the tumor microenvironment. Specifically, fibroblast-secreted amphiregulin promoted breast cancer cell survival, whereas the chemokine CCL7 stimulated tumor cell proliferation while CCL2 promoted innate immune cell infiltration and angiogenesis. The other two factors tested had minor (CCL8) or minimally (STC1) significant effects on the ability of fibroblasts to promote tumor growth. The importance of parallel interactions between fibroblasts and cancer cells was tested by simultaneously targeting fibroblast-secreted amphiregulin and the CCL7 receptor on cancer cells, and this was significantly more efficacious than blocking either pathway alone. We further explored the concept of parallel interactions by testing the extent to which induction of critical fibroblast-secreted proteins could be achieved by single, previously identified, factors produced by breast cancer cells. We found that although single factors could induce a subset of genes, even combinations of factors failed to induce the full repertoire of functionally important fibroblast secreted proteins. Together, these results delineate a complex network of tumor fibroblast interactions that act in parallel to promote tumorigenicity and suggest that effective anti-stromal therapeutic strategies will need to be multi targeted. PMID- 24068960 TI - miR-1/133a clusters cooperatively specify the cardiomyogenic lineage by adjustment of myocardin levels during embryonic heart development. AB - miRNAs are small RNAs directing many developmental processes by posttranscriptional regulation of protein-coding genes. We uncovered a new role for miR-1-1/133a-2 and miR-1-2/133a-1 clusters in the specification of embryonic cardiomyocytes allowing transition from an immature state characterized by expression of smooth muscle (SM) genes to a more mature fetal phenotype. Concomitant knockout of miR-1-1/133a-2 and miR-1-2/133a-1 released suppression of the transcriptional co-activator myocardin, a major regulator of SM gene expression, but not of its binding partner SRF. Overexpression of myocardin in the embryonic heart essentially recapitulated the miR-1/133a mutant phenotype at the molecular level, arresting embryonic cardiomyocytes in an immature state. Interestingly, the majority of postulated miR-1/133a targets was not altered in double mutant mice, indicating that the ability of miR-1/133a to suppress target molecules strongly depends on the cellular context. Finally, we show that myocardin positively regulates expression of miR-1/133a, thus constituting a negative feedback loop that is essential for early cardiac development. PMID- 24068961 TI - The condition-dependent transcriptional landscape of Burkholderia pseudomallei. AB - Burkholderia pseudomallei (Bp), the causative agent of the often-deadly infectious disease melioidosis, contains one of the largest prokaryotic genomes sequenced to date, at 7.2 Mb with two large circular chromosomes (1 and 2). To comprehensively delineate the Bp transcriptome, we integrated whole-genome tiling array expression data of Bp exposed to >80 diverse physical, chemical, and biological conditions. Our results provide direct experimental support for the strand-specific expression of 5,467 Sanger protein-coding genes, 1,041 operons, and 766 non-coding RNAs. A large proportion of these transcripts displayed condition-dependent expression, consistent with them playing functional roles. The two Bp chromosomes exhibited dramatically different transcriptional landscapes--Chr 1 genes were highly and constitutively expressed, while Chr 2 genes exhibited mosaic expression where distinct subsets were expressed in a strongly condition-dependent manner. We identified dozens of cis-regulatory motifs associated with specific condition-dependent expression programs, and used the condition compendium to elucidate key biological processes associated with two complex pathogen phenotypes--quorum sensing and in vivo infection. Our results demonstrate the utility of a Bp condition-compendium as a community resource for biological discovery. Moreover, the observation that significant portions of the Bp virulence machinery can be activated by specific in vitro cues provides insights into Bp's capacity as an "accidental pathogen", where genetic pathways used by the bacterium to survive in environmental niches may have also facilitated its ability to colonize human hosts. PMID- 24068963 TI - A Link between ORC-origin binding mechanisms and origin activation time revealed in budding yeast. AB - Eukaryotic DNA replication origins are selected in G1-phase when the origin recognition complex (ORC) binds chromosomal positions and triggers molecular events culminating in the initiation of DNA replication (a.k.a. origin firing) during S-phase. Each chromosome uses multiple origins for its duplication, and each origin fires at a characteristic time during S-phase, creating a cell-type specific genome replication pattern relevant to differentiation and genome stability. It is unclear whether ORC-origin interactions are relevant to origin activation time. We applied a novel genome-wide strategy to classify origins in the model eukaryote Saccharomyces cerevisiae based on the types of molecular interactions used for ORC-origin binding. Specifically, origins were classified as DNA-dependent when the strength of ORC-origin binding in vivo could be explained by the affinity of ORC for origin DNA in vitro, and, conversely, as 'chromatin-dependent' when the ORC-DNA interaction in vitro was insufficient to explain the strength of ORC-origin binding in vivo. These two origin classes differed in terms of nucleosome architecture and dependence on origin-flanking sequences in plasmid replication assays, consistent with local features of chromatin promoting ORC binding at 'chromatin-dependent' origins. Finally, the 'chromatin-dependent' class was enriched for origins that fire early in S-phase, while the DNA-dependent class was enriched for later firing origins. Conversely, the latest firing origins showed a positive association with the ORC-origin DNA paradigm for normal levels of ORC binding, whereas the earliest firing origins did not. These data reveal a novel association between ORC-origin binding mechanisms and the regulation of origin activation time. PMID- 24068962 TI - Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. AB - Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E 11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis. PMID- 24068964 TI - N-acetylglucosamine (GlcNAc) triggers a rapid, temperature-responsive morphogenetic program in thermally dimorphic fungi. AB - The monosaccharide N-acetylglucosamine (GlcNAc) is a major component of microbial cell walls and is ubiquitous in the environment. GlcNAc stimulates developmental pathways in the fungal pathogen Candida albicans, which is a commensal organism that colonizes the mammalian gut and causes disease in the setting of host immunodeficiency. Here we investigate GlcNAc signaling in thermally dimorphic human fungal pathogens, a group of fungi that are highly evolutionarily diverged from C. albicans and cause disease even in healthy individuals. These soil organisms grow as polarized, multicellular hyphal filaments that transition into a unicellular, pathogenic yeast form when inhaled by a human host. Temperature is the primary environmental cue that promotes reversible cellular differentiation into either yeast or filaments; however, a shift to a lower temperature in vitro induces filamentous growth in an inefficient and asynchronous manner. We found GlcNAc to be a potent and specific inducer of the yeast-to-filament transition in two thermally dimorphic fungi, Histoplasma capsulatum and Blastomyces dermatitidis. In addition to increasing the rate of filamentous growth, micromolar concentrations of GlcNAc induced a robust morphological transition of H. capsulatum after temperature shift that was independent of GlcNAc catabolism, indicating that fungal cells sense GlcNAc to promote filamentation. Whole-genome expression profiling to identify candidate genes involved in establishing the filamentous growth program uncovered two genes encoding GlcNAc transporters, NGT1 and NGT2, that were necessary for H. capsulatum cells to robustly filament in response to GlcNAc. Unexpectedly, NGT1 and NGT2 were important for efficient H. capsulatum yeast-to-filament conversion in standard glucose medium, suggesting that Ngt1 and Ngt2 monitor endogenous levels of GlcNAc to control multicellular filamentous growth in response to temperature. Overall, our work indicates that GlcNAc functions as a highly conserved cue of morphogenesis in fungi, which further enhances the significance of this ubiquitous sugar in cellular signaling in eukaryotes. PMID- 24068965 TI - Mitochondrial transcription terminator family members mTTF and mTerf5 have opposing roles in coordination of mtDNA synthesis. AB - All genomes require a system for avoidance or handling of collisions between the machineries of DNA replication and transcription. We have investigated the roles in this process of the mTERF (mitochondrial transcription termination factor) family members mTTF and mTerf5 in Drosophila melanogaster. The two mTTF binding sites in Drosophila mtDNA, which also bind mTerf5, were found to coincide with major sites of replication pausing. RNAi-mediated knockdown of either factor resulted in mtDNA depletion and developmental arrest. mTTF knockdown decreased site-specific replication pausing, but led to an increase in replication stalling and fork regression in broad zones around each mTTF binding site. Lagging-strand DNA synthesis was impaired, with extended RNA/DNA hybrid segments seen in replication intermediates. This was accompanied by the accumulation of recombination intermediates and nicked/broken mtDNA species. Conversely, mTerf5 knockdown led to enhanced replication pausing at mTTF binding sites, a decrease in fragile replication intermediates containing single-stranded segments, and the disappearance of species containing segments of RNA/DNA hybrid. These findings indicate an essential and previously undescribed role for proteins of the mTERF family in the integration of transcription and DNA replication, preventing unregulated collisions and facilitating productive interactions between the two machineries that are inferred to be essential for completion of lagging-strand DNA synthesis. PMID- 24068966 TI - PAQR-2 regulates fatty acid desaturation during cold adaptation in C. elegans. AB - C. elegans PAQR-2 is homologous to the insulin-sensitizing adiponectin receptors in mammals, and essential for adaptation to growth at 15 degrees C, a low but usually acceptable temperature for this organism. By screening for novel paqr-2 suppressors, we identified mutations in genes involved in phosphatidylcholine synthesis (cept-1, pcyt-1 and sams-1) and fatty acid metabolism (ech-7, hacd-1, mdt-15, nhr-49 and sbp-1). We then show genetic evidence that paqr-2, phosphatidylcholines, sbp-1 and Delta9-desaturases form a cold adaptation pathway that regulates the increase in unsaturated fatty acids necessary to retain membrane fluidity at low temperatures. This model is supported by the observations that the paqr-2 suppressors normalize the levels of saturated fatty acids, and that low concentrations of detergents that increase membrane fluidity can rescue the paqr-2 mutant. PMID- 24068967 TI - Tracking of chromosome and replisome dynamics in Myxococcus xanthus reveals a novel chromosome arrangement. AB - Cells closely coordinate cell division with chromosome replication and segregation; however, the mechanisms responsible for this coordination still remain largely unknown. Here, we analyzed the spatial arrangement and temporal dynamics of the 9.1 Mb circular chromosome in the rod-shaped cells of Myxococcus xanthus. For chromosome segregation, M. xanthus uses a parABS system, which is essential, and lack of ParB results in chromosome segregation defects as well as cell divisions over nucleoids and the formation of anucleate cells. From the determination of the dynamic subcellular location of six genetic loci, we conclude that in newborn cells ori, as monitored following the ParB/parS complex, and ter regions are localized in the subpolar regions of the old and new cell pole, respectively and each separated from the nearest pole by approximately 1 um. The bulk of the chromosome is arranged between the two subpolar regions, thus leaving the two large subpolar regions devoid of DNA. Upon replication, one ori region remains in the original subpolar region while the second copy segregates unidirectionally to the opposite subpolar region followed by the rest of the chromosome. In parallel, the ter region of the mother chromosome relocates, most likely passively, to midcell, where it is replicated. Consequently, after completion of replication and segregation, the two chromosomes show an ori-ter ter-ori arrangement with mirror symmetry about a transverse axis at midcell. Upon completion of segregation of the ParB/parS complex, ParA localizes in large patches in the DNA-free subpolar regions. Using an Ssb-YFP fusion as a proxy for replisome localization, we observed that the two replisomes track independently of each other from a subpolar region towards ter. We conclude that M. xanthus chromosome arrangement and dynamics combine features from previously described systems with new features leading to a novel spatiotemporal arrangement pattern. PMID- 24068968 TI - Genotype-environment interactions reveal causal pathways that mediate genetic effects on phenotype. AB - Unraveling the molecular processes that lead from genotype to phenotype is crucial for the understanding and effective treatment of genetic diseases. Knowledge of the causative genetic defect most often does not enable treatment; therefore, causal intermediates between genotype and phenotype constitute valuable candidates for molecular intervention points that can be therapeutically targeted. Mapping genetic determinants of gene expression levels (also known as expression quantitative trait loci or eQTL studies) is frequently used for this purpose, yet distinguishing causation from correlation remains a significant challenge. Here, we address this challenge using extensive, multi-environment gene expression and fitness profiling of hundreds of genetically diverse yeast strains, in order to identify truly causal intermediate genes that condition fitness in a given environment. Using functional genomics assays, we show that the predictive power of eQTL studies for inferring causal intermediate genes is poor unless performed across multiple environments. Surprisingly, although the effects of genotype on fitness depended strongly on environment, causal intermediates could be most reliably predicted from genetic effects on expression present in all environments. Our results indicate a mechanism explaining this apparent paradox, whereby immediate molecular consequences of genetic variation are shared across environments, and environment-dependent phenotypic effects result from downstream integration of environmental signals. We developed a statistical model to predict causal intermediates that leverages this insight, yielding over 400 transcripts, for the majority of which we experimentally validated their role in conditioning fitness. Our findings have implications for the design and analysis of clinical omics studies aimed at discovering personalized targets for molecular intervention, suggesting that inferring causation in a single cellular context can benefit from molecular profiling in multiple contexts. PMID- 24068969 TI - N-alpha-terminal acetylation of histone H4 regulates arginine methylation and ribosomal DNA silencing. AB - Post-translational modifications of histones play a key role in DNA-based processes, like transcription, by modulating chromatin structure. N-terminal acetylation is unique among the numerous histone modifications because it is deposited on the N-alpha amino group of the first residue instead of the side chain of amino acids. The function of this modification and its interplay with other internal histone marks has not been previously addressed. Here, we identified N-terminal acetylation of H4 (N-acH4) as a novel regulator of arginine methylation and chromatin silencing in Saccharomyces cerevisiae. Lack of the H4 N alpha acetyltransferase (Nat4) activity results specifically in increased deposition of asymmetric dimethylation of histone H4 arginine 3 (H4R3me2a) and in enhanced ribosomal-DNA silencing. Consistent with this, H4 N-terminal acetylation impairs the activity of the Hmt1 methyltransferase towards H4R3 in vitro. Furthermore, combinatorial loss of N-acH4 with internal histone acetylation at lysines 5, 8 and 12 has a synergistic induction of H4R3me2a deposition and rDNA silencing that leads to a severe growth defect. This defect is completely rescued by mutating arginine 3 to lysine (H4R3K), suggesting that abnormal deposition of a single histone modification, H4R3me2a, can impact on cell growth. Notably, the cross-talk between N-acH4 and H4R3me2a, which regulates rDNA silencing, is induced under calorie restriction conditions. Collectively, these findings unveil a molecular and biological function for H4 N-terminal acetylation, identify its interplay with internal histone modifications, and provide general mechanistic implications for N-alpha-terminal acetylation, one of the most common protein modifications in eukaryotes. PMID- 24068970 TI - A genome-wide systematic analysis reveals different and predictive proliferation expression signatures of cancerous vs. non-cancerous cells. AB - Understanding cell proliferation mechanisms has been a long-lasting goal of the scientific community and specifically of cancer researchers. Previous genome scale studies of cancer proliferation determinants have mainly relied on knockdown screens aimed to gauge their effects on cancer growth. This powerful approach has several limitations such as off-target effects, partial knockdown, and masking effects due to functional backups. Here we employ a complementary approach and assign each gene a cancer Proliferation Index (cPI) that quantifies the association between its expression levels and growth rate measurements across 60 cancer cell lines. Reassuringly, genes found essential in cancer gene knockdown screens exhibit significant positive cPI values, while tumor suppressors exhibit significant negative cPI values. Cell cycle, DNA replication, splicing and protein production related processes are positively associated with cancer proliferation, while cellular migration is negatively associated with it - in accordance with the well known "go or grow" dichotomy. A parallel analysis of genes' non-cancerous proliferation indices (nPI) across 224 lymphoblastoid cell lines reveals surprisingly marked differences between cancerous and non-cancerous proliferation. These differences highlight genes in the translation and spliceosome machineries as selective cancer proliferation-associated proteins. A cross species comparison reveals that cancer proliferation resembles that of microorganisms while non-cancerous proliferation does not. Furthermore, combining cancerous and non-cancerous proliferation signatures leads to enhanced prediction of patient outcome and gene essentiality in cancer. Overall, these results point to an inherent difference between cancerous and non-cancerous proliferation determinants, whose understanding may contribute to the future development of novel cancer-specific anti-proliferative drugs. PMID- 24068971 TI - Predicting the risk of rheumatoid arthritis and its age of onset through modelling genetic risk variants with smoking. AB - The improved characterisation of risk factors for rheumatoid arthritis (RA) suggests they could be combined to identify individuals at increased disease risks in whom preventive strategies may be evaluated. We aimed to develop an RA prediction model capable of generating clinically relevant predictive data and to determine if it better predicted younger onset RA (YORA). Our novel modelling approach combined odds ratios for 15 four-digit/10 two-digit HLA-DRB1 alleles, 31 single nucleotide polymorphisms (SNPs) and ever-smoking status in males to determine risk using computer simulation and confidence interval based risk categorisation. Only males were evaluated in our models incorporating smoking as ever-smoking is a significant risk factor for RA in men but not women. We developed multiple models to evaluate each risk factor's impact on prediction. Each model's ability to discriminate anti-citrullinated protein antibody (ACPA) positive RA from controls was evaluated in two cohorts: Wellcome Trust Case Control Consortium (WTCCC: 1,516 cases; 1,647 controls); UK RA Genetics Group Consortium (UKRAGG: 2,623 cases; 1,500 controls). HLA and smoking provided strongest prediction with good discrimination evidenced by an HLA-smoking model area under the curve (AUC) value of 0.813 in both WTCCC and UKRAGG. SNPs provided minimal prediction (AUC 0.660 WTCCC/0.617 UKRAGG). Whilst high individual risks were identified, with some cases having estimated lifetime risks of 86%, only a minority overall had substantially increased odds for RA. High risks from the HLA model were associated with YORA (P<0.0001); ever-smoking associated with older onset disease. This latter finding suggests smoking's impact on RA risk manifests later in life. Our modelling demonstrates that combining risk factors provides clinically informative RA prediction; additionally HLA and smoking status can be used to predict the risk of younger and older onset RA, respectively. PMID- 24068972 TI - Phenotypic and genetic consequences of protein damage. AB - Although the genome contains all the information necessary for maintenance and perpetuation of life, it is the proteome that repairs, duplicates and expresses the genome and actually performs most cellular functions. Here we reveal strong phenotypes of physiological oxidative proteome damage at the functional and genomic levels. Genome-wide mutations rates and biosynthetic capacity were monitored in real time, in single Escherichia coli cells with identical levels of reactive oxygen species and oxidative DNA damage, but with different levels of irreversible oxidative proteome damage (carbonylation). Increased protein carbonylation correlates with a mutator phenotype, whereas reducing it below wild type level produces an anti-mutator phenotype identifying proteome damage as the leading cause of spontaneous mutations. Proteome oxidation elevates also UV-light induced mutagenesis and impairs cellular biosynthesis. In conclusion, protein damage reduces the efficacy and precision of vital cellular processes resulting in high mutation rates and functional degeneracy akin to cellular aging. PMID- 24068973 TI - The molecular mechanism of a cis-regulatory adaptation in yeast. AB - Despite recent advances in our ability to detect adaptive evolution involving the cis-regulation of gene expression, our knowledge of the molecular mechanisms underlying these adaptations has lagged far behind. Across all model organisms, the causal mutations have been discovered for only a handful of gene expression adaptations, and even for these, mechanistic details (e.g. the trans-regulatory factors involved) have not been determined. We previously reported a polygenic gene expression adaptation involving down-regulation of the ergosterol biosynthesis pathway in the budding yeast Saccharomyces cerevisiae. Here we investigate the molecular mechanism of a cis-acting mutation affecting a member of this pathway, ERG28. We show that the causal mutation is a two-base deletion in the promoter of ERG28 that strongly reduces the binding of two transcription factors, Sok2 and Mot3, thus abolishing their regulation of ERG28. This down regulation increases resistance to a widely used antifungal drug targeting ergosterol, similar to mutations disrupting this pathway in clinical yeast isolates. The identification of the causal genetic variant revealed that the selection likely occurred after the deletion was already present at high frequency in the population, rather than when it was a new mutation. These results provide a detailed view of the molecular mechanism of a cis-regulatory adaptation, and underscore the importance of this view to our understanding of evolution at the molecular level. PMID- 24068974 TI - dTULP, the Drosophila melanogaster homolog of tubby, regulates transient receptor potential channel localization in cilia. AB - Mechanically gated ion channels convert sound into an electrical signal for the sense of hearing. In Drosophila melanogaster, several transient receptor potential (TRP) channels have been implicated to be involved in this process. TRPN (NompC) and TRPV (Inactive) channels are localized in the distal and proximal ciliary zones of auditory receptor neurons, respectively. This segregated ciliary localization suggests distinct roles in auditory transduction. However, the regulation of this localization is not fully understood. Here we show that the Drosophila Tubby homolog, King tubby (hereafter called dTULP) regulates ciliary localization of TRPs. dTULP-deficient flies show uncoordinated movement and complete loss of sound-evoked action potentials. Inactive and NompC are mislocalized in the cilia of auditory receptor neurons in the dTulp mutants, indicating that dTULP is required for proper cilia membrane protein localization. This is the first demonstration that dTULP regulates TRP channel localization in cilia, and suggests that dTULP is a protein that regulates ciliary neurosensory functions. PMID- 24068975 TI - Fragile site instability in Saccharomyces cerevisiae causes loss of heterozygosity by mitotic crossovers and break-induced replication. AB - Loss of heterozygosity (LOH) at tumor suppressor loci is a major contributor to cancer initiation and progression. Both deletions and mitotic recombination can lead to LOH. Certain chromosomal loci known as common fragile sites are susceptible to DNA lesions under replication stress, and replication stress is prevalent in early stage tumor cells. There is extensive evidence for deletions stimulated by common fragile sites in tumors, but the role of fragile sites in stimulating mitotic recombination that causes LOH is unknown. Here, we have used the yeast model system to study the relationship between fragile site instability and mitotic recombination that results in LOH. A naturally occurring fragile site, FS2, exists on the right arm of yeast chromosome III, and we have analyzed LOH on this chromosome. We report that the frequency of spontaneous mitotic BIR events resulting in LOH on the right arm of yeast chromosome III is higher than expected, and that replication stress by low levels of polymerase alpha increases mitotic recombination 12-fold. Using single-nucleotide polymorphisms between the two chromosome III homologs, we mapped the locations of recombination events and determined that FS2 is a strong hotspot for both mitotic reciprocal crossovers and break-induced replication events under conditions of replication stress. PMID- 24068977 TI - SKN-1/Nrf, a new unfolded protein response factor? PMID- 24068978 TI - Microwave Assisted Rapid and Green Synthesis of Silver Nanoparticles Using a Pigment Produced by Streptomyces coelicolor klmp33. AB - Traditional synthesis of silver nanoparticles using chemical methods produces toxic substances. In contrast biological synthesis is regarded as a safe and nontoxic process but the major drawback of biological synthesis is, this process is slow. In the present investigation, we developed a rapid and green synthesis of silver nanoparticles employing a pigment produced by Streptomyces coelicolor klmp33 in just 90 s. The silver nanoparticles were characterized by UV-visible spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). The biobased synthesis developed in this method is a safe, rapid, and appropriate way for bulky synthesis of silver nanoparticles. PMID- 24068979 TI - 10 Years of German Medical Science. PMID- 24068976 TI - The genome and development-dependent transcriptomes of Pyronema confluens: a window into fungal evolution. AB - Fungi are a large group of eukaryotes found in nearly all ecosystems. More than 250 fungal genomes have already been sequenced, greatly improving our understanding of fungal evolution, physiology, and development. However, for the Pezizomycetes, an early-diverging lineage of filamentous ascomycetes, there is so far only one genome available, namely that of the black truffle, Tuber melanosporum, a mycorrhizal species with unusual subterranean fruiting bodies. To help close the sequence gap among basal filamentous ascomycetes, and to allow conclusions about the evolution of fungal development, we sequenced the genome and assayed transcriptomes during development of Pyronema confluens, a saprobic Pezizomycete with a typical apothecium as fruiting body. With a size of 50 Mb and ~13,400 protein-coding genes, the genome is more characteristic of higher filamentous ascomycetes than the large, repeat-rich truffle genome; however, some typical features are different in the P. confluens lineage, e.g. the genomic environment of the mating type genes that is conserved in higher filamentous ascomycetes, but only partly conserved in P. confluens. On the other hand, P. confluens has a full complement of fungal photoreceptors, and expression studies indicate that light perception might be similar to distantly related ascomycetes and, thus, represent a basic feature of filamentous ascomycetes. Analysis of spliced RNA-seq sequence reads allowed the detection of natural antisense transcripts for 281 genes. The P. confluens genome contains an unusually high number of predicted orphan genes, many of which are upregulated during sexual development, consistent with the idea of rapid evolution of sex-associated genes. Comparative transcriptomics identified the transcription factor gene pro44 that is upregulated during development in P. confluens and the Sordariomycete Sordaria macrospora. The P. confluens pro44 gene (PCON_06721) was used to complement the S. macrospora pro44 deletion mutant, showing functional conservation of this developmental regulator. PMID- 24068981 TI - Computational and experimental approaches to the molecular structure of the HCl adduct of Me3PO. AB - The reaction of anhydrous HCl(g) with trimethyl phosphane oxide yields trimethylhydroxy phosphonium chloride. A crystal structure analysis showed that the prevalent mesomeric structure in the solid state is the phosphonium chloride ion pair. Ab initio calculations in the gas phase cannot reproduce these findings, whereas higher correlated methods (CISD) and solvation models predict the experimental structure correctly. PMID- 24068980 TI - Actinobacillus equuli ssp. haemolyticus in a semi-occlusively treated horse bite wound in a 2-year-old girl. AB - We report on the isolation of Actinobacillus equuli ssp. haemolyticus from wound smears of a 2-year-old girl who was admitted to the hospital due to partial amputation of the distal phalanx of her right middle finger caused by a horse bite. A. equuli typically causes diseases in horses and only very few reports describing human infections (mostly associated with wounds) are available in the literature. Interestingly, although the bacteria could be found in consecutive samples taken at different points in time, there were no signs of advancing infection or inflammation. Moreover, the fingertip regenerated after 74 days under semi-occlusive dressings with very pleasant results. For strain identification two automated systems were employed producing discrepant results: VITEK 2 described the pathogens as Pasteurella pneumotropica while MALDI-TOF MS analysis revealed A. equuli. Sequence analysis of 16S rDNA gene finally confirmed A. equuli ssp. haemolyticus as the isolated strain. The antimicrobial susceptibility testing was performed according to the CLSI criteria for Pasteurella spp. Additionally we conducted a test according to the EUCAST criteria. PMID- 24068982 TI - A BMI-based occupational therapy assist suit: asynchronous control by SSVEP. AB - A brain-machine interface (BMI) is an interface technology that uses neurophysiological signals from the brain to control external machines. Recent invasive BMI technologies have succeeded in the asynchronous control of robot arms for a useful series of actions, such as reaching and grasping. In this study, we developed non-invasive BMI technologies aiming to make such useful movements using the subject's own hands by preparing a BMI-based occupational therapy assist suit (BOTAS). We prepared a pre-recorded series of useful actions a grasping-a-ball movement and a carrying-the-ball movement-and added asynchronous control using steady-state visual evoked potential (SSVEP) signals. A SSVEP signal was used to trigger the grasping-a-ball movement and another SSVEP signal was used to trigger the carrying-the-ball movement. A support vector machine was used to classify EEG signals recorded from the visual cortex (Oz) in real time. Untrained, able-bodied participants (n = 12) operated the system successfully. Classification accuracy and time required for SSVEP detection were ~88% and 3 s, respectively. We further recruited three patients with upper cervical spinal cord injuries (SCIs); they also succeeded in operating the system without training. These data suggest that our BOTAS system is potentially useful in terms of rehabilitation of patients with upper limb disabilities. PMID- 24068983 TI - Improved genetically-encoded, FlincG-type fluorescent biosensors for neural cGMP imaging. AB - Genetically-encoded biosensors are powerful tools for understanding cellular signal transduction mechanisms. In aiming to investigate cGMP signaling in neurones using the EGFP-based fluorescent biosensor, FlincG (fluorescent indicator for cGMP), we encountered weak or non-existent fluorescence after attempted transfection with plasmid DNA, even in HEK293T cells. Adenoviral infection of HEK293T cells with FlincG, however, had previously proved successful. Both constructs were found to harbor a mutation in the EGFP domain and had a tail of 17 amino acids at the C-terminus that differed from the published sequence. These discrepancies were systematically examined, together with mutations found beneficial for the related GCaMP family of Ca(2+) biosensors, in a HEK293T cell line stably expressing both nitric oxide (NO) activated guanylyl cyclase and phosphodiesterase-5. Restoring the mutated amino acid improved basal fluorescence whereas additional restoration of the correct C terminal tail resulted in poor cGMP sensing as assessed by superfusion of either 8-bromo-cGMP or NO. Ultimately, two improved FlincGs were identified: one (FlincG2) had the divergent tail and gave moderate basal fluorescence and cGMP response amplitude and the other (FlincG3) had the correct tail, a GCaMP-like mutation in the EGFP region and an N-terminal tag, and was superior in both respects. All variants tested were strongly influenced by pH over the physiological range, in common with other EGFP-based biosensors. Purified FlincG3 protein exhibited a lower cGMP affinity (0.89 MUM) than reported for the original FlincG (0.17 MUM) but retained rapid kinetics and a 230-fold selectivity over cAMP. Successful expression of FlincG2 or FlincG3 in differentiated N1E-115 neuroblastoma cells and in primary cultures of hippocampal and dorsal root ganglion cells commends them for real-time imaging of cGMP dynamics in neural (and other) cells, and in their subcellular specializations. PMID- 24068984 TI - Plasmid-based target protectors allow specific blockade of miRNA silencing activity in mammalian developmental systems. AB - Over the past decade, microRNAs (miRNAs) have emerged as essential posttranscriptional regulators of gene expression. Though a great deal has been discovered about miRNA genomics, biogenesis, mechanisms, and functions, the challenge of attributing phenotypes of altered miRNA expression to specific targets still remains. Here, we apply the existing target protector concept of blocking miRNA action at a single binding site in the 3'untranslated region (3'UTR) of its target to a plasmid-based approach. We optimize and demonstrate target protector efficacy in vitro, where it blocks repression of a luciferase construct and an endogenous protein. Using the developing mouse cortex as a model, we validate that target protectors are effective in vivo, where protectors for the miR-19a binding sites in the Pten 3'UTR alter proliferation and specification of neural progenitors, phenocopying Pten ectopic expression phenotypes. Our study introduces a new tool for analyzing specific miRNA:target interactions across mammalian developmental systems, facilitating further miRNA functional discoveries. PMID- 24068985 TI - C9orf72 mutation is rare in Alzheimer's disease, Parkinson's disease, and essential tremor in China. AB - GGGGCC repeat expansions in the C9orf72 gene have been identified as a major contributing factor in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Given the overlapping of clinical phenotypes and pathological characteristics between these two diseases and Alzheimer's disease (AD), Parkinson's disease (PD), and essential tremor (ET), we speculated regarding whether C9orf72 repeat expansions also play a major role in these three diseases. Using the repeat-primed polymerase chain reaction method, we screened for C9orf72 in three groups of patients with PD (n = 911), AD (n = 279), and ET (n = 152) in the Chinese Han population. There were no pathogenic repeats (>30 repeats) detected in either the patients or controls (n = 314), which indicated that the pathogenic expansions of C9orf72 might be rare in these three diseases. However, the analysis of the association between the number of repeats (p = 0.001), short/intermediate genotype (short: <7 repeats; intermediate: >=7 repeats) (odds ratio 1.37 [1.05, 1.79]), intermediate/intermediate genotype (Odds ratio 2.03 [1.17, 3.54]), and PD risks indicated that intermediate repeat alleles could act as contributors to PD. To the best of our knowledge, this study is the first to reveal the correlation between C9orf72 and Chinese PD, AD, or ET patients. Additionally, the results of this study suggest the novel idea that the intermediate repeat allele in C9orf72 is most likely a risk factor for PD. PMID- 24068986 TI - Release properties of individual presynaptic boutons expressed during homosynaptic depression and heterosynaptic facilitation of the Aplysia sensorimotor synapse. AB - Much of what we know about the mechanisms underlying Homosynaptic Depression (HSD) and heterosynaptic facilitation is based on intracellular recordings of integrated postsynaptic potentials (PSPs). This methodological approach views the presynaptic apparatus as a single compartment rather than taking a more realistic representation reflecting the fact that it is made up of tens to hundreds of individual and independent Presynaptic Release Boutons (PRBs). Using cultured Aplysia sensorimotor synapses, we reexamined HSD and its dishabituation by imaging the release properties of individual PRBs. We find that the PRB population is heterogeneous and can be clustered into three groups: ~25% of the PRBs consistently release neurotransmitter throughout the entire habituation paradigm (35 stimuli, 0.05 Hz) and have a relatively high quantal content, 36% of the PRBs display intermittent failures only after the tenth stimulation, and 39% are low quantal-content PRBs that exhibit intermittent release failures from the onset of the habituation paradigm. 5HT-induced synaptic dishabituation by a single 5HT application was generated by the enhanced recovery of the quantal content of the habituated PRBs and did not involve the recruitment of new release boutons. The characterization of the PRB population as heterogeneous in terms of its temporal pattern of release-probability and quantal content provides new insights into the mechanisms underlying HSD and its dishabituation. PMID- 24068987 TI - Target dependence of orientation and direction selectivity of corticocortical projection neurons in the mouse V1. AB - Higher order visual areas that receive input from the primary visual cortex (V1) are specialized for the processing of distinct features of visual information. However, it is still incompletely understood how this functional specialization is acquired. Here we used in vivo two photon calcium imaging in the mouse visual cortex to investigate whether this functional distinction exists at as early as the level of projections from V1 to two higher order visual areas, AL and LM. Specifically, we examined whether sharpness of orientation and direction selectivity and optimal spatial and temporal frequency of projection neurons from V1 to higher order visual areas match with that of target areas. We found that the V1 input to higher order visual areas were indeed functionally distinct: AL preferentially received inputs from V1 that were more orientation and direction selective and tuned for lower spatial frequency compared to projection of V1 to LM, consistent with functional differences between AL and LM. The present findings suggest that selective projections from V1 to higher order visual areas initiates parallel processing of sensory information in the visual cortical network. PMID- 24068988 TI - Glucocorticoid receptor activity regulates light adaptation in the zebrafish retina. AB - Glucocorticoids modulate diverse aspects of physiology and behavior, including energy homeostasis, stress response, and memory, through activation of the glucocorticoid receptor (GR). Light perception has profound effects on the production of glucocorticoids via functional connections of the retina to the hypothalamus-pituitary-adrenal axis. We report here that glucocorticoids can also signal in the reverse direction, i. e., regulate visual function in zebrafish, Danio rerio. The zebrafish GR mutant, gr (s357) , harbors a missense mutation that completely blocks the transcriptional activity of GR. In this mutant, visual behavior was abolished following a period of darkness and recovered sluggishly after return to the light. Electrophysiological measurements showed that the photoresponse of the dark-adapted retina was reduced in the mutant and re-adapted to light with a substantial delay. Several gene products, including some that are important for dopaminergic signaling, were misregulated in gr (s357) mutants. We suggest that GR controls a gene network required for visual adaptation in the zebrafish retina and potentially integrates neuroendocrine and sensory responses to environmental changes. PMID- 24068989 TI - Pain predictability reverses valence ratings of a relief-associated stimulus. AB - Relief from pain is positively valenced and entails reward-like properties. Notably, stimuli that became associated with pain relief elicit reward-like implicit responses too, but are explicitly evaluated by humans as aversive. Since the unpredictability of pain makes pain more aversive, this study examined the hypotheses that the predictability of pain also modulates the valence of relief associated stimuli. In two studies, we presented one conditioned stimulus (FORWARDCS+) before a painful unconditioned stimulus (US), another stimulus (BACKWARDCS+) after the painful US, and a third stimulus (CS-) was never associated with the US. In Study 1, FORWARDCS+ predicted half of the USs while the other half was delivered unwarned and followed by BACKWARDCS+. In Study 2, all USs were predicted by FORWARDCS+ and followed by BACKWARDCS+. In Study 1 both FORWARDCS+ and BACKWARDCS+ were rated as negatively valenced and high arousing after conditioning, while BACKWARDCS+ in Study 2 acquired positive valence and low arousal. Startle amplitude was significantly attenuated to BACKWARDCS+ compared to FORWARDCS+ in Study 2, but did not differ among CSs in Study 1. In summary, predictability of aversive events reverses the explicit valence of a relief-associated stimulus. PMID- 24068991 TI - Oblique effect in visual mismatch negativity. AB - We investigated whether visual orientation anisotropies (known as oblique effect) exist in non-attended visual changes using event-related potentials (ERP). We recorded visual mismatch negativity (vMMN) which signals violation of sequential regularities. In the visual periphery unattended, task-irrelevant Gabor patches were displayed in an oddball sequence while subjects performed a tracking task in the central field. A moderate change (50 degrees ) in the orientation of stimuli revealed no consistent change-related components. However, we found orientation related differences around 170 ms in occipito-temporal areas in the amplitude of the ERPs evoked by standard stimuli. In a supplementary experiment we determined the amount of orientation difference that is needed for change detection in an active, attended paradigm. Results exhibited the classical oblique effect; subjects detected 10 degrees deviations from cardinal directions, while threshold from oblique directions was 17 degrees . These results provide evidence that perception of change could be accomplished at significantly smaller thresholds, than what elicits vMMN. In Experiment 2 we increased the orientation change to 90 degrees . Deviant-minus-standard difference was negative in occipito parietal areas, between 120 and 200 ms after stimulus onset. VMMNs to changes from cardinal angles were larger and more sustained than vMMNs evoked by changes from oblique angles. Changes from cardinal orientations represent a more detectable signal for the automatic change detection system than changes from oblique angles, thus increased vMMN to these "larger" deviances might be considered a variant of the magnitude of deviance effect rarely observed in vMMN studies. PMID- 24068990 TI - Mindfulness-induced selflessness: a MEG neurophenomenological study. AB - Contemporary philosophical and neurocognitive studies of the self have dissociated two distinct types of self-awareness: a "narrative" self-awareness (NS) weaving together episodic memory, future planning and self-evaluation into a coherent self-narrative and identity, and a "minimal" self-awareness (MS) focused on present momentary experience and closely tied to the sense of agency and ownership. Long-term Buddhist meditation practice aims at realization of a "selfless" mode of awareness (SL), where identification with a static sense of self is replaced by identification with the phenomenon of experiencing itself. NS mediating mechanisms have been explored by neuroimaging, mainly fMRI, implicating prefrontal midline structures, but MS processes are not well characterized and SL even less so. To this end we tested 12 long-term mindfulness meditators using a neurophenomenological study design, incorporating both magnetoencephalogram (MEG) recordings and first person descriptions. We found that (1) NS attenuation involves extensive frontal, and medial prefrontal gamma band (60-80 Hz) power decreases, consistent with fMRI and intracranial EEG findings; (2) MS attenuation is related to beta-band (13-25 Hz) power decreases in a network that includes ventral medial prefrontal, medial posterior and lateral parietal regions; and (3) the experience of selflessness is linked to attenuation of beta-band activity in the right inferior parietal lobule. These results highlight the role of dissociable frequency-dependent networks in supporting different modes of self processing, and the utility of combining phenomenology, mindfulness training and electrophysiological neuroimaging for characterizing self-awareness. PMID- 24068992 TI - Relating spatial perspective taking to the perception of other's affordances: providing a foundation for predicting the future behavior of others. AB - Understanding what another agent can see relates functionally to the understanding of what they can do. We propose that spatial perspective taking and perceiving other's affordances, while two separate spatial processes, together share the common social function of predicting the behavior of others. Perceiving the action capabilities of others allows for a common understanding of how agents may act together. The ability to take another's perspective focuses an understanding of action goals so that more precise understanding of intentions may result. This review presents an analysis of these complementary abilities, both in terms of the frames of reference and the proposed sensorimotor mechanisms involved. Together, we argue for the importance of reconsidering the role of basic spatial processes to explain more complex behaviors. PMID- 24068993 TI - Resting-State Oscillatory Activity in Children Born Small for Gestational Age: An MEG Study. AB - Growth restriction in utero during a period that is critical for normal growth of the brain, has previously been associated with deviations in cognitive abilities and brain anatomical and functional changes. We measured magnetoencephalography (MEG) in 4- to 7-year-old children to test if children born small for gestational age (SGA) show deviations in resting-state brain oscillatory activity. Children born SGA with postnatally spontaneous catch-up growth [SGA+; six boys, seven girls; mean age 6.3 year (SD = 0.9)] and children born appropriate for gestational age [AGA; seven boys, three girls; mean age 6.0 year (SD = 1.2)] participated in a resting-state MEG study. We calculated absolute and relative power spectra and used non-parametric statistics to test for group differences. SGA+ and AGA born children showed no significant differences in absolute and relative power except for reduced absolute gamma band power in SGA children. At the time of MEG investigation, SGA+ children showed significantly lower head circumference (HC) and a trend toward lower IQ, however there was no association of HC or IQ with absolute or relative power. Except for reduced absolute gamma band power, our findings suggest normal brain activity patterns at school age in a group of children born SGA in which spontaneous catch-up growth of bodily length after birth occurred. Although previous findings suggest that being born SGA alters brain oscillatory activity early in neonatal life, we show that these neonatal alterations do not persist at early school age when spontaneous postnatal catch-up growth occurs after birth. PMID- 24068994 TI - Electrophysiological correlates of morphological processing in Chinese compound word recognition. AB - The present study investigated the electrophysiological correlates of morphological processing in Chinese compound word reading using a delayed repetition priming paradigm. Participants were asked to passively view lists of two-character compound words containing prime-target pairs separated by a few items. In a Whole Word repetition condition, the prime and target were the same real words (e.g., , manager-manager). In a Constituent repetition condition, the prime and target were swapped in terms of their constituent position (e.g., , the former is a pseudo-word and the later means nurse). Two ERP components including N200 and N400 showed repetition effects. The N200 showed a negative shift upon repetition in the Whole Word condition but this effect was delayed for the Constituent condition. The N400 showed comparable amplitude reduction across the two priming conditions. The results reveal different aspects of morphological processing with an early stage associated with N200 and a late stage with N400. There was also a possibility that the N200 effect reflect general cognitive processing, i.e., the detection of low-probability stimuli. PMID- 24068995 TI - The effect of transcranial direct current stimulation: a role for cortical excitation/inhibition balance? AB - Transcranial direct current stimulation (tDCS) is a promising tool for cognitive enhancement and neurorehabilitation in clinical disorders in both cognitive and clinical domains (e.g., chronic pain, tinnitus). Here we suggest the potential role of tDCS in modulating cortical excitation/inhibition (E/I) balance and thereby inducing improvements. We suggest that part of the mechanism of action of tDCS can be explained by non-invasive modulations of the E/I balance. PMID- 24068996 TI - Congruency of gaze metrics in action, imagery and action observation. AB - The aim of this paper is to provide a review of eye movements during action execution, action observation, and movement imagery. Furthermore, the paper highlights aspects of congruency in gaze metrics between these states. The implications of the imagery, observation, and action gaze congruency are discussed in terms of motor learning and rehabilitation. Future research directions are outlined in order to further the understanding of shared gaze metrics between overt and covert states. Suggestions are made for how researchers and practitioners can structure action observation and movement imagery interventions to maximize (re)learning. PMID- 24068997 TI - Ephaptic communication in the vertebrate retina. AB - In the vertebrate retina, cones project to the horizontal cells (HCs) and bipolar cells (BCs). The communication between cones and HCs uses both chemical and ephaptic mechanisms. Cones release glutamate in a Ca(2+)-dependent manner, while HCs feed back to cones via an ephaptic mechanism. Hyperpolarization of HCs leads to an increased current through connexin hemichannels located on the tips of HC dendrites invaginating the cone synaptic terminals. Due to the high resistance of the extracellular synaptic space, this current makes the synaptic cleft slightly negative. The result is that the Ca(2+)-channels in the cone presynaptic membrane experience a slightly depolarized membrane potential and therefore more glutamate is released. This ephaptic mechanism forms a very fast and noise free negative feedback pathway. These characteristics are crucial, since the retina has to perform well in demanding conditions such as low light levels. In this mini review we will discuss the critical components of such an ephaptic mechanism. Furthermore, we will address the question whether such communication appears in other systems as well and indicate some fundamental features to look for when attempting to identify an ephaptic mechanism. PMID- 24068998 TI - C-C chemokine receptor-7 mediated endocytosis of antibody cargoes into intact cells. AB - The C-C chemokine receptor-7 (CCR7) is a G protein coupled receptor that has a role in leukocyte homing, but that is also expressed in aggressive tumor cells. Preclinical research supports that CCR7 is a valid target in oncology. In view of the increasing availability of therapeutic monoclonal antibodies that carry cytotoxic cargoes, we studied the feasibility of forcing intact cells to internalize known monoclonal antibodies by exploiting the cycle of endocytosis and recycling triggered by the CCR7 agonist CCL19. Firstly, an anti-CCR7 antibody (CD197; clone 150503) labeled surface recombinant CCR7 expressed in intact HEK 293a cells and the fluorescent antibody was internalized following CCL19 treatment. Secondly, a recombinant myc-tagged CCL19 construction was exploited along the anti-myc monoclonal antibody 4A6. The myc-tagged ligand was produced as a conditioned medium of transfected HEK 293a cells that contained the equivalent of 430 ng/ml of immunoreactive CCL19 (average value, ELISA determination). CCL19 myc, but not authentic CCL19, carried the fluorophore-labeled antibody 4A6 into other recipient cells that expressed recombinant CCR7 (microscopy, cytofluorometry). The immune complexes were apparent in endosomal structures, co localized well with the small GTPase Rab5 and progressed toward Rab7-positive endosomes. A dominant negative form of Rab5 (GDP-locked) inhibited this endocytosis. Further, endosomes in CCL19-myc- or CCL19-stimulated cells were positive for beta-arrestin2, but rarely for beta-arrestin1. Following treatment with CCL19-myc and the 4A6 antibody, the melanoma cell line A375 that expresses endogenous CCR7 was specifically stained using a secondary peroxidase-conjugated antibody. Agonist-stimulated CCR7 can transport antibody-based cargoes, with possible therapeutic applications in oncology. PMID- 24068999 TI - Targeting pain and inflammation by peripherally acting opioids. PMID- 24069000 TI - The impact of escitalopram on vagally mediated cardiovascular function to stress and the moderating effects of vigorous physical activity: a randomized controlled treatment study in healthy participants. AB - Recent concerns over the impact of antidepressant medications, including the selective serotonin reuptake inhibitors (SSRIs), on cardiovascular function highlight the importance of research on the moderating effects of specific lifestyle factors such as physical activity. Studies in affective neuroscience have demonstrated robust acute effects of SSRIs, yet the impact of SSRIs on cardiovascular stress responses and the moderating effects of physical activity remain to be determined. This was the goal of the present study, which involved a double-blind, randomized, placebo-controlled, cross-over trial of a single-dose of escitalopram (20 mg) in 44 healthy females; outcomes were heart rate (HR) and its variability. Participants engaging in at least 30 min of vigorous physical activity at least 3 times per week (regular exercisers) showed a more resilient cardiovascular stress response than irregular vigorous exercisers, a finding associated with a moderate effect size (Cohen's d = 0.48). Escitalopram attenuated the cardiovascular stress response in irregular exercisers only (HR decreased: Cohen's d = 0.80; HR variability increased: Cohen's d = 0.33). HR during stress under escitalopram in the irregular exercisers was similar to that during stress under placebo in regular exercisers. These findings highlight that the effects of regular vigorous exercise during stress are comparable to the effects of an acute dose of escitalopram, highlighting the beneficial effects of this particular antidepressant in irregular exercisers. Given that antidepressant drugs alone do not seem to protect patients from cardiovascular disease (CVD), longitudinal studies are needed to evaluate the impact of exercise on cardiovascular stress responses in patients receiving long-term antidepressant treatment. PMID- 24069001 TI - Modeling steady state SO2-dependent changes in capillary ATP concentration using novel O2 micro-delivery methods. AB - Adenosine triphosphate (ATP) is known to be released from the erythrocyte in an oxygen (O2) dependent manner. Since ATP is a potent vasodilator, it is proposed to be a key regulator in the pathway that mediates micro-vascular response to varying tissue O2 demand. We propose that ATP signaling mainly originates in the capillaries due to the relatively long erythrocyte transit times in the capillary and the short ATP diffusion distance to the electrically coupled endothelium. We have developed a computational model to investigate the effect of delivering or removing O2 to limited areas at the surface of a tissue with an idealized parallel capillary array on total ATP concentration. Simulations were conducted when exposing full surface to perturbations in tissue O2 tension (PO2) or locally using a circular micro-outlet (~100 MUm in diameter), a square micro-slit (200 * 200 MUm), or a rectangular micro-slit (1000 MUm wide * 200 MUm long). Results indicated the rectangular micro-slit has the optimal dimensions for altering hemoglobin saturations (SO2) in sufficient number capillaries to generate effective changes in total [ATP]. This suggests a threshold for the minimum number of capillaries that need to be stimulated in vivo by imposed tissue hypoxia to induce a conducted micro-vascular response. SO2 and corresponding [ATP] changes were also modeled in a terminal arteriole (9 MUm in diameter) that replaces 4 surface capillaries in the idealized network geometry. Based on the results, the contribution of terminal arterioles to the net change in [ATP] in the micro-vascular network is minimal although they would participate as O2 sources thus influencing the O2 distribution. The modeling data presented here provide important insights into designing a novel micro-delivery device for studying micro-vascular O2 regulation in the capillaries in vivo. PMID- 24069002 TI - Import of proteins into the peroxisomal matrix. AB - Peroxisomes constitute a dynamic compartment in all nucleated cells. They fulfill diverse metabolic tasks in response to environmental changes and cellular demands. This adaptation is implemented by modulation of the enzyme content of the organelles, which is accomplished by dynamically operating peroxisomal protein transport machineries. Soluble import receptors recognize their newly synthesized cargo proteins in the cytosol and ferry them to the peroxisomal membrane. Subsequently, the cargo is translocated into the matrix, where the receptor is ubiquitinated and exported back to the cytosol for further rounds of matrix protein import. This review discusses the recent progress in our understanding of the peroxisomal matrix protein import and its regulation by ubiquitination events as well as the current view on the translocation mechanism of folded proteins into peroxisomes. This article is part of a Special Issue entitled: Origin and spatiotemporal dynamics of the peroxisomal endomembrane system. PMID- 24069003 TI - Effects of transcranial direct current stimulation on consolidation of fear memory. AB - It has been shown that applying transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) influences declarative memory processes. This study investigates the efficacy of tDCS on emotional memory consolidation, especially experimental fear conditioning. We applied an auditory fear-conditioning paradigm, in which two differently colored squares (blue and yellow) were presented as conditioned stimuli (CS) and an auditory stimulus as unconditioned stimulus (UCS). Sixty-nine participants were randomly assigned into three groups: anodal, cathodal, and sham stimulation. The participants of the two active groups (i.e., anodal and cathodal) received tDCS over the left DLPFC for 12 min after fear conditioning. The effect of fear conditioning and consolidation (24 h later) was measured by assessing the skin conductance response (SCR) to the CS. The results provide evidence that cathodal stimulation of the left DLPFC leads to an inhibitory effect on fear memory consolidation compared to anodal and sham stimulation, as indicated by decreased SCRs to CS+ presentation during extinction training at day 2. In conclusion, current work suggests that cathodal stimulation interferes with processes of fear memory consolidation. PMID- 24069005 TI - Failure of conflict to modulate central executive network activity associated with delusions in schizophrenia. AB - Dual-stream modulation failure (DSMF) proposes that dysfunctional regulation of logical and intuitive decision-making processes by conflict and emotional salience may be the underlying cognitive mechanism for the formation and maintenance of delusions in schizophrenia. The present study utilizes a combination of emotionally salient and neutral stimuli in conflict and non conflict conditions in a sentence verification task to test specific hypotheses predicted by the model. Twenty-one patients with schizophrenia and 21 controls completed a sentence verification task with fMRI acquisition. The results are consistent with the predictions based on the conflict modulation component of the model, but do not support the emotional modulation component of the model. PMID- 24069006 TI - Mismatch negativity as a "translatable" brain marker toward early intervention for psychosis: a review. AB - Recent reviews and meta-analyses suggest that reducing the duration of untreated psychosis leads to better symptomatic and functional outcome in patients with psychotic disorder. Early intervention attenuates the symptoms of individuals at clinical high-risk (HR) for psychosis and may delay or prevent their transition to psychosis. Identifying biological markers in the early stages of psychotic disorder is an important step toward elucidating the pathophysiology, improving prediction of the transition to psychosis, and introducing targeted early intervention for help-seeking individuals aiming for better outcome. Mismatch negativity (MMN) is a component of event-related potentials that reflects preattentive auditory sensory memory and is a promising biomarker candidate for schizophrenia. Reduced MMN amplitude is a robust finding in patients with chronic schizophrenia. Recent reports have shown that people in the early stages of psychotic disorder exhibit attenuation of MMN amplitude. MMN in response to duration deviants and in response to frequency deviants reveals different patterns of deficits. These findings suggest that MMN may be useful for identifying clinical stages of psychosis and for predicting the risk of development. MMN may also be a "translatable" biomarker since it reflects N methyl-d-aspartte receptor function, which plays a fundamental role in schizophrenia pathophysiology. Furthermore, MMN-like responses can be recorded in animals such as mice and rats. This article reviews MMN studies conducted on individuals with HR for psychosis, first-episode psychosis, recent-onset psychosis, and on animals. Based on the findings, the authors discuss the potential of MMN as a clinical biomarker for early intervention for help-seeking individuals in the early stages of psychotic disorder, and as a translatable neurophysiological marker for the preclinical assessment of pharmacological agents used in animal models that mimic early stages of the disorder. PMID- 24069007 TI - Brain activation patterns resulting from learning letter forms through active self-production and passive observation in young children. AB - Although previous literature suggests that writing practice facilitates neural specialization for letters, it is unclear if this facilitation is driven by the perceptual feedback from the act of writing or the actual execution of the motor act. The present study addresses this issue by measuring the change in BOLD signal in response to hand-printed letters, unlearned cursive letters, and cursive letters that 7-year-old children learned actively, by writing, and passively, by observing an experimenter write. Brain activation was assessed using fMRI while perceiving letters-in both cursive and manuscript forms. Results showed that active training led to increased recruitment of the sensori-motor network associated with letter perception as well as the insula and claustrum, but passive observation did not. This suggests that perceptual networks for newly learned cursive letters are driven by motor execution rather than by perceptual feedback. PMID- 24069008 TI - Behavioral biases when viewing multiplexed scenes: scene structure and frames of reference for inspection. AB - Where people look when viewing a scene has been a much explored avenue of vision research (e.g., see Tatler, 2009). Current understanding of eye guidance suggests that a combination of high and low-level factors influence fixation selection (e.g., Torralba et al., 2006), but that there are also strong biases toward the center of an image (Tatler, 2007). However, situations where we view multiplexed scenes are becoming increasingly common, and it is unclear how visual inspection might be arranged when content lacks normal semantic or spatial structure. Here we use the central bias to examine how gaze behavior is organized in scenes that are presented in their normal format, or disrupted by scrambling the quadrants and separating them by space. In Experiment 1, scrambling scenes had the strongest influence on gaze allocation. Observers were highly biased by the quadrant center, although physical space did not enhance this bias. However, the center of the display still contributed to fixation selection above chance, and was most influential early in scene viewing. When the top left quadrant was held constant across all conditions in Experiment 2, fixation behavior was significantly influenced by the overall arrangement of the display, with fixations being biased toward the quadrant center when the other three quadrants were scrambled (despite the visual information in this quadrant being identical in all conditions). When scenes are scrambled into four quadrants and semantic contiguity is disrupted, observers no longer appear to view the content as a single scene (despite it consisting of the same visual information overall), but rather anchor visual inspection around the four separate "sub-scenes." Moreover, the frame of reference that observers use when viewing the multiplex seems to change across viewing time: from an early bias toward the display center to a later bias toward quadrant centers. PMID- 24069004 TI - Modulation of the endocannabinoid system: vulnerability factor and new treatment target for stimulant addiction. AB - Cannabis is one of the most widely used illicit substance among users of stimulants such as cocaine and amphetamines. Interestingly, increasing recent evidence points toward the involvement of the endocannabinoid system (ECBS) in the neurobiological processes related to stimulant addiction. This article presents an up-to-date review with deep insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. This article aims to: (1) review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and (2) evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction. A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoids in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants. PMID- 24069009 TI - Brain morphometry shows effects of long-term musical practice in middle-aged keyboard players. AB - To what extent does musical practice change the structure of the brain? In order to understand how long-lasting musical training changes brain structure, 20 male right-handed, middle-aged professional musicians and 19 matched controls were investigated. Among the musicians, 13 were pianists or organists with intensive practice regimes. The others were either music teachers at schools or string instrumentalists, who had studied the piano at least as a subsidiary subject, and practiced less intensively. The study was based on T1-weighted MR images, which were analyzed using deformation-based morphometry. Cytoarchitectonic probabilistic maps of cortical areas and subcortical nuclei as well as myeloarchitectonic maps of fiber tracts were used as regions of interest to compare volume differences in the brains of musicians and controls. In addition, maps of voxel-wise volume differences were computed and analyzed. Musicians showed a significantly better symmetric motor performance as well as a greater capability of controlling hand independence than controls. Structural MRI-data revealed significant volumetric differences between the brains of keyboard players, who practiced intensively and controls in right sensorimotor areas and the corticospinal tract as well as in the entorhinal cortex and the left superior parietal lobule. Moreover, they showed also larger volumes in a comparable set of regions than the less intensively practicing musicians. The structural changes in the sensory and motor systems correspond well to the behavioral results, and can be interpreted in terms of plasticity as a result of intensive motor training. Areas of the superior parietal lobule and the entorhinal cortex might be enlarged in musicians due to their special skills in sight-playing and memorizing of scores. In conclusion, intensive and specific musical training seems to have an impact on brain structure, not only during the sensitive period of childhood but throughout life. PMID- 24069010 TI - Reconciling the influence of task-set switching and motor inhibition processes on stop signal after-effects. AB - Executive response functions can be affected by preceding events, even if they are no longer associated with the current task at hand. For example, studies utilizing the stop signal task have reported slower response times to "GO" stimuli when the preceding trial involved the presentation of a "STOP" signal. However, the neural mechanisms that underlie this behavioral after-effect are unclear. To address this, behavioral and electroencephalography (EEG) measures were examined in 18 young adults (18-30 years) on "GO" trials following a previously "Successful Inhibition" trial (pSI), a previously "Failed Inhibition" trial (pFI), and a previous "GO" trial (pGO). Like previous research, slower response times were observed during both pSI and pFI trials (i.e., "GO" trials that were preceded by a successful and unsuccessful inhibition trial, respectively) compared to pGO trials (i.e., "GO" trials that were preceded by another "GO" trial). Interestingly, response time slowing was greater during pSI trials compared to pFI trials, suggesting executive control is influenced by both task set switching and persisting motor inhibition processes. Follow-up behavioral analyses indicated that these effects resulted from between-trial control adjustments rather than repetition priming effects. Analyses of inter electrode coherence (IEC) and inter-trial coherence (ITC) indicated that both pSI and pFI trials showed greater phase synchrony during the inter-trial interval compared to pGO trials. Unlike the IEC findings, differential ITC was present within the beta and alpha frequency bands in line with the observed behavior (pSI > pFI > pGO), suggestive of more consistent phase synchrony involving motor inhibition processes during the ITI at a regional level. These findings suggest that between-trial control adjustments involved with task-set switching and motor inhibition processes influence subsequent performance, providing new insights into the dynamic nature of executive control. PMID- 24069011 TI - Can mergers-in-progress be unmerged in speech accommodation? AB - This study examines spontaneous phonetic accommodation of a dialect with distinct categories by speakers who are in the process of merging those categories. We focus on the merger of the NEAR and SQUARE lexical sets in New Zealand English, presenting New Zealand participants with an unmerged speaker of Australian English. Mergers-in-progress are a uniquely interesting sound change as they showcase the asymmetry between speech perception and production. Yet, we examine mergers using spontaneous phonetic imitation, which is phenomenon that is necessarily a behavior where perceptual input influences speech production. Phonetic imitation is quantified by a perceptual measure and an acoustic calculation of mergedness using a Pillai-Bartlett trace. The results from both analyses indicate spontaneous phonetic imitation is moderated by extra-linguistic factors such as the valence of assigned conditions and social bias. We also find evidence for a decrease in the degree of mergedness in post-exposure productions. Taken together, our results suggest that under the appropriate conditions New Zealanders phonetically accommodate to Australian English and that in the process of speech imitation, mergers-in-progress can, but do not consistently, become less merged. PMID- 24069012 TI - Predicting individual differences in decision-making process from signature movement styles: an illustrative study of leaders. AB - There has been a surge of interest in examining the utility of methods for capturing individual differences in decision-making style. We illustrate the potential offered by Movement Pattern Analysis (MPA), an observational methodology that has been used in business and by the US Department of Defense to record body movements that provide predictive insight into individual differences in decision-making motivations and actions. Twelve military officers participated in an intensive 2-h interview that permitted detailed and fine-grained observation and coding of signature movements by trained practitioners using MPA. Three months later, these subjects completed four hypothetical decision-making tasks in which the amount of information sought out before coming to a decision, as well as the time spent on the tasks, were under the partial control of the subject. A composite MPA indicator of how a person allocates decision-making actions and motivations to balance both Assertion (exertion of tangible movement effort on the environment to make something occur) and Perspective (through movements that support shaping in the body to perceive and create a suitable viewpoint for action) was highly correlated with the total number of information draws and total response time-individuals high on Assertion reached for less information and had faster response times than those high on Perspective. Discussion focuses on the utility of using movement-based observational measures to capture individual differences in decision-making style and the implications for application in applied settings geared toward investigations of experienced leaders and world statesmen where individuality rules the day. PMID- 24069013 TI - Analysis of eye movements in the judgment of enjoyment and non-enjoyment smiles. AB - Enjoyment smiles are more often associated with the simultaneous presence of the Cheek raiser and Lip corner puller action units, and these units' activation is more often symmetric. Research on the judgment of smiles indicated that individuals are sensitive to these types of indices, but it also suggested that their ability to perceive these specific indices might be limited. The goal of the current study was to examine perceptual-attentional processing of smiles by using eye movement recording in a smile judgment task. Participants were presented with three types of smiles: a symmetric Duchenne, a non-Duchenne, and an asymmetric smile. Results revealed that the Duchenne smiles were judged happier than those with characteristics of non-enjoyment. Asymmetric smiles were also judged happier than the non-Duchenne smiles. Participants were as effective in judging the latter smiles as not really happy as they were in judging the symmetric Duchenne smiles as happy. Furthermore, they did not spend more time looking at the eyes or mouth regardless of types of smiles. While participants made more saccades between each side of the face for the asymmetric smiles than the symmetric ones, they judged the asymmetric smiles more often as really happy than not really happy. Thus, processing of these indices do not seem limited to perceptual-attentional difficulties as reflected in viewing behavior. PMID- 24069014 TI - Switching among graphic patterns is governed by oscillatory coordination dynamics: implications for understanding handwriting. AB - Revisiting an original idea by Hollerbach (1981), previous work has established that the production of graphic shapes, assumed to be the blueprint for handwriting, is governed by the dynamics of orthogonal non-linear coupled oscillators. Such dynamics determines few stable coordination patterns, giving rise to a limited set of preferred graphic shapes, namely, four lines and four ellipsoids independent of orientation. The present study investigates the rules of switching among such graphic coordination patterns. Seven participants were required to voluntarily switch within twelve pairs of shapes presented on a graphic tablet. In line with previous theoretical and experimental work on bimanual coordination, results corroborated our hypothesis that the relative stability of the produced coordination patterns determines the time needed for switching: the transition to a more stable pattern was shorter, and inversely. Moreover, switching between patterns with the same orientation but different eccentricities was faster than with a change in orientation. Nonetheless, the switching time covaried strictly with the change in relative phase effected by the transition between two shapes, whether this implied a change in eccentricity or in orientation. These findings suggest a new operational definition of what the (motor) units or strokes of handwriting are and shed a novel light on how coarticulation and recruitment of degrees of freedom may occur in graphic skills. They also yield some leads for understanding the acquisition and the neural underpinnings of handwriting. PMID- 24069015 TI - Multisensory integration across the menstrual cycle. AB - Evidence suggests that spatial processing changes across time in naturally cycling women, which is likely due to neuromodulatory effects of steroid hormones. Yet, it is unknown whether crossmodal spatial processes depend on steroid hormones as well. In the present experiment, the crossmodal congruency task was used to assess visuo-tactile interactions in naturally cycling women, women using hormonal contraceptives and men. Participants adopted either a crossed or uncrossed hands posture. It was tested whether a postural effect of hand crossing on multisensory interactions in the crossmodal congruency task is modulated by women's cycle phase. We found that visuotactile interactions changed according to cycle phase. Naturally cycling women showed a significant difference between the menstrual and the luteal phase for crossed, but not for uncrossed hands postures. The two control groups showed no test sessions effects. Regression analysis revealed a positive relation between estradiol levels and the size of crossmodal congruency effects (CCE), indicating that estradiol seems to have a neuromodulatory effect on posture processing. PMID- 24069016 TI - Spanish parents' emotion talk and their children's understanding of emotion. AB - Relations between parent-child emotion talk and children's emotion understanding were examined in 63 Spanish mothers and fathers and their 4- (M = 53.35 months, SD = 3.86) and 6-year-old (M = 76.62 months, SD = 3.91) children. Parent-child emotion talk was analyzed during two storytelling tasks: a play-related storytelling task and a reminiscence task (conversation about past experiences). Children's emotion understanding was assessed twice through a standardized test of emotion comprehension (TEC; Pons et al., 2004), once before one of the two parent-child storytelling sessions and again 6 months later. Mothers' use of emotion labels during the play-related storytelling task predicted children's emotion understanding after controlling for children's previous emotion understanding. Whereas fathers' use of emotion labels during the play-related storytelling task was correlated with children's emotion understanding, it did not predict children's emotion understanding after controlling for previous emotion understanding. Implications of these findings for future research on children's socioemotional development are discussed. PMID- 24069017 TI - Neanderthal language? Just-so stories take center stage. PMID- 24069018 TI - Immunity Against Tetanus Infection, Risk Factors for Non-Protection, and Validation of a Rapid Immunotest Kit among Hospitalized Children in Nigeria. AB - Seroepidemiological studies of tetanus in Africans have focused mainly on adults especially pregnant women and data on children are scarcely reported. We investigated the seroprevalence of protective immunity level, determined risk factors for non-protection against tetanus, and evaluated the performance of Tetanos Quick Stick((r)) (TQS) among hospitalized children aged 1-9 years in Nigeria. Blood IgG antibody levels to tetanus was determined using enzyme-linked immunosorbent assay (ELISA) in the laboratory and TQS (an immunochromatographic test) at the bedside for 304 children admitted into emergency unit of a tertiary hospital in Ibadan, Nigeria. Demographic information and vaccination history were also collected. TQS results were compared with anti-tetanus antibody measured by ELISA using seroprotection cut-off of 0.1 IU/ml. Seroprevalence of protective level of immunity against tetanus using ELISA and TQS methods was 44.7 and 45.4% respectively. Protective level of immunity increased as age increases. Of the seven potential factors assessed, male gender and being second or more position among mother's children were independent predictors of non-protective level of immunity. Absence of history of recent tetanus toxoid injection was significantly associated with non-protective level of immunity in univariate analysis but not logistic regression model. The agreement between the ELISA and the TQS results was good with a k coefficient of 0.931. TQS sensitivity was 95.7%, specificity 97.6%, positive predictive value 98.0%, and negative predictive values 96.0%. This study showed that lack of protective immunity against tetanus is common; few demographic characteristics correctly predict non-protection and IgG antibody levels to tetanus was accurately detected by TQS. PMID- 24069020 TI - Tophaceous gout - even today. PMID- 24069019 TI - Coupled high-throughput functional screening and next generation sequencing for identification of plant polymer decomposing enzymes in metagenomic libraries. AB - Recent advances in sequencing technologies generate new predictions and hypotheses about the functional roles of environmental microorganisms. Yet, until we can test these predictions at a scale that matches our ability to generate them, most of them will remain as hypotheses. Function-based mining of metagenomic libraries can provide direct linkages between genes, metabolic traits and microbial taxa and thus bridge this gap between sequence data generation and functional predictions. Here we developed high-throughput screening assays for function-based characterization of activities involved in plant polymer decomposition from environmental metagenomic libraries. The multiplexed assays use fluorogenic and chromogenic substrates, combine automated liquid handling and use a genetically modified expression host to enable simultaneous screening of 12,160 clones for 14 activities in a total of 170,240 reactions. Using this platform we identified 374 (0.26%) cellulose, hemicellulose, chitin, starch, phosphate and protein hydrolyzing clones from fosmid libraries prepared from decomposing leaf litter. Sequencing on the Illumina MiSeq platform, followed by assembly and gene prediction of a subset of 95 fosmid clones, identified a broad range of bacterial phyla, including Actinobacteria, Bacteroidetes, multiple Proteobacteria sub-phyla in addition to some Fungi. Carbohydrate-active enzyme genes from 20 different glycoside hydrolase (GH) families were detected. Using tetranucleotide frequency (TNF) binning of fosmid sequences, multiple enzyme activities from distinct fosmids were linked, demonstrating how biochemically confirmed functional traits in environmental metagenomes may be attributed to groups of specific organisms. Overall, our results demonstrate how functional screening of metagenomic libraries can be used to connect microbial functionality to community composition and, as a result, complement large-scale metagenomic sequencing efforts. PMID- 24069021 TI - Role of inositol poly-phosphatases and their targets in T cell biology. AB - T lymphocytes play a critical role in host defense in all anatomical sites including mucosal surfaces. This not only includes the effector arm of the immune system, but also regulation of immune responses in order to prevent autoimmunity. Genetic targeting of PI3K isoforms suggests that generation of PI(3,4,5)P3 by PI3K plays a critical role in promoting effector T cell responses. Consequently, the 5'- and 3'-inositol poly-phosphatases SHIP1, SHIP2, and phosphatase and tensin homolog capable of targeting PI(3,4,5)P3 are potential genetic determinants of T cell effector functions in vivo. In addition, the 5'-inositol poly-phosphatases SHIP1 and 2 can shunt PI(3,4,5)P3 to the rare but potent signaling phosphoinositide species PI(3,4)P2 and thus these SHIP1/2, and the INPP4A/B enzymes that deplete PI(3,4)P2 may have precise roles in T cell biology to amplify or inhibit effectors of PI3K signaling that are selectively recruited to and activated by PI(3,4)P2. Here we summarize recent genetic and chemical evidence that indicates the inositol poly-phosphatases have important roles in both the effector and regulatory functions of the T cell compartment. In addition, we will discuss future genetic studies that might be undertaken to further elaborate the role of these enzymes in T cell biology as well as potential pharmaceutical manipulation of these enzymes for therapeutic purposes in disease settings where T cell function is a key in vivo target. PMID- 24069022 TI - Regulatory T Cells Control Immune Responses through Their Non-Redundant Tissue Specific Features. AB - Regulatory T cells (Treg) are needed in the control of immune responses and to maintain immune homeostasis. Of this subtype of regulatory lymphocytes, the most potent are Foxp3 expressing CD4+ T cells, which can be roughly divided into two main groups; natural Treg cells (nTreg), developing in the thymus, and induced or adaptive Treg cells (iTreg), developing in the periphery from naive, conventional T cells. Both nTreg cells and iTreg cells have their own, non-redundant roles in the immune system, with nTreg cells mainly maintaining tolerance toward self structures, and iTreg developing in response to externally delivered antigens or commensal microbes. In addition, Treg cells acquire tissue specific features and are adapted to function in the tissue they reside. This review will focus on some specific features of Treg cells in different compartments of the body. PMID- 24069024 TI - How aging affects T lymphocyte-mediated immunity. PMID- 24069023 TI - A role for NADPH oxidase in antigen presentation. AB - The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expressed in phagocytes is a multi-subunit enzyme complex that generates superoxide (O2 (.-)). This radical is an important precursor of hydrogen peroxide (H2O2) and other reactive oxygen species needed for microbicidal activity during innate immune responses. Inherited defects in NADPH oxidase give rise to chronic granulomatous disease (CGD), a primary immunodeficiency characterized by recurrent infections and granulomatous inflammation. Interestingly, CGD, CGD carrier status, and oxidase gene polymorphisms have all been associated with autoinflammatory and autoimmune disorders, suggesting a potential role for NADPH oxidase in regulating adaptive immune responses. Here, NADPH oxidase function in antigen processing and presentation is reviewed. NADPH oxidase influences dendritic cell (DC) crosspresentation by major histocompatibility complex class I molecules through regulation of the phagosomal microenvironment, while in B lymphocytes, NADPH oxidase alters epitope selection by major histocompatibility complex class II molecules. PMID- 24069025 TI - Functional analysis of embolism induced by air injection in Acer rubrum and Salix nigra. AB - The goal of this study was to assess the effect of induced embolism with air injection treatments on the function of xylem in Acer rubrum L. and Salix nigra Marsh. Measurements made on mature trees of A. rubrum showed that pneumatic pressurization treatments that created a pressure gradient of 5.5 MPa across pit membranes (DeltaP pit) had no effect on stomatal conductance or on branch-level sap flow. The same air injection treatments made on 3-year-old potted A. rubrum plants also had no effect on whole plant transpiration. A separate study made on mature A. rubrum trees showed that 3.0 and 5.5 MPa of DeltaP pit values resulted in an immediate 100% loss in hydraulic conductance (PLC) in petioles. However, the observed change in PLC was short lived, and significant hydraulic recovery occurred within 5-10 min post air-pressurization treatments. Similar experiments conducted on S. nigra plants exposed to DeltaP pit of 3 MPa resulted in a rapid decline in whole plant transpiration followed by leaf wilting and eventual plant death, showing that this species lacks the ability to recover from induced embolism. A survey that measured the effect of air-pressurization treatments on seven other species showed that some species are very sensitive to induction of embolism resulting in leaf wilting and branch death while others show minimal to no effect despite that in each case, the applied DeltaP pit of 5.5 MPa significantly exceeded any native stress that these plants would experience naturally. PMID- 24069027 TI - Plant-mediated links between detritivores and aboveground herbivores. AB - Most studies on plant-mediated above-belowground interactions focus on soil biota with direct trophic links to plant roots such as root herbivores, pathogens, and symbionts. Detritivorous soil fauna, though ubiquitous and present in high abundances and biomasses in soil, are under-represented in those studies. Understanding of their impact on plants is mainly restricted to growth and nutrient uptake parameters. Detritivores have been shown to affect secondary metabolites and defense gene expression in aboveground parts of plants, with potential impacts on aboveground plant-herbivore interactions. The proposed mechanisms range from nutrient mobilization effects and impacts on soil microorganisms to defense induction by passive or active ingestion of roots. Since their negative effects (disruption or direct feeding of roots) may be counterbalanced by their overall beneficial effects (nutrient mobilization), detritivores may not harm, but rather enable plants to respond to aboveground herbivore attacks in a more efficient way. Both more mechanistic and holistic approaches are needed to better understand the involvement of detritivores in plant-mediated above-belowground interactions and their potential for sustainable agriculture. PMID- 24069026 TI - Plant phloem sterol content: forms, putative functions, and implications for phloem-feeding insects. AB - All eukaryotes contain sterols, which serve as structural components in cell membranes, and as precursors for important hormones. Plant vegetative tissues are known to contain mixtures of sterols, but very little is known about the sterol composition of phloem. Plants are food for many animals, but plant-feeding arthropods (including phloem-feeding insets) are unique among animals in that they have lost the ability to synthesize sterols, and must therefore acquire these essential nutrients from their food, or via endosymbionts. Our paper starts by providing a very brief overview of variation in plant sterol content, and how different sterols can affect insect herbivores, including those specializing on phloem. We then describe an experiment, where we bulk collected phloem sap exudate from bean and tobacco, and analyzed its sterol content. This approach revealed two significant observations concerning phloem sterols. First, the phloem exudate from each plant was found to contain sterols in three different fractions - free sterols, sterols conjugated to lipids (acylated), and sterols conjugated to carbohydrates (glycosylated). Second, for both plants, cholesterol was identified as the dominant sterol in each phloem exudate fraction; the remaining sterols in each fraction were a mixture of common phytosterols. We discuss our phloem exudate sterol profiles in a plant physiology/biochemistry context, and how it relates to the nutritional physiology/ecology of phloem feeding insects. We close by proposing important next steps that will advance our knowledge concerning plant phloem sterol biology, and how phloem-sterol content might affect phloem-feeding insects. PMID- 24069028 TI - A method for calling copy number polymorphism using haplotypes. AB - Single nucleotide polymorphism (SNP) and copy number variation (CNV) are both widespread characteristic of the human genome, but are often called separately on common genotyping platforms. To capture integrated SNP and CNV information, methods have been developed for calling allelic specific copy numbers or so called copy number polymorphism (CNP), using limited inter-marker correlation. In this paper, we proposed a haplotype-based maximum likelihood method to call CNP, which takes advantage of the valuable multi-locus linkage disequilibrium (LD) information in the population. We also developed a computationally efficient algorithm to estimate haplotype frequencies and optimize individual CNP calls iteratively, even at presence of missing data. Through simulations, we demonstrated our model is more sensitive and accurate in detecting various CNV regions, compared with commonly-used CNV calling methods including PennCNV, another hidden Markov model (HMM) using CNP, a scan statistic, segCNV, and cnvHap. Our method often performs better in the regions with higher LD, in longer CNV regions, and in common CNV than the opposite. We implemented our method on the genotypes of 90 HapMap CEU samples and 23 patients with acute lung injury (ALI). For each ALI patient the genotyping was performed twice. The CNPs from our method show good consistency and accuracy comparable to others. PMID- 24069029 TI - Temporal clustering of gene expression links the metabolic transcription factor HNF4alpha to the ER stress-dependent gene regulatory network. AB - The unfolded protein response (UPR) responds to disruption of endoplasmic reticulum (ER) function by initiating signaling cascades that ultimately culminate in extensive transcriptional regulation. Classically, this regulation includes genes encoding ER chaperones, ER-associated degradation factors, and others involved in secretory protein folding and processing, and is carried out by the transcriptional activators that are produced as a consequence of UPR activation. However, up to half of the mRNAs regulated by ER stress are downregulated rather than upregulated, and the mechanisms linking ER stress and UPR activation to mRNA suppression are poorly understood. To begin to address this issue, we used a "bottom-up" approach to study the metabolic gene regulatory network controlled by the UPR in the liver, because ER stress in the liver leads to lipid accumulation, and fatty liver disease is the most common liver disease in the western world. qRT-PCR profiling of mouse liver mRNAs during ER stress revealed that suppression of the transcriptional regulators C/EBPalpha, PPARalpha, and PGC-1alpha preceded lipid accumulation, and was then followed by suppression of mRNAs encoding key enzymes involved in fatty acid oxidation and lipoprotein biogenesis and transport. Mice lacking the ER stress sensor ATF6alpha, which experience persistent ER stress and profound lipid accumulation during challenge, were then used as the basis for a functional genomics approach that allowed genes to be grouped into distinct expression profiles. This clustering predicted that ER stress would suppress the activity of the metabolic transcriptional regulator HNF4alpha-a finding subsequently confirmed by chromatin immunopreciptation at the Cebpa and Pgc1a promoters. Our results establish a framework for hepatic gene regulation during ER stress and suggest that HNF4alpha occupies the apex of that framework. They also provide a unique resource for the community to further explore the temporal regulation of gene expression during ER stress in vivo. PMID- 24069030 TI - Preoperative screening and case cancellation in cocaine-abusing veterans scheduled for elective surgery. AB - Background. Perioperative management of cocaine-abusing patients scheduled for elective surgery varies widely based on individual anecdotes and personal experience. Methods. Chiefs of the anesthesia departments in the Veterans Affairs (VA) health system were surveyed to estimate how often they encounter surgical patients with cocaine use. Respondents were asked about their screening criteria, timing of screening, action resulting from positive screening, and if they have a formal policy for management of these patients. Interest in the development of VA guidelines for the perioperative management of patients with a history of cocaine use was also queried. Results. 172 VA anesthesia departments' chiefs were surveyed. Response rate was 62%. Over half of the facilities see cocaine-abusing patients at least once a week (52%). Two thirds of respondents canceled or delayed patients with a positive screen regardless of clinical symptoms. Only eleven facilities (10.6%) have a formal policy. The majority of facilities (80%) thought that having formal guidelines for perioperative management of cocaine abusing patients would be helpful to some extent. Results. 172 VA anesthesia departments' chiefs were surveyed. Response rate was 62%. Over half of the facilities see cocaine-abusing patients at least once a week (52%). Two thirds of respondents canceled or delayed patients with a positive screen regardless of clinical symptoms. Only eleven facilities (10.6%) have a formal policy. The majority of facilities (80%) thought that having formal guidelines for perioperative management of cocaine-abusing patients would be helpful to some extent. Conclusions. There is a general consensus that formal guidelines would be helpful. Further studies are needed to help formulate evidence-based guidelines for managing patients screening positive for cocaine prior to elective surgery. PMID- 24069031 TI - Mental health problems and sociodemographic correlates in elderly medical inpatients in a university hospital in egypt. AB - Background. Depression and cognitive impairment are two common mental and public health problems especially among elderly. In this study, we determined the prevalence of these problems and their associations with sociodemographic factors among hospitalized elderly in Egypt. To achieve this, 200 elderly medical inpatients were included in this cross-sectional study. Methods. Comprehensive geriatric assessment was done for every participant. Sociodemographic variables were assessed by interviews with patients and their family members. Depressive symptoms were screened for by the 15-item Geriatric Depression Scale (GDS), and the presence of depressive symptoms was defined as a GDS score of >=6. Cognitive impairment was assessed by the Mini-Mental State Examination (MMSE) Scale, and cognitive impairment was defined as a MMSE score of <=23 out of a total score of 30. Results. The prevalence of both depressive symptoms and cognitive impairment was 72% and 30%, respectively. Significant associations were noticed between each of depressive symptoms and cognitive impairment, and low income and advancing age (P < 0.01), respectively. Other associations were insignificant. Conclusions. The findings of this study may be an alarm for health authorities and staffs involved in elderly care to increase their awareness of social and mental health problems among the elderly. PMID- 24069032 TI - Effect of dentin biomodification using naturally derived collagen cross-linkers: one-year bond strength study. AB - Purpose. This study investigated the long-term resin-dentin bond strength of dentin biomodified by proanthocyanidin-rich (PA) agents. Materials and Methods. Forty molars had their coronal dentin exposed, etched, and treated for 10 minutes with 6.5% grape seed extract (GSE), 6.5% cocoa seed extract ethanol-water (CSE ET), 6.5% cocoa seed extract acetone-water (CSE-AC), and distilled water (CO). Samples were restored either with One-Step Plus (OS) or Adper Single-Bond Plus (SB). Bond strength test was performed immediately or after 3, 6, and 12 months. Results. Higher MU TBS were observed for GSE immediately (SB- 62.9 MPa; OS- 51.9 MPa) when compared to CSE-ET (SB- 56.95 MPa; OS- 60.28 MPa), CSE-AC (SB- 49.97 MPa; OS- 54.44 MPa), and CO (SB- 52.0 MPa; OS- 44.0 MPa) (P < 0.05). CSE outcomes were adhesive system and solvent dependant. After 12 months storage SB results showed no difference among treatment types (GSE- 57.15 MPa; CSE/ET- 54.04 MPa; CSE/AC- 48.22 MPa; CO- 51.68 MPa; P = 0.347),while OS results where treatment dependent (GSE- 42.62 MPa; CSE/ET- 44.06 MPa; CSE/AC- 41.30 MPa; CO- 36.85 MPa; P = 0.036). Conclusions. GSE and CSE-ET agents provided enhanced immediate adhesion and stabilization to demineralized dentin after long-term storage, depending on adhesive system. PMID- 24069033 TI - Phosphorylation-mediated regulation of alternative splicing in cancer. AB - Alternative splicing (AS) is one of the key processes involved in the regulation of gene expression in eukaryotic cells. AS catalyzes the removal of intronic sequences and the joining of selected exons, thus ensuring the correct processing of the primary transcript into the mature mRNA. The combinatorial nature of AS allows a great expansion of the genome coding potential, as multiple splice variants encoding for different proteins may arise from a single gene. Splicing is mediated by a large macromolecular complex, the spliceosome, whose activity needs a fine regulation exerted by cis-acting RNA sequence elements and trans acting RNA binding proteins (RBP). The activity of both core spliceosomal components and accessory splicing factors is modulated by their reversible phosphorylation. The kinases and phosphatases involved in these posttranslational modifications significantly contribute to AS regulation and to its integration in the complex regulative network that controls gene expression in eukaryotic cells. Herein, we will review the major canonical and noncanonical splicing factor kinases and phosphatases, focusing on those whose activity has been implicated in the aberrant splicing events that characterize neoplastic transformation. PMID- 24069035 TI - The role of vaginal mesh procedures in pelvic organ prolapse surgery in view of complication risk. AB - Synthetic transvaginal mesh has been employed in the treatment of pelvic organ prolapse for more than a decade. As the use of these devices increased during this period so did adverse event reporting. In 2008, the Food and Drug Administration (FDA) Public Health Notification informed physicians and patients of rising concerns with the use of synthetic transvaginal mesh. Shortly thereafter and in parallel to marked increases in adverse event reporting within the Manufacturer and User Device Experience (MAUDE), the FDA released a Safety Communication regarding urogynecologic surgical mesh use. Following this report and in the wake of increased medical industry product withdrawal, growing medicolegal concerns, patient safety, and clinical practice controversy, many gynecologists and pelvic reconstructive surgeons are left with limited long-term data, clinical guidance, and growing uncertainty regarding the role of synthetic transvaginal mesh use in pelvic organ prolapse. This paper reviews the reported complications of synthetic transvaginal mesh with an evidence-based approach as well as providing suggested guidance for the future role of its use amidst the controversy. PMID- 24069034 TI - Alternative Splicing Regulation of Cancer-Related Pathways in Caenorhabditis elegans: An In Vivo Model System with a Powerful Reverse Genetics Toolbox. AB - Alternative splicing allows for the generation of protein diversity and fine tunes gene expression. Several model systems have been used for the in vivo study of alternative splicing. Here we review the use of the nematode Caenorhabditis elegans to study splicing regulation in vivo. Recent studies have shown that close to 25% of genes in the worm genome undergo alternative splicing. A big proportion of these events are functional, conserved, and under strict regulation either across development or other conditions. Several techniques like genome wide RNAi screens and bichromatic reporters are available for the study of alternative splicing in worms. In this review, we focus, first, on the main studies that have been performed to dissect alternative splicing in this system and later on examples from genes that have human homologs that are implicated in cancer. The significant advancement towards understanding the regulation of alternative splicing and cancer that the C. elegans system has offered is discussed. PMID- 24069036 TI - Anemia among HIV-Infected Patients Initiating Antiretroviral Therapy in South Africa: Improvement in Hemoglobin regardless of Degree of Immunosuppression and the Initiating ART Regimen. AB - Among those with HIV, anemia is a strong risk factor for disease progression and death independent of CD4 count and viral load. Understanding the role of anemia in HIV treatment is critical to developing strategies to reduce morbidity and mortality. We conducted a prospective analysis among 10,259 HIV-infected adults initiating first-line ART between April 2004 and August 2009 in Johannesburg, South Africa. The prevalence of anemia at ART initiation was 25.8%. Mean hemoglobin increased independent of baseline CD4. Females, lower BMI, WHO stage III/IV, lower CD4 count, and zidovudine use were associated with increased risk of developing anemia during follow-up. After initiation of ART, hemoglobin improved, regardless of regimen type and the degree of immunosuppression. Between 0 and 6 months on ART, the magnitude of hemoglobin increase was linearly related to CD4 count. However, between 6 and 24 months on ART, hemoglobin levels showed a sustained overall increase, the magnitude of which was similar regardless of baseline CD4 level. This increase in hemoglobin was seen even among patients on zidovudine containing regimens. Since low hemoglobin is an established adverse prognostic marker, prompt identification of anemia may result in improved morbidity and mortality of patients initiating ART. PMID- 24069037 TI - Methodological and statistical comments on T helper cytokines profile and hepatitis C. PMID- 24069038 TI - Development of a Chemiluminescence Immunoassay for Serum YB-1 and its Clinical Application as a Potential Diagnostic Marker for Hepatocellular Carcinoma. AB - BACKGROUND: Y-box binding protein 1 (YB-1) overexpression has been shown in various tumor cells including hepatocellular carcinoma (HCC); moreover, this protein can be actively secreted. OBJECTIVES: The aim of this study was to establish a method to quantify serum YB-1 and evaluate its clinical application in the clinical diagnosis of HCC. PATIENTS AND METHODS: Recombinant YB-1 and two populations of its antibodies were prepared. A monoclonal antibody was specific to the N-terminus of YB-1 amino acids 134-160; and another was a polyclonal antibody. A sandwich-type chemiluminescence immunoassay (CLIA) was developed and evaluated. Levels of YB-1 and alpha fetoprotein (AFP) in serum samples from 105 HCC patients, 25 hepatitis B virus patients, 25 cirrhosis patients, and 50 healthy donors were detected using the established method and an AFP electrochemiluminescence kit. RESULTS: The developed method was linear to 150 MUg/L of YB-1 with a minimum detection limit of 0.01 MUg/L. The average recoveries were between 93.9% and 109.0%. The mean intra- and inter-assay coefficients of variation (CVs) were 4.0-4.8% and 8.2-10.2%, respectively. The relationship between the concentration of diluted YB-1 and the dilution ratios gave a good linear correlation coefficient of 0.9986. The YB-1 concentration was increased in serum of HCC patients (33.0 +/- 23.39 MUg/L) compared to healthy individuals (13.2 +/- 5.29 MUg/L, P < 0.0001), patients with HBV (17.9 +/- 7.49 MUg/L, P = 0.0003), and patients with HBV cirrhosis (20.7 +/- 8.75 MUg/L, P < 0.05). Moreover, the combination of YB-1 and alpha-fetoprotein had a high sensitivity (89.5%) and reasonable specificity (62.0%) in identifying HCC. CONCLUSIONS: The established method has an acceptable performance in quantifying YB-1. In addition, serum YB-1 may aid in the diagnosis of HCC. PMID- 24069039 TI - Effectiveness of Methadone Maintenance Treatment in Prevention of Hepatitis C Virus Transmission among Injecting Drug Users. AB - BACKGROUND: Injecting drug users (IDUs) are a major and most important risk factor for rising hepatitis C virus (HCV) prevalence in Iran. OBJECTIVES: The objective of this study was to determine the effectiveness of methadone maintenance treatment (MMT) in prevention of HCV infection transmission among IDUs. PATIENTS AND METHODS: A mathematical modeling has been used to estimate number of HCV infections averted. The input parameters used in the model were collected by self-reported method from 259 IDUs before registering and one year after MMT. Nonparametric statistical tests have been used to compare risky injecting and sexual behaviors among IDUs before and after participating in MMT program. Deterministic sensitivity analyses were done to show the effects of parameters' uncertainty on outcome. RESULTS: Of the 259 participants, 98.4% (255) were men, the mean age +/- SD was 33.1 +/- 7.58 years and HCV prevalence was 50%. The studied IDUs reported lower rate of risky injecting and sexual behavior after participation in MMT program. The cumulative incidence of HCV per 100 IDUs due to sharing injection and unsafe sexual contact with MMT program were 13.84 (95% CI: 6.17 -21.51), 0.0003 (0.0001 - 0.0005) and without it 36.48 (25.84 - 47.11) and 0.0004 (0.0002-0.0006) respectively. CONCLUSIONS: The MMT program is an effective intervention to prevent HCV infection transmission, although it is essential to compare its effectiveness with other interventions before implementing it in nationwide. PMID- 24069041 TI - The subcellular localization of the receptor for platelet-activating factor in neutrophils affects signaling and activation characteristics. AB - The localization in neutrophils, of the receptor for platelet-activating factor (PAFR), has been determined using subcellular fractionation and a receptor mobilization protocol. We show that the PAFR is expressed primarily in the plasma membrane. Although activation of neutrophils by PAF induces responses typical also of agonists that bind the formyl peptide receptors (FPR), known to be stored in mobilizable organelles, some quantitative as well as qualitative differences were observed when neutrophils were activated through these receptors. PAF is equipotent to fMLF (high affinity agonist for FPR1) to cleave off L-selectin and to induce granule/vesicle secretion but is more potent than fMLF to induce a rise in intracellular Ca(2+). Similar to fMLF, PAF induced also a robust release of reactive oxygen species, but with higher EC50 value and was less sensitive to a PI3K inhibitor compared to the fMLF response. Despite the lack of a granule localized storage pool of receptors, the PAF-induced superoxide production could be primed; receptor mobilization was, thus, not required for priming of the PAF response. The desensitized PAFR could not be reactivated, suggesting that distinct signaling pathways are utilized for termination of the responses triggered through FPR1 and PAFR. PMID- 24069040 TI - The role of anesthetic drugs in liver apoptosis. AB - CONTEXT: The modern practice of anesthesia is highly dependent ona group of anesthetic drugs which many of them are metabolized in the liver. EVIDENCE ACQUISITION: The liver, of course, usually tolerates this burden. However, this is not always an unbroken rule. Anesthetic induced apoptosis has gained great concern during the last years; especially considering the neurologic system. RESULTS: However, we have evidence that there is some concern regarding their effects on the liver cells. Fortunately not all the anesthetics are blamed and even some could be used safely, based on the available evidence. CONCLUSIONS: Besides, there are some novel agents, yet under research, which could affect the future of anesthetic agents' fate regarding their hepatic effects. PMID- 24069042 TI - Allergen-specific IgG antibodies purified from mite-allergic patients sera block the IgE recognition of Dermatophagoides pteronyssinus antigens: an in vitro study. AB - One of the purposes of specific immunotherapy (SIT) is to modulate humoral immune response against allergens with significant increases in allergen-specific IgG levels, commonly associated with blocking activity. The present study investigated in vitro blocking activity of allergen-specific IgG antibodies on IgE reactivity to Dermatophagoides pteronyssinus (Dpt) in sera from atopic patients. Dpt-specific IgG antibodies were purified by ammonium sulfate precipitation followed by protein-G affinity chromatography. Purity was checked by SDS-PAGE and immunoreactivity by slot-blot and immunoblot assays. The blocking activity was evaluated by inhibition ELISA. The electrophoretic profile of the ammonium sulfate precipitated fraction showed strongly stained bands in ligand fraction after chromatography, compatible with molecular weight of human whole IgG molecule. The purity degree was confirmed by detecting strong immunoreactivity to IgG, negligible to IgA, and no reactivity to IgE and IgM. Dpt specific IgG fraction was capable of significantly reducing levels of IgE anti Dpt, resulting in 35%-51% inhibition of IgE reactivity to Dpt in atopic patients sera. This study showed that allergen-specific IgG antibodies purified from mite allergic patients sera block the IgE recognition of Dermatophagoides pteronyssinus antigens. This approach reinforces that intermittent measurement of serum allergen-specific IgG antibodies will be an important objective laboratorial parameter that will help specialists to follow their patients under SIT. PMID- 24069043 TI - Increased numbers of NK cells, NKT-like cells, and NK inhibitory receptors in peripheral blood of patients with chronic obstructive pulmonary disease. AB - T cells and B cells participate in the pathogenesis of COPD. Currently, NK cells and NKT cells have gained increasing attention. In the present study, 19 COPD patients and 12 healthy nonsmokers (HNS) were recruited, and their pulmonary function was assessed. The frequencies of CD3(+) T, CD4(+) T, CD8(+) T, B, NK, and NKT-like cells were determined using flow cytometry. The frequencies of spontaneous and inducible IFN- gamma (+) or CD107a(+) NK and NKT-like cells as well as activating or inhibitory receptors were also detected. The potential association of lymphocyte subsets with disease severity was further analyzed. Significantly decreased numbers of CD3(+) and CD4(+) T cells, and the CD4(+)/CD8(+) ratio, but increased numbers of CD3(-)CD56(+) NK and CD3(+)CD56(+) NKT-like cells were observed in COPD patients compared to HNS. The frequencies of inducible IFN- gamma -secreting NK and NKT-like cells were less in COPD patients. The frequencies of CD158a and CD158b on NK cells and CD158b on NKT-like cells were greater. The frequency of CD158b(+) NK cells was negatively correlated with FEV1% prediction and FEV1/FVC. Our data indicate that COPD patients have immune dysfunction, and higher frequencies of inhibitory NK cells and NKT-like cells may participate in the pathogenesis of COPD. PMID- 24069044 TI - Increased frequency of bone marrow T follicular helper cells in patients with immune-related pancytopenia. AB - Immune-related pancytopenia (IRP) is one kind of bone marrow failure diseases which is related to autoantibodies. Autoantibodies have been detected on the membrane of various bone marrow (BM) hemopoietic cells by BM mononuclear-cell Coombs test or flow cytometric analysis. There are autoantibodies in the BM supernatant of IRP patients, which can target several antigens on hematopoietic cells membranes by western blot. T follicular helper (Tfh) cells are the true helper cells for Ab responses, which represent one of the most numerous and important subsets of effector T cells. Dysregulation of Tfh cell function or expression of Tfh cell-associated molecules could contribute to the pathogenesis of autoimmune diseases. Currently, there are no studies regarding the role of Tfh cells in IRP patients. The percentages of Tfh cells, Tfh-related molecules ICOS, CD40L, IL-21, and Bcl-6 in BM were investigated in 90 patients with IRP, and 25 healthy controls. We observed that there exist increased quantity and hyperfunction of Tfh cells in IRP, and the results were correlated with patient characteristics. It was indicated that dysregulated Tfh cells might be involved in the pathogenesis of IRP and that inhibition of Tfh cells effector molecules might provide opportunities for new therapeutic approaches to IRP and even other human autoimmune diseases. PMID- 24069046 TI - Potential Osteoporosis Recovery by Deep Sea Water through Bone Regeneration in SAMP8 Mice. AB - The aim of this study is to examine the therapeutic potential of deep sea water (DSW) on osteoporosis. Previously, we have established the ovariectomized senescence-accelerated mice (OVX-SAMP8) and demonstrated strong recovery of osteoporosis by stem cell and platelet-rich plasma (PRP). Deep sea water at hardness (HD) 1000 showed significant increase in proliferation of osteoblastic cell (MC3T3) by MTT assay. For in vivo animal study, bone mineral density (BMD) was strongly enhanced followed by the significantly increased trabecular numbers through micro-CT examination after a 4-month deep sea water treatment, and biochemistry analysis showed that serum alkaline phosphatase (ALP) activity was decreased. For stage-specific osteogenesis, bone marrow-derived stromal cells (BMSCs) were harvested and examined. Deep sea water-treated BMSCs showed stronger osteogenic differentiation such as BMP2, RUNX2, OPN, and OCN, and enhanced colony forming abilities, compared to the control group. Interestingly, most untreated OVX-SAMP8 mice died around 10 months; however, approximately 57% of DSW-treated groups lived up to 16.6 months, a life expectancy similar to the previously reported life expectancy for SAMR1 24 months. The results demonstrated the regenerative potentials of deep sea water on osteogenesis, showing that deep sea water could potentially be applied in osteoporosis therapy as a complementary and alternative medicine (CAM). PMID- 24069047 TI - An Experimental Novel Study: Angelica sinensis Prevents Epidural Fibrosis in Laminectomy Rats via Downregulation of Hydroxyproline, IL-6, and TGF- beta 1. AB - With laminectomy being widely accepted as the treatment for lumbar disorders, epidural fibrosis (EF) is a common complication for both the patients and the surgeons alike. Currently, EF is thought to cause recurrent postoperative pain after laminectomy or after discectomy. Angelica sinensis is a traditional Chinese medicine which has shown anti-inflammatory, antifibrotic, and antiproliferative properties. The object of this study was to investigate the effects of Angelica sinensis on the prevention of post-laminectomy EF formation in a rat model. A controlled double-blinded study was conducted in sixty healthy adult Wistar rats that underwent laminectomy at the L1-L2 levels. They were divided randomly into 3 groups according to the treatment method, with 20 in each group: (1) Angelica sinensis treatment group, (2) saline treatment group, and (3) sham group (laminectomy without treatment). All rats were euthanized humanely 4 weeks after laminectomy. The hydroxyproline content, Rydell score, vimentin cells density, fibroblasts density, inflammatory cells density, and inflammatory factors expressions all suggested better results in Angelica sinensis group than the other two groups. Topical application of Angelica sinensis could inhibit fibroblasts proliferation and TGF- beta 1 and IL-6 expressions and prevent epidural scar adhesion in postlaminectomy rat model. PMID- 24069045 TI - Rapamycin ameliorates proteinuria and restores nephrin and podocin expression in experimental membranous nephropathy. AB - OBJECTIVE: Recent studies have shown a beneficial effect of rapamycin in passive and active Heymann Nephritis (HN). However, the mechanisms underlying this beneficial effect have not been elucidated. METHODS: Passive Heymann Nephritis (PHN) was induced by a single intravenous infusion of anti-Fx1 in 12 Sprague Dawley male rats. One week later, six of these rats were commenced on daily treatment with subcutaneous rapamycin 0.5 mgr/kg (PHN-Rapa). The remaining six rats were used as the proteinuric control group (PHN) while six more rats without PHN were given the rapamycin solvent and served as the healthy control group (HC). All rats were sacrificed at the end of the 7th week. RESULTS: Rapamycin significantly reduced proteinuria during the autologous phase of PHN. Histological lesions were markedly improved by rapamycin. Immunofluorescence revealed attenuated deposits of autologous alloantibodies in treated rats. Untreated rats showed decreased glomerular content of both nephrin and podocin whereas rapamycin restored their expression. CONCLUSIONS: Rapamycin monotherapy significantly improves proteinuria and histological lesions in experimental membranous nephropathy. This beneficial effect may be mediated by inhibition of the alloimmune response during the autologous phase of PHN and by restoration of the normal expression of the podocyte proteins nephrin and podocin. PMID- 24069048 TI - Berry and Citrus Phenolic Compounds Inhibit Dipeptidyl Peptidase IV: Implications in Diabetes Management. AB - Beneficial health effects of fruits and vegetables in the diet have been attributed to their high flavonoid content. Dipeptidyl peptidase IV (DPP-IV) is a serine aminopeptidase that is a novel target for type 2 diabetes therapy due to its incretin hormone regulatory effects. In this study, well-characterized anthocyanins (ANC) isolated from berry wine blends and twenty-seven other phenolic compounds commonly present in citrus, berry, grape, and soybean, were individually investigated for their inhibitory effects on DPP-IV by using a luminescence assay and computational modeling. ANC from blueberry-blackberry wine blends strongly inhibited DPP-IV activity (IC50, 0.07 +/- 0.02 to >300 MU M). Of the twenty-seven phenolics tested, the most potent DPP-IV inhibitors were resveratrol (IC50, 0.6 +/- 0.4 nM), luteolin (0.12 +/- 0.01 MU M), apigenin (0.14 +/- 0.02 MU M), and flavone (0.17 +/- 0.01 MU M), with IC50 values lower than diprotin A (4.21 +/- 2.01 MU M), a reference standard inhibitory compound. Analyses of computational modeling showed that resveratrol and flavone were competitive inhibitors which could dock directly into all three active sites of DPP-IV, while luteolin and apigenin docked in a noncompetitive manner. Hydrogen bonding was the main binding mode of all tested phenolic compounds with DPP-IV. These results indicate that flavonoids, particularly luteolin, apigenin, and flavone, and the stilbenoid resveratrol can act as naturally occurring DPP-IV inhibitors. PMID- 24069049 TI - Inhibitory effects of glycyrrhetinic Acid on the delayed rectifier potassium current in Guinea pig ventricular myocytes and HERG channel. AB - Background. Licorice has long been used to treat many ailments including cardiovascular disorders in China. Recent studies have shown that the cardiac actions of licorice can be attributed to its active component, glycyrrhetinic acid (GA). However, the mechanism of action remains poorly understood. Aim. The effects of GA on the delayed rectifier potassium current (I K), the rapidly activating (I Kr) and slowly activating (I Ks) components of I K, and the HERG K(+) channel expressed in HEK-293 cells were investigated. Materials and Methods. Single ventricular myocytes were isolated from guinea pig myocardium using enzymolysis. The wild type HERG gene was stably expressed in HEK293 cells. Whole cell patch clamping was used to record I K (I Kr, I Ks) and the HERG K(+) current. Results. GA (1, 5, and 10 MU M) inhibited I K (I Kr, I Ks) and the HERG K(+) current in a concentration-dependent manner. Conclusion. GA significantly inhibited the potassium currents in a dose- and voltage-dependent manner, suggesting that it exerts its antiarrhythmic action through the prolongation of APD and ERP owing to the inhibition of I K (I Kr, I Ks) and HERG K(+) channel. PMID- 24069050 TI - Preliminary Research of Relationship between Acute Peritonitis and Celiac Primo Vessels. AB - Previous studies demonstrated that primo vessels (PVs) were distributed in different parts of the body in mammals, and PVs were also involved in some processes of pathology such as cancer. Whether PVs are intrinsic structures in mammals or not is still ignored. In this study, a peritonitis model rat was induced by i.p. administration of E. coli in rats. PVs were observed in all infected rats, but it appeared less in untreated rats, taking 10.53% (4/38). In addition, we examined cell types in celiac PVs by fluorescent staining with 4',6 diamidino-2-phenylindole (DAPI) and Alexa Fluor 488 phalloidin, as well as immunofluorescent staining with CD11b and intercellular adhesion molecule-1(ICAM 1), and found the following. (1) The rod-shaped nuclei aligned longitudinally along PVs. (2) DAPI-, phalloidin-, CD11b-, and ICAM-1-positive labeling coexisted in PVs, suggesting that fibroblasts and leucocytes might be two kinds of cell types in PVs for both infected and control rats. (3) The difference was that numerous cells in PVs of the infected rats contained DAPI-labeled multilobal nucleus and were expressed with CD11b- and ICAM-1-positive labeling on the cytoplasm and membrane, showing the typical characteristics of neutrophil. (4) The cells in PVs from the untreated rats are those of loose connective tissue. Therefore, it is reasonably considered that PVs from infected rats might be the pathological products which might be involved in inflammation. PMID- 24069051 TI - Camel Milk as a Potential Therapy as an Antioxidant in Autism Spectrum Disorder (ASD). AB - Extensive studies have demonstrated that oxidative stress plays a vital role in the pathology of several neurological diseases, including autism spectrum disorder (ASD); those studies proposed that GSH and antioxidant enzymes have a pathophysiological role in autism. Furthermore, camel milk has emerged to have potential therapeutic effects in autism. The aim of the current study was to evaluate the effect of camel milk consumption on oxidative stress biomarkers in autistic children, by measuring the plasma levels of glutathione, superoxide dismutase, and myeloperoxidase before and 2 weeks after camel milk consumption, using the ELISA technique. All measured parameters exhibited significant increase after camel milk consumption (P < 0.5). These findings suggest that camel milk could play an important role in decreasing oxidative stress by alteration of antioxidant enzymes and nonenzymatic antioxidant molecules levels, as well as the improvement of autistic behaviour as demonstrated by the improved Childhood Autism Rating Scale (CARS). PMID- 24069052 TI - Increased risk of atopic dermatitis in preschool children with kawasaki disease: a population-based study in taiwan. AB - Kawasaki disease (KD) is an acute febrile systemic vasculitis and has been reported to be associated with allergic disease. The risk of atopic dermatitis (AD) in preschool children with KD has not been investigated. The study was to determine the longitudinal risk of the development of AD in preschool children with KD. A nationwide 5-year population-based study was performed using data from the National Health Insurance Database in Taiwan between 1999 and 2003. The risk factors for AD were compared between the 2 study groups during the follow-up period using the Cox proportional hazards model. In addition, plasma interleukin (IL)-5 levels were analyzed in normal subjects and KD patients. Among the 1440 subjects included, 21.6% developed AD during the 5-year follow-up period, of which 30.3% and 18.7% belonged to the study cohort and the comparison group, respectively. Children with KD were 1.25 times more likely to have AD than those in controls (P = 0.04). Levels of IL-5 and IgE were significantly higher in KD patients. Children with KD had a higher risk of developing AD during the 5-year follow-up period than the control group. Increased IL-5 and IgE levels may be key factors contributing to the risk of AD. PMID- 24069053 TI - Protective Role of Psoralea corylifolia L. Seed Extract against Hepatic Mitochondrial Dysfunction Induced by Oxidative Stress or Aging. AB - The accumulation of oxidative damage and mitochondrial dysfunction is an important factor that contributes to aging. The Psoralea corylifolia seeds (PCS), commonly known as "Boh-Gol-Zhee" in Korea, have been used traditionally as a medicinal remedy. We investigated whether an extract of PCS has protective effects on oxidative stress and mitochondrial function in hepatocytes. The PCS extract showed an antisenescence effect on human diploid fibroblasts as evidenced by a decreased expression of p16(INK4a) mRNA and senescence-associated beta galactosidase staining. PCS extract treatment reduced H2O2-induced reactive oxygen species (ROS) production in HepG2 cells, inhibited ROS production in hepatocytes of aged mice, and increased superoxide dismutase activity. In H2O2 treated HepG2 cells, PCS extract treatment recovered ATP production. PCS extract treatment recovered the oxygen consumption rate and inhibited reduction of mitochondrial membrane potential induced by oxidative stress, suggesting improvement of mitochondrial function. In addition, PCS extract treatment recovered peroxisome proliferator-activated receptor gamma coactivator 1 alpha and carnitine palmitoyltransferase 1 mRNA and protein expression, and inhibited mitochondrial genome damage. Treatment with the major component of PCS extract, bakuchiol, also recovered mitochondrial dysfunction. On the basis of these results, we conclude that PCS extract inhibits ROS production and mitochondrial dysfunction induced by oxidative stress in hepatocytes. PMID- 24069054 TI - Extension trial of qigong for fibromyalgia: a quantitative and qualitative study. AB - This extension trial is an open-label observational trial of 20 subjects with fibromyalgia who undertook level 2 Chaoyi Fanhuan Qigong (CFQ) training following an earlier controlled trial of level 1 CFQ. Subjects practiced 60 min/day for 8 weeks and continued some daily practice for 6 months. Quantitative measures, assessed at baseline, 8 weeks, 4 and 6 months, were of pain, impact, sleep, physical and mental functions, and practice time. Qualitative comments also were recorded. Compared to baselines, CFQ practice led to significant improvements in pain, impact, sleep, and physical function in the 13 subjects (65%) who completed the trial; changes were present at 8 weeks and were maintained for the 6-month trial duration. A highly motivated subgroup of N = 5, who practiced the most, had the best outcomes in terms of end symptomology, and qualitative comments indicated health benefits in other domains as well. Qualitative comments by the remaining N = 8 trial completers and N = 7 withdrawals indicate different experiences with the practice. This extension trial indicates that diligent CFQ practice over time produces significant health gains in fibromyalgia in a subset of individuals. Future studies will need to address factors that might predispose to favourable outcomes. PMID- 24069055 TI - Effect of Gambisan on the Inhibition of Adipogenesis in 3T3-L1 Adipocytes. AB - This study was conducted to explore the antiadipogenic effect and possible mechanism of Gambisan on 3T3-L1 cells. For quality control, Gambisan was standardized by HPLC and the standard compounds ephedrine, epigallocatechin-3 gallate, and caffeine were screened. Cultured 3T3-L1 cells that had been induced to differentiate were treated with various concentrations of Gambisan or its major component extracts (Ephedra intermedia Schrenk, Atractylodes lancea DC., and Thea sinensis L.) for 72 hours for MTT assay to determine cell viability or 10 days for LDH assay, triglyceride assay, DNA content measurement, Oil red O staining, RT-PCR, and western blot. Gambisan significantly inhibited adipogenesis in 3T3-L1 cells by reducing triglyceride contents and lipid accumulation in a dose-dependent manner without obvious cytotoxicity. Viability and DNA content in 3T3-L1 cells treated with Gambisan were significantly higher than cells treated with the major component extracts at every concentration. The anti-adipogenic effects of Gambisan appeared to be mediated by a significant downregulation of the expression of lipoprotein lipase mRNA and PPAR gamma , C/EBP alpha , and SREBP-1 protein apart from the expression of hormone-sensitive lipase. Gambisan could act as a possible therapeutic agent for obesity. However, further studies including in vivo assays and clinical trials are needed to confirm the efficacy, safety and mechanisms of the antiobesity effects of Gambisan. PMID- 24069056 TI - Primary Prevention Programme for Burnout-Endangered Teachers: Follow-Up Effectiveness of a Combined Group and Individual Intervention of AFA Breathing Therapy. AB - Background. Early retirement of teachers due to burnout is frequent in Germany. In this study short- and medium-term effects of AFA breathing therapy were evaluated. Methods. This study was designed as a longitudinal controlled intervention design with four points of measurements: before assessment (T1), after intervention (T2), three months (follow up 1) (T3) after intervention, and six months (follow up 2) after intervention (T4). The intervention lasted a total of 11 weeks (weekly group therapy for eight weeks and three weeks of individual breathing session). The effects of intervention were measured with the questionnaire "work-related behaviour and experience Patterns" (AVEM) at four times. Results. In the intervention group 64 teachers and in the self-selected control group 27 teachers were included. The AVEM scales "subjective significance of work" and "professional ambition" changed over time and within both groups (interaction effect). Significant improvements over the four measurements were observed in the intervention group in two AVEM scales: "emotional distancing" (F = 6.3; P < 0.01) and "balance and mental stability" (F = 4.4; P < 0.02). Conclusions. AFA breathing therapy showed short- and medium-term effects in the intervention group over four points of measurements. It may be assumed that breath therapy supports teachers in resisting occupational demand. PMID- 24069057 TI - Tongxinluo Improves Cardiac Function and Ameliorates Ventricular Remodeling in Mice Model of Myocardial Infarction through Enhancing Angiogenesis. AB - Background. Myocardial infarction (MI) is a major cause of morbidity and mortality in the world. Tongxinluo (TXL) is a traditional Chinese compound prescription which has cardioprotective functions. The present study was aimed to determine the effect of TXL on postischemic cardiac dysfunction and cardiac remodeling and to elucidate the underlying mechanisms. Methods and Results. MI was performed by ligation of left anterior descending coronary artery (LAD) in male adult mice. Mice were randomly divided into four groups: (1) sham group (Sham); (2) MI-control group (Control); (3) MI-low dose TXL group (TXL-L); and (4) MI-high dose TXL (TXL-H) group. Compared with the control group, TXL treatment restored cardiac function, increased revascularization, attenuated cardiomyocyte apoptosis, and reduced interstitial fibrosis. TXL treatment increased the phosphorylation of Akt, extracellular signal regulated kinase (ERK), and endothelial nitric oxide synthase (eNOS); the expression of phosphatidylinositol3-kinase (PI3K), hypoxia-inducible factors 1 alpha (HIF-1 alpha ), and vascular endothelial growth factor (VEGF); and the DNA binding activity of HIF-1 alpha after MI. Conclusion. TXL may improve cardiac function and ameliorate cardiac remodeling by increasing neovascularization through enhancing the phosphorylation of Akt and ERK, the expression and activity of HIF 1 alpha , and the protein level of VEGF and p-eNOS. PMID- 24069058 TI - Meta-analysis of the clinical value of danshen injection and huangqi injection in liver cirrhosis. AB - Objective. To evaluate the clinical value of Danshen injection and Huangqi injection for the treatment of liver cirrhosis. Methods. The Chinese Biomedical Literature Database (CBM), Chinese Scientific Journals Full-Text Database (VIP), Wanfang Database, China National Knowledge Infrastructure (CNKI), PubMed, and EMBASE database were searched to collect the literatures about the randomized controlled trials involving the treatment of liver cirrhosis with Danshen injection combined with Huangqi injection, and the data analyses were performed using RevMan 4.2 software. Results. A total of 11 studies involving 1086 patients (trials group: 554 cases, control group: 532 cases) were included in this study. Compared with those in control group, the meta-analysis showed-that the total effectiveness rate and the level of serum albumin increased, while serum total bilirubin, alanine transmninase, type III procollagen, hyaluronic acid, laminin, and type-IV collagen decreased in trials group. The Jadad score ranged from 1 to 2 and the funnel plot analysis suggests that publication bias may occur. Conclusions. Danshen injection combined with Huangqi injection may promote the curative efficacy of liver cirrhosis, which is a promising novel treatment approach. The exact outcome needs to perform rigorously designed, multicenter, and large randomized controlled trials. PMID- 24069059 TI - The Observation of the Change of TCE Caused by Different Acupuncture Stimulation. AB - Purpose. To observe the change of transcutaneous CO2 emission on meridian points or nonacupoints when the different needle sensations were gotten and study the associativity between Deqi acupuncture and periphery constitution energy metabolism effect. Method. 20 healthy volunteers were punctured on Neiguan (P6) in different ways including sham, shallow, Deqi acupuncture, and Deqi plus pressed P5, and measured TCE of different points before, during, and after acupuncture. Result. Needle sensations of sham acupuncture and shallow acupuncture were less than those of Deqi acupuncture. TCE of meridian points increased significantly and showed the specificity of meridian/channels. Conclusion. Verum acupuncture could cause the stronger needling sensations including distention, aching, numbness, and tingling than sham and shallow acupuncture. The strength of needling sensation caused by Deqi acupuncture is moderate and brought the best curative effects in TCE measurement. Deqi acupuncture could improve the energy metabolism of the points on the corresponding meridian/channel. PMID- 24069060 TI - Patterns of traditional chinese medicine diagnosis in thermal laser acupuncture treatment of knee osteoarthritis. AB - Knee osteoarthritis (OA) manifests with pain, joint stiffness, and limited function. In traditional Chinese medicine, knee OA is differentiated into three patterns: yang deficiency and cold coagulation, kidney deficiency, and blood stasis. The objective of this study was to determine whether yang deficiency cold coagulation patients respond better to thermal laser acupuncture treatment than do non-yang deficient patients. Fifty-two patients with OA were allocated to group A (yang deficient, n = 26) or B (non-yang deficient, n = 26). All patients received a 20-min thermal laser acupuncture treatment at acupoint Dubi (ST 35) three times a week for two weeks and twice a week for another four weeks. Outcome assessments were performed immediately after the first treatment, and at weeks 2, 6, and 10. Group A function scores were significantly better than those of Group B at weeks 2 (P = 0.049), 6 (P = 0.046), and 10 (P = 0.042), but no significant differences were found between the two groups in pain and stiffness scores at any time point. No significant adverse effect was observed. The combined 10.6 MU m 650 nm laser treatment might be most beneficial to yang deficiency cold coagulation knee OA patients, particularly in improving function. PMID- 24069061 TI - Erectogenic and Aphrodisiac Effects of Butea frondosa Koenig ex Roxb. in Rats: Involvement of Enzyme Inhibition. AB - Butea frondosa Koenig ex Roxb. (BF) is traditionally used to manage male sexual disorders including erectile dysfunction (ED). Methanol extract of BF (bark) inhibited Rho-kinase 2 (ROCK-II) enzyme activity in vitro with an IC50 of 20.29 +/- 1.83 MU g/mL. The relaxant effect of methanol extract of BF (MEBF) was studied on phenylephrine precontracted corpus cavernosum smooth muscle (CCSM) isolated from young rats. The effect of MEBF treatment on sexual behaviour of both young (5 month) and aged (24 month) rats was also studied in addition to the influence on smooth muscle, collagen (collagen-I and -III) level in penis, and sperm characteristics of young and aged rats. MEBF relaxed CCSM up to 21.77 +/- 2.57% and increased sexual behavior of young and aged rats. This increase in sexual function could be attributed to ROCK-II inhibition and increase in ratio of smooth muscle to collagen level in rat penile tissue. Increased sperm production and decreased defective sperms in young and aged rats corroborate the usefulness of Butea frondosa in male infertility in addition to ED. PMID- 24069062 TI - Dangguijakyak-San Protects against 1-Methyl-4-phenyl-1,2,3,6,-tetrahydropyridine Induced Neuronal Damage via Anti-Inflammatory Action. AB - Dangguijakyak-san (DJS), a famous traditional Korean multiherbal medicine, has been used to treat gynecological and neuro-associated disease. Recent studies demonstrated that DJS has multiple bioactivities including neuroprotection. In the present study, we were to investigate the effect of DJS and its mechanism in an in vitro and in vivo model of Parkinson's disease (PD). In primary mesencephalic culture system, DJS attenuated the dopaminergic cell damage induced by 1-methyl-4-phenylpyridine toxicity, and it inhibited production of inflammatory factors such as tumor necrosis factor alpha (TNF- alpha ), nitric oxide (NO), and activation of microglial cells. Then, we confirmed the effect of DJS in a mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the pole test, DJS at 50 mg/kg/day for 5 days showed increase of motor activity showing shortened time to turn and locomotor activity compared with the MPTP only treated mice. In addition, DJS significantly protected nigrostriatal dopaminergic neuron from MPTP stress. Moreover, DJS showed inhibition of gliosis in the substantia nigra pars compacta. These results have therapeutic implications for DJS in the treatment of PD via anti-inflammatory effects. PMID- 24069063 TI - Detection of severe respiratory disease epidemic outbreaks by CUSUM-based overcrowd-severe-respiratory-disease-index model. AB - A severe respiratory disease epidemic outbreak correlates with a high demand of specific supplies and specialized personnel to hold it back in a wide region or set of regions; these supplies would be beds, storage areas, hemodynamic monitors, and mechanical ventilators, as well as physicians, respiratory technicians, and specialized nurses. We describe an online cumulative sum based model named Overcrowd-Severe-Respiratory-Disease-Index based on the Modified Overcrowd Index that simultaneously monitors and informs the demand of those supplies and personnel in a healthcare network generating early warnings of severe respiratory disease epidemic outbreaks through the interpretation of such variables. A post hoc historical archive is generated, helping physicians in charge to improve the transit and future allocation of supplies in the entire hospital network during the outbreak. The model was thoroughly verified in a virtual scenario, generating multiple epidemic outbreaks in a 6-year span for a 13-hospital network. When it was superimposed over the H1N1 influenza outbreak census (2008-2010) taken by the National Institute of Medical Sciences and Nutrition Salvador Zubiran in Mexico City, it showed that it is an effective algorithm to notify early warnings of severe respiratory disease epidemic outbreaks with a minimal rate of false alerts. PMID- 24069064 TI - Recent progress on the factorization method for electrical impedance tomography. AB - The Factorization Method is a noniterative method to detect the shape and position of conductivity anomalies inside an object. The method was introduced by Kirsch for inverse scattering problems and extended to electrical impedance tomography (EIT) by Bruhl and Hanke. Since these pioneering works, substantial progress has been made on the theoretical foundations of the method. The necessary assumptions have been weakened, and the proofs have been considerably simplified. In this work, we aim to summarize this progress and present a state of-the-art formulation of the Factorization Method for EIT with continuous data. In particular, we formulate the method for general piecewise analytic conductivities and give short and self-contained proofs. PMID- 24069065 TI - Esophagus segmentation from 3D CT data using skeleton prior-based graph cut. AB - The segmentation of organs at risk in CT volumes is a prerequisite for radiotherapy treatment planning. In this paper, we focus on esophagus segmentation, a challenging application since the wall of the esophagus, made of muscle tissue, has very low contrast in CT images. We propose in this paper an original method to segment in thoracic CT scans the 3D esophagus using a skeleton shape model to guide the segmentation. Our method is composed of two steps: a 3D segmentation by graph cut with skeleton prior, followed by a 2D propagation. Our method yields encouraging results over 6 patients. PMID- 24069066 TI - Analytical solutions for the mathematical model describing the formation of liver zones via Adomian's method. AB - The formation of liver zones is modeled by a system of two integropartial differential equations. In this research, we introduce the mathematical formulation of these integro-partial differential equations obtained by Bass et al. in 1987. For better understanding of this mathematical formulation, we present a medical introduction for the liver in order to make the formulation as clear as possible. In applied mathematics, the Adomian decomposition method is an effective procedure to obtain analytic and approximate solutions for different types of operator equations. This Adomian decomposition method is used in this work to solve the proposed model analytically. The stationary solutions (as time tends to infinity) are also obtained through it, which are in full agreement with those obtained by Bass et al. in 1987. PMID- 24069067 TI - Breast cancer characterization based on image classification of tissue sections visualized under low magnification. AB - Rapid assessment of tissue biopsies is a critical issue in modern histopathology. For breast cancer diagnosis, the shape of the nuclei and the architectural pattern of the tissue are evaluated under high and low magnifications, respectively. In this study, we focus on the development of a pattern classification system for the assessment of breast cancer images captured under low magnification (*10). Sixty-five regions of interest were selected from 60 images of breast cancer tissue sections. Texture analysis provided 30 textural features per image. Three different pattern recognition algorithms were employed (kNN, SVM, and PNN) for classifying the images into three malignancy grades: I III. The classifiers were validated with leave-one-out (training) and cross validation (testing) modes. The average discrimination efficiency of the kNN, SVM, and PNN classifiers in the training mode was close to 97%, 95%, and 97%, respectively, whereas in the test mode, the average classification accuracy achieved was 86%, 85%, and 90%, respectively. Assessment of breast cancer tissue sections could be applied in complex large-scale images using textural features and pattern classifiers. The proposed technique provides several benefits, such as speed of analysis and automation, and could potentially replace the laborious task of visual examination. PMID- 24069068 TI - AGRO-ECOLOGICAL DRIVERS OF RURAL OUT-MIGRATION TO THE MAYA BIOSPHERE RESERVE, GUATEMALA. AB - Migration necessarily precedes environmental change in the form of deforestation and soil degradation in tropical agricultural frontiers. But what environmental factors may contribute to these migration streams in the first place? Identifying environmental characteristics related to this process is crucial for understanding how environmental change and migration may form recurrent feedback loops. Further understanding this process could be useful for developing policies to reduce both environmentally induced migration from origin areas and also to palliate significant environmental change unleashed by settler deforestation in destination areas. Evidently, apprehending this holistic process cannot be approached only from the destination since this ignores environmental and other antecedents to rural out-migration. This paper presents data from surveys conducted in areas of high out-migration to the agricultural frontier in northern Guatemala. Results suggest that land scarcity and degradation in origin communities are linked to out-migration in general and to the forest frontier of northern Guatemala in particular. PMID- 24069069 TI - The autophagy inhibitor verteporfin moderately enhances the antitumor activity of gemcitabine in a pancreatic ductal adenocarcinoma model. AB - Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy. It has been described as requiring elevated autophagy for growth and inhibiting autophagy has been proposed as a treatment strategy. To date, all preclinical reports and clinical trials investigating pharmacological inhibition of autophagy have used chloroquine or hydroxychloroquine, which interfere with lysosomal function and block autophagy at a late stage. Verteporfin is a newly discovered autophagy inhibitor that blocks autophagy at an early stage by inhibiting autophagosome formation. Here we report that PDAC cell lines show variable sensitivity to verteporfin in vitro, suggesting cell-line specific autophagy dependence. Using image-based and molecular analyses, we show that verteporfin inhibits autophagy stimulated by gemcitabine, the current standard treatment for PDAC. Pharmacokinetic and efficacy studies in a BxPC-3 xenograft mouse model demonstrated that verteporfin accumulated in tumors at autophagy-inhibiting levels and inhibited autophagy in vivo, but did not reduce tumor volume or increase survival as a single agent. In combination with gemcitabine verteporfin moderately reduced tumor growth and enhanced survival compared to gemcitabine alone. While our results do not uphold the premise that autophagy inhibition might be widely effective against PDAC as a single-modality treatment, they do support autophagy inhibition as an approach to sensitize PDAC to gemcitabine. PMID- 24069070 TI - Daily Pomegranate Intake Has No Impact on PSA Levels in Patients with Advanced Prostate Cancer - Results of a Phase IIb Randomized Controlled Trial. AB - Pomegranate has been shown to prolong PSA doubling time in early prostate cancer, but no data from a placebo controlled trial has been published yet. The objective of this study was to prospectively evaluate the impact of pomegranate juice in patients with prostate cancer. We conducted a phase IIb, double blinded, randomized placebo controlled trial in patients with histologically confirmed prostate cancer. Only patients with a PSA value >= 5ng/ml were included. The subjects consumed 500 ml of pomegranate juice or 500 ml of placebo beverage every day for a 4 week period. Thereafter, all patients received 250 ml of the pomegranate juice daily for another 4 weeks. PSA values were taken at baseline, day 14, 28 and on day 56. The primary endpoint was the detection of a significant difference in PSA serum levels between the groups after one month of treatment. Pain scores and adherence to intervention were recorded using patient diaries. 102 patients were enrolled. The majority of patients had castration resistant prostate cancer (68%). 98 received either pomegranate juice or placebo between October 2008 and May 2011. Adherence to protocol was good, with 94 patients (96%) completing the first period and 87 patients (89%) completing both periods. No grade 3 or higher toxicities occurred within the study. No differences were detected between the two groups with regard to PSA kinetics and pain scores. Consumption of pomegranate juice as an adjunct intervention in men with advanced prostate cancer does not result in significant PSA declines compared to placebo. PMID- 24069071 TI - Fear of dental treatment--an underrecognized symptom in people with impaired mental health. AB - BACKGROUND: In industrialized countries, about 5% to 15% of all adults have a pathologically severe fear of dental treatment, and some 3% avoid going to the dentist altogether. The affected persons may, in turn, suffer from severe dental diseases and their psychosocial effects. Many people with dental phobia have other mental disorders as well. These facts motivated us to study the prevalence of fear of dental treatment in a group of patients being treated by our psychosomatic service. METHOD: 212 patients of our psychosomatic service and 95 healthy controls were studied with the Hierarchical Anxiety Questionnaire (HAQ) to determine the intensity of their fear of dental treatment. Mental disorders were diagnosed with structured clinical interviews according to DSM-IV. RESULTS: Nearly one patient in three (30.5%, n = 64) suffered from pathologically severe fear of dental treatment; 24 of them (38.5%) had avoided visiting a dentist for longer than one year. Only 4 (4.2%) of the healthy controls were greatly afraid of dental treatment. Certain types of mental disorder were especially highly associated with fear of dental treatment: in particular, anxiety disorders (relative risk [RR] 7.44, 95% confidence interval [CI] 2.68-20.70) and depressive disorders (RR 4.92, 95% CI 1.73-14.05). Patients with post-traumatic stress disorder were affected most commonly: 34 (42%) of these patients were greatly afraid of dental treatment (RR 9.97, 95% CI 3.69-26.90). 75 of the 134 study participants who were afraid of dental treatment (56%) had cancelled a dental appointment, or failed to appear for a scheduled appointment, because of their fears. CONCLUSION: Fear of dental treatment commonly accompanies certain types of mental disorder. Patients at high risk should be asked about such fears so that the problem can be recognized early and appropriately treated. PMID- 24069072 TI - Anticoagulation in atrial fibrillation: NOAC's the word. PMID- 24069073 TI - The perioperative management of treatment with anticoagulants and platelet aggregation inhibitors. AB - BACKGROUND: When giving anticoagulants and inhibitors of platelet aggregation either prophylactically or therapeutically, physicians face the challenge of protecting patients from thromboembolic events without inducing harmful bleeding. Especially in the perioperative period, the use of these drugs requires a carefully balanced evaluation of their risks and benefits. Moreover, the choice of drug is difficult, because many different substances have been approved for clinical use. METHOD: We selectively searched for relevant publications that appeared from 2003 to February 2013, with particular consideration of the guidelines of the European Society of Cardiology, the Association of Scientific Medical Societies in Germany (AWMF), the American College of Cardiology, and the American Heart Association. RESULTS: Vitamin K antagonists (VKA), low molecular weight heparins, and fondaparinux are the established anticoagulants. The past few years have seen the introduction of orally administered selective inhibitors of the clotting factors IIa (dabigatran) and Xa (rivaroxaban, apixaban). The timing of perioperative interruption of anticoagulation is based on pharmacokinetic considerations rather than on evidence from clinical trials. Recent studies have shown that substituting short-acting anticoagulants for VKA before a procedure increases the risk of bleeding without lowering the risk of periprocedural thromboembolic events. The therapeutic spectrum of acetylsalicylic acid and clopidogrel has been broadened by the newer platelet aggregation inhibitors prasugrel and ticagrelor. Patients with drug eluting stents should be treated with dual platelet inhibition for 12 months because of the risk of in stent thrombosis. CONCLUSION: Anticoagulants and platelet aggregation inhibitors are commonly used drugs, but the evidence for their perioperative management is limited. The risks of thrombosis and of hemorrhage must be balanced against each other in the individual case. Anticoagulation need not be stopped for minor procedures. PMID- 24069074 TI - The prevalence of nosocomial and community acquired infections in a university hospital: an observational study. AB - BACKGROUND: Nosocomial infections (NI) increase morbidity and mortality. Studies of their prevalence in single institutions can reveal trends over time and help to identify risk factors. METHODS: In March and April 2010, data were prospectively recorded from all inpatients at the Hannover Medical School (Germany) except those treated in the pediatric, psychosomatic, and psychiatric services. The data were acquired systematically by chart review and by interviews with the medical staff. Infections were classified according to the definitions of the Centers for Disease Control and Prevention (CDC). Information was obtained on underlying diseases, invasive procedures, the use of antibiotics, devices (the application of specific medical techniques such as drainage, vascular catheters, etc.), and detected pathogens. RESULTS: Of the 1047 patients studied, 117 (11.2%) had a total of 124 nosocomial infections, while 112 (10.7%) had 122 community acquired infections. The most common NI were surgical site infections (29%), infections of the gastrointestinal tract (26%) and respiratory tract (19%), urinary tract infections (16%), and primary sepsis (4%). The most common pathogens were Escherichia coli, coagulase-negative staphylococci, Candida spp., Enterococcus spp., and Pseudomonas aeruginosa. Multivariable regression analysis revealed the following independent risk factors for NI: antibiotic treatment in the last 6 months (odds ratio [OR] = 2.9), underlying gastrointestinal diseases (OR = 2.3), surgery in the last 12 months (OR = 1.8), and more than two underlying diseases (OR = 1.7). Each additional device that was used gave rise to an OR of 1.4. Further risk factors included age, length of current or previous hospital stay, trauma, stay on an intensive care unit, and artificial ventilation. CONCLUSION: In this prevalence study, NI were a common complication. Surgical site infections were the single most common type of NI because of the large number of patients that underwent surgical procedures in our institution. More investigation will be needed to assess the benefit of prevalence studies for optimizing appropriate, effective preventive measures. PMID- 24069075 TI - Excessive treatment with anticoagulants. PMID- 24069076 TI - Education for patients taking anticoagulants. PMID- 24069077 TI - In reply. PMID- 24069078 TI - Extracorporeal lung support in H1N1 provoked acute respiratory failure: the experience of the German ARDS Network. AB - BACKGROUND: During the H1N1 pandemic of 2009 and 2010, the large number of patients with severe respiratory failure due to H1N1 infection strained the capacities of treatment facilities for extracorporeal membrane oxygenation (ECMO) around the world. No data on this topic have yet been published for Germany. METHODS: During the pandemic, the German ARDS Network (a task force of the DIVI's respiratory failure section) kept track of the availability of ECMO treatment facilities with a day-to-day, Internet-based capacity assessment. In cooperation with the Robert Koch Institute, epidemiological and clinical data were obtained on all patients treated for influenza in intensive care units. RESULTS: 116 patients were identified who had H1N1 disease and were treated in the intensive care units of 9 university hospitals and 3 other maximum medical care hospitals. 61 of them received ECMO. The overall mortality was 38% (44 of 116 patients); among patients receiving ECMO, the mortality was 54% (33 of 61 patients). The mortality was higher among patients who had an accompanying malignancy or immune deficiency (72.2%). CONCLUSION: Even persons without any other accompanying disease developed life-threatening respiratory failure as a result of H1N1 infection, and many of these patients needed ECMO. This study reveals for the first time that the mortality of H1N1 infection in Germany is comparable to that in other countries. H1N1 patients with acute respiratory failure had a worse outcome if they also had serious accompanying diseases. PMID- 24069080 TI - Correspondence (letter to the editor): Numerous errors. PMID- 24069079 TI - The incidence and determinants of decubitus ulcers in hospital care: an analysis of routine quality management data at a university hospital. AB - BACKGROUND: The incidence of decubitus ulcers is an established quality indicator for external quality assurance in the inpatient setting. Epidemiologic analyses of the frequency of, and risk factors for, decubitus ulcers in routine care are lacking. METHOD: We analyzed routine decubitus-ulcer documentation data relating to all inpatients of the University Hospital of Dresden, Germany, from 2007 to 2011 (n = 246 162 patients). The prevalence and incidence of decubitus ulcers and demographic and illness-related risk factors for them were determined with the use of descriptive techniques and logistic regression models. The effort-to benefit ratio of documenting decubitus ulcers in various care scenarios was calculated in terms of the number of additional patients to be documented for each patient with incident decubitus ulcer. RESULTS: The prevalence of decubitus ulcers was 1.21%, and their incidence during inpatient treatment was 0.78%, with significant differences across clinical care units (range of ward-specific incidences: 0.0% to 12.7%). Predictors for the development of a new decubitus ulcer during a hospital stay included higher age (odds ratio [OR] 1.03 per year, 95% confidence interval [CI] 1.02-1.03), longer hospital stay (OR 1.03 per day, 95% CI 1.031-1.033), treatment in an intensive care unit (OR 2.88, 95% CI 2.58 3.22), and transfer to the hospital from a residential nursing-care facility (OR 6.05, 95% CI 5.13-7.11). The patient's sex and the severity of disease were not correlated with the incidence of decubitus ulcers. The effort-to-benefit ratio could be improved if wards with a low incidence of decubitus ulcers (<0.5%) either entirely discontinued the current hospital-wide procedure for documenting decubitus ulcers (with one new ulcer for every 645 patients) or continued it only for patients aged 65 or older (with one new ulcer for every 902 patients). CONCLUSION: There are major differences between clinical care units in the risk of decubitus ulcers. Epidemiological analysis of routine quality management data is useful to assess the benefit of measures taken in medical care. Continuing evaluation is essential. PMID- 24069081 TI - Correspondence (letter to the editor): Primary prevention of premature labor was given short shrift. PMID- 24069082 TI - Correspondence (letter to the editor): thyroid function as a possible cause. PMID- 24069083 TI - Correspondence (letter to the editor): Administration of vitamin D. PMID- 24069084 TI - Correspondence (letter to the editor): Previous induced terminations. PMID- 24069085 TI - Correspondence (letter to the editor): The coagulation status should be determined. PMID- 24069086 TI - Correspondence (reply): In reply. PMID- 24069087 TI - Correspondence (letter to the editor): Ancient healing arts. PMID- 24069088 TI - Correspondence (letter to the editor): Umbilical cord vein. PMID- 24069089 TI - Correspondence (letter to the editor): Self-help. PMID- 24069090 TI - Correspondence (reply): In reply. PMID- 24069093 TI - The global technical potential of bio-energy in 2050 considering sustainability constraints. AB - Bio-energy, that is, energy produced from organic non-fossil material of biological origin, is promoted as a substitute for non-renewable (e.g., fossil) energy to reduce greenhouse gas (GHG) emissions and dependency on energy imports. At present, global bio-energy use amounts to approximately 50 EJ/yr, about 10% of humanity's primary energy supply. We here review recent literature on the amount of bio-energy that could be supplied globally in 2050, given current expectations on technology, food demand and environmental targets ('technical potential'). Recent studies span a large range of global bio-energy potentials from ~30 to over 1000 EJ/yr. In our opinion, the high end of the range is implausible because of (1) overestimation of the area available for bio-energy crops due to insufficient consideration of constraints (e.g., area for food, feed or nature conservation) and (2) too high yield expectations resulting from extrapolation of plot-based studies to large, less productive areas. According to this review, the global technical primary bio-energy potential in 2050 is in the range of 160-270 EJ/yr if sustainability criteria are considered. The potential of bio-energy crops is at the lower end of previously published ranges, while residues from food production and forestry could provide significant amounts of energy based on an integrated optimization ('cascade utilization') of biomass flows. PMID- 24069092 TI - Racial and Ethnic Disparities in Leisure-time Physical Activity in California: Patterns and Mechanisms. AB - Evidence has shown that racial-ethnic minorities in the U.S. are less likely than whites to engage in leisure-time physical activity (LTPA); yet few studies to date have included Asian subgroups in the analyses and mechanisms underlying these disparities are not well-known. This study uses data from the 2007 California Health Interview Survey (N=37,164) to examine racial-ethnic disparities in self-reported adherence to LTPA recommendations and explore the mediating roles of socioeconomic status (SES), acculturation, and neighborhood perceptions. Nine racial-ethnic groups were included: non-Hispanic whites, non Hispanic blacks, Mexicans, and six largest Asian subgroups. Results confirm that racial-ethnic minorities are, in general, less likely than whites to meet LTPA recommendations, whereas heterogeneity is also evident across Asian subgroups. No significant disparity is revealed for the Japanese and Filipinos but whites are advantaged compared to all other Asian groups. Educational attainment, percent of lifetime spent in the U.S., and access to park, playground, or open space are significantly associated with meeting the LTPA recommendations. SES and acculturation play differential roles in explaining group disparities for blacks, Mexicans, and some Asian subgroups. Perceived neighborhood environment does not mediate LTPA disparities by race-ethnicity. Net of these mediators, the advantages of whites in meeting LTPA recommendations persist for blacks, Mexicans, the Chinese, and Koreans. Future research should theorize and operationalize additional multilevel pathways linking race-ethnicity and LTPA while assessing measurement errors in the existing constructs. PMID- 24069091 TI - Shortness of breath and cough in patients in palliative care. AB - BACKGROUND: Shortness of breath and cough are common, disturbing symptoms in patients receiving palliative care. They arise in 10% to 70% of patients with advanced cancer and in 60% to nearly 100% of patients with non-malignant underlying diseases, depending on the type of disease. METHODS: This review is based on a selective literature search in the Medline, Embase, and PsycInfo databases and on current recommendations from Germany and other countries, as well as on the authors' personal experience. RESULTS: Some general measures to address these problems are reassurance, development of an emergency plan, physical activity, and relaxation exercises. Supportive non-pharmacological measures may include the use of a rollator (level of evidence [LoE] 1-), a cool draft of air as from a handheld fan (LoE 1-), physiotherapy, and respiratory therapy. There is good evidence (LoE 1+) to support the administration of opioids as the medications of choice; benzodiazepines are often used, but a meta-analysis did not reveal any statistically significant benefit (LoE 1+). Expectorants can help patients who cough with marked sputum formation. Antitussants suppress the cough reflex both peripherally and centrally (LoE 1+ to 3). Opioids, including morphine (LoE 1-) and dextromethorphan (LoE 1-), are effective antitussants with low toxicity. CONCLUSION: In most patients, shortness of breath and cough can be relieved by a series of therapeutic measures. PMID- 24069094 TI - [Not Available]. PMID- 24069095 TI - Updated assessment of neobladder utilization and morbidity according to urinary diversion after radical cystectomy: A contemporary US-population-based cohort. AB - BACKGROUND: In this paper, we examine contemporary utilization rates and determinants of neobladder (NB) after radical cystectomy (RC) relative to ileal conduit (IC), as well as provide an updated assessment of postoperative morbidity and mortality between NB and IC. METHODS: Relying on the Nationwide Inpatient Sample (NIS), we abstracted patients who underwent RC between 2000 and 2010. Subsequently, NB and IC recipients were identified. Use of NB was assessed after accounting for case-mix. Propensity-based matched analyses were used to account for treatment selection biases. Generalized linear regression analyses focused on intra- and postoperative complications, prolonged length of stay, blood transfusions and in-hospital mortality. RESULTS: The utilization rate of NB was 6.9% in 2000 and 9.1% in 2010 (p < 0.001). Younger, healthier, privately-insured and wealthier male individuals were more likely to receive a NB. High-volume hospitals were more likely to offer NB. In the post-propensity matched cohort, urinary diversion type failed to be significantly associated with the examined endpoints, except for intra- and postoperative complications (IC vs. NB odds ratio [OR]: 1.15, p = 0.04). INTERPRETATION: Despite comparable morbidity and mortality odds between NB and IC, as of the most contemporary year of the study (2010), IC remains the preferred urinary diversion type. Several sociodemographic factors were associated with NB. PMID- 24069096 TI - Positive surgical margins at radical prostatectomy: Population-based averages within PSA and Gleason strata. AB - BACKGROUND: Positive surgical margins (PSM) are an important determinant of biochemical recurrence after radical prostatectomy (RP). We use a population based cancer registry to evaluate PSM by stage, Gleason and prostate-specific antigen (PSA). METHODS: We identified men undergoing RP from the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2007. Differences between those with and without PSM were compared with chi-squared tests. The proportion of cases with PSM were stratified by PSA and Gleason sum for both pT2 and pT3a tumours. Factors associated with PSM were analyzed using chi square and multivariate logistic regression analysis. A composite variable was used in a second multivariate analysis to display the odds ratio (OR) for a PSM for each discrete combination of PSA, Gleason score and pT stage. RESULTS: In total, 28 461 RP patients were identified and a PSM was present in 19.5%. PSM were 42% in pT3a and 16% in pT2 cases. Higher PSAs (<4.0, 4-9.9, >10) were associated with higher proportions of PSM (12%, 20% and 28%, p < 0.001). Similarly, higher Gleason scores (<=6, 3+4, 4+3, >=8) were associated with higher PSM (12%, 22%, 27% and 33%, p < 0.001). For pT2 tumours, the proportion of PSM ranged from 8% (Gleason <=6, PSA <4.0) to 28% (Gleason 8-10, PSA >=10). For pT3a tumours, the PSM was higher in each Gleason/PSA strata compared to those with pT2 tumours, reaching 63% for those with pT3a, Gleason 8-10, PSA >10 disease. On multivariate analysis, stage was the largest predictor for PSM (OR 3.05, 95% confidence interval 2.81-3.30), although Gleason score and PSA remained statistically significant. CONCLUSION: In this population-based study of PSM after RP, the proportion of PSM vary significantly within different PSA and Gleason strata for organ-confined and extracapsular disease. These data can be used as a reference for urologist self-assessment. PMID- 24069097 TI - Needle biopsy size and pathological Gleason Score diagnosis: No evidence for a link. AB - BACKGROUND: Biopsy Gleason score (GS), in combination with other clinical parameters, is important to take a therapeutic decision for patients with diagnosis of localized prostate cancer. However, preoperative GS is often upgraded after a radical prostatectomy. Increasing the amount of tissue in prostate biopsy may be a way to avoid this issue. We evaluate the influence of a larger biopsy needle size on the concordance between biopsy and pathological GS. METHODS: We analyzed paired biopsies and prostatectomy specimens from 104 cases of men with clinically localized prostate cancer. At the time of prostate biopsy, the patients were prospectively randomized into two needle groups (16-Gauge [G] and 18G) using a 1:1 ratio. GS concordance was estimated performing kappa statistic testing, overall concordance rate and risk to under grade biopsy GS=6. A logistic regression analysis was performed to evaluate the patients' characteristics as possible risk factors. RESULTS: The overall concordance between prostate biopsy and pathological GS was 76.9% and 75.6% (p = 0.875) and the k values were 0.821 and 0.811 (p = 0.424), respectively, for 16G and 18G needle study groups. The risk to undergrade a biopsy GS=6 was 21.1% and 15.4% (p = 0.709) using a 16G and 18G needle, respectively. Age, prostate-specific antigen, prostate volume and needle calibre were not independently associated with a higher risk of GS discordance. CONCLUSIONS: Needle size does not affect the concordance between biopsy and pathological GS. Although GS is not the only way to determine treatment, it is still an unresolved urological issue. PMID- 24069098 TI - Evaluation of epidemiology, concomitant urethral disruption and seasonal variation of penile fracture: A report of 86 cases. AB - INTRODUCTION: Penile fracture (PF) is a well-recognized clinical entity and is often deemed a urological emergency. It is not uncommon in our region. The main objective of this study is to describe the clinical characteristics of patients diagnosed with penile fracture in the Qom Province, Iran. We evaluate surgical treatment, concomitant urethral disruption and its seasonal variation. METHODS: This is a descriptive retrospective study, reviewing all the medical records of patients admitted with penile fracture from 2003 to 2012 at Kamkar Hospital of Qom, Iran. It takes into account variables related to the urological history, etiology, diagnosis and its surgical treatment. The epidemiologic data, marriage status and the seasonal variation were evaluated. In total, 86 patients, aged between 17 and 62, with PF were hospitalized in our centre. The average age of patients was 36.74 years. All operated cases were followed 3 months and 6 months after surgery. RESULTS: Of the 86 patients, 34 (68%) were the ages of 20 and 40. In terms of marital status, 56 (65%) were married and 30 (35%) were single at the time of presentation. Twenty-six patients (30.2%) had episodes related to intercourse and 48 patients (56%) to manual habitual trauma; the remaining 12 patients had a direct blow to an erect penis or rolled/fell off a bed. Patients presented with swelling, pain and a popping or cracking sound in the penis. The diagnosis was made using history and physical examination in all patients. Unilateral corporeal ruptures were present in 80 (93%) and bilateral in 2 cases (2.32%). Surgical repair was performed with a circumferential sub-coronal degloving incision in 82 cases (95.35%). There were seasonal variations: 22 cases in spring; 25 in summer; 17 in autumn; 22 in winter. Patients had an average postoperative hospital stay of 1 day. CONCLUSION: Habitual manual trauma was the most common cause of PF in our study. Immediate surgical intervention has low morbidity, short hospital stay and rapid functional recovery. In the case of urethrorhagia, concomitant urethral injury should be evaluated. On the basis of our study, PF may have seasonal variation. PMID- 24069099 TI - A population-based study of surgeon characteristics associated with the uptake of contemporary techniques in renal surgery. AB - INTRODUCTION: We have witnessed the slow uptake of many contemporary techniques in the surgical management of renal tumours. We sought to evaluate surgeon-level characteristics associated with the uptake of laparoscopy, partial nephrectomy (PN) and adrenal-sparing approaches in surgically managing these tumours. METHODS: Using the Ontario Cancer Registry, we identified surgeons treating renal cell carcinoma (RCC) in the province of Ontario, Canada between 2002 and 2004. We then classified individuals within this cohort as either high or low utilizers of laparoscopy, PN or adrenal-sparing approaches. Further variables analyzed included academic status, surgeon graduation year and surgical volume status. We then used univariable and multivariable logistic regression models to assess predictors of uptake. RESULTS: We evaluated a total of 108 surgeons for their uptake of both laparoscopy and adrenal-sparing approaches and 94 surgeons for their uptake of PN. We identified 32 surgeons (30%) as high users of laparoscopy. Predictors of uptake of laparoscopy included graduation year after 1990 (odds ratio [OR] 4.81, confidence interval [CI] 1.57-14.8) and high-surgeon volume (OR 4.33, CI 1.60-10.4). We identified 41 surgeons (44%) as high users of PN. The only predictor of uptake of PN was academic status (OR 5.83, CI 1.96-17.3). We identified 69 surgeons (65%) as high users of adrenal-sparing approaches, but did not identify any significant predictors for uptake in this group. DISCUSSION: We identify unique factors contributing to the uptake of distinct surgical techniques in the management of RCC. This information sheds lights on the underlying mechanisms and helps us understand how to further encourage the dissemination of these practices. PMID- 24069100 TI - Canadian trend in surgical management of benign prostatic hyperplasia and laser therapy from 2007-2008 to 2011-2012. AB - INTRODUCTION: Clinically benign prostatic hyperplasia (BPH) is classically associated by the progressive development of lower urinary tract symptoms (LUTS). The incidence of bothersome LUTS is associated with age and may vary in patients over 50 years old. In many developing countries with an aging population, BPH associated with LUTS has become a major health issue. To optimize quality of care and control of cost, there is an imperative need to examine the pattern of BPH management. The goal of this study is to capture the Canadian trend in surgical management of BPH and the use of laser therapy during the last 5 years from 2007 2008 to 2011-2012. METHODS: We collected the number of transurethral resection of the prostate (TURP) procedures performed in each province in Canada from the Canadian Institute for Health Information (CIHI) reports for the fiscal years (April 1(st)-March 31(st)) of 2007-2008, 2008-2009, 2009-2010, 2010-2011 and 2011 2012. RESULTS: Overall, the total number of TURP procedures remained stable from 20 294 procedures per year in 2007 to 20 629 in 2011. In terms of distribution according to provinces, in 2011, about 40% of procedures were performed in Ontario, 20% in BC, 18 in Quebec and 8% in Alberta. These proportions between provinces have remained similar and stable between 2007 and 2011. In contrast, the number of alternative minimally invasive procedures has slowly grown from 767 interventions in 2007 to 1559 in 2011. Overall, laser procedures represented 7.6% of the total number of BPH surgeries in Canada in 2011. The contribution of laser therapy to the amount of total BPH procedures largely varied between provinces. CONCLUSIONS: The use of minimally invasive laser procedure alternatives to TURP is progressively growing. Among the novel laser therapies, HoLEP and GreenLight vaporization are the only procedures that have demonstrated equivalent outcomes compared to TURP in randomized clinical trials. Furthermore, due to shorter hospital stay, these novel laser modalities have the potential to reduce healthcare expenses for the treatment of BPH. We can infer that following the trend observed in the United States, the number of laser therapies for BPH in Canada may increase significantly during the coming years. PMID- 24069101 TI - Spontaneous regression of metastatic pulmonary renal cell carcinoma in the setting of sarcomatoid differentiation of the primary tumour. AB - We present a case of spontaneous regression of pulmonary metastases from renal cell carcinoma (RCC) with sarcomatoid differentiation, prior to intervention. The patient presented with conventional type RCC with Furhman Grade 4/4 and sarcomatoid differentiation, complicated by pulmonary metastases. Palliative systemic therapy was planned, but prior to the onset of treatment, serial computed tomography scans demonstrated regression of metastatic disease. Spontaneous regression of metastases is rare, but well-documented in conventional clear cell RCC. To the best of our knowledge, this has not previously been described in the setting of sarcomatoid differentiation of the primary tumour. PMID- 24069102 TI - Lymphoepithelioma-like carcinoma of the renal pelvis: Pathological and therapeutic implications. AB - A 75-year-old woman presented with a presumed urothelial carcinoma of the right renal pelvis. A radical nephroureterectomy was carried out and histological analysis of the specimen revealed lymphoepithelioma-like carcinoma. This is the seventh reported case of this normally nasopharyngeal tumour found in the renal pelvis. These tumours have a distinct histological appearance comprising sheets of undifferentiated syncytial cells on a background of lymphoid stroma. We review the pathological features of lymphoepithelioma-like carcinoma and make arguments for managing these tumours in a similar way to urothelial carcinoma. PMID- 24069103 TI - Classification, diagnosis and treatment of ACTH-independent macronodular adrenal hyperplasia. AB - ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a distinctive subtype of Cushing's syndrome (CS), with different clinical manifestations according to the level of serum cortisol. Based on clinical manifestations and serum cortisol, we divide AIMAH into three types, subclinical AIMAH, clinical AIMAH and high-risk AIMAH, with varied treatment methods being adapted to different subtypes. At the same time, we describe 3 patients who represent these subtypes of this disease, and review some cases of AIMAH which have been previously reported in the English literature. To our knowledge, this is the first article discussing classification, diagnosis and treatment of this disease and should be useful for future therapy of AIMAH. PMID- 24069104 TI - A severe complication of mid-urethral tapes solved by laparoscopic tape removal and ureterocutaneostomy. AB - Mid-urethral tapes are largely used to manage stress urinary incontinence (SUI). In certain cases, however, this procedure results in bothersome complications that lead to complete resection. We present the case of an 85-year-old woman who presented with ongoing suprapubic pain, hematuria, vaginal bleeding and recurrent urinary tract infections. The patient had undergone a tension-free vaginal tape (TVT) procedure in 1999 and a transobturator tape (TOT) placement in 2003 for SUI. Investigations revealed a urethral stone, erosion of both TOT and TVT and an urethra-vaginal fistula. Under local anesthesia the urethral stone was removed endoscopically and the TOT removed via a vaginal approach. Due to her comorbidity, she underwent a laparoscopic intraperitoneal removal of the TVT and a definitive ureterocutaneostomy to relieve her pain, inflammation and incontinence. This is the first ever presented case of erosion of mid-urethral tapes and incontinence treated with a laparoscopic resection of the tape and ureterocutaneostomy as definitive urinary diversion. PMID- 24069105 TI - Malignant peripheral nerve sheath tumour of the renal parenchyma presenting as a fast growing atypical renal cyst. AB - Malignant peripheral nerve sheath tumours (MPNST) of the kidney are very rare, with only 3 cases reported in the English and French literature. However, we report the first case of fast growing atypical renal cyst where a magnetic resonance imaging was an interesting adjunct to the computed tomography scan in imaging this rare tumour. PMID- 24069106 TI - Delayed massive hemorrhage due to external iliac artery pseudo-aneurysm and uretero-iliac artery fistula following robotic radical cystectomy and intracorporeal Studer pouch reconstruction: Endovascular management of an unusual complication. AB - We report a very unusual complication of uretero-iliac artery fistula that developed following robotic radical cystectomy (RARC), bilateral extended pelvic lymph node dissection and intracorporeal Studer pouch reconstruction. Our patient was a 54-year-old male who was admitted 1 month after undergoing robotic surgery due to intermittently occurring massive transurethral bleeding necessitating blood transfusion that stopped by itself. Angiography showed a right external iliac artery pseudo-aneurysm and a fistula tract between the pseudo-aneurysm and Wallace type ureteral anostomosis that was successfully treated by an angiographic endovascular stent insertion at this level. Uretero-iliac artery fistula might occur following RARC, bilateral extended pelvic lymph node dissection and intracorporeal Studer pouch reconstruction leading to intermittently massive transurethral bleeding. Angiography and stenting are important for diagnosis and successful treatment of this rare entity. PMID- 24069107 TI - Pediatric bladder neuroblastoma: Case report and literature review. AB - Neuroblastoma (NBL) of the urinary bladder is an extremely rare diagnosis, with only 6 cases reported in the literature to date. We report the case of a 3-year old boy who presented with gross hematuria, and was diagnosed with bladder NBL after partial cystectomy. Two-year follow-up has been unremarkable. This case highlights a rare neoplasm of the urinary bladder in a pediatric patient. PMID- 24069108 TI - Leiomyoma in Retzius' space: An unusual location. AB - We report the case of a 54-year-old woman who presented to our hospital with microscopic hematuria. An imaging study revealed a tumour in the Retzius' space. The tumour was surgically removed by an abdominal approach. Pathological examination revealed a leiomyoma. This case demonstrates a leiomyoma in an unusual location. PMID- 24069109 TI - Uncommon testicular metastasis of a primary neuroendocrine tumour of the lung. AB - A 52-year-old male presented with an asymptomatic palpable mass of the right testicle. Ultrasound confirmed the presence of a testicular tumour and a hemicastration was performed. None of the testis cancer-related tumour markers were elevated and histological findings revealed a neuroendocrine carcinoma, possibly a metastasis from another primary site. The radiological findings showed a lesion in the lung, and a positron emission tomography (PET)-scan was made. The PET scan revealed an increased fluorodeoxyglucose (FDG) uptake in the pulmonary lesion. It also showed lymphatic and hepatic metastases. The patient had no complaints besides a palpable testicular mass and was diagnosed with a cT1aN3M1b neuroendocrine carcinoma of the lower left field of the lung, stage IV. To our knowledge, the presentation of testicular metastasis of a neuroendocrine carcinoma of the lung has not been described in the literature. No curative options were available and the patient is being treated with salvage chemotherapy. PMID- 24069110 TI - Management of pediatric penile keloid. AB - Keloids are abnormal scar tissue growths that extend beyond the original area of injury, occasionally occurring post-surgery. Risk factors for keloids include skin trauma, infection, prolonged wound healing and individuals of certain ethnicities. Keloid formation on the penis, however, is a rare occurrence even among circumcised males, and can produce both aesthetic and functional complications. We document the tenth patient in the literature, to our knowledge, to present with a keloid of the penis. PMID- 24069111 TI - Giant fibroepithelial polyp of the glans penis not associated with condom catheter use: A case report and literature review. AB - Fibroepithelial polyps are rare benign tumours of the glans penis; there are only a few reported cases. The pathogenesis is unknown. However, they have been linked with chronic condom catheter use or prior penile surgery. We report a case of a 62-year-old man with a large fibroepithelial polyp of the glans penis of 11 years duration, which was not associated with condom catheter use or prior surgery. The mass was large, measuring 7 * 5 * 3 cm. Fibroepithelial polyps have been reported in a range of genito-urinary sites in males and females, adults and children, and in rare cases may be associated with malignant transformation. They should be considered in the differential diagnosis of both cutaneous and mucosal genitourinary lesions. PMID- 24069112 TI - THE SCREENING AND RANKING ALGORITHM TO DETECT DNA COPY NUMBER VARIATIONS. AB - DNA Copy number variation (CNV) has recently gained considerable interest as a source of genetic variation that likely influences phenotypic differences. Many statistical and computational methods have been proposed and applied to detect CNVs based on data that generated by genome analysis platforms. However, most algorithms are computationally intensive with complexity at least O(n2), where n is the number of probes in the experiments. Moreover, the theoretical properties of those existing methods are not well understood. A faster and better characterized algorithm is desirable for the ultra high throughput data. In this study, we propose the Screening and Ranking algorithm (SaRa) which can detect CNVs fast and accurately with complexity down to O(n). In addition, we characterize theoretical properties and present numerical analysis for our algorithm. PMID- 24069133 TI - Effect and safety of interferon for hepatocellular carcinoma: a systematic review and meta-analysis. AB - BACKGROUND: The effect of interferon(IFN) in the management of hepatocellular carcinoma (HCC) remains controversial, and no clear recommendations have been proposed. OBJECTIVES: To evaluate the effect and safety of IFN for HCC. METHODS: PubMed, OvidSP, and Cochrane Library were searched from their establishment date until August 30, 2012. Studies that met the inclusion criteria were systematically evaluated and then subjected to meta-analysis. RESULTS: Thirteen randomized control trials (RCTs) involving 1344 patients were eligible for this study. When IFN was used as an adjuvant therapy for HCC patients after curative therapy, the meta-analysis showed that IFN reduced the 1-, 2-, 3-, 4-, and 5-year recurrence rates. Subgroup analysis showed that IFN reduced the 2-, 3-, 4-, and 5 year recurrence rates of hepatitis C viral (HCV)-related HCC. The effect of IFN for on hepatitis B virus(HBV)-related HCC patients could not be determined because of isufficient data. After surgical resection, adjuvant IFN therapy reduced the 4- and 5- recurrence rates. All studies reported that IFN could not improve the overall survival of HCV-realated HCC patients after curative therapies. Only one study showed that IFN was associated with better overall survival in HCC patients after curative therapy and subgroup of HCC patients after surgical resection. Thus, meta-analysis was not performed. Different treatment options were used as control to study the effect of IFN for intermediate and advanced HCC patients, thus meta-analysis was not appropriate. All included studies, except for one, reported that IFN treatment was well tolerated. CONCLUSIONS: After curative therapies, adjuvant IFN reduced the recurrence of HCC. IFN did not improve the survival of HCV-related HCC patients after curative therapy. Whether IFN is effective for intermediate and advanced HCC patients could not be determined because of insufficient data. The toxicity of IFN was acceptable. PMID- 24069134 TI - Quantifying Microstegium vimineum seed movement by non-riparian water dispersal using an ultraviolet-marking based recapture method. AB - Microstegium vimineum is a shade tolerant annual C4 invasive grass in the Eastern US, which has been shown to negatively impact species diversity and succession in hardwood forests. To date, empirical studies have shown that population expansion is limited to <1 m yr(-1), which is largely driven by gravity dispersal. However, this likely does not fully account for all mechanisms of population-scale dispersal as we observe greater rates of population expansion. Though water, both riparian and non-riparian water (i.e., ephemeral overland flow), have been speculated mechanisms for M. vimineum dispersal, few studies have empirically tested this hypothesis. We designed an experiment along the slopes of a Southwest Virginia hardwood forest to test the role of non-riparian water on local seed dispersal. We developed a seed marking technique by coating each seed with an ultraviolet (UV) powder that did not affect buoyancy to aid in situ seed recapture. Additionally, a new image analysis protocol was developed to automate seed identification from UV photos. Total seed mobility (summation of individual seed movement within each transect) was positively correlated with precipitation. Over a period of one month with 52.32 mm of precipitation, the maximum dispersal distance of any single recaptured seed was 2.4 m, and the average distance of dispersed seed was 0.21+/-0.04 m. This is the first quantitative evidence of non riparian water dispersal in a forest understory, which accounts for an additional pathway of population expansion. PMID- 24069135 TI - Mesenchymal stem cells develop tumor tropism but do not accelerate breast cancer tumorigenesis in a somatic mouse breast cancer model. AB - The role of mesenchymal stem cells (MSCs) on breast cancer progression, growth and tumorigenesis remains controversial or unknown. In the present study, we investigated the role of MSCs on breast tumor induction and growth in a clinically relevant somatic breast cancer model. We first conducted in vitro studies and found that conditioned media (CM) of RCAS-Neu and RCAS-PyMT breast cancer cell lines and tumor cells themselves dramatically increased the proliferation and motility of MSCs and induced morphological changes of MSCs and differentiation into fibroblast-like cells. In contrast, the CM of MSCs inhibited the proliferation of two breast cancer cell lines by arresting the cell cycle at the G0/G1 phase. In vivo studies revealed that fluorescence dye-labeled MSCs migrated into tumor tissues. Unexpectedly, single or multiple intravenous injections of MSCs did not affect the latency of breast cancer in TVA- transgenic mice induced by intraductal injection of the RCAS vector encoding polyoma middle T antigen (PyMT) or Neu oncogenes. Moreover, MSCs had no effect on RCAS-Neu tumor growth in a syngeneic ectopic breast cancer model. While our studies consistently demonstrated the ability of breast cancer cells to profoundly induce MSCs migration, differentiation, and proliferation, the anti-proliferative effect of MSCs on breast tumor cells observed in vitro could not be translated into an antitumor activity in vivo, probably reflecting the antagonizing or complex effects of MSCs on tumor environment and tumor cells themselves. PMID- 24069136 TI - Breast cancer cells induce osteolytic bone lesions in vivo through a reduction in osteoblast activity in mice. AB - Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients. PMID- 24069137 TI - High brain ammonia tolerance and down-regulation of Na+:K+:2Cl(-) Cotransporter 1b mRNA and protein expression in the brain of the Swamp Eel, Monopterus albus, exposed to environmental ammonia or terrestrial conditions. AB - Na(+):K(+):2Cl(-) cotransporter 1 (NKCC1) has been implicated in mediating ischemia-, trauma- or ammonia-induced astrocyte swelling/brain edema in mammals. This study aimed to determine the effects of ammonia or terrestrial exposure on ammonia concentrations in the plasma and brain, and the mRNA expression and protein abundance of nkcc/Nkcc in the brain, of the swamp eel Monopterusalbus. Ammonia exposure led to a greater increase in the ammonia concentration in the brain of M. albus than terrestrial exposure. The brain ammonia concentration of M. albus reached 4.5 umol g(-1) and 2.7 umol g(-1) after 6 days of exposure to 50 mmol l(-1) NH4Cl and terrestrial conditions, respectively. The full cDNA coding sequence of nkcc1b from M. albus brain comprised 3276 bp and coded for 1092 amino acids with an estimated molecular mass of 119.6 kDa. A molecular characterization indicated that it could be activated through phosphorylation and/or glycosylation by osmotic and/or oxidative stresses. Ammonia exposure for 1 day or 6 days led to significant decreases in the nkcc1b mRNA expression and Nkcc1b protein abundance in the brain of M. albus. In comparison, a significant decrease in nkcc1b mRNA expression was observed in the brain of M. albus only after 6 days of terrestrial exposure, but both 1 day and 6 days of terrestrial exposure resulted in significant decreases in the protein abundance of Nkcc1b. These results are novel because it has been established in mammals that ammonia up-regulates NKCC1 expression in astrocytes and NKCC1 plays an important role in ammonia-induced astrocyte swelling and brain edema. By contrast, our results indicate for the first time that M. albus is able to down-regulate the mRNA and protein expression of nkcc1b/Nkcc1b in the brain when confronted with ammonia toxicity, which could be one of the contributing factors to its extraordinarily high brain ammonia tolerance. PMID- 24069138 TI - Boolean network model predicts knockout mutant phenotypes of fission yeast. AB - BOOLEAN NETWORKS (OR: networks of switches) are extremely simple mathematical models of biochemical signaling networks. Under certain circumstances, Boolean networks, despite their simplicity, are capable of predicting dynamical activation patterns of gene regulatory networks in living cells. For example, the temporal sequence of cell cycle activation patterns in yeasts S. pombe and S. cerevisiae are faithfully reproduced by Boolean network models. An interesting question is whether this simple model class could also predict a more complex cellular phenomenology as, for example, the cell cycle dynamics under various knockout mutants instead of the wild type dynamics, only. Here we show that a Boolean network model for the cell cycle control network of yeast S. pombe correctly predicts viability of a large number of known mutants. So far this had been left to the more detailed differential equation models of the biochemical kinetics of the yeast cell cycle network and was commonly thought to be out of reach for models as simplistic as Boolean networks. The new results support our vision that Boolean networks may complement other mathematical models in systems biology to a larger extent than expected so far, and may fill a gap where simplicity of the model and a preference for an overall dynamical blueprint of cellular regulation, instead of biochemical details, are in the focus. PMID- 24069139 TI - The insulin receptor is required for the development of the Drosophila peripheral nervous system. AB - The Insulin Receptor (InR) in Drosophila presents features conserved in its mammalian counterparts. InR is required for growth; it is expressed in the central and embryonic nervous system and modulates the time of differentiation of the eye photoreceptor without altering cell fate. We show that the InR is required for the formation of the peripheral nervous system during larval development and more particularly for the formation of sensory organ precursors (SOPs) on the fly notum and scutellum. SOPs arise in the proneural cluster that expresses high levels of the proneural proteins Achaete (Ac) and Scute (Sc). The other cells will become epidermis due to lateral inhibition induced by the Notch (N) receptor signal that prevents its neighbors from adopting a neural fate. In addition, misexpression of the InR or of other components of the pathway (PTEN, Akt, FOXO) induces the development of an abnormal number of macrochaetes that are Drosophila mechanoreceptors. Our data suggest that InR regulates the neural genes ac, sc and sens. The FOXO transcription factor which is localized in the cytoplasm upon insulin uptake, displays strong genetic interaction with the InR and is involved in Ac regulation. The genetic interactions between the epidermal growth factor receptor (EGFR), Ras and InR/FOXO suggest that these proteins cooperate to induce neural gene expression. Moreover, InR/FOXO is probably involved in the lateral inhibition process, since genetic interactions with N are highly significant. These results show that the InR can alter cell fate, independently of its function in cell growth and proliferation. PMID- 24069140 TI - Difference in visual processing assessed by eye vergence movements. AB - Orienting visual attention is closely linked to the oculomotor system. For example, a shift of attention is usually followed by a saccadic eye movement and can be revealed by micro saccades. Recently we reported a novel role of another type of eye movement, namely eye vergence, in orienting visual attention. Shifts in visuospatial attention are characterized by the response modulation to a selected target. However, unlike (micro-) saccades, eye vergence movements do not carry spatial information (except for depth) and are thus not specific to a particular visual location. To further understand the role of eye vergence in visual attention, we tested subjects with different perceptual styles. Perceptual style refers to the characteristic way individuals perceive environmental stimuli, and is characterized by a spatial difference (local vs. global) in perceptual processing. We tested field independent (local; FI) and field dependent (global; FD) observers in a cue/no-cue task and a matching task. We found that FI observers responded faster and had stronger modulation in eye vergence in both tasks than FD subjects. The results may suggest that eye vergence modulation may relate to the trade-off between the size of spatial region covered by attention and the processing efficiency of sensory information. Alternatively, vergence modulation may have a role in the switch in cortical state to prepare the visual system for new incoming sensory information. In conclusion, vergence eye movements may be added to the growing list of functions of fixational eye movements in visual perception. However, further studies are needed to elucidate its role. PMID- 24069141 TI - Inhibition of HIV-1 reverse transcriptase-catalyzed synthesis by intercalated DNA Benzo[a]Pyrene 7,8-Dihydrodiol-9,10-Epoxide adducts. AB - To aid in the characterization of the relationship of structure and function for human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT), this investigation utilized DNAs containing benzo[a]pyrene-7,8-dihydrodiol-9,10 epoxide (BPDE)-modified primers and templates as a probe of the architecture of this complex. BPDE lesions that differed in their stereochemistry around the C10 position were covalently linked to N (6)-adenine and positioned in either the primer or template strand of a duplex template-primer. HIV-1 RT exhibited a stereoisomer-specific and strand-specific difference in replication when the BPDE lesion was placed in the template versus the primer strand. When the C10 R-BPDE adduct was positioned in the primer strand in duplex DNA, 5 nucleotides from the 3? end of the primer terminus, HIV-1 RT could not fully replicate the template, producing truncated products; this block to further synthesis did not affect rates of dissociation or DNA binding affinity. Additionally, when the adducts were in the same relative position, but located in the template strand, similar truncated products were observed with both the C10 R and C10 S BPDE adducts. These data suggest that the presence of covalently-linked intercalative DNA adducts distant from the active site can lead to termination of DNA synthesis catalyzed by HIV-1 RT. PMID- 24069142 TI - A genetic polymorphism in TOX3 is associated with survival of gastric cancer in a Chinese population. AB - PURPOSE: Recently, genetic polymorphism (rs3803662C>T) in TOX3 was reported to induce the risk of breast cancer. In this study, we hypothesized that rs3803662 could influence gastric cancer survival outcomes. METHODS: With multiplex SNaPshot method, we genotyped TOX3 rs3803662 in 880 gastric patients with surgical resection. The association between genotype and survival outcomes was performed by the Kaplan-Meier method, Cox regression analysis models and the log rank test. RESULTS: There was no association in the analyses of rs3803662 and survival of gastric cancer. However, the stratified analysis by histology showed that rs3803662 CT/TT genotype was associated with a significantly better survival for diffuse-type gastric cancer (log-rank p = 0.030, hazard ratio [HR] = 0.67, 95% confidence interval [CI] = 0.46-0.96), than the CC genotype. In addition, this favorable effect was especially obvious among gastric cancer patients with tumor size >5 cm, T3 and T4 depth of invasion, lymph node metastasis, no drinking, no distant metastasis, no chemotherapy and gastric cardia cancer. CONCLUSIONS: TOX3 rs3803662 might play an important role in the prognostic outcome and treatment of gastric cancer, especially perhaps further help in explaining the reduced risk of death associated with diffuse-type gastric cancer. PMID- 24069143 TI - Completeness of maternal smoking status recording during pregnancy in United Kingdom primary care data. AB - BACKGROUND: Given the health impacts of smoking during pregnancy and the opportunity for primary healthcare teams to encourage pregnant smokers to quit, our primary aim was to assess the completeness of gestational smoking status recording in primary care data and investigate whether completeness varied with women's characteristics. As a secondary aim we assessed whether completeness of recording varied before and after the introduction of the Quality and Outcomes Framework (QOF). METHODS: In The Health Improvement Network (THIN) database we calculated the proportion of pregnancies ending in live births or stillbirths where there was a recording of maternal smoking status for each year from 2000 to 2009. Logistic regression was used to assess variation in the completeness of maternal smoking recording by maternal characteristics, before and after the introduction of QOF. RESULTS: Women had a record of smoking status during the gestational period in 28% of the 277,552 pregnancies identified. In 2000, smoking status was recorded in 9% of pregnancies, rising to 43% in 2009. Pregnant women from the most deprived group were 17% more likely to have their smoking status recorded than pregnant women from the least deprived group before QOF implementation (OR 1.17, 95% CI 1.10-1.25) and 42% more likely afterwards (OR 1.42, 95% CI 1.37-1.47). A diagnosis of asthma was related to recording of smoking status during pregnancy in both the pre-QOF (OR 1.63, 95% CI 1.53-1.74) and post-QOF periods (OR 2.08, 95% CI 2.02-2.15). There was no association between having a diagnosis of diabetes and recording of smoking status during pregnancy pre-QOF however, post-QOF diagnosis of diabetes was associated with a 12% increase in recording of smoking status (OR 1.12, 95% CI 1.05-1.19). CONCLUSION: Recording of smoking status during pregnancy in primary care data is incomplete though has improved over time, especially after the implementation of the QOF, and varies by maternal characteristics and QOF-incentivised morbidities. PMID- 24069144 TI - Polymorphism of 9p21.3 locus is associated with 5-year survival in high-risk patients with myocardial infarction. AB - OBJECTIVE: The rs1333049, rs10757278 and rs4977574 are single nucleotide polymorphisms (SNPs) of chromosome 9p21 locus that are associated with prevalence of acute coronary syndromes (ACS). The rs1333049 SNP was also associated with cardiac outcome 6 months post ACS. No data concerning their association with long term prognosis after myocardial infarction is available. The aim of our study was to investigate the association of the 9p21.3 locus with 5-year overall mortality in patients with ST-elevation myocardial infarction (STEMI) treated invasively. MATERIALS AND METHODS: We performed a retrospective analysis of data collected prospectively in a registry of consecutive patients with STEMI treated with primary PCI. Genotyping was performed with a TaqMan method. The analyzed end point was total 5-year mortality. RESULTS: The study group comprised 589 patients: 25.3% of females (n = 149), mean age 62.4+/-11.9 years, total 5-year mortality 16.6% (n = 98). When all the study group was analyzed, no significant differences in mortality were found between the genotypes. However, in high-risk patients (Grace risk score >=155 points, n = 238), low-risk homozygotes had significantly better 5-year survival compared to other genotypes. The hazard ratio associated with high-risk genotype (high-risk homozygote or heterozygote) was: HR = 2.9 (95%CI 1.4-6.1) for the rs4977574 polymorphism, HR = 2.6 (1.25-5.3) for the rs1333049 one and HR = 2.35 (1.2-4.6) for the rs10757278 one (Cox proportional hazards model). CONCLUSIONS: The 9p21.3 locus is associated with 5 year mortality in high-risk patients with STEMI. This finding, due to very high effect size, could potentially be applied into clinical practice, if appropriate methods are elaborated. PMID- 24069145 TI - Characterization of the complete mitochondrion genome of diurnal Moth Amata emma (Butler) (Lepidoptera: Erebidae) and its phylogenetic implications. AB - Mitogenomes can provide information for phylogenetic analyses and evolutionary biology. The complete mitochondrial genome of Amata emma (Lepidoptera: Erebidae) was sequenced and analyzed in the study. The circular genome is 15,463 bp in size, with the gene content, orientation and order identical to other ditrysian insects. The genome composition of the major strand shows highly A+T biased and exhibits negative AT-skew and GC-skew. The initial codons are the canonical putative start codons ATN with the exception of cox1 gene which uses CGA instead. Ten genes share complete termination codons TAA, and three genes use incomplete stop codons TA or T. Additionally, the codon distribution and Relative Synonymous Codon Usage of the 13 PCGs in the A. emma mitogenome are consistent with those in other Noctuid mitogenomes. All tRNA genes have typical cloverleaf secondary structures, except for the trnS1 (AGN) gene, in which the dihydrouridine (DHU) arm is simplified down to a loop. The secondary structures of two rRNA genes broadly conform with the models proposed for these genes of other Lepidopteran insects. Except for the A+T-rich region, there are three major intergenic spacers, spanning at least 10 bp and five overlapping regions. There are obvious differences in the A+T-rich region between A. emma and other Lepidopteran insects reported previously except that the A+T-rich region contains an 'ATAGA' -like motif followed by a 19 bp poly-T stretch and a (AT)9 element preceded by the 'ATTTA' motif. It neither has a poly-A (in the alpha strand) upstream trnM nor potential stem-loop structures and just has some simple structures like (AT)nGTAT. The phylogenetic relationships based on nucleotide sequences of 13 PCGs using Bayesian inference and maximum likelihood methods provided a well supported a broader outline of Lepidoptera and which agree with the traditional morphological classification and recently working, but with a much higher support. PMID- 24069146 TI - Plasma MIC-1 and PAPP-a levels are decreased among women presenting to an early pregnancy assessment unit, have fetal viability confirmed but later miscarry. AB - BACKGROUND: We have recently shown first trimester Macrophage inhibitory cytokine 1 (MIC-1) and Pregnancy Associated Plasma Protein-A (PAPP-A) serum concentrations are depressed among asymptomatic women destined to miscarry. Here we examined whether plasma levels of MIC-1 and PAPP-A are depressed among women presenting to an Early Pregnancy Assessment Unit (EPAU), noted to have a confirmed viable fetus, but subsequently miscarry. METHODS: We performed a prospective cohort study, recruiting 462 women in the first trimester presenting to EPAU and had fetal viability confirmed by ultrasound. We obtained plasma samples on the same day and measured MIC-1, PAPP-A and human chorionic gonadotrophin (hCG), grouping the cohort according to whether they later miscarried or not. To correct for changes in analyte levels across gestation, we expressed the data as Multiples of the normal Median (MoMs). RESULTS: We recruited 462 participants presenting to EPAU at 5-12 weeks gestation. Most (80%) presented with symptoms of threatened miscarriage (e.g. abdominal pain, vaginal bleeding). 34 (7.4%) subsequently miscarried. Median plasma MIC-1 levels among those who miscarried were 50% of those with ongoing pregnancies (Miscarriage cohort MoM 0.50 (25(th)-75(th) centiles: 0.29-1.33) vs ongoing pregnancies MoM 1.00 (0.65-1.38); p=0.0025). Median plasma PAPP-A MoMs among those who miscarried was 0.57 (0.00-1.12), significantly lower than those with ongoing pregnancies (MoMs 1.00 (0.59-1.59); p=0.036). Plasma hCG levels were also significantly depressed among those who miscarried compared to those with ongoing pregnancies. However, the performance of MIC-1 as a diagnostic marker to predict miscarriage in this cohort was modest, and not improved with the addition of hCG. CONCLUSION: MIC-1 and PAPP-A levels are significantly depressed in women presenting to EPAU with ultrasound evidence of fetal viability, but later miscarry. While they are unlikely to be useful as predictive biomarkers in this clinical setting, they probably play important roles in the maintenance of early pregnancy. PMID- 24069147 TI - Engraftment of mouse embryonic stem cells differentiated by default leads to neuroprotection, behaviour revival and astrogliosis in parkinsonian rats. AB - We report here protection against rotenone-induced behavioural dysfunction, striatal dopamine depletion and nigral neuronal loss, following intra-striatal transplantation of neurons differentiated from murine embryonic stem cells (mES). mES maintained in serum free medium exhibited increase in neuronal, and decrease in stem cell markers by 7th and 10th days as revealed by RT-PCR and immunoblot analyses. Tyrosine hydroxylase, NURR1, PITX3, LMX1b and c-RET mRNA showed a significant higher expression in differentiated cells than in mES. Dopamine level was increased by 3-fold on 10th day as compared to 7 days differentiated cells. Severity of rotenone-induced striatal dopamine loss was attenuated, and amphetamine-induced unilateral rotations were significantly reduced in animals transplanted with 7 days differentiated cells, but not in animals that received undifferentiated ES transplant. However, the ratio of contralateral to ipsilateral swings in elevated body swing test was significantly reduced in both the transplanted groups, as compared to control. Striatal grafts exhibited the presence of tyrosine hydroxylase positive cells, and the percentage of dopaminergic neurons in the substantia nigra was also found to be higher in the ipsilateral side of 7 days and mES grafted animals. Increased expression of CD11b and IBA-1, suggested a significant contribution of these microglia-derived factors in controlling the limited survival of the grafted cells. Astrocytosis in the grafted striatum, and significant increase in the levels of glial cell line derived neurotrophic factor may have contributed to the recovery observed in the hemiparkinsonian rats following transplantation. PMID- 24069148 TI - Effect of an E-mental health approach to workers' health surveillance versus control group on work functioning of hospital employees: a cluster-RCT. AB - OBJECTIVE: To evaluate an e-mental health (EMH) approach to workers' health surveillance (WHS) targeting work functioning (WF) and mental health (MH) of healthcare professionals in a randomised controlled trial. METHODS: Nurses and allied health professionals (N = 1140) were cluster-randomised at ward level to the intervention (IG) or control group (CG). The intervention consisted of two parts: (a) online screening and personalised feedback on impaired WF and MH, followed by (b) a tailored offer of self-help EMH interventions. CG received none of these parts. Primary outcome was impaired WF (Nurses Work Functioning Questionnaire), assessed at baseline and after three and six months. Analyses were performed in the positively screened subgroup (i) and in all participants (ii). RESULTS: Participation rate at baseline was 32% (NIG = 178; NCG = 188). Eighty-two percent screened positive for at least mild impairments in WF and/or MH (NIG = 139; NCG = 161). All IG-participants (N = 178) received part (a) of the intervention, nine participants (all positively screened, 6%) followed an EMH intervention to at least some extent. Regarding the subgroup of positively screened participants (i), both IG and CG improved over time regarding WF (non significant between-group difference). After six months, 36% of positively screened IG-participants (18/50) had a relevant WF improvement compared to baseline, versus 28% (32/115) of positively screened CG-participants (non significant difference). In the complete sample (ii), IG and CG improved over time but IG further improved between three and six months while CG did not (significant interaction effect). CONCLUSIONS: In our study with a full compliance rate of 6% and substantial drop-out leading to a small and underpowered sample, we could not demonstrate that an EMH-approach to WHS is more effective to improve WF and MH than a control group. The effect found in the complete sample of participants is not easily interpreted. Reported results may be useful for future meta-analytic work. TRIAL REGISTRATION: Dutch Trial Register NTR2786. PMID- 24069150 TI - Carbohydrate-active enzymes in pythium and their role in plant cell wall and storage polysaccharide degradation. AB - Carbohydrate-active enzymes (CAZymes) are involved in the metabolism of glycoconjugates, oligosaccharides, and polysaccharides and, in the case of plant pathogens, in the degradation of the host cell wall and storage compounds. We performed an in silico analysis of CAZymes predicted from the genomes of seven Pythium species (Py. aphanidermatum, Py. arrhenomanes, Py. irregulare, Py. iwayamai, Py. ultimum var. ultimum, Py. ultimum var. sporangiiferum and Py. vexans) using the "CAZymes Analysis Toolkit" and "Database for Automated Carbohydrate-active Enzyme Annotation" and compared them to previously published oomycete genomes. Growth of Pythium spp. was assessed in a minimal medium containing selected carbon sources that are usually present in plants. The in silico analyses, coupled with our in vitro growth assays, suggest that most of the predicted CAZymes are involved in the metabolism of the oomycete cell wall with starch and sucrose serving as the main carbohydrate sources for growth of these plant pathogens. The genomes of Pythium spp. also encode pectinases and cellulases that facilitate degradation of the plant cell wall and are important in hyphal penetration; however, the species examined in this study lack the requisite genes for the complete saccharification of these carbohydrates for use as a carbon source. Genes encoding for xylan, xyloglucan, (galacto)(gluco)mannan and cutin degradation were absent or infrequent in Pythium spp.. Comparative analyses of predicted CAZymes in oomycetes indicated distinct evolutionary histories. Furthermore, CAZyme gene families among Pythium spp. were not uniformly distributed in the genomes, suggesting independent gene loss events, reflective of the polyphyletic relationships among some of the species. PMID- 24069149 TI - A complex of BBS1 and NPHP7 is required for cilia motility in zebrafish. AB - Bardet-Biedl syndrome (BBS) and nephronophthisis (NPH) are hereditary autosomal recessive disorders, encoded by two families of diverse genes. BBS and NPH display several overlapping phenotypes including cystic kidney disease, retinitis pigmentosa, liver fibrosis, situs inversus and cerebellar defects. Since most of the BBS and NPH proteins localize to cilia and/or their appendages, BBS and NPH are considered ciliopathies. In this study, we characterized the function of the transcription factor Nphp7 in zebrafish, and addressed the molecular connection between BBS and NPH. The knockdown of zebrafish bbs1 and nphp7.2 caused similar phenotypic changes including convergent extension defects, curvature of the body axis, hydrocephalus, abnormal heart looping and cystic pronephros, all consistent with an altered ciliary function. Immunoprecipitation assays revealed a physical interaction between BBS1 and NPHP7, and the simultaneous knockdown of zbbs1 and znphp7.2 enhanced the cystic pronephros phenotype synergistically, suggesting a genetic interaction between zbbs1 and znphp7.2 in vivo. Deletion of zBbs1 or zNphp7.2 did not compromise cilia formation, but disrupted cilia motility. Although NPHP7 has been shown to act as transcriptional repressor, our studies suggest a crosstalk between BBS1 and NPHP7 in regulating normal function of the cilium. PMID- 24069151 TI - Different neural processes accompany self-recognition in photographs across the lifespan: an ERP study using dizygotic twins. AB - Our appearance changes over time, yet we can recognize ourselves in photographs from across the lifespan. Researchers have extensively studied self-recognition in photographs and have proposed that specific neural correlates are involved, but few studies have examined self-recognition using images from different periods of life. Here we compared ERP responses to photographs of participants when they were 5-15, 16-25, and 26-45 years old. We found marked differences between the responses to photographs from these time periods in terms of the neural markers generally assumed to reflect (i) the configural processing of faces (i.e., the N170), (ii) the matching of the currently perceived face to a representation already stored in memory (i.e., the P250), and (iii) the retrieval of information about the person being recognized (i.e., the N400). There was no uniform neural signature of visual self-recognition. To test whether there was anything specific to self-recognition in these brain responses, we also asked participants to identify photographs of their dizygotic twins taken from the same time periods. Critically, this allowed us to minimize the confounding effects of exposure, for it is likely that participants have been similarly exposed to each other's faces over the lifespan. The same pattern of neural response emerged with only one exception: the neural marker reflecting the retrieval of mnemonic information (N400) differed across the lifespan for self but not for twin. These results, as well as our novel approach using twins and photographs from across the lifespan, have wide-ranging consequences for the study of self-recognition and the nature of our personal identity through time. PMID- 24069152 TI - Pneumococcal polysaccharide abrogates conjugate-induced germinal center reaction and depletes antibody secreting cell pool, causing hyporesponsiveness. AB - BACKGROUND: Plain pneumococcal polysaccharide (PPS) booster administered during second year of life has been shown to cause hyporesponsiveness. We assessed the effects of PPS booster on splenic memory B cell responses and persistence of PPS specific long-lived plasma cells in the bone marrow (BM). METHODS: Neonatal mice were primed subcutanously (s.c.) or intranasally (i.n.) with pneumococcal conjugate (Pnc1-TT) and the adjuvant LT-K63, and boosted with PPS+LT-K63 or saline 1, 2 or 3 times with 16 day intervals. Seven days after each booster, spleens were removed, germinal centers (GC), IgM(+), IgG(+) follicles and PPS specific antibody secreting cells (AbSC) in spleen and BM enumerated. RESULTS: PPS booster s.c., but not i.n., compromised the Pnc1-TT-induced PPS-specific Abs by abrogating the Pnc1-TT-induced GC reaction and depleting PPS-specific AbSCs in spleen and limiting their homing to the BM. There was no difference in the frequency of PPS-specific AbSCs in spleen and BM between mice that received 1, 2 or 3 PPS boosters s.c.. Repeated PPS+LT-K63 booster i.n. reduced the frequency of PPS-specific IgG(+) AbSCs in BM. CONCLUSIONS: PPS booster-induced hyporesponsiveness is caused by abrogation of conjugate-induced GC reaction and depletion of PPS-specific IgG(+) AbSCs resulting in no homing of new PPS-specific long-lived plasma cells to the BM or survival. These results should be taken into account in design of vaccination schedules where polysaccharides are being considered. PMID- 24069153 TI - Population size and cultural evolution in nonindustrial food-producing societies. AB - Modeling work suggests that population size affects cultural evolution such that larger populations can be expected to have richer and more complex cultural repertoires than smaller populations. Empirical tests of this hypothesis, however, have yielded conflicting results. Here, we report a study in which we investigated whether the subsistence toolkits of small-scale food-producers are influenced by population size in the manner the hypothesis predicts. We applied simple linear and standard multiple regression analysis to data from 40 nonindustrial farming and pastoralist groups to test the hypothesis. Results were consistent with predictions of the hypothesis: both the richness and the complexity of the toolkits of the food-producers were positively and significantly influenced by population size in the simple linear regression analyses. The multiple regression analyses demonstrated that these relationships are independent of the effects of risk of resource failure, which is the other main factor that has been found to influence toolkit richness and complexity in nonindustrial groups. Thus, our study strongly suggests that population size influences cultural evolution in nonindustrial food-producing populations. PMID- 24069154 TI - Dynamic quantitative intravital imaging of glioblastoma progression reveals a lack of correlation between tumor growth and blood vessel density. AB - The spatiotemporal and longitudinal monitoring of cellular processes occurring in tumors is critical for oncological research. We focused on glioblastoma multiforme (GBM), an untreatable highly vascularized brain tumor whose progression is thought to critically depend on the oxygen and metabolites supplied by blood vessels. We optimized protocols for orthotopic GBM grafting in mice that were able to recapitulate the biophysical constraints normally governing tumor progression and were suitable for intravital multiphoton microscopy. We repeatedly imaged tumor cells and blood vessels during GBM development. We established methods for quantitative correlative analyses of dynamic imaging data over wide fields in order to cover the entire tumor. We searched whether correlations existed between blood vessel density, tumor cell density and proliferation in control tumors. Extensive vascular remodeling and the formation of new vessels accompanied U87 tumor cell growth, but no strong correlation was found between local cell density and the extent of local blood vessel density irrespective of the tumor area or time points. The technique moreover proves useful for comparative analysis of mice subjected either to Bevacizumab anti-angiogenic treatment that targets VEGF or to AMD3100, an antagonist of CXCR4 receptor. Bevacizumab treatment massively reduced tumoral vessel densities but only transiently reduced U87 tumor growth rate. Again, there was no correlation between local blood vessel density and local cell density. Moreover, Bev applied only prior to tumor implantation inhibited tumor growth to the same extent as post-grafting treatment. AMD3100 achieved a potent inhibition of tumor growth without significant reduction in blood vessel density. These results indicate that in the brain, in this model, tumor growth can be sustained without an increase in blood vessel density and suggest that GBM growth is rather governed by stromal properties. PMID- 24069155 TI - A minimal set of tissue-specific hypomethylated CpGs constitute epigenetic signatures of developmental programming. AB - BACKGROUND: Cell specific states of the chromatin are programmed during mammalian development. Dynamic DNA methylation across the developing embryo guides a program of repression, switching off genes in most cell types. Thus, the majority of the tissue specific differentially methylated sites (TS-DMS) must be un methylated CpGs. METHODOLOGY AND PRINCIPAL FINDINGS: Comparison of expanded Methyl Sensitive Cut Counting data (eMSCC) among four tissues (liver, testes, brain and kidney) from three C57BL/6J mice, identified 138,052 differentially methylated sites of which 23,270 contain CpGs un-methylated in only one tissue (TS-DMS). Most of these CpGs were located in intergenic regions, outside of promoters, CpG islands or their shores, and up to 20% of them overlapped reported active enhancers. Indeed, tissue-specific enhancers were up to 30 fold enriched in TS-DMS. Testis showed the highest number of TS-DMS, but paradoxically their associated genes do not appear to be specific to the germ cell functions, but rather are involved in organism development. In the other tissues the differentially methylated genes are associated with tissue-specific physiological or anatomical functions. The identified sets of TS-DMS quantify epigenetic distances between tissues, generated during development. We applied this concept to measure the extent of reprogramming in the liver of mice exposed to in utero or early postnatal nutritional stress. Different protocols of food restriction reprogrammed the liver methylome in different but reproducible ways. CONCLUSION AND SIGNIFICANCE: Thus, each identified set of differentially methylated sites constituted an epigenetic signature that traced the developmental programing or the early nutritional reprogramming of each exposed mouse. We propose that our approach has the potential to outline a number of disease-associated epigenetic states. The composition of differentially methylated CpGs may vary with each situation, behaving as a composite variable, which can be used as a pre symptomatic marker for disease. PMID- 24069156 TI - Factors affecting compliance with clinical practice guidelines for pap smear screening among healthcare providers in africa: systematic review and meta summary of 2045 individuals. AB - BACKGROUND: Although the importance of the Pap smear in reducing cancer incidence and mortality is known, many countries in Africa have not initiated yet widespread national cervical cancer screening programs. The World Health Organization (WHO) has published Clinical Practice Guidelines (CPGs) on cervical cancer screening in developing countries; however, there is a gap between expectations and clinical performance. Thus, the aim of this study was to conduct a systematic review and meta-summary to identify factors affecting compliance with CPGs for Pap screening among healthcare providers in Africa. METHODS: And Findings: MEDLINE, Scirus, Opengate and EMBASE databases were searched in January 2012. Studies involving medical personnel practicing in Africa, whose outcome measured any factors that affect medical personnel from using a Pap smear to screen for cervical cancer, were included. Two reviewers independently evaluated titles and abstracts, then full-texts, extracted data and assessed quality of the included studies. A descriptive analysis of the included studies was conducted. We calculated Frequency effect sizes (FES) for each finding and Intensity effect sizes (IES) for each article to represent their magnitudes in the analyses. Of 1011 studies retrieved, 11 studies were included (2045 individuals). Six different themes related to the factors affecting compliance with CPGs were identified: Insufficient Knowledge/Lack of awareness (FES = 82%), Negligence/Misbeliefs (FES = 82%), Psychological Reasons (FES = 73%), Time/Cost Constraint (FES = 36%), Insufficient infrastructure/training (FES = 45%) and also no reason given (FES = 36%). IES for articles ranged between 33 and 83%. CONCLUSIONS: These results suggest that prevention initiatives should be comprehensive to include education and resources needs assessments and improvement, Pap smear test training, strategies on costing, and practitioner time studies. PMID- 24069157 TI - Cortisol as a prognostic marker of short-term outcome in chinese patients with acute ischemic stroke. AB - BACKGROUND: Early prediction of outcome is important for allocation of therapeutic strategies. Endocrine alterations of the hypothalamus-pituitary-axis are one of the first stress-induced alterations after cerebral ischemia. We therefore evaluated the prognostic value of serum cortisol in Chinese patients with an acute ischemic stroke. METHODS: In a prospective observational study, serum cortisol was measured using a solid-phase, competitive chemiluminescent enzyme immunoassay on admission in serum of 226 consecutive Chinese patients with an acute ischemic stroke. The prognostic value of serum cortisol to predict the functional outcome, mortality within 90 days, was compared with clinical variables (e.g., advanced age and the National Institutes of Health Stroke Scale [NHISS] score) and with other known predictors. RESULTS: Patients with a poor outcome and nonsurvivors had significantly increased serum cortisol levels on admission (P<0.0001, P<0.0001). There was a positive correlation between levels of cortisol and the NIHSS (r = 0.298, P<0.0001), glucose levels (r = 0.324, P<0.0001) and infarct volume (r = 0.328, P<0.0001). Cortisol was an independent prognostic marker of functional outcome and death [odds ratio 3.44 (2.58-6.23) and 4.21 (1.89-9.24), respectively, P<0.0001 for both, adjusted for age, the NIHSS and other predictors] in patients with ischemic stroke. In receiver operating characteristic curve analysis, cortisol could improve the NIHSS score in predicting short-term functional outcome (Area under the curve [AUC] of the combined model, 0.87; 95% CI, 0.82-0.92; P = 0.01) and mortality (AUC of the combined model, 0.90; 95% CI, 0.84-0.95; P = 0.01). CONCLUSION: Cortisol can be seen as an independent short-term prognostic marker of functional outcome and death in Chinese patients with acute ischemic stroke even after correcting confounding factors. Combined model can add significant additional predictive information to the clinical score of the NIHSS. PMID- 24069159 TI - Intraspecific combinations of flower and leaf volatiles act together in attracting hawkmoth pollinators. AB - Insects pinpoint mates, food and oviposition sites by olfactory cues. Recognizing and localizing a suitable target by olfaction is demanding. Odor sources emit characteristic blends of compounds that have to be identified against an environmentally derived olfactory background. This background, however, does not necessarily disturb the localization of a source. Rather, the contrary. Sex pheromones become more attractive to male moths when being presented against a relevant plant background. Here we asked whether such olfactory coaction also characterizes foraging cues. The tobacco hornworm Manduca sexta feeds on nectar from wild tobacco Nicotiana attenuata and sacred datura Datura wrightii flowers. We tested how leaf-derived volatile blends as a background affect the moths' approach to flower blends. We found coaction when a flower blend was presented against a conspecific leaf volatile background but not when the blend was presented against volatiles emitted by the other host plant or by a non-host plant. Hence, our results reveal a species-specific coaction between flower blend and leaf volatile background. The ability to integrate information from different odor sources on one plant might provide the moth with a fine-grained analysis of food site quality. PMID- 24069158 TI - TNF-alpha induces cytosolic phospholipase A2 expression in human lung epithelial cells via JNK1/2- and p38 MAPK-dependent AP-1 activation. AB - BACKGROUND: Cytosolic phospholipase A2 (cPLA2) plays a pivotal role in mediating agonist-induced arachidonic acid (AA) release for prostaglandin (PG) synthesis during inflammation triggered by tumor necrosis factor-alpha (TNF-alpha). However, the mechanisms underlying TNF-alpha-induced cPLA2 expression in human lung epithelial cells (HPAEpiCs) were not completely understood. PRINCIPAL FINDINGS: We demonstrated that TNF-alpha induced cPLA2 mRNA and protein expression, promoter activity, and PGE2 secretion in HPAEpiCs. These responses induced by TNF-alpha were inhibited by pretreatment with the inhibitor of MEK1/2 (PD98059), p38 MAPK (SB202190), JNK1/2 (SP600125), or AP-1 (Tanshinone IIA) and transfection with siRNA of TNFR1, p42, p38, JNK2, c-Jun, c-Fos, or ATF2. We showed that TNF-alpha markedly stimulated p42/p44 MAPK, p38 MAPK, and JNK1/2 phosphorylation which were attenuated by their respective inhibitors. In addition, TNF-alpha also stimulated c-Jun and ATF2 phosphorylation which were inhibited by pretreatment with SP600125 and SB202190, respectively, but not PD98059. Furthermore, TNF-alpha-induced cPLA2 promoter activity was abrogated by transfection with the point-mutated AP-1 cPLA2 construct. Finally, we showed that TNF-alpha time-dependently induced p300/c-Fos/c-Jun/ATF2 complex formation in HPAEpiCs. On the other hand, TNF-alpha induced in vivo binding of c-Jun, c-Fos, ATF2, and p300 to the cPLA2 promoter in these cells. In an in vivo study, we found that TNF-alpha induced leukocyte count in BAL fluid of mice and cPLA2 mRNA levels in lung tissues via MAPKs and AP-1. SIGNIFICANCE: Taken together, these results demonstrated that TNF-alpha-induced cPLA2 expression was mediated through p38 MAPK- and JNK1/2-dependent p300/c-Fos/c-Jun/ATF2 complex formation in HPAEpiCs. PMID- 24069160 TI - Theory of mind in the wild: toward tackling the challenges of everyday mental state reasoning. AB - A complete understanding of the cognitive systems underwriting theory of mind (ToM) abilities requires articulating how mental state representations are generated and processed in everyday situations. Individuals rarely announce their intentions prior to acting, and actions are often consistent with multiple mental states. In order for ToM to operate effectively in such situations, mental state representations should be generated in response to certain actions, even when those actions occur in the presence of mental state content derived from other aspects of the situation. Results from three experiments with preschool children and adults demonstrate that mental state information is indeed generated based on an approach action cue in situations that contain competing mental state information. Further, the frequency with which participants produced or endorsed explanations that include mental states about an approached object decreased when the competing mental state information about a different object was made explicit. This set of experiments provides some of the first steps toward identifying the observable action cues that are used to generate mental state representations in everyday situations and offers insight into how both young children and adults processes multiple mental state representations. PMID- 24069161 TI - Outcome risk factors during respiratory infections in a paediatric ward in Antananarivo, Madagascar 2010-2012. AB - BACKGROUND: Acute respiratory infections are a leading cause of infectious disease-related morbidity, hospitalisation and mortality among children worldwide, and particularly in developing countries. In these low-income countries, most patients with acute respiratory infection (ARI), whether it is mild or severe, are still treated empirically. The aim of the study was to evaluate the risk factors associated with the evolution and outcome of respiratory illnesses in patients aged under 5 years old. MATERIALS AND METHODS: We conducted a prospective study in a paediatric ward in Antananarivo from November 2010 to July 2012 including patients under 5 years old suffering from respiratory infections. We collected demographic, socio-economic, clinical and epidemiological data, and samples for laboratory analysis. Deaths, rapid progression to respiratory distress during hospitalisation, and hospitalisation for more than 10 days were considered as severe outcomes. We used multivariate analysis to study the effects of co-infections. RESULTS: From November 2010 to July 2012, a total of 290 patients were enrolled. Co-infection was found in 192 patients (70%). Co-infections were more frequent in children under 36 months, with a significant difference for the 19-24 month-old group (OR: 8.0). Sixty-nine percent (230/290) of the patients recovered fully and without any severe outcome during hospitalisation; the outcome was scored as severe for 60 children and nine patients (3%) died. Risk factors significantly associated with worsening evolution during hospitalisation (severe outcome) were admission at age under 6 months (OR = 5.3), comorbidity (OR = 4.6) and low household income (OR = 4.1). CONCLUSION: Co-mordidity, low-income and age under 6 months increase the risk of severe outcome for children infected by numerous respiratory pathogens. These results highlight the need for implementation of targeted public health policy to reduce the contribution of respiratory diseases to childhood morbidity and mortality in low income countries. PMID- 24069162 TI - Rasputin functions as a positive regulator of orb in Drosophila oogenesis. AB - The determination of cell fate and the establishment of polarity axes during Drosophila oogenesis depend upon pathways that localize mRNAs within the egg chamber and control their on-site translation. One factor that plays a central role in regulating on-site translation of mRNAs is Orb. Orb is a founding member of the conserved CPEB family of RNA-binding proteins. These proteins bind to target sequences in 3' UTRs and regulate mRNA translation by modulating poly(A) tail length. In addition to controlling the translation of axis-determining mRNAs like grk, fs(1)K10, and osk, Orb protein autoregulates its own synthesis by binding to orb mRNA and activating its translation. We have previously shown that Rasputin (Rin), the Drosophila homologue of Ras-GAP SH3 Binding Protein (G3BP), associates with Orb in a messenger ribonucleoprotein (mRNP) complex. Rin is an evolutionarily conserved RNA-binding protein believed to function as a link between Ras signaling and RNA metabolism. Here we show that Orb and Rin form a complex in the female germline. Characterization of a new rin allele shows that rin is essential for oogenesis. Co-localization studies suggest that Orb and Rin form a complex in the oocyte at different stages of oogenesis. This is supported by genetic and biochemical analyses showing that rin functions as a positive regulator in the orb autoregulatory pathway by increasing Orb protein expression. Tandem Mass Spectrometry analysis shows that several canonical stress granule proteins are associated with the Orb-Rin complex suggesting that a conserved mRNP complex regulates localized translation during oogenesis in Drosophila. PMID- 24069163 TI - Lack of increased immediate early gene expression in rats reinstating cocaine seeking behavior to discrete sensory cues. AB - Drug-seeking behavior elicited by drug-associated cues contributes to relapse in addiction; however, whether relapse elicited by drug-associated conditioned reinforcers (CR) versus discriminative stimuli (DS) involves distinct or overlapping neuronal populations is unknown. To address this question, we developed a novel cocaine self-administration and cue-induced reinstatement paradigm that exposed the same rats to distinct cocaine-associated CR and DS. Rats were trained to self-administer cocaine in separate sessions. In one, a DS signaled cocaine availability; in the other, cocaine delivery was paired with a different CR. After extinction training and reinstatement testing, where both cues were presented in separate sessions, rats were sacrificed and processed for cellular analysis of temporal activity by fluorescent in situ hybridization (CatFISH) for activity regulated cytoskeleton-associated protein (Arc) mRNA and for radioactive in situ hybridization for Arc and zif268 mRNAs. CatFISH did not reveal significant changes in Arc mRNA expression. Similar results were obtained with radioactive in situ hybridization. We have shown that while rats reinstate drug seeking in response to temporally discrete presentations of distinct drug associated cues, such reinstatement is not associated with increased transcriptional activation of Arc or zif268 mRNAs, suggesting that expression of these genes may not be necessary for cue-induced reinstatement of drug-seeking behavior. PMID- 24069164 TI - RNA-Seq reveals spliceosome and proteasome genes as most consistent transcripts in human cancer cells. AB - Accurate quantification of gene expression by qRT-PCR relies on normalization against a consistently expressed control gene. However, control genes in common use often vary greatly between samples, especially in cancer. The advent of Next Generation Sequencing technology offers the possibility to better select control genes with the least cell to cell variability in steady state transcript levels. Here we analyze the transcriptomes of 55 leukemia samples to identify the most consistent genes. This list is enriched for components of the proteasome (ex. PSMA1) and spliceosome (ex. SF3B2), and also includes the translation initiation factor EIF4H, and many heterogeneous nuclear ribonucleoprotein genes (ex. HNRNPL). We have validated the consistency of our new control genes in 1933 cancer and normal tissues using publically available RNA-seq data, and their usefulness in qRT-PCR analysis is clearly demonstrated. PMID- 24069165 TI - Therapeutic potential of mesenchymal stromal cells and MSC conditioned medium in Amyotrophic Lateral Sclerosis (ALS)--in vitro evidence from primary motor neuron cultures, NSC-34 cells, astrocytes and microglia. AB - Administration of mesenchymal stromal cells (MSC) improves functional outcome in the SOD1G93A mouse model of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) as well as in models of other neurological disorders. We have now investigated the effect of the interaction between MSC and motor neurons (derived from both non-transgenic and mutant SOD1G93A transgenic mice), NSC-34 cells and glial cells (astrocytes, microglia) (derived again from both non transgenic and mutant SOD1G93A ALS transgenic mice) in vitro. In primary motor neurons, NSC-34 cells and astrocytes, MSC conditioned medium (MSC CM) attenuated staurosporine (STS) - induced apoptosis in a concentration-dependent manner. Studying MSC CM-induced expression of neurotrophic factors in astrocytes and NSC 34 cells, we found that glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) gene expression in astrocytes were significantly enhanced by MSC CM, with differential responses of non-transgenic and mutant astrocytes. Expression of Vascular Endothelial Growth Factor (VEGF) in NSC-34 cells was significantly upregulated upon MSC CM-treatment. MSC CM significantly reduced the expression of the cytokines TNFalpha and IL-6 and iNOS both in transgenic and non-transgenic astrocytes. Gene expression of the neuroprotective chemokine Fractalkine (CX3CL1) was also upregulated in mutant SOD1G93A transgenic astrocytes by MSC CM treatment. Correspondingly, MSC CM increased the respective receptor, CX3CR1, in mutant SOD1G93A transgenic microglia. Our data demonstrate that MSC modulate motor neuronal and glial response to apoptosis and inflammation. MSC therefore represent an interesting candidate for further preclinical and clinical evaluation in ALS. PMID- 24069166 TI - Combined effects of icam-1 single-nucleotide polymorphisms and environmental carcinogens on oral cancer susceptibility and clinicopathologic development. AB - BACKGROUND: In Taiwan, oral cancer has causally been associated with environmental carcinogens. Intercellular adhesion molecule (ICAM)-1, a cell adhesion molecule with a key role in inflammation and immunosurveillance, was implicated in carcinogenesis by facilitating instability in the tumor environment. The current study explored the combined effect of ICAM-1 gene polymorphisms and exposure to environmental carcinogens on the susceptibility of developing oral squamous cell carcinoma (OSCC) and the clinicopathological characteristics of the tumors. METHODOLOGY AND PRINCIPAL FINDINGS: Four single nucleotide polymorphisms (SNPs) of the ICAM-1 gene from 595 patients with oral cancer and 561 non-cancer controls were analyzed by a real-time PCR. We found that the ICAM-1 rs5498 polymorphism and the TAGG or TACG haplotype of 4 ICAM-1 SNPs (rs3093030, rs5491, rs281432, and rs5498) combined were associated with oral cancer susceptibility. Among 727 smokers, ICAM-1 polymorphisms carriers with the betel-nut chewing habit had a 27.49-36.23-fold greater risk of having oral cancer compared to ICAM-1 wild-type (WT) carriers without the betel-nut chewing habit. Among 549 betel-nut chewers, ICAM-1 polymorphisms carriers who smoked had a 9.93 14.27-fold greater risk of having oral cancer compared to those who carried the WT but did not smoke. Finally, patients with oral cancer who had at least 1 T allele of ICAM-1 rs5491 or 1 G allele of rs281432 were at lower risk of developing an advanced clinical stage (III/IV) (p<0.05), compared to those patients with AA or CC homozygotes. CONCLUSIONS: Our results suggest that the ICAM-1 rs5498 SNP and either of 2 haplotypes of 4 SNPs combined have potential predictive significance in oral carcinogenesis. Gene-environment interactions of ICAM-1 polymorphisms, smoking, and betel-nut chewing might alter oral-cancer susceptibility. ICAM-1 rs5491 and rs281432 may be applied as factors to predict the clinical stage in OSCC patients. PMID- 24069167 TI - Normal mutation rate variants arise in a Mutator (Mut S) Escherichia coli population. AB - The rate at which mutations are generated is central to the pace of evolution. Although this rate is remarkably similar amongst all cellular organisms, bacterial strains with mutation rates 100 fold greater than the modal rates of their species are commonly isolated from natural sources and emerge in experimental populations. Theoretical studies postulate and empirical studies teort the hypotheses that these "mutator" strains evolved in response to selection for elevated rates of generation of inherited variation that enable bacteria to adapt to novel and/or rapidly changing environments. Less clear are the conditions under which selection will favor reductions in mutation rates. Declines in rates of mutation for established populations of mutator bacteria are not anticipated if such changes are attributed to the costs of augmented rates of generation of deleterious mutations. Here we report experimental evidence of evolution towards reduced mutation rates in a clinical isolate of Escherichia coli with an hyper-mutable phenotype due a deletion in a mismatch repair gene, (DeltamutS). The emergence in a DeltamutS background of variants with mutation rates approaching those of the normal rates of strains carrying wild-type MutS was associated with increase in fitness with respect to ancestral strain. We postulate that such an increase in fitness could be attributed to the emergence of mechanisms driving a permanent "aerobic style of life", the negative consequence of this behavior being regulated by the evolution of mechanisms protecting the cell against increased endogenous oxidative radicals involved in DNA damage, and thus reducing mutation rate. Gene expression assays and full sequencing of evolved mutator and normo-mutable variants supports the hypothesis. In conclusion, we postulate that the observed reductions in mutation rate are coincidental to, rather than, the selective force responsible for this evolution. PMID- 24069169 TI - The effect of contact angles and capillary dimensions on the burst frequency of super hydrophilic and hydrophilic centrifugal microfluidic platforms, a CFD study. AB - This paper employs the volume of fluid (VOF) method to numerically investigate the effect of the width, height, and contact angles on burst frequencies of super hydrophilic and hydrophilic capillary valves in centrifugal microfluidic systems. Existing experimental results in the literature have been used to validate the implementation of the numerical method. The performance of capillary valves in the rectangular and the circular microfluidic structures on super hydrophilic centrifugal microfluidic platforms is studied. The numerical results are also compared with the existing theoretical models and the differences are discussed. Our experimental and computed results show a minimum burst frequency occurring at square capillaries and this result is useful for designing and developing more sophisticated networks of capillary valves. It also predicts that in super hydrophilic microfluidics, the fluid leaks consistently from the capillary valve at low pressures which can disrupt the biomedical procedures in centrifugal microfluidic platforms. PMID- 24069168 TI - Bortezomib-induced painful peripheral neuropathy: an electrophysiological, behavioral, morphological and mechanistic study in the mouse. AB - Bortezomib is the first proteasome inhibitor with significant antineoplastic activity for the treatment of relapsed/refractory multiple myeloma as well as other hematological and solid neoplasms. Peripheral neurological complications manifesting with paresthesias, burning sensations, dysesthesias, numbness, sensory loss, reduced proprioception and vibratory sensitivity are among the major limiting side effects associated with bortezomib therapy. Although bortezomib-induced painful peripheral neuropathy is clinically easy to diagnose and reliable models are available, its pathophysiology remains partly unclear. In this study we used well-characterized immune-competent and immune-compromised mouse models of bortezomib-induced painful peripheral neuropathy. To characterize the drug-induced pathological changes in the peripheral nervous system, we examined the involvement of spinal cord neuronal function in the development of neuropathic pain and investigated the relevance of the immune response in painful peripheral neuropathy induced by bortezomib. We found that bortezomib treatment induced morphological changes in the spinal cord, dorsal roots, dorsal root ganglia (DRG) and peripheral nerves. Neurophysiological abnormalities and specific functional alterations in Adelta and C fibers were also observed in peripheral nerve fibers. Mice developed mechanical allodynia and functional abnormalities of wide dynamic range neurons in the dorsal horn of spinal cord. Bortezomib induced increased expression of the neuronal stress marker activating transcription factor-3 in most DRG. Moreover, the immunodeficient animals treated with bortezomib developed a painful peripheral neuropathy with the same features observed in the immunocompetent mice. In conclusion, this study extends the knowledge of the sites of damage induced in the nervous system by bortezomib administration. Moreover, a selective functional vulnerability of peripheral nerve fiber subpopulations was found as well as a change in the electrical activity of wide dynamic range neurons of dorsal horn of spinal cord. Finally, the immune response is not a key factor in the development of morphological and functional damage induced by bortezomib in the peripheral nervous system. PMID- 24069170 TI - Multilocus sequence typing of Borrelia burgdorferi suggests existence of lineages with differential pathogenic properties in humans. AB - The clinical manifestations of Lyme disease, caused by Borrelia burgdorferi, vary considerably in different patients, possibly due to infection by strains with varying pathogenicity. Both rRNA intergenic spacer and ospC typing methods have proven to be useful tools for categorizing B. burgdorferi strains that vary in their tendency to disseminate in humans. Neither method, however, is suitable for inferring intraspecific relationships among strains that are important for understanding the evolution of pathogenicity and the geographic spread of disease. In this study, multilocus sequence typing (MLST) was employed to investigate the population structure of B. burgdorferi recovered from human Lyme disease patients. A total of 146 clinical isolates from patients in New York and Wisconsin were divided into 53 sequence types (STs). A goeBURST analysis, that also included previously published STs from the northeastern and upper Midwestern US and adjoining areas of Canada, identified 11 major and 3 minor clonal complexes, as well as 14 singletons. The data revealed that patients from New York and Wisconsin were infected with two distinct, but genetically and phylogenetically closely related, populations of B. burgdorferi. Importantly, the data suggest the existence of B. burgdorferi lineages with differential capabilities for dissemination in humans. Interestingly, the data also indicate that MLST is better able to predict the outcome of localized or disseminated infection than is ospC typing. PMID- 24069171 TI - Tiam1 transgenic mice display increased tumor invasive and metastatic potential of colorectal cancer after 1,2-dimethylhydrazine treatment. AB - BACKGROUND: T lymphoma invasion and metastasis 1 (Tiam1) is a potential modifier of tumor development and progression. Our previous study in vitro and in nude mice suggested a promotion role of Tiam1 on invasion and metastasis of colorectal cancer (CRC). In the present study, we generated Tiam1/C1199-CopGFP transgenic mice to investigate the tumorigenetic, invasive and metastatic alterations in the colon and rectum of wild-type and Tiam1 transgenic mice under 1,2 dimethylhydrazine (DMH) treatment. METHODS: Transgenic mice were produced by the method of pronuclear microinlectlon. Whole-body fluorescence imaging (Lighttools, Edmonton, Alberta, Canada), PCR, and immunohistochemical techniques (IHC) were applied sequentially to identify the transgenic mice. The carcinogen DMH (20 mg/kg) was used to induce colorectal tumors though intraperitoneal (i.p.) injections once a week for 24 weeks from the age of 4 weeks on Tiam1 transgenic or non-transgenic mice. RESULTS: We successfully generated Tiam1/C1199-CopGFP transgenic mice and induced primary tumors in the intestine of both wild type and Tiam1 transgenic mice by DMH treatment. In addition, Tiam1 transgenic mice developed larger and more aggressive neoplasm than wild-type mice. Moreover, immunohistochemical staining revealed that upregulation of Tiam1 was correlated with increased expression of beta-Catenin and Vimentin, and downregulation of E Cadherin in these mice. CONCLUSIONS: Our study has provided in vivo evidence supporting that Tiam1 promotes invasion and metastasis of CRC, most probably through activation of Wnt/beta-catenin signaling pathway, in a Tiam1 transgenic mouse model. PMID- 24069172 TI - Development of a short version of the visual function questionnaire using item response theory. AB - PURPOSE: In clinical ophthalmology as in other fields, measuring patient-reported outcomes imposes a burden on patients. To decrease that burden, we used item response theory (IRT) to develop and test a short version of the National Eye Institute's Visual Function Questionnaire (VFQ). METHODS: We analyzed VFQ data from 276 adults in Japan. Most of them had glaucoma, cataract, or macular degeneration. Their visual acuity (Snellen fraction) averaged 20/120 (range: 20/13 to 20/2000) for the better eye, and 20/200 (range: 20/13 to 20/2000) for the worse eye. We used a polytomous IRT model, the Generalized Partial Credit Model as implemented in software for parameter scaling of rating data (PARSCALE). To select items for inclusion in the short version we examined each item's location on the latent-trait continuum, its slope, and its frequency of missing data. We also ensured representation of all 7 domains that are important in Japan. To examine the characteristics of the resulting scale, we computed its test information (an index of precision that can vary with the value of the latent trait), and carried out validation testing. RESULTS: From 32 of the original VFQ items, we selected 11. The scale comprising those 11 items (the VFQ J11) had test information greater than 9 for values of the latent trait between 2.0 and +0.8. The item thresholds were well-targeted for patients with vision problems. Scores on the VFQ-J11 correlated strongly and in the expected direction with measures of visual field and corrected visual acuity. As expected for a valid measure, those scores also improved by a large amount (almost one standard deviation) after cataract surgery. CONCLUSION: This 11-item instrument can provide reliable and the valid data on visual functioning in patients with ophthalmic problems. It is expected to be less of a burden on respondents, while it maintains good psychometric properties. PMID- 24069173 TI - Intranasal delivery of plasma and platelet growth factors using PRGF-Endoret system enhances neurogenesis in a mouse model of Alzheimer's disease. AB - Neurodegeneration together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD) induced by a combination of toxic amyloid-beta peptide (Abeta) and a loss of trophic factor support. Amelioration of these was assessed with diverse neurotrophins in experimental therapeutic approaches. The aim of this study was to investigate whether intranasal delivery of plasma rich in growth factors (PRGF-Endoret), an autologous pool of morphogens and proteins, could enhance hippocampal neurogenesis and reduce neurodegeneration in an amyloid precursor protein/presenilin-1 (APP/PS1) mouse model. Neurotrophic and neuroprotective actions were firstly evident in primary neuronal cultures, where cell proliferation and survival were augmented by Endoret treatment. Translation of these effects in vivo was assessed in wild type and APP/PS1 mice, where neurogenesis was evaluated using 5-bromodeoxyuridine (BdrU), doublecortin (DCX), and NeuN immunostaining 5 weeks after Endoret administration. The number of BrdU, DCX, and NeuN positive cell was increased after chronic treatment. The number of degenerating neurons, detected with fluoro Jade-B staining was reduced in Endoret treated APP/PS1 mice at 5 week after intranasal administration. In conclusion, Endoret was able to activate neuronal progenitor cells, enhancing hippocampal neurogenesis, and to reduce Abeta-induced neurodegeneration in a mouse model of AD. PMID- 24069174 TI - Striatal infusion of glial conditioned medium diminishes huntingtin pathology in r6/1 mice. AB - Huntington's disease is a neurodegenerative disorder caused by an expansion of CAG repeats in the huntingtin gene which produces widespread neuronal and glial pathology. We here investigated the possible therapeutic role of glia or glial products in Huntington's disease using striatal glial conditioned medium (GCM) from fetus mice (E16) continuously infused for 15 and 30 days with osmotic minipumps into the left striatum of R6/1 mice. Animals infused with GCM had significantly less huntingtin inclusions in the ipsilateral cerebral cortex and in the ipsilateral and contralateral striata than mice infused with cerebrospinal fluid. The numbers of DARPP-32 and TH positive neurons were also greater in the ipsilateral but not contralateral striata and substantia nigra, respectively, suggesting a neuroprotective effect of GCM on efferent striatal and nigro striatal dopamine neurons. GCM increases activity of the autophagic pathway, as shown by the reduction of autophagic substrate, p-62, and the augmentation of LC3 II, Beclin-1 and LAMP-2 protein levels, direct markers of autophagy, in GCM infused mice. GCM also increases BDNF levels. These results suggest that CGM should be further explored as a putative neuroprotective agent in Huntington's disease. PMID- 24069175 TI - The effect of attending steiner schools during childhood on health in adulthood: a multicentre cross-sectional study. AB - BACKGROUND: It is speculated that attending Steiner schools, whose pedagogical principles include an account for healthy psycho-physical development, may have long-term beneficial health effects. We examined whether the current health status differed between former attendees of German Steiner schools and adults from the general population. Furthermore, we examined factors that might explain those differences. METHODS: We included former Steiner school attendees from 4 schools in Berlin, Hanover, Nuremberg and Stuttgart and randomly selected population controls. Using a self-report questionnaire we assessed sociodemographics, current and childhood lifestyle and health status. Outcomes were self-reports on 16 diseases: atopic dermatitis, allergic rhinitis, bronchial asthma, chronic obstructive pulmonary disease (COPD), cardiac arrhythmia, cardiac insufficiency, angina pectoris, arteriosclerosis, hypertension, hypercholesterolemia, osteoarthritis, rheumatism, cancer, diabetes, depression and multiple sclerosis. Furthermore, participants rated the symptom burden resulting from back pain, cold symptoms, headache, insomnia, joint pain, gastrointestinal symptoms and imbalance. Unadjusted and adjusted odds ratios were calculated for each outcome. RESULTS: 1136 Steiner school attendees and 1746 controls were eligible for analysis. Both groups were comparable regarding sex, age and region, but differed in nationality and educational status. After adjusting for possible confounders, we found statistically significant effects of Steiner school attendance for osteoarthritis (OR 0.69 [0.49-0.97]) and allergic rhinitis (OR 0.77, [0.59-1.00]) as well as for symptom burden from back pain (OR 0.80, [0.64-1.00]), insomnia (OR 0.65, [0.50-0.84]), joint pain (OR 0.62, [0.48 0.82]), gastrointestinal symptoms (OR 0.76, [0.58-1.00]) and imbalance (OR 0.60, [0.38-0.93]). CONCLUSIONS: The risk of most examined diseases did not differ between former Steiner school attendees and the general population after adjustment for sociodemographics, current and childhood lifestyle features, but symptom burden from some current health complaints was reported less by former Steiner school attendees. Results must be interpreted with caution since the analysis was exploratory. PMID- 24069176 TI - Structure, gene flow, and recombination among geographic populations of a Russula virescens ally from Southwestern China. AB - Mushrooms that are morphologically indistinguishable from Russula virescens (Schaeff.) Fr. are among the most popular wild edible mushrooms in Yunnan province, southwestern China. However, almost nothing is known about their biology. This study investigated the diversity and population genetics of a R. virescens ally from Yunnan. A total of 210 samples were collected from 13 geographical locations throughout the main distribution range in Yunnan. The patterns of genetic variation within and among these geographic populations were analyzed using sequences from three nuclear and two mitochondrial DNA fragments. Analysis of the ITS sequences revealed that samples from Yunnan showed 3-6% sequence difference from R. virescens samples from North America and Europe and formed a distinct clade. Our multilocus population genetic analyses suggested frequent gene flow among geographic populations of the R. virescens ally in Yunnan. Interestingly, the nuclear and mitochondrial genes exhibited different levels of gene flow and recombination. We discuss the implications of our results for understanding speciation, reproduction and conservation of this important biological resource. PMID- 24069177 TI - Cell organisation in the colonic crypt: a theoretical comparison of the pedigree and niche concepts. AB - The intestinal mucosa is a monolayer of rapidly self-renewing epithelial cells which is not only responsible for absorption of water and nutrients into the bloodstream but also acts as a protective barrier against harmful microbes entering the body. New functional epithelial cells are produced from stem cells, and their proliferating progeny. These stem cells are found within millions of crypts (tubular pits) spaced along the intestinal tract. The entire intestinal epithelium is replaced every 2-3 days in mice (3-5 days in humans) and hence cell production, differentiation, migration and turnover need to be tightly regulated. Malfunctions in this regulation are strongly linked to inflammatory bowel diseases and to the formation of adenomas and ultimately cancerous tumours. Despite a great deal of biological experimentation and observation, precisely how colonic crypts are regulated to produce mature colonocytes remains unclear. To assist in understanding how cell organisation in crypts is achieved, two very different conceptual models of cell behaviour are developed here, referred to as the 'pedigree' and the 'niche' models. The pedigree model proposes that crypt cells are largely preprogrammed and receive minimal prompting from the environment as they move through a routine of cell differentiation and proliferation to become mature colonocytes. The niche model proposes that crypt cells are primarily influenced by the local microenvironments along the crypt, and that predetermined cell behaviour plays a negligible role in their development. In this paper we present a computational model of colonic crypts in the mouse, which enables a comparison of the quality and controllability of mature coloncyte production by crypts operating under these two contrasting conceptual models of crypt regulation. PMID- 24069178 TI - Differential oxidative stress induced by dengue virus in monocytes from human neonates, adult and elderly individuals. AB - Changes in immune response during lifespan of man are well known. These changes involve decreased neonatal and elderly immune response. In addition, it has been shown a relationship between immune and oxidative mechanisms, suggesting that altered immune response could be associated to altered oxidative response. Increased expression of nitric oxide (NO) has been documented in dengue and in monocyte cultures infected with different types of dengue virus. However, there is no information about the age-dependent NO oxidative response in humans infected by dengue virus. In this study, monocyte cultures from neonatal, elderly and adult individuals (n = 10 each group) were infected with different dengue virus types (DENV- 1 to 4) and oxidative/antioxidative responses and apoptosis were measured at days 1 and 3 of culture. Increased production of NO, lipid peroxidation and enzymatic and nonenzymatic anti-oxidative responses in dengue infected monocyte cultures were observed. However, neonatal and elderly monocytes had lower values of studied parameters when compared to those in adult-derived cultures. Apoptosis was present in infected monocytes with higher values at day 3 of culture. This reduced oxidant/antioxidant response of neonatal and elderly monocytes could be relevant in the pathogenesis of dengue disease. PMID- 24069180 TI - WINROP identifies severe retinopathy of prematurity at an early stage in a nation based cohort of extremely preterm infants. AB - OBJECTIVE: To evaluate the ability of a postnatal weight-gain algorithm (WINROP) to identify sight-threatening retinopathy of prematurity (ROP type 1) in a nation based extremely preterm infant cohort. METHODS: This study enrolled all 707 live born extremely preterm (gestational age [GA] <27 weeks) infants, born 2004-2007 in Sweden; the Extremely preterm Infants in Sweden Study (EXPRESS). WINROP analysis was performed retrospectively in 407 of the infants using weekly weight gain to assess the preterm infant's risk of developing ROP type 1 requiring treatment. GA, birthweight (BW), and weekly postnatal weight measurements were entered into WINROP. WINROP signals with an alarm to indicate if the preterm infant is at risk for ROP type 1. RESULTS: In this extremely preterm population, WINROP correctly identified 96% (45/47) of the infants who required treatment for ROP type 1. The median time from alarm to treatment was 9 weeks (range, 4-20 weeks). CONCLUSIONS: WINROP, an online surveillance system using weekly weight gain, identified extremely preterm infants at risk for ROP type 1 requiring treatment at an early stage and with high sensitivity in a Swedish nation-based cohort. PMID- 24069181 TI - Structural analysis of peptide-analogues of human Zona Pellucida ZP1 protein with amyloidogenic properties: insights into mammalian Zona Pellucida formation. AB - Zona pellucida (ZP) is an extracellular matrix surrounding and protecting mammalian and fish oocytes, which is responsible for sperm binding. Mammalian ZP consists of three to four glycoproteins, called ZP1, ZP2, ZP3, ZP4. These proteins polymerize into long interconnected filaments, through a common structural unit, known as the ZP domain, which consists of two domains, ZP-N and ZP-C. ZP is related in function to silkmoth chorion and in an evolutionary fashion to the teleostean fish chorion, also fibrous structures protecting the oocyte and embryo, that both have been proven to be functional amyloids. Two peptides were predicted as 'aggregation-prone' by our prediction tool, AMYLPRED, from the sequence of the human ZP1-N domain. Here, we present results from transmission electron microscopy, X-ray diffraction, Congo red staining and attenuated total reflectance Fourier-transform infrared spectroscopy (ATR FT-IR), of two synthetic peptide-analogues of these predicted 'aggregation-prone' parts of the human ZP1-N domain, that we consider crucial for ZP protein polymerization, showing that they both self-assemble into amyloid-like fibrils. Based on our experimental data, we propose that human ZP (hZP) might be considered as a novel, putative, natural protective amyloid, in close analogy to silkmoth and teleostean fish chorions. Experiments are in progress to verify this proposal. We also attempt to provide insights into ZP formation, proposing a possible model for hZP1-N domain polymerization. PMID- 24069182 TI - Cord blood-derived macrophage-lineage cells rapidly stimulate osteoblastic maturation in mesenchymal stem cells in a glycoprotein-130 dependent manner. AB - In bone, depletion of osteoclasts reduces bone formation in vivo, as does osteal macrophage depletion. How osteoclasts and macrophages promote the action of bone forming osteoblasts is, however, unclear. Since recruitment and differentiation of multi-potential stromal cells/mesenchymal stem cells (MSC) generates new active osteoblasts, we investigated whether human osteoclasts and macrophages (generated from cord blood-derived hematopoietic progenitors) induce osteoblastic maturation in adipose tissue-derived MSC. When treated with an osteogenic stimulus (ascorbate, dexamethasone and beta-glycerophosphate) these MSC form matrix-mineralising, alkaline phosphatase-expressing osteoblastic cells. Cord blood-derived progenitors were treated with macrophage colony stimulating factor (M-CSF) to form immature proliferating macrophages, or with M-CSF plus receptor activator of NFkappaB ligand (RANKL) to form osteoclasts; culture medium was conditioned for 3 days by these cells to study their production of osteoblastic factors. Both osteoclast- and macrophage-conditioned medium (CM) greatly enhanced MSC osteoblastic differentiation in both the presence and absence of osteogenic medium, evident by increased alkaline phosphatase levels within 4 days and increased mineralisation within 14 days. These CM effects were completely ablated by antibodies blocking gp130 or oncostatin M (OSM), and OSM was detectable in both CM. Recombinant OSM very potently stimulated osteoblastic maturation of these MSC and enhanced bone morphogenetic protein-2 (BMP-2) actions on MSC. To determine the influence of macrophage activation on this OSM-dependent activity, CM was collected from macrophage populations treated with M-CSF plus IL-4 (to induce alternative activation) or with GM-CSF, IFNgamma and LPS to cause classical activation. CM from IL-4 treated macrophages stimulated osteoblastic maturation in MSC, while CM from classically-activated macrophages did not. Thus, macrophage-lineage cells, including osteoclasts but not classically activated macrophages, can strongly drive MSC-osteoblastic commitment in OSM-dependent manner. This supports the notion that eliciting gp130-dependent signals in human MSC would be a useful approach to increase bone formation. PMID- 24069183 TI - Influence of COMT val158met genotype on the depressed brain during emotional processing and working memory. AB - Major depressive disorder (MDD) has been associated with abnormal prefrontal limbic interactions and altered catecholaminergic neurotransmission. The val158met polymorphism on the catechol-O-methyltransferase (COMT) gene has been shown to influence prefrontal cortex (PFC) activation during both emotional processing and working memory (WM). Although COMT-genotype is not directly associated with MDD, it may affect MDD pathology by altering PFC activation, an endophenotype associated with both COMT and MDD. 125 participants, including healthy controls (HC, n=28) and MDD patients were genotyped for the COMT val158met polymorphism and underwent functional magnetic resonance imaging (fMRI neuroimaging) during emotion processing (viewing of emotional facial expressions) and a WM task (visuospatial planning). Within HC, we observed a positive correlation between the number of met-alleles and right inferior frontal gyrus activation during emotional processing, whereas within patients the number of met alleles was not correlated with PFC activation. During WM a negative correlation between the number of met-alleles and middle frontal gyrus activation was present in the total sample. In addition, during emotional processing there was an effect of genotype in a cluster including the amygdala and hippocampus. These results demonstrate that COMT genotype is associated with relevant endophenotypes for MDD. In addition, presence of MDD only interacts with genotype during emotional processing and not working memory. PMID- 24069184 TI - Reduced vancomycin susceptibility found in methicillin-resistant and methicillin sensitive Staphylococcus aureus clinical isolates in Northeast China. AB - BACKGROUND: Strains of Staphylococcus aureus with an intermediate level of resistance to vancomycin (vancomycin-intermediate S. aureus, or VISA) or which contain subpopulations of mixed susceptibility (heterogeneous VISA, or hVISA) have been reported worldwide. However, the prevalence of VISA and hVISA infections in Northeast China is unknown. From 2007 through 2010, we surveyed the vancomycin susceptibility of methicillin-resistant and methicillin-sensitive S. aureus (MRSA and MSSA, respectively) clinical isolates in Northeast China. METHODS: S. aureus clinical isolates (369 MRSA and 388 MSSA) were screened for hVISA and VISA on brain heart infusion agar containing 3 MUg/mL vancomycin, and their identity confirmed using a modified population analysis profile-area under the curve method and broth microdilution. All hVISA and VISA isolates were characterized genotypically and phenotypically. RESULTS: Ten percent and 0.5 percent of the isolates were hVISA and VISA, respectively. The proportion of hVISA among MSSA isolates for the entire study period was 4.1%, but increased significantly year-by-year, from 1.2% in 2007 to 7.2% in 2010. The predominant sources of hVISA and VISA isolates were sputum (56.3%), pus (18.8%), and blood (8.8%). Molecular typing of hVISA and VISA strains revealed that, taken together, 80% contained the accessory gene regulator (agr) group II, and of these, 85.7% of the MR-hVISA and MR-VISA strains were staphylococcal cassette chromosome mec (SCCmec) type II. The adherence ability of all hVISA and VISA strains was reduced compared with that of vancomycin-susceptible strains, shown by biofilm assay. CONCLUSIONS: The percentage of hVISA strains was high and increased each year. The proportion of hVISA among MSSA specifically also increased significantly each year. In isolates collected from diverse infection sites, hVISA and VISA strains were found predominantly in sputum, pus, and blood, in descending order. Testing for vancomycin susceptibility should include both MRSA and MSSA isolates collected from different clinical sites. PMID- 24069185 TI - Mitochondrial inverted repeats strongly correlate with lifespan: mtDNA inversions and aging. AB - Mitochondrial defects are implicated in aging and in a multitude of age-related diseases, such as cancer, heart failure, Parkinson's disease, and Huntington's disease. However, it is still unclear how mitochondrial defects arise under normal physiological conditions. Mitochondrial DNA (mtDNA) deletions caused by direct repeats (DRs) are implicated in the formation of mitochondrial defects, however, mitochondrial DRs show relatively weak (Pearson's r = -0.22, p<0.002; Spearman's rho = -0.12, p = 0.1) correlation with maximum lifespan (MLS). Here we report a stronger correlation (Pearson's r = -0.55, p<10(-16); Spearman's rho = 0.52, p<10(-14)) between mitochondrial inverted repeats (IRs) and lifespan across 202 species of mammals. We show that, in wild type mice under normal conditions, IRs cause inversions, which arise by replication-dependent mechanism. The inversions accumulate with age in the brain and heart. Our data suggest that IR mediated inversions are more mutagenic than DR-mediated deletions in mtDNA, and impose stronger constraint on lifespan. Our study identifies IR-induced mitochondrial genome instability during mtDNA replication as a potential cause for mitochondrial defects. PMID- 24069179 TI - Population genetics of Lactobacillus sakei reveals three lineages with distinct evolutionary histories. AB - Lactobacillus sakei plays a major role in meat fermentation and in the preservation of fresh meat. The large diversity of L. sakei strains represents a valuable and exploitable asset in the development of a variety of industrial applications; however, an efficient method to identify and classify these strains has yet to be developed. In this study, we used multilocus sequence typing (MLST) to analyze the polymorphism and allelic distribution of eight loci within an L. sakei population of 232 strains collected worldwide. Within this population, we identified 116 unique sequence types with an average pairwise nucleotide diversity per site (pi) of 0.13%. Results from Structure, goeBurst, and ClonalFrame software analyses demonstrated that the L. sakei population analyzed here is derived from three ancestral lineages, each of which shows evidence of a unique evolutionary history influenced by independent selection scenarios. However, the signature of selective events in the contemporary population of isolates was somewhat masked by the pervasive phenomenon of homologous recombination. Our results demonstrate that lineage 1 is a completely panmictic subpopulation in which alleles have been continually redistributed through the process of intra-lineage recombination. In contrast, lineage 2 was characterized by a high degree of clonality. Lineage 3, the earliest-diverging branch in the genealogy, showed evidence of both clonality and recombination. These evolutionary histories strongly indicate that the three lineages may correspond to distinct ecotypes, likely linked or specialized to different environmental reservoirs. The MLST scheme developed in this study represents an easy and straightforward tool that can be used to further analyze the population dynamics of L. sakei strains in food products. PMID- 24069186 TI - Severe septic patients with mitochondrial DNA haplogroup JT show higher survival rates: a prospective, multicenter, observational study. AB - OBJECTIVE: In a previous cohort study (n=96), we found an association between mitochondrial (mt) DNA haplogroup JT and increased survival of severe septic patients, after controlling for age and serum lactic acid levels. The aim of this research was to increase the predictive accuracy and to control for more confounder variables in a larger cohort (n=196) of severe septic patients, to confirm whether mtDNA haplogroup JT influences short and medium-term survival in these patients. METHODS: We conducted a prospective, multicenter, observational study in six Spanish Intensive Care Units. We determined 30-day and 6-month survival and mtDNA haplogroup in this second cohort of 196 patients and in the global cohort (first and second cohorts combined) with 292 severe septic patients. Multiple logistic regression and Cox regression analyses were used to test for the association of mtDNA haplogroups JT with survival at 30-days and 6 months, controlling for age, sex, serum interleukin-6 levels and SOFA score. RESULTS: Logistic and Cox regression analyses showed no differences in 30-day and 6-month survival between patients with mtDNA haplogroup JT and other haplogroups in the first cohort (n=96). In the second cohort (n=196), these analyses showed a trend to higher 30-day and 6-month survival in those with haplogroup JT. In the global cohort (n=292), logistic and Cox regression analyses showed higher 30-day and 6-month survival for haplogroup JT. There were no significant differences between J and T sub-haplogroups in 30-day and 6-month survival. CONCLUSIONS: The global cohort study (first and second cohorts combined), the largest to date reporting on mtDNA haplogroups in septic patients, confirmed that haplogroup JT patients showed increased 30-day and 6-month survival. This finding may be due to single nucleotide polymorphism defining the whole haplogroup JT and not separately for J or T sub-haplogroups. PMID- 24069187 TI - TaMFT-A1 is associated with seed germination sensitive to temperature in winter wheat. AB - The ability of seed to germinate under favorable environmental conditions is critical for seedling emergence, plant establishment, subsequent development and growth of adult plants, and it is controlled by internal genetic factors and external environmental factors. Winter wheat in the southern Great Plains is often planted six weeks before the optimal planting date to produce more biomass for cattle grazing during the winter season. A high seed germination rate in this higher soil temperature environment is required for this specific management system. In this study, a major QTL for temperature-sensitive germination was mapped on the short arm of chromosome 3A (QTsg.osu-3A) in a RIL population generated from two winter wheat cultivars. Furthermore, TaMFT-A1, previously reported to regulate seed dormancy and pre-harvest sprouting in spring wheat cultivars, was mapped tightly associated with the peak of QTsg.osu-3A. However, allelic variation in TaMFT-A1 between the two winter wheat cultivars differed from that was observed in spring wheat cultivars. There were 87 SNPs (single nucleotide polymorphisms) and 12 indels (insertions/deletions) in TaMFT-A1 between the Jagger allele for high germination and the 2174 allele for low germination in the after-ripened seeds, in comparison with 2 SNPs between the two alleles for differential pre-harvest sprouting in spring wheat cultivars. The Jagger TaMFT-A1 allele is a novel haplotype and appears extensively in winter wheat cultivars. TaMFT-A1 transcript levels were up-regulated by high temperature but down-regulated by low temperature or seed storage time. These findings suggest that TaMFT-A1 may invoke different mechanisms for controlling seed dormancy/germination among winter wheat cultivars. PMID- 24069188 TI - Function of survivin in trophoblastic cells of the placenta. AB - BACKGROUND: Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity worldwide and its pathogenesis is not totally understood. As a member of the chromosomal passenger complex and an inhibitor of apoptosis, survivin is a well-characterized oncoprotein. Its roles in trophoblastic cells remain to be defined. METHODS: The placental samples from 16 preeclampsia patients and 16 well-matched controls were included in this study. Real-time PCR, immunohistochemistry and Western blot analysis were carried out with placental tissues. Primary trophoblastic cells from term placentas were isolated for Western blot analysis. Cell proliferation, cell cycle analysis and immunofluorescence staining were performed in trophoblastic cell lines BeWo, JAR and HTR-8/SVneo. RESULTS: The survivin gene is reduced but the protein amount is hardly changed in preeclamptic placentas, compared to control placentas. Upon stress, survivin in trophoblastic cells is phosphorylated on its residue serine 20 by protein kinase A and becomes stabilized, accompanied by increased heat shock protein 90. Depletion of survivin induces chromosome misalignment, abnormal centrosome integrity, and reduced localization and activity of Aurora B at the centromeres/kinetochores in trophoblastic metaphase cells. CONCLUSIONS: Our data indicate that survivin plays pivotal roles in cell survival and proliferation of trophoblastic cells. Further investigations are required to define the function of survivin in each cell type of the placenta in the context of proliferation, differentiation, apoptosis, angiogenesis, migration and invasion. PMID- 24069189 TI - Differential protective effects of exenatide, an agonist of GLP-1 receptor and Piragliatin, a glucokinase activator in beta cell response to streptozotocin induced and endoplasmic reticulum stresses. AB - BACKGROUND: Agonists of glucagon-like peptide-1 receptor (GLP-1R) and glucokinase activators (GKA) act as antidiabetic agents by their ability protect beta cells, and stimulate insulin secretion. Oxidative and endoplasmic reticulum (ER) stresses aggravate type 2 diabetes by causing beta cell loss. It was shown that GLP-1R agonists protect beta cells from oxidative and ER stresses. On the other hand, little is known regarding how GKAs protect beta cells. We hypothesized that GKAs protect beta cells by mechanisms distinct from those underlying GLP-1R agonist and tested our hypothesis by comparing the molecular effects of exenatide, a GLP-1R agonist, and piragliatin, a GKA, on INS-1 cells under oxidative and ER-induced stresses. METHODS: BETA CELLS WERE TREATED WITH STREPTOZOTOCIN (STZ) TO INDUCE OXIDATIVE STRESS AND WITH PALMITATE OR THAPSIGARGIN (TG) TO INDUCE ER STRESS RESPECTIVELY, AND THE EFFECTS OF EXENATIDE AND PIRAGLIATIN ON THESE CELLS WERE INVESTIGATED BY: a) characterizing the kinases involved employing specific kinase inhibitors, and b) by identifying the differentially regulated proteins in response to stresses with proteomic analysis. RESULTS: Exenatide protected INS-1 cells from both ER and STZ-induced death. In contrast, piragliatin rescued the cells only from STZ-induced stress. Akt activation by exenatide appeared to contribute to its protective effects of beta cells while enhanced glucose utilization was the contributing factor in the case of piragliatin. Also, exenatide, not piragliatin, blocked changes in proteins 14-3-3beta, epsilon and theta, and preserved the 14-3-3theta levels under the ER stress. Isoform-specific modifications of 14-3-3, and the reduction of 14-3-3theta, commonly associated with beta cell death were assessed. CONCLUSIONS: Exenatide and piragliatin exert distinct effects on beta cell survival and thus on type 2 diabetes. This study which confirmed our hypothesis is also the first to observe specific modulation of 14-3-3 isoform in stress induced beta cell death associated with progressive deterioration of type 2 diabetes. PMID- 24069190 TI - Endothelin-1 single nucleotide polymorphisms and risk of pulmonary metastatic osteosarcoma. AB - Pulmonary metastases are the major cause of death of osteosarcoma (OS) patients. Endothelin-1 (ET-1) reportedly plays an important role in OS metastasis. In the present study, we for the first time explored the association of ET-1 SNPs with the risk of pulmonary metastatic OS. We genotyped three SNPs (rs1800541, rs2070699 and rs5370) in the ET-1 gene in a case-control study, using 260 pairs of age-, sex-, residence area- and tumor location-matched subjects. Patients with pulmonary metastatic OS and patients with localized high-grade (stage IIB) OS were enrolled as cases and controls, respectively. The G allele at rs1800541 was found associated with reduced risk of pulmonary metastatic OS after adjustment for body mass index, systolic blood pressure, diastolic blood pressure and the plasma ET-1 level (P=10(-4); adjusted OR, 0.55; 95% CI, 0.42-0.70), while the G allele at rs2070699 was not significantly associated with the risk of pulmonary metastatic OS (P=0.15; adjusted OR, 1.15; 95% CI, 0.87-1.50). The mRNA and the secreted protein levels of ET-1 in primary OS cell cultures (POCCs) established from surgically resected primary OS in the rs1800541 TT homozygotes were higher than those from the TG heterozygotes (P<0.05), who in turn showed higher ET-1 mRNA and secreted ET-1 levels than the GG homozygotes (P<0.05). In the control subjects, the rs1800541 TT homozygotes showed an 18.4% relapse rate, significantly higher than that of the GG homozygotes (0%) (P<0.01). On the other hand, the GG homozygotes showed a 71.4% complete recovery rate, significantly higher than that of the TG heterozygotes (7.3%) and the TT homozygotes (0%) (P<0.01). This study provides the first evidence of an association between the ET 1 gene SNPs and the risk of pulmonary metastatic OS. PMID- 24069191 TI - Clinical features and factors associated with outcomes of patients infected with a Novel Influenza A (H7N9) virus: a preliminary study. AB - OBJECTIVE: The present study aimed to analyze clinical features and factors associated with treatment outcomes of H7N9 influenza A virus infection. METHODS: The clinical progress in 18 H7N9-infected patients was monitored and recorded. The clinical features of H7N9 infection were noted and factors associated with treatment outcomes were analyzed by univariate analyses. RESULTS: The average ages of patients in recovered and critical conditions were 67.0+/-10.83 years and 72.75+/-12.0 years, respectively. Renal insufficiency developed more frequently in critically ill patients (P = 0.023). The duration of traditional Chinese medicine (TCM) therapy was longer in recovered patients than in critically ill patients (P = 0.01). Laboratory tests showed that levels of C-reactive protein, serum creatinine, and myoglobin were significantly higher in critically ill patients than in recovered patients (P = 0.011, 0.04, and 0.016, respectively). Meanwhile, levels of all T cell subsets examined including total CD3(+), CD4(+), CD8(+), and CD45(+) T cells were lower in critically ill patients than in recovered patients (P = 0.033, 0.059, 0.015, and 0.039, respectively). Logistic regression analysis demonstrated that C-reactive protein level, myoglobin level and TCM therapy duration were likely associated with treatment outcomes of H7N9 infection (P = 0.032, 0.041 and 0.017, respectively). CONCLUSION: Elderly people may have increased risk for H7N9 virus infection. T cell-mediated responses play an important role in defense against the H7N9 virus. C-reactive protein level, myoglobin level and TCM duration may be associated with treatment outcomes of H7N9 infection. PMID- 24069192 TI - Reliable DNA barcoding performance proved for species and island populations of comoran squamate reptiles. AB - In the past decade, DNA barcoding became increasingly common as a method for species identification in biodiversity inventories and related studies. However, mainly due to technical obstacles, squamate reptiles have been the target of few barcoding studies. In this article, we present the results of a DNA barcoding study of squamates of the Comoros archipelago, a poorly studied group of oceanic islands close to and mostly colonized from Madagascar. The barcoding dataset presented here includes 27 of the 29 currently recognized squamate species of the Comoros, including 17 of the 18 endemic species. Some species considered endemic to the Comoros according to current taxonomy were found to cluster with non Comoran lineages, probably due to poorly resolved taxonomy. All other species for which more than one barcode was obtained corresponded to distinct clusters useful for species identification by barcoding. In most species, even island populations could be distinguished using barcoding. Two cryptic species were identified using the DNA barcoding approach. The obtained barcoding topology, a Bayesian tree based on COI sequences of 5 genera, was compared with available multigene topologies, and in 3 cases, major incongruences between the two topologies became evident. Three of the multigene studies were initiated after initial screening of a preliminary version of the barcoding dataset presented here. We conclude that in the case of the squamates of the Comoros Islands, DNA barcoding has proven a very useful and efficient way of detecting isolated populations and promising starting points for subsequent research. PMID- 24069193 TI - Impact of microRNA expression in human atrial tissue in patients with atrial fibrillation undergoing cardiac surgery. AB - BACKGROUND: Although microRNA (miRNA) regulates initiation and/or progression of atrial fibrillation (AF) in canine AF models, the underlying mechanism in humans remains unclear. We speculated that certain miRNAs in atrial tissue are related to AF, and evaluated the relationship of miRNA expression in human atrial tissue in cardiac surgery patients. METHODS: Right atrial tissues from 29 patients undergoing cardiovascular surgery were divided into 3 groups [A: chronic AF or unsuccessful maze, n=6; B: successful maze, n=10; C: sinus rhythm (SR) n=13]. miRNA expression was determined using high density microarrays and with Reverse transcriptase-polymerase chain reaction (RT-PCR). Fibrosis was examined using Masson trichrome staining. RESULTS: miRNA microarray analysis showed elevated miRNA-21, miRNA-23b, miRNA-199b, and miRNA-208b in AF as compared to SR groups. RT-PCR showed elevated miRNA-21 (1.9-fold) and miRNA-208b (4.2-fold) in AF as compared to the SR groups. miRNA-21 expression increased from Group C to A (A: 2.1-fold, B: 1.8-fold, C: 1.0-fold). Fibrosis increased from C to A (A: 43.0+/ 12.9%, B: 21.3+/-6.1%, C: 11.9+/-3.1%). Percent fibrosis and miRNA-21 expression were correlated (r=0.508, p<0.05). The plasma levels of miRNA-21 in AF patients was significantly decreased as compared to the healthy volunteers (p<0.05). CONCLUSION: The expression of miRNA-21 in human atrial tissue was found to be related to atrial fibrosis and might affect AF occurrence, indicating its usefulness as a biomarker for cardiac surgery management. PMID- 24069194 TI - Cross-link guided molecular modeling with ROSETTA. AB - Chemical cross-links identified by mass spectrometry generate distance restraints that reveal low-resolution structural information on proteins and protein complexes. The technology to reliably generate such data has become mature and robust enough to shift the focus to the question of how these distance restraints can be best integrated into molecular modeling calculations. Here, we introduce three workflows for incorporating distance restraints generated by chemical cross linking and mass spectrometry into ROSETTA protocols for comparative and de novo modeling and protein-protein docking. We demonstrate that the cross-link validation and visualization software Xwalk facilitates successful cross-link data integration. Besides the protocols we introduce XLdb, a database of chemical cross-links from 14 different publications with 506 intra-protein and 62 inter protein cross-links, where each cross-link can be mapped on an experimental structure from the Protein Data Bank. Finally, we demonstrate on a protein protein docking reference data set the impact of virtual cross-links on protein docking calculations and show that an inter-protein cross-link can reduce on average the RMSD of a docking prediction by 5.0 A. The methods and results presented here provide guidelines for the effective integration of chemical cross link data in molecular modeling calculations and should advance the structural analysis of particularly large and transient protein complexes via hybrid structural biology methods. PMID- 24069195 TI - C-reactive protein, high-molecular-weight adiponectin and development of metabolic syndrome in the Japanese general population: a longitudinal cohort study. AB - AIMS: To clarify predictive values of C-reactive protein (CRP) and high-molecular weight (HMW) adiponectin for development of metabolic syndrome. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study of Japanese workers who had participated in an annual health checkup in 2007 and 2011. A total of 750 subjects (558 men and 192 women, age 46+/-8 years) who had not met the criteria of metabolic syndrome and whose CRP and HMW-adiponectin levels had been measured in 2007 were enrolled in this study. Associations between CRP, HMW-adiponectin and development of metabolic syndrome after 4 years were assessed by logistic regression analysis and their predictive values were compared by receiver operating characteristic analysis. RESULTS: Among 750 subjects, 61 (8.1%) developed metabolic syndrome defined by modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria and 53 (7.1%) developed metabolic syndrome defined by Japan Society for the Study of Obesity (JASSO) in 2011. Although CRP and HMW-adiponectin were both significantly correlated with development of metabolic syndrome, multivariate logistic regression analysis revealed that HMW-adiponectin but not CRP was associated with metabolic syndrome independently of BMI or waist circumference. Adding these biomarkers to BMI or waist circumference did not improve the predictive value for metabolic syndrome. CONCLUSION: Our findings indicate that the traditional markers of adiposity such as BMI or waist circumference remain superior markers for predicting metabolic syndrome compared to CRP, HMW-adiponectin, or the combination of both among the Japanese population. PMID- 24069196 TI - Tracing carbon sources through aquatic and terrestrial food webs using amino acid stable isotope fingerprinting. AB - Tracing the origin of nutrients is a fundamental goal of food web research but methodological issues associated with current research techniques such as using stable isotope ratios of bulk tissue can lead to confounding results. We investigated whether naturally occurring delta(13)C patterns among amino acids (delta(13)CAA) could distinguish between multiple aquatic and terrestrial primary production sources. We found that delta(13)CAA patterns in contrast to bulk delta(13)C values distinguished between carbon derived from algae, seagrass, terrestrial plants, bacteria and fungi. Furthermore, we showed for two aquatic producers that their delta(13)CAA patterns were largely unaffected by different environmental conditions despite substantial shifts in bulk delta(13)C values. The potential of assessing the major carbon sources at the base of the food web was demonstrated for freshwater, pelagic, and estuarine consumers; consumer delta(13)C patterns of essential amino acids largely matched those of the dominant primary producers in each system. Since amino acids make up about half of organismal carbon, source diagnostic isotope fingerprints can be used as a new complementary approach to overcome some of the limitations of variable source bulk isotope values commonly encountered in estuarine areas and other complex environments with mixed aquatic and terrestrial inputs. PMID- 24069197 TI - Characterization of partial ligation-induced carotid atherosclerosis model using dual-modality molecular imaging in ApoE knock-out mice. AB - BACKGROUND: Recently, partial ligation of the common carotid artery (CCA) was reported to induce carotid atheromata rapidly in apolipoprotein-E knockout (ApoE( /-)) mice. We investigated this new atherosclerosis model by using combined matrix-metalloproteinase (MMP) near-infrared fluorescent (NIRF) imaging and macrophage-tracking luciferase imaging. METHODOLOGY AND PRINCIPAL FINDINGS: Partial ligation of the left CCA was performed in 10-week-old ApoE(-/-) mice on a high fat diet (n=33); the internal and external carotid arteries and occipital artery were ligated, while the superior thyroid artery was left intact. Two thirds of the animals were treated with either LiCl or atorvastatin. At 1-week, Raw264.7 macrophages modified to express the enhanced firefly-luciferase reporter gene (10(7) Raw-luc cells) were injected intravenously. At 2-week, NIRF molecular imaging visualized strong MMP-2/9 activity in the ligated area of the left CCA as well as in the aortic arch. Left-to-right ratios of the NIRF signal intensities in the CCA had a decreasing gradient from the highest value in the upper-most ligated area to the lowest value in the lower-most region adjacent to the aortic arch. Luciferase imaging showed that most Raw-luc macrophages were recruited to the ligated area of the CCA rather than to the aortic arch, despite similarly strong MMP-2/9-related NIRF signal intensities in both areas. In addition, LiCl or atorvastatin could reduce MMP-2/9 activity in the aortic arch but not in the ligated area of the CCA. CONCLUSIONS/SIGNIFICANCE: This is the first molecular imaging study to characterize the partial ligation-induced carotid atherosclerosis model. Molecularly divergent types of atherosclerosis were identified: conventional lipogenic atherosclerosis in the aorta vs. flow-related mechanical atherosclerosis in the partially ligated left system. PMID- 24069198 TI - Gestational zinc deficiency impairs humoral and cellular immune responses to hepatitis B vaccination in offspring mice. AB - BACKGROUND: Gestational zinc deficiency has been confirmed to impair the infant immune function. However, knowledge about effects of maternal mild zinc deficiency during pregnancy on hepatitis B vaccine responsiveness in offspring is limited. In this report, we aimed to examine how maternal zinc deficiency during pregnancy influences humoral and cellular immune responses to hepatitis B vaccination in offspring of BALB/c mice. METHODOLOGY/PRINCIPAL FINDINGS: From day 1 of pregnancy upon delivery, maternal mice were given a standard diet (30 mg/kg/day zinc), zinc deficient diet (8 mg/kg/day zinc), or combination of zinc deficient diet (8 mg/kg/day zinc in the first 2 weeks of gestation) and zinc supplement diet (150 mg/kg/day zinc for the last week of pregnancy), respectively. Newborn pups of these maternal mice were immunized with hepatitis B vaccine at postnatal weeks 0, 2 and 4. Then, splenocytes and blood samples from the offspring mice were harvested for detection of serum zinc concentrations, humoral and cell-mediated immune responses, expression of cytokines using ELISA, CCK-8 and flow cytometric analysis. Results from the present study demonstrated that gestational zinc deficiency inhibited antibody responses, and decreased the proliferative capacity of T cells in offsprings immunized with hepatitis B vaccine. Additionally, HBsAg-specific cytokines analysis revealed that gestational zinc deficiency could inhibit secretion of IFN-gamma from splenocytes, and decrease IFN-gamma expression of CD4(+) and CD8(+) T cells. CONCLUSIONS/SIGNIFICANCE: Gestational zinc deficiency can weaken the humoral and cell-mediated immune responses to hepatitis B vaccine via decreasing B cell counts and hepatitis B virus-specific immunoglobulin G production, as well as reducing T cell proliferation, CD4(+)/CD8(+) T cell ratio, and Th1-type immune responses. PMID- 24069200 TI - Diet and carbohydrate food knowledge of multi-ethnic women: a comparative analysis of pregnant women with and without Gestational Diabetes Mellitus. AB - BACKGROUND: Diet therapy is the cornerstone for the management of gestational diabetes mellitus (GDM). Carbohydrate is the primary nutrient affecting postprandial blood glucose levels. Hence, knowledge of food containing carbohydrates can assist women with GDM optimize glycemic control. Despite that, there is a paucity of research on carbohydrate-related knowledge of women with GDM. The United Arab Emirates (UAE) has one of the highest prevalence of diabetes (19.2%) in the world. This study compared diet and knowledge of carbohydrate containing foods among pregnant women with and without GDM in the UAE. METHODS: The sample consisted of multi-ethnic women with GDM (n = 94) and a control group of healthy pregnant women (n = 90) attending prenatal clinics in three hospitals in Al Ain, UAE. Data were collected using a questionnaire and a 24-hour recall. Knowledge of food sources of carbohydrate, dietary patterns, and nutrient intakes of the two groups were compared. RESULTS: There were no significant differences in the mean knowledge score of food sources of carbohydrate between women with GDM and that of pregnant women without GDM. Similarly, there were no significant differences in energy and nutrient intakes between the two groups with the exception of percent energy from protein. Women with GDM reported significantly lower intake of fruits and fruit juices (P = 0.012) and higher consumption of milk and yogurt (P = 0.004) compared to that of women without GDM. Twenty-two percent of women with GDM indicated they never visited a dietitian for counseling while 65% reported they visited a dietitian only once or twice during the pregnancy. Predictors of carbohydrate knowledge score were perceived knowledge of diet and GDM and parity among women with GDM and parity and educational level among those without GDM. CONCLUSION: The results of the study highlight the urgent need to provide nutrition education for women with GDM in the UAE. PMID- 24069199 TI - Identification and characterization of cancer mutations in Japanese lung adenocarcinoma without sequencing of normal tissue counterparts. AB - We analyzed whole-exome sequencing data from 97 Japanese lung adenocarcinoma patients and identified several putative cancer-related genes and pathways. Particularly, we observed that cancer-related mutation patterns were significantly different between different ethnic groups. As previously reported, mutations in the EGFR gene were characteristic to Japanese, while those in the KRAS gene were more frequent in Caucasians. Furthermore, during the course of this analysis, we found that cancer-specific somatic mutations can be detected without sequencing normal tissue counterparts. 64% of the germline variants could be excluded using a total of 217 external Japanese exome datasets. We also show that a similar approach may be used for other three ethnic groups, although the discriminative power depends on the ethnic group. We demonstrate that the ATM gene and the PAPPA2 gene could be identified as cancer prognosis related genes. By bypassing the sequencing of normal tissue counterparts, this approach provides a useful means of not only reducing the time and cost of sequencing but also analyzing archive samples, for which normal tissue counterparts are not available. PMID- 24069201 TI - De novo assembly of the sea cucumber Apostichopus japonicus hemocytes transcriptome to identify miRNA targets associated with skin ulceration syndrome. AB - BACKGROUND: De novo transcriptome sequencing is a robust method of predicting miRNA target genes, especially samples without reference genomes. Differentially expressed miRNAs have been previously identified in hemocytes collected from healthy skin and from skin affected by skin ulceration syndrome (SUS) in Apostichopusjaponicus. Target identification for these differentially expressed miRNAs is a major challenge for this non-model organism. METHODOLOGY/PRINCIPAL FINDINGS: To thoroughly understand the function of miRNAs, a normalized cDNA library was sequenced with the Illumina Hiseq2000 technology. A total of 91,098,474 clean reads corresponding to 251,148 unigenes, each with an average length of 494bp, were obtained. Blastx analysis against a nonredundant (nr) NCBI protein database revealed that in this set, 52,680 unigenes coded for 3,893 annotated proteins. Two digital gene expression (DGE) libraries from healthy and SUS samples showed that 4,858 of the unigenes were expressed at significantly different levels; 2,163 were significantly up-regulated, while 2,695 were significantly down-regulated. The computational prediction of miRNA targets from these differentially expressed genes identified 732 unigenes as the targets of 57 conserved and 8 putative novel miRNA families, including spu-miRNA-31 and spu miRNA-2008. CONCLUSION: This study demonstrates the feasibility of identifying miRNA targets by transcriptome analysis. The DGE assembly data represent a substantial increase in the genomic resources available for this species and will provide insights into the gene expression profile analysis and the miRNAs function annotations of further studies. PMID- 24069202 TI - Hospital-based colorectal cancer survival trend of different tumor locations from 1960s to 2000s. AB - BACKGROUND: Our aim is to explore the trend of association between the survival rates of colorectal cancer (CRC) and the different clinical characteristics in patients registered from 1960s to 2000s. We hypothesized that the survival rate of CRC increases over time and varies according to anatomic subsites. METHODS: Information from a total of 4558 stage T(1-4)N(1-2)M0 CRC patients registered from 1960s to 2008 were analyzed. The association of CRC overall survival with age, gender, tumor locations, time, histopathology types, pathology grades, no. of examined lymph nodes, the T stage, and the N stage was analyzed. The assessment of the influence of prognostic factors on patient survival was performed using Cox's proportional hazard regression models. RESULTS: From 1960 to 2008, the studied CRC patients included 2625 (57.6%) and 1933 (42.4%) males and females, respectively. These included 1896 (41.6%) colon cancers, and 2662 (58.4%) rectum cancers. The 5-year survival rate was 49%, 58%, 58%, 70%, and 77% for the time duration of 1960s, 1970s, 1980s, 1990s and 2000s, respectively. An increased 5-year survival rate was observed in the colon cancer and rectum cancer patients. Patients older than 60 years of age were more likely to develop colonic cancer (sigmoid) than rectum cancer (49.2% vs. 39.9%). The Cox regression model showed that only rectum cancer survival was related to time duration. CONCLUSION: The overall survival and 5-year survival rates showed an increase from the 1960s to 2000s. There is a trend of rightward shift of tumor location in CRC patients. PMID- 24069203 TI - The Salmon Louse Lepeophtheirus salmonis (Copepoda: Caligidae) life cycle has only two Chalimus stages. AB - Each year the salmon louse (Lepeophtheirussalmonis Kroyer, 1838) causes multi million dollar commercial losses to the salmon farming industry world-wide, and strict lice control regimes have been put in place to reduce the release of salmon louse larvae from aquaculture facilities into the environment. For half a century, the Lepeophtheirus life cycle has been regarded as the only copepod life cycle including 8 post-nauplius instars as confirmed in four different species, including L. salmonis. Here we prove that the accepted life cycle of the salmon louse is wrong. By observations of chalimus larvae molting in incubators and by morphometric cluster analysis, we show that there are only two chalimus instars: chalimus 1 (comprising the former chalimus I and II stages which are not separated by a molt) and chalimus 2 (the former chalimus III and IV stages which are not separated by a molt). Consequently the salmon louse life cycle has only six post-nauplius instars, as in other genera of caligid sea lice and copepods in general. These findings are of fundamental importance in experimental studies as well as for interpretation of salmon louse biology and for control and management of this economically important parasite. PMID- 24069204 TI - Rapid structural and compositional change in an old-growth subtropical forest: using plant traits to identify probable drivers. AB - Recent studies have shown directional changes in old-growth tropical forests, but changes are complex and diverse, and their drivers unclear. Here, we report rapid net structural and compositional changes in an old-growth subtropical forest and we assess the functional nature of these changes to test hypothetical drivers including recovery from past disturbances, reduction in ungulate browsing, CO2 fertilization, and increases in rainfall and temperature. The study relies on 15 years of demographic monitoring within 8 ha of subtropical montane forest in Argentina. Between 1992 and 2007, stem density markedly increased by 50% (12 stems ha(-1) y(-1)) and basal area by 6% (0.13 m(2) ha(-1) y(-1)). Increased stem density resulted from enhanced recruitment of understory treelets (Piper tucumanum, Eugenia uniflora, Allophylus edulis) into small size classes. Among 27 common tree species, net population growth was negatively correlated with maximum tree size and longevity, and positively correlated with leaf size and leaf nutrient content, especially so when initial population size was controlled for. Changes were inconsistent with predictions derived from past disturbances (no increase in shade-tolerant or long-lived late-succesional species), rainfall or temperature increase (no increase in evergreen or deciduous species, respectively). However, the increase in nutrient-rich soft-leaved species was consistent with exclusion of large herbivores two decades before monitoring started; and CO2 fertilization could help explain the disproportionate increase in small stems. Reductions in populations of large vertebrates have been observed in many otherwise undisturbed tropical forests, and our results suggest they can have important structural and functional repercussions in these forests. PMID- 24069205 TI - Clinical factors associated with abnormal postures in Parkinson's disease. AB - BACKGROUND: Abnormal posture (AP) is often seen in Parkinson's disease (PD), and marked forms known as dropped head syndrome and camptocormia encumber daily living activities. Unlike other motor disabilities such as bradykinesia or muscular rigidity, AP is not always improved but rather deteriorated by PD medication. PURPOSE: To clarify factors associated with neck and thoracolumbar AP. METHODS: Neck flexion (NF) and thoracolumbar (TL) angles were measured in 216 consecutive PD patients and 175 elderly healthy controls. The differences in NF and TL angles between PD patients and controls were designated as DeltaNFA and DeltaTLA, respectively. The association of DeltaNFA or DeltaTLA and predictable factors such as age, sex, duration of PD, Hoehn Yahr (H-Y) stage, Unified Parkinson's Disease Rating Scale Part 3 (UPDRS-3), daily dose of dopamine agonists, and comorbid orthopedic spinal lesions was investigated in PD patients. Patients were divided into quartiles according to DeltaNFA or DeltaTLA. The association between predictable factors and DeltaNFA or DeltaTLA was estimated as odds ratio (OR), comparing with the lowest quartile as the reference by multivariate regression analysis. RESULTS: Compared with controls, distributions of all three posture angles were significantly shifted rightward in PD patients. Although there were no difference in UPDRS-3 scores in the quartiles of DeltaNFA, the highest quartile was associated with H-Y stage >=3 [OR 2.99, 95% confidence interval (CI) 1.33-6.70, p = 0.008] after adjustment for age, sex and comorbid orthopedic spinal lesions. The highest quartile of DeltaTLA was associated with comorbid orthopedic spinal lesions [OR 5.83 (1.42-23.8), p = 0.014], and UPDRS-3 score [OR 3.04 (1.80-5.15)/10 points, p<0.0001]. CONCLUSION: Thoraco-lumbar AP was associated with UPDRS-3 scores and orthopedic spinal lesions, and in contrast, neck AP was not associated with these factors, suggesting that they had different pathomechanisms. PMID- 24069206 TI - Kite aerial photography for low-cost, ultra-high spatial resolution multi spectral mapping of intertidal landscapes. AB - Intertidal ecosystems have primarily been studied using field-based sampling; remote sensing offers the ability to collect data over large areas in a snapshot of time that could complement field-based sampling methods by extrapolating them into the wider spatial and temporal context. Conventional remote sensing tools (such as satellite and aircraft imaging) provide data at limited spatial and temporal resolutions and relatively high costs for small-scale environmental science and ecologically-focussed studies. In this paper, we describe a low-cost, kite-based imaging system and photogrammetric/mapping procedure that was developed for constructing high-resolution, three-dimensional, multi-spectral terrain models of intertidal rocky shores. The processing procedure uses automatic image feature detection and matching, structure-from-motion and photo textured terrain surface reconstruction algorithms that require minimal human input and only a small number of ground control points and allow the use of cheap, consumer-grade digital cameras. The resulting maps combine imagery at visible and near-infrared wavelengths and topographic information at sub centimeter resolutions over an intertidal shoreline 200 m long, thus enabling spatial properties of the intertidal environment to be determined across a hierarchy of spatial scales. Results of the system are presented for an intertidal rocky shore at Jervis Bay, New South Wales, Australia. Potential uses of this technique include mapping of plant (micro- and macro-algae) and animal (e.g. gastropods) assemblages at multiple spatial and temporal scales. PMID- 24069207 TI - Estradiol and progesterone exhibit similar patterns of hepatic gene expression regulation in the bovine model. AB - Female sex steroid hormones, estradiol-17beta (E2-17beta) and progesterone (P4) regulate reproductive function and gene expression in a broad range of tissues. Given the central role of the liver in regulating homeostasis including steroid hormone metabolism, we sought to understand how E2-17beta and P4 interact to affect global gene expression in liver. Ovariectomized cows (n = 8) were randomly assigned to 4 treatment groups applied in a replicated Latin Square design: 1) No hormone supplementation, 2) E2-17beta treatment (ear implant), 3) P4 treatment (intravaginal inserts), and 4) E2-17beta combined with P4. After 14 d of treatment, liver biopsies were collected, allowing 28 d intervals between periods. Changes in gene expression in the liver biopsies were monitored using bovine-specific arrays. Treatment with E2-17beta altered expression of 479 genes, P4 472 genes, and combined treatment significantly altered expression of 468 genes. In total, 578 genes exhibited altered expression including a remarkable number (346 genes) that responded similarly to E2-17beta, P4, or combined treatment. Additional evidence for similar gene expression actions of E2-17beta and/or P4 were: principal component analysis placed almost every treatment array at a substantial distance from controls; Venn diagrams indicated overall treatment effects for most regulated genes; clustering analysis indicated the two major clusters had all treatments up-regulating (172 genes) or down-regulating (173 genes) expression. Thus, unexpectedly, common biological pathways were regulated by E2-17beta and/or P4 in liver. This indicates that the mechanism of action of these steroid hormones in the liver might be either indirect or might occur through non-genomic pathways. This unusual pattern of gene expression in response to steroid hormones is consistent with the idea that there are classical and non-classical tissue-specific responses to steroid hormone actions. Future studies are needed to elucidate putative mechanism(s) responsible for overlapping actions of E2-17beta and P4 on the liver transcriptome. PMID- 24069208 TI - Identification of multipath genes differentially expressed in pathway-targeted microarrays in zebrafish infected and surviving spring viremia carp virus (SVCV) suggest preventive drug candidates. AB - Spring viremia carp virus (SVCV) is a rhabdovirus seasonally affecting warm-water cyprinid fish farming causing high impacts in worldwide economy. Because of the lack of effective preventive treatments, the identification of multipath genes involved in SVCV infection might be an alternative to explore the possibilities of using drugs for seasonal prevention of this fish disease. Because the zebrafish (Danio rerio) is a cyprinid susceptible to SVCV and their genetics and genome sequence are well advanced, it has been chosen as a model for SVCV infections. We have used newly designed pathway-targeted microarrays 3-4-fold enriched for immune/infection functional-relevant probes by using zebrafish orthologous to human genes from selected pathways of the Kyoto Encyclopedia of Genes and Genomes (KEGG). The comparative analysis of differential expression of genes through 20 pathways in 2-day exposed or 30-day survivors of SVCV infection allowed the identification of 16 multipath genes common to more than 6 pathways. In addition, receptors (Toll-like, B-cell, T-cell, RIG1-like) as well as viral RNA infection pathways were identified as the most important human-like pathways targeted by SVCV infection. Furthermore, by using bioinformatic tools to compare the promoter sequences corresponding to up and downregulated multipath gene groups, we identified putative common transcription factors which might be controlling such responses in a coordinated manner. Possible drug candidates to be tested in fish, can be identified now through search of data bases among those associated with the human orthologous to the zebrafish multipath genes. With the use of pathway-targeted microarrays, we identified some of the most important genes and transcription factors which might be implicated in viral shutoff and/or host survival responses after SVCV infection. These results could contribute to develop novel drug-based prevention methods and consolidate the zebrafish/SVCV as a model for vertebrate viral diseases. PMID- 24069209 TI - Accumulation of protease mutations among patients failing second-line antiretroviral therapy and response to salvage therapy in Nigeria. AB - BACKGROUND: To date, antiretroviral therapy (ART) guidelines and programs in resource-limited settings (RLS) have focused on 1(st)- and 2(nd)-line (2 L) therapy. As programs approach a decade of implementation, policy regarding access to 3(rd)-line (3 L) ART is needed. We aimed to examine the impact of maintaining patients on failing 2 L ART on the accumulation of protease (PR) mutations. METHODS AND FINDINGS: From 2004-2011, the Harvard/APIN PEPFAR Program provided ART to >100,000 people in Nigeria. Genotypic resistance testing was performed on a subset of patients experiencing 2 L failure, defined as 2 consecutive viral loads (VL)>1000 copies/mL after >=6 months on 2 L. Of 6714 patients who received protease inhibitor (PI)-based ART, 673 (10.0%) met virologic failure criteria. Genotypes were performed on 61 samples. Patients on non-suppressive 2 L therapy for <12 months prior to genotyping had a median of 2 (IQR: 0-5) International AIDS Society (IAS) PR mutations compared with 5 (IQR: 0-6) among patients failing for >24 months. Patients developed a median of 0.6 (IQR: 0-1.4) IAS PR mutations per 6 months on failing 2 L therapy. In 38% of failing patients no PR mutations were present. For patients failing >24 months, high- or intermediate-level resistance to lopinavir and atazanavir was present in 63%, with 5% to darunavir. CONCLUSIONS: This is the first report assessing the impact of duration of non suppressive 2 L therapy on the accumulation of PR resistance in a RLS. This information provides insight into the resistance cost of failing to switch non suppressive 2 L regimens and highlights the issue of 3 L access. PMID- 24069210 TI - Globalization of stem cell science: an examination of current and past collaborative research networks. AB - Science and engineering research has becoming an increasingly international phenomenon. Traditional bibliometric studies have not captured the evolution of collaborative partnerships between countries, particularly in emerging technologies such as stem cell science, in which an immense amount of investment has been made in the past decade. Analyzing over 2,800 articles from the top journals that include stem cell research in their publications, this study demonstrates the globalization of stem cell science. From 2000 to 2010, international collaborations increased from 20.9% to 36% of all stem cell publications analyzed. The United States remains the most prolific and the most dominant country in the field in terms of publications in high impact journals. But Asian countries, particularly China are steadily gaining ground. Exhibiting the largest relative growth, the percent of Chinese-authored stem cell papers grew more than ten-fold, while the percent of Chinese-authored international papers increased over seven times from 2000 to 2010. And while the percent of total stem cell publications exhibited modest growth for European countries, the percent of international publications increased more substantially, particularly in the United Kingdom. Overall, the data indicated that traditional networks of collaboration extant in 2000 still predominate in stem cell science. Although more nations are becoming involved in international collaborations and undertaking stem cell research, many of these efforts, with the exception of those in certain Asian countries, have yet to translate into publications in high impact journals. PMID- 24069211 TI - The ral exchange factor rgl2 promotes cardiomyocyte survival and inhibits cardiac fibrosis. AB - Cardiomyocytes compensate to acute cardiac stress by increasing in size and contractile function. However, prolonged stress leads to a decompensated response characterized by cardiomyocyte death, tissue fibrosis and loss of cardiac function. Identifying approaches to inhibit this transition to a decompensated response may reveal important targets for treating heart failure. The Ral guanine nucleotide disassociation (RalGDS) proteins are Ras-interacting proteins that are upregulated by hypertrophic stimuli. The Ral guanine nucleotide dissociation stimulator-like 2 (Rgl2) is a member of the RalGDS family that modulates expression of hypertrophic genes in cardiomyocytes. However, the pathophysiologic consequence of increased Rgl2 expression in cardiomyoctyes remains unclear. To evaluate the effect of increasing Rgl2 activity in the heart, transgenic mice with cardiac-targeted over-expression of Rgl2 were generated. Although Ral activation was increased, there were no apparent morphologic or histological differences between the hearts of Rgl2 transgenic and nontransgenic mice indicating that increased Rgl2 expression had no effect on basal cardiac phenotype. To determine if Rgl2 modulates the cardiac response to stress, mice were infused with the beta-adrenergic receptor agonist, isoproterenol. Isoproterenol infusion increased heart mass in both Rgl2 transgenic and nontransgenic mice. However, unlike nontransgenic mice, Rgl2 transgenic mice showed no morphologic evidence of cardiomyocyte damage or increased cardiac fibrosis following isoproterenol infusion. Increased Rgl2 expression in cultured cardiomyocytes stimulated Ral activation and inhibited staurosporine-induced apoptosis via increased activation of PI3-kinase. Activation of the PI3-kinase signaling pathway was confirmed in hearts isolated from Rgl2 transgenic mice. Increased expression and function of Rgl2 in cardiomyocytes promotes activation of the PI3-kinase signaling cascade and protects from carciomyocyte death and pathologic cardiac fibrosis. Taken further, these results suggest that Rgl2 upregulation in hypertrophic hearts may be a protetive mechanism, and that Rgl2 may be a novel therapeutic target in treating heart disease. PMID- 24069212 TI - Water regime influences bulk soil and Rhizosphere of Cereus jamacaru bacterial communities in the Brazilian Caatinga biome. AB - We used the T-RFLP technique combined with Ion Torrent (PGM) sequencing of 16S rRNA and multivariate analysis to study the structure of bulk soil and rhizosphere bacterial communities of a cactus, Cereus jamacaru, from the Brazilian Caatinga biome, which is unique to Brazil. The availability of water shapes the rhizosphere communities, resulting in different patterns during the rainy and dry seasons. Taxonomic approaches and statistical analysis revealed that the phylum Actinobacteria strongly correlated with the dry season, while samples from the rainy season exhibited a strong correlation with the phylum Proteobacteria for rhizosphere samples and with the phyla Bacteroidetes, Firmicutes, Lentisphaerae, and Tenericutes for bulk soil samples. The STAMP software also indicated that the phylum Bacteroidetes, as well as two classes in the Proteobacteria phylum (gamma and delta), were the most significant ones during the rainy season. The average abundance of the phylum Actinobacteria and the genus Bacillus was significantly greater during the dry season. Some significant genera found during the dry season might reflect their tolerance to the extreme conditions found in the Caatinga biome. They may also indicate the ecological function that microorganisms play in providing plants with some degree of tolerance to water stress or in assisting in their development through mechanisms of growth promotion. Alterations in microbial communities can be due to the different abilities of native microorganisms to resist and adapt to environmental changes. PMID- 24069213 TI - Dimerization mediates thermo-adaptation, substrate affinity and transglycosylation in a highly thermostable maltogenic amylase of Geobacillus thermoleovorans. AB - BACKGROUND: Maltogenic amylases belong to a subclass of cyclodextrin-hydrolyzing enzymes and hydrolyze cyclodextrins more efficiently than starch unlike typical alpha-amylases. Several bacterial malto-genic amylases with temperature optima of 40-60 degrees C have been previously characterized. The thermo-adaption, substrate preferences and transglycosylation aspects of extremely thermostable bacterial maltogenic amylases have not yet been reported. METHODOLOGY/PRINCIPAL FINDINGS: The recombinant monomeric and dimeric forms of maltogenic alpha-amylase (Gt-Mamy) of the extremely thermophilic bacterium Geobacillus thermoleovorans are of 72.5 and 145 kDa, which are active optimally at 80 degrees C. Extreme thermostability of this enzyme has been explained by analyzing far-UV CD spectra. Dimerization increases T1/2 of Gt-Mamy from 8.2 h to 12.63 h at 90 degrees C and mediates its enthalpy-driven conformational thermostabilization. Furthermore, dime-rization regulates preferential substrate binding of the enzyme. The substrate preference switching of Gt-Mamy upon dimerization has been confirmed from the substrate-binding affinities of the enzyme for various high and low molecular weight substrates. There is an alteration in Km and substrate hydrolysis efficiency (Vmax/Km) of the enzyme (for cyclodex-trins/starch) upon dimerization. N-terminal truncation indicated the role of N-terminal 128 amino acids in the thermostabilization and modulation of substrate-binding affinity. This has been confirmed by molecular docking of beta-cyclodextrin to Gt-Mamy that indicated the requirement of homodimer formation by the interaction of a few N terminal residues of chain A with the catalytic residues of (alpha/beta)8 barrel of chain B and vice-versa for stable cyclodextrin binding. Site directed mutagenesis provided evidence for the role of N-terminal D109 at the dimeric interface in substrate affinity modulation and thermostabilization. The dimeric Gt-Mamy transglycosylates hydrolytic products of G4/G5 and acarbose, while the truncated form does not because of the lack of extra sugar-binding space formed due to dimerization. CONCLUSION/SIGNIFICANCE: N-terminal domain controls enthalpy driven thermostabilization, substrate-binding affinity and transglycosylation activity of Gt-Mamy by homodimer formation. PMID- 24069214 TI - Prevalence of hepatitis C virus subgenotypes 1a and 1b in Japanese patients: ultra-deep sequencing analysis of HCV NS5B genotype-specific region. AB - BACKGROUND: Hepatitis C virus (HCV) subgenotypes 1a and 1b have different impacts on the treatment response to peginterferon plus ribavirin with direct-acting antivirals (DAAs) against patients infected with HCV genotype 1, as the emergence rates of resistance mutations are different between these two subgenotypes. In Japan, almost all of HCV genotype 1 belongs to subgenotype 1b. METHODS AND FINDINGS: To determine HCV subgenotype 1a or 1b in Japanese patients infected with HCV genotype 1, real-time PCR-based method and Sanger method were used for the HCV NS5B region. HCV subgenotypes were determined in 90% by real-time PCR based method. We also analyzed the specific probe regions for HCV subgenotypes 1a and 1b using ultra-deep sequencing, and uncovered mutations that could not be revealed using direct-sequencing by Sanger method. We estimated the prevalence of HCV subgenotype 1a as 1.2-2.5% of HCV genotype 1 patients in Japan. CONCLUSIONS: Although real-time PCR-based HCV subgenotyping method seems fair for differentiating HCV subgenotypes 1a and 1b, it may not be sufficient for clinical practice. Ultra-deep sequencing is useful for revealing the resistant strain(s) of HCV before DAA treatment as well as mixed infection with different genotypes or subgenotypes of HCV. PMID- 24069215 TI - Cardiomyocyte MEA data analysis (CardioMDA)--a novel field potential data analysis software for pluripotent stem cell derived cardiomyocytes. AB - Cardiac safety pharmacology requires in-vitro testing of all drug candidates before clinical trials in order to ensure they are screened for cardio-toxic effects which may result in severe arrhythmias. Micro-electrode arrays (MEA) serve as a complement to current in-vitro methods for drug safety testing. However, MEA recordings produce huge volumes of data and manual analysis forms a bottleneck for high-throughput screening. To overcome this issue, we have developed an offline, semi-automatic data analysis software, 'Cardiomyocyte MEA Data Analysis (CardioMDA)', equipped with correlation analysis and ensemble averaging techniques to improve the accuracy, reliability and throughput rate of analysing human pluripotent stem cell derived cardiomyocyte (CM) field potentials. With the program, true field potential and arrhythmogenic complexes can be distinguished from one another. The averaged field potential complexes, analysed using our software to determine the field potential duration, were compared with the analogous values obtained from manual analysis. The reliability of the correlation analysis algorithm, evaluated using various arrhythmogenic and morphology changing signals, revealed a mean sensitivity and specificity of 99.27% and 94.49% respectively, in determining true field potential complexes. The field potential duration of the averaged waveforms corresponded well to the manually analysed data, thus demonstrating the reliability of the software. The software has also the capability to create overlay plots for signals recorded under different drug concentrations in order to visualize and compare the magnitude of response on different ion channels as a result of drug treatment. Our novel field potential analysis platform will facilitate the analysis of CM MEA signals in semi-automated way and provide a reliable means of efficient and swift analysis for cardiomyocyte drug or disease model studies. PMID- 24069216 TI - Enzyme immobilisation on amino-functionalised multi-walled carbon nanotubes: structural and biocatalytic characterisation. AB - BACKGROUND: The aim of this work is to investigate the structure and function of enzymes immobilised on nanomaterials. This work will allow better understanding of enzyme-nanomaterial interactions, as well as designing functional protein nanomaterial conjugates. METHODOLOGY/PRINCIPAL FINDINGS: Multiwalled carbon nanotubes (MWNTs) were functionalised with amino groups to improve solubility and biocompatibility. The pristine and functionalised forms of MWNTs were characterised with Fourier-transform infrared spectroscopy. Thermogravimetric analysis was done to examine the degree of the functionalisation process. An immobilised biocatalyst was prepared on functionalised nanomaterial by covalent binding. Thermomyces lanuginosus lipase was used as a model enzyme. The structural change of the immobilised and free lipases were characterised with transmission electron Microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy and Circular dichroism spectroscopy. Biochemical characterisation of immobilised enzyme showed broader pH and thermal optima compared to soluble form. Reusability of the immobilised enzyme for hydrolysis of long chain esters was demonstrated up to ten cycles. CONCLUSION/SIGNIFICANCE: Lipase immobilised on MWNTs has exhibited significantly improved thermal stability. The exploration of advanced nanomaterial for enzyme immobilisation support using sophisticated techniques makes nanobiocatalyst of potential interest for biosensor applications. PMID- 24069217 TI - Antifreeze protein prolongs the life-time of insulinoma cells during hypothermic preservation. AB - It is sometimes desirable to preserve mammalian cells by hypothermia rather than freezing during short term transplantation. Here we found an ability of hypothermic (+4 degrees C) preservation of fish antifreeze protein (AFP) against rat insulinoma cells denoted as RIN-5F. The preservation ability was compared between type I-III AFPs and antifreeze glycoprotein (AFGP), which could be recently mass-prepared by a developed technique utilizing the muscle homogenates, but not the blood serum, of cold-adapted fishes. For AFGP, whose molecular weight is distributed in the range from 2.6 to 34 kDa, only the proteins less than 10 kDa were examined. The viability rate was evaluated by counting of the preserved RIN-5F cells unstained with trypan blue. Significantly, either AFPI or AFPIII dissolved into Euro-Collins (EC) solution at a concentration of 10 mg/ml could preserve approximately 60% of the cells for 5 days at +4 degrees C. The 5-day preserved RIN-5F cells retained the ability to secrete insulin. Only 2% of the cells were, however, preserved for 5 days without AFP. Confocal photomicroscopy experiments further showed the significant binding ability of AFP to the cell surface. These results suggest that fish AFP enables 5-day quality storage of the insulinoma cells collected from a donor without freezing. PMID- 24069218 TI - Energy expenditure evaluation in humans and non-human primates by SenseWear Armband. Validation of energy expenditure evaluation by SenseWear Armband by direct comparison with indirect calorimetry. AB - INTRODUCTION: The purpose of this study was to compare and validate the use of SenseWear Armband (SWA) placed on the arm (SWA ARM) and on the back (SWA BACK) in healthy humans during resting and a cycle-ergometer exercise and to evaluate the SWA to estimate Resting Energy Expenditure (REE) and Total Energy Expenditure (TEE) in healthy baboons. METHODS: We studied 26 (15F/11M) human subjects wearing SWA in two different anatomical sites (arm and back) during resting and a cycle ergometer test and directly compared these results with indirect calorimetry evaluation (IC), performed at the same time. We then inserted the SWA in a metabolic jacket for baboons and evaluated the TEE and REE in free living condition for 6 days in 21 (8F/13M) non-human primates. RESULTS: In humans we found a good correlation between SWA place on the ARM and on the BACK with IC during the resting experiment (1.1+/-0.3 SWAs, 1+/-0.2 IC kcal/min) and a slight underestimation in the SWAs data compared with IC during the cycle-ergometer exercise (5+/-1.9 SWA ARM, 4.5+/-1.5 SWA BACK and 5.4+/-2.1 IC kcal/min). In the non-human primate (baboons) experiment SWA estimated a TEE of 0.54+/-0.009 kcal/min during free living and a REE of 0.82+/-0.06 kcal/min. CONCLUSION: SWA, an extremely simple and inexpensive apparatus, provides quite accurate measurements of energy expenditure in humans and in baboons. Energy expenditure data obtained with SWA are highly correlated with the data obtained with "gold standard", IC, in humans. PMID- 24069219 TI - Unraveling regulatory programs for NF-kappaB, p53 and microRNAs in head and neck squamous cell carcinoma. AB - In head and neck squamous cell carcinoma (HNSCC), mutations of p53 usually coexist with aberrant activation of NF-kappaB (NF-kappaB), other transcription factors and microRNAs, which promote tumor pathogenesis. However, how these factors and microRNAs interact to globally modulate gene expression and mediate oncogenesis is not fully understood. We devised a novel bioinformatics method to uncover interactive relationships between transcription factors or microRNAs and genes. This approach is based on matrix decomposition modeling under the joint constraints of sparseness and regulator-target connectivity, and able to integrate gene expression profiling and binding data of regulators. We employed this method to infer the gene regulatory networks in HNSCC. We found that the majority of the predicted p53 targets overlapped with those for NF-kappaB, suggesting that the two transcription factors exert a concerted modulation on regulatory programs in tumor cells. We further investigated the interrelationships of p53 and NF-kappaB with five additional transcription factors, AP1, CEBPB, EGR1, SP1 and STAT3, and microRNAs mir21 and mir34ac. The resulting gene networks indicate that interactions among NF-kappaB, p53, and the two miRNAs likely regulate progression of HNSCC. We experimentally validated our findings by determining expression of the predicted NF-kappaB and p53 target genes by siRNA knock down, and by examining p53 binding activity on promoters of predicted target genes in the tumor cell lines. Our results elucidating the cross regulations among NF-kappaB, p53, and microRNAs provide insights into the complex regulatory mechanisms underlying HNSCC, and shows an efficient approach to inferring gene regulatory programs in biological complex systems. PMID- 24069220 TI - Mapping the voxel-wise effective connectome in resting state FMRI. AB - A network approach to brain and dynamics opens new perspectives towards understanding of its function. The functional connectivity from functional MRI recordings in humans is widely explored at large scale, and recently also at the voxel level. The networks of dynamical directed connections are far less investigated, in particular at the voxel level. To reconstruct full brain effective connectivity network and study its topological organization, we present a novel approach to multivariate Granger causality which integrates information theory and the architecture of the dynamical network to efficiently select a limited number of variables. The proposed method aggregates conditional information sets according to community organization, allowing to perform Granger causality analysis avoiding redundancy and overfitting even for high-dimensional and short datasets, such as time series from individual voxels in fMRI. We for the first time depicted the voxel-wise hubs of incoming and outgoing information, called Granger causality density (GCD), as a complement to previous repertoire of functional and anatomical connectomes. Analogies with these networks have been presented in most part of default mode network; while differences suggested differences in the specific measure of centrality. Our findings could open the way to a new description of global organization and information influence of brain function. With this approach is thus feasible to study the architecture of directed networks at the voxel level and individuating hubs by investigation of degree, betweenness and clustering coefficient. PMID- 24069221 TI - Violet light down-regulates the expression of specific differentiation markers through Rhodopsin in normal human epidermal keratinocytes. AB - Several recent reports have demonstrated that photoreceptors are expressed in human skin. The rod and cone photoreceptor-like proteins are expressed in human skin and rhodopsin, long wavelength-opsin, and short wavelength-opsin are also present in cultured murine melanocytes. Furthermore, the photopigment rhodopsin is expressed in human melanocytes and is involved in ultraviolet A phototransduction which induces early melanin synthesis. In this study, we investigated whether rhodopsin is expressed and plays any physiological roles in the normal human epidermal keratinocytes (NHEKs). We found that rhodopsin was expressed and localized on the plasma membrane in NHEKs, and only violet light among several wavelengths within the visible range significantly increased the expression of rhodopsin mRNA. We further found that rhodopsin over-expression decreased the mRNA expression levels of keratinocyte differentiation markers, such as keratin-1 and keratin-10, and violet light also decreased the mRNA expression levels of keratinocyte differentiation markers and these decreased expression levels were recovered by a rhodopsin-directed siRNA. Moreover, we further demonstrated that violet light significantly decreased the phosphorylation levels of cAMP responsive element-binding protein (CREB) and that it more effectively decreased the phosphorylation of CREB when rhodopsin was over expressed. In addition, we observed that pertussis toxin, a Galphai protein inhibitor, restored the rhodopsin-induced decrease in the differentiation markers in NHEKs. Taken together, these results suggest that rhodopsin down-regulates the expression levels of specific keratinocyte differentiation markers via the Galphai signaling pathway in NHEKs. PMID- 24069222 TI - The association of a panel of biomarkers with the presence and severity of carcinoid heart disease: a cross-sectional study. AB - PURPOSE: Metastatic neuroendocrine tumors secrete serotonin and other vasoactive substances that are responsible for carcinoid syndrome and carcinoid heart disease. We sought to evaluate the discriminatory utility of diagnostic biomarkers in determining the presence and severity of carcinoid heart disease in patients with metastatic neuroendocrine tumors. PATIENTS AND METHODS: A cross sectional study of patients with neuroendocrine tumors with documented liver metastases and/or carcinoid syndrome between April 2009-October 2012 in 5 tertiary referral centers. Serum was analyzed for Chromogranin A, Chromogranin B and N-terminal pro Brain Natriuretic Peptide (NT-proBNP). Plasma was analyzed for Neurokinin A and 5-Hydroxyindoleacetic acid (5HIAA). Echocardiography was used to determine the presence and severity of carcinoid heart disease. Non-parametric receiver operating characteristic curves were constructed for biomarkers, and the area under the curve determined. The severity of cardiac involvement was correlated with the concentration of each biomarker. RESULTS: A total of 187 patients were identified of whom 37 (20%) had carcinoid heart disease. Significantly higher median values of all biomarkers were found in the patients with cardiac involvement. NT-proBNP and plasma 5HIAA had the highest areas under the curve for the prediction of carcinoid heart disease [NT-proBNP 0.82 (95% confidence interval 0.74-0.90, p<0.0001) and 5HIAA 0.85 (95% confidence interval 0.78-0.92, p<0.0001]. NT-proBNP was moderately correlated (r = 0.48, p<0.001) whereas plasma 5HIAA was only weakly correlated (r = 0.34, p<0.001) with the echocardiographic severity score. CONCLUSION: NT-proBNP and plasma 5HIAA are both sensitive and specific biomarkers for the presence of carcinoid heart disease whereas only NT-proBNP is moderately correlated with disease severity. PMID- 24069223 TI - Network dynamics underlying speed-accuracy trade-offs in response to errors. AB - The ability to dynamically and rapidly adjust task performance based on its outcome is fundamental to adaptive, flexible behavior. Over trials of a task, responses speed up until an error is committed and after the error responses slow down. These dynamic adjustments serve to optimize performance and are well described by the speed-accuracy trade-off (SATO) function. We hypothesized that SATOs based on outcomes reflect reciprocal changes in the allocation of attention between the internal milieu and the task-at-hand, as indexed by reciprocal changes in activity between the default and dorsal attention brain networks. We tested this hypothesis using functional MRI to examine the pattern of network activation over a series of trials surrounding and including an error. We further hypothesized that these reciprocal changes in network activity are coordinated by the posterior cingulate cortex (PCC) and would rely on the structural integrity of its white matter connections. Using diffusion tensor imaging, we examined whether fractional anisotropy of the posterior cingulum bundle correlated with the magnitude of reciprocal changes in network activation around errors. As expected, reaction time (RT) in trials surrounding errors was consistent with predictions from the SATO function. Activation in the default network was: (i) inversely correlated with RT, (ii) greater on trials before than after an error and (iii) maximal at the error. In contrast, activation in the right intraparietal sulcus of the dorsal attention network was (i) positively correlated with RT and showed the opposite pattern: (ii) less activation before than after an error and (iii) the least activation on the error. Greater integrity of the posterior cingulum bundle was associated with greater reciprocity in network activation around errors. These findings suggest that dynamic changes in attention to the internal versus external milieu in response to errors underlie SATOs in RT and are mediated by the PCC. PMID- 24069224 TI - Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4. AB - Lymphatic vessels are derived from venous endothelial cells and their formation is governed by the Vascular endothelial growth factor C (VegfC)/Vegf receptor 3 (Vegfr3; Flt4) signaling pathway. Recent studies show that Collagen and Calcium Binding EGF domains 1 protein (Ccbe1) enhances VegfC-dependent lymphangiogenesis. Both Ccbe1 and Flt4 have been shown to be indispensable for lymphangiogenesis. However, how these essential players are transcriptionally regulated remains poorly understood. In the case of angiogenesis, atypical E2fs (E2f7 and E2f8) however have been recently shown to function as transcriptional activators for VegfA. Using a genome-wide approach we here identified both CCBE1 and FLT4 as direct targets of atypical E2Fs. E2F7/8 directly bind and stimulate the CCBE1 promoter, while recruitment of E2F7/8 inhibits the FLT4 promoter. Importantly, inactivation of e2f7/8 in zebrafish impaired venous sprouting and lymphangiogenesis with reduced ccbe1 expression and increased flt4 expression. Remarkably, over-expression of e2f7/8 rescued Ccbe1- and Flt4-dependent lymphangiogenesis phenotypes. Together these results identified E2f7/8 as novel in vivo transcriptional regulators of Ccbe1 and Flt4, both essential genes for venous sprouting and lymphangiogenesis. PMID- 24069225 TI - Retinal nerve fibre layer thickness and contrast sensitivity in HIV-infected individuals in South Africa: a case-control study. AB - BACKGROUND: Antiretroviral treatment (ART) has altered the spectrum of HIV related eye disease, resulting in a lower prevalence of retinal opportunistic infections (OIs). However, abnormalities in visual function have been reported in HIV-infected individuals despite effective viral suppression and the absence of retinal OIs. These changes may be mediated by an HIV-associated 'neuroretinal disorder', characterized by changes in the retinal nerve fibre layer (RNFL). HIV infection may also be associated with accelerated biological aging. The aim of this study was to investigate the relationships between contrast sensitivity, RNFL thickness, HIV infection and frailty in South African adults. METHODS: Case control study of 225 HIV-infected individuals without retinal OIs and 203 gender/age-matched HIV-seronegative individuals. Peri-papillary RNFL thickness was determined with spectral domain optical coherence tomography in four quadrants. CS was measured using a Pelli-Robson chart. Frailty was assessed using standard criteria. Multivariable linear and logistic regression were used to assess associations between HIV status and RNFL/CS and frailty. RESULTS: The median age of both groups was similar (41.2 vs. 41.9 years, p = 0.37). 88% of HIV infected individuals were receiving ART and their median CD4 count was 468 cells/MUl. Adjusted CS score was lower in HIV-infected participants compared to HIV-seronegative individuals (1.76 vs. 1.82, p = 0.002). Independent predictors of poor CS in the HIV-infected group were positive frailty status and current HIV viral load >2 log copies/ml. Lower CS score was also associated with thin temporal RNFL in HIV-infected individuals (p = 0.04). Superior quadrant RNFL thickness was greatest in ART-naive participants relative to the HIV-uninfected group (p-trend = 0.04). Longer ART duration was associated with thinning of inferior and nasal RNFL quadrants (p-trend = 0.03 and 0.04, respectively). CONCLUSIONS: Contrast sensitivity is reduced in HIV-infected individuals and functionally associated with frailty and unsuppressed viraemia. This may reflect structural changes in the RNFL that are evident despite the absence of OIs. PMID- 24069226 TI - Characterization of mesenchymal stem cells of "no-options" patients with critical limb ischemia treated by autologous bone marrow mononuclear cells. AB - BACKGROUND: Application of autologous bone marrow mononuclear cells to "no option" patients with advanced critical limb ischemia (CLI) prevented major limb amputation in 73% patients during the 6-month follow-up. We examined which properties of bone marrow stromal cells also known as bone-marrow derived mesenchymal stem cells of responding and non-responding patients are important for amputation-free survival. METHODS AND FINDINGS: Mesenchymal stem cells of 41 patients with CLI unsuitable for revascularisation were isolated from mononuclear bone marrow concentrate used for their treatment. Based on the clinical outcome of the treatment, we divided patients into two groups: responders and non responders. Biological properties of responders' and non-responders' mesenchymal stem cells were characterized according to their ability to multiply, to differentiate in vitro, quantitative expression of cell surface markers, secretion of 27 cytokines, chemokines and growth factors, and to the relative expression of 15 mesenchymal stem cells important genes. Secretome comparison between responders (n=27) and non-responders (n=14) revealed significantly higher secretion values of IL-4, IL-6 and MIP-1b in the group of responders. The expression of cell markers CD44 and CD90 in mesenchymal stem cells from responders was significantly higher compared to non-responders (p<0.01). The expression of mesenchymal stem cells surface markers that was analyzed in 22 patients did not differ between diabetic (n=13) and non-diabetic (n=9) patient groups. Statistically significant higher expression of E-cadherin and PDX-1/IPF1 genes was found in non-responders, while expression of Snail was higher in responders. CONCLUSIONS: The quality of mesenchymal stem cells shown in the expression of cell surface markers, secreted factors and stem cell genes plays an important role in therapeutic outcome. Paracrine mechanisms are main drivers in the induction of reparatory processes in CLI patients. Differences in mesenchymal stem cells properties are discussed in relation to their involvement in the reparatory process. PMID- 24069227 TI - Evaluation of a continuous indicator for syndromic surveillance through simulation. application to vector borne disease emergence detection in cattle using milk yield. AB - Two vector borne diseases, caused by the Bluetongue and Schmallenberg viruses respectively, have emerged in the European ruminant populations since 2006. Several diseases are transmitted by the same vectors and could emerge in the future. Syndromic surveillance, which consists in the routine monitoring of indicators for the detection of adverse health events, may allow an early detection. Milk yield is routinely measured in a large proportion of dairy herds and could be incorporated as an indicator in a surveillance system. However, few studies have evaluated continuous indicators for syndromic surveillance. The aim of this study was to develop a framework for the quantification of both disease characteristics and model predictive abilities that are important for a continuous indicator to be sensitive, timely and specific for the detection of a vector-borne disease emergence. Emergences with a range of spread characteristics and effects on milk production were simulated. Milk yields collected monthly in 48 713 French dairy herds were used to simulate 576 disease emergence scenarios. First, the effect of disease characteristics on the sensitivity and timeliness of detection were assessed: Spatio-temporal clusters of low milk production were detected with a scan statistic using the difference between observed and simulated milk yields as input. In a second step, the system specificity was evaluated by running the scan statistic on the difference between observed and predicted milk yields, in the absence of simulated emergence. The timeliness of detection depended mostly on how easily the disease spread between and within herds. The time and location of the emergence or adding random noise to the simulated effects had a limited impact on the timeliness of detection. The main limitation of the system was the low specificity i.e. the high number of clusters detected from the difference between observed and predicted productions, in the absence of disease. PMID- 24069228 TI - Structural analysis of the wheat genes encoding NADH-dependent glutamine-2 oxoglutarate amidotransferases and correlation with grain protein content. AB - BACKGROUND: Nitrogen uptake and the efficient absorption and metabolism of nitrogen are essential elements in attempts to breed improved cereal cultivars for grain or silage production. One of the enzymes related to nitrogen metabolism is glutamine-2-oxoglutarate amidotransferase (GOGAT). Together with glutamine synthetase (GS), GOGAT maintains the flow of nitrogen from NH4 (+) into glutamine and glutamate, which are then used for several aminotransferase reactions during amino acid synthesis. RESULTS: The aim of the present work was to identify and analyse the structure of wheat NADH-GOGAT genomic sequences, and study the expression in two durum wheat cultivars characterized by low and high kernel protein content. The genomic sequences of the three homoeologous A, B and D NADH GOGAT genes were obtained for hexaploid Triticum aestivum and the tetraploid A and B genes of Triticum turgidum ssp. durum. Analysis of the gene sequences indicates that all wheat NADH-GOGAT genes are composed of 22 exons and 21 introns. The three hexaploid wheat homoeologous genes have high conservation of sequence except intron 13 which shows differences in both length and sequence. A comparative analysis of sequences among di- and mono-cotyledonous plants shows both regions of high conservation and of divergence. qRT-PCR performed with the two durum wheat cvs Svevo and Ciccio (characterized by high and low protein content, respectively) indicates different expression levels of the two NADH GOGAT-3A and NADH-GOGAT-3B genes. CONCLUSION: The three hexaploid wheat homoeologous NADH-GOGAT gene sequences are highly conserved - consistent with the key metabolic role of this gene. However, the dicot and monocot amino acid sequences show distinctive patterns, particularly in the transit peptide, the exon 16-17 junction, and the C-terminus. The lack of conservation in the transit peptide may indicate subcellular differences between the two plant divisions - while the sequence conservation within enzyme functional domains remains high. Higher expression levels of NADH-GOGAT are associated with higher grain protein content in two durum wheats. PMID- 24069229 TI - Manual acupuncture for treatment of diabetic peripheral neuropathy: a systematic review of randomized controlled trials. AB - OBJECTIVE: Manual acupuncture has commonly been used in China, either alone or in combination with conventional medicine, to treat diabetic peripheral neuropathy (DPN). The objective of this study was to perform a systematic review to evaluate the potential benefits and harms of manual acupuncture for DPN to justify its clinical use. METHODS: We searched for published and unpublished randomized controlled trials of manual acupuncture for DPN till 31 March 2013. Revman 5.2 software was used for data analysis with effect estimate presented as relative risk (RR) and mean difference (MD) with a 95% confidence interval (CI). RESULTS: A total of 25 trials involving 1649 participants were included. The methodological quality of included trials was generally poor. Meta-analysis showed that manual acupuncture had better effect on global symptom improvement compared with mecobalamin (RR 1.31, 95%CI 1.21 to 1.42), vitamin B1 and B12 (RR 1.55, 95%CI 1.33 to 1.80), and no treatment (RR 1.56, 95%CI 1.31 to 1.85), and that the combination of manual acupuncture and mecobalamin had better effect compared with mecobalamin alone on global symptom improvement (RR 1.56, 95%CI 1.28 to 1.90). Adverse events were not reported in any trials. The asymmetric funnel plot suggested publication bias. CONCLUSIONS: Despite the number of trials of manual acupuncture for DPN and their uniformly positive results, no clinically relevant conclusions can be drawn from this review due to the trials' high risks of bias and the possibility of publication bias. Clearly defined and internationally acknowledged outcome measures are required for future study. There remains an urgent need for training Chinese researchers in conducting unbiased trials as well as prospectively registering all initiated Chinese trials to avoid publication bias. PMID- 24069231 TI - Rab-GDI complex dissociation factor expressed through translational frameshifting in filamentous ascomycetes. AB - In the model fungus Podospora anserina, the PaYIP3 gene encoding the orthologue of the Saccharomyces cerevisiae YIP3 Rab-GDI complex dissociation factor expresses two polypeptides, one of which, the long form, is produced through a programmed translation frameshift. Inactivation of PaYIP3 results in slightly delayed growth associated with modification in repartition of fruiting body on the thallus, along with reduced ascospore production on wood. Long and short forms of PaYIP3 are expressed in the mycelium, while only the short form appears expressed in the maturing fruiting body (perithecium). The frameshift has been conserved over the evolution of the Pezizomycotina, lasting for over 400 million years, suggesting that it has an important role in the wild. PMID- 24069230 TI - A randomised, placebo-controlled, first-in-human study of a novel clade C therapeutic peptide vaccine administered ex vivo to autologous white blood cells in HIV infected individuals. AB - BACKGROUND: Preclinical studies of overlapping 15mer peptides, spanning SIV, SHIV or HIV, pulsed on autologous PBMC ex vivo have demonstrated high level, virus specific T cell responses and viral suppression in non-human primates (NHP). Opal HIV-Gag(c) consists of 120 synthetic 15mer peptides spanning Clade C, consensus Gag, manufactured to current good manufacturing practice; having been evaluated in a good laboratory practice toxicology study in Macaca mulatta. We evaluated the safety and preliminary immunogenicity of such peptides administered intravenously after short-duration ex vivo incubation, to HIV-positive adults on suppressive antiretroviral therapy. METHODS AND FINDINGS: A first-in-human, placebo-controlled, double-blind, dose escalation study was conducted. Twenty three patients with virus suppressed by antiretroviral therapy were enrolled in four groups 12 mg (n = 6), 24 mg (n = 6), 48 mg (n = 2) or matching placebo (n = 8). Treatment was administered intravenously after bedside enrichment of 120 mL whole blood for white cells using a closed system (Sepax S-100 device), with ex vivo peptide admixture (or diluent alone) and 37 degrees C incubation for one hour prior to reinfusion. Patients received 4 administrations at monthly intervals followed by a 12-week observation post-treatment. Opal-HIV-Gag(c) was reasonably tolerated at doses of 12 and 24 mg. There was an increased incidence of temporally associated pyrexia, chills, and transient/self-limiting lymphopenia in Opal-HIV-Gag(c) recipients compared to placebo. The study was terminated early, after two patients were recruited to the 48 mg cohort; a serious adverse event of hypotension, tachycardia secondary to diarrhoea occurred following a single product administration. An infectious cause for the event could not be identified, leaving the possibility of immunologically mediated product reaction. CONCLUSIONS: A serious, potentially life-threatening event of hypotension led to early, precautionary termination of the study. In the absence of a clearly defined mechanism or ability to predict such occurrence, further development of Opal-HIV-Gag(c) will not be undertaken in the current form. REGISTRATION: ClinicalTrials.gov NCT01123915; EudraCT: 2008-005142-23. PMID- 24069232 TI - Population structure of manganese-oxidizing bacteria in stratified soils and properties of manganese oxide aggregates under manganese-complex medium enrichment. AB - Manganese-oxidizing bacteria in the aquatic environment have been comprehensively investigated. However, little information is available about the distribution and biogeochemical significance of these bacteria in terrestrial soil environments. In this study, stratified soils were initially examined to investigate the community structure and diversity of manganese-oxidizing bacteria. Total 344 culturable bacterial isolates from all substrata exhibited Mn(II)-oxidizing activities at the range of 1 uM to 240 uM of the equivalent MnO2. The high Mn(II) oxidizing isolates (>50 mM MnO2) were identified as the species of phyla Actinobacteria, Firmicutes and Proteobacteria. Seven novel Mn(II)-oxidizing bacterial genera (species), namely, Escherichia, Agromyces, Cellulomonas, Cupriavidus, Microbacterium, Ralstonia, and Variovorax, were revealed via comparative phylogenetic analysis. Moreover, an increase in the diversity of soil bacterial community was observed after the combined enrichment of Mn(II) and carbon-rich complex. The phylogenetic classification of the enriched bacteria represented by predominant denaturing gradient gel electrophoresis bands, was apparently similar to culturable Mn(II)-oxidizing bacteria. The experiments were further undertaken to investigate the properties of the Mn oxide aggregates formed by the bacterial isolates with high Mn(II)-oxidizing activity. Results showed that these bacteria were closely encrusted with their Mn oxides and formed regular microspherical aggregates under prolonged Mn(II) and carbon-rich medium enrichment for three weeks. The biotic oxidation of Mn(II) to Mn(III/IV) by these isolates was confirmed by kinetic examinations. X-ray diffraction assays showed the characteristic peaks of several Mn oxides and rhodochrosite from these aggregates. Leucoberbelin blue tests also verified the Mn(II)-oxidizing activity of these aggregates. These results demonstrated that Mn oxides were formed at certain amounts under the enrichment conditions, along with the formation of rhodochrosite in such aggregates. Therefore, this study provides insights into the structure and diversity of soil-borne bacterial communities in Mn(II) oxidizing habitats and supports the contribution of soil-borne Mn(II)-oxidizing bacteria to Mn oxide mineralization in soils. PMID- 24069233 TI - A computational model for histone mark propagation reproduces the distribution of heterochromatin in different human cell types. AB - Chromatin is a highly compact and dynamic nuclear structure that consists of DNA and associated proteins. The main organizational unit is the nucleosome, which consists of a histone octamer with DNA wrapped around it. Histone proteins are implicated in the regulation of eukaryote genes and they carry numerous reversible post-translational modifications that control DNA-protein interactions and the recruitment of chromatin binding proteins. Heterochromatin, the transcriptionally inactive part of the genome, is densely packed and contains histone H3 that is methylated at Lys 9 (H3K9me). The propagation of H3K9me in nucleosomes along the DNA in chromatin is antagonizing by methylation of H3 Lysine 4 (H3K4me) and acetylations of several lysines, which is related to euchromatin and active genes. We show that the related histone modifications form antagonized domains on a coarse scale. These histone marks are assumed to be initiated within distinct nucleation sites in the DNA and to propagate bi directionally. We propose a simple computer model that simulates the distribution of heterochromatin in human chromosomes. The simulations are in agreement with previously reported experimental observations from two different human cell lines. We reproduced different types of barriers between heterochromatin and euchromatin providing a unified model for their function. The effect of changes in the nucleation site distribution and of propagation rates were studied. The former occurs mainly with the aim of (de-)activation of single genes or gene groups and the latter has the power of controlling the transcriptional programs of entire chromosomes. Generally, the regulatory program of gene transcription is controlled by the distribution of nucleation sites along the DNA string. PMID- 24069234 TI - Age-specific average head template for typically developing 6-month-old infants. AB - Due to the rapid anatomical changes that occur within the brain structure in early human development and the significant differences between infant brains and the widely used standard adult templates, it becomes increasingly important to utilize appropriate age- and population-specific average templates when analyzing infant neuroimaging data. In this study we created a new and highly detailed age specific unbiased average head template in a standard MNI152-like infant coordinate system for healthy, typically developing 6-month-old infants by performing linear normalization, diffeomorphic normalization and iterative averaging processing on 60 subjects' structural images. The resulting age specific average templates in a standard MNI152-like infant coordinate system demonstrate sharper anatomical detail and clarity compared to existing infant average templates and successfully retains the average head size of the 6-month old infant. An example usage of the average infant templates transforms magnetoencephalography (MEG) estimated activity locations from MEG's subject specific head coordinate space to the standard MNI152-like infant coordinate space. We also created a new atlas that reflects the true 6-month-old infant brain anatomy. Average templates and atlas are publicly available on our website (http://ilabs.washington.edu/6-m-templates-atlas). PMID- 24069235 TI - Changes in the personal dignity of nursing home residents: a longitudinal qualitative interview study. AB - BACKGROUND: Most nursing home residents spend the remainder of their life, until death, within a nursing home. As preserving dignity is an important aim of the care given here, insight into the way residents experience their dignity throughout their entire admission period is valuable. AIM: To investigate if and how nursing home residents' personal dignity changes over the course of time, and what contributes to this. DESIGN: A longitudinal qualitative study. METHODS: Multiple in-depth interviews, with an interval of six months, were carried out with 22 purposively sampled nursing home residents of the general medical wards of four nursing homes in The Netherlands. Transcripts were analyzed following the principles of thematic analysis. RESULTS: From admission onwards, some residents experienced an improved sense of dignity, while others experienced a downward trend, a fluctuating one or no change at all. Two mechanisms were especially important for a nursing home resident to maintain or regain personal dignity: the feeling that one is in control of his life and the feeling that one is regarded as a worthwhile person. The acquirement of both feelings could be supported by 1) finding a way to cope with one's situation; 2) getting acquainted with the new living structures in the nursing home and therefore feeling more at ease; 3) physical improvement (with or without an electric wheelchair); 4) being socially involved with nursing home staff, other residents and relatives; and 5) being amongst disabled others and therefore less prone to exposures of disrespect from the outer world. CONCLUSION: Although the direction in which a resident's personal dignity develops is also dependent on one's character and coping capacities, nursing home staff can contribute to dignity by creating optimal conditions to help a nursing home resident recover feelings of control and of being regarded as a worthwhile person. PMID- 24069236 TI - Geminin is required for the maintenance of pluripotency. AB - Pluripotency requires the expression of the three core transcriptions factors Oct4, Sox2 and Nanog, as well as further, complementary proteins. The geminin protein is part of this network, and was shown to play a role in the regulation of DNA replication, the control of the cell cycle, and the acquisition of neural fate. It is highly expressed in the early embryo, in particular the epiblast and the early neural ectoderm, and also in pluripotent embryonic stem cells. The genetic inactivation of geminin resulted in lethality after the first few cell divisions, and thus prohibited the outgrowth of pluripotent cells. We established embryonic stem cells allowing the deletion of the geminin gene by induction of of Cre-recombinase with tamoxifen. Here, we show that geminin deficiency quickly leads to a loss of pluripotency, and to differentiation into the mesendodermal direction with high Oct4/low Sox2 levels. Simultaneous loss of geminin and induction of the neural lineage resulted in immediate apoptosis. These results suggested that in early development geminin functions via the co-expressed Sox2 gene. We found that the stem cell enhancer SRR2 of Sox2 is occupied by the activating esBAF complex in the presence of geminin, but becomes epigenetically repressed in its absence by the Polycomb repressive complex PRC2. The importance of geminin for Sox2 expression also explains the absolute requirement for geminin during the induction of pluripotency by OSKM viruses. In summary, geminin is required for Sox2 expression, and thus for the maintenance of totipotency, pluripotency and the early neural lineage. PMID- 24069237 TI - Regional HLA differences in Poland and their effect on stem cell donor registry planning. AB - Regional HLA frequency differences are of potential relevance for the optimization of stem cell donor recruitment. We analyzed a very large sample (n = 123,749) of registered Polish stem cell donors. Donor figures by 1-digit postal code regions ranged from n = 5,243 (region 9) to n = 19,661 (region 8). Simulations based on region-specific haplotype frequencies showed that donor recruitment in regions 0, 2, 3 and 4 (mainly located in the south-eastern part of Poland) resulted in an above-average increase of matching probabilities for Polish patients. Regions 1, 7, 8, 9 (mainly located in the northern part of Poland) showed an opposite behavior. However, HLA frequency differences between regions were generally small. A strong indication for regionally focused donor recruitment efforts can, therefore, not be derived from our analyses. Results of haplotype frequency estimations showed sample size effects even for sizes between n~5,000 and n~20,000. This observation deserves further attention as most published haplotype frequency estimations are based on much smaller samples. PMID- 24069239 TI - Who cries wolf, and when? Manipulation of perceived threats to preserve rank in cooperative groups. AB - People perform greater within-group cooperation when their groups face external threats, such as hostile outgroups or natural disasters. Researchers and social commentators suggest that high-ranking group members manipulate this "threat dependent" cooperation by exaggerating threats in order to promote cooperation and suppress competition for their position. However, little systematic research tests this claim or possible situational moderators. In three studies, we use a cooperative group game to show that participants pay to increase others' perceptions of group threats, and spend more on manipulation when holding privileged positions. This manipulation cost-effectively elicits cooperation and sustains privilege, and is fostered by competition over position, not only position per se. Less cooperative people do more manipulation than more cooperative people do. Furthermore, these effects generalize to broader definitions of privilege. Conceptually, these results offer new insights into an understudied dimension of group behavior. Methodologically, the research extends cooperative group games to allow for analyzing more complex group dynamics. PMID- 24069238 TI - NudC deacetylation regulates mitotic progression. AB - Mitosis is largely driven by posttranslational modifications of proteins. Recent studies suggest that protein acetylation is prevalent in mitosis, but how protein acetylation/deacetylation regulates mitotic progression remains unclear. Nuclear distribution protein C (NudC), a conserved protein that regulates cell division, was previously shown to be acetylated. We found that NudC acetylation was decreased during mitosis. Using mass spectrometry analysis, we identified K39 to be an acetylation site on NudC. Reconstitution of NudC-deficient cells with wild type or K39R acetylation-defective NudC rescued mitotic phenotypes, including chromosome misalignment, chromosome missegregation, and reduced spindle width, observed after NudC protein knockdown. In contrast, the K39Q acetylation-mimetic NudC was unable to rescue these mitotic phenotypes, suggesting that NudC deacetylation is important for mitotic progression. To examine proteins that may play a role in NudC deacetylation during mitosis, we found that NudC co-localizes on the mitotic spindle with the histone deacetylase HDAC3, an HDAC shown to regulate mitotic spindle stability. Further, NudC co-immunoprecipitates with HDAC3 and loss of function of HDAC3 either by protein knockdown or inhibition with a small molecule inhibitor increased NudC acetylation. These observations suggest that HDAC3 may be involved in NudC deacetylation during mitosis. Cells with NudC or HDAC3 knockdown exhibited overlapping mitotic abnormalities, including chromosomes arranged in a "dome-like" configuration surrounding a collapsed mitotic spindle. Our studies suggest that NudC acetylation/deacetylation regulates mitotic progression and NudC deacetylation, likely through HDAC3, is critical for spindle function and chromosome congression. PMID- 24069240 TI - The cooperative roles of two kinetoplastid-specific kinesins in cytokinesis and in maintaining cell morphology in bloodstream trypanosomes. AB - The cytoskeleton of Trypanosoma brucei, a unicellular eukaryote and a parasitic protozoan, is defined by the subpellicular microtubule corset that is arranged underneath the plasma membrane. We recently identified two orphan kinesins, TbKIN C and TbKIN-D, that cooperate to regulate the organization of the subpellicular microtubule corset and thereby maintain cell morphology in the procyclic form of T. brucei. In this report, we characterize the function of TbKIN-C and TbKIN-D in the bloodstream form of T. brucei and investigate their functional cooperation in both the bloodstream and procyclic forms. TbKIN-C and TbKIN-D form a tight complex in vivo in the bloodstream form. TbKIN-C is strongly enriched at the posterior tip of the cell, whereas TbKIN-D is distributed throughout the cell body at all cell cycle stages. RNAi of TbKIN-C or TbKIN-D in the bloodstream form inhibits cell proliferation and leads to cell death, due to cytokinesis defects. RNAi of TbKIN-C and TbKIN-D also results in defects in basal body segregation, but does not affect the synthesis and segregation of the flagellum and the flagellum attachment zone (FAZ) filament. Knockdown of TbKIN-C and TbKIN-D does not disrupt the organization of the subpellicular microtubule corset, but produces multinucleated cells with an enlarged flagellar pocket and misplaced flagella. Interestingly, depletion of TbKIN-C results in rapid degradation of TbKIN-D and, similarly, knockdown of TbKIN-C destabilizes TbKIN-D, suggesting that formation of TbKIN-C/TbKIN-D complex stabilizes both kinesins and is required for the two kinesins to execute their essential cellular functions. Altogether, our results demonstrate the essential role of the two kinesins in cell morphogenesis and cytokinesis in the bloodstream form and the requirement of heteromeric complex formation for maintaining the stability of the two kinesins. PMID- 24069241 TI - Cancer stemness in Apc- vs. Apc/KRAS-driven intestinal tumorigenesis. AB - Constitutive activation of the Wnt pathway leads to adenoma formation, an obligatory step towards intestinal cancer. In view of the established role of Wnt in regulating stemness, we attempted the isolation of cancer stem cells (CSCs) from Apc- and Apc/KRAS-mutant intestinal tumours. Whereas CSCs are present in Apc/KRAS tumours, they appear to be very rare (<10(-6)) in the Apc-mutant adenomas. In contrast, the Lin(-)CD24(hi)CD29(+) subpopulation of adenocarcinoma cells appear to be enriched in CSCs with increased levels of active beta-catenin. Expression profiling analysis of the CSC-enriched subpopulation confirmed their enhanced Wnt activity and revealed additional differential expression of other signalling pathways, growth factor binding proteins, and extracellular matrix components. As expected, genes characteristic of the Paneth cell lineage (e.g. defensins) are co-expressed together with stem cell genes (e.g. Lgr5) within the CSC-enriched subpopulation. This is of interest as it may indicate a cancer stem cell niche role for tumor-derived Paneth-like cells, similar to their role in supporting Lgr5(+) stem cells in the normal intestinal crypt. Overall, our results indicate that oncogenic KRAS activation in Apc-driven tumours results in the expansion of the CSCs compartment by increasing (r)-catenin intracellular stabilization. PMID- 24069242 TI - The combined effect of individual and neighborhood socioeconomic status on nasopharyngeal cancer survival. AB - BACKGROUND: The relationship between individual and neighborhood socioeconomic status (SES) and mortality rates in patients with nasopharyngeal carcinoma (NPC) is unknown. This population-based study aimed to examine the association between SES and survival of patients with NPC in Taiwan. MATERIALS AND METHODS: A population-based follow-up study was conducted of 4691 patients diagnosed with NPC between 2002 and 2006. Each patient was traced to death or for 5 years. Individual SES was defined by enrollee job category. Neighborhood SES was based on household income dichotomized into advantaged and disadvantaged areas. Cox proportional hazards model was used to compare the death-free survival rates between the different SES groups after adjusting for possible confounding factors and risk factors. RESULTS: In NPC patients below the age of 65 years, 5-year overall survival rates were worst for those with low individual SES living in disadvantaged neighborhoods. After adjusting for patient characteristics (age, gender, Charlson Comorbidity Index Score), NPC patients with low individual SES residing in disadvantaged neighborhoods were found to have a 2-fold higher risk of mortality than patients with high individual SES residing in advantaged neighborhoods. We found no significant difference in mortality rates between different SES groups in NPC patients aged 65 and above. CONCLUSIONS: Our findings indicate that NPC patients with low individual SES who live in disadvantaged neighborhoods have the higher risk of mortality than their more privileged counterparts. Public health strategies and welfare policies would be well advised to try to offset the inequalities in health care and pay more attention to addressing the needs of this vulnerable group. PMID- 24069243 TI - Facile synthesis of phosphatidyl saccharides for preparation of anionic nanoliposomes with enhanced stability. AB - Physical stability during storage and against processing such as dehyration/rehydration are the cornerstone in designing delivery vehicles. In this work, mono-, di- and tri-saccharides were enzymatically conjugated to phosphatidyl group through a facile approach namely phospholipase D (PLD) mediated transphosphatidylation in a biphasic reaction system. The purified products were structurally identified and the connectivities of carbohydrate to phosphatidyl moiety precisely mapped by (1)H, (31)P, (13)C NMR pulse sequences and LC-ESI-FTMS. The synthetic phosphatidyl saccharides were employed as the sole biomimetic component for preparation of nanoliposomes. It was found that the critical micelle concentration (CMC) of phosphatidyl saccharides increases as more bulky sugar moiety (mono- to tri-) is introduced. Phosphatidyl di-saccharide had the largest membrane curvature. In comparison to the zwitterionic phosphatidylcholine liposome, all phosphatidyl saccharides liposomes are anionic and demonstrated significantly enhanced stability during storage. According to the confocal laser scan microscopy (CLSM) and atom force microscopy (AFM) analyses, the nanoliposomes formed by the synthetic phosphatidyl saccharides also show excellent stability against dehydration/rehydration process in which most of the liposomal structures remained intact. The abundance hydroxyl groups in the saccharide moieties might provide sufficient H-bondings for stabilization. This work demonstrated the synthesized phosphatidyl saccharides are capable of functioning as enzymatically liable materials which can form stable nanoliposomes without addition of stabilizing excipients. PMID- 24069244 TI - Comparison of properties of medial entorhinal cortex layer II neurons in two anatomical dimensions with and without cholinergic activation. AB - Mechanisms underlying grid cell firing in the medial entorhinal cortex (MEC) still remain unknown. Computational modeling studies have suggested that cellular properties such as spike frequency adaptation and persistent firing might underlie the grid cell firing. Recent in vivo studies also suggest that cholinergic activation influences grid cell firing. Here we investigated the anatomical distribution of firing frequency adaptation, the medium spike after hyperpolarization potential (mAHP), subthreshold membrane potential oscillations, sag potential, input resistance and persistent firing, in MEC layer II principal cells using in vitro whole-cell patch clamp recordings in rats. Anatomical distributions of these properties were compared along both the dorso-ventral and medio-lateral axes, both with and without the cholinergic receptor agonist carbachol. We found that spike frequency adaptation is significantly stronger in ventral than in dorsal neurons both with and without carbachol. Spike frequency adaptation was significantly correlated with the duration of the mAHP, which also showed a gradient along the dorso-ventral axis. In carbachol, we found that about 50% of MEC layer II neurons show persistent firing which lasted more than 30 seconds. Persistent firing of MEC layer II neurons might contribute to grid cell firing by providing the excitatory drive. Dorso-ventral differences in spike frequency adaptation we report here are opposite from previous predictions by a computational model. We discuss an alternative mechanism as to how dorso-ventral differences in spike frequency adaptation could contribute to different scales of grid spacing. PMID- 24069245 TI - In-depth glycoproteomic characterization of gamma-conglutin by high-resolution accurate mass spectrometry. AB - The molecular characterization of bioactive food components is necessary for understanding the mechanisms of their beneficial or detrimental effects on human health. This study focused on gamma-conglutin, a well-known lupin seed N glycoprotein with health-promoting properties and controversial allergenic potential. Given the importance of N-glycosylation for the functional and structural characteristics of proteins, we studied the purified protein by a mass spectrometry-based glycoproteomic approach able to identify the structure, micro heterogeneity and attachment site of the bound N-glycan(s), and to provide extensive coverage of the protein sequence. The peptide/N-glycopeptide mixtures generated by enzymatic digestion (with or without N-deglycosylation) were analyzed by high-resolution accurate mass liquid chromatography-multi-stage mass spectrometry. The four main micro-heterogeneous variants of the single N-glycan bound to gamma-conglutin were identified as Man2(Xyl) (Fuc) GlcNAc2, Man3(Xyl) (Fuc) GlcNAc2, GlcNAcMan3(Xyl) (Fuc) GlcNAc2 and GlcNAc 2Man3(Xyl) (Fuc) GlcNAc2. These carry both core beta1,2-xylose and core alpha1-3-fucose (well known Cross Reactive Carbohydrate Determinants), but corresponding fucose-free variants were also identified as minor components. The N-glycan was proven to reside on Asn131, one of the two potential N-glycosylation sites. The extensive coverage of the gamma-conglutin amino acid sequence suggested three alternative N-termini of the small subunit, that were later confirmed by direct-infusion Orbitrap mass spectrometry analysis of the intact subunit. PMID- 24069246 TI - Pathological role of interleukin-17 in poly I:C-induced hepatitis. AB - Immune-mediated responses were the main causes of liver damage during viral hepatitis, and recently viral RNA mimetic Poly I:C was used to induce a NK cell dominated acute hepatitis. Interleukin-17A (IL-17A), the cytokine tightly associated with various autoimmune diseases, was known to play protective or pathological roles in LPS and ConA-induced hepatitis. However, its role in NK cell-mediated acute hepatitis remains unknown. Here we demonstrated that Poly I:C treatment triggered IL-17A production from hepatic gammadeltaT cells. Neutralizing IL-17A by monoclonal antibodies reduced Poly I:C-induced intrahepatic inflammatory responses and the liver injury through decreased accumulation, activation and cytolytic activity of NK cells in the liver. Furthermore, Poly I:C didn't trigger IL-17A secretion from gammadeltaT cells directly, and Kuppfer cells were demonstrated to be the accessory cell that can secrete IL-23. Finally, our findings demonstrated a pathological role of IL-17A and gammadeltaT cells in Poly I:C-induced acute hepatitis, which provides novel insights into viral infection-induced hepatitis and may serve as potential target in clinic immunotherapy against these disease. PMID- 24069247 TI - The ferredoxin ThnA3 negatively regulates tetralin biodegradation gene expression via ThnY, a ferredoxin reductase that functions as a regulator of the catabolic pathway. AB - The genes for tetralin (thn) utilization in Sphingomonasmacrogolitabida strain TFA are regulated at the transcriptional level by ThnR, ThnY and ThnA3. ThnR, a LysR-type transcriptional activator activates transcription specifically in response to tetralin, and ThnY is an iron-sulfur flavoprotein that may activate ThnR by protein-protein interaction. ThnA3, a Rieske-type ferredoxin that transfers electrons to the tetralin dioxygenase, prevents transcription of thn genes when the inducer molecule of the pathway is a poor substrate for the dioxygenase. The mechanism by which ThnA3 transduces this signal to the regulatory system is a major question concerning thn gene regulation. Here, we have confirmed the discriminatory function of ThnA3 and the negative role of its reduced form. We have generated ThnY variants with amino acid exchanges in the [2Fe-2S], FAD and NAD(P) H binding domains and their regulatory properties have been analyzed. Two variants, ThnY-C40S and ThnY-N201G,S206P have completely lost the discriminatory function of the regulatory system because they induced thn gene expression with different molecules such us cis-decalin, cyclohexane, trans decalin, or benzene, which are not real inducers of the pathway. These results support a model in which ThnA3 exerts its negative modulation via the regulator ThnY. PMID- 24069248 TI - Enhancement of osteogenic differentiation and proliferation in human mesenchymal stem cells by a modified low intensity ultrasound stimulation under simulated microgravity. AB - Adult stem cells can differentiate into multiple lineages depending on their exposure to differing biochemical and biomechanical inductive factors. Lack of mechanical signals due to disuse can inhibit osteogenesis and induce adipogenesis of mesenchymal stem cells (MSCs). Long-term bed rest due to both brain/spinal cord injury and space travel can lead to disuse osteoporosis that is in part caused by a reduced number of osteoblasts. Thus, it is essential to provide proper mechanical stimulation for cellular viability and osteogenesis, particularly under disuse conditions. The objective of this study was to examine the effects of low intensity pulsed ultrasound (LIPUS) on the osteogenic differentiation of adipose-derived human stem cells (Ad-hMSC) in simulated microgravity conditions. Cells were cultured in a 1D clinostat to simulate microgravity (SMG) and treated with LIPUS at 30mW/cm(2) for 20 min/day. It was hypothesized that the application of LIPUS to SMG cultures would restore osteogenesis in Ad-hMSCs. The results showed significant increases in ALP, OSX, RANKL, RUNX2, and decreases in OPG in LIPUS treated SMG cultures of Ad-MSC compared to non-treated cultures. LIPUS also restored OSX, RUNX2 and RANKL expression in osteoblast cells. SMG significantly reduced ALP positive cells by 70% (p<0.01) and ALP activity by 22% (p<0.01), while LIPUS treatment restored ALP positive cell number and activity to equivalence with normal gravity controls. Extracellular matrix collagen and mineralization was assessed by Sirius red and Alizarin red staining, respectively. SMG cultures showed little or no collagen or mineralization, but LIPUS treatment restored collagen content to 50% (p<0.001) and mineralization by 45% (p<0.001) in LIPUS treated-SMG cultures relative to SMG only cultures. The data suggest that LIPUS treatment can restore normal osteogenic differentiation of MSCs from disuse by daily short duration stimulation. PMID- 24069249 TI - Health-related quality of life and sense of coherence among the unemployed with autotelic, average, and non-autotelic personalities: a cross-sectional survey in Hiroshima, Japan. AB - BACKGROUND: Unemployment is known to have a negative effect on the quality of life (QOL) of individuals. However, the influence of an autotelic personality on QOL and SOC of unemployed individuals remains unclear. Our study compared health related quality of life (HRQOL) and sense of coherence (SOC) among 3 groups: (i) an autotelic personality group (AP), which tends to "go with the flow," (ii) an average group (AV), and (iii) a non-autotelic personality group (NAP). METHODS: In October 2010, we conducted a cross-sectional survey among 140 job trainees not receiving unemployment benefits in Hiroshima, Japan. We collected 134 completed questionnaires. Autotelic personality was investigated using the Flow Experience Checklist, health-related quality of life was assessed using the Short Form (SF 8) Health Survey, and SOC was measured using the University of Tokyo Health Sociology version of the SOC3 scale (SOC3-UTHS). RESULTS: The average age of participants was 36.14+/-11.54 year. Participants were classified into 3 groups based on daily activity values: 4+ for AP (n = 22), 1-3 for AV (n = 82), and 0 for NAP (n = 30). Significant differences were observed in mental component summary (MCS) score and SOC3-UTHS total scores in the ranking order of AP (highest), AV, and NAP. CONCLUSION: Our findings indicate a need to develop programs for facilitating AP among unemployed people to enhance mental QOL and SOC. PMID- 24069250 TI - Ets-2 regulates cell apoptosis via the Akt pathway, through the regulation of urothelial cancer associated 1, a long non-coding RNA, in bladder cancer cells. AB - The majority of the human genome is transcribed and generates non-coding RNAs (ncRNAs) that fail to encode protein information. Long non-coding RNAs (lncRNAs) are emerging as a novel class of ncRNAs, but our knowledge about these ncRNAs is limited. Previously, our laboratory has identified that a lncRNA, Urothelial cancer associated 1 (UCA1), played an important role in bladder cancer. Despite the recent interest in UCA1 as a diagnostic marker for bladder cancer, little is known about its transcriptional regulation. To elucidate the regulation of UCA1 gene expression, we have characterized the human UCA1 gene promoter. A 2.0-kb fragment of its 5' flanking region was cloned into a luciferase reporter vector. Deletion and mutation analysis suggested that an Ets-2 binding site was critical for UCA1 gene promoter activity. Further analysis of this site by gel shifting, chromatin immune precipitation (ChIP), and co-transfection experiments showed that transcription factor Ets-2 directly bound to the UCA1 promoter region and stimulated UCA1 promoter activity in bladder cancer cells. Taking into account the anti-apoptosis function of Ets-2, our data suggested that Ets-2 regulates apoptosis process by regulating the expression of UCA1, moreover UCA1 may be involved in the activation of Akt signaling pathway by Ets-2 in bladder cancer cells. PMID- 24069251 TI - Long-term recovery patterns and limited spillover of large predatory fish in a Mediterranean MPA. AB - Based on 19 y of visual census data from the Medes Islands MPA (NW Mediterranean), this study analyzes the carrying capacity (K) and population recovery time of six species of fish strongly affected by harvesting pressure along the Mediterranean coast. Three of these species (Epinephelus marginatus, Diplodus cervinus and Dicentrachus labrax) have practically reached carrying capacity in the Medes Islands MPA, while others are still approaching population stabilization (Sciaena umbra) or are still increasing in biomass (Dentex dentex). The one exception to these trends is S. aurata, which tended to decrease inside the MPA, probably due to fishing just outside its borders. These results confirm that fish populations may require decadal time scales to recover from exploitation, both in terms of total abundance (21 to 29 y to exceed 95% K) as well as total biomass (25 to 35 y), and that rates of recovery differ between species (13 to 31 y). The recovery and saturation observed within the no-take zone contrasts with results obtained in the partially protected buffer area and the peripheral area open for fishing, which show much lower biomass values. In general, the spillover from the MPA is very moderate, and its effects extend only to the partially protected area. PMID- 24069252 TI - Caspases and p38 MAPK regulate endothelial cell adhesiveness for mesenchymal stem cells. AB - Mesenchymal stem cells natively circulating or delivered into the blood stream home to sites of injury. The mechanism of mesenchymal stem cell homing to sites of injury is poorly understood. We have shown that the development of apoptosis in endothelial cells stimulates endothelial cell adhesiveness for mesenchymal stem cells. Adhesion of mesenchymal stem cells to apoptotic endothelial cells depends on the activation of endothelial caspases and p38 MAPK. Activation of p38 MAPK in endothelial cells has a primary effect while the activation of caspases potentiates the mesenchymal stem cell adhesion. Overall, our study of the mesenchymal stem cell interaction with endothelial cells indicates that mesenchymal stem cells recognize and specifically adhere to distressed/apoptotic endothelial cells. PMID- 24069253 TI - Flexible composition: MEG evidence for the deployment of basic combinatorial linguistic mechanisms in response to task demands. AB - The present study investigates whether a minimal manipulation in task demands can induce core linguistic combinatorial mechanisms to extend beyond the bounds of normal grammatical phrases. Using magnetoencephalography, we measured neural activity evoked by the processing of adjective-noun phrases in canonical (red cup) and reversed order (cup red). During a task not requiring composition (verification against a color blob and shape outline), we observed significant combinatorial activity during canonical phrases only - as indexed by minimum norm source activity localized to the left anterior temporal lobe at 200-250 ms(cf. [1], [2]). When combinatorial task demands were introduced (by simply combining the blob and outline into a single colored shape) we observed significant combinatorial activity during reversed sequences as well. These results demonstrate the first direct evidence that basic linguistic combinatorial mechanisms can be deployed outside of normal grammatical expressions in response to task demands, independent of changes in lexical or attentional factors. PMID- 24069254 TI - Mutations in GTP binding protein Obg of Mycoplasma synoviae vaccine strain MS-H: implications in temperature-sensitivity phenotype. AB - Mycoplasma synoviae strain MS-H, developed by chemical mutagenesis of the Australian field strain 86079/7NS, is a live temperature-sensitive (ts (+)) vaccine used for control of M. synoviae infection in poultry worldwide. Genetic basis of temperature sensitivity and attenuation of MS-H has not been revealed thus far. Comparison of the complete genome sequence of MS-H, its parent strain 86079/7NS and two non-temperature sensitive (ts (-)) reisolates of MS-H revealed a mutation in a highly conserved domain of GTP binding protein Obg of MS-H, with reversion in ts (-) MS-H reisolates. Nucleotide change from G to A at position 369 of the obg gene resulted in an alteration of glycine to arginine at position 123 in Obg fold. Further analysis of the complete obg gene sequence in several MS H reisolates revealed that a Gly123Arg substitution was associated with alteration in temperature sensitivity phenotype of MS-H. A second mutation, C to T at position 629, in obg gene was found in some of the MS-H reisolates and appeared to suppress the effects of the Gly123Arg substitution. In silico analysis of point mutations revealed that Gly123Arg has highly destabilizing effect on the MS-H Obg structure that can potentially abolish its biological functions in vivo especially at non-permissive temperature. Findings of this study implicate Obg alteration (Gly123Arg) as one of the possible causes of MS-H attenuation/temperature sensitivity and warrant further investigations into exploring the role of Obg-like proteins, an evolutionarily conserved protein from human to bacteria, in the biology of mycoplasmas. PMID- 24069255 TI - Migration of T cells on surfaces containing complex nanotopography. AB - T cells navigate complex microenvironments to initiate and modulate antigen specific immune responses. While recent intravital microscopy study revealed that migration of T cells were guided by various tissue microstructures containing unique nanoscale topographical structures, the effects of complex nanotopographical structures on the migration of T cells have not been systematically studied. In this study, we fabricated surfaces containing nanoscale zigzag structures with various side lengths and turning angles using UV assisted capillary force lithography and motility of T cells on zigzag patterned surfaces was studied. Motility of T cells was mostly affected by the turning angle, not by the side length, of the zigzag structures. In particular, motility behaviors of T cells near interfaces formed by turning points of zigzag patterns were significantly affected by turning angles. For obtuse turning angles, most of the T cells smoothly crossed the interfaces, but as the turning angle decreased, a substantial fraction of the T cells migrated along the interfaces. When the formation of lamellipodia, thin sheet-like structures typically generated at the leading edges of migrating cells by actin polymerization-driven membrane protrusion, was inhibited by an Arp2/3 inhibitor CK-636, a substantial fraction of T cells on those surfaces containing zigzag patterns with an acute turning angle were trapped at the interfaces formed by the turning points of the zigzag patterns. This result suggests that thin, wide lamellipodia at the leading edges of T cells play critical roles in motility of T cells in complex topographical microenvironments. PMID- 24069256 TI - Anti-tumor activity of a miR-199-dependent oncolytic adenovirus. AB - The down-regulation of miR-199 occurs in nearly all primary hepatocellular carcinomas (HCCs) and HCC cell lines in comparison with normal liver. We exploited this miR-199 differential expression to develop a conditionally replication-competent oncolytic adenovirus, Ad-199T, and achieve tumor-specific viral expression and replication. To this aim, we introduced four copies of miR 199 target sites within the 3' UTR of E1A gene, essential for viral replication. As consequence, E1A expression from Ad-199T virus was tightly regulated both at RNA and protein levels in HCC derived cell lines, and replication controlled by the level of miR-199 expression. Various approaches were used to asses in vivo properties of Ad-199T. Ad-199T replication was inhibited in normal, miR-199 positive, liver parenchyma, thus resulting in reduced hepatotoxicity. Conversely, the intrahepatic delivery of Ad-199T in newborn mice led to virus replication and fast removal of implanted HepG2 liver cancer cells. The ability of Ad-199T to control tumor growth was also shown in a subcutaneous xenograft model in nude mice and in HCCs arising in immune-competent mice. In summary, we developed a novel oncolytic adenovirus, Ad-199T, which could demonstrate a therapeutic potential against liver cancer without causing significant hepatotoxicity. PMID- 24069257 TI - Does cardiorespiratory fitness modify the association between birth weight and insulin resistance in adult life? AB - OBJECTIVE: Lower birth weight is associated with higher insulin resistance in later life. The aim of this study was to determine whether cardiorespiratory fitness modifies the association of birth weight with insulin resistance in adults. METHODS: The subjects were 379 Japanese individuals (137 males, 242 females) aged 20-64 years born after 1943. Insulin resistance was assessed using a homeostasis model assessment of insulin resistance (HOMA-IR), which is calculated from fasting blood glucose and insulin levels. Cardiorespiratory fitness (maximal oxygen uptake, VO2max) was assessed by a maximal graded exercise test on a cycle ergometer. Birth weight was reported according to the Maternal and Child Health Handbook records or the subject's or his/her mother's memory. RESULTS: The multiple linear regression analysis revealed that birth weight was inversely associated with HOMA-IR (beta = -0.141, p = 0.003), even after adjustment for gender, age, current body mass index, mean blood pressure, triglycerides, HDL cholesterol, and smoking status. Further adjustments for VO2max made little difference in the relationship between birth weight and HOMA IR (beta = -0.148, p = 0.001), although VO2max (beta = -0.376, p<0.001) was a stronger predictor of HOMA-IR than birth weight. CONCLUSIONS: The results showed that the association of lower birth weight with higher insulin resistance was little modified by cardiorespiratory fitness in adult life. However, cardiorespiratory fitness was found to be a stronger predictor of insulin resistance than was birth weight, suggesting that increasing cardiorespiratory fitness may have a much more important role in preventing insulin resistance than an individual's low birth weight. PMID- 24069258 TI - Human pancreatic cancer contains a side population expressing cancer stem cell associated and prognostic genes. AB - In many types of cancers, a side population (SP) has been identified based on high efflux capacity, thereby enriching for chemoresistant cells as well as for candidate cancer stem cells (CSC). Here, we explored whether human pancreatic ductal adenocarcinoma (PDAC) contains a SP, and whether its gene expression profile is associated with chemoresistance, CSC and prognosis. After dispersion into single cells and incubation with Hoechst dye, we analyzed human PDAC resections specimens using flow cytometry (FACS). We identified a SP and main population (MP) in all human PDAC resection specimens (n = 52) analyzed, but detected immune (CD45(+)) and endothelial (CD31(+)) cells in this fraction together with tumor cells. The SP and MP cells, or more purified fractions depleted from CD31(+)/CD45(+) cells (pSP and pMP), were sorted by FACS and subjected to whole-genome expression analysis. This revealed upregulation of genes associated with therapy resistance and of markers identified before in putative pancreatic CSC. pSP gene signatures of 32 or 10 up- or downregulated genes were developed and tested for discriminatory competence between pSP and pMP in different sets of PDAC samples. The prognostic value of the pSP genes was validated in a large independent series of PDAC patients (n = 78) using nCounter analysis of expression (in tumor versus surrounding pancreatic tissue) and Cox regression for disease-free and overall survival. Of these genes, expression levels of ABCB1 and CXCR4 were correlated with worse patient survival. Thus, our study for the first time demonstrates that human PDAC contains a SP. This tumor subpopulation may represent a valuable therapeutic target given its chemoresistance- and CSC-associated gene expression characteristics with potential prognostic value. PMID- 24069259 TI - Methanogenic pathway and fraction of CH(4) oxidized in paddy fields: seasonal variation and effect of water management in winter fallow season. AB - A 2-year field and incubation experiment was conducted to investigate delta(13)C during the processes of CH4 emission from the fields subjected to two water managements (flooding and drainage) in the winter fallow season, and further to estimate relative contribution of acetate to total methanogenesis (Fac ) and fraction of CH4 oxidized (Fox ) based on the isotopic data. Compared with flooding, drainage generally caused CH4, either anaerobically or aerobically produced, depleted in (13)C. There was no obvious difference between the two in transport fractionation factor (epsilontransport ) and delta(13)C-value of emitted CH4. CH4 emission was negatively related to its delta(13)C-value in seasonal variation (P<0.01). Acetate-dependent methanogenesis in soil was dominant (60-70%) in the late season, while drainage decreased Fac -value by 5 10%. On roots however, CH4 was mostly produced through H2/CO2 reduction (60-100%) over the season. CH4 oxidation mainly occurred in the first half of the season and roughly 10-90% of the CH4 was oxidized in the rhizosphere. Drainage increased Fox -value by 5-15%, which is possibly attributed to a significant decrease in production while no simultaneous decrease in oxidation. Around 30-70% of the CH4 was oxidized at the soil-water interface when CH4 in pore water was released into floodwater, although the amount of CH4 oxidized therein might be negligible relative to that in the rhizosphere. CH4 oxidation was also more important in the first half of the season in lab conditions and about 5-50% of the CH4 was oxidized in soil while almost 100% on roots. Drainage decreased Fox -value on roots by 15% as their CH4 oxidation potential was highly reduced. The findings suggest that water management in the winter fallow season substantially affects Fac in the soil and Fox in the rhizosphere and roots rather than Fac on roots and Fox at the soil-water interface. PMID- 24069260 TI - Downregulation of GAS5 promotes bladder cancer cell proliferation, partly by regulating CDK6. AB - Long non-coding RNAs (lncRNAs) play important roles in diverse biological processes, such as transcriptional regulation, cell growth and tumorigenesis. However, little is known about whether lncRNA-GAS5 (growth arrest-specific 5) regulates bladder cancer progression. In the present study, we found that the GAS5 expression is commonly downregulated in bladder cancer cell lines and human specimens. Knockdown of GAS5 promotes bladder cancer cell proliferation, whereas forced expression of GAS5 suppresses cell proliferation. We further demonstrated that knockdown of GAS5 increases CDK6 mRNA and protein levels in bladder cancer cells. Expectedly, GAS5 inhibition induces a significant decrease in G0/G1 phase and an obvious increase in S phase. Gain-of-function and loss-of-function studies showed that GAS5 inhibits bladder cancer cell proliferation, at least in part, by regulating CDK6 expression. CONCLUSIONS: Downregulated GAS5 promotes bladder cancer cell proliferation, partly by regulating CDK6, and thus may be helpful in the development of effective treatment strategies against bladder cancer. PMID- 24069261 TI - BMP7 expression correlates with secondary drug resistance in mantle cell lymphoma. AB - PURPOSE: We designed a gene profiling experiment to identify genes involved in secondary drug resistance in mantle cell lymphomas (MCL). EXPERIMENTAL DESIGN: We obtained paired tissue samples collected from the same patients before treatment and after relapse or progression. Variations in gene expression between the 2 samples were estimated for 5 patients. For each gene, the mean variation was estimated for patients with a refractory primary tumor and for responders who developed secondary drug resistance. Nine genes of interest were selected on the basis of the magnitude and statistical significance of the variation of expression in responders and non-responders. RESULTS: BMP7 was the only one with significantly increased expression at relapse in patients who developed secondary resistance. Validation of BMP7 as a key gene involved in secondary resistance was performed using cultures of cell line. Incubation of BMP7 with MCL cell lines increased their resistance to bortezomib and cytarabine, while inhibition of BMP7 expression by siRNA correlated with increased cell death linked to drug application. CONCLUSION: Variations in gene expression after treatment point out BMP7 as a key gene involved in secondary resistance in mantle cell lymphoma. PMID- 24069262 TI - Quantitative evaluation of the mitochondrial proteomes of Drosophila melanogaster adapted to extreme oxygen conditions. AB - Mitochondria are the primary organelles that consume oxygen and provide energy for cellular activities. To investigate the mitochondrial mechanisms underlying adaptation to extreme oxygen conditions, we generated Drosophila strains that could survive in low- or high-oxygen environments (LOF or HOF, respectively), examined their mitochondria at the ultrastructural level via transmission electron microscopy, studied the activity of their respiratory chain complexes, and quantitatively analyzed the protein abundance responses of the mitochondrial proteomes using Isobaric tag for relative and absolute quantitation (iTRAQ). A total of 718 proteins were identified with high confidence, and 55 and 75 mitochondrial proteins displayed significant differences in abundance in LOF and HOF, respectively, compared with the control flies. Importantly, these differentially expressed mitochondrial proteins are primarily involved in respiration, calcium regulation, the oxidative response, and mitochondrial protein translation. A correlation analysis of the changes in the levels of the mRNAs corresponding to differentially regulated mitochondrial proteins revealed two sets of proteins with different modes of regulation (transcriptional vs. post transcriptional) in both LOF and HOF. We believe that these findings will not only enhance our understanding of the mechanisms underlying adaptation to extreme oxygen conditions in Drosophila but also provide a clue in studying human disease induced by altered oxygen tension in tissues and cells. PMID- 24069264 TI - Factors determining nestedness in complex networks. AB - Understanding the causes and effects of network structural features is a key task in deciphering complex systems. In this context, the property of network nestedness has aroused a fair amount of interest as regards ecological networks. Indeed, Bastolla et al. introduced a simple measure of network nestedness which opened the door to analytical understanding, allowing them to conclude that biodiversity is strongly enhanced in highly nested mutualistic networks. Here, we suggest a slightly refined version of such a measure of nestedness and study how it is influenced by the most basic structural properties of networks, such as degree distribution and degree-degree correlations (i.e. assortativity). We find that most of the empirically found nestedness stems from heterogeneity in the degree distribution. Once such an influence has been discounted - as a second factor - we find that nestedness is strongly correlated with disassortativity and hence - as random networks have been recently found to be naturally disassortative - they also tend to be naturally nested just as the result of chance. PMID- 24069263 TI - Differential requirement for CCR4 in the maintenance but not establishment of the invariant Vgamma5(+) dendritic epidermal T-cell pool. AB - Thymocytes expressing the invariant Vgamma5 gammadeltaT-cell receptor represent progenitors of dendritic epidermal T-cells (DETC) that play an important immune surveillance role in the skin. In contrast to the bulk of alphabetaT-cell development, Vgamma5(+) DETC progenitor development occurs exclusively in fetal thymus. Whilst alphabetaT-cell development is known to require chemokine receptor mediated migration through distinct thymus regions, culminating in medullary entry and thymic egress, the importance and control of intrathymic migration for DETC progenitors is unclear. We recently revealed a link between Vgamma5(+) DETC progenitor development and medullary thymic epithelial cells expressing Aire, a known regulator of thymic chemokine expression, demonstrating that normal Vgamma5(+) DETC progenitor development requires regulated intramedullary positioning. Here we investigate the role of chemokines and their receptors during intrathymic Vgamma5(+) DETC progenitor development and establishment of the DETC pool in the skin. We report that thymic medullary accumulation of Vgamma5(+) DETC progenitors is a G-protein coupled receptor dependent process. However, this process occurs independently of Aire's influences on intrathymic chemokines, and in the absence of CCR4 and CCR7 expression by DETC progenitors. In contrast, analysis of epidermal gammadeltaT-cells at neonatal and adult stages in CCR4(-/-) mice reveals that reduced numbers of DETC in adult epidermis are not a consequence of diminished intrathymic embryonic development, nor deficiencies in initial epidermal seeding in the neonate. Collectively, our data reveal differences in the chemokine receptor requirements for intrathymic migration of alphabeta and invariant gammadeltaT-cells, and highlight a differential role for CCR4 in the maintenance, but not initial seeding, of DETC in the epidermis. PMID- 24069266 TI - The effect of font size on reading comprehension on second and fifth grade children: bigger is not always better. AB - Research on reading development has focused on the linguistic, cognitive, and recently, metacognitive skills children must master in order to learn to read. Less focus has been devoted to how the text itself, namely the perceptual features of the words, affects children's learning and comprehension. In this study, we manipulated perceptual properties of text by presenting reading passages in different font sizes, line lengths, and line spacing to 100 children in the second and fifth grades. For second graders (Experiment 1), decreasing font size, as well as increasing line length, yielded significantly lower comprehension scores. Line spacing had no effect on performance. For fifth graders (Experiment 2), decreasing font size yielded higher comprehension scores, yet there were no effects for line length and line spacing. Results are discussed within a "desirable difficulty" approach to reading development. PMID- 24069265 TI - Morphological features of the porcine lacrimal gland and its compatibility for human lacrimal gland xenografting. AB - In this study, we present first data concerning the anatomical structure, blood supply and location of the lacrimal gland of the pig. Our data indicate that the porcine lacrimal gland may serve as a potential xenograft candidate in humans or as an animal model for engineering of a bioartificial lacrimal gland tissue construct for clinical application. For this purpose, we used different macroscopic preparation techniques and digital reconstruction of the histological gland morphology to gain new insights and important information concerning the feasibility of a lacrimal gland transplantation from pig to humans in general. Our results show that the lacrimal gland of the pig reveals a lot of morphological similarities to the analogous human lacrimal gland and thus might be regarded as a xenograft in the future. This is true for a similar anatomical location within the orbit as well as for the feeding artery supply to the organ. Functional differences concerning the composition of the tear fluid, due to a different secretory unit distribution within the gland tissue will, however, be a challenge in future investigations. PMID- 24069267 TI - Virological Surveillance of Influenza Viruses during the 2008-09, 2009-10 and 2010-11 Seasons in Tunisia. AB - BACKGROUND: The data contribute to a better understanding of the circulation of influenza viruses especially in North-Africa. OBJECTIVE: The objective of this surveillance was to detect severe influenza cases, identify their epidemiological and virological characteristics and assess their impact on the healthcare system. METHOD: We describe in this report the findings of laboratory-based surveillance of human cases of influenza virus and other respiratory viruses' infection during three seasons in Tunisia. RESULTS: The 2008-09 winter influenza season is underway in Tunisia, with co-circulation of influenza A/H3N2 (56.25%), influenza A(H1N1) (32.5%), and a few sporadic influenza B viruses (11.25%). In 2010-11 season the circulating strains are predominantly the 2009 pandemic influenza A(H1N1)pdm09 (70%) and influenza B viruses (22%). And sporadic viruses were sub typed as A/H3N2 and unsubtyped influenza A, 5% and 3%, respectively. Unlike other countries, highest prevalence of influenza B virus Yamagata-like lineage has been reported in Tunisia (76%) localised into the clade B/Bangladesh/3333/2007. In the pandemic year, influenza A(H1N1)pdm09 predominated over other influenza viruses (95%). Amino acid changes D222G and D222E were detected in the HA gene of A(H1N1)pdm09 virus in two severe cases, one fatal case and one mild case out of 50 influenza A(H1N1)pdm09 viruses studied. The most frequently reported respiratory virus other than influenza in three seasons was RSV (45.29%). CONCLUSION: This article summarises the surveillance and epidemiology of influenza viruses and other respiratory viruses, showing how rapid improvements in influenza surveillance were feasible by connecting the existing structure in the health care system for patient records to electronic surveillance system for reporting ILI cases. PMID- 24069268 TI - Anogenital distance and condition as predictors of litter sex ratio in two mouse species: a study of the house mouse (Mus musculus) and mound-building mouse (Mus spicilegus). AB - The Trivers - Willard hypothesis (1973) suggests that the maternal condition may affect the female's litter size and sex ratio. Since then other factors had been found. Previous findings revealed in the case of some mammalian species, that females with larger anogenital distance have smaller litters, while the sex ratio is male-biased. That has only been demonstrated in laboratory animals, while the genetic diversity of a wild population could mask the phenomenon seen in laboratory colonies. We examined the connection between morphological traits (weight and anogenital distance) and the reproductive capacity of two wild mice species, the house mouse and the mound-building mice. We showed in both species that anogenital distance and body weight correlated positively in pre-pubertal females, but not in adults. Neither the house mouse nor the mound-building mouse mothers' weight had effect on their litter's size and sex ratio. Otherwise connection was found between the mothers' anogenital distance and their litters' sex ratio in both species. The results revealed that females with larger anogenital distance delivered male biased litter in both species. The bias occurred as while the number of female pups remained the same; mothers with large anogenital distance delivered more male pups compared to the mothers with small anogenital distance. We concluded that a female's prenatal life affects her reproductive success more than previously anticipated. PMID- 24069269 TI - Tracing the origin and northward dissemination dynamics of HIV-1 subtype C in Brazil. AB - Previous studies indicate that the HIV-1 subtype C epidemic in southern Brazil was initiated by the introduction of a single founder strain probably originating from east Africa. However, the exact country of origin of such a founder strain as well as the origin of the subtype C viruses detected outside the Brazilian southern region remains unknown. HIV-1 subtype C pol sequences isolated in the southern, southeastern and central-western Brazilian regions (n = 209) were compared with a large number (n ~ 2,000) of subtype C pol sequences of African origin. Maximum-likelihood analyses revealed that most HIV-1 subtype C Brazilian sequences branched in a single monophyletic clade (CBR-I), nested within a larger monophyletic lineage characteristic of east Africa. Bayesian analyses indicate that the CBR-I clade most probably originated in Burundi and was introduced into the Parana state (southern region) around the middle 1970s, after which it rapidly disseminated to neighboring regions. The states of Parana and Santa Catarina have been the most important hubs of subtype C dissemination, and routine travel and spatial accessibility seems to have been the major driving forces of this process. Five additional introductions of HIV-1 subtype C strains probably originated in eastern (n = 2), southern (n = 2) and central (n = 1) African countries were detected in the Rio de Janeiro state (southeastern region). These results indicate a continuous influx of HIV-1 subtype C strains of African origin into Brazil and also unveil the existence of unrecognized transmission networks linking this country to east Africa. PMID- 24069270 TI - PNPLA3 GG genotype and carotid atherosclerosis in patients with non-alcoholic fatty liver disease. AB - BACKGROUND AND AIM: To evaluate if the presence of carotid atherosclerosis in patients with NAFLD, could be related to gene variants influencing hepatic fat accumulation and the severity of liver damage. METHODS: We recorded anthropometric, metabolic and histological data(Kleiner score) of 162 consecutive, biopsy-proven Sicilian NAFLD patients. Intima-media thickness(IMT), IMT thickening(IMT>=1 mm) and carotid plaques(focal thickening of >1.3 mm at the level of common carotid artery) were evaluated using ultrasonography. IL28B rs12979860 C>T, PNPLA3 rs738409 C>G, GCKR rs780094 C>T, LYPLAL1 rs12137855 C>T, and NCAN rs2228603 C>T single nucleotide polymorphisms were also assessed. The results were validated in a cohort of 267 subjects with clinical or histological diagnosis of NAFLD from Northern Italy, 63 of whom had follow-up examinations. RESULTS: Carotid plaques, IMT thickening and mean maximum IMT were similar in the two cohorts, whereas the prevalence of diabetes, obesity, NASH, and PNPLA3 GG polymorphism(21%vs.13%, p = 0.02) were significantly higher in the Sicilian cohort. In this cohort, the prevalence of carotid plaques and IMT thickening was higher in PNPLA3 GG compared to CC/CG genotype(53%vs.32%, p = 0.02; 62%vs.28%, p<0.001, respectively). These associations were confirmed at multivariate analyses (OR2.94;95%C.I. 1.12-7.71, p = 0.02, and OR4.11;95%C.I. 1.69-9.96, p = 0.002, respectively), although have been observed only in patients <50years. Also in the validation cohort, PNPLA3 GG genotype was independently associated with IMT thickening in younger patients only (OR: 6.00,95%C.I. 1.36-29, p = 0.01), and to IMT progression (p = 0.05) in patients with follow-up examinations. CONCLUSION: PNPLA3 GG genotype is associated with higher severity of carotid atherosclerosis in younger patients with NAFLD. Mechanisms underlying this association, and its clinical relevance need further investigations. PMID- 24069271 TI - Time course analysis reveals gene-specific transcript and protein kinetics of adaptation to short-term aerobic exercise training in human skeletal muscle. AB - Repeated bouts of episodic myofibrillar contraction associated with exercise training are potent stimuli for physiological adaptation. However, the time course of adaptation and the continuity between alterations in mRNA expression and protein content are not well described in human skeletal muscle. Eight healthy, sedentary males cycled for 60 min at 80% of peak oxygen consumption (VO2peak) each day for fourteen consecutive days, resulting in an increase in VO2peak of 17.5+/-3.8%. Skeletal muscle biopsies were taken at baseline, and on the morning following (+16 h after exercise) the first, third, seventh, tenth and fourteenth training sessions. Markers of mitochondrial adaptation (Cyt c and COXIV expression, and citrate synthase activity) were increased within the first week of training, but the mtDNA/nDNA ratio was unchanged by two weeks of training. Accumulation of PGC-1alpha and ERRalpha protein during training suggests a regulatory role for these factors in adaptations of mitochondrial and metabolic gene expression. A subset of genes were transiently increased after one training session, but returned to baseline levels thereafter, which is supportive of the concept of transcriptional capacity being particularly sensitive to the onset of a new level of contractile activity. Thus, gene-specific temporal patterns of induction of mRNA expression and protein content are described. Our results illustrate the phenomenology of skeletal muscle plasticity and support the notion that transcript level adjustments, coupled to accumulation of encoded protein, underlie the modulation of skeletal muscle metabolism and phenotype by regular exercise. PMID- 24069272 TI - TOX3 mutations in breast cancer. AB - TOX3 maps to 16q12, a region commonly lost in breast cancers and recently implicated in the risk of developing breast cancer. However, not much is known of the role of TOX3 itself in breast cancer biology. This is the first study to determine the importance of TOX3 mutations in breast cancers. We screened TOX3 for mutations in 133 breast tumours and identified four mutations (three missense, one in-frame deletion of 30 base pairs) in six primary tumours, corresponding to an overall mutation frequency of 4.5%. One potentially deleterious missense mutation in exon 3 (Leu129Phe) was identified in one tumour (genomic DNA and cDNA). Whilst copy number changes of 16q12 are common in breast cancer, our data show that mutations of TOX3 are present at low frequency in tumours. Our results support that TOX3 should be further investigated to elucidate its role in breast cancer biology. PMID- 24069273 TI - Doppler echocardiography imaging in detecting multi-valvular lesions: a clinical evaluation in children with acute rheumatic fever. AB - RATIONALE: Doppler echocardiography has been demonstrated to be accurate in diagnosing valvular lesions in rheumatic heart disease (RHD) when compared to clinical evaluation alone. OBJECTIVE: To perform Doppler echocardiography in children clinically diagnosed by the Jones criteria to have acute rheumatic fever (ARF), and to then compare the effectiveness of echo in detecting single/multi valvular lesions with that of the initial clinical evaluation. METHODS AND RESULTS: We enrolled 93 children who were previously diagnosed with ARF by clinical examination. Presence of valvular lesions were enlisted, first by clinical auscultation, and then by performing Doppler echocardiography. We found that Doppler echocardiography was a sensitive technique, capable of detecting valvular lesions that were missed by clinical auscultation alone. Echocardiography of patients with carditis revealed mitral regurgitation to be the most common lesion present (53 patients, 56.98%), followed by aortic regurgitation in 21 patients (22.6%). The difference between clinical and echocardiographic diagnosis in ARF children with carditis was statistically significant for mitral regurgitation, aortic regurgitation and tricuspid regurgitation. Clinical auscultation alone revealed 4 cases of mitral stenosis, 39 mitral regurgitation, 14 aortic regurgitation, 9 tricuspid regurgitation; in contrast, echo revealed 5 cases of mitral stenosis, 53 mitral regurgitation, 21 aortic regurgitation, 18 tricuspid regurgitation. CONCLUSION: Doppler echocardiography is a more sensitive technique for detecting valvular lesions. In the setting of ARF, echo enables a 46.9% higher detection level of carditis, as compared to the clinical examination alone. Echo was very significant in detecting regurgitation lesions, especially for cases of tricuspid regurgitation in the setting of multivalvular involvement. The results of our study are in accordance with previous clinical studies, all of which clearly demonstrate the advantages of Doppler echocardiography, paving the way for its probable inclusion as one of the Jones major criteria for diagnosing ARF. PMID- 24069275 TI - Are inventory based and remotely sensed above-ground biomass estimates consistent? AB - Carbon emissions resulting from deforestation and forest degradation are poorly known at local, national and global scales. In part, this lack of knowledge results from uncertain above-ground biomass estimates. It is generally assumed that using more sophisticated methods of estimating above-ground biomass, which make use of remote sensing, will improve accuracy. We examine this assumption by calculating, and then comparing, above-ground biomass area density (AGBD) estimates from studies with differing levels of methodological sophistication. We consider estimates based on information from nine different studies at the scale of Africa, Mozambique and a 1160 km(2) study area within Mozambique. The true AGBD is not known for these scales and so accuracy cannot be determined. Instead we consider the overall precision of estimates by grouping different studies. Since an the accuracy of an estimate cannot exceed its precision, this approach provides an upper limit on the overall accuracy of the group. This reveals poor precision at all scales, even between studies that are based on conceptually similar approaches. Mean AGBD estimates for Africa vary from 19.9 to 44.3 Mg ha( 1), for Mozambique from 12.7 to 68.3 Mg ha(-1), and for the 1160 km(2) study area estimates range from 35.6 to 102.4 Mg ha(-1). The original uncertainty estimates for each study, when available, are generally small in comparison with the differences between mean biomass estimates of different studies. We find that increasing methodological sophistication does not appear to result in improved precision of AGBD estimates, and moreover, inadequate estimates of uncertainty obscure any improvements in accuracy. Therefore, despite the clear advantages of remote sensing, there is a need to improve remotely sensed AGBD estimates if they are to provide accurate information on above-ground biomass. In particular, more robust and comprehensive uncertainty estimates are needed. PMID- 24069274 TI - Genetic characterization of atypical Citrobacter freundii. AB - The ability of a bacterial population to survive in different niches, as well as in stressful and rapidly changing environmental conditions, depends greatly on its genetic content. To survive such fluctuating conditions, bacteria have evolved different mechanisms to modulate phenotypic variations and related strategies to produce high levels of genetic diversity. Laboratories working in microbiological diagnosis have shown that Citrobacter freundii is very versatile in its colony morphology, as well as in its biochemical, antigenic and pathogenic behaviours. This phenotypic versatility has made C. freundii difficult to identify and it is frequently confused with both Salmonella enterica and Escherichia coli. In order to determine the genomic events and to explain the mechanisms involved in this plasticity, six C. freundii isolates were selected from a phenotypic variation study. An I-CeuI genomic cleavage map was created and eight housekeeping genes, including 16S rRNA, were sequenced. In general, the results showed a range of both phenotypes and genotypes among the isolates with some revealing a greater similarity to C. freundii and some to S. enterica, while others were identified as phenotypic and genotypic intermediary states between the two species. The occurrence of these events in natural populations may have important implications for genomic diversification in bacterial evolution, especially when considering bacterial species boundaries. In addition, such events may have a profound impact on medical science in terms of treatment, course and outcomes of infectious diseases, evading the immune response, and understanding host-pathogen interactions. PMID- 24069276 TI - Conscious wireless electroretinogram and visual evoked potentials in rats. AB - The electroretinogram (ERG, retina) and visual evoked potential (VEP, brain) are widely used in vivo tools assaying the integrity of the visual pathway. Current recordings in preclinical models are conducted under anesthesia, which alters neural physiology and contaminates responses. We describe a conscious wireless ERG and VEP recording platform in rats. Using a novel surgical technique to chronically implant electrodes subconjunctivally on the eye and epidurally over the visual cortex, we are able to record stable and repeatable conscious ERG and VEP signals over at least 1 month. We show that the use of anaesthetics, necessary for conventional ERG and VEP measurements, alters electrophysiology recordings. Conscious visual electrophysiology improves the viability of longitudinal studies by eliminating complications associated with repeated anaesthesia. It will also enable uncontaminated assessment of drug effects, allowing the eye to be used as an effective biomarker of the central nervous system. PMID- 24069277 TI - Prediabetes is associated with an increased risk of testosterone deficiency, independent of obesity and metabolic syndrome. AB - OBJECTIVE: The association between type 2 diabetes and low testosterone has been well recognized. However, testosterone levels in men with prediabetes have been rarely reported. We aimed to investigate whether prediabetes was associated with an increased risk of testosterone deficiency. METHODS: This study included 1,306 men whose sex hormones was measured during a medical examination. Serum total testosterone and sex hormone-binding globulin were measured; free and bioavailable testosterone concentrations were calculated by Vermeulen's formula. Prediabetes was defined by impaired fasting glucose (IFG), impaired postprandial glucose (IPG), or glycated hemoglobin (HbA1c) 5.7%-6.4%. Logistic regression was performed to obtain the odds ratios (OR) for subnormal total testosterone (<300 ng/dL) or free testosterone (<6 ng/dL) in prediabetic and diabetic men compared with normoglycemic individuals, while adjusting for age, BMI, waist circumference, and metabolic syndrome (MetS). RESULTS: Normoglycemia, prediabetes, and diabetes were diagnosed in 577 (44.2%), 543 (41.6%), and 186 (14.2%) men, respectively. Prediabetes was associated with an increased risk of subnormal total testosterone compared to normoglycemic individuals (age-adjusted OR=1.87; 95%CI=1.38-2.54). The risk remained significant in all multivariate analyses. After adjusting for MetS, the OR in prediabetic men equals that of diabetic patients (1.49 versus 1.50). IFG, IPG, and HbA1c 5.7%-6.4% were all associated with an increased risk of testosterone deficiency, with different levels of significance in multivariate analyses. However, neither prediabetes nor diabetes was associated with subnormal free testosterone in multivariate analyses. CONCLUSIONS: Prediabetes is associated with an increased risk of testosterone deficiency, independent of obesity and MetS. After adjusting for MetS, the risk equals that of diabetes. Our data suggest that testosterone should be measured routinely in men with prediabetes. PMID- 24069278 TI - Prevalence of major chronic conditions among older Chinese adults: the Study on Global AGEing and adult health (SAGE) wave 1. AB - BACKGROUND: The likely corresponding increase in prevalence of chronic disease will be a major challenge for the health care system. Few nationwide epidemiological studies include a large enough sample of older adults to provide estimates of chronic conditions in the older adult population. This study aimed to estimate the prevalence of eight common chronic health conditions and examine socioeconomic inequalities in the diseases among older adults in China. METHOD: Data are from SAGE-China Wave 1, including 13,157 people aged 50-plus years. Respondents were asked if they had been diagnosed with any of the following chronic medical conditions: angina, arthritis, asthma, stroke, diabetes, depression, chronic lung disease and hypertension. A set of validated symptom based questions and related diagnostic algorithms were also used to estimate disease prevalence for angina, arthritis, asthma and depression. Multivariate logistic regression was performed to examine the probability of developing chronic conditions in relation to sociodemographic variables such as gender, age, urban/rural setting and household wealth level. RESULTS: Fifty percent of respondents reported having one of the selected chronic conditions, 18.9% two conditions, 5.8% three conditions, and 1.4% reported having four or more chronic conditions. Self-reported prevalence was generated for angina (8%), arthritis (22%), asthma (2%), stroke (3%), diabetes (7%), depression (0.3%), chronic lung disease (8%) and hypertension (27%). The symptom-based prevalence of angina, arthritis, asthma and depression was 10%, 20%, 4% and 2%, respectively. CONCLUSION: This study provides the best available prevalence estimates for major chronic health conditions among older Chinese adults. Findings from this study indicated that major chronic conditions were common, so prevention and early intervention targeting adults aged 50 years and older should be prioritized. PMID- 24069279 TI - Development of genomic resources for a thraustochytrid pathogen and investigation of temperature influences on gene expression. AB - Understanding how environmental changes influence the pathogenicity and virulence of infectious agents is critical for predicting epidemiological patterns of disease. Thraustochytrids, part of the larger taxonomic class Labyrinthulomycetes, contain several highly pathogenic species, including the hard clam pathogen quahog parasite unknown (QPX). QPX has been associated with large-scale mortality events along the northeastern coast of North America. Growth and physiology of QPX is temperature-dependent, and changes in local temperature profiles influence pathogenicity. In this study we characterize the partial genome of QPX and examine the influence of temperature on gene expression. Genes involved in several biological processes are differentially expressed upon temperature change, including those associated with altered growth and metabolism and virulence. The genomic and transcriptomic resources developed in this study provide a foundation for better understanding virulence, pathogenicity and life history of thraustochytrid pathogens. PMID- 24069281 TI - Adverse events related to emergency department care: a systematic review. AB - OBJECTIVE: To systematically review the literature regarding the prevalence, preventability, severity and types of adverse events (AE) in the Emergency Department (ED). METHODS: We systematically searched major bibliographic databases, relevant journals and conference proceedings, and completed reference reviews of primary articles. Observational studies (cohort and case-control), quasi-experimental (e.g. before/after) studies and randomized controlled trials, were considered for inclusion if they examined a broad demographic group reflecting a significant proportion of ED patients and described the proportion of AE. Studies conducted outside of the ED setting, those examining only a subpopulation of patients (e.g. a specific entrance complaint or receiving a specific intervention), or examining only adverse drug events, were excluded. Two independent reviewers assessed study eligibility, completed data extraction, and assessed study quality with the Newcastle Ottawa Scale. RESULTS: Our search identified 11,624 citations. Ten articles, representing eight observational studies, were included. Methodological quality was low to moderate with weaknesses in study group comparability, follow-up, and outcome ascertainment and reporting. There was substantial variation in the proportion of patients with AE related to ED care, ranging from 0.16% (n = 9308) to 6.0% (n = 399). Similarly, the reported preventability of AE ranged from 36% (n = 250) to 71% (n = 24). The most common types of events were related to management (3 studies), diagnosis (2 studies) and medication (2 studies). CONCLUSIONS: The variability in findings and lack of high quality studies on AE in the high risk ED setting highlights the need for research in this area. Further studies with rigorous, standardized outcome assessment and reporting are required. PMID- 24069280 TI - Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset Alzheimer's disease patients alter calcium homeostasis. AB - Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer's disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non selective Ca(2+)-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca(2+) permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca(2+) influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca(2+) influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid beta-peptide (Abeta) production or Abeta-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca(2+) dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Abeta cascade. PMID- 24069282 TI - The national one week prevalence audit of universal meticillin-resistant Staphylococcus aureus (MRSA) admission screening 2012. AB - INTRODUCTION: The English Department of Health introduced universal MRSA screening of admissions to English hospitals in 2010. It commissioned a national audit to review implementation, impact on patient management, admission prevalence and extra yield of MRSA identified compared to "high-risk" specialty or "checklist-activated" screening (CLAS) of patients with MRSA risk factors. METHODS: National audit May 2011. Questionnaires to infection control teams in all English NHS acute trusts, requesting number patients admitted and screened, new or previously known MRSA; MRSA point prevalence; screening and isolation policies; individual risk factors and patient management for all new MRSA patients and random sample of negatives. RESULTS: 144/167 (86.2%) trusts responded. Individual patient data for 760 new MRSA patients and 951 negatives. 61% of emergency admissions (median 67.3%), 81% (median 59.4%) electives and 47% (median 41.4%) day-cases were screened. MRSA admission prevalence: 1% (median 0.9%) emergencies, 0.6% (median 0.4%) electives, 0.4% (median 0%) day-cases. Approximately 50% all MRSA identified was new. Inpatient MRSA point prevalence: 3.3% (median 2.9%). 104 (77%) trusts pre-emptively isolated patients with previous MRSA, 63 (35%) pre-emptively isolated admissions to "high-risk" specialties; 7 (5%) used PCR routinely. Mean time to MRSA positive result: 2.87 days (+/-1.33); 37% (219/596) newly identified MRSA patients discharged before result available; 55% remainder (205/376) isolated post-result. In an average trust, CLAS would reduce screening by 50%, identifying 81% of all MRSA. "High risk" specialty screening would reduce screening by 89%, identifying 9% of MRSA. CONCLUSIONS: Implementation of universal screening was poor. Admission prevalence (new cases) was low. CLAS reduced screening effort for minor decreases in identification, but implementation may prove difficult. Cost effectiveness of this and other policies, awaits evaluation by transmission dynamic economic modelling, using data from this audit. Until then trusts should seek to improve implementation of current policy and use of isolation facilities. PMID- 24069283 TI - Altered antioxidant-oxidant status in the aqueous humor and peripheral blood of patients with retinitis pigmentosa. AB - Retinitis Pigmentosa is a common form of hereditary retinal degeneration constituting the largest Mendelian genetic cause of blindness in the developed world. It has been widely suggested that oxidative stress possibly contributes to its pathogenesis. We measured the levels of total antioxidant capacity, free nitrotyrosine, thiobarbituric acid reactive substances (TBARS) formation, extracellular superoxide dismutase (SOD3) activity, protein, metabolites of the nitric oxide/cyclic GMP pathway, heme oxygenase-I and inducible nitric oxide synthase expression in aqueous humor or/and peripheral blood from fifty-six patients with retinitis pigmentosa and sixty subjects without systemic or ocular oxidative stress-related disease. Multivariate analysis of covariance revealed that retinitis pigmentosa alters ocular antioxidant defence machinery and the redox status in blood. Patients with retinitis pigmentosa present low total antioxidant capacity including reduced SOD3 activity and protein concentration in aqueous humor. Patients also show reduced SOD3 activity, increased TBARS formation and upregulation of the nitric oxide/cyclic GMP pathway in peripheral blood. Together these findings confirmed the hypothesis that patients with retinitis pigmentosa present reduced ocular antioxidant status. Moreover, these patients show changes in some oxidative-nitrosative markers in the peripheral blood. Further studies are needed to clarify the relationship between these peripheral markers and retinitis pigmentosa. PMID- 24069284 TI - Deletion of lipoprotein PG0717 in Porphyromonas gingivalis W83 reduces gingipain activity and alters trafficking in and response by host cells. AB - P. gingivalis (Pg), a causative agent of chronic generalized periodontitis, has been implicated in promoting cardiovascular disease. Expression of lipoprotein gene PG0717 of Pg strain W83 was found to be transiently upregulated during invasion of human coronary artery endothelial cells (HCAEC), suggesting this protein may be involved in virulence. We characterized the virulence phenotype of a PG0717 deletion mutant of pg W83. There were no differences in the ability of W83Delta717 to adhere and invade HCAEC. However, the increased proportion of internalized W83 at 24 hours post-inoculation was not observed with W83?717. Deletion of PG0717 also impaired the ability of W83 to usurp the autophagic pathway in HCAEC and to induce autophagy in Saos-2 sarcoma cells. HCAEC infected with W83Delta717 also secreted significantly greater amounts of MCP-1, IL-8, IL 6, GM-CSF, and soluble ICAM-1, VCAM-1, and E-selectin when compared to W83. Further characterization of W83Delta717 revealed that neither capsule nor lipid A structure was affected by deletion of PG0717. Interestingly, the activity of both arginine (Rgp) and lysine (Kgp) gingipains was reduced in whole-cell extracts and culture supernatant of W83Delta717. RT-PCR revealed a corresponding decrease in transcription of rgpB but not rgpA or kgp. Quantitative proteome studies of the two strains revealed that both RgpA and RgpB, along with putative virulence factors peptidylarginine deiminase and Clp protease were significantly decreased in the W83Delta717. Our results suggest that PG0717 has pleiotropic effects on W83 that affect microbial induced manipulation of host responses important for microbial clearance and infection control. PMID- 24069285 TI - Combining next-generation sequencing and immune assays: a novel method for identification of antigen-specific T cells. AB - In this study, we combined a novel sequencing method, which can identify individual clonotypes based on their unique T cell receptor (TCR) rearrangement, with existing immune assays to characterize antigen-specific T cell responses. We validated this approach using three types of assays routinely used to measure antigen-specific responses: pentamers which enable identification of T cells bearing specific TCRs, activation marker expression following antigen stimulation and antigen-induced proliferation to identify cytomegalovirus (CMV) specific clonotypes. In one individual, 8 clonotypes were identified using a pentamer reagent derived from the CMV pp65 protein. The same 8 clonotypes were also identified following sequencing of cells that upregulated an activation marker following incubation with an identical peptide derived from pp65. These 8 and an additional 8 clonotypes were identified using a more sensitive CFSE-based proliferation assay. We found clear sequence homology among some of the clonotypes identified, and the CDR3 region in one clonotype was identical to a previously published pp65-specific clonotype sequence. Many of these CMV-specific clonotypes were present at frequencies below 10(-5) which are undetectable using standard flow-cytometric methods. These studies suggest that an immune response is comprised of a diverse set of clones, many of which are present at very low frequencies. Thus, the combination of immune assays and sequencing depicts the richness and diversity of an immune response at a level that is not possible using standard immune assays alone. The methods articulated in this work provide an enhanced understanding of T cell-mediated immune responses at the clonal level. PMID- 24069286 TI - Prediction beyond the borders: ERP indices of boundary extension-related error. AB - Boundary extension (BE) is a rapidly occurring memory error in which participants incorrectly remember having seen beyond the boundaries of a view. However, behavioral data has provided no insight into how quickly after the onset of a test picture the effect is detected. To determine the time course of BE from neural responses we conducted a BE experiment while recording EEG. We exploited a diagnostic response asymmetry to mismatched views (a closer and wider view of the same scene) in which the same pair of views is rated as more similar when the closer item is shown first than vice versa. On each trial, a closer or wider view was presented for 250 ms followed by a 250-ms mask and either the identical view or a mismatched view. Boundary ratings replicated the typical asymmetry. We found a similar asymmetry in ERP responses in the 265-285 ms interval where the second member of the close-then-wide pairs evoked less negative responses at left parieto-temporal sites compared to the wide-then-close condition. We also found diagnostic ERP effects in the 500-560 ms range, where ERPs to wide-then-close pairs were more positive at centro-parietal sites than in the other three conditions, which is thought to be related to participants' confidence in their perceptual decision. The ERP effect in the 265-285 ms range suggests the falsely remembered region beyond the view-boundaries of S1 is rapidly available and impacts assessment of the test picture within the first 265 ms of viewing, suggesting that extrapolated scene structure may be computed rapidly enough to play a role in the integration of successive views during visual scanning. PMID- 24069287 TI - Impact of social franchising on contraceptive use when complemented by vouchers: a quasi-experimental study in rural Pakistan. AB - BACKGROUND: Pakistan has had a low contraceptive prevalence rate for the last two decades; with preference for natural birth spacing methods and condoms. Family planning services offered by the public sector have never fulfilled the demand for contraception, particularly in rural areas. In the private sector, cost is a major constraint. In 2008, Marie Stopes Society - a local NGO started a social franchise programme along with a free voucher scheme to promote uptake of IUCDs amongst the poor. This paper evaluates the effectiveness of this approach, which is designed to increase modern long term contraceptive awareness and use in rural areas of Pakistan. METHODOLOGY: We used a quasi-experimental study design with controls, selecting one intervention district and one control district from the Sindh and Punjab provinces. In each district, we chose a total of four service providers. A baseline survey was carried out among 4,992 married women of reproductive age (MWRA) in February 2009. Eighteen months after the start of intervention, an independent endline survey was conducted among 4,003 women. We used multilevel logistic regression for analysis using Stata 11. RESULTS: Social franchising used alongside free vouchers for long term contraceptive choices significantly increased the awareness of modern contraception. Awareness increased by 5% in the intervention district. Similarly, the ever use of modern contraceptive increased by 28.5%, and the overall contraceptive prevalence rate increased by 19.6%. A significant change (11.1%) was recorded in the uptake of IUCDs, which were being promoted with vouchers. CONCLUSION: Family planning franchise model promotes awareness and uptake of contraceptives. Moreover, supplemented with vouchers, it may enhance the use of IUCDs, which have a significant cost attached. Our research also supports a multi-pronged approach- generating demand through counselling, overcoming financial constraints by offering vouchers, training, accreditation and branding of the service providers, and ensuring uninterrupted contraceptive supplies. PMID- 24069288 TI - Evaluation of smoking status identification using electronic health records and open-text information in a large mental health case register. AB - BACKGROUND: High smoking prevalence is a major public health concern for people with mental disorders. Improved monitoring could be facilitated through electronic health record (EHR) databases. We evaluated whether EHR information held in structured fields might be usefully supplemented by open-text information. The prevalence and correlates of EHR-derived current smoking in people with severe mental illness were also investigated. METHODS: All cases had been referred to a secondary mental health service between 2008-2011 and received a diagnosis of schizophreniform or bipolar disorder. The study focused on those aged over 15 years who had received active care from the mental health service for at least a year (N=1,555). The 'CRIS-IE-Smoking' application used General Architecture for Text Engineering (GATE) natural language processing software to extract smoking status information from open-text fields. A combination of CRIS IE-Smoking with data from structured fields was evaluated for coverage and the prevalence and demographic correlates of current smoking were analysed. RESULTS: Proportions of patients with recorded smoking status increased from 11.6% to 64.0% through supplementing structured fields with CRIS-IE-Smoking data. The prevalence of current smoking was 59.6% in these 995 cases for whom this information was available. After adjustment, younger age (below 65 years), male sex, and non-cohabiting status were associated with current smoking status. CONCLUSIONS: A natural language processing application substantially improved routine EHR data on smoking status above structured fields alone and could thus be helpful in improving monitoring of this lifestyle behaviour. However, limited information on smoking status remained a challenge. PMID- 24069289 TI - The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia. AB - The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2) is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia) and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445) and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445) and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605), in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605) may be involved in the susceptibility to paranoid schizophrenia. PMID- 24069290 TI - Transmembrane and Juxtamembrane Structure of alphaL Integrin in Bicelles. AB - The accepted model for the interaction of alpha and beta integrins in the transmembrane (TM) domain is based on the pair alphaIIbbeta3. This involves the so-called outer and inner membrane association clasps (OMC and IMC, respectively). In the alpha chain, the OMC involves a GxxxG-like motif, whereas in the IMC a conserved juxtamembrane GFFKR motif experiences a backbone reversal that partially fills the void generated by TM separation towards the cytoplasmic half. However, the GFFKR motif of several alpha integrin cytoplasmic tails in non bicelle environments has been shown to adopt an alpha-helical structure that is not membrane-embedded and which was shown to bind a variety of cytoplasmic proteins. Thus it is not known if a membrane-embedded backbone reversal is a conserved structural feature in alpha integrins. We have studied the system alphaLbeta2 because of its importance in leukocytes, where integrin deactivation is particularly important. Herein we show that the backbone reversal feature is not only present in alphaIIb but also in alphaL-TM when reconstituted in bicelles. Additionally, titration with beta2 TM showed eight residues clustering along one side of alphaL-TM, forming a plausible interacting face with beta2. The latter orientation is consistent with a previously predicted reported polar interaction between alphaL Ser-1071 and beta2 Thr-686. PMID- 24069291 TI - Environmental influences on mate preferences as assessed by a scenario manipulation experiment. AB - Many evolutionary psychology studies have addressed the topic of mate preferences, focusing particularly on gender and cultural differences. However, the extent to which situational and environmental variables might affect mate preferences has been comparatively neglected. We tested 288 participants in order to investigate the perceived relative importance of six traits of an ideal partner (wealth, dominance, intelligence, height, kindness, attractiveness) under four different hypothetical scenarios (status quo/nowadays, violence/post nuclear, poverty/resource exhaustion, prosperity/global well-being). An equal number of participants (36 women, 36 men) was allotted to each scenario; each was asked to allocate 120 points across the six traits according to their perceived value. Overall, intelligence was the trait to which participants assigned most importance, followed by kindness and attractiveness, and then by wealth, dominance and height. Men appraised attractiveness as more valuable than women. Scenario strongly influenced the relative importance attributed to traits, the main finding being that wealth and dominance were more valued in the poverty and post-nuclear scenarios, respectively, compared to the other scenarios. Scenario manipulation generally had similar effects in both sexes, but women appeared particularly prone to trade off other traits for dominance in the violence scenario, and men particularly prone to trade off other traits for wealth in the poverty scenario. Our results are in line with other correlational studies of situational variables and mate preferences, and represent strong evidence of a causal relationship of environmental factors on specific mate preferences, corroborating the notion of an evolved plasticity to current ecological conditions. A control experiment seems to suggest that our scenarios can be considered as realistic descriptions of the intended ecological conditions. PMID- 24069292 TI - Desensitization by progressive up-titration prevents first-dose effects on the heart: guinea pig study with ponesimod, a selective S1P1 receptor modulator. AB - Ponesimod, a selective S1P1 receptor modulator, reduces the blood lymphocyte count in all tested species by preventing egress of T and B cells from thymus and peripheral lymphoid organs. In addition, ponesimod transiently affects heart rate and atrioventricular (AV) conduction in humans, effects not observed in mice, rats, and dogs with selective S1P1 receptor modulators, suggesting that the regulation of heart rate and rhythm is species dependent. In the present study, we used conscious guinea pigs implanted with a telemetry device to investigate the effects of single and multiple oral doses of ponesimod on ECG variables, heart rate, and blood pressure. Oral administration of ponesimod did not affect the sinus rate (P rate) but dose-dependently induced AV block type I to III. A single oral dose of 0.1 mg/kg had no effect on ECG variables, while a dose of 3 mg/kg induced AV block type III in all treated guinea pigs. Repeated oral dosing of 1 or 3 mg/kg ponesimod resulted in rapid desensitization, so that the second dose had no or a clearly reduced effect on ECG variables as compared with the first dose. Resensitization of the S1P1 receptor in the heart was concentration dependent. After desensitization had been induced by the first dose of ponesimod, the cardiac system remained desensitized as long as the plasma concentration was >=75 ng/ml. By using a progressive up-titration regimen, the first-dose effect of ponesimod on heart rate and AV conduction was significantly reduced due to desensitization of the S1P1 receptor. In summary, conscious guinea pigs implanted with a telemetry device represent a useful model to study first-dose effects of S1P1 receptor modulators on heart rate and rhythm. This knowledge was translated to a dosing regimen of ponesimod to be tested in humans to avoid or significantly reduce the first-dose effects. PMID- 24069293 TI - Efficient interruption of infection chains by targeted removal of central holdings in an animal trade network. AB - Centrality parameters in animal trade networks typically have right-skewed distributions, implying that these networks are highly resistant against the random removal of holdings, but vulnerable to the targeted removal of the most central holdings. In the present study, we analysed the structural changes of an animal trade network topology based on the targeted removal of holdings using specific centrality parameters in comparison to the random removal of holdings. Three different time periods were analysed: the three-year network, the yearly and the monthly networks. The aim of this study was to identify appropriate measures for the targeted removal, which lead to a rapid fragmentation of the network. Furthermore, the optimal combination of the removal of three holdings regardless of their centrality was identified. The results showed that centrality parameters based on ingoing trade contacts, e.g. in-degree, ingoing infection chain and ingoing closeness, were not suitable for a rapid fragmentation in all three time periods. More efficient was the removal based on parameters considering the outgoing trade contacts. In all networks, a maximum percentage of 7.0% (on average 5.2%) of the holdings had to be removed to reduce the size of the largest component by more than 75%. The smallest difference from the optimal combination for all three time periods was obtained by the removal based on out degree with on average 1.4% removed holdings, followed by outgoing infection chain and outgoing closeness. The targeted removal using the betweenness centrality differed the most from the optimal combination in comparison to the other parameters which consider the outgoing trade contacts. Due to the pyramidal structure and the directed nature of the pork supply chain the most efficient interruption of the infection chain for all three time periods was obtained by using the targeted removal based on out-degree. PMID- 24069294 TI - Macronutrient composition of the diet affects the feeding-mediated down regulation of autophagy in muscle of rainbow trout (O. mykiss). AB - Autophagy functions as an important catabolic mechanism by mediating the turnover of intracellular organelles and protein complexes through a lysosome dependent degradative pathway. Although the induction of autophagy by starvation has been extensively studied, we still know very little about how autophagy is regulated under normal nutritional conditions. The purpose of the present study was to characterize both in vivo and in vitro the response of the autophagy-lysosomal degradative pathway to nutrient (amino acids and carbohydrates) availability in the muscle of the carnivorous rainbow trout. We report that meal feeding is accompanied by a rapid activation of Akt, FoxO1 and the Target of Rapamycin (TOR) signaling pathways and a concomitant decrease of autophagosome formation. We also show that this effect occurs only when the proportion of dietary proteins increases at the expense of carbohydrates. Concurrently, our in vitro study on primary culture of trout muscle cells demonstrates an opposite effect of amino acids and glucose on the regulation of autophagy-lysosomal pathways. More specifically, the addition of amino acids in cell culture medium inhibited the formation of autophagosomes, whereas the addition of glucose had an opposite effect. The effect of amino acids was accompanied by an activation of TOR, considered as an important regulator of autophagosomal formation. However, the mechanisms involved in the effect of glucose were independent of Akt, TOR and AMPK and remain to be determined. Together, these results demonstrated the specific role of macronutrients as well as that of their interactions in the regulation of autophagy and highlight the interest to consider the macronutrient composition of the diets in the control of this degradative pathway. PMID- 24069295 TI - Nanosecond pulsed electric field inhibits cancer growth followed by alteration in expressions of NF-kappaB and Wnt/beta-catenin signaling molecules. AB - Cancer remains a leading cause of death worldwide and total number of cases globally is increasing. Novel treatment strategies are therefore desperately required for radical treatment of cancers and long survival of patients. A new technology using high pulsed electric field has emerged from military application into biology and medicine by applying nsPEF as a means to inhibit cancer. However, molecular mechanisms of nsPEF on tumors or cancers are still unclear. In this paper, we found that nsPEF had extensive biological effects in cancers, and clarified its possible molecular mechanisms in vitro and in vivo. It could not only induce cell apoptosis via dependent-mitochondria intrinsic apoptosis pathway that was triggered by imbalance of anti- or pro-apoptosis Bcl-2 family proteins, but also inhibit cell proliferation through repressing NF-kappaB signaling pathway to reduce expressions of cyclin proteins. Moreover, nsPEF could also inactivate metastasis and invasion in cancer cells by suppressing Wnt/beta Catenin signaling pathway to down-regulating expressions of VEGF and MMPs family proteins. More importantly, nsPEF could function safely and effectively as an anti-cancer therapy through inducing tumor cell apoptosis, destroying tumor microenvironment, and depressing angiogenesis in tumor tissue in vivo. These findings may provide a creative and effective therapeutic strategy for cancers. PMID- 24069296 TI - Prognostic value of CD109+ circulating endothelial cells in recurrent glioblastomas treated with bevacizumab and irinotecan. AB - BACKGROUND: Recent data suggest that circulating endothelial and progenitor cells (CECs and CEPs, respectively) may have predictive potential in cancer patients treated with bevacizumab, the antibody recognizing vascular endothelial growth factor (VEGF). Here we report on CECs and CEPs investigated in 68 patients affected by recurrent glioblastoma (rGBM) treated with bevacizumab and irinotecan and two Independent Datasets of rGBM patients respectively treated with bevacizumab alone (n=32, independent dataset A: IDA) and classical antiblastic chemotherapy (n=14, independent dataset B: IDB). METHODS: rGBM patients with KPS >=50 were treated until progression, as defined by MRI with RANO criteria. CECs expressing CD109, a marker of tumor endothelial cells, as well as other CEC and CEP subtypes, were investigated by six-color flow cytometry. RESULTS: A baseline count of CD109+ CEC higher than 41.1/ml (1(st) quartile) was associated with increased progression free survival (PFS; 20 versus 9 weeks, P=0.008) and overall survival (OS; 32 versus 23 weeks, P=0.03). Longer PFS (25 versus 8 weeks, P=0.02) and OS (27 versus 17 weeks, P=0.03) were also confirmed in IDA with CD109+ CECs higher than 41.1/ml but not in IDB. Patients treated with bevacizumab with or without irinotecan that were free from MRI progression after two months of treatment had significant decrease of CD109+ CECs: median PFS was 19 weeks; median OS 29 weeks. The presence of two non-contiguous lesions (distant disease) at baseline was an independent predictor of shorter PFS and OS (P<0.001). CONCLUSIONS: Data encourage further studies on the predictive potential of CD109+ CECs in GBM patients treated with bevacizumab. PMID- 24069297 TI - Selective pressure along a latitudinal gradient affects subindividual variation in plants. AB - Individual plants produce repeated structures such as leaves, flowers or fruits, which, although belonging to the same genotype, are not phenotypically identical. Such subindividual variation reflects the potential of individual genotypes to vary with micro-environmental conditions. Furthermore, variation in organ traits imposes costs to foraging animals such as time, energy and increased predation risk. Therefore, animals that interact with plants may respond to this variation and affect plant fitness. Thus, phenotypic variation within an individual plant could be, in part, an adaptive trait. Here we investigated this idea and we found that subindividual variation of fruit size of Crataegus monogyna, in different populations throughout the latitudinal gradient in Europe, was explained at some extent by the selective pressures exerted by seed-dispersing birds. These findings support the hypothesis that within-individual variation in plants is an adaptive trait selected by interacting animals which may have important implications for plant evolution. PMID- 24069298 TI - The crystal structure of the orphan nuclear receptor NR2E3/PNR ligand binding domain reveals a dimeric auto-repressed conformation. AB - Photoreceptor-specific nuclear receptor (PNR, NR2E3) is a key transcriptional regulator of human photoreceptor differentiation and maintenance. Mutations in the NR2E3-encoding gene cause various retinal degenerations, including Enhanced S cone syndrome, retinitis pigmentosa, and Goldman-Favre disease. Although physiological ligands have not been identified, it is believed that binding of small molecule agonists, receptor desumoylation, and receptor heterodimerization may switch NR2E3 from a transcriptional repressor to an activator. While these features make NR2E3 a potential therapeutic target for the treatment of retinal diseases, there has been a clear lack of structural information for the receptor. Here, we report the crystal structure of the apo NR2E3 ligand binding domain (LBD) at 2.8 A resolution. Apo NR2E3 functions as transcriptional repressor in cells and the structure of its LBD is in a dimeric auto-repressed conformation. In this conformation, the putative ligand binding pocket is filled with bulky hydrophobic residues and the activation-function-2 (AF2) helix occupies the canonical cofactor binding site. Mutations designed to disrupt either the AF2/cofactor-binding site interface or the dimer interface compromised the transcriptional repressor activity of this receptor. Together, these results reveal several conserved structural features shared by related orphan nuclear receptors, suggest that most disease-causing mutations affect the receptor's structural integrity, and allowed us to model a putative active conformation that can accommodate small ligands in its pocket. PMID- 24069300 TI - Busulfan administration flexibility increases the applicability of scid repopulating cell assay in NSG mouse model. AB - BACKGROUND: Xenotransplantation models allowing the identification and quantification of human Hematopoietic stem cells (HSC) in immunodeficient mice remain the only way to appropriately address human HSC function despite the recent progress in phenotypic characterization. However, these in vivo experiments are technically demanding, time consuming and expensive. Indeed, HSCs engraftment in mouse requires pre-conditioning of animals either by irradiation or cytotoxic drugs to allow homing of injected cells in specific stem cell niches and their subsequent expansion and differentiation in bone marrow. Recently, the development of busulfan pre-conditioning of animals improved the flexibility of experimentation in comparison with irradiation. DESIGN AND METHODS: In order to further facilitate the organization of these complex experiments we investigated the effect of extending the period between mice pre-conditioning and cell injection on the engraftment efficiency. In the meantime, we also explored the role of busulfan doses, mouse gender and intravenous injection route (caudal or retro orbital) on engraftment efficiency. RESULTS AND CONCLUSION: We showed that a period of up to 7 days did not modify engraftment efficiency of human HSCs in NSG model. Moreover, retro orbital cell injection to female mice pre-conditioned with 2x25 mg/kg of busulfan seems to be the best adapted schema to detect the human HSC in xenotransplantation experiments. PMID- 24069299 TI - Polarisation of major histocompatibility complex II host genotype with pathogenesis of European Brown Hare syndrome virus. AB - A study was conducted in order to determine the occurrence of European Brown Hare Syndrome virus (EBHSV) in Denmark and possible relation between disease pathogenesis and Major Histocompatibility Complex (MHC) host genotype. Liver samples were examined from 170 brown hares (hunted, found sick or dead), collected between 2004 and 2009. Macroscopical and histopathological findings consistent with EBHS were detected in 24 (14.1%) hares; 35 (20.6%) had liver lesions not typical of the syndrome, 50 (29.4%) had lesions in other tissues and 61 (35.9%) had no lesions. Sixty five (38.2%) of 170 samples were found to be EBHSV-positive (RT-PCR, VP60 gene). In order to investigate associations between viral pathogenesis and host genotype, variation within the exon 2 DQA gene of MHC was assessed. DQA exon 2 analysis revealed the occurrence of seven different alleles in Denmark. Consistent with other populations examined so far in Europe, observed heterozygosity of DQA (H o = 0.1180) was lower than expected (H e = 0.5835). The overall variation for both nucleotide and amino acid differences (2.9% and 14.9%, respectively) were lower in Denmark than those assessed in other European countries (8.3% and 16.9%, respectively). Within the peptide binding region codons the number of nonsynonymous substitutions (dN) was much higher than synonymous substitutions (dS), which would be expected for MHC alleles under balancing selection. Allele frequencies did not significantly differ between EBHSV-positive and -negative hares. However, allele Leeu-DQA*30 was detected in significantly higher (P = 0.000006) frequency among the positive hares found dead with severe histopathological lesions than among those found sick or apparently healthy. In contrast, the latter group was characterized by a higher frequency of the allele Leeu-DQA*14 as well as the proportion of heterozygous individuals (P = 0.000006 and P = 0.027). These data reveal a polarisation between EBHSV pathogenesis and MHC class II genotype within the European brown hare in Denmark. PMID- 24069301 TI - Hypertonic saline solution drives neutrophil from bystander organ to infectious site in polymicrobial sepsis: a cecal ligation and puncture model. AB - The effects of hypertonic saline solution (HSS) have been shown in several animal models of ischemia and shock. Literature has shown potential benefits of HSS modulating inflammatory response after sepsis in an animal model. We studied the HSS effects in sepsis through cecal ligation and puncture (CLP) in Balb-C mice. Groups studied: 1- CLP without treatment (CLP-C); 2- CLP treated with normal saline solution NaCl 0.9% - 34 ml/Kg (CLP-S); 3- CLP treated with HSS NaCl 7.5% - 4 ml/Kg (CLP-H); and 4- group (Basal) without no CLP or treatment. Volume infusion was always applied 30 min after CLP. Lung and peritoneal lavage were harvested after 6h and 24h of CLP to analyze cytokines amount, oxide nitric, lipid peroxidation and neutrophil infiltration. Neutrophil infiltration, ICAM-1, CXCR-2, and CXCL-1 in lung were reduced by HSS (CLP-H) compared to CLP-C or CLP S. Neutrophil in peritoneal lavage was increased in 24h with HSS (CLP-H) compared to CLP and CLP-S. Peritoneal CXCR-2 was increased in CLP-C and CLP-S but presented a lower increase with HSS (CLP-H) after 6 hours. GRK-2 presented difference among the groups at 24 h, showing a profile similar to neutrophil infiltration. Pro-inflammatory cytokines (TNF-alpha and IL-6) were reduced by HSS treatment; CLP-S increased TNF-alpha. IL-10 was increased in lung tissue by the HSS treatment. The oxidative stress (TBARS and nitric oxide biochemistry markers) was reduced with HSS. Animal survival was 33.3% in CLP-C group, 46.6% in CLP-S group and 60% in the CLP-H group after the sixth day. The HSS protects the animal against sepsis. Our results suggest that the volume replacement modulate pro and anti-inflammatory mediators of an inflammatory response, but HSS presented a more effective and potent effect. PMID- 24069302 TI - A qualitative evaluation of hand drying practices among Kenyans. AB - BACKGROUND: Recommended disease prevention behaviors of hand washing, hygienic hand drying, and covering one's mouth and nose in a hygienic manner when coughing and sneezing appear to be simple behaviors but continue to be a challenge to successfully promote and sustain worldwide. We conducted a qualitative inquiry to better understand current hand drying behaviors associated with activities of daily living, and mouth and nose covering practices, among Kenyans. METHODS AND FINDINGS: We conducted 7 focus group discussions; 30 in-depth interviews; 10 structured household observations; and 75 structured observations in public venues in the urban area of Kisumu; rural communities surrounding Kisumu; and a peri-urban area outside Nairobi, Kenya. Using a grounded theory approach, we transcribed and coded the narrative data followed by thematic analysis of the emergent themes. Hand drying, specifically on a clean towel, was not a common practice among our participants. Most women dried their hands on their waist cloth, called a leso, or their clothes whether they were cooking, eating or cleaning the nose of a young child. If men dried their hands, they used their trousers or a handkerchief. Children rarely dried their hands; they usually just wiped them on their clothes, shook them, or left them wet as they continued with their activities. Many people sneezed into their hands and wiped them on their clothes. Men and women used a handkerchief fairly often when they had a runny nose, cold, or the flu. Most people coughed into the air or their hand. CONCLUSIONS: Drying hands on dirty clothes, rags and lesos can compromise the benefits of handwashing. Coughing and sneezing in to an open hand can contribute to spread of disease as well. Understanding these practices can inform health promotion activities and campaigns for the prevention and control of diarrheal disease and influenza. PMID- 24069303 TI - 454 pyrosequencing to describe microbial eukaryotic community composition, diversity and relative abundance: a test for marine haptophytes. AB - Next generation sequencing of ribosomal DNA is increasingly used to assess the diversity and structure of microbial communities. Here we test the ability of 454 pyrosequencing to detect the number of species present, and assess the relative abundance in terms of cell numbers and biomass of protists in the phylum Haptophyta. We used a mock community consisting of equal number of cells of 11 haptophyte species and compared targeting DNA and RNA/cDNA, and two different V4 SSU rDNA haptophyte-biased primer pairs. Further, we tested four different bioinformatic filtering methods to reduce errors in the resulting sequence dataset. With sequencing depth of 11000-20000 reads and targeting cDNA with Haptophyta specific primers Hap454 we detected all 11 species. A rarefaction analysis of expected number of species recovered as a function of sampling depth suggested that minimum 1400 reads were required here to recover all species in the mock community. Relative read abundance did not correlate to relative cell numbers. Although the species represented with the largest biomass was also proportionally most abundant among the reads, there was generally a weak correlation between proportional read abundance and proportional biomass of the different species, both with DNA and cDNA as template. The 454 sequencing generated considerable spurious diversity, and more with cDNA than DNA as template. With initial filtering based only on match with barcode and primer we observed 100-fold more operational taxonomic units (OTUs) at 99% similarity than the number of species present in the mock community. Filtering based on quality scores, or denoising with PyroNoise resulted in ten times more OTU99% than the number of species. Denoising with AmpliconNoise reduced the number of OTU99% to match the number of species present in the mock community. Based on our analyses, we propose a strategy to more accurately depict haptophyte diversity using 454 pyrosequencing. PMID- 24069304 TI - Riccardin D Exerts Its Antitumor Activity by Inducing DNA Damage in PC-3 Prostate Cancer Cells In Vitro and In Vivo. AB - We recently reported that Riccardin D (RD) was able to induce apoptosis by targeting Topo II. Here, we found that RD induced cell cycle arrest in G2/M phase in PC-3 cells, and caused remarkable DNA damage as evidenced by induction of gammaH2AX foci, micronuclei, and DNA fragmentation in Comet assay. Time kinetic and dose-dependent studies showed that ATM/Chk2 and ATR/Chk1 signaling pathways were sequentially activated in response to RD. Blockage of ATM/ATR signaling led to the attenuation of RD-induced gammaH2AX, and to the partial recovery of cell proliferation. Furthermore, RD exposure resulted in the inactivation of BRCA1, suppression of HR and NHEJ repair activity, and downregulation of the expressions and DNA-end binding activities of Ku70/86. Consistent with the observations, microarray data displayed that RD triggered the changes in genes responsible for cell proliferation, cell cycle, DNA damage and repair, and apoptosis. Administration of RD to xenograft mice reduced tumor growth, and coordinately caused alterations in the expression of genes involved in DNA damage and repair, along with cell apoptosis. Thus, this finding identified a novel mechanism by which RD affects DNA repair and acts as a DNA damage agent in prostate cancer. PMID- 24069305 TI - Modulation of mononuclear phagocyte inflammatory response by liposome encapsulated voltage gated sodium channel inhibitor ameliorates myocardial ischemia/reperfusion injury in rats. AB - BACKGROUND: Emerging evidence shows that anti-inflammatory strategies targeting inflammatory monocyte subset could reduce excessive inflammation and improve cardiovascular outcomes. Functional expression of voltage-gated sodium channels (VGSCs) have been demonstrated in monocytes and macrophages. We hypothesized that mononuclear phagocyte VGSCs are a target for monocyte/macrophage phenotypic switch, and liposome mediated inhibition of mononuclear phagocyte VGSC may attenuate myocardial ischemia/reperfusion (I/R) injury and improve post infarction left ventricular remodeling. METHODOLOGY/PRINCIPAL FINDINGS: Thin film dispersion method was used to prepare phenytoin (PHT, a non-selective VGSC inhibitor) entrapped liposomes. Pharmacokinetic study revealed that the distribution and elimination half-life of PHT entrapped liposomes were shorter than those of free PHT, indicating a rapid uptake by mononuclear phagocytes after intravenous injection. In rat peritoneal macrophages, several VGSC alpha subunits (NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaVX, Scn1b, Scn3b and Scn4b) and beta subunits were expressed at mRNA level, and PHT could suppress lipopolysaccharide induced M1 polarization (decreased TNF-alpha and CCL5 expression) and facilitate interleukin-4 induced M2 polarization (increased Arg1 and TGF-beta1 expression). In vivo study using rat model of myocardial I/R injury, demonstrated that PHT entrapped liposome could partially suppress I/R injury induced CD43+ inflammatory monocyte expansion, along with decreased infarct size and left ventricular fibrosis. Transthoracic echocardiography and invasive hemodynamic analysis revealed that PHT entrapped liposome treatment could attenuate left ventricular structural and functional remodeling, as shown by increased ejection fraction, reduced end-systolic and end-diastolic volume, as well as an amelioration of left ventricular systolic (+dP/dt max) and diastolic ( dP/dt min) functions. CONCLUSIONS/SIGNIFICANCE: Our work for the first time demonstrates the therapeutic potential of VGSC antagonism via liposome mediated monocyte/macrophage targeting in acute phase after myocardial I/R injury. These results suggest that VGSCs in mononuclear phagocyte system might be a novel target for immunomodulation and treatment of myocardial I/R injury. PMID- 24069306 TI - A glycosphingolipid binding domain controls trafficking and activity of the mammalian notch ligand delta-like 1. AB - The activity of Notch ligands is tightly regulated by trafficking events occurring both before and after ligand-receptor interaction. In particular endocytosis and recycling have been shown to be required for full signaling activity of the ligands before they encounter the Notch receptor. However little is known about the precise endocytic processes that contribute to ligand internalization. Here we demonstrate that endocytosis contributes to Dll1 signaling activity by preserving the ligand from shedding and degradation. We further show that the glycosphingolipid-binding motif originally identified in Drosophila Notch ligands is conserved in mammals and is necessary for Dll1 internalization. Mutation of its conserved tryptophan residue results in a Dll1 molecule which is rapidly inactivated by shedding and degradation, does not recycle to the cell surface and does not activate Notch signaling. Finally, silencing in the signal-sending cells of glucosylceramide synthase, the enzyme implicated in the initial phase of glycosphingolipid synthesis, down-regulates Notch activation. Our data indicate that glycosphingolipids, by interacting with Dll1, may act as functional co-factors to promote its biological activity. PMID- 24069307 TI - Transcriptome sequences resolve deep relationships of the grape family. AB - Previous phylogenetic studies of the grape family (Vitaceae) yielded poorly resolved deep relationships, thus impeding our understanding of the evolution of the family. Next-generation sequencing now offers access to protein coding sequences very easily, quickly and cost-effectively. To improve upon earlier work, we extracted 417 orthologous single-copy nuclear genes from the transcriptomes of 15 species of the Vitaceae, covering its phylogenetic diversity. The resulting transcriptome phylogeny provides robust support for the deep relationships, showing the phylogenetic utility of transcriptome data for plants over a time scale at least since the mid-Cretaceous. The pros and cons of transcriptome data for phylogenetic inference in plants are also evaluated. PMID- 24069308 TI - Lock, stock and two different barrels: comparing the genetic composition of morphotypes of the indo-pacific sponge Xestospongia testudinaria. AB - The giant barrel sponge Xestospongiatestudinaria is an ecologically important species that is widely distributed across the Indo-Pacific. Little is known, however, about the precise biogeographic distribution and the amount of morphological and genetic variation in this species. Here we provide the first detailed, fine-scaled (<200 km(2)) study of the morphological and genetic composition of X. testudinaria around Lembeh Island, Indonesia. Two mitochondrial (CO1 and ATP6 genes) and one nuclear (ATP synthase beta intron) DNA markers were used to assess genetic variation. We identified four distinct morphotypes of X. testudinaria around Lembeh Island. These morphotypes were genetically differentiated with both mitochondrial and nuclear markers. Our results indicate that giant barrel sponges around Lembeh Island, which were all morphologically identified as X. testudinaria, consist of at least two different lineages that appear to be reproductively isolated. The first lineage is represented by individuals with a digitate surface area, CO1 haplotype C5, and is most abundant around the harbor area of Bitung city. The second lineage is represented by individuals with a predominantly smooth surface area, CO1 haplotype C1 and can be found all around Lembeh Island, though to a lesser extent around the harbor of Bitung city. Our findings of two additional unique genetic lineages suggests the presence of an even broader species complex possibly containing more than two reproductively isolated species. The existence of X. testudinaria as a species complex is a surprising result given the size, abundance and conspicuousness of the sponge. PMID- 24069309 TI - Prevalence and correlates of alcohol dependence disorder among TB and HIV infected patients in Zambia. AB - OBJECTIVES: To determine the prevalence and correlates of alcohol dependence disorders in persons receiving treatment for HIV and Tuberculosis (TB) at 16 Primary Health Care centres (PHC) across Zambia. METHODS: 649 adult patients receiving treatment for HIV and/or TB at PHCs in Zambia (363 males, 286 females) were recruited between 1st December 2009 and 31st January 2010. Data on socio demographic variables, clinical disease features (TB and HIV), and psychopathological status were collected. The Mini International Neuropsychiatric Interview (MINI) was used to diagnose alcohol dependence disorder. Correlates of alcohol dependence were analyzed for men only, due to low prevalence in women. Univariable and multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI), using general estimating equations to allow for within-PHC clustering. RESULTS: The prevalence of alcohol dependence was 27.2% (95%CI: 17.7-39.5%) for men and 3.9% (95%CI: 1.4-0.1%) for women. Factors associated with alcohol dependence disorder in men included being single, divorced or widowed compared with married (adjusted OR = 1.47, 95%CI: 1.00-2.14) and being unemployed (adjusted OR=1.30, 95%CI: 1.01-1.67). The highest prevalence of alcohol dependence was among HIV-test unknown TB patients (34.7%), and lowest was among HIV positive patients on treatment but without TB (14.1%), although the difference was not statistically significant (p=0.38). CONCLUSIONS: Male TB/HIV patients in this population have high prevalence of alcohol dependence disorder, and prevalence differs by HIV/TB status. Further work is needed to explore interventions to reduce harmful drinking in this population. PMID- 24069310 TI - VEZT, a novel putative tumor suppressor, suppresses the growth and tumorigenicity of gastric cancer. AB - Vezatin (VEZT), an adherens junctions transmembrane protein, was identified as a putative tumor suppressor in our previous study. However, the role of VEZT in tumorigenesis remains elusive. We aimed to clarify its epigenetic regulation and biological functions in gastric cancer. In this study, we show that the expression level of VEZT is involved in lymphatic metastasis, depth of cancer invasion and TNM stage in 104 gastric cancer patients. Bisulfate sequencing polymerase chain reaction (BSP) methods showed that VEZT was hypermethylated in tissues and corresponding blood of gastric cancer patients compared with healthy controls. Helicobacter pylori (H. pylori) infection induces the methylation and silencing of VEZT in GES-1 cells. Restoring VEZT expression in MKN-45 and NCI-N87 gastric cancer cells inhibited growth, invasion and tumorigenesis in vitro and in vivo. Global microarray analysis was applied to analyze the molecular basis of the biological functions of VEZT after VEZT transfection combined with real-time PCR and chromatin immunoprecipitation assay. G protein-coupled receptor 56(GPR56), cell growth, cell division cycle 42(CDC42), migration/invasion and transcription factor 19(TCF19), cell cycle progression, were identified as direct VEZT target genes. TCF19, a novel target of VEZT, was functionally validated. Overexpression of TCF19 in MKN-45 cells increased cell cycle progress and growth ability. This study provides novel insight into the regulation of the VEZT gene, which could represent a potential target for therapeutic anti-cancer strategies. PMID- 24069311 TI - Combined inhibition of p97 and the proteasome causes lethal disruption of the secretory apparatus in multiple myeloma cells. AB - Inhibition of the proteasome is a widely used strategy for treating multiple myeloma that takes advantage of the heavy secretory load that multiple myeloma cells (MMCs) have to deal with. Resistance of MMCs to proteasome inhibition has been linked to incomplete disruption of proteasomal endoplasmic-reticulum (ER) associated degradation (ERAD) and activation of non-proteasomal protein degradation pathways. The ATPase p97 (VCP/Cdc48) has key roles in mediating both ERAD and non-proteasomal protein degradation and can be targeted pharmacologically by small molecule inhibition. In this study, we compared the effects of p97 inhibition with Eeyarestatin 1 and DBeQ on the secretory apparatus of MMCs with the effects induced by the proteasome inhibitor bortezomib, and the effects caused by combined inhibition of p97 and the proteasome. We found that p97 inhibition elicits cellular responses that are different from those induced by proteasome inhibition, and that the responses differ considerably between MMC lines. Moreover, we found that dual inhibition of both p97 and the proteasome terminally disrupts ER configuration and intracellular protein metabolism in MMCs. Dual inhibition of p97 and the proteasome induced high levels of apoptosis in all of the MMC lines that we analysed, including bortezomib-adapted AMO-1 cells, and was also effective in killing primary MMCs. Only minor toxicity was observed in untransformed and non-secretory cells. Our observations highlight non redundant roles of p97 and the proteasome in maintaining secretory homeostasis in MMCs and provide a preclinical conceptual framework for dual targeting of p97 and the proteasome as a potential new therapeutic strategy in multiple myeloma. PMID- 24069312 TI - Transforming growth factor beta signaling upregulates the expression of human GDP fucose transporter by activating transcription factor Sp1. AB - GDP-fucose transporter plays a crucial role in fucosylation of glycoproteins by providing activated fucose donor, GDP-fucose, for fucosyltransferases in the lumen of the Golgi apparatus. Fucose-containing glycans are involved in many biological processes, which are essential for growth and development. Mutations in the GDP-fucose transporter gene cause leukocyte adhesion deficiency syndrome II, a disease characterized by slow growth, mental retardation and immunodeficiency. However, no information is available regarding its transcriptional regulation. Here, by using human cells, we show that TGF-beta1 specifically induces the GDP-fucose transporter expression, but not other transporters tested such as CMP-sialic acid transporter, suggesting a diversity of regulatory pathways for the expression of these transporters. The regulatory elements that are responsive to the TGF-beta1 stimulation are present in the region between bp -330 and -268 in the GDP-fucose transporter promoter. We found that this region contains two identical octamer GC-rich motifs (GGGGCGTG) that were demonstrated to be essential for the transporter expression. We also show that the transcription factor Sp1 specifically binds to the GC-rich motifs in vitro and Sp1 coupled with phospho-Smad2 is associated with the promoter region covering the Sp1-binding motifs in vivo using chromatin immunoprecipitation (ChIP) assays. In addition, we further confirmed that Sp1 is essential for the GDP-fucose transporter expression stimulated by TGF-beta1 using a luciferase reporter system. These results highlight the role of TGF-beta signaling in regulation of the GDP-fucose transporter expression via activating Sp1. This is the first transcriptional study for any nucleotide sugar transporters that have been identified so far. Notably, TGF-beta1 receptor itself is known to be modified by fucosylation. Given the essential role of GDP-fucose transporter in fucosylation, the finding that TGF-beta1 stimulates the expression of this transporter, suggests a possible intracellular link between the function of nucleotide sugar transporter and the TGF-beta signaling pathway. PMID- 24069313 TI - An automated microfluidic multiplexer for fast delivery of C. elegans populations from multiwells. AB - Automated biosorter platforms, including recently developed microfluidic devices, enable and accelerate high-throughput and/or high-resolution bioassays on small animal models. However, time-consuming delivery of different organism populations to these systems introduces a major bottleneck to executing large-scale screens. Current population delivery strategies rely on suction from conventional well plates through tubing periodically exposed to air, leading to certain disadvantages: 1) bubble introduction to the sample, interfering with analysis in the downstream system, 2) substantial time drain from added bubble-cleaning steps, and 3) the need for complex mechanical systems to manipulate well plate position. To address these concerns, we developed a multiwell-format microfluidic platform that can deliver multiple distinct animal populations from on-chip wells using multiplexed valve control. This Population Delivery Chip could operate autonomously as part of a relatively simple setup that did not require any of the major mechanical moving parts typical of plate-handling systems to address a given well. We demonstrated automatic serial delivery of 16 distinct C. elegans worm populations to a single outlet without introducing any bubbles to the samples, causing cross-contamination, or damaging the animals. The device achieved delivery of more than 90% of the population preloaded into a given well in 4.7 seconds; an order of magnitude faster than delivery modalities in current use. This platform could potentially handle other similarly sized model organisms, such as zebrafish and drosophila larvae or cellular micro-colonies. The device's architecture and microchannel dimensions allow simple expansion for processing larger numbers of populations. PMID- 24069314 TI - Comparative genome analysis of Enterobacter cloacae. AB - The Enterobacter cloacae species includes an extremely diverse group of bacteria that are associated with plants, soil and humans. Publication of the complete genome sequence of the plant growth-promoting endophytic E. cloacae subsp. cloacae ENHKU01 provided an opportunity to perform the first comparative genome analysis between strains of this dynamic species. Examination of the pan-genome of E. cloacae showed that the conserved core genome retains the general physiological and survival genes of the species, while genomic factors in plasmids and variable regions determine the virulence of the human pathogenic E. cloacae strain; additionally, the diversity of fimbriae contributes to variation in colonization and host determination of different E. cloacae strains. Comparative genome analysis further illustrated that E. cloacae strains possess multiple mechanisms for antagonistic action against other microorganisms, which involve the production of siderophores and various antimicrobial compounds, such as bacteriocins, chitinases and antibiotic resistance proteins. The presence of Type VI secretion systems is expected to provide further fitness advantages for E. cloacae in microbial competition, thus allowing it to survive in different environments. Competition assays were performed to support our observations in genomic analysis, where E. cloacae subsp. cloacae ENHKU01 demonstrated antagonistic activities against a wide range of plant pathogenic fungal and bacterial species. PMID- 24069315 TI - Anti-Trypanosoma cruzi cross-reactive antibodies detected at high rate in non exposed individuals living in non-endemic regions: seroprevalence and association to other viral serologies. AB - Cross-reactive antibodies are characterized by their recognition of antigens that are different from the trigger immunogen. This happens when the similarity between two different antigenic determinants becomes adequate enough to enable a specific binding with such cross-reactive antibodies. In the present manuscript, we report the presence, at an "abnormal" high frequency, of antibodies in blood samples from French human subjects cross-reacting with a synthetic-peptide antigen derived from a Trypanosoma cruzi (T. cruzi) protein sequence. As the vector of T. cruzi is virtually confined to South America, the parasite is unlikely to be the trigger immunogen of the cross-reactive antibodies detected in France. At present, the cross-reactive antibodies are measured by using an in house ELISA method that employs the T. cruzi -peptide antigen. However, to underline their cross-reactive characteristics, we called these antibodies "Trypanosoma cruzi Cross Reactive Antibodies" or TcCRA. To validate their cross reactive nature, these antibodies were affinity-purified from plasma of healthy blood donor and were then shown to specifically react with the T. cruzi parasite by immunofluorescence. Seroprevalence of TcCRA was estimated at 45% in serum samples of French blood donors while the same peptide-antigen reacts with about 96% of T. cruzi -infected Brazilian individuals. In addition, we compared the serology of TcCRA to other serologies such as HSV 1/2, EBV, HHV-6, CMV, VZV, adenovirus, parvovirus B19, mumps virus, rubella virus, respiratory syncytial virus, measles and enterovirus. No association was identified to any of the tested viruses. Furthermore, we tested sera from different age groups for TcCRA and found a progressive acquisition starting from early childhood. Our findings show a large seroprevalence of cross-reactive antibodies to a well-defined T. cruzi antigen and suggest they are induced by a widely spread immunogen, acquired from childhood. The etiology of TcCRA and their clinical relevance still need to be investigated. PMID- 24069316 TI - Overweight and severe acute maternal morbidity in a low-risk pregnant population in the Netherlands. AB - OBJECTIVE: To investigate the association between overweight and severe acute maternal morbidity (SAMM) in a low-risk pregnant population. DESIGN: Nationwide case-control study. SETTING: The Netherlands, august 2004 to august 2006. POPULATION: 1567 cases from initially primary care and 2994 women from primary care practices as controls, out of 371 012 women delivering in the Netherlands during the study period. METHODS: Cases were women with SAMM obtained from a nationwide prospective study. All women in this cohort who initially had low-risk pregnancies were compared with low-risk women without SAMM to calculate odd ratios (ORs) to develop SAMM by body mass index (BMI) category. We divided body mass index in three overweight categories and calculated the ORs (95% CI) of total SAMM and per specific endpoint by logistic regression, with normal weight as reference. We adjusted for age, parity and socio-economic status. MAIN OUTCOME MEASURES: SAMM, defined as Intensive Care Unit (ICU)-admission, Uterine Rupture, Eclampsia or Major Obstetric Haemorrhage (MOH). RESULTS: SAMM was reported in 1567 cases which started as low-risk pregnancies. BMI was available in 1097 (70.0%) cases and 2994 control subjects were included. Analysis showed a dose response relation for overweight (aOR, 1.3; 95% CI, 1.0-1.5), obese (aOR, 1.4; 95% CI, 1.1-1.9) and morbidly obese (aOR, 2.1; 95% CI, 1.3-3.2) women to develop SAMM compared to normal weight. Sub analysis showed the same dose response relation for ICU-admission, Uterine Rupture and Eclampsia. We found no association for MOH. CONCLUSION: Overweight without pre-existent co-morbidity is an important risk-indicator for developing SAMM. This risk increases with an increasing body mass index. PMID- 24069317 TI - MR volumetric study of piriform-cortical amygdala and orbitofrontal cortices: the aging effect. AB - INTRODUCTION: The piriform cortex and cortical amygdala (PCA) and the orbitofrontal cortex (OFC) are considered olfactory-related brain regions. This study aims to elucidate the normal volumes of PCA and OFC of each age groups (20.0-70.0 year old), and whether the volumes of PCA and OFC decline with increasing age and diminishing olfactory function. METHODS: One hundred and eleven healthy right-handed participants (54 males, 57 females), age 20.0 to 70.0 years were recruited to join this study after excluding all the major causes of olfactory dysfunction. Volumetric measurements of PCA and OFC were performed using consecutive 1-mm thick coronal slices of high-resolution 3-D MRIs. A validated olfactory function test (Sniffin' Sticks) assessed olfactory function, which measured odor threshold (THD), odor discrimination (DIS), and odor identification (ID) as well as their sum score (TDI). RESULTS: The volume of OFC decreased with age and significantly correlated with age-related declines in olfactory function. The volume of OFC showed significant age-group differences, particularly after 40 years old (p < 0.001), while olfactory function decreased significantly after 60 years old (p < 0.001). Similar age-related volumetric changes were not found for PCA (p = 0.772). Additionally, there was significant correlation between OFC and DIS on the Right Side (p = 0.028) and between OFC and TDI on both sides (p < 0.05). There was no similar correlation for PCA. CONCLUSIONS: Aging can have a great impact on the volume of OFC and olfactory function while it has much smaller effect on the volume of PCA. The result could be useful to establish normal volumes of PCA and OFC of each age group to assess neurological disorders that affect olfactory function. PMID- 24069318 TI - Abnormalities of frontal-parietal resting-state functional connectivity are related to disease activity in patients with systemic lupus erythematosus. AB - Cerebral involvement is common in patients with systemic Lupus erythematosus (SLE) and is characterized by multiple clinical presentations, including cognitive disorders, headaches, and syncope. Several neuroimaging studies have demonstrated cerebral dysfunction during different tasks among SLE patients; however, there have been few studies designed to characterize network alterations or to identify clinical markers capable of reflecting the cerebral involvement in SLE patients. This study was designed to characterize the profile of the cerebral activation area and the functional connectivity of cognitive function in SLE patients by using a task-based and a resting state functional magnetic resonance imaging (fMRI) technique, and to determine whether or not any clinical biomarkers could serve as an indicator of cerebral involvement in this disease. The well established cognitive function test (Paced Visual Serial Adding Test [PVSAT]) was used. Thirty SLE patients without neuropsychiatric symptoms and 25 age- and gender-matched healthy controls were examined using PVSAT task-based and resting state fMRI. Outside the scanner, the performance of patients and the healthy controls was similar. In the PVSAT task-based fMRI, patients presented significantly expanded areas of activation, and the activated areas exhibited significantly higher functional connectivity strength in patients in the resting state. A positive correlation existed between individual connectivity strength and disease activity scoring. No correlation with cerebral involvement existed for serum markers, such as C3, C4, and anti-dsDNA. Thus, our findings may shed new light on the pathologic mechanism underlying neuropsychiatric SLE, and suggests that disease activity may be a potential effective biomarker reflecting cerebral involvement in SLE. PMID- 24069319 TI - SLC25A13 gene analysis in citrin deficiency: sixteen novel mutations in East Asian patients, and the mutation distribution in a large pediatric cohort in China. AB - BACKGROUND: The human SLC25A13 gene encodes citrin, the liver-type mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), and SLC25A13 mutations cause citrin deficiency (CD), a disease entity that encompasses different age-dependant clinical phenotypes such as Adult-onset Citrullinemia Type II (CTLN2) and Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD). The analyses of SLC25A13 gene and its protein/mRNA products remain reliable tools for the definitive diagnoses of CD patients, and so far, the SLC25A13 mutation spectrum in Chinese CD patients has not been well-characterized yet. METHODS AND RESULTS: By means of direct DNA sequencing, cDNA cloning and SNP analyses, 16 novel pathogenic mutations, including 9 missense, 4 nonsense, 1 splice-site, 1 deletion and 1 large transposal insertion IVS4ins6kb (GenBank accession number KF425758), were identified in CTLN2 or NICCD patients from China, Japan and Malaysia, respectively, making the SLC25A13 variations worldwide reach the total number of 81. A large NICCD cohort of 116 Chinese cases was also established, and the 4 high-frequency mutations contributed a much larger proportion of the mutated alleles in the patients from south China than in those from the north (chi(2) = 14.93, P<0.01), with the latitude of 30 degrees N as the geographic dividing line in mainland China. CONCLUSIONS: This paper further enriched the SLC25A13 variation spectrum worldwide, and formed a substantial contribution to the in-depth understanding of the genotypic feature of Chinese CD patients. PMID- 24069320 TI - Bacterial clearance is improved in septic mice by platelet-activating factor acetylhydrolase (PAF-AH) administration. AB - Current evidence indicates that dysregulation of the host inflammatory response to infectious agents is central to the mortality of patients with sepsis. Strategies to block inflammatory mediators such as PAF have been investigated as adjuvant therapies for sepsis. PAF-AH, the enzyme responsible for PAF degradation, showed positive results in pre-clinical studies and phase II clinical trials, but the results of a phase III study were disappointing. In this study, we investigated the potential protective mechanism of PAF-AH in sepsis using the murine model of cecal ligation and puncture (CLP). Treatment with rPAF AH increased peritoneal fluid levels of the anti-inflammatory mediators MCP 1/CCL2 after CLP. The numbers of bacteria (CFU) in the peritoneal cavity were decreased in the rPAF-AH-treated group, indicating more efficient bacterial clearance after rPAF-AH treatment. Interestingly, we observed increased levels of nitric oxide (NO) after PAF-AH administration, and rPAF-AH treatment did not decrease CFU numbers either in iNOS-deficient mice or in CCR2-deficient mice. We concluded that administration of exogenous rPAF-AH reduced inflammatory injury, altered cytokine levels and favored bacterial clearance with a clear impact on mortality through modulation of MCP-1/CCL2 and NO levels in a clinically relevant sepsis model. PMID- 24069322 TI - Circulating CD36 is reduced in HNF1A-MODY carriers. AB - INTRODUCTION: Premature atherosclerosis is a significant cause of morbidity and mortality in type 2 diabetes mellitus. Maturity onset diabetes of the young (MODY) accounts for approximately 2% of all diabetes, with mutations in the transcription factor; hepatocyte nuclear factor 1 alpha (HNF1A) accounting for the majority of MODY cases. There is somewhat limited data available on the prevalence of macrovascular disease in HNF1A-MODY carriers with diabetes. Marked insulin resistance and the associated dyslipidaemia are not clinical features of HNF1A-MODY carriers. The scavenger protein CD36 has been shown to play a substantial role in the pathogenesis of atherosclerosis, largely through its interaction with oxidised LDL. Higher levels of monocyte CD36 and plasma CD36(sCD36) are seen to cluster with insulin resistance and diabetes. The aim of this study was to determine levels of sCD36 in participants with HNF1A-MODY diabetes and to compare them with unaffected normoglycaemic family members and participants with type 2 diabetes mellitus. METHODS: We recruited 37 participants with HNF1A-MODY diabetes and compared levels of sCD36 with BMI-matched participants with type 2 diabetes mellitus and normoglycaemic HNF1A-MODY negative family controls. Levels of sCD36 were correlated with phenotypic and biochemical parameters. RESULTS: HNF1A-MODY participants were lean, normotensive, with higher HDL and lower triglyceride levels when compared to controls and participants with type 2 diabetes mellitus. sCD36 was also significantly lower in HNF1A-MODY participants when compared to both the normoglycaemic family controls and to lean participants with type 2 diabetes mellitus. CONCLUSION: In conclusion, sCD36 is significantly lower in lean participants with HNF1A-MODY diabetes when compared to weight-matched normoglycaemic familial HNF1A-MODY negative controls and to lean participants with type 2 diabetes mellitus. Lower levels of this pro atherogenic marker may result from the higher HDL component in the lipid profile of HNF1A-MODY participants. PMID- 24069321 TI - bba, a synthetic derivative of 23-hydroxybutulinic acid, reverses multidrug resistance by inhibiting the efflux activity of MRP7 (ABCC10). AB - Natural products are frequently used for adjuvant chemotherapy in cancer treatment. 23-O-(1,4'-bipiperidine-1-carbonyl) betulinic acid (BBA) is a synthetic derivative of 23-hydroxybutulinic acid (23-HBA), which is a natural pentacyclic triterpene and the major active constituent of the root of Pulsatillachinensis. We previously reported that BBA could reverse P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR). In the present study, we investigated whether BBA has the potential to reverse multidrug resistance protein 7 (MRP7/ABCC10)-mediated MDR. We found that BBA concentration-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine. Accumulation and efflux experiments demonstrated that BBA increased the intracellular accumulation of [(3)H]-paclitaxel by inhibiting the efflux of [(3)H]-paclitaxel from HEK293/MRP7 cells. In addition, immunoblotting and immunofluorescence analyses indicated no significant alteration of MRP7 protein expression and localization in plasma membranes after treatment with BBA. These results demonstrate that BBA reverses MRP7-mediated MDR through blocking the drug efflux function of MRP7 without affecting the intracellular ATP levels. Our findings suggest that BBA has the potential to be used in combination with conventional chemotherapeutic agents to augment the response to chemotherapy. PMID- 24069323 TI - Increased risk of colorectal cancer in type 2 diabetes is independent of diet quality. AB - BACKGROUND: Poor diet increases the risk of both colorectal cancer and type 2 diabetes. We investigated the role of diet in the association between diabetes and colorectal cancer. METHODS: We analyzed data from 484,020 individuals, aged 50-71 years who participated in the prospective National Institutes of Health AARP Diet and Health Study and were cancer free at baseline (1995-1996). History of diabetes was self-reported. Diet quality was measured with the Healthy Eating Index-2005 (HEI-2005), using a self-administered food-frequency questionnaire. Cox regression models were constructed to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of first primary incident colorectal cancer, overall and by anatomical location. RESULTS: During an average follow-up of 9.2 years, we identified 7,598 new cases of colorectal cancer. After controlling for non dietary confounders, diabetes was associated with increased risk of colorectal cancer (HR 1.27, 95% CI: 1.18, 1.36). Further adjustment for diet quality did not attenuate this association. Diabetes was associated with a HR of 1.23 (95% CI: 1.07, 1.40) in individuals with good diet (quartile 4 of HEI-2005) and 1.58 (95% CI: 1.34, 1.86) in those with poor diet (quartile 1 of HEI-2005), compared to those with no diabetes and good diet. Moreover, diabetes was associated with a stronger risk of proximal than distal colon cancer (HR: 1.33 vs. HR: 1.20), while poor diet was associated with a weaker risk of proximal colon cancer (HR: 1.18 vs. HR: 1.46). CONCLUSION: Diabetes and poor diet, independently and additively are associated with the increased risk of colorectal cancer. PMID- 24069324 TI - Sex- and subtype-specific analysis of H2AFX polymorphisms in non-Hodgkin lymphoma. AB - H2AFX encodes a histone variant involved in signaling sites of DNA damage and recruiting repair factors. Genetic variants in H2AFX may influence risk of non Hodgkin lymphoma (NHL), a heterogeneous group of lymphoid tumors that are characterized by chromosomal translocations. We previously reported that rs2509049, a common variant in the promoter of H2AFX, was associated with risk for NHL in the British Columbia population. Here we report results for 13 single nucleotide polymorphisms (SNPs) in 100 Kb surrounding H2AFX in an expanded collection of 568 NHL cases and 547 controls. After correction for multiple testing, significant associations were present for mantle cell lymphoma (p=0.007 for rs604714) and all B-cell lymphomas (p=0.046 for rs2509049). Strong linkage disequilibrium in the 5 Kb upstream of H2AFX limited the ability to determine which specific SNP (rs2509049, rs7759, rs8551, rs643788, rs604714, or rs603826), if any, was responsible. There was a significant interaction between sex and rs2509049 in the all B-cell lymphomas group (p=0.002); a sex-stratified analysis revealed that the association was confined to females (p=0.001). Neither the overall nor the female-specific association with rs2509049 was replicated in any of four independent NHL sample sets. Meta-analysis of all five study populations (3,882 B-cell NHL cases and 3,718 controls) supported a weak association with B cell lymphoma (OR=0.92, 95% CI=0.86-0.99, p=0.034), although this association was not significant after exclusion of the British Columbia data. Further research into the potential sex-specificity of the H2AFX-NHL association may identify a subset of NHL cases that are influenced by genotype at this locus. PMID- 24069325 TI - Regulation of CD4(+) T cells by pleural mesothelial cells via adhesion molecule dependent mechanisms in tuberculous pleurisy. AB - BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been demonstrated to be expressed on pleural mesothelial cells (PMCs), and to mediate leukocyte adhesion and migration; however, little is known about whether adhesion molecule-dependent mechanisms are involved in the regulation of CD4(+) T cells by PMCs in tuberculous pleural effusion (TPE). METHODS: Expressions of ICAM-1 and VCAM-1 on PMCs, as well as expressions of CD11a and CD29, the counter-receptors for ICAM-1 and VCAM-1, respectively, expressed on CD4(+) T cells in TPE were determined using flow cytometry. The immune regulations on adhesion, proliferation, activation, selective expansion of CD4(+) helper T cell subgroups exerted by PMCs via adhesion molecule-dependent mechanisms were explored. RESULTS: Percentages of ICAM-1-positive and VCAM-1 positive PMCs in TPE were increased compared with PMC line. Interferon-gamma enhanced fluorescence intensity of ICAM-1, while IL-4 promoted VCAM-1 expression on PMCs. Percentages of CD11a(high)CD4(+) and CD29(high)CD4(+) T cells in TPE significantly increased as compared with peripheral blood. Prestimulation of PMCs with anti-ICAM-1 or -VCAM-1 mAb significantly inhibited adhesion, activation, as well as effector regulatory T cell expansion induced by PMCs. CONCLUSIONS: Our current data showed that adhesion molecule pathways on PMCs regulated adhesion and activation of CD4(+) T cells, and selectively promoted the expansion of effector regulatory T cells. PMID- 24069326 TI - Association between DNA methyltransferases 3B gene polymorphisms and the susceptibility to acute myeloid leukemia in Chinese Han population. AB - DNMT3B plays a crucial role in the generation of aberrant methylation during carcinogenesis. Polymorphisms in the DNMT3B gene may influence the DNA methylation enzymatic activity of DNMT3B, thereby modulating the susceptibility to AML. Thus, we investigated the association between SNPs in the DNMT3Bgene and their haplotypes with the risk of AML in the Chinese Han population. The DNMT3B genotype was determined by HRM in 317 de novo AML patients and 406 healthy control subjects matched for age and gender. Among the 5 SNPs investigated in this study, rs2424913 demonstrated no polymorphisms in the Chinese Han populations, rs1569686 and rs2424908 were significantly associated with AML risk. The GG genotype of rs1569686 was associated with increased AML risk (OR: 5.76; 95%CI: 2.60-12.73; P<0.01) compared with the TT genotype, and individuals with a G allele had a significantly increased risk (OR: 1.89; 95%CI: 1.41-2.52; P<0.01) for AML compared with those harboring a C allele, this polymorphism can predict the risk of AML in a minority of patients. While the CC genotype of rs2424908 appeared to reduce the AML risk (OR: 0.57; 95%CI: 0.36-0.91; P=0.01) compared with the TT genotype, individuals with a C allele were associated with a lower risk (OR: 0.79, 95%CI: 0.64-0.97, P=0.03) for developing AML compared with those harboring a T allele. The other 2 SNPs, rs6087990 and rs6119954, had no significant association with AML risk in the study population. The CGGT, CTAT, TGAT, and CGAT haplotypes of rs6087990, rs1569686, rs6119954, and rs2424908 appeared to significantly increase the AML risk, and the TTGC haplotype appeared to significantly reduce the risk. These results suggest that DNMT3B polymorphisms may contribute to the genetic susceptibility to AML; in particular, the G allele of rs1569686 serves as a risk factor for AML, whereas the C allele of rs2424908 represents a potential protective factor. PMID- 24069327 TI - Laboratory investigations on the diagnosis of tuberculosis in the malnourished tribal population of melghat, India. AB - BACKGROUND: Malnutrition is a major risk factor for the development of tuberculosis (TB). In India, Melghat is among the tribal regions which consist of highest number of malnutrition cases. Because of the paucity of TB data from these malnourished areas there is an urgent need for the development and evaluation of improved TB diagnostic tests. In the present study, three in house developed diagnostic tests namely TB-Ag(antigen) ELISA, Adenosine deaminase (ADA) estimation and IS6110 polymerase chain reaction (PCR) assay were investigated for the detection of Mycobacterium tuberculosis (M. tb.) infection. METHODS: For investigation, blood samples were collected from 128 study subjects from six villages of Melghat tribal area and evaluated using three in house developed assays, namely TB-Ag ELISA, ADA estimation and IS6110 PCR. RESULTS: The TB-Ag ELISA method yielded 83% sensitivity and 94% specificity. The ADA and PCR assay gave a sensitivity of 61% and 49% and specificity of 62% and 98% respectively. A considerable good agreement of 82.81% (k=0.472) between TB-Ag ELISA and PCR was observed. The overall sensitivity of TB-Ag ELISA was significantly higher (p<0.05) than the ADA and PCR while PCR yielded highest specificity among all the three evaluated tests. CONCLUSIONS: We concluded that the routine use of TB-Ag ELISA can be useful for screening of suspected TB patients in the malnourished population where sophisticated laboratory set up is difficult. PMID- 24069328 TI - Area-specific alterations of synaptic plasticity in the 5XFAD mouse model of Alzheimer's disease: dissociation between somatosensory cortex and hippocampus. AB - Transgenic mouse models of Alzheimer's disease (AD) that overproduce the amyloid beta peptide (Abeta) have highlighted impairments of hippocampal long-term synaptic plasticity associated with the progression of the disease. Here we examined whether the characteristics of one of the hallmarks of AD, i.e. Abeta deposition, in both the somatosensory cortex and the hippocampus, correlated with specific losses of synaptic plasticity in these areas. For this, we evaluated the occurrence of long-term potentiation (LTP) in the cortex and the hippocampus of 6 month old 5xFAD transgenic mice that exhibited massive Abeta deposition in both regions but with different features: in cortical areas a majority of Abeta deposits comprised a dense core surrounded by a diffuse corona while such kind of Abeta deposition was less frequently observed in the hippocampus. In order to simultaneously monitor synaptic changes in both areas, we developed a method based on the use of Multi-Electrode Arrays (MEA). When compared with wild-type (WT) mice, basal transmission was significantly reduced in both areas in 5xFAD mice, while short-term synaptic plasticity was unaffected. The induction of long term changes of synaptic transmission by different protocols revealed that in 5xFAD mice, LTP in the layer 5 of the somatosensory cortex was more severely impaired than LTP triggered in the CA1 area of the hippocampus. We conclude that cortical plasticity is deficient in the 5xFAD model and that this deficit could be correlated with the proportion of diffuse plaques in 5xFAD mice. PMID- 24069329 TI - Identification and characterization of a novel hemolysis-related gene in Streptococcus suis serotype 2. AB - Streptococcussuis serotype 2 (SS 2) is an important zoonotic pathogen that has caused two major infectious outbreaks of streptococcal toxic shock syndrome (STSS) in China. A novel gene located in the 89K pathogenicity island (PAI) encoding a putative hemolysin-III-related protein (Hhly3) has been previously characterized. In this study, the SS2 deletion mutant of the exogenous gene hhly3 was constructed by homologous recombination. This protein was found to exhibit cytolytic activity, and hemolytic activity of the hhly3 gene knockout mutant (Deltahhly3) was significantly lower than that in the wild-type strain ZY05719. In addition, qRT-PCR revealed that Hhly3 played an important role in the expression of the secreted hemolysin SLY, which may be the key reason for the decreased hemolytic activity. Consequently, compared with the WT strain, the infection and pathogenicity of Deltahhly3 was also decreased, as evidenced by in vitro bacterial growth in whole blood and by the in vivo zebrafish test, suggesting that hhly3 is a novel exogenous hemolysis-related gene in SS2 strains. PMID- 24069330 TI - Gpr3 stimulates Abeta production via interactions with APP and beta-arrestin2. AB - The orphan G protein-coupled receptor (GPCR) GPR3 enhances the processing of Amyloid Precursor Protein (APP) to the neurotoxic beta-amyloid (Abeta) peptide via incompletely understood mechanisms. Through overexpression and shRNA knockdown experiments in HEK293 cells, we show that beta-arrestin2 (betaarr2), a GPCR-interacting scaffold protein reported to bind gamma-secretase, is an essential factor for GPR3-stimulated Abeta production. For a panel of GPR3 receptor mutants, the degree of stimulation of Abeta production correlates with receptor-beta-arrestin binding and receptor trafficking to endocytic vesicles. However, GPR3's recruitment of betaarr2 cannot be the sole explanation, because interaction with betaarr2 is common to most GPCRs, whereas GPR3 is relatively unique among GPCRs in enhancing Abeta production. In addition to beta-arrestin, APP is present in a complex with GPR3 and stimulation of Abeta production by GPR3 mutants correlates with their level of APP binding. Importantly, among a broader selection of GPCRs, only GPR3 and prostaglandin E receptor 2 subtype EP2 (PTGER2; another GPCR that increases Abeta production) interact with APP, and PTGER2 does so in an agonist-stimulated manner. These data indicate that a subset of GPCRs, including GPR3 and PTGER2, can associate with APP when internalized via betaarr2, and thereby promote the cleavage of APP to generate Abeta. PMID- 24069331 TI - Single nucleotide polymorphisms within LIPA (Lysosomal Acid Lipase A) gene are associated with susceptibility to premature coronary artery disease. a replication in the genetic of atherosclerotic disease (GEA) Mexican study. AB - AIM: The rs1412444 and rs2246833 polymorphisms within the LIPA gene were recently found to be significantly associated with coronary artery disease (CAD) in genome wide association studies in Caucasian and Asian populations. The aim of the present study was to replicate this association in an independent population with a different genetic background. METHODS: The rs1412444 and rs2246833 polymorphisms of the LIPA gene were genotyped by 5' exonuclease TaqMan genotyping assays in a sample of 899 Mexican patients with premature CAD, 270 individuals with subclinical atherosclerosis, and 677 healthy unrelated controls. Haplotypes were constructed after linkage disequilibrium analysis. RESULTS: Under recessive and additive models, the rs1412444 T and rs2246833 T alleles were associated with an increased risk of premature CAD when compared to controls adjusting for age, gender, BMI, and total cholesterol (OR = 1.53, PRec = 0.0013 and OR = 1.34, PAdd = 5 * 10(-4) for rs1412444 and OR = 1.45, PRec = 0.0039 and OR = 1.28, PAdd = 0.0023 for rs2246833). The effect of the two polymorphisms on various metabolic cardiovascular risk factors was analyzed in premature CAD and controls (CAC score = 0). The T alleles in both polymorphisms after adjusting for age, gender, BMI, and medication were associated with hypo-alpha-lipoproteinemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome, and type 2 diabetes mellitus using recessive and additive models. The polymorphisms were in strong linkage disequilibrium and, based on SNP functional prediction software, only the rs1412444 polymorphism seemed to be functional. CONCLUSIONS: These results indicate that the rs1412444 and rs2246833 of the LIPA gene are shared susceptibility polymorphisms for CAD among different ethnicities. PMID- 24069332 TI - Mu opioid receptors on primary afferent nav1.8 neurons contribute to opiate induced analgesia: insight from conditional knockout mice. AB - Opiates are powerful drugs to treat severe pain, and act via mu opioid receptors distributed throughout the nervous system. Their clinical use is hampered by centrally-mediated adverse effects, including nausea or respiratory depression. Here we used a genetic approach to investigate the potential of peripheral mu opioid receptors as targets for pain treatment. We generated conditional knockout (cKO) mice in which mu opioid receptors are deleted specifically in primary afferent Nav1.8-positive neurons. Mutant animals were compared to controls for acute nociception, inflammatory pain, opiate-induced analgesia and constipation. There was a 76% decrease of mu receptor-positive neurons and a 60% reduction of mu-receptor mRNA in dorsal root ganglia of cKO mice. Mutant mice showed normal responses to heat, mechanical, visceral and chemical stimuli, as well as unchanged morphine antinociception and tolerance to antinociception in models of acute pain. Inflammatory pain developed similarly in cKO and controls mice after Complete Freund's Adjuvant. In the inflammation model, however, opiate-induced (morphine, fentanyl and loperamide) analgesia was reduced in mutant mice as compared to controls, and abolished at low doses. Morphine-induced constipation remained intact in cKO mice. We therefore genetically demonstrate for the first time that mu opioid receptors partly mediate opiate analgesia at the level of Nav1.8-positive sensory neurons. In our study, this mechanism operates under conditions of inflammatory pain, but not nociception. Previous pharmacology suggests that peripheral opiates may be clinically useful, and our data further demonstrate that Nav1.8 neuron-associated mu opioid receptors are feasible targets to alleviate some forms of persistent pain. PMID- 24069333 TI - A degenerative retinal process in HIV-associated non-infectious retinopathy. AB - HIV retinopathy is the most common non-infectious complication in the eyes of HIV positive individuals. Oncotic lesions in the retinal nerve fiber layer, referred to as cotton wool spots (CWS), and intraretinal (IR) hemorrhages are frequently observed but are not unique to this pathology. HIV-positive patients have impaired color vision and contrast sensitivity, which worsens with age. Evidence of inner-retinal lesions and damage have been documented ophthalmoscopically, however their long term structural effect has not been investigated. It has been hypothesized that they may be partially responsible for loss of visual function and visual field. In this study we utilized clinical data, retinal imaging and transcriptomics approaches to comprehensively interrogate non-infectious HIV retinopathy. The methods employed encompassed clinical examinations, fundus photography, indirect ophthalmoscopy, Farmsworth-Munsell 100 hue discrimination testing and Illumina BeadChip analyses. Here we show that changes in the outer retina, specifically in the retinal pigment epithelium (RPE) and photoreceptor outer segments (POS) contribute to vision changes in non-infectious HIV retinopathy. We find that in HIV-positive retinae there is an induction of rhodopsin and other transcripts (including PDE6A, PDE6B, PDE6G, CNGA1, CNGB1, CRX, NRL) involved in visual transduction, as well as structural components of the rod photoreceptors (ABCA4 and ROM1). This is consistent with an increased rate of renewal of rod outer segments induced via increased phagocytosis by HIV infected RPE previously reported in culture. Cone-specific transcripts (OPN1SW, OPN1LW, PDE6C, PDE6H and GRK7) are uniformly downregulated in HIV positive retina, likely due to a partial loss of cone photoreceptors. Active cotton wool spots and intraretinal hemorrhages (IRH) may not affect photoreceptors directly and the interaction of photoreceptors with the aging RPE may be the key to the progressive vision changes in HIV-positive patients. PMID- 24069335 TI - Burst feeding of Pelagia noctiluca ephyrae on Atlantic bluefin tuna (Thunnus thynnus) eggs. AB - This study investigates the predation of P. noctiluca ephyrae on Atlantic Bluefin tuna (ABFT) eggs under different experimental conditions. The specific factors considered in the experimental design were: a) water mix conditions to explore predation under two-dimensional (2D) and three-dimensional (3D) prey distributions, b) prey density to investigate the ingestion rate capacity, and c) incubation time to inspect gut saturation. The eggs and jellyfish ephyrae were collected during the 2012 ABFT spawning survey off Ibiza (Balearic Isl., Western Mediterranean). The results showed that the proportion of feeding ephyrae increased with size. The mean clearance rate of feeding ephyrae, 4.14 L h(-1), was the highest ever recorded for ephyrae. Under calm conditions the eggs floated at the surface (2D spatial arrangement) and the clearance rates, at low prey densities, were at least twice those under mixed conditions (3D spatial arrangement). At high prey density, clearance rate did not differ between mix conditions, probably due to the fast gut saturation, which was reached in c.a. 15 min, as revealed by time series observations of gut contents. The fast saturation of ephyrae and their slow digestion time of approximately 18 h suggest the existence of a diel feeding periodicity. We conclude that in the Western Mediterranean, P. noctiluca ephyrae are capable of predating on ABFT eggs, a highly pulsed and spatially restricted resource that potentially switches from a 3D to a 2D configuration in the absence of wind-generated turbulence. The P. noctiluca and Atlantic Bluefin tuna egg system might represent an example of a general mechanism linking pelagic and neustonic food webs. PMID- 24069334 TI - Protective activity of the CnaBE3 domain conserved among Staphylococcus aureus Sdr proteins. AB - Staphylococcus aureus is an opportunistic pathogen, commensal of the human skin and nares, but also responsible for invasive nosocomial as well as community acquired infections. Staphylococcus aureus adheres to the host tissues by means of surface adhesins, such as SdrC, SdrD, and SdrE proteins. The Sdr family of proteins together with a functional A domain, contain respectively two, three or five repeated sequences called B motifs which comprise the CnaB domains. SdrD and SdrE proteins were reported to be protective in animal models against invasive diseases or lethal challenge with human clinical S. aureus isolates. In this study we identified a 126 amino acid sequence containing a CnaB domain, conserved among the three Sdr proteins. The three fragments defined here as CnaBC2, D5 and E3 domains even though belonging to phylogenetically distinct strains, displayed high sequence similarity. Based on the sequence conservation data, we selected the CnaBE3 domain for further analysis and characterization. Polyclonal antibodies raised against the recombinant CnaBE3 domain recognized SdrE, SdrC and SdrD proteins of different S. aureus lineages. Moreover, we demonstrated that the CnaBE3 domain was expressed in vivo during S. aureus infections, and that immunization of this domain alone significantly reduces the bacterial load in mice challenged with S. aureus. Furthermore, we show that the reduction of bacteria by CnaBE3 vaccination is due to functional antibodies. Finally, we demonstrated that the region of the SdrE protein containing the CnaBE3 domain was resistant to trypsin digestion, a characteristic often associated with the presence of an isopeptide bond. PMID- 24069336 TI - A missense mutation in the alpha-actinin 1 gene (ACTN1) is the cause of autosomal dominant macrothrombocytopenia in a large French family. AB - Inherited thrombocytopenia is a heterogeneous group of disorders characterized by a reduced number of blood platelets. Despite the identification of nearly 20 causative genes in the past decade, approximately half of all subjects with inherited thrombocytopenia still remain unexplained in terms of the underlying pathogenic mechanisms. Here we report a six-generation French pedigree with an autosomal dominant mode of inheritance and the identification of its genetic basis. Of the 55 subjects available for analysis, 26 were diagnosed with isolated macrothrombocytopenia. Genome-wide linkage analysis mapped a 10.9 Mb locus to chromosome 14 (14q22) with a LOD score of 7.6. Candidate gene analysis complemented by targeted next-generation sequencing identified a missense mutation (c.137GA; p.Arg46Gln) in the alpha-actinin 1 gene (ACTN1) that segregated with macrothrombocytopenia in this large pedigree. The missense mutation occurred within actin-binding domain of alpha-actinin 1, a functionally critical domain that crosslinks actin filaments into bundles. The evaluation of cultured mutation-harboring megakaryocytes by electron microscopy and the immunofluorescence examination of transfected COS-7 cells suggested that the mutation causes disorganization of the cellular cytoplasm. Our study concurred with a recently published whole-exome sequence analysis of six small Japanese families with congenital macrothrombocytopenia, adding ACTN1 to the growing list of thrombocytopenia genes. PMID- 24069337 TI - Lack of endogenous IL-10 enhances production of proinflammatory cytokines and leads to Brucella abortus clearance in mice. AB - IL-10 is a cytokine that regulates the balance between pathogen clearance and immunopathology. Brucella abortus is an intracellular bacterium that causes chronic disease in humans and domestic animals. Here we evaluated the contribution of IL-10 in host immune response and pathology during B. abortus infection. To assess the role of IL-10 in vivo, IL-10 knockout (KO) or 129 Sv/Ev (wild-type) mice were infected with B. abortus and the number of viable bacteria from the spleen was determined at 1, 2, 3, 6 and 14-weeks postinfection. IL-10 KO mice showed reduced bacterial loads in the spleen when compared to wild-type mice during all time points studied. Additionally, at 14-weeks postinfection IL-10 KO mice had totally cleared the infection. This clearance was preceded by an enhanced IFN-gamma, TNF-alpha and IL-17 responses in both the serum and the spleen of IL-10 KO mice. Additionally, dendritic cells from infected IL-10 KO mice produced elevated levels of IL-12 and TNF-alpha compared to wild-type animals. Histopathology analysis was performed and both KO and wild-type mice developed multifocal granulomas and necrosis in the liver. However, at six-weeks postinfection reduced numbers of granulomas was detected in IL-10 KO mice compared to wild-type animals. This reduced liver pathology at later stage of infection was accompanied by increased numbers of CD4+CD25+foxp3+ T cells and expression of TGF-beta in IL-10 KO splenocytes. Taken together, our findings demonstrate that IL-10 modulates the proinflammatory immune response to B. abortus infection and the lack of IL-10 increases resistance to Brucella infection. PMID- 24069339 TI - Increase in bloodstream infection due to vancomycin-susceptible Enterococcus faecium in cancer patients: risk factors, molecular epidemiology and outcomes. AB - We conducted a prospective study to assess the risk factors, molecular epidemiology and outcome of bloodstream infection (BSI) due to Enterococcus faecium in hospitalized cancer patients. Between 2006 and 2012, a significant increase in vancomycin-susceptible E. faecium BSI was observed among cancer patients. Comparison of 54 episodes of BSI due to E. faecium with 38 episodes of BSI due to E. faecalis showed that previous use of carbapenems was the only independent risk factor for E. faecium acquisition (OR 10.24; 95% CI, 1.35 77.66). All E. faecium isolates were susceptible to glycopeptides, whereas 97% showed high-level resistance to ampicillin and ciprofloxacin. All 30 isolates available for genotyping belonged to the hospital-associated E. faecium lineages 17, 18 and 78. After 2009, most of the isolates belonged to ST117 (lineage 78). Patients with E. faecium BSI were more likely to receive inadequate initial empirical antibiotic therapy than patients with E. faecalis BSI, and time to adequate empirical antibiotic therapy was also longer in the former group. No significant differences were found between the two groups regarding early and overall case-fatality rates. Independent risk factors for overall case-fatality were current corticosteroids (OR 4.18; 95% CI, 1.34-13.01) and intensive care unit admission (OR 9.97; 95% CI, 1.96-50.63). The emergence of E. faecium among cancer patients is a concern since there are limited treatment options and it may presage the emergence of vancomycin-resistant enterococci. A rationale approach that combines infection control with antimicrobial stewardship. PMID- 24069338 TI - The endogenous Th17 response in NO2-promoted allergic airway disease is dispensable for airway hyperresponsiveness and distinct from Th17 adoptive transfer. AB - Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. PMID- 24069340 TI - The inhibitory helix controls the intramolecular conformational switching of the C-terminus of STIM1. AB - Store-operated Ca(2+) entry (SOCE) is a critical Ca(2+) signaling pathway in many cell types. After sensing Ca(2+) store depletion in the endoplasmic reticulum (ER) lumen, STIM1 (STromal Interaction Molecule 1) oligomerizes and then interacts with and activates the Orai1 calcium channel. Our previous research has demonstrated that the inhibitory helix (IH) adjacent to the first coiled-coil region (CC1) of STIM1 may keep the whole C-terminus of STIM1 in an inactive state. However, the specific conformational change of CC1-IH that drives the transition of STIM1 from the resting state to the active state remains elusive. Herein, we report the structural analysis of CC1-IH, which revealed that the entire CC1-IH molecule forms a very long helix. Structural and biochemical analyses indicated that IH, and not the CC1 region, contributes to the oligomerization of STIM1. Small-angle X-ray scattering (SAXS) analysis suggested that the C-terminus of STIM1 including the IH region displays a collapsed conformation, whereas the construct without the IH region has an extended conformation. These two conformations may correspond to the conformational states of the C-terminus of STIM1 before and after activation. Taken together, our results provide direct biochemical evidence that the IH region controls the conformational switching of the C-terminus of STIM1. PMID- 24069341 TI - Human umbilical cord blood mononuclear cells in a double-hit model of bronchopulmonary dysplasia in neonatal mice. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) presents a major threat of very preterm birth and treatment options are still limited. Stem cells from different sources have been used successfully in experimental BPD, induced by postnatal hyperoxia. OBJECTIVES: We investigated the effect of umbilical cord blood mononuclear cells (MNCs) in a new double-hit mouse model of BPD. METHODS: For the double-hit, date mated mice were subjected to hypoxia and thereafter the offspring was exposed to hyperoxia. Human umbilical cord blood MNCs were given intraperitoneally by day P7. As outcome variables were defined: physical development (auxology), lung structure (histomorphometry), expression of markers for lung maturation and inflammation on mRNA and protein level. Pre- and postnatal normoxic pups and sham treated double-hit pups served as control groups. RESULTS: Compared to normoxic controls, sham treated double-hit animals showed impaired physical and lung development with reduced alveolarization and increased thickness of septa. Electron microscopy revealed reduced volume density of lamellar bodies. Pulmonary expression of mRNA for surfactant proteins B and C, Mtor and Crabp1 was reduced. Expression of Igf1 was increased. Treatment with umbilical cord blood MNCs normalized thickness of septa and mRNA expression of Mtor to levels of normoxic controls. Tgfb3 mRNA expression and pro-inflammatory IL-1beta protein concentration were decreased. CONCLUSION: The results of our study demonstrate the therapeutic potential of umbilical cord blood MNCs in a new double-hit model of BPD in newborn mice. We found improved lung structure and effects on molecular level. Further studies are needed to address the role of systemic administration of MNCs in experimental BPD. PMID- 24069342 TI - Gene expression profile of peripheral blood monocytes: a step towards the molecular diagnosis of celiac disease? AB - AIM: Celiac disease (CD) is a multifactorial autoimmune disease induced by ingestion of gluten in genetically predisposed individuals. Despite technological progress, the diagnosis of CD is still based on duodenal biopsy as it was 50 years ago. In this study we analysed the expression of CD-associated genes in small bowel biopsies of patients and controls in order to explore the multivariate pathway of the expression profile of CD patients. Then, using multivariant discriminant analysis, we evaluated whether the expression profiles of these genes in peripheral blood monocytes (PBMs) differed between patients and controls. PARTICIPANTS: Thirty-seven patients with active and 11 with treated CD, 40 healthy controls and 9 disease controls (Crohn's disease patients) were enrolled. RESULTS: Several genes were differentially expressed in CD patients versus controls, but the analysis of each single gene did not provided a comprehensive picture. A multivariate discriminant analysis showed that the expression of 5 genes in intestinal mucosa accounted for 93% of the difference between CD patients and controls. We then applied the same approach to PBMs, on a training set of 20 samples. The discriminant equation obtained was validated on a testing cohort of 10 additional cases and controls, and we obtained a correct classification of all CD cases and of 91% of the control samples. We applied this equation to treated CD patients and to disease controls and obtained a discrimination of 100%. CONCLUSIONS: The combined expression of 4 genes allows one to discriminate between CD patients and controls, and between CD patients on a gluten-free diet and disease controls. Our results contribute to the understanding of the complex interactions among CD-associated genes, and they may represent a starting point for the development of a molecular diagnosis of celiac disease. PMID- 24069343 TI - Genetic diversity of hepatitis A virus in China: VP3-VP1-2A genes and evidence of quasispecies distribution in the isolates. AB - Hepatitis A virus (HAV) is the most common cause of infectious hepatitis throughout the world, spread largely by the fecal-oral route. To characterize the genetic diversity of the virus circulating in China where HAV in endemic, we selected the outbreak cases with identical sequences in VP1-2A junction region and compiled a panel of 42 isolates. The VP3-VP1-2A regions of the HAV capsid coding genes were further sequenced and analyzed. The quasispecies distribution was evaluated by cloning the VP3 and VP1-2A genes in three clinical samples. Phylogenetic analysis demonstrated that the same genotyping results could be obtained whether using the complete VP3, VP1, or partial VP1-2A genes for analysis in this study, although some differences did exist. Most isolates clustered in sub-genotype IA, and fewer in sub-genotype IB. No amino acid mutations were found at the published neutralizing epitope sites, however, several unique amino acid substitutions in the VP3 or VP1 region were identified, with two amino acid variants closely located to the immunodominant site. Quasispecies analysis showed the mutation frequencies were in the range of 7.22 x 10(-4) -2.33 x 10(-3) substitutions per nucleotide for VP3, VP1, or VP1-2A. When compared with the consensus sequences, mutated nucleotide sites represented the minority of all the analyzed sequences sites. HAV replicated as a complex distribution of closely genetically related variants referred to as quasispecies, and were under negative selection. The results indicate that diverse HAV strains and quasispecies inside the viral populations are presented in China, with unique amino acid substitutions detected close to the immunodominant site, and that the possibility of antigenic escaping mutants cannot be ruled out and needs to be further analyzed. PMID- 24069344 TI - Tocotrienol-adjuvanted dendritic cells inhibit tumor growth and metastasis: a murine model of breast cancer. AB - Tocotrienol-rich fraction (TRF) from palm oil is reported to possess anti-cancer and immune-enhancing effects. In this study, TRF supplementation was used as an adjuvant to enhance the anti-cancer effects of dendritic cells (DC)-based cancer vaccine in a syngeneic mouse model of breast cancer. Female BALB/c mice were inoculated with 4T1 cells in mammary pad to induce tumor. When the tumor was palpable, the mice in the experimental groups were injected subcutaneously with DC-pulsed with tumor lysate (TL) from 4T1 cells (DC+TL) once a week for three weeks and fed daily with 1 mg TRF or vehicle. Control mice received unpulsed DC and were fed with vehicle. The combined therapy of using DC+TL injections and TRF supplementation (DC+TL+TRF) inhibited (p<0.05) tumor growth and metastasis. Splenocytes from the DC+TL+TRF group cultured with mitomycin-C (MMC)-treated 4T1 cells produced higher (p<0.05) levels of IFN-gamma and IL-12. The cytotoxic T lymphocyte (CTL) assay also showed enhanced tumor-specific killing (p<0.05) by CD8(+) T-lymphocytes isolated from mice in the DC+TL+TRF group. This study shows that TRF has the potential to be used as an adjuvant to enhance effectiveness of DC-based vaccines. PMID- 24069345 TI - Ginkgolide B reduces LOX-1 expression by inhibiting Akt phosphorylation and increasing Sirt1 expression in oxidized LDL-stimulated human umbilical vein endothelial cells. AB - Oxidized low-density lipoprotein (ox-LDL) is an important risk factor in the development of atherosclerosis. LOX-1, a lectin-like receptor for ox-LDL, is present primarily on endothelial cells and upregulated by ox-LDL, tumor necrosis factor a, shear stress, and cytokines in atherosclerosis. Recent studies demonstrated that ginkgolide B, a platelet-activating factor receptor antagonist, has antiinflammatory and antioxidant effects on endothelial and nerve cells. The present study investigated the effects of ginkgolide B on LOX-1 expression and the possible mechanism of action. Our results showed that ginkgolide B inhibited LOX-1 and intercellular cell adhesion molecule-1 (ICAM-1) expression in ox-LDL stimulated endothelial cells through a mechanism associated with the attenuation of Akt activation. Similar data were obtained by silencing Akt and LY294002. We also evaluated Sirt1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. These molecules play a protective role in endothelial cell injury. The results showed that ginkgolide B increased Sirt1 expression in ox-LDL-treated cells. The inhibitory effects of ginkgolide B on LOX-1 and ICAM-1 expression were reduced in Sirt1 siRNA-transfected cells. Nrf2 expression was increased in ox-LDL treated cells, and ginkgolide B downregulated Nrf2 expression. These results suggest that ginkgolide B reduces Nrf2 expression by inhibiting LOX-1 expression, consequently reducing oxidative stress injury in ox-LDL-stimulated cells. Altogether, these results indicate that the protective effect of ginkgolide B on endothelial cells may be attributable to a decrease in LOX-1 expression and an increase in Sirt1 expression in ox-LDL-stimulated endothelial cells, the mechanism of which is linked to the inhibition of Akt activation. Ginkgolide B may be a multiple-target drug that exerts protective effects in ox-LDL-treated human umbilical vein endothelial cells. PMID- 24069346 TI - Behavioral and metabolic effects of the atypical antipsychotic ziprasidone on the nematode Caenorhabditis elegans. AB - Atypical antipsychotics are associated with metabolic syndrome, primarily associated with weight gain. The effects of Ziprasidone, an atypical antipsychotic, on metabolic syndrome has yet to be evaluated. Here in, we evaluated lipid accumulation and behavioral changes in a new experimental model, the nematode Caenorhabditis elegans (C. elegans). Behavioral parameters in the worms were evaluated 24 h after Ziprasidone treatment. Subsequently, lipid accumulation was examined using Nile red, LipidTox green and BODIPY labeling. Ziprasidone at 40 uM for 24 h effectively decreased the fluorescence labeling of all markers in intestinal cells of C. elegans compared to control (0.16% dimethyl sulfoxide). Ziprasidone did not alter behaviors related to energetic balance, such as pharynx pumping, defecation cycles and movement. There was, however, a reduction in egg-production, egg-laying and body-length in nematodes exposed to Ziprasidone without any changes in the progression of larval stages. The serotoninergic pathway did not appear to modulate Ziprasidone's effects on Nile red fluorescence. Additionally, Ziprasidone did not alter lipid accumulation in daf-16 or crh-1 deletion mutants (orthologous of the transcription factors DAF-16 and CREB, respectively). These results suggest that Ziprasidone alters reproductive behavior, morphology and lipid reserves in the intestinal cells of C. elegans. Our results highlight that the DAF-16 and CREB transcription factors are essential for Ziprasidone-induced fat store reduction. PMID- 24069347 TI - The structural basis of Erwinia rhapontici isomaltulose synthase. AB - Sucrose isomerase NX-5 from Erwiniarhapontici efficiently catalyzes the isomerization of sucrose to isomaltulose (main product) and trehalulose (by product). To investigate the molecular mechanism controlling sucrose isomer formation, we determined the crystal structures of native NX-5 and its mutant complexes E295Q/sucrose and D241A/glucose at 1.70 A, 1.70 A and 2.00 A, respectively. The overall structure and active site architecture of NX-5 resemble those of other reported sucrose isomerases. Strikingly, the substrate binding mode of NX-5 is also similar to that of trehalulose synthase from Pseudomonasmesoacidophila MX-45 (MutB). Detailed structural analysis revealed the catalytic RXDRX motif and the adjacent 10-residue loop of NX-5 and isomaltulose synthase PalI from Klebsiella sp. LX3 adopt a distinct orientation from those of trehalulose synthases. Mutations of the loop region of NX-5 resulted in significant changes of the product ratio between isomaltulose and trehalulose. The molecular dynamics simulation data supported the product specificity of NX-5 towards isomaltulose and the role of the loop(330-339) in NX-5 catalysis. This work should prove useful for the engineering of sucrose isomerase for industrial carbohydrate biotransformations. PMID- 24069348 TI - JARID1A, JMY, and PTGER4 polymorphisms are related to ankylosing spondylitis in Chinese Han patients: a case-control study. AB - Susceptibility to ankylosing spondylitis (AS) is largely genetically determined. JARID1A, JMY and PTGER4 have recently been found to be associated with AS in patients of western European descent. We aim to examine the influence of JARID1A, JMY, and PTGER4 polymorphisms on the susceptibility to and the severity of ankylosing spondylitis in Chinese ethnic majority Han population. This work can lead the clinical doctors to intervene earlier. Blood samples were drawn from 396 AS patients and 404 unrelated healthy controls. Both the AS patients and the controls are Han Chinese. The AS patients are classified based on the severity of the disease. Thirteen tag single nucleotide polymorphisms (tagSNPs) in JARID1A, JMY and PTGER4 are selected and genotyped. Frequencies of different genotypes and alleles are analyzed among the different severity AS patients and the controls. The rs2284336 SNP in JARID1A, the rs16876619 and rs16876657 SNPs in JMY are associated with susceptibility of AS. The rs11062357 SNP in JARID1A, the rs2607142 SNP in JMY and rs10440635 in PTGER4 are related to severity of AS. Haplotype analyses indicate PTGER4 is related to susceptibility to AS; JARID1A and JMY are related to severity of AS. PMID- 24069349 TI - Surface glycosylation profiles of urine extracellular vesicles. AB - Urinary extracellular vesicles (uEVs) are released by cells throughout the nephron and contain biomolecules from their cells of origin. Although uEV associated proteins and RNA have been studied in detail, little information exists regarding uEV glycosylation characteristics. Surface glycosylation profiling by flow cytometry and lectin microarray was applied to uEVs enriched from urine of healthy adults by ultracentrifugation and centrifugal filtration. The carbohydrate specificity of lectin microarray profiles was confirmed by competitive sugar inhibition and carbohydrate-specific enzyme hydrolysis. Glycosylation profiles of uEVs and purified Tamm Horsfall protein were compared. In both flow cytometry and lectin microarray assays, uEVs demonstrated surface binding, at low to moderate intensities, of a broad range of lectins whether prepared by ultracentrifugation or centrifugal filtration. In general, ultracentrifugation-prepared uEVs demonstrated higher lectin binding intensities than centrifugal filtration-prepared uEVs consistent with lesser amounts of co purified non-vesicular proteins. The surface glycosylation profiles of uEVs showed little inter-individual variation and were distinct from those of Tamm Horsfall protein, which bound a limited number of lectins. In a pilot study, lectin microarray was used to compare uEVs from individuals with autosomal dominant polycystic kidney disease to those of age-matched controls. The lectin microarray profiles of polycystic kidney disease and healthy uEVs showed differences in binding intensity of 6/43 lectins. Our results reveal a complex surface glycosylation profile of uEVs that is accessible to lectin-based analysis following multiple uEV enrichment techniques, is distinct from co-purified Tamm Horsfall protein and may demonstrate disease-specific modifications. PMID- 24069350 TI - The prevalence of nine genetic disorders in a dog population from Belgium, the Netherlands and Germany. AB - The objective of this study was to screen a dog population from Belgium, the Netherlands and Germany for the presence of mutant alleles associated with hip dysplasia (HD), degenerative myelopathy (DM), exercise-induced collapse (EIC), neuronal ceroid lipofuscinosis 4A (NCL), centronuclear myopathy (HMLR), mucopolysaccharidosis VII (MPS VII), myotonia congenita (MG), gangliosidosis (GM1) and muscular dystrophy (Duchenne type) (GRMD). Blood samples (K3EDTA) were collected for genotyping with Kompetitive Allele Specific PCR (n = 476). Allele and genotype frequencies were calculated in those breeds with at least 12 samples (n = 8). Hardy-Weinberg equilibrium was tested. Genetic variation was identified for 4 out of 9 disorders: mutant alleles were found in 49, 15, 3 and 2 breeds for HD, DM, EIC and NCL respectively. Additionally, mutant alleles were identified in crossbreeds for both HD and EIC. For HD, DM, EIC and NCL mutant alleles were newly discovered in 43, 13, 2 and 1 breed(s), respectively. In 9, 2 and 1 breed(s) for DM, EIC and NCL respectively, the mutant allele was detected, but the respective disorder has not been reported in those breeds. For 5 disorders (HMLR, MPS VII, MG, GM1, GRMD), the mutant allele could not be identified in our population. For the other 4 disorders (HD, DM, EIC, NCL), prevalence of associated mutant alleles seems strongly breed dependent. Surprisingly, mutant alleles were found in many breeds where the disorder has not been reported to date. PMID- 24069351 TI - Hyaluronan-CD44 interaction promotes growth of decidual stromal cells in human first-trimester pregnancy. AB - Hyaluronan (HA) and its receptor CD44 are expressed at the maternal-fetal interface, but its role in early pregnancy remains unclear. Here, we found that primary decidual stromal cells (DSCs) continuously secreted HA and expressed its receptor CD44. Pregnancy-associated hormones up-regulated HA synthetase (HAS) 2 transcription and HA release from DSCs. High molecular weight-HA (HMW-HA), but not medium molecular weight (MMW-HA) or low molecular weight (LMW-HA), promoted proliferation and inhibited apoptosis of DSCs in a CD44-dependent manner. The in cell Western analysis revealed HMW-HA activated PI3K/AKT and mitogen-activated protein kinase (MAPK)/ERK1/2 signaling pathways time-dependently. Blocking these pathways by specific inhibitor LY294002 or U0126 abrogated HMW-HA-regulated DSc proliferation and apoptosis. Finally, we have found that HA content, HA molecular weight, HAS2 mRNA level, and CD44 expression were significantly decreased in DSCs from unexplained miscarriage compared with the normal pregnancy. Collectively, our results indicate that higher level and greater molecular mass of HA at maternal-fetal interface contributes to DSc growth and maintenance of DSCs in human early pregnancy. PMID- 24069352 TI - Prospectively collected characteristics of adult patients, their consultations and outcomes as they report breathlessness when presenting to general practice in Australia. AB - INTRODUCTION: Breathlessness is a subjective sensation, so understanding its impacts requires patients' reports, including prospective patient-defined breathlessness as a reason for presenting to general practitioners (GP).The aim of this study was to define the prevalence of breathlessness as a reason for GP consultations while defining the clinico-demographic factors of these patients and the characteristics and outcomes of those consultations. METHODS: Using nine years of the Family Medicine Research Centre database of 100 consecutive encounters from 1,000 practices annually, the patient-defined reason for encounter 'breathlessness' was explored using prospectively collected data in people >= 18 years with clinical data coded using the International Classification for Primary Care V2. Dichotomous variables were analysed using chi square and 95% confidence intervals calculated using Kish's formula for a single stage clustered design. RESULTS: Of all the 755,729 consultations collected over a nine year period from 1 April, 2000, 7255 included breathlessness as a reason for encounter (0.96%; 95% CI 0.93 to 0.99) most frequently attributed to chronic obstructive pulmonary disease. Only 48.3% of GPs saw someone reporting breathlessness. The proportion of consultations with breathlessness increased with age. Breathlessness trebled the likelihood that the consultation occurred in the community rather than the consulting room (p<0.0001) and increased 2.5 fold the likelihood of urgent referral to hospital (p<0.0001). Of those with breathlessness, 12% had undiagnosed breathlessness at the end of the consultation (873/7255) with higher likelihood of being younger females. DISCUSSION: Breathlessness is a prevalent symptom in general practitioner. Such prevalence enables future research focused on understanding the temporal pattern of breathlessness and the longitudinal care offered to, and outcomes for these patients, including those who leave the consultation without a diagnosis. PMID- 24069353 TI - Incongruence between nuclear and chloroplast DNA phylogenies in pedicularis section Cyathophora (Orobanchaceae). AB - Pedicularis section Cyathophora is a monophyletic group characterized by perfoliate leaf and/or bract bases at each node. This section comprises four series, corresponding to four general corolla types of Pedicularis, i.e. toothless, toothed, beaked and long-tubed corollas. In this study, we aim to reconstruct a comprehensive phylogeny of section Cyathophora, and compare phylogenetic incongruence between nuclear and chloroplast datasets. Sixty-seven accessions belonging to section Cyathophora and 9 species for other Pedicularis were sampled, and one nuclear gene (nrITS) and four chloroplast genes (matK, rbcL, trnH-psbA and trnL-F) were sequenced. Phylogenetic analyses show that the topologies and networks inferred from nrITS and the concatenated chloroplast datasets were incongruent, and the nrITS phylogenies and network agreed with the morphology-based taxonomy to some degree. The chloroplast genome of two Sichuan samples of P. cyathophylloides (E4 and E5) may show introgression from an ancestor of P. cyathophylla. Neither the nrITS dataset nor the concatenated chloroplast dataset were able to adequately resolve relationships among species in the series Reges; this is most likely due to incomplete lineage sorting and/or introgression/hybridization. The nrITS phylogeny indicates the beakless (toothed and toothless) and beaked galeas may have evolved independently within section Cyathophora, and the chloroplast phylogeny reveals that the long corolla tube with beaked galea is derived from the short one. PMID- 24069354 TI - Deletion of the vaccinia virus gene A46R, encoding for an inhibitor of TLR signalling, is an effective approach to enhance the immunogenicity in mice of the HIV/AIDS vaccine candidate NYVAC-C. AB - Viruses have developed strategies to counteract signalling through Toll-like receptors (TLRs) that are involved in the detection of viruses and induction of proinflammatory cytokines and IFNs. Vaccinia virus (VACV) encodes A46 protein which disrupts TLR signalling by interfering with TLR: adaptor interactions. Since the innate immune response to viruses is critical to induce protective immunity, we studied whether deletion of A46R gene in a NYVAC vector expressing HIV-1 Env, Gag, Pol and Nef antigens (NYVAC-C) improves immune responses against HIV-1 antigens. This question was examined in human macrophages and in mice infected with a single A46R deletion mutant of the vaccine candidate NYVAC-C (NYVAC-C-DeltaA46R). The viral gene A46R is not required for virus replication in primary chicken embryo fibroblast (CEF) cells and its deletion in NYVAC-C markedly increases TNF, IL-6 and IL-8 secretion by human macrophages. Analysis of the immune responses elicited in BALB/c mice after DNA prime/NYVAC boost immunization shows that deletion of A46R improves the magnitude of the HIV-1 specific CD4 and CD8 T cell immune responses during adaptive and memory phases, maintains the functional profile observed with the parental NYVAC-C and enhances anti-gp120 humoral response during the memory phase. These findings establish the immunological role of VACV A46R on innate immune responses of macrophages in vitro and antigen-specific T and B cell immune responses in vivo and suggest that deletion of viral inhibitors of TLR signalling is a useful approach for the improvement of poxvirus-based vaccine candidates. PMID- 24069355 TI - Novel spontaneous deletion of artemis exons 10 and 11 in mice leads to T- and B cell deficiency. AB - Here we describe a novel, spontaneous, 4035 basepairs long deletion in the DNA cross-link repair 1C (Dclre1c)-locus in C57BL/6-mice, which leads to loss of exons 10 and 11 of the gene encoding for Artemis, a protein involved into V(D) J recombination of antigen receptors of T and B cells. While several spontaneous mutations of Artemis have been described to cause SCID in humans, in mice, only targeted deletions by knockout technology are known to cause the same phenotype so far. The deletion we observed causes a loss of Artemis function in the C57BL/6 strain and, consequently, the absence of T and B cells, in presence of normal numbers of NK cells and cells of the myeloid lineage. Thus, for the first time we present T(-)B(-)NK(+) severe combined immunodeficiency (SCID) phenotype after spontaneously occurring modification of Artemis gene in mice. Our mouse model may serve as a valuable tool to study mechanisms as well as potential therapies of SCID in humans. PMID- 24069356 TI - Stress mediators and immune dysfunction in patients with acute cerebrovascular diseases. AB - BACKGROUND: Post-stroke immune depression contributes to the development of infections which are major complications after stroke. Previous experimental and clinical studies suggested that humoral stress mediators induce immune dysfunction. However, prospective clinical studies testing this concept are missing and no data exists for other cerebrovascular diseases including intracerebral hemorrhage (ICH) and TIA. METHODS: We performed a prospective clinical study investigating 166 patients with TIA, ischemic and hemorrhagic stroke. We measured a broad panel of stress mediators, leukocyte subpopulations, cytokines and infection markers from hospital admission to day 7 and on follow-up after 2-3 months. Multivariate regression analyses detected independent predictors of immune dysfunction and bacterial infections. ROC curves were used to test the diagnostic value of these parameters. RESULTS: Only severe ischemic strokes and ICH increased some catecholamine metabolites, ACTH and cortisol levels. Immunodysfunction was eminent already on hospital admission after large brain lesions with lymphocytopenia as a key feature. None of the stress mediators was an independent predictor of lymphocytopenia or infections. However, lymphocytopenia on hospital admission was detected as an independent explanatory variable of later infections. NIHSSS and lymphocytopenia on admission were excellent predictors of infection. CONCLUSIONS: Our results question the present pathophysiological concept of stress-hormone mediated immunodysfunction after stroke. Early lymphocytopenia was identified as an early independent predictor of post-stroke infections. Absence of lymphocytopenia may serve as a negative predictive marker for stratification for early antibiotic treatment. PMID- 24069357 TI - Enhancement of host immune responses by oral vaccination to Salmonella enterica serovar Typhimurium harboring both FliC and FljB flagella. AB - Flagellin, the structural component of the flagellar filament in various motile bacteria, can contribute to the activation of NF-kappaB and proinflammatory cytokine expression during the innate immune response in host cells. Thus, flagellin proteins represent a particularly attractive target for the development of vaccine candidates. In this study, we investigated the immune response by increasing the flagella number in the iacP mutant strain and the adjuvant activity of the flagellin component FljB of Salmonella enterica serovar Typhimurium. We found that the iacP mutant strain expresses two flagellin proteins (FliC and FljB), which result in increased NF-kappaB-dependent gene expression in bone marrow derived macrophages. Using an oral immunization mouse model, we observed that the administration of a live attenuated S. typhimurium BRD509 strain expressing the FliC and FljB flagellins induced significantly enhanced flagellin-specific IgG responses in the systemic compartment. The mice immunized with the recombinant attenuated S. typhimurium strain that has two types of flagella were protected from lethal challenge with the Salmonella SL1344 strain. These results indicate that overexpression of flagella in the iacP mutant strain enhance the induction of an antigen-specific immune responses in macrophage cell, and both the FliC and FljB flagellar filament proteins-producing S. typhimurium can induce protective immune responses against salmonellosis. PMID- 24069358 TI - The Prp19 complex directly functions in mitotic spindle assembly. AB - The conserved Prp19 (pre-RNA processing 19) complex is required for pre-mRNA splicing in eukaryotic nuclei. Recent RNAi screens indicated that knockdown of Prp19 complex subunits strongly delays cell proliferation. Here we show that knockdown of the smallest subunit, BCAS2/Spf27, destabilizes the entire complex and leads to specific mitotic defects in human cells. These could result from splicing failures in interphase or reflect a direct function of the complex in open mitosis. Using Xenopus extracts, in which cell cycle progression and spindle formation can be reconstituted in vitro, we tested Prp19 complex functions during a complete cell cycle and directly in open mitosis. Strikingly, immunodepletion of the complex either before or after interphase significantly reduces the number of intact spindles, and increases the percentage of spindles with lower microtubule density and impaired metaphase alignment of chromosomes. Our data identify the Prp19 complex as the first spliceosome subcomplex that directly contributes to mitosis in vertebrates independently of its function in interphase. PMID- 24069359 TI - Role of efflux pumps and intracellular thiols in natural antimony resistant isolates of Leishmania donovani. AB - BACKGROUND: In view of the recent upsurge in the phenomenon of therapeutic failure, drug resistance in Leishmania, developed under natural field conditions, has become a great concern yet little understood. Accordingly, the study of determinants of antimony resistance is urgently warranted. Efflux transporters have been reported in Leishmania but their role in clinical resistance is still unknown. The present study was designed to elucidate the mechanism of natural antimony resistance in L. donovani field isolates by analyzing the functionality of efflux pump(s) and expression profiles of known genes involved in transport and thiol based redox metabolism. METHODOLOGY/PRINCIPAL FINDINGS: We selected 7 clinical isolates (2 sensitive and 5 resistant) in addition to laboratory sensitive reference and SbIII resistant mutant strains for the present study. Functional characterization using flow cytometry identified efflux pumps that transported substrates of both P-gp and MRPA and were inhibited by the calmodulin antagonist trifluoperazine. For the first time, verapamil sensitive efflux pumps for rhodamine 123 were observed in L. donovani that were differentially active in resistant isolates. RT-PCR confirmed the over-expression of MRPA in isolates with high resistance index only. Resistant isolates also exhibited consistent down regulation of AQP1 and elevated intracellular thiol levels which were accompanied with increased expression of ODC and TR genes. Interestingly, gamma-GCS is not implicated in clinical resistance in L. donovani isolates. CONCLUSIONS/SIGNIFICANCE: Here we demonstrate for the first time, the role of P gp type plasma membrane efflux transporter(s) in antimony resistance in L. donovani field isolates. Further, decreased levels of AQP1 and elevated thiols levels have emerged as biomarkers for clinical resistance. PMID- 24069360 TI - Virulence potential and genome-wide characterization of drug resistant Streptococcus pneumoniae clones selected in vivo by the 7-valent pneumococcal conjugate vaccine. AB - We used mouse models of pneumococcal colonization and disease combined with full genome sequencing to characterize three major drug resistant clones of S. pneumoniae that were recovered from the nasopharynx of PCV7-immunized children in Portugal. The three clones--serotype 6A (ST2191), serotype 15A (ST63) and serotype 19A (ST276) carried some of the same drug resistance determinants already identified in nasopharyngeal isolates from the pre-PCV7 era. The three clones were able to colonize efficiently the mouse nasopharyngeal mucosa where populations of these pneumococci were retained for as long as 21 days. During this period, the three clones were able to asymptomatically invade the olfactory bulbs, brain, lungs and the middle ear mucosa and established populations in these tissues. The virulence potential of the three clones was poor even at high inoculum (10(5) CFU per mouse) concentrations in the mouse septicemia model and was undetectable in the pneumonia model. Capsular type 3 transformants of clones 6A and 19A prepared in the laboratory produced lethal infection at low cell concentration (10(3) CFU per mouse) but the same transformants became impaired in their potential to colonize, indicating the importance of the capsular polysaccharide in both disease and colonization. The three clones were compared to the genomes of 56 S. pneumoniae strains for which sequence information was available in the public databank. Clone 15A (ST63) only differed from the serotype 19F clone G54 in a very few genes including serotype so that this clone may be considered the product of a capsular switch. While no strain with comparable degree of similarity to clone 19A (ST276) was found among the sequenced isolates, by MLST this clone is a single locust variant (SLV) of Denmark14-ST230 international clone. Clone 6A (ST2191) was most similar to the penicillin resistant Hungarian serotype 19A clone. PMID- 24069361 TI - Possible role of intestinal fatty acid oxidation in the eating-inhibitory effect of the PPAR-alpha agonist Wy-14643 in high-fat diet fed rats. AB - PPAR-alpha plays a key role in lipid metabolism; it enhances fatty acid oxidation (FAO) and ketogenesis. Pharmacological PPAR-alpha activation improves insulin sensitivity and reduces food intake, but its mechanisms of action remain unknown. We here report that intraperitoneal (IP) administration of the PPAR-alpha agonist Wy-14643 (40 mg/kg BW) reduced food intake in adult male rats fed a high-fat diet (HFD, 49% of the energy) mainly through an increase in the latency to eat after injection, and without inducing a conditioned taste avoidance. Also, IP administered Wy-14643 caused an acute (the first 60 min) decrease in the respiratory quotient (RQ) and an increase in hepatic portal vein beta hydroxybutyrate level (at 35 min) without affecting plasma non-esterified fatty acids. Given the known stimulatory effect of PPAR-alpha on FAO and ketogenesis, we measured the protein expression level of carnitine palmitoyltransferase-1 (CPT 1A) and mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMG-CoAS2), two key enzymes for FAO and ketogenesis, respectively, in liver, duodenum and jejunum. Wy-14643 induced a significant increase in the expression of CPT 1A in the jejunum and duodenum and of HMG-CoAS2 in the jejunum, but neither CPT 1A nor HMG-CoAS2 expression was increased in the liver. The induction of CPT 1A and HMG CoAS2 expression was associated with a decrease in the lipid droplet content selectively in the jejunum. Our findings indicate that Wy-14643 stimulates FAO and ketogenesis in the intestine, in particular in the jejunum, rather than in the liver, thus supporting the hypothesis that PPAR-alpha activation inhibits eating by stimulating intestinal FAO. PMID- 24069362 TI - Citral is renoprotective for focal segmental glomerulosclerosis by inhibiting oxidative stress and apoptosis and activating Nrf2 pathway in mice. AB - The pathogenesis of focal segmental glomerulosclerosis (FSGS) is considered to be associated with oxidative stress, mononuclear leukocyte recruitment and infiltration, and matrix production and/or matrix degradation, although the exact etiology and pathogenic pathways remain to be determined. Establishment of a pathogenesis-based therapeutic strategy for the disease is clinically warranted. Citral (3,7-dimethyl-2,6-octadienal), a major active compound in Litseacubeba, a traditional Chinese herbal medicine, can inhibit oxidant activity, macrophage and NF-kappaB activation. In the present study, first, we used a mouse model of FSGS with the features of glomerular epithelial hyperplasia lesions (EPHLs), a key histopathology index of progression of FSGS, peri-glomerular inflammation, and progressive glomerular hyalinosis/sclerosis. When treated with citral for 28 consecutive days at a daily dose of 200 mg/kg of body weight by gavage, the FSGS mice showed greatly reduced EPHLs, glomerular hyalinosis/sclerosis and peri glomerular mononuclear leukocyte infiltration, suggesting that citral may be renoprotective for FSGS and act by inhibiting oxidative stress and apoptosis and early activating the Nrf2 pathway. Meanwhile, a macrophage model involved in anti oxidative and anti-inflammatory activities was employed and confirmed the beneficial effects of citral on the FSGS model. PMID- 24069363 TI - Fenretinide corrects the imbalance between omega-6 to omega-3 polyunsaturated fatty acids and inhibits macrophage inflammatory mediators via the ERK pathway. AB - We previously identified Fragile X-related protein 1 (FXR1) as an RNA-binding protein involved in the post-transcriptional control of TNF and other cytokines in macrophages. Macrophages derived from FXR1-KO mice overexpress several inflammatory cytokines including TNF. Recently, we showed that fenretinide (4HPR) is able to inhibit several inflammatory cytokines in the lungs of cystic fibrosis mice, which also have abnormal immune responses. Therefore, we hypothesized that 4HPR might also be able to downregulate excessive inflammation even in macrophages with ablated FXR1. Indeed, our results demonstrate that 4HPR inhibited the excessive production of inflammatory mediators, including TNF, IL 6, CCL2 and CCL-5 in LPS-stimulated FXR1-KO macrophages, by selectively inhibiting phosphorylation of ERK1/2, which is naturally more phosphorylated in FXR1-KO cells. We also found that LPS stimulation of FXR1-KO macrophages led to significantly higher ratio of arachidonic acid/docosahexaenoic acid than observed in FXR1-WT macrophages. Interestingly, treatment with 4HPR was associated with the normalization of arachidonic acid/docosahexaenoic acid ratio in macrophages, which we found to impact phosphorylation of ERK1/2. Overall, this study shows for the first time that 4HPR modulates inflammatory cytokine expression in macrophages by correcting a phospholipid-bound fatty acid imbalance that impacts the phosphorylation of ERK1/2. PMID- 24069364 TI - Interferon signature in the blood in inflammatory common variable immune deficiency. AB - About half of all subjects with common variable immune deficiency (CVID) are afflicted with inflammatory complications including hematologic autoimmunity, granulomatous infiltrations, interstitial lung disease, lymphoid hyperplasia and/or gastrointestinal inflammatory disease. The pathogenesis of these conditions is poorly understood but singly and in aggregate, these lead to significantly increased (11 fold) morbidity and mortality, not experienced by CVID subjects without these complications. To explore the dysregulated networks in these subjects, we applied whole blood transcriptional profiling to 91 CVID subjects, 47 with inflammatory conditions and 44 without, in comparison to subjects with XLA and healthy controls. As compared to other CVID subjects, males with XLA or healthy controls, the signature of CVID subjects with inflammatory complications was distinguished by a marked up-regulation of IFN responsive genes. Chronic up-regulation of IFN pathways is known to occur in autoimmune disease due to activation of TLRs and other still unclarified cytoplasmic sensors. As subjects with inflammatory complications were also more likely to be lymphopenic, have reduced B cell numbers, and a greater reduction of B, T and plasma cell networks, we suggest that more impaired adaptive immunity in these subjects may lead to chronic activation of innate IFN pathways in response to environmental antigens. The unbiased use of whole blood transcriptome analysis may provides a tool for distinguishing CVID subjects who are at risk for increased morbidity and earlier mortality. As more effective therapeutic options are developed, whole blood transcriptome analyses could also provide an efficient means of monitoring the effects of treatment of the inflammatory phenotype. PMID- 24069365 TI - Khellin and visnagin differentially modulate AHR signaling and downstream CYP1A activity in human liver cells. AB - Khellin and visnagin are two furanochromones that can be frequently found in ethnomedical formulations in Asia and the Middle East. Both compounds possess anti-inflammatory and analgesic properties, therefore modern medicine uses these compounds or structurally related derivatives for treatment of vitiligo, bronchial asthma and renal colics. Despite their frequent usage, the potential toxic properties of visnagin and khellin are not well characterized up-to-now. Many natural compounds modulate the expression and activity of cytochrome P450 1A1 (CYP1A1), which is well-known to bioactivate pro-carcinogens. The expression of this enzyme is controlled by the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor and regulator of drug metabolism. Here, we investigated the influence of both furanochromones on AHR signaling in human HepG2 hepatocarcinoma cells and primary human hepatocytes. Both compounds transactivated xenobiotic response element (XRE)-driven reporter gene activity in a dose-dependent manner and induced CYP1A1 transcription in HepG2 cells and primary hepatocytes. The latter was abolished in presence of a specific AHR antagonist. CYP1A enzyme activity assays done in HepG2 cells and primary hepatocytes revealed an inhibition of enzyme activity by both furanochromones, which may become relevant regarding the metabolism of xenobiotics and co administered therapeutic drugs. The observed induction of several other members of the AHR gene battery, whose gene products are involved in regulation of cell growth, differentiation and migration, indicates that a further toxicological characterization of visnagin and khelllin is urgently required in order to minimize potential drug-drug interactions and other toxic side-effects that may occur during therapeutic usage of these furanochromones. PMID- 24069366 TI - Actin structure-dependent stepping of myosin 5a and 10 during processive movement. AB - How myosin 10, an unconventional myosin, walks processively along actin is still controversial. Here, we used single molecule fluorescence techniques, TIRF and FIONA, to study the motility and the stepping mechanism of dimerized myosin 10 heavy-meromyosin-like fragment on both single actin filaments and two-dimensional F-actin rafts cross-linked by fascin or alpha-actinin. As a control, we also tracked and analyzed the stepping behavior of the well characterized processive motor myosin 5a. We have shown that myosin 10 moves processively along both single actin filaments and F-actin rafts with a step size of 31 nm. Moreover, myosin 10 moves more processively on fascin-F-actin rafts than on alpha-actinin-F actin rafts, whereas myosin 5a shows no such selectivity. Finally, on fascin-F actin rafts, myosin 10 has more frequent side steps to adjacent actin filaments than myosin 5a in the F-actin rafts. Together, these results reveal further single molecule features of myosin 10 on various actin structures, which may help to understand its cellular functions. PMID- 24069367 TI - Time to intubation is associated with outcome in patients with community-acquired pneumonia. AB - INTRODUCTION: It has been suggested that delayed intensive care unit (ICU) transfer is associated with increased mortality for patients with community acquired pneumonia (CAP). However, ICU admission policies and patient epidemiology vary widely across the world depending on local hospital practices and organizational constraints. We hypothesized that the time from the onset of CAP symptoms to invasive mechanical ventilation could be a relevant prognostic factor. METHODS: One hundred patients with a CAP and necessitating invasive mechanical ventilation were included. Prospectively collected data were retrospectively analysed. Two study groups were identified based on the time of the initiation of invasive mechanical ventilation (rapid respiratory failure requiring mechanical ventilation within 72 h of the onset of CAP and progressive respiratory failure requiring invasive mechanical ventilation 4 or more days after the onset of CAP). RESULTS: Excepting more COPD patients in the rapid respiratory failure group and more patients with diabetes in the progressive respiratory failure group, these patients had similar characteristics. The overall in-hospital mortality rate was 28% in the rapid respiratory failure group and 51% in the progressive respiratory failure group (P = 0.03). The ICU and the day 30 mortality rates were higher in the progressive respiratory failure group (47% vs. 23%, P = 0.02; and 37.7% vs. 21.3%, P = 0.03; respectively). After adjusting for the propensity score and other potential confounding factors, progressive respiratory failure remained associated with hospital mortality only after 12 days of invasive mechanical ventilation. CONCLUSIONS: This study suggested that the duration or delay in the time to intubation from the onset of CAP symptoms was associated with the outcomes in those patients who ultimately required invasive mechanical ventilation. PMID- 24069368 TI - The relationship between self-awareness of attentional status, behavioral performance and oscillatory brain rhythms. AB - High-level cognitive factors, including self-awareness, are believed to play an important role in human visual perception. The principal aim of this study was to determine whether oscillatory brain rhythms play a role in the neural processes involved in self-monitoring attentional status. To do so we measured cortical activity using magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) while participants were asked to self-monitor their internal status, only initiating the presentation of a stimulus when they perceived their attentional focus to be maximal. We employed a hierarchical Bayesian method that uses fMRI results as soft-constrained spatial information to solve the MEG inverse problem, allowing us to estimate cortical currents in the order of millimeters and milliseconds. Our results show that, during self-monitoring of internal status, there was a sustained decrease in power within the 7-13 Hz (alpha) range in the rostral cingulate motor area (rCMA) on the human medial wall, beginning approximately 430 msec after the trial start (p < 0.05, FDR corrected). We also show that gamma-band power (41-47 Hz) within this area was positively correlated with task performance from 40-640 msec after the trial start (r = 0.71, p < 0.05). We conclude: (1) the rCMA is involved in processes governing self-monitoring of internal status; and (2) the qualitative differences between alpha and gamma activity are reflective of their different roles in self monitoring internal states. We suggest that alpha suppression may reflect a strengthening of top-down interareal connections, while a positive correlation between gamma activity and task performance indicates that gamma may play an important role in guiding visuomotor behavior. PMID- 24069369 TI - No evidence for reproductive isolation through sexual conflict in the bulb mite Rhizoglyphus robini. AB - Sexual conflict leading to sexual antagonistic coevolution has been hypothesized to drive reproductive isolation in allopatric populations and hence lead to speciation. However, the generality of this speciation mechanism is under debate. We used experimental evolution in the bulb mite Rhizoglyphusrobini to investigate whether sexual conflict promotes reproductive isolation measured comprehensively to include all possible pre- and post-zygotic mechanisms. We established replicate populations in which we either enforced monogamy, and hence removed sexual conflict by making male and female evolutionary interests congruent, or allowed promiscuity. After 35 and 45 generations of experimental evolution, we found no evidence of reproductive isolation between the populations in any of the mating systems. Our results indicate that sexual conflict does not necessarily drive fast reproductive isolation and it may not be a ubiquitous mechanism leading to speciation. PMID- 24069370 TI - Insulin-like growth factor binding protein-2 level is increased in blood of lung cancer patients and associated with poor survival. AB - BACKGROUND: We recently showed that IGFBP2 is overexpressed in primary lung cancer tissues. This study aims to determine whether IGFBP2 is elevated in blood samples of lung cancer patients and whether its level is associated with clinical outcomes. METHODOLOGY/PRINCIPAL FINDINGS: Plasma IGFBP2 levels were determined blindly by enzyme-linked immunosorbent assay in 80 lung cancer patients and 80 case-matched healthy controls for comparison. We analyzed blood samples for IGFBP2 levels from an additional 84 patients with lung cancer and then tested for associations between blood IGFBP2 levels and clinical parameters in all 164 lung cancer patients. All statistical tests were two-sided and differences with p<0.05 were considered significant. The mean plasma concentration of IGFBP2 in lung cancer patients was significantly higher than that in healthy controls (388.12 +/ 261.00 ng/ml vs 219.30 +/- 172.84 ng/ml, p<0.001). IGFBP2 was increased in all types of lung cancer, including adenocarcinoma, squamous cell cancer, and small cell cancer, regardless of patients' age, sex, or smoking status. IGFBP2 levels were mildly but significantly associated with tumor size and were significantly higher in stage IV than stage I or III disease. A multivariate analysis showed that lung cancer patients whose blood IGFBP2 was higher than 160.9 ng/ml had a poor survival outcome, with a hazard ratio of 8.76 (95% CI 1.12-68.34, p=0.038 after adjustment for tumor size, pathology, and stage). The median survival time for patients with blood IGFBP2 >160.9 ng/ml is 15.1 months; whereas median survival time was 128.2 months for the patients whose blood IGFBP2 was <= 160.9 ng/ml (p =0.0002). CONCLUSIONS/SIGNIFICANCE: Blood IGFBP2 is significantly increased in lung cancer patients. A high circulating level of IGFBP2 is significantly associated with poor survival, suggesting that blood IGFBP2 levels could be a prognostic biomarker for lung cancer. PMID- 24069371 TI - Helicobacter pylori infection synergizes with three inflammation-related genetic variants in the GWASs to increase risk of gastric cancer in a Chinese population. AB - BACKGROUND: Three recent genome-wide association studies (GWASs) have reported that three SNPs (rs4072037, rs13361707 and rs2274223) located on genes related to host inflammatory response are significantly associated with susceptibility to gastric cancer (GC) in Chinese populations. Helicobacter pylori infection is also an important risk factor for GC through causing inflammatory response in the gastric mucosa. However, no study has established whether there are potential gene-environment interactions between these genetic variants and H. pylori infection to the risk of GC. METHODS: We genotyped three polymorphisms (rs4072037 at 1q22, rs13361707 at 5p13, and rs2274223 at 10q23) in 335 Chinese gastric adenocarcinoma patients and 334 controls. H. pylori serology was examined by enzyme-linked immunosorbent assay. Multivariable logistic regression models were used to evaluate the association between the variables and GC risk. RESULTS: We confirmed that the three SNPs (rs4072037, rs13361707 and rs2274223) were significantly associated with GC susceptibility. H. pylori infection also significantly increased the risk of GC. Furthermore, there were joint effects between H. pylori infection and the three SNPs on the risk of GC. The most elevated risk of GC was found in subjects with H. pylori seropositivity and AA genotypes for rs4072037 [odds ratio (OR), 3.95; 95% confidence interval (CI), 2.29-6.79], H. pylori seropositivity and CT/CC genotypes for rs13361707 (OR, 2.68; 95% CI, 1.62-4.43), H. pylori seropositivity and AG/GG genotypes for rs2274223 (OR, 2.45; 95% CI, 1.55-3.88) compared with those with H. pylori seronegativity and other genotypes of each SNP. Significant interactions were observed between H. pylori seropositivity and the three SNPs (all P(G* E) <0.05) to the risk of GC. CONCLUSION: These findings indicate that the three SNPs (rs4072037, rs13361707 and rs2274223) identified in the GWASs may interact with H. pylori infection to increase the risk of GC. PMID- 24069372 TI - Claudin-3 overexpression increases the malignant potential of colorectal cancer cells: roles of ERK1/2 and PI3K-Akt as modulators of EGFR signaling. AB - The altered expressions of claudin proteins have been reported during the tumorigenesis of colorectal cancer. However, the molecular mechanisms that regulate these events in this cancer type are poorly understood. Here, we report that epidermal growth factor (EGF) increases the expression of claudin-3 in human colorectal adenocarcinoma HT-29 cells. This increase was related to increased cell migration and the formation of anchorage-dependent and anchorage-independent colonies. We further showed that the ERK1/2 and PI3K-Akt pathways were involved in the regulation of these effects because specific pharmacological inhibition blocked these events. Genetic manipulation of claudin-1 and claudin-3 in HT-29 cells showed that the overexpression of claudin-1 resulted in decreased cell migration; however, migration was not altered in cells that overexpressed claudin 3. Furthermore, the overexpression of claudin-3, but not that of claudin-1, increased the tight junction-related paracellular flux of macromolecules. Additionally, an increased formation of anchorage-dependent and anchorage independent colonies were observed in cells that overexpressed claudin-3, while no such changes were observed when claudin-1 was overexpressed. Finally, claudin 3 silencing alone despite induce increase proliferation, and the formation of anchoragedependent and -independent colonies, it was able to prevent the EGF induced increased malignant potential. In conclusion, our results show a novel role for claudin-3 overexpression in promoting the malignant potential of colorectal cancer cells, which is potentially regulated by the EGF-activated ERK1/2 and PI3K-Akt pathways. PMID- 24069373 TI - Sortilin-related receptor SORCS3 is a postsynaptic modulator of synaptic depression and fear extinction. AB - SORCS3 is an orphan receptor of the VPS10P domain receptor family, a group of sorting and signaling receptors central to many pathways in control of neuronal viability and function. SORCS3 is highly expressed in the CA1 region of the hippocampus, but the relevance of this receptor for hippocampal activity remained absolutely unclear. Here, we show that SORCS3 localizes to the postsynaptic density and that loss of receptor activity in gene-targeted mice abrogates NMDA receptor-dependent and -independent forms of long-term depression (LTD). Consistent with a loss of synaptic retraction, SORCS3-deficient mice suffer from deficits in behavioral activities associated with hippocampal LTD, particularly from an accelerated extinction of fear memory. A possible molecular mechanism for SORCS3 in synaptic depression was suggested by targeted proteomics approaches that identified the ability of SORCS3 to functionally interact with PICK1, an adaptor that sorts glutamate receptors at the postsynapse. Faulty localization of PICK1 in SORCS3-deficient neurons argues for altered glutamate receptor trafficking as the cause of altered synaptic plasticity in the SORCS3-deficient mouse model. In conclusion, our studies have identified a novel function for VPS10P domain receptors in control of synaptic depression and suggest SORCS3 as a novel factor modulating aversive memory extinction. PMID- 24069374 TI - The small molecule Wnt signaling modulator ICG-001 improves contractile function in chronically infarcted rat myocardium. AB - The adult mammalian heart has limited capability for self-repair after myocardial infarction. Therefore, therapeutic strategies that improve post-infarct cardiac function are critically needed. The small molecule ICG-001 modulates Wnt signaling and increased the expression of genes beneficial for cardiac regeneration in epicardial cells. Lineage tracing experiments, demonstrated the importance of beta-catenin/p300 mediated transcription for epicardial progenitor contribution to the myocardium. Female rats given ICG-001 for 10 days post occlusion significantly improved ejection fraction by 8.4%, compared to controls (P<0.05). Taken together, Wnt modulation via beta-catenin/CBP inhibition offers a promising therapeutic strategy towards restoration of myocardial tissues and an enhancement of cardiac functions following infarction. PMID- 24069375 TI - Noise-induced tinnitus using individualized gap detection analysis and its relationship with hyperacusis, anxiety, and spatial cognition. AB - Tinnitus has a complex etiology that involves auditory and non-auditory factors and may be accompanied by hyperacusis, anxiety and cognitive changes. Thus far, investigations of the interrelationship between tinnitus and auditory and non auditory impairment have yielded conflicting results. To further address this issue, we noise exposed rats and assessed them for tinnitus using a gap detection behavioral paradigm combined with statistically-driven analysis to diagnose tinnitus in individual rats. We also tested rats for hearing detection, responsivity, and loss using prepulse inhibition and auditory brainstem response, and for spatial cognition and anxiety using Morris water maze and elevated plus maze. We found that our tinnitus diagnosis method reliably separated noise exposed rats into tinnitus((+)) and tinnitus((-)) groups and detected no evidence of tinnitus in tinnitus((-)) and control rats. In addition, the tinnitus((+)) group demonstrated enhanced startle amplitude, indicating hyperacusis-like behavior. Despite these results, neither tinnitus, hyperacusis nor hearing loss yielded any significant effects on spatial learning and memory or anxiety, though a majority of rats with the highest anxiety levels had tinnitus. These findings showed that we were able to develop a clinically relevant tinnitus((+)) group and that our diagnosis method is sound. At the same time, like clinical studies, we found that tinnitus does not always result in cognitive-emotional dysfunction, although tinnitus may predispose subjects to certain impairment like anxiety. Other behavioral assessments may be needed to further define the relationship between tinnitus and anxiety, cognitive deficits, and other impairments. PMID- 24069376 TI - Genetic variation in attachment glycoprotein genes of human respiratory syncytial virus subgroups a and B in children in recent five consecutive years. AB - Human respiratory syncytial virus (HRSV) outranks other viral agents as the cause of respiratory tract diseases in children worldwide. Molecular epidemiological study of the virus provides useful information for the development of globally effective vaccine. We investigated the circulating pattern and genetic variation in the attachment glycoprotein genes of HRSV in Beijing during 5 consecutive seasons from 2007 to 2012. Out of 19,942 tested specimens, 3,160 (15.8%) were HRSV antigen-positive. The incidence of HRSV infection in males was significantly higher than in females. Of the total 723 (23.1%) randomly selected HRSV antigen positive samples, 462 (63.9%) and 239 (33.1%) samples were identified as subgroup A and B, respectively. Subgroups A and B co-circulated in the 5 consecutive HRSV seasons, which showed a shifting mixed pattern of subgroup dominance. Complete G gene sequences were obtained from 190 HRSV-A and 72 HRSV-B by PCR for phylogenetic analysis. Although 4 new genotypes, NA3 and NA4 for HRSV-A and BA-C and CB1 for HRSV-B, were identified here, they were not predominant; NA1 and BA9 were the prevailing HRSV-A and -B genotypes, respectively. We provide the first report of a 9 consecutive nucleotide insertion in 3 CB1 genotype strains. One Beijing strain of ON1 genotype with a 72 nucleotide insertion was found among samples collected in February 2012. The reversion of codon states in glycosylation sites to previous ones were found from HRSV strains in this study, suggesting an immune-escape strategy of this important virus. PMID- 24069377 TI - Inflammation markers in multiple sclerosis: CXCL16 reflects and may also predict disease activity. AB - BACKGROUND: Serum markers of inflammation are candidate biomarkers in multiple sclerosis (MS). omega-3 fatty acids are suggested to have anti-inflammatory properties that might be beneficial in MS. We aimed to explore the relationship between serum levels of inflammation markers and MRI activity in patients with relapsing remitting MS, as well as the effect of omega-3 fatty acids on these markers. METHODS: We performed a prospective cohort study in 85 relapsing remitting MS patients who participated in a randomized clinical trial of omega-3 fatty acids versus placebo (the OFAMS study). During a period of 24 months 12 repeated magnetic resonance imaging (MRI) scans and nine serum samples were obtained. We measured 10 inflammation markers, including general down-stream markers of inflammation, specific markers of up-stream inflammatory pathways, endothelial action, and matrix regulation. RESULTS: After Bonferroni correction, increasing serum levels of CXCL16 and osteoprotegerin were associated with low odds ratio for simultaneous MRI activity, whereas a positive association was observed for matrix metalloproteinase (MMP) 9. CXCL16 were also associated with low MRI activity the next month, but this was not significant after Bonferroni correction. In agreement with previously reported MRI and clinical results, omega 3 fatty acid treatment did not induce any change in the inflammation markers. CONCLUSIONS: Serum levels of CXCL16, MMP-9, and osteoprotegerin reflect disease activity in MS, but are not affected by omega-3 fatty acid treatment. CXCL16 could be a novel biomarker and potential predictor of disease activity in MS. PMID- 24069378 TI - Proteome profiling of neuroblastoma-derived exosomes reveal the expression of proteins potentially involved in tumor progression. AB - Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, with grim prognosis in a half of patients. Exosomes are nanometer-sized membrane vesicles derived from the multivesicular bodies (MVBs) of the endocytic pathway and released by normal and neoplastic cells. Tumor-derived exosomes have been shown in different model systems to carry molecules that promote cancer growth and dissemination. In this respect, we have here performed the first characterization and proteomic analysis of exosomes isolated from human NB cell lines by filtration and ultracentrifugation. Electron microscopy demonstrated that NB-derived exosomes exhibited the characteristic cup-shaped morphology. Dynamic light scattering studies showed a bell-shaped curve and a polydispersity factor consistent with those of exosomes. Zeta potential values suggested a good nanoparticle stability. We performed proteomic analysis of NB-derived exosomes by two dimension liquid chromatography separation and mass spectrometry analyses using the multidimensional protein identification technology strategy. We found that the large majority of the proteins identified in NB derived exosomes are present in Exocarta database including tetraspanins, fibronectin, heat shock proteins, MVB proteins, cytoskeleton-related proteins, prominin-1 (CD133), basigin (CD147) and B7-H3 (CD276). Expression of the CD9, CD63 and CD81 tetraspanins, fibronectin, CD133, CD147 and CD276 was validated by flow cytometry. Noteworthy, flow cytometric analysis showed that NB-derived exosomes expressed the GD2 disialoganglioside, the most specific marker of NB. In conclusion, this study shows that NB-derived exosomes express a discrete set of molecules involved in defense response, cell differentiation, cell proliferation and regulation of other important biological process. Thus, NB-derived exosomes may play an important role in the modulation of tumor microenvironment and represent potential tumor biomarkers. PMID- 24069379 TI - Ocular expression and distribution of products of the POAG-associated chromosome 9p21 gene region. AB - It has recently been shown that there are highly significant associations for common single nucleotide polymorphisms (SNPs) near the CDKN2B-AS1 gene region at the 9p21 locus with primary open angle glaucoma (POAG), a leading cause of irreversible blindness. This gene region houses the CDKN2B/p15(INK4B) , CDKN2A/p16(INK4A) and p14ARF (rat equivalent, p19(ARF) ) tumour suppressor genes and is adjacent to the S-methyl-5'-thioadenosine phosphorylase (MTAP) gene. In order to understand the ocular function of these genes and, therefore, how they may be involved in the pathogenesis of POAG, we studied the distribution patterns of each of their products within human and rat ocular tissues. MTAP mRNA was detected in the rat retina and optic nerve and its protein product was localised to the corneal epithelium, trabecular meshwork and retinal glial cells in both human and rat eyes. There was a very low level of p16(INK4A) mRNA present within the rat retina and slightly more in the optic nerve, although no protein product could be detected in either rat or human eyes with any of the antibodies tested. P19(ARF) mRNA was likewise only present at very low levels in rat retina and slightly higher levels in the optic nerve. However, no unambiguous evidence was found to indicate expression of specific P19(ARF)/p14(ARF) proteins in either rat or human eyes, respectively. In contrast, p15(INK4B) mRNA was detected in much higher amounts in both retina and optic nerve compared with the other genes under analysis. Moreover, p15(INK4B) protein was clearly localised to the retinal inner nuclear and ganglion cell layers and the corneal epithelium and trabecular meshwork in rat and human eyes. The presented data provide the basis for future studies that can explore the roles that these gene products may play in the pathogenesis of glaucoma and other models of optic nerve damage. PMID- 24069380 TI - Withania somnifera root extract inhibits mammary cancer metastasis and epithelial to mesenchymal transition. AB - Though clinicians can predict which patients are at risk for developing metastases, traditional therapies often prove ineffective and metastatic disease is the primary cause of cancer patient death; therefore, there is a need to develop anti-metastatic therapies that can be administered over long durations to specifically inhibit the motility of cancer cells. Withaniasomnifera root extracts (WRE) have anti-proliferative activity and the active component, Withaferin A, inhibits the pro-metastatic protein, vimentin. Vimentin is an intermediate filament protein and is part of the epithelial to mesenchymal transition (EMT) program to promote metastasis. Here, we determined whether WRE standardized to Withaferin A (sWRE) possesses anti-metastatic activity and whether it inhibits cancer motility via inhibition of vimentin and the EMT program. Several formulations of sWRE were created to enrich for Withaferin A and a stock solution of sWRE in EtOH could recover over 90% of the Withaferin A found in the original extract powder. This sWRE formulation inhibited breast cancer cell motility and invasion at concentrations less than 1uM while having negligible cytotoxicity at this dose. sWRE treatment disrupted vimentin morphology in cell lines, confirming its vimentin inhibitory activity. To determine if sWRE inhibited EMT, TGF-beta was used to induce EMT in MCF10A human mammary epithelial cells. In this case, sWRE prevented EMT induction and inhibited 3-D spheroid invasion. These studies were taken into a human xenograft and mouse mammary carcinoma model. In both models, sWRE and Withaferin A showed dose-dependent inhibition of tumor growth and metastatic lung nodule formation with minimal systemic toxicity. Taken together, these data support the hypothesis that low concentrations of sWRE inhibit cancer metastasis potentially through EMT inhibition. Moreover, these doses of sWRE have nearly no toxicity in normal mouse organs, suggesting the potential for clinical use of orally administered WRE capsules. PMID- 24069381 TI - Estimation of CT-derived abdominal visceral and subcutaneous adipose tissue depots from anthropometry in Europeans, South Asians and African Caribbeans. AB - BACKGROUND: South Asians and African Caribbeans experience more cardiometabolic disease than Europeans. Risk factors include visceral (VAT) and subcutaneous abdominal (SAT) adipose tissue, which vary with ethnicity and are difficult to quantify using anthropometry. OBJECTIVE: We developed and cross-validated ethnicity and gender-specific equations using anthropometrics to predict VAT and SAT. DESIGN: 669 Europeans, 514 South Asians and 227 African Caribbeans (70 +/- 7 years) underwent anthropometric measurement and abdominal CT scanning. South Asian and African Caribbean participants were first-generation migrants living in London. Prediction equations were derived for CT-measured VAT and SAT using stepwise regression, then cross-validated by comparing actual and predicted means. RESULTS: South Asians had more and African Caribbeans less VAT than Europeans. For basic VAT prediction equations (age and waist circumference), model fit was better in men (R(2) range 0.59-0.71) than women (range 0.35-0.59). Expanded equations (+ weight, height, hip and thigh circumference) improved fit for South Asian and African Caribbean women (R(2) 0.35 to 0.55, and 0.43 to 0.56 respectively). For basic SAT equations, R(2) was 0.69-0.77, and for expanded equations it was 0.72-0.86. Cross-validation showed differences between actual and estimated VAT of <7%, and SAT of <8% in all groups, apart from VAT in South Asian women which disagreed by 16%. CONCLUSION: We provide ethnicity- and gender specific VAT and SAT prediction equations, derived from a large tri-ethnic sample. Model fit was reasonable for SAT and VAT in men, while basic VAT models should be used cautiously in South Asian and African Caribbean women. These equations will aid studies of mechanisms of cardiometabolic disease in later life, where imaging data are not available. PMID- 24069382 TI - Dietary cadmium intake and the risk of cancer: a meta-analysis. AB - BACKGROUND: Diet is a major source of cadmium intake among the non-smoking general population. Recent studies have determined that cadmium exposure may produce adverse health effects at lower exposure levels than previously predicted. We conducted a meta-analysis to combine and analyze the results of previous studies that have investigated the association of dietary cadmium intake and cancer risk. METHODS: We searched PubMed, EMBASE, and MEDLINE database for case-control and cohort studies that assessed the association of dietary cadmium intake and cancer risk. We performed a meta-analysis using eight eligible studies to summarize the data and summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random effects model. RESULTS: Overall, dietary cadmium intake showed no statistically significant association with cancer risk (RR = 1.10; 95% CI: 0.99-1.22, for highest vs. lowest dietary cadmium group). However, there was strong evidence of heterogeneity, and subgroup analyses were conducted using the study design, geographical location, and cancer type. In subgroup analyses, the positive associations between dietary cadmium intake and cancer risk were observed among studies with Western populations (RR = 1.15; 95% CI: 1.08-1.23) and studies investigating some hormone-related cancers (prostate, breast, and endometrial cancers). CONCLUSION: Our analysis found a positive association between dietary cadmium intake and cancer risk among studies conducted in Western countries, particularly with hormone-related cancers. Additional experimental and epidemiological studies are required to verify our findings. PMID- 24069383 TI - A new murine model of osteoblastic/osteolytic lesions from human androgen resistant prostate cancer. AB - BACKGROUND: Up to 80% of patients dying from prostate carcinoma have developed bone metastases that are incurable. Castration is commonly used to treat prostate cancer. Although the disease initially responds to androgen blockade strategies, it often becomes castration-resistant (CRPC for Castration Resistant Prostate Cancer). Most of the murine models of mixed lesions derived from prostate cancer cells are androgen sensitive. Thus, we established a new model of CRPC (androgen receptor (AR) negative) that causes mixed lesions in bone. METHODS: PC3 and its derived new cell clone PC3c cells were directly injected into the tibiae of SCID male mice. Tumor growth was analyzed by radiography and histology. Direct effects of conditioned medium of both cell lines were tested on osteoclasts, osteoblasts and osteocytes. RESULTS: We found that PC3c cells induced mixed lesions 10 weeks after intratibial injection. In vitro, PC3c conditioned medium was able to stimulate tartrate resistant acid phosphatase (TRAP)-positive osteoclasts. Osteoprotegerin (OPG) and endothelin-1 (ET1) were highly expressed by PC3c while dikkopf-1 (DKK1) expression was decreased. Finally, PC3c highly expressed bone associated markers osteopontin (OPN), Runx2, alkaline phosphatase (ALP), bone sialoprotein (BSP) and produced mineralized matrix in vitro in osteogenic conditions. CONCLUSIONS: We have established a new CRPC cell line as a useful system for modeling human metastatic prostate cancer which presents the mixed phenotype of bone metastases that is commonly observed in prostate cancer patients with advanced disease. This model will help to understand androgen independent mechanisms involved in the progression of prostate cancer in bone and provides a preclinical model for testing the effects of new treatments for bone metastases. PMID- 24069384 TI - Changes in mouse thymus and spleen after return from the STS-135 mission in space. AB - Our previous results with flight (FLT) mice showed abnormalities in thymuses and spleens that have potential to compromise immune defense mechanisms. In this study, the organs were further evaluated in C57BL/6 mice after Space Shuttle Atlantis returned from a 13-day mission. Thymuses and spleens were harvested from FLT mice and ground controls housed in similar animal enclosure modules (AEM). Organ and body mass, DNA fragmentation and expression of genes related to T cells and cancer were determined. Although significance was not obtained for thymus mass, DNA fragmentation was greater in the FLT group (P<0.01). Spleen mass alone and relative to body mass was significantly decreased in FLT mice (P<0.05). In FLT thymuses, 6/84 T cell-related genes were affected versus the AEM control group (P<0.05; up: IL10, Il18bp, Il18r1, Spp1; down: Ccl7, IL6); 15/84 cancer related genes had altered expression (P<0.05; up: Casp8, FGFR2, Figf, Hgf, IGF1, Itga4, Ncam1, Pdgfa, Pik3r1, Serpinb2, Sykb; down: Cdc25a, E2F1, Mmp9, Myc). In the spleen, 8/84 cancer-related genes were affected in FLT mice compared to AEM controls (P<0.05; up: Cdkn2a; down: Birc5, Casp8, Ctnnb1, Map2k1, Mdm2, NFkB1, Pdgfa). Pathway analysis (apoptosis signaling and checkpoint regulation) was used to map relationships among the cancer-related genes. The results showed that a relatively short mission in space had a significant impact on both organs. The findings also indicate that immune system aberrations due to stressors associated with space travel should be included when estimating risk for pathologies such as cancer and infection and in designing appropriate countermeasures. Although this was the historic last flight of NASA's Space Shuttle Program, exploration of space will undoubtedly continue. PMID- 24069385 TI - SCD1 Expression is dispensable for hepatocarcinogenesis induced by AKT and Ras oncogenes in mice. AB - Increased de novo lipogenesis is one of the major metabolic events in cancer. In human hepatocellular carcinoma (HCC), de novo lipogenesis has been found to be increased and associated with the activation of AKT/mTOR signaling. In mice, overexpression of an activated form of AKT results in increased lipogenesis and hepatic steatosis, ultimately leading to liver tumor development. Hepatocarcinogenesis is dramatically accelerated when AKT is co-expressed with an oncogenic form of N-Ras. SCD1, the major isoform of stearoyl-CoA desaturases, catalyzing the conversion of saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA), is a key enzyme involved in de novo lipogenesis. While many studies demonstrated the requirement of SCD1 for tumor cell growth in vitro, whether SCD1 is necessary for tumor development in vivo has not been previously investigated. Here, we show that genetic ablation of SCD1 neither inhibits lipogenesis and hepatic steatosis in AKT-overexpressing mice nor affects liver tumor development in mice co-expressing AKT and Ras oncogenes. Molecular analysis showed that SCD2 was strongly upregulated in liver tumors from AKT/Ras injected SCD1(-/-) mice. Noticeably, concomitant silencing of SCD1 and SCD2 genes was highly detrimental for the growth of AKT/Ras cells in vitro. Altogether, our study provides the evidence, for the first time, that SCD1 expression is dispensable for AKT/mTOR-dependent hepatic steatosis and AKT/Ras-induced hepatocarcinogenesis in mice. Complete inhibition of stearoyl-CoA desaturase activity may be required to efficiently suppress liver tumor development. PMID- 24069386 TI - Fracture in asian women with breast cancer occurs at younger age. AB - BACKGROUND: Western breast cancer survivors have an increased risk of osteoporosis and bone fracture. Breast cancer occurs 10 to 20 years earlier in Asian women than in Western women. We investigated if younger Asian women with breast cancer also have increased risk of fracture. METHODS: We used the universal insurance claims data from 2000 to 2003 to identify 22,076 patients with breast cancer and 88,304 women without cancer, frequency matched with age and index date (the date for a health care visit). The incidence of fracture in both cohorts and the hazard ratios (HRs) of fracture in the cancer cohort were estimated by the end of 2009. RESULTS: The incidence of all types of fracture was higher in the breast cancer cohort than in the comparison cohort (46.72 vs. 42.52 per 10,000 person-years), with adjusted HRs (aHRs) of 1.18 (95% confidence intervals [CI], 1.03-1.35) for hip fractures, 1.12 (95% CI, 0.98-1.28) for forearm fractures and 1.24 (95% CI, 1.04-1.48) for vertebral fractures. The aHRs were significant in both non-traumatic fractures (1.29; 95% CI, 1.11-1.51) and traumatic fractures (1.12; 95% CI, 1.01-1.23). The age-specific aHR was higher for younger breast cancer patients, and was significant for <50 years old patients in both traumatic (aHR 1.35; 95% CI 1.08-1.68) and non-traumatic (aHR, 1.72; 95% CI, 1.21-2.44) fractures. CONCLUSION: This study suggests that Asian women with breast cancer might have an increased risk of fracture. PMID- 24069388 TI - NuChart: an R package to study gene spatial neighbourhoods with multi-omics annotations. AB - Long-range chromosomal associations between genomic regions, and their repositioning in the 3D space of the nucleus, are now considered to be key contributors to the regulation of gene expression and important links have been highlighted with other genomic features involved in DNA rearrangements. Recent Chromosome Conformation Capture (3C) measurements performed with high throughput sequencing (Hi-C) and molecular dynamics studies show that there is a large correlation between colocalization and coregulation of genes, but these important researches are hampered by the lack of biologists-friendly analysis and visualisation software. Here, we describe NuChart, an R package that allows the user to annotate and statistically analyse a list of input genes with information relying on Hi-C data, integrating knowledge about genomic features that are involved in the chromosome spatial organization. NuChart works directly with sequenced reads to identify the related Hi-C fragments, with the aim of creating gene-centric neighbourhood graphs on which multi-omics features can be mapped. Predictions about CTCF binding sites, isochores and cryptic Recombination Signal Sequences are provided directly with the package for mapping, although other annotation data in bed format can be used (such as methylation profiles and histone patterns). Gene expression data can be automatically retrieved and processed from the Gene Expression Omnibus and ArrayExpress repositories to highlight the expression profile of genes in the identified neighbourhood. Moreover, statistical inferences about the graph structure and correlations between its topology and multi-omics features can be performed using Exponential family Random Graph Models. The Hi-C fragment visualisation provided by NuChart allows the comparisons of cells in different conditions, thus providing the possibility of novel biomarkers identification. NuChart is compliant with the Bioconductor standard and it is freely available at ftp://fileserver.itb.cnr.it/nuchart. PMID- 24069387 TI - Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment. AB - Disturbed proteostasis as a particular phenotype of the aging organism has been advanced in C. elegans experiments and is also conceived to underlie neurodegenerative diseases in humans. Here, we investigated whether particular changes in non-disease related proteostasis can be identified in the aged mammalian brain, and whether a particular signature of aberrant proteostasis is related to behavioral performance of learning and memory. Young (adult, n = 30) and aged (2 years, n = 50) Wistar rats were tested in the Morris Water Maze (MWM) to distinguish superior and inferior performers. For both young and old rats, the best and worst performers in the MWM were selected and the insoluble proteome, termed aggregome, was purified from the hippocampus as evidence for aberrant proteostasis. Quantitative proteomics (iTRAQ) was performed. The aged inferior performers were considered as a model for spontaneous, age-associated cognitive impairment. Whereas variability of the insoluble proteome increased with age, absolute changes in the levels of insoluble proteins were small compared to the findings in the whole C. elegans insoluble proteome. However, we identified proteins with aberrant proteostasis in aging. For the cognitively impaired rats, we identified a changed molecular circuitry of proteins selectively involved in F actin remodeling, synapse building and long-term depression: actin related protein 3 (ARP3), neurabin II (NEB2) and IQ motif and SEC7 domain-containing protein 1 (BRAG2). We demonstrate that aberrant proteostasis is a specific phenotype of brain aging in mammals. We identify a distinct molecular circuitry where changes in proteostasis are characteristic for poor learning and memory performance in the wild type, aged rat. Our findings 1. establish the search for aberrant proteostasis as a successful strategy to identify neuronal dysfunction in deficient cognitive behavior, 2. reveal a previously unknown functional network of proteins (ARP3, NEB2, BRAG2) involved in age-associated cognitive dysfunction. PMID- 24069389 TI - Activated T cell trans-endothelial migration relies on myosin-IIA contractility for squeezing the cell nucleus through endothelial cell barriers. AB - Following activation, T cells are released from lymph nodes to traffic via the blood to effector sites. The re-entry of these activated T cells into tissues represents a critical step for them to carry out local effector functions. Here we have assessed defects in effector T cells that are acutely depleted in Myosin IIA (MyoIIA) and show a T cell intrinsic requirement for this motor to facilitate the diapedesis step of extravasation. We show that MyoIIA accumulates at the rear of T cells undergoing trans-endothelial migration. T cells can extend protrusions and project a substantial portion of their cytoplasm through the endothelial wall in the absence of MyoIIA. However, this motor protein plays a crucial role in allowing T cells to complete the movement of their relatively rigid nucleus through the endothelial junctions. In vivo, this defect manifests as poor entry into lymph nodes, tumors and into the spinal cord, during tissue-specific autoimmunity, but not the spleen. This suggests that therapeutic targeting of this molecule may allow for differential attenuation of tissue-specific inflammatory responses. PMID- 24069391 TI - Epidemiology and outcome of pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) in Canadian hospitals. AB - BACKGROUND: MRSA remains a leading cause of hospital-acquired (HAP) and healthcare-associated pneumonia (HCAP). We describe the epidemiology and outcome of MRSA pneumonia in Canadian hospitals, and identify factors contributing to mortality. METHODS: Prospective surveillance for MRSA pneumonia in adults was done for one year (2011) in 11 Canadian hospitals. Standard criteria for MRSA HAP, HCAP, ventilator-associated pneumonia (VAP), and community-acquired pneumonia (CAP) were used to identify cases. MRSA isolates underwent antimicrobial susceptibility testing, and were characterized by pulsed-field gel electrophoresis (PFGE) and Panton-Valentine leukocidin (PVL) gene detection. The primary outcome was all-cause mortality at 30 days. A multivariable analysis was done to examine the association between various host and microbial factors and mortality. RESULTS: A total of 161 patients with MRSA pneumonia were identified: 90 (56%) with HAP, 26 (16%) HCAP, and 45 (28%) CAP; 23 (14%) patients had VAP. The mean (+/- SD) incidence of MRSA HAP was 0.32 (+/- 0.26) per 10,000 patient days, and of MRSA VAP was 0.30 (+/- 0.5) per 1,000 ventilator-days. The 30-day all-cause mortality was 28.0%. In multivariable analysis, variables associated with mortality were the presence of multiorgan failure (OR 8.1; 95% CI 2.5-26.0), and infection with an isolate with reduced susceptibility to vancomycin (OR 2.5, 95% CI 1.0-6.3). CONCLUSIONS: MRSA pneumonia is associated with significant mortality. Severity of disease at presentation, and infection caused by an isolate with elevated MIC to vancomcyin are associated with increased mortality. Additional studies are required to better understand the impact of host and microbial variables on outcome. PMID- 24069392 TI - Depletion of proBNP1-108 in patients with heart failure prevents cross-reactivity with natriuretic peptides. AB - BACKGROUND: After synthesis by cardiomyocytes, precursor proBNP1-108 is cleaved into NT-proBNP and BNP. Recently, cross-reactivity between these assays was discussed. The aim of this study was to characterize the cross-reactivities, through a new biochemical innovative approach consisting in the total depletion of the circulating proBNP1-108 in patients with heart failure (HF). METHODS: This prospective study included 180 patients with chronic HF. BNP and NT-proBNP were dosed with commercial kits. ProBNP1-108 was determined using an ELISA research assay specific to the precursor. ProBNP1-108 depletion was performed by immunocapture with a specific antibody targeting exclusively the ProBNP1-108 hinge region. ProBNP1-108, BNP and NT-proBNP levels were determined before and after depletion using this process in HF patients. RESULTS: Mean age was 74.34 +/ 12.5 y, and 69% of patients were males. NYHA classes II and III were the most frequent (32% and 45% respectively). Before depletion, ProBNP1-108, NT-proBNP and BNP levels were 316.8+/-265.9 pg/ml; 6,054.0+/-11,539 pg/ml and 684.3+/-82.1 pg/ml respectively, and were closely correlated with NHYA classes. After immuno depletion, proBNP1-108 was decreased in mean by 96% (p<0.0001), BNP by 53% (p<0.0001) and NT-proBNP by 5%. The relationship between BNP or NT-proBNP and NHYA classes remained unchanged. CONCLUSION: Current BNP and NT-proBNP assays measured as well proBNP molecule. This cross reactivity percentage has been controversial. Thanks to the removal of circulating proBNP1-108 with our immunodepletion process, we are now able to assess the remaining "true" BNP and NT-proBNP molecules and further evaluate their clinical relevance. PMID- 24069390 TI - Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer. AB - Lactate accumulation in tumors has been associated with metastases and poor overall survival in cancer patients. Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount produced, amount carried away by vasculature and if/how it is catabolized by aerobic tumor or stromal cells. We examined lactate metabolism in human normal and breast tumor cell lines and rat breast cancer: 1. at relevant concentrations, 2. under aerobic vs. hypoxic conditions, 3. under conditions of normo vs. hypoglucosis. We also compared the avidity of tumors for lactate vs. glucose and identified key lactate catabolites to reveal how breast cancer cells process it. Lactate was non-toxic at clinically relevant concentrations. It was taken up and catabolized to alanine and glutamate by all cell lines. Kinetic uptake rates of lactate in vivo surpassed that of glucose in R3230Ac mammary carcinomas. The uptake appeared specific to aerobic tumor regions, consistent with the proposed "metabolic symbiont" model; here lactate produced by hypoxic cells is used by aerobic cells. We investigated whether treatment with alpha-cyano-4-hydroxycinnamate (CHC), a MCT1 inhibitor, would kill cells in the presence of high lactate. Both 0.1 mM and 5 mM CHC prevented lactate uptake in R3230Ac cells at lactate concentrations at <= 20 mM but not at 40 mM. 0.1 mM CHC was well-tolerated by R3230Ac and MCF7 cells, but 5 mM CHC killed both cell lines +/- lactate, indicating off-target effects. This study showed that breast cancer cells tolerate and use lactate at clinically relevant concentrations in vitro (+/- glucose) and in vivo. We provided additional support for the metabolic symbiont model and discovered that breast cells prevailingly take up and catabolize lactate, providing rationale for future studies on manipulation of lactate catabolism pathways for therapy. PMID- 24069393 TI - Gastric epithelial expression of IL-12 cytokine family in Helicobacter pylori infection in human: is it head or tail of the coin? AB - Recently, there has been a growing interest in an expanding group of cytokines known as "IL-12 family". The so far gained knowledge about these cytokines, as crucial playmakers in mucosal immunity, has not yet been sufficiently investigated in the context of Helicobacter pylori infection. All genes encoding the monomeric components of these cytokines and their corresponding receptors were examined in gastric epithelial cell lines (AGS and MKN-28) after being infected with 4 H. pylori strains: BCM-300, P1 wild-type, and P1-derived isogenic mutants lacking cytotoxin-associated gene A (cagA) or virulence gene virB7 (multiplicity of infection=50). Both infected and uninfected samples were analyzed after 24h and 48h using real-time quantitative polymerase chain reaction (RT-qPCR). Gene expression analysis demonstrated a strong upregulation of IL23A (encodes p19) by infection, whereas IL23R, Epstein-Barr virus-induced gene 3 (EBI3), IL6ST, IL12A, and IL27RA were found to be expressed, but not regulated, or to a lesser extent. Transcripts of IL12RB2, IL12B, IL12RB1, and IL27A were not detected. Interestingly, P1 resulted in stronger alterations of expression than CagA mutant and BCM-300, particularly for IL23A (59.7-fold versus 32.4- and 6.7 fold, respectively in AGS after 48h, P<.05), whereas no changes were seen with VirB7 mutant. In a proof-of-principle experiment, we demonstrated epithelial derived expression of IL-12, p19, and Ebi3 in gastric mucosa of gastritis patients using immunohistochemistry (IHC). Unlike IL-12 and Ebi3, increased immunostaining of p19 was observed in H. pylori gastritis. Herein, we highlight the potential role of gastric epithelial cells in mucosal immunity, not only because they are predominant cell type in mucosa and initial site of host bacterial interaction, but also as a major contributor to molecules that are thought to be primarily expressed by immune cells so far. Of these molecules, p19 was the most relevant one to H. pylori infection in terms of expression and localization. PMID- 24069394 TI - Magmas overexpression inhibits staurosporine induced apoptosis in rat pituitary adenoma cell lines. AB - Magmas is a nuclear gene that encodes for the mitochondrial import inner membrane translocase subunit Tim16. Magmas is overexpressed in the majority of human pituitary adenomas and in a mouse ACTH-secreting pituitary adenoma cell line. Here we report that Magmas is highly expressed in two out of four rat pituitary adenoma cell lines and its expression levels inversely correlate to the extent of cellular response to staurosporine in terms of apoptosis activation and cell viability. Magmas over-expression in rat GH/PRL-secreting pituitary adenoma GH4C1 cells leads to an increase in cell viability and to a reduction in staurosporine induced apoptosis and DNA fragmentation, in parallel with the increase in Magmas protein expression. These results indicate that Magmas plays a pivotal role in response to pro-apoptotic stimuli and confirm and extend the finding that Magmas protects pituitary cells from staurosporine-induced apoptosis, suggesting its possible involvement in pituitary adenoma development. PMID- 24069395 TI - Sonic hedgehog mediates the proliferation and recruitment of transformed mesenchymal stem cells to the stomach. AB - Studies using Helicobacter-infected mice show that bone marrow-derived mesenchymal stem cells (MSCs) can repopulate the gastric epithelium and promote gastric cancer progression. Within the tumor microenvironment of the stomach, pro inflammatory cytokine interferon-gamma (IFNgamma) and Sonic hedgehog (Shh) are elevated. IFNgamma is implicated in tumor proliferation via activation of the Shh signaling pathway in various tissues but whether a similar mechanism exists in the stomach is unknown. We tested the hypothesis that IFNgamma drives MSC proliferation and recruitment, a response mediated by Shh signaling. The current study uses transplantation of an in vitro transformed mesenchymal stem cell line (stMSC(vect)), that over-expresses hedgehog signaling, in comparison to non transformed wild-type MSCs (wtMSCs), wtMSCs transfected to over-express Shh (wtMSC(Shh)), and stMSCs transduced with lentiviral constructs containing shRNA targeting the Shh gene (stMSC(ShhKO)). The effect of IFNgamma on MSC proliferation was assessed by cell cycle analysis in vitro using cells treated with recombinant IFNgamma (rmIFNgamma) alone, or in combination with anti-Shh 5E1 antibody, and in vivo using mice transplanted with MSCs treated with PBS or rmIFNgamma. In vitro, IFNgamma significantly increased MSC proliferation, a response mediated by Shh that was blocked by 5E1 antibody. The MSC population collected from bone marrow of PBS- or IFNgamma-treated mice showed that IFNgamma significantly increased the percentage of all MSC cell lines in S phase, with the exception of the stMSCs(ShhKO) cells. While the MSC cell lines with intact Shh expression were recruited to the gastric mucosa in response to IFNgamma, stMSCs(ShhKO) were not. Hedgehog signaling is required for MSC proliferation and recruitment to the stomach in response to IFNgamma. PMID- 24069396 TI - Theranostic protein targeting ErbB2 for bioluminescence imaging and therapy for cancer. AB - A combination of molecular-targeted cancer imaging and therapy is an emerging strategy to improve cancer diagnosis and minimize the side effects of conventional treatments. Here, we generated a recombinant protein, EC1-GLuc-p53C, by fusing EC1 peptide, an artificial ligand of ErbB2, with Gaussia luciferase (GLuc) and a p53-activating peptide, p53C. EC1-GLuc-p53C was expressed and purified from E. coli BL21. In vitro experiments showed that EC1-GLuc-p53c was stable in luminescent activity and selectively targeted ErbB2-overexpressing BT474 cells for bioluminescence imaging. Moreover, the internalized EC1-GLuc-p53C in BT474 cells exerted its function to reactivate p53 and significantly inhibited cellular proliferation. In tumor-bearing mice, the ErbB2-targeted bioluminescence imaging and therapeutic effect of EC1-GLuc-p53C were also observed specifically in BT474 tumors but not in MCF7 tumors, which does not overexpress ErbB2. Thus, the present study demonstrates EC1-GLuc-p53C to be an effective theranostic reagent targeting ErbB2 for bioluminescence imaging and cancer therapy. PMID- 24069397 TI - Major transcriptome reprogramming underlies floral mimicry induced by the rust fungus Puccinia monoica in Boechera stricta. AB - Pucciniamonoica is a spectacular plant parasitic rust fungus that triggers the formation of flower-like structures (pseudoflowers) in its Brassicaceae host plant Boecherastricta. Pseudoflowers mimic in shape, color, nectar and scent co occurring and unrelated flowers such as buttercups. They act to attract insects thereby aiding spore dispersal and sexual reproduction of the rust fungus. Although much ecological research has been performed on P. monoica-induced pseudoflowers, this system has yet to be investigated at the molecular or genomic level. To date, the molecular alterations underlying the development of pseudoflowers and the genes involved have not been described. To address this, we performed gene expression profiling to reveal 256 plant biological processes that are significantly altered in pseudoflowers. Among these biological processes, plant genes involved in cell fate specification, regulation of transcription, reproduction, floral organ development, anthocyanin (major floral pigments) and terpenoid biosynthesis (major floral volatile compounds) were down-regulated in pseudoflowers. In contrast, plant genes involved in shoot, cotyledon and leaf development, carbohydrate transport, wax biosynthesis, cutin transport and L phenylalanine metabolism (pathway that results in phenylethanol and phenylacetaldehyde volatile production) were up-regulated. These findings point to an extensive reprogramming of host genes by the rust pathogen to induce floral mimicry. We also highlight 31 differentially regulated plant genes that are enriched in the biological processes mentioned above, and are potentially involved in the formation of pseudoflowers. This work illustrates the complex perturbations induced by rust pathogens in their host plants, and provides a starting point for understanding the molecular mechanisms of pathogen-induced floral mimicry. PMID- 24069398 TI - Cost and effectiveness of decontamination strategies in radiation contaminated areas in Fukushima in regard to external radiation dose. AB - The objective of the present study is to evaluate the cost and effectiveness of decontamination strategies in the special decontamination areas in Fukushima in regard to external radiation dose. A geographical information system (GIS) was used to relate the predicted external dose in the affected areas to the number of potential inhabitants and the land use in the areas. A comprehensive review of the costs of various decontamination methods was conducted as part of the analysis. The results indicate that aerial decontamination in the special decontamination areas in Fukushima would be effective for reducing the air dose rate to the target level in a short period of time in some but not all of the areas. In a standard scenario, analysis of cost and effectiveness suggests that decontamination costs for agricultural areas account for approximately 80% of the total decontamination cost, of which approximately 60% is associated with storage. In addition, the costs of decontamination per person per unit area are estimated to vary greatly. Appropriate selection of decontamination methods may significantly decrease decontamination costs, allowing more meaningful decontamination in terms of the limited budget. Our analysis can help in examining the prioritization of decontamination areas from the viewpoints of cost and effectiveness in reducing the external dose. Decontamination strategies should be determined according to air dose rates and future land-use plans. PMID- 24069399 TI - ALG-2 attenuates COPII budding in vitro and stabilizes the Sec23/Sec31A complex. AB - Coated vesicles mediate the traffic of secretory and membrane cargo proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. The coat protein complex (COPII) involved in vesicle budding is constituted by a GTPase, Sar1, the inner coat components of Sec23/Sec24 and the components of the outer coat Sec13/Sec31A. The Ca(2+)-binding protein ALG-2 was recently identified as a Sec31A binding partner and a possible link to Ca(2+) regulation of COPII vesicle budding. Here we show that ALG-2/Ca(2+) is capable of attenuating vesicle budding in vitro through interaction with an ALG-2 binding domain in the proline rich region of Sec31A. Binding of ALG-2 to Sec31A and inhibition of COPII vesicle budding is furthermore dependent on an intact Ca(2+)-binding site at EF-hand 1 of ALG-2. ALG 2 increased recruitment of COPII proteins Sec23/24 and Sec13/31A to artificial liposomes and was capable of mediating binding of Sec13/31A to Sec23. These results introduce a regulatory role for ALG-2/Ca(2+) in COPII tethering and vesicle budding. PMID- 24069400 TI - Role for Kruppel-like transcription factor 11 in mesenchymal cell function and fibrosis. AB - Kruppel-like factor 11 (KLF11) and the highly homologous KLF10 proteins are transcription factors originating from duplication of the Drosophila melanogaster ancestor cabut. The function of these proteins in epithelial cells has been previously characterized. In the current study, we report a functional role for KLF11 in mesenchymal cells and in mesenchymal cell dysfunction, namely, fibrosis, and subsequently perform a detailed cellular, molecular, and in vivo characterization of this phenomenon. We find that, in cultured mesenchymal cells, enhanced expression of KLF11 results in activated extracellular matrix pathways, including collagen gene silencing and matrix metalloproteinases activation without changes in tissue inhibitors of metalloproteinases. Combined, reporter and chromatin immunoprecipitation assays demonstrate that KLF11 interacts directly with the collagen 1a2 (COL1A2) promoter in mesenchymal cells to repress its activity. Mechanistically, KLF11 regulates collagen gene expression through the heterochromatin protein 1 gene-silencing pathway as mutants defective for coupling to this epigenetic modifier lose the ability to repress COL1A2. Expression studies reveal decreased levels of KLF11 during liver fibrogenesis after chemically induced injury in vivo. Congruently, KLF11(-/-) mice, which should be deficient in the hypothesized anti-fibrogenic brake imposed by this transcription factor, display an enhanced response to liver injury with increased collagen fibril deposition. Thus, KLFs expands the repertoire of transcription factors involved in the regulation of extracellular matrix proteins in mesenchymal cells and define a novel pathway that modulates the fibrogenic response during liver injury. PMID- 24069401 TI - Circulating TFH subset distribution is strongly affected in lupus patients with an active disease. AB - Follicular helper T cells (TFH) represent a distinct subset of CD4(+) T cells specialized in providing help to B lymphocytes, which may play a central role in autoimmune diseases having a major B cell component such as systemic lupus erythematosus. Recently, TFH subsets that share common phenotypic and functional characteristics with TFH cells from germinal centers, have been described in the peripheral blood from healthy individuals. The aim of this study was to analyze the distribution of such populations in lupus patients. Circulating TFH cell subsets were defined by multicolor flow cytometry as TFH17 (CXCR3(-)CCR6(+)), TFH1 (CXCR3 (+) CCR6(-)) or TFH2 (CXCR3(-)CCR6(-)) cells among CXCR5 (+) CD45RA( )CD4(+) T cells in the peripheral blood of 23 SLE patients and 23 sex and age matched healthy controls. IL-21 receptor expression by B cells was analyzed by flow cytometry and the serum levels of IL-21 and Igs were determined by ELISA tests. We found that the TFH2 cell subset frequency is strongly and significantly increased in lupus patients with an active disease (SLEDAI score>8), while the TFH1 cell subset percentage is greatly decreased. The TFH2 and TFH1 cell subset frequency alteration is associated with the presence of high Ig levels and autoantibodies in patient's sera. Moreover, the TFH2 cell subset enhancement correlates with an increased frequency of double negative memory B cells (CD27( )IgD(-)CD19(+) cells) expressing the IL-21R. Finally, we found that IgE levels in lupus patients' sera correlate with disease activity and seem to be associated with high TFH2 cell subset frequency. In conclusion, our study describes for the first time the distribution of circulating TFH cell subsets in lupus patients. Interestingly, we found an increased frequency of TFH2 cells, which correlates with disease activity. Our results suggest that this subset might play a key role in lupus pathogenesis. PMID- 24069402 TI - LIA5 is required for nuclear reorganization and programmed DNA rearrangements occurring during tetrahymena macronuclear differentiation. AB - During macronuclear differentiation of the ciliate Tetrahymena thermophila, genome-wide DNA rearrangements eliminate nearly 50 Mbp of germline derived DNA, creating a streamlined somatic genome. The transposon-like and other repetitive sequences to be eliminated are identified using a piRNA pathway and packaged as heterochromatin prior to their removal. In this study, we show that LIA5, which encodes a zinc-finger protein likely of transposon origin, is required for both chromosome fragmentation and DNA elimination events. Lia5p acts after the establishment of RNAi-directed heterochromatin modifications, but prior to the excision of the modified sequences. In ?LIA5 cells, DNA elimination foci, large nuclear sub-structures containing the sequences to be eliminated and the essential chromodomain protein Pdd1p, do not form. Lia5p, unlike Pdd1p, is not stably associated with these structures, but is required for their formation. In the absence of Lia5p, we could recover foci formation by ectopically inducing DNA damage by UV treatment. Foci in both wild-type or UV-treated ?LIA5 cells contain dephosphorylated Pdd1p. These studies of LIA5 reveal that DNA elimination foci form after the excision of germ-line limited sequences occurs and indicate that Pdd1p reorganization is likely mediated through a DNA damage response. PMID- 24069403 TI - Proteomic analysis of liver in rats chronically exposed to fluoride. AB - Fluoride (F) is a potent anti-cariogenic element, but when ingestion is excessive, systemic toxicity may be observed. This can occur as acute or chronic responses, depending on both the amount of F and the time of exposure. The present study identified the profile of protein expression possibly associated with F-induced chronic hepatotoxicity. Weanling male Wistar rats (three-weeks old) were divided into three groups and treated with drinking water containing 0, 5 or 50 mg/L F for 60 days (n=6/group). At this time point, serum and livers were collected for F analysis, which was done using the ion-sensitive electrode, after hexamethyldisiloxane-facilitated diffusion. Livers were also submitted to histological and proteomic analyses (2D-PAGE followed by LC-MS/MS). Western blotting was done for confirmation of the proteomic data A dose-response was observed in serum F levels. In the livers, F levels were significantly increased in the 50 mg/L F group compared to groups treated with 0 and 5 mg/L F. Liver morphometric analysis did not reveal alterations in the cellular structures and lipid droplets were present in all groups. Proteomic quantitative intensity analysis detected 33, 44, and 29 spots differentially expressed in the comparisons between control vs. 5 mg/L F, control vs. 50 mg/L F, and 5 mg/L vs. 50 mg/L F, respectively. From these, 92 proteins were successfully identified. In addition, 18, 1, and 5 protein spots were shown to be exclusive in control, 5, and 50 mg/L F, respectively. Most of proteins were related to metabolic process and pronounced alterations were seen for the high-F level group. In F-treated rats, changes in the apolipoprotein E (ApoE) and GRP-78 expression may account for the F-induced toxicity in the liver. This can contribute to understanding the molecular mechanisms underlying hepatoxicity induced by F, by indicating key proteins that should be better addressed in future studies. PMID- 24069404 TI - Enhanced production of recombinant secretory proteins in Pichia pastoris by optimizing Kex2 P1' site. AB - Pichiapastoris is one of the most widely used expression systems for the production of recombinant secretory proteins. Its universal application is, however, somewhat hampered by its unpredictable yields for different heterologous proteins, which is now believed to be caused in part by their varied efficiencies to traffic through the host secretion machinery. The yeast endoprotease Kex2 removes the signal peptides from pre-proteins and releases the mature form of secreted proteins, thus, plays a pivotal role in the yeast secretory pathways. In this study, we found that the yields of many recombinant proteins were greatly influenced by Kex2 P1' site residues and the optimized P1's amino acid residue could largely determine the final amount of secretory proteins synthesized and secreted. A further improvement of secretory yield was achieved by genomic integration of additional Kex2 copies, which again highlighted the importance of Kex2 cleavage to the production of recombinant secretory proteins in Pichia yeast. PMID- 24069405 TI - Ubp2 regulates Rsp5 ubiquitination activity in vivo and in vitro. AB - The yeast HECT-family E3 ubiquitin ligase Rsp5 has been implicated in diverse cell functions. Previously, we and others [1], [2] reported the physical and functional interaction of Rsp5 with the deubiquitinating enzyme Ubp2, and the ubiquitin associated (UBA) domain-containing cofactor Rup1. To investigate the mechanism and significance of the Rsp5-Rup1-Ubp2 complex, we examined Rsp5 ubiquitination status in the presence or absence of these cofactors. We found that, similar to its mammalian homologues, Rsp5 is auto-ubiquitinated in vivo. Association with a substrate or Rup1 increased Rsp5 self-ubiquitination, whereas Ubp2 efficiently deubiquitinates Rsp5 in vivo and in vitro. The data reported here imply an auto-modulatory mechanism of Rsp5 regulation common to other E3 ligases. PMID- 24069406 TI - Differences in process management and in-hospital delays in treatment with iv thrombolysis. AB - OBJECTIVES: Rapid initiation of intravenous thrombolysis improves patient's outcome in acute stroke. We analyzed inter-center variability and factors that influence the door-to-needle time with a special focus on process measurements in all Austrian stroke units. METHODS: Case level data of patients receiving intravenous thrombolysis in the Austrian Stroke Unit Registry were enriched with information of a structured questionnaire on center specific process measures of all Austrian stroke units. Influence of case and center specific variables was determined by LASSO procedure. RESULTS: Center specific median door-to-needle time ranged between 30 and 78 minutes. Between April 2004 and November 2012, 6246 of 57991 patients treated in Austrian stroke units with acute ischemic stroke received intravenous thrombolysis. An onset-to-door time >120 minutes, patients with total anterior circulation stroke, recent year of admission, patient transportation with ambulance crew and emergency physician, the use of point of care tests reduced the door-to-needle time, whereas onset-to-door <= 60 minutes, unknown onset-to-door, patients with an NIHSS <= 4 or posterior circulation stroke, initial admission to a general emergency department, a distant radiology department, primary imaging modality other than plain CT and waiting for the lab results were associated with an increase in door-to-needle time. Case level and center specific factors could explain the inter center variability of door-to needle times in 31 of 34 stroke units in Austria. CONCLUSIONS: In light of our results it seems crucial that every single stroke center documents and critically reviews possibilities of optimizing practice strategies in acute stroke care. PMID- 24069407 TI - Pseudomonas aeruginosa adaptation to lungs of cystic fibrosis patients leads to lowered resistance to phage and protist enemies. AB - Pathogenic life styles can lead to highly specialized interactions with host species, potentially resulting in fitness trade-offs in other ecological contexts. Here we studied how adaptation of the environmentally transmitted bacterial pathogen, Pseudomonas aeruginosa, to cystic fibrosis (CF) patients affects its survival in the presence of natural phage (14/1, PhiKZ, PNM and PT7) and protist (Tetrahymena thermophila and Acanthamoebae polyphaga) enemies. We found that most of the bacteria isolated from relatively recently intermittently colonised patients (1-25 months), were innately phage-resistant and highly toxic for protists. In contrast, bacteria isolated from long time chronically infected patients (2-23 years), were less efficient in both resisting phages and killing protists. Moreover, chronic isolates showed reduced killing of wax moth larvae (Galleria mellonella) probably due to weaker in vitro growth and protease expression. These results suggest that P. aeruginosa long-term adaptation to CF lungs could trade off with its survival in aquatic environmental reservoirs in the presence of microbial enemies, while lowered virulence could reduce pathogen opportunities to infect insect vectors; factors that are both likely to result in poorer environmental transmission. From an applied perspective, phage therapy could be useful against chronic P. aeruginosa lung infections that are often characterized by multidrug resistance: chronic isolates were least resistant to phages and their poor growth will likely slow down the emergence of beneficial resistance mutations. PMID- 24069408 TI - HIV testing patterns among black men who have sex with men: a qualitative typology. AB - BACKGROUND: Black men who have sex with men (MSM) in the Southeastern United States are disproportionately affected by HIV. Black MSM are more likely to have unrecognized HIV infection, suggesting that testing may occur later and/or infrequently relative to current recommendations. The objective of this qualitative study was to explore the HIV testing behaviors of Black MSM in Atlanta, Georgia, who were participants in the HIV Prevention Trials Network Brothers Study (HPTN 061). METHODS AND FINDINGS: We conducted 29 in-depth interviews and four focus groups with a community-recruited sample. Modified grounded theory methodologies were used to guide our inductive analysis, which yielded a typology comprised of four distinct HIV testing patterns. Participants could be categorized as: (1) Maintenance Testers, who tested regularly as part of routine self-care; (2) Risk-Based Testers, whose testing depended on relationship status or sexual behavior; (3) Convenience Testers, who tested irregularly depending on what testing opportunities arose; or (4) Test Avoiders, who tested infrequently and/or failed to follow up on results. We further characterized these groups with respect to age, socioeconomic factors, identity, stigma and healthcare access. CONCLUSIONS: Our findings highlight the heterogeneity of HIV testing patterns among Black MSM, and offer a framework for conceptualizing HIV testing in this group. Public health messaging must account for the diversity of Black MSM's experiences, and multiple testing approaches should be developed and utilized to maximize outreach to different types of testers. PMID- 24069409 TI - An evaluation of community assessment tools (CATs) in predicting use of clinical interventions and severe outcomes during the A(H1N1)pdm09 pandemic. AB - During severe influenza pandemics healthcare demand can exceed clinical capacity to provide normal standards of care. Community Assessment Tools (CATs) could provide a framework for triage decisions for hospital referral and admission. CATs have been developed based on evidence that supports the recognition of severe influenza and pneumonia in the community (including resource limited settings) for adults, children and infants, and serious feverish illness in children. CATs use six objective criteria and one subjective criterion, any one or more of which should prompt urgent referral and admission to hospital. A retrospective evaluation of the ability of CATs to predict use of hospital-based interventions and patient outcomes in a pandemic was made using the first recorded routine clinical assessment on or shortly after admission from 1520 unselected patients (800 female, 480 children <16 years) admitted with PCR confirmed A(H1N1)pdm09 infection (the FLU-CIN cohort). Outcome measures included: any use of supplemental oxygen; mechanical ventilation; intravenous antibiotics; length of stay; intensive or high dependency care; death; and "severe outcome" (combined: use of intensive or high dependency care or death during admission). Unadjusted and multivariable analyses were conducted for children (age <16 years) and adults. Each CATs criterion independently identified both use of clinical interventions that would in normal circumstances only be provided in hospital and patient outcome measures. "Peripheral oxygen saturation <= 92% breathing air, or being on oxygen" performed well in predicting use of resources and outcomes for both adults and children; supporting routine measurement of peripheral oxygen saturation when assessing severity of disease. In multivariable analyses the single subjective criterion in CATs "other cause for clinical concern" independently predicted death in children and in adults predicted length of stay, mechanical ventilation and "severe outcome"; supporting the role of clinical acumen as an important independent predictor of serious illness. PMID- 24069410 TI - Functional language shift to the right hemisphere in patients with language eloquent brain tumors. AB - OBJECTIVES: Language function is mainly located within the left hemisphere of the brain, especially in right-handed subjects. However, functional MRI (fMRI) has demonstrated changes of language organization in patients with left-sided perisylvian lesions to the right hemisphere. Because intracerebral lesions can impair fMRI, this study was designed to investigate human language plasticity with a virtual lesion model using repetitive navigated transcranial magnetic stimulation (rTMS). EXPERIMENTAL DESIGN: Fifteen patients with lesions of left sided language-eloquent brain areas and 50 healthy and purely right-handed participants underwent bilateral rTMS language mapping via an object-naming task. All patients were proven to have left-sided language function during awake surgery. The rTMS-induced language errors were categorized into 6 different error types. The error ratio (induced errors/number of stimulations) was determined for each brain region on both hemispheres. A hemispheric dominance ratio was then defined for each region as the quotient of the error ratio (left/right) of the corresponding area of both hemispheres (ratio >1 = left dominant; ratio <1 = right dominant). RESULTS: Patients with language-eloquent lesions showed a statistically significantly lower ratio than healthy participants concerning "all errors" and "all errors without hesitations", which indicates a higher participation of the right hemisphere in language function. Yet, there was no cortical region with pronounced difference in language dominance compared to the whole hemisphere. CONCLUSIONS: This is the first study that shows by means of an anatomically accurate virtual lesion model that a shift of language function to the non-dominant hemisphere can occur. PMID- 24069411 TI - Whey proteins are more efficient than casein in the recovery of muscle functional properties following a casting induced muscle atrophy. AB - The purpose of this study was to investigate the effect of whey supplementation, as compared to the standard casein diet, on the recovery of muscle functional properties after a casting-induced immobilization period. After an initial (I0) evaluation of the contractile properties of the plantarflexors (isometric torque frequency relationship, concentric power-velocity relationship and a fatigability test), the ankle of 20 male adult rats was immobilized by casting for 8 days. During this period, rats were fed a standard diet with 13% of casein (CAS). After cast removal, rats received either the same diet or a diet with 13% of whey proteins (WHEY). A control group (n = 10), non-immobilized but pair-fed to the two other experimental groups, was also studied and fed with the CAS diet. During the recovery period, contractile properties were evaluated 7 (R7), 21 (R21) and 42 days (R42) after cast removal. The immobilization procedure induced a homogeneous depression of average isometric force at R7 (CAS: - 19.0 +/- 8.2%; WHEY: - 21.7 +/- 8.4%; P<0.001) and concentric power (CAS: - 26.8 +/- 16.4%, P<0.001; WHEY: - 13.5 +/- 21.8%, P<0.05) as compared to I0. Conversely, no significant alteration of fatigability was observed. At R21, isometric force had fully recovered in WHEY, especially for frequencies above 50 Hz, whereas it was still significantly depressed in CAS, where complete recovery occurred only at R42. Similarly, recovery of concentric power was faster at R21 in the 500-700 degrees /s range in the WHEY group. These results suggest that recovery kinetics varied between diets, the diet with the whey proteins promoting a faster recovery of isometric force and concentric power output as compared to the casein diet. These effects were more specifically observed at force level and movement velocities that are relevant for functional abilities, and thus natural locomotion. PMID- 24069412 TI - Solution-phase vs surface-phase aptamer-protein affinity from a label-free kinetic biosensor. AB - Aptamers are selected DNA ligands that target biomolecules such as proteins. In recent years, they are showing an increasing interest as potential therapeutic agents or recognition elements in biosensor applications. In both cases, the need for characterizing the mating between the target and the aptamer either in solution or immobilized on a surface, is pressing. In this context, we have developed a kinetic biosensor made of micro-arrayed anti-thrombin aptamers to assess the kinetic parameters of this interaction. The binding of label-free thrombin on the biosensor was monitored in real-time by Surface Plasmon Resonance imaging. Remarkable performances were obtained for the quantification of thrombin without amplification (sub-nanomolar limit of detection and linear range of quantification to two orders of magnitude). The independent determinations of both the solution- and surface-phase affinities, respectively KD(Sol) and KD(Surf), revealed distinct values illustrating the importance of probes, targets or surface interactions in biosensors. Interestingly, KD(Surf) values depend on the aptamer grafting density and linearly extrapolate towards KD(Sol) for highly diluted probes. This suggests a lesser impact of the surface compared to the probe or target cooperativity interactions since the latter decrease with a reduced grafting density. PMID- 24069413 TI - Identification and structural characterization of interneurons of the Drosophila brain by monoclonal antibodies of the wurzburg hybridoma library. AB - Several novel synaptic proteins have been identified by monoclonal antibodies (mAbs) of the Wurzburg hybridoma library generated against homogenized Drosophila brains, e.g. cysteine string protein, synapse-associated protein of 47 kDa, and Bruchpilot. However, at present no routine technique exists to identify the antigens of mAbs of our library that label only a small number of cells in the brain. Yet these antibodies can be used to reproducibly label and thereby identify these cells by immunohistochemical staining. Here we describe the staining patterns in the Drosophila brain for ten mAbs of the Wurzburg hybridoma library. Besides revealing the neuroanatomical structure and distribution of ten different sets of cells we compare the staining patterns with those of antibodies against known antigens and GFP expression patterns driven by selected Gal4 lines employing regulatory sequences of neuronal genes. We present examples where our antibodies apparently stain the same cells in different Gal4 lines suggesting that the corresponding regulatory sequences can be exploited by the split-Gal4 technique for transgene expression exclusively in these cells. The detection of Gal4 expression in cells labeled by mAbs may also help in the identification of the antigens recognized by the antibodies which then in addition to their value for neuroanatomy will represent important tools for the characterization of the antigens. Implications and future strategies for the identification of the antigens are discussed. PMID- 24069414 TI - Neural correlates of musical creativity: differences between high and low creative subjects. AB - Previous studies of musical creativity suggest that this process involves multi regional intra and interhemispheric interactions, particularly in the prefrontal cortex. However, the activity of the prefrontal cortex and that of the parieto temporal regions, seems to depend on the domains of creativity that are evaluated and the task that is performed. In the field of music, only few studies have investigated the brain process of a creative task and none of them have investigated the effect of the level of creativity on the recruit networks. In this work we used magnetic resonance imaging to explore these issues by comparing the brain activities of subjects with higher creative abilities to those with lesser abilities, while the subjects improvised on different rhythmic fragments. We evaluated the products the subjects created during the fMRI scan using two musical parameters: fluidity and flexibility, and classified the subjects according to their punctuation. We examined the relation between brain activity and creativity level. Subjects with higher abilities generated their own creations based on modifications of the original rhythm with little adhesion to it. They showed activation in prefrontal regions of both hemispheres and the right insula. Subjects with lower abilities made only partial changes to the original musical patterns. In these subjects, activation was only observed in left unimodal areas. We demonstrated that the activations of prefrontal and paralimbic areas, such as the insula, are related to creativity level, which is related to a widespread integration of networks that are mainly associated with cognitive, motivational and emotional processes. PMID- 24069415 TI - c-Src and neural Wiskott-Aldrich syndrome protein (N-WASP) promote low oxygen induced accelerated brain invasion by gliomas. AB - Malignant gliomas remain associated with poor prognosis and high morbidity because of their ability to invade the brain; furthermore, human gliomas exhibit a phenotype of accelerated brain invasion in response to anti-angiogenic drugs. Here, we study 8 human glioblastoma cell lines; U251, U87, D54 and LN229 show accelerated motility in low ambient oxygen. Src inhibition by Dasatinib abrogates this phenotype. Molecular discovery and validation studies evaluate 46 molecules related to motility or the src pathway in U251 cells. Demanding that the molecular changes induced by low ambient oxygen are reversed by Dasatinib in U251 cells, identifies neural Wiskott-Aldrich syndrome protein (NWASP), Focal adhesion Kinase (FAK), [Formula: see text]-Catenin, and Cofilin. However, only Src mediated NWASP phosphorylation distinguishes the four cell lines that exhibit enhanced motility in low ambient oxygen. Downregulating c-Src or NWASP by RNA interference abrogates the low-oxygen-induced enhancement in motility by in vitro assays and in organotypic brain slice cultures. The findings support the idea that c-Src and NWASP play key roles in mediating the molecular pathogenesis of low oxygen-induced accelerated brain invasion by gliomas. PMID- 24069416 TI - A mariner transposon-based signature-tagged mutagenesis system for the analysis of oral infection by Listeria monocytogenes. AB - Listeria monocytogenes is a Gram-positive foodborne pathogen and the causative agent of listerosis a disease that manifests predominately as meningitis in the non-pregnant individual or infection of the fetus and spontaneous abortion in pregnant women. Common-source outbreaks of foodborne listeriosis are associated with significant morbidity and mortality. However, relatively little is known concerning the mechanisms that govern infection via the oral route. In order to aid functional genetic analysis of the gastrointestinal phase of infection we designed a novel signature-tagged mutagenesis (STM) system based upon the invasive L. monocytogenes 4b serotype H7858 strain. To overcome the limitations of gastrointestinal infection by L. monocytogenes in the mouse model we created a H7858 strain that is genetically optimised for oral infection in mice. Furthermore our STM system was based upon a mariner transposon to favour numerous and random transposition events throughout the L. monocytogenes genome. Use of the STM bank to investigate oral infection by L. monocytogenes identified 21 insertion mutants that demonstrated significantly reduced potential for infection in our model. The sites of transposon insertion included lmOh7858_0671 (encoding an internalin homologous to Lmo0610), lmOh7858_0898 (encoding a putative surface expressed LPXTG protein homologous to Lmo0842), lmOh7858_2579 (encoding the HupDGC hemin transport system) and lmOh7858_0399 (encoding a putative fructose specific phosphotransferase system). We propose that this represents an optimised STM system for functional genetic analysis of foodborne/oral infection by L. monocytogenes. PMID- 24069417 TI - Automatic identification of highly conserved family regions and relationships in genome wide datasets including remote protein sequences. AB - Identifying shared sequence segments along amino acid sequences generally requires a collection of closely related proteins, most often curated manually from the sequence datasets to suit the purpose at hand. Currently developed statistical methods are strained, however, when the collection contains remote sequences with poor alignment to the rest, or sequences containing multiple domains. In this paper, we propose a completely unsupervised and automated method to identify the shared sequence segments observed in a diverse collection of protein sequences including those present in a smaller fraction of the sequences in the collection, using a combination of sequence alignment, residue conservation scoring and graph-theoretical approaches. Since shared sequence fragments often imply conserved functional or structural attributes, the method produces a table of associations between the sequences and the identified conserved regions that can reveal previously unknown protein families as well as new members to existing ones. We evaluated the biological relevance of the method by clustering the proteins in gold standard datasets and assessing the clustering performance in comparison with previous methods from the literature. We have then applied the proposed method to a genome wide dataset of 17793 human proteins and generated a global association map to each of the 4753 identified conserved regions. Investigations on the major conserved regions revealed that they corresponded strongly to annotated structural domains. This suggests that the method can be useful in predicting novel domains on protein sequences. PMID- 24069418 TI - Predicting the long-term impact of antiretroviral therapy scale-up on population incidence of tuberculosis. AB - OBJECTIVE: To investigate the impact of antiretroviral therapy (ART) on long-term population-level tuberculosis disease (TB) incidence in sub-Saharan Africa. METHODS: We used a mathematical model to consider the effect of different assumptions about life expectancy and TB risk during long-term ART under alternative scenarios for trends in population HIV incidence and ART coverage. RESULTS: All the scenarios we explored predicted that the widespread introduction of ART would initially reduce population-level TB incidence. However, many modelled scenarios projected a rebound in population-level TB incidence after around 20 years. This rebound was predicted to exceed the TB incidence present before ART scale-up if decreases in HIV incidence during the same period were not sufficiently rapid or if the protective effect of ART on TB was not sustained. Nevertheless, most scenarios predicted a reduction in the cumulative TB incidence when accompanied by a relative decline in HIV incidence of more than 10% each year. CONCLUSIONS: Despite short-term benefits of ART scale-up on population TB incidence in sub-Saharan Africa, longer-term projections raise the possibility of a rebound in TB incidence. This highlights the importance of sustaining good adherence and immunologic response to ART and, crucially, the need for effective HIV preventive interventions, including early widespread implementation of ART. PMID- 24069419 TI - Habitat selection and risk of predation: re-colonization by lynx had limited impact on habitat selection by roe deer. AB - Risk of predation is an evolutionary force that affects behaviors of virtually all animals. In this study, we examined how habitat selection by roe deer was affected by risk of predation by Eurasian lynx - the main predator of roe deer in Scandinavia. Specifically, we compared how habitat selection by roe deer varied (1) before and after lynx re-established in the study area and (2) in relation to habitat-specific risk of predation by lynx. All analyses were conducted at the spatial and temporal scales of home ranges and seasons. We did not find any evidence that roe deer avoided habitats in which the risk of predation by lynx was greatest and information-theoretic model selection showed that re colonization by lynx had limited impact on habitat selection by roe deer despite lynx predation causing 65% of known mortalities after lynx re-colonized the area. Instead we found that habitat selection decreased when habitat availability increased for 2 of 5 habitat types (a pattern referred to as functional response in habitat selection). Limited impact of re-colonization by lynx on habitat selection by roe deer in this study differs from elk in North America altering both daily and seasonal patterns in habitat selection at the spatial scales of habitat patches and home ranges when wolves were reintroduced to Yellowstone National Park. Our study thus provides further evidence of the complexity by which animals respond to risk of predation and suggest that it may vary between ecosystems and predator-prey constellations. PMID- 24069420 TI - Changes in the distribution of atlantic bluefin tuna (Thunnus thynnus) in the Gulf of Maine 1979-2005. AB - The Gulf of Maine, NW Atlantic Ocean, is a productive, seasonal foraging ground for Atlantic bluefin tuna (Thunnus thynnus), but commercial landings of adult size classes were up to 40% below the allocated total allowable catch between 2004 to 2008 for the rod and reel, harpoon, and purse seine categories in the Gulf of Maine. Reduction in Atlantic bluefin tuna catches in the Gulf of Maine could represent a decline in spawning stock biomass, but given wide-ranging, complex migration patterns, and high energetic requirements, an alternative hypothesis is that their dispersal patterns shifted to regions with higher prey abundance or profitability, reducing availability to U.S. fishing fleets. This study fit generalized linear models to Atlantic bluefin tuna landings data collected from fishermen's logbooks (1979-2005) as well as the distances between bluefin tuna schools and Atlantic herring (Clupeaharengus), a primary prey species, to test alternative hypotheses for observed shifts in Atlantic bluefin tuna availability in the Gulf of Maine. For the bluefin model, landings varied by day of year, latitude and longitude. The effect of latitude differed by day of year and the effect of longitude differed by year. The distances between Atlantic bluefin tuna schools and Atlantic herring schools were significantly smaller (p<0.05) than would be expected from a randomly distributed population. A time series of average bluefin tuna school positions was positively correlated with the average number of herring captured per tow on Georges Bank in spring and autumn surveys respectively (p<0.01, r(2)=0.24, p<0.01, r(2)=0.42). Fishermen's logbooks contributed novel spatial and temporal information towards testing these hypotheses for the bluefin tuna fishery. PMID- 24069421 TI - Tree diversity mediates the distribution of longhorn beetles (Coleoptera: Cerambycidae) in a changing tropical landscape (southern Yunnan, SW China). AB - LONGHORN BEETLES (COLEOPTERA: Cerambycidae) have been used to identify sites of high biological diversity and conservation value in cultivated landscapes, but were rarely studied in changing landscapes of humid tropics. This study was conducted in a region of southern Yunnan, China, which was dominated by natural rainforest until 30 years ago, but is successively transformed into commercial rubber monoculture plantations since that time. The objectives were to investigate longhorn beetle species diversity and distribution in the major land use types of this landscape and to estimate the effects of an expected expansion of rubber plantations on the longhorn beetle assemblages. The results showed that tree species diversity (181 species in total) and longhorn beetle diversity (220 species in total) were closely related with no significant differences between the tree and longhorn beetles assemblages shown by similarity distance analysis. There was a highly positive relationship between the estimated species richness of longhorn beetles and the number of tree species. Individual numbers of longhorn beetles and trees were also highly positive related at the sampling sites. Non-metric multidimensional scaling revealed that the degree of canopy coverage, succession age and tree diversity explained 78.5% of the total variation in longhorn beetle assemblage composition. Natural forest sites had significantly higher numbers of species and individuals than any other type of habitat. Although young rubber plantations bear the highest longhorn beetle diversity outside forests (half of the total number of longhorn beetle species recorded in total), they can not provide permanent habitats for most of these species, because they develop into closed canopy plantations with less suitable habitat conditions. Therefore, along with an expected expansion of rubber cultivation which largely proceeds at the expense of forest areas, the habitat conditions for longhorn beetles in this region might decrease dramatically in future. PMID- 24069422 TI - Cadherin 6 is a new RUNX2 target in TGF-beta signalling pathway. AB - Modifications in adhesion molecules profile may change the way tumor cells interact with the surrounding microenvironment. The Cadherin family is a large group of transmembrane proteins that dictate the specificity of the cellular interactions. The Cadherin switch that takes place during epithelial-mesenchymal transition (EMT) contributes to loosening the rigid organization of epithelial tissues and to enhancing motility and invasiveness of tumor cells. Recently, we found Cadherin-6 (CDH6, also known as K-CAD) highly expressed in thyroid tumor cells that display mesenchymal features and aggressive phenotype, following the overexpression of the transcriptional regulator Id1. In this work, we explored the possibility that CDH6 is part of the EMT program in thyroid tumors. We demonstrate that CDH6 is a new transforming growth factor-beta (TGF-beta) target and that its expression is modulated similarly to other EMT mesenchymal markers, both in vitro and in thyroid tumor patients. We show for the first time that CDH6 is expressed in human thyroid carcinomas and that its expression is enhanced at the invasive front of the tumor. Finally, we show that CDH6 is under the control of the transcription factor RUNX2, which we previously described as a crucial mediator of the Id1 pro-invasive function in thyroid tumor cells. Overall, these observations provide novel information on the mechanism of the EMT program in tumor progression and indicate CDH6 as a potential regulator of invasiveness in thyroid tumors. PMID- 24069423 TI - The business case for bariatric surgery revisited: a non-randomized case-control study. AB - BACKGROUND AND AIM: Prior studies reporting that bariatric surgery (including laparoscopic adjustable gastric band (LAGB) and [laparoscopic Roux-en-Y] Gastric Bypass (LRYGB)) is cost-saving relied on a comparison sample of those with a morbid obesity (MO) diagnosis code, a high cost group who may not be reflective of those who opt for the procedures. We re-estimate net costs and time to breakeven using an alternative sample that does not rely on this code. MATERIALS AND METHODS: Non-randomized case-control study using medical claims data from a commercial database in the USA. LAGB and LRYGB claimants were propensity score matched to two control samples: one restricted to those with a MO diagnosis code and one without this restriction. RESULTS: When using the MO sample, costs for LAGB and LRYGB are recovered in 1.5 (Confidence Interval [CI]: 1.45 to 1.55) and 2.25 years (CI: 2.07 to 2.43), and 5 year savings are $78,980 (CI: 62,320 to 100,550) for LAGB and $61,420 (CI: 44,710 to 82,870) for LRYGB. Without the MO requirement, time to breakeven for LAGB increases to 5.25 (CI: 4.25 to 10+) years with a 5 year net cost of $690 (CI: 6,800 to 8.400). For LRYGB, time to breakeven exceeds 10 years and 5 year net costs are $18,940 (CI: 10,390 to 26,740). CONCLUSIONS: The net costs and time to breakeven resulting from bariatric surgery are likely less favorable than has been reported in prior studies, and especially for LRYGB, with a time to breakeven of more than twice the 5.25 year estimate for LAGB. PMID- 24069425 TI - Climate change and water use partitioning by different plant functional groups in a grassland on the Tibetan Plateau. AB - The Tibetan Plateau (TP) is predicted to experience increases in air temperature, increases in snowfall, and decreases in monsoon rains; however, there is currently a paucity of data that examine the ecological responses to such climate changes. In this study, we examined the effects of increased air temperature and snowfall on: 1) water use partitioning by different plant functional groups, and 2) ecosystem CO2 fluxes throughout the growing season. At the individual plant scale, we used stable hydrogen isotopes (deltaD) to partition water use between shallow- and deep-rooted species. Prior to the arrival of summer precipitation (typically mid-July), snowmelt was the main water source in the soils. During this time, shallow and deep-rooted species partitioned water use by accessing water from shallow and deep soils, respectively. However, once the monsoon rains arrived, all plants used rainwater from the upper soils as the main water source. Snow addition did not result in increased snowmelt use throughout the growing season; instead, snowmelt water was pushed down into deeper soils when the rains arrived. At the larger plot scale, CO2 flux measurements demonstrated that rain was the main driver for net ecosystem productivity (NEP). NEP rates were low during June and July and reached a maximum during the monsoon season in August. Warming decreased NEP through a reduction in gross primary productivity (GPP), and snow additions did not mitigate the negative effects of warming by increasing NEP or GPP. Both the isotope and CO2 flux results suggest that rain drives productivity in the Nam Tso region on the TP. This also suggests that the effects of warming-induced drought on the TP may not be mitigated by increased snowfall. Further decreases in summer monsoon rains may affect ecosystem productivity, with large implications for livestock-based livelihoods. PMID- 24069424 TI - Structure-activity relationships of FMRF-NH2 peptides demonstrate A role for the conserved C terminus and unique N-terminal extension in modulating cardiac contractility. AB - FMRF-NH2 peptides which contain a conserved, identical C-terminal tetrapeptide but unique N terminus modulate cardiac contractility; yet, little is known about the mechanisms involved in signaling. Here, the structure-activity relationships (SARs) of the Drosophila melanogaster FMRF-NH2 peptides, PDNFMRF-NH2, SDNFMRF NH2, DPKQDFMRF-NH2, SPKQDFMRF-NH2, and TPAEDFMRF-NH2, which bind FMRFa-R, were investigated. The hypothesis tested was the C-terminal tetrapeptide FMRF-NH2, particularly F1, makes extensive, strong ligand-receptor contacts, yet the unique N terminus influences docking and activity. To test this hypothesis, docking, binding, and bioactivity of the C-terminal tetrapeptide and analogs, and the FMRF NH2 peptides were compared. Results for FMRF-NH2 and analogs were consistent with the hypothesis; F1 made extensive, strong ligand-receptor contacts with FMRFa-R; Y -> F (YMRF-NH2) retained binding, yet A -> F (AMRF-NH2) did not. These findings reflected amino acid physicochemical properties; the bulky, aromatic residues F and Y formed strong pi-stacking and hydrophobic contacts to anchor the ligand, interactions which could not be maintained in diversity or number by the small, aliphatic A. The FMRF-NH2 peptides modulated heart rate in larva, pupa, and adult distinctly, representative of the contact sites influenced by their unique N terminal structures. Based on physicochemical properties, the peptides each docked to FMRFa-R with one best pose, except FMRF-NH2 which docked with two equally favorable poses, consistent with the N terminus influencing docking to define specific ligand-receptor contacts. Furthermore, SDNAMRF-NH2 was designed and, despite lacking the aromatic properties of one F, it binds FMRFa-R and demonstrated a unique SAR, consistent with the N terminus influencing docking and conferring binding and activity; thus, supporting our hypothesis. PMID- 24069426 TI - Evidence for DNA cleavage caused directly by a transfer RNA-targeting toxin. AB - The killer yeast species Pichiaacaciae produces a heteromeric killer protein, PaT, that causes DNA damage and arrests the cell cycle of sensitive Saccharomyces cerevisiae in the S phase. However, the mechanism by which DNA damage occurs remains elusive. A previous study has indicated that Orf2p, a subunit of PaT, specifically cleaves an anticodon loop of an S. cerevisiae transfer RNA (tRNA(Gln)mcm5s2UUG). This finding raised a question about whether the DNA damage is a result of the tRNA cleavage or whether Orf2p directly associates with and cleaves the genomic DNA of sensitive yeast cells. We showed that Orf2p cleaves genomic DNA in addition to cleaving tRNA in vitro. This DNA cleavage requires the same Orf2p residue as that needed for tRNA cleavage, His299. The expression of Orf2p, in which His299 was substituted to alanine, abolished the cell cycle arrest of the host cell. Moreover, the translation impairment induced by tRNA cleavage enabled Orf2p to enter the nucleus, thereby inducing histone phosphorylation. PMID- 24069427 TI - Access to resources shapes maternal decision making: evidence from a factorial vignette experiment. AB - The central assumption of behavioral ecology is that natural selection has shaped individuals with the capacity to make decisions that balance the fitness costs and benefits of behavior. A number of factors shape the fitness costs and benefits of maternal care, but we lack a clear understanding how they, taken together, play a role in the decision-making process. In animal studies, the use of experimental methods has allowed for the tight control of these factors. Standard experimentation is inappropriate in human behavioral ecology, but vignette experiments may solve the problem. I used a confounded factorial vignette experiment to gather 640 third-party judgments about the maternal care decisions of hypothetical women and their children from 40 female karo Batak respondents in rural Indonesia. This allowed me to test hypotheses derived from parental investment theory about the relative importance of five binary factors in shaping maternal care decisions with regard to two distinct scenarios. As predicted, access to resources--measured as the ability of a woman to provide food for her children--led to increased care. A handful of other factors conformed to prediction, but they were inconsistent across scenarios. The results suggest that mothers may use simple heuristics, rather than a full accounting for costs and benefits, to make decisions about maternal care. Vignettes have become a standard tool for studying decision making, but have made only modest inroads to evolutionarily informed studies of human behavior. PMID- 24069428 TI - A serotonin transporter gene (SLC6A4) polymorphism is associated with reduced risk of irritable bowel syndrome in American and Asian population: a meta analysis. AB - AIM: Association studies of serotonin transporter gene SLC6A4 I/S polymorphism and irritable bowel syndrome (IBS) have shown inconsistent and contradictory results among different populations. In the present study, meta-analysis was performed to evaluate the association between SLC6A4 I/S polymorphism and IBS susceptibility. METHODOLOGY: Systemic assessment was performed for the published studies based on the association of SLC6A4 I/S polymorphism and IBS risk from PubMed (Medline), EMBASE search. A meta-analysis was done to appraise the said association. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for allele contrast, homozygous, heterozygous, dominant and recessive genetic model. RESULTS: A total of twelve studies comprising 2068 IBS cases and 2076 controls were included in this meta-analysis. Overall, no significant results were obtained for S allele carrier (S vs. I: p=0.488; OR=1.073, 95% CI=0.879 to 1.311) Co-dominant (SS vs. II; p=0.587; OR=1.112, 95% CI=0.758 to 1.631), (IS vs. II; p=0.361; OR=0.878, 95% CI=0.665 to 1.160). Similarly, dominant (SS+IS vs. II: p=0.853; OR=0.974, 95% CI=0.736 to 1.288) and recessive (SS vs. II+IS: p=0.267; OR=1.172, 95% CI=0.886 to 1.522) genetic models did not demonstrate risk. In the subgroup population based analysis, reduced risks were found in American (IS vs. II: p=0.009; OR=0.685, 95% CI=0.516 to 0.908) and Asian (SS+IS vs. II; p=0.001; OR=0.116, 95% CI=0.068 to 0.197) population. However, no risk was observed in European population. CONCLUSIONS: This investigation clearly demonstrates that SLC6A4 (Ins/Del) polymorphism is associated with reduced risk of IBS in American and Asian population. However, future well-designed studies with stratified case control and biological characterization will be needed to validate this finding. PMID- 24069429 TI - Erythrocyte-bound apolipoprotein B in relation to atherosclerosis, serum lipids and ABO blood group. AB - INTRODUCTION: Erythrocytes carry apolipoprotein B on their membrane, but the determining factors of erythrocyte-bound apolipoprotein B (ery-apoB) are unknown. We aimed to explore the determinants of ery-apoB to gain more insight into potential mechanisms. METHODS: Subjects with and without CVD were included (N = 398). Ery-apoB was measured on fresh whole blood samples using flow cytometry. Subjects with ery-apoB levels <= 0.20 a.u. were considered deficient. Carotid intima media thickness (CIMT) was determined as a measure of (subclinical) atherosclerosis. RESULTS: Mean ery-apoB value was 23.2% lower in subjects with increased CIMT (0.80 +/- 0.09 mm, N = 140) compared to subjects with a normal CIMT (0.57 +/- 0.08 mm, N = 258) (P = 0.007, adjusted P<0.001). CIMT and ery-apoB were inversely correlated (Spearman's r: -0.116, P = 0.021). A total of 55 subjects (13.6%) were considered ery-apoB deficient, which was associated with a medical history of CVD (OR: 1.86, 95% CI 1.04-3.33; adjusted OR: 1.55; 95% CI 0.85-2.82). Discontinuation of statins in 54 subjects did not influence ery-apoB values despite a 58.4% increase in serum apolipoprotein B. Subjects with blood group O had significantly higher ery-apoB values (1.56 +/- 0.94 a.u.) when compared to subjects with blood group A (0.89 +/- 1.15 a.u), blood group B (0.73 +/- 0.1.12 a.u.) or blood group AB (0.69 +/- 0.69 a.u.) (P-ANOVA = 0.002). CONCLUSION: Absence or very low values of ery-apoB are associated with clinical and subclinical atherosclerosis. While serum apolipoprotein B is not associated with ery-apoB, the ABO blood group seems to be a significant determinant. PMID- 24069430 TI - Epidemiology of hepatitis C virus infection and risk factor analysis in the Hebei Province, China. AB - BACKGROUND: In 1985, a hepatitis C virus (HCV) outbreak caused by plasmapheresis donation was reported in the Hebei Province, China. However, studies assessing the epidemic features and risk factors of HCV in the general population of Hebei have been limited until now. METHODS: The multicenter cluster sampling method was used to collect samples. The participants were interviewed. Relevant information was obtained from the general population using a standardized questionnaire, and association and logistic regression analyses were conducted. Serum samples were taken to test anti-HCV by enzyme immunoassays. RESULTS: A total of 4562 participants from 11 cities of the Hebei Province were enrolled. The average anti HCV positive rate was 0.62% (29/4562), which was 1.07% in the rural population, compared with 0.22% in the urban population. The anti-HCV positive rate in the 40 59-year age group was higher than in those aged <40 years. History of blood transfusion and transmission in families were the main risk factors for HCV infection in this area. CONCLUSION: The anti-HCV positive rate in Hebei has decreased significantly from that two decades ago. Safety of blood products and health education about HCV still need to be improved. PMID- 24069431 TI - Dietary flavonoid intake and smoking-related cancer risk: a meta-analysis. AB - PURPOSE: To systematically investigate the effects of dietary flavonoids and flavonoid subclasses on the risk of smoking-related cancer in observational studies. METHODS: Summary estimates and corresponding standard errors were calculated using the multivariate-adjusted odds ratio (OR) or relative risk (RR) and 95% CI of selected studies and weighted by the inverse variance. RESULTS: A total of 35 studies, including 19 case-controls (9,525 cases and 15,835 controls) and 15 cohort studies (988,082 subjects and 8,161 cases), were retrieved for the meta-analysis. Total dietary flavonoids and most of the flavonoid subclasses were inversely associated with smoking-related cancer risk (OR: 0.82, 95% CI: 0.72 0.93). In subgroup analyses by cancer site, significant associations were observed in aerodigestive tract and lung cancers. Total dietary flavonoid intake was significantly associated with aerodigestive tract cancer risk (OR: 0.67, 95% CI: 0.54-0.83) marginally associated with lung cancer risk (OR: 0.84, 95% CI: 0.71-1.00). Subgroup analyses by smoking status showed significantly different results. The intake of total flavonoids, flavonols, flavones, and flavanones, as well as the flavonols quercetin and kaempferol was significantly associated with decreased risk of smoking-related cancer in smokers, whereas no association was observed in non-smokers, except for flavanones. In meta-analysis for the effect of subclasses of dietary flavonoids by cancer type, aerodigestive tract cancer was inversely associated with most flavonoid subclasses. CONCLUSION: The protective effects of flavonoids on smoking-related cancer risk varied across studies, but the overall results indicated that intake of dietary flavonoids, especially flavonols, was inversely associated with smoking-related cancer risk. The protective effects of flavonoids on smoking-related cancer risk were more prominent in smokers. PMID- 24069432 TI - Identification of reference genes for qRT-PCR analysis in Yesso scallop Patinopecten yessoensis. AB - BACKGROUND: Bivalves comprise around 30,000 extant species and have received much attention for their importance in ecosystems, aquaculture and evolutionary studies. Despite the increasing application of real-time quantitative reverse transcription PCR (qRT-PCR) in gene expression studies on bivalve species, little research has been conducted on reference gene selection which is critical for reliable and accurate qRT-PCR analysis. For scallops, systematic evaluation of reference genes that can be used among tissues or embryo/larva stages is lacking, and beta-actin (ACT) is most frequently used as qRT-PCR reference gene without validation. RESULTS: In this study, 12 commonly used candidate reference genes were selected from the transcriptome data of Yesso scallop (Patinopectenyessoensis) for suitable qRT-PCR reference genes identification. The expression of these genes in 36 tissue samples and 15 embryo/larva samples under normal physiological conditions was examined by qRT-PCR, and their expression stabilities were evaluated using three statistic algorithms, geNorm, NormFinder, and comparative ?Ct method. Similar results were obtained by the three approaches for the most and the least stably expressed genes. Final comprehensive ranking for the 12 genes combing the results from the three programs showed that, for different tissues, DEAD-box RNA helicase (HELI), ubiquitin (UBQ), and 60S ribosomal protein L16 (RPL16) were the optimal reference genes combination, while for different embryo/larva stages, gene set containing Cytochrome B (CB), Cytochrome C (CC), Histone H3.3 (His3.3), and Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were recommended for qRT-PCR normalization. ACT was among the least stable genes for both adult tissues and embryos/larvae. CONCLUSIONS: This work constitutes the first systematic analysis on reference genes selection for qRT-PCR normalization in scallop under normal conditions. The suitable reference genes we recommended will be useful for the identification of genes related to biological processes in Yesso scallop, and also in the reference gene selection for other scallop or bivalve species. PMID- 24069433 TI - Inhibition of HCV replication by oxysterol-binding protein-related protein 4 (ORP4) through interaction with HCV NS5B and alteration of lipid droplet formation. AB - Hepatitis C virus (HCV) RNA replication involves complex interactions among the 3'x RNA element within the HCV 3' untranslated region, viral and host proteins. However, many of the host proteins remain unknown. In this study, we devised an RNA affinity chromatography /2D/MASS proteomics strategy and identified nine putative 3' X-associated host proteins; among them is oxysterol-binding protein related protein 4 (ORP4), a cytoplasmic receptor for oxysterols. We determined the relationship between ORP4 expression and HCV replication. A very low level of constitutive ORP4 expression was detected in hepatocytes. Ectopically expressed ORP4 was detected in the endoplasmic reticulum and inhibited luciferase reporter gene expression in HCV subgenomic replicon cells and HCV core expression in JFH-1 infected cells. Expression of ORP4S, an ORP4 variant that lacked the N-terminal pleckstrin-homology domain but contained the C-terminal oxysterol-binding domain also inhibited HCV replication, pointing to an important role of the oxysterol binding domain in ORP4-mediated inhibition of HCV replication. ORP4 was found to associate with HCV NS5B and its expression led to inhibition of the NS5B activity. ORP4 expression had little effect on intracellular lipid synthesis and secretion, but it induced lipid droplet formation in the context of HCV replication. Taken together, these results demonstrate that ORP4 is a negative regulator of HCV replication, likely via interaction with HCV NS5B in the replication complex and regulation of intracellular lipid homeostasis. This work supports the important role of lipids and their metabolism in HCV replication and pathogenesis. PMID- 24069434 TI - The impact of the receptor of hyaluronan-mediated motility (RHAMM) on human urothelial transitional cell cancer of the bladder. AB - Hyaluronan (HA) is a carbohydrate of the extracellular matrix with tumor promoting effects in a variety of cancers. The present study addressed the role of HA matrix for progression and prognosis of human bladder cancer by studying the expression and function of HA-related genes. METHODS: Tissue samples of 120 patients with different stages of transitional cell bladder cancer, who underwent surgical treatment for bladder cancer at the University Hospital of Essen were analysed. mRNA-expression levels of HA synthases (HAS1-3) and HA-receptors (RHAMM and CD44) were evaluated by real time RT-PCR in comparison to healthy bladder tissue as control. In uni- and multivariate cox proportional hazard survival regression analysis, the impact of the gene expression levels on survival was assessed. In vitro knock-down of RHAMM, CD44 and HAS isoenzymes was achieved by siRNA and lentiviral shRNA in J82 bladder cancer cells. Transfected cells were analysed in vitro with regard to proliferation, cell cycle and apoptosis. J82 cells after knock-down of RHAMM were xenografted into male nu/nu athymic mice to monitor tumor progression in vivo. RESULTS: In invasive tumor stages RHAMM-, HAS1 and HAS2 mRNA-expression levels were elevated whereas HAS3v1 was reduced as compared to non-invasive tumors. Subsequently, Kaplan-Meier analysis revealed reduced bladder cancer specific survival in patients with high RHAMM mRNA and low HAS3v1 expression. Elevated RHAMM in invasive tumors was confirmed by RHAMM immunohistochemistry. Furthermore, multivariate analysis revealed that only RHAMM expression was associated with poor prognosis independent from other survival factors (HR=2.389, 95% CI 1.227-4.651, p=0.01). Lentiviral RHAMM knock-down revealed reduced J82 cell proliferation in vitro and reduced xenograft tumor growth in vivo. CONCLUSION: The data suggest that RHAMM plays a crucial role in mediating progression of muscle-invasive bladder cancer and recommends RHAMM for further evaluation as a prognostic marker or therapeutic target in bladder cancer therapy. PMID- 24069435 TI - Prediction of reproductive outcomes according to different serum anti-Mullerian hormone levels in females undergoing intracystoplasmic sperm injection. AB - BACKGROUND AND AIM OF THE STUDY: Serum anti-Mullerian hormone (AMH) is a reliable marker of ovarian reserve, and it has been shown to be correlated with reproductive outcomes in grouped analyses. However, practical data is scarce for the physician and the patients to predict these outcomes in an individual couple according to serum AMH measured prior to assisted reproduction technology (ART) procedures. STUDY DESIGN: To address this question, we performed an analytic observational study including 145 females undergoing intracytoplasmic sperm injection (ICSI) in a single center. Results were analyzed according to serum AMH; subgroup analyses were performed by grouping patients according to patient's age and FSH levels. RESULTS: The risk of cycle cancellation decreased from 64% in patients with serum AMH <= 3 pmol/L (0.42 ng/mL) to 21% with AMH >= 15 pmol/L (2.10 ng/mL). Cycle cancellation occurred in approximately two-thirds of the patients with AMH <= 3 pmol/L irrespective of the FSH level. However, with higher AMH values the risk of cycle cancellation decreased more significantly in patients with normal FSH. The rate of good response increased from almost null in patients with AMH <= 3 pmol/L to 61% in those with AMH >= 15 pmol/L. The positive correlation between good response and AMH was also significant, but with lower absolute rates, when patients were grouped according to their age or FSH levels. Pregnancy rate increased moderately, but significantly, from 31% with AMH <= 3 pmol/L to 35% with AMH >= 15 pmol/L. CONCLUSIONS: We provide estimates of reproductive outcomes according to individualized values of serum AMH, in general and in subgroups according to patient's age or serum FSH, which are helpful for the clinician and the couple in their decision making about starting an assisted reproductive treatment. PMID- 24069436 TI - Maturation of calcium-dependent GABA, glycine, and glutamate release in the glycinergic MNTB-LSO pathway. AB - The medial nucleus of the trapezoid body (MNTB) is a key nucleus in high-fidelity temporal processing that underlies sound localization in the auditory brainstem. While the glycinergic principal cells of the MNTB project to all primary nuclei of the superior olive, during development the projection from MNTB to the lateral superior olive (LSO) is of interest because this immature inhibitory projection is known to undergo tonotopic refinement during an early postnatal period, and because during this period individual MNTB terminals in the LSO transiently release glycine GABA and glutamate. Developmental changes in calcium-dependent release are understood to be required to allow various auditory nuclei to follow high frequency activity; however, little is known about maturation of calcium dependent release in the MNTB-LSO pathway, which has been presumed to have less stringent requirements for high-fidelity temporal following. In acute brainstem slices of rats age postnatal day 1 to 15 we recorded whole-cell responses in LSO principal neurons to electrical stimulation in the MNTB in order to measure sensitivity to external calcium, the contribution of different voltage-gated calcium channel subtypes to vesicular release, and the maturation of these measures for both GABA/glycine and glutamate transmission. Our results establish that release of glutamate at MNTB-LSO synapses is calcium-dependent. Whereas no significant developmental changes were evident for glutamate release, GABA/glycine release underwent substantial changes over the first two postnatal weeks: soon after birth L-type, N-type, and P/Q-type voltage-gated calcium channels (VGCCs) together mediated release, but after hearing onset P/Q-type VGCCs predominated. Blockade of P/Q-type VGCCs reduced the estimated quantal number for GABA/gly and glutamate transmission at P5-8 and the frequency of evoked miniature glycinergic events at P12-15, without apparent effects on spontaneous release of neurotransmitter, supporting a model in which P/Q-type VGCCs are required for mature synchronous synaptic transmission, but not for spontaneous vesicle release. PMID- 24069437 TI - A cross sectional study of knowledge and attitudes towards tuberculosis amongst front-line tuberculosis personnel in high burden areas of Lima, Peru. AB - INTRODUCTION: Tuberculosis, reported as the second most common infectious cause of death worldwide, is a key mortality contributor in developing countries and globally. The disease is endemic in Peru and while relative success was achieved during the 1990s in its control, this slowed as new complications, such as multi drug resistant TB arose. Health centre workers participating in the national DOTS program, create the front-line TB work-force in Peru meaning their knowledge and attitudes about the disease are key in its control. METHODS: A Spanish language, multiple choice knowledge and attitudes survey was designed based on previous successful studies and the national Peruvian TB control guidelines. It was applied to two health networks in Lima, Peru amongst 301 health workers participating in the national TB control program from 66 different health centres. The study results were analysed to test mean knowledge scores amongst different groups, overall gaps in key areas of TB treatment and control knowledge, and attitudes towards the disease and the national TB control program. RESULTS: A mean knowledge score of 10.1 (+/- 1.7) out of 15 or 67.3% correct was shown. Demographics shown to have an effect on knowledge score were age and level of education. Major knowledge gaps were noted primarily in themes relating to treatment and diagnostics. Greater community involvement including better patient education about TB was seen as important in implementing the national TB control program. Participants were in disagreement about the current distribution of health resources throughout the study area. Discussion Serious knowledge gaps were identified from the survey; these reflect findings from a previous study in Lima and other studies from TB endemic areas throughout the world. Understanding these gaps and observations made by front-line TB workers in Lima may help to improve the national TB control program and other control efforts globally. PMID- 24069438 TI - Disruption of the endothelial barrier by proteases from the bacterial pathogen Pseudomonas aeruginosa: implication of matrilysis and receptor cleavage. AB - Within the vasculature, uncontrolled pericellular proteolysis can lead to disruption of cell-to-cell and cell-to-matrix interactions and subsequent detachment-induced cell apoptosis, or anoikis, contributing to inflammatory vascular diseases, with the endothelium as the major target. Most studies so far have focused on endogenous proteinases. However, during bloodstream infections, bacterial proteinases may also trigger endothelial anoikis. We thus investigated the potential apoptotic activity of the proteinases secreted by the haematotropic opportunistic pathogen, Pseudomonas aeruginosa, and particularly its predominant metalloproteinase, LasB. For this, we used the secretome of the LasB-expressing pseudomonal strain, PAO1, and compared it with that from the isogenic, LasB deficient strain (PAO1?lasB), as well as with purified LasB. Secretomes were tested for apoptotic activity on cultured human endothelial cells derived from the umbilical vein or from the cerebral microvasculature. We found that the PAO1 secretome readily induced endothelial cell anoikis, as did secretomes of LasB positive clinical pseudomonal isolates, while the PAO1?lasB secretome had only a limited impact on endothelial adherence and viability. Notably, purified LasB reproduced most of the effects of the LasB-containing secretomes, and these were drastically reduced in the presence of the LasB-selective inhibitor, phosphoramidon. A precocious and extensive LasB-dependent degradation of several proteins associated with the endothelial extracellular matrix, fibronectin and von Willebrand factor, was observed by immunofluorescence and/or immunoblotting analysis of cell cultures. Moreover, the PAO1 secretome, but not that from PAO1?lasB, specifically induced rapid endoproteolysis of two major interendothelial junction components, VE-cadherin and occludin, as well as of the anti-anoikis, integrin-associated urokinase receptor, uPAR. Taken as a prototype for exogenous haemorrhagic proteinases, pseudomonal LasB thus appears to induce endothelial anoikis not only via matrilysis, as observed for many pro-apoptotic proteinases, but also via cleavage of some essential cell-to-cell and cell-to matrix adhesion receptors implicated in the maintenance of the endothelial barrier. PMID- 24069439 TI - Ketogenic diet improves motor performance but not cognition in two mouse models of Alzheimer's pathology. AB - Dietary manipulations are increasingly viewed as possible approaches to treating neurodegenerative diseases. Previous studies suggest that Alzheimer's disease (AD) patients present an energy imbalance with brain hypometabolism and mitochondrial deficits. Ketogenic diets (KDs), widely investigated in the treatment and prevention of seizures, have been suggested to bypass metabolic deficits present in AD brain by providing ketone bodies as an alternative fuel to neurons. We investigated the effects of a ketogenic diet in two transgenic mouse lines. Five months old APP/PS1 (a model of amyloid deposition) and Tg4510 (a model of tau deposition) mice were offered either a ketogenic or a control (NIH 31) diet for 3 months. Body weight and food intake were monitored throughout the experiment, and blood was collected at 4 weeks and 4 months for ketone and glucose assessments. Both lines of transgenic mice weighed less than nontransgenic mice, yet, surprisingly, had elevated food intake. The ketogenic diet did not affect these differences in body weight or food consumption. Behavioral testing during the last two weeks of treatment found that mice offered KD performed significantly better on the rotarod compared to mice on the control diet independent of genotype. In the open field test, both transgenic mouse lines presented increased locomotor activity compared to nontransgenic, age-matched controls, and this effect was not influenced by KD. The radial arm water maze identified learning deficits in both transgenic lines with no significant differences between diets. Tissue measures of amyloid, tau, astroglial and microglial markers in transgenic lines showed no differences between animals fed the control or the ketogenic diet. These data suggest that ketogenic diets may play an important role in enhancing motor performance in mice, but have minimal impact on the phenotype of murine models of amyloid or tau deposition. PMID- 24069440 TI - High resolution measurement of light in terrestrial ecosystems using photodegrading dyes. AB - Incoming solar radiation is the main determinant of terrestrial ecosystem processes, such as primary production, litter decomposition, or soil mineralization rates. Light in terrestrial ecosystems is spatially and temporally heterogeneous due to the interaction among sunlight angle, cloud cover and tree canopy structure. To integrate this variability and to know light distribution over time and space, a high number of measurements are needed, but tools to do this are usually expensive and limited. An easy-to-use and inexpensive method that can be used to measure light over time and space is needed. We used two photodegrading fluorescent organic dyes, rhodamine WT (RWT) and fluorescein, for the quantification of light. We measured dye photodegradation as the decrease in fluorescence across an irradiance gradient from full sunlight to deep shade. Then, we correlated it to accumulated light measured with PAR quantum sensors and obtained a model for this behavior. Rhodamine WT and fluorescein photodegradation followed an exponential decay curve with respect to accumulated light. Rhodamine WT degraded slower than fluorescein and remained unaltered after exposure to temperature changes. Under controlled conditions, fluorescence of both dyes decreased when temperatures increased, but returned to its initial values after cooling to the pre-heating temperature, indicating no degradation. RWT and fluorescein can be used to measure light under a varying range of light conditions in terrestrial ecosystems. This method is particularly useful to integrate solar radiation over time and to measure light simultaneously at different locations, and might be a better alternative to the expensive and time consuming traditional light measurement methods. The accuracy, low price and ease of this method make it a powerful tool for intensive sampling of large areas and for developing high resolution maps of light in an ecosystem. PMID- 24069441 TI - Interactions between parents and parents and pups in the monogamous California mouse (Peromyscus californicus). AB - The California mouse (Peromyscuscalifornicus) may be a valuable animal model to study parenting as it is one of the few monogamous and biparental rodent species. By using automated infra-red imaging and video documentation of established pairs spanning two days prior to birth of the litter until d 5 of post natal development (PND), it was possible to follow interactions between parents and between parents and pups. The paired males were attentive to their partners in the form of grooming and sniffing throughout the time period studied. Both these and other activities of the partners, such as eating and drinking, peaked during late light/ mid-dark period. Beginning the day before birth, and most significantly on PND 0, the female made aggressive attempts to exclude the male from nest-attending, acts that were not reciprocated by the male, although he made repeated attempts to mate his partner during that period. By PND 1, males were permitted to return to the nest, where they initiated grooming, licking, and huddling over the litter, although time spent by the male on parental care was still less than that of the female. Male and female pups were of similar size and grew at the same rate. Pups, which are believed to be exothermic for at least the first two weeks post-natally, maintained a body temperature higher than that of their parents until PND 16. Data are consistent with the inference that the male California mouse parent is important in helping retain pup body heat and permit dams increased time to procure food to accommodate her increased energy needs for lactation. These assessments provide indices that may be used to assess the effects of extrinsic factors, such as endocrine disrupting chemicals, on biparental behaviors and offspring development. PMID- 24069442 TI - A protein-based hydrogel for in vitro expansion of mesenchymal stem cells. AB - Hydrogels are widely used as scaffolds in tissue engineering because they can provide excellent environments for bioactive components including growth factors and cells. We reported in this study on a physical hydrogel formed by a specific protein-peptide interaction, which could be used for the three dimensional (3D) cell culture of murine mesenchymal stem cells (mMSC). The mMSC kept dividing during the 7-day culture period and the metabolic-active cell number at day 7 was 359% more than that at day 1. This kind of physical hydrogel could be converted to a homogeneous solution by firstly adding an equal volume of culture medium and then pipeting for several times. Therefore, mMSC post culture could be easily separated from cell-gel constructs. We believed that the protein-based hydrogel system in this study could be developed into a promising scaffold for in vitro expansion of stem cells and cell therapy. This work would be in the general interests of researchers in the fields of biomaterials and supramolecular chemistry. PMID- 24069443 TI - The formin protein mDia2 serves as a marker of spindle pole dynamics in vitrified warmed mouse oocytes. AB - The mouse diaphanous 2 (mDia2) protein belongs to the formin family and has been shown to nucleate actin filaments and stabilize microtubules, thus indicating a role in cytoskeleton organization. Our previous study, which showed that mDia2 specifically localizes to spindle poles of metaphase I mouse oocytes and NIH3T3 cells, provided the first evidence of its spindle pole-associated cellular function. In the present study, we aim to determine whether spindle pole proteins, such as mDia2 and pericentrin, can be used to monitor the status of spindle poles in cryopreserved mouse oocytes. We show herein that mDia2 exhibits an overlapping distribution with pericentrin, which is a crucial component of centrosomes and microtubule organizing centers (MTOCs). In vitrified-warmed oocytes, the overlapping distribution of mDia2 and pericentrin was immediately detected after thawing, thereby suggesting that mDia2 maintains a tight association with the spindle pole machinery. Interestingly, we observed that microtubules extend from mDia2 clusters in cytoplasmic MTOCs after thawing. This result suggests that mDia2 is a major MTOC component that is closely associated with pericentrin and that it plays a role in microtubule growth from MTOCs. Collectively, our results provide evidence that mDia2 is a novel marker of spindle pole dynamics before and after cryopreservation. PMID- 24069444 TI - Lipopolysaccharide-induced neuronal activation in the paraventricular and dorsomedial hypothalamus depends on ambient temperature. AB - Systemic inflammatory response syndrome is associated with either fever or hypothermia, but the mechanisms responsible for switching from one to the other are unknown. In experimental animals, systemic inflammation is often induced by bacterial lipopolysaccharide (LPS). To identify the diencephalic and brainstem structures involved in the fever-hypothermia switch, we studied the expression of c-Fos protein, a marker of neuronal activation, in rats treated with the same high dose of LPS (0.5 mg/kg, intravenously) either in a thermoneutral (30 degrees C) or cool (24 degrees C) environment. At 30 degrees C, LPS caused fever; at 24 degrees C, the same dose caused profound hypothermia. Both fever and hypothermia were associated with the induction of c-Fos in many brain areas, including several structures of the anterior preoptic, paraventricular, lateral, and dorsal hypothalamus, the bed nucleus of the stria terminalis, the posterior pretectal nucleus, ventrolateral periaqueductal gray, lateral parabrachial nucleus, area postrema, and nucleus of the solitary tract. Every brain area studied showed a comparable response to LPS at the two different ambient temperatures used, with the exception of two areas: the dorsomedial hypothalamic nucleus (DMH), which we studied together with the adjacent dorsal hypothalamic area (DA), and the paraventricular hypothalamic nucleus (PVH). Both structures had much stronger c-Fos expression during LPS hypothermia than during fever. We propose that PVH and DMH/DA neurons are involved in a circuit, which - depending on the ambient temperature - determines whether the thermoregulatory response to bacterial LPS will be fever or hypothermia. PMID- 24069445 TI - Strategy for sensitive and specific detection of Yersinia pestis in skeletons of the black death pandemic. AB - Yersinia pestis has been identified as the causative agent of the Black Death pandemic in the 14(th) century. However, retrospective diagnostics in human skeletons after more than 600 years are critical. We describe a strategy following a modern diagnostic algorithm and working under strict ancient DNA regime for the identification of medieval human plague victims. An initial screening and DNA quantification assay detected the Y. pestis specific pla gene of the high copy number plasmid pPCP1. Results were confirmed by conventional PCR and sequence analysis targeting both Y. pestis specific virulence plasmids pPCP1 and pMT1. All assays were meticulously validated according to human clinical diagnostics requirements (ISO 15189) regarding efficiency, sensitivity, specificity, and limit of detection (LOD). Assay specificity was 100% tested on 41 clinically relevant bacteria and 29 Y. pseudotuberculosis strains as well as for DNA of 22 Y. pestis strains and 30 previously confirmed clinical human plague samples. The optimized LOD was down to 4 gene copies. 29 individuals from three different multiple inhumations were initially assessed as possible victims of the Black Death pandemic. 7 samples (24%) were positive in the pPCP1 specific screening assay. Confirmation through second target pMT1 specific PCR was successful for 4 of the positive individuals (14%). A maximum of 700 and 560 copies per ul aDNA were quantified in two of the samples. Those were positive in all assays including all repetitions, and are candidates for future continuative investigations such as whole genome sequencing. We discuss that all precautions taken here for the work with aDNA are sufficient to prevent external sample contamination and fulfill the criteria of authenticity. With regard to retrospective diagnostics of a human pathogen and the uniqueness of ancient material we strongly recommend using a careful strategy and validated assays as presented in our study. PMID- 24069446 TI - Spatial genetic analyses reveal cryptic population structure and migration patterns in a continuously harvested grey wolf (Canis lupus) population in north eastern Europe. AB - Spatial genetics is a relatively new field in wildlife and conservation biology that is becoming an essential tool for unravelling the complexities of animal population processes, and for designing effective strategies for conservation and management. Conceptual and methodological developments in this field are therefore critical. Here we present two novel methodological approaches that further the analytical possibilities of STRUCTURE and DResD. Using these approaches we analyse structure and migrations in a grey wolf (Canislupus) population in north-eastern Europe. We genotyped 16 microsatellite loci in 166 individuals sampled from the wolf population in Estonia and Latvia that has been under strong and continuous hunting pressure for decades. Our analysis demonstrated that this relatively small wolf population is represented by four genetic groups. We also used a novel methodological approach that uses linear interpolation to statistically test the spatial separation of genetic groups. The new method, which is capable of using program STRUCTURE output, can be applied widely in population genetics to reveal both core areas and areas of low significance for genetic groups. We also used a recently developed spatially explicit individual-based method DResD, and applied it for the first time to microsatellite data, revealing a migration corridor and barriers, and several contact zones. PMID- 24069447 TI - Age-related differences in cortical activity during a visuo-spatial working memory task with facial stimuli. AB - Emotion, importantly displayed by facial expressions, is one of the most significant memory modulators. The interaction between memory and the different emotional valences change across lifespan, while young adults (YA) are expected to better recall negative events (Negativity Bias Hypothesis), older adults (OA) tend to focus on positive stimuli (Positivity Effect Hypothesis). This research work aims at verifying whether cortical electrical activity of these two age groups would also be differently influenced by emotional valences in a visuo spatial working memory task. 27 YA (13 males) and 25 OA (14 males), all healthy volunteers, underwent electroencephalographic recordings (21 scalp electrodes montage), while performing the Spatial Delayed Recognition Span Task using a touch screen with different stimuli categories: neutral, positive and negative faces and geometric pictures. YA obtained higher scores than OA, and showed higher activation of theta and alpha bands in the frontal and midline regions, besides a more evident right-hemispheric asymmetry on alpha band when compared to OA. For both age groups, performance in the task was worse for positive faces than to negative and to neutral faces. Facial stimuli induced a better performance and higher alpha activation on the pre-frontal region for YA, and on the midline, occipital and left temporal regions for OA when compared to geometric figures. The superior performance of YA was expected due to the natural cognitive deficits connected to ageing, as was a better performance with facial stimuli due to the evolutionary importance of faces. These results were related to cortical activity on areas of importance for action-planning, decision making and sustained attention. Taken together, they are in accordance with the Negativity Bias but do not support the Positivity Effect. The methodology used was able to identify age-related differences in cortical activity during emotional mnemonic processing and may be interesting to future investigations. PMID- 24069448 TI - Inadvertent occlusion of the anterior choroidal artery explains infarct variability in the middle cerebral artery thread occlusion stroke model. AB - Intraluminal occlusion of the middle cerebral artery (MCAo) in rodents is perhaps the most widely used model of stroke, however variability of infarct volume and the ramifications of this on sample sizes remains a problem, particularly for preclinical testing of potential therapeutics. Our data and that of others, has shown a dichotomous distribution of infarct volumes for which there had previously been no clear explanation. When studying perfusion computed tomography cerebral blood volume (CBV) maps obtained during intraluminal MCAo in rats, we observed inadvertent occlusion of the anterior choroidal artery (AChAo) in a subset of animals. We hypothesized that the combined occlusion of the MCA and AChA may be a predictor of larger infarct volume following stroke. Thus, we aimed to determine the correlation between AChAo and final infarct volume in rats with either temporary or permanent MCA occlusion (1 h, 2 h, or permanent MCAo). Outbred Wistar rats (n = 28) were imaged prior to and immediately following temporary or permanent middle cerebral artery occlusion. Presence of AChAo on CBV maps was shown to be a strong independent predictor of 24 h infarct volume (beta = 0.732, p <0.001). This provides an explanation for the previously observed dichotomous distribution of infarct volumes. Interestingly, cortical infarct volumes were also larger in rats with AChAo, although the artery does not supply cortex. This suggests an important role for perfusion of the MCA territory beyond the proximal occlusion through AChA-MCA anastomotic collateral vessels in animals with a patent AChAo. Identification of combined MCAo and AChAo will allow other investigators to tailor their stroke model to reduce variability in infarct volumes, improve statistical power and reduce sample sizes in preclinical stroke research. PMID- 24069449 TI - Serotonin 2B receptor (5-HT2B R) signals through prostacyclin and PPAR-beta/delta in osteoblasts. AB - Osteoporosis is due to an imbalance between decreased bone formation by osteoblasts and increased resorption by osteoclasts. Deciphering factors controlling bone formation is therefore of utmost importance for the understanding and the treatment of osteoporosis. Our previous in vivo results showed that bone formation is reduced in the absence of the serotonin receptor 5 HT2B, causing impaired osteoblast proliferation, recruitment, and matrix mineralization. In this study, we investigated the signaling pathways responsible for the osteoblast defect in 5-HT2BR(-/-) mice. Notably, we investigated the phospholipase A2 pathway and synthesis of eicosanoids in 5-HT2BR(-/-) compared to wild type (WT) osteoblasts. Compared to control osteoblasts, the lack of 5-HT2B receptors was only associated with a 10-fold over-production of prostacyclin (PGI2). Also, a specific prostacyclin synthase inhibitor (U51605) rescued totally osteoblast aggregation and matrix mineralization in the 5-HT2BR(-/-) osteoblasts without having any effect on WT osteoblasts. Prostacyclin is the endogenous ligand of the nuclear peroxisome proliferator activated receptor beta/delta (PPAR beta/delta), and its inhibition in 5-HT2BR(-/-) cells rescued totally the alkaline phosphatase and osteopontin mRNA levels, cell-cell adhesion, and matrix mineralization. We conclude that the absence of 5-HT2B receptors leads to the overproduction of prostacyclin, inducing reduced osteoblast differentiation due to PPAR-beta/delta -dependent target regulation and defective cell-cell adhesion and matrix mineralization. This study thus reveals a previously unrecognized cell autonomous osteoblast defect in the absence of 5-HT2BR and highlights a new pathway linking 5-HT2B receptors and nuclear PPAR- beta/delta via prostacyclin. PMID- 24069450 TI - The implications of temperature-mediated plasticity in larval instar number for development within a marine invertebrate, the shrimp Palaemonetes varians. AB - Variations in larval instar number are common among arthropods. Here, we assess the implications of temperature-mediated variations in larval instar number for larval development time, larval growth rates, and juvenile dry weight within the palaemonid shrimp, Palaemonetes varians. In contrast with previous literature, which focuses on terrestrial arthropods, particularly model and pest species often of laboratory lines, we use wild shrimp, which differ in their life history from previous models. Newly-hatched P. varians larvae were first reared at 5, 10, 17, 25, and 30 degrees C to assess their thermal scope for development. Larvae developed at 17, 25, and 30 degrees C. At higher temperatures, larvae developed through fewer larval instars. Two dominant developmental pathways were observed; a short pathway of four instars and a long pathway of five instars. Longer developmental pathways of six to seven instars were rarely observed (mostly at lower temperatures) and consisted of additional instars as 'repeat' instars; i.e. little developmental advance over the preceding instar. To assess the implications of temperature-mediated variation in larval instar number, newly hatched larvae were then reared at 15, 20, and 25 degrees C. Again, the proportion of larvae developing through four instars increased with temperature. At all temperatures, larval development time and juvenile dry weight were greater for larvae developing through five instars. Importantly, because of the increasing proportion of larvae developing through four instars with increasing temperature, larval traits associated with this pathway (reduced development time and juvenile dry weight) became more dominant. As a consequence of increasing growth rate with temperature, and the shift in the proportion of larvae developing through four instars, juvenile dry weight was greatest at intermediate temperatures (20 degrees C). We conclude that at settlement P. varians juveniles do not follow the temperature-size rule; this is of importance for life-history ecology in response to environmental change, as well as for aquaculture applications. PMID- 24069451 TI - Structured pro-active care for chronic depression by practice nurses in primary care: a qualitative evaluation. AB - PURPOSE: This qualitative study explored the impact and appropriateness of structured pro-active care reviews by practice nurses for patients with chronic or recurrent depression and dysthymia within the ProCEED trial. ProCEED (Pro active Care and its Evaluation for Enduring Depression) was a United Kingdom wide randomised controlled trial, comparing usual general practitioner care with structured 'pro-active care' which involved 3 monthly review appointments with practice nurses over 2 years for patients with chronic or recurrent depression. METHOD: In-depth interviews were completed with 41 participants: 26 patients receiving pro-active care and 15 practice nurses providing this care. Interview transcripts were analysed thematically using a 'framework' approach. RESULTS: Patients perceived the practice nurses to be appropriate professionals to engage with regarding their depression and most nurses felt confident in a case management role. The development of a therapeutic alliance between the patient and nurse was central to this model and, where it appeared lacking, dissatisfaction was felt by both patients and nurses with a likely negative impact on outcomes. Patient and nurse factors impacting on the therapeutic alliance were identified and nurse typologies explored. DISCUSSION: Pro-active care reviews utilising practice nurses as case managers were found acceptable by the majority of patients and practice nurses and may be a suitable way to provide care for patients with long-term depression in primary care. Motivated and interested practice nurses could be an appropriate and valuable resource for this patient group. This has implications for resource decisions by clinicians and commissioners within primary care. PMID- 24069453 TI - A reverse engineering approach to optimize experiments for the construction of biological regulatory networks. AB - One of the major objectives in systems biology is to understand the relation between the topological structures and the dynamics of biological regulatory networks. In this context, various mathematical tools have been developed to deduct structures of regulatory networks from microarray expression data. In general, from a single data set, one cannot deduct the whole network structure; additional expression data are usually needed. Thus how to design a microarray expression experiment in order to get the most information is a practical problem in systems biology. Here we propose three methods, namely, maximum distance method, trajectory entropy method, and sampling method, to derive the optimal initial conditions for experiments. The performance of these methods is tested and evaluated in three well-known regulatory networks (budding yeast cell cycle, fission yeast cell cycle, and E. coli. SOS network). Based on the evaluation, we propose an efficient strategy for the design of microarray expression experiments. PMID- 24069452 TI - Vasodilatory effect of the stable vasoactive intestinal peptide analog RO 25-1553 in murine and rat lungs. AB - RATIONALE: Stable analogs of vasoactive intestinal peptide (VIP) have been proposed as novel line of therapy in chronic obstructive pulmonary disease (COPD) based on their bronchodilatory and anti-inflammatory effects. We speculated that VIP analogs may provide additional benefits in that they exert vasodilatory properties in the lung, and tested this hypothesis in both ex vivo and in vivo models. METHODS: In isolated perfused mouse lungs and in an in vivo rat model, pulmonary blood vessels were preconstricted by hypoxia and hemodynamic changes in response to systemic (ex vivo) or inhaled (in vivo) administration of the cyclic VIP analog RO 25-1553 were determined. RESULTS: In mouse lungs, RO 25-1553 reduced intrinsic vascular resistance at normoxia, and attenuated the increase in pulmonary artery pressure in response to acute hypoxia. Consistently, inhalation of RO 25-1553 (1 mg . mL(-1) for 3 min) caused an extensive and sustained (> 60 min) inhibition of the pulmonary arterial pressure increase in response to hypoxia in vivo that was comparable to the effects of inhaled sildenafil. This effect was not attributable to systemic cardiovascular effects of RO 25-1553, but to a lung specific reduction in pulmonary vascular resistance, while cardiac output and systemic arterial hemodynamics remained unaffected. No adverse effects of RO 25-1553 inhalation on pulmonary gas exchange, ventilation-perfusion matching, or lung fluid content were detected. CONCLUSION: Our findings demonstrate that inhaled delivery of the stable VIP analog RO 25-1553 induces a potent and sustained vasodilatory effect in the pulmonary circulation with no detectable adverse effects. Therapeutic inhalation of RO 25-1553 may provide vascular benefits in addition to its reported anti-inflammatory and bronchodilatory effects in COPD, yet caution is warranted given the overall poor results of vasodilator therapies for pulmonary hypertension secondary to COPD in a series of recent clinical trials. PMID- 24069454 TI - Combining phylogenetic profiling-based and machine learning-based techniques to predict functional related proteins. AB - Annotating protein functions and linking proteins with similar functions are important in systems biology. The rapid growth rate of newly sequenced genomes calls for the development of computational methods to help experimental techniques. Phylogenetic profiling (PP) is a method that exploits the evolutionary co-occurrence pattern to identify functional related proteins. However, PP-based methods delivered satisfactory performance only on prokaryotes but not on eukaryotes. This study proposed a two-stage framework to predict protein functional linkages, which successfully enhances a PP-based method with machine learning. The experimental results show that the proposed two-stage framework achieved the best overall performance in comparison with three PP-based methods. PMID- 24069455 TI - A hybrid NRPS-PKS gene cluster related to the bleomycin family of antitumor antibiotics in Alteromonas macleodii strains. AB - Although numerous marine bacteria are known to produce antibiotics via hybrid NRPS-PKS gene clusters, none have been previously described in an Alteromonas species. In this study, we describe in detail a novel hybrid NRPS-PKS cluster identified in the plasmid of the Alteromonasmacleodii strain AltDE1 and analyze its relatedness to other similar gene clusters in a sequence-based characterization. This is a mobile cluster, flanked by transposase-like genes, that has even been found inserted into the chromosome of some Alteromonasmacleodii strains. The cluster contains separate genes for NRPS and PKS activity. The sole PKS gene appears to carry a novel acyltransferase domain, quite divergent from those currently characterized. The predicted specificities of the adenylation domains of the NRPS genes suggest that the final compound has a backbone very similar to bleomycin related compounds. However, the lack of genes involved in sugar biosynthesis indicates that the final product is not a glycopeptide. Even in the absence of these genes, the presence of the cluster appears to confer complete or partial resistance to phleomycin, which may be attributed to a bleomycin-resistance-like protein identified within the cluster. This also suggests that the compound still shares significant structural similarity to bleomycin. Moreover, transcriptomic evidence indicates that the NRPS-PKS cluster is expressed. Such sequence-based approaches will be crucial to fully explore and analyze the diversity and potential of secondary metabolite production, especially from increasingly important sources like marine microbes. PMID- 24069456 TI - A TNF variant that associates with susceptibility to musculoskeletal disease modulates thyroid hormone receptor binding to control promoter activation. AB - Tumor necrosis factor (TNF) is a powerful pro-inflammatory cytokine and immuno regulatory molecule, and modulates susceptibility to musculoskeletal diseases. Several meta-analyses and replicated association studies have implicated the minor 'A' variant within the TNF promoter single nucleotide polymorphism (SNP) rs361525 (-238A/G) as a risk allele in joint related disorders, including psoriatic and juvenile idiopathic arthritis, and osteolysis after joint arthroplasty. Here we characterized the effect of this variant on TNF promoter function. A transcriptional reporter, encoding the -238A variant of the TNF promoter, resulted in 2.2 to 2.8 times greater transcriptional activation versus the 'G' variant in murine macrophages when stimulated with pro-inflammatory stimuli. Bioinformatic analysis predicted a putative binding site for thyroid hormone receptor (TR) for the -238A but not the -238G allele. Overexpression of TR-alpha induced promoter expression 1.8-fold in the presence of the 'A' allele only. TR-alpha expression both potentiated and sensitized the -238A response to LPS or a titanium particulate stimulus, whilst siRNA knockdown of either THRA or THRB impaired transcriptional activation for the -238A variant only. This effect was independent of receptor-ligand binding of triiodothyronine. Immunohistochemical analysis of osteolysis interface membranes from patients undergoing revision surgery confirmed expression of TR-alpha within osteoclast nuclei at the resorption surface. The 'A' allele at rs361525 confers increased transcriptional activation of the TNF promoter and influences susceptibility to several arthritic conditions. This effect is modulated, at least in part, by binding of TR, which both sensitizes and potentiates transcriptional activation of the 'A' variant independent of its endogenous ligand. PMID- 24069457 TI - Hyperactivity of ON-type retinal ganglion cells in streptozotocin-induced diabetic mice. AB - Impairment of visual function has been detected in the early stage of diabetes but the underlying neural mechanisms involved are largely unknown. Morphological and functional alterations of retinal ganglion cells, the final output neurons of the vertebrate retina, are thought to be the major cause of visual defects in diabetes but direct evidence to support this notion is limited. In this study we investigated functional changes of retinal ganglion cells in a type 1-like diabetic mouse model. Our results demonstrated that the spontaneous spiking activity of ON-type retinal ganglion cells was increased in streptozotocin diabetic mice after 3 to 4 months of diabetes. At this stage of diabetes, no apoptotic signals or cell loss were detected in the ganglion cell layer of the retina, suggesting that the functional alterations in ganglion cells occur prior to massive ganglion cell apoptosis. Furthermore, we found that the increased activity of ON-type ganglion cells was mainly a result of reduced inhibitory signaling to the cells in diabetes. This novel mechanism provides insight into how visual function is impaired in diabetic retinopathy. PMID- 24069458 TI - Adipose weight gain during chronic insulin treatment of mice results from changes in lipid storage without affecting de novo synthesis of palmitate. AB - Insulin treatment is associated with increased adipose mass in both humans and mice. However, the underlying dynamic basis of insulin induced lipid accumulation in adipose tissue remains elusive. To assess this, young female C57BL6/J mice were fed a low fat diet for 3 weeks, treated subsequently with 7 days of constant subcutaneous insulin infusion by osmotic minipumps and compared to mice with only buffer infused. To track changes in lipid deposition during insulin treatment, metabolic labeling was conducted with heavy water for the final 4 days. Blood glucose was significantly lowered within one hour after implantation of insulin loaded mini pumps and remained lower throughout the study. Insulin treated animals gained significantly more weight during treatment and the mean weight of the subcutaneous adipose depots was significantly higher with the highest dose of insulin. Surprisingly, de novo palmitate synthesis within the subcutaneous and the gonadal depots was not affected significantly by insulin treatment. In contrast insulin treatment caused accumulation of triglycerides in both depots due to either deposition of newly synthesised triglycerides (subcutaneous depot) or inhibition of lipolysis (gonadal depot). PMID- 24069459 TI - Healthcare environments and spatial variability of healthcare associated infection risk: cross-sectional surveys. AB - Prevalence of healthcare associated infections remains high in patients in intensive care units (ICU), estimated at 23.4% in 2011. It is important to reduce the overall risk while minimizing the cost and disruption to service provision by targeted infection control interventions. The aim of this study was to develop a monitoring tool to analyze the spatial variability of bacteriological contamination within the healthcare environment to assist in the planning of interventions. Within three cross-sectional surveys, in two ICU wards, air and surface samples from different heights and locations were analyzed. Surface sampling was carried out with tryptic Soy Agar contact plates and Total Viable Counts (TVC) were calculated at 48 hrs (incubation at 37 degrees C). TVCs were analyzed using Poisson Generalized Additive Mixed Model for surface type analysis, and for spatial analysis. Through three cross-sectional survey, 370 samples were collected. Contamination varied from place-to-place, height-to height, and by surface type. Hard-to-reach surfaces, such as bed wheels and floor area under beds, were generally more contaminated, but the height level at which maximal TVCs were found changed between cross-sectional surveys. Bedside locations and bed occupation were risk factors for contamination. Air sampling identified clusters of contamination around the nursing station and surface sampling identified contamination clusters at numerous bed locations. By investigating dynamic hospital wards, the methodology employed in this study will be useful to monitor contamination variability within the healthcare environment and should help to assist in the planning of interventions. PMID- 24069461 TI - Metabolic rate limits the effect of sperm competition on mammalian spermatogenesis. AB - Sperm competition leads to increased sperm production in many taxa. This response may result from increases in testes size, changes in testicular architecture or changes in the kinetics of spermatogenesis, but the impact of each one of these processes on sperm production has not been studied in an integrated manner. Furthermore, such response may be limited in species with low mass-specific metabolic rate (MSMR), i.e., large-bodied species, because they cannot process energy and resources efficiently enough both at the organismic and cellular levels. Here we compare 99 mammalian species and show that higher levels of sperm competition correlated with a) higher proportions of seminiferous tubules, b) shorter seminiferous epithelium cycle lengths (SECL) which reduce the time required to produce sperm, and c) higher efficiencies of Sertoli cells (involved in sperm maturation). These responses to sperm competition, in turn, result in higher daily sperm production, more sperm stored in the epididymides, and more sperm in the ejaculate. However, the two processes that require processing resources at faster rates (SECL and efficiency of Sertoli cells) only respond to sperm competition in species with high MSMR. Thus, increases in sperm production with intense sperm competition occur via a complex network of mechanisms, but some are constrained by MSMR. PMID- 24069460 TI - Transcriptome sequencing reveals differences between primary and secondary hair follicle-derived dermal papilla cells of the Cashmere goat (Capra hircus). AB - The dermal papilla is thought to establish the character and control the size of hair follicles. Inner Mongolia Cashmere goats (Capra hircus) have a double coat comprising the primary and secondary hair follicles, which have dramatically different sizes and textures. The Cashmere goat is rapidly becoming a potent model for hair follicle morphogenesis research. In this study, we established two dermal papilla cell lines during the anagen phase of the hair growth cycle from the primary and secondary hair follicles and clarified the similarities and differences in their morphology and growth characteristics. High-throughput transcriptome sequencing was used to identify gene expression differences between the two dermal papilla cell lines. Many of the differentially expressed genes are involved in vascularization, ECM-receptor interaction and Wnt/beta-catenin/Lef1 signaling pathways, which intimately associated with hair follicle morphogenesis. These findings provide valuable information for research on postnatal morphogenesis of hair follicles. PMID- 24069462 TI - Development of monoclonal antibodies and immunoassays for sensitive and specific detection of Shiga toxin Stx2f. AB - BACKGROUND: Shiga toxin 2 (Stx2) is a major virulence factor in gastrointestinal diseases caused by Escherichia coli. Although Stx2a (prototypical Stx2) is well studied, all seven subtypes of Stx2 have been associated with disease in mammals. Several subtypes of Stx2, including Stx2f, are difficult to detect immunologically. METHODS AND FINDINGS: Four novel monoclonal antibodies (mAbs) against the Stx2f subtype were produced and characterized. These mAbs react exclusively to the Stx2f A subunit, and do not cross-react with other subtypes of Stx2. A Stx2f-specific sandwich ELISA was established and a limit of detection of 0.123 ng/mL was obtained using one pair of the mAbs. The receptor preference of Stx2f was confirmed using this sandwich ELISA. Three out of four mAbs can partially neutralize the toxicity of Stx2f in a cell-based assay. These mAbs were also demonstrated to be highly specific and reactive when applied to colony immunoblot assays. CONCLUSIONS: Novel mAbs specific to Stx2f were developed for the first time, providing new assets for the STEC community. Immunoassays with improved sensitivity and specificity will be useful for the detection of Stx2f present in food, environmental, and clinical samples. PMID- 24069463 TI - Review of climate, landscape, and viral genetics as drivers of the Japanese encephalitis virus ecology. AB - The Japanese encephalitis virus (JEV), an arthropod-born Flavivirus, is the major cause of viral encephalitis, responsible for 10,000-15,000 deaths each year, yet is a neglected tropical disease. Since the JEV distribution area has been large and continuously extending toward new Asian and Australasian regions, it is considered an emerging and reemerging pathogen. Despite large effective immunization campaigns, Japanese encephalitis remains a disease of global health concern. JEV zoonotic transmission cycles may be either wild or domestic: the first involves wading birds as wild amplifying hosts; the second involves pigs as the main domestic amplifying hosts. Culex mosquito species, especially Cx. tritaeniorhynchus, are the main competent vectors. Although five JEV genotypes circulate, neither clear-cut genotype-phenotype relationship nor clear variations in genotype fitness to hosts or vectors have been identified. Instead, the molecular epidemiology appears highly dependent on vectors, hosts' biology, and on a set of environmental factors. At global scale, climate, land cover, and land use, otherwise strongly dependent on human activities, affect the abundance of JEV vectors, and of wild and domestic hosts. Chiefly, the increase of rice cultivated surface, intensively used by wading birds, and of pig production in Asia has provided a high availability of resources to mosquito vectors, enhancing the JEV maintenance, amplification, and transmission. At fine scale, the characteristics (density, size, spatial arrangement) of three landscape elements (paddy fields, pig farms, human habitations) facilitate or impede movement of vectors, then determine how the JEV interacts with hosts and vectors and ultimately the infection risk to humans. If the JEV is introduced in a favorable landscape, either by live infected animals or by vectors, then the virus can emerge and become a major threat for human health. Multidisciplinary research is essential to shed light on the biological mechanisms involved in the emergence, spread, reemergence, and genotypic changes of JEV. PMID- 24069464 TI - Atypical human infections by animal trypanosomes. AB - The two classical forms of human trypanosomoses are sleeping sickness due to Trypanosoma brucei gambiense or T. brucei rhodesiense, and Chagas disease due to T. cruzi. However, a number of atypical human infections caused by other T. species (or sub-species) have been reported, namely due to T. brucei brucei, T. vivax, T. congolense, T. evansi, T. lewisi, and T. lewisi-like. These cases are reviewed here. Some infections were transient in nature, while others required treatments that were successful in most cases, although two cases were fatal. A recent case of infection due to T. evansi was related to a lack of apolipoprotein L-I, but T. lewisi infections were not related to immunosuppression or specific human genetic profiles. Out of 19 patients, eight were confirmed between 1974 and 2010, thanks to improved molecular techniques. However, the number of cases of atypical human trypanosomoses might be underestimated. Thus, improvement, evaluation of new diagnostic tests, and field investigations are required for detection and confirmation of these atypical cases. PMID- 24069465 TI - Coming out of the shell: building the molecular infrastructure for research on parasite-harbouring snails. PMID- 24069466 TI - Presence of virus neutralizing antibodies in cerebral spinal fluid correlates with non-lethal rabies in dogs. AB - BACKGROUND: Rabies is traditionally considered a uniformly fatal disease after onset of clinical manifestations. However, increasing evidence indicates that non lethal infection as well as recovery from flaccid paralysis and encephalitis occurs in laboratory animals as well as humans. METHODOLOGY/PRINCIPAL FINDINGS: Non-lethal rabies infection in dogs experimentally infected with wild type dog rabies virus (RABV, wt DRV-Mexico) correlates with the presence of high level of virus neutralizing antibodies (VNA) in the cerebral spinal fluid (CSF) and mild immune cell accumulation in the central nervous system (CNS). By contrast, dogs that succumbed to rabies showed only little or no VNA in the serum or in the CSF and severe inflammation in the CNS. Dogs vaccinated with a rabies vaccine showed no clinical signs of rabies and survived challenge with a lethal dose of wild type DRV. VNA was detected in the serum, but not in the CSF of immunized dogs. Thus the presence of VNA is critical for inhibiting virus spread within the CNS and eventually clearing the virus from the CNS. CONCLUSIONS/SIGNIFICANCE: Non lethal infection with wt RABV correlates with the presence of VNA in the CNS. Therefore production of VNA within the CNS or invasion of VNA from the periphery into the CNS via compromised blood-brain barrier is important for clearing the virus infection from CNS, thereby preventing an otherwise lethal rabies virus infection. PMID- 24069467 TI - The functional, social and economic impact of acute encephalitis syndrome in Nepal--a longitudinal follow-up study. AB - BACKGROUND: Over 133,000 children present to hospitals with Acute Encephalitis Syndrome (AES) annually in Asia. Japanese encephalitis (JE) accounts for approximately one-quarter of cases; in most cases no pathogen is identified and management is supportive. Although JE is known to result in neurological impairment, few studies have examined the wider impact of JE and AES on patients and their families. METHODOLOGY/PRINCIPAL FINDINGS: Children (aged 1 month-14 years) with AES were assessed 5-12 months after discharge from two Nepali hospitals. Assessment included clinical examination, the Liverpool Outcome Score (LOS) - a validated assessment of function following encephalitis, questionnaires about the child's social participation since discharge, and out-of-pocket costs to the family. Children were classified as JE or 'other AES' based on anti-JE virus antibody titres during acute illness. Contact was made with the families of 76% (73/96) of AES children. Six children had died and one declined participation. 48% (32/66) reported functional impairment at follow-up, most frequently affecting behaviour, language or limb use. Impairment was more frequent in JE compared to 'other AES' cases (68% [13/19] versus 40% [19/47]; p = 0.06). 49% (26/53) had improvement in LOS between discharge and follow-up. The median out-of-pocket cost to families, including medical bills, medication and lost earnings was US$ 1151 (10 times their median monthly income) for children with severe/moderate impairment and $524 (4.6 times their income) for those with mild/no impairment (P = 0.007). Acute admission accounted for 74% of costs. Social participation was limited in 21% of children (n = 14). CONCLUSIONS/SIGNIFICANCE: Prolonged functional impairment was common following AES. Economic impact to families was substantial. Encouragingly, almost half the children improved after discharge and most reported sustained social participation. This study highlights a need for long-term medical support following AES. Rationalisation of initial expensive hospital treatments may be warranted, especially since only supportive treatment is available. PMID- 24069468 TI - A novel clinical grading scale to guide the management of crusted scabies. AB - BACKGROUND: Crusted scabies, or hyperinfestation with Sarcoptes scabiei, occurs in people with an inadequate immune response to the mite. In recent decades, data have emerged suggesting that treatment of crusted scabies with oral ivermectin combined with topical agents leads to lower mortality, but there are no generally accepted tools for describing disease severity. Here, we describe a clinical grading scale for crusted scabies and its utility in real world practice. METHODOLOGY/PRINCIPAL FINDINGS: In 2002, Royal Darwin Hospital (RDH), a hospital in tropical Australia developed and began using a clinical grading scale to guide the treatment of crusted scabies. We conducted a retrospective observational study including all episodes of admission to RDH for crusted scabies during the period October 2002-December 2010 inclusive. Patients who were managed according to the grading scale were compared with those in whom the scale was not used at the time of admission but was calculated retrospectively. There were 49 admissions in 30 patients during the study period, of which 49 (100%) were in Indigenous Australians, 29 (59%) were male and the median age was 44.1 years. According to the grading scale, 8 (16%) episodes were mild, 24 (49%) were moderate, and 17 (35%) were severe. Readmission within the study period was significantly more likely with increasing disease severity, with an odds ratio (95% CI) of 12.8 (1.3-130) for severe disease compared with mild. The patients managed according to the grading scale (29 episodes) did not differ from those who were not (20 episodes), but they received fewer doses of ivermectin and had a shorter length of stay (11 vs. 16 days, p = 0.02). Despite this the outcomes were no different, with no deaths in either group and a similar readmission rate. CONCLUSIONS/SIGNIFICANCE: Our grading scale is a useful tool for the assessment and management of crusted scabies. PMID- 24069469 TI - Impact of health education on soil-transmitted helminth infections in schoolchildren of the Peruvian Amazon: a cluster-randomized controlled trial. AB - BACKGROUND: To control soil-transmitted helminth (STH) infections, the World Health Organization recommends school-based deworming programs with a health hygiene education component. The effect of such health hygiene interventions, however, has not been adequately studied. The objective of the present study was to determine the effectiveness of a health hygiene education intervention on the occurrence of STH re-infection four months post-de-worming. METHODOLOGY/PRINCIPAL FINDINGS: An open-label pair-matched cluster-randomized trial was conducted in Grade 5 schoolchildren of 18 primary schools (9 intervention and 9 control) in the Peruvian Amazon. Baseline assessment included interview with a pre-tested questionnaire and collection of single stool specimens that were examined using the single Kato-Katz thick smear. All schoolchildren were then treated with single-dose albendazole (400 mg). Schoolchildren in intervention schools then received 1) an initial one hour in-class activity on health hygiene and sanitation and 30-minute refresher activities every two weeks over four months; and 2) a half-day workshop for teachers and principals, while children in control schools did not. Four months later, STH infection was re-assessed in all schools by laboratory technologists blinded to intervention status. From April 21-October 20, 2010, a total of 1,089 schoolchildren (518 and 571 from intervention and control schools, respectively) participated in this study. Intervention children scored significantly higher on all aspects of a test of STH-related knowledge compared with control children (aOR = 18.4; 95% CI: 12.7 to 26.6). The intensity of Ascaris lumbricoides infection at follow-up was statistically significantly lower (by 58%) in children in intervention schools compared with children in control schools (aIRR = 0.42; 95% CI = 0.21 to 0.85). No significant changes in hookworm or Trichuris trichiura intensity were observed. CONCLUSIONS/SIGNIFICANCE: A school-based health hygiene education intervention was effective in increasing STH knowledge and in reducing Ascaris lumbricoides infection. The benefits of school-based periodic deworming programs are likely to be enhanced when a sustained health hygiene education intervention is integrated into school curricula. PMID- 24069470 TI - Sex-biased expression of microRNAs in Schistosoma mansoni. AB - Schistosomiasis is an important neglected tropical disease caused by digenean helminth parasites of the genus Schistosoma. Schistosomes are unusual in that they are dioecious and the adult worms live in the blood system. MicroRNAs play crucial roles during gene regulation and are likely to be important in sex differentiation in dioecious species. Here we characterize 112 microRNAs from adult Schistosoma mansoni individuals, including 84 novel microRNA families, and investigate the expression pattern in different sexes. By deep sequencing, we measured the relative expression levels of conserved and newly identified microRNAs between male and female samples. We observed that 13 microRNAs exhibited sex-biased expression, 10 of which are more abundant in females than in males. Sex chromosomes showed a paucity of female-biased genes, as predicted by theoretical evolutionary models. We propose that the recent emergence of separate sexes in Schistosoma had an effect on the chromosomal distribution and evolution of microRNAs, and that microRNAs are likely to participate in the sex differentiation/maintenance process. PMID- 24069472 TI - Improved completion rates and characterization of drug reactions with an intensive Chagas disease treatment program in rural Bolivia. AB - BACKGROUND: Chagas disease treatment is limited by drug availability, adverse side effect profiles of available medications, and poor adherence. METHODS: Adult Chagas disease patients initiating 60-days of benznidazole were randomized to weekly or twice-weekly evaluations of medication adherence and screening for adverse drug events (ADEs). Mid-week evaluations employed phone-based evaluations. Adherence was measured by self-report, pill counts with intentional over-distribution, and Medication Event Monitoring Systems (MEMS). Prospective data were compared to historical controls treated with benznidazole at the same hospital. RESULTS: 162 prospective patients were compared to 172 historical patients. Pill counts correlated well with MEMS data (R = 0.498 for 7-day intervals, R = 0.872 for intervals >7 days). Treatment completion rates were higher among prospective than historical patients (82.1% vs. 65.1%), primarily due to lower abandonment rates. Rates of ADEs were lower among prospective than historical patients (56.8% vs. 66.9%). Twice-weekly evaluations increased identification of mild ADEs, prompting higher suspension rates than weekly evaluations. While twice-weekly evaluations identified ADEs earlier, they did not reduce incidence of moderate or severe ADEs. Many dermatologic ADEs were moderately severe upon presentation (35.6%), were not reduced by use of antihistamines, occurred among adult patients of all ages, and occurred throughout treatment, rather than the first few weeks alone. CONCLUSIONS: Intensive management improved completion and identified more ADEs, but did not reduce moderate or severe ADEs. Risk of dermatologic ADEs cannot be reduced by selecting younger adults or monitoring only during the first few weeks of treatment. Pill counts and phone-based encounters are reliable tools for treatment programming in rural Bolivia. PMID- 24069471 TI - Transcriptome analysis of human peripheral blood mononuclear cells exposed to Lassa virus and to the attenuated Mopeia/Lassa reassortant 29 (ML29), a vaccine candidate. AB - Lassa virus (LASV) is the causative agent of Lassa Fever and is responsible for several hundred thousand infections and thousands of deaths annually in West Africa. LASV and the non-pathogenic Mopeia virus (MOPV) are both rodent-borne African arenaviruses. A live attenuated reassortant of MOPV and LASV, designated ML29, protects rodents and primates from LASV challenge and appears to be more attenuated than MOPV. To gain better insight into LASV-induced pathology and mechanism of attenuation we performed gene expression profiling in human peripheral blood mononuclear cells (PBMC) exposed to LASV and the vaccine candidate ML29. PBMC from healthy human subjects were exposed to either LASV or ML29. Although most PBMC are non-permissive for virus replication, they remain susceptible to signal transduction by virus particles. Total RNA was extracted and global gene expression was evaluated during the first 24 hours using high density microarrays. Results were validated using RT-PCR, flow cytometry and ELISA. LASV and ML29 elicited differential expression of interferon-stimulated genes (ISG), as well as genes involved in apoptosis, NF-kB signaling and the coagulation pathways. These genes could eventually serve as biomarkers to predict disease outcomes. The remarkable differential expression of thrombomodulin, a key regulator of inflammation and coagulation, suggests its involvement with vascular abnormalities and mortality in Lassa fever disease. PMID- 24069473 TI - Socio-cultural aspects of Chagas disease: a systematic review of qualitative research. AB - BACKGROUND: Globally, more than 10 million people are infected with Trypanosoma cruzi, which causes about 20 000 annual deaths. Although Chagas disease is endemic to certain regions of Latin America, migratory flows have enabled its expansion into areas where it was previously unknown. Economic, social and cultural factors play a significant role in its presence and perpetuation. This systematic review aims to provide a comprehensive overview of qualitative research on Chagas disease, both in endemic and non-endemic countries. METHODOLOGY/PRINCIPAL FINDINGS: Searches were carried out in ten databases, and the bibliographies of retrieved studies were examined. Data from thirty-three identified studies were extracted, and findings were analyzed and synthesized along key themes. Themes identified for endemic countries included: socio structural determinants of Chagas disease; health practices; biomedical conceptions of Chagas disease; patient's experience; and institutional strategies adopted. Concerning non-endemic countries, identified issues related to access to health services and health seeking. CONCLUSIONS: The emergence and perpetuation of Chagas disease depends largely on socio-cultural aspects influencing health. As most interventions do not address the clinical, environmental, social and cultural aspects jointly, an explicitly multidimensional approach, incorporating the experiences of those affected is a potential tool for the development of long term successful programs. Further research is needed to evaluate this approach. PMID- 24069474 TI - The diagnosis of human fascioliasis by enzyme-linked immunosorbent assay (ELISA) using recombinant cathepsin L protease. AB - BACKGROUND: Fascioliasis is a worldwide parasitic disease of domestic animals caused by helminths of the genus Fasciola. In many parts of the world, particularly in poor rural areas where animal disease is endemic, the parasite also infects humans. Adult parasites reside in the bile ducts of the host and therefore diagnosis of human fascioliasis is usually achieved by coprological examinations that search for parasite eggs that are carried into the intestine with the bile juices. However, these methods are insensitive due to the fact that eggs are released sporadically and may be missed in low-level infections, and fasciola eggs may be misclassified as other parasites, leading to problems with specificity. Furthermore, acute clinical symptoms as a result of parasites migrating to the bile ducts appear before the parasite matures and begins egg laying. A human immune response to Fasciola antigens occurs early in infection. Therefore, an immunological method such as ELISA may be a more reliable, easy and cheap means to diagnose human fascioliasis than coprological analysis. METHODOLOGY/PRINCIPAL FINDINGS: Using a panel of serum from Fasciola hepatica infected patients and from uninfected controls we have optimized an enzyme-linked immunosorbent assay (ELISA) which employs a recombinant form of the major F. hepatica cathepsin L1 as the antigen for the diagnosis of human fascioliasis. We examined the ability of the ELISA test to discern fascioliasis from various other helminth and non-helminth parasitic diseases. CONCLUSIONS/SIGNIFICANCE: A sensitive and specific fascioliasis ELISA test has been developed. This test is rapid and easy to use and can discriminate fasciola-infected individuals from patients harbouring other parasites with at least 99.9% sensitivity and 99.9% specificity. This test will be a useful standardized method not only for testing individual samples but also in mass screening programs to assess the extent of human fascioliasis in regions where this zoonosis is suspected. PMID- 24069475 TI - First-time detection of Mycobacterium bovis in livestock tissues and milk in the West Bank, Palestinian Territories. AB - BACKGROUND: Bovine tuberculosis, bTB, is classified by the WHO as one of the seven neglected zoonontic diseases that cause animal health problems and has high potential to infect humans. In the West Bank, bTB was not studied among animals and the prevalence of human tuberculosis caused by M. bovis is unknown. Therefore, the aim of this study was to estimate the prevalence of bTB among cattle and goats and identify the molecular characteristics of bTB in our area. METHODOLOGY/PRINCIPAL FINDINGS: A total of 208 tissue samples, representing 104 animals, and 150 raw milk samples, obtained from cows and goats were examined for the presence of mycobacteria. The tissue samples were collected during routine meat inspection from the Jericho abattoir. DNA was extracted from all samples, milk and tissue biopsies (n = 358), and screened for presence of TB DNA by amplifying a 123-bp segment of the insertion sequence IS6110. Eight out of 254 animals (3.1%) were found to be TB positive based on the IS6110-PCR. Identification of M. bovis among the positive TB samples was carried out via real time PCR followed by high resolution melt curve analysis, targeting the A/G transition along the oxyR gene. Spoligotyping analysis revealed a new genotype of M. bovis that was revealed from one tissue sample. SIGNIFICANCE: Detection of M. bovis in tissue and milk of livestock suggests that apparently healthy cattle and goats are a potential source of infection of bTB and may pose a risk to public health. Hence, appropriate measures including meat inspection at abattoirs in the region are required together with promotion of a health campaign emphasizing the importance of drinking pasteurized milk. In addition, further studies are essential at the farm level to determine the exact prevalence of bTB in goats and cattle herds in the West Bank and Israel. PMID- 24069477 TI - Discriminating malaria from dengue fever in endemic areas: clinical and biological criteria, prognostic score and utility of the C-reactive protein: a retrospective matched-pair study in French Guiana. AB - BACKGROUND: Dengue and malaria are two major public health concerns in tropical settings. Although the pathogeneses of these two arthropod-borne diseases differ, their clinical and biological presentations are unspecific. During dengue epidemics, several hundred patients with fever and diffuse pain are weekly admitted at the emergency room. It is difficult to discriminate them from patients presenting malaria attacks. Furthermore, it may be impossible to provide a parasitological microscopic examination for all patients. This study aimed to establish a diagnostic algorithm for communities where dengue fever and malaria occur at some frequency in adults. METHODOLOGY/PRINCIPAL FINDINGS: A sub-study using the control groups of a case-control study in French Guiana--originally designed to compare dengue and malaria co-infected cases to single infected cases -was performed between 2004 and 2010. In brief, 208 patients with malaria matched to 208 patients with dengue fever were compared in the present study. A predictive score of malaria versus dengue was established using .632 bootstrap procedures. Multivariate analysis showed that male gender, age, tachycardia, anemia, thrombocytopenia, and CRP>5 mg/l were independently associated with malaria. The predictive score using those variables had an AUC of 0.86 (95%CI: 0.82-0.89), and the CRP was the preponderant predictive factor. The sensitivity and specificity of CRP>5 mg/L to discriminate malaria from dengue were of 0.995 (95%CI: 0.991-1) and 0.35 (95%CI 0.32-0.39), respectively. CONCLUSIONS/SIGNIFICANCE: The clinical and biological score performed relatively well for discriminating cases of dengue versus malaria. Moreover, using only the CRP level turned to be a useful biomarker to discriminate feverish patients at low risk of malaria in an area where both infections exist. It would avoid more than 33% of unnecessary parasitological examinations with a very low risk of missing a malaria attack. PMID- 24069476 TI - Update on the mapping of prevalence and intensity of infection for soil transmitted helminth infections in Latin America and the Caribbean: a call for action. AB - It is estimated that in Latin America and the Caribbean (LAC) at least 13.9 million preschool age and 35.4 million school age children are at risk of infections by soil-transmitted helminths (STH): Ascaris lumbricoides, Trichuris trichiura and hookworms (Necator americanus and Ancylostoma duodenale). Although infections caused by this group of parasites are associated with chronic deleterious effects on nutrition and growth, iron and vitamin A status and cognitive development in children, few countries in the LAC Region have implemented nationwide surveys on prevalence and intensity of infection. The aim of this study was to identify gaps on the mapping of prevalence and intensity of STH infections based on data published between 2000 and 2010 in LAC, and to call for including mapping as part of action plans against these infections. A total of 335 published data points for STH prevalence were found for 18 countries (11.9% data points for preschool age children, 56.7% for school age children and 31.3% for children from 1 to 14 years of age). We found that 62.7% of data points showed prevalence levels above 20%. Data on the intensity of infection were found for seven countries. The analysis also highlights that there is still an important lack of data on prevalence and intensity of infection to determine the burden of disease based on epidemiological surveys, particularly among preschool age children. This situation is a challenge for LAC given that adequate planning of interventions such as deworming requires information on prevalence to determine the frequency of needed anthelmintic drug administration and to conduct monitoring and evaluation of progress in drug coverage. PMID- 24069478 TI - Current and future niche of North and Central American sand flies (Diptera: psychodidae) in climate change scenarios. AB - Ecological niche models are useful tools to infer potential spatial and temporal distributions in vector species and to measure epidemiological risk for infectious diseases such as the Leishmaniases. The ecological niche of 28 North and Central American sand fly species, including those with epidemiological relevance, can be used to analyze the vector's ecology and its association with transmission risk, and plan integrated regional vector surveillance and control programs. In this study, we model the environmental requirements of the principal North and Central American phlebotomine species and analyze three niche characteristics over future climate change scenarios: i) potential change in niche breadth, ii) direction and magnitude of niche centroid shifts, iii) shifts in elevation range. Niche identity between confirmed or incriminated Leishmania vector sand flies in Mexico, and human cases were analyzed. Niche models were constructed using sand fly occurrence datapoints from Canada, USA, Mexico, Guatemala and Belize. Nine non-correlated bioclimatic and four topographic data layers were used as niche components using GARP in OpenModeller. Both B2 and A2 climate change scenarios were used with two general circulation models for each scenario (CSIRO and HadCM3), for 2020, 2050 and 2080. There was an increase in niche breadth to 2080 in both scenarios for all species with the exception of Lutzomyia vexator. The principal direction of niche centroid displacement was to the northwest (64%), while the elevation range decreased greatest for tropical, and least for broad-range species. Lutzomyia cruciata is the only epidemiologically important species with high niche identity with that of Leishmania spp. in Mexico. Continued landscape modification in future climate change will provide an increased opportunity for the geographic expansion of NCA sand flys' ENM and human exposure to vectors of Leishmaniases. PMID- 24069479 TI - A neutralizing monoclonal antibody targeting the acid-sensitive region in chikungunya virus E2 protects from disease. AB - The mosquito-borne alphavirus, chikungunya virus (CHIKV), has recently reemerged, producing the largest epidemic ever recorded for this virus, with up to 6.5 million cases of acute and chronic rheumatic disease. There are currently no licensed vaccines for CHIKV and current anti-inflammatory drug treatment is often inadequate. Here we describe the isolation and characterization of two human monoclonal antibodies, C9 and E8, from CHIKV infected and recovered individuals. C9 was determined to be a potent virus neutralizing antibody and a biosensor antibody binding study demonstrated it recognized residues on intact CHIKV VLPs. Shotgun mutagenesis alanine scanning of 98 percent of the residues in the E1 and E2 glycoproteins of CHIKV envelope showed that the epitope bound by C9 included amino-acid 162 in the acid-sensitive region (ASR) of the CHIKV E2 glycoprotein. The ASR is critical for the rearrangement of CHIKV E2 during fusion and viral entry into host cells, and we predict that C9 prevents these events from occurring. When used prophylactically in a CHIKV mouse model, C9 completely protected against CHIKV viremia and arthritis. We also observed that when administered therapeutically at 8 or 18 hours post-CHIKV challenge, C9 gave 100% protection in a pathogenic mouse model. Given that targeting this novel neutralizing epitope in E2 can potently protect both in vitro and in vivo, it is likely to be an important region both for future antibody and vaccine-based interventions against CHIKV. PMID- 24069480 TI - Neutral polymorphisms in putative housekeeping genes and tandem repeats unravels the population genetics and evolutionary history of Plasmodium vivax in India. AB - The evolutionary history and age of Plasmodium vivax has been inferred as both recent and ancient by several studies, mainly using mitochondrial genome diversity. Here we address the age of P. vivax on the Indian subcontinent using selectively neutral housekeeping genes and tandem repeat loci. Analysis of ten housekeeping genes revealed a substantial number of SNPs (n = 75) from 100 P. vivax isolates collected from five geographical regions of India. Neutrality tests showed a majority of the housekeeping genes were selectively neutral, confirming the suitability of housekeeping genes for inferring the evolutionary history of P. vivax. In addition, a genetic differentiation test using housekeeping gene polymorphism data showed a lack of geographical structuring between the five regions of India. The coalescence analysis of the time to the most recent common ancestor estimate yielded an ancient TMRCA (232,228 to 303,030 years) and long-term population history (79,235 to 104,008) of extant P. vivax on the Indian subcontinent. Analysis of 18 tandem repeat loci polymorphisms showed substantial allelic diversity and heterozygosity per locus, and analysis of potential bottlenecks revealed the signature of a stable P. vivax population, further corroborating our ancient age estimates. For the first time we report a comparable evolutionary history of P. vivax inferred by nuclear genetic markers (putative housekeeping genes) to that inferred from mitochondrial genome diversity. PMID- 24069481 TI - Prevention of tungiasis and tungiasis-associated morbidity using the plant-based repellent Zanzarin: a randomized, controlled field study in rural Madagascar. AB - BACKGROUND: Tungiasis, a parasitic skin disease caused by the female sand flea Tunga penetrans, is a prevalent condition in impoverished communities in the tropics. In this setting, the ectoparasitosis is associated with important morbidity. It causes disfigurement and mutilation of the feet. Feasible and effective treatment is not available. So far prevention is the only means to control tungiasis-associated morbidity. METHODOLOGY: In two villages in Central Madagascar, we assessed the efficacy of the availability of closed shoes and the twice-daily application of a plant-based repellent active against sand fleas (Zanzarin) in comparison to a control group without intervention. The study population was randomized into three groups: shoe group, repellent group and control group and monitored for ten weeks. The intensity of infestation, the attack rate and the severity of tungiasis-associated morbidity were assessed every two weeks. FINDINGS: In the repellent group, the median attack rate became zero already after two weeks. The intensity of the infestation decreased constantly during the observation period and tungiasis-associated morbidity was lowered to an insignificant level. In the shoe group, only a marginal decrease in the intensity of infestation and in the attack rate was observed. At week 10, the intensity of infestation, the attack rate and the severity score for acute tungiasis remained significantly higher in the shoe group than in the repellent group. Per protocol analysis showed that the protective effect of shoes was closely related to the regularity with which shoes were worn. CONCLUSIONS: Although shoes were requested by the villagers and wearing shoes was encouraged by the investigators at the beginning of the study, the availability of shoes only marginally influenced the attack rate of female sand fleas. The twice-daily application of a plant-based repellent active against sand fleas reduced the attack to zero and lowered tungiasis-associated morbidity to an insignificant level. PMID- 24069482 TI - Public acceptance and willingness-to-pay for a future dengue vaccine: a community based survey in Bandung, Indonesia. AB - BACKGROUND: All four serotypes of dengue virus are endemic in Indonesia, where the population at risk for infection exceeds 200 million people. Despite continuous control efforts that were initiated more than four decades ago, Indonesia still suffers from multi-annual cycles of dengue outbreak and dengue remains as a major public health problem. Dengue vaccines have been viewed as a promising solution for controlling dengue in Indonesia, but thus far its potential acceptability has not been assessed. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a household survey in the city of Bandung, Indonesia by administering a questionnaire to examine (i) acceptance of a hypothetical pediatric dengue vaccine; (ii) participant's willingness-to-pay (WTP) for the vaccine, had it not been provided for free; and (iii) whether people think vector control would be unnecessary if the vaccine was available. A proportional odds model and an interval regression model were employed to identify determinants of acceptance and WTP, respectively. We demonstrated that out of 500 heads of household being interviewed, 94.2% would agree to vaccinate their children with the vaccine. Of all participants, 94.6% were willing to pay for the vaccine with a median WTP of US$1.94. In addition, 7.2% stated that vector control would not be necessary had there been a dengue vaccination program. CONCLUSIONS/SIGNIFICANCE: Our results suggest that future dengue vaccines can have a very high uptake even when delivered through the private market. This, however, can be influenced by vaccine characteristics and price. In addition, reduction in community vector control efforts may be observed following vaccine introduction but its potential impact in the transmission of dengue and other vector-borne diseases requires further study. PMID- 24069483 TI - Schistosoma mansoni Sirtuins: characterization and potential as chemotherapeutic targets. AB - BACKGROUND: The chemotherapy of schistosomiasis currently depends on the use of a single drug, praziquantel. In order to develop novel chemotherapeutic agents we are investigating enzymes involved in the epigenetic modification of chromatin. Sirtuins are NAD+ dependent lysine deacetylases that are involved in a wide variety of cellular processes including histone deacetylation, and have been demonstrated to be therapeutic targets in various pathologies, including cancer. METHODOLOGY PRINCIPAL FINDINGS: In order to determine whether Schistosoma mansoni sirtuins are potential therapeutic targets we first identified and characterized their protein sequences. Five sirtuins (SmSirt) are encoded in the S. mansoni genome and phylogenetic analysis showed that they are orthologues of mammalian Sirt1, Sirt2, Sirt5, Sirt6 and Sirt7. Both SmSirt1 and SmSirt7 have large insertion in the catalytic domain compared to their mammalian orthologues. SmSirt5 is the only mitochondrial sirtuin encoded in the parasite genome (orthologues of Sirt3 and Sirt4 are absent) and transcripts corresponding to at least five splicing isoforms were identified. All five sirtuins are expressed throughout the parasite life-cycle, but with distinct patterns of expression. Sirtuin inhibitors were used to treat both schistosomula and adult worms maintained in culture. Three inhibitors in particular, Sirtinol, Salermide and MS3 induced apoptosis and death of schistosomula, the separation of adult worm pairs, and a reduction in egg laying. Moreover, Salermide treatment led to a marked disruption of the morphology of ovaries and testes. Transcriptional knockdown of SmSirt1 by RNA interference in adult worms led to morphological changes in the ovaries characterized by a marked increase in mature oocytes, reiterating the effects of sirtuin inhibitors and suggesting that SmSirt1 is their principal target. CONCLUSION SIGNIFICANCE: Our data demonstrate the potential of schistosome sirtuins as therapeutic targets and validate screening for selective sirtuin inhibitors as a strategy for developing new drugs against schistosomiasis. PMID- 24069484 TI - Co-circulation of Toscana virus and Punique virus in northern Tunisia: a microneutralisation-based seroprevalence study. AB - BACKGROUND: In northern Tunisia, the co-circulation of two related sand fly-borne phleboviruses, Toscana virus (TOSV) and Punique virus (PUNV) was previously demonstrated. In contrast to TOSV, a prominent human pathogen, there is no data supporting that PUNV is capable to infect and cause disease to humans. We studied the respective involvement of TOSV and PUNV in human infections in northern Tunisia through a seroprevalence study. METHODS: The presence of TOSV and PUNV neutralising antibodies (NT-Ab) was tested in human sera collected from 5 districts of the governorate of Bizerte, and the titres of NT-Ab were estimated by microneutralisation (MN) assay. PRINCIPAL FINDINGS: A total of 1,273 sera were processed. TOSV and PUNV NT-Ab were detected in 522 (41%) and 111 sera (8.72%) respectively. TOSV seroprevalence varied from 17.2% to 59.4% depending on the district. Analysis of TOSV geometric mean titre values demonstrated a constant increase according to the age. The vast majority of sera containing NT-Ab were found to be more reactive toward TOSV than PUNV. Indeed, past infections with PUNV and TOSV were undisputable for 5 and 414 sera, respectively. CONCLUSIONS: PUNV may be capable to infect humans but at a low rate. TOSV is responsible for the vast majority of human infections by sand fly-borne phleboviruses in northern Tunisia. TOSV must be considered by physician and tested in diagnostic laboratories for patients with meningitis and unexplained fever in northern Tunisia. PMID- 24069485 TI - A fusion-inhibiting peptide against Rift Valley fever virus inhibits multiple, diverse viruses. AB - For enveloped viruses, fusion of the viral envelope with a cellular membrane is critical for a productive infection to occur. This fusion process is mediated by at least three classes of fusion proteins (Class I, II, and III) based on the protein sequence and structure. For Rift Valley fever virus (RVFV), the glycoprotein Gc (Class II fusion protein) mediates this fusion event following entry into the endocytic pathway, allowing the viral genome access to the cell cytoplasm. Here, we show that peptides analogous to the RVFV Gc stem region inhibited RVFV infectivity in cell culture by inhibiting the fusion process. Further, we show that infectivity can be inhibited for diverse, unrelated RNA viruses that have Class I (Ebola virus), Class II (Andes virus), or Class III (vesicular stomatitis virus) fusion proteins using this single peptide. Our findings are consistent with an inhibition mechanism similar to that proposed for stem peptide fusion inhibitors of dengue virus in which the RVFV inhibitory peptide first binds to both the virion and cell membranes, allowing it to traffic with the virus into the endocytic pathway. Upon acidification and rearrangement of Gc, the peptide is then able to specifically bind to Gc and prevent fusion of the viral and endocytic membranes, thus inhibiting viral infection. These results could provide novel insights into conserved features among the three classes of viral fusion proteins and offer direction for the future development of broadly active fusion inhibitors. PMID- 24069486 TI - Meta-analysis of urine heme dipstick diagnosis of Schistosoma haematobium infection, including low-prevalence and previously-treated populations. AB - BACKGROUND: Urogenital schistosomiasis remains highly endemic in Africa. Current control is based on drug administration, targeted either to school-age children or to high-risk communities at-large. Urine dipsticks for detection of microhematuria offer an inexpensive means for estimating infection prevalence. However, their diagnostic performance has not been systematically evaluated after community treatment, or in areas with continuing low prevalence. The objective of the present study was to perform meta-analysis of dipstick accuracy for S. haematobium infection in endemic regions, with special attention to performance where infection intensity or prevalence was low. METHODOLOGY/PRINCIPAL FINDINGS: This review was registered at inception with PROSPERO (CRD42012002165). Included studies were identified by computerized search of online databases and hand search of bibliographies and existing study archives. Eligible studies included published or unpublished population surveys irrespective of date, location, or language that compared dipstick diagnosis of S. haematobium infection to standard egg-count parasitology. For 95 included surveys, variation in dipstick sensitivity and specificity were evaluated according to study size, age- and sex specific participation, region, local prevalence, treatment status, and other factors potentially affecting test performance. Independent of prevalence, accuracy was greater in surveys of school-age children (vs. adults), whereas performance was less good in North Africa, as compared to other regions. By hierarchical ROC analysis, overall dipstick sensitivity and specificity for detection of egg-positive urine were estimated at 81% and 89%, respectively. Sensitivity was lower among treated populations (72%) and in population subgroups having lower intensity infection (65%). When the insensitivity of egg count testing was considered (and diagnosis inferred instead from combined hematuria and egg-count findings), overall dipstick sensitivity/specificity were 82%/97%, with significantly better sensitivity (92%) in high prevalence settings. CONCLUSIONS/SIGNIFICANCE: This analysis suggests that dipsticks will continue to serve as very useful adjuncts for monitoring community prevalence following implementation of population-based control of urogenital schistosomiasis. PMID- 24069487 TI - Lipidated dengue-2 envelope protein domain III independently stimulates long lasting neutralizing antibodies and reduces the risk of antibody-dependent enhancement. AB - BACKGROUND: Dengue virus is a mosquito-transmitted virus that can cause self limiting dengue fever, severe life-threatening dengue hemorrhagic fever and dengue shock syndrome. The existence of four serotypes of dengue virus has complicated the development of an effective and safe dengue vaccine. Recently, a clinical phase 2b trial of Sanofi Pasteur's CYD tetravalent dengue vaccine revealed that the vaccine did not confer full protection against dengue-2 virus. New approaches to dengue vaccine development are urgently needed. Our approach represents a promising method of dengue vaccine development and may even complement the deficiencies of the CYD tetravalent dengue vaccine. METHODOLOGY/PRINCIPAL FINDINGS: Two important components of a vaccine, the immunogen and immunopotentiator, were combined into a single construct to generate a new generation of vaccines. We selected dengue-2 envelope protein domain III (D2ED III) as the immunogen and expressed this protein in lipidated form in Escherichia coli, yielding an immunogen with intrinsic immunopotentiation activity. The formulation containing lipidated D2ED III (LD2ED III) in the absence of exogenous adjuvant elicited higher D2ED III-specific antibody responses than those obtained from its nonlipidated counterpart, D2ED III, and dengue-2 virus. In addition, the avidity and neutralizing capacity of the antibodies induced by LD2ED III were higher than those elicited by D2ED III and dengue-2 virus. Importantly, we showed that after lipidation, the subunit candidate LD2ED III exhibited increased immunogenicity while reducing the potential risk of antibody-dependent enhancement of infection in mice. CONCLUSIONS/SIGNIFICANCE: Our study suggests that the lipidated subunit vaccine approach could be applied to other serotypes of dengue virus and other pathogens. PMID- 24069488 TI - Mosquito-parasite interactions can shape filariasis transmission dynamics and impact elimination programs. AB - The relationship between mosquito vectors and lymphatic filariasis (LF) parasites can result in a range of transmission outcomes. Anophelines are generally characterized as poor vectors due to an inability to support development at low densities. However, it is important to understand the potential for transmission in natural vectors to maximize the success of elimination efforts. Primary vectors in Papua New Guinea (n = 1209) were dissected following exposure to microfilaremic blood (range 8-233 mf/20 ul). We examined density dependent and species-specific parasite prevalence, intensity and yield, barriers to parasite development as well as impacts on mosquito survival. We observed strikingly different parasite prevalence and yield among closely related species. Prevalence of infective stage larvae (L3s) ranged from 4.2% to 23.7% in An. punctulatus, 24.5% to 68.6% in An. farauti s.s. and 61.9% to 100% in An. hinesorum at low and high density exposures, respectively. Injection experiments revealed the greatest barrier to parasite development involved passage from the midgut into the hemocoel. The ratio of L3 to ingested mf at low densities was higher in An. hinesorum (yield = 1.0) and An. farauti s.s. (yield = 0.5) than has been reported in other anopheline vectors. There was a negative relationship between mosquito survival and bloodmeal mf density. In An. farauti s.s., increased parasite yield and survival at low densities suggest greater competence at low microfilaremias. In Papua New Guinea the likelihood of transmission will be strongly influenced by vector composition and changes in the mf reservoir as a result of elimination efforts. Global elimination efforts will be strengthened by the knowledge of transmission potential in the context of current control measures. PMID- 24069489 TI - Ecological and control techniques for sand flies (Diptera: Psychodidae) associated with rodent reservoirs of leishmaniasis. AB - BACKGROUND: Leishmaniasis remains a global health problem because of the substantial holes that remain in our understanding of sand fly ecology and the failure of traditional vector control methods. The specific larval food source is unknown for all but a few sand fly species, and this is particularly true for the vectors of Leishmania parasites. We provide methods and materials that could be used to understand, and ultimately break, the transmission cycle of zoonotic cutaneous leishmaniasis. METHODS AND FINDINGS: We demonstrated in laboratory studies that analysis of the stable carbon and nitrogen isotopes found naturally in plant and animal tissues was highly effective for linking adult sand flies with their larval diet, without having to locate or capture the sand fly larvae themselves. In a field trial, we also demonstrated using this technique that half of captured adult sand flies had fed as larvae on rodent feces. Through the identification of rodent feces as a sand fly larval habitat, we now know that rodent baits containing insecticides that have been shown in previous studies to pass into the rodents' feces and kill sand fly larvae also could play a future role in sand fly control. In a second study we showed that rubidium incorporated into rodent baits could be used to demonstrate the level of bloodfeeding by sand flies on baited rodents, and that the elimination of sand flies that feed on rodents can be achieved using baits containing an insecticide that circulates in the blood of baited rodents. CONCLUSIONS: Combined, the techniques described could help to identify larval food sources of other important vectors of the protozoa that cause visceral or dermal leishmaniasis. Unveiling aspects of the life cycles of sand flies that could be targeted with insecticides would guide future sand fly control programs for prevention of leishmaniasis. PMID- 24069490 TI - Hospital-based surveillance for viral hemorrhagic fevers and hepatitides in Ghana. AB - BACKGROUND: Viral hemorrhagic fevers (VHF) are acute diseases associated with bleeding, organ failure, and shock. VHF may hardly be distinguished clinically from other diseases in the African hospital, including viral hepatitis. This study was conducted to determine if VHF and viral hepatitis contribute to hospital morbidity in the Central and Northern parts of Ghana. METHODOLOGY/PRINCIPAL FINDINGS: From 2009 to 2011, blood samples of 258 patients with VHF symptoms were collected at 18 hospitals in Ashanti, Brong-Ahafo, Northern, Upper West, and Upper East regions. Patients were tested by PCR for Lassa, Rift Valley, Crimean-Congo, Ebola/Marburg, and yellow fever viruses; hepatitis A (HAV), B (HBV), C (HCV), and E (HEV) viruses; and by ELISA for serological hepatitis markers. None of the patients tested positive for VHF. However, 21 (8.1%) showed anti-HBc IgM plus HBV DNA and/or HBsAg; 37 (14%) showed HBsAg and HBV DNA without anti-HBc IgM; 26 (10%) showed anti-HAV IgM and/or HAV RNA; and 20 (7.8%) were HCV RNA-positive. None was positive for HEV RNA or anti HEV IgM plus IgG. Viral genotypes were determined as HAV-IB, HBV-A and E, and HCV 1, 2, and 4. CONCLUSIONS/SIGNIFICANCE: VHFs do not cause significant hospital morbidity in the study area. However, the incidence of acute hepatitis A and B, and hepatitis B and C with active virus replication is high. These infections may mimic VHF and need to be considered if VHF is suspected. The data may help decision makers to allocate resources and focus surveillance systems on the diseases of relevance in Ghana. PMID- 24069491 TI - Concurrent infections of Giardia duodenalis, Enterocytozoon bieneusi, and Clostridium difficile in children during a cryptosporidiosis outbreak in a pediatric hospital in China. AB - BACKGROUND: Over 200 cryptosporidiosis outbreaks have been reported, but little is known if other enteric pathogens were also involved in some of these outbreaks. Recently, an outbreak of cryptosporidiosis linked to poor hygiene by two Cryptosporidium hominis subtypes occurred in a pediatric hospital ward (Ward A) in China, lasting for more than 14 months. In this study, the concurrence during the outbreak of three other enteric pathogens with a similar transmission route, Giardia duodenalis, Enterocytozoon bieneusi, and Clostridium difficile, was assessed. METHODS/PRINCIPAL FINDINGS: The occurrence of G. duodenalis, E. bieneusi, and C. difficile in 78 inpatients from Ward A and 283 and 216 inpatients from two control wards (Wards C and D) in the same hospital was examined using molecular diagnostic tools. Significantly higher infection rates were found in children in Ward A for all study pathogens than in Wards C and D (P<0.01): 9.5% versus 1.4% and 0% for G. duodenalis, 10.8% versus 2.8% and 3.7% for E. bieneusi, and 60.8% versus 37.8% and 27.8% for C. difficile, respectively. These differences were mostly seen in children <= 12 months. Enteric pathogen positive children in Ward A (31/58 or 53.4%) were more likely to have mixed infections than those in Ward C (4/119 or 3.4%) or D (5/68, 7.4%; P<0.01). Having cryptosporidiosis was a risk factor for G. duodenalis (OR = 4.3; P = 0.08), E. bieneusi (OR = 3.1; P = 0.04), and C. difficile (OR = 4.7; P<0.01) infection. In addition, a lower diversity of G. duodenalis, E. bieneusi, and C. difficile genotypes/subtypes was observed in Ward A. CONCLUSIONS/SIGNIFICANCE: Data from this study suggest that multiple pathogens were concurrently present during the previous cryptosporidiosis outbreak. Examination of multiple enteric pathogens should be conducted when poor hygiene is the likely cause of outbreaks of diarrhea. PMID- 24069492 TI - Temephos resistance in Aedes aegypti in Colombia compromises dengue vector control. AB - BACKGROUND: Control and prevention of dengue relies heavily on the application of insecticides to control dengue vector mosquitoes. In Colombia, application of the larvicide temephos to the aquatic breeding sites of Aedes aegypti is a key part of the dengue control strategy. Resistance to temephos was recently detected in the dengue-endemic city of Cucuta, leading to questions about its efficacy as a control tool. Here, we characterize the underlying mechanisms and estimate the operational impact of this resistance. METHODOLOGY/PRINCIPAL FINDINGS: Larval bioassays of Ae. aegypti larvae from Cucuta determined the temephos LC50 to be 0.066 ppm (95% CI 0.06-0.074), approximately 15* higher than the value obtained from a susceptible laboratory colony. The efficacy of the field dose of temephos at killing this resistant Cucuta population was greatly reduced, with mortality rates <80% two weeks after application and <50% after 4 weeks. Neither biochemical assays nor partial sequencing of the ace-1 gene implicated target site resistance as the primary resistance mechanism. Synergism assays and microarray analysis suggested that metabolic mechanisms were most likely responsible for the temephos resistance. Interestingly, although the greatest synergism was observed with the carboxylesterase inhibitor, DEF, the primary candidate genes from the microarray analysis, and confirmed by quantitative PCR, were cytochrome P450 oxidases, notably CYP6N12, CYP6F3 and CYP6M11. CONCLUSIONS/SIGNIFICANCE: In Colombia, resistance to temephos in Ae. aegypti compromises the duration of its effect as a vector control tool. Several candidate genes potentially responsible for metabolic resistance to temephos were identified. Given the limited number of insecticides that are approved for vector control, future chemical-based control strategies should take into account the mechanisms underlying the resistance to discern which insecticides would likely lead to the greatest control efficacy while minimizing further selection of resistant phenotypes. PMID- 24069494 TI - Larval breeding sites of Lutzomyia longipalpis (Diptera: Psychodidae) in visceral leishmaniasis endemic urban areas in Southeastern Brazil. AB - BACKGROUND: The scarcity of information on the immature stages of sand flies and their preferred breeding sites has resulted in the focus of vectorial control on the adult stage using residual insecticide house-spraying. This strategy, along with the treatment of human cases and the euthanasia of infected dogs, has proven inefficient and visceral leishmaniasis continues to expand in Brazil. Identifying the breeding sites of sand flies is essential to the understanding of the vector's population dynamic and could be used to develop novel control strategies. METHODOLOGY/PRINCIPAL FINDING: In the present study, an intensive search for the breeding sites of Lutzomyia longipalpis was conducted in urban and peri-urban areas of two municipalities, Promissao and Dracena, which are endemic for visceral leishmaniasis in Sao Paulo State, Brazil. During an exploratory period, a total of 962 soil emergence traps were used to investigate possible peridomiciliary breeding site microhabitats such as: leaf litter under tree, chicken sheds, other animal sheds and uncovered debris. A total of 160 sand flies were collected and 148 (92.5%) were L. longipalpis. In Promissao the proportion of chicken sheds positive was significantly higher than in leaf litter under trees. Chicken shed microhabitats presented the highest density of L. longipalpis in both municipalities: 17.29 and 5.71 individuals per square meter sampled in Promissao and Dracena respectively. A contagious spatial distribution pattern of L. longipalpis was identified in the emergence traps located in the chicken sheds. CONCLUSION: The results indicate that chicken sheds are the preferential breeding site for L. longipalpis in the present study areas. Thus, control measures targeting the immature stages in chicken sheds could have a great effect on reducing the number of adult flies and consequently the transmission rate of Leishmania (Leishmania) infantum chagasi. PMID- 24069493 TI - Comparison of phylogeny, venom composition and neutralization by antivenom in diverse species of bothrops complex. AB - In Latin America, Bothrops snakes account for most snake bites in humans, and the recommended treatment is administration of multispecific Bothrops antivenom (SAB- soro antibotropico). However, Bothrops snakes are very diverse with regard to their venom composition, which raises the issue of which venoms should be used as immunizing antigens for the production of pan-specific Bothrops antivenoms. In this study, we simultaneously compared the composition and reactivity with SAB of venoms collected from six species of snakes, distributed in pairs from three distinct phylogenetic clades: Bothrops, Bothropoides and Rhinocerophis. We also evaluated the neutralization of Bothrops atrox venom, which is the species responsible for most snake bites in the Amazon region, but not included in the immunization antigen mixture used to produce SAB. Using mass spectrometric and chromatographic approaches, we observed a lack of similarity in protein composition between the venoms from closely related snakes and a high similarity between the venoms of phylogenetically more distant snakes, suggesting little connection between taxonomic position and venom composition. P-III snake venom metalloproteinases (SVMPs) are the most antigenic toxins in the venoms of snakes from the Bothrops complex, whereas class P-I SVMPs, snake venom serine proteinases and phospholipases A2 reacted with antibodies in lower levels. Low molecular size toxins, such as disintegrins and bradykinin-potentiating peptides, were poorly antigenic. Toxins from the same protein family showed antigenic cross reactivity among venoms from different species; SAB was efficient in neutralizing the B. atrox venom major toxins. Thus, we suggest that it is possible to obtain pan-specific effective antivenoms for Bothrops envenomations through immunization with venoms from only a few species of snakes, if these venoms contain protein classes that are representative of all species to which the antivenom is targeted. PMID- 24069495 TI - A retrospective study of the epidemiology of leprosy in Cebu: an eleven-year profile. AB - BACKGROUND: Cebu has been one of the most leprosy endemic areas in the Philippines. Despite the high coverage rates of multiple drug therapy (MDT) and high BCG-vaccine coverage in children, leprosy control authorities believe that leprosy transmission and incidence (as evidence by continuing new case detection in both adults and children) have not declined as expected, once leprosy had been eliminated. In response to the concerns communicated by the authorities regarding ongoing leprosy transmission in Cebu, this study aims to examine the evidence for the hypothesized ongoing transmission, both in children and adults. Furthermore, it will be assessed which groups and areas are experiencing a continuing risk of leprosy infection; this can form a starting point for more targeted approaches to leprosy control. METHODOLOGY & PRINCIPAL FINDINGS: Case records from 2000-2010 were retrospectively collected from the Leonard Wood Memorial Clinic archives, and all other clinics on the island where leprosy was treated. Between 2000 and 2010, 3288 leprosy cases were detected. The overall five year case notification rate (CNR) dropped significantly from 47.35 (2001-2005) to 29.21 cases (2006 2010) per 100.000 population. Smaller CNRs were reported for children; however the decline in child-CNR over the same period was minimal. Furthermore, no increase in median age of notification in children or adults was found between 2000 and 2010. Population-adjusted clustering of leprosy cases was mainly detected in urban and peri-urban areas. CONCLUSIONS & SIGNIFICANCE: Although the overall CNR declined significantly, CNR seems to be rather static in lower risk populations and areas. Cases are mainly found in urban areas, however CNRs in these areas decline at a much faster rate than in the lower endemic rural areas. A similar situation was found when comparing adults and children: CNRs observed in children were lower than in adults, but further decline (and elimination) of these childhood CNRs was found to be difficult. Moreover, the median age of notification in children has remained stable, suggesting transmission is still on going. It is unclear why many years of good MDT-coverage and a gradual decline in CNR have not been accompanied by evidence of reduced transmission, especially beyond a certain threshold level of case notification. We believe that a new approach to leprosy control is required to tackle transmission more directly. The most promising approach may involve chemoprophylaxis and/or immunoprophylaxis interventions, targeted at high risk (urban) areas and groups such as household contacts, followed by a different approach once decline in CNR starts to level off. Identified clusters and trends can form the starting point for implementing this approach. PMID- 24069496 TI - Analysis of cross-reactive antibodies recognizing the fusion loop of envelope protein and correlation with neutralizing antibody titers in Nicaraguan dengue cases. AB - Dengue virus (DENV) is the leading cause of arboviral diseases in humans worldwide. The envelope (E) protein of DENV is the major target of neutralizing antibodies (Abs). Previous studies have shown that a significant proportion of anti-E Abs in human serum after DENV infection recognize the highly conserved fusion loop (FL) of E protein. The role of anti-FL Abs in protection against subsequent DENV infection versus pathogenesis remains unclear. A human anti-E monoclonal Ab was used as a standard in a virion-capture ELISA to measure the concentration of anti-E Abs, [anti-E Abs], in dengue-immune sera from Nicaraguan patients collected 3, 6, 12 and 18 months post-infection. The proportion of anti FL Abs was determined by capture ELISA using virus-like particles containing mutations in FL, and the concentration of anti-FL Abs, [anti-FL Abs], was calculated. Neutralization titers (NT50) were determined using a previously described flow cytometry-based assay. Analysis of sequential samples from 10 dengue patients revealed [anti-E Abs] and [anti-FL Abs] were higher in secondary than in primary DENV infections. While [anti-FL Abs] did not correlate with NT50 against the current infecting serotype, it correlated with NT50 against the serotypes to which patients had likely not yet been exposed ("non-exposed" serotypes) in 14 secondary DENV3 and 15 secondary DENV2 cases. These findings demonstrate the kinetics of anti-FL Abs and provide evidence that anti-FL Abs play a protective role against "non-exposed" serotypes after secondary DENV infection. PMID- 24069497 TI - The cost of annual versus biannual community-directed treatment of onchocerciasis with ivermectin: Ghana as a case study. AB - BACKGROUND: It has been proposed that switching from annual to biannual (twice yearly) mass community-directed treatment with ivermectin (CDTI) might improve the chances of onchocerciasis elimination in some African foci. However, historically, relatively few communities have received biannual treatments in Africa, and there are no cost data associated with increasing ivermectin treatment frequency at a large scale. Collecting cost data is essential for conducting economic evaluations of control programmes. Some countries, such as Ghana, have adopted a biannual treatment strategy in selected districts. We undertook a study to estimate the costs associated with annual and biannual CDTI in Ghana. METHODOLOGY: The study was conducted in the Brong-Ahafo and Northern regions of Ghana. Data collection was organized at the national, regional, district, sub-district and community levels, and involved interviewing key personnel and scrutinizing national records. Data were collected in four districts; one in which treatment is delivered annually, two in which it is delivered biannually, and one where treatment takes place biannually in some communities and annually in others. Both financial and economic costs were collected from the health care provider's perspective. PRINCIPAL FINDINGS: The estimated cost of treating annually was US Dollars (USD) 0.45 per person including the value of time donated by the community drug distributors (which was estimated at USD 0.05 per person per treatment round). The cost of CDTI was approximately 50-60% higher in those districts where treatment was biannual than in those where it was annual. Large-scale mass biannual treatment was reported as being well received and considered sustainable. CONCLUSIONS/SIGNIFICANCE: This study provides rigorous evidence of the different costs associated with annual and biannual CDTI in Ghana which can be used to inform an economic evaluation of the debate on the optimal treatment frequency required to control (or eliminate) onchocerciasis in Africa. PMID- 24069498 TI - Sequence analysis and serological responses against Borrelia turicatae BipA, a putative species-specific antigen. AB - BACKGROUND: Relapsing fever spirochetes are global yet neglected pathogens causing recurrent febrile episodes, chills, nausea, vomiting, and pregnancy complications. Given these nonspecific clinical manifestations, improving diagnostic assays for relapsing fever spirochetes will allow for identification of endemic foci and expedite proper treatment. Previously, an antigen designated the Borrelia immunogenic protein A (BipA) was identified in the North American species Borrelia hermsii. Thus far, BipA appears unique to relapsing fever spirochetes. The antigen remains unidentified outside of these pathogens, while interspecies amino acid identity for BipA in relapsing fever spirochetes is only 24-36%. The current study investigated the immunogenicity of BipA in Borrelia turicatae, a species distributed in the southern United States and Latin America. METHODOLOGY/PRINCIPAL FINDINGS: bipA was amplified from six isolates of Borrelia turicatae, and sequence analysis demonstrated that the gene is conserved among isolates. A tick transmission system was developed for B. turicatae in mice and a canine, two likely vertebrate hosts, which enabled the evaluation of serological responses against recombinant BipA (rBipA). These studies indicated that BipA is antigenic in both animal systems after infection by tick bite, yet serum antibodies failed to bind to B. hermsii rBipA at a detectable level. Moreover, mice continued to generate an antibody response against BipA one year after the initial infection, further demonstrating the protein's potential toward identifying endemic foci for B. turicatae. CONCLUSIONS/SIGNIFICANCE: These initial studies support the hypothesis that BipA is a spirochete antigen unique to a relapsing fever Borrelia species, and could be used to improve efforts for identifying B. turicatae endemic regions. PMID- 24069499 TI - Non-invasive sampling of schistosomes from humans requires correcting for family structure. AB - For ethical and logistical reasons, population-genetic studies of parasites often rely on the non-invasive sampling of offspring shed from their definitive hosts. However, if the sampled offspring are naturally derived from a small number of parents, then the strong family structure can result in biased population-level estimates of genetic parameters, particularly if reproductive output is skewed. Here, we document and correct for the strong family structure present within schistosome offspring (miracidia) that were collected non-invasively from humans in western Kenya. By genotyping 2,424 miracidia from 12 patients at 12 microsatellite loci and using a sibship clustering program, we found that the samples contained large numbers of siblings. Furthermore, reproductive success of the breeding schistosomes was skewed, creating differential representation of each family in the offspring pool. After removing the family structure with an iterative jacknifing procedure, we demonstrated that the presence of relatives led to inflated estimates of genetic differentiation and linkage disequilibrium, and downwardly-biased estimates of inbreeding coefficients (FIS). For example, correcting for family structure yielded estimates of FST among patients that were 27 times lower than estimates from the uncorrected samples. These biased estimates would cause one to draw false conclusions regarding these parameters in the adult population. We also found from our analyses that estimates of the number of full sibling families and other genetic parameters of samples of miracidia were highly intercorrelated but are not correlated with estimates of worm burden obtained via egg counting (Kato-Katz). Whether genetic methods or the traditional Kato-Katz estimator provide a better estimate of actual number of adult worms remains to be seen. This study illustrates that family structure must be explicitly accounted for when using offspring samples to estimate the genetic parameters of adult parasite populations. PMID- 24069500 TI - Cytokine response signatures in disease progression and development of severe clinical outcomes for leptospirosis. AB - BACKGROUND: The role of the immune response in influencing leptospirosis clinical outcomes is not yet well understood. We hypothesized that acute-phase serum cytokine responses may play a role in disease progression, risk for death, and severe pulmonary hemorrhage syndrome (SPHS). METHODOLOGY/PRINCIPAL FINDINGS: We performed a case-control study design to compare cytokine profiles in patients with mild and severe forms of leptospirosis. Among patients hospitalized with severe disease, we compared those with fatal and nonfatal outcomes. During active outpatient and hospital-based surveillance we prospectively enrolled 172 patients, 23 with mild disease (outpatient) and 149 with severe leptospirosis (hospitalized). Circulating concentrations of pro- and anti-inflammatory cytokines at the time of patient presentation were measured using a multiplex bead array assay. Concentrations of IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL 17A, and TNF-alpha were significantly higher (P<0.05) in severe disease compared to mild disease. Among severe patients, levels of IL-6 (P<0.001), IL-8 (P = 0.0049) and IL-10 (P<0.001), were higher in fatal compared to non-fatal cases. High levels of IL-6 and IL-10 were independently associated (P<0.05) with case fatality after adjustment for age and days of symptoms. IL-6 levels were higher (P = 0.0519) among fatal cases who developed SPHS than among who did not. CONCLUSION/SIGNIFICANCE: This study shows that severe cases of leptospirosis are differentiated from mild disease by a "cytokine storm" process, and that IL-6 and IL-10 may play an immunopathogenic role in the development of life-threatening outcomes in human leptospirosis. PMID- 24069502 TI - Southernmost Asia is the source of Japanese encephalitis virus (genotype 1) diversity from which the viruses disperse and evolve throughout Asia. AB - BACKGROUND: Although a previous study predicted that Japanese encephalitis virus (JEV) originated in the Malaysia/Indonesia region, the virus is known to circulate mainly on the Asian continent. However, there are no reported systematic studies that adequately define how JEV then dispersed throughout Asia. METHODOLOGY/PRINCIPAL FINDINGS: In order to understand the mode of JEV dispersal throughout the entire Asian continent and the factors that determine the dispersal characteristics of JEV, a phylogenetic analysis using Bayesian Markov chain Monte Carlo simulations was conducted on all available JEV E gene sequences in GenBank, plus strains recently isolated in China. Here we demonstrate for the first time that JEV lineages can be divided into four endemic cycles, comprising southern Asia, eastern coastal Asia, western Asia, and central Asia. The isolation places of the viruses in each endemic cycle were geographically independent regardless of years, vectors, and hosts of isolation. Following further analysis, we propose that the southernmost region (Thailand, Vietnam, and Yunnan Province, China) was the source of JEV transmission to the Asian continent following its emergence. Three independent transmission routes from the south to north appear to define subsequent dispersal of JEV. Analysis of JEV population dynamics further supports these concepts. CONCLUSIONS/SIGNIFICANCE: These results and their interpretation provide new insights into our understanding of JEV evolution and dispersal and highlight its potential for introduction into non endemic areas. PMID- 24069501 TI - Spinal cystic echinococcosis--a systematic analysis and review of the literature: part 2. Treatment, follow-up and outcome. AB - Bone involvement in human cystic echinococcosis (CE) is rare, but affects the spine in approximately 50% of cases. Despite significant advances in diagnostic imaging techniques, surgical treatment and introduction of pharmacological therapy, spinal echinococcosis remains associated with a high degree of morbidity, disability and mortality. We systematically reviewed the published literature of the last five decades to update and summarize the currently existing data on treatment, follow-up and outcome of spinal CE. PMID- 24069503 TI - Protective and antioxidant effects of a chalconoid from Pulicaria incisa on brain astrocytes. AB - Oxidative stress is involved in the pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Astrocytes, the most abundant glial cells in the brain, protect neurons from reactive oxygen species (ROS) and provide them with trophic support, such as glial-derived neurotrophic factor (GDNF). Thus, any damage to astrocytes will affect neuronal survival. In the present study, by activity-guided fractionation, we have purified from the desert plant Pulicaria incisa two protective compounds and determined their structures by spectroscopic methods. The compounds were found to be new chalcones pulichalconoid B and pulichalconoid C. This is the first study to characterize the antioxidant and protective effects of these compounds in any biological system. Using primary cultures of astrocytes, we have found that pulichalconoid B attenuated the accumulation of ROS following treatment of these cells with hydrogen peroxide by 89% and prevented 89% of the H2O2-induced death of astrocytes. Pulichalconoid B exhibited an antioxidant effect both in vitro and in the cellular antioxidant assay in astrocytes and microglial cells. Pulichalconoid B also caused a fourfold increase in GDNF transcription in these cells. Thus, this chalcone deserves further studies in order to evaluate if beneficial therapeutic effect exists. PMID- 24069504 TI - Red chicory (Cichorium intybus L. cultivar) as a potential source of antioxidant anthocyanins for intestinal health. AB - Fruit- and vegetable-derived foods have become a very significant source of nutraceutical phytochemicals. Among vegetables, red chicory (Cichorium Intybus L. cultivar) has gained attention for its content of phenolic compounds, such as the anthocyanins. In this study, we evaluated the nutraceutical effects, in terms of antioxidant, cytoprotective, and antiproliferative activities, of extracts of the whole leaf or only the red part of the leaf of Treviso red chicory (a typical Italian red leafy plant) in various intestinal models, such as Caco-2 cells, differentiated in normal intestinal epithelia and undifferentiated Caco-2 cells. The results show that the whole leaf of red chicory can represent a good source of phytochemicals in terms of total phenolics and anthocyanins as well as the ability of these phytochemicals to exert antioxidant and cytoprotective effects in differentiated Caco-2 cells and antiproliferative effects in undifferentiated Caco-2 cells. Interestingly, compared to red chicory whole leaf extracts, the red part of leaf extracts had a significantly higher content of both total phenolics and anthocyanins. The same extracts effectively corresponded to an increase of antioxidant, cytoprotective, and antiproliferative activities. Taken together, these findings suggest that the red part of the leaf of Treviso red chicory with a high content of antioxidant anthocyanins could be interesting for development of new food supplements to improve intestinal health. PMID- 24069505 TI - Nutrition and healthy ageing: calorie restriction or polyphenol-rich "MediterrAsian" diet? AB - Diet plays an important role in mammalian health and the prevention of chronic diseases such as cardiovascular disease (CVD). Incidence of CVD is low in many parts of Asia (e.g., Japan) and the Mediterranean area (e.g., Italy, Spain, Greece, and Turkey). The Asian and the Mediterranean diets are rich in fruit and vegetables, thereby providing high amounts of plant bioactives including polyphenols, glucosinolates, and antioxidant vitamins. Furthermore, oily fish which is rich in omega-3 fatty acids is an important part of the Asian (e.g., Japanese) and also of the Mediterranean diets. There are specific plant bioactives which predominantly occur in the Mediterranean (e.g., resveratrol from red wine, hydroxytyrosol, and oleuropein from olive oil) and in the Asian diets (e.g., isoflavones from soybean and epigallocatechin gallate from green tea). Interestingly, when compared to calorie restriction which has been repeatedly shown to increase healthspan, these polyphenols activate similar molecular targets such as Sirt1. We suggest that a so-called "MediterrAsian" diet combining sirtuin-activating foods (= sirtfoods) of the Asian as well as Mediterranean diet may be a promising dietary strategy in preventing chronic diseases, thereby ensuring health and healthy ageing. Future (human) studies are needed which take the concept suggested here of the MediterrAsian diet into account. PMID- 24069507 TI - Transgenic mammary epithelial osteopontin (spp1) expression induces proliferation and alveologenesis. AB - Osteopontin (OPN) Spp1 is involved in differentiation of the mammary gland. We engineered mice to overexpress OPN in mammary epithelium and describe an altered mammary phenotype. Three transgenic (Tg) founder lines FVB/N Tg(MMTV-Opn)((1 3BOR)) were propagated after FVB/NJ pronuclear injections. Mammary glands from Tg OPN mice compared to littermate controls showed, at 4 weeks of age, exaggerated terminal end buds; at 8 and 12 weeks, more numerous and complex ducts with increased luminal protein; and at 16 weeks, increased lobulogenesis. Lactational Tg-OPN mammary glands showed more rapid lobulogenesis and lactational changes with slower gland involution and regression following weaning. Ex vivo lobulogenesis was noticeably increased from organoids of Tg-OPN mice. Immunohistochemistry revealed cytoplasmic OPN accumulation and increased Ki-67 positive mammary epithelial cells in Tg-OPN mammary glands. OPN appears to convey a proliferative stimulus for mammary epithelial cells and alters development and differentiation. These OPN mammary overexpressing mice provide a means to study the role of OPN in cancer progression. PMID- 24069506 TI - Survival of HER2-Positive Breast Cancer Cells: Receptor Signaling to Apoptotic Control Centers. AB - HER2 is overexpressed in a subset of breast cancers and controls an oncogenic signaling network that inhibits tumor cell death through the specific biochemical regulation of apoptotic pathways. In particular, the mitochondrial pathway for apoptosis is important for death induced by inhibitors of HER2. This review focuses on the connections between this oncogenic signaling network and individual components of the mitochondrial pathway. A comprehensive view of this signaling network is crucial for developing novel drugs in this area and to gain an understanding of how these regulatory interactions are altered in drug refractory cancers. PMID- 24069508 TI - EWS and RE1-Silencing Transcription Factor Inhibit Neuronal Phenotype Development and Oncogenic Transformation in Ewing Sarcoma. AB - The gene encoding EWS (EWSR1) is involved in various chromosomal translocations that cause the production of oncoproteins responsible for multiple cancers including Ewing sarcoma, myxoid liposarcoma, soft tissue clear cell sarcoma, and desmoplastic small round cell sarcoma. It is well known that EWS fuses to FLI to create EWS/FLI, which is the abnormal transcription factor that drives tumor development in Ewing sarcoma. However, the role of wild-type EWS in Ewing sarcoma pathogenesis remains unclear. In the current study, we identified EWS-regulated genes and cellular processes through RNA interference combined with RNA sequencing and functional annotation analyses. Interestingly, we found that EWS and EWS/FLI co-regulate a significant cluster of genes, indicating an interplay between the 2 proteins in regulating cellular functions. We found that among the EWS-down-regulated genes are a subset of neuronal genes that contain binding sites for the RE1-silencing transcription factor (REST or neuron-restrictive silencer factor [NRSF]), neuron-restrictive silencer element (NRSE), suggesting a cooperative interaction between REST and EWS in gene regulation. Co immunoprecipitation analysis demonstrated that EWS interacts directly with REST. Genome-wide binding analysis showed that EWS binds chromatin at or near NRSE. Furthermore, functional studies revealed that both EWS and REST inhibit neuronal phenotype development and oncogenic transformation in Ewing sarcoma cells. Our data implicate an important role of EWS in the development of Ewing sarcoma phenotype and highlight a potential value in modulating EWS function in the treatment of Ewing sarcoma and other EWS translocation-based cancers. PMID- 24069509 TI - The S100A4 Oncoprotein Promotes Prostate Tumorigenesis in a Transgenic Mouse Model: Regulating NFkappaB through the RAGE Receptor. AB - S100A4, a calcium-binding protein, is known for its role in the metastatic spread of tumor cells, a late event of cancer disease. This is the first report showing that S100A4 is not merely a metastatic protein but also an oncoprotein that plays a critical role in the development of tumors. We earlier showed that S100A4 expression progressively increases in prostatic tissues with the advancement of prostate cancer (CaP) in TRAMP, an autochthonous mouse model. To study the functional significance of S100A4 in CaP, we generated a heterozygously deleted S100A4 (TRAMP/S100A4(+/-)) genotype by crossing TRAMP with S100A4(-/-) mice. TRAMP/S100A4(+/-) did not show a lethal phenotype, and transgenes were functional. As compared to age-matched TRAMP littermates, TRAMP/S100A4(+/-) mice exhibited 1) an increased tumor latency period (P < 0.001), 2) a 0% incidence of metastasis, and 3) reduced prostatic weights (P < 0.001). We generated S100A4 positive clones from S100A4-negative CaP cells and tested their potential. S100A4 positive tumors grew at a faster rate than S100A4-negative tumors in vitro and in a xenograft mouse model. The S100A4 protein exhibited growth factor-like properties in multimode (intracellular and extracellular) forms. We observed that 1) the growth-promoting effect of S100A4 is due to its activation of NFkappaB, 2) S100A4-deficient tumors exhibit reduced NFkappaB activity, 3) S100A4 regulates NFkappaB through the RAGE receptor, and 4) S100A4 and RAGE co-localize in prostatic tissues of mice. Keeping in view its growth-promoting role, we suggest that S100A4 qualifies as an excellent candidate to be exploited for therapeutic agents to treat CaP in humans. PMID- 24069510 TI - Identification of TET1 Partners That Control Its DNA-Demethylating Function. AB - Several recent reports have identified TET1 as the main enzyme modulating DNA methylation and gene transcription via hydroxylation of 5-methylcytosine. However, little is known about the protein network that controls TET1 activity. By using a new proximity ligation in situ assay, we identified MeCP2, HDAC1/6/7, EZH2, mSin3A, PCNA, and LSD1 as TET1-interacting proteins. We also discerned that TET1/PCNA acts as a demethylator of the cyclical methylation/demethylation process, the perturbation of which promotes the aberrant methylation hallmarks frequently observed in cancer cells. PMID- 24069511 TI - Primary hepatocellular carcinoma and metabolic syndrome: An update. AB - Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The incidence of hepatocellular carcinoma has increased dramatically by 80% over the past two decades in the United States. Numerous basic science and clinical studies have documented a strong association between hepatocellular carcinoma and the metabolic syndrome. These studies have documented that, in most patients, non alcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome, which may progress to hepatocellular carcinoma through the cirrhotic process. However, minority of patients with non-alcoholic fatty liver disease may progress to hepatocellular carcinoma without cirrhosis. This review summarizes the current literature of the link between hepatocellular carcinoma and metabolic syndrome with special emphasis on various components of the metabolic syndrome including risk of association with obesity, diabetes mellitus, hyperlipidemia, and hypertension. Current understanding of pathophysiology, clinical features, treatments, outcomes, and surveillance of hepatocellular carcinoma in the background of metabolic syndrome and non-alcoholic fatty liver disease is reviewed. With the current epidemic of metabolic syndrome, the number of patients with non-alcoholic fatty liver disease is increasing. Subsequently, it is expected that the incidence and prevalence of HCC will also increase. It is very important for the scientific community to shed more light on the pathogenesis of HCC with metabolic syndrome, both with and without cirrhosis. At the same time it is also important to quantify the risk of hepatocellular carcinoma associated with the metabolic syndrome in a prospective setting and develop surveillance recommendations for detection of hepatocellular carcinoma in patients with metabolic syndrome. PMID- 24069512 TI - Exploring Histidine Conformations in the M2 Channel Lumen of the Influenza A Virus at Neutral pH via Molecular Simulations. AB - The pH-regulated M2 proton channel from the influenza A virus has a His-tetrad in its transmembrane (TM) domain that is essential for proton conduction. At neutral pH, the tetrad has been observed in two distinct configurations, the "His-box" and "dimer-of-dimers", with similar backbone structures suggesting competing models for proton conduction. Here, we propose that both conformations can play a role. In support of this hypothesis, we used molecular dynamics simulations based on density functional theory to simulate the M2-TM domain and force-field-based simulations to estimate the relevant free-energy barriers. Both configurations are stable on accessible simulation time scales, and transitions between them occur faster than the millisecond time scale of proton conduction. Moreover, the deprotonation energy is too high for spontaneous conduction, consistent with their occurrence in the low-current regime. Our computations support a multiconfiguration model with different population levels, thereby connecting experimental data obtained under different conditions. PMID- 24069513 TI - Dysphagia in Head and Neck Cancer Patients: Pretreatment Evaluation, Predictive Factors, and Assessment during Radio-Chemotherapy, Recommendations. AB - Progress in head and neck cancer (HNC) therapies has improved tumor response, loco-regional control, and survival. However, treatment intensification also increases early and late toxicities. Dysphagia is an underestimated symptom in HNC patients. Impairment of swallowing process could cause malnutrition, dehydration, aspiration, and pneumonia. A comprehensive literature review finalized in May 2012 included searches of electronic databases (Medline, Embase, and CAB abstracts) and scientific societies meetings materials (American Society of Clinical Oncology, Associazione Italiana Radioterapia Oncologica, Associazione Italiana di Oncologia Cervico-Cefalica, American Head and Neck Society, and European Society for Medical Oncology). Hand-searches of HNC journals and reference lists were carried out. Approximately one-third of dysphagia patients developed pneumonia requiring treatment. Aspiration pneumonia associated mortality ranged from 20% to 65%. Unidentified dysphagia caused significant morbidity, increased mortality, and decreased the quality of life. In this review we underline definition, causes, predictive factors of dysphagia and report on pretreatment and on-treatment evaluation, suggesting some key points to avoid underestimation. A multi-parameter assessment of swallowing problems may allow an earlier diagnosis. An appropriate evaluation might lead to a better treatment of both symptoms and cancer. PMID- 24069514 TI - Clinical Significance of beta-Tricalcium Phosphate and Polyphosphate for Mastoid Cavity Obliteration during Middle Ear Surgery: Human and Animal Study. AB - OBJECTIVES: Mastoid obliteration is used to obliterate the mastoid cavity following a mastoidectomy or to prevent the formation of a retraction pocket. This study evaluated the effectiveness of beta-tricalcium phosphate and polyphosphate (beta-TPP) for mastoid obliteration in middle ear surgeries in prospective human and animal studies. METHODS: Twenty patients with chronic otitis media underwent mastoid obliteration using beta-TPP after a intact canal wall mastoidectomy or simple mastoidectomy. The clinical data were prospectively evaluated including: the diagnosis, temporal bone computed tomography (TBCT), otoscopic findings, pure tone audiogram, and complications. In the animal experiment, beta-TPP was applied into the right bulla in five rats, and the opposite bulla was used as the control in the non-obliterated state. The skulls of five other rats were drilled out and the holes were obliterated with beta-TPP. TBCT were obtained at 3, 6, and 9 months after the obliteration and histologic analysis was done at 3 and 9 months after surgery. RESULTS: In the human study, fourteen TBCTs were obtained at 12 months after the surgery. All demonstrated no bone resorption in the obliterated mastoids. Among the 15 cases displaying retracted tympanic membranes preoperatively, 11 showed no retraction, 2 showed retraction postoperatively, 1 was lost to follow-up and 1 was a case of postoperative wound infection. Among 20 cases, one case developed a postoperative infection that necessitated a second operation. Sixteen underwent ossiculoplasty; hearing improvements were obtained in 15 cases and 1 case showed decreased hearing. In the animal study, new bone formation without significant bone resorption in the radiologic and histologic findings were noted in both the skull and bulla groups. CONCLUSION: Although beta-TPP is a foreign material having the possibility of infection, mastoid obliteration with it can be a treatment option in middle ear surgeries to prevent retraction pockets or the recurrence of diseases. PMID- 24069515 TI - Agreement between the Facial Nerve Grading System 2.0 and the House-Brackmann Grading System in Patients with Bell Palsy. AB - OBJECTIVES: We have analyzed the correlation between the House-Brackmann (HB) scale and Facial Nerve Grading System 2.0 (FNGS 2.0) in patients with Bell palsy, and evaluated the usefulness of the new grading system. METHODS: Sixty patients diagnosed with Bell palsy from May 2009 to December 2010 were evaluated using the HB scale and FNGS 2.0 scale during their initial visit, and after 3 and 6 weeks and 3 months. RESULTS: The overall intraclass correlation coefficient (ICC) was 0.908 (P=0.000) and the Spearman correlation coefficient (SCC) was 0.912 (P<0.05). ICC and SCC displayed differences over time, being 0.604 and 0.626, respectively, at first visit; 0.834 and 0.843, respectively, after 3 weeks; 0.844 and 0.848, respectively, after 6 weeks; and 0.808 and 0.793, respectively, after 3 months. There was a significant difference in full recovery, depending on the scale used (HB, P=0.000; FNGS 2.0, P<0.05). The exact agreements between regional assessment and FNGS 2.0 for the mouth, eyes, and brow were 72%, 63%, and 52%, respectively. CONCLUSION: FNGS 2.0 shows moderate agreement with HB grading. Regional assessment, rather than HB grading, yields stricter evaluation, resulting in better prognosis and determination of grade. PMID- 24069516 TI - Temperature enhances activation and inactivation kinetics of potassium currents in inner hair cells isolated from Guinea-pig cochlea. AB - OBJECTIVES: Until recently, most patch-clamp recordings in inner hair cells (IHCs) have been performed at room temperature. The results acquired at room temperature should be corrected if they are to be related to in vivo findings. However, the temperature dependency to ion channels in IHCs is unknown. The aim of this study was to investigate the effect of temperature on the potassium currents in IHCs. METHODS: IHCs were isolated from a mature guinea-pig cochlea and potassium currents were recorded at room temperature (around 25C) and physiological temperatures (35C-37C). RESULTS: IHCs showed outwardly rectifying currents in response to depolarizing voltage pulses, with only a slight inward current when hyperpolarized. The amplitude of both outward and inward currents demonstrated no temperature dependency, however, activation and inactivation rates were faster at 36C than at room temperature. Half-time for activation was shorter at 36C than at room temperature at membrane potentials of -10, +10, +20, +30, and +40 mV. Q10 for the activation rate was 1.83. The inactivation time constant in outward tetraethylammonium-sensitive potassium currents was much smaller at 36C than at room temperature between the membrane potentials of -20 and +60 mV. Q10 for the inactivation time constant was 3.19. CONCLUSION: The results of this study suggest that the amplitude of potassium currents in IHCs showed no temperature dependence either in outward or inward-going currents, however, activation and inactivation accelerated at physiological temperatures. PMID- 24069517 TI - Postoperative olfactory results in chronic rhinosinusitis with nasal polyposis according to wound healing status. AB - OBJECTIVES: Postoperative wound healing status has not been considered in earlier studies on olfactory changes after surgery. This may be a factor accounting for the equivocal postoperative olfactory results. The aim of this study was to investigate postoperative olfactory results according to wound healing status. METHODS: Fifty patients who underwent endoscopic sinus surgery for chronic rhinosinusitis with nasal polyps with smelling disturbance were examined preoperatively, and at 6 months after surgery. Patients were divided into two groups according to postoperative Lund-Kennedy score: favorable and unfavorable wound healing. Preoperative ostiomeatal unit computed tomography (CT), such as Lund-Mackay score and olfactory cleft opacification score, clinical characteristics and olfactory function tests such as the butanol threshold test and cross-cultural smell identification test, and questionnaire responses were compared between the two groups. RESULTS: There were no differences in preoperative clinical characteristics between the favorable and unfavorable wound healing groups. The favorable wound healing group displayed greater improvement of olfactory results after surgery than the unfavorable wound healing group. Postoperative olfactory improvement patterns showed a hierarchy from subjective to objective improvement and from threshold to identification improvement. Patients who had postoperative favorable wound healing but showed no success of olfaction were characterized by more severe preoperative subjective symptoms and higher olfactory cleft opacification, especially in the upper part of olfactory cleft on preoperative CT scan. CONCLUSION: Wound healing status is an apparent risk factor for postoperative olfactory improvement. Moreover, preoperative opacification in the olfactory cleft may predict bad olfactory results after surgery, even in patients with favorable wound healing. PMID- 24069518 TI - The role of platelet-derived growth factor in the pathogenesis of sinonasal polyps: immunohistochemical assessment in epithelial, subepithelial and deep layers of the mucosa. AB - OBJECTIVES: The aim of this study is to investigate the role of platelet-derived growth factor (PDGF) in the pathogenesis of sinonasal polyps. METHODS: Study group (groups 1-3) consisted of nasal polyp samples of patients with sinonasal polyps and the control group consisted of inferior turbinate samples of patients without nasal polyp. In group 1, 14 specimens from ethmoid sinus; in group 2, 10 specimens from nasal cavity; in group 3, 10 specimens from maxillary sinus; and in group 4 (control), 9 specimens from inferior turbinate were included. By immunohistochemical staining technique, the PDGF positivity index (PI) in mucosal layers and in the inflammatory cells were assessed at the epithelium (EP), subepithelial layer of lamina propria (SE), and deep paraglandular layer of the mucosa (D). RESULTS: Polymorphonuclear cell (PMNC)-percentage (%) values of ethmoid and maxillary sinus, and the PDGF PI from all cells of ethmoid sinus and nasal cavity were significantly higher than those of the control group. As mononuclear cell-% (MNC-%) increased, the PDGF_EP_basal PI, PDGF_SE_endothelial PI, and PDGF_D_endothelial PI decreased. As PMNC-PDGF PI increased, the PDGF_D_perivascular PI decreased and PDGF_D_endothelial PI increased. As PDGF-MNC PI increased, the PDGF_EP_apical PI, PDGF_SE_endothelial PI, and PDGF_D_endothelial PI decreased. As PDGF-all cells (PMNCs, MNCs, and fibroblasts) PI increased, the PDGF_EP_basal PI and PDGF_D_endothelial PI decreased, and the PDGF_D_perivascular PI increased. CONCLUSION: We concluded that the PDGF systems play important roles in polyp pathogenesis. Fibroblast-derived PDGF may be more important than MNC-derived PDGF in polyp developing process. Increased perivascular-PDGF-PI in deep layers of the mucosa may result in sinonasal polyp formation by causing an increase in vascular permeability and extracellular edema, and thus promoting migration of inflammatory cells to extracellular area. Tissue oxygenization may be important for the initiation of PDGF release system. Because of this reason, nasal obstruction should be medically treated earlier, and, if necessary, by surgical approaches. PMID- 24069519 TI - Effect of isolated uvulopalatopharyngoplasty on subjective obstructive sleep apnea symptoms. AB - OBJECTIVES: The aims of this study were 1) to evaluate the effect of isolated uvulopalatopharyngoplasty (UPPP) on subjective obstructive sleep apnea (OSA) symptoms in adult patients regardless of the response to surgery, and ultimately 2) to investigate the differences in changes in subjective OSA symptoms between successful and unsuccessful surgery groups. METHODS: Twenty consecutive adult patients who underwent isolated UPPP were enrolled. Pre- and postoperative subjective OSA symptoms (snoring, witnessed apnea, daytime sleepiness, morning headache, daytime fatigue, restless sleep, difficulty with morning arousal) and polysomnographic data were evaluated in all subjects. Changes in subjective OSA symptoms before and after surgery were investigated in the successful (n=11) and unsuccessful (n=9) groups. Surgical success was defined as a reduction of at least 50% in the preoperative apnea-hypopnea index (AHI) and a postoperative AHI less than 20 per hour. RESULTS: After isolated UPPP, all subjective OSA symptoms changed significantly in the patients, especially in the successful group. In the unsuccessful group, snoring, witnessed apnea and daytime fatigue changed significantly, while other symptoms did not change significantly after surgery. CONCLUSION: Isolated UPPP may improve subjective OSA symptoms in adult patients whom surgery was successful or unsuccessful. However, after isolated UPPP, the improvements in subjective OSA symptoms in the unsuccessful group may be different from those in the successful group. PMID- 24069520 TI - Persistent dysphonia after laryngomicrosurgery for benign vocal fold disease. AB - OBJECTIVES: Laryngomicrosurgery (LMS) is used to manage most vocal fold lesions. However, the functional voice outcome of the LMS might be diverse due to the influence of various factors. We intend to evaluate the incidence and etiologic factors of persistent dysphonia after LMS for benign vocal fold disease (BVFD). METHODS: We performed a retrospective review of 755 patients who underwent LMS for BVFD. We analyzed the clinical characteristics, preoperative and postoperative two onths voice studies. Postsurgical dysphonia was defined as grade 1 or above in GRBAS (grade, roughness, breathiness, asthenia, and strain) scale. Thirty nine patients (5.2%; 25 males and 14 females; average, 42.9 years; range, 21 to 70 years) were diagnosed with postsurgical dysphonia. RESULTS: There was no correlation between the diagnosis, coexistence with laryngopharyngeal reflux disease, habit of smoking, or occupational voice abuse and voice outcome. The patients with a worse preoperative acoustic parameter had aworse voice outcome. Stroboscopic findings showed excessive scarring or bowing in 21 cases, presence of lesion remnant in eight cases, prolonged laryngeal edema in five and no abnormal findings in three. CONCLUSION: Great care should be taken in patients with worse preoperative jitter. With a few exceptions, postoperative dysphonia can be avoided by the use of an ppropriate surgical technique. PMID- 24069521 TI - Vascular leiomyoma in the head and neck region: 11 years experience in one institution. AB - OBJECTIVES: Vascular leiomyoma is an uncommon benign tumor of smooth muscle origin that arises from the muscularis layer of blood vessel walls. We report our experiences with the clinical manifestations, pathologic characteristics, and management of vascular leiomyoma in the head and neck. METHODS: The clinical records of 12 patients with vascular leiomyoma of the head and neck in the 11 year period were reviewed retrospectively. RESULTS: The 12 patients included nine men and three women. The locations of the tumors were variable, including nasal cavity, auricle, hard palate, upper lip, upper eyelid, and supraclavicular space. All but three patients reported an asymptomatic spherical mass; the other three patients complained of intermittent epistaxis or unilateral nasal obstruction resulting from the tumor originating in the nasal cavity. All tumors were painless. Computed tomography consistently revealed a well-defined, intensely enhanced small mass on the mucosa. No case was dignosed corretly as vascular leiomyoma before surgical excision. All patients underwent localized surgical excision of the tumor without recurrence. Five of 12 tumors (42%) were of solid type, four (33%) were of venous type, and three (25%) were of cavernous in histological classification. The histologic type was not related to gender, site of occurrence, and presence of pain. CONCLUSION: Vascular leiomyoma presents as a small, painless mass in various locations of the head and neck region. Localized surgical excision is the only way to make the diagnosis and yields excellent results. PMID- 24069522 TI - Selective delivery of a therapeutic gene for treatment of head and neck squamous cell carcinoma using human neural stem cells. AB - OBJECTIVES: Based on studies of the extensive tropism of neural stem cells (NSCs) toward malignant brain tumor, we hypothesized that NSCs could also target head and neck squamous cell carcinoma (HNSCC) and could be used as a cellular therapeutic delivery system. METHODS: To apply this strategy to the treatment of HNSCC, we used a human NSC line expressing cytosine deaminase (HB1.F3-CD), an enzyme that converts 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU), an anticancer agent. HB1. F3-CD in combination with 5-FC were cocultured with the HNSCC (SNU-1041) to examine the cytotoxicity on target tumor cells in vitro. For in vivo studies, an HNSCC mouse model was created by subcutaneous implantation of human HNSCC cells into athymic nude mice. HB1.F3-CD cells were injected into mice using tumoral, peritumoral, or intravenous injections, followed by systemic 5-FC administration. RESULTS: In vitro, the HB1.F3-CD cells significantly inhibited the growth of an HNSCC cell line in the presence of the 5-FC. Independent of the method of injection, the HB1.F3-CD cells migrated to the HNSCC tumor, causing a significant reduction in tumor volume. In comparison to 5-FU administration, HB1.F3-CD cell injection followed by 5-FC administration reduced systemic toxicity, but achieved the same level of therapeutic efficacy. CONCLUSION: Transplantation of human NSCs that express the suicide enzyme cytosine deaminase combined with systemic administration of the prodrug 5-FC may be an effective regimen for the treatment of HNSCC. PMID- 24069523 TI - Primary Burkitt's Lymphoma in the Nasal Cavity and Paranasal Sinuses. AB - Burkitt's lymphoma is a highly aggressive small B-cell lymphoma. The treatment of choice is complex chemotherapy. As a rare tumor in the head and neck area, Burkitt's lymphoma usually involves cervical lymph nodes, and only fewer than 25% of cases involves extranodal regions. Involvement of the paranasal sinuses has been reported in only 14 cases in the past century. We describe here two patients with rare, sporadic, American type Burkitt's lymphoma involving the nasal cavity and paranasal sinuses manifesting nasal obstruction. We also review clinical and histological features of Burkitt's lymphoma. PMID- 24069524 TI - A thyroglossal duct cyst causing obstructive sleep apnea in adult. AB - Obstructive sleep apnea (OSA) is a common disorder. It usually results from the structural compromise of the upper airway. In patients with OSA, the obstruction predominantly occurs along the pharyngeal airway, and also a variety of tumors have been reported to cause such a condition. We present here the case of a thyroglossal duct cyst causing OSA in adult. This case demonstrates that thyroglossal duct cyst or some kind of mass lesions in the airway lesions should be considered in the differential diagnosis of OSA patients. PMID- 24069525 TI - Congenital epidermoid cyst of the oral cavity: prenatal diagnosis by sonography. AB - Epidermoid cysts are benign developmental anomalies that are rarely observed in the oral cavity of neonate. If large in size, especially in the developing fetus or newborn infant, they can cause swallowing difficulty and occasionally respiratory difficulty. We report a case of epidermoid cyst in the oral cavity detected prenatal sonography. The sonographic finding was large cystic mass, measuring 30*25 mm. In this case, supplies and equipment for an emergency tracheostomy were made available prior to the delivery. However, the infant did not require intervention to secure the airway. The lesion was surgically excised, and histologic diagnosis was epidermoid cyst. After 6 months of follow up, the cyst had not recurred. This case illustrates the value of accurate prenatal diagnosis and planned perinatal management using a team approach. PMID- 24069526 TI - Negative-pressure wound therapy in the management of diabetic Charcot foot and ankle wounds. AB - As the prevalence of diabetes mellitus continues to rise, innovative medical and surgical treatment options have increased dramatically to address diabetic related foot and ankle complications. Among the most challenging clinical case scenarios is Charcot neuroarthropathy associated with soft tissue loss and/or osteomyelitis. In this review article, the authors present a review of the most common utilizations of negative-pressure wound therapy as an adjunctive therapy or combined with plastic surgery as it relates to the surgical management of diabetic Charcot foot and ankle wounds. PMID- 24069527 TI - Direct observation of frequency modulated transcription in single cells using light activation. AB - Single-cell analysis has revealed that transcription is dynamic and stochastic, but tools are lacking that can determine the mechanism operating at a single gene. Here we utilize single-molecule observations of RNA in fixed and living cells to develop a single-cell model of steroid-receptor mediated gene activation. We determine that steroids drive mRNA synthesis by frequency modulation of transcription. This digital behavior in single cells gives rise to the well-known analog dose response across the population. To test this model, we developed a light-activation technology to turn on a single steroid-responsive gene and follow dynamic synthesis of RNA from the activated locus. DOI:http://dx.doi.org/10.7554/eLife.00750.001. PMID- 24069529 TI - Eiger triggers death from afar. AB - Cells undergoing programmed cell death release signals that can trigger the death of cells at remote locations. PMID- 24069530 TI - A new regulator of caveolae signalling. AB - Cavin-3 regulates metabolism and cell proliferation by coordinating the activities of growth factor signalling cascades. PMID- 24069528 TI - Cavin-3 dictates the balance between ERK and Akt signaling. AB - Cavin-3 is a tumor suppressor protein of unknown function. Using both in vivo and in vitro approaches, we show that cavin-3 dictates the balance between ERK and Akt signaling. Loss of cavin-3 increases Akt signaling at the expense of ERK, while gain of cavin-3 increases ERK signaling at the expense Akt. Cavin-3 facilitates signal transduction to ERK by anchoring caveolae to the membrane skeleton of the plasma membrane via myosin-1c. Caveolae are lipid raft specializations that contain an ERK activation module and loss of the cavin-3 linkage reduces the abundance of caveolae, thereby separating this ERK activation module from signaling receptors. Loss of cavin-3 promotes Akt signaling through suppression of EGR1 and PTEN. The in vitro consequences of the loss of cavin-3 include induction of Warburg metabolism (aerobic glycolysis), accelerated cell proliferation, and resistance to apoptosis. The in vivo consequences of cavin-3 knockout are increased lactate production and cachexia. DOI:http://dx.doi.org/10.7554/eLife.00905.001. PMID- 24069532 TI - Evaluation of the HB&L System for the Microbiological Screening of Storage Medium for Organ-Cultured Corneas. AB - Aims. To compare HB&L and BACTEC systems for detecting the microorganisms contaminating the corneal storage liquid preserved at 31 degrees C. Methods. Human donor corneas were stored at 4 degrees C followed by preservation at 31 degrees C. Samples of the storage medium were inoculated in BACTEC Peds Plus/F (aerobic microorganisms), BACTEC Plus Anaerobic/F (anaerobic microorganisms), and HB&L bottles. The tests were performed (a) after six days of storage, (b) end of storage, and (c) after 24 hours of preservation in deturgescent liquid sequentially. 10,655 storage and deturgescent media samples were subjected to microbiological control using BACTEC (6-day incubation) and HB&L (24-hour incubation) systems simultaneously. BACTEC positive/negative refers to both/either aerobic and anaerobic positives/negatives, whereas HB&L can only detect the aerobic microbes, and therefore the positives/negatives depend on the presence/absence of aerobic microorganisms. Results. 147 (1.38%) samples were identified positive with at least one of the two methods. 127 samples (134 identified microorganisms) were positive with both HB&L and BACTEC. 14 HB&L+/BACTEC- and 6 BACTEC+/HB&L- were identified. Sensitivity (95.5%), specificity (99.8%), and positive (90.1%) and negative predictive values (99.9%) were high with HB&L considering a 3.5% annual contamination rate. Conclusion. HB&L is a rapid system for detecting microorganisms in corneal storage medium in addition to the existing methods. PMID- 24069531 TI - Coronary artery disease and its risk factors status in iran: a review. AB - BACKGROUND: Coronary artery disease (CAD) is a leading cause of mortality, morbidity, and disability in the world. The high prevalence and morbidity associated with CAD in Iran is one of the most pressing health problems. METHODS: We have reviewed the status of CAD and prevalence of its traditional and novel risk factors based on the published papers in recent years that may have an impact on the rate of CAD in Iran. Evaluation of current impact of metabolic syndrome in Iran was the other aim of this review, as it contributes to pathogenesis of coronary artery disease. We reviewed all PubMed indexed related studies. Some evidences from national articles which were published by the Ministry Of Health and Medical Education Research Council Certified Medical Journals of Islamic Republic of Iran were also included. RESULTS: The prevalence of CAD, coronary risk factors and metabolic syndrome in Iran is higher than Western countries and similar to some Middle East countries. There are limited data with regard to novel coronary risk factors in Iran. CONCLUSION: Primary and secondary prevention of CAD including life style modifications and dietary interventions strongly recommended in Iranian population. PMID- 24069533 TI - Predictors of visual response to intravitreal bevacizumab for treatment of neovascular age-related macular degeneration. AB - Purpose. To identify the predictors of visual response to the bevacizumab treatment of neovascular age-related macular degeneration (AMD). Design. A cohort study within the Neovascular AMD Treatment Trial Using Bevacizumab (NATTB). Methods. This was a multicenter trial including 144 participants from the NATTB study. Visual outcomes measured by change in visual acuity (VA) score, proportion gaining >=15 letters, and change in central retinal thickness (CRT) were compared among groups according to the baseline, demographic, and ocular characteristics and genotypes. Results. Mean change in the VA score was 9.2 +/- 2.3 SD letters with a total of 46 participants (31.9%) gaining >=15 letters. Change in median CRT was -81.5 MU m. Younger age, lower baseline VA score, shorter duration of neovascular AMD, and TT genotype in rs10490924 were significantly associated with greater VA score improvement (P = 0.028, P < 0.001, P = 0.02, and P = 0.039, resp.). Lower baseline VA score and TT genotype in rs10490924 were significantly associated with a higher likelihood of gaining >=15 letters (P = 0.028, and P = 0.021, resp.). Conclusions. Baseline VA and genotype of rs10490924 were both important predictors for visual response to bevacizumab at 6 months. This trial is registered with the Registration no. NCT01306591. PMID- 24069535 TI - A 10-Week Multimodal Nutrition Education Intervention Improves Dietary Intake among University Students: Cluster Randomised Controlled Trial. AB - The aim of the study was to evaluate the effectiveness of implementing multimodal nutrition education intervention (NEI) to improve dietary intake among university students. The design of study used was cluster randomised controlled design at four public universities in East Coast of Malaysia. A total of 417 university students participated in the study. They were randomly selected and assigned into two arms, that is, intervention group (IG) or control group (CG) according to their cluster. The IG received 10-week multimodal intervention using three modes (conventional lecture, brochures, and text messages) while CG did not receive any intervention. Dietary intake was assessed before and after intervention and outcomes reported as nutrient intakes as well as average daily servings of food intake. Analysis of covariance (ANCOVA) and adjusted effect size were used to determine difference in dietary changes between groups and time. Results showed that, compared to CG, participants in IG significantly improved their dietary intake by increasing their energy intake, carbohydrate, calcium, vitamin C and thiamine, fruits and 100% fruit juice, fish, egg, milk, and dairy products while at the same time significantly decreased their processed food intake. In conclusion, multimodal NEI focusing on healthy eating promotion is an effective approach to improve dietary intakes among university students. PMID- 24069534 TI - Genetics of psoriasis and pharmacogenetics of biological drugs. AB - Psoriasis is a chronic inflammatory disease of the skin. The causes of psoriasis are unknown, although family and twin studies have shown genetic factors to play a key role in its development. The many genes associated with psoriasis and the immune response include TNF alpha , IL23, and IL12. Advances in knowledge of the pathogenesis of psoriasis have enabled the development of new drugs that target cytokines (e.g., etanercept, adalimumab, and infliximab, which target TNF alpha , and ustekinumab, which targets the p40 subunit of IL23 and IL12). These drugs have improved the safety and efficacy of treatment in comparison with previous therapies. However, not all patients respond equally to treatment, possibly owing to interindividual genetic variability. In this review, we describe the genes associated with psoriasis and the immune response, the biological drugs used to treat chronic severe plaque psoriasis, new drugs in phase II and III trials, and current knowledge on the implications of pharmacogenomics in predicting response to these treatments. PMID- 24069536 TI - Direct Comparison of the Safety and Efficacy of Ferric Carboxymaltose versus Iron Dextran in Patients with Iron Deficiency Anemia. AB - Several intravenous iron complexes are available for the treatment of iron deficiency anemia (IDA). Iron dextran (DEX) is associated with an elevated risk of potentially serious anaphylactic reactions, whereas others must be administered in several small infusions to avoid labile iron reactions. Ferric carboxymaltose (FCM) is a nondextran intravenous iron which can be administered in high single doses. A randomized, open label, and multicenter comparison of FCM to DEX in adults with IDA and baseline hemoglobin of <=11.0 g/dL was conducted. A total of 160 patients were in the safety population (FCM n = 82; DEX n = 78). Adverse events, including immune system disorders (0% in FCM versus 10.3% in DEX, P = 0.003) and skin disorders (7.3% in FCM versus 24.4% in DEX, P = 0.004), were less frequently observed in the FCM group. A greater portion of patients in the FCM group experienced a transient, asymptomatic decrease in phosphate compared to patients in the DEX group (8.5% in FCM versus 0% in DEX, P = 0.014). In the FCM arm, the change in hemoglobin from baseline to the highest observed level was 2.8 g/dL, whereas the DEX arm displayed a change of 2.4 g/dL (P = 0.20). Treatment of IDA with FCM resulted in fewer hypersensitivity-related reactions than DEX. PMID- 24069537 TI - Central Venous-to-Arterial CO2 Gap Is a Useful Parameter in Monitoring Hypovolemia-Caused Altered Oxygen Balance: Animal Study. AB - Monitoring hypovolemia is an everyday challenge in critical care, with no consensus on the best indicator or what is the clinically relevant level of hypovolemia. The aim of this experiment was to determine how central venous oxygen saturation (ScvO2) and central venous-to-arterial carbon dioxide difference (CO2 gap) reflect hypovolemia-caused changes in the balance of oxygen delivery and consumption. Anesthetized, ventilated Vietnamese minipigs (n = 10) were given a bolus followed by a continuous infusion of furosemide. At baseline and then in five stages hemodynamic, microcirculatory measurements and blood gas analysis were performed. Oxygen extraction increased significantly, which was accompanied by a significant drop in ScvO2 and a significant increase in CO2 gap. There was a significant negative correlation between oxygen extraction and ScvO2 and significant positive correlation between oxygen extraction and CO2 gap. Taking ScvO2 < 73% and CO2 gap >6 mmHg values together to predict an oxygen extraction >30%, the positive predictive value is 100%; negative predicted value is 72%. Microcirculatory parameters, capillary perfusion rate and red blood cell velocity, decreased significantly over time. Similar changes were not observed in the sham group. Our data suggest that ScvO2 < 73% and CO2 gap >6 mmHg can be complementary tools in detecting hypovolemia-caused imbalance of oxygen extraction. PMID- 24069538 TI - Bone-targeted therapies in metastatic castration-resistant prostate cancer: evolving paradigms. AB - Majority of patients with metastatic castrate resistant prostate cancer (mCRPC) develop bone metastases which results in significant morbidity and mortality as a result of skeletal-related events (SREs). Several bone-targeted agents are either in clinical use or in development for prevention of SREs. Bisphosphonates were the first class of drugs investigated for prevention of SREs and zoledronic acid is the only bisphosphonate that is FDA-approved for this indication. Another bone targeted agent is denosumab which is a fully humanized monoclonal antibody that binds to the RANK-L thereby inhibiting RANK-L mediated bone resorption. While several radiopharmaceuticals were approved for pain palliation in mCRPC including strontium and samarium, alpharadin is the first radiopharmaceutical to show significant overall survival benefit. Contemporary therapeutic options including enzalutamide and abiraterone have effects on pain palliation and SREs as well. Other novel bone-targeted agents are currently in development, including the receptor tyrosine kinase inhibitors cabozantinib and dasatinib. Emerging therapeutics in mCRPC has resulted in great strides in preventing one of the most significant sources of complications of bone metastases. PMID- 24069539 TI - Resection and Reconstruction of Maxillary Class IIIc Defect in a Case of Adenoid Cystic Carcinoma: Cost-Sensitive Technique without Microvascular Grafts. AB - ACC is a rare malignant tumor that affects most commonly the major and minor salivary glands and rarely the paranasal sinuses, lacrimal gland, larynx, ear, vulva, and so forth. The maxillary sinus when affected is considered having a poor prognosis due to delayed diagnosis and delayed treatment credited to its slow spread, late symptoms, and complex anatomy which hampers surgical resection. The expressions of tumor markers too have a significant role in determining the prognosis. The treatment of choice consists of wide radical resection of the tumor followed by radiotherapy. Rehabilitation options in cases with huge maxillary defects still need further exploration. PMID- 24069540 TI - Vulvar nonclear cell syringoma associated with pruritus and diabetes mellitus. AB - Background. Syringoma is a benign eccrine sweat gland tumor, characterized by multiple skin colored or slightly yellowish papules. Vulvar syringoma without extragenital involvement is an extremely rare variant of syringoma. Mail Observations. Herein, we report a 40-year-old diabetic female patient who presented with only lichenified plaques on the vulvar region without any extragenital lesions. Diagnosis of vulvar syringoma was made depending on the characteristic double lined cystic enlargements and comma-like tails found in histopathological examination. Immunohistochemical stains for estrogen and progesterone receptors were negative. Conclusion. Vulvar syringoma may present with no obvious papules on lichenified plaques. PMID- 24069541 TI - Rapidly developing toxic epidermal necrolysis. AB - Severe cutaneous reactions with potentially fatal outcomes can have many different causes. The Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare. They are characterized by a low incidence but high mortality, and drugs are most commonly implicated. Urgent active therapy is required. Prompt recognition and withdrawal of suspect drug and rapid intervention can result in favourable outcome. No further international guidelines for treatment exist, and much of the treatment relies on old or experimental concepts with no scientific evidence. We report on a 54-year-old man experiencing rapidly developing drug-induced severe TEN and presented multiorgan failure involving the respiratory and circulatory system, coagulopathy, and renal insufficiency. Detachment counted 30% of total body surface area (TBSA). SCORTEN = 5, indicating a mortality rate >90%. The patient was sedated and mechanically ventilated, supported with fluids and inotropes to maintain a stable circulation. Component therapy was guided by thromboelastography (TEG). The patient received plasmapheresis, and shock reversal treatment was initiated. He was transferred to a specialized intensive care burn unit within 24 hours from admittance. The initial care was continued, and hemodialysis was started. Pulmonary, circulatory, and renal sequelae resolved with intensive care, and re-epithelialization progressed slowly. The patient was discharged home on hospital day 19. PMID- 24069542 TI - A case of pulmonary tumor thrombotic microangiopathy diagnosed by transbronchial lung biopsy and treated with chemotherapy and long-term oxygen and anticoagulation therapies. AB - A 41-year-old woman, who underwent breast resection for cancer of the right breast and adjuvant chemotherapy 2 years ago, was admitted to our hospital due to shortness of breath upon exertion. High-resolution computed tomography of the chest showed small nodular opacities in the peribronchiolar area in both lungs, as well as mediastinal and hilar lymphadenopathy. A transbronchial lung biopsy revealed breast cancer metastasis and pulmonary tumor thrombotic microangiopathy (PTTM). Treatment of PTTM is rarely reported due to the difficulty of antemortem diagnosis; however, the patient was effectively treated with chemotherapy and oxygen and anticoagulation therapies for 3 months. PMID- 24069543 TI - Multiple intracranial meningiomas: a review of the literature and a case report. AB - Multiple intracranial meningiomas are a condition where there is more than one meningioma in several intracranial locations in the same patient without signs of neurofibromatosis. Incidence varies from 1 to 10%. The prognosis of multiple intracranial meningioma does not differ from benign solitary meningiomas despite the multiplicity. However, the simultaneous occurrence of different grades of malignancy is observed in one-third of multiple meningiomas. Surgery remains the best option for treatment of symptomatic lesions. Our case review aims to present and discuss a 75-year-old female patient diagnosed with multiple intracranial meningiomas, describing their clinical, radiological, histological characteristics. It also highlights the fact that the patient had two tumours, underwent surgery, and so far has a good quality of life. PMID- 24069545 TI - Rehabilitation and Parkinson's disease 2013. PMID- 24069544 TI - Utility of the mini-cog for detection of cognitive impairment in primary care: data from two spanish studies. AB - Objectives. To study the utility of the Mini-Cog test for detection of patients with cognitive impairment (CI) in primary care (PC). Methods. We pooled data from two phase III studies conducted in Spain. Patients with complaints or suspicion of CI were consecutively recruited by PC physicians. The cognitive diagnosis was performed by an expert neurologist, after formal neuropsychological evaluation. The Mini-Cog score was calculated post hoc, and its diagnostic utility was evaluated and compared with the utility of the Mini-Mental State (MMS), the Clock Drawing Test (CDT), and the sum of the MMS and the CDT (MMS + CDT) using the area under the receiver operating characteristic curve (AUC). The best cut points were obtained on the basis of diagnostic accuracy (DA) and kappa index. Results. A total sample of 307 subjects (176 CI) was analyzed. The Mini-Cog displayed an AUC (+/-SE) of 0.78 +/- 0.02, which was significantly inferior to the AUC of the CDT (0.84 +/- 0.02), the MMS (0.84 +/- 0.02), and the MMS + CDT (0.86 +/- 0.02). The best cut point of the Mini-Cog was 1/2 (sensitivity 0.60, specificity 0.90, DA 0.73, and kappa index 0.48 +/- 0.05). Conclusions. The utility of the Mini-Cog for detection of CI in PC was very modest, clearly inferior to the MMS or the CDT. These results do not permit recommendation of the Mini-Cog in PC. PMID- 24069546 TI - Exploring the Ethics of Observational Research: The Case of an HIV Study in Tanzania. AB - BACKGROUND: Observational studies have generally been viewed as incurring minimal risk to participants, resulting in fewer ethical obligations for investigators than intervention studies. In 2004, the lead author (AN) carried out an observational study measuring sexual behavior and the prevalence of HIV, syphilis, and herpes simplex virus type 2 (HSV-2), among Tanzanian agricultural plantation residents (results reported elsewhere). This article uses an ethical lens to consider the consequences of the observational study and explore what, if any, effects it had on participants and their community. METHODS: Using a case study approach, we critically examine three core principles of research ethics respect for persons/autonomy; beneficence/nonmaleficence; and distributive justice-as manifested in the 2004 observational study. We base our findings on three sources: discussions with plantation residents following presentations of observational research findings; in-depth interviews with key informants; and researcher observations. RESULTS: The observational research team was found to have ensured confidentiality and noncoercive recruitment. Ironically, maintenance of confidentiality and voluntary participation led some participants to doubt study results. Receiving HIV test results was important for participants and contributed to changing community norms about HIV testing. CONCLUSIONS: Observational studies may act like de facto intervention studies and thus incur obligations similar to those of intervention studies. We found that ensuring respect for persons may have compromised the principles of beneficence and distributive justice. While in theory these three ethical principles have equal moral force, in practice, researchers may have to prioritize one over the others. Careful community engagement is necessary to promote well-considered ethical decisions. PMID- 24069547 TI - Nkx2-5 Regulates Tdgf1 (Cripto) Early During Cardiac Development. AB - Congenital Heart Disease (CHD) is the most frequent and deadly birth defect. Patients with CHD that survive the neonatal period often progress to develop advanced heart failure requiring specialized treatment including cardiac transplantation. A full understanding of the transcriptional networks that direct cardiac progenitors during heart development will enhance our understanding of both normal cardiac function and pathological states. These findings will also have important applications for emerging therapies and the treatment of congenital heart disease. Furthermore, a number of shared transcriptional pathways or networks have been proposed to regulate the development and regeneration of tissues such as the heart. We have utilized transgenic technology to isolate and characterize cardiac progenitor cells from the developing mouse heart and have begun to define specific transcriptional networks of cardiovascular development. Initial studies identified Tdgf1 as a potential target of Nkx2-5. To mechanistically dissect the regulation of this molecular program, we utilized an array of molecular biological techniques to confirm that Nkx2-5 is an upstream regulator of the Tdgf1 gene in early cardiac development. These studies further define Nkx2-5 mediated transcriptional networks and enhance our understanding of cardiac morphogenesis. PMID- 24069548 TI - JAK-STAT and bone metabolism. AB - Emerging evidences suggest Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway plays an important role in bone development and metabolism. Effects of JAK-STAT pathway on skeletal development are summarized based on skeletal phenotype of individual JAK and STAT gene knockout mouse. Furthermore, STAT3 has more profound effects on bone homeostasis compared with the other STATs. STAT3 mutation causes a disease called Job syndrome, most patients with which have associated craniofacial and skeletal features. Selective inactivation of STAT3 in osteoblasts decreases bone formation and skeletal responsiveness to mechanical loading. Future research includes investigating JAK-STAT signaling in osteoclasts and osteocytes. PMID- 24069549 TI - Transcriptional regulation by STAT1 and STAT2 in the interferon JAK-STAT pathway. AB - STAT1 and STAT2 proteins are key mediators of type I and type III interferon (IFN) signaling, and are essential components of the cellular antiviral response and adaptive immunity. They associate with IFN regulatory factor 9 (IRF9) to form a heterotrimeric transcription factor complex known as ISGF3. The regulation of IFN-stimulated gene (ISG) expression has served as a model of JAK-STAT signaling and mammalian transcriptional regulation, but to date has primarily been analyzed at the single gene level. While many aspects of ISGF3-mediated gene regulation are thought to be common features applicable to several ISGs, there are also many reports of distinct cases of non-canonical STAT1 or STAT2 signaling events and distinct patterns of co-regulators that contribute to gene-specific transcription. Recent genome-wide studies have begun to uncover a more complete profile of ISG regulation, moving toward a genome-wide understanding of general mechanisms that underlie gene-specific behaviors. PMID- 24069551 TI - ROCKing the JAKs. AB - The endocrine cytokine leptin is mainly secreted by white adipose tissue and plasma leptin levels positively correlate with body fat mass. Via its action on neurons in the hypothalamic arcuate nucleus (ARC), leptin regulates body weight by stimulating energy expenditure and inhibiting food intake. The main signaling pathway of the leptin receptor is the JAK2-STAT3 pathway. A recent publication of Huang et al. in Nature Neuroscience shows that leptin's hypothalamic signaling via JAK2 requires the kinase ROCK1 (Rho-associated coiled-coil-containing protein kinase 1). ROCK1 directly phosphorylates JAK2, and this phosphorylation is required for the JAK2-STAT3 pathway of the leptin receptor. Gene deletion of ROCK1 in ARC neurons targeted by leptin makes these neurons less sensitive to leptin. This is reflected by a pronounced weight gain with hyperphagia, reduced locomotor activity, and increased fat accumulation. In this article we comment on the article of Huang et al. While the mechanism of ROCK1 activation in the neurons remains uncharacterized for the moment, a literature survey suggests that the interplay between ROCK1 and a JAK kinase may be a common theme for receptors that function via a JAK2 and even for other members of the JAK kinase family. PMID- 24069550 TI - SOCS, inflammation, and cancer. AB - Signal transduction pathways elicited by cytokines and hormones have been shown to regulate distinct stages of development. Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of cytokine signaling mediated by the JAK-STAT signaling pathway. In particular, SOCS1 and SOCS3 are potent inhibitors of JAKs and can play pivotal roles in inflammation, as well as in the development and progression of cancers. Abnormal expression of SOCS1 and SOCS3 in cancer cells has been reported in human carcinoma associated with dysregulation of signals from cytokine receptors, Toll-like receptors (TLRs), and hormone receptors, resulting in malignancies. In this review, we focus on the role of SOCS1 and SOCS3 in cancer development. In addition, the potential of SOCS as a therapeutic target and diagnostic aid will be discussed. PMID- 24069554 TI - How are STAT1 and cholesterol metabolism associated in antiviral responses? AB - Sterol metabolites are known to be associated with immune responses. 25 Hydroxycholesterol (25HC) is a cholesterol metabolite that is produced by macrophages. The production of 25HC was reported to be TLR-dependent, indicating the involvement of 25HC in innate immunity. Now Blanc et al. show that macrophages synthesize 25HC to exert an antiviral effect. STAT1 was shown to be the most essential transcriptional factor involved in the induction of cholesterol 25-hydroxylase (Ch25h), the enzyme required to produce 25HC, indicating the importance of STAT1 in oxysterol-mediated innate immunity. PMID- 24069553 TI - Sphingosine-1-phosphate: Driver of NFkappaB and STAT3 persistent activation in chronic intestinal inflammation and colitis-associated cancer. AB - Inflammatory bowel disease is associated with an increased risk of colorectal cancer. Colitis-associated cancer is a classical inflammation-driven cancer in which constitutive NFkappaB and STAT3 activation drive tumorigenesis. Recent findings published by Liang et al. in Cancer Cell demonstrate that sphingosine kinase 1 (SphK1)-mediated upregulation of sphingosine-1-phosphate (S1P) drives a persistent NFkappaB/IL-6/STAT3/sphingosine-1-phosphate receptor 1 (S1PR1) amplification loop that is critical to the development of chronic colitis and colitis-associated cancer. FTY720, an antagonist of S1PR1, abolished persistent NFkappaB/IL-6/STAT3 signaling and reduced the development and progression of colitis-associated cancer. Targeting SphK1/S1P/S1PR1 may provide a therapeutic option to prevent the progression of colitis to cancer. PMID- 24069552 TI - The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. AB - Atopic dermatitis (AD), a common chronic inflammatory skin disease, is characterized by inflammatory cell skin infiltration. The JAK-STAT pathway has been shown to play an essential role in the dysregulation of immune responses in AD, including the exaggeration of Th2 cell response, the activation of eosinophils, the maturation of B cells, and the suppression of regulatory T cells (Tregs). In addition, the JAK-STAT pathway, activated by IL-4, also plays a critical role in the pathogenesis of AD by upregulating epidermal chemokines, pro inflammatroy cytokines, and pro-angiogenic factors as well as by downregulating antimicrobial peptides (AMPs) and factors responsible for skin barrier function. In this review, we will highlight the recent advances in our understanding of the JAK-STAT pathway in the pathogenesis of AD. PMID- 24069555 TI - CDK8 as the STAT1 serine 727 kinase? AB - Whereas cytokine-induced tyrosine phosphorylation of STAT (signal transducer and activator of transcription) proteins by JAK kinases has been well studied, much less is known about STAT-specific serine kinases and their signal-dependent regulation. The paper by Joanna Bancerek and colleagues published recently in Immunity reports that upon interferon-gamma (IFNgamma) stimulation of cells the chromatin-associated cyclin-dependent kinase 8 (CDK8) phosphorylates the regulatory serine residue 727 in the transactivation domain of STAT1. The authors state that the CDK8 module of the Mediator complex is a key component in the STAT1 signal pathway, linking serine phosphorylation to gene-specific transcriptional events. PMID- 24069557 TI - STAT3 as a new autophagy regulator. AB - Signal transducers and activators of transcription 3 (STAT3) proteins are cytoplasmic transcription factors that translocate into the nucleus to induce transcription following growth factor or cytokine stimulation. Besides their normal functions, these proteins play an important role in cancer cells through the abnormal activation of cell cycle progression and the deregulation of survival and senescence pathways. New data obtained from the laboratory of Guido Kroemer identifies STAT3 as a new autophagy regulator. In the cytoplasm, in the absence of conventional phosphorylation on the tyrosine 705 residue, STAT3 interacts with the PKR kinase to inhibit eIF2A phosphorylation and so reduce autophagic pathways. This new and nonconventional function of STAT3 has an important role in normal cells but we suggest that it might also affect cancer cells and the response to chemotherapy treatment. PMID- 24069556 TI - Dancing rhinos in stilettos: The amazing saga of the genomic and nongenomic actions of STAT3 in the heart. AB - A substantial body of evidence has shown that signal transducer and activator of transcription 3 (STAT3) has an important role in the heart in protecting the myocardium from ischemia and oxidative stress. These actions are attributed to STAT3 functioning as a transcription factor in upregulating cardioprotective genes. Loss of STAT3 has been implicated as well in the pathogenesis of heart failure and, in that context and in addition to the loss of a cardioprotective gene program, nuclear STAT3 has been identified as a transcriptional repressor important for the normal functioning of the ubiquitin-proteasome system for protein degradation. The later finding establishes a genomic role for STAT3 in controlling cellular homeostasis in cardiac myocytes independent of stress. Surprisingly, although a well-studied area, very few downstream gene targets of STAT3 in the heart have been definitively identified. In addition, STAT3 is now known to induce gene expression by noncanonical means that are not well characterized in the heart. On the other hand, recent evidence has shown that STAT3 has important nongenomic actions in cardiac myocytes that affect microtubule stability, mitochondrial respiration, and autophagy. These extranuclear actions of STAT3 involve protein-protein interactions that are incompletely understood, as is their regulation in both the healthy and injured heart. Moreover, how the diverse genomic and nongenomic actions of STAT3 crosstalk with each other is unchartered territory. Here we present an overview of what is and is not known about both the genomic and nongenomic actions of STAT3 in the heart from a structure-function perspective that focuses on the impact of posttranslational modifications and oxidative stress in regulating the actions and interactions of STAT3. Even though we have learnt a great deal about the role played by STAT3 in the heart, much more awaits to be discovered. PMID- 24069558 TI - JAK2-V617F-induced MAPK activity is regulated by PI3K and acts synergistically with PI3K on the proliferation of JAK2-V617F-positive cells. AB - The identification of a constitutively active JAK2 mutant, namely JAK2-V617F, was a milestone in the understanding of Philadelphia chromosome-negative myeloproliferative neoplasms. The JAK2-V617F mutation confers cytokine hypersensitivity, constitutive activation of the JAK-STAT pathway, and cytokine independent growth. In this study we investigated the mechanism of JAK2-V617F dependent signaling with a special focus on the activation of the MAPK pathway. We observed JAK2-V617F-dependent deregulated activation of the multi-site docking protein Gab1 as indicated by constitutive, PI3K-dependent membrane localization and tyrosine phosphorylation of Gab1. Furthermore, we demonstrate that PI3K signaling regulates MAPK activation in JAK2-V617F-positve cells. This cross regulation of the MAPK pathway by PI3K affects JAK2-V617F-specific target gene induction, erythroid colony formation, and regulates proliferation of JAK2-V617F positive patient cells in a synergistically manner. PMID- 24069559 TI - Computational models of the JAK1/2-STAT1 signaling. AB - Despite a conceptually simple mechanism of signaling, the JAK-STAT pathway exhibits considerable behavioral complexity. Computational pathway models are tools to investigate in detail signaling process. They integrate well with experimental studies, helping to explain molecular dynamics and to state new hypotheses, most often about the structure of interactions. A relatively small amount of experimental data is available for a JAK1/2-STAT1 variant of the pathway, hence, only several computational models were developed. Here we review a dominant approach of kinetic modeling of the JAK1/2-STAT1 pathway, based on ordinary differential equations. We also give a brief overview of attempts to computationally infer topology of this pathway. PMID- 24069560 TI - How should we define STAT3 as an oncogene and as a potential target for therapy? AB - Aberrant activation of the STAT3 transcription factor has been reported in a large group of tumors and a strong biological basis now defines this protein as an oncogenic driver. Consequently, STAT3 is considered to be a promising target in the field of cancer therapy. For its inhibition to result in a successful therapeutic approach, the definition of a target tumor population identified by specific and detectable alterations is critical. The canonical activation model of STAT3 relies on a constitutive phosphorylation on its 705 tyrosine site, resulting in its dimerization, nuclear translocation, and the consequent activation of cancer genes. Therefore, it is expected that tumors expressing this phosphorylated form are addicted to STAT3 and will be sensitive to existing drugs which are targeting this dimeric form. However, recent results have shown that STAT3 can function as an oncogene in the absence of this tyrosine phosphorylation. This indicates that different forms of the transcription factor also play an important role in tumor growth and chemotherapy resistance. This complicates the definition of STAT3 as an oncogene and as a potential prognosis and predictive biomarker. The obligation to target a defined tumor type implies that future clinical trials should use a precise definition of STAT3 activation. This will allow tumors addicted to this oncogene to be identified correctly, leading to a strong rationale for patient stratification. PMID- 24069561 TI - STATs and macrophage fusion. AB - Macrophages play a pivotal role in host defense against multiple foreign materials such as bacteria, parasites and artificial devices. Some macrophage lineage cells, namely osteoclasts and foreign body giant cells (FBGCs), form multi-nuclear giant cells by the cell-cell fusion of mono-nuclear cells. Osteoclasts are bone-resorbing cells, and are formed in the presence of RANKL on the surface of bones, while FBGCs are formed in the presence of IL-4 or IL-13 on foreign materials such as artificial joints, catheters and parasites. Recently, fusiogenic mechanisms and the molecules required for the cell-cell fusion of these macrophage lineage cells were, at least in part, clarified. Dendritic cell specific transmembrane protein (DC-STAMP) and osteoclast stimulatory transmembrane protein (OC-STAMP), both of which comprise seven transmembrane domains, are required for both osteoclast and FBGC cell-cell fusion. STAT6 was demonstrated to be required for the cell-cell fusion of FBGCs but not osteoclasts. In this review, advances in macrophage cell-cell fusion are discussed. PMID- 24069562 TI - The cardioprotective effects of urocortin are mediated via activation of the Src tyrosine kinase-STAT3 pathway. AB - Src tyrosine kinase family was recently identified as a novel upstream modulator of MAP kinase subfamily, p42/p44, whose activation is required for urocortin (Ucn)-mediated cardioprotection. Src kinase was also shown to reduce apoptosis in different cancer cell lines, enhancing phosphorylation and DNA binding affinity of signal transducer and activator of transcription (STAT)3. In order to evaluate the effects of Ucn on the activation status of different STAT family members, HL 1 cardiac cells were incubated with Ucn (10 nM) for increasing periods of time. STAT3 was rapidly phosphorylated at Tyr705, while neither phosphorylation at Ser727 nor induction of total STAT3 was observed. Pretreatment with PP2, a selective inhibitor of Src tyrosine kinase, reduced the pSTAT(-T705) phosphorylation and transcriptional activity induced by Ucn in a dose-dependent manner. Overexpression of STAT3 in HL-1 cardiac myocytes pretreated with Ucn reduced the magnitude of cell death as compared with Ucn treatment alone, while transfection of HL-1 cells with a STAT3 mutant functionally inactive, acting as a dominant negative (DN-STAT3), enhanced the extent of cell death in a dose dependent manner. In line with this finding, in HL-1 cardiac myocytes overexpressing STAT3 treated with Ucn, addition of the Src kinase inhibitor PP2 reversed the cytoprotective effects of Ucn, proving that the cytoprotective effects of Ucn are also mediated via the Src-pSTAT(-T705) phosphorylation pathway. By immunocytochemistry, Ucn induced nuclear translocation of pST3-T705, which was inhibited by pretreatment with PP2. Together, these data strongly suggest that Ucn can mediate cardioprotection by activating the Src-pSTAT-T705 phosphorylation pathway. PMID- 24069564 TI - The Drosophila JAK-STAT pathway. AB - The conservation of signaling cascades between humans and Drosophila, over more than 500 million years of evolutionary time, means that the genetic tractability of the fly can be used to its full advantage to understand the functional requirements for JAK-STAT pathway signaling across species. Here we review the background to how the pathway was first identified and the first characterization of JAK-STAT pathway phenotypes in the Drosophila system, highlighting the molecular, functional, and disease-related conservation of the pathway. PMID- 24069563 TI - JAK2 mutants (e.g., JAK2V617F) and their importance as drug targets in myeloproliferative neoplasms. AB - The Janus kinase 2 (JAK2) mutant V617F and other JAK mutants are found in patients with myeloproliferative neoplasms and leukemias. Due to their involvement in neoplasia and inflammatory disorders, Janus kinases are promising targets for kinase inhibitor therapy. Several small-molecule compounds are evaluated in clinical trials for myelofibrosis, and ruxolitinib (INCB018424, Jakafi(r)) was the first Janus kinase inhibitor to receive clinical approval. In this review we provide an overview of JAK2V617F signaling and its inhibition by small-molecule kinase inhibitors. In addition, myeloproliferative neoplasms are discussed regarding the role of JAK2V617F and other mutant proteins of possible relevance. We further give an overview about treatment options with special emphasis on possible combination therapies. PMID- 24069565 TI - Regulation of proliferation, cell competition, and cellular growth by the Drosophila JAK-STAT pathway. AB - The JAK-STAT pathway is a key regulator of tissue size in Drosophila melanogaster. Here we provide an overview of its roles in processes that regulate the size of Drosophila imaginal discs, epithelia of diploid cells that proliferate and acquire specific fates in the larvae and that become functional in the adult. Drosophila has a single JAK and a single STAT gene, which has facilitated genetic dissection of this pathway. Moreover, the sophisticated genetic tools available in flies for clonal growth assays have made Drosophila an ideal organism in which to dissect the multiple roles of the JAK-STAT pathway in growth control. Studies in flies have revealed JAK-STAT pathway activity as a central node for diverse signals that control proliferation and mass accumulation. In addition, recent work has establish a new role for the pathway in cell competition, a process thought to be akin to the early stages of transformation in which more robust cells kill and take the place of less robust ones. PMID- 24069566 TI - JAK-STAT signaling in stem cells and their niches in Drosophila. AB - JAK-STAT signaling is a highly conserved regulator of stem cells and their niches. Aberrant activation in hematopoietic stem cells is the underlying cause of a majority of myeloproliferative diseases. This review will focus on the roles of JAK-STAT activity in three different adult stem cell systems in Drosophila. Tightly controlled levels of JAK-STAT signaling are required for stem cell maintenance and self-renewal, as hyperactivation of the pathway is associated with stem cell overproliferation. JAK-STAT activity is further essential for anchoring the stem cells in their respective niches by regulating different adhesion molecules. PMID- 24069567 TI - The Drosophila JAK-STAT pathway in blood cell formation and immunity. AB - Genetic alterations affecting the JAK-STAT signaling pathway are linked to several malignancies and hematological disorders in humans. Despite being one of the most extensively studied pathways, there remain many gaps to fill. JAK-STAT components are widely conserved during evolution. Here, we review the known roles of the JAK-STAT pathway in Drosophila immunity: controlling the different steps of hematopoiesis, both under physiological conditions and in response to immune challenge, and contributing to antiviral responses. We then summarize what is currently known about JAK-STAT signaling in renewal of the adult intestine, under physiological conditions or in response to ingestion of pathogenic bacteria. PMID- 24069568 TI - JAK-STAT pathway in Drosophila morphogenesis: From organ selector to cell behavior regulator. AB - One of the main contributions of Drosophila to the JAK-STAT field is the study of morphogenesis. JAK-STAT signaling controls the formation of many different structures through surprisingly different morphogenetic behaviors that include induction of cell rearrangements, invagination, folding of tissues, modulation of cell shape, and migration. This variability may be explained by the many transcription factors and signaling molecules STAT regulates at early stages of development. But is STAT just acting as an upstream inducer of morphogenesis or does it have a more direct role in controlling cell behaviors? Here we review what is known about how the canonical phosphorylation of STAT contributes to shaping the embryonic and imaginal structures. PMID- 24069569 TI - JAK-STAT in heterochromatin and genome stability. AB - The canonical JAK-STAT signaling pathway transmits signals from the cell membrane to the nucleus, to regulate transcription of particular genes involved in development and many other physiological processes. It has been shown in Drosophila that JAK and STAT also function in a non-canonical mode, to regulate heterochromatin. This review discusses the non-canonical functioning of JAK and STAT, and its effects on biological processes. Decreased levels of activated JAK and increased levels of unphosphorylated STAT generate higher levels of heterochromatin. These higher heterochromatin levels result in suppression of hematopoietic tumor-like masses, increased resistance to DNA damage, and longer lifespan. PMID- 24069570 TI - Factors affecting healthy eating and physical activity behaviors among multiethnic blue- and white-collar workers: a case study of one healthcare institution. AB - Worksite health promotion programs can reduce prevalence of chronic disease among employees, but little research has been done to discern whether they meet the needs and incorporate the preferences of workers of different occupational types. The objective of this study is to examine differences in influences to healthy eating and physical activity and preferences for programs among multiethnic blue- and white-collar workers in Hawai'i. A total of 57 employees from a major health care corporation in Hawai'i participated. A mixed-methods approach was employed, in which findings from focus groups with white-collar workers (WCW) (n=18) were used to inform development of a questionnaire with closed and open-ended items for use with blue-collar workers (BCW) (n=39), whose jobs did not provide adequate time to participate in focus groups. Focus groups with WCW revealed that onsite availability of healthy food and fitness opportunities provided the most support for healthy eating and physical activity at work; work demands, easy access to unhealthy foods, and lack of onsite fitness opportunities were barriers; and lifestyle management was a topic of substantial interest. BCW cited the ability to bring home lunch and their (physically active) jobs as being supportive of healthy behaviors; not having enough time to eat and personal illness/injury were barriers; and chronic disease topics were of greatest interest. Knowing differences in influences to healthy eating and physical activity, as well as preferences for worksite wellness programming, among BCW and WCW, is important when planning and implementing worksite health promotion programs. PMID- 24069571 TI - Emergence of Burkholderia cepacia in Honolulu: a case of nursing home-acquired B. cepacia sepsis. AB - Burkholderia cepacia has rarely been reported in Honolulu. Its emergence as a nursing home-acquired pathogen with high mortality rate is concerning. This case report describes a local nursing home patient who was diagnosed with B. cepacia sepsis in 2012. PMID- 24069572 TI - Knowledge and perceptions about community-acquired staphylococcal infections among health care workers in Hawai'i. AB - Since the early 1990s, national rates of methicillin-resistant Staphylococcus aureus (MRSA) infections have increased dramatically.1,2 Initially identified in health care settings, community-acquired MRSA is now a major public health concern. With Hawai'i's expanding S. aureus and MRSA epidemic closely approximating the national trend in inpatient and outpatient settings,7,8 a high level of knowledge and awareness among health care workers is essential to successfully control this evolving epidemic. Health care and related workers were surveyed to assess their knowledge and perceptions about staphylococcal and MRSA infections. Knowledge was estimated by demonstrated ability to correctly identify risk factors including diabetes and obesity, as well as to demonstrate awareness of a growing staphylococcal and MRSA epidemic.9,10 Perceptions were estimated by level of concern of antibiotic resistance as well as of the severity of the staphylococcal and MRSA epidemic. Variations in knowledge and perception concerning basic principles associated with S. aureus infections as well as characteristics of the evolving S. aureus and MRSA epidemic were observed among various occupations (advance clinical practitioners, nurses, public health professionals, athletic trainers, and non-medical workers) as well as work locations (hospital, community, and non-clinical community). Overall, health care and related workers in community settings demonstrated disparities in knowledge regarding S. aureus and MRSA infections. They were also more likely to misperceive this growing threat. These findings provide support for focused educational interventions targeting community health care and related workers to improve awareness of staphylococcal infections in order to successfully address and combat this evolving epidemic. PMID- 24069573 TI - Domestic violence against women on Yap, Federated States of Micronesia. AB - Anecdotally there are high rates of domestic violence in the small Micronesian State of Yap, Federated States of Micronesia (FSM), but there have been no studies to quantify the prevalence or characteristics of domestic violence in Yap or in any other state of the FSM. A survey was administered to women at the Yap hospital and community health centers from February through June 2011. Survey data were on domestic violence, which was supplemented by a focus group to explore the issues involved in greater detail. A high prevalence of domestic violence was documented by the survey; perceptions about this were explored in the focus group. On the questionnaire, 148 of 194 (76%) women reported at least one form of abuse. Given the small number of adult women in Yap, these findings suggest that domestic violence is a serious, pervasive problem that Yap needs urgently to address. The issue clearly needs to be investigated throughout the other states of the FSM and addressed at the national policy level as well as at the state level. PMID- 24069575 TI - Project Kealahou--forging a new pathway for girls in Hawai'i's public mental health system. PMID- 24069577 TI - Current trends in robotic surgery for otolaryngology. AB - As minimally invasive surgery has become common in head and neck surgery, the role of robotic surgery has expanded from thyroid surgery and transoral robotic surgery (TORS) of the oropharynx and supraglottic to other areas. Surgeons have advanced the limits of TORS, adapting lasers to the Da Vinci robot for glottic cancer, and combining existing techniques for transoral supraglottic laryngectomy and hypopharyngectomy to perform transoral total laryngectomy. Skull base approaches have been reported with some success in case reports and cadaver models, but the current instrument size and configuration limit the applicability of the current robotic system. Surgeons have reported reconstruction of the head and neck via local and free flaps. Using the previously reported approaches for thyroidectomy via modified facelift incision, neck dissection has also been reported. Future applications of robotic surgery in otolaryngology may be additionally expanded, as several new robotic technologies are under development for endolaryngeal work and neurotology. PMID- 24069578 TI - Parallel Excitation in Ultrahigh Field Human MR Imaging and Multi-Channel Transmit System. PMID- 24069579 TI - Advanced MR Imaging Technologies in Fetuses. AB - Fetal Magnetic Resonance Imaging (MRI) on clinical scanners has increasingly been realized as a powerful imaging tool and applied for studying the brain abnormalities and the potential of neurodevelopmental disabilities in vivo. The primarily used multi-echo fast imaging sequences reduce the motion artifacts with a tradeoff of image Signal-to-Noise Ratio (SNR) and resolution. In Radio Frequency (RF) hardware for MR signal excitation and reception, there are lack of dedicated RF coils for fetal imaging providing optimized performance in acquisition and safety. There is an urgent demand for novel hardware and fast imaging technology developments to overcome motion artifacts and improve sensitivity and safety. Recent studies have demonstrated that dedicated fetal RF transceiver arrays can improve the SNR, image coverage, and safety. In addition, emerging fast imaging technologies such as parallel imaging and compressed sensing would be advantageous in improving imaging speed and thus reducing motion artifacts in fetal imaging. PMID- 24069580 TI - In Vitro Dissolution Testing Strategies for Nanoparticulate Drug Delivery Systems: Recent Developments and Challenges. AB - Nanoparticulate systems have emerged as prevalent drug delivery systems over the past few decades. These delivery systems (such as liposomes, emulsions, nanocrystals, and polymeric nanocarriers) have been extensively used to improve bioavailability, prolong pharmacological effects, achieve targeted drug delivery, as well as reduce side effects. Considering that any unanticipated change in product performance of such systems may result in toxicity and/or change in vivo efficacy, it is essential to develop suitable in vitro dissolution/release testing methods to ensure product quality and performance, and to assist in product development. The present review provides an overview of the current in vitro dissolution/release testing methods such as dialysis, sample and separate, as well as continuous flow methods. Challenges and future directions in the development of standardized and biorelevant in vitro dissolution/release testing methods for novel nanoparticulate systems are discussed. PMID- 24069581 TI - Prospects in folate receptor-targeted radionuclide therapy. AB - Targeted radionuclide therapy is based on systemic application of particle emitting radiopharmaceuticals which are directed toward a specific tumor associated target. Accumulation of the radiopharmaceutical in targeted cancer cells results in high doses of absorbed radiation energy whereas toxicity to non targeted healthy tissue is limited. This strategy has found widespread application in the palliative treatment of neuroendocrine tumors using somatostatin-based radiopeptides. The folate receptor (FR) has been identified as a target associated with a variety of frequent tumor types (e.g., ovarian, lung, brain, renal, and colorectal cancer). In healthy organs and tissue FR-expression is restricted to only a few sites such as for instance the kidneys. This demonstrates why FR-targeting is an attractive strategy for the development of new therapy concepts. Due to its high FR-binding affinity (K D < 10(-9) M) the vitamin folic acid has emerged as an almost ideal targeting agent. Therefore, a variety of folic acid radioconjugates for nuclear imaging have been developed. However, in spite of the large number of cancer patients who could benefit of a folate-based radionuclide therapy, a therapeutic concept with folate radioconjugates has not yet been envisaged for clinical application. The reason is the generally high accumulation of folate radioconjugates in the kidneys where emission of particle-radiation may result in damage to the renal tissue. Therefore, the design of more sophisticated folate radioconjugates providing improved tissue distribution profiles are needed. This review article summarizes recent developments with regard to a therapeutic application of folate radioconjugates. A new construct of a folate radioconjugate and an application protocol which makes use of a pharmacological interaction allowed the first preclinical therapy experiments with radiofolates. These results raise hope for future application of such new concepts also in the clinic. PMID- 24069582 TI - Targeted therapy for breast cancer prevention. AB - With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer. PMID- 24069583 TI - Platinum-sensitive recurrence in ovarian cancer: the role of tumor microenvironment. AB - Despite several advances in the understanding of ovarian cancer pathobiology, in terms of driver genetic alterations in high-grade serous cancer, histologic heterogeneity of epithelial ovarian cancer, cell-of-origin for ovarian cancer, the survival rate from ovarian cancer is disappointingly low when compared to that of breast or prostate cancer. One of the factors contributing to the poor survival rate from ovarian cancer is the development of chemotherapy resistance following several rounds of chemotherapy. Although unicellular drug resistance mechanisms contribute to chemotherapy resistance, tumor microenvironment and the extracellular matrix (ECM), in particular, is emerging as a significant determinant of a tumor's response to chemotherapy. In this review, we discuss the potential role of the tumor microenvironment in ovarian cancer recurrence and resistance to chemotherapy. Finally, we propose an alternative view of platinum sensitive recurrence to describe a potential role of the ECM in the process. PMID- 24069585 TI - A comparative histopathology, serology and molecular study, on experimental ocular toxocariasis by Toxocara cati in Mongolian gerbils and Wistar rats. AB - The aim of this study was to compare the performance of three in-house diagnostic tests, that is, histopathology, enzyme-linked immunosorbent assay (ELISA), and polymerase chain reaction (PCR), for the diagnosis after experimental infection with Toxocara cati. Twenty Mongolian gerbils and Wistar rats were divided into ten groups (n = 2/group). Toxocara cati infections were established in Mongolian gerbils and Wistar rats by administering doses of 240 and 2500 embryonated Toxocara cati eggs by gavage, respectively. Tissue sections were stained with Haematoxylin and Eosin and observed under the light microscope. Sera and vitreous fluid collected from separate infected groups were tested against Toxocara cati antigens, for 92 days postinfection. Genomic DNA was extracted from formalin fixed paraffin-embedded (FFPE) blocks, and aqueous fluids belong to the animals. The histopathology test gave negative results among the groups of animals examined between 5 and 92 days postinfection. The ELISA results showed that anti Toxocara antibodies have risen between 7 and 61 days postinfection in sera and vitreous fluid in the animals infected, respectively. Analysis of PCR products revealed positive band (660 bp) in the orbital tissue infected Mongolian gerbils at 5 days postinfection. Of the three evaluated methods, the PCR could be recommended for scientific and laboratory diagnoses of toxocariasis in experimentally infected animals. PMID- 24069586 TI - Effect of Nerium oleander (N.O.) leaves extract on serum hepcidin, total iron, and infiltration of ED1 positive cells in albino rat. AB - To gain insight into the hepatohistological alterations in noninjured rat liver, Nerium oleander (N.O.) leaves extract was injected intramuscularly to induce an acute phase reaction (APR). Histopathological changes were studied after 3, 12, and 24 h time course of sterile muscle abscess. Tissue integrity and any infiltration of inflammatory cells in the liver were investigated by Hematoxylin and Eosin and ED1 peroxidase stainings. The administration of N.O. leaves extract (10 mL/kg) in H & E stained sections showed a general vacuolization of cytoplasm resulting loss of polarity with prominent nucleoli after 3 h of induction. At 12 h, eccentric nuclei were also observed in the sections. Marked infiltration of leucocytes with predominate macrophages was also found after 24 h as seen by ED1 positive staining. In the present study, a possible relationship between serum hepcidin and total iron level was also investigated in vivo. An early increase of hepcidin and total iron level (3 h) with a maximum at 12 h (P < 0.01; P < 0.001) was observed. These changes indicate that sterile muscle abscess may induce APR resulting in hepatic damage which is evident with the recruitment of inflammatory cells into the organ. PMID- 24069587 TI - Difference of morphology and immunophenotype between central and peripheral squamous cell carcinomas of the lung. AB - BACKGROUND: Recent agents, that is, pemetrexed and bevacizumab, have shown reproductive negative association between squamous histology. According to these agents' effectiveness, ruling out of the squamous histology is a significant issue for surgical pathologists. Several articles have proposed the distinction of peripheral type from central type of squamous cell carcinoma (SqCC) due to its similarity to adenocarcinoma, although little evidence to support the difference between these two types was published. In this study, we compared the clinicopathologic findings of central and peripheral pulmonary SqCCs. MATERIAL AND METHODS: 15 central and 35 peripheral types of SqCC from 2005 to 2010 were examined. Twelve morphological features were scored based on their intensity in the original H&E slides, and then, tissue microarray holding triplicated cores from 43 cases was immunohistochemically examined for cytokeratin (CK)7, CK14, TTF 1, Napsin A, p63, CK34 beta E12, CK5/6, and p53. RESULT: Most of the histological findings did not separate central and peripheral SqCCs; only the presence of emphysema, interstitial fibrosis, and entrapped pneumocytes inside the tumor showed statistic predominance in peripheral SqCC. This is the first immunophenotypic research in the central and peripheral types of SqCC. PMID- 24069584 TI - Melanoma biomolecules: independently identified but functionally intertwined. AB - The majority of patients diagnosed with melanoma present with thin lesions and generally these patients have a good prognosis. However, 5% of patients with early melanoma (<1 mm thick) will have recurrence and die within 10 years, despite no evidence of local or metastatic spread at the time of diagnosis. Thus, there is a need for additional prognostic markers to help identify those patients that may be at risk of recurrent disease. Many studies and several meta-analyses have compared gene and protein expression in melanocytes, naevi, primary, and metastatic melanoma in an attempt to find informative prognostic markers for these patients. However, although a large number of putative biomarkers have been described, few of these molecules are informative when used in isolation. The best approach is likely to involve a combination of molecules. We believe one approach could be to analyze the expression of a group of interacting proteins that regulate different aspects of the metastatic pathway. This is because a primary lesion expressing proteins involved in multiple stages of metastasis may be more likely to lead to secondary disease than one that does not. This review focuses on five putative biomarkers - melanoma cell adhesion molecule (MCAM), galectin-3 (gal-3), matrix metalloproteinase 2 (MMP-2), chondroitin sulfate proteoglycan 4 (CSPG4), and paired box 3 (PAX3). The goal is to provide context around what is known about the contribution of these biomarkers to melanoma biology and metastasis. Although each of these molecules have been independently identified as likely biomarkers, it is clear from our analyses that each are closely linked with each other, with intertwined roles in melanoma biology. PMID- 24069588 TI - Protective effect of Egyptian propolis against rabbit pasteurellosis. AB - The present study was conducted to study the protective effect of ethanolic extract of propolis given subcutaneously (S/C) either alone or in combination with inactivated formalized Pasteurella multocida (P. multocida) vaccine in rabbits challenged with virulent P. multocida strain. Twenty-eight New-Zealand rabbits, 6-8 weeks old and not vaccinated against pasteurellosis, were randomly divided into four equal groups. Group (1) was kept as nonvaccinated control. Group (2) was injected S/C with propolis. Group (3) was vaccinated (S/C) with P. multocida vaccine only. Group (4) was injected with vaccine mixed with propolis as adjuvant. Groups (2, 3, and 4) received the same doses of propolis and vaccine after 4 weeks as a booster dose. The experiment continued for six weeks during which clinical signs, body weight, and mortality rate were recorded. Blood samples were collected every 2 weeks of treatment for evaluating the erythrogram and biochemical parameters. At the end of six weeks, all groups were subjected to challenge with a virulent strain of P. multocida. Two weeks later, tissue specimens were collected from different organs for histopathological investigation. Results showed that before challenge all rabbits of different groups were apparently healthy and had good appetite. After challenge, control group (1) showed acute form of the disease, 100% mortality rate, and severe histopathological changes. Rabbits of groups (2 and 3) showed less severe clinical signs, mortality rate, and histopathological changes than control. Rabbits of group (4) were apparently healthy with normal histological picture. In conclusion, an ethanolic extract of propolis injected alone or combined with formalized inactivated P. multocida vaccine improved general health conditions, liver and kidney functions in addition to reduction of the severity of adverse clinical signs, mortality rates, and histopathological changes associated with challenge of rabbits with P. multocida strain. PMID- 24069589 TI - Management of cosmetic embarrassment caused by Malassezia spp. with fruticose lichen Cladia using phylogenetic approach. AB - During anti-Malassezia screening of plants by CLSI broth microdilution method, Cladia aggregata (Swartz) Nyl. (family Cladoniaceae), a fruticose lichen from Sikkim (northeast Himalayan region), has been found effective at minimum inhibitory concentrations (mg/mL) of 2.72, 0.63, and 1.28 against yeast-like fungi namely, M. furfur, M. globosa and M. sympodialis, respectively. These test pathogens are responsible for pityriasis versicolor (PV) and seborrheic dermatitis (SD) in humans. We tried to establish the reason for variable MICs against various Malassezia spp. using bioinformatical tools, thereby reducing the cost of the experimentation. This is the first report on anti-Malassezia activity of C. aggregata and thus can serve as a potential source for the development of cosmaceuticals. PMID- 24069590 TI - Relationship between malnutrition and the number of permanent teeth in Filipino 10- to 13-year-olds. AB - In the present study, we determined whether there is a delay in the eruption of permanent teeth (PT) among Filipino adolescents with stunting or thinness. Height, weight, and number of PT were recorded in 1554 Filipino 10- to 13-year olds (711 boys; 843 girls). z-scores for height (HAZ) and body mass index (BMI) were calculated according to the WHO growth reference, and their correlations to the number of PT were assessed. 54.9% of the children have at least one form of malnutrition. Significantly, more boys (22.9%) than girls (16.5%) were thin, while no sex difference in stunting was noted (boys 48.5%; girls 44.0%). The number of PT was significantly correlated to HAZ and BMI-z-score. Stunted and thin students had significantly fewer PT than their nonaffected peers. These differences tended to be the result of delay in tooth eruption in thin and stunted adolescents. In 13-year-old girls, all PT were erupted regardless of their nutritional status indicating a catch-up. Thin and stunted boys had one tooth less than normal boys at this age. Impaired physical growth and dental development seem to have common risk factors. Therefore, regular monitoring of growth and dental development might be helpful for targeting support programmes in developing countries. PMID- 24069591 TI - Plasma and ocular prednisolone disposition after oral treatment in cats. AB - OBJECTIVE: To evaluate the plasma and aqueous humor disposition of prednisolone after oral administration in cats. METHODS: Six cats were administered with a single oral dose of prednisolone (10 mg). Blood and aqueous humor samples were serially collected after drug administration. Prednisolone concentrations in plasma and aqueous humor were measured at 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, and 5.0 h after administration by a high-performance liquid chromatographic analytical method developed and validated for this purpose. RESULTS: Mean +/- standard error (SE) of maximum plasma prednisolone concentration (300.8 +/- 67.3 ng/mL) was reached at 1 h after administration. Prednisolone was distributed to the aqueous humor reaching a mean peak concentration of 100.9 +/- 25.5 ng/mL at 1.25 h after administration. The mean +/- SE systemic and aqueous humor exposure (AUC) was 553.3 +/- 120.0 ng h/mL and 378.8 +/- 64.9 ng h/mL, respectively. A high AUC(aqueous humor)/AUC(plasma) ratio was observed (0.68 +/- 0.13). The mean half-life time of elimination in plasma and aqueous humor was 0.87 +/- 0.16 h and 2.25 +/- 0.44 h, respectively. CLINICAL SIGNIFICANCE: The observed high ratio between aqueous humor and plasma prednisolone concentrations indicates that extensive penetration of prednisolone to the anterior segment of the eye may occur. This is the first step that contributes to the optimization of the pharmacological therapeutics for the clinical treatment of uveitis. PMID- 24069592 TI - The role of morphine in animal models of human cancer: does morphine promote or inhibit the tumor growth? AB - Morphine, a highly potent analgesic agent, is widely used to relieve pain and suffering of patients with cancer. Additionally, it has been reported that morphine is important in the regulation of cancerous tissue. Morphine relieves pain by acting directly on the central nervous system, although its activities on peripheral tissues are responsible for many adverse side effects. For these reasons, it is very important also to understand the role of morphine in cancer treatment. The published literature reporting the effect of morphine on tumor growth presents some discrepancies, with reports suggesting that morphine may either promote or inhibit the tumor growth. It has been also demonstrated that morphine modulates angiogenesis which is important for primary tumour growth, invasiveness, and the development of metastasis. This review will focus on the latest findings on the role of morphine in the regulation of cancer cell growth and angiogenesis. PMID- 24069593 TI - Codetection of Trichomonas vaginalis and Candida albicans by PCR in urine samples in a low-risk population attended in a clinic first level in central Veracruz, Mexico. AB - The aim of this study is to estimate the prevalence of Trichomonas vaginalis and Candida albicans in low-risk patients treated at a first level clinic (primary health care represents the first level of contact of individuals, families, and the community with the system national health). Using a cross-sectional study in patients treated in clinical laboratory of the Sanitary District no. 7 of the city of Orizaba during the months June-July, 252 urine samples were collected for the identification of T. vaginalis and C. albicans by PCR. Furthermore, we analyzed the sociodemographic characteristics of the studied population. We observed an overall prevalence of 23.41% (95% CI 22.10-24.72) for T. vaginalis and 38.88% (95% CI 37.73-40.03) for C. albicans. There was also presence of coinfection in 14.28% (95% CI 13.10-15.46), which was associated with the presence of pain. Most of the positive cases were observed in women house-maker (80%, 95% CI 50.36-48.98). The results of this study provide evidence that the majority of positive cases observed in the studied population are presented in an asymptomatic form and usually are not associated with any risk factor. PMID- 24069594 TI - Genetic susceptibility to Chagas disease: an overview about the infection and about the association between disease and the immune response genes. AB - Chagas disease, which is caused by the flagellate parasite Trypanosoma cruzi, affects 8-10 million people in Latin America. The disease is endemic and is characterised by acute and chronic phases that develop in the indeterminate, cardiac, and/or gastrointestinal forms. The immune response during human T. cruzi infection is not completely understood, despite its role in driving the development of distinct clinical manifestations of chronic infection. Polymorphisms in genes involved in the innate and specific immune response are being widely studied in order to clarify their possible role in the occurrence or severity of disease. Here we review the role of classic and nonclassic MHC, KIR, and cytokine host genetic factors on the infection by T. cruzi and the clinical course of Chagas disease. PMID- 24069595 TI - The role of changes in extracellular matrix of cartilage in the presence of inflammation on the pathology of osteoarthritis. AB - Osteoarthritis (OA) is a degenerative disease that affects various tissues surrounding joints such as articular cartilage, subchondral bone, synovial membrane, and ligaments. No therapy is currently available to completely prevent the initiation or progression of the disease partly due to poor understanding of the mechanisms of the disease pathology. Cartilage is the main tissue afflicted by OA, and chondrocytes, the sole cellular component in the tissue, actively participate in the degeneration process. Multiple factors affect the development and progression of OA including inflammation that is sustained during the progression of the disease and alteration in biomechanical conditions due to wear and tear or trauma in cartilage. During the progression of OA, extracellular matrix (ECM) of cartilage is actively remodeled by chondrocytes under inflammatory conditions. This alteration of ECM, in turn, changes the biomechanical environment of chondrocytes, which further drives the progression of the disease in the presence of inflammation. The changes in ECM composition and structure also prevent participation of mesenchymal stem cells in the repair process by inhibiting their chondrogenic differentiation. This review focuses on how inflammation-induced ECM remodeling disturbs cellular activities to prevent self-regeneration of cartilage in the pathology of OA. PMID- 24069596 TI - Effect of cyclic precalcification of nanotubular TiO2 layer on the bioactivity of titanium implant. AB - The objective of this study is to investigate the effect of cyclic precalcification treatment to impart bioactive properties for titanium implants. Before precalcification, the titanium implants were subjected to blasting using hydroxyapatite (HAp), a resorbable blasting medium (RBM treated), and anodized using an electrolyte containing glycerol, H2O, and NH4F. Precalcification treatment was performed by two different methods, namely, continuous immersion treatment (CIT) and alternate immersion treatment (AIT). In CIT, the RBM treated and anodized titanium implants were immersed in 0.05 M NaH2PO4 solution at 80 degrees C and saturated Ca(OH)2 solution at 100 degrees C for 20 min, whereas during AIT, they were immersed alternatively in both solutions for 1 min for 20 cycles. Anodizing of the titanium implants enables the formation of self organized TiO2 nanotubes. Cyclic precalcification treatment imparts a better bioactive property and enables an increase in activation level of the titanium implants. The removal torque values of the RBM treated, CIT treated, and AIT treated titanium implants are 10.8 +/- 3.7 Ncm, 17.5 +/- 3.5 Ncm, and 28.1 +/- 2.4 Ncm, respectively. The findings of the study indicate the cyclic precalcification in an effective surface treatment method that would help accelerate osseointegration and impart bioactive property of titanium implants. PMID- 24069597 TI - Staphylococcus aureus clinical isolates: antibiotic susceptibility, molecular characteristics, and ability to form biofilm. AB - Periodic monitoring of Staphylococcus aureus characteristics in a locality is imperative as their drug-resistant variants cause treatment problem. In this study, antibiograms, prevalence of toxin genes (sea-see, seg-ser, seu, tsst-1, eta, etb, and etd), PFGE types, accessory gene regulator (agr) groups, and ability to form biofilm of 92 S. aureus Thailand clinical isolates were investigated. They were classified into 10 drug groups: groups 1-7 (56 isolates) were methicillin resistant (MRSA) and 8-10 (36 isolates) were methicillin sensitive (MSSA). One isolate did not have any toxin gene, 4 isolates carried one toxin gene (seq), and 87 isolates had two or more toxin genes. No isolate had see, etb, or tsst-1; six isolates had eta or etd. Combined seg-sei-sem-sen-seo of the highly prevalent egc locus was 26.1%. The seb, sec, sel, seu, and eta associated significantly with MSSA; sek was more in MRSA. The sek-seq association was 52.17% while combined sed-sej was not found. Twenty-three PFGE types were revealed, no association of toxin genes with PFGE types. All four agr groups were present; agr group 1 was predominant (58.70%) but agr group 2 strains carried more toxin genes and were more frequent toxin producers. Biofilm formation was found in 72.83% of the isolates but there was no association with antibiograms. This study provides insight information on molecular and phenotypic markers of Thailand S. aureus clinical isolates which should be useful for future active surveillance that aimed to control a spread of existing antimicrobial resistant bacteria and early recognition of a newly emerged variant. PMID- 24069598 TI - Evaluation of in vitro cytoxicity and genotoxicity of size-fractionated air particles sampled during road tunnel construction. AB - In tunnel construction, workers exposed to dust from blasting, gases, diesel exhausts, and oil mist have shown higher risk for pulmonary diseases. A clear mechanism to explain how these pollutants determine diseases is lacking, and alveolar epithelium's capacity to ingest inhaled fine particles is not well characterized. The objective of this study was to assess the genotoxic effect exerted by fine particles collected in seven tunnels using the cytokinesis-block micronuclei test in an in vitro model on type II lung epithelium A549 cells. For each tunnel, five fractions with different aerodynamic diameters of particulate matter were collected with a multistage cascade sampler. The human epithelial cell line A549 was exposed to 0.2 m(3)/mL equivalent of particulate for 24 h before testing. The cytotoxic effects of particulate matter on A549 cells were also evaluated in two different viability tests. In order to evaluate the cells' ability to take up fine particles, imaging with transmission electron microscopy of cells after exposure to particulate matter was performed. Particle endocytosis after 24 h exposure was observed as intracellular aggregates of membrane-bound particles. This morphologic evidence did not correspond to an increase in genotoxicity detected by the micronucleus test. PMID- 24069599 TI - Activation of the ERK1/2 signaling pathway during the osteogenic differentiation of mesenchymal stem cells cultured on substrates modified with various chemical groups. AB - The current study examined the influence of culture substrates modified with the functional groups -OH, -COOH, -NH2, and -CH3 using SAMs technology, in conjunction with TAAB control, on the osteogenic differentiation of rabbit BMSCs. The CCK-8 assay revealed that BMSCs exhibited substrate-dependent cell viability. The cells plated on -NH2- and -OH-modified substrates were well spread and homogeneous, but those on the -COOH- and -CH3-modified substrates showed more rounded phenotype. The mRNA expression of BMSCs revealed that -NH2-modified substrate promoted the mRNA expression and osteogenic differentiation of the BMSCs. The contribution of ERK1/2 signaling pathway to the osteogenic differentiation of BMSCs cultured on the -NH2-modified substrate was investigated in vitro. The -NH2-modified substrate promoted the expression of integrins; the activation of FAK and ERK1/2. Inhibition of ERK1/2 activation by PD98059, a specific inhibitor of the ERK signaling pathway, blocked ERK1/2 activation in a dose-dependent manner, as revealed for expression of Cbf alpha -1 and ALP. Blockade of ERK1/2 phosphorylation in BMSCs by PD98059 suppressed osteogenic differentiation on chemical surfaces. These findings indicate a potential role for ERK in the osteogenic differentiation of BMSCs on surfaces modified by specific chemical functional groups, indicating that the microenvironment affects the differentiation of BMSCs. This observation has important implications for bone tissue engineering. PMID- 24069600 TI - Combinatorial control of gene expression. AB - The complexity and diversity of eukaryotic organisms are a feat of nature's engineering. Pulling the strings of such an intricate machinery requires an even more masterful and crafty approach. Only the number and type of responses that they generate exceed the staggering proportions of environmental signals perceived and processed by eukaryotes. Hence, at first glance, the cell's sparse stockpile of controlling factors does not seem remotely adequate to carry out this response. The question as to how eukaryotes sense and respond to environmental cues has no single answer. It is an amalgamation, an interplay between several processes, pathways, and factors-a combinatorial control. A short description of some of the most important elements that operate this entire conglomerate is given in this paper. PMID- 24069601 TI - Characterization of the bacterial community associated with larvae and adults of Anoplophora chinensis collected in Italy by culture and culture-independent methods. AB - The wood-boring beetle Anoplophora chinensis Forster, native to China, has recently spread to North America and Europe causing serious damage to ornamental and forest trees. The gut microbial community associated with these xylophagous beetles is of interest for potential biotechnological applications in lignocellulose degradation and development of pest-control measures. In this study the gut bacterial community of larvae and adults of A. chinensis, collected from different host trees in North Italy, was investigated by both culture and culture-independent methods. Larvae and adults harboured a moderately diverse bacterial community, dominated by Proteobacteria, Actinobacteria, and Firmicutes. The gammaproteobacterial family Enterobacteriaceae (genera Gibbsiella, Enterobacter, Raoultella, and Klebsiella) was the best represented. The abundance of such bacteria in the insect gut is likely due to the various metabolic abilities of Enterobacteriaceae, including fermentation of carbohydrates derived from lignocellulose degradation and contribution to nitrogen intake by nitrogen fixing activity. In addition, bacteria previously shown to have some lignocellulose-degrading activity were detected at a relatively low level in the gut. These bacteria possibly act synergistically with endogenous and fungal enzymes in lignocellulose breakdown. The detection of actinobacterial symbionts could be explained by a possible role in the detoxification of secondary plant metabolites and/or protection against pathogens. PMID- 24069602 TI - Inferring phylogenetic networks from gene order data. AB - Existing algorithms allow us to infer phylogenetic networks from sequences (DNA, protein or binary), sets of trees, and distance matrices, but there are no methods to build them using the gene order data as an input. Here we describe several methods to build split networks from the gene order data, perform simulation studies, and use our methods for analyzing and interpreting different real gene order datasets. All proposed methods are based on intermediate data, which can be generated from genome structures under study and used as an input for network construction algorithms. Three intermediates are used: set of jackknife trees, distance matrix, and binary encoding. According to simulations and case studies, the best intermediates are jackknife trees and distance matrix (when used with Neighbor-Net algorithm). Binary encoding can also be useful, but only when the methods mentioned above cannot be used. PMID- 24069604 TI - Predictors of attrition in patients ineligible for antiretroviral therapy after being diagnosed with HIV: data from an HIV cohort study in India. AB - In newly HIV-diagnosed patients, the CD4+ lymphocyte count is measured to determine the need for antiretroviral therapy (ART). Studies from Sub-Saharan Africa have shown that patients who are ART ineligible at the first assessment have poor retention in care, but data from other low- or middle-income countries are scarce. In this study we describe the retention in pre-ART care of 1696 patients who were ineligible for ART after being diagnosed with HIV in a cohort study in India. More than one-third of ART ineligible patients had poor retention in care, and the attrition was higher in those with longer follow-up periods. Of those patients with poor retention, only 10% came back to the clinics, and their CD4 cell counts were lower than the ones of patients retained in care. After 4.5 years of follow-up, the cumulative incidence of loss to follow-up was 50%. Factors associated with attrition were being homeless, being illiterate, belonging to a disadvantaged community, being symptomatic at the time of the HIV diagnosis, male gender, and not living near a town. Widows were given nutritional support and, therefore, had better retention in care. The results of this study highlight the need to improve the retention in care of ART ineligible patients in India. PMID- 24069605 TI - Molecular prevalence of Babesia bigemina and Trypanosoma evansi in dairy animals from Punjab, India, by duplex PCR: a step forward to the detection and management of concurrent latent infections. AB - Specific duplex polymerase chain reaction (PCR) was employed on 411 (386 cattle and 25 buffaloes) blood samples of dairy animals from 9 districts of Punjab, India, for simultaneous detection of Babesia bigemina and Trypanosoma evansi. The results were compared and correlated with conventional Giemsa stained thin blood smear (GSTBS) examination and haematological alterations to know the clinical status and pathogenicity of infections. The Bg3/Bg4 and TR3/TR4 primers were used in duplex PCR for B. bigemina and T. evansi amplified products of 689 bp and 257 bp, respectively. The overall prevalence by duplex PCR was found to be 36.49, 2.43, and 3.41% for T. evansi, B. bigemina, and dual infection, respectively. A more significant difference was observed for dual infection status (P <= 0.005) as compared to T. evansi (P <= 0.05) and B. bigemina (P <= 0.01) among various districts under study. A very low prevalence of T. evansi (0.73%) and B. bigemina (0.48%) was seen by GSTBS. The highly sensitive, specific, and cost-effective duplex PCR was able to detect latent T. evansi and B. bigemina infection in cattle and buffaloes. Haematological evaluation revealed marked pathology in B. bigemina infected group and in dual infected group in contrast to that infected with T. evansi alone. PMID- 24069603 TI - Neuroprotective effect of ginseng against alteration of calcium binding proteins immunoreactivity in the mice hippocampus after radiofrequency exposure. AB - Calcium binding proteins (CaBPs) such as calbindin D28-k, parvalbumin, and calretinin are able to bind Ca(2+) with high affinity. Changes in Ca(2+) concentrations via CaBPs can disturb Ca(2+) homeostasis. Brain damage can be induced by the prolonged electromagnetic field (EMF) exposure with loss of interacellular Ca(2+) balance. The present study investigated the radioprotective effect of ginseng in regard to CaBPs immunoreactivity (IR) in the hippocampus through immunohistochemistry after one-month exposure at 1.6 SAR value by comparing sham control with exposed and ginseng-treated exposed groups separately. Loss of dendritic arborization was noted with the CaBPs in the Cornu Ammonis areas as well as a decrease of staining intensity of the granule cells in the dentate gyrus after exposure while no loss was observed in the ginseng treated group. A significant difference in the relative mean density was noted between control and exposed groups but was nonsignificant in the ginseng-treated group. Decrease in CaBP IR with changes in the neuronal staining as observed in the exposed group would affect the hippocampal trisynaptic circuit by alteration of the Ca(2+) concentration which could be prevented by ginseng. Hence, ginseng could contribute as a radioprotective agent against EMF exposure, contributing to the maintenance of Ca(2+) homeostasis by preventing impairment of intracellular Ca(2+) levels in the hippocampus. PMID- 24069606 TI - SeedSeq: off-target transcriptome database. AB - Detection of potential cross-reaction between a short oligonucleotide sequence and a longer (unintended) sequence is crucial for many biological applications, such as high content screening (HCS), microarray nucleotide probes, or short interfering RNAs (siRNAs). However, owing to a tolerance for mismatches and gaps in base-pairing with target transcripts, siRNAs could have up to hundreds of potential target sequences in a genome, and some small RNAs in mammalian systems have been shown to affect the levels of many messenger RNAs (off-targets) besides their intended target transcripts (on-targets). The reference sequence (RefSeq) collection aims to provide a comprehensive, integrated, nonredundant, well annotated set of sequences, including mRNA transcripts. We performed a detailed off-target analysis of three most commonly used kinome siRNA libraries based on the latest RefSeq version. To simplify the access to off-target transcripts, we created a SeedSeq database, a new unique format to store off-target information. PMID- 24069607 TI - Radioprotective effects of gallic acid in mice. AB - Radioprotecting ability of the natural polyphenol, gallic acid (3,4,5 trihydroxybenzoic acid, GA), was investigated in Swiss albino mice. Oral administration of GA (100 mg/kg body weight), one hour prior to whole body gamma radiation exposure (2-8 Gy; 6 animals/group), reduced the radiation-induced cellular DNA damage in mouse peripheral blood leukocytes, bone marrow cells, and spleenocytes as revealed by comet assay. The GA administration also prevented the radiation-induced decrease in the levels of the antioxidant enzyme, glutathione peroxidise (GPx), and nonprotein thiol glutathione (GSH) and inhibited the peroxidation of membrane lipids in these animals. Exposure of mice to whole body gamma radiation also caused the formation of micronuclei in blood reticulocytes and chromosomal aberrations in bone marrow cells, and the administration of GA resulted in the inhibition of micronucleus formation and chromosomal aberrations. In irradiated animals, administration of GA elicited an enhancement in the rate of DNA repair process and a significant increase in endogenous spleen colony formation. The administration of GA also prevented the radiation-induced weight loss and mortality in animals (10 animals/group) exposed to lethal dose (10 Gy) of gamma radiation. (For every experiment unirradiated animals without GA administration were taken as normal control; specific dose (Gy) irradiated animals without GA administration serve as radiation control; and unirradiated GA treated animals were taken as drug alone control). PMID- 24069608 TI - Microtubule-associated proteins in mesial temporal lobe epilepsy with and without psychiatric comorbidities and their relation with granular cell layer dispersion. AB - BACKGROUND: Despite strong association between epilepsy and psychiatric comorbidities, biological substrates are unknown. We have previously reported decreased mossy fiber sprouting in mesial temporal lobe epilepsy (MTLE) patients with psychosis and increased in those with major depression. Microtubule associated proteins (MAPs) are essentially involved in dendritic and synaptic sprouting. METHODS: MTLE hippocampi of subjects without psychiatric history, MTLE + major depression, and MTLE + interictal psychosis derived from epilepsy surgery and control necropsies were investigated for neuronal density, granular layer dispersion, and MAP2 and tau immunohistochemistry. RESULTS: Altered MAP2 and tau expression in MTLE and decreased tau expression in MTLE with psychosis were found. Granular layer dispersion correlated inversely with verbal memory scores, and with MAP2 and tau expression in the entorhinal cortex. Patients taking fluoxetine showed increased neuronal density in the granular layer and those taking haloperidol decreased neuronal density in CA3 and subiculum. CONCLUSIONS: Our results indicate relations between MAPs, granular layer dispersion, and memory that have not been previously investigated. Differential MAPs expression in human MTLE hippocampi with and without psychiatric comorbidities suggests that psychopathological states in MTLE rely on differential morphological and possibly neurochemical backgrounds. This clinical study was approved by our institution's Research Ethics Board (HC-FMRP no. 1270/2008) and is registered under the Brazilian National System of Information on Ethics in Human Research (SISNEP) no. 0423.0.004.000-07. PMID- 24069609 TI - In vivo evidence of increased nNOS activity in acute MPTP neurotoxicity: a functional pharmacological MRI study. AB - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin commonly used to produce an animal model of Parkinson's disease. Previous studies have suggested a critical role for neuronal nitric oxide (NO) synthase- (nNOS-) derived NO in the pathogenesis of MPTP. However, NO activity is difficult to assess in vivo due to its extremely short biological half-life, and so in vivo evidence of NO involvement in MPTP neurotoxicity remains scarce. In the present study, we utilized flow-sensitive alternating inversion recovery sequences, in vivo localized proton magnetic resonance spectroscopy, and diffusion-weighted imaging to, respectively, assess the hemodynamics, metabolism, and cytotoxicity induced by MPTP. The role of NO in MPTP toxicity was clarified further by administering a selective nNOS inhibitor, 7-nitroindazole (7-NI), intraperitoneally to some of the experimental animals prior to MPTP challenge. The transient increase in cerebral blood flow (CBF) in the cortex and striatum induced by systemic injection of MPTP was completely prevented by pretreatment with 7-NI. We provide the first in vivo evidence of increased nNOS activity in acute MPTP-induced neurotoxicity. Although the observed CBF change may be independent of the toxicogenesis of MPTP, this transient hyperperfusion state may serve as an early indicator of neuroinflammation. PMID- 24069612 TI - On medical life-histories. PMID- 24069611 TI - The 2nd China Congress on Controversies to Consensus in Diabetes, Obesity, and Hypertension (CODHy). PMID- 24069610 TI - Molecular mechanisms involved in the pathogenesis of alphavirus-induced arthritis. AB - Arthritogenic alphaviruses, including Ross River virus (RRV), Chikungunya virus (CHIKV), Sindbis virus (SINV), Mayaro virus (MAYV), O'nyong-nyong virus (ONNV), and Barmah Forest virus (BFV), cause incapacitating and long lasting articular disease/myalgia. Outbreaks of viral arthritis and the global distribution of these diseases point to the emergence of arthritogenic alphaviruses as an important public health problem. This review discusses the molecular mechanisms involved in alphavirus-induced arthritis, exploring the recent data obtained with in vitro systems and in vivo studies using animal models and samples from patients. The factors associated to the extension and persistence of symptoms are highlighted, focusing on (a) virus replication in target cells, and tissues, including macrophages and muscle cells; (b) the inflammatory and immune responses with recruitment and activation of macrophage, NK cells and T lymphocytes to the lesion focus and the increase of inflammatory mediators levels; and (c) the persistence of virus or viral products in joint and muscle tissues. We also discuss the importance of the establishment of novel animal models to test new molecular targets and to develop more efficient and selective drugs to treat these diseases. PMID- 24069613 TI - Current world literature. Molecular cell biology and physiology of solute transport. PMID- 24069614 TI - [Intraoperative diagnosis]. PMID- 24069615 TI - Author response. PMID- 24069616 TI - Author reponse. PMID- 24069617 TI - Careful screening and scrutiny needed to select ambulatory surgery patients. PMID- 24069625 TI - One-fifth of adolescents suffered TBI. PMID- 24069624 TI - Children with autism may have elevated immune response to gluten. PMID- 24069626 TI - White teenage girls hospitalized more often for chronic pain. PMID- 24069627 TI - Neurocysticercosis: control and eradication. PMID- 24069628 TI - Response from the authors. PMID- 24069629 TI - Authors reply. PMID- 24069630 TI - Authors reply. PMID- 24069631 TI - Author's reply: To PMID 23354220. PMID- 24069632 TI - Deceased heart beating donor and organ donation and transplantation in the Kingdom of Saudi Arabia 2012. PMID- 24069633 TI - Reply from the author. PMID- 24069634 TI - [Nicotine and neurologic diseases--even a noxious substance may possess beneficial properties]. AB - According to investigations, nicotine and its agonists may prevent the development of Parkinson's disease and reduce motor symptoms and dyskinesias in Parkinson's disease. It was shown recently that a transdermal nicotine patch reliefs the symptoms in patients suffering from mild cognitive impairment. In Alzheimer's disease an alpha7-selective agonist has been found to have positive effects on cognitive symptoms. Mutations of nicotinic receptors are underlying certain nocturnal frontal lobe epilepsies. The partial nicotine agonist varenicline may alleviate ataxia symptoms. PMID- 24069635 TI - [MicroRNAs and cancer]. AB - MicroRNAs (miRNAs) are group of noncoding RNAs that have been shown to regulate posttranscriptional gene expression. They have been under intense investigation since their association with cancer a decade ago. Genome wide detection methods have been developed to identify miRNA profiles in variety of biological systems and to confirm their involvement in different physiological and pathological processes. MiRNA implication in cancer pathology (tumor development, progression and response to therapy), perhaps the most widely studied miRNA topic, make them potential diagnostic, prognostic and predictive biomarkers. Currently, researchers are exploiting the possibilities of miRNA-based anti-cancer therapies and in the near future such therapies alone or in combination with other treatment modalities might be a reality. PMID- 24069636 TI - [Fecal transfusion as treatment of Clostridium difficile infection]. AB - Clostridium difficile is the major identified cause of antibiotic-associated diarrhea. Metronidazole has been applied as the first-line treatment, while vancomycin has been used in recurring cases of the disease. Fecal transfusion has already long been applied as experimental therapy in the treatment of recurring C. difficile infection. The aim of fecal transfusion is normalization of the intestinal microbial flora. An only recently published extensive Finnish patient series and a randomized study have confirmed fecal transfusion as a highly efficient and safe form of treatment in recurrent C. difficile infection. PMID- 24069637 TI - [Fulminant Clostridium difficile colitis]. AB - Clostridium difficile is a common cause of nosocomial diarrhea and it's most difficult Fulminant form is increasing in prevalence and severity in hospitalized patients. The early diagnostics and intensive conservative therapy are essential in the treatment of this ominous disease. The physicians must be aware of the possibility of this disease, when treating patients, who have received preceding antibiotic therapy. These patients have to be followed up in the surgical units. If the general condition of these patients is deteriorating, they must be transferred to emergency units. Surgery becomes mandatory before the development of multi organ failure. PMID- 24069638 TI - [Non-animal toxicology in the safety testing of chemicals]. AB - There is an urgent need to develop predictive test methods better than animal experiments for assessing the safety of chemical substances to man. According to today's vision this is achieved by using human cell based tissue and organ models. In the new testing strategy the toxic effects are assessed by the changes in the critical parameters of the cellular biochemical routes (AOP, adverse toxic outcome pathway-principle) in the target tissues. In vitro-tests are rapid and effective, and with them automation can be applied. The change in the testing paradigm is supported by all stakeholders: scientists, regulators and people concerned on animal welfare. PMID- 24069639 TI - [Assessing adolescents with school massacre threats]. AB - School massacres have increased pressure on health-care authorities for assessing risk for severe violence. In acute situations, threat analysis focuses at thought processes and actions of adolescents presenting threat of violence, in order to assess to which extent the adolescent has progressed from thoughts to actions. Because of great variability in aggressive behavior, separate interventions for individual, family and other developmental surroundings are often needed. Structured risk-assessment in special health care is aimed for conducting decision making towards risk reduction and adequate help for adolescents at risk. PMID- 24069640 TI - [Endobronchial ultrasonography--when needed?]. AB - Endobronchial ultrasonography (EBUS) and associated needle biopsy is a mini invasive means to study mediastinal and hilar lymph nodes and tumors. Guidance by real-time ultrasound image allows the biopsy of even small targets with high accuracy. The investigation is well tolerated, highly specific and its main indication is the staging of lung cancer. The method is also suitable for primary diagnosis of mediastinal lymphadenopathy of unknown origin or central tumors. PMID- 24069641 TI - [Self-sampling and reminder letters increase participation in the Finnish cervical cancer screening programme]. AB - BACKGROUND: Participation rate in the national cervical cancer screening programme is currently less than 70% in Finland. A new potential method of increasing the attendance are self-taken samples for hrHPV-testing. METHODS: All cervical cancer screening non-attendees in 22 municipalities received first a reminder letter. Non-attendees after the reminder letter were offered a self sampling device. RESULTS: Reminder letters increased total participation from 72.6% to 79.9%, and self-sampling tests further to 83.4%. If reminder letters were sent with fixed appointments, participation was significantly higher (30 vs. 14%). CONCLUSIONS: If self-sampling is used after the recommended two invitations, overall screening attendance could reach the desired 80% to 85%. PMID- 24069642 TI - [Symptomatic treatment with a self-adjusting CPAP device of dyspnea caused by Reinke's edema and vocal cord paralysis]. AB - Prolonged external irritation to the vocal cords may cause an edematous state of the vocal cords known as Reinke's edema. This may lead to hoarseness and dyspnea. We describe a successful syptomatic treatment of severe dyspnea due to Reinke's edema with a self-adjusting CPAP device. An operation ended the symptom of dyspnea of our patient, but before that the CPAP therapy brought about an effective remedy for dyspnea. PMID- 24069643 TI - [Update in current care guidelines: epilepsy and febrile seizures (children)]. AB - Suspicion of epilepsy is an indication for an urgent referral to a pediatric or child neurology care unit. Diagnosis of epilepsy is based on medical history and clinical examination, supplemented with EEG, brain imaging and laboratory tests. Antiepileptic medication is usually initiated after the second epileptic seizure. Drug choice is based on seizure type and epilepsy classification. Some children with epilepsy may benefit from ketogenic diet. Surgical treatment options should be considered in children with drug-resistant epilepsy. Acute treatment for febrile seizures follows the same principles as treatment of epileptic seizures, but long-term preventive anticonvulsants are not recommended. PMID- 24069644 TI - [Updated STIKO vaccination recommendations published]. PMID- 24069645 TI - [Common errors in blood pressure monitoring]. AB - Monitoring blood pressure is an important diagnostic tool in the management of hypertension. Many patients measure their blood pressure at home. However, the results are only reliable if some rules are observed. These are mainly related to the right choice of devices, execution of the monitoring as well as documentation and assessment of the measurement. PMID- 24069646 TI - [Food supplements--potential and limits: part 3]. AB - Ageing processes are associated with physiological changes, e.g. a reduction of metabolically active body mass and an impaired hunger-satiety regulation, which- combined with chronic diseases and psychosocial problems--significantly increase the risk for malnutrition. However, considering their nutrition and health status elderly people are a very heterogeneous group. The nutrition situation of "young" seniors does generally not differ from the situation of working-age adults while institutionalized elderly people and those in need of care often show signs of a global malnutrition. The critical nutrients in the nutrition of the elderly particularly include vitamin B12 and D. Six percent of all elderly have a manifest and 10 to 30% a functional vitamin B12 deficiency. The main cause is vitamin B12 malabsorption resulting from a type B atrophic gastritis. The functional vitamin B12 deficiency and the associated hyperhomocysteinemia are risk factors for neurodegenerative diseases and accelerate bone loss. With increasing age the vitamin D status is deteriorating. About 50% of the elderly living in private households is deficient in vitamin D; in geriatrics vitamin D deficiency is more the rule than an exception. This is caused by a reduced endogenous biosynthesis, low UVB exposure and a diet low in vitamin D. A vitamin D deficiency increases the risk for falls and fractures as well as the risk for neurodegenerative diseases. Also the overall mortality is increased. PMID- 24069647 TI - [Short bowel syndrome. GLP-2 analog teduglutide]. PMID- 24069648 TI - [Can serotonin syndrome also be caused by tramadol administration alone?]. PMID- 24069649 TI - [Supplementary carotinoids and omega-3-fatty acids are ineffective]. PMID- 24069650 TI - [Dirofilaria repens detected in mosquitoes in Germany for the first time]. PMID- 24069651 TI - [Tocilizumab as monotherapy is clinically more effective than adalimumab]. PMID- 24069652 TI - [Melatonin secretion is associated with diabetes risk]. PMID- 24069653 TI - Helping hands. PMID- 24069654 TI - MOM volunteers give, but also receive. PMID- 24069655 TI - Oklahoma case highlights: Importance of reviewing office sterilization procedures. PMID- 24069656 TI - Thermo-mechanical properties of NiTi closed coil springs--force degradation and force regeneration over time, viscous properties. AB - INTRODUCTION: The aim of this study was to find out the impact of degradation and regeneration of force over time at NiTi springs on the value and course of the final acting force and to verify the possibility of using these phenomena for a directed transition to the reverse plateau and its maintaining. METHODS: Static and cyclic mechanical loadings were performed. At first unused springs were tested. Afterwards the springs were mechanically stabilized by stress cycling and finally tested again. The difference in shape of the working curves was assessed. For simulation and description of the force degradation the modified Voight model was used. RESULTS: New springs, mainly those with large hysteresis, showed a significant stress-strain curve movement and shape changes during the cycling. The effect of the stress-strain curve course change disappeared fully in the stabilized springs. Multiple loading led to an overall decrease of force value during the measurement. The effect of force degradation and regeneration over time by simple static loading varies in the range of percentage of the nominal force in the plateau area. The transition between stress-strain curve phases caused by the degradation or regeneration of the force wasn't observed in case of mechanically stabilized springs. CONCLUSIONS: Springs should be mechanically stabilized before their application. The degree of force degradation over time is insignificant for mechanically stabilized springs. Degradation or regeneration of force over time, mechanical stabilization or micromovements in the mouth don't cause any transition between individual stress-strain curve phases. PMID- 24069657 TI - Secular trends and latitude gradients in the male-female ratio at birth in Yugoslavia and the ex-Yugoslavian States. AB - BACKGROUND: Latitude gradients and secular trends in Europe and North America have been found in the male-female ratio at birth (M/F: male births divided by total births) which approximates 0.515. METHODS: Annual national data for Yugoslavia and the post-Yugoslavia States for male and female live births were obtained from the World Health Organisation and analysed with contingency tables. RESULTS: This study analysed 22,020,729 live births. There was a increasing trend in M/F prior to the breakup of the former Yugoslavia (1950-1990, p = 0.002), followed by a decreasing trend after 1990 (p = 0.02). A latitude gradient was also noted, with more males being born in southern, warmer latitudes (p < 0.0001). There was an overall excess of 42,753 male births based on an anticipated M/F of 0.515. CONCLUSION: M/F is decreasing in this region, similar to the rest of Europe and North America. A latitude gradient is also present with more males being born in warmer (more Southern) latitudes (p < 0.0001), even in this small region and over the short time-frame studied. PMID- 24069658 TI - Invasive aspergillosis in intensive care unit patients in Iran. AB - We assessed the intensive care unit (ICU) patients for Invasive aspergillosis (IA) with culture and non-culture based diagnostic methods from Iran. Thirty-six ICU patients with underlying predisposing conditions for IA were enrolled in the study. Sixty eight Bronchoalveolar lavage (BAL) samples were collected by bronchoscope twice a weekly. BAL samples were analyzed by microscopic examination, fungal culture and galactomannan (GM) detection. The Platelia Aspergillus GM EIA was used to quantify GM indices. Samples with a BAL GM index > or = 1 were considered as positive for GM. Patients were classified as having probable or possible IA. Out of 36 suspected patients to IA, 36.1% of cases showed IA which were categorized as: 4 cases of possible IA and 9 of probable IA. 76.2% of BAL samples were positive for GM. From 13 patients with IA, 11 (84.6%) had at least one positive BAL GM index. Of these patients, 9 (81.8%) showed probable IA. The main underlying predisposing conditions were neutropenia (53.8%) and COPD (30.8%). Our study has indicated that COPD must be considered as one of the main predisposing condition for occurrence of aspergillosis in ICU patients. Our data have also revealed that GM detection in BAL samples play a significant role to IA diagnosis. PMID- 24069659 TI - TLR2 and TLR4 expression on blood monocytes and granulocytes of cardiac surgical patients is not affected by the use of cardiopulmonary bypass. AB - Cardiac surgery is inseparably linked to the activation of innate immunity cells recognizing danger signals of both endogenous and exogenous origin via pattern recognition receptors such as TLR receptors. Therefore, we followed by flow cytometry TLR2 and TLR4 expression on blood monocytes and granulocytes of patients who underwent coronary artery bypass grafting using beating heart surgery (off-pump, n = 34), with use of standard cardiopulmonary bypass (CPB), (on-pump, n = 30), and miniinvasive CPB (mini on-pump, n = 25), respectively, before, during surgery, and up to 7th postoperative day. TLR2 and TLR4 expression both on monocytes and granulocytes was significantly diminished already at the end of CPB being highly significantly decreased at the end of surgery in all patients' groups. TLR2 and TLR4 expression reached preoperative value at the 1st postoperative day being significantly higher at the 3rd postoperative day. Using intracellular staining we found the peak of TLR2 and TLR4 expression inside of monocytes and granulocytes at the first postoperative day in a subgroup of on pump patients. In conclusion, TLR2 and TLR4 expression is significantly modulated in patients undergoing coronary artery bypass grafting as a part of adaptive homeostatic mechanisms induced by major surgery. The very surgical trauma is responsible for TLR2 and TLR4 modulation. Surprisingly, cardiopulmonary bypass itself was little contributing to the modulation of TLR2 and TLR4 expression. PMID- 24069660 TI - Results of treatment of periprosthetic femoral fractures after total hip arthroplasty. AB - Periprosthetic fractures are the third most common reason for revision total hip arthroplasty. Surgical treatment of periprosthetic fractures belongs to the most difficult procedures due to the extensive surgery, elderly polymorbid patients and the high frequency of other complications. The aim of this study was to evaluate the results of operatively treated periprosthetic femoral fractures after total hip arthroplasty. We evaluated 47 periprosthetic fractures in 40 patients (18 men and 22 women) operated on between January 2004 and December 2010. The mean follow-up period was 27 months (within a range of 12-45 months). For the clinical evaluation, we used modified Merle d'Aubigne scoring system. In group of Vancouver A fractures, 3 patients were treated with a mean score of 15.7 points (good result). We recorded a mean score of 14.2 points (fair result) in 6 patients with Vancouver B1 fractures, 12.4 points (fair result) in 24 patients with Vancouver B2 fractures and 12.7 points (fair result) in 7 patients with Vancouver B3 fractures. In group of Vancouver C fractures, we found a mean score of 16.2 points (good result) in 7 patients. Therapeutic algorithm based on the Vancouver classification system is, in our opinion, satisfactory. Accurate differentiation of B1 and B2 type of fractures is essential. Preoperative radiographic images may not be reliable. If in doubt, checking the stability of the prosthesis fixation during surgery should be performed. PMID- 24069661 TI - Effect of collagen I gel on apoptosis of rat hepatic stellate cells. AB - Activated hepatic stellate cells (HSC) are a major source offibrous proteins in cirrhotic liver. Inducing or accelerating their apoptosis is a potential way of liver fibrosis treatment. Extracellular matrix (ECM) surrounding cells in tissue affects their differentiation, migration, proliferation and function. Type I collagen is the main ECM component in fibrotic liver. We have examined how this protein modifies apoptosis of normal rat HSC induced by gliotoxin, cycloheximide and cytochalasin D in vitro and spontaneous apoptosis of HSC isolated from CCl4 damaged liver. We have found that type I collagen gel enhances HSC apoptosis regardless of the agent triggering this process. PMID- 24069662 TI - "Elephant trunk" and endovascular stentgrafting--a hybrid approach to the treatment of extensive thoracic aortic aneurysm. AB - A hybrid approach to elephant trunk technique for treatment of thoracic aortic aneurysms combines a conventional surgical and endovascular therapy. Compared to surgery alone, there is a presumption that mortality and morbidity is reduced. We present a case report of a 42-year-old man with a giant aneurysm of the entire thoracic aorta, significant aortic and tricuspid regurgitation and ventricular septum defect. The patient underwent multiple consecutive operations and interventions having, among others, finally replaced the entire thoracic aorta with the use of the hybrid elephant trunk technique. PMID- 24069663 TI - Brown tumor at the jaw in patients with secondary hyperparathyroidism due to chronic renal failure. AB - Brown tumors are bony lesions caused by rapid osteoclastic activity, which rare involved jaws. Renal osteodystrophy (ROD) is associated with different pathogenetic mechanisms--disorder of calcium-phosphate metabolism, impaired metabolism of vitamin D, increased parathyroid activity that lead to extreme concentrations of parathormone. The authors report two cases of jaw enlargement in patients received haemodialysis with excessive increase values of alkaline phosphatase and parathormone in serum. The patients were treated surgically with corrective procedures in maxillo-facial area. ROD of the jaws could be severe complication in dialysis patients with end stage of CKD if no appropriate care aimed at correction or prevention of parathyroid hyperfunction was applied to them. PMID- 24069664 TI - Health insurance and chocolate. PMID- 24069665 TI - Codeine and acetaminophen recommendations for children. AB - The FDA recommends avoiding codeine in children after tonsillectomy and adenoidectomy for obstructive sleep apnea, due to the risk of respiratory depression. Also, changes to acetaminophen concentrations and dosages for children may help reduce the risk of unintentional overdoses. PMID- 24069666 TI - Large plaques in a patient with diabetes. Diagnosis: Necrobiosis lipoidica. PMID- 24069667 TI - A guide for screening, diagnosing, and managing Chagas disease in the United States. AB - A potentially lifelong and fatal parasitic tropical infection, Chagas disease is increasing in the United States. This article reviews the causes and risk factors for Chagas disease and how PAs can screen, diagnose, and manage affected patients. PMID- 24069668 TI - Acute respiratory distress syndrome: an overview for physician assistants. AB - An acute, diffuse, inflammatory lung injury, acute respiratory distress syndrome (ARDS) affects up to 10% of patients in the ICU and leads to multiorgan failure and death in nearly half the patients affected. This article reviews the causes, signs and symptoms, and treatment of ARDS. PMID- 24069669 TI - Ictal asystole: a rare cause of cardiac arrest. AB - Ictal asystole, a rare cause of transient cardiac arrest, is triggered by seizure activity. Long-term seizure control and pacemaker implantation can reduce the risk of this complication. PMID- 24069670 TI - The changing physician assistant profession: a gender shift. AB - The physician assistant (PA) movement originally served as an avenue for male veterans to transition into the civilian workforce. After a half-century of development, the profession in the United States is now predominantly female and nonveteran. Using archival data and other resources, this article documents the influences on gender and age shifts in the PA profession with related policy perspectives. Now entering its sixth decade, the profession continues to evolve as demand for PA services outpaces supply. PMID- 24069671 TI - Tibial osteotomy in a young, active patient. AB - High tibial osteotomies are valuable treatment options in the young, active patient with single-compartment arthritis who wishes to return to high load bearing sports. Patients with limited areas of degenerative wear should be referred to an orthopedic surgeon. PMID- 24069672 TI - Compartment syndrome. PMID- 24069673 TI - Age-based screening recommendations for hepatitis C virus infection. PMID- 24069674 TI - Diagnosis and management of group A beta-hemolytic streptococcal pharyngitis. AB - Viral and Group A beta-hemolytic streptococcal (GAS) pharyngitis have overlapping signs and symptoms, but distinguishing between the two is critical to proper treatment. Antibacterial therapy is appropriate for GAS pharyngitis and may help prevent complications. PMID- 24069675 TI - Vaccines in trials for nicotine cessation therapy. AB - Three nicotine vaccines currently in clinical trials may offer alternatives to traditional pharmacologic smoking cessation therapy. Although the trial results are promising, these vaccines pose ethical questions and their role in clinical practice remains unclear. PMID- 24069676 TI - A puzzling lymphadenopathy. Diagnosis: Hodgkin lymphoma. PMID- 24069678 TI - How do you best engage your counterparts at the local level to advance teamwork, best practices and other initiatives? PMID- 24069679 TI - The conversation revolution. Interview by Susan Solomon. PMID- 24069680 TI - The consummate host. PMID- 24069681 TI - Gather 'round. PMID- 24069682 TI - 10 minutes with David Feinberg. Interview by Rhoda Weiss. PMID- 24069683 TI - Improve & expand. PMID- 24069684 TI - The art of assurance. PMID- 24069685 TI - Patient voice. PMID- 24069686 TI - Living up to expectations. PMID- 24069687 TI - Daredevils: practice managers juggle daily risks to create a culture of caring. PMID- 24069688 TI - Medicare to provide Quality Resource Use Reports. PMID- 24069689 TI - Free online tools for physician practices. PMID- 24069690 TI - Risky business: risk management is about more than reducing malpractice costs- it's about improving care. PMID- 24069691 TI - Are you covered? Evolving practice and service models prompt review of insurance coverage. PMID- 24069692 TI - To understand new payment methods, go back to the future. PMID- 24069693 TI - The face of lean: retooling processes enhances patient care. PMID- 24069694 TI - Assessing the other 'R' in RHIOS: risk and liability of electronic privacy implications. PMID- 24069695 TI - Technology can't always cure process woes. PMID- 24069696 TI - A 57-year industry perspective. PMID- 24069697 TI - Implementation of a foot assessment program in a regional satellite hemodialysis setting. AB - Individuals with chronic kidney disease are at higher risk for foot problems (i.e., ulcers, deformities, amputations) than the general population. Research demonstrates that assessment and active monitoring, teaching, and timely interventions can reduce the number and severity of lower limb amputations in the hemodialysis population. This paper reports on a quality improvement project aimed at implementation of a foot assessment program in a regional satellite hemodialysis setting based on the Registered Nurses' Association of Ontario's (2005) best practice guideline (BPG), The Assessment and Management of Foot Ulcers for People with Diabetes. Elements of the program include a one-time full assessment of risk for all patients transferring to the satellite program followed by monthly foot checks for those deemed high risk (i.e., people with diabetes). Evaluation of the program has been positive from both patients and hemodialysis nursing staff. There has been a greater emphasis on self-management around the care and management of patients and their high-risk feet. At the same time, the program has resulted in prompt identification of problems and timelier referral to the appropriate services in the patient's local community. PMID- 24069698 TI - Applying the PARiHS framework in a knowledge dissemination initiative. AB - This paper describes the process of facilitating knowledge dissemination using the Promoting Action on Research Implementation in Health Services (PARiHS) framework, including articulation of findings, barriers, implications, and recommendations. Advanced practice nurses (APNs) are in a unique position to facilitate the dissemination of evidence-based knowledge to front-line staff in health care organizations. At a community acute care hospital in Toronto, Ontario, the collaborative competency of an APN was used to develop partnerships with three units in order to implement interprofessional knowledge dissemination via education sessions. The goal was to increase nurses' knowledge of best practices and, consequently, improve outcomes for nephrology patients under their care. The PARiHS framework was used to facilitate the process of knowledge dissemination. The framework consists of three elements: evidence, context, and facilitation. In order for the implementation of a project to be successful, it is necessary to understand the context of the organization. Implications and recommendations for advance practice nurses will be described. PMID- 24069699 TI - Review of available intravenous iron preparations in hemodialysis. PMID- 24069700 TI - Medical equipment donations. PMID- 24069702 TI - Designing for future care. Facilities need to respond to changing system. Interview by Jeff Ferenc. PMID- 24069701 TI - The 5th modality: psychonephrology. PMID- 24069703 TI - The next step. BIM's role expands as facility managers take ownership. PMID- 24069704 TI - Double image. Adding PET/MR systems into the imaging unit mix. PMID- 24069705 TI - Legalities of waste stream management. PMID- 24069706 TI - Fresh air. New ASHRAE reference guides hospital HVAC design. PMID- 24069707 TI - Lean ES. Process improvement for environmental services leaders. PMID- 24069708 TI - High-tech disinfection. Decontamination systems for hospitals gain momentum. PMID- 24069709 TI - Applying UV light in HVAC systems. PMID- 24069710 TI - Evidence-based practice--we must all be educators! PMID- 24069711 TI - Evidence-based oral care for oral mucositis. AB - Nurses must intervene to provide evidence-based supportive care and symptom management for cancer patients. Oral mucositis, a distressing side effect of cancer treatment, is both a research and clinical priority. Nurses can lead improvements with evidence-based oral mucositis interventions. This article describes application of evidence-based clinical recommendations for oral mucositis across diverse patient populations. PMID- 24069712 TI - The IOM Future of Nursing report update. PMID- 24069713 TI - Evidence for practice, ORL-head and neck nursing. PMID- 24069714 TI - The cost of care in America: $2.7 trillion. PMID- 24069715 TI - Specialized new graduate RN pediatric orientation: a strategy for nursing retention and its financial impact. AB - New graduate RN retention in the first year of employment is a challenge for hospitals, ranging from a low of 25% to a high of 64%. In 2005, hospitals in New York state spent 11.7% of their nursing budgets on temporary nursing staffing. The objectives of this study were to determine the retention and costs associated with the employment of new graduate RNs before and after the initiation of specialized year-long pediatric critical care, emergency department, and hematology/oncology orientation programs. The major study findings were improved retention of 84% to 94%, significant retention between the two groups at 9 months, and an annual financial savings related to decreased nursing turnover in the specialized orientation group. Specialized orientation programs that support new graduate RNs have documented increased RN retention and decreased RN turnover. In concert with the increased retention and decreased turnover, health care finances were positively impacted by specialized orientation programs. PMID- 24069716 TI - Transitional orientation: a cost-effective alternative to traditional RN residency programs. AB - Recruitment, orientation, and development costs, particularly for inexperienced RNs, challenge hospitals to find cost-effective methods to assure patients receive competent nursing care. Nurse leaders at the Lee Memorial Health System (LMHS) initiated a multifaceted development methodology called the Transitional Orientation Program, designed to develop and retain competent RNs. To assist in the intensive development needs required by the transitional unit interns and for other inexperienced RNs assigned initially to their unit of hire, LMHS established new clinical educator positions called intern development specialists (IDS). Results of this initiative showed a significant decrease in total orientation times and costs, and a dramatic increase in retention rates of inexperienced RNs. PMID- 24069717 TI - Cost effectiveness of a palliative care program in a rural community hospital. AB - Palliative care benefits patients and their families because care is focused on improving the quality of life rather than aggressively treating life-limiting illnesses. Although it would seem logical that palliative care could reduce expenses and improve quality of life, there is a need to examine the cost effectiveness of palliative care before full-scale implementation. Key success factors for implementing the palliative care program included assessing the facility's desire to implement palliative care and a readiness for major change in medical and nursing practice. Even in a small hospital, effective palliative care services can be provided with positive financial outcomes for dying patients and their families. This study demonstrated the important benefits of palliative care services and the need to offer this delivery care option to every patient regardless of the hospital's size, budget, or location. PMID- 24069718 TI - Comparing nurses' perceptions of governance related to hospitals' journeys to excellence status the Middle East. AB - The interest in the Magnet Journey extends to the Middle East. The results of this study revealed nurses in hospitals that are on the Journey to Magnet perceive that decision making is shared between nursing management/administration and staff nurses. Nurses in these hospitals positively attribute their involvement and engagement in every aspect of the nursing profession. This scheme of shared governance promotes professional accountability and enhances individual autonomy, authority, and control. The growth of health care in the Middle East region with rising expectations for patient care outcomes will challenge the nursing profession in the future. Shared governance will certainly help nurses take ownership in making decisions for patient care and as a result achieve better patient outcomes. PMID- 24069719 TI - Human factors engineering, bar coding medication administration, and nursing: an interview with Drs. Richard Holden and Laurie L. Novak. Interview by Peter I Buerhaus. PMID- 24069720 TI - The financial and clinical benefits of a hospital-based PhD nurse researcher. AB - Aligning quality outcomes with cost effectiveness is the cornerstone of the direction of health care in the United States. Implementing and supporting an evidence-based practice (EBP) environment requires resources. Because research is a foundational element of the EBP process, resources allocated for nursing research are essential. As part of operational costs, PhD nurse researchers can affirmatively impact an organization by improving quality of care and patient outcomes. Incorporation of a PhD nurse researcher can favorably alter the organization in a pay-for-performance environment. PMID- 24069721 TI - Self-care is a lifelong journey. AB - As the most influential catalysts for health care reform in America, the time for nurses to emulate wellness and prevention has never been more critical. By creating healthy habits for ourselves, we flourish as ambassadors of self-care for our patients, families, colleagues, and communities. By taking care of ourselves first, we bring positive energy and vitality to work that positively affects others and influences the overall landscape. In essence, the practice of self-care should be expected as part of the professional role of nursing. PMID- 24069722 TI - Increasing acuity, increasing technology, and the changing demands on nurses. AB - As the work environment for nurses continues to evolve, the demands on nurses increase along with the potential for nurses to become more distant from their patients. Among the key changes in the environment are the increasing acuity of patients in all settings, the introduction and evolution of the electronic health record, the expansion of telemetry and smart bed technology, increased use of video monitoring and telemedicine, and changes in payment that will focus attention on specific aspects of care. Nurses and nursing departments will need to aggressively manage the changing environment so that patient care is enhanced. How these demands and new technologies can be harnessed to enhance the patient experience and the quality of the nurse-patient interaction is a central question that will shape the future of nursing. PMID- 24069723 TI - How can we obtain data on the demand for nurses? AB - Sources related to demand for nurses data are more difficult to find, and also more difficult to interpret relative to supply. When people talk about the "demand" for nurses, they can have multiple concepts in mind. Even if the concept is well-defined, the data may not clearly align with the intended concept. As with data on RN supply, the relative value of different data sources on RN demand depends on the goals of the data collection and analysis. To measure the current demand for nurses, employer surveys are ideal. Such surveys can explicitly obtain information about vacant positions to measure the total demand for nurses. PMID- 24069724 TI - WHO Expert Consultation on Rabies. Second report. AB - Although there is debate about the estimated health burden of rabies, the estimates of direct mortality and the DALYs due to rabies are among the highest of the neglected tropical diseases. Poor surveillance, underreporting in many developing countries, frequent misdiagnosis of rabies, and an absence of coordination among all the sectors involved are likely to lead to underestimation of the scale of the disease It is clear, however, that rabies disproportionately affects poor rural communities, and particularly children. Most of the expenditure for postexposure prophylaxis is borne by those who can least afford it. As a result of growing dog and human populations, the burden of human deaths from rabies and the economic costs will continue to escalate in the absence of concerted efforts and investment for control. Since the first WHO Expert Consultation on Rabies in 2004, WHO and its network of collaborating centres on rabies, specialized national institutions, members of the WHO Expert Advisory Panel on Rabies and partners such as the Gates Foundation, the Global Alliance for Rabies Control and the Partnership for Rabies Prevention, have been advocating the feasibility of rabies elimination regionally and globally and promoting research into sustainable cost-effective strategies. Those joint efforts have begun to break the cycle of rabies neglect, and rabies is becoming recognized as a priority for investment. This Consultation concluded that human dog-transmitted rabies is readily amenable to control, regional elimination in the medium- term and even global elimination in the long-term. A resolution on major neglected tropical diseases, including rabies, prepared for submission to the World Health Assembly in May 2013 aims at securing Member States' commitment to the control, elimination or eradication of these diseases. Endorsement of the resolution would open the door for exciting advances in rabies prevention and control. PMID- 24069725 TI - Human genetic enhancement has become one of the most controversial issues in bioethics during the past decade. PMID- 24069726 TI - Making better babies: pro and con. PMID- 24069727 TI - In defence of male circumcision. AB - Controversies over the acceptability of male circumcision (MC) are not new to the international bioethical community. I do not expect to add much to the arguments or evidence presented elsewhere, but I want to acknowledge the often-overlooked political element in which the debate is entrenched. In fairness to those sympathetic to the circumcision ban, I will first introduce some supportive arguments to their position. Next, I will show the limits of those critiques, affirming that MC should not be outlawed in any liberal country, but that its permissibility only be evaluated within its medico-ethical dimension without the political charge often associated with the issue. PMID- 24069728 TI - The red tape waltz. Where multi-centre ethical and research governance review can step on the toes of good research practice. AB - How could it happen that the very processes intended to assure ethical research in Australia might, themselves, undermine good research practice? This paper describes one PhD candidate's recent experiences of multi-centre review for a Human Research Ethics Committee approved, low/negligible risk, qualitative study, at the crossroad of health services research and organisational research. A retrospective review of international literature about multi-centre review processes revealed that many of these experiences were not unique and might have been expected, notwithstanding Australian efforts at harmonisation of multi centre review. This paper examines not only the burden of red-tape that was applied to a small doctoral study, but also the way in which the red-tape threatened the anonymity of potential study participants and risked exposing them to undue pressure and distress. These experiences support the view that harmonisation initiatives have not yet developed as the Australian National Health and Medical Research Council may have hoped and that further attention is needed to harmonise research governance processes. PMID- 24069729 TI - Justice in human research ethics. A conceptual and practical guide. AB - One of the core values to be applied by a body reviewing the ethics of human research is justice. The inclusion of justice as a requirement in the ethical review of human research is relatively recent and its utility had been largely unexamined until debates arose about the conduct of international biomedical research in the late 1990s. The subsequent amendment of authoritative documents in ways that appeared to shift the meaning of conceptions of justice generated a great deal of controversy. Another difficulty has been that both the theory and the substance of justice that are applied by researchers or reviewers can be frequently seen to be subjective. Both the concept of justice--hether distributive or commutative--and what counts as a just distribution or exchange- are given different weight and meanings by different people. In this paper, the origins and more recent debates about the requirement to consider justice as a criterion in the ethical review of human research are traced, relevant conceptions of justice are distinguished, and the manner in which they can be applied meaningfully in the ethical review of all human research is identified. We also explain the way that these concepts are articulated in, and the intent and function of, specific paragraphs of the National Statement on Ethical Conduct in Human Research (2007). The National Statement identifies a number of issues that should be considered when a human research ethics committee is reviewing the justice aspects of an application. We provide guidance to researchers as to how they can show that there is a fair distribution of burdens and benefits in the participant experience and the research outcomes. We also provide practical guidance to researches on how to think through issues of justice so that they can demonstrate that the design of their research projects meets this ethical requirement. PMID- 24069730 TI - Integrated Maternal, Newborn and Child Health (IMNCH) strategy: how has it advanced in Africa? PMID- 24069731 TI - Shifting norms: pregnant women's perspectives on skilled birth attendance and facility-based delivery in rural Ghana. AB - Skilled birth attendance (SBA) and healthcare facility (HCF) delivery are effective means of reducing maternal mortality. However, their uptake remains low in many low-income countries. The present study utilized semi-structured interviews with 85 pregnant women attending an antenatal clinic in Akwatia, Ghana (May-July 2010) to better understand the barriers to SBA and HCF delivery through the underrepresented perspective of pregnant women. Interview transcripts were analyzed using grounded theory methodology. Participants described community support for and uptake of HCF delivery as increasing and becoming normalized, but barriers remain: (1) maltreatment by midwives; (2) cost associated with HCF delivery despite waived facility fees; (3) the need for a support person for HCF delivery; (4) difficulties in transportation; and (5) precipitous labor. Given the importance of community in Ghanaian health care decision-making, increasing community support for HCF delivery suggests progress toward increasing uptake of SBA and HCF delivery, however important actionable barriers remain. PMID- 24069732 TI - Birth and emergency planning: a cross sectional survey of postnatal women at Korle Bu Teaching Hospital, Accra, Ghana. AB - Birth and emergency planning encourages early decision making, helps overcome barriers to skilled maternity care and reduces preventable maternal and newborn deaths. A facility based postnatal survey of 483 childbearing women in Accra, Ghana determined birth and emergency planning steps, awareness of obstetric danger signs, reported maternal and newborn complications and birth outcome based on length of hospital stay. Supervised antenatal care and delivery were nearly universal. Overall, 62% had a birth plan, 74% had adequate knowledge of danger signs, while 64% and 37% reported maternal and newborn complications respectively. Accompaniment by a birth companion and saving money were considered the most useful planning steps. Knowledge of danger signs was associated with birth and emergency planning, and birth and emergency planning was associated with reported birth outcome. Birth and emergency planning as a critical component of antenatal care can influence birth outcomes and should be extended to all pregnant women. PMID- 24069733 TI - An assessment of essential maternal health services in Kwara State, Nigeria. AB - The objective of this study is to evaluate the levels of emergency obstetrics care (EOC) signal functions in health facilities in a developing setting with high maternal morbidity and mortality indices and to determine if there are differences between public and private health facilities in terms of availability of these signal functions. A survey of health facilities was carried out in six of the 16 Local Government Areas (LGAs) of Kwara State Nigeria. All health facilities in these LGAs including public and private health facilities offering some services to pregnant women were surveyed using an interviewer- administered, facility-assessment questionnaire adapted from the WHO/UNFPA/UNICEF international guidelines for monitoring the availability and use of obstetric services. Frequency tables, percentages and charts were used for presenting the data. Comparing public and private facilities was done using chi-square tests. A total of 258 health facilities that provide maternal health services were surveyed in this study, out of which 76 (29.5%) were private facilities and 182 (70.5%) were public sector facilities. Most of the UN indicators were not met by the health facilities in Kwara state. The availability of EOC facilities was more among the private sector and this was statistically significant. This study shows that all stakeholders involved in reducing maternal mortality have a big challenge in the areas of availability, inequity in geographical distribution of EOC facilities and poor utilisation of these EOC services by women. PMID- 24069734 TI - [Sexual behavioral among adolescents and young people in Subsaharan Africa and related factors]. AB - This study has as specific objective to analyze the prevalence of risky sexual behaviors and their social factors in Francophone sub-Saharan African countries among young people by highlighting the differences between countries. The data used are those of the national Demographic and Health Surveys. The following are the main results of the study: 1) Among males, the average age at first sex is lower in two Central African countries, the Congo and DRC and in Benin than in Burkina Faso, and in strongly Islamized countries such as Chad, Senegal and Mali; 2) Among girls, an opposite schema has, to some extent, been observed; 3) In the countries studied, multi-partner sexual activity persists, but Cameroon, Congo, Cote-d'Ivoire, Benin and Guinea are more affected by this problem than other countries; 4) the rate of condom use at last sex has improved but some countries like Burkina Faso, Cote-d'Ivoire, Senegal and Cameroon are more advanced than others; 5) Several family, extra-family and individual factors influence risky sexual behaviors in the countries studied but the intensity and direction of observed statistical relations do not necessarily converge. Therefore, the global explanation approach of young people's sexual behaviors is relevant in the countries studied, but the weight of its various dimensions in the explanation varies according to the country. These results should be considered in the orientation of strategies of the fight against HIV/AIDS in these countries. PMID- 24069735 TI - [Epidemiological and clinical aspects of the management of sexual aggression among female victims in Lome]. AB - This is a retrospective study whose objective is to describe the epidemiological and clinical aspects of the management of sexual violence in Black Africa. The study included 373 cases of alleged female victims of sexual assault registered in the Department of Obstetrics and Gynecology of the University Teaching Hospital, Tokoin, Lome, from 2007 to 2009. Sexual assault accounted for 4.37% of reasons for consultation and vaginal penetration (62.2%) was the predominant mode. The victim was often a small girl of an average age of 12 years. The mean reporting delay which was about 13 days has considerably limited some aspects of the management. We found 14.5% signs of genital trauma, nine cases of HIV serological conversions (2.4%) and eight induced pregnancies. Sexual assault among female victims in Lome affected the young and vulnerable population. Governments must further inform about this issue and create multidisciplinary free management centres. PMID- 24069736 TI - Reaching adolescents and youth in Burkina Faso, Guinea-Bissau and Mauritania. AB - Who are the young people reached by peer education programs and/or by youth centers? The present study intends to better know about the activities of the peer educators who are involved in organizations that promote reproductive health information and services in three West African countries. A special research tool was created to collect data to evaluate the composition and characteristics of the populations that such programs reach; therefore, to evaluate the populations left behind. We found that the typical profile of individuals in contact with peer educators or attending youth centers tended to be males aged 15 and more, schooled or highly educated, never married, and living in urban areas. We also found a relationship between peer educators' and peers' socio-demographic characteristics in rural Burkina Faso and urban Guinea Bissau. Finally, the main topics discussed included HIV/AIDS and Sexually Transmitted Infections, but omitting other aspects of sexual and reproductive health. PMID- 24069737 TI - Experiences of girls with hearing impairment in accessing reproductive health care services in Ibadan, Nigeria. AB - Delivery of health services to people with hearing impairment is poorly understood in Nigeria and limited research has been done to throw more light on the process involved. This study described experiences of 167 girls with hearing impairment in accessing reproductive health services in Ibadan using a validated questionnaire. Descriptive statistics and binary logistic regression were used to analyze the data. Almost 95.0% of respondents had ever visited health facility for reproductive health issues. Of these 6.2% and 4.6% went for treatment of STIs and pregnancy termination respectively; 36.7% were embarrassed to ask questions in the presence of an interpreter, communication (40.5%) and cost (10.8%) were key barriers to access and 85.6% would use facility if hearing impairment friendly services are provided. Respondents who were currently working were 20 times more likely to receive services they wanted (OR = 20.29, CI = 1.05-392.16). Availability of certified interpreters and ensuring confidentiality are key to effective service delivery for the hearing impaired. PMID- 24069738 TI - Sexually transmitted infections: prevalence, knowledge and treatment practices among female sex workers in a cosmopolitan city in Nigeria. AB - Sexually transmitted infections constitute economic burden for developing countries, exposure to causative agents is an occupational hazard for female sex workers. Targeted interventions for this population can reduce the incidence and prevalence of sexually transmitted infections including human immunodeficiency virus, but barriers exists which can hinder effective implementation of such programs. This descriptive cross sectional study sought to assess the prevalence, knowledge and treatment practices of sexually transmitted infections among brothel based female sex workers. Three hundred and twenty three consenting female sex workers were surveyed using pre tested, interviewer administered questionnaires. More than half of the respondents (54.2%) had poor knowledge of symptoms of sexually transmitted infections. Only 13.9% were aware that sexually transmitted infections could be asymptomatic. The self reported prevalence of symptomatic sexually transmitted infections was 36.5%. About half of those with sexually transmitted infectionss sought treatment in a hospital or health centre while 32.5% from a patent medicine vendor. Most respondents (53.8%) mentioned the perceived quality of care as the main reason for seeking treatment in their chosen place. More of the respondents with good knowledge of sexually transmitted infections reported symptoms compared to those with fair and poor knowledge. The knowledge of sexually transmitted infections among these female sex workers is poor and the prevalence is relatively high. Efforts to improve knowledge promote and encourage preventive as well as effective treatment practices must be made for this population. PMID- 24069739 TI - Marital status and risk of HIV infection in slum settlements of Nairobi, Kenya: results from a cross-sectional survey. AB - Kenya still faces major challenges due to the HIV/AIDS epidemic. This study examined the association between marital status and risk of HIV infection in urban slums of Nairobi. Data were derived from a cross-sectional population-based survey nested in an ongoing Demographic Surveillance System in two urban slums in Nairobi. Descriptive statistics and multivariate logistic regression analysis were used to describe the characteristics of the sample and to assess the association between marital status and risk of HIV infection. HIV prevalence among married men and women was 10.4% and 11.1% and among divorced/separated/widowed men and women was 14.9% and 27.9%. Multivariate results showed the risk of acquiring HIV was significantly associated with being married, divorced/separated/widowed, being in the older age groups and the Luo ethnic group. There is urgent need for appropriate HIV prevention interventions targeted at the urban poor to address the high risk of HIV infections in this population. PMID- 24069740 TI - HIV/AIDS-related knowledge and misconceptions among women attending government owned antenatal clinics in Gwagwalada Area Council of Abuja, Nigeria. AB - This study assessed the level of knowledge and misconceptions about HIV/AIDS transmission and prevention among women. Using a semi-structured pretested questionnaire we obtained relevant data from 420 respondents in five randomly selected antenatal clinics (ANCs) in Gwagwalada Area Council (GAC) of Abuja, Nigeria. Knowledge about the existence of HIV/AIDS was high (92.8%). Only 52.1% knew the cause of AIDS and 58.6% were aware that AIDS had no cure. About twenty percent of respondents believed that breast-milk could not transmit HIV and 27.9% were unaware that condom protects against HIV. Only 33.3% were aware that HIV infected persons may look and feel healthy. Mothers with at least secondary level education had significantly higher knowledge scores on HIV/AIDS transmission (X2 = 14.8, p = 0.01) than less educated mothers and less educated mothers were more likely to relate HIV infection to past misdeeds (X2 = 13.6, p = 0.01). Significant misconception concerning HIV transmission existed in the study population. More community outreach programmes to intensify HIV education and counseling in GAC is required. PMID- 24069741 TI - Challenges facing early infant diagnosis of HIV among infants in resource poor settings. AB - The number of children who have HIV continues to grow. Studies have confirmed dramatic survival benefits and mortality reduction for infants confirmed and managed as early as possible after diagnosis. With the advent of the Polymerase Chain Reaction technology, early infant diagnosis of HIV among children is easier and more reliable worldwide. Most HIV programmes in developing countries are donor dependent with less encouraging moves towards sustainability drive by the local health authority. The health systems also face a lot of challenges while implementing these programmes that would promptly identify HIV exposed babies as well as enrolment into care. This review examined challenges facing early infant diagnosis of HIV among infants in Nigeria. PMID- 24069742 TI - Opinion of obstetricians and gynaecologists on ethical issues in the practice of in-vitro fertilisation and embryo transfer in Nigeria. AB - The objective of this study was to bring ethical issues in the practice of in vitro fertilisation (IVF) in Nigeria to the fore, to determine and articulate the views of Obstetricians and Gynaecologists on treatment modalities and to drive regulation of this specialised field. A plenary session was organised by The Bridge Clinic at the 2010 Society of Gynaecology and Obstetrics of Nigeria (SOGON) annual general meeting. Participants self-administered a 33-point questionnaire on their views on ethical issues in IVF. The results buttress the conclusions of an earlier publication, clearly indicating that even amongst specialised medical professionals; there are varying views which really cannot be challenged as being either right or wrong as they represent the individuals' position and his culture. Within the context of our society, ethics and morality especially as they affect patient care can and must be hinged on a code or framework which should be developed, implemented and its implementation monitored by a legally bound regulatory body for the protection of the rights and safety of our patients, their unborn children and for the integrity of our health care systems. PMID- 24069743 TI - Knowledge and practice of family planning in Dschang municipality, Cameroon. AB - This study was conducted to examine factors which influence contraception in order to ameliorate services. For 12 consecutive months, 706 consenting women on fertility control presenting at the Dschang District Hospital, Cameroon were interviewed and cervical/blood samples collected for analysis. Study respondents were aged 15-50 years (mean 33.61 +/- 6.29 years). Levonorgestrel implants (46.7%) and medroxyprogesterone injections (27.6%) were cost effective over the intrauterine copper device (9.5%), Norgestrel (7.8%), Norethisterone enanthate (6.7%), male condoms (6.4%), Progestin only pills (1.4%) and spermicides (1.1%). Lack of expertise precluded tubal ligation or implants and vasectomy. Stigmatization, male rejection, giving or taking methods without adequate laboratory services or regular health checks and failure to recognize or report adverse reproductive health changes impacted on contraception. Genital infections were identified in 33.7% respondents, vaginal candidiasis 20%, bacterial vaginosis 19%, HIV/AIDS 90%, chlamydia 6% and < 2% other traditional venereal diseases. Sensitization, education, improved diagnostics and attitude change were adopted. PMID- 24069744 TI - A comparative study of factors influencing decisions on desired family size among married men and women in Bokkos, a rural local government area in Plateau state. AB - The total fertility rate of Nigerian women has remained high at 5.7. This is even higher for women in rural areas. Men and women in rural areas desire more children than those in urban areas. This study was aimed at describing and comparing the factors that influence family size decisions among men and women in Bokkos, a rural Local Government Area in Plateau state, Nigeria. A cross sectional descriptive comparative study was used. Data was collected using structured interviewer administered questionnaires. Seventy two percent of women and 83.6% of men who desire to have 1-4 children had at least a secondary school education. Close to seventy percent of both men and women would have fewer children if they are certain of their survival to adulthood. Over 50% of the respondents believe that the husbands should have the final say on family size decisions. Preference for male children influences decisions on family size among men and women in the study population. PMID- 24069745 TI - An analysis of key stakeholders' attitudes and beliefs about barriers and facilitating factors in the development of a cervical cancer prevention program in South Africa. AB - Cervical cancer is the leading cause of cancer related deaths among women. Each year there are approximately 250,000 deaths; most of which occurred in Sub Saharan Africa, South Asia, and Latin America. The purpose of this report is to examine key stakeholders experience and knowledge of HPV and cervical cancer, examine their experiences with the current cervical cancer screening and treatment policy, and identify barriers and facilitating factors to vaccine implementation and uptake. Fifteen indepth interviews were conducted with key stakeholders in Cape Town and Johannesburg, South Africa. The interviews revealed several key findings including: 1) knowledge about HPV and cervical cancer varied across participants, 2) knowledge about cervical cancer was also mixed while knowledge about the relationship between HPV and cervical cancer was low among participants. Our findings indicate that key stakeholders are concerned about women's health and wellbeing. In addition, they believe that the government, families, and the media need to play a prominent role in prevention efforts. PMID- 24069746 TI - Use of cervical cerclage as a treatment option for cervical incompetence: patient characteristics, presentation and management over a 9 year period in a Kenyan centre. AB - Treatment of cervical incompetence by cerclage and other methods has yet to be standardized, as its diagnosis is not uniformly accepted. Its diagnosis, particularly in the African setting, is mostly based on past obstetric history of pregnancy losses, while in developed centres; ultrasound diagnosis is increasingly being used. The mainstay of treatment in developing countries is cervical cerclage, although the indications and contraindications of this mode of treatment are not documented. Our aim was to appraise this practice in terms of patient characteristics, the diagnostic process and management at the Kenyatta National Hospital, Nairobi, Kenya. This was a descriptive retrospective study over 9 years. Predesigned questionnaires were employed to collect data on patient's socio-demographic profile, presentation, risk factors, diagnosis and management of cervical incompetence. Chi-squared test and student's t-test were used to correlate variables. A total of 199 patients were treated for cervical incompetence, with the patient mean age being 27.97. 87.4% of the patients (p = 0.02) were in the 20 to 35 years category. Most of the patients (60.1%) were of low socio-economic status. Cervical cerclage was employed in all the patients, although ultrasound investigation was not employed in 65.8% of them. Diagnosis of cervical incompetence still relies on history of previous pregnancy losses, with the standard transvaginal ultrasound relatively unemployed. There is need to intensify investigations for this condition, standardize the indications for cerclage, and diversify management to other newer modalities. PMID- 24069747 TI - Tackling maternal mortality in Africa after 2015: what should the priorities be? PMID- 24069748 TI - Confronting maternal mortality due to postpartum hemorrhage and unsafe abortion: a call for commitment. PMID- 24069749 TI - The impact of family planning on primary school enrolment in sub-national areas within 25 African countries. AB - We study how the availability and use of family planning services in African countries influences the family planning situation of households and through this the educational participation of young children. A district panel dataset is used for 441 urban and rural areas within 233 districts of 25 countries. Path analysis shows that a decrease in the number of births is associated with an increase in educational participation in the area. The number of births is negatively associated with acceptance, knowledge and actual use of contraceptives in the area. As reversed causality and selection bias seem unlikely, the identified relationship probably is at least partially causal. Hence, investments in family planning services in poor areas are not only important because they allow women to plan their births better, but also because they may lead to higher primary enrolment rates and thus contribute to the region's future economic growth. PMID- 24069750 TI - Birth interval and its predictors among married women in Dabat District, Northwest Ethiopia: a retrospective follow up study. AB - Birth intervals (time between two successive live births) if short are associated with diverse complications. We assessed birth interval and its predictors among 613 married women who gave birth from January 1 to December 30, 2008. Data were collected in April 2012. Life table and Kaplan-Meier curve were used to estimate cumulative probabilities and median birth interval, respectively. Log rank test was employed to compare survival between categories of explanatory variables. Cox proportional hazards model was fitted to compute hazard ratios with their 95% confidence intervals. Median birth interval was 32.6 months (95% CI: 31.2-34.1). The cumulative probabilities of survival at 12, 24, and 36 months were 0.97, 0.82 and 0.56 respectively. Death of the index child (AHR = 3.12), contraceptive non use (AHR = 4.29) and husband's education (AHR = 2.20) were significant predictors. Birth interval was short. Contraceptive use and paternal education should be given greater attention in addition to prevention of infant and child mortality. PMID- 24069751 TI - Delaying sexual debut as a strategy for reducing HIV epidemic in Kenya. AB - The study purpose was to determine the association between sexual debut and HIV sero-status, and factors contributing to a positive HIV sero-status. Retrospective cross-sectional data from the Kenya Demographic and Health Survey 2003 were used. Data on women aged 15-49 (n = 3,273) and men aged 15-54 (n = 2,917) accepting HIV testing were retained from three datasets. Stata version 10.1 was used for analyses, p < 0.05. Nine percent of women and 5% of men tested positive for HIV, of whom 46% and 49%, p < 0.001 were aged 16-21 respectively. After adjusting for confounding, women and men who had sexual debut aged 16-21 were 2.31 (95% CI: 1.52-3.51), p < 0.001 and 1.83 (95% CI: 1.07-3.13), p < 0.05 times more likely to test positive for HIV compared to those who never had sex respectively. Early sexual debut continues to be a major risk factor for acquiring HIV infection later in life, suggesting earlier interventions could have a major impact towards fighting the disease. PMID- 24069752 TI - Modern contraceptive use among women in the Asuogyaman district of Ghana: is reliability more important than health concerns? AB - This study examines the socio-demographic determinants of modern contraceptive use among women in the Asuogyaman district of Ghana. The results reveal that although 97% of the survey respondents knew of at least one modern method of contraception, only 16% of them were using modern contraceptives. Statistical tests show that level of education, place of residence, and work status significantly influence modern contraceptive use among women in the study area. Fear of side effects, desire for more children, and partner's disapproval were the main barriers to modern contraceptive use in the study area. The use of traditional methods of contraception was very high because of the perception that they are safer. Based on these findings, it has been suggested that in addition to making family planning services available and accessible, health workers must address attitudinal factors such as fear of side effects and high fertility preferences. PMID- 24069753 TI - Immediate postpartum versus 6-week postpartum intrauterine device insertion: a feasibility study of a randomized controlled trial. AB - This study aimed to evaluate the feasibility of conducting a randomized controlled trial of postpartum intrauterine device insertion and to demonstrate that the postpartum intrauterine device is acceptable to women. Women attending prenatal care at a maternity hospital in Lilongwe, Malawi were recruited into a trial comparing immediate (10 minutes to 48 hours) to 6 week postpartum insertion. Feasibility of recruiting and consenting 140 women and randomizing 70% of them was evaluated. Satisfaction with the intrauterine device was also assessed. One hundred fifteen women consented and 49 (61%) were randomized. Twenty-six women were assigned to immediate insertion, and 23 to insertion at 6 weeks postpartum. Thirty (24%) women received the device as part of the study protocol, and 28 (93%) had the device in place at 12 weeks postpartum. The intrauterine device is acceptable to some postpartum women in Malawi, but conducting a randomized clinical trial may not be feasible. PMID- 24069754 TI - The effectiveness of community based distribution of injectable contraceptives using community health extension workers in Gombe State, Northern Nigeria. AB - This study reports on findings of a pilot of community-based distribution (CBD) of injectable contraceptives in two local government areas (LGAs) of Gombe State, Nigeria. From August 2009 to January 2010, the project enrolled, trained and equipped community health extension workers (CHEWs) to distribute condoms, oral and injectable contraceptives in communities. The project mobilized communities and stakeholders to promote Family Planning (FP) services in the selected communities. Using anonymised unlinked routine service data, the mean couple years of protection (CYP) achieved through CBD was compared to that achieved in FP clinics. The CBD mean CYP for injectables- depo medroxy-progesterone acetate (DMPA) and norethisterone enantate was higher (27.72 & 18.16 respectively) than the facility CYP (7.21 & 5.08 respectively) (p < 0.05) with no injection related complications. The CBD's mean CYP for all methods was also found to be four times higher (11.65) than that generated in health facilities (2.86) (p < 0.05). This suggests that the CBD of injectable contraceptives is feasible and effective, even in a setting like northern Nigeria that has sensitivities about FP. PMID- 24069755 TI - Socio-cultural perspectives on causes and intervention strategies of male infertility: a case study of Mhondoro-Ngezi, Zimbabwe. AB - The subject of male infertility has, to a large extent, been broached from a western perspective that often insists on the biological factor. This approach has led to a narrowed and narrowing perception of male infertility in that it often neglects other possible crucial socio-cultural dimensions pertaining to the issue. The study is purely qualitative. Focus group discussions and key informant interviews (with males and females) are used to collect qualitative data. The study notes that, unlike in western inclined discourses, male infertility is an intricate condition that transcends biology. Witchcraft and punishment either from God or angry ancestors were avowed to be the determinants of male infertility. The study notes that the Shona people in Mhondoro-Ngezi exclusively rely on socio-cultural intervention strategies to solve the problem of male infertility. The study thus recommends a holistic approach to male infertility which integrates the socio-cultural perspectives in policy and programming, if progress is to be made in unearthing the underlying causes and treatment options. PMID- 24069756 TI - The work of a woman is to give birth to children: cultural constructions of infertility in Nigeria. AB - Infertility is a condition loaded with meaning spanning across biomedical, psychological, social, economic, cultural and religious spheres. Given its disruptive power over women's lives, it provides a unique lens through which issues of kinship, gender, sexuality, cosmology and religion can be examined. The paper presents the results of an ethnographic study of infertility in Central Nigeria. Explanatory models of infertility were variegated, encompassing biomedical, folk and religious elements. Like other ethnographic studies of help seeking for infertility in Nigeria, among this group resort was made to biomedical treatments, traditional healers and religious healing with no one system being hegemonic. The findings of this study accord with studies of infertility in other cultural groups indicating the disruptive influence of missing motherhood. PMID- 24069758 TI - Identifying obstetrical emergencies at Kintampo Municipal Hospital: a perspective from pregnant women and nursing midwives. AB - A hospital based cross-sectional qualitative study was conducted at Kintampo Municipal Hospital in Northern Ghana, to identify obstetric emergencies and barriers to emergency care seeking; examine the perspective of midwives regarding their role in maternity care and management of obstetric emergencies, and explore women's knowledge and response to obstetric emergencies. Study subjects comprised of 2 emergency obstetric cases, 29 antenatal focus group discussants and 5 midwives at the maternity unit. Data was collected from 23rd March to 9th April, 2012 using in-depth interviews, focus group discussions and record reviews. The most common obstetric emergencies were hemorrhage, eclampsia and anemia. Potential obstetric complications were poorly understood by antenatal women and known barriers limited access to emergency obstetric care. Service challenges included insufficient staffing and well as inadequate equipment and physical space in the maternity ward. Local community efforts can address communication and service access gaps. Government intervention is required to address service provision gaps for improved maternity care in Kintampo. PMID- 24069757 TI - Why women are dying from unsafe abortion: narratives of Ghanaian abortion providers. AB - In Ghana, despite the availability of safe, legally permissible abortion services, high rates of morbidity and mortality from unsafe abortion persist. Through interviews with Ghanaian physicians on the front lines of abortion provision, we begin to describe major barriers to widespread safe abortion. Their stories illustrate the life-threatening impact that stigma, financial restraints, and confusion regarding abortion law have on the women of Ghana who seek abortion. They posit that the vast majority of serious abortion complications arise in the setting of clandestine or self-induced second trimester attempts, suggesting that training greater numbers of physicians to perform second trimester abortion is prerequisite to reducing maternal mortality. They also recognized that an adequate supply of abortion providers alone is a necessary but insufficient step toward reducing death from unsafe abortion. Rather, improved accessibility and cultural acceptability of abortion are integral to the actual utilization of safe services. Their insights suggest that any comprehensive plan aimed at reducing maternal mortality must consider avenues that address the multiple dimensions which influence the practice and utilization of safe abortion, especially in the second trimester. PMID- 24069759 TI - The social dynamics of selling sex in Mombasa, Kenya: a qualitative study contextualizing high risk sexual behaviour. AB - Female sex workers (FSWs) in sub-Saharan Africa have one of the highest HIV seroprevelance rates of any population. Effective safe sex interventions are urgently needed to stop the transmission of HIV during commercial sex. Despite widespread education, counselling, and condom distribution interventions among FSWs, unprotected sexual intercourse remains a large behavioural challenge. Research on this topic has been limited primarily to establishing the frequency of high risk sexual behaviour without a comprehensive analysis of the social environment creating these factors, especially gender inequality. Through qualitative indepth interviews and focus group discussions with FSWs, this article contextualizes the selling of sex in one large urban city of Kenya. The results of this study indicate that FSWs will never be able to enforce safe sex among male clients in such settings without structural interventions that address gendered socioeconomic power imbalances. Policy implications based on these findings include re-evaluating laws against the selling of sex and prioritizing female education and economic opportunities. PMID- 24069760 TI - Knowledge of the human papilloma virus vaccines, and opinions of gynaecologists on its implementation in Nigeria. AB - The objective of this study was to determine the knowledge and perception of Nigerian Obstetricians and Gynaecologists towards human papilloma virus vaccine use in Nigeria. A cross sectional study was conducted amongst participants that attended the 42nd Society of Gynaecology and Obstetrics of Nigeria. The findings revealed that 44.5% knew the correct HPV vaccine schedule. Regarding implementation in Nigeria, 87.4% suggested its incorporation into the national immunization program and about a third agreed that it should be a precondition for school enrolment. Regression analysis showed that senior residents were more likely to have adequate knowledge of the vaccine compared to junior residents (AOR 7.181 95% CI OR = 1.792 - 28.782). We conclude that the knowledge of eligibility and schedule is poor. It is recommended that adequate information should be provided to this group of health workers because of their strategic position in its implementation in Nigeria. PMID- 24069761 TI - Exposure to media content and sexual health behaviour among adolescents in Lagos metropolis, Nigeria. AB - The influence of adolescents' exposure to sexual health content of mass media in their sexual health behaviour in Nigeria is still not clear. Data were gathered through a survey conducted among adolescents aged 12-19 years in Lagos metropolis between November 2009 and February 2010. A multistage sampling strategy was adopted in selecting respondents. Logistic regression technique was utilised in the analysis. The results indicate that the respondents were most frequently exposed to TV (male = 92.2; female = 94.9) and radio (male = 88.2; female = 91.7) media. The odds ratios indicate that sexual health content of mass media significantly predicted condom use, multiple sexual relationship, sexual intercourse and self reported occurrence of abortion in the study sample. The findings imply that positive media sexual health content is likely to promote sexual health among adolescents but negative contents can put adolescents' sexual health in danger. In addition, safe sex can be advanced among adolescents if the media provide accurate information on sexuality, emphasising the dangers of risky sexual practices. Finally, this study posits that accurate portrayal of sexuality in the media would contribute immensely to improving public health in the metropolis. PMID- 24069762 TI - [Premarital sex in Antananarivo (Madagascar): how are students freeing themselves from the norms?]. AB - This paper aims to analyze the representations of premarital sexuality among young people in a context where they are strongly encouraged not to engage in premarital sexual relations. This link between prevention messages, representations and behaviours has been studied among a student population in Madagascar. The analysis is based on a socio-demographic survey conducted in 2006. Results show that young men and women share the ideal of abstinence before marriage. The promotion of premarital sexual abstinence within AIDS programs reinforces gender differences. It is mainly young women who are urged to be abstinent, whereas young men have the means--condom use--to transgress the taboo of premarital sex and protect themselves against health risks. Thus, young men have a dual strategy. On the one hand, they attach great importance to premarital abstinence with their future wife; on the other hand, they can have sex with occasional partners and are then protected by condoms. PMID- 24069763 TI - Big issues deserve bold responses: population and climate change in the Sahel. PMID- 24069764 TI - Linking population, fertility, and family planning with adaptation to climate change: perspectives from Ethiopia. AB - Global climate change is felt disproportionately in the world's most economically disadvantaged countries. As adaption to an evolving climate becomes increasingly salient on national and global scales, it is important to assess how people at the local-level are already coping with changes. Understanding local responses to climate change is essential for helping countries to construct strategies to bolster resilience to current and future effects. This qualitative research investigated responses to climate change in Ethiopia; specifically, how communities react to and cope with climate variation, which groups are most vulnerable, and the role of family planning in increasing resilience. Participants were highly aware of changing climate effects, impacts of rapid population growth, and the need for increased access to voluntary family planning. Identification of family planning as an important adaptation strategy supports the inclusion of rights-based voluntary family planning and reproductive health into local and national climate change adaptation plans. PMID- 24069765 TI - Facility-based delivery and maternal and early neonatal mortality in sub-Saharan Africa: a regional review of the literature. AB - Regional variability in facility-based delivery (FBD) rates in sub-Saharan Africa (SSA) is not well understood, nor is the relationship between FBD and national maternal and early neonatal mortality rates. A systematic literature review identified studies documenting the factors associated with FBD, stratified by region. Rates of skilled birth attendance, facility delivery, maternal mortality, and early neonatal mortality were compared across nations and regions. 70 articles met inclusion criteria, reflecting wide variability in the number, type, and quality of studies by region. Within-country differences were most pronounced in nations where multiple studies were conducted. Correlation between FBD and maternal mortality rates throughout SSA was -0.69 (p=.008), and the correlation between facility delivery rates and early neonatal mortality rates was -0.41 (p=0.08). This study demonstrates the need to attend to regional differences both across and within SSA nations if facility delivery rates are to be improved to reduce maternal and early neonatal mortality. PMID- 24069766 TI - An examination of postpartum family planning in western Kenya: "I want to use contraception but I have not been told how to do so". AB - Postpartum family planning (FP) in Kenya is low due to inadequate sensitization and awareness among women, particularly in rural areas. This paper identifies most widely used types of FP, intent and unmet needs among women, FP counseling and barriers to FP uptake. Focus group discussions with providers, traditional birth attendants (TBAs) and mothers, as well as in-depth interviews identify key themes including preferred postpartum FP, limits to existing FP counseling and barriers to FP uptake. Postpartum FP is common including injectable contraceptives, oral contraceptives, coils, condoms, and calendar methods. FP counseling is provided by peers, friends, TBAs and formal health providers. FP practices are associated with family support, literacy, access to FP information, side effects, costs and religion. In conclusion, changes in service provision and education could encourage increase in postpartum FP use in Kenya. PMID- 24069767 TI - Programmatic aspects of postpartum family planning in developing countries: a qualitative analysis of key informant interviews in Kenya and Ethiopia. AB - To achieve the improved maternal and child outcomes of birth spacing, family planning in the postpartum period is essential. The objective of this study is to determine the perceptions regarding programmatic aspects of postpartum family planning by key informants in 17 countries determined to have high unmet need for postpartum family planning. We present interim data from structured interviews of key informants in Kenya and Ethiopia. Important themes included the need for documentation of contraceptive use to aid in commodity assessment and delivery, need for additional informational materials, and challenges of delivering services to those women who deliver away from a health care facility. PMID- 24069768 TI - Communication, knowledge, social network and family planning utilization among couples in Mwanza, Tanzania. AB - Family planning utilization in Tanzania is low. This study was cross sectional. It examined family planning use and socio demographic variables, social networks, knowledge and communication among the couples, whereby a stratified sample of 440 women of reproductive age (18-49), married or cohabiting was studied in Mwanza, Tanzania. A structured questionnaire with questions on knowledge, communication among the couples and practice of family planning was used. Descriptive statistics and Logistic regression were used to identify factors associated with family planning (FP) use at four levels. The findings showed that majority (73.2%) of respondents have not used family planning. Wealth was positive related to FP use (p=.000, OR = 3.696, and 95% C.I = 1.936 lower and upper 7.055). Religion was associated with FP use (p=.002, OR =2.802, 95% C.I = 1.476 lower and 5.321 upper), communication and FP use were significantly associated, (p=.000, OR = 0.323 and 95% C.I = 0.215) lower and upper = 0.483), social network and FP use (p=.000, OR = 2.162 and 95% C.I = 1.495 lower and upper =3.125) and knowledge and FP use(p=.000, OR = 2.224 and 95% C.I = 1.509 lower and upper =3.278). Wealth showed a significant association with FP use (p=.001, OR = 1.897, 95% C.I = 0.817 lower and 4.404).Urban area was positively associated with FP use (p= .000, OR = 0.008 and 95% C.I = 0.001 lower and upper =0.09), semi urban was significant at (p= .004, OR = 3.733 and C.I = 1.513 lower and upper =9.211). Information, education and communication materials and to promote family planning in Tanzania should designed and promoted. PMID- 24069769 TI - Impediments to media communication of social change in family planning and reproductive health: experiences from East Africa. AB - The media has been employed to increase uptake of Family Planning through behaviour change communication (BCC). Understanding the barriers encountered in effectively undertaking this function would increase the strategy's effectiveness. Sixty journalists from East Africa participated in trainings to enhance their BCC skills for Family Planning in which a qualitative study was nested to identify barriers to effective Family Planning BCC in the region's media. The barriers were observed to be insufficient BCC skills, journalists' conflict of interest, interests of media houses, inaccessible sources of family planning information, editorial ideologies and absence of commercially beneficial demand. Coupled with the historical ideologies of the media in the region, the observed barriers have precipitated ineffective family planning BCC in the regions media. Effective BCC for family planning in the regions media requires capacity building among practitioners and alignment of the concept to the media's and consumers' aspirations. PMID- 24069770 TI - Partner communication, discordant fertility goals, and contraceptive use in urban Kenya. AB - This study assesses the degree of partner communication and perceived partner concordance and their association with contraceptive use among 2,891 women and 1,362 men in urban Kenya. Twenty-three percent of men and 30% of women report never discussing FP with their partner. Approximately 70% of participants perceive their partner to have concordant fertility desires. Multivariate analyses revealed that both male (AOR = 7.7 [95% CI = 5.5-10.7]) and female (AOR = 2.8 [95% CI = 2.3-3.3]) participants were more likely to use contraception if they report discussing FP with their partner. Participants who perceive that their partner wants fewer children also were more likely to use contraception (AOR, females = 1.8 [95% CI = 1.2-2.8]), (AOR, males = 1.9 [95% CI = 1.2-3.1]). Discussion of FP is a key determinant of contraceptive use; in couples with discordant fertility goals, pro-natalist males do not always dictate contraceptive behavior in urban Kenya. PMID- 24069771 TI - Socio-economic and demographic factors affecting contraceptive use in Malawi. AB - Malawi has one of the highest Contraceptive Prevalence Rate (CPR) in Sub-Saharan Africa. However, fertility remains high and fertility decline is slow. This paper uses data from the 2000 and 2004 Demographic and Health Surveys to examine correlates of contraceptive use among currently married women in Malawi. Bivariate and multivariate logistic regression analyses were used to establish the relationships between socioeconomic variables and current use of contraception. The results show that the major determinants of contraceptive use are age, respondents' and partners' approval of family planning, family planning discussion with partner, number of living children, work status, education and visit to a health centre. As a policy measure, information, education and communication programmes on family planning should be intensified, particularly in rural areas and targeting men. PMID- 24069772 TI - Audit of maternal mortality ratio and causes of maternal deaths in the largest maternity hospital in Cairo, Egypt (Kasr Al Aini) in 2008 and 2009: lessons learned. AB - This study examined maternal deaths at Cairo University Maternity Hospital between January 2008 and December 2009. The aim was to calculate Maternal Mortality Ratio (MMR) as well as identify the causes and predisposing factors to maternal deaths. Data were collected from the files of the hospitalized pregnant women in the hospital. There were 38 maternal deaths and MMR was 79 per 100,000 live births for the two years examined. The main causes of death were obstetric hemorrhage, hypertensive disorders of pregnancy and cardiac arrest. Substandard medical care and the delay in seeking of medical advice were two contributing factors to maternal deaths recorded. The need for audit and publication of all obstetric hospitals MMR to compare and identify areas of improvements is recommended. PMID- 24069773 TI - Maternal risk factors for childhood anaemia in Ethiopia. AB - A total of 8260 children between the ages of 6-59 months were analyzed to identify the risk factors associated with childhood anaemia in Ethiopia. The overall mean (SD/standard deviation) haemoglobin (Hgb) level among the under-five children was 10.7 (2.2) g/dl and 50.3% were anaemic. Childhood anaemia demonstrated an increasing trend with maternal anaemia levels of mild, moderate and severe anaemia: odds ratio of 1.82, 2.16 and 3.73 respectively (p< 0.01). Children whose mothers had no formal education were 1.38 times more likely to be anaemic (p<0.01). The poorest and poorer wealth index groups had 1.52 and 1.25 increased odds of childhood anaemia respectively (p< 0.01). Childhood anaemia in Ethiopia is a severe public health problem. Maternal anaemia and socio-economic status were found to be associated with anaemia in children. A holistic approach of addressing mothers and children is of paramount importance. PMID- 24069774 TI - Causes and risk factors for maternal mortality in rural Tanzania--case of Rufiji Health and Demographic Surveillance Site (HDSS). AB - Complications of childbirth and pregnancy are leading causes of death among women of reproductive age. Developing countries account for 99% of maternal deaths. The aim of this study was to explore levels, causes and risk factors associated with maternal mortality in rural Tanzania. Longitudinal data (2002-2006) from Rufiji HDSS was used where a total of 26 427 women aged 15-49 years were included in the study; 64 died and there were 15 548 live births. Cox proportional hazards regression was used to assess the risk factors associated with maternal deaths. MMR was 412 per 100 000 live births. The main causes of death were haemorrhage (28%), eclampsia (19%) and puerperal sepsis (8%). An increased risk of 154% for maternal death was found for women aged 30-39 versus 15-19 years (HR=2.54, 95% CI=1.001-6.445). Married women had a protective effect of 62% over unmarried ones (HR=0.38, 95% CI=0.176-0.839). PMID- 24069775 TI - A shortened versus standard matched postpartum magnesium sulphate regimen in the treatment of eclampsia: a randomised controlled trial. AB - Magnesium sulphate is currently the most ideal drug for the treatment of eclampsia but its use in Nigeria is still limited due its cost and clinicians inexperience with the drug. The purpose of this study was to determine whether a shortened postpartum course of magnesium sulphate is as effective as the standard Pritchard regimen in controlling fits in eclampsia Between January and June 2011, 98 eclamptic mothers presenting at the labour ward of the University of Maiduguri Teaching Hospital were randomised to receive either the standard Pritchard regimen of magnesium sulphate or a shortened postpartum course in which only two doses of intramuscular magnesium sulphate is given four hours apart. The maternal and fetal outcomes were compared. The primary outcome measure was recurrence of fits. The recurrence of fits and other maternal complications were similar in the two groups. The total dosage of magnesium sulphate in the shortened group was reduced by 40% in 66% of patients. The shortened postpartum course of magnesium sulphate is as effective as the standard Pritchard regimen in the management of eclampsia. PMID- 24069777 TI - Patterns and correlates of condom use among unmarried male youths in Nigeria: NDHS 2008. AB - The HIV/STDs constitute public health problem. Condom use during sexual intercourse has been proved to be a good means of protection against HIV/STDs. Unmarried male youths which constitute a high proportion of Nigerians will be at risk of HIV/STDs if they fail to use condom. Reducing HIV/STDs in Nigeria will be difficult if research on condom use among youths is neglected. This retrospective cross-sectional design study utilized 2008 NDHS dataset. It focused on unmarried male youths aged 15-24 (n=1575) who ever had sexual intercourse (vaginal, oral and anal). The dependent variables were ever used and current use of condom. Data was analyzed using Chi-square and logistic regression (alpha=5.0%). Mean age of the respondent was 20.5 +/- 2.4, 62.0% ever used condom and 49.5% currently using condom. Among the sexually active; age, region, residence, education, wealth index, ever undergone HIV test and total life-time number of sexual partners were significantly associated with current use of condom. Living in the southern regions of Nigeria promotes the use of condom. The odds of ever use of condom was higher among male youths who were in the middle (OR=2.36; C.I=1.48-3.78), richer (OR=2.93; C.I=1.81-4.72) and richest (OR=3.52; C.I=2.07-6.00) wealth quintiles than the poorest. Ever undergone HIV test increased the likelihood of using condom. Condom use among unmarried male youths in Nigeria is low. Distribution of condom at no cost and undergoing HIV test will increase utilization of condom among unmarried male youths in Nigeria. PMID- 24069776 TI - Knowledge and perceptions of date rape among female undergraduates of a Nigerian university. AB - This paper focuses on knowledge and perceptions of Date Rape (DR) among female undergraduates of the University of Ibadan. The cross-sectional survey was conducted among 651 female undergraduates selected using a four-stage random sampling technique. A semi-structured questionnaire which included a 6-point knowledge scale and a 21-points perceptions scale was used to collect data. Knowledge scores of 0- 2, 3- 4 and 5- 6 were rated as poor, fair and good respectively. Perception scores of 0-10 and 11-21 were categorized as supportive and non-supportive perception of DR respectively. Data were analyzed using descriptive statistics and Chi-square at p < 0.05. Mean knowledge score was 2.3 +/- 2.1 and 50.0% participants had poor knowledge of DR. Knowledge of DR increased significantly by level of study. Participants' had a mean perception score of 9.1 +/- 2.8 and 66.9% had perceptions supportive of DR. Campus-based educational programme have potentials for addressing the phenomenon. PMID- 24069778 TI - Pregnancy, obstetric and neonatal outcomes in HIV positive Nigerian women. AB - While the effect of HIV infection on some maternal outcomes is well established, for some others there is conflicting information on possible association with HIV. In this study we investigated pregnancy and neonatal outcome of HIV positive women in large HIV treatment centre over a period of 84 months. They were managed according to the Nigerian PMTCT protocol. Adverse obstetric and neonatal outcome were observed in 48.3% HIV positives compared 30.3% to the negatives (OR: 2.08; CI: 1.84-2.34). Low birth weight ( OR:2.95; CI:1.95-3.1), preterm delivery (OR:2.05; CI:1.3-3.1), perinatal death (OR:1.9;CI:1.3-3.2), and spontaneous abortion (OR:1.37; CI:1.1-2.3) were factors found to be independently associated with HIV. Low CD4 count (OR: 2.45; CI: 1.34- 4.56) and opportunistic infections (OR: 2.11; CI: 1.56-3.45) were to be associated with adverse obstetric and neonatal outcome. This study confirms the association of HIV, severe immunosuppression and opportunistic infection and adverse obstetric and neonatal outcome. PMID- 24069779 TI - Predictors of risky sexual behaviour among young people in the era of HIV/AIDS: evidence from the 2008 Botswana AIDS Impact Survey III. AB - The objective of this study is to fill in that research gap by investigating factors that are likely to predict Botswana's young people's practicing risky sexual behaviour in the era of HIV/AIDS. Data used in this study were obtained from a nationally representative sample of 5,810 young people aged 15 to 29 who had completed an individual questionnaire of the 2008 Botswana AIDS Impact Survey III. Both descriptive and multiple regression analyses were used for analysis. Elevated odds ratio (OR) values were obtained from a linear model analysis, showing statistically significant predictors of risky sexual behaviour among young people who have experienced coerced sex (OR=2.2), substance use (OR=1.8), having had sex before the age of 15 (OR=1.9), being older (OR=1.1) and lack of sexual self-efficacy (OR=1.6). Therefore risk reduction strategies aimed at addressing these potential problems should target young people before they enter adolescence and should develop gender-specific strategies. PMID- 24069780 TI - Breast cancer micrometastasis--a mortality abstract. AB - This article presents an analysis of a survival study involving women with a history of breast cancer and either no nodal metastases, nodal micrometastases or nodal macrometastases, for the purpose of determining approximate life insurance ratings. In addition, a modification to the traditional method of determining the mortality rates of a comparison population is presented. PMID- 24069781 TI - Associations between selected laboratory tests and all-cause mortality. AB - OBJECTIVE: Evaluate the association of selected laboratory tests including liver function, kidney function, bilirubin, and albumin, with all-cause mortality METHOD: Associations between several laboratory tests and mortality were assessed in two longitudinal datasets: (1) the Third National Health and Nutritional Examination Survey (NHANES III) with 4610 deaths during the 240,428 person-year follow up: and (2) a life insurance dataset containing historical life insurance policies issued as standard and better risk class, with 837 death claims generated during the approximate 1.4 million person-years of follow up. A Cox proportional hazards model was used to compute the hazard ratio of each selected laboratory test while adjusting for age, gender, and other health conditions. Separate analyses were conducted for laboratory results within and beyond the respective normal clinical range. RESULTS: When outside the normal clinical range, the results of several selected laboratory tests were associated with higher mortality, as indicated by a hazard ratio greater than 1. Comparisons of hazard ratios when laboratory results were within the normal range demonstrated that blood albumin and blood urea nitrogen (BUN) were both negatively associated with mortality and alkaline phosphatase (AP) was positively associated with mortality. The associations were shown to be independent and were consistent in two datasets. CONCLUSIONS: Although abnormal laboratory results are significant predictors of higher mortality, when results fall within the normal clinical range, only three tests--albumin, AP, and BUN--provided mortality differentiation. These findings support the utilization of the actual, continuous value from albumin, AP, and BUN tests to evaluate mortality during underwriting, even when these results are categorized as clinically normal. Furthermore, the results provide an insightful perspective for evaluating the utility of recently developed, laboratory test-based underwriting toools. PMID- 24069782 TI - The Collaborative Ocular Melanoma Study, mortality by therapeutic approach, age and tumor size. AB - OBJECTIVES: Determine the mortality ratios and excess deaths associated with the two therapeutic options for both the small and the large tumor groups and for subsets of age and tumor size within each group as presented in the Collaborative Ocular Melanoma Study (COMS). METHODS: Mortality ratios and excess deaths are determined using standard mortality methodology. Expectant mortality is determined from appropriate general population life mortality tables. RESULTS: The smaller tumor group comparing brachytherpy to enucleation revealed similar mortality ratios (MR) of 134% and 137% for each treatment approach and respective Total Excess Deaths per Thousand (Total ED/K) of 131 and 128. The larger tumor group comparing results of pre-enucleation radiation therapy (PERT) followed by enucleation to enucleatic alone revealed respective mortality ratios of 291% and 305% and Total ED/K of 520 and 547. Those over 60 years of age having a maximum basal tumor diameter (MBTD) < or = 11 mm had MR = 101% and Total ED/K = 26, the best mortality experience in the study. Those over 60 years of age had better relative mortality, depending on the MBTD, when compared to the younger group. CONCLUSIONS: Mortality associated with ocular melanoma does not vary according to whether brachytherapy (smaller melanomas) or PERT followed by enucleation (larger melanomas) is used vs simple enucleation. Mortality increases as the MBTD increases. PMID- 24069783 TI - Recent advances in cardiac stress testing. PMID- 24069784 TI - Malignant neoplasm related mortality and morbidity of hypertensive outpatients in Japanese men and women. AB - OBJECTIVES: To investigate the cause of reduced malignant neoplasm-related mortality in hypertensive outpatients. BACKGROUND: In previous studies, hypertensive outpatients have had modest improvement in overall mortality rate as compared with standard risk groups. While excessive mortality rates for cardiovascular disease and stroke were evident in hypertensive outpatients, the mortality rate of malignant neoplasm was greatly reduced. METHODS: Using database systems of Sumitomo Life Insurance Co, Japan, standard life tables were generated, and ratios or rates for mortality and morbidity of hypertensive outpatients were extrapolated and analyzed. RESULTS: The mortality ratio of all cancers was significantly low, 85% (95% CI: 77%-93%), and the morbidity ratio was significantly increased, 121% (95% CI: 109%-133%). The mortality ratio of each of categorized malignant neoplasm was below 100% except for colorectal cancer (111%, 95% CI: 83%-138%). The mortality ratios of stomach cancer (56%, 95% CI: 41%-72%) and liver cancer (52%, 95% CI: 32%-80%) were significantly decreased. The morbidity ratios of colorectal cancer, breast cancer, esophageal cancer, and others were over 100%, and was statistically significant in colorectal cancer (140%, 95% CI: 112%-167%) and others (139%, 95% CI: 113%-165%). The differences between the mortality ratio and the morbidity ratio of stomach cancer and others were statistically significant. The relative lethality of all but pancreatic cancer and leukemia were less than 1.0, and there was a positive correlation between the general prognosis of each cancer and the relative lethality. CONCLUSIONS: The decreased malignant neoplasm-related mortality ratio in hypertensive outpatients was indicative of an improved prognosis and likely benefited from close medical surveillance. PMID- 24069785 TI - Brief case report: dopa-responsive dystonia. AB - A 42-year-old female applied for life insurance. She was diagnosed with dopa responsive dystonia as a child. Just prior to applying for insurance, she attempted to go off her carbidopa-levodopa resulting in increased symptoms of stiffness with some imbalance. Her neurologist advised her to restart her Sinemet and titrate dosages to maintain her best function. The diagnosis and risks are discussed. PMID- 24069786 TI - A drop dead healthy ECG. AB - The diagnostic and risk stratification implications of a borderline electrocardiogram, which could be a normal variant or a marker for sudden cardiac death, are explored. PMID- 24069787 TI - Castleman's disease. PMID- 24069788 TI - Emergency preparednes: Managing crisis in the community during Hurricane Sandy. PMID- 24069789 TI - Home care emergency response: Hurricane Sandy lessons learned and actions taken. PMID- 24069790 TI - Home care responds to the Boston Marathon bombing. PMID- 24069791 TI - As long-term care insurers abandon the marketplace, what other options will appear? AB - Less than 20 years ago there were more than 100 major insurance companies selling long-term care insurance (LTCi). Today there are less than 30. Home care providers stood to be one of the primary recipients of LTCi payments for their services, but there's a paradox at work. Just as the baby boomers started turning 65 at a pace of 10,000 per day, the LTCi market is shrinking instead of "booming." PMID- 24069792 TI - Nurses take center stage in private duty home care. AB - The Affordable Care Act gives America's largest group of health care providers- nurses--a unique chance to lead in improving outcomes, increasing patient satisfaction, and lowering costs. Nurses' roles continue to grow in settings from hospitals and long-term care facilities to home health and hospice agencies. Nurses are also key players in private duty home care, where they serve as care coordinators for clients. Working directly with doctors, therapists, in-home caregivers, and families, nurses are critical in delivering quality, seamless in home care. PMID- 24069793 TI - Understanding hospital observation status and bringing those patients home. PMID- 24069794 TI - Beyond basic Medicare: Understanding Medicare supplemental coverage. PMID- 24069795 TI - Decorating: the last touch. PMID- 24069796 TI - Managing your loved one from a distance. PMID- 24069797 TI - How to help abandoned seniors. PMID- 24069798 TI - Congress can't cut our caring attitude. PMID- 24069799 TI - Shrink bot. PMID- 24069800 TI - Breaking the bond. PMID- 24069802 TI - A profession to honor. PMID- 24069801 TI - Dream, inspire and make things happen. PMID- 24069803 TI - Hope is not a strategy. PMID- 24069804 TI - Lost major donors. PMID- 24069805 TI - Teaching physicians grateful patient fundraising. PMID- 24069806 TI - Community benefit: friend or foe? PMID- 24069807 TI - A cute, cuddly squirrel leads to a great idea. PMID- 24069808 TI - Human biometeorology. PMID- 24069809 TI - The role of duodenogastric reflux in formation of precarcinogenic gastric lesions -an experimental study. AB - INTRODUCTION: Duodenogastric reflux, commonly encountered as an aftermath of gastroenteroanastomosis, with or without gastric resection (Billroth I, Billroth II), vagotomy and pyloroplastic surgery, is known to cause inflammatory dystrophic-metaplastic lesions of gastric mucosa. Our objective was to determine the effects of surgery-induced duodenogastric reflux on the development of precarcinogenic lesions or carcinoma in correlation with the reflux duration. MATERIAL AND METHODS: The experiment was performed on three groups of Wistar rats with 1) Billroth II-induced reflux surgery, 2) resection of the Rouxr-en-Y type reconstruction, and 3) control group with no resection. The aim of the experiment was to study the effects ofduodenogastric reflux on the rat gastric mucosa in correlation with two different types of gastroenteroanastomosis 8, 16 and 24 weeks after the surgery. RESULTS: In Billroth II group, hyperplastic changes were observed as early as in week 16. Statistically significant results were recorded in week 24, with 6.7% of metaplastic alterations, including dysplasia of all three degrees, dominantly severe dysplasia in 66.67%, early carcinoma in 20% and gastric carcinoma in 6.67%. In the Roux-en-Y group, gastric mucosa remained predominantly normal (60%), with somewhat increased frequency ofgastritis and dysplasia in week 24. In the control group, the finding of normal gastric mucosa was constant. CONCLUSION: The experiment confirms that direct contact of duodenal juice with gastric mucosa associated with Billroth II resection causes precarcinogenic lesions. Development of adenocarcinoma caused solely by duodenogastric reflux, excluding a carcinogenic agent is possible 20 weeks after the experiment--earlier than suggested by previous researchers. PMID- 24069810 TI - [Diagnostic efficacy of biophysical tests and cerebral-umbilical index when assessing fetal oxygenation]. AB - INTRODUCTION: Perinatal morbidity and mortality are the ultimate indicators of antenatal care today, whose responsible task is to assess the respiratory function of the placenta, fetal growth and placental maturation in order to provide conditions for the delivery of a living and viable newborn. The diagnostic procedures of antenatal care tested within this study were the biophysical tests of cardiotocography and the fetal biophysical profile, along with the colour doppler evaluation of the cerebral-umbilical ratio. The objective of this study was to determine the most effective diagnostic procedure when assessing fetal oxygenation. MATERIALS AND METHODS: The prospective study included 119 pregnant women. They all underwent cardiotocography, biophysical profile and colour doppler evaluation of the cerebral-umbilical ratio. The babies' umbilical artery blood pH was determined in the first minute upon birth, along with the Apgar score. RESULTS: The results were processed statistically and the most effective diagnostic procedure for the evaluation of fetal oxygenation was selected, after which the rates of perinatal morbidity and mortality were calculated. The findings revealed that cardiotocography was the most sensitive antepartal predictor of fetal acidosis, while the fetal biophysical profile proved the most specific. The rates of perinatal morbidity and of perinatal mortality were 24.37% and 1.68%, respectively. CONCLUSION: The findings analysis revealed a high statistical significance of both biophysical tests and the cerebral-umbilical ratio evaluation as predictors of the fetal distress syndrome. The analysis of the cerebral-umbilical ratio and biophysical tests showed that the cerebral-umbilical ratio evaluation not only was more sensitive as a parameter compared to biophysical tests but it was also more specific than cardiotocography. Cardiotocography is the most sensitive antepartal predictor of fetal acidosis, followed by the cerebral-umbilical ratio, and the biophysical profile as the least sensitive. The biophysical profile proved to be the most specific, followed by the cerebral-umbilical ratio, and cardiotocography as the least specific. PMID- 24069811 TI - [Pathophysiological mechanisms of angiogenesis in atherogenesis]. AB - INTRODUCTION: Atherosclerosis is a progressive, multifactorial, diffuse, multisystemic, chronic, inflammatory disease, which is manifested by disorders of vascular, immune and metabolic system. Pathogenesis of this disease is not fully understood. Accordingly, angiogenesis represents a special field of research due to its role in atherogenesis. STEPS OF ANGIOGENESIS: Angiogenesis is a complex biological process, which requires the precise coordination of its four steps (vasodilatation and permeability, vessel destabilization and matrix degradation, endothelial cell proliferation and migration, and lumen formation and vessel stabilization). MEDIATORS OF ANGIOGENIC PROCESS: The process of forming new blood vessels is regulated by a delicate balance between proangiogenic and antiangiogenic molecules. Numerous soluble growth factors and inhibitors, cytokines, proteases, extracellular matrix proteins and adhesion molecules, as well as hypoxia, inflammatory process, shear stress, hypertension and interaction between cells and extracellular matrix strictly control the angiogenic process. Neovascularization is halted due to the downregulation of angiogenic factors or the increase of inhibitors of this process. TUMOR VASCULARIZATION: In the asymptomatic phase of cancerogenesis, cancer rarely exceeds the diameter of 1-2 millimeters. However, when the metabolic demand increases, it leads to tumor vascularization. In this way, tumor switches to an angiogenic phenotype. The molecular basis of angiogenic switch refers to increased production of angiogenic factors and/or loss of angiogenic inhibitors. CONCLUSION: The contribution of angiogenic process has become increasingly meaningful in understanding the pathogenesis ofatherosclerosis. PMID- 24069812 TI - [Peritonealization in gynecologyand obstetrics--review of literature]. AB - INTRODUCTION: Our purpose was to review the literature on the subject of peritoneal closure and to evaluate the advantages and disadvantages of this procedure. EXPERIMENTAL STUDIES: Experimental studies have proved that peritoneal defects demonstrate mesothelial integrity (reperitonealization) 48-72 hours after injury and gross healing occurs within five days. A foreign body in the peritoneum causes tissue ischemia, necrosis, inflammation, and it stimulates numerous and dense adhesions. SURGERY (GENERAL AND GYNECOLOGICAL): The major advantage of peritoneal non-closure is a decreased adhesion formation, quicker return of bowel activity and reduced risk of bowel obstruction after surgery. Not only does peritoneal closure provide no immediate postoperative benefits, but it also prolongs surgical time, exposure to anesthesia and post-operative hospital stay unnecessarily, thus increasing surgery expenses. In summary, the existing data do not show advantages of this technique. Since many surgical tenets are based on limited data or opinion of the individual surgeons, they should be changed according to evidence-based medicine. CONCLUSION: Therefore, we suggest that the traditional practice of peritoneal closure be abolished in gynecology and obstetrics. It is our strong wish to encourage clinicians not to close both parietal and visceral peritoneum. PMID- 24069813 TI - Necessity for introducing the procedure of percutaneous aortic valve implantation in the province of Vojvodina. AB - INTRODUCTION: Percutaneous aortic valve implantation is an alternative that offers hope to patients who are too old or sick to undergo the conventional surgical aortic valve replacement. The aim of this study was to determine the number of high-risk patients with severe aortic stenosis, hospitalized at the Institute for Cardiovascular Diseases, who are the candidates for percutaneous aortic valve implantation. MATERIAL AND METHODS: The paper prospectively analyzed all patients diagnosed to have severe aortic stenosis who had been hospitalized at the Institute for Cardiovascular Diseases from April 1st, 2011 to October 31st, 2012. Each of these patients was analyzed in relation to the inclusive criteria for percutaneous aortic valve implantation. We analyzed the distribution of these risk factors in relation to age and gender, and the presence of aortic valve replacement surgery by age groups. RESULTS: In the period from April 1st, 2011 to October 31st, 2012, 374 patients diagnosed to have severe aortic stenosis were hospitalized at the Institute for Cardiovascular Diseases. The group of patients older than 80 years had a higher percentage of those patients with low ejection fraction of the heart, chronic pulmonary hypertension and mitral regurgitation. On the other hand, when the total number of surgical aortic valve replacement was taken into consideration with respect to age, there was a significant decrease in their number in the group of patients older than 75 years (41.6%), especially in the age group over 80 years (90.2%). CONCLUSION: The data obtained in this study indicate a high percentage of conservatively treated patients with severe aortic stenosis and high operative risk in patients over 75 years. These data confirm the necessity for the implementation of percutaneous aortic valve replacement in the Province of Vojvodina. PMID- 24069814 TI - [The importance of immunohematology testing in the neonatal period]. AB - INTRODUCTION: In order to diagnose hemolytic disease of the newborn it is necessary to determine ABO/Rh blood group, direct antiglobulin test and indirect antiglobulin test in newborns as well as ABO/Rh and indirect antiglobulin test in their mothers due to a possible incompatibility between the blood types of the mother and her baby. The study was aimed at reviewing and analyzing the results of screening of the newborns and pregnant women on the territory of South Backa District during 2011, as well as at estimating the necessity to give blood transfusion to the newborns in the same period. MATERIAL AND METHODS: Data obtained from the information system and protocol of the Institute for Blood Transfusion of Vojvodina were used in a retrospective analysis of screening of newborns and pregnant women. RESULTS: Blood samples taken from 3313 newborns were tested and the following distribution of the ABO blood types was recorded: O in 45.6%, A in 35%, B in 15.9%, AB in 3.5%; 78.9%, newborns were found to be D positive, 21.1% were D-negative. The direct antiglobulin test was positive in 165 (4.9%) cases, it was weakly positive +/- in 85 (51.5%), positive 1+ in 45 (27.3%), positive 2+ in 17 (10.3%), positive 3+ in 12 (7.3%), positive 4+ in 6 (3.6%). In all cases, the monospecific direct antiglobulin test was positive with IgG antibodies. Of four newborns with positive direct antiglobulin test who required exchange blood transfusion, two had RhD incompatibility and two had ABO incompatibility. Blood samples of 3429 (100%) women were tested and 36 (1.05%) were actively immunized: 23 (0.67%) to RhD antigen, 8 (0.23%) to blood group antigens other than ABH and Rh, specificity could not be determined in 5 (0.15%). Anti-D antibodies were found in 19 (0.55%) pregnant women, in two (0.06%) cases newborns required exchange blood transfusion. CONCLUSION: Testing neonates and pregnant women contributes to the detection of blood type incompatibility between the mother and her child; it provides an opportunity for clinicians to implement the adequate prevention of RhD alloimmunization as well as to make timely diagnosis and to introduce treatment of hemolytic disease in newborns. PMID- 24069815 TI - [Epidemiology of lower jaw fracture in patients treated at the Department of Maxillofacial and Oral Surgery of the Clinical Centre of Vojvodina]. AB - INTRODUCTION: The position and prominence are the reasons why the lower jaw is one of the most commonly injured facial bones. MATERIAL AND METHODS: A retrospective study was conducted to analyze medical records of patients who had been treated at the Department of Maxillofacial and Oral Surgery in the period from January 1st, 1998 to December 31st, 2012. These data included patients' age and gender, mechanism of injury, anatomic localization of the fracture, associated injuries and treatment of fractures. RESULTS: Out of 630 treated patients, 531 were men (84.3%) and 99 were women (15.7%). The highest incidence of the lower jaw fractures was found in the age group 21-30 years (36.2%) and the lowest in the age group over 70 years (1.1%). The most common causes, of injuries were physical assault (47.3%), followed by traffic accidents (24.3%) and falls (20.8%). Most patients referred to our Department were treated non-surgically 436 (69.2%), 165 of them (26.2%) were treated surgically, whereas in 29 patients (4.6%) none of the above treatments was performed. DISCUSSION AND CONCLUSION: This study has shown that fractures of the lower jaw are mainly found in men aged 21-30 years. The obtained statistical data could certainly be used to establish the health system that would allow better prevention of these injuries, and the possibility of an adequate and effective treatment modality. PMID- 24069816 TI - [Surgical anatomy of the initial segment of the lateral circumflex femoral artery]. AB - INTRODUCTION: The lateral circumflex femoral artery usually originates from the lateral side of the initial part of the deep femoral artery, or less frequently from the femoral artery. If it is a branch of the femoral artery, it arises directly above the point of origin of the deep femoral artery. The aim of this study was to determine the origin of the lateral circumflex femoral artery, its origin distance from the midpoint of the inguinal ligament and the topographical relations of the origin, which have a great significance in clinical work. MATERIAL AND METHODS: A dissection was performed on the autopsy group of 42 thighs, followed by the analysis of anatomical relationships of the lateral circumflex femoral artery. All data were entered into the custom-made protocol, which contained the case number, age and sex, side, topographical-anatomical relations of the lateral circumflex femoral artery, artery dimensions and variations, and the distance between the place of origin of the lateral circumflex femoral artery and the midpoint of the inguinal ligament. RESULTS: In our study, the lateral circumflex femoral artery most frequently originated from the deep femoral artery, i.e. in 78.6% of cases. In 19.0% of limbs, it originated from the femoral artery, and in one case (2.4%) from a common stem of the deep femoral artery and the lateral circumflex femoral artery, coming from the femoral artery. CONCLUSION: In clinical practice, it is of great importance to know the origin variations of the lateral circumflex femoral artery while planning and performing various surgical and invasive diagnostic procedures in the inguino femoral region. PMID- 24069817 TI - [Rare blood donors with irregular antibodies]. AB - INTRODUCTION: Blood groups are inherited biological characteristics that do not change throughout life in healthy people. Blood groups represent antigens found on the surface of red blood cells. Kell blood group system consists of 31 antigens. Kell antigen (K) is present in 0.2% of the population (the rare blood group). Cellano antigen is present in more than 99% (the high-frequency antigen). These antigens have a distinct ability to cause an immune response in the people after blood transfusion or pregnancy who, otherwise, did not have them before. CASE REPORT: This paper presents a blood donor with a rare blood group, who was found to have an irregular antibody against red blood cells by indirect antiglobulin test. Further testing determined the specificity of antibody to be anti-Cellano. The detected antibody was found in high titers (1024) with erythrocyte phenotype Kell-Cellano+. The blood donor was found to have a rare blood group KellKell. This donor was excluded from further blood donation. It is difficult to find compatible blood for a person who has developed an antibody to the high-frequency antigen. The donor's family members were tested and Cellano antigen was detected in her husband and child. A potential blood donor was not found among the family members. There was only one blood donor in the Register of blood donors who was compatible in the ABO and Kell blood group system. CONCLUSION: For the successful management of blood transfusion it is necessary to establish a unified national register of donors of rare blood groups and cooperate with the International Blood Group Reference Laboratory in Bristol with the database that registers donors of rare blood groups from around the world. PMID- 24069818 TI - Virtual simulation as a learning method in interventional radiology. AB - INTRODUCTION: Radiology is the fastest growing discipline of medicine thanks to the implementation of new technologies and very rapid development of imaging diagnostic procedures in the last few decades. On the other hand, the development of imaging diagnostic procedures has put aside the traditional gaining of experience by working on real patients, and the need for other alternatives of learning interventional radiology procedures has emerged. A new method of virtual approach was added as an excellent alternative to the currently known methods of training on physical models and animals. Virtual reality represents a computer generated reconstruction of anatomical environment with tactile interactions and it enables operators not only to learn on their own mistakes without compromising the patient's safety, but also to enhance their knowledge and experience. DISCUSSION: It is true that studies published so far on the validity of endovascular simulators have shown certain improvement of operator's technical skills and reduction in time needed for the procedure, but on the other hand, it is still a question whether these skills are transferable to the real patients in the angio room. CONCLUSION: With further improvement of technology, shortcomings of virtual approach to interventional procedures learning will be less significant and this procedure is likely to become the only method of learning in the near future. PMID- 24069819 TI - Treatment of chronic hepatitis C in injecting drug users--a 5-year follow-up. AB - BACKGROUND/AIM: Hepatitic C infection (HCV) is a systemic, generalised disease with the prevalence of inflammation in the liver. The aim of this study was to determine the success of treatment for chronic hepatitis C with pegilated interferon alfa 2a and ribavirin in injecting drug users. METHODS: This a 5-year follow-up study included 30 patients [63.3% men and 36.7% women, average age 30.2 years (SD 7.1 years)] injecting drug users in one-year abstinence, with chronic hepatitis C, treated with the pegilated interferon alpha 2a and ribavirin. Complete history with possible route of infection, the standard biochemical tests, liver biopsy, quantification of the viral genome in sera and HCV genotyping and subtyping were done prior to the therapy initiation. Depending on the HCV genotype, the therapy was conducted over a period of 48 weeks for genotype 1 and 24 weeks for genotype non 1. Five years later all 30 patients were invited on control examination; 22 of them appeared at the check-up and quantification of the viral genome in their sera were analized. RESULTS: The established degree of liver fibrosis was: F0 in 40%, F1 in 23.33%, F2 in 26.67%, F3 in 3.33% and F4 in 6.67% of the patients. Genotype 3a was dominant (50.0%), 1b was registered in 40.0%, 1a in 6.66% and 2b in 3.33% of the patients. Sustained virologic response (SVR) was achieved in 86.7% of the patients, 10.0% of the patients were non-responders, while 3.33% of them revealed recurrence of HCV. Opiate abuse recurrence during antiviral therapy happened in 6.7% of the patients. Five years after the antiviral therapy 73.3% of the patients appeared at the check-up and all of them were in stable abstinence from opiate abuse. All of those, with a sustained viral response of five-year duration, had the negative PCR HCV RNA test (< 50 IU ml(-1)). In the patients showing unsatisfactory therapy response 5 years before, antiviral therapy was repeated by the same therapeutic regimen, but without adequate therapeutic response. A total of 26.7% of the patients were lost from the records. CONCLUSION: In a 5-year follow-up period 73.3% of the patients used to come regularly to check-ups and among them neither the opiate abuse recurrence nor HCV infection recurrence were registered. PMID- 24069820 TI - Correlation of N-terminal pro-B-type natriuretic peptide with clinical parameters in patients with hypertension. AB - BACKGROUND/AIM: Identification of patients with arterial hypertension and a possible onset of heart failure by determining the concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) enables timely intensification of treatment and allows clinicians to prescribe and implement optimal and appropriate care. The aim of this study was to evaluate NT-proBNP in patients with longstanding hypertension and in patients with signs of hypertensive cardiomyopathy. METHODS: The study involved 3 groups, with 50 subjects each: "healthy" persons (control group), patients with hypertension and normal left ventricular systolic function (group 1) and patients with longstanding hypertension and signs of hypertensive cardiomyopathy with impaired left ventricular systolic function (group 2). We measured levels of NT-proBNP, C reactive protein and creatinine according to the manufacturer's instructions. All the patients were clinically examined including physical examination of the heart with blood pressure, pulse rate, electrocardiogram (ECG) and echocardiogram. RESULTS: Our results showed that the determined parameters generally differed significantly (Student's t-test) among the groups. The mean (+/- SD) values of NT proBNP in the control group, group 1 and group 2 were: 2.794 (+/- 1.515) pmol/L, 9.575 (+/- 5.449) pmol/L and 204.60 (84,93) pmol/L, respectively. NT-proBNP correlated significantly with the determined parameters both in the group 1 and the group 2. In the group 1, the highest correlation was obtained with C-reactive protein (r = 0.8424). In the group 2, the highest correlation was obtained with ejection fraction (r = -0.9111). NT-proBNP showed progressive increase in proportion to the New York Heart Association (NYHA) classification. The patients in the- group 2 who belonged to the II and III NYHA class had significantly higher levels of NT-proBNP than those in the NYHA class I (ANOVA test, p = 0.001). CONCLUSION: The obtained results suggest that NT-proBNP is a useful biomarker in the treatment of patients with longstanding hypertension who are at risk for heart failure. PMID- 24069821 TI - Radiotherapy treatment planning: benefits of CT-MR image registration and fusion in tumor volume delineation. AB - BACKGROUND/AIM: Development of imaging techniques, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), made great impact on radiotherapy treatment planning by improving the localization of target volumes. Improved localization allows better local control of tumor volumes, but also minimizes geographical misses. Mutual information is obtained by registration and fusion of images achieved manually or automatically. The aim of this study was to validate the CT-MRI image fusion method and compare delineation obtained by CT versus CT-MRI image fusion. METHODS: The image fusion software (XIO CMS 4.50.0) was applied to delineate 16 patients. The patients were scanned on CT and MRI in the treatment position within an immobilization device before the initial treatment. The gross tumor volume (GTV) and clinical target volume (CTV) were delineated on CT alone and on CT+MRI images consecutively and image fusion was obtained. RESULTS: Image fusion showed that CTV delineated on a CT image study set is mainly inadequate for treatment planning, in comparison with CTV delineated on CT-MRI fused image study set. Fusion of different modalities enables the most accurate target volume delineation. CONCLUSION: This study shows that registration and image fusion allows precise target localization in terms of GTV and CTV and local disease control. PMID- 24069822 TI - Long-term graft occlusion in aortobifemoral position. AB - BACKGROUND/AIM: Aortobifemoral (AFF) bypass is still the most common surgical procedure used in treatment of aortoiliac occlusive disease. One of the most common complications of AFF bypass procedure is long-term graft oclussion. The aim of this study was to determine the cause of long-term graft occlusion in AFF position, as well as the results of early treatment of this complication. METHODS: This retrospective study, performed at the Clinic of Vascular and Endovascular Surgery, Clinical Center of Serbia in Belgrade, involved 100 patients treated for long-term occlusion of bifurcated Dacron graft which was ensued at least one year after the primary surgical pro cedure. RESULTS: The most common cause of the long-term graft occlusion was the process at the level of distal anastomosis or below it (Z = 3.8, p = 0.0001). End-to-end type of proximal anastomosis has been associated with a significantly increased rate of long-term graft occlusion (Z = 2.2, p = 0.0278). Five different procedures were used for the treatment of long-term graft occlusion: thrombectomy and distal anastomosis patch plasty (46% of the cases); thrombectomy and elongation (26% of the cases); thrombectomy and femoropopliteal bypass (24% of the cases); crossover bypass (2% of the cases) and a new AFF bypass (2% of the cases). The primary early graft patency was 87%. All 13 early occlusions occurred after the thrombectomy associated with patch plasty of distal anastomosis. Thrombectomy with distal anastomosis patch plasty showed a statistically highest percentage of failures in comparison to thrombectomy with graft elongation, or thrombectomy with femoro popliteal bypass (Z = 2 984, p = 0.0028). Redo procedures were performed in all the cases of early occlusions. In a 30-day follow-up period after the secondary surgery, 90 (90%) patients had their limbs saved, and above knee amputation was made in 10 (10%) patients. CONCLUSION: Long-term AFF bypass patency can be obtained by proximal end-to-end anastomosis on the juxtarenal part of aorta and distal anastomosis on the bifurcation of the common femoral, or on the deep femoral artery. PMID- 24069823 TI - The role of hysteroscopy in diagnosis and treatment of postmenopausal bleeding. AB - BACKGROUND/AIM: Abnormal uterine bleeding is the most common problem which brings woman to the gynecologist during the postmenopausal period. The aim of this study was to define the significance of hysteroscopy as a diagnostic procedure for the evaluation of patients with postmenopausal bleeding, as well as to define it as a surgical procedure by which the cause of bleeding can be treated in most cases in the same sitting. METHODS: The study involved 148 female patients referred to the Clinic for Gynecology and Obstetrics in Nis for postmenopausal bleeding in the period of 12 months. Hysteroscopy with endometrial biopsy were performed in all the patients. Biopsy materials were directed to histological examination, and the hysteroscopic and histological findings were compared afterwards. Polyps and submucous miomas were hysteroscopically removed in the same sitting and also directed to histological examination. RESULTS: The success rate of the method was 95.1%, while complications occurred in 1.37% of the cases. The hysteroscopic findings were normal in almost 30% of the cases, and the most common pathological finding was endometrial polyp. The sensitivity of hysteroscopy in the detection of intrauterine pathology was 100%, the specificity 81%, the positive predictive value 92% and the negative predictive value 100%. In 69.7% of the patients the cause of bleeding was hysteroscopically removed. Hysteroscopy was performed in 58.1% of the patients in the same sitting, and in 11.6% of the patients after obtaining histological findings. CONCLUSION: Hysteroscopy is a safe, highly sensitive diagnostic procedure, thus being an ideal method for evaluation of patients with postmenopausal bleeding. The application of hysteroscopy with endometrial biopsy leads to accurate diagnosis. An adequate diagnosis is crucial for the selection of relevant treatment of postmenopausal bleeding and avoidance of unnecessary major surgical procedures. Except for being a diagnostic method hysteroscopy, is also an outpatient minimally invasive surgical procedure for treating the cause of bleeding in the majority of cases in the same sitting. PMID- 24069824 TI - Environmental lead pollution and its possible influence on tooth loss and hard dental tissue lesions. AB - BACKGROUND/AIM: Environmental lead (Pb) pollution is a global problem. Hard dental tissue is capable of accumulating lead and other hard metals from the environment. The aim of this study was to investigate any correlation between the concentration of lead in teeth extracted from inhabitants of Pancevo and Belgrade, Serbia, belonging to different age groups and occurrence of tooth loss, caries and non-carious lesions. METHODS: A total of 160 volunteers were chosen consecutively from Pancevo (the experimental group) and Belgrade (the control group) and divided into 5 age subgroups of 32 subjects each. Clinical examination consisted of caries and hard dental tissue diagnostics. The Decayed Missing Filled Teeth (DMFT) Index and Significant Caries Index were calculated. Extracted teeth were freed of any organic residue by UV digestion and subjected to voltammetric analysis for the content of lead. RESULTS: The average DMFT scores in Pancevo (20.41) were higher than in Belgrade (16.52); in the patients aged 31 40 and 41-50 years the difference was significant (p < 0.05) and highly significant in the patients aged 51-60 (23.69 vs 18.5, p < 0.01). Non-carious lesions were diagnosed in 71 (44%) patients from Pancevo and 39 (24%) patients from Belgrade. The concentrations of Pb in extracted teeth in all the groups from Pancevo were statistically significantly (p < 0.05) higher than in all the groups from Belgrade. In the patients from Pancevo correlations between Pb concentration in extracted teeth and the number of extracted teeth, the number of carious lesions and the number of non-carious lesions showed a statistical significance (p < 0.001, p < 0.01 andp < 0.001, respectively). CONCLUSION: According to correlations between lead concentration and the number of extracted teeth, number of carious lesions and non-carious lesions found in the patients living in Pancevo, one possible cause of tooth loss and hard dental tissue damage could be a long-term environmental exposure to lead. PMID- 24069825 TI - Blunt trauma of bone structures of the chest--computed tomography vs multidetector computed tomography. AB - BACKGROUND/AIM: Computerized tomography (CT), especially multidetector CT (MDCT), has had a revolutionary impact in diagnostic in traumatized patients. The aim of the study was to identify and compare the frequency of injuries to bone structures of the thorax displayed with 5-mm-thick axial CT slices and thin-slice (MDCT) examination with the use of 3D reconstructions, primarily multiplanar reformations (MPR). METHODS: This prospective study included 61 patients with blunt trauma submitted to CT scan of the thorax as initial assessment. The two experienced radiologists inde pendently and separately described the findings for 5-mm-thick axial CT slices (5 mm CT) as in monoslice CT examination; MPR and other 3D reconstructions along with thin-slice axial sections which were available in modern MDCT technologies. After describing thin-slice examination in case of disagreement in the findings, the examiners redescribed thin-slice examination together which was ultimately considered as a real, true finding. RESULTS: No statistically significant difference in interobserver evaluation of 5 mm CT examination was recorded (p > 0.05). Evaluation of fractures of sternum with 5 mm CT and MDCT showed a statistically significant difference (p < 0.05) in favor of better display of injury by MDCT examination. CONCLUSION: MDCT is a powerful diagnostic tool that can describe higher number of bone fractures of the chest in traumatized patients compared to 5 mm CT, especially in the region of sternum for which a statistical significance was obtained using MPR. Moreover, the importance of MDCT is also set by easier and more accurate determination of the level of bone injury. PMID- 24069826 TI - Pseudoexfoliation syndrome. PMID- 24069827 TI - News in the pathophysiology of asthma. PMID- 24069828 TI - Treatment options for childhood medulloblastoma. PMID- 24069829 TI - Primary nasal tuberculosis: a case report. AB - INTRODUCTION: During the past two decades, tuberculosis (TBC) both pulmonary and extrapulmonary, has emerged to be a major health problem. Nasal tuberculosis is a specific inflammatory process which is, in most cases, joined by the inflammation of neck lymph nodes. CASE REPORT: Thirty-year-old man presented with shortness of breath through the nose and periodical headaches. Clinical examination showed signs of chronic rhinitis, with slight granular changes of nasal septal mucosa. Laboratory analyses were within the reference ranges. Nasal and throat swabs for bacteria and fungi were normal. Skin allergy testing to standard inhalatory allergens was positive. Computer rhinomanometry showed increased nasal resistance at medium difficulty level, on the right. Radiography of paranasal sinuses indicated chronic polysinusitis on the right. Anti-allergy therapy was prescribed. The patient came for checkup after a month with subjective deterioration and a neck tumefact on the right. Nasal endoscopy revealed the presence of dark red infiltrates with the 3 mm diameter on nasal septal mucosa, dominantly on the right, with small greyish nodules. This findings indicated a potential specific nasal inflammatory process. In the upper jugulodigastric area, on the left, painless tumefact 3 x 5 cm in size was palpated, it was mobile comparing to supra- and infrastructure, with unaltered skin above. The definite diagnosis was established on the basis of the results of nasal mucosa biopsy. After histopathological diagnosis was obtained, we started with antituberculosis therapy at once. CONCLUSION: Due to actual trends of TBC incidences, otolaryngologist should have in mind nasal TBC, when granulomatose lesions are found in nose. PMID- 24069830 TI - Use of mineral trioxide aggregate in the treatement of traumatized teeth in children--two case reports. AB - INTRODUCTION: Dental injuries in immature permanent teeth often result in endodontic complications. Apexification technique using calcium hydroxide is associated with certain flaws, such as long treatment time, the possibility of tooth fracture and incomplete calcification. The use of an apical plug employing mineral trioxide aggregate (MTA) is an alternative treatment option. CASE REPORT: We reported the successful treatment of 4 maxillary incisors (in a 7-year-old boy and a 10-year-old girl) with open apices and periapical lesions. Apical portions of the canals were filled with MTA plugs in both cases. Coronal parts of the root canals were filled with gutta-percha and sealer. Clinical findings were clear 6 months after the definite obturation with no pathological changes on the radiographs in both cases. CONCLUSION: The use of MTA for apical plugging appears to be a valid treatment option in traumatized immature teeth with endodontic complications. PMID- 24069831 TI - Central pontine myelinolysis in a chronic alcoholic: a clinical and brain magnetic resonance imaging follow-up. AB - INTRODUCTION: Central pontine myelinolysis (CPM) is a noninflammatory, demyelinating lesion usually localised in the basis pontis. Chronic alcoholism is frequently associated with this condition which may have a variable clinical outcome. Until now, brain magnetic resonance imaging (MRI) follow-up in alcoholic CPM cases after alcohol withdrawal has been rarely described. CASE REPORT: We reported a 30-year-old male with a 12-year history of alcohol abuse, who presented with inability to stand and walk, nausea, vomiting and somnolence. Neurological examination revealed: impared fixation on lateral gaze, dysarthria, mild spastic quadriparesis, truncal and extremity ataxia, sock-like hypesthesia and moderate decrease in vibration sense in legs. Brain MRI showed a trident shaped non-enhancing pontine lesion highly suggestive of CPM. After an eight month alcohol-free follow-up period, the patient's clinical status significantly improved, while the extent of MRI pontine lesion was merely slightly reduced. CONCLUSION: The presented case demonstrates that CPM in chronic alcoholics may have a benign clinical course after alcohol withdrawal, which is not necessarily associated with the reduction of lesions on brain MRI. PMID- 24069832 TI - Early reconstruction of bone defect created after initial surgery of a large keratocystic odontogenic tumor: a case report. AB - INTRODUCTION: Keratocystic odontogenic tumor (KCOT) is defined as a benign cystic neoplasm of the jaws of odontogenic origin with a high rate of recurrence. The most lesions occur in the posterior part of the mandible. Treatment of KCOT remains controversial, but the goals of treatment should involve eliminating the potential for recurrence while minimizing surgical morbidity. However, another significant therapeutic problem related to the management of KCOT is an adequate and early reconstruction of the existing jaw defect, as well as appropriate aesthetic and functional rehabilitation of a patient, especially in cases of a very large destruction of the jaws bone. CASE REPORT: We presented a 65-year-old female patient with very large KCOT of the mandible. Orthopantomographic radiography showed a very large elliptical multilocular radiolucency, located on the right side of the mandible body and the ascending ramus of the mandible, with radiographic evidence of cortical perforation at the anterior border of the mandibular ramus and the superior border of the alveolar part of the mandible. The surgical treatment included two phases. In the first phase, the tumor was removed by enucleation and additional use of Carnoy solution, performing peripheral ostectomy and excision of the affected overlying mucosa, while in the second phase, restorative surgery of the existing mandibular defect was performed 6 months later. Postoperatively, we did not register any of postoperative complications, nor recurrence within 2 years of the follow-up. CONCLUSION: Adequate and early reconstruction of the existing jaw defect and appropriate aesthetic and functional rehabilitation of the patient should be the primary goal in the treatment of KCOT, having in mind the need for a long-term post-surgical follow-up. PMID- 24069833 TI - [Remembrance on the occasion of the Day of Armed Forces Medical Services of Serbia: Staff Doctor Emmerich P. Lindenmayer (1806-1883)]. PMID- 24069834 TI - Tougher laws on violence against nurses. PMID- 24069835 TI - Health care reform in Tennessee: an economic and health care crisis. How did this happen? What is next? PMID- 24069836 TI - Helping Tennesseans gain health care coverage. PMID- 24069837 TI - Focus on patients, not titles. PMID- 24069838 TI - Full practice authority: what does it mean? PMID- 24069839 TI - Keeping health care reform healthy, patients informed. PMID- 24069840 TI - Combating the prescription drug crisis in TN: a nurse practitioner's view. PMID- 24069841 TI - Benefits and risks associated with genetically modified food products. AB - Scientists employing methods of genetic engineering have developed a new group of living organisms, termed 'modified organisms', which found application in, among others, medicine, the pharmaceutical industry and food distribution. The introduction of transgenic products to the food market resulted in them becoming a controversial topic, with their proponents and contestants. The presented study aims to systematize objective data on the potential benefits and risks resulting from the consumption of transgenic food. Genetic modifications of plants and animals are justified by the potential for improvement of the food situation worldwide, an increase in yield crops, an increase in the nutritional value of food, and the development of pharmaceutical preparations of proven clinical significance. In the opinions of critics, however, transgenic food may unfavourably affect the health of consumers. Therefore, particular attention was devoted to the short- and long-lasting undesirable effects, such as alimentary allergies, synthesis of toxic agents or resistance to antibiotics. Examples arguing for the justified character of genetic modifications and cases proving that their use can be dangerous are innumerable. In view of the presented facts, however, complex studies are indispensable which, in a reliable way, evaluate effects linked to the consumption of food produced with the application of genetic engineering techniques. Whether one backs up or negates transgenic products, the choice between traditional and non-conventional food remains to be decided exclusively by the consumers. PMID- 24069842 TI - Exposure to aerosols during high-pressure cleaning and relationship with health effects. AB - In different occupations cleaning has been identified as the work task causing the highest exposure to aerosol components. High pressure cleaning (hpc) is a cleaning method used in many environments and seems to be considered as a cleaning method causing high exposure. In the presented study, the literature concerning exposure to aerosols during hpc is reviewed. Only a few studies have been published about exposure to aerosols during hpc. Exposure during hpc has been measured on farms, at waste water treatment plants, at a chemical factory and for graffiti removers. High exposures to bacterial endotoxin or chemical components were found in these environments during hpc. Few cases have been published documenting acute health effects caused by exposure to microorganisms and endotoxin during hpc. High pressure cleaners are also used in private settings but no papers have been found about exposure or related health effects during work in private settings. The use of clean water during hpc is important since effluent water or roof-collected rain water can cause a higher exposure to bioaerosols and related health effects. However, tap water in some areas also seems to have a high content of endotoxin, and this too should be considered when deliberating the protection of the airways of workers. Different attempts have been made to reduce workers' exposure and the health effects of exposure during hpc, among them the use of respiratory protection, ventilation and automation of work processes have been used with some degree of success. However, some of these studies only show tendencies. A high number of repeats seem to be necessary in order to obtain conclusive results. The material to be cleaned, as well as the degree of dirtiness, highly influences the exposure level; therefore, in comparative studies it is important also to consider these parameters. No study has been found which compares exposure during the use of different high pressure cleaners. The comparison of exposure levels during the use of different equipment for hpc and other cleaning methods are necessary steps for developing hygienic recommendations. PMID- 24069843 TI - Babesia canis and tick-borne encephalitis virus (TBEV) co-infection in a sled dog. AB - INTRODUCTION AND OBJECTIVES: Sporting dogs, including sled dogs, are particularly prone to tick-borne infection either due to training/racing in forest areas or through visits to endemic areas. The aim was to present tick-borne infections in a 6-dog racing team after a race in Estonia. MATERIALS AND METHODS: On the 4th day after return to Poland, the first dog presented with babesiosis symptoms and was diagnosed and treated accordingly. Next morning, the dog showed neurological symptoms and was diagnosed with tick-borne encephalitis (TBE). Diagnosis was confirmed by a high level of IgG antibodies (922 IU/ml), detected in serum 3 months later. The second dog presented with babesiosis symptoms on the 7th day after return. Babesia DNA was extracted from blood, amplified and sequenced to answer the question of whether the dogs became infected during the race in Estonia or in Poland. RESULTS AND CONCLUSIONS: Sequencing of a fragment of Babesia 18S rDNA revealed that these two isolates were identical to one another and closely related to the B. canis sequence originally isolated from the dog and Dermacentor reticulatus ticks in Poland. Thus, this is the first confirmed case of B.canis and TBEV co-infection and first confirmed case of TBE in a dog in Poland. PMID- 24069844 TI - The evaluation of enamel matrix derivative on subgingival microbial environment in non-surgical periodontal therapy. AB - INTRODUCTION AND OBJECTIVE: Recent in vitro studies indicate that enamel matrix derivative (EMD) could modulate the growth of periodontopathogens. The aim of the presented study was an analysis of the influence of EMD on the presence of Porphyromonas and Prevotella bacteria in the periodontal pockets of patients with chronic periodontitis in non-surgical periodontal therapy. MATERIALS AND METHODS: The studies were conducted on 20 patients. The condition of the periodontium was evaluated by clinical indexes: API. SBI. PD. CAL before and 3 months after the therapy in two selected quadrants. The material was collected for investigation. The periodontopathogens were cultured and identified. Two days after EMD-scaling root planing (SRP) was applied into the pockets. RESULTS: In the group of patients under investigation before the EMD application the presence of P. gingivalis was found in 6 patients and P. intermedia in 8 patients. After root planing and EMD application no periodontopathogens were identified in those patients either in the periodontal pockets treated with EMD or in the periodontal pockets free from EMD (control). In the statistical analysis of changes in clinical indexes, the application of SRP and SRP combined with EMD was proved to significantly influence the improvement of the clinical state. However, no significant differences between the individual parameters were found in either group. CONCLUSIONS: The SRP is an effective method of limiting the development of periopathogens in periodontal pockets. The non-surgical therapy with EMD does not change the clinical parameters significantly, compared with the SRP. Simultaneously, the application of EMD inhibits the development of periopathogens, such as Porphyromonas gingivalis and Prevotella. PMID- 24069845 TI - Sequence-based typing of Legionella pneumophila strains isolated from hospital water distribution systems as a complementary element of risk assessment of legionellosis in Poland. AB - Many factors affect the risk of Legionella infection, such as the design, construction and maintenance of water distribution systems, the presence of individuals who may be exposed and their vulnerability to infection, and the degree of water system colonization and properties of Legionella strains. For epidemiological investigations, two properties of the Legionella strains are usually determined: serotyping and genotyping (sequence-based typing, SBT). In Poland, data regarding legionellosis are fragmentary, despite the fact that this has been a notifiable disease since 2002. The number of reported cases is very low; moreover, the main method of diagnosis is serological examination (delayed diagnosis and cheaper methods), and only single cases of LD were confirmed by culture of bacteria. Therefore, after 10 years of mandatory reporting of the Legionella spp. infection in Poland, the real epidemiological situation is still unknown; however, risk assessment should be carried out, especially in hospitals. In the presented study, comparison of the sequence types of 111 isolated L. pneumophila strains (from hospital water systems) with those present in the EWGLI SBT data was undertaken for complex risk analysis as a complementary element. In total, strains of L. pneumophila belonging to 12 out of 19 STs determined in the presented study were previously reported to the EWGLI SBT database (ST1, ST42, ST59, ST81, ST87, ST114, ST152, ST191, ST371, ST421, ST461, ST520). Among these strains, only 7 STs were previously reported in the amount of >=10 (mainly ST1, ST42, ST81). Analysis of EWGLI data were carried out and, proportionally, the highest percentage of hospital-acquired strains (clinical and environmental) was found for ST 81, ST421 and ST152, but the largest number was for ST1. Based on the EWGLI data and the presented results, it was found that persistent colonization of HWS of 3 hospitals by strains belonging to ST42, ST1, ST87 indicated an increased risk of legionellosis, especially ST42. PMID- 24069846 TI - Determination of the parameters of the parasitic stage in Ixodes ricinus females. AB - INTRODUCTION AND OBJECTIVES: Ixodes ricinus is a tick commonly found on human and animals and of great medical and veterinary importance. The aim of the study was to determine the parameters of different stages of feeding in Ixodes ricinus females. METHODS: 229 Ixodes ricinus females were collected from 102 animals--roe deer (Capreolus capreolus) and red deer (Cervus elaphus) culled in southern and south-eastern Poland in 2002. Each female was weighed and the length and width of the scutum as well as the width of the idiosoma were measured. 20 tick females were collected from vegetation growing in the region and analysed in order to compare the changes in the parameters studied to those exhibited by unengorged specimens. RESULTS: Three groups were identified on the basis of female body weight; group I consisted of 52 females in feeding phase I with body weight in the range of 0.0003-0.0043 g (mean 0.0019 g), group II comprised 150 females in feeding phase II with weight in the range of 0.0017-0.3075 g (mean 0.0263 g), and group III consisted of 27 females in feeding phase III with weight in the range of 0.0904-0.3122 g (mean 0.1913 g). Indices characterizing the various feeding phases, such as body index, scutal index, alloscutal index, growth index, engorgement index I and II, and the relative body mass index, were determined. The investigations demonstrated that the values of the morphometric traits in feeding phase I, II and III differe in I. ricinus females. CONCLUSIONS: The values of the morphometric features and indices can be helpful in identification of the parasitic stage of I. ricinus females removed from host skin, and assessment of the risk of infection of the host with various parasites injected with tick saliva at the respective feeding phases. PMID- 24069847 TI - Evaluation of the effect of various concentrations of selected pyrethroids on the development of Dermacentor reticulatus eggs and larvae. AB - The Palearctic three-host species Dermacentor reticulatus contributes to the circulation of numerous pathogens in the environment. Reduction of its abundance may therefore decrease the risk of tick-borne diseases in a given area. The aim of the study is to determine the effect of various concentrations of three pyrethroids--(D), cypermethrin (C), and alpha-cypermethrin (AC) on the development of D. reticulatus eggs and larvae. 217 engorged D. reticulatus females were examined in the investigations. After the feeding period, they were sprayed with 0.015625%, 0.03125%, 0.0625%, and 0.125% solutions of D, C, and AC, and kept at a temperature of 25 o C and 90% relative humidity throughout the preoviposition and oviposition periods. Eggs laid by females were kept in the same conditions until larval hatch. Based on the results obtained, parameters of the course of maturation and oviposition, as well as parameters of embryonic development, were determined. The investigations showed that the pyrethroids tested prolonged the egg maturation period, reduced the number and weight of eggs, and caused disturbances in embryogenesis in D. reticulatus. Upon treatment with as little as 0.015625% AC, larvae did not develop and all eggs died 1-2 days after oviposition. C led to a decreased percentage of normal larval hatch- 31.96%, 15.51% and 12.5%, respectively, after using three increasing concentrations (control 98.15%), and a high rate of egg and embryo mortality. The least detrimental effect on the D. reticulatus maturation and embryonic periods was exerted by deltamethrin (82.74%, 84.37% and 16.80% of normal larvae in treatment with the three concentrations). Morphological anomalies were observed in larvae during the experimental period. AC appeared to have the most toxic effect during the maturity and egg development periods, while C exhibited lower toxicity. Application of these pyrethroids in engorged D. reticulatus females exerts distant effects that lead to substantial reduction of tick offspring abundance. PMID- 24069848 TI - Hantavirus RNA was not detected in Dermacentor reticulatus ticks. AB - A total of 190 Dermacentor reticulatus ticks (80 males, 110 females) collected on the territory of Ostrow Lubelski, Suchawa, Zalutyn and Kazimierz Dolny (Lublin Province, eastern Poland) were examined by reverse transcription PCR and nested PCR methods for the presence of hantavirus RNA. None of the examined Dermacentor reticulatus specimens showed the presence of the hantavirus-specific RNA in spite of using two pairs of primers and the clearly positive results obtained with the positive control. Thus, the hypothesis about the possible participation of ticks in the transmission of hantaviruses was not confirmed. PMID- 24069849 TI - Molecular evolution and phylogenetic implications in clinical research. AB - A phylogenetic tree shows graphically the evolutionary relationships among various organisms. The dynamic development of molecular biology and bioinformatics has led to a revolution in our knowledge of biological evolution and the kinships between living organisms and viruses. Nowadays, the available laboratory techniques and computer software allow reconstruction of the actual changes which occurred in the evolutionary process. The derivation of molecular evolution models and several methods for building phylogenetic trees have played a huge role in that enterprise. The emergence of new infectious agents is a problem afflicting mankind since prehistoric times. The study of phylogenetic implications among pathogenic microorganisms allows tracking the process of evolution, the indirect understanding of their biology, and thus facilitates the implementation of treatment. The presented article demonstrates the basic methods for constructing phylogenetic trees, as well as the benefits of reconstructing the evolution process and kinship with the study of microorganisms; in particular, viruses are considered from the clinical aspect. PMID- 24069850 TI - Harmonisation of standards related to limiting chemical risk associated with work processes. AB - The presented paper tackles the issue of risk factors specific to work processes that involve the presence of chemicals. The reason that supports the present approach is the fact that the risks most likely to affect health in the workplace have been lately associated with the exposure of workers engaged in industrial activities to aggressive chemical agents. In order to tackle this problem, we shall resort to the normative regulations that have been adjusted upon Romania's inclusion in the European Union. The harmonization and alignment of the national standards--applied to the work systems that make use of various chemical substances likely to affect the health of the human resource--to the European guidelines and regulations has brought about a significant improvement in workplace security practices. Consequently, the arguments and demonstrations in the presented study are based on elements of the European acquis and the Romanian regulations which are all related to the chemical risk factors generated by harmful chemicals, or the potentially accident-prone properties of the substances used in work processes. PMID- 24069851 TI - Chemical exposure early in life and the neurodevelopment of children--an overview of current epidemiological evidence. AB - A number of chemicals have been shown to demonstrate neurotoxic effects either in human or laboratory animal studies. This article aims at evaluating the impact of exposure to several chemicals including: organophosphate, organochlorine pesticides, polychlorinated biphenyls (PCBs), mercury and lead on the neurodevelopment of children by reviewing the most recent published literature, and answer the question whether any progress has been made in the epidemiology of the neurodevelopment of children induced by exposure to those chemicals. The result of the presented studies show that exposure to the above-mentioned chemicals may impair the neurodevelopment of children. Neonates exposed to organophosphate pesticides demonstrated a higher proportion of abnormal reflexes, and young children had more attention problems. Exposure to organochlorine pesticides in children was associated with alertness, quality of alert responsiveness, cost of attention and other potential attention associated measures. The majority of studies indicate the negative impact of lead exposure at the level <10 ug/dl or even <5 ug/dl on the neurodevelopment of children. The results of studies on exposure to PCBs, mercury, and their effect on neurodevelopment are inconsistent. Some suggest that prenatal exposure to PCBs and mercury is related to performance impairments, attention and concentration problems, while other do not present any statistically significant association. The studies were mostly well designed, using prospective cohorts with the exposure assessment based on the biomarker of exposure. Concerning the covariates and confounders affecting the endpoints in most of the presented studies, confounders were included in data analysis. In order to recognize the early cognitive, motor and language outcomes of chemical exposures, well standardized tools were used for evaluating the neurodevelopmental effects and offer an early and fairly comprehensive measure of child development. Because the neurotoxicants may cross the placenta and the fetal brain, exposure consideration regarding the reduction of exposure to those chemicals should be implemented. PMID- 24069852 TI - The effect of environmental factors on concentration of trace elements in hip joint bones of patients after hip replacement surgery. AB - The aim of this study was to assess the impact of environmental factors: cigarette smoking, dental amalgam fillings, eating habits and osteoporosis, on the concentrations of copper (Cu), zinc (Zn), lead (Pb), cadmium (Cd) and mercury (Hg) in the bone of hip joint in patients in the Orthopedics Clinic in Szczecin, Poland. Amalgam dental fillings had an effect on the Cu concentration in the cartilage with the adjacent compact bone, and on Hg concentration in the spongy bone. The highest concentrations of Cu and Hg were found in people with multiple amalgam fillings. Smoking appeared to influence Pb concentration in the cartilage with the adjacent compact bone, and Cd concentration in the spongy bone. Increased Pb was detected in smokers, and increased Cd in non-smokers. Diets rich in fish and seafood correlated with Cd concentration in the cartilage with adjacent compact bone. The greatest concentration was in people who ate fish or seafood at least once a month. PMID- 24069853 TI - Influence of the type of tree habitat on the character of co-occurrence of Fe, Mn, Zn, Cu, Pb, Ni, Cr and Co in the soil of the Tatra Mountain National Park. AB - The objective of the research was to determine the effect of habitat type of selected species of trees on the nature of co-occurrence of Fe, Mn, Zn, Cu, Pb, Cd, Ni, Cr and Co. The presence of speciation forms of these metals was investigated, with reference to the species composition of tree stands in selected areas of the Tatra Mountain National Park (Chocholowska Valley, Strazyska Valley, Koscieliska Valley, as well as Mala Laka Valley).Contents of selected metals in samples were determined by the flame ASA method, with an accuracy of 0.1 ug/g. In habitats dominated by maples, the Pb content in the Chocholowska Valley, unlike Koscieliska Valley covered with beeches, the Pb content in the form directly bioavailable, was twice as high. This was clearly proved in the case of Strazyska Valley where the soil in beech tree habitats contained larger quantities of exchangeable forms of Pb, than that in the Chocholowska Valley. The soil of the valleys, including the Mala Laka Valley, showed peculiar characteristic averaging of the contents of selected speciation forms of metals in the soil. Content corresponding to 10 percentile and geometrical average may be regarded as benchmarks in future studies of the Tatra Mountain National Park, or other protected areas. PMID- 24069854 TI - Allergenic potential of moulds isolated from buildings. AB - INTRODUCTION: Moulds are the one of the known biological factors that have a negative impact on human health. Moulds are commonly present in residential and work environments. Materials plentiful in organic compounds, such as building materials or paints, are a splendid substrate for the development of moulds. The first documented mention of a study describing the harmful effects caused by moulds in buildings emerged in the early nineteenth century. In Copenhagen and then in Padua, moulds of the genus Penicillium, Cladosporium and Mucor were found in buildings. OBJECTIVE: To present the current state of the allergic properties and other negative health effects caused by moulds isolated from buildings. BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE: The literature and own research clearly shows that moulds and their secondary metabolites can evoke toxic effects on human and animal health, and cause symptoms similar to allergic diseases. These allergens have been noted in spores as well as other fungal fragments; however, most allergens are located in germinating spores, in the hyphal tips and in mycelia. Fungal allergy can express in different ways: asthma, rhinitis, conjunctivitis, urticaria and atopic dermatitis. Fungal allergy antigen is bound to IgE-dependent reactions but also to reactions independent of IgE. CONCLUSIONS: Moulds are a significant but difficult to detect etiologic agent of different allergic diseases. Prevention of this diseases is important for patients with suspected connection between common allergic symptoms and affinity with moulds. PMID- 24069855 TI - Analysis of the role of selected demographic and psychological variables (anxiety and depression) as risk factors of inadequate control of bronchial asthma. AB - OBJECTIVE: The aim of the study was to analyze selected potential demographic and psychological variables (anxiety and depression) as risk factors of inadequate control of bronchial asthma. MATERIALS AND METHOD: The study consisted a group of 223 randomly selected asthma patients with varying degrees of asthma control. The study was designed as a diagnostic survey using the asthma control test (ACT), Beck's Depression Inventory (BDI), State- and Trait-Anxiety Inventory (STAI questionnaires X-1 and X-2), and the questionnaire for demographic data collection developed for the purposes of the presented study. RESULTS: Inadequate control of asthma was significantly more frequent amongst females (p=0.008) who were rural inhabitants (p=0.020) and professionally active (p=0.000) patients diagnosed with any grade of depression with an aid of BDI (p=0.000). Patients with inadequate control of asthma were characterized by a significantly higher level of depression, compared to patients controlling this condition adequately (p=0.001). CONCLUSIONS: The female gender, living in a rural environment, professional activity, and even a slight degree of depression can promote inadequate control of asthma. Consequently, asthma patients with such characteristics should be provided with careful allergological surveillance. Since none of the abovementioned variables represents an independent risk factor of inadequate asthma control, it is not possible to classify asthma patients into risk groups on the basis of single parameter assessment. The risk of inadequate asthma control involves also individuals with a low severity of depression (more than 9 points on BDI), i.e. the patients who would not be diagnosed with even mild depression based on the existing criteria. PMID- 24069856 TI - Severe influenza outbreak in Western Ukraine in 2009--a molecular-epidemiological study. AB - INTRODUCTION: In the autumn of 2009 the authors participated in a humanitarian operation in Western Ukraine by undertaking an epidemiological investigation of an influenza-like-illness (ILI) in the L'viv Oblast region. Mobile biological survey teams took samples from civilian patients with severe acute respiratory distress syndrome, rapid transportation of the samples, and their molecular analysis in Poland to provide accurate results. OBJECTIVE: The aim of the study was the molecular and epidemiological analysis of the biological samples collected. MATERIAL AND METHODS: Real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR), multiplex PCR techniques, traditional Sanger Sequencing and classical viral culture methods were used. RESULTS: Among the 124 influenza-like illness cases, ~50% (58) were positive for influenza A virus in WHO-CDC molecular assay, including subtyping. The specimens were further analyzed to confirm results and determine the genetic sequence. Phylogenetically, the nucleotide similarity of both the Ukraine specimens and reference A/California/7/2009 (pH1N1) was 99.2-99.3%. Oseltamivir resistance was not registered. HA1 region characterization showed an overall protein identity of 98.5-99.4%. CONCLUSIONS: An unexpected high contribution of influenza A was confirmed among ILI patients, as well as a very limited number of other detected viruses, indicate that the 2009 epidemic in western Ukraine was strongly related to novel influenza A/H1N1. The importance of swift sharing of information and reference laboratories networking in surveillance, as well as serving governments and international agencies in pursuing adequate actions, should be stressed. PMID- 24069857 TI - Problems of health education in rural areas in Poland. AB - Health promotion is aimed at the reduction of the differences in society's access to factors determining the frequency of occurrence of pro-health behaviours. This means the construction of health resources and increase in the level of egalitarianism in access to these resources. Health education carried out on a high level in rural schools provides actual possibilities for gaining these resources. Many examples of educational practices confirm that the establishment of health conditioning and health behaviours of schoolchildren, and the diagnosis of rural school on the background of the specificity of the community in which it functions. These are a basis for the construction of effective educational programmes, and not analysis of the differences between urban and rural children and adolescents. In Poland, the performance of health education in rural schools encounters many problems associated both with the lack of infrastructure for health promotion, insufficient perception of the importance of health education at school by the educational authorities, underestimation of primary health care, low activity of the local governments, and lack of qualified rural health promoters. Current health education in Polish rural schools deepens inequalities in access to health, and postpones the moment of providing equal opportunities for rural and urban schoolchildren with access to the resources which condition the maintenance or even an enhancement of health. The objective of the study is to present selected problems in the performance of health education in a Polish rural school in the light of international trends, experiences and discussions related with an optimum form of health promotion in the environment of rural a school and the community. PMID- 24069858 TI - Altered tissue electrical properties in women with breast cancer--preliminary observations. AB - INTRODUCTION AND OBJECTIVES: In the United States, breast cancer (BC) is the most common non-skin cancer. In Poland, it is estimated that the number of new breast cancer cases affects about 13,500 women each year. There are many methods for nutritional status assessment. One of them is bioimpedance analysis (BIA). Direct bioimpedance measures (resistance, reactance, phase angle (PA)) determined by bioelectrical impedance analysis (BIA) detectf changes in tissue electrical properties. The study was conducted to investigate whether there are any tissue electrical differences in patients with breast cancer. MATERIALS AND METHODS: The direct bioimpedance measures determined by bioelectrical impedance analysis (BIA) were performed on 34 patients with BC and 34 healthy volunteers. The measurements were made with ImpediMed bioimpedance analysis SFB7 BioImp v1.55 (Pinkenba Qld 4008, Australia). RESULTS: Reactance and resistance at 50 kHz was found to be significantly greater in patients with BC than in the control group (53.59 degrees +/- 1.53 vs. 47.26 degrees +/- 1.25, respectively, p=0.0031; 603.24 degrees +/- 15.38 ohm vs. 515.87 degrees +/- 11.48 ohm, respectively, p=0.00004). CONCLUSION: Pre-surgical patients diagnosed with BC have altered tissue electrical properties. Further observations of a larger patient group would be valuable to calculate survival, validate the prognostic significance of PA, and monitor nutritional and therapeutic interventions in this patient population. PMID- 24069859 TI - Insulin resistance assessment in patients with polycystic ovary syndrome using different diagnostic criteria--impact of metformin treatment. AB - INTRODUCTION AND OBJECTIVE: Polycystic ovary syndrome (PCOS) is one of the most frequent reasons for anovulation in infertile women. It can affect 5%-10% of women of reproductive age. One of the important factors associated with the typical clinical signs and hormonal disorders could be insulin resistance and hyperinsulinaemia. The primary objective of this study was to assess the prevalence of insulin resistance in PCOS women. The secondary objective was to evaluate changes in body mass index (BMI), waist-to-hip ratio (WHR), and insulin sensitivity after 3 months of metformin therapy. MATERIALS AND METHODS: 68 patients were enrolled in the study. In all participants fasting and 2-h post load glucose and insulin levels, WHR and BMI were evaluated before and after metformin (2 x 850 mg) therapy. Insulin resistance was assessed using G0/I0, G120/I120, and HOMA-IR indexes. RESULTS: Before the treatment, insulin resistance was observed in 26% patients according to HOMA-IR, and in 16% or 28% according to G0/I0 or G120/I120, respectively. Metformin therapy was associated with improvement in insulin sensitivity in HOMA-IR and G120/I120 defined insulin resistant patients. CONCLUSIONS: The percentage of insulin resistant PCOS patients differed depending on the method applied. It is necessary to find a single most useful method to measure insulin resistance. Metformin treatment significantly improves insulin sensitivity in insulin resistant patients. PMID- 24069860 TI - Perceived and desired body weight among female university students in relation to BMI-based weight status and socio-economic factors. AB - The aim of the study was to verify if the accuracy of weight perception among young women depends on their socio-economic status and BMI-based weight status. In addition, the survey contained questions whether women were satisfied with their weight and tested if the desire to change weight is affected by real body weight and weight perception. The sample consisted of 1,129 female university students, aged 20-24. BMI was calculated from measured weight and height. The questionnaire contained questions about socio-economic status, weight perception and desired body weight. 71.9% of the surveyed students correctly estimated, 24.2% overestimated and 3.9% underestimated their body weight. Underweight women tended to incorrectly assess their body weight more often than normal weight women or overweight women (43.2% vs. 75.4% vs. 77.2%). Students from families of high socio-economic status slightly more often estimated their weight status correctly than students with average and low status, but the difference was statistically significant only in the case of the factor "mother's education". Most of surveyed women expressed the desire to weigh less or/and to have thinner waist, hips or thighs. The desire to be thinner was associated with body weight status and body weight perception. PMID- 24069861 TI - Psychosocial factors and health status of employees at the Poznan University of Medical Sciences. AB - INTRODUCTION: New opportunities in the labour market, competition in services and globalization have contributed to the increase in load factors in the psychosocial work environment. Availability, readiness to help, work with the sick, the suffering patient--night shifts, overtime, workaholic (as a new form of addiction), and bullying--are becoming more pronounced causes of stress, fatigue and burnout in medicine. Thus, difficult working conditions are largely the cause of unhealthy lifestyles in the medical professions and foster the development of various types of addiction and physical illness. The negative effects of psychosocial factors--in the form of immune disorders, increased incidence of mental and somatic diseases, and metabolic and hormonal disorders--more often cause increase absence through sickness and the shortening of working life. OBJECTIVE: The main aim of the presented study was to provide results concerning the health state of employees of the Poznan University of Medical Sciences (PUMS), and also to analyze relations between selected psychosocial risks factors and the state of health of PUMS employees. MATERIAL AND METHODS: The results of research conducted in 2009-2010 which covered 2,468 employees of the PUMS and the results of studies using an anonymous own questionnaire survey, evaluating exposure to psychosocial factors, which included the 1,096th members of staff of the PUMS. RESULTS: There was a clear effect of psychosocial risk factors for health workers. The greatest burden of these factors was observed among workers with higher education, mostly doctors. This occupational group also worked in several places of work more often than other employees of the university. These workers often complained of chronic fatigue, recurrent respiratory infections, hypertension, sleep disorders, neurotic disorders and depression. The complaints quite often diagnosed were immune disease, allergies, skin diseases, gastrointestinal diseases, and disorders of carbohydrate and lipid metabolism, which clearly intensified under stress. The clearest negative impact of psychosocial factors on the health of the workers were observed in those a with higher education, employed at several jobs, and complained about poor work organization. CONCLUSIONS: 1) It is necessary to implement prevention programs for the staff of the PUMS, aimed at the primary and secondary negative impact of psychosocial factors. 2) Psychological counseling is advisable for employees. 3) It is essential that the issue of voice training, and interpersonal communication techniques to teach and control the schedule of classes, in order to reduce the workload, and encourage physical activity and other forms of relaxation. 4) It is advisable to periodically check on the work conditions and organization of work to help eliminate stressors in the work environment. PMID- 24069862 TI - New cases of suspected HFRS (Hantavirus infection) in south-eastern Poland. AB - INTRODUCTION: HFRS--hemorrhagic fever with renal syndrome, found in Europe, is an acute viral zoonosis due to the hantavirus infection. The disease is characterized by the triad of symptoms: sudden, febrile onset, acute renal failure and haemorrhagic diathesis. The range of hantavirus infections in humans has not been yet established on the territory of Poland. The medical literature described 18 cases of seropositive HFRS in Poland--mainly in the district of Sanok, and single cases in the districts of: Brzozow, Debica, Krosno, Lesko, Przemysl and Stalowa Wola. AIM: The aim of the study was to verify the hypothesis, assuming that patients hospitalized in the Department of Nephrology, located in the Regional Hospital in Przemysl were infected with hantavirus and had HFRS. MATERIAL AND METHODS: Due to the fact that patients selected for the study were not tested serologically, verification was based on statistical comparison of the retrospectively selected group of patients suspected of HFRS with the seropositive group described in the study of Nowakowska, Heyman, Knap et al. in 2009, in terms of individual symptoms prevalence in conjunction with the structure of selected clinical and epidemiological parameters. RESULTS: 26 individuals with renal failure and influenza-like episode of several-day fever of unknown origin were indentified on the base of the retrospectively analyzed records of the patients hospitalized in the Department of Nephrology in Przemysl between 2001-2011. The significant differences in age, frequency of selected laboratory parameters (platelet count, serum electrolytes) and oliguria were not found in both compared groups. However, the study group included the higher percentage of men. Additionally, the differences in prevalence of symptoms (cough, diarrhea), which are not considered specific for HFRS were detected. Analogously to the reference group, seasonal morbidity was observed also in the study group, but the peak intensity was delayed for 4 weeks. CONCLUSIONS: The hypothesis cannot be rejected that, the group analyzed in the prestent study, hospitalized in the Department of Nephrology in the Regional Hospital in Przemysl -is the sample of patients with HFRS (similarly to the group described by Nowakowska et al.). The cases described in this study can be considered as suspected of HFRS. It is justifiable to perform serological testing in these individuals. PMID- 24069863 TI - Tourist activity of young people as a factor contributing to their health and proper development. AB - INTRODUCTION AND OBJECTIVE: The aim of this paper is to assess the level of tourist activity of pupils and students from schools in Warsaw, as well as factors influencing this level of activity. METHODS: A two-part questionnaire was used that included questions related to participation in tourist trips (day, long, short, and trips abroad) and the International Physical Activity Questionnaire (IPAQ). RESULTS: Among the analyzed factors (gender, level of school, level of physical activity), only the level of school turned out to be the factor which significantly (p=0.000) influenced the physical activity of the respondents. It was observed that tourist activity among pupils and students decreased with age. CONCLUSION: There is an urgent need for a systematic approach towards promoting and supporting the participation of children and young people in tourism. as well as setting examples of how to travel and rest. Carrying out intervention programmes demands the further identification of factors determining them (e.g. influence of parents' leisure time behaviour), as well as the application of standardized research tools. PMID- 24069864 TI - Environmental risks perception--a study of the awareness of families to threats in areas with increased health disorders in children. AB - INTRODUCTION: Children are at greater risk than adults to experience adverse effects from environmental agents. Significant neurological damage to children can occur even at very low levels of exposure. Reliable protection of children living in areas with high environmental hazards is not possible without their parent's' understanding of where, how and why children's exposures occur. OBJECTIVES: The aim of the presented study was to indicate families' awareness of environmental risks with increased health disorders in children in the chosen area of the Silesian Province. MATERIALS AND METHODS: Rates of development disorders in general, including physical and psychomotor development disorders, in a population of children from the study area were estimated. A questionnaire was used in order to explore through a door-to-door survey the perceptions of environmental risk in a population of 2,491 residents. RESULTS: The presented study shows that the parents' awareness of environmental health risks is not satisfactory. The majority expressed an opinion that the outdoor environment exerts a major influence upon the state of health, but less than 1% of the parents were aware of the indoor environmental risk. CONCLUSION: The most effective way to prevent children's exposure is to teach the community to identify environmental threats and educate them on how to their protect children. The appropriate policies and programmes should be developed and implemented as this seems to be the most effective and cheapest way to prevent children's exposure to environmental risks. PMID- 24069865 TI - The level of health education in the Polish population. AB - BACKGROUND: The study assessed factors influencing awareness of Poles concerning lifestyle factors that affect development of obesity, type 2 diabetes and cardiovascular diseases (CVD). METHODS: A questionnaire survey covering awareness of lifestyle factors performed by general practitioners in 37,557 unselected patients. RESULTS: 96.1% of respondents believed that lifestyle has an impact on the occurrence of CVDs, especially: tobacco smoking (91.4%), excessive intake of fat (81.3%), alcohol (67.5%), salt (64.9%), and stress (64.9%). 79.0% respondents believed the smoking cessation, 77.5% weight loss and 66.8% healthy diet are most important to prevent diseases. Additionally, the belief in the need for an early weight reduction decreased with increasing BMI (82.9% with normal weight vs. 77.5% overweight and 70.4% obese). The most common source of health education was a physician (75.8%), the mass media, such as television and the press (62.0% and 64.8%, respectively), less often were educational materials (37.8%) and books (20.3 %), the Internet (3.8%) and radio (0.8%). Younger respondents presented a higher level of awareness about all analysed aspects of healthy lifestyle. The multiple regression analysis revealed that low education level and rural residence are the most important factors decreasing awareness of the lifestyle effect on health. CONCLUSIONS: 1. The level of knowledge about non pharmacological methods of preventing lifestyle diseases in the Polish population is high except of the role of physical activity and daily vegetables consumption. This, however, has no impact on reducing the percentage of overweight and obese people and on increasing the tendency to pursue lifestyle changes. 2. Frustrating is the fact that more than one fifth of the study population is unaware that excessive weight reduction prevents development of cardiovascular diseases. Moreover, the convince to early weight decreases with increasing BMI. 3. The highest level of the knowledge among younger subjects reflect improvement of health education in Polish population. 4. In addition to education performed by physician the main sources of patients knowledge are television and the press with the growing role of the Internet among younger. 5. Further health education programs are necessary, which should include not only activities that increase the level of health education and health awareness, but also aspects such as changes in beliefs, sense of self-efficacy and social support. PMID- 24069866 TI - Weekday and weekend moderate to vigorous physical activity of young musicians in the context of public health recommendations. AB - INTRODUCTION: Physical activity is very important for the proper mental and physical development of children and youths, especially for the development of the locomotor system. The students of music schools are a unique group of children and youths, because of specific loads on the organs of locomotion, associated with the playing of musical instruments. They can therefore be exposed to a variety of health problems, particularly in the case of insufficient physical activity. OBJECTIVE: The aim of the presented study was to assess the level of physical activity of music schools' students on weekdays and weekends against the parameters of physical efforts beneficial to health. METHOD AND MATERIALS: The study involved 225 musicians from the Katowice School of Music, Complex of I and II degrees, aged 10-18 years (138 girls and 87 boys). The level of physical activity was assessed on the basis of moderate to vigorous rates (MVPA). RESULTS: Both on weekdays as well as at the weekends, boys presented a higher level of physical activity of at least moderate intensity (MVPA), which also resulted in a greater total weekly pro-health physical activity. Both boys and girls dedicated significantly more time to beneficial pro-health efforts physical health at weekends (p<0.01). The percentage of young musicians who meet accepted (in this study) standards for the optimal amount of physical activity in both groups was dramatically low (3.6% of girls and 11.5% of boys). CONCLUSION: Both boys and girls from the music schools often undertake moderate to vigorous physical activity (MVPA) at the weekends. The boys more often than the girls made pro-health physical efforts of moderate and high intensity. PMID- 24069867 TI - Anti-epileptic drugs inhibit viability of synoviocytes in vitro. AB - INTRODUCTION AND OBJECTIVE: The hyperplasia of synovial fibroblasts is considered to be essential for the evolution of joint destruction in rheumatoid arthritis (RA). Previously, we reported that anti-rheumatic drugs, both COX inhibitors and disease-modifying anti-rheumatic drugs inhibit proliferation of synoviocytes in vitro. The presented study investigates the effect of anti-epileptic drugs on the viability and proliferation of synovial fibroblasts in vitro. METHODS: Experiments were conducted on human synoviocytes derived from an RA patient and rabbit synoviocytes cell line HIG-82. Cell proliferation and viability were assessed by means of BrdU assay and MTT assay, respectively. The IC50 value (the concentration of drug necessary to induce 50% inhibition) together with confidence limits was calculated. RESULTS: Carbamazepine inhibited proliferation of human fibroblasts and viability of HIG-82 with IC 50 values of 86 uM and 82 uM, respectively. Diphenylhydantoin, valproate and phenobarbital inhibited viability of HIG-82 cells with the IC50 values of 110, 500 and 1031 uM, respectively. CONCLUSION: Based on these findings, it can be suggested that anti epileptic drugs may have a disease-modifying effect on rheumatoid synovial proliferation. PMID- 24069868 TI - Neuroprotective activity of 2-amino-1,3,4-thiadiazole derivative 4BrABT--an in vitro study. AB - 4BrABT (2-(4-Bromophenylamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole) is a compound known for its interesting in vitro anticancer profile. 4BrABT inhibited proliferation and motility of several cancer cell lines in concentrations which were not toxic to normal cells. A major problem associated with cancer chemotherapy, but also caused by environmental factors such as pesticides, is neurotoxicity. Therefore, the aim of the presented study was an in vitro evaluation of the neuroprotective activity of this compound. 4BrABT activity (1 100 MUM) was tested in cultures of mouse neurons, rat astrocytes and rat oligodendrocytes. A possible protective action of the compound in different neurodegenerative models, as serum deprivation (SD), excitotoxicity (presence of 500 MUM glutamate in culture medium), as well as cisplatin toxicity (astroglia- 50 MUM and oligodendroglia--100 MUM) was investigated. Cell viability in the tested cultures was assessed with the use of LDH and MTT methods. Moreover, 4BrABT ability to prevent the cisplatin-induced apoptosis in astrocyte and oligodendrocyte cultures was analysed after Hoechst 33342 fluorostaining. The obtained results indicate that 4BrABT was not toxic to neurons, astrocytes and oligodendrocytes. Moreover, a decrease in the neuronal LDH level was observed, which may suggest the ability of 4BrABT to act as a trophic agent. Furthermore, the protective action of the studied compound was shown in neuronal cultures exposed to neurotoxic conditions (presence of glutamate and trophic stress) and in cisplatin-treated astrocytes and oligodendrocytes. The expression of anticancer and neuroprotective activity raises hopes for the potential use of 4BrABT as a safe anticancer drug, or neuroprotective agent in chemotherapy associated neurotoxicity. PMID- 24069869 TI - Environmental pollution and parental smoking influence on the appearance of pseudocroup in children. AB - OBJECTIVE: The aim of the study was to assess the effect of environmental pollution and parental tobacco smoking on the occurrence of pseudocroup in children. MATERIAL AND METHODS: A questionnaire-study was performed in 345 children with pseudocroup admitted to the ENT Dept between 1997-2007. 116 children had smoking and 229 had non-smoking parents. Both groups were compared with respect to environmental pollution (urban, rural), parents' level of education, household crowding and breast feeding period. The prevalence of upper and lower respiratory tract infections and the presence of allergy were also anlaysed. The results were compared to those performed in the ENT Dept in 1977 1986. RESULTS: In the group of rural children, 21 were children with pseudocroup from smoking parents and 36 children of non-smoking parents. Among children living in the urban areas there were 95 from smoking parents and 193 from non smoking parents. Both non-smoking parents presented a large group of people with a higher level of education, and in the smoking families both parents presented a lower level of education. Analysis of the breast feeding period revealed that it was the longest (up to 9 months) in non-smoking mothers--21% of the group, and only in 4.3% of smoking mothers. PMID- 24069870 TI - Risk factors of postural defects in children at school age. AB - INTRODUCTION AND OBJECTIVE: Postural defects increasingly more often concern children and adolescents at school age. The lack of prophylaxis and neglecting adequate procedures may lead to limitations of physical and motor abilities, back pain, or the development of severe spinal deformities. Recognition of the risk factors conducive to the occurrence of the disorder allows the creation of adequate conditions for the psychomotor development of children, as well as the elaboration and implementation of specified educational schemes directed at schools and parents. The study concerned determination of the risk factors for the development of postural defects in school age children. MATERIAL AND METHODS: The study was conducted by means of a diagnostic survey. The study group covered 380 children aged 14 (175 girls (46.1%) and 205 boys (53.9%))--selected at random from schools in eastern Poland and the Czech Republic. The significance of the relationships between variables was investigated by means of chi-square test for independence. The differences between the empirical and theoretical sample distribution was examined by means of chi-square goodness-of-fit test. The significance level was set at p=0.05. RESULTS: The BMI in the population examined was 20.2, on average (from 14-39). Respondents living in rural areas and small towns constituted 57.63% of the study group, while inhabitants of medium-size and large cities--42.37%. The majority of children in the study had been previously examined for the occurrence of postural defects (74.2%), whereas nearly every tenth child had never undergone such an examination. As many as 16.3% of adolescents did not know whether they had ever participated in a screening test. A defect was detected in 14.7% of children, in 56.6% no asymmetry was detected, while approximately 30% were not aware if their body posture was normal or not. CONCLUSIONS: 1. There is a relationship between physical activity of the child and the occurrence of postural defects. 2. There is a relationship between the economic standard of the family and awareness of own state of health. 3. There is a need for the creation of a system of education for parents and children concerning postural defects and risks resulting from these defects. PMID- 24069872 TI - Health impact of wind farms. AB - INTRODUCTION AND OBJECTIVE: Wind power is employed worldwide as an alternative source of energy. At the same time, however, the health effects of wind turbines have become a matter of discussion. The purpose of this study is a critical review of available reports providing arguments both for and against the construction of wind farms. The authors also attempt to propose recommendations in accordance with the Evidence-Based Medicine (EBM) guidelines. In the case of exposure to wind farms, a randomized controlled trial (RCT) is impossible. To obtain the highest-level recommendations, analysis of case-control studies or cohort studies with control groups should be performed. Preferably, it should include geostatistical analysis conducted with the use of variograms and the kriging technique. Combinations of key words were entered into the Thomson Reuters Web of Knowledge (SM) and the Internet search engine Google. SHORT DESCRIPTION OF STATE OF THE ART: The nuisance caused by wind turbines is stereotypically linked with the noise that they produce. Nevertheless, the visual aspect of wind farms, opinions about them, and sensitivity to sound seem to be of the greater importance. To date, the direct correlations between the vicinity of modern wind farms, the noise that wind turbines make, and possible consequences to health have not been described in peer reviewed articles. Health effects are more probably associated with some environmental factors leading to annoyance or frustration. All types of studies share the same conclusion: wind turbines can provoke annoyance. As with any project involving changes in the local environment, a certain level of irritation among the population can be expected. There are elected officials and government representatives who should decide what level of social annoyance is acceptable, and whether wind power advantages outweigh its potential drawbacks. The influence of wind turbines on human emotional and physical health is a relatively new field of research. Further analyses of these issues are justified, especially because none of the studies published in peer-reviewed journals so far meet the criteria for cohort or case control studies. SUMMARY: Due to methodology, currently available research results do not allow for higher than C-level recommendations. In the case of wind farms, the ideal types of research would be: a retrospective observation of a particular group of residents before and after the wind farm construction, case control studies or cohort studies with control groups matched in respect of socioeconomic factors, predisposition for chronic diseases, exposure to environmental risk factors, and only one variable which would differentiate cases from controls--the distance between place of residence and a wind farm. PMID- 24069871 TI - Daily tobacco smoking patterns in rural and urban areas of Poland--the results of the GATS study. AB - INTRODUCTION AND OBJECTIVE: Cigarette smoking is one of the main causes of premature death worldwide. Tobacco smoking is influenced by social and economic factors such as age, gender, level of education and place of residence. The objective of this paper is to describe the occurrence of daily tobacco use in urban and rural populations in Poland. MATERIALS AND METHOD: The data was collected between 2009-2010 as part of the International Global Adult Tobacco Survey project. The study was conducted based on population of age 15 and older. 7,840 full individual interviews were conducted (51.2% in rural and 48.8% in urban areas). The total response rate was equal to 65.1%. RESULTS: 25.4% of rural residents at the age of 15 and above smoke tobacco daily (32.5% men and 17.9% women). In cities, this percentage corresponds to 30.3% (35.4% males and 25.8% females, respectively). Among the males and females, the highest percentage of daily tobacco smokers was found among respondents with vocational education (males 47.3% in urban and 41.8% in rural areas; females 36.8% and 23.5%, respectively). In both the rural and urban areas the lowest percentage of daily cigarette smokers among male respondents were those with higher education (24.9% in urban and 16.1% in rural areas). In the group of female respondents, the lowest incidence was observed among those with primary education (16.4% in urban, 11.7% in rural areas). CONCLUSIONS: Daily smoking patterns in Poland differ according to the place of residence (urban/rural) and gender. A decrease in the percentage of daily tobacco users should be observed in the next few years. Along with age exceeding 60 years, the percentage of daily cigarette smokers is clearly on the decline. PMID- 24069873 TI - Comprehensive rehabilitation in chronic heart failure. AB - Chronic heart failure (CHF) is a complex disease process connected with cardiovascular system as well as other organs and skeletal muscles. In connection with the above, cardiac rehabilitation, consisting of exercise training and diet supplementation, aims at recovery of physical, social and psychic function and removing risk factors influencing the occurrence of circulatory system diseases. Evidence has shown that exercise training in CHF patients, both aerobic and resistance, can increase peak oxygen consumption and exercise capacity, improve NYHA (New York Heart Association) functional class, reduce mortality and improve the quality of life. Evidence suggests that most improvement is due to the effects of training on the peripheral circulation and skeletal muscle, rather than on the heart itself. Exercise training can improve skeletal muscle metabolism, increase blood flow within the active skeletal muscles, increase capillary density, promote the synthesis and release of nitric oxide, improve angiogenesis, and decrease oxidative stress. Physical effort reduces sympathetic arousal and increases parasympathetic arousal, thus reducing cardiac dysrythmia and ischemia. Mitochondria start working harder, as the demand for energy is higher and electron flow provides energy in the form of ATP. Studies have consistently demonstrated that exercise training is safe and has no deleterious effect on central haemodynamics, left ventricular remodeling, systolic or diastolic function, or myocardial metabolism. Taking several supplements that have documented roles in medical therapy, including vitamins B, C and E, coenzyme Q10, alpha-lipoic acid, chromium, omega-3 polyunsaturated fatty acids, L carnitine, and quercetin, has beneficiary effect on many diseases, including CHF. In our experience, 19 patients with CHF who undertook resistance (weight) training and food supplementation, returned to their normal activities after 4 months, without any complaints. PMID- 24069874 TI - To tell the truth. A critical trend in medical sociology--an introduction to the problems. AB - INTRODUCTION AND OBJECTIVE: The presented analysis is a reconstruction of the origins, inspirations for development, and theoretical foundations of the critical and unmasking trend in Polish and Western medical sociology. ABBREVIATED DESCRIPTION OF THE STATE OF KNOWLEDGE: As a part of the critical medical sociology initiated in Poland by Professor Magdalena Sokolowska, a diagnosis of the (dys)functionality of contemporary medicine is carried out, emphasizing pathologies in the realization of its basic social functions, both at the level of systemic and institutional solutions, as well as stressing their consequences which include inter alia social health inequalities. Within the critical sociomedical research orientation, the diagnoses of the social role of medicine and distortions in the ways it is exercised are placed in the broad structural, political, and cultural contexts, which makes it possible to point to the principal causes of the analyzed phenomena. SUMMARY: The crucial 'value added' of critical sociological analyses of medicine and health policy are directives intended to humanize medicine and health systems in contemporary societies, taking social and cultural realities into consideration. We understand the humanization of medicine in terms of its better adjustment to human needs that emerge in the situations of illness and being ill, with the simultaneous guarantee of universal and equal access to medical services. PMID- 24069875 TI - Health consequences of work in childhood in opinions of respondents from agricultural families. AB - INTRODUCTION: The engagement of children in work on a family farm is a common phenomenon in many countries worldwide. An excessive loading of children with work creates many risks for their health or even life. Studies concerning the effect of work on health concern mainly the negative consequences for the health of working children. OBJECTIVE: The objective of the study was the recognition of opinions of adults from agricultural families concerning the effect of work in childhood on their state of health. MATERIALS AND METHOD: The study was conducted by the method of a diagnostic survey using a questionnaire technique, and covered a group of 482 adults from agricultural families. The selection of the study group was targeted according to the following criteria: 1) agricultural family origin, 2) respondents' age 20-65, 3) completed education. RESULTS: The majority of respondents expressed the opinion that work in childhood had no impact on their health. At the same time, 2/5 of respondents considered that work on their parents' farm exerted an effect on their health in childhood (current effects), whereas nearly 1/3 admitted that an engagement in work in childhood also affected their present state of health as adults (distant effects). Respondents who experienced the impact of work on health perceived both positive and negative consequences of performing agricultural work activities in their childhood. Opinions concerning the effect of work on health depended on loading with agricultural work in childhood. The higher the level of loading with work activities, the more frequently the respondents perceived the impact of work on their health. CONCLUSION: The engagement of children in agricultural work in a small amount of working time, and adjustment of the endowed jobs to their capabilities brings about many benefits for health with low health risk. In turn, the engagement of children in work from their youngest years and overloading them with work exerts a negative effect on health, especially in later life. PMID- 24069876 TI - Is there the gap in public health literature in Europe? AB - INTRODUCTION AND OBJECTIVE: The growing expectations for the effectiveness of public health increase the demand for scientific literature, concerning research, reviews and other forms of information. The bibliographic databases are of crucial importance for researchers and policy makers. The objective of this study is to estimate the supply of scientific literature related to public health in selected European countries, which are available to a wide range of users. MATERIALS AND METHODS: Analysis of the number of bibliographic records on topics related to public health was based on searches in Ovid MEDLINE (R) in May and June 2011. According to MeSH terms, 11 keywords and names of 13 European countries were used in the search. Publications from the years 2001-2010 were analyzed. A number of publications indexed under 'public health', and related to selected countries were compared with the size of the population of those countries, GDP, total expenditure on health and burden of disease (DALYS's). RESULTS: The most popular topic was 'health policy', whereas the topics 'occupational health' and 'environmental health' were less prevalent. There were no significant changes in the number of publications in 2001-2010. The number of articles indexed under 'public health' had significant positive correlation with national GDP, expenditure on health and population size, and negative with DALY's. CONCLUSIONS: According to the criteria accepted in this study, the Nordic countries--Finland, Sweden and Norway--were very productive in this respect. Poland and other Central European Countries were less productive. PMID- 24069877 TI - Tooth loss among adult rural and urban inhabitants of the Lublin Region. AB - Dental diseases and tooth loss result in various health, psychological, and even social problems. The objective of the study was determination of the number of missing teeth among adult rural and urban inhabitants of the Lublin Region, and whether or not there is a relationship between missing teeth and place of residence, and other socio-economic factors, such as: gender, age, education level and the occupation performed (farmer/non-farmer). Data concerning the number of missing teeth were collected from 3,388 individuals. The mean number of missing teeth among the respondents in the study was 13.6. This mean value was significantly higher among the rural than urban inhabitants. Tooth loss was significantly more often found among females than males, this relationship being statistically significant only in the subpopulation of rural inhabitants. According to expectations, the largest number of missing teeth was found in respondents aged over 60, among those aged 31-60 this number was nearly 2.5-fold smaller, while the smallest number of missing teeth was observed among respondents aged 18-30. The largest number of missing teeth was noted among respondents who possessed incomplete elementary or elementary education, followed by those with elementary vocational and secondary school/post-secondary school education, whereas this number was the smallest among respondents who had university education level. Farmers had a significantly larger number of missing teeth, compared to respondents who performed non-agricultural occupations. Using an analysis of regression, the relationship was confirmed between the number of missing teeth, and the respondents' gender, age, education level, place of residence, and occupation performed. Discrimination analysis was applied to show the relationship between the occurrence of total edentulism and the respondents' age, gender, education level and place of residence. It was observed that age was the variable which most strongly discriminated the occurrence of this characteristic, followed by education level, as well as gender and place of residence, which were the weakest discriminatory variables. PMID- 24069878 TI - Charge trapping dynamics in PbS colloidal quantum dot photovoltaic devices. AB - The efficiency of solution-processed colloidal quantum dot (QD) based solar cells is limited by poor charge transport in the active layer of the device, which originates from multiple trapping sites provided by QD surface defects. We apply a recently developed ultrafast electro-optical technique, pump-push photocurrent spectroscopy, to elucidate the charge trapping dynamics in PbS colloidal-QD photovoltaic devices at working conditions. We show that IR photoinduced absorption of QD in the 0.2-0.5 eV region is partly associated with immobile charges, which can be optically detrapped in our experiment. Using this absorption as a probe, we observe that the early trapping dynamics strongly depend on the nature of the ligands used for QD passivation, while it depends only slightly on the nature of the electron-accepting layer. We find that weakly bound states, with a photon-activation energy of 0.2 eV, are populated instantaneously upon photoexcitation. This indicates that the photogenerated states show an intrinsically bound-state character, arguably similar to charge transfer states formation in organic photovoltaic materials. Sequential population of deeper traps (activation energy 0.3-0.5 eV) is observed on the ~0.1 10 ns time scales, indicating that most of carrier trapping occurs only after substantial charge relaxation/transport. The reported study disentangles fundamentally different contributions to charge trapping dynamics in the nanocrystal-based optoelectronic devices and can serve as a useful tool for QD solar cell development. PMID- 24069879 TI - Parents' preferences regarding appearance and attire of orthodontists. AB - OBJECTIVE: To evaluate parents' preferences regarding the appearance and attire of orthodontists. MATERIALS AND METHODS: Parents attending their child's first orthodontic appointment were asked to choose from among sets of photographs of potential orthodontic providers. Selected factors were varied within the sets, including sex and age of the provider as well as attire (casual, formal, white coat, or scrubs), hairstyle (loose or tied back for women, facial hair or clean shaven for men), and presence of a nametag. RESULTS: A total of 77 parents participated. There were significant differences in choice of provider in terms of the provider's sex (P<.0001), age (P=.0013), dress (P<.0001), hair (P<.0001), and nametag (P=.0065). There were no significant differences in preference attributable to parent characteristics (P>.05). CONCLUSION: Parents of orthodontic patients demonstrated clear preferences for choosing a provider related to factors that are not within the control of the practitioner (sex and age) as well as factors that can be changed by the practitioner (attire, hairstyle, and wearing a nametag). PMID- 24069880 TI - Protonation equilibrium and hydrogen production by a dinuclear cobalt-hydride complex reduced by cobaltocene with trifluoroacetic acid. AB - A dinuclear Co complex with bis(pyridyl)pyrazolato (bpp(-)) and terpyridine (trpy) ligands, [Co(III)2(trpy)2(MU-bpp)(OH)(OH2)](4+) (1(4+)), undergoes three electron reduction by cobaltocene in acetonitrile to produce 1(+), which is in the protonation equilibrium with the Co(II)Co(III)-hydride complex, and the further protonation of the hydride by trifluoroacetic acid yields hydrogen quantitatively. The kinetic study together with the detection of the Co(II)Co(III)-hydride complex revealed the mechanism of the hydrogen production by the reaction of 1(+) with trifluoroacetic acid. PMID- 24069881 TI - A new strategy to improve the metabolic stability of lactone: discovery of (20S,21S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase I inhibitors. AB - Lactone is a common structural motif in biologically active natural products. However, the metabolic instability of lactone significantly reduces their in vivo potency. In the present investigation, a new strategy to improve the metabolic stability of lactone was provided by the design of alpha-fluoro ether as a novel bioisostere of lactone. The effectiveness of the alpha-fluoro ether/lactone replacement was validated by the discovery of (20S,21S)-21-fluorocamptothecins as hydrolytically stable topoisomerase I inhibitors. A highly potent camptothecin derivative, 8l, was successfully identified, which showed excellent in vitro and in vivo antitumor activities and represents a promising lead for the discovery of novel antitumor agents. Interestingly, this study also provided a new structure activity relationship for the C21-carbonyl group of camptothecin, which has been regarded as an essential pharmacophore. Our results revealed that the conserved C21-carbonyl group can be replaced by a fluorine substituent. alpha-Fluoro ether may have general application in improving the metabolic stability of lactone. PMID- 24069882 TI - Risk, responsibility and surgery in the 1890s and early 1900s. PMID- 24069883 TI - The research council system and the politics of medical and agricultural research for the British Colonial Empire, 1940-52. PMID- 24069884 TI - Travelling knowledge and forensic medicine: infanticide, body and mind in the Netherlands, 1811-1911. PMID- 24069885 TI - Failing to professionalise, struggling to specialise: the rise and fall of health promotion as a putative specialism in England, 1980-2000. PMID- 24069886 TI - A 'textbook pattern'? Malaria control and eradication in Jamaica, 1910-65. PMID- 24069899 TI - A direct method for oxidizing quinoxaline, tetraazaphenanthrene, and hexaazatriphenylene moieties using hypervalent lambda3-iodinane compounds. AB - An efficient oxidation reaction of various electron-poor quinoxaline-core containing compounds, such as quinoxalines, 1,4,5,8-tetraazaphenanthrenes, and 1,4,5,8,9,12-hexaazatriphenylene, using [bis(trifluoroacetoxy)iodo]benzene is reported. These compounds are converted into the corresponding quinoxalinediones in good to high yields at room temperature using an acetonitrile/water solvent mixture. This unprecedented reaction should enable the synthesis of a wide variety of compounds useful in several fields of chemistry. PMID- 24069887 TI - History of the leech trade in Ireland, 1750-1915: microcosm of a global commodity. PMID- 24069900 TI - Iron speciation of airborne subway particles by the combined use of energy dispersive electron probe X-ray microanalysis and Raman microspectrometry. AB - Quantitative energy-dispersive electron probe X-ray microanalysis (ED-EPMA), known as low-Z particle EPMA, and Raman microspectrometry (RMS) were applied in combination for an analysis of the iron species in airborne PM10 particles collected in underground subway tunnels. Iron species have been reported to be a major chemical species in underground subway particles generated mainly from mechanical wear and friction processes. In particular, iron-containing particles in subway tunnels are expected to be generated with minimal outdoor influence on the particle composition. Because iron-containing particles have different toxicity and magnetic properties depending on their oxidation states, it is important to determine the iron species of underground subway particles in the context of both indoor public health and control measures. A recently developed analytical methodology, i.e., the combined use of low-Z particle EPMA and RMS, was used to identify the chemical species of the same individual subway particles on a single particle basis, and the bulk iron compositions of airborne subway particles were also analyzed by X-ray diffraction. The majority of airborne subway particles collected in the underground tunnels were found to be magnetite, hematite, and iron metal. All the particles collected in the tunnels of underground subway stations were attracted to permanent magnets due mainly to the almost ubiquitous ferrimagnetic magnetite, indicating that airborne subway particles can be removed using magnets as a control measure. PMID- 24069901 TI - The attractiveness of family medicine among Polish medical students. AB - BACKGROUND: In many developed countries tuning supply and demand of medical doctors is a continuous challenge to meet the ever changing needs of community and individual patients. The long study period for medical doctors creates the opportunity to observe the current career preferences of medical students and evolution in time. OBJECTIVES: To investigate the career choices of Polish students in different stages of their medical education. METHODS: Medical students at five Polish medical universities were questioned about their career aspirations in the first, third and sixth year. RESULTS: A total of 2020 students were recruited for the survey. Among first year students 17% preferred family medicine as final career option, compared to 20% in the third year, and 30% in the sixth year (significant trend, P < 0.0001). In particular, female students prefer family medicine: 71% women versus 62% women in the group with a preference for a non-family medicine orientation (P = 0.008). Medical students rejecting a career as a family doctor stated that the impossibility to work in a hospital environment was the determining factor. CONCLUSION: The opportunity for professional development seems to be an important determining factor in the choice of a medical specialty in Poland. The proportion of Polish students choosing family medicine increases during their progress in medical education, with one third of students interested in a career in family medicine by year six. PMID- 24069903 TI - n-BuLi/LiCH2CN-mediated one-carbon homologation of aryl epoxides into conjugated allyl alcohols. AB - A series of styrene oxides in the presence of a 1:1 mixture of n-butyllithium (n BuLi) and lithioacetonitrile (LiCH2CN) in THF are converted into one-carbon homologated allyl alcohols in an unusual regioselective manner. PMID- 24069902 TI - Renal protection with calcium antagonists: the role of lercanidipine. AB - BACKGROUND: Clinical research in the field of hypertension is now increasingly focusing on the potential effects of antihypertensive treatments that may go beyond the reduction of blood pressure (BP). In particular, renal protection appears as a desirable goal, especially considering that hypertension is associated with an increased risk of developing kidney damage, which may eventually lead to end-stage renal disease and a higher mortality. Dihydropyridine calcium channel blockers (CCBs) are widely used in the field of hypertension therapy but the different renal effects of the various CCBs have been poorly explored to date. SCOPE: This review will discuss available evidence on the renal effects of two calcium channel blockers: amlodipine and lercanidipine, on the basis of clinical data. METHODS: MEDLINE and EMBASE were searched for inclusion of relevant studies. No limitations in time were considered. RESULTS: Results from preclinical and clinical studies suggest that amlodipine is overall less effective in terms of renal protection when compared with other antihypertensive tested agents. Its beneficial effect in retarding the progression of renal disease is achievable only when combined with a blocker of the renin-angiotensin system. Conversely lercanidipine seems to provide renal protection in a similar way to ACE inhibitors, probably thanks to its mechanism of action which acts directly on the afferent and efferent renal arterioles. CONCLUSIONS: Treatment of hypertension with CCBs should take into consideration the special effects of each single agent at different levels; lercanidipine for example may play a useful role in the management not only of hypertension but also in renal protection of hypertensive patients. PMID- 24069904 TI - Children's sensitivity to ulterior motives when evaluating prosocial behavior. AB - Reasoning about ulterior motives was investigated among children ages 6-10 years (total N = 119). In each of two studies, participants were told about children who offered gifts to peers who needed help. Each giver chose to present a gift in either a public setting, which is consistent with having an ulterior motive to enhance one's reputation, or in a private setting, which is not consistent with having an ulterior motive. In each study, the 6- to 7-year olds showed no evidence of understanding that the public givers might have ulterior motives, but the 8- to 10-year olds rated the private givers more favorably. In , the older children were more likely than the younger children to refer to impression management when explaining their judgments of the givers. The younger children who mentioned impression management did so to justify a preference for public givers (e.g., by explaining that public givers are nicer because more of their peers will know that they are nice). Results from suggest that developmental change in children's reasoning about intentions and social outcomes contributes to their understanding of ulterior motives. PMID- 24069905 TI - Risks for STIs/HIV infection among Madawalabu university students, Southeast Ethiopia: a cross sectional study. AB - INTRODUCTION: In developing nations, the spread of STIs/HIV infection continues to affect millions of young and productive population. In Ethiopia youths including university/college students are at greater risk of STIs including HIV infection often due to many risky sexual behaviors. Although there are some anecdotal evidences suggesting widespread unsafe sexual practices among university students, the paucity of research finding, especially in newly established public universities are the major bottle necks to commence feasible interventions. Therefore, this study was designed to assess the magnitudes and factors associated with risks for STIs/HIV infections among Madawalabu university students in Southeast Ethiopia. METHODOLOGY: An institution based cross sectional study was conducted from May-June 2012. A total of 390 students were selected using stratified then simple random sampling method. Descriptive statistics, binary logistic and multivariable logistic regression analyses were employed to identify factors associated with risks for STIs/HIV infection. RESULT: Combined risk measure showed that 51.4% of students were at risk of having STIs and/or HIV infection. Practicing casual sex/sex for benefits with first sexual partner (OR = 3.9[95%C.I: 1.86-8.03]), life time multiple sexual partner (had more than three sexual partners) (OR = 2.7[95%C.I: 1.13-6.28]), and number of sexual partners in the last 12 months (four and above) (OR = 4.8[95%C.I: 1.77-13.53]) showed statistically significant association with risks for STIs and/or HIV infection. Practicing casual sex/ sex for any benefit with their first sexual partner (AOR = 3.9 [95%CI: 1.80-8.50]) and multiple sexual partners in the last 12 months (four and above) (AOR = 3.7 [95%C.I: 1.15-11.80]) were found to be the independent predictors of risks for STIs and/or HIV infection. CONCLUSION: This study has identified risks and risk sexual behaviors for STIs and/or HIV infection on university students. The knowledge of the students towards STIs and/or HIV is unsatisfactory. More than half of the students were at risk for STIs and/or HIV infection. Casual/benefit based sexual relationship with first sexual partner and having multiple sexual partners (>=4 sexual partners) in the last 12 months were independent predictors of STIs and/or HIV infections. Therefore, university based, risk reduction and behavior change focused interventions are recommended. PMID- 24069906 TI - Assessment of population exposure to PM10 for respiratory disease in Lanzhou (China) and its health-related economic costs based on GIS. AB - BACKGROUND: Evaluation of the adverse health effects of PM10 pollution (particulate matter less than 10 microns in diameter) is very important for protecting human health and establishing pollution control policy. Population exposure estimation is the first step in formulating exposure data for quantitative assessment of harmful PM10 pollution. METHODS: In this paper, we estimate PM10 concentration using a spatial interpolation method on a grid with a spatial resolution 0.01 degrees * 0.01 degrees . PM10 concentration data from monitoring stations are spatially interpolated, based on accurate population data in 2000 using a geographic information system. Then, an interpolated population layer is overlaid with an interpolated PM10 concentration layer, and population exposure levels are calculated. Combined with the exposure-response function between PM10 and health endpoints, economic costs of the adverse health effects of PM10 pollution are analyzed. RESULTS: The results indicate that the population in Lanzhou urban areas is distributed in a narrow and long belt, and there are relatively large population spatial gradients in the XiGu, ChengGuan and QiLiHe districts. We select threshold concentration C0 at: 0 MUg m(-3) (no harmful health effects), 20 MUg m(-3) (recommended by the World Health Organization), and 50 MUg m(-3) (national first class standard in China) to calculate excess morbidity cases. For these three scenarios, proportions of the economic cost of PM10 pollution-related adverse health effects relative to GDP are 0.206%, 0.194% and 0.175%, respectively. The impact of meteorological factors on PM10 concentrations in 2000 is also analyzed. Sandstorm weather in spring, inversion layers in winter, and precipitation in summer are important factors associated with change in PM10 concentration. CONCLUSIONS: The population distribution by exposure level shows that the majority of people live in polluted areas. With the improvement of evaluation criteria, economic damage of respiratory disease caused by PM10 is much bigger. The health effects of Lanzhou urban residents should not be ignored. The government needs to find a better way to balance the health of residents and economy development. And balance the pros and cons before making a final policy. PMID- 24069908 TI - Strategies to Enhance the Efficiency of Endothelial Progenitor Cell Therapy by Ephrin B2 Pretreatment and Coadministration with Smooth Muscle Progenitor Cells on Vascular Function During the Wound-Healing Process in Irradiated or Nonirradiated Condition. AB - Endothelial progenitor cell (EPC) transplantation has beneficial effects for therapeutic neovascularization. We therefore assessed the effect of a therapeutic strategy based on EPC administration in the healing of radiation-induced damage. To improve cell therapy for clinical use, we used pretreatment with ephrin B2-Fc (Eph-B2-Fc) and/or coadministration with smooth muscle progenitor cells. At day 3, EPCs promoted dermal wound healing in both nonirradiated and irradiated mice by 1.2- and 1.15-fold, respectively, compared with animals injected with phosphate-buffered saline. In addition, EPCs also improved skin-blood perfusion and capillary density in both irradiated and nonirradiated mice compared with PBS injected animals. We also demonstrated that activation with Eph-B2-Fc increased wound closure by 1.6-fold compared with unstimulated EPCs in nonirradiated mice. Interestingly, the beneficial effect of Eph-B2-Fc was abolished in irradiated animals. In addition, we found that Eph-B2-Fc stimulation did not improve EPC induced vascular permeability or adhesiveness compared to unstimulated EPCs. We hypothesized that this effect was due to high oxidative stress during irradiation, leading to inhibition of EPCs' beneficial effect on vascular function. In this line, we demonstrated that, in irradiated conditions, N-acetyl l-cysteine treatment restored the beneficial effect of EPC stimulation with Eph B2-Fc in the wound healing process. In conclusion, stimulation by Eph-B2-Fc improved the beneficial effect of EPCs in physiological conditions and irradiated conditions only in association with antioxidant treatment. Additionally, cotherapy was beneficial in pathological conditions. PMID- 24069909 TI - Genome mining reveals the genus Xanthomonas to be a promising reservoir for new bioactive non-ribosomally synthesized peptides. AB - BACKGROUND: Various bacteria can use non-ribosomal peptide synthesis (NRPS) to produce peptides or other small molecules. Conserved features within the NRPS machinery allow the type, and sometimes even the structure, of the synthesized polypeptide to be predicted. Thus, bacterial genome mining via in silico analyses of NRPS genes offers an attractive opportunity to uncover new bioactive non ribosomally synthesized peptides. Xanthomonas is a large genus of Gram-negative bacteria that cause disease in hundreds of plant species. To date, the only known small molecule synthesized by NRPS in this genus is albicidin produced by Xanthomonas albilineans. This study aims to estimate the biosynthetic potential of Xanthomonas spp. by in silico analyses of NRPS genes with unknown function recently identified in the sequenced genomes of X. albilineans and related species of Xanthomonas. RESULTS: We performed in silico analyses of NRPS genes present in all published genome sequences of Xanthomonas spp., as well as in unpublished draft genome sequences of Xanthomonas oryzae pv. oryzae strain BAI3 and Xanthomonas spp. strain XaS3. These two latter strains, together with X. albilineans strain GPE PC73 and X. oryzae pv. oryzae strains X8-1A and X11-5A, possess novel NRPS gene clusters and share related NRPS-associated genes such as those required for the biosynthesis of non-proteinogenic amino acids or the secretion of peptides. In silico prediction of peptide structures according to NRPS architecture suggests eight different peptides, each specific to its producing strain. Interestingly, these eight peptides cannot be assigned to any known gene cluster or related to known compounds from natural product databases. PCR screening of a collection of 94 plant pathogenic bacteria indicates that these novel NRPS gene clusters are specific to the genus Xanthomonas and are also present in Xanthomonas translucens and X. oryzae pv. oryzicola. Further genome mining revealed other novel NRPS genes specific to X. oryzae pv. oryzicola or Xanthomonas sacchari. CONCLUSIONS: This study revealed the significant potential of the genus Xanthomonas to produce new non-ribosomally synthesized peptides. Interestingly, this biosynthetic potential seems to be specific to strains of Xanthomonas associated with monocotyledonous plants, suggesting a putative involvement of non-ribosomally synthesized peptides in plant-bacteria interactions. PMID- 24069910 TI - Characterization of the head-to-trunk orientation with handheld optical 3D apparatus based on the fringe projection technique. AB - BACKGROUND: Knowing the orientation of the head is important in many fields, including medicine. Many methods and measuring systems exist, but usually they use different markers or sensors attached to the subject's head for head orientation determination. In certain applications these attachments may represent a burden or a distraction to the subject under study which may have an unfavourable impact on the measurement. We propose a non-contact optical method for head-to-trunk orientation measurement that does not require any attachments to the subject under study. METHODS: An innovative handheld 3D apparatus has been developed for non-invasive and fast 3D shape measurements. It is based on the triangulation principle in combination with fringe projection. The shape of the subject's upper trunk and head is reconstructed from a single image using the Fourier transform profilometry method. Two shape measurements are required to determine the head-to-trunk orientation angles: one in the reference (neutral) position and the other one in the position of interest. The algorithm for the head-to-trunk orientation angle extraction is based on the separate alignment of the shape of the subject's upper trunk and head against the corresponding shape in the reference pose. Single factor analysis of variance (ANOVA) was used for statistical characterisation of the method precision. RESULTS: The method and the 3D apparatus were verified in-vitro using a mannequin and a reference orientation tracker. The uncertainty of the calculated orientation was 2 degrees . During the in-vivo test with a human subject diagnosed with cervical dystonia (aged 60), the repeatability of the measurements was 3 degrees . In-vitro and in-vivo comparison was done on the basis of an experiment with the mannequin and a healthy male (aged 29). These results show that only the difference between flexion/extension measured angles was statistically significant. The differences between means were less than 1 degrees for all ranges. CONCLUSIONS: The new non-contact method enables the compensation of the movement of the measuring instrument or the subject's body as a whole, is non-invasive, requires little additional equipment and causes little stress for the subject and operator. We find that it is appropriate for measurements of the head orientation with respect to the trunk for the characterization of the cervical dystonia. PMID- 24069912 TI - Detection of CTX-M-type extended-spectrum beta-lactamases among Jordanian clinical isolates of Enterobacteriaceae. PMID- 24069913 TI - International health and the limits of its global influence: bhutan and the worldwide smallpox eradication programme. PMID- 24069914 TI - Mediators between Theoretical and Practical Medieval Knowledge: Medical Notebooks from the Cairo Genizah and their Significance. PMID- 24069915 TI - Cure or Protection? The meaning of smallpox inoculation, ca 1750-1775. PMID- 24069916 TI - Tom Tiddler's Ground: Irregular Medical Practitioners and Male Sexual Problems in New Zealand, 1858-1908. PMID- 24069917 TI - 'As His was Not a Surgical Case it was Not My Duty to Attend Him': The Surgeon's Role in the Nineteenth-Century Royal Dockyards. PMID- 24069918 TI - Ritual circumcision in the age of germ theory amongst nineteenth-century new york immigrants. PMID- 24069931 TI - Review of Contagion: Historical Views of Diseases and Epidemics, Harvard University, http://ocp.hul.harvard.edu/contagion/. PMID- 24069930 TI - Review of Brought to Life: Exploring the History of Medicine, Science Museum, London, www.sciencemuseum.org.uk/broughttolife.aspx. PMID- 24069932 TI - The william bynum prize - celebration lecture. PMID- 24069935 TI - Green tea catechins: Proposed mechanisms of action in breast cancer focusing on the interplay between survival and apoptosis. AB - Recent data have shown strong chemopreventive and possibly cancer chemotherapeutic effects of green tea polyphenols against cancer. Despite advances in breast cancer treatment, mortality from breast cancer is still high. Undoubtedly novel treatment strategies are needed for chemoprevention of high risk women and for the treatment of receptor negative breast cancer. Green tea catechins have been shown to inhibit proliferation of breast cancer cells and to block carcinogenesis. This review attempts a critical presentation of the mechanisms of action of green tea catechins in breast cancer. Several mechanisms of action of green tea catechins in breast cancer have been proposed including modulation of extracellular signalling, induction of apoptosis through redox regulation, or through modulation of epigenetic alterations. A number of molecular targets of green tea catechins have been suggested i.e molecular chaperones, telomerase, apoptotic cascade. Although the molecular links among the proposed mechanisms of action of green tea catechins are often missing, it must be emphasized that all the proposed mechanisms indicate that green tea catechins inhibit growth and /or promote apoptosis. It would be interesting if future experimental trials could take into account that green tea catechins are multi target agents and attempt to link every novel proposed target with the other already proposed targets of green tea catechins. PMID- 24069936 TI - Childhood mitochondrial encephalomyopathies: clinical course, diagnosis, neuroimaging findings, mtDNA mutations and outcome in six children. AB - Mitochondrial dysfunction manifests in many forms during childhood. There is no effective therapy for the condition; hence symptomatic therapy is the only option. The effect of symptomatic therapy are not well known. We present clinical course, diagnosis and effect of current treatments for six children suffering from mitochondrial encephalomyopathy identified by clinical demonstrations, brain MRI findings and DNA mutations. Two were male and four were female. Their age ranged between 2 and 17 years. Skeletal muscle biopsies were obtained in three and one showed misshaped and enlarged mitochondria under electron microscope. mtDNA mutation frequency was >30%. Five children were diagnosed with MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) and one with Leigh's syndrome (LS). All were given cocktail and symptomatic treatments. One of the five MELAS children died from severe complications. The other four MELAS children remain alive; four showed improvement, and one remained unresponsive. Of the four who showed improvement, two do not have any abnormal signs and the other two have some degree of motor developmental delay and myotrophy. The LS child is doing well except for ataxia. Until better therapy such as mitochondrial gene therapy is available, cocktail and symptomatic treatments could at least stabilize these children. PMID- 24069937 TI - Influence of gender roles and rising food prices on poor, pregnant women's eating and food provisioning practices in Dhaka, Bangladesh. AB - BACKGROUND: Maternal malnutrition in Bangladesh is a persistent health issue and is the product of a number of complex factors, including adherence to food 'taboos' and a patriarchal gender order that limits women's mobility and decision making. The recent global food price crisis is also negatively impacting poor pregnant women's access to food. It is believed that those who are most acutely affected by rising food prices are the urban poor. While there is an abundance of useful quantitative research centered on maternal nutrition and food insecurity measurements in Bangladesh, missing is an understanding of how food insecurity is experienced by people who are most vulnerable, the urban ultra-poor. In particular, little is known of the lived experience of food insecurity among pregnant women in this context. This research investigated these lived experiences by exploring food provisioning strategies of urban, ultra-poor, pregnant women. This knowledge is important as discussions surrounding the creation of new development goals are currently underway. METHODS: Using a focused-ethnographic approach, household food provisioning experiences were explored. Data from participant observation, a focus group discussion and semi structured interviews were collected in an urban slum in Dhaka, Bangladesh. Interviews were undertaken with 28 participants including 12 pregnant women and new mothers, two husbands, nine non-pregnant women, and five health care workers. RESULTS: The key findings are: 1) women were aware of the importance of good nutrition and demonstrated accurate, biomedically-based knowledge of healthy eating practices during pregnancy; 2) the normative gender rules that have traditionally constrained women's access to nutritional resources are relaxing in the urban setting; however 3) women are challenged in accessing adequate quality and quantities of food due to the increase in food prices at the market. CONCLUSIONS: Rising food prices and resultant food insecurity due to insufficient incomes are negating the recent efforts that have increased women's knowledge of healthy eating during pregnancy and their gendered empowerment. In order to maintain the gains in nutritional knowledge and women's increased mobility and decision-making capacity; policy must also consider the global political economy of food in the creation of the new development goals. PMID- 24069938 TI - Sustained impact of community-based physical activity interventions: key elements for success. AB - BACKGROUND: Compelling evidence supports the cost effectiveness and potential impact of physical activity on chronic disease prevention and health promotion. Quality of evidence is one piece, but certainly not the sole determinant of whether public health interventions, physical activity focused or otherwise, achieve their full potential for impact. Health promotion at both population and community levels must progress beyond health intervention models that isolate individuals from social, environmental, and political systems of influence.We offer a critical evaluation of lessons learned from two successful research initiatives to provide insights as to how health promotion research contributes to sustained impact. We highlight factors key to success including the theoretical and methodological integration of: i) a social ecological approach; ii) participatory action research (PAR) methods; and iii) an interdisciplinary team. METHODS: To identify and illustrate the key elements of our success we layered an evaluation of steps taken atop a review of relevant literature. RESULTS: In the school-based case study (Action Schools! BC), the success of our approach included early and sustained engagement with a broad cross-section of stakeholders, establishing partnerships across sectors and at different levels of government, and team members across multiple disciplines. In the neighbourhood built environment case study, the three domains guided our approach through study design and team development, and the integration of older adults' perspectives into greenway design plans. In each case study we describe how elements of the domains serve as a guide for our work. CONCLUSION: To sustain and maximize the impact of community-based public health interventions we propose the integration of elements from three domains of research that acknowledge the interplay between social, environmental and poilitical systems of influence. We emphasize that a number of key factors determine whether evidence from public health interventions in school and built environment settings is applied in practice and policy sectors. These include relationship building at individual, community, and societal levels of the social ecological model, using participatory action research methods, and involving an engaged and committed interdisciplinary team. PMID- 24069940 TI - Why are pro-poor exemption policies in Tanzania better implemented in some districts than in others? AB - BACKGROUND: Like other African countries, Tanzania has in recent years, been implementing various exemptions and targeting programmes to protect and ensure equitable access to health care by poorer segments of the population. A body of evidence indicates that exemption policies, while potentially effective in principle, are ineffective in implementation. However, there is evidence that some districts, despite the challenges, perform better than others in terms of identifying the poor and allocating funds for the poor and vulnerable groups. METHODS: Drawing from the review of minutes, health facility visits, and key informant interviews with the community representatives and the district health managers, the study explored why exemption policies in Tanzania are relatively better implemented in some districts than in others. RESULTS: The findings indicate that in Lindi district the pro-poor exemption mechanism was ineffective in implementation. There were no clear ways of identifying and protecting the poor household members. In contrast, in Iramba district the policy was relatively better implemented. The poor were identified at the village, ward, health facility and district levels. In some villages, the poor were grouped in 10s to form one household. Then, using the village funds, the Community Health Fund cards were purchased for them. Personal initiatives of the key district leaders, commitment of the district health management team and local government officials, regular supervisory visits, as well as incentives to the health facility committees and boards were the main factors that facilitated the implementation of the pro-poor exemption policy. CONCLUSIONS: It is concluded from this study that management and leadership practices including personal initiatives of the key district leaders, effective supervision mechanisms, commitment of the district health management team and local government officials, as well as incentives for the health facility committees and board members are pivotal for the implementation of the pro-poor exemption policies. PMID- 24069939 TI - A structural comparison of lipopolysaccharide biosynthesis loci of Legionella pneumophila serogroup 1 strains. AB - BACKGROUND: The lipopolysaccharide (LPS) is the major immuno-dominant antigen of all Legionella species including L. pneumophila. Its diversity is the basis for the classification of L. pneumophila into serogroups and monoclonal subgroups and is thought to be involved in strain specific virulence. The understanding of the genetic basis of the LPS-antigen is incomplete. Thus, we analyzed the genetic locus involved in LPS-biosynthesis of L. pneumophila serogroup 1 (Sg1) strains with the focus on strain specific gene composition. RESULTS: The LPS-biosynthesis loci of 14 L. pneumophila Sg1 strains comprise two distinct regions: A 15 kb region containing LPS-biosynthesis genes that can be found in all L. pneumophila strains and a Sg1-specific 18 kb region. The 15 kb region is highly conserved among Sg1 strains as reflected by high homologies of single ORFs and by a consistent ORF arrangement. In contrast, the Sg1 specific 18 kb region is variable and partially disrupted by phage related genes. We propose that the region spanning from ORF 6 to ORF 11 of the Sg1-specific region is likely involved in late LPS-modification. Due to the high variability of this small region and various combinations of single ORFs within this region a strain specific LPS-structure could be synthesized including modifications of legionaminic acid derivates. CONCLUSIONS: Our data clearly demonstrate that the gene structure of the LPS-biosynthesis locus of L. pneumophila Sg1 strains show significant interstrain variability. These data can be used for further functional analysis of the LPS synthesis to understand pathogenesis and reactivity with monoclonal antibodies. Moreover, variable but strain specific regions can serve as basis for the development of novel genotyping assays. PMID- 24069941 TI - Accuracy of early prediction of duration of mechanical ventilation by intensivists. AB - RATIONALE: Predictions of duration of mechanical ventilation are frequently made by intensivists and influence clinical decisions. OBJECTIVES: We aimed to measure the accuracy of these clinical early predictions. METHODS: One hundred fifty-five patients within 48 hours of initiation of mechanical ventilation on a general intensive care unit had clinical data prospectively collected and were followed to determine actual duration of mechanical ventilation. Intensivists, after evaluating patients in the first 2 consecutive days, predicted each duration of mechanical ventilation by selecting between less than 3, 4 to 7, 8 to 14, or more than 14 days. Accuracy of predictions was evaluated by comparisons between predicted and actual durations. MEASUREMENTS AND MAIN RESULTS: Raw agreement (95% confidence interval) between predicted and actual durations, classified into the four categories, was 37% (29-45%). Predictions of duration of more than 7 and more than 14 days showed raw agreements of 59% (51-66%) and 83% (76-88%); sensitivities of 40% (28-54%) and 29% (13-51%); specificities of 71% (61-80%) and 93% (87-97%); positive predictive values of 48% (34-63%) and 44% (20-70%); and negative predictive values of 64% (54-73%) and 87% (81-92%), respectively. CONCLUSIONS: The accuracy of intensivists' early clinical predictions of duration of mechanical ventilation is limited, particularly for identifying patients who will require prolonged mechanical ventilation. PMID- 24069942 TI - Endothelial progenitor cells enhance islet engraftment, influence beta-cell function, and modulate islet connexin 36 expression. AB - The success of pancreatic islet transplantation is limited by delayed engraftment and suboptimal function in the longer term. Endothelial progenitor cells (EPCs) represent a potential cellular therapy that may improve the engraftment of transplanted pancreatic islets. In addition, EPCs may directly affect the function of pancreatic beta-cells. The objective of this study was to examine the ability of EPCs to enhance pancreatic islet transplantation in a murine syngeneic marginal mass transplant model and to examine the mechanisms through which this occurs. We found that cotransplanted EPCs improved the cure rate and initial glycemic control of transplanted islets. Gene expression data indicate that EPCs, or their soluble products, modulate the expression of the beta-cell surface molecule connexin 36 and affect glucose-stimulated insulin release in vitro. In conclusion, EPCs are a promising candidate for improving outcomes in islet transplantation, and their mechanisms of action warrant further study. PMID- 24069943 TI - Overuse, tissue fatigue, and injuries. AB - Research has provided abundant evidence that overtraining is associated with fatigue and subsequent injury. For many years, it has been axiomatic that the vast majority of dance injuries are the result of overuse, and that dancers frequently persist in movement activities in the presence of microscopic injury- i.e., "dance through" injuries. While it is well-established fact that rest and adequate nutrition are vital components of training and conditioning, for various reasons it remains problematic for dancers to assimilate these requirements into their daily regimen. This review article provides some physiologically and biomechanically based information about the causes, inter-relationships, and consequences of these fundamental premises in dance science. PMID- 24069944 TI - What is known about the effect of fatigue on injury occurrence among dancers? AB - Fatigue is often thought of as any transient exercise-induced reduction of work capacity. In fact, it is a complex phenomenon caused by overlapping and interacting peripheral and central mechanisms. There is a known relationship between fatigue, diminished performance, and injury. This paper reviews what is currently known about fatigue in the current literature. PMID- 24069945 TI - Fatigue effects on quadriceps and hamstrings activation in dancers performing drop landings. AB - Fatigue may reduce a dancer's ability to maintain the muscle synergies required for stable human movement. Therefore, fatigue presents as a potential risk factor for injury in dancers. Activation patterns of the quadriceps and hamstrings muscle groups in athletic populations have been consistently reported to alter in response to fatigue during landing tasks. It is unknown whether dancers demonstrate similar muscle activation patterns, nor if dancers respond to fatiguing protocols, with regard to muscle activation, in the same manner as their athletic counter-parts. The purpose of this study was to assess quadriceps and hamstrings activation levels in a cohort of dancers performing drop landings before and after completion of a dance-specific fatigue protocol, the High Intensity Dance Performance Fitness Test. Quadriceps and hamstrings co contraction ratios significantly increased between pre- and post-fatigue conditions in a similar fashion to that reported in the literature. Therefore, the neuromuscular activation of the knee extensors and flexors in dancers changed in response to the dance-specific fatiguing protocol. Furthermore, quadriceps and hamstrings co-contraction ratios were substantially greater than previously reported in other athletic populations, due to low hamstrings activation levels. Future investigation of dancer biomechanical adaptations to fatigue would be beneficial to further examine the potential implications for injury risk. PMID- 24069946 TI - Psychological distress among dancers seeking outpatient treatment for musculoskeletal injury. AB - The purpose of this study was to investigate the incidence and magnitude of clinically significant psychological symptoms among outpatient injured dancers presenting for musculoskeletal issues and to identify features of "at risk" dancer-patients who might require additional psychological support when injured. The Brief Symptom Inventory(r) (BSI), a highly reliable and valid screening tool for psychological distress, was administered to first- and last-visit injured dancers at an orthopedic clinic in the Netherlands from February to May 2008. In all, 153 BSI surveys were completed, including 82 among first-visit patients and 71 among end-treatment patients. Scores were examined for the influence of age, gender, dance level, style, pain, perceived level of artistic compromise, and anatomic location of injury. Dancers' scores were compared to normative values for adult non-psychiatric patient community members. Ninety-two dancers (60.1%) met requirements for clinical referral to a psychologist or psychiatrist, having scored two or more standard deviations (SD) above the norm in at least one of nine psychopathological symptoms. Across first- and last-visit groups, dancers met referral criteria for an average of four psychopathological symptoms. First visit dancers demonstrated higher distress than the general population on 90% of BSI dimensional symptoms and last-visit dancers on 50%. On the Global Symptom Index, a summary score for overall distress and the best measure of psychological discomfort, 46.6% of dancers demonstrated "above average" distress (>= 1 SD) compared to the general population, and 19.6% demonstrated "high" (>= 2 SD) or "very high" (>= 2.5 SD) distress. Compared to academy level pre-professional students, professionals showed reduction in BSI scores on somatic, cognitive, interpersonal sensitivity, anxious, hostile, phobic, and global scores following resolution of injury, particularly among those greater than 25 years of age. Students and professionals less than 25 years of age demonstrated little change in scores from the initial visit to the end of treatment. In addition, students worsened in somatization and depression domains over time, suggesting perseverative or brooding behavior and poor coping skills. Amateurs overall scored average or below average on the BSI compared to the general population at both time points. It is concluded that healthcare providers should be made aware that outpatient injured dancers presenting for musculoskeletal assessment may additionally have high levels of psychological distress, and this may warrant formal evaluation by a mental health professional. PMID- 24069947 TI - Lower-limb proprioceptive awareness in professional ballet dancers. AB - Enhanced proprioceptive feedback strengthens synergistic muscle groups and stabilizes the coordination of limbs, thus contributing to the movement efficiency of ballet dancers. The present study compared lower-limb proprioceptive awareness in professional ballet dancers to matched controls who had no dance training. Two assessment methods were used to test the hypothesis that ballet dancers would demonstrate increased proprioceptive awareness in the ankle, knee, and hip: 1. a joint-position matching task to assess static proprioceptive joint awareness, and 2. an eyes-closed, quiet standing task to assess both static and dynamic proprioceptive awareness through measures of center of pressure (COP) variability. Results of the matching task indicated that the dancers exhibited greater proprioceptive awareness than controls for all three joints (p < 0.001). Also, dancers were equally aware of the positioning of their ankle, knee, and hip joints (p > 0.05), whereas controls were less aware of their ankle position compared to their knee and hip joints (p < 0.001). Measures indexing COP variability during quiet standing did not differ between groups and thus failed to reflect increased proprioceptive awareness in dancers (all p > 0.05). This indicates that quiet stance may have limited value as a means for evaluating proprioception. These findings provide preliminary evidence that enhanced proprioceptive awareness of lower limb joints should be considered as an evaluative criterion for dancers' ability to learn complex ballet skills. They also indicate that quiet standing tasks may not provide sufficient challenge for dancers' enhanced proprioceptive awareness to manifest. PMID- 24069950 TI - Molecular mechanisms and cell targets of Th17 cells in the gastrointestinal tract: an innate sense of adaptivity. AB - T-helper (TH) 17 activation is crucial for protective immune responses against bacteria and fungi at mucosal surfaces, but it can also be implicated in the pathogenesis of several autoimmune and chronic inflammatory diseases, such as inflammatory bowel diseases (IBD). Although rapid progress was made elucidating induction and functional heterogeneity of Th17 responses, the underlying molecular effects of Th17 response including the most relevant different cell targets of Th17 cytokines remain poorly understood. Cytokines produced by Th17 cells have broad effects on both hematopoietic and nonhematopoietic cells and can act in synergy with various inflammatory factors. In this review, we will focus on the effects of Th17-derived cytokines in the gastrointestinal tract and discuss how Th17 responses can affect both innate and adaptive immunity and may contribute to the pathogenesis of inflammatory GI processes. PMID- 24069951 TI - Changes of PI3K/AKT/BCL2 signaling proteins in congenital Giant Nevi: melanocytes contribute to their increased survival and integrity. AB - Congenital Giant Nevi (CGN) are rare melanocytic lesions with the potential to regress into malignant melanoma. Simultaneous up-regulation and cooperative interactions of signaling pathways are crucial events in the pathogenesis of melanocytes. Our study aimed to identify changes in the expression and activation of proteins controlling survival and/or apoptosis of the key signaling pathways PI3K/AKT/BCL2 and Wnt/beta-catenin of CGN melanocytes. We applied a model of cultured melanocytes from paired CGN and normal appearing skin, and Western blot (WB) analyzed the expression and activation profile of survival and anti apoptotic proteins of these signaling pathways, growth pattern, cell cycle and apoptosis. WB analysis demonstrated a significant higher expression level of activated AKT and of BCL2 proteins in the CGN melanocytes compared with paired melanocytes from normal appearing skin. A relative increase in the level of GSK3 and FOXO1 proteins, down stream targets of AKT, as well as of pbeta-catenin was also detected in the CGN melanocytes compared with the controls. These changes were not affected by growth of the CGN melanocytes in reduced serum (starvation). Both cell populations shared a similar growth pattern, with no significant differences in the proportion of apoptotic cells and in cell cycle fractions. These data demonstrate for the first time, changes in signaling proteins of cultured CGN melanocytes. Further, suggesting that the changes in AKT/BCL2 signaling molecules might mediate growth and anti-apoptosis processes at least in part, thus increasing the survival potential of CGN melanocytes and maintaining their integrity. PMID- 24069952 TI - Tuning the reactivity of an actor ligand for tandem CO2 and C-H activations: from spectator metals to metal-free. AB - The 4,5-diazafluorenide ligand (L(-)) serves as an actor ligand in the formal insertion of CO2 into a C-H bond remote from the metal center. With the Ru(II) complex of L(-) as the starting point, Rh(III), Rh(I), and Cu(I) were used as spectator metal centers to tune the reactivity of the actor ligand toward CO2. In the case of Rh(III)-diazafluorenide a room temperature reversible activation of CO2 was observed, similar to the isoelectronic Ru(II) analogue. In the case of Rh(I)- and Cu(I)-diazafluorenide CO2 is trapped by the formation of dinuclear carboxylate complexes and diazafluorene (LH). The spectator metal center could even be replaced entirely with an organic group allowing for the first metal-free reversible tandem CO2 and C-H activation. PMID- 24069954 TI - Prosecuting child abusers, respecting victims: a contrast of approaches in the UK, Tajikistan and Tanzania. AB - This article summarises child abuse as a global problem of increasing breadth and complexity. It reviews the development of procedures for prosecuting alleged abusers and treating complainants appropriately in the course of investigations, medical examinations and court hearings. It contrasts the diverse environments of the UK, Tajikistan and Tanzania. The author draws on his experience of practising criminal law since 1984 in England and Wales and working as a consultant in 2011 with the Girls Support Service in Tajikistan, a European-and UN-funded NGO, and with UNICEF in Tanzania in 2012. PMID- 24069953 TI - Discovery of a novel series of potent non-nucleoside inhibitors of hepatitis C virus NS5B. AB - Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Toward those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition that has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics, and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19. PMID- 24069956 TI - ICP-MS-based multiplex and ultrasensitive assay of viruses with lanthanide-coded biospecific tagging and amplification strategies. AB - Highly sensitive and a multiplex assay of viruses and viral DNAs in complex biological samples is extremely important for clinical diagnosis and prognosis of pathogenic diseases as well as virology studies. We present an effective ICP-MS based multiplex and ultrasensitive assay of viral DNAs with lanthanide-coded oligonucleotide hybridization and rolling circle amplification (RCA) strategies on biofunctional magnetic nanoparticles (MNPs), in which single-stranded capture DNA (ss-Cap-DNA)-functionalized MNPs (up to 1.65 * 10(4) ss-Cap-DNA per MNP) were used to recognize and enrich target DNAs, and single-stranded report DNA (ss-Rep DNA-DOTA-Ln) coded by the lanthanide-DOTA complex hybridized with the targeted DNA for highly sensitive readout of HIV (28 amol), HAV (48 amol), and HBV (19 amol). When utilizing the RCA technique in association with the design and synthesis of a "bridge" DNA and a corresponding ss-Rep-DNA-DOTA-Ho, as low as 90 zmol HBV could be detected. Preliminary applications to the determination of the viral DNAs in 4T1 cell lysates and in serum confirmed the feasibility of this ICP MS-based multiplex DNA assay for clinical use. One can expect that this element coded ICP-MS-based multiplex and ultrasensitive DNA assay will play an ever more important role in the fields of bioanalysis and virology and in medical studies after further sophisticated modifications. PMID- 24069957 TI - Palladium-catalyzed decarboxylative ortho acylation of azobenzenes with alpha oxocarboxylic acids. AB - A palladium-catalyzed decarboxylative ortho acylation of azobenzenes with alpha oxocarboxylic acids via ligand-directed C-H activation has been explored. The reaction proceeded smoothly with potassium persulfate as the oxidant to afford acylated unsymmetrical azobenzenes in moderate to good yields and tolerated chloro, bromo, iodo, and methoxy groups. Para, ortho, and disubstituted as well as unsymmetrical azobenzenes could be used. PMID- 24069955 TI - Eye tracking in early autism research. AB - Eye tracking has the potential to characterize autism at a unique intermediate level, with links 'down' to underlying neurocognitive networks, as well as 'up' to everyday function and dysfunction. Because it is non-invasive and does not require advanced motor responses or language, eye tracking is particularly important for the study of young children and infants. In this article, we review eye tracking studies of young children with autism spectrum disorder (ASD) and children at risk for ASD. Reduced looking time at people and faces, as well as problems with disengagement of attention, appear to be among the earliest signs of ASD, emerging during the first year of life. In toddlers with ASD, altered looking patterns across facial parts such as the eyes and mouth have been found, together with limited orienting to biological motion. We provide a detailed discussion of these and other key findings and highlight methodological opportunities and challenges for eye tracking research of young children with ASD. We conclude that eye tracking can reveal important features of the complex picture of autism. PMID- 24069958 TI - Computational studies on the excited states of luminescent platinum(II) alkynyl systems of tridentate pincer ligands in radiative and nonradiative processes. AB - Platinum(II) alkynyl complexes of various tridentate pincer ligands, [Pt(trpy)(C=CR)](+) (trpy = 2,2':6',2"-terpyridine), [Pt(R'-bzimpy)(C=CR)](+) (R' bzimpy = 2,6-bis(N-alkylbenzimidazol-2'-yl)pyridine and R' = alkyl), [Pt(R' bzimb)(C=CR)] (R'-bzimb = 1,3-bis(N-alkylbenzimidazol-2'-yl)benzene and R' = C4H9), have been found to possess rich photophysical properties. The emission in dilute solutions of [Pt(trpy)(C=CR)](+) originated from a triplet alkynyl-to tridentate pincer ligand-to-ligand charge transfer (LLCT) excited state, with mixing of a platinum-to-tridentate pincer ligand metal-to-ligand charge transfer (MLCT) excited state, while that of [Pt(R'-bzimb)(C=CR)] originated from a triplet excited state of intraligand (IL) character of the tridentate ligand mixed with a platinum-to-tridentate ligand MLCT character. Interestingly, both emissions were observed in [Pt(R'-bzimpy)(C=CR)](+) in some cases. In addition, [Pt(R'-bzimb)(C=CR)] displayed a photoluminescence quantum yield higher than that of [Pt(R'-bzimpy)(C=CR)](+). Computational studies have been performed on the representative complexes [Pt(trpy)(C=CPh)](+) (1), [Pt(R'-bzimpy)(C=CPh)](+) (2), and [Pt(R'-bzimb)(C=CPh)] (3), where R' = CH3 and Ph = C6H5, to provide an in depth understanding of the nature of their emissive origin as well as the radiative and nonradiative processes. In particular, the factors governing the ordering of the triplet excited states and radiative decay rate constants of the emissive state ((3)ES) have been examined. The potential energy profiles for the deactivation process from the (3)ES via triplet metal-centered ((3)MC) states have also been explored. This work reveals for the first time the potential energy profiles for the thermal deactivation pathway of square planar platinum(II) complexes. PMID- 24069959 TI - The two peptide lantibiotic lacticin 3147 acts synergistically with polymyxin to inhibit Gram negative bacteria. AB - BACKGROUND: The emergence of bacterial drug resistance encourages the re evaluation of the potential of existing antimicrobials. Lantibiotics are post translationally modified, ribosomally synthesised antimicrobial peptides with a broad spectrum antimicrobial activity. Here, we focussed on expanding the potential of lacticin 3147, one of the most studied lantibiotics and one which possesses potent activity against a wide range of Gram positive species including many nosocomial pathogens. More specifically, our aim was to investigate if lacticin 3147 activity could be enhanced when combined with a range of different clinical antibiotics. RESULTS: Initial screening revealed that polymyxin B and polymyxin E (colistin) exhibited synergistic activity with lacticin 3147. Checkerboard assays were performed against a number of strains, including both Gram positive and Gram negative species. The resultant fractional inhibitory concentration (FIC) index values established that, while partial synergy was detected against Gram positive targets, synergy was obvious against Gram negative species, including Cronobacter and E. coli. CONCLUSIONS: Combining lacticin 3147 with low levels of a polymyxin could provide a means of broadening target specificity of the lantibiotic, while also reducing polymyxin use due to the lower concentrations required as a result of synergy. PMID- 24069960 TI - Assessing the effects of variables and background selection on the capture of the tick climate niche. AB - BACKGROUND: Modelling the environmental niche and spatial distribution of pathogen-transmitting arthropods involves various quality and methodological concerns related to using climate data to capture the environmental niche. This study tested the potential of MODIS remotely sensed and interpolated gridded covariates to estimate the climate niche of the medically important ticks Ixodes ricinus and Hyalomma marginatum. We also assessed model inflation resulting from spatial autocorrelation (SA) and collinearity (CO) of covariates used as time series of data (monthly values of variables), principal components analysis (PCA), and a discrete Fourier transformation. Performance of the models was measured using area under the curve (AUC), autocorrelation by Moran's I, and collinearity by the variance inflation factor (VIF). RESULTS: The covariate spatial resolution slightly affected the final AUC. Consistently, models for H. marginatum performed better than models for I. ricinus, likely because of a species-derived rather than covariate effect because the former occupies a more limited niche. Monthly series of interpolated climate always better captured the climate niche of the ticks, but the SA was around 2 times higher and the maximum VIF between covariates around 30 times higher in interpolated than in MODIS derived covariates. Interpolated or remotely sensed monthly series of covariates always had higher SA and CO than their transformations by PCA or Fourier. Regarding the effects of background point selection on AUC, we found that selection based on a set of rules for the distance to the core distribution and the heterogeneity of the landscape influenced model outcomes. The best selection relied on a random selection of points as close as possible to the target organism area of distribution, but effects are variable according to the species modelled. CONCLUSION: Testing for effects of SA and CO is necessary before incorporating these covariates into algorithms building a climate envelope. Results support a higher SA and CO in an interpolated climate dataset than in remotely sensed covariates. Satellite-derived information has fewer drawbacks compared to interpolated climate for modelling tick relationships with environmental niche. Removal of SA and CO by a harmonic regression seems most promising because it retains both biological and statistical meaning. PMID- 24069961 TI - Therapeutic use of stories for children with atopic eczema and other chronic skin conditions. AB - Children with chronic skin diseases often experience significant psychological difficulties, yet pediatric dermatologists rarely have psychology professionals on hand to help address them. This article presents personalized stories as a technique for integrating psychologically developed interventions into day-to-day clinical practice with a view to improving treatment outcomes. PMID- 24069962 TI - Multimodality therapy in fistula-associated perianal mucinous adenocarcinoma. PMID- 24069963 TI - Laparoscopic-assisted sigmoid colectomy for diverticular colovesical fistula. PMID- 24069964 TI - Volar flap closure of a broad-based supernumerary finger. PMID- 24069965 TI - Is conservative management expedient in the treatment of Zargar's grade 3b gastric injuries after formalin ingestion? PMID- 24069966 TI - Remote group A beta-hemolytic Streptococcal fasciitis and myositis: a rare complication from hematogenous spread of Streptococcal pharyngitis. PMID- 24069967 TI - Horseshoe kidney transplantation. PMID- 24069968 TI - Reverse intestinal rotation in an adult resulting in concomitant small and large bowel obstruction. PMID- 24069969 TI - Morbidity after surgical treatment of hidradenitis suppurativa: reconstruction of severe genital lymphedema. PMID- 24069970 TI - Primary small cell carcinoma of the stomach: clinical outcomes and prognoses. PMID- 24069971 TI - Elevated creatinine after kidney transplantation. PMID- 24069972 TI - Left profunda femoris artery bullet embolus resulting from a 0.22 caliber gunshot wound to the back. PMID- 24069973 TI - Organoaxial gastric volvulus caused by incarceration of a gastric stromal tumor in paraesophageal hiatal hernia. PMID- 24069974 TI - Traumatic rupture of a previously undiagnosed giant hepatic hemangioma. PMID- 24069975 TI - Financial impact of surgical technique in the treatment of acute appendicitis in children. AB - Appendicitis is the most common emergent problem encountered by pediatric surgeons. Driven by improved cosmetic outcomes, many surgeons are offering pediatric patients single-incision laparoscopic appendectomy. We sought to investigate the financial impact of different surgical approaches to appendectomy. A retrospective study of patients with acute appendicitis undergoing appendectomy from February 2010 to September 2011 was conducted. Based on surgeon preference, patients underwent open appendectomy (OA), laparoscopic appendectomy (LA), or single-incision laparoscopic appendectomy (SILA). Demographic information, surgical outcomes, surgical supply costs, and total direct costs were recorded. A total of 465 patients underwent appendectomy during the study. The mean age of all patients was 11.2 years (range, 1 to 18 years). There were no conversions in the LA or SILA groups. There was a significant difference among surgical technique in regard to surgical supply costs (OA $159 vs. LA $650 vs. SILA $814, P < 0.01) and total direct costs (OA $2129 vs. LA $2624 vs. SILA $2991, P < 0.01). In our institution, both multiport laparoscopic and SILA carry higher costs when compared with OA, largely as a result of the cost of disposable instrumentation. Cost efficiency should be considered by surgeons when undertaking a minimally invasive approach to appendectomy. PMID- 24069976 TI - Comparing the cost and outcomes of laparoscopic versus open appendectomy for perforated appendicitis in children. AB - Although laparoscopic appendectomy (LA) is accepted treatment for perforated appendicitis (PA) in children, concerns remain whether it has equivalent outcomes with open appendectomy (OA) and increased cost. A retrospective review was conducted of patients younger than age 17 years treated for PA over a 12.5-year period at a tertiary medical center. Patient characteristics, preoperative indices, and postoperative outcomes were analyzed for patients undergoing LA and OA. Of 289 patients meeting inclusion criteria, 86 had LA (29.8%) and 203 OA (70.2%), the two groups having equivalent patient demographics and preoperative indices. Inpatient costs were not significantly different between LA and OA. LA had a lower rate of wound infection (1.2 vs. 8.9%, P = 0.017), total parenteral nutrition use (23.3 vs. 50.7%, P < 0.0001), and length of stay (5.56 +/- 2.38 days vs. 7.25 +/- 3.77 days, P = 0.0001). There was no significant difference in the rate of postoperative organ space abscess, surgical re-exploration, or rehospitalization. In children with PA, LA had fewer surgical site infections and shorter lengths of hospital stay compared with OA without an increase in inpatient costs. PMID- 24069977 TI - Allocation of healthcare dollars: analysis of nonneonatal circumcisions in Florida. AB - Circumcision remains a controversial operation. Most procedures are performed in the neonatal period and avoid general anesthesia. Legislation driven by policy statements from the American Academy of Pediatrics led to significant changes in circumcisions in Florida with a shift to nonneonatal procedures as a result of costs. We sought to study the prevalence and financial implications of nonneonatal circumcisions in Florida. A retrospective population study was performed using the Florida Agency for Health Care Administration outpatient procedure database. We queried for patients 0 to 17 years of age undergoing circumcision between 2003 and 2008. Demographics, charges, and insurance status were analyzed. From 2003 to 2008, 31,741 outpatient circumcisions were performed. Publicly funded circumcisions accounted for 17,537 charging the state $6,263 on average for each circumcision at an expense of $111.8 million for the 5-year time period analyzed. Publicly funded circumcision procedures increased more than sixfold (P < 0.0001) than those covered by private insurance. Black circumcision procedures increased 77.3 per cent, whereas white circumcisions increased 28.7 per cent. There has been a significant increase in the number of nonneonatal circumcisions performed. This has resulted in an increase in economic health care. Public funding of neonatal circumcision could result in significant cost savings and avoid potential complications of general anesthesia. PMID- 24069978 TI - Cystic biliary atresia: a wolf in sheep's clothing. AB - Neonatal obstructive jaundice is frequently explained by biliary atresia (BA) or the presence of a choledochal cyst (CC). Cystic biliary atresia (CBA) has been a proposed as a subtype of BA with projected improved outcomes. We aimed to characterize these lesions further. We conducted an Institutional Review Board approved review of all patients treated for obstructive jaundice at our tertiary children's hospital over 10 years. Over the decade we evaluated 91 children with obstructive jaundice: 13 CBA, 52 BA, and 26 CC. Patients with isolated CBA and BA were diagnosed significantly earlier than those with CC (15.9, 54, and 281 days, respectively; P = 0.0001). There was a significant delay between diagnosis and surgical intervention for patients with CBA compared with BA: 17 days versus 5.7 days (P = 0.004). There was no difference in rate of transplant between CBA and BA (31 vs. 50%; P = 0.35). The time from surgery until transplant was 13.9 and 18.6 months for CBA and BA, respectively (P = 0.62). Although radiographically similar to CC, CBA behaves similarly to isolated BA. Delay in recognition and surgical treatment may affect outcomes and lead to an increased incidence of liver failure. The presence of a cystic biliary malformation in the setting of neonatal jaundice should be regarded as CBA until proven otherwise. PMID- 24069979 TI - Manifestations of pediatric appendicopathia oxyurica. AB - Enterobius vermicularis is a parasite that inhabits the human digestive tract. We present two pediatric patients with symptoms mimicking acute appendicitis who were found to have E. vermicularis infection. The first case is a 5-year-old female who presented with flank and abdominal pain associated with low-grade fever and anorexia. She had localized tenderness in the right lower quadrant and a leukocytosis with left shift. Intraoperative findings included a normal appearing appendix, but ex vivo examination revealed Enterobius vermicularis. The second case is a 7-year-old female who presented with periumbilical abdominal pain, anorexia, and emesis. She had tenderness at McBurney's point, and ultrasound revealed a small echogenic focus within the appendix. Intraoperatively, the distal tip of the appendix appeared inflamed. Again, ex vivo examination revealed E. vermicularis. Enterobius vermicularis infection of the appendix can present with a clinical picture similar to acute appendicitis. In at-risk populations, it should be included in the differential diagnosis for children with right lower quadrant abdominal pain. Complete therapy requires treatment with mebendazole. PMID- 24069980 TI - Delays in treatment of pediatric appendicitis: a more accurate variable for measuring pediatric healthcare inequalities? AB - Racial and socioeconomic factors may cause barriers to healthcare access that result in delayed treatment. Because perforated appendicitis (PA) in children is thought to result from delays in treatment, it is often used as an index of barrier to access. Recent literature suggests that PA is not an inevitable consequence of delayed treatment, so it may not be the best marker for evaluating such barriers. Therefore we investigated whether racial and socioeconomic factors led directly to delays in treatment. We performed a retrospective study of 667 children undergoing appendectomy in a tertiary care center over 12.5 years. Univariate and multivariable regression analyses were used to determine if racial and socioeconomic variables were associated with increased risk of PA and increased risk of symptom duration greater than 48 hours. Hispanic children have higher rates of PA regardless of delays in treatment whereas black children had higher PA rates likely due to delays in treatment. These differences were not from socioeconomic factors in our cohort. PA, a heterogeneous disease whose course is determined by multiple factors, is not a good metric for evaluation healthcare disparities in the pediatric population. Delays in treatment may be a more appropriate measure of healthcare inequalities in children. PMID- 24069981 TI - Hyperkinetic gallbladder: an indication for cholecystectomy? AB - Cholecystectomy may benefit children with biliary colic without stones on ultrasound (US) or low ejection fraction on cholecystokinin-hepatobiliary iminodiacetic acid (CCK-HIDA) scan. Children with symptomatic biliary colic and abnormal HIDA scan, specifically those with high ejection fractions, may benefit from cholecystectomy. All patients younger than 18 years old undergoing cholecystectomy from 2008 to 2012 in our practice were reviewed. Patients with a negative US and CCK-HIDA ejection fractions 80 per cent or greater were included in the study. Patient data were extracted from charts, whereas postoperative symptoms were obtained by phone interviews. Of 174 patients who underwent cholecystectomy, 12 (7%) met study criteria. All patients (12 of 12) had evidence of cholecystitis on the final pathology note. All 11 patients contacted had relief of colic after gallbladder removal with a mean follow-up of 16 months. A subset of pediatric patients with high ejection fractions on CCK-HIDA and symptomatic biliary colic may have symptomatic relief with cholecystectomy. PMID- 24069982 TI - Self-reported barriers to pediatric surgical care in Guatemala. AB - Access to pediatric surgical care is limited in low- and middle-income countries. Barriers must be identified before improvements can be made. This pilot study aimed to identify self-reported barriers to pediatric surgical care in Guatemala. We surveyed 78 families of Guatemalan children with surgical conditions who were seen at a pediatric surgical clinic in Guatemala City. Spanish translators were used to complete questionnaires regarding perceived barriers to surgical care. Surgical conditions included hernias, rectal prolapse, anorectal malformations, congenital heart defects, cryptorchidism, soft tissue masses, and vestibulourethral reflux. Average patient age was 8.2 years (range, 1 month to 17 years) with male predominance (62%). Families reported an average symptom duration of 3.7 years before clinic evaluation. Families traveled a variety of distances to obtain surgical care: 36 per cent were local (less than 10 km), 17 per cent traveled 10 to 50 km, and 47 per cent traveled greater than 50 km. Other barriers to surgery included financial (58.9%), excessive wait time in the national healthcare system (10. 2%), distrust of local surgeons (37.2%), and geographic inaccessibility to surgical care (10.2%). The majority of study patients required outpatient procedures, which could improve their quality of life. Many barriers to pediatric surgical care exist in Guatemala. Interventions to remove these obstacles may enhance access to surgery and benefit children in low- and middle-income countries. PMID- 24069983 TI - Resection of a giant hepatic adenoma in an eight-year-old girl. AB - Hepatic adenomas are benign tumors typically diagnosed in women of reproductive age, however, these tumors occur in the pediatric population although rare. We present the case of a giant hepatic adenoma in an 8-year-old female without established risk factors with progressive abdominal pain, and po intolerance, biliary obstruction, anemia, and fever. Right trisegmentectomy afforded extirpation of the 16 * 14.5 * 8.5 cm mass. The postoperative course was complicated by transient encephalopathy and a bile leak which resolved with appropriate care. The patient is well over 1 year from resection. She demonstrates age appropriate mental and physical function without disease recurrence or complication. PMID- 24069984 TI - Ultrasound-guided thoracoscopic dental extraction. AB - Recurrent pneumonias in children may be from an unrecognized aspirated foreign body. Our patient was a 10-year-old neurologically impaired child with an aspirated tooth in the right lower lobe segmental bronchus that was inaccessible to extraction using flexible bronchoscopy because of its extremely distal location. We used intraoperative ultrasound during thoracoscopy to locate the foreign body, a tooth, and to facilitate a wedge resection of the involved lung. This combined approach with ultrasound and thoracoscopy can be useful in managing an aspirated foreign body that cannot be extracted from the airway using conventional rigid or flexible bronchoscopy. PMID- 24069985 TI - A simple technique for thoracoscopic treatment of diaphragmatic eventration. AB - True diaphragmatic eventration is a rare congenital defect that is most commonly asymptomatic, but can result in dyspnea and recurrent respiratory infections. Advancements in endoscopic technology and technique have resulted in minimally invasive methods for repair of this defect with pronounced benefit when compared to the open thoracotomy. We report a case in which a two year old male who suffered from recurrent respiratory infections was found to have unilateral right diaphragmatic eventration that underwent plication utilizing thoracoscopy and cutting endostaplers with Peri-strips. This procedure was followed by a remarkably fast recovery and discharge, improved radiological findings, and a reprieve from respiratory infection. PMID- 24069986 TI - Pyloric stenosis after gastroschisis closure. AB - Hypertrophic pyloric stenosis is a very common surgical problem in infants. It occurs most often in otherwise well babies with normal gestation and birth history. Rarely, pyloric stenosis has been described in babies with history of prior abdominal surgery. Below we discuss the management of hypertrophic pyloric stenosis in a child who remained hospitalized, recovering from repair of a congenital abdominal wall defect. PMID- 24069987 TI - Current state of single-port laparoscopic cholecystectomy in children. AB - Single-incision laparoscopic surgery (SILS) has recently increased in number. A systematic review of English-language literature from 2009 to 2011 was performed to evaluated the feasibility and outcomes of SILS for various indications in children. Our study reports seven previously published studies of 218 cases. There were insignificant differences in operative time and length of hospital stay of SILS when compared to multiport laparoscopic cholecystectomy. Despite SILS is a more challenging technique to perform, it is a safe and feasible alternative for cholecystectomy in children. PMID- 24069988 TI - Samuel D. Gross, M.D. (1805-1884): an innovator, even in death. PMID- 24069989 TI - Times and trends in the treatment of spontaneous perforation of the esophagus: from Herman Boerhaave to the present age. AB - Spontaneous rupture of the esophagus is a rare devastating condition, which was first described by Herman Boerhaave in 1724. Only a handful of cases were recorded during the 18th and 19th centuries. Diagnosis was usually obtained on autopsy. Only in 1914 Irving Walker achieved the first antemortem diagnosis of spontaneous rupture of the esophagus. The dawn of thoracic surgery during the first decades of the 20th century opened up the way for operative cure. More than 200 years after Boerhaave's initial report, Barrett as well as Clagett and Olsen independently accomplished the first successful surgical treatment by primary repair of the esophageal lesion in 1947. Since those pioneer days, various suggestions for proper treatment have been made ranging from conservative, nonoperative means to extended procedures such as esophagectomy. Invention of minimally invasive surgery and endoscopic measures has further broadened the spectrum of available therapeutic options. The aim of this history article is to outline the development of diagnosis and management of spontaneous rupture of the esophagus from the age of Herman Boerhaave to the present times. PMID- 24069991 TI - Risk factors for conversion from laparoscopic to open surgery: analysis of 2138 converted operations in the American College of Surgeons National Surgical Quality Improvement Program. AB - Minimal access procedures have influenced surgical practice and patient expectations. Risk of laparoscopic conversion to open surgery is frequently cited but vaguely quantified. The present study examines three common procedures to identify risk factors for laparoscopic conversion to open (LCO) events. Cross sectional analysis using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP; 2005 to 2009) identified cases with laparoscopic procedure codes for appendectomy, cholecystectomy, and bariatric procedures. The primary outcome was conversion of a laparoscopic procedure to its open equivalent. Summary statistics for laparoscopic and LCO groups were compared and logistic regression analysis was used to estimate patient and operative risk factors for conversion. Of 176,014 selected laparoscopic operations, 2,138 (1.2%) were converted. Most patients were female (68%) and white (71.2%); mean age was 45.1 years. LCO cholecystectomy was significantly more likely (n = 1526 [1.9%]) and LCO bariatric procedures were less likely (n = 121 [0.3%]); appendectomy was intermediate (n = 491 [1.0%], P < 0.001). Patient factors associated with LCO included male sex (P < 0.001), age 30 years or older (P < 0.025), American Society of Anesthesiologists Class 2 to 4 (P < 0.001), obesity (P < 0.01), history of bleeding disorder (P = 0.036), or preoperative systemic inflammatory response syndrome or sepsis (P < 0.001). LCO was associated with greater incidence of postoperative complications, including death, organ space surgical site infection, sepsis, wound dehiscence, and return to the operating room (P < 0.001). Overall LCO incidence is low in hospitals participating in ACS-NSQIP. Conversion risk factors include patient age, sex, obesity, and preoperative comorbidity as well as the procedure performed. This information should be valuable to clinicians in discussing conversion risk with patients. PMID- 24069990 TI - Interhospital transfer: an independent risk factor for mortality in the surgical intensive care unit. AB - Interhospital transfer (IHT) is associated with mortality in medical and mixed intensive care units (ICUs), but few studies have examined this relationship in a surgical ICU (SICU) setting. We hypothesized that IHT is associated with increased mortality in SICU patients relative to ICU patients admitted within the hospital. We reviewed SICU and transfer center databases from a tertiary academic center over a 2-year period. Inclusion criteria included age 18 years or older and SICU admission 24 hours or greater. Demographic data, admission service, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were captured. The primary end point was ICU mortality. Univariate logistic regression was used to test the association between variables and mortality. Factors found to be associated with mortality at P < 0.1 were entered into a multivariable model. Of 4542 admissions, 416 arrived by IHT. Compared with the non-IHT group, the IHT group was older (age 58.3 years [interquartile range, 47.8 to 70.6] vs. 57.8 years [interquartile range, 44.1 to 68.8] years, P = 0.036), sicker (APACHE II score 16.5 [interquartile range, 12 to 23] vs. 14 [interquartile range, 10 to 20], P < 0.001), and more likely to be white (82% [n = 341] vs. 69% [n = 2865], P < 0.001). Mortality rates in IHT patients were highest on the emergency surgery (18%), transplant surgery (16%), and gastrointestinal surgery (8%) services. After adjusting for age and APACHE II score, IHT remained a risk factor for ICU mortality (odds ratio, 1.60; 95% confidence interval, 1.04 to 2.45; P = 0.032) in SICU patients. Interhospital transfer is an independent risk factor for mortality in the SICU population; this risk is unevenly distributed through service lines. Further efforts to determine the cause of this association are warranted. PMID- 24069992 TI - Dilemma of blunt bowel injury: what are the factors affecting early diagnosis and outcomes. AB - Blunt bowel and mesenteric injury (BBMI) is frequently a difficult diagnosis at initial presentation. We aimed to study the predictors for early diagnosis and outcomes in patients with BBMI. Data were collected retrospectively from the database registry between January 2008 and December 2011 in the only Level I trauma unit in Qatar. Patients with BBMI were divided into Group A (surgically treated within 8 hours) and Group B (treated after 8 hours). Data were analyzed and chi2, Student's t test, and multivariate regression analysis were performed appropriately. Among 984 patients admitted with blunt abdominal trauma (BAT), 11 per cent had BBMI with mean age of 35 +/- 9.5 years. Polytrauma and isolated bowel injury were identified in 53 and 42 per cent, respectively. Mean Injury Severity Score (ISS) was higher in Group A in comparison to Group B (18 +/- 11 vs. 13 +/- 8; P = 0.02). Presence of pain and seatbelt sign (P = 0.02) were evident in Group B. Hypotension (P = 0.004) and hypothermia (P = 0.01) were prominent in Group A. The rate of positive Focused Assessment Sonography for Trauma was greater in Group A (P = 0.001). Among operative findings, bowel perforation was more frequent in Group B (P = 0.04), whereas mesenteric full thickness hematoma was significantly higher in Group A. Pelvic fracture was more frequent finding in Group A (P = 0.005). The overall mortality rate was 15.6 per cent. In patients with BAT, the presence of abdominal pain, hypotension, ISS greater than 16, hypothermia, pelvic fracture, and mesenteric hematoma might help in early diagnosis of BBMI. Moreover, base deficit and mean ISS were independent predictors of mortality. Delayed operative interventions greater than 8 hours increased morbidity rate but had no significant impact on mortality. PMID- 24069993 TI - Effects of race and insurance on outcomes of the open abdomen. AB - Recent studies have suggested improved outcomes in surgical patients with healthcare insurance, whereas several others have noted disparities in access to health care, the care provided, and the aftercare of uninsured patients. Several different strategies exist in the management and prevention of the open abdomen secondary to abdominal compartment syndrome. To date, no study has evaluated the effects of race and insurance in patients with an open abdomen (OA). A retrospective review from our OA database was queried. All patients with an OA from January 2002 to December 2010 were included for analysis. Data analyzed included patients' demographics, race, insurance status, hospital charges, Injury Severity Scores, and outcomes. Insured patients were identified and compared with their uninsured counterparts. A total of 720 patients were treated for an OA during the study period. Of these, 273 (37.9%) died within their hospital stay. Patients who died were noted to be older and sicker with higher Acute Physiology and Chronic Health Evaluation (APACHE) II and Simplified Acute Physiologic Scores (27.6 vs. 18.2, P < 0.001 and 54.6 vs. 38.5, P < 0.001, respectively). Logistic regression analysis revealed that age, APACHE II, and Injury Severity Scores were independently associated with mortality. From our categorical variables, race was not associated with worse outcomes. In addition, being uninsured was significantly associated with increased mortality (odds ratio, 1.67; 95% confidence interval, 1.1 to 2.6; P = 0.05). "Self-pay" status was associated with increased mortality even after adjusting for severity of illness. Further studies incorporating baseline comorbidities need to be undertaken to further assess the reasons for these disparities. PMID- 24069994 TI - Surgical alternatives in the treatment of intestinal intussusceptions resulting from polyps in adults. AB - Adult intussusception is an uncommon disease requiring surgical intervention. The aim of this study is to discuss the surgical alternatives and share our experience in the treatment of adult patients with intussusceptions formed as a result of polyps. The retrospective study included 16 adult patients who underwent surgery after the diagnosis of intestinal invaginations resulting from polyps between the years 2000 and 2011. Sixteen patients (seven males and nine females; mean age, 48.18 years; range, 18 to 76 years) presented with intestinal intussusceptions. Although a preoperative diagnosis was carried out in 11 (68.75%) patients, the diagnosis was made intraoperatively in five patients (31.25%). Among the patients, seven (43.8%) had undergone emergency surgeries and nine (52.8) had elective surgery. The invagination in 12 patients (75%) was located in the small intestine, in two patients (12.5%) in the colon, and in a further two patients (12.5%), it was ileocecally located. Ten patients (62.5%) had segmental resection + anastomosis; three patients underwent (18.8%) segmental resection + enterostomy, and three (18.8%) received hemicolectomies. In adults, surgical treatment is always the primary option in intussusceptions resulting from polyps. Although the surgical method of choice in colonically located ones is en bloc resection without reduction, because the polyps located in the small intestine are usually of a benign nature, segmental resection with reduction should be performed in elective surgery and segmental resection without reduction should be performed in emergency cases. PMID- 24069995 TI - Multi-institutional comparison of helicopter transfers directly to the operating room versus the pit stop in the emergency department. PMID- 24069996 TI - Impact of hormonal protection in blunt and penetrating trauma: a retrospective analysis of the National Trauma Data Bank. AB - Over the last decade, gender and age-related hormonal status of trauma patients have been increasingly recognized as outcome factors. In the present study, we examine a large cohort of trauma patients to better appraise the effects of gender and age on patient outcome after blunt and penetrating trauma. We hypothesize that adult females are at lower risk for complications and mortality relative to adult males after both blunt and penetrating trauma. A retrospective analysis was conducted of the National Trauma Data Bank examining hormonally active females for advantages in survival and outcome after blunt and/or penetrating trauma. Over 1.4 million incident trauma cases were identified between 2002 and 2006. Multiple logistic regressions were calculated for associations between gender and outcome, stratified by injury type, age, comorbidity, Injury Severity Score (ISS), and complications. Risk factors associated with mortality in our multiple logistic regression analyses included: penetrating trauma (odds ratio [OR, 2.31; 95% confidence interval [CI], 2.27 to 2.36); adult male (OR, 1.45; 95% CI, 1.41 to 1.49); and ISS 15 or greater (OR, 14.68; 95% CI, 14.38 to 14.98). Adult females demonstrated a survival advantage over adult males (OR, 0.69; 95% CI, 0.67 to 0.71). Adult females with ISS less than 15 demonstrated a distinct survival advantage compared with adult males after both blunt and penetrating trauma. These results warrant further investigation into the role of sex hormones in trauma. PMID- 24069997 TI - Tension-free open mesh Cooper's ligament repair for femoral hernia. PMID- 24069998 TI - The use of multidetector computed tomography in lower gastrointestinal bleeding. PMID- 24069999 TI - Moving toward laparoscopic pyloromyotomy: an initial Italian experience and national survey. PMID- 24070000 TI - Scheduling 101: A method to the application of Sudoku game theory to surgical rotation scheduling. PMID- 24070001 TI - Palladium-catalyzed insertion of N-tosylhydrazones and trapping with carbon nucleophiles. AB - A Pd-catalyzed three-component cross-coupling reaction of vinyl iodide, N tosylhydrazone, and carbon nucleophiles is reported, and a one-pot procedure is also developed. The cross-coupling is proposed to proceed through a palladium carbene migratory insertion, carbopalladation other than classic palladium carbene migratory insertion, and beta-H elimination. Moreover, the reaction proceeds under mild conditions and with high stereoselectivity. PMID- 24070002 TI - Metformin toxicity: a report of 204 cases from Iran. AB - OBJECTIVE: The aim of this study was to evaluate the frequency of metformin associated lactic acidosis in our metformin-intoxicated patients, the general approach for their management, and determine the frequency of hypoglycemia and outcome in these patients. We also wanted to see if there was a significant difference in the course and outcome of metformin poisoning between our patients and those reported in the literature. MATERIALS AND METHODS: Files of all patients diagnosed with metformin toxicity were retrospectively evaluated. A purposemade questionnaire containing the patients' demographic data, vital signs and lab tests on presentation, time of development of hypoglycemia and metabolic acidosis (if any), treatment modalities performed for the patients and their indications, and the patients' outcomes was filled. The patients were evaluated in total and then assigned into two groups of metformin alone (group 1) and multi drug toxicity including metformin (group 2) and were compared. RESULTS: A total of 204 patients were reviewed. Fifty-five (26.9%) were in group 1 and 149 (73.1%) were in group 2. Sixteen and 52 patients in groups 1 and 2 had acidosis. Dialysis was performed in only four patients, all of whom belonged to group 1 (P = 0.005). They were all dialyzed only once. Two patients (1%) died both of whom were in group 2. Groups 1 and 2 were insignificantly different in all characteristics except for their aspartate transaminase and creatine phosphokinase. Almost 23% of the patients in group 1 had experienced hypoglycemia sometime during their course of hospitalization. CONCLUSIONS: Although lactic acidosis is considered to be a serious condition resulting in high mortality and morbidity rates, it seems that our patients can easily and safely be managed with conservative therapies. Most of them do not need aggressive treatments including hemodialysis. Metformin seems to cause hypoglycemia more than what was previously considered. PMID- 24070006 TI - Activity of ceftaroline and comparator agents tested against contemporary Gram positive and -negative (2011) isolates collected in Europe, Turkey, and Israel. AB - The activity of ceftaroline was tested against 8233 isolates mainly collected from bloodstream, urinary, respiratory and skin and soft tissue specimens in European medical centers during 2011. This cephalosporin displayed activity against Staphylococcus aureus (MIC(50), 0.25 mg/l), with greater activity against MRSA (MIC(50), 1 mg/l) than other beta-lactams tested. Against Streptococcus pneumoniae, including penicillin-resistant strains, other streptococcal groups and Haemophilus spp., ceftaroline was highly active and MIC90 values ranged from <=0.015 to 0.12 mg/l. Ceftaroline, like other cephalosporins, had limited activity against ESBL-phenotype Enterobacteriaceae, but showed good activity against isolates not displaying an ESBL-phenotype. Ceftaroline remains very active against MRSA and other organisms than could be associated with its approved indications in the EU (complicated skin and soft tissue infections and community-acquired pneumonia). PMID- 24070007 TI - Posttraumatic stress disorder and health: a preliminary study of group differences in health and health behaviors. AB - BACKGROUND: Individuals with posttraumatic stress disorder (PTSD) are more likely to undertake harmful health behaviors like substance use. Less is known about the association of PTSD with healthful behaviors such as healthy diet and exercise. The purpose of this study was to examine differences across physical health indicators and health behaviors in individuals with and without PTSD. METHODS: A cross-sectional, case-control study of health indicators and self-reported health behaviors in a community and military veteran sample was used. RESULTS: Based on a structured psychiatric interview, 25 participants had PTSD, and the remaining 55 without PTSD served as the comparison group. Participants were 40 years old on average and 45% were female. Multivariate analysis of variance analyses revealed that participants with PTSD had significantly higher body mass index (p = 0.004), had more alcohol use (p = 0.007), and reported fewer minutes of vigorous exercise (p = 0.020) than those without PTSD. Chi-square analysis of diet content and eating behavior constructs found that individuals with PTSD ate fewer fruits (p = 0.035) and had more guilt after overeating (p = 0.006). CONCLUSIONS: These findings replicate prior research on the link between PTSD and negative health outcomes and engagement in harmful health behaviors and highlight the need for further examination of the association between PTSD and other health behaviors like diet content, eating behaviors, and exercise. PMID- 24070008 TI - Hydroxylated bisabolol oxides: evidence for secondary oxidative metabolism in Matricaria chamomilla. AB - German chamomile (Matricaria chamomilla) is one of the most popular medicinal plants used in Western herbal medicine. Among the various phytochemicals present in the essential oil of the flowers of German chamomile, bisabolol and its oxidized metabolites are considered as marker compounds for distinguishing different chemotypes. These compounds are influential in mediating the aroma of the essential oil of M. chamomilla and contribute to the therapeutic properties (anti-inflammatory, antibacterial, insecticidal, and antiulcer) of this species. In order to find other possible bisabolol derivatives as marker compounds for authentication of German chamomile in botanical and commercial products, an in depth investigation using a GC-assisted fractionation procedure was performed on nonpolar fractions. As a result of this approach, three new hydroxylated derivatives of bisabolol oxides A and B (1-3) have been isolated from M. chamomilla. Plausible biogenetic pathways are presented. PMID- 24070009 TI - Gene hunting in autoinflammation. AB - Steady progress in our understanding of the genetic basis of autoinflammatory diseases has been made over the past 16 years. Since the discovery of the familial Mediterranean fever gene MEFV (also known as marenostrin) in 1997, 18 other genes responsible for monogenic autoinflammatory diseases have been identified to date. The discovery of these genes was made through the utilisation of many genetic mapping techniques, including next generation sequencing platforms. This review article clearly describes the gene hunting approaches, methods of data analysis and the technological platforms used, which has relevance to all those working within the field of gene discovery for Mendelian disorders. PMID- 24070010 TI - Etanercept (Enbrel) in the treatment of juvenile idiopathic arthritis. AB - INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a relatively common multidimensional and heterogeneous chronic disease of childhood. Children with JIA are at risk for significant morbidity in terms of joint damage, impairments in physical function and health-related quality of life. Outcomes for children with JIA have significantly improved with the use of biologic therapies in the past 15 years, with the most clinical experience being with etanercept . AREAS COVERED: Basic pharmacokinetic and pharmacodynamic data for etanercept will be highlighted. This article will review the clinical trials and open-label registry data for the efficacy and safety of etanercept for use in JIA. EXPERT OPINION: Etanercept is very effective for the treatment of JIA. Data from clinical trials and open-label studies support its clinical efficacy in 80% of patients which appears to be sustained over several years for the majority of treated patients. The safety profile is also acceptable with a serious adverse event rate of 0.03 - 0.12 per patient-year. Further research is needed to evaluate any possible link between biologic therapy, JIA and malignancy, to obtain more long-term safety data, and to document improvements in quality of care and cost-benefit for associated with biologic therapies which may additionally assist in access to these medications. Further, identification of potential clinical or laboratory markers allowing for prediction of response and timing of starting and cessation of this biologic therapy are urgently required. PMID- 24070011 TI - Copper(II)-catalyzed sequential C,N-difunctionalization of 1,4-naphthoquinone for the synthesis of benzo[f]indole-4,9-diones under base-free condition. AB - An efficient synthesis of benzo[f]indole-4,9-diones has been achieved by copper(II)-catalyzed naphthoquinone sequential C,N-difunctionalization reactions with beta-enaminones. New C-C and C-N bonds are easily formed in the reaction course. Copper(II) salt plays a dual role as Lewis acid and oxidative catalyst, and O2 acts as the terminal oxidant. The advantage of this reaction is the high atom economy with broad substrate scope and excellent yields. The reaction can be scaled up to using at least grams of substrates. PMID- 24070012 TI - Small molecule probe suitable for in situ profiling and inhibition of protein disulfide isomerase. AB - Proper folding of cellular proteins is assisted by protein disulfide isomerases (PDIs) in the endoplasmic reticulum of mammalian cells. Of the at least 21 PDI family members known in humans, the 57-kDa PDI has been found to be a potential therapeutic target for a variety of human diseases including cancer and neurodegenerative diseases. Consequently, small molecule PDI-targeting inhibitors have been actively pursued in recent years, and thus far, compounds possessing moderate inhibitory activities (IC50 between 0.1 and 100 MUM against recombinant PDI) have been discovered. In this article, by using in situ proteome profiling experiments in combination with in vitro PDI enzymatic inhibition assays, we have discovered a phenyl vinyl sulfonate-containing small molecule (P1; shown) as a relatively potent and specific inhibitor of endogenous human PDI in several mammalian cancer cells (e.g., GI50 ~ 4 MUM). It also possesses an IC50 value of 1.7 +/- 0.4 MUM in an in vitro insulin aggregation assay. Our results indicate P1 is indeed a novel, cell-permeable small molecule PDI inhibitor, and the electrophilic vinyl sulfonate scaffold might serve as a starting point for future development of next-generation PDI inhibitors and probes. PMID- 24070013 TI - Diazoxide, a K(ATP) channel opener, prevents ischemia-reperfusion injury in rodent pancreatic islets. AB - Diazoxide (DZ) is a pharmacological opener of ATP-sensitive K(+) channels that has been used for mimicking ischemic preconditioning and shows protection against ischemic damage. Here we investigated whether diazoxide supplementation to University of Wisconsin (UW) solution has cellular protection during islet isolation and improves in vivo islet transplant outcomes in a rodent ischemia model. C57/B6 mice pancreata were flushed with UW or UW + DZ solution and cold preserved for 6 or 10 h prior to islet isolation. Islet yield, in vitro and in vivo function, mitochondrial morphology, and apoptosis were evaluated. Significantly higher islet yields were observed in the UW + DZ group than in the UW group (237.5 +/- 25.6 vs. 108.7 +/- 49.3, p < 0.01). The islets from the UW + DZ group displayed a significantly higher glucose-induced insulin secretion (0.97 ng/ml +/- 0.15 vs. 0.758 ng/ml +/- 0.21, p = 0.009) and insulin content (60.96 ng/islet +/- 13.94 vs. 42.09 ng/islet +/- 8.15, p = 0.002). The DZ-treated islets had well-preserved mitochondrial morphology with superior responses of mitochondrial potentials, and calcium influx responded to glucose. A higher number of living cells and less late apoptotic cells were observed in the UW + DZ group (p < 0.05). Additionally, the islets from the UW + DZ group had a significantly higher cure rate and improved glucose tolerance. This study is the first to report mitoprotective effects of DZ for pancreas preservation and islet isolation. In the future, it will be necessary to further understand the underlying mechanism for the mitoprotection and to test this promising approach for pancreas preservation and the islet isolation process in nonhuman primates and ultimately humans. PMID- 24070015 TI - Sarcoidosis with involvement of the paranasal sinuses - a retrospective analysis of 12 biopsy-proven cases. AB - BACKGROUND: Extrapulmonary involvement by sarcoidosis is observed in about 30-40% of patients with sarcoidosis. Little is known about the frequency and clinical characteristics of sinonasal sarcoidosis. METHODS: We retrospectively analyzed 12 cases of biopsy-proven sinonasal sarcoidosis. Patients were identified from a patient population of 1360 patients with sarcoidosis at the Outpatient Clinic for Sarcoidosis and Rare Lung Diseases at LungClinic Grosshansdorf, a tertiary care hospital for respiratory medicine. RESULTS: The most frequent signs and symptoms were nasal polyps (4 cases), epistaxis (3 cases), nasal crusts (8 cases) and anosmia (5 cases). Pulmonary sarcoidosis of the patients was staged as stage I (n = 1) and stage II (n = 11) on chest radiographs. Spirometry was normal in 11 patients. 7 patients had a diffusion capacity of the lung for carbon monoxide of less than 90% of predicted. Other organs were affected in 8 patients. All patients received systemic corticosteroid treatment and most patients received topical steroids. 5 patients received steroid sparing agents. Repeated sinus surgery had to be performed in 4 patients. CONCLUSIONS: Sinonasal involvement is a rare disease manifestation of sarcoidosis with a frequency slightly lower than 1% in our patient population. The clinical course of sinonasal sarcoidosis can be complicated by relapse despite systemic immunosuppressive treatment and repeated sinus surgery. PMID- 24070016 TI - On the nature and scope of reported child maltreatment in high-income countries: opportunities for improving the evidence base. AB - Although high-income countries share and value the goal of protecting children from harm, national data on child maltreatment and the involvement of social services, the judiciary and health services remain relatively scarce. To explore potential reasons for this, a number of high-income countries across the world (Belgium, Canada, Germany, the Netherlands, New Zealand, South Korea, Switzerland and the United States) were compared. Amongst other aspects, the impact of service orientation (child protection-vs-family-services-orientated), the complexity of systems, and the role of social work as a lead profession in child welfare are discussed. Special consideration is given to indigenous and minority populations. The call for high-income countries to collect national data on child maltreatment is to promote research to better understand the risks to children. Its remit ranges well beyond these issues and reflects a major gap in a critical resource to increase prevention and intervention in these complex social situations. Fortunately, initiatives to close this gap are increasing. PMID- 24070014 TI - The quest for selective nox inhibitors and therapeutics: challenges, triumphs and pitfalls. AB - SIGNIFICANCE: Numerous studies in animal models and human subjects corroborate that elevated levels of reactive oxygen species (ROS) play a pivotal role in the progression of multiple diseases. As a major source of ROS in many organ systems, the NADPH oxidase (Nox) has become a prime target for therapeutic development. RECENT ADVANCES: In recent years, intense efforts have been dedicated to the development of pan- and isoform-specific Nox inhibitors as opposed to antioxidants that proved ineffective in clinical trials. Over the past decade, an array of compounds has been proposed in an attempt to fill this void. CRITICAL ISSUES: Although many of these compounds have proven effective as Nox enzyme family inhibitors, isoform specificity has posed a formidable challenge to the scientific community. This review surveys the most prominent Nox inhibitors, and discusses potential isoform specificity, known mechanisms of action, and shortcomings. Some of these inhibitors hold substantial promise as targeted therapeutics. FUTURE DIRECTIONS: Increased insight into the mechanisms of action and regulation of this family of enzymes as well as atomic structures of key Nox subunits are expected to give way to a broader spectrum of more potent, efficacious, and specific molecules. These lead molecules will assuredly serve as a basis for drug development aimed at treating a wide array of diseases associated with increased Nox activity. PMID- 24070018 TI - Morphological change and phenotypic plasticity in native and non-native pumpkinseed sunfish in response to sustained water velocities. AB - Phenotypic plasticity can contribute to the proliferation and invasion success of nonindigenous species by promoting phenotypic changes that increase fitness, facilitate range expansion and improve survival. In this study, differences in phenotypic plasticity were investigated using young-of-year pumpkinseed sunfish from colonies established with lentic and lotic populations originating in Canada (native) and Spain (non-native). Individuals were subjected to static and flowing water treatments for 80 days. Inter- and intra-population differences were tested using ancova and discriminant function analysis, and differences in phenotypic plasticity were tested through a manova of discriminant function scores. Differences between Iberian and North American populations were observed in dorsal fin length, pectoral fin position and caudal peduncle length. Phenotypic plasticity had less influence on morphology than genetic factors, regardless of population origin. Contrary to predictions, Iberian pumpkinseed exhibited lower levels of phenotypic plasticity than native populations, suggesting that canalization may have occurred in the non-native populations during the processes of introduction and range expansion. PMID- 24070017 TI - Meta-analysis of gene coexpression networks in the post-mortem prefrontal cortex of patients with schizophrenia and unaffected controls. AB - BACKGROUND: Gene expression profiling of the postmortem human brain is part of the effort to understand the neuropathological underpinnings of schizophrenia. Existing microarray studies have identified a large number of genes as candidates, but efforts to generate an integrated view of molecular and cellular changes underlying the illness are few. Here, we have applied a novel approach to combining coexpression data across seven postmortem human brain studies of schizophrenia. RESULTS: We generated separate coexpression networks for the control and schizophrenia prefrontal cortex and found that differences in global network properties were small. We analyzed gene coexpression relationships of previously identified differentially expressed 'schizophrenia genes'. Evaluation of network properties revealed differences for the up- and down-regulated 'schizophrenia genes', with clustering coefficient displaying particularly interesting trends. We identified modules of coexpressed genes in each network and characterized them according to disease association and cell type specificity. Functional enrichment analysis of modules in each network revealed that genes with altered expression in schizophrenia associate with modules representing biological processes such as oxidative phosphorylation, myelination, synaptic transmission and immune function. Although a immune-function enriched module was found in both networks, many of the genes in the modules were different. Specifically, a decrease in clustering of immune activation genes in the schizophrenia network was coupled with the loss of various astrocyte marker genes and the schizophrenia candidate genes. CONCLUSION: Our novel network-based approach for evaluating gene coexpression provides results that converge with existing evidence from genetic and genomic studies to support an immunological link to the pathophysiology of schizophrenia. PMID- 24070019 TI - Learning by doing: observing an interprofessional process as an interprofessional team. AB - New competencies exist for interprofessional education, which are centered on the goal of improving quality of care and patient safety through improved interprofessional collaboration. Interprofessional education and effective interprofessional collaboration are cornerstones of the Veterans Affairs Quality Scholars fellowship program. The purpose of this project was to evaluate an innovative interprofessional education strategy in which teams of physicians and nurses were "learning by doing" as they observed and analyzed the functioning of an interprofessional process, specifically, inpatient discharge. Fellows completed voluntary, anonymous surveys seeking their perspectives about the project. Fellows' feedback revealed several themes, with both positive and negative characteristics related to team functioning, interprofessional understanding, microsystem knowledge, pooled knowledge and assignment challenges. The strength of this strategy is exemplified by the fact that fellows not only learned from each other's separate professional observations, but also observed the emergence of a shared interprofessional perspective through working together. PMID- 24070021 TI - Ileal conduit without cystectomy may be an appropriate option in the treatment of intractable bladder pain syndrome/interstitial cystitis. AB - OBJECTIVE: The aim of this study was to report the outcomes of urinary diversion for bladder pain syndrome/interstitial cystitis (BPS/IC) at a large university hospital over a period of more than 10 years. MATERIAL AND METHODS: Chart reviews were performed for BPS/IC patients who had undergone ileal conduit with or without cystectomy. Questionnaires on quality of life, BPS/IC symptoms and pain were mailed to patients. Outcomes in the cystectomy and the non-cystectomy groups were compared with Fisher's exact test. RESULTS: Ileal conduit without cystectomy was performed in 20 patients. Two underwent a subsequent cystectomy owing to persistent symptoms. Three patients underwent ileal conduit with concomitant primary cystectomy. Nineteen patients were alive at the time of the study and 15 returned the questionnaires. Twelve responders had been treated with ileal conduit and three had undergone primary cystectomy. The quality of life in both the cystectomy and the non-cystectomy groups was comparable with that in the general population. Seven patients in the non-cystectomy group were free of specific BPS/IC symptoms. The remaining five patients had minimal symptoms. Two cystectomy patients were free of symptoms, while one still suffered from severe symptoms. Eleven patients reported having no pain while four patients had visual analogue scale (VAS) scores between 2 and 9.5. Three patients experiencing pain belonged to the non-cystectomy group. There was no difference between the cystectomy group and the non-cystectomy group with regard to the proportion of patients who were symptom free. CONCLUSION: Ileal conduit without cystectomy may be an appropriate option when performing urinary diversion in BPS/IC patients. PMID- 24070020 TI - Group X secreted phospholipase A(2) induces lipid droplet formation and prolongs breast cancer cell survival. AB - BACKGROUND: Alterations in lipid metabolism are inherent to the metabolic transformations that support tumorigenesis. The relationship between the synthesis, storage and use of lipids and their importance in cancer is poorly understood. The human group X secreted phospholipase A2 (hGX sPLA2) releases fatty acids (FAs) from cell membranes and lipoproteins, but its involvement in the regulation of cellular FA metabolism and cancer is not known. RESULTS: Here we demonstrate that hGX sPLA2 induces lipid droplet (LD) formation in invasive breast cancer cells, stimulates their proliferation and prevents their death on serum deprivation. The effects of hGX sPLA2 are shown to be dependent on its enzymatic activity, are mimicked by oleic acid and include activation of protein kinase B/Akt, a cell survival signaling kinase. The hGX sPLA2-stimulated LD biogenesis is accompanied by AMP-activated protein kinase (AMPK) activation, up regulation of FA oxidation enzymes and the LD-coating protein perilipin 2, and suppression of lipogenic gene expression. Prolonged activation of AMPK inhibited hGX sPLA2-induced LD formation, while etomoxir, an inhibitor of FA oxidation, abrogated both LD formation and cell survival. The hGX sPLA2-induced changes in lipid metabolism provide a minimal immediate proliferative advantage during growth under optimal conditions, but they confer to the breast cancer cells a sustained ability to resist apoptosis during nutrient and growth factor limitation. CONCLUSION: Our results identify hGX sPLA2 as a novel modulator of lipid metabolism that promotes breast cancer cell growth and survival by stimulating LD formation and FA oxidation. PMID- 24070022 TI - Diterpenoids and sesquiterpenoids from the roots of Illicium majus. AB - Five new diterpenoids (1-5), five new sesquiterpenoids (6-10), and three known compounds (11-13) were isolated from the roots of Illicium majus. Their structures were elucidated by extensive spectroscopic analysis. The absolute configuration of 1 was assigned by X-ray crystallography, whereas those of the 1,2-diol moieties in 3 and 4 were determined using Snatzke's method. The abietane acids 1, 2, 11, 12, and 13 displayed antiviral activity against the Coxsackie B3 virus, with IC50 values of 3.3-51.7 MUM/mL. PMID- 24070023 TI - Pharmacokinetics of a polyene antifungal agent, liposomal amphotericin B (L-AMB), in a severely burned patient. PMID- 24070024 TI - 'I'm not complaining because I'm alive': barriers to the emergence of a discourse of cancer-related fatigue. AB - OBJECTIVE: Cancer-related fatigue (CRF) is a potentially chronic condition that is inadequately discussed, diagnosed and treated. This study examined the factors that contribute to the absence of a discourse of CRF. METHOD: A thematic discourse analysis was carried out on the 'additional comments' left by 73 fatigued cancer patients and survivors as part of a questionnaire study on CRF. RESULTS: The findings indicated that conflict between patients' own conceptualisations of CRF and those of family/friends and/or medical professionals hampers social and medical dialogue of CRF. Fatigue forms a part of patients' ongoing cancer identity even after cancer treatment has been completed; however, because of the dominance of wider social discourses on recovery from illness and cancer survivorship, others fail to recognise individual narratives of CRF when these deviate from or oppose such established discourses. Furthermore, the development of a discourse of CRF is actively obstructed because the enormity of cancer invalidates and overshadows patients' postcancer experiences. CONCLUSION: 'Additional comments' are a rich source of data that can give insight into issues facing patients. Beyond the lack of recognition, support and interventions available for CRF, broader discourses of health, illness and cancer hamper communication regarding this side effect. PMID- 24070025 TI - Correlation of Nrf2 and HIF-1alpha in glioblastoma and their relationships to clinicopathologic features and survival. AB - OBJECTIVES: Glioblastoma (GB) is the most common, aggressive, and proliferative among all brain tumors. The prognosis of GB is still far from satisfactory currently, thus demanding great modification and enhancement, which may be acquired by the help of the molecular target therapy. Nuclear factor E2-related factor 2 (Nrf2), a pivotal transcriptional factor of cellular responses to oxidative stress, was observed to function remarkably in cancer pathobiology. In the current study, we analyzed the correlation between Nrf2 and Hypoxia-inducible factor-1alpha (HIF-1alpha) in GB, together with their association to the features and survival of clinicopathology. METHODS: We examined the expression of Nrf2 and HIF-1alpha in 68 specimens of GB by tissue microarray and immunohistochemistry, and correlated this investigation to the outcome of GB patients. RESULTS: Nrf2 and HIF-1alpha were overexpressed in GB tissues. There was significant correlation between the high level of Nrf2 and tumor necrosis on MRI and 1-year survival. There was significant correlation between HIF-1alpha level and Nrf2 status (r = 0.294, P = 0.015). Kaplan-Meier analysis showed that high Nrf2 expression was significantly associated with shorter overall survival (OS) (log rank test, P = 0.006), and was identified as an independent prognostic factor in multivariate analysis (P = 0.034). HIF-1alpha was another independent factor for both OS and progression-free survival by Cox regression analysis (P = 0.048 and P = 0.032, respectively). DISCUSSION: Mutual association between Nrf2 and HIF 1alpha was found in GB: higher Nrf2 expression and poorer outcome of GB patients. Nrf2 would therefore be a new molecular marker for the targeted treatment of GB. PMID- 24070026 TI - Plasma metabolomic profiling of dairy cows affected with ketosis using gas chromatography/mass spectrometry. AB - BACKGROUND: Ketosis is an important problem for dairy cows' production performance. However, it is still little known about plasma metabolomics details of dairy ketosis. RESULTS: A gas chromatography/mass spectrometry (GC/MS) technique was used to investigate plasma metabolic differences in cows that had clinical ketosis (CK, n=22), subclinical ketosis (SK, n=32), or were clinically normal controls (NC, n=22). The endogenous plasma metabolome was measured by chemical derivatization followed by GC/MS, which led to the detection of 267 variables. A two-sample t-test of 30, 32, and 13 metabolites showed statistically significant differences between SK and NC, CK and NC, and CK and SK, respectively. Orthogonal signal correction-partial least-square discriminant analysis (OPLS-DA) revealed that the metabolic patterns of both CK and SK were mostly similar, with the exception of a few differences. The development of CK and SK involved disturbances in many metabolic pathways, mainly including fatty acid metabolism, amino acid metabolism, glycolysis, gluconeogenesis, and the pentose phosphate pathway. A diagnostic model arbitrary two groups was constructed using OPLS-DA and receiver-operator characteristic curves (ROC). Multivariate statistical diagnostics yielded the 19 potential biomarkers for SK and NC, 31 for CK and NC, and 8 for CK and SK with area under the curve (AUC) values. Our results showed the potential biomarkers from CK, SK, and NC, including carbohydrates, fatty acids, amino acids, even sitosterol and vitamin E isomers, etc. 2-piperidinecarboxylic acid and cis-9-hexadecenoic acid were closely associated with metabolic perturbations in ketosis as Glc, BHBA and NEFA for dealing with metabolic disturbances of ketosis in clinical practice. However, further research is needed to explain changes of 2,3,4-trihydroxybutyric acid, 3,4-dihydroxybutyric acid, alpha-aminobutyric acid, methylmalonic acid, sitosterol and alpha-tocopherol in CK and SK, and to reveal differences between CK and SK. CONCLUSION: Our study shows that some new biomarkers of ketosis from plasma may find new metabolic changes to have clinically new utility and significance in diagnosis, prognosis, and prevention of ketosis in the future. PMID- 24070027 TI - Reply to "Comment on 'Coherence and uncertainty in nanostructured organic photovolatics'". PMID- 24070028 TI - Direct formation of tethered Ru(II) catalysts using arene exchange. AB - An 'arene exchange' approach has been successfully applied for the first time to the synthesis of Ru(II)-based 'tethered' reduction catalysts directly from their ligands in one step. This provides an alternative method for the formation of known complexes, and a route to a series of novel complexes. The novel complexes are highly active in both asymmetric transfer and pressure hydrogenation of ketones. PMID- 24070029 TI - Mercury trends in colonial waterbird eggs downstream of the oil sands region of Alberta, Canada. AB - Mercury levels were measured in colonial waterbird eggs collected from two sites in northern Alberta and one site in southern Alberta, Canada. Northern sites in the Peace-Athabasca Delta and Lake Athabasca were located in receiving waters of the Athabasca River which drains the oil sands industrial region north of Fort McMurray, Alberta. Temporal trends in egg mercury (Hg) levels were assessed as were egg stable nitrogen isotope values as an indicator of dietary change. In northern Alberta, California and Ring-billed Gulls exhibited statistically significant increases in egg Hg concentrations in 2012 compared to data from the earliest year of sampling. Hg levels in Caspian and Common Tern eggs showed a nonstatistically significant increase. In southern Alberta, Hg concentrations in California Gull eggs declined significantly through time. Bird dietary change was not responsible for any of these trends. Neither were egg Hg trends related to recent forest fires. Differences in egg Hg temporal trends between northern and southern Alberta combined with greater Hg levels in eggs from northern Alberta identified the likely importance of local Hg sources in regulating regional Hg trends. Hg concentrations in gull and Common Tern eggs were generally below generic thresholds associated with toxic effects in birds. However, in 2012, Hg levels in the majority of Caspian Tern eggs exceeded the lower toxicity threshold. Increasing Hg levels in eggs of multiple species nesting downstream of the oil sands region of northern Alberta warrant continued monitoring and research to further evaluate Hg trends and to conclusively identify sources. PMID- 24070031 TI - NADPH oxidases in redox regulation of cell adhesion and migration. AB - SIGNIFICANCE: Adhesion and migration induced by cytokines or growth factors are well-organized processes in cellular motility. Reactive oxygen species (ROS) are specifically produced by the Nox family of NADPH oxidases. RECENT ADVANCES: The signal transduction of migration and adhesion depends on ROS produced by Nox enzymes and factors that initiate migration and adhesion and stimulate cellular ROS formation. CRITICAL ISSUES: The identification of molecular targets of ROS formation in the signal transduction of adhesion and migration is still in its beginnings, but a site and isoform-specific contribution of Nox enzymes to this process becomes apparent. Nox-derived ROS, therefore, act as second messengers that are specifically modifying signaling proteins involved in adhesion and migration. FUTURE DIRECTIONS: Individual protein targets of Nox-mediated redox signaling in different cell types and tissues will be identified. Isoform specific Nox inhibitors will be developed to modulate the ROS-dependent component of migration and adhesion. These compounds might be suited to elicit differential effects between pathophysiologic and physiologic adhesion and migration. PMID- 24070030 TI - Tissue sparing, behavioral recovery, supraspinal axonal sparing/regeneration following sub-acute glial transplantation in a model of spinal cord contusion. AB - BACKGROUND: It has been shown that olfactory ensheathing glia (OEG) and Schwann cell (SCs) transplantation are beneficial as cellular treatments for spinal cord injury (SCI), especially acute and sub-acute time points. In this study, we transplanted DsRED transduced adult OEG and SCs sub-acutely (14 days) following a T10 moderate spinal cord contusion injury in the rat. Behaviour was measured by open field (BBB) and horizontal ladder walking tests to ascertain improvements in locomotor function. Fluorogold staining was injected into the distal spinal cord to determine the extent of supraspinal and propriospinal axonal sparing/regeneration at 4 months post injection time point. The purpose of this study was to investigate if OEG and SCs cells injected sub acutely (14 days after injury) could: (i) improve behavioral outcomes, (ii) induce sparing/regeneration of propriospinal and supraspinal projections, and (iii) reduce tissue loss. RESULTS: OEG and SCs transplanted rats showed significant increased locomotion when compared to control injury only in the open field tests (BBB). However, the ladder walk test did not show statistically significant differences between treatment and control groups. Fluorogold retrograde tracing showed a statistically significant increase in the number of supraspinal nuclei projecting into the distal spinal cord in both OEG and SCs transplanted rats. These included the raphe, reticular and vestibular systems. Further pairwise multiple comparison tests also showed a statistically significant increase in raphe projecting neurons in OEG transplanted rats when compared to SCs transplanted animals. Immunohistochemistry of spinal cord sections short term (2 weeks) and long term (4 months) showed differences in host glial activity, migration and proteoglycan deposits between the two cell types. Histochemical staining revealed that the volume of tissue remaining at the lesion site had increased in all OEG and SCs treated groups. Significant tissue sparing was observed at both time points following glial SCs transplantation. In addition, OEG transplants showed significantly decreased chondroitin proteoglycan synthesis in the lesion site, suggesting a more CNS tolerant graft. CONCLUSIONS: These results show that transplantation of OEG and SCs in a sub-acute phase can improve anatomical outcomes after a contusion injury to the spinal cord, by increasing the number of spared/regenerated supraspinal fibers, reducing cavitation and enhancing tissue integrity. This provides important information on the time window of glial transplantation for the repair of the spinal cord. PMID- 24070033 TI - The Massachusetts Emergency Medical Service Stroke Quality Improvement Collaborative, 2009-2012. AB - INTRODUCTION: Quality improvement collaboratives are a popular model used to address gaps between evidence-based practice and patient care. Little is known about use of such collaboratives in emergency medical services, particularly for improving prehospital stroke care. To determine the feasibility of using this approach to improve prehospital stroke care, we conducted a pilot study of the Emergency Medical Services Stroke Quality Improvement Collaborative. METHODS: Seventeen Massachusetts emergency medical service agencies participated in the quality improvement collaborative pilot project. We identified 5 prehospital stroke performance measures to assess the quality of prehospital care, guide collaborative activities, and monitor change in performance over time. During learning sessions, participants were trained in quality improvement and performance measurement, analyzed performance measure results, and shared successes and challenges. Focus groups were conducted to understand participants' experiences with the collaborative. RESULTS: Participating emergency medical service agencies collected stroke performance measures on 3,009 stroke patients during the pilot study. Adherence to 4 of 5 performance measures increased significantly over time. Participants acknowledged that the collaborative provided them with an efficient and effective framework for stroke quality improvement and peer-learning opportunities. CONCLUSION: As evidenced in Massachusetts, quality improvement collaboratives can be an effective tool to improve prehospital stroke care. The data collected, improvements made, participation of emergency medical service agencies, and positive experiences within the collaborative support the continued use of this approach. PMID- 24070034 TI - Multiple chronic medical conditions and health-related quality of life in older adults, 2004-2006. AB - INTRODUCTION: Understanding longitudinal relationships among multiple chronic conditions, limitations in activities of daily living, and health-related quality of life is important for identifying potential opportunities for health promotion and disease prevention among older adults. METHODS: This study assessed longitudinal associations between multiple chronic conditions and limitations in activities of daily living on health-related quality of life among older adults (>=65 years) from 2004 through 2006, using data from the Medicare Health Outcomes Survey (N = 27,334). RESULTS: Using a longitudinal path model, we found the numbers of chronic conditions at baseline and 2-year follow-up were independently associated with more limitations in activities of daily living at 2-year follow up. In addition, more limitations in activities of daily living at 2-year follow up were associated with worse health-related quality of life during the follow-up time period. The association between multiple chronic conditions and indices of health-related quality of life was mediated by changes in limitations in activities of daily living. CONCLUSION: Both baseline and new multiple chronic conditions led to worse health in terms of activities of daily living and health related quality of life and should be considered important outcomes to intervene on for improved long-term health. In addition, public health practitioners should consider addressing classes of multiple chronic conditions by using interventions designed to reduce the emergence of multiple chronic conditions, such as physical activity, reductions in smoking rates, and improved and coordinated access to health care services. PMID- 24070035 TI - The impact of New York City's Health Bucks Program on electronic benefit transfer spending at farmers markets, 2006-2009. AB - INTRODUCTION: Increasing the accessibility and affordability of fresh produce is an important strategy for municipalities combatting obesity and related health conditions. Farmers markets offer a promising venue for intervention in urban settings, and in recent years, an increasing number of programs have provided financial incentives to Supplemental Nutrition Assistance Program (SNAP) recipients. However, few studies have explored the impact of these programs on use of SNAP benefits at farmers markets. METHODS: New York City's Health Bucks Program provides SNAP recipients with a $2 coupon for every $5 spent using SNAP benefits at participating farmers markets. We analyzed approximately 4 years of electronic benefit transfer (EBT) sales data, from July 2006 through November 2009, to develop a preliminary assessment of the effect of the Health Bucks Program on EBT spending at participating markets. RESULTS: Farmers markets that offered Health Bucks coupons to SNAP recipients averaged higher daily EBT sales than markets without the incentive ($383.07, 95% confidence interval [CI], 333.1 433.1, vs $273.97, 95% CI, 243.4-304.5, P < 0.001) following the introduction of a direct point-of-purchase incentive. Multivariate analysis indicated this difference remained after adjusting for the year the market was held and the neighborhood poverty level. CONCLUSION: When a $2 financial incentive was distributed with EBT, use of SNAP benefits increased at participating New York City farmers markets. We encourage other urban jurisdictions to consider adapting the Health Bucks Program to encourage low-income shoppers to purchase fresh produce as one potential strategy in a comprehensive approach to increasing healthful food access and affordability in low-income neighborhoods. PMID- 24070036 TI - Weight status and weight-management behaviors among Philadelphia high school students, 2007-2011. AB - INTRODUCTION: The prevalence of obesity among youth may be stabilizing and even declining in some areas of the United States. The objective of our study was to examine whether the stabilization in obesity prevalence among Philadelphia high school students was accompanied by changes in weight-management behaviors. METHODS: We evaluated changes in self-reported weight status and weight management behaviors by using data collected by the Youth Risk Behavior Survey in 2007, 2009, and 2011. We used multivariable regression models controlling for race/ethnicity and age to estimate prevalence. RESULTS: Although the proportion of overweight and obese students did not change significantly during the study period, we found that approximately half of female students and 30% of male students reported trying to lose weight. Among female students, we observed significant increases in the proportion engaging in 5 or more days of physical activity per week (26.0% in 2007 to 31.9% in 2011; P = .003) and significant decreases in the proportion consuming at least 1 soda per day (31.1% in 2007 to 22.5% in 2011, P = .001). The proportion of female students who fasted for weight loss also increased significantly during the study period (12.2% in 2007 to 17.0% in 2011, P = .02). We found no significant changes in behavior among male students. CONCLUSION: Although the prevalence of obesity and overweight may have reached a plateau among Philadelphia high school students, most students still failed to meet recommendations for healthful weight-management behaviors. Continued public health initiatives are necessary to promote participation in healthful weight-management behaviors. PMID- 24070037 TI - Consistency of nutrition recommendations for foods marketed to children in the United States, 2009-2010. AB - INTRODUCTION: Food marketing has emerged as an environmental factor that shapes children's dietary behaviors. "Advergames," or free online games designed to promote branded products, are an example of evolving food marketing tactics aimed at children. Our primary objective was to classify foods marketed to children (aged 2-11 y) in advergames as those meeting or not meeting nutrition recommendations of the US Department of Agriculture (USDA), Food & Drug Administration (FDA), Center for Science in the Public Interest (CSPI), and the Institute of Medicine (IOM). We document the consistency of classification of those foods across agency guidelines and offer policy recommendations. METHODS: We used comScore Media Builder Metrix to identify 143 websites that marketed foods (n = 439) to children aged 2 to 11 years through advergames. Foods were classified on the basis of each of the 4 agency criteria. Food nutrient labels provided information on serving size, calories, micronutrients, and macronutrients. RESULTS: The websites advertised 254 meals, 101 snacks, and 84 beverages. Proportions of meals and snacks meeting USDA and FDA recommendations were similarly low, with the exception of saturated fat in meals and sodium content in snacks. Inconsistency in recommendations was evidenced by only a small proportion of meals and fewer snacks meeting the recommendations of all the agencies per their guidelines. Beverage recommendations were also inconsistent across the 3 agencies that provide recommendations (USDA, IOM, and CSPI). Most (65%-95%) beverages advertised in advergames did not meet some of these recommendations. CONCLUSION: Our findings indicate that a large number of foods with low nutritional value are being marketed to children via advergames. A standardized system of food marketing guidance is needed to better inform the public about healthfulness of foods advertised to children. PMID- 24070038 TI - International collaboration on prevention of shaken baby syndrome - an ongoing project/intervention. AB - Caring for young infants can be stressful. Non-accidental brain or head injury (shaken baby syndrome) is a result of parental stress, and a lack of knowledge of how to respond to a crying infant and the dangers of shaking a child. This article demonstrates the value of international collaboration in projects to prevent child maltreatment. It includes reports of prevention of shaken baby syndrome programmes in Australia, Hungary, Greece, Brazil and Turkey. PMID- 24070039 TI - A data-based study on survival of permanent molar restorations in adolescents. AB - OBJECTIVE: The aim of this epidemiological, data-based survival study was to study the longevity of restorations in permanent molars of adolescents in the 1990 and 1995 birth cohorts during the period of 1992-2005 in the City of Vantaa, Finland. MATERIALS AND METHODS: The dental records of 2975 (1990 cohort) and 3147 (the 1995 cohort) adolescents were analyzed. The longevity of restorations from their placement until replacement was illustrated using the Kaplan-Meier survival curves. The influence of the cohort, gender and caries risk on the survival rate was assessed using the Cox proportional hazards regression analysis. RESULTS: A majority of the restorations were tooth-colored. The proportion of amalgam restorations was almost non-existent in both cohorts. The survival of tooth colored restorations on the occlusal surfaces of molars was lower in the 1995 cohort compared to the 1990 cohort. The need of replacement of glass-ionomer restorations was twice that of composite restorations' hazard ratio 2.27 (1.62 3.16). CONCLUSIONS: Composites are the most frequently used dental materials and have the longest survival times among adolescents. The survival of restorations per se is poorer in the more recent than in the earlier birth cohort. PMID- 24070040 TI - Parents' perceptions of the HPV vaccine: a key target for improving immunization rates. PMID- 24070041 TI - Did the influenza A (H1N1) 2009 monovalent inactivated vaccines increase the risk for Guillain-Barre syndrome? PMID- 24070043 TI - MP29-02 for the treatment of seasonal allergic rhinitis: a review of clinical pharmacology, efficacy and safety. AB - This review presents the pharmacology, clinical efficacy and safety of MP29-02 (Dymista(r)), a unique product for the treatment of allergic rhinitis. Allergic rhinitis is often thought of more as a nuisance than a meaningful medical condition, and the health impact of allergic rhinitis can easily be underestimated. As a result, allergic rhinitis can be undertreated, expectations for relief may not be met, and patients may be left dissatisfied and non compliant with their medications. MP29-02 is the only currently available allergic rhinitis medication to provide potent early-phase histamine-receptor blocking and long-term anti-inflammatory effects in a single intranasal formulation and delivery system that represents an advance in the therapy of allergic rhinitis, in particular for patients with moderate-to-severe disease. PMID- 24070044 TI - Highlights on the EAACI-WAO Congress 2013. AB - European Academy of Allergy and Clinical Immunology and World Allergy Organization. World Allergy and Asthma Congress. Milano, Italy, 22-26 June 2013 The European Academy of Allergy and Clinical Immunology and World Allergy Organization congress provided a meeting for researchers and clinicians interested in allergy and clinical immunology from all over the world and a unique opportunity to exchange experience with other professionals in this fields. PMID- 24070045 TI - Vitamin D in pregnancy and early life: the right target for prevention of allergic disease? AB - EVALUATION OF: Weisse et al. Maternal and newborn vitamin D status and its impact on food allergy development in the German LINA cohort study. Allergy 68, 220-228 (2013). Allergic diseases are the most common chronic disorders of childhood. The alarming trend is that these diseases are expressed early in life and are no longer outgrown in childhood. Over the last 10 years, the rates of food allergy and eczema have continued to increase dramatically in children as part of what appears to be a 'second wave' of the allergy epidemic. Although the risk factors for allergic disease are multifactorial, the early onset has implicated lifestyle and environmental factors as significant contributors to this escalating trend. Weisse et al. present supporting evidence for vitamin D being positively associated with children's risk for food allergy or sensitization against food allergens during their first 2 years of life and argue against the use of vitamin D supplements to protect against allergy. Here, the authors provide a mechanistic insight into how high cord blood vitamin D levels can result in increased food allergy risk in children. PMID- 24070046 TI - Immune response in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a major public health problem because of its high prevalence, rising incidence and associated socio-economic cost. The inhalation of toxic particles and gases, mostly tobacco smoke, is the main risk factor for COPD. Yet, not all smokers are equally susceptible to these toxic effects and only a percentage of them develop the disease (so-called 'susceptible smokers'). This, in combination with the observation that COPD shows familial aggregation, suggests that the genetic background of the smoker is a key element in the pathogenesis of the disease. On the other hand, it is well established that 'susceptible' smokers exhibit an enhanced inflammatory response of the lung parenchyma as compared with 'resistant' smokers (i.e., those who manage to maintain lung function within the normal age range despite their habit). Importantly, in COPD patients this inflammatory response does not resolve after quitting smoking, again at variance with resistant smokers. All in all, these observations suggest that the pathogenesis of COPD may involve, in some patients, an autoimmune component which contributes to the enhanced and persistent inflammatory response that characterizes the disease. Here we: i) review briefly the pathobiology of COPD; ii) present the available scientific evidence supporting a potential role for autoimmunity in COPD; iii) propose a three-step pathogenic hypothesis in the transition from smoking to COPD; and iv) discuss potential implications for the diagnosis and treatment of this frequent, growing, devastating and costly disease. PMID- 24070047 TI - Impact of donor-specific antibodies in reconstructive transplantation. AB - For many devastating injuries and tissue defects where conventional reconstruction is not possible, reconstructive transplantation such as hand and face transplantation has become a viable alternative. This novel approach allows for improved restoration of appearance, anatomy and function not feasible by other available treatment options. However, clinical management of these injuries prior to transplantation frequently requires multiple blood transfusion or skin grafts resulting in the formation of alloantibodies (anti-HLA IgG Abs) and a high degree of sensitization. The role of donor-specific antibodies (DSA) and mechanisms of antibody-mediated rejection (AMR) in reconstructive transplantation are still largely unknown. Thus there is an imminent need to develop a better understanding of the mechanisms related to DSA and AMR after reconstructive transplantation. In this review, we will define the role of DSA and mechanisms of AMR in reconstructive transplantation and compare them to established measures and treatment concepts in solid organ transplantation. PMID- 24070048 TI - A clinical and pathomechanistic profile of chronic nonbacterial osteomyelitis/chronic recurrent multifocal osteomyelitis and challenges facing the field. AB - Sporadic chronic nonbacterial osteomyelitis (CNO) is the most common auto inflammatory bone disorder. The clinical picture is highly variable ranging from nonsymptomatic monofocal lesions to chronic recurrent multifocal disease. Symptoms include pain, local swelling and warmth in the absence or presence of fever. A subset of CNO patients exhibits additional symptoms of psoriatic skin involvement, palmoplantar pustulosis and inflammatory bowel disease. Novel insights into the pathogenesis of CNO link the failure to produce IL-10 and the resulting imbalance toward pro-inflammatory IL-6 and TNF-alpha with disease expression. Treatment is empiric and includes NSAIDs, corticosteroids, sulfasalazine, methotrexate, TNF inhibitors and bisphosphonates. Laboratory studies and clinical trials are warranted to: establish biomarkers that predict flares and clinical outcomes, identify patients that require additional treatment on top of NSAIDs, establish evidence-based treatment regimens, allow a risk benefit assessment for the available therapeutic strategies, and identify novel therapeutic targets. PMID- 24070049 TI - Prevention of anaphylaxis in healthcare settings. AB - In this paper, we review recent evidence on preventing anaphylaxis in healthcare settings and contexts where the risk of developing anaphylaxis is known to be increased. These include investigation units in which patients are undergoing challenge testing, outpatient clinics undertaking immunotherapy and vaccination, inpatient settings in which patients receive antibiotics, non-steroidal anti inflammatory drugs, opiates and biological agents and operating theatres in which patients receive general anesthetics. Anaphylaxis may however develop unpredictably in any patient exposed to a wide range of drugs, food and other triggers (e.g., latex, iodinated contrast media and exercise), so it is important that all healthcare professionals and systems have effective, well-rehearsed protocols for risk assessment and management of this allergic emergency. Where available, we consider evidence for the effectiveness of interventions aiming to reduce the risk of developing anaphylaxis. PMID- 24070050 TI - Clinical aspects of mucosal healing in inflammatory bowel diseases: what is it and what is the real value for the everyday practice? AB - The course of inflammatory bowel diseases is heterogeneous and varies over time. Therefore, the search for predictive factors has increasingly become the focus of research. Mucosal healing has emerged as an important objective, as evidence indicates that it is associated with improved disease outcome. Nevertheless, many unsolved questions remain, including the definition of complete or partial healing as well as the best assessment method using endoscopic or imaging techniques, most of which are relatively invasive and expensive procedures, which therefore are not ideal for frequent monitoring and it is not clear. This review summarizes the available evidence in order to assist clinicians when assessing the mucosal status in the everyday practice. PMID- 24070051 TI - Investigation into temperature-induced aggregation of an antibody drug conjugate. AB - Conjugation of an antibody to a drug can produce heterogeneous species that may have different physical stabilities and safety profiles. We explored the effect of thermal stress on the physical stability, specifically aggregation, of an antibody drug conjugate (ADC), ADC 1, wherein the antibody was linked to the val cit-Monomethyl Auristatin E (vc-MMAE) linker drug through the reduction of interchain disulfides. We also explored the effects of conjugation on the secondary and tertiary structures of ADC 1. Circular dichroism, intrinsic tryptophan fluorescence, and differential scanning calorimetry showed that for species with high drug loading, conjugation does not measurably alter the secondary structure, but it does render the CH2 domain less stable to thermal stress such that ADC 1 rapidly forms high molecular weight species (HMWS) at 40 degrees C. Characterization of the HMWS using chromatographic and electrophoretic methods showed that it is an irreversible, noncovalent, and structurally altered form of ADC 1 primarily composed of molecules with six or eight drugs. Furthermore, the variable domain of the antibody may contribute to the extent of aggregation, since eight ADCs with over 90% sequence homology exhibited monthly rates of HMWS formation that differ by up to a factor of 2. PMID- 24070053 TI - Structural and vibrational properties of imidazo[4,5-c]pyridine, a structural unit in natural products. AB - The molecular structures and vibrational properties of 1H-imidazo[4,5-c]pyridine in its monomeric and dimeric forms are analyzed and related to the experimental results derived from the XRD, IR, and Raman studies. The theoretical data are discussed on the basis of DFT quantum chemical calculations using the B3LYP correlation functional and 6-311G(2d,2p) basis set. This compound crystallizes in the non-centrosymmetric orthorhombic space group Fdd2. The asymmetric unit contains one molecule of 1H-imidazo[4,5-c]pyridine and disordered molecules of solvents. The molecules are organized in hydrogen-bonded chains propagating along the [1 0 -3] direction. The stability of the dimeric form arising from charge delocalization and the existence of an N-H...N intermolecular hydrogen bond has been analyzed using the natural bond orbital approach. The normal modes, which are unique for the imidazopyridine skeleton, have been identified. The spectra of other compounds containing the imidazopyridine unit have been analyzed. PMID- 24070054 TI - Asymmetric total synthesis of (-)-jorunnamycins A and C and (-)-jorumycin from L tyrosine. AB - Three renieramycin-type antitumor alkaloids, (-)-jorunnamycins A (1) and C (2) and (-)-jorumycin (3), have been synthesized by a new convergent approach, which features a highly regio- and stereoselective Pictet-Spengler cyclization to couple the isoquinoline and the trisubstituted phenylalaninol partners. This synthetic strategy opens an economical access to these important antitumor alkaloids with high yields: (-)-jorunnamycin A, as a common precursor to other renieramycin-type alkaloids and their analogues, is obtained with 18.1% overall yield from l-tyrosine. PMID- 24070055 TI - Elevated preoperative neutrophil/lymphocyte ratio as a predictor of increased long-term survival in minimal invasive coronary artery bypass surgery compared to sternotomy. AB - BACKGROUND: Neutrophil lymphocyte ratio (NLR) is a predictor of major adverse cardiovascular outcomes. Our study explores the value of NLR in predicting long term mortality after minimally invasive coronary artery bypass surgery (MICS) via lateral left-thoracotomy versus conventional sternotomy coronary artery bypass grafting (CABG) surgery. METHODS: A total of 1126 consecutive patients (729 sternotomy CABG and 397 MICS) from a single tertiary center between 2005 and 2008 were followed until 2011. We stratified the patients into equal tertiles according to preoperative NLR. The primary outcome, all-cause mortality, was compared among the NLR tertiles. RESULTS: Out of the 1126 patients included in the study, 1030 (91%) patients underwent off-pump CABG . The first (NLR <2.3) tertile had a significantly lower 5-year mortality (30/371 =8%) in comparison to the second (NLR =2.3-3.4) and third (NLR >=3.5) tertiles (49/375 =13% and 75/380 =20%), respectively with p < 0.0001. After multivariate adjustment, NLR was a significant independent predictor of mortality (hazard ratio [HR] per each unit increase of NLR was 1.05, 95% confidence interval [CI] 1.01-1.10, p = 0.008). MICS and sternotomy CABG groups with NLR <3 had similar mortality (21/221 =9.5% and 40/403 =9.9%), p = 1. However among patients with NLR >=3, MICS had a significantly lower mortality (23/176 =13.1%) compared to the sternotomy CABG (70/326 =21.5%), p = 0.02. According to the multivariate analysis of patients with NLR >=3, MICS had a significantly lower mortality compared to sternotomy CABG (HR = 0.44, 95% CI 0.24-0.78, p = 0.005). CONCLUSION: Elevated preoperative NLR is an independent predictor of long-term mortality after CABG. Among the patients with NLR >= 3, MICS was associated with a significantly improved survival compared with sternotomy CABG. PMID- 24070056 TI - Neurodynamics of somatosensory cortices studied by magnetoencephelography. AB - From the viewpoint of statistical inverse problems, identification of transfer functions in feedback models is applied for neurodynamics of somatosensory cortices, and brain communication among active regions can be expressed in terms of transfer functions. However, brain activities have been investigated mainly by averaged waveforms in the conventional magnetoencephalography analysis, and thus brain communication among active regions has not yet been identified. It is shown that brain communication among two more than three brain regions is determined, when fluctuations related to concatenate averaged waveforms can be obtained by using a suitable blind source separation method. In blind identification of feedback model, some transfer functions or their impulse responses between output variables of current dipoles corresponding to active regions are identified from reconstructed time series data of fluctuations by the method of inverse problem. Neurodynamics of somatosensory cortices in 5 Hz median nerve stimuli can be shown by cerebral communication among active regions of somatosensory cortices in terms of impulse responses of feedback model. PMID- 24070057 TI - Implementation of a beam forming technique in real-time magnetoencephalography. AB - Real-time magnetoencephalography (rtMEG) is an emerging neurofeedback technology that could potentially benefit multiple areas of basic and clinical neuroscience. In the present study, we implemented voxel-based real-time coherence measurements in a rtMEG system in which we employed a beamformer to localize signal sources in the anatomical space prior to computing imaginary coherence. Our rtMEG experiment showed that a healthy subject could increase coherence between the parietal cortex and visual cortex when attending to a flickering visual stimulus. This finding suggests that our system is suitable for neurofeedback training and can be useful for practical brain-machine interface applications or neurofeedback rehabilitation. PMID- 24070058 TI - Frequency diversity of posterior oscillatory activity in human revealed by spatial filtered MEG. AB - The posterior EEG alpha rhythm is a distinctive feature of the normal brain in the waking state, consisting of oscillations within the 8-15 Hz frequency range over posterior cortical regions. This activity appears in resting, eyes-closed condition and is typically suppressed by eyes-opening. Other physiological rhythms in the alpha band, in particular the Rolandic mu rhythm, are proposed to include a fast component in the beta range. In this study we used spatial filtering techniques and permutation analysis to explore cortical source-power changes related to the magnetoencephalography (MEG) counterpart of the posterior alpha rhythm. We also aimed at determining a possible implication of components outside the alpha frequency range in the posterior rhythm reactivity to eye closure. We recorded resting brain activity using a whole-head MEG system in fifteen normal subjects. We applied an eyes-open/eyes-closed paradigm. A significant increase in alpha oscillations after eyes closing, representing the posterior alpha rhythm, was observed bilaterally in the occipital and parietal cortex, including the calcarine fissure and the parieto-occipital sulcus. We also found significant increase in beta (15-30 Hz) and low gamma (30-60 Hz) oscillations. This fast components and the classical alpha rhythm had similar topographic distribution in posterior brain regions, although with different strength and spatial extension. These features were highest for alpha synchronized oscillations, intermediate for beta, and lowest for gamma activity. These results suggest that, like the Rolandic mu rhythm, the MEG posterior dominant rhythm may be impure, with a mixture of predominant alpha oscillations and high-frequency components. PMID- 24070059 TI - Dynamic cortical activity during the perception of three-dimensional object shape from two-dimensional random-dot motion. AB - Recent neuroimaging studies implicate that both the dorsal and ventral visual pathways, as well as the middle temporal (MT) areas which are critical for the perception of visual motion, are involved in the perception of three-dimensional (3D) structure from two-dimensional (2D) motion (3D-SFM). However, the neural dynamics underlying the reconstruction of a 3D object from 2D optic flow is not known. Here we combined magnetoencephalography (MEG) and functional MRI (fMRI) measurements to investigate the spatiotemporal brain dynamics during 3D-SFM. We manipulated parametrically the coherence of randomly moving groups of dots to create different levels of 3D perception and to study the associated changes in brain activity. At different latencies, the posterior infero-temporal (pIT), the parieto-occipital (PO), and the intraparietal (IP) regions showed increased neural activity during highly coherent motion conditions in which subjects perceived a robust 3D object. Causality analysis between these regions indicated significant causal influence from IP to pIT and from pIT to PO only in conditions where subjects perceived a robust 3D object. Current results suggest that the perception of a 3D object from 2D motion includes integration of global motion and 3D mental image processing, as well as object recognition that are accomplished by interactions between the dorsal and ventral visual pathways. PMID- 24070060 TI - fMRI measurement of the integrative effects of visual and chemical senses stimuli in humans. AB - The purpose of this study was to evaluate the integrative effects of visual stimuli with chemical senses (olfactory and gustatory) stimuli in humans. Noninvasive measurement tools such as magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) are used to describe the mechanism of olfactory information processing in the human brain, and the neurophysiological properties of olfactory-related neurons are described. The first study analyzed the interaction between visual and olfactory stimuli. Two odors (lemon and iso valeric acid) were selected as pleasant and unpleasant odors, respectively and pleasant and unpleasant images were also selected. These cross-modal stimulus combinations were presented to the subject at random, and responses were measured by fMRI using an event related task. These results revealed that active brain areas with pleasant/unpleasant stimuli and matched/mismatched stimuli were different for memory and cognition. The second study analyzed the interaction between visual and gustatory stimuli. Total four conditions (hunger-not hunger, and intake-not intake of monosodium glutamate (MSG)) were tested. Visual stimuli were food-related and nonfood-related photos. A visual analog scale (VAS) was also used to evaluate before and at regular time intervals after intake of MSG, and responses were measured using fMRI. Brain activity related to feeding desire after intake of MSG occurred near the insula cortex, and orbito-frontal cortex, among other areas. These results on the integrative effects of visual stimuli with olfactory and gustatory stimuli, cross-modal and complex effects on olfaction and gustation were suggested to be obtained as an emotional response such as "pleasantness/unpleasantness" and as cognitive and memory responses such as "matching/mismatching" or the responses such as "feeding desire" afterwards intake of foods. PMID- 24070061 TI - Early auditory change detection implicitly facilitated by ignored concurrent visual change during a Braille reading task. AB - Unconscious monitoring of multimodal stimulus changes enables humans to effectively sense the external environment. Such automatic change detection is thought to be reflected in auditory and visual mismatch negativity (MMN) and mismatch negativity fields (MMFs). These are event-related potentials and magnetic fields, respectively, evoked by deviant stimuli within a sequence of standard stimuli, and both are typically studied during irrelevant visual tasks that cause the stimuli to be ignored. Due to the sensitivity of MMN/MMF to potential effects of explicit attention to vision, however, it is unclear whether multisensory co-occurring changes can purely facilitate early sensory change detection reciprocally across modalities. We adopted a tactile task involving the reading of Braille patterns as a neutral ignore condition, while measuring magnetoencephalographic responses to concurrent audiovisual stimuli that were infrequently deviated either in auditory, visual, or audiovisual dimensions; 1000 Hz standard tones were switched to 1050-Hz deviant tones and/or two-by-two standard check patterns displayed on both sides of visual fields were switched to deviant reversed patterns. The check patterns were set to be faint enough so that the reversals could be easily ignored even during Braille reading. While visual MMFs were virtually undetectable even for visual and audiovisual deviants, significant auditory MMFs were observed for auditory and audiovisual deviants, originating from bilateral supratemporal auditory areas. Notably, auditory MMFs were significantly enhanced for audiovisual deviants from about 100 ms post stimulus, as compared with the summation responses for auditory and visual deviants or for each of the unisensory deviants recorded in separate sessions. Evidenced by high tactile task performance with unawareness of visual changes, we conclude that Braille reading can successfully suppress explicit attention and that simultaneous multisensory changes can implicitly strengthen automatic change detection from an early stage in a cross-sensory manner, at least in the vision to audition direction. PMID- 24070063 TI - Haemophagocytic syndrome after intravesical bacille Calmette-Guerin instillation. AB - Abstract Intravesical bacille Calmette-Guerin (BCG) is used to treat high-risk superficial bladder cancer. This article reports a case of secondary haemophagocytosis after intravesical BCG instillation in a 70-year-old man with bladder cancer and presents a literature review of this very rare but potentially fatal complication of intravesical BCG treatment. PMID- 24070062 TI - Proteomic analysis of Fusarium oxysporum f. sp. cubense tropical race 4 inoculated response to Fusarium wilts in the banana root cells. AB - BACKGROUND: Fusarium wilt of banana is one of the most destructive diseases in the world. This disease has caused heavy losses in major banana production areas. Except for molecular breeding methods based on plant defense mechanisms, effective methods to control the disease are still lacking. Dynamic changes in defense mechanisms between susceptible, moderately resistant, and highly resistant banana and Fusarium oxysporum f. sp. cubense tropical race 4 (Foc4) at the protein level remain unknown. This research reports the proteomic profile of three banana cultivars in response to Foc4 and transcriptional levels correlated with their sequences for the design of disease control strategies by molecular breeding. RESULTS: Thirty-eight differentially expressed proteins were identified to function in cell metabolism. Most of these proteins were positively regulated after Foc4 inoculation. These differentially regulated proteins were found to have important functions in banana defense response. Functional categories implicated that these proteins were associated with pathogenesis-related (PR) response; isoflavonoid, flavonoid, and anthocyanin syntheses; cell wall strengthening; cell polarization; reactive oxygen species production and scavenging; jasmonic acid-, abscisic acid-, and auxin-mediated signaling conduction; molecular chaperones; energy; and primary metabolism. By comparing the protein profiles of resistant and susceptible banana cultivars, many proteins showed obvious distinction in their defense mechanism functions. PR proteins in susceptible 'Brazil' were mainly involved in defense. The proteins related to PR response, cell wall strengthening and antifungal compound synthesis in moderately resistant 'Nongke No.1' were mainly involved in defense. The proteins related to PR response, cell wall strengthening, and antifungal compound synthesis in highly resistant 'Yueyoukang I' were mainly involved in defense. 12 differentially regulated genes were selected to validate through quantitative real time PCR method. Quantitative RT-PCR analyses of these selected genes corroborate with their respective protein abundance after pathogen infection. CONCLUSIONS: This report is the first to use proteomic profiling to study the molecular mechanism of banana roots infected with Foc4. The differentially regulated proteins involved in different defense pathways are likely associated with different resistant levels of the three banana cultivars. PMID- 24070064 TI - Activity of linezolid and daptomycin against methicillin-resistant coagulase negative staphylococci with increased MIC for vancomycin isolated from blood cultures in pediatric patients. AB - We evaluated minimal inhibitory concentration (MIC) for vancomycin, daptomycin, and linezolid in methicillin-resistant coagulase-negative staphylococci (MR CoNS). Minimal inhibitory concentration of 2-4 mg/l for vancomycin was observed in 16% of strains, and among them 19% had MIC at breakpoint for daptomycin or linezolid. Among strains completely susceptible to vancomycin, 16% had MIC at breakpoint for daptomycin and 11% had for linezolid. This large proportion of pathogens with MIC around the breakpoint suggests a possible risk of treatment failure with these drugs. This phenomenon is worth further and constant monitoring. PMID- 24070065 TI - The aPC treatment improves microcirculation in severe sepsis/septic shock syndrome. AB - BACKGROUND: The role of recombinant activated protein C (aPC) during sepsis is still controversial. It showed anti-inflammatory effect and improved the microvascular perfusion in experimental models of septic shock. The present study was aimed at testing the hypothesis that recombinant aPC therapy improves the microcirculation during severe sepsis. METHODS: Prospective observational study on patients admitted in a 12-beds intensive care unit of a university hospital from July 2010 to December 2011, with severe sepsis and at least two sepsis induced organ failures occurring within 48 hours from the onset of sepsis, who received an infusion of aPC (24 mcg/kg/h for 96 hours) (aPC group). Patients with contraindications to aPC administration were also monitored (no-aPC group).At baseline (before starting aPC infusion, T0), after 24 hours (T1a), 48 hours (T1b), 72 hours (T1c) and 6 hours after the end of aPC infusion (T2), general clinical and hemodynamic parameters were collected and the sublingual microcirculation was evaluated with sidestream dark-field imaging. Total vessel density (TVD), perfused vessel density (PVD), De Backer score, microvascular flow index (MFIs), the proportion of perfused vessels (PPV) and the flow heterogeneity index (HI) were calculated for small vessels. The perfused boundary region (PBR) was measured as an index of glycocalyx damage. Variables were compared between time points and groups using non parametric or parametric statistical tests, as appropriate. RESULTS: In the 13 aPC patients mean arterial pressure (MAP), base excess, lactate, PaO2/FiO2 and the Sequential Organ Failure Assessment (SOFA) score significantly improved over time, while CI and ITBVI did not change. MFIs, TVD, PVD, PPV significantly increased over time and the HI decreased (p < 0.05 in all cases), while the PBR did not change. No-aPC patients (n = 9) did not show any change in the microcirculation over time. A positive correlation was found between MFIs and MAP. TVD, PVD and De Backer score negatively correlated with norepinephrine dose, and the SOFA score negatively correlated with MFIs, TVD and PVD. CONCLUSIONS: aPC significantly improves the microcirculation in patients with severe sepsis/septic shock. TRIAL REGISTRATION: NCT01806428. PMID- 24070066 TI - Comparative analysis of Tunisian wild Crataegus azarolus (yellow azarole) and Crataegus monogyna (red azarole) leaf, fruit, and traditionally derived syrup: phenolic profiles and antioxidant and antimicrobial activities of the aqueous acetone extracts. AB - Quantitative and qualitative analyses of the yellow and red azarole phenolic extracts prepared from leaf, fruit peel/pulp, and syrup were comparatively investigated. The yellow azarole was found significantly richer in polyphenols than the red-fruit species. Hyperoside was the main phenolic in both yellow and red azarole leaves and only in yellow fruits, whereas procyanidin B2 was the major compound in red fruits. Yellow azarole leaf and fruit peel extracts exhibited the strongest antioxidant activities using DPPH (~168 and 79 MUmol TEAC/g fw, respectively) and FRAP (~378 and 161 MUmol Fe(2+)/g fw, respectively) assays. The highest antibacterial activities were recorded for the yellow azarole leaf and fruit peel extracts, especially against Staphylococcus aureus and Streptococcus faecalis . The low phenolic content of the syrups contrasted with their significant antioxidant and antimicrobial potentials, which were correlated to their hydroxymethylfurfural (HMF) (furan derivative amounts) content. PMID- 24070068 TI - Factors associated with survival and recurrence for patients undergoing surgery of cerebellar metastases. AB - OBJECTIVE: Patients with cerebellar and non-cerebellar metastases are often included in the same study population, even though posterior fossa lesions typically have different presenting symptoms, clinical outcomes, and complications. This is because the outcomes for patients with cerebellar metastases are unclear. METHODS: Adult patients who underwent surgery for an intracranial metastasis (single or multiple) between 2007 and 2011 were retrospectively reviewed. Stepwise multivariate proportional hazards regression analysis was used to identify an association between cerebellar location with survival and recurrence. RESULTS: Of the 708 patients who underwent intracranial metastatic surgery, 140 (19.8%) had surgery for cerebellar metastasis. A cerebellar location was associated with poorer survival [RR (95% CI); 1.231 (1.016-1.523), P = 0.04] and increased spinal recurrence [RR (95% CI); 2.895 (1.491-5.409), P = 0.002], but not local (P = 0.61) or distal recurrence (P = 0.88). The factors independently associated with prolonged survival for patients with cerebellar metastases were: decreasing number of intracranial metastases (P = 0.0002), decreasing tumor size (P = 0.002), and radiation (P = 0.0006). The factors associated with prolonged local progression free survival were: decreasing tumor size (P = 0.0009), non small cell lung cancer (NSCLC) (P = 0.006), non-bladder cancer (P = 0.0005), and post-operative radiation therapy (P = 0.02). The factors independently associated with prolonged distal progression free survival were: age > 40 years (P = 0.02), surgical resection (P = 0.01), and whole brain radiation (WBRT) therapy (P = 0.02). DISCUSSION: Patients with cerebellar metastases have more distinct clinical presentations and outcomes than patients with non-cerebellar lesions. The findings of this study may help risk stratify and guide treatment regimens aimed at maximizing outcomes for patients with cerebellar metastases. PMID- 24070069 TI - Living with a pituitary tumour: a narrative analysis. AB - This study aimed to synthesise the illness narratives of individuals living with a pituitary tumour. Eight adults with a pituitary tumour were recruited from an endocrinology service in the north-west of England. A narrative methodology was adopted which investigated elements of the individual narratives such as metaphor and structure but which also aimed to produce a joint account of experience in this particular illness context by extracting themes across the stories; these are presented as part of a chronological narrative. However, the resulting group story was also analysed in terms of different types of narrative plots. The group narrative started from the recognition of symptoms and then diagnosis though treatment to post-treatment and future plans. In terms of narrative plots, one notable element of the joint narrative was the flow between the culturally dominant restitution narrative, where participants focused on treatment and recovery and the chaos narrative when recovery did not seem possible. The findings contain many elements consistent with previous research; however, the use of a celebrity figure to communicate about the illness experience and a perception that objects or individuals should not be taken at face value emerged as more novel findings. PMID- 24070067 TI - Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor. AB - DAPK1 and ZIPK (also called DAPK3) are closely related serine/threonine protein kinases that regulate programmed cell death and phosphorylation of non-muscle and smooth muscle myosin. We have developed a fluorescence linked enzyme chemoproteomic strategy (FLECS) for the rapid identification of inhibitors for any element of the purinome and identified a selective pyrazolo[3,4 d]pyrimidinone (HS38) that inhibits DAPK1 and ZIPK in an ATP-competitive manner at nanomolar concentrations. In cellular studies, HS38 decreased RLC20 phosphorylation. In ex vivo studies, HS38 decreased contractile force generated in mouse aorta, rabbit ileum, and calyculin A stimulated arterial muscle by decreasing RLC20 and MYPT1 phosphorylation. The inhibitor also promoted relaxation in Ca(2+)-sensitized vessels. A close structural analogue (HS43) with 5-fold lower affinity for ZIPK produced no effect on cells or tissues. These findings are consistent with a mechanism of action wherein HS38 specifically targets ZIPK in smooth muscle. The discovery of HS38 provides a lead scaffold for the development of therapeutic agents for smooth muscle related disorders and a chemical means to probe the function of DAPK1 and ZIPK across species. PMID- 24070070 TI - Evolution of egg dummies in Tanganyikan cichlid fishes: the roles of parental care and sexual selection. AB - Sexual selection has been suggested to be an important driver of speciation in cichlid fishes of the Great Lakes of Africa, and the presence of male egg dummies is proposed to have played a key role. Here, we investigate how mouthbrooding and egg dummies have evolved in Tanganyikan cichlids, the lineage which seeded the other African radiations, with a special emphasis on the egg dummies. Using modern phylogenetic comparative analyses and a phylogeny including 86% of the 200 described species, we provide formal evidence demonstrating correlated evolution between mouthbrooding and egg dummies in Tanganyikan cichlids. These results concur with existing evidence, suggesting that egg dummies have evolved through sensory exploitation. We also demonstrate that there is a strong evolutionary correlation between the presence of egg dummies and both pre- and post-copulatory sexual selection. Moreover, egg dummy evolution was contingent on the intensity of pre- and post-copulatory sexual selection in Tanganyikan cichlids. In sum, our results provide evidence supporting the hypothesis of egg dummies evolving through sensory exploitation and highlight the role of sexual selection in favouring the evolution and maintenance of this trait. PMID- 24070071 TI - Transplantation of human adipose tissue-derived stem cells delays clinical onset and prolongs life span in ALS mouse model. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects motor neurons in the cortex, brain stem, and spinal cord. The precise pathogenic mechanism remains unknown, and there is currently no effective therapy. We evaluated the therapeutic effects of human adipose tissue-derived stem cells (ASCs) in an animal model of ALS. Human abdominal subcutaneous fat tissues were obtained by simple liposuction from donors, and ASCs were isolated from the fat stromal vascular fraction. ASCs were found to differentiate into adipocytes, chondrocytes, osteocytes, and neurons. SOD1G93A ALS mice were divided into three groups: sham, intravenous (IV), and intracerebroventricular (ICV) groups. Human ASCs were transplanted in the ALS mice at 70 postnatal days before the appearance of clinical symptoms. Behavior of transplanted animals was assessed by rotarod test, paw grip endurance (PaGE), and reflex index. Mice in every group were sacrificed after 4 weeks posttransplantation. Transplanted ASCs were identified in the lumbar spinal cords with an antihuman mitochondria antibody and cell type-specific markers for neurons or astrocytes. Delayed onset of clinical symptoms (26 days) and extended survival of animals (24 days) were observed in ALS mice transplanted with ASCs via ICV route. ASCs were found to secrete high levels of neurotrophic factors such as NGF, BDNF, IGF-1, and VEGF. Reduction of apoptotic cell death by these factors was confirmed in cultured CNS cells and in the ALS spinal cord. These results indicate that transplantation of ASCs in ALS mice provides neuroprotective effects by production of cytokines/growth factors, delays disease progression, and prolongs the life span of ALS mice. PMID- 24070072 TI - How should we evaluate the risk of bias of physical therapy trials?: a psychometric and meta-epidemiological approach towards developing guidelines for the design, conduct, and reporting of RCTs in Physical Therapy (PT) area: a study protocol. AB - BACKGROUND: Numerous tools and items have been developed in all health areas to assess the risk of bias of randomized controlled trials (RCTs). The Cochrane Collaboration (CC) released a new tool to assess bias in RCTs, based on empirical evidence quantifying the association between some design features and estimates of treatment effects (TEs). However, this evidence is limited to medicine and investigating a selected set of components. No such studies have been conducted in other health areas such as Physical Therapy (PT) and allied health professions. Evidence specific to the PT area is needed to understand and quantify the association between design features and TE estimates to inform practice and decision-making in this field. The overall goal of this project is to provide direction for the design, conduct, reporting and bias assessment of PT RCTs. We will achieve this through the following specific objectives and methods. METHODS/DESIGN: 1) to measure the association between methodological components and other factors (for example, PT area, type of intervention, type of outcomes) and TE estimates in RCTs in PT, 40 randomly selected meta-analyses of RCTs involving PT interventions will be identified from the Cochrane Database of Systematic Reviews. Trials will be evaluated independently by two reviewers using the most commonly used tools in the PT field. A two-level analysis will be conducted using a meta-meta-analytic approach; 2) to identify relevant items to evaluate risk of bias of PT trials, an exploratory factor analysis (EFA) will be used to identify the latent structure of the items; 3) to develop guidelines for the design, conduct, reporting, and risk of bias assessment of PT RCTs, items obtained from the factor analysis and the meta-epidemiological approach will be further evaluated by experts in PT through a web-based survey following a Delphi procedure. DISCUSSION: The results of this project will have a direct impact on research and practice in PT and are valuable to a number of stakeholders: researchers when designing, conducting, and reporting trials; systematic reviewers and meta-analysts when synthesizing trial results; physiotherapists when making day-to-day treatment decision; and, other healthcare decision-makers, such as those developing policy or practice guidelines. PMID- 24070073 TI - "Interventional Neuroradiology: a neuroscience sub-specialty?". AB - Interventional Neuroradiology (INR) is not bound by the classical limits of a specialty, and is not restricted by standard formats of teaching and education. Open and naturally linked towards neurosciences, INR has become a unique source of novel ideas for research, development and progress allowing new and improved approaches to challenging pathologies resulting in better anatomo-clinical results. Opening INR to Neurosciences is the best way to keep it alive and growing. Anchored in Neuroradiology, at the crossroad of neurosciences, INR will further participate to progress and innovation as it has often been in the past. PMID- 24070074 TI - Structural analysis for Wingspan stent in a perforator model. AB - Perforator infarction represents a critical problem after intracranial Wingspan stent. To explore the mechanism of perforator infarction, we simulated the stent artery interaction at an atheromatous plaque with perforator. Structural deformation and biomechanical stress distribution after stenting were analyzed. High radial stress values were located along the stent struts, which surrounded the area with high circumferential stress. Stretched perforator orifice in a circumferential direction after stenting was simulated. These results show that structural deformation could play a role in the mechanism of perforator occlusion after Wingspan stenting. PMID- 24070075 TI - Intracranial stenting for severe symptomatic stenosis: self-expandable versus balloon-expandable stents. AB - Intracranial atherosclerosis against optimal medical treatment requires reperfusion therapy to improve the clinical outcome. We compared outcomes between self-expandable stent (SES) and/or balloon-expandable stent (BES) and present the potential advantages of using each stent. During the same time frame before and after Wingspan introduction to our institute, 115 consecutive patients underwent intracranial stenting for symptomatic severe intracranial stenosis against optimal medical treatment using BES alone (n = 71) vs. BES or SES (n = 44). We analyzed 15 factors including outcome related to an adverse event (AE), modified Rankin Scale (mRS) and restenosis at six months and retrospectively compared the potential advantages of using each stent. BES or SES groups had a significantly lower AE rate (2.3%) than the BES only group (14%) (P = 0.049) revealing mRS of <= 2 in all patients at six months compared to 93% of the patients in the BES group. Analysis of BES or SES subgroups revealed that BES was associated with less residual stenosis after stenting than SES (18 vs. 32%; P < 0.001). Both SES and BES can improve the clinical outcome of intracranial stenting especially with a selective choice of SES or BES. Further study is needed to analyse the difference in long-term outcome and the restenosis rate between SES and BES. PMID- 24070076 TI - Stent-assisted coiling of ruptured wide-necked intracranial aneurysms. AB - This study aimed to report the results and outcome of stent-assisted coiling of ruptured wide-necked intracranial aneurysms. We retrospectively reviewed 19 consecutive patients (11 men, eight women; mean age, 59.5 years; range, 43-78 years) with acutely ruptured wide-necked intracranial aneurysms who were treated with stent-assisted coil embolization. The mean length of angiographic follow-up was 5.2 months (range, 3-10 months). There was no technique-related complication and the 30-day mortality rate was 10.5% (two of 19). There was one case of rebleeding, and clinical outcome was poor for the patient (5.3% [one of 19] who had a Glasgow Outcome Scale score of 2 at the end of the study period). Stent assisted coiling is a feasible treatment for ruptured wide-necked intracranial aneurysms that are difficult to treat surgically or with balloon-assisted embolization. PMID- 24070077 TI - Treatment of ruptured saccular aneurysms of the fenestrated vertebrobasilar junction with balloon remodeling technique. A short case series and review of the literature. AB - Fenestration of the intracranial arteries is a relatively common occurrence. This anatomic variation may predispose to aneurysm formation at certain sites. Treatment of such aneurysms is difficult as it may occlude one of the limbs of fenestration with resultant deficit. Thus, preservation of both the limbs with adequate exclusion of the aneurysm from the circulation should be the aim of any treatment. We describe a series of four cases of ruptured aneurysms arising from a fenestrated vertebrobasilar junction treated with endovascular balloon remodeling technique. PMID- 24070078 TI - Stent/balloon combination assist technique for wide-necked basilar terminal aneurysms. AB - We describe an enhanced endovascular procedure for the coiling of broad-necked basilar terminal aneurysms with a combined balloon/stent assist technique. A balloon-assisted catheter is inserted in the origin of one posterior cerebral artery (PCA) and an assisted stent is deployed from the opposite PCA to the basilar artery. A microcatheter for coiling is inserted through the stent strut (trans-cell approach), and the aneurysm is coiled under stent support and assisted balloon inflation to keep the patency of both PCAs. This technique is more beneficial for reducing the risk of stent deformity than Y-stenting, and it provides a simpler procedure than other advanced stent techniques. Additionally, it enables an easy approach when retreatment is necessary for aneurysm recurrence. This technique may be one of the useful procedures for embolizing broad-necked basilar terminal aneurysms safely and effectively. PMID- 24070079 TI - Tuberothalamic artery infarction following coil embolization of a ruptured posterior communicating artery aneurysm belonging to a transitional type posterior cerebral artery. A case report. AB - There are many potential anatomical variations in the connection between the internal carotid artery and the posterior circulation through the posterior communicating artery (PCoA). We describe the endovascular treatment of an aneurysm arising near the origin of the PCoA belonging to a transitional type posterior cerebral artery. Coil embolization subsequently resulted in thrombo occlusion of the adjacent PCoA causing thalamic infarction even though sufficient retrograde flow had been confirmed pre-operatively by Allcock's test. PMID- 24070080 TI - Endovascular treatment of a mycotic intracavernous carotid artery aneurysm using a stent graft. AB - Intracavernous carotid artery mycotic aneurysms are rare and management is determined by clinical presentation. We describe the first documented proximal intracranial mycotic aneurysm treated by a balloon expandable Aneugraft PCS covered stent. An 11-year-old female child presented with acute onset fever, headache, chemosis followed by diplopia, right-sided ptosis with ophthalmoplegia. Magnetic resonance imaging revealed bilateral cavernous sinus thrombosis. Subsequent work-up included serial computed tomographic arteriography and digital subtraction angiography which revealed a progressively enlarging intracavernous carotid aneurysm. An Aneugraft PCS covered stent was successfully deployed endovascularly, and complete exclusion of the aneurysm was achieved while maintaining the patency of the parent artery. The use of covered stents in intracranial vasculature can be an effective and safe treatment modality for exclusion of the mycotic aneurysm in selected cases. PMID- 24070081 TI - Feasibility of the superselective test with propofol for determining eloquent brain regions in the endovascular treatment of arteriovenous malformations. AB - The superselective test for determining eloquent brain areas, carried out prior to the embolization treatment for arteriovenous malformations (AVMs), is a tool contributing to increase the safety of endovascular procedures. Taking into account amobarbital unavailability, it was decided to carry out the present study to demonstrate the efficacy and safety of propofol as an alternative to amobarbital to perform this test. A group of 58 patients were treated in 91 embolization sessions for brain AVMs using endovascular surgery between February 2006 and February 2011. The superselective test was performed prior to embolization with Histoacryl, using the intra-arterial administration of 20 mg propofol through a microcatheter positioned near the AVM nidus. Ten (7.8%) of the 128 superselective tests were positive. Neurological deficits appeared immediately after propofol administration, lasted for one minute and disappeared after five minutes. Only one of the patients showing a negative test result developed neurological deficits after embolization, for 99.2% negative predictive vale. Despite their positive test results, six patients were embolized and five developed post-embolization neurological deficits, for 83.3% positive predictive value. The test showed 83.3% sensitivity and 99.2% specificity. The use of propofol to perform the superselective test during brain AVM embolization is a safe and effective alternative to amobarbital, and may predict the occurrence of post-embolization ischemic complications. PMID- 24070082 TI - Brain reorganization after endovascular treatment in a patient with a large arteriovenous malformation: the role of diagnostic and functional neuroimaging techniques. AB - We describe a case of brain cortical reorganization after embolization of a large right temporal arteriovenous malformation. A comprehensive imaging protocol, including functional magnetic resonance imaging (fMRI), cortical thickness analysis and 320-row computed tomography (CT) perfusion was used to provide information on brain plasticity and potential steal phenomenon. A 25-year-old man known for a right temporal grade V Spetzler-Martin classification arteriovenous malformation (AVM) presented with left progressive hemiparesis. He underwent functional 3T magnetic resonance imaging (fMRI), cortical thickness analysis, and CT perfusion (CT 320 row, Aquilion ONE, Toshiba, Tokyo, Japan) before and after endovascular treatment. The results were compared to look for modifications in brain perfusion and organization. An improvement in the left hemiparesis and a reorganization of motor function were observed after endovascular treatment. Modifications in the angioarchitecture and perfusion of an extensive AVM may be accompanied by a functional and structural reorganization of the brain. The location in the so-called eloquent regions may not be sufficient to explain the wide spectrum of symptoms that these patients can present. A more comprehensive approach considering a global involvement of the brain in patients with large AVMs is suggested to achieve the best treatment strategy and to stage treatment in incurable AVMs. PMID- 24070083 TI - Bilateral persistent trigeminal arteries with unilateral trigeminal artery to cavernous sinus fistula. A case report. AB - A 59-year-old man who denied a history of trauma presented with left pulsatile tinnitus and left orbital swelling for six months. Digital subtraction angiography showed a left persistent trigeminal artery (PTA) with a trigeminal artery to cavernous sinus (trigeminal-cavernous sinus) fistula and a right PTA. Transarterial detachable coil embolization of the left trigeminal-cavernous sinus fistula was performed, and the symptoms subsided. There has been no report of bilateral PTAs with a spontaneous fistula connected from one PTA to the ipsilateral cavernous sinus. This paper reports such a rare circumstance. PMID- 24070084 TI - Balloon-assisted coiling of the cavernous sinus to treat direct carotid cavernous fistula. A single center experience of 13 consecutive patients. AB - This study evaluated clinical and neuroradiological results in 13 consecutive patients with spontaneous and traumatic direct carotid cavernous fistulas treated at our center between January 2006 and September 2012. All patients were treated by coiling of the cavernous sinus. Coiling was always performed while a semi compliant non-detachable balloon was temporarily inflated in the internal carotid artery. This technique (balloon-assisted coiling) permitted a clear visualization of the fistula, facilitated coil positioning and protected the patency of the artery. All patients' clinical data and radiological examinations were reviewed; nine patients underwent radiological and clinical follow-up, with a mean duration of 3.8 years (range: six months-six years). Overall results at discharge showed a complete occlusion of the fistula in seven patients (7/13, 54%) and a resolution of symptoms in eight patients (8/12, 67%). Radiological follow-up showed complete occlusion of the fistula in all patients (9/9, 100%) and clinical follow-up showed a resolution of symptoms in eight patients (8/9, 89%) and persistent symptoms in one (1/9, 11%). No procedure-related complications occurred. Balloon assisted coiling of the cavernous sinus for the treatment of direct carotid cavernous fistulas proved an effective and safe technique, both in angiographic and clinical terms, and may be considered a technical improvement. PMID- 24070085 TI - Safety and feasibility of a novel vascular closure device in neurointerventional procedures. AB - This retrospective study evaluated the safety and feasibility of a new arterial femoral access closure device in neurointerventional procedures. The study includes all consecutive adult patients who underwent femoral arteriotomy closure with the MynxGripTM closure device after Neurointerventional procedures performed between June and December 2012. All patients had a follow-up color Doppler ultrasound (US) within 48 hours after the procedure, which was independently interpreted by two experienced radiologists to evaluate for access site complications. Device success/failure, sheath size, ambulation time, and periprocedural complications were recorded. Fifty-five closure devices were deployed in 53 patients. There were 23 (43%) males and 30 (57%) females; age ranged from 22 to 84 years (mean: 52.1 years). Thirty of the 55 procedures (55%) were therapeutic and 25 were diagnostic interventions (45%). Sheath sizes used were 5F in 35 procedures (64 %) and 6F in 20 procedures (36%). The right femoral artery was accessed in 51 procedures (93 %) and the left in four procedures (7%). There was only one (1.8 %) minor periprocedural complication (small hematoma). Hemostasis was successful in 51 of the 55 procedures (93 %) with subsequent early ambulation. No device-induced complications associated with serious clinical sequelae were reported. In our small series, the MynxGripTM femoral access closure device provided a safe and feasible way of closing the femoral artery puncture site after neurointerventional procedures with low minor complication rates and no major complications. Further large prospective randomized trials are necessary to evaluate the efficacy of the device. PMID- 24070086 TI - Percutaneous microballoon compression for trigeminal neuralgia using Dyna-CT. AB - Percutaneous microballoon compression (PMC) is a well-established technique for treatment of trigeminal neuralgia (TN). However, direct puncture of the foramen ovale (FO) is sometimes difficult and there have been well-reported complications from cannulating the FO. We describe our experiences in using Dyna-CT for cannulating the FO and determining balloon position and volume. Dyna-CT was used to perform image reconstruction in 21 cases. The optimal working projection was generated and further fluoroscopic data were used to determine the needle's relationship to the foramen during puncture. Furthermore, the balloon position and three-dimensional shape were verified by Dyna-CT during balloon compression. The balloon volume and puncture angle were further calculated. Patients' prognosis was further discussed. Dyna-CT allowed quick, safe, and easy cannulation of the FO. It provided three-dimensional images which were more elaborate than the classic 'pear-shaped' images for determining correct positioning in 21 cases. The volume of the flattened balloon ranged from 568.2 mm(3) to 891.4 mm(3) with an average of 775.9 mm(3). The angle of introducing the cannula ranged from 15.17 degrees -35.48 degrees rotation to the midline with an average of 26.24 degrees and 38.47 degrees -51.89 degrees angulation to the Reid line with an average of 46.09 degrees . All the patients were pain free after PMC. Four patients had resolvable masseter weakness and fine touch loss. There was no recurrence of TN during follow-up. Dyna-CT demonstrated three advantages in assisting PMC. Firstly, the FO can be better visualized irrespective of the patient's position. Secondly, needle correction or insertion can be performed much more easily because of the direct fluoroscopic control. Thirdly, the needle position, balloon position, balloon configuration and the volume of the inflated balloon are more reliably determined. The use of dyna-CT provided an assisted method to PMC with a low incidence of complications and good prognosis. PMID- 24070087 TI - CT-guided core needle biopsy of deep suprahyoid head and neck lesions in untreated patients. AB - This study aimed to evaluate the efficacy of CT-guided core needle biopsy (CNB) in the diagnosis of deep head and neck tumors in untreated patients. We retrospectively reviewed the records of ten consecutive CT-guided CNB procedures from ten patients without a related history from March 2004 to February 2012. The surgical results, treatment response and clinical follow-up were used as the diagnostic standards. All specimens were considered adequate. Nine out of ten cases matched the final diagnosis. Biopsy failed to diagnose the infratemporal meningioma en plaque in a particular case. Three cases were carcinomas. No complication was encountered. CT-guided core needle biopsy is an efficient and safe technique for histological diagnosis of skull base lesions in patients without a related history. This technique can offer a definite tissue diagnosis and avoid unnecessary surgical interventions for such patients. PMID- 24070088 TI - Endovascular treatment of vertebral artery injury during cervical posterior fusion (C1 lateral mass screw). A case report. AB - We describe two cases of vertebral artery injury during posterior cervical fusion. We treated both cases by an endovascular technique. The vertebral artery injury may result in catastrophic situations, such as, infarction, massive blood loss and even death. Our clinical outcome was good and we prove that endovascular treatment is an effective and less invasive way to treat vertebral artery injury. PMID- 24070089 TI - Preoperative embolization of hypervascular thoracic, lumbar, and sacral spinal column tumors: technique and outcomes from a single center. AB - The existing literature on preoperative spine tumor embolization is limited in size of patient cohorts and diversity of tumor histologies. This report presents our experience with preoperative embolization of hypervascular thoracic, lumbar, and sacral spinal column tumors in the largest series to date. We conducted a retrospective review of 228 angiograms and 188 pre-operative embolizations for tumors involving thoracic, lumbar and sacral spinal column. Tumor vascularity was evaluated with conventional spinal angiography and was graded from 0 (same as normal adjacent vertebral body) to 3 (severe tumor blush with arteriovenous shunting). Embolic materials included poly vinyl alcohol (PVA) particles and detachable platinum coils and rarely, liquid embolics. The degree of embolization was graded as complete, near-complete, or partial. Anesthesia records were reviewed to document blood loss during surgery. Renal cell carcinoma (44.2%), thyroid carcinoma (9.2%), and leiomyosarcoma (6.6%) were the most common tumors out of a total of 40 tumor histologies. Hemangiopericytoma had the highest mean vascularity (2.6) of all tumor types with at least five representative cases followed by renal cell carcinoma (2.0) and thyroid carcinoma (2.0). PVA particles were used in 100% of cases. Detachable platinum coils were used in 51.6% of cases. Complete, near-complete, and partial embolizations were achieved in 86.1%, 12.7%, and 1.2% of all cases, respectively. There were no new post-procedure neurologic deficits or other complications with long-term morbidity. The mean intra-operative blood loss for the hypervascular tumors treated with pre operative embolization was 1745 cc. Preoperative embolization of hypervascular thoracic, lumbar, and sacral spine tumors can be performed with high success rates and a high degree of safety at high volume centers. PMID- 24070090 TI - Oxidative stress elicits platelet/leukocyte inflammatory interactions via HMGB1: a candidate for microvessel injury in sytemic sclerosis. AB - AIMS: An abnormal generation of reactive oxygen species (ROS) is thought to contribute to systemic sclerosis (SSc), fostering autoimmunity, fibrosis, and vascular inflammation. The function of the prototypic damage-associated molecular pattern, high mobility group box 1 (HMGB1), depends on its redox status. Here we investigate whether oxidative stress regulates the cross-talk between leukocytes and platelets via HMGB1, thus contributing to vessel inflammation in SSc. RESULTS: The oxidation of HMGB1 amplified its ability to activate neutrophils, as detected assessing the redistribution of primary granule molecules and the transactivation of the beta2 integrin chain CD18. Activated platelets are a source of bioactive HMGB1 and via P-selectin stimulated neutrophils to generate ROS. Oxidized extracellular HMGB1, soluble or associated to platelet membrane or to platelet-derived microparticles (PDMUPs), further increased leukocyte activation. Leukocyte activation abated in the presence of inhibitors of HMGB1 or of catalase, which catalyzes the dismutation of hydrogen peroxide into water and molecular oxygen. The redistribution of the content of primary granules and the transactivation of beta2 integrins characterized blood leukocytes of SSc patients and membrane HMGB1 was significantly higher in patients with pulmonary hypertension or with diffuse SSc. HMGB1(+) microparticles (MUPs) purified from SSc patients, but not HMGB1(-) MUPs purified from control subjects, activated in vitro healthy neutrophils, and HMGB1 inhibitors reversed the effects of MUPs. INNOVATION AND CONCLUSION: ROS dramatically increase the ability of extracellular HMGB1 to activate blood leukocytes. This event might contribute to maintain the microvascular injury of patients with SSc. PMID- 24070091 TI - Management of physical child abuse in South Africa: literature review and children's hospital data analysis. AB - BACKGROUND: The reason for this review is the lack of data on the management of physical abused children in Africa. The primary goal of the first part is to outline the management of physical child abuse in (South) Africa and provide suggestions for other governments in Africa on which to base their management of physical child abuse, at both governmental and hospital management level. The main aim of the second part is to outline the extent of the problem as seen at the Red Cross Memorial Children's Hospital (RCH) in Cape Town. MATERIAL AND METHODS: The National Library of Medicine's PubMed database was searched for articles specifically about the management of physical child abuse. Hospital data were analysed in two phases: one addressed various types of assault in order to assess the number of patients admitted to the trauma unit of RCH between 1991 and 2009, and the other to identify all children with suspected non-accidental injury (NAI) presenting to the trauma unit at RCH from January 2008 until December 2010. RESULTS: Information on physical abuse of children in Africa in the English scientific literature remains disappointing with only two articles focusing on its management. RCH data for the period 1991-2009 recorded a total number of 6415 children hospitalised with injuries following assault, who accounted for 4.2% of all trauma admissions. Types of abuse included assault with a blunt or sharp instrument, rape/sexual assault and human bite wounds. Over the last 2 decades, there has been a minor decline in the number of cases of severe abuse requiring admission; admissions for other injuries have remained stable. More detailed analysis of hospital data for 2008-2010, found that boys were far more commonly assaulted than girls (70.5% vs 29.5%). Physical abuse appeared to be the most common cause of abuse; 89.9% of all boys and 60.5% of all girls presented after physical abuse. CONCLUSION: In order to eradicate child abuse, awareness of it as to be promoted in the community at large. Because the types of child abuse vary between countries, each requires its own research in order to develop a policy tailored to their particular requirements. In summary, an increased focus on the prevention of violence against children is urgently needed in order to curb the increasing trend of assaults on children. As the causes and risk factors for violence against children vary, multi-disciplinary and multi-sectoral co operation and collaboration will be required. It is hoped that this report will help raise awareness among health-care practitioners of NAI and its complexities. PMID- 24070092 TI - Urea activation of nitrimines: a mild, metal-free approach to sterically hindered enamines. AB - Nitrimines have been identified as impressive starting points for the syntheses of otherwise inaccessible, sterically encumbered enamines. The activation of nitrimines with urea catalysts for reaction with a variety of amines enables the formation of highly substituted enamines in high yield. The reactions benefit from mild, metal-free conditions, high functional group tolerance, and straightforward scale up. PMID- 24070094 TI - Study on delacquer used beverage cans by vacuum pyrolysis for recycle. AB - So far, conventional processes that have been employed to delacquer the paints decorated on used beverage cans (UBCs) are less than satisfactory in economic and environmental effect. Therefore, a new method combining vacuum pyrolysis with dilute sulfuric acid leaching to delacquer the paints was investigated. The results of vacuum pyrolysis showed that the decoating rate increased with the increase of temperature and the paints were almost 100% removed from UBCs under the following conditions: temperature of 650 degrees C, holding time of 20 min, and residual gas pressure lower than 0.1 kPa. The pyrolysis oil was mainly composed of phenol and 2-methy-phenol analyzed by GC-MS. The delacquered UBCs were subsequently leached with 5% H2SO4 for 60 s and TiO2 was recovered by calcining the residuals in muffle furnace at 450 degrees C for 15 min. This innovative technology offers an effective method to delacquer paints from UBCs, which obtains excellent stripping effect and avoids the production of toxic substances generated in direct combustion process. Furthermore, the pyrolysis oil can be reused as chemical feedstock in other fields. PMID- 24070093 TI - Exogenous mRNA delivery and bioavailability in gene transfer mediated by piggyBac transposition. AB - BACKGROUND: Up to now, the different uptake pathways and the subsequent intracellular trafficking of plasmid DNA have been largely explored. By contrast, the mode of internalization and the intracellular routing of an exogenous mRNA in transfected cells are poorly investigated and remain to be elucidated. The bioavailability of internalized mRNA depends on its intracellular routing and its potential accumulation in dynamic sorting sites for storage: stress granules and processing bodies. This question is of particular significance when a secure transposon-based system able to integrate a therapeutic transgene into the genome is used. Transposon vectors usually require two components: a plasmid DNA, carrying the gene of interest, and a source of transposase allowing the integration of the transgene. The principal drawback is the lasting presence of the transposase, which could remobilize the transgene once it has been inserted. Our study focused on the pharmacokinetics of the transposition process mediated by the piggyBac transposase mRNA transfection. Exogenous mRNA internalization and trafficking were investigated towards a better apprehension and fine control of the piggyBac transposase bioavailability. RESULTS: The mRNA prototype designed in this study provides a very narrow expression window of transposase, which allows high efficiency transposition with no cytotoxicity. Our data reveal that exogenous transposase mRNA enters cells by clathrin and caveolae-mediated endocytosis, before finishing in late endosomes 3 h after transfection. At this point, the mRNA is dissociated from its carrier and localized in stress granules, but not in cytoplasmic processing bodies. Some weaker signals have been observed in stress granules at 18 h and 48 h without causing prolonged production of the transposase. So, we designed an mRNA that is efficiently translated with a peak of transposase production 18 h post-transfection without additional release of the molecule. This confines the integration of the transgene in a very small time window. CONCLUSION: Our results shed light on processes of exogenous mRNA trafficking, which are crucial to estimate the mRNA bioavailability, and increase the biosafety of transgene integration mediated by transposition. This approach provides a new way for limiting the transgene copy in the genome and their remobilization by mRNA engineering and trafficking. PMID- 24070095 TI - A friend in need may not be a friend indeed: role of microglia in neurodegenerative diseases. AB - Inflammation plays a critical role in the progression of neurodegenerative diseases. Microglia are the resident macrophages of the central nervous system (CNS) which actively take part in the neuronal development of CNS and are involved in clearance of pathogens as well as cellular debris from the system upon insult to this organization. Chronic activation of microglia in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) as well as inflammatory conditions of CNS such as multiple sclerosis (MS) results in overall upregulation of pro-inflammatory cytokines and chemokines in the brain parenchyma. This compromises the neuronal health which further activates microglia by releasing death associated molecules such as neuromelanin, Abeta peptides and cellular debris at the lesion site thereby forming a vicious cycle of disease advancement. Targeting microglial activation has proven to be a viable option in the treatment of inflammation related neurodegenerative diseases. This review will discuss the central position of inflammation and therapeutic strategies aiming to alleviate disease progression in some of the important inflammatory conditions of CNS. PMID- 24070097 TI - NIHR Medicines for Children Research Network: improving children's health through clinical research. AB - The need to evaluate medicines for children is widely acknowledged due to pervasive unlicensed medicine use in the pediatric setting. The EU Paediatric Regulation was developed to address these considerations, which subsequently led to the establishment of the National Institute of Health Research (NIHR) Medicines for Children Research Network (MCRN) in England. MCRN supports public and industry studies, and facilitates feasibility, site setup, recruitment and other services. The MCRN and other networks are members of the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA). Enpr-EMA was established to foster and coordinate research, and develop collaborations across Europe. MCRN works with Enpr-EMA, industry and others to improve the conduct of research for the benefit of children's health. PMID- 24070098 TI - The impact of the HEART risk score in the early assessment of patients with acute chest pain: design of a stepped wedge, cluster randomised trial. AB - BACKGROUND: Chest pain remains a diagnostic challenge: physicians do not want to miss an acute coronary syndrome (ACS), but, they also wish to avoid unnecessary additional diagnostic procedures. In approximately 75% of the patients presenting with chest pain at the emergency department (ED) there is no underlying cardiac cause. Therefore, diagnostic strategies focus on identifying patients in whom an ACS can be safely ruled out based on findings from history, physical examination and early cardiac marker measurement. The HEART score, a clinical prediction rule, was developed to provide the clinician with a simple, early and reliable predictor of cardiac risk. We set out to quantify the impact of the use of the HEART score in daily practice on patient outcomes and costs. METHODS/DESIGN: We designed a prospective, multi-centre, stepped wedge, cluster randomised trial. Our aim is to include a total of 6600 unselected chest pain patients presenting at the ED in 10 Dutch hospitals during an 11-month period. All clusters (i.e. hospitals) start with a period of 'usual care' and are randomised in their timing when to switch to 'intervention care'. The latter involves the calculation of the HEART score in each patient to guide clinical decision; notably reassurance and discharge of patients with low scores and intensive monitoring and early intervention in patients with high HEART scores. Primary outcome is occurrence of major adverse cardiac events (MACE), including acute myocardial infarction, revascularisation or death within 6 weeks after presentation. Secondary outcomes include occurrence of MACE in low-risk patients, quality of life, use of health care resources and costs. DISCUSSION: Stepped wedge designs are increasingly used to evaluate the real-life effectiveness of non-pharmacological interventions because of the following potential advantages: (a) each hospital has both a usual care and an intervention period, therefore, outcomes can be compared within and across hospitals; (b) each hospital will have an intervention period which enhances participation in case of a promising intervention; (c) all hospitals generate data about potential implementation problems. This large impact trial will generate evidence whether the anticipated benefits (in terms of safety and cost-effectiveness) of using the HEART score will indeed be achieved in real-life clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov 80-82310-97-12154. PMID- 24070099 TI - Cataract incidence in sub-Saharan Africa: what does mathematical modeling tell us about geographic variations and surgical needs? AB - PURPOSE: To apply a previously described mathematical model, designed to estimate cataract incidence from age-specific prevalence, to Rapid Assess of Avoidable Blindness survey data from Sub-Saharan Africa in order to estimate the incidence of cataract and therefore surgical needs. METHODS: All Rapid Assessment of Avoidable Blindness surveys from Sub-Saharan Africa were identified. A previously developed mathematical model, designed to estimate the incidence of operable cataract was applied to those (27/32) meeting the inclusion criteria. RESULTS: Incidence varied significantly across the continent with the result that cataract surgery rate targets required to eliminate cataract vary too. When variation in age structure is also taken into account, the cataract surgery rate needed to eliminate cataract visual impairment at the level of 6/18 ranges from 1200-4500 surgeries per year per million population. CONCLUSIONS: This is important evidence of significant variation in the incidence of cataract within Sub-Saharan Africa. The variation may be related to genetic or cultural variations on the continent and has important implications for planning services. PMID- 24070100 TI - Access to ophthalmologic care in Thailand: a regional analysis. AB - PURPOSE: The World Health Organization (WHO) recommends that Southeast Asian countries have >= 1 ophthalmologist per 100,000 persons, equally distributed in urban and rural areas. However, regional patterns of eye care have been poorly characterized. This study investigates the distribution of ophthalmologists in Thailand and provides regional estimates of access to ophthalmologists. METHODS: We geocoded the work address of ophthalmologists listed in the 2008 directory of the Royal College of Ophthalmologists of Thailand. We determined the number of ophthalmologists per 100,000 persons at the national, provincial, and district levels using data from the 2000 Thai Population Census, and assessed demographic factors associated with meeting the WHO recommendation of >= 1 ophthalmologist per 100,000 persons. RESULTS: In 2008, Thailand had 1.52 ophthalmologists per 100,000 persons; however, only 20 of 76 provinces (26%) and 134 of 926 districts (14%) met the WHO recommendation of >= 1 ophthalmologist per 100,000 persons. District factors associated with not meeting the WHO recommendation included a high proportion of children, a high proportion of elderly, and a high proportion of rural residents. CONCLUSION: Thailand meets the WHO's goal for access to ophthalmologic care, but the distribution of ophthalmologists is uneven, with less access to ophthalmologic care in rural areas. PMID- 24070101 TI - Review of blindness and visual impairment in Paraguay: changes between 1999 and 2011. AB - PURPOSE: To report the prevalence and causes of blindness in people aged 50 years and older in Paraguay, and to compare these with the previous national survey in 1999, focusing on planning of future eye care activities. METHODS: A rapid assessment of avoidable blindness (RAAB) was conducted in 2011. A total of 60 clusters of 50 residents aged 50 years and older were randomly selected and visited, and 2862 people were examined (95.4%). Survey data were analyzed with the RAAB software and compared with findings of a similar survey from 1999. RESULTS: The prevalence of bilateral blindness in Paraguay was 1.0% (95% confidence interval, CI, 0.6-1.6) in 2011, significantly less than the 3.1% (95% CI 2.2-4.4) in 1999. Prevalence of bilateral cataract and cataract eyes had also reduced significantly for visual acuity, VA, <3/60, VA < 6/60 and VA < 6/18. Cataract surgical coverage in persons doubled to 90% for VA < 3/60, 78% for VA < 6/60 and 63% for VA < 6/18. Visual outcome after cataract surgery also improved to nearly the World Health Organization norm. Cataract was the main cause of blindness (43.8%), followed by severe visual impairment (40.5%). Uncorrected refractive errors were the main cause of moderate (78.0%) and the second cause of severe (18.9%) visual impairment. CONCLUSION: The reduction in blindness and visual impairment due to cataract in Paraguay between 1999 and 2011 was highly significant. Results and coverage of cataract surgical services improved substantially. The reported numbers of cataract operations may not have been complete as these do not seem to match the dramatic improvement in the cataract situation in Paraguay. PMID- 24070102 TI - Cluster randomized trial to compare spectacle delivery systems at outreach eye camps in South India. AB - PURPOSE: To study the optimal method for delivery of spectacles at eye camps to maximize procurement and use. METHODS: A cluster randomized controlled trial, undertaken in the catchment districts of Aravind Eye Hospital - Theni, in the state of Tamil Nadu, India. Community eye camps (n = 21) were allocated to offer one of three types of service for purchase of spectacles to correct refractive error: (1) Issuance of a prescription only; (2) booking orders for spectacles with subsequent delivery; (3) on-the-spot fitting and dispensing of spectacles. Follow-up questionnaires were administered 6 weeks after interventions to assess patient outcomes. The primary outcome measured was spectacle procurement at follow-up 6 weeks post-screening. Secondary outcomes included use of and satisfaction with spectacles. Reasons for purchase/non-purchase were also assessed. RESULTS: Compared to those who were issued only a prescription and adjusting for distance from base hospital, spectacle procurement was significantly higher for those allowed to book spectacles for subsequent delivery (odds ratio, OR, 8.79, 95% confidence interval, CI, 4.61-16.78) and for those receiving spectacles on the spot (OR 13.97, 95% CI 8.12-24.05). Among those with spectacles at 6 weeks, spectacle use was nearly universal and satisfaction with spectacles varied between 92 and 94% among the three different dispensing modalities. CONCLUSION: Making spectacles available on the spot is important to ensure procurement in a context where availability and access to dispensing opticians is poor. PMID- 24070103 TI - Self-vision testing and intervention seeking behavior among school children: a pilot study. AB - PURPOSE: Refractive error is the most common cause of visual impairment among school children. Worldwide, school vision testing is one major area of thrust to address vision screening among school children, and is carried out by a diverse group of professionals and non-professionals, with variable success rates. In a pilot study we aimed to determine how efficiently and reliably students could self-examine their vision and how many actually seek intervention for refraction and eventually wear glasses. METHODS: The pilot study was done in 25 schools in a rural area of northern India. The methodology of self-assisted vision examination (SAVE) was directly demonstrated to school children. School children self examined their visual acuity, and sensitivity, specificity and positive and negative predictive values were calculated after secondary screening by professionals. Students requiring refraction were given referral slips. Frequency of uptake of glasses for those referred for refractive services was assessed in a follow-up visit. RESULTS: A total of 7411 students in 6th to 12th standard were enrolled in the pilot study. Sensitivity and specificity of the SAVE strategy were 96.22% (95% confidence interval [CI] 94.52-97.43%) and 90.23% (95% CI 87.79 92.23%), respectively. The positive predictive value was 90.83% (95% CI 88.55 92.71%) and negative predictive value was 95.95% (95% CI 94.13-97.24%). At the time of follow-up 66% of students had undergone refraction and 81% of these were wearing glasses. CONCLUSION: SAVE provides a simple, acceptable and valid alternate strategy for school vision screening. However, factors influencing procurement of glasses and their use will require further study. PMID- 24070104 TI - Integrated depression management: a proposed trial of a new model of care in a low vision rehabilitation setting. AB - PURPOSE: Depression is a common problem among people with visual impairment and contributes to functional decline. This article presents a study protocol to evaluate a new model of care for those patients with depressive symptoms in which psychological treatment is integrated into low vision rehabilitation services. Low vision staff will be trained to deliver "problem solving therapy for primary care" (PST-PC), an effective psychological treatment developed specifically for delivery by non-mental health care staff. PST-PC is delivered in 8 weekly telephone sessions of 30-45 minutes duration and 4 monthly maintenance sessions. We predict this new integrated model of care will significantly reduce depressive symptoms and improve the quality of life for people with visual impairment. METHODS AND DESIGN: A randomized controlled trial of PST-PC will be implemented nationally across low vision rehabilitation services provided by Vision Australia. Clients who screen positive for depressive symptoms and meet study criteria will be randomized to receive PST-PC or usual care, consisting of a referral to their general practitioner for more detailed assessment and treatment. Outcome measures include depressive symptoms and behaviors, quality of life, coping and psychological adjustment to visual impairment. Masked assessments will take place pre- and post-intervention as well as at 6- and 12 month follow-up. CONCLUSION: We anticipate that this innovative service delivery model will lead to sustained improvements in clients' quality of life in a cost effective manner and provide an innovative service delivery model suitable for other health care areas in which depression is co-morbid. PMID- 24070107 TI - Geometric and electronic structure contributions to function in non-heme iron enzymes. AB - Mononuclear non-heme Fe (NHFe) enzymes play key roles in DNA repair, the biosynthesis of antibiotics, the response to hypoxia, cancer therapy, and many other biological processes. These enzymes catalyze a diverse range of oxidation reactions, including hydroxylation, halogenation, ring closure, desaturation, and electrophilic aromatic substitution (EAS). Most of these enzymes use an Fe(II) site to activate dioxygen, but traditional spectroscopic methods have not allowed researchers to insightfully probe these ferrous active sites. We have developed a methodology that provides detailed geometric and electronic structure insights into these NHFe(II) active sites. Using these data, we have defined a general mechanistic strategy that many of these enzymes use: they control O2 activation (and limit autoxidation and self-hydroxylation) by allowing Fe(II) coordination unsaturation only in the presence of cosubstrates. Depending on the type of enzyme, O2 activation either involves a 2e(-) reduced Fe(III)-OOH intermediate or a 4e(-) reduced Fe(IV)?O intermediate. Nuclear resonance vibrational spectroscopy (NRVS) has provided the geometric structure of these intermediates, and magnetic circular dichroism (MCD) has defined the frontier molecular orbitals (FMOs), the electronic structure that controls reactivity. This Account emphasizes that experimental spectroscopy is critical in evaluating the results of electronic structure calculations. Therefore these data are a key mechanistic bridge between structure and reactivity. For the Fe(III)-OOH intermediates, the anticancer drug activated bleomycin (BLM) acts as the non-heme Fe analog of compound 0 in heme (e.g., P450) chemistry. However BLM shows different reactivity: the low-spin (LS) Fe(III)-OOH can directly abstract a H atom from DNA. The LS and high-spin (HS) Fe(III)-OOHs have fundamentally different transition states. The LS transition state goes through a hydroxyl radical, but the HS transition state is activated for EAS without O-O cleavage. This activation is important in one class of NHFe enzymes that utilizes a HS Fe(III)-OOH intermediate in dioxygenation. For Fe(IV)?O intermediates, the LS form has a pi-type FMO activated for attack perpendicular to the Fe-O bond. However, the HS form (present in the NHFe enzymes) has a pi FMO activated perpendicular to the Fe-O bond and a sigma FMO positioned along the Fe-O bond. For the NHFe enzymes, the presence of pi and sigma FMOs enables enzymatic control in determining the type of reactivity: EAS or H-atom extraction for one substrate with different enzymes and halogenation or hydroxylation for one enzyme with different substrates. PMID- 24070109 TI - A clinical study shows safety and efficacy of autologous bone marrow mononuclear cell therapy to improve quality of life in muscular dystrophy patients. AB - Muscular dystrophy is a genetic disorder with no definite cure. A study was carried out on 150 patients diagnosed with muscular dystrophy. These included Duchenne muscular dystrophy, limb-girdle muscular dystrophy, and Becker muscular dystrophy variants. They were administered autologous bone marrow-derived mononuclear cells intrathecally and intramuscularly at the motor points of the antigravity weak muscles followed by vigorous rehabilitation therapy. No significant adverse events were noted. Assessment after transplantation showed neurological improvements in trunk muscle strength, limb strength on manual muscle testing, gait improvements, and a favorable shift on assessment scales such as the Functional Independence Measure and the Brooke and Vignos Scales. Furthermore, imaging and electrophysiological studies also showed significant changes in selective cases. On a mean follow-up of 12 +/- 1 months, overall 86.67% cases showed symptomatic and functional improvements, with six patients showing changes with respect to muscle regeneration and a decrease in fatty infiltration on musculoskeletal magnetic resonance imaging and nine showing improved muscle electrical activity on electromyography. Fifty-three percent of the cases showed an increase in trunk muscle strength, 48% showed an increase in upper limb strength, 59% showed an increase in lower limb strength, and approximately 10% showed improved gait. These data were statistically analyzed using Student's paired t test and found to be significant. The results show that this treatment is safe and efficacious and also improves the quality of life of patients having muscular dystrophy. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation. PMID- 24070108 TI - DNA detection using origami paper analytical devices. AB - We demonstrate the hybridization-induced fluorescence detection of DNA on an origami-based paper analytical device (oPAD). The paper substrate was patterned by wax printing and controlled heating to construct hydrophilic channels and hydrophobic barriers in a three-dimensional fashion. A competitive assay was developed where the analyte, a single-stranded DNA (ssDNA), and a quencher labeled ssDNA competed for hybridization with a fluorophore-labeled ssDNA probe. Upon hybridization of the analyte with the fluorophore-labeled ssDNA, a linear response of fluorescence vs analyte concentration was observed with an extrapolated limit of detection <5 nM and a sensitivity relative standard deviation as low as 3%. The oPAD setup was also tested against OR/AND logic gates, proving to be successful in both detection systems. PMID- 24070110 TI - A systematic review of evidence on malignant spinal metastases: natural history and technologies for identifying patients at high risk of vertebral fracture and spinal cord compression. AB - BACKGROUND: Spinal metastases can lead to significant morbidity and reduction in quality of life due to spinal cord compression (SCC). Between 5% and 20% of patients with spinal metastases develop metastatic spinal cord compression during the course of their disease. An early study estimated average survival for patients with SCC to be between 3 and 7 months, with a 36% probability of survival to 12 months. An understanding of the natural history and early diagnosis of spinal metastases and prediction of collapse of the metastatic vertebrae are important. OBJECTIVES: To undertake a systematic review to examine the natural history of metastatic spinal lesions and to identify patients at high risk of vertebral fracture and SCC. DATA SOURCES: The search strategy covered the concepts of metastasis, the spine and adults. Searches were undertaken from inception to June 2011 in 13 electronic databases [MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; EMBASE; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials (CENTRAL); Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED), HTA databases (NHS Centre for Reviews and Dissemination); Science Citation Index and Conference Proceedings (Web of Science); UK Clinical Research Network (UKCRN) Portfolio Database; Current Controlled Trials; ClinicalTrials.gov]. REVIEW METHODS: Titles and abstracts of retrieved studies were assessed by two reviewers independently. Disagreement was resolved by consensus agreement. Full data were extracted independently by one reviewer. All included studies were reviewed by a second researcher with disagreements resolved by discussion. A quality assessment instrument was used to assess bias in six domains: study population, attrition, prognostic factor measurement, outcome measurement, confounding measurement and account, and analysis. Data were tabulated and discussed in a narrative review. Each tumour type was looked at separately. RESULTS: In all, 2425 potentially relevant articles were identified, of which 31 met the inclusion criteria. No study examined natural history alone. Seventeen studies reported retrospective data, 10 were prospective studies, and three were other study designs. There was one systematic review. There were no randomised controlled trials (RCTs). Approximately 5782 participants were included. Sample sizes ranged from 41 to 859. The age of participants ranged between 7 and 92 years. Types of cancers reported on were lung alone (n= 3), prostate alone (n= 6), breast alone (n= 7), mixed cancers (n= 13) and unclear (n= 1). A total of 93 prognostic factors were identified as potentially significant in predicting risk of SCC or collapse. Overall findings indicated that the more spinal metastases present and the longer a patient was at risk, the greater the reported likelihood of development of SCC and collapse. There was an increased risk of developing SCC if a cancer had already spread to the bones. In the prostate cancer studies, tumour grade, metastatic load and time on hormone therapy were associated with increased risk of SCC. In one study, risk of SCC before death was 24%, and 2.37 times greater with a Gleason score >= 7 than with a score of < 7 (p= 0.003). Other research found that patients with six or more bone lesions were at greater risk of SCC than those with fewer than six lesions [odds ratio (OR) 2.9, 95% confidence interval (CI) 1.012 to 8.35, p= 0.047]. For breast cancer patients who received a computerised tomography (CT) scan for suspected SCC, multiple logistic regression in one study identified four independent variables predictive of a positive test: bone metastases >= 2 years (OR 3.0 95% CI 1.2 to 7.6; p= 0.02); metastatic disease at initial diagnosis (OR 3.4, 95% CI 1.0 to 11.4; p= 0.05); objective weakness (OR 3.8, 95% CI 1.5 to 9.5; p= 0.005); and vertebral compression fracture on spine radiograph (OR 2.6, 95% CI 1.0 to 6.5; p= 0.05). A further study on mixed cancers, among patients who received surgery for SCC, reported that vertebral body compression fractures were associated with presurgery chemotherapy (OR 2.283, 95% CI 1.064 to 4.898; p= 0.03), cancer type [primary breast cancer (OR 4.179, 95% CI 1.457 to 11.983; p= 0.008)], thoracic involvement (OR 3.505, 95% CI 1.343 to 9.143; p= 0.01) and anterior cord compression (OR 3.213, 95% CI 1.416 to 7.293; p= 0.005). LIMITATIONS: Many of the included studies provided limited information about patient populations and selection criteria and they varied in methodological quality, rigour and transparency. Several studies identified type of cancer (e.g. breast, lung or prostate cancer) as a significant factor in predicting SCC, but it remains difficult to determine the risk differential partly because of residual bias. Consideration of quantitative results from the studies does not easily allow generation of a coherent numerical summary, studies were heterogeneous especially with regard to population, results were not consistent between studies, and study results almost universally lacked corroboration from other independent studies. CONCLUSION: No studies were found which examined natural history. Overall burden of metastatic disease, confirmed metastatic bone involvement and immediate symptomatology suggestive of spinal column involvement are already well known as factors for metastatic SCC, vertebral collapse or progression of vertebral collapse. Although we identified a large number of additional possible prognostic factors, those which currently offer the most potential are unclear. Current clinical consensus favours magnetic resonance imaging and CT imaging modalities for the investigation of SCC and vertebral fracture. Future research should concentrate on: (1) prospective randomised designs to establish clinical and quality-of-life outcomes and cost-effectiveness of identification and treatment of patients at high risk of vertebral collapse and SCC; (2) Service Delivery and Organisation research on magnetic resonance imaging (MRI) scans and scanning (in tandem with research studies on use of MRI to monitor progression) in order to understand best methods for maximising use of MRI scanners; and (3) investigation of prognostic algorithms to calculate probability of a specified event using high quality prospective studies, involving defined populations, randomly selected and clearly identified samples, and with blinding of investigators. FUNDING: This report was commissioned by the National Institute for Health Research Health Technology Assessment Programme NIHR HTA Programme as project number HTA 10/91/01. PMID- 24070111 TI - Relaxin has anti-apoptotic effects on human trophoblast-derived HTR-8/SV neo cells. AB - The study was conducted to evaluate the effects of human relaxin on apoptosis in the human trophoblast derived HTR-8/SV neo cell line, which is a possible model of human extravillous trophoblasts (EVTs). HTR-8/SV neo cells, cultured in phenol red free RPMI1640 medium, were treated with different doses of human recombinant (rH2) relaxin in serum-deprived conditions. RT-PCR was used for evaluating relaxin receptor: RXFP1 and RXFP2 expression in HTR-8/SV neo cells. The cell death was examined by TUNEL assay. Furthermore, we investigated caspase-3, cleaved PARP and Bcl-2 expressions by Western blot analysis to recognize the translational effects of anti-apoptotic and pro-apoptotic proteins. RXFP1 and RXFP2 mRNA expression was observed in HTR-8/SV neo cells. Compared with untreated control cultures, treatment with rH2 relaxin, decreased TUNEL-positive rate in HTR-8/SV neo cells was observed. Western blot analysis revealed that treatment with rH2 relaxin decreased the expression of caspase-3 and cleaved PARP, but in contrast increased Bcl-2 expression in those cells. These results suggest that rH2 relaxin has anti-apoptotic effects on HTR8/SV neo cells by decreasing pro apoptotic caspase-3 and cleaved PARP expression and up-regulating anti-apoptotic Bcl-2 expression. PMID- 24070112 TI - Carbapenem-resistant Klebsiella pneumoniae sepsis in corticosteroid receipt mice: tigecycline or colistin monotherapy versus tigecycline/colistin combination. AB - This study compared the effect of monotherapy of colistin, tigecycline, and their combination in sepsis model of mice. OXA-48 producing Carbapenem-resistant Klebsiella pneumoniae (CRKP) strain was used in Balb/c mice. The mice were divided into competent and Methylprednisolone acetate (MPA)-treated groups. Each group was sub-divided into (1) colistin or (2) tigecycline monotherapy and (3) colistin/tigecycline combination therapy. After 3 hours of intraperitoneal bacterial inoculation, antimicrobials were administered, and mice were sacrificed at 24 and 48 hours Time-kill curve study demonstrated that colistin sulphate had early bactericidal activity following re-growth. In competent and MPA-treated groups of mice at 24 hours, bacterial counts in liver samples significantly lowered compared to control, however, there were no statistically differences between monotherapy and combination therapy subgroup. Bacterial count in lung samples of competent group was significantly lesser than control for all three antimicrobial subgroups at 24 hours Colistin plus tigecycline combination therapy was not superior against colistin or tigecycline monotherapy. PMID- 24070114 TI - Lambda interferon serum levels in patients with chronic hepatitis C virus infection according to their response to therapy with pegylated interferon and ribavirin. AB - Lambda interferon IL-28A/B and IL-29 serum levels have been associated with the course of hepatitis C virus (HCV) infection. However, there is not information about these cytokine in patients with antiviral therapy. We investigated IL-28A/B and IL-29 serum levels in 45 samples from patients chronically infected with HCV genotype 1, and undergoing therapy with PEG-IFN/RBV, at baseline and after 12 weeks of therapy, comparing those that developed a sustained virologic response (SVR) with null responders (NR). IL-28B polymorphisms (rs12979860, rs12980275, and rs8099917) were also considered. We found that, IL-28A/B and IL-29 levels were not significantly different between SVR and NR patients at baseline or after 12 weeks of therapy. TT rs8099917 genotype carriers had significantly higher IL29 levels at baseline (60.5 vs 19.5 pg/mL; p=0.045) and after 12 weeks of therapy (35 vs 16.5 pg/mL; p=0.023) than non-TT carriers. In conclusion, there were no differences in IL-28A/B or IL-29 levels according to response to therapy, suggesting that these cytokines do not play an important role in viral elimination during treatment, at least not during the first 12 weeks of therapy. Genotypes associated with high IL-28B levels may be related to a mechanism of protection against infection but are not involved in the response to antiviral therapy. PMID- 24070115 TI - Minimal dose interferon suppository treatment suppresses viral replication with platelet counts and serum albumin levels increased in chronically hepatitis C virus-infected patients: a phase 1b, placebo-controlled, randomized study. AB - Animal studies have shown that rectally administrated interferon (IFN) is transferred into the lymphatic system via the rectal mucous membrane, suggesting that an IFN suppository could serve as another drug delivery method. We developed an IFN suppository and administered it to patients with chronic hepatitis C to evaluate its efficacy and safety. Twenty-eight patients with chronic hepatitis C participated in the study. The low-dose IFN suppository containing 1,000 international units (IU) of lymphoblastoid IFNalpha was administered to 14 patients daily for 24 weeks. Others had a placebo dosing. In 13 of the 14 IFN suppository-treated patients, viral load decreased at week 4. The serum hepatitis C virus (HCV) RNA levels (Log IU/mL, mean+/-standard error) were 5.65+/-0.18 before the treatment and 5.17+/-0.27 at week 4 (P=0.01). The 2'-5' oligoadenylate synthetase activity increased, while the CD4/CD8 ratio decreased significantly. Interestingly, platelet counts and serum albumin levels were significantly increased during and after the treatment. No serious adverse events were observed. The low-dose IFN suppository treatment suppressed HCV replication, modifying host immunity, with increased platelet counts and serum albumin levels. The IFN suppository could be considered a new drug delivery method to preserve the quality of life of patients. PMID- 24070116 TI - Correlation between the Japanese Aging Male Questionnaire (JAMQ) and Aging Male's Symptom (AMS) scale in Japanese male. AB - OBJECTIVES: To clarify the correlation between the Japanese Aging Male Questionnaire (JAMQ) and the Aging Males' Symptoms (AMS) scale through the factor analysis in Japanese male. MATERIALS AND METHODS: In 61 male patients who visited the LOH outpatient clinic of Teikyo University Hospital, subjective symptoms featuring LOH were evaluated using the JAMQ and AMS. Factor analysis was performed on each questionnaire to clarify the LOH-related factors. Correlational analysis between the subscale scores representing such factors and the serum hormone profiles was also performed. RESULTS: Factor analysis of the JAMQ revealed an internal structure consisting of three subgroups: somatic, psychological and sexual factors with good categorization of the indicators to the appropriate subgroup. In contrast, the indicators of the AMS showed incomplete conformity to the subgroups of the JAMQ. Correlational analysis showed that each score on the JAMQ subgroups had the highest coefficient of correlation with the corresponding AMS subgroup (p < 0.001). There was no significant association between total and free serum testosterone levels and the total and subscale scores on either AMS or JAMQ. CONCLUSIONS: The results of factor analysis suggest that the sexual perceptions of Japanese populations might differ from those of Caucasian populations. JAMQ would be useful to separately assess individual aspects of somatic, psychological and sexual symptoms related to LOH among Japanese males. PMID- 24070117 TI - Stereoselective synthesis of gamma-lactams from imines and cyanosuccinic anhydrides. AB - A reaction between imines and anhydrides has been developed with chiral disubstituted anhydrides and chiral imines. The synthesis of highly substituted gamma-lactams with three stereogenic centers, including one quaternary center, proceeds at room temperature in high yield and with high diastereoselectivity in most cases. Enantiomerically pure alkyl-substituted anhydrides proceed with no epimerization, thus providing access to enantiomerically pure penta-substituted lactam products. PMID- 24070118 TI - Lessons from history: morbidity of cold injury in the Royal Marines during the Falklands Conflict of 1982. AB - BACKGROUND: Environmental conditions in the Falklands Conflict of 1982 favoured the genesis of cold injuries. Immediately, post-war, cold injury morbidity and its contributory factors were assessed, in the personnel of UK 3 Commando Brigade (3 Cdo Bde). METHODS: A questionnaire survey of the 3,006 members of 3 Cdo Bde who landed on the islands was conducted within 6-10 weeks of the end of hostilities. Questions included those relating to features of cold injury, body morphology, age, symptoms experienced, past medical history and other possible contributory causes. Additionally, the unit medical team conducted a cursory examination. Data were sent to the Royal Navy Institute of Naval Medicine (INM), where the degree of likely cold injury was broadly classified ('asymptomatic' 'mild', 'moderate' or 'severe'). A sample (total 109) was then selected at random from each category and subsequently examined and tested at the INM (nerve conduction, photoplethysmography and thermography testing). Forty-seven non-cold exposed sailors acted as a control group. These contemporaneous records have now been identified and interrogated. RESULTS: Some 2,354 (78%) completed questionnaires were returned, revealing that 1,505 (64%) had experienced symptoms of non-freezing cold injury. The morbidity in the infantry units was significantly greater than that in the support troops (1,051 (76%) vs 454 (46%), p < 0.05). No evidence was found to support an influence of a number of factors, commonly believed to have an aetiological role in the production of cold injury. Whilst there was no significant relationship between past history and cold injury morbidity in the brigade as a whole, or within the infantry units alone, an association was identified in the collective infantry units (73%) and the support/headquarter units (59%) (p < 0.05).In comparison with uninjured sailors who acted as controls (n = 47), nerve conduction was impaired in 35% of those screened some months after returning to the UK, while the photoplethysmography and thermographic responses to a cold sensitivity test showed that most (including those classed by questionnaire as asymptomatic) had residual 'cold sensitivity'. CONCLUSIONS: Although the passage of time has made retrospective interrogation of historical documents hard, the available data do appear to offer valuable historical and clinical insights. Cold injury affected the majority of those fighting in the cold temperate climate of the Falklands. The overwhelming environmental conditions meant that, for most, a past history of cold injury did not appear to represent a risk factor for subsequent injury, as is the case for less severe conditions. Importantly, even asymptomatic individuals when tested often showed physiological evidence of cold injury-perhaps predisposing them to subsequent elevation in risk. PMID- 24070119 TI - Clinical events in psychogenic non-epileptic seizures based on semiological seizure classification. AB - OBJECTIVES: None of the classifications of psychogenic non-epileptic seizures (PNES) have been widely accepted and used by physicians so far. In this study we aimed at classifying PNES on the basis of a modified version of semiological seizure classification (SSC). We also sought to assess the interrater reliability (IRR) of the PNES diagnosis based on SSC. METHODS: We classified PNES into four types on the basis of our modification of SSC: pseudoaura, dialeptic, motor, and special (atonic, astatic, hypotonic) spells. Pseudoauras were not included in the statistical analysis. Ninety-one PNES attacks were observed during the 55 video EEG sessions recorded for all patients. The interrater agreement was assessed by the kappa coefficient. RESULTS: Twenty-nine women (78.3%) and eight men (21.6%) were surveyed, with a mean age of 28.4 +/- 9.6 (range 16-54). The final diagnosis of PNES was established after a mean of 4.5 +/- 2.3 years following the onset of PNES attacks in the patients. The mean seizure duration in the PNES was 241 seconds and 40.5% of our patients had PNES longer than 300 seconds. Motor and special PNES were the most common types observed by all the raters. The kappa values for each pair were as follows: Observers I-II 0.51 (p = 0.000), Observers I-III 0.47 (p = 0.000), and Observers II-III 0.73 (p = 0.000). CONCLUSIONS: Interobserver agreement was moderate and substantial for three observers who classified PNES according to our modified SSC. The modified version of SSC could be used without difficulty in classifying PNES. Using SSC for PNES both shortens the period before diagnosis and eliminates the need to learn another new and acceptable classification for PNES. PMID- 24070120 TI - Selection on quantitative colour variation in Centaurea cyanus: the role of the pollinator's visual system. AB - Even though the importance of selection for trait evolution is well established, we still lack a functional understanding of the mechanisms underlying phenotypic selection. Because animals necessarily use their sensory system to perceive phenotypic traits, the model of sensory bias assumes that sensory systems are the main determinant of signal evolution. Yet, it has remained poorly known how sensory systems contribute to shaping the fitness surface of selected individuals. In a greenhouse experiment, we quantified the strength and direction of selection on floral coloration in a population of cornflowers exposed to bumblebees as unique pollinators during 4 days. We detected significant selection on the chromatic and achromatic (brightness) components of floral coloration. We then studied whether these patterns of selection are explicable by accounting for the visual system of the pollinators. Using data on bumblebee colour vision, we first showed that bumblebees should discriminate among quantitative colour variants. The observed selection was then compared to the selection predicted by psychophysical models of bumblebee colour vision. The achromatic but not the chromatic channel of the bumblebee's visual system could explain the observed pattern of selection. These results highlight that (i) pollinators can select quantitative variation in floral coloration and could thus account for a gradual evolution of flower coloration, and (ii) stimulation of the visual system represents, at least partly, a functional mechanism potentially explaining pollinators' selection on floral colour variants. PMID- 24070121 TI - Review of latent and lytic phase biomarkers in Kaposi's sarcoma. AB - INTRODUCTION: Kaposi's sarcoma (KS) is a vascular neoplasm with distinct clinical epidemiological subtypes and varied clinical presentations. While the association of KS with human herpesvirus-8 (HHV8, KSHV) infection is well known, additional factors are needed for tumorigenesis. The precise sequence of events involved in KS development, progression and regression continues to be investigated. The discovery of KSHV biomarkers is helpful for diagnostic purposes, for understanding KS pathogenesis and for identifying potential druggable targets. AREAS COVERED: This article reviews a number of key biomarkers relevant for the diagnosis of KS and HHV8-related pathogenesis. New developments in KS, potential therapeutic targets and the challenges involved in their discovery are highlighted. EXPERT OPINION: Although there is currently no cure for KS, continued research devoted to uncovering biomarkers and understanding their pathogenic roles remains encouraging. The hope is that sometime soon one of these candidate targets will provide a curative therapy for this enigmatic sarcoma. PMID- 24070122 TI - Functional and genetic characterization of the non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease. AB - BACKGROUND: Gaucher disease (GD) is the most common inherited lysosomal storage disorder in humans, caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). GD is clinically heterogeneous and although the type of GBA1 mutation plays a role in determining the type of GD, it does not explain the clinical variability seen among patients. Cumulative evidence from recent studies suggests that GBA2 could play a role in the pathogenesis of GD and potentially interacts with GBA1. METHODS: We used a framework of functional and genetic approaches in order to further characterize a potential role of GBA2 in GD. Glucosylceramide (GlcCer) levels in spleen, liver and brain of GBA2-deficient mice and mRNA and protein expression of GBA2 in GBA1-deficient murine fibroblasts were analyzed. Furthermore we crossed GBA2-deficient mice with conditional Gba1 knockout mice in order to quantify the interaction between GBA1 and GBA2. Finally, a genetic approach was used to test whether genetic variation in GBA2 is associated with GD and/ or acts as a modifier in Gaucher patients. We tested 22 SNPs in the GBA2 and GBA1 genes in 98 type 1 and 60 type 2/3 Gaucher patients for single- and multi-marker association with GD. RESULTS: We found a significant accumulation of GlcCer compared to wild-type controls in all three organs studied. In addition, a significant increase of Gba2-protein and Gba2-mRNA levels in GBA1-deficient murine fibroblasts was observed. GlcCer levels in the spleen from Gba1/Gba2 knockout mice were much higher than the sum of the single knockouts, indicating a cross-talk between the two glucosylceramidases and suggesting a partially compensation of the loss of one enzyme by the other. In the genetic approach, no significant association with severity of GD was found for SNPs at the GBA2 locus. However, in the multi-marker analyses a significant result was detected for p.L444P (GBA1) and rs4878628 (GBA2), using a model that does not take marginal effects into account. CONCLUSIONS: All together our observations make GBA2 a likely candidate to be involved in GD etiology. Furthermore, they point to GBA2 as a plausible modifier for GBA1 in patients with GD. PMID- 24070123 TI - Child maltreatment in India. AB - Child maltreatment is a global problem but is more difficult to assess and manage in developing countries such as India where one-fifth of the world's total child population resides. Certain forms of maltreatment such as feticide, infanticide, abandonment, child labour, street-begging, corporal punishment and battered babies are particularly prevalent in India. Most physicians still need to be sensitized in order to suspect child abuse on the basis of unexplained trauma, multiple fractures, parental conflict and other corroborative evidence. This article summarizes the various aspects of this major problem in resource-poor settings in the hope that it will assist in the planning of services addressing child physical and sexual abuse and neglect in India and in other developing countries. A culture of non-violence towards children needs to be built into communities in order to provide an environment conducive to the overall development of the child. Rehabilitation of abused children and their families requires a multi-disciplinary service including paediatricians, child psychologists and social workers, and the training of police forces in how to tackle the problem. PMID- 24070125 TI - Quantum method for fluorescence background removal in DNA melting analysis. AB - Fluorescent high-resolution DNA melting analysis is a robust method of genotyping and mutation scanning. However, removing background fluorescence is important for accurate classification and to correctly display helicity. Linear baseline extrapolation, commonly used with absorbance, often fails at low temperatures when fluorescence is used. A new quantum method of background removal based on the inherent decrease of fluorescence with temperature is described. Absorbance and fluorescence melting curves were compared using synthetic targets including hairpins, unlabeled probes, and a 50 bp duplex. In addition, the quantum method was compared to a previously described exponential method for analysis of genotyping data produced after polymerase chain reaction (PCR), including those from small amplicons, unlabeled probes, and snapback primers. The quantum method best matched absorbance data and predicted helicity, with the exponential method displaying low-temperature bulges and domain artifacts that can lead to incorrect genotyping. When two melting domains were widely separated, quantum analysis produced a flat baseline between domains, while exponential analysis was temperature-dependent. Both methods have little effect on the melting temperature (Tm) although some differences were significant (hairpin Tm values increased 0.7 degrees C by the quantum method and decreased 1.5 degrees C by exponential method, p = 0.01). However, peak heights on derivative plots were strongly algorithm-dependent, with exponential analysis enhancing low-temperature peaks while dampening high-temperature peaks. Quantum-analyzed fluorescence curves were a better match to absorbance data in terms of shape, area, and peak height compared to other methods, indicating that DNA helicity is best approximated by the quantum method. PMID- 24070124 TI - Microfluidic chip-based technologies: emerging platforms for cancer diagnosis. AB - The development of early and personalized diagnostic protocols is considered the most promising avenue to decrease mortality from cancer and improve outcome. The emerging microfluidic-based analyzing platforms hold high promises to fulfill high-throughput and high-precision screening with reduced equipment cost and low analysis time, as compared to traditional bulky counterparts in bench-top laboratories. This article overviewed the potential applications of microfluidic technologies for detection and monitoring of cancer through nucleic acid and protein biomarker analysis. The implications of the technologies in cancer cytology that can provide functional personalized diagnosis were highlighted. Finally, the future niches for using microfluidic-based systems in tumor screening were briefly discussed. PMID- 24070126 TI - The cost-utility of catheter ablation of atrial fibrillation: a systematic review and critical appraisal of economic evaluations. AB - BACKGROUND: A health technology assessment (HTA) of catheter ablation for atrial fibrillation (CA-AF) was commissioned by the Belgian government and performed by the Belgian Health Care Knowledge Centre (KCE). In this context, a systematic review of the economic literature was performed to assess the procedure's value for money. METHODS: A systematic search for economic literature about the cost effectiveness of CA-AF was performed by consulting various databases: CRD (Centre for Reviews and Dissemination) HTA and CDSR (Cochrane Database of Systematic Reviews) Technology Assessment, websites of HTA institutes, NHS EED (NHS Economic Evaluation Database), Medline (OVID), EMBASE and EconLit. No time or language restrictions were imposed and pre-defined selection criteria were used. The two step selection procedure was performed by two persons. References of the selected studies were checked for additional relevant citations. RESULTS: Out of 697 references, seven relevant studies were selected. Based on current evidence and economic considerations, the rationale to support catheter ablation as first-line treatment was lacking.The economic evaluations for second-line catheter ablation included several assumptions that make the results rather optimistic or subject to large uncertainty. First, overall AAD (antiarrhythmic drugs) use after ablation was higher in reality than assumed in the economic evaluations, which had its impact on costs and effects. Second, several models focused on the impact of ablation on preventing stroke. This was questionable because there was no direct hard evidence from RCTs to support this assumption. An indirect impact through stroke on mortality should also be regarded with caution. Furthermore, all models included an impact on quality of life (QoL)/utility and assumed a long term impact. Unfortunately, none of the RCTs measured QoL with a generic utility instrument and information on the long-term impact on both mortality and QoL was lacking. CONCLUSIONS: Catheter ablation is associated with high initial costs and may lead to life-threatening complications. Its cost-effectiveness depends on the belief one places on the impact on utility and/or preventing stroke, and the duration of these effects. Having no hard evidence for these important variables is rather troublesome. Although the technique is widely spread, the scientific evidence is insufficient for drawing conclusions about the intervention's cost effectiveness. PMID- 24070127 TI - Effect of alkyl chain length on the rotational diffusion of nonpolar and ionic solutes in 1-alkyl-3-methylimidazolium-bis(trifluoromethylsulfonyl)imides. AB - Rotational diffusion of a nonpolar solute 9-phenylanthracene (9-PA) and a cationic solute rhodamine 110 (R110) has been examined in a series of 1-alkyl-3 methylimidazolium (alkyl = octyl, decyl, dodecyl, tetradecyl, hexadecyl, and octadecyl) bis(trifluoromethylsulfonyl)imides to understand the influence of alkyl chain length on solute rotation. In this study, reorientation times (taur) have been measured as a function of viscosity (eta) by varying the temperature (T) of the solvents. These results have been analyzed using the Stokes-Einstein Debye (SED) hydrodynamic theory along with the ones obtained for the same solutes in 1-alkyl-3-methylimidazolium (alkyl = methyl, ethyl, propyl, butyl, and hexyl) bis(trifluoromethylsulfonyl)imides (Gangamallaiah and Dutt, J. Phys. Chem. B 2012, 116, 12819-12825). It has been noticed that the data for 9-PA and R110 follows the relation taur = A(eta/T)(n) with A being the ratio of hydrodynamic volume of the solute to the Boltzmann constant and n = 1 as envisaged by the SED theory. However, upon increasing the alkyl chain length from methyl to octadecyl significant deviations from the SED theory have been observed especially from the octyl derivative onward. From methyl to octadecyl derivatives, the value of A decreases by a factor of 3 for both the solutes and n by a factor of 1.4 and 1.6 for 9-PA and R110, respectively. These observations have been rationalized by taking into consideration the organized structure of the ionic liquids, whose influence appears to be pronounced when the number of carbon atoms in the alkyl chain attached to the imidazolium cation exceeds eight. PMID- 24070128 TI - Sustainable hand hygiene efforts; a review of a successful campaign. AB - AIM: The aim of this paper is to provide a review of the hand hygiene literature and to give an example of the use of this literature to create a multimodal sustainable hand hygiene program. BACKGROUND: The literature describes six key ingredients to consider when designing a hand hygiene program. These ingredients include leadership engagement, environmental assessment, education, a tight feedback loop, communication and routine revitalization. Programs tend to be more successful when several of these ingredients are utilized. PROGRAM IMPLEMENTATION: The multimodal program created and implemented at one academic medical center is described. This program is an example of using the six key ingredients found in the literature with an interesting marketing and revitalization strategy. CONCLUSION: The literature offers strategies that have led to successful programs in the past. The multimodal use of these strategies was demonstrated in the creation of a successful hand hygiene program at one academic medical center. PMID- 24070130 TI - Neural stem/progenitor cell transplantation for cortical visual impairment in neonatal brain injured patients. AB - The purpose of this study was to investigate the clinical efficacy of neural stem/progenitor cell (NS/PC) transplantation to treat severe cortical visual impairment (CVI), a sequela of neonatal brain injury. Fifty-two patients with cerebral injury and CVI were randomly divided into two groups: the treatment group (n = 25, with the median age of 18 months) and the control group (n = 27, with the median age of 19.5 months). The treatment group received intracerebroventricular transplantation of human NS/PCs and rehabilitation training. The control group received rehabilitation only. The visual function was assessed by Holt's method at various time points after transplantation. One in five patients with fundus abnormalities accompanied by blindness regained light perception. The visual functions of 75% of the patients with normal fundus were improved by one level or more in a 2-year follow-up. The median efficacy appeared 60 days posttransplantation. The total effective rate of cell transplantation on visual improvement was 64% (16 patients of 25), among which one blind patient regained light perception, five (31.2%) CVI patients improved by one level, and 10 (62.5%) improved by more than one level. Functional magnetic resonance imaging (fMRI) in a subpopulation of patients showed enhanced signals in the occipital lobe, visual pathway, and apical lobe after transplantation. In the control group, four patients with fundus abnormalities showed no improvement. Nine of 23 CVI patients with normal fundus improved visual function by more than one level. At the 2-year follow-up, no blind patients showed visual improvement. The total effective rate was 33.33% (9 of 27 patients). Among those showing visual improvement in the control group, six patients (66.67%) improved by one level, and three (33.33%) by more than one level. The median efficacy occurred in 365 days. Human NS/PC transplantation is effective to treat patients with severe CVI after neonatal brain injury. Compared with the traditional rehabilitation training, cell transplantation showed not only earlier visual improvement but also higher improvement rates and degrees. This article is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation. PMID- 24070129 TI - Association of SOD2 Mutation (c.47T > C) with Various Primary Angle Closure Glaucoma Clinical Indices. AB - We investigated whether the c.47T>C polymorphism (SNP rs4880) in the manganese superoxide dismutase (SOD2) gene is a risk factor for primary angle closure glaucoma (PACG) in the Saudi population. Among cases (n=139), the prevalence of various genotypes were 25.9%, 46.8% and 27.3% for T/T, C/T and C/C genotypes respectively. This trend was similar in the controls (n=403); 22.6%, 50.1% and 27.3% for T/T, C/T and C/C respectively. The differences in genotype distribution were not statistically significant (p=0.391 and 0.682 respectively). The minor allele frequency was 50.7% in cases and 52.4% in controls; this difference was not statistically significant (p=0.676). Investigating the potential association between this SOD2 polymorphism and different clinical indices, there was a statistically significant difference among different genotype groups in terms of three important clinical indices for PACG; Mean age at onset, duration of onset to and the mean LogMAR visual acuity (p=0.041, 0.018 and 0.033 respectively). The three markers are highly associated prognostic factors to diseases severity. If our results are proven in larger cohort and in various populations, then this SNP may have potentiality to be used as an indicator for PACG severity. PMID- 24070131 TI - Liquid crystalline phase behavior and sol-gel transition in aqueous halloysite nanotube dispersions. AB - The liquid crystalline phase behavior and sol-gel transition in halloysite nanotubes (HNTs) aqueous dispersions have been investigated by applying polarized optical microscopy (POM), macroscopic observation, rheometer, small-angle X-ray scattering, scanning electron microscopy, and transmission electron microscopy. The liquid crystalline phase starts to form at the HNT concentration of 1 wt %, and a full liquid crystalline phase forms at the HNT concentration of 25 wt % as observed by POM and macroscopic observation. Rheological measurements indicate a typical shear flow behavior for the HNT aqueous dispersions with concentrations above 20 wt % and further confirm that the sol-gel transition occurs at the HNT concentration of 37 wt %. Furthermore, the HNT aqueous dispersions exhibit pH induced gelation with more intense birefringence when hydrochloric acid (HCl) is added. The above findings shed light on the phase behaviors of diversely topological HNTs and lay the foundation for fabrication of the long-range ordered nano-objects. PMID- 24070132 TI - Anti-inflammatory and wound healing potential of citrus auraptene. AB - Auraptene is the most abundant naturally occurring geranyloxycoumarin. It is primarily isolated from plants in the Rutaceae family, many of which, like citrus fruits, are used as food in many countries. Auraptene is a biologically active secondary metabolite with valuable properties. The aim of our study was to identify novel properties of auraptene with potential for managing periodontal diseases, an inflammatory disease of bacterial origin affecting the tissues surrounding and supporting the teeth. In vitro assays showed that auraptene decreased, in a dose-dependent manner, the secretion of matrix metalloproteinase 2 as well as key inflammatory mediators, including interleukin-6 (IL-6), IL-8, and chemokine (C-C motif) ligand-5 secreted by Aggregatibacter actinomycetemcomitans lipopolysaccharide-stimulated oral epithelial cells. Using gingival fibroblasts, auraptene showed a significant (P<.05) wound healing effect by its capacity to increase cell migration. In conclusion, auraptene shows promise for promoting wound healing and controlling periodontal diseases through its capacity to interfere with inflammatory mediator secretion. PMID- 24070133 TI - Antibiotic induced liver injury: what about children? AB - Antimicrobial agents are important causes of drug-induced liver injury. They are responsible for about 45% of cases of drug hepatotoxicity. Hepatic damage mechanisms are intrinsic or idiosyncratic. Usually, antibiotics are responsible for idiosyncratic toxicity. This review summarizes the rate of incidence and clinical features of hepatotoxicity due to antibiotics and chemotherapics, with particular attention to data regarding paediatric population. Liver injury features have been systematically evaluated for the most commonly administered antibiotics and chemotherapics in adults, even though there is little information about other widely used compounds, as cephalosporine or clarithromycin, and about antibiotics active against multi-resistant bacteria, as carbapenems, vancomycin, clindamycin, and linezolid. By contrast, there is an abundance of case reports in paediatrics, but very few structured studies have been carried out in children. Children are an important class of antibiotic users, with specific metabolic characteristics, so more studies on them should be carried out. PMID- 24070134 TI - Difference in nephrotoxicity of vancomycin administered once daily and twice daily in rats. AB - We compared the degree of nephrotoxicity of vancomycin (VCM) administered once daily and twice daily in rats. VCM was intraperitoneally administered once daily to rats at a dose of 400 mg/kg (VCM-1-treated) or administered at a dose of 200 mg/kg twice daily at 12-hour intervals (VCM-2-treated) for 7 consecutive days. Creatinine clearance was decreased more markedly in VCM-1 rats relative to VCM-2 rats, although there was no significant difference in renal accumulation of VCM between the two groups. Renal superoxide dismutase activity was lower in VCM-1 rats than that in VCM-2 rats. The magnitude of histological change in kidney tissue was in agreement with the degree of alterations in the abovementioned biochemical values. These results suggest that the nephrotoxic effect of once daily VCM administration is more pronounced than that of the twice-daily treatment. Our findings provide fundamental evidence for the advantage in choosing a divided VCM administration to attenuate nephrotoxicity. PMID- 24070135 TI - The impact of an antimicrobial cycling strategy for febrile neutropenia in a haematology unit. AB - Antibiotic cycling has been proposed as a strategy to combat the emergence of antimicrobial resistance but has been implemented with conflicting results. A cycling strategy including four broad-spectrum antimicrobial regimens administrated sequentially over 3-month cycles in patients with febrile neutropenia was implemented in a haematology unit, during a 2-year period (2001 2003). Compliance to the strategy ranged between 57 and 100% and overall successful clinical response was 83%. Resistance rates of Gram negatives remained either stable or decreased (for Pseudomonas aeruginosa) at the end of the cycling period and no rectal colonization with resistant pathogens was recorded during the study period. The incidence of Gram-negative infections showed a decreasing trend while Gram-positive infections and resistance rates remained unaffected and at low rates. PMID- 24070136 TI - Can low-dose preemptive valganciclovir replace standard intravenous ganciclovir treatment in recipients of allogeneic stem cell transplantation? AB - The aim of this retrospective study was to compare the efficacy and safety of standard intravenous ganciclovir (GCV) with low-dose oral valganciclovir (VGC) in preemptive treatment of cytomegalovirus (CMV) infection in patients who received allogeneic stem cell transplantation (ASCT). Fifty-nine adult ASCT patients with asymptomatic 68 CMV reactivations were included. For preemptive CMV treatment, VGC (900 mg/day) in 44 reactivations or GCV (5 mg/kg twice daily during the first week and once daily afterwards) in 24 CMV reactivations were administered for 21 days. Two consecutive negative results for PCR and/or CMV antigenemia were considered as treatment success. All patients with CMV reactivations were on immunosuppressive treatment. While no positivity was identified in any of the patients who received GCV on day 21, low-titer CMV positivity was noted in three of the patients in the VGC group (P = 0.264). In all three patients, VGC was continued at same dose and no positivity result was detected after 2-3 weeks. Low grade neutropenia and high grade thrombocytopenia were significantly higher in the GCV group than in the VGC group (P = 0.018 and P = 0.04 respectively). Preemptive strategy of oral low-dose VGC appears preferable to the prevention of CMV disease in ASCT. These results require confirmation in prospective larger clinical studies. PMID- 24070137 TI - Anticancer activity of an antisense oligonucleotide targeting TRADD combined with proteasome inhibitors in chemoresistant hepatocellular carcinoma cells. AB - Chemoresistance is a major cause of mortality of patients with advanced and metastatic hepatocellular carcinoma (HCC), the fifth most common cancer in the world. We employed a molecular approach to inhibit cell proliferation and induce apoptosis in HepG2 cells, originated from human hepatocarcinoma. TRADD gene expression was knocked down by an antisense oligonucleotide (ASO TRADD), resulting in TRADD protein decrease by 60%, coinciding with increase of apoptotic cell death of up to 30%. Combination of the ASO TRADD with the cytotoxic drugs 5 fluorouracil or paclitaxel did not improve chemosensitivity of HepG2 cells, while the combined administration of the ASO TRADD with proteasome inhibitors MG132 or ALLN inhibited cell proliferation by 80% and 93%, respectively. Taken together, these findings reveal the importance to combine proteasome inhibitors with silencing of anti-apoptotic signalling components to target HCC cells effectively and provide useful data for developing potential treatments of HCC. PMID- 24070138 TI - Isogambogenic acid inhibits tumour angiogenesis by suppressing Rho GTPases and vascular endothelial growth factor receptor 2 signalling pathway. AB - Isogambogenic acid (iso-GNA) is a well-known herbal medicine extracted from Garcinia hanburyi. Although it is thought to have anti-tumour effects, its function is still unknown. This study carried out in vitro and in vivo evaluations of the anti-tumour and anti-angiogenic activity of iso-GNA and underlying mechanisms. A standard methyl thiazolyl tetrazolium assay showed that iso-GNA was more effective in inhibiting the proliferation of human umbilical vascular endothelial cells than A549 cancer cells. Iso-GNA demonstrated potent anti-angiogenic activity and low toxicity at appropriate concentrations in zebrafish embryos. In a xenograft nude mouse model of lung tumour, iso-GNA effectively inhibited tumour growth and tumour angiogenesis. Iso-GNA suppressed neovascularization of implanted matrigel plugs in vivo and inhibited vascular endothelial growth factor (VEGF)-induced microvessel sprouting from mouse aortic rings ex vivo. Iso-GNA inhibited VEGF-induced migration, invasion, and tube formation in vitro and affected cytoskeletal rearrangement in human umbilical vascular endothelial cells. The results show that iso-GNA suppressed angiogenesis mediated tumour growth by targeting VEGFR2, Akt, mitogen-activated protein kinase, Rho GTPase, vascular endothelium-cadherin, and focal adhesion kinase signalling pathways. Together, these data suggest that iso-GNA inhibits angiogenesis and may be a viable drug candidate in anti-angiogenesis and anti cancer therapies. PMID- 24070139 TI - The Pan European Emesis Registry (PEER): a critical appraisal of the Italian experience. AB - PURPOSE: Data from a large European prospective observational study were analysed to describe the antiemetic prescribing pattern for chemotherapy-induced nausea and vomiting (CINV) in Italian clinical practice. METHODS: Post hoc analysis of the Pan European Emesis Registry in chemo-naive adults initiating single-day highly or moderately emetogenic chemotherapy (HEC or MEC) for cancer. RESULTS: A total of 211 eligible patients were enrolled in the Italian centres, 180 were included in the analyses for cycle 1; 50.6% received MEC. The use of guideline consistent CINV prophylaxis (GCCP) varied substantially between acute and delayed phases (54.4% during the acute phase vs. 29.4% in the overall 120-hour study period, acute plus delayed phases). Neurokinin-1 receptor antagonist was added to the prophylaxis with dexamethasone+5-hydroxytryptamine type 3 receptor antagonists in only 11.1% of patients (vs. 57.2% of the entire European study population). In the GCCP group, the complete response rate was significantly higher than that recorded in the guideline-inconsistent CINV prophylaxis (GICP) group (75.5 vs. 53.5%, P = 0.006). CONCLUSION: The proportion of guideline consistent antiemetic therapy was quite low in the Italian population as it was in the overall European population. The implementation of specific guidelines' recommendations for chemotherapeutic regimens administered according to standard protocols could be considered as a means to reduce the burden of CINV. PMID- 24070140 TI - Adjusting biomaterial composition to achieve controlled multiple-day release of dexamethasone from an extended-wear silicone hydrogel contact lens. AB - PURPOSE: To alter the composition and structure of silicone hydrogel contact lenses to achieve controlled release of dexamethasone and evaluate the lens optical and mechanical properties compared to commercial lenses. There is a tremendous need for controlled release of drugs from ocular biomaterials as the majority of ophthalmic drugs are delivered via topical eye drops, which have low bioavailability and patient compliance. METHODS: Poly(PDMS-co-TRIS-co-DMA) contact lenses were synthesized with varying PDMS/TRIS:DMA ratios (0.25:1, 0.67:1, 1.5:1) as well as with additional crosslinking monomers. Lenses were characterized via in vitro release studies in a microfluidic device at ocular flowrates and in large well-mixed volumes, optical quality studies over visible wavelengths, mechanical analysis, and determination of polymer volume fraction in the swollen state. RESULTS: Extended and controlled release of therapeutically relevant concentrations of dexamethasone was achieved for multiple day, continuous wear up to 60 days at in vitro ocular flowrates. Release was delayed due to a combination of increased hydrophobic to hydrophilic composition and the inclusion of additional structural constraints, both of which decreased the polymer volume fraction in the swollen state. However, decreased mass release rates were at the expense of increased modulus and decreased lens flexibility. All lenses had high optical clarity (~90% transmittance) and contained highly oxygen permeable siloxane composition similar to those found in commercial silicone hydrogel lenses, but they had poor flexibility for use as soft contact lenses. CONCLUSIONS: Based on our results, the lenses described herein likely have too high of a modulus for use as extended-wear, soft contact lenses with drug release. Therefore, other controlled release methods would be better suited for maintaining adequate mechanical properties and achieving controlled and extended release for the duration of wear in soft, silicone hydrogel contact lens biomaterials. However, these biomaterials may find clinical use as more rigid gas permeable contact lenses or inserts. PMID- 24070141 TI - Talking with the alien: interaction with computers in the GP consultation. AB - This study examines New Zealand GPs' interaction with computers in routine consultations. Twenty-eight video-recorded consultations from 10 GPs were analysed in micro-detail to explore: (i) how doctors divide their time and attention between computer and patient; (ii) the different roles ascribed to the computer; and (iii) how computer use influences the interactional flow of the consultation. All GPs engaged with the computer in some way for at least 20% of each consultation, and on average spent 12% of time totally focussed on the computer. Patterns of use varied; most GPs inputted all or most notes during the consultation, but a few set aside dedicated time afterwards. The computer acted as an additional participant enacting roles like information repository and legitimiser of decisions. Computer use also altered some of the normal 'rules of engagement' between doctor and patient. Long silences and turning away interrupted the smooth flow of conversation, but various 'multitasking' strategies allowed GPs to remain engaged with patients during episodes of computer use (e.g. signposting, online commentary, verbalising while typing, social chat). Conclusions were that use of computers has many benefits but also significantly influences the fine detail of the GP consultation. Doctors must consciously develop strategies to manage this impact. PMID- 24070142 TI - Conjugates of magnetic nanoparticle-actinide specific chelator for radioactive waste separation. AB - A novel nanotechnology for the separation of radioactive waste that uses magnetic nanoparticles (MNPs) conjugated with actinide specific chelators (MNP-Che) is reviewed with a focus on design and process development. The MNP-Che separation process is an effective way of separating heat generating minor actinides (Np, Am, Cm) from spent nuclear fuel solution to reduce the radiological hazard. It utilizes coated MNPs to selectively adsorb the contaminants onto their surfaces, after which the loaded particles are collected using a magnetic field. The MNP Che conjugates can be recycled by stripping contaminates into a separate, smaller volume of solution, and then become the final waste form for disposal after reusing number of times. Due to the highly selective chelators, this remediation method could be both simple and versatile while allowing the valuable actinides to be recovered and recycled. Key issues standing in the way of large-scale application are stability of the conjugates and their dispersion in solution to maintain their unique properties, especially large surface area, of MNPs. With substantial research progress made on MNPs and their surface functionalization, as well as development of environmentally benign chelators, this method could become very flexible and cost-effective for recycling used fuel. Finally, the development of this nanotechnology is summarized and its future direction is discussed. PMID- 24070143 TI - Sex-specific recombination rates and allele frequencies affect the invasion of sexually antagonistic variation on autosomes. AB - The introduction and persistence of novel, sexually antagonistic alleles can depend upon factors that differ between males and females. Understanding the conditions for invasion in a two-locus model can elucidate these processes. For instance, selection can act differently upon the sexes, or sex linkage can facilitate the invasion of genetic variation with opposing fitness effects between the sexes. Two factors that deserve further attention are recombination rates and allele frequencies - both of which can vary substantially between the sexes. We find that sex-specific recombination rates in a two-locus diploid model can affect the invasion outcome of sexually antagonistic alleles and that the sex averaged recombination rate is not necessarily sufficient to predict invasion. We confirm that the range of permissible recombination rates is smaller in the sex benefitting from invasion and larger in the sex harmed by invasion. However, within the invasion space, male recombination rate can be greater than, equal to or less than female recombination rate in order for a male-benefit, female detriment allele to invade (and similarly for a female-benefit, male-detriment allele). We further show that a novel, sexually antagonistic allele that is also associated with a lowered recombination rate can invade more easily when present in the double heterozygote genotype. Finally, we find that sexual dimorphism in resident allele frequencies can impact the invasion of new sexually antagonistic alleles at a second locus. Our results suggest that accounting for sex-specific recombination rates and allele frequencies can determine the difference between invasion and non-invasion of novel, sexually antagonistic alleles in a two-locus model. PMID- 24070144 TI - Multiple traumatic brain injury and concussive symptoms among deployed military personnel. AB - OBJECTIVE: To identify if concussive symptoms occur with greater frequency among military personnel with multiple lifetime TBIs and if a history of TBI increases risk for subsequent TBI. PATIENTS: One hundred and sixty-one military personnel referred to a TBI clinic for evaluation and treatment of suspected head injury at a military clinic in Iraq. METHODS: Military patients completed standardized self report measures of concussion, depression and post-traumatic stress symptoms; clinical interview; and physical examination. Group comparisons were made according to number of lifetime TBIs and logistic regression was utilized to determine the association of past TBIs on current TBI. RESULTS: Patients with one or more previous TBIs were more likely to report concussion symptoms immediately following a recent injury and during the evaluation. Although differences between single and multiple TBI groups were observed, these did not reach the level of statistical significance. A history of any TBI increased the likelihood of current TBI diagnosis, but this relationship was no longer significant when adjusting for injury mechanism, depression and post-traumatic stress symptoms. CONCLUSION: Among deployed military personnel, the relationship of previous TBI with recent TBI and concussive symptoms may be largely explained by the presence of psychological symptoms. PMID- 24070146 TI - Endoglucanases: insights into thermostability for biofuel applications. AB - Obtaining bioethanol from cellulosic biomass involves numerous steps, among which the enzymatic conversion of the polymer to individual sugar units has been a main focus of the biotechnology industry. Among the cellulases that break down the polymeric cellulose are endoglucanases that act synergistically for subsequent hydrolytic reactions. The endoglucanases that have garnered relatively more attention are those that can withstand high temperatures, i.e., are thermostable. Although our understanding of thermostability in endoglucanases is incomplete, some molecular features that are responsible for increased thermostability have been recently identified. This review focuses on the investigations of endoglucanases and their implications for biofuel applications. PMID- 24070145 TI - Assessment of weight-related factors of adolescents by private practitioners. AB - BACKGROUND: Few studies have examined how common physicians assess various weight related variables and patient characteristics that predict such assessments based on adolescents' reports. We aimed to examine how common adolescents received weight-related physical measurements and lifestyle enquiries (dietary habits and physical activity) from private practitioners and to identify factors associated with these assessments. METHODS: In the Hong Kong Student Obesity Surveillance (HKSOS) project, 33692 students (44.9% boys; mean age 14.8, SD 1.9 years, age range 11-18) from 42 randomly selected schools completed an anonymous questionnaire. The students were asked "In the past 12 months, has any private practitioners (or their nurses) measured or asked about these items?" Response options included height, weight, waist circumference (WC), blood pressure (BP), BMI, diet, and physical activity. Weight status was based on self-reported weight and height. Logistic regression was used to identify student characteristics associated with each assessment. Analyses were conducted using STATA 10.0. RESULTS: Among 13283 students who had doctor consultations in the past 12 months, 37.9% received physical measurements or lifestyle enquiries, with weight (20.8%), height (16.8%) and blood pressure (11.5%) being the most common, followed by diet (8.1%), BMI (6.3%), WC and physical activity (both 4.6%). In general, adolescents who were female, older, underweight or overweight/obese, had parents with higher education level, and had actively asked private practitioners for advice about weight were more likely to receive assessments of weight-related factors. CONCLUSIONS: Weight-related factors in adolescents were infrequently assessed by private practitioners in Hong Kong. Generally, unhealthy weight, higher parental education and advice-seeking by adolescents predicted these assessments. PMID- 24070147 TI - The potential of probiotics in the fight against necrotizing enterocolitis. PMID- 24070148 TI - Probiotics in diverticular disease: not ready for prime time? PMID- 24070150 TI - Crofelemer, a novel agent for treatment of non-infectious diarrhea in HIV infected persons. AB - Crofelemer is the first US FDA-approved drug for symptomatic relief in HIV infected persons on antiretroviral therapy (ART) who have non-infectious diarrhea. With the availability of ART, there is increased survival and decrease in gastrointestinal opportunistic infections. However, diarrhea secondary to ART and HIV enteropathy is common in HIV-infected persons. Crofelemer is manufactured from the red latex sap of the Croton lechleri tree in South America. It has a unique mechanism leading to inhibition of chloride ion secretion by blocking chloride channels in the gastrointestinal lumen. This reduces efflux of sodium and water, which in turn reduces the frequency and consistency of diarrhea. Crofelemer is well tolerated due to minimal systemic absorption and has a good safety profile. The availability of crofelemer will likely have a positive impact on the quality of life in HIV-infected persons and also increase compliance to ART. PMID- 24070151 TI - Is there any link between dietary pattern and development of nonalcoholic fatty liver disease in adolescence? An expert review. AB - The prevalence of overweight and obesity in childhood is a major public health concern. According to the obesity trend, the prevalence of pediatric nonalcoholic fatty liver disease (NAFLD) is also increasing. Nonalcoholic fatty liver disease is characterized by a spectrum of hepatic lesions (i.e., steatosis, ballooning, necroinflammation and fibrosis) that can progress to cirrhosis, hepatocellular carcinoma and liver failure with the consequent need for liver transplantation. Pediatric NAFLD is typically of primary origin and it is strongly associated with several features of the metabolic syndrome such as obesity, insulin resistance, dyslipidemia and Type 2 diabetes. The evaluated article reports the prospective relationship between dietary patterns at age 14 years and the presence of NAFLD at age 17 years. A total of 995 adolescents completed a food frequency questionnaire at 14 years and had liver ultrasound at 17 years. Prospective associations between the dietary pattern scores and the risk of NAFLD were analyzed using multiple logistic regression analyses. Nonalcoholic fatty liver disease was present in 15.2% of adolescents. A healthy dietary pattern at 14 years appeared protective against NAFLD at 17 years in centrally obese adolescents. On the contrary, a western dietary pattern at 14 years in this cohort was associated with an increased risk of NAFLD at 17 years, particularly in obese adolescents. PMID- 24070152 TI - A review of ischemic colitis: is our clinical recognition and management adequate? AB - Ischemic colitis is a common cause of hospital admissions; however it is frequently confused intellectually with mesenteric ischemia and often misdiagnosed as infectious diarrhea or Clostridium difficile colitis. Ischemic colitis is caused by non-occlusive insult to the small vessels supplying the colon without a clear precipitating factor. It is more common in females and in patients above 60 years of age. The classic presentation includes sudden onset of lower abdominal pain followed by the urge to defecate and bloody diarrhea. Focal right-sided ischemic colitis has more pain and a worse prognosis. Choosing the correct diagnostic studies is challenging and requires proficient knowledge of the disease. Management is usually conservative, however around 10-20% of the patients will require surgery. Acute ischemic colitis usually resolves; nevertheless some patients may develop chronic segmental colitis or a stricture. One ischemic colitis caveat is that it may be the first sign of undiagnosed cardiac disease. A firm grasp on this common yet little discussed condition is valuable to a gastrointestinal consultant and hospitalist alike. PMID- 24070153 TI - Alteration of the intestinal microbiome: fecal microbiota transplant and probiotics for Clostridium difficile and beyond. AB - Clostridium difficile infection is increasingly common with a high risk of recurrence despite antibiotic treatment. In cases of recurrent C. difficile infection, fecal microbiota transplant (FMT) is a highly effective treatment option promoting the restoration of normal gut microbiota. Furthermore, preliminary uncontrolled evidence demonstrates possible benefit of FMT in the management of some cases of inflammatory bowel disease and chronic constipation. In addition to presenting an overview of FMT, we discuss the role of probiotics, a more common approach to modifying the intestinal microbiome. Probiotics have been utilized broadly for many disease processes, including gastrointestinal, cardiovascular and allergic disease settings, although with limited and inconsistent results. Multiple potential areas for research are also identified. PMID- 24070154 TI - Pediatric liver transplantation: where do we stand? Where we are going to? AB - Pediatric liver transplantation (LT) is one of the most successful solid organ transplants with long-term survival more than 80%. Many aspects have contributed to improve survival, especially advancements in pre-, peri- and post-transplant management. The development of new surgical techniques, such as split-LT and the introduction of living related LT, has extended LT to small infants. Progress in the last 30 years has also been characterized by the introduction of calcineurin inhibitors. One problem remains the lack of donors. Donation after cardiac death offers a new possibility to increase the pool of potential donors. In children with acute liver failure, increasing interest has centered on the possibility of providing temporary liver support based on extracorporeal devices or hepatocyte transplantation. Similarly, hepatocyte transplantation offers new perspective in children with metabolic failure. As long-term survival increases, attention has now focused on the quality of life achieved by children undergoing LT. PMID- 24070155 TI - Diagnostic dilemmas in celiac disease. AB - Celiac disease (CD) is an immune-mediated systemic condition triggered by dietary gluten occurring in genetically susceptible individuals. Our understanding of its numerous and varied clinical presentations has evolved over time, which has contributed to the incidence of CD increasing. In most cases, the diagnosis is readily established and patients promptly improve after commencing a gluten-free diet (GFD). However, in some, the diagnosis is not straightforward and presents a challenge to clinicians. Potential dilemmas include those with positive serology but normal histology, negative serology but abnormal duodenal mucosal histology, failure to respond to a GFD or response to a GFD without evidence of CD. In recent years, development of new assays and modifications to existing diagnostic algorithms for CD has also challenged the traditional role of small-bowel histology as critical in CD diagnosis. PMID- 24070156 TI - Review of organic causes of fecal incontinence in children: evaluation and treatment. AB - Even though fecal incontinence (FI) in children is most commonly the result of functional constipation, there are organic conditions that can be associated with incontinence. FI has a major impact on the quality of life of those children who experience it. The general objectives of any bowel program are to achieve predictability and independence. This is achieved by manipulating colonic transit and stool consistency and by producing more controlled evacuations, usually with the use of rectal interventions. Dietary interventions and medications can be used to change stool consistency or to manipulate transit by accelerating or slowing it down. Biofeedback or other interventions that increase sphincter pressure can also be used to improve anorectal function. Enemas or suppositories can be used to empty the sigmoid colon in a more controlled manner. With the recent advent of the antegrade colonic enemas, the patient can have predictable bowel movements and become independent. PMID- 24070157 TI - Deprotonation reactions and electrochemistry of substituted open-chain pentapyrroles and sapphyrins in basic nonaqueous media. AB - Electrochemical and spectroelectrochemical properties of three open-chain pentapyrroles and the corresponding sapphyrins were examined in pyridine containing 0.1 M tetra-n-butylammonium perchlorate and dichloromethane (CH2Cl2) or benzonitrile (PhCN) containing tetra-n-butylammonium hydroxide (TBAOH). The investigated compounds are represented as (Ar)4PPyH3 and (Ar)4SH3, where Ar is a F(-) or Cl(-) substituted phenyl group, PPy is a trianion of the open-chain pentapyrrole, and S is a trianion of the sapphyrin. The pentapyrroles, (Ar)4PPyH3, undergo two reversible one-electron reductions in pyridine, while the structurally related sapphyrins exhibit four reductions in this solvent, the first two of which are irreversible due to coupled chemical reactions following the electron transfers. Both series of neutral compounds could be deprotonated in CH2Cl2 or PhCN by addition of TBAOH to solution, and the progress of these reactions was monitored as a function of the base concentration by cyclic voltammetry and UV-vis spectroscopy. The neutral pentapyrroles were spectroscopically shown to undergo a loss of two protons in a single step to generate the [(Ar)4PPyH](2-) dianion while the sapphyrins could only be monodeprotonated, leading to formation of the [(Ar)4SH2](-) monoanion under the same solution conditions. The deprotonation constants were measured for each series of compounds in benzonitrile, and oxidation-reduction mechanisms are examined as a function of the solution 'basicity'. PMID- 24070158 TI - Organocatalytic activation of alkylacetic esters as enolate precursors to react with alpha,beta-unsaturated imines. AB - Asymmetric functionalization of alkylacetic esters and their derivatives is traditionally achieved via preformed enolates with chiral auxiliaries. Catalytic versions of such transformations are attractive but challenging. A direct catalytic activation of simple alkylacetic esters via N-heterocyclic carbene organocatalysts to generate chiral enolate intermediates for highly enantioselective reactions is reported. PMID- 24070159 TI - Rapid fabrication of large-area concave microlens arrays on PDMS by a femtosecond laser. AB - A fast and single-step process is developed for the fabrication of low-cost, high quality, and large-area concave microlens arrays (MLAs) by the high-speed line scanning of femtosecond laser pulses. Each concave microlens can be generated by a single laser pulse, and over 2.78 million microlenses were fabricated on a 2 * 2 cm(2) polydimethylsiloxane (PDMS) sheet within 50 min, which greatly enhances the processing efficiency compared to the classical laser direct writing method. The mechanical pressure induced by the expansion of the laser-induced plasmas as well as a long resolidifing time is the reason for the formation of smooth concave spherical microstructures. We show that uniform microlenses with different diameters and depths can be controlled by adjusting the power of laser pulses. Their high-quality optical performance is also demonstrated in this work. PMID- 24070161 TI - The use of child soldiers in war with special reference to Sri Lanka. AB - Throughout history, the involvement of children in military operations has been extensively documented. The issue of child conscription is multi-faceted, with very few medical but more sociological aspects, including terrorism, politics, economics, history, culture and religion amongst other factors. Many United Nations Instruments as well as the International Criminal Court have documented that child conscription is detrimental to a child's development, violates Child Rights, and is a war crime. Efforts by international bodies to address conscription as child abuse have failed since the process is undertaken by groups rather than individuals, and because the law has no access to the perpetrators. The background to a conflict in Sri Lanka and various ethno-religious and political factors are discussed. The role of the diaspora community, the internet and various fund-raising mechanisms for war are discussed. The history of child conscription and studies examining reasons and the tasks assigned to them as conscripts as well as abusive aspects, especially in relation to emotional abuse, neglect and physical harm, are discussed. Documentation of conscription as child abuse needing a definition including a new definition of 'suicide by proxy' is stressed. The importance of culture and history, and the manipulation of the idealistic mind are discussed in the context of 'setting the stage' for child conscription. The toy weapon industry and the real arms industry, especially small arms, are important in maintaining conflicts, especially in the developing world. The conflicts of interests of members of the UN Security Council and the 'peace-keepers' of the world is discussed. PMID- 24070160 TI - Antioxidant, anti-adipocyte differentiation, antitumor activity and anthelmintic activities against Anisakis simplex and Hymenolepis nana of yakuchinone A from Alpinia oxyphylla. AB - BACKGROUND: Alpinia oxyphylla is a common remedy in traditional Chinese medicine. Yakuchinone A is a major constituent of A. oxyphylla and exhibits anti inflammatory, antitumor, antibacterial, and gastric protective activities. METHODS: Antioxidant and antitumor characteristics of yakuchinone A in skin cancer cells as well as novel mechanisms for the inhibition of adipocyte differentiation, cestocidal activities against Hymenolepis nana adults, and nematocidal activities against Anisakis simplex larvae are investigated. RESULTS: Yakuchinone A presents the ability of the removal of DPPH.and ABTS+ free radicals and inhibition of lipid peroxidation. Yakuchinone A suppresses intracellular lipid accumulation during adipocyte differentiation in 3 T3-L1 cells and the expressions of leptin and peroxisome proliferator-activated receptor gamma (PPARgamma). Yakuchinone A induces apoptosis and inhibits cell proliferation in skin cancer cells. The inhibition of cell growth by yakuchinone A is more significant for non-melanoma skin cancer (NMSC) cells than for melanoma (A375 and B16) and noncancerous (HaCaT and BNLCL2) cells. Treatment BCC cells with yakuchinone A shows down-regulation of Bcl-2, up-regulation of Bax, and an increase in cleavage poly (ADP-ribose) polymerase (PARP). This suggests that yakuchinone A induces BCC cells apoptosis through the Bcl-2-mediated signaling pathway. The anthelmintic activities of yakuchinone A for A. simplex are better than for H. nana. CONCLUSIONS: In this work, yakuchinone A exhibits antioxidative properties, anti-adipocyte differentiation, antitumor activity, and anthelmintic activities against A. simplex and H. nana. PMID- 24070162 TI - Study protocol for valuing EQ-5D-3L and EORTC-8D health states in a representative population sample in Sri Lanka. AB - BACKGROUND: Economic evaluations to inform decisions about allocation of health resources are scarce in Low and Middle Income Countries, including in Sri Lanka. This is in part due to a lack of country-specific utility weights, which are necessary to derive appropriate Quality Adjusted Life Years. The EQ-5D-3 L, a generic multi-attribute instrument (MAUI), is most widely used to measure and value health states in high income countries; nevertheless, the sensitivity of generic MAUIs has been criticised in some conditions such as cancer. This article describes a protocol to produce both a generic EQ-5D-3 L and cancer specific EORTC-8D utility index in Sri Lanka. METHOD: EQ-5D-3 L and EORTC-8D health states will be valued using the Time Trade-Off technique, by a representative population sample (n = 780 invited) identified using stratified multi-stage cluster sampling with probability proportionate to size method. Households will be randomly selected within 30 clusters across four districts; one adult (>= 18 years) within each household will be selected using the Kish grid method.Data will be collected via face-to-face interview, with a Time Trade-Off board employed as a visual aid. Of the 243 EQ-5D-3 L and 81,290 EORTC-8D health states, 196 and 84 respectively will be directly valued. In EQ-5D-3 L, all health states that combine level 3 on mobility with either level 1 on usual activities or self-care were excluded. Each participant will first complete the EQ-5D-3 L, rank and value 14 EQ-5D-3 L states (plus the worst health state and "immediate death"), and then rank and value seven EORTC-8D states (plus "immediate death"). Participant demographic and health characteristics will be also collected.Regression models will be fitted to estimate utility indices for EQ-5D-3 L and EORTC-8D health states for Sri Lanka. The dependent variable will be the utility value. Different specifications of independent variables will be derived from the ordinal EQ-5D-3 L to test for the best-fitting model. DISCUSSION: In Sri Lanka, a LMIC health state valuation will have to be carried out using face to face interview instead of online methods. The proposed study will provide the first country-specific health state valuations for Sri Lanka, and one of the first valuations to be completed in a South Asian Country. PMID- 24070165 TI - Counselling and Pentecostal modalities of social engineering of relationships in Botswana. AB - In African societies where HIV and AIDS are widespread, counselling is being used in an attempt to control people's sexual relationships and has become an important industry. Counselling is centrally placed in many AIDS-related policies in Botswana and is sponsored by both the government and religious organisations. Within the broad spectrum of Christianity, Pentecostal churches are very active. They emphasise the refashioning of relationships by mediating moral imperatives and by engaging with psychological knowledge on personal behaviour and on techniques of counselling in a changing context of sexuality. This paper explores the significance of religious counselling in terms of the disciplining effects concerning personal behaviour and the ways in which this form of communication is generating a wider interest in this society. This is particularly attractive to members of the educated classes who are engaging with Pentecostal counselling as a way of refashioning their domain of intimate relations. Yet, it does not only provide informed ideas on intimate relations--being often one of the proclaimed objectives of counselling - it also produces a communication about intimate matters that is intended to inform a critique of socio-cultural conventions. This is a counter-cultural dynamic of counselling, which has been little noticed in the academic study of counselling practices in Africa. PMID- 24070164 TI - A phase II FOLFOX-4 regimen as second-line treatment in advanced biliary tract cancer refractory to gemcitabine/cisplatin. AB - OBJECTIVE: We aimed to evaluate the efficacy and safety of oxaliplatin, 5 fluorouracil (5-FU), and leucovorin (LV) (FOLFOX-4) as second-line treatment in patients with advanced biliary tract cancer (BTC) failing gemcitabine/cisplatin first-line chemotherapy. METHODS: Thirty-seven patients with advanced BTC refractory to gemcitabine/cisplatin chemotherapy were included in the study. FOLFOX-4 regimen consisted of oxaliplatin (85 mg/m(2)) as a 2-hour infusion on day 1 and 2-hour infusion of LV (200 mg/m(2)/day) followed by a 5-FU bolus (400 mg/m(2)/day) and 22-hour infusion of 5-FU (600 mg/m(2)/day) for two consecutive days every 2 weeks. The primary end point was the time to progression (TTP). RESULTS: Between January 2009 and January 2012, a total of 37 patients were enrolled. The median age was 57 years (range 32-70) and male to female ratio was 21:16. Median TTP was 3.1 months (95% CI 2.3-3.6). The objective response rate was 21.6% (eight partial responses), and disease control rate was 62.2% (15 stable disease). Grade 3-4 toxicities were observed in 37.8% of the patients with neutropenia and fatigue being the most frequent (21.6%). CONCLUSIONS: FOLFOX-4 regimen is a feasible and moderately efficacious second-line chemotherapy for advanced BTC. PMID- 24070166 TI - Factors influencing the adoption, implementation, and continuation of physical activity interventions in primary health care: a Delphi study. AB - BACKGROUND: The introduction of efficacious physical activity interventions in primary health care is a complex process. Understanding factors influencing the process can enhance the development of effective introduction strategies. This Delphi study aimed to identify factors most relevant for the adoption, implementation, and continuation of physical activity interventions in primary health care by examining experts' opinions on the importance and changeability of factors previously identified as potentially relevant for the process. METHODS: In the first round, 44 experts scored factors on their importance for each stage of the introduction process, as well as on their changeability. In the second round, the same experts received a questionnaire containing a reduced list of factors, based on the first-round results. They were asked to indicate their top 10 most important factors for each stage, and to re-rate factors' changeability. Thirty-seven experts completed this round. RESULTS: Most important factors could be identified for each stage. Some factors were found important for a specific stage, e.g., the presence of intervention champions within the organization (adoption), provider knowledge (implementation), and the intervention's sustainability (continuation), while others were perceived important for all stages, i.e., the intervention's financial feasibility, the intervention's accessibility to the target group, and time to deliver the intervention. The majority of most important factors was perceived changeable. However, for some factors no consensus could be reached regarding their changeability. CONCLUSIONS: This study identified general and stage-specific factors relevant for the introduction of physical activity interventions in primary health care. It emphasizes the importance of taking these factors into account when designing introduction strategies, and of giving special attention to the distinct stages of the process. Due to lack of consensus on the changeability of most important factors, the extent to which these factors can be influenced by introduction strategies remains unclear. PMID- 24070167 TI - Synthesis and preliminary biological evaluation of polyamine-aniline acridines as P-glycoprotein inhibitors. AB - We have synthesized a series of polyamine-based anilinoacridine derivatives. The preliminary biological evaluation indicated that the 9-anilinoacridine-polyamine derivatives had low or insignificant in vitro cytotoxicity against K562 cell line and K562/ADM, the drug-resistant cell line. However, the evaluation for P-gp modulation showed that they held potent P-gp inhibitory ability. Among them, the effect of compound 7c on P-gp was even greater than that of Verapamil, the known P-gp modulator. The results suggest that 9-anilinoacridine-polyamine derivatives can be employed as effective P-gp modulators. PMID- 24070168 TI - A cantilever biosensor-based assay for toxin-producing cyanobacteria Microcystis aeruginosa using 16S rRNA. AB - Monitoring of cyanotoxins in source waters is currently done through toxin targeting assays which suffer from low sensitivity due to poor antibody avidity. We present a biosensor-based method as an alternative for detecting toxin producing cyanobacteria M. aeruginosa via species-selective region of 16S rRNA at concentrations as low as 50 cells/mL, and over a five-log dynamic range. The cantilever biosensor was immobilized with a 27-base DNA strand that is complementary to the target variable region of 16S rRNA of M. aeruginosa. The cantilever sensor detects mass-changes through shifts in its resonant frequency. Increase in the biosensor's effective mass, caused by hybridization of target strand with the biosensor-immobilized complementary strand, showed consistent and proportional frequency shift to M. aeruginosa concentrations. The sensor hybridization response was verified in situ by two techniques: (a) presence of duplex DNA structure postdetection via fluorescence measurements, and (b) secondary hybridization of nanogold-labeled DNA strands to the captured 16S rRNA strands. The biosensor-based assay, conducted in a flow format (~ 0.5 mL/min), is relatively short, and requires a postextraction analysis time of less than two hours. The two-step detection protocol (primary and secondary hybridization) is less prone to false negatives, and the technique as a whole can potentially provide an early warning for toxin presence in source waters. PMID- 24070169 TI - Lathyrism: has the scenario changed in 2013? AB - Lathyrism is now rarely seen as a clinical disease in general, medical or neurology outpatient departments, throughout the world. Eating patterns of seeds of Lathyrus sativus are still prevalent focal points in parts of the world. Question arises, why are we not seeing cases of lathyrism? Is it that the disease has changed its profile, with the changing socioeconomic status of the poor or underdeveloped or moderately developed countries? Is it that the seeds of lathyrus are less toxic now? Is it that the body defence against toxins of lathyrus has genetically modified? To find out answers to these interesting questions, an extensive questionnaire-based sampling was done among 1000 subjects from northern India to identify the human behaviour regarding the knowledge, attitude, and practices (KAPs) for L. sativus. Four clinically suspected cases of Lathyrism were also fully worked up. It was concluded that many areas of India are still being fed with lathyrus seeds, but not many cases have appeared. Many questions have to be answered, as to what has reduced the incidence of lathyrism. PMID- 24070171 TI - Modelling the evolution of common cuckoo host-races: speciation or genetic swamping? AB - Co-evolutionary arms races have provided clear evidence for evolutionary change, especially in host-parasite systems. The evolution of host-specific races in the common cuckoo (Cuculus canorus), however, is also an example where sexual conflict influences the outcome. Cuckoo females benefit from better adaptation to overcome host defences, whereas cuckoo males face a trade-off between the benefits of better adaptation to a host and the benefits of multiple mating with females from other host-races. The outcome of this trade-off might be genetic differentiation or prevention of it by genetic swamping. We use a simulation model to test which outcome is more likely with three sympatric cuckoo host races. We assume a cost for cuckoo chicks that express a host adaptation allele not suited to their foster host species and that cuckoo males that switch to another host-race experience either a fitness benefit or cost. Over most of the parameter space, cuckoo male host-race fidelity increases significantly with time, and gene flow between host-races ceases within a few thousand to a hundred thousand generations. Our results hence support the idea that common cuckoo host races might be in the incipient stages of speciation. PMID- 24070170 TI - Quantitative measures of estrogen receptor expression in relation to breast cancer-specific mortality risk among white women and black women. AB - INTRODUCTION: The association of breast cancer patients' mortality with estrogen receptor (ER) status (ER + versus ER-) has been well studied. However, little attention has been paid to the relationship between the quantitative measures of ER expression and mortality. METHODS: We evaluated the association between semi quantitative, immunohistochemical staining of ER in formalin-fixed paraffin embedded breast carcinomas and breast cancer-specific mortality risk in an observational cohort of invasive breast cancer in 681 white women and 523 black women ages 35-64 years at first diagnosis of invasive breast cancer, who were followed for a median of 10 years. The quantitative measures of ER examined here included the percentage of tumor cell nuclei positively stained for ER, ER Histo (H)-score, and a score based on an adaptation of an equation presented by Cuzick and colleagues, which combines weighted values of ER H-score, percentage of tumor cell nuclei positively stained for the progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) results. This is referred to as the ER/PR/HER2 score. RESULTS: After controlling for age at diagnosis, race, study site, tumor stage, and histologic grade in multivariable Cox proportional hazards regression models, both percentage of tumor cell nuclei positively stained for ER (Ptrend = 0.0003) and the ER H-score (Ptrend = 0.0004) were inversely associated with breast cancer-specific mortality risk. The ER/PR/HER2 score was positively associated with breast cancer-specific mortality risk in women with ER + tumor (Ptrend = 0.001). Analyses by race revealed that ER positivity was associated with reduced risk of breast cancer-specific mortality in white women and black women. The two quantitative measures for ER alone provided additional discrimination in breast cancer-specific mortality risk only among white women with ER + tumors (both Ptrend <= 0.01) while the ER/PR/HER2 score provided additional discrimination for both white women (Ptrend = 0.01) and black women (Ptrend = 0.03) with ER + tumors. CONCLUSIONS: Our data support quantitative immunohistochemical measures of ER, especially the ER/PR/HER2 score, as a more precise predictor for breast cancer-specific mortality risk than a simple determination of ER positivity. PMID- 24070172 TI - Rotational spectroscopy of isotopologues of silicon monoxide, SiO, and spectroscopic parameters from a combined fit of rotational and rovibrational data. AB - Pure rotational transitions of silicon monoxide, involving the main ((28)Si(16)O) as well as several rare isotopic species, were observed in their ground vibrational states by employing long-path absorption spectroscopy between 86 and 825 GHz (1 <= J" <= 18). Fourier transform microwave spectroscopy was used to study the J" = 0 transition frequencies in the ground and several vibrationally excited states. The vibrational excitation of the newly studied isotopologues extend to between upsilon = 9 and 29 for (28)Si(17)O and (30)Si(16)O, respectively. Data were extended for some previously investigated species up to upsilon = 51 for the main isotopologue. The high spectral resolution allowed us to resolve the hyperfine structure in (28)Si(17)O caused by the nuclear electric quadrupole and magnetic dipole moments of (17)O for the first time, and to resolve the much smaller nuclear spin-rotation splitting for isotopic species containing (29)Si. These data were combined with previous rotational and rovibrational (infrared) data to determine an improved set of spectroscopic parameters of SiO in one global fit which takes the breakdown of the Born Oppenheimer approximation into account. Highly accurate rotational transition frequencies for this important astronomical molecule can now be predicted well into the terahertz region with this parameter set. In addition, a more complete comparison among physical properties of group 14/16 diatomics is possible. PMID- 24070175 TI - Encapsulation of mesenchymal stem cells by bioscaffolds protects cell survival and attenuates neuroinflammatory reaction in injured brain tissue after transplantation. AB - Since the brain is naturally inefficient in regenerating functional tissue after injury or disease, novel restorative strategies including stem cell transplantation and tissue engineering have to be considered. We have investigated the use of such strategies in order to achieve better functional repair outcomes. One of the fundamental challenges of successful transplantation is the delivery of cells to the injured site while maintaining cell viability. Classical cell delivery methods of intravenous or intraparenchymal injections are plagued by low engraftment and poor survival of transplanted stem cells. Novel implantable devices such as 3D bioactive scaffolds can provide the physical and metabolic support required for successful progenitor cell engraftment, proliferation, and maturation. In this study, we performed in situ analysis of laminin-linked dextran and gelatin macroporous scaffolds. We revealed the protective action of gelatin-laminin (GL) scaffolds seeded with mesenchymal stem cells derived from donated human Wharton's jelly (hUCMSCs) against neuroinflammatory reactions of injured mammalian brain tissue. These bioscaffolds have been implanted into (i) intact and (ii) ischemic rat hippocampal organotypic slices and into the striatum of (iii) normal and (iv) focally injured brains of adult Wistar rats. We found that transplantation of hUCMSCs encapsulated in GL scaffolds had a significant impact on the prevention of glial scar formation (low glial acidic fibrillary protein) and in the reduction of neuroinflammation (low interleukin-6 and the microglial markers ED1 and Iba1) in the recipient tissue. Moreover, implantation of hUCMSCs encapsulated within GL scaffolds induced matrix metalloproteinase-2 and -9 proteolytic activities in the surrounding brain tissue. This facilitated scaffold biodegradation while leaving the remaining grafted hUCMSCs untouched. In conclusion, transplanting GL scaffolds preseeded with hUCMSCs into mammalian brain tissue escaped the host's immune system and protected neural tissue from neuroinflammatory injury. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation. PMID- 24070173 TI - Genome replication engineering assisted continuous evolution (GREACE) to improve microbial tolerance for biofuels production. AB - BACKGROUND: Microbial production of biofuels requires robust cell growth and metabolism under tough conditions. Conventionally, such tolerance phenotypes were engineered through evolutionary engineering using the principle of "Mutagenesis followed-by Selection". The iterative rounds of mutagenesis-selection and frequent manual interventions resulted in discontinuous and inefficient strain improvement processes. This work aimed to develop a more continuous and efficient evolutionary engineering method termed as "Genome Replication Engineering Assisted Continuous Evolution" (GREACE) using "Mutagenesis coupled-with Selection" as its core principle. RESULTS: The core design of GREACE is to introduce an in vivo continuous mutagenesis mechanism into microbial cells by introducing a group of genetically modified proofreading elements of the DNA polymerase complex to accelerate the evolution process under stressful conditions. The genotype stability and phenotype heritability can be stably maintained once the genetically modified proofreading element is removed, thus scarless mutants with desired phenotypes can be obtained.Kanamycin resistance of E. coli was rapidly improved to confirm the concept and feasibility of GREACE. Intrinsic mechanism analysis revealed that during the continuous evolution process, the accumulation of genetically modified proofreading elements with mutator activities endowed the host cells with enhanced adaptation advantages. We further showed that GREACE can also be applied to engineer n-butanol and acetate tolerances. In less than a month, an E. coli strain capable of growing under an n butanol concentration of 1.25% was isolated. As for acetate tolerance, cell growth of the evolved E. coli strain increased by 8-fold under 0.1% of acetate. In addition, we discovered that adaptation to specific stresses prefers accumulation of genetically modified elements with specific mutator strengths. CONCLUSIONS: We developed a novel GREACE method using "Mutagenesis coupled-with Selection" as core principle. Successful isolation of E. coli strains with improved n-butanol and acetate tolerances demonstrated the potential of GREACE as a promising method for strain improvement in biofuels production. PMID- 24070176 TI - Phonological facilitation of object naming in agrammatic and logopenic primary progressive aphasia (PPA). AB - Phonological processing deficits are characteristic of both the agrammatic and logopenic subtypes of primary progressive aphasia (PPA-G and PPA-L). However, it is an open question which substages of phonological processing (i.e., phonological word form retrieval, phonological encoding) are impaired in these subtypes of PPA, as well as how phonological processing deficits contribute to anomia. In the present study, participants with PPA-G (n = 7), participants with PPA-L (n = 7), and unimpaired controls (n = 17) named objects as interfering written words (phonologically related/unrelated) were presented at different stimulus onset asynchronies (SOAs) of 0, +100, +300, and +500 ms. Phonological facilitation (PF) effects (faster naming times with phonologically related interfering words) were found for the controls and PPA-L group only at SOA = 0 and +100 ms. However, the PPA-G group exhibited protracted PF effects (PF at SOA = 0, +100, and +300 ms). These results may reflect deficits in phonological encoding in PPA-G, but not in PPA-L, supporting the neuropsychological reality of this substage of phonological processing and the distinction between these two PPA subtypes. PMID- 24070177 TI - Protective effect of Pterostilbene against free radical mediated oxidative damage. AB - BACKGROUND: Pterostilbene, a methoxylated analog of Resveratrol, is gradually gaining more importance as a therapeutic drug owing to its higher lipophilicity, bioavailability and biological activity than Resveratrol. This study was undertaken to characterize its ability to scavenge free radicals such as superoxide, hydroxyl and hydrogen peroxide and to protect bio-molecules within a cell against oxidative insult. METHODS: Anti-oxidant activity of Pterostilbene was evaluated extensively by employing several in vitro radical scavenging/inhibiting assays and pulse radiolysis study. In addition, its ability to protect rat liver mitochondria against tertiary-butyl hydroperoxide (TBHP) and hydroxyl radical generated oxidative damage was determined by measuring the damage markers such as protein carbonyls, protein sulphydryls, lipid hydroperoxides, lipid peroxides and 8-hydroxy-2'-deoxyguanosine. Pterostilbene was also evaluated for its ability to inhibit *OH radical induced single strand breaks in pBR322 DNA. RESULT: Pterostilbene exhibited strong anti-oxidant activity against various free radicals such as DPPH, ABTS, hydroxyl, superoxide and hydrogen peroxide in a concentration dependent manner. Pterostilbene conferred protection to proteins, lipids and DNA in isolated mitochondrial fractions against TBHP and hydroxyl radical induced oxidative damage. It also protected pBR322 DNA against oxidative assault. CONCLUSIONS: Thus, present study provides an evidence for the strong anti-oxidant property of Pterostilbene, methoxylated analog of Resveratrol, thereby potentiating its role as an anti oxidant. PMID- 24070178 TI - Study of the mechanism of thermal chemical processes in the crystals of YAF tripeptides by means of mass spectrometry and solid state NMR. AB - Thermal reactions in two Tyr-Ala-Phe (YAF) tripeptide crystals with different molecular packing (monoclinic and hexagonal), distinct stereochemistry of central amino acid (D or L alanine) and specific arrangement of molecules in the crystal lattice (head-to-tail) were investigated. Samples were heated up to 180 degrees C, while the melting point for YAF crystals is above the 220 degrees C. Below the melting temperature, in both cases the chemical reactions leading to formation of cyclic dipeptides (YA diketopiperazine) and leaving of phenylalanine were observed. Two possible mechanisms of chemical reaction in the crystal lattice assuming intra- and/or intermolecular pathways were considered. (13)C and (15)N enriched YAF samples were employed to study of mechanism of solid state reactivity using mass spectrometry and advanced solid state NMR techniques (2D DARR (Dipolar Assisted Rotational Resonance) and 2D Double CP (Cross Polarization) correlations). PMID- 24070179 TI - Impact of caffeic acid addition on phenolic composition of tempranillo wines from different winemaking techniques. AB - The effect of prefermentative and postfermentative caffeic acid (CFA) addition, prefermentative cold maceration, and a simulation of the micro-oxygenation technique through acetaldehyde addition on the phenolic and color composition of Tempranillo wines was investigated. Cold soaking and dry ice addition were performed as prefermentative techniques. Wines were analyzed after the end of the malolactic fermentation and after 6 and 12 months' storage. The results showed an important effect in wines to which CFA had been added, suggesting intramolecular copigmentation reactions through direct interaction between anthocyanins and free phenolic acids, thereby increasing the acylated anthocyanin fraction with an increase in color stability. The higher concentration of total phenols and lower hue values in CFA-added wines also contributed to the stability of these compounds during storage. Prefermentative cold maceration was shown to be influenced by the vintage. Phenolic acids, the acylated anthocyanin fraction, and total phenolics showed higher values in CFA-added and acetaldehyde-added wines. No differences were found in color density between the control wines and both the prefermentative and postfermentative CFA-added wines. However, a higher anthocyanin polymeric fraction and higher acylated anthocyanins, phenolic acids, and total phenols were observed in the CFA-added wines. The implications of this for the color stability of Tempranillo are also discussed. PMID- 24070180 TI - Evaluating the impact of treatment for sleep/wake disorders on recovery of cognition and communication in adults with chronic TBI. AB - OBJECTIVE: To longitudinally examine objective and self-reported outcomes for recovery of cognition, communication, mood and participation in adults with traumatic brain injury (TBI) and co-morbid post-traumatic sleep/wake disorders. DESIGN: Prospective, longitudinal, single blind outcome study. SETTING: Community based. PARTICIPANTS: Ten adults with moderate-severe TBI and two adults with mild TBI and persistent symptoms aged 18-58 years. Six males and six females, who were 1-22 years post-injury and presented with self-reported sleep/wake disturbances with onset post-injury. INTERVENTIONS: Individualized treatments for sleep/wake disorders that included sleep hygiene recommendations, pharmacological interventions and/or treatments for sleep apnea with follow-up. MAIN OUTCOME MEASURES: Insomnia Severity Index, Beck Depression and Anxiety Inventories, Latrobe Communication Questionnaire, Speed and Capacity of Language Processing, Test of Everyday Attention, Repeatable Battery for the Assessment of Neuropsychological Status, Daily Cognitive-Communication and Sleep Profile. RESULTS: Group analysis revealed positive trends in change for each measure and across sub-tests of all measures. Statistically significant changes were noted in insomnia severity, p = 0.0003; depression severity, p = 0.03; language, p = 0.01; speed of language processing, p = 0.007. CONCLUSIONS: These results add to a small but growing body of evidence that sleep/wake disorders associated with TBI exacerbate trauma-related cognitive, communication and mood impairments. Treatment for sleep/wake disorders may optimize recovery and outcomes. PMID- 24070182 TI - Investigational drugs for onychomycosis. AB - INTRODUCTION: Onychomycosis is the fungal infection of the nail plate by dermatophytes, yeasts and nondermatophyte molds. The treatment of onychomycosis poses many challenges due to low initial cure rates and a high rate of relapse and recurrence. Oral therapy is limited by adverse events and drug-drug interactions, whereas topical therapy has limited penetrance through the nail plate. AREAS COVERED: New and reformulated drugs are in development for the treatment of onychomycosis. Experimental molecules include both oral and topical azole molecules, topical reformulations of terbinafine, the benzoxaboroles tavaborole and AN2718, the aganocide NVC-422 and the photosensitizer Sylsens B. These drugs are in varying stages of development so results from in vitro studies to Phase III clinical trials are discussed to present a complete picture of the current development pipeline for onychomycosis. EXPERT OPINION: The development of new molecules from familiar and novel classes for both oral and topical administration is encouraging. It is clear that there is currently more emphasis on the development of topical drugs than orals, due to their lower potential for adverse events and drug-drug interactions. The emergence of novel molecular targets is encouraging for the possibility of combination therapy and any future drug-resistant strains of fungi. PMID- 24070181 TI - Implementation of national guidelines, incorporated within structured diabetes and hypertension records at primary level care in Cape Town, South Africa: a randomised controlled trial. AB - BACKGROUND AND OBJECTIVES: Many clinical management guidelines for chronic diseases have been published, but they have not been put into practice by busy clinicians at primary care levels. This study evaluates the implementation of national guidelines incorporated within a structured diabetes and hypertension clinical record (SR) in Cape Town in a randomised controlled trial (RCT). METHODS: Eighteen public sector community health centres (CHC) were randomly selected and allocated as intervention or control CHC. At each clinic, 25 patients with diabetes and 35 patients with hypertension were enrolled at baseline. Questionnaires were completed, blood samples were collected, blood pressure (BP) and anthropometric measures were taken and patient records were audited. SR with clinical guideline prompts were introduced at the intervention clinics after training doctors in their use and suggestions to incorporate them in regular patient records. Contact was maintained during the year of intervention with the clinic staff. A follow-up survey was conducted 1 year later to assess BP and HbA1c, and the patient records were examined to ascertain the extent of use of the SR in the intervention clinics. In-depth interviews were conducted with doctors and nurses to record their response to the intervention. RESULTS: The intervention evaluated in this RCT had no impact on either diabetes or hypertension control. In the intervention clinics, less than 60% of the patient folders contained the SR and when present was seldom used. Although the staff were well disposed to the research team, their workload prohibited them from undertaking a true evaluation of the SR, and overall they did not perceive the SR as supporting their current process of patient care. CONCLUSIONS: No benefit to diabetes of hypertension care by introducing and availability of the staff in the use of the SR was shown in this RCT. The process measures suggest that the SR was not widely used by the healthcare provided in the primary care clinics. PMID- 24070183 TI - Expression of the gamma 2 chain of laminin-332 in eutopic and ectopic endometrium of patients with endometriosis. AB - BACKGROUND: Endometrial cells, which are shed by retrograde menstruation, may aberrantly express molecules involved in invasion and migration, leading to endometriosis. The aim of this study was to investigate the expression of the laminin gamma 2 chain (LAMC2) in the tissues of women with and without endometriosis. METHODS: Endometrial biopsy specimens were collected from healthy volunteers and from endometriosis patients. Biopsy specimens from the corresponding endometriotic lesions were also collected. The expression of laminin gamma 2 chain was evaluated by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Endometrial tissue from women with or without endometriosis showed constitutive expression of LAMC2 mRNA throughout the menstrual cycle. A higher mRNA level was observed in ectopic endometrium (Ec) from women with endometriosis compared with eutopic endometrium (Eu) from women with endometriosis. Immunohistochemistry revealed a varied pattern of laminin gamma 2 chain expression, with increased epithelial expression in eutopic endometrium from women with endometriosis compared with those without endometriosis. CONCLUSIONS: The altered expression of laminin gamma 2 chain in eutopic endometrium from women with endometriosis may provide new opportunities for diagnosis and treatment. PMID- 24070184 TI - How light-harvesting semiconductors can alter the bias of reversible electrocatalysts in favor of H2 production and CO2 reduction. AB - The most efficient catalysts for solar fuel production should operate close to reversible potentials, yet possess a bias for the fuel-forming direction. Protein film electrochemical studies of Ni-containing carbon monoxide dehydrogenase and [NiFeSe]-hydrogenase, each a reversible electrocatalyst, show that the electronic state of the electrode strongly biases the direction of electrocatalysis of CO2/CO and H(+)/H2 interconversions. Attached to graphite electrodes, these enzymes show high activities for both oxidation and reduction, but there is a marked shift in bias, in favor of CO2 or H(+) reduction, when the respective enzymes are attached instead to n-type semiconductor electrodes constructed from CdS and TiO2 nanoparticles. This catalytic rectification effect can arise for a reversible electrocatalyst attached to a semiconductor electrode if the electrode transforms between semiconductor- and metallic-like behavior across the same narrow potential range (<0.25 V) that the electrocatalytic current switches between oxidation and reduction. PMID- 24070186 TI - Protecting children from abuse: a neglected but crucial priority for the international child health agenda. PMID- 24070185 TI - Association between obesity and Barrett's esophagus in a Japanese population: a hospital-based, cross-sectional study. AB - BACKGROUND: The association between obesity and Barrett's esophagus (BE) in the Japanese population remains unclear. The prevalence of BE and its associated risk factors was examined. METHODS: A cross-sectional study of 1581 consecutive individuals who underwent upper gastrointestinal endoscopy was conducted. The prevalence of endoscopically suspected BE (ESBE) was evaluated. Obesity was evaluated by body mass index (BMI, >= 25 kg/m2) and waist circumference (WC) (males, >= 85 cm; females, >= 90 cm). Because endoscopic diagnosis of ultra-short ESBE (<1 cm in extent) is difficult and highly unreliable, this type of ESBE was excluded from the study. RESULTS: In proton pump inhibitor (PPI) non-users, the prevalence of ESBE >= 1 cm was 5.6%. In univariate analysis, male sex and reflux esophagitis (RE) were significantly associated with BE, but BMI, WC, and reflux symptoms were not. In multivariate logistic regression analysis, only RE (odds ratio [OR] = 3.48, 95% confidence interval [CI] 1.89-6.41, p < 0.0001) was an independent risk factor for BE; obesity and the other factors were not. In contrast, RE (OR 5.67, p = 0.0004) and large WC (OR 5.09, p = 0.0005) were significant risk factors for ESBE >= 1 cm in PPI users. Only male sex, but not obesity or the other risk factors, was associated with an increased risk of RE in patients not taking PPIs. CONCLUSIONS: RE, but not obesity, may have an independent association with the risk of ESBE in the Japanese population. Furthermore, obesity measures were not independent risks for RE. Interestingly, PPI-refractory RE and large WC were risk factors for ESBE >=1 cm in patients taking PPIs. PMID- 24070187 TI - 1,7-diazaspiro[5.5]undecane--a neglected heterocycle. AB - A convenient and simple three step synthesis of 1,7-diazaspiro[5.5]undecane via Claisen condensation and acid catalyzed decarboxylation and spirocyclization of N Boc-delta-valerolactam is described. Reactions of this spiroaminal with electrophiles including alkyl halides, alkane dihalides, acid chlorides, and sulfonyl chlorides gave either spirocyclic adducts or tetrahydropyridine derivatives. Additionally, the parent heterocycle is a novel bidentate ligand and formed complexes with ruthenium(II) and copper(II). PMID- 24070188 TI - A novel ruthenium(II)-polypyridyl complex inhibits cell proliferation and induces cell apoptosis by impairing DNA damage repair. AB - Ruthenium complexes are widely recognized as one of the most promising DNA damaging chemotherapeutic drugs. The main goal of this study was to explore the anticancer activity and underlying mechanisms of [Ru(phen)(2)(p BrPIP)](ClO(4))(2), a novel chemically synthesized ruthenium (Ru) complex. To this end, we employed MTT assays to determine the anticancer activity of the complex, and performed single-cell gel electrophoresis (SCGE) and Western blotting to evaluate DNA damage. Our results showed that the Ru(II)-poly complex caused severe DNA damage, possibly by downregulating key factors involved in DNA repair pathways, such as proliferating cell nuclear antigen (PCNA) and ring finger protein 8 (RNF8). In addition, this complex induced cell apoptosis by upregulating both p21 and p53. Taken together, our findings demonstrate that the Ru(II)-poly complex exhibits antitumour activity by inducing cell apoptosis, which results from the accumulation of large amounts of unrepaired DNA damage. PMID- 24070189 TI - Infrared, Raman, and ultraviolet absorption spectra and theoretical calculations and structure of 2,6-difluoropyridine in its ground and excited electronic states. AB - The infrared and Raman spectra of 2,6-difluoropyridine (26DFPy) along with ab initio and DFT computations have been used to assign the vibrations of the molecule in its S0 electronic ground state and to calculate its structure. The ultraviolet absorption spectrum showed the electronic transition to the S1(pi,pi*) state to be at 37,820.2 cm(-1). With the aid of ab initio computations the vibrational frequencies for this excited state were also determined. TD-B3LYP and CASSCF computations for the excited states were carried out to calculate the structures for the S1(pi,pi*) and S2(n,pi*) excited states. The CASSCF results predict that the S1(pi,pi*) state is planar and that the S2(n,pi*) state has a barrier to planarity of 256 cm(-1). The TD-B3LYP computations predict a barrier of 124 cm(-1) for the S1(pi,pi*) state, but the experimental results support the planar structure. Hypothetical models for the ring-puckering potential energy function were calculated for both electronic excited states to show the predicted quantum states. The changes in the vibrational frequencies in the two excited states reflect the weaker pi bonding within the pyridine ring. PMID- 24070191 TI - DNA nanotechnology: from sensing and DNA machines to drug-delivery systems. AB - DNA/nanoparticle hybrid systems combine the unique electronic and optical properties of nanomaterials with the recognition and catalytic properties of nucleic acids. These materials hold great promise for the development of new sensing platforms, the programmed organization of nanoparticles, the switchable control of plasmonic phenomena in the nanostructures, and the controlled delivery of drugs. In this Perspective, we summarize recent advances in the application of DNA/nanoparticle (NP) hybrids in these different disciplines. Nucleic acid semiconductor quantum dot hybrids are implemented to develop multiplexed sensing platforms for targeted DNA. The chemiluminescence resonance energy transfer mechanism is introduced as a new transduction signal, and the amplified detection of DNA targets through the biocatalytic regeneration of analytes is demonstrated. DNA machines consisting of catenanes or tweezers, and modified with fluorophore/Au NP pairs are used as functional devices for the switchable "mechanical" control of the fluorescence properties of the fluorophore. Also, nucleic acid nanostructures act as stimuli-responsive caps for trapping drugs in the pores of mesoporous SiO2 nanoparticles. In the presence of appropriate biomarker triggers, the pores are unlocked, leading to the controlled release of anticancer drugs. Selective cancer-cell death is demonstrated with the stimuli responsive SiO2 nanoparticles. PMID- 24070190 TI - Novel protein isoforms of carcinoembryonic antigen are secreted from pancreatic, gastric and colorectal cancer cells. AB - BACKGROUND: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is an oncofetal cell surface glycoprotein. Because of its high expression in cancer cells and secretion into serum, CEA has been widely used as a serum tumor marker. Although other members of CEACAM family were investigated for splice variants/variants-derived protein isoforms, few studies about the variants of CEACAM5 have been reported. In this study, we demonstrated the existence of novel CEACAM5 splice variants and splice variant-derived protein isoforms in gastrointestinal cancer cell lines. RESULTS: We identified two novel CEACAM5 splice variants in gastrointestinal (pancreatic, gastric, and colorectal) cancer cell lines. One of the variants possessed an alternative minor splice site that allowed generation of GC-AG intron. Furthermore, CEA protein isoforms derived from the novel splice variants were expressed in cancer cell lines and those protein isoforms were secreted into the culture medium. Although CEA protein isoforms always co-existed with the full-length protein, the secretion patterns of these isoforms did not correlate with the expression patterns. CONCLUSIONS: This is the first study to identify the expression of CEA isoforms derived from the novel splice variants processed on the unique splice site. In addition, we also revealed the secretion of those isoforms from gastrointestinal cancer cell lines. Our findings suggested that discrimination between the full-length and identified protein isoforms may improve the clinical utility of CEA as a tumor marker. PMID- 24070193 TI - In vivo optical imaging correlates with improvement of cerebral ischemia treated by intravenous bone marrow stromal cells (BMSCs) and edaravone. AB - OBJECTIVE: Recent studies show that modern In vivo optical imaging can detect matrix metallopeptidase (MMP) activation in the ischemic brain. In this study, we analyze the protective effects of bone marrow stromal cells (BMSCs) and edaravone (EDA) against tissue plasminogen activator (tPA) risk in the ischemic brain with In vivo optical fluorescence MMP imaging. METHODS: At 48 hours after 60 minutes of transient middle cerebral artery occlusion (tMCAO) with tPA, C57BL/6J mice were subjected to motor function analysis, In vivo and ex vivo optical imaging for MMP activation, gelatin zymography, and double immunofluorescent analyses with or without intravenous BMSC transplantation and the intravenous free radical scavenger EDA. RESULTS: In vivo fluorescent signals for MMP were detected over the heads of living mice 48 hours after tMCAO; the strongest were in the tPA group, which were reduced by BMSC or EDA treatment. These In vivo data were confirmed by ex vivo fluorescence imaging. While massive intracerebral hemorrhages were observed in the ischemic hemispheres of the tPA group, only slight hemorrhages were found in the tPA/BMSC, tPA/EDA, and EDA groups. Gelatin zymography showed the strongest MMP-9 activation in the tPA group after tMCAO, which was reduced by BMSC or EDA treatment. CONCLUSION: The present study provides a correlation between In vivo optical imaging of MMP activation and the improvement of ischemic brain damage caused by tPA after tMCAO and treated by BMSC and EDA. PMID- 24070195 TI - Mesenchymal stem cells from pediatric patients with aplastic anemia: isolation, characterization, adipogenic, and osteogenic differentiation. AB - Aplastic anemia is a syndrome of bone marrow (BM) failure characterized by peripheral pancytopenia and marrow hypoplasia. Its exact pathophysiology is still not clear. Mesenchymal stem cells (MSCs) play an important role in providing the specialized BM microenvironment for hematopoietic stem cells survival and differentiation. MSCs were isolated from BM of five patients with aplastic anemia and five controls. MSCs were characterized by morphology and immunophenotyping. Their viability, proliferative capacity, and adipogenic as well as osteogenic differentiation potentials were assessed. MSCs from aplastic anemia patients and controls shared similar spindle-shaped morphology and surface marker expression. MSCs derived from patients with aplastic anemia showed lower viability (74.2 +/- 4.44% vs. 97.0 +/- 1.58, p < 0.0001) and slower expansion rate as indicated by smaller population doubling and smaller cumulative population doubling from passages 1 to 4 (0.70 +/- 0.22 vs. 2.34 +/- 0.84; p = 0.009). Besides, aplastic anemia MSCs had poor capacity to differentiate into adipocytic and osteocytic lineages. PMID- 24070194 TI - Pint lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb repressive complex 2. AB - BACKGROUND: The p53 transcription factor is located at the core of a complex wiring of signaling pathways that are critical for the preservation of cellular homeostasis. Only recently it has become clear that p53 regulates the expression of several long intergenic noncoding RNAs (lincRNAs). However, relatively little is known about the role that lincRNAs play in this pathway. RESULTS: Here we characterize a lincRNA named Pint (p53 induced noncoding transcript). We show that Pint is aubiquitously expressed lincRNA that is finely regulated by p53. In mouse cells, Pint promotes cell proliferation and survival by regulating the expression of genes of the TGF-b, MAPK and p53 pathways. Pint is a nuclear lincRNA that directly interacts with the Polycomb repressive complex 2 (PRC2), and is required for PRC2 targeting of specific genes for H3K27 tri-methylation and repression. Furthermore, Pint functional activity is highly dependent on PRC2 expression. We have also identified Pint human ortholog (PINT), which presents suggestive analogies with the murine lincRNA. PINT is similarly regulated by p53, and its expression significantly correlates with the same cellular pathways as the mouse ortholog, including the p53 pathway. Interestingly, PINT is downregulated in colon primary tumors, while its overexpression inhibits the proliferation of tumor cells, suggesting a possible role as tumor suppressor. CONCLUSIONS: Our results reveal a p53 autoregulatory negative mechanism where a lincRNA connects p53 activation with epigenetic silencing by PRC2. Additionally, we show analogies and differences between the murine and human orthologs, identifying a novel tumor suppressor candidate lincRNA. PMID- 24070196 TI - Remediation of at-risk medical students: theory in action. AB - BACKGROUND: Previous work has shown that a programme that draws on a blend of theories makes a positive difference to outcomes for students who fail and repeat their first semester at medical school. Exploration of student and teacher perspectives revealed that remediation of struggling medical students can be achieved through a cognitive apprenticeship within a small community of inquiry. This community needs expert teachers capable of performing a unique combination of roles (facilitator, nurturing mentor, disciplinarian, diagnostician and role model), with high levels of teaching presence and practical wisdom. Yet, despite participants' convergent opinions on the elements of effective remediation, significant differences were found between outcomes of students working with experienced and inexperienced teachers. The current study explores the actual practice of teachers on this remediation course, aiming to exemplify elements of our theory of remediation and explore differences between teachers. METHODS: Since it is in the classroom context that the interactions that constitute the complex process of remediation emerge, this practice-based research has focused on direct observation of classroom teaching. Nineteen hours of small group sessions were recorded and transcribed. Drawing on ethnography and sociocultural discourse analysis, selected samples of talk-in-context demonstrate how the various elements of remediation play out in practice, highlighting aspects that are most effective, and identifying differences between experienced and novice teachers. RESULTS: Long-term student outcomes are strongly correlated to teacher experience (r, 0.81). Compared to inexperienced teachers, experienced teachers provide more challenging, disruptive facilitation, and take a dialogic stance that encourages more collaborative group dynamics. They are more expert at diagnosing cognitive errors, provide frequent metacognitive time-outs and make explicit links across the curriculum. CONCLUSIONS: Remediation is effective in small groups where dialogue is used for collaborative knowledge construction and social regulation. This requires facilitation by experienced teachers who attend to details of both content and process, and use timely interventions to foster curiosity and the will to learn. These teachers should actively challenge students' language use, logical inconsistencies and uncertainties, problematize their assumptions, and provide a metacognitive regulatory voice that can generate attitudinal shifts and nurture the development of independent critical thinkers. PMID- 24070197 TI - Zinc(II) interactions with brain-derived neurotrophic factor N-terminal peptide fragments: inorganic features and biological perspectives. AB - Brain-derived neurotrophic factor (BDNF) is a neurotrophin essential for neuronal differentiation, growth, and survival; it is involved in memory formation and higher cognitive functions. The N-terminal domain of BDNF is crucial for the binding selectivity and activation of its specific TrkB receptor. Zn(2+) ion binding may influence BDNF activity. Zn(2+) complexes with the peptide fragment BDNF(1-12) encompassing the sequence 1-12 of the N-terminal domain of BDNF were studied by means of potentiometry, electrospray mass spectrometry, NMR, and density functional theory (DFT) approaches. The predominant Zn(2+) complex species, at physiological pH, is [ZnL] in which the metal ion is bound to an amino, an imidazole, and two water molecules (NH2, N(Im), and 2O(water)) in a tetrahedral environment. DFT-based geometry optimization of the zinc coordination environment showed a hydrogen bond between the carboxylate and a water molecule bound to zinc in [ZnL]. The coordination features of the acetylated form [AcBDNF(1-12)] and of a single mutated peptide [BDNF(1-12)D3N] were also characterized, highlighting the role of the imidazole side chain as the first anchoring site and ruling out the direct involvement of the aspartate residue in the metal binding. Zn(2+) addition to the cell culture medium induces an increase in the proliferative activity of the BDNF(1-12) peptide and of the whole protein on the SHSY5Y neuroblastoma cell line. The effect of Zn(2+) is opposite to that previously observed for Cu(2+) addition, which determines a decrease in the proliferative activity for both peptide and protein, suggesting that these metals might discriminate and modulate differently the activity of BDNF. PMID- 24070198 TI - Intracerebral transplantation of adipose-derived mesenchymal stem cells alternatively activates microglia and ameliorates neuropathological deficits in Alzheimer's disease mice. AB - Recent studies suggest that transplantation of mesenchymal stem cells might have therapeutic effects in preventing pathogenesis of several neurodegenerative disorders. Adipose-derived mesenchymal stem cells (ADSCs) are a promising new cell source for regenerative therapy. However, whether transplantation of ADSCs could actually ameliorate the neuropathological deficits in Alzheimer's disease (AD) and the mechanisms involved has not yet been established. Here, we evaluated the therapeutic effects of intracerebral ADSC transplantation on AD pathology and spatial learning/memory of APP/PS1 double transgenic AD model mice. Results showed that ADSC transplantation dramatically reduced beta-amyloid (Abeta) peptide deposition and significantly restored the learning/memory function in APP/PS1 transgenic mice. It was observed that in both regions of the hippocampus and the cortex there were more activated microglia, which preferentially surrounded and infiltrated into plaques after ADSC transplantation. The activated microglia exhibited an alternatively activated phenotype, as indicated by their decreased expression levels of proinflammatory factors and elevated expression levels of alternative activation markers, as well as Abeta-degrading enzymes. In conclusion, ADSC transplantation could modulate microglial activation in AD mice, mitigate AD symptoms, and alleviate cognitive decline, all of which suggest ADSC transplantation as a promising choice for AD therapy. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation. PMID- 24070199 TI - Kinetics of action of a two-stage pro-inhibitor of serine beta-lactamases. AB - beta-Lactamase inhibitors are important in medicine in the protection of beta lactam antibiotics from beta-lactamase-catalyzed destruction. The most effective inhibitors of serine beta-lactamases covalently modify the enzyme active site. We have recently studied O-acyl and O-phosphyl hydroxamates as a new class of such inhibitors. In this paper, we describe our studies of the N-acyl derivatives of a cyclic O-acyl hydroxamic acid, 3H-benzo[d][1,2]oxazine-1,4-dione, and, in particular, the N-tert-butoxycarbonyl derivative. This compound is not a beta lactamase inhibitor itself but undergoes spontaneous hydrolysis in aqueous solution, yielding an O-phthaloyl hydroxamic acid, which is a beta-lactamase inhibitor. This compound spontaneously, but reversibly, cyclizes in solution to form phthalic anhydride, which is also a beta-lactamase inhibitor. Both inhibitors react to form the same transiently stable phthaloyl-enzyme complex. Thus, we have a two-step cascade, beginning with a pro-inhibitor, in which each step leads to a different inhibitor, presumably with different enzyme specificities. The kinetics of these transformations have been elucidated in detail. The phthaloyl derivatives, where the free carboxylate is important for facile reaction with the enzyme, represent a new lead for serine beta-lactamase inhibitors. Analogues can be conveniently constructed in situ by reaction of nucleophiles with phthalic anhydrides and then screened for activity. Active hits may then become new leads. PMID- 24070200 TI - Relaxation of bulk metallic glasses studied by mechanical spectroscopy. AB - The relaxational dynamics in metallic glasses (MGs) is investigated by using mechanical spectroscopy. The spectra show that in MGs there are two relaxations: (i) the alpha relaxation, linked to the glass transition, as observed in other classes of amorphous materials; and (ii) the beta relaxation, well observed below the glass transition, with an intensity strongly dependent on the MG composition, the nature of which has been linked to the local microstructure of MGs. For the investigated MGs we find that the intensity and relaxation time of the beta relaxation depends, in a reproducible fashion, on the thermal history of the samples. During aging experiments, the intensity decreases (as well as the taubeta) with a time dependence described well by a stretched exponential, with an exponent beta(aging) independent of the driving frequency. Moreover, we find that the activation energy Ubeta and the peak temperature Tbetap of the beta relaxation follow the approximate relationship: Ubeta ~ 31.5RTbetap (for driving frequency 1 Hz), indicating that the high temperature limit of the peak frequency is approximately the same for all the MGs investigated. Finally, the frequency separation of the alpha and beta processes in the mechanical loss spectra for La and Pd-based metallic glasses is tested against the prediction of the Coupling Model. PMID- 24070201 TI - Development and evaluation of an HPLC method for accurate determinations of enzyme activities of naringinase complex. AB - An HPLC method that can separate naringin, prunin, and naringenin was used to help accurately measure the activities of naringinase and its subunits (alpha-L rhamnosidase and beta-D-glucosidase). The activities of the naringinase and beta d-glucosidase were determined through an indirect calculation of the naringenin concentration to avoid interference from its poor solubility. The measured enzymatic activities of the naringinase complex, alpha-L-rhamnosidase, and beta-D glucosidase were the as same as their theoretical activities when the substrates' (i.e., naringin or prunin) concentrations were 200 MUg/mL, and the enzyme concentrations were within the range of 0.06-0.43, 0.067-0.53, and 0.15-1.13 U/mL, respectively. The beta-D-glucosidase had a much higher Vmax than either naringinase or alpha-L-rhamnosidase, implying the hydrolysis of naringin to prunin was the limiting step of the enzyme reaction. The reliability of the method was finally validated through the repeatability test, indicating its feasibility for the determinations of the naringinase complex. PMID- 24070202 TI - Complete staghorn calculus in polycystic kidney disease: infection is still the cause. AB - BACKGROUND: Kidney stones in patients with autosomal dominant polycystic kidney disease are common, regarded as the consequence of the combination of anatomic abnormality and metabolic risk factors. However, complete staghorn calculus is rare in polycystic kidney disease and predicts a gloomy prognosis of kidney. For general population, recent data showed metabolic factors were the dominant causes for staghorn calculus, but for polycystic kidney disease patients, the cause for staghorn calculus remained elusive. CASE PRESENTATION: We report a case of complete staghorm calculus in a polycystic kidney disease patient induced by repeatedly urinary tract infections. This 37-year-old autosomal dominant polycystic kidney disease female with positive family history was admitted in this hospital for repeatedly upper urinary tract infection for 3 years. CT scan revealed the existence of a complete staghorn calculus in her right kidney, while there was no kidney stone 3 years before, and the urinary stone component analysis showed the composition of calculus was magnesium ammonium phosphate. CONCLUSION: UTI is an important complication for polycystic kidney disease and will facilitate the formation of staghorn calculi. As staghorn calculi are associated with kidney fibrosis and high long-term renal deterioration rate, prompt control of urinary tract infection in polycystic kidney disease patient will be beneficial in preventing staghorn calculus formation. PMID- 24070203 TI - The impact and treatment of allergic rhinitis in the Middle East: a comparison with the landmark allergy surveys from other worldwide regions. AB - BACKGROUND: Allergic rhinitis is a global health problem that significantly affects quality of life. It is associated with illness, disability, health care costs, and comorbidities such as asthma. METHODS: Between 2006 and 2011, a series of patient surveys were conducted covering the United States, Asia-Pacific, Latin America, and the Middle East. This article compares data regarding disease burden, treatment patterns, and patient expectations in Middle Eastern countries with those from other regions. RESULTS: The surveys highlighted the relatively low use of intranasal corticosteroids (INCSs), the current "gold standard" treatment for allergic rhinitis. This may be because of side effects, lack of efficacy, or reduced effectiveness over time. A higher proportion of patients in the Middle East reported bothersome side effects of their prescription nasal sprays, and a higher proportion of these patients strongly agreed that there were no truly effective treatments for allergic rhinitis. This suggests that health care practitioners in the Middle East should be encouraged to explain the use of INCSs in greater depth to their patients. CONCLUSION: There remains an unmet need in the treatment of nasal allergies worldwide. The allergy surveys highlight the key factors in choosing an INCS: fast, complete, and long-lasting symptom relief. There is opportunity for novel INCS treatments that address these needs while reducing troublesome side effects. Patient education must play a central role in treatment decision making, particularly in the Middle East, to achieve higher patient satisfaction. PMID- 24070204 TI - Your injury, my accident: talking at cross-purposes in rehabilitation after traumatic brain injury. AB - PRIMARY OBJECTIVE: To explore how traumatic brain injury (TBI) rehabilitation staff and adults who have sustained TBI refer during clinical interaction to the precipitating event. DESIGN: Interviews conducted during the initial assessment phase of TBI rehabilitation were examined using Conversation Analysis. PARTICIPANTS: Participants were nine men and one woman, all of whom had sustained TBI of sufficient severity to warrant referral for community rehabilitation. Age range was 24-50 years (mean 35 years). The period between injury and interview was between 9 months and 20 years. MAIN OUTCOMES AND RESULTS: Analysis of interactions between rehabilitation staff and people with TBI indicated discrepancies in the way they refer to the original event. Staff tended to use 'head/brain injury' in contrast to the use by people with TBI of 'accident/crash'. There were also differences of expression in terms of 'ownership' (e.g., your injury vs. the injury) and 'agency' (the degree to which the person with TBI was portrayed as having been part of the process of sustaining the TBI). CONCLUSION: The implications of these discrepancies are discussed in relation to self-identity and insight after TBI. The possible impact of this terminological tension on the rehabilitation process is also discussed. PMID- 24070205 TI - The potential of sunitinib as a therapy in ovarian cancer. AB - INTRODUCTION: Sunitinib malate (SU11248; Sutent(r); Pfizer, Inc., New York) is a multi-kinase inhibitor currently approved for use in advanced renal cell carcinoma (RCC), imatinib-resistant/-intolerant gastrointestinal stromal tumours and progressive, well-differentiated pancreatic neuroendocrine tumours in patients with unresectable, locally advanced or metastatic disease. AREAS COVERED: This article describes the mechanism of action and of the pharmacokinetics of sunitinib; further, it summarizes Phase I and II trials on the clinical efficacy, tolerability and safety of this agent in the setting of ovarian cancer (OC) treatment. EXPERT OPINION: On the basis of the current literature, sunitinib has shown modest antitumour activity and acceptable toxicity. Studies investigating the impact of horizontal and vertical combinations should represent a priority of future research. Although clinical Phase II trials on the use of sunitinib in the treatment of OC demonstrated an acceptable profile of AEs, a greater comprehension of the toxicity of this compound is recommended. PMID- 24070206 TI - Malaria and artemisinin derivatives: an updated review. AB - Malaria is the world's most prevalent disease that affects 515-600 million people each year and about 40% of the world's population live at risk for this infection. The prevalence of morbidity and mortality from drug resistant malaria (Plasmodium falciparum) is increasing in most of the developing countries, which is also a global threat because international travel is common now and imported malaria is increasingly a serious problem. Since rapid schizonticidal action of naturally occurring endoperoxides pharmacophore present in artemisinin against drug-resistant malaria has been documented, researchers have focused more on artemisinin analogs than any other antimalarials. In this review, drugs of choice about malaria i.e. artemisinin and its analogus/derivatives (arteether, artemether, artemiside, artemisinin, artemisone, artesunate, dihydroartemisinin) have been discussed in detail e.g. bioavailability, formulation development, stability, combination therapy, additional benefits, drug resistance and toxicity have been reviewed. PMID- 24070207 TI - Resorcylic acid lactones as the protein kinase inhibitors , naturally occuring toxins. AB - Resorcylic acid lactones (RALs) are polyketide natural products with a large macrocyclic ring fused to a resorcylic acid residue. Some RALs contain an alpha,beta-unsaturated ketone in the macrocycle. So far 46 kinases have been identified that could be potentially targeted by this family of compounds. RALs are of interest for their modulation of growth, and tentatively for the treatment of cancer and neurodegenerative diseases. RALs containing a cis-enone are susceptible to Michael addition reactions with the cysteine residue in the kinase nucleotide binding site, and thus serve as potent inhibitors of several protein kinases - they therefore represent a unique pharmacophore. Notably, this moiety has been shown to be effective also in vivo. This mini-review focuses on the structure and biological effects of the most important RALs, namely zearalenone, hypothemycin, pochonins, lasiodiplodins, aigialomycins, cochlicomycins, zaenols, and paecilomycins. Finally, the review also deals with radicicol, which is a nanomolar inhibitor of the chaperone Hsp90, whose suppression leads to a combinatorial block of cancer-causing pathways. PMID- 24070208 TI - 2-Aminoimidazoles in medicinal chemistry. AB - 2-Aminoimidazole skeleton represents a unique building block which is often used in the design of modulators of different targets and small molecule drugs. Alkaloids isolated from marine sponges are known to be one of the most common sources of the 2-aminoimidazole compounds and from a medicinal chemistry perspective, the marine alkaloids' fascinating structures as well as their broad spectrum of pharmacological activity make them promising lead compounds for various druggable targets. This review will focus on the presentation of biologically evaluated 2-aminoimidazole compounds showing a variety of pharmacological properties and their structure-activity relationship. The importance of 2-aminoimidazoles as bioisosteres of guanidine, acylguanidine, benzamidine and triazole groups will be highlighted. PMID- 24070209 TI - Targeting heat shock protein 90 for malaria. AB - Heat shock protein 90 (Hsp90), an ATP-dependent molecular chaperone, is a highly conserved and ubiquitously expressed stress protein in eukaryotes. It is responsible for activation of various proteins involved in signal transduction, cell cycle control, hormone signaling, and transcription. Anomalous expression of this family can be associated with several disease states. Current article focuses on the novel use of Hsp90 inhibitors as antimalarial agents. The present armamentarium of antimalarial therapy is not proving itself as an adequate treatment to eradicate malaria completely. This inadequacy is mainly due to the increasing drug resistance rate in Plasmodium species. The parasite Plasmodium falciparum requires Hsp90 (Pfhsp90) for regulating its development. Analysis of PfHsp90 function suggests that it regulates parasite development during the frequent febrile episodes that are characteristic of malaria. This crucial role of Hsp90 in the growth and development of the parasite has attracted many researchers as a potential target for malaria and other infectious diseases. Currently there are about seven antimalarial and more than thirty anticancer Hsp90 inhibitors in various phases of drug development. Addition of alternatives with novel mechanism to the current treatment armoury may eventually help improve the outcomes of malaria. It is prudent to remain optimistic as the research in this field continues to evolve. PMID- 24070210 TI - Copper complexes of bioactive ligands with superoxide dismutase activity. AB - Free radicals or reactive oxygen species (ROS) are highly toxic and their damaging effects result in a variety of detrimental health issues such as neurodegenerative, cardiovascular and age-related diseases. Human body has evolved an effective defense system including superoxide dismutase (SOD) and catalase against the toxicity of these free radicals. SOD is a metalloenzyme and it acts as an excellent antioxidant to protect the body from superoxide radicals that are generated in the biological system. However, the clinical use of SOD is limited due to its short in vivo life span, and its large size that hampered its penetration across the cell membranes. Pharmaceuticals that provide ROS scavenging systems are the most effective when the production of ROS exceeds the scavenging capacity of endogenous SOD as a result of aging or pathological processes. Inspired by the Nature, scientists have designed metal-based mimics of the superoxide dismutase. This review focuses on different copper complexes that are developed from bioactive ligands and mimic the protecting action of the SOD. PMID- 24070212 TI - Dual bonding between H2O/H2S and AgCl/CuCl: Cu/Ag bond, sister bond to Au bond. AB - Recently, Legon et al. reported the first generation and characterization of H2O/H2S...AgCl complexes by rotational spectroscopy and proposed whether there is a silver bond analogous to the more familiar hydrogen and halogen bonds. In this study, a theoretical investigation was performed to answer this question and to deepen the nature of intermolecular interactions for H2O/H2S...M-Cl (M = Cu, Ag, and Au) complexes. NBO analyses reveal that two types of delocalization interactions coexist in these complexes. Apart from the expected sigma-donation interaction, the hyperconjugation interaction between H2O/H2S and M-Cl also takes part in the bonding. On the basis of such a dual-bonding mechanism, one class of bond, termed Cu/Ag bond, was defined in this study. In addition, the topological properties at a bond critical point, binding energies, and stretching frequency shifts studied here support that Cu/Ag bond is a sister bond to Au bond put forward previously by Sadlej et al. The Cu/Ag/Au bond is partially covalent and partially electrostatic in nature. Finally, the dual-bonding mechanism of Cu/Ag/Au bond was further discussed. This dual-bonding scheme may be considered a new synergistic bonding model for coordination compounds. PMID- 24070211 TI - Bone regeneration potential of stem cells derived from periodontal ligament or gingival tissue sources encapsulated in RGD-modified alginate scaffold. AB - Mesenchymal stem cells (MSCs) provide an advantageous alternative therapeutic option for bone regeneration in comparison to current treatment modalities. However, delivering MSCs to the defect site while maintaining a high MSC survival rate is still a critical challenge in MSC-mediated bone regeneration. Here, we tested the bone regeneration capacity of periodontal ligament stem cells (PDLSCs) and gingival mesenchymal stem cells (GMSCs) encapsulated in a novel RGD- (arginine-glycine-aspartic acid tripeptide) coupled alginate microencapsulation system in vitro and in vivo. Five-millimeter-diameter critical-size calvarial defects were created in immunocompromised mice and PDLSCs and GMSCs encapsulated in RGD-modified alginate microspheres were transplanted into the defect sites. New bone formation was assessed using microcomputed tomography and histological analyses 8 weeks after transplantation. Results confirmed that our microencapsulation system significantly enhanced MSC viability and osteogenic differentiation in vitro compared with non-RGD-containing alginate hydrogel microspheres with larger diameters. Results confirmed that PDLSCs were able to repair the calvarial defects by promoting the formation of mineralized tissue, while GMSCs showed significantly lower osteogenic differentiation capability. Further, results revealed that RGD-coupled alginate scaffold facilitated the differentiation of oral MSCs toward an osteoblast lineage in vitro and in vivo, as assessed by expression of osteogenic markers Runx2, ALP, and osteocalcin. In conclusion, these results for the first time demonstrated that MSCs derived from orofacial tissue encapsulated in RGD-modified alginate scaffold show promise for craniofacial bone regeneration. This treatment modality has many potential dental and orthopedic applications. PMID- 24070213 TI - Downregulation of KPNA2 in non-small-cell lung cancer is associated with Oct4 expression. AB - BACKGROUND: Oct4 is a major transcription factor related to stem cell self renewal and differentiation. To fulfill its functions, it must be able to enter the nucleus and remain there to affect transcription. KPNA2, a member of the karyopherin family, plays a central role in nucleocytoplasmic transport. The objective of the current study was to examine the association between Oct4 and KPNA2 expression levels with regard to both the clinicopathological characteristics and prognoses of patients with non-small-cell lung cancer (NSCLC). METHODS: Immunohistochemistry was used to detect the expression profile of Oct4 and KPNA2 in NSCLC tissues and adjacent noncancerous lung tissues. Real time polymerase chain reaction and western blotting were used to detect the mRNA and protein expression profiles of Oct4 and KPNA2 in lung cancer cell lines. Small interfering RNAs were used to deplete Oct4 and KPNA2 expressions. Double immunofluorescence was used to detect Oct4 expression in KPNA2 knockdown cells. Co-immunoprecipitation was used to detect the interaction of Oct4 and KPNA2. RESULTS: Oct4 was overexpressed in 29 of 102 (28.4%) human lung cancer samples and correlated with differentiation (P = 0.002) and TNM stage (P = 0.003). KPNA2 was overexpressed in 56 of 102 (54.9%) human lung cancer samples and correlated with histology (P = 0.001) and differentiation (P = 0.045). Importantly, Oct4 and KPNA2 expression levels correlated significantly (P < 0.01). Expression of Oct4 and KPNA2 was associated with short overall survival. In addition, depleting Oct4 and KPNA2 expression using small interfering RNAs inhibited proliferation in lung cancer cell lines. Real-time polymerase chain reaction and western blotting analysis indicated that reduction of KPNA2 expression significantly reduced mRNA and nucleoprotein levels of Oct4. Double immunofluorescence analysis revealed that nuclear Oct4 signals were reduced significantly in KPNA2 knockdown cells. Co immunoprecipitation experiments revealed that KPNA2 interacts with Oct4 in lung cancer cell lines. CONCLUSION: Oct4 and KPNA2 play an important role in NSCLC progression. Oct4 nuclear localization may be mediated by its interaction with KPNA2. PMID- 24070214 TI - What is sexual satisfaction? Thematic analysis of lay people's definitions. AB - Sexual satisfaction is an important indicator of sexual health and is strongly associated with relationship satisfaction. However, research exploring lay definitions of sexual satisfaction has been scarce. We present thematic analysis of written responses of 449 women and 311 men to the question "How would you define sexual satisfaction?" The participants were heterosexual individuals with a mean age of 36.05 years (SD = 8.34) involved in a committed exclusive relationship. In this exploratory study, two main themes were identified: personal sexual well-being and dyadic processes. The first theme focuses on the positive aspects of individual sexual experience, such as pleasure, positive feelings, arousal, sexual openness, and orgasm. The second theme emphasizes relational dimensions, such as mutuality, romance, expression of feelings, creativity, acting out desires, and frequency of sexual activity. Our results highlight that mutual pleasure is a crucial component of sexual satisfaction and that sexual satisfaction derives from positive sexual experiences and not from the absence of conflict or dysfunction. The findings support definitions and models of sexual satisfaction that focus on positive sexual outcomes and the use of measures that incorporate items linked to personal and dyadic sexual rewards for both men and women. PMID- 24070215 TI - Genome sequencing reveals fine scale diversification and reticulation history during speciation in Sus. AB - BACKGROUND: Elucidating the process of speciation requires an in-depth understanding of the evolutionary history of the species in question. Studies that rely upon a limited number of genetic loci do not always reveal actual evolutionary history, and often confuse inferences related to phylogeny and speciation. Whole-genome data, however, can overcome this issue by providing a nearly unbiased window into the patterns and processes of speciation. In order to reveal the complexity of the speciation process, we sequenced and analyzed the genomes of 10 wild pigs, representing morphologically or geographically well defined species and subspecies of the genus Sus from insular and mainland Southeast Asia, and one African common warthog. RESULTS: Our data highlight the importance of past cyclical climatic fluctuations in facilitating the dispersal and isolation of populations, thus leading to the diversification of suids in one of the most species-rich regions of the world. Moreover, admixture analyses revealed extensive, intra- and inter-specific gene-flow that explains previous conflicting results obtained from a limited number of loci. We show that these multiple episodes of gene-flow resulted from both natural and human-mediated dispersal. CONCLUSIONS: Our results demonstrate the importance of past climatic fluctuations and human mediated translocations in driving and complicating the process of speciation in island Southeast Asia. This case study demonstrates that genomics is a powerful tool to decipher the evolutionary history of a genus, and reveals the complexity of the process of speciation. PMID- 24070218 TI - Silica-coated gold nanorod arrays for nanoplasmonics devices. AB - A facile method for growing silica layer on lithographically designed gold nanorod arrays (GNRAs) using a convenient sol-gel method is presented herein. The silica layer thickness was controlled on GNRAs with the reaction time. The localized surface plasmon resonance (LSPR) spectra of these hybrid metal/dielectric nanoparticles were recorded before and after the coating and the effect of different solvents on the LSPR were also assessed. The change in the fluorescence and SERS intensities of a probe molecule (Rh6G) deposited on GNRAs and silica-coated GNRAs revealed that the as-fabricated silica layer does inhibit the quenching of molecular excited states and enhances photophysical/photochemical processes. This kind of hybrid metal/dielectric nanoparticle arrays hence turn out to be real good candidates to design new "plasmonic-active" devices. PMID- 24070216 TI - Stereocontrol in asymmetric gamma-lactam syntheses from imines and cyanosuccinic anhydrides. AB - Computations (SCS-MP2//B3LYP) reveal that the asymmetric synthesis of highly substituted gamma-lactams with three stereogenic centers, including one quaternary center, proceeds through a Mannich reaction between the enol form of the anhydride and the E-imine, followed by a transannular acylation. This new mechanistic picture accounts for both the observed reactivity and stereoselectivity. CH-O and hydrogen bonding interactions in the Mannich step and torsional steering effects in the acylation step are responsible for stereocontrol. It is demonstrated that this new mechanistic picture applies to the related reactions of homophthalic anhydrides with imines and presents new vistas for the design of a new reaction to access complex molecular architectures. PMID- 24070217 TI - Sleep medicine education and knowledge among medical students in selected Saudi Medical Schools. AB - BACKGROUND: Limited information is available regarding sleep medicine education worldwide. Nevertheless, medical education has been blamed for the under recognition of sleep disorders among physicians. This study was designed to assess the knowledge of Saudi undergraduate medical students about sleep and sleep disorders and the prevalence of education on sleep medicine in medical schools as well as to identify the obstacles to providing such education. METHODS: We surveyed medical schools that were established more than 10 years ago, asking fourth- and fifth-year medical students (men and women) to participate. Seven medical schools were selected. To assess knowledge on sleep and sleep disorders, we used the Assessment of Sleep Knowledge in Medical Education (ASKME) Survey, which is a validated 30-item questionnaire. The participants were separated into two groups: those who scored >=60% and those who scored <60%. To assess the number of teaching hours dedicated to sleep medicine in the undergraduate curricula, the organizers of the major courses on sleep disorders were contacted to obtain the curricula for those courses and to determine the obstacles to education. RESULTS: A total of 348 students completed the survey (54.9% male). Among the participants, 27.7% had a specific interest in sleep medicine. More than 80% of the study sample had rated their knowledge in sleep medicine as below average. Only 4.6% of the respondents correctly answered >=60% of the questions. There was no difference in the scores of the respondents with regard to university, gender, grade-point average (GPA) or student academic levels. Only five universities provided data on sleep medicine education. The time spent teaching sleep medicine in the surveyed medical schools ranged from 0 8 hours with a mean of 2.6 +/-2.6 hours. Identified obstacles included the following: (1) sleep medicine has a lower priority in the curriculum (53%) and (2) time constraints do not allow the incorporation of sleep medicine topics in the curriculum (47%). CONCLUSIONS: Medical students in the surveyed institutions possess poor knowledge regarding sleep medicine, which reflects the weak level of education in this field of medicine. To improve the recognition of sleep disorders among practicing physicians, medical schools must provide adequate sleep medicine education. PMID- 24070219 TI - Surgical management of ichtyosis-related ectropion. Description of four cases and a literature review. AB - Ichtyosis is an heterogeneous group of diseases characterized by formation of hyperkeratotic, squamous, tile-like scales virtually on the whole body. Depending on the severity and localization of the symptoms, the disease may lead to serious complications including ectropion of the eyelids, which may further lead to ocular disorders, including blindness. The aim of the work was to outline major characteristics of the entity and to focus on surgical methods of ichtyosis related eyelid ectropion management. Four cases of ichtyosis-related eyelid ectropion, which occurred in patients presenting severe symptoms of the disease treated surgically in the clinic between 2003-2011, were described. In all patients the eyelid contractures were successfully released and relief of conjunctival inflammation was obtained. No postoperative complications occurred. In two patients, a secondary operation was necessary due to skin graft contracture and ectropion recurrence. In some cases, ichtyosis may lead to serious ocular complications. Surgical management of eyelid ectropion is challenging due to the shortage of available lesion-free skin for grafting and due to possible skin graft contracture leading to recurrence. PMID- 24070220 TI - Encephalocraniocutaneous lipomatosis: congenital alopecia treatment in a rare neurocutaneous syndrome. AB - Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous syndrome that include skin, ocular, and neurological disorders. This study describes the case of a 16-year-old girl that came to observation for the treatment of a congenital alopecia causing great psychological distress. After two expansion procedures the hairless patch was restored with high patient satisfaction. The case met all the criteria for definite diagnosis of ECCL. PMID- 24070221 TI - The prevalence of isolated systolic hypertension in adult populations from the Han, Uygur and Kazakh ethnic groups in Xinjiang, China. AB - OBJECTIVES: To estimate the current prevalence and epidemiology of isolated systolic hypertension (ISH) among adult populations from different ethnic groups in Xinjiang province and to further establish a theoretical basis for developing personalized therapeutic strategies for hypertensive populations. METHODS: To analyze the prevalence and risk factors of ISH in different ethnic groups in Xinjiang province, a cluster sampling method was adopted to conduct a cross sectional study on people aged 35 years and older from the Han, Uygur and Kazakh populations in the Urumqi, Kelamayi, Hetian, Zhaosu, Fukang, Tulufan and Fuhai. RESULTS: A total of 14,618 adults were surveyed with a response rate of 88.80%. The overall prevalence of ISH was 11.95% (men: 10.84% vs women: 12.92%); the prevalence of ISH in women was significantly higher (chi(2) = 15.06, p = 0.00) than that in men. The prevalence varied significantly with age (chi(2) = 822.71, p = 0.00) and increased in the elderly (chi(2) = 769.59, p = 0.00). A logistic regression analysis revealed that age, obesity, diabetes and dyslipidemia are major risk factors for ISH; patients with hypertension combined with obesity or diabetes are at a high risk of ISH. CONCLUSIONS: The prevalence of ISH in Xinjiang is higher than average and exhibits a gender difference. There is a trend of increased prevalence with increasing age. Populations with obesity, diabetes or dyslipidemia, and patients who have hypertension combined with obesity and/or diabetes, should be aware of early preventive interventions. PMID- 24070222 TI - Zirconium tungstate/epoxy nanocomposites: effect of nanoparticle morphology and negative thermal expansivity. AB - The ability to tailor the coefficient of thermal expansion (CTE) of a polymer is essential for mitigating thermal residual stress and reducing microcracks caused by CTE mismatch of different components in electronic applications. This work studies the effect of morphology and thermal expansivity of zirconium tungstate nanoparticles on the rheological, thermo-mechanical, dynamic-mechanical, and dielectric properties of ZrW2O8/epoxy nanocomposites. Three types of ZrW2O8 nanoparticles were synthesized under different hydrothermal conditions and their distinct properties were characterized, including morphology, particle size, aspect ratio, surface area, and CTE. Nanoparticles with a smaller particle size and larger surface area led to a more significant reduction in gel-time and glass transition temperature of the epoxy nanocomposites, while a higher initial viscosity and significant shear thinning behavior was found in prepolymer suspensions containing ZrW2O8 with larger particle sizes and aspect ratios. The thermo- and dynamic-mechanical properties of epoxy-based nanocomposites improved with increasing loadings of the three types of ZrW2O8 nanoparticles. In addition, the introduced ZrW2O8 nanoparticles did not negatively affect the dielectric constant or the breakdown strength of the epoxy resin, suggesting potential applications of ZrW2O8/epoxy nanocomposites in the microelectronic insulation industry. PMID- 24070223 TI - Synthesis of optically pure 3,3'-diaryl binaphthyl disulfonic acids via stepwise N-S bond cleavage. AB - We developed a practical synthesis of optically pure 3,3'-diaryl-1,1'-binaphthyl 2,2'-disulfonic acids (i.e., (R)- or (S)-3,3'-Ar2-BINSAs) from the parent chiral sulfonimides via stepwise N-S bond cleavage of the sulfonimides and the resultant sulfonamides. This unusual synthesis, which provides arylsulfonic acids from arylsulfonamides, is valuable since common methods particularly give amines with the decomposition of sulfone groups during deprotection. PMID- 24070224 TI - Resting metabolic rate in obese diabetic and obese non-diabetic subjects and its relation to glycaemic control. AB - BACKGROUND: Both obesity and type II diabetes mellitus are associated with insulin resistance and abnormal metabolic reactions. This study was conducted to evaluate resting metabolic rate in obese diabetic patients and to assess its relation to glycaemic control. RESULTS: This is a case control study conducted in Gabir AbuEliz centre in Khartoum, Sudan. A random sample of 40 obese diabetic patients (cases) and 40 obese non-diabetic subjects (controls) were interviewed and examined clinically to exclude presence of acute or chronic medical illness. Haemoglobin A1c was measured for each participant using the "NycoCard Haemoglobin A1c test" (Axis -Shield/ Norway). Fasting blood sugar was measured using one touch(R) glucometer (LifeScan Canada Ltd). The PowerLab 8/35 with a gas analyzer (AD Instruments, Castle Hill Australia) was used for measurement of VO2, VCO2 and Respiratory exchange ratio (RER). Resting metabolic rate was calculated using the Weir equation. VO2 (mean+/-SD) ml/min was significantly higher among cases (209.9+/-42.7) compared to the controls (192.4+/-28.1), (P = 0.034). Similarly, VCO2 (mean+/-SD) ml/min was higher among cases (191.4+/-35.0) than controls (178.3+/-22.5), (P = 0.05). Resting metabolic rate "RMR" (mean+/-SD) kcal/day was higher in obese diabetic patients (1480.7 +/- 274.2) than obese non-diabetic subjects (1362.4+/- 184.8), (P = 0.027). Participants with high glycated haemoglobin had higher RMR than those with normal glycated haemoglobin (P = 0.016). CONCLUSION: It is concluded that resting metabolic rate is significantly higher in obese diabetic patients compared to obese non-diabetics, especially in those with poor glycaemic control. PMID- 24070225 TI - The experience of acculturative stress-related growth from immigrants' perspectives. AB - Previous literature has mainly focused on the positive effects of stress associated with disability and illness, called stress-related growth. Little research has explored positive changes as a result of acculturative stress among a group of immigrants. In particular, older Asian immigrants may experience a high level of stress related to acculturation because they may face more challenges to adapt to and navigate a new culture. This study was designed to capture the characteristics of stress-related growth associated with acculturative stress. Using in-depth interviews among 13 older Korean immigrants, three main themes associated with the stress-coping strategies were identified: (a) the development of mental toughness, (b) engagement in meaningful activities, and (c) promotion of cultural understanding. These themes indicate that by following the stressful acculturation process, participants developed a better understanding of the new culture, engaged in various leisure activities, and enhanced mental strength. This finding provides information on how immigrants deal with acculturative stress and have positive psychological changes, which results in a sense of happiness and psychological well-being. PMID- 24070226 TI - Early predictors of remission in newly diagnosed epilepsy: a systematic approach to reviewing prognostic factor studies. AB - BACKGROUND: It is necessary to select a range of consistently identified prognostic factors from exploratory studies to include in multivariate models of confirmatory studies. We illustrate a systematic approach to selecting consistently identified prognostic factors using the example of predictors of remission in newly diagnosed epilepsy. METHODS: Medline and Embase were searched for reports of cohort studies enrolling at least 100 people with epilepsy within 1 year of diagnosis, and followed up for at least 1 year. We included studies that identified predictors of remission after adjusting for confounders using multivariate regression analysis. To identify consistent predictors a chart was designed to list the variables considered for inclusion in each model and those retained in more than one model from different cohorts were deemed to be consistent. RESULTS: Remission off medication was less likely if there was more than one seizure between 6 and 12 months on medication and if there was comorbid intellectual disability in childhood onset epilepsy. The likelihood of remission on or off medication reduces with mixed seizure types at onset, intellectual disability, symptomatic aetiology, and also with increasing number of seizures before diagnosis or in the first 6 months after diagnosis. CONCLUSION: A greater number of seizures before diagnosis and early in treatment, intellectual disability, and symptomatic aetiology are consistent predictors of less likelihood of remission. This suggests that early identification, diagnosis of epilepsy, and seizure control should be the primary aim of medical intervention, and that these predictors should be included in future confirmatory studies of prognostic factors of remission in newly diagnosed epilepsy. PMID- 24070227 TI - Variation in caffeine concentration in single coffee beans. AB - Twenty-eight coffee samples from around the world were tested for caffeine levels to develop near-infrared reflectance spectroscopy (NIRS) calibrations for whole and ground coffee. Twenty-five individual beans from five of those coffees were used to develop a NIRS calibration for caffeine concentration in single beans. An international standard high-performance liquid chromatography method was used to analyze for caffeine content. Coffee is a legal stimulant and possesses a number of heath properties. However, there is variation in the level of caffeine in brewed coffee and other caffeinated beverages. Being able to sort beans on the basis of caffeine concentration will improve quality control in the level of caffeine in those beverages. The range in caffeine concentration was from 0.01 mg/g (decaffeinated coffee) to 19.9 mg/g (Italian coffee). The majority of coffees were around 10.0-12.0 mg/g. The NIRS results showed r(2) values for bulk unground and ground coffees were >0.90 with standard errors <2 mg/g. For the single-bean calibration the r(2) values were between 0.85 and 0.93 with standard errors of cross validation of 0.8-1.6 mg/g depending upon calibration. The results showed it was possible to develop NIRS calibrations to estimate the caffeine concentration of individual coffee beans. One application of this calibration could be sorting beans on caffeine concentration to provide greater quality control for high-end markets. Furthermore, bean sorting may open new markets for novel coffee products. PMID- 24070228 TI - Tribute to Rienk van Grondelle. PMID- 24070229 TI - Autobiography of Rienk van Grondelle. PMID- 24070231 TI - Publications of Rienk van Grondelle. PMID- 24070232 TI - The impact of an exercise physiologist coordinated resistance exercise program on the physical function of people receiving hemodialysis: a stepped wedge randomised control study. AB - BACKGROUND: Exercise during hemodialysis treatments improves physical function, markers of cardiovascular disease and quality of life. However, exercise programs are not a part of standard therapy in the vast majority of hemodialysis clinics internationally. Hemodialysis unit-based accredited exercise physiologists may contribute to an increased intradialytic exercise uptake and improved physical function. METHODS AND DESIGN: This is a stepped wedge cluster randomised controlled trial design. A total of 180 participants will be recruited from 15 community satellite hemodialysis clinics in a large metropolitan Australian city. Each clinic will represent a cluster unit. The stepped wedge design will consist of three groups each containing five randomly allocated cluster units, allocated to either 12, 24 or 36 weeks of the intervention. The intervention will consist of an accredited exercise physiologist-coordinated program consisting of six lower body resistance exercises using resistance elastic bands and tubing. The resistance exercises will include leg abduction, plantar flexion, dorsi flexion, straight-leg/bent-knee raise, knee extension and knee flexion. The resistance training will incorporate the principle of progressive overload and completed in a seated position during the first hour of hemodialysis treatment. The primary outcome measure is objective physical function measured by the 30-second sit to stand test. Secondary outcome measures include the 8-foot timed-up-and-go test, the four square step test, quality of life, cost-utility analysis, uptake and involvement in community activity, self-reported falls, fall's confidence, medication use, blood pressure and morbidity (hospital admissions). DISCUSSION: The results of this study are expected to determine the efficacy of an accredited exercise physiologist supervised resistance training on the physical function of people receiving hemodialysis and the cost-utility of exercise physiologists in hemodialysis centres. This may contribute to intradialytic exercise as standard therapy using an exercise physiologist workforce model. TRIAL REGISTRATION: Current Controlled Trials ACTRN12612001223820. PMID- 24070233 TI - Boosting angiogenesis and functional vascularization in injectable dextran hyaluronic acid hydrogels by endothelial-like mesenchymal stromal cells. AB - Angiogenesis and neovascularization are fundamental for the success of clinically relevant-sized tissue-engineered (TE) constructs. The next generation of TE constructs relies on providing instructive materials combined with the delivery of angiogenic growth factors and cells to avoid tissue ischemia. However, the majority of materials and cell types screened so far show limited clinical relevance, either due to insufficient number of cells or due to the use of animal derived matrixes. Here, we investigated whether endothelial-like cells derived from mesenchymal stromal cells (EL-MSCs) can be used for vascular TE in combination with injectable dextran-hyaluronic acid (Dex-g-HA) hydrogels. These hydrogels can be easily modified, as demonstrated by the incorporation of vascular endothelial growth factor (VEGF). We examined in vitro the reciprocal influences between cells and matrix. Dex-g-HA enabled higher EL-MSC metabolic rates associated with optimal cell sprouting in vitro compared to human umbilical vein endothelial cells. In vivo evaluation demonstrated the absence of an acute inflammatory response, and EL-MSCs incorporated within Dex-g-HA formed a functional vascular network integrated with the host vascular system. This work demonstrates that Dex-g-HA is an efficient delivery method of VEGF to induce angiogenesis. Additionally, functional neovascularization can be achieved in vitro and in vivo by the combination of Dex-g-HA with EL-MSC. PMID- 24070234 TI - Role of ring-constrained gamma-amino acid residues in alpha/gamma-peptide folding: single-conformation UV and IR spectroscopy. AB - The capped alpha/gamma-peptide foldamers Ac-gammaACHC-Ala-NH-benzyl (gammaalpha) and Ac-Ala-gammaACHC-NH-benzyl (alphagamma) were studied in the gas phase under jet-cooled conditions using single-conformation spectroscopy. These molecules serve as models for local segments of larger heterogeneous 1:1 alpha/gamma peptides that have recently been synthesized and shown to form a 12-helix composed of repeating C12 H-bonded rings both in crystalline form and in solution [Guo, L.; et al. J. Am. Chem. Soc. 2009, 131, 16018]. The gammaalpha and alphagamma peptide subunits are structurally constrained at the Cbeta-Cgamma bond of the gamma-residue with a cis-cyclohexyl ring and by an ethyl group at the Calpha position. These triamides are the minimum length necessary for the formation of the C12 H-bond. Resonant two-photon ionization (R2PI) provides ultraviolet spectra that have contributions from all conformational isomers, while IR-UV hole-burning (IR-UV HB) and resonant ion-dip infrared (RIDIR) spectroscopies are used to record single-conformation UV and IR spectra, respectively. Four and six conformers are identified in the R2PI spectra of the gammaalpha and alphagamma peptides, respectively. RIDIR spectra in the NH stretch, amide I (C?O stretch), and amide II (NH bend) regions are compared with the predictions of density functional theory (DFT) calculations at the M05-2X/6 31+G* level, leading to definite assignments for the H-bonding architectures of the conformers. While the C12 H-bond is present in both gammaalpha and alphagamma, C9 rings are more prevalent, with seven of ten conformers incorporating a C9 H-bond involving in the gamma-residue. Nevertheless, comparison of the assigned structures of gas-phase gammaalpha and alphagamma with the crystal structures for gammaalpha and larger alpha/gamma-peptides reveals that the constrained gamma-peptide backbone formed by the C9 ring is structurally similar to that formed by the larger C12 ring present in the 12-helix. These results confirm that the ACHC/ethyl constrained gamma-residue is structurally preorganized to play a significant role in promoting C12 H-bond formation in larger alpha/gamma-peptides. PMID- 24070236 TI - Surface chemistry architecture of silica nanoparticles determine the efficiency of in vivo fluorescence lymph node mapping. AB - Near-infrared (NIR) imaging of the lymphatic system offers a sensitive, versatile, and accurate lymph node mapping to locate the first, potentially metastatic, draining nodes in the operating room. Many luminescent nanoprobes have received great attention in this field, and the design of nontoxic and bright nanosystems is of crucial importance. Fluorescent NIR-emitting dye doped silica nanoparticles represent valuable platforms to fulfill these scopes, providing sufficient brightness, resistance to photobleaching, and hydrophilic nontoxic materials. Here, we synthesized these highly stable core-shell nanoparticles with a programmable surface charge positioning and determined the effect of these physicochemical properties on their in vivo behavior. In addition, we characterized their fluorescence kinetic profile in the right axillary lymph node (RALN) mapping. We found that nanoparticles with negative charges hidden by a PEG shell are more appropriate than those with external negative charges in the mapping of lymph nodes. We also demonstrated the efficient excretion of these nanostructures by the hepatobiliary route and their nontoxicity in mice up to 3 months postinjection. These results indicate the potential future development of these fluorescent nanosystems for LN mapping. PMID- 24070235 TI - Complex contributions of fibronectin to initiation and maturation of microfibrils. AB - Fibrillins constitute the backbone of extracellular multifunctional assemblies present in elastic and non-elastic matrices, termed microfibrils. Assembly of fibrillins into microfibrils and their homoeostasis is poorly understood and is often compromised in connective tissue disorders such as Marfan syndrome and other fibrillinopathies. Using interaction mapping studies, we demonstrate that fibrillins require the complete gelatin-binding region of fibronectin for interaction, which comprises domains FNI6-FNI9. However, the interaction of fibrillin-1 with the gelatin-binding domain of fibronectin is not involved in fibrillin-1 network assembly mediated by human skin fibroblasts. We show further that the fibronectin network is essential for microfibril homoeostasis in early stages. Fibronectin is present in extracted mature microfibrils from tissue and cells as well as in some in situ microfibrils observed at the ultrastructural level, indicating an extended mechanism for the involvement of fibronectin in microfibril assembly and maturation. PMID- 24070237 TI - Tetradihydrobenzoquinonate and tetrachloranilate Zr(IV) complexes: single-crystal to-single-crystal phase transition and open-framework behavior for K4Zr(DBQ)4. AB - The molecular complexes K4[Zr(DBQ)4] and K4[Zr(CA)4], where DBQ(2-) and CA(2-) stand respectively for deprotonated dihydroxybenzoquinone and chloranilic acid, are reported. The anionic metal complexes consist of Zr(IV) surrounded by four O,O-chelating ligands. Besides the preparation and crystal structures for the two complexes, we show that in the solid state the DBQ complex forms a 3-D open framework (with 22% accessible volume) that undergoes a crystal-to-crystal phase transition to a compact structure upon guest molecule release. This process is reversible. In the presence of H2O, CO2, and other small molecules, the framework opens and accommodates guest molecules. CO2 adsorption isotherms show that the framework breathing occurs only when a slight gas pressure is applied. Crystal structures for both the hydrated and guest free phases of K4[Zr(DBQ)4] have been investigated. PMID- 24070238 TI - A SNP profiling panel for sample tracking in whole-exome sequencing studies. AB - Whole-exome sequencing provides a cost-effective means to sequence protein coding regions within the genome, which are significantly enriched for etiological variants. We describe a panel of single nucleotide polymorphisms (SNPs) to facilitate the validation of data provenance in whole-exome sequencing studies. This is particularly significant where multiple processing steps necessitate transfer of sample custody between clinical, laboratory and bioinformatics facilities. SNPs captured by all commonly used exome enrichment kits were identified, and filtered for possible confounding properties. The optimised panel provides a simple, yet powerful, method for the assignment of intrinsic, highly discriminatory identifiers to genetic samples. PMID- 24070240 TI - Monitoring picoliter sessile microdroplet dynamics shows that size does not matter. AB - We monitor the dissolution of arrayed picoliter-size sessile microdroplets of the aqueous phase in oil, generated using a recently developed fluidic device. Initial pinning of the microdroplet perimeter leads to a nearly constant contact diameter, thus contraction proceeds via microdroplet (micrometer-diameter) height and contact angle reductions. This confirms that picoliter microdroplets contraction or dissolution due to the selective diffusion of water in oil has comparable dynamics with microliter droplet evaporation in air. We observe a constant microdroplet dissolution rate in different aqueous solutions. The application of this simple model to solvent-diffusion-driven crystallization experiments in confined volumes, for instance, would allow us to determine precisely the concentration in the microdroplet during an experiment and particularly at nucleation. PMID- 24070239 TI - Oral caffeine during voluntary exercise markedly inhibits skin carcinogenesis and decreases inflammatory cytokines in UVB-treated mice. AB - Ultraviolet B (UVB)-pretreated SKH-1 mice were treated with water, caffeine (0.1 mg/ml), voluntary running wheel exercise (RW) or caffeine together with RW for 14 wk. Treatment of the mice with caffeine, RW, or caffeine plus RW decreased skin tumors per mouse by 27%, 35%, and 62%, respectively, and the tumor volume per mouse was decreased by 61%, 70%, and 85%, respectively. In mechanistic studies, mice were treated with water, caffeine, RW, or caffeine plus RW for 2 wk prior to a single irradiation with UVB. Caffeine plus RW increased RW activity by 22% when compared with RW alone. Caffeine ingestion was not significantly different between groups. Treatment of mice with caffeine plus RW for 2 wk decreased the weight of the parametrial fat pads and stimulated the formation of UVB-induced apoptosis to a greater extent than treatment with caffeine or RW alone. An antibody array revealed that caffeine plus RW administered to mice fed a high-fat diet and irradiated with UVB decreased the epidermal levels of lipopolysaccharide induced CXC chemokine, soluble TNF alpha receptor-1, and macrophage inflammatory protein-1gamma. Overall, caffeine during RW exerts a stronger effect than either treatment alone for decreasing tissue fat, increasing UVB-induced apoptosis, lowering the levels of cytokines associated with inflammation and for inhibiting UVB-induced carcinogenesis. PMID- 24070241 TI - The role of quizartinib in the treatment of acute myeloid leukemia. AB - INTRODUCTION: Approximately one-third of the patients with acute myeloid leukemia (AML) harbor internal tandem duplication (ITD) in the gene encoding FMS-like tyrosine kinase 3 (FLT3-ITD), which is associated with poor prognosis. Over the course of the last decade, several FLT3 inhibitors have been developed. Nevertheless, the pharmacokinetic limitations of some of these compounds as well as their potency have limited their therapeutic efficacy. Quizartinib (AC220) is a second-generation FLT3 inhibitor that has shown promising activity in AML in Phase II clinical trials. AREAS COVERED: The pharmacokinetic, mechanism of action and resistance as well as clinical studies of quizartinib in AML are reported here in detail. EXPERT OPINION: Quizartinib is potent and selective FLT3 tyrosine kinase inhibitor with significant activity in both FLT3-mutant and wild-type AML. The quality and duration of achievable response thus far seen with this agent is suboptimal. Quizartinib in combination with chemotherapy might result in improved outcome and results of these trials are eagerly awaited. In addition, quizartinib in combination with other agents tackling the bone marrow microenvironment and FLT3 cooperative pathways may enhance response to quizartinib. PMID- 24070242 TI - Ahead of the curve. PMID- 24070243 TI - The journey to creating safety net accountable care in New Jersey. AB - New Jersey's 3-year Medicaid Accountable Care Organization (ACO) Demonstration Project was the result of a bipartisan effort to address the quality and cost issues regarding the State's safety net population. The legislation sets forth a framework that allows communities to customize ACOs to meet the unique needs of their population. Camden, Trenton, and Newark are currently experimenting with implementation at various levels. This article documents the context, journey, challenges, and future direction of the legislation through the accounts of 7 stakeholders whose roles were integral in the process of its creation, marketing, and eventual implementation. Their individual perspectives serve not only as an historical record of events but also as a guide for states seeking reference for implementing their own ACO framework. PMID- 24070244 TI - Bending the cost curve and improving quality of care in America's poorest city. AB - In Camden, New Jersey--as in many urban areas--health care costs are concentrated in a disproportionately small number of patients. These "super-utilizers" typically have multiple chronic conditions combined with social barriers that make it hard to access and coordinate the care they need to manage these conditions and stay healthy. Launched in 2002, the Camden Coalition of Healthcare Providers strives to reform the quality, capacity, and accessibility of the health care system for the city's vulnerable populations. PMID- 24070245 TI - Community health collaboratives: supporting innovation in public policy, care delivery, and coordination. PMID- 24070246 TI - Building a citywide, all-payer, hospital claims database to improve health care delivery in a low-income, urban community. AB - Developing data-driven local solutions to address rising health care costs requires valid and reliable local data. Traditionally, local public health agencies have relied on birth, death, and specific disease registry data to guide health care planning, but these data sets provide neither health information across the lifespan nor information on local health care utilization patterns and costs. Insurance claims data collected by local hospitals for administrative purposes can be used to create valuable population health data sets. The Camden Coalition of Healthcare Providers partnered with the 3 health systems providing emergency and inpatient care within Camden, New Jersey, to create a local population all-payer hospital claims data set. The combined claims data provide unique insights into the health status, health care utilization patterns, and hospital costs on the population level. The cross-systems data set allows for a better understanding of the impact of high utilizers on a community-level health care system. This article presents an introduction to the methods used to develop Camden's hospital claims data set, as well as results showing the population health insights obtained from this unique data set. PMID- 24070247 TI - Generating hypotheses about care needs of high utilizers: lessons from patient interviews. AB - Informed by a largely secondary and quantitative literature, efforts to improve care and outcomes for complex patients with high levels of emergency and hospital based health care utilization have offered mixed results. This qualitative study identifies psychosocial factors and life experiences described by these patients that may be important to their care needs. Semi-structured interviews were conducted with 19 patients of the Camden Coalition of Healthcare Providers' Care Management Team. Investigators coded transcripts using a priori and inductively derived codes, then identified 3 key themes: (1) Early-life instability and traumas, including parental loss, unstable or violent relationships, and transiency, informed many participants' health and health care experiences; (2) Many "high utilizers" described a history of difficult interactions with health care providers during adulthood; (3) Over half of the participants described the importance to their well-being of positive and "caring" relationships with primary health care providers and the outreach team. Additionally, the transient and vulnerable nature of this complex population posed challenges to follow-up, both for research and care delivery. These themes illuminate potentially important hypotheses to be explored in more generalizable samples using robust and longitudinal methods. Future work should explore the prevalence and impact of adverse childhood experiences among "high utilizers," and the different types of relationships they have with providers. Investigators should test new modes of care delivery that attend to patients' trauma histories. This qualitative study was well suited to provide insight into the life stories of these complex, vulnerable patients, informing research questions for further investigation. PMID- 24070248 TI - Improving population health through collaboration and innovation. AB - As a health care collaborative among Trenton's hospitals, its only Federally Qualified Health Center, its Division of Health, and more than 40 community organizations serving on the Community Advisory Board, Trenton Health Team has leveraged unprecedented data sharing and direct engagement with community residents to identify the health needs and priorities for its geography. This process has resulted in a unified Community Health Needs Assessment and Community Health Improvement Plan for the city of Trenton, allowing collaborative allocation of resources to manage and improve population health in the city. PMID- 24070249 TI - Early experiences with accountable care in Medicaid: special challenges, big opportunities. AB - Accountable care organizations (ACOs) and the more general movement toward accountable care, in which payments are aligned directly with improvements in quality and cost, are intended to increase the incentives and support for higher value in health care. As of mid-2013, there are over 4 million beneficiaries covered by Medicare ACOs, and large private payers continue to enter new ACO arrangements with providers in all parts of the country. An increasing number of states have approved and are implementing accountable care models for their Medicaid programs. A review of some of these early state adopters demonstrates how the features of Medicaid populations, Medicaid providers, and Medicaid financing create some distinct issues for implementing ACOs in Medicaid. Many states that have relied on Medicaid managed care plans are moving to accountable care through these private plans. Some states also are implementing accountable care reforms through direct reforms in their payments to Medicaid providers, both through specific providers and regionally-based contracts. Others are implementing a mixture of private plan and public management approaches. States are moving toward more comprehensive accountable care payments through patient centered medical homes, episode-based payments, and patient-level accountable care payment reforms; these payment reforms can be sequential and synergistic. Accountable care in Medicaid involves some distinct considerations such as performance measures, additional complications in shared savings related to the federal-state Medicaid funding structure, and potential antitrust issues in cases where states are pursuing reforms with implications for most or all providers in a geographic area. The evidence on the impact of the various early approaches to accountable care in Medicaid is just beginning to emerge, and it is likely that the best course for states will continue to depend on the distinctive institutional features of their Medicaid programs and health care delivery systems. As in other parts of the health care system, accountable care in Medicaid is likely to continue to expand and to evolve. PMID- 24070251 TI - An orange fluorescent protein tagging system for real-time pollen tracking. AB - BACKGROUND: Monitoring gene flow could be important for future transgenic crops, such as those producing plant-made-pharmaceuticals (PMPs) in open field production. A Nicotiana hybrid (Nicotiana. tabacum * Nicotiana glauca) shows limited male fertility and could be used as a bioconfined PMP platform. Effective assessment of gene flow from these plants is augmented with methods that utilize fluorescent proteins for transgenic pollen identification. RESULTS: We report the generation of a pollen tagging system utilizing an orange fluorescent protein to monitor pollen flow and as a visual assessment of transgene zygosity of the parent plant. This system was created to generate a tagged Nicotiana hybrid that could be used for the incidence of gene flow. Nicotiana tabacum 'TN 90' and Nicotiana glauca were successfully transformed via Agrobacterium tumefaciens to express the orange fluorescent protein gene, tdTomato-ER, in pollen and a green fluorescent protein gene, mgfp5-er, was expressed in vegetative structures of the plant. Hybrids were created that utilized the fluorescent proteins as a research tool for monitoring pollen movement and gene flow. Manual greenhouse crosses were used to assess hybrid sexual compatibility with N. tabacum, resulting in seed formation from hybrid pollination in 2% of crosses, which yielded non-viable seed. Pollen transfer to the hybrid formed seed in 19% of crosses and 10 out of 12 viable progeny showed GFP expression. CONCLUSION: The orange fluorescent protein is visible when expressed in the pollen of N. glauca, N. tabacum, and the Nicotiana hybrid, although hybrid pollen did not appear as bright as the parent lines. The hybrid plants, which show limited ability to outcross, could provide bioconfinement with the benefit of detectable pollen using this system. Fluorescent protein-tagging could be a valuable tool for breeding and in vivo ecological monitoring. PMID- 24070253 TI - Gelsolin-like activation of villin: calcium sensitivity of the long helix in domain 6. AB - Villin is a gelsolin-like cytoskeleton regulator localized in the brush border at the apical end of epithelial cells. Villin regulates microvilli by bundling F actin at low calcium levels and severing it at high calcium levels. The villin polypeptide consists of six gelsolin-like repeats (V1-V6) and the unique, actin binding C-terminal headpiece domain (HP). Villin modular fragment V6-HP requires calcium to stay monomeric and bundle F-actin. Our data show that isolated V6 is monomeric and does not bind F-actin at any level of calcium. We propose that the 40-residue unfolded V6-to-HP linker can be a key regulatory element in villin's functions such as its interactions with F-actin. Here we report a calcium-bound solution nuclear magnetic resonance (NMR) structure of V6, which has a gelsolin like fold with the long alpha-helix in the extended conformation. Intrinsic tryptophan fluorescence quenching reveals two-Kd calcium binding in V6 (Kd1 of 22 MUM and Kd2 of 2.8 mM). According to our NMR data, the conformation of V6 responds the most to micromolar calcium. We show that the long alpha-helix and the adjacent residues form the calcium-sensitive elements in V6. These observations are consistent with the calcium activation of F-actin severing by villin analogous to the gelsolin helix-straightening mechanism. PMID- 24070252 TI - Distraction-induced intestinal growth: the role of mechanotransduction mechanisms in a mouse model of short bowel syndrome. AB - Novel strategies are needed to address the problem of patients with short bowel syndrome. We previously demonstrated a three-fold lengthening of pig bowel after 2 weeks of applied distractive forces, but we have not elucidated the mechanisms facilitating this growth. We used a mouse model of distraction-induced enterogenesis. High molecular weight polyethylene glycol (PEG) osmotically stretched an isolated small bowel segment (PEG-stretch). Significant increases in villus height and crypt depth and in intestinal epithelial cell length and numbers suggested epithelial remodeling in addition to proliferation during enterogenesis. LC-MS/MS analysis showed a two-fold upregulation of alpha-actinin 1 and -4. We also demonstrated that p-focal adhesion kinase (FAK), FAK, alpha actinin, and Rac1 were significantly upregulated and that F-actin was relocalized in PEG-stretch versus controls. Blockade of the phosphotidyl inositol 3' kinase pathway failed to influence the increase in proliferation or decline in apoptosis after stretch, suggesting alternative signaling pathways are used, including MEK and P38MAPK, which were both upregulated during enterogenesis. Our data suggests that several known mechanotransduction pathways drive distraction-induced enterogenesis. PMID- 24070254 TI - Supercapacitance from cellulose and carbon nanotube nanocomposite fibers. AB - Multiwalled carbon nanotube (MWNT)/cellulose composite nanofibers have been prepared by electrospinning a MWNT/cellulose acetate blend solution followed by deacetylation. These composite nanofibers were then used as precursors for carbon nanofibers (CNFs). The effect of nanotubes on the stabilization of the precursor and microstructure of the resultant CNFs were investigated using thermogravimetric analysis, transmission electron microscopy and Raman spectroscopy. It is demonstrated that the incorporated MWNTs reduce the activation energy of the oxidative stabilization of cellulose nanofibers from ~230 to ~180 kJ mol(-1). They also increase the crystallite size, structural order, and electrical conductivity of the activated CNFs (ACNFs). The surface area of the ACNFs increased upon addition of nanotubes which protrude from the fiber leading to a rougher surface. The ACNFs were used as the electrodes of a supercapacitor. The electrochemical capacitance of the ACNF derived from pure cellulose nanofibers is demonstrated to be 105 F g(-1) at a current density of 10 A g(-1), which increases to 145 F g(-1) upon the addition of 6% of MWNTs. PMID- 24070255 TI - Serum acute phase reactants hallmark healthy individuals at risk for acetaminophen-induced liver injury. AB - BACKGROUND: Acetaminophen (APAP) is a commonly used analgesic. However, its use is associated with drug-induced liver injury (DILI). It is a prominent cause of acute liver failure, with APAP hepatotoxicity far exceeding other causes of acute liver failure in the United States. In order to improve its safe use this study aimed to identify individuals at risk for DILI prior to drug treatment by searching for non-genetic serum markers in healthy subjects susceptible to APAP induced liver injury (AILI). METHODS: Healthy volunteers (n = 36) received either placebo or acetaminophen at the maximum daily dose of 4 g for 7 days. Blood samples were taken prior to and after APAP treatment. Serum proteomic profiling was done by 2D SDS-PAGE and matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. Additionally, the proteins C-reactive protein, haptoglobin and hemopexin were studied by quantitative immunoassays. RESULTS: One third of study subjects presented more than four-fold increased alanine transaminase activity to evidence liver injury, while serum proteomics informed on 20 proteins as significantly regulated. These function primarily in acute phase and immune response. Pre-treatment associations included C-reactive protein, haptoglobin isoforms and retinol binding protein being up to six-fold higher in AILI susceptible individuals, whereas alpha1-antitrypsin, serum amyloid A, kininogen and transtyretin were regulated by nearly five-fold in AILI responders. When compared with published findings for steatohepatitis and cases of hepatocellular, cholestatic and mixed DILI, 10 proteins were identified as uniquely associated with risk for AILI, including plasminogen. Notably, this zymogen facilitates macrophage chemotactic migration and inflammatory response as reported for plasminogen-deficient mice shown to be resistant to APAP hepatotoxicity. Finally, analysis of a publicly available database of gene expression profiles of cultures of human hepatocytes treated with drugs labeled as no- (n = 8), low- (n = 45) or most-DILI-concern (n = 39) confirmed regulation of the identified biomarkers to demonstrate utility in predicting risk for liver injury. CONCLUSIONS: The significant regulation of acute phase reactants points to an important link between AILI and the immune system. Monitoring of serum acute phase reactants prior to drug treatment may contribute to prevention and management of AILI, and may also be of utility for other drugs with known liver liabilities. PMID- 24070257 TI - Ice adhesion on lubricant-impregnated textured surfaces. AB - Ice accretion is an important problem and passive approaches for reducing ice adhesion are of great interest in various systems such as aircrafts, power lines, wind turbines, and oil platforms. Here, we study the ice-adhesion properties of lubricant-impregnated textured surfaces. Force measurements show ice adhesion strength on textured surfaces impregnated with thermodynamically stable lubricant films to be higher than that on surfaces with excess lubricant. Systematic ice adhesion measurements indicate that the ice-adhesion strength is dependent on texture and decreases with increasing texture density. Direct cryogenic SEM imaging of the fractured ice surface and the interface between ice and lubricant impregnated textured surface reveal stress concentrators and crack initiation sites that can increase with texture density and result in lowering adhesion strength. Thus, lubricant-impregnated surfaces have to be optimized to outperform state-of-the-art icephobic treatments. PMID- 24070258 TI - Defining the interaction of perforin with calcium and the phospholipid membrane. AB - Following its secretion from cytotoxic lymphocytes into the immune synapse, perforin binds to target cell membranes through its Ca(2+)-dependent C2 domain. Membrane-bound perforin then forms pores that allow passage of pro-apoptopic granzymes into the target cell. In the present study, structural and biochemical studies reveal that Ca(2+) binding triggers a conformational change in the C2 domain that permits four key hydrophobic residues to interact with the plasma membrane. However, in contrast with previous suggestions, these movements and membrane binding do not trigger irreversible conformational changes in the pore forming MACPF (membrane attack complex/perforin-like) domain, indicating that subsequent monomer-monomer interactions at the membrane surface are required for perforin pore formation. PMID- 24070259 TI - Reaction of diphenylphosphanylacetylene with RB(C6F5)2 reagents: evidence for a remarkable sequence of synergistic frustrated Lewis pair addition reactions. AB - Diphenylphosphanylethyne (3a) reacts with tris(pentafluorophenyl)borane at room temperature by a typical frustrated Lewis pair (FLP) reaction. It undergoes a sequential series of 1,2-phosphane/borane additions to the alkyne unit in an overall 2:2 molar ratio to selectively form the dimeric product 5a. Product 5 features a pentafulvene-reminiscent structure with a pair of phosphonium units in the ring and B(C6F5)3 substituents at the periphery. At elevated temperature, the reaction becomes less selective, now favoring the formation of cis- and trans-1,1 carboboration products from a 1:1 stoichiometry. After photolytic trans/cis isomerization, the vicinal FLP 6a becomes the major product, featuring an intramolecular P...B interaction. The reaction of 3a with H3CB(C6F5)2 also gives a heterocyclic dimer (11), except that here a substituent H/CH3 exchange by an addition/elimination pathway has taken place. In the B(C6F5)3-derived system, we were able to trap an alleged intermediate of this rearrangement reaction by adding n-butyl isocyanide. Five products in the Ph2P- and (p-tolyl)2P-derived systems were characterized by X-ray diffraction. PMID- 24070256 TI - Incidence and prevalence of multiple sclerosis in Europe: a systematic review. AB - BACKGROUND: Multiple sclerosis (MS) is the most common cause of neurological disability in young adults worldwide and approximately half of those affected are in Europe. The assessment of differential incidence and prevalence across populations can reveal spatial, temporal and demographic patterns which are important for identifying genetic and environmental factors contributing to MS. However, study methodologies vary and the quality of the methods can influence the estimates. This study aimed to systematically review European studies of incidence and prevalence of MS and to provide a quantitative assessment of their methodological quality. METHODS: A comprehensive literature search was performed to obtain all original population-based studies of MS incidence and prevalence in European populations conducted and published between January 1985 and January 2011. Only peer-reviewed full-text articles published in English or French were included. All abstracts were screened for eligibility and two trained reviewers abstracted the data and graded the quality of each study using a tool specifically designed for this study. RESULTS: There were 123 studies that met the inclusion criteria. The study estimates were highly heterogeneous, even within regions or countries. Quality was generally higher in the more recent studies, which also tended to use current diagnostic criteria. Prevalence and incidence estimates tended to be higher in the more recent studies and were higher in the Nordic countries and in northern regions of the British Isles. With rare exceptions, prevalence and incidence estimates were higher in women with ratios as high as 3:1. Few studies examined ethnicity. Epidemiological data at the national level was uncommon and there were marked geographical disparities in available data, with large areas of Europe unrepresented and other regions well represented in the literature. Only 37% of the studies provided standardized estimates. CONCLUSIONS: Despite the breadth of the literature on the epidemiology of MS in Europe, inter-study comparisons are hampered by the lack of standardization. Further research should focus on regions not yet studied and the evaluation of ethnic differences in MS prevalence and incidence. National-level studies using current diagnostic criteria, validated case definitions and similar age- and sex-standardization would allow better geographical comparisons. PMID- 24070260 TI - Increased resistin in brain dead organ donors is associated with delayed graft function after kidney transplantation. AB - INTRODUCTION: Resistin increases during several inflammatory diseases and after intracerebral bleeding or head trauma. Resistin activates the endothelium and may initiate an inflammatory response. No data are available on resistin in brain dead donors (DBD) that regularly manifest a pronounced inflammatory state. METHODS: We analyzed plasma resistin in 63 DBDs and correlated results with donor variables and the postoperative course following kidney transplantation using organs from these donors. Endocan and monocyte chemotactic protein (MCP)-1 were also studied. Twenty-six live kidney donors (LD) and the corresponding kidney transplantations were used as controls. RESULTS: DBDs had higher resistin (median/range 30.75 ng/ml, 5.41-173.6) than LD (7.71 ng/ml, 2.41-15.74, p < 0.0001). Resistin in DBD correlated with delayed graft function (DGF) in the kidney recipients (r = 0.321, p < 0.01); receiver operating characteristic curve revealed an area under the curve of 0.765 (95% confidence interval [CI] 0.648 0.881, p < 0.01) and a cut-off value for resistin of 25 ng/ml; MCP-1 and endocan were higher in DBDs (p < 0.0001) but did not correlate with DGF or acute rejection. No relationship was found between the studied molecules and the postoperative course of LD kidney transplants. CONCLUSIONS: High resistin levels in the DBD before organ retrieval are associated with DGF after kidney transplantation. The resistin increase seems related to the inflammatory state after brain death but not to the cause of death. PMID- 24070262 TI - The distinguishing cellular features of pulmonary artery smooth muscle cells from chronic thromboembolic pulmonary hypertension patients. AB - In chronic thromboembolic pulmonary hypertension (CTEPH), central thrombi are the most likely disease initiators, and progressive pulmonary vascular remodeling, which is characterized by marked proliferation of pulmonary artery smooth muscle cells (PASMCs), may also contribute to the long-term progression of CTEPH. This study was designed to investigate the cellular characteristics of PASMCs isolated from the organized thrombotic tissues of CTEPH. In the present study, analysis of PASMCs isolated from five CTEPH patients and three control subjects showed that cells from CTEPH patients had certain characteristics that distinguished them from control cells, including inferior or no cell-cell contact inhibition growth, increased sensitivity to hypoxia-induced proliferation, resistance to serum starvation-induced apoptosis, and mitochondrial metabolism disorder. These differences in the PASMCs in endarterectomized tissue of CTEPH patients may prove useful in understanding the pathobiology of CTEPH. PMID- 24070261 TI - Knowledge and ethical perception regarding organ donation among medical students. AB - BACKGROUND: To determine the knowledge and ethical perception regarding organ donation amongst medical students in Karachi- Pakistan. METHODS: Data of this cross sectional study was collected by self administered questionnaire from MBBS students of Ziauddin University from 2010 to 2011. Sample size of 158 (83 First years and 75 Fourth years) were selected by convenient sampling and those students who were present and gave consent were included in the study. The data was analyzed by SPSS version 20. RESULTS: A total of 158 participants from Ziauddin Medical University filled out the questionnaire out of which 83(52.5%) were first years and 75(47.5%) were fourth year medical students. Mean age of sample was 20 +/- 1.7. Majority of students were aware about organ donation with print and electronic media as the main source of information. 81.6% agreed that it was ethically correct to donate an organ. In the students' opinion, most commonly donated organs and tissues were kidney, cornea, blood and platelet. Ideal candidates for donating organ were parents (81%). Regarding list of options for preference to receive an organ, most of the students agreed on young age group patients and persons with family. Willingness to donate was significantly associated with knowledge of allowance of organ donation in religion (P = 0.000). CONCLUSION: Both 1st year and 4th year students are aware of Organ Donation, but there is a significant lack of knowledge regarding the topic. PMID- 24070263 TI - The acute effect of cigarette smoking on the respiratory function and FENO production among young smokers. AB - INTRODUCTION: Smoking is known to have a long-term impact on lung function; however, the acute physiological response of smoking a single cigarette and the influential role of pack years and cigarettes per day on pulmonary indices remains an area of interest, especially among young smokers. METHODS: 50 naive smokers (ages: 18-26, 24 males: mean pack years 3.8) participated in this experimental study. Respiratory resistance (R), reactance (X), and impedance (Z) were assessed through impulse oscillometry. The participants' fraction of exhaled nitric oxide (FENO) was measured. All tests were performed immediately before and after smoking one single cigarette. RESULTS: Smoking a single cigarette was found to immediately increase airway impedance (Z 5 Hz) by 0.024 kPa/(L/s) (P = .002), airway resistance at R 5 Hz, R 10 Hz, and R 20 Hz by 0.024 kPa/(L/s)(P < .001), 0.016 kPa/(L/s)(P = .019), and 0.023 kPa/(L/s) (P = .007), respectively, after adjusting for BMI, age, gender, and pack years. FENO concentrations also decreased from 11.70 ppb to 9.85 ppb, P < .001. Sensitivity analyses indicated that the participants' number of pack years and cigarettes per day influenced pulmonary reactance at 10 Hz and 20 Hz, however only at baseline with these differences found to disappear immediately after smoking. CONCLUSIONS: The present study indicates that the consumption of a single cigarette may alter lung mechanics and FENO production among young smokers. Further research is needed to assess the mechanisms and washout period after which these parameters return to normal. PMID- 24070264 TI - 1,4-Cyclohexanedione. Composition, molecular structures, and internal dynamics of the vapor: an electron diffraction investigation augmented by molecular orbital calculations. AB - Electron diffraction experiments on the vapor of 1,4-cyclohexanedione have been carried out at a nominal temperature of 435 K. The results are consistent with the presence of a mixture of a chair form of C2h symmetry and a twisted boat form of D2 symmetry. The former has the familiar dynamic properties of a semirigid molecule, but the D2 form undergoes a large-amplitude twisting motion (pseudorotation) that degrades the symmetry to C2. The analysis was designed to elucidate parameter values and internal dynamics of each conformer and the composition of the system. The large-amplitude motion of the twisted boat form was modeled by placement of 10 pseudoconformers at approximately 5 degrees intervals along a pseudorotational coordinate that began at the D2 position and that reflected the angle between the C?O bond vectors. A Gaussian weighting of the pseudeoconformers centered on the (lowest-energy) D2 position was assumed. Differences in the interatomic distances and bond angles of these pseudoconformers were calculated via B3LYP/cc-pVTZ theory and introduced as constraints. The bond length averages over the twisted boat forms followed by values for the chair in square brackets are (rg/A; [angle]alpha/deg) r(C-H) = 1.115(11) [1.124(11)], r(C?O) = 1.211(3) [1.233(6)], r(C1-C2) = 1.524(5) [1.526(5)], and r(C2-C3) = 1.533(11) [1.539(11)]. The corresponding ring angle values are [angle](C1C2C3) = 111.1(5) [111.0(4)] and [angle](C6C1C2) = 116.3(8) [115.7(8)]. In the twisted boat form, pseudorotation leads to a weighted average displacement of the angle between the C?O bond vectors, [angle]Delta(CO,CO), equal to 21.3 degrees from the 180 degrees value in the D2 form corresponding to an average angle between the CO bond vectors of 158.7(1) degrees . The amount of the chair form in the gas at 435 K is 24(10)%. The listed uncertainties are estimated at 2sigma. PMID- 24070265 TI - Effects of the modulation of microbiota on the gastrointestinal immune system and bowel function. AB - The gastrointestinal tract harbors a tremendous number and variety of commensal microbiota. The intestinal mucosa simultaneously absorbs essential nutrients and protects against detrimental antigens or pathogenic microbiota as the first line of defense. Beneficial interactions between the host and microbiota are key requirements for host health. Although the gut microbiota has been previously studied in the context of inflammatory diseases, it has recently become clear that this microbial environment has a beneficial role during normal homeostasis, by modulating the immune system or bowel motor function. Recent studies revealed that microbiota, including their metabolites, modulate key signaling pathways involved in the inflammation of the mucosa or the neurotransmitter system in the gut-brain axis. The underlying molecular mechanisms of host-microbiota interactions are still unclear; however, manipulation of microbiota by probiotics or prebiotics is becoming increasingly recognized as an important therapeutic option, especially for the treatment of the dysfunction or inflammation of the intestinal tract. PMID- 24070266 TI - Physical activity is associated with malignant and benign breast diseases in low income Brazilian women. AB - We compared the relationships among percentage of body fat (%BF) and physical activity with breast cancer (BC) and benign breast diseases (BBD) in low-income Brazilian women. A case-control study including 106 incident BC cases, 178 incident BBD cases, and 181 control women recruited from a public hospital-based screening center was conducted. Logistic regression models showed that sedentary women have a higher odds of developing BC in the age adjusted model [odds ratio (OR) = 2.39, 95% confidence interval (CI) 1.43-3.99]. After adjusting for hormonal-related risk factors and family history of breast cancer (OR = 2.94, 95% CI 1.50-5.79) and also for the % BF (OR = 2.71, 95% CI 1.36-5.37) the odds remained high. Independent of the adjustments made, %BF did not affect the odds for developing BC. When the same models were tested for women with BBD, we found a significant association with sedentary lifestyle in all models tested, with an OR = 3.03 (95% CI 1.69-5.42) in the fully adjusted model. In the same way, in the fully adjusted model %BF was significantly associated to risk for BBD (OR = 0.54, 95% CI 0.30-0.98). Similar to results found in other populations, our data suggest that physical activity is an important, independent protective factor for the risk of developing BC and BBD in low-income women from an admixed population. PMID- 24070267 TI - Target-induced displacement reaction accompanying cargo release from magnetic mesoporous silica nanocontainers for fluorescence immunoassay. AB - A new fluorescence immunoassay strategy based on a target-induced displacement reaction with cargo release from protein-gated carbohydrate-functionalized magnetic mesoporous silica nanoparticles (MMSN) was developed for sensitive detection of small molecular mycotoxins (aflatoxin B1, AFB1 used in this case). To construct such an assay system, MMSN was initially functionalized with mannose terminated silanes, then capped with biotinylated concanavalin A (Con A) entrapped rhodamine B (RB) within the pores through the carbohydrate-protein interaction, and then biotinylated monoclonal anti-AFB1 capture antibody was conjugated to Con A-functionalized MMSN by the streptavidin-biotin chemistry. Gold nanoparticles (AuNP) heavily functionalized with invertase and bovine serum albumin-AFB1 conjugate were utilized as the trace tag. With AFB1 introduction, a competitive immunoreaction for the immobilized anti-AFB1 antibody on the MMSN was started between target analyte and the labeled AFB1 on the AuNP. Accompanied by AuNP, the carried invertase hydrolyzed sucrose in glucose and fructose. The generated glucose competed with the mannose for Con A and displaced the Con A antibody complex from the MMSN, resulting in the opening of molecular gates owing to the uncapping of MMSN, thereby the entrapped RB could release from the pores. The released RB could be quantitatively determined by a fluorometer. Under optimal conditions, the fluorescence intensity decreased with the increasing AFB1 concentration in the range from 0.01 to 5 ng mL(-1) with a detection limit (LOD) of 8 pg mL(-1) at the 3sblank criterion. Intra- and interbatch assay precisions were lower than 9 and 9.5% (CV), respectively. The method featured unbiased identification of negative (blank) and positive samples. No significant differences at the 0.05 significance level were encountered in the analysis of naturally contaminated peanut samples between the fluorescence immunoassay and a commercialized enzyme-linked immunosorbent assay (ELISA) method. PMID- 24070268 TI - A review of current imaging methods used in stroke research. AB - Stroke is a serious healthcare problem with high mortality and long-term disability. However, to date, our ability to prevent and cure stroke remains limited. One important goal in stroke research is to identify the extent and location of lesion for treatment. In addition, accurately differentiating salvageable tissue from infarct and evaluating therapeutic efficacies are indispensible. These objectives could potentially be met with the assistance of modern neuroimaging techniques. This paper reviews current imaging methods commonly used in ischemic stroke research. These methods include positron emission tomography, computed tomography, T1 MRI, T2 MRI, diffusion and perfusion MRI, diffusion tensor imaging, blood-brain barrier permeability MRI, pH-weighted MRI, and functional MRI. PMID- 24070269 TI - Molecular characterization of Rifr mutations in Enterococcus faecalis and Enterococcus faecium. AB - Mutation rate is an important factor affecting the appearance and spread of acquired antibiotic resistance. The frequencies and types of enterococci mutations were determined in this study. The MICs of rifampicin in enterococci and their rifampicin-resistant mutants were determined by the Clinical and Laboratory Standards Institute (CLSI) agar dilution method. The Enterococcus faecalis isolates A15 and 18165 showed no significant differences in mutation frequencies or mutation rates. In Enterococcus faecium, the mutation frequency and mutation rate were both 6.4-fold lower than in E. faecalis. The spectrum of mutations characterized in E. faecium B42 differed significantly from that of E. faecalis. The types and rate of mutations indicated that E. faecalis had a higher potential to develop linezolid resistance. Rifampicin resistance was associated with mutations in the rpoB gene. Rifampicin MICs for the E. faecalis mutant were 2048 mg/l, but rifampicin MICs for E. faecium mutants ranged from 64 to 1024 mg/l. PMID- 24070270 TI - Communication: In search of four-atom chiral metal clusters. AB - A combined study utilizing anion photoelectron spectroscopy and density functional theory was conducted to search for four-atom, chiral, metal, and mostly metal clusters. The clusters considered were AuCoMnBi(-/0), AlAuMnO(-/0), AgMnOAl(-/0), and AuAlPtAg(-/0), where the superscripts, (-/0), refer to anionic and neutral cluster species, respectively. Based on the agreement of experimentally and theoretically determined values of both electron affinities and vertical detachment energies, the calculated cluster geometries were validated and examined for chirality. Among both anionic and neutral clusters, five structures were identified as being chiral. PMID- 24070271 TI - Communication: Kinetics of chemical ordering in Ag-Au and Ag-Ni nanoalloys. AB - The energy landscape and kinetics of medium-sized Ag-Au and Ag-Ni nanoalloy particles are explored via a discrete path sampling approach, focusing on rearrangements connecting regions differing in chemical order. The highly miscible Ag27Au28 supports a large number of nearly degenerate icosahedral homotops. The transformation from reverse core-shell to core-shell involves large displacements away from the icosahedron through elementary steps corresponding to surface diffusion and vacancy formation. The immiscible Ag42Ni13 naturally forms an asymmetric core-shell structure, and about 10 eV is required to extrude the nickel core to the surface. The corresponding transformation occurs via a long and smooth sequence of surface displacements. For both systems the rearrangement kinetics exhibit Arrhenius behavior. These results are discussed in the light of experimental observations. PMID- 24070272 TI - Communication: Synperiplanar to antiperiplanar conformation changes as underlying the mechanism of Debye process in supercooled ibuprofen. AB - In this Communication, we present experimental studies that put new insight into the puzzling nature of the Debye relaxation found in the supercooled liquid state of racemic ibuprofen. The appearance of D-relaxation in the loss spectra of non hydrogen bonding methylated derivate of ibuprofen has proven that Debye relaxation is related solely with conformational changes of the carboxyl group, termed in this paper as synperiplanar-antiperiplanar. Our studies indicate that the presence of hydrogen bonding capabilities is not here the necessary condition to observe Debye process, however, their occurrence might strongly influence alpha- and D-relaxations dynamics. Interestingly, the activation energy of the D process in ibuprofen methyl ester on approaching T(g) was found to be perfectly consistent with that reported for ibuprofen by Affouard and Correia [J. Phys. Chem. B 114, 11397-11402 (2010)] (~39 kJ/mol). Finally, IR measurements suggest that the equilibrium between conformers concentration depends on time and temperature, which might explain why the appearance of D-relaxation in supercooled ibuprofen depends on thermal history of the sample. PMID- 24070273 TI - Energy benchmarks for water clusters and ice structures from an embedded many body expansion. AB - We show how an embedded many-body expansion (EMBE) can be used to calculate accurate ab initio energies of water clusters and ice structures using wavefunction-based methods. We use the EMBE described recently by Bygrave et al. [J. Chem. Phys. 137, 164102 (2012)], in which the terms in the expansion are obtained from calculations on monomers, dimers, etc., acted on by an approximate representation of the embedding field due to all other molecules in the system, this field being a sum of Coulomb and exchange-repulsion fields. Our strategy is to separate the total energy of the system into Hartree-Fock and correlation parts, using the EMBE only for the correlation energy, with the Hartree-Fock energy calculated using standard molecular quantum chemistry for clusters and plane-wave methods for crystals. Our tests on a range of different water clusters up to the 16-mer show that for the second-order Moller-Plesset (MP2) method the EMBE truncated at 2-body level reproduces to better than 0.1 mE(h)/monomer the correlation energy from standard methods. The use of EMBE for computing coupled cluster energies of clusters is also discussed. For the ice structures Ih, II, and VIII, we find that MP2 energies near the complete basis-set limit reproduce very well the experimental values of the absolute and relative binding energies, but that the use of coupled-cluster methods for many-body correlation (non additive dispersion) is essential for a full description. Possible future applications of the EMBE approach are suggested. PMID- 24070274 TI - Theoretical modeling of UV-Vis absorption and emission spectra in liquid state systems including vibrational and conformational effects: the vertical transition approximation. AB - In this paper we describe in detail a general and efficient methodology, based on the perturbed matrix method and molecular dynamics simulations, to model UV-Vis absorption and emission spectra including vibrational and conformational effects. The basic approximation used is to consider all the chromophore atomic coordinates as semiclassical degrees of freedom, hence allowing the calculation of the complete spectral signal by using the electronic vertical transitions as obtained at each possible chromophore configuration, thus including the contributions of vibrations and conformational transitions into the spectrum. As shown for the model system utilized in this paper, solvated 1-phenyl-naphthalene, such an approximation can be rather accurate to reproduce the absorption and emission spectral line shape and properties when, as it often occurs, the vertical vibronic transition largely overlaps the other non-negligible vibronic transitions. PMID- 24070275 TI - Implementation of the CCSD-PCM linear response function for frequency dependent properties in solution: application to polarizability and specific rotation. AB - This work reports the first implementation of the frequency dependent linear response (LR) function for the coupled cluster singles and doubles method (CCSD) combined with the polarizable continuum model of solvation for the calculation of frequency dependent properties in solution. In particular, values of static and dynamic polarizability as well as specific rotation are presented for various test molecules. Model calculations of polarizability show that a common approximation used in the definition of the LR function with solvation models recovers over 70% of the full response while maintaining a computational cost comparable to gas phase LR-CCSD. Calculations of specific rotation for three compounds for which gas phase methods predict the wrong sign of the rotation show that accounting for the electronic response of the solvent may be essential to assign the correct absolute configuration of chiral molecules. PMID- 24070276 TI - Rethinking first-principles electron transport theories with projection operators: the problems caused by partitioning the basis set. AB - We revisit the derivation of electron transport theories with a focus on the projection operators chosen to partition the system. The prevailing choice of assigning each computational basis function to a region causes two problems. First, this choice generally results in oblique projection operators, which are non-Hermitian and violate implicit assumptions in the derivation. Second, these operators are defined with the physically insignificant basis set and, as such, preclude a well-defined basis set limit. We thus advocate for the selection of physically motivated, orthogonal projection operators (which are Hermitian) and present an operator-based derivation of electron transport theories. Unlike the conventional, matrix-based approaches, this derivation requires no knowledge of the computational basis set. In this process, we also find that common transport formalisms for nonorthogonal basis sets improperly decouple the exterior regions, leading to a short circuit through the system. We finally discuss the implications of these results for first-principles calculations of electron transport. PMID- 24070277 TI - Investigation of the linear and second-order nonlinear optical properties of molecular crystals within the local field theory. AB - In this paper it is shown that modest calculations combining first principles evaluations of the molecular properties with electrostatic interaction schemes to account for the crystal environment effects are reliable for predicting and interpreting the experimentally measured electric linear and second-order nonlinear optical susceptibilities of molecular crystals within the experimental error bars. This is illustrated by considering two molecular crystals, namely: 2 methyl-4-nitroaniline and 4-(N,N-dimethylamino)-3-acetamidonitrobenzene. Three types of surrounding effects should be accounted for (i) the polarization due to the surrounding molecules, described here by static electric fields originating from their electric dipoles or charge distributions, (ii) the intermolecular interactions, which affect the geometry and particularly the molecular conformation, and (iii) the screening of the external electric field by the constitutive molecules. This study further highlights the role of electron correlation on the linear and nonlinear responses of molecular crystals and the challenge of describing frequency dispersion. PMID- 24070278 TI - Computing molecular correlation energies with guaranteed precision. AB - We present an approach to compute accurate correlation energies for atoms and molecules in the framework of multiresolution analysis (MRA), using an adaptive discontinuous multiresolution spectral-element representation for the six dimensional (two-electron) pair function. The key features of our approach that make it feasible, namely (1) low-rank tensor approximations of functions and operators and (2) analytic elimination of operator singularities via explicit correlation, were retained from the previous work [F. A. Bischoff, R. J. Harrison, and E. F. Valeev, J. Chem. Phys. 137, 104103 (2012)]. Here we generalized the working equations to handle general (non-symmetric) many-electron systems at the MP2 level. The numerical performance is shown for the beryllium atom and the water molecule where literature data for the basis set limits could be reproduced to a few tens of MUE(h). The key advantages of molecular MRA-MP2 are the absence of bias and arbitrariness in the choice of the basis set, high accuracy, and low scaling with respect to the system size. PMID- 24070280 TI - Insights into the semiclassical Wigner treatment of bimolecular collisions. AB - The semiclassical Wigner treatment of bimolecular collisions, proposed by Lee and Scully on a partly intuitive basis [J. Chem. Phys. 73, 2238 (1980)], is derived here from first principles. The derivation combines Heller's ideas [J. Chem. Phys. 62, 1544 (1975); ibid. 65, 1289 (1976); ibid. 75, 186 (1981)], the backward picture of molecular collisions [L. Bonnet, J. Chem. Phys. 133, 174108 (2010)] and the microreversibility principle. PMID- 24070279 TI - Reaction-diffusion approach to prevertebrae formation: effect of a local source of morphogen. AB - Periodic structure formation is an essential feature of embryonic development. Many models of this phenomenon, most of them based on time oscillations, have been proposed. However, temporal oscillations are not always observed during development and how a spatial periodic structure is formed still remains under question. We investigate a reaction-diffusion model, in which a Turing pattern develops without temporal oscillations, to assess its ability to account for the formation of prevertebrae. We propose a correspondence between the species of the reaction scheme and biologically relevant molecules known as morphogens. It is shown that the model satisfactorily reproduces experiments involving grafting of morphogen sources into the embryos. Using a master equation approach and the direct simulation Monte Carlo method, we examine the robustness of the results to internal fluctuations. PMID- 24070281 TI - Asymptotic equivalence of the shell-model and local-density descriptions of Coulombic systems confined by radially symmetric potentials in two and three dimensions. AB - Asymptotic equivalence of the shell-model and local-density (LDA) descriptions of Coulombic systems confined by radially symmetric potentials in two and three dimensions is demonstrated. Tight upper bounds to the numerical constants that enter the LDA expressions for the Madelung energy are derived and found to differ by less than 0.5% from the previously known approximate values. Thanks to the variational nature of the shell-model approximate energies, asymptotic expressions for other properties, such as mean radial positions of the particles and number densities, are also obtained. A conjecture that generalizes the present results to confining potentials with arbitrary symmetries is formulated. PMID- 24070282 TI - Space group symmetry applied to SCF calculations with periodic boundary conditions and Gaussian orbitals. AB - Space group symmetry is exploited and implemented in density functional calculations of extended systems with periodic boundary conditions. Our scheme for reducing the number of two-electron integrals employs the entire set of operations of the space group, including glide plains and screw axes. Speedups observed for the Fock matrix formation in simple 3D systems range from 2X to 9X for the near field Coulomb part and from 3X to 8X for the Hartree-Fock-type exchange, the slowest steps of the procedure, thus leading to a substantial reduction of the computational time. The relatively small speedup factors in special cases are attributed to the highly symmetric positions atoms occupy in crystals, including the ones tested here, as well as to the choice of the smallest possible unit cells. For quasi-1D systems with most atoms staying invariant only under identity, the speedup factors often exceed one order of magnitude reaching almost 70X (near-field Coulomb) and 57X (HFx) for the largest tested (16,7) single-walled nanotube with 278 symmetry operations. PMID- 24070284 TI - Wave function for time-dependent harmonically confined electrons in a time dependent electric field. AB - The many-body wave function of a system of interacting particles confined by a time-dependent harmonic potential and perturbed by a time-dependent spatially homogeneous electric field is derived via the Feynman path-integral method. The wave function is comprised of a phase factor times the solution to the unperturbed time-dependent Schrodinger equation with the latter being translated by a time-dependent value that satisfies the classical driven equation of motion. The wave function reduces to that of the Harmonic Potential Theorem wave function for the case of the time-independent harmonic confining potential. PMID- 24070283 TI - Induced spin filtering in electron transmission through chiral molecular layers adsorbed on metals with strong spin-orbit coupling. AB - Recent observations of considerable spin polarization in photoemission from metal surfaces through monolayers of chiral molecules were followed by several efforts to rationalize the results as the effect of spin-orbit interaction that accompanies electronic motion on helical, or more generally strongly curved, potential surfaces. In this paper we (a) argue, using simple models, that motion in curved force-fields with the typical energies used and the characteristic geometry of DNA cannot account for such observations; (b) introduce the concept of induced spin filtering, whereupon selectivity in the transmission of the electron orbital angular momentum can induce spin selectivity in the transmission process provided there is strong spin-orbit coupling in the substrate; and (c) show that the spin polarization in the tunneling current as well as the photoemission current from gold covered by helical adsorbates can be of the observed order of magnitude. Our results can account for most of the published observations that involved gold and silver substrates; however, recent results obtained with an aluminum substrate can be rationalized within the present model only if strong spin-orbit coupling is caused by the built-in electric field at the molecule-metal interface. PMID- 24070285 TI - Optimal geometries and harmonic vibrational frequencies of the global minima of water clusters (H2O)n, n = 2-6, and several hexamer local minima at the CCSD(T) level of theory. AB - We report the first optimum geometries and harmonic vibrational frequencies for the ring pentamer and several water hexamer (prism, cage, cyclic and two book) at the coupled-cluster including single, double, and full perturbative triple excitations (CCSD(T))/aug-cc-pVDZ level of theory. All five examined hexamer isomer minima previously reported by Moller-Plesset perturbation theory (MP2) are also minima on the CCSD(T) potential energy surface (PES). In addition, all CCSD(T) minimum energy structures for the n = 2-6 cluster isomers are quite close to the ones previously obtained by MP2 on the respective PESs, as confirmed by a modified Procrustes analysis that quantifies the difference between any two cluster geometries. The CCSD(T) results confirm the cooperative effect of the homodromic ring networks (systematic contraction of the nearest-neighbor (nn) intermolecular separations with cluster size) previously reported by MP2, albeit with O-O distances shorter by ~0.02 A, indicating that MP2 overcorrects this effect. The harmonic frequencies at the minimum geometries were obtained by the double differentiation of the CCSD(T) energy using an efficient scheme based on internal coordinates that reduces the number of required single point energy evaluations by ~15% when compared to the corresponding double differentiation using Cartesian coordinates. Negligible differences between MP2 and CCSD(T) frequencies are found for the librational modes, while uniform increases of ~15 and ~25 cm(-1) are observed for the bending and "free" OH harmonic frequencies. The largest differences between CCSD(T) and MP2 are observed for the harmonic hydrogen bonded frequencies, for which the former produces larger absolute values than the latter. Their CCSD(T) redshifts from the monomer values (Deltaomega) are smaller than the MP2 ones, due to the fact that CCSD(T) produces shorter elongations (DeltaR) of the respective hydrogen bonded OH lengths from the monomer value with respect to MP2. Both the MP2 and CCSD(T) results for the hydrogen bonded frequencies were found to closely follow the relation -Deltaomega = s . DeltaR, with a rate of s = 20.2 cm(-1)/0.001 A for hydrogen bonded frequencies with IR intensities >400 km/mol. The CCSD(T) harmonic frequencies, when corrected using the MP2 anharmonicities obtained from second order vibrational perturbation theory, produce anharmonic CCSD(T) estimates that are within <60 cm(-1) from the measured infrared (IR) active bands of the n = 2-6 clusters. Furthermore, the CCSD(T) harmonic redshifts (with respect to the monomer) trace the measured ones quite accurately. The energetic order between the various hexamer isomers on the PES (prism has the lowest energy) previously reported at MP2 was found to be preserved at the CCSD(T) level, whereas the inclusion of anharmonic corrections further stabilizes the cage among the hexamer isomers. PMID- 24070286 TI - State to state photodissociation dynamics of D2O in the B band. AB - State-to-state photodissociation dynamics of D2O in the B band has been investigated using the recently developed diabatic potential energy surfaces. Quantum dynamical calculations including the electronic X and B states were carried out using a Chebyshev real wave packet method. The nonadiabatic channel via the DOD conical intersection is facile, direct, and fast, which produces rotationally hot and vibrationally cold OD(X) product. On the other hand, the adiabatic channel on the excited state, leading to the OD(A) product, is dominated by long-lived resonances, which depend sensitively on the potential energy surface. The calculated absorption spectra, product state distributions, branching ratios, and angular distributions are in reasonably good agreement with the latest experimental results. PMID- 24070287 TI - Dynamic of negative ions in potassium-D-ribose collisions. AB - We present negative ion formation from collisions of neutral potassium atoms with D-ribose (C5H10O5), the sugar unit in the DNA/RNA molecule. From the negative ion time-of-flight (TOF) mass spectra, OH(-) is the main fragment detected in the collision range 50-100 eV accounting on average for 50% of the total anion yield. Prominence is also given to the rich fragmentation pattern observed with special attention to O(-) (16 m/z) formation. These results are in sharp contrast to dissociative electron attachment experiments. The TOF mass spectra assignments show that these channels are also observed, albeit with a much lower relative intensity. Branching ratios of the most abundant fragment anions as a function of the collision energy are obtained, allowing to establish a rationale on the collision dynamics. PMID- 24070288 TI - Vibrationally enhanced charge transfer and mode/bond-specific H+ and D+ transfer in the reaction of HOD+ with N2O. AB - The reaction of HOD(+) with N2O was studied over the collision energy (E(col)) range from 0.20 eV to 2.88 eV, for HOD(+) in its ground state and in each of its fundamental vibrational states: bend (010), OD stretch (100), and OH stretch (001). The dominant reaction at low E(col) is H(+) and D(+) transfer, but charge transfer becomes dominant for E(col) > 0.5 eV. Increasing E(col) enhances charge transfer only in the threshold region (E(col) < 1 eV), but all modes of HOD(+) vibrational excitation enhance this channel over the entire energy range, by up to a factor of three. For reaction of ground state HOD(+), the H(+) and D(+) transfer channels have similar cross sections, enhanced by increasing collision energy for E(col) < 0.3 eV, but suppressed by E(col) at higher energies. OD stretch excitation enhances D(+) transfer by over a factor of 2, but has little effect on H(+) transfer, except at low E(col) where a modest enhancement is observed. Excitation of the OH stretch enhances H(+) transfer by up to a factor of 2.5, but actually suppresses D(+) transfer over most of the E(col) range. Excitation of the bend mode results in ~60% enhancement of both H(+) and D(+) transfer at low E(col) but has little effect at higher energies. Recoil velocity distributions at high E(col) are strongly backscattered in the center-of-mass frame, indicating direct reaction dominated by large impact parameter collisions. At low E(col) the distributions are compatible with mediation by a short-lived collision complex. Ab initio calculations find several complexes that may be important in this context, and RRKM calculations predict lifetimes and decay branching that is consistent with observations. The recoil velocity distributions show that HOD(+) vibrational excitation enhances reactivity in all collisions at low E(col), while for high E(col) with enhancement comes entirely from the subset of collisions that generate strongly back-scattered product ions. PMID- 24070289 TI - Solvation properties and behaviour of lutetium(III) in aqueous solution--a quantum mechanical charge field (QMCF) study. AB - This work presents the first ab initio molecular dynamics study of trivalent lutetium in aqueous solution. The hybrid quantum and molecular mechanics simulation has been carried out on Hartree-Fock level and the results were compared to extended X-ray absorption fine structure and X-ray diffraction data. In addition to the structural characterisation via radial and angular distribution functions, the influence of the ion on the surrounding solvent was further investigated by local-density-corrected three-body distribution functions and frequency calculations. The obtained results for the mean Lu-O bond distance and force constant were in very good agreement with the literature. Furthermore, deeper insight into the dynamics and geometry of the solvation shell and the number of involved solvent molecules was obtained. PMID- 24070290 TI - Structural changes in the series of boron-carbon mixed clusters C(x)B(10-x)- (x = 3-10) upon substitution of boron by carbon. AB - We report a theoretical investigation on the ten-atom boron-carbon mixed clusters C(x)B(10-x)(-) (x = 3-10), revealing a molecular wheel to monocyclic ring and linear species structural change as a function of x upon increasing the number of carbon atoms in the studied series. The unbiased searches for the global minimum structures of the clusters with x ranging from 3 to 9 were conducted using the Coalescence Kick program for different spin multiplicities. Subsequent geometry optimizations with follow-up frequency calculations at the hybrid density functional B3LYP/6-311+G(d) level of theory along with the single point coupled cluster calculations (UCCSD(T)/aug-cc-pVTZ//B3LYP/6-311+G(d) and RCCSD(T)/aug-cc pVTZ//B3LYP/6-311+G(d)) revealed that the C3B7(-) and C4B6(-) clusters possess planar distorted wheel-type structures with a single inner boron atom, similar to the recently reported CB9(-) and C2B8(-). Going from C5B5(-) to C9B(-) inclusive, monocyclic and ring-like structures are observed as the most stable ones on the PES. The first linear species in the presented series is found for the C10(-) cluster, which is almost isoenergetic with the one possessing a monocyclic geometry. The classical 2c-2e sigma bonds are responsible for the peripheral bonding in both carbon- and boron-rich clusters, whereas multicenter sigma bonding (nc-2e bonds with n > 2) on the inner fragments in boron-rich clusters is found to be the effective tool to describe their chemical bonding nature. It was shown that the structural transitions in the C(x)B(10-x)(-) series occur in part due to the preference of carbon to form localized bonds, which are found on the periphery of the clusters. Chemical bonding picture of C10(-) is explained on the basis of the geometrical structures of the C10 and C10(2-) clusters and their chemical bonding analyses. PMID- 24070291 TI - Cooling rate and size effects on the medium-range structure of multicomponent oxide glasses simulated by molecular dynamics. AB - A set of molecular dynamics simulations were performed to investigate the effect of cooling rate and system size on the medium-range structure of melt-derived multicomponent silicate glasses, represented by the quaternary 45S5 Bioglass composition. Given the significant impact of the glass degradation on applications of these materials in biomedicine and nuclear waste disposal, bulk structural features which directly affect the glass dissolution process are of particular interest. Connectivity of the silicate matrix, ion clustering and nanosegregation, distribution of ring and chain structural patterns represent critical features in this context, which can be directly extracted from the models. A key issue is represented by the effect of the computational approach on the corresponding glass models, especially in light of recent indications questioning the suitability of conventional MD approaches (that is, involving melt-and-quench of systems containing ~10(3) atoms at cooling rates of 5-10 K/ps) when applied to model these glasses. The analysis presented here compares MD models obtained with conventional and nonconventional cooling rates and system sizes, highlighting the trend and range of convergence of specific structural features in the medium range. The present results show that time-consuming computational approaches involving much lower cooling rates and/or significantly larger system sizes are in most cases not necessary in order to obtain a reliable description of the medium-range structure of multicomponent glasses. We identify the convergence range for specific properties and use them to discuss models of several glass compositions for which a possible influence of cooling-rate or size effects had been previously hypothesized. The trends highlighted here represent an important reference to obtain reliable models of multicomponent glasses and extract converged medium-range structural features which affect the glass degradation and thus their application in different fields. In addition, as a first application of the present findings, the fully converged structure of the 45S5 glass was further analyzed to shed new light on several dissolution-related features whose interpretation has been rather controversial in the past. PMID- 24070292 TI - Revisiting a many-body model for water based on a single polarizable site: from gas phase clusters to liquid and air/liquid water systems. AB - We present a revised version of the water many-body model TCPE [M. Masella and J. P. Flament, J. Chem. Phys. 107, 9105 (1997)], which is based on a static three charge sites and a single polarizable site to model the molecular electrostatic properties of water, and on an anisotropic short range many-body energy term specially designed to accurately model hydrogen bonding in water. The parameters of the revised model, denoted TCPE/2013, are here developed to reproduce the ab initio energetic and geometrical properties of small water clusters (up to hexamers) and the repulsive water interactions occurring in cation first hydration shells. The model parameters have also been refined to reproduce two liquid water properties at ambient conditions, the density and the vaporization enthalpy. Thanks to its computational efficiency, the new model range of applicability was validated by performing simulations of liquid water over a wide range of temperatures and pressures, as well as by investigating water liquid/vapor interfaces over a large range of temperatures. It is shown to reproduce several important water properties at an accurate enough level of precision, such as the existence liquid water density maxima up to a pressure of 1000 atm, the water boiling temperature, the properties of the water critical point (temperature, pressure, and density), and the existence of a "singularity" temperature at about 225 K in the supercooled regime. This model appears thus to be particularly well-suited for characterizing ion hydration properties under different temperature and pressure conditions, as well as in different phases and interfaces. PMID- 24070293 TI - Correlation of ion dynamics with characteristic length scales and network structural units in bismuth borate glasses. AB - Ion dynamics in lithium bismuth borate conducting glasses have been reported in wide composition and temperature ranges. The activation energy for the dc conduction has been analysed using Anderson-Stuart model and a correlation between the dc conductivity and the doorway radius has been predicted. The characteristic length scales for ion dynamics, such as mean square displacement and spatial extent of sub-diffusive motion of lithium ions have been determined from the ac conductivity and dielectric spectra, respectively. A direct connection between the ion dynamics and the characteristic length scales and the network structural units have been established. PMID- 24070294 TI - Core-softened fluids as a model for water and the hydrophobic effect. AB - An interaction model with core-softened potential in three dimensions was studied by Monte Carlo computer simulations and integral equation theory. We investigated the possibility that a fluid with a core-softened potential can reproduce anomalies found experimentally in liquid water, such as the density anomaly, the minimum in the isothermal compressibility as a function of temperature, and others. Critical points of the fluid were also determined. We provided additional arguments that the old notion, postulating that only angular-dependent interactions result in density anomaly, is incorrect. We showed that potential with two characteristic distances is sufficient for the system to exhibit water like behavior and anomalies, including the famous density maximum. We also found that this model can properly describe the hydrophobic effect. PMID- 24070295 TI - High-frequency acoustic modes in an ionic liquid. AB - High-frequency collective dynamics of the ionic liquid 1-hexyl-3 methylimidazolium bromide, [C6C1im]Br, has been investigated by molecular dynamics simulations. Time correlation functions of mass current fluctuations were calculated for several wavevectors and the dispersion curves of excitations, omega(k), for longitudinal and transverse acoustic sound modes were obtained at different temperatures and pressures. Two different thermodynamic states have the same high-frequency sound velocity irrespective of the temperature provided that both have the same density. Partial time correlation functions of mass currents were calculated for the atoms belonging to the polar or the non-polar domains resulting from the heterogeneous structure of [C6C1im]Br. The partial correlation functions indicate that the polar domains are stiffer than the non-polar domains of the simulated ionic liquid. PMID- 24070296 TI - Relation between the activation energy of oxygen diffusion and the instantaneous shear modulus in propylene carbonate near the glass transition temperature. AB - We discuss the transport of small gas molecules in organic glassy matrices using oxygen diffusion in propylene carbonate as an example. The jumps of a penetrant from one interstitial cavity to another require energy to expand the channel between cavities to the size of the penetrant. It has been established that at temperatures below and slightly above the glass transition temperature, the activation energy of oxygen diffusion, E, is related to the instantaneous shear modulus Ginfinity of propylene carbonate via the equation E = V * Ginfinity, where V is the temperature-independent parameter that characterizes the volume of the channel. Consequently, the E value is the work necessary for elastic deformation of the surrounding matrix to expand the channel available for oxygen diffusion. PMID- 24070297 TI - Structural, electronic and vibrational properties of N,N'-1H,1H-perfluorobutyl dicyanoperylenecarboxydiimide (PDI-FCN2) crystal. AB - We present a theoretical and experimental investigation of the crystalline structure of N,N'-1H,1H-perfluorobutyl dicyanoperylenecarboxydiimide (PDI-FCN2) that has been deduced combining experimental XRD data, obtained from powders, with global-optimization algorithms which allow to identify Bravais lattice, primitive cell parameters, and space group of the crystal. The XRD spectrum calculated for the proposed crystalline structure very well reproduces the measured XRD data. Our results suggest the triclinic lattice structure of spatial groups P1 and P1, respectively, for the crystalline PDI-FCN2-1,7 and PDI-FCN2-1,6 isomers. In both cases, the primitive cell contains a single molecule. On the proposed crystalline structures, KS-DFT cell energy calculations, including van der Waals interactions, have been performed to assign the minimum energy geometrical structure and orientation of the molecule inside the corresponding primitive cell. These calculations evidence the molecular packing that characterizes the strong anisotropy of the PDI-FCN2 crystal. Electronic band structures calculated for both isomers within the Kohn-Sham density-functional theory indicate that the crystalline P1 structure is an indirect gap semiconductor, while the P1 structure is a direct gap semiconductor. The electronic band structure calculations on the optimized crystal geometries highlight strong anisotropy in the dispersion curves E(k), which roots at the molecular packing in the crystal. Finally, the vibrational spectrum of both crystalline isomers has been calculated in the harmonic approximation and the dominant vibrational frequencies have been associated to collective motions of selected atoms in the molecules. PMID- 24070298 TI - Effect of ion structure on conductivity in lithium-doped ionic liquid electrolytes: a molecular dynamics study. AB - Molecular dynamics simulations were performed to examine the role cation and anion structure have on the performance of ionic liquid (IL) electrolytes for lithium conduction over the temperature range of 320-450 K. Two model ionic liquids were studied: 1-butyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([bmim][Tf2N]) and 1-butyl-4-methylpyridinium pyrrolide ([bmpyr][pyl]) doped with Li[Tf2N] and Li[pyl], respectively. The results have demonstrated that the Li(+) doped IL containing the planar [bmpyr] cation paired with the planar [pyl] anion significantly outperformed the [bmim][Tf2N] IL. The different coordination of Li(+) with the [Tf2N](-) or [pyl]( ) anions produces a remarkable change in IL structure with a concomitant effect on the transport of all ions. For the doped [bmim][Tf2N], each Li(+) is coordinated by four oxygen atoms from [Tf2N](-) anions. Formation of a rigid structure between Li(+) and [Tf2N](-) induces a decrease in the mobility of all ions. In contrast, for the doped [bmpyr][pyl], each Li(+) is coordinated by two nitrogen atoms from [pyl](-) anions. The original alternating structure cation?anion?cation in the neat [bmpyr][pyl] is replaced by another alternating structure cation?anion?Li(+)?anion?cation in the doped [bmpyr][pyl]. Increases of Li(+) mole fraction in doped [bmpyr][pyl] affects the dynamics to a much lesser extent compared with [bmim][Tf2N] and leads to reduced diffusivities of cations and anions, but little change in the dynamics of Li(+). More importantly, the calculations predict that the Li(+) ion conductivity of doped [bmpyr][pyl] is comparable to that observed in organic liquid electrolytes and is about an order of magnitude higher than that of doped [bmim][Tf2N]. Such Li(+) conductivity improvement suggests that this and related ILs may be promising candidates for use as electrolytes in lithium ion batteries and capacitors. PMID- 24070299 TI - Effects of impact velocity on pressure-driven nanofluid. AB - Using molecular dynamics simulations, we investigate the pressure-driven water infiltration behavior of carbon nanotubes (CNTs), in which water molecules can infiltrate into CNTs from outside upon an external impact load. According to the direction of impact mechanical wave, the infiltration procedure can be divided into the forward stage (stage I) and the reflected stage (stage II). At the forward stage of mechanical wave, the flow behavior strongly depends on the impact velocity but it is essentially not very sensitive to the tube radius. With a higher impact velocity, the water flow has a higher transport velocity, a lower density, a weaker CNT-water interaction, a higher potential energy, and a more disordered structure shown by a wider distribution of water dipole and OH bonds orientations. At the reflected stage, due to the impact pressure effect, the water structure is significantly changed, and the flow behavior is less sensitive to the impact velocity but more sensitive to the tube radius. After the reflected wave passed the water molecules inside CNTs, the water density and potential are significantly increased, which initiates a significant change for the water structure inside CNTs, especially for small size tubes. In a small tube like (10,10), a new water conformation is created in the reflected procedure, while there is no such new structure created in a larger tube like (20,20). Due to the different structures, the behavior of the pressure-driven water flow inside CNTs is significantly different than the steady flow. PMID- 24070300 TI - Ion selection of charge-modified large nanopores in a graphene sheet. AB - Water desalination becomes an increasingly important approach for clean water supply to meet the rapidly growing demand of population boost, industrialization, and urbanization. The main challenge in current desalination technologies lies in the reduction of energy consumption and economic costs. Here, we propose to use charged nanopores drilled in a graphene sheet as ion exchange membranes to promote the efficiency and capacity of desalination systems. Using molecular dynamics simulations, we investigate the selective ion transport behavior of electric-field-driven KCl electrolyte solution through charge modified graphene nanopores. Our results reveal that the presence of negative charges at the edge of graphene nanopore can remarkably impede the passage of Cl(-) while enhance the transport of K(+), which is an indication of ion selectivity for electrolytes. We further demonstrate that this selectivity is dependent on the pore size and total charge number assigned at the nanopore edge. By adjusting the nanopore diameter and electric charge on the graphene nanopore, a nearly complete rejection of Cl( ) can be realized. The electrical resistance of nanoporous graphene, which is a key parameter to evaluate the performance of ion exchange membranes, is found two orders of magnitude lower than commercially used membranes. Our results thus suggest that graphene nanopores are promising candidates to be used in electrodialysis technology for water desalinations with a high permselectivity. PMID- 24070301 TI - Determination of the surface structure of CeO2(111) by low-energy electron diffraction. AB - We determine the atomic structure of the (111) surface of an epitaxial ceria film using low-energy electron diffraction (LEED). The 3-fold-symmetric LEED patterns are consistent with a bulk-like termination of the (111) surface. By comparing the experimental dependence of diffraction intensity on electron energy (LEED I(V) data) with simulations of dynamic scattering from different surface structures, we find that the CeO2(111) surface is terminated by a plane of oxygen atoms. We also find that the bond lengths in the top few surface layers of CeO2(111) are mostly undistorted from their bulk values, in general agreement with theoretical predictions. However, the topmost oxygen layer is further from the underlying cerium layer than the true bulk termination, an expansion that differs from theoretical predictions. PMID- 24070302 TI - Influence of confinement on thermodiffusion. AB - This work focuses on a possible influence of a nanoporous medium on the thermodiffusion of a fluid "isotopic" mixture. To do so, we performed molecular dynamics simulations of confined Lennard-Jones binary equimolar mixtures using grand-canonical like and non-equilibrium approaches in sub- and super-critical conditions. The study was conducted in atomistic slit pore of three adsorbent natures for various widths (from 5 to 35 times the size of a molecule). The simulation results indicate that for all thermodynamic conditions and whatever the pore characteristics, the confinement has a negligible effect on the thermal diffusion factor/Soret coefficient. However, when considered separately, the mass diffusion and thermodiffusion coefficients have been found to be largely influenced by the pore characteristics. These two coefficients decrease noticeably when adsorption is stronger and pore width smaller, a behavior that is consistent with a simple hydrodynamic explanation. PMID- 24070303 TI - Freezing point and solid-liquid interfacial free energy of Stockmayer dipolar fluids: a molecular dynamics simulation study. AB - Stockmayer fluids are a prototype model system for dipolar fluids. We have computed the freezing temperatures of Stockmayer fluids at zero pressure using three different molecular-dynamics simulation methods, namely, the superheating undercooling method, the constant-pressure and constant-temperature two-phase coexistence method, and the constant-pressure and constant-enthalpy two-phase coexistence method. The best estimate of the freezing temperature (in reduced unit) for the Stockmayer (SM) fluid with the dimensionless dipole moment MU*=1, ?2, ?3 is 0.656 +/- 0.001, 0.726 +/- 0.002, and 0.835 +/- 0.005, respectively. The freezing temperature increases with the dipolar strength. Moreover, for the first time, the solid-liquid interfacial free energies gamma of the fcc (111), (110), and (100) interfaces are computed using two independent methods, namely, the cleaving-wall method and the interfacial fluctuation method. Both methods predict that the interfacial free energy increases with the dipole moment. Although the interfacial fluctuation method suggests a weaker interfacial anisotropy, particularly for strongly dipolar SM fluids, both methods predicted the same trend of interfacial anisotropy, i.e., gamma100 > gamma110 > gamma111. PMID- 24070304 TI - Hydrophobic and hydrophilic interactions in aqueous mixtures of alcohols at a hydrophobic surface. AB - Aqueous solutions of alcohols are interesting because of their anomalous behavior that is believed to be due to the molecular structuring of water and alcohol around each other in solution. The interfacial structuring and properties are significant for application in alcohol purification processes and biomolecular structure. Here we study aqueous mixtures of short alcohols (methanol, ethanol, 1 propanol, and 2-propanol) at a hydrophobic surface using interfacial statistical associating fluid theory which is a perturbation density functional theory. The addition of a small amount of alcohol decreases the interfacial tension of water drastically. This trend in interfacial tension can be explained by the structure of water and alcohol next to the surface. The hydrophobic group of an added alcohol preferentially goes to the surface preserving the structure of water in the bulk. For a given bulk alcohol concentration, water mixed with the different alcohols has different interfacial tensions with propanol having a lower interfacial tension than methanol and ethanol. 2-propanol is not as effective in decreasing the interfacial tension as 1-propanol because it partitions poorly to the surface due to its larger excluded volume. But for a given surface alcohol mole fraction, all the alcohol mixtures give similar values for interfacial tension. For separation of alcohol from water, methods that take advantage of the high surface mole fraction of alcohol have advantages compared to separation using the vapor in equilibrium with a water-alcohol liquid. PMID- 24070305 TI - Monte Carlo simulation of flexible trimers: from square well chains to amphiphilic primitive models. AB - In this work, we present Monte Carlo computer simulation results of a primitive model of self-assembling system based on a flexible 3-mer chain interacting via square-well interactions. The effect of switching off the attractive interaction in an extreme sphere is analyzed, since the anisotropy in the molecular potential promotes self-organization. Before addressing studies on self-organization it is necessary to know the vapor liquid equilibrium of the system to avoid to confuse self-organization with phase separation. The range of the attractive potential of the model, lambda, is kept constant and equal to 1.5sigma, where sigma is the diameter of a monomer sphere, while the attractive interaction in one of the monomers was gradually turned off until a pure hard body interaction was obtained. We present the vapor-liquid coexistence curves for the different models studied, their critical properties, and the comparison with the SAFT-VR theory prediction [A. Gil-Villegas, A. Galindo, P. J. Whitehead, S. J. Mills, G. Jackson, and A. N. Burgess, J. Chem. Phys. 106, 4168 (1997)]. Evidence of self assembly for this system is discussed. PMID- 24070306 TI - Reassessment of structure of smectic phases: nano-segregation in smectic E phase in 4-n-alkyl-4'-isothiocyanato-1,1'-biphenyls. AB - Based on new diffraction data from aligned samples of smectic E (SmE) phase of 4 n-alkyl-4'-isothiocyanato-1,1'-biphenyls, systematics against the alkyl chain length n is analyzed. In order to perform the analysis, the molecular form factor approximated by a box-shaped distribution is calculated while taking the rounding of the distribution at corners into account. The analysis clearly shows the nano segregated layered structure, which does not fit to the traditional structural view of SmE phase but does fit to the model the present authors proposed recently. Some implications of this conclusion are discussed in relation to the importance of the molten state of alkyl chains in most of real mesogens revealed previously through thermodynamic analyses. PMID- 24070307 TI - The red-phase of poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEH PPV): a disordered HJ-aggregate. AB - The ratio of the 0-0 to 0-1 peak intensities in the photoluminescence (PL) spectrum of red-phase poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene], better known as MEH-PPV, is significantly enhanced relative to the disordered blue-phase and is practically temperature independent in the range from T = 5 K to 180 K. The PL lifetime is similarly temperature independent. The measured trends are accounted for by modeling red-phase MEH-PPV as disordered pi-stacks of elongated chains. Using the HJ-aggregate Hamiltonian expanded to include site disorder amongst electrons and holes, the absorption and PL spectra of cofacial MEH-PPV dimers are calculated. The PL 0-0/0-1 line strength ratio directly responds to the competition between intrachain interactions which promote J aggregate-like behavior (enhanced PL ratio) and interchain interactions which promote H-aggregate-like behavior (attenuated PL ratio). In MEH-PPV aggregates, J like behavior is favored by a relatively large intrachain exciton bandwidth- roughly an order of magnitude greater than the interchain bandwidth--and the presence of disorder. The latter is essential for allowing 0-0 emission at low temperatures, which is otherwise symmetry forbidden. For Gaussian disorder distributions consistent with the measured (inhomogeneous) line widths of the vibronic peaks in the absorption spectrum, calculations show that the 0-0 peak maintains its dominance over the 0-1 peak, with the PL ratio and radiative lifetime practically independent of temperature, in excellent agreement with experiment. Interestingly, interchain interactions lead only to about a 30% drop in the PL ratio, suggesting that the MEH-PPV pi-stacks--and strongly disordered HJ-aggregates in general--can masquerade as single (elongated) chains. Our results may have important applications to other emissive conjugated polymers such as the beta-phase of polyfluorenes. PMID- 24070308 TI - Morphology evolution and rheological properties of polybutadiene/polyisoprene blend after the cessation of steady shear. AB - The morphology evolution and rheological response of a near-critical composition polybutadiene/polyisoprene blend after the cessation of steady shear was studied with an ARES rheometer and a shear light scattering photometer equipped with an optical microscope in this work. The relationship between the morphology of the blend during the relaxation after the cessation of steady shear with different shear rates and their corresponding rheological properties was successfully established. It was found that the different shear-induced morphologies under steady shear would relax to the equilibrium states via varied mechanisms after the shear cessation. The average size of the dispersed domains in the coarsening process was influenced by the pre-shear history. The results indicated that the pre-shear history could slow down the growth rate of phase domains during the coarsening process. It had effect on the coarsening mechanism on the early stage of relaxation after the cessation of very strong shear when the homogenization effects were strong, but no effect on the late stage. The storage modulus G' increased significantly in the breakup process of the string-like phase. After all the string-like structures were broken up into small ellipsoids, then G' gradually decreased and finally approached to an invariant value. The characteristic rheological behavior can be attributed to the different structure on the relaxation process. PMID- 24070309 TI - Sketching protein aggregation with a physics-based toy model. AB - We explore the applicability of a single-bead coarse-grained molecular model to describe the competition between protein folding and aggregation. We have designed very simple and regular sequences, based on our previous studies on peptide aggregation, that successfully fold into the three main protein structural families (all-alpha, all-beta, and alpha + beta). Thanks to equilibrium computer simulations, we evaluate how temperature and concentration promote aggregation. Aggregates have been obtained for all the amino acid sequences considered, showing that this process is common to all proteins, as previously stated. However, each structural family presents particular characteristics that can be related to its specific balance between hydrogen bond and hydrophobic interactions. The model is very simple and has limitations, yet it is able to reproduce both the cooperative folding of isolated polypeptide chains with regular sequences and the formation of different types of aggregates at high concentrations. PMID- 24070310 TI - On the influence of hydrated imidazolium-based ionic liquid on protein structure stability: a molecular dynamics simulation study. AB - The structure stability of three alpha-helix bundle (the B domain of protein A) in an imidazolium-based ionic liquid (1-butyl-3-methylimidazolium chloride (BMIM Cl)) is studied by molecular dynamics simulations. Consistent with previous experiments, the present simulation results show that the native structure of the protein is consistently stabilized in BMIM-Cl solutions with different concentrations. It is observed that BMIM(+) cations have a strong tendency to accumulate on protein surface whereas Cl(-) anions are expelled from protein. BMIM(+) cations cannot only have electrostatic interactions with the carbonyl groups on backbone and the carboxylate groups on negatively charged side chains, but also have hydrophobic interactions with the side chains of non-polar residues. In the meanwhile, the accumulation of large-size BMIM(+) cations on protein surface could remove the surrounding water molecules, reduce the hydrogen bonding from water to protein, and thus stabilize the backbone hydrogen bonds. In summary, the present study could improve our understanding of the molecular mechanism of the impact of water-miscible ionic liquid on protein structure. PMID- 24070311 TI - Hydrophobic interactions and hydrogen bonds in beta-sheet formation. AB - In this study, we investigate interactions of extended conformations of homodimeric peptides made of small (glycine or alanine) and large hydrophobic (valine or leucine) sidechains using all-atom molecular dynamics simulations to decipher driving forces for beta-sheet formation. We make use of a periodic boundary condition setup in which individual peptides are infinitely long and stretched. Dimers adopt beta-sheet conformations at short interpeptide distances (xi ~ 0.5 nm) and at intermediate distances (~0.8 nm), valine and leucine homodimers assume cross-beta-like conformations with side chains interpenetrating each other. These two states are identified as minima in the potential of mean force. While the number of interpeptide hydrogen bonds increases with decreasing interpeptide distance, the total hydrogen bond number in the system does not change significantly, suggesting that formation of beta-sheet structures from extended conformations is not driven by hydrogen bonds. This is supported by an increase in electrostatic energy at short interpeptide distances. A remarkable correlation between the volume of the system and the total electrostatic energy is observed, further reinforcing the idea that excluding water in proteins comes with an enthalpic penalty. We also discuss microscopic mechanisms accounting for beta-sheet formation based on computed enthalpy and entropy and we show that they are different for peptides with small and large side chains. PMID- 24070312 TI - Synergistic behavior of glycine betaine-urea mixture: a molecular dynamics study. AB - Glycine betaine (GB) is one of the most important osmolyte which is known to stabilize proteins as well as counteract the denaturing effect of urea. There have been many studies indicating protein stabilization and counteraction of the effect of urea by GB. However, the exact mechanism of counteraction is still debated and is of important research interest. In this study, distribution functions, hydrogen bonds, and energetics were analysed to understand different interactions between GB and urea, and their solvation properties in presence of each other. The results show that in the GB-urea mixture, GB acted as a stronger osmolyte and urea became a weaker denaturing agent than its individual counterparts. The increase in the solvation of urea and GB in GB-urea mixture and their mutual interactions through hydrogen bonding and coulombic energy resulted in more involvement of GB and urea with solvent as well as with themselves. This might result in the increase of the exclusion of GB from protein surface and decrease in the protein-urea interactions in the mixture. This synergistic behavior might be the prime reason for the counteraction of denaturing effect of urea by GB. PMID- 24070314 TI - Comment on "Photoelectron angular distributions as a probe of alignment in a polyatomic molecule: picosecond time- and angle-resolved photoelectron spectroscopy of S1 p-difluorobenzene" [J. Chem. Phys. 111, 1438 (1999)]. PMID- 24070313 TI - Efficient stochastic simulation of chemical kinetics networks using a weighted ensemble of trajectories. AB - We apply the "weighted ensemble" (WE) simulation strategy, previously employed in the context of molecular dynamics simulations, to a series of systems-biology models that range in complexity from a one-dimensional system to a system with 354 species and 3680 reactions. WE is relatively easy to implement, does not require extensive hand-tuning of parameters, does not depend on the details of the simulation algorithm, and can facilitate the simulation of extremely rare events. For the coupled stochastic reaction systems we study, WE is able to produce accurate and efficient approximations of the joint probability distribution for all chemical species for all time t. WE is also able to efficiently extract mean first passage times for the systems, via the construction of a steady-state condition with feedback. In all cases studied here, WE results agree with independent "brute-force" calculations, but significantly enhance the precision with which rare or slow processes can be characterized. Speedups over "brute-force" in sampling rare events via the Gillespie direct Stochastic Simulation Algorithm range from ~10(12) to ~10(18) for characterizing rare states in a distribution, and ~10(2) to ~10(4) for finding mean first passage times. PMID- 24070316 TI - Effect of dialysis on the proacrosin/acrosin system and motility of turkey (Meleagris gallopavo) spermatozoa during liquid storage. AB - 1. The effect of dialysis on the proacrosin/acrosin system and motility of turkey spermatozoa were examined after 24 and 48 h of liquid storage at 4 degrees C. 2. Fifteen pools of semen diluted in extender were dialysed against Clemson Turkey Semen Diluent (dialysed semen) or stored in aerobic conditions (undialysed semen). Semen quality was assessed by measuring spermatozoa motility, amidase activity of spermatozoa suspension, spermatozoa extract and seminal plasma and anti-trypsin activity of seminal plasma. 3. Extracted amidase activity of dialysed semen was lower than undialysed by 28%. Higher values for speed parameters of spermatozoa were found in dialysed semen in comparison to undialysed, for example, 81.6 um/s versus 75.0 um/s for straight-line velocity (VSL), 114.7 um/s versus 110.3 um/s for curvilinear velocity (VCL) and 86.6 um/s versus 79.8 um/s for average path velocity (VAP). 4. It was concluded that dialysis caused lower amidase activity of spermatozoa and increased speed parameters of progressively motile turkey spermatozoa during storage. Lower extracted amidase activity of dialysed semen reflected better membrane integrity of dialysed semen and suggests that the proacrosin/acrosin system of dialysed spermatozoa is less susceptible to activation compared to undialysed semen. PMID- 24070318 TI - A case of paroxysmal atrial fibrillation following low voltage electrocution. AB - BACKGROUND: Electrical injury may result in arrhythmias, however atrial fibrillation following low voltage electrocution is not a common occurrence. CASE PRESENTATION: A 70-year-old South-Asian woman with no prior history of cardiovascular disease presented following an accidental low voltage electrocution with loss of consciousness. On initial assessment she was found to be in atrial fibrillation with a moderate to rapid ventricular rate. Troponin I and 2D echo were normal. Transient rise in markers of muscle damage were noted. The arrhythmia resolved spontaneously without active intervention. CONCLUSION: Loss of consciousness and the path of electrical conduction involving the heart may herald cardiac involvement following electrocution. Low voltage electrocution may cause cardiac insult. Conservative management may suffice in management of atrial fibrillation without cardiovascular compromise. PMID- 24070320 TI - Selective determination of thiram residues in fruit and vegetables by hydrophilic interaction LC-MS. AB - Thiram belongs to the most important class of dithiocarbamate (DTC) fungicides including dimethyldithiocarbamates (DMDs), ethylenebis(dithiocarbamtes) (EBDs) and propylenebis(dithiocarbamates) (PBDs). During the surface extraction of fruit and vegetables for the LC-MS determination of residues of DMDs, EBDs and PBDs, thiram is reduced by the penicillamine buffer to the DMD anion, thus resulting in false-positive findings of DMD fungicides like ziram. Therefore, an alkaline sulfite buffer was applied for surface extraction, quantitatively transforming thiram into the DMD anion and a stable DMD-sulfite adduct that was used as a selective marker for thiram. Separation was performed isocratically on a ZIC pHILIC column with acetonitrile-10 mM ammonium hydroxide solution (85/15). Mass selective detection was carried out on a single-quadrupole mass spectrometer coupled to an electrospray ionisation interface operating in negative mode. Using d12-thiram as the internal standard, recoveries of 80-108% were obtained from apples, tomatoes, grapes and sweet peppers, spiked in the range of 0.02-1 mg kg( 1). Limits of detection and quantification were 0.6 and 2 ug kg(-1), respectively. PMID- 24070321 TI - Azilsartan medoxomil in the treatment of hypertension: the definitive angiotensin receptor blocker? AB - INTRODUCTION: Azilsartan medoxomil is the newest angiotensin receptor blocker marketed for the treatment of arterial hypertension. The aim of this article was to review the available evidence about this drug alone or combined with other antihypertensive agents in the treatment of hypertensive population. AREAS COVERED: For this purpose, a search on MEDLINE and EMBASE databases was performed. The MEDLINE and EMBASE search included both medical subject headings (MeSHs) and keywords including azilsartan or azilsartan medoxomil or angiotensin receptor blockers or renin angiotensin system or chlorthalidone and hypertension. References of the retrieved articles were also screened for additional studies. There were no language restrictions. EXPERT OPINION: Azilsartan medoxomil has a potent and persistent ability to inhibit binding of angiotensin II to AT1 receptors, which may play a role in its superior blood pressure (BP) -lowering efficacy compared with other drugs, including ramipril, candesartan, valsartan or olmesartan, without an increase of side effects. Chlortalidone is a diuretic which significantly differs from other classic thiazides and has largely demonstrated clinical benefits in outcome trials. The fixed-dose combination of azilsartan and chlorthalidone has been shown to be more effective than other potent combinations of angiotensin receptor blockers plus hydrochlorothiazide, with a good tolerability profile. PMID- 24070317 TI - Small ruminant macrophage polarization may play a pivotal role on lentiviral infection. AB - Small ruminant lentiviruses (SRLV) infect the monocyte/macrophage lineage inducing a long-lasting infection affecting body condition, production and welfare of sheep and goats all over the world. Macrophages play a pivotal role on the host's innate and adaptative immune responses against parasites by becoming differentially activated. Macrophage heterogeneity can tentatively be classified into classically differentiated macrophages (M1) through stimulation with IFN gamma displaying an inflammatory profile, or can be alternatively differentiated by stimulation with IL-4/IL-13 into M2 macrophages with homeostatic functions. Since infection by SRLV can modulate macrophage functions we explored here whether ovine and caprine macrophages can be segregated into M1 and M2 populations and whether this differential polarization represents differential susceptibility to SRLV infection. We found that like in human and mouse systems, ovine and caprine macrophages can be differentiated with particular stimuli into M1/M2 subpopulations displaying specific markers. In addition, small ruminant macrophages are plastic since M1 differentiated macrophages can express M2 markers when the stimulus changes from IFN-gamma to IL-4. SRLV replication was restricted in M1 macrophages and increased in M2 differentiated macrophages respectively according to viral production. Identification of the infection pathways in macrophage populations may provide new targets for eliciting appropriate immune responses against SRLV infection. PMID- 24070322 TI - Dynamics of chloroplast proteome in salt-stressed mangrove Kandelia candel (L.) Druce. AB - Kandelia candel is being established as a model xylophyte for ecoadaptation due to its salt tolerance. To adapt to high salinity, the photosynthesis apparatus must function efficiently under these conditions. Proteomic analysis of chloroplasts isolated from plants under different degrees of salt stress was performed to quantify the changes of individual proteins and to gain a global view of the total chloroplast protein dynamics. Among the 1030 proteins quantified (unique peptide >= 1), 76 showed a more than 1.5-fold change in abundance, of which 36 are involved in the light-dependent reactions and 12 in the Calvin cycle. The dynamic change of these proteins indicates that light dependent reactions are maintained by up-regulating the levels of component proteins at both moderate and high salinity, and the Calvin cycle remained functional at moderate salinity but showed a decline at high salinity. In addition to proteins related to photosynthesis, some known abiotic-stress proteins and plastoglobuli were up-regulated in salt-stressed plants. Plastoglobuli might contribute to maintaining membrane integrity and fluidity. In conclusion, this extensive proteomic investigation on intact chloroplasts of the salt-tolerant xylophyte under salt stress provides some important novel information on adaptative mechanisms involving photosynthesis in responses to salt stress in K. candel. PMID- 24070324 TI - Heteroleptic (2-fluoro-3-pyridyl)arylborinic 8-oxyquinolinates for the potential application in organic light-emitting devices. AB - A one-pot protocol has been developed to obtain a series of luminescent heteroleptic diarylborinic complexes bearing the 2-fluoro-3-pyridyl and another aryl group attached to the boron atom chelated with a simple or functionalized 8 oxyquinolinato ligand. The tetrahedral geometry around the boron atom in all compounds has been established by the (11)B NMR spectroscopy and/or X-ray diffraction technique. In the solution, the obtained complexes have emission maxima ranging from 502 to 525 nm at room temperature. The quantum yield of emission significantly depends on the type and position of the substituents in the 8-oxyquinolinato ligands and aryl rings. An interpretation of the experimental UV-vis absorption and emission spectral data is supported by theoretical calculations of the frontier molecular orbitals. Marcus theory was used to theoretically evaluate charge-transport properties of the obtained complexes. PMID- 24070323 TI - Saposin C protects glucocerebrosidase against alpha-synuclein inhibition. AB - Mutations in GBA1, the gene for glucocerebrosidase (GCase), are genetic risk factors for Parkinson disease (PD). alpha-Synuclein (alpha-Syn), a protein implicated in PD, interacts with GCase and efficiently inhibits enzyme activity. GCase deficiency causes the lysosomal storage disorder Gaucher disease (GD). We show that saposin C (Sap C), a protein vital for GCase activity in vivo, protects GCase against alpha-syn inhibition. Using nuclear magnetic resonance spectroscopy, site-specific fluorescence, and Forster energy transfer probes, Sap C was observed to displace alpha-syn from GCase in solution and on lipid vesicles. Our results suggest that Sap C might play a crucial role in GD-related PD. PMID- 24070325 TI - Statement of Retraction: Sellitto M, Messina F. "Central venous catheterization and thrombosis in newborns: update on diagnosis and management". PMID- 24070326 TI - Effects of auricular acupressure using Sinapsis alba seeds on obesity and self efficacy in female college students. AB - OBJECTIVES: To examine the effects of auricular acupressure with Sinapsis alba seeds on obesity and self-efficacy. DESIGN: Randomized controlled trial. SETTINGS: College settings located in metropolitan areas of Korea. PARTICIPANTS: A total of 49 female college students who were overweight or obese (body-mass index [BMI] >=25.0 kg/m(2)) were recruited and randomly assigned to the experimental group (n=25) or the control group (n=24). INTERVENTIONS: The experimental group applied three S. alba seeds to each of five auricular points (Shenmen, mouth, stomach, endocrine, and small intestine points). These participants were asked to stimulate those points 10 times at a rate of two times per second 30 minutes before mealtime, three times daily, for 1 month. They performed the procedure for each earlobe for alternating weeks (a total of 2 weeks' treatment for each ear). OUTCOME MEASURES: The obesity index included weight (kg), BMI (kg/m(2)), percentage body fat, and waist-to-hip ratio. Self efficacy was measured by using a self-efficacy scale. RESULTS: Female students in the experimental group showed significant decreases in weight (t=10.76; p<0.001) and BMI (t=9.60; p<0.001) and significant improvement in self-efficacy (t=1.85; p<0.05) compared with those in the control group. However, percentage body fat (t=1.27; p>0.05) and waist-to-hip ratio (t=0.60; p>0.05) changes did not significantly differ between the two groups. CONCLUSIONS: These findings suggest that auricular acupressure using S. alba seeds may be an effective intervention for decreasing weight and BMI and increasing self-efficacy of overweight and obese individuals. PMID- 24070328 TI - Inhibition of actin polymerization decreases osteogeneic differentiation of mesenchymal stem cells through p38 MAPK pathway. AB - BACKGROUND: Mesenchymal Stem Cells (MSC) are important candidates for therapeutic applications due to their ex vivo proliferation and differentiation capacity. MSC differentiation is controlled by both intrinsic and extrinsic factors and actin cytoskeleton plays a major role in the event. In the current study, we tried to understand the initial molecular mechanisms and pathways that regulate the differentiation of MSC into osteocytes or adipocytes. RESULTS: We observed that actin modification was important during differentiation and differentially regulated during adipogenesis and osteogenesis. Initial disruption of actin polymerization reduced further differentiation of MSC into osteocytes and osteogenic differentiation was accompanied by increase in ERK1/2 and p38 MAPK phosphorylation. However, only p38 MAPK phosphorylation was down regulated upon inhibition of actin polymerization which as accompanied by decreased CD49E expression. CONCLUSION: Taken together, our results show that actin modification is a pre-requisite for MSC differentiation into osteocytes and adipocytes and osteogenic differentiation is regulated through p38 MAPK phosphorylation. Thus by modifying their cytoskeleton the differentiation potential of MSC could be controlled which might have important implications for tissue repair and regeneration. PMID- 24070327 TI - Multidrug resistance in chronic myeloid leukaemia: how much can we learn from MDR CML cell lines? AB - The hallmark of CML (chronic myeloid leukaemia) is the BCR (breakpoint cluster region)-ABL fusion gene. CML evolves through three phases, based on both clinical and pathological features: a chronic phase, an accelerated phase and blast crisis. TKI (tyrosine kinase inhibitors) are the treatment modality for patients with chronic phase CML. The therapeutic potential of the TKI imatinib is affected by BCR-ABL dependent an independent mechanisms. Development of MDR (multidrug resistance) contributes to the overall clinical resistance. MDR involves overexpression of ABC -transporters (ATP-binding-cassette transporter) among other features. MDR studies include the analysis of cancer cell lines selected for resistance. CML blast crisis is accompanied by increased resistance to apoptosis. This work reviews the role played by the influx transporter OCT1 (organic cation transporter 1), by efflux ABC transporters, molecules involved in the modulation of apoptosis (p53, Bcl-2 family, CD95, IAPs (inhibitors of apoptosis protein)], Hh and Wnt/beta-catenin pathways, cytoskeleton abnormalities and other features described in leukaemic cells of clinical samples and CML cell lines. An MDR cell line, Lucena-1, generated from K562 by stepwise exposure to vincristine, was used as our model and some potential anticancer drugs effective against the MDR cell line and patients' samples are presented. PMID- 24070330 TI - Component processes in voluntary task switching. AB - The present study investigated the involvement of bottom-up and top-down control in task-switching situations in which tasks are selected on a voluntary basis. We tested for indices of both types of control in the reduction in switch cost that is observed when more time is available before executing a task. Participants had to indicate their task choice overtly prior to the actual task execution, and two time intervals were manipulated: the interval between the task-execution response of the previous trial and task-indication response of the current trial and the interval between task-indication response and task-execution response of a particular trial. In Experiment 1, the length of these intervals was manipulated orthogonally, and indices for top-down and bottom-up control were observed. Concerned with the validity of these results, Experiments 2-3 additionally discouraged participants from preparing the upcoming task before their task indication response. Indices for bottom-up control remained, but not for top-down control. The characteristics of top-down and bottom-up control in voluntary task switching and task switching in general are discussed. PMID- 24070329 TI - Patients undergoing surgery of intracranial metastases have different outcomes based on their primary pathology. AB - OBJECTIVES: Patients with a variety of different primary cancers can develop intracranial metastases. Patients who develop intracranial metastases are often grouped into the same study population, and therefore an understanding of outcomes for patients with different primary cancers remain unclear. METHODS: Adults who underwent intracranial metastatic tumor surgery from 1997-2011 at a single institution were retrospectively reviewed. Primary pathologies were compared using Fisher's exact and Student's t-test, and Cox regression analysis was used to identify factors associated with survival. RESULTS: About 708 patients underwent surgery during the reviewed period, where 269 (38%) had non small cell lung cancer (NSCLC), 106 (15%) breast cancer (BC), 72 (10%) gastrointestinal (GI) cancers, 88 (12%) renal cell cancer (RCC), and 88 (12%) melanoma. The most notable differences were that NSCLC patients were older, BC younger, BC had more primary tumor control, and NSCLC less extracranial spread. BC had longer survival, RCC had longer local progression free survival (PFS), and NSCLC had longer distal PFS. The factors independently associated with survival for NSCLC (female, recursive partitioning analysis (RPA) class, primary tumor control, solitary metastasis, tumor size, adenocarcinoma, radiation, discharge to home), BC (age, no skull base involvement, radiation), GI cancer (age, RPA class, Karnofsky performance scale (KPS), lack of preoperative motor deficit, non esophageal tumors, non-hemorrhagic tumors, avoidance of new deficits), melanoma (preoperative seizures, solitary metastasis, smaller tumor size, discharge to home, chemotherapy), and RCC (KPS, chemotherapy) were distinctly different. DISCUSSION: These differences between patients with different primary cancers support the fact that patients with intracranial disease are not all the same and should be studied by their primary pathology. PMID- 24070331 TI - Picosecond pulse radiolysis of the liquid diethyl carbonate. AB - The diethyl carbonate, DEC, is an ester that is used as a solvent in Li-ion batteries, but its behavior under ionizing radiation was unknown. The transient optical absorption spectra, the decay kinetics, and the influence of various scavengers have been studied by using the picosecond laser-triggered electron accelerator ELYSE. In neat DEC, the intense near-IR (NIR) absorption spectrum is assigned to the solvated electron. It is overlapped in the visible range by another transient but longer-lived and less intense band that is assigned to the oxidized radical DEC(-H). The solvated electron molar absorption coefficients and radiolytic yield evolution from 25 ps, the geminate recombination kinetics, and the rate constants of electron transfer reactions to scavengers are determined. The radiolytic mechanism, indicating a certain radioresistance of DEC, is compared with that for other solvents. PMID- 24070332 TI - Fungal spore concentrations in indoor and outdoor air in university libraries, and their variations in response to changes in meteorological variables. AB - The fungal spore concentration (FSC) in the air poses a risk for human health. This work studied the FSC in university libraries and how it is affected by environmental factors. A total of 347 samples were obtained using a Microbio MB2((r)) Aerosol Sampler. The wind speed (WS), cross wind (CW), temperature (T), relative humidity (HR), barometric pressure (BP) and dew point (DP) were recorded using a Kestrel((r)) 4500 weather station. The median indoor/outdoor FSC was 360/1230 CFU m(-3). FSC correlated inversely with BP, HR and DP; and positively with WS and CW; whereas T showed negative or positive correlation with FSC, depending on the region or sampling time. Eleven fungal genera were found and the dominant isolates were identified as Aspergillus niger, Aspergillus tamarii and Aspergillus oryzae. All fungi identified are known to be allergenic. It was concluded that environmental variables can influence the air FSC in different ways. PMID- 24070334 TI - Molecular flux dependence of chemical patterning by microcontact printing. AB - We address the importance of the dynamic molecular ink concentration at a polymer stamp/substrate interface during microcontact displacement or insertion printing. We demonstrate that by controlling molecular flux, we can influence both the molecular-scale order and the rate of molecular exchange of self-assembled monolayers (SAMs) on gold surfaces. Surface depletion of molecular ink at a polymer stamp/substrate interface is driven predominantly by diffusion into the stamp interior; depletion occurs briefly at the substrate by SAM formation, but diffusion of molecules into the bulk of the stamp dominates over practical experimental time scales. As contact time is increased, the interface concentration varies significantly due to diffusion, affecting the quality and coverage of printed films. Controlling interfacial concentration improves printed film reproducibility and the fractional coverage of multicomponent films can be controlled to within a few percent. We first briefly review the important aspects of molecular ink diffusion at a stamp interface and how it relates to experimental duration. We then describe two examples that illustrate control over ink transfer during experiments: the role of contact time on monolayer reproducibility and molecular order, and the fine control of fractional monolayer coverage for the displacement printing of 1-adamantanethiolate SAMs by 1 dodecanethiol. PMID- 24070333 TI - Creating biocompatible oil-water interfaces without synthesis: direct interactions between primary amines and carboxylated perfluorocarbon surfactants. AB - Currently, one of the most prominent methods used to impart biocompatibility to aqueous-in-oil droplets is to synthesize a triblock copolymer surfactant composed of perfluoropolyether and polyether blocks. The resulting surfactants (EA surfactant, KryJeffa, etc.) allow generation of highly biocompatible droplet surfaces while maintaining the heat stability of the starting material. However, production of these surfactants requires expertise in synthetic organic chemistry, creating a barrier to widespread adoption in the field. Herein, we describe a simple alternative to synthetic modification of surfactants to impart biocompatibility. We have observed that aqueous-in-oil droplet surfaces can be made biocompatible and heat stable by merely exploiting binding interactions between polyetherdiamine additives in the aqueous phase and carboxylated perfluorocarbon surfactants in the oil phase. Droplets formed under these conditions are shown to possess biocompatible surfaces capable of supporting picoliter-scale protein assays, droplet polymerase chain reaction (PCR), and droplet DNA amplification with isothermal recombinase polymerase amplification (RPA). Droplets formed with polyetherdiamine aqueous additives are stable enough to withstand temperature cycling during PCR (30-40 cycles at 60-94 degrees C) while maintaining biocompatibility, and the reaction efficiency of RPA is shown to be similar to that with a covalently modified surfactant (KryJeffa). The binding interaction was confirmed with various methods, including FT-IR spectroscopy, NMR spectroscopy, electrospray ionization mass spectrometry (ESI MS), and fluorescence microscopy. Overall, our results suggest that, by simply introducing a commercially-available, polyetherdiamine additive (Jeffamine ED 900) to the aqueous phase, researchers can avoid synthetic methods in generating biocompatible droplet surfaces capable of supporting DNA and protein analysis at the subnanoliter scale. PMID- 24070335 TI - Use and satisfaction with key functions of a common commercial electronic health record: a survey of primary care providers. AB - BACKGROUND: Despite considerable financial incentives for adoption, there is little evidence available about providers' use and satisfaction with key functions of electronic health records (EHRs) that meet "meaningful use" criteria. METHODS: We surveyed primary care providers (PCPs) in 11 general internal medicine and family medicine practices affiliated with 3 health systems in Texas about their use and satisfaction with performing common tasks (documentation, medication prescribing, preventive services, problem list) in the Epic EHR, a common commercial system. Most practices had greater than 5 years of experience with the Epic EHR. We used multivariate logistic regression to model predictors of being a structured documenter, defined as using electronic templates or prepopulated dot phrases to document at least two of the three note sections (history, physical, assessment and plan). RESULTS: 146 PCPs responded (70%). The majority used free text to document the history (51%) and assessment and plan (54%) and electronic templates to document the physical exam (57%). Half of PCPs were structured documenters (55%) with family medicine specialty (adjusted OR 3.3, 95% CI, 1.4-7.8) and years since graduation (nonlinear relationship with youngest and oldest having lowest probabilities) being significant predictors. Nearly half (43%) reported spending at least one extra hour beyond each scheduled half-day clinic completing EHR documentation. Three quarters were satisfied with documenting completion of pneumococcal vaccinations and half were satisfied with documenting cancer screening (57% for breast, 45% for colorectal, and 46% for cervical). Fewer were satisfied with reminders for overdue pneumococcal vaccination (48%) and cancer screening (38% for breast, 37% for colorectal, and 31% for cervical). While most believed the problem list was helpful (70%) and kept an up-to-date list for their patients (68%), half thought they were unreliable and inaccurate (51%). CONCLUSIONS: Dissatisfaction with and suboptimal use of key functions of the EHR may mitigate the potential for EHR use to improve preventive health and chronic disease management. Future work should optimize use of key functions and improve providers' time efficiency. PMID- 24070337 TI - Excess-entropy scaling for gas diffusivity in nanoporous materials. AB - We present an efficient computational procedure for the rapid prediction of the self-diffusivity of gas molecules in nanoporous materials by a combination of the Knudsen model, Rosenfeld's excess-entropy scaling method, and a classical density functional theory (DFT). The self-diffusivity conforms to the Knudsen model at low density, and the effects of intermolecular interactions at higher densities are accounted for by Rosenfeld's excess-entropy scaling method. The classical DFT provides a convenient way to calculate the excess entropy used in the scaling analysis. The hybrid computational procedure has been calibrated with MD simulation for the adsorption of H2, He, Ne, and Ar gases in several nanoporous materials over a broad range of pressure. It predicts adsorption isotherms and different types of diffusion behavior in excellent agreement with the simulation results. Although the simulation of gas diffusion in nanoporous materials is extremely time-consuming, the new procedure is computationally very efficient because it uses only single molecular and thermodynamic parameters. PMID- 24070336 TI - Biodistribution of AAV8 vectors expressing human low-density lipoprotein receptor in a mouse model of homozygous familial hypercholesterolemia. AB - Recombinant adeno-associated viral vectors based on serotype 8 (AAV8) transduce liver with superior tropism following intravenous (IV) administration. Previous studies conducted by our lab demonstrated that AAV8-mediated transfer of the human low-density lipoprotein receptor (LDLR) gene driven by a strong liver specific promoter (thyroxin-binding globulin [TBG]) leads to high level and persistent gene expression in the liver. The approach proved efficacious in reducing plasma cholesterol levels and resulted in the regression of atherosclerotic lesions in a murine model of homozygous familial hypercholesterolemia (hoFH). Prior to advancing this vector, called AAV8.TBG.hLDLR, to the clinic, we set out to investigate vector biodistribution in an hoFH mouse model following IV vector administration to assess the safety profile of this investigational agent. Although AAV genomes were present in all organs at all time points tested (up to 180 days), vector genomes were sequestered mainly in the liver, which contained levels of vector 3 logs higher than that found in other organs. In both sexes, the level of AAV genomes gradually declined and appeared to stabilize 90 days post vector administration in most organs although vector genomes remained high in liver. Vector loads in the circulating blood were high and close to those in liver at the early time point (day 3) but rapidly decreased to a level close to the limit of quantification of the assay. The results of this vector biodistribution study further support a proposed clinical trial to evaluate AAV8 gene therapy for hoFH patients. PMID- 24070338 TI - Comprehensive screening for multi-class veterinary drug residues and other contaminants in muscle using column-switching UPLC-MS/MS. AB - A quantitative multi-class analytical method covering more than 226 veterinary drugs and other contaminants in muscle, belonging to different drug families, was developed. The method is based on liquid-liquid extraction, purification by low temperature clean-up and dispersive solid-phase extraction (D-SPE), and analysis was conducted in two analytical runs by column-switching UPLC coupled with electrospray ionisation and tandem mass spectrometry (UPLC-ESI-MS/MS). For most of the target analytes, the optimised pre-treatment processes led to no significant interference from the sample matrix. The limit of quantification varied from 0.05 to 10 ug kg(-1). Statistical evaluation indicated that average recoveries spiked into pork were in the range from 62.4% to 138.8%, and the relative standard deviations were in the range from 2.8% to 26.6% (intra-day precision). The availability of this method will contribute to a better safety assurance of meat with a significant reduction of both effort and time. PMID- 24070339 TI - Ferulic Acid content and appearance determine the antioxidant capacity of arabinoxylanoligosaccharides. AB - To investigate the antioxidant capacity of ferulic acid (FA) in conjunction with prebiotic arabinoxylanoligosaccharides (AXOS), procedures for the production of FA-enriched, -depleted and cross-linked AXOS were developed, and samples were analyzed using the Trolox equivalent antioxidant capacity (TEAC) and oxygen radical absorbance capacity (ORAC) assays. Results showed that not only the level of FA but also the condition under which it appears (free, bound, or dimerized) impacts the antioxidant capacity of FA-containing AXOS samples. Although esterification of FA on AXOS and cross-linking of AXOS through dehydrodiferulic acid formation lowered the antioxidant capacity of FA by 30 and 55%, respectively, as determined with the TEAC test, the antioxidant capacity of these components still remained high compared to Trolox, a water-soluble vitamin E analog. Total antioxidant capacity of the AXOS samples determined by the ORAC assay resulted in less prominent differences between the different forms of FA than those seen with the TEAC test. Feruloylated AXOS can hence function as strong, water-soluble antioxidants. PMID- 24070340 TI - TIP peptide inhalation in oleic acid-induced experimental lung injury: a post-hoc comparison. AB - BACKGROUND: The lectin-like domain of TNF-alpha mimicked by an inhaled TIP peptide represents a novel approach to attenuate a pulmonary edema in respiratory failure, which is on the threshold to clinical application. In extension to a previously published study, which reported an improved pulmonary function following TIP peptide inhalation in a porcine model of lavage-induced lung injury, a post-hoc comparison to additional experiments was conducted. This analysis addresses the hypothesis that oleic acid injection-induced capillary leakage and alveolar necrosis blunts the previously reported beneficial effects of TIP peptide inhalation in a porcine model. FINDINGS: Following animal care committee approval lung injury was induced by oleic acid injection in six pigs with a setting strictly according to a previously published protocol that was used for lung-lavaged pigs. Ventilation/perfusion-distribution by multiple inert gas elimination, parameters of gas exchange and pulmonary edema were assessed as surrogates of the pulmonary function. A significantly improved ventilation/perfusion-distribution following TIP inhalation was recognized only in the bronchoalveolar lavage model but not following oleic acid injection. The time course after oleic acid injection yielded no comparable impact of the TIP peptide on gas exchange and edema formation. CONCLUSIONS: Reported beneficial effects of the TIP peptide on gas exchange and pulmonary edema were not reproducible in the oleic acid injection model. This analysis assumes that sustained alveolar epithelial necrosis as induced by oleic acid injection may inhibit the TIP-induced edema resolution. Regarding the on-going clinical development of the TIP peptide this approach should hardly be effective in states of severe alveolar epithelial damage. PMID- 24070341 TI - Low-dose azathioprine is effective in maintaining remission among Chinese patients with Crohn's disease. AB - BACKGROUND: Azathiopurine (AZA) is efficacious for maintenance remission of Crohn's disease (CD) at the standard dose of 2.0-2.5 mg/kg for Caucasian. It has been reported that the lower dose (1.0-2.0 mg/kg) in some Asian countries was as effective as the standard dose. In the present study we analyzed the efficacy of <1.0 mg/kg AZA in maintaining remission for Chinese patients. METHODS: The clinical data of all CD patients were reviewed from 1993 to December 2012. The patients who initiated AZA treatment and were followed for >= 2 years with complete medical data were included. We divided the patients into two groups according to their initial dose: <1.0 mg/kg group and 1.0-2.0 mg/kg group. RESULTS: Among 77 patients, 39 (50.6%) started treatment with <1.0 mg/kg AZA and 38 (49.4%) with 1.0-2.0 mg/kg. The mean dose of <1.0 mg/kg group remained under 1.0 mg/kg at 6, 12 and 24 months, even if the doses were adjusted according to efficacy and tolerance. The remission rate in patients of <1.0 mg/kg group was significantly higher than that in those of 1.0-2.0 mg/kg group (P = 0.025). A dose of <1.0 mg/kg AZA was more commonly associated with male gender, older age, heavier body weight and L1 location. Adverse events were observed in 21 of 77 patients (27.3%) and no significant difference in occurrence of adverse events or leucopenia between two groups. CONCLUSIONS: <1.0 mg/kg AZA was effective as 1.0 2.0 mg/kg in maintaining remission among Chinese patients with CD. PMID- 24070342 TI - Depression among women with obstetric fistula, and pelvic organ prolapse in northwest Ethiopia. AB - BACKGROUND: The prevalence of depression is not well studied among women with pelvic floor disorders. Hence, this study aimed to determine the prevalence of depression and its associated factors among women with pelvic floor disorders. METHODS: A cross-sectional study was conducted among 306 women with one or more of the advanced pelvic floor disorders who attended at the gynaecologic outpatient clinic of Gondar university referral hospital in the six months data collection period. Women who complained of urinary or faecal incontinence or protruding mass per vagina were assessed and staged accordingly. Eligible women i.e. those with advanced pelvic organ prolapse or obstetric fistula were included consecutively. A structured questionnaire was used to obtain socio-demographic data and medical histories for all consenting women. Interviews were done by a female midwife nurse. Depression measures were obtained using the Beck's Depression Inventory (BDI) tool administered by the midwife nurse after intensive training. Data were entered into a computer using Epi Info version 3. 5.3, and then exported to SPSS version 20 for analysis. Multiple logistic regressions were fitted and Odds ratios with 95% confidence intervals were calculated to identify associated factors. RESULTS: Of the 306 women interviewed, 269 had advanced pelvic organ prolapse (stages 3 and 4), 37 had obstetric fistula. All four women (100%) with both faecal and urinary incontinence, 97.0% those with urinary incontinence due to obstetric fistula and 67.7% of those with advanced pelvic organ prolapse (stages 3 and 4) had symptoms of depression. Depression was significantly associated with age 50 years or older (P < 0.01), marital status (P < 0.05), history of divorce (p < 0.01), self perception of severe problem (P < 0.05), and having stage 3 pelvic organ prolapse (P < 0.01). CONCLUSION: Women with advanced pelvic organ prolapse, and obstetric fistula had high prevalence of depressive symptoms. A holistic management approach, including mental health care is recommended for women having such severe forms of pelvic floor disorders. PMID- 24070343 TI - Chemokine receptors in psoriasis. AB - INTRODUCTION: Psoriasis is a prevalent immune-mediated disease involving primarily the skin. Infiltrating leukocytes play key roles in driving the disease. Along with an array of adhesion proteins, leukocyte trafficking into tissue is controlled by chemoattractants, including chemokines, and their receptors. This review summarizes the data on roles for the chemokine system in psoriasis in order to highlight opportunities for inhibiting this system for therapeutic benefit. AREAS COVERED: The review covers the roles of various leukocyte subsets in psoriasis, focusing on the chemokine receptors that are thought to be responsible for the trafficking of these cells into tissue. The review also discusses in some detail the significance of the IL-23/IL-17/IL-22 cytokine axis in disease. EXPERT OPINION: Many of the new therapies developed for psoriasis are antibodies to neutralize cytokines that have pleiotropic functions in host defense. Inhibiting chemokine receptors can be accomplished using small molecules, and would be expected to block inflammation while resulting in more limited immunosuppression. There has been limited success to date in treating inflammatory disease with chemokine receptor antagonists, which has often been ascribed to the system's redundancy. Other factors may also be important, however, including sub-optimal choices of targets based on incomplete understandings of disease pathogenesis. PMID- 24070344 TI - Regulating the 1918-19 pandemic: flu, stoicism and the Northcliffe press. AB - Social historians have argued that the reason the 1918-19 'Spanish' influenza left so few traces in public memory is that it was 'overshadowed' by the First World War, hence its historiographical characterisation as the 'forgotten' pandemic. This paper argues that such an approach tends to overlook the crucial role played by wartime propaganda. Instead, I put emotion words, emotives and metaphors at the heart of my analysis in an attempt to understand the interplay between propaganda and biopolitical discourses that aimed to regulate civilian responses to the pandemic. Drawing on the letters of Wilfred Owen, the diaries of the cultural historian Caroline Playne and the reporting in the Northcliffe press, I argue that the stoicism exhibited by Owen and amplified in the columns of The Times and the Daily Mail is best viewed as a performance, an emotional style that reflected the politicisation of 'dread' in war as an emotion with the potential to undermine civilian morale. This was especially the case during the final year of the conflict when war-weariness set in, leading to the stricter policing of negative emotions. As a protean disease that could present as alternately benign and plague-like, the Spanish flu both drew on these discourses and subverted them, disrupting medical efforts to use the dread of foreign pathogens as an instrument of biopower. The result was that, as dread increasingly became attached to influenza, it destabilised medical attempts to regulate the civilian response to the pandemic, undermining Owen's and the Northcliffe press's emotives of stoicism. PMID- 24070345 TI - Indian hospitals and government in the colonial Andes. AB - This article examines the reception of the early modern hospital among the indigenous people of the Andes under Spanish colonial rule. During the period covered by this study (sixteenth to mid-eighteenth centuries), the hospital was conceived primarily as a manifestation of the sovereign's paternalistic concern for his subjects' spiritual well being. Hospitals in the Spanish American colonies were organised along racial lines, and those catering to Indians were meant to complement the missionary endeavour. Besides establishing hospitals in the main urban centres, Spanish colonial legislation instituted hospitals for Indians in provincial towns and in small rural jurisdictions throughout the Peruvian viceroyalty. Indian hospitals often met with the suspicion and even hostility of their supposed beneficiaries, especially indigenous rulers. By conceptualising the Indian hospital as a tool of colonial government, this article investigates the reasons behind its negative reception, the work of adaptation that allowed a few of them to thrive, and the eventual failure of most of these institutions. PMID- 24070346 TI - 'Just a quack who can cure cancer': John Braund, and regulating cancer treatment in New South Wales, Australia. AB - In 1948 the New South Wales government instituted an inquiry into the claims of John Braund - a 78-year-old self-described 'quack' - that his secret treatment had cured 317 cancer sufferers. The 'Braund controversy', as it became known, was one of Australia's most prominent cases of medical fraud. This paper examines that controversy and its effects on cancer philanthropy, medical research, and especially on legislation regulating treatment providers up to the present. With the Braund controversy in mind, the New South Wales (NSW) parliament struggled to develop legislation that would protect patients and punish quacks but also allow for serendipitous, unorthodox discoveries. Recent decades saw new elements added to this calculus - allowing a wide-ranging health marketplace, and allowing patients to choose their therapies. This paper argues that the particular body of law legislatures used in regulating cancer treatment and how regulations were framed reflected the changing context of healthcare and illustrates the calculus legislatures have undertaken in regulating the health marketplace, variously factoring in public safety, serendipitous discovery, the authority of orthodox medicine, patient choice, and economic opportunity. PMID- 24070347 TI - The borderline of 'empire': Japanese maritime quarantine in Busan c.1876-1910. AB - This paper seeks to balance the regional and thematic focus of cholera historiography by examining maritime quarantine in Busan, as it was devised and implemented by Japanese officials and doctors during the pre-colonial period. It also places the relationship between Korea and Japan in the context of relations with China, Russia and Britain. This paper shows that quarantine measures in Busan and other Korean ports reflected the rise of Japanese imperial power and the increasing desire on the part of the Japanese to establish an effective borderline for their regional empire. From 1879 Japan began to impose maritime quarantine in Busan, where Japanese influence was very strong even before the colonial period, though at that time Japan was unable to perform quarantine in its own ports independently due to the objections of Western powers, particularly Britain. Victories in the Sino-Japanese and Russo-Japanese wars established Japan as a regional power on equal terms with the West, and as the dominant power in Korea and Eastern Asia. With the acquisition of the right to impose quarantine in its homeland, Japan strengthened and extended the range of quarantine from Japan to Korea, China and Russia. Now quarantine screened Japan from potentially harmful agents - pathogenic and political - and its functions diversified further as modernisation and imperial expansion gathered pace. The reliance which Japan placed upon quarantine in maintaining its empire explains why it was increasingly out of step with other powers regarding international sanitary precautions. The Japanese maritime quarantine in Busan during this period therefore shows many aspects of Japan's 'national empire'. PMID- 24070348 TI - Cure for empire: the 'Conquer-Russia-Pill', pharmaceutical manufacturers, and the making of patriotic Japanese, 1904-45. AB - Seirogan, a popular anti-diarrhoeal pill, is arguably one of the most successful pharmaceutical products of modern Japan. What is less known is that the Japanese army initially developed Seirogan during the Russo-Japanese War as the 'Conquer Russia-Pill', which was later marketed to the public by private manufacturers. Previous scholars have emphasised the top-down governmental method of mobilising private sectors to manipulate public opinion for the cause of external imperialist expansion and domestic stability during wartime Japan. But the matrix that the Conquer-Russia-Pill allows us to glimpse is an inverted power relation among the state, commercial sectors, and imperial citizens. While the Japanese government remained indifferent if not hostile to jingoistic pharmaceutical manufacturers who could easily disrupt international relations, pharmaceutical companies quickly recognised and exploited the opportunities that the Conquer Russia-Pill and its symbolism provided under the banner of the empire. In turn, Japanese consumers reacted to commercial sermons carefully anchored in patriotic and militaristic discourses and images by opening their wallets. In other words, the popularity of the Conquer-Russia-Pill was a culmination of the convergence of a governmental initiative to enhance military capabilities, the commercial ingenuity of pharmaceutical manufacturers, and a consumer response to patriotic exhortations. PMID- 24070349 TI - Black doctors and discrimination under South Africa's apartheid regime. AB - This article discusses an under-researched group and provides an analytical overview of the comparative experiences of African, Indian and Coloured doctors at South African universities during the apartheid era. It probes diversity of experience in training and practice as well as gendered differentiation amongst black students before going on to discuss the careers and political activism of black doctors as well as the impact of recent transformational change on their position. It briefly assesses how singular this South African experience was. PMID- 24070365 TI - Topographic optic disc changes after successful trabeculectomy evaluated using spectral domain optical coherence tomography. AB - PURPOSE: To investigate topographic optic disc changes after surgical intraocular pressure (IOP) reduction in adults with open angle glaucoma (OAG). METHODS: Optic discs of patients with advanced primary open angle or exfoliation glaucoma were imaged using optical coherence tomography within 1 week before trabeculectomy. Patients were rescanned 1 week, 1 month, and 1 year after surgery. Maximum cup depth (MCD), and average cup depth (ACD) were calculated. RESULTS: Twenty-two eyes from 20 patients (age, 70.5 +/- 10.6 years; average mean defect of visual field, -15.0 +/- 9.8 dB) were followed up for 1 year. The IOP decreased from 22.1 +/- 2.8 mmHg at baseline to 11.5+/-2.6 mmHg 1 year following surgery (P<0.001). One-week and 1-month postoperative IOPs were 11.2 +/- 2.8 and 11.2 +/- 3.5 mmHg, respectively (P<0.001). Compared to the baseline values (356 +/- 172 MUm), postoperative ACD showed a significant decrease at 1 week (312 +/- 164 MUm; P<0.001) and 1 month (338 +/- 175 MUm; P=0.007) after surgery, but not at 1 year (339 +/- 176 MUm; P=0.354). Similarly, MCD significantly decreased from baseline (477 +/- 190 MUm) 1 week (431 +/- 203 MUm; P=0.029) and 1 month (448 +/- 198 MUm; P=0.047) after the surgery, but not after 1 year (479 +/- 188 MUm; P=1.0). CONCLUSIONS: Trabeculectomy reduces IOP in eyes with advanced OAG, which induces topographic optic disc changes. Such optic disc changes became less pronounced over time and were no longer detectable 1 year after surgery. PMID- 24070366 TI - Efficacy of daptomycin on experimental methicillin-resistant Staphylococcus aureus keratitis in rabbits. AB - PURPOSE: We aimed to compare the efficacy of topical daptomycin (DAP) with that of vancomycin (VA) in the treatment of keratitis caused by methicillin-resistant Staphylococcus aureus (MRSA). METHODS: One hundred colony-forming unit MRSA bacteria were injected intrastromally into both corneas of 28 rabbits. Sixteen hours after injection, the rabbits' eyes were treated with 1 drop of topical DAP (10 or 50 mg/mL), VA (50 mg/mL), or isotonic saline for 19 doses. Their eyes were examined for clinical severity before and after treatment. RESULTS: The minimum inhibitory concentration values of VA and DAP against the bacterial strain were found to be 2 and 0.5 MUg/mL, respectively. The mean pre- and post-treatment clinical scores of the eyes did not differ significantly among the groups. However, the mean difference between the post- and pretreatment clinical scores was significantly lower in the 50 mg/mL DAP group than in the other groups (P=0.042). A marked decrease in bacterial load was detected in all treatment groups compared to the control group (P=0.002). Although there were no significant differences in bacterial load among the treatment groups, the 50 mg/mL DAP group showed the greatest decrease. The mean % epithelial erosion rate tended to be higher in the 50 mg/mL VA group than in the other groups (P=0.31). CONCLUSIONS: Topical DAP significantly reduced the bacterial load and showed activity against MRSA comparable to that of fortified VA in this experimental model. PMID- 24070367 TI - A randomized, prospective study of bimatoprost 0.01% or travoprost/timolol in patients previously treated with latanoprost and timolol to reduce intraocular pressure. AB - PURPOSE: To compare the efficacy and safety of bimatoprost 0.01% with the fixed combination travoprost 0.004%/timolol 0.5% in subjects with stable intraocular pressure (IOP) control on latanoprost and timolol. METHODS: This was a randomized, prospective, investigator masked, crossover study comparing bimatoprost 0.01% with travoprost/timolol in 40 subjects diagnosed with primary open-angle glaucoma. Subjects were randomized to bimatoprost 0.01% qpm or travoprost/timolol qam and followed for 12 weeks, at which time they were crossed over to the alternate medication and followed for another 12 weeks. Intraocular pressure and hyperemia (rated on a standardized, 5-point photographic scale) were evaluated as change from baseline to 12 weeks following each therapy, and subject preference was elicited at the end of the study. RESULTS: Both treatments were well tolerated and the majority of patients achieved effective IOP control relative to baseline. After 12 weeks of treatment, mean reductions from baseline IOP were -1.68 mmHg OD (right eye) and -1.58 mmHg OS (left eye) with bimatoprost and -0.45 mmHg OD and -0.53 mmHg OS with travoprost/timolol, although the differences between drugs were not statistically significant. Hyperemia scores were significantly higher with the fixed combination of travoprost/timolol than bimatoprost 0.01% as measured at 8 am (both P<0.01). Subject preference at the end of the study was more than 3 to 1 in favor of bimatoprost, with most citing greater tolerability. CONCLUSION: Bimatoprost 0.01% and travoprost/timolol are both effective at reducing IOP in subjects with stable IOP control on latanoprost and timolol, but bimatoprost 0.01% is associated with less hyperemia. PMID- 24070369 TI - Nontrivial behavior of water in the vicinity and inside lipid bilayers as probed by molecular dynamics simulations. AB - The atomic-scale diffusion of water in the presence of several lipid bilayers mimicking biomembranes is characterized via unconstrained molecular dynamics (MD) simulations. Although the overall water dynamics corresponds well to literature data, namely, the efficient braking near polar head groups of lipids, a number of interesting and biologically relevant details observed in this work have not been sufficiently discussed so far; for instance, the fact that waters "sense" the membrane unexpectedly early, before water density begins to decrease. In this "transitional zone" the velocity distributions of water and their H-bonding patterns deviate from those in the bulk solution. The boundaries of this zone are well preserved even despite the local (<1 nm size) perturbation of the lipid bilayer, thus indicating a decoupling of the surface and bulk dynamics of water. This is in excellent agreement with recent experimental data. Near the membrane surface, water movement becomes anisotropic, that is, solvent molecules preferentially move outward the bilayer. Deep in the membrane interior, the velocities can even exceed those in the bulk solvent and undergo large-scale fluctuations. The analysis of MD trajectories of individual waters in the middle part of the acyl chain region of lipids reveals a number of interesting rare phenomena, such as the fast (ca. 50 ps) breakthrough across the membrane or long time (up to 750 ps) "roaming" between lipid leaflets. The analysis of these events was accomplished to delineate the mechanisms of spontaneous water permeation inside the hydrophobic membrane core. It was shown that such nontrivial dynamics of water in an "alien" environment is driven by the dynamic heterogeneities of the local bilayer structure and the formation of transient atomic-scale "defects" in it. The picture observed in lipid bilayers is drastically different from that in a primitive membrane mimic, a hydrated cyclohexane slab. The possible biological impact of such phenomena in equilibrated lipid bilayers is discussed. PMID- 24070368 TI - Hyperfine coupling constants on inner-sphere water molecules of a triazacyclononane-based Mn(II) complex and related systems relevant as MRI contrast agents. AB - We report the synthesis of the ligand H2MeNO2A (1,4-bis(carboxymethyl)-7-methyl 1,4,7-triazacyclononane) and a detailed experimental and computational study of the hyperfine coupling constants (HFCCs) on the inner-sphere water molecules of [Mn(MeNO2A)] and related Mn(2+) complexes relevant as potential contrast agents in magnetic resonance imaging (MRI). Nuclear magnetic relaxation dispersion (NMRD) profiles, (17)O NMR chemical shifts, and transverse relaxation rates of aqueous solutions of [Mn(MeNO2A)] were recorded to determine the parameters governing the relaxivity in this complex and the (17)O and (1)H HFCCs. DFT calculations (TPSSh model) performed in aqueous solution (PCM model) on the [Mn(MeNO2A)(H2O)].xH2O and [Mn(EDTA)(H2O)](2-).xH2O (x = 0-4) systems were used to determine theoretically the (17)O and (1)H HFCCs responsible for the (17)O NMR chemical shifts and the scalar contributions to (17)O and (1)H NMR relaxation rates. The use of a mixed cluster/continuum approach with the explicit inclusion of a few second-sphere water molecules is critical for an accurate calculation of HFCCs of coordinated water molecules. The impact of complex dynamics on the calculated HFCCs was evaluated with the use of molecular dynamics simulations within the atom-centered density matrix propagation (ADMP) approach. The (17)O and (1)H HFCCs calculated for these complexes and related systems show an excellent agreement with the experimental data. Both the (1)H and (17)O HFCCs (A(iso) values) are dominated by the spin delocalization mechanism. The A(iso) values are significantly affected by the distance between the oxygen atom of the coordinated water molecule and the Mn(2+) ion, as well as by the orientation of the water molecule plane with respect to the Mn-O vector. PMID- 24070370 TI - Single-handed helical wrapping of single-walled carbon nanotubes by chiral, ionic, semiconducting polymers. AB - We establish the requisite design for aryleneethynylene polymers that give rise to single-handed helical wrapping of single-walled carbon nanotubes (SWNTs). Highly charged semiconducting polymers that utilize either an (R)- or (S)-1,1'-bi 2-naphthol component in their respective conjugated backbones manifest HRTEM and AFM images of single-chain-wrapped SWNTs that reveal significant preferences for the anticipated helical wrapping handedness; statistical analysis of these images, however, indicates that ~20% of the helical structures are formed with the "unexpected" handedness. CD spectroscopic data, coupled with TDDFT-based computational studies that correlate the spectral signatures of semiconducting polymer-wrapped SWNT assemblies with the structural properties of the chiral 1,1' binaphthyl unit, suggest strongly that two distinct binaphthalene SWNT binding modes, cisoid-facial and cisoid-side, are possible for these polymers, with the latter mode responsible for inversion of helical chirality and the population of polymer-SWNT superstructures that feature the unexpected polymer helical wrapping chirality at the nanotube surface. Analogous aryleneethynylene polymers were synthesized that feature a 2,2'-(1,3-benzyloxy)-bridged (b)-1,1'-bi-2-naphthol unit: this 1,1'-bi-2-naphthol derivative is characterized by a bridging 2,2'-1,3 benzyloxy tether that restricts the torsional angle between the two naphthalene subunits along its C1-C1' chirality axis to larger, oblique angles that facilitate more extensive van der Waals contact of the naphthyl subunits with the nanotube. Similar microscopic, spectroscopic, and computational studies determine that chiral polymers based on conformationally restricted transoid binaphthyl units direct preferential facial binding of the polymer with the SWNT and thereby guarantee helically wrapped polymer-nanotube superstructures of fixed helical chirality. Molecular dynamics simulations provide an integrated picture tying together the global helical superstructure and conformational properties of the binaphthyl units: a robust, persistent helical handedness is preferred for the conformationally restricted transoid binaphthalene polymer. Further examples of similar semiconducting polymer-SWNT superstructures are reported that demonstrate that the combination of single-handed helical wrapping and electronic structural modification of the conjugated polymer motif opens up new opportunities for engineering the electro-optic functionality of nanoscale objects. PMID- 24070371 TI - Attitudes towards hastened death in ALS: a prospective study of patients and family caregivers. AB - Amyotrophic lateral sclerosis (ALS) may be associated with the wish to hasten death (WTHD). We aimed to determine the prevalence and stability of WTHD and end of-life attitudes in ALS patients, identify predictive factors, and explore communication about WTHD. We conducted a prospective questionnaire study among patients and their primary caregivers attending ALS clinics in Germany and Switzerland. We enrolled 66 patients and 62 caregivers. Half of the patients could imagine asking for assisted suicide or euthanasia; 14% expressed a current WTHD at the baseline survey. While 75% were in favour of non-invasive ventilation, only 55% and 27% were in favour of percutaneous endoscopic gastrostomy and invasive ventilation, respectively. These attitudes were stable over 13 months. The WTHD was predicted by depression, anxiety, loneliness, perceiving to be a burden to others, and a low quality of life (all p < 0.05). Lower religiosity predicted whether patients could imagine assisted suicide or euthanasia. Two-thirds of patients had communicated their WTHD to relatives; no one talked to the physician about it, yet half of them would like to do so. In conclusion, physicians should consider proactively asking for WTHD, and be sensitive towards neglected psychosocial problems and psychiatric comorbidity. PMID- 24070372 TI - An association study between SUFU gene polymorphisms and neural tube defects. AB - Neural tube defects (NTDs) in mammals are rooted in aberrant neural tube closure during early embryogenesis, which is caused by multiple environmental and genetic factors. The Sonic Hedgehog pathway is involved in the induction of the floor plate and participates in formation of the neural tube. Mutation of the suppressor of fused gene (SUFU), an essential repressor of Sonic Hedgehog signaling pathway, can result in NTDs. A case-control study was designed to compare the frequencies of the polymorphism at four sites in the SUFU gene in control and NTDs group, as well as in subtype groups, including anencephaly, spina bifida and encephalocele. We also explored the association between polymorphism and NTDs risk in a high prevalence population in China. Rs10786691, but not the other three SNPs, had an association between polymorphisms and NTDs. The heterozygous AG allele of rs10786691 was significantly related with NTDs and encephalocele (OR = 1.60, 95% CI: 1.04-2.48, p = 0.034; OR = 2.83, 95% CI: 1.07 7.47, p = 0.036). In female but not male fetuses, the AG genotype of rs10786691 increased the risk of NTDs (OR = 1.88, 95% CI: 1.03-3.41, p = 0.040). The SUFU rs10786691 A>G polymorphism may be a potential risk factor for NTDs and encephalocele in this high-risk population, but the association between the polymorphism and NTDs was probably influenced by gender. PMID- 24070373 TI - Characterization, design, and function of the mitochondrial proteome: from organs to organisms. AB - Mitochondria are a common energy source for organs and organisms; their diverse functions are specialized according to the unique phenotypes of their hosting environment. Perturbation of mitochondrial homeostasis accompanies significant pathological phenotypes. However, the connections between mitochondrial proteome properties and function remain to be experimentally established on a systematic level. This uncertainty impedes the contextualization and translation of proteomic data to the molecular derivations of mitochondrial diseases. We present a collection of mitochondrial features and functions from four model systems, including two cardiac mitochondrial proteomes from distinct genomes (human and mouse), two unique organ mitochondrial proteomes from identical genetic codons (mouse heart and mouse liver), as well as a relevant metazoan out-group (drosophila). The data, composed of mitochondrial protein abundance and their biochemical activities, capture the core functionalities of these mitochondria. This investigation allowed us to redefine the core mitochondrial proteome from organs and organisms, as well as the relevant contributions from genetic information and hosting milieu. Our study has identified significant enrichment of disease-associated genes and their products. Furthermore, correlational analyses suggest that mitochondrial proteome design is primarily driven by cellular environment. Taken together, these results connect proteome feature with mitochondrial function, providing a prospective resource for mitochondrial pathophysiology and developing novel therapeutic targets in medicine. PMID- 24070374 TI - The conserved RGxxE motif of the bacterial FAD assembly factor SdhE is required for succinate dehydrogenase flavinylation and activity. AB - Succinate dehydrogenase (SDH) is an important respiratory enzyme that plays a critical role in the generation of energy in the majority of eukaryotes, bacteria, and archaea. The activity of SDH is dependent on the covalent attachment of the redox cofactor FAD to the flavoprotein subunit SdhA. In the Gram-negative bacteria Escherichia coli and Serratia sp. ATCC 39006, the covalent attachment of FAD to SdhA is dependent on the FAD assembly factor SdhE (YgfY). Although mechanisms have been proposed, experimental evidence that elucidates the molecular details of SdhE-mediated flavinylation are scarce. In this study, truncation and alanine swap mutagenesis of SdhE identified a highly conserved RGxxE motif that was important for SdhE function. Interestingly, RGxxE site directed variants were not impaired in terms of protein folding or interactions with SdhA. Purification and analysis of SdhA from different mutant backgrounds demonstrated that SdhE interacts with and flavinylates folded SdhA without a requirement for the assembly of the entire SDH complex. SdhA was also partially active in the absence of SdhE, suggesting that SdhA is able to attach FAD through an inefficient autocatalytic mechanism. The results presented are of widespread relevance because SdhE and SDH are required for bacterial pathogenesis and mutations in the eukaryotic homologues of SdhE and SDH are associated with cancer in humans. PMID- 24070375 TI - Physical and functional interaction of Rnf2 with Af9 regulates basal and aldosterone-stimulated transcription of the alpha-ENaC gene in a renal collecting duct cell line. AB - The physical and functional interaction of Rnf2 (RING finger protein 2), a central component of the PRC (Polycomb repressive complex) 1 and Af9 (ALL1-fused gene from chromosome 9 protein), an aldosterone-sensitive transcription factor, in regulating basal and aldosterone-stimulated transcription of the alpha-ENaC (epithelial Na+ channel alpha-subunit) gene was explored in mIMCD3 CD (collecting duct) cells. Since Rnf2 lacks DNA-specific binding activity, other factors must mediate its site-specific chromatin recruitment. Rnf2 and Af9 co-localized in the nucleus and co-immunoprecipitated. A GST (glutathione transferase)-Af9 carboxy terminal fusion protein directly interacted with in vitro translated Rnf2 in GST pull-down assays. Rnf2 knock down enhanced basal and aldosterone-stimulated alpha ENaC mRNA levels and alpha-ENaC promoter activity. ChIP/QPCR (chromatin immunoprecipitation/quantitative PCR) assays demonstrated enrichment of Rnf2, H2AK119 (mono-ubiquitinated histone H2A lysine 119), and H3K27me3 (histone H3 lysine 27 trimethylated), a PRC2 chromatin mark, at multiple alpha-ENaC promoter subregions corresponding to regions of known Af9 enrichment, under basal conditions. Sequential ChIP confirmed Rnf2-Af9 co-occupancy of the alpha-ENaC promoter. Aldosterone provoked early and sustained depletion of Rnf2, ubiquitinated H2AK119, and trimethylated H3K27 associated with the subregions of the alpha-ENaC promoter. Thus, Af9 mediates site-selective physical and functional recruitment of Rnf2 to the alpha-ENaC promoter to constrain basal alpha-ENaC transcription in collecting duct cells, and aldosterone reverses this process. PMID- 24070376 TI - Comparing performance in discrete and continuous comparison tasks. AB - The approximate number system (ANS) theory suggests that all magnitudes, discrete (i.e., number of items) or continuous (i.e., size, density, etc.), are processed by a shared system and comply with Weber's law. The current study reexamined this notion by comparing performance in discrete (comparing numerosities of dot arrays) and continuous (comparisons of area of squares) tasks. We found that: (a) threshold of discrimination was higher for continuous than for discrete comparisons; (b) while performance in the discrete task complied with Weber's law, performance in the continuous task violated it; and (c) performance in the discrete task was influenced by continuous properties (e.g., dot density, dot cumulative area) of the dot array that were not predictive of numerosities or task relevant. Therefore, we propose that the magnitude processing system (MPS) is actually divided into separate (yet interactive) systems for discrete and continuous magnitude processing. Further subdivisions are discussed. We argue that cooperation between these systems results in a holistic comparison of magnitudes, one that takes into account continuous properties in addition to numerosities. Considering the MPS as two systems opens the door to new and important questions that shed light on both normal and impaired development of the numerical system. PMID- 24070377 TI - Wide linear-range detecting nonenzymatic glucose biosensor based on CuO nanoparticles inkjet-printed on electrodes. AB - Inkjet-printed copper oxide nanoparticles (CuO NPs) on silver electrodes were used to fabricate the nonenzymatic glucose biosensor. The inkjet-printed CuO NPs electrodes produced high and reproducible sensitivity of 2762.5 MUAm M(-1) cm(-2) at an applied potential of +0.60 V with the wide linear-detecting range of 0.05 18.45 mM and the detection limit of ~0.5 MUM (S/N = 3). The long-term stability and reproducibility of sensor in glucose electro-oxidation resulted from the chemical stability of CuO NPs and pore-like structure formed on Ag surface, which prevented the CuO NPs from conglomeration and the interference of oxygen in the air. Significantly, the effect of interfering species, such as AA, UA, and DA were negligible, whereas sugar derivatives (lactose, fructose, and mannose) show insignificant interference. Finally, the electrode was applied to analyze glucose concentration in human serum samples. PMID- 24070378 TI - Utilizing dynamic tensiometry to quantify contact angle hysteresis and wetting state transitions on nonwetting surfaces. AB - Goniometric techniques traditionally quantify two parameters, the advancing and receding contact angles, that are useful for characterizing the wetting properties of a solid surface; however, dynamic tensiometry, which measures changes in the net force on a surface during the repeated immersion and emersion of a solid into a probe liquid, can provide further insight into the wetting properties of a surface. We detail a framework for analyzing tensiometric results that allows for the determination of wetting hysteresis, wetting state transitions, and characteristic topographical length scales on textured, nonwetting surfaces, in addition to the more traditional measurement of apparent advancing and receding contact angles. Fluorodecyl POSS, a low-surface-energy material, was blended with commercially available poly(methyl methacrylate) (PMMA) and then dip- or spray-coated onto glass substrates. These surfaces were probed with a variety of liquids to illustrate the effects of probe liquid surface tension, solid surface chemistry, and surface texture on the apparent contact angles and wetting hysteresis of nonwetting surfaces. Woven meshes were then used as model structured substrates to add a second, larger length scale for the surface texture. When immersed into a probe liquid, these spray-coated mesh surfaces can form a metastable, solid-liquid-air interface on the largest length scale of surface texture. The increasing hydrostatic pressure associated with progressively greater immersion depths disrupts this metastable, composite interface and forces penetration of the probe liquid into the mesh structure. This transition is marked by a sudden change in the wetting hysteresis, which can be systematically probed using spray-coated, woven meshes of varying wire radius and spacing. We also show that dynamic tensiometry can accurately and quantitatively characterize topographical length scales that are present on microtextured surfaces. PMID- 24070379 TI - Ontogeny and functional specialization of dendritic cells in human and mouse. AB - Dendritic cells (DCs) are a heterogeneous group of functionally specialized antigen-presenting cells that initiate and orchestrate immune responses. Our understanding of DC immunobiology has been largely shaped by research using murine models. The relevance of murine findings on human DC organization and function is only just beginning to be investigated. In this chapter, we present the key historical developments and recent advances in human and mouse DC research to contextualize the existing knowledge on DC subset origin and functional specializations. We also propose a framework to align human and mouse DC networks to enhance our understanding of the parallel organization of DCs in both species in order to facilitate the full exploitation of our knowledge on DC biology and function for clinical therapeutic strategies. PMID- 24070380 TI - Dendritic cell migration through the lymphatic vasculature to lymph nodes. AB - The mobilization of antigen-presenting dendritic cells (DCs) from peripheral tissues to draining lymph nodes drives the initiation of adaptive immune responses. Recent advances have been made in understanding how and where DCs enter the lymphatic vasculature and what mechanisms control this process. In this chapter, we highlight these advances. Delineating DC-lymphatic vessel interactions is critical for our fundamental understanding of DC trafficking in states of health and disease and for efforts to manipulate DC mobilization for immunotherapy and vaccination. PMID- 24070381 TI - A close encounter of the third kind: monocyte-derived cells. AB - Recent insights into discrete myeloid developmental pathways have provided critical information about the organization of the murine mononuclear phagocyte compartment. Short-lived dendritic cells (DCs) have been shown to continuously arise from dedicated bone marrow-derived precursors. In contrast, it is now appreciated that most tissue macrophage populations are established before birth and subsequently maintain themselves throughout adulthood by longevity and limited self-renewal. Both of these classical tissue-resident mononuclear phagocyte compartments can be complemented on demand by monocyte infiltrates giving rise to macrophage or DC-like cells, depending on the tissue context they encounter upon extravasation. Monocytes hence have emerged as a versatile emergency squad that can be rapidly recruited to sites of injury to provide a transient supplement with proinflammatory or resolving activities for local mononuclear phagocytes. PMID- 24070382 TI - Plasmacytoid dendritic cell development. AB - Interferon-producing plasmacytoid dendritic cells (pDC) are a specialized branch of the dendritic cell (DC) family, and their differentiation in mice is closely linked to that of conventional DC (cDC). Several different developmental pathways retain the potential to form pDC and are likely to contribute to the steady-state pDC population. A lymphoid pathway to DC development produces mainly pDC as a branch otherwise leading to B-cell development; such pDC may carry relics of a lymphoid past such as DJ rearrangements of immunoglobulin heavy chain (IgH) genes. The myeloid pathway to pDC and cDC is better known, but recent reassessment has revealed several substreams of development with separate DC committed precursors. One substream has a lymphoid-like aspect, involving a precursor expressing RAG-1 and producing pDC with IgH gene rearrangements. Another more biased to cDC production produces pDC without such IgH gene rearrangements. Finally, there is the production of interferon-producing pDC-like cells that are not pDC but appear to be cDC precursors; these do not express key pDC markers such as CCR9. Initiation of the DC and then the pDC developmental program overrides any surface marker-expressed developmental bias to other myeloid or lymphoid lineages, resulting in an apparent convergent differentiation to the pDC form. A DC fate is sometimes imprinted early in development, upstream of identifiable myeloid, or lymphoid precursors. This suggests that DC, including pDC, represent a distinct hematopoietic lineage separate from conventional myeloid or lymphoid cells. PMID- 24070384 TI - Macrophage activation and polarization as an adaptive component of innate immunity. AB - Innate immunity has an adaptive component, which has been referred to as "memory," "trained," "imprinted" or "adaptive." Plasticity is a hallmark of cells of the monocyte-macrophage lineage. Microbial recognition and cytokines profoundly affect macrophage function causing a range of adaptive responses including activation, priming, or tolerance. These adaptive responses of macrophages include production of humoral fluid-phase pattern recognition molecules such as the prototypic long pentraxin PTX3. These components of humoral innate immunity in turn cooperate with and regulate phagocyte function. Progress has been made in defining the molecular basis underlying the polarized activation of macrophages, including signaling mediators, transcription factors, epigenetic modifications, and the microRNA network. The definition of molecules and mechanisms associated with plasticity and polarized activation of macrophages may provide a basis for innovative diagnostic and therapeutic approaches. PMID- 24070385 TI - Terminal differentiation of dendritic cells. AB - Dendritic cells (DCs) are essential for the initiation of an effective immune response. Despite this, our understanding of the molecular regulation of this important cell type has lagged significantly behind that of other lymphoid populations such as B and T cells, but recent development of various tools has greatly facilitated progress in the field. Here, we review the transcription factors that drive peripheral DC subset fate decisions. While Pu.1, Ikaros, and Gfi-1 are essential for precursor DCs to give rise to monocytes, conventional DCs, and plasmacytoid DCs, the balance between E2-2 and Id2 directs committed precursors along a pDC or cDC lineage, respectively. Several transcription factors such as Batf3, Nfil3, and Id2 are required for different DC subsets at steady-state and drive segregation into the individual DCs subsets late in development in the CD8 lineage. During inflammation, CD8-expressing DCs emerge that feature many of the hallmarks of classical CD8alpha(+) DCs but surprisingly do not depend on the same transcription factors. Thus, the immune system has developed two pathways of DC differentiation that enable it to maintain homeostatic balance and to respond rapidly to the emergency requirement for DCs that might occur during infection. PMID- 24070386 TI - Diversity of pathogen sensors in dendritic cells. AB - Dendritic cells (DCs) associate the capacity to sense pathogens with the initiation of adaptive immunity. Pathogens can be sensed through pathogen associated molecular patterns by pathogen-recognition receptors expressed on host cells. Pathogen-encoded activities can also be sensed when they modify normal host cellular processes. The diversity of pathogen sensors has been highlighted by the identification of several cytosolic sensors involved in the recognition of nucleic acids from pathogens. The number of these pathogen cytosolic sensors has dramatically increased recently. Different DC populations appear to be equipped with distinct sensors but the precise expression pattern and the regulation of these sensors remain to be established, especially in humans. The engagement of sensors in DCs by pathogens leads to antipathogen effects through multiple mechanisms including interferon responses and promotes effector pathways that can shape the adaptive immune response. How the diversity of cytosolic pathogen sensors impacts these processes is incompletely understood. Investigating the expression, regulation, and crosstalk of the sensors should shed light on how pathogen sensing impacts pathogen replication and host immune responses. PMID- 24070383 TI - Pathological consequence of misguided dendritic cell differentiation in histiocytic diseases. AB - Histiocytic disorders represent a group of complex pathologies characterized by the accumulation of histiocytes, an old term for tissue-resident macrophages and dendritic cells. Langerhans cell histiocytosis is the most frequent of histiocytosis in humans and has been thought to arise from the abnormal accumulation of epidermal dendritic cells called Langerhans cells. In this chapter, we discuss the origin and differentiation of Langerhans cells and dendritic cells and present accumulated evidence that suggests that Langerhans cell histiocytosis does not result from abnormal Langerhans cell homeostasis but rather is a consequence of misguided differentiation programs of myeloid dendritic cell precursors. We propose reclassification of Langerhans cell histiocytosis, juvenile xanthogranuloma, and Erdheim-Chester disease as inflammatory myeloid neoplasias. PMID- 24070387 TI - Transcriptional control of dendritic cell development. AB - Dendritic cells (DCs) drive both adaptive and innate immunity. Recent findings support the notion that distinct subsets of classical DCs favor alternative modules of immunity, acting on innate lymphoid-like cells (ILCs) and T cells similarly to promote either ILC1/Th1/CTL- or ILC3/Th17-type responses. Coordination between DC subsets and their favored immune module might imply that the genetic programs for DC diversification preceded the emergence of recombination-activating gene-dependent adaptive immunity and operate initially in coordinating ILC repertoires for appropriate responses against pathogens. Consequently, understanding the molecular basis of DC developmental and diversification is important for an underlying appreciation of immune regulation. Currently, the basis for DC development into the recognized subsets/lineages is only partially understood, based on the requirements for several transcription factors including PU.1, Bcl11a, Irf8, E2-2, Id2, Irf4, Irf8, Batf3, and other BATF family members. This chapter will briefly review recent transcriptional aspects of DC development and function and then highlight some currently unresolved questions. PMID- 24070388 TI - Transcriptional control of macrophage identity, self-renewal, and function. AB - Macrophages not only are prominent effector cells of the immune system that are critical in inflammation and innate immune responses but also fulfill important functions in tissue homeostasis. Transcription factors can define macrophage identity and control their numbers and functions through the induction and maintenance of specific transcriptional programs. Here, we review the mechanisms employed by lineage-specific transcription factors to shape macrophage identity during the development from hematopoietic stem and progenitor cells. We also present current insight into how specific transcription factors control macrophage numbers, by regulating coordinated proliferation and differentiation of myeloid progenitor cells and self-renewal of mature macrophages. We finally discuss how functional specialization of mature macrophages in response to environmental stimuli can be induced through synergistic activity of lineage- and stimulus-specific transcription factors that plug into preexisting transcriptional programs. Understanding the mechanisms that define macrophage identity, numbers, and functions will provide important insights into the differential properties of macrophage populations under various physiological and pathological conditions. PMID- 24070389 TI - Effects of inclusion level on nutrient digestibility and energy content of wheat middlings and soya bean meal for growing pigs. AB - Two experiments were conducted to determine the effects of inclusion level of wheat middlings and soya bean meal on apparent total tract digestibility (ATTD) of energy and chemical components of these ingredients in growing pigs. Furthermore, the effects of the inclusion level on their contents of digestible energy (DE) and metabolisable energy (ME) were also determined by the difference method. In Experiment 1, six diets were fed to 36 growing pigs according to a completely randomised design. The basal diet was a corn-soya bean meal diet while the other five diets contained 9.6%, 19.2%, 28.8%, 38.4% or 48.0% of wheat middlings added at the expense of corn and soya bean meal. The measured digestibility of energy and most nutrients of wheat middlings increased (p < 0.05) with increasing levels of that ingredient. Equations were obtained to predict digestibility by inclusion level. At an inclusion level of 9.6% wheat middlings, their DE contents were significantly lower (8.9 MJ/kg DM) than for the higher levels (10.7 to 11.9 MJ/kg DM, p < 0.01). In Experiment 2, three diets were fed to 18 growing pigs according to a completely randomised block design. The basal diet was a corn-based diet while the other two diets were based on corn and two levels of soya bean meal (22.2% and 33.6%). The content of DE in soya bean meal did not differ at 22.2% and 33.6% inclusion levels (16.2 and 16.3 MJ/kg DM, respectively), but the digestibility of dry matter (DM), organic matter and carbohydrates was increased at a higher inclusion level (p < 0.05). This study revealed that the estimated digestibility of nutrients from soya bean meal and wheat middlings was affected by their dietary inclusion levels. For soya bean meal, the estimated energy contents was independent of its inclusion level, but not for wheat middlings. Therefore, the inclusion level of wheat middlings has to be considered for estimating their energy value. PMID- 24070390 TI - Using exogenous enzymes to increase the rumen degradability of wheat dried distillers grains with solubles. AB - Wheat dried distillers grains with solubles (DDGS) is widely used as a partial replacement for forages or concentrates in ruminant diets. We hypothesised that using exogenous enzymes (ENZ) would increase neutral detergent fibre (NDF) degradability of DDGS. The aims of the study were to (i) evaluate the effects of ENZ and their doses on in vitro gas production (GP) and degradability of wheat DDGS; and (ii) explore possible relationships between the major added enzymic activities and degradation, especially NDF degradation. Three commercially produced ENZ products that provided a range of xylanase, endoglucanase, exoglucanase and protease activities were used. Enzyme activities were assayed under normal rumen conditions with pH 6.0 and temperature 39 degrees C. All three ENZ had a xylanase:endoglucanase ratio of 5:1 to 4:1, but ENZ3 had lower activity per millilitre. ENZ2 had relatively higher exoglucanase activity compared with the other products, with a ratio of xylanase:exoglucanase of 4:1 for ENZ2 compared with 23:1 for ENZ1 and 9:1 for ENZ3. Variable effects of the three ENZ products were observed on GP variables. Degradabilities of dry matter (DM), NDF, acid detergent fibre (ADF) and crude protein (CP) linearly (p < 0.05) increased with increasing ENZ doses, but ENZ1 and ENZ2 exhibited greater (p < 0.05) effects on degradabilities of DM, NDF and ADF compared to the ENZ3. There were positive correlations between added enzymatic activities and degradabilities of DM, NDF and ADF, except for degradability of CP. A multiple regression model analysis showed that xylanase was the main enzymic activity associated with increased degradation of NDF. The results demonstrated the potential of enzyme addition to improve ruminal degradability of wheat DDGS, with xylanase being the main enzymic activity associated with NDF degradability. PMID- 24070391 TI - Intramolecular hydrogen bond in alkoxyamines. Influence on the C-ON bond homolysis. AB - The C-ON bond homolysis in alkoxyamines can be influenced by the presence of an intramolecular hydrogen bond (IHB) between the alkyl and the nitroxyl fragments, which leads to an 8-fold decrease in the homolysis rate constant k(d). When the IHB is disrupted by the solvent or by substitution of the hydrogen involved in the IHB by a protecting group (OMe, OAc, OBz, OBn, or OTBDMS), a higher homolysis rate constant k(d) is observed, as expected from the correlations developed by Marque (Bertin, D.; Gigmes, D.; Marque, S.; Tordo, P. Macromolecules 2005, 38, 2638-2650). Results were confirmed by DFT calculations at the B3LYP/6-31G(d,p) level. PMID- 24070392 TI - Multilayer dual-polymer-coated upconversion nanoparticles for multimodal imaging and serum-enhanced gene delivery. AB - Upconversion nanoparticles (UCNPs) have been widely explored for various bioapplications because of their unique optical properties, easy surface functionalization, and low cytotoxicity. Herein, we synthesize gadolinium (Gd3+) doped UCNPs, which are modified first with poly(ethylene glycol) (PEG) and then with two layers of poly(ethylenimine) (PEI) via covalent conjugation and layer-by layer assembly, respectively. Compared with UCNP-PEG@1*PEI with only one layer of PEI coating, the final complex, UCNP-PEG@2*PEI, with two PEI layers exhibits reduced cytotoxicity and enhanced gene transfection efficiency. It is interesting to find that while free PEI polymer is only effective in gene transfection in a serum-free medium and shows drastically reduced transfection ability if serum is added, UCNP-PEG@2*PEI is able to transfect cells in both serum-free and containing media and, surprisingly, offers even higher gene transfection efficiency if serum is added. This is likely due to the formation of protein corona on the nanoparticle surface, which triggers the receptor-mediated endocytosis of our UCNP vectors. Considering the upconversion luminescence and magnetic resonance imaging contrasting ability of UCNPs, our novel nanovector could serve as a "trackable" gene-delivery carrier promising for theranostic applications. PMID- 24070393 TI - Relationship between gallium pyramidalization in L.GaCl3 complexes and the electronic ligand properties. AB - Six new molecular GaCl3 adducts of electron rich compounds of the carbone (carbodiphosphorane, tetraaminoallene) and cyclic alkyl amino carbene (CAAC) families have been synthesized and characterized by X-ray crystallography. The sum of their Cl-Ga-Cl angles has been compared to those of 20 other complexes exhibiting various oxygen-, nitrogen-, phosphorus-, and carbon-donor ligands for which good quality X-ray analyses have been reported. The pyramidalization of the GaCl3 moiety in L.GaCl3 complexes has been checked against the computed antisymmetric stretching of the Ga-Cl bonds. It has also been compared to the symmetric stretching of the C-O bonds of the corresponding L.Ni(CO)3 complexes (Tolman Electronic Parameter). On this basis, a relationship between the pyramidalization observed in the gallium complexes and the electronic ligand properties has been established. PMID- 24070394 TI - Prevalence of nocturia in Parkinson's disease patients from various ethnicities. AB - OBJECTIVES: One of the most common non-motor symptoms in Parkinson's disease (PD) is nocturia. This paper seeks to address the prevalence of nocturia in PD and correlate it to various factors such as gender, Hoehn and Yahr (H&Y) stage, age, and ethnicities. METHODS: In particular, 332 PD patients were seen in a community movement disorders clinic and their charts were analyzed from 2005 to 2010. Within this population, more than one-third (34.9%) patients were diagnosed with nocturia. RESULTS: Age, gender, and PD stage were significant predictors of nocturia in PD. With every one-year increase in age, the odds of developing nocturia in PD increases by 3.1% while an increase in H&Y stage increases the odds of nocturia in PD by 1.645 times. Also, males had greater odds of experiencing nocturia in PD. Ethnicities alone were of no significant importance. However, after performing interaction analyses, Asian and Indian males, especially, were at significantly greater risk than other ethnicities. DISCUSSION: Future research is indeed required to understand why certain ethnicities are especially at risk. Clinicians must also be aware of the epidemiology of nocturia in PD to prevent and treat this debilitating symptom. PMID- 24070395 TI - Flavonoids from the grains of C1/R-S transgenic rice, the transgenic Oryza sativa spp. japonica, and their radical scavenging activities. AB - The transgenic rice cultivar of Oryza sativa spp. japonica cv. Hwa-Young, C1/R-S transgenic rice (C1/R-S rice), is a flavonoid-rich cultivar of rice. The grains of C1/R-S rice were extracted with aqueous MeOH, and the concentrated extract was partitioned with EtOAc, n-BuOH, and H2O, successively. Repeated silica gel, octadecyl silica gel (ODS), and Sephadex LH-20 column chromatographies for the EtOAc and n-BuOH fractions afforded four new flavonoids (compounds 2, 3, 7, and 8) along with four known flavonoids: (+)-3'-O-methyltaxifolin (1), brassicin (4), isorhamnetin-4'-O-beta-D-glucosyranoside (5), and 3'-O-methyltaxifolin-5-O-beta-D glucopyranoside (6). The new flavonoids were identified as 3'-O-methyltaxifolin-7 O-beta-D-glucopyranoside (2), 3'-O-methyltaxifolin-4'-O-beta-D-glucopyranoside (3), isorhamnetin-7-O-beta-D-cellobioside (brassicin-4"-O-beta-D-glucopyranoside) (7), and brassicin-4'-O-beta-D-glucosyranoside (8) from the result of spectroscopic data including nuclear magnetic resonance spectrometry (NMR), mass spectrometry (MS), and infrared spectroscopy (IR). Also, quantitative analysis of major flavonoids (compounds 2, 3, and 8) in C1/R-S rice, O. sativa spp. japonica cv. Hwa-Young (HY), and a hybrid of two cultivar (C1/R-S rice/HY) extracts was performed using HPLC experiment. The isolated flavonoids were evaluated for their radical-scavenging effect on DPPH and ABTS radicals. PMID- 24070396 TI - Transplacental transfer and distribution of pravastatin. AB - OBJECTIVE: The objective of the study was to determine the bidirectional transfer of pravastatin across the dually perfused term human placental lobule and its distribution between the tissue and maternal and fetal circuits. STUDY DESIGN: The transfer of pravastatin was determined in the maternal-to-fetal (n = 11) and fetal-to-maternal (n = 10) directions. Pravastatin was coperfused with its [(3)H] isotope and the marker compound antipyrine (20 MUg/mL) and its [(14)C]-isotope. The concentration of pravastatin in the perfused tissue and the maternal and fetal circuits was determined using liquid scintillation spectrometry. Inside-out vesicles prepared from placental brush border membranes were utilized to investigate the role of efflux transporters in the transplacental transfer of pravastatin. RESULTS: Pravastatin was transferred from the maternal to the fetal circuit and vice versa. In the maternal-to-fetal direction, the distribution of pravastatin at the end of experiment was as follows: 14 +/- 5% of the drug was retained by the tissue, 68 +/- 5% remained in the maternal circuit, and 18 +/- 4% was transferred to the fetal circuit. The normalized transfer of pravastatin (clearance index) to antipyrine in the fetal-to-maternal direction (0.48 +/- 0.07) was higher than its transfer in the maternal-to-fetal direction (0.36 +/- 0.07, P < .01). Furthermore, pravastatin inhibited the adenosine triphosphate (ATP)-dependent uptake of the paclitaxel and estrone sulfate. CONCLUSION: The transfer of pravastatin across the dually perfused placental lobule suggests that fetal exposure to pravastatin is plausible. The higher transfer of pravastatin in the fetal-to-maternal direction than the reverse as well as its inhibition of the ATP-dependent uptake of [(3)H]-paclitaxel and [(3)H]-estrone sulfate strongly suggest the involvement of efflux transporters in decreasing its transfer across the placenta and support pravastatin's favorable pharmacokinetic profile in pregnancy. PMID- 24070397 TI - Echogenic intracardiac foci: disclosure and the rate of amniocentesis in low-risk patients. AB - OBJECTIVE: Our objective was to determine the impact of disclosure of echogenic intracardiac focus (EIF) on the rate of amniocentesis in women who have undergone sequential testing. STUDY DESIGN: This was a retrospective study of women who had sequential testing for Down syndrome from 2009 through 2011. The Down syndrome risk was doubled in pregnancies with EIF, consistent with counseling provided to patients. In the control group Down syndrome risk was based on sequential testing. Within risk categories (1 in <250, 251-1000, 1001-5000, >5000) rates of amniocentesis with and without documented EIF were compared using Fisher exact test. RESULTS: In all, 4429 women at a median maternal age were included, including 229 with EIF (5.2%). In those at highest Down syndrome risk (1 in <250), rates of amniocentesis were similar between the 2 groups. In those at lower levels of risk, the rate of amniocentesis was significantly higher following disclosure of EIF compared to pregnancies without EIF at similar levels of risk. CONCLUSION: Except for those at highest risk, rates of invasive testing were significantly higher in pregnancies with isolated EIF vs those at comparable risk. PMID- 24070398 TI - Ultraviolet photodissociation of the N-methylpyridinium ion: action spectroscopy and product characterization. AB - The ultraviolet photodissociation of gas-phase N-methylpyridinium ions is studied at room temperature using laser photodissociation mass spectrometry and structurally diagnostic ion-molecule reaction kinetics. The C5H5N-CH3(+) (m/z 94), C5H5N-CD3(+) (m/z 97), and C5D5N-CH3(+)(m/z 99) isotopologues are investigated, and it is shown that the N-methylpyridinium ion photodissociates by the loss of methane in the 36,000 - 43,000 cm(-1) (280 - 230 nm) region. The dissociation likely occurs on the ground state surface following internal conversion from the S1 state. For each isotopologue, by monitoring the photofragmentation yield as a function of photon wavenumber, a broad vibronically featured band is recorded with origin (0-0) transitions assigned at 38 130, 38 140 and 38 320 cm(-1) for C5H5N-CH3(+) C5H5N-CD3+ and C5D5N-CH3(+), respectively. With the aid of quantum chemical calculations (CASSCF(6,6)/aug-cc-pVDZ), most of the observed vibronic detail is assigned to two in-plane ring deformation modes. Finally, using ion-molecule reactions, the methane coproduct at m/z 78 is confirmed as a 2-pyridinylium ion. PMID- 24070399 TI - Patient experiences of recovery after heart valve replacement: suffering weakness, struggling to resume normality. AB - BACKGROUND: Heart valve disease is becoming a public health problem due to increasing life expectancy and new treatment methods. Patients are at risk of developing depression, anxiety or post-traumatic stress disorder after heart valve surgery. To better plan proper care, describing and understanding patients' perception of recovery after heart valve replacement is essential. The objective was to describe the experience of recovery at home after heart valve replacement. METHODS: Qualitative interviews were conducted with 10 patients representing the population and these were later transcribed. The analysis was inspired by Ricoeur's theory of interpretation, which consists of three levels: naive reading, structured analysis, and critical interpretation and discussion. RESULTS: The overall concept that emerged was suffering weakness and struggling to resume normality. Patients all struggled to resume normal living, both in regaining physical strength and in reestablishing balance in overall living. The overall concept can be interpreted in terms of the following themes: Disturbed network: Invaluable relatives, Contact with healthcare staff, Rehabilitation. Disturbed body: Stressful complications, Bodily attention, Physically affected, Physical capability. Recovery: Interrupted living, Suffering weakness, Gradual recovery, Achieving normality. Reflections: Thoughts about the procedure and Feeling sad and fragile. CONCLUSION: The study presents the main themes of network, body, recovery and reflection for ten patients after heart valve replacement. These main themes can overall be summarized as suffering weakness and struggling to resume normality. Patients felt weak with a changed body, but after a long recovery process regained vitality and returned to their daily life. PMID- 24070400 TI - Interferon-gamma, interleukins-6 and -4, and factor XIII-A as indirect markers of the classical and alternative macrophage activation pathways in chronic periodontitis. AB - BACKGROUND: Macrophages account for 5% to 30% of the inflammatory infiltrate in periodontitis and are activated by the classic and alternative pathways. These pathways are identified by indirect markers, among which interferon (IFN)-gamma and interleukin-6 (IL)-6 of the classic pathway and IL-4 of the alternative pathway have been studied widely. Recently, factor XIII-A (FXIII-A) was reported to be a good marker of alternative pathway activation. The aim of this study is to determine the macrophage activation pathways involved in chronic periodontitis (CP) by the detection of the indirect markers IFN-gamma, IL-6, FXIII-A, and IL-4. METHODS: Biopsies were taken from patients with CP (n = 10) and healthy individuals (n = 10) for analysis of IFN-gamma, IL-6, IL-4, and FXIII-A by Western blot (WB), immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA). The same biopsies of healthy and diseased gingival tissue were used, and the expressions of these markers were compared between healthy individuals and those with CP. RESULTS: The presence of macrophages was detected by CD68+ immunohistochemistry and their IFN-gamma, IL-6, IL-4, and FXIII-A markers by WB, IHC, and ELISA in all samples of healthy and diseased tissue. IL 6, IL-4, and FXIII-A were significantly higher in patients with CP, whereas FXIII A was higher in healthy individuals. CONCLUSION: The presence of IFN-gamma, IL-6, IL-4, and FXIII-A in healthy individuals and in patients with CP suggests that macrophages may be activated by both classic and alternative pathways in health and in periodontal disease. PMID- 24070401 TI - Generation of site-appropriate tissue by a living cellular sheet in the treatment of mucogingival defects. AB - BACKGROUND: Generation of site-appropriate tissue in the oral cavity includes the restoration of the correct anatomic type, amount, and distribution of the tissue. This study is a post hoc analysis of data collected during previously published results from two randomized clinical trials of a living cellular sheet (LCS; allogenic cultured keratinocytes and fibroblasts in bovine collagen) versus a free gingival graft (FGG), evaluating their ability to augment keratinized tissue or gingiva. METHODS: Post hoc histologic and clinical (photographic) comparisons of the outcomes of treatment were performed on histologic and photographic data gathered in the two randomized clinical trials. RESULTS: Histologic findings showed that LCS-treated sites resembled gingiva rather than alveolar mucosa. Photographic analysis indicated that LCS treatment resulted in more site appropriate tissue than FGG in terms of tissue color, with adjacent untreated tissue, absence of scar formation or keloid-like appearance, and mucogingival junction alignment. CONCLUSION: Treatment of mucogingival defects with LCS resulted in the generation of tissue that is more site appropriate than tissue transplanted from the palate. PMID- 24070402 TI - Using PPI network autocorrelation in hierarchical multi-label classification trees for gene function prediction. AB - BACKGROUND: Ontologies and catalogs of gene functions, such as the Gene Ontology (GO) and MIPS-FUN, assume that functional classes are organized hierarchically, that is, general functions include more specific ones. This has recently motivated the development of several machine learning algorithms for gene function prediction that leverages on this hierarchical organization where instances may belong to multiple classes. In addition, it is possible to exploit relationships among examples, since it is plausible that related genes tend to share functional annotations. Although these relationships have been identified and extensively studied in the area of protein-protein interaction (PPI) networks, they have not received much attention in hierarchical and multi-class gene function prediction. Relations between genes introduce autocorrelation in functional annotations and violate the assumption that instances are independently and identically distributed (i.i.d.), which underlines most machine learning algorithms. Although the explicit consideration of these relations brings additional complexity to the learning process, we expect substantial benefits in predictive accuracy of learned classifiers. RESULTS: This article demonstrates the benefits (in terms of predictive accuracy) of considering autocorrelation in multi-class gene function prediction. We develop a tree-based algorithm for considering network autocorrelation in the setting of Hierarchical Multi-label Classification (HMC). We empirically evaluate the proposed algorithm, called NHMC (Network Hierarchical Multi-label Classification), on 12 yeast datasets using each of the MIPS-FUN and GO annotation schemes and exploiting 2 different PPI networks. The results clearly show that taking autocorrelation into account improves the predictive performance of the learned models for predicting gene function. CONCLUSIONS: Our newly developed method for HMC takes into account network information in the learning phase: When used for gene function prediction in the context of PPI networks, the explicit consideration of network autocorrelation increases the predictive performance of the learned models. Overall, we found that this holds for different gene features/ descriptions, functional annotation schemes, and PPI networks: Best results are achieved when the PPI network is dense and contains a large proportion of function-relevant interactions. PMID- 24070403 TI - Evaluation of left ventricular diastolic function by fractional area change using cine cardiovascular magnetic resonance: a feasibility study. AB - BACKGROUND: Evaluation of left ventricular (LV) diastolic function is essential for the management of heart failure. We verified whether LV diastolic function could be evaluated by measuring the fractional area change (FAC) using cine cardiovascular magnetic resonance (CMR). METHODS: We collected clinical data from 59 patients who underwent echocardiography and cine CMR. Normal, impaired relaxation, pseudonormal, and restrictive LV filling were observed in 15, 28, 11, and 5 patients, respectively. We calculated FAC during the first 30% of diastole (diastolic-index%) in the short-axis view, by tracing the contours on only three MR cine images. RESULTS: The diastolic index was significantly lower (p < 0.0001) in patients with impaired relaxation (32.4 +/- 7.5), pseudonormal filling (25.4 +/- 5.6), and restrictive filling (9.5 +/- 1.5) compared to those with normal diastolic function (67.7 +/- 10.8), and the index decreased significantly with worsening of diastolic dysfunction. The diastolic index correlated positively with early diastolic mitral annular velocity measured by tissue Doppler imaging (r = 0.75, p < 0.0001), respectively. CONCLUSIONS: Measurement of FAC can be useful for the evaluation of LV diastolic function using cine CMR. PMID- 24070404 TI - Amyotrophic lateral sclerosis disease progression model. AB - Our objective was to develop: 1) a longitudinal model to describe amyotrophic lateral sclerosis (ALS) disease progression using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R); and 2) a probabilistic model to estimate the presence of clusters of trajectories in ALS progression over 12 months of treatment. Three hundred and thirty-eight patients treated with placebo from the PRO-ACT database were included in the analyses. A non-linear Weibull model best described the ALS disease progression, and a stepwise logistic regression approach was used to select the variables predicting a slow or fast disease progression. Results identified two clusters of trajectories: 1) slow disease progressors (46% of patients with a change from baseline of 13%); 2) fast disease progressors (54% of patients with a change from baseline of 49%). ROC curve analysis estimated the optimal cut-off for classifying patients as slow or fast disease progressors given ALSFRS-R measurements at 2-4 weeks. Results showed that the degree of ALS disease progression quantified by the ALSFRS-R symptomatic change on placebo is highly heterogeneous. In conclusion, this finding indicates the potential interest of disease progression models for implementing a population enrichment strategy to control the level of heterogeneity in the patients included in new trials. PMID- 24070405 TI - Isolation and purification of glycoconjugates from complex biological sources by recycling high-performance liquid chromatography. AB - Among of the most urgent needs of the glycobiology community is to generate libraries of pure carbohydrate standards. While many oligosaccharides have recently been synthesized, some glycans of biomedical importance are still missing in existing collections or are available in only limited amounts. To address this need, we demonstrate the use of the relatively unexplored technique of recycling high-performance liquid chromatography (R-HPLC) to isolate and purify glycoconjugates from several natural sources. We were able to routinely achieve purities greater than 98%. In several cases, we were able to obtain isomerically pure substances, particularly for glycans with different positional isomerism. These purified substances can then be used in different analytical applications, for example, as standards for mass spectrometry (MS) and capillary based separations. Moreover, using a bifunctional aromatic amine, the same derivatization agent can be used to enable UV detection of oligosaccharides during their purification and link the isolated molecules to functionalized surfaces and potentially create glycan arrays. PMID- 24070406 TI - Reactive and proactive control adjustments under increased depressive symptoms: insights from the classic and emotional-face Stroop task. AB - The current research investigated differences in reactive and proactive cognitive control as a function of depressive symptomatology. Three participant groups with varying symptom levels (Beck Depression Inventory-II, BDI-II score) completed both the classic and an emotional-face Stroop task separately under speed and accuracy instructions. All groups made equivalent speed-accuracy trade-offs independent of task, suggesting that proactive adjustments are unaffected by depressive symptoms. Additionally, groups made equivalent reactive control adjustments (Stroop effects, congruency sequence effects) in the classic Stroop task, suggesting that these reactive control adjustments are spared across a wide range of BDI-II scorers. In contrast, the high BDI-II group displayed a selective impairment in the resolution of conflict in the emotional-face Stroop task. Thus, while proactive control and many aspects of reactive control were unaffected by the level of depressive symptoms, specific impairments occurred when current task demands required the trial-to-trial regulation of emotional processing. PMID- 24070407 TI - Nuclear lipid droplets identified by electron microscopy of serial sections. AB - BACKGROUND: Recent studies have suggested that nuclear lipid droplets (LDs) are organized into domains similar to those of cytoplasmic LDs. As cytoplasmic LDs are formed at the endoplasmic reticulum (ER) membrane, which is structurally continuous with the nuclear envelope, it could be suggested however that nuclear LDs are cytoplamic LDs trapped within an invagination of the nuclear envelope. The resolution of fluorescence confocal microscopy is not sufficiently high to exclude this hypothesis. FINDINGS: We therefore addressed this question by electron microscopy (EM) of serial sections. In human liver tissue, we observed some cytoplamic LDs partly surrounded by the nuclear compartment, but we were also able to identify LDs residing in the nuclear compartment that were not connected to the nuclear envelope. CONCLUSION: These findings indicate that nuclear LDs constitute specific subdomains of the nuclear compartment probably involved in nuclear lipid homeostasis. PMID- 24070408 TI - Near-infrared light photocontrolled targeting, bioimaging, and chemotherapy with caged upconversion nanoparticles in vitro and in vivo. AB - The major challenge in current chemotherapy is to increase local effective therapeutic concentration of drugs as well as to minimize toxicity and side effects for patients. The targeted delivery of drugs to their desired site of action in a controlled manner plays an essential role in the development of drug formulations. A photocage refers to a caged molecule rendered biologically inert by a photolabile protecting group. Molecules are illuminated with light to liberate the caged group and then become active forms. In this study, we formulate upconversion nanoparticles (UCNPs) as the NIR-triggered targeting and drug delivery vehicles that successfully deliver in vitro and in vivo for near infrared light photocontrolled targeting, bioimaging, and chemotherapy. It is noted that there has been no report on the systemic administration UCNP-based drug delivery agents for evaluation of bioimaging and chemotherapy. To achieve phototargeting, the tumor-homing agent (i.e., folic acid) has been constructed as a photoresponsive molecule. For the chemotherapeutic effect, the antitumor drug doxorubicin is thiolated on the surface of UCNPs, forming a disulfide bond that can be cleaved by lysosomal enzymes within the cells. The caged UNCPs can serve as a platform for the improvement of selective targeting and possible reduction of adverse side effects from chemotherapy. PMID- 24070409 TI - Child abuse and neglect in Turkey: professional, governmental and non governmental achievements in improving the national child protection system. AB - Since ratification of the United Nations Convention on the Rights of the Child in 1995, significant efforts were made in Turkey to improve protection of children from abuse and neglect. The government took steps to amend relevant laws. Several state departments recognized the need for professional in-service training of relevant governmental agency staff. University hospitals established numerous hospital-based multidisciplinary child protection centres. The government established an Interministerial Higher Council, which has been overseeing the foundation of 13 child advocacy centres for a multidisciplinary and interagency response to child sexual abuse. In addition to undertaking research, non governmental organizations contributed to this process by instituting professional and public education. These ground-breaking developments in the last decade give promise of even further improvement in the national child protection system from investigative, child protective and rehabilitative perspectives. PMID- 24070410 TI - Shear-directed assembly of graphene oxide in aqueous dispersions into ordered arrays. AB - A wide variety of new carbon-based materials are being developed from graphene oxide (GO) precursor sheets, whose assembly in aqueous phases determines the form, structure, and properties of the resultant carbon. Here we show that graphene oxide forms ordered linear arrays of aggregates when aqueous suspensions are subjected to shear flow in the presence of soluble salts. These linear arrays align along the vorticity direction, normal to the direction of flow. We propose that salt addition screens electrostatic repulsion and allows formation of fractal-like GO sheet aggregates by hydrophobic forces. Fluid shear in a confined gap then guides the assembly of these primary aggregates into optically visible, ordered linear arrays or "superaggregates" whose characteristics are a function of GO concentration, salt valency, salt concentration, and gap confinement. This is the first reported observation of vorticity banding in graphene oxide suspensions and the first reported observation of such banding based on salt induced interactions. We also demonstrate that simple isometric nanoparticles of carbon or gold do not form such linear superaggregate arrays but can be assembled into such arrays using graphene oxide as a two-dimensional colloidal template. PMID- 24070411 TI - Palladacycle-catalyzed deacetonative Sonogashira coupling of aryl propargyl alcohols with aryl chlorides. AB - An efficient and general protocol for the deacetonative Sonogashira coupling of aryl propargyl alcohols with aryl chlorides is described. The reaction proceeded smoothly with the catalyst system of palladacycle/Xphos. This result represents the first successful deacetonative Sonogashira version for electron-poor, electron-neutral, and even inactive sterically hindered electron-rich aryl chlorides. PMID- 24070412 TI - Insights into discharge argon-mediated biofilm inactivation. AB - Formation of bacterial biofilms at solid-liquid interfaces creates numerous problems in biomedical sciences. Conventional sterilization and decontamination methods are not suitable for new and more sophisticated biomaterials. In this paper, the efficiency and effectiveness of gas discharges in the inactivation and removal of biofilms on biomaterials were studied. It was found that although discharge oxygen, nitrogen and argon all demonstrated excellent antibacterial and antibiofilm activity, gases with distinct chemical/physical properties underwent different mechanisms of action. Discharge oxygen- and nitrogen-mediated decontamination was associated with strong etching effects, which can cause live bacteria to relocate thus spreading contamination. On the contrary, although discharge argon at low powers maintained excellent antibacterial ability, it had negligible etching effects. Based on these results, an effective decontamination approach using discharge argon was established in which bacteria and biofilms were killed in situ and then removed from the contaminated biomaterials. This novel procedure is applicable for a wide range of biomaterials and biomedical devices in an in vivo and clinical setting. PMID- 24070413 TI - Surgical management of epilepsy due to cerebral cavernomas using neuronavigation and intraoperative MR imaging. AB - Objectives: Cure from seizures due to cavernomas might be surgically achieved dependent on both, the complete removal of the cavernoma as well as its surrounding hemosiderin rim. High field intraoperative MRI imaging (iopMRI) and neuronavigation might play a crucial role to achieve both goals. We retrospectively investigated the long-term results and impact of intraoperative 1.5T MRI (iopMRI) and neuronavigation on the completeness of surgical removal of a cavernous malformation (CM) and its perilesional hemosiderin rim as well as reduction of surgical morbidity. Methods: 26 patients (14 female, 12 male, mean age 39.1 years, range: 17-63 years) with CM related epilepsy were identified. Eighteen patients suffered from drug resistant epilepsy (69.2%). Mean duration of epilepsy was 11.9 years in subjects with drug resistant epilepsy (n = 18) and 0.3 years in subjects presenting with first-time seizures (n = 8). We performed 24 lesionectomies and two lesionectomies combined with extended temporal resections. Seven lesions were located extratemporally. Results: Complete CM removal was documented by postsurgical MRI in all patients. As direct consequence of iopMRI, refined surgery was necessary in 11.5% of patients to achieve complete cavernoma removal and in another 11.5% for complete resection of additional adjacent epileptogenic cortex. Removal of the hemosiderin rim was confirmed by iopMRI in 92% of patients. Two patients suffered from mild (7.7%) and one from moderate (3.8%) visual field deficits. Complete seizure control (Engel class 1A) was achieved in 80.8% of patients with a mean follow-up period of 47.7 months. Discussion: We report excellent long-term seizure control with minimal surgical morbidity after complete resection of CM using our multimodal approach. PMID- 24070415 TI - Safety and liver transduction efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute intermittent porphyria. AB - Acute intermittent porphyria (AIP) results from haplo-insufficient activity of porphobilinogen deaminase (PBGD) and is characterized clinically by life threatening, acute neurovisceral attacks. To date, liver transplantation is the only curative option for AIP. The aim of the present preclinical nonhuman primate study was to determine the safety and transduction efficacy of an adeno associated viral vector encoding PBGD (recombinant AAV serotype 5-codon-optimized human porphobilinogen deaminase, rAAV5-cohPBGD) administered intravenously as part of a safety program to start a clinical study in patients with AIP. Macaques injected with either 1 * 10(13) or 5 * 10(13) vector genomes/kg of clinical-grade rAAV5-cohPBGD were monitored by standardized clinical parameters, and vector shedding was analyzed. Liver transduction efficacy, biodistribution, vector integration, and histopathology at day 30 postvector administration were determined. There was no evidence of acute toxicity, and no adverse effects were observed. The vector achieved efficient and homogenous hepatocellular transduction, reaching transgenic PBGD expression levels equivalent to 50% of the naturally expressed PBGD mRNA. No cellular immune response was detected against the human PBGD or AAV capsid proteins. Integration site analysis in transduced liver cells revealed an almost random integration pattern supporting the good safety profile of rAAV5-cohPBGD. Together, data obtained in nonhuman primates indicate that rAAV5-cohPBGD represents a safe therapy to correct the metabolic defect present in AIP patients. PMID- 24070416 TI - Resonance Raman spectra of a perylene bis(dicarboximide) chromophore in ground and lowest triplet states. AB - Resonance Raman spectroscopy is employed to probe the ground (S0) and lowest triplet (T1) excited states of a perylene bis(dicarboximide) (PDI) dimer. Four bands at ~1324, 1507, ~1535, and 1597 cm(-1) are signatures of the T1 excited state; a fifth band at ~1160 cm(-1) is tentatively assigned. Density functional calculations of an asymmetrically substituted PDI monomer match the experimental bands of the PDI dimer in both S0 and T1 states. The match supports a T1 excited state that is localized on a single PDI moiety of the dimer. The normal modes of the asymmetrically substituted PDI are correlated with ones calculated for the unsubstituted PDI in the D2h point group. Patterns in the Raman intensities are consistent with an A-term mechanism of enhancement. The positions of six bands are predicted for the resonance Raman spectrum of unsubstituted PDI in its T1 excited state. The spectra and normal-mode analysis reported here are expected to facilitate future studies of singlet fission in PDI crystals or other assemblies. PMID- 24070414 TI - Health economic evaluation of vaccination strategies for the prevention of herpes zoster and postherpetic neuralgia in Germany. AB - BACKGROUND: Herpes zoster (HZ) is a self-limiting painful skin rash affecting mostly individuals from 50 years of age. The main complication is postherpetic neuralgia (PHN), a long-lasting pain after rash has resolved. A HZ-vaccine has recently been licensed in Europe for individuals older than 50 years. To support an informed decision-making for a potential vaccination recommendation, we conducted a health economic evaluation to identify the most cost-effective vaccination strategy. METHODS: We developed a static Markov-cohort model, which compared a vaccine-scenario with no vaccination. The cohort entering the model was 50 years of age, vaccinated at age 60, and stayed over life-time in the model. Transition probabilities were based on HZ/PHN-epidemiology and demographic data from Germany, as well as vaccine efficacy (VE) data from clinical trials. Costs for vaccination and HZ/PHN-treatment (in Euros; 2010), as well as outcomes were discounted equally with 3% p.a. We accounted results from both, payer and societal perspective. We calculated benefit-cost-ratio (BCR), number-needed-to vaccinate (NNV), and incremental cost-effectiveness ratios (ICERs) for costs per HZ-case avoided, per PHN-case avoided, and per quality-adjusted life-year (QALY) gained. Different target age-groups were compared to identify the most cost effective vaccination strategy. Base-case-analysis as well as structural, descriptive-, and probabilistic-sensitivity-analyses (DSA, PSA) were performed. RESULTS: When vaccinating 20% of a cohort of 1 million 50 year old individuals at the age of 60 years, approximately 20,000 HZ-cases will be avoided over life time. The NNV to avoid one HZ (PHN)-case was 10 (144). However, with a BCR of 0.34 this vaccination-strategy did not save costs. The base-case-analysis yielded an ICER of 1,419 (20,809) Euros per avoided HZ (PHN)-case and 28,146 Euros per QALY gained. Vaccination at the age of 60 was identified in most (sensitivity) analyses to be the most cost-effective vaccination strategy. In DSA, vaccine price and VE were shown to be the most critical input-data. CONCLUSIONS: According to our evaluation, HZ-vaccination is expected to avoid HZ/PHN-cases and gain QALYs to higher costs. However, the vaccine price had the highest impact on the ICERs. Among different scenarios, targeting individuals aged 60 years seems to represent the most cost-effective vaccination-strategy. PMID- 24070417 TI - Imbalanced matriptase pericellular proteolysis contributes to the pathogenesis of malignant B-cell lymphomas. AB - Membrane-associated serine protease matriptase is widely expressed by epithelial/carcinoma cells in which its proteolytic activity is tightly controlled by the Kunitz-type protease inhibitor, hepatocyte growth factor activator inhibitor (HAI-1). We demonstrate that, although matriptase is not expressed in lymphoid hyperplasia, roughly half of the non-Hodgkin B-cell lymphomas analyzed express significant amounts of matriptase. Furthermore, a significant proportion of these tumors express matriptase in the absence of HAI 1. Aggressive Burkitt lymphoma was more likely than indolent follicular lymphoma to express matriptase alone (86% versus 36%). In the absence of significant HAI-1 expression, the lymphoma cells activate and shed active matriptase when the cells are stimulated with mildly acidic buffer or the hypoxia-mimicking agent, CoCl2. The shed active matriptase can initiate pericellular proteolytic cascades by activating urokinase-type plasminogen activator on the cell surface of monocytes, and it can activate prohepatocyte growth factor. In addition, matriptase knockdown suppressed proliferation and colony-forming ability of neoplastic B cells in culture and growth as tumor xenografts in mice. Furthermore, exogenous expression of HAI-1 significantly suppressed proliferation of neoplastic B cells. These studies suggest that dysregulated pericellular proteolysis as a result of unregulated matriptase expression with limited HAI-1 may contribute to the pathological characteristics of several human B-cell lymphomas through modulation of the tumor microenvironment and enhanced tumor growth. PMID- 24070419 TI - Wafer-scale arrays of nonvolatile polymer memories with microprinted semiconducting small molecule/polymer blends. AB - Nonvolatile ferroelectric-gate field-effect transistors (Fe-FETs) memories with solution-processed ferroelectric polymers are of great interest because of their potential for use in low-cost flexible devices. In particular, the development of a process for patterning high-performance semiconducting channel layers with mechanical flexibility is essential not only for proper cell-to-cell isolation but also for arrays of flexible nonvolatile memories. We demonstrate a robust route for printing large-scale micropatterns of solution-processed semiconducting small molecules/insulating polymer blends for high performance arrays of nonvolatile ferroelectric polymer memory. The nonvolatile memory devices are based on top-gate/bottom-contact Fe-FET with ferroelectric polymer insulator and micropatterned semiconducting blend channels. Printed micropatterns of a thin blended semiconducting film were achieved by our selective contact evaporation printing, with which semiconducting small molecules in contact with a micropatterned elastomeric poly(dimethylsiloxane) (PDMS) mold were preferentially evaporated and absorbed into the PDMS mold while insulating polymer remained intact. Well-defined micrometer-scale patterns with various shapes and dimensions were readily developed over a very large area on a 4 in. wafer, allowing for fabrication of large-scale printed arrays of Fe-FETs with highly uniform device performance. We statistically analyzed the memory properties of Fe-FETs, including ON/OFF ratio, operation voltage, retention, and endurance, as a function of the micropattern dimensions of the semiconducting films. Furthermore, roll-up memory arrays were produced by successfully detaching large-area Fe-FETs printed on a flexible substrate with a transient adhesive layer from a hard substrate and subsequently transferring them to a nonplanar surface. PMID- 24070418 TI - Deletion of the olfactomedin 4 gene is associated with progression of human prostate cancer. AB - The olfactomedin 4 (OLFM4) gene is located on chromosome 13q14.3, which frequently is deleted in human prostate cancer. However, direct genetic evidence of OLFM4 gene alteration in human prostate cancer has not yet been obtained. In this study, we investigated the genetics, protein expression, and functions of the OLFM4 gene in human prostate cancer. We found overall 25% deletions within the OLFM4 gene in cancerous epithelial cells compared with adjacent normal epithelial cells that were microdissected from 31 prostate cancer specimens using laser-capture microdissection and genomic DNA sequencing. We found 28% to 45% hemizygous and 15% to 57% homozygous deletions of the OLFM4 gene via fluorescence in situ hybridization analysis from 44 different prostate cancer patient samples. Moreover, homozygous deletion of the OLFM4 gene significantly correlated with advanced prostate cancer. By using immunohistochemical analysis of 162 prostate cancer tissue array samples representing a range of Gleason scores, we found that OLFM4 protein expression correlated inversely with advanced prostate cancer, consistent with the genetic results. We also showed that a truncated mutant of OLFM4 that lacks the olfactomedin domain eliminated suppression of PC-3 prostate cancer cell growth. Together, our findings indicate that OLFM4 is a novel candidate tumor-suppressor gene for chromosome 13q and may shed new light on strategies that could be used for the diagnosis, prognosis, and treatment of prostate cancer patients. PMID- 24070421 TI - Focused ion beam processing to fabricate ohmic contact electrodes on a bismuth nanowire for Hall measurements. AB - Ohmic contact electrodes for four-wire resistance and Hall measurements were fabricated on an individual single-crystal bismuth nanowire encapsulated in a cylindrical quartz template. Focused ion beam processing was utilized to expose the side surfaces of the bismuth nanowire in the template, and carbon and tungsten electrodes were deposited on the bismuth nanowire in situ to achieve electrical contacts. The temperature dependence of the four-wire resistance was successfully measured for the bismuth nanowire, and a difference between the resistivities of the two-wire and four-wire methods was observed. It was concluded that the two-wire method was unsuitable for estimation of the resistivity due to the influence of contact resistance, even if the magnitude of the bismuth nanowire resistance was greater than the kilo-ohm order. Furthermore, Hall measurement of a 4-MUm-diameter bismuth microwire was also performed as a trial, and the evaluated temperature dependence of the carrier mobility was in agreement with that for bulk bismuth, which indicates that the carrier mobility was successfully measured using this technique. PACS: 81.07.Gf. PMID- 24070420 TI - In vitro three-dimensional modeling of fallopian tube secretory epithelial cells. AB - BACKGROUND: Fallopian tube secretory epithelial cells (FTSECs) have been implicated as a cell-of-origin for high-grade serous epithelial ovarian cancer. However, there are relatively few in vitro models of this tissue type available for use in studies of FTSEC biology and malignant transformation. In vitro three dimensional (3D) cell culture models aim to recreate the architecture and geometry of tissues in vivo and restore the complex network of cell-cell/cell matrix interactions that occur throughout the surface of the cell membrane. RESULTS: We have established and characterized 3D spheroid culture models of primary FTSECs. FTSEC spheroids contain central cores of hyaline matrix surrounded by mono- or multi-layer epithelial sheets. We found that 3D culturing alters the molecular characteristics of FTSECs compared to 2D cultures of the same cells. Gene expression profiling identified more than a thousand differentially expressed genes between 3D and 2D cultures of the same FTSEC lines. Pathways significantly under-represented in 3D FTSEC cultures were associated with cell cycle progression and DNA replication. This was also reflected in the reduced proliferative indices observed in 3D spheroids stained for the proliferation marker MIB1. Comparisons with gene expression profiles of fresh fallopian tube tissues revealed that 2D FTSEC cultures clustered with follicular phase tubal epithelium, whereas 3D FTSEC cultures clustered with luteal phase samples. CONCLUSIONS: This 3D model of fallopian tube secretory epithelial cells will advance our ability to study the underlying biology and etiology of fallopian tube tissues and the pathogenesis of high-grade serous epithelial ovarian cancer. PMID- 24070422 TI - Advances in siRNA delivery to T-cells: potential clinical applications for inflammatory disease, cancer and infection. AB - The specificity of RNAi and its ability to silence 'undruggable' targets has made inhibition of gene expression in T-cells with siRNAs an attractive potential therapeutic strategy for the treatment of inflammatory disease, cancer and infection. However, delivery of siRNAs into primary T-cells represents a major hurdle to their use as potential therapeutic agents. Recent advances in siRNA delivery through the use of electroporation/nucleofection, viral vectors, peptides/proteins, nanoparticles, aptamers and other agents have now enabled efficient gene silencing in primary T-cells both in vitro and in vivo. Overcoming such barriers in siRNA delivery offers exciting new prospects for directly targeting T-cells systemically with siRNAs, or adoptively transferring T-cells back into patients following ex vivo manipulation with siRNAs. In the present review, we outline the challenges in delivering siRNAs into primary T-cells and discuss the mechanism and therapeutic opportunities of each delivery method. We emphasize studies that have exploited RNAi-mediated gene silencing in T-cells for the treatment of inflammatory disease, cancer and infection using mouse models. We also discuss the potential therapeutic benefits of manipulating T-cells using siRNAs for the treatment of human diseases. PMID- 24070423 TI - PIKfyve: a new fish in the growing pool of AMPK substrates. AB - Skeletal muscle is critical for whole-body glucose homoeostasis. Insulin and muscle contractions induced by exercise can increase glucose uptake through distinct intracellular signalling pathways involving PKB (protein kinase B)/Akt and AMPK (AMP-activated protein kinase) respectively. Whereas the proximal events governing these processes are becoming well understood, less is known about the regulation of the complex events necessary for the control of glucose uptake at the plasma membrane. In recent years, a number of common targets of AMPK and PKB/Akt have emerged as important components controlling glucose uptake, but the necessary phosphorylation events required for the control of glucose uptake have remained more elusive. In the current issue of the Biochemical Journal, Liu et al. identify that PIKfyve, a phosphoinositide phosphate kinase, is required for contraction-stimulated glucose uptake. They demonstrate that AMPK directly phosphorylates PIKfyve at Ser307, the same site as PKB/Akt, and that phosphorylation is increased in response to muscle contractions. These data provide compelling evidence for a new AMPK substrate that converges with PKB/Akt signalling and may be critical for the control of glucose uptake in skeletal muscle. PMID- 24070424 TI - Treatment with cyclophosphamide, vindesine, cytarabine, dexamethasone and bleomycin in patients with relapsed/refractory diffuse large B-cell lymphoma. AB - Several chemotherapy regimens have been used as second-line therapies for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). None have emerged as a preferred regimen. This retrospective study aimed to identify a regimen with high efficacy and low toxicity for patients with relapsed and refractory DLBCL. Fifty-eight patients diagnosed with relapsed or refractory DLBCL were included in the study. Patients were treated with cyclophosphamide, vindesine, cytarabine, dexamethasone and bleomycin (COAD-B). The overall response rate (ORR) was 70.7%, and the median remission duration was 13 months (3-48 months). The 1-, 2- and 4 year overall survival rates were 62.4%, 45.7% and 34.6%, respectively. The 1-, 2- and 4-year progression-free survival rates were 50.0%, 36.7% and 20.7%, respectively. The responses of patients with relapsed DLBCL to COAD-B were significantly better than those of patients with refractory DLBCL (p = 0.005). The main adverse reaction of patients was myelosuppression. Our data indicate that COAD-B should be used in treatment of patients with relapsed DLBCL. PMID- 24070425 TI - Isolated bone marrow Hodgkin lymphoma in a human immunodeficiency virus-negative patient: a second case. PMID- 24070426 TI - Spontaneous transformation of lamellar structures from simple to more complex states. AB - Spontaneous transformation of lamellar structures, such as multilamellar vesicles from micelles or unilamellar vesicles, is an important challenge in the field of amphiphile molecules, which may serve as models to understand biologically relevant bilayer membranes. Herein, we report a progressive self-assembly progress of N-tetradecyllactobionamide (C14G2) and tetraethylene glycol monododecyl ether (C12EO4) mixtures in aqueous solution. Increasing temperature or surfactant compositions causes spontaneous transformation from simple to high level aggregates, i.e., from unilamellar vesicles, to coexisting multilamellar vesicles, terraced planar bilayers, and finally terraced planar bilayers. Deuterium nuclear magnetic resonance ((2)H NMR), freeze-fracture transmission electron microscopy (FF-TEM), and small-angle X-ray scattering (SAXS) measurements clearly demonstrate the spontaneously progressive self-assembly process. The interlamellar spacing (d) of the bilayers decreases from unilamellar vesicles to the terraced planar bilayers with an increase of the temperature or surfactant compositions. Lamellar samples consisting of terraced planar bilayers at higher temperature still show viscoelastic properties, being Bingham fluids, and both the viscoelasticity and yield stress increase with the composition and decrease with the temperature. The spontaneous transformation of the progressive self-assembly progress of C14G2 and C12EO4 aqueous mixtures is due to a balance of three driving forces, hydrophobic interactions, hydrogen bonding, and steric effects. PMID- 24070427 TI - Depth profiling of metal overlayers on organic substrates with cluster SIMS. AB - Molecular depth profiling of organic thin films by erosion with energetic cluster ion beams is a unique aspect of secondary ion mass spectrometry (SIMS) experiments. Although depth profiles of complex multilayer organic structures can be acquired with little damage accumulation and with depth resolution of <10 nm using either C60(+) or Arx(+) with x = 500-5000, hybrid materials consisting of both organic and inorganic layers often yield poor results. To unravel the factors that lead to this difficulty, we developed a model system composed of a thin gold layer of 1.4 to 3.5 nm deposited either on top of or sandwiched within a cholesterol thin film matrix which is several hundred nanometers thick. For these systems, the results show that by erosion with a 40 keV C60(+) beam, reliable depth profiles can always be acquired as indicated by the presence of a steady state molecular ion signal. During the erosion process, however, gold atoms from the gold overlayer are implanted into the cholesterol matrix beneath it, resulting in a reduced sputter yield, an increase in the amount of cholesterol fragmentation and an increase in the thickness of the cluster ion induced altered layer. The results also show that the effects of the metal film on the organic substrate are independent of the gold film thickness once the film thickness exceeds 1.4 nm. In general, this model study provides mechanistic insight into the depth profiling of heterogeneous thin film structures and offers a possible path for improving the quality of the depth profiles by employing low energy atomic ion sputtering in the region of the metal layer. PMID- 24070428 TI - Self-assembly and applications of ultraconcentrated nanoparticle solutions. AB - We demonstrate a highly efficient method for concentrating, purifying and separating gold nanoparticles. The method relies on localized density gradients that can be formed at an aqueous | organic phase interface. We show that this method is able to concentrate aqueous gold nanoparticles to the point where confinement leads to variable interparticle separations. Furthermore, the physical properties of the resulting solution are drastically altered when compared to water. For example, densities higher than 4.5 g/cm(3) could be generated without nanoparticle aggregation. As far as we are aware, this is one of the highest reported densities of an aqueous solution at room temperature. Finally, the compositions of the solutions generated are highly dependent on parameters such as particle size and background analyte making this technique highly advantageous for the separation of multimodal NP populations and chemical purification, with 99.5% and >99.9% efficiency, respectively. PMID- 24070429 TI - Maternal depressive symptoms: associations with adolescents' internalizing and externalizing problems and social competence. AB - BACKGROUND: The negative effect of maternal depressive symptoms on child wellbeing has been quite extensively studied. There is, however, debate as to whether it is the timing, the recurrence or the chronicity of maternal depressive symptoms that puts the child's wellbeing at risk. AIMS: This study explores the associations between the timing, recurrence and the patterns of maternal depressive symptoms and adolescent psychosocial functioning. METHODS: One hundred and ninety-one mothers and 192 adolescents were followed up from the mother's pregnancy to the child's adolescence. Maternal depressive symptoms were screened with the Edinburgh Postnatal Depression Scale prenatally, postnatally, in early and middle childhood, and at adolescence. The adolescents' outcomes were screened using Child Behavior Checklists and Youth Self Reports. RESULTS: The results indicate that the initial exposure to maternal depressive symptoms at pregnancy is associated with more externalizing problems in adolescence, 2 months postnatally with more internalizing problems, in early childhood with poorer social competence and concurrently with more externalizing problems. Combined analyses indicate that recurrent maternal depressive symptoms best explain adolescents' internalizing problems and the chronic pattern of maternal depressive symptoms externalizing problems. The chronic and intermittent patterns of maternal depressive symptoms best explained adolescents' poorer social competence. CONCLUSIONS: Recurrent or chronic maternal depressive symptoms rather than the timing predict adolescents' psychosocial problems better. The timing, however, may explain the different kinds of problems in adolescence depending on the developmental task at the time of the exposure. The findings should be noted when treating both mothers and children in psychiatric clinics and other health services. PMID- 24070431 TI - A randomized male tolerance study of dapivirine gel following multiple topical penile exposures (MTN 012/IPM 010). AB - Dapivirine (DPV) is a nonnucleoside reverse transcriptase inhibitor with a favorable safety profile following vaginal application. A penile tolerance study was conducted prior to further development of DPV as a candidate vaginal microbicide. Twenty-four circumcised and 24 uncircumcised (N=48) healthy HIV negative male participants aged 18 years or older were randomized 2:1:1 to apply DPV 0.05% gel, matched placebo gel, or universal placebo gel, respectively, to their penis once daily for 7 sequential days. The safety, acceptability, and pharmacokinetic profile of DPV 0.05% gel were assessed by the presence of Grade 2 or higher genitourinary adverse events (AEs) and systemic AEs, a behavioral questionnaire, and pharmacokinetic plasma blood draw, respectively, at the final clinic visit (FCV). There were no Grade 2 genitourinary AEs in 47 participants completing the FCV. One participant in the DPV arm failed to attend the FCV. There were 13 AEs reported; all were Grade 1 except one Grade 2 corneal laceration unrelated to study product. Participants liked the gel to a moderate extent, yet 72% reported they would be "very likely" to use a gel like the one they used in the study every time they have intercourse. DPV was detectable in plasma in all 23 DPV arm study participants at the FCV. On average, the circumcised participants' DPV concentrations were 54% of those in uncircumcised participants (p=0.07). Topical seven-day penile application of DPV 0.05% gel was locally and systemically safe, was acceptable to male participants, and resulted in systemic exposure to the drug. PMID- 24070432 TI - Molecular epidemiology and mechanisms of antimicrobial resistance in Pseudomonas aeruginosa isolates causing burn wound infection in Iran. AB - In this study, the contributions of different resistance mechanisms in Pseudomonas aeruginosa isolates were investigated among burned patients. The real time reverse transcription polymerase chain reaction was performed to determine the expression level of mexY, ampC, and oprD for isolates. Also the isolates were typed by multilocus sequence typing (MLST). Seventy-five per cent of clinical isolates were multidrug resistant. The bla(OXA group-I) and blaPER alleles were identified in 28 and 10 P. aeruginosa isolates, respectively. The majority of bla(PER) positive isolates belonged to the same MLST clone and was identified as ST235. The types of remaining isolates were ST360 and ST861. Among 10 bla(PER) positive isolates, eight isolates demonstrated reduced oprD expression and mexY overexpression. Our data further highlight the epidemic potential of the international clone ST235. According to the results, different resistant mechanisms identified among ST235 isolates that were resistant to ceftazidime, imipenem, ciprofloxacin, and amikacin. PMID- 24070433 TI - The influence of yield surface shape and damage in the depth-dependent response of bone tissue to nanoindentation using spherical and Berkovich indenters. AB - Prevention and treatment of osteoporosis rely on understanding of the micromechanical behaviour of bone and its influence on fracture toughness and cell-mediated adaptation processes. Postyield properties may be assessed by nonlinear finite element simulations of nanoindentation using elastoplastic and damage models. This computational study aims at determining the influence of yield surface shape and damage on the depth-dependent response of bone to nanoindentation using spherical and conical tips. Yield surface shape and damage were shown to have a major impact on the indentation curves. Their influence on indentation modulus, hardness, their ratio as well as the elastic-to-total work ratio is well described by multilinear regressions for both tip shapes. For conical tips, indentation depth was not statistically significant (p < 0.0001). For spherical tips, damage was not a significant parameter (p < 0.0001). The gained knowledge can be used for developing an inverse method for identification of postelastic properties of bone from nanoindentation. PMID- 24070434 TI - Spiritual coping and anxiety in palliative care patients: a pilot study. AB - Patients often rely on spirituality to cope with anxiety, yet it is not known if spiritual coping actually helps patients deal with anxiety. The present study was designed, therefore, to examine this relationship. A series of patients who were referred to the palliative care team at New York University, Langone Medical Center (N = 44) were interviewed about their spiritual coping and anxiety. Anxiety was measured using the first three items of the GAD-7. Fourteen items, which were adapted from existing scales, were used to create the "Beliefs and Activities Spirituality Scale" (BASS), having two subscales: Activities (alpha = .79) and Beliefs (alpha = .82). Anxiety had a significant negative correlations with the total BASS (r = -.56), and the Activities (r = -.52) and Beliefs (r = .42) subscales. The salubrious association of spiritual coping and anxiety remained for the BASS and the Activities subscale, after controlling for demographic variables. PMID- 24070435 TI - Doctors' attentiveness to the spirituality/religion of their patients in pediatric and oncology settings in the Northwest USA. AB - Research indicates that spirituality/religion is important to many patients and they want this to be an integrated component of their care. This study's aim was to better understand doctors' attentiveness to patients'/families' spiritual/religious concerns and the contributing factors for this in the Northwest USA as well as doctor's attitudes about referrals to chaplains. Study participants included 108 pediatricians and oncologists who completed an online self-report questionnaire regarding their beliefs about the health relevance of patients' spirituality/religion and their attentiveness to this. Few doctors routinely addressed this concern. Doctors who were Christian, did not expect negative reactions to inquiring, and were knowledgeable regarding chaplains were more likely to address spirituality/religion. Doctors who felt less adequate in addressing spirituality/religion and were concerned about patients negative reactions were less likely to value referral to chaplains. On the other hand, those who had an understanding regarding chaplains were more likely to support referral. PMID- 24070439 TI - Reciprocal altruism. PMID- 24070440 TI - Animal signals. PMID- 24070441 TI - Sleep physiology: setting the right tone. AB - Humans prone to cataplexy experience sudden losses of postural muscle tone without a corresponding loss of conscious awareness. The brain mechanisms underlying this debilitating decoupling are now better understood, thanks to a new study using cataplectic mice. PMID- 24070442 TI - Memory processing: the critical role of neuronal replay during sleep. AB - Patterns of neuronal activity present during learning in the hippocampus are replayed during sleep. A new study highlights the functional importance of this neurophysiological phenomenon by showing that neuronal replay is critical for memory processing over a night of sleep. PMID- 24070443 TI - Membrane traffic: the exocyst meets the cell cycle. AB - A new study describes a novel regulatory event that results in the inhibition of exocytic transport of a specific class of Golgi-derived vesicles during mitosis. The mechanism of inhibition is shown to involve direct phosphorylation of a subunit of the exocyst by a specific cyclin-dependent kinase complex. PMID- 24070444 TI - Spatial navigation: head direction cells are anchored by gravity. AB - Thalamic neurons that signal an animal's direction of heading are crucial for spatial navigation. Both directional coding and flexible use of spatial memory are upended, however, when a rat has to find its way while upside down. PMID- 24070445 TI - Visual working memory: now you see it, now you don't. AB - Flies can form a visually-guided working memory. A new study shows that the gene termed ellipsoid body open influences multiple signals to regulate a competence factor in the ellipsoid body to support normal working memory. PMID- 24070446 TI - Gastrulation: cell polarity comes full circle. AB - The bending and internalization of tissues during embryonic development is a conserved process driven by dramatic cell-shape changes. A recent study details the molecules required for mesoderm internalization in Drosophila and their unique spatial localization pattern. PMID- 24070447 TI - Evolution: from autosomes to sex chromosomes--and back. AB - Heteromorphic sex chromosomes are thought to represent a terminal evolutionary endpoint due to their specialized gene content and chromosome-specific regulation. New findings, however, show that an ancient X chromosome reverted to an autosome in the lineage leading to Drosophila. PMID- 24070448 TI - Brain connectivity: revealing the fly visual motion circuit. AB - A new semi-automated method for high-throughput identification of visual neurons and their synaptic partners has been combined with optical recording of activity and behavioral analysis to give the first complete description of an elementary circuit for detecting visual motion. PMID- 24070449 TI - Partially fluorinated tetraazaacenes by nucleophilic aromatic substitution. AB - We report the sodium hydride-mediated reactions of a diethynylated diaminophenazine with perfluorobenzene, perfluoronaphthalene, and two octafluoroanthracene derivatives. In all of the cases, an N,N-dihydropyrazine ring is formed, and partially fluorinated tetraazapentacenes, tetraazahexacenes, and tetraazaheptacenes (in their respective N,N-dihydro forms) are easily prepared. In the case of the dihydrotetraazapentacenes and -hexacenes, oxidation with manganese dioxide is possible to give the desired, fully unsaturated tetraazaacenes; two molecules of the azahexacene undergo a Diels-Alder reaction in which an alkyne substituent in the conserved hexacene unit works as the dienophile while the tetraazahexacene participates as the diene to give an unsymmetrical dimer. All of the coupling targets were investigated by NMR and UV vis spectroscopies, and several single-crystal structures of the N,N dihydrotetraazaacenes and also that of the tetrafluorotetraazaacene were obtained. PMID- 24070450 TI - Cognitive impairment and whole brain diffusion in patients with carotid artery disease and ipsilateral transient ischemic attack. AB - OBJECTIVES: Transient ischemic attack (TIA) with carotid artery disease (CAD) can increase the risk of cognitive decline. However, the neural mechanisms of the disorder remain unclear. The aim of this study was, using diffusion tensor imaging (DTI), to detect microstructural changes in patients with symptomatic CAD presenting with TIA, and to explore their relationship with cognitive functions. METHODS: In all, 35 patients with right-sided CAD and ipsilateral TIA and 35 healthy controls were investigated using cognitive tests and voxel-based analysis (VBA) of DTI. The whole brain DTI parameters, fractional anisotropy (FA) and mean diffusivity (MD), were calculate and compared between two groups. A correlation analysis was also performed to explore the relationship between cognitive test scores and whole brain FA and MD values in the patients. RESULTS: We observed two interesting findings. First, compared with the controls, the patients showed significantly increased MD in the right anterior cingulate gyrus (ACG) and decreased FA in the right amygdala. Second, the MD values in the right ACG were negatively correlated with Montreal Cognitive Assessment (MoCA) in the patients. CONCLUSIONS: Diffusion tensor imaging parameters are altered in patients with CAD and ipsilateral TIA, which indicates the existence of microstructural abnormalities in the brain of the patients. The significant correlation between DTI abnormalities and cognition reveals the potential of DTI for investigating the pathophysiology mechanism related to the cognitive dysfunction of the disease. PMID- 24070452 TI - Rehab@home: a tool for home-based motor function rehabilitation. AB - PURPOSE: This paper presents the Rehab@home system, a tool specifically developed for helping neurological patients performing rehabilitation exercises at home, without the presence of a physiotherapist. It is centred on the rehabilitation of balance and on the sit-to-stand (STS) movement. METHOD: Rehab@home is composed of two Wii balance boards, a webcam and a computer, and it has two main software applications: one for patients to perform rehabilitation exercises and another one for therapists to visualize the data of the exercises. During the exercises, data from the boards and the webcam are processed in order to automatically assess the correctness of movements. RESULTS: Rehab@home provides exercises for the rehabilitation of balance (in sitting and in standing positions), and for the execution of the STS movement. It gives automatic feedback to the patient and data are saved for future analysis. The therapist is able to adapt the difficulty of the exercises to match with each patient's needs. A preliminary study with seven patients was conducted for evaluating their feedback. They appreciated using the system and felt the exercises more engaging than conventional therapy. CONCLUSIONS: Feedback from patients gives the hope that Rehab@home can become a great tool for complementing their rehabilitation process. Implications for Rehabilitation Rehab@home can be used at home by patients with motor deficits, without the presence of a therapist, as a complement to conventional therapy for accelerating the rehabilitation process. The system provides exercises for improving the balance and the STS movement capabilities of patients, gives automatic feedback, and saves video and load information from the movements for future analysis by the therapist. Its most important feature is adaptability: the therapist is able to tune the difficulty of the exercises for adapting them to the needs of each patient. Patients get more engaged for this type of exercises and think they can take profit from using it. PMID- 24070453 TI - Tailoring hexagonally packed metal hollow-nanocones and taper-nanotubes by template-induced preferential electrodeposition. AB - We report a template-induced preferential electrodeposition method for tailoring hexagonally packed metal hollow-nanocones and taper-nanotubes. After sputtering a layer of Au film, anodized aluminum foils with controllable periods and depths of taper-nanopore templates can be directly used as cathodes. Nanonipples on the top layer of alumina taper-nanopores can cause the "tip effect" during electrodeposition, which makes the metal deposition rate far rapider at the surface of templates than that at the lateral walls and the bottom of nanopores. Accordingly, the pore opening of the template can be rapidly closed while their interior is still hollow. Based on this principle, ordered arrayed of hollow nanocones with controllable periods (e.g., 100, 200, and 300 nm) and material composition (e.g., Ni, Fe, and Cu) can be realized in a simple, inexpensive, and accessible way. Besides, hexagonally packed metal taper-nanotubes can also be obtained by skillfully making use of the combination of both the "tip effect" and "self-masking" effect of relatively deeper (e.g., 576 nm) taper-nanopores during Au sputtering. Our work opens a door for studying the physical and chemical properties of hexagonally packed hollow-nanocones and tapered-nanotubes made of various metal materials. PMID- 24070451 TI - Combining solvent thermodynamic profiles with functionality maps of the Hsp90 binding site to predict the displacement of water molecules. AB - Intermolecular interactions in the aqueous phase must compete with the interactions between the two binding partners and their solvating water molecules. In biological systems, water molecules in protein binding sites cluster at well-defined hydration sites and can form strong hydrogen-bonding interactions with backbone and side-chain atoms. Displacement of such water molecules is only favorable when the ligand can form strong compensating hydrogen bonds. Conversely, water molecules in hydrophobic regions of protein binding sites make only weak interactions, and the requirements for favorable displacement are less stringent. The propensity of water molecules for displacement can be identified using inhomogeneous fluid solvation theory (IFST), a statistical mechanical method that decomposes the solvation free energy of a solute into the contributions from different spatial regions and identifies potential binding hotspots. In this study, we employed IFST to study the displacement of water molecules from the ATP binding site of Hsp90, using a test set of 103 ligands. The predicted contribution of a hydration site to the hydration free energy was found to correlate well with the observed displacement. Additionally, we investigated if this correlation could be improved by using the energetic scores of favorable probe groups binding at the location of hydration sites, derived from a multiple copy simultaneous search (MCSS) method. The probe binding scores were not highly predictive of the observed displacement and did not improve the predictivity when used in combination with IFST-based hydration free energies. The results show that IFST alone can be used to reliably predict the observed displacement of water molecules in Hsp90. However, MCSS can augment IFST calculations by suggesting which functional groups should be used to replace highly displaceable water molecules. Such an approach could be very useful in improving the hit-to-lead process for new drug targets. PMID- 24070454 TI - Effects of fish farming on phytoplankton community under the thermal stress caused by a power plant in a eutrophic, semi-enclosed bay: induce toxic dinoflagellate (Prorocentrum minimum) blooms in cold seasons. AB - Six cruises were conducted in a fish farm adjacent to the Ninghai Power Plant in Xiangshan Bay, East China Sea. Fish farming significantly increased NH4(+), DIP, and TOC concentrations, while it significantly decreased the DO level. These increase/decrease trends were more pronounced in warmer seasons. Although culture practices did not significantly increase phytoplankton density, it drastically enhanced dinoflagellate abundance and domination. Significant differences in species diversity and community composition between the cages and the control area were also observed. Temperature elevation caused by thermal discharge associated with eutrophication resulted in a dominant species shift from diatoms alone to dinoflagellates and diatoms. This is the first report of stress-induced toxic dinoflagellate (Prorocentrum minimum) blooms in winter and the winter spring transition in this bay. Therefore, the effects of aquaculture activity and power plant construction in such a eutrophic, semi-enclosed bay require further attention. PMID- 24070455 TI - Optimization of nutrient component for diesel oil degradation by Acinetobacter beijerinckii ZRS. AB - A new bacterial strain that is capable of using diesel as the sole carbon source was isolated from the petroleum-contaminated soil of Xinjiang oil field, Northwest China. This bacterium was identified on the basis of its morphological and physiological characteristics and 16S rRNA gene sequence analysis, and it showed the greatest similarity with Acinetobacter beijerinckii 302-PWB-OH1 (99.86%). In order to enhance degradation efficiency, single-factor experiments and response surface methodology (RSM) were employed to optimize the nutrients used in artificial seawater. The results of this study revealed that 2.05 g L(-1) (NH4)2SO4, 1.46 g L(-1) Na2HPO4, and 14 mg L(-1) yeast extract in artificial seawater resulted in increasing the diesel degradation rate of the bacterial strain from 20.87% to 80.40% within 7 days. The actual experimental results were in agreement with the prediction. PMID- 24070456 TI - Intervention to prevent further falls in older people who call an ambulance as a result of a fall: a protocol for the iPREFER randomised controlled trial. AB - BACKGROUND: An increasing number of falls result in an emergency call and the subsequent dispatch of paramedics. In the absence of physical injury, abnormal physiological parameters or change in usual functional status, it could be argued that routine conveyance by ambulance to the Emergency Department (ED) is not the most effective or efficient use of resources. Further, it is likely that non conveyed older fallers have the potential to benefit from timely access to fall risk assessment and intervention. The aim of this randomised controlled trial is to evaluate the effect of a timely and tailored falls assessment and management intervention on the number of subsequent falls and fall-related injuries for non conveyed older fallers. METHODS: Community dwelling people aged 65 years or older who are not conveyed to the ED following a fall will be eligible to be visited at home by a research physiotherapist. Consenting participants will receive individualised intervention strategies based on risk factors identified at baseline. All pre-test measures will be assessed prior to randomisation. Post test measures will be undertaken by a researcher blinded to group allocation 6 months post-baseline. Participants in the intervention group will receive individualised pro-active fall prevention strategies from the clinical researcher to ensure that risk factors are addressed adequately and interventions carried out. The primary outcome measure will be the number of falls recorded by a falls diary over a 12 month period. Secondary outcome measures assessed six months after baseline will include the subsequent use of medical and emergency services and uptake of recommendations. Data will be analysed using the intention-to-treat principle. DISCUSSION: As there is currently little evidence regarding the effectiveness or feasibility of alternate models of care following ambulance non conveyance of older fallers, there is a need to explore assessment and intervention programs to help reduce subsequent falls, related injuries and subsequent use of health care services. By linking existing services rather than setting up new services, this pragmatic trial aims to utilise the health care system in an efficient and timely manner. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN 12611000503921. PMID- 24070458 TI - Comprehensive geriatric assessment in older patients with cancer: two steps forward? PMID- 24070457 TI - Hypnotics and mortality in an elderly general population: a 12-year prospective study. AB - BACKGROUND: Hypnotics are widely used by the elderly, and their impact on mortality remains controversial. The inconsistent findings could be due to methodological limitations, notably the lack of control for underlying sleep symptoms or illness associated with hypnotic use, for example, insomnia symptoms and excessive daytime sleepiness, depression and anxiety. Our objective was to examine the association between the use of hypnotics and mortality risk in a large cohort of community-dwelling elderly, taking into account a wide range of potential competing risks including sociodemographic characteristics, lifestyle, and chronic disorders as well as underlying psychiatric disorders and sleep complaints. METHODS: Analyses were carried out on 6,696 participants aged 65 years or older randomly recruited from three French cities and free of dementia at baseline. Adjusted Cox proportional hazards models with delayed entry, and age of the participants as the time scale, were used to determine the association between hypnotic use and 12-year survival. RESULTS: At baseline, 21.7% of the participants regularly used at least one hypnotic. During follow-up, 1,307 persons died, 480 from cancer and 344 from cardiovascular disease. Analyses adjusted for study center, age and gender showed a significantly greater risk of all-cause and cardiovascular-related mortality with hypnotics, particularly benzodiazepines, and this increased with the number of hypnotics used. None of these associations were significant in models adjusting for sociodemographic and lifestyle characteristics, chronic disorders including cardiovascular pathologies, sleep and psychiatric disorders. Results remained unchanged when duration of past hypnotic intake or persistent versus intermittent use during follow-up were taken into account. CONCLUSIONS: When controlling for a large range of potential confounders, the risk of mortality was not significantly associated with hypnotic use regardless of the type and duration. Underlying psychiatric disorders appear to be the principal confounders of the observed association. PMID- 24070459 TI - Does the Multidimensional Prognostic Index (MPI), based on a Comprehensive Geriatric Assessment (CGA), predict mortality in cancer patients? Results of a prospective observational trial. AB - OBJECTIVE: Despite the lack of definitive data on the impact of Comprehensive Geriatric Assessment (CGA) in the geriatric oncology setting, the broad use of any form of CGA is strongly recommended before any treatment decision in elderly cancer patients (ECP); currently there is no consensus about the best format for this geriatric assessment. The aim of this study was to firstly test the Multidimensional Prognostic Index (MPI) in ECP with locally advanced or metastatic disease. MATERIALS AND METHODS: Patients aged >=70years with inoperable or metastatic solid cancer consecutively admitted to our Program of Geriatric Oncology were assessed by a multidisciplinary team and received a basal CGA to calculate the MPI score. RESULTS: A hundred and sixty patients entered the study. In the Cox's regression model, MPI, CIRS-SI, BSA, GDS, MMSE, chemotherapy and a diagnosis of primary lung cancer were associated with mortality at 6 and 12months. The ROC curves confirmed the prognostic value of MPI, with the best discriminatory power for mortality at both 6 and 12months. CONCLUSION: The present study is the first to indicate that the MPI retains its prognostic value even in elderly cancer patients with advanced stage of disease. The CIRS-SI and the GDS may potentiate the prognostic value of MPI. PMID- 24070460 TI - Frailty and malnutrition predictive of mortality risk in older patients with advanced colorectal cancer receiving chemotherapy. AB - INTRODUCTION: In general, geriatric assessment (GA) provides the combined information on comorbidity and functional, nutritional and psychosocial status and may be predictive for mortality outcome of cancer patients. The impact of geriatric assessment on the outcome of older patients with colorectal cancer treated with chemotherapy is largely unknown. METHODS: In a prospective study, 143 patients with colorectal cancer who were 70years and older were assessed before chemotherapy by Mini Nutritional Assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Indicator (GFI) and Mini Mental State Examination (MMSE). RESULTS: Fifty-four (38%) patients received adjuvant chemotherapy and 89 (62%) patients received palliative chemotherapy. Malnutrition and frailty were prevalent in 39 (27%, assessed by MNA) and 34 (24%, by GFI) patients, respectively; whereas cognitive impairment was prevalent in 19 (13%, by IQCODE) and 11 (8%, by MMSE) patients, respectively. In patients with palliative chemotherapy, poor MNA scores were associated with receiving less than 4cycles of chemotherapy (p=0.008). Poor MNA and GFI scores were associated with increased hazard ratios (HR) for mortality for patients with palliative chemotherapy: HR=2.76 (95% confidence interval [CI]: 1.60-4.77; p<0.001) and HR=2.72 (95% CI: 1.58-4.69; p<0.001), respectively, after adjustment for several clinical parameters. CONCLUSIONS: Malnutrition and frailty were strongly associated with an increased mortality risk in patients who underwent palliative chemotherapy. Furthermore, a poor score on MNA was predictive for less tolerance of chemotherapy. Our findings may help the oncologist in future decision making and advice for elderly patients with colorectal cancer. PMID- 24070461 TI - The influence of clinical assessment (including age) and geriatric assessment on treatment decisions in older patients with cancer. AB - OBJECTIVES: The aim of this prospective study in older patients with cancer was to evaluate how clinical assessment (including age) determines the physician's treatment decisions, and how geriatric assessment (GA) further influences these decisions. PATIENTS AND METHODS: Patients aged >=70years old with cancer were included if a new therapy was considered. All patients underwent a GA and results were communicated to the treating physician. After the final treatment decision, a predefined questionnaire was completed by the physician. RESULTS: In total, 937 patients with median age of 76years old were included. A total of 902 (96.3%) questionnaires were completed by the treating physicians. In 381/902 patients (42.2%) clinical assessment led to a different treatment decision compared to younger patients without co-morbidities. This difference was most prominent for chemotherapy/targeted therapy decisions. In 505/902 cases (56%) the treating physician consulted GA results before the final treatment decision. In these patients, the treatment decision was influenced by clinical assessment in 44.2%. In 31/505 patients (6.1%) the GA further influenced treatment, mostly concerning chemotherapy/targeted therapy. In eight patients GA influenced the physician to choose a more aggressive chemotherapy. CONCLUSIONS: Physicians use different treatment regimens in older versus younger patients, based on clinical assessment, including age. GA results further influence treatment decisions in a minority of patients and may trigger the use of less aggressive as well as more aggressive treatments. GA information is not always utilized by oncologists, indicating the need for better education and sensitization. PMID- 24070462 TI - A retrospective study on 73 elderly patients (>=75years) with aggressive B-cell non Hodgkin lymphoma: clinical significance of treatment intensity and comprehensive geriatric assessment. AB - OBJECTIVE: The clinical outcome of elderly (>=75years) patients with aggressive B cell non-Hodgkin lymphoma (B-NHL) is not firmly established because few studies have specifically addressed this issue. In addition, the usefulness of a comprehensive geriatric assessment (CGA) in B-NHL still needs to be deeply explored. MATERIALS AND METHODS: We evaluated the prognostic factors of 73 patients aged >=75years (median age: 78) with B-NHL treated by clinical judgment with curative anthracycline-based approaches (n=36) or with conservative treatments without anthracyclines (n=37). Analysis of clinical outcomes also included baseline CGA stratification. RESULTS: The curative approaches resulted in a better clinical outcome than conservative approaches [overall response rate: 91.2% vs. 69.7%, P=0.003; 2-year progression-free survival: 47.2% vs. 21.6%, P=0.006; and 2-year overall survival (OS): 58.3% vs 24.3%, P=0.003] with similar safety profiles. Independent of treatment type, patients classified as "fit" and "intermediate" by CGA presented with better OS compared to patients classified as "frail" (P<0.001). Patients classified as "fit" and "intermediate" who were receiving curative treatments presented with a significantly better OS when compared with those treated conservatively on the basis of clinical judgment. A curative anthracycline-based therapy (P=0.048), the response to treatment (P=0.017) and a "frail" condition (P=0.031) were the only factors affecting OS in multivariate analysis. CONCLUSIONS: Present data indicates that even in elderly patients with B-NHL curative anthracycline-based therapies are more effective than conservative approaches. However, choice of treatment should rely more on objective than on subjective parameters. Therefore, further prospective trials are warranted to better define the CGA role in hematopoietic malignancies. PMID- 24070463 TI - Sorafenib and sunitinib for elderly patients with renal cell carcinoma. AB - BACKGROUND: Sunitinib and sorafenib are small-molecule tyrosine kinase inhibitors with known antitumor activity in advanced renal cell carcinoma. MATERIALS AND METHODS: We retrospectively assess the response and tolerance of elderly patients with renal cell carcinoma to these two agents. Data of patients aged >=70years receiving sorafenib or sunitinib at the Centre Leon Berard were analyzed. Forty eight patients received sorafenib or sunitinib as a first line treatment, 8 received sorafenib followed by sunitinib and 4 received the reverse sequence. Objective responses (ORs), stable disease (SD), toxicity, overall survival (OS) and progression-free survival (PFS) were reported. RESULTS: Sorafenib and sunitinib achieved similar OR+SD rates (79% vs. 71% respectively). Median PFS was 6months in first-line sorafenib treated patients and 5months in the sunitinib group. Median OS was 16months in first-line sorafenib-treated patients and 15months in the sunitinib group. In patients receiving sorafenib followed by sunitinib, median PFS was 11.5months, and median OS was 13.1months. With the reverse sequence, median PFS was 8.1months and median OS was 15months. Treatment modifications were more frequent in sunitinib-treated patients, in first or second line (75% vs. 50%). Limitations are the retrospective design of the study and the small number of patients. CONCLUSION: First-line sunitinib and sorafenib seem equally efficient in elderly patients treated for advanced renal carcinomas, but sunitinib is less well tolerated. Sequential treatment with sorafenib followed by sunitinib seems to be better tolerated. These results should be confirmed in a larger prospective study. PMID- 24070464 TI - Improved targeting of cancer care for older patients: a systematic review of the utility of comprehensive geriatric assessment. AB - A comprehensive geriatric assessment (CGA) provides clinicians with detailed information on a patient's physiological age and may aid in the treatment decision-making process. Conducting a CGA, however, is time-consuming, requiring extensive data collection and, in some cases, the involvement of multiple healthcare professionals. The CGA is also not specifically targeted towards assessing patients presenting with neoplastic pathologies. These limitations have precluded this tool's inclusion in routine oncologic practice involving seniors. In order to identify CGA domains most predictive of important cancer-specific outcomes, we conducted a systematic review (PROSPERO registration number CRD42012002476) using MEDLINE, CINAHL, EMBASE and CANCERLIT databases. Studies published in English or French between May 1997 and May 2012, in which a CGA was conducted in patients over the age of 65 initiating cancer treatment, were assessed for eligibility, of which 9 studies were selected for this review. As part of the inclusion criteria, all studies must have assessed, at minimum, the following domains: nutritional, cognitive and functional status, polypharmacy, comorbidities and the presence of geriatric syndromes. In predicting mortality, in at least one study or another, all of the aforementioned CGA domains were found to be significant. Most frequently, however, the following domains were reported for predicting mortality: nutritional status (HR=1.84-2.54), the presence of geriatric syndromes such as depression (HR=1.51-1.81), and functional status (HR=1.04-1.33). With regards to chemotherapy-related toxicity, similar findings were obtained where functional status (OR=1.71-2.47) and the presence of geriatric syndromes, such as impaired hearing (OR=1.67, 95% CI 1.04-2.69), had the most significant predictive value. Only one study reported on the incidence of post-operative complications for which severe comorbidity was found to be highly associated with experiencing severe complications (OR=5.62, 95% CI 2.18 14.50), while functional status was found to be significantly associated with experiencing any complication (OR=4.02, 95% CI 1.24-13.09). PMID- 24070465 TI - Medical treatment of advanced non-small cell lung cancer in elderly patients: a review of the role of chemotherapy and targeted agents. AB - Lung cancer is the leading cause of cancer related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all cases. Half of the patients at diagnosis of NSCLC are over seventy years old; therefore, the elderly represent a large subgroup of patients affected by advanced NSCLC in our clinical practice. Nevertheless, the elderly are under-represented in clinical trials. Given the fact that old age is frequently associated with several comorbidities, poor general conditions and physiologic reduction in organ function, clinicians must carefully choose the best treatment option for elderly patients with advanced NSCLC, always taking into account the expected risks and benefits. In this paper we perform a review of literature evidence regarding the medical treatment of elderly patients affected by advanced NSCLC, encompassing single-agent chemotherapy, doublet chemotherapy and targeted agents. We conclude that single agent chemotherapy with a third generation agent (vinorelbine, taxanes, gemcitabine) represents a valid treatment option for elderly patients who are not eligible for a combination chemotherapy due to clinical features such as comorbidities, poor performance status and inadequate organ function. Platinum based doublet chemotherapy shows similar efficacy in elderly patients as compared to their younger counterpart, despite greater treatment related toxicity and it is indicated in elderly patients with ECOG PS: 0-2, adequate organ function and no major comorbidities. Elderly patients affected by epidermal growth factor receptor (EGFR) mutated NSCLC benefit mostly from a tyrosine kinase inhibitor of EGFR (erlotinib, gefitinib) which is associated with a good toxicity profile. Currently there are no available data to strongly support the use of bevacizumab in combination with first line chemotherapy in the treatment of older adults. Elderly patients affected by NSCLC harboring the EML4-ALK translocation could benefit mostly from a treatment with an oral inhibitor of such a rearrangement (crizotinib). PMID- 24070466 TI - From suboptimal to optimal treatment in older patients with cancer. PMID- 24070467 TI - Early signalling events of autophagy. AB - Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1-ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1-ULK1 signalling module. PMID- 24070468 TI - Omegasomes: PI3P platforms that manufacture autophagosomes. AB - Autophagy is a conserved survival pathway, which cells and tissues will activate during times of stress. It is characterized by the formation of double-membrane vesicles called autophagosomes inside the cytoplasm. The molecular mechanisms and the signalling components involved require specific control to ensure correct activation. The present chapter describes the formation of autophagosomes from within omegasomes, newly identified membrane compartments enriched in PI3P (phosphatidylinositol 3-phosphate) that serve as platforms for the formation of at least some autophagosomes. We discuss the signalling events required to nucleate the formation of omegasomes as well as the protein complexes involved. PMID- 24070469 TI - Current views on the source of the autophagosome membrane. AB - Autophagy was discovered in the late 1950s when scientists using the first electron microscopes saw membrane-bound structures in cells that contained cytoplasmic organelles, including mitochondria. Pursuant to further morphological characterization it was recognized that these vesicles, now called autophagosomes, are found in all eukaryotic cells and undergo changes in morphology from a double-membraned vesicle with recognizable content, i.e. sequestered organelles, to a uniformly dense core autolysosome. Genetic screens in the yeast Saccharomyces cerevisiae in the 1990s provided a molecule framework for the next era of discovery during which the interest in, and research into, autophagy has rapidly expanded into many areas of human biology and disease. A relatively small cohort of approximately 36 proteins, called Atgs (autophagy related proteins), orchestrate the formation of the autophagosome, and these are now being studied and functionally characterized. Although the function of these proteins is being elucidated, the underlying molecular mechanisms of how autophagosomes form are still not completely understood. Recent advances have, however, provided a significant advance in both our understanding of the molecular control of the Atg proteins and the source of the membranes. A consensus view is emerging from these advances that the endoplasmic reticulum is the nucleation site for the autophagosome, and that contributions from other compartments (Golgi, endosomes and plasma membrane) are required. In the present chapter, I review the data from the pre-molecular decades, and discuss the most recent publications to give an overview of the current view of where, and how, autophagosomes form in mammalian cells. PMID- 24070470 TI - Two ubiquitin-like conjugation systems that mediate membrane formation during autophagy. AB - In autophagy, the autophagosome, a transient organelle specialized for the sequestration and lysosomal or vacuolar transport of cellular constituents, is formed via unique membrane dynamics. This process requires concerted actions of a distinctive set of proteins named Atg (autophagy-related). Atg proteins include two ubiquitin-like proteins, Atg12 and Atg8 [LC3 (light-chain 3) and GABARAP (gamma-aminobutyric acid receptor-associated protein) in mammals]. Sequential reactions by the E1 enzyme Atg7 and the E2 enzyme Atg10 conjugate Atg12 to the lysine residue in Atg5, and the resulting Atg12-Atg5 conjugate forms a complex with Atg16. On the other hand, Atg8 is first processed at the C-terminus by Atg4, which is related to ubiquitin-processing/deconjugating enzymes. Atg8 is then activated by Atg7 (shared with Atg12) and, via the E2 enzyme Atg3, finally conjugated to the amino group of the lipid PE (phosphatidylethanolamine). The Atg12-Atg5-Atg16 complex acts as an E3 enzyme for the conjugation reaction of Atg8; it enhances the E2 activity of Atg3 and specifies the site of Atg8-PE production to be autophagy-related membranes. Atg8-PE is suggested to be involved in autophagosome formation at multiple steps, including membrane expansion and closure. Moreover, Atg4 cleaves Atg8-PE to liberate Atg8 from membranes for reuse, and this reaction can also regulate autophagosome formation. Thus these two ubiquitin-like systems are intimately involved in driving the biogenesis of the autophagosomal membrane. PMID- 24070471 TI - The Atg8 family: multifunctional ubiquitin-like key regulators of autophagy. AB - Autophagy is an evolutionarily-conserved catabolic process initiated by the engulfment of cytosolic components in a crescent-shaped structure, called the phagophore, that expands and fuses to form a closed double-membrane vesicle, the autophagosome. Autophagosomes are subsequently targeted to the lysosome/vacuole with which they fuse to degrade their content. The formation of the autophagosome is carried out by a set of autophagy-related proteins (Atg), highly conserved from yeast to mammals. The Atg8s are Ubl (ubiquitin-like) proteins that play an essential role in autophagosome biogenesis. This family of proteins comprises a single member in yeast and several mammalian homologues grouped into three subfamilies: LC3 (light-chain 3), GABARAP (gamma-aminobutyric acid receptor associated protein) and GATE-16 (Golgi-associated ATPase enhancer of 16 kDa). The Atg8s are synthesized as cytosolic precursors, but can undergo a series of post translational modifications leading to their tight association with autophagosomal structures following autophagy induction. Owing to this feature, the Atg8 proteins have been widely served as key molecules to monitor autophagosomes and autophagic activity. Studies in both yeast and mammalian systems have demonstrated that Atg8s play a dual role in the autophagosome formation process, coupling between selective incorporation of autophagy cargo and promoting autophagosome membrane expansion and closure. The membrane remodelling activity of the Atg8 proteins is associated with their capacity to promote tethering and hemifusion of liposomes in vitro. PMID- 24070472 TI - Autophagosome maturation and lysosomal fusion. AB - Compartmentalization is essential in the eukaryotic cell and this is most often achieved by sequestering specific components that perform a related function in a membrane-bound organelle. To function normally these organelles must transiently fuse with other compartments in order to transfer protein and lipid that is needed for them to function. These events must be highly coordinated otherwise non-specific fusion could occur leading to loss of compartment identity and function. The autophagosome is a specialized membrane compartment that delivers cytosolic components to the lysosome for degradation. Likewise, this delivery is coordinated so that only when the autophagosome is fully formed is it imparted with the information to allow it to specifically fuse with the endocytic system and deliver its contents to the lysosome. In the present chapter, I discuss our current understanding of how this happens. PMID- 24070473 TI - Selective autophagy. AB - During the last decade it has become evident that autophagy is not simply a non selective bulk degradation pathway for intracellular components. On the contrary, the discovery and characterization of autophagy receptors which target specific cargo for lysosomal degradation by interaction with ATG8 (autophagy-related protein 8)/LC3 (light-chain 3) has accelerated our understanding of selective autophagy. A number of autophagy receptors have been identified which specifically mediate the selective autophagosomal degradation of a variety of cargoes including protein aggregates, signalling complexes, midbody rings, mitochondria and bacterial pathogens. In the present chapter, we discuss these autophagy receptors, their binding to ATG8/LC3 proteins and how they act in ubiquitin-mediated selective autophagy of intracellular bacteria (xenophagy) and protein aggregates (aggrephagy). PMID- 24070474 TI - Mitophagy. AB - Mitophagy describes the selective targeting and degradation of mitochondria by the autophagy pathway. In this process, defective mitochondria are first purged from the mitochondrial network then delivered to the lysosome by the autophagy machinery. Mitophagy has emerged as a key facet of mitochondrial quality control and has been implicated in a variety of human diseases. Disturbances in the cellular control of mitophagy can result in a dysfunctional mitochondrial network with grave implications for high energy demanding tissue. The present chapter reviews the recent advancements in the study of mitophagy mechanisms and regulation. PMID- 24070475 TI - Autophagy and cell death. AB - Autophagy is intimately associated with eukaryotic cell death and apoptosis. Indeed, in some cases the same proteins control both autophagy and apoptosis. Apoptotic signalling can regulate autophagy and conversely autophagy can regulate apoptosis (and most likely other cell death mechanisms). However, the molecular connections between autophagy and cell death are complicated and, in different contexts, autophagy may promote or inhibit cell death. Surprisingly, although we know that, at its core, autophagy involves degradation of sequestered cytoplasmic material, and therefore presumably must be mediating its effects on cell death by degrading something, in most cases we have little idea of what is being degraded to promote autophagy's pro- or anti-death activities. Because autophagy is known to play important roles in health and many diseases, it is critical to understand the mechanisms by which autophagy interacts with and affects the cell death machinery since this will perhaps allow new ways to prevent or treat disease. In the present chapter, we discuss the current state of understanding of these processes. PMID- 24070476 TI - Autophagy and ageing: implications for age-related neurodegenerative diseases. AB - Autophagy is a process of lysosome-dependent intracellular degradation that participates in the liberation of resources including amino acids and energy to maintain homoeostasis. Autophagy is particularly important in stress conditions such as nutrient starvation and any perturbation in the ability of the cell to activate or regulate autophagy can lead to cellular dysfunction and disease. An area of intense research interest is the role and indeed the fate of autophagy during cellular and organismal ageing. Age-related disorders are associated with increased cellular stress and assault including DNA damage, reduced energy availability, protein aggregation and accumulation of damaged organelles. A reduction in autophagy activity has been observed in a number of ageing models and its up-regulation via pharmacological and genetic methods can alleviate age related pathologies. In particular, autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Indeed, in certain situations, reduced autophagosome induction may actually provide benefits to ageing cells. Future studies will undoubtedly improve our understanding of exactly how the multiple signals that are integrated to control appropriate autophagy activity change during ageing, what affect this has on autophagy and to what extent autophagy contributes to age-associated pathologies. Identification of mechanisms that influence a healthy lifespan is of economic, medical and social importance in our 'ageing' world. PMID- 24070477 TI - Role of autophagy in cancer prevention, development and therapy. AB - Autophagy is a process that takes place in all mammalian cells and ensures homoeostasis and quality control. The term autophagy [self (auto)-eating (phagy)] was first introduced in 1963 by Christian de Duve, who discovered the involvement of lysosomes in the autophagy process. Since then, substantial progress has been made in understanding the molecular mechanism and signalling regulation of autophagy and several reviews have been published that comprehensively summarize these findings. The role of autophagy in cancer has received a lot of attention in the last few years and autophagy modulators are now being tested in several clinical trials. In the present chapter we aim to give a brief overview of recent findings regarding the mechanism and key regulators of autophagy and discuss the important physiological role of mammalian autophagy in health and disease. Particular focus is given to the role of autophagy in cancer prevention, development and in response to anticancer therapy. In this regard, we also give an updated list and discuss current clinical trials that aim to modulate autophagy, alone or in combination with radio-, chemo- or targeted therapy, for enhanced anticancer intervention. PMID- 24070478 TI - Autophagy as a defence against intracellular pathogens. AB - Autophagy is a membrane trafficking pathway that results in the formation of autophagosomes which deliver portions of the cytosol to lysosomes for degradation. When autophagosomes engulf intracellular pathogens, the pathway is called 'xenophagy' because it leads to the removal of foreign material. Autophagy is activated during infection by Toll-like receptors that recognize pathogen associated molecular patterns. This allows autophagy to kill micro-organisms and present pathogen components to the innate and acquired immune systems. The targeting of pathogens by autophagy is selective and involves a growing family of autophagy receptors that bind to the autophagosome membrane protein LC3 (light chain 3)/Atg8 (autography-related protein 8). Ubiquitination of microbes identifies them as substrates for autophagy and they are delivered to autophagosomes by autophagy receptors that bind both ubiquitin and LC3/Atg8. Bacteria can also be detected before they enter the cytosol by autophagy receptors that scan the surface of membrane compartments for evidence of damage. The observation that some pathogens survive in cells suggests they can evade complete destruction by autophagy. For some bacteria this involves proteins that shield the surface of the bacteria from recognition by autophagy receptors. Other viruses and bacteria are resistant to degradation in lysosomes and use autophagosomes and/or lysosomes as sites for replication. Most of our current understanding of the role played by autophagy during microbial infection has come from studies of bacteria and viruses in tissue culture cell lines. Future work will focus on understanding how autophagy determines the outcome of infection 'in vivo', and how autophagy pathways can be exploited therapeutically. PMID- 24070479 TI - Liquid chromatography coupled to on-line post column derivatization for the determination of organic compounds: a review on instrumentation and chemistries. AB - Analytical derivatization either in pre or post column modes is one of the most widely used sample pretreatment techniques coupled to liquid chromatography. In the present review article we selected to discuss the post column derivatization mode for the analysis of organic compounds. The first part of the review focuses to the instrumentation of post-column setups including not only fundamental components such as pumps and reactors but also less common parts such as static mixers and back-pressure regulators; the second part of the article discusses the most popular "chemistries" that are involved in post column applications, including reagent-less approaches and new sensing platforms such as the popular gold nanoparticles. Some representative recent applications are also presented as tables. PMID- 24070480 TI - Nano composite system based on coumarin derivative-titanium dioxide nanoparticles and ionic liquid: determination of levodopa and carbidopa in human serum and pharmaceutical formulations. AB - The combination of coumarin derivative (7-(1,3-dithiolan-2-yl)-9,10-dihydroxy-6H benzofuro[3,2-c]chromen-6-on), (DC)-titanium dioxide nanoparticles (TiO2) and ionic liquid (IL) yields nanostructured electrochemical sensor, formed a novel kind of structurally uniform and electrocatalytic activity material. This new ionic liquid-TiO2 nanoparticles modified carbon paste electrode (IL-CTP) due to its enhanced conductivity presented very large current response from electroactive substrates. The modified electrode was characterized by different methods including a scanning electron microscope (SEM), electrochemical impedance spectroscopy (EIS) and voltammetry. A pair of well-defined quasi reversible redox peaks of coumarin derivative was obtained at the modified carbon paste electrode (DC/IL-CTP) by direct electron transfer between the coumarin derivative and the CP electrode. Dramatically enhanced electrocatalytic activity was exemplified at the DC/IL-CTP electrode, as an electrochemical sensor to study the electro oxidation of levodopa (LD) and carbidopa (CD). Based on differential pulse voltammetry (DPV), the oxidation of LD and CD exhibited the dynamic range between 0.10- 900.0 MUM and 20.0-900.0 MUM respectively, and the detection limit (3sigma) for LD and CD were 41 nM and 0.38 MUM, respectively. DPV was used for simultaneous determination of LD and CD at the DC/IL-CTP electrode, and quantitation of LD and CD in some real samples (such as tablets of Parkin-C Fort and Madopar, Sinemet, water, urine, and human blood serum) by the standard addition method. PMID- 24070481 TI - An aptasensor for sensitive detection of human breast cancer cells by using porous GO/Au composites and porous PtFe alloy as effective sensing platform and signal amplification labels. AB - A novel aptamer biosensor for cancer cell assay has been reported on the basis of ultrasensitive electrochemical detection. The assay uses the aptamer as a capture probe to recognize and bind the tumor marker on the surface of the cancer cells, forming an aptamer-based sandwich structure for MCF-7 cells detection. Functionalized nanoporous materials, porous graphene oxide/Au composites (GO/Au composites) and porous PtFe alloy have been introduced into the biosensor. Owing to the large surface area and versatile porous structure, the use of nanoporous materials can significantly improve the analysis performance of the biosensors by loading of large amounts of molecules and accelerating diffusion rate. Under the optimized experimental conditions, the proposed aptamer biosensor exhibited excellent analytical performance for MCF-7 cells determination, ranging from 100 to 5.0*10(7) cells mL(-1) with the detection limit of 38 cells mL(-1). The biosensor showed good selectivity, acceptable stability and reproducibility, and developed a highly sensitive and selective method for cancer cells detection. PMID- 24070482 TI - Preconcentration of milk proteins using octadecylated monolithic silica microchip. AB - Sample preparation is a bottleneck in systems for chemical analysis and it is a required step in order to remove interference and preconcentrate the target analytes. Much research in recent years has focused on porous monolithic materials since they are highly permeable to liquid flow and show high mass transfer compared with common packed beds. This study has focused on the use of a glass microchip containing an inorganic silica-based monolithic material modified with octadecyl groups for preconcentration of milk proteins from skimmed cows' milk that vary in molecular weight, hydrophobicity, and abundance. Comparison between the fabricated device and a commercial cartridge for the preconcentration of proteins in skimmed cows' milk showed the ability of the device to successfully enrich protein mixtures from the sample. The three replicate experiments showed that the RSD of the mass to charge ratio of milk proteins ranged from 0.01 to 0.46%. In addition, it was found that there were no significant differences between the observed and reported masses of the milk proteins and the relative percentage error of the molecular masses ranged between 0.03 and 0.90%. The fact that the small amounts of sample required and short sample preparation time suggest that this new microfluidic device may be a viable alternative to existing procedures for protein extraction from real samples. PMID- 24070483 TI - A new strategy for synthesis of an in-tube molecularly imprinted polymer-solid phase microextraction device: selective off-line extraction of 4-nitrophenol as an example of priority pollutants from environmental water samples. AB - In this study a novel preparation protocol has been developed for the construction of an in-tube molecularly imprinted polymer-solid phase microextraction (MIP-SPME) device. Open tubular capillaries have been molded from a polymer sorbent imprinted for 4-nitrophenol as target molecule. Different parameters like inner diameter and volume of the polymer, porogen volume, swelling and shrinking effects of the polymer tubes, polymerization time, pH of the sample, extraction time, 'salting out' effect and serial connection of the tubes were evaluated and optimized. Particularly, an optimized polymer preparation process and extraction condition enhanced the final extraction recovery of 4-nitrophenol substantially. Using this new MIP-SPME technique with high-performance liquid chromatography-ultraviolet (HPLC-UV) analysis of the extracts, the linear range and the limits of detection and quantification are 0.001-10 mg L(-1), 0.33 MUg L(-1) and 1.1 MUg L(-1) respectively. At optimized conditions, a mixture of nitrophenols, alkylated and chlorinated phenols spiked into municipal waste water were analyzed to evaluate the matrix effects and cross selectivity of the new MIP capillary tubes. PMID- 24070484 TI - 1,8-bis(dimethylamino)naphthalene/9-aminoacridine: a new binary matrix for lipid fingerprinting of intact bacteria by matrix assisted laser desorption ionization mass spectrometry. AB - The effectiveness of a novel binary matrix composed of 1,8 bis(dimethylamino)naphthalene (DMAN; proton sponge) and 9-aminoacridine (9AA) for the direct lipid analysis of whole bacterial cells by matrix assisted laser desorption ionization mass spectrometry (MALDI MS) is demonstrated. Deprotonated analyte signals nearly free of matrix-related ions were observed in negative ion mode. The effect of the most important factors (laser energy, pulse voltage, DMAN/9AA ratio, analyte/matrix ratio) was investigated using a Box-Behnken response surface design followed by multi-response optimization in order to simultaneously maximize signal-to-noise (S/N) ratio and resolution. The chemical surface composition of single or mixed matrices was explored by X-ray photoelectron spectroscopy (XPS). Moreover, XPS imaging was used to map the spatial distribution of a model phospholipid in single or binary matrices. The DMAN/9AA binary matrix was then successfully applied to the analysis of intact Gram positive (Lactobacillus sanfranciscensis) or Gram negative (Escherichia coli) microorganisms. About fifty major membrane components (free fatty acids, mono-, di- and tri-glycerides, phospholipids, glycolipids and cardiolipins) were quickly and easily detected over a mass range spanning from ca. 200 to ca. 1600 m/z. Moreover, mass spectra with improved S/N ratio (compared to single matrices), reduced chemical noise and no formation of matrix-clusters were invariably obtained demonstrating the potential of this binary matrix to improve sensitivity. PMID- 24070485 TI - Isolation of strontium pools and isotope ratios in modern human hair. AB - The elements of human hair record specific information about an individual's health, diet, and surrounding environment. Strontium isotope ratios of human hair have attracted interest as they potentially record an individual's environment. Yet, separating the external environmental signals from the internal dietary indicators has remained a challenge. Here, we examined the effects of five different hair-cleaning methodologies to determine the extent that internal and external strontium signals can be isolated from human hair. In the first study of its kind, we employed an in-line strontium purification methodology and a multi collector inductively coupled plasma mass spectrometer to obtain high-precision strontium isotope ratio of human hair and of leachates of the different washing treatments. We found that the different applications of an individual treatment removed a consistent amount of strontium from hair and that replicate analyses showed each treatment altered the strontium isotope ratios of hair consistently. A mass-balance approach was applied to demonstrate that strontium was quantitatively removed and was accounted for in either the treated hair or the leachate. We observed that strontium isotope ratio varied as a function of treatment aggressiveness so as to suggest that there was a fine-scale structuring of strontium within hair (transverse cross-sectional variations); these variations existed as differences in strontium concentrations and isotope ratios. As a result, the Sr isotope ratio of hair and hair leachates treated with the most aggressive cleaning methods reflected the isotope ratios of the interior and total exterior strontium signatures, respectively. The results of this study indicate that external environmental strontium signals can be distinguished from the internal signals and therefore permit the application of strontium isotope ratios of modern human hair for geospatial applications. PMID- 24070486 TI - A colorimetric method for highly sensitive and accurate detection of iodide by finding the critical color in a color change process using silver triangular nanoplates. AB - In this contribution, we demonstrated a novel colorimetric method for highly sensitive and accurate detection of iodide using citrate-stabilized silver triangular nanoplates (silver TNPs). Very lower concentration of iodide can induce an appreciable color change of silver TNPs solution from blue to yellow by fusing of silver TNPs to nanoparticles, as confirmed by UV-vis absorption spectroscopy and transmission electron microscopy (TEM). The principle of this colorimetric assay is not an ordinary colorimetry, but a new colorimetric strategy by finding the critical color in a color change process. With this strategy, 0.1 MUM of iodide can be recognized within 30 min by naked-eyes observation, and lower concentration of iodide down to 8.8 nM can be detected using a spectrophotometer. Furthermore, this high sensitive colorimetric assay has good accuracy, stability and reproducibility comparing with other ordinary colorimetry. We believe this new colorimetric method will open up a fresh insight of simple, rapid and reliable detection of iodide and can find its future application in the biochemical analysis or clinical diagnosis. PMID- 24070487 TI - Quantum dots based electrochemiluminescent immunosensor by coupling enzymatic amplification for ultrasensitive detection of clenbuterol. AB - An ultrasensitive electrochemiluminescence (ECL) immunosensor based on CdSe quantum dots (QDs) has been designed for the detection of clenbuterol. The immunosensor was fabricated by layer by layer and characterized with atomic force microscopic images (AFM) and electrochemical impedance spectra (EIS). In oxygen saturated pH=9.0 Tris-HCl buffer, a strong ECL emission of QDs could be observed during the cathodic process due to the H2O2 product from electrochemical reduction of dissolved oxygen. Upon the formation of immunocomplex, the second antibody labeled with horseradish peroxidase was simply immobilized on the electrode surface. The ECL emission decreased since steric hindrance of the immunocomplex slowed down the electron-transfer speed of dissolved oxygen, and also could be greatly amplified by an enzymatic cycle to consume the self produced coreactant. Using clenbuterol as model analyte, the ECL intensity was determined by the concentration of competitive immunoassay of clenbuterol with a wide calibration in the range of 0.05 ng mL(-1) to 1000 ng mL(-1), and a low detection limit was 0.02 ng mL(-1). The immunosensor shows good stability and fabrication reproducibility. It was applied to detecting practical samples with the satisfactory results. This immunosensing strategy opens a new avenue for detection of residue and application of QDs in ECL biosensing. PMID- 24070488 TI - Magneto immunofluorescence assay for diagnosis of celiac disease. AB - A magneto immunofluorescence assay for the detection of anti-transglutaminase antibodies (ATG2) in celiac disease was developed. The ATG2 were recognized by transglutaminase enzyme immobilized on the magnetic beads and then the immunological reaction was revealed by antibodies labeled with peroxidase. The fluorescent response of the enzymatic reaction with o-phenylenediamine and H2O2 as substrates was correlated with anti-transglutaminase titer, showing EC50 and LOD values of 1:11,600 and 1:74,500 of antibody titers, respectively. A total number of 29 sera samples from clinically confirmed cases of celiac disease and 19 negative control samples were tested by the novel magneto immunofluorescence assay. The data were submitted to the receiver-operating characteristic plot (ROC) analysis which indicated that 8.1 U was the most effective cut-off value to discriminate correctly between celiac and non-celiac patients. The immunofluorescence assay exhibited a sensitivity of 96.6%, a specificity of 89.5% and an efficiency 93.8% compared with the commercial optical ELISA kit. PMID- 24070489 TI - Simultaneous determination of amino acids and carbohydrates in culture media of Clostridium thermocellum by valve-switching ion chromatography. AB - An improved method for the simultaneous determination of 20 amino acids and 7 carbohydrates using one-valve switching after injection, ion chromatography, and integrated pulsed amperometric detection is proposed. The resolution of the amino acids and carbohydrates in the cation trap column was investigated. In addition, parameters including flow liquid type, flow rate, concentration, and valve-switch timing were optimized. The method is time-saving, effective, and accurate for the simultaneous separation of amino acids and carbohydrates, with a mean correlation coefficient of >0.99 and repeatability of 0.5-4.6% for eight replicates. The method was successfully applied in the analysis of amino acids and carbohydrates in aseptic media and in extracellular culture media of three phenotypes of Clostridium thermocellum. PMID- 24070490 TI - Qualitative and quantitative high performance thin layer chromatography analysis of Calendula officinalis using high resolution plate imaging and artificial neural network data modelling. AB - Calendula officinalis, commonly known Marigold, has been traditionally used for its anti-inflammatory effects. The aim of this study was to investigate the capacity of an artificial neural network (ANN) to analyse thin layer chromatography (TLC) chromatograms as fingerprint patterns for quantitative estimation of chlorogenic acid, caffeic acid and rutin in Calendula plant extracts. By applying samples with different weight ratios of marker compounds to the system, a database of chromatograms was constructed. A hundred and one signal intensities in each of the HPTLC chromatograms were correlated to the amounts of applied chlorogenic acid, caffeic acid, and rutin using an ANN. The developed ANN correlation was used to quantify the amounts of 3 marker compounds in calendula plant extracts. The minimum quantifiable level (MQL) of 610, 190 and 940 ng and the limit of detection (LD) of 183, 57 and 282 ng were established for chlorogenic, caffeic acid and rutin, respectively. A novel method for quality control of herbal products, based on HPTLC separation, high resolution digital plate imaging and ANN data analysis has been developed. The proposed method can be adopted for routine evaluation of the phytochemical variability in calendula extracts. PMID- 24070491 TI - Specificity of noble metals dynamic sorption preconcentration on reversed-phase sorbents. AB - The reversible sorption preconcentration of noble metals (NMs) using different schemes "sorbent-reagent-eluent" was investigated. The extraction of Au, Pd, Pt, Ir, Rh and Ru chlorocomplexes from hydrochloric acid solutions on hyper crosslinked polysterene MN-200 in the form of ion associates with tributylamine (TBA) and 4-(n-octyl)diethylenetriamine (ODETA) was investigated. It was found that Pd, Pt and Au were quantitatively and reversibly extracted using TBA on hyper-crosslinked polysterene; the appropriate eluent for desorption was 1M solution of HCl in ethanol. Ir, Rh and Ru under these conditions were not sorbed quantitatively. It was found that sorbent hydrophobicity is not the main characteristic that defines the efficiency of sorption of a particular NM ion associate. Different efficiencies of hyper-crosslinked polysterene MN-200 for sorption of square-planar chlorcomplexes of Pt, Pd and Au and octahedral complexes of Ir, Rh and Ru were found. For the first time, the sorbents with their own N-atoms - StrataX and StrataX-AW - were used for the sorption of Ir, Rh and Ru. Using these sorbents, the sorption of Ir was increased up to 95%, and the sorption of Ru and Rh was increased to about 40%. We can explain these results by nonspecific interaction of chlorcomplexes of Ir, Rh and Ru with ethylenediamine groups of the sorbent. Weak bases with large anions may be applied for desorption of Ir, Rh and Ru. Two schemes of dynamic sorption preconcentration of NMs from hydrochloric acid solutions were proposed - hyper-crosslinked polysterene MN-200 for the determination of Au, Pd, Pt, and StrataX-AW for Ir, Rh and Ru. PMID- 24070492 TI - Quantitative fingerprinting by headspace--two-dimensional comprehensive gas chromatography-mass spectrometry of solid matrices: some challenging aspects of the exhaustive assessment of food volatiles. AB - The study proposes an investigation strategy that simultaneously provides detailed profiling and quantitative fingerprinting of food volatiles, through a "comprehensive" analytical platform that includes sample preparation by Headspace Solid Phase Microextraction (HS-SPME), separation by two-dimensional comprehensive gas chromatography coupled with mass spectrometry detection (GC*GC MS) and data processing using advanced fingerprinting approaches. Experiments were carried out on roasted hazelnuts and on Gianduja pastes (sugar, vegetable oil, hazelnuts, cocoa, nonfat dried milk, vanilla flavorings) and demonstrated that the information potential of each analysis can better be exploited if suitable quantitation methods are applied. Quantitation approaches through Multiple Headspace Extraction and Standard Addition were compared in terms of performance parameters (linearity, precision, accuracy, Limit of Detection and Limit of Quantitation) under headspace linearity conditions. The results on 19 key analytes, potent odorants, and technological markers, and more than 300 fingerprint components, were used for further processing to obtain information concerning the effect of the matrix on volatile release, and to produce an informative chemical blueprint for use in sensomics and flavoromics. The importance of quantitation approaches in headspace analysis of solid matrices of complex composition, and the advantages of MHE, are also critically discussed. PMID- 24070493 TI - Patient-ventilator interactions. Implications for clinical management. AB - Assisted/supported modes of mechanical ventilation offer significant advantages over controlled modes in terms of ventilator muscle function/recovery and patient comfort (and sedation needs). However, assisted/supported breaths must interact with patient demands during all three phases of breath delivery: trigger, target, and cycle. Synchronous interactions match ventilator support with patient demands; dyssynchronous interactions do not. Dyssynchrony imposes high pressure loads on ventilator muscles, promoting muscle overload/fatigue and increasing sedation needs. On current modes of ventilation there are a number of features that can monitor and enhance synchrony. These include adjustments of the trigger variable, the use of pressure versus fixed flow targeted breaths, and a number of manipulations of the cycle variable. Clinicians need to know how to use these modalities and monitor them properly, especially understanding airway pressure and flow graphics. Future strategies are emerging that have theoretical appeal but they await good clinical outcome studies before they become commonplace. PMID- 24070495 TI - Episodic future thinking in children compared to adolescents. AB - Episodic thinking involves the ability to re-create past and to construct future personal events, which contain event-specific (episodic) and general (semantic) details. The richness of episodic thought for past events improves as children move into adolescence. The current study aims to examine changes in episodic future thinking and to establish the cognitive underpinning of these changes. Typically developing children (n = 14) and adolescents (n = 15) were tested using an adapted version of the Child Autobiographical Interview (CAI) that required generation of past and future personally relevant events. Relational memory and executive skills were also examined. Significant developmental gains were found in richness of events recall across temporal directions (past and future) and across different types of details (episodic and semantic). Developmental gains in richness of past events were also shown to correspond to developmental gains in generation of future events. Moreover, developmental changes in relational memory and (to a lesser extent) executive functions were found to relate to increases in the amount of episodic (but not semantic) details provided. Our study highlighted the similarities between past and future episodic thinking in typically developing children and adolescents. It also raises a possibility that children with developmental and neurological disorders with impaired relational memory and/or executive skills may be at risk of difficulties with episodic thinking. PMID- 24070494 TI - Inhaled long-acting beta2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD. AB - BACKGROUND: Combination inhaled therapy with long-acting beta2 agonists (LABAs) and corticosteroids is beneficial in treating asthma and chronic obstructive pulmonary disease (COPD). OBJECTIVE: In asthma, LABAs enhance glucocorticoid receptor (GR) nuclear translocation in the presence of corticosteroids. Whether this biological mechanism occurs in COPD, a relatively corticosteroid-resistant disease, is uncertain. METHODS: Eight patients with mild/moderate COPD participated in a double-blind, placebo-controlled, crossover study and inhaled single doses of fluticasone propionate (FP) 100 MUg, FP 500 MUg, salmeterol xinafoate (SLM) 50 MUg, and combination FP 100 MUg + SLM 50 MUg. One hour postinhalation, sputum was induced, nuclear proteins isolated from purified macrophages, and levels of activated nuclear GR quantified by using a GR glucocorticoid response element ELISA-based assay. RESULTS: Nuclear GR significantly increased after the inhalation of FP 500 MUg (P < .01), but not after the inhalation of FP 100 MUg or SLM 50 MUg, compared with placebo. Interestingly, SLM in combination with FP 100 MUg increased nuclear GR levels equivalent to those of FP 500 MUg alone. This was significantly greater than either FP 100 MUg (P < .05) or SLM 50 MUg (P < .01) alone. In vitro in a human macrophage cell line, SLM (10(-8) mol/L) enhanced FP (10(-9) mol/L)-induced mitogen-activated protein kinase phosphatase-1 mRNA (5.8 +/- 0.6 vs 8.4 +/- 1.1 * 10(-6) copies, P < .05) and 2 * glucocorticoid response element-luciferase reporter gene activity (250.1 +/- 15.6 vs 103.1 +/- 23.6-fold induction, P < .001). Addition of SLM (10(-9) mol/L) to FP (10(-11) mol/L) significantly enhanced FP-mediated suppression of IL-1beta-induced CXCL8 (P < .05). CONCLUSIONS: Addition of SLM 50 MUg to FP 100 MUg enhanced GR nuclear translocation equivalent to that seen with a 5-fold higher dose of FP in sputum macrophages from patients with COPD. This may account for the superior clinical effects of combination LABA/corticosteroid treatment compared with either as monotherapy observed in COPD. PMID- 24070496 TI - The ectodysplasin pathway: from diseases to adaptations. AB - The ectodysplasin (EDA) pathway, which is active during the development of ectodermal organs, including teeth, hairs, feathers, and mammary glands, and which is crucial for fine-tuning the developmental network controlling the number, size, and density of these structures, was discovered by studying human patients affected by anhidrotic/hypohidrotic ectodermal dysplasia. It comprises three main gene products: EDA, a ligand that belongs to the tumor necrosis factor (TNF)-alpha family, EDAR, a receptor related to the TNFalpha receptors, and EDARADD, a specific adaptor. This core pathway relies on downstream NF-kappaB pathway activation to regulate target genes. The pathway has recently been found to be associated with specific adaptations in natural populations: the magnitude of armor plates in sticklebacks and the hair structure in Asian human populations. Thus, despite its role in human disease, the EDA pathway is a 'hopeful pathway' that could allow adaptive changes in ectodermal appendages which, as specialized interfaces with the environment, are considered hot-spots of morphological evolution. PMID- 24070497 TI - Novel dynamic elongational flow procedure for reinforcing strong, tough, thermally stable polypropylene/thermoplastic polyurethane blends. AB - Thermoplastic polyurethane (TPU)/polypropylene (PP) blends of different weight ratios were prepared with a self-made vane extruder (VE), which generates global dynamic elongational flow, and a traditional twin-screw extruder (TSE), which generates shear flow. High-resolution scanning electron microscopy and polarizing microscopy showed a structure feature of fiber morphology and a clear interlocking structure of spherulites of PP/TPU blends prepared with a VE. The wide-angle X-ray diffraction results showed that the TPU/PP blend based on dynamic elongational flow had evident crystalline structure of the beta form as a function of PP (90 wt %), compared to that of the conventional shear flow processing techniques. A significant improvement of the mechanical properties was obtained; the samples prepared with a VE had superior mechanical properties compared to those of the samples prepared with a TSE. Interestingly, differential scanning calorimetry curves showed that dynamic elongational flow could successfully improve the crystallinity of the PP/TPU blends. Furthermore, dynamic thermomechanical and thermogravimetric analysis curves revealed the apparent partial miscibility and strong interaction of the PP/TPU blends influenced by dynamic elongational flow, compared to that of TSE-extruded. Further research will provide significant understanding of the spherulite interface and high performance manipulation of PP/TPU blends under dynamic elongational flow, achieving superior PP/TPU blends. PMID- 24070499 TI - Mechanical reinforcement of polymeric fibers through peptide nanotube incorporation. AB - High aspect ratio nanotubular assemblies can be effective fillers in mechanically reinforced composite materials. However, most existing nanotubes used for structural purposes are limited in their range of mechanical, chemical, and biological properties. We demonstrate an alternative approach to mechanical reinforcement of polymeric systems by incorporating synthetic D,L-cyclic peptide nanotube bundles as a structural filler in electrospun poly D-, L-lactic acid fibers. The nanotube bundles self-assemble through dynamic hydrogen bonding from synthetic cyclic peptides to yield structures whose dimensions can be altered based on processing conditions, and can be up to hundreds of micrometers long and several hundred nanometers wide. With 8 wt % peptide loading, the composite fibers are >5-fold stiffer than fibers composed of the polymer alone, according to atomic force microscopy-based indentation experiments. This represents a new use for self-assembling cyclic peptides as a load-bearing component in biodegradable composite materials. PMID- 24070498 TI - Crozier's paradox revisited: maintenance of genetic recognition systems by disassortative mating. AB - BACKGROUND: Organisms are predicted to behave more favourably towards relatives, and kin-biased cooperation has been found in all domains of life from bacteria to vertebrates. Cooperation based on genetic recognition cues is paradoxical because it disproportionately benefits individuals with common phenotypes, which should erode the required cue polymorphism. Theoretical models suggest that many recognition loci likely have some secondary function that is subject to diversifying selection, keeping them variable. RESULTS: Here, we use individual based simulations to investigate the hypothesis that the dual use of recognition cues to facilitate social behaviour and disassortative mating (e.g. for inbreeding avoidance) can maintain cue diversity over evolutionary time. Our model shows that when organisms mate disassortatively with respect to their recognition cues, cooperation and recognition locus diversity can persist at high values, especially when outcrossed matings produce more surviving offspring. Mating system affects cue diversity via at least four distinct mechanisms, and its effects interact with other parameters such as population structure. Also, the attrition of cue diversity is less rapid when cooperation does not require an exact cue match. Using a literature review, we show that there is abundant empirical evidence that heritable recognition cues are simultaneously used in social and sexual behaviour. CONCLUSIONS: Our models show that mate choice is one possible resolution of the paradox of genetic kin recognition, and the literature review suggests that genetic recognition cues simultaneously inform assortative cooperation and disassortative mating in a large range of taxa. However, direct evidence is scant and there is substantial scope for future work. PMID- 24070500 TI - Exposure to toxic environmental agents. AB - Reducing exposure to toxic environmental agents is a critical area of intervention for obstetricians, gynecologists, and other reproductive health care professionals. Patient exposure to toxic environmental chemicals and other stressors is ubiquitous, and preconception and prenatal exposure to toxic environmental agents can have a profound and lasting effect on reproductive health across the life course.Prenatal exposure to certain chemicals has been documented to increase the risk of cancer in childhood; adult male exposure to pesticides is linked to altered semen quality, sterility, and prostate cancer; and postnatal exposure to some pesticides can interfere with all developmental stages of reproductive function in adult females, including puberty, menstruation and ovulation, fertility and fecundity, and menopause. Many environmental factors harmful to reproductive health disproportionately affect vulnerable and underserved populations,which leaves some populations, including underserved women, more vulnerable to adverse reproductive health effects than other populations. The evidence that links exposure to toxic environmental agents and adverse reproductive and developmental health outcomes is sufficiently robust, and the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine join leading scientists and other clinical practitioners in calling for timely action to identify and reduce exposure to toxic environmental agents while addressing the consequences of such exposure. PMID- 24070501 TI - Predictive factors for recurrence of ovarian mature cystic teratomas after surgical excision. AB - OBJECTIVE: To study the recurrence rate and predictive factors for recurrence after surgical excision of ovarian mature cystic teratomas (MCT). STUDY DESIGN: Retrospective study of 382 patients who underwent surgical excision of MCT and whose post-surgical follow-up data were available over six months. Patients who underwent concomitant oophorectomy or had a history of oophorectomy were excluded. Medical records were reviewed for evidence of recurrence. The Cox hazard model was used for the estimation of predictive factors for recurrence. Categorical data were compared using the Chi-square and Fisher's exact tests. RESULTS: There were 16 recurrences within a mean follow-up period of 43.0 months, with a recurrence rate of 4.2%. Young age (<30 years old, Y) (hazard ratio (HR) 2.98; 95% confidence interval (CI) 1.04-8.62, P=0.043), large cyst (>=8 cm in diameter, L) (HR 2.75; 95% CI 1.03-7.37, P=0.044), and bilaterality (B) (HR 2.88; 95% CI 1.07-7.76, P=0.036) were shown to be significant predictive factors. When a patient had all these three factors, the recurrence rate was 21.0%, otherwise 3.4% (P<0.01). Patients with Y+L, Y+B, and B+L also showed significantly higher recurrence rate (21.4%, 15.9%, and 11.4%, respectively). CONCLUSION: The long term recurrence rate after surgical excision of MCT in this study is 4.2%. A patient with young age (<30 years old) or large cyst (>=8 cm in diameter) or bilateral cysts is at high risk of recurrence, which is even higher when a patient has more than one of these factors. PMID- 24070502 TI - Activity of the colistin-rifampicin combination against colistin-resistant, carbapenemase-producing Gram-negative bacteria. AB - Colistin (COL) is one of the few antimicrobials that retain activity against carbapenemase-producing Gram-negative bacteria (GNB). However, the emergence of COL resistance has renewed the use of combination therapy. The aim of this study was to determine the activity of COL plus rifampicin (RIF) against clinical isolates of COL-resistant, carbapenemase-producing GNB. We employed 36 COL resistant carbapenemase-producing isolates (27 Klebsiella pneumoniae, 5 Serratia marcescens, and 4 Acinetobacter baumannii) belonging to 36 patients. E-test/agar dilution of all strains was performed with E-test strips of COL placed on agar plates with and without RIF. In 11 patients, the synergy was confirmed by time kill studies. Synergy was detected in 34 isolates, whereas indifference was detected in two S. marcescens. The E-test/agar dilution method showed comparable results to the time-kill studies. Seven patients infected with these isolates (two meningitis, four sepsis, and one urinary tract infection) were treated with the combination successfully. PMID- 24070503 TI - Chronic complicated aortic dissection. PMID- 24070504 TI - Delayed intimal blowout after endovascular repair of aortic dissection. AB - The authors have seen four cases of asymptomatic delayed intimal injury adjacent to a stent graft diagnosed 7 to 16 months after thoracic endovascular aortic repair. Endovascular repeat intervention was successfully performed in three of the four cases as described in the present report. A second consecutive "intimal blowout" in one patient remains under close radiologic surveillance. Possible causes for the intimal blowouts, including stent-graft size, landing zone anatomy, and intrinsically weak aortic tissue, are discussed. PMID- 24070505 TI - Interventional radiology peer, a newly developed peer-review scoring system designed for interventional radiology practice. AB - PURPOSE: Existing diagnostic radiology peer-review systems do not address the specificities of interventional radiology (IR) practice. The purpose of this study was to assess the feasibility of a specifically developed interventional peer review method, IR Peer. MATERIALS AND METHODS: Retrospective review of a prospectively encoded pilot database aimed at demonstrating the feasibility of IR Peer in a multiphysician practice was performed. This scoring system used morning peer review of selected IR cases from the previous day in the form of a five-item questionnaire and an ordinal answer scale that grades reviewers' agreement with imaging findings, procedural/technical management, early outcomes, and follow-up plan. Patient lists from IR Peer and morbidity and mortality (M&M) conferences were compared to evaluate the amount of overlap and capability of IR Peer to help detect adverse events (AEs). RESULTS: A total of 417 consecutive reviews of IR attending physician cases by peers were performed in 163 consecutive patients over 18 months, and 94% of cases were reviewed by two or three IR attending physicians. Each question was answered 99%-100% of the time. Answers showed disagreement in 10% of cases (2% by a single reviewer, 8% by several), most related to procedural technique. Overall AE incidence was 1.8%. IR Peer contributed 10.7% of cases to the M&M list. CONCLUSIONS: IR Peer is feasible, relevant, and easy to implement in a multiphysician IR practice. When used along with other quality-assurance processes, it might help in the detection of AEs for M&M; the latter will require further confirmatory research. PMID- 24070506 TI - Thirty-day hospital re-admissions: a metric that matters. PMID- 24070507 TI - Microwave ablation of pancreatic head cancer: safety and efficacy. AB - PURPOSE: To evaluate the safety and efficacy of percutaneous microwave (MW) ablation treatment in locally advanced, nonresectable, nonmetastatic pancreatic head cancer. MATERIALS AND METHODS: Ten patients with pancreatic head cancer treated with percutaneous (n = 5) or laparotomic (n = 5) MW ablation were retrospectively reviewed. The MW generator used (45 W at 915 MHz) was connected by coaxial cable to 14-gauge straight MW antennas with a 3.7- or 2-cm radiating section. One or two antennae were used, with an ablation time of 10 minutes. Ultrasonographic (US) and combined US/cone-beam computed tomographic (CT) guidance were used in five patients each. Follow-up was performed by CT after 1, 3, 6, and, when possible, 12 months. Tumor response was assessed per Response Evaluation Criteria In Solid Tumors (version 1.1) and Choi criteria. The feasibility, safety, and major and minor complications associated with quality of life (QOL) were recorded prospectively. RESULTS: The procedure was feasible in all patients (100%). One late major complication was observed in one patient, and no visceral injury was detected. No patient had further surgery, and all minor complications resolved during the hospital stay. An improvement in QOL was observed in all patients despite a tendency to return to preoperative levels in the months following the procedure, without the influence of minor complications. No repeat treatment was performed. CONCLUSIONS: Despite the small number of patients, the present results can be considered encouraging, showing that MW ablation is a feasible approach in the palliative treatment of pancreatic tumors. PMID- 24070510 TI - Programmed cell death in a patient with hepatocellular carcinoma treated with yttrium-90 and doxorubicin-loaded beads. AB - Molecular analysis of apoptosis and autophagy pathways was performed from a single hepatocellular carcinoma treated with yttrium-90 and doxorubicin-loaded beads before resection and compared with normal liver tissue from the margins. Both bead formulations activated apoptosis-associated mechanisms and increased autophagy pathway protein levels. Increased DNA fragmentation and autophagy markers were seen in tumor treated with drug-eluting beads compared with yttrium 90-treated tumor. These results suggest that both microembolic therapies activate cell death signaling, although differences in apoptosis and autophagy pathways were seen in this patient. Knowledge of mechanisms of action for each treatment may enhance future therapeutic strategies. PMID- 24070511 TI - Catch of the day: forceps removal of embedded fish bone. PMID- 24070512 TI - First experience with the use of a collagen fistula plug to treat enterocutaneous fistulas. AB - This report describes the authors' first experiences with the use of the Biodesign Enterocutaneous Fistula Plug (EFP). Six patients presented with intraperitoneal abscess and associated chronic bowel fistulas. The fistulas were treated by delivering an EFP by using radiologic guidance. The EFP placement procedure was successfully performed in all patients. All fistulas were closed within 2 weeks. Fistula recurrence occurred in two patients (33%) at 9 and 12 months after the procedure. One recurrence was associated with an adverse reaction to chemotherapy. The other was associated with the silicone flange migrating out of the bowel lumen. The Biodesign EFP offers a promising new approach for the treatment of enterocutaneous fistulas. PMID- 24070513 TI - Ruptured penetrating aortic ulcer in the ascending aorta treated with two parallel stent grafts. PMID- 24070514 TI - Blood supply by left inferior phrenic artery to stomach and spleen in a case of occlusion of all gastric arteries and splenic artery. PMID- 24070515 TI - Treating bronchopleural fistulae percutaneously with N-butyl cyanoacrylate glue. PMID- 24070516 TI - Transbronchial treatment of a bleeding pulmonary mycetoma refractory to arterial embolization. PMID- 24070517 TI - Unique case of pinch-off syndrome in a patient presenting with acute stroke. PMID- 24070518 TI - Left atrial and systemic air embolism after lung biopsy: importance of treatment positioning. PMID- 24070519 TI - The relationship between physical abilities, ball-carrying and tackling among elite youth rugby league players. AB - This study investigated the relationship between the physical abilities of adolescent rugby league players and tackling and ball-carrying skills performed during matches, across three seasons (under-15 to under-17). The players were measured each season for acceleration (10-30 m), peak and mean speed (10-30 m), sprinting force (10-30 m), aerobic power, counter-movement jump (CMJ) height and jumping power. The matches were filmed and analysed for ball-carrying and tackling frequency per minute (successful and unsuccessful outcomes). There were strong relationships between successful carries?min(-1) and 10 m force in the under-15 (R = 0.61, P < 0.001), under-16 (R = 0.69, P < 0.001) and under-17 groups (R = 0.64, P < 0.001). There were also strong and moderate relationships between predicted vertical power and successful carries?min(-1) in the under-15 (R = 0.63, P = 0.011) and under-17 group (R = 0.40, P = 0.030), respectively. There were no relationships between carries or tackles and any other performance indicators. These findings suggest that acceleration, in accordance with gains in body mass, support ball-carrying but not tackling performance. Performance measurements, such as CMJ or aerobic power, do not support ball-carrying ability among youth rugby league players. PMID- 24070520 TI - Stroke and renal dysfunction. AB - Stroke is the most frequent neurological disease and represents a continuously evolving medical and social problem. Chronic kidney disease (CKD) is also an important worldwide public health problem. Renal dysfunction carries a substantial risk of cardiovascular morbidity and mortality and an independent, graded association between renal function and cardiovascular events was found. In the last 15years the link between CKD and cerebrovascular disease has become more apparent. Patients with end stage renal disease treated with maintenance hemodialysis have a much higher incidence of stroke than the general population and stroke is one of the major causes of death in these patients. Nowadays ischemic subtype of stroke is present in approximately 70% of dialysis patients. In population based studies conflicting results have been reported about the association between stroke and CKD before replacement therapy. However, in high risk patients, defined by the presence of either cardiovascular disease or cardiovascular risk factors, different stages of CKD are clearly associated with subsequent stroke. In patients with stroke the exact prevalence of renal dysfunction is not known. Reported prevalence from a few published studies is up to 38% and it is higher than that in age-matched control groups. Furthermore, in patients suffering from stroke renal dysfunction is associated with short and long term mortality. The most effective treatment of stroke in patients with CKD is not known and further studies are needed. PMID- 24070521 TI - Mineralocorticoid receptor antagonism in acutely decompensated chronic heart failure. AB - BACKGROUND/OBJECTIVES: Mineralocorticoid receptor antagonist (MRA) use in acutely decompensated chronic heart failure (ADCHF) may improve congestion through diuretic effect and prevent neurohormonal activation. We aimed to evaluate the clinical effect and safety of spironolactone in ADCHF. METHODS: Prospective, experimental, single-center, and single-blinded trial. Patients were treated with: standard ADCHF therapy or oral spironolactone 50-100mg/d plus standard ADCHF therapy. RESULTS: During a 1year period, 100 patients were enrolled, 50 included in the treatment group. Mean (SD) spironolactone dose (mg) at day 1 was 94.5+/-23.3 and at day 3 was 62.7+/-24.3. Worsening renal function (increase in pCr>=0.3mg/dL from day 1 to day 3) was more likely to occur in control group (20% vs. 4%; p=0.038), serum potassium did not differ between groups, and plasma NTproBNP had a significant decrease in spironolactone group at day 3 (median [IQR], 2488 [4579] vs. 1555 [1832]; p=0.05). Furthermore, a greater proportion of patients in the treatment group were free of congestion at day 3: less edema, rales, jugular venous pressure (JVP) and orthopnea (all, p<0.05). In addition, a significantly higher proportion of patients were on oral furosemide at day 3 (44% vs. 82%; p<0.001). CONCLUSIONS: Our study supports the safety of high dose spironolactone in ADCHF and suggests a positive impact in the resolution of congestion. The important findings of our pilot study need to be confirmed in larger trials. PMID- 24070522 TI - Exhaled matrix metalloproteinase-9 (MMP-9) in different biological phenotypes of asthma. AB - BACKGROUND AND OBJECTIVES: Airway remodeling is a main feature of asthma. Different biological phenotypes of severe asthma have been recently recognized by the ENFUMOSA study group and among these one is characterized by neutrophilic airway inflammation. Concentrations of MMP-9 in airways have been suggested as a marker to monitor airway remodeling in asthma. OBJECTIVE: The aim of the present study was to explore airway remodeling in different biological phenotypes of asthma by measuring MMP-9 in EBC and correlating these with other variables. METHODS: Sixty consecutive subjects with asthma and 20 healthy controls were enrolled in the study. Exhaled MMP-9, pH and NO levels and inflammatory cells in sputum were measured in all subjects enrolled. RESULTS: We observed an increase of exhaled MMP-9 in asthmatic subjects compared to controls. Higher exhaled MMP-9 concentrations were described in severe asthmatics compared to mild to moderate especially in those with neutrophilic airway inflammation. We further found a correlation between exhaled MMP-9 and percentage of neutrophils in sputum, FEV1, exhaled NO and pH. CONCLUSION: Our results seem to substantiate the feasibility of measuring exhaled MMP-9 in the breath of asthmatic patients. MMP-9 may be considered a proxy of the amount of the ongoing airway remodeling in asthma. MMP 9 has been shown to be differentially released in different phenotypes of asthma. The measure of exhaled MMP-9 could help to monitor the ongoing airway remodeling, recognize severe stages of asthma, and possibly help determine the appropriate choice of therapy. PMID- 24070532 TI - A proposed job description for the modern division director. PMID- 24070533 TI - 50 Years Ago in The Journal of Pediatrics: anomalous left coronary artery arising from the pulmonary artery with large left-to-right shunt in infancy. PMID- 24070534 TI - 50 years ago in the Journal of Pediatrics: polyarteritis nodosa in infancy. PMID- 24070535 TI - 50 Years Ago in The Journal of Pediatrics: cat-scratch disease without cat contact. PMID- 24070536 TI - 50 Years Ago in The Journal of Pediatrics: the XO syndrome: a study of the differential phenotype in 25 patients. PMID- 24070537 TI - 50 Years Ago in The Journal of Pediatrics: hepatolenticular degeneration: observations on a case treated with D-penicillamine. PMID- 24070538 TI - Risky driving and pedunculopontine nucleus-thalamic cholinergic denervation in Parkinson disease. AB - BACKGROUND: It is unknown whether driving difficulty in Parkinson disease (PD) is attributable to nigrostriatal dopaminergic or extranigral non-dopaminergic neurodegeneration. OBJECTIVE: To investigate in vivo imaging differences in dopaminergic and cholinergic innervation between PD patients with and without a history of risky driving. METHODS: Thirty non-demented PD subjects (10 women/20 men) completed a driving survey. These subjects had previously undergone (+) [(11)C] dihydrotetrabenazine vesicular monoamine transporter 2 and [(11)C] methyl 4-piperidinyl propionate acetylcholinesterase PET imaging. Acetylcholinesterase PET imaging assesses cholinergic terminal integrity with cortical uptake largely reflecting basal forebrain and thalamic uptake principally reflecting pedunculopontine nucleus integrity. RESULTS: Eight of thirty subjects reported a history of risky driving (been pulled over, had a traffic citation, or been in an accident since PD onset) while 22 had no such history (safe drivers). There was no difference in striatal dihydrotetrabenazine vesicular monoamine transporter uptake between risky and safe drivers. There was significantly less thalamic acetylcholinesterase activity in the risky drivers compared to safe drivers (0.0513 +/- 0.006 vs. 0.0570 +/- 0.006, p = 0.022) but no difference in neocortical acetylcholinesterase activity. Using multivariable logistic regression, decreased thalamic acetylcholinesterase activity remained an independent predictor of risky driving in PD even after controlling for age and disease duration. CONCLUSIONS: Risky driving is related to pedunculopontine nucleus-thalamic but not neocortical cholinergic denervation or nigrostriatal dopaminergic denervation in PD. This suggests that degeneration of the pedunculopontine nucleus, a brainstem center responsible for postural and gait control, plays a role in the ability of PD patients to drive. PMID- 24070539 TI - Sexual abuse of children in low-income settings: time for action. AB - In this article, child sexual abuse in low-income settings is reviewed, including the extent of the problem, the way children present, and how they should be managed. Liaising with other agencies, training in all aspects of sexual abuse and creating an environment that is conducive to good care by all groups involved is essential. Technical details of medical examination are not covered as appropriate guidelines are accessible. PMID- 24070540 TI - Interplay between conformational selection and induced fit in multidomain protein ligand binding probed by paramagnetic relaxation enhancement. AB - The binding of ligands and substrates to proteins has been extensively studied for many years and can be described, in its simplest form, by two limiting mechanisms: conformational selection and induced fit. Conformational selection involves the binding of ligand to a pre-existing sparsely-populated conformation of the free protein that is the same as that in the final protein-ligand complex. In the case of induced fit, the ligand binds to the major conformation of the free protein and only subsequent to binding undergoes a conformational change to the final protein-ligand complex. While these two mechanisms can be dissected and distinguished by transient kinetic measurements, direct direction, characterization and visualization of transient, sparsely-populated states of proteins are experimentally challenging. Unless trapped, sparsely-populated states are generally invisible to conventional structural and biophysical techniques, including crystallography and most NMR measurements. In this review we summarize some recent developments in the use of paramagnetic relaxation enhancement to directly study sparsely-populated states of proteins and illustrate the application of this approach to two proteins, maltose binding protein and calmodulin, both of which undergo large rigid body conformational rearrangements upon ligand binding from an open apo state to a closed ligand bound holo state. We show that the apo state ensemble comprises a small population of partially-closed configurations that are similar but not identical to that of the holo state. These results highlight the complementarity and interplay of induced fit and conformational selection and suggest that the existence of partially-closed states in the absence of ligand facilitates the transition to the closed ligand-bound state. PMID- 24070541 TI - The Toll-like receptor 3 L412F polymorphism and disease progression in idiopathic pulmonary fibrosis. AB - RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive interstitial pneumonia. The innate immune system provides a crucial function in the recognition of tissue injury and infection. Toll-like receptor 3 (TLR3) is an innate immune system receptor. We investigated the role of a functional TLR3 single-nucleotide polymorphism in IPF. OBJECTIVES: To characterize the effects of the TLR3 Leu412Phe polymorphism in primary pulmonary fibroblasts from patients with IPF and disease progression in two independent IPF patient cohorts. To investigate the role of TLR3 in a murine model of pulmonary fibrosis. METHODS: TLR3-mediated cytokine, type 1 IFN, and fibroproliferative responses were examined in TLR3 wild-type (Leu/Leu), heterozygote (Leu/Phe), and homozygote (Phe/Phe) primary IPF pulmonary fibroblasts by ELISA, real-time polymerase chain reaction, and proliferation assays. A murine model of bleomycin-induced pulmonary fibrosis was used in TLR3 wild-type (tlr3(+/+)) and TLR3 knockout mice (tlr3(-/ )). A genotyping approach was used to investigate the role of the TLR3 L412F polymorphism in disease progression in IPF using survival analysis and longitudinal decline in FVC. MEASUREMENTS AND MAIN RESULTS: Activation of TLR3 in primary lung fibroblasts from TLR3 L412F-variant patients with IPF resulted in defective cytokine, type I IFN, and fibroproliferative responses. We demonstrate increased collagen and profibrotic cytokines in TLR3 knockout mice (tlr3(-/-)) compared with wild-type mice (tlr3(+/+)). TLR3 L412F was also associated with a significantly greater risk of mortality and an accelerated decline in FVC in patients with IPF. CONCLUSIONS: This study reveals the crucial role of defective TLR3 function in promoting progressive IPF. PMID- 24070542 TI - Computer-aided diagnosis of mass-like lesion in breast MRI: differential analysis of the 3-D morphology between benign and malignant tumors. AB - This study aimed to evaluate the value of using 3-D breast MRI morphologic features to differentiate benign and malignant breast lesions. The 3-D morphological features extracted from breast MRI were used to analyze the malignant likelihood of tumor from ninety-five solid breast masses (44 benign and 51 malignant) of 82 patients. Each mass-like lesion was examined with regards to three categories of morphologic features, including texture-based gray-level co occurrence matrix (GLCM) feature, shape, and ellipsoid fitting features. For obtaining a robust combination of features from different categories, the biserial correlation coefficient (|r(pb)|)?0.4 was used as the feature selection criterion. Receiver operating characteristic (ROC) curve was used to evaluate performance and Student's t-test to verify the classification accuracy. The combination of the selected 3-D morphological features, including conventional compactness, radius, spiculation, surface ratio, volume covering ratio, number of inside angular regions, sum of number of inside and outside angular regions, showed an accuracy of 88.42% (84/95), sensitivity of 88.24% (45/51), and specificity of 88.64% (39/44), respectively. The AZ value was 0.8926 for these seven combined morphological features. In conclusion, 3-D MR morphological features specified by GLCM, tumor shape and ellipsoid fitting were useful for differentiating benign and malignant breast masses. PMID- 24070543 TI - Determination of ECoG information flow activity based on Granger causality and Hilbert transformation. AB - Analysis of directional information flow patterns among different regions of the brain is important for investigating the relation between ECoG (electrocorticographic) and mental activity. The objective is to study and evaluate the information flow activity at different frequencies in the primary motor cortex. We employed Granger causality for capturing the future state of the propagation path and direction between recording electrode sites on the cerebral cortex. A grid covered the right motor cortex completely due to its size (approx. 8 cm*8 cm) but grid area extends to the surrounding cortex areas. During the experiment, a subject was asked to imagine performing two activities: movement of the left small finger and/or movement of the tongue. The time series of the electrical brain activity was recorded during these trials using an 8*8 (0.016 300 Hz band with) ECoG platinum electrode grid, which was placed on the contralateral (right) motor cortex. For detection of information flow activity and communication frequencies among the electrodes, we have proposed a method based on following steps: (i) calculation of analytical time series such as amplitude and phase difference acquired from Hilbert transformation, (ii) selection of frequency having highest interdependence for the electrode pairs for the concerned time series over a sliding window in which we assumed time series were stationary, (iii) calculation of Granger causality values for each pair with selected frequency. The information flow (causal influence) activity and communication frequencies between the electrodes in grid were determined and shown successfully. It is supposed that information flow activity and communication frequencies between the electrodes in the grid are approximately the same for the same pattern. The successful employment of Granger causality and Hilbert transformation for the detection of the propagation path and direction of each component of ECoG among different sub-cortex areas were capable of determining the information flow (causal influence) activity and communication frequencies between the populations of neurons successfully. PMID- 24070545 TI - A parallel computational model for GATE simulations. AB - GATE/Geant4 Monte Carlo simulations are computationally demanding applications, requiring thousands of processor hours to produce realistic results. The classical strategy of distributing the simulation of individual events does not apply efficiently for Positron Emission Tomography (PET) experiments, because it requires a centralized coincidence processing and large communication overheads. We propose a parallel computational model for GATE that handles event generation and coincidence processing in a simple and efficient way by decentralizing event generation and processing but maintaining a centralized event and time coordinator. The model is implemented with the inclusion of a new set of factory classes that can run the same executable in sequential or parallel mode. A Mann Whitney test shows that the output produced by this parallel model in terms of number of tallies is equivalent (but not equal) to its sequential counterpart. Computational performance evaluation shows that the software is scalable and well balanced. PMID- 24070544 TI - Anatomical model-based finite element analysis of the combined cryosurgical and hyperthermic ablation for knee bone tumor. AB - This paper is aimed at investigating the capacity of using combined cryosurgical and hyperthermic modality for treating knee bone tumor with complex shape. An anatomical model for human knee was constructed and a three-dimensional (3D) finite element analysis was developed to determine temperature distribution of the tissues subject to single freezing (SF), single heating (SH) and alternate freezing-heating (AFH), respectively. The heat fluxes of the probes wall and the ablation volume are particularly tracked to comparatively evaluate the ablation ability of different probe configurations with varied diameter, number and active working length. As example, an effective conformal treatment strategy via one time's insertion while cyclic freezing-heating using multiple probes is designed for a predefined knee bone tumor ablation. Both SF and SH could create large enough ablation volume, while it is hard for them to perform a conformal treatment on irregular and slender knee tumor. As an alternative, AFH could form a flexible and controlled shape and volume of the ablation by changing the size and number of the probes and adjusting their insertion depth. In addition, a thermal protection method is considered to reduce cryoinjury of the health tissue. PMID- 24070546 TI - Using image processing technology and mathematical algorithm in the automatic selection of vocal cord opening and closing images from the larynx endoscopy video. AB - The human larynx is an important organ for voice production and respiratory mechanisms. The vocal cord is approximated for voice production and open for breathing. The videolaryngoscope is widely used for vocal cord examination. At present, physicians usually diagnose vocal cord diseases by manually selecting the image of the vocal cord opening to the largest extent (abduction), thus maximally exposing the vocal cord lesion. On the other hand, the severity of diseases such as vocal palsy, atrophic vocal cord is largely dependent on the vocal cord closing to the smallest extent (adduction). Therefore, diseases can be assessed by the image of the vocal cord opening to the largest extent, and the seriousness of breathy voice is closely correlated to the gap between vocal cords when closing to the smallest extent. The aim of the study was to design an automatic vocal cord image selection system to improve the conventional selection process by physicians and enhance diagnosis efficiency. Also, due to the unwanted fuzzy images resulting from examination process caused by human factors as well as the non-vocal cord images, texture analysis is added in this study to measure image entropy to establish a screening and elimination system to effectively enhance the accuracy of selecting the image of the vocal cord closing to the smallest extent. PMID- 24070547 TI - A simplified cervix model in response to induction balloon in pre-labour. AB - BACKGROUND: Induction of labour is poorly understood even though it is performed in 20% of births in the United States. One method of induction, the balloon dilator applied with traction to the interior os of the cervix, engages a softening process, permitting dilation and effacement to proceed until the beginning of active labour. The purpose of this work is to develop a simple model capable of reproducing the dilation and effacement effect in the presence of a balloon. METHODS: The cervix, anchored by the uterus and the endopelvic fascia was modelled in pre-labour. The spring-loaded, double sliding-joint, double pin joint mechanism model was developed with a Modelica-compatible system, MapleSoft MapleSim 6.1, with a stiff Rosenbrock solver and 1E-4 absolute and relative tolerances. Total simulation time for pre-labour was seven hours and simulations ended at 4.50 cm dilation diameter and 2.25 cm effacement. RESULTS: Three spring configurations were tested: one pin joint, one sliding joint and combined pin joint-sliding-joint. Feedback, based on dilation speed modulated the spring values, permitting controlled dilation. Dilation diameter speed was maintained at 0.692 cm.hr-1 over the majority of the simulation time. In the sliding-joint-only mode the maximum spring constant value was 23800 N.m-1. In pin-joint-only the maximum spring constant value was 0.41 N.m.rad-1. With a sliding-joint-pin-joint pair the maximum spring constants are 2000 N.m-1 and 0.41 N.m.rad-1, respectively. CONCLUSIONS: The model, a simplified one-quarter version of the cervix, is capable of maintaining near-constant dilation rates, similar to published clinical observations for pre-labour. Lowest spring constant values are achieved when two springs are used, but nearly identical tracking of dilation speed can be achieved with only a pin joint spring. Initial and final values for effacement and dilation also match published clinical observations. These results provide a framework for development of electro-mechanical phantoms for induction training, as well as dilator testing and development. PMID- 24070548 TI - Adolescents and parents' perceptions of best time for sex and sexual communications from two communities in the Eastern and Volta Regions of Ghana: implications for HIV and AIDS education. AB - BACKGROUND: Adolescents and parents' differ in their perceptions regarding engaging in sexual activity and protecting themselves from pregnancy and sexually transmitted infections (STIs). The views of adolescents and parents from two south-eastern communities in Ghana regarding best time for sex and sexual communications were examined. METHODS: Focus Group interviews were conducted with parents and adolescents (both In-school and Out-of school) from two communities (Somanya and Adidome) in the Eastern and Volta regions of Ghana with epidemiological differentials in HIV infection. RESULTS: Findings showed parents and adolescents agree that the best timing for sexual activity amongst adolescents is determined by socioeconomic viability. In practice however, there were tensions between adolescents and parents crystallized by spoilt generation and physiological drive ideologies. Whilst one community relied on a more communal approach in controlling their children; the other relied on a confrontational approach. Sex-talk is examined as a measure to reduce these tensions, and children in both communities were ambivalent over sexual communication between their parents and themselves. Parents from the two communities however differed in their perceptions. Whilst parents in one community attributed reduced teenage pregnancies to sex education, those in the other community indicated a generalized adolescents' sexual activeness manifested in the perceived widespread delinquency in the community. CONCLUSION: Parents in both communities reported significant barriers to parents-adolescents sexual communication. Parents in both communities should be educated to discuss the broader issues on sexuality that affects adolescents and their reproductive health needs. PMID- 24070549 TI - Should proximal LAD be treated differently? Insights from a large DES stent registry. AB - BACKGROUND: The current revascularization treatment recommendation is different according to lesion location and a higher recommendation is given to surgery for proximal LAD (pLAD) lesions over PCI. This is based on previous studies and expert opinion. We aimed to investigate whether indeed there is a difference in outcome with respect to LAD lesion location while using a drug eluting stent (DES). METHODS: The NOBORI-2 trial, enrolled 3067 consecutive patients in 125 centers who were treated with DES for single and multivessel disease. We compared 834 [27.2%] patients who underwent PCI of the pLAD as part of their revascularization, to 2203 [71.8%] patients in which stenting to other lesion(s) but not the pLAD was performed. RESULTS: The pLAD group had lower incidence of hypertension, peripheral vascular disease, prior PCI and CABG, but had more lesions treated [1.55 +/- 0.8 vs. 1.35 +/- 0.6], more stents implanted [1.98 +/- 1.2 vs. 1.66 +/- 1.0] and longer overall stent length [31.8 +/- 20.2 vs. 28.2 +/- 17.8 mm]. There was no difference in the occurrence of the primary endpoint [cardiac death, myocardial infarction and target lesion revascularization] at 1 or 2 years of follow up between the pLAD and non pLAD [6.0% vs. 4.6%, p=0.14 and 7.7% vs. 6.6%; p=0.22, respectively]. The relief from anginal symptoms was similar. Multivariate analysis showed that pLAD location was not a variable that predicted MACE or TLF. Stent thrombosis rate was similar. CONCLUSION: When considering PCI with DES, there is no difference in outcome between patients with and without proximal LAD lesions. PMID- 24070550 TI - Regioselective hydronickelation of allenes and its application to the hydrocyanative carbocyclization reaction of allene-ynes and bis-allenes. AB - The carbocyanative cyclization of allene-ynes and bis-allenes under nickel catalysis is described. The key steps are the regioselective hydronickelation of allenes and subsequent cyclization via carbometalation. The former step determines the reaction pathway, and the latter controls the stereochemistry of substituted olefins. The products are useful carbo- and heterocycles that include a cyano group, functionalized double bonds, and quaternary carbons. PMID- 24070551 TI - Rational design of network properties in guest-host assembled and shear-thinning hyaluronic acid hydrogels. AB - Shear-thinning hydrogels afford direct injection or catheter delivery to tissues without potential premature gel formation and delivery failure or the use of triggers such as chemical initiators or heat. However, many shear-thinning hydrogels require long reassembly times or exhibit rapid erosion. We developed a shear-thinning hyaluronic acid (HA) hydrogel based on the guest-host interactions of adamantane modified HA (guest macromer, Ad-HA) and beta-cyclodextrin modified HA (host macromer, CD-HA). The ability of the guest and host molecules to interact with their counterpart following conjugation to HA was confirmed by (1)H NMR spectroscopy and was similar to that of the native complex. Mixing of Ad-HA and CD-HA resulted in rapid formation of a hydrogel composed of guest-host bonds. The hydrogel physical properties, including mechanics and flow characteristics, were dependent on cross-link density and network structure, which were controlled through macromer concentration, the extent of guest macromer modification, and the molar ratio of guest and host functional groups. The guest-host assembly mechanism permitted both shear-thinning behavior for ease of injection and near instantaneous reassembly for material retention at the target sight. The hydrogel erosion and release of a model biomolecule were also dependent on design parameters and were sustained for over 60 days. These hydrogels show potential as a minimally invasive injectable hydrogel for biomedical applications. PMID- 24070553 TI - The Lancet Infectious Diseases--the state of play. PMID- 24070552 TI - Targets of light signalling in Trichoderma reesei. AB - BACKGROUND: The tropical ascomycete Trichoderma reesei (Hypocrea jecorina) represents one of the most efficient plant cell wall degraders. Regulation of the enzymes required for this process is affected by nutritional signals as well as other environmental signals including light. RESULTS: Our transcriptome analysis of strains lacking the photoreceptors BLR1 and BLR2 as well as ENV1 revealed a considerable increase in the number of genes showing significantly different transcript levels in light and darkness compared to wild-type. We show that members of all glycoside hydrolase families can be subject to light dependent regulation, hence confirming nutrient utilization including plant cell wall degradation as a major output pathway of light signalling. In contrast to N. crassa, photoreceptor mediated regulation of carbon metabolism in T. reesei occurs primarily by BLR1 and BLR2 via their positive effect on induction of env1 transcription, rather than by a presumed negative effect of ENV1 on the function of the BLR complex. Nevertheless, genes consistently regulated by photoreceptors in N. crassa and T. reesei are significantly enriched in carbon metabolic functions. Hence, different regulatory mechanisms are operative in these two fungi, while the light dependent regulation of plant cell wall degradation appears to be conserved.Analysis of growth on different carbon sources revealed that the oxidoreductive D-galactose and pentose catabolism is influenced by light and ENV1. Transcriptional regulation of the target enzymes in these pathways is enhanced by light and influenced by ENV1, BLR1 and/or BLR2. Additionally we detected an ENV1-regulated genomic cluster of 9 genes including the D-mannitol dehydrogenase gene lxr1, with two genes of this cluster showing consistent regulation in N. crassa. CONCLUSIONS: We show that one major output pathway of light signalling in Trichoderma reesei is regulation of glycoside hydrolase genes and the degradation of hemicellulose building blocks. Targets of ENV1 and BLR1/BLR2 are for the most part distinct and indicate individual functions for ENV1 and the BLR complex besides their postulated regulatory interrelationship. PMID- 24070554 TI - Preventive measures against MERS-CoV for Hajj pilgrims. PMID- 24070555 TI - Sampling bias in transgender studies. PMID- 24070556 TI - Sampling bias in transgender studies--authors' reply. PMID- 24070557 TI - Antibiotics in acute non-pneumonic lower-respiratory tract infection--authors' reply. PMID- 24070558 TI - Antibiotics in acute non-pneumonic lower-respiratory tract infection. PMID- 24070559 TI - Addressing the need for new antibacterials. PMID- 24070560 TI - Addressing the need for new antibacterials--authors' reply. PMID- 24070561 TI - HIV and helminths: time for a new direction. PMID- 24070562 TI - Related actions of probiotics and antibiotics on gut microbiota and weight modification. AB - Antibiotics and probiotics are widely used as growth promoters in agriculture. Most antibiotics prescribed in clinical practice are natural products that originate from Streptomyces spp, which were first used as agricultural probiotics. Antibiotics and probiotics both modify the gut microbiota. The effect of a probiotic species on the digestive flora depends on the strain and is largely determined by bacteriocin production. In human beings, as in animals, specific probiotics are associated with weight gain or loss. Improved understanding of the ability of specific probiotics to harvest energy from the host diet might lead to development of new treatments for obesity and malnutrition. In this Review, we present the effects of probiotics and antibiotics on the gut microbiota of human beings and animals and discuss their potential therapeutic use as interventions for weight gain and loss in human beings. PMID- 24070563 TI - Toward an instructionally oriented theory of example-based learning. AB - Learning from examples is a very effective means of initial cognitive skill acquisition. There is an enormous body of research on the specifics of this learning method. This article presents an instructionally oriented theory of example-based learning that integrates theoretical assumptions and findings from three research areas: learning from worked examples, observational learning, and analogical reasoning. This theory has descriptive and prescriptive elements. The descriptive subtheory deals with (a) the relevance and effectiveness of examples, (b) phases of skill acquisition, and (c) learning processes. The prescriptive subtheory proposes instructional principles that make full exploitation of the potential of example-based learning possible. PMID- 24070564 TI - Opening of the uterine isthmus at 11-13 weeks' gestation is not related to developmental abnormalities of the placenta. AB - OBJECTIVES: To clarify whether openning of the uterine isthmus between 11 and 13weeks' gestation adversely affects the placental development. METHODS: The uterine cervix and isthmus lengths were measured prospectively using transabdominal ultrasound at 11 to 13+6 weeks' gestation. Following delivery, the pregnancy and delivery course were reviewed. The associations between the conditions of the uterine isthmus during the first trimester and the perinatal complications associated with placental abnormalities were analyzed. RESULTS: A total of 653 cases were analyzed. The isthmus had been completely opened (isthmus length = 0mm) in 15.9%, 21.6% and 24.1% of the cases at 11, 12 and 13 weeks' gestation. The frequencies of perinatal complications in the cases whose isthmus had been opened (cases) and the other cases (controls) were as follows; 1.4% and 1.0% (ns) for placenta previa, 1.4% and 1.2% (ns) for abnormal cord insertion, 3.5% and 4.3% (ns) for pre-eclampsia, 9.9% and 9.0% (ns) for small for gestational age, and 12.0% and 7.6% (ns) for preterm delivery, respectively. CONCLUSION: Early opening of the uterine isthmus at 11 to 13 weeks' gestation does not appear to adversely affect either the placental development or the course of pregnancy. PMID- 24070565 TI - Mounier-Kuhn syndrome or congenital tracheobronchomegaly: a literature review. AB - Mounier-Kuhn syndrome or congenital tracheobronchomegaly is a chronic airway condition which for currently unknown reasons mostly affects males. It is commonly overlooked on conventional chest X-rays, and is considered to be rare, but the prevalence might be higher as commonly assumed. The hallmark of it is a dilatation of the main airways which frequently, but not always, causes marked, mainly respiratory, symptoms, and patients usually present with varying degrees of recurrent infections, breathlessness, haemoptysis, dyspnoea. Although at least 200 case reports have been published, there have been only a few attempts to review them, and none in the last 20 years. Due to the lack of clinical trials and wide variability of case-report format, a systematic review was deemed not feasible, therefore PubMed and Medline databases were searched using terms "Mounier-Kuhn syndrome", "tracheobronchomegaly", "tracheomegaly", and "bronchomegaly", without any time restrictions, to summarize currently known facts about the syndrome. To the authors' best knowledge, the result is currently the most comprehensive review of previously published literature about the congenital tracheobronchomegaly, and summarizes what's known about symptoms, prevalence, disease associations, and treatment options for this syndrome. PMID- 24070566 TI - Clinical and economic impact of non-adherence in COPD: a systematic review. AB - BACKGROUND: Medication for Chronic Obstructive Pulmonary Disease (COPD) has shown to substantially reduce symptoms and slow progression of disease. However, non adherence to medication is common and associated with worsened clinical and economic outcomes. OBJECTIVE: The objective of this study was to perform a systematic review of published literature to assess the impact of non-adherence to COPD medication on clinical and economic outcomes. METHODS: A search in PubMed and Web of Science databases was conducted of original studies published from database inception to 2012. Studies must report on the association between adherence to COPD medication and outcomes, published in English in peer-reviewed journals and full texts needed to be available. RESULTS: Twelve full articles were included in the review. Most studies were retrospective database studies. Seven studies reported on the association between adherence and clinical outcomes, two on mortality, three on costs, four on quality of life and one on work productivity. Results indicated a clear association between adherence and both clinical and economic outcomes. Evidence from studies revealed increased hospitalizations, mortality, quality of life and loss of productivity among non adherent patients. CONCLUSION: This review revealed a clear association between non-adherence to COPD medication and worsened clinical and economic outcomes making non-adherent patients a priority for cost-effective interventions. PMID- 24070567 TI - Severe adenovirus pneumonia requiring extracorporeal membrane oxygenation support -Serotype 7 revisited. AB - INTRODUCTION: Adenovirus causing severe fatal pneumonia has been well described in infants, children, and patients with immunocompromised function, but reports in previously healthy adults are rare. We report 3 cases of severe adenovirus pneumonia in whom conventional mechanical ventilation failed and required extracorporeal membrane oxygenation support. METHODS: Retrospective case records review of 3 patients admitted to the medical intensive care unit, Singapore General Hospital, a tertiary care university-affiliated hospital, with severe adenovirus pneumonia requiring extracorporeal membrane oxygenation support from February to March 2013. RESULTS: All 3 patients were previously healthy immunocompetent adults from the community with negative HIV serology. Duration prior to development of respiratory failure requiring intubation and invasive mechanical ventilation was 2, 8 and 3 days. Veno-venous extracorporeal membrane oxygenation (ECMO) support as rescue ventilation was instituted in all 3 patients after 2, 16, and 5 days of conventional mechanical ventilator support. Duration on ECMO support was 16, 22, and 9 days and mechanical ventilation was 18, 62, and 19 days respectively. Length of stay in intensive care unit was 18, 68, and 21 days, and length of stay in hospital was 20, 70, and 31 days respectively. Two of the 3 patients died. CONCLUSION: The mainstay of treatment for patients with severe adenovirus pneumonia is still supportive, with the use of antivirals not apparently effective. Whilst ECMO support for rescue ventilation may be considered, the outcomes do not appear as promising as other viral pneumonias, mirroring that previously described in the paediatric population. PMID- 24070568 TI - Community perceptions of the social determinants of child health in Western Cape, South Africa: neglect as a major indicator of child health and wellness. AB - BACKGROUND: Worldwide, neglect is the most common form of child maltreatment. Data on neglect are scarce in low- and middle-income countries, and almost no qualitative research includes the voices of children. OBJECTIVES: The main objective was to understand community perceptions of the social determinants of child health. The study was also intended to test the feasibility of health professionals undertaking qualitative studies of the social determinants of child health which can be used to inform clinical care and policy. METHODS: The target population was people living in deprived circumstances in rural South Africa. Data collected included focus group discussions with children and adults, children's drawings, semi-structured in-depth interviews, documentary review and transect drives. Purposive sampling of poorer households was done. Recurring themes were explored using a continuous repetitive process. Data were examined using framework analysis. RESULTS: The main finding was that neglect owing to substance abuse was a major predictor of poor child health and wellness. This sensitive topic was introduced by children, who created a platform for discussion with and among adult participants. Adults attributed neglect to a breakdown in family structure and changing norms regarding the responsibilities of parents. Community programmes were cited by children as a source of support, while some adults felt they undermined parental responsibility. CONCLUSION: Understanding social arrangements and community support structures is best achieved at community level through a participatory, qualitative approach. These methods also enable the views of children to inform the findings. Children's input will help uncover neglect and other hidden predictors of challenges to child health, and promote a rights-based approach to care and research. PMID- 24070569 TI - Effects of amphiphilic diblock copolymer on drug nanoparticle formation and stability. AB - This study systematically compares the effects of amphiphilic diblock copolymer (di-BCP) on stabilizing hydrophobic drug nanoparticles formed by flash nanoprecipitation (FNP), and provides a guideline on choosing suitable di-BCPs. Four widely used di-BCPs, i.e., polystyrene-block-poly(ethylene glycol) (PS-b PEG), polycaprolactone-block-poly(ethylene glycol) (PCL-b-PEG), polylactide-block poly(ethylene glycol) (PLA-b-PEG), and poly(lactic-co-glycolic acid) (PLGA-b PEG), and beta-carotene as a model drug were used. The study showed that PLGA-b PEG was the most suitable one, whose hydrophobic block was biodegradable and noncrystallizable as well as had relatively high glass transition temperature (Tg) and a right solubility parameter (delta). The molecular weight of PLGA block over the range from 5k to 15k showed an insignificant effect on controlling the particle size. Amorphous drug particles with a high drug loading of over 83 wt% can be achieved. Much remarkable evidence supported the nanoparticles with kinetically frozen and non-equilibrium packing structures of polymer chains rather than either the micelles or micellar nanoparticles with two well segregated polymer blocks. The thermodynamic effects of the drug and BCP on the particle stability, size and structures were discussed by using solubility parameters. PMID- 24070570 TI - BMP10 as a potent inducer of trophoblast differentiation in human embryonic and induced pluripotent stem cells. AB - Bone morphogenetic proteins (BMPs) are known to induce diverse differentiation fates in human embryonic stem cells (hESCs). In the present study, we compared the potency at which BMP5, BMP10 and BMP13, which are members of distinct BMP subgroups due to differences in sequential and structural homology, induce differentiation in hESCs and human induced pluripotent stem cells (hiPSCs). We observed, in agreement with previous BMP4 model studies, that all ligands induced differentiation to the trophoblast lineage in the absence of bFGF. However, distinct BMPs exerted differences in the kinetics of induced differentiation, with BMP10 being the most potent. hiPSCs and hESCs shared comparable expression patterns of BMP type-I and -II receptor subtypes, which might explain conserved properties with respect to ligand potency and activation of SMAD-dependent (via SMAD1/5/8) and -independent (via MAPK p38) signal transduction pathways. The tested BMPs had distinct and also conserved target genes such as CDX2, DLX3, DLX5, GATA2, GATA3, HAND1, ID2, MSX2 and TFAP2A, known to be associated with the emergence of trophoblast cells. hESCs induced expression of the BMP antagonist NOGGIN as a protection mechanism to constrict extensive BMP action. Unlike BMP4, BMP10 has been shown to be resistant to NOGGIN-induced inhibition which in part might explain its potency. BMPs, in particular BMP4, are commonly used cytokines in differentiation protocols to generate diverse mesoderm- and endoderm-derivates from human pluripotent stem cells. Our study has identified BMP10, a cardiac specific protein, as a superior alternative to BMP4 for inducing trophoblast differentiation in human pluripotent stem cells. PMID- 24070571 TI - A magnetic chitosan hydrogel for sustained and prolonged delivery of Bacillus Calmette-Guerin in the treatment of bladder cancer. AB - The aim of this study was to develop a magnetic thermosensitive hydrogel as intravesical Bacillus Calmette-Guerin (BCG) delivery system, which was formulated with chitosan (CS), beta-glycerophosphate (GP) and Fe3O4 magnetic nanoparticle (Fe3O4-MNP). The gelation time and magnetic response of the gel system were investigated. The morphology of the gel was displayed by scanning electron microscope. Frozen section examination was creatively employed for exhibiting the structure of the gel and determining its intravesical residence time. The antitumor effect and local immune activity of BCG loaded magnetic gel were evaluated. The flowing solution of CS/GP under room temperature could gelate rapidly at body temperature both in vitro and in vivo. The magnetic injectable hydrogels significantly prolonged intravesical BCG residence time under an applied magnetic field. In comparison to traditional BCG therapy for superficial bladder tumor, BCG delivered by the gel system induced a stronger Th1 immune response and revealed higher antitumor efficacy. PMID- 24070572 TI - Endovascular stent placement for treatment of spontaneous isolated dissection of the superior mesenteric artery. AB - BACKGROUND: Spontaneous isolated dissection of the superior mesenteric artery (SIDSMA) is a rare condition often associated with a poor prognosis. The goal of this study is to assess the efficacy of endovascular treatment of SIDSMA with stenting and investigate the possible therapeutic mechanisms involved. METHODS: This is a retrospective review of all patients undergoing endovascular treatment of SIDSMA from January 2009 to December 2011. Patient demographics, history, clinical presentation, laboratory tests, image characteristics, endovascular treatments, and follow-up outcome were analyzed. RESULTS: Twenty-four patients with symptoms were treated. All except 1 patient (23 of 24, 96%) underwent successful stent placement (16 with single stent and 7 with overlapping stents). A total of 30 stents (4 balloon-expanded and 26 self-expanding) were placed during the procedures. In the perioperative period and during follow-up, symptom relief was achieved in 20 (83%) patients, and abdominal pain remained unchanged in 4 (17%). No death or serious complications occurred. The median length of hospital stay and follow-up was 3.25 +/- 2.23 days (range 2-7 days) and 13.15 +/- 8.27 months (range 6-23 months), respectively. Computed tomography angiography (CTA) performed 6 months postoperatively revealed stent patency in 23 cases (100%), false lumen patency in 5 cases (22%), and new development of dissection in the SMA distal to the stent in 1 case (4%). No significant differences were observed in the incidence of false lumen patency between patients treated with a single stent and those treated with overlapping stents, and between patients with and without symptom relief (P > 0.05 for both). CONCLUSIONS: For symptomatic SIDSMA patients without intra-abdominal hemorrhage and intestinal infarction, endovascular stent placement is a feasible treatment choice with a high success rate and good clinical outcome. Overlapping stenting may be proposed for patients with aneurysmal dilation. False lumen patency may occur in some cases during follow-up, but it does not affect improvement of SIDSMA symptoms. PMID- 24070573 TI - Effect of textured insoles on balance and gait in people with multiple sclerosis: an exploratory trial. AB - OBJECTIVES: To investigate the immediate effects of textured insoles on balance and gait in people with multiple sclerosis (MS), and to explore any effects after 2 weeks of wear. STUDY DESIGN: Within-session repeated-measures design with an exploratory follow-up period. SETTING: Hospital gait laboratory. PARTICIPANTS: Forty-six individuals with MS (34 females, 12 males), with a mean (SD) age of 49 (7) years, who could walk 100m unassisted or using one stick/crutch. INTERVENTION: Participants were tested wearing three types of insoles in a random order: control (smooth), Texture 1 (Algeos) or Texture 2 (CrocsTM). Participants were allocated at random to wear one type of textured insoles for 2 weeks, after which they were retested. MAIN OUTCOME MEASURES: Standing balance (centre of pressure excursions and velocity) was measured with eyes open and eyes closed on a Kistler force platform. Spatio-temporal parameters of gait were measured using a GAITRite system. RESULTS: The textured insoles had no significant immediate effects on balance or gait, apart from an increase in anteroposterior sway range with eyes open for Texture 2 insoles [mean difference 4.5 (95% confidence interval 0.6 to 8.4)mm]. After 2 weeks, balance was not significantly different, but both types of textured insoles showed significant effects on spatio-temporal parameters of gait, with mean stride length increases of 3.5cm (Texture 1) and 5.3cm (Texture 2) when wearing the insoles. CONCLUSIONS: After 2 weeks of wear, there were improvements in spatio-temporal parameters of gait. However, it is unclear whether this was a placebo effect or a learning effect. PMID- 24070574 TI - Serological investigation of the clinical significance of fascin in non-small cell lung cancer. AB - OBJECTIVES: Fascin, a conserved actin bundling protein family member, is frequently up-regulated in various cancer types, including non-small-cell lung cancer (NSCLC), and it plays increasingly important roles in the progression of tumor invasion and metastasis. However, variations in the serum fascin level in tumor patients are usually neglected. MATERIALS AND METHODS: In the present study, serum samples from 501 stage I-IV NSCLC patients and 109 healthy volunteers were investigated by an enzyme-linked immunosorbent assay. RESULTS: The serum fascin level was markedly increased in the NSCLC patients (P < 0.05), particularly in advanced cases (P < 0.01), compared with that in the healthy controls. We also found that the serum fascin level was significantly correlated with female sex (P = 0.02), non-smoking status (P = 0.044), and adenocarcinoma histology (P < 0.001), with a higher positive rate relative to each counterpart. Furthermore, our results suggested that the serum fascin level reflects the aggressive progress of both lymphatic (P < 0.001) and distant (P < 0.001) metastases in NSCLC. A survival analysis of 283 eligible patients who underwent a follow-up examination after 3 years revealed that the patients in the serum fascin-positive group had a significantly lower overall survival rate compared with those in the negative group for 134 non-distant metastatic (stage M0) cases (P = 0.044). A subsequent Cox regression analysis revealed that the serum fascin level was an independent prognostic factor for M0-stage NSCLC (univariate, P = 0.001; multivariate, P = 0.038). CONCLUSION: Our study suggests that the serum fascin level is an effective indicator of tumor aggressiveness, and that it plays an important role in the prognosis of NSCLC, particularly for non-distant metastatic patients. PMID- 24070575 TI - Mentorship in an academic medical center. PMID- 24070576 TI - Highlights in basic autonomic neurosciences: sympathetic neuroplasticity in the post-ischemic heart. PMID- 24070578 TI - Foreword for diagnostic errors and how to improve them. PMID- 24070579 TI - Diagnosing diagnostic error. AB - Diagnostic errors are the most common errors in primary care. Diagnostic errors have been found to be the leading cause of malpractice litigation, accounting for twice as many claims and settled cases as medication errors. Diagnostic error is common, harmful, costly, and very critical to the patient-safety issues in health care. Diagnostic errors have received relatively little attention, however. Of what is known, diagnostic errors are an important source of preventable harm. Focused research in this area is highly needed because the causes of diagnostic errors are subtle and solutions are less obvious than for other types of errors. As opposed to medication errors, where the factors predisposing to their occurrence and the resultant preventive strategies are better defined, the relationship between factors influencing the diagnostic reasoning or decision making and a diagnostic error are not as clear. This may include any failure in timely access to care; elicitation or interpretation of symptoms, signs, or laboratory results, formulation and weighing of differential diagnosis; and timely follow-up and specialty referral or evaluation. The literature reveals that diagnostic errors are often caused by the combination of cognitive errors and system failure. Increased understanding about diagnostic decision making, sources of errors, and applying some existing strategies into clinical practice would help clinicians reduce these types of errors and encourage more optimal diagnostic processes. PMID- 24070577 TI - Prediction of intravesical recurrence after radical nephroureterectomy: development of a clinical decision-making tool. AB - BACKGROUND: Intravesical recurrence after radical nephroureterectomy (RNU) is a frequent event requiring intense cystoscopic surveillance. Recently, a prospective randomized clinical trial has shown that a single intravesical postoperative dose of mitomycin C (MMC) reduces the absolute risk of intravesical recurrence after RNU. OBJECTIVE: The aim of the current study was to identify predictors of intravesical recurrence and to develop a tool to allow a risk stratified approach supporting patient counseling for cystoscopic surveillance and postoperative intravesical MMC administration. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective analysis of 1839 patients with upper tract urothelial carcinoma (UTUC). The data set was split into a development cohort of 1261 patients from North America and a validation cohort of 578 patients from Europe. INTERVENTIONS: RNU with bladder cuff excision was performed. The surgical approach was open in 1424 patients (77.4%) and laparoscopic in 415 patients (22.6%). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Univariable and multivariable Cox regression models addressed time to intravesical recurrence after RNU. We developed a nomogram for prediction of the probability of intravesical recurrence at 3, 6, 9, 12, 18, 24, and 36 mo. Predictive accuracy was quantified using the concordance index. Decision curve analysis was performed to evaluate the clinical benefit associated with the use of our nomograms. RESULTS AND LIMITATIONS: With a median follow-up of 45 mo, intravesical recurrence occurred in 577 patients (31%). The probability of intravesical recurrence-free survival at 6, 12, 24, and 36 mo was 85% +/- 1%, 78% +/- 1%, 68% +/- 1%, and 47% +/- 2%, respectively. In multivariable Cox regression analysis, advanced age, male gender, ureteral tumor location, laparoscopic surgical technique, endoscopic distal ureteral management, previous bladder cancer, higher tumor stage, concomitant carcinoma in situ, and lymph node involvement were all significantly associated with intravesical recurrence (p values <= 0.04). The nomograms were highly accurate for predicting intravesical recurrence in the external validation cohort (concordance index of 67.8% and 69.0% for the reduced model and the full model, respectively), and calibration plots revealed only minor overestimation beyond 24 mo. If one decided to perform postoperative instillation based on the risk of intravesical recurrence of 15% at 24 mo, one would spare 23% of the patients while not preventing only 0.3% of intravesical recurrences. The lack of information on the stage and grade of the intravesical recurrences is the main limitation of the study. CONCLUSIONS: Intravesical recurrence after RNU is a common event in patients with UTUC. We developed nomograms that predict intravesical recurrence after RNU with reasonable accuracy. Such nomograms could improve the clinical decision-making process with regard to cystoscopic surveillance scheduling and postoperative intravesical instillations of MMC after RNU. PMID- 24070580 TI - Diagnostic decision-making and strategies to improve diagnosis. AB - A significant portion of diagnostic errors arises through cognitive errors resulting from inadequate knowledge, faulty data gathering, and/or faulty verification. Experts estimate that 75% of diagnostic failures can be attributed to clinician diagnostic thinking failure. The cognitive processes that underlie diagnostic thinking of clinicians are complex and intriguing, and it is imperative that clinicians acquire explicit appreciation and application of different cognitive approaches to make decisions better. A dual-process model that unifies many theories of decision-making has emerged as a promising template for understanding how clinicians think and judge efficiently in a diagnostic reasoning process. The identification and implementation of strategies for decreasing or preventing such diagnostic errors has become a growing area of interest and research. Suggested strategies to decrease diagnostic error incidence include increasing clinician's clinical expertise and avoiding inherent cognitive errors to make decisions better. Implementing Interventions focused solely on avoiding errors may work effectively for patient safety issues such as medication errors. Addressing cognitive errors, however, requires equal effort on expanding the individual clinician's expertise. Providing cognitive support to clinicians for robust diagnostic decision-making serves as the final strategic target for decreasing diagnostic errors. Clinical guidelines and algorithms offer another method for streamlining decision-making and decreasing likelihood of cognitive diagnostic errors. Addressing cognitive processing errors is undeniably the most challenging task in reducing diagnostic errors. While many suggested approaches exist, they are mostly based on theories and sciences in cognitive psychology, decision-making, and education. The proposed interventions are primarily suggestions and very few of them have been tested in the actual practice settings. Collaborative research effort is required to effectively address cognitive processing errors. Researchers in various areas, including patient safety/quality improvement, decision-making, and problem solving, must work together to make medical diagnosis more reliable. PMID- 24070581 TI - System-related factors contributing to diagnostic errors. AB - Several studies in primary care, internal medicine, and emergency departments show that rates of errors in test requests and result interpretations are unacceptably high and translate into missed, delayed, or erroneous diagnoses. Ineffective follow-up of diagnostic test results could lead to patient harm if appropriate therapeutic interventions are not delivered in a timely manner. The frequency of system-related factors that contribute directly to diagnostic errors depends on the types and sources of errors involved. Recent studies reveal that the errors and patient harm in the diagnostic testing loop have occurred mainly at the pre- and post-analytic phases, which are directed primarily by clinicians who may have limited expertise in the rapidly expanding field of clinical pathology. These errors may include inappropriate test requests, failure/delay in receiving results, and erroneous interpretation and application of test results to patient care. Efforts to address system-related factors often focus on technical errors in laboratory testing or failures in delivery of intended treatment. System-improvement strategies related to diagnostic errors tend to focus on technical aspects of laboratory medicine or delivery of treatment after completion of the diagnostic process. System failures and cognitive errors, more often than not, coexist and together contribute to the incidents of errors in diagnostic process and in laboratory testing. The use of highly structured hand off procedures and pre-planned follow-up for any diagnostic test could improve efficiency and reliability of the follow-up process. Many feedback pathways should be established so that providers can learn if or when a diagnosis is changed. Patients can participate in the effort to reduce diagnostic errors. Providers should educate their patients about diagnostic probabilities and uncertainties. The patient-safety strategies focusing on the interface between diagnostic system and therapeutic intervention are strategies that involve both processes to facilitate appropriate follow-up and structural changes, such as the use of electronic tracking systems and patient navigation programs. PMID- 24070582 TI - Educational strategies for improving clinical reasoning. AB - Clinical reasoning serves as a crucial skill for all physicians regardless of their area of expertise. Helping trainees develop effective and appropriate clinical reasoning abilities is a central aim of medical education. Teaching clinical reasoning however can be a very difficult challenge for practicing physicians. Better understanding of the different cognitive processes involved in physician clinical reasoning provides a foundation from which to guide learner development of effective reasoning skills, while pairing assessment of learner reasoning abilities with understanding of different improvement strategies offers the opportunity to maximize educational efforts for learners. Clinical reasoning errors often can occur as a result of one of four problems in trainees as well as practicing physicians; inadequate knowledge, faulty data gathering, faulty data processing, or faulty metacognition. Educators are encouraged to consider at which point a given learner's reasoning is breaking down. Experimentation with different strategies for improving clinical reasoning can help address learner struggles in each of these domains. In this chapter, various strategies for improving reasoning related to knowledge acquisition, data gathering, data processing, and clinician metacognition will be discussed. Understanding and gaining experience using the different educational strategies will provide practicing physicians with a toolbox of techniques for helping learners improve their reasoning abilities. PMID- 24070583 TI - Mitochondrial content and gene expression profiles in oocyte-derived embryos of cattle selected on the basis of brilliant cresyl blue staining. AB - The aim of this study was to investigate the developmental rate, lipid and mitochondrial distribution and gene expression in oocyte-derived embryos selected on the basis of brilliant cresyl blue (BCB) staining. Lipid content and mitochondrial distribution in Day 8 blastocysts were evaluated by fluorescence intensity, while gene expression was analyzed by real-time PCR. The proportion of blastocysts (30.9%) was greater (P<0.05) in BCB+ than in BCB- oocytes (13%) but not different (P>0.05) from the control group (28.2%). Total cell number was also greater in BCB+ (155.1 +/- 36.2) than in BCB- (116.6 +/- 40.5) and control (127.5 +/- 35.7) blastocysts. Furthermore, the apoptotic cell number was less in BCB+ (3.7 +/- 4.4) than in BCB- blastocysts (8.7 +/- 8.7) but not different from the control group (5.9 +/- 3.9). BCB+ embryos contained more mitochondria compared to BCB- embryos (P<0.05). There was no significant difference in intercellular lipid accumulation in embryos from all groups. Interferon-tau (IFNtau), transforming growth factor beta1 (TGFB1) and secreted seminal-vesicle Ly-6 protein 1 (SSLP1) gene expression was greater in BCB+ than in BCB- blastocysts. By contrast, Bcl2 associated X protein (BAX) and heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) gene expression was greater in BCB- than in BCB+ and control embryos. In conclusion, oocyte-derived embryos selected on the basis of BCB staining showed differences in developmental rate, quality, mitochondrial content and target gene expression compared to control embryos. PMID- 24070584 TI - Dietary fatty acid enrichment increases egg size and quality of yellow seahorse Hippocampus kuda. AB - Seahorses populations in the wild have been declining and to restore them a better knowledge of seahorse reproduction is required. This study examines the effect of dietary quality on seahorse fecundity and egg quality. Two different diets were tested with Hippocampus kuda females: frozen mysis (control) and frozen mysis enriched with a liposome spray containing essential fatty acids. Diets were given to females (two groups of five) over a seven week period. After this period, males (fed the control diet) and females were paired and the eggs dropped by the females were collected. Fatty acid profile were analysed and eggs were counted and measured. Results showed that females fed on enriched mysis had larger eggs and that these had a higher content of total polyunsaturated fatty acids. The size of the egg was especially affected in the first spawn, where egg size for females fed the enriched diet was significantly higher than the egg size from control females. This effect was reduced in the following spawning where no significant differences were found. Egg size is an important quality descriptor as seahorse juveniles originating from smaller eggs and/or eggs of poor quality will have less chances of overcoming adverse conditions in the wild and consequently have lower survival and growth rates. This study shows that enriching frozen mysis with polyunsaturated fatty acids increases egg size and egg quality of H. kuda. PMID- 24070585 TI - Coordinated role of voltage-gated sodium channels and the Na+/H+ exchanger in sustaining microglial activation during inflammation. AB - Persistent neuroinflammation and microglial activation play an integral role in the pathogenesis of many neurological disorders. We investigated the role of voltage-gated sodium channels (VGSC) and Na(+)/H(+) exchangers (NHE) in the activation of immortalized microglial cells (BV-2) after lipopolysaccharide (LPS) exposure. LPS (10 and 100 ng/ml) caused a dose- and time-dependent accumulation of intracellular sodium [(Na(+))i] in BV-2 cells. Pre-treatment of cells with the VGSC antagonist tetrodotoxin (TTX, 1 MUM) abolished short-term Na(+) influx, but was unable to prevent the accumulation of (Na(+))i observed at 6 and 24h after LPS exposure. The NHE inhibitor cariporide (1 MUM) significantly reduced accumulation of (Na(+))i 6 and 24h after LPS exposure. Furthermore, LPS increased the mRNA expression and protein level of NHE-1 in a dose- and time-dependent manner, which was significantly reduced after co-treatment with TTX and/or cariporide. LPS increased production of TNF-alpha, ROS, and H2O2 and expression of gp91(phox), an active subunit of NADPH oxidase, in a dose- and time-dependent manner, which was significantly reduced by TTX or TTX+cariporide. Collectively, these data demonstrate a closely-linked temporal relationship between VGSC and NHE-1 in regulating function in activated microglia, which may provide avenues for therapeutic interventions aimed at reducing neuroinflammation. PMID- 24070587 TI - Vegetarianism: advantages and drawbacks in patients with chronic kidney diseases. AB - Vegetarian diet is a very old practice that is liable to confer some health benefits. Recent studies have demonstrated that modification of the dietary pattern with a reduction of animal protein intake and increased consumption of plant-based foods could influence cardiovascular risk profile and mortality rate. Moreover, phosphate bioavailability from plant proteins is reduced. These statements could lead to some benefits for chronic kidney disease (CKD) patients. This review summarizes the characteristics and benefits of vegetarian diets in the general population and the potential beneficial effects of such a diet on phosphate balance, insulin sensitivity, and the control of metabolic acidosis in CKD patients. Potential drawbacks exist when a vegetarian diet is associated with protein intake that is too restrictive and/or insufficient energy intake, justifying an early and regular nutritional follow-up jointly assumed by a nephrologist and a renal dietitian. PMID- 24070588 TI - Morbid obesity is not an independent predictor of graft failure or patient mortality after kidney transplantation. AB - OBJECTIVE: Obesity is often an absolute contraindication to kidney transplant, but an internal analysis of our center's recipients suggests that not all obese populations exhibit poor outcomes. We used national data to compare outcomes in select groups of morbidly obese and normal-weight recipients after kidney transplant. DESIGN: This study was a retrospective analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing database. SUBJECTS: The study sample consisted of 30,132 morbidly obese (body mass index [BMI] 35-40 kg/m(2)) and normal-weight (BMI 18.5-24.9 kg/m(2)) patients who underwent primary kidney-only transplantation between 2001 and 2006. MAIN OUTCOME MEASURE: Crude 3-year graft and patient survival rates of morbidly obese and normal-weight subgroups were evaluated. Logistic regression modeling compared 3 year graft failure and patient mortality in morbidly obese and normal-weight subgroups with opposite characteristics. Kaplan-Meier survival curves were created for 3-year graft and patient survival. Cox proportional hazard regression modeling was used to determine hazards for patient and graft mortality. RESULTS: No differences in crude graft and patient survival rates were seen between normal weight and morbidly obese recipients who were African American, diabetic, and 50 to 80 years of age. Morbidly obese recipients who were nondialysis dependent, nondiabetic, had good functional status, and received living-donor transplants had significantly lower 3-year graft failure and patient mortality risk compared with normal-weight recipients who were dialysis dependent, diabetic, had poor functional status, and received a deceased-donor transplant, respectively (P < .01). Morbidly obese recipients have significantly lower graft and patient survival curves compared with normal-weight recipients; however, multivariate regression analysis reveals that morbid obesity is not an independent predictor of graft failure or patient mortality. CONCLUSIONS: Morbid obesity is not independently associated with graft failure or patient mortality; therefore, it should not be used as a contraindication to kidney transplantation. PMID- 24070586 TI - The gap junction inhibitor 2-aminoethoxy-diphenyl-borate protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes and c-jun N terminal kinase activation. AB - Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the US. Although many aspects of the mechanism are known, recent publications suggest that gap junctions composed of connexin32 function as critical intercellular communication channels which transfer cytotoxic mediators into neighboring hepatocytes and aggravate liver injury. However, these studies did not consider off-target effects of reagents used in these experiments, especially the gap junction inhibitor 2-aminoethoxy-diphenyl-borate (2-APB). In order to assess the mechanisms of protection of 2-APB in vivo, male C56Bl/6 mice were treated with 400 mg/kg APAP to cause extensive liver injury. This injury was prevented when animals were co-treated with 20 mg/kg 2-APB and was attenuated when 2-APB was administered 1.5 h after APAP. However, the protection was completely lost when 2-APB was given 4-6 h after APAP. Measurement of protein adducts and c-jun-N-terminal kinase (JNK) activation indicated that 2-APB reduced both protein binding and JNK activation, which correlated with hepatoprotection. Although some of the protection was due to the solvent dimethyl sulfoxide (DMSO), in vitro experiments clearly demonstrated that 2-APB directly inhibits cytochrome P450 activities. In addition, JNK activation induced by phorone and tert butylhydroperoxide in vivo was inhibited by 2-APB. The effects against APAP toxicity in vivo were reproduced in primary cultured hepatocytes without use of DMSO and in the absence of functional gap junctions. We conclude that the protective effect of 2-APB was caused by inhibition of metabolic activation of APAP and inhibition of the JNK signaling pathway and not by blocking connexin32 based gap junctions. PMID- 24070589 TI - Diagnostic imaging agents for Alzheimer's disease: copper radiopharmaceuticals that target Abeta plaques. AB - One of the pathological hallmarks of Alzheimer's disease is the presence of amyloid-beta plaques in the brain and the major constituent of these plaques is aggregated amyloid-beta peptide. New thiosemicarbazone-pyridylhydrazine based ligands that incorporate functional groups designed to bind amyloid-beta plaques have been synthesized. The new ligands form stable four coordinate complexes with a positron-emitting radioactive isotope of copper, (64)Cu. Two of the new Cu(II) complexes include a functionalized styrylpyridine group and these complexes bind to amyloid-beta plaques in samples of post-mortem human brain tissue. Strategies to increase brain uptake by functional group manipulation have led to a (64)Cu complex that effectively crosses the blood-brain barrier in wild-type mice. The new complexes described in this manuscript provide insight into strategies to deliver metal complexes to amyloid-beta plaques. PMID- 24070590 TI - Determination of strain field on the superior surface of excised larynx vocal folds using DIC. AB - OBJECTIVE/HYPOTHESIS: The objective of the present study was to quantify the mechanical strain and stress in excised porcine larynges during self-oscillation using digital image correlation (DIC) method. The use of DIC in the excised larynx setup may yield accurate measurements of the vocal fold displacement field. STUDY DESIGN: Ex vivo animal larynx. METHODS: Measurements were performed using excised porcine larynges on a humidified flow bench, equipped with two high speed cameras and a commercially available DIC software. Surface deformations were calculated from digital images recorded at 3000 frames per second during continuous self-oscillation for four excised porcine larynges. Larynx preparation consisted of removing the supraglottal wall and the false folds. DIC yielded the deformation field on the superior visible surface of the vocal folds. Measurement data for adducted and freely suspended vocal folds were also used to estimate the distribution of the initial prephonatory strain field. An isotropic constitutive law, the polymer eight-chain model, was used to estimate the surface distributions of planar stresses from the strain data. RESULTS: The Lagrangian normal strain values were between ~16% and ~29% along the anterior-posterior direction. The motion of material points on the vocal fold surface described an elliptical trajectory during oscillation. A phase difference was observed between the anterior-posterior and the medial-lateral component of the displacement. The strain data and eight-chain model yielded a maximum stress of ~4 kPa along the medial-lateral direction on the superior surface. CONCLUSION: DIC allowed the strain field over the superior surface of an excised porcine larynx to be quantified during self-oscillation. The approach allowed the determination of the trajectory of specific points on the vocal fold surface. The results for the excised larynx were found to be significantly different than previous results obtained using synthetic replicas. The present study provides suggestions for future studies in human subjects. PMID- 24070591 TI - The role of voice therapy in the treatment of dyspnea and dysphonia in a patient with a vagal nerve stimulation device. AB - Vagal nerve stimulators (VNS) are implanted to treat medically refractory epilepsy and depression. The VNS stimulates the vagus nerve in the left neck. Laryngeal side effects are common and include dysphagia, dysphonia, and dyspnea. The current case study represents a patient with severe dyspnea and dysphonia, persisting even with VNS deactivation. The case demonstrates the use of voice and respiratory retraining therapy for the treatment of VNS-induced dysphonia and dyspnea. It also highlights the importance of a multidisciplinary approach, including laryngology, neurology, and speech-language pathology, in the treatment of these challenging patients. PMID- 24070592 TI - Differences in shimmer across formant regions. AB - OBJECTIVES: Objective acoustic measures used to analyze phonatory dysfunction include shimmer and jitter. These measures are limited in that they do not take into account auditory processing. However, previous studies have indicated that shimmer may be processed differently along the tonotopic axis of the ear and, in particular, may be perceptually and physiologically significant around the third and fourth formants. METHODS: This study investigated the relationship between shimmer around the first four formants (F1-F4) and in the broadband unfiltered speech waveform for 18 normal speakers from the voice disorders database of KayPENTAX. The voice samples were filtered around each formant with a bandwidth of 400Hz and then shimmer was assessed using five built-in different measures from Praat software. RESULTS: Comparisons of means tests revealed that shimmer increases significantly with formant frequency from F1 to F4, for all shimmer measures. Furthermore, for all shimmer measures, shimmer in the unfiltered speech was significantly and more strongly correlated with shimmer around F1 (r = 0.45 0.61) and F2 (r = 0.69-0.74), significantly but more weakly correlated with F4 (r = 0.42-0.47), and not significantly correlated with F3. CONCLUSIONS: The findings indicate that there are differences in the shimmer found around the different formants and that shimmer information around F3 and F4 is not well captured in standard shimmer measurements based on the broadband unfiltered waveform. PMID- 24070593 TI - Loudness and pitch of Kunqu opera. AB - Equivalent sound level (Leq), sound pressure level (SPL), and fundamental frequency (F0) are analyzed in each of five Kunqu Opera roles, Young girl and Young woman, Young man, Old man, and Colorful face. Their pitch ranges are similar to those of some western opera singers (alto, alto, tenor, baritone, and baritone, respectively). Differences among tasks, conditions (stage speech, singing, and reading lyrics), singers, and roles are examined. For all singers, Leq of stage speech and singing were considerably higher than that of conversational speech. Interrole differences of Leq among tasks and singers were larger than the intrarole differences. For most roles, time domain variation of SPL differed between roles both in singing and stage speech. In singing, as compared with stage speech, SPL distribution was more concentrated and variation of SPL with time was smaller. With regard to gender and age, male roles had higher mean Leq and lower average F0, MF0, as compared with female roles. Female singers showed a wider F0 distribution for singing than for stage speech, whereas the opposite was true for male singers. The Leq of stage speech was higher than in singing for young personages. Younger female personages showed higher Leq, whereas older male personages had higher Leq. The roles performed with higher Leq tended to be sung at a lower MF0. PMID- 24070594 TI - Neurogenic vocal fold motion impairment after routine intubation for tonsillectomy in a pediatric patient. AB - OBJECTIVES/HYPOTHESIS: Vocal fold motion impairment is a rare complication of general anesthesia and is more common in older patients undergoing longer duration of anesthesia. We present a case of recurrent laryngeal nerve (RLN) axonotmesis in a 16-year-old patient undergoing general anesthesia for tonsillectomy. STUDY DESIGN: Case report. METHODS: The patient was intubated with a 6-0 oral RAE tube for routine tonsillectomy and was dysphonic postoperatively. Right vocal fold motion impairment was discovered on flexible laryngoscopy, and serial examinations with videostroboscopy were performed. She underwent laryngeal electromyography 3 months postoperatively. RESULTS: Initial videostroboscopy demonstrated findings consistent with right RLN injury. Laryngeal electromyography showed severe active denervation of the right thyroarytenoid muscle with signs of early reinnervation, consistent with axonotmesis. Complete recovery was achieved 4 months postoperatively. CONCLUSIONS: This case demonstrates RLN axonotmesis after brief routine intubation. The presumed mechanism of injury is compression of the nerve between the thyroid cartilage and the arytenoid or cricoid cartilage. The use of an oral RAE endotracheal tube may have contributed to the injury owing to the short distance between the bend of the tube and the cuff, placing the cuff at a higher level within the airway. PMID- 24070595 TI - Management of pericarditis and myocarditis: could heart-rate-reducing drugs hold a promise? AB - Rest is usually recommended in acute pericarditis and acute myocarditis. Given that myocarditis often leads to hospitalization, this task seems easy to carry out in hospital practice; however, it could be a real challenge at home in daily life. Heart rate-lowering treatments (mainly beta-blockers) are usually recommended in case of acute myocarditis, especially in case of heart failure or arrhythmias, but level of proof remains weak. Calcium channel inhibitors and digoxin are sometimes proposed, albeit in limited situations. It is possible that rest or even heart rate-lowering treatments could help to manage these patients by preventing heart failure as well as by limiting "mechanical inflammation" and controlling arrhythmias, especially life-threatening ones. Whether heart rate has an effect on inflammation remains unclear. Several questions remain unsolved, such as the duration of such treatments, especially in light of new heart rate lowering treatments, such as ivabradine. In this review, we discuss rest and heart-rate lowering medications for the treatment of pericarditis and myocarditis. We also highlight some work in experimental models that indicates the beneficial effects of such treatments for these conditions. Finally, we suggest certain experimental avenues, through the use of animal models and clinical studies, which could lead to improved management of these patients. PMID- 24070596 TI - Characterization of untyped cardiac amyloidosis by mass spectrometry in a patient with Gly6Ser transthyretin polymorphism in fatal cardiogenic shock. PMID- 24070597 TI - Persistent atrial fibrillation presenting in sinus rhythm: pulmonary vein isolation versus pulmonary vein isolation plus electrogram-guided ablation. AB - BACKGROUND: The classification of atrial fibrillation as paroxysmal or persistent (PsAF) is clinically useful, but does not accurately reflect the underlying pathophysiology and is therefore a suboptimal guide to selection of ablation strategy. AIM: To determine if additional substrate ablation is beneficial for a subset of patients with PsAF, in whom long periods of sinus rhythm (SR) can be maintained. METHODS: We included patients presenting with PsAF in whom continuous periods of SR>3months were documented. All patients were in SR on the day of the procedure. Electrical pulmonary vein isolation (PVI) was performed in all patients. Additional electrogram (EGM)-guided ablation was left to the discretion of the operator. Patient characteristics and follow-up were analysed with respect to presence or absence of additional EGM-guided ablation. RESULTS: Sixty-five patients (mean age 60.1+/-8.9years; 81.5% men) met the inclusion criteria. EGM guided ablation was performed in 32 (49%) patients. Patients with and without EGM guided ablation had similar baseline characteristics. Absence of EGM-guided ablation was one of the independent predictors for arrhythmia recurrences after the index procedure (hazard ratio 0.24; confidence interval 0.12-0.47). After a median follow-up of 18+/-10months, the number of procedures required was significantly higher in the 'PVI-only' group (2.24+/-0.75 vs. 1.84+/-0.81; P=0.04) to achieve a similar success rate (84% vs. 81%; P=0.833). CONCLUSION: The addition of EGM-guided ablation requires fewer procedures to achieve similar clinical efficacy in mid-term follow-up compared with a PVI-only strategy in patients with PsAF presenting for ablation in SR. PMID- 24070598 TI - Impact of initial clinical presentation on clopidogrel low response. AB - BACKGROUND: Large interindividual variability exists in clopidogrel response. Clopidogrel low response correlates with poor prognosis after percutaneous coronary intervention. Some authors also suggest intraindividual variability over time. AIM: To assess the impact of initial clinical presentation on clopidogrel low response. METHODS: In this prospective study, clopidogrel response was assessed in 100 patients. Fifty patients presenting with acute coronary syndromes (ACS group) were compared with 50 patients with stable coronary artery disease matched 1:1 for age, sex, body mass index and diabetes (stable group). All patients were tested 18-24h after a 600 mg loading dose of clopidogrel using the VerifyNow-P2Y12 test (results expressed as platelet reaction units [PRUs]). Patients under chronic clopidogrel therapy or treated with glycoprotein IIb/IIIa inhibitors, bivalirudin or thrombolytics were excluded. RESULTS: Mean age was 61 +/- 12 years in each group; 28% of patients in each group were diabetic; mean body mass index was 27.6 +/- 5.6 kg/m(2) in the ACS group and 27.9 +/- 5.9 kg/m(2) in the stable group (p=0.80). Mean PRU values were 197 +/- 81 in the ACS group and 159 +/- 94 in the stable group (p=0.03). By multivariable analysis, the ACS group was significantly associated with a higher PRU value (p=0.02). There were significantly more clopidogrel low responders (PRU value>230) in the ACS group (38% vs. 18%; p=0.04). CONCLUSION: Our study confirms that initial clinical presentation, especially ACS, is a strong predictor of clopidogrel low response; this suggests that the evolution of coronary artery disease for one patient influences the clopidogrel response over time. These results are in accordance with recent trials showing a benefit for more aggressive antiplatelet therapy in ACS patients. PMID- 24070599 TI - Comparison of two- and three-dimensional transthoracic echocardiography for measurement of aortic annulus diameter in children. AB - BACKGROUND: Accurate evaluation of aortic root geometry is necessary in congenital aortic valve lesions in children, to guide surgical or angiographical intervention. AIM: To compare aortic annulus diameters measured by two- and three dimensional transthoracic echocardiography (2D- and 3D-TTE), to determine the feasibility and reproducibility of 3D imaging and assess the dynamic changes during the cardiac cycle. METHODS: Thirty children without heart disease were prospectively included. Two orthogonal aortic annulus diameters were measured offline using multiplanar reconstruction in diastole and in systole and were compared with the measurement of the aortic annulus diameter by 2D-TTE. RESULTS: Mean age was 11+/-3.6 years. Feasibility of 3D imaging was 100%. The coefficients of intra- and interobserver variability were 3.5% and 6%, respectively. The 2D mean diameter was significantly smaller than the 3D maximum diameter in systole (1.94 vs. 2.01mm; p=0.005). 2D and 3D measurements were well correlated (p<0.0001). The maximum and minimum diameters in 3D were significantly different both in systole and in diastole (p<0.001) underlining an aortic annulus eccentricity. The mean aortic annulus diameters were not significantly different between systole and diastole, with important individual variability during the cardiac cycle. CONCLUSION: This study demonstrated the feasibility and reproducibility of 3D-TTE for the assessment of the aortic annulus diameter in a normal paediatric population. Because of an underestimation of the maximum diameter by 2D-TTE and the asymmetry of the aortic annulus, 3D measurements could be important before percutaneous aortic valvuloplasty or surgical replacement. PMID- 24070600 TI - Cardiac amyloidosis: updates in diagnosis and management. AB - Amyloidosis is a severe systemic disease. Cardiac involvement may occur in the three main types of amyloidosis (acquired monoclonal light-chain, hereditary transthyretin and senile amyloidosis) and has a major impact on prognosis. Imaging the heart to characterize and detect early cardiac involvement is one of the major aims in the assessment of this disease. Electrocardiography and transthoracic echocardiography are important diagnostic and prognostic tools in patients with cardiac involvement. Cardiac magnetic resonance imaging better characterizes myocardial involvement, functional abnormalities and amyloid deposition due to its high spatial resolution. Nuclear imaging has a role in the diagnosis of transthyretin amyloid cardiomyopathy. Cardiac biomarkers are now used for risk stratification and staging of patients with light-chain systemic amyloidosis. Different types of cardiac complications may occur, including diastolic followed by systolic heart failure, atrial and/or ventricular arrhythmias, conduction disturbances, embolic events and sometimes sudden death. Senile amyloid and hereditary transthyretin amyloid cardiomyopathy have better prognoses than light-chain amyloidosis. Cardiac treatment of heart failure is usually ineffective and is often poorly tolerated because of its hypotensive and bradycardiac effects. The three main types of amyloid disease, despite their similar cardiac appearance, have specific new aetiological treatments that may change the prognosis of this disease. Cardiologists should be aware of this disease to allow early treatment. PMID- 24070601 TI - Chroman-like cyclic prenylflavonoids promote neuronal differentiation and neurite outgrowth and are neuroprotective. AB - Flavonoids target a variety of pathophysiological mechanisms and are therefore increasingly considered as compounds encompassed with therapeutic potentials in diseases such as cancer, diabetes, arteriosclerosis, and neurodegenerative diseases and mood disorders. Hops (Humulus lupulus L.) is rich in flavonoids such as the flavanone 8-prenylnaringenin, which is the most potent phytoestrogen identified so far, and the prenylchalcone xanthohumol, which has potent tumor preventive, anti-inflammatory and antiviral activities. In the present study, we questioned whether hops-derived prenylflavonoids and synthetic derivatives thereof act on neuronal precursor cells and neuronal cell lines to induce neuronal differentiation, neurite outgrowth and neuroprotection. Therefore, mouse embryonic forebrain-derived neural precursors and Neuro2a neuroblastoma-derived cells were stimulated with the prenylflavonoids of interest, and their potential to activate the promoter of the neuronal fate-specific doublecortin gene and to stimulate neuronal differentiation and neurite outgrowth was analyzed. In this screening, we identified highly "neuroactive" compounds, which we termed "enhancement of neuronal differentiation factors" (ENDFs). The most potent molecule, ENDF1, was demonstrated to promote neuronal differentiation of neural stem cells and neurite outgrowth of cultured dorsal root ganglion neurons and protected neuronal PC12 cells from cobalt chloride-induced as well as cholinergic neurons of the nucleus basalis of Meynert from deafferentation-induced cell death. The results indicate that hops-derived prenylflavonoids such as ENDFs might be powerful molecules to promote neurogenesis, neuroregeneration and neuroprotection in cases of chronic neurodegenerative diseases, acute brain and spinal cord lesion and age-associated cognitive impairments. PMID- 24070602 TI - Dietary carbohydrate dictates development of Type 2 diabetes in the Nile rat. AB - Amount and type of dietary carbohydrate (CHO), as well as the CHO:fat ratio, are thought to be critical for both the rate of development and severity of Type 2 diabetes mellitus. Thus, these nutritional considerations were examined in the previously described "spontaneous" model of diabetes and metabolic syndrome, the Nile rat. Weanling male Nile rats (n=92) were fed semipurified diets, modifying glycemic index and load by changing the amount of fiber or altering the CHO:fat ratio. Random and fasting blood glucose and body weight were assessed, and diabetes was characterized in terms of blood glucose, relevant plasma and liver parameters, food and water intake and terminal organ weights. Nile rats fed with hiCHO became more hyperglycemic than rats fed with modCHO (P<.05), while loCHO and hiCHO+hiFiber rats remained essentially normoglycemic. Liver lipid and glycogen accumulation was associated with severe hyperlipemia in diabetic rats, analogous to metabolic syndrome in humans. Advanced diabetes was linked to liver and kidney damage and elevated blood urea nitrogen with weight loss. Dispersing dietary CHO by fiber or replacing it by moderate fat (reducing the glycemic index and load) delayed the onset of diabetes but did not prevent signs of insulin resistance. A very low content of dietary CHO (high fat) seemed to prevent even these early indicators of insulin resistance. Thus, the Nile rat represents a novel CHO-sensitive model for study of Type 2 diabetes that reliably follows the course of disease in humans. PMID- 24070603 TI - Glial cell line-derived neurotrophic factor induces cell migration in human oral squamous cell carcinoma. AB - OBJECTIVES: Perineural invasion is a prominent clinical feature of various cancers, which causes difficulty in curative resection. Glial cell-derived neurotrophic factor (GDNF), a potent neurotrophic factor, plays an important role in the invasive and metastatic behavior of various cancers. The aim of this study was to examine the role of GDNF on oral squamous cell carcinoma. MATERIALS AND METHODS: GDNF expression in tissue samples was analyzed by immunohistochemistry. Transwell assay, zymography, Western blot, reverse transcription-PCR, and electrophoretic mobility shift assay (EMSA) were carried out to assess the effects of GDNF on oral cancer cells. RESULTS: Human oral cancer tissues showed higher GDNF expression than that in normal tissues. We also found that application of human GDNF enhanced the cell migration ability of human oral cancers. Moreover, treatment with GDNF increased matrix metalloproteinase (MMP)-9 and MMP-13 expression in oral cancer. Inhibition of MMP-9 and MMP-13 in oral cancer cells by pharmacological inhibitors or neutralizing antibodies reduced GDNF-enhanced cell migration. Moreover, transfection with siRNA against MMP-13 inhibited GDNF-enhanced cell migration. Treatment with GDNF also increased ERK, p38 and JNK phosphorylation, and AP-1 DNA binding activity in human oral cancer cells. Inhibition of MAP kinase or AP-1 also reduced GDNF-induced oral cancer cell migration. In migration-prone sublines, oral cancer cells showed a higher migration ability than that of the original oral cancer cells. Surprisingly, the enhancement of cell migratory activity in migration-prone sublines was reduced by a GDNF-neutralizing antibody. Importantly, migration-prone sublines of oral cancer revealed higher GDNF expression. CONCLUSION: These results indicate a regulatory effect on cell migration by GDNF in oral squamous cancer. PMID- 24070604 TI - Comment on the article "A new classification for potentially malignant disorders of the oral cavity" by Sachin C. Sarode et al. published in Oral Oncology 47 (2011) 920-921. PMID- 24070605 TI - The PIKfyve-ArPIKfyve-Sac3 triad in human breast cancer: Functional link between elevated Sac3 phosphatase and enhanced proliferation of triple negative cell lines. AB - The phosphoinositide 5-kinase PIKfyve and 5-phosphatase Sac3 are scaffolded by ArPIKfyve in the PIKfyve-ArPIKfyve-Sac3 (PAS) regulatory complex to trigger a unique loop of PtdIns3P-PtdIns(3,5)P2 synthesis and turnover. Whereas the metabolizing enzymes of the other 3-phosphoinositides have already been implicated in breast cancer, the role of the PAS proteins and the PtdIns3P PtdIns(3,5)P2 conversion is unknown. To begin elucidating their roles, in this study we monitored the endogenous levels of the PAS complex proteins in cell lines derived from hormone-receptor positive (MCF7 and T47D) or triple-negative breast cancers (TNBC) (BT20, BT549 and MDA-MB-231) as well as in MCF10A cells derived from non-tumorigenic mastectomy. We report profound upregulation of Sac3 and ArPIKfyve in the triple negative vs. hormone-sensitive breast cancer or non tumorigenic cells, with BT cell lines showing the highest levels. siRNA-mediated knockdown of Sac3, but not that of PIKfyve, significantly inhibited proliferation of BT20 and BT549 cells. In these cells, knockdown of ArPIKfyve had only a minor effect, consistent with a primary role for Sac3 in TNBC cell proliferation. Intriguingly, steady-state levels of PtdIns(3,5)P2 in BT20 and T47D cells were similar despite the 6-fold difference in Sac3 levels between these cell lines. However, steady-state levels of PtdIns3P and PtdIns5P, both regulated by the PAS complex, were significantly reduced in BT20 vs. T47D or MCF10A cell lines, consistent with elevated Sac3 affecting directly or indirectly the homeostasis of these lipids in TNBC. Together, our results uncover an unexpected role for Sac3 phosphatase in TNBC cell proliferation. Database analyses, discussed herein, reinforce the involvement of Sac3 in breast cancer pathogenesis. PMID- 24070606 TI - Oxidized low density lipoprotein increases RANKL level in human vascular cells. Involvement of oxidative stress. AB - Receptor Activator of NFkappaB Ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) have been shown to play a role not only in bone remodeling but also in inflammation, arterial calcification and atherosclerotic plaque rupture. In human smooth muscle cells, Cu(2+)-oxidized LDL (CuLDL) 10-50 MUg/ml increased reactive oxygen species (ROS) and RANKL level in a dose-dependent manner, whereas OPG level was not affected. The lipid extract of CuLDL reproduced the effects of the whole particle. Vivit, an inhibitor of the transcription factor NFAT, reduced the CuLDL-induced increase in RANKL, whereas PKA and NFkappaB inhibitors were ineffective. LDL oxidized by myeloperoxidase (MPO-LDL), or other pro-oxidant conditions such as ultraviolet A (UVA) irradiation, incubation with H2O2 or with buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, also induced an oxidative stress and enhanced RANKL level. The increase in RANKL in pro-oxidant conditions was also observed in fibroblasts and endothelial cells. Since RANKL is involved in myocardial inflammation, vascular calcification and plaque rupture, this study highlights a new mechanism whereby OxLDL might, by generation of an oxidative stress, exert a deleterious effect on different cell types of the arterial wall. PMID- 24070607 TI - Satellite cells isolated from aged or dystrophic muscle exhibit a reduced capacity to promote angiogenesis in vitro. AB - Deficits in skeletal muscle function exist during aging and muscular dystrophy, and suboptimal function has been related to factors such as atrophy, excessive inflammation and fibrosis. Ineffective muscle regeneration underlies each condition and has been attributed to a deficit in myogenic potential of resident stem cells or satellite cells. In addition to reduced myogenic activity, satellite cells may also lose the ability to communicate with vascular cells for coordination of myogenesis and angiogenesis and restoration of proper muscle function. Objectives of the current study were to determine the angiogenic promoting capacity of satellite cells from two states characterized by dysfunctional skeletal muscle repair, aging and Duchenne muscular dystrophy. An in vitro culture model composed of satellite cells or their conditioned media and rat adipose tissue microvascular fragments (MVF) was used to examine this relationship. Microvascular fragments cultured in the presence of rat satellite cells from adult muscle donors (9-12 month of age) exhibited greater indices of angiogenesis (endothelial cell sprouting, tubule formation and extensive branching) than MVF co-cultured with satellite cells from aged muscle donors (24 month of age). We sought to determine if the differential degree of angiogenesis we observed in the co-culture setting was due to soluble factors produced by each satellite cell age group. Similar to the co-culture experiment, conditioned media produced by adult satellite cells promoted greater angiogenesis than that of aged satellite cells. Next, we examined differences in angiogenesis-stimulating ability of satellite cells from 12 mo old MDX mice or age-matched wild-type mice. A reduction in angiogenesis activity of media conditioned by satellite cells from dystrophic muscle was observed as compared to healthy muscle. Finally, we found reduced gene expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in both aged and dystrophic satellite cells compared to their adult and normal counterparts, respectively. These results indicate that functional deficits in satellite cell activities during aging and diseased muscle may extend to their ability to communicate with other cells in their environment, in this case cells involved in angiogenesis. PMID- 24070608 TI - Characterization of a novel mutant KCNQ1 channel subunit lacking a large part of the C-terminal domain. AB - A mutation of KCNQ1 gene encoding the alpha subunit of the channel mediating the slow delayed rectifier K(+) current in cardiomyocytes may cause severe arrhythmic disorders. We identified KCNQ1(Y461X), a novel mutant gene encoding KCNQ1 subunit whose C-terminal domain is truncated at tyrosine 461 from a man with a mild QT interval prolongation. We made whole-cell voltage-clamp recordings from HEK-293T cells transfected with either of wild-type KCNQ1 [KCNQ1(WT)], KCNQ1(Y461X), or their mixture plus KCNE1 auxiliary subunit gene. The KCNQ1(Y461X)-transfected cells showed no delayed rectifying current. The cells transfected with both KCNQ1(WT) and KCNQ1(Y461X) showed the delayed rectifying current that is thought to be mediated largely by homomeric channel consisting of KCNQ1(WT) subunit because its voltage-dependence of activation, activation rate, and deactivation rate were similar to the current in the KCNQ1(WT)-transfected cells. The immunoblots of HEK-293T cell-derived lysates showed that KCNQ1(Y461X) subunit cannot form channel tetramers by itself or with KCNQ1(WT) subunit. Moreover, immunocytochemical analysis in HEK-293T cells showed that the surface expression level of KCNQ1(Y461X) subunit was very low with or without KCNQ1(WT) subunit. These findings suggest that the massive loss of the C-terminal domain of KCNQ1 subunit impairs the assembly, trafficking, and function of the mutant subunit containing channels, whereas the mutant subunit does not interfere with the functional expression of the homomeric wild-type channel. Therefore, the homozygous but not heterozygous inheritance of KCNQ1(Y461X) might cause major arrhythmic disorders. This study provides a new insight into the structure function relation of KCNQ1 channel and treatments of cardiac channelopathies. PMID- 24070609 TI - Crystal structure of Pseudomonas aeruginosa transcriptional regulator PA2196 bound to its operator DNA. AB - Pseudomonas aeruginosa is a major opportunistic human pathogen. PA2196 from P. aeruginosa is a member of TetR family of transcriptional repressors, which is involved in adaptation to environmental changes as well as bacterial antibiotic resistance. PA2196 consists of nine alpha-helical bundles divided into two separate domains. The N-terminal domain, called the DNA-binding domain, is composed of helices alpha1-alpha3 and has a helix-turn-helix motif. The C terminal domain, called the ligand-binding domain, has a hydrophobic pocket for ligand binding. Here, PA2196 was shown to bind to a 25 bp semi-palindromic dsDNA located in the upstream region of its own gene. The crystal structure of the PA2196-25mer dsDNA complex determined at a resolution of 2.9 A revealed that two dimers of PA2196 bound to one dsDNA, with each monomer interacting with the major groove of DNA. Especially, residues in helix alpha3, including Lys41, Gly42, Ser43, and Tyr45, interacted mainly with the base and phosphate backbone of dsDNA. PA2196 underwent large conformational changes upon DNA binding, as the distances between DNA-binding domains measured between two G42s in subunits A and B decreased from 41.7 A to 36.8 A. Our crystal structure of PA2196-25mer dsDNA complex revealed that PA2196 is similar to QacR in that two dimers bound to one dsDNA through specific interactions. PMID- 24070610 TI - A small compound targeting the interaction between nonstructural proteins 2B and 3 inhibits dengue virus replication. AB - The non-structural protein NS2B/NS3 serine-protease complex of the dengue virus (DENV) is required for the maturation of the viral polyprotein. Dissociation of the NS2B cofactor from NS3 diminishes the enzymatic activity of the complex. In this study, we identified a small molecule inhibitor that interferes with the interaction between NS2B and NS3 using structure-based screening and a cell-based viral replication assay. A library containing 661,417 small compounds derived from the Molecular Operating Environment lead-like database was docked to the NS2B/NS3 structural model. Thirty-nine compounds with high scores were tested in a secondary screening using a cell-based viral replication assay. SK-12 was found to inhibit replication of all DENV serotypes (EC50=0.74-4.92 MUM). In silico studies predicted that SK-12 pre-occupies the NS2B-binding site of NS3. Steady state kinetics using a fluorogenic short peptide substrate demonstrated that SK 12 is a noncompetitive inhibitor against the NS2B/NS3 protease. Inhibition to Japanese encephalitis virus by SK-12 was relatively weak (EC50=29.81 MUM), and this lower sensitivity was due to difference in amino acid at position 27 of NS3. SK-12 is the promising small-molecule inhibitor that targets the interaction between NS2B and NS3. PMID- 24070611 TI - Cell recognition molecule L1 promotes embryonic stem cell differentiation through the regulation of cell surface glycosylation. AB - Cell recognition molecule L1 (CD171) plays an important role in neuronal survival, migration, differentiation, neurite outgrowth, myelination, synaptic plasticity and regeneration after injury. Our previous study has demonstrated that overexpressing L1 enhances cell survival and proliferation of mouse embryonic stem cells (ESCs) through promoting the expression of FUT9 and ST3Gal4, which upregulates cell surface sialylation and fucosylation. In the present study, we examined whether sialylation and fucosylation are involved in ESC differentiation through L1 signaling. RNA interference analysis showed that L1 enhanced differentiation of ESCs into neurons through the upregulation of FUT9 and ST3Gal4. Furthermore, blocking the phospholipase Cgamma (PLCgamma) signaling pathway with either a specific PLCgamma inhibitor or knockdown PLCgamma reduced the expression levels of both FUT9 and ST3Gal4 mRNAs and inhibited L1-mediated neuronal differentiation. These results demonstrate that L1 promotes neuronal differentiation from ESCs through the L1-mediated enhancement of FUT9 and ST3Gal4 expression. PMID- 24070612 TI - Determinants of the tumor suppressor INPP4B protein and lipid phosphatase activities. AB - The tumor suppressor INPP4B is an important regulator of phosphatidyl-inositol signaling in the cell. Reduced INPP4B expression is associated with poor outcomes for breast, prostate, and ovarian cancer patients. INPP4B contains a CX5R catalytic motif characteristic of dual-specificity phosphatases, such as PTEN. Lipid phosphatase activity of INPP4B has previously been described. In this report we show that INPP4B can dephosphorylate para-nitrophenyl phosphate (pNPP) and 6,8-difluoro-4-methylumbelliferyl (DiFMUP), synthetic phosphotyrosine analogs, suggesting that INPP4B has protein tyrosine phosphatase (PTP) activity. Using mutagenesis, we examined the functional role of specific amino acids within the INPP4B C842KSAKDR catalytic site. The K843M mutant displayed increased pNPP hydrolysis, the K846M mutant lost lipid phosphatase activity with no effect on PTP activity, and the D847E substitution ablated PTP activity and significantly reduced lipid phosphatase activity. Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and PTP activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation. Taken together our data identified key residues in the INPP4B catalytic domain associated with lipid and protein phosphatase activities and found a robust downstream target regulated by INPP4B but not PTEN. PMID- 24070613 TI - Thermodynamic and kinetic characterization of hydroxyethylamine beta-secretase-1 inhibitors. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disease affecting millions of people. beta-Secretase-1 (BACE-1), an enzyme involved in the processing of the amyloid precursor protein (APP) to form Abeta, is a well validated target for AD. Herein, the authors characterize 10 randomly selected hydroxyethylamine (HEA) BACE-1 inhibitors in terms of their association and dissociation rate constants and thermodynamics of binding using surface plasmon resonance (SPR). Rate constants of association (ka) measured at 25 degrees C ranged from a low of 2.42*10(4) M(-1) s(-1) to the highest value of 8.3*10(5) M( 1) s(-1). Rate constants of dissociation (kd) ranged from 1.09*10(-4) s(-1) (corresponding to a residence time of close to three hours), to the fastest of 0.028 s(-1). Three compounds were selected for further thermodynamic analysis where it was shown that equilibrium binding was enthalpy driven while unfavorable entropy of binding was observed. Structural analysis revealed that upon ligand binding, the BACE-1flap folds down over the bound ligand causing an induced fit. The maximal difference between alpha carbon positions in the open and closed conformations of the flap was over 5 A. Thus the negative entropy of binding determined using SPR analysis was consistent with an induced fit observed by structural analysis. PMID- 24070614 TI - A functional magnetic resonance imaging study of working memory in youth after sports-related concussion: is it still working? AB - Abstract In children, the importance of detecting deficits after mild traumatic brain injury (mTBI) or concussion has grown with the increasing popularity of leisure physical activities and contact sports. Whereas most postconcussive symptoms (PCS) are similar for children and adults, the breadth of consequences to children remains largely unknown. To investigate the effect of mTBI on brain function, we compared working memory performance and related brain activity using blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in 15 concussed youths and 15 healthy age-matched control subjects. Neuropsychological tests, self-perceived PCS, and levels of anxiety and depression were also assessed. Our results showed that, behaviorally, concussed youths had significantly worse performances on the working memory tasks, as well as on the Rey figure delayed recall and verbal fluency. fMRI results revealed that, compared to healthy children, concussed youths had significantly reduced task-related activity in bilateral dorsolateral prefrontal cortex, left premotor cortex, supplementary motor area, and left superior parietal lobule during performance of verbal and nonverbal working memory tasks. Additionally, concussed youths also showed less activation than healthy controls in the dorsal anterior cingulate cortex, left thalamus, and left caudate nucleus during the nonverbal task. Regression analysis indicated that BOLD signal changes in bilateral dorsolateral prefrontal cortex were significantly correlated with performance such that greater activities in these regions, relative to the control condition, were associated with greater accuracy. Our findings confirmed functional alterations in brain activity after concussion in youths, a result similar to that observed in adults. However, significant differences were noted. In particular, the observation of reduced working memory accuracy suggests that youths may be unable to engage compensatory strategies to maintain cognitive performance after mTBI. This has significant implications for safe return to daily activities, including competitive sport. PMID- 24070615 TI - Molecular dynamics, physical stability and solubility advantage from amorphous indapamide drug. AB - This study for the first time investigates physicochemical properties of amorphous indapamide drug (IND), which is a known diuretic agent commonly used in the treatment of hypertension. The solid-state properties of the vitrified, cryomilled and ball-milled IND samples were analyzed using X-ray powder diffraction (XRD), mass spectrometry, nuclear magnetic resonance (NMR), infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS). These analytical techniques enabled us (i) to confirm the purity of obtained amorphous samples, (ii) to describe the molecular mobility of IND in the liquid and glassy state, (iii) to determine the parameters describing the liquid-glass transition i.e. Tg and dynamic fragility, (iv) to test the chemical stability of amorphous IND in various temperature conditions and finally (v) to confirm the long-term physical stability of the amorphous samples. These studies were supplemented by density functional theory (DFT) calculations and apparent solubility studies of the amorphous IND in 0.1 M HCl, phosphate buffer (pH=6.8), and water (25 and 37 degrees C). PMID- 24070616 TI - Rotating with rotated text: a natural behavior approach to investigating cognitive offloading. AB - Determining how we use our body to support cognition represents an important part of understanding the embodied and embedded nature of cognition. In the present investigation, we pursue this question in the context of a common perceptual task. Specifically, we report a series of experiments investigating head tilt (i.e., external normalization) as a strategy in letter naming and reading stimuli that are upright or rotated. We demonstrate that the frequency of this natural behavior is modulated by the cost of stimulus rotation on performance. In addition, we demonstrate that external normalization can benefit performance. All of the results are consistent with the notion that external normalization represents a form of cognitive offloading and that effort is an important factor in the decision to adopt an internal or external strategy. PMID- 24070617 TI - Phenolic compounds from Trifolium echinatum Bieb. and investigation of their tyrosinase inhibitory and antioxidant activities. AB - Two bischromones, 3,3'-dimethoxy-2'-oxychromone (1), 3,3'-dihydroxy-2,2' oxychromone (2) and a biflavone, 5,7,4',5",3'",4""-hexahydroxy-3"-O-beta-glucosyl 3',7"-O-biflavone (3) have been isolated from whole plant of Trifolium echinatum Bieb. together with five known flavonoids. The structures of the compounds were elucidated by 1D and 2D NMR analysis as well as HRESIMS. The isolated compounds were investigated for their antioxidant activity and tyrosinase inhibitory activity. Highly potent inhibition was found for compounds 1 (IC50=0.41 mM), 5 (IC50=0.47 mM) and 8 (IC50=0.45 mM) compared to those of standard tyrosinase inhibitors kojic acid (IC50=0.67 mM) and l-mimosine (IC50=0.64 mM). The antioxidative effect of the extracts was determined by using beta-carotene linoleic acid, DPPH scavenging, ABTS(+) scavenging, and CUPRAC assays. The experimental findings indicated that the compounds 2 and 8 were found to be active in radical scavenging and CUPRAC assays. PMID- 24070618 TI - Extensive phytochemical investigation of the polar constituents of Diospyros bipindensis Gurke traditionally used by Baka pygmies. AB - The water maceration and methanolic extract of the stem barks of Diospyros bipindensis, which is a medicinal plant used in Cameroon by Baka pygmies, revealed a complex high-performance liquid chromatography (HPLC) profile primarily composed of coumarin and naphthoquinone glycosides. The methanolic and apolar extracts also exhibited significant antifungal activity on a TLC bioautography assay against Candida albicans. HPLC-microfractionation in 96-well plates combined with bioautography enabled the rapid localization of the antifungal compound that was identified by HPLC-PDA and HPLC-MS analysis as plumbagin. These on-line structural information were also used to dereplicate four known compounds. The isolation of the polar constituents from the methanolic extract enabled the identification of eleven other compounds also present in the traditional preparation, nine of which are reported for the first time. The structures of those compounds were elucidated by UV, NMR and HR-MS analysis. PMID- 24070619 TI - Substituent effects of cis-cinnamic acid analogues as plant growh inhibitors. AB - 1-O-cis-Cinnamoyl-beta-D-glucopyranose is one of the most potent allelochemicals that has been isolated from Spiraea thunbergii Sieb by Hiradate et al. It derives its strong inhibitory activity from cis-cinnamic acid (cis-CA), which is crucial for phytotoxicity. By preparing and assaying a series of cis-CA analogues, it was previously found that the key features of cis-CA for lettuce root growth inhibition are a phenyl ring, cis-configuration of the alkene moiety, and carboxylic acid. On the basis of a structure-activity relationship study, the substituent effects on the aromatic ring of cis-CA were examined by systematic synthesis and the lettuce root growth inhibition assay of a series of cis-CA analogues having substituents on the aromatic ring. While ortho- and para substituted analogues exhibited low potency in most cases, meta-substitution was not critical for potency, and analogues having a hydrophobic and sterically small substituent were more likely to be potent. Finally, several cis-CA analogues were found to be more potent root growth inhibitors than cis-CA. PMID- 24070620 TI - Autophagy in placentas from acidotic newborns: an immunohistochemical study of LC3 expression. AB - Autophagy is an inducible catabolic process activated during compromised conditions, such as hypoxia. Neonatal encephalopathy (NE) is a syndrome of disturbed neurological function. No absolute prognostic indicators are available at birth to identify neonates at high risk to develop NE. Immunohistochemical staining with LC3 antibody was performed on 40 placentas from uneventful term singleton pregnancies with umbilical artery pH <= 7.00 at birth; semi quantitative analysis was carried-out to estimate autophagy level. 6/40 (15%) neonates developed NE. Placentas from newborns with NE exhibited a higher LC3 expression. Autophagy protein expression in placentas with severe acidosis is a potential marker for poor outcome. PMID- 24070622 TI - Festschrift dedicated to Dr Isabelle Penisson-Besnier, French expert in neuromuscular diseases deceased recently. Foreword. PMID- 24070621 TI - Second harmonic generation microscopy of fetal membranes under deformation: normal and altered morphology. AB - INTRODUCTION: Insight into the microstructure of fetal membrane and its response to deformation is important for understanding causes of preterm premature rupture of the membrane. However, the microstructure of fetal membranes under deformation has not been visualized yet. Second harmonic generation microscopy, combined with an in-situ stretching device, can provide this valuable information. METHODS: Eight fetal membranes were marked over the cervix with methylene blue during elective caesarean section. One sample per membrane of reflected tissue, between the placenta and the cervical region, was cyclically stretched with a custom built inflation device. Samples were mounted on an in-situ stretching device and imaged with a multiphoton microscope at different deformation levels. Microstructural parameters such as thickness and collagen orientation were determined. Image entropy was evaluated for the spongy layer. RESULTS: The spongy layer consistently shows an altered collagen structure in the cervical and cycled tissue compared with the reflected membrane, corresponding to a significantly higher image entropy. An increased thickness of collagenous layers was found in cervical and stretched samples in comparison to the reflected tissue. Significant collagen fibre alignment was found to occur already at moderate deformation in all samples. CONCLUSIONS: For the first time, second harmonic generation microscopy has been used to visualize the microstructure of fetal membranes. Repeated mechanical loading was shown to affect the integrity of the amnion chorion interface which might indicate an increased risk of premature rupture of fetal membrane. Moreover, mechanical loading might contribute to morphological alterations of the fetal membrane over the cervical region. PMID- 24070623 TI - Influence of sample and mobile phase composition on peptide retention behaviour and sensitivity in reversed-phase liquid chromatography/mass spectrometry. AB - Because the chromatographic behaviour of peptides is totally different from that of small molecules, a good understanding of the mechanisms that occur from injection to detection in reversed-phase LC-MS is strongly recommended to successfully develop not only qualitative but also quantitative methods. In this study, design of experiments was used in order to investigate the influence of the experimental parameters, i.e. sample and mobile phase composition, on a peptide mixture covering a wide range of molecular weights, isoelectric points and hydropathies. First, a screening design was developed to identify the significant factors concerning mobile phase (ion-pairing reagent nature and concentration) and sample composition (organic modifier proportion and ion pairing reagent nature) on retention and response intensity (sensitivity). Then, after having selected the experimental domain and the significant factors, a full factorial design was used to further investigate the role of the considered factors and their interactions. Interestingly, ion-pairing reagent nature present in the sample had a tremendous effect on retention and response intensity. Optimal conditions leading to good sensitivity and adequate peptide retention without band splitting were selected and could be used as starting point for rapid method development using classical solvents and ion-pairing reagents. PMID- 24070624 TI - Parallel analysis of volatile fatty acids, indole, skatole, phenol, and trimethylamine from waste-related source environments. AB - An experimental technique based on sorbent tube-thermal desorption-gas chromatography (ST-TD-GC) was investigated for the simultaneous determination of a cluster of eight volatile odorants (propionic acid, n-butyric acid, i-valeric acid, n-valeric acid, trimethylamine, phenol, indole, and skatole) and a reference compound (benzene). Calibration was made by direct injection of a liquid working standard (L-WS) into a quartz tube packed with three bed sorbent (Tenax TA, Carbopack B, and Carbopack X). To assess the relative performance between different detector systems, a comparative analysis was made using both mass spectrometry (MS) and a flame ionization detector (FID) with the aid of a TD system. In the TD-GC-MS analysis, calibration results were evaluated in two different modes, namely total ion chromatogram (TIC) and extracted ion chromatogram (EIC). In both FID and MS, the elution order of investigated odorants complied with the retention time index (RTI) values for the polar column with a coefficient of determination (R(2)) at or above 0.99. As a means to validate our detection approach, environmental samples from a bathroom and manhole (vacuum samples) as well as cat stool and wastewater (headspace samples) were also collected. The ST-TD method tested for the concurrent analysis of diverse odorants allowed us to measure a list of offensive odorants from those samples. PMID- 24070625 TI - Maximizing kinetic performance in supercritical fluid chromatography using state of-the-art instruments. AB - Recently, there has been a renewed interest in supercritical fluid chromatography (SFC), due to the introduction of state-of-the-art instruments and dedicated columns packed with small particles. However, the achievable kinetic performance and practical possibilities of such modern SFC instruments and columns has not been described in details until now. The goal of the present contribution was to provide some information about the optimal column dimensions (i.e. length, diameter and particle size) suitable for such state-of the-art systems, with respect to extra-column band broadening and system upper pressure limit. In addition, the reliability of the kinetic plot methodology, successfully applied in RPLC, was also evaluated under SFC conditions. Taking into account the system variance, measured at ~85MUL(2), on modern SFC instruments, a column of 3mm I.D. was ideally suited for the current technology, as the loss in efficiency remained reasonable (i.e. less than 10% decrease for k>6). Conversely, these systems struggle with 2.1mm I.D. columns (55% loss in N for k=5). Regarding particle size, columns packed with 5MUm particles provided unexpectedly high minimum reduced plate height values (hmin=3.0-3.4), while the 3.5 and 1.7MUm packing provided lower reduced plate heights hmin=2.2-2.4 and hmin=2.7-3.2, respectively. Considering the system upper pressure limit, it appears that columns packed with 1.7MUm particles give the lowest analysis time for efficiencies up to 40,000 60,000 plates, if the mobile phase composition is in the range of 2-19% MeOH. The 3.5MUm particles were attractive for higher efficiencies, particularly when the modifier percentage was above 20%, while 5MUm was never kinetically relevant with modern SFC instruments, due to an obvious limitation in terms of upper flow rate value. The present work also confirms that the kinetic plot methodology could be successfully applied to SFC, without the need for isopycnic measurements, as the difference in plate count between predicted and experimental values obtained by coupling several columns in series (up to 400mm) was on average equal to 3-6% and with a maximum of 13%. PMID- 24070626 TI - Application of gas chromatography-(triple quadrupole) mass spectrometry with atmospheric pressure chemical ionization for the determination of multiclass pesticides in fruits and vegetables. AB - A multi-residue method for the determination of 142 pesticide residues in fruits and vegetables has been developed using a new atmospheric pressure chemical ionization (APCI) source for coupling gas chromatography (GC) to tandem mass spectrometry (MS). Selected reaction monitoring (SRM) mode has been applied, acquiring three transitions for each compound. In contrast to the extensive fragmentation typically obtained in classical electron ionization (EI), the soft APCI ionization allowed the selection of highly abundant protonated molecules ([M+H](+)) as precursor ions for most compounds. This was favorable for both sensitivity and selectivity. Validation of the method was performed in which both quantitative and qualitative parameters were assessed using orange, tomato and carrot samples spiked at two levels, 0.01 and 0.1mg/kg. The QuEChERS method was used for sample preparation, followed by a 10-fold dilution of the final acetonitrile extract with a mixture of hexane and acetone. Recovery and precision were satisfactory in the three matrices, at both concentration levels. Very low limits of detection (down 0.01MUg/kg for the most sensitive compounds) were achieved. Ion ratios were consistent and identification according to EU criteria was possible in 80% (0.01mg/kg) to 96% (0.1mg/kg) of the pesticide/matrix combinations. The method was applied to the analysis of various fruits and vegetables from the Mediterranean region of Spain. PMID- 24070627 TI - Simultaneous determination of total fatty acid esters of chloropropanols in edible oils by gas chromatography-mass spectrometry with solid-supported liquid liquid extraction. AB - This study aimed to establish a novel robust method for the simultaneous determination of total fatty acid esters of 4 chloropropanols including fatty acid esters of 3-monochloropropane-1,2-diol (3-MCPD esters), 2-monochloropropane 1,3-diol (2-MCPD esters), 1,3-dichloropropan-2-ol (1,3-DCP esters) and 2,3 dichloropropan-1-ol (2,3-DCP esters) in edible oils. In this method, sodium methylate in methanol was used as the reagent for the ester cleavage reaction of chloropropanols esters. The reaction products were extracted by a sodium sulfate solution, and then purified by solid-supported liquid-liquid extraction (SLE) using diatomaceous earth (HydromatrixTM) as the sorbent. Finally, the extracts were derivatized with heptafluorobutyrylim idazole (HFBI) and analyzed by gas chromatography-mass spectrometry (GC-MS). Quantification was achieved using deuterated chloropropanols as their respective internal standards, including 3 MCPD-d5, 2-MCPD-d5, 1,3-DCP-d5 and 2,3-DCP-d5. A good linear relationship between peak area and concentrations was obtained within the range of 0.025-2.000mgL(-1) with a correlation coefficients not less than 0.999 for all the chloropropanols esters. The limits of detection (LODs) of esters of 3-MCPD, 2-MCPD, 1,3-DCP and 2,3-DCP (calculated as corresponding chloropropanols) were 30, 30, 100 and 30MUgkg(-1), respectively. The average recoveries of the 3-MCPD esters and the 4 chloropropanols spiked at 0.1, 0.5 and 2mgkg(-1) into blank oil matrix were typically in a range from 70.7% to 113.3%. The robust method validation data including calibration, LOD/LOQ, accuracy and repeatability and proficiency test results (Z-score: -0.5) of the official Food Analysis Performance Assessment Scheme (FAPAS) indicated that the present quantitative method could be successfully applied to the determination of total chloropropanols esters in various edible oils. PMID- 24070628 TI - Advances in food analysis. PMID- 24070629 TI - Sesamol and naringenin reverse the effect of rotenone-induced PD rat model. AB - In the previous report (Sonia Angeline et al., 2012), we showed an altered expression of protective proteins in rotenone-induced Parkinson's disease (PD) like rat model. This model exhibited a marked attenuation in the expression of parkin, C terminus Hsp70 interacting protein (CHIP) and PARK 7 protein (DJ1) while enhanced levels of caspases and ubiquitin were seen. Herein, we confirmed the neuroprotective role of sesamol and naringenin individually on rotenone induced rodent model of PD. Rotenone administration was given for 11days to generate the PD model (Sonia Angeline et al., 2012). From 11th day onward individual doses of sesamol (15mg/kg) and naringenin (10mg/kg) drugs were given orally to the rotenone PD rat model for 10 consecutive days. The impact of drugs markedly improved the motor skills, body weight, expression of parkin, DJ1, tyrosine hydroxylase and CHIP compared to the group treated with rotenone alone in the striatum and substantia nigra. These results were correlated with the reduction in caspase and ubiquitin levels by immunostaining and immunoblotting. Moreover, improved morphology and survivability of neurons were seen upon sesamol and naringenin treatment in the same rat PD model. Further we confirmed the efficacy of neuroprotective biomolecule administration on muscle from the above PD model and observed the restoration in muscle morphology, elevated level of parkin, DJ1, differential expression of heat shock proteins and reduced cell death. To conclude, for the first time we are demonstrating the comprehensive role of sesamol and naringenin (rotenone-induced PD model) in neuro and myoprotection that would have great clinical significance. PMID- 24070630 TI - Effects of hypocretin and norepinephrine interaction in bed nucleus of the stria terminalis on arterial pressure. AB - Forebrain neuronal circuits containing hypocretin-1 (hcrt-1) and norepinephrine (NE) are important components of central arousal-related processes. Recently, these two systems have been shown to have an overlapping distribution within the bed nucleus of the stria terminalis (BST), a limbic structure activated by stressful challenges, and which functions to adjust arterial pressure (AP) and heart rate (HR) to the stressor. However, whether hcrt-1 and NE interact in BST to alter cardiovascular function is unknown. Experiments were done in urethane alpha-chloralose anesthetized, paralyzed, and artificially ventilated male Wistar rats to investigate the effect of hcrt-1 and NE on the cardiovascular responses elicited by l-glutamate (Glu) stimulation of BST neurons. Microinjections of hcrt 1, NE or tyramine into BST attenuated the decrease in AP and HR to Glu stimulation of BST. Additionally, combined injections of hcrt-1 with NE or tyramine did not elicit a greater attenuation than either compound alone. Furthermore, injections into BST of the alpha2-adrenergic receptor (alpha2-AR) antagonist yohimbine, but not the alpha1-AR antagonist 2-{[beta-(4 hydroxyphenyl)ethyl]aminomethyl}-1-tetralone hydrochloride, blocked both the hcrt 1 and NE-induced inhibition of the BST cardiovascular depressors responses. Finally, injections into BST of the GABAA receptor antagonist bicuculline, but not the GABAB receptor antagonist phaclofen, blocked the hcrt-1 and NE attenuation of the BST Glu-induced depressor and bradycardia responses. These data suggest that hcrt-1 effects in BST are mediated by NE neurons, and hcrt-1 likely acts to facilitate the synaptic release of NE. NE neurons, acting through alpha2-AR may activate Gabaergic neurons in BST, which in turn through the activation of GABAA receptors inhibit a BST sympathoinhibitory pathway. Taken together, these data suggest that hcrt-1 pathways to BST through their interaction with NE and Gabaergic neurons may function in the coordination of cardiovascular responses associated with different behavioral states. PMID- 24070632 TI - Arterial catheter-related bloodstream infection: incidence, pathogenesis, risk factors and prevention. AB - BACKGROUND: Arterial catheters are essential in critical care for haemodynamic and blood gas monitoring. The risk of infection remains ill defined. AIMS: To delineate the incidence, pathogenesis and risk factors for arterial catheter related bloodstream infection (BSI). METHODS: Arterial catheters in two randomized trials in 1998-2000 were studied prospectively. One trial studied the effect of a 1% chlorhexidine-75% alcohol solution for cutaneous antisepsis for intravascular catheters, and the other trial studied the efficacy of a chlorhexidine-impregnated sponge dressing, both for prevention of catheter related BSI. At catheter removal, skin of the insertion site, catheter segments, hub and infusate were cultured quantitatively in all cases. Catheter-related BSI was confirmed by concordance between isolates from the catheter and from blood cultures by restriction-fragment DNA subtyping. Risk factors for arterial catheter-related BSI were determined using univariate analysis. FINDINGS: Of 834 arterial catheters studied (3273 catheter-days), 109 (13%) were colonized and 11 caused bacteraemia (1.3%, 3.4 per 1000 catheter-days). The majority of catheter related BSIs were acquired extraluminally from skin of the insertion site (63%). The risk of arterial catheter-related BSI was comparable with that for short-term non-cuffed central venous catheters (2.7%, 5.9 per 1000 CVC-days). CONCLUSION: In patients in intensive care with cryptogenic sepsis or bacteraemia, arterial catheter-related BSI must also be suspected and excluded. The most common route of infection is extraluminal; as such, novel technologies shown to prevent bloodstream infection with CVCs, such as chlorhexidine for cutaneous antisepsis and chlorhexidine-impregnated dressings, may also be of benefit with arterial catheters. PMID- 24070631 TI - Inhibition of glycogen synthase kinase 3beta activity with lithium prevents and attenuates paclitaxel-induced neuropathic pain. AB - Paclitaxel (taxol) is a first-line chemotherapy-drug used to treat many types of cancers. Neuropathic pain and sensory dysfunction are the major toxicities, which are dose-limiting and significantly reduce the quality of life in patients. Two known critical spinal mechanisms underlying taxol-induced neuropathic pain are an increased production of pro-inflammatory cytokines including interleukin-1beta (IL-1beta) and suppressed glial glutamate transporter activities. In this study, we uncovered that increased activation of glycogen synthase kinase 3beta (GSK3beta) in the spinal dorsal horn was concurrently associated with increased protein expressions of GFAP, IL-1beta and a decreased protein expression of glial glutamate transporter 1 (GLT-1), as well as the development and maintenance of taxol-induced neuropathic pain. The enhanced GSK3beta activities were supported by the concurrently decreased AKT and mTOR activities. The changes of all these biomarkers were basically prevented when animals received pre-emptive lithium (a GSK3beta inhibitor) treatment, which also prevented the development of taxol induced neuropathic pain. Further, chronic lithium treatment, which began on day 11 after the first taxol injection, reversed the existing mechanical and thermal allodynia induced by taxol. The taxol-induced increased GSK3beta activities and decreased AKT and mTOR activities in the spinal dorsal horn were also reversed by lithium. Meanwhile, protein expressions of GLT-1, GFAP and IL-1beta in the spinal dorsal horn were improved. Hence, suppression of spinal GSK3beta activities is a key mechanism used by lithium to reduce taxol-induced neuropathic pain, and targeting spinal GSK3beta is an effective approach to ameliorate GLT-1 expression and suppress the activation of astrocytes and IL-1beta over-production in the spinal dorsal horn. PMID- 24070633 TI - Laboratory exposure to Brucella melitensis in Denmark: a prospective study. AB - Brucella species are a frequent cause of laboratory-acquired infections. This report describes the handling of a laboratory exposure of 17 laboratory staff members exposed to Brucella melitensis in a large microbiology laboratory in a brucella-non-endemic area. We followed the US Centers for Disease Control and Prevention guidelines, but, of 14 staff members classified as high-risk exposure, none accepted post-exposure prophylaxis. However, in a period of 6 months of follow-up, none of the exposed laboratory workers developed brucellosis and all obtained sera were negative for antibrucella antibodies. We therefore question the value of routine serological follow-up. PMID- 24070634 TI - Enhanced mesenchymal stem cell survival induced by GATA-4 overexpression is partially mediated by regulation of the miR-15 family. AB - We reported previously that pre-programming mesenchymal stem cells with the GATA 4 gene increases significantly cell survival in an ischemic environment. In this study, we tested whether regulation of microRNAs and their target proteins was associated with the cytoprotective effects of GATA-4. METHODS AND RESULTS: Mesenchymal stem cells were harvested from adult rat bone marrow and transduced with GATA-4 (MSC(GATA-4)) using the murine stem cell virus retroviral expression system. Cells transfected with empty vector (MSC(Null)) were used as controls. Quantitative real-time PCR data showed that the expression levels of miR-15 family members (miR-15b, miR-16, and miR-195) were significantly down-regulated in MSC(GATA-4). The protein expression of Bcl-w (Bcl-2-like-2), an anti-apoptotic Bcl-2 family protein, was increased in MSC(GATA-4). Hypoxic culture (low glucose and low oxygen) induced the release of lactate dehydrogenase from mesenchymal stem cells and reduced cell survival. Compared to MSC(Null), MSC(GATA-4) showed less lactate dehydrogenase release and greater cell survival following 72 h hypoxia exposure. The mitochondrial membrane potential, detected with the dye JC 1, was well maintained, and mitochondrial membrane permeability, expressed as caspase 3 and 7 activities in response to the ischemic environment was lower in MSC(GATA-4). Moreover, transfection with miR-195 significantly down-regulated Bcl w expression in mesenchymal stem cells through a binding site in the 3'-UTR of the Bcl-w mRNA and reduced mesenchymal stem cell resistance to ischemic injury. CONCLUSIONS: The overexpression of GATA-4 in mesenchymal stem cells down regulates miR-15 family members, causing increased resistance to ischemia through the up-regulation of anti-apoptotic proteins in the Bcl-2 family. PMID- 24070635 TI - Aerobic exercise as a treatment for vasomotor menopausal symptoms: randomised controlled trial protocol. AB - BACKGROUND: Evidence suggests that a high proportion of perimenopausal and postmenopausal women experience vasomotor symptoms (hot flushes/night sweats) that can be severe and disruptive and which are the principal reason for seeking medical intervention. Hormone therapy (HT) is known to be an effective treatment for troublesome hot flushes/night sweats but research has raised questions about the safety of HT and there have been negative high profile media reports about its use. Consequently many women are seeking alternatives and exercise might be one such option but there is a lack of high quality evidence on its effectiveness. AIMS: This RCT initially aims to investigate the feasibility/acceptability of two exercise interventions identified from our previous preference study in 165 women, and if found to be feasible/acceptable, continue to recruit sufficient women (n=261) to examine the effect of these interventions on hot flushes/night sweats and other outcomes relevant to menopausal women. METHOD: We aim to recruit inactive perimenopausal and menopausal symptomatic women not using HT and randomise them to one of two exercise interventions or usual care for six months. RESULTS: We will assess outcomes at baseline and 6 and 12 months from randomisation. CONCLUSION: We hope this RCT will contribute towards increasing the evidence regarding the question of whether exercise is an effective treatment for vasomotor symptoms in women not taking HT. PMID- 24070636 TI - Core/shell colloidal quantum dot exciplex states for the development of highly efficient quantum-dot-sensitized solar cells. AB - Searching suitable panchromatic QD sensitizers for expanding the light-harvesting range, accelerating charge separation, and retarding charge recombination is an effective way to improve power conversion efficiency (PCE) of quantum-dot sensitized solar cells (QDSCs). One possible way to obtain a wide absorption range is to use the exciplex state of a type-II core/shell-structured QDs. In addition, this system could also provide a fast charge separation and low charge recombination rate. Herein, we report on using a CdTe/CdSe type-II core/shell QD sensitizer with an absorption range extending into the infrared region because of its exciplex state, which is covalently linked to TiO2 mesoporous electrodes by dropping a bifunctional linker molecule mercaptopropionic acid (MPA)-capped QD aqueous solution onto the film electrode. High loading and a uniform distribution of QD sensitizer throughout the film electrode thickness have been confirmed by energy dispersive X-ray (EDX) elemental mapping. The accelerated electron injection and retarded charge-recombination pathway in the built CdTe/CdSe QD cells in comparison with reference CdSe QD-based cells have been confirmed by impedance spectroscopy, fluorescence decay, and intensity-modulated photocurrent/photovoltage spectroscopy (IMPS/IMVS) analysis. With the combination of the high QD loading and intrinsically superior optoelectronic properties of type-II core/shell QD (wide absorption range, fast charge separation, and slow charge recombination), the resulting CdTe/CdSe QD-based regenerative sandwich solar cells exhibit a record PCE of 6.76% (J(sc) = 19.59 mA cm(-2), V(oc) = 0.606 V, and FF = 0.569) with a mask around the active film under a full 1 sun illumination (simulated AM 1.5), which is the highest reported to date for liquid junction QDSCs. PMID- 24070638 TI - Hemostasis dynamics during coagulopathy resulting from Echis envenomation. AB - This work provides a graphic description of the time course of hemostasis tests results during spontaneous evolution of Echis envenoming and correction of hemostasis disorders with antivenom therapy. The dynamics of fibrinogenemia (g L( 1)), prothrombin time (PT, %), activated partial thromboplastin time (aPTT, patient/normal ratio) and platelet count (Giga L(-1)) were collected from coagulopathic envenomed patients of a 12 years prospective study in Africa. Sixty patients were included. 47 of them (78%) received an antivenom (33 +/- 12 ml) and 13 did not. Thirty patients (50%) presented bleeding. Only one patient died. The time for fibrinogen to be more than 1 g L(-1) was 181 +/- 116 h (7.5 days) in the spontaneous evolution group versus 40 +/- 21 h in the antivenom group (p < 0.0001). The times for reaching a PT above 50% were 140 +/- 64 min (5.8 days) versus 25 +/- 15 h (p < 0.00001) and for reaching an aPTT less than 1.5 times the normal values, 116 +/- 76 h (4.7 days) versus 10 +/- 9 h respectively (p < 0.0002). Thrombopenia was not a common feature of Echis envenomation. This study is the first one to provide a chart of the evolution of the hemostatic tests during envenomation caused by Echis bites. The plots enable to estimate that, in Echis envenomation, in the absence of antivenom administration, hemostasis remains severely affected until the 8-10th day of evolution. On the contrary, efficient antivenom against African vipers corrects clotting functions within a few hours. PMID- 24070637 TI - Neuroprotective efficacy of a proneurogenic compound after traumatic brain injury. AB - Traumatic brain injury (TBI) is characterized by histopathological damage and long-term sensorimotor and cognitive dysfunction. Recent studies have reported the discovery of the P7C3 class of aminopropyl carbazole agents with potent neuroprotective properties for both newborn neural precursor cells in the adult hippocampus and mature neurons in other regions of the central nervous system. This study tested, for the first time, whether the highly active P7C3-A20 compound would be neuroprotective, promote hippocampal neurogenesis, and improve functional outcomes after experimental TBI. Sprague-Dawley rats subjected to moderate fluid percussion brain injury were evaluated for quantitative immunohistochemical and behavioral changes after trauma. P7C3-A20 (10 mg/kg) or vehicle was initiated intraperitoneally 30 min postsurgery and twice per day every day thereafter for 7 days. Administration of P7C3-A20 significantly reduced overall contusion volume, preserved vulnerable anti-neuronal nuclei (NeuN) positive pericontusional cortical neurons, and improved sensorimotor function 1 week after trauma. P7C3-A20 treatment also significantly increased both bromodeoxyuridine (BrdU)- and doublecortin (DCX)-positive cells within the subgranular zone of the ipsilateral dentate gyrus 1 week after TBI. Five weeks after TBI, animals treated with P7C3-A20 showed significantly increased BrdU/NeuN double-labeled neurons and improved cognitive function in the Morris water maze, compared to TBI-control animals. These results suggest that P7C3-A20 is neuroprotective and promotes endogenous reparative strategies after TBI. We propose that the chemical scaffold represented by P7C3-A20 provides a basis for optimizing and advancing new pharmacological agents for protecting patients against the early and chronic consequences of TBI. PMID- 24070639 TI - Head circumference: the forgotten tool for hydrocephalus management. A reference interval study in the Spanish population. AB - INTRODUCTION: In children, deviations from the normal range of head circumference (HC) have traditionally been related with CSF dynamics abnormalities. In adults, this neglected parameter is helpful in the diagnosis and understanding of the pathophysiology of some CSF abnormalities. It has been demonstrated that HC is related to height. Because humans have increased in stature dramatically during the last 50 years, pediatric charts for head growth physiology and normal HC values in adults should be reevaluated. OBJECTIVES: The main aim of the present study was to assess HC in a series of 270 normal healthy Spanish adults and to determine any differences between sexes and age groups. A secondary aim was to discuss the relevance of this parameter in the management of hydrocephalus in adult people. METHODS: HC measurements were taken using a measuring tape placed over the greatest frontal and occipital protuberances. The reference interval and the upper and lower thresholds for HC were calculated by 3 different methods: normal distribution, the non-parametrical percentile method, and the "robust method". RESULTS: The results were consistent and showed that Spanish adult men with a HC greater than 60 cm, and Spanish adult women with a HC greater than 58 cm should be considered macrocephalic. Microcephaly should be considered when HC is 53.6 cm in men and 51.3 cm in women. Adult age groups of either sex do not present any statistically significant differences in HC. CONCLUSIONS: HC obtained in Spanish adult people are greater than those reported in the classical Nellhaus graphs in both men and women aged 18. These findings should be considered in the management of hydrocephalus in adults today. PMID- 24070640 TI - A clinical prediction model to estimate the risk for coarctation of the aorta in the presence of a patent ductus arteriosus. AB - BACKGROUND: Diagnosing coarctation of the aorta (CoA) in the presence of a patent ductus arteriosus (PDA) may require observation until PDA closure. The aim of this study was to create a model incorporating previously published indices to estimate the probability of neonatal CoA in the presence of a PDA. METHODS: A retrospective "investigation" cohort of 80 neonates was divided into two groups: (1) neonates with PDA and suspicion for CoA requiring observation to confirm the presence or absence of CoA and (2) neonates with PDA and confirmed diagnosis of either CoA or unobstructed aortic arch. Multivariate logistic regression was used to create the coarctation probability model (CPM), which was used to calculate a neonate's probability of CoA. The CPM was validated internally using bootstrapping and subsequently validated prospectively using a "validation" cohort of 74 neonates with PDA. RESULTS: The CPM had an area under the receiver operating characteristic curve of 0.96 and demonstrated good clinical significance in the risk stratification of neonates with PDA and CoA. No neonate with a CPM probability of <15% had CoA after PDA closure. Neonates with CPM probability < 15% were classified at low risk, between 15% and 60% at moderate risk, and >60% at high risk for CoA. CONCLUSIONS: On the basis of these results, the authors recommend measurement of the CPM in all neonates with PDA. Those with CPM probability < 15% no longer require observation, which could decrease observation in as many as half of neonates with unobstructed aortic arches; those with CPM probabilities between 15% and 60% require follow-up imaging, while those with CPM probabilities > 60% should be observed as inpatients until PDA closure. PMID- 24070641 TI - Barriers and resources to PMTCT of HIV: Luba-Kasai men's perspective in Lusaka, Zambia. AB - The purpose of this study was to describe the views of Luba-Kasai (a Congolese tribe) men on barriers inhibiting them from the prevention of mother-to-child transmission (PMTCT) of HIV and the resources they need to implement such prevention in Lusaka, Zambia. Twenty-one men were interviewed and the data were analyzed using qualitative content analysis. The barriers identified in the data were poverty, refugee status, absence of support arrangements, and the working culture in antenatal care, passivity, ignorance, marital disharmony, HIV-related stigma, and cultural characteristics, such as ways of being a man and religious beliefs. The resources were spiritual outlook on life, knowledge of HIV issues, support and availability of advanced health services, and satisfaction of basic needs. Improving male participation in PMTCT in this subpopulation presupposes cooperation between different sectors of society and inspiring trust in antenatal care. PMID- 24070642 TI - Differences in risk behaviors, care utilization, and comorbidities in homeless persons based on HIV status. AB - This cross-sectional pilot project measured differences by HIV status in chronic health conditions, primary care and emergency department use, and high-risk behaviors of homeless persons through self-report. Using selective random sampling, 244 individuals were recruited from a homeless shelter. The reported HIV prevalence was 6.56% (n = 16), with the odds of HIV higher in persons reporting crack cocaine use. HIV-infected persons were more likely to report a source of regular medical care and less likely to use the emergency department than uninfected persons. Validation of findings through exploration of HIV and health care access in homeless persons is needed to confirm that HIV-infected homeless persons are more likely to have primary care. Distinctions between primary care and specialty HIV care also need to be explored in this context. If findings are consistent, providers who care for the homeless could learn more effective ways to engage homeless patients. PMID- 24070643 TI - Abuse and mental health concerns among HIV-infected Haitian women living in the United States. AB - This study describes the prevalence of abuse and mental health issues among a cohort of HIV-infected Haitian women living in the United States. We present data on 96 women, ages 19-73 years (M = 47.6, SD = 11.1), who were screened for mental health concerns between 2009 and 2012. Results demonstrated that 12.5% of the women reported a history of abuse. However, posttraumatic stress disorder (PTSD) secondary to HIV was reported by approximately 34% of women. Depression and anxiety were also highly reported, with rates of 49% and 43%, respectively. Women who reported a history of abuse were more likely to report anxiety, PTSD, and PTSD related to HIV symptoms than those without. Our findings suggest that Haitian HIV-infected women may underreport abuse and experience significant depression and anxiety. These preliminary results could be used to develop future studies and to design and implement culturally sensitive interventions for this underserved population. PMID- 24070644 TI - Impact of hepatitis C treatment initiation on adherence to concomitant medications. AB - Our study investigated whether initiating hepatitis C virus (HCV) treatment affected adherence to concomitant medications. Mixed-effects linear regression was used to analyze data from 57 patients (29 co-infected with HIV) in a prospective study of HCV treatment-naive patients initiating HCV treatment. Adherence was assessed using structured self-report at the time of treatment initiation, and at 12 weeks and 24 weeks into treatment. There was no change in adherence to concomitant medications over the first 24 weeks of HCV treatment. There was a significant interaction effect such that the change in adherence to concomitant medications between baseline and 12 weeks differed between the HIV infected and HIV-uninfected patients. Adherence to concomitant medications in the HIV-infected patients was found to decrease, whereas adherence in the HIV uninfected patients was found to increase. HIV-infected patients may be more at risk for adherence problems in the first 12 weeks of HCV treatment as compared to HIV-uninfected patients. PMID- 24070645 TI - Cardiovascular risk-factor knowledge and risk perception among HIV-infected adults. AB - Cardiovascular disease (CVD) has emerged as a major cause of morbidity and mortality in HIV-infected adults. Research in noninfected populations has suggested that knowledge of CVD risk factors significantly influences perceptions of risk. This cross-sectional study describes CVD risk factor knowledge and risk perception in HIV-infected adults. We recruited 130 HIV-infected adults (mean age = 48 years, 62% male, 56% current smokers, mean years since HIV diagnosis, 14.7). The mean CVD risk factor knowledge score was fairly high. However, controlling for age, CVD risk factor knowledge was not predictive of perceived risk [F(1, 117) = 0.13, p > .05]. Estimated risk and perceived risk were weakly but significantly correlated; r (126) = .24, p = .01. HIV-infected adults are at increased risk for CVD. Despite having adequate risk-factor knowledge, CVD risk perception was inaccurate. Improving risk perception and developing CVD risk reduction interventions for this population are imperative. PMID- 24070646 TI - A systematic review of the frequency and correlates of partner abuse in HIV infected women and men who partner with men. AB - Partner abuse (PA) is a highly prevalent and devastating social phenomenon, extracting an economic toll of more than $8 billion annually in the United States due to lost productivity alone. Many of the risk factors for PA increase vulnerability to acquiring HIV as well, yet little research has explored these overlapping epidemics. In this systematic review, we examine the frequency of PA victimization from male partners among persons living with HIV-both men who have sex with men (MSM) and women. We located 31 manuscripts reporting data from 24 unique samples, indicating a high lifetime frequency (but large range) of estimates for women/MSM, respectively, for physical (26-62%/15-39%), sexual (22 44%/8-33%), and psychological abuse (55%/22-73%). Data indicate strong and consistent associations of PA with poor mental health, engagement in health risk behaviors, and nonadherence to HIV medication for both groups. We discuss implications for clinical practice as well as future research directions. PMID- 24070647 TI - Sexual sensation seeking, transactional sex, and rural African American cocaine users. AB - The purpose of this study was to explore correlates of sexual sensation seeking (SSS) in a sample of rural African American cocaine users. Respondent-driven sampling was used to recruit 251 participants from two impoverished rural counties in eastern Arkansas. Consistent with previous investigations, SSS scores were associated with being younger, being male, having more sexual partners, and having more unprotected sexual encounters in the previous 30 days. Multiple regression revealed that SSS was correlated with a number of oral sex acts, transactional sex (exchanging sex for food, shelter, drugs, money, or other commodities), and Addiction Severity Index drug composite. SSS continues to demonstrate a strong association with sexual risk behaviors in diverse populations, including vulnerable groups like this community. Interventions to reduce unsafe sexual behaviors among high-risk groups, including drug users and individuals who engage in transactional sex, should incorporate approaches that include high sensation seekers' needs for novelty and variety. PMID- 24070648 TI - Synthesis, spectroscopic, coordination and biological activities of some organometallic complexes derived from thio-Schiff base ligands. AB - Two series of mono- and binuclear complexes cyclic or acyclic thio-ferocine Schiff base ligands, derived from the condensation of 2-aminobenzenthiol (L) with monoacetyl ferrocene in the molar ratio 1:1 or in the molar ratio 1:2 for diacetyl ferocine have been prepared. The condensation reactions yield the corresponding Schiff Base ligands, HLa-Maf and H2Lb-Daf. The chelation of the ligands to metal ions occurs through the sulfur of the thiol group as well as the nitrogen atoms of the azomethine group of the ligands. HLa-Maf acts as monobasic bidentate or dibasic tetradentate, while H2Lb-Daf behaves as twice negatively cargend tetradentate ligand. The structures of these ligands were elucidated by elemental analysis, infrared, ultraviolet-visible spectra, as well as (1)H NMR spectra. Reactions of the Schiff bases ligands with ruthenium(III), oxovanadium(IV) and dioxouranium(VI) afforded the corresponding transition metal complexes. The properties of the newly prepared complexes were analyse by elemental analyses, infrared, electronic spectra, (1)H NMR as well as the magnetic susceptibility and conductivity measurement. The metal complexes exhibits different geometrical arrangements such as octahedral and square pyramidal coordination. Schiff base ligands and their metal complexes were tested against two pathogenic bacteria as Gram-positive and Gram-negative bacteria as well as one kind of fungi to study their biological activity. All the complexes exhibit antibacterial and antifungal activities against these organisms. PMID- 24070649 TI - Average orientation of water in CH2F2?H2O from the (17)O quadrupole effects in the rotational spectrum of CH2F2?H2(17)O. AB - The rotational spectrum of the CH2F2?H2(17)O adduct has been measured in the 6.5 18.5 GHz range using a pulsed jet Fourier-transform microwave spectrometer. The experimental values of the (17)O quadrupole coupling constants have been determined to be chiaa=-3.853(6), chibb=-3.259(1) and chicc=7.112(9) MHz, respectively. These data correspond to an average value of the angle between the water plane and the FCF plane of about 23 degrees . PMID- 24070650 TI - Determination of the tautomeric equilibria of pyridoyl benzoyl beta-diketones in the liquid and solid state through the use of deuterium isotope effects on (1)H and (13)C NMR chemical shifts and spin coupling constants. AB - The tautomeric equilibria for 2-pyridoyl-, 3-pyridoyl-, and 4-pyridoyl-benzoyl methane have been investigated using deuterium isotope effects on (1)H and (13)C chemical shifts both in the liquid and the solid state. Equilibria are established both in the liquid and the solid state. In addition, in the solution state the 2-bond and 3-bond J((1)H-(13)C) coupling constants have been used to confirm the equilibrium positions. The isotope effects due to deuteriation at the OH position are shown to be superior to chemical shift in determination of equilibrium positions of these almost symmetrical -pyridoyl-benzoyl methanes. The assignments of the NMR spectra are supported by calculations of the chemical shifts at the DFT level. The equilibrium positions are shown to be different in the liquid and the solid state. In the liquid state the 4-pyridoyl derivative is at the B-form (C-1 is OH), whereas the 2-and 3-pyridoyl derivatives are in the A form. In the solid state all three compounds are on the B-form. The 4-pyridoyl derivative shows unusual deuterium isotope effects in the solid, which are ascribed to a change of the crystal structure of the deuteriated compound. PMID- 24070651 TI - Optimization of co-digestion of various industrial sludges for biogas production and sludge treatment: methane production potential experiments and modeling. AB - Optimal biogas production and sludge treatment were studied by co-digestion experiments and modeling using five different wastewater sludges generated from paper, chemical, petrochemical, automobile, and food processing industries situated in Ulsan Industrial Complex, Ulsan, South Korea. The biomethane production potential test was conducted in simplex-centroid mixture design, fitted to regression equation, and some optimal co-digestion scenarios were given by combined desirability function based multi-objective optimization technique for both methane yield and the quantity of sludge digested. The co-digestion model incorporating main and interaction effects among sludges were utilized to predict the maximum possible methane yield. The optimization routine for methane production with different industrial sludges in batches were repeated with the left-over sludge of earlier cycle, till all sludges have been completely treated. Among the possible scenarios, a maximum methane yield of 1161.53 m(3) is anticipated in three batches followed by 1130.33 m(3) and 1045.65 m(3) in five and two batches, respectively. This study shows a scientific approach to find a practical solution to utilize diverse industrial sludges in both treatment and biogas production perspectives. PMID- 24070653 TI - Polypurine reverse Hoogsteen hairpins as a gene therapy tool against survivin in human prostate cancer PC3 cells in vitro and in vivo. AB - As a new approach for gene therapy, we recently developed a new type of molecule called polypurine reverse Hoogsteen hairpins (PPRHs). We decided to explore the in vitro and in vivo effect of PPRHs in cancer choosing survivin as a target since it is involved in apoptosis, mitosis and angiogenesis, and overexpressed in different tumors. We designed four PPRHs against the survivin gene, one of them directed against the template strand and three against different regions of the coding strand. These PPRHs were tested in PC3 prostate cancer cells in an in vitro screening of cell viability and apoptosis. PPRHs against the promoter sequence were the most effective and caused a decrease in survivin mRNA and protein levels. We confirmed the binding between the selected PPRHs and their target sequences in the survivin gene. In addition we determined that both the template- and the coding-PPRH targeting the survivin promoter were interfering with the binding of transcription factors Sp1 and GATA-3, respectively. Finally, we conducted two in vivo efficacy assays using the Coding-PPRH against the survivin promoter and performing two routes of administration, namely intratumoral and intravenous, in a subcutaneous xenograft tumor model of PC3 prostate cancer cells. The results showed that the chosen Coding-PPRH proved to be effective in decreasing tumor volume, and reduced the levels of survivin protein and the formation of blood vessels. These findings represent the preclinical proof of principle of PPRHs as a new silencing tool for cancer gene therapy. PMID- 24070652 TI - Methylation of the DPH1 promoter causes immunotoxin resistance in acute lymphoblastic leukemia cell line KOPN-8. AB - Moxetumomab pasudotox (HA22) is an immunotoxin with an anti-CD22 Fv fused to a portion of Pseudomonas exotoxin A that kills CD22 expressing ALL cells. HA22 produced significant responses in some cases of ALL. To understand how to increase response rate, we isolated HA22-resistant KOPN-8 cells and found that HA22 cannot inactivate elongation factor-2 (EF2) due to low levels of DPH1 RNA and protein. Resistance was associated with methylation of the CpG island in the DPH1 promoter. 5-Azacytidine prevented resistance and methylation of the CpG residues and merits evaluation to determine if it can increase the efficacy of HA22 in ALL. PMID- 24070654 TI - Dancing with chemical formulae of antivirals: A panoramic view (Part 2). AB - In this second part of "Dancing with antivirals as chemical formulae" I will focus on a number of chemical compounds that in the last few years have elicited more than common attraction from a commercial viewpoint: (i) favipiravir (T-705), as it is active against influenza, but also several other RNA viruses; (ii) neuraminidase inhibitors such as zanamivir and oseltamivir; (iii) peramivir and laninamivir octanoate, which might be effective against influenza virus following a single (intravenous or inhalation) administration; (iv) sofosbuvir, the (anticipated) cornerstone for the interferon-free therapy of HCV infections; (v) combinations of DAAs (direct antiviral agents) to achieve, in no time, a sustained virus response (SVR) against HCV infection; (vi) HIV protease inhibitors, the latest and most promising being darunavir; (vii) the integrase inhibitors (INIs) (raltegravir, elvitegravir, dolutegravir), representing a new dimension in the anti-HIV armamentarium; (viii), a new class of helicase primase inhibitors (HPIs) that may exceed acyclovir and the other anti-herpes compounds in both potency and safety; (ix) CMX-001, as the latest of Dr. Antonin Holy's legacy for its activity against poxviruses and CMV infections, and (x) noroviruses for which the ideal antiviral compounds are still awaited for. PMID- 24070655 TI - The role of mutant protein level in autosomal recessive catecholamine dependent polymorphic ventricular tachycardia (CPVT2). AB - Humans and genetically engineered mice with recessively inherited CPVT develop arrhythmia which may arise due to malfunction or degradation of calsequestrin (CASQ2). We investigated the relation between protein level and arrhythmia severity in CASQ2(D307H/D307H) (D307H), compared to CASQ2(Delta/Delta) (KO) and wild type (WT) mice. CASQ2 expression and Ca2+ transients were recorded in cardiomyocytes from neonatal or adult mice. Arrhythmia was studied in vivo using heart rhythm telemetry at rest, exercise and after epinephrine injection. CASQ2 protein was absent in KO heart. Neonatal D307H and WT hearts expressed significantly less CASQ2 protein than the level found in the adult WT. Adult D307H expressed only 20% of CASQ2 protein found in WT. Spontaneous Ca2+ release was more prevalent in neonatal KO cardiomyocytes (89%) compared to 33-36% of either WT or D307H, respectively, p<0.001. Adult cardiomyocytes from both mutant mice had more Ca2+ abnormalities compared to control (KO: 82%, D307H 63%, WT 12%, p<0.01). Calcium oscillations were most common in KO cardiomyocytes. We then treated mice with bortezomib to inhibit CASQ2(D307H) degradation. Bortezomib increased CASQ2 expression in D307H hearts by ~50% (p<0.05). Bortezomib-treated D307H mice had lower CPVT prevalence and less premature ventricular beats during peak exercise. No benefit against arrhythmia was observed in bortezomib treated KO mice. These results indicate that the mutant CASQ2(D307H) protein retains some of its physiological function. Its expression decreases with age and is inversely related to arrhythmia severity. Preventing the degradation of mutant protein should be explored as a possible therapeutic strategy in appropriate CPVT2 patients. PMID- 24070656 TI - The fall and rise of pharmacology--(re-)defining the discipline? AB - Pharmacology is an integrative discipline that originated from activities, now nearly 7000 years old, to identify therapeutics from natural product sources. Research in the 19th Century that focused on the Law of Mass Action (LMA) demonstrated that compound effects were dose-/concentration-dependent eventually leading to the receptor concept, now a century old, that remains the key to understanding disease causality and drug action. As pharmacology evolved in the 20th Century through successive biochemical, molecular and genomic eras, the precision in understanding receptor function at the molecular level increased and while providing important insights, led to an overtly reductionistic emphasis. This resulted in the generation of data lacking physiological context that ignored the LMA and was not integrated at the tissue/whole organism level. As reductionism became a primary focus in biomedical research, it led to the fall of pharmacology. However, concerns regarding the disconnect between basic research efforts and the approval of new drugs to treat 21st Century disease tsunamis, e.g., neurodegeneration, metabolic syndrome, etc. has led to the reemergence of pharmacology, its rise, often in the semantic guise of systems biology. Against a background of limited training in pharmacology, this has resulted in issues in experimental replication with a bioinformatics emphasis that often has a limited relationship to reality. The integration of newer technologies within a pharmacological context where research is driven by testable hypotheses rather than technology, together with renewed efforts in teaching pharmacology, is anticipated to improve the focus and relevance of biomedical research and lead to novel therapeutics that will contain health care costs. PMID- 24070657 TI - The molecular and electrophysiological mechanism of buyanghuanwu decoction in learning and memory ability of vascular dementia rats. AB - Buyanghuanwu Decoction (BYHWD), as a traditional Chinese medicine, has been developed to treat vascular dementia for hundreds of years, but the underlying mechanisms remain unknown. In this research, the protective effects of BYHWD on hippocampal neuron were examined in the rats of ischemia-reperfusion. Ischemia reperfusion injury was induced by the four-vessel occlusion method and continued for 30 days. BYHWD (per 6.25g/kg/d) was orally given to rats twice each day for 30 days after ischemia-reperfusion, Nimodipine (per 10mg/kg/d) was orally given to rats twice each day for 30 days. In VD+BYHWD group rats, the neuronal injury in the hippocampal CA1 region was significantly less than that of VD group's. BYHWD of intragastric administration also markedly increased the expression of Extracellular signal-regulated kinase 2 (ERK2) and Calcium/calmodulin-dependent protein kinaseII (CaMKIIIy)in the CA1 region. Our results suggested that increased ERK2 and CaMKIIIy due to BYHWD may partially account for its effect of neuroprotection standing against ischemic injury in the hippocampal CA1 region, and participated in the rebuilding of synapse, strengthened the expression of LTP, promoted the ability recover of learning and memory in VD rats. PMID- 24070659 TI - On carts and horses: professionalism and the crisis in assessment of graduate medical education. PMID- 24070658 TI - Clinician gestalt estimate of pretest probability for acute coronary syndrome and pulmonary embolism in patients with chest pain and dyspnea. AB - STUDY OBJECTIVE: Pretest probability helps guide diagnostic testing for patients with suspected acute coronary syndrome and pulmonary embolism. Pretest probability derived from the clinician's unstructured gestalt estimate is easier and more readily available than methods that require computation. We compare the diagnostic accuracy of physician gestalt estimate for the pretest probability of acute coronary syndrome and pulmonary embolism with a validated, computerized method. METHODS: This was a secondary analysis of a prospectively collected, multicenter study. Patients (N=840) had chest pain, dyspnea, nondiagnostic ECGs, and no obvious diagnosis. Clinician gestalt pretest probability for both acute coronary syndrome and pulmonary embolism was assessed by visual analog scale and from the method of attribute matching using a Web-based computer program. Patients were followed for outcomes at 90 days. RESULTS: Clinicians had significantly higher estimates than attribute matching for both acute coronary syndrome (17% versus 4%; P<.001, paired t test) and pulmonary embolism (12% versus 6%; P<.001). The 2 methods had poor correlation for both acute coronary syndrome (r(2)=0.15) and pulmonary embolism (r(2)=0.06). Areas under the receiver operating characteristic curve were lower for clinician estimate compared with the computerized method for acute coronary syndrome: 0.64 (95% confidence interval [CI] 0.51 to 0.77) for clinician gestalt versus 0.78 (95% CI 0.71 to 0.85) for attribute matching. For pulmonary embolism, these values were 0.81 (95% CI 0.79 to 0.92) for clinician gestalt and 0.84 (95% CI 0.76 to 0.93) for attribute matching. CONCLUSION: Compared with a validated machine-based method, clinicians consistently overestimated pretest probability but on receiver operating curve analysis were as accurate for pulmonary embolism but not acute coronary syndrome. PMID- 24070660 TI - Neuropsychiatric conditions associated with anesthesia exposure. AB - BACKGROUND: Although anesthetics have been used for more than a century, their mechanisms of action remain poorly understood. Given that a number of intraoperative and postoperative neuropsychiatric syndromes have been linked to the use of anesthetics, practitioners should familiarize themselves with these conditions. METHODS: Basic concepts about anesthesia are reviewed and neuropsychiatric syndromes associated with anesthesia exposure described. CONCLUSIONS: Emergence delirium, postoperative delirium, postoperative cognitive dysfunction, and intraoperative awareness can develop in association with use of inhalation anesthetics and intravenously administered anesthetics. PMID- 24070661 TI - Lymphopenia helps early diagnosis of systemic lupus erythematosus for patients with psychosis as an initial symptom. PMID- 24070662 TI - Quality of life after thyroid surgery in women with benign euthyroid goiter: influencing factors including Hashimoto's thyroiditis. AB - BACKGROUND: Hashimoto's thyroiditis is associated with decreased quality of life (QoL). Thyroid surgery could hypothetically lead to an increase in QoL. METHODS: In a follow-up analysis of a prospective cohort study that included euthyroid women undergoing thyroid surgery for benign thyroid disease, 248 patients were willing to answer the SF-36 QoL questionnaire. RESULTS: At follow-up after a median of 26 months, only the SF-36 module of "bodily pain" had increased (P = .046). Preoperative anti-thyroid peroxidase antibody levels were positively correlated with increasing QoL in the SF-36 modules "bodily pain" (P < .001) and "role emotional" (P < .001). For the presence of histologically confirmed Hashimoto's thyroiditis, a significant positive correlation (P < .001) was found for all modules apart from "physical functioning." CONCLUSIONS: In women with benign euthyroid goiter, thyroid surgery does not lead to an overall improvement in health-related QoL. It should not be recommended for patients with elevated anti-thyroid peroxidase antibody levels. Patients with histologically confirmed Hashimoto's thyroiditis might benefit in terms of QoL. PMID- 24070663 TI - Determination of independent predictive factors for anastomotic leak: analysis of 682 intestinal anastomoses. AB - BACKGROUND: The objective of this study was to identify risk factors associated with intestinal anastomotic leakage in order to practically assist in surgical decision making. METHODS: A retrospective review of an academic surgery database was performed over 5 years to identify patients who had intestinal (small bowel and colon) anastomoses to determine independent predictors of anastomotic leakage. RESULTS: Over the study period, 682 patients were identified with intestinal anastomoses; the overall leak rate was 5.6% (38/682). In bivariate analysis, 9 factors were associated with anastomotic leaks. Of these, 3 were found to be independent predictors of anastomotic leakage using a logistic regression model: anastomotic tension (odds ratio [OR] = 10.1, 95% Confidence Interval [CI] 1.3 to 76.9), use of drains (OR = 8.9, 95% CI 4.3 to 18.4), and perioperative blood transfusion (OR = 4.2, 95% CI 1.4 to 12.3). CONCLUSIONS: The recognition of factors associated with anastomotic leakage after intestinal operations can assist surgeons in mitigating these risks in the perioperative period and guide intraoperative decisions. PMID- 24070664 TI - Weight-based enoxaparin dosing for venous thromboembolism prophylaxis in the obese trauma patient. AB - BACKGROUND: Limited data exist regarding the efficacy of weight-based dosing of low-molecular weight heparin for venous thromboembolism (VTE) prophylaxis in obese trauma patients. METHODS: Consecutive obese trauma patients were placed on a weight-based protocol for VTE prophylaxis (enoxaparin .5 mg/kg subcutaneously every 12 hours). Peak anti-Xa levels were drawn, and bilateral lower extremity duplex ultrasound was performed. The incidence of VTE and bleeding complications were recorded. RESULTS: Eighty-six patients met the study criteria. Seventy-four patients achieved target prophylactic anti-Xa concentrations, with a mean level of .42 +/- .01 IU/mL. Eighteen patients were found to have deep vein thrombosis. However, in 16 of these patients, deep vein thrombosis was diagnosed before weight-based low-molecular weight heparin initiation. No bleeding complications occurred, and no symptomatic pulmonary emboli were identified. CONCLUSIONS: In obese trauma patients, weight-based enoxaparin is an efficacious regimen that provides adequate VTE prophylaxis, as measured by anti-Xa levels, and appears to be safe without bleeding complications. PMID- 24070665 TI - The role of endoscopic biliary sphincterotomy for the treatment of type 1 biliary dysfunction (papillary stenosis) with or without biliary stones. AB - BACKGROUND: This study assesses the safety and effectiveness of endoscopic biliary sphincterotomy (ES) in the treatment of papillary stenosis (PS) with and without biliary stones. METHODS: The records of all patients who had endoscopic retrograde cholangiopancreatography (2,689 patients) from January 1, 1991, to August 1, 2010, were reviewed. There were 117 patients with PS who had ES. RESULTS: All patients had biliary pain, a dilated common bile duct (CBD) with a maximum diameter of 10 to 25 mm, and elevated liver function tests. There were 46 patients who had prior cholecystectomy of whom 20 patients had CBD stones. The remaining 71 patients had no prior biliary surgery; there were no biliary stones in 14 patients. All patients were symptom free after ES with or without CBD stone retrieval. CONCLUSIONS: ES is the optimal treatment for PS in patients with or without biliary stones. ES eliminates pain, corrects CBD dilation, and restores LFTs to normal. PMID- 24070666 TI - Unshuntable extrahepatic portal hypertension revisited: 43 years' experience with radical esophagogastrectomy treatment of bleeding esophagogastric varices. AB - BACKGROUND: In 1994, the authors reported their experience with radical esophagogastrectomy for bleeding esophagogastric varices due to unshuntable extra hepatic portal hypertension. Since then, the series has expanded from 22 to 44 patients. The aim of this study was to assess the validity of the previous observations and conclusions in the largest series with the longest follow-up. METHODS: From 1968 to 2005, 44 patients with unshuntable extra-hepatic portal hypertension were treated by total gastrectomy and resection of the distal two thirds of the esophagus. Before referral, the patients experienced 4 to 24 episodes of variceal bleeding requiring a mean 130 U of blood transfusion, 15 hospital admissions, and 6 previous unsuccessful operations. RESULTS: Transient postoperative complications occurred in 50% of patients. The survival rate is 100%, with no recurrence of variceal bleeding during 7 to 43 years of follow-up. Liver function and biopsy results have been normal. Quality of life has been excellent or good in 91%. Eighty-six percent have resumed employment or full-time housekeeping. CONCLUSIONS: In unshuntable extra-hepatic portal hypertension, radical esophagogastrectomy is the only consistently effective treatment of variceal hemorrhage. Prompt use of this lifesaving procedure is warranted. PMID- 24070667 TI - Effect of alcohol on surgical dexterity after a night of moderate alcohol intake. AB - BACKGROUND: Alcohol misuse is commonplace among health professionals. The effects of alcohol on cognition and dexterity have been shown up to 14 hours after alcohol intake. The aerospace industry has restrictions on alcohol intake, and there is pressure for the health care industry to do the same. Few studies have addressed the lingering impact alcohol has on surgical performance, and none have measured surgical dexterity using well-established Fundamentals of Laparoscopic Surgery benchmarks. METHODS: Twenty-seven surgeons participated in this study: 11 attending surgeons, 2 fellows, and 14 resident surgeons. Three Fundamentals of Laparoscopic Surgery tasks measured surgical dexterity: peg transfer, pattern cutting, and intracorporeal suturing. Performance on these tasks was measured before alcohol intake and the morning after a night of social drinking. Alcohol levels were measured via breathalyzer 20 minutes after completion of drinking and the following morning before testing. Time and accuracy were compared. RESULTS: The mean blood alcohol level was .076 mg/100 mL blood. Times for peg transfer, pattern cutting, and intracorporeal suturing showed no differences. Accuracy in pattern cutting was not different, but accuracy for intracorporeal suturing was significantly worse the morning after alcohol intake. CONCLUSIONS: The morning after moderate alcohol intake, the time to complete Fundamentals of Laparoscopic Surgery tasks was unchanged, but accuracy was worse. PMID- 24070668 TI - Text mining for systems biology. AB - Scientific communication in biomedicine is, by and large, still text based. Text mining technologies for the automated extraction of useful biomedical information from unstructured text that can be directly used for systems biology modelling have been substantially improved over the past few years. In this review, we underline the importance of named entity recognition and relationship extraction as fundamental approaches that are relevant to systems biology. Furthermore, we emphasize the role of publicly organized scientific benchmarking challenges that reflect the current status of text-mining technology and are important in moving the entire field forward. Given further interdisciplinary development of systems biology-orientated ontologies and training corpora, we expect a steadily increasing impact of text-mining technology on systems biology in the future. PMID- 24070669 TI - Electrokinetic behavior of a pH-regulated, zwitterionic nanocylinder in a cylindrical nanopore filled with multiple ionic species. AB - Recent advances in fabrication techniques make nano-sized pores as promising platforms for both detection and sequencing of individual biopolymers such as DNA. To simulate the electrokinetic behavior of a particle in this case, we consider the electrophoresis of a soft nanocylinder comprising a rigid core and a pH-regulated, zwitterionic polyelectrolyte layer along the axis of a rigid cylindrical nanopore. Extending the conventional electrophoresis analysis, where the liquid phase contains only one kind each of cations and anions, we assume that it contains multiple ionic species, as is usually the case in practice. The key parameters are examined for their influences on the electrokinetic behavior of a particle. These include pH, the thickness of the polyelectrolyte layer and the density of its functional groups, and the pore size. The results gathered provide necessary information for the design of an electrokinetic apparatus. PMID- 24070670 TI - Automatic transfer function design for medical visualization using visibility distributions and projective color mapping. AB - Transfer functions play a key role in volume rendering of medical data, but transfer function manipulation is unintuitive and can be time-consuming; achieving an optimal visualization of patient anatomy or pathology is difficult. To overcome this problem, we present a system for automatic transfer function design based on visibility distribution and projective color mapping. Instead of assigning opacity directly based on voxel intensity and gradient magnitude, the opacity transfer function is automatically derived by matching the observed visibility distribution to a target visibility distribution. An automatic color assignment scheme based on projective mapping is proposed to assign colors that allow for the visual discrimination of different structures, while also reflecting the degree of similarity between them. When our method was tested on several medical volumetric datasets, the key structures within the volume were clearly visualized with minimal user intervention. PMID- 24070671 TI - Micro-CT image reconstruction based on alternating direction augmented Lagrangian method and total variation. AB - Micro-computed tomography (micro-CT) plays an important role in pre-clinical imaging. The radiation from micro-CT can result in excess radiation exposure to the specimen under test, hence the reduction of radiation from micro-CT is essential. The proposed research focused on analyzing and testing an alternating direction augmented Lagrangian (ADAL) algorithm to recover images from random projections using total variation (TV) regularization. The use of TV regularization in compressed sensing problems makes the recovered image quality sharper by preserving the edges or boundaries more accurately. In this work TV regularization problem is addressed by ADAL which is a variant of the classic augmented Lagrangian method for structured optimization. The per-iteration computational complexity of the algorithm is two fast Fourier transforms, two matrix vector multiplications and a linear time shrinkage operation. Comparison of experimental results indicate that the proposed algorithm is stable, efficient and competitive with the existing algorithms for solving TV regularization problems. PMID- 24070672 TI - 3D assessment of stent cell size and side branch access in intravascular optical coherence tomographic pullback runs. AB - We present a semi-automatic approach to assess the maximum circular unsupported surface area (MCUSA) of selected stent cells and the side branch access through stent cells in intravascular optical coherence tomography (IVOCT) pullback runs. Such 3D information may influence coronary interventions, stent design, blood flow analysis or prognostic evaluation. First, the stent struts are detected automatically and stent cells are reconstructed with users' assistance. Using cylinder fitting, a 2D approximation of the stent cell is generated for MCUSA detection and measurement. Next, a stent surface is reconstructed and stent covered side branches are detected. Both the stent cell contours and side branch lumen contours are projected onto the stent surface to indicate their areas, and the overlapping regions are measured as the side branch access through these stent cells. The method was evaluated on phantom data sets and the accuracy of the MCUSA and side branch access was found to be 95% and 91%, respectively. The usability of this approach for clinical research was proved on 12 in vivo IVOCT pullback runs. PMID- 24070673 TI - Age-related decrease in sensitivity to electrical stimulation is unrelated to skin conductance: an evoked potentials study. AB - OBJECTIVE: With aging, skin is likely to become less hydrated, thereby increasing its resistance to electrical current. This, rather than sensorial/perceptual differences per se, may be the primary cause of differences between younger and older adults in somatosensorial perception in response to electrical stimuli. METHODS: To assess whether aging alters the perception of electrical stimulation, we compared the perceived intensity of electrical stimuli in younger and older subjects, considering both setpoint intensities and the actual intensities of the current passing through subjects' skin. This resulted in reliable information about electrical somatosensory perception in both groups at equivalent received amounts of current. Somatosensory evoked potentials (SEPs) enabled the objective evaluation of somatosensitivity in both groups. RESULTS: At equivalent received intensities, the mean ratings were significantly lower in older than in younger subjects. SEPs confirmed these results, with older adults having longer latencies and reduced amplitudes. CONCLUSIONS: Our results suggest that age-related decreases in somatosensitivity to electrical stimuli are not due to cutaneous physiological changes. SIGNIFICANCE: Age-related increases in electrical somatosensorial and pain thresholds seem to be more attributable to dysfunctions of the peripheral and/or central nervous system, than to non-optimal activation of somatosensorial receptors/nerve fibers due to cutaneous physiological changes. PMID- 24070674 TI - Nerve ultrasound score in distinguishing chronic from acute inflammatory demyelinating polyneuropathy. AB - OBJECTIVE: Aim of this study was to develop and evaluate the applicability of an ultrasound score (Bochum ultrasound score - BUS) in distinguishing chronic (CIDP) from acute inflammatory demyelinating polyneuropathy (AIDP). METHODS: Step 1: For the development of BUS 75 healthy-controls, 20 CIDP, 20 AIDP patients underwent US 4.55 +/- 3.5 and 3.4 +/- 2.91 years, respectively after onset. After comparing the distribution pattern and frequency of pathological US changes between the two study groups, we developed BUS, summarizing the cross sectional area (CSA) of: (1) the ulnar nerve in Guyons' canal, (2) the ulnar nerve in upper-arm, (3) the radial nerve in spiral groove, (4) the sural nerve between the gastrocnemius muscle. Step 2: The BUS underwent blinded evaluation in further 10 CIDP, 21 AIDP patients 3.8 +/- 2.7 and 2.3 +/- 1.5 years, respectively after onset. Step 3: The BUS underwent blinded, prospective evaluation in 8 patients with acute/subacute polyradiculoneuropathy (5 CIDP, 3 AIDP) 2.6 +/- 1.8 weeks after onset. RESULTS: The BUS showed a sensitivity of 90% and specificity of 90.4% (positive predictive value, PPV=81.8%; negative predictive value, NPV=95%) in distinguishing CIDP from AIDP, when they showed no differences in disease duration (p=0.0551).In addition, the BUS distinguished subacute-CIDP from AIDP with a sensitivity of 80%, specificity of 100% (PPV=100%, NPV=75%). CONCLUSION: The BUS seems to allow a reliable distinction of CIDP from AIDP. SIGNIFICANCE: The BUS may be helpful in distinguishing subacute-CIDP from AIDP. PMID- 24070675 TI - Fibular nerve neurotmesis secondary to knee trauma: a diagnosis requiring nerve ultrasound. PMID- 24070676 TI - Enhanced accumulation of Kir4.1 protein, but not mRNA, in a murine model of cuprizone-induced demyelination. AB - Two channel proteins, inwardly rectifying potassium channel 4.1 (Kir4.1) and water channel aquaporin-4 (AQP4), were recently identified as targets of an autoantibody response in patients with multiple sclerosis and neuromyelitis optica, respectively. In the present study, we examined the expression patterns of Kir4.1 and AQP4 in a mouse model of demyelination induced by cuprizone, a copper chelator. Demyelination was confirmed by immunohistochemistry using an anti-proteolipid protein antibody in various brain regions, including the corpus callosum, of cuprizone-fed mice. Activation of microglial and astroglial cells was also confirmed by immunohistochemistry, using an anti-ionized calcium binding adapter molecule and a glial fibrillary acidic protein antibody. Western blot analysis revealed the induction of Kir4.1 protein, but not AQP4, in the cortex of cuprizone-fed mice. Immunohistochemical analysis confirmed the Kir4.1 protein induction in microvessels of the cerebral cortex. Real-time polymerase chain reaction analysis revealed that mRNA levels of Kir4.1 and AQP4 in the cortex did not change during cuprizone administration. These findings suggest that enhanced accumulation of Kir4.1 protein in the brain with an inflammatory condition facilitates the autoantibody formation against Kir4.1 in patients with multiple sclerosis. PMID- 24070677 TI - The internalization and lysosomal degradation of brain AQP4 after ischemic injury. AB - The membrane-bound water channel aquaporin-4 (AQP4) plays a significant role in maintaining brain water homeostasis. In ischemic brain, changes in the expression level of AQP4 have been reported. Previous studies suggest that the internalization of several membrane-bound proteins, including AQP4, may occur with or without lysosomal degradation. In this study, the internalization of AQP4 was detected in the ischemic rat brain via double immunofluorescence labeling. Specifically, AQP4 and early endosome antigen-1 (EEA1) co-localized after 1 h post-ischemic injury. Moreover, the co-expression of AQP4 and lysosomal associated membrane protein-1 (LAMP1) was observed after 3 h post-ischemia. These findings suggest that AQP4 is internalized and the lysosome is involved in degrading the internalized AQP4 in the ischemic brain. AQP4 is known to be downregulated by the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) in vivo and in vitro. The results in this study displayed that PMA infusion could decrease brain edema accompanied by AQP4 downregulation in ischemic brain. However, compared with vehicle infusion, PKC activator infusion did not increase the ratio of internalized or lysosomal degraded AQP4. That is, we have not found out evidence to prove protein kinase C activator PMA can promote the internalization or lysosomal degradation of AQP4 in the ischemic brain. PMID- 24070678 TI - Introduction: Seizures in the small animal patient. PMID- 24070679 TI - Terminology and classification of seizures and epilepsy in veterinary patients. AB - The classification of epileptic seizures and epilepsy is a controversial and dynamic topic that has undergone many iterations in human medicine. The International League against Epilepsy is a multinational organization that has formed a number of task forces and subcommittees to study this issue, and has ratified several reports outlining recommended terminology and classification schemes for human patients. Veterinary publications on this issue have generally adapted these schemes to fit small animal patients, but a formally endorsed system to classify seizures and epilepsy has never been developed for veterinary patients. This review outlines the classification systems that have been published for human patients and summarizes previous efforts by veterinary authors to utilize these methods. Finally, a set of definitions and terminology for use in veterinary patients is proposed, which includes a glossary of descriptive terminology for ictal semiology and a diagnostic scheme for classification of individual patients. This document is intended as a starting point of discussion, which will hopefully eventually result in a formally ratified document that will be useful for communication between health professionals, the design of clinical trials and for guiding treatment decisions and prognostication for veterinary patients with seizures. PMID- 24070680 TI - Epileptogenesis and companion animals. AB - Epileptogenesis is the process by which a normal brain develops into an epileptic brain. There are 3 distinct phases of epileptogenesis-the latent period before seizures occur, the occurrence of recurrent seizures, and in about 30% of patients, the development of refractory epilepsy. Understanding the basic epileptic circuit abnormalities associated with recurrent seizures via aberrations in glutamate, gamma-aminobutyric acid, and ligand- and voltage-gated ion channel activity can help the small-animal practitioner understand the mechanism of action of the antiepileptic drugs currently used for dogs and cats for new-onset and refractory epilepsy. Understanding the latest research results and theories about the pathophysiology of the latent period of epileptogenesis, where recurrent seizures have not yet developed, would help the practitioner understand possible target areas for future treatments to treat epilepsy by preventing it rather than just symptomatically preventing recurrent seizures. The current areas of focus of research on the latent period include neurodegeneration, neurogenesis, axonal sprouting, glial cell activation, invasion of inflammatory cells, angiogenesis, and subclinical alteration of ligand- and receptor-gated ion channels. PMID- 24070681 TI - A clinical and diagnostic approach to the patient with seizures. AB - Seizures are one of the most common neurologic problems encountered by the small animal practitioner. Successful management of the patient with seizure is facilitated by an appropriate diagnostic workup to identify underlying causes when they exist. Veterinary patients with seizures can be divided in to 3 main categories based on underlying cause: those with primary epilepsy, those with structural epilepsy, and those with reactive seizures. Additionally, some patients may be given a label of unknown epilepsy when they do not meet the criteria for a diagnosis of primary epilepsy, but no structural or reactive cause of seizures can be identified. This article reviews the key clinical findings associated with each of the 3 main categories of seizures and suggests a standardized approach to the diagnostic workup for patients with seizure based on their signalment and neurologic examination findings. PMID- 24070682 TI - Inherited epilepsy in dogs. AB - Epilepsy is the most common neurologic disease in dogs and many forms are considered to have a genetic basis. In contrast, some seizure disorders are also heritable, but are not technically defined as epilepsy. Investigation of true canine epilepsies has uncovered genetic associations in some cases, however, many remain unexplained. Gene mutations have been described for 2 forms of canine epilepsy: primary epilepsy (PE) and progressive myoclonic epilepsies. To date, 9 genes have been described to underlie progressive myoclonic epilepsies in several dog breeds. Investigations into genetic PE have been less successful, with only 1 causative gene described. Genetic testing as an aid to diagnosis, prognosis, and breeding decisions is available for these 10 forms. Additional studies utilizing genome-wide tools have identified PE loci of interest; however, specific genetic tests are not yet developed. Many studies of dog breeds with PE have failed to identify genes or loci of interest, suggesting that, similar to what is seen in many human genetic epilepsies, inheritance is likely complex, involving several or many genes, and reflective of environmental interactions. An individual dog's response to therapeutic intervention for epilepsy may also be genetically complex. Although the field of inherited epilepsy has faced challenges, particularly with PE, newer technologies contribute to further advances. PMID- 24070683 TI - Antiepileptic drug therapy and monitoring. AB - Over the past 2 decades, the number of antiepileptic drugs (AEDs) available to veterinarians has grown exponentially. Coupled with this increase is the ability to rapidly and accurately diagnose underlying brain disease with readily accessible magnetic resonance imaging. As a result, the veterinary community is attuned to the need for early treatment intervention. As more treatment choices become available, the unrelenting questions still arise are when should treatment begin, which initial drug therapy is best for our patients, when should treatment changes be considered, and finally, what are the advantages that newer drugs provide for our patients. The purpose of this chapter is to review decision making strategies for AED therapy, provide an overview of the applicability of current AED available, and present information on the therapeutic advances in epilepsy. PMID- 24070684 TI - Management of refractory epilepsy. AB - The term refractory epilepsy is utilized in veterinary medicine to describe a condition in which an animal with epilepsy fails to attain satisfactory seizure control or suffers intolerable side effects despite appropriate therapy with conventional antiepileptic drugs. Refractory epilepsy is an important problem in small animal practice as it occurs in approximately one-third of dogs with epilepsy. Consequently, there is much interest in identifying ways to more effectively treat this population of animals. More than a dozen new antiepileptic drugs have been approved for humans over the last 2 decades, and several of these drugs, including gabapentin, zonisamide, levetiracetam, and pregabalin, have been evaluated for the treatment of refractory seizures in veterinary patients. Nonmedical methods to treat poorly controlled epilepsy are also being explored. The 2 alternative forms of therapy that have shown the most promise in humans with epilepsy are electrical stimulation of the brain and dietary modification, both of which have also been evaluated in dogs. This overview summarizes the available data on pharmacologic as well as nonmedical treatment options for dogs and cats with refractory epilepsy. Although many forms of therapy are currently being utilized in clinical practice, our knowledge of the safety and efficacy of these treatments is limited. Additional randomized controlled trials are needed to better evaluate these novel therapies for refractory epilepsy in dogs and cats. PMID- 24070685 TI - Waist circumference is the best index for obesity-related cardiovascular disease risk in individuals with spinal cord injury. AB - Obesity is an important identifier of cardiovascular disease (CVD) risk, but is challenging to determine accurately in individuals with spinal cord injury (SCI). Body mass index (BMI) is used worldwide as a simple indicator of obesity, but is difficult to measure in individuals with SCI. Furthermore, standard BMI cutoffs underestimate obesity in this population. Therefore, we aimed to identify the best marker of obesity in individuals with SCI, considering both practicality, and ability to detect adiposity and CVD risk. Five anthropometric measures were evaluated: BMI; waist circumference (WC); waist-to-height ratio (WHtR); waist-to hip ratio; and neck circumference. We evaluated relationships between these measures and abdominal and total body-fat percentage, seven cardiovascular metabolic risk factors (fasting insulin, glucose, glucose tolerance, triglycerides, high-density lipoprotein, low-density lipoprotein, and total cholesterol), and the Framingham risk score. BMI, WC, and WHtR were correlated with abdominal fat percentage. WC and WHtR were correlated with five metabolic risk factors as well as the Framingham risk score. WC is a more practical measure for an SCI population. The optimal cutoff for identifying adverse CVD risk in individuals with SCI was identified as WC >=94 cm, with 100% sensitivity and 79% specificity. We propose that WC is a simple, more sensitive alternative to BMI in this population that is easy to use in multiple settings. The cutoff provides a simple tool to predict adverse CVD risk profiles that can be used to guide risk management, as well as as a practical aid for individuals with SCI to maintain a healthy body composition. PMID- 24070686 TI - Antioxidant vitamins and brain dysfunction in alcoholics. AB - AIMS: Alcohol induces cytokine secretion by Kupffer cells, which may exert also deleterious effects on distant organs, mediated in part by cytokine-derived increased production of reactive oxygen species (ROS). It is therefore important to assess antioxidant levels. The objective of this study is to analyse the relation of antioxidant vitamins with brain atrophy and cognitive dysfunction. METHODS: In 77 alcoholic patients admitted for withdrawal syndrome, subjected to brain computed tomography (CT), and 19 controls, we determined antioxidant vitamin levels and analysed their relationships with data of brain atrophy and dysfunction. Searching for causes of altered vitamin levels, we also assessed liver function, nutritional status, eating habits, alcohol intake, proinflammatory cytokine (TNF-alpha, IL-6, IL-8) levels and malondialdehyde (MDA) levels. RESULTS: Both retinol (vitamin A) and tocopherol (vitamin E) levels were decreased in alcoholics, the former in relation with liver failure, and the latter in relation with triglyceride levels and fat mass. Both were related to data of brain atrophy and cerebellar shrinkage (to which also IL-6 was significantly related). CONCLUSION: Among alcoholics, liver function impairment leads to altered serum vitamin A levels, which are related to brain alterations. Vitamin E levels are also decreased, but although in relation with liver function impairment, its decrease seems to be more dependent on nutritional status and irregular eating habits. Both vitamins are lower in patients with cerebellar atrophy and other features related to brain atrophy. PMID- 24070687 TI - Encoding of episodic information through fast task-irrelevant perceptual learning. AB - The mechanisms guiding our learning and memory processes are of key interest to human cognition. While much research shows that attention and reinforcement processes help guide the encoding process, there is still much to know regarding how our brains choose what to remember. Recent research of task-irrelevant perceptual learning (TIPL) has found that information presented coincident with important events is better encoded even if participants are not aware of its presence (see Seitz & Watanabe, 2009). However a limitation of existing studies of TIPL is that they provide little information regarding the depth of encoding supported by pairing a stimulus with a behaviorally relevant event. The objective of this research was to understand the depth of encoding of information that is learned through TIPL. To do so, we adopted a variant of the "remember/know" paradigm, recently reported by Ingram, Mickes, and Wixted (2012), in which multiple confidence levels of both familiar (know) and remember reports are reported (Experiment 1), and in which episodic information is tested (Experiment 2). TIPL was found in both experiments, with higher recognition performance for target-paired than for distractor-paired images. Furthermore, TIPL benefitted both "familiar" and "remember" reports. The results of Experiment 2 indicate that the most confident "remember" response was associated with episodic information, where participants were able to access the location of image presentation for these items. Together, these results indicate that TIPL results in a deep enhancement in the encoding of target-paired information. PMID- 24070688 TI - Contrast sensitivity, healthy aging and noise. AB - At least three studies have used external noise paradigms to investigate the cause of contrast sensitivity losses due to healthy aging. These studies have used noise that was spatiotemporally localized on the target. Yet, Allard and Cavanagh (2011) have recently shown that the processing strategy can change with localized noise thereby violating the noise-invariant processing assumption and compromising the application of external noise paradigms. The present study reassessed the cause of age-related contrast sensitivity losses using spatiotemporally extended external noise (i.e., full-screen, continuously displayed dynamic noise). Contrast thresholds were measured for young (mean=24 years) and older adults (mean=69 years) at 3 spatial frequencies (1, 3 and 9 cpd) and 3 noise conditions (noise-free, local noise and extended noise). At the two highest spatial frequencies, the results were similar with local and extended noise: the sensitivity loss was mainly due to lower calculation efficiency. At the lowest spatial frequency, age-related contrast sensitivity losses were attributed to the internal equivalent noise when using extended noise and, like in previous studies, due to calculation efficiency with local noise. These results show that the interpretation of external noise paradigms can drastically differ depending on the noise type suggesting that external nose paradigms should use external noise that is spatiotemporally extended like internal noise to avoid triggering a processing strategy change. Contrary to previous studies, we conclude that healthy aging does not affect the calculation efficiency of the detection process at low spatial frequencies. PMID- 24070689 TI - A pilot comparison of forefoot plantar pressures in newly diagnosed rheumatoid arthritis patients and non-rheumatic subjects. AB - BACKGROUND: In rheumatoid arthritis (RA) forefoot pathology is often related to increased peak plantar pressures under the metatarsal heads. OBJECTIVES: This study sought to assess peak plantar pressures in newly diagnosed RA patients compared to non-rheumatic subjects. METHOD: Plantar pressure in a group of 10 pain free RA patients diagnosed within two years before the starting date of the study and 10 healthy volunteers matched for gender, age and weight were assessed. Each group consisted of seven females and three males aged between 30 and 55 years. RESULTS: The results showed no significant difference (rho=0.420) at the hallux, however there was a statistical difference in all the other regions (rho=0.000 and p=0.011 for 1st MPJ and 2nd-4th MPJ respectively and p=0.007 for 5th MPJ). The RA group had higher pressure underneath the 1st and 2nd-4th MPJ regions and lower pressures underneath the 5th MPJ. CONCLUSION: Although it is for a small group of patients, the results from this pilot study show that even at an early stage of RA, forefoot pressures are shifted toward the medial MPJs. PMID- 24070690 TI - Comparison of three-colour flow cytometry and slide-based microscopy for the scoring of micronucleated reticulocytes in rat bone-marrow and peripheral blood. AB - The aim of this study was to perform the first transferability assessment in China of the micronucleus (MN) scoring method based on three-colour flow cytometry (FCM). This was accomplished for both rat bone-marrow and peripheral blood specimens following exposure to a variety of genotoxic and non-genotoxic chemicals, whereby micronucleus induction was measured both with FCM and with traditional microscopy. In an initial study, rats were treated with vehicle or cyclophosphamide (CP) for 2 consecutive days by oral gavage, and blood and bone marrow were sampled at 24 h after the second treatment. Staining with acridine orange (AO) of methanol-fixed slides was used for microscopical analysis and 2000 reticulocytes (RET) or polychromatic erythrocytes (PCE) were scored for MN frequency. The erythrocytes in the remaining bone-marrow cell suspensions were eluted on cellulose columns. The eluted bone marrow as well as the peripheral blood cells was fixed, incubated and analyzed by FCM. In another experiment, the performance of the FCM-MN method was further evaluated with five clastogens (urethane, 5-fluorouracil, mitomycin C, methylmethane sulfonate and 6 thioguanine), two aneugens (vincristine sulfate and colchicine) and two non genotoxic new drugs (compounds A and B), whose results were negative in the routine mouse-micronucleus test (MNT). The MN frequencies in rat peripheral blood induced by the positive chemicals were found to be lower than the frequencies in rat bone-marrow by both scoring methods. However, a high level of agreement for the MN frequencies in both compartments was obtained. Good correspondence between the two analysis methods was also achieved. These data provide support that the three-colour FCM method is more rapid and objective than manual microscopy, while yielding comparable data. It further supports the premise that rat peripheral blood may be an alternative to rat bone marrow in the MNT. PMID- 24070691 TI - Oxinium femoral head damage generated by a metallic foreign body within the polyethylene cup following recurrent dislocation episodes. AB - Oxinium femoral heads are supposed to be more scratch-resistant thanks to their oxidized layer. However, damages to this thin layer can jeopardize implant's properties. Following revision total hip arthroplasty performed for recurrent posterior dislocations, the Oxinium femoral head initially implanted was observed to be dramatically damaged. A metallic foreign body from a trochanteric fixation wire was found within the polyethylene cup. Only few cases of damaged Oxinium femoral heads have been reported and all were related to either dislocation or reduction of THA. The aim of this report is to describe a non-reported mechanism of damaged Oxinium femoral head due to a broken trochanteric fixation wire device. Any broken metallic wire from a transtrochanteric approach should be carefully followed to detect migration within the polyethylene cup. If such a migration occurs, revision surgery should be rapidly scheduled. PMID- 24070692 TI - Bone defect reconstruction in children using the induced membrane technique: a series of 14 cases. AB - INTRODUCTION: In pediatrics, Masquelet's induced membrane reconstructive technique has mainly been used in the context of cancer surgery reconstruction or congenital pseudarthrosis of the tibia. This retrospective study consisted of a series of pediatric patients where bone defects were reconstructed with this technique. MATERIALS AND METHODS: Between 2006 and 2011, 14 children underwent bone reconstruction using this technique in the context of trauma, tumor resection or congenital pseudarthrosis. The mean age was 10.6years (range: 12 to 17years) at the time of reconstruction. The length of the defect to be reconstructed relative to the length of the bone (index of reconstruction, expressed as a percentage) and bone healing was evaluated on standard radiographs. Complications were recorded. RESULTS: The mean index of reconstruction was 32.8% (range: 13.9 to 51%). The mean follow-up was 30months (range: 1 to 63). Bone union was achieved in 9.5months (range: 2 to 25). Complications mainly consisted of non-union in 35% of cases, which consolidated after grafting and rigid fixation. Two cases of wound dehiscence were noted. Massive graft resorption occurred in a single case. DISCUSSION: A technical error was identified in each non-union case (insufficient cement overlap of the bone ends or fixation not stiff enough). These long defects required a large volume of autograft, which constitutes the limiting factor especially in very young children. We used allograft bone chips or a tibial bone strut to increase the graft volume in the largest reconstructions. In this pediatric-only series, an average of one-third of the bone length was successfully reconstructed. Although the technique appears simple, it must be performed rigorously to ensure the cement sufficiently overlaps the bone ends and the defect is properly stabilized to prevent non-union, which is the main complication. LEVEL OF EVIDENCE: Level IV (retrospective study). PMID- 24070693 TI - Hereditary sensory and autonomic neuropathy type IV and orthopaedic complications. AB - Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) is a very rare autosomal recessive disorder characterized by recurrent episodes of unexplained fever, extensive anhidrosis, total insensitivity to pain, hypotonia, and mental retardation. The most frequent complications of this disease are corneal scarring, multiple fractures, joint deformities, osteomyelitis, and disabling self-mutilations. We reported the case of a 12-year-old boy. The goal was to discuss our decision-making and compare this case with cases described in the literature. PMID- 24070694 TI - Rationalising predictors of child sexual exploitation and sex-trading. AB - Although there is evidence for specific risk factors leading to child sexual exploitation and prostitution, these influences overlap and have rarely been examined concurrently. The present study examined case files for 175 young persons who attended a voluntary organization in Leicester, United Kingdom, which supports people who are sexually exploited or at risk of sexual exploitation. Based on the case files, the presence or absence of known risk factors for becoming a sex worker was coded. Data were analyzed using t-test, logistic regression, and smallest space analysis. Users of the voluntary organization's services who had been sexually exploited exhibited a significantly greater number of risk factors than service users who had not been victims of sexual exploitation. The logistic regression produced a significant model fit. However, of the 14 potential predictors--many of which were associated with each other- only four variables significantly predicted actual sexual exploitation: running away, poverty, drug and/or alcohol use, and having friends or family members in prostitution. Surprisingly, running away was found to significantly decrease the odds of becoming involved in sexual exploitation. Smallest space analysis of the data revealed 5 clusters of risk factors. Two of the clusters, which reflected a desperation and need construct and immature or out-of-control lifestyles, were significantly associated with sexual exploitation. Our research suggests that some risk factors (e.g. physical and emotional abuse, early delinquency, and homelessness) for becoming involved in sexual exploitation are common but are part of the problematic milieu of the individuals affected and not directly associated with sex trading itself. Our results also indicate that it is important to engage with the families and associates of young persons at risk of becoming (or remaining) a sex worker if one wants to reduce the numbers of persons who engage in this activity. PMID- 24070695 TI - Masculine norms, disclosure, and childhood adversities predict long-term mental distress among men with histories of child sexual abuse. AB - Child sexual abuse (CSA) can have a profound effect on the long-term mental health of boys/men. However, not all men with histories of CSA experience psychopathology. To improve prevention and intervention services, more research is needed to understand why some male survivors experience mental health problems and others do not. The purpose of this study was to examine factors related to mental distress among a large, non-clinical sample of men with histories of CSA (N=487). Using a cross-sectional design with purposive sampling from three national survivor organizations, data were collected through an anonymous Internet-based survey. Multivariate analyses found that only one of the four CSA severity variables-use of physical force by the abuser-was related to mental distress. Additional factors that were related to mental distress included the number of other childhood adversities, years until disclosure, overall response to disclosure, and conformity to masculine norms. Overall, the final model predicted 36% of the variance in the number of mental health symptoms. Mental health practitioners should include masculine norms, disclosure history, and childhood adversities in assessments and intervention planning with male survivors. To more fully explicate risk factors for psychopathology in this population, future studies with probability samples of men that focus on mediational processes and use longitudinal designs are needed. PMID- 24070696 TI - Exploratory evaluation of variation in statin take up among high risk patients in Nottingham City. PMID- 24070697 TI - Airway compression in children with congenital heart disease evaluated using computed tomography. AB - BACKGROUND: Extrinsic airway compression often complicates the course of congenital heart disease (CHD) repair. This study investigated the risk factors and outcome of airway compression evaluated using computed tomography (CT) in CHD patients. METHODS: Of the 2,729 patients who underwent heart surgery for CHD between 1999 and 2007, airway compression was confirmed using CT in 58 (2.1%) patients. The patients were divided into groups according to the underlying CHD, and their medical records and CT scans were reviewed retrospectively. RESULTS: Airway compression was found more frequently in the vascular ring or absent pulmonary valve syndrome (8 of 11) and repaired aortic arch (22 of 213) groups than in the other groups (28 of 2,505) (p < 0.001). Patients with more severe respiratory manifestations showed greater airway compression on CT (p < 0.001) and had a higher rate of additional surgery to relieve airway compression using multivariate analysis (p = 0.005). Airway compression was ameliorated in 13 of 17 patients after surgery for airway compression. Funnel chest deformity worsened after aortic arch repair and was associated with the need for surgical relief of airway compression. Pulmonary overflow disease could be followed up without additional surgery for airway compression. CONCLUSIONS: Early airway compression detection and management may reduce further morbidity, especially after aortic arch repair. The patient's respiratory manifestation and the underlying disease characteristics must be considered when determining the need for additional surgery for airway compression. PMID- 24070699 TI - Effect of coronary artery disease extent on contemporary outcomes of combined aortic valve replacement and coronary artery bypass graft surgery. AB - BACKGROUND: Concomitant aortic valve replacement (AVR) and coronary artery bypass graft surgery (CABG) is a common procedure. Whether the extent of coronary artery disease (CAD) influences outcomes of AVR plus CABG is unknown. METHODS: All AVR plus CABG cases from 2008 to 2010 were extracted from the California CABG Outcomes Reporting Program database. Patients with left main coronary artery stenosis greater than 50% or at least three diseased vessels were defined as having extensive CAD, and patients with one or two diseased coronary vessels were defined as having less extensive CAD. Multivariable logistic regression models were developed for predicting major postoperative complications and 30-day mortality. A Cox proportional hazards model was developed to predict the risk of 1-year mortality. RESULTS: Between 2008 and 2010, 6,151 AVR plus CABG were performed in California. Compared with patients with one- or two-vessel CAD, patients with extensive CAD undergoing AVR plus CABG were on average older, more often male, had greater prevalence of multiple comorbidities, and underwent more urgent or emergent operations (all p < 0.05). After adjusting for baseline risk factors, AVR plus CABG with extensive CAD was associated with significantly increased risk of major postoperative complications (adjusted odds ratio, 1.24; 95% confidence interval, 1.10 to 1.40; p = 0.001) but not operative mortality (adjusted odds ratio, 1.00; 95% confidence interval, 0.77 to 1.29; p = 0.978). A Cox proportional hazards model showed that age and other medical comorbidities, but not extensive CAD, were significant risk factors for 1-year mortality. CONCLUSIONS: Compared with AVR plus CABG for one- or two-vessel CAD, AVR plus CABG for left main or three or more vessel CAD had higher observed and risk adjusted rates of postoperative complications but not operative or 1-year mortality. PMID- 24070698 TI - Regional annular geometry in patients with mitral regurgitation: implications for annuloplasty ring selection. AB - BACKGROUND: The saddle shape of the normal mitral annulus has been quantitatively described by several groups. There is strong evidence that this shape is important to valve function. A more complete understanding of regional annular geometry in diseased valves may provide a more educated approach to annuloplasty ring selection and design. We hypothesized that mitral annular shape is markedly distorted in patients with diseased valves. METHODS: Real-time 3-dimensional echocardiography was performed in 20 patients with normal mitral valves, 10 with ischemic mitral regurgitation, and 20 with myxomatous mitral regurgitation (MMR). Thirty-six annular points were defined to generate a 3-dimensional model of the annulus. Regional annular parameters were measured from these renderings. Left ventricular inner diameter was obtained from 2-dimensional echocardiographic images. RESULTS: Annular geometry was significantly different among the three groups. The annuli were larger in the MMR and in the ischemic mitral regurgitation groups. The annular enlargement was greater and more pervasive in the MMR group. Both diseases were associated with annular flattening, although though the regional distribution of that flattening was different between groups. Left ventricular inner diameter was increased in both groups. However, relative to the Left ventricular inner diameter, the annulus was disproportionately dilated in the MMR group. CONCLUSIONS: Patients with MMR and ischemic mitral regurgitation have enlarged and flattened annuli. In the case of MMR, annular distortions may be the driving factor leading to valve incompetence. These data suggest that the goal of annuloplasty should be the restoration of normal annular saddle shape and that the use of flexible, partial, and flat rings may be ill advised. PMID- 24070700 TI - Prediction of paravalvular regurgitation after transcatheter aortic valve implantation by computed tomography: value of aortic valve and annular calcification. AB - BACKGROUND: The purpose of this study was to quantify and characterize aortic valve leaflet and aortic annular calcification with computed tomography angiography (CTA) and to define whether they predict paravalvular regurgitation (PAR) after transcatheter aortic valve implantation. METHODS: In all, 94 patients (aged 83.6 years) with severe aortic stenosis underwent CTA. Annular calcification was measured in two planes and defined as "protruding" (depth greater than length), "round," or "adherent" (length less than depth) for the right, left, and noncoronary annulus. Leaflet calcification severity and asymmetry were scored. Transthoracic echocardiography graduation of PAR severity was performed after the procedure (0.5 scale). RESULTS: Thirty-two percent of patients had no or trivial PAR (grade less than 1) and 68% had mild to severe PAR (>= 1 [mild 45.7%, moderate 20.2%, moderate to severe 2.1%]). The size of annular calcium was higher in patients with moderate to severe PAR greater than 1 (p = 0.015, p = 0.007, and p = 0.004) and predictive (c = 0.67, 0.71, and 0.711) for noncoronary, left, and total annular calcium size, respectively. Increasing PAR severity was correlated with increasing total calcium size (r = 0.422, p < 0.001). Protruding annular calcification greater than 4 mm (p = 0.02) was more frequently found in moderate to severe PAR greater than 1, and predictive (c = 0.7). Adherent calcium greater than 4 mm did not predict PAR greater than 1 and PAR of 1 or less. There was no association of leaflet calcium severity and asymmetry with PAR severity. CONCLUSIONS: Protruding annular calcium greater than 4 mm predicts moderate to severe PAR after transcatheter aortic valve implantation. Increasing annular calcium size is another predictor, whereas adherent calcium has a "sealing" effect. PMID- 24070702 TI - Trends and outcomes of tricuspid valve surgery in North America: an analysis of more than 50,000 patients from the Society of Thoracic Surgeons database. AB - BACKGROUND: This study evaluated trends and outcomes of tricuspid valve surgery (TVS) in North America over the past decade. METHODS: Adults undergoing TVS between 2000 and 2010 were identified in The Society of Thoracic Surgeons (STS) National Database. Trends were evaluated using linear regression. Multivariable logistic regression analysis was conducted using covariates from the STS valve risk model to identify significant predictors of operative mortality. RESULTS: A total of 54,375 patients underwent TVS during the study period. The majority of cases were repairs (89%; n = 48,322) and were performed concomitant with another major procedure (86%; n = 46,593). The proportion of TVS that were repairs increased from 84.6% in 2000 to 89.8% in 2010 (p = 0.01). Trend analysis revealed significant changes in patient characteristics with time, including increasing age, a higher comorbidity burden, and a higher proportion of emergency cases. Despite worsening risk factors, unadjusted operative mortality for TVS declined from 10.6% in 2000 to 8.2% in 2010 (p < 0.001), and this trend persisted after risk adjustment. In the multivariable model, concomitant procedures involving multiple valves or coronary artery bypass grafting were associated with an increased risk of mortality compared with isolated TVS, although other factors including renal failure, congestive heart failure, nonelective presentation, reoperation, and tricuspid valve replacement exerted equal or stronger effects. CONCLUSIONS: During the past decade, repair rates for TVS have increased significantly. Although patients undergoing TVS have demonstrated worsening risk factors, unadjusted and adjusted operative mortalities have declined. Finally, the data suggest that tricuspid valve repair when technically feasible, together with early elective surgical intervention, should be emphasized as potential candidates for continued outcome improvement. PMID- 24070701 TI - Acute obstruction by Pannus in patients with aortic medtronic-hall valves: 30 years of experience. AB - BACKGROUND: Acute dysfunction of mechanical aortic valve prostheses is a life threatening adverse event. Pannus overgrowth, which is fibroelastic hyperplasia originating from the periannular area, is one cause of dysfunction. The aim of this study was to determine the annual incidence of readmittance resulting from acute obstruction caused by pannus during 30 years of observation in patients with Medtronic-Hall aortic valve prostheses and to analyze the risk factors associated with pannus development. METHODS: From 1982 to 2004, 1,187 patients in our department underwent aortic valve replacement with Medtronic-Hall mechanical monoleaflet valve prostheses. As of December 31, 2012, 27 of these patients (2.3%) had presented with acute valve dysfunction caused by pannus obstruction. RESULTS: The annual incidence of pannus was 0.7 per 1,000. The median time from the primary operation to prosthetic dysfunction was 11.1 years (range, 1.2 to 26.8 years). Of the 20 patients who underwent reoperation, 2 died. Seven patients died before reoperation. Women had a higher risk for the development of obstructing pannus, and patients with pannus obstruction were younger. Valve size was not an independent risk factor. CONCLUSIONS: Women and younger patients are at higher risk for pannus development. When acute dysfunction by pannus is suspected in a mechanical aortic valve, an immediate echocardiogram and an emergency aortic valve replacement should be carried out because of the potential of a fatal outcome. PMID- 24070703 TI - Rethinking the ross procedure in adults. AB - BACKGROUND: Although questionable durability has tempered enthusiasm for the Ross procedure in the last decade, the perioperative risks of the Ross procedure relative to conventional aortic valve replacement are not well described. The goal of this study is to describe both the perioperative outcomes and utilization trends of the Ross procedure in adults in The Society of Thoracic Surgeons Adult Cardiac Surgery Database. METHODS: The Society of Thoracic Surgeons Adult Cardiac Surgery Database was used to review all Ross procedures performed between 1994 and 2010. The utilization of the procedure in the database was assessed. Then the preoperative comorbidities, patient demographics, and risk factors were reviewed, as were intraoperative and perioperative outcomes. RESULTS: Of 648,541 aortic valve replacements during the study period, 3,054 (0.47%) were identified as Ross procedures. Utilization of the procedures as a percent of total aortic valve replacements peaked in 1998 at 1.2%, followed by a steady decline to 0.09% by 2010. More than a quarter of all Ross operations were performed at six sites. Using propensity-matching analyses, Ross patients experienced significantly more perioperative complications including reexploration (9.4% versus 5.8%; p < 0.01), renal failure (2.6% versus 0.8%; p < 0.001), and operative mortality (2.7% versus 0.9%; p = 0.001). CONCLUSIONS: These data suggest that the Ross procedure is associated with greater perioperative morbidity and mortality risks compared with conventional aortic valve replacement. Recognition of these risks along with durability concerns have resulted in a dramatic decline in the number of Ross procedures performed in North America in the last decade. PMID- 24070704 TI - Impact of perfusion strategy on outcome after repair for acute type a aortic dissection. AB - BACKGROUND: The impact of antegrade versus retrograde perfusion during cardiopulmonary bypass on short- and long-term outcome after repair for acute type A aortic dissection is controversial. METHODS: We reviewed 401 consecutive patients (age, 59.2 +/- 14 years) with acute type A aortic dissection who underwent aggressive resection of the intimal tear and aortic replacement (March 1995 through July 2011). Arterial perfusion was antegrade in 78% (n = 311), either by means of the right axillary artery (n = 297) or through direct aortic cannulation (n = 15). Retrograde perfusion through the femoral artery was used in 22% (n = 90). RESULTS: Of the 401 patients with acute type A aortic dissection, 16% (n = 64) presented in critical condition and 10% (n = 39) entered the operating room under cardiopulmonary resuscitation. In 14% (n = 54) the dissection did not extend beyond the ascending aorta (DeBakey II); 82% of dissections did involve at least the aortic arch (n = 326, DeBakey I+III). Mean age was not significantly different between patients undergoing antegrade (59.4 +/- 14 years) versus retrograde (59.2 +/- 13 years; p = 0.489) perfusion. Operative mortality was 20% and did not differ significantly between the groups (p = 0.766); postoperative stroke occurred also with a similar prevalence (antegrade, 15% versus retrograde, 18%; p = 0.623). Patients undergoing antegrade perfusion had a better long-term survival. Survival at 10 years after discharge was 71% versus 51% (p = 0.025) in favor of antegrade perfusion. Retrograde perfusion was identified to be an independent risk factor for late mortality in multivariate analysis (hazard ratio = 2; p = 0.009). CONCLUSIONS: Survival during the initial perioperative period was equivalent comparing antegrade and retrograde perfusion. Antegrade perfusion to the true lumen, however, appears to be associated with superior long-term survival after hospital discharge. PMID- 24070705 TI - The role of age in complicated acute type B aortic dissection. AB - BACKGROUND: Complicated acute type B aortic dissection (cABAD) generally requires urgent intervention. Advanced age is a risk factor for mortality after thoracic aortic intervention, including surgery for aortic dissection. The purpose of this study was to investigate the exact impact of increasing age on the management and outcomes of cABAD. METHODS: We analyzed the outcomes of 583 patients with cABAD enrolled in the International Registry of Acute Aortic Dissection (IRAD) between 1996 and 2012. All patients with cABAD were categorized according to age by decade and management type (medical, surgical, or endovascular treatment), and outcomes were subsequently investigated in the different age groups. RESULTS: The mean age of the cohort was 63.4 +/- 14.2 years, 36% of patients (n = 209) were greater than 70 years of age and 64% (n = 374) were less than 70 years. The utilization of surgery and endovascular techniques progressively decreased with patient age, while the rate of medical management significantly increased with age (p < 0.001). The in-hospital mortality rates for complicated patients younger than 70 years versus 70 years or more were 10.1% versus 30.0% for endovascular treatment (p = 0.001), 17.2% versus 34.2% for surgical treatment (p = 0.027), and 14.2% versus 32.2% for medical treatment (p = 0.001). Age 70 years or greater was a predictor of in-hospital mortality in multivariate analysis (odds ratio 2.37, 95% confidence interval: 1.23 to 4.54, p = 0.010). CONCLUSIONS: Advanced age has a dramatic impact on the management and outcomes of patients with cABAD. A nonsignificant trend toward lower mortality after endovascular management was observed, both for younger patients and for elderly patients. PMID- 24070706 TI - Half of Americans without insurance will be able to get cover for $100 a month, government says. PMID- 24070707 TI - Pick on someone your own size: the detection of threatening facial expressions posed by both child and adult models. AB - For decades, researchers have documented a bias for the rapid detection of angry faces in adult, child, and even infant participants. However, despite the age of the participant, the facial stimuli used in all of these experiments were schematic drawings or photographs of adult faces. The current research is the first to examine the detection of both child and adult emotional facial expressions. In our study, 3- to 5-year-old children and adults detected angry, sad, and happy faces among neutral distracters. The depicted faces were of adults or of other children. As in previous work, children detected angry faces more quickly than happy and neutral faces overall, and they tended to detect the faces of other children more quickly than the faces of adults. Adults also detected angry faces more quickly than happy and sad faces even when the faces depicted child models. The results are discussed in terms of theoretical implications for the development of a bias for threat in detection. PMID- 24070708 TI - The p38 MAPK inhibitor JLU1124 inhibits the inflammatory response induced by lipopolysaccharide through the MAPK-NF-kappaB pathway in RAW264.7 macrophages. AB - Our previous results showed that JLU1124 is a potent p38 mitogen-activated protein kinase (MAPK) inhibitor. Compared to the classic p38 MAPK inhibitor SB203580, JLU1124 inhibits p38 phosphorylation at low concentrations without cytotoxicity on cells. p38 MAPK is a known target for inflammation treatment. Thus, we became interested in whether JLU1124 has anti-inflammatory effects. We used LPS stimulated RAW264.7 macrophages as a model of inflammation to evaluate the anti-inflammatory effects of JLU1124. Our results showed that p38 phosphorylation, the production of nitric oxide (NO), interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, the mRNA and protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were enhanced by lipopolysaccharide (LPS). At concentrations of less than 10 MUmol/L, JLU1124 inhibits p38 phosphorylation in a dose-dependent manner and significantly suppresses LPS-induced production of NO, IL-6 and TNF-alpha, and decreases the expressions of iNOS and COX-2 in RAW264.7 macrophages which indicate that JLU1124 has anti-inflammatory effects. However, JLU1124 has no significant effect on the phosphorylation of extracellular signal-regulated kinase1/2 and c-Jun NH2 terminal kinase which was involved in inflammation. Furthermore, our results showed that JLU1124 inhibits NF-kappaB inhibitor (IkappaB)alpha phosphorylation, nuclear translocation and transcriptional activity of NF-kappaB induced by LPS which may be through suppression of Akt phosphorylation. In conclusion, our study indicates that JLU1124 efficiently inhibits p38 phosphorylation and has anti inflammatory effects in LPS-treated RAW264.7 macrophages. The anti-inflammatory mechanism of JLU1124 is mainly through decreasing Akt phosphorylation and inhibiting IkappaBalpha phosphorylation, thus suppressing NF-kappaB activation and nuclear translocation. PMID- 24070709 TI - Role of the JNK pathway on the expression of inflammatory factors in alveolar macrophages under mechanical ventilation. AB - The aim of this study was to investigate the regulatory role of the c-JUN N terminal kinase (JNK) pathway on interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha expression in alveolar macrophages (AMs) of injured lung. Lung injury was induced in the New Zealand white rabbit by applying continuous mechanical ventilation with or without inhibitor of JNK (SP600125), p38 (SB203580), or ERK (PD98059). Non-ventilated rabbits (controls) were compared with the different ventilation-days groups, and untreated rabbits ventilated for 3 days (controls) were compared with the different inhibitor groups. We found that mechanical ventilation caused significant decreases in partial pressures of carbon dioxide (pCO2) and oxygen (pO2) of untreated rabbits (all times, P<0.05), but the inhibitor-treated groups showed no change in either blood-gas indicator (all times, P>0.05). Mechanical ventilation caused time-dependent increases in mRNA and protein levels of TNF-alpha and IL-8 in AMs and in serum of untreated rabbits, with the peak levels occurring at day 3 of ventilation. The SP600125 treated group showed significantly decreased TNF-alpha expression, but no significant change in IL-8 expression. Neither the SB203580- nor PD98059-treated groups showed any significant change in TNF-alpha or IL-8 expression. MAPKs' inhibitors could reduce mechanical ventilation-induced inflammation, and SP600125 produced the most robust decrease in inflammation. Mechanical ventilation-induced lung injury stimulates IL-8 and TNF-alpha expression in rabbit AMs in a time dependent manner. The JNK pathway plays an important role in mechanical ventilation-stimulated TNF-alpha expression in AMs, but the injury-stimulated IL 8 expression may be regulated by other signaling pathways. PMID- 24070710 TI - Association between MDR1 C3435T polymorphism and risk of breast cancer. AB - The C3435T (rs1045642) polymorphism, located in multi-drug resistance gene 1 (MDR1), has demonstrated its role in decreasing the P-gp activity level which is related to the carcinogenesis. Many published studies have evaluated the association between the MDR1 C3435T polymorphism and breast cancer risk. However, the results remain conflicting rather than conclusive. To derive a more precise estimation of the association between MDR1 C3435T polymorphism and risk of breast cancer, we performed a meta-analysis comprised of 10 case-control studies, including 5282 breast cancer cases and 7703 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the association. The overall results indicated that the variant genotypes were associated with a significantly increased risk of breast cancer (TT versus CC: OR=1.45, 95% CI=1.14 1.30, TT versus CT/CC: OR=1.13, 95% CI=1.04-1.23, TT/CT versus CC: OR=1.22, 95% CI=1.02-1.46). Our results suggest that the MDR1 C3435T polymorphism may contribute to individual susceptibility to breast cancer. PMID- 24070711 TI - Letter from the guest editor. PMID- 24070713 TI - A comprehensive review of the retroperitoneal anatomy, neoplasms, and pattern of disease spread. AB - A clear understanding of the normal anatomy and pattern of disease spread is important in evaluating many retroperitoneal disorders. Primary retroperitoneal tumors are uncommon, accounting for 0.1%-0.2% of all malignancies in the body; 80%-90% of all primary retroperitoneal tumors are malignant. The primary retroperitoneal neoplasms can be divided into solid or cystic masses. The solid neoplasms can be classified according to their tissue of origin into 3 main categories: mesodermal tumors, neurogenic tumors, and extragonadal germ cell tumors. Computed tomography and magnetic resonance imaging play a vital role in the localization, characterization, evaluation of the extent of local invasion, assessment of metastases, and determination of treatment response for these tumors. The diagnosis of a primary retroperitoneal malignancy is often challenging owing to overlap of imaging findings. A definitive diagnosis can be established only at histopathologic analysis. However, knowledge of the important tumor characteristics, growth pattern, and vascularity can assist in narrowing the differential diagnosis. PMID- 24070712 TI - Radiologic-pathologic correlation of uncommon mesenchymal liver tumors. AB - Mesenchymal liver tumors are rarely encountered in clinical practice. We review the spectrum of mesenchymal liver tumors with radiologic-pathologic correlation. There is an overlap of cross-sectional imaging findings of mesenchymal liver tumors with that of the more common malignant epithelial tumors. Familiarity with the radiologic findings and its pathologic basis would help radiologists to include these uncommon liver tumors in their differential diagnosis. PMID- 24070714 TI - An update on criteria for assessing tumor response to treatment. AB - Standardized tumor response criteria have been developed over time since the advent of cytotoxic anticancer therapies. The criteria have evolved and continue to do so as the understanding of the therapeutic basis of various anticancer agents increases and as novel therapeutic agents are developed. Currently, the criteria can be divided into the following main categories: anatomical-based criteria; tumor- and therapy-specific criteria; metabolic-based criteria; and response assessment of lymphomas. The standardized criteria are critical to the successful conduct of clinical trials during the development of cancer therapeutic agents as they offer uniform end points that facilitate comparison of therapeutic agents and interpretation of studies. The criteria are also relevant in clinical practice as they standardize how radiologists select, measure, and report lesions in oncology patients, and they provide standardized definitions for tumor response categories. To remain relevant in a rapidly evolving oncology field and provide up-to-date imaging information that meets the needs of oncologists in both research trials and clinical practice, radiologists need to familiarize themselves with the various standardized tumor response criteria. PMID- 24070715 TI - Effective use of low-dose computed tomography lung cancer screening. AB - Lung cancer screening programs for high-risk populations using low-dose computed tomography (LDCT) have been shown by a class I clinical trial to reduce lung cancer mortality by 20%. We present an overview of randomized and nonrandomized lung cancer screening trials and review some of the arguments advocating for or against the widespread implementation of such a screening program. Concerns regarding the use of LDCT screening for lung cancer include increased risk from radiation exposure, overdiagnosis of indolent tumors, and high numbers of false positive results, which may increase patient anxiety and result in unnecessary procedures with potential complications. Current recommendations regarding diagnostic criteria and workup of positive screens as well as the risks and benefits of using LDCT for lung cancer screening are provided. PMID- 24070716 TI - Inhibition of human and bovine insulin fibril formation by designed peptide conjugates. AB - The aggregation of insulin, to afford amyloidogenic fibers, is a well-studied phenomenon, which has interesting biological ramifications and pharmaceutical implications. These fibers have been ascribed an intriguing role in certain disease states and stability of pharmaceutical formulations of this hormone. The present study describes the design and inhibitory effects of novel peptide conjugates toward fibrillation of insulin as investigated by thioflavin T assay, circular dichroism (CD), and atomic force microscopy (AFM). Possible interaction of insulin with peptide-based fibrillation inhibitors is also probed by other solution phase studies, which reveal an important role of aromatic pi-pi interactions in the inhibition process. CD studies suggest that a freshly prepared solution of insulin, rich in alpha-helices, transforms into a beta-sheet structure upon aggregation, which gets perturbed in the presence of synthesized inhibitors. Therefore, these newly designed peptides could serve as potential leads as inhibitors of insulin aggregation. PMID- 24070717 TI - Agricultural exposure and asthma risk in the AGRICAN French cohort. AB - Epidemiological studies have reported an increased risk of respiratory diseases in agricultural population, but a protective "farm-effect" has also been reported for asthma. In the AGRICAN cohort, self-reported doctor-diagnosed asthma was analyzed according to allergy, in relation with history of life-time exposure to 13 crops and 5 livestock, pesticide exposure and early life on a farm, taking into account sex, age, education and body mass index. Among the 1246 asthmatics (8.0%), 505 were allergic (3.3%) and 719 non-allergic (4.6%). In multivariate analysis, a significant excess was observed, only for allergic asthma, in vine growing (OR=1.43, p=0.002), fruit-growing (OR=1.58, p=0.001), greenhouses (OR=1.66, p=0.02), grasslands (OR=1.35, p=0.009), beets (OR=1.52, p=0.003) and horses (OR=1.35, p=0.04). Pesticide use and history of pesticide poisoning were significantly associated with allergic asthma in grassland, vineyards and fruit growing and with non-allergic asthma in beets. Living on a farm in the first year of life tended to be protective for childhood allergic asthma in farms with livestock (OR=0.72, p=0.07) but deleterious in farms with vineyards, fruit or vegetables (OR=1.44, p=0.07). In AGRICAN, an increased risk of allergic asthma was observed with crop exposure, pesticide use and early life on a farm, especially in vine-growing, grassland, beets, fruit and vegetable-growing. PMID- 24070718 TI - Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy. AB - BACKGROUND: Mutations in genes encoding for desmosomal proteins are the most common cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). We assessed the value of genotype for prediction of lifetime major arrhythmic events and sudden cardiac death (SCD) in desmosomal gene-related ARVC. METHODS AND RESULTS: The overall study population included 134 desmosomal gene mutation carriers (68 men; median age 36 years [22-52]) from 44 consecutive ARVC families undergoing comprehensive genetic screening. The probability of experiencing a first major arrhythmic event or SCD during a lifetime was determined by using date of birth as start point for the time-to-event analysis, and was stratified by sex, desmosomal genes, mutation types, and genotype complexity (single versus multiple mutations). One hundred thirteen patients (84%) carried a single desmosomal gene mutation in desmoplakin (n=44; 39%), plakophilin-2 (n=38; 34%), desmoglein-2 (n=30; 26%), and desmocollin-2 (n=1; 1%), whereas 21 patients (16%) had a complex genotype with compound heterozygosity in 7 and digenic heterozygosity in 14. Over a median observation period of 39 (22-52) years, 22 patients (16%) from 20 different families had arrhythmic events, such as SCD (n=1), aborted SCD because of ventricular fibrillation (n=6), sustained ventricular tachycardia (n=14), and appropriate defibrillator intervention (n=1). Multiple desmosomal gene mutations and male sex were independent predictors of lifetime arrhythmic events with a hazard ratio of 3.71 (95% confidence interval, 1.54-8.92; P=0.003) and 2.76 (95% confidence interval, 1.19-6.41; P=0.02), respectively. CONCLUSIONS: Compound/digenic heterozygosity was identified in 16% of ARVC-causing desmosomal gene mutation carriers and was a powerful risk factor for lifetime major arrhythmic events and SCD. These results support the use of comprehensive genetic screening of desmosomal genes for arrhythmic risk stratification in ARVC. PMID- 24070719 TI - Perceptions of partner drinking problems, regulation strategies and relationship outcomes. AB - The current research evaluates how perceptions of one's partner's drinking problem relate to attempts to regulate partner behavior and relationship functioning, and whether this varies by perceptions of one's own drinking. New measures are offered for Thinking about your Partner's Drinking (TPD) and Partner Management Strategies (PMS). Participants included 702 undergraduates who had been in a romantic relationship for at least three months. Participants completed an online survey assessing perceptions of problematic drinking for one's self and partner, ways in which attempts were made to regulate or restrain their partner's drinking, relationship outcomes (i.e., satisfaction, commitment, trust, and need fulfillment), and alcohol use and consequences for self and partner. Factor analyses supported a single factor for Thinking about your Partner's Drinking (TPD) and two factors for the Partner Management Strategies (PMS) scale (i.e., punishment and reward). Results using structural equation modeling indicated that perceiving one's partner to have a drinking problem was associated with lower relationship functioning. Further, this association was mediated by strategies using punishment aimed at changing one's partner's drinking, but was not mediated by strategies using rewards. Finally, moderation results suggested that this relationship was not as detrimental for participants who perceived they also had an alcohol problem. In sum, perceiving one's partner to have a drinking problem was associated with relationship problems through punishing regulation strategies, and was weaker among individuals who also perceived themselves to have a drinking problem. PMID- 24070720 TI - Increase of gastrointestinal bleeding with new oral anticoagulants: problems of a meta-analysis. PMID- 24070721 TI - Reply: To PMID 23470618. PMID- 24070722 TI - Roles for microRNA 23b in regulating autophagy and development of pancreatic adenocarcinoma. PMID- 24070723 TI - Evidence for dual pathway for nitrergic neuromuscular transmission in doubt: evidence favors lack of role of ICC. PMID- 24070724 TI - Lymphoma: the bete noire of the long-term use of thiopurines in adult and elderly patients with inflammatory bowel disease. PMID- 24070725 TI - A surprising cause of abdominal pain and bloating. PMID- 24070726 TI - Hickam's dictum in a patient with diarrhea. PMID- 24070727 TI - Reply: To PMID 23528627. PMID- 24070728 TI - A man with diffuse vesicular rash and epigastric pain. PMID- 24070729 TI - Unifying diagnosis for adenomatous polyps, cafe-au-lait macules, and a brain mass? PMID- 24070730 TI - Unusual endoscopic finding. PMID- 24070731 TI - A rare cause of abdominal pain. PMID- 24070732 TI - Beneficial effect of agmatine in the acute phase of experimental autoimmune encephalomyelitis in iNOS-/- knockout mice. AB - The aim of the study was to investigate the hypothesis that agmatine (AGM) provides protection against oxidative stress in experimental autoimmune encephalomyelitis (EAE). Wild-type (WT) and knockout (KO) CBA/H iNOS-/- 3 months old (15 +/- 5 g) mice, were used for EAE induction by myelin basic protein (MBP), dissolved in Complete Freund's Adjuvant (CFA). The animals were divided into control, EAE, CFA, EAE+AGM and AGM groups. After the development of full clinical remission, animals were decapitated and oxidative stress parameters were determined in whole encephalitic mass (WEM) and cerebellum homogenates. The EAE clinical expression manifested to greater extent in WT than KO mice, was significantly decreased during AGM treatment. We demonstrated significant elevations of superoxide dismutase activity in WT and KO EAE animals, in WEM and cerebellum tissues, which were decreased during AGM treatment in both groups. Superoxide anion content was increased in WEM of both study groups, with a decrease during AGM treatment. The observed changes were more pronounced in WT than in KO animals. Also, the increased expressions of transferrin receptor and glial fibrillary acidic protein observed in WT and KO EAE mice were significantly decreased during AGM treatment. The results suggest potentially beneficial AGM effects in EAE, which might be used for a modified antioxidative approach in MS therapy. PMID- 24070733 TI - The effect of CD137-CD137 ligand interaction on phospholipase C signaling pathway in human endothelial cells. AB - We previously reported the emerging role of CD137-CD137L interaction in inflammation and atherosclerosis. The mechanism of CD137-CD137L interaction may be related to a variety of signaling pathways. The most important signaling pathway involves the activation of phospholipase C(PLC) which induces the diacylglycerol-protein kinase C(DAG-PKC) and the inositol trisphosphate intracellular free calcium (IP3-[Ca(2+)]i) pathway. In the current study, we investigated whether CD137-CD137L interaction can stimulate the PLC signaling pathway in human umbilical vein endothelial cells (HUVEC). The diacylglycerol (DAG) and inositol trisphosphate (IP3) levels in HUVEC were measured by radioenzymatic assay. The activity of protein kinase (PKC) was detected by its ability to transfer phosphate from [gamma-(32)P]ATP to lysine-rich histone. The [Ca(2+)]i concentrations were measured by flow cytometric analysis. The DAG level and PKC activity were increased in a concentration-dependent, biphasic manner in HUVEC induced by anti-CD137. PKC activity was mainly in the cytosol at rest, and then translocated to the membrane when stimulated by anti-CD137. Similarly, rapid IP3 formation induced by anti-CD137 coincided with the peak of the DAG level. Moreover, anti-CD137 induced peak [Ca(2+)]i responses including the rapid transient phase and the sustained phase. However, anti-CD137L suppressed the activation of the DAG-PKC and IP3-[Ca(2+)]i signaling pathway, which was stimulated by anti-CD137 in HUVEC. In conclusion, the data suggested that CD137 CD137L interaction induces robust activation of the PLC signaling pathway in HUVEC. PMID- 24070734 TI - Learning effects in the lane change task (LCT)--realistic secondary tasks and transfer of learning. AB - Driver distraction is a factor that is heavily involved in traffic crashes. With in-vehicle devices like navigation systems or mobile phones on the rise, the assessment of their potential to distract the driver has become a pressing issue. Several easy-to-use methods have been developed in recent years to allow for such an assessment in the early stages of product development. One of these methods is the lane change task (LCT), a simple driving simulation in which the driver has to change lanes as indicated by different signs along the road. Although the LCT is an ISO sanctioned procedure, there are still open questions. One issue are learning effects which have been found in previous studies and which have the potential to compromise the comparability of test results. In this paper, we present results on two experiments that further explored the effect of previous experience on LCT and secondary task performance. The results confirm that learning effects occur when combining the LCT with a realistic secondary task. Also, we found evidence for the transfer of learning from one secondary task to another to some degree, provided that the two tasks are sufficiently similar. PMID- 24070735 TI - Atomic scale structure changes induced by charged domain walls in ferroelectric materials. AB - Charged domain walls (CDWs) are of significant scientific and technological importance as they have been shown to play a critical role in controlling the switching mechanism and electric, photoelectric, and piezoelectric properties of ferroelectric materials. The atomic scale structure and properties of CDWs, which are critical for understanding the emergent properties, have, however, been rarely explored. In this work, using a spherical-aberration-corrected transmission electron microscope with subangstrom resolution, we have found that the polarization bound charge of the CDW in rhombohedral-like BiFeO3 thin films not only induces the formation of a tetragonal-like crystal structure at the CDW but also stabilizes unexpected nanosized domains with new polarization states and unconventional domain walls. These findings provide new insights on the effects of bound charge on ferroelectric domain structures and are critical for understanding the electrical switching in ferroelectric thin films as well as in memory devices. PMID- 24070736 TI - Crotonaldehyde induces heat shock protein 72 expression that mediates anti apoptotic effects in human endothelial cells. AB - Crotonaldehyde is a highly reactive aldehyde and a common environmental pollutant. It occurs in cigarette smoke and automobile exhaust, and is also endogenously generated by lipid peroxidation. Reactive aldehydes, such as crotonaldehyde, are considered to be important mediators of cell damage. Since endothelial apoptosis is considered to be the first step in the pathogenesis of cardiovascular disease, there have been many efforts to protect endothelial cell from oxidative stress. Heat shock protein 72 (HSP72) is a representative stress inducible HSP70 family protein, and its synthesis is increased in response to multiple stressors. In the present study, we investigated the effect of crotonaldehyde on the up-regulation of HSP72 in human umbilical vein endothelial cells (HUVECs). Crotonaldehyde treatment caused nuclear accumulation of the heat shock transcription factor 1 (HSF1), leading to the induction of HSP72. Inhibition of the c-Jun N-terminal kinases (JNK) signaling pathways, reduction of intracellular calcium level and blocking of reactive oxygen species (ROS) generation resulted in significant blockage of crotonaldehyde-mediated HSP72 induction. In addition, HSP72 silencing by siRNA or calcium chelating by BAPTA/AM resulted in an obvious increase in the rate of apoptosis in crotonaldehyde stimulated HUVECs. In summary, our data demonstrated that crotonaldehyde-induced HSP72 expression in HUVECs is mediated by the JNK-HSF1 pathway, and involves calcium ions and ROS, which is an adaptive response to oxidative stress caused by crotonaldehyde. PMID- 24070737 TI - 4-Nitrophenol induces Leydig cells hyperplasia, which may contribute to the differential modulation of the androgen receptor and estrogen receptor-alpha and beta expression in male rat testes. AB - 4-Nitrophenol (PNP) is generally regarded as an environmental endocrine disruptor capable of estrogenic and anti-androgenic activities. To investigate PNP-induced reproductive effects, immature male rats were injected subcutaneously with PNP (0.1, 1, 10mg/kg body weight or vehicle) daily for 4 weeks. We assessed reproductive tract alterations, sex hormone balance in the serum and estrogen receptor (ER)-alpha, -beta and androgen receptor (AR) expression in testes. Although no significant difference was observed in body weight or testes weights of PNP-treated rats compared with the controls, the serum concentrations of testosterone in the 10mg/kg PNP-treated group were significantly elevated. This effect was accompanied by Leydig cells hyperplasia in the testes. Conversely, there was a significant decrease in estradiol concentration and aromatase expression in the testes of the 10mg/kg PNP-treated group. Furthermore, we observed a significant increase in ERalpha expression in the testes of the 10mg/kg PNP-treated group compared with the control group. Conversely, ERbeta expression displayed a significant reduction. Moreover, AR expression was significantly increased in the 10mg/kg PNP-treated group compared with the control group. The existence of AR, ER-alpha and -beta in the testes suggests that estradiol and testosterone directly affect germ cells and that differential modulation of AR, ER-alpha and -beta in the testis may be involved in the direct effects of PNP or either the indirect effects of PNP-induced disruption of the estradiol-to-testosterone balance or the Leydig cells hyperplasia. Thus, the measurement of many endpoints is necessary for good risk assessment. PMID- 24070738 TI - Strategic formulation of apigenin-loaded PLGA nanoparticles for intracellular trafficking, DNA targeting and improved therapeutic effects in skin melanoma in vitro. AB - The aim of the present study was the evaluation of anti-proliferative potentials of apigenin (Ap), (a dietary flavonoid) loaded in poly (lactic-co-glycolide) nanoparticles (NAp) in A375 cells in vitro. NAp was characterized for particle size, morphology, zeta potential, drug release and encapsulation. Cellular entry and intracellular localization of NAp were assessed by transmission electron and confocal microscopies. Circular dichroic spectral analysis and stability curve for Gibb's free energy of dsDNA of A375 cells were also analyzed. DNA fragmentation, intracellular ROS accumulation, superoxide-dismutase activity, intracellular glutathione-reductase content and mitochondrial functioning through relevant markers like mitochondrial transmembrane potential, ATPase activity, ATP/ADP ratio, volume changes/swelling, cytochrome-c release, expressions of Apaf 1, bax, bcl-2, caspase-9, 3, and PARP cleavage were analyzed. NAp produced better effects due to their smaller size, faster mobility and site-specific action. Photostability studies revealed that PLGA encapsulations were efficient at preserving apigenin ultraviolet-light mediated photodegradation. NAp readily entered cancer cells, could intercalate with dsDNA, inducing conformational change. Corresponding increase in ROS accumulation and depletion of the antioxidant enzyme activities exacerbated DNA damage, mediating apoptosis through mitochondrial dysfunction. Overall results indicate that therapeutic efficacy of NAp may be enhanced by PLGA nanoparticle formulations to have better ameliorative potentials in combating skin melanoma. PMID- 24070739 TI - Caveolin-1 promotes gastric cancer progression by up-regulating epithelial to mesenchymal transition by crosstalk of signalling mechanisms under hypoxic condition. AB - Gastric cancer is the second most fatal common form of cancer. The crosstalk among signalling pathways that results in the acceleration of epithelial to mesenchymal transition (EMT) plays a pivotal role in the molecular mechanism of gastric carcinogenesis. To understand the role of caveolin-1 (Cav-1), the expression pattern was studied in human gastric adenocarcinoma tissues and also in AGS and KATO III cell lines. Here, we show that during hypoxic condition, the increase in the levels of hypoxia-inducible factor-1alpha (HIF-1alpha) results in a significant decrease in the expression of caveolin-1 which is regulated by heat shock protein 90 (HSP90). The reduced levels of Cav-1 correlated with the increased epidermal growth factor receptor (EGFR) activation resulting in the significant activation of its downstream target STAT3. Accumulation of pSTAT3 in the nucleus results in the decreased expression of E-cadherin and increased expression of mesenchymal markers (Slug, alpha-SMA, N-cadherin and vimentin). Crosstalk of EGFR and transforming growth factor beta (TGF-beta) signalling with Wnt signalling enhances cell proliferation, cell survival and upregulates EMT. There was no significant alteration in the expression of epithelial and mesenchymal molecules in both the cell lines studied. Thus, we provide evidence that Cav-1 was modulated by HSP90 and functions as a crucial regulator of EMT in gastric cancer. PMID- 24070740 TI - We've come a long way...haven't we? PMID- 24070741 TI - Diabetes self-management: what are we really talking about? PMID- 24070742 TI - The CHANGE program: comparing an interactive vs. prescriptive approach to self management among university students with obesity. AB - OBJECTIVE: To assess the effectiveness of 2 self-management (SM) approaches on obesity via a 12-week telephone-based intervention. An interactive motivational interviewing administered via Co-Active Life Coaching (MI-via-CALC) and a structured lifestyle treatment following the LEARN Program for Weight Management were compared. A secondary purpose was to explore the experiences of participants qualitatively. METHODS: University students 18-24 years of age with a body mass index >=30 kg/m(2) (n = 45) were randomized to either the: 1) MI-via-CALC condition that involved working with a certified Co-Active coach to achieve personal goals through dialogue, or 2) LEARN Program that entailed learning from a trained specialist who provided scripted, education-based lessons pertaining to lifestyle, exercise, attitudes, relationships and nutrition. Food consumption patterns, anthropometric and lipid profiles were examined at baseline, mid- and immediately posttreatment, and 3 and 6 months after the program. A semistructured questionnaire was completed at all follow-ups. RESULTS: Analyses revealed a significant time effect for weight (p = 0.01) with the LEARN group decreasing more (M = -7.76 lb) than the MI-VIA-CALC group (M = -2.5 lb) between baseline and week 12. MI-via-CALC participants decreased caloric intake more (M = -662.76) than LEARN participants (M = -105.5) during this same period. The MI-via-CALC group focused on self-understanding, and self-responsibility as primary outcomes of their experience; the LEARN group stressed their appreciation of practical knowledge gained. CONCLUSIONS: Both conditions seem similarly effective and are warranted as SM treatments. The best fit and unique contributions of each approach should be considered when working with this population. PMID- 24070743 TI - "An ounce of prevention": a primary care based prevention program for pre diabetic population. AB - OBJECTIVE: Given the existing and projected number of individuals with diabetes mellitus, there is an urgent need to implement effective prevention programs. Research trials have demonstrated reductions in risk through programs targeted at adopting a healthier lifestyle however translating this research evidence into primary care can be challenging. We examined the feasibility of implementing a pre-diabetes program into a primary care clinic in Ottawa, Canada. METHOD: "An Ounce of Prevention" Healthy Lifestyle and Diabetes Program was adapted from best evidence clinical trials and uses educational tools developed by the Diabetes Prevention Program for long-term behavior change, relies on principles of self management, is group based and includes an integrated exercise component. We used a multimethod evaluation approach and examined feasibility and practical implementation aspects such as space, staffing, recruitment and retention issues. RESULTS: We have implemented the program and have offered 10 courses from June 2010 through to August 2012 with 74 participants in total. Results of the evaluation surveys show that participants are highly satisfied with the content as well as the format of the program and think that the content is relevant to them. Recruitment of patients is time- intensive and requires dedicated resources. Evaluation of effectiveness with follow-up surveys and clinical measures has been challenging due to limited resources and is ongoing. CONCLUSIONS: The translation and implementation of research evidence into clinical practice is complex and requires consideration of real-life practicalities such as time demands on participants, staffing costs, effective recruiting and ongoing evaluation. PMID- 24070744 TI - Behaviour change counselling--how do I know if I am doing it well? The development of the Behaviour Change Counselling Scale (BCCS). AB - OBJECTIVE: The purpose of this article is to operationalize behaviour change counselling skills (motivation enhancement, behaviour modification, emotion management) that facilitate self-management support activities and evaluate the psychometric properties of an expert rater scale, the Behaviour Change Counselling Scale (BCCS). METHODS: Twenty-one healthcare providers with varying levels of behaviour change counselling training interviewed a simulated patient. Videotapes were independently rated by 3 experts on 2 occasions over 6 months. Data on item/subscale characteristics, interrater and test-retest reliability, preliminary data on construct reliability, were reported. RESULTS: All items of the BCCS performed well with the exception of 3 that were dropped due to infrequent endorsement. Most subscales showed strong psychometric properties. Interrater and test-retest reliability coefficients were uniformly high. Competency scores improved significantly from pre- to posttraining. CONCLUSIONS: Behaviour change counselling skills to guide lifestyle interventions can be operationalized and assessed in a reliable and valid manner. PRACTICE IMPLICATIONS: The BCCS can be used to guide clinical training in lifestyle counselling by operationalizing the component skills and providing feedback on skill achieved. Further research is needed to establish cut scores for competency and scale construct and criterion validity. PMID- 24070745 TI - Embedding islet in a liquid scaffold increases islet viability and function. AB - INTRODUCTION: Islet transplantation is a promising strategy to restore efficient insulin regulation in type 1 diabetes mellitus patients. However, shortage of islet donors, poor islet survival and toxicity of immunosuppressants often reduce the graft functional lifetime. METHODS: We previously showed that a fibroblast populated-collagen matrix (CM) significantly improved engrafted islet viability/function. However, this composite was prone to gradual biodegradation and contraction. Moreover, to avoid use of systemic immunosuppressants, we proposed the use of a local immunosuppressive enzyme, indoleamine-2,3-dioxygenase (IDO). We developed a novel bioengineered crosslinked CM (CCM) to provide optimal matrix biomimetic. Viability and insulin secretory function of islets embedded within fibroblast populated CCM (FP-CCM) was evaluated in vitro and in vivo. IDO expression was transduced in fibroblasts by a lentiviral vector carrying IDO gene and islet viability was evaluated in the presence and absence of IDO producing cells. RESULTS: Islet survival/function markedly improved within FP-CCM. Furthermore, our data shows that local lentiviral induction of IDO delivered by FP-CCM is nontoxic to the embedded islets. CONCLUSIONS: This promising finding offers a new approach to improving islet transplant outcome. PMID- 24070746 TI - Psychosocial issues in diabetes self-management: strategies for healthcare providers. AB - Education and training for diabetes mellitus self-management is widely available and an essential part of many diabetes centres. Nonetheless, the majority of individuals with diabetes do not adhere to optimal self-management recommendations. It is believed that psychosocial issues play an important role in individuals' ability to undertake the extensive behavioural demands involved in managing diabetes. The goal of the present article is to provide an overview of psychosocial issues and suggest strategies for healthcare providers in supporting patients with the challenges of diabetes self-management. First, motivational enhancement strategies have the potential to augment patients' own motivation to engage in health behaviours. Second, behavior modification principles can increase patients' self-efficacy and their experiences of success. Third, managing distressing emotions, including anxiety, depression, distress specifically related to diabetes care, and fear of hypoglycemia, can facilitate motivation and ability to undertake diabetes self-management efforts. Recognizing and addressing psychosocial challenges allows healthcare providers to better support their patients in the demanding tasks of diabetes self-management. PMID- 24070747 TI - Health coaching in diabetes: empowering patients to self-manage. AB - To effectively manage diabetes mellitus, patients must adhere to treatment recommendations and healthy lifestyle behaviors, but research shows many patients do not do this. Education is effective when combined with self-management support but peer-support programs do not lead to lasting changes. Health coaching, or professional support, can be highly effective if it focuses on developing self efficacy and skills such as goal-setting, problem-solving and managing cognitive and emotional barriers. This overview discusses the benefits of patient self management for chronic conditions such as diabetes, core competencies for health coaching, theoretical bases and principles of health coaching interventions, delivery methods and the evidence that health coaching works for diabetes self management. PMID- 24070748 TI - The challenge of integrating self-management support into clinical settings. AB - Best practice diabetes mellitus clinical treatment and education takes place in the medical clinic, however, patient outcomes are largely mediated through their own behaviour and lifestyle that occurs after they leave the clinical setting. Once they return home, people usually continue to engage in the social, cultural and lifestyle behaviours that had contributed to having diabetes in the first place. Although a host of factors (e.g. economic, health care team and system, condition and client-related) can impact a client's capacity to self-manage, there are client, organizational and community level strategies that may partially mitigate these difficulties. To address client behaviour, clinicians are increasingly becoming skilled to incorporate self-management support including behavioural counselling interventions into routine practice. At the organizational level, the operation and structure of the clinical setting may create difficulty for staff to provide self-management support. Sustaining benefits on a day-to-day basis presents an additional challenge. This article will review several common implementation barriers to self-management support and describe strategies and techniques used elsewhere to successfully integrate self management support as a core care component for persons with diabetes. PMID- 24070749 TI - Food and dietary pattern-based recommendations: an emerging approach to clinical practice guidelines for nutrition therapy in diabetes. AB - Clinical practice guidelines (CPGs) for the nutritional management of diabetes mellitus have evolved considerably over the last 25 years. As major diabetes associations have focussed on the individualization of nutrition therapy, there has been a move toward a broader more flexible macronutrient distribution that emphasizes macronutrient quality over quantity. There is now a call for the integration of food- and dietary pattern-based approaches into diabetes association CPGs. The main argument has been that an approach that focuses on nutrients alone misses important nutrient interactions oversimplifying the complexity of foods and dietary patterns, both of which have been shown to have a stronger influence on disease risk than nutrients alone. Although cancer and heart associations have begun to integrate this approach into their dietary guidelines, diabetes associations have not yet adopted this approach. We provide a rationale for the adoption of this approach for The Canadian Diabetes Association (CDA) 2013 CPGs for nutrition therapy. The systematic review for the development of these guidelines revealed emerging evidence to support the use of vegetarian, Mediterranean, and Dietary Approaches to Stop Hypertension (DASH) dietary patterns as well as specific foods such as dietary pulses and nuts in people with diabetes. Popular and conventional weight loss diets were also found to have similar advantages in people with diabetes, although poor dietary adherence remains an issue with these diets. The CDA 2013 CPGs will support an even greater individualization of nutrition therapy for people with diabetes and appeal to a broader range of practice styles of health professionals. PMID- 24070768 TI - IL-7 promotes long-term in vitro survival of unique long-lived memory subset generated from mucosal effector memory CD4+ T cells in chronic colitis mice. AB - Colitogenic memory CD4(+) T cells are important in the pathogenesis of inflammatory bowel disease (IBD). Although memory stem cells with high survival and self-renewal capacity were recently identified in both mice and humans, it is unclear whether a similar subset is present in chronic colitis mice. We sought to identify and purify a long-lived subset of colitogenic memory CD4(+) T cells, which may be targets for treatment of IBD. A long-lived subset of colitogenic memory CD4(+) T cells was purified using a long-term culture system. The characteristics of these cells were assessed. Interleukin (IL)-7 promoted the in vitro survival for >8 weeks of lamina propria (LP) CD4(+) T cells from colitic SCID mice previously injected with CD4(+)CD45RB(high) T cells. These cells were in a quiescent state and divided a maximum of 5 times in 4 weeks. LP CD4(+) T cells expressed higher levels of Bcl-2, integrin-alpha4beta7, CXCR3 and CD25 after than before culture, as well as secreting high concentrations of IL-2 and low concentrations of IFN-gamma and IL-17 in response to intestinal bacterial antigens. LP CD4(+) T cells from colitic mice cultured with IL-7 for 8 weeks induced more severe colitis than LP CD4(+) T cells cultured for 4 weeks. We developed a novel culture system to purify a long-lived, highly pathogenic memory subset from activated LP CD4(+) T cells. IL-7 promoted long-term in vitro survival of this subset in a quiescent state. This subset will be a novel, effective target for the treatment of IBD. PMID- 24070769 TI - Supervised methods for symptom name recognition in free-text clinical records of traditional Chinese medicine: an empirical study. AB - Clinical records of traditional Chinese medicine (TCM) are documented by TCM doctors during their routine diagnostic work. These records contain abundant knowledge and reflect the clinical experience of TCM doctors. In recent years, with the modernization of TCM clinical practice, these clinical records have begun to be digitized. Data mining (DM) and machine learning (ML) methods provide an opportunity for researchers to discover TCM regularities buried in the large volume of clinical records. There has been some work on this problem. Existing methods have been validated on a limited amount of manually well-structured data. However, the contents of most fields in the clinical records are unstructured. As a result, the previous methods verified on the well-structured data will not work effectively on the free-text clinical records (FCRs), and the FCRs are, consequently, required to be structured in advance. Manually structuring the large volume of TCM FCRs is time-consuming and labor-intensive, but the development of automatic methods for the structuring task is at an early stage. Therefore, in this paper, symptom name recognition (SNR) in the chief complaints, which is one of the important tasks to structure the FCRs of TCM, is carefully studied. The SNR task is reasonably treated as a sequence labeling problem, and several fundamental and practical problems in the SNR task are studied, such as how to adapt a general sequence labeling strategy for the SNR task according to the domain-specific characteristics of the chief complaints and which sequence classifier is more appropriate to solve the SNR task. To answer these questions, a series of elaborate experiments were performed, and the results are explained in detail. PMID- 24070770 TI - Cassandra's prophecy fulfilled: a response to Khalaf. PMID- 24070771 TI - Tomographic follow-up of bone regeneration after bone block harvesting from the mandibular ramus. AB - Autogenous bone is still considered the gold standard, and the applicability of autogenous bone grafts is well established. However, the possibility of second harvesting from the same donor region remains unclear. The aim of this study was to perform a prospective evaluation of hard tissue deposition in the mandibular ramus after bone block harvesting using cone beam computed tomography (CBCT). Twenty-two patients with indications for augmentation procedures using autogenous bone from the mandibular ramus were selected. Three CBCT scans were performed with a tomographic guide before bone harvesting (T1) and at 14 days (T2) and 6 months (T3) after the surgical procedures. Measurements were obtained in 2D (area, mm(2)) and 3D (volume, mm(3)), and were subsequently compared. In the 2D analysis, the mean bone formation rate was 56%, while for the 3D analysis the mean rate was 9.7%. Despite this difference, there was a significant correlation between area and volume measurements. Our findings demonstrated the presence of hard tissue in the mandibular ramus at 6 months after bone harvesting, which suggests that it would be possible to reuse the same region for a second block harvesting. However, the second bone harvesting would involve less bone for transplantation when compared to the first bone harvesting. PMID- 24070772 TI - The retromandibular transparotid approach for reduction and rigid internal fixation using two locking miniplates in mandibular condylar neck fractures. AB - We evaluated the safety, efficacy, and morbidity associated with the treatment of displaced mandibular condylar neck fractures using a retromandibular transparotid approach to reduce and rigidly fix using two 2.0-mm locking miniplates. Our surgical inclusion criteria were: patient selection of open reduction and fixation, displaced unilateral condylar fractures with derangement of occlusion, and bilateral condylar fractures with an anterior open bite. The study group consisted of 19 patients who underwent surgery for 19 mandibular condylar neck fractures; patients were analyzed prospectively, with more than 6 months of follow-up, and were evaluated in terms of functional results, scar formation, postoperative complications, and stability of fixation. The results showed that functional occlusion identical to the preoperative condition and correct anatomical reduction of the condylar segments in centric occlusion, followed by immediate functional recovery, was achieved in all patients. No patient suffered from any major or permanent complication postoperatively, although there were two cases (11%) of temporary facial nerve palsy, which resolved completely within 3 months. Surgical scars were barely visible. The retromandibular transparotid approach with open reduction and rigid internal fixation for displaced condylar neck fractures of the mandible is a feasible and safe, minimally invasive surgical technique that provides reliable clinical results. PMID- 24070773 TI - Antioxidant response, CYP450 system, and histopathological changes in the liver of nitrobenzene-treated drakes. AB - Nitrobenzene (NB) has become an important pollutant in the environment, but its potential effects on non-target species such as drake remain unknown. In this study, we investigated the oxidative stress response, the CYP450 system and histopathological changes of the liver of NB-treated drakes for 40 d. Our results indicated that NB induced significant changes in antioxidant enzyme (SOD, CAT and GSH-Px) activities and the MDA content in the liver of the drakes. NB caused a condition-dependent increase in APND, EROD and ECOD isoenzyme activities and CYP450 content with increased exposure dose. Significant histological alternations were observed in the liver of NB-treated drakes and the pathological changes revealed tissue damage that was more severe with increasing of exposure dose. To our knowledge, this is the first study to report the chronic effects of NB on oxidative stress, the CYP450 system and histopathology in the drakes. These significant effects caused by NB reveal that these indices can be used as biomarker for monitoring NB as an environmental pollutant. Thus, future studies are needed to fully understand the exact mechanisms of these findings. PMID- 24070774 TI - Detection of three common alpha-thalassemia in non-deletion types and six common thalassemia in deletion types by QF-PCR. AB - OBJECTIVE: Thalassemia is one of the most common monogenic hereditary diseases in tropical and subtropical regions. An effective way to avoid the birth of severe thalassemia patients is to strengthen the thalassemia screening of couples before wives are pregnant. Thalassemia gene carriers can be diagnosed by molecular biology in order to conduct effective guidance for fertility. DESIGNS AND METHODS: For --(SEA) and --(THAI) of alpha-thalassemia and HPFH-SEA and DBT of beta-thalassemia, we design the fGap-PCR primer; for alpha(CS)alpha, alpha(QS)alpha and alpha(WS)alpha, we design the fAS-PCR primer; for alpha(3.7)and -alpha(4.2), we design the QF-PCR primer; and lastly, we use universal primers and multiple-tailed primers to make a single-tube QF-PCR system. RESULTS: When the QF-PCR system is used to diagnose 123 screening samples of thalassemia genotyping, the typing result is consistent with conventional diagnosis of Gap-PCR and PCR-RDB. CONCLUSIONS: Compared with conventional Gap-PCR and PCR-RDB, this QF-PCR system is easy to operate, has high precision, and can diagnose genotypes in a large scale. Its automatic operation is more suitable for the large-scale screening of the thalassemia gene. PMID- 24070775 TI - Integrated ecotoxicological assessment of bottom sediments from the Parana basin, Argentina. AB - Parana River, the six largest in the world, is receptor of pollution loads from tributaries traversing urban and industrialized areas, and extensive agriculture, particularly in its middle and low stretch along the Argentinean sector, where most of the productive activities of the country develop. Within the frame of monitoring surveys, the quality of bottom sediments from distal positions of twenty tributaries and three of the main course was evaluated. The assessment covered testing lethal and sublethal effects with the Hyalella curvispina based toxicity test, a benthic macrofauna survey and physicochemical variables of sediment matrix composition. A multivariate statistical analysis approach permitted integrating the obtained data from the different survey lines of evidence, explaining potential causes of the measured biological effects. The main perturbations detected were associated to tributaries in the middle sector of the basin, where anoxic conditions with high sulfide contents prevail mostly related to organic matter inputs of diverse combined activities, where sediments induce high lethality, and a consequent strong reduction of the benthic community population and diversity. The integrated survey approach proved being a robust tool in the assessment of causative-adverse effects relationships. PMID- 24070776 TI - Protozoans as indicators of sequential batch processes for phenol treatment; an autoecological approach. AB - The objective of this study was the investigation of the potential use of protistan species as quality indicators of the activated sludge performance in sequential batch processes receiving toxic compounds. Two laboratory scale sequential batch reactors (SBR) were used, a conventional one and a system with plastic biofilm carriers (SBBR), treating wastewater containing phenol at concentrations ranging from 1 up to 40 mg/L. Physicochemical analyses of the samples included the determination of MLSS, effluent suspended solids, BOD5, nitrogen-ammonia, nitrogen-nitrate and phenol. The activated sludge protistan community was identified and enumerated in each reactor. Statistical analyses included Canonical Correspondence Analysis and Indicator Species Analysis of the collected experimental data. Canonical Correspondence Analysis showed inversely proportional relationships between the protozoa and the physicochemical parameters of the effluent as well as protozoan species competition. Indicator species analysis revealed the presence and the prevalence of different species under various phenol influent concentrations. No indicator species were observed for the period of operation under 5 mg/L influent phenol in both reactors, while no indicator species were observed for 20 mg/L influent phenol in the SBR reactor. Carchesium and Epistylis sp. showed the higher values for 1 mg/L phenol in the SBR, while Holophrya sp. showed lower indicator values for the same period in the SBBR. Although several species showed a good correlation to the treatment efficiency of the reactors, Blepharisma sp., could be used as the primary indicator species in both reactors for the operation period under 40 mg/L phenol, as deduced by statistical analysis. PMID- 24070777 TI - The toxicity of nitrofuran compounds on melanoma and neuroblastoma cells is enhanced by Olaparib and ameliorated by melanin pigment. AB - Nitrofurans are commonly used for the treatment of trypanosomal diseases including Chagas disease. More recently, following the fortuitous discovery that nifurtimox was clinically active against neuroblastoma, nitrofuran compounds are being investigated for activity against cancer. Herein, we show that nitrofuran compounds are similarly potent to human malignant melanoma and neuroblastoma cells. Furthermore, a recently discovered nitrofuran compound, NFN1, was 50- to 175-fold more potent than nifurtimox against human melanoma and neuroblastoma cell lines. As nitrofuran compounds are known to act as pro-drugs, producing DNA damaging reactive intermediates upon activation, we investigated the DNA repair pathways involved. We show that, contrary to research in Escherichia coli, the Nucleotide Excision Repair pathway is not required to repair nitrofuran-induced DNA damage in mammalian cells. Instead, we show that inhibiting repair of single strand DNA breaks with the poly(ADP-ribose) polymerase (PARP) inhibitor, Olaparib, enhances nitrofuran toxicity in melanoma and neuroblastoma cells. We propose that this is due to mammalian cells utilising Type 2 nitroreductases for nitrofuran activation producing Reactive Oxygen Species which cause DNA damage that is repaired by the Single Strand Break Repair and/or Base Excision Repair pathways, whereas in bacteria and trypanosomes, Type 1 nitroreductases are also utilised resulting in different DNA lesions. In addition we show that, consistent with Reactive Oxygen Species being formed upon nitrofuran activation and the ability of melanin to absorb Reactive Oxygen Species, production of melanin in melanoma cells offers some protection from NFN1- and hydrogen peroxide-induced toxicity. Our data suggest that combinations of Olaparib and nitrofuran compounds may be advantageous for the treatment of melanoma and neuroblastoma, but that the protection offered to melanoma cells by their melanin pigment must be taken into account. PMID- 24070778 TI - Evaluation of an antiparasitic compound extracted from Galla chinensis against fish parasite Ichthyophthirius multifiliis. AB - Ichthyophthirius multifiliis (Ich) is an important ectoparasitic ciliate that parasitizes gills and skin of freshwater fish resulting in massive mortality of fish. Currently there is no chemotherapeutant available to treat Ich effectively and economically. There is an urgent need to discover effective and safe parasiticides to control ichthyophthiriasis. In this study, anti-Ich efficacy of pentagalloylglucose, a compound extracted from the plant Galla chinensis was evaluated and the toxicity of the compound on channel catfish was determined. Pentagalloylglucose can kill all theronts at concentrations of 2.5-20 mg/L during 5.6-233.9 min and terminate reproduction of tomonts at 40 mg/L. Pentagalloylglucose significantly reduced infective ability of theronts at 1, 2 and 5 mg/L. The survival of naive channel catfish was 70% when treated with 10 mg/L and 100% when treated with 20 mg/L of pentagalloylglucose. For Ich infected catfish, the survival was 53.3% when treated with 10 mg/L and 93.3% when treated with 20 mg/L of pentagalloylglucose. Pentagalloylglucose at 20 mg/L was effective for treating Ich infected catfish or preventing naive catfish from Ich infestation. Median lethal concentration of the compound to catfish was 151.3 mg/L, which was 5 times the median effective concentration (30.5 mg/L) for killing tomonts. The compound killed Ich by destroying the plasma membrane of the parasite. The result demonstrated pentagalloylglucose as a safe, effective potential parasiticide against I. multifiliis. PMID- 24070779 TI - Development of EMA-2 recombinant antigen based enzyme-linked immunosorbent assay for seroprevalence studies of Theileria equi infection in Indian equine population. AB - Equine piroplasmosis is a tick-transmitted protozoan disease caused by Theileria equi and/or Babesia caballi. In the present study, we expressed a 53kDa protein from the truncated EMA-2 gene of T. equi (Indian strain) and developed EMA-2ELISA using this expressed protein. This ELISA is able to detect T. equi-specific antibodies in experimentally infected animals as early as 9 days post-infection. The assay developed was validated with the OIE recommended competitive ELISA (cELISA) on 120 serum samples and significant agreement (kappa=0.93) was observed between results of both the ELISAs which indicates suitability of EMA-2ELISA for use in sero-diagnosis. Diagnostic sensitivity and specificity of EMA-2ELISA - as compared with cELISA - were 0.97 and 0.96, respectively. Analysis of 5651 equine serum samples - collected during 2007-2012 from 12 states of India representing eight agro-climatic zones - by EMA-2ELISA revealed 32.65% seroprevalence of T. equi in India. In conclusion, the EMA-2ELISA developed using the T. equi EMA-2 recombinant protein as antigen for detecting T. equi-specific antibodies has good diagnostic potential for sero-epidemiological surveys. PMID- 24070780 TI - Effects of test sample shape and surface production method on the fatigue behaviour of PMMA bone cement. AB - There is no consensus over the optimal criterion to define the fatigue life of bone cement in vitro. Fatigue testing samples have been made into various shapes using different surface preparation techniques with little attention being paid to the importance of these variations on the fatigue results. The present study focuses on the effect of test sample shape and surface production method on the fatigue results. The samples were manufactured with two cross sectional shapes: rectangular according to ISO 527 and circular according to ASTM F2118. Each shape was produced using two methods: direct moulding of the cement dough and machining from oversized rods. Testing was performed using two different bone cements: SmartSet GHV and DePuy CMW1. At least 10 samples of each category were tested, under fully reversed tension-compression fatigue stress at +/-20MPa, to allow for Weibull analysis to compare results. The growth of fatigue cracks was observed by means of the changes in the absorbed energy and apparent modulus. It was found that fatigue crack growth can be altered by the sample shape and production method; however it is also dependent on the chemical composition of the cement. The results revealed that moulded samples, particularly those based on the ASTM F2118 standard, can lead to up to 5.5 times greater fatigue lives compared to the machined samples of the same cement. It is thus essential, when comparing the fatigue results of bone cement, to consider the effect of production method along with the shape of the test sample. PMID- 24070781 TI - Synthesis and bioactivities of novel thioether/sulfone derivatives containing 1,2,3-thiadiazole and 1,3,4-oxadiazole/thiadiazole moiety. AB - A series of new thioether/sulfone compounds containing 1,2,3-thiadiazole and 1,3,4-oxadiazole/1,3,4-thiadiazole moiety were synthesized, the structures of all products were confirmed by IR, (1)H NMR, (13)C NMR, and element analysis. Preliminary antifungal activity test showed that compound 8a exhibited moderate antifungal activity against Fusarium oxysporum at 50MUg/mL. Preliminary antiviral activity results showed that compounds 7a, 7c, 7d, 8a, and 9a displayed high antiviral activity against tobacco mosaic virus. The present work demonstrates that thioether/sulfone heterocyclic derivatives could be considered as new lead compounds for antiviral studies. PMID- 24070782 TI - Structure-activity relationships of lanostane-type triterpenoids from Ganoderma lingzhi as alpha-glucosidase inhibitors. AB - A series of lanostane-type triterpenoids, identified as ganoderma alcohols and ganoderma acids, were isolated from the fruiting body of Ganoderma lingzhi. Some of these compounds were confirmed as active inhibitors of the in vitro human recombinant aldose reductase. This paper aims to explain the structural requirement for alpha-glucosidase inhibition. Our structure-activity studies of ganoderma alcohols showed that the OH substituent at C-3 and the double-bond moiety at C-24 and C-25 are necessary to increase alpha-glucosidase inhibitory activity. The structure-activity relationships of ganoderma acids revealed that the OH substituent at C-11 is an important feature and that the carboxylic group in the side chain is essential for the recognition of alpha-glucosidase inhibitory activity. Moreover, the double-bond moiety at C-20 and C-22 in the side chain and the OH substituent at C-3 of ganoderma acids improve alpha glucosidase inhibitory activity. These results provide an approach with which to consider the structural requirements of lanostane-type triterpenoids from G. lingzhi. An understanding of these requirements is considered necessary in order to improve a new type of alpha-glucosidase inhibitor. PMID- 24070783 TI - Discovery of (S,E)-3-(2-fluorophenyl)-N-(1-(3-(pyridin-3-yloxy)phenyl)ethyl) acrylamide as a potent and efficacious KCNQ2 (Kv7.2) opener for the treatment of neuropathic pain. AB - Acrylamide (S)-6, a potent and efficacious KCNQ2 (Kv7.2) opener, demonstrated significant activity in two models of neuropathic pain and in the formalin test, suggesting that KCNQ2 openers may be useful in the treatment of neuropathic pain including diabetic neuropathy. PMID- 24070784 TI - Three new resorcylic acid derivatives from Sporotrichum laxum. AB - Sporotrichum laxum ATCC 15155 is the producing strain of the potent anti Helicobacter pylori natural product spirolaxine (1). Investigation of the secondary metabolites in this fungus led to the isolation of five phthalides (1, 2, 3, 6 and 9) and five resorcylic acid derivatives (4, 5, 7, 8 and 10), among which 5, 7 and 8 are new compounds. The structures were elucidated by spectroscopic analyses, and the absolute configurations of 7 and 8 were determined by Mosher's method. Addition of soy flour into the potato dextrose agar has led to the increased production of 4-10. A biosynthetic pathway consisting of a highly reducing polyketide synthase (PKS), a nonreducing PKS and a series of tailoring enzymes was proposed to produce these fungal natural products. The resorcylic acid derivatives are proposed to result from early hydrolysis of the polyketide chain or incorporation of a longer fatty acyl starter unit. PMID- 24070785 TI - Optimization of one-step real-time reverse transcription-polymerase chain reaction assays for norovirus detection and molecular epidemiology of noroviruses in Thailand. AB - Noroviruses (NoVs) are an important human pathogen associated with acute viral gastroenteritis worldwide. NoVs display a significant amount of genetic heterogeneity, making it difficult to develop comprehensive detection assays. In this study, primer sets and probes were designed for a TaqMan((r))-based real time reverse transcription-polymerase chain reaction (RT-PCR) for norovirus detection purposes. The assay was optimized and utilized as a multiplex real-time RT-PCR assay for genogroup I (GI) detection, and a singleplex real-time RT-PCR assay for genogroup II (GII) detection. The assays showed high specificity for NoV detection and no cross-reactivity was observed between GI and GII. The detection limit of the assay was as low as 10 and 50 RNA copies per reaction for GI and GII, respectively. The optimized protocol was employed to assess the presence of NoV strains in clinical samples collected throughout Thailand during December 2005 to November 2006. The percentage of NoV infections among children with acute gastroenteritis (case) was 23.8% (119/500) and for children without acute gastroenteritis (control) it was 6.8% (30/441). The frequency of NoV infections varied geographically, with the highest frequency observed in the central region and the lowest frequency in the northern region (P>0.0001). Of the 149 positive case and control specimens, GII was found to be the predominant genogroup (98.6%). Partial capsid sequences were successfully obtained from 67 NoV-positive specimens and a phylogenetic analysis was performed to genotype the viral strains. GII.4 was the most common genotype detected. PMID- 24070787 TI - Investigation of tyrphostin AG 556 for testicular torsion-induced ischemia reperfusion injury in rat. AB - OBJECTIVE: To investigate the effects of tyrphostin AG 556, a tyrosine kinase inhibitor (TKI) in an experimental model of testicular ischemia-reperfusion (I/R) injury. MATERIAL AND METHODS: Twenty-four adult male rats were randomly divided into four groups (n = 6): sham, torsion/detorsion (T/D), T/D + dimethylsulfoxide (DMSO) (vehicle group), and T/D + DMSO + tyrphostin AG 556. Testicular torsion was achieved by rotating the left testis 720 degrees clockwise for 4 h. Thirty minutes before detorsion, 3 mg/kg tyrphostin AG 556 was injected transperitoneally in the AG 556 group and DMSO was injected transperitoneally in the DMSO group. After 2 h of reperfusion arterial blood samples were collected for biochemical analysis for malondialdehyde (MDA), ischemia modified albumin (IMA), SCUBE1 (signal peptide-CUB [complement C1r/C1s, Uegf, and Bmp1] and EGF [epidermal growth factor] like domain-containing protein 1), total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) parameters, and ipsilateral orchiectomies were performed for histopathological examination based on the semi-quantitative Johnsen's mean testicular biopsy score (MTBS) in all groups. RESULTS: Tyrphostin AG 556 exhibited a protective effect against I/R injury in testicular torsion. Of the biochemical parameters evaluated as a result of testicular I/R, IMA, MDA, and TOS levels were significantly elevated. There was no significant difference in terms of these biochemical parameters between the sham and AG 556 groups. Significant histopathological injury was determined by comparing the T/D and sham groups. According to histopathological injury scores, significant differences were determined between T/D and AG 556 groups and between AG 556 and sham groups. AG 556 had a superior improving effect on Johnsen's scores than DMSO. CONCLUSIONS: Our results suggest that the use of tyrphostin AG 556 prior to testicular reperfusion has a protective effect against testicular I/R injury. PMID- 24070788 TI - Clinical trials in "emerging markets": regulatory considerations and other factors. AB - Clinical studies are being placed in emerging markets as part of global drug development programs to access large pool of eligible patients and to benefit from a cost effective structure. However, over the last few years, the definition of "emerging markets" is being revisited, especially from a regulatory perspective. For purposes of this article, countries outside US, EU and the traditional "western countries" are discussed. Multiple factors are considered for placement of clinical studies such as adherence to Good Clinical Practice (GCP), medical infrastructure & standard of care, number of eligible patients, etc. This article also discusses other quantitative factors such as country's GDP, patent applications, healthcare expenditure, healthcare infrastructure, corruption, innovation, etc. These different factors and indexes are correlated to the number of clinical studies ongoing in the "emerging markets". R&D, healthcare expenditure, technology infrastructure, transparency, and level of innovation, show a significant correlation with the number of clinical trials being conducted in these countries. This is the first analysis of its kind to evaluate and correlate the various other factors to the number of clinical studies in a country. PMID- 24070789 TI - The STEP (Safety and Toxicity of Excipients for Paediatrics) database: part 2 - the pilot version. AB - The screening and careful selection of excipients is a critical step in paediatric formulation development as certain excipients acceptable in adult formulations, may not be appropriate for paediatric use. While there is extensive toxicity data that could help in better understanding and highlighting the gaps in toxicity studies, the data are often scattered around the information sources and saddled with incompatible data types and formats. This paper is the second in a series that presents the update on the Safety and Toxicity of Excipients for Paediatrics ("STEP") database being developed by Eu-US PFIs, and describes the architecture data fields and functions of the database. The STEP database is a user designed resource that compiles the safety and toxicity data of excipients that is scattered over various sources and presents it in one freely accessible source. Currently, in the pilot database data from over 2000 references/10 excipients presenting preclinical, clinical, regulatory information and toxicological reviews, with references and source links. The STEP database allows searching "FOR" excipients and "BY" excipients. This dual nature of the STEP database, in which toxicity and safety information can be searched in both directions, makes it unique from existing sources. If the pilot is successful, the aim is to increase the number of excipients in the existing database so that a database large enough to be of practical research use will be available. It is anticipated that this source will prove to be a useful platform for data management and data exchange of excipient safety information. PMID- 24070790 TI - Coronary artery diseases in Japanese patients with nonvalvular atrial fibrillation. AB - BACKGROUND: Both the prevalence of atrial fibrillation and coronary artery disease (CAD) is increasing in aged societies. However, limited data are available regarding the prevalence of CAD and the incidence of coronary events in Japanese patients with nonvalvular atrial fibrillation (NVAF). METHODS AND RESULTS: The data in this study were derived from Shinken Database 2004-2010, which includes 15,227 new patient visitors to the Cardiovascular Institute between June 2004 and March 2011. In the database, 1835 patients were diagnosed with NVAF (mean age 63 years, mean CHADS2 score 1.1 +/- 1.1, and 75% were men). The prevalence of CAD at the initial visit was 118 patients (6.4%). They were older age and had a greater prevalence of men, more history of congestive heart failure and more history of cardiovascular risk factors rather than those without. During the follow-up period of 532 +/- 599 days, coronary events (myocardial infarction, unstable angina, and stable angina) occurred in 51 patients (1.9%/year). Multivariate analysis showed that a history of CAD (p<0.001) and older age (p=0.024) were independent predictors of the incidence of future coronary events. CONCLUSIONS: In Japanese patients with NVAF, both the presence of CAD and the occurrence of coronary events are not uncommon. History of CAD and older age are strongly associated with the incidence of coronary events. PMID- 24070791 TI - Trans-vaccenate is Delta13-desaturated by FADS3 in rodents. AB - Fatty acid desaturases play critical roles in regulating the biosynthesis of unsaturated fatty acids in all biological kingdoms. As opposed to plants, mammals are so far characterized by the absence of desaturases introducing additional double bonds at the methyl-end site of fatty acids. However, the function of the mammalian fatty acid desaturase 3 (FADS3) gene remains unknown. This gene is located within the FADS cluster and presents a high nucleotide sequence homology with FADS1 (Delta5-desaturase) and FADS2 (Delta6-desaturase). Here, we show that rat FADS3 displays no common Delta5-, Delta6- or Delta9-desaturase activity but is able to catalyze the unexpected Delta13-desaturation of trans-vaccenate. Although there is no standard for complete conclusive identification, structural characterization strongly suggests that the Delta11,13-conjugated linoleic acid (CLA) produced by FADS3 from trans-vaccenate is the trans11,cis13-CLA isomer. In rat hepatocytes, knockdown of FADS3 expression specifically reduces trans vaccenate Delta13-desaturation. Evidence is presented that FADS3 is the first "methyl-end" fatty acid desaturase functionally characterized in mammals. PMID- 24070792 TI - [Tubular renal acidosis]. AB - Renal tubular acidosis (RTAs) are a group of metabolic disorders characterized by metabolic acidosis with normal plasma anion gap. There are three main forms of RTA: a proximal RTA called type II and a distal RTA (type I and IV). The RTA type II is a consequence of the inability of the proximal tubule to reabsorb bicarbonate. The distal RTA is associated with the inability to excrete the daily acid load and may be associated with hyperkalaemia (type IV) or hypokalemia (type I). The most common etiology of RTA type IV is the hypoaldosteronism. The RTAs can be complicated by nephrocalcinosis and obstructive nephrolithiasis. Alkalinization is the cornerstone of treatment. PMID- 24070793 TI - [Skin manifestations of monoclonal gammopathies]. AB - Whatever their aetiology, monoclonal gammopathies can be associated to several clinical features. Mechanisms are various and sometimes unknown. Skin is frequently involved and may represent a challenging diagnosis. Indeed, skin manifestations are either the presenting features and isolated, or at the background of a systemic syndrome. Our objective was to review the various skin manifestations that have been associated with monoclonal gammopathies. PMID- 24070794 TI - Obesity and type 2 diabetes mellitus. PMID- 24070795 TI - Joint effect of family history of diabetes with obesity on prevalence of type 2 diabetes mellitus among Chinese and Finnish men and women. AB - OBJECTIVE: To study joint effect of family history of diabetes (FHD) with obesity on prevalence of type 2 diabetes mellitus in the Chinese and in the Finns. METHODS: A total of 1091 Chinese men and 1706 women, 1472 Finnish men and 1694 women, 45-74 years of age were studied. The probability and odds ratio (OR) of having diabetes were estimated using logistic regression analysis. The synergy index (SI) and relative excess risk due to interaction (RERI) of FHD with body mass index (BMI) or waist circumference (WC) was calculated. RESULTS: Age standardized prevalence of diabetes was higher in individuals with FHD than in those without in both the Chinese and Finns. Compared with individuals without FHD and with BMI <30 kg/m(2), ORs (95% confidence intervals [CI]) for diabetes were 2.7 (1.8, 4.0), 2.8 (1.9, 4.0), 9.1 (5.9, 13.9), respectively, in Finnish men with BMI >=30 kg/m(2) alone, with FHD alone and with both (SI [95% CI] = 2.4 [1.4, 3.9], RERI = 4.6 [1.3, 8.0]); the corresponding figures were 1.7 (1.0, 2.9), 2.7 (1.8, 4.2) and 4.4 (1.9, 10.4) in Chinese men (SI = 1.4 [0.4, 4.9] RERI = 1.0 [-2.9, 5.0]). They were 3.5 (2.1, 5.8), 2.1 (1.3, 3.4) and 6.8 (4.1, 11.2) in Finnish women (SI = 1.6 [0.9, 2.8], RERI = 2.2 [-0.4, 4.9]), and 1.6 (1.1, 2.2), 2.1 (1.5, 3.0), 3.5 (1.9, 6.4) in Chinese women (SI = 1.5 [0.6, 3.8], RERI = 0.8 [-1.4, 3.0]). The pattern of synergistic effect of FHD with WC on diabetes was similar to that seen with BMI in the Finns but no effect was seen in the Chinese. CONCLUSIONS: Both obesity and FHD are independent risk factors for diabetes, but their joint effect is significant only in Finnish men. PMID- 24070796 TI - Process evaluation of the Living Green, Healthy and Thrifty (LiGHT) web-based child obesity management program: combining health promotion with ecology and economy. AB - OBJECTIVE: To conduct a process evaluation of the Living Green, Healthy and Thrifty (LiGHT) program, a novel virtual child obesity management program that combines health promotion with ecology and economy (Phase 1). METHODS: We carried out a mixed methods process evaluation involving qualitative and quantitative data collection in 3 phases: among 3 child-parent units, (group 1) that informed program development; 9 child-parent units (group 2) that tested the draft program and further aided program refinement; and 17 child-parent units (group 3) for a 4 week pilot of the program. In the program pilot, we assessed participants' knowledge and readiness to change pre- and postintervention and explored perceptions of the program. RESULTS: Participants generally felt that the online format for program delivery was convenient and accessible, the content was practical, and the integration of health-environment-economy was well received. Many parents also appreciated the involvement of the family. However, the lack of visual appeal and overabundance of text was identified as a challenge, and children/youth in particular requested assurance that their personal information (e.g. weight) was not seen by their parents. The online method of program delivery holds the unique challenge of requiring special efforts to create a sense of personal connection and community. The presence of a "Way-finder" to assist participants and discussion boards/forums are potential solutions. CONCLUSION: The LiGHT online weight management program offers an accessible, convenient weight management resource that children and families appreciate for its availability, broader educational scope, and practicality. Outcome evaluation of LiGHT will be carried out in Phase 2 of the project. PMID- 24070797 TI - Type 2 diabetes mellitus management in Canada: is it improving? AB - OBJECTIVE: To gain insight into the current management of patients with type 2 diabetes mellitus by Canadian primary care physicians. METHOD: A total of 479 primary care physicians from across Canada submitted data on 5123 type 2 diabetes patients whom they had seen on a single day on or around World Diabetes Day, November 14, 2012. RESULTS: Mean glycated hemoglobin (A1C) was 7.4%, low-density lipoprotein (LDL-C) was 2.1 mmol/L and blood pressure (BP) was 128/75 mm Hg. A1C <=7.0% was met by 50%, LDL-C <=2.0 mmol/L by 57%, BP <130/80 mm Hg by 36% and the composite triple target by 13% of patients. Diet counselling had been offered to 38% of patients. Of the 87% prescribed antihyperglycemic agents, 18% were on 1 non-insulin antihyperglycemic agent (NIAHA) (85% of which was metformin), 15% were on 2 NIAHAs, 6% were on >=3 NIAHAs, 19% were on insulin only and 42% were on insulin + >=1 NIAHA(s). Amongst the 81% prescribed lipid-lowering therapy, 88% were on monotherapy (97% of which was a statin). Among the 83% prescribed antihypertensive agents, 39%, 34%, 21% and 6% received 1, 2, 3 and >3 drugs, respectively, with 59% prescribed angiotensin-converting enzyme inhibitors and 35% angiotensin II receptor blockers. CONCLUSIONS: The Diabetes Mellitus Status in Canada survey highlights the persistent treatment gap associated with the treatment of type 2 diabetes and the challenges faced by primary care physicians to gain glycemic control and global vascular protection in these patients. It also reveals a higher use of insulin therapy in primary care practices relative to previous surveys. Practical strategies aimed at more effectively managing type 2 diabetes patients are urgently needed. PMID- 24070798 TI - The public health burden of obesity in Canada. AB - The purpose of this review was to provide an overview of the public health burden of obesity in Canada. Based on nationally representative surveys that obtained measured heights and weights and that defined obesity using a body mass index (BMI) cutpoint of 30 kg/m(2), the prevalence of obesity in Canadian adults increased from 10% in 1970/72 to 26% in 2009/11. The prevalence of obesity in children has tripled since 1981, and based on the World Health Organization BMI growth standards, 12% of Canadian school-aged children were obese in 2009/11. At present, there are approximately 7 million obese adults and 600 000 obese school aged children in Canada. Prevalence estimates based on waist circumference are even more troubling as they indicate that 37% of adults and 13% of youth are abdominally obese. Obesity is a major contributor to morbidity and mortality in the Canadian population. For instance, 61% to 74% of type 2 diabetes cases, 17% to 32% of osteoarthritis cases, 14% to 21% of colorectal cancers, 8% to 14% of depression cases, and 20% of premature deaths that occur in Canadian adults are estimated to be directly attributable to obesity. Obesity also places a large economic burden on the country. In 2006 obesity accounted for $3.9 billion in direct health care costs (e.g., hospitalizations, medications, physician and emergency room visits) and $3.2 billion in indirect costs (e.g., costs related to disability and lost productivity due to illness or premature death). PMID- 24070799 TI - Building a strategy for obesity prevention one piece at a time: the case of sugar sweetened beverage taxation. AB - Obesity is a major public health issue in Canada that is reaching historically high levels in spite of efforts, targeted primarily at individual behaviour, to promote changes in diet and physical activity. Urgency for change at the population level compels moving "upstream" toward multilevel, societal approaches for obesity prevention. Public health researchers, advocates and policy makers are increasingly recognizing the current food environment, including availability, pricing, and marketing of foods and beverages, promotes overconsumption of unhealthy food and beverage choices and have identified the food environment as a point for intervention for obesity prevention. In April 2011, a consensus conference with invited experts from research, policy and practice fields was held. The conference aimed to build consensus around policy levers to address environmental determinants of obesity, including next logical steps toward further policy action. Using economic policies, such as taxation of sugar-sweetened beverages (SSB), was discussed as one opportunity to promote healthy eating. This article reports on the consensus discussion that led to recommendations to tax sugar-sweetened beverages as one step in a multipronged comprehensive approach to obesity prevention. This recommendation is based on a synthesis of available evidence, including evidence regarding political feasibility, and potential impacts of a tax. In addition, we present additional primary research using current SSB consumption data to model the economic and behavioural impact of such a tax in Canada. PMID- 24070800 TI - Inadequate sleep as a contributor to obesity and type 2 diabetes. AB - Epidemiological studies suggest that adults and children who are habitual short sleepers tend to have a higher body mass index, fat percentage and abdominal circumference when compared to average-duration sleepers. Reduced or disturbed sleep is also associated with certain predictors of type 2 diabetes, such as glucose intolerance, insulin resistance, reduced insulin response to glucose and a reduction in the disposition index. Current experimental evidence suggests that sleep restriction may lead to increased food intake but does not appear to result in decreased energy expenditure. Furthermore, sleep restriction has been reported to increase evening cortisol levels, which may decrease insulin sensitivity the next morning. This notion was further supported by studies, which noted decreases in the effectiveness of insulin-mediated glucose uptake the following morning. Further evidence suggests that short sleepers have glucose responses that are similar to average-duration sleepers, but at the cost of an increase in insulin release, which may be the result of decreased insulin sensitivity over time. Recent studies also provide evidence that sleep restriction enhances susceptibility to food stimuli, especially for energy-dense, high-carbohydrate foods. In summary, inadequate sleep, in both quality and quantity, should be regarded as a plausible risk factor for the development of obesity and type 2 diabetes. In addition to other health promotion measures, a good night's sleep should be seen as a critical health component by clinicians in the prevention and treatment of obesity and type 2 diabetes. PMID- 24070801 TI - The 2012 CDA-CIHR INMD young investigator award lecture: dysfunction of adipose tissues and the mechanisms of ectopic fat deposition in type 2 diabetes. AB - Ectopic fat deposition in skeletal muscles, liver, heart, and other tissues has been closely linked with the development of lean tissues' insulin resistance and progression toward type 2 diabetes mellitus. Mechanisms of overexposure of these tissues to fatty acids include increased de novo lipogenesis, impaired fatty acid oxidation and increased fatty acid flux to these organs. White adipose tissues are the main organs responsible for the regulation of circulating fatty acids. It has been clearly demonstrated that pre-diabetes individuals and individuals with diabetes display impaired adipose tissue dietary fatty acid storage that may lead to increased circulating flux and exaggerated lean tissue fatty acid exposure. Additionally, brown adipose tissue depots are less metabolically active in individuals with type 2 diabetes. We have developed a series of novel in vivo investigative tools using positron emission tomography to comprehensively assess postprandial interorgan fatty acid partitioning and white and brown adipose tissue metabolism in subjects with pre-diabetes and type 2 diabetes. Our findings shed new lights into the sophisticated mechanisms that regulate fatty acid partitioning and energy homeostasis during the development of type 2 diabetes. New links between abnormal dietary fatty acid metabolism and early myocardial metabolic and functional defects are now being uncovered in humans with the hope to find novel ways to predict and avoid the devastating complications of diabetes. PMID- 24070802 TI - Insulin resistance of protein metabolism in type 2 diabetes and impact on dietary needs: a review. AB - Evidence shows that the metabolism of protein is altered in type 2 diabetes mellitus and insulin resistance not only applies to glucose and lipid but protein metabolism as well. Population surveys report greater susceptibility to loss of lean tissue and muscle strength with aging in diabetes. Prevention of sarcopenia requires that protein receives more attention in dietary prescriptions. Protein intake of 1-1.2 g/kg of body weight (with weight at a body mass index of 25 kg/m(2))/day may be distributed equally among 3 meals a day, including breakfast, to optimize anabolism. Adopting a dietary pattern that provides a high plant-to animal ratio and greater food volume favouring consumption of vegetables, legumes, fruits, complemented with fish, low fat dairy and meat (preferably cooked slowly in moisture), soy and nuts may assist with metabolic and weight control. Depending on the magnitude of energy restriction, usual protein intake should be maintained or increased, and the caloric deficit taken from fat and carbohydrate foods. Exercise before protein-rich meals improves skeletal muscle protein anabolism. Because high levels of amino acids lower glucose uptake in individuals without diabetes, the challenge remains to define the optimal protein intake and exercise regimen to protect from losses of muscle mass and strength while maintaining adequate glucose control in type 2 diabetes. PMID- 24070803 TI - The maintenance of energy balance is compromised after weight loss. AB - Available literature reveals that of the majority of individuals who are able to lose weight, only a small number are able to maintain their weight loss over time. Effective weight maintenance strategies after weight loss are illusive, which is most likely the result of a number of yet poorly understood factors. In fact, both appetite and energy expenditure are profoundly altered in response to reductions in body energy reserves. Weight reduction leads to decreased energy needs, but to an augmented drive to eat, thus compromising the maintenance of energy balance in the weight-reduced state by widening the theoretical gap between the 2 components of energy balance. This review first provides a summary of the factors related to the control of feeding and energy expenditure during weight stability. More specifically related to the topic of this review, the bulk of the literature presented depicts the post weight-loss control of appetite and energy expenditure. The integration of the literature presented in this paper reveals that body weight loss seems to orchestrate a coordinated response to resist further energy depletion, that would seem to create a state of increased vulnerability of weight regain. It is argued that these changes are largely responsible for the more than apparent difficulty in maintaining weight maintenance after weight loss. PMID- 24070804 TI - Benefits of modest weight loss on the management of type 2 diabetes mellitus. AB - The epidemic of overweight and obesity is a major driver of the growing prevalence of type 2 diabetes mellitus globally. The risk of type 2 diabetes increases exponentially as body mass index rises above 25 kg/m(2). Obesity currently costs the Canadian economy approximately $7.1 billion annually whereas per capita health care cost for individuals with diabetes are 3 to 4 times that for persons without the disease. Each kilogram of weight lost through health behaviour changes in people with impaired glucose tolerance is associated with a relative diabetes risk reduction of 16%. As 80% to 90% of people with type 2 diabetes are overweight or obese, and adiposity worsens the metabolic and physiologic abnormalities associated with type 2 diabetes, weight loss is recommended as the cornerstone management measure. A modest weight loss of 5% to 10% is an achievable and realistic goal for preventing type 2 diabetes in susceptible individuals and improving glycemic and metabolic control in people with type 2 diabetes. When health behaviour modification fails to achieve glycemic and metabolic goal targets, priority should be given to antihyperglycemic agents that are associated with weight loss or weight neutrality. Every pound of body fat loss matters and every kilogram counts in the management of type 2 diabetes. PMID- 24070806 TI - Resistance to HCV nucleoside analogue inhibitors of hepatitis C virus RNA dependent RNA polymerase. AB - Despite the approval of protease inhibitors Telaprevir and Boceprevir and the increased SVR rates observed in GT 1 infected patients, new compounds are needed to achieve higher cure rates, shorten duration of treatment and reduce side effects. Emergence of resistance continues to be a key factor limiting antiviral efficacy and is therefore an important parameter to control for in clinical trials. Understanding the nature of the resistance mechanism(s), natural prevalence of resistant mutants and their fitness and persistence will allow a better design of treatment options. Nucleos(t)ide analogues present a high barrier to resistance, pangenotypic activity and are not cross resistant to other direct acting antivirals which make them good candidates for combination therapy for the treatment of hepatitis. PMID- 24070807 TI - The association between scholarly impact and National Institutes of Health funding in ophthalmology. AB - OBJECTIVE: To examine whether there is an association between scholarly impact, as measured by the h-index, academic rank, and National Institutes of Health (NIH) awards in academic ophthalmology. DESIGN: Retrospective analysis of NIH RePORTER and Scopus databases. PARTICIPANTS: Not applicable. METHODS: Five hundred seventy-three NIH awards to 391 primary investigators (PIs) in ophthalmology departments were examined. Grant recipients were organized by academic rank, obtained from online listings, and h-index, calculated using the Scopus database. Non-NIH-funded faculty from 20 randomly chosen academic ophthalmology departments also were organized by rank and h-index for comparison with their NIH-funded colleagues. MAIN OUTCOME MEASURES: Scholarly impact, as measured by the h-index, and NIH funding. RESULTS: The h-index increased with successive academic rank among non-NIH-funded and NIH-funded faculty, as did NIH funding among the latter group. The NIH-funded faculty had higher scholarly impact, as measured by the h-index, than their non-NIH-funded PIs (h = 18.3 vs. 7.8; P <0.0001), even when considering publications only in the prior 5 years; h index increased with increasing NIH funding ranges. The h-indices of those holding an MD degree (21.4+/-1.6 standard error of mean) were not statistically higher than those of PhD holders (17.9+/-0.6) and those with both an MD and PhD degree (18.1+/-1.7; P = 0.14). CONCLUSIONS: The h-index increases with increasing academic rank among NIH-funded and non-NIH-funded faculty in ophthalmology departments. This bibliometric is associated strongly with NIH funding because NIH-funded PIs had higher scholarly impact than their non-NIH-funded colleagues, and increasing impact was noted with higher funding. The h-index is an objective and easily calculable measure that may be valuable as an adjunct in assessing research productivity, a significant factor for academic promotion in academic ophthalmology. PMID- 24070808 TI - Randomized trial of multifocal intraocular lenses versus monovision after bilateral cataract surgery. AB - OBJECTIVE: To compare spectacle independence in patients randomized to receive bilateral multifocal intraocular lenses (IOLs) or monofocal IOLs with the powers adjusted to produce monovision. DESIGN: Randomized, multicenter clinical trial. PARTICIPANTS: A total of 212 patients with bilateral, visually significant cataract. METHODS: Before bilateral sequential cataract surgery, patients were randomized (allocation ratio 1:1) to receive bilateral Tecnis ZM900 diffractive multifocal lenses (Abbott Medical Optics, Santa Ana, CA) or Akreos AO monofocal lenses (Bausch & Lomb, Rochester, NY) with the powers adjusted to target -1.25 diopters (D) monovision. Outcomes were assessed 4 months after the second eye underwent operation. MAIN OUTCOME MEASURES: The primary outcome was spectacle independence. Secondary outcomes included questionnaires (VF-11R, dysphotopsia symptoms, and satisfaction) and visual function measures (near, intermediate, and distance logarithm of minimum angle of resolution [logMAR] visual acuity, stereoacuity, contrast sensitivity, and forward light scatter). RESULTS: A total of 212 patients were randomized, and 187 patients (88%) returned for assessment 4 months after surgery. Uniocular distance refractions in the monovision arm showed a mean spherical equivalent of +0.075 D in the distance eye and -0.923 in the near eye. In the multifocal arm, the mean distance spherical equivalents were 0.279 D and -0.174 D in the right and left eyes, respectively. A total of 24 of 93 patients (25.8%) in the monovision arm and 67 of 94 patients (71.3%) in the multifocal arm reported never wearing glasses (P<0.001, Fisher exact test). The adjusted odds ratio of being spectacle free was 7.51 (95% confidence interval, 3.89-14.47). Binocular uncorrected acuities did not differ significantly for distance (0.058 logMAR for monovision vs. 0.076 for multifocal, P = 0.3774) but were significantly worse in the multifocal arm for intermediate acuity (0.149 vs. 0.221, P = 0.0001) and in the monovision arm for near acuity (0.013 vs. -0.025, P = 0.037). In the first postoperative year, 6 patients (5.7%) in the multifocal arm underwent IOL exchange (4 had a bilateral and 2 had a unilateral exchange). No patients in the monovision arm underwent IOL exchange. CONCLUSIONS: Patients randomized to bilateral implantation with the diffractive multifocal Tecnis ZM900 were more likely to report being spectacle independent but also more likely to undergo IOL exchange than those randomized to receive monofocal implants (Akreos AO) with the powers adjusted to give low monovision. PMID- 24070809 TI - Pharmacogenetic associations with vascular endothelial growth factor inhibition in participants with neovascular age-related macular degeneration in the IVAN Study. AB - PURPOSE: To determine if prespecified genetic polymorphisms influence responsiveness to vascular endothelial growth factor (VEGF) inhibition in neovascular age-related macular degeneration (nAMD). The objectives were to replicate 3 reported pharmacogenetic associations of response in nAMD and to test for novel associations. DESIGN: Cohort study, combining information about patients' genotypes with information from a randomized controlled trial about responsiveness to anti-VEGF therapy for nAMD. PARTICIPANTS: Five hundred nine participants with nAMD, enrolled in the Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) trial. METHODS: Participants were classified as responders or nonresponders to VEGF inhibition based on the optical coherence tomography (OCT) metric of total retinal thickness (TRT). We computed the change in TRT from baseline to the latest time point for which OCT data were available (3, 6, 9, or 12 months). Eyes with changes in TRT greater than or equal to the 75th percentile or more were classified as responders, and those with changes less than or equal to the 25th percentile or lower were classified as non-responders. Three previously reported associations of response to VEGF inhibition in nAMD involving single nucleotide polymorphisms (SNPs) at the CFH, FZD4, and HTRA1/ARMS2 loci were tested for replication. An additional 482 SNPs also were tested using a candidate gene approach. Associations were estimated as odds ratios (ORs) with confidence intervals (CIs). MAIN OUTCOME MEASURES: The primary outcome was evidence of a genetic association with response to VEGF inhibition as measured by change in TRT. RESULTS: One hundred twenty-six participants were classified as responders and 128 were classified as nonresponders. The SNP rs10490924 in HTRA1/ARMS2 showed a borderline association with responsiveness after Bonferroni correction (OR, 1.53; CI, 0.99-2.36; P = 0.055, Bonferroni correction). None of the other 484 additional SNPs tested for association was significant after Bonferroni correction for multiple testing. The smallest corrected P value was 0.84 (P = 0.002, uncorrected) for rs9679290 in the EPAS1 (HIF2A) gene on chromosome 2. Four of the 10 most significant results were in this gene. CONCLUSIONS: We estimated pharmacogenetic associations using high-quality phenotype data from a randomized controlled clinical trial of nAMD. No significant association or replication of previous associations were observed. Further investigation of the EPAS1 (HIF2A) gene, however, may, be merited. PMID- 24070810 TI - Effectiveness of nonpharmacologic treatments for acute seasonal allergic conjunctivitis. AB - OBJECTIVE: To investigate whether artificial tears and cold compress alone or in combination provide a treatment benefit and whether they were as effective as or could enhance topical antiallergic medication. DESIGN: Randomized, masked clinical trial. PARTICIPANTS: Eighteen subjects (mean age, 29.5+/-11.0 years) allergic to grass pollen. INTERVENTION: Controlled exposure to grass pollen using an environmental chamber to stimulate an ocular allergic reaction followed by application of artificial tears (ATs), 5 minutes of cold compress (CC), ATs combined with CC, or no treatment applied at each separate visit in random order. A subset of 11 subjects also had epinastine hydrochloride (EH) applied alone and combined with CC in random order or instillation of a volume-matched saline control. MAIN OUTCOME MEASURES: Bulbar conjunctival hyperemia, ocular surface temperature, and ocular symptoms repeated before and every 10 minutes after treatment for 1 hour. RESULTS: Bulbar conjunctival hyperemia and ocular symptoms decreased and temperature recovered to baseline faster with nonpharmaceutical treatments compared with no treatment (P <0.05). Artificial tears combined with CC reduced hyperemia more than other treatments (P <0.05). The treatment effect of EH was enhanced by combining it with a CC (P <0.001). Cold compress combined with ATs or EH lowered the antigen-raised ocular surface temperature to less than the pre-exposure baseline. Artificial tear instillation alone or CC combined with ATs or EH significantly reduced the temperature (P <0.05). Cold compress combined with ATs or EH had a similar cooling effect (P >0.05). At all measurement intervals, symptoms were reduced for both EH and EH combined with CC than CC or ATs alone or in combination (P <0.014). CONCLUSIONS: After controlled exposure to grass pollen, CC and AT treatment showed a therapeutic effect on the signs and symptoms of allergic conjunctivitis. A CC enhanced the use of EH alone and was the only treatment to reduce symptoms to baseline within 1 hour of antigenic challenge. Signs of allergic conjunctivitis generally were reduced most by a combination of a CC in combination with ATs or EH. PMID- 24070811 TI - Trabeculectomy in the 21st century: a multicenter analysis. AB - OBJECTIVE: To evaluate the efficacy and safety of current trabeculectomy surgery in the United Kingdom. DESIGN: Cross-sectional, multicenter, retrospective follow up. PARTICIPANTS: A total of 428 eyes of 395 patients. METHODS: Consecutive trabeculectomy cases with open-angle glaucoma and no previous incisional glaucoma surgery from 9 glaucoma units were evaluated retrospectively. Follow-up was a minimum of 2 years. MAIN OUTCOME MEASURES: Surgical success, intraocular pressure (IOP), visual acuity, complications, and interventions. Success was stratified according to IOP, use of hypotensive medications, bleb needling, and resuturing/revision for hypotony. Reoperation for glaucoma and loss of perception of light were classified as failures. RESULTS: Antifibrotics were used in 400 cases (93%): mitomycin C (MMC) in 271 (63%), 5-fluorouracil (5-FU) in 129 (30%), and no antifibrotic in 28 (7%). At 2 years, IOP (mean +/- standard deviation) was 12.4 +/- 4 mmHg, and 342 patients (80%) achieved an IOP <= 21 mmHg and 20% reduction of preoperative IOP without IOP-lowering medication, whereas 374 patients (87%) achieved an IOP <= 21 mmHg and 20% reduction of preoperative IOP overall. An IOP <=18 mmHg and 20% reduction of preoperative IOP were achieved by 337 trabeculectomies (78%) without IOP-lowering treatment and by 367 trabeculectomies (86%) including hypotensive medication. Postoperative treatments included suture manipulation in 184 patients (43%), resuturing or revision for hypotony in 30 patients (7%), bleb needling in 71 patients (17%), and cataract extraction in 111 of 363 patients (31%). Subconjunctival 5-FU injection was performed postoperatively in 119 patients (28%). Visual loss of >2 Snellen lines occurred in 24 of 428 patients (5.6%). A total of 31 of the 428 patients (7.2%) had late-onset hypotony (IOP <6 mmHg after 6 months). In 3 of these, visual acuity decreased by >2 Snellen lines. Bleb leaks were observed in 59 cases (14%), 56 (95%) of which occurred within 3 months. Two patients developed blebitis. Bleb related endophthalmitis developed in 1 patient within 1 month postoperatively and in 1 patient at 3 years. There was an endophthalmitis associated with subsequent cataract surgery. CONCLUSIONS: This survey shows that good trabeculectomy outcomes with low rates of surgical complications can be achieved, but intensive proactive postoperative care is required. PMID- 24070812 TI - Effects of xaliproden, a 5-HT1A agonist, on mechanical allodynia caused by chemotherapeutic agents in mice. AB - In the present study we investigated whether xaliproden, a selective 5-HT1A receptor agonist, could relieve allodynia induced by three types of chemotherapeutic agents (paclitaxel, vincristine, and oxaliplatin) in mice. A single intraperitoneal injection of paclitaxel (5mg/kg), vincristine (0.1mg/kg), or oxaliplatin (3mg/kg) time-dependently increased punctate stimulation-evoked allodynia over 10-14 days; the intensities of allodynia were similar between the treatment groups. A single oral dose of xaliproden (0.3-3mg/kg) inhibited paclitaxel-induced allodynia in a dose-dependent manner. Xaliproden (3mg/kg) administration produced a slight and no suppression of vincristine-induced and oxaliplatin-induced allodynia, respectively. The firing response of the tibial nerve to punctate stimulation increased in mice that received paclitaxel or oxaliplatin. Xaliproden (3mg/kg) markedly inhibited the firing response in the mice treated with paclitaxel, while it partially inhibited the firing response in the oxaliplatin-treated animals. Vincristine did not significantly increase the tibial nerve response. Paclitaxel significantly increased the mRNA expression of 5-HT1A receptor in the dorsal root ganglia, but not in the spinal dorsal horn. In contrast, oxaliplatin significantly increased the mRNA expression of 5-HT1A receptor in the spinal dorsal horn, but not in the dorsal root ganglia. Vincristine did not affect the mRNA expression of 5-HT1A receptor in both these regions. These results suggest that xaliproden produces acute inhibition of mechanical allodynia induced by paclitaxel, but not by vincristine and oxaliplatin, via inhibition of the hyper-response of the primary afferent neurons. PMID- 24070813 TI - Class I antiarrhythmic drugs inhibit human cardiac two-pore-domain K(+) (K2 2p) channels. AB - Class IC antiarrhythmic drugs are commonly used for rhythm control in atrial fibrillation. In addition, class I drugs are administered to suppress ventricular tachyarrhythmia in selected cases. The multichannel blocking profile of class I compounds includes reduction of cardiac potassium currents in addition to their primary mechanism of action, sodium channel inhibition. Blockade of two-pore domain potassium (K2P) channels in the heart causes action potential prolongation and may provide antiarrhythmic action in atrial fibrillation. This study was designed to elucidate inhibitory effects of class I antiarrhythmic drugs on K2P channels. Human K2P2.1 (TREK1) and hK2P3.1 (TASK1) channels were systematically tested for their sensitivity to clinically relevant class IA (ajmaline), class IB (mexiletine), and class IC (propafenone) antiarrhythmic compounds using whole cell patch clamp and two-electrode voltage clamp electrophysiology in Chinese hamster ovary cells and in Xenopus oocytes. Mexiletine and propafenone inhibited hK2P2.1 (IC50,mexiletine=173uM; IC50,propafenone=7.6uM) and hK2P3.1 channels (IC50,mexiletine=97.3uM; IC50,propafenone=5.1uM) in mammalian cells. Ajmaline did not significantly reduce current amplitudes. K2P channels were blocked in open and closed states, resulting in resting membrane potential depolarization. Open rectification properties of the channels were not affected by class I drugs. In summary, class I antiarrhythmic drugs target cardiac K2P K(+) channels. Blockade of hK2P2.1 and hK2P3.1 potassium currents provides mechanistic evidence to establish cardiac K2P channels as antiarrhythmic drug targets. PMID- 24070814 TI - Transferrin modified PEG-PLA-resveratrol conjugates: in vitro and in vivo studies for glioma. AB - Glioblastoma is one of the most malignant brain tumors with a poor prognosis. In this study, we examined the effects of transferrin (Tf)-modified poly ethyleneglycol-poly lactic acid (PEG-PLA) nanoparticles conjugated with resveratrol (Tf-PEG-PLA-RSV) to glioma therapy in vitro and in vivo. The cell viability of Tf-PEG-PLA-RSV on C6 and U87 glioma cells was determined by the MTT assay. In vivo biodistribution and antitumor activity were investigated in Brain glioma bearing rat model of C6 glioma by i.p. administration of RSV-polymer conjugates. We found that the average diameter of each Tf-PEG-PLA-RSV is around 150 nm with 32 molecules of Tf on surface. In vitro cytotoxicity of PEG-PLA-RSV against C6 and U87 cells was higher than that of free RSV, and further the modification of Tf enhanced the cytotoxicity of the RSV-polymer conjugates as a result of the increased cellular uptake of the RSV-modified conjugates by glioma cells. In comparison with free RSV, RSV conjugates could significantly decrease tumor volume and accumulate in brain tumor, which resulted in prolonging the survival of C6 glioma-bearing rats. These results suggest that Tf-NP-RSV had a potential of therapeutic effect to glioma both in vitro and in vivo and might be a potential candidate for targeted therapy of glioma and worthy of further investigation. PMID- 24070817 TI - 198th ENMC International Workshop: 7th Workshop on Centronuclear (Myotubular) myopathies, 31st May - 2nd June 2013, Naarden, The Netherlands. PMID- 24070815 TI - Insulin, cognition, and dementia. AB - Cognitive disorders of aging represent a serious threat to the social and economic welfare of current society. It is now widely recognized that pathology related to such conditions, particularly Alzheimer's disease, likely begins years or decades prior to the onset of clinical dementia symptoms. This revelation has led researchers to consider candidate mechanisms precipitating the cascade of neuropathological events that eventually lead to clinical Alzheimer's disease. Insulin, a hormone with potent effects in the brain, has recently received a great deal of attention for its potential beneficial and protective role in cognitive function. Insulin resistance, which refers to the reduced sensitivity of target tissues to the favorable effects of insulin, is related to multiple chronic conditions known to impact cognition and increase dementia risk. With insulin resistance-associated conditions reaching epidemic proportions, the prevalence of Alzheimer's disease and other cognitive disorders will continue to rise exponentially. Fortunately, these chronic insulin-related conditions are amenable to pharmacological intervention. As a result, novel therapeutic strategies that focus on increasing insulin sensitivity in the brain may be an important target for protecting or treating cognitive decline. The following review will highlight our current understanding of the role of insulin in brain, potential mechanisms underlying the link between insulin resistance and dementia, and current experimental therapeutic strategies aimed at improving cognitive function via modifying the brain's insulin sensitivity. PMID- 24070818 TI - Prevention of central venous catheter infections: a survey of paediatric ICU nurses' knowledge and practice. AB - BACKGROUND: Central venous catheters are important in the management of paediatric intensive care unit patients, but can have serious complications which worsen the patients' health, prolong hospital stays and increase the cost of care. Evidence-based recommendations for preventing catheter-related bloodstream infections are available, but it is unknown how widely these are known or practiced in the paediatric intensive care environment. OBJECTIVES: To assess nursing knowledge of evidence based guidelines to prevent catheter-related bloodstream infections; the extent to which Australia and New Zealand paediatric intensive cares have adopted prevention practices; and to identify the factors that encouraged their adoption and improve nursing knowledge. DESIGN: Cross sectional surveys using convenience sampling. SETTINGS: Tertiary level paediatric intensive care units in Australia and New Zealand. PARTICIPANTS: Paediatric intensive care nursing staff and nurse managers. METHODS: Between 2010 and 2011, the 'Paediatric Intensive Care Nurses' Knowledge of Evidence-Based Catheter Related Bloodstream Infection Prevention Questionnaire' was distributed to paediatric intensive care nursing staff and the 'Catheter-Related Bloodstream Infection Prevention Practices Survey' was distributed to nurse managers to measure knowledge, practices and culture. RESULTS: The questionnaires were completed by 253 paediatric intensive care nurses (response rate: 34%). The mean total knowledge score was 5.5 (SD=1.4) out of a possible ten, with significant variation of total scores between paediatric intensive care sites (p=0.01). Other demographic characteristics were not significantly associated with variation in total knowledge scores. All nursing managers from Australian and New Zealand paediatric intensive care units participated in the survey (n=8; response rate: 100%). Wide practice variation was reported, with inconsistent adherence to recommendations. Safety culture was not significantly associated with mean knowledge scores per site. CONCLUSIONS: This study has identified that there is variation in the infection prevention approach and nurses' knowledge about catheter-related bloodstream infection prevention. The presence of an improved safety culture, years of paediatric intensive care experience and higher qualifications did not influence the nurses' uptake of recommendations, therefore further factors need to be explored in order to improve understanding and implementation of best practice. PMID- 24070816 TI - 'Double trouble': diagnostic challenges in Duchenne muscular dystrophy in patients with an additional hereditary skeletal dysplasia. AB - Duchenne muscular dystrophy (DMD) is caused by mutations in Dystrophin and affects 1 in 3600-6000 males. It is characterized by progressive weakness leading to loss of ambulation, respiratory insufficiency, cardiomyopathy, and scoliosis. We describe the unusual phenotype of 3 patients with skeletal dysplasias in whom an additional diagnosis of DMD was later established. Two unrelated boys presented with osteogenesis imperfecta due to point mutations in COL1A1 and were both subsequently found to have a 1 bp frameshift deletion in the Dystrophin gene at age 3 and age 15 years, respectively. The third patient had a diagnosis of pseudoachondroplasia caused by a mutation in the COMP gene and was found to have a deletion of exons 48-50 in Dystrophin at age 9. We discuss the atypical presentation caused by the concomitant presence of 2 conditions affecting the musculoskeletal system, emphasizing aspects that may confound the presentation of a well-characterized disease like DMD. Additional series of patients with DMD and a secondary inherited condition are necessary to establish the natural history in this "double trouble" population. The recognition and accurate diagnosis of patients with two independent genetic disease processes is essential for management, prognosis, genetic risk assessment, and discussion regarding potential therapeutic interventions. PMID- 24070819 TI - A cross-sectional study of drinking patterns, prelicensure nursing education, and professional identity formation. AB - BACKGROUND: Professional identity has been described as being an important outcome of nursing education, but how this identity forms is not well understood. Even less is known about how students' personal substance use/abuse patterns factor into their professional identity formation. OBJECTIVES: The purpose of this study was to describe drinking behaviors and professional identity formation among baccalaureate of nursing students. DESIGN: This cross-sectional, descriptive study used a survey design. SETTING: The study took place on three campuses of a large system university in the Midwestern United States. PARTICIPANTS: The convenience sample consisted of 333 students enrolled in the first semester of the second, third, and last year of a traditional baccalaureate of nursing program. METHODS: Data were collected using the Nurse Self-Concept Questionnaire and the Student Alcohol Questionnaire. ANOVA and Pearson r statistical tests were used to analyze data. RESULTS: Self-perceptions related to leadership were found to be the weakest aspect of the students' self-concepts, and the only dimensions of professional self-concept that differed significantly among students enrolled at varying program levels were knowledge and communication. A negative relationship was found between increased alcohol use and general self-concept and communication, but the associations were very weak. CONCLUSIONS: More research is needed to understand how best to facilitate the acquisition of an identity consistent with the profession's values and how to recruit candidates that embody nursing's preferred future. PMID- 24070822 TI - Psychosocial interventions for the treatment of perinatal depression. AB - Epidemiological investigations and meta-analyses of predictive studies have consistently demonstrated the importance of psychosocial variables as postpartum depression risk factors. To address this, several psychosocial treatment strategies have been evaluated for the treatment of postpartum depression. The purpose of this paper is to determine the current state of scientific knowledge related to the treatment of postpartum depression from a psychosocial perspective. Thirteen trials were included in the review that evaluated the following interventions: peer support, partner support, non-directive counselling, home visits by mental health nurses, and collaborative models of care. Owing to methodological limitations of the included trials, the effectiveness of most psychosocial approaches for the treatment of postpartum depression is equivocal. Large, multisite randomised-controlled trials are needed to compare different treatment approaches, examine the effectiveness of individual treatment components, and determine which treatments are most useful for women with different risk factors or clinical presentations of postpartum depression. PMID- 24070820 TI - Inhibition of cellular STAT3 synergizes with the cytomegalovirus kinase inhibitor maribavir to disrupt infection. AB - Therapeutic strategies controlling human cytomegalovirus (hCMV) infection are limited due to adverse side effects and emergence of antiviral resistance variants. A compound being evaluated for treating hCMV disease is maribavir (MBV) which disrupts replication by inhibiting the viral kinase pUL97. Previous studies have demonstrated that the antiviral activity of MBV is sensitive to the proliferation state of the infected cell. In these studies, we were interested in determining whether inhibition of the pro-proliferative transcription factor, signal transducer and activator of transcription-3 (STAT3), could influence the antiviral activity of MBV. The addition of the STAT3 inhibitor, S3i-201, during infection altered hCMV-mediated changes in cell cycle protein expression. Upon combining S3i-201 with MBV, our data suggest that STAT3 inhibition is acting synergistically with MBV to inhibit infection in vitro. Furthermore, specific concentrations of S3i-201 and MBV induced caspase-dependent death of infected but not uninfected cell. Our studies suggest that treating infection with both S3i 201 and MBV is a novel approach to inhibit hCMV replication. PMID- 24070823 TI - Impact of reduced-intensity conditioning allogeneic stem cell transplantation on women's fertility. AB - INTRODUCTION: Available data on women fertility for younger patients treated using RIC Allo-SCT are still limited. We evaluated ovarian function and fertility among female patients younger than 35 years who received RIC Allo-SCT for hematological malignancy or aplastic anemia (AA). PATIENTS AND METHODS: Information on therapies before RIC Allo-SCT were collected. Data on ovarian function and fertility evaluation after RIC Allo-SCT included clinical and biological criteria. Twenty-two patients were evaluated. RESULTS: After RIC Allo SCT, amenorrhea affects 68.1% of patients. Ovarian function was impaired for 86.3% of cases. All 3 AA patients have regular cycles and became pregnant after RIC Allo-SCT. Only 6 (27.2%) patients declared to have been correctly informed before RIC Allo-SCT on potential deleterious effects on fertility of anticancer treatment and only 36.8% of patients with ovarian failure had a hormonal supplementation. CONCLUSION: Results showed a high rate of ovarian failure, evaluated by clinical and biological criteria. The difference between AA and malignant diseases might suggest that a potential deleterious role was played by previous anticancer treatments rather than by RIC Allo-SCT. PMID- 24070824 TI - Associated cancers in Waldenstrom macroglobulinemia: clues for common genetic predisposition. AB - BACKGROUND: Several population-based and cohort studies have reported an increased risk of second cancers in lymphoproliferative disorders (LPDs). The cause of second cancers in LPDs is probably multifactorial, and the relative contribution of treatments, genetic predisposition, and immune dysfunction typical of LPDs is still unclear. PATIENTS AND METHODS: We retrospectively studied 230 patients with Waldenstrom macroglobulinemia (WM) to assess the frequency, characteristics, and predictive factors of second cancers and to evaluate whether patients with WM are at higher risk of second cancers compared with an age- and sex-matched control population. RESULTS: In a competing-risk model, the cumulative incidence of solid cancers was 6% at 5 years, 11% at 10 years, and 17% at 15 years, whereas the incidence of hematologic malignancies was 4% at 5 years, 7% at 10 years, and 8% at 15 years. Compared with an age- and sex matched population, the overall risk of second cancers was 1.7-fold higher than expected (95% confidence interval [CI], 1.22-2.38; P = .002). Patients with WM were at increased risk for diffuse large B-cell lymphoma (DLBCL) (standardized incidence ratio [SIR], 8.64; 95% CI, 3.88-19.22; P < .0001), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (SIR 9.5; 95% CI, 3.6-25.3; P < .0001), and brain cancer (SIR, 7.59; 95% CI, 1.9-30.4; P < .0001). The risk of a second hematologic malignancy was 5-fold higher in treated than in untreated patients (P = .08). CONCLUSION: Patients with WM are at increased risk of DLBCL, MDS/AML, and brain cancers compared with the general population. Further studies are needed to clarify whether the increased incidence of second cancers is related to treatments, to the immunologic impairment associated with the disease, or to genetic predisposition. PMID- 24070825 TI - Perturbation method for the second-order nonlinear effect of focused acoustic field around a scatterer in an ideal fluid. AB - Two nonlinear models are proposed to investigate the focused acoustic waves that the nonlinear effects will be important inside the liquid around the scatterer. Firstly, the one dimensional solutions for the widely used Westervelt equation with different coordinates are obtained based on the perturbation method with the second order nonlinear terms. Then, by introducing the small parameter (Mach number), a dimensionless formulation and asymptotic perturbation expansion via the compressible potential flow theory is applied. This model permits the decoupling between the velocity potential and enthalpy to second order, with the first potential solutions satisfying the linear wave equation (Helmholtz equation), whereas the second order solutions are associated with the linear non homogeneous equation. Based on the model, the local nonlinear effects of focused acoustic waves on certain volume are studied in which the findings may have important implications for bubble cavitation/initiation via focused ultrasound called HIFU (High Intensity Focused Ultrasound). The calculated results show that for the domain encompassing less than ten times the radius away from the center of the scatterer, the non-linear effect exerts a significant influence on the focused high intensity acoustic wave. Moreover, at the comparatively higher frequencies, for the model of spherical wave, a lower Mach number may result in stronger nonlinear effects. PMID- 24070826 TI - Osteoporosis detection in postmenopausal women using axial transmission multi frequency bone ultrasonometer: clinical findings. AB - The objective of this study was to evaluate if the Bone UltraSonic Scanner (BUSS) can detect osteoporosis in postmenopausal women. BUSS is an axial transmission multi-frequency ultrasonometer for acquisition of wave propagation profiles along the proximal anterior tibia. We derived 10 diagnostically significant BUSS parameters that were then compared with the DXA spine T-score, which was used in this study as the "gold standard" for the assessment of osteoporosis (T-score< 2.5). BUSS wave parameters were studied in 331 postmenopausal women examined by 9 trained operators at 3 clinical sites with use of 3 devices. The efficiency of each BUSS parameter in osteoporosis detection was assessed using a receiver operating characteristic curve analysis. Area under the curve (AUC) for each of 10 parameters ranged from 58.1% to 70.2%. Using these parameters a linear classifier was derived which provided at its output 83.0% AUC, 87.7% sensitivity and 63.2% specificity to DXA-identified osteoporosis. The results of this study confirm BUSS's capability to detect osteoporosis in postmenopausal women. PMID- 24070827 TI - Early adversity, socioemotional development, and stress in urban 1-year-old children. AB - OBJECTIVE: To determine demographic, maternal, and child factors associated with socioemotional (SE) problems and chronic stress in 1-year-old children. STUDY DESIGN: This was a prospective, longitudinal, community-based study, which followed mother-infant dyads (n = 1070; representative of race, education, and income status of Memphis/Shelby County, Tennessee) from midgestation into early childhood. Child SE development was measured using the Brief Infant-Toddler Social and Emotional Assessment in all 1097 1-year-olds. Chronic stress was assessed by hair cortisol in a subsample of 1-year-olds (n = 297). Multivariate regression models were developed to predict SE problems and hair cortisol levels. RESULTS: More black mothers than white mothers reported SE problems in their 1 year-olds (32.9% vs 10.2%; P < .001). In multivariate regression, SE problems in blacks were predicted by lower maternal education, greater parenting stress and maternal psychological distress, and higher cyclothymic personality score. In whites, predictors of SE problems were Medicaid insurance, higher maternal depression score at 1 year, greater parenting stress and maternal psychological distress, higher dysthymic personality score, and male sex. SE problem scores were associated with higher hair cortisol levels (P = .01). Blacks had higher hair cortisol levels than whites (P < .001). In the entire subsample, increased hair cortisol levels were associated with higher parenting stress (P = .001), lower maternal depression score (P = .01), lower birth length (P < .001), and greater length at 1 year of age (P = .003). CONCLUSION: Differences in maternal education, insurance, mental health, and early stress may disrupt SE development in children. Complex relationships between hair cortisol level in 1-year-olds and maternal parenting stress and depression symptoms suggest dysregulation of the child's hypothalamic-pituitary-adrenal axis. PMID- 24070828 TI - Preterm birth and adolescent social functioning-alterations in emotion-processing brain areas. AB - OBJECTIVE: To investigate the relationship between preterm birth, adolescent, and adult psychosocial outcomes, and alterations in gray matter volume. STUDY DESIGN: Individuals (n = 73) born at <33 weeks of gestation (very preterm) and 49 controls completed the Child Behavior Checklist (CBCL) at age 15 years to identify 'social immaturity' (SI) cases. Voxel-based morphometry was used to investigate gray matter volumes according to CBCL-SI 'caseness.' The Clinical Interview Schedule-Revised (CIS-R) was administered at age 19 years. RESULTS: Very preterm adolescents were almost 4 times more likely to reach CBCL-SI 'caseness' compared with controls. Ex-preterm SI 'cases' had increased gray matter volume in the fusiform gyrus bilaterally (Talairach coordinates: x = 60, y = -27, z = -30; Z = 3.78; x = -61, y = -35, z = -27; Z = 3.56, after correction for multiple comparisons) compared with ex-preterm SI 'noncases.' Left fusiform volume displayed a stronger correlation with ipsilateral orbitofrontal cortex in SI 'cases' (x = -15, y = 22, z = -26; Z = 3.64). CIS-R total scores were slightly higher in ex-preterm individuals compared with controls. In the whole sample, SI 'cases' in midadolescence also had higher CIS-R scores in adulthood compared with 'noncases' (SI 'cases': mean = 5.7, 95% CI = 4.0-7.4; SI 'noncases': mean = 2.7, 95% CI = 1.1-4.3; F = 6.4, df = 74; P = .013). CONCLUSIONS: Ex-preterm adolescents had increased socialization problems in adolescence, which were associated with volumetric alterations in an emotion-processing brain network. Atypical social development is linked to an increased vulnerability to psychiatric disorder. PMID- 24070829 TI - Beau lines. PMID- 24070830 TI - Massive hepatomegaly in poorly controlled insulin-dependent diabetes mellitus. PMID- 24070831 TI - Species spectrum of nontuberculous mycobacteria isolated from suspected tuberculosis patients, identification by multi locus sequence analysis. AB - Identification of Mycobacterium species is difficult due to a complex and rapidly changing taxonomy, the failure of 16S rRNA to discriminate many closely related species and the unreliability of phenotypic testing. We investigated a collection of nontuberculous mycobacteria (NTM) strains isolated from suspected tuberculosis patients at Tuberculosis Reference Centre (Ahvaz, Iran) and Masoud Laboratory (Tehran, Iran) during 2008-2012 to evaluate the species spectrum of NTM isolates. Based on phenotypic tests, the isolates were identified up to species or complex level; however they were heterogonous by hsp65-PCR restriction fragment length polymorphism analysis (PRA) method. Representative isolates from each hsp65-PRA pattern, were subjected to identification using single locus and multi locus sequence analysis (MLSA) based on 16S rRNA, rpoB, hsp65 and 16S-23S internal transcribes spacer (ITS) fragments to determine their taxonomic affiliations. All 92 NTM isolates from different clinical specimens were considered as etiological agents causing disease according to American Thoracic Society (ATS) guideline. Phenotypic evaluation alone assigned 66 (72%) isolates to a species or complex level and consequently 76 (82%) isolates showed previously reported hsp65-PRA patterns. Although sequence base identification using single locus such as 16S rRNA, rpoB, hsp65 or ITS identified the isolates up to species level, MLSA correctly identified 16 different species of NTM from clinical isolates. In summary, four-locus MLSA is a reliable method for elucidating taxonomic data and reliable species identification of Mycobacterium isolates and therefore, would be more feasible for routine use in Tuberculosis (TB) reference laboratory. PMID- 24070832 TI - Long-term survival after sequential chemotherapy and surgery for advanced gastric cancer. AB - INTRODUCTION: We experienced a case with long relapse-free survival after successful treatment of chemotherapy and surgery to advanced gastric cancer. PRESENTATION OF CASE: A 56-year-old man was examined because of rapid weight loss and was diagnosed as having far-advanced gastric cancer with portal vein tumor thrombus (PVTT) and liver, lymph node and peritoneal metastases. Immediately after beginning chemotherapy, gastric obstruction due to gastric cancer was discovered. Therefore gastrojejunostomy, a bypass operation, was performed, and this was followed by the first course chemotherapy with S-1 and cisplatin. After 4 courses of this regimen were completed, PVTT and the peritoneal metastasis could no longer be confirmed, and new lesion had not appeared; therefore, the patient underwent a radical operation with distal gastrectomy, lymph node dissection and partial hepatectomy. After the operation, he received second-line chemotherapy with S-1 and paclitaxel for 1 year. He has been in good health without any signs of recurrence for 3 years and 8 months after the radical operation. DISCUSSION AND CONCLUSION: Although complete recovery from far advanced gastric cancer is rarely expected, this case demonstrates that long-term survival is achievable with carefully considered treatment plans. PMID- 24070834 TI - The Canadian Diabetes Association 2013 clinical practice guidelines-raising the bar and setting higher standards! PMID- 24070833 TI - Evaluation of the toxicity and antimicrobial activity of hydroethanolic extract of Arrabidaea chica (Humb. & Bonpl.) B. Verl. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Arrabidaea chica (Bignoniaceae) is a vine native to the Amazon Rainforest, popularly known as "crajiru" and whose infusion and decoction of the leaves are used to treat diseases such as gastric ulcers, inflammations, infections, anemia, herpes, jaundice among others. It is also used as a natural dye. This work aimed to evaluate the in vitro and in vivo toxicity, antimicrobial activity including analysis of chemical constitution of the hydroethanolic extract of the leaves of Arrabidaea chica (HEAc). MATERIALS AND METHODS: Acute and subchronic toxicity of HEAc was evaluated in mice and rats, respectively, and by Alamar blue (cytotoxicity assay) using CHO-K1 cells. Antimicrobial activity of HEAc was tested by broth microdilution method using a panel of bacteria and yeast of clinical interest. The preliminary phytochemical analysis of HEAc was performed by electrospray ionization mass spectrometry [ESI(+)-MS]. Secondary metabolites were quantified by colorimetric methods. RESULTS: When administered in vivo at doses up to 3000 mg/kg v.o., HEAc did not cause any signs and symptoms of acute toxicity in mice and no cytotoxicity in CHO K1 cells. Administration for 30 days caused leukocytosis (200 mg/kg) and reversible reductions in non-dose dependent of body weight, total weight gain and feed intake in rats given 200mg/kg and 500 mg/kg of HEAc, but were not accompanied by behavioral and clinical changes (laboratory and histopathological) that may have demonstrated evidences of subchronic toxicity HEAc demonstrated a pronounced activity against Helicobacter pylori (MIC=12.5 MUg/mL) and moderate activity against Enterococcus faecalis (MIC=100 MUg/mL) in broth microdilution. Preliminary phytochemical analysis of HEAc by colorimetric methods revealed that mainly the presence of phenolic compounds (16.6%), especially flavones and flavonols (4.02%). [ESI(+)-MS] fingerprint analyses of HEAc revealed the presence of 3-deoxyanthocyanidins and kaempferol. CONCLUSION: Our data provide evidence that HEAc is safe and can be useful in infections related to Helicobacter pylori and Enterococcus faecalis. Phytochemical analysis revealed the predominant presence of flavones and flavonols, possibly involved in the antimicrobial action of HEAc. PMID- 24070835 TI - Is insulin pump therapy a treatment option for some type 2 diabetes patients requiring intensified insulin regimen? PMID- 24070836 TI - Hypoglycemia-related emergency department visits and hypoglycemia-related hospitalizations among new users of antidiabetes treatments. AB - OBJECTIVE: To describe the burden of severe hypoglycemia among new users of insulin and oral antidiabetes drugs (OAD) in terms of 2 hypoglycemia-related outcomes: emergency department (ED) visit and hospitalization. METHODS: We conducted an inception cohort study using the databases of the Quebec health insurance board and the Quebec registry of hospitalizations. The source population was made of individuals 18 years of age or older who were newly dispensed an antidiabetes treatment made of either insulin or OAD between January 1, 2000 and December 31, 2008. Individuals were followed from initiation of antidiabetes treatment to December 31, 2008, occurrence of hypoglycemia-related outcome, loss of eligibility to the drug plan or death, whichever came first. Individuals' characteristics at antidiabetes treatment initiation were described using frequency distributions. The incidence rate for the occurrence of hypoglycemia-related ED visit and hypoglycemia-related hospitalization were calculated using the Kaplan-Meier method. RESULTS: A total of 188 659 new users of antidiabetes treatment were included in the cohort. A total of 3575 (1.9%) individuals had at least 1 hypoglycemia-related ED visit whereas 194 (0.1%) had at least 1 hypoglycemia-related hospitalization. Incidence rates for the occurrence of hypoglycemia-related ED visits and hypoglycemia-related hospitalizations were 5.2 and 0.3 cases per 1000 patient years, respectively. CONCLUSION: Although the incidence of ED visit or hospitalization due to hypoglycemia seems low, severe hypoglycemia episodes could be associated with a high economic burden. PMID- 24070837 TI - The association between smoking and depression in a Canadian community-based sample with type 2 diabetes. AB - OBJECTIVE: To investigate the association between depression and smoking status within a community-based sample with type 2 diabetes mellitus, while controlling for socio-demographic, diabetes-related characteristics and complications, disability, other chronic illness and other health-related variables. METHOD: A total of 1868 adults with type 2 diabetes were recruited via random digit dialing for the Montreal Health and Well Being Study (DHS). Smoking was classified as never, former, light (<=10 cigarettes a day) and moderate/heavy (11+ cigarettes a day). Depression was assessed using the Patient Health Questionnaire-9 and individuals were classified as no major depression vs. major depression syndrome. Logistic regression was used to test the association between major depression and smoking status, while controlling for other demographic and health-related variables. RESULTS: Major depression was associated with an increased likelihood of being a light or moderate/heavy smoker, having 2 or more diabetes complications, moderate-severe disability, and having 2 or more other chronic illnesses. In the fully adjusted model, having major dpression was associated with an increased likelihood of being a moderate/heavy smoker (odds ratio = 2.62, 95% confidence interval = 1.43-4.81). The association between light smoking and major depression was not significant when adjusting for confounding variables. CONCLUSIONS: Smoking and depression are strongly associated in patients with type 2 diabetes, and this association appears to be strongest for moderate/heavy smokers. This finding has important clinical implications given that smoking cessation is an important health recommendation, and potentially means depression status may be an important consideration when targeting clients with diabetes who continue to smoke. PMID- 24070838 TI - Angiotensin II receptor blocker telmisartan prevents new-onset diabetes in pre diabetes OLETF rats on a high-fat diet: evidence of anti-diabetes action. AB - OBJECTIVES: This study aims to investigate the effects of telmisartan, pioglitazone and metformin administration on the prevention of new-onset type 2 diabetes mellitus in pre-diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed with a high-fat diet (HFD). METHODS: OLETF rats 22 weeks of age were treated with pioglitazone (O-P), metformin (O-M), telmisartan (O-T) and low telmisartan starting from their pre-diabetes period. The weight, glucose tolerance and insulin sensitivity were measured. The lipid profiles were obtained. The abdominal subcutaneous (SC) and omental (OM) fat pads were dissected to measure the expression of mRNA and protein levels (adiponectin, proinflammatory cytokines, etc.). RESULTS: Telmisartan significantly reversed glucose tolerance and improved insulin resistance. The incidence rates of impaired glucose tolerance and type 2 diabetes in the O-P (chi(2) = 11.025, p=0.001) and O-T (chi(2)=5.495, p=0.019) groups were significantly reduced. The mRNA expression of proinflammatory cytokines was downregulated by telmisartan. The expression of adiponectin, PPARgamma1 and gamma2 was markedly improved by telmisartan and pioglitazone compared with the OLETF control (O-C) group. The correlation analysis showed that the systolic and diastolic blood pressures were not correlated with the homeostasis model assessment-insulin resistance (p>0.05). CONCLUSIONS: Telmisartan acts beneficially against diabetes-induced inflammation and improves insulin resistance in pre-diabetes OLETF rats fed with HFD. In view of this improved responsiveness to insulin sensitivity, telmisartan may prove to be a promising candidate for the intervention treatment of the pre-diabetes state. PMID- 24070839 TI - Goal disturbance and coping in children with type I diabetes mellitus: relationships with health-related quality of life and A1C. AB - OBJECTIVE: Our first objective was to compare the health-related quality of life (HRQoL) of children with type 1 diabetes mellitus (8-12 years) with that of a healthy reference group, and to compare glycated hemoglobin (A1C) values of these children to recommended guidelines. Our second objective was to examine how goal disturbance and coping behaviour were related to HRQoL and A1C. METHOD: Forty three children, 8-12 years of age, completed a set of questionnaires that assessed generic and diabetes-specific HRQoL, goal disturbance and coping behaviour. Demographic and clinical characteristics were extracted from medical records. RESULTS: Children with type 1 diabetes reported lower psychosocial HRQoL than healthy references (d=-0.48), especially on emotional functioning (d=-0.58). Goal disturbance was associated with lower generic HRQoL. Furthermore, the coping strategies avoidance, emotional reaction and wishful thinking were negatively associated with lower generic and disease-specific HRQoL (r ranged from -0.33 to 0.65), whereas acceptance was positively associated with disease-specific HRQoL (r=0.36). The average A1C was with 8.1% significantly above the recommended guidelines of 7.5%. Moreover, the coping strategies avoidance (r=0.31) and emotional reaction (r=0.32) were positively associated with higher blood glucose levels. CONCLUSIONS: The psychosocial HRQoL of children with type 1 diabetes was affected, which was directly associated with the inability to reach personal goals (goal disturbance). An accepting coping strategy might solve these HRQoL problems and additionally improve A1C values. PMID- 24070841 TI - How do international trade obligations affect policy options for obesity prevention? Lessons from recent developments in trade and tobacco control. AB - OBJECTIVE: Regulatory measures, including taxes and subsidies on food and beverage products, food labelling requirements, regulation of food content and regulation of food marketing, have been proposed to encourage healthier eating and prevent obesity. The objective of this article is to explore the extent to which international trade agreements affect governments' choices to use such regulatory measures. METHODS: It reviews key provisions of relevant World Trade Organization (WTO) agreements and their implications. Some insights can be gained by examining 2 recent developments in the WTO regarding tobacco control: a current dispute involving Australia's plain packaging law and its effect on trademarks, and a recent decision involving the United States law banning flavoured cigarettes. RESULTS: This decision said that the ban did not restrict trade more than necessary to fulfil its legitimate health objective, but it was discriminatory because it banned imported products (clove cigarettes) while exempting domestic products (menthol cigarettes) with similar characteristics. CONCLUSION: The conclusion we can draw from this decision is that WTO member states probably enjoy a significant degree of latitude in developing food regulations as part of an obesity prevention strategy, so long as those do not disproportionately affect imported products and therefore raise questions of discrimination. The approach taken in this case encourages the adoption of public health policies that are consistent with strong scientific evidence, but may restrict governments' ability to make political compromises, which could frustrate some proposals. The ongoing development of WTO law will continue to affect policy choices in public health. PMID- 24070840 TI - Adolescents, parents and physicians: a comparison of perspectives on type 1 diabetes self-care. AB - OBJECTIVE: No research to date has compared the beliefs of adolescents, parents and physicians with respect to type 1 diabetes mellitus self-care perceptions and barriers. This study examined how adolescents with type 1 diabetes, their parents and physicians perceive 4 key diabetes self-care behaviours (testing blood glucose, taking insulin, exercise and diet) and what influences those behaviours. METHOD: Forty-eight adolescent/parent dyads and 21 pediatric endocrinologists rated importance, difficulty and proficiency for 4 self-care behaviours, and provided up to 5 perceived influences on these behaviours. We compared adolescents to parents and families to physicians. RESULTS: Groups rated all self care behaviours as important, with taking insulin as most important. Families rated behaviours as relatively easy compared to physicians. All groups agreed that diet was both the most difficult self-care behaviour and the behaviour at which adolescents were least proficient. Although families rated teens as proficient overall, physicians disagreed. Adolescent and parent perception of diet difficulty was related to poorer glycemic control, and blood glucose testing and insulin administration proficiency were linked to better glycemic control. Compared to other groups, teens were especially likely to mention internal and hindering influences, and more likely to mention other people as negative influences. CONCLUSIONS: Although all groups agreed that all self-care behaviours are important, there are key areas of discrepancy in perceptions, particularly between families and physicians. Further research should connect the beliefs examined in this study to actual self-care behaviours. PMID- 24070842 TI - Predicting exercise adherence for patients with obesity and diabetes referred to a cardiac rehabilitation and secondary prevention program. AB - BACKGROUND: Cardiac rehabilitation (CR) is associated with mortality and morbidity benefits. Treatment adherence rates of 20% to 60% for patients with diabetes and obesity undermines CR effectiveness. Identification of factors that account for poorer adherence to CR in these populations is needed. METHODS: Data from 12 003 CR patients from 1995 to 2010 were analyzed. Differences in characteristics were compared between groups of patients classified by the presence or absence of diabetes mellitus and obesity. Sequential logistic regression was conducted to examine the extent to which biopsychosocial factors account for the higher likelihood of CR non-adherence. RESULTS: The proportion of CR non-adherence was 44% for patients without obesity or diabetes, 52% for patients with diabetes and no obesity, 56% for patients with obesity and no diabetes and 59% for patients with diabetes and obesity. After adjustment for all baseline factors, the presence of obesity or diabetes remained associated with an increased risk of CR nonadherence compared to no obesity or no diabetes (diabetes only [odds ratio (OR) 1.22; 95% confidence interval (CI) 1.08-1.38; p=0.001]; obesity only [OR 1.19; 95% CI 1.04-1.36; p=0.01]). The presence of both diabetes and obesity and their relationship to CR nonadherence is not significant (OR 1.14, 95% CI 0.947-1.37; p=0.16) after adjusting for body fat percentage and waist circumference. CONCLUSIONS: Diabetes and obesity were independent determinants of CR program nonadherence. The influence of having both diabetes and obesity was moderated by waist circumference and body fat percentage. Patients with diabetes mellitus, obesity or both may require greater attention and consideration with respect to CR delivery. PMID- 24070843 TI - Feasibility, acceptability and effects of a foot self-care educational intervention on minor foot problems in adult patients with diabetes at low risk for foot ulceration: a pilot study. AB - OBJECTIVES: The objectives of the pilot study were to examine the feasibility and acceptability of the foot self-care educational intervention, and to explore its preliminary effects on reducing the occurrence of minor foot problems in adult patients with diabetes at low risk for foot ulceration. METHODS: A one-group repeated-measures design was used. The intervention given over 3 weeks consisted of a 1 hour 1-on-1 provider-patient interaction to discuss foot self-care strategies, 1 hour hands-on practice of strategies and 2 10-minute telephone contact booster sessions. Of the 70 eligible consenting participants, 56 completed the study. The outcomes were assessed at pretest and at 3-month follow up. Chi-square and Fisher's exact test were used to examine changes in outcomes over time. RESULTS: The findings provided initial evidence suggesting the foot self-care educational intervention is feasible and acceptable to adult patients with type 2 diabetes mellitus. It was effective in reducing the occurrence of minor foot skin and toenails problems (all p<0.05) at 3-month follow up. CONCLUSIONS: The findings support the effects of the intervention. Future research should evaluate its efficacy using a randomized clinical trial design, and a large sample of patients with diabetes at low risk for foot ulcerations. PMID- 24070844 TI - Patient barriers to insulin use in multi-ethnic populations. AB - Insulin administration is often required in the management of type 2 diabetes mellitus for optimal glycemic control. Despite this, however, many patients are reluctant to initiate insulin treatment. In the general population, there are multiple factors leading to this reluctance including fear of hypoglycemia, needle phobia and weight gain. These barriers are also present in multi-ethnic populations. However, there are several patient barriers that are more prevalent in various ethnic backgrounds that need to be addressed. These barriers include language barriers, poor health literacy, social factors and religious implications. The awareness of these factors as well as potential strategies to help overcome them can lead to the improved management of patients with diabetes from multi-ethnic populations. PMID- 24070845 TI - Inequities in healthcare: a review of bias and discrimination in obesity treatment. AB - This review is based on an exploration of the published literature over the past 20 years in the area of weight bias, stigma and discrimination and its association with obesity treatment. National and international obesity organizations have identified obesity stigma as a key barrier to effectively addressing the obesity epidemic and have called for theory driven interventions to reduce it. Both the Canadian Obesity Network (http://www.obesitynetwork.ca) and the Obesity Society (http://www.obesity.org) have strategic directions, mission statements and collaborations that strongly oppose weight bias and recognize the potential of such bias to negatively impact obesity treatment. Comprehensive reviews of the literature in the area of weight bias have been published and have subsequently raised awareness of the potential impact of weight bias and discrimination on the health and well-being of individuals living with obesity. The purpose of this review is to highlight drivers of weight bias and to discuss its impact on obesity treatment. PMID- 24070847 TI - Reduced susceptibility of Candida albicans clinical isolates to azoles and detection of mutations in the ERG11 gene. AB - We investigated the susceptibility of Candida albicans isolated from clinic specimens to azole antifungal agents and estimated the association of the ERG11 mutations with azole resistance during recent 5years in China. In this study, novel mutations G346A, A434V, and L480F in ERG11 may be related to azole resistance in C. albicans. PMID- 24070846 TI - Electrographic seizures are significantly reduced by in vivo inhibition of neuronal uptake of extracellular glutamine in rat hippocampus. AB - Rats were given unilateral kainate injection into hippocampal CA3 region, and the effect of chronic electrographic seizures on extracellular glutamine (GLNECF) was examined in those with low and steady levels of extracellular glutamate (GLUECF). GLNECF, collected by microdialysis in awake rats for 5h, decreased to 62+/-4.4% of the initial concentration (n=6). This change correlated with the frequency and magnitude of seizure activity, and occurred in the ipsilateral but not in contralateral hippocampus, nor in kainate-injected rats that did not undergo seizure (n=6). Hippocampal intracellular GLN did not differ between the Seizure and No-Seizure Groups. These results suggested an intriguing possibility that seizure-induced decrease of GLNECF reflects not decreased GLN efflux into the extracellular fluid, but increased uptake into neurons. To examine this possibility, neuronal uptake of GLNECF was inhibited in vivo by intrahippocampal perfusion of 2-(methylamino)isobutyrate, a competitive and reversible inhibitor of the sodium-coupled neutral amino acid transporter (SNAT) subtypes 1 and 2, as demonstrated by 1.8+/-0.17 fold elevation of GLNECF (n=7). The frequency of electrographic seizures during uptake inhibition was reduced to 35+/-7% (n=7) of the frequency in pre-perfusion period, and returned to 88+/-9% in the post perfusion period. These novel in vivo results strongly suggest that, in this well established animal model of temporal-lobe epilepsy, the observed seizure-induced decrease of GLNECF reflects its increased uptake into neurons to sustain enhanced glutamatergic epileptiform activity, thereby demonstrating a possible new target for anti-seizure therapies. PMID- 24070848 TI - Banking and use of glycerol preserved full-thickness skin allograft harvested from body contouring procedures. AB - INTRODUCTION: The use of glycerol preserved skin allograft (GPA) became a main stay in burn treatment. However, harvesting of cadaveric skin is not yet legalized in many countries including Egypt. OBJECTIVES: To estimate the feasibility of using skin harvested from body contouring procedures as a source of GPA and its clinical efficacy. PATIENTS AND METHODS: Skin harvested from body contouring procedures done in Al-Azhar university hospitals was preserved by glycerolization and used in management of burn and complicated wounds. RESULTS: In the period between February 2012 and February 2013 skin was harvested from 24 abdomenoplasty cases, 6 bilateral breast reduction cases, and 1 case of thigh lift done in Al-Azhar university hospitals. This yielded about 22,000 cm(2) of skin preserved by glycerolization. This GPA was used in 15 excised burn wounds, in 9 cases of chronic burn wounds, and in 6 complicated wounds. Partial graft loss occurred in 3 cases and total graft loss occurred in 1 case. CONCLUSION: The glycerolized full-thickness skin harvested from body contouring procedures is clinically effective in burn and wound management. In the presence of regional coordination, it can serve as an abundant source for skin banking in where cadaveric skin use is not legalized. PMID- 24070849 TI - Response to letter to the editor: "Modernized standards in burns management: a comparative study in Komfo Anokye Teaching Hospital, Kumasi, Ghana" and I have some opinions about it. PMID- 24070850 TI - Bed net related burns at Mulago national referral hospital, Uganda: a case series report. AB - BACKGROUND: Insecticide-treated bed nets are essential tools to prevent malaria in endemic regions, however, increasing trends in bed net related burns in Kampala, Uganda are concerning. METHODS: Data were collected from burns unit admission records at Mulago National Referral Hospital in Kampala, Uganda for the years 2008-2011 inclusive. Retrospective analyses on the characteristics of patients admitted with bed net related burns within this period were conducted. RESULTS: A total of 45 patients were admitted to the burns unit with bed net related burns during the study period. Most burns occurred among individuals who were 0-1 years old (33.3%) and 26-35 years old (24.2%) and the majority were male (71%). Bed net related burns at Mulago Hospital are severe, as evidenced by the fact that 15 of 45 patients died (crude mortality rate=33%) and that 26 patients (57.8%) had total body surface area burn percentages that were greater than 20%. The average length of stay in hospital for patients with bed net related burns was 30.4 days. CONCLUSION: Organizations responsible for malaria prevention should consider incorporating fire and burn prevention awareness, strategies and training into their bed net distribution programs. PMID- 24070851 TI - Foam sclerosants are more stable at lower temperatures. AB - OBJECTIVES: Sclerosant foams are aqueous and break down under the influence of gravity, pressure, and temperature. The aim of this study was to investigate the effects of temperature on foam stability. METHODS: Sodium tetradecyl sulphate (STS) and polidocanol (POL) liquid and foam (1 + 4, liquid-plus-air fraction) were investigated in a range of concentrations (0.5%, 1.5%, 3.0%) and temperatures. Surface tension was measured by the Du Nuoy ring method. Liquid drainage from foam was measured and documented by serial photography. Both pre- and post-cooling variations were investigated. RESULTS: Surface tension decreased at higher temperatures. Surface tension of POL was higher than STS at concentrations tested. POL foam half-time increased significantly at higher concentrations while the half-time of STS foam was not affected by concentration. Heating the sclerosant foam above the ambient temperature reduced its half-time while cooling below the ambient temperature prolonged the half-time. Both pre- and post-cooling of the foams resulted in significant prolongation of half-times when compared to no cooling. Maximum stability of the two sclerosant foams tested was achieved at 10 degrees C. CONCLUSIONS: Foam sclerosants are more stable at cooler temperatures. PMID- 24070852 TI - A review of the management of ductal carcinoma in situ following breast conserving surgery. AB - Ductal carcinoma in situ (DCIS) is a heterogeneous, pre-malignant disease accounting for 10-20% of all new breast tumours. Evidence shows a statistically significant local control benefit for adjuvant radiotherapy (RT) following breast conserving surgery (BCS) for all patients. The baseline recurrence risk of individual patients varies according to clinical-pathological criteria and in selected patients, omission of RT may be considered, following a discussion with the patient. The role of adjuvant endocrine therapy remains uncertain. Ongoing studies are attempting to define subgroups of patients who are at sufficiently low risk of recurrence that RT may be safely omitted; investigating RT techniques and dose fractionation schedules; and defining the role of endocrine therapy. Future directions in the management of patients with DCIS will include investigation of prognostic and predictive biomarkers to inform individualised therapy tailored to the risk of recurrence. PMID- 24070853 TI - The many roads to tremor. AB - Tremor represents one of the most prominent examples of aberrant synchronisation within the human motor system, and Essential Tremor (ET) is by far the most common tremor disorder. Yet, even within ET there is considerable variation, and patients may have contrasting amounts of postural and intention tremor. Recently, Pedrosa et al. (2013) challenged tremor circuits in a cohort of patients presenting with ET, by applying low-frequency deep brain stimulation within thalamus. This interventional approach provided strong evidence that distinct (yet possibly overlapping) neural substrates are responsible for postural and intention tremor in ET. Intention tremor, and not postural tremor, was exacerbated by low frequency stimulation, and the effect was localised in the region of the ventrolateral thalamus in such a way as to implicate cerebello thalamic pathways. These results, taken in conjunction with the contemporary literature, reveal that pathological changes exaggerate oscillatory synchrony in selective components of an extensive and distributed motor network, and that synchronisation within these networks is further regulated according to motor state. Through a combination of pathological and more dynamic physiological factors, activity then spills out into the periphery in the form of tremor. The findings of Pedrosa et al. (2013) are timely as they coincide with an emerging notion that tremor may result through selective dysregulation within a broader tremorgenic network. PMID- 24070854 TI - Modeling Parkinson's disease in monkeys for translational studies, a critical analysis. AB - The non-human primate MPTP model of Parkinson's disease is an essential tool for translational studies. However, the currently used methodologies to produce parkinsonian monkeys do not follow unified criteria, and the applied models may often fall short of reproducing the characteristics of patients in clinical trials. Pooling of data from the parkinsonian monkeys produced in our Centers provided the opportunity to evaluate thoroughly the behavioral outcomes that may be considered for appropriate modeling in preclinical studies. We reviewed records from 108 macaques including rhesus and cynomolgus species used to model moderate to advanced parkinsonism with systemic MPTP treatment. The attained motor disability and the development of levodopa-induced dyskinesias, as primary outcomes, and the occurrence of clinical complications and instability of symptoms were all analyzed for correlations with the parameters of MPTP administration and for estimation of sample sizes. Results showed that frequently the MPTP-treated macaque can recapitulate the phenotype of patients entering clinical trials, but to produce this model consistently it is important to adapt the MPTP exposure tightly according to individual animal responses. For studies of reduced animal numbers it is also important to produce stable models, and stability of parkinsonism in macaques critically depends on reaching "marked" motor disability. The analyzed data also led to put forward recommendations for successfully producing the primate MPTP model of Parkinson's disease for translational studies. PMID- 24070856 TI - Behavioral evaluation of eight rat lines selected for high and low anxiety related responses. AB - Anxiety traits can be stable and permanent characteristics of an individual across time that is less susceptible of influences by a particular situation. One way to study trait anxiety in an experimental context is through the use of rat lines, selected according to contrasting phenotypes of fear and anxiety. It is not clear whether the behavioral differences between two contrasting rat lines in one given anxiety test are also present in others paradigms of state anxiety. Here, we examine the extent to which multiple anxiety traits generalize across selected animal lines originally selected for a single anxiety trait. We review the behavioral results available in the literature of eight rat genetic models of trait anxiety - namely Maudsley Reactive and Non-reactive rats, Floripa H and L rats, Tsukuba High and Low Emotional rats, High and Low Anxiety-related rats, High and Low Ultrasonic Vocalization rats, Roman High and Low Avoidance rats, Syracuse High and Low Avoidance rats, and Carioca High and Low Conditioned Freezing rats - across 11 behavioral paradigms of innate anxiety or aversive learning frequently used in the experimental setting. We observed both convergence and divergence of behavioral responses in these selected lines across the 11 paradigms. We find that predisposition for specific anxiety traits will usually be generalized to other anxiety provoking stimuli. However this generalization is not observed across all genetic models indicating some unique trait and state interactions. Genetic models of enhanced-anxiety related responses are beginning to help define how anxiety can manifest differently depending on the underlying traits and the current environmentally induced state. PMID- 24070855 TI - Corticomotor excitability changes seen in the resting forearm during contralateral rhythmical movement and force manipulations: a TMS study. AB - The aim of this study was to examine changes in corticomotor excitability to a resting wrist extensor muscle during contralateral rhythmical isotonic and static isometric wrist contractions (flexion/extension) at different loads and positions, using transcranial magnetic stimulation (TMS). TMS-induced motor evoked potentials (MEPs) were recorded from the relaxed right extensor carpi radialis (ECR) and flexor carpi radialis (FCR) respectively, while the left arm underwent unimanual manipulations. Rhythmical isotonic (0.5 Hz) flexion and extension movements of the left wrist under 3 load conditions (no, low and high force) and a frequency matched passive movement condition were collected, along with isometric flexion/extension contractions in each position (low and high force). TMS was delivered at eight positions (4 in the flexion phase and 4 in the extension phase) during the continuous movement conditions and each of these positions was sampled with isometric contraction. The potentials evoked by TMS in right ECR were potentiated when the left ECR was engaged, independent of position within that phase of contraction or contraction type (isotonic and isometric). Motor cortical excitability of the resting right ECR increased as load demands increased to the left wrist. Passive rhythmical movement did not influence excitability to the resting ECR implying that voluntary motor drive is required. Our findings indicated that the increase in corticomotor drive during both rhythmic isotonic and static isometric contractions of the opposite limb is likely mediated by interhemispheric interactions between cortical motor areas. Improving our understanding of these cortical networks can be useful in future methods to enhance neuroplasticity through neurorehabilitation methods. PMID- 24070857 TI - 7,8-Dihydroxyflavone improves memory consolidation processes in rats and mice. AB - Brain-derived neurotrophic factor (BDNF) is a crucial regulator of neuronal survival and neuroplasticity in the central nervous system (CNS). As a result, there has been a growing interest in the role of BDNF in neuropsychiatric disorders associated with neurodegeneration, including depression and dementia. However, until now, BDNF-targeting therapies have yielded disappointing results. BDNF is thought to exert its beneficial effects on synaptic and neuronal plasticity mainly through binding to the tyrosine kinase B (TrkB) receptor. Recently, 7,8-dihydroxyflavone (7,8-DHF) was identified as the first selective TrkB agonist. In the present study the effect of 7,8-DHF on memory consolidation processes was evaluated. In healthy rats, 7,8-DHF improved object memory formation in the object recognition task when administered both immediately and 3h after learning. In a transgenic mouse model of Alzheimer's disease, i.e. APPswe/PS1dE9 mice, spatial memory as measured in the object location task was improved after administration of 7,8-DHF. A similar memory improvement was found when their wild-type littermates were treated with 7,8-DHF. The acute beneficial effects in healthy mice suggest that effects might be symptomatic rather than curing. Nevertheless, this study suggests that 7,8-DHF might be a promising therapeutic target for dementia. PMID- 24070858 TI - Association analyses identifying two common susceptibility loci shared by psoriasis and systemic lupus erythematosus in the Chinese Han population. AB - BACKGROUND: Genome-wide association studies (GWASs) have revealed a large number of genetic risk loci for many autoimmune diseases. One clear finding emerging from the published genetic studies of autoimmunity is that different autoimmune diseases, such as psoriasis and systemic lupus erythematosus (SLE), share susceptibility loci. Our study explores additional susceptibility loci shared by psoriasis and SLE in the Chinese Han population. METHODS: In total, 20 single nucleotide polymorphisms (SNPs) in 17 previously reported psoriasis susceptibility loci and 34 SNPs from 24 previously reported SLE susceptibility loci were investigated in our initial psoriasis and SLE GWAS dataset. Among these SNPs, we selected two SNPs (rs8016947 and rs4649203) with association values of p<5*10(-2) for both diseases in the GWAS data for further investigation in psoriasis (7260 cases and 9842 controls) and SLE (2207 cases and 9842 controls) using a Sequenom MassARRAY system. RESULTS: We found that these two SNPs (rs8016947 and rs4649203) in two loci (NFKBIA and IL28RA) were associated with psoriasis and SLE with genome-wide significance (Pcombined<5*10(-8) in psoriasis and Pcombined<5*10(-8) in SLE): rs8016947 at NFKBIA (Pcombined-psoriasis=3.90*10( 10), Pcombined-SLE=1.08*10(-13)) and rs4649203 at IL28RA (Pcombined psoriasis=3.91*10(-12), Pcombined-SLE=9.90*10(-9)). CONCLUSIONS: These results showed that two common susceptibility loci (NFKBIA and IL28RA) are shared by psoriasis and SLE in the Chinese Han population. PMID- 24070859 TI - Chilling-induced water stress: variation in shoot turgor maintenance among wild tomato species from diverse habitats. AB - PREMISE OF THE STUDY: Cultivated tomato, Solanum lycopersicum, suffers chilling induced wilting because water movement through its roots decreases with declining soil temperatures. Certain wild tomato species exhibit resistance to chilling induced wilting, but the extent of this chilling tolerance in wild tomatoes is not known. * METHODS: We measured shoot wilting during root chilling in wild Solanum accessions from habitats differing in elevation, temperature, and precipitation. We also measured shoot wilting during root chilling in introgression lines (ILs) with chromosome 9 segments collinear to the shoot turgor maintenance QTL stm9 region from chilling-tolerant S. habrochaites, chilling and drought-tolerant S. lycopersicoides, or drought-tolerant S. pennellii. * KEY RESULTS: Wild tomato species, which experience chilling temperatures (<10 degrees C) in their native habitat, maintain shoot turgor under root chilling. Among accessions of S. lycopersicum var. cerasiforme, a typically chilling sensitive species, shoot turgor maintenance during root chilling was correlated with the precipitation of the native habitat. By contrast, S. pennellii, a species that is typically drought adapted, did not maintain turgor under root chilling. Grafted plants with roots containing S. habrochaites and S. lycopersicoides introgressions improved shoot turgor maintenance under root chilling. * CONCLUSIONS: Resistance to chilling-induced water stress is an important adaptation to chilling temperatures in wild tomatoes. There is some overlap in adaptation to drought and chilling stress in some tomato species. Root based resistance to chilling-induced water stress in wild tomatoes may involve orthologous gene(s). PMID- 24070860 TI - Allometry of cells and tissues within leaves. AB - PREMISE OF THE STUDY: Allometric relationships among the dimensions of leaf cells, cell walls, and tissues, and whole-leaf thickness and area are likely to have key implications for leaf construction and function, but have remained virtually untested, despite the explosion of interest in allometric analysis of numerous plant properties at larger scales. * METHODS: Using leaf transverse cross sections and light microscopy, we measured leaf dimensions, tissue thicknesses, mesophyll and xylem cell sizes, and cell wall thicknesses for 14 diverse angiosperm species of wet and dry habitats and tested hypothesized allometric relationships based on geometric scaling due to development and/or function. * KEY RESULTS: We found strong novel allometries relating the dimensions of cells, cell walls, tissues, and gross leaf form. Cell sizes and cell wall thicknesses tended to scale isometrically across mesophyll tissues within the leaf, such that species with large cells or thick cell walls in one tissue had these also in the other tissues; however, leaf vein xylem conduit sizes were independent of those of other cell types. We also found strong geometric scaling of cell wall thicknesses with cell sizes throughout the mesophyll, but not in the leaf vein xylem. Further, leaf thickness scaled with cell sizes, cell wall thicknesses and the thicknesses of component mesophyll tissues, but leaf area was independent of anatomical traits across species. * CONCLUSIONS: These novel allometries suggest design rules operating at the smallest scales of leaf construction and the possibility of applying these relationships to better characterizing the basis for differences among species in leaf form and functional traits. PMID- 24070861 TI - Transfusion tracheids in the conifer leaves of Thuja plicata (Cupressaceae) are derived from parenchyma and their differentiation is induced by auxin. AB - PREMISE OF THE STUDY: Conifer leaves are characterized by the differentiation of transfusion tracheids either adjacent to the vascular bundle or away from bundles. Toward uncovering the mechanism regulating this differentiation, we tested the hypotheses that transfusion tracheids differentiate from parenchyma rather than from procambium and that auxin acts as an inducer of this process. * METHODS: Transfusion tracheids were studied at different developmental stages in both dissected and cleared juvenile and mature leaves. Auxin accumulation was induced by application of either auxin to juvenile leaves or of auxin transport inhibitors in lanolin to stems. * KEY RESULTS: Transfusion tracheids originate from parenchyma cells during late stages of leaf development, after the activity of the procambium has ceased. Transfusion tracheids differentiate also in the leaf tip, a region in which there are no procambial cells. Application of either auxin or auxin transport inhibitors resulted in a significant increase in transfusion tracheids in leaves. Disruption of the leaf vascular bundle combined with auxin application resulted in direct differentiation of transfusion tracheids from parenchyma cells; the regeneration of a vascular bundle around the disruption was polar and supports both hypotheses. * CONCLUSIONS: The results provide experimental support for a parenchymatic origin of the transfusion tracheids in a conifer leaf and for auxin acting as an inducer of these cells. Our results suggest a new model in which auxin production in the leaf apex continues after primary tracheids and parenchyma cells have differentiated, and this late auxin flow induces transfusion tracheids from parenchyma cells. PMID- 24070862 TI - Composition of Cypripedium calceolus (Orchidaceae) seeds analyzed by attenuated total reflectance IR spectroscopy: in search of understanding longevity in the ground. AB - PREMISE OF THE STUDY: Orchid seeds are minute and covered with a thin coat, yet they often have a long life after dispersal. They are notorious for low and irregular germination, in nature as well as in vitro. Since orchids are often rare species of conservational and commercial interest, reproduction by seeds is an important concern. The purpose of this study was to learn more about the resilience of these highly specialized seeds and stimulatory processes toward germination. * METHODS: We studied testa and embryos of Cypripedium calceolus to identify natural components in intact seeds and the impact of 7 yr in soil in its natural habitat. We also analyzed the effects of Ca(OCl)2, used technically to enhance germination for cultivation in vitro. For the first time with this kind of plant material, we used attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, an ideal method for minute sample sizes and surface selectivity. Thus, we could link treatments with changes in seed surface chemistry. * KEY RESULTS: A lignin-like polymer is an essential testa component that undergoes degradation by soil or hypochlorite processes. In both cases, we found a build-up of CaCO3 on the testa, which could interact with lignin to enhance germination. Very minor changes occurred in embryo reserve nutrient content after a long sojourn underground, which supports their continued viability. * CONCLUSIONS: We suggest that degradation of lignin and enrichment of the testa surface with CaCO3 are important stimulants of germination both in the habitat and during laboratory sowing. PMID- 24070863 TI - Effect of mechanical loading on the removal torque of different types of tapered connection abutments for dental implants. AB - STATEMENT OF PROBLEM: The mechanical behavior of internal taper implant abutment designs needs to be evaluated. PURPOSE: The purpose of this study was to evaluate the effect of simulated mechanical loading on the removal torque of 1-piece and 2 piece abutments connected to internal taper oral implants. MATERIAL AND METHODS: Forty-eight internally notched taper implants were divided into 2 groups of 24. Group OP received solid (1-piece) abutments; group TP received esthetic (2-piece) abutments. Each group was further subdivided into subgroups C (control) without mechanical loading and T (test) with mechanical loading. In groups OPC and TPC, the abutments were placed and removed and the removal torque values (RTVs) registered. In groups OPT and TPT, abutments were placed, mechanically loaded (500 000 cycles), removed, and the RTVs registered. Groups TPC and TPT were further tested for the traction force necessary to dislodge the abutment from the implant. For data analysis, the Student t test (for RTVs) and the Mann-Whitney U test (for TFVs) (alpha=.05) were performed. RESULTS: All abutments tested presented torque loss with RTVs lower than the placement torque. A statistically significant difference (P=.002) was found between groups OPC (81.6% of placement torque) and OPT mean RTVs results (85.0% of placement torque), while no statistical differences (P=.362) were found between groups TPC (63.7% of placement torque) and TPT (59.1% of placement torque). The traction force values necessary to dislodge the abutment from the implant, however, were significantly higher (P<.001) for group TPT than for group TPC. CONCLUSIONS: Cold welding did not occur in any of the abutment specimens tested. Even after the mechanical loading, esthetic abutments presented similar RTVs. The traction force necessary to remove esthetic abutments from inside the implants presented a 2-fold increase after mechanical loading. PMID- 24070865 TI - Surge block method for controlling well clogging and sampling sediment during bioremediation. AB - A surge block treatment method (i.e. inserting a solid rod plunger with a flat seal that closely fits the casing interior into a well and stocking it up and down) was performed for the rehabilitation of wells clogged with biomass and for the collection of time series sediment samples during in situ bioremediation tests for U(VI) immobilization at a the U.S. Department of Energy site in Oak Ridge, TN. The clogging caused by biomass growth had been controlled by using routine surge block treatment for 18 times over a nearly four year test period. The treatment frequency was dependent of the dosage of electron donor injection and microbial community developed in the subsurface. Hydraulic tests showed that the apparent aquifer transmissivity at a clogged well with an inner diameter (ID) of 10.16 cm was increased by 8-13 times after the rehabilitation, indicating the effectiveness of the rehabilitation. Simultaneously with the rehabilitation, the surge block method was successfully used for collecting time series sediment samples composed of fine particles (clay and silt) from wells with ID 1.9-10.16 cm for the analysis of mineralogical and geochemical composition and microbial community during the same period. Our results demonstrated that the surge block method provided a cost-effective approach for both well rehabilitation and frequent solid sampling at the same location. PMID- 24070864 TI - Altered sphingoid base profiles predict compromised membrane structure and permeability in atopic dermatitis. AB - BACKGROUND: Ceramide hydrolysis by ceramidase in the stratum corneum (SC) yields both sphingoid bases and free fatty acids (FFA). While FFA are key constituents of the lamellar bilayers that mediate the epidermal permeability barrier, whether sphingoid bases influence permeability barrier homeostasis remains unknown. Pertinently, alterations of lipid profile, including ceramide and ceramidase activities occur in atopic dermatitis (AD). OBJECT: We investigated alterations in sphingoid base levels and/or profiles (sphingosine to sphinganine ratio) in the SC of normal vs. AD mice, a model that faithfully replicates human AD, and then whether altered sphingoid base levels and/or profiles influence(s) membrane stability and/or structures. METHODS: Unilamellar vesicles (LV), incorporating the three major SC lipids (ceramides/FFA/cholesterol) and different ratios of sphingosine/sphinganine, encapsulating carboxyfluorescein, were used as the model of SC lipids. Membrane stability was measured as release of carboxyfluorescein. Thermal analysis of LV was conducted by differential scanning calorimetry (DSC). RESULTS: LV containing AD levels of sphingosine/sphinganine (AD-LV) displayed altered membrane permeability vs. normal-LV. DSC analyses revealed decreases in orthorhombic structures that form tightly packed lamellar structures in AD-LV. CONCLUSION: Sphingoid base composition influences lamellar membrane architecture in SC, suggesting that altered sphingoid base profiles could contribute to the barrier abnormality in AD. PMID- 24070866 TI - Alginate block fractions and their effects on membrane fouling. AB - Alginate has been commonly used as a model foulant in studies of membrane organic fouling. As a complex polymer, alginate is composed of two different monomers, namely M ((1 -> 4) linked beta-D-mannopyranuronic acid) and G ((1 -> 4) linked alpha-L-gulopyranuronic acid) which are randomly arranged into MG-, MM- and GG blocks. So far, little information is available about fouling propensity of each block in microfiltration. In this study, microfiltration experiments were conducted respectively with MG-, MM- and GG-blocks separated from alginate under defined conditions. Results showed the severest fouling in the filtration of MG block, and the least flux decline in the filtration of MM-block. The initial pore blocking was found to be responsible for the fouling observed in MG-block filtration, while the cake layer formed on membrane surface during the MM-block filtration could serve as a pre-filter that prevented membrane from further pore blocking. In order to look into fouling mechanisms, the effects of transparent exopolymeric particles (TEP) on membrane fouling were also studied. TEP were found to form through aggregation or cross-link of alginate blocks. As TEP were bigger than original alginate blocks, they could facilitate the formation of cake layer on membrane surface. It was observed that more TEP were produced from MM blocks than from MG-blocks in solutions. This in turn explained why cake resistance was dominant in the filtration of MM-blocks as compared to MG-blocks. The analysis by the extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) theory further revealed that MM-blocks had lowest cohesive interaction energy among all three alginate blocks, which favoured aggregation of MM-blocks, and ultimately leading to the formation of more TEP. This study provided insights into the roles of different alginate blocks in development of membrane fouling, and suggested that the membrane fouling would be related to molecular structure of alginate. PMID- 24070867 TI - Occurrence and fate of the angiotensin II receptor antagonist transformation product valsartan acid in the water cycle--a comparative study with selected beta blockers and the persistent anthropogenic wastewater indicators carbamazepine and acesulfame. AB - The substantial transformation of the angiotensin II receptor antagonist valsartan to the transformation product 2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4 carboxylic acid (referred to as valsartan acid) during the activated sludge process was demonstrated in the literature and confirmed in the here presented study. However, there was a severe lack of knowledge regarding the occurrence and fate of this compound in surface water and its behavior during drinking water treatment. In this work a comparative study on the occurrence and persistency of valsartan acid, three frequently used beta-blockers (metoprolol, atenolol, and sotalol), atenolol acid (one significant transformation product of atenolol and metoprolol), and the two widely distributed persistent anthropogenic wastewater indicators carbamazepine and acesulfame in raw sewage, treated wastewater, surface water, groundwater, and tap water is presented. Median concentrations of valsartan acid in the analyzed matrices were 101, 1,310, 69, <1.0, and 65 ng L( 1), respectively. Treated effluents from wastewater treatment plants were confirmed as significant source. Regarding concentration levels of pharmaceutical residues in surface waters valsartan acid was found just as relevant as the analyzed beta-blockers and the anticonvulsant carbamazepine. Regarding its persistency in surface waters it was comparable to carbamazepine and acesulfame. Furthermore, removal of valsartan acid during bank filtration was poor, which demonstrated the relevance of this compound for drinking water suppliers. Regarding drinking water treatment (Muelheim Process) the compound was resistant to ozonation but effectively eliminated (>=90%) by subsequent activated carbon filtration. However, without applying activated carbon filtration the compound may enter the drinking water distribution system as it was demonstrated for Berlin tap water. PMID- 24070868 TI - p53 increases caspase-6 expression and activation in muscle tissue expressing mutant huntingtin. AB - Activation of caspase-6 in the striatum of both presymptomatic and affected persons with Huntington's disease (HD) is an early event in the disease pathogenesis. However, little is known about the role of caspase-6 outside the central nervous system (CNS) and whether caspase activation might play a role in the peripheral phenotypes, such as muscle wasting observed in HD. We assessed skeletal muscle tissue from HD patients and well-characterized mouse models of HD. Cleavage of the caspase-6 specific substrate lamin A is significantly increased in skeletal muscle obtained from HD patients as well as in muscle tissues from two different HD mouse models. p53, a transcriptional activator of caspase-6, is upregulated in neuronal cells and tissues expressing mutant huntingtin. Activation of p53 leads to a dramatic increase in levels of caspase-6 mRNA, caspase-6 activity and cleavage of lamin A. Using mouse embryonic fibroblasts (MEFs) from YAC128 mice, we show that this increase in caspase-6 activity can be mitigated by pifithrin-alpha (pifalpha), an inhibitor of p53 transcriptional activity, but not through the inhibition of p53's mitochondrial pro-apoptotic function. Remarkably, the p53-mediated increase in caspase-6 expression and activation is exacerbated in cells and tissues of both neuronal and peripheral origin expressing mutant huntingtin (Htt). These findings suggest that the presence of the mutant Htt protein enhances p53 activity and lowers the apoptotic threshold, which activates caspase-6. Furthermore, these results suggest that this pathway is activated both within and outside the CNS in HD and may contribute to both loss of CNS neurons and muscle atrophy. PMID- 24070869 TI - DJ-1 modulates aggregation and pathogenesis in models of Huntington's disease. AB - The oxidation-sensitive chaperone protein DJ-1 has been implicated in several human disorders including cancer and neurodegenerative diseases. During neurodegeneration associated with protein misfolding, such as that observed in Alzheimer's disease and Huntington's disease (HD), both oxidative stress and protein chaperones have been shown to modulate disease pathways. Therefore, we set out to investigate whether DJ-1 plays a role in HD. We found that DJ-1 expression and its oxidation state are abnormally increased in the human HD brain, as well as in mouse and cell models of HD. Furthermore, overexpression of DJ-1 conferred protection in vivo against neurodegeneration in yeast and Drosophila. Importantly, the DJ-1 protein directly interacted with an expanded fragment of huntingtin Exon 1 (httEx1) in test tube experiments and in cell models and accelerated polyglutamine aggregation and toxicity in an oxidation sensitive manner. Our findings clearly establish DJ-1 as a potential therapeutic target for HD and provide the basis for further studies into the role of DJ-1 in protein misfolding diseases. PMID- 24070870 TI - Integrative genome and transcriptome analyses reveal two distinct types of ring chromosome in soft tissue sarcomas. AB - Gene amplification is a common phenomenon in malignant neoplasms of all types. One mechanism behind increased gene copy number is the formation of ring chromosomes. Such structures are mitotically unstable and during tumor progression they accumulate material from many different parts of the genome. Hence, their content varies considerably between and within tumors. Partly due to this extensive variation, the genetic content of many ring-containing tumors remains poorly characterized. Ring chromosomes are particularly prevalent in specific subtypes of sarcoma. Here, we have combined fluorescence in situ hybridization (FISH), global genomic copy number and gene expression data on ring containing soft tissue sarcomas and show that they harbor two fundamentally different types of ring chromosome: MDM2-positive and MDM2-negative rings. While the former are often found in an otherwise normal chromosome complement, the latter seem to arise in the context of general chromosomal instability. In line with this, sarcomas with MDM2-negative rings commonly show complete loss of either CDKN2A or RB1 -both known to be important for genome integrity. Sarcomas with MDM2-positive rings instead show co-amplification of a variety of potential driver oncogenes. More than 100 different genes were found to be involved, many of which are known to induce cell growth, promote proliferation or inhibit apoptosis. Several of the amplified and overexpressed genes constitute potential drug targets. PMID- 24070871 TI - Assessment of multi-chemical pollution in aquatic ecosystems using toxic units: compound prioritization, mixture characterization and relationships with biological descriptors. AB - Chemical pollution is typically characterized by exposure to multiple rather than to single or a limited number of compounds. Parent compounds, transformation products and other non-targeted compounds yield mixtures whose composition can only be partially identified by monitoring, while a substantial proportion remains unknown. In this context, risk assessment based on the application of additive ecotoxicity models, such as concentration addition (CA), is rendered somewhat misleading. Here, we show that ecotoxicity risk information can be better understood upon consideration of the probabilistic distribution of risk among the different compounds. Toxic units of the compounds identified in a sample fit a lognormal probability distribution. The parameters characterizing this distribution (mean and standard deviation) provide information which can be tentatively interpreted as a measure of the toxic load and its apportionment among the constituents in the mixture (here interpreted as mixture complexity). Furthermore, they provide information for compound prioritization tailored to each site and enable prediction of some of the functional and structural biological variables associated with the receiving ecosystem. The proposed approach was tested in the Llobregat River basin (NE Spain) using exposure and toxicity data (algae and Daphnia) corresponding to 29 pharmaceuticals and 22 pesticides, and 5 structural and functional biological descriptors related to benthic macroinvertebrates (diversity, biomass) and biofilm metrics (diatom quality, chlorophyll-a content and photosynthetic capacity). Aggregated toxic units based on Daphnia and algae bioassays provided a good indication of the pollution pattern of the Llobregat River basin. Relative contribution of pesticides and pharmaceuticals to total toxic load was variable and highly site dependent, the latter group tending to increase its contribution in urban areas. Contaminated sites' toxic load was typically dominated by fewer compounds as compared to cleaner sites where more compounds contribute. PMID- 24070872 TI - Dietary intakes of pesticides based on community duplicate diet samples. AB - The calculation of dietary intake of selected pesticides was accomplished using food samples collected from individual representatives of a defined demographic community using a community duplicate diet approach. A community of nine participants was identified in Apopka, FL from which intake assessments of organophosphate (OP) and pyrethroid pesticides were made. From these nine participants, sixty-seven individual samples were collected and subsequently analyzed by gas chromatography/mass spectrometry. Measured concentrations were used to estimate dietary intakes for individuals and for the community. Individual intakes of total OP and pyrethroid pesticides ranged from 6.7 to 996 ng and 1.2 to 16,000 ng, respectively. The community intake was 256 ng for OPs and 3430 ng for pyrethroid pesticides. The most commonly detected pesticide was permethrin, but the highest overall intake was of bifenthrin followed by esfenvalerate. These data indicate that the community in Apopka, FL, as represented by the nine individuals, was potentially exposed to both OP and pyrethroid pesticides at levels consistent with a dietary model and other field studies in which standard duplicate diet samples were collected. Higher levels of pyrethroid pesticides were measured than OPs, which is consistent with decreased usage of OPs. The diversity of pyrethroid pesticides detected in food samples was greater than expected. Continually changing pesticide usage patterns need to be considered when determining analytes of interest for large scale epidemiology studies. The Community Duplicate Diet Methodology is a tool for researchers to meet emerging exposure measurement needs that will lead to more accurate assessments of intake which may enhance decisions for chemical regulation. Successfully determining the intake of pesticides through the dietary route will allow for accurate assessments of pesticide exposures to a community of individuals, thereby significantly enhancing the research benefit realized from epidemiological exposure studies. PMID- 24070873 TI - Characterisation and modelling of mixing processes in groundwaters of a potential geological repository for nuclear wastes in crystalline rocks of Sweden. AB - This paper presents the mixing modelling results for the hydrogeochemical characterisation of groundwaters in the Laxemar area (Sweden). This area is one of the two sites that have been investigated, under the financial patronage of the Swedish Nuclear Waste and Management Co. (SKB), as possible candidates for hosting the proposed repository for the long-term storage of spent nuclear fuel. The classical geochemical modelling, interpreted in the light of the palaeohydrogeological history of the system, has shown that the driving process in the geochemical evolution of this groundwater system is the mixing between four end-member waters: a deep and old saline water, a glacial meltwater, an old marine water, and a meteoric water. In this paper we put the focus on mixing and its effects on the final chemical composition of the groundwaters using a comprehensive methodology that combines principal component analysis with mass balance calculations. This methodology allows us to test several combinations of end member waters and several combinations of compositional variables in order to find optimal solutions in terms of mixing proportions. We have applied this methodology to a dataset of 287 groundwater samples from the Laxemar area collected and analysed by SKB. The best model found uses four conservative elements (Cl, Br, oxygen-18 and deuterium), and computes mixing proportions with respect to three end member waters (saline, glacial and meteoric). Once the first order effect of mixing has been taken into account, water-rock interaction can be used to explain the remaining variability. In this way, the chemistry of each water sample can be obtained by using the mixing proportions for the conservative elements, only affected by mixing, or combining the mixing proportions and the chemical reactions for the non-conservative elements in the system, establishing the basis for predictive calculations. PMID- 24070874 TI - Size-fractionation of groundwater arsenic in alluvial aquifers of West Bengal, India: the role of organic and inorganic colloids. AB - Dissolved organic carbon (DOC) and Fe mineral phases are known to influence the mobility of arsenic (As) in groundwater. Arsenic can be associated with colloidal particles containing organic matter and Fe. Currently, no data is available on the dissolved phase/colloidal association of As in groundwater of alluvial aquifers in West Bengal, India. This study investigated the fractional distribution of As (and other metals/metalloids) among the particulate, colloidal and dissolved phases in groundwater to decipher controlling behavior of organic and inorganic colloids on As mobility. The result shows that 83-94% of As remained in the 'truly dissolved' phases (i.e., <0.05 MUm size). Strong positive correlation between Fe and As (r(2) between 0.65 and 0.94) is mainly observed in the larger (i.e., >0.05 MUm size) colloidal particles, which indicates the close association of As with larger Fe-rich inorganic colloids. In smaller (i.e., <0.05 MUm size) colloidal particles strong positive correlation is observed between As and DOC (r(2)=0.85), which highlights the close association of As with smaller organic colloids. As(III) is mainly associated with larger inorganic colloids, whereas, As(V) is associated with smaller organic/organometallic colloids. Scanning Electron Microscopy and Energy Dispersive X-ray spectroscopy confirm the association of As with DOC and Fe mineral phases suggesting the formation of dissolved organo-Fe complexes and colloidal organo-Fe oxide phases. Attenuated total reflectance-Fourier transform infrared spectroscopy further confirms the formation of As-Fe-NOM organometallic colloids, however, a detailed study of these types of colloids in natural waters is necessary to underpin their controlling behavior. PMID- 24070875 TI - In vitro cultivation of Schistosoma japonicum-parasites and cells. AB - Schistosomiasis is a serious parasitic zoonosis caused by blood-dwelling flukes of the genus Schistosoma. Understanding functions of genes and proteins of this parasite is important for uncovering this pathogen's complex biology, which will provide valuable information to design new strategies for schistosomiasis control. Effective applications of molecular tools reported to investigate schistosome gene function, such as inhibitor studies and transgenesis, rely on the developments of in vitro cultivation system of this parasite and cells. Besides the in vitro culture studies dealing with Schistosoma mansoni, there are also numerous excellent studies about the in vitro cultivation of Schistosoma japonicum, which were performed by Chinese researchers and published in Chinese journals. Nearly every stage of the life-cycle of S. japonicum, including miracidia, mother sporocysts, cercariae, schistosomula, and egg-laying adult worms, was employed for developing in vitro cultivation methods, being accompanied by the introduction of several media and supplements that helped to improve culture conditions. It was not only possible to generate mother sporocysts from miracidia in vitro, but also to obtain adult worms from cercariae through in vitro cultivation. The main obstacles to complete the life cycle of S. japonicum in the lab are the transition from mother sporocysts to cercariae, and the production of fertilized and completely developed eggs by adult worms generated in vitro. With regard to cells from S. japonicum, besides established isolation protocols and morphological observations, media optimizations were conducted by using different chemical reagents, biological supplements and physical treatment. Among these, mutagens like N-methyl-N-nitro-N nitrosoguanidine and the addition of extracellular matrix were found to be able to induce mitogenic activities. Although enzyme activities or the level of silver stained nucleolar region associated protein in cultured cells indicated still suboptimal conditions, the achievements made point to the possibility of reaching the aim of establishing cell lines for S. japonicum. Both the improvements of the in vitro culture of larval and adult worms of S. japonicum as well as the access of cells of this parasite provide excellent advances for research on this important parasite in the future. PMID- 24070876 TI - E-cigarettes and the marketing push that surprised everyone. PMID- 24070877 TI - Hospitals and care homes that fail to provide basic care will face prosecution, says UK regulator. PMID- 24070878 TI - Doctor who fabricated claims she had been raped is suspended for 12 months. PMID- 24070879 TI - Preliminary experience with a new system for vagus nerve stimulation for the treatment of refractory focal onset seizures. AB - Vagus nerve stimulation (VNS) is an accepted therapy for the treatment of drug resistant epilepsy. A new VNS system ("FitNeS"; manufactured by BioControl Medical (B.C.M.) Ltd., Yehud, Israel) was implanted in 5 patients with refractory focal epilepsy. The system is composed of a programmable pulse generator and a cuff electrode that is able to provide unidirectional stimulation, both of which are implanted in the left chest and in the neck, respectively. FitNeS is based on the CardioFit vagus nerve stimulation system, which is intended for the treatment of heart failure and which is currently in a randomized controlled phase III clinical trial. Long-term stimulation in the 5 patients resulted in a 50% seizure reduction in 2 patients, 25% in 2 patients, and no effect in one patient, with few reports concerning side effects. There were no complaints of hoarseness at levels of stimulation below 2mA nor were there any reports of dysphagia or cough. The lack of perceived stimulation effects might finally allow for the design of a truly blinded randomized controlled study to evaluate the efficacy of VNS compared to placebo. PMID- 24070880 TI - Psychiatric adverse effects of zonisamide in patients with epilepsy and mental disorder comorbidities. AB - Over the last few years, zonisamide has been proposed as a potentially useful medication for patients with focal seizures, with or without secondary generalization. Since psychiatric adverse effects, including mania, psychosis, and suicidal ideation, have been associated with its use, it was suggested that the presence of antecedent psychiatric disorders is an important factor associated with the discontinuation of zonisamide therapy in patients with epilepsy. We, therefore, set out to assess the tolerability profile of zonisamide in a retrospective chart review of 23 patients with epilepsy and comorbid mental disorders, recruited from two specialist pediatric (n=11) and adult (n=12) neuropsychiatry clinics. All patients had a clinical diagnosis of treatment refractory epilepsy after extensive neurophysiological and neuroimaging investigations. The vast majority of patients (n=22/23, 95.7%) had tried previous antiepileptic medications, and most adult patients (n=9/11, 81.8%) were on concomitant medication for epilepsy. In the majority of cases, the psychiatric adverse effects of zonisamide were not severe. Four patients (17.4%) discontinued zonisamide because of lack of efficacy, whereas only one patient (4.3%) discontinued it because of the severity of psychiatric adverse effects (major depressive disorder). The low discontinuation rate of zonisamide in a selected population of patients with epilepsy and neuropsychiatric comorbidity suggests that this medication is safe and reasonably well-tolerated for use in patients with treatment-refractory epilepsy. Given the limitations of the present study, including the relatively small sample size, further research is warranted to confirm this finding. PMID- 24070881 TI - An urgent call for action: promoting healthy behaviour changes in Canada! PMID- 24070882 TI - Re: Leiter LA, Berard L, Bowering CK, et al. Type 2 Diabetes mellitus management in Canada: is it improving? Can J Diabetes 37;2:82-9. PMID- 24070884 TI - Diabetes care and mental illness: constraining elements to physical activity and social participation in a residential care facility. AB - OBJECTIVE: To explore barriers and constraints to physical activity, as an integral component of diabetes care, in those with serious mental illness who reside in a for-profit group home. METHODS: Institutional ethnography was the approach used to explore diabetes-related care practices among 26 women in a rural residential care facility in southern Ontario. Semi-structured, in-depth interviews were conducted with residents who had diabetes as well as with care providers, field workers and health professionals. Observations and document analysis were further methods used to reveal the disjuncture between diabetes care guidelines and the actualities of living within imposed constraints of group home care. RESULTS: The residents in this government-regulated group home were sedentary, obtaining approximately 10 minutes per day of low-intensity exercise. The overarching government interest in cost containment created a context of rationing that resulted in a lack of opportunities to exercise and fully participate in social life. Furthermore, group home policies regulated systems of safety, reporting and financial accountability, but did not promote health. CONCLUSIONS: The findings indicate an urgent need for government financial support for quality of life initiatives and amendments to group home policies that give primacy to health promotion, illness prevention and medical management of prevalent comorbid conditions such as diabetes. PMID- 24070883 TI - The effects of an exercise and lifestyle intervention program on cardiovascular, metabolic factors and cognitive performance in middle-aged adults with type II diabetes: a pilot study. AB - BACKGROUND: Canada is experiencing a rise in type II diabetes mellitus (T2DM), a known risk factor for accelerated cognitive decline and dementia. Within the context of an aging population, this will impose significant individual and societal burden, making the development of prevention programs imperative. OBJECTIVE: This pilot study examines the effects of the Diabetes Exercise and Healthy Lifestyle Service, a 24-week intervention program, on cardiovascular, metabolic regulation and cognitive function in adults with T2DM. METHODS: Seventeen middle-aged participants provided blood samples for biological markers, underwent cognitive testing and a physical stress test pre- and post intervention. Cognitive performance was evaluated using the California Verbal Learning Test (CVLT), Digit Symbol Substitution Tasl (DSST) and fluency test. RESULTS: Adjusted models reveal participants displayed increased cardiovascular fitness (VO2 peak: Mchange=4.09 mL?kg?min(-1) SE=1.4), peak heart rate (Mchange= 9.28 beats?min(-1) SE=2.68) and change in heart rate (Mchange=10.71 SE=1.76) in response to the stress test (ps<0.05) following the 24-week intervention. A decrease in body mass index (BMI) (Mchange= -1.03 SE=0.40) and depressive symptomatology (CES-D: Mchange = -3.62 SE=1.44) was also found (ps<0.05). No change was found for lipid and glucose levels. Surprisingly, analyses showed that cognitive performance on the CVLT immediate recall (M= -4.37 SE=2.21), CVTL short delay recall (M= -1.06 SE=0.55), DSST (Mchange= -3 SE=0.53) and category fluency (Mchange= -1.69 SE=0.78) declined following the intervention (ps<0.05); however, decline on the CVLT was limited to adults with co-morbid T2DM and hypertension. CONCLUSION: Additional research is needed to evaluate the benefit of an exercise and lifestyle program that targets cognitive health in those with T2DM. PMID- 24070885 TI - Assessment of serum creatinine and kidney function among incident metformin users. AB - OBJECTIVE: Metformin is considered the first-line antihyperglycemic therapy for type 2 diabetes, but should be used with caution in people with renal insufficiency. Our study objective was to describe the proportion of patients who have an assessment of kidney function (serum creatinine [SCr] and estimated glomerular filtration rate [eGFR]) around the time of initiation of metformin in new users. METHODS: We used data from the Alberta Kidney Disease Network to identify patients with diabetes (age, >=66 y) with a new prescription for metformin from November 1, 2002, to March 31, 2008. We assessed whether SCr measurement was completed before and after metformin initiation. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and categorized into CKD stages. Frequency of metformin use based on SCr measurement and CKD stage was reported using descriptive statistics. RESULTS: A total of 22 051 subjects were identified as new metformin users. Overall, 25.4% (n=5608) had no measurement of SCr or assessment of eGFR before metformin prescription. In addition, of patients with an eGFR measurement, 38.7% (n=8544) of individuals had an eGFR of less than 60 mL/min/1.73 m(2). CONCLUSIONS: One quarter of patients started on metformin did not have a SCr measurement completed beforehand. Also, metformin was used commonly among patients with diabetes and CKD, potentially putting these individuals at risk for adverse events. PMID- 24070886 TI - Optimizing diabetes literacy: lessons from African Canadians in Calgary about type 2 diabetes diagnosis. AB - OBJECTIVE: With the aim of optimizing diabetes education, type 2 diabetes awareness, primary prevention and secondary prevention, we studied how African Canadians experience type 2 diabetes. Specifically, we studied stories told by African Canadians living in Calgary, Alberta, Canada, about significant events and experiences at the time of their diagnosis with type 2 diabetes. METHODS: From recorded interviews, we extracted themes from stories about diagnosis, using hermeneutic phenomenology. Participants included 11 African Canadians older than age 18 and at least 1-year post-diagnosis. Transcribed stories were analyzed for units of meaning describing significant themes/experiences about the diagnosis. Extracted units of meaning were organized into themes that were presented to a focus group of African Canadians in Calgary to garner their perspective on the findings, discuss the implications and make recommendations for improvements. RESULTS: All participants reported experiencing shock, disbelief, fear and a sense of helplessness immediately after their diagnosis. These rendered them unable to think clearly or start their treatment regimen until propelled by additional forces. Also, 73% of participants reported experiencing anger/denial about the diagnosis for some time, whereas 18% reported a short-lived relief that they could finally put a name to their symptoms. However, the overarching issue associated with all of the themes appeared to emanate from a lack of type 2 diabetes awareness. CONCLUSIONS: Emotions experienced by participants seemed precipitated by a lack of type 2 diabetes awareness. Some community-specific factors contributed to the lack of type 2 diabetes awareness, which appeared to impede primary and secondary prevention among participants. Recommendations for ameliorating these factors are presented. PMID- 24070887 TI - The lived experience of Canadian university students with type 1 diabetes mellitus. AB - OBJECTIVE: The purpose of this study was to examine the lived experiences of university students with type 1 diabetes mellitus. METHODS: University students participated in a 2-part focus group. Transcripts were analyzed thematically using an open-coding approach. Data analysis was guided by a framework analysis method and emergent themes were triangulated between study authors for validity. RESULTS: Three major themes identified in this study were food issues within the university environment, lack of diabetes awareness on campus and internal struggles related to the participants' relationships with their diabetes. CONCLUSIONS: Results illustrate some of the unique challenges that interfere with diabetes self-management, academic performance and quality of life among this sample of university students. Findings can provide insight for diabetes educators and other healthcare practitioners regarding the issues that may interfere with optimal diabetes self-care in this population. Findings also can be used to inform university administrators how to make the university environment more diabetes friendly for its students. PMID- 24070888 TI - Changes in depressive symptoms and changes in lifestyle-related indicators: a 1 year follow-up study among adults with type 2 diabetes in Quebec. AB - OBJECTIVE: The study purpose was to examine the association between changes in depressive symptoms and changes in lifestyle-related indicators among adults with type 2 diabetes. METHODS: A longitudinal survey was conducted among individuals with type 2 diabetes in Quebec. The sample consisted of 1183 subjects who responded to the baseline and 1-year follow-up telephone interviews, with complete data for depressive symptoms (Patient Health Questionnaire 9). Regression models were used to determine associations between changes in depressive symptoms and changes in lifestyle-related indicators (physical activity, body mass index (BMI)) and, perception-related indicators (control of body weight and of amount of food eaten). RESULTS: After 1 year, 136 subjects (11.5%) developed depression (major or minor), 118 (10%) remained depressed, 829 (70%) remained not depressed and 100 (8.5%) reverted to not depressed. Subjects who developed depression, compared with those who remained not depressed, were more likely to be inactive at baseline, remain inactive at 1 year, report a worsening of their perception of controlling body weight, report maintaining a poor perception of controlling amount of food eaten and report maintaining a poor perception of controlling body weight (p<0.05). The same factors were associated with maintenance of depression at 1 year (p<0.05). Changes in BMI were not associated with changes in depressive symptoms. CONCLUSIONS: Physical inactivity, perception of poor control of body weight and amount of food eaten have been found to be associated prospectively with the development and persistence of depression and, therefore, should be considered priority targets for diabetes treatment. Depression is related to the continuation of poor lifestyle and perception-related indicators. PMID- 24070889 TI - Concordance between self-report and a survey-based algorithm for classification of type 1 and type 2 diabetes using the 2011 population-based Survey on Living with Chronic Diseases in Canada (SLCDC)-Diabetes component. AB - OBJECTIVE: There are 2 major forms of diabetes mellitus: types 1 and 2. A major limitation of most current population-based diabetes surveillance systems is the classification of diabetes types. Our objective was to examine the concordance of self-reported diabetes type with a previously developed classification algorithm, using a nationally representative survey sample. METHODS: Self-reported data were available from 2544 adults with self-reported diabetes, aged >=20 years and older, who responded to the diabetes component of the 2011 Survey of Living with Chronic Diseases in Canada. We examined the concordance of self-reported diabetes type with an algorithm based on self-reported, but objective, respondent characteristics, such as age of diagnosis and treatment patterns. Concordance was measured using kappa coefficients. Sensitivity, specificity and positive and negative predictive values were calculated using the algorithm as the reference "standard." RESULTS: Approximately 11% of the estimated population did not self report diabetes type; almost all of these respondents would be classified as having type 2 diabetes by the algorithm. Of those self-reporting diabetes type, we found moderate overall agreement between the algorithm and self-reported type (kappa, 0.52; 95% confidence interval [CI], 0.52 to 0.53). Perfect agreement was noted in the youngest age group (kappa, 1.0; 95% CI, 1.0-1.0) but agreement was poor for the oldest age group (kappa, 0.20; 95% CI, 0.19 to 0.20). CONCLUSIONS: An algorithm based on self-reported, objective characteristics related to diabetes diagnosis and treatment patterns may have the potential to overcome limitations of simple self-report diabetes type for the classification of diabetes type in older adults. PMID- 24070890 TI - Alberta Healthy Living Program--a model for successful integration of chronic disease management services. AB - The most common presentation of chronic disease is multimorbidity. Disease management strategies are similar across most chronic diseases. Given the prevalence of multimorbidity and the commonality in approaches, fragmented single disease management must be replaced with integrated care of the whole person. The Alberta Healthy Living Program, a community-based chronic disease management program, supports adults with, or at risk for, chronic disease to improve their health and well being. Participants gain confidence and skills in how to manage their chronic disease(s) by learning to understand their health condition, make healthy eating choices, exercise safely and cope emotionally. The program includes 3 service pillars: disease-specific and general health patient education, disease-spanning supervised exercise and Better Choices, Better Health(TM) self-management workshops. Services are delivered in the community by an interprofessional team and can be tailored to target specific diverse and vulnerable populations, such as Aboriginal, ethno-cultural and francophone groups and those experiencing homelessness. Programs may be offered as a partnership between Alberta Health Services, primary care and community organizations. Common standards reduce provincial variation in care, yet maintain sufficient flexibility to meet local and diverse needs and achieve equity in care. The model has been implemented successfully in 108 communities across Alberta. This approach is associated with reduced acute care utilization and improved clinical indicators, and achieves efficiencies through an integrated, disease-spanning patient-centred approach. PMID- 24070891 TI - Nutritional controls of food reward. AB - The propensity to select and consume palatable nutrients is strongly influenced by the rewarding effects of food. Neural processes integrating reward, emotional states and decision-making can supersede satiety signals to promote excessive caloric intake and weight gain. While nutritional habits are influenced by reward based neural mechanisms, nutrition and its impact on energy metabolism, in turn, plays an important role in the control of food reward. Feeding modulates the release of metabolic hormones that have an important influence on central controls of appetite. Nutrients themselves are also an essential source of energy fuel, while serving as key metabolites and acting as signalling molecules in the neural pathways that control feeding and food reward. Along these lines, this review discusses the impact of nutritionally regulated hormones and select macronutrients on the behavioural and neural processes underlying the rewarding effects of food. PMID- 24070892 TI - Understanding type 1 diabetes: etiology and models. AB - Type 1 diabetes is a complex disease involving a combination of factors, such as genetic susceptibility, immunologic dysregulation and exposure to environmental triggers. Animal models serve an important function both in elucidating the pathophysiology and preliminary screening of antidiabetic molecules. Hence, the development of models for type 1 diabetes can be broadly divided into 3 categories, namely: identification of spontaneously developing type 1 diabetes mellitus strains, creating diabetes-prone species through gene transfer techniques and forced destruction of islet cells through chemical or surgical means. This review discusses the models used to study type 1 diabetes with special emphasis on genetics. PMID- 24070894 TI - Forearm muscle oxygenation responses during and following arterial occlusion in patients with mitochondrial myopathy. AB - The aim was to study whether mitochondrial myopathy induces different oxygenation (deoxy[Hb+Mb] and oxy[Hb+Mb]) responses during and following arterial occlusion. In 10 mitochondrial myopathy patients (MMpatients) (age: 29+/-7 years; body mass: 59.9+/-15.7kg; heigth: 166.2+/-11.4cm) and age- and gender-matched healthy subjects (age: 28+/-9 years; body mass: 72.7+/-16.9kg; height: 174.4+/-8.7cm) arterial occlusion was performed by inflating a cuff to 240mmHg. Deoxy[Hb+Mb] and oxy[Hb+Mb] were registered during (AOoxy and AOdeoxy) and following (POdeoxy and POoxy) arterial occlusion. Amplitude of AOdeoxy did not differ (p=0.47) between MMpatients (44.9+/-28.0MUM) and healthy subjects (38.6+/-22.8MUM), The time constant of the exponential model was greater in MMpatients (263.4+/-49.1s vs. 200.3+/-73.7s, p=0.03). Following cuff release, in both populations a transient increase in total[Hb+Mb] was observed induced by different kinetics of POoxy and POdeoxy. The increase in POoxy (TD=6.6+/-2.2s and 11.9+/-3.5s; tau=3.8+/-1.4s and 6.4+/-2.9s for MMpatients and healthy subjects, respectively) was faster (p<0.001 for TD and tau) compared to the decrease in POdeoxy (TD=13.2+/-3.6s and 26.5+/ 4.6s; tau=-6.2+/-2.2s and -9.6+/-2.4s for MMpatients and healthy subjects, respectively). POoxy and POdeoxy showed faster kinetics (p<0.001 and p<0.01 for TD and tau, respectively) in MMpatients compared to healthy subjects. MMpatients display altered oxygenation responses during and following arterial occlusion reflecting pathology related changes in the relationship between muscle blood flow and oxygen uptake. PMID- 24070895 TI - Remodelling pattern of the ramus on submentovertex cephalographs after intraoral vertical ramus osteotomy. AB - The aim of this study was to evaluate postoperative changes in proximal segments and condyles on the transverse plane after intraoral vertical ramus osteotomy. This is a retrospective study that included 200 subjects operated on, from 2003 to 2010, from whom we compared preoperative and postoperative (7 days, and 1, 3, 6, and 12 months) submentovertex radiographs. Postoperative positional changes in the condyles showed a mean (SD) of 15.05 (8.97) degrees lateral rotation, which slowly returned towards the original position. However, 4.53 (6.03) degrees lateral rotation remained on the postoperative radiographs at 1 year. There were no remarkable differences in intercondylar distance at any given time interval, which showed pure rotation of condyles without any bodily shift. The length of horizontal overlapping was also increased after operation, and was later decreased by 48% on postoperative radiographs at 1 year through the remodelling process. Condyles had rotated laterally without a lateral shifting movement only after intraoral vertical ramus osteotomy. Further studies to evaluate the physiological effects of rotational movement of the condyles after the operation in patients with symptoms in the temporomandibular joint are indicated. PMID- 24070896 TI - Targeting PKCepsilon by miR-143 regulates cell apoptosis in lung cancer. AB - Non-small cell lung cancer (NSCLC) is one of the most common causes for lung cancer and cancer-related death. The imbalance between cell proliferation and apoptosis was suggested to play an important role in cancer pathogenesis and PKCepsilon is one of the widely recognized targets. Here, we demonstrate that miR 143 is aberrantly downregulated in NSCLC tissue and negatively correlates with expression of PKCepsilon. We show that miR-143 specifically targets the 3'-UTR of PKCepsilon and regulates its expression. Treatment with miR-143 inhibitor mimics cell proliferation and apoptosis imbalance in NSCLC, while inhibition of PKCepsilon can reverse it. Our findings suggest that targeting PKCepsilon overexpression in NSCLC should be beneficial for lung cancer therapy. PMID- 24070897 TI - Triose phosphate isomerase from the blood fluke Schistosoma mansoni: biochemical characterisation of a potential drug and vaccine target. AB - The glycolytic enzyme triose phosphate isomerase from Schistosoma mansoni is a potential target for drugs and vaccines. Molecular modelling of the enzyme predicted that a Ser-Ala-Asp motif which is believed to be a helminth-specific epitope is exposed. The enzyme is dimeric (as judged by gel filtration and cross linking), resistant to proteolysis and highly stable to thermal denaturation (melting temperature of 82.0 degrees C). The steady-state kinetic parameters are high (Km for dihydroxyacetone phosphate is 0.51 mM; Km for glyceraldehyde 3 phosphate is 1.1 mM; kcat for dihydroxyacetone phosphate is 7800 s(-1) and kcat for glyceraldehyde 3-phosphate is 6.9s(-1)). PMID- 24070898 TI - Progranulin directly binds to the CRD2 and CRD3 of TNFR extracellular domains. AB - We previously reported that PGRN directly bound to TNF receptors (TNFR) in vitro and in chondrocytes (Tang, et al., Science, 2011). Here we report that PGRN also associated with TNFR in splenocytes, and inhibited the binding of TNFalpha to immune cells. Proper folding of PGRN is essential for its binding to TNFR, as DTT treatment abolished its binding to TNFR. In contrast, the binding of PGRN to Sortilin was enhanced by DTT. Protein interaction assays with mutants of the TNFR extracellular domain demonstrated that CRD2 and CRD3 of TNFR are important for the interaction with PGRN, similar to the binding to TNFalpha. Taken together, these findings provide the molecular basis underlying PGRN/TNFR interaction and PGRN-mediated anti-inflammatory activity in various autoimmune diseases and conditions. PMID- 24070899 TI - Phospho-DeltaNp63alpha regulates AQP3, ALOX12B, CASP14 and CLDN1 expression through transcription and microRNA modulation. AB - Cisplatin-induced and ATM-phosphorylated (p)-DeltaNp63alpha regulates the expression of epidermal differentiation and skin barrier regulators (AQP3, CASP14, ALOX12B, and CLDN1) in squamous cell carcinoma (SCC) cells by dual transcriptional and post-transcriptional mechanisms. We found that p DeltaNp63alpha bound to target gene promoters, and regulated the activity of the tested promoters in vitro. P-DeltaNp63alpha was shown to upregulate miR-185-5p and downregulate let7-5p, which subsequently modulated AQP3, CASP14, ALOX12B and CLDN1 through their respective 3'-untranslated regions. The introduction of miR 185-5p into resistant SCC-11M cells, which are unable to phosphorylate DeltaNp63alpha, render these cells more sensitive to cisplatin treatment. Further studies of the AQP3, CASP14, ALOX12B, and CLDN1 contributions to chemoresistance may assist in developing novel microRNA-based therapies for human SCC. PMID- 24070900 TI - Targeted therapies and complete responses in first line treatment of metastatic renal cell carcinoma. A meta-analysis of published trials. AB - Antiangiogenic agents (AAs) have reported grater efficacy compared to interferon. Despite these advances, radiological complete response to therapy is rare. We meta-analyzed the incidence of complete response in patients treated with AAs and in controls in main randomized clinical trials for first-line therapy in metastatic renal cell carcinoma. PubMed was reviewed for phase II-III randomized clinical trials with AAs vs. non-AAs in patients with good or intermediate prognosis. We calculated the relative risk of events in patients assigned to AAs compared to control. Five RCTs were found; four were phase III and one was phase II. A total of 2747 patients was valuable for final analysis and randomized to receive AAs or control. Patients in the control-group had interferon (85%) or placebo (15%); patients in the AAs-group received bevacizumab (48%), sunitinib (26%), pazopanib (20%) or sorafenib (6%). The incidence of complete response in patients treated with AAs was 2.0% (95% CI, 1.2-2.8) compared to 1.4% (95% CI, 0.7-2.1) in the control arm. Comparing the different type of AAs, the incidence of complete response was 2.5% (95% CI, 1.2-3.8) in the bevacizumab group and 1.6% (95% CI, 0.1-2.5) in the TKIs group. The relative risk to have a complete response was 1.52 (95% CI, 0.85-2.73; p=0.16) in patients treated with AAs compared to controls; this was found higher in patients treated with TKIs compared to bevacizumab. The complete response is a rare event in metastatic kidney tumor, even if AAs reported greater efficacy in terms of progression-free survival and of overall response rate, they did not increase the curative rate of metastatic disease. Probably, some biologic factors other than angiogenesis may influence the complete response in this disease. PMID- 24070901 TI - Autoimmune hepatitis in a patient affected by neuromyelitis optica: a new association. PMID- 24070902 TI - Top-down motif engineering of a cytokine receptor for directing ex vivo expansion of hematopoietic stem cells. AB - The technique to expand hematopoietic stem cells (HSCs) ex vivo is eagerly anticipated to secure an enough amount of HSCs for clinical applications. Previously we developed a scFv-thrombopoietin receptor (c-Mpl) chimera, named S Mpl, which can transduce a proliferation signal in HSCs in response to a cognate antigen. However, a remaining concern of the S-Mpl chimera may be the magnitude of the cellular expansion level driven by this molecule, which was significantly less than that mediated by endogenous wild-type c-Mpl. In this study, we engineered a tyrosine motif located in the intracellular domain of S-Mpl based on a top-down approach in order to change the signaling properties of the chimera. The truncated mutant (trunc.) and an amino-acid substitution mutant (Q to L) of S Mpl were constructed to investigate the ability of these mutants to expand HSCs. The result showed that the truncated and Q to L mutants gave higher and considerably lower number of the cells than unmodified S-Mpl, respectively. The proliferation level through the truncated mutant was even higher than that of non transduced HSCs with the stimulation of a native cytokine, thrombopoietin. Moreover, we analyzed the signaling properties of the S-Mpl mutants in detail using a pro-B cell line Ba/F3. The data indicated that the STAT3 and STAT5 activation levels through the truncated mutant increased, whereas activation of the Q to L mutant was inhibited by a negative regulator of intracellular signaling, SHP-1. This is the first demonstration that a non-natural artificial mutant of a cytokine receptor is effective for ex vivo expansion of hematopoietic cells compared with a native cytokine receptor. PMID- 24070903 TI - Functional expression of FIP-fve, a fungal immunomodulatory protein from the edible mushroom Flammulina velutipes in Pichia pastoris GS115. AB - FIP-fve is a bioactive protein isolated from the mushroom Flammulina velutipes, which belongs to the fungal immunomodulatory protein (FIP) family and demonstrates several kinds of biological activities including anti-allergy, anti tumor and immunomodulation. In the current study, the FIP-fve gene was cloned and expressed in the yeast Pichia pastoris GS115, and its correctness was confirmed by SDS-PAGE and Western blot. Optimal expression of rFIP-fve was observed when the P. pastoris cells were cultured in 1% methanol for 9 6h, which resulted in a yield of 258.2 mg l(-1). The rFIP-fve protein was subsequently purified via ammonium sulfate precipitation and Sephadex G-100 gel chromatography. In vitro bioactivity examination showed that rFIP-fve could agglutinate human red blood cells and stimulate the cell viability of murine splenocytes. The immunomodulatory capacity and anti-tumor activity of rFIP-fve were demonstrated by enhanced interleukin-2 secretion and interferon-gamma release from the murine lymphocytes, similar to the biological FIP-fve. In conclusion, the FIP-fve gene was functionally and effectively expressed in P. pastoris, and rFIP-fve displayed biological activities similar to those of native FIP-fve. These results indicated the potential use of rFIP-fve from P. pastoris as an effective and feasible source for therapeutic studies and medical applications. PMID- 24070905 TI - Risk behaviors, suicidal ideation and suicide attempts in a nationally representative French sample. AB - BACKGROUND: Data from large nationally representative samples are needed to provide the empirical foundation to inform health policies for the prevention of suicide risk and risk behaviors in men and women. METHODS: Data were extracted from the 2010 Health Barometer, a large telephone survey on a representative sample of the general population aged 15-85 years living in France (n=27,653), carried out by the National Institute for Health Promotion and Health Education. Data were collected between October 2009 and July 2010. A computer-assisted telephone interview (CATI) system was used. RESULTS: Overall, 3.9% of respondents aged 15 to 85 reported past year suicidal ideation, and 0.5% reported a suicide attempt in that time period. Increased rates of risky sexual behavior are associated with ideation and attempt in both men and women, after controlling for sociodemographic variables. Homosexuality or bisexuality are associated with suicidal ideation for both men and women, but not with attempts. Substance misuse, physical and sexual assaults are strongly associated with suicidal symptoms for both men and women. Early first experiences with sex, tobacco, and alcohol are associated with suicidal symptoms though somewhat differentially for men and women. LIMITATIONS: Cross-sectional survey. CONCLUSION: The findings underscore associations between suicidal thoughts and behaviors and risk behaviors such as unprotected sex and substance use in men and women throughout the lifespan. These associations highlight the need for preventive strategies such as screening for risk behaviors in order to identify men and women particularly at risk for suicidal behavior. PMID- 24070904 TI - Novel recombinant human lactoferrin: differential activation of oxidative stress related gene expression. AB - Lactoferrin, an iron-binding protein found in high concentrations in mammalian exocrine secretions, is an important component of the host defense system. It is also a major protein of the secondary granules of neutrophils from which is released upon activation. Due to its potential clinical utility, recombinant human lactoferrin (rhLF) has been produced in various eukaryotic expression systems; however, none of these are fully compatible with humans. Most of the biopharmaceuticals approved by the FDA for use in humans are produced in mammalian expression systems. The Chinese hamster ovary cells (CHO) have become the system of choice for proteins that require post-translational modifications, such as glycoproteins. The aim of this study was to scale-up expression and purification of rhLF in a CHO expression system, verify its glycan primary structure, and assess its biological properties in cell culture models. A stable CHO cell line producing >200mg/L of rhLF was developed and established. rhLF was purified by a single-step cation-exchange chromatography procedure. The highly homogenous rhLF has a molecular weight of approximately 80 kDa. MALDI-TOF mass spectrometric analysis revealed N-linked, partially sialylated glycans at two glycosylation sites, typical for human milk LF. This novel rhLF showed a protective effect against oxidative stress in a similar manner to its natural counterpart. In addition, rhLF revealed a modulatory effect on cellular redox via upregulation of key antioxidant enzymes. These data imply that the CHO-derived rhLF is fully compatible with the native molecule, thus it has promise for human therapeutic applications. PMID- 24070907 TI - A multinational study to pilot the modified Hypomania Checklist (mHCL) in the assessment of mixed depression. AB - BACKGROUND: Mixed depression is a common, dimensional phenomenon that is increasingly recognized in unipolar and bipolar disorders. We piloted a modified version of the Hypomania Checklist (mHCL-32) to assess the prevalence and clinical correlates of concurrent manic (hypo) symptoms in depressed patients. METHODS: The mHCL-32, Young Mania Rating Scale (YMRS) and Hamilton Rating Scale for Depression (HAMD-24) were utilized in the assessment of unipolar (UP=61) and bipolar (BP=44) patients with an index major depressive episode confirmed by the Structured Clinical Interview for DSM-IV (SCID). Differential mHLC-32 item endorsement was compared between UP and BP. Correlation analyses assessed the association of symptom dimensions measured by mHCL-32, YMRS and HAMD-24. RESULTS: There was no significant difference between mood groups in the mean mHCL-32 and YMRS scores. Individual mHLC-32 items of increased libido, quarrels, and caffeine intake were endorsed more in BP vs. UP patients. The mHCL-32 active-elevated subscale score was positively correlated with the YMRS in BP patients and negatively correlated with HAMD-24 in UP patients. Conversely, the mHCL-32 irritable-risk taking subscale score was positively correlated with HAMD-24 in BP and with YMRS in UP patients. LIMITATIONS: Small sample size and cross-sectional design. CONCLUSION: Modifying the HCL to screen for (hypo) manic symptoms in major depression may have utility in identifying mixed symptoms in both bipolar vs. unipolar depression. Further research is encouraged to quantify mixed symptoms with standardized assessments. PMID- 24070908 TI - CT pulmonary angiography using a reduced volume of high-concentration iodinated contrast medium and multiphasic injection to achieve dose reduction. AB - AIM: To evaluate whether a reduced volume of a higher-concentration iodinated contrast medium delivered with a multiphasic injection could be used in computed tomography pulmonary angiography (CTPA) to achieve a reduction in dose without adversely affecting image quality. MATERIALS AND METHODS: The CTPA images were retrospectively evaluated of 69 patients who received 100 ml of 300 mg iodine/ml ioversol, injected at constant rate of 5 ml/s and 70 patients who received 75 ml of 350 mg iodine/ml ioversol contrast medium delivered using a multiphasic injection protocol (starting at 5 ml/s and reducing exponentially). The degree of opacification in the proximal pulmonary arteries was measured in Hounsfield units. RESULTS: The groups did not differ in terms of age, sex distribution, or weight. The mean iodine dose was lower in the 75 ml of 350 mg iodine/ml group (26.25 versus 29.5 g, p < 0.0001). Mean opacification did not differ significantly between the 75 ml of 350 mg iodine/ml and 100 ml of 300 mg iodine/ml groups in the main pulmonary artery (365 versus 331, p = 0.055) although it was significantly higher in the 75 ml group in the right (352 versus 315, p = 0.024) and left pulmonary arteries (347 versus 312, p = 0.028). Opacification correlated positively with age and negatively with weight (p < 0.001) and when these effects had been accounted for, the differences in opacification were not statistically significant in the main (p = 0.23), right (p = 0.11), or left pulmonary arteries (p = 0.13). The number of suboptimally opacified studies (opacification of less than 250 HU in main pulmonary artery) did not differ between the groups (12 versus 13, p = 0.83). CONCLUSION: A reduction in iodine dose can be achieved without adversely affecting pulmonary arterial enhancement in CTPA by administering a smaller volume of high concentration contrast medium using a multiphasic injection protocol. PMID- 24070906 TI - Emotion perception and quality of life in bipolar I disorder. AB - BACKGROUND: Across two studies we examined the role of emotion perception as a correlate of quality of life and occupational functioning in bipolar I disorder. METHOD: In Study 1, we tested a multifactorial model of quality of life and occupational functioning, including the role of emotion perception and other established correlates of functional outcomes, among 42 participants diagnosed with bipolar I disorder. In Study 2, participants diagnosed with bipolar I disorder and age- and gender-matched controls completed an affect recognition task and a quality of life measure. RESULTS: Across both studies, emotion perception related to functional outcomes. In Study 1, self-rated emotion perception explained unique variance in subjective well-being after controlling for illness characteristics, education, and executive function. In Study 2, a behavioral measure of facial affect recognition accuracy was related to quality of life, even after controlling for illness severity. LIMITATIONS: Limitations include the use of a cross-sectional design, relatively small sample sizes, and the focus on only one aspect of social cognition. CONCLUSIONS: Findings indicate that emotion perception may protect quality of life in bipolar disorder. This dimension may help predict important outcomes and, with further research, could serve as a potential treatment target. PMID- 24070909 TI - On the quest for a biomechanism of transsexualism: is there a role for BDNF? AB - Previous studies hypothesized a neurobiological mechanism for gender identity disorder (GID). Recently a possible role for serum brain-derived neurotrophic factor (BDNF) was suggested on the basis of reduced serum BDNF levels in male-to female individuals. Here we review the question whether there is indeed a role of BDNF in the development of transsexualism. PMID- 24070910 TI - Functional neuroanatomy of response inhibition in bipolar disorders--combined voxel based and cognitive performance meta-analysis. AB - OBJECTIVES: Impaired response inhibition underlies symptoms and altered functioning in patients with bipolar disorders (BD). The interpretation of fMRI studies requires an accurate estimation of neurocognitive performance, for which individual studies are typically underpowered. Thus, we performed the first combined meta-analysis of fMRI activations and neurocognitive performance in studies investigating response inhibition in BD. METHODS: We used signed differential mapping to combine anatomical coordinates of activation and standardized differences between means to evaluate neurocognitive performance in 30 fMRI studies of response inhibition comparing controls (n = 667) and patients with BD (n = 635). RESULTS: Relative to controls, BD patients underactivated the right inferior frontal gyrus (rIFG) regardless of current mood state and behavioral performance. Unique to euthymia were cortical hyperactivations (left superior temporal, right middle frontal gyri) combined with subcortical hypoactivations (basal ganglia), whereas unique to mania were subcortical hyperactivations (bilateral basal ganglia), combined with cortical hypoactivations (right inferior and medial frontal gyri). The fMRI changes in euthymia were associated with normal cognitive performance, whereas manic patients committed more errors during response inhibition. CONCLUSIONS: The rIFG hypoactivations were congruent with a BD trait, which may underlie the impaired response inhibition in mania. Euthymic BD subjects may compensate for the rIFG hypoactivations by hyperactivations of adjacent cortical areas, yielding comparable performance in inhibitory functions and suggesting possibilities for neuromodulation treatment of these cognitive impairments. The reversal of the activation pattern between mania and euthymia has implications for monitoring of treatment response and identification of imminent relapse. PMID- 24070912 TI - Uranium in Kosovo's drinking water. AB - The results of this paper are an initiation to capture the drinking water and/or groundwater elemental situation in the youngest European country, Kosovo. We aim to present a clear picture of the natural uranium concentration in drinking water and/or groundwater as it is distributed to the population of Kosovo. Nine hundred and fifty-one (951) drinking water samples were analyzed by inductively coupled plasma mass spectrometry (ICPMS). The results are the first countrywide interpretation of the uranium concentration in drinking water and/or groundwater, directly following the Kosovo war of 1999. More than 98% of the samples had uranium concentrations above 0.01 MUg L(-1), which was also our limit of quantification. Concentrations up to 166 MUg L(-1) were found with a mean of 5 MUg L(-1) and median 1.6 MUg L(-1) were found. Two point six percent (2.6%) of the analyzed samples exceeded the World Health Organization maximum acceptable concentration of 30 MUg L(-1), and 44.2% of the samples exceeded the 2 MUg L(-1) German maximum acceptable concentrations recommended for infant food preparations. PMID- 24070911 TI - High-dose atorvastatin reduces periodontal inflammation: a novel pleiotropic effect of statins. AB - OBJECTIVES: The purpose of this study was to test whether high-dose statin treatment would result in a reduction in periodontal inflammation as assessed by (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT). BACKGROUND: Periodontal disease (PD) is an independent risk factor for atherosclerosis. METHODS: Eighty-three adults with risk factors or with established atherosclerosis and who were not taking high-dose statins were randomized to atorvastatin 80 mg vs. 10 mg in a multicenter, double-blind trial to evaluate the impact of atorvastatin on arterial inflammation. Subjects were evaluated using FDG-PET/CT at baseline and at 4 and 12 weeks. Arterial and periodontal tracer activity was assessed while blinded to treatment allocation, clinical characteristics, and temporal sequence. Periodontal bone loss (an index of PD severity) was evaluated using contrast-enhanced CT images while blinded to clinical and imaging data. RESULTS: Seventy-one subjects completed the study, and 59 provided periodontal images for analysis. At baseline, areas of severe PD had higher target-to-background ratio (TBR) compared with areas without severe PD (mean TBR: 3.83 [95% confidence interval (CI): 3.36 to 4.30] vs. 3.18 [95% CI: 2.91 to 3.44], p = 0.004). After 12 weeks, there was a significant reduction in periodontal inflammation in patients randomized to atorvastatin 80 mg vs. 10 mg (DeltaTBR 80 mg vs. 10 mg group: mean -0.43 [95% CI: -0.83 to -0.02], p = 0.04). Between-group differences were greater in patients with higher periodontal inflammation at baseline (mean -0.74 [95% CI: -1.29 to -0.19], p = 0.01) and in patients with severe bone loss at baseline (-0.61 [95% CI: -1.16 to -0.054], p = 0.03). Furthermore, the changes in periodontal inflammation correlated with changes in carotid inflammation (R = 0.61, p < 0.001). CONCLUSIONS: High-dose atorvastatin reduces periodontal inflammation, suggesting a newly recognized effect of statins. Given the concomitant changes observed in periodontal and arterial inflammation, these data raise the possibility that a portion of that beneficial impact of statins on atherosclerosis relate to reductions in extra arterial inflammation, for example, periodontitis. (Evaluate the Utility of 18FDG PET as a Tool to Quantify Atherosclerotic Plaque; NCT00703261). PMID- 24070913 TI - Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children. PMID- 24070926 TI - Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Introduction. PMID- 24070914 TI - Consciousness in the universe: a review of the 'Orch OR' theory. AB - The nature of consciousness, the mechanism by which it occurs in the brain, and its ultimate place in the universe are unknown. We proposed in the mid 1990's that consciousness depends on biologically 'orchestrated' coherent quantum processes in collections of microtubules within brain neurons, that these quantum processes correlate with, and regulate, neuronal synaptic and membrane activity, and that the continuous Schrodinger evolution of each such process terminates in accordance with the specific Diosi-Penrose (DP) scheme of 'objective reduction' ('OR') of the quantum state. This orchestrated OR activity ('Orch OR') is taken to result in moments of conscious awareness and/or choice. The DP form of OR is related to the fundamentals of quantum mechanics and space-time geometry, so Orch OR suggests that there is a connection between the brain's biomolecular processes and the basic structure of the universe. Here we review Orch OR in light of criticisms and developments in quantum biology, neuroscience, physics and cosmology. We also introduce a novel suggestion of 'beat frequencies' of faster microtubule vibrations as a possible source of the observed electro encephalographic ('EEG') correlates of consciousness. We conclude that consciousness plays an intrinsic role in the universe. PMID- 24070927 TI - Vascular protection in people with diabetes. PMID- 24070928 TI - Screening for the presence of coronary artery disease. PMID- 24070929 TI - Dyslipidemia. PMID- 24070930 TI - Treatment of hypertension. PMID- 24070931 TI - Management of acute coronary syndromes. PMID- 24070932 TI - Screening for type 1 and type 2 diabetes. PMID- 24070933 TI - Management of stroke in diabetes. PMID- 24070934 TI - Treatment of diabetes in people with heart failure. PMID- 24070935 TI - Chronic kidney disease in diabetes. PMID- 24070936 TI - Retinopathy. PMID- 24070937 TI - Neuropathy. PMID- 24070938 TI - Foot care. PMID- 24070939 TI - Erectile dysfunction. PMID- 24070940 TI - Type 1 diabetes in children and adolescents. PMID- 24070941 TI - Reducing the risk of developing diabetes. PMID- 24070942 TI - Type 2 diabetes in children and adolescents. PMID- 24070943 TI - Diabetes and pregnancy. PMID- 24070944 TI - Diabetes in the elderly. PMID- 24070945 TI - Type 2 diabetes in Aboriginal peoples. PMID- 24070948 TI - Organization of diabetes care. PMID- 24070958 TI - Self-management education. PMID- 24070959 TI - Targets for glycemic control. PMID- 24070960 TI - Monitoring glycemic control. PMID- 24070961 TI - Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Methods. PMID- 24070962 TI - Physical activity and diabetes. PMID- 24070963 TI - Nutrition therapy. PMID- 24070964 TI - Pharmacotherapy in type 1 diabetes. PMID- 24070965 TI - Pharmacologic management of type 2 diabetes. PMID- 24070967 TI - Hyperglycemic emergencies in adults. PMID- 24070966 TI - Hypoglycemia. PMID- 24070968 TI - In-hospital management of diabetes. PMID- 24070969 TI - Definition, classification and diagnosis of diabetes, prediabetes and metabolic syndrome. PMID- 24070970 TI - Weight management in diabetes. PMID- 24070971 TI - Diabetes and mental health. PMID- 24070972 TI - Influenza and pneumococcal immunization. PMID- 24070973 TI - Pancreas and islet transplantation. PMID- 24070974 TI - Natural health products. PMID- 24070975 TI - The role of sphingosine 1-phosphate in inflammation and cancer. AB - The enzymes that catalyze formation of the bioactive sphingolipid, sphingosine 1 phosphate, sphingosine kinase 1 and 2, are predictive markers in inflammatory diseases and cancer as evidenced by data from patients, knockout mice and the use of available molecular and chemical inhibitors. Thus, there is a compelling case for therapeutic targeting of sphingosine kinase. In addition, there are several examples of functional interaction between sphingosine 1-phosphate receptors and sphingosine kinase 1 that can drive malicious amplification loops that promote cancer cell growth. These novel aspects of sphingosine 1-phosphate pathobiology are reviewed herein. PMID- 24070976 TI - Acute myocardial infarction with normal coronary arteries associated with subclinical Graves disease. AB - Myocardial infarction occurring with angiographically normal coronary arteries is rare and often described in young people. This report describes a case of myocardial infarction with normal coronary arteries in a young female patient related to coronary thrombosis complicated by left ventricular apical thrombus in the setting of an unknown and subclinical Graves disease. PMID- 24070977 TI - Review of techniques for the removal of trapped rings on fingers with a proposed new algorithm. AB - Various removal techniques for rings trapped on the finger have been described in the current literature. However, despite this being a frequently encountered situation in emergency departments, there is no comprehensive algorithm to manage and follow these patients in the current literature. The purposes of this study were to describe the most commonly used ring removal techniques and to establish an algorithm for the removal of rings trapped on fingers. We performed a comprehensive literature search in several databases to identify all articles, case reports, letters, and book chapters that focus on ring removal techniques in English language from 1960 to the present. There are 2 methods of removal: (1) noncutting techniques in which the rings can be removed without breaking the integrity of the ring and (2) various ring-cutting equipments and tools. All these techniques are classified into distinct groups and described in detail with illustrations. Furthermore, an algorithm for handling such patients is established according to case-based patient care. Following an algorithm for the removal of trapped rings on the finger will be useful for patients and emergency physicians. It will also prevent possible complications and will save time. PMID- 24070978 TI - Absence of jolt accentuation of headache cannot accurately rule out meningitis in adults. AB - BACKGROUND: Meningitis is a common emergency disease. Signs and symptoms easily observed at the bedside are needed because early recognition of the possibility of meningitis is necessary for the decision to perform lumbar puncture. Jolt accentuation of headache has been reported to be the most sensitive diagnostic test; however, limited articles have reproduced its sensitivity. METHODS: This is a single-center retrospective medical record review between 2007 and 2012. We diagnosed meningitis based on the criterion standard that cerebrospinal fluid total cells is more than 5/mm(3), in accordance with previous studies. All diagnostic and management decisions including Kernig sign, nuchal rigidity, and jolt accentuation of headache were at the physician's discretion. We calculated the sensitivity and specificity of well-known signs and symptoms of meningitis and, especially, compared the efficacy of jolt accentuation of headache with previous studies. RESULTS: We investigated 531 adult patients who were suspected of meningitis and had lumbar puncture performed. Of these patients, 139 had meningitis. Background characteristics and vital signs were not clinically different between the 2 groups, although classic tetralogy of bacterial meningitis (fever, nuchal rigidity, mental disturbance, and headache) was worth investigated. The sensitivity and specificity of jolt accentuation of headache were 63.9% (95% confidence interval, 51.9%-76.0%) and 43.2% (34.7%-51.6%), respectively. CONCLUSION: The absence of jolt accentuation of headache test cannot, on its own, accurately rule out meningitis in adults. Further studies are warranted to reproduce this result and to discover better bedside diagnostic tests. PMID- 24070979 TI - Outpatient diagnosis and therapeutic units linked with ED referrals: a sustainable quality-centered approach. PMID- 24070980 TI - A rare cause of dyspnea in emergency medicine: transfusion-related acute lung injury. AB - The earliest definition of transfusion-related acute lung injury (TRALI) included all patients who developed acute respiratory distress, moderate to severe hypoxemia, rapid onset of pulmonary edema, mild to moderate hypotension, and fever within 6 hours of receiving a plasma containing blood transfusion. The definition excluded patients if they had underlying cardiac or respiratory disease. The mechanism is not known exactly but it causes morbidity and mortality. Incidence of TRALI changes between 0.08% and 15% of patients receiving a blood transfusion. A 78 year old female patient with history of myelodysplastic syndrome, coronary artey disease and hypertansion, was admitted to the hospital because of dyspnea after the blood transfusion. She was managed as TRALI after diagnostic workup and transported to the intensive care unit. In the following days her clinical status changed dramatically with complete recovery. PMID- 24070981 TI - Torsade de pointes indicates early neurologic damage in acute ischemic stroke. AB - Torsade de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia that is related to QT prolongation. Although QT prolongation is commonly seen in acute stroke, TdP is rare. We report the case of a 78-year-old woman with ischemic stroke who presented with TdP as the initial manifestation of early neurologic deterioration. We hypothesized that an increase in intracranial pressure may result in neurohormonal activation, QT prolongation, and then myocardial damage, leading to TdP. We highlight that new onset of TdP in a patient with stroke may reflect neurologic deterioration, requiring further evaluation and specific intervention. PMID- 24070982 TI - Prevalence of non-convulsive seizure and other electroencephalographic abnormalities in ED patients with altered mental status. AB - Four to ten percent of patients evaluated in emergency departments (ED) present with altered mental status (AMS). The prevalence of non-convulsive seizure (NCS) and other electroencephalographic (EEG) abnormalities in this population is unknown. OBJECTIVES: To identify the prevalence of NCS and other EEG abnormalities in ED patients with AMS. METHODS: A prospective observational study at 2 urban ED. Inclusion: patients >=13 years old with AMS. Exclusion: An easily correctable cause of AMS (e.g. hypoglycemia). A 30-minute standard 21-electrode EEG was performed on each subject upon presentation. OUTCOME: prevalence of EEG abnormalities interpreted by a board-certified epileptologist. EEGs were later reviewed by 2 blinded epileptologists. Inter-rater agreement (IRA) of the blinded EEG interpretations is summarized with kappa. A multiple logistic regression model was constructed to identify variables that could predict the outcome. RESULTS: Two hundred fifty-nine patients were enrolled (median age: 60, 54% female). Overall, 202/259 of EEGs were interpreted as abnormal (78%, 95% confidence interval [CI], 73-83%). The most common abnormality was background slowing (58%, 95% CI, 52-68%) indicating underlying encephalopathy. NCS (including non-convulsive status epilepticus [NCSE]) was detected in 5% (95% CI, 3-8%) of patients. The regression analysis predicting EEG abnormality showed a highly significant effect of age (P < .001, adjusted odds ratio 1.66 [95% CI, 1.36-2.02] per 10-year age increment). IRA for EEG interpretations was modest (kappa: 0.45, 95% CI, 0.36-0.54). CONCLUSIONS: The prevalence of EEG abnormalities in ED patients with undifferentiated AMS is significant. ED physicians should consider EEG in the evaluation of patients with AMS and a high suspicion of NCS/NCSE. PMID- 24070983 TI - Polymerase complex with lysine at position 627 of the PB2 of influenza virus A/Hong Kong/483/97 (H5N1) efficiently transcribes and replicates virus genes in mouse cells. AB - Influenza virus A/Hong Kong/483/97 (H5N1) (HK483-K) has the PB2 with lysine at position 627 (PB2-627K) and is highly pathogenic in chickens and mice. On the other hand, the pathogenicity of mutant virus (HK483-E), which was generated by substituting lysine with glutamic acid at the position of the PB2, is lower than that of HK483-K in mice, but is highly pathogenic in chickens. The PB2 is one of the components of heterotrimeric polymerase complex, which plays roles in the transcription and replication of virus genes. Cell-free polymerase assay revealed that intrinsic transcription activity of the polymerase complex with PB2-627K is higher than that of glutamic acid (PB2-627E). In chicken cells, transcription efficiency of the polymerase complex with PB2-627E was not lower than those with PB2-627K, indicating that transcription of virus genes is modulated by some host factors in chicken cells, resulting in high growth. Polymerase complex with PB2 627K efficiently transcribes and replicates virus polymerase genes in mouse cells, leading to high growth of HK483-K compared with that of HK483-E. The results of our experiments clearly suggest that efficient transcription and replication of virus genes by polymerase complex result in the higher pathogenicity in mice. PMID- 24070984 TI - Identification and characterization of a tumor necrosis factor receptor like protein encoded by Singapore grouper iridovirus. AB - Virus encoded tumor necrosis factor receptors (TNFRs) have been demonstrated to facilitate virus to escape from apoptosis or other host immune response for viral replication. Singapore grouper iridovirus (SGIV), a large DNA virus which belongs to genus Ranavirus, is a major pathogen resulting in heavy economic losses to grouper aquaculture. Here, SGIV ORF096 (VP96) encoding a putative homolog of TNFR was identified and characterized. Multiple sequence alignment indicated that SGIV VP96 contained two extracellular cysteine-rich domains (CRDs) with conserved four or six cysteine residues, but lacked the transmembrane domain at the C-terminus. SGIV-VP96 was identified as an early (E) gene and localized in the cytoplasm in transfected or infected cells. Overexpression of SGIV-VP96 in vitro enhanced cell proliferation, and improved cell survival against SGIV infection. Furthermore, virus infection induced apoptosis and caspase-3 activity were inhibited in SGIV VP96 expressing FHM cells compared to the control cells. Taken together, our results suggested that SGIV might utilize virus encoded TNFR like genes to modulate the host apoptotic response for effective virus replication. PMID- 24070985 TI - Role of nucleocapsid protein of hantaviruses in intracellular traffic of viral glycoproteins. AB - To understand the role of nucleocapsid protein (NP) of hantaviruses in viral assembly, the effect of NP on intracellular traffic of viral glycoproteins Gn and Gc was investigated. Double staining of viral and host proteins in Hantaan virus (HTNV)-infected Vero E6 cells showed that Gn and Gc were localized to cis-Golgi, in which virus particles are thought to be formed. When HTNV Gn and Gc were expressed by a plasmid encoding glycoprotein precursor (GPC), which is posttranslationally cleaved into Gn and Gc, Gn was localized to cis-Golgi, whereas Gc showed diffuse distribution in the cytoplasm in 32.9% of Gc-positive cells. The ratio of the diffused Gc-positive cells was significantly decreased to 15.0% by co-expression of HTNV NP. Co-expression of HTNV GPC with NPs of other hantaviruses, such as Seoul virus, Puumala virus and Sin Nombre virus, also reduced the ratios of diffused Gc-positive cells to 13.5%, 25.2%, and 11.6%, respectively. Among amino- and carboxyl-terminally truncated HTNV NPs, NP75-429, NP116-429, NP1-333, NP1-233, and NP1-155 possessed activity to reduce the ratio of diffused Gc-positive cells, while NP155-429 and NP1-116 did not. NP30-429 has partial activity. These results indicate that amino acid region 116-155 of NP is important for the activity, although amino acid region 1-30 is partially related. Truncation of the HTNV Gc cytoplasmic tail caused an increase in diffused Gc positive cells. In addition, the effect of coexpression of HTNV NP was weakened. These results suggest that HTNV NP has a role to promote Golgi localization of Gc through a mechanism possibly mediated by the Gc cytoplasmic tail. PMID- 24070986 TI - Sex-specific association of the ST8SIAII gene with schizophrenia in a Spanish population. AB - We investigated the association between ST8SIAII and schizophrenia in a sample of Spanish origin. We found that the G allele (P=0.044) and the AG genotype (P=0.040) of rs3759916 were associated in females. The ACAG haplotype (rs3759914, rs3759915, rs3759916 and rs2305561) was associated in males (P=0.028). PMID- 24070987 TI - Risk factors for equine laminitis: a case-control study conducted in veterinary registered horses and ponies in Great Britain between 2009 and 2011. AB - Laminitis is a highly debilitating disease of the foot known to have a complex and multifactorial aetiology of metabolic, inflammatory, traumatic or vascular origin. The disease has major welfare implications due to unrelenting pain associated with degenerative changes, which often necessitate euthanasia on welfare grounds. Despite this, there have been few high-quality studies investigating risk factors for equine laminitis, and only a limited number of risk factors have been previously investigated. The aim of this study was to conduct a case-control study of risk factors for active episodes of veterinary diagnosed laminitis in horses and ponies attended by veterinary practitioners in Great Britain, based on multivariable statistical analyses. Questionnaires were received for 1010 animals, comprising 191 laminitis cases and 819 controls. Factors associated with an increased risk of laminitis were weight gain in the previous 3 months, summer and winter months compared to spring, new access to grass in the previous 4 weeks, box rest in the previous week, owner-reported history of laminitis, lameness or foot-soreness after shoeing/trimming, existing endocrinopathic (pituitary pars intermedia dysfunction and equine metabolic syndrome) disease and increasing time since the last anthelmintic treatment. Factors associated with a decreased risk of laminitis were increasing height (cm), feeding of additional supplements in the previous week and transportation in the previous week. Novel associated factors were identified that may aid in the management and prevention of the disease in the veterinary-registered equine population. PMID- 24070988 TI - A mindful eating group intervention for obese women: a mixed methods feasibility study. AB - The purpose of this mixed methods study was to: 1) describe the effect of an 8 week mindful eating intervention on mindful eating, weight loss self-efficacy, depression, and biomarkers of weight in urban, underserved, obese women; and 2) identify themes of the lived experience of mindful eating. A convenience sample of 12 obese women was recruited with data collected at baseline and 8 weeks followed by a focus group. Only self-efficacy for weight loss significantly increased over 8 weeks (t=-2.63, P=.04). Qualitative findings of mindful eating supported quantitative findings and extended understanding about the effect of the intervention. PMID- 24070989 TI - Is depression associated with glucose tolerance abnormality in pregnant women? A cross-sectonal study. AB - This study aims to examine the association between glucose tolerance abnormality and depression and anxiety in pregnant women. One hundred and sixty-seven women with gestational ages ranging from 24 to 28 weeks were screened with the 50 g oral glucose challenge test. All participants were assessed with the Beck Depression Inventory and the Beck Anxiety Inventory. The rate of depression was higher in women with abnormal glucose results (44.3%) than in women with normal glucose results (21.7%). Similarly, depressed women had higher glucose levels than non-depressed women. Findings suggest that depression and anxiety may be associated with glucose tolerance abnormality in pregnant women. PMID- 24070990 TI - Effects of music therapy on self- and experienced stigma in patients on an acute care psychiatric unit: a randomized three group effectiveness study. AB - Stigma is a major social barrier that can restrict access to and willingness to seek psychiatric care. Psychiatric consumers may use secrecy and withdrawal in an attempt to cope with stigma. The purpose of this study was to determine the effects of music therapy on self- and experienced stigma in acute care psychiatric inpatients using a randomized design with wait-list control. Participants (N=83) were randomly assigned by cluster to one of three single session group-based conditions: music therapy, education, or wait-list control. Participants in the music therapy and education conditions completed only posttests while participants in the wait-list control condition completed only pretests. The music therapy condition was a group songwriting intervention wherein participants composed lyrics for "the stigma blues." Results indicated significant differences in measures of discrimination (experienced stigma), disclosure (self-stigma), and total stigma between participants in the music therapy condition and participants in the wait-list control condition. From the results of this randomized controlled investigation, music therapy may be an engaging and effective psychosocial technique to treat stigma. Limitations, suggestions for future research, and implications for clinical practice and psychiatric music therapy research are provided. PMID- 24070991 TI - Internalization of stigma and self-esteem as it affects the capacity for intimacy among patients with schizophrenia. AB - The study examines the relationship between internalization of stigma, self esteem, and the ability of people diagnosed with schizophrenia to form intimate attachments with loved ones. The study included sixty patients with schizophrenia, ages 18-60, men and women. After providing informed consent, all participants completed four questionnaires: Demographics Questionnaire, Self Esteem Scale, Internalized Stigma of Mental Illness Scale and the Intimacy Attitude Scale-Revised. Internalization of social stigma was found to be a statistically significant core factor that affects self-esteem and the ability to create intimacy among patients with schizophrenia. There was statistically significantly less internalization of stigma of mental illness among hospitalized patients than among individuals with schizophrenia who live in the community. PMID- 24070992 TI - Defining happiness for young adults with schizophrenia: a building block for recovery. AB - PURPOSE: Findings from this mixed methods descriptive study include a definition of happiness for young adults with schizophrenia (SCZ). METHODS: Thirteen men and women, ages 23 to 35, completed a series of three individual 1-hour interviews over 6 weeks. RESULTS: This definition included themes of material happiness, relational happiness, and health happiness. Although these themes correspond to those for young adults without SCZ, four barriers to happiness were identified for this vulnerable population: 1) fear, 2) isolation, 3) medication, 4) not being considered "normal." CONCLUSIONS: Implications of these findings include designing interventions to support recovery by overcoming barriers to happiness. PMID- 24070994 TI - End-of-life (care) perspectives and expectations of patients with schizophrenia. AB - BACKGROUND: Schizophrenia is a disabling and life-shortening psychiatric disorder due to disease, medication, and lifestyle-related factors. It is therefore not unreasonable to assume that existential themes are important for these patients. METHODS: Transcripts of 20 patients were coded and analyzed thematically, using a modified grounded theory approach in the exploration of perspectives and expectations of end-of-life (care). RESULTS: No fear of death, skilled companionship and preserving quality of life were major themes in the interviews. CONCLUSION: This study showed that patients, despite emotional flattening and cognitive deficits, find the possibility to discuss end-of-life topics reassuring and some even therapeutic. PMID- 24070993 TI - Smoking among individuals with schizophrenia in Korea: gender differences. AB - OBJECTIVE: This study examined gender differences in smoking and quitting among individuals diagnosed with schizophrenia in Korea. In addition, the study investigated differences in caffeine use by gender and smoking status. METHOD: An anonymous self-report survey was conducted with psychiatric inpatients. RESULTS: Compared to males, females were less likely to be current smokers (P<.001) and more likely to be former smokers (P<.01). Females were also less likely to be daily caffeine users (P<.001). Having more years of education (P<.05) and higher nicotine dependence scores (P<.05) were associated with decreased odds of intending to quit smoking, whereas having more previous quit attempts (P<.01) was associated with increased odds. These findings were significant even after adjusting for gender. Smokers were more likely to be daily caffeine users (P<.001) than their non-smoking counterparts. CONCLUSION: Nurses in Korea should play an active role in tobacco control for patients with schizophrenia by providing cessation counseling and educating the effect of caffeine use on cigarette consumption, while tailoring the service to gender differences found in this study. PMID- 24070995 TI - Gender-specific factors of suicide ideation among adolescents in the Republic of Korea: a nationally representative population-based study. AB - The purposes of this study are to explore the differences in the rates of suicide ideation (SI) between male and female youths, and to investigate gender-specific factors strongly associated with SI. This study analyzed nationally representative secondary data, the Fourth Korea National Health and Nutrition Examination Survey collected over a 3 year period (2007-2009) (N=2358; youths aged 12-18 years). Significant differences in characteristics between adolescents with and without SI were analyzed using either t-test or chi-square test. After adjusting for demographics (i.e., age, monthly household income, and family intactness), gender-specific factors associated with SI were examined using multivariate logistic regression. Current research reveals that (a) the prevalence of SI is higher among female adolescents than among their male counterparts, (b) depression and stress are strong factors in both males and females, and (c) psychological counseling and experimentation with smoking and drinking are strong factors among females only. Different factors influencing SI between males and females should be considered when identifying youths at risk for SI and providing targeted interventions. PMID- 24070996 TI - Predictors of psychiatric readmission among veterans at high risk of suicide: the impact of post-discharge aftercare. PMID- 24070998 TI - Inter- and intra-observer variability of time-lapse annotations. AB - STUDY QUESTION: How consistent is the time-lapse annotation of dynamic and static morphologic parameters of embryo development, within and between observers? SUMMARY ANSWER: The assessment of dynamic parameters is characterized by almost perfect agreement within and between observers. WHAT IS KNOWN ALREADY: The commonly employed method used to assess embryos in IVF treatments is based on static evaluation of morphology in a microscope, but this is limited by substantial intra- and inter-observer variation. Time-lapse imaging has been proposed as a method to refine embryo selection by adding new dynamic predictors of viability to the assessment. Yet, there are no data regarding the consistency of estimates of the time-lapse parameters. STUDY DESIGN, SIZE, DURATION: Infertile patients were recruited at the Fertility Clinic, Arhus University Hospital from February 2011 to June 2012. All embryos were cultured for 6 days in a time-lapse incubator (EmbryoScope(TM)). Automated image recording was performed every 20 min. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 158 fertilized embryos from 20 different patients were annotated. Three observers made independent annotations on time-lapse recordings. One observer performed the assessment twice. Twenty-five parameters were annotated and the inter- and intra observer agreement was assessed by calculating intra-class correlation coefficients (ICCs). MAIN RESULTS AND THE ROLE OF CHANCE: Extremely close agreement (ICC 0.99) was found for dynamic parameters including the timing of the following: pronuclei breakdown, completion of blastocyst hatching and the appearance and disappearance of the first nucleus after the first division. Observations of cleavage divisions were strongly correlated (ICC > 0.8), indicating close agreement. Measurements of the static morphologic parameters, i.e. multi-nucleation and evenness of blastomeres at 2-cell stage showed fair-to moderate agreement (ICC <= 0.5). LIMITATIONS, REASON FOR CAUTION: The study was conducted at a single clinic. Only embryos with a good prognosis were included. The influence of training sessions was not measured. WIDER IMPLICATIONS OF THE FINDINGS: Consistency is crucial to the validity of embryo scoring and selection. All of the time-lapse parameters suggested by the literature showed in our study high intra- and inter-observer correlation, thus validating the precision of time lapse annotations. This provides the basis for further investigation of embryo assessment and selection by time-lapse imaging in prospective trials. STUDY FUNDING/COMPETING INTEREST(S): Research at the Fertility Clinic was funded by an unrestricted grant from Ferring and MSD. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: NCT01139268. PMID- 24070997 TI - Telomere biology and translational research. PMID- 24071000 TI - In vitro assessment of three-dimensionally plotted nagelschmidtite bioceramic scaffolds with varied macropore morphologies. AB - It is known that porous scaffolds play an important role in bone/periodontal tissue engineering. A new nagelschmidtite (NAGEL, Ca7Si2P2O16) ceramic has recently been prepared which shows excellent apatite mineralization ability and osteo-/cementostimulation properties in vitro. However, up to now porous NAGEL scaffolds have not been developed yet. There has been no systematic study of the effect of macropore morphology of bioceramic scaffolds on their physico-chemical and biological properties. The aim of this study was to prepare NAGEL scaffolds for bone tissue engineering applications. We applied a modified three-dimensional (3-D) plotting method to prepare highly controllable NAGEL scaffolds and investigated the effect of macropore morphology on the physico-chemical and biological properties. The results showed that the macropore size and morphology of 3-D plotted NAGEL scaffolds could be effectively controlled. Compared with beta-tricalcium phosphate (beta-TCP) scaffolds NAGEL scaffolds possess a significantly enhanced compressive strength, a higher modulus and better degradability. Nagel scaffolds with a square pore morphology presented a higher compressive strength, a higher modulus and greater weight loss rate than those with triangular and parallelogram pore morphologies. In addition, all of the NAGEL scaffolds with the three macropore morphologies supported the attachment and proliferation of MC3T3 cells. The proliferation of MC3T3 cells on NAGEL scaffolds with triangular and parallelogram structures was higher than that on beta-TCP scaffolds with the same pore structure. Cells on all three groups of NAGEL scaffolds revealed higher alkaline phosphatase (ALP) activity compared with cells on beta-TCP scaffolds, and among the three NAGEL scaffolds groups those with a parallelogram pore structure showed the highest ALP activity. Furthermore, the angiogenic cell experiments showed that the ionic products from NAGEL scaffolds promoted tube formation, expression of pro-angiogenic factors and their receptors on human umbilical vein endothelial (HUVECs) compared with beta-TCP scaffolds, indicating that NAGEL scaffolds possessed improved angiogenesis capacity. Our results suggest that 3-D plotted NAGEL scaffolds are a promising bioactive material for bone tissue engineering by virtue of their highly controllable macropore structure, excellent mechanical strength, degradability and in vitro biological response to osteogenic/angiogenic cells. PMID- 24070999 TI - Identification of three novel Toxoplasma gondii rhoptry proteins. AB - The rhoptries are key secretory organelles from apicomplexan parasites that contain proteins involved in invasion and modulation of the host cell. Some rhoptry proteins are restricted to the posterior bulb (ROPs) and others to the anterior neck (RONs). As many rhoptry proteins have been shown to be key players in Toxoplasma invasion and virulence, it is important to identify, understand and characterise the biological function of the components of the rhoptries. In this report, we identified putative novel rhoptry genes by identifying Toxoplasma genes with similar cyclical expression profiles as known rhoptry protein encoding genes. Using this approach we identified two new rhoptry bulb (ROP47 and ROP48) and one new rhoptry neck protein (RON12). ROP47 is secreted and traffics to the host cell nucleus, RON12 was not detected at the moving junction during invasion. Deletion of ROP47 or ROP48 in a type II strain did not show major influence in in vitro growth or virulence in mice. PMID- 24071001 TI - Chitosan-g-hematin: enzyme-mimicking polymeric catalyst for adhesive hydrogels. AB - Phenol derivative-containing adhesive hydrogels has been widely recognized as having potential for biomedical applications, but their conventional production methods, utilizing a moderate/strong base, alkaline buffers, the addition of oxidizing agents or the use of enzymes, require alternative approaches to improve their biocompatibility. In this study, we report a polymeric, enzyme-mimetic biocatalyst, hematin-grafted chitosan (chitosan-g-hem), which results in effective gelation without the use of alkaline buffers or enzymes. Furthermore, gelation occurs under mild physiological conditions. Chitosan-g-hem biocatalyst (0.01%, w/v) has excellent catalytic properties, forming chitosan-catechol hydrogels rapidly (within 5 min). In vivo adhesive force measurement demonstrated that the hydrogel formed by the chitosan-g-hem activity showed an increase in adhesion force (33.6 +/- 5.9 kPa) compared with the same hydrogel formed by pH induced catechol oxidation (20.6 +/- 5.5 kPa) in mouse subcutaneous tissue. Using the chitosan-g-hem biocatalyst, other catechol-functionalized polymers (hyaluronic acid-catechol and poly(vinyl alcohol)-catechol) also formed hydrogels, indicating that chitosan-g-hem can be used as a general polymeric catalyst for preparing catechol-containing hydrogels. PMID- 24071002 TI - Quantification of the interaction between biomaterial surfaces and bacteria by 3 D modeling. AB - It is general knowledge that bacteria/surface interactions depend on the surface topography. However, this well-known dependence has so far not been included in the modeling efforts. We propose a model for calculating interaction energies between spherical bacteria and arbitrarily structured 3-D surfaces, combining the Derjaguin, Landau, Verwey, Overbeek theory and an extended surface element integration method. The influence of roughness on the interaction (for otherwise constant parameters, e.g. surface chemistry, bacterial hydrophobicity) is quantified, demonstrating that common experimental approaches which consider amplitude parameters of the surface topography but which ignore spacing parameters fail to adequately describe the influence of surface roughness on bacterial adhesion. The statistical roughness profile parameters arithmetic average height (representing an amplitude parameter) and peak density (representing a spacing parameter) both exert a distinct influence on the interaction energy. The influence of peak density on the interaction energy increases with decreasing arithmetic average height and contributes significantly to the total interaction energy with an arithmetic average height below 70 nm. With the aid of the proposed model, different sensitivity ranges of the interaction between rough surfaces and bacteria are identified. On the nanoscale, the spacing parameter of the surface dominates the interaction, whereas on the microscale the amplitude parameter adopts the governing role. PMID- 24071003 TI - The interface of genetics with pathology in alport nephritis. PMID- 24071004 TI - BP control and left ventricular hypertrophy regression in children with CKD. AB - In adult patients with CKD, hypertension is linked to the development of left ventricular hypertrophy, but whether this association exists in children with CKD has not been determined conclusively. To assess the relationship between BP and left ventricular hypertrophy, we prospectively analyzed data from the Chronic Kidney Disease in Children cohort. In total, 478 subjects were enrolled, and 435, 321, and 142 subjects remained enrolled at years 1, 3, and 5, respectively. Echocardiograms were obtained 1 year after study entry and then every 2 years; BP was measured annually. A linear mixed model was used to assess the effect of BP on left ventricular mass index, which was measured at three different visits, and a mixed logistic model was used to assess left ventricular hypertrophy. These models were part of a joint longitudinal and survival model to adjust for informative dropout. Predictors of left ventricular mass index included systolic BP, anemia, and use of antihypertensive medications other than angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Predictors of left ventricular hypertrophy included systolic BP, female sex, anemia, and use of other antihypertensive medications. Over 4 years, the adjusted prevalence of left ventricular hypertrophy decreased from 15.3% to 12.6% in a systolic BP model and from 15.1% to 12.6% in a diastolic BP model. These results indicate that a decline in BP may predict a decline in left ventricular hypertrophy in children with CKD and suggest additional factors that warrant additional investigation as predictors of left ventricular hypertrophy in these patients. PMID- 24071005 TI - Origin of parietal podocytes in atubular glomeruli mapped by lineage tracing. AB - Parietal podocytes are fully differentiated podocytes lining Bowman's capsule where normally only parietal epithelial cells (PECs) are found. Parietal podocytes form throughout life and are regularly observed in human biopsies, particularly in atubular glomeruli of diseased kidneys; however, the origin of parietal podocytes is unresolved. To assess the capacity of PECs to transdifferentiate into parietal podocytes, we developed and characterized a novel method for creating atubular glomeruli by electrocoagulation of the renal cortex in mice. Electrocoagulation produced multiple atubular glomeruli containing PECs as well as parietal podocytes that projected from the vascular pole and lined Bowman's capsule. Notably, induction of cell death was evident in some PECs. In contrast, Bowman's capsules of control animals and normal glomeruli of electrocoagulated kidneys rarely contained podocytes. PECs and podocytes were traced by inducible and irreversible genetic tagging using triple transgenic mice (PEC- or Pod-rtTA/LC1/R26R). Examination of serial cryosections indicated that visceral podocytes migrated onto Bowman's capsule via the vascular stalk; direct transdifferentiation from PECs to podocytes was not observed. Similar results were obtained in a unilateral ureter obstruction model and in human diseased kidney biopsies, in which overlap of PEC- or podocyte-specific antibody staining indicative of gradual differentiation did not occur. These results suggest that induction of atubular glomeruli leads to ablation of PECs and subsequent migration of visceral podocytes onto Bowman's capsule, rather than transdifferentiation from PECs to parietal podocytes. PMID- 24071006 TI - A Pkd1-Fbn1 genetic interaction implicates TGF-beta signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure that is due to mutations in two genes, PKD1 and PKD2. Vascular complications, including aneurysms, are a well recognized feature of ADPKD, and a subgroup of families exhibits traits reminiscent of Marfan syndrome (MFS). MFS is caused by mutations in fibrillin-1 (FBN1), which encodes an extracellular matrix protein with homology to latent TGF-beta binding proteins. It was recently demonstrated that fibrillin-1 deficiency is associated with upregulation of TGF beta signaling. We investigated the overlap between ADPKD and MFS by breeding mice with targeted mutations in Pkd1 and Fbn1. Double heterozygotes displayed an exacerbation of the typical Fbn1 heterozygous aortic phenotype. We show that the basis of this genetic interaction results from further upregulation of TGF-beta signaling caused by Pkd1 haploinsufficiency. In addition, we demonstrate that loss of PKD1 alone is sufficient to induce a heightened responsiveness to TGF beta. Our data link the interaction of two important diseases to a fundamental signaling pathway. PMID- 24071007 TI - Spatial-temporal expressions of Crumbs and Nagie oko and their interdependence in zebrafish central nervous system during early development. AB - A vast number of apicobasal polarity proteins play essential roles in the polarization and morphogenesis of the neuroepithelia. Crumbs (Crb) type I transmembrane cell-cell adhesion proteins are among these proteins. Five crb genes have been identified in zebrafish. However, their expressional and functional differences during early neural development remain to be fully elucidated. Here, we study the spatial-temporal expression patterns and functions of Crb1, Crb2a, and Crb2b in the central nervous system (CNS) during the neurulation period. We show that: 1, the optic vesicle and undifferentiated retinal neuroepithelium only express Crb2a; 2, Crb1 and Crb2a expressions overlap extensively in the undifferentiated neural tube epithelium; 3, Crb2b expression is the weakest of the three and is restricted to the ventral-most regions of the anterior CNS; and 4, Nok and Crb proteins require each other for their apical localization in neuroepithelium. The commencements of Crb1, Crb2a, and Crb2b expressions follow a spatial-temporal spread from anterior to posterior and from ventral to dorsal and lag behind that of adherens junction components, such as ZO 1 and actin bundles. Genetic and morpholino suppression analyses suggest that in regions where these Crb expressions overlap, they are functionally redundant in maintaining apicobasal polarity of the undifferentiated neuroepithelium. PMID- 24071008 TI - Delayed physical and neurobehavioral development and increased aggressive and depression-like behaviors in the rat offspring of dams fed a high-fat diet. AB - Early maternal exposure to a high-fat diet (HFD) may influence the brain development of rat offspring and consequently affect physiology and behavior. Thus, in the present study, we investigated the somatic, physical, sensory-motor and neurobehavioral development of the offspring of dams fed an HFD (52% calories from fat, mainly saturated) and the offspring of dams fed a control diet (CD - 14.7% fat) during lactation from the 1st to the 21st postnatal day (P). Maternal body weights were evaluated during lactation. In the progeny, somatic (body weight, head and lengths axes) and physical (ear unfolding, auditory conduit opening, eruption of the incisors and eye opening) development and the consolidation of reflex responses (palm grasp, righting, vibrissa placing, cliff avoidance, negative geotaxis, auditory startle response and free-fall righting) were determined during suckling. Depressive and aggressive behaviors were tested with the forced swimming test (FST) and the "foot-shock" test on days 60 and 110, respectively. The open field test was used to assess motor function. Compared to controls, the HFD-pups exhibited decreases in body weight (P7-P21) and body length (P4-P18), but by days P71 and P95, these pups were overweight. All indicators of physical maturation and the consolidation of the following reflexes, vibrissa placing, auditory startle responses, free-fall righting and negative geotaxis, were delayed in HFD-progeny. In addition, the pups from HFD dam rats also exhibited reduced swimming and climbing times in the FST and increased aggressive behavior. No changes in locomotion were observed. These findings show developmental and neurobehavioral changes in the rat offspring of dams fed the HFD during lactation and suggest possible disruption of physical and sensory-motor maturation and increased susceptibility to depressive and aggressive-like behavior. PMID- 24071009 TI - The association of low serum alanine aminotransferase activity with mortality in the US population. AB - Elevated alanine aminotransferase (ALT) activity, an important marker of liver injury, has been associated inconsistently with higher mortality. We evaluated whether persons with nonelevated ALT levels are the most appropriate comparison group by examining the relationships of low ALT with mortality and body composition in the US National Health and Nutrition Examination Survey (NHANES). In NHANES 1988-1994, the mortality risk of persons in ALT deciles 1, 2, 3, and 10 was compared with that of persons in deciles 4-9 (mortality was relatively flat across these deciles) over an 18-year period (through 2006) among 14,950 viral hepatitis-negative adults. In NHANES 1999-2006, low ALT was evaluated in association with dual-energy x-ray absorptiometry body composition measures among 15,028 adults. Multivariate-adjusted mortality was higher for decile 1 (hazard ratio (HR) = 1.42, 95% confidence interval (CI): 1.24, 1.63), decile 2 (HR = 1.27, 95% CI: 1.06, 1.53), and decile 3 (HR = 1.25, 95% CI: 1.04, 1.50) and nonsignificantly higher for decile 10 (HR = 1.21, 95% CI: 0.91, 1.61) than for deciles 4-9. Adjusted appendicular lean mass was decreased among the lowest ALT deciles. In the US population, low ALT was associated with higher mortality risk, possibly attributable to decreased appendicular lean mass. For mortality studies of elevated ALT levels, the most appropriate comparison group is persons in the middle range of ALT rather than all persons with nonelevated ALT. PMID- 24071010 TI - Hume, Mill, Hill, and the sui generis epidemiologic approach to causal inference. AB - The epidemiologic approach to causal inference (i.e., Hill's viewpoints) consists of evaluating potential causes from the following 2, noncumulative angles: 1) established results from comparative, observational, or experimental epidemiologic studies; and 2) reviews of nonepidemiologic evidence. It does not involve statements of statistical significance. The philosophical roots of Hill's viewpoints are unknown. Superficially, they seem to descend from the ideas of Hume and Mill. Hill's viewpoints, however, use a different kind of evidence and have different purposes than do Hume's rules or Mill's system of logic. In a nutshell, Hume ignores comparative evidence central to Hill's viewpoints. Mill's logic disqualifies as invalid nonexperimental evidence, which forms the bulk of epidemiologic findings reviewed from Hill's viewpoints. The approaches by Hume and Mill cannot corroborate successful implementations of Hill's viewpoints. Besides Hume and Mill, the epidemiologic literature is clueless about a plausible, pre-1965 philosophical origin of Hill's viewpoints. Thus, Hill's viewpoints may be philosophically novel, sui generis, still waiting to be validated and justified. PMID- 24071011 TI - The role of GATA binding protein 3 in the differential diagnosis of collecting duct and upper tract urothelial carcinomas. AB - Differential diagnosis of collecting duct carcinoma (CDC) from invasive upper tract urothelial carcinoma (UTUC) can be challenging. PAX8 and p63 are 2 markers often used in this setting. GATA binding protein 3 (GATA3) is a marker of urothelial differentiation. We investigated GATA3 expression in CDC and UTUC and its use in this differential. Eighteen CDC and 25 UTUC cases were used to build 2 tissue microarrays. GATA3, p63, and PAX8 nuclear expression was evaluated using standard immunohistochemistry. Staining intensity and percentage of positive cells were assessed. Sensitivity, specificity, and positive and negative predictive values of the markers and their combination were also evaluated. We found GATA3 positivity in 22 (88%) of 25 UTUCs and 1 (6%) of 18 CDCs. The median GATA3 extent of expression was higher in UTUC than in CDC (74% versus 0%, P = .00). We found p63 positivity in 23 (92%) of 25 UTUCs and 2 (11%) of 18 CDCs. PAX8 was positive in 3 (12%) of 25 UTUCs and all (100%) CDCs. GATA3 sensitivity and specificity for UTUC were 88% and 94%, respectively. p63 sensitivity and specificity for UTUC were 92% and 89%, respectively. The p63+/PAX8- profile showed higher sensitivity for UTUC than did the GATA3+/PAX8- profile (80% versus 76%). Both showed a specificity of 100% for UTUC. GATA3+ or p63+/PAX8- sensitivity and specificity for UTUC were 84% and 100%, respectively. Immunohistochemical expression of GATA3 was higher in UTUC, suggesting a potential role for distinguishing UTUC from CDC. Adding this marker to the combination panel of p63 and PAX8 might improve its performance in the diagnosis of epithelial neoplasms involving the renal sinus. PMID- 24071012 TI - Clonally related composite follicular lymphoma and mantle cell lymphoma with clinicopathologic features and biological implications. AB - Composite lymphoma with follicular lymphoma (FL) and mantle cell lymphoma (MCL) components is rare and can pose a substantial diagnostic challenge. We report two cases of composite lymphoma with FL and MCL components occurring in lymph nodes. Both cases showed near total effacement of the lymph node architecture by grade 1 FL (CD10+ and BCL2+) with accompanying in situ MCL component (CD5+ and cyclin D1+) surrounding neoplastic follicles. The diagnosis of composite FL and MCL was confirmed by detecting the t(14;18)(q32;q21) and t(11;14)(q13;q32) in the FL and MCL components, respectively. Immunoglobulin heavy chain fragment length analysis in both cases showed identical dominant monoclonal peaks in microdissected neoplastic lymphoid cells from FL and MCL components. These findings suggest a common clonal origin for the FL and MCL components in both cases. PMID- 24071013 TI - Primary cutaneous carcinosarcoma: insights into its clonal origin and mutational pattern expression analysis through next-generation sequencing. AB - Primary cutaneous carcinosarcoma is a rare biphenotypic neoplasm exhibiting both epithelial and sarcomatous elements. Even though its origin and biological aspects remain poorly understood, it has been postulated that this tumor may arise from progenitor cells, which subsequently differentiate into distinct tumor components. We have investigated the histological and immunohistochemical staining patterns of a cutaneous carcinosarcoma case, as well as its ultrastructural aspects. In addition, sarcomatous and epithelial tumor components were separated by laser capture microdissection and subjected to targeted, high depth, next-generation sequencing of a 46-cancer gene panel to asses the gene mutational pattern amongst both components. There were transitional cells at the epithelial/mesenchymal transition that labeled with putative progenitor cell markers (K19, c-kit, CD34 and Bcl-2). There was shared reactivity to antibodies directed against the progenitor cell marker EpCAM (epithelial cell adhesion molecule) in both components. Ultrastructurally, individual cells were demonstrated to have overlapping features of epithelial and mesenchymal differentiation. The mutational analysis revealed point mutations in exon 5 of TP53, which were identical in both the epithelial and sarcomatous components, and which were concordant with p53 expression at a tissue level. The aforementioned histological, ultrastructural, immunohistochemical and mutational pattern is strongly suggestive of a common clonal origin to the distinct elements of this tumor. PMID- 24071014 TI - Helicobacter gastritis induces changes in the oxyntic mucosa indistinguishable from the effects of proton pump inhibitors. AB - A causal relationship between oxyntic glands dilatation with protruding parietal cells, referred to as proton pump inhibitor (PPI) effects, and PPI use has been suspected but not established. We designed this study to evaluate the association between these changes and the use of PPIs and histamine2-receptor blockers (H2 blockers). We obtained five Sydney System-compliant biopsy specimens from patients recruited into a therapeutic trial for H. pylori. Medication history with details on PPI and H2-blockers use was collected. Two blinded pathologists graded gastritis and the intensity of putative PPI effects using a 0 to 3 scale. PPI and H2-blocker use was then disclosed and the accuracy of pathologists' assessment was analyzed. There were 138 H. pylori-negative and 104 positive patients. In H. pylori-negative patients the histologic assessment for PPI use had 77.5% sensitivity and 51.8% specificity, with a positive predictive value of 86.9% and a negative predictive value of 35.9%. In H. pylori-positive patients, sensitivity was 74.1% and specificity 26.1%. Positive and negative predictive values were 55.8% and 44.4%, respectively. Neither glandular dilatations nor parietal cell protrusions related to H2-blocker use. We conclude that these changes are associated with PPI use only in H. pylori-negative subjects. In H. pylori gastritis, so-called PPI-effects were equally prevalent in PPI-users and non-users, indicating that other factors are involved in the induction of oxyntic cell hyperplasia. We suggest that comments regarding the supposed evidence of PPI use are too often wrong to be useful and should be avoided in the diagnosis of gastric biopsy specimens. PMID- 24071015 TI - Down-regulation of miR-145 and miR-143 might be associated with DNA methyltransferase 3B overexpression and worse prognosis in endometrioid carcinomas. AB - The aim of this study was to determine the clinicopathologic significance of miR 145 and miR-143 down-regulation in endometrial cancers. The microRNA profiles were analyzed by microRNA microarray. The expression levels of miR-145 and miR 143 in 73 endometrial cancers were further determined by quantitative real-time polymerase chain reaction. Potential targets of miR-145/143 were defined. The status of DNA methyltransferase 3B (DNMT3B), mutL homologs 1, and phosphatase and tensin homolog was assessed using immunohistochemistry. miR-145 and miR-143 frequently co-down-regulated in endometrial cancers, but the expression levels varied greatly between endometrioid carcinomas (ECs) and non-ECs (NECs); they were significantly lower in ECs than in NECs (P < .05). DNMT3B was defined as a potential target of miR-145/143 by Internet algorithms. In ECs, DNMT3B overexpression occurred more often in the miR-145 and miR-143 down-regulation subgroups, and the correlation between DNMT3B and miR-145 status reached statistical significance (P = .021), whereas such phenomena were not present in NECs (P > .05). In univariate analysis, the combination of DNMT3B overexpression and miR-145 or miR-143 down-regulation was more powerful in predicting shorter survival (P < .05) than use of the biomarkers individually (P > .05). In multivariate analysis, such combination was not an independent predictor of disease-free survival (P > .05). Our findings suggest that the target and function of miR-145 and miR-143 may differ in ECs versus NECs. DNMT3B might be a potential target of miR-145 and miR-143 in ECs. Furthermore, the combined miR-145 or miR-143 and DNMT3B status may have a prognostic impact on ECs. PMID- 24071016 TI - Verrucous carcinomas of the head and neck, including those with associated squamous cell carcinoma, lack transcriptionally active high-risk human papillomavirus. AB - Most oropharyngeal squamous cell carcinomas (SCC) and histologic variants harbor transcriptionally active human papillomavirus (HPV). While HPV DNA can be found in many non-oropharyngeal head and neck carcinomas, transcriptionally active HPV is rare. Verrucous carcinoma is a variant with bland cytology, warty appearance, locally destructive growth, and lack of metastasis when lacking a frankly invasive carcinoma component. Studies have shown variable rates of HPV DNA and p16 protein expression in such tumors but still have not clearly addressed if the virus has biological activity or clinical relevance in the positive cases. Department files were searched for verrucous neoplasms, including pure verrucous carcinoma, verrucous carcinoma with dysplasia or minimal invasion, and SCC arising in verrucous carcinoma (ie, having a major component of frankly invasive carcinoma). p16 immunohistochemistry, HPV DNA polymerase chain reaction (PCR) and E6/E7 mRNA reverse transcription PCR for high-risk HPV types were performed. Of the 49 cases, 6 (12.2%) showed strong (>50%) staining for p16. HPV DNA was detected in 7/49 (14.3%) cases, but only one case was positive for both p16, and HPV DNA. A total of 36 cases yielded sufficient RNA for RT-PCR (18 verrucous carcinomas, 13 atypical verrucous carcinomas, and 5 SCC arising in verrucous carcinoma). All 36 were negative, including the four p16-positive and three HPV DNA-positive tumors tested. Although a minority of verrucous carcinoma lesions are p16 and HPV DNA positive, transcriptionally active high-risk HPV is uniformly absent. These findings argue that verrucous carcinoma and its related squamous cell carcinomas are not HPV-driven tumors. PMID- 24071017 TI - Comparison of 2 monoclonal antibodies for immunohistochemical detection of BRAF V600E mutation in malignant melanoma, pulmonary carcinoma, gastrointestinal carcinoma, thyroid carcinoma, and gliomas. AB - BRAF mutation is seen in a variety of human neoplasms including cutaneous malignant melanoma, papillary thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, pleomorphic xanthoastrocytoma, and others. Currently, there are 2 commercially available monoclonal antibodies for the detection of BRAF V600E mutation; however, a full and practical comparison of their performance in various tumor types on an automated staining platform has not been done. We investigated their sensitivity and specificity in detecting the BRAF V600E mutation in a series of 152 tumors including 31 malignant melanomas, 25 lung carcinomas, 32 gastrointestinal carcinomas, 23 thyroid carcinomas, 35 gliomas, and 6 other malignancies. In this series, the concordance rate between immunohistochemistry (IHC) and mutational analyses was 97% (148/152) for VE1 and 88% (131/149) for anti-B-Raf. The sensitivity and specificity were 98% (60/61) and 97% (88/91) for monoclonal VE1 and 95% (58/61) and 83% (73/88) for anti-B Raf, respectively. There were 4 cases with discordant IHC and mutational results for monoclonal VE1 in contrast to 18 cases for anti-B-Raf. Our studies showed that IHC with monoclonal VE1 has a better performance compared with anti-B-Raf in an automated staining platform and confirmed that clone VE1 provides excellent sensitivity and specificity for detecting the BRAF V600E mutation in a variety of tumor types in a clinical setting. PMID- 24071018 TI - Segmental muscular defects of the intestine: a possible cause of spontaneous perforation of the bowel in adults. AB - Idiopathic intestinal perforation has been described as spontaneous bowel perforation; only a few cases of the condition have been reported in adults. We conducted a histologic analysis of 7 adult cases of spontaneous intestinal perforation (mean patient age, 63.3 [range, 44-89] years; male-to-female ratio, 1:1.3), which revealed some previously unreported findings. None of the patients had congenital disease. All patients presented with acute abdomen, and intestinal perforations were detected during laparotomy. Perforations, ranging in diameter from a pinpoint size to 3 cm, developed in the colon and small bowel in 4 and 3 cases, respectively. One patient had 2 perforations. Histologic examinations revealed segmental muscularis propria defects around the perforation sites. The extent and degree of the muscular defect varied from case to case; however, all lesions included full-thickness muscular defects. No significant infiltration of inflammatory cells was observed associated with the defects. The mucosa and muscularis mucosa were maintained normally, except in 1 hemorrhagic case. Reparative changes such as granulation were not found; however, short spindle cells or fibroblasts occasionally proliferated around the edges of the disrupted muscularis propria. In 1 case, a muscular defect was also observed in an area far from the perforation site. These findings closely resemble those of neonatal intestine with spontaneous perforation. Etiology of segmental muscular defects in adults is unclear. It may be focal congenital anomaly. In any case, the segmental muscular defects can explain bowel wall weakening, and it can be a major cause of spontaneous perforation of the adult bowel. PMID- 24071019 TI - Microinvasive breast carcinoma carries an excellent prognosis regardless of the tumor characteristics. AB - The clinical implication of microinvasive breast carcinoma (MIBC), especially when multiple foci are identified, is still not clearly defined. This study is designed to collect clinicopathologic and follow up data on patients with MIBC. Histologic data including invasive breast cancer type, nuclear grade, number of microinvasive foci and lymph node status, as well as associated in situ component histologic and biomarkers parameters were recorded. Clinical follow-up data, such as local recurrence, distant metastasis and survival was also noted. Forty MIBC cases were identified among 1180 invasive breast cancer cases between 1998 and 2012, representing 3.4% of the overall invasive cases. The majority of the cases (28/40) had three or less foci of microinvasion and had high nuclear grade (26/40). The associated carcinoma in situ was also mostly high grade. The biomarker expression for estrogen receptor/human epidermal growth factor receptor 2 (ER/HER2) of the in situ component was heterogeneous. Of the 35 cases with known nodal status, 1 had macrometastasis, 1 had micrometastasis, 3 had isolated tumor cells, and the remaining had negative nodes. In the follow-up period (mean 30 months, median 15 months) none of the patients had recurrence, distant metastasis or died of disease. In conclusion, MIBC represents a small portion of invasive carcinomas. The majority of cases have high nuclear grade and are associated with high grade ductal carcinoma in situ. The latter doesn't show consistent ER/HER2 expression. Overall, the number of microinvasive foci, the extent and biomarker expression of the in situ component do not appear to impact the overall excellent outcome. PMID- 24071020 TI - An individual-specific gait pattern prediction model based on generalized regression neural networks. AB - Robotics is gaining its popularity in gait rehabilitation. Gait pattern planning is important to ensure that the gait patterns induced by robotic systems are tailored to each individual and varying walking speed. Most research groups planned gait patterns for their robotics systems based on Clinical Gait Analysis (CGA) data. The major problem with the method using the CGA data is that it cannot accommodate inter-subject differences. In addition, CGA data is limited to only one walking speed as per the published data. The objective of this work was to develop an individual-specific gait pattern prediction model for gait pattern planning in the robotic gait rehabilitation systems. The waveforms of lower limb joint angles in the sagittal plane during walking were obtained with a motion capture system. Each waveform was represented and reconstructed by a Fourier coefficient vector which consisted of eleven elements. Generalized regression neural networks (GRNNs) were designed to predict Fourier coefficient vectors from given gait parameters and lower limb anthropometric data. The generated waveforms from the predicted Fourier coefficient vectors were compared to the actual waveforms and CGA waveforms by using the assessment parameters of correlation coefficients, mean absolute deviation (MAD) and threshold absolute deviation (TAD). The results showed that lower limb joint angle waveforms generated by the gait pattern prediction model were closer to the actual waveforms compared to the CGA waveforms. PMID- 24071021 TI - Temporal trends of persistent organic pollutants in digested sewage sludge (1993 2012). AB - The analysis of temporal trends is a key tool to assess the success of national and international regulations on chemical pollution. Persistent organic pollutants (POPs) are chemical pollutants, which are not only harmful, but also because of their slow environmental degradation they pose a long-time risk. In this study, concentrations of selected POPs were measured between 1993 and 2012 in digested sewage sludge from eight municipal waste water treatment plants. Polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-dioxins and furans (PCDD/Fs), which have been banned or restricted for decades, exhibited decreasing trends with apparent half-lives between 9 and 12years. Polybrominated diphenyl ethers (PBDEs) and long-chain perfluorinated acids showed no clear trend, which reflects the recent introduction of regulations. The analysis of octabromodiphenyl ethers did not reveal indications for reductive debromination of decabromodiphenyl ether; however the analysis of total bromine showed that up to 14% of the total bromine load in sewage sludge originated from PBDEs (average 2%). This is the first study to report temporal trends for more than 20years of series POPs in sewage sludge. PMID- 24071022 TI - Maternal dietary intake of dioxins and polychlorinated biphenyls and birth size in the Norwegian Mother and Child Cohort Study (MoBa). AB - Maternal diet not only provides essential nutrients to the developing fetus but is also a source of prenatal exposure to environmental contaminants. We investigated the association between dietary intake of dioxins and PCBs during pregnancy and birth size. The study included 50,651 women from the Norwegian Mother and Child Cohort Study (MoBa). Dietary information was collected by FFQs and intake estimates were calculated by combining food consumption and food concentration of dioxins, dioxin-like PCBs and non-dioxin-like PCBs. We used multivariable regression models to estimate the association between dietary intake of dioxins and PCBs and fetal growth. The contribution of fish and seafood intake during pregnancy was 41% for dietary dioxins and dioxin-like PCBs and 49% for dietary non-dioxin-like PCBs. Further stratified analysis by quartiles of seafood intake during pregnancy was conducted. We found an inverse dose-response association between dietary intake of dioxins and PCBs and fetal growth after adjustment for confounders. Newborns of mothers in the upper quartile of dioxin and dioxin-like PCBs intake had 62g lower birth weight (95% CI: -73, -50), 0.26cm shorter birth length (95% CI: -0.31, -0.20) and 0.10cm shorter head circumference (95% CI: -0.14, -0.06) than newborns of mothers in the lowest quartile of intake. Similar negative associations for intake of dioxins and dioxin-like PCBs were found after excluding women with intakes above the tolerable weekly intake (TWI=14pg TEQ/kg bw/week). The negative association of dietary dioxins and PCBs with fetal growth was weaker as seafood intake was increasing. No association was found between dietary dioxin and PCB intake and the risk for small-for gestational age neonate. In conclusion, dietary intakes of dioxins and PCBs during pregnancy were negatively associated with fetal growth, even at intakes below the TWI. PMID- 24071023 TI - Dietary benzo(a)pyrene intake during pregnancy and birth weight: associations modified by vitamin C intakes in the Norwegian Mother and Child Cohort Study (MoBa). AB - BACKGROUND: Maternal exposure to polycyclic aromatic hydrocarbons (PAH) during pregnancy has been associated with reduced fetal growth. However, the role of diet, the main source of PAH exposure among non-smokers, remains uncertain. OBJECTIVE: To assess associations between maternal exposure to dietary intake of the genotoxic PAH benzo(a)pyrene [B(a)P] during pregnancy and birth weight, exploring potential effect modification by dietary intakes of vitamins C, E and A, hypothesized to influence PAH metabolism. METHODS: This study included 50,651 women in the Norwegian Mother and Child Cohort Study (MoBa). Dietary B(a)P and nutrient intakes were estimated based on total consumption obtained from a food frequency questionnaire (FFQ) and estimated based on food composition data. Data on infant birth weight were obtained from the Medical Birth Registry of Norway (MBRN). Multivariate regression was used to assess associations between dietary B(a)P and birth weight, evaluating potential interactions with candidate nutrients. RESULTS: The multivariate-adjusted coefficient (95%CI) for birth weight associated with maternal energy-adjusted B(a)P intake was -20.5g (-31.1, 10.0) in women in the third compared with the first tertile of B(a)P intake. Results were similar after excluding smokers. Significant interactions were found between elevated intakes of vitamin C (>85mg/day) and dietary B(a)P during pregnancy for birth weight (P<0.05), but no interactions were found with other vitamins. The multivariate-adjusted coefficients (95%CI) for birth weight in women in the third compared with the first tertile of B(a)P intake were -44.4g ( 76.5, -12.3) in the group with low vitamin C intakes vs. -17.6g (-29.0, -6.1) in the high vitamin C intake group. CONCLUSION: The results suggest that higher prenatal exposure to dietary B(a)P may reduce birth weight. Lowering maternal intake of B(a)P and increasing dietary vitamin C intake during pregnancy may help to reduce any adverse effects of B(a)P on birth weight. PMID- 24071024 TI - Characterizing lobular carcinoma of the male breast using the SEER database. AB - BACKGROUND: Lobular carcinoma of the male breast is rare. We sought to investigate the clinical characteristics, treatment, and outcomes of men and women with lobular breast cancer, using a population-based database. METHODS: We reviewed the Surveillance, Epidemiology, and End Results database 1988-2008 and identified patients with a lobular breast cancer diagnosis (invasive lobular carcinoma [ILC] and lobular carcinoma in situ [LCIS]) using the "International Classification of Diseases for Oncology, Third Edition" codes. Bivariate analyses compared the male and female patients on demographics, clinical characteristics, and treatment modalities. Multivariate logistic regression analysis determined the risk-adjusted likelihood of receiving treatment. Survival analysis was done and hazard ratios were obtained using Cox proportional models. RESULTS: Overall, 133,339 patients were identified, including 133,168 women (99.9%) and 171 men (0.1%). Most had ILC (82.08%). The median age was 66 +/- 20 y for the men and 61 +/- 21 y for the women. The men with ILC were more likely to have poorly differentiated tumors (26.45% versus 15.61%; P < 0.001) and stage IV disease (9.03% versus 4.18%; P = 0.005) than were the women. The cancer-specific 5-year survival rates for ILC were 82.9% for the men and 91.9% for the women. Adjusted survival was better for patients with ILC receiving surgery plus radiotherapy than patients receiving neither (hazard ratio 0.52, 95% confidence interval 0.49 0.56). Women with ILC had a 55% increased odds of receiving surgery plus radiotherapy compared with men (odds ratio 1.55, 95% confidence interval 1.08 2.22). CONCLUSIONS: ILC presents at a higher grade and stage in men. The difference in disease characteristics and survival rates suggests that the treatment of men with lobular breast cancer should be adjusted to improve their outcomes. PMID- 24071025 TI - Transplantation of bone marrow-derived mesenchymal stem cells after regional hepatic irradiation ameliorates thioacetamide-induced liver fibrosis in rats. AB - BACKGROUND: Recent studies have demonstrated that bone marrow-derived mesenchymal stem cells (BM-MSCs) can potentially revert liver fibrosis, but it is not known if preparative hepatic irradiation (HIR) contributes to the therapeutic effect of transplanted BM-MSCs. In this study, we investigate the effects of HIR on transplanted BM-MSCs in cirrhotic rats and the underlying mechanism by which mesenchymal stem cells (MSCs) relieve liver fibrosis. MATERIALS AND METHODS: The BM-MSCs from male rats were labeled with CM-Dil and injected via portal vein into two groups of thioacetamide-induced cirrhotic rats, and the controls were injected with the same volume of saline. The right hemiliver of one cirrhotic rat group was irradiated (15 Gy) 4 d before transplantation. Liver function tests and histologic experiments were performed, and the liver population of BM-MSCs was estimated. RESULTS: The transplantation of MSCs alleviated liver fibrosis and reduced expression of transforming growth factor-beta1, Smad2, collagen type I, and alpha-SMA. HIR preconditioning promoted homing and repopulation of MSCs and resulted in better treatment outcomes. CONCLUSIONS: HIR preconditioning enhances the effect of BM-MSCs in improving thioacetamide-induced liver fibrosis in rats by promoting their homing and repopulation. BM-MSCs may function by inhibiting transforming growth factor-beta1-Smad signaling pathway in the liver. PMID- 24071026 TI - Role of probiotics in the prevention and treatment of meticillin-resistant Staphylococcus aureus infections. AB - Meticillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant micro organism and is the principal nosocomial pathogen worldwide. Following initial in vitro experiments demonstrating that Lactobacillus acidophilus CL1285((r)) and Lactobacillus casei LBC80R((r)) commercial strains exhibit antibacterial activity against clinical MRSA isolates, we conducted a literature search to find any evidence of probiotic efficacy in decolonisation or treatment of S. aureus infection. As summarised below, many strains of lactobacilli and bifidobacteria isolated from a variety of sources inhibited the growth of S. aureus and clinical isolates of MRSA in vitro. The most active strains were Lactobacillus reuteri, Lactobacillus rhamnosus GG, Propionibacterium freudenreichii, Propionibacterium acnes, Lactobacillus paracasei, L. acidophilus, L. casei, Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus fermentum and Lactococcus lactis. Their effects were mediated both by direct cell competitive exclusion as well as production of acids or bacteriocin-like inhibitors. L. acidophilus also inhibited S. aureus biofilm formation and lipase production. In vitro antimicrobial activity did not necessarily assure efficacy in vivo in animal infectious models, e.g. S. aureus 8325-4 was most sensitive in vitro to L. acidophilus, whilst in vivo Bifidobacterium bifidum best inhibited experimental intravaginal staphylococcosis in mice. On the other hand, L. plantarum, which showed the highest inhibition activity against S. aureus in vitro, was also very effective topically in preventing skin wound infection with S. aureus in mice. Very few clinical data were found on the interactions between probiotics and MRSA, but the few identified clinical cases pointed to the feasibility of elimination or reduction of MRSA colonisation with probiotic use. PMID- 24071027 TI - Epidemiology and clinical outcomes of bloodstream infections caused by extended spectrum beta-lactamase-producing Escherichia coli in patients with cancer. AB - Patients with cancer can be vulnerable to infection with antimicrobial-resistant pathogens such as extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. A cohort study was performed to evaluate the epidemiology and impact of ESBL-producing Escherichia coli (ESBL-EC) bacteraemia on the outcomes of adult patients with cancer. During the 2.5-year study period, a total of 350 cases of E. coli bacteraemia were documented in cancer patients, of which 95 (27.1%) were due to ESBL-EC. Significant factors associated with ESBL-EC bacteraemia were liver disease, immunosuppressant use, recent surgery, and prior use of cephalosporins or fluoroquinolones. The overall 30-day mortality rate was 14.9% (52/350), and the mortality rate was higher in patients with ESBL-EC than in those without ESBL-EC (22.1% vs.12.2%; P=0.02). Multivariate analysis showed that ESBL-EC was an independent risk factor for mortality (odds ratio=3.01, 95% confidence interval 1.45-6.28; P=0.003), along with the presence of septic shock, mechanical ventilation, the severity of underlying diseases, and pneumonia as a source of bacteraemia. Of the 69 isolates in which ESBLs and their molecular relationships were studied, 68 (98.6%) produced CTX-M-type and 51 (73.9%) produced CTX-M-14 and/or CTX-M-15. Twenty-four sequence types (STs) were identified among CTX-M-14- and CTX-M-15-producing E. coli isolates, with ST131 being the most prevalent (12/51; 23.5%). In conclusion, this study confirms that CTX-M-producing E. coli and ST131, which have been shown to be an emerging public health threat, are widely prevalent in cancer patients and can adversely affect the outcome of E. coli bacteraemia in these patients. PMID- 24071028 TI - Capsular serotypes and antimicrobial susceptibilities of Streptococcus pneumoniae causing invasive pneumococcal disease from 2009-2012 with an emphasis on serotype 19A in bacteraemic pneumonia and empyema and beta-lactam resistance. AB - Capsular serotypes and antimicrobial susceptibilities of Streptococcus pneumoniae isolates that cause invasive pneumococcal disease (IPD) were studied and the role of serotype 19A in the development of bacteraemic pneumonia and empyema was investigated. Subjects comprised 98 patients (56 adults and 42 children) who were treated for IPD at a university-affiliated tertiary referral centre in Taiwan during 2009-2012. Serotypes of the isolates were identified using the latex agglutination method. In vitro susceptibilities of the isolates to 13 antimicrobial agents were determined using the broth microdilution method and were interpreted as recommended by the Clinical and Laboratory Standards Institute. During the study period, bacteraemic pneumonia was the most common type of infection (43/98; 43.9%), followed by primary bacteraemia (30/98; 30.6%). Serotype 19A was the most common serotype (23/98; 23.5%) in all patients. Fourteen (70.0%) of 20 children (47.6% of all children) with serotype 19A infection had pneumonia with empyema, whilst eight patients had concomitant bacteraemia. 7-valent pneumococcal conjugated vaccine (PCV-7), PCV-10, PCV-13 and 23-valent pneumococcal polysaccharide vaccine (PPV-23) had coverage rates of 37.8%, 38.8%, 79.6% and 77.6%, respectively. A substantial increase in the proportion of serotype 15A (6.1%) and 6A (8.2%) was found. In addition, there was a significant reduction in rates of susceptibility of serotype 19A isolates to penicillin, cefotaxime and ceftriaxone but not to azithromycin or any quinolone tested compared with those of non-19A isolates. The prevalence of serotypes 19A, 15A and 6A in patients with IPD increased markedly during the period, especially in children with bacteraemic pneumonia and empyema. PMID- 24071029 TI - Preparing emergency physicians for malpractice litigation: a joint emergency medicine residency-law school mock trial competition. AB - BACKGROUND: Fear of malpractice affects the daily life of many emergency physicians. Educational programs to prepare for litigation are lacking. OBJECTIVES: An educational collaboration between an emergency medicine residency and a law school, whereby a medical malpractice mock trial competition is used to teach residents basic skills for testifying in legal proceedings. METHODS: Ten residents in an academic emergency medicine program volunteered as witnesses in a malpractice mock trial competition at a law school. Residents testified two or three times and, after each appearance, were provided feedback to prepare them for subsequent rounds of testimony. They were also given access to videotaped testimony. Judges rated each resident using a nine-question survey scored on a 10 point Likert scale. Scores were compared as a group between rounds of testimony. RESULTS: Participants demonstrated significant improvement in seven of nine measured categories. p-Values reached significance in: Worked Well on Direct Examination (p < 0.001), Demeanor/Body Language (p < 0.001), Was Not Arrogant/Did Not Lose Poise on Cross-Examination (p = 0.001), Convincing Witness (p = 0.001), Appeared Knowledgeable (p = 0.012), Courtroom Attire (p = 0.012), and Expressed Themselves Clearly (p = 0.017). In addition, residents anonymously reported broad educational benefit. CONCLUSION: This novel educational collaboration taught residents about the process of litigation. It improved their communication skills and expanded their knowledge of documentation pitfalls, problems with staff interaction, and consequences of medical errors. This mutually beneficial partnership between a medical residency and a law school solidified it as a permanent feature of the residency program. PMID- 24071030 TI - Severe subarachnoid hemorrhage associated with cerebral venous thrombosis in early pregnancy: a case report. AB - BACKGROUND: Cerebral venous thrombosis (CVT) rarely induces subarachnoid hemorrhage (SAH). During late pregnancy and puerperium, CVT is an uncommon but important cause of stroke. However, severe SAH resulting from CVT is extremely rare during early pregnancy. OBJECTIVE: We report on a rare case of severe SAH due to CVT, and discuss the potential pitfalls of CVT diagnosis in early pregnancy. CASE REPORT: A 32-year-old pregnant woman (9th week of pregnancy) presented with slight head dullness. Initial magnetic resonance imaging (MRI) revealed focal, abnormal signal intensity in the left thalamus. Nine days later, the patient developed a generalized seizure and severe SAH was detected with computed tomography (CT) scan. MRI and cerebral angiography revealed a completely thrombosed superior sagittal sinus, vein of Galen, straight sinus, and right transverse sinus. Transvaginal sonography indicated a missed abortion. The day after admission, the patient presented again with a progressive loss of consciousness and signs of herniation. The patient underwent emergency decompressive craniotomy, followed by intrauterine curettage. Two months later, she made an excellent recovery except for a slight visual field defect. CONCLUSIONS: A rare case of severe SAH due to CVT is reported, with emphasis on the potential pitfalls of CVT diagnosis in early pregnancy. PMID- 24071031 TI - Randomized trial of bilevel versus continuous positive airway pressure for acute pulmonary edema. AB - BACKGROUND: Studies have shown different clinical outcomes of noninvasive positive pressure ventilation (NPPV) from those of continuous positive airway pressure (CPAP). OBJECTIVE: We evaluated whether bilevel positive airway pressure (BPAP) more rapidly improves dyspnea, ventilation, and acidemia without increasing the myocardial infarction (MI) rate compared to continuous positive pressure ventilation (CPAP) in patients with acute cardiogenic pulmonary edema (APE). METHODS: Patients with APE were randomized to either BPAP or CPAP. Vital signs and dyspnea scores were recorded at baseline, 30 min, 1 h, and 3 h. Blood gases were obtained at baseline, 30 min, and 1 h. Patients were monitored for MI, endotracheal intubation (ETI), lengths of stay (LOS), and hospital mortality. RESULTS: Fourteen patients received CPAP and 13 received BPAP. The two groups were similar at baseline (ejection fraction, dyspnea, vital signs, acidemia/oxygenation) and received similar medical treatment. At 30 min, PaO2:FIO2 was improved in the BPAP group compared to baseline (283 vs. 132, p < 0.05) and the CPAP group (283 vs. 189, p < 0.05). Thirty-minute dyspnea scores were lower in the BPAP group compared to the CPAP group (p = 0.05). Fewer BPAP patients required intensive care unit (ICU) admission (38% vs. 92%, p < 0.05). There were no differences between groups in MI or ETI rate, LOS, or mortality. CONCLUSIONS: Compared to CPAP to treat APE, BPAP more rapidly improves oxygenation and dyspnea scores, and reduces the need for ICU admission. Further, BPAP does not increase MI rate compared to CPAP. PMID- 24071032 TI - Intramuscular ziprasidone: influence of alcohol and benzodiazepines on vital signs in the emergency setting. AB - BACKGROUND: Ziprasidone is a second-generation antipsychotic (SGA) approved for agitation. Few previous studies have examined ziprasidone in the emergency department (ED). For instance, it is unknown how often emergency physicians prescribe ziprasidone, whether it is typically prescribed in combination with a benzodiazepine, or whether use of intramuscular (i.m.) ziprasidone and benzodiazepines affects vital signs compared to i.m. ziprasidone alone. OBJECTIVE: Our aims were to determine the demographics of patients receiving ziprasidone in an urban-suburban ED; the relative frequency with which ziprasidone is prescribed; and the effects on vital signs, repeat medication dosage, and lengths of stay. METHODS: This is a multicentered structured chart review from 2003 to 2010 of ziprasidone use at two hospitals. If documented, vital signs were compared in patients who received concurrent benzodiazepines and in those who did not, and in patients who ingested alcohol and in those who did not. RESULTS: Patients on 95 visits received ziprasidone during the study period, with one third of these receiving accompanying benzodiazepines. Forty-nine unique patients who were treated with i.m. ziprasidone had documented vital signs. In these patients, alcohol intoxication was associated with decreased oxygen saturations irrespective of benzodiazepines. Concurrent benzodiazepines had no other deleterious effect on vital signs but resulted in longer ED stays. CONCLUSIONS: This study suggests that many ED physicians, who commonly prescribe a benzodiazepine with a first-generation antipsychotic like haloperidol, have transferred this practice to SGAs like ziprasidone. In this sample, this pairing did not adversely affect vital signs but was associated with marginally longer ED stays. Caution should be exercised when treating alcohol-intoxicated patients with ziprasidone, as this can decrease oxygen saturations. PMID- 24071033 TI - Observational study and estimate of cost savings from use of a health information exchange in an academic emergency department. AB - BACKGROUND: Federal initiatives to improve health care information sharing have led to the development of a new type of regional electronic medical record known as a health information exchange (HIE). OBJECTIVE: Our aim was to investigate the ability of an HIE to decrease health services use for emergency department (ED) patients. METHODS: We performed an observational, prospective study using a voluntary, anonymous survey among clinicians at an urban academic ED. All ED clinicians were eligible to participate. Survey items addressed clinician perception of whether information from the HIE avoided the use of hospital resources, improved quality of care, and reduced length of stay (LOS). Cost savings were estimated by multiplying the number of services the clinicians completing our survey reported they avoided through use of the HIE by the costs of those services at our facility. The study was approved by the Institutional Review Board at the study site. RESULTS: The study was conducted between August and December of 2011. There were 18,529 patient encounters during the study period and 60 clinicians at the study site who were eligible to participate. The clinicians consulted the HIE for 5.39% of these encounters (998 patients). Surveys were completed by the clinicians caring for 13.8% (n = 138) of these patients. Of the completed surveys, 76% (105 surveys) referenced patients for whom the HIE was found to contain information on the patient under care by the clinician participant. These 105 patients formed the sample on which our analysis was based. Within this sample of patients, the following studies were reported to have been avoided by the clinicians participating in our survey: values are percent of patients for whom a study was reported to have been avoided (actual number of studies avoided): laboratory/microbiology: 30.5% (32 studies); radiologic studies: 47.6% (50 studies); consultations: 19% (20 consultations); and admissions: 11.4% (12 admissions). Calculated cost savings based on these estimates were as follows: laboratory/microbiology: $462.85; radiologic studies: $160,893.00; consultations: $3,990.00; and admissions: $118,131.84. Total savings: $283,477. Clinicians participating in the study reported improved quality of care for 86.7% of their patients, as well as a mean time savings of 120.8 minutes. CONCLUSIONS: According to clinician estimates, use of an HIE in this urban academic ED resulted in reduced use of hospital resources, noteworthy cost savings, decreased LOS, and improved quality of care. Limitations included the observational nature of the study, selection bias, the Hawthorne effect, and cost estimates being from a single institution. Allowance was not made for additional services used because of information obtained from the HIE. PMID- 24071034 TI - The human antimicrobial peptide LL-37 and its fragments possess both antimicrobial and antibiofilm activities against multidrug-resistant Acinetobacter baumannii. AB - Acinetobacter baumannii infections are difficult to treat due to multidrug resistance. Biofilm formation by A. baumannii is an additional factor in its ability to resist antimicrobial therapy. The antibacterial and antibiofilm activities of the human antimicrobial peptide LL-37 and its fragments KS-30, KR 20 and KR-12 against clinical isolates of multidrug-resistant (MDR) A. baumannii were evaluated. The minimal inhibitory concentration (MIC) of LL-37 against MDR A. baumannii isolates ranged from 16 to 32 MUg/mL. The MIC of KS-30 fragment varied from 8.0 to 16 MUg/mL and the KR-20 fragment MIC ranged from 16 to 64 MUg/mL. LL-37 and KS-30 fragment exhibited 100% bactericidal activity against five A. baumannii strains, including four MDR clinical isolates, within 30 min at concentrations of 0.25-1 MUg/mL. By 0.5h, the fragments KR-20 and KR-12 eliminated all tested strains at 8 and 64 MUg/mL respectively. LL-37 and its fragments displayed anti-adherence activities between 32-128 MUg/mL. A minimum biofilm eradication concentration (MBEC) biofilm assay demonstrated that LL-37 inhibited and dispersed A. baumannii biofilms at 32 MUg/mL respectively. Truncated fragments of LL-37 inhibited biofilms at concentrations of 64-128 MUg/mL. KS-30, the truncated variant of LL-37, effectively dispersed biofilms at 64 MUg/mL. At 24h, no detectable toxicity was observed at the efficacious doses when cytotoxicity assays were performed. Thus, LL-37, KS-30 and KR-20 exhibit significant antimicrobial activity against MDR A. baumannii. The prevention of biofilm formation in vitro by LL-37, KS-30 and KR-20 adds significance to their efficacy. These peptides can be potential therapeutics against MDR A. baumannii infections. PMID- 24071035 TI - Childbirth in exile: asylum seeking women's experience of childbirth in Ireland. AB - OBJECTIVES: the purpose of this study was to gain insight into women's experiences of childbirth in Ireland while in the process of seeking asylum. This paper will focus on one of the primary findings of the study, how lack of connection, communication and cultural understanding impacted the health and well being of the women who participated. DESIGN: researchers adopted a structural approach to narrative analysis using Burke's (1969) dramatistic pentad to analyse 22 women's narrative accounts of their childbirth experiences. Ethical approval was granted, and the study was funded by the Irish Health Research Board. FINDINGS: Burke's (1969) dramatistic pentad revealed numerous accounts of Scene/Agent and Act/Agency imbalance in the women's experiences, highlighting lack of communication, connection and culturally competent care evident in their experiences and how this impacted the care they received. CONCLUSION: inadequate, poorly organised maternity services complicated by lack of training in cultural understanding and sporadic access to interpreter services had a detrimental impact on care provision. Providers appeared to have little insight into the specific needs of this vulnerable group already traumatised by pre and post migratory stressors. The resulting lack of effective connection and communication exacerbated women's experiences of alienation, loneliness, and isolation and were universal in the women's accounts. Implications for practice need to focus in Burkean terms on 'How' (Agency) providers can meet the maternity care needs of asylum seeking women. Dedicated community based services, mandatory training in cultural competence, 24 hour access to interpreters, information leaflets in several languages are essential measures. Further research looking specifically at the antenatal care and childbirth education needs of ethnic minority women is needed. Also, there is an urgent need for further exploration of the barriers to communication and the utilisation of trained interpreters in the provision of effective care to non-English speaking ethnic minority women. PMID- 24071036 TI - Thoracolumbar spinal angiolipoma demonstrating high signal on STIR imaging: a case report and review of the literature. AB - BACKGROUND: Angiolipomas are rare benign tumors, accounting for 0.14% to 1.2% of all tumors of the spinal axis with vascular and fatty histological features. Spinal angiolipoma (SAL) is most commonly found in the thoracic region and has high signal on contrast enhanced fat-saturated T1-weighted imaging. Although the international literature is extensive, there are few cases reported in United States. OBJECTIVE: To present a case of SAL located in the thoracolumbar region without high signal on contrast enhanced fat-saturated T1-weighted imaging and to review previously reported cases. STUDY DESIGN/METHODS: Case report and review the literature. RESULTS: Magnetic resonance imaging obtained in a 68-year-old man with a long history of lumbago showed a heterogeneous mass (T10-L1) hyperintense on T1-weighted imaging but not enhancing on suppression fat sequences, suggesting epidural hematoma. Surgical excision of the lesion was performed, and SAL was diagnosed and confirmed by pathology. The patient became asymptomatic. CONCLUSIONS: The predominance of either vascular or fatty components inside the tumor might alter the expected results on magnetic resonance imaging with suppression fat sequences. PMID- 24071037 TI - Incidence and morbidity of concomitant spine fractures in combat-related amputees. AB - BACKGROUND CONTEXT: High-energy blasts are the most frequent cause of combat related amputations in Operations Iraqi and Enduring Freedom (OIF/OEF). The nondiscriminating effects of this mechanism often result in both appendicular and axial skeletal injuries. Despite this recognized coincident injury pattern, the incidence and consequence of spine fractures in trauma-related combat amputees are unknown. PURPOSE: This study sought to determine the incidence and morbidity of the associated spine fractures on patients with traumatic lower extremity amputation sustained during OIF/OEF. STUDY DESIGN/SETTING: Retrospective case control. PATIENT SAMPLE: Two hundred twenty-six combat-related lower extremity amputees presenting to a single institution and injured between 2003 and 2008 were included for analysis. OUTCOME MEASURES: Physiologic and functional outcome measures were used to determine the influence of spine fractures on combat amputees. Physiologic measures included intensive care unit (ICU) admission rates, injury severity score (ISS), rate of narcotic/neuropathic pain use, and heterotopic ossification (HO) rates. Functional outcome measures included return to-duty rates and ambulatory status at final follow-up. METHODS: Data from 300 consecutive combat-related lower extremity amputations were retrospectively reviewed and grouped. Group 1 consisted of amputees with associated spine fractures, and Group 2 consisted of amputees without spine fractures. The results of the two groups were compared with regard to initial presentation and final functional outcomes. RESULTS: A total of 226 patients sustained 300 lower extremity amputations secondary to combat-related injuries, the most common mechanism being an improvised explosive device. Twenty-nine of these patients had a spine fracture (13%). Group 1 had a higher ISS than Group 2 (30 vs. 19, p<.001). Group 1 patients were also more likely to be admitted to the ICU (86% vs. 46%, p<.001). Furthermore, Group 1 patients had a significantly higher rate of HO in their residual limbs (82% vs. 55%, p<.005). CONCLUSIONS: The incidence of spine fractures in combat-related amputees is 13%. The results suggest that combat-related amputees with spine fractures are more likely to sustain severe injuries to other body systems, as indicated by the significantly higher ISS and rates of ICU admission. This group also had a significantly higher rate of HO formation, which may be attributable to the greater local and/or systemic injuries sustained by these patients. PMID- 24071038 TI - [Treatment of proximal radioulnar synostosis using a posterior interosseous antegrade flow pedicled flap]. AB - The aim of this study is to determine the different therapeutic options described for the treatment of radioulnar synostosis, and report our experience with posterior interosseous antegrade flow pedicled flap with technical amendments. Two patients, who were treated with the designed flap, and with more than one year of follow-up, were reviewed. The technical innovations, end result and complications are described. In the two cases described, there was no recurrence of synostosis, which is the most frequent complication described in this condition, and no postoperative complications were observed. In the literature, many filler materials, from artificial to biological free or vascularized, have been used the radioulnar space after excision of synostosis. The technique that provides the best results is the interposition of muscle or vascularized adipofascial flaps. The Interosseous posterior antegrade flow pedicled flap is reliable, with a low morbidity, and is an effective alternative for the treatment of proximal radioulnar synostosis. PMID- 24071039 TI - [Early onset scoliosis. What are the options?]. AB - The prognosis of children with progressive early onset scoliosis has improved considerably due to recent advances in surgical and non-surgical techniques and the understanding of the importance of preserving the thoracic space. Improvements in existing techniques and development of new methods have considerably improved the management of this condition. Derotational casting can be considered in children with documented progression of a <60 degrees curve without previous surgical treatment. Both single and dual growing rods are effective, but the latter seem to offer better results. Hybrid constructs may be a better option in children who require a low-profile proximal anchor. The vertical expandable prosthetic titanium rib (VEPTR((r))) appears to be beneficial for patients with congenital scoliosis and fused ribs, and thoracic Insufficiency Syndrome. Children with medical comorbidities who may not tolerate repeated lengthenings should be considered for Shilla or Luque Trolley technique. Growth modulation using shape memory alloy staples or other tethers seem promising for mild curves, although more research is required to define their precise indications. PMID- 24071040 TI - [Effect of intramedullary reaming and nailing on the production of growth factors in the femur fracture callus in rats]. AB - INTRODUCTION: Many studies have been conducted to determine the different effects that reaming or intramedullary nailing have on fracture healing, but there is no evidence in the literature of the effect of intramedullary reaming on osteogenesis. We performed a prospective study to analyse the effect of intramedullary reaming and nailing on the production of growth factors during the process of fracture healing in the femur of rats. MATERIAL AND METHODS: A transverse mid-shaft non-comminuted femur fracture was produced in 64 rats; 34 rats did not receive any treatment, and a standardized surgical procedure was performed on 30 rats, by exposing the left knee, reaming the medullary canal from distal to proximal, and then fixing the fracture with a steel pin. The rats were sacrificed at the 24th hour, 4th, 7th and 15th days after the fracture. The amount of growth factors that appeared in the callus fracture was measured using histopathology studies. The primary categorical variables analysed were PDGFA, TGF2 and TGFbeta-R2. These variables were analysed in each group at the different sacrifice times. RESULTS: The results of the primary variables of the study, stratified by the time until sacrifice, showed no statistically significant differences. DISCUSSION: Even if the presence of an intramedullary wire facilitates the fracture repair and the stabilising the bridge of bone between both edges of the fracture site, no evidence was found that reaming changes the expression of the growth factors studied (PDGFA, TGFbeta-R2 and TGFbeta2) during the callus formation in rats. PMID- 24071041 TI - [Treatment of Dupuytren's disease using collagenase from Clostridium histolyticum]. AB - OBJECTIVE: The collagenase from Clostridium histolyticum is a new therapeutic option, and the first pharmacological one, in the treatment of Dupuytren's disease. MATERIAL AND METHODS: A prospective study was conducted on 35 patients with Dupuytren's disease. The clinical and functional variables, as well as patient satisfaction and drug safety were evaluated. RESULTS: The functional and clinical results after its administration were good, with a rapid recovery, especially at the metacarpophalangeal (MCP) joint. The index finger contracture prior to MCP puncture was 64 degrees and after puncture it was 4 degrees. In the proximal interphalangeal (PIP) prior to puncture it was 83.3 degrees and after puncture it was 15 degrees; In the MCP/PIP prior to puncture it was 140 degrees, and after puncture it 25 degrees. CONCLUSIONS: Collagenase from Clostridium histolyticum an alternative of treatment of Dupuytren's disease, mainly in the elderly. More research is required in order to clarify the rate of recurrence of the disease, the possible adverse reactions, and to compare the efficiency and permanence with other treatment options. PMID- 24071042 TI - [Arthroscopy- assisted resection-interposition of post-traumatic central physeal bridges]. AB - INTRODUCTION: Physeal bridge resection and insertion of interposition material has had mixed success rates in the literature. Using the arthroscopic approach, some authors have reported good results in their patients. The aim of the study was to evaluate the treatment of post-traumatic central physeal bridges with arthroscopically assisted resection and fat interposition. MATERIAL AND METHODS: A retrospective study was conducted on 5 patients (6 procedures), who developed a physeal bridge after a traumatic injury. A CT or MRI scan was performed preoperatively in all patients to assess the size of the physeal bridge. Inclusion criteria were patients with documented existing or developing deformities, a physeal bridge <50% of the physeal area, and with at least 2 years of growth remaining. Clinical outcomes were classified according to Marsch and Polzhofer criteria (excellent, good or poor). RESULTS: Excellent results were obtained in two patients, good in one, and the other two cases were rated as poor. In patients with a poor outcome, high energy trauma mechanisms were identified in both cases. Moreover, incorrect initial treatment or delayed physeal bridge resection was identified. CONCLUSIONS: The arthroscopically assisted technique provides best visualization with minimal morbidity. Although our results are not as good as previous studies, it cannot be considered that the technique itself is the cause of the failure, as several risk factors associated to bad prognosis of these injuries were found. PMID- 24071043 TI - [SECOT consensus on painful knee replacement]. AB - The opinions of 21 experts in knee surgery were evaluated in this study, using a DELPHI questionnaire method in two successive rounds, on 64 controversial scenarios that covered both the diagnosis and possible treatment of painful knee replacements. The level of consensus was significantly unanimous in 42 items and of the design in 5, with no agreement in 17 of the questions presented. light of the published scientific evidence, the surgeons who took part showed to have a notable level of information on the most effective diagnostic tests, although, it should be pointed out that there was a lack of confidence in the possibility of ruling out an infection when the erythrocyte sedimentation rate and the C reactive protein were within normal values, which have been demonstrated in the literature to have a high negative predictive value As regards the treatments to employ in the different situations, the responses of the expert panel were mainly in agreement with the data in the literature. The conclusions of this consensus may help other surgeons when they are faced with a painful knee prosthesis. PMID- 24071044 TI - [Patients with hemodynamic unstable pelvic fractures in extremis: pelvic packing or angiography?]. AB - The multidisciplinary management of patients with pelvic trauma has improved prognosis, but mortality is still very high. The appropriate treatment strategy remains controversial, especially regarding the control of bleeding in patients whose clinical situation is extreme by using angiography or pelvic packing. We propose using a tool of evidence-based medicine (CAT) the benefit of the completion of pelvic packing in relation to a specific clinical question from a specific situation. What is best for the management of bleeding, extraperitoneal pelvic packing or angiography, in patients with hemodynamically unstable pelvic fracture in extremis? From this study we can conclude that angiography may improve control of bleeding in patients with arterial bleeding and hemodynamically stable but the packing has priority in patients with pelvic fractures and hemodynamic instability. PMID- 24071045 TI - [Modulation of scoliotic spine growth in experimental animals using intelligent metal bars]. AB - OBJECTIVE: To create an experimental structural scoliosis model in mice to evaluate the efficacy of shape-memory metals to gradually correct the deformity over time. MATERIAL AND METHOD: Experimental scoliosis was generated in 3 week old mice by means of a suture between the left scapula and pelvis for 8 weeks. They were then randomised into two groups: a control group, in which the suture was cut, and another, in those that also had a Nitinol straight memory-wire implant fixed to the column. Serial X-rays were performed to determine the efficacy of the Nitinol in the correction of the scoliosis. In a second time, the histological changes at apical vertical body level and the adjacent discs were evaluated pre- and post-correction. RESULTS: A mean 81.5 degrees kyphoscoliosis was gradually induced. In the control group, after cutting the suture, an initial reduction in the deformity was observed, but later it remained stable throughout the time (54 degrees at two weeks). In the Nitinol group, a gradual reduction was observed in the scoliosis angle value, to a mean of 8.7 degrees at two weeks. The curvature of the apical vertebral body and adjacent discs were partially corrected after two weeks of correcting the deformity. CONCLUSION: This scoliosis model has demonstrated the efficacy of a straight Nitinol wire fixed to the spinal column in the gradual correction of kyphoscoliosis and in the changes in its adjacent structures. PMID- 24071046 TI - [Is local bone graft sufficient to maintain the surgical correction in adolescent idiopathic scoliosis curves?]. AB - OBJECTIVE: The purpose of this study was to compare postoperative clinical and radiological results in adolescent idiopathic scoliosis curves treated by posterior arthrodesis using autogenous bone graft from iliac crest (CI) versus only local autograft bone (HL). PATIENTS AND METHODS: A retrospective matched cohort study was conducted on 73 patients (CI n=37 and HL n=36) diagnosed with adolescent idiopathic scoliosis and treated surgically by posterior arthrodesis. The mean post-operative follow-up was 126 months in the CI group vs. 66 months in the HL group. The radiographic data collected consisted of preoperative, postoperative, and final follow-up antero-posterior and lateral full-length radiographs. Loss of correction and quality of arthrodesis were evaluated by comparing the scores obtained from the Spanish version of the SRS-22 questionnaire. RESULTS: There were significant differences in the post-operative results as regards the correction of the Cobb angle of the main curve (HL 61 +/- 15% vs. CI 51 +/- 14%, P<.004), however a greater loss of correction was found in the local bone group (CI 4.5 +/- 7.3 degrees vs. HL 8.5 +/- 6.3 degrees , P=.02). There were no significant differences as regards the correction of the Cobb angle of the main curve at the end of follow-up. There were no clinical differences between the two groups in the SRS-22 scores. CONCLUSION: At 5 years of follow-up, there was a statistically significant greater loss of radiographic correction at the end of final follow-up in the local bone graft group. However clinical differences were not observed as regards the SRS-22 scores. PMID- 24071047 TI - [Multifocal necrotizing fasciitis: presentation of a case]. AB - INTRODUCTION: Multifocal necrotizing fasciitis is a condition in which there is more than one non-contiguous body area affected, and it is usually the result of the dissemination of septic emboli. CLINICAL CASE: We present a 67 year-old patient, on oral corticosteroid treatment, who was admitted with a septic shock. The previous week he had been operated on due to the perforation of a colon diverticulum. He had signs that suggested necrotizing fasciitis on all four limbs which progressed quickly. Emergency fasciotomies on all limbs were performed, and empirical antibiotic treatment was started. RESULTS: After the surgery the patient improved, and seven days after the debridement, primary closure of the wounds was performed. Tissue cultures were negative. DISCUSSION: Being a rare entity, there is no consensus regarding the management of multifocal necrotizing fasciitis. However, early and aggressive debridement (including fasciotomies and even amputation) and broad-spectrum antibiotics are essential for its treatment. PMID- 24071048 TI - [Paravertebral and intra-abdominal abscess due to oxygen-ozone therapy for lower back pain]. AB - Complications secondary to oxygen-ozone therapy are rare, but they have been described in medical literature. There are only two cases of infectious complications after oxygen-ozone therapy. Our aim is to describe a rare case of purulent complication that was secondary to oxygen-ozone therapy for the treatment of lower back pain. We report the clinical improvement with conservative treatment for a local complication after percutaneous oxygen-ozone treatment. According to the clinical improvement of our patient, conservative treatment should be considered before any aggressive surgery. PMID- 24071049 TI - [Triple fracture of the shoulder suspensory complex]. AB - The superior suspensory complex of the shoulder (SSCS) is a ring shaped structure composed of bones and soft tissues that play a fundamental role in the stability of the shoulder joint. Isolated injuries of the SSCS are relatively common, but injuries that affect 3 components are extremely unusual. We present a triple injury of the SSCS in a 26 year old patient with a Neer type ii clavicular fracture, a Kuhn type iii acromion fracture and an Ogawa type i coracoid fracture. An open reduction and stabilization of the clavicle was performed with 2 Kirschner nails. The acromial fracture was synthesized with 2 cannulated screws, and the coracoid fracture was treated conservatively. After 24 months of follow up the patient had an excellent functional outcome according to the Constat-Murley shoulder score and QuickDASH scoring system, and all the fractures healed correctly. PMID- 24071050 TI - [Incarcerated epitrochlear fracture with a cubital nerve injury]. AB - Injuries of the medial epicondyle are relatively common, mostly affecting children between 7 and 15 years. The anatomical characteristics of this apophysis can make diagnosis difficult in minimally displaced fractures. In a small percentage of cases, the fractured fragment may occupy the retroepitrochlear groove. The presence of dysesthesias in the territory of the ulnar nerve requires urgent open reduction of the incarcerated fragment. A case of a seven-year-old male patient is presented, who required surgical revision due to a displaced medial epicondyle fracture associated with ulnar nerve injury. A review of the literature is also made. PMID- 24071051 TI - [Caudal epidural steroid injection in the treatment of chronic discogenic low back pain. Comparative, prospective and randomized study]. AB - OBJECTIVE: There is no consensus on the treatment of chronic low back pain of disc origin in the medical literature. The few prospective, randomized, controlled studies evaluating the effectiveness of caudal epidural steroid injections (CESI) have obtained contradictory results. The aim of this study is to evaluate the efficacy of CEI in reducing pain and improving the associated disability. MATERIAL AND METHOD: This is a prospective, randomized, case-control study of a group of 46 patients with chronic low back disc pain. Patients were randomly allocated into 2 groups to either receive fluoroscopy guided CESI (CESI group), or oral non-steroidal anti-inflammatory drugs (NSAID-group). All patients were clinically evaluated at 4, 12, and 24 weeks, and according to the indications of the Spanish Society for Study of Diseases of the Spine (GEER). RESULTS: Lumbar pain, measured by the visual analog scale (VAS) and the Oswestry Low Back Pain Disability Questionnaire (ODQ), did not improve significantly during follow-up in any of the two study groups (P>.05). Younger patients, women, patients with shorter duration of symptoms, low physical job demand, without leg pain, and sport-active, included in CESI-group showed a trend towards better results, but none reached statistical significance (P>.05). CONCLUSIONS: The present study has not demonstrated the superiority of CESI over NSAIDs in treating chronic low back pain of disc origin. While CESI could show some improvement in patients with degenerative lumbar disc disease, we consider it should be used with caution, informing patients about realistic expectations on the success of treatment. PMID- 24071052 TI - [Sauve-Kapandji procedure in distal radioulnar joint disorders]. AB - OBJECTIVE: To evaluate the functional and subjective results of the Sauve Kapandji procedure as a treatment for distal radioulnar joint disorders. MATERIAL AND METHOD: A retrospective study was conducted on 27 patients treated using the Sauve-Kapandji technique from January 2001 to March 2012. The aetiologia, age, sex, laterality, articular movement, radiographical signs of joint degeneration, and cubitus varus, were analysed. The Mayo Clinic wrist assessment scale and the DASH questionnaire were used for the postoperative evaluation. The mean follow-up was 24 months (6-48 months). The mean age was 47.2 years, with 66.7% females, and 55% the dominant side. RESULTS: At one year after surgery, 16 cases had mild or no pain (59.2%), 8 cases with moderate (29.6%) and 3 cases with severe pain (11.1%). The pronation-supination went from a pre-operative average of 96.8 degrees to 136.4 degrees postoperative, operatorios, which was a significant statistical difference (Wilcoxon test). The radioulnar ratio went from an pre operative average of +2.6mm to -0.39 mm postoperative. Full functional recovery was observed in 48%. A grip strength of 50.6%, compared to the contralateral wrist was achieved. CONCLUSIONS: The Sauve-Kapandji technique could avoid the complications common in other procedures, such as cubital-carpal migration. Our study agrees with that in the literature with good results as regards the range of joint movement, with an acceptable improvement in pain compared to the previous stage, but it also demonstrates the frequent loss of grip strength and instability of the proximal radio-ulnar joint. PMID- 24071053 TI - Colchicine-induced myoneuropathy mimicking polyradiculoneuropathy. AB - We report a patient with colchicine-induced myoneuropathy. Myoneuropathy is an under-recognized complication of colchicine. The weakness seen in our patient improved fairly rapidly after discontinuation of colchicine. PMID- 24071054 TI - Cerebral arteriostenosis associated with elevated serum-immunoglobulin E level in young adults without risk factors for ischemic stroke: a possible manifestation of cerebral vasculitis? AB - We report a series of young adults with symptomatic cerebral arteriostenosis characterized by elevated serum immunoglobulin (Ig) E levels. All patients had no definite risk factors for cerebral vascular diseases. The clinical data of 26 young adults (age 18-50 years) with ischemic stroke, characterized only by increased serum IgE levels and without risk factors for cerebral vascular disease, were retrospectively reviewed. Arteriostenosis was surveyed and followed up by digital subtraction angiography (DSA), and the stenosis rate was estimated using the warfarin-aspirin symptomatic intracranial disease technique. All patients were treated with corticosteroids according to the common strategy for vasculitis. There was no recurrent stroke during follow-up. The mean degree of stenosis before and after treatment was 69.3+/-29.8% and 47.9+/-45.1%, respectively. The difference of stenosis rates between initial and follow-up DSA evaluation was significant using a paired samples test (21.31+/-26.88, 95% confidence interval [CI] 13.58-29.03, t=5.55, p<0.001). Kaplan-Meier survival analysis revealed that the 13-month cumulative improved lesion rate was 40.3+/ 8.7%. This remained the same at 18 months. The mean time to lesion improvement was 12.58 +/- 0.96 months (95% CI 10.70-14.46) and median time was 13+/-3.88 months (95% CI 5.39-20.61). To our knowledge, cerebral arteriostenosis with only elevated IgE serum levels has not been reported. Our data showed that corticosteroid treatment can achieve clinical and artery improvement. This suggests that the cerebral arteriostenosis seen in our study might be caused by some specific type of vessel inflammation. PMID- 24071055 TI - Idiopathic granulomatous hypophysitis presenting as pituitary apoplexy. AB - Idiopathic granulomatous hypophysitis (IGH) is an extremely rare chronic inflammatory lesion of the pituitary gland. This condition typically presents with chronic onset of headache and slow development of visual deficits. Pituitary apoplexy is a clinical syndrome characterized by sudden onset of headache, vision loss, opthalmoplegia, and signs of meningeal irritation. Although IGH has been previously described in the literature, its presentation as clinical pituitary apoplexy is novel. We report, to our knowledge, the first patient with IGH manifesting as clinical pituitary apoplexy. Physicians involved in the treatment of pituitary disease should be aware of this rare entity. PMID- 24071056 TI - Phenotypical analysis, relation to malignancy and prognostic relevance of ICOS+T regulatory and dendritic cells in patients with gliomas. AB - We determined circulating T helper, T regulatory and ICOS+T regulatory as well as DC cell counts in 29 patients with cerebral gliomas. Samples from patients with gliomas vs. healthy controls and from patients with glioblastomas vs. patients with glioma WHO grades I-III contained significantly (p<0.05) decreased numbers of total as well as mature, i.e. myeloid and plasmacytoid DCs. Patients with glioblastomas demonstrated significantly lower values of CD4+ as well as an increased fraction of ICOS+T regulatory/CD4+ cells. Higher CD4+ cell counts (>=225 cells/MUl, median) were associated with improved survival in glioblastomas. PMID- 24071058 TI - Increase of tibial slope reduces backside wear in medial mobile bearing unicompartmental knee arthroplasty. AB - BACKGROUND: Unicondylar knee arthroplasty is a good alternative for patients in monocompartmental osteoarthritis. The revision rate in unicondylar knee arthroplasty is higher than in total knee arthroplasty. The influence of the tibial slope on wear in unicondylar knee arthroplasty has not been investigated so far. METHODS: The influence of the tibial slope on wear was investigated in mobile bearing unicondylar knee prosthesis. This was positioned with four different tibial slopes (-4 degrees , 0 degrees , 4 degrees , 8 degrees ) in a knee wear simulator simulating the human gait in a plane according to ISO 14243 2:2002(E). After this a kinematic analysis was performed and the inlays were observed under reflected-light-microscopy. FINDINGS: Wear was significantly reduced with an increasing tibial slope (0 degrees : 3.46 mg/millioncycles, SD: 0.59, 4 degrees slope: 1.52 mg/millioncycles, SD: 0.06, 8 degrees slope group: 0.99 mg/millioncycles, SD: 0.42). An anterior slope of -4 degrees also reduced wear (2.08 mg/millioncycles, SD: 0.37). Kinematic analysis revealed a reduced translation between the inlay and the tibia with an increasing tibial slope. The backside of the inlays of the 4 degrees and 8 degrees slope group showed less wear pattern when observed under reflected-light microscopy. INTERPRETATION: Increasing the tibial slope led to a reduced translation between the inlay and the prosthesis in the analysed mobile-bearing unicondylar knee arthroplasty and with this to a reduced backside wear. A tibial slope between 4 and 8 degrees can be recommended in mobile UKA to reduce wear, however, the influence on the ligaments has to be considered and needs to be investigated in further studies. PMID- 24071057 TI - XLMR protein related to neurite extension (Xpn/KIAA2022) regulates cell-cell and cell-matrix adhesion and migration. AB - X-linked mental retardation (XLMR) is a common cause of moderate to severe intellectual disability in males. XLMR protein related to neurite extension (Xpn, also known as KIAA2022) has been implicated as a gene responsible for XLMR in humans. Although Xpn is highly expressed in the developing brain and is involved in neurite outgrowth in PC12 cells and neurons, little is known about the functional role of Xpn. Here, we show that Xpn regulates cell-cell and cell matrix adhesion and migration in PC12 cells. Xpn knockdown enhanced cell-cell and cell-matrix adhesion mediated by N-cadherin and beta1-integrin, respectively. N Cadherin and beta1-integrin expression at the mRNA and protein levels was significantly increased in Xpn knockdown PC12 cells. Furthermore, overexpressed Xpn protein was strongly expressed in the nuclei of PC12 and 293T cells. Finally, depletion of Xpn perturbed cellular migration by enhancing N-cadherin and beta1 integrin expression in a PC12 cell wound healing assay. We conclude that Xpn regulates cell-cell and cell-matrix adhesion and cellular migration by regulating the expression of adhesion molecules. PMID- 24071060 TI - Is treatment with liraglutide efficient? AB - In the current context of limited economic and health resources, efficiency of drug treatments is of paramount importance, and their clinical effects and related direct costs should therefore be analyzed. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM) which, in addition to its normoglycemic effects, induces a significant improvement in body weight and several cardiovascular risk factors. The aim of this narrative review is to summarize the available evidence about the effects of liraglutide upon cardiovascular risk factors and how these improve its cost-effectiveness profile. Despite the relatively higher cost of liraglutide as compared to other alternative therapies, liraglutide has been shown to be cost effective when clinical indicators and total costs associated to T2DM management are analyzed. PMID- 24071059 TI - Complete genome sequence of the endosymbiont Blattabacterium from the cockroach Nauphoeta cinerea (Blattodea: Blaberidae). AB - All cockroaches, with the exception of one cave-dwelling genus, harbor endosymbiotic bacteria, Blattabacterium. After much confusion concerning their function, recent genomic studies indicate that Blattabacterium synthesize amino acids, vitamins, and other compounds. However, the Blattabacterium genomes sequenced so far suggest that the endosymbionts are variable in their genome size, gene composition, and compounds they synthesize. Therefore, there is a need for sequencing additional Blattabacterium genomes to fully comprehend their evolution. Here, we report the complete genome sequence of Blattabacterium (BNCIN) harbored by the host Nauphoeta cinerea (Blaberidae). The BNCIN genome is 622,952 bp long and consists of 581 protein coding regions and 627 genes of putative function. The genome of BNCIN is comparable, with a few structural and functional differences, to the genomes of the other sequenced Blattabacterium. The endosymbiont is involved in complete or partial synthesis of 15 amino acids. PMID- 24071061 TI - A tiered approach for the human health risk assessment for consumption of vegetables from with cadmium-contaminated land in urban areas. AB - Consumption of vegetables that are grown in urban areas takes place worldwide. In developing countries, vegetables are traditionally grown in urban areas for cheap food supply. In developing and developed countries, urban gardening is gaining momentum. A problem that arises with urban gardening is the presence of contaminants in soil, which can be taken up by vegetables. In this study, a scientifically-based and practical procedure has been developed for assessing the human health risks from the consumption of vegetables from cadmium-contaminated land. Starting from a contaminated site, the procedure follows a tiered approach which is laid out as follows. In Tier 0, the plausibility of growing vegetables is investigated. In Tier 1 soil concentrations are compared with the human health based Critical soil concentration. Tier 2 offers the possibility for a detailed site-specific human health risk assessment in which calculated exposure is compared to the toxicological reference dose. In Tier 3, vegetable concentrations are measured and tested following a standardized measurement protocol. To underpin the derivation of the Critical soil concentrations and to develop a tool for site-specific assessment the determination of the representative concentration in vegetables has been evaluated for a range of vegetables. The core of the procedure is based on Freundlich-type plant-soil relations, with the total soil concentration and the soil properties as variables. When a significant plant-soil relation is lacking for a specific vegetable a geometric mean of BioConcentrationFactors (BCF) is used, which is normalized according to soil properties. Subsequently, a 'conservative' vegetable-group-consumption-rate weighted BioConcentrationFactor is calculated as basis for the Critical soil concentration (Tier 1). The tool to perform site-specific human health risk assessment (Tier 2) includes the calculation of a 'realistic worst case' site specific vegetable-group-consumption-rate-weighted BioConcentrationFactor. PMID- 24071062 TI - Subtle roles of microRNAs let-7, miR-100 and miR-125 on wing morphogenesis in hemimetabolan metamorphosis. AB - In most insect species, the microRNA (miRNA) let-7 clusters with miR-100 and miR 125 in the same primary transcript. The three miRNAs are involved in developmental timing in the nematode Caenorhabditis elegans and in the fly Drosophila melanogaster. In the cockroach Blattella germanica, the expression of these miRNAs increases dramatically in the wing pads around the molting peak of 20-hydroxyecdysone (20E) of the last instar nymph. When let-7 and miR-100 were depleted with specific anti-miRNAs in this instar, the resulting adults showed wings reduced in size (when miR-100 was depleted) or with malformed vein patterning (when let-7 and miR-100 were depleted). Depletion of miR-125 induced no apparent effects. Interestingly, the wing phenotype obtained after depleting let-7 and miR-100 is similar to that resulting from silencing the expression of Broad-Complex (BR-C) transcription factors with RNA interference (hindwings with a short CuP vein, with the vein/inter-vein pattern disorganized in the anterior part and showing anomalous bifurcations of the A-veins in the posterior part). PMID- 24071063 TI - Comparability of fish-based ecological quality assessments for geographically distinct Iberian regions. AB - In this work we compare two Iberian and a pan-European fish-based methods to assess ecological quality in rivers: the Fish-based Index of Biotic Integrity for Portuguese Wadeable Streams (F-IBIP), the Mediterranean Index of Biotic Integrity (IBIMED) and the pan-European Fish Index (EFI+). The results presented herein were developed in the context of the 2nd phase of the Intercalibration Exercise (IC), as required by the Water Frame Directive (WFD). The IC is aimed at ensuring comparability of the quality boundaries among the different WFD assessment methods developed by the Member States for each biological quality element. Although the two national assessment methods were developed for very distinct regions of Iberia (Western and Eastern Iberian Peninsula) they share the same methodological background: both are type-specific and guild-based multimetric indices. EFI+ is a multimetric guild-based model, but it is site-specific and uses a predictive modelling approach. The three indices were computed for all sites included in the Iberian Intercalibration database to allow the direct comparison, by means of linear regressions, of the resulting three quality values per site. The quality boundary harmonization between the two Iberian methods was only possible through an indirect comparison between the two indices, using EFI+ as a common metric. The three indices were also shown to be responsive to a common set of human induced pressures. This study highlights the need to develop general assessment methods adapted to wide geographical ranges with high species turnover to help intercalibrating assessment methods tailored for geographically more restricted regions. PMID- 24071064 TI - Neurosarcoidosis: correlation of cerebrospinal fluid findings with diffuse leptomeningeal gadolinium enhancement on MRI and clinical disease activity. AB - BACKGROUND: Cerebrospinal fluid (CSF) examination is considered important in the diagnosis of neurosarcoidosis, however, data on whether and how CSF parameters may be related to MRI findings and clinical disease activity of patients with neurosarcoidosis are scarce. OBJECTIVE: To correlate CSF findings in patients with neurosarcoidosis with MRI findings and clinical disease activity. MATERIAL AND METHODS: Results of 51 comprehensive CSF examinations of 25 patients with probable or definite neurosarcoidosis according to the Zajicek-criteria were analyzed retrospectively. RESULTS: Patients with diffuse leptomeningeal gadolinium enhancement on MRI had significantly higher cell counts (>=50 cells/MUl in 80%), total protein (>=200 mg/dl in 80%), CSF/serum albumin quotients (Q(Alb), >=30 in 80%), and lactate (>=30 mg/dl in 70%), but significantly lower glucose levels (<=40 mg/dl in 67%) than patients without leptomeningeal enhancement. Irrespective of MRI findings, activated lymphocytes and plasma cells were detected in the initial CSF examination in 60% and 47% of patients, and an intrathecal synthesis of IgG, IgA, and IgM in 22%, 29%, and 22%. Patients with clinically active disease had significantly higher CSF cell counts, total protein, Q(Alb), and lactate, but significantly lower glucose levels than patients with stable disease. CONCLUSION: CSF abnormalities in neurosarcoidosis are most pronounced in patients with diffuse leptomeningeal enhancement on MRI. CSF analyses may thus aid in the distinction of different radiographic and pathologic manifestations of neurosarcoidosis. Furthermore, CSF examinations may allow monitoring disease activity in patients with neurosarcoidosis. PMID- 24071065 TI - Flow diversion of giant curved sidewall and bifurcation experimental aneurysms with very-low-porosity devices. AB - OBJECTIVE: Flow diverters (FDs) are increasingly used to treat difficult intracranial aneurysms. The objective of this study was to test whether treatment challenges posed by giant curved sidewall (cSW) and endwall bifurcation (EwB) aneurysms can be overcome with the use of very-low-porosity devices. METHODS: Large and giant EwB (n = 12) and cSW aneurysms (n = 5) were constructed in 17 dogs. EwB aneurysms were treated with 48 (n = 4), 64 (n = 4), or two overlapping 64-wire low-porosity devices (n = 4), whereas all cSW aneurysms were treated with single 64-wire devices. Angiographic results were recorded immediately and at 12 weeks before euthanasia. Pathologic specimens were photographed and neointimal coverage of devices measured and scored. RESULTS: By 12 weeks, 1 of 12 EwB and 1 of 5 cSW aneurysms were occluded. All other aneurysms were patent. Device-related arterial stenoses occurred in 13 of 17 animals, hemodynamically significant in two. All branches jailed by the FDs remained patent. There was a significant correlation between angiographic scores and the degree of neointima formation on the device (Rho = 0.527; P = 0.04). Failures of aneurysm occlusion could be explained by holes, sometimes barely visible, in the neointima that formed over FDs. CONCLUSION: Low-porosity FDs fail to reliably occlude experimental giant EwB and cSW aneurysms. PMID- 24071066 TI - Spinal cord stimulation for visceral pain related to chronic pancreatitis: report of 2 cases. AB - OBJECTIVE: To report our experience related to the use of spinal cord stimulation (SCS) for relief of chronic pancreatitis-related neuropathic visceral pain. METHODS: Two patients, 50 years old and 39 years old, presented with intractable visceral pain related to chronic pancreatitis. A quadripolar electrode for SCS was inserted at the T8-10 level using a percutaneous technique. After a successful trial, a permanent stimulator was inserted. RESULTS: At a mean follow up of 7 years, both patients showed a marked improvement, with 80% and 90% decrease of pain, respectively, as assessed by Visual Analogue Scale. Pain medications were discontinued in both cases. CONCLUSIONS: SCS appears to be an effective long-term treatment for neuropathic visceral pain related to chronic pancreatitis. PMID- 24071362 TI - Population bottlenecks, genetic diversity and breeding ability of the three spined stickleback (Gasterosteus aculeatus) from three polluted English Rivers. AB - Pollution is a significant environmental pressure on fish populations in both freshwater and marine environments. Populations subjected to chronic exposure to pollutants can experience impacts ranging from altered reproductive capacity to changes in population genetic structure. Few studies, however, have examined the reproductive vigor of individuals within populations inhabiting environments characterized by chronic pollution. In this study we undertook an analysis of populations of three-spined sticklebacks (Gasterosteus aculeatus) from polluted sites, to determine levels of genetic diversity, assess for evidence of historic population genetic bottlenecks and determine the reproductive competitiveness of males from these locations. The sites chosen included locations in the River Aire, the River Tees and the River Birket, English rivers that have been impacted by pollution from industrial and/or domestic effluents for over 100 years. Male reproductive competitiveness was determined via competitive breeding experiments with males and females derived from a clean water site, employing DNA microsatellites to determine parentage outcome. Populations of stickleback collected from the three historically polluted sites showed evidence of recent population bottlenecks, although only the River Aire population showed low genetic diversity. In contrast, fish collected from two relatively unpolluted sites within the River Gowy and Houghton Springs showed weak, or no evidence of such bottlenecks. Nevertheless, males derived from polluted sites were able to reproduce successfully in competition with males derived from clean water exposures, indicating that these bottlenecks have not resulted in any substantial loss of reproductive fitness in males. PMID- 24071363 TI - Structure effect on graphene-modified enzyme electrode glucose sensors. AB - Using structural characterizations and electrochemical measurements, we explored and investigated the effect of the structure of enzyme electrodes with glucose oxidase (GOD) that were modified by reduced graphene oxide (rGO) sheets. The rGO sheets with different defect density, layers, and oxygen concentrations were chosen to modify the enzyme electrode, and all the modified enzyme electrodes exhibited excellent electrocatalytic activities and performances towards glucose. The abundant defects in rGO induce easy absorption of GOD. At a low oxygen concentration, rGO sheets help to induce the direct electron transfer (DET) on the rGO-modified electrode, and at a higher oxygen concentration, the reduction of H2O2 occurred instead of DET on the surface of the rGO-modified electrode. When rGO modified the enzyme electrode under the working model of H2O2 reduction, an increase in the number of the oxygen functional groups could lead to an increase in the absorption of GOD, resulting in the improvement of the affinity and sensitivity of the biosensor. The rGO-modified enzyme electrode can provide faster response, higher sensitivity, and better affinity by optimizing and controlling the structure of graphene and its derivatives. PMID- 24071364 TI - Cyclic GMP recognition using ratiometric QD-fluorophore conjugate nanosensors. AB - Novel luminescent ratiometric nanosensors (QD-NAPTHs) were prepared based on cadmium telluride (CdTe655) quantum dots as luminescent nanoscaffolds with naphthyridine dyes as fluorescent receptors. This biosensing bifluorophoric nanosystem has been designed to achieve detection of guanosine 3',5'-cyclic monophosphate (cyclic GMP) in buffered media. Cyclic GMP is a secondary messenger that is an important factor for detecting cancer, diabetes and, cardiovascular diseases. Due to low concentration levels, even in pathological conditions, sensitive cGMP detection remains a challenge for modern biomedical diagnostics. Here, QD-NAPTH nanosensors were tested in the presence of a target nucleotide and with various structural cGMP analogues. Steady-state fluorescence spectroscopy was used to monitor a change in the nucleotide concentration. A 5-fold increase in naphthyridine fluorescence with a simultaneous decrease in QD luminescence was observed after adding 50 MUM of cGMP. Using this novel nanosystem with ratiometric detection, it was possible to recognize cGMP with limit of detection (3sigma) equal to 70 ng/ml. Moreover, the enhancement in fluorescence upon interaction with the target nucleotide constitutes a favourable approach towards the detection of cGMP in buffered media. These bifluorophoric nanosensors have a potential for application in fluorescence microscopy imaging and in-vitro assays. PMID- 24071365 TI - The influence of age on postoperative complications after total laryngectomy or pharyngolaryngectomy. AB - OBJECTIVE: This study aimed to evaluate the role of age in the occurrence of postoperative complications after total laryngopharyngectomy (TLP) or total laryngectomy (TL). MATERIALS AND METHODS: This was a retrospective study including all patients who underwent TLP or TL in our institution between January 2005 and December 2010. The impact of age (greater than 65 years), history of cancer treatments and comorbidities on early postoperative course was analyzed using univariate and multivariate analyses. RESULTS: Out of the 97 patients operated on, 21% had cancer of the hypopharynx and 79% of the larynx. Mean age at surgery was 63 years (41-90 years). 44% of patients were more than or equal to 65 years of age. Regarding local complications, only age (p = 0.004) had a statistically significant influence in univariate analysis. In multivariate analysis, age (OR 21.4, p = 0.0001) and alcohol consumption (OR 0.18, p = 0.04) were significant. Factors influencing the occurrence of general complications were, in univariate analysis: age >65 years (p = 0.003), type of surgery (p = 0.042), the presence of cardiovascular history (p = 0.47) and ASA score >2 (p = 0.007). In multivariate analysis, only age >65 years remained significant (OR 3.31, p = 0.013). CONCLUSION: Our results highlight the importance of preoperative oncogeriatric evaluation from the age of 65 years to optimize surgical management. PMID- 24071366 TI - Warburg effect increases steady-state ROS condition in cancer cells through decreasing their antioxidant capacities (anticancer effects of 3-bromopyruvate through antagonizing Warburg effect). AB - Cancer cells undergo an increased steady-state ROS condition compared to normal cells. Among the major metabolic differences between cancer cells and normal cells is the dependence of cancer cells on glycolysis as a major source of energy even in the presence of oxygen (Warburg effect). In Warburg effect, glucose is catabolized to lactate that is extruded through monocarboxylate transporters to the microenvironment of cancer cells, while in normal cells, glucose is metabolized into pyruvate that is not extruded. Pyruvate is a potent antioxidant, while lactate has no antioxidant effect. Pyruvate in normal cells may be further metabolized to acetyl CoA and then through Krebs cycle with production of antioxidant intermediates e.g. citrate, malate and oxaloacetate together with the reducing equivalents (NADH.H+). Through activity of mitochondrial transhydrogenase, NADH.H+ replenishes NADPH.H+, coenzyme of glutathione reductase which replenishes reduced form of glutathione (potent antioxidant). This enhances antioxidant capacities of normal cells, while cancer cells exhibiting Warburg effect may be deprived of all that antioxidant capabilities due to loss of extruded lactate (substrate for Krebs cycle). Although intrinsic oxidative stress in cancer cells is high, it may be prevented from reaching progressively increasing levels that are cytotoxic to cancer cells. This may be due to some antioxidant effects exerted by hexokinase II (HK II) and NADPH.H+ produced through HMP shunt. Glycolytic phenotype in cancer cells maintains a high non toxic oxidative stress in cancer cells and may be responsible for their malignant behavior. Through HK II, glycolysis fuels the energetic arm of malignancy, the mitotic arm of malignancy (DNA synthesis through HMP shunt pathway) and the metastatic arm of malignancy (hyaluronan synthesis through uronic acid pathway) in addition to the role of phosphohexose isomerase (autocrine motility factor). All those critical three arms start with the substrate G6P that is a direct product of HK II. 3-bromopyruvate (3BP, inhibitor of HK II) may prove as a promising anticancer and antimetastatic agent based on antagonizing the Warburg effect and disturbing the malignant behavior in cancer cells. PMID- 24071367 TI - Low single dose gabapentin does not affect prefrontal and occipital gamma aminobutyric acid concentrations. AB - The gamma-aminobutyric acid (GABA) system has been proposed as a target for novel antidepressant and anxiolytic treatments. Emerging evidence suggests that gabapentin (GBP), an anticonvulsant drug that significantly increases brain GABA levels, is effective in the treatment of anxiety disorders. The current study was designed to measure prefrontal and occipital GABA levels in medication-free healthy subjects after taking 0mg, 150mg and 300mg GBP. Subjects were scanned on a 3T scanner using a transmit-receive head coil that provided a relatively homogenous radiofrequency field to obtain spectroscopy measurement in the medial prefrontal (MPFC) and occipital cortex (OCC). There was no dose-dependent effect of GBP on GABA levels in the OCC or MPFC. There was also no effect on Glx, choline or N-acetyl-aspartate concentrations. The previously reported finding of increased GABA levels after GBP treatment is not evident for healthy subjects at the dose of 150 and 300mg. As a result, if subjects are scanned on a 3T scanner, low dose GPB is not useful as an experimental challenge agent on the GABA system. PMID- 24071368 TI - Predictors of patellar alignment during weight bearing: an examination of patellar height and trochlear geometry. AB - BACKGROUND: Patellar malalignment is thought to be an etiological factor with respect to the development of patellofemoral pain. Although previous studies have suggested that the geometry of the femoral trochlea and the height of the patella play an important role in determining patellar alignment, no investigation has systematically examined these relationships during weight bearing. The aim of this study was to determine whether patellar height and/or trochlear geometry predicts patellar alignment (lateral patellar displacement and lateral patellar tilt) during weight bearing. METHODS: MR images of the patellofemoral joint were acquired from 36 participants during weight bearing (25% of body weight) at 4 knee flexion angles (0 degrees , 20 degrees , 40 degrees and 60 degrees ). Using the axial images, patellar alignment (lateral displacement and tilt) and femoral trochlear geometry (sulcus angle and inclination of the lateral femoral trochlea) were measured. Patellar height (Insall-Salvati ratio) was measured on reconstructed sagittal plane images. RESULTS: Stepwise regression analysis revealed that at 0 degrees of knee flexion, the height of the patella was the best predictor of lateral patellar tilt while the lateral trochlea inclination angle was the best predictor of lateral patellar displacement. Lateral trochlear inclination was the best predictor of patellar lateral displacement and tilt at 20 degrees , 40 degrees and 60 degrees of knee flexion. CONCLUSION: Similar to a previous study performed under non-weight bearing condition, our findings suggest that lateral trochlear inclination is an important determinant of patellar alignment in weight bearing. LEVEL OF EVIDENCE: Level III. PMID- 24071369 TI - Primary closure using Redon drains for the treatment of post-sternotomy mediastinitis. AB - OBJECTIVES: Post-sternotomy mediastinitis is a severe complication of open heart surgery resulting in prolonged hospital stay and increased mortality. Vacuum assisted closure is commonly used as treatment for post-sternotomy mediastinitis, but has some disadvantages. Primary closure over high vacuum suction Redon drains previously has shown to be an alternative approach with promising results. We report our short- and long-term results of Redon therapy-treated mediastinitis. METHODS: We performed a retrospective analysis of 124 patients who underwent primary closure of the sternum over Redon drains as treatment for post-sternotomy mediastinitis in Amphia Hospital (Breda, Netherlands) and St. Antonius Hospital (Nieuwegein, Netherlands). Patient characteristics, preoperative risk factors and procedure-related variables were analysed. Duration of therapy, hospital stay, treatment failure and mortality as well as C-reactive protein and blood leucocyte counts on admission and at various time intervals during hospital stay were determined. RESULTS: Mean age of patients was 68.7 +/- 11.0 years. In 77.4%, the primary surgery was coronary artery bypass grafting. Presentation of mediastinitis was 15.2 +/- 9.8 days after surgery. Duration of Redon therapy was 25.9 +/- 18.4 days. Hospital stay was 32.8 +/- 20.7 days. Treatment failure occurred in 8.1% of patients. In-hospital mortality was 8.9%. No risk factors were found for mortality or treatment failure. The median follow-up time was 6.6 years. One- and 5-year survivals were 86 and 70%, respectively. CONCLUSIONS: Primary closure using Redon drains is a feasible, simple and efficient treatment modality for post-sternotomy mediastinitis. PMID- 24071370 TI - Meniscus tear patterns in relation to skeletal immaturity: children versus adolescents. AB - BACKGROUND: Meniscus tear patterns in the pediatric population have not been well described. PURPOSE: To delineate the pattern of meniscus tears and the likelihood of repair at the time of surgery in both children and adolescents. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A retrospective review was performed on all patients between the ages of 10 and 19 years who underwent arthroscopic surgery for a meniscus injury at a single institution. Patients with open growth plates were classified as children, while those with closed growth plates were classified as adolescents. Demographic data were documented, including age, sex, body mass index (BMI), mechanism of injury, and time from injury to surgery. Operative reports and intraoperative photographs were used to assess the tear pattern (type, location, zone) as well as all concomitant procedures and injuries. Tears were classified as discoid, vertical, bucket handle, radial, oblique, horizontal, fray, root detachment, or complex. RESULTS: Of the 293 patients reviewed, 197 (67%) had lateral meniscus tears, 65 (22%) had medial meniscus tears, and 31 (11%) had tears to both menisci. The cohort was separated into 119 (41%) children (mean age, 13.5 years) and 174 (59%) adolescents (mean age, 16.4 years). Children were more likely to have discoid meniscus tears, lower BMI, and meniscus injuries not associated with ligamentous injuries (P < .05). The rate of associated ligament injuries in children was 28% compared with 51% in adolescents. Overall, the most frequent tear pattern was complex (28%), followed by vertical (16%), discoid (14%), bucket-handle (14%), radial (10%), horizontal (8%), oblique (5%), fray (3%), and root detachment (2%). Complex tears were associated with boys (32% vs 20% in girls; P < .03) and greater mean BMI (27.4 vs 25.1 kg/m(2) in those with noncomplex tears; P < .002), even when taking sex into account. Surgical repair was performed in 47% of all cases (56% in those treated within 3 months of injury vs 42% in those treated after 6 months; P < .03), and there was no difference in the repair rate between the two age groups (49% in children vs 46% in adolescents; P > .05). CONCLUSION: Adolescents and children sustain more complex meniscus injuries that are often less repairable than previously reported in the literature. Factors that are associated with greater tear complexity include male sex and obesity. Our findings also suggest that the earlier treatment of meniscus tears may increase the likelihood of repair in younger patients. PMID- 24071371 TI - Inflammatory mediators from monocytes down-regulate cellular proliferation and enhance cytokines production in patients with polar clinical forms of Chagas disease. AB - Exposure to Trypanosoma cruzi parasites induces monocytes and macrophages to produce various endogenous mediators, including prostaglandins and cytokines. To clarify the involvement of monocytes as an important source of inflammatory mediators in Chagas disease patients, we evaluated PBMC before and after depletion of adherent cells (monocytes) from patients with indeterminate (IND) and cardiac (CARD) clinical forms and from non-infected individuals (NI). We demonstrated that after the partial depletion of adherent cells, production of PGE2 was slightly decreased in patients with Chagas disease. Inhibition of the cells by indomethacin increased the proliferation in PBMC cells from patients after antigen stimulation. Pro-inflammatory cytokines as IL-2 and IFN-gamma also had a greater decrease after partial depletion of adherent cells in both clinical forms of Chagas disease. IL-10 and IL-5 levels were also reduced after partial depletion of adherent cells both in IND and CARD patients. In addition, we evaluated the APC potential of B cells and observed that the MHCII and CD80 molecules had an increased expression after partial depletion of most monocytes in all groups. Thus, inflammatory mediators produced by monocytes seem to be important to modulate immune responses in Chagas disease by regulating the processes of inflammation and antigen presentation. PMID- 24071372 TI - Carpentering in septorhinoplasty: a novel technique to straighten the deviated nasal septum. AB - Septal deviation presents a considerable challenge in septorhinoplasty because it leads to functional and esthetic problems. This deformity may displace the nasal tip, disturb nasal valve patency, and affect the final outcomes of septorhinoplasty. This report describes an innovative technique that can be used in patients with C-shaped deviation of the septum in a cephalocaudal direction. Because the procedure is similar to carpentering, it was named a "carpenter spreader graft." In this technique, the deviated dorsal cartilage is separated and displaced to a new straightened position. PMID- 24071373 TI - An experimental study addressing the promotion of mandibular defect repair through the intermittent subcutaneous injection of parathyroid hormone. AB - PURPOSE: Parathyroid hormone (PTH) is a major regulator of bone metabolism. Various animal studies and clinical trials have addressed the treatment of osteoporosis and fracture healing with the intermittent administration of PTH, whereas few studies have investigated the effects of PTH on mandibular defect repair. This study sought to examine the feasibility of using recombinant human PTH (rhPTH) to promote the repair of mandibular defects and to provide a preliminary investigation of the underlying mechanisms of this phenomenon. MATERIALS AND METHODS: A mandibular defect model was established using Japanese white rabbits. The experimental animals were randomly divided into a control group that received postoperative subcutaneous injections of normal saline on alternate days and an experimental group that received postoperative subcutaneous injections of rhPTH 25 MUg on alternate days. The experimental animals were sacrificed at 1, 2, 3, and 4 weeks after the operation to perform x-ray imaging and bone histomorphometric examinations of the defect areas. Changes in serum levels of bone-specific alkaline phosphatase (bALP) and osteoprotegerin (OPG) over time were examined. RESULTS: Compared with the control group, the experimental group exhibited newly generated bone matrix in the mandibular defect area at earlier stages. In the experimental group, the bone trabeculae were arranged in an orderly manner, and uniform calcification was observed. Marked hyperplasia of osteoblasts was observed in the new bone tissue of the experimental group, but significantly less hyperplasia of osteoblasts was observed in the control group. In the 2 groups, the average serum bALP and OPG levels increased after the operation and then gradually decreased. In the experimental group, levels of bALP and OPG at 1 week and 2 weeks after the operation were significantly different from preoperative levels. In the control group, the OPG level at 2 weeks after the operation was significantly different from the preoperative OPG level. A comparison of serum bALP and OPG levels at each examined time point showed no significant difference between the 2 groups. CONCLUSION: The intermittent subcutaneous injection of rhPTH 25 MUg/day promotes the healing of mandibular defects in rabbits. The application of rhPTH may facilitate mandible regeneration by increasing quantities of osteoblasts, accelerating bone turnover metabolism, and upregulating OPG levels. PMID- 24071374 TI - Condylar positional changes up to 12 months after bimaxillary surgery for skeletal class III malocclusions. AB - PURPOSE: Postsurgical changes in the condylar position are of great importance to surgical stability, especially in asymmetric double-jaw surgery. The aims of this study were to evaluate positional changes of the condyle up to 12 months after surgery in patients with Class III malocclusion and to identify the factors affecting postsurgical condylar position. MATERIALS AND METHODS: The study included 33 adult patients diagnosed with skeletal Class III malocclusion who underwent bimaxillary surgery and had full cone-beam volumetric imaging (CBVI) records up to 1 year after surgery. The CBV images were obtained before surgery and 2 weeks, 3 months (T2), 6 months (T3), and 12 months after surgery. Condyles with deviated and nondeviated sides were examined separately regardless of the degree of asymmetry. Analyses of variance and multiple regression analysis were performed to identify factors that could affect the position of the mandibular condyles. RESULTS: The condyles exhibited anterior displacement at T2, which returned to a more distal position afterward in the axial view, and an inward rotation in the coronal view up to T3. From the sagittal view, the deviated and nondeviated condylar sides rotated forward and remained stable after T2. The degree of menton deviation affected the angle of condylar rotation (horizontal angle). CONCLUSION: The results of this study suggest that condyles tend to move in a certain direction, and this can influence postsurgical relapse up to 6 months after surgery. However, they remain relatively stable afterward. PMID- 24071375 TI - Decompression as a treatment for odontogenic cystic lesions of the jaw. AB - PURPOSE: To evaluate the effectiveness of decompression as the primary treatment of odontogenic cystic lesions of the jaw involving factors that affect relative shrinking speed and bone regeneration. PATIENTS AND METHODS: A total of 32 patients with odontogenic cystic lesions of the jaw underwent decompression with customized thermoplastic resin stents. Clinical examinations and pre- and postdecompression panoramic radiographs were analyzed. RESULTS: The mean relative speed of shrinkage of radicular cysts (RCs; 3.37 cm(2)/month) was faster than those of keratocystic odontogenic tumors (KCOTs; 2.87 cm(2)/month) and unicystic ameloblastomas (UABs; 2.71 cm(2)/month). The relative shrinking size increased linearly in a time-dependent manner for KCOTs (r = 0.849, P < .001), RCs (r = 0.681, P = .319), and UABs (r = 0.146, P = .730); a similar relation was detected between the primary radiolucent area of cystic lesions before decompression and relative shrinking speed after decompression in KCOTs (r = 0.481, P = .032), RCs (r = 0.260, P = .673), and UABs (r = 0.370, P = .366), but patient age did not affect the relative speed of shrinkage (P > .05). Furthermore, the increase in bone density was more significant in RCs than in KCOTs (P = .026) and UABs (P = .012) after decompression. CONCLUSION: Decompression was effective in reducing odontogenic cystic lesions of the jaw and increasing bone density. For aggressive lesions, secondary definitive surgery was necessary. PMID- 24071377 TI - Radiological infrabony defects after impacted mandibular third molar extractions in young adults. AB - PURPOSE: To estimate the prevalence of infrabony defects and their healing at the distal aspect of mandibular second molars (M2s) after extraction of impacted mandibular third molars (M3s). MATERIALS AND METHODS: This prospective clinical study included 22 young healthy patients (21.03 +/- 4.51 yr old). Thirty-seven surgical extractions of high-risk periodontal and mesioangular impacted M3s in close contact with adjacent M2s were performed. Radiographic bone height (RBH), radiographic infrabony defects (RIDs), and bone loss (BL) were recorded at baseline and 3, 6, and 12 months after surgery. RBH and RIDs were measured from the tip of a periodontal gauge to the root apex and to the cementoenamel junction of the M2, respectively; BL was calculated by dividing the length of the M2 root into thirds and categorized as slight, moderate, or severe. RESULTS: Only 26 extracted teeth were included in all radiographic assessments. Mean RID size at baseline was 4.54 +/- 1.87 mm. At 12 months, an average recovery of 2.80 +/- 2.36 mm (P < .001) was recorded, for a mean RID size of 1.78 +/- 1.65 mm. Statistically significant differences in RBH and RIDs were found at all assessments (P < .05). Improved bone healing was registered during the postoperative period, with higher values during the first 3 months (1.3 mm; P < .01). Most RIDs of at least 4 mm associated with moderate or slight BL decreased to no larger than 3 mm without BL. For moderate BL, the bone gain pattern was gradual and continuous, whereas for slight BL, the pattern was variable. CONCLUSIONS: In young healthy patients, a high-risk periodontal impacted M3 leads to an RID of at least 4 mm associated with slight or moderate BL at the distal aspect of the M2, which decreases to no larger than 3 mm 12 months after surgery. Bone healing is clinically and statistically significant at 12 months, with the most notable changes at the first 3-month follow-up. PMID- 24071376 TI - Nicardipine infusion for hypotensive anesthesia during orthognathic surgery has protective effect on renal function. AB - PURPOSE: Hypotensive anesthesia may adversely affect renal function. The purpose of this study was to evaluate the renoprotective effect of nicardipine in patients undergoing orthognathic surgery under hypotensive anesthesia. MATERIALS AND METHODS: In this double-blinded randomized controlled study, healthy patients undergoing orthognathic surgery were enrolled to evaluate renal function during and after hypotensive anesthesia. The predictor variable was the agent, nicardipine vs remifentanil, used to maintain mean arterial pressure at 50 to 65 mm Hg. Primary outcome variables were renal function markers and secondary outcome variables were hemodynamic data, which were measured before hypotension, 2 hours after hypotension, 1 hour postoperatively (t3), and 24 hours postoperatively. Linear mixed model was used to analyze repeatedly measured data. RESULTS: Forty-six patients were randomly allocated to receive remifentanil (R group; n = 23) or nicardipine (N group; n = 23). The renal tubular function marker, urinary N-acetyl-1-beta-D-glucosaminidase (NAG), was lower at t3 in the N group than in the R group (P = .014). In the N group, fractional excretion of sodium was significantly higher at t3 compared with baseline (P < .0001). The 2 groups did not show any differences in estimated creatinine clearance and serum cystatin C. CONCLUSION: Subclinical and reversible renal dysfunction appears during hypotensive anesthesia in patients undergoing orthognathic surgery. Continuous infusion of nicardipine attenuated the increase in NAG, which is a marker of renal tubular injury, during hypotensive anesthesia with desflurane and remifentanil. PMID- 24071378 TI - Correlation between Schneiderian membrane perforation and sinus lift graft outcome: a retrospective evaluation of 359 augmented sinus. AB - PURPOSE: The aim of this study was to estimate the incidence of sinus membrane perforation in maxillary sinus augmentation surgery using a lateral approach and the impact of sinus integrity on incidence of sinusitis and bone graft survival in the maxillary sinus. PATIENTS AND METHODS: A total of 359 sinus augmentation procedures (208 patients) were evaluated retrospectively for sinus integrity during augmentation, complications, graft failure, and implant loss. RESULTS: The incidence of sinus membrane perforation was 41%. There was an overall sinus graft failure rate of 6.7%; of the failed sinus grafts, 70.8% had a perforated sinus membrane at augmentation. There were 11.3% of sinuses with perforated membranes at graft placement that failed compared with 3.4% of sinuses with intact membranes failing (general linear model [GLM], P = .003). Age, gender, and provider type were not significantly associated with sinus integrity at 1 year. Overall, 11.3% of sinuses with perforated membranes at graft placement required secondary antibiotics for sinusitis and infection compared with 1.4% of sinuses with intact membranes (GLM, P < .0006). Of the sinuses requiring secondary antibiotics, 30% failed compared with 5% of untreated sinuses (GLM, P = .0071). Of the sinuses developing sinusitis or secondary infection requiring antibiotics, 85% had a membrane perforation during augmentation compared with 39.2% of those not requiring antibiotics; gender, age, and provider were not associated with antibiotic use. CONCLUSIONS: In the present study, antibiotic use for postoperative sinusitis and infection and graft failure were shown to be statistically higher in sinuses with perforated membranes at augmentation. PMID- 24071379 TI - Lethal action of the nitrothiazolyl-salicylamide derivative nitazoxanide via induction of oxidative stress in Leishmania (L.) infantum. AB - Studying the cellular death pathways in Leishmania is an important aspect of discovering new antileishmanials. While using a drug repositioning approach, the lethal action of the nitrothiazolyl-salicylamide derivative nitazoxanide (NTZ) was investigated against Leishmania (L.) infantum. The in vitro antileishmanial activity and cytotoxicity were assessed using both parasite stages and mammalian NCTC cells, respectively. The lethal action of NTZ was investigated by detecting the phosphatidylserine (PS) exposure, reactive oxygen species (ROS) regulation, plasma membrane permeability, mitochondrial membrane potential and ultrastructural modifications by transmission electron microscopy. NTZ's activity against L. infantum was confirmed, producing IC50 values of 42.71MUg/mL against promastigotes and 6.78MUg/mL against intracellular amastigotes. NTZ rapidly altered the cellular metabolism of promastigotes by depolarising the mitochondrial membrane and up-regulating the reactive oxygen species (ROS). In addition, the flow cytometry data revealed an intense and time-dependent exposure of PS in promastigotes. When using SYTOX((r)) Green as a fluorescent probe, NTZ demonstrated no interference in plasma membrane permeability. The ultrastructural alterations in promastigotes were time-dependent and caused chromatin condensation, plasma membrane blebbing and mitochondrial swelling. These data suggest that NTZ induced oxidative stress in L. (L.) infantum and might be a useful compound for investigating new therapeutic targets. PMID- 24071380 TI - Imperviousness as a predictor for infestation levels of container-breeding mosquitoes in a focus of dengue and Saint Louis encephalitis in Argentina. AB - Dengue and Saint Louis encephalitis virus are among the most important emerging viruses transmitted by mosquitoes at the global scale, and from 2009 onward both diseases have reached temperate Argentina. To test whether the urbanization level can be used as a predictor for the infestation levels of container-breeding mosquito vectors, we searched for Aedes aegypti and Culex pipiens in 8400 water filled containers from 14 cemeteries of Buenos Aires Province and we used generalized linear models to relate positive containers with the impervious area quantified inside (internal PIA) and outside (external PIA) cemeteries. The best model for Ae. aegypti explained 91% of the variability and included the season, the internal PIA and the external PIA at 1km as a quadratic function, showing a parabolic response peaking in ~75%. Regarding the infestation levels of Cx. pipiens, the final model explained 75% of the variability and included only the season. In view of these results, the percentage of impervious area efficiently predicted the infestation levels of Ae. aegypti but not of Cx. pipiens. Considering the worldwide relevance of the former in dengue transmission, the simple quantification of imperviousness proposed herein provides a helpful basis for vector surveillance and control in urbanized areas. PMID- 24071381 TI - Cangrelor infusion is associated with an increased risk for bleeding: meta analysis of randomized trials. AB - CONTEXT: Aggressive antiplatelet strategies unquestionably cause extra hemorrhagic risks. Bleeding episodes are associated with poor outcomes including increased mortality. However, lack of uniform reporting and adjudication of bleeding events might prevent objective evaluation of the efficacy/safety profile of antithrombotic agents. OBJECTIVE: We analyzed the bleeding rates by several previously used bleeding scales (TIMI, GUSTO, ACUITY, and BARC) after cangrelor in recent head-to-head randomized, controlled clinical trials (RCTs). RESULTS: Data for meta-analyses were pooled from 3 RCTs (CHAMPION-PLATFORM, CHAMPION-PCI and CHAMPION-PHOENIX) including 25,106 patients. In addition, the bleeding risks were also assessed from the small (n=210) BRIDGE RCT. Cangrelor caused a significantly increased risk for major bleeding at 48 h according to the ACUITY scale (RR: 1.51, 95% CI: 1.32-1.72, p<0.00001); however, this impact was less prominent according to less sensitive bleeding scales (GUSTO severe: RR: 1.21, 95% CI: 0.70-2.11, p=0.49; TIMI major: RR: 1.00, 95% CI: 0.59-1.68, p=0.99). There was also an obvious trend towards an increased risk for any transfusions (RR: 1.31, 95% CI: 0.97-1.77, p=0.08) and TIMI major+minor bleeding events (RR: 1.30, 95% CI: 0.96-1.76, p=0.09). CONCLUSIONS: Cangrelor on top of aspirin or/and clopidogrel increases the risk for early bleeding events after PCI; however, it largely depends on the bleeding definition used, and how this excess risk of bleeding was captured. The bleeding hazard needs to be verified in the ongoing FDA secondary cangrelor review. PMID- 24071382 TI - The impact of co-morbidities on the wealth of people with heart disease. PMID- 24071383 TI - Response to the letter "Worsened diastology after radiofrequency catheter ablation in AF patients: more touches more stiff left atrium". PMID- 24071384 TI - Is vernakalant better or not, compared with other treatments for conversion of acute atrial fibrillation? AB - Vernakalant has proved to be more rapid in converting recent onset AF to sinus rhythm compared to placebo, amiodarone, propafenone and flecainide. In many centers around the world the electrical cardioversion is the first line of treatment of acute atrial fibrillation. Recently a group published that vernakalant had a 90% conversion rate in patients with recent onset atrial fibrillation without structural heart disease versus 100% conversion rate in the electrical cardioversion group. In this study there was no statistical differences between both groups (p=NS). Vernakalant has been approved in Europe and South America, but it has not been approved in the United States and Canada. FDA wants a megatrial to show the real benefits of vernakalant compared to other drugs including electrical cardioversion. The trial ACT V has been canceled because one patient who received vernakalant died and this is the reason why FDA has not approved vernakalant yet. We do not know the real condition of the patient and if it was corrected to conclude that the severe adverse event had a direct relationship with the drug. I can conclude that it is time to design a megatrial to show if vernakalant is better or not for conversion of recent onset atrial fibrillation compared with other antiarrhythmic drugs and electrical cardioversion because all the topics about this drug have been published but in brief reports. We need a big trial to know the real safety of this drug. PMID- 24071385 TI - Early- and late-term clinical outcome and their predictors in patients with ST segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction. AB - BACKGROUNDS: The disparity between ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) remains controversial. We compared clinical outcomes and prognostic factors between STEMI and NSTEMI using large-scale registry data. METHODS: We recruited 28,421 patients with STEMI (n=16,607) and NSTEMI (n=11,814) between November 2005 and April 2010 from a nationwide registry in Korea. We performed landmark analysis of cardiac death, recurrent acute myocardial infarction (re-AMI), revascularization, and major adverse cardiac events (MACE) at 30 days (early term) and 1 year (late term) after admission. RESULTS: Patients with NSTEMI had a greater number of co-morbidities than STEMI patients. Early term MACE (6.9% vs. 4.5%, p<0.001) and cardiac death (6.1% vs. 3.7%, p<0.001) were higher in STEMI patients. However, late-term MACE (8.0% vs. 9.1%, p=0.007), cardiac death (1.9% vs. 2.6%, p=0.001), and re-AMI (0.6% vs. 1.3%, p<0.001) were lower in the STEMI group. The independent predictors of cardiac death were old age, renal dysfunction, LV dysfunction, Killip class, post thrombolysis in myocardial infarction (TIMI) flow, and major bleeding in both groups. Female gender, previous ischemic heart disease, diabetes, current smoking, multivessel disease, and body mass index were MI type- or time-dependent predictors. CONCLUSION: The STEMI group displayed poor early term clinical outcome, whereas the NSTEMI group displayed poor late-term clinical outcome. The STEMI and NSTEMI groups had different predictor profiles for cardiac death, suggesting that different strategies are required for improving the late-term outcome of STEMI and NSTEMI patients. PMID- 24071386 TI - Percutaneous patent foramen ovale occlusion: current evidence and evolving clinical practice. AB - Patent foramen ovale (PFO) has long been implicated with cryptogenic stroke, migraine and decompression illness. PFO is common and its implicated pathologies cause devastating neurological sequelae; and hence have drawn the attention of medical practitioners across disciplines. The pathogenesis is hypothesized to be caused by micro-emboli or neuro-hormones which would otherwise being filtered by the lungs, astraying into the systemic circulation via the atrial communication especially during Valsalva maneuver. Treatment options have been proposed; among others are medical therapy, PFO closure or both. While medical therapy as secondary prevention is being adopted by most centers in the world, PFO closure is performed in selected patients only. The reason being is that most studies linking PFO to these pathologies are observational in nature. And these associations do not equate to a firm cause and effect relationship. For causal relationship to be established, good quality prospective data is required. Recently, there has been emergence of new prospective trials which improve the understanding of PFO closure in these pathologies. This article reviews the associations between PFO and the three main implicated pathologies as well as the evidence for PFO closure in the current era. PMID- 24071388 TI - China's little emperors: medical consequences of China's one-child policy. PMID- 24071387 TI - Postoperative arrhythmias in adults with congenital heart disease: incidence and risk factors. AB - BACKGROUND: Little is known about the clinical impact of arrhythmias after surgery for congenital heart disease (CHD) in adults. Therefore, we investigated the prevalence of in-hospital arrhythmias after CHD surgery and their impact on clinical outcome. METHODS: This was a multicenter retrospective study and included adults who underwent congenital cardiac surgery between January 2009 and December 2011. Clinical events were defined as all cause mortality, heart failure (HF) requiring medical treatment, thrombo-embolic event, major infections and permanent pacemaker (PM) implantation. RESULTS: Overall, 419 patients were included (mean age 38 +/- 14 years, 55% male). Arrhythmias occurred in 134 patients (32%) and included supraventricular tachycardia (SVT, n = 100), bradycardias (n = 47) and ventricular tachycardia (VT, n = 19). In multivariate analysis age >=40 years at surgery (OR 2.48, 95% Cl 1.40-4.60, P = 0.003), NYHA class >= II (OR 2.42, 95% Cl 1.18-4.67, P = 0.009), significant subpulmonary AV valve regurgitation (OR 2.84, 95% Cl 1.19-6.72, P = 0.018), coronary bypass time (OR 1.35/60 minute increase, 95% Cl 1.06-1.82, P = 0.019) and CK-MB (OR 1.05 per 10 U/L increase, 95% Cl 1.01-1.09, P = 0.021) were associated with in-hospital arrhythmias. Overall, 58 clinical events occurred in 55 patients (13%) and included in the majority of the cases permanent PM implantation (5%), HF (4%) and death (2%). In-hospital arrhythmias were independently associated with clinical events (OR 7.80, 95% CI 2.41-25.54, P = 0.001). CONCLUSION: Arrhythmias are highly prevalent after congenital heart surgery in adults and are associated with worse clinical outcome. Older and symptomatic patients with significant valvular heart disease at baseline are at risk of in-hospital arrhythmias. PMID- 24071389 TI - Diagnostic value of ultrasound and computed tomographic arthrography in diagnosing anterosuperior acetabular labral tears. AB - PURPOSE: This study investigated the sensitivity, specificity, and accuracy of ultrasound as well as the computed tomography arthrography (CTA) findings and arthroscopic findings for the diagnosis of anterosuperior acetabular tear and correlated tear types using the Lage classification system on ultrasound and CTA compared with the arthroscopic findings. METHODS: We retrospectively reviewed the results of ultrasonographic examinations conducted before injection and after injection of contrast for subsequent CTA in 36 hips (34 patients; 24 men [71%] and 10 women [29%]; mean age, 36 years). All patients had chronic groin pain and a positive impingement test. We analyzed the sensitivity, specificity, and accuracy before injection, after injection, and at CTA and compared these with findings with the arthroscopic findings. Interobserver agreement and intraobserver reproducibility of the presence of a tear and tear type in the anterosuperior quadrant of the acetabular labrum on ultrasonography and CTA were calculated by use of kappa coefficients. RESULTS: The sensitivity, specificity, and accuracy for sonographic detection of labral tear before injection/after injection were 58%/79%, 67%/58%, and 61%/72%, respectively, for observer 1 and 75%/92%, 25%/42%, and 58%/75%, respectively, for observer 2. The sensitivity, specificity, and accuracy for CTA detection of labral tears were 96%, 92%, and 94%, respectively, for observer 1 and 88%, 92%, and 89%, respectively, for observer 2. When the sonographic classification was compared with the arthroscopic findings of observer 1 and observer 2, the accuracy before injection/after injection was only 53%/67% and 58%/75%, respectively. The accuracy of morphologic classification of CTA and arthroscopic findings of observer 1 and observer 2 was 83% and 75%, respectively. Interobserver correlation before injection and at CTA was poor (kappa = 0.056) and moderate (kappa = 0.642), respectively. CONCLUSIONS: Although intra-articular injection during sonographic examination could improve diagnosis of labral tears, sonographic examination as a diagnostic technique is still of limited use. However, CTA shows reliable validity in the diagnosis of acetabular labral tears. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24071390 TI - Comparison of subjective and objective outcomes after rotator cuff repair. AB - PURPOSE: To determine whether subjective (pain by visual analog scale) or objective (strength by dynamometer) measures correlate with disease-specific measures and quality-of-life metrics in arthroscopic rotator cuff repair. METHODS: The study population included patients who underwent primary arthroscopic rotator cuff repair at a single institution between 2006 and 2009. Within these parameters, data from 166 patients was obtained. Data were collected prospectively and reviewed retrospectively. Preoperative and 1-year postoperative data were compared. Correlation was determined in (1) disease-specific metrics including American Shoulder and Elbow Surgeons (ASES) score, Constant score (CS), and Simple Shoulder Test (SST) score and (2) quality of life measured by the Short Form 12. RESULTS: Preoperative strength and pain are closely associated with postoperative changes (P < 1 * 10(-5), with beta coefficients of 0.8 to 1.0). Change in ASES score was most closely associated with change in pain and change in CS with change in strength (R(2) = 0.82 and R(2) = 0.54, respectively). Only the SST score was found to be statistically linked to changes in both strength and pain (P < .05). CONCLUSIONS: Patients, despite sex and age, with good preoperative strength and high preoperative pain will benefit most from arthroscopic rotator cuff repair. The CS best captures changes in strength, and the ASES score best captures changes in pain. Only changes in the SST score show a statistically significant link with changes in both strength and pain. LEVEL OF EVIDENCE: Level IV. PMID- 24071436 TI - Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency. AB - BACKGROUND: Guanidinoacetate methyltransferase (GAMT) deficiency causes cerebral creatine deficiency. Patients can have autistic behavior, seizures, intellectual disability, and severe speech delay. The goal of therapy is to increase creatine while reducing potentially neurotoxic guanidinoacetate concentrations. Here we evaluate how different therapies affect plasma guanidinoacetate levels in patients with GAMT deficiency. METHODS: Retrospective analysis of data from five new patients with GAMT deficiency (four with delays and seizures, one diagnosed at birth). RESULTS: The four symptomatic patients had decreased brain creatine by magnetic resonance spectroscopy and three also had abnormal globi pallidi by MRI. GAMT sequencing identified four previously reported mutations and one novel missense mutation (c.233T>A/p.V78E). Treatment with creatine (250-1000 mg/kg/day), ornithine (100-800 mg/kg/day), and sodium benzoate (50-135 mg/kg/day) supplements along with dietary protein restriction (0.8-1.5 g/kg/day) improved seizures and development with all patients becoming verbal. The patient treated at birth remains developmentally normal. Reduction in glycine and increase in ornithine levels significantly decreased plasma guanidinoacetate, with glycine levels being the best predictor of guanidinoacetate levels. In contrast, arginine levels were not significantly correlated with plasma guanidinoacetate. CONCLUSIONS: Our results show that supplements of creatine, sodium benzoate (to reduce glycine) and ornithine reduce guanidinoacetate levels in patients with GAMT deficiency (dietary therapy was not evaluated in our study). Normal development with early therapy renders GAMT deficiency an ideal candidate for inclusion in newborn screening panels. PMID- 24071437 TI - Neurocognitive functioning in adults with phenylketonuria: results of a long term study. AB - OBJECTIVES: A controlled long-term study was performed to assess the neurological and neuropsychological performance in adult patients with early-treated phenylketonuria (PKU). METHODS: We investigated 57 patients with early-treated classical PKU aged 19 to 41 years (mean age 31 years) and 46 matched healthy controls, matched for age and socioeconomic status. Patients and controls were assessed for their intelligence quotient (IQ), and attention and information processing abilities. Magnetic resonance imaging (MRI) of the brain was performed in all patients. Neuropsychological assessments and MRI were repeated at a five year-follow-up. RESULTS: In the five-year interval IQ, information processing and attention of patients and controls remained constant. At both assessment times the IQ scores were significantly lower in patients compared to controls. Older adult patients (>32 years) showed poorer information processing and attention at both assessment times compared to young adult patients (<32 years) and controls. IQ, information processing and attention showed no correlation to imaging results but were significantly correlated to blood phenylalanine (Phe) levels in patients' childhood and adolescence, and Phe levels had been higher in the adolescent years of older adult patients. CONCLUSIONS: Cognitive performance in adult patients with early-treated PKU does not seem to be subject to deterioration observable in a five-year interval. Neuropsychological assessment in adults with PKU revealed neurocognitive impairment particularly in older adult patients. This seems to refer to an early relaxation of diet that was recommended when the older patients were adolescents. Results indicate a benefit of dietary control during adolescence in PKU. PMID- 24071438 TI - [Lupus-like associated with chronic granulomatous disease]. PMID- 24071440 TI - Does augmentation or induction of labor with oxytocin increase the risk for autism? PMID- 24071441 TI - Biological and chemical reactivity and phosphorus forms of buffalo manure compost, vermicompost and their mixture with biochar. AB - This study characterized the carbon and phosphorus composition of buffalo manure, its compost and vermicompost and investigated if presence of bamboo biochar has an effect on their chemical and biological reactivity. The four substrates were characterized for chemical and biochemical composition and P forms. The biological stability of the four substrates and their mixtures were determined during an incubation experiment. Their chemical reactivity was analyzed after acid dichromate oxidation. Biological reactivity of these substrates was related to their soluble organic matter content, which decreased in the order buffalo manure>compost>vermicompost. Phosphorus was labile in all organic substrates and composting transformed organic P into plant available P. The presence of biochar led to a protection of organic matter against chemical oxidation and changed their susceptibility to biological degradation, suggesting that biochar could increase the carbon sequestration potential of compost, vermicompost and manure, when applied in mixture. PMID- 24071442 TI - Anaerobic co-digestion of the marine microalga Nannochloropsis salina with energy crops. AB - Anaerobic co-digestion of corn silage with the marine microalga Nannochloropsis salina was investigated under batch and semi-continuous conditions. Under batch conditions process stability and biogas yields significantly increased by microalgae addition. During semi-continuous long-term experiments anaerobic digestion was stable in corn silage mono- and co-digestion with the algal biomass for more than 200 days. At higher organic loading rates (4.7 kg volatile solids m(-3)d(-1)) inhibition and finally process failure occurred in corn silage mono digestion, whereas acid and methane formation remained balanced in co-digestion. The positive influences in co-digestion can be attributed to an adjusted carbon to nitrogen ratio, enhanced alkalinity, essential trace elements and a balanced nutrient composition. The results suggest that N. salina biomass is a suitable feedstock for anaerobic co-digestion of energy crops, especially for regions with manure scarcity. Enhanced process stability may result in higher organic loading rates or lower digester volumes. PMID- 24071443 TI - Tumoral FOXP3 has potential oncogenic function in conjunction with the p53 tumor suppressor protein and infiltrated Tregs in human breast carcinomas. AB - FOXP3 is a transcription factor and a well-known hallmark of immune suppressive T regulatory cells. Recent studies indicate that in tumor cells, FOXP3 plays an important role in tumor development in addition to its well-established Treg function in the immune system. We investigated tumoral FOXP3 expression in breast carcinoma, and the relationships between tumoral FOXP3 expression and p53, HER 2/ErbB2, Ki67, infiltrated Tregs, and other clinicopathological variables. Tissue samples from 272 cases of breast carcinoma were used. We assessed tumoral FOXP3, p53, HER-2/ErbB2, Ki67, and infiltrated Tregs using immunohistochemical staining. Positive expression of tumoral FOXP3 was observed in 38.6% (105/272) of breast carcinomas. Positive tumoral FOXP3 expression was significantly related with positive p53 and higher Ki67 expression. Higher histological grade was significantly correlated to increased tumoral FOXP3 expression. Tumoral FOXP3 expression was positively correlated with infiltrated FOXP3-expressing Tregs. From these data, we argue that tumoral FOXP3 has a potential oncogenic function in conjunction with the p53 tumor suppressor protein and infiltrated Tregs in human breast carcinomas. PMID- 24071444 TI - Sperm capacitation: a distant landscape glimpsed but unexplored. AB - Capacitation is a remarkable process whereby spermatozoa prepare themselves for engagement with the oocyte. Although the existence of this process has been appreciated as a biological phenomenon for more than half a century, its molecular underpinnings still await clarification. We know that some of the major changes involve sterol oxidation and efflux from the plasma membrane, the anterior movement of lipid rafts, changes in the surface expression of a variety of proteins including hyaluronidase and receptors for the zona pellucida, an increase in intracellular cyclic adenosine monophosphate (cAMP), the induction of tyrosine phosphorylation and the expression of hyperactivated motility. These changes are dependent on the presence of bicarbonate, to facilitate cAMP generation, maintain an alkaline intracellular pH and support an optimal level of reactive oxygen species generation and are enhanced by the presence of albumin to provide antioxidant protection to the plasma membrane and promote cholesterol efflux. In vivo, the rate at which sperm cells capacitate is carefully controlled in order to ensure that the release of capacitated spermatozoa from a post insemination reservoir in the isthmic region of the oviduct is synchronized with ovulation. The factors that control these critical events are now being resolved, aided by proteomic studies that are providing critical definitive information on the range of receptors that exist in the sperm plasma membrane and define the manner in which these exquisitely complex cells interact with their environment. Progress in this area has been enhanced by IVF technology pioneered by Bob Edwards and will ultimately facilitate the design of safe, effective culture conditions for optimization of this revolutionary therapy. PMID- 24071439 TI - The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. AB - Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Abeta) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Abeta at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late onset AD is and how to best treat it. PMID- 24071445 TI - Synthesis and biological evaluation of novel C-aryl d-glucofuranosides as sodium dependent glucose co-transporter 2 inhibitors. AB - Novel C-aryl-d-glucofuranosides were synthesized and evaluated for their capacity to inhibit human sodium-dependent glucose co-transporter 2 (hSGLT2) and hSGLT1. Compound 21q demonstrated the best in vitro inhibitory activity against SGLT2 in this series (EC50=0.62MUM). PMID- 24071446 TI - Design and bio-evaluation of indole derivatives as potent Kv1.5 inhibitors. AB - Atrial fibrillation (AF) is one of the common arrhythmias that threaten human health. Kv1.5 potassium channel is reported as an efficacious and safe target for the treatment of AF. In this paper, we designed and synthesized three series of compounds through modifying the lead compound RH01617 that was screened out by the pharmacophore model we reported earlier. All of the compounds were evaluated by the whole-patch lamp technology and most of them possessed potent inhibitory activities against Kv1.5. Compounds IIIi and IIIl were evaluated for the target selectivity as well as the pharmacodynamic effects in an isolated rat model. Due to the promising pharmacological behavior, compound IIIl deserves further pharmacodynamic and pharmacokinetic evaluations. PMID- 24071447 TI - Synthesis and structure-activity relationship of 2-phenyliminochromene derivatives as inhibitors for aldo-keto reductase (AKR) 1B10. AB - Inhibitors of a human member (AKR1B10) of the aldo-keto reductase superfamily are regarded as promising therapeutics for the treatment of cancer. Recently, we have discovered (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3 carboxamide (1) as the potent competitive inhibitor using the virtual screening approach, and proposed its 4-methoxy group on the 2-phenylimino moiety as an essential structural prerequisite for the inhibition. In this study, 18 derivatives of 1 were synthesized and their inhibitory potency against AKR1B10 evaluated. Among them, 7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3 carboxylic acid benzylamide (5n) was the most potent inhibitor showing a Ki value of 1.3nM. The structure-activity relationship of the derivatives indicated that the 7-hydroxyl group on the chromene ring, but not the 4-methoxy group, was absolutely required for inhibitory activity, The molecular docking of 5n in AKR1B10 and site-directed mutagenesis of the enzyme residues suggested that the hydrogen-bond interactions between the 7-hydroxyl group of 5n and the catalytic residues (Tyr49 and His111) of the enzyme, together with a pi-stacking interaction of the benzylamide moiety of 5n with Trp220, are important for the potent inhibition. PMID- 24071449 TI - Synthesis and biological evaluation of novel acylhydrazone derivatives as potential antitumor agents. AB - We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4 yl)anthranilic acid hydrazide, and some analogues bearing a (2 trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4 (diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI50 values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents. PMID- 24071448 TI - Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors. AB - The complexity of matrix metalloproteinase inhibitors (MMPIs) design derives from the difficulty in carefully addressing their inhibitory activity towards the MMP isoforms involved in many pathological conditions. In particular, specific metalloproteinases, such as MMP-2 and MMP-9, are key regulators of the 'vicious cycle' occurring between tumor metastases growth and bone remodeling. In an attempt to devise new approaches to selective inhibitor derivatives, we describe novel bisphosphonate bone seeking MMP inhibitors (BP-MMPIs), capable to be selectively targeted and to overcome undesired side effects of broad spectrum MMPIs. In vitro activity (IC50 values) for each inhibitor was determined against MMP-2, -8, -9 and -14, because of their relevant role in skeletal development and renewal. The results show that BP-MMPIs reached IC50 values of enzymatic inhibition in the low micromolar range. Computational studies, used to rationalize some trends in the observed inhibitory profiles, suggest a possible differential binding mode in MMP-2 that explains the selective inhibition of this isoform. In addition, survival assay was conducted on J774 cell line, a well known model system used to evaluate the structure-activity relationship of BPs for inhibiting bone resorption. The resulting data, confirming the specific activity of BP-MMPIs, and their additional proved propensity to bind hydroxyapatite powder in vitro, suggest a potential use of BP-MMPIs in skeletal malignancies. PMID- 24071450 TI - Stereotactic body radiotherapy in prostate cancer: is rapidarc a better solution than cyberknife? AB - AIMS: There is increasing interest in stereotactic body radiotherapy (SBRT) for the management of prostate adenocarcinoma, with encouraging initial biological progression-free survival results. However, the limited literature is dominated by the use of the Cyberknife platform. This led to an international phase III study comparing outcomes for Cyberknife SBRT with both surgery and conventionally fractionated intensity-modulated radiotherapy (the PACE study). We aim to compare Cyberknife delivery with Rapidarc, a more widely available treatment platform. MATERIALS AND METHODS: The scans of six previous prostate radiotherapy patients with a range of prostate sizes were chosen. The clinical target volume was defined as the prostate gland, with 3 mm added for the Cyberknife planning target volume (PTV) and 5 mm for the Rapidarc PTV. Accuray multiplan v. 4.5 was used for planning with delivery on a Cyberknife VSI system v9.5; Varian Eclipse v10 was used for Rapidarc planning with delivery using a Varian 21EX linear accelerator. Both systems attempted to deliver at least 35 Gy to the PTV in five fractions with PTV heterogeneity <12%. RESULTS: All organ at risk (OAR) constraints were achieved by both platforms, whereas the Cyberknife failed to achieve the desired PTV homogeneity constraint in two cases. In other OARs without constraints, Cyberknife delivered higher doses. The volume of the 35 Gy isodose was slightly larger with Rapidarc, but conversely at doses <35 Gy normal tissues received higher doses with Cyberknife. The mean planning and delivery time was in favour of Rapidarc. CONCLUSIONS: We have shown that there is no discernible dosimetric advantage to choosing Cyberknife over Rapidarc for SBRT delivery in prostate cancer. Given the significant benefits of Rapidarc in terms of availability, planning and delivery time, the authors suggest that phase III trials of SBRT should include Rapidarc or equivalent rotational delivery platforms. PMID- 24071451 TI - Two alpha-dicarbonyls downregulate migration, invasion, and adhesion of liver cancer cells in a p53-dependent manner. AB - BACKGROUND: Hepatocellular carcinoma accounts for more than 600,000 deaths per year due to it being a highly invasive tumor. The alpha-dicarbonyl, methylglyoxal demonstrates efficacy at reducing tumor burden, however the anti-cancerous activities of 3-deoxyglucosone, have never been studied. AIMS: To determine the anti-cancerous potential of methylglyoxal and 3-deoxyglucosone on liver tumor cells. METHODS: The in vitro effects of methylglyoxal and 3-deoxyglucosone were studied by investigating migration, invasion, and adhesion of Huh-7, HepG2, and Hep3B cells. RESULTS: 3-Deoxyglucosone inhibited migration of Huh-7 and HepG2 cells. Methylglyoxal decreased migration of HepG2 cells. Additionally, 3 deoxyglucosone and methylglyoxal impaired invasion, and adhesion of Huh-7 and HepG2 cells. In Hep3B cells, a p53 null cell line, 3-deoxyglucosone and methylglyoxal had no effect on migration, invasion, or adhesion. However, both compounds inhibited invasion of wild-type p53 transfected Hep3B cells. Silencing of p53 in Huh-7 and HepG2 cells abrogated the effects of the alpha-dicarbonyls on cell invasion. 3DG and MG did not alter p53 total protein but promoted nuclear translocation of p53. CONCLUSIONS: These studies suggest that 3-deoxyglucosone and methylglyoxal impair invasion, migration, and adhesion of hepatocellular carcinoma. The effects of both compounds on cell invasion are dependent on p53 and imply that alpha-dicarbonyls could be efficacious in the treatment of p53 expressing invasive liver tumors. PMID- 24071452 TI - Choosing Smads: smooth muscle origin-specific transforming growth factor-beta signaling. PMID- 24071453 TI - A MERry response after myocardial infarction. PMID- 24071454 TI - CEACAM1: an adhesion molecule that limits blood-brain barrier damage by neutrophils after stroke. PMID- 24071455 TI - The real decoy: an antidote for factor Xa-directed anticoagulants. PMID- 24071456 TI - Sarcoplasmic reticulum Ca-ATPase and heart failure 20 years later. PMID- 24071457 TI - Stefanie Dimmeler: passionate, persistent, and highly productive. Interview by Ruth Williams. PMID- 24071458 TI - Effect of omega-3 fatty acid supplementation on endothelial function, endogenous fibrinolysis and platelet activation in patients with a previous myocardial infarction: a randomised controlled trial. AB - OBJECTIVE: The mechanisms through which omega-3 fatty acids reduce adverse cardiac events remain uncertain. We aimed to investigate the effect of omega-3 fatty acid supplementation on endothelial vasomotor function, endogenous fibrinolysis, and platelet and monocyte activation in patients with coronary heart disease. DESIGN: Randomised, double-blind, placebo-controlled, cross-over trial. SETTING: Academic cardiac centre. PARTICIPANTS: 20 male patients with a previous myocardial infarction. INTERVENTION: omega-3 Fatty acid supplementation (2 g/day for 6 weeks) versus olive oil placebo. OUTCOME MEASURES: Peripheral blood was taken for analysis of platelet and monocyte activation, and forearm blood flow (FBF) was assessed in a subset of 12 patients during intrabrachial infusions of acetylcholine, substance P and sodium nitroprusside. Stimulated plasma tissue plasminogen activator (t-PA) concentrations were measured during substance P infusion. RESULTS: All vasodilators caused dose-dependent increases in FBF (p<0.0001). omega-3 Fatty acid supplementation did not affect endothelium dependent vasodilation with acetylcholine and substance P compared with placebo (p=0.5 and 0.9). Substance P caused a dose-dependent increase in plasma t-PA concentrations (p<0.0001), which was not affected by omega-3 fatty acid supplementation (p=0.9). omega-3 Fatty acids did not affect platelet-monocyte aggregation, platelet P-selectin or CD40L, or monocyte CD40. CONCLUSIONS: We have demonstrated that dietary supplementation with omega-3 fatty acids does not affect endothelial vasomotor function, endothelial t-PA release, or platelet and monocyte activation in patients with coronary heart disease. Cardiac benefits conferred by omega-3 fatty acids in coronary heart disease are unlikely to be mediated through effects on these systems. PMID- 24071459 TI - Depression and blood pressure in high-risk children and adolescents: an investigation using two longitudinal cohorts. AB - OBJECTIVE: To examine the relationship between blood pressure and depressive disorder in children and adolescents at high risk for depression. DESIGN: Multisample longitudinal design including a prospective longitudinal three-wave high-risk study of offspring of parents with recurrent depression and an on-going birth cohort for replication. SETTING: Community-based studies. PARTICIPANTS: High-risk sample includes 281 families where children were aged 9-17 years at baseline and 10-19 years at the final data point. Replication cohort includes 4830 families where children were aged 11-14 years at baseline and 14-17 years at follow-up and a high-risk subsample of 612 offspring with mothers that had reported recurrent depression. MAIN OUTCOME MEASURES: The new-onset of Diagnostic and Statistical Manual of Mental Disorder, fourth edition defined depressive disorder in the offspring using established research diagnostic assessments-the Child and Adolescent Psychiatric Assessment in the high-risk sample and the Development and Wellbeing Assessment in the replication sample. RESULTS: Blood pressure was standardised for age and gender to create SD scores and child's weight was statistically controlled in all analyses. In the high-risk sample, lower systolic blood pressure at wave 1 significantly predicted new-onset depressive disorder in children (OR=0.65, 95% CI 0.44 to 0.96; p=0.029) but diastolic blood pressure did not. Depressive disorder at wave 1 did not predict systolic blood pressure at wave 3. A significant association between lower systolic blood pressure and future depression was also found in the replication cohort in the second subset of high-risk children whose mothers had experienced recurrent depression in the past. CONCLUSIONS: Lower systolic blood pressure predicts new-onset depressive disorder in the offspring of parents with depression. Further studies are needed to investigate how this association arises. PMID- 24071460 TI - Where to buy OTC medications? A cross-sectional survey investigating consumers' confidence in over-the-counter (OTC) skills and their attitudes towards the availability of OTC painkillers. AB - OBJECTIVE: To examine consumers' confidence in their own, and also in other people's, over-the-counter (OTC) skills and to describe their attitude towards the availability of OTC painkillers. Moreover we examined the association between confidence in OTC skills and attitudes. DESIGN: Cross-sectional survey. Mixed methods (postal and electronic) self-administered questionnaire. PARTICIPANTS: Members of the Dutch Health Care Consumer Panel. MAIN OUTCOME MEASURES: Consumers' confidence in their own, and in other people's, OTC skills was examined. Confidence was measured by three questions regarding obtaining information on, choosing and using OTC medication. Consumers' attitudes towards availability were assessed using six safety profiles, by asking which channel consumers prefer for each profile. RESULTS: The response rate was 68% (n=972). Consumers feel confident about their own OTC skills (mean 3.74; 95% CI 3.69 to 3.79, on a 5-point Likert scale), but have less confidence in OTC skills of others (mean 2.92; 95% CI 2.88 to 2.96). Consumers are conservative in their attitudes towards the availability of OTC painkillers. Most consumers prefer painkillers to be available exclusively in pharmacies (41-71% per profile indicated pharmacy only). Moreover, there is an association between confidence in OTC skills and attitudes (p=0.005; beta=-0.114). Consumers who are more confident about their own OTC skills prefer OTC painkillers to be more generally available. CONCLUSIONS: Consumers feel confident about their own OTC skills. However, they would prefer painkillers with safety profiles resembling those currently available OTC, to be available as OTC in pharmacies exclusively. Consumers' confidence in the OTC skills of others is more consistent with their attitudes towards availability of OTC painkillers. Until consumers themselves realise that they are also one of the others, they may overestimate their own OTC skills, which may entail health risks. PMID- 24071461 TI - Protocol for a randomised controlled trial: efficacy of donepezil against psychosis in Parkinson's disease (EDAP). AB - INTRODUCTION: Psychosis, including hallucinations and delusions, is one of the important non-motor problems in patients with Parkinson's disease (PD) and is possibly associated with cholinergic neuronal degeneration. The EDAP (Efficacy of Donepezil against Psychosis in PD) study will evaluate the efficacy of donepezil, a brain acetylcholine esterase inhibitor, for prevention of psychosis in PD. METHODS AND ANALYSIS: Psychosis is assessed every 4 weeks using the Parkinson Psychosis Questionnaire (PPQ) and patients with PD whose PPQ-B score (hallucinations) and PPQ-C score (delusions) have been zero for 8 weeks before enrolment are randomised to two arms: patients receiving donepezil hydrochloride or patients receiving placebo. The patients are then followed for 96 weeks. The primary outcome measure is the time to the event, defined as getting 2 points or more on the PPQ-B score or PPQ-C score, which is assessed using a survival time analysis. The hypothesis being tested is that donepezil prevents psychosis in patients with PD. Efficacy will be tested statistically using the intention-to treat analysis including a log-rank test or Cox proportional hazard models. Secondary outcomes, such as changes of PPQ scores and Unified Parkinson's Disease Rating Scale scores from baseline will be assessed. ETHICS AND DISSEMINATION: Ethics approval was received from the Central Review Board of the National Hospital Organization, Tokyo, Japan. The trial was declared and registered to the Pharmaceuticals and Medical Devices Agency(PMDA), Japan (No. 22-4018). All participants will receive a written informed consent that was approved by the Central Review. A completed written informed consent is required to enrol in the study. Severe adverse events will be monitored by investigators and in cases where a severe adverse event was previously unreported, it will be reported to the PMDA. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000005403. PMID- 24071462 TI - Physical activity during pregnancy and offspring cardiovascular risk factors: findings from a prospective cohort study. AB - OBJECTIVES: The long-term consequences of maternal physical activity during pregnancy for offspring cardiovascular health are unknown. We examined the association of maternal self-reported physical activity in pregnancy (18 weeks gestation) with offspring cardiovascular risk factors at age 15. DESIGN: Prospective cohort study. SETTING: The Avon Longitudinal Study of Parents and Children (ALSPAC). PARTICIPANTS: 4665 maternal-offspring pairs (based on a sample with multiple imputation to deal with missing data) from the ALSPAC, a prospective cohort based in the South West of England with mothers recruited in pregnancy in 1991-1992. PRIMARY AND SECONDARY OUTCOME MEASURES: Offspring cardiovascular risk factors at age 15; body mass index (BMI), waist circumference, systolic blood pressure, diastolic blood pressure, glucose, insulin, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides. RESULTS: Greater maternal physical activity was associated with lower BMI, waist circumference, glucose and insulin in unadjusted analyses. The magnitude of associations was generally small with wide CIs, and most associations attenuated towards the null after adjusting for confounders. The strongest evidence of association after adjustment for confounders was for glucose, although the 95% CI for this association includes the null; a one SD greater physical activity during pregnancy was associated with a -0.013 mmol/L difference in offspring glucose levels (equivalent to approximately one-third of a SD; 95% CI -0.027 to 0.001 mmol/L). CONCLUSIONS: Our results suggest that maternal physical activity in pregnancy, measured at 18 weeks gestation, is unlikely to be an important determinant of later offspring cardiovascular health. There was some suggestion of association with offspring glucose, but given that all other associations (including insulin) were null after adjustment for confounders, this result should be interpreted with caution. PMID- 24071463 TI - Impact on cardiovascular risk follow-up from a shift to the CKD-EPI formula for eGFR reporting: a cross-sectional population-based primary care study. AB - OBJECTIVE: To assess the impact on cardiovascular risk factor management in primary care by the introduction of chronic kidney disease epidemiological collaboration (CKD-EPI) for estimated-glomerular filtration rate (eGFR) reporting. DESIGN AND SETTING: Cross-sectional study of routine healthcare provision in 47 primary care practices in The Netherlands with Modification of Diet and Renal Disease Study eGFR reporting. METHODS: eGFR values were recalculated using CKD-EPI in patients with available creatine tests. Patients reclassified from CKD stage 3a to CKD stage 2 eGFR range were compared to those who remained in stage 3a for differences in demographic variables, blood pressure, comorbidity, medication usage and laboratory results. RESULTS: Among the 60 673 adult patients (37% of adult population) with creatine values, applying the CKD-EPI equation resulted in a 16% net reduction in patients with CKD stage 3 or worse. Patients reclassified from stage 3a to 2 had lower systolic blood pressure (139.7 vs 143.3 mm Hg p<0.0001), higher diastolic blood pressure (81.5 vs 78.4 mm Hg p<0.0001) and higher cholesterol (5.4 vs 5.1 mmol/L p<0.0001) compared to those who remained in stage 3a. Of those reclassified out of a CKD diagnosis 463 (32%) had no comorbidities that would qualify for annual CVD risk factor assessment and 20 (12% of those with sufficient data) had a EuroSCORE CVD risk >20% within 10 years. CONCLUSIONS: Use of the CKD-EPI equation will result in many patients being removed from CKD registers and the associated follow-up. Current risk factor assessment in this group may be lacking from routine data and some patients within this group are at an increased risk for cardiovascular events. PMID- 24071464 TI - Nucleoside triphosphates inhibit ADP, collagen, and epinephrine-induced platelet aggregation: role of P2Y1 and P2Y12 receptors. AB - BACKGROUND: Platelets express two ADP receptors namely P2Y1 and P2Y12 that regulate ADP and other agonists-induced platelet aggregation. P2Y1 receptor activation causes platelet shape change while P2Y12 receptor activation induces platelet aggregation. Previously, anti-aggregatory effects of ATP on ADP-induced and pro-aggregatory effects on epinephrine-induced platelet aggregation have been reported. However, the effects of other nucleoside triphosphates on platelet aggregation have never been described. The aim of the present study was to characterise the effects of nucleoside triphosphates (ATP, UTP, GTP, and CTP) on agonist-induced platelet aggregation. METHODS: The experiments were performed on platelet rich plasma freshly isolated from blood donated by healthy human volunteers. RESULTS: All the nucleoside triphosphates tested inhibited ADP- and collagen-induced platelet aggregation in a concentration-dependent manner with a rank order of potency, 2MeSATP >ATP >= alpha,beta,methyleneATP>UTP >>CTP >= GTP. The IC50 values against ADP (10 MUM)-induced platelet aggregation were 0.039 +/- 0.013, 18 +/- 7, 25 +/- 6, 32 +/- 9, 360 +/- 130, and 400 +/- 160 MUM, respectively. Low concentrations of ATP induced platelet shape change which was due to contaminating ADP. However, higher concentrations antagonised ADP and MRS2365-induced platelet shape change. The ATP analogue alpha,beta,methyleneATP and CTP but not UTP and GTP also antagonised ADP-induced platelet shape change. Similarly, low ATP concentrations potentiated epinephrine-induced platelet aggregation that was abolished by P2Y1 antagonist MRS2500 suggesting P2Y1 receptor activation due to contaminating ADP. Higher ATP concentrations, alpha,beta,methyleneATP, UTP, CTP, and GTP antagonised epinephrine-induced platelet aggregation. CONCLUSION: Thus, the data demonstrate nucleoside triphosphates in general act as P2Y12 receptor antagonists and antagonise ADP-, collagen-, and epinephrine-induced platelet aggregation. PMID- 24071465 TI - Surfactant impairs coagulation in-vitro: a risk factor for pulmonary hemorrhage? AB - BACKGROUND: Pulmonary hemorrhage (PHEM) complicates the hospital course of 3-5% of preterm infants with respiratory distress syndrome (RDS), and bears a high mortality rate. Impaired thrombin generation and poor clot formation in premature neonates affect PHEM severity. OBJECTIVES: We evaluated the impact of surfactant upon in-vitro clot formation in order to assess the role of surfactant in the pathogenesis of PHEM. METHODS: Blood samples were obtained from healthy volunteers for measuring complete blood count, PT, PTT, and platelet function. Surfactant at increasing concentrations was added to blood samples, and whole blood clotting assays were performed using rotation thromboelastogram (ROTEM(r), Pentapharm Munich, Germany) and whole blood platelet adhesion and aggregation (Impact-R(r), Diamed, Switzerland). RESULTS: The mean PT level increased from 10.05 +/- 033 to 11.64 +/- 0.85 sec (p=0.06) in the presence of surfactant. Platelet aggregation with the agonists adenosine diphosphate and epinephrine significantly decreased with escalating surfactant concentration (p<0.001). Adhesion, manifested by surface coverage (SC), significantly decreased with increasing surfactant concentration: mean SC 9.25 +/- 2.96 compared to 6.1 +/- 0.96 and 0.05 +/- 0.058 with 0/0.1/5mg/ml surfactant, respectively, p<0.001 Whole blood ROTEM studies showed a trend towards lengthening of clotting time with increased surfactant concentration and lower clot strength. CONCLUSION: The presence of surfactant impairs coagulation in-vitro. The risk of PHEM may therefore be greater in extremely premature infants. Future studies are required to assess the clinical significance and relevance of our preliminary findings. PMID- 24071466 TI - Patient factors against stable control of warfarin therapy for Japanese non valvular atrial fibrillation patients. AB - INTRODUCTION: Effectiveness and safety of warfarin therapy for non-valvular atrial fibrillation (NVAF) patients are strongly associated with its stability presented such as time in therapeutic range (TTR) of PT-INR. However, the factors that affect TTR have not been fully elucidated in Japan where majority of patients are controlled within the range of 1.6-2.6 of PT-INR irrespective of the age. METHODS: We retrospectively analyzed 163 NVAF patients taking warfarin to determine the factors that affect TTR including metabolic enzymes polymorphisms after TTR calculation with both the standard PT-INR range and the actual control range of 1.6-2.6. RESULTS: Overall TTR calculated using Japanese Guideline was 69.7 +/- 25.1% (<70 and >= 70 years; 49.6 +/- 24.8% and 77.8 +/- 20.3%, respectively). After confirming that PT-INR values in patients < 70 years distributed in the same range as in those >= 70 years, as in a Japanese large cohort, we recalculated TTR of those < 70 years with 1.6-2.6 of PT-INR and found that it was 79.5 +/- 20.1%. Poor control of this new TTR were significantly associated with the lower height, the higher serum creatinine, the lower creatinine clearance, female gender, and presence of congestive heart failure, (p<0.05 respectively). Multivariate analysis revealed female gender and presence of congestive heart failure as independent predictor of the lower TTR (p<0.05, p<0.01, respectively). Polymorphism of CYP2C9 and VKORC1 were related to the dosage of warfarin but not determinant of TTR. CONCLUSIONS: When evaluated using a range of PT-INR actually used in Japan, TTR is generally well controlled and female gender and presence of congestive heart failure significantly affected the poorer TTR control. PMID- 24071467 TI - Effective mechanical cardiac support in a child in the absence of a mitral valve. PMID- 24071468 TI - Is the liberal use of preoperative 3-dimensional imaging and presternotomy femoral cutdown beneficial in reoperative adult congenital heart surgery? AB - OBJECTIVE: Patients with congenital heart disease frequently survive into adulthood, and many of them will require repeat surgery. Often, the unique anatomy can make reoperative sternotomy and the conduct of cardiopulmonary bypass challenging. We evaluated the utility of preoperative 3-dimensional imaging and presternotomy femoral cutdown in reoperative adult congenital heart disease surgery. METHODS: We retrospectively studied 205 adult patients, who had undergone reoperative cardiac surgery for congenital heart disease from 2006 to 2011. Using the operative history and 3-dimensional preoperative imaging findings, an algorithm was created to determine whether femoral cutdown or cannulation should be performed before sternal reentry. Analyses were performed to determine the benefits of this strategy. In addition, analyses were performed to identify adverse outcomes related to this strategy. RESULTS: Presternotomy femoral intervention was performed in 112 of 205 patients (55%)-femoral cutdown alone in 69 (34%) and femoral cutdown, cannulation, and institution of cardiopulmonary bypass in 43 (21%). Of the 19 patients (9%) with a cardiac injury, femoral cutdown had already been performed in 17, of whom 10 had also undergone cannulation. Only 2 patients required urgent femoral cutdown or cannulation. A strong correlation was found between the site of injury predicted by the preoperative algorithm and the actual site of cardiac injury (88%). In both univariate and multivariate models, the risk factors for cardiac injury included a history of cardiac injury during sternal reentry (18% vs 1%, P = .0001), proximity of the right ventricular outflow tract to the posterior chest wall (35% vs 14%, P = .04), and increased reoperative sternotomy incidence (P = .01). In 31 patients, despite safe reentry, the femoral vessels were used as a preferential site of venous (n = 6), arterial (n = 9), or venous and arterial cannulation (n = 16) because of anatomic constraints within the chest cavity. Three patients experienced groin complications (pseudoaneurysm, abscess, ischemia) requiring surgery. CONCLUSIONS: Cardiac injury during reoperative surgery in adults with congenital heart disease is not uncommon. The preoperative history and imaging findings could be predictive of certain cardiac injury patterns. Using the preoperative history and 3-dimensional imaging findings, a more selective algorithm for presternotomy femoral intervention might be warranted. PMID- 24071469 TI - Modified Blalock-Taussig shunt versus ductal stenting for palliation of cardiac lesions with inadequate pulmonary blood flow. AB - OBJECTIVE: The modified Blalock-Taussig shunt is the most commonly used palliative procedure for infants with ductal-dependent pulmonary circulation. Recently, catheter-based stenting of the ductus arteriosus has been used by some centers to avoid surgical shunt placement. We evaluated the durability and safety of ductal stenting as an alternative to the modified Blalock-Taussig shunt. METHODS: A single-institution, retrospective review of patients undergoing modified Blalock-Taussig shunt versus ductal stenting was performed. Survival, procedural complications, and freedom from reintervention were the primary outcome variables. RESULTS: A total of 42 shunted and 13 stented patients with similar age and weight were identified. Survival to second-stage palliation, definitive repair, or 12 months was similar between the 2 groups (88% vs 85%; P = .742). The incidence of surgical or catheter-based reintervention to maintain adequate pulmonary blood flow was 26% in the shunted patients and 25% in the stented patients (P = 1.000). Three shunted patients (7%) required intervention to address contralateral pulmonary artery stenosis and 3 (7%) required surgical reintervention to address nonpulmonary blood flow-related complications. The need for ipsilateral or juxtaductal pulmonary artery intervention at, or subsequent to, second-stage palliation or definitive repair was similar between the 2 groups. CONCLUSIONS: Freedom from reintervention to maintain adequate pulmonary blood flow was similar between infants undergoing modified Blalock-Taussig shunt or ductal stenting as an initial palliative procedure. However, a greater percentage of shunted patients experienced procedure-related complications and distal branch pulmonary artery stenosis. Palliative ductal stenting appears to be a safe and effective alternative to modified Blalock-Taussig in selected infants. PMID- 24071470 TI - Discussion. PMID- 24071471 TI - Severe bleeding as a result of platelet inhibition caused by floxacillin treatment for endocarditis. PMID- 24071472 TI - Hemodynamics of the Edwards Sapien XT transcatheter heart valve in noncircular aortic annuli. AB - OBJECTIVES: During implantation of transcatheter aortic valves into severe calcified aortic annuli, misdeployments due to asymmetric shapes of the target region were reported. Whether the resultant stent deformations influence valve performance has not been quantified. The objective of this study was to investigate in vitro hemodynamics of the Edwards Sapien XT (Edwards Lifesciences, Irvine, Calif) after valve deployment in noncircular aortic annuli. METHODS: Six Edwards Sapien XT valves were implanted into a model of the aortic annulus with different shapes (elliptical, triangular, and bulged compared with ideal circular) and investigated in a pulsatile flow simulator. Leakage was determined by ultrasonic flow measurements, and leaflet coaptation was visualized by high speed video. In addition, the origin of leakage was investigated under static pressure. RESULTS: The lowest amount of leakage occurred in the ideal circular shape, whereas in most of the noncircular configurations increased transvalvular leakage due to paravalvular leaks and folds at the free edges of the leaflets was found, more often by implantation of the valve within a triangular annulus shape. Implantation of the valves into the elliptical configuration with the prosthesis commissure directed to the longitudinal axis of the annular plane showed similar values compared with the circular annulus. Pressure gradients were not influenced by the valve distortion. CONCLUSIONS: Implantation of the Edwards Sapien XT transcatheter valve into non-circular-shaped aortic annuli leads to increased leakage. Annulus shape and relative position of the prosthesis are main determinants of leakage. Implantation into elliptical annuli, as found in bicuspid aortic valves, seems feasible. PMID- 24071473 TI - Suitability of Macrolampis firefly and Pyrearinus click beetle luciferases for bacterial light off toxicity biosensor. AB - Bioluminescence is widely used in biosensors. For water toxicity analysis, the naturally bioluminescent bacteria Vibrio fischeri have been used extensively. We investigated the suitability of two new beetle luciferases for Escherichia coli light off biosensors: Macrolampis firefly and Pyrearinus termitilluminans click beetle luciferases. The bioluminescence detection assay using this system is very sensitive, being comparable or superior to V. fischeri. The luciferase of P. termitilluminans produces a strong and sustained bioluminescence that is useful for less sensitive and inexpensive assays that require integration of the emission, whereas Macrolampis luciferase displays a flash-like luminescence that is useful for fast and more sensitive assays. The effect of heavy metals and sanitizing agents was analyzed. Zinc, copper, 1-propanol, and iodide had inhibitory effects on bioluminescence and growth assays; however, in these cases the bioluminescence was not a very reliable indicator of cell growth and metabolic activity because these agents also inhibited the luciferase. On the other hand, mercury and silver strongly affected cell bioluminescence and growth but not the luciferase activity, indicating that bioluminescence was a reliable indicator of cell growth and metabolic activity in this case. Finally, bioluminescent E. coli immobilized in agarose matrix gave a more stable format for environmental assays. PMID- 24071475 TI - The toxicity mechanism of sodium fluoride on fertility in female rats. AB - Recognition of the harmful effects of sodium fluoride (NaF) on human reproduction is increasing, especially as it relates to female reproduction. However, the mechanism by which NaF interferes with female reproduction is unclear. The aims of the present study were to investigate the effects of fluoride exposure on female fertility and to elucidate the mechanisms underlying these effects. Female Sprague-Dawley rats were divided into three groups: one control group and two NaF treated groups (100 and 200 mg/L in the drinking water for 12 weeks). Several parameters were evaluated, including: (i) fluoride concentrations; (ii) estrogen (E2) and progesterone (P) concentrations; (iii) estrogen receptor alpha protein (ERalpha); (iv) progesterone receptor (PgR) protein; (v) follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) protein. The results indicated that administration of NaF lead to significant decreases in E2 and P levels in the serum and in the expression of FSHR protein. In addition, fluoride exposure significantly increased Eralpha and PgR protein expression levels and LHR protein expression. These results suggest that the reproductive hormone reduction and the abnormalities of related receptor proteins expression are important factors underlying the decreased fertility observed in female rats that have been exposed to NaF. PMID- 24071474 TI - Ursolic acid induces apoptosis of SW480 cells via p53 activation. AB - The purpose of this study is to assess the effect of ursolic acid, a triterpene, on induction of apoptosis in human colon adenocarcinoma cells, SW480. The cells treated with nontoxic concentration of ursolic acid showed the presence of apoptotic bodies and DNA fragmentation in a dose dependent manner. Both the expression level and transcriptional activity of p53, an apoptotic protein, were remarkably up-regulated in cells treated with ursolic acid compared to blank group. In addition, the expression levels of p-p53, acetyl-p53, NF-kappaB, p-p21, Bax, Caspase-3 and Caspase-9, apoptotic proteins, were increased in cells treated with ursolic acid compared to blank group. Above results demonstrate that ursolic acid induces the activation of p53, NF-kappaB and Bax, leading to the enhancement of p21 transcriptional activity and activation of Caspase-9 and -3, thus finally induces apoptosis of SW480 cells. PMID- 24071476 TI - Pre-clinical safety assessment of the synthetic human milk, nature-identical, oligosaccharide Lacto-N-neotetraose (LNnT). AB - Lacto-N-neotetraose (LNnT) is a tetrasaccharide naturally occurring in human breast milk, but not in cow's milk. The safety data generated on a potential new LNnT ingredient produced by chemical synthesis is presented. Standard in vitro genotoxicity tests were performed. LNnT was also administered via gavage in 14-, 28- and 90-day studies at levels corresponding to 0 (control), 1000, 2500 and 5000 mg/kg bw/day in juvenile rats. Fructooligosaccharide (FOS) currently approved for use in infant formulae was used as a reference control at one dose level of 5000 mg/kg bw/day. LNnT was non-mutagenic in in vitro assays. Oral administration up to 5000 mg/kg bw/day to rats over 90 days was not associated with any adverse effects, based on clinical observations, body weight gain, feed consumption, clinical pathology, organ weights and histopathology findings. Regarding gastrointestinal effects, LNnT was better tolerated than FOS during the first 2 weeks of treatment. A No Observed Adverse Effect Level (NOAEL) of 5000 mg/kg bw/day for both male and female rats was identified for LNnT when administered by gavage for 90 days. These findings in the juvenile rat support the safety of LNnT for possible use in infant foods and allow further investigation in clinical studies. PMID- 24071477 TI - Genotoxic, antigenotoxic and phytochemical assessment of Terminalia actinophylla ethanolic extract. AB - Terminalia actinophylla has been used for anti-diarrheic and haemostatic purposes in Brazil. The fly spot data obtained after exposure of marker-heterozygous Drosophila melanogaster larvae to T. actinophylla ethanolic extract (TAE) in the standard (ST) and high bioactivation (HB) crosses revealed that TAE did not induce any statistically significant increment in any spot categories. Differences between the two crosses are related to cytochrome P450 (CYPs) levels. In this sense, our data pointed out the absence of TAE-direct and indirect mutagenic and recombinagenic action in the Somatic Mutation and Recombination Test (SMART). When the anti-genotoxicity of TAE was analyzed, neither mitomycin C (MMC) nor ethylmethanesulfonate (EMS) genotoxicity was modified by the post exposure to TAE, which suggests that TAE has no effect on the mechanisms involved in the processing of the lesions induced by both genotoxins. In the mwh/flr(3) genotype, co-treatment with TAE may lead to a significant protection against the genotoxicity of MMC and a weak but significant effect in the toxic genetic action of EMS. The overall findings suggested that the favorable modulations by TAE could be, at least in part, due to its antioxidative potential. PMID- 24071478 TI - Mucilaginibacter soyangensis sp. nov., isolated from a lake. AB - A non-motile, yellow-orange-pigmented bacterial strain, designated HME6664(T), was isolated from Lake Soyang, Republic of Korea. The major fatty acids of strain HME6664(T) were summed feature 3 (comprising C16 : 1omega6c and/or C(16 : 1)omega7c; 44.7%) and iso-C15 : 0 (20.2%). The DNA G+C content was 40.8 mol%. A phylogenetic tree based on 16S rRNA gene sequences showed that strain HME6664(T) formed a lineage within the genus Mucilaginibacter. Strain HME6664(T) was closely related to Mucilaginibacter ximonensis (96.7%), Mucilaginibacter dorajii (96.5%) and Mucilaginibacter lappiensis (96.3%). On the basis of the evidence presented in this study, strain HME6664(T) represents a novel species of the genus Mucilaginibacter, for which the name Mucilaginibacter soyangensis sp. nov., is proposed. The type strain is HME6664(T) ( = KCTC 23261(T) = CECT 7824(T)). PMID- 24071479 TI - Relationship between C-reactive protein and kidney stone prevalence. AB - PURPOSE: We evaluated the relationship between serum C-reactive protein and the lifetime kidney stone prevalence. MATERIALS AND METHODS: We performed a cross sectional study of participants from the Continuous National Health and Nutrition Examination Survey (NHANES) from 2007 to 2008 and 2008 to 2009. Data were available on 11,033 participants. RESULTS: On univariate analysis we noted a strong correlation between C-reactive protein quintile and kidney stone history. After adjusting for known confounders multivariate logistic regression revealed a significant relationship between C-reactive protein and the lifetime prevalence of kidney stones in younger individuals (age 20 to 39 years, p for trend = 0.002). In individuals 20 to 39 years old the lifetime prevalence of kidney stones increased with increasing C-reactive protein quintile (p = 0.002 for trend), specifically, those in the third quintile (OR 3.86, 95% CI 1.07-13.88, p = 0.04) and the fifth quintile (OR 3.85, 95% CI 1.46-10.17, p = 0.009). The fourth quintile of C-reactive protein approached statistical significance (OR 2.56, 95% CI 0.96-6.81, p = 0.059). The relationship between C-reactive protein and kidney stone history was not significant in the older age groups (40 to 59 and 60 years or greater). CONCLUSIONS: There exists a significant relationship between serum C-reactive protein and self-reported kidney stones in younger individuals. This may shed light on potential mechanisms of stone formation in this age group and help gain a better understanding of stone risk mediators. Further studies are needed to understand the mechanisms underlying these epidemiological findings. PMID- 24071480 TI - A simple procedure to prevent postoperative inguinal hernia after robot-assisted laparoscopic radical prostatectomy: a plugging method of the internal inguinal floor for patients with patent processus vaginalis. AB - PURPOSE: We introduce a simple procedure to prevent postoperative inguinal hernia after robot-assisted laparoscopic radical prostatectomy. We developed the inguinal hernia prevention procedure based on our prior study. Patent processus vaginalis is an independent predictor of inguinal hernia after robot-assisted laparoscopic radical prostatectomy. MATERIALS AND METHODS: We reviewed 74 patients (98 groins) with patent processus vaginalis during robot-assisted laparoscopic radical prostatectomy between May 2007 and April 2013. Of these patients 38 (47 groins) did not undergo the inguinal hernia prevention procedure and 36 (51 groins) were treated with this procedure. For the inguinal hernia prevention the lateral side internal inguinal floor of the patent processus vaginalis was incised and dissected along the spermatic cord. Hemostatic agents were plugged into the end of the dissected canal. After plugging, the internal inguinal floor was closed. We compared the incidence of postoperative inguinal hernia between the 2 groups. RESULTS: Among the 47 groins of the patients who did not undergo the inguinal hernia prevention procedure, postoperative inguinal hernia occurred in 16 groins (34.0%) and developed by a mean of 13.8 +/- 8.5 months. In contrast, none of the patients who underwent the inguinal hernia prevention procedure experienced postoperative inguinal hernia during the followup of 11.8 +/- 6.2 months. This inguinal hernia prevention procedure required approximately 3 extra minutes. During followup there were no intraoperative or postoperative complications related to the inguinal hernia prevention procedure. CONCLUSIONS: Using our simple inguinal hernia prevention procedure, the preventive effect was remarkable. However, studies in a larger patient population with a longer followup should be performed to prove the ultimate clinical impact of this inguinal hernia prevention procedure. PMID- 24071481 TI - Population based study of predictors of adverse pathology among candidates for active surveillance with Gleason 6 prostate cancer. AB - PURPOSE: Approximately a third of prostate cancer cases with a Gleason score of 6 are upgraded at radical prostatectomy. We studied trends and predictors of upgrading and up staging among men with Gleason 6 prostate cancer who were potential candidates for active surveillance in a population based cohort. MATERIALS AND METHODS: From 2007 to 2011, 13,159 men were diagnosed with Gleason 6, clinical stage T1c/T2 prostate cancer in the NPCR (National Prostate Cancer Register of Sweden). Of these men 4,500 underwent radical prostatectomy, including 2,205 with data on the extent of prostate cancer in the biopsy cores. Logistic regression was used to examine variables associated with adverse pathology (defined as upgrading to Gleason 7 or greater, or up staging to pT3 or greater) in the full group and in potential candidates for active surveillance using 6 current published protocols. RESULTS: Among Swedish men with clinically localized Gleason 6 prostate cancer approximately 50% had adverse pathology at radical prostatectomy. Of the men who met the study inclusion criteria of 6 different active surveillance protocols, adverse pathology was present in 33% to 45%. Predictors of adverse pathology were older age, higher prostate specific antigen, prostate specific antigen density greater than 0.15 ng/ml/cm(3), palpable disease and extent of cancer greater than 4 mm on biopsy. Larger prostate volume had an inverse relationship with adverse pathology. CONCLUSIONS: More than a third of men meeting the most stringent active surveillance criteria had adverse pathology at radical prostatectomy in this population based cohort. Active surveillance programs should consider prostate specific antigen density and extent of cancer on biopsy for patient selection. PMID- 24071484 TI - Laparoscopic adjustable gastric band erosion and migration into the proximal jejunum. PMID- 24071485 TI - Anemia and iron deficiency before and after bariatric surgery. AB - BACKGROUND: Iron deficiency and anemia are changes often associated with obesity. Bariatric surgery is responsible for increasing the iron loss and reducing its absorption. The objective of this study was to evaluate anemia and iron deficiency before and after bariatric surgery and to relate them to possible predisposing factors. METHODS: A retrospective study was conducted on obese patients submitted to open Roux-en-Y gastric bypass, in which clinical and laboratory data were obtained up to 48 months postoperatively. Patients were divided into groups according to the presence or absence of anemia and to the presence or absence of iron deficiency (even without anemia), and all data were compared between these groups. RESULTS: Preoperatively, 21.5% of patients had anemia and 20% had iron deficiency. The number of patients with anemia did not vary through the 4 years of the study, but ferritin levels significantly decreased with time (P<.01). Younger patients and patients with greater weight loss had a higher incidence of anemia. Female gender was a variable associated with a greater incidence of iron deficiency. CONCLUSIONS: Anemia and iron deficiency are frequent in obese patients and must be treated before surgery. Medical and nutritional surveillance is important in the postoperative period of bariatric surgery. Management of each condition must be directed at correcting the 2 major sources of iron deficiency and anemia: food intolerance (mostly meat intolerance) and losses (frequently due to menstruation). These are the factors more related to iron deficient anemia. PMID- 24071482 TI - Microbiota regulation of inflammatory bowel disease and colorectal cancer. AB - The host and microbiota have evolved mechanisms for coexistence over millions of years. Accumulating evidence indicates that a dynamic mutualism between the host and the commensal microbiota has important implications for health, and microbial colonization contributes to the maintenance of intestinal immune homeostasis. However, alterations in communication between the mucosal immune system and gut microbial communities have been implicated as the core defect that leads to chronic intestinal inflammation and cancer development. We will discuss the recent progress on how gut microbiota regulates intestinal homeostasis and the pathogenesis of inflammatory bowel disease and colorectal cancer. PMID- 24071486 TI - [Off-label use of rhuFVIIa: Allegro ma non tropo]. PMID- 24071487 TI - [Management of sudden neurosensory hearing loss in a Primary Care Centre]. AB - Sudden hearing loss is a rapid loss of neurosensory hearing that may occur within hours or days in an apparently healthy patient. Its origins are variable and multifactorial. Most patients do not recover hearing if not treated, and some even develop cophosis (deafness) in the affected ear. It is an otological emergency, as early therapeutic management offers a better hearing prognosis. As there is limited knowledge on this condition, it may be underdiagnosed in Primary Health Care Centers. It should be suspected in patients with abrupt hearing loss or tinnitus. Sophisticated instruments are not required for its diagnosis, just a detailed history, basic otoscopy, and proper interpretation of the hearing test. In this way, an accurate diagnosis is achieved in most cases, which is confirmed by audiometry. PMID- 24071488 TI - Is cancer incidence decreased in the frail elderly? Evidence from a prospective cohort study. AB - OBJECTIVES: Lower rates of cancer in the oldest old and in nursing home populations may reflect the increasing prevalence of frailty and a diminished capacity to sustain cancer cell growth and proliferation. This study aimed to determine cancer incidence in the frail relative to non-frail community resident older adults. MATERIALS AND METHODS: Data from 3969 participants free of diagnosed cancer at the sixth follow-up from three sites of the Established Populations for Epidemiologic Studies of the Elderly (EPESE), a population-based cohort study. Frailty status was determined from physical performance testing and self reported dependency in activities of daily living. Cancer incidence over the four subsequent years was identified through linkage with Medicare claims data. Logistic regression was used to estimate the odds of cancer incidence with respect to frailty status in multiple models with progressive adjustment for covariates. RESULTS: Of the 3969 participants, 1340 (33.8%) were identified as frail. Cancer incidence at 4years was lower in frail participants overall (OR 0.64; 95% CI 0.46-0.89) and frail men in particular (OR 0.54; 95% CI 0.33-0.87). Incidence was lower in women (3.7%) than in men (8.8%), but was not lower in frail women compared with non-frail women (OR 0.77; 95% CI 0.48-1.23). CONCLUSION: Frailty status was associated with decreased cancer incidence, particularly in men, and suggests that mechanisms related to the pathogenesis of frailty may also play a role in inhibiting tumorigenesis. Why this would be more apparent in men than women remains to be clarified. PMID- 24071489 TI - Inclusion of frail elderly patients in clinical trials: solutions to the problems. AB - With the aging of the population, the interest in clinical trials concerning frail elderly patients has increased. Evidence-based practice for the elderly patient is difficult because elderly patients, especially the frail, are often excluded from clinical trials. To facilitate the participation of frail elderly patients in clinical trials, investigators should be more aware of possible barriers when setting up research. While conducting a trial entitled 'A randomized controlled trial of geriatric liaison intervention in frail surgical oncology patients' (LIFE) the main problem was low inclusion rates. This was due to: 1) limited physical and cognitive reserve of frail elderly patients making participation and extra visits to the hospital a burden for patients; 2) difficulty with understanding written information and information given by telephone; and 3) insufficient awareness of the study by health care professionals. To increase inclusion rates, follow-up measurements were taken at a home visit. To overcome barriers to understanding written information and information given over the phone, patients were informed face to face and questionnaires were filled in an interview format. To increase awareness, posters, pencil and sweets with the logo of the study were distributed and the study protocol was repeatedly explained to new staff. Moreover, it was checked if possible eligible patients coming to the hospital were indeed screened for participation. The mentioned measures, increased inclusion rates but also caused an increased time investment and consequently extra financial resources for staff costs. PMID- 24071490 TI - Evaluation of the Groningen Frailty Indicator and the G8 questionnaire as screening tools for frailty in older patients with cancer. AB - OBJECTIVE: In this study, we evaluated the Groningen Frailty Indicator (GFI) and the G8 questionnaire as screening tools for a Comprehensive Geriatric Assessment (CGA) in older patients with cancer. PATIENTS AND METHODS: Eligible patients with various types and stages of cancer were evaluated for frailty before treatment. Patients were categorized as patients with a normal CGA and abnormal CGA (>=2 impaired tests). The diagnostic performance of the screening tools was evaluated against the CGA with Receiver Operating Characteristic analysis. RESULTS: In total, 170 patients (79 women) with median age 77years old (range 66-97years) were included. Sixty-four percent of patients had an abnormal CGA while according to the GFI (GFI>=4) and G8 questionnaire (G8<=14) 47% and 76% of patients had an abnormal screening test, respectively. Overall, there was no significant difference (p=0.97) in diagnostic performance between the two screening tools. The Area Under the Curve was 0.87 for both tools. For the GFI and G8 questionnaire the sensitivity was respectively 66% (95% CI: 56-75%), 92% (95% CI: 85-96%); the negative predictive value (NPV): 59% (95 CI%: 49-69%), 78% (95% CI: 63-88%); and the specificity: 87% (95% CI: 76-94%), 52% (95% CI: 39-65%). CONCLUSION: In this study, we showed that overall both the GFI and the G8 questionnaire were able to separate older patients with cancer with a normal and abnormal CGA. For the G8 questionnaire, an adequate sensitivity and NPV were demonstrated, however at the expense of the specificity. For the GFI, we suggest to lower the threshold with one point to GFI >=3 to screen patients for a CGA. PMID- 24071491 TI - Treatment of breast cancer in the elderly: a prospective, population-based Swiss study. AB - OBJECTIVES: The primary objective of this population-based study is to describe the patterns of care of elderly patients with breast cancer (BC), and evaluate potential causative factors for the decrease in BC-specific survival (BCSS) in the elderly. PATIENTS AND METHODS: We included all or representative samples of patients with newly diagnosed BC from seven Swiss cancer registries between 2003 and 2005 (n=4820). Surgical and non-surgical BC treatment was analyzed over 5 age groups (<65, 65 to <70, 70 to <75, 75 to <80 and >=80years), and the predictive impact of patient age on specific treatments was calculated using multivariate logistic regression analysis. RESULTS: The proportion of locally advanced, metastatic and incompletely staged BC increased with age. The odds ratio for performing breast-conserving surgery (BCS) in stages I-II BC (0.37), sentinel lymph node dissection (SLND) in patients with no palpable adenopathy (0.58), post BCS radiotherapy (0.04) and adjuvant endocrine treatment (0.23) were all in disfavor of patients >=80years of age compared to their younger peers. Only 36% of patients >=80years of age with no palpable adenopathy underwent SLND. In the adjusted model, higher age was a significant risk factor for omitting post-BCS radiotherapy, SLND and adjuvant endocrine treatment. CONCLUSIONS: This study found an increase in incomplete diagnostic assessment, and a substantial underuse of BCS, post-BCS radiotherapy, SLND and adjuvant endocrine treatment in elderly patients with BC. There is a need for improved management of early BC in the elderly even in a system with universal access to health care services. PMID- 24071492 TI - Can we predict chemo-induced hematotoxicity in elderly patients treated with pegylated liposomal doxorubicin? Results of a population-based model derived from the DOGMES phase II trial of the GINECO. AB - INTRODUCTION: Use of anthracyclines is often limited in older patients due to cardiac and hematologic toxicities. Thanks to its reduced toxicity profile, Pegylated Liposomal Doxorubicin (PLD) allows an extended use of doxorubicin to this population. We aimed at modeling PLD-induced hematotoxicity in patients with metastatic breast cancer >=70 years old and at finding predictive factors of neutrophil nadir value. METHODS: Sixty patients, enrolled in the DOGMES prospective multicentric phase II trial, were treated with PLD at 40mg/m(2) every 28days during six cycles. Trial design included geriatric covariates assessment at inclusion and monitoring of cells count every week for three cycles. A population model was developed to describe hematopoiesis and hematopoietic reserve in these patients. The effect of co-administered G-CSF (granulocyte colony-stimulating factor) was also examined. RESULTS: A pharmacodynamic model was built using data from 53 patients not receiving G-CSF. This model assumed an instantaneous effect of PLD on the system. Based on this model, exact neutrophil nadir value was computed and ranged between 0.069K/mm(3) and 2.63K/mm(3) confirming the weak hematotoxicity of PLD. The same model was then applied to the 7 patients receiving G-CSF and showed that basal neutrophil count was higher for these patients. No other difference was found between both cohorts. Among the covariates collected, three were predictive of neutrophil nadir value: diabetes, frailty syndrome and assistance at home. CONCLUSION: This developed model allowed the identification of predictive factors of nadir ANC and the identification of patients that are more likely to develop hematotoxicity that should be monitored with attention. PMID- 24071493 TI - Interventional oncology in the elderly: complications and early response in liver and kidney malignancies. AB - OBJECTIVES: The complication rate, loco-regional responses and length of hospital stay were analyzed in patients with liver and kidney cancer older than 70years treated with interventional oncology procedures. The findings from the older population were compared with the younger patients (<70years) to detect any difference not related to chance. MATERIALS AND METHODS: Prospectively collected data on patients who underwent hepatic artery embolization (with or without radiofrequency ablation) and kidney radiofrequency ablation were retrospectively analyzed. Complication rates, loco-regional responses and length of hospital stay for patients older and younger than 70 were compared. RESULTS: 163 patients were treated, 66 (40.5%) older and 97 (59.5%) younger than 70years. The complication rate in patients older than 70 was 4.5% (3/66 pts) versus 3.1% (3/97 pts) (p=0.69) in the younger age-group. The complication rates for the liver embolization group, liver embolization plus radiofrequency and kidney radiofrequency group were 2/90 pts (2.2%), 2/42 pts (4.8%) and 2/31 pts (6.5%), respectively (p=0.46). Median hospital stay was three nights in both older and younger patients. Response rates were not significantly influenced by age. CONCLUSION: Liver embolization with or without radiofrequency and renal radiofrequency are safe and effective in older patients. Age alone should not be considered a contraindication to treatment in carefully selected patients. PMID- 24071494 TI - Symptom distress in older adults during cancer therapy: impact on performance status and quality of life. AB - BACKGROUND: This study aims to identify a sub-group of older patients who experience a higher level of symptoms of distress during cancer therapy. The symptoms that had the greatest impact on the patients' performance status and quality of life (QoL) are also identified. METHODS: This cross-sectional study used secondary data from a convenience sample of 120 patients, 65years of age and older, receiving cancer therapy. The measuring instruments used included the Symptom Distress Scale, the Karnofsky Performance Scale (KPS) and the Functional Assessment of Cancer Therapy-General (FACT-G). Hierarchical cluster analysis was used to categorize the patients into groups. RESULTS: The patients had multiple symptoms, with a mean number of 5+/-3 symptoms per patient. Mood disturbance was the most prevalent (87%), while nausea (28%) was the least prevalent. Approximately 28% and 72% of the patients fell into the high-symptom and low symptom groups, respectively. The high-symptom group reported significantly lower mean KPS scores, and FACT-G sub-scale and total scores (p<0.01). Impaired mobility had the strongest standardized coefficients in the KPS (-0.63; p<0.01), the FACT-G functional (-0.49; p<0.05) and the physical (-0.45; p<0.05) sub scales. Concentration difficulties had the strongest standardized coefficients ( 0.47; p<0.01) in the FACT-G total. CONCLUSION: Most of the older patients in this study reported suffering from a multitude of symptoms, with mood disturbance being the most prevalent. The older patients in the high-symptom group had a significantly lower performance status and QoL compared to the patients in the low-symptom group. PMID- 24071495 TI - Efficacy of aprepitant among patients aged 65 and over receiving moderately to highly emetogenic chemotherapy: a meta-analysis of unpublished data from previously published studies. AB - BACKGROUND: Various antiemetic agents are commonly administered during and after chemotherapy to prevent nausea and vomiting depending on the emetogenic risk. Data specific for patients older than 65 are rarely discussed and it is often assumed that such patients have less risk of nausea and vomiting and might not need the same prevention. OBJECTIVE: To determine whether response to antiemetic regimens incorporating aprepitant varies with patient age, we combined previously unpublished subgroup analyses from four previously published studies. METHODS: Risk ratios were combined using standard meta-analytic techniques to determine whether antiemetic regimens including aprepitant lead to more complete responses to antiemetic therapy than regimens without aprepitant, among patients aged 65 and over. RESULTS: Patients aged 65 and over have a significantly greater chance of experiencing a complete response (no vomiting or use of rescue therapy) to antiemetic treatment when aprepitant is included in the antiemetic regimen (Risk Ratio 1.25, 95% Confidence Interval 1.11 to 1.40, p=0.0002) than when it is not. This risk ratio is not significantly different (Q=0.281, p=0.596) from the risk ratio calculated for patients under age 65 (1.30, 95% Confidence Interval 1.19 to 1.42), from the same set of studies. LIMITATIONS: This meta-analysis combines studies utilizing different antiemetic regimens and different patient populations. Only a single efficacy outcome is included, and safety is not assessed. CONCLUSION: We conclude that for both the under 65years and the age 65 and over populations, antiemetic regimens including aprepitant, along with a 5 HT3 antagonist and a corticosteroid, are more effective in reducing chemotherapy induced nausea and vomiting than regimens that do not include aprepitant. PMID- 24071496 TI - Changes in body mass index and stoma related problems in the elderly. AB - OBJECTIVES: Weight gain can cause retraction of an intestinal stoma, possibly resulting in difficulty with wafer and pouch fit, daily care challenges, and discomfort. This cross-sectional study examined the association between body mass index (BMI) and ostomy-related problems among long-term (>5years post-diagnosis) colorectal cancer (CRC) survivors. MATERIALS AND METHODS: CRC survivors from three Kaiser Permanente Regions completed a mailed survey. The response rate for those with an ostomy was 53% (283/529). Questions included stoma-related problems, and time to conduct daily ostomy care. Poisson regression evaluated associations between report of problems and change in BMI. Our analysis sample included 235 survivors. RESULTS: Sample was 76% >=65years of age. Since their surgeries, BMI remained stable (ST) in 44% (103), decreased (DE) in 20% (48), and increased (IN) in 36% (84). Compared to ST, male IN (RR 2.15 [1.09-4.25]) and female DE (RR 5.06 [1.26-25.0]) were more likely to spend more than 30min per day on stoma care. IN (vs. ST) were more likely to report interference with clothing (RR 1.51 [1.06-2.17]) and other stoma-related problems (RR 2.32 [1.30-4.14]). Survivors who were obese at time of survey were more likely to report interference with clothing (RR 1.88 [1.38-2.56]) and other stoma-related problems (RR 1.68 [1.07-2.65]). CONCLUSION: A change in BMI is associated with ostomy related problems among long-term CRC survivors. Equipment and care practices may need to be adapted for changes in abdominal shape. Health care providers should caution that a significant increase or decrease in BMI may cause ostomy-related problems. PMID- 24071497 TI - Disparity in the use of combined modality therapy for rectal cancer in the older adult. AB - OBJECTIVES: The standard treatment strategy for patients with rectal adenocarcinoma having T3 or T4 tumors or positive lymph nodes includes concurrent chemoradiation, surgery and chemotherapy. Population based studies show relatively low rates of usage of standard therapy for rectal cancer in the older adult. MATERIALS AND METHODS: Two decades of cases of stage II and stage III rectal cancer from two academic teaching hospitals were reviewed. Comparisons were made of subjects <=70 or >=71years with regard to initiation and completion of radiation, chemotherapy and surgery. RESULTS: Subjects >=71years of age had significantly lower proportions of surgical resection (84 vs. 94%) and of initiation of all three component of standard therapy (49 vs. 66%) compared to those <=70years of age. Subjects >=71years had significantly more co-morbidities; however, the difference in initiation of therapy remained after adjusting for stage, treating hospital, co-morbid status, race or sex in multivariable analysis. The odds for initiation of therapy were reduced by ~22% in older adults in the adjusted analysis. Among all patients who started therapy only 56% completed it without dose reduction or delay. There were trends to increased completion among those receiving neo-adjuvant vs. post-operative chemoradiation and among those with stage III as opposed to stage II cancer. CONCLUSIONS: Our study indicates that a major disparity in the use of standard therapy for rectal cancer in the older adult exists in academic hospital settings. It will be important for oncologists to reconsider increasing the usage of curative therapy in these patients. PMID- 24071499 TI - Do pollinator distributions underlie the evolution of pollination ecotypes in the Cape shrub Erica plukenetii? AB - BACKGROUND AND AIMS: According to the Grant-Stebbins model of pollinator-driven divergence, plants that disperse beyond the range of their specialized pollinator may adapt to a new pollination system. Although this model provides a compelling explanation for pollination ecotype formation, few studies have directly tested its validity in nature. Here we investigate the distribution and pollination biology of several subspecies of the shrub Erica plukenetii from the Cape Floristic Region in South Africa. We analyse these data in a phylogenetic context and combine these results with information on pollinator ranges to test whether the evolution of pollination ecotypes is consistent with the Grant-Stebbins model. METHODS AND KEY RESULTS: Pollinator observations showed that the most common form of E. plukenetii with intermediate corolla length is pollinated by short-billed Orange-breasted sunbirds. Populations at the northern fringe of the distribution are characterized by long corollas, and are mainly pollinated by long-billed Malachite sunbirds. A population with short corollas in the centre of the range was mainly pollinated by insects, particularly short-tongued noctuid moths. Bird exclusion in this population did not have an effect on fruit set, while insect exclusion reduced fruit set. An analysis of floral scent across the range, using coupled gas chromatography-mass spectrometry, showed that the scent bouquets of flowers from moth-pollinated populations are characterized by a larger number of scent compounds and higher emission rates than those in bird pollinated populations. This was also reflected in clear separation of moth- and bird-pollinated populations in a two-dimensional phenotype space based on non metric multidimensional scaling analysis of scent data. Phylogenetic analyses of chloroplast and nuclear DNA sequences strongly supported monophyly of E. plukenetii, but not of all the subspecies. Reconstruction of ancestral character states suggests two shifts from traits associated with short-billed Orange breasted sunbird pollination: one towards traits associated with moth pollination, and one towards traits associated with pollination by long-billed Malachite sunbirds. The latter shift coincided with the colonization of Namaqualand in which Orange-breasted sunbirds are absent. CONCLUSIONS: Erica plukenetii is characterized by three pollination ecotypes, but only the evolutionary transition from short- to long-billed sunbird pollination can be clearly explained by the Grant-Stebbins model. Corolla length is a key character for both ecotype transitions, while floral scent emission was important for the transition from bird to moth pollination. PMID- 24071500 TI - Adaptive liver stereotactic body radiation therapy: automated daily plan reoptimization prevents dose delivery degradation caused by anatomy deformations. AB - PURPOSE: To investigate how dose distributions for liver stereotactic body radiation therapy (SBRT) can be improved by using automated, daily plan reoptimization to account for anatomy deformations, compared with setup corrections only. METHODS AND MATERIALS: For 12 tumors, 3 strategies for dose delivery were simulated. In the first strategy, computed tomography scans made before each treatment fraction were used only for patient repositioning before dose delivery for correction of detected tumor setup errors. In adaptive second and third strategies, in addition to the isocenter shift, intensity modulated radiation therapy beam profiles were reoptimized or both intensity profiles and beam orientations were reoptimized, respectively. All optimizations were performed with a recently published algorithm for automated, multicriteria optimization of both beam profiles and beam angles. RESULTS: In 6 of 12 cases, violations of organs at risk (ie, heart, stomach, kidney) constraints of 1 to 6 Gy in single fractions occurred in cases of tumor repositioning only. By using the adaptive strategies, these could be avoided (<1 Gy). For 1 case, this needed adaptation by slightly underdosing the planning target volume. For 2 cases with restricted tumor dose in the planning phase to avoid organ-at-risk constraint violations, fraction doses could be increased by 1 and 2 Gy because of more favorable anatomy. Daily reoptimization of both beam profiles and beam angles (third strategy) performed slightly better than reoptimization of profiles only, but the latter required only a few minutes of computation time, whereas full reoptimization took several hours. CONCLUSIONS: This simulation study demonstrated that replanning based on daily acquired computed tomography scans can improve liver stereotactic body radiation therapy dose delivery. PMID- 24071502 TI - Sensitivity and resistance to treatment in the primary management of epithelial ovarian cancer. AB - Ovarian carcinoma is the most lethal gynaecologic malignancy. Despite wide initial sensibility to chemotherapy especially to platinum-based regimens, the vast majority of patients with advanced stages of the disease develop recurrences and subsequent resistance to treatments. Ovarian cancer is actually considered as a heterogeneous disease at the clinical, histological and molecular level. In this review, the mechanisms of intrinsic sensitivity or resistance to treatment, especially to platinum-based chemotherapy are considered with particular reference to the significance of tumour heterogeneity. The molecular features involved in acquired resistance are reviewed and the current hypotheses are discussed. In particular, potential disruptions of the DNA reparation pathways are highlighted. PMID- 24071503 TI - Treatment innovations for metastatic breast cancer: nanoparticle albumin-bound (NAB) technology targeted to tumors. AB - In spite of recent advances in the treatment of metastatic breast cancer, this disease remains essentially incurable. Anthracyclines and taxanes have been widely demonstrated to be the most active cytotoxic drugs for the treatment of breast cancer. Paclitaxel and docetaxel are both hydrophobic drugs that need to be administered with detergent-like substances as solvents. In contrast, nanoparticle albumin-bound (nab) paclitaxel uses the natural characteristics of albumin to reversibly bind paclitaxel, transport it across endothelial cells and concentrate the active ingredient within the tumor. Several trials have demonstrated that nab-paclitaxel results in superior efficacy, with more complete responses, prolonged time to recurrence and survival, than paclitaxel and docetaxel in MBC. As second-line treatment, the novel formulation has almost doubled overall response rate, increased time to progression and overall survival in comparison with paclitaxel. Due to these results, to date nab-paclitaxel stands out as a promising treatment of metastatic breast cancer. PMID- 24071504 TI - Announcing "New Leaders in Cardiovascular Science". PMID- 24071501 TI - Bone sialoprotein and osteopontin in bone metastasis of osteotropic cancers. AB - The mechanisms underlying malignant cell metastasis to secondary sites such as bone are complex and no doubt multifactorial. Members of the small integrin binding ligand N-linked glycoproteins (SIBLINGs) family, particularly bone sialoprotein (BSP) and osteopontin (OPN), exhibit multiple activities known to promote malignant cell proliferation, detachment, invasion, and metastasis of several osteotropic cancers. The expression level of BSP and OPN is elevated in a variety of human cancers, particularly those that metastasize preferentially to the skeleton. Recent studies suggest that the "osteomimicry" of malignant cells is not only conferred by transmembrane receptors bound by BSP and OPN, but includes the "switch" in gene expression repertoire typically expressed in cells of skeletal lineage. Understanding the role of BSP and OPN in tumor progression, altered pathophysiology of bone microenvironment, and tumor metastasis to bone will likely result in development of better diagnostic approaches and therapeutic regimens for osteotropic malignant diseases. PMID- 24071506 TI - Should grade of tracer uptake on somatostatin receptor-targeted imaging be the major determinant and break the barrier of histopathologic criteria for determining the suitability of Peptide receptor radionuclide therapy? PMID- 24071505 TI - Quantification of human and rodent brown adipose tissue function using 99mTc methoxyisobutylisonitrile SPECT/CT and 18F-FDG PET/CT. AB - For brown adipose tissue (BAT) to be effective at consuming calories, its blood flow must increase enough to provide sufficient fuel to sustain energy expenditure and also transfer the heat created to avoid thermal injury. Here we used a combination of human and rodent models to assess changes in BAT blood flow and glucose utilization. METHODS: (99m)Tc-methoxyisobutylisonitrile (MIBI) SPECT (n = 7) and SPECT/CT (n = 74) scans done in adult humans for parathyroid imaging were reviewed for uptake in regions consistent with human BAT. Site-directed biopsies of subcutaneous and deep neck fat were obtained for electron microscopy and gene expression profiling. In mice, tissue perfusion was measured with (99m)Tc-MIBI (n = 16) and glucose uptake with (18)F-FDG (n = 16). Animals were kept fasting overnight, anesthetized with pentobarbital, and given intraperitoneally either the beta3-adrenergic receptor agonist CL-316,243, 1 mg/kg (n = 8), or saline (n = 8) followed by radiotracer injection 5 min later. After 120 min, the mice were imaged using SPECT/CT or PET/CT. Vital signs were recorded over 30 min during the imaging. BAT, white adipose tissue (WAT), muscle, liver, and heart were resected, and tissue uptake of both (99m)Tc-MIBI and (18)F FDG was quantified by percentage injected dose per gram of tissue and normalized to total body weight. RESULTS: In 5.4% of patients (4/74), (99m)Tc-MIBI SPECT/CT showed increased retention in cervical and supraclavicular fat that displayed multilocular lipid droplets, dense capillary investment, and a high concentration of ovoid mitochondria. Expression levels of the tissue-specific uncoupling protein-1 were 180 times higher in BAT than in subcutaneous WAT (P < 0.001). In mice, BAT tissue perfusion increased by 61% (P < 0.01), with no significant changes in blood flow to WAT, muscle, heart, or liver. CL-316,243 increased glucose uptake in BAT even more, by 440% (P < 0.01). CONCLUSION: Pharmacologic activation of BAT requires increased blood flow to deliver glucose and oxygen for thermogenesis. However, the glucose consumption far exceeds the vascular response. These findings demonstrate that activated BAT increases glucose uptake beyond what might occur by increased blood flow alone and suggest that activated BAT likely uses glucose for nonthermogenic purposes. PMID- 24071507 TI - Synthetic lipid nanoparticles targeting steroid organs. AB - Lipidots are original nanoparticulate lipid delivery vectors for drugs and contrast agents made from materials generally regarded as safe. Here, we characterized the in vivo stability, biodistribution, and pharmacokinetics of lipidots. METHODS: Lipidots 55 nm in diameter and coated with a phospholipid/poly(ethyleneglycol) surfactant shell were triply labeled with (3)H cholesteryl-hexadecyl-ether, cholesteryl-(14)C-oleate, and the 1,1'-dioctadecyl 3,3,3',3'-tetramethylindotricarbocyanine infrared fluorescent dye and injected intravenously into immunocompetent Friend virus B-type mice. The pharmacokinetics and biodistribution of lipidots were analyzed quantitatively in serial samples of blood and tissue and with in vivo optical imaging and were refined by microscopic examination of selected target tissues. RESULTS: The plasmatic half-life of lipidots was approximately 30 min. Radioactive and fluorescent tracers displayed a similar nanoparticle-driven biodistribution, indicative of the lipidots' integrity during the first hours after injection. Lipidots distributed in the liver and, surprisingly, in the steroid-rich organs adrenals and ovaries, but not in the spleen. This tropism was confirmed at the microscopic level by histologic detection of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine. Nanoparticle loading with cholesterol derivatives increased accumulation in ovaries in a dose-dependent manner. CONCLUSION: This previously unreported distribution pattern is specific to lipidots and attributed to their nanometric size and composition, conferring on them a lipoproteinlike behavior. The affinity of lipidots for steroid hormone-rich areas is of interest to address drugs and contrast agents to lipoprotein-receptor-overexpressing cancer cells found in hormone-dependent tumors. PMID- 24071510 TI - Radioembolization for treatment of salvage patients with colorectal cancer liver metastases: a systematic review. AB - Currently, there is no consensus on the use of (90)Y radioembolization for salvage patients with colorectal cancer liver metastases. The purpose of this study was to provide a comprehensive overview of the available data on tumor response and survival after (90)Y radioembolization for this group of patients. METHODS: A systematic literature search was conducted in PubMed (Medline), Excerpta Medica (EMBASE), and the Cochrane Library (September 2012) with synonyms for "radioembolization" and "colorectal cancer liver metastases." Results were described separately for patient cohorts treated with (90)Y radioembolization as monotherapy and with (90)Y radioembolization in combination with chemotherapy. RESULTS: The search yielded 13 relevant articles for systematic review on (90)Y radioembolization as monotherapy and 13 relevant articles on (90)Y radioembolization combined with chemotherapy. Disease control rates (i.e., complete response, partial response, and stable disease) ranged from 29% to 90% for (90)Y radioembolization as monotherapy and from 59% to 100% for (90)Y radioembolization combined with chemotherapy. Heterogeneity in the data prohibited pooling of response rates. Survival proportions at 12 mo ranged from 37% to 59% for (90)Y radioembolization as monotherapy and from 43% to 74% for (90)Y radioembolization combined with chemotherapy. CONCLUSION: In the studies included in this systematic review, approximately 50% of salvage patients with colorectal cancer liver metastases survive more than 12 mo after treatment with (90)Y radioembolization, either as monotherapy or in combination with chemotherapy. Heterogeneity between studies has unfortunately prohibited pooling of data. Future research will discern the precise role of (90)Y radioembolization in general clinical practice in comparison with chemotherapy. PMID- 24071511 TI - Quantification of the specific translocator protein signal of 18F-PBR111 in healthy humans: a genetic polymorphism effect on in vivo binding. AB - PET is used to image active inflammatory processes by targeting the translocator protein (TSPO). In vitro, second-generation TSPO radioligands, such as PBR111, have been shown to bind to human tissue samples with either high affinity (high affinity binders, HABs), low affinity (low-affinity binders, LABs), or an intermediate, mixed affinity (mixed-affinity binders, MABs). We previously explained these differences in affinity in human tissue via the rs6971 polymorphism in the TSPO gene and predicted that the specific signal from PET ligands in vivo would vary accordingly. In silico modeling predicted that (18)F PBR111 would have a moderate to high specific-to-nonspecific ratio in the normal human brain. To test these predictions, we present here the analysis and modeling of (18)F-PBR111 data in healthy humans. METHODS: Twenty-one subjects (9 HABs, 8 MABs, and 4 LABs), 28-62 y old, genotyped for the rs6971 polymorphism, underwent 120-min PET scans with arterial sampling after a bolus injection of (18)F-PBR111. Compartmental models and Logan graphical methods enabled estimation of the total volume of distribution (VT) in regions of interest (ROIs). To evaluate the specific signal, we developed 2 methods to estimate the nondisplaceable volume of distribution (V(ND)): the first assumed that the in vitro affinity ratio of (18)F PBR111 in HABs relative to LABs (4-fold) is preserved in vivo; the second modeled the difference in the HAB and MAB signals in the context of an occupancy plot. RESULTS: A 2-tissue-compartment model described the data well, and a significant difference was found between the VT of HABs, MABs, and LABs across all ROIs examined (P < 0.05). We also found a significant correlation between VT and age for both HABs and MABs in most ROIs. The average V(ND) estimated by the 2 methods was 1.18 +/- 0.35 (method I: V(ND) = 0.93, method II: V(ND) = 1.42), implying that the (18)F-PBR111 BPND was 2.78 +/- 0.46 in HABs, 1.48 +/- 0.28 in MABs, and 0.51 +/- 0.17 in LABs and that the in vivo affinity ratio was similar to that measured in vitro. CONCLUSION: (18)F-PBR111 shows a high specific signal in the healthy human brain in vivo. A large component of the variability in the signal across subjects is explained by genetic variation and age, indicating that (18)F PBR111 can be used for the quantitative assessment of TSPO expression. PMID- 24071512 TI - 18F-FDG PET/CT for early prediction of response to neoadjuvant lapatinib, trastuzumab, and their combination in HER2-positive breast cancer: results from Neo-ALTTO. PMID- 24071513 TI - The structural dynamics of alpha-tropomyosin on F-actin shape the overlap complex between adjacent tropomyosin molecules. AB - Coiled-coil tropomyosin, localized on actin filaments in virtually all eukaryotic cells, serves as a gatekeeper regulating access of the motor protein myosin and other actin-binding proteins onto the thin filament surface. Tropomyosin's modular pseudo-repeating pattern of approximately 39 amino acid residues is designed to allow binding of the coiled-coil to successive actin subunits along thin filaments. Even though different tropomyosin isoforms contain varying numbers of repeat modules, the pseudo-repeat length, in all cases, matches that of a single actin subunit. Thus, the seven pseudo-repeats of 42nm long muscle tropomyosin bind to seven successive actin subunits along thin filaments, while simultaneously bending into a super-helical conformation that is preshaped to the actin filament helix. In order to form a continuous cable on thin filaments that is free of gaps, adjacent tropomyosin molecules polymerize head-to-tail by means of a short (~9 residue) overlap. Several laboratories have engineered peptides to mimic the N- and C-terminal tropomyosin association and to characterize the overlap structure. All overlapping domains examined show a compact N-terminal coiled-coil inserting into a partially opened C-terminal partner, where the opposing coiled-coils at the overlap junction face each other at up to ~90 degrees twist angles. Here, Molecular Dynamics (MD) simulations were carried out to determine constraints on the formation of the tropomyosin overlap complex and to assess the amount of twisting exhibited by full-length tropomyosin when bound to actin. With the exception of the last 20-40 C- and N-terminal residues, we find that the average tropomyosin structure closely resembles a "canonical" model proposed in the classic work of McLachlan and Stewart, displaying perfectly symmetrical supercoil geometry matching the F-actin helix with an integral number of coiled-coil turns, a coiled-coil helical pitch of 137A, a superhelical pitch of 770A, and no localized pseudo-rotation. Over the middle 70% of tropomyosin, the average twisting of the coiled-coil deviates only by 10 degrees from the canonical model and the torsional freedom is very small (std. dev. of 7 degrees ). This small degree of twisting cannot yield the orthogonal N- and C-termini configuration observed experimentally. In marked contrast, considerable coiled coil unfolding, splaying and twisting at N- and C-terminal ends is observed, providing the conformational plasticity needed for head-to-tail nexus formation. PMID- 24071514 TI - beta-carotene regulates expression of beta-carotene 15,15'-monoxygenase in human alveolar epithelial cells. AB - beta-Carotene 15,15'-monooxygenase (CMO1, BCMO1) converts beta-carotene to retinaldehyde (retinal) and is a key enzyme in vitamin A metabolism. CMO1 activity is robust in the intestine and liver, where cmo1 gene transcription may be subject to negative feedback by accumulation of its metabolic products. Evidence from CMO1 null animals also indicates that non-gastrointestinal CMO1 may be required for tissue-specific conversion of beta-carotene into vitamin A. The aim of this study was to investigate the effects of the enzymatic substrate, beta carotene, on regulation of CMO1 in a cell model of human alveolar pneumocytes. We demonstrate that CMO1 is expressed in human alveolar epithelial (A549) cells and converts beta-carotene into retinal and biologically active retinoic acids (RA). Exposure to beta-carotene suppresses CMO1 expression at both mRNA and protein levels. beta-Carotene, but not all-trans RA, decreases CMO1 promoter activity in a time- and dosage-dependent manner. This beta-carotene-mediated inhibition of CMO1 expression results from decreased binding of peroxisome proliferator activated receptor gamma (PPARgamma) and retinoid X receptor alpha (RXRalpha) in the CMO1 promoter. beta-Carotene treatment also antagonizes PPARgamma activity in HEK293 cells that stably express CMO1 wild-type, but not in cells that express the CMO1 mutant or vector alone. These findings have implications for local vitamin A synthesis in the lung, especially during systemic vitamin A insufficiency and may also help to explain, in part, the mechanism underlying the increased lung cancer risk upon beta-carotene supplementation in smokers. PMID- 24071515 TI - Binding modes of DL-2-haloacid dehalogenase revealed by crystallography, modeling and isotope effects studies. AB - Several pathways of biotic dechlorination can be found in enzymes, each characterized by different chlorine isotopic fractionation, which can thus serve as a signature of a particular mechanism. Unlike other dehalogenases, DL-2 haloacid dehalogenase, DL-DEX, converts both enantiomers of the substrate. Chlorine isotope effects for this enzyme are larger than in the case of other dehalogenases. Recently, the 3D structure of this enzyme became available and enabled us to model these isotope effects and seek their origin. We show that the elevated values of the chlorine kinetic isotope effects originate in part in the processes of binding and migration within the enzyme active site that precede the dehalogenation step. PMID- 24071516 TI - Prevalence of latent tuberculosis infection in BCG-vaccinated healthcare workers by using an interferon-gamma release assay and the tuberculin skin test in an intermediate tuberculosis burden country. AB - BACKGROUND: The risk of healthcare workers (HCWs) acquiring tuberculosis (TB) infection is high. We determined the prevalence of latent TB infection (LTBI) in HCWs with a high Bacille Calmette-Guerin (BCG) vaccine coverage in an intermediate TB burden country by using an interferon-gamma release assay [QuantiFERON-TB Gold (QFT-G)] and by using the tuberculin skin test (TST). Risk factors associated with a positive test were determined. METHODS: This prospective cross-sectional study enrolled HCWs from a medical center in Taiwan. Participants were grouped into workers without exposure (Group 1) and workers who self-reported a history of TB exposure (Group 2). All participants completed a questionnaire to collect demographic information and risk factors for acquiring TB. The QFT-G test and the TST were administered and risk factors for a positive test were analyzed. RESULTS: We recruited 193 HCWs [149 (77.2%) female workers] with a mean age of 35.6 years. All were BCG-vaccinated. The prevalence of LTBI was 88.8% (based on the TST) and 14.5% (based on the QFT-G test). There was no difference between HCWs with and without known exposure to TB. Agreement between the tests was poor (i.e., the kappa value was less than 0.05). Multivariable logistic regression showed that only the QFT-G test was associated with age (35 years or greater) (adjusted OR, 2.53; p = 0.03). CONCLUSION: By using the QFT-G test or TST, this study found a similar prevalence of LTBI in HCWs with and without known exposure to TB. This suggests that in intermediate TB burden countries exposure to TB may occur within the hospital and within the community. Compared to the TST, the QFT-G test was correlated better with age, which is a known risk factor for latent TB infection. PMID- 24071517 TI - Tetramethylpyrazine reduces glucose and insulin-induced activation of hepatic stellate cells by inhibiting insulin receptor-mediated PI3K/AKT and ERK pathways. AB - Hepatic stellate cell (HSC) activation is the central event during liver fibrogenesis. Metabolic syndrome characterized by hyperglycemia and hyperinsulinemia contributes to nonalcoholic steatohepatitis-associated liver fibrosis. This study was to investigate the effects of tetramethylpyrazine (TMP) on HSC activation induced by glucose and insulin (Glu/Ins) and the underlying mechanisms. Results showed that Glu/Ins significantly stimulated proliferation, invasion, adhesion, and extracellular matrix (ECM) production in HSCs. TMP inhibited HSC proliferation, invasion and adhesion, and reduced the expression of marker genes related to HSC activation in Glu/Ins-activated HSCs. Mechanistic evidence revealed that TMP reduced insulin receptor (InsR) expression and blocked the downstream phosphatidylinositol-3-kinase (PI3K)/AKT and extracellular signal regulated kinase (ERK) cascades, which was required for TMP attenuation of HSC activation. Moreover, TMP modulated the genes relevant to ECM homeostasis favoring ECM degradation. It could be concluded that TMP inhibited Glu/Ins stimulated HSC activation and ECM production by inhibiting InsR-mediated PI3K/AKT and ERK pathways. PMID- 24071518 TI - Estrogen receptor-mediated long-range chromatin interactions and transcription in breast cancer. AB - Estrogen induces the binding of ERalpha to thousands of locations in the breast cancer genome, preferring intergenic and distal regions rather than near the promoters of estrogen-regulated genes. With recent technological innovations in mapping and characterization of global chromatin organization, evidence now indicates ERalpha mediates long-range chromatin interactions to control gene transcription. The principles that govern how ERalpha communicates with their putative target genes via chromosomal interactions are also beginning to unravel. Herein, we summarize our current knowledge on the functional significance of chromatin looping in estrogen-mediated transcription. ERalpha collaborative factors and other players that contribute to define the genomic interactions in breast cancer cells will also be discussed. Defects in chromatin organization are emerging key players in diseases such as cancer, thus understanding how ERalpha mediated chromatin looping affects genome organization will clarify the receptor's role in estrogen responsive pathways sensitive to defects in chromatin organization. PMID- 24071519 TI - Heat stress promotes skeletal muscle regeneration after crush injury in rats. AB - Influences of heat stress on skeletal muscle regeneration were examined in experimental rats. After crush injury to the Extensor digitorum longus muscle (EDL) of the left hindlimb, animals were randomly divided into non-heat and heat groups. In the latter, packs filled with hot water (42 degrees C) were percutaneously applied to the injured EDL muscle for 20min to the front of the lower leg, soon after the injury. During the early stages of muscle regeneration, due to the heat stress, secondary degeneration at the injured site progressed faster, and migration of macrophages, proliferation and differentiation of satellite cells were facilitated. At 14 and 28 days after the injury, the ratio of regenerating muscle fibers exhibiting central nuclei in the heat treated group was significantly lower than that in the non-heat group, and cross sectional area in the heat group was evidently larger than that in the non-heat group. Moreover, in the heat group, the ratio of collagen fiber area at 14 and 28 days after the injury was smaller than in the non-heat group. Together, these findings suggest that acceleration of degeneration processes by heat stress soon after injury is likely to promote skeletal muscle regeneration and inhibit collagen deposition. PMID- 24071520 TI - Serotonin (5HT) expression in rat pups treated with high-tryptophan diet during fetal and early postnatal development. AB - Serotonin (5HT) is a neurotransmitter synthesized in serotonergic neurons of the central nervous system and in the enterochromaffin cells of the gastrointestinal tract. 5HT regulates growth and maturation of some cerebral regions in the developing brain as well as the secretion of pituitary growth hormone. This hormone is necessary for development and growth through the stimulation of insulin-like growth factor synthesis. The precursor of 5HT, tryptophan (Trp), is an essential amino acid, since the human organism is unable to synthesize it and it is assumed only through diet. The aim of our study was to analyze how a high tryptophan diet in pregnant rats affects growth and survival of pups until weaning. We monitored the number and weight of pups until weaning. Then, we detected serotonin and growth hormone levels in whole blood by ELISA of surviving pups at the end of the lactation period. We also analyzed by means of immunohistochemistry and Western blot the expression of serotonin in rat gastric tissue and the morphological structure of skeletal muscle tissue of both control and experimental pups. Hyperserotonemia and very low levels of growth hormone were detected in experimental pups compared to controls. Immunohistochemistry demonstrated a strong serotonin expression in stomach samples confirming that a high intake of tryptophan increases the production of serotonin in enterochromaffin cells, thereby resulting in hyperserotonemia in pups. These data were also strengthened by Western blot analysis. Histological alterations of skeletal muscle fibers in experimental pups were found and showed that in experimental samples the muscle tissue demonstrated deleterious alterations, being less developed and defined. Our data suggest that a high-tryptophan diet in pregnant rats induces hyperserotonemia in the fetus. Hyperserotonemia results in an excess of serotonin in the brain where it has a negative influence on development of serotonergic neurons and consequently on growth hormone production. PMID- 24071521 TI - High-fat-cholesterol diet mainly induced necrosis in fibrotic steatohepatitis rat by suppressing caspase activity. AB - AIM: Apoptosis and necrosis occur in nonalcoholic steatohepatitis (NASH) and are thought to be related to fibrosis. A stroke-prone spontaneously hypertensive (SHRSP5/Dmcr) rat fed a high-fat-cholesterol (HFC) diet exhibited similar pathological features to human NASH with severe liver fibrosis. We aimed to reveal the molecular pathway and to confirm the relationship between cell death, fibrosis and K18Asp396 levels, a neoepitope generated during cleavage of keratin 18 by caspases, as a candidate for biomarker of hepatic damage in this animal model. MAIN METHODS: Male rats were fed with control and HFC diets for 2, 8 and 14 weeks. Liver apoptosis cells, necrosis score, and the molecular mechanism and K18Asp396 levels were investigated. KEY FINDINGS: HFC diet increased TUNEL positive cells only at 2 weeks and necrosis scores strongly in the livers of rats during the entire period. This diet increased hepatic Bax/Bak but decreased Bcl 2/Bcl-xl expression during the entire period; however, it upregulated caspase 8, 9, and 3/7 activities only at 2 weeks, but downregulated them at 14 weeks. Additionally, this diet did not increase hepatic cytochrome c expression. Serum K18Asp396 levels have a positive correlation with necrosis score. SIGNIFICANCE: In SHRSP5/Dmcr rats, HFC diet caused hepatocyte necrosis rather than apoptosis by the downregulation of all caspase activity. Serum K18Asp396 levels may be a good biomarker of hepatocyte necrosis. PMID- 24071523 TI - Intervention research to enhance community pharmacists' cognitive services: a systematic review. AB - BACKGROUND: Positive impact of community pharmacists' cognitive pharmaceutical services (CPS) is well documented. However, community pharmacists have been slow to expand CPS roles. This systematic review explores how community pharmacy intervention research can help inform efforts to expand cognitive pharmaceutical service delivery. OBJECTIVES: To: 1) identify community pharmacy CPS intervention studies that report data on pharmacist behaviors, either as a final study outcome itself or as a fidelity measure in patient outcome studies, and 2) describe the state of this research to help frame future research agendas. METHODS: Empirical articles examining improvement or expansion of community pharmacist cognitive services published through December 2010 were searched using various search engines, bibliography searches and authors' libraries. Studies were included if they: 1) reported findings on pharmacist behaviors during cognitive service delivery, 2) employed a minimum of pre-post design or two study arms for pharmacists/pharmacies, and 3) were in community-based pharmacies. RESULTS: A total of 50 studies evaluated impact of community pharmacy based CPS delivery; however, only 21 included a pharmacist behavior outcome measure as a final outcome or as a fidelity measure. The majority (14 out of 21) of studies used a randomized controlled trial design. Nearly half (10 of 21) addressed asthma or tobacco cessation. Limited details were provided about interventions to prepare pharmacists for CPS delivery. The most frequent measures of pharmacist behavior were patient surveys and observation of pharmacists' behavior by secret shoppers; electronic data sets were rarely used. CONCLUSIONS: There is a need for well designed intervention research that evaluates how interventions impact on pharmacist cognitive service behavior. Positive findings from this review reinforce that planned interventions have the potential to improve and expand pharmacist cognitive service delivery; however, more detail is needed in study publications for this potential to be fully realized. PMID- 24071522 TI - Moving around the molecule: relationship between chemical structure and in vivo activity of synthetic cannabinoids. AB - Originally synthesized for research purposes, indole- and pyrrole-derived synthetic cannabinoids are the most common psychoactive compounds contained in abused products marketed as "spice" or "herbal incense." While CB1 and CB2 receptor affinities are available for most of these research chemicals, in vivo pharmacological data are sparse. In mice, cannabinoids produce a characteristic profile of dose-dependent effects: antinociception, hypothermia, catalepsy and suppression of locomotion. In combination with receptor binding data, this tetrad battery has been useful in evaluation of the relationship between the structural features of synthetic cannabinoids and their in vivo cannabimimetic activity. Here, published tetrad studies are reviewed and additional in vivo data on synthetic cannabinoids are presented. Overall, the best predictor of likely cannabimimetic effects in the tetrad tests was good CB1 receptor affinity. Further, retention of good CB1 affinity and in vivo activity was observed across a wide array of structural manipulations of substituents of the prototypic aminoalkylindole molecule WIN55,212-2, including substitution of an alkyl for the morpholino group, replacement of an indole core with a pyrrole or phenylpyrrole, substitution of a phenylacetyl or tetramethylcyclopropyl group for JWH-018's naphthoyl, and halogenation of the naphthoyl group. This flexibility of cannabinoid ligand-receptor interactions has been a particular challenge for forensic scientists who have struggled to identify and regulate each new compound as it has appeared on the drug market. One of the most pressing future research needs is determination of the extent to which the pharmacology of these synthetic cannabinoids may differ from those of classical cannabinoids. PMID- 24071524 TI - Quasi-periodic patterns (QPP): large-scale dynamics in resting state fMRI that correlate with local infraslow electrical activity. AB - Functional connectivity measurements from resting state blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) are proving a powerful tool to probe both normal brain function and neuropsychiatric disorders. However, the neural mechanisms that coordinate these large networks are poorly understood, particularly in the context of the growing interest in network dynamics. Recent work in anesthetized rats has shown that the spontaneous BOLD fluctuations are tightly linked to infraslow local field potentials (LFPs) that are seldom recorded but comparable in frequency to the slow BOLD fluctuations. These findings support the hypothesis that long-range coordination involves low frequency neural oscillations and establishes infraslow LFPs as an excellent candidate for probing the neural underpinnings of the BOLD spatiotemporal patterns observed in both rats and humans. To further examine the link between large-scale network dynamics and infraslow LFPs, simultaneous fMRI and microelectrode recording were performed in anesthetized rats. Using an optimized filter to isolate shared components of the signals, we found that time-lagged correlation between infraslow LFPs and BOLD is comparable in spatial extent and timing to a quasi-periodic pattern (QPP) found from BOLD alone, suggesting that fMRI-measured QPPs and the infraslow LFPs share a common mechanism. As fMRI allows spatial resolution and whole brain coverage not available with electroencephalography, QPPs can be used to better understand the role of infraslow oscillations in normal brain function and neurological or psychiatric disorders. PMID- 24071526 TI - Using carbogen for calibrated fMRI at 7Tesla: comparison of direct and modelled estimation of the M parameter. AB - Task-evoked changes in cerebral oxygen metabolism can be measured using calibrated functional Magnetic Resonance Imaging (fMRI). This technique requires the use of breathing manipulations such as hypercapnia, hyperoxia or a combination of both to determine a calibration factor M. The M-value is usually obtained by extrapolating the BOLD signal measured during the gas manipulation to its upper theoretical physiological limit using a biophysical model. However, a recently introduced technique uses a combination of increased inspired concentrations of O2 and CO2 to saturate the BOLD signal completely. In this study, we used this BOLD saturation technique to measure M directly at 7Tesla (T). Simultaneous carbogen-7 (7% CO2 in 93% O2) inhalation and visuo-motor task performance were used to elevate venous oxygen saturation in visual and motor areas close to their maximum, and the BOLD signal measured during this manipulation was used as an estimate of M. As accurate estimation of M is crucial for estimation of valid oxidative metabolism values, these directly estimated M values were assessed and compared with M-values obtained via extrapolation modelling using the generalized calibration model (GCM) on the same dataset. Average M-values measured using both methods were 10.4+/-3.9% (modelled) and 7.5+/-2.2% (direct) for a visual-related ROI, and 11.3+/-5.2% (modelled) and 8.1+/-2.6% (direct) for a motor-related ROI. Results from this study suggest that, for the CO2 concentration used here, modelling is necessary for the accurate estimation of the M parameter. Neither gas inhalation alone, nor gas inhalation combined with a visuo-motor task, was sufficient to completely saturate venous blood in most subjects. Calibrated fMRI studies should therefore rely on existing models for gas inhalation-based calibration of the BOLD signal. PMID- 24071525 TI - Cognitive ability changes and dynamics of cortical thickness development in healthy children and adolescents. AB - Intelligence quotient (IQ) scores tend to remain stable across the lifespan. Nevertheless, in some healthy individuals, significant decreases or increases in IQ have been observed over time. It is unclear whether such changes reflect true functional change or merely measurement error. Here, we applied surface-based corticometry to investigate vertex-wise cortical surface area and thickness correlates of changes in Full Scale IQ (FSIQ), Performance IQ (PIQ) and Verbal IQ (VIQ) in a representative sample of children and adolescents (n=188, mean age=11.59years) assessed two years apart as part of the NIH Study of Normal Brain Development. No significant associations between changes in IQ measures and changes in cortical surface area were observed, whereas changes in FSIQ, PIQ, and VIQ were related to rates of cortical thinning, mainly in left frontal areas. Participants who showed reliable gains in FSIQ showed no significant changes in cortical thickness on average, whereas those who exhibited no significant FSIQ change showed moderate declines in cortical thickness. Importantly, individuals who showed large decreases in FSIQ displayed the steepest and most significant reductions in cortical thickness. Results support the view that there can be meaningful cognitive ability changes that impact IQ within relatively short developmental periods and show that such changes are associated with the dynamics of cortical thickness development. PMID- 24071527 TI - Structure of fructo-oligosaccharides from leaves and stem of Agave tequilana Weber, var. azul. AB - Fructo-oligosaccharides (FOSs) of a six year old agave plant variety, Agave tequilana, were isolated and fractionated by 2D preparative chromatography (SEC and rpHPLC). Structural analyses of different FOS-fractions were performed by reductive methylation analysis connected to GC/FID identification and NMR analysis. FOSs from leaves (d.p. 3-8) contain single alpha-d-Glcp residues as well in terminal as internal position, however (2->1)-linked beta-d-Fruf residues only. FOSs from stem, however, contain as well (2->1)- and (2->6)-linked beta-d Fruf residues with branched oligomeric repeating units. These characteristics indicate an enzymatically catalyzed metabolic regulation for the biosynthesis and transformation of fructans in A. tequilana which strongly depends on location and transport activities. PMID- 24071528 TI - [Comparison of the Latissimus dorsi insertions on the iliac crest in chimpanzee (Pan troglodytes) and in man]. AB - INTRODUCTION: Comparing to other primates, one of the most important specificities of the human anatomy are consequences of bipedalism. Although bone consequences are well known (lumbar lordosis, horizontal position of the foramen magnum, lengthening of the lower limbs, reduction of the pelvis, specialization of the foot), consequences of our locomotion on the Latissimus dorsi are still unclear. MATERIALS AND METHODS: One dissection of a chimpanzee Latissimus dorsi (Pan troglodytes) has been performed and compared to 30 human Latissimus dorsi dissections (10 fresh cadavers and 20 formoled cadavers). In each dissection, the existence of direct muscular insertions on the iliac crest has been investigated and the constitution of the thoracolumbar fascia has been described. RESULTS: In chimpanzee dissection, a muscular direct insertion of the Latissimus dorsi was present on the iliac crest of 9 cm long. The TLF was made of the superficial and the deep fascias of the Latissimus dorsi and the superficial fascia of the erector spinae muscles which was deeper. In man, there was no direct muscular insertion of the Latissimus dorsi in 90 % of cases, the TLF was constituted the same way. CONCLUSION: This study suggests that the Latissimus dorsi has been separated from the iliac crest in man during the evolution because of the permanent bipedalism and that it stayed inserted on the iliac crest in chimpanzee because of the brachiation. PMID- 24071529 TI - Editorial comment. PMID- 24071530 TI - Subthalamic stimulation modulates self-estimation of patients with Parkinson's disease and induces risk-seeking behaviour. AB - Patients with Parkinson's disease with deep brain stimulation in the subthalamic nucleus postoperatively often display higher impulsivity and therefore may experience difficulties in social interactions. Here, we examined social interactions of patients with Parkinson's disease with and without deep brain stimulation in the subthalamic nucleus in competitive situations. We hypothesized altered self-estimation and risk-seeking behaviour in this patient group induced by deep brain stimulation in the subthalamic nucleus. To test the hypothesis, an experimental setting was used in which participants performed a calculation task and chose their preferred compensation. Based on their actual calculation performance, more patients with Parkinson's disease with deep brain stimulation chose a competitive tournament compensation. Assuming rational behaviour, this self-selection pattern reflects increased risk tolerance. Since patients who performed in the lowest quartile chose the tournament option, the data suggest that deep brain stimulation in the subthalamic nucleus results in a loss of the correct reference frame against which patients with Parkinson's disease evaluate their performance. The stimulation-induced combination of overestimation of their own performance, increased risk-taking, and preference for competitive environments despite poor performance is likely to impact considerably on the patients' social and work life. PMID- 24071531 TI - The invalidity of the Laplace law for biological vessels and of estimating elastic modulus from total stress vs. strain: a new practical method. AB - There are strong medical motivations to measure changes in material properties of tubular organs, in vivo and in vitro. The current approach estimates hoop stress from intraluminal pressure using the Laplace law and identifies 'elastic modulus' as the slope of a curve fitted hoop stress plotted against strain data. We show that this procedure is fundamentally flawed because muscle and other soft tissue are closely incompressible, so that the total stress includes a volume-preserving material-dependent hydrostatic response that invalidates the method. Furthermore, we show that the Laplace law incorrectly estimates total stress in biological vessels. However, the great need to estimate elastic modulus leads us to develop an alternative practical method, based on shear stress-strain, i.e. insensitive to nonelastic response from incompressibility, but that uses the same measurement data as the current (incorrect) method. The individual material parameters in the underlying (unknown) constitutive relation combine into an effective shear modulus that is a true measure of elastic response, unaffected by incompressibility and without reference to the Laplace law. Furthermore, our effective shear modulus is determined directly as a function of deformation, rather than as the slope of a fitted curve. We validate our method by comparing effective shear moduli against exact shear moduli for four theoretical materials with different degrees of nonlinearity and numbers of material parameters. To further demonstrate applicability, we reanalyse an in vivo study with our new method and show that it resolves an inconsistent change in modulus with the current method. PMID- 24071532 TI - [Fetal weight estimation during labour: comparison of the clinical and ultrasonographic approaches]. AB - OBJECTIVE: The estimation of the fetal weight is of major interest in many situations when the route of delivery has to be determined: breech presentations, diabetes and suspected macrosomia. The objective was to evaluate the accuracy of different methods for estimating fetal weight (EFW) during labour. A quality audit of the ultrasound images was also performed. PATIENTS AND METHODS: This was a prospective study performed in thirty patients at 37 weeks gestation or more, during the second stage of labour. The accuracy of clinical versus ultrasonographic (US) approach for EFW was tested (by two formulas according to Hadlock, with one that does not account head circumference [HC]). The ultrasound images' quality was also evaluated. RESULTS: The clinical assessment was significantly more accurate (-1 +/- 8.5%) than the US approach using the formula with HC (-8 +/- 9.8 %) (P<0.01). This difference was not found when choosing the formula without HC. Analysis of ultrasound images for abdomen and femur showed 74% and 89% of satisfactory measurements respectively, but only 43% for HC. CONCLUSION: These results did not demonstrate a superiority of the US over the clinical approach for EFW during labour. Taking into account the cephalic measurements appeared as a limitation of the accuracy of US formulas. PMID- 24071533 TI - Drug dosing and estimates of kidney function. PMID- 24071534 TI - The effect of age and comorbidity on patient-centered health outcomes in patients receiving adjuvant chemotherapy for colon cancer. AB - OBJECTIVES: While the impact of age, comorbidity and receipt of adjuvant chemotherapy on survival are known, less is known about their effect on patient centered outcomes including living situation and unplanned health care services. The current study describes the impact of age and comorbidity on patient-centered outcomes in patients with colon cancer. MATERIALS AND METHODS: Patients with resected stage III colon cancer and high risk stage II colon cancer were identified from a colorectal cancer center database. Using data collected from chart abstraction, we describe unplanned health care utilization and trajectories of living situation (use of home health, skilled nursing facility, etc.) among high-risk stage II and III colon cancer patients with regard to age categories and receipt of adjuvant chemotherapy. RESULTS: Among 126 eligible patients, 66% received adjuvant chemotherapy and 34% did not. Older patients receiving chemotherapy were more likely to be living independently (81%) compared to those older patients who did not receive chemotherapy (63%). Older patients receiving chemotherapy were less likely to be started on an oxaliplatin-containing regimen compared to younger patients (54% vs. 81%, p=0.02). On multivariate analysis, both diabetes mellitus (OR 3.70 [95% CI 1.3-10.2]) and chronic obstructive pulmonary disease (OR 4.26 [95% CI 1.1-16.0]) were significantly associated with unplanned health care service use. CONCLUSION: Medical oncologists appear to factor clinical and sociodemographic variables when making recommendations for adjuvant chemotherapy. Older patients deemed eligible for chemotherapy did not experience significant changes in living situation. Among patients with colon cancer receiving adjuvant chemotherapy, diabetes mellitus and COPD are associated with emergency visits and hospital admissions. PMID- 24071535 TI - Targeting therapy for esophageal cancer in patients aged 70 and over. AB - BACKGROUND: While cancer is a disease of the elderly, these patients are under represented in randomized trials. Esophageal cancer-management in the elderly is challenging because of the morbidity and mortality associated with surgery. OBJECTIVES: We examined a strategy of neo-adjuvant chemo-radiotherapy (naCRT), followed by surgery or surveillance, in selected patients with cancer aged 70 and older. METHODS: A prospectively-accrued database identified 56 consecutive patients over a 90-month period, who were aged 70years and over, presented with esophageal carcinoma and were treated with neo-adjuvant CRT (naCRT)+/-surgery. RESULTS: Of 129 eligible patients, 66 (51%) received palliative measures, while 63 (49%) had curative intervention, namely 7 had surgery and 56 had naCRT+/ surgery. Of these 56 patients, 33 (59%) had adenocarcinoma (AC) and 23 (41%) had squamous cell carcinoma (SCC). Twenty-five (45%) had a complete clinical response (cCR), of which 6 had immediate resection; 4 (67%) had a complete pathological response (pCR); 19 patients with a cCR declined or were unfit for surgery and underwent surveillance; of these, 3 had interval esophagectomy; 16 were not offered or declined resection. Eight (50%) have survived >=3years. Mean overall survival was 28months for the entire cohort; 47months for cCRs; 61months for patients undergoing primary resection, 46months for cCRs who did not undergo resection and 29months for those undergoing interval resection for recurrent disease. In cCRs, surgery did not provide a survival advantage (p=0.861). CONCLUSION: cCR yields an overall 3-year survival of 50% without operation. As 45% of patients have a cCR to naCRT, obligatory resection in high-risk cCR patients makes little sense. With the option for salvage esophagectomy in re emergent disease, this selective strategy is an attractive alternative for elderly patients with cancer. PMID- 24071536 TI - Biweekly XELOX (capecitabine and oxaliplatin) as first-line treatment in elderly patients with metastatic colorectal cancer. AB - OBJECTIVE: The combination of oxaliplatin and oral capecitabine (XELOX) has shown to be an active regimen in metastatic colorectal cancer (MCRC). However, the experience with XELOX in elderly patients is limited. This study aimed to evaluate the efficacy and safety of XELOX as first-line treatment in elderly patients with MCRC. PATIENTS AND METHODS: Patients aged >=70years with previously untreated MCRC received oxaliplatin 85mg/m(2) on day 1, every 2weeks plus capecitabine 1000mg/m(2) (or capecitabine 750mg/m(2) if creatinine clearance was 30-50mL/min) twice daily on days 1-7, every 2weeks. Treatment was continued until progression, intolerable toxicity, or for a maximum of 12cycles. RESULTS: Thirty five patients were enrolled. Median age was 78years (range, 70-83). Patients received a median of 11cycles of treatment. The objective response rate (ORR) was 49% and the tumor control rate was 86%. Median time to progression and overall survival were 8.6 (95% CI: 5.5-11.7) and 15.5 (95% CI: 9.6-21.3) months, respectively. Toxicities were generally mild to moderate. Major grade 1-2 toxicities were asthenia (40%), nausea (43%), and diarrhea (40%). No grade 4 toxicity was detected and grade 3 toxicities were reported in 17% of patients. There was no treatment-related death. CONCLUSION: Our findings show that the biweekly XELOX regimen represents an effective and tolerable first-line treatment option for elderly patients with MCRC. PMID- 24071537 TI - Risk-adapted, dose escalation study of weekly docetaxel in the first-line treatment of elderly patients with advanced cancer. AB - OBJECTIVES: As a consequence of under-representation of elderly patients in clinical trials, the recommended dose of chemotherapy is often based on results observed in younger patients. We designed a risk-adapted, dose escalation study of weekly docetaxel in the first-line treatment of elderly patients with cancer in order to determine the optimal dose according to age, comorbidity and functional status. PATIENTS AND METHODS: Sixty-eight patients aged 70 or more were stratified into three risk groups according to a combination of age, performance status, and comorbidity. The study was conducted using a standard phase I design with sequential cohorts of patients receiving docetaxel at increasing doses in each risk group. RESULTS: The maximum tolerated dose was not reached in the intermediate-risk group and was 45mg/m(2)/week in the high-risk group. Because of a slow recruitment rate, it was not possible to conclude the trial in the good-risk category. Neutropenia, asthenia and diarrhea were the most frequently encountered severe toxicities. CONCLUSIONS: Docetaxel can be used at a dose of 40mg/m(2)/week as a first-line treatment for elderly patients with locally advanced or metastatic cancer without excessive toxicity. The risk groups defined in the study are not able to accurately distinguish between subgroups of patients with divergent toxicity profiles. PMID- 24071538 TI - Factors affecting survival in patients aged 60 and over with diffuse large B cell lymphoma failing first-line therapy. AB - OBJECTIVES: Elderly patients with diffuse large B cell lymphoma (DLBCL) without prohibitive co-morbidities may be cured with standard immuno-chemotherapeutic regimens, as used in younger patients. Less is known about the survival prospects in older people, if first-line therapy fails. This study aimed to provide additional information regarding prognosis in this group. MATERIALS AND METHODS: Databases were collated from three randomized trials of first-line therapy in those aged 60 and over, deemed fit enough for standard therapy. Overall survival from the point of treatment failure was calculated and comparisons were made between age groups and types of treatment failure. RESULTS: Overall survival (OS) at 2years in 862 patients was 46%, 38%, 37% and 23%, respectively, for those aged 60-64, 65-69, 70-74 and >74. Type of treatment failure impacted on 2year OS as follows: initial partial remission (PR): 48%; complete response (CR) with late relapse: 37%; CR with early relapse: 17%; and less than PR to initial therapy: 12%. CONCLUSION: Older patients failing first-line therapy for DLBCL should be counseled differently regarding prognosis depending upon age and type of treatment failure. The chance of survival was greater in those achieving PR or CR with relapse more than 12months from diagnosis. This data may support the consideration of aggressive salvage therapy in fit patients in these categories, regardless of biological age per se. Palliative management may be more appropriate for those achieving less than PR to initial therapy or who enter CR but relapse within one year of diagnosis. PMID- 24071539 TI - First immunochemotherapy outcomes in elderly patients with CLL: a retrospective analysis. AB - BACKGROUND: To date, the majority of trials on chronic lymphocytic leukemia (CLL) focused on patients considerably younger than the median age of onset for CLL. As a result, no definitive treatment exists for elderly patients, especially less medically fit patients. OBJECTIVES: The objectives of this study are to examine the impact of comorbidities on outcome as well as to compare three different therapeutic regimens in outcome efficacy. MATERIALS AND METHODS: We retrospectively identified 143 patients aged >65 years, who received fludarabine, cyclophosphamide, and rituximab (FCR) (n=49), fludarabine and rituximab (FR) (n=74), or rituximab with chlorambucil (R-CLB) (n=20) as first initial immunochemotherapy. RESULTS: At current follow-up (median: 24 months), the proportion of patients with a clinical response was higher with FCR (75%) than FR (57%) and R-CLB (28%). For FCR, FR, and R-CLB patients, 2-year overall survival (OS) was 94%, 76%, and 73%, respectively, (p=0.14), while 2-year progression-free survival (PFS) was 90%, 58%, and 30% (p<0.001). In the fludarabine based regimen (FR and FCR) population, higher rituximab doses (500mg/m(2) vs. 375mg/m(2)) correlated with prolonged PFS. CONCLUSION: Despite the retrospective nature of this study, we demonstrate that elderly patients with CLL benefit from frontline immunochemotherapy, and emphasize the importance of maintaining rituximab dose intensity. PMID- 24071540 TI - Adjuvant chemotherapy and differential invasive breast cancer specific survival in elderly women. AB - OBJECTIVE: To assess adjuvant chemotherapy recommendations, administration and disease-specific survival for invasive breast cancer (BC) among patients 75years and older compared with that of younger women. MATERIALS AND METHODS: A cohort of patients with primary breast cancer, aged 65-94, stages I-III from 1990 to 2010 was identified and tracked by our breast cancer registry (n=2329). Stage, treatment recommendations and outcomes were chart abstracted at diagnosis and follow-up. Associations were tested with logistic regression and the Kaplan-Meier method was used for disease-specific survival (DSS). RESULTS: Seventy-five percent of patients aged 75+ were seen by an oncologist compared with 78% aged 70 74 and 84% aged 65-69. Women aged 75+ seen by an oncologist were more likely age 75-79, stage II/III, hormone receptor negative (HR-) or her-2/neu positive. Of these patients, age, stage and HR status were related to a chemotherapy recommendation. Of 106 patients recommended for chemotherapy, 18 refused (17%) and 24 did not complete treatment due to complications, patient choice, disease progression or death not related to treatment. DSS was equivalent for patients 75 and older with stage I BC compared to 65-74year olds, but significantly worse in stage II and III patients, respectively (stage II 5year DSS 90% vs. 97%, stage III 5year DSS 65% vs. 81%). CONCLUSION: Patients aged 75 and older with invasive breast cancer who were recommended for adjuvant chemotherapy have a high rate of refusal and complications from therapy. Their disease specific mortality disadvantage is restricted to stage II and III patients, a group in need of effective therapy to improve disease survival. PMID- 24071541 TI - Health and personal resources in older patients with cancer undergoing chemotherapy. AB - OBJECTIVES: The purpose of this study was to gather preliminary data on both direct and moderating effects of health status, the social environment, and perceived personal control on the symptom distress and quality of life (QOL) for older patients with cancer during a treatment regimen of chemotherapy. MATERIALS AND METHODS: Participants were patients with cancer aged>=65years being treated with a variety of chemotherapy regimens specific to their particular diagnosis. Using a longitudinal study design, we measured patients at baseline prior to beginning chemotherapy, midpoint in the regimen, and upon discharge (approximately 2weeks after chemotherapy completion). Outcomes of interest were symptom distress and QOL. Multivariate linear regression was used to determine the association between the predictors and outcomes, controlling for demographic and clinical characteristics. RESULTS: Our final sample consisted of 94 patients with cancer (35 males; 59 females; mean age 73.5years). In the health status domain, lower body strength was inversely associated with symptom distress (p=0.025) and positively associated with QOL (p=0.015). In the social environment domain, social support was inversely associated with fatigue (p=0.001) and depression (p<0.001), and positively associated with QOL (p=0.016 and p=0.029 at midpoint and endpoint, respectively). Personal control variables, mastery and self-efficacy, were significantly associated with multiple outcomes of interest. DISCUSSION: Mastery was the best predictor of symptom distress and QOL. Self efficacy, social support, and lower body functioning are important predictors of these outcomes among older patients with cancer undergoing chemotherapy. PMID- 24071542 TI - Use of the Freund clock drawing test within the Mini-Cog as a screening tool for cognitive impairment in elderly patients with or without cancer. AB - OBJECTIVES: We aimed to determine an optimal cut-off score for the Clock Drawing Test (CDT), scored by the scale of Freund, for efficient screening for cognitive impairment in elderly (cancer) patients within a Comprehensive Geriatric Assessment (CGA) and to compare the Freund CDT to the Mini-Cog. MATERIALS AND METHODS: Data of 221 elderly (>=70years) patients, comprising of an OncoGeriatric (OG) and General Geriatric (GG) group, were retrospectively reviewed. All patients were evaluated with both the CDT and Mini Mental State Examination (MMSE) as the gold standard. Receiver Operating Characteristics (ROC) analysis was used to determine diagnostic performance. A pre-established algorithm was applied to retrieve Mini-Cog results through a combination of the CDT and the 3 Word Delayed Recall (3-WDR) test (included within MMSE). RESULTS: Data of 105 OG and 116 GG patients were evaluated. Potential cognitive impairment (MMSE<=23) was detected in 29.5% and 65.8% of patients, respectively. The CDT showed good diagnostic accuracy in the OG (0.88+/-0.03) and GG (0.85+/-0.03) group, based on the area under the ROC curve (AUC+/-SE). CDT (cut-off<=4) provided good sensitivity (80.7%) and specificity (81.1%) in the OG group and excellent sensitivity (89.6%) and moderate specificity (51.3%) in the GG group. Addition of the 3-WDR test, to form the Mini-Cog, resulted in similar positive and negative predictive values for the OG group and higher negative predictive value for the GG group. CONCLUSION: These data suggest that the Freund CDT, at the cut-off score of <=4, is promising for use within a CGA. The Mini-Cog might be preferable in the GG population. PMID- 24071543 TI - Metabolic, nutritional and inflammatory characteristics in elderly women with advanced cancer. AB - OBJECTIVE: Few studies have focused on the metabolic profiling of patients with advanced cancer and the relationship with nutritional and inflammatory characteristics, which have important diagnostic, treatment and prognostic implications, particularly in the elderly. Our objective was to determine differences in energy expenditure during rest and activity, body composition, nutrition, and inflammatory markers between healthy elderly females and those with advanced cancer. MATERIALS AND METHODS: Twenty elderly (74.8+/-6.7years) females (9 with solid malignancies, 11 healthy) were evaluated for energy expenditure using indirect calorimetry at rest and throughout a 6-min walk test (6MWT). Body composition (dual-energy x-ray absorptiometry); nutritional intake (3-day 24-h food recall); and markers of nutrition and inflammation (complete blood count, albumin and C-reactive protein) were also measured. RESULTS: Compared to healthy controls, patients with cancer had similar energy expenditures, but significantly lower (p<0.05) respiratory quotients at rest. During the 6MWT, the group with cancer walked shorter distances at slower speeds (p<0.001), consumed less oxygen (p<0.05), and trended toward an increased oxygen cost while walking. The patients with cancer ingested fewer calories and presented with higher levels of inflammatory markers (p<0.05). No differences in body composition were observed. CONCLUSION: Early signs of cachexia (i.e. reduced caloric intake, inflammation and greater fat metabolism) may be present in older patients with cancer, along with poorer levels of functional capacity, compared to healthy controls. Timely recognition of these signs may allow therapeutic interventions to better prevent or delay nutritional and functional demise in elderly patients with cancer. PMID- 24071544 TI - Health-care associated bacteremia in geriatric cancer patients with febrile neutropenia. AB - OBJECTIVE: The aim of this study was to determine the epidemiology, clinical manifestations, and outcome of health-care associated bacteremia in geriatric cancer patients with febrile neutropenia. MATERIALS AND METHODS: We retrospectively evaluated cancer patients with febrile neutropenia aged >=60years with culture proven health-care associated bacteremia between January 2005 and December 2011. The date of the first positive blood culture was regarded as the date of bacteremia onset. Primary outcome was the infection related mortality, defined as the death within 14days of bacteremia onset. RESULTS: The two most common pathogens responsible for bacteremia were Staphylococcus epidermidis (36.1%) and Escherichia coli (31.5%), with high rates of methicillin resistance and extended-spectrum beta-lactamase (ESBL) production, respectively. There were no statistically significant differences in infection related mortality rate according to the type of malignancy (p=0.776). By the univariate analysis, factors associated with 14day mortality among febrile neutropenic episodes were prolonged neutropenia (p=0.024), persistent fever (p=0.001), hospitalization in ICU (p<0.001) and the initial clinical presentations including respiratory failure (p<0.001), hepatic failure (p=0.013), hematological failure (p<0.001), neurological failure (p<0.001), severe sepsis (p<0.001), and septic shock (p=0.036). Multivariate analysis showed that persistent fever was an independent factor associated with infection related mortality (odds ratio, 18.0; 95% confidence interval, 5.2-62.6; p<0.001). CONCLUSIONS: The only independent risk factor for mortality was persistent fever. Although the most frequently isolated pathogens were S. epidermidis and E. coli, high rates of methicillin resistance and ESBL production were found respectively. PMID- 24071545 TI - Modeling of treatment response to erythropoiesis-stimulating agents in older (age>=70years) and younger (age<70years) patients with cancer and anemia: findings from the Anemia Cancer Treatment study. AB - INTRODUCTION: The Anemia Cancer Treatment study assessed hemoglobin (Hb) outcomes following treatment with erythropoiesis-stimulating agents (ESA) in anemic (Hb<=11g/dL) patients in Europe. We replicated the original analyses stratifying by age, namely patients aged >=70 (n=637) versus those aged<70 (n=1555). MATERIALS AND METHODS: A secondary analysis of Hb outcomes was assessed over 8 10weeks. Treatment response criteria included increases of Hb>=1g/dL, Hb>=1g/dL over 8weeks, and Hb>=2g/dL over the course of the study period. RESULTS: Mean Hb increased from similar levels of 9.5g/dL [p=not significant (ns)] at visit one to 10.9g/dL (p=ns) at visit three (both p<0.001). Patients aged>=70 had higher mean Hb at visit two (10.6g/dL vs. 10.3g/dL, p<0.001). Cohorts did not differ in treatment response rates (all p=ns). Mean performance status differed between cohorts at each visit (all p<=0.011); both groups showed significant improvements (both p<0.001). Immediacy of response was a consistent determinant but was more pronounced among patients aged>=70. Less consistent determinants included performance status in the age>=70 group, as well as hematological malignancy and Hb at ESA start in the age<70 group. The proportion of variance in Hb outcomes attributable to treatment center ranged from 0.090 to 0.289 in the age>=70 cohort and 0.126 to 0.361 in the age<70 cohort. CONCLUSIONS: Both groups achieved similar Hb levels with the age>=70 cohort showing a higher initial evolution rate and potentially a different Hb response trajectory. Patients age>=70 were more likely to benefit from ESAs if showing an early erythropoietic response and exhibiting no or little impairment in performance status. Differential attribution of variability in older vs. younger adults suggests that individualization of ESA therapy may facilitate Hb response in geriatric patients with cancer. PMID- 24071546 TI - Geriatric oncology: European Union regulatory perspectives and initiatives. AB - The world population is gradually ageing. With cancer being prominently a disease of the elderly, availability of information for oncology drugs in this patient population is becoming critical for their safe and effective use. Drug regulatory thinking and recommendations towards obtaining this information continue to evolve over time accordingly in order to address this information gap. PMID- 24071547 TI - Outcomes of long tapered hydroxyapatite-coated stems in revision total hip arthroplasty. AB - The purpose of this study was to evaluate the outcome of femoral component revisions using a long tapered HA coated femoral revision stem. Between 2001 and 2008, 55 femoral component revisions were performed using this stem. Forty-one patients were available for follow up evaluation at average of 59 months. The clinical results were evaluated using the HHS and serial radiographs were evaluated for loosening. The mean HHS was 71 (range 22-100). Three hips required revision of KAR stem (1 aseptic loosening, 1 infection, 1 limb length discrepancy). Only one prosthesis demonstrated radiographic evidence of subsidence. Our study suggests that long tapered HA coated revision femoral components can provide stable fixation and in-growth in cases where there is good proximal femoral bone stock and favorable canal geometry. PMID- 24071548 TI - Dynamic stability control during perturbed walking can be assessed by a reduced kinematic model across the adult female lifespan. AB - The current study aimed to determine potential differences in dynamic stability control during perturbed walking across the adult female lifespan and to test the hypothesis that such differences can be assessed by a reduced kinematic model. 11 young-aged (22-30years), 9 middle-aged (41-59years) and 14 old-aged (62-75years) female adults walked on a treadmill while the right leg was unexpectedly perturbed once during the swing phase. Margin of stability (MS) at touchdown was investigated using a full body and a reduced kinematic model. After the perturbation, all age groups showed a lower MS compared to non-perturbed gait (baseline), leading to negative MS. Four old-aged adults failed to cope with the task (only preventing a fall by grasping). The remaining ten old-aged and the middle-aged subjects required three more recovery steps than the young-aged adults to get back to baseline MS. Moreover, there were no differences between kinematic models, and both methods demonstrated similar age-related findings. We concluded that the ability to control dynamic stability during perturbed walking by enlarging the base of support has already begun to deteriorate by middle age. Further, the valid agreement between kinematic models shows that such differences can be assessed by using just four body markers. PMID- 24071549 TI - Biomechanical and energetic determinants of technique selection in classical cross-country skiing. AB - Classical cross-country skiing can be performed using three main techniques: diagonal stride (DS), double poling (DP), and double poling with kick (DK). Similar to other forms of human and animal gait, it is currently unclear whether technique selection occurs to minimize metabolic cost or to keep some mechanical factors below a given threshold. The aim of this study was to find the determinants of technique selection. Ten male athletes roller skied on a treadmill at different slopes (from 0 degrees to 7 degrees at 10km/h) and speeds (from 6 to 18km/h at 2 degrees ). The technique preferred by skiers was gathered for every proposed condition. Biomechanical parameters and metabolic cost were then measured for each condition and technique. Skiers preferred DP for skiing on the flat and they transitioned to DK and then to DS with increasing slope steepness, when increasing speed all skiers preferred DP. Data suggested that selections mainly occur to remain below a threshold of poling force. Second, critically low values of leg thrust time may limit the use of leg-based techniques at high speeds. A small role has been identified for the metabolic cost of locomotion, which determined the selection of DP for flat skiing. PMID- 24071550 TI - Reorganised anticipatory postural adjustments due to experimental lower extremity muscle pain. AB - Automated movements adjusting postural control may be hampered during musculoskeletal pain leaving a risk of incomplete control of balance. This study investigated the effect of experimental muscle pain on anticipatory postural adjustments by reaction task movements. While standing, nine healthy males performed two reaction time tasks (shoulder flexion of dominant side and bilateral heel lift) before, during and after experimental muscle pain. On two different days experimental pain was induced in the m. vastus medialis (VM) or the m. tibialis anterior (TA) of the dominant side by injections of hypertonic saline (1ml, 5.8%). Isotonic saline (1ml, 0.9%) was used as control injection. Electromyography (EMG) was recorded from 13 muscles. EMG onset, EMG amplitude, and kinematic parameters (shoulder and ankle joint) were extracted. During shoulder flexion and VM pain the onset of the ipsilateral biceps femoris was significantly faster than baseline and post injection sessions. During heels lift in the VM and TA pain conditions the onset of the contralateral TA was significantly faster than baseline and post injection sessions in bilateral side. VM pain significantly reduced m. quadriceps femoris activity and TA pain significantly reduced ipsilateral VM activity and TA activity during bilateral heel lift. The EMG reaction time was delayed in bilateral soleus muscles during heels lift with VM and TA pain. The faster onset of postural muscle activity during anticipatory postural adjustments may suggest a compensatory function to maintain postural control whereas the reduced postural muscle activity during APAs may indicate a pain adaptation strategy to avoid secondary damage. PMID- 24071551 TI - Postural tasks are associated with center of pressure spatial patterns of three dimensional statokinesigrams in young and elderly healthy subjects. AB - The present study investigated the association between postural tasks and center of pressure spatial patterns of three-dimensional statokinesigrams. Young (n=35; 27.0+/-7.7years) and elderly (n=38; 67.3+/-8.7years) healthy volunteers maintained an undisturbed standing position during postural tasks characterized by combined sensory (vision/no vision) and biomechanical challenges (feet apart/together). A method for the analysis of three-dimensional statokinesigrams based on nonparametric statistics and image-processing analysis was employed. Four patterns of spatial distribution were derived from ankle and hip strategies according to the quantity (single; double; multi) and location (anteroposterior; mediolateral) of high-density regions on three-dimensional statokinesigrams. Significant associations between postural task and spatial pattern were observed (young: gamma=0.548, p<.001; elderly: gamma=0.582, p<.001). Robustness analysis revealed small changes related to parameter choices for histogram processing. MANOVA revealed multivariate main effects for postural task [Wilks' Lambda=0.245, p<.001] and age [Wilks' Lambda=0.308, p<.001], with interaction [Wilks' Lambda=0.732, p<.001]. The quantity of high-density regions was positively correlated to stabilogram and statokinesigram variables (p<.05 or lower). In conclusion, postural tasks are associated with center of pressure spatial patterns and are similar in young and elderly healthy volunteers. Single-centered patterns reflected more stable postural conditions and were more frequent with complete visual input and a wide base of support. PMID- 24071552 TI - Characterization of speed fluctuation and drag force in young swimmers: a gender comparison. AB - The aim of this study was to compare the speed fluctuation and the drag force in young swimmers between genders. Twenty-three young pubertal swimmers (12 boys and 11 girls) volunteered as subjects. Speed fluctuation was measured using a kinematical mechanical method (i.e., speedo-meter) during a maximal 25-m front crawl bout. Active drag, active drag coefficient and power needed to overcome drag were measured with the velocity perturbation method for another two maximal 25m front crawl bouts with and without the perturbation device. Passive drag and the passive drag coefficient were estimated using the gliding decay velocity method after a maximal push-off from the wall while being fully immersed. The technique drag index was also assessed as a ratio between active and passive drag. Boys presented meaningfully higher speed fluctuation, active drag, power needed to overcome drag and technique drag index than the girls. There were no significant gender differences for active drag coefficient, passive drag and passive drag coefficient. There were positive and moderate-strong associations between active drag and speed fluctuation when controlling the effects of swim velocity. So, increasing speed fluctuation leads to higher drag force values and those are even higher for boys than for girls. PMID- 24071553 TI - Predictive markers of safety and immunogenicity of adjuvanted vaccines. AB - Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/. PMID- 24071554 TI - Detection of contaminants in cell cultures, sera and trypsin. AB - The aim of this study was standardization and application of polymerase chain reaction (PCR) for the detection of contaminants in cell cultures, sera and trypsin. Five PCR protocols were standardized to assess the presence of genetic material from mycoplasma, porcine circovirus 1 (PCV1), bovine leukemia virus (BLV) or bovine viral diarrhea virus (BVDV) in cell culture samples. PCR reactions for the genes GAPDH and beta-actin were used to evaluate the efficiency of nucleic acid extraction. The PCR protocols were applied to 88 cell culture samples from eight laboratories. The tests were also used to assess potential contamination in 10 trypsin samples and 13 fetal calf serum samples from different lots from five of the laboratories. The results showed the occurrence of the following as DNA cell culture contaminants: 34.1% for mycoplasma, 35.2% for PCV1, 23.9% for BVDV RNA and 2.3% for BLV. In fetal calf sera and trypsin samples BVDV RNA and PCV1 DNA was detected. The results demonstrated that cell culture, sera and trypsin used by different laboratories show a high rate of contaminants. The results highlight the need for monitoring cell cultures and controlling for biological contaminants in laboratories and cell banks working with these materials. PMID- 24071555 TI - Validity of simple gait-related dual-task tests in predicting falls in community dwelling older adults. AB - OBJECTIVE: To investigate the predictive validity of simple gait-related dual task (DT) tests in predicting falls in community-dwelling older adults. DESIGN: A validation cohort study with 6 months' follow-up. SETTING: General community. PARTICIPANTS: Independently ambulant community-dwelling adults (N=66) aged >=65 years, with normal cognitive function. Sixty-two completed the follow-up. No participants required frames for walking. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Occurrence of falls in the follow-up period and performance on primary and secondary tasks of 8 DT tests and 1 triple-task (TT) test. RESULTS: A random forest classification analysis identified the top 5 predictors of a fall as (1) absolute difference in time between the Timed Up & Go (TUG) as a single task (ST) and while carrying a cup; (2) time required to complete the walking task in the TT test; (3 and 4) walking and avoiding a moving obstacle as an ST and while carrying a cup; and (5) performing the TUG while carrying a cup. Separate bivariate logistic regression analyses showed that performance on these tasks was significantly associated with falling (P<.01). Despite the random forest analysis being a more robust approach than multivariate logistic regression, it was not clinically useful for predicting falls. CONCLUSIONS: This study identified the most important outcome measures in predicting falls using simple DT tests. The results showed that measures of change in performance were not useful in a multivariate model when compared with an "allocated all to falls" rule. PMID- 24071556 TI - [Neonatal osteogenic mandibular distraction in patient diagnosed with Treacher Collins syndrome]. PMID- 24071557 TI - Do adolescent drug users fare the worst? Onset type, juvenile delinquency, and criminal careers. AB - Although substance abuse often accompanies delinquency and other forms of antisocial behavior, there is less scholarly agreement about the timing of substance use vis-a-vis an individual's antisocial trajectory. Similarly, although there is extraordinary evidence that onset is inversely related to the severity of the criminal career, there is surprisingly little research on the offense type of onset or the type of antisocial behavior that was displayed when an individual initiated his or her offending career. Drawing on data from a sample of serious adult criminal offenders (N = 500), the current study examined 12 forms of juvenile delinquency (murder, rape, robbery, aggravated assault, burglary, larceny, auto theft, arson, weapons, sexual offense, drug sales, and drug use) in addition to age at arrest onset, age, sex, race to explore their association with chronicity (total arrests), extreme chronicity (1 SD above the mean which was equivalent to 90 career arrests), and lambda (offending per year). The only onset offense type that was significantly associated with all criminal career outcomes was juvenile drug use. Additional research on the offense type of delinquent onset is needed to understand launching points of serious antisocial careers. PMID- 24071558 TI - Molecular systematics and plumage coloration evolution of an enigmatic babbler (Pomatorhinus ruficollis) in East Asia. AB - The streak-breasted scimitar babbler, Pomatorhinus ruficollis, is a polytypic and taxonomically enigmatic babbler common in southern, eastern, and southeastern Asia. To infer the phylogeny of the P. ruficollis, we examined the sequences of two complete mitochondrial genes (2184 bp in total) from fourteen of the fifteen known subspecies, and an additional five nuclear genes (2657 bp in total) from ten subspecies. The mitochondrial phylogeny indicates four major clades with large geographical identity in P. ruficollis and paraphyly of the P. ruficollis species complex, with the inclusion of the olivaceus group of congeneric P. schisticeps. Together with their interbreeding in northern Indochina, we propose to lump this group into P. ruficollis. Analysis of both multilocus networks and species-tree inference recovered poor phylogenetic structure among mainland/ Hainan subspecies and exclusive groupings of the Taiwanese subspecies, consistent with the recent taxonomic revision of its species status. Our analyses also suggest strong incongruence between the morphological-based classification and molecular systematics, implying the strength of multilocus data for taxonomy. PMID- 24071559 TI - Inside the Melanoplinae: new molecular evidence for the evolutionary history of the Eurasian Podismini (Orthoptera: Acrididae). AB - The Podismini are melanopline grasshoppers with a Holarctic distribution and well represented in the Eurasian fauna. To investigate their controversial taxonomy and evolutionary history, we studied 86%, 78% and 33% respectively of the Eurasian, European and Asian Palaearctic genera (Otte, 1995; Eades et al., 2013). We reconstructed parsimony, maximum likelihood and Bayesian phylogenies using fragments of four genes (ITS1, 16S, 12S, CO2). We applied a Bayesian molecular clock to estimate the times of species divergence, and the event-based parsimony method to depict the biogeographic framework of the diversification. Our results suggest that the selected Eurasian Podismini constitute a monophyletic group inside the Melanoplinae, provided it includes the North American genus Phaulotettix. The clades proposed by the present study inside the Podismini do not fit the older morphological or cytological classifications, but are in agreement with more recent proposals. Furthermore, our results can be explained by a plausible biogeographic history in which the present geographical distribution of the Eurasian Podismini resulted from known changes, to the Cenozoic climate and vegetation, induced by major geological events including the genesis of high mountain chains (e.g., Himalayas, Altay, Alps) and large deserts (e.g., Gobi, Karakoum, Taklamakan), and the opening of marginal seas (e.g., Bering, Japanese and Yellow Seas). PMID- 24071560 TI - Phylogenetic position of the enigmatic clawless eutardigrade genus Apodibius Dastych, 1983 (Tardigrada), based on 18S and 28S rRNA sequence data from its type species A. confusus. AB - The systematics of Eutardigrada, the largest lineage among the three classes of the phylum Tardigrada, is based mainly on the morphology of the leg claws and of the buccal apparatus. However, three members of the rarely recorded and poorly known limno-terrestrial eutardigrade genus Apodibius have no claws on their strongly reduced legs, a unique character among all tardigrades. This absence of all claws makes the systematic position of Apodibius one of the most enigmatic among the whole class. Until now all known associates of the genus Apodibius have been located in the incertae sedis species group or, quite recently, included into the Necopinatidae family. In the present study, phylogenetic analyses of 18S and 28S rRNA sequence data from 31 tardigrade species representing four parachelan superfamilies (Isohypsibioidea, Hypsibioidea, Macrobiotoidea, Eohypsibioidea), the apochelan Milnesium tardigradum, and the type species of the genus Apodibius, A. confusus, indicated close relationship of the Apodibius with tardigrade species recently included in the superfamily Isohypsibioidea. This result was well-supported and consistent across all markers (separate 18S rRNA, 28S rRNA, and combined 18S rRNA+28S rRNA datasets) and methods (MP, ML) applied. PMID- 24071561 TI - Comparisons between conventional, ultrasound-assisted and microwave-assisted methods for extraction of anthraquinones from Heterophyllaea pustulata Hook f. (Rubiaceae). AB - This work reports a comparative study about extraction methods used to obtain anthraquinones (AQs) from stems and leaves of Heterophyllae pustulata Hook (Rubiaceae). One of the conventional procedures used to extract these metabolites from a vegetable matrix is by successive Soxhlet extractions with solvents of increasing polarity: starting with hexane to eliminate chlorophylls and fatty components, following by benzene and finally ethyl acetate. However, this technique shows a low extraction yield of total AQs, and consumes large quantities of solvent and time. Ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE) have been investigated as alternative methods to extract these compounds, using the same sequence of solvents. It was found that UAE increases the extraction yield of total AQs and reduces the time and amount of solvent used. Nevertheless, the combination UAE with benzene, plus MAE with ethyl acetate at a constant power of 900 W showed the best results. A higher yield of total AQs was obtained in less time and using the same amount of solvent that UAE. The optimal conditions for this latter procedure were UAE with benzene at 50 degrees C during 60 min, followed by MAE at 900 W during 15 min using ethyl acetate as extraction solvent. PMID- 24071562 TI - The sonochemical decolourisation of textile azo dye Orange II: effects of Fenton type reagents and UV light. AB - The removal of Orange II (O-II) from aqueous solution under irradiation at 850 kHz has been studied. The effects of both homogeneous (with FeSO4/H2O2), and heterogeneous (Fe containing ZSM-5 zeolite/H2O2) Fenton type reagents are reported together with the effect of UV irradiation in combination with ultrasound both alone and with homogeneous Fenton-type reagent. Degrees of decolourisation of 6.5% and 28.9% were observed using UV radiation and ultrasound, respectively, whereas under the simultaneous irradiation of ultrasound and UV light, the decolourisation degree reached 47.8%, indicating a synergetic effect of ultrasound and UV light. The decolourisation was increased with the addition of Fenton's reagent with an optimal Fenton molar reagent ratio, Fe(2+):H2O2 of 1:50. In the combined process of ultrasound and UV light with the homogeneous Fenton system 80.8% decolourisation could be achieved after 2h indicating that UV improves this type of Orange II degradation. The degree of decolourisation obtained using the heterogeneous sono-Fenton system (Fe containing ZSM-5 zeolite catalysts+H2O2+ultrasound) were consistently lower than the traditional homogeneous ultrasound Fenton system. This can be attributed to the greater difficulty of the reaction between Fe ions and hydrogen peroxide. In all cases the Orange II ultrasonic decolourisation was found to follow first order kinetics. PMID- 24071563 TI - Fabrication of piezoelectric components for a tunable and efficient device for DNA delivery into mammalian cells. AB - We fabricated three piezoelectric components (PZT) that can produce ultrasonic waves with various generated power in order to improve the delivery of DNA molecule and polymer/DNA complexes into cells. Two cationic polymers (PEI and PDMAEMA) were interacted with DNA to form nano-scaled DNA/polymer complexes with/without the help of PZT devices. The application of PZT devices under optimal conditions helped to avoid cytotoxicity and greatly increased the transfection (DNA delivery) efficiency of these complexes in mammalian cells. The cytotoxicity and transfection efficiency were found to be correlated with the PZT generated power, waveforms and duration of ultrasonic treatment. There was no observable cytotoxicity in our experimental models and, a maximum transfection efficiency 700% greater than that of polymer/DNA complexes without applying ultrasound was achieved. The transfection efficiency of plain polymer/DNA complexes (without PZT treatment) corresponded to a 630-fold increase in comparison to the naked DNA. The waveforms of generated ultrasound greatly influenced the transfection efficiency, while cytotoxicity was not significantly affected. This means that, for optimal DNA delivery, duration of the peak voltage (Vmax/Div) also plays a role. In addition, the generated waves from PZT do not cause dissociation of polymer/DNA complexes or a change in the particle sizes of these complexes. In conclusion, these results suggest that the operation of PZT devices can be a tunable/safe way to greatly improve DNA delivery for gene therapy. PMID- 24071564 TI - Piperine inhibits LPS induced expression of inflammatory mediators in RAW 264.7 cells. AB - The aim of the present study was to investigate the effects of piperine on the inflammatory responses to lipopolysaccharide (LPS) in RAW264.7 cells and the signal transduction pathways involved. RAW264.7 cells were pretreated with piperine at 10, 50 or 100 MUg/ml and subsequently stimulated with LPS (1 MUg/ml) for 24 h. We found that piperine inhibited the production of prostaglandin E2 (PGE2) and nitric oxide (NO) induced by LPS. Piperine significantly decreased LPS stimulated gene expression and production of tumor necrosis factor-alpha (TNF), inducible NO synthase (iNOS) and COX-2 in RAW264.7 cells. Piperine inhibited the LPS-mediated activation of nuclear factor-kappa B (NF-kappaB) by suppressing the degradation of inhibitor-kappaB proteins (IkappaB) and the translocations of p65 subunit of NF-kB from the cytosol to the nucleus. Our results demonstrate the anti-inflammatory activity of piperine in RAW264.7 cells; suggesting that piperine may be a potential agent in the treatment of inflammation. PMID- 24071565 TI - Testosterone inhibits trust but promotes reciprocity. AB - The steroid hormone testosterone has been associated with behavior intended to obtain or maintain high social status. Although such behavior is typically characterized as aggressive and competitive, it is clear that high social status is achieved and maintained not only through antisocial behavior but also through prosocial behavior. In the present experiment, we investigated the impact of testosterone administration on trust and reciprocity using a double-blind randomized control design. We found that a single dose of 0.5 mg of testosterone decreased trust but increased generosity when repaying trust. These findings suggest that testosterone may mediate different types of status-seeking behavior. It may increase competitive, potentially aggressive, and antisocial behavior when social challenges and threats (i.e., abuse of trust and betrayal) need to be considered; however, it may promote prosocial behavior in the absence of these threats, when high status and good reputation may be best served by prosocial behavior. PMID- 24071567 TI - (-)-Epigallocatechin-3-gallate (EGCG) modulates neurological function when intravenously infused in acute and, chronically injured spinal cord of adult rats. AB - Spinal cord injury (SCI) causes severe and long lasting motor and sensory deficits, chronic pain, and autonomic dysreflexia. (-)-epigallocatechin-3-gallate (EGCG) has shown to produce neuroprotective effect in a broad range of neurodegenerative disease animal models. This study designed to test the efficacy of intravenous infusion of EGCG for 36 h, in acutely injured rats' spinal cord: within first 4 h post-injury and, in chronically SC injured rats: after one year of injury. Functional outcomes measured using standard BBB scale, The Louisville Swim Scale (LSS) and, pain behavior assessment tests. 72 Female adult rats subjected to moderate thoracic SCI using MASCIS Impactor, blindly randomized as the following: (I) Acute SCI + EGCG (II) Acute SCI + saline. (III) Chronic SCI + EGCG. (IV) Chronic SCI + saline and, sham SCI animals. EGCG i.v. treatment of acute and, chronic SCI animals resulted in significantly better recovery of motor and sensory functions, BBB and LSS (P < 0.005) and (P < 0.05) respectively. Tactile allodynia, mechanical nociception (P < 0.05) significantly improved. Paw withdrawal and, tail flick latencies increase significantly (P < 0.05). Moreover, in the EGCG treated acute SCI animals the percentage of lesion size area significantly reduced (P < 0.0001) and, the number of neurons in the spinal cord increased (P < 0.001). Percent areas of GAP-43 and GFAP immunohistochemistry showed significant (P < 0.05) increase. We conclude that the therapeutic window of opportunity for EGCG to depict neurological recovery in SCI animals, is viable up to one year post SCI when intravenously infused for 36 h. PMID- 24071566 TI - LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders. AB - Kappa opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward system, and appear to play a key role in modulating stress and mood. Growing literature indicates that kappa receptor antagonists may be beneficial in the treatment of mood and addictive disorders. However, existing literature on kappa receptor antagonists has used extensively JDTic and nor-BNI which exhibit long lasting pharmacokinetic properties that complicate experimental design and interpretation of results. Herein, we report for the first time the in vitro and in vivo pharmacological profile of a novel, potent kappa opioid receptor antagonist with excellent selectivity over other receptors and markedly improved drug-like properties over existing research tools. LY2456302 exhibits canonical pharmacokinetic properties that are favorable for clinical development, with rapid absorption (t(max): 1-2 h) and good oral bioavailability (F = 25%). Oral LY2456302 administration selectively and potently occupied central kappa opioid receptors in vivo (ED50 = 0.33 mg/kg), without evidence of mu or delta receptor occupancy at doses up to 30 mg/kg. LY2456302 potently blocked kappa-agonist mediated analgesia and disruption of prepulse inhibition, without affecting mu agonist-mediated effects at doses >30-fold higher. Importantly, LY2456302 did not block kappa-agonist-induced analgesia one week after administration, indicating lack of long-lasting pharmacodynamic effects. In contrast to the nonselective opioid antagonist naltrexone, LY2456302 produced antidepressant-like effects in the mouse forced swim test and enhanced the effects of imipramine and citalopram. LY2456302 reduced ethanol self-administration in alcohol-preferring (P) rats and, unlike naltrexone, did not exhibit significant tolerance upon 4 days of repeated dosing. LY2456302 is a centrally-penetrant, potent, kappa-selective antagonist with pharmacokinetic properties favorable for clinical development and activity in animal models predictive of efficacy in mood and addictive disorders. PMID- 24071568 TI - Outcome specificity in deepened extinction may limit treatment feasibility: co presentation of a food cue interferes with extinction of cue-elicited cocaine seeking. AB - BACKGROUND: We previously showed that presenting two cocaine cues simultaneously during extinction deepens the extinction of cue-elicited cocaine seeking (Kearns et al., 2012). The present study investigated whether compounding a non-drug appetitive cue with a cocaine cue would similarly deepen extinction. METHODS: In Experiment 1, tone and click were each first established as discriminative stimuli for cocaine-reinforced responding and light was a cue for food-reinforced responding. In an initial extinction phase, all stimuli were presented individually. Then, during an additional compound extinction session, rats received 8 presentations of one of the cocaine cues (counterbalanced over subjects) simultaneously with light and 8 presentations of the other cue alone. A spontaneous recovery test was used to evaluate the effectiveness of the extinction treatments. Experiment 2 was performed under conditions designed to match those of Experiment 1, except food was the reinforcer in tone and click instead of cocaine. RESULTS: In Experiment 1, the cocaine cue compounded with the food cue during extinction controlled greater spontaneous recovery of cocaine seeking than the cocaine cue always presented alone. In contrast, Experiment 2 demonstrated deepened extinction of responding to a food cue when both compounded cues were food cues. CONCLUSIONS: Results suggest that deepened extinction depends on the compound presentation of cues associated with the same reinforcer. Compound presentation of cues associated with different reinforcers could lead to an enhancement of responding. Care is urged in attempts to deepen the extinction of cue-elicited drug seeking by compounding drug cues with non-drug cues. PMID- 24071569 TI - Alcohol stigma and persistence of alcohol and other psychiatric disorders: a modified labeling theory approach. AB - BACKGROUND: We sought to apply modified labeling theory in a cross-sectional study of alcohol use disorder (AUD) to investigate the mechanisms through which perceived alcohol stigma (PAS) may lead to the persistence of AUD and risk of psychiatric disorder. METHODS: We conducted structural equation modeling (SEM) including moderated mediation analyses of two waves (W1 and W2) of data from the National Epidemiologic Survey on Alcohol and Related Conditions. We analyzed validated measures of PAS, perceived social support, social network involvement, and psychiatric disorders among (n=3608) adults with two or more DSM-5 AUD symptoms in the first two of the three years between the W1 and W2 survey. Cross sectional analyses were conducted owing to the assessment of PAS only at W2. RESULTS: Per mediation analyses, lower levels of perceived social support explained the association of PAS with past-year AUD and past-year internalizing psychiatric disorder at W2. The size of the mediated relationship was significantly larger for those classified as labeled (i.e., alcoholic) per their prior alcohol treatment or perceived need (n=938) as compared to unlabeled (n=2634), confirming a hypothesis of moderated mediation. Unexpectedly, mediation was also present for unlabeled individuals. CONCLUSIONS: Lower levels of social support may be an important intermediate outcome of alcohol stigma. Longitudinal data are needed to establish the temporal precedence of PAS and its hypothesized intermediate and distal outcomes. Research is needed to evaluate direct measures of labeling that could replace proxy measures (e.g., prior treatment status) commonly employed in studies of the stigma of psychiatric disorders. PMID- 24071571 TI - What do you feel? Adolescent drug and alcohol users show altered brain response to pleasant interoceptive stimuli. AB - BACKGROUND: Altered interoception, i.e., processing of stimuli from inside the body, has been considered an important component of drug-taking behavior. However, approaches to examine interoceptive sensitivity in humans have been limited. This study examined the hypothesis that adolescents with substance use disorder show altered interoceptive processing, measured by stimulating mechano receptive C-fibers (MR-CF) via soft touch. METHODS: Adolescents with substance use disorders (SUD, n=15) and comparison youth (CON, n=17) underwent functional magnetic resonance imaging (fMRI) during anticipation or reception of a positively valenced "Soft Touch" consisting of MR-CF stimulation to the palm or forearm. Visual analog scales (VAS) indexed subjective interoceptive experience (e.g., pleasantness, intensity). RESULTS: Across all conditions, SUD displayed attenuated left posterior insula activation compared to CON. Greater left anterior insula and right lentiform nucleus activation was evident during the application of soft touch for SUD but not for CON. Whereas for CON, greater left anterior insula activation was associated with higher pleasantness ratings, pleasantness was linked to less anterior insula activation in SUD. Finally, within SUD, attenuated posterior insula activation was related to more recent cannabis use. CONCLUSIONS: SUD adolescents exhibit blunted somatovisceral processing of pleasant stimulation, heightened sensitivity in regions responsible for processing reward value, and altered relationships between interoceptive processing and subjective experience. PMID- 24071570 TI - Smoking and psychopathology increasingly associated in recent birth cohorts. AB - BACKGROUND: In recent decades, smoking has become an increasingly non-normative behavior. Because deviant behaviors are associated with greater clinical and genetic risks, current-generation smokers may have greater concentrations of psychiatric comorbidity than previous generations. We examined this question empirically by testing whether associations between measures of smoking, psychiatric diagnoses, and risk-associated personality traits, increased across seven birth-cohorts of the 20th century. METHOD: 4326 subjects from a cross sectional NIMH control sample were categorized into one of seven groups based on birth (born before 1930, and 1930s-80s) and one of three smoking levels (lifetime dependent smoker, never dependent smoker, never smoker). Smoking and ND were assessed using the Fagerstrom Test for Nicotine Dependence; psychiatric diagnoses (drug and alcohol dependence, major depression, and generalized anxiety disorder) using the Composite International Diagnostic Interview-Short Form, and personality traits (neuroticism and extraversion) with the Eysenck Personality Questionnaire. RESULT: Lifetime prevalence of smoking decreased across the seven cohorts. Associations between smoking and drug dependence, generalized anxiety, and neuroticism, as well as total psychiatric comorbidity, were greater in more recent cohorts [smoking-by-cohort interaction: p<0.01], with greatest increases contributed by nicotine-dependent smokers. Smoking was also independently associated with alcohol dependence and depression, but these associations did not significantly vary across cohorts. CONCLUSIONS: More recent generations included fewer persons who smoked, but their smoking was associated with greater psychiatric morbidity. Failure to account for systematic variation in comorbidity across smoking cohorts may lead to unwanted heterogeneity in clinical, and possibly genetic, studies of nicotine dependence. PMID- 24071573 TI - Physcion from marine-derived fungus Microsporum sp. induces apoptosis in human cervical carcinoma HeLa cells. AB - Recently, the relationship between apoptosis and cancer has been emphasized and the induction of apoptosis is recognized as one of the key mechanisms of anti cancer agents. Marine-derived fungi are valuable sources of structurally diverse bioactive anticancer agents. In the present study, a marine-derived fungus, Microsporum sp. was cultured and an anthraquinone derivative, physcion (11.8 mg) was isolated from the culture broth extract (1710 mg). Physcion has shown cytotoxic effect on human cervical carcinoma HeLa cells and its apoptosis induction in HeLa cells was investigated by the expressions of p53, p21, Bax, Bcl 2, caspase-9, and caspase-3 proteins. The Western blot analysis has revealed that physcion could significantly induce cell apoptosis through down-regulating of Bcl 2 expression, up-regulating of Bax expression, and activating the caspase-3 pathway. Furthermore, physcion induced the formation of reactive oxygen species (ROS) in HeLa cells. Collectively, these results suggest that physcion could be a potential candidate in the field of anticancer drug discovery against human cervical cancer. PMID- 24071574 TI - The development and potential clinical utility of biomarkers for HDAC inhibitors. AB - Drug discovery has always been a complex process including many phases from target validation to clinical development. Data from the Food and Drug Administration (FDA) has estimated that the elimination rate for investigational new drugs entering clinical trials is up to 80%. In recent years, many kinds of biomarkers have been used to predict response in cancer treatment and for evaluation of new drugs. By increasing the understanding of histone deactylase (HDAC) inhibitors cellular mechanism of action, we have elucidated how HDAC inhibitors exert their effect by the use of proper biomarkers. In this paper, we mainly focus on the development and potential clinical utility of HDAC inhibitor biomarkers. PMID- 24071572 TI - beta-Catenin signaling in hepatocellular cancer: Implications in inflammation, fibrosis, and proliferation. AB - beta-Catenin signaling is implicated in hepatocellular carcinoma (HCC), although its role in inflammation, fibrosis, and proliferation is unclear. Commercially available HCC tissue microarray (TMA) of 89 cases was assessed for beta-catenin, one of its transcriptional targets glutamine synthetase (GS), proliferation (PCNA), inflammation (CD45), and fibrosis (Sirius Red). HCC cells transfected with wild-type (WT) or mutant-beta-catenin were evaluated for beta-catenin-T cell factor transactivation by TOPFlash reporter activity and expression of certain targets. Hepatocyte-specific-serine-45-mutated beta-catenin transgenic mice (TG) and controls (Con) were used to study thioacetamide (TAA)-induced hepatic fibrosis and tumorigenesis. Sustained beta-catenin activation was only observed in mutant-, not WT-beta-catenin transfected HCC cells. Aberrant intratumoral beta catenin stabilization was evident in 33% cases with 9% showing predominant nuclear with some cytoplasmic (N/C) localization and 24% displaying predominant cytoplasmic with occasional nuclear (C/N) localization. N/C beta-catenin was associated with reduced fibrosis (p=0.017) and tumor-wide GS staining (p<0.001) while C/N correlated with increased intratumoral inflammation (p=0.064) and proliferation (p=0.029). A small subset of HCC patients (15.5%) lacked beta catenin staining and exhibited low inflammation and fibrosis (p<0.05). TG and Con mice exposed to TAA showed comparable development of fibrosis and progression to cirrhosis and HCC. Taken together the data suggests a complex relationship of beta-catenin, inflammation, fibrosis and HCC. GS staining is highly sensitive in identifying HCC with nuclear beta-catenin, which may in turn represent beta catenin mutations, and does so with high negative predictive value. Also, beta catenin mutations and cirrhosis do not appear to cooperate in HCC pathogenesis in mice and men. PMID- 24071575 TI - Adjuvant therapy for hepatocellular carcinoma: current situation and prospect. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, accounting for 90% of primary liver cancers, and its incidence is still increasing. While the curative treatment for HCC is surgical resection and liver transplantation, most patients are in advanced stage, and lose the chance of surgery. Other palliative treatments include radiofrequency ablation, transarterial embolization, chemotherapy, and radiotherapy. Although there are so many treatments, the prognosis of HCC is still very poor. A major obstacle for the treatment for HCC is the high frequency of tumor recurrence even after curative resection and liver transplantation. Since HCC is frequently resistant to conventional chemotherapy and radiotherapy, clinical development of novel therapeutic agents against HCC has begun in earnest. Thus far, a series of adjuvant therapies for HCC have emerged, including small molecular target agents, monocolonal antibodies, microRNA, and Chinese herbal medicine. Some agents such as sorafenib have shown an advantage in prolonging the overall survival time, and has been approved by FDA for the treatment of advanced HCC. In this article we review the current situation and prospects of adjuvant therapies for HCC. PMID- 24071576 TI - Synthesis and biological evaluation of novel anthranilamide derivatives as anticancer agents. AB - A new series of anthranilamide derivatives were synthesized and evaluated for their antiproliferative activities against human colon carcinoma cell lines (HCT 116) and human breast adenocarcinoma cell lines (MDA-MB-231) in vitro. The bioassay results indicated that compounds 7a-7d, 11a, and 11b with flexible linkers showed promising antiproliferative activity against both cell lines. Among the compounds synthesized, 7c showed the most significant antiproliferative activity. Flow cytometric analysis indicated that 7c inhibited HCT 116 and MDA-MB 231 cell growth by inducing apoptosis in a dose-dependent manner and suppressed HCT 116 cell proliferation by G1 and S phase arrest. Compound 7c may serve as a lead candidate in the development of novel anticancer agents. PMID- 24071577 TI - Use of silkworms to evaluate the pathogenicity of bacteria attached to cedar pollen. AB - Injection of a Japanese cedar pollen suspension into silkworm hemolymph kills the silkworms. A certain species of bacteria proliferated in the hemolymph of the dead silkworms. A 16S rDNA analysis demonstrated that the proliferating bacteria were Bacillus cereus, Bacillus thuringiensis, Bacillus weihenstephanensis, and Bacillus amyloliquefaciens. Among them, B. cereus, B. thuringiensis, and B. weihenstephanensis exhibited hemolysis against sheep red blood cells and were lethal to mice. A culture filtrate of B. amyloliquefaciens showed enzyme activity toward the pectic membrane of cedar pollen. These results suggest that silkworms as an animal model are useful for evaluating the pathogenicity of bacteria attached to cedar pollen. PMID- 24071578 TI - Pharmacokinetics and safety of single-dose ribavirin in patients with chronic renal impairment. AB - This open-label study assessed the pharmacokinetics of a single 400-mg oral dose of ribavirin in 6 healthy volunteers and 18 subjects with varying degrees of renal impairment (mild:creatinine clearance [CLcr] 61-90 mL/min/1.73 m2, moderate: CLcr 31-60 mL/min/1.73 m(2), severe: CLcr 10-30 mL/min/1.73 m2, n = 6 in each group). Blood and urine samples were collected pre-dose and up to 168 hours post-dose for pharmacokinetic analyses. Compared with control subjects, ribavirin area under the plasma concentration-time curve from time zero to the time of the final quantifiable sample (AUC(tf)) and maximum plasma concentration (C(max)) values were increased, and apparent clearance (CL/F), clearance (CLr), and amount excreted (Ae) values were reduced in subjects with renal impairment. Mean ribavirin AUC(tf) was increased 2- to 3-fold in patients with moderate severe renal impairment compared with control subjects. Ribavirin CL/F and CLr were significantly correlated with CLcr. Single-dose ribavirin was safe and well tolerated in all subjects. The pharmacokinetics of ribavirin were substantially altered in subjects with stable chronic renal impairment, possibly reflecting changes in ribavirin metabolism associated with renal impairment. PMID- 24071579 TI - Adjuvant systemic drug therapy and recurrence of hepatocellular carcinoma following curative resection. AB - Postoperative recurrence of hepatocellular carcinoma (HCC) has a negative impact on long-term survival. According to available evidence, many systemic untargeted agents are ineffective as adjuvant therapy to prevent the recurrence of HCC following curative resection. Interferon alpha has potential effectiveness as adjuvant therapy for HCC in the presence of underlying conditions such as HBV or HCV infection. Oral polyprenoic acid has also proven its effectiveness according to a prospective study; however, no other studies have reported polyprenoicacid (acyclic retinoid) to be effective. Sorafenib is the only systemic molecular targeted agent that has proven effectiveness as adjuvant therapy according to a pilot study. To date, 11 randomized clinical trials are underway with different agents as adjuvant systemic drug therapy to prevent the recurrence of HCC following curative resection according to Clinicaltrial.gov. Adjuvant systemic drugs may be the most promising of all adjuvant modalities in the near future since HCC may be a systemic disease rather than a local disease. PMID- 24071580 TI - Intensive research on the prospective use of complementary and alternative medicine to treat systemic lupus erythematosus. AB - Traditional Chinese medicine has gained increasing acceptance worldwide as a form of complementary and alternative medicine and has been used to treat systemic lupus erythematosus (SLE) inside and outside of China. Herbal medicines are generally low in cost, plentiful, and cause very little toxicity or few adverse reactions in clinical practice. However, the mechanisms by which traditional Chinese medicine treats SLE remain unclear. The immunosuppressive properties of traditional Chinese medicines and/or immunomodulation by those medicines could play an important role in their treatment of SLE. PMID- 24071581 TI - Structural basis for the molecular recognition of polyadenosine RNA by Nab2 Zn fingers. AB - The yeast poly(A) RNA binding protein, Nab2, facilitates poly(A) tail length regulation together with targeting transcripts to nuclear pores and their export to the cytoplasm. Nab2 binds polyadenosine RNA primarily through a tandem repeat of CCCH Zn fingers. We report here the 2.15 A resolution crystal structure of Zn fingers 3-5 of Chaetomium thermophilum Nab2 bound to polyadenosine RNA and establish the structural basis for the molecular recognition of adenosine ribonucleotides. Zn fingers 3 and 5 each bind two adenines, whereas finger 4 binds only one. In each case, the purine ring binds in a surface groove, where it stacks against an aromatic side chain, with specificity being provided by a novel pattern of H-bonds, most commonly between purine N6 and a Zn-coordinated cysteine supplemented by H-bonds between purine N7 and backbone amides. Residues critical for adenine binding are conserved between species and provide a code that allows prediction of finger-binding stoichiometry based on their sequence. Moreover, these results indicate that, in addition to poly(A) tails, Nab2 can also recognize sequence motifs elsewhere in transcripts in which adenosines are placed at key positions, consistent with its function in mRNP organization and compaction as well as poly(A) tail length regulation. PMID- 24071583 TI - Long insert whole genome sequencing for copy number variant and translocation detection. AB - As next-generation sequencing continues to have an expanding presence in the clinic, the identification of the most cost-effective and robust strategy for identifying copy number changes and translocations in tumor genomes is needed. We hypothesized that performing shallow whole genome sequencing (WGS) of 900-1000-bp inserts (long insert WGS, LI-WGS) improves our ability to detect these events, compared with shallow WGS of 300-400-bp inserts. A priori analyses show that LI WGS requires less sequencing compared with short insert WGS to achieve a target physical coverage, and that LI-WGS requires less sequence coverage to detect a heterozygous event with a power of 0.99. We thus developed an LI-WGS library preparation protocol based off of Illumina's WGS library preparation protocol and illustrate the feasibility of performing LI-WGS. We additionally applied LI-WGS to three separate tumor/normal DNA pairs collected from patients diagnosed with different cancers to demonstrate our application of LI-WGS on actual patient samples for identification of somatic copy number alterations and translocations. With the evolution of sequencing technologies and bioinformatics analyses, we show that modifications to current approaches may improve our ability to interrogate cancer genomes. PMID- 24071582 TI - Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein. AB - Infection by oncogenic viruses is a frequent cause for tumor formation as observed in cervical cancer. Viral oncoproteins cause inactivation of p53 function and false transcriptional regulation of central cell cycle genes. Here we analyze the regulation of Plk4, serving as an example of many cell cycle- and p53-regulated genes. Cell cycle genes are often repressed via CDE and CHR elements in their promoters and activated by NF-Y binding to CCAAT-boxes. In contrast, general activation of Plk4 depends on NRF1 and CRE sites. Bioinformatic analyses imply that NRF1 and CRE are central elements of the transcriptional network controlling cell cycle genes. We identify CDE and CHR sites in the Plk4 promoter, which are necessary for binding of the DREAM (DP, RB-like, E2F4 and MuvB) complex and for mediating repression in G0/G1. When cells progress to G2 and mitosis, DREAM is replaced by the MMB (Myb-MuvB) complex that only requires the CHR element for binding. Plk4 expression is downregulated by the p53 p21(WAF1/CIP1)-DREAM signaling pathway through the CDE and CHR sites. Cell cycle- and p53-dependent repression is abrogated by HPV E7 oncoprotein. Together with genome-wide analyses our results imply that many cell cycle genes upregulated in tumors by viral infection are bound by DREAM through CDE/CHR sites. PMID- 24071584 TI - macroH2A1 histone variant represses rDNA transcription. AB - The regulation of ribosomal DNA transcription is an important step for the control of cell growth. Epigenetic marks such as DNA methylation and posttranslational modifications of canonical histones have been involved in this regulation, but much less is known about the role of histone variants. In this work, we show that the histone variant macroH2A1 is present on the promoter of methylated rDNA genes. The inhibition of the expression of macroH2A1 in human HeLa and HepG2 cells and in a mouse ES cell line resulted in an up to 5-fold increase of pre-rRNA levels. This increased accumulation of pre-rRNA is accompanied by an increase of the loading of RNA polymerase I and UBF on the rDNA without any changes in the number of active rDNA genes. The inhibition of RNA polymerase I transcription by actinomycin D or by knocking down nucleolin, induces the recruitment of macroH2A1 on the rDNA and the relocalization of macroH2A1 in the nucleolus. Interestingly, the inhibition of rDNA transcription induced by nucleolin depletion is alleviated by the inactivation of macroH2A1. These results demonstrate that macroH2A1 is a new factor involved in the regulation of rDNA transcription. PMID- 24071585 TI - Wellington: a novel method for the accurate identification of digital genomic footprints from DNase-seq data. AB - The expression of eukaryotic genes is regulated by cis-regulatory elements such as promoters and enhancers, which bind sequence-specific DNA-binding proteins. One of the great challenges in the gene regulation field is to characterise these elements. This involves the identification of transcription factor (TF) binding sites within regulatory elements that are occupied in a defined regulatory context. Digestion with DNase and the subsequent analysis of regions protected from cleavage (DNase footprinting) has for many years been used to identify specific binding sites occupied by TFs at individual cis-elements with high resolution. This methodology has recently been adapted for high-throughput sequencing (DNase-seq). In this study, we describe an imbalance in the DNA strand specific alignment information of DNase-seq data surrounding protein-DNA interactions that allows accurate prediction of occupied TF binding sites. Our study introduces a novel algorithm, Wellington, which considers the imbalance in this strand-specific information to efficiently identify DNA footprints. This algorithm significantly enhances specificity by reducing the proportion of false positives and requires significantly fewer predictions than previously reported methods to recapitulate an equal amount of ChIP-seq data. We also provide an open source software package, pyDNase, which implements the Wellington algorithm to interface with DNase-seq data and expedite analyses. PMID- 24071587 TI - Testing the horizontal-vertical stereo anisotropy with the critical-band masking paradigm. AB - Stereo vision has a well-known anisotropy: At low frequencies, horizontally oriented sinusoidal depth corrugations are easier to detect than vertically oriented corrugations (both defined by horizontal disparities). Previously, Serrano-Pedraza and Read (2010) suggested that this stereo anisotropy may arise because the stereo system uses multiple spatial-frequency disparity channels for detecting horizontally oriented modulations but only one for vertically oriented modulations. Here, we tested this hypothesis using the critical-band masking paradigm. In the first experiment, we measured disparity thresholds for horizontal and vertical sinusoids near the peak of the disparity sensitivity function (0.4 cycles/ degrees ), in the presence of either broadband or notched noise. We fitted the power-masking model to our results assuming a channel centered on 0.4 cycles/ degrees . The estimated channel bandwidths were 2.95 octaves for horizontal and 2.62 octaves for vertical corrugations. In our second experiment we measured disparity thresholds for horizontal and vertical sinusoids of 0.1 cycles/ degrees in the presence of band-pass noise centered on 0.4 cycles/ degrees with a bandwidth of 0.5 octaves. This mask had only a small effect on the disparity thresholds, for either horizontal or vertical corrugations. We simulated the detection thresholds using the power-masking model with the parameters obtained in the first experiment and assuming either single channel and multiple-channel detection. The multiple-channel model predicted the thresholds much better for both horizontal and vertical corrugations. We conclude that the human stereo system must contain multiple independent disparity channels for detecting horizontally oriented and vertically oriented depth modulations. PMID- 24071586 TI - Epigenetic regulatory elements associate with specific histone modifications to prevent silencing of telomeric genes. AB - In eukaryotic cells, transgene expression levels may be limited by an unfavourable chromatin structure at the integration site. Epigenetic regulators are DNA sequences which may protect transgenes from such position effect. We evaluated different epigenetic regulators for their ability to protect transgene expression at telomeres, which are commonly associated to low or inconsistent expression because of their repressive chromatin environment. Although to variable extents, matrix attachment regions (MARs), ubiquitous chromatin opening element (UCOE) and the chicken cHS4 insulator acted as barrier elements, protecting a telomeric-distal transgene from silencing. MARs also increased the probability of silent gene reactivation in time-course experiments. Additionally, all MARs improved the level of expression in non-silenced cells, unlike other elements. MARs were associated to histone marks usually linked to actively expressed genes, especially acetylation of histone H3 and H4, suggesting that they may prevent the spread of silencing chromatin by imposing acetylation marks on nearby nucleosomes. Alternatively, an UCOE was found to act by preventing deposition of repressive chromatin marks. We conclude that epigenetic DNA elements used to enhance and stabilize transgene expression all have specific epigenetic signature that might be at the basis of their mode of action. PMID- 24071588 TI - Transfer from blue light or green light to white light partially reverses changes in ocular refraction and anatomy of developing guinea pigs. AB - Relative to the broadband white light (BL), postnatal guinea pigs develop myopia in a monochromic middle-wavelength light (ML, 530 nm) environment and develop hyperopia in a monochromic short-wavelength light (SL, 430 nm) environment. We investigated whether transfer from SL or ML to BL leads to recuperation of ocular refraction and anatomy of developing guinea pigs. Two-week-old guinea pigs were given (a) SL for 20 weeks, (b) SL recuperation (SLR, SL for 10 weeks then BL for 10 weeks), (c) ML for 20 weeks, (d) ML recuperation (MLR, ML for 10 weeks then BL for 10 weeks), or (e) BL for 20 weeks. Two weeks after transfer from ML to BL (MLR group), ocular refraction increased from 1.95 +/- 0.35 D to 2.58 +/- 0.24 D, and vitreous length decreased from 3.48 +/- 0.06 mm to 3.41 +/- 0.06 mm. Two weeks after transfer from SL to BL (SLR group), ocular refraction decreased from 5.65 +/- 0.61 D to 4.33 +/- 0.49 D, and vitreous length increased from 3.18 +/- 0.07 mm to 3.26 +/- 0.11 mm. The MLR and SLR groups had final ocular refractions that were significantly different from those of the ML and SL groups at 20 weeks (ML vs. MLR: p < 0.0001; SL vs. SLR: p < 0.0001) but were still significantly different from the BL group (BL vs. MLR: p = 0.0120; BL vs. SLR: p = 0.0010). These results suggest that recuperation was not complete after return to BL for 10 weeks. PMID- 24071589 TI - Eye-specific information biases perceived direction of bistable motion. AB - While eye-of origin information is normally not accessible to observers, processing of visual information within a monocular channel does contribute to our final percept. Here we investigate if visual information is processed more efficiently when it is contained within a monocular channel or across two eyes and how it affects visual perception. Specifically, we used a bistable apparent motion display, a motion quartet, to investigate the role of eye-specific information in determining perceived motion direction. To an observer, this ambiguous display leads to the perception of either horizontal or vertical motion. We attempted to bias perceived direction by presenting separate spatial halves of the motion quartet to each eye. Our results show that observers were more likely to see horizontal motion when top and bottom halves of the quartet was presented to separate eyes. Similarly, when left and right halves were presented dichoptically, observers reported viewing more vertical motion. This change in proportion of observed motion direction indicates that eye specific information is processed more efficiently and can bias overall perception. PMID- 24071590 TI - A constructed HLA-A2-restricted pMAGE-A1(278-286) tetramer detects specific cytotoxic T lymphocytes in tumour tissues in situ. AB - OBJECTIVE: To construct a human leucocyte antigen (HLA)-A2-restricted peptide 278 286 of melanoma-associated antigen family A, 1 (pMAGE-A1(278-286)) tetramer to analyse the distribution of cytotoxic T lymphocytes (CTLs) in tumour tissue and tumour-adjacent normal tissue. METHODS: A HLA-A2-pMAGE-A1(278-286) tetramer was constructed. The distribution of pMAGE-A1(278-286)-specific CTLs was investigated in tumour tissues and tumour-adjacent normal tissues from patients with hepatocellular carcinoma using in situ HLA-A2-pMAGE-A1(278-286) tetramer staining. RESULTS: Sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis indicated that HLA-A2 heavy and light chain proteins were successfully obtained. The successful construction of the HLA-A2-pMAGE-A1(278-286) monomer was confirmed with Western blot analysis using W6/32 antibody. Flow cytometry confirmed the specific binding of HLA-A2-pMAGE-A1(278-286) tetramer to pMAGE A1(278-286)-specific CTLs. In situ HLA-A2-pMAGE-A1(278-286) tetramer staining demonstrated that the number of pMAGE-A1(278-286)-specific CTLs in tumour tissues was significantly higher than in tumour-adjacent normal tissues. CONCLUSIONS: The HLA-A2-pMAGE-A1(278-286) tetramer was useful for the detection of pMAGE-A1(278 286)-specific CTLs in both tumour tissues and tumour-adjacent normal tissues. In situ tetramer staining is a powerful tool for investigating the distribution of pMAGE-A1278-286-specific CTLs in the tumour microenvironment. PMID- 24071591 TI - Geographic variation in human papillomavirus vaccination uptake among young adult women in the United States during 2008-2010. AB - Very little is known about geographic variation in human papillomavirus (HPV) vaccine uptake among young adult women in the US. To investigate this, we analyzed data from 12 US states collected through the Behavioral Risk Factor Surveillance System between 2008 and 2010. Among 2632 young adult women (18-26 years old) who responded to HPV vaccine uptake questions, weighted vaccine initiation and completion rates were: 28.0% and 17.0% overall, 14.0% and 6.6% in the South, 28.7% and 19.3% in the Midwest/West, and 37.2% and 23.1% in the Northeast (P<0.001), respectively. Log-binomial regression analysis showed that women living in the South were less likely to initiate (adjusted prevalence ratio (aPR) 0.71, 95% confidence interval (CI) 0.60-0.83) or complete (aPR 0.61, 95% CI, 0.53-0.71) the HPV vaccine series compared to women living in the Northeast. Interventions programs to improve HPV vaccine uptake in the Southern states are warranted. PMID- 24071592 TI - Tubulin, actin and heterotrimeric G proteins: coordination of signaling and structure. AB - G proteins mediate signals from membrane G protein coupled receptors to the cell interior, evoking significant regulation of cell physiology. The cytoskeleton contributes to cell morphology, motility, division, and transport functions. This review will discuss the interplay between heterotrimeric G protein signaling and elements of the cytoskeleton. Also described and discussed will be the interplay between tubulin and G proteins that results in atypical modulation of signaling pathways and cytoskeletal dynamics. This will be extended to describe how tubulin and G proteins act in concert to influence various aspects of cellular behavior. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters.This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Herve. PMID- 24071594 TI - TMS to V1 spares discrimination of emotive relative to neutral body postures. AB - This study used TMS to examine the role played by striate cortex (V1) in processing the emotional content of visual stimuli. Participants learned to discriminate two sets of body posture images. For half of each set, the posture's emotional significance (threat versus pleasant) provided a redundant cue for the discrimination; the other half were emotionally neutral. An image was briefly presented at a lateral location in the visual field where a TMS pulse produced a phosphene, or at a control location in the opposite hemifield. A TMS pulse 70-140 ms after stimulus presentation at the phosphene location impaired discrimination of neutral stimuli with little effect on discrimination of emotional stimuli; the two classes of stimuli were equally discriminable when presented at the control location. The results are consistent with the proposal that emotionally salient patterns, such as social threat, can be discriminated independently of the geniculo-striate pathway. PMID- 24071593 TI - A thermodynamic approach to alamethicin pore formation. AB - The structure and energetics of alamethicin Rf30 monomer to nonamer in cylindrical pores of 5 to 11A radius are investigated using molecular dynamics simulations in an implicit membrane model that includes the free energy cost of acyl chain hydrophobic area exposure. Stable, low energy pores are obtained for certain combinations of radius and oligomeric number. The trimer and the tetramer formed 6A pores that appear closed while the larger oligomers formed open pores at their optimal radius. The hexamer in an 8A pore and the octamer in an 11A pore give the lowest effective energy per monomer. However, all oligomers beyond the pentamer have comparable energies, consistent with the observation of multiple conductance levels. The results are consistent with the widely accepted "barrel stave" model. The N terminal portion of the molecule exhibits smaller tilt with respect to the membrane normal than the C terminal portion, resulting in a pore shape that is a hybrid between a funnel and an hourglass. Transmembrane voltage has little effect on the structure of the oligomers but enhances or decreases their stability depending on its orientation. Antiparallel bundles are lower in energy than the commonly accepted parallel ones and could be present under certain experimental conditions. Dry aggregates (without an aqueous pore) have lower average effective energy than the corresponding aggregates in a pore, suggesting that alamethicin pores may be excited states that are stabilized in part by voltage and in part by the ion flow itself. PMID- 24071595 TI - Comparison of intravenous with oral busulfan in allogeneic hematopoietic stem cell transplantation with myeloablative conditioning regimens for pediatric acute leukemia. AB - Recent reports revealed that intravenous (iv) busulfan (BU) may not only reduce early nonrelapse mortality (NRM) but also improve overall survival (OS) probability in adults. Therefore, we retrospectively compared outcomes for 460 children with acute leukemia who underwent hematopoietic stem cell transplantation with either iv-BU (n = 198) or oral busulfan (oral-BU) (n = 262) myeloablative conditioning. OS at 3 years was 53.4% +/- 3.7% with iv-BU and 55.1% +/- 3.1% with oral-BU; the difference was not statistically significant (P = .77). OS at 3 years in 241 acute lymphoblastic leukemia and 219 acute myeloid leukemia patients was 56.4% +/- 5.5% with iv-BU and 54.6% +/- 4.1 with oral-BU (P = .51) and 51.0% +/- 5.0% with iv-BU and 55.8% +/- 4.8% with oral-BU (P = .83), respectively. Cumulative incidence of relapse at 3 years with iv-BU was similar to that with oral-BU (39.0% +/- 3.6% and 36.4% +/- 3.1%, respectively; P = .67). Cumulative incidence of NRM at 3 years was 16.6% +/- 2.7% with iv-BU and 18.3% +/ 2.5% with oral-BU (P = .51). Furthermore, multivariate analysis showed no significant survival advantage with iv-BU. In conclusion, iv-BU failed to show a significant survival advantage in children with acute leukemia. PMID- 24071596 TI - Changing presentation of prostate cancer in a UK population--10 year trends in prostate cancer risk profiles in the East of England. AB - BACKGROUND: Prostate cancer incidence is rising in the United Kingdom but there is little data on whether the disease profile is changing. To address this, we interrogated a regional cancer registry for temporal changes in presenting disease characteristics. METHODS: Prostate cancers diagnosed from 2000 to 2010 in the Anglian Cancer Network (n=21,044) were analysed. Risk groups (localised disease) were assigned based on NICE criteria. Age standardised incidence rates (IRs) were compared between 2000-2005 and 2006-2010 and plotted for yearly trends. RESULTS: Over the decade, overall IR increased significantly (P<0.00001), whereas metastasis rates fell (P<0.0007). For localised disease, IR across all risk groups also increased but at different rates (P<0.00001). The most striking change was a three-fold increase in intermediate-risk cancers. Increased IR was evident across all PSA and stage ranges but with no upward PSA or stage shift. In contrast, IR of histological diagnosis of low-grade cancers fell over the decade, whereas intermediate and high-grade diagnosis increased significantly (P<0.00001). CONCLUSION: This study suggests evidence of a significant upward migration in intermediate and high-grade histological diagnosis over the decade. This is most likely to be due to a change in histological reporting of diagnostic prostate biopsies. On the basis of this data, increasing proportions of newly diagnosed cancers will be considered eligible for radical treatment, which will have an impact on health resource planning and provision. PMID- 24071598 TI - Heritability of nociception IV: neuropathic pain assays are genetically distinct across methods of peripheral nerve injury. AB - Prior genetic correlation analysis of 22 heritable behavioral measures of nociception and hypersensitivity in the mouse identified 5 genetically distinct pain types. In the present study, we reanalyzed that dataset and included the results of an additional 9 assays of nociception and hypersensitivity, with the following goals: to replicate the previously identified 5 pain types; to test whether any of the newly added pain assays represent novel genetically distinct pain types; and to test the level of genetic relatedness among 9 commonly used neuropathic pain assays. Multivariate analysis of pairwise correlations between assays shows that the newly added zymosan-induced heat hypersensitivity assay does not conform to the 2 previously identified groups of heat hypersensitivity assays and cyclophosphamide-induced cystitis, the first organ-specific visceral pain model examined, is genetically distinct from other inflammatory assays. The 4 included mechanical hypersensitivity assays are genetically distinct and do not comprise a single pain type as previously reported. Among the 9 neuropathic pain assays including autotomy, chemotherapy, nerve ligation and spared nerve injury assays, at least 4 genetically distinct types of neuropathic sensory abnormalities were identified, corresponding to differences in nerve injury method. In addition, 2 itch assays and Comt genotype were compared to the expanded set of nociception and hypersensitivity assays. Comt genotype was strongly related only to spontaneous inflammatory nociception assays. These results indicate the priority for continued investigation of genetic mechanisms in several assays newly identified to represent genetically distinct pain types. PMID- 24071599 TI - Interpreting patient treatment response in analgesic clinical trials: implications for genotyping, phenotyping, and personalized pain treatment. PMID- 24071600 TI - The distinct role of palliative care in the surgical intensive care unit. AB - Palliative care is expanding its role into the surgical intensive care units (SICU). Embedding palliative philosophies of care into SICUs has considerable potential to improve the quality of care, especially in complex patient care scenarios. This article will explore palliative care, identifying patients/families who benefit from palliative care services, how palliative care complements SICU care, and opportunities to integrate palliative care into the SICU. Palliative care enhances the SICU team's ability to recognize pain and distress; establish the patient's wishes, beliefs, and values and their impact on decision making; develop flexible communication strategies; conduct family meetings and establish goals of care; provide family support during the dying process; help resolve team conflicts; and establish reasonable goals for life support and resuscitation. Educational opportunities to improve end-of-life management skills are outlined. It is necessary to appreciate how traditional palliative and surgical cultures may influence the integration of palliative care into the SICU. Palliative care can provide a significant, "value added" contribution to the care of seriously ill SICU patients. PMID- 24071601 TI - The "cost disease" in medical education. PMID- 24071597 TI - Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter dependent drug resistance. AB - BACKGROUND: Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy. METHODS: We generated drug-resistant cells by continuous low dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy. RESULTS: We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 A(2)) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively. CONCLUSION: We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer. PMID- 24071602 TI - Atrial fibrillation and the 4P medicine. AB - Although the paradigm of the 4P medicine - Predictive, Personalized, Preemptive, and Participatory - has been suggested several years ago, its application to atrial fibrillation is still far away. Given the increasing prevalence and incidence of this pathology it is the time to promote preventive strategies, by identifying the risk factors associated to life style and by incentivizing innovative diagnostic technologies. The promotion of the correct life style and of the use of diagnostic devices based on innovative and reliable technologies, represent a first step towards the full realization of the revolution of 4P medicine in atrial fibrillation. PMID- 24071603 TI - Asbestos case and its current implications for global health. AB - Notwithstanding a major body of evidence on the carcinogenicity of all asbestos fibres and a general consensus of the scientific community on the health impact of this agent, asbestos is still produced and used in a large number of countries, thus determining further harm for future generations. Prevention of asbestos-related disease requires international cooperation, transfer of know-how and dissemination of successful procedures in order to contrast asbestos exposure in the frame of a global environmental health approach. PMID- 24071604 TI - Effect of low-level laser irradiation on osteoblast-like cells cultured on porous hydroxyapatite scaffolds. AB - OBJECTIVE: To determine the effect of laser irradiation at a low dose on human osteoblastlike cells. MATERIALS AND METHODS: 32 porous hydroxyapatite scaffolds currently used for bone tissue engineering were seeded with MG63 cells and irradiated or not with a GaAlAs diode laser (wavelength 915 nm, dose 2 J/cm2) using different power density and exposure duration. RESULTS: After 72-h incubation, cells showed well spread morphology and good adhesion on both laser treated and untreated scaffolds. Laser irradiation did not interfere in cell viability and proliferation as compared with the non-irradiated controls. CONCLUSION: This study suggests that there is no effect of 915 nm laser irradiation at a dose of 2 J/cm2 on the proliferation rate of MG63 cells. Future investigations are needed to compare different dose and wavelength regimens in order to determine the optimal set of laser parameters for maximum cell yield and safe clinical application. PMID- 24071605 TI - Comparative evaluation of the accuracy of linear measurements between cone beam computed tomography and 3D microtomography. AB - OBJECTIVE: The aim of this study was to evaluate the influence of artifacts on the accuracy of linear measurements estimated with a common cone beam computed tomography (CBCT) system used in dental clinical practice, by comparing it with microCT system as standard reference. MATERIALS AND METHODS: Ten bovine bone cylindrical samples containing one implant each, able to provide both points of reference and image quality degradation, have been scanned by CBCT and microCT systems. Thanks to the software of the two systems, for each cylindrical sample, two diameters taken at different levels, by using implants different points as references, have been measured. Results have been analyzed by ANOVA and a significant statistically difference has been found. RESULTS AND DISCUSSION: Due to the obtained results, in this work it is possible to say that the measurements made with the two different instruments are still not statistically comparable, although in some samples were obtained similar performances and therefore not statistically significant. CONCLUSION: With the improvement of the hardware and software of CBCT systems, in the near future the two instruments will be able to provide similar performances. PMID- 24071606 TI - Are age and gender associated to tobacco use and knowledge among general practitioners? Results of a survey in Italy. AB - OBJECTIVES: The aim of this study was to assess knowledge and opinions of Italian general practitioners about the effectiveness of smoking cessation interventions and physicians' attitudes in addressing tobacco-related issues. METHODS: The survey was carried out through a questionnaire administered to general practitioners (GPs) attending a medical refresher course. 133 Italian GPs participated in the study with a mean age of 51.4 years (SD = 6.2). RESULTS: The GPs had good knowledge about the predictors of smoking onset, pharmacotherapies for tobacco cessation and the clinical guidelines recommendations. Wrong answers were encountered for the prevalence of smokers in Italy, the Fagerstrom Test for nicotine dependence and minimal advice. Females were more subjected to higher knowledge about tobacco, and at lower risk to be a smoker/ex smoker. Furthermore, physicians >= 50 years old living in northern Italy had higher knowledge score. CONCLUSIONS: Physician education on tobacco counseling is associated to increased comfort and practice in advising patients who smoke. Tobacco cessation training might increase the success rate of helping patients to quit smoking. PMID- 24071608 TI - Ethical considerations for evaluating the issue of physical restraint in psychiatry. AB - This article examines some of the ethical issues associated with the use of physical restraint in psychiatry and neurology. It offers no specific answers to individual operational problems, but a methodological matrix is proposed as an aid to experts in the various settings in which decisions are taken. The subject is addressed mainly by considering two sources: reference documents published by eminent organisations, and the theoretical framework of ethical values (or principles). A number of analytical criteria arising from these sources are then identified and proposed. The proposed criteria can be applied in cases for which the legitimate use of restraint may be an option, bearing in mind that restraint is an extremely serious affront to human dignity and is widely held to be of no therapeutic value. Its abuse is illegitimate in both ethical and legal terms. PMID- 24071607 TI - Dietary exposure to trace elements and radionuclides: the methodology of the Italian Total Diet Study 2012-2014. AB - This article presents the methodology of the Italian Total Diet Study 2012-2014 aimed at assessing the dietary exposure of the general Italian population to selected nonessential trace elements (Al, inorganic As, Cd, Pb, methyl-Hg, inorganic Hg, U) and radionuclides (40K, 134Cs, 137Cs, 90Sr). The establishment of the TDS food list, the design of the sampling plan, and details about the collection of food samples, their standardized culinary treatment, pooling into analytical samples and subsequent sample treatment are described. Analytical techniques and quality assurance are discussed, with emphasis on the need for speciation data and for minimizing the percentage of left-censored data so as to reduce uncertainties in exposure assessment. Finally the methodology for estimating the exposure of the general population and of population subgroups according to age (children, teenagers, adults, and the elderly) and gender, both at the national level and for each of the four main geographical areas of Italy, is presented. PMID- 24071609 TI - HPV vaccination acceptability in young boys. AB - PURPOSE: The aim of this study was to evaluate the comprehension and acceptance of HPV vaccination in parents of adolescent boys aged 11 to 15 years. METHODS: A cross-sectional survey was conducted by means of questionnaires sent directly to the homes of all families with young males aged between 11 and 15, residents of three municipalities of the Province of Brescia, Italy. The documentation also contained an informative leaflet summarizing the HPV-related disease characteristics, the burden of disease and the available strategies for prevention and treatment, illustrating the rationale of vaccination and describing the project and its phases. The questionnaire included questions on demographic data, acceptance and motivations for HPV vaccination. The collected data was analyzed using descriptive statistics. At the end of the study, parents who received the questionnaires were also offered the possibility of vaccinating their male sons for free. RESULTS: From a total of 1072 questionnaires sent, 161 where returned from the three selected municipalities (average response rate 15%); 97% of adolescent males involved in the study were Italian and 91% Catholic; 97% of parents declared themselves to be willing to vaccinate their sons: the principal motivation given (92%) was prevention of the disease, cancerous or not, related to viral infection. Among the respondents not willing to vaccinate their sons, the motivation was lack of information about the vaccine and the disease. At the end of the study, around 71 boys were vaccinated. DISCUSSION: To our knowledge, this is the first survey in Italy exclusively conducted on parents of adolescent males about the acceptability and feasibility of vaccination against HPV: a very high percentage of respondents was favorable to accept the vaccination for their sons, the main motivation being the fact that parents considered protecting their sons from HPV-related diseases highly important. Of the 161 boys targeted by the questionnaire, 71 decided to receive the 3 doses of HPV vaccination (44%). Data suggests that HPV vaccination is acceptable to families for their male sons and that information is important in the decision-making process. PMID- 24071610 TI - University psychiatry in Italy. Organisation and integration of university clinics and the National Health Service. AB - INTRODUCTION: In the Italian psychiatric system, community-based care has become increasingly important and widespread since the national reform of 1978. This report aims to provide an overview of the involvement of university medical schools in this process, considering their responsibility for teaching and training specialist practitioners and professionals. METHODS: The study was carried out between early 2010 and February 2011. An 18-items, self-administered, questionnaire was designed to investigate the number of faculty members that are responsible both for running a clinical ward and for providing communitybased healthcare. RESULTS: Nine out of 53 faculty members (17%) manage a Mental Health Department, 9 (17%) manage a University Department, and 2 (3.8%) manage both types of department. Less than half of the teachers have full responsibility (hospital and community); however the percentage reaches 73.2% if we include the hospital wards open to the community emergencies. The remaining 26.8% have no responsibility for community psychiatry. Moreover there were undoubtedly still too many universities with specialisation schools that are without an appropriate network of facilities enabling them to offer complex psychiatric training. DISCUSSION: As expected, there were several types of healthcare management that were not uniformly distributed throughout Italy and there were also marked differences between mental health care provision in the North, Centre, and South of Italy. The university involvement in clinical responsibility was great, but at the management level there was a lack of equality in terms of clinical care, which risks being reflected also on the institutional functions of teaching and research. PMID- 24071611 TI - Technique for bone volume measurement from human femur head samples by classification of micro-CT image histograms. AB - INTRODUCTION: Micro-CT analysis is a powerful technique for a non-invasive evaluation of the morphometric parameters of trabecular bone samples. This elaboration requires a previous binarization of the images. A problem which arises from the binarization process is the partial volume artifact. Voxels at the external surface of the sample can contain both bone and air so thresholding operates an incorrect estimation of volume occupied by the two materials. AIM: The aim of this study is the extraction of bone volumetric information directly from the image histograms, by fitting them with a suitable set of functions. METHODS: Nineteen trabecular bone samples were extracted from femoral heads of eight patients subject to a hip arthroplasty surgery. Trabecular bone samples were acquired using micro-CT Scanner. Hystograms of the acquired images were computed and fitted by Gaussian-like functions accounting for: a) gray levels produced by the bone x-ray absorption, b) the portions of the image occupied by air and c) voxels that contain a mixture of bone and air. This latter contribution can be considered such as an estimation of the partial volume effect. RESULTS: The comparison of the proposed technique to the bone volumes measured by a reference instrument such as by a helium pycnometer show the method as a good way for an accurate bone volume calculation of trabecular bone samples. PMID- 24071612 TI - Immunokinetics: a new approach to vaccines. A working hypothesis. AB - This paper outlines the working hypothesis that immune response is triggered, beside antigenicity referred to by the two major theories of Burnet (1959) and Jerne (1974) by the kinetics of the antigen that enters the body or, in the case of an endogenous origin, there is released from compartments where it is normally sequestered. This hypothesis, for simplicity called immunokinetics, postulates that the intensity of the immune response grows with the increase of the rapidity of the above contact or release and, conversely, declines with its decrease. Sublingual administration allows, by speeding up the vaccines absorption, to optimize their efficacy, safety and uses. Kinetics is also discussed in connection with homeostatic and adaptive processes involved in evolution. PMID- 24071613 TI - Cugini's syndrome: its clinical history and diagnosis. AB - INTRODUCTION: This article deals with the description and diagnosis of a new nosographic syndrome, which received the eponym of "Cugini's syndrome" by the name of the Author who discovered its clinical picture. This syndrome is characterized by the binomial: "minimal target organ damage associated to monitoring prehypertension". CLINICAL HISTORY AND DIAGNOSIS: Between the years 1997 and 2002, the Author published a series of investigations regarding some office normotensives who inexplicably showed incipient signs of target organ damage (TOD). Investigated via ambulatory (A) blood (B) pressure (P) monitoring (M), these subjects were surprisingly found not to be hypertensive. Neverthless, the office normotensives with TOD exibited the daily mean level of their systolic (S) and diastolic (D) BP (DMLSBP/DBP) significantly more elevated as compared to true normotensives. Because of these ABPM findings, the Author realized that the investigated subjects were false normotensives whose TOD was associated with a monitoring prehypertension (ABPM-diagnosable prehypertension alias monitoring prehypertension alias masked prehypertension). The year after the last Cugini's investigation, the INC-7 Reports introduced the term: "prehypertension" in its classification of arterial hypertension, as an office sphygmomanometric condition in between office normotension and office hypertension. The ABPM cut-off upper limits for a differential diagnosis between monitoring normotension, prehypertension and hypertension are reported, as calculated by the Author in its collection of ABPMs. The eponym of "Cugini's syndrome" was assigned in 2007 and confirmed in 2009. CONCLUSIVE REMARKS: The monitoring prehypertension is a further condition of discrepancy between office sphygmomanometry and ABPM, as per a masked prehypertension, whose diagnosis has to be immediately diagnosed, for preventing the onset of a TOD. There are reported the present investigations dealing with the possible need for an early antihypertensive treatment of prehypertension. A pharmacological treatment seems to be especially justified in the presence of a Cugini's syndrome. PMID- 24071614 TI - Idiopathic macular hole: post-operative morpho-functional assessment and prognostic factors for recovery of visual acuity. AB - INTRODUCTION: Idiopathic macular hole (MH) is a full-thickness retinal damage typical of the advanced age with a high social impact because, as it affects the macula, it produces severe loss of vision. AIM: This study aims to evaluate the therapeutic efficacy of surgery and to determine prognostic factors, considering how hypovision weighs on individual quality of life and on public health. METHODS: All patients affected by MH were evaluated with an ophthalmic visit, measurement of visual acuity and Optical Coherence Tomography (OCT) documentation before surgical intervention. Surgical treatment followed and, subsequently, all the patients were examined with the same documentation at 7 days, 1 month, 3 months, 6 months and 12 months. RESULTS: Surgical therapy, with the modern techniques available, demonstrated the efficacy of anatomical recovery and retinal function. Furthermore, the quantitative characteristics of the MH in the OCT scanning revealed an important prognostic function. PMID- 24071615 TI - Antihyperalgesic/antinociceptive effects of ceftriaxone and its synergistic interactions with different analgesics in inflammatory pain in rodents. AB - BACKGROUND: The beta-lactam antibiotic ceftriaxone stimulates glutamate transporter GLT-1 expression and is effective in neuropathic and visceral pain models. This study examined the effects of ceftriaxone and its interactions with different analgesics (ibuprofen, celecoxib, paracetamol, and levetiracetam) in somatic and visceral pain models in rodents. METHODS: The effects of ceftriaxone (intraperitoneally/intraplantarly), analgesics (orally), and their combinations were examined in the carrageenan-induced paw inflammatory hyperalgesia model in rats (n = 6-12) and in the acetic acid-induced writhing test in mice (n = 6-10). The type of interaction between ceftriaxone and analgesics was determined by isobolographic analysis. RESULTS: Pretreatment with intraperitoneally administered ceftriaxone (10-200 mg/kg per day) for 7 days produced a significant dose-dependent antihyperalgesia in the somatic inflammatory model. Acute administration of ceftriaxone, via either intraperitoneal (10-200 mg/kg) or intraplantar (0.05-0.2 mg per paw) routes, produced a significant and dose dependent but less efficacious antihyperalgesia. In the visceral pain model, significant dose-dependent antinociception of ceftriaxone (25-200 mg/kg per day) was observed only after the 7-day pretreatment. Isobolographic analysis in the inflammatory hyperalgesia model revealed approximately 10-fold reduction of doses of both drugs in all examined combinations. In the visceral nociception model, more than 7- and 17-fold reduction of doses of both drugs was observed in combinations of ceftriaxone with ibuprofen/paracetamol and celecoxib/levetiracetam, respectively. CONCLUSIONS: Ceftriaxone exerts antihyperalgesia/antinociception in both somatic and visceral inflammatory pain. Its efficacy is higher after a 7-day pretreatment than after acute administration. The two-drug combinations of ceftriaxone and the nonsteroidal analgesics/levetiracetam have synergistic interactions in both pain models. These results suggest that ceftriaxone, particularly in combinations with ibuprofen, celecoxib, paracetamol, or levetiracetam, may provide useful approach to the clinical treatment of inflammation-related pain. PMID- 24071616 TI - Ultrasound-guided multilevel paravertebral blocks and total intravenous anesthesia improve the quality of recovery after ambulatory breast tumor resection. AB - BACKGROUND: Regional anesthesia improves postoperative analgesia and enhances quality of recovery (QoR) after ambulatory surgery. This randomized, double blinded, parallel-group, placebo-controlled trial examines the effects of multilevel ultrasound-guided paravertebral blocks (PVBs) and total intravenous anesthesia on QoR after ambulatory breast tumor resection. METHODS: Sixty-six women were randomized to standardized general anesthesia (control group) or PVBs and propofol-based total intravenous anesthesia (PVB group). The PVB group received T1-T5 PVBs with 5 ml of 0.5% ropivacaine per level, whereas the control group received sham subcutaneous injections. Postoperative QoR was designated as the primary outcome. The 29-item ambulatory QoR tool was administered in the preadmission clinic, before discharge, and on postoperative days 2, 4, and 7. Secondary outcomes included block success, pain scores, intra- and postoperative morphine consumption, time to rescue analgesia, incidence of nausea and vomiting, and hospital discharge time. RESULTS: Data from sixty-four patients were analyzed. The PVB group had higher QoR scores than control group upon discharge (146 vs. 131; P < 0.0001) and on postoperative day 2 (145 vs. 135; P = 0.013); improvements beyond postoperative day 2 lacked statistical significance. None of the PVB group patients required conversion to inhalation gas-based general anesthesia or experienced block-related complications. PVB group patients had improved pain scores on postanesthesia care unit admission and discharge, hospital discharge, and postoperative day 2; their intraoperative morphine consumption, incidence of nausea and vomiting, and discharge time were also reduced. CONCLUSION: Combining multilevel PVBs with total intravenous anesthesia provides reliable anesthesia, improves postoperative analgesia, enhances QoR, and expedites discharge compared with inhalational gas- and opioid-based general anesthesia for ambulatory breast tumor resection. PMID- 24071618 TI - On the fabric of the human body and modern ultrasound imaging. PMID- 24071617 TI - Incidence, predictors, and outcome of difficult mask ventilation combined with difficult laryngoscopy: a report from the multicenter perioperative outcomes group. AB - BACKGROUND: Research regarding difficult mask ventilation (DMV) combined with difficult laryngoscopy (DL) is extremely limited even though each technique serves as a rescue for one another. METHODS: Four tertiary care centers participating in the Multicenter Perioperative Outcomes Group used a consistent structured patient history and airway examination and airway outcome definition. DMV was defined as grade 3 or 4 mask ventilation, and DL was defined as grade 3 or 4 laryngoscopic view or four or more intubation attempts. The primary outcome was DMV combined with DL. Patients with the primary outcome were compared to those without the primary outcome to identify predictors of DMV combined with DL using a non-parsimonious logistic regression. RESULTS: Of 492,239 cases performed at four institutions among adult patients, 176,679 included a documented face mask ventilation and laryngoscopy attempt. Six hundred ninety-eight patients experienced the primary outcome, an overall incidence of 0.40%. One patient required an emergent cricothyrotomy, 177 were intubated using direct laryngoscopy, 284 using direct laryngoscopy with bougie introducer, 163 using videolaryngoscopy, and 73 using other techniques. Independent predictors of the primary outcome included age 46 yr or more, body mass index 30 or more, male sex, Mallampati III or IV, neck mass or radiation, limited thyromental distance, sleep apnea, presence of teeth, beard, thick neck, limited cervical spine mobility, and limited jaw protrusion (c-statistic 0.84 [95% CI, 0.82-0.87]). CONCLUSION: DMV combined with DL is an infrequent but not rare phenomenon. Most patients can be managed with the use of direct or videolaryngoscopy. An easy to use unweighted risk scale has robust discriminating capacity. PMID- 24071619 TI - "Masters of Anaesthesia": M.S.A. degrees during the 1893 World's Fair from Chicago's Post-Graduate School of Anaesthesia. PMID- 24071620 TI - Barriers to physical activity and healthy diet among children ages 6 through 13 in a Mississippi elementary school. AB - The purpose of this study was to identify barriers to adequate physical activity and a healthy diet, investigate differences in the perceived barriers among subgroups, and determine predictors of high versus low total barrier scores in one inner-city elementary school. A mixed method design was used and included students ages 6 through 13 (n=110) and parents, teachers, and community leaders (n=20). Data were collected using questionnaires and focus groups. Quantitative findings revealed no differences in total barriers based on age, gender, number of parents, or household income; however, subscale differences among groups were noted. Qualitative findings indicated that perceived barriers to physical activity were knowledge-related, and barriers to healthy diet concerned access to healthy foods. PMID- 24071621 TI - A review of published case reports of inadvertent pulmonary placement of nasogastric tubes in children. AB - PROBLEM: Little is known about the incidence of inadvertent pulmonary placement of nasogastric tubes during blind insertions in children. PURPOSE: The purpose of this paper was to conduct a review of published case reports over the past two decades. METHODS: An OVID Medline search was conducted of articles published from 1993 through 2012. RESULTS: Fifteen published case reports were located; four patients died as a result of their malpositioned tubes. The auscultatory bedside method failed to detect the malpositioned tubes in all seven cases in which it was used. CONCLUSIONS: The incidence of inadvertent pulmonary placement of nasogastric tubes is relatively low but can lead to serious and even lethal results in children. The auscultatory method to predict tube location is unreliable. PMID- 24071622 TI - Beyond lung cancer: a strategic approach to interpreting screening computed tomography scans on the basis of mortality data from the National Lung Screening Trial. AB - Low-dose computed tomography screening in older patients with a heavy-smoking history can be viewed as an opportunity to screen for smoking-related illnesses and not just for lung cancer. Within the National Lung Screening Trial, 24.1% of all deaths were attributed to lung cancer, but there were significant competing causes of mortality in this patient population. Cardiovascular illness caused 24.8% of deaths. Other neoplasms were listed as the cause of death in 22.3%, and respiratory illness was the cause of death in 10.4%. All of these illnesses might be attributed to smoking. Low-dose computed tomography of the thorax may provide information about these diseases, which could be used to guide therapeutic intervention and, hopefully, alter the courses of these diseases. Information about coronary artery calcification, chronic obstructive pulmonary disease, and potential extrapulmonary malignancy should be provided in the report of the screening examination. This must be balanced against the risk of the burden of false-positive findings and the costs, both psychological and financial, associated with additional investigative evaluations. PMID- 24071623 TI - CT screening for lung cancer: filling in the gaps. PMID- 24071624 TI - Density dependence in Caenorhabditis larval starvation. AB - Availability of food is often a limiting factor in nature. Periods of food abundance are followed by times of famine, often in unpredictable patterns. Reliable information about the environment is a critical ingredient of successful survival strategy. One way to improve accuracy is to integrate information communicated by other organisms. To test whether such exchange of information may play a role in determining starvation survival strategies, we studied starvation of L1 larvae in C. elegans and other Caenorhabditis species. We found that some species in genus Caenorhabditis, including C. elegans, survive longer when starved at higher densities, while for others survival is independent of the density. The density effect is mediated by chemical signal(s) that worms release during starvation. This starvation survival signal is independent of ascarosides, a class of small molecules widely used in chemical communication of C. elegans and other nematodes. PMID- 24071626 TI - Validation of the palliative prognostic index and palliative prognostic score in a palliative care consultation team setting for patients with advanced cancers in an acute care hospital in Japan. AB - This study aims to clarify the predictive value of two prognostic prediction tools, the palliative prognostic index (PPI) and the palliative prognostic score (PaPS), in a setting of general hospital palliative care team for patients with advanced cancers in an acute care hospital in Japan. The retrospective observational study includes 247 patients for the PPI analysis and 187 patients for the PaPS analysis, all patients are older than 18 years, hospitalized with an advanced cancer, and referred to the palliative care team in an acute care hospital in Japan. The study successfully show that both the PPI and PaPS have an ability to divide patients into three groups, each with significantly different survival length (p<0.001). However, there are discrepancies in the results for predicting the length of survival between the study and the original studies conducted in hospice settings. The results suggest that although PPI and PaPS successfully divide patients into three groups with significantly different survival times, discrepancies exist in predicting the actual length of survival. PMID- 24071625 TI - Species differences and molecular determinant of TRPA1 cold sensitivity. AB - TRPA1 is an ion channel and has been proposed as a thermosensor across species. In invertebrate and ancestral vertebrates such as fly, mosquito, frog, lizard and snakes, TRPA1 serves as a heat receptor, a sensory input utilized for heat avoidance or infrared detection. However, in mammals, whether TRPA1 is a receptor for noxious cold is highly controversial, as channel activation by cold was observed by some groups but disputed by others. Here we attribute the discrepancy to species differences. We show that cold activates rat and mouse TRPA1 but not human or rhesus monkey TRPA1. At the molecular level, a single residue within the S5 transmembrane domain (G878 in rodent but V875 in primate) accounts for the observed difference in cold sensitivity. This residue difference also underlies the species-specific effects of menthol. Together, our findings identify the species-specific cold activation of TRPA1 and reveal a molecular determinant of cold-sensitive gating. PMID- 24071627 TI - To be truly alive: motivation among prison inmate hospice volunteers and the transformative process of end-of-life peer care service. AB - Some US prisons are meeting the growing need for end-of-life care through inmate volunteer programs, yet knowledge of the motivations of inmate caregivers is underdeveloped. This study explored the motivations of inmate hospice volunteers from across Louisiana State (n = 75) through an open-ended survey, a grounded theory approach to analysis, and comparison of responses by experience level and gender. Participants expressed complex motivations; Inter-related themes on personal growth, social responsibility and ethical service to vulnerable peers suggested that inmate caregivers experience an underlying process of personal and social transformation, from hospice as a source of positive self-identity to peer caregiving as a foundation for community. Better understanding of inmate caregiver motivations and processes will help prisons devise effective and sustainable end of life peer-care programs. PMID- 24071628 TI - Use of prognostic tools in the hospital, assessment of factors behind their use or lack thereof through a physician-oriented survey. AB - Physician's use of prognostic tools may help to decide on the intensity of therapies provided and communicate with patients and their caregivers in a timely fashion. However, literature that describes knowledge, perceived limitations and overall use of these tools by doctors is lacking. By way of a physician survey, we attempted to look at the use of prognostic tools in our community of doctors in our department of internal medicine. Our results showed that overall physicians have superficial knowledge of prognostic tools. We also discovered that physicians believe these tools to be helpful, yet their availability is compromised by lack of exposure during formative years, their cumbersome structure and the impracticalities of remembering them at bedside. PMID- 24071629 TI - Jackknife-corrected parametric bootstrap estimates of growth rates in bivalve mollusks using nearest living relatives. AB - Quantitative estimates of growth rates can augment ecological and paleontological applications of body-size data. However, in contrast to body-size estimates, assessing growth rates is often time-consuming, expensive, or unattainable. Here we use an indirect approach, a jackknife-corrected parametric bootstrap, for efficient approximation of growth rates using nearest living relatives with known age-size relationships. The estimate is developed by (1) collecting a sample of published growth rates of closely related species, (2) calculating the average growth curve using those published age-size relationships, (3) resampling iteratively these empirically known growth curves to estimate the standard errors and confidence bands around the average growth curve, and (4) applying the resulting estimate of uncertainty to bracket age-size relationships of the species of interest. This approach was applied to three monophyletic families (Donacidae, Mactridae, and Semelidae) of mollusk bivalves, a group characterized by indeterministic shell growth, but widely used in ecological, paleontological, and geochemical research. The resulting indirect estimates were tested against two previously published geochemical studies and, in both cases, yielded highly congruent age estimates. In addition, a case study in applied fisheries was used to illustrate the potential of the proposed approach for augmenting aquaculture management practices. The resulting estimates of growth rates place body size data in a constrained temporal context and confidence intervals associated with resampling estimates allow for assessing the statistical uncertainty around derived temporal ranges. The indirect approach should allow for improved evaluation of diverse research questions, from sustainability of industrial shellfish harvesting to climatic interpretations of stable isotope proxies extracted from fossil skeletons. PMID- 24071631 TI - The nest site lottery: how selectively neutral density dependent growth suppression induces frequency dependent selection. AB - Modern developments in population dynamics emphasize the role of the turnover of individuals. In the new approaches stable population size is a dynamic equilibrium between different mortality and fecundity factors instead of an arbitrary fixed carrying capacity. The latest replicator dynamics models assume that regulation of the population size acts through feedback driven by density dependent juvenile mortality. Here, we consider a simplified model to extract the properties of this approach. We show that at the stable population size, the structure of the frequency dependent evolutionary game emerges. Turnover of individuals induces a lottery mechanism where for each nest site released by a dead adult individual a single newborn is drawn from the pool of newborn candidates. This frequency dependent selection leads towards the strategy maximizing the number of newborns per adult death. However, multiple strategies can maximize this value. Among them, the strategy with the greatest mortality (which implies the greatest instantaneous growth rate) is selected. This result is important for the discussion about universal fitness measures and which parameters are maximized by natural selection. This is related to the fitness measures R0 and r, because the number of newborns per single dead individual equals the lifetime production of newborn R0 in models without aging. We thus have a two-stage procedure, instead of a single fitness measure, which is a combination of R0 and r. According to the nest site lottery mechanism, at stable population size, selection favors strategies with the greatest r, i.e. those with the highest turnover, from those with the greatest R0. PMID- 24071632 TI - An SIS model for cultural trait transmission with conformity bias. AB - Epidemiological models have been applied to human health-related behaviors that are affected by social interaction. Typically these models have not considered conformity bias, that is, the exaggerated propensity to adopt commonly observed behaviors or opinions, or content biases, where the content of the learned trait affects the probability of adoption. Here we consider an interaction of these two effects, presenting an SIS-type model for the spread and persistence of a behavior which is transmitted via social learning. Uptake is controlled by a nonlinear dependence on the proportion of individuals demonstrating the behavior in a population. Three equilibrium solutions are found, their linear stability is analyzed and the results are compared with a model for unbiased social learning. Our analysis focuses on the effects of the strength of conformity bias and the effects of content biases which alter a conformity threshold frequency of the behavior, above which there is an exaggerated propensity for adoption. The strength of the conformity bias is found to qualitatively alter the predictions regarding whether the trait becomes endemic within the population and the proportion of individuals who display the trait when it is endemic. As the conformity strength increases, the number of feasible equilibrium solutions increases from two to three, leading to a situation where the stable equilibrium attained is dependent upon the initial state. Varying the conformity threshold frequency directionally alters the behavior invasion threshold. Finally we discuss the possible application of this model to binge drinking behavior. PMID- 24071633 TI - The Moran model with selection: fixation probabilities, ancestral lines, and an alternative particle representation. AB - We reconsider the Moran model in continuous time with population size N, two allelic types, and selection. We introduce a new particle representation, which we call the labelled Moran model, and which has the same distribution of type frequencies as the original Moran model, provided the initial values are chosen appropriately. In the new model, individuals are labelled 1,2,...,N; neutral resampling events may take place between arbitrary labels, whereas selective events only occur in the direction of increasing labels. With the help of elementary methods only, we not only recover fixation probabilities, but also obtain detailed insight into the number and nature of the selective events that play a role in the fixation process forward in time. PMID- 24071634 TI - Identification of lead sources in residential environments: Sydney Australia. AB - Interior and exterior dust, soil and paint were analysed at five brick urban Sydney homes over 15 months to evaluate temporal variations and discriminate sources of lead (Pb) exposure. Exterior dust gauge Pb loading rates (MUg/m(2)/28 days), interior vacuum dust Pb concentrations (mg/kg) and interior petri-dish Pb loading rates (MUg/m(2)/28 days), were correlated positively with soil Pb concentrations. Exterior dust gauge Pb loading rates and interior vacuum dust Pb concentrations peaked in the summer. Lead isotope and Pb speciation (XAS) were analysed in soil and vacuum dust samples from three of the five houses that had elevated Pb concentrations. Results show that the source of interior dust lead was primarily from soil in two of the three houses and from soil and Pb paint in the third home. IEUBK child blood Pb modelling predicts that children's blood Pb levels could exceed 5 MUg/dL in two of the five houses. PMID- 24071635 TI - Impact of reclaimed water irrigation on antibiotic resistance in public parks, Beijing, China. AB - The abundance and distribution of antibiotics and antibiotic resistance genes (ARGs) in soils from six parks using reclaimed water in Beijing, China, were characterized. Three classes of commonly used antibiotics (tetracycles, quinolones, and sulfonamides) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The highest concentrations of tetracyclines and quinolones were 145.2 MUg kg(-1) and 79.2 MUg kg(-1), respectively. Detected tetG, tetW, sulI, and sulII genes were quantified by quantitative PCR. ARGs exhibited various abundances for different park soils. The integrase gene (intI1) as an indicator of horizontal gene transfer potential was also detected in high abundance, and had significant positive correlation with tetG, sulI, and sulII genes, suggesting that intI1 may be involved in ARGs dissemination. Both sulII and intI1 clones had high homology with some classes of pathogenic bacteria, such as Klebsiella oxytoca, Acinetobacter baumannii, Shigella flexneri, which could trigger potential public health concern. PMID- 24071636 TI - Effects of calcination treatment on the morphology, crystallinity, and photoelectric properties of all-solid-state dye-sensitized solar cells assembled by TiO2 nanorod arrays. AB - TiO2 has been extensively investigated due to its unique photoelectric properties. In this study, oriented single-crystal rutile TiO2 nanorod arrays were synthesized and then calcined at different temperatures in the atmosphere. The morphology and crystalline characterization indicated that the length of TiO2 nanorods increased rapidly and the nanorods became aggregated and fragile after calcination, yet the sintering treatment seemed to have almost no effect on the crystallinity. To obtain the all-solid-state, dye-sensitized solar cells (DSSCs), a newly reported solid inorganic semiconductor, CsSnI2.95F0.05, was employed as the electrolyte, and the Pt deposited on the conductive side of the fluorine doped tin oxide (FTO) glass substrate was used as the counter-electrode. The effects of the calcination treatment on the photoelectric properties of the solar cells, including external quantum efficiency (EQE), open circuit voltage (V(OC)), short-circuit current (J(SC)), and photoelectric conversion efficiency (eta), were investigated under the illumination of a solar simulator. As a result, all of the EQE, V(OC), J(SC), and eta values of the cells first increased and then declined with the increase of calcination temperatures, and the highest eta of 2.81% was obtained by the cell assembled with its TiO2 electrode sintered at 450 degrees C for 3 h, a value almost 2.5 times that of the non-sintered sample (1.1%). PMID- 24071637 TI - A computational model for task inference in visual search. AB - We develop a probabilistic framework to infer the ongoing task in visual search by revealing what the subject is looking for during a search process. Based on the level of difficulty, two types of tasks, easy and difficult, are investigated in this work, and individual models are customized for them according to their specific dynamics. We use Hidden Markov Models (HMMs) to serve as a model for the human cognitive process that is responsible for directing the center of gaze (COG) according to the task at hand during visual search and generating task dependent eye trajectories. This generative model, then, is used to estimate the likelihood term in a Bayesian inference formulation to infer the task given the eye trajectory. In the easy task, focus of attention (FOA) often lands on targets, whereas in the difficult one, in addition to the on-target foci of attention, deployment of attention on nontarget objects happens very often. Therefore, we suggest a single-state and a multi-state HMM to serve as the cognitive process model of attention for the easy and difficult tasks, respectively. PMID- 24071638 TI - The nematophagous fungus Monacrosporium thaumasium and its nematicidal activity on Angiostrongylus vasorum. AB - BACKGROUND: The dog acts as a reservoir and environmental disseminator of potentially zoonotic parasites. AIMS: The objective of this work was to study the fungus Monacrosporium thaumasium regarding its nematicidal potential in laboratory trials and its proteolytic profile. METHODS: The in vitro test was carried out through two assays (A and B). In assay A, conidia of the fungus N34a were added in positive coprocultures for Angiostrongylus vasorum. In assay B, crude extract (treated group) and distilled water (control group) were added to coprocultures. Next, the proteolytic profile of crude extract of the nematophagous fungus M. thaumasium (NF34a) was revealed by performing a zymogram. RESULTS: There was a reduction (p<0.01) in the averages of larvae recovered from the treated groups (conidia and crude extract) in relation to control groups. The zymogram suggested that the nematophagous fungus M. thaumasium produces a protease of approximately 40 kDa. CONCLUSIONS: The results of this work confirm that the conidia as well as the crude extract of the fungus M. thaumasium may be used to control A. vasorum L1. The proteolytic profile suggested the presence of one protease (Mt1) of approximately 40 kDa that in the future may be used in biological control of L1 of this nematode. PMID- 24071639 TI - [Fungemia due to Trichosporon asahii in a patient with hematological malignancy]. AB - BACKGROUND: Trichosporonosis is an opportunistic infection caused by the genus Trichosporon. The majority of cases of invasive trichosporonosis occurs in immunocompromised individuals. CASE REPORT: We describe a case of disseminated infection by Trichosporon asahii in a hematology patient. A 52-year-old man diagnosed with acute lymphoblastic leukemia developed a febrile episode during the third cycle of the induction chemotherapy. The blood cultures were positive after 24h incubation, showing elongated structures compatible with fungal elements in the Gram stain. The identification of the fungus as Trichosporon asahii was carried out by the assimilation of compounds of carbon and the amplification and sequencing of the D1/D2 domain and the internal transcribed spacer of the ribosomal DNA. The fungus was also isolated from the pustular lesions that the patient had in the chest. After treatment with amphotericin B, the patient progressed satisfactorily. CONCLUSIONS: Trichosporon asahii is an emergent pathogen in immunosupressed patients and its presence should not be considered as colonization, as there is risk of invasive infection. PMID- 24071640 TI - Efficacy of ravuconazole in a murine model of vaginitis by Candida albicans. AB - BACKGROUND: The incidence of vulvovaginal candidiasis, a common infection among healthy women primarily caused by the yeast Candida albicans, has increased significantly in recent years. AIMS: The purpose of this study was to compare the efficacy of ravuconazole (RVC) and fluconazole (FLC) in the treatment of experimental C. albicans vaginitis. METHODS: Forty isolates of C. albicans were screened for their in vitro susceptibility to RVC and FLC. A strain of C. albicans that was resistant to FLC (minimum inhibitory concentration [MIC] of >64 MUg/ml) was selected for the in vivo study. Treatment regimens for the murine vaginal infection model were (1) 1, 5, 10, and 20 mg/kg RVC once daily, (2) 20 mg/kg RVC twice daily, (3) 20 mg/kg FLC once daily, and (4) 20 mg/kg FLC twice daily. RESULTS: The geometric means of the MIC values at 48 h for all isolates tested were 0.05 and 0.5 MUg/ml for RVC and FLC, respectively. Regimens of either RVC or FLC at 20 mg/kg twice daily were more effective to reduce the load of FLC resistant C. albicans than single dose administration. CONCLUSIONS: Complete eradication of C. albicans from the vagina was not observed with RVC or FLC treatment in the animal model, although RVC treatment showed a lower fungal concentration 14 days after drug administration. PMID- 24071642 TI - [Characterization of air mycobiota in two repositories of the National Archives of the Republic of Cuba]. AB - BACKGROUND: The high relative humidity and temperatures in tropical countries create favorable conditions for development of fungi that are not only a risk to human health but they can also colonize documentary support. AIMS: To study the concentration of the airborne fungi in two repositories of the National Archives of the Republic of Cuba, the mycobiota deposited on different photographic supports and maps preserved in these repositories, and to determine the taxonomic characterization of the fungi isolated. METHODS: The air sampling was performed using a sedimentation method, and the supports (6 pictures and 7 maps) were analyzed using moistened sterile swabs. RESULTS: The Cladosporium genus was predominant, followed by Aspergillus and Penicillium genera. Filamentous fungi were isolated in all the photos and maps, and yeasts were only isolated from a photographic supports and a map. We identified several species of Aspergillus and Penicillium genera, but Aspergillus niger and Aspergillus flavus predominated. Candida and Rhodotorula were the yeast genera isolated. CONCLUSIONS: The fungal concentration of the air demonstrated that the environments were not contaminated. From the 26 species of filamentous fungi isolated only 5 were detected in the indoor air of the repositories and on one or more of the document supports analyzed (representing a 19.3%). This shows that there is a low ecological relationship between the fungi detected in the indoor air and those that were isolated from the supports studied. PMID- 24071641 TI - [Proteinase activity in Candida albicans strains isolated from the oral cavity of immunocompromised patients, with oral candidiasis and in healthy subjects]. AB - BACKGROUND: Candida albicans has a variety of virulence factors, including secreted aspartyl proteases, which are determinant factors in the pathogenesis of this yeast in immunocompromised patients. AIMS: Proteinase activity was identified in C. albicans strains isolated from the oral cavity of immunocompromised patients with cancer, diabetes and HIV+, with oral candidiasis and in healthy subjects. METHODS: Two hundred and fifty C. albicans strains were analyzed, distributed in 5 different groups: patients with cancer, diabetes, HIV+, with oral candidiasis and healthy subjects. RESULTS: Proteolytic activity was identified in 46% of the strains from cancer patients, 54% from HIV+ patients, 60% from diabetics, 70% from oral candidiasis patients, and 42% from healthy subjects. Activity was higher in strains from immunocompromised and oral candidiasis patients than in healthy subjects. Differences were observed between the candidiasis-healthy, candidiasis-HIV+, and diabetic-healthy groups. No differences were observed between the oral candidiasis, diabetes and cancer patients, between the diabetes and HIV+ patients, or between the cancer patients, HIV+ patients and healthy subjects. CONCLUSIONS: The present results suggest that although secreted aspartyl proteases are important in the pathogenesis of C. albicans, their activity depends on host conditions. PMID- 24071643 TI - [Determination of the profiles of secondary metabolites characteristic of Alternaria strains isolated from tomato]. AB - BACKGROUND: Many Alternaria species have been studied for their ability to produce bioactive secondary metabolites, such as tentoxin (TEN), some of which have toxic properties. The main food contaminant toxins are tenuazonic acid, alternariol (AOH), alternariol monomethyl ether (AME), altenuene, and altertoxins i, ii and iii. AIMS: To determine the profiles of secondary metabolites characteristic of Alternaria strains isolated from tomato for their chemotaxonomic classification. METHODS: The profiles of secondary metabolites were determined by HPLC MS. RESULTS: The Alternaria isolates obtained from spoiled tomatoes belong, according to their morphological characteristics, to the species groups Alternaria alternata, Alternaria tenuissima and Alternaria arborescens, with A. tenuissima being the most frequent. The most frequent profiles of secondary metabolites belonging to the species groups A. alternata (AOH, AME, TEN), A. tenuissima (AOH, AME, TEN, tenuazonic acid) and A. arborescens (AOH, AME, TEN, tenuazonic acid) were determined, with some isolates of the latter being able to synthesize AAL toxins. CONCLUSIONS: Secondary metabolite profiles are a useful tool for the differentiation of small spored Alternaria isolates not easily identifiable by their morphological characteristics. PMID- 24071647 TI - Integrated all-optical logic discriminators based on plasmonic bandgap engineering. AB - Optical computing uses photons as information carriers, opening up the possibility for ultrahigh-speed and ultrawide-band information processing. Integrated all-optical logic devices are indispensible core components of optical computing systems. However, up to now, little experimental progress has been made in nanoscale all-optical logic discriminators, which have the function of discriminating and encoding incident light signals according to wavelength. Here, we report a strategy to realize a nanoscale all-optical logic discriminator based on plasmonic bandgap engineering in a planar plasmonic microstructure. Light signals falling within different operating wavelength ranges are differentiated and endowed with different logic state encodings. Compared with values previously reported, the operating bandwidth is enlarged by one order of magnitude. Also the SPP light source is integrated with the logic device while retaining its ultracompact size. This opens up a way to construct on-chip all-optical information processors and artificial intelligence systems. PMID- 24071644 TI - USP2a alters chemotherapeutic response by modulating redox. AB - Cancer cells are characterized by altered ubiquitination of many proteins. The ubiquitin-specific protease 2a (USP2a) is a deubiquitinating enzyme overexpressed in prostate adenocarcinomas, where it exhibits oncogenic behavior in a variety of ways including targeting c-Myc via the miR-34b/c cluster. Here we demonstrate that USP2a induces drug resistance in both immortalized and transformed prostate cells. Specifically, it confers resistance to typically pro-oxidant agents, such as cisplatin (CDDP) and doxorubicin (Doxo), and to taxanes. USP2a overexpression protects from drug-induced oxidative stress by reducing reactive oxygen species (ROS) production and stabilizing the mitochondrial membrane potential (DeltaPsi), thus impairing downstream p38 activation and triggering of apoptosis. The molecular mediator of the USP2a protective function is the glutathione (GSH). Through miR-34b/c-driven c-Myc regulation, USP2a increases intracellular GSH content, thus interfering with the oxidative cascade triggered by chemotherapeutic agents. In light of these findings, targeting Myc and/or miR 34b/c might revert chemo-resistance. PMID- 24071646 TI - Atorvastatin overcomes gefitinib resistance in KRAS mutant human non-small cell lung carcinoma cells. AB - The exact influence of statins on gefitinib resistance in human non-small cell lung cancer (NSCLC) cells with KRAS mutation alone or KRAS/PIK3CA and KRAS/PTEN comutations remains unclear. This work found that transfection of mutant KRAS plasmids significantly suppressed the gefitinib cytotoxicity in Calu3 cells (wild type KRAS). Gefitinib disrupted the Kras/PI3K and Kras/Raf complexes in Calu3 cells, whereas not in Calu3 KRAS mutant cells. These trends were corresponding to the expression of pAKT and pERK in gefitinib treatment. Atorvastatin (1 MUM) plus gefitinib treatment inhibited proliferation, promoted cell apoptosis, and reduced the AKT activity in KRAS mutant NSCLC cells compared with gefitinib alone. Atorvastatin (5 MUM) further enhanced the gefitinib cytotoxicity through concomitant inhibition of AKT and ERK activity. Atorvastatin could interrupt Kras/PI3K and Kras/Raf complexes, leading to suppression of AKT and ERK activity. Similar results were also obtained in comutant KRAS/PTEN or KRAS/PIK3CA NSCLC cells. Furthermore, mevalonate administration reversed the effects of atorvastatin on the Kras/Raf and Kras/PI3K complexes, as well as AKT and ERK activity in both A549 and Calu1 cells. The in vivo results were similar to those obtained in vitro. Therefore, mutant KRAS-mediated gefitinib insensitivity is mainly derived from failure to disrupt the Kras/Raf and Kras/PI3K complexes in KRAS mutant NSCLC cells. Atorvastatin overcomes gefitinib resistance in KRAS mutant NSCLC cells irrespective of PIK3CA and PTEN statuses through inhibition of HMG-CoA reductase-dependent disruption of the Kras/Raf and Kras/PI3K complexes. PMID- 24071648 TI - Synergistic increase of oxygen reduction favourable Fe-N coordination structures in a ternary hybrid of carbon nanospheres/carbon nanotubes/graphene sheets. AB - A Fe/N co-doped ternary nanocarbon hybrid, with uniform bamboo-like carbon nanotubes (CNTs) in situ grown on/between the single/few-layer graphene sheets interspaced by carbon nanosphere aggregates, was prepared through a one-pot heat treatment of a precursor mixture containing graphene oxide, Vulcan XC-72 carbon nanospheres, nitrogen rich melamine and small amounts of Fe ions. Physical characterization including electron microscopic images, N2 adsorption-desorption isotherms, pore size distribution, XPS, XRD, Mossbauer spectra, and EDX revealed that the 0-D/1-D/2-D ternary hybrid architecture not only offered an optimized morphology for high dispersion of each nanocarbon moiety, while the carbon nanosphere interspaced graphene sheets have provided a platform for efficient reaction between Fe ions and melamine molecules, resulting in uniform nucleation and growth of CNTs and formation of high density Fe-N coordination assemblies that have been believed to be the active centers for the oxygen reduction reaction (ORR) in carbon-based nonprecious metal electrocatalysts. In the absence of graphene oxides or carbon nanospheres, a similar heat treatment was found to result in large amounts of elemental Fe and Fe carbides and entangled CNTs with wide diameter distributions. As a result, the ternary Fe/N-doped nanocarbon hybrid exhibits ORR activity much higher than the Fe-N doped single or binary nanocarbon materials prepared under similar heat treatment conditions, and approaching that of the state-of-the-art carbon-supported platinum catalyst (Pt/C) in acidic media, as well as superior stability and methanol tolerance to Pt/C. PMID- 24071649 TI - Factors influencing multiplate whole blood impedance platelet aggregometry measurements, during aspirin treatment in acute ischemic stroke: a pilot study. AB - Among patients with stroke, the phenomenon of resistance to treatment with low dose aspirin acetylsalicylic acid (ASA) is quite common. The study included 133 patients hospitalized with acute ischemic stroke. Impedance platelet aggregometry (IPA) and levels of vWF and thromboxane (TXB2) were assessed - with the efficacy of aspirin in daily clinical investigation. Responses to treatment with doses of 150 and 300 mg/day were measured. In addition, we analyzed the response of proinflammatory factors [fibrinogen, C-reactive protein (CRP), white blood corpuscles (WBC)], lipids and hemoglobin A1c, which may alter platelet aggregation response to treatment. After a week of treatment at 150 mg/day, ASA patients were classified as laboratory resistant (42%) or sensitive (58%). Values of IPA in the resistant group were significantly higher (472 +/- 150 vs. 222 +/- 59 AUC, P < 0.0001). In resistant patients were also found higher levels of fibrinogen (3.90 +/- 0.89 vs. 3.46 +/- 0.74 g/l, P = 0.0046), CRP (6.97 +/- 5.66 vs. 4.17 +/- 4.03 mg/l, P = 0.0011), WBC (9.2 +/- 2.4 vs. 8.3 +/- 2.2 * 10/l, P = 0.0207) and lower HDL cholesterol (46 +/- 12 vs. 52 +/- 15 mg/dl, P = 0.016). This research shows that aspirin resistance assessment by IPA well reflects the clinical status of patients and should be used routinely. Resistance generally fails to 'break' at higher doses, hence our suggestion that patients resistant to low doses of the drug immediately switch to a thienopyridine class antiplatelet agent, for example, clopidogrel. PMID- 24071650 TI - Better understanding live donor risk through big data. PMID- 24071651 TI - Comorbidity burden and perioperative complications for living kidney donors in the United States. AB - BACKGROUND AND OBJECTIVES: Since 1998, 35% of kidney transplants in the United States have been derived from living donors. Research suggests minimal long-term health consequences after donation, but comprehensive studies are limited. The primary objective was to evaluate trends in comorbidity burden and complications among living donors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The National Inpatient Sample (NIS) was used to identify donors from 1998 to 2010 (n=69,117). Comorbid conditions, complications, and length of stay during hospitalization were evaluated. Outcomes among cohorts undergoing appendectomies, cholecystectomies and nephrectomy for nonmetastatic carcinoma were compared, and sample characteristics were validated with the Scientific Registry of Transplant Recipients (SRTR). Survey regression models were used to identify risk factors for outcomes. RESULTS: The NIS captured 89% (69,117 of 77,702) of living donors in the United States. Donor characteristics were relatively concordant with those noted in SRTR (mean age, 40.1 versus 40.3 years [P=0.18]; female donors, 59.0% versus 59.1% [P=0.13]; white donors, 68.4% versus 69.8% [P<0.001] for NIS versus SRTR). Incidence of perioperative complications was 7.9% and decreased from 1998 to 2010 (from 10.1% to 7.6%). Men (adjusted odds ratio [AOR], 1.37; 95% confidence interval [CI], 1.20 to 1.56) and donors with hypertension (AOR, 3.35; 95% CI, 2.24 to 5.01) were more likely to have perioperative complications. Median length of stay declined over time (from 3.7 days to 2.5 days), with longer length of stay associated with obesity, depression, hypertension, and pulmonary disorders. Presence of depression (AOR, 1.08; 95% CI, 1.04 to 1.12), hypothyroidism (AOR, 1.07; 95% CI, 1.04 to 1.11), hypertension (AOR, 1.38; 95% CI, 1.27 to 1.49), and obesity (AOR, 1.07; 95% CI, 1.03 to 1.11) increased over time. Complication rates and length of stay were similar for patients undergoing appendectomies and cholecystectomies but were less than those with nephrectomies for carcinoma. CONCLUSIONS: The NIS is a representative sample of living donors. Complications and length of stay after donation have declined over time, while presence of documented comorbid conditions has increased. Patients undergoing appendectomy and cholecystectomy have similar outcomes during hospitalization. Monitoring the health of living donors remains critically important. PMID- 24071653 TI - Employment status, residential and workplace food environments: associations with women's eating behaviours. AB - There remains a lack of consistent evidence linking food environments with eating behaviours. Studies to date have largely ignored the way different individuals interact with their local food environment and have primarily focussed on exposures within the residential neighbourhood without consideration of exposures around the workplace, for example. In this study we firstly examine whether associations between the residential food environment and eating behaviours differ by employment status and, secondly, whether food environments near employed women's workplaces are more strongly associated with dietary behaviours than food environments near home. Employment status did not modify the associations between residential food environments and eating behaviours, however results showed that having access to healthy foods near the workplace was associated with healthier food consumption. Policies focused on supportive environments should consider commercial areas as well as residential neighbourhoods. PMID- 24071652 TI - Glomerular diseases: emerging tests and therapies for IgA nephropathy. AB - The last decade has seen major progress in understanding the pathogenesis as well as the prognosis and treatment of patients with IgA nephropathy (IgAN). Although the diagnostic criterion of a kidney biopsy demonstrating dominant or codominant IgA deposition remains unchanged, much more is known about the genetic and environmental factors predisposing to disease development and progression. These advances have led to the identification of novel diagnostic and prognostic markers. Among the most promising clinically are genetic profiling, quantification of galactose-deficient IgA1 levels, and measurement of anti-IgA1 immunoglobulins. While targeted treatment for IgAN remains elusive, there is mounting evidence for therapeutic interventions that alter the disease course. The appropriate validation and integration of these discoveries into clinical care represent a major challenge, but one that holds tremendous promise for refining prognostication, guiding therapy, and improving the lives of patients with IgAN. PMID- 24071654 TI - The combined impact of rural residence and socio-economic status on premature mortality. AB - The health of rural and urban populations differs, with rural areas appearing healthier. However, it is unknown whether the benefit of living in rural areas is felt by individuals in all levels of deprivation, or whether some suffer a disadvantage of rural residence. For England and Wales 2001-2003 premature mortality rates were calculated, subdivided by individual deprivation and gender, for areas with differing rurality characteristics. Premature mortality data (age 50-retirement) and a measure of the individual's deprivation (National Statistics Socio-economic Classification 1-7) was obtained from death certificates. Overall premature mortality was examined as well as premature mortality subdivided by major cause. Male premature mortality rates (age 50-64) fell with increasing rurality for individuals in all socio-economic status classifications. The most deprived individuals benefitted most from residence in increasingly rural areas. Similar trends were observed when premature mortality was subdivided by the major causes of death. Female premature mortality rates (age 50-59) demonstrated similar trends but the differences between urban and rural areas were less marked. PMID- 24071655 TI - Healthier land, healthier farmers: considering the potential of natural resource management as a place-focused farmer health intervention. AB - Farmers have particular wellbeing-related vulnerabilities that conventional health interventions struggle to address. We consider the potential of natural resource management (NRM) programs, which reach large numbers of farmers, as non conventional place-focused wellbeing interventions. Although designed to address environmental degradation, NRM can influence the wellbeing of farmers. We used qualitative meta-synthesis to reanalyse studies examining social dimensions of NRM in Australia and generate a theoretical framework identifying potential pathways between NRM and wellbeing, intended to inform subsequent empirical work. Our results suggest NRM programs influence several important determinants of farmer wellbeing, in particular social capital, self-efficacy, social identity, material wellbeing, and health itself. The pathways by which NRM influences these determinants are mediated by distal factors such as changes in land conditions, farmer skills and knowledge and resources accessible to farmers. These, in turn, are moderated by the design and delivery of NRM programs, suggesting potential to enhance the health benefits of NRM through specific attention to program design. PMID- 24071656 TI - Net costs of health worker rural incentive packages: an example from the Lao People's Democratic Republic. AB - BACKGROUND: Many developing countries are examining whether to institute incentive packages that increase the share of health workers who opt to locate in rural settings; however, uncertainty exists with respect to the expected net cost (or benefit) from these packages. METHODS: We utilize the findings from the discrete choice experiment surveys applied to students training to be health professionals and costing analyses in Lao People's Democratic Republic to model the anticipated effect of incentive packages on new worker location decisions and direct costs. Incorporating evidence on health worker density and health outcomes, we then estimate the expected 5-year net cost (or benefit) of each incentive packages for 3 health worker cadres--physicians, nurses/midwives, and medical assistants. RESULTS: Under base case assumptions, the optimal incentive package for each cadre produced a 5-year net benefit (maximum net benefit for physicians: US$ 44,000; nurses/midwives: US$ 5.6 million; medical assistants: US$ 485,000). CONCLUSIONS: After accounting for health effects, the expected net cost of select incentive packages would be substantially less than the original estimate of direct costs. In the case of Lao People's Democratic Republic, incentive packages that do not invest in capital-intensive components generally should produce larger net benefits. Combining discrete choice experiment surveys, costing surveys and cost-benefit analysis methods may be replicated by other developing countries to calculate whether health worker incentive packages are viable policy options. PMID- 24071657 TI - Strong Casimir force reduction through metallic surface nanostructuring. AB - The Casimir force between bodies in vacuum can be understood as arising from their interaction with an infinite number of fluctuating electromagnetic quantum vacuum modes, resulting in a complex dependence on the shape and material of the interacting objects. Becoming dominant at small separations, the force has a significant role in nanomechanics and object manipulation at the nanoscale, leading to a considerable interest in identifying structures where the Casimir interaction behaves significantly different from the well-known attractive force between parallel plates. Here we experimentally demonstrate that by nanostructuring one of the interacting metal surfaces at scales below the plasma wavelength, an unexpected regime in the Casimir force can be observed. Replacing a flat surface with a deep metallic lamellar grating with sub-100 nm features strongly suppresses the Casimir force and for large inter-surfaces separations reduces it beyond what would be expected by any existing theoretical prediction. PMID- 24071659 TI - The effect of bariatric surgery on renal function and disease: a focus on outcomes and inflammation. AB - Renal dysfunction and disease, including hyperfiltration, proteinuria and hypofiltration, are commonly associated with obesity. Diabetic kidney disease is also common in obese cohorts. Weight loss interventions, including bariatric surgery, can effectively reduce weight and improve renal outcomes. Some of this effect may be due to the remission of Type 2 diabetes and hypertension. However, other mechanisms, including the resolution of inflammatory processes, may also contribute. The effect of bariatric surgery on renal function has only recently become a focus of particular investigation. In this study, we will review the effects of bariatric surgery on obesity-associated kidney disease. We will discuss the pitfalls in assessing renal function in obese cohorts and will examine the effect of bariatric surgery on renal function and urinary protein excretion using different mechanisms. We will give particular attention to the evidence for bariatric surgery in cohorts with established renal disease and suggest future directions. In particular, we will outline the evidence for inflammation as an important therapeutic target, and the emerging medical therapies being considered to exploit this target in obesity- and diabetes related kidney disease. PMID- 24071658 TI - Culture-dependent and independent approaches for identifying novel halogenases encoded by Crambe crambe (marine sponge) microbiota. AB - Sponges harbour microbial communities that contribute to the genetic and metabolic potential of their host. Among metabolites produced by sponge associated microbial communities, halogenated compounds are of special interest because of their biotechnological potential. In this study, we have examined the diversity of the cultivable fraction of the marine demosponge Crambe crambe microbiota. Application of complementary cultivation methods yielded 107 bacterial isolates, some of which may be sponge-specific based on their phylogenetic analysis. Among these, Psychrobacter sp. was found to contain a putative halogenase gene. In addition to the culture-dependent approach for discovering halogenase genes, a cDNA library was constructed to determine the diversity of halogenase genes expressed in situ by the C. crambe microbiota. To this end, seventeen putative tryptophan halogenase cDNA sequences were identified, most of which were only remotely related to known halogenase genes, indicating the potential for novel bioactive compounds being produced by the C. crambe microbiota. PMID- 24071660 TI - Early failure in patients starting peritoneal dialysis: a competing risks approach. AB - BACKGROUND: Technical failure is more likely to occur in the first 6 months of peritoneal dialysis (PD). This study was carried out to identify risk factors for early transfer from PD to haemodialysis (HD) in a country where assisted PD is available. METHODS: All patients from the French Language Peritoneal Dialysis Registry (RDPLF) who started PD between 1 January 2002 and 31 December 2010 were included. Time to transfer, death and transplantation during the first 6 months on PD were analysed by the multivariate Cox proportional hazard model. The Fine and Gray model was used to examine the occurrence of technical failure by considering death and transplantation as competing events. RESULTS: Of 9675 patients included, 615 (6.3%) moved to HD during the first 6 months of PD. Cumulative incidence of transfer to HD was 6.6% at 6 months. On multivariate analysis by both the Cox model and the Fine and Gray model, HD prior to PD, allograft failure and early peritonitis were associated with a higher risk of early technical failure, whereas being dialysed in a centre treating more than 20 new patients per year was associated with a lower risk of early transfer to HD. CONCLUSIONS: Patients treated by HD before PD and failed transplant patients had a higher risk of early PD failure when competing events were considered. PMID- 24071661 TI - A European Renal Best Practice (ERBP) position statement on the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the management of blood pressure in non-dialysis-dependent chronic kidney disease: an endorsement with some caveats for real-life application. AB - Developing guidelines on a subject as broad as hypertension is difficult, especially when the guidance relates to hypertension in the chronic kidney disease (CKD) population. The Kidney Disease: Improving Global Outcomes Guideline Development Group has applied a rigorous methodology in reviewing all available evidence, and their recommendations are consistent with the evidence-based approach. As a result, the European Renal Best Practice endorses most of its recommendations. However, the Work Group feels that some additional advice could help clinicians in daily practice: (i) individualization of treatment should be taken into account, especially (cardiovascular) co-morbidities, age, gender and race; (ii) side-effects, such as postural dizziness should be monitored closely, particularly in elderly, diabetics and patients with arterial stiffness; (iii) the importance of salt restriction should not be neglected; (iv) although angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blocker (ARBs) remain a cornerstone in the management of hypertension, and especially cardiovascular protection, in some particular situations such as in advanced CKD and in patients without proteinuria, their role is less well defined; (v) as most CKD patients need more than one antihypertensive drug to achieve blood pressure control, the specific (renal) (dis)advantages of other classes than ACE-I or ARB should be taken into account. PMID- 24071662 TI - The IRS1 G972R polymorphism and glomerular filtration rate in patients with type 2 diabetes of European ancestry. AB - BACKGROUND: In Mexican Americans, the IRS1 G972R polymorphism (rs1801278) has been associated to such a marked reduction in glomerular filtration rate (GFR) (i.e. beta = -8.3 mL/min/1.73 m(2)) to be considered a major determinant of kidney function. METHODS: This was a cross-sectional study to investigate whether a similarly strong effect can also be observed among individuals of European ancestry. We investigated a total of 3973 White patients with type 2 diabetes. Standardized serum creatinine was measured by the modified kinetic Jaffe reaction and estimated GFR (eGFR) calculated by the modification diet renal disease (MDRD) formula; rs1801278 was genotyped by TaqMan assay. RESULTS: No significant association was observed, with R972 carriers showing only a modestly, not significant, lower eGFR level as compared with other subjects (beta = -1.82 mL/min/1.73 m(2), P = 0.086). CONCLUSIONS: Our data indicate that IRS1 G972R is not a strong determinant of GFR in diabetic patients of European ancestry as in Mexican Americans. Since we had 100% power to detect the previously reported association, the risk our finding is a false negative one is minimal. PMID- 24071663 TI - Molecular structure and hydrogen bonding in pure liquid ethylene glycol and ethylene glycol-water mixtures studied using NIR spectroscopy. AB - The molecular structure and hydrogen bonding of ethylene glycol (EG) and EG-water mixtures in the liquid phase were studied by using near-infrared (NIR) spectroscopy. The spectra were evaluated using a two-dimensional (2D) correlation approach, moving-window 2D correlation analysis and chemometric methods. The minor changes for the CH stretching bands indicate that the structures of pure liquid EG and EG-water mixtures are determined by the intermolecular hydrogen bonding through the OH groups. The analysis of the nu2 + nu3 combination band of water reveals that in EG-rich solutions the molecules of water are predominantly bonded with two molecules of EG and this cooperative hydrogen bonding is stronger than that in bulk water. Further increase in the water content leads to formation of small water clusters around OH groups of EG. Comparing results for the binary mixtures of water with different organic solvents one can conclude that the total amount and distribution of the polar groups are the most important factors determining the solubility of water in the organic phase. The distribution of these groups depends on the length and structure of the hydrocarbon chain. Due to high population and relatively uniform distribution of the OH groups of EG water has unlimited solubility in liquid EG. PMID- 24071664 TI - Predicting clinical concussion measures at baseline based on motivation and academic profile. AB - OBJECTIVE: The purpose of this study was to predict baseline neurocognitive and postural control performance using a measure of motivation, high school grade point average (hsGPA), and Scholastic Aptitude Test (SAT) score. DESIGN: Cross sectional. SETTING: Clinical research center. PARTICIPANTS: Eighty-eight National Collegiate Athletic Association Division I incoming student-athletes (freshman and transfers). INTERVENTIONS: Participants completed baseline clinical concussion measures, including a neurocognitive test battery (CNS Vital Signs), a balance assessment [Sensory Organization Test (SOT)], and motivation testing (Rey Dot Counting). Participants granted permission to access hsGPA and SAT total score. MAIN OUTCOME MEASURES: Standard scores for each CNS Vital Signs domain and SOT composite score. RESULTS: Baseline motivation, hsGPA, and SAT explained a small percentage of the variance of complex attention (11%), processing speed (12%), and composite SOT score (20%). CONCLUSIONS: Motivation, hsGPA, and total SAT score do not explain a significant amount of the variance in neurocognitive and postural control measures but may still be valuable to consider when interpreting neurocognitive and postural control measures. PMID- 24071665 TI - Priorities for investment in injury prevention in community Australian football. AB - OBJECTIVE: High-quality sport-specific information about the nature, type, cause, and frequency of injuries is needed to set injury prevention priorities. This article describes the type, nature, and mechanism of injuries in community Australian Football (community AF) players, as collected through field-based monitoring of injury in teams of players. DATA SOURCES: Compilation of published prospectively collected injury data from 3 studies in junior community AF (1202 injuries in 1950+ players) and 3 studies in adult community AF (1765 injuries in 2265 players). This was supplemented with previously unpublished data from the most recent adult community AF injury cohort study conducted in 2007 to 2008. Injuries were ranked according to most common body regions, nature of injury, and mechanism. MAIN RESULTS: In all players, lower limb injuries were the most frequent injury in community AF and were generally muscle strains, joint sprains, and superficial injuries. These injuries most commonly resulted from incidental contact with other players, or from "overexertion." Upper limb injuries were less common but included fractures, strains, and sprains that were generally caused by incidental contact between players and the result of players falling to the ground. CONCLUSIONS: Lower limb injuries are common in community AF and could have an adverse impact on sustained participation in the game. Based on what is known about their mechanisms, it is likely that a high proportion of lower limb injuries could be prevented and they should therefore be a priority for injury prevention in community AF. PMID- 24071666 TI - Hispanic nurses' experiences of bias in the workplace. AB - PURPOSE: The continuing issue of health inequity for Hispanics highlights the importance of retaining Hispanic nurses in the workplace. This article describes the use of short answers such as "Describe the bias you experienced" and "If a patient refused care, what was the reason given?" to increase understandings about bias through the descriptions of Hispanic nurses. In this study, bias was defined as those implicit negative stereotypes and attitudes that negatively affect judgments about, evaluations of, and actions toward others. DESIGN/METHOD: For this qualitative component of a descriptive study employing both qualitative and quantitative methods, 111 Hispanic nurses responded to open-ended questions about experiences of bias that were included with a survey tool and demographic questionnaire. FINDINGS: Three themes emerged: being overlooked and undervalued, having to prove competency, and living with "only-ness." Respect was an overarching concept. DISCUSSION/CONCLUSIONS: The written descriptions of bias provided depth and understanding to the quantitative findings. Nurse leaders are well positioned to develop and implement strategies to more effectively support Hispanic nurses and to promote nonbiased interactions in the workplace. IMPLICATIONS: Retaining Hispanic nurses is a vital component to address issues of health inequity for Hispanic patients. PMID- 24071667 TI - Prevalence and risk factors for incontinence among Emirati women with diabetes. AB - PURPOSE: To estimate the prevalence and risk factors for urinary incontinence among a sample of Emirati women with diabetes. DESIGN: A cross-sectional survey design using probability sampling was employed to evaluate incontinence among 350 Emirati diabetic women. Age, body mass index, history of urinary tract infections, parity, diabetes duration, and type of diabetes management were evaluated as potential risk factors for incontinence. To assess type and frequency of incontinence, items from the National Health and Nutrition Examination Survey-Kidney Condition-Urology were used. FINDINGS: A total of 225 (64.3%) participants reported incontinence, with 110 (31.4%) expressed having an episode once a week or more. Both stress (n = 197, 56.3%) and urge incontinence (n = 208, 59.4%) were seen; 96 (48.7%) reported at least weekly stress incontinence episodes, and 109 (52.4%) reported weekly or more urge episodes. Results of logistic regression indicated that diabetes duration was the most significant risk factor for incontinence. CONCLUSION: Prevalence of incontinence in Emirati women was higher than that reported by diabetic women in other cultures. PRACTICE IMPLICATIONS: Clinicians working with Emirati diabetic women should endeavor to enhance screening for incontinence and design culturally appropriate strategies for teaching and treating this complication of diabetes. PMID- 24071668 TI - Prevention, prevention, prevention. PMID- 24071669 TI - Multifaceted and mixed didactic-interactive methods are more effective ways to learn and change behaviour. AB - DATA SOURCES: The following electronic databases were searched from 1986 to the present: Cochrane Library (Cochrane Database of Systematic Reviews, DARE and HTA Databases, and Cochrane CENTRAL Register of Controlled Trials), Medline In Process and Other Non-Indexed Citations and Medline (Ovid), Embase (Ovid), ERIC (CSA), Index to Theses (Expert Information Services), and ZETOC (British Library Electronic Table of Contents and conference proceedings). No language restrictions. STUDY SELECTION: Randomised controlled trials or quasi-experimental designs were eligible which evaluated continuing professional development (CPD) interventions in dentistry (for dentists and professions complimentary to dentistry) on learning gains, behaviour change or patient outcomes. These could be compared against no intervention or another CPD intervention. There were no minimum follow up times. DATA EXTRACTION AND SYNTHESIS: The following data were extracted by two reviewers: bibliographic details, settings, characteristics about participants, intervention and control conditions, outcome measures, findings and conclusions. Studies were grouped thematically according to the intervention, and the studies were quality assessed using a custom system based on the CONSORT statement. The results were reported in a narrative form and no attempt was made to combine them in a meta-analysis. RESULTS: Ten studies were included. Eight studies were judged to be of high to moderately high quality. None of the studies measured patient outcomes, but a multifaceted black box intervention resulted in self-reported patient care and face-to-face contact to change antibiotic prescribing habits showed a change in clinician behaviour. The size of this effect for both of these is not reported here. There was some effect on knowledge but not on behaviour for courses and workshops, written material, computer-assisted learning and audit and feedback. CONCLUSIONS: Multi-method and multi-phased dental CPD has potential for the greatest impact on practitioner behaviour. PMID- 24071670 TI - Strong evidence for the effectiveness of resin based sealants. AB - DATA SOURCES: Cochrane Oral Health Group's Trials Register, CENTRAL, Medline via OVID, EMBASE via OVID; SCISEARCH, CAplus, INSPEC, NTIS and PASCAL via STN Easy and DARE, NHS EED, HTA (all to September/ November 2012) and ClinicalTrials.gov (to July 2012). There were no restrictions on language or date of publication. STUDY SELECTION: Randomised and quasi-randomised controlled trials of at least 12 months duration comparing no sealant with sealant, or different types of sealants, for preventing caries of occlusal or approximal surfaces of premolar or molar teeth in children and adolescents under 20 years of age. DATA EXTRACTION AND SYNTHESIS: Screening of search results, data extraction and assessment of trial quality (using GRADE methods) were by two reviewers independently. RESULTS: There were 34 trials of children aged five to 16 years, with 12 trials (2575 participants) comparing sealants with no sealant, 21 trials (3202 participants) comparing one sealant with another and one trial (752 participants) comparing two types of sealant with no sealant.Resin sealants compared with no sealants prevented caries in the first permanent molars of children five to 10 years old (six trials at low risk of bias with two years follow up), (odds ratio (OR) 0.12, 95% confidence interval (CI) 0.07 to 0.19). At 48 to 54 months follow-up, the caries preventive effect was maintained (OR 0.21, 95% CI 0.16 to 0.28) although there were only four trials (two were at low and two at high risk of bias).No conclusions could be drawn as to whether glass ionomer sealants compared with no sealants prevented caries at 2 year follow-up. The mean difference in DFS was 0.18, 95% CI -0.39 to 0.03.The relative effectiveness of one type of sealant compared to a different type of sealant was inconclusive as there was great variation in comparisons, outcomes, times of outcomes and background fluoride levels in the 21 studies. There was insufficient evidence for the relative superiority of glass ionomer and resin sealants (very low event rate in many of the 15 trials). There were inconsistent results for resin-modified glass ionomer sealants compared with resin sealants. No difference in caries increments were found in the two small trials of polyacid-modified resin sealants compared with resin sealants. CONCLUSIONS: Sealants compared with no sealants, on the occlusal surfaces of permanent molars in children and adolescents, are effective at reducing caries up to 48 months. There is less evidence for longer term follow-up and little for the relative effectiveness of sealing in less high caries risk children. No conclusions could be drawn on the relative effectiveness of different types of sealants. PMID- 24071671 TI - Trial shows caries reductions at one year in school-based sealant programme. AB - DESIGN: Pragmatic split-mouth randomised controlled trial. INTERVENTION: Children from low-income backgrounds were randomised to have one of each first molar tooth pairs sealed. Tooth pairs were excluded when a dental sealant or dentinal caries was present on one of the teeth. Clinical examinations took place at baseline and at one year. Caries risk status was assessed at baseline and included Streptococcus mutans (SM) and Lactobacillus counts. OUTCOME MEASURE: The primary outcome was new carious lesions (ICDAS code 3-6). Secondary outcomes included sealant status. RESULTS: 343 children consented, 253 (91.7%) of the 276 children who had sealants were seen at one-year giving 421 tooth pairs for analysis. The adjusted analysis showed that seared molars were less at risk of developing new caries compared with controls (OR = 0.26, 95% CI: 0.14-0.49). The effect of the sealants was significant only when the analyses included subjects with active caries (OR = 0.25; 95% CI: 0.12-0.50) or with a high SM count (>105, OR = 0.20; 95% CI: 0.10-0.41) at baseline. Total retention was recorded in 52.7% (n = 222) of the treated teeth, with retention in the maxilla being significantly lower than in the mandible. CONCLUSIONS: The one-year effectiveness of the school-based program was demonstrated in low socio-economic areas. Selection of schoolchildren according to individual caries risk factors should be considered in school-based programmes. PMID- 24071672 TI - Substantial reduction in caries from regular fluoride varnish application. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL, LILACS and BBO, ProQuest Dissertations and Theses, Web of Science Conference Proceedings and ClinicalTrials.gov databases were searched. Reference lists of identified articles were also scanned for relevant papers. Study authors were contacted for additional information. STUDY SELECTION: Randomised or quasi-randomised controlled trials using or indicating blind outcome assessment that compared fluoride varnish to placebo or no treatment for at least one year were included. Risk of bias assessment was undertaken. DATA EXTRACTION AND SYNTHESIS: Study assessment and data extraction was carried out independently by at least two reviewers. The primary measure of effect was the prevented fraction, that is the difference in mean caries increments between the treatment and control groups expressed as a percentage of the mean increment in the control group. The caries increments nearest to three years were used from each included study. Random effects meta-analyses were performed where data could be pooled. Potential sources of heterogeneity were examined in random-effects meta-regression analyses. Adverse effects information was collected from the included trials. RESULTS: Twenty-two trials (12,455 participants) were included. Thirteen trials were included in the permanent tooth surfaces meta-analysis, the pooled D(M)FS prevented fraction estimate comparing fluoride varnish with placebo or no treatment was 43% (95% confidence interval (CI) 30% to 57%; P < 0.0001). There was substantial heterogeneity, confirmed statistically (P < 0.0001; I(2) = 75%), however this body of evidence was assessed as of moderate quality. Ten trials contributed to the meta-analysis of primary teeth, the pooled d(e/m)fs prevented fraction estimate was 37% (95% CI 24% to 51%; P < 0.0001), there was some heterogeneity (P = 0.009; I(2) = 59%) this evidence was assessed as of moderate quality. No significant associations in either dentitions were found with baseline caries severity, background exposure to fluorides, application features such as prior prophylaxis, concentration of fluoride or frequency of application. There was little information concerning possible adverse effects or acceptability of treatment. CONCLUSIONS: The conclusions of this updated review remain the same as when it was first published. The review suggests a substantial caries inhibiting effect of fluoride varnish in both permanent and primary teeth; however the quality of the evidence was assessed as moderate, as it included mainly high risk of bias studies, with considerable heterogeneity. PMID- 24071673 TI - Partial caries removal may have advantages but limited evidence on restoration survival. AB - DATA SOURCES: Cochrane Oral Health Group's Trials Register, CENTRAL, Medline via OVID, EMBASE via OVID; no restrictions on language or date of publication. STUDY SELECTION: Parallel group and split mouth randomised and quasi-randomised controlled trials comparing stepwise, partial and no dentinal caries removal with complete caries removal in unrestored primary and permanent teeth were included in this review. DATA EXTRACTION AND SYNTHESIS: Title and abstract screening was by two reviewers, with disagreements resolved by a third. Full texts of eligible studies were assessed by the team until consensus, and data extraction was by three reviewers independently and in triplicate. Two reviewers assessed risk of bias. Trial authors were contacted where possible . RESULTS: Eight trials (all assessed as high risk of bias) with 934 participants and 1372 teeth were included in this updated review (Previously complete or ultraconservative removal of decayed tissue in unfilled teeth, Ricketts, 2006) with four new trials being included. There were a number of different comparisons in the trials (stepwise or partial or no dentinal caries removal compared to complete caries removal) with one study including more than one of these comparisons. Four studies investigated primary teeth, three permanent teeth and one included both.For stepwise caries removal, (four studies), there was a 56% reduction in incidence of pulp exposure (RR 0.44, 95% CI 0.33 to 0.60, P < 0.00001) compared to complete caries removal. The mean pulp exposure incidence was 34.7% in the complete caries removal group and 15.4% in the stepwise groups. There was no difference in signs and symptoms of pulp disease (RR 0.78, 95% CI 0.39 to 1.58, P = 0.50).In the two partial caries removal studies, the incidence of pulp exposure reduction was 77% for the partial caries removal group (RR 0.23, 95% CI 0.08 to 0.69, P = 0.009) with a mean pulp exposure incidence of 21.9% in the complete caries removal groups and 5% in the partial caries removal groups. There was insufficient evidence to determine whether or not there was a difference in signs and symptoms of pulp disease (RR 0.27, 95% CI 0.05 to 1.60, P = 0.15), or restoration failure (one study showing no difference and another study showing no failures in either group).There were two very different studies which looked at no dentinal caries removal compared to complete caries removal. There was some evidence of no difference between these techniques for the outcome of signs and symptoms of pulp disease and reduced risk of restoration failure, favouring no dentinal caries removal, from one study. There were no instances of pulp disease or restoration failure in either group from the second study. Meta-analysis of these two studies was not carried out because of the substantial clinical differences between the studies. CONCLUSIONS: For management of dentinal caries, both stepwise and partial excavation showed clinical advantage over complete caries removal by reducing the incidence of pulp exposure in symptomless, vital, carious primary as well as permanent teeth. The review found no difference in signs or symptoms of pulpal disease between stepwise excavation and complete caries removal.There was insufficient evidence to determine whether there was a difference in signs and symptoms of pulp disease or a difference in the risk of restoration failure with partial caries removal.For the two no dentinal caries removal studies, the one investigating permanent teeth found no difference in restoration failure and the one investigating primary teeth found a statistically significant difference in restoration failure favouring the intervention.Due to the short term follow-up, low reporting of patient centred outcomes and high risk of bias, further high quality, long-term clinical trials are still required to assess the most effective intervention. PMID- 24071674 TI - Lack of reliable evidence of the effectiveness of remineralising agents for the treatment of post orthodontic white spot lesions. AB - DATA SOURCES: PubMed, Medline, Web of Science and the Cochrane Library databases were searched. STUDY SELECTION: Selection was conducted independently by two reviewers, only randomised controlled trials were included. Study quality was assessed using the Cochrane risk of bias approach. DATA EXTRACTION AND SYNTHESIS: Data abstraction was carried out independently by two reviewers and qualitative summary presented, because of the heterogeneity of the interventions and outcome measures. RESULTS: Seven studies were included, all except one (of medium risk) were considered to be at high risk of bias. Three studies evaluated fluoride preparations (50-ppm sodium fluoride mouth rinse, 5% sodium fluoride varnish and 0.5% sodium fluoride chewing sticks). Four compared remineralising agents containing casein phosphopeptide amorphous calcium phosphate or casein phosphopeptide amorphous calcium fluoride phosphate. CONCLUSIONS: Based on the literature, there is a lack of reliable evidence to support the effectiveness of remineralising agents for the treatment of post orthodontic white spot lesions. PMID- 24071675 TI - Low quality evidence on the stability of orthodontic mini-implants. AB - DATA SOURCES: Medline, Embase, LILACS, Cochrane Library, Google Scholar, Web of Science, African Journals Online, Digital Dissertations. STUDY SELECTION: Randomised controlled trials (RCTs), prospective controlled clinical trials(CCTs) and prospective cohort studies were included. Studies on implants with a diameter greater than 2 mm were excluded. DATA EXTRACTION AND SYNTHESIS: Data were extracted independently by two authors. Bias in RCTs was assessed using the Cochrane risk of bias tool, with non-randomised studies being assessed using the Newcastle-Ottawa Scale. Failures of mini-screw implants were expressed as event rates with 95% confidence intervals. Risk factors were assessed using random effects model and sub-group and meta-regression analyses were also conducted. RESULTS: Fifty-two studies; five RCTs, eight CCTs, twenty-seven prospective cohort studies and twelve studies with unclear designs that were assessed to be prospective cohort studies were included. A funnel plot suggested there may be publication bias. Analysis of 4987 miniscrew implants used in 2281 patients indicated an overall failure rate of 13.5% (95% confidence interval, 11.5% 15.8%). Failures were not associated with patient sex or age and mini-screw implant insertion side, whereas they were significantly associated with jaw of insertion. Some trends were identified through exploratory analysis but no definite conclusions could be drawn. CONCLUSIONS: Orthodontic miniscrew implants have a modest small mean failure rate, indicating their usefulness in clinical practice. Although many factors seem to affect their failure rates, the majority of them still need additional evidence to support any possible associations. PMID- 24071676 TI - No differences seen in outcomes between three different methods of orthodontic retention. AB - DESIGN: Three arm, parallel group, patient randomised trial. INTERVENTION: Seventy-five patients who had just completed a course of treatment with four premolar extractions and fixed straight wire appliances in both jaws (0.022 inch, MBT) having had no previous orthodontics, were randomised by participant ballot sampling. To be eligible they had to be in the permanent dentition, with space deficiencies in both jaws, normal skeletal and dentoalveolar sagittal, vertical and transverse relationships, Class I molars or 3mm anterior or posterior deviation. The three retention methods were: 1) removable vacuum-formed retainer with maxillary canine-to-canine and palatal coverage plus a mandibular canine-to canine bonded retainer (GroupV-CTC); 2) an identical maxillary vacuum-formed retainer as in Group V-CTC plus stripping of mandibular anterior teeth (Group V S); and 3) a prefabricated positioner covering all erupted teeth in both jaws (Group P). Patients were given appliances within one hour of debonding, which were worn more for the first than second year then discontinued. OUTCOME MEASURE: Dental casts were taken at four time points; before treatment, on removal of fixed appliances, after 12 months and 24 months of retention. Twenty randomly selected casts were measured by a single blinded assessor on two separate occasions, four weeks apart, using electronic digital callipers for inter-canine width; inter-molar width; arch length; overjet; and overbite. Height and estimated compliance was recorded at every visit. Successful retention using Little's Irregularity Index was considered to be <3.5mm. RESULTS: Seventy-five patients were enrolled, and 69 completed, the trial. The mean active treatment time was 1.7 years and mean age was 14.4 years (SD 1.5) at start of retention. Although there were statistically significant differences for some of the parameters measured, there were no clinically significant differences between the three retention methods. All three were equally effective in retaining orthodontic treatment results and controlling relapse to a clinically significant level even when the results were adjusted for cooperation, initial crowding, growth and gender. The major part of relapse took place during the first year of retention. CONCLUSIONS: All three retention methods, V-CTC, V-S and P, retained the orthodontic treatment results and prevented relapse within clinically acceptable levels. Most relapse took place within the first year of retention and changes during the second year were small or negligible. PMID- 24071677 TI - No evidence for effectiveness of interventions used to treat displaced permanent anterior teeth. AB - DATA SOURCES: The Cochrane Oral Health Group Trials register, Cochrane Central Register of Controlled trials (CENTRAL), Medline, Embase, LILACS and Dissertation, Theses and Abstracts databases. STUDY SELECTION: Randomised controlled trials or quasi-randomised controlled trials that included a minimum follow-up period of 12 months.Data extraction and synthesisTwo review authors independently and in duplicate assessed the eligibility of all reports identified in the searches. Authors were contacted for additional information where required. RESULTS: No randomised or quasi-randomised controlled trials were found. CONCLUSIONS: We found no randomised or quasi-randomised trials of interventions to treat displaced luxated permanent front teeth. Current clinical guidelines are based on available information from case series studies and expert opinions. Randomised controlled trials in this area of dental trauma are required to robustly identify the benefits of different treatment strategies. PMID- 24071678 TI - Cast or fiber posts a summary of evidence from vitro studies. AB - DATA SOURCES: Medline, the Cochrane Controlled Trials Register, China National Knowledge Infrastructure and China Biology Medicine disc were searched. STUDY SELECTION: Only randomised studies were included. DATA EXTRACTION AND SYNTHESIS: Data were independently extracted. Standardised mean differences were combined and analysed using meta-analysis. RESULTS: Thirteen studies were included; premolars were used as specimens in six studies, central incisors in five studies and canines in three articles. There was considerable variation in both alloy and fibre materials used between studies. The standardised mean difference of the combined data was 0.64 (95% confidence interval, 0.08-1.20; P < .001), indicating that the cast post group displayed significantly higher fracture resistance than the fibre post group. CONCLUSIONS: On the basis of the current best available evidence, we concluded that cast posts had higher fracture resistance than fibre posts. PMID- 24071679 TI - Study confirms certain risk factors for development of alveolar osteitis. AB - DESIGN: Prospective nested case-control study. CASE/CONTROL SELECTION: From a cohort of 1423 Patents age 18 and older undergoing dental extractions at a public dental clinic in Chile examined at four days post-extraction. Eighty cases of alveolar osteitis were identified. Eighty matched controls were selected from the cohort at random. DATA ANALYSIS: Eight predictor variables (risk factors), namely patient gender, hygiene, tooth location, previous surgical site infection, traumatic extraction, systemic diseases, alcohol consumption and tobacco use were considered. A binary regression logistic analysis was performed to determine significant associations. RESULTS: The overall incidence of alveolar osteitis was 6.14%. Logistic regression analysis after adjustment showed a statistically significant association between three variables and the development of alveolar osteitis; previous surgical site infection (odds ratio [OR], 3.3; 95% CI, 1.4 to 7.7), traumatic extraction (OR, 13.1; 95% CI, 5.4 to 31.7) and smoking of tobacco after extraction (OR, 3.5; 95% CI, 1.3 to 9.0). CONCLUSIONS: Previous surgical site infection, traumatic extraction and tobacco smoking are associated with an increased risk of alveolar osteitis. PMID- 24071680 TI - Local antimicrobials in addition to scaling and root planing provide statistically significant but not clinically important benefit. AB - DATA SOURCES: The databases Medline, Embase and the Cochrane Oral Health Group Trials Register were searched. Handsearching of the Journal of Periodontology, Journal of Clinical Periodontology and Journal of Periodontal Research was also carried out. STUDY SELECTION: Randomised controlled trials published in English were included. DATA EXTRACTION AND SYNTHESIS: Risk of bias and quality assessment were conducted following Cochrane recommendations with data being extracted independently in duplicate. Because of the nature of the available data, qualitative summary is presented with meta-analysis conducted where appropriate. RESULTS: The overall effect of the subgingival application of antimicrobials was statistically significant (p = 0.000) for both changes in probing pocket depth (PPD) and clinical attachment level (CAL), with a weighted mean difference (WMD) of -0.407 and -0.310 mm respectively. No significant differences occurred for changes in bleeding on probing (BOP) and plaque index (PlI). Subgingival application of tetracycline fibres, sustained released doxycycline and minocycline demonstrated a significant benefit in PPD reduction (WMD between 0.5 and 0.7 mm). The rest of the tested outcomes demonstrated a high heterogeneity. The local application of chlorhexidine and metronidazole showed a minimal effect when compared with placebo (WMD between 0.1 and 0.4 mm). CONCLUSIONS: In conclusion, the scientific evidence supports the adjunctive use of local antimicrobials to SRP in deep or recurrent periodontal sites, mostly when the vehicle has shown pharmacodynamic properties assuring the sustained release of the antimicrobial. This evidence must be interpreted with caution, as the reported data were highly heterogeneous and most of the selected studies were categorised with a high degree of bias. PMID- 24071681 TI - Toothbrushing may reduce ventilator-associated pneumonia. AB - DATA SOURCES: The databases Embase, Medline, CINAHL, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, clinical trials.gov and controlled-trials.com were searched. Reference lists of reviewed articles and eligible trials were also searched, and toothpaste and toothbrush manufactures were contacted. STUDY SELECTION: Randomised controlled trials in adults over 18 years receiving mechanical ventilation were included where any kind of oral care involving toothbrushing was compared with any other kind of oral care or control with or without toothbrushing. DATA EXTRACTION AND SYNTHESIS: Data were extracted in duplicate and quality assessed using the Cochrane risk of bias tool. The results were combined using a random effects model. The main outcome was VAP. RESULTS: Six trials involving a total of 1408 patients were included. The risk of bias was high in four trials, low in one and unclear in the other. In four trials, there was a trend toward lower ventilator associated pneumonia rates (risk ratio, 0.77; 95% confidence interval, 0.50-1.21; p = 0.26). The only trial with low risk of bias suggested that toothbrushing significantly reduced ventilator-associated pneumonia (risk ratio, 0.26; 95% confidence interval, 0.10-0.67; p = 0.006). Use of chlorhexidine antisepsis seems to attenuate the effect of toothbrushing on ventilator-associated pneumonia (p for the interaction = 0.02). One trial comparing electric vs. manual toothbrushing showed no difference in ventilator-associated pneumonia rates (risk ratio, 0.96; 95% confidence interval, 0.47-1.96; p = 0.91). Toothbrushing did not impact on length of ICU stay, or ICU or hospital mortality. CONCLUSIONS: In summary, randomised trials to date show that toothbrushing is associated with a trend toward lower rates of VAP in intubated, mechanically ventilated critically ill patients. There is no clear difference between electric and manual toothbrushing. Toothbrushing has no effect on ICU mortality, hospital mortality, or ICU length of stay. PMID- 24071682 TI - Oral hygiene regimes for mechanically ventilated patients that use chlorhexidine reduce ventilator-associated pneumonia. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL, LILACS, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wan Fang Database, OpenGrey and ClinicalTrials.gov databases were searched. Reference lists of identified articles were also scanned for relevant papers. There were no language restrictions. STUDY SELECTION: Randomised controlled trials (RCTs) evaluating OHC in the form of mouthwashes, swabs, toothbrushing or in combination in critically ill patients receiving mechanical ventilation were included. DATA EXTRACTION AND SYNTHESIS: Data extraction was carried out independently by two reviewers. Study authors were contracted for additional information. Random-effects meta-analyses were performed where data could be pooled. RESULTS: Thirty-five RCTs (5374 participants) were included. Five trials (14%) were assessed at low risk of bias, 17 studies (49%) were at high risk of bias and 13 studies (37%) were assessed at unclear risk of bias in at least one domain. There were four main comparisons; chlorhexidine (CHX mouthrinse or gel) versus placebo/usual care, toothbrushing versus no toothbrushing, powered versus manual toothbrushing and comparisons of oral care solutions.Seventeen RCTs (2402 participants, two at high, 11 at unclear and four at low risk of bias) provide moderate quality evidence that CHX mouthrinse or gel, as part of OHC, compared to placebo or usual care is associated with a reduction in VAP (OR 0.60, 95% confidence intervals (CI) 0.47 to 0.77, P < 0.001, I(2) = 21%) A number needed to treat (NNT) of 15 (95% CI 10 to 34). There is no evidence of a difference between CHX and placebo/usual care in the outcomes of mortality, duration of mechanical ventilation or duration of ICU stay. There was insufficient evidence to determine whether there is a difference between CHX and placebo/usual care in the outcomes of duration of use of systemic antibiotics, oral health indices, microbiological cultures, caregivers' preferences or cost. Only three studies reported any adverse effects, and these were mild with similar frequency in CHX and control groups.Three trials in children found no evidence of a difference between OHC with CHX and placebo, and there was insufficient evidence to determine the effect of other outcomes. Four RCTs (828 participants, low quality evidence) compared to OHC without toothbrushing (+/- CHX), and for the outcome of VAP no evidence of a difference was found (OR 0.69, 95% CI 0.36 to 1.29, P = 0.24, I(2) = 64%). There was insufficient evidence to determine the effect of other outcomes.Only one trial compared use of a powered toothbrush with a manual toothbrush, providing insufficient evidence to determine the effect on any of the outcomes of this review.A range of other oral care solutions were compared. There is some weak evidence that povidone iodine mouthrinse is more effective than saline in reducing VAP (OR 0.35, 95% CI 0.19 to 0.65, P = 0.0009, I(2) = 53%) (two studies, 206 participants, high risk of bias). Due to the variation in comparisons and outcomes among the trials in this group there is insufficient evidence concerning the effects of other oral care solutions on the outcomes of this review. CONCLUSIONS: Effective OHC is important for ventilated patients in intensive care. OHC that includes either chlorhexidine mouthwash or gel is associated with a 40% reduction in the odds of developing ventilator-associated pneumonia in critically ill adults. However, there is no evidence of a difference in the outcomes of mortality, duration of mechanical ventilation or duration of ICU stay. There is no evidence that OHC including both CHX and toothbrushing is different from OHC with CHX alone, and some weak evidence to suggest that povidone iodine mouthrinse is more effective than saline in reducing VAP. There is insufficient evidence to determine whether powered toothbrushing or other oral care solutions are effective in reducing VAP. PMID- 24071685 TI - Novel surface-based methodologies for investigating GH11 xylanase-lignin derivative interactions. AB - The recalcitrance of lignocellulose to bioprocessing represents the core problem and remains the limiting factor in creating an economy based on lignocellulosic ethanol production. Lignin is responsible for unproductive interactions with enzymes, and understanding how lignin impairs the susceptibility of biomass to enzymatic hydrolysis represents a significant aim in optimising the biological deconstruction of lignocellulose. The objective of this study was to develop methodologies based on surface plasmon resonance (SPR), which provide novel insights into the interactions between xylanase (Tx-xyn11) and phenolic compounds or lignin oligomers. In a first approach, Tx-xyn11 was fixed onto sensor surfaces, and phenolic molecules were applied in the liquid phase. The results demonstrated weak affinity and over-stoichiometric binding, as several phenolic molecules bound to each xylanase molecule. This approach, requiring the use of soluble molecules in the liquid phase, is not applicable to insoluble lignin oligomers, such as the dehydrogenation polymer (DHP). An alternative approach was developed in which a lignin oligomer was fixed onto a sensor surface. Due to their hydrophobic properties, the preparation of stable lignin layers on the sensor surfaces represented a considerable challenge. Among the various chemical and physico-chemical approaches assayed, two approaches (physisorption via the Langmuir-Blodgett technique onto self-assembled monolayer (SAM)-modified gold and covalent coupling to a carboxylated dextran matrix) led to stable lignin layers, which allowed the study of its interactions with Tx-xyn11 in the liquid phase. Our results indicated the presence of weak and non-specific interactions between Tx-xyn11 and DHP. PMID- 24071686 TI - Functional interlocked systems. AB - With the advent of supramolecular chemistry and later nanotechnology a great deal of research has been focused on new types of molecular structures, which are not held together by covalent bonds but by non-covalent mechanical interactions. Examples include the catenane, rotaxane, and knot interlocked structures. The design and synthesis of these architectures is an art by itself and as such is worth being reviewed. In this tutorial review we will focus, however, on the functional aspects of interlocked molecules and discuss how these can find applications, e.g. as artificial muscles, as molecular valves, as components of electronic devices, and as catalysts. PMID- 24071687 TI - Social interaction among people with psychiatric disabilities--does attending a day centre matter? AB - BACKGROUND: Engaging in social interaction has, for people with psychiatric disabilities, been shown to enhance well-being and the experience of meaning and to generally prevent the worsening of mental illness. AIM: The aim of the study was to investigate how day centre attendees differed from non-attendees regarding different aspects of social interaction and to investigate how occupational factors, including day centre attendance, and previously known predictors were related to social interaction in the study sample as a whole. METHODS: A total of 93 day centre attendees and 82 non-attendees with psychiatric disabilities were examined regarding social interaction, subjective perception of occupation, activity level, sense of self-mastery and socio-demographic and clinical variables. Data were analysed with non-parametric statistics, mainly logistic regression. RESULTS: Social support was mainly provided by informal caregivers such as family members. The day centre attendees had more social relations but did not experience better quality or closeness in their relationships than non attendees. Important factors for social interaction were subjective perceptions of daily occupation, being married/cohabiting, self-mastery and severity of psychiatric symptoms. CONCLUSION: Alternative ways of enhancing social interactions in the community is needed, targeting the group's feeling of satisfaction and value in daily life together with self-mastery. PMID- 24071688 TI - [Effect of metformin on the expression of SIRT1 and UCP2 in rat liver of type 2 diabetes mellitus and nonalcoholic fatty liver]. AB - OBJECTIVE: To observe the effect of metformin on the expression of SIRT1 and UCP2 in rat liver of type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD), and discuss the pathogenesis of T2DM with NAFLD, and the treatment with and possible mechanism of metformin. METHODS: Thirty-six male SD rats were randomly divided into a normal control group (group NC, n=12), a T2DM with NAFLD group (group MC, n=12), and a metformin group (group A, n=12). We established the model of T2DM with NAFLD rats by feeding high-fat and high-sugar diet and injecting STZ. After the success establishment of the model, the metformin group was given metformin 300 mg/(kg.d) for 8 weeks. At the end of the experiment, we measured FBG, ALT, AST, TC, TG, HDL-C, LDL-C, VLDL, FFAs, FINs and HOMA-IR respectively in group NC, MC and A. We observed the change of liver tissue pathology by HE, determined the expression of SIRT1 and UCP2 in rat liver by immunohistochemical method and real-time quantitative method. RESULTS: FBG, ALT, AST, TC, TG, LDL-C, VLDL, FFAs, FINs and HOMA-IR were higher in group MC than in group NC (P<0.05), while HDL-C was obviously lower in group MC than in group NC (P<0.05). After the metformin treatment, the serum parameters in the rats had improved in group NC compared with in group MC (P<0.05). On immunohistochemical staining and mRNA level, the expression of SIRT1 was obviously lower in group MC than in group NC (P<0.05), and the expression of UCP2 was obviously higher in group MC than in group NC (P<0.05). After the metformin treatment, the expression of SIRT1 was higher than in group MC (P<0.05), and the expression of UCP2 was lower than in group MC (P<0.05). There was negative correlation between the expression of SIRT1 and UCP2 (r=-0.61, P<0.01). CONCLUSION: The expression of SIRT1 is low and the expression of UCP2 is high in rat liver of T2DM with NAFLD. Metformin can increase the expression of SIRT1 and reduce the expression of UCP2, with negative correlation between the expression of SIRT1 and UCP2. PMID- 24071689 TI - [Expression of galectin-7 and S100A9 and development of cervical squamous carcinoma]. AB - OBJECTIVE: To observe the correlation between the expression of galectin-7 and S100A9 with the development of cervical squamous carcinoma. METHODS: Immunohistochemical SP staining was used to detect the expression of galectin-7 and S100A9 in 243 patients with cervical intraepithelial neoplasia (CIN) or cervical squamous carcinoma. The association of clinical data with galectin-7 and S100A9 expression was examined. RESULTS: The expression of galectin-7 and S100A9 in CIN and cervical squamous carcinoma was significantly different (P<0.05). The positive rates of galectin-7 in normal cervical tissues, CIN I, CIN II, CIN III, and cervical squamous carcinoma were 56.7%, 41.9%, 32.0%, 27.3%, and 25.0%, respectively. Statistic analysis found significant difference between the normal cervical tissues and cervical squamous carcinoma (P<0.0045). The positive rates of S100A9 in CIN I, CIN II, CIN III, and cervical squamous carcinoma were 80.0%, 77.4%, 48.0%, 27.3%, and 20.2%. Statistic analysis showed significant difference between the normal tissues and CIN III, the normal cervical tissues and cervical squamous carcinoma, CIN I and CIN III, CIN I and cervical squamous carcinoma, CIN II and cervical squamous carcinoma (P<0.0045). A positive correlation was found between galectin-7 and S100A9 expression in CIN and cervical squamous carcinoma (rs=0.298, P<0.001). Expressions of both galectin-7 and S100A9 in cervical squamous carcinoma were associated with the clinical stage and lymph nodes (P<0.05), but not with patient's age and degree of differentiation (P>0.05). Expression of galectin-7 was associated with the survival rate of patients with cervical squamous carcinoma (P<0.05). Univariate analysis of Cox proportional hazards regression model revealed that the FIGO stage, lymph nodes metastasis, and the expression of galectin-7 were relevant to the 5 year survival rate of patients with cervical squamous carcinoma, which was confirmed by multiple analysis of Cox proportional hazards regression model. CONCLUSION: Expression of galectin-7 and S100A9 is related with cervical the tumorigenesis of carcinoma, clinical stage, and lymph nodes of cervical squamous carcinoma. Galectin-7 is probably associated with the prognosis. The long-term survival of patients with cervical carcinoma may be associated with FIGO stage, lymph node metastasis, and the expression of galectin-7. PMID- 24071690 TI - [Effect of acute exposure to high altitude on the pharmacokinetics of propranolol]. AB - OBJECTIVE: To study the pharmacokinetics of propranolol in Wistar rats after acute exposure to high altitude. METHODS: Fourteen male Wistar rats (200+/-20) g were selected. After administration of propranolol tablets (0.05 g/kg, i.g.), blood samples (3 mL) were collected at 0, 20, 40 min,1, 1.5, 2, 4, 6, 8, 12 and 24 h, respectively. The pharmacokinetic parameters were determined by LC-MS/MS and DAS 2.0 software. RESULTS: The main pharmacokinetic area under concentration time curve (AUC), mean retention time (MRT), half-life (t1/2) and peak plasma concentration (Cmax) of propranolol were increased by 442.61%, 47.45%, 73.13% and 352.97%, respectively, whereas Tmax and clearance (CL) were decreased by 80.87% and 68.94%, respectively. CONCLUSION: This study displays significant changes in the pharmacokinetics of propranolol under high altitude, which may provide evidence for clinical rational application of propranolol at high altitude. PMID- 24071691 TI - [Effect of calcitriol on secondary hyperparathyroidism]. AB - OBJECTIVE: To investigate the calcium-phosphate metabolic condition in maintenance hemodialysis patients with chronic kidney disease (CKD), and to observe the effect of large dose calcitriol on secondary hyperparathyroidism (SHPT). METHODS: We tested and compared the serum levels of calcium, phosphate, intact parathyroid hormone (iPTH), and alkaline phosphatase (AKP) in hemodialysis patients at different hemodialysis time (Group A with hemodialysis period <=3 years and Group B with hemodialysis period >3 years). We also detected those indexes before and after treating SHPT with large dose calcitriol. Twenty SHPT patients were divided into Group I (enlargement of parathyroid gland or nodule detected by color Doppler ultrasound) and Group II (normal parathyroid gland detected by color Doppler ultrasound). RESULTS: In the maintenance hemodialysis patients, the serum phosphate was (2.11+/-0.38) mmol/L and iPTH was (581.11+/ 487.75) pg/mL. The serum level of iPTH in Group B was higher than that in Group A [(828.13+/-690.39) pg/mL vs (477.94+/-324.73) pg/mL, P<0.001]. In Group I, the serum level of iPTH [before vs after: (2471.7+/-898.3) pg/mL vs (2510.4+/-825.7) pg/mL] and AKP [before vs after: (524.2+/-18.8)U/L vs (511.3+/-19.3)U/L] did not change after the treatment of large dose calcitriol (P>0.05). In Group II, the serum level of iPTH [before vs after: (1358.5+/-302.8) pg/mL vs (369.3+/-43.4) pg/mL, P<0.001] and AKP [before vs after: (565.9+/-23.9)U/L vs (234.8+/-21.1)U/L, P<0.001] decreased significantly after the treatment of large dose calcitriol. CONCLUSION: Patients with longer time of hemodialysis have a higher level of iPTH. Large dose calcitriol can improve the clinical syndrome of SHPT, and decrease the level of iPTH and AKP in SHPT patients with normal parathyroid gland. PMID- 24071692 TI - [Measurement of proximal femoral morphology and analysis of 500 cases in Hunan Province]. AB - OBJECTIVE: To evaluate the effect of age and gender on the femoral morphology to guide prosthesis selection in operation and design. METHODS: A total of 500 females and males were collected from the departments of orthopedics and medical radiology, Second Xiangya Hospital, Central South University. Informed consent was obtained from all subjects. All patients underwent anteroposterior position scan of the left or right hip joint using Philips Digital Diagnost DR system. The shooting range included the hip joint and at least 2/3 of the proximal femur. The images were measured with Onis 2.3 software. We measured 13 parameters from the patients, including the external parameters of the femur, radius-length parameters of femoral medullary cavity, and morphological parameters of the femoral medullary cavity. RESULTS: Compared with Westeners, the offset was smaller, while the neck shaft angle was significantly larger in Chinese population (P<0.05). Most parameters of the proximal femoral medullary cavity diameter were significantly smaller in Chinese population than those in Westerners (P<0.05). The canal flare index in Chinese population was significantly larger than that in the Westerners (P<0.01). According to the Noble classification, in Chinese population, the proportion of champagne flute type was significantly larger, while the proportion of standard type was significantly smaller than that in Westerners. There was significant difference in the proximal femur between Chinese population and Westerners. The largest difference of the proximal morphology was presented between males and females in the 31-50 years old people (P<0.05), while the smallest was in the over 70 years old population (P>0.05). The main differences between 31 and 70 years old were the diameter of femoral head, the offset of isthmus, the medullary cavity diameter and extracortical width at isthmus level and the medullary cavity diameter at the level of the lesser trochanter (P<0.05). The modullary transverse diameter at 20 mm below the lesser trochanter and isthmus and extracortical width of isthmus in the male and female group was positively correlated with age (P<0.01), while the parameters of the proximal femoral canal morphology in the female group were negatively correlated with age. The female canal parameters had a stronger correlation. CONCLUSION: Chinese proximal femoral parameters are significantly different from Westerners. When people, especially females, get older, the medullary cavity diameter of the isthmus and proximal femur becomes wider and the morphology of the femur becomes straight. The difference in the femoral morphology between the male and female decline with the age. There is almost no difference for the over 70 years old. For the 31-70 years old, The male femoral cavity diameter is larger and the position of isthmus is lower than in the females. PMID- 24071693 TI - [Related factors and effectiveness of rapid teeth movement through reducing resistance and distraction]. AB - OBJECTIVE: To investigate the role of reducing resistance and distraction in rapid teeth movement and its reliability by establishing the Beagle dogs' experimental model. METHODS: The left or right sides in mandibles of 20 beagles were randomly operated with different treatments: distraction twice a day through reducing resistance; distraction 6 times a day through reducing resistance; conventional distraction through reducing resistance; and conventional distraction (the control group). Each treatment was carried out in 10 sides. The pulp vitality, tooth mobility and distance of teeth transportation were evaluated at different time points: before the distraction, distraction after 15 days, retaining 30 days after 15 days of distraction. The degree of inclination, root resorption and alveolar bone density of the compressive areas were evaluated by cone-beam computed tomography images. RESULTS: The distance of teeth transportation was similar in groups distraction twice daily and 6 times a day through reducing resistance (P>0.05), but their speed of transportation was significantly higher than that of conventional distraction through reducing resistance. The conventional distraction group had the lowest speed of transportation. The pulp vitality of distracted teeth was normal, and no root comprehensive resorption and periodontal defect were found. Distracted teeth in the reduced resistance and distraction groups (13.9 degrees +/-3.5 degrees ) tipped more that in the conventional distraction group (6.6 degrees +/-1.3 degrees ) (P<0.05). CONCLUSION: Reducing resistance and distraction are inseparable factors to realize fast teeth moving. The rate of orthodontic tooth movement can be accelerated through resistance reduction and periodontal distraction without obvious unfavorable effects but at minimal acceptable teeth inclination. PMID- 24071694 TI - [Development of green hospitals home and abroad]. AB - Green hospital construction is a new challenge for medical industry after global sustainable development strategy was put forward. The core connotation of green hospital includes green building, green healthcare, patient safety, and doctor patient harmony. Many countries have established green building evaluation system to deal with energy crisis. Leadership in Energy and Environmental Design (LEED), Green Guide for Health Care (GGHC) in the U.S., and Evaluation System for Green Hospital Building (CSUS/GBC 2-2011) in China have guiding significance for the development of green hospitals in China. The evaluation system of green hospitals home and abroad still focuses on green building, and establishment of suitable synthesis evaluation system of green hospitals in China needs further research. PMID- 24071695 TI - [Progress of anti-infection of high density lipoprotein]. AB - Bacterial infection is likely to develop into sepsis, which is regarded as the main reason for high mortality rate. High-density lipoprotein cholesterol (HDL-C) and its associated apolipoprotein can combine with lipopolysaccharide, regulate the body's inflammatory response and reduce the mortality, which can provide a new method for treatment of bacterial infection. PMID- 24071696 TI - [Diagnosis and treatment of ketamine-associated cystitis: a report of 3 cases and literature review]. AB - OBJECTIVE: To determine the diagnosis, treatment, and pathogenesis of ketamine associated cystitis. METHODS: Clinical data from 3 patients with ketamine associated cystitis were analyzed retrospectively and discussed in light of relevant literature. RESULTS: In the 3 cases, 2 presented severe lower urinary tract symptoms, including frequency, urgency, dysuria, urge incontinence, and painful haematuria. Urinalysis and urine culture were negative. Imaging examination demonstrated thickening of the bladder wall and a small capacity. Inflammatory changes in the bladder mucosa were observed by cystoscopy and biopsies. After cessation of ketamine use, with the addition of steroids or hydrodistension, the symptoms in the 3 patients improved. The symptoms recurred in 2 patients, as 1 was exposed to ketamine again and 1 had severe bladder contraction after for 3 - 4 month follow-up. CONCLUSION: Ketamine-associated cystitis is a new urinary system inflammatory damage. Its etiology and treatment methods are not clear. Early abstinence from ketamine use and early treatment are crucial for patients with ketamine-associated cystitis to avoid irreversible damage. PMID- 24071697 TI - [Two cases of pulmonary thromboembolism associated with protein C and protein S deficiency and literature review]. AB - To explore the clinical manifestations, diagnosis and treatment of pulmonary thromboembolism associated with protein C (PC)/protein S (PS) deficiency. Two male patients 29 and 26 years old diagnosed with PC deficiency and/or PS deficiency were retrospectively analyzed and related literatures were reviewed. The most common symptoms were pain in the lower limbs with chest pain or decreased vision. Color dopper flow imaging (CDFI) showed lower deep venous phlebothrombosis. Multislice CT angiography (CTA) revealed pulmonary embolism. The level of serum homocysteine (HCY) increased and the level of plasma PC/PS content decreased to PC 57.4%, and PS 28.9% in patient 1, while PS 33.4% in patient 2. Poor routine anticoagulant response was observed. After the diagnosis of PC/PS deficiency, vitamin B6 and B12 anticoagulant therapy was added, and the symptoms in the patients improved significantly. Congenital thrombophilia should be taken into consideration for young patients with lower deep venous thrombosis and pulmonary embolism which occur recurrently without obvious predisposing causes before 40. Plasma PC/PS concentrations or activity help a lot in the diagnosis and treatment. PMID- 24071698 TI - [Molecular cloning and alternative splicing analysis of hepatoma associated gene HTA]. AB - OBJECTIVE: To obtain the full length cDNA sequences of hepatoma associated gene HTA, analyze its alternative splicing, detect the expression pattern of 2 HTA gene transcripts in different hepatic cell lines, and to establish a base for further study of HTA gene function in hepatocellular carcinoma (HCC) occurrence and development. METHODS: The full length cDNA of HTA gene was cloned by rapid amplification of cDNA 3' ends (3'-RACE), rapid amplification of cDNA 5' ends (5' RACE) and DNA sequencing. The gene structure and alternative splicing were analysed. Northern blot assay was performed to detect the expression pattern of 2 HTA gene transcripts in different hepatic cell lines. RESULTS: The full length of HTA gene was 1414 bp, composed of 3 exons and 2 introns, and the second intron could be retained in mRNA. Northern blot assay showed that 2 transcripts of HTA mRNA(1.4 kb and 1.7 kb) could express in the HCC cell lines HepG2 and QGY-7703, but not in the non-malignant cell line L-02 and HUVEC. The expression level of 1.4 kb transcript was much higher than 1.7 kb one. CONCLUSION: This study successfully has obtained the full length cDNA of HTA gene, and analysed the gene sequence and alternative splicing, 2 transcripts of HTA mRNA specifically expressed in HCC cell lines. As a hepatoma associated gene, HTA deserves further investigation. PMID- 24071699 TI - [Expression and clinical significance of Nusap1 in hepatical carcinoma]. AB - OBJECTIVE: To investigate the expression and clinical significance of Nusap1 in hepatical carcinoma. METHODS: The expression of Nusap1 protein in 61 specimens of hepatical carcinoma was examined by immunohistochemistry. Based on the levels of Nusap1 expression, the 61 specimens were divided into a high Nusap1 expression group and a low Nusap1 expression group. The correlation between Nusap1 expression with clinicopathologic features and prognosis of hepatical carcinoma was analyzed. RESULTS: The rate of high Nusap1 expression was 54.1% in hepatical carcinoma. The rate of high Nusap1 expression was 21.3% in noncarcinoma, with significant difference between the 2 groups (P<0.01).Nusap1 overexpression had significant correlation with histological differentiation, tumor size, liver cirrhosis, lymphatic metastasis, tumor thrombi and early recurrence (P<0.05), but not with sex, age, AFP level, tumor number, TNM classification and tumor encapsulation (P>0.05). Survival analysis suggested that the 6 month and 12 month noncarcinoma survival rate was significantly lower in the high Nusap1 expression group [33.3% (11/33), 17.9% (5/33)] than that in the low Nusap1 expression group [89.3% (25/28), 53.6% (15/28); P<0.005]. CONCLUSION: Nusap1 is overexpressed in hepatical carcinoma and is a valuable prognostic factor for hepatical carcinoma. PMID- 24071700 TI - [Effect of stellate ganglion block on cardiomyocyte apoptosis and expression of Bcl-2/Bax protein in spontaneously hypertensive rats]. AB - OBJECTIVE: To investigate the relationship between apoptosis of myocardial cells in spontaneously hypertensive rats (SHRs) and the expressions of Bcl-2 and Bax protein, and the protective effect of stellate ganglion block on apoptosis of myocardial cells. METHODS: A total of 32 ten-week-old male SHRs were assigned randomly into 4 groups: a left stellate ganglion block group (group LS), a right stellate ganglion block group (group RS), a captopril group (group D) and a control group (group C). The arterial systolic blood pressure was measured by ALC NIBP system. After 10 weeks, all rats were anaesthetized by 3% pentobarbital sodium, cardiomyocyte apoptosis index of left ventricle was assessed by TUNEL, and the localization of myocardium Bcl-2, Bax was investigated by immunohistochemistry. RESULTS: Compared with group LS and C, the apoptotic index decreased (P<0.05). SHR myocardial expression of Bcl-2 significantly increased (P<0.05), Bax expression significantly decreased (P<0.05) and Bcl-2/Bax was significantly higher (P<0. 05) in group RS. CONCLUSION: Bcl-2 and Bax play an important role in the apoptosis of myocardial cells in SHRs. Right stellate ganglion block can reduce the apoptosis of myocardial cells and reverse the reconstruction of the left ventricle in SHRs via regulation of apoptosis-related gene proteins. PMID- 24071701 TI - [Effect of angiotensin II and aldosterone on the proliferation of cardiac fibroblasts in rats]. AB - OBJECTIVE: To investigate the effect of angiotensin II (ang II), aldosterone (ald) and their receptor antagonists losartan (los) and spironolactone (spi) on the proliferation and collagen production of cardiac fibroblasts (CFs) in rats. METHODS: CFs were isolated from neonatal SD rats by collagenase II method and purified with differential attachment and detachment method. The 3 or 4 passages of the CFs were divided into the following groups: angiotensin II, angiotensin II+aldosterone, aldosterone, angiotensin II+losartan, and aldosterone+spironolactone. The cell viability of the CFs was assessed by Cell Counting Kit-8 (CCK-8) after the drug administration. The mRNA and protein expression levels of COL1A1, COL3A1, MMP1 and TIMP1 were detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot respectively. RESULTS: Ang II and Ald facilitated the proliferation rate of the CFs independently compared with that in the control group (38.5% vs 28.5%; P<0.05), and the proliferation rate in the ang II+ald group was higher than that in the ang II group and ald group alone (54.4%, P<0.05). Los and spi inhibited the effect induced by ang II and ald respectively (P<0.05). Compared with the control group, ang II and ald significantly enhanced COL1A1, COL3A1 and MMP1 expression both at the mRNA and protein levels (P<0.05), but the TIMP1 expression was inhibited (P<0.05), which could be abolished by corresponding receptor antagonists los and spi (P<0.05). CONCLUSION: Ang II and ald can promote the proliferation of CFs, and the COL1A1 and COL3A1 expression is enhanced both at mRNA and protein levels. Ang II and ald have synergistic effect when they are used together, while los and spi may restrain the effect. The mechanism is probably linked with the balance of MMPs/TIMPs. PMID- 24071702 TI - [Social support and negative emotion in parents of children with congenital heart disease before operation]. AB - OBJECTIVE: To explore the relationship between social support and negative emotion in parents of children with congenital heart disease before the operation. METHODS: Social support rating scale (SSRS), self-rating anxiety scale (SAS), and Center for epidemiological survey-depression scale (CES-D) were used to assess the association between social support and anxiety and depression in 226 parents. RESULTS: The mean SSRS score was significantly lower than the normal. There was significant difference in social support of parents in monthly family earning and knowledge about surgery. Parents with monthly family income<=1000 yuan had lower scores than the other groups. Parents who knew nothing about the surgery approach had lower scores. Social support was significantly correlated to negative emotion (anxiety and depression). Social support could predict anxiety and depression. CONCLUSION: Social support is widely and significantly correlated to negative emotion in parents of children with congenital heart disease before the surgery. PMID- 24071703 TI - [Manifestation, distribution of pathogen, and resistance of bloodstream infections after renal transplantation: clinical analysis of 71 patients]. AB - OBJECTIVE: To investigate the clinical manifestation and determine the distribution of pathogens and their characteristics of drug susceptibility to bloodstream infections (BSIs), and provide evidence for clinical anti-infection treatments after renal transplantation. METHODS: Totally 81 episodes of BSIs occurred in 71 patients between July 2003 and June 2013. We retrospectively analyzed the pathogens and their drug susceptibility characteristics with BD microbiological assay system. We also collected the clinical and laboratory data of the patients . RESULTS: The main pathogens were gram negative bacteria (67.90%), followed by gram positive bacteria (28.40%) and fungi (3.70%). The most common gram negative bacillus was Escherichia coli. While for gram positive bacteria, the main bacillus was coagulase-negative staphylococci. The gram negative bacteria were relatively sensitive to aminoglycosides and carbapenem. The gram positive bacteria were sensitive to glycopeptides and oxazolidone. CONCLUSION: The clinical manifestations included high body temperature, onset in the early period after kidney transplantation and high mortality. Though gram positive coccus plays an important role, most infections are caused by gram negative bacteria in BSIs after the renal transplantation. The antibiotic resistant rate for gram negative bacteria is very high as well as gram positive bacteria. PMID- 24071704 TI - [Expression and significance of thrombonspondin-1 in oxygen-induced retinopathy in mice]. AB - OBJECTIVE: To examine the expression and function of thrombonspondin-1 (TSP-1) in oxygeninduced retinopathy in new-born mice, and to investigate its role in retinal neovascularization. METHODS: A total of 40 C57BL / 6J newborn mice were divided equally into a model group (n=20) and a normal control group (n=20). Mice in the model group were exposed to 75% oxygen to establish the oxygen-induced retinopathy (OIR) model. On the 7th, 9th, and 11th day after the birth of mice, 5 mice were randomly selected each time from the 2 groups to examine the expression of TSP-1 mRNA with reverse transcription polymerase chain reaction (RT-PCR). After that, 5 mice were selected on the 11th day to observe the retinal neovascularization by fluorescein angiography retinal flatmount. RESULTS: On the 11th day, fluorescein angiography retinal flatmount showed that the retinal blood vessels presented mean network distribution in the normal control group, while in the model group, a lot of dilatated areas in the retinal main vessels surrounded the optic disc. Meanwhile lots of new blood vessels were found surrounding the optic disc with irregular distribution but well distributed peripheral retinal small vessels, which was typical of early stage OIR. There was no significant difference in the retinal TSP-1 mRNA level between the model group and the normal control group in the postnatal 7-day mice (P>0.05). Compared with the normal control group, the expression of TSP-1 mRNA in the model group was significantly lower in postnatal 9-day and 11-day mice (P<0.05, P<0.01) , and the expression of TSP-1 mRNA in postnatal 9-day mice was lower than that in the postnatal 11-day mice(P<0.05). CONCLUSION: In the early stage of OIR model (retinal vascular growth and development stage), the expression of TSP-1 mRNA in the retinal tissue is gradually decreased, implying that TSP-1 (as a negative regulatory factor) may be involved in the formation of retinal neovascularization in the early stage. PMID- 24071705 TI - [BMPs and cancer]. AB - Bone morphogenetic proteins (BMPs) were first studied as growth factors or morphogens of the transforming growth factor-beta super family. These growth molecules, originally associated with bone and cartilage development, are now known to play important roles in morphogenesis and homeostasis in many other tissues. Recently, significant contributions of BMPs, their receptors, and interacting molecules have been linked to carcinogenesis and tumor progression. BMPs can sometimes play a role as a tumor suppressor. This article explains the composition and biological characteristics of BMPs, and investigates their new roles in the pathogenesis of cancer. PMID- 24071706 TI - Synthesis of nanostructured materials by using metal-cyanide coordination polymers and their lithium storage properties. AB - Herein, we demonstrate a novel and simple two-step process for preparing LiCoO2 nanocrystals by using a Prussian blue analogue Co3[Co(CN)6]2 as a precursor. The resultant LiCoO2 nanoparticles possess single crystalline nature and good uniformity with an average size of ca. 360 nm. The unique nanostructure of LiCoO2 provides relatively shorter Li(+) diffusion pathways, thus facilitating the fast kinetics of electrochemical reactions. As a consequence, high reversible capacity, excellent cycling stability and rate capability are achieved with these nanocrystals as cathodes for lithium storage. The LiCoO2 nanocrystals deliver specific capacities of 154.5, 135.8, 119, and 100.3 mA h g(-1) at 0.2, 0.4, 1, and 2 C rates, respectively. Even at a high current density of 4 C, a reversible capacity of 87 mA h g(-1) could be maintained. Importantly, a capacity retention of 83.4% after 100 cycles is achieved at a constant discharge rate of 1 C. Furthermore, owing to facile control of the morphology and size of Prussian blue analogues by varying process parameters, as well as the tailored design of multi component metal-cyanide hybrid coordination polymers, with which we have successfully prepared porous Fe2O3@NixCo3-xO4 nanocubes, one of the potential anode materials for lithium-ion batteries, such a simple and scalable approach could also be applied to the synthesis of other nanomaterials for energy storage devices. PMID- 24071707 TI - Configural processing in body posture recognition: an eye-tracking study. AB - The body inversion effect is the finding that inverted body posture pictures are more difficult to recognize than upright body posture pictures are. The present study reinvestigated the body inversion effect in human observers using behavioral and eye movement measures to explore whether the body inversion effect correlates with specific eye movement features. Results showed that body postures elicited a robust and stable body inversion effect in reaction time throughout the experimental sessions. Eye-tracking data showed that the body inversion effect was robust only in the first fixation duration, but not in the second fixation duration. The analysis of the regions of interest showed that most fixations were located in the upper body for both the upright and the inverted body postures. Compared with inverted body postures, the upright postures led to a shorter reaction time and a shorter first fixation duration, but a larger portion of time to fixate on the head region, suggesting that participants tended to use head as a reference point to process upright body postures. For both the behavioral and the eye movement measures, the body inversion effect was robust for biomechanically possible body postures. However, for biomechanically impossible body postures (with angular manipulation of two joints), the effect was mixed. Although the error rate failed to show the body inversion effect, the reaction time measure and most eye movement measures, however, showed a body inversion effect. Overall, these results suggested that upright body postures are processed in expertise recognition and are processed configurally by human observers. PMID- 24071708 TI - Starburst amacrine cells express parvalbumin but not calbindin and calretinin in rabbit retina. AB - Calcium-binding proteins (CBPs) are important components in calcium-mediated cellular signal transduction. Among the many CBPs, at least three EF-hand CBPs, calbindin-D28K (CB), calretinin (CR), and parvalbumin (PV), have been extensively studied in the retina. In the present study, we investigated the expression patterns of these three CBPs in cholinergic starburst amacrine cells (SACs), which are the most important element for direction selectivity in the rabbit retina. Double-label immunocytochemical analysis of vibratome sections and single cell injection after immunocytochemical analysis on whole mounts were carried out in rabbit retinas. We found that all SACs in the inner nuclear layer and the ganglion cell layer contained PV. However, none of the SACs in the inner nuclear layer or ganglion cell layer contained either CB or CR. These results suggest that PV, but not CR or CB, may act as a calcium-buffering protein in the SACs of the rabbit retina. PMID- 24071709 TI - The evaluation of NIR-absorbing porphyrin derivatives as contrast agents in photoacoustic imaging. AB - Six free base tetrapyrrolic chromophores, three quinoline-annulated porphyrins and three morpholinobacteriochlorins, that absorb light in the near-IR range and possess, in comparison to regular porphyrins, unusually low fluorescence emission and (1)O2 quantum yields were tested with respect to their efficacy as novel molecular photo-acoustic imaging contrast agents in a tissue phantom, providing an up to ~2.5-fold contrast enhancement over that of the benchmark contrast agent ICG. The testing protocol compares the photoacoustic signal output strength upon absorption of approximately the same light energy. Some relationships between photophysical parameters of the dyes and the resulting photoacoustic signal strength could be derived. PMID- 24071710 TI - Comprehensive mutation analysis of the CYP21A2 gene: an efficient multistep approach to the molecular diagnosis of congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia, due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of adrenal steroidogenesis caused by mutations in the CYP21A2 gene. Direct comparison of established and novel methodologies of CYP21A2 genetic analysis in a large cohort representing a wide range of genotypes has not been previously reported. We genotyped a cohort of 129 unrelated patients with 21-OHD, along with 145 available parents, using Southern blot (SB) analysis, multiplex ligation-dependent probe amplification (MLPA), PCR-based restriction fragment length polymorphism (RFLP) analysis, multiplex minisequencing and conversion-specific PCR, duplication-specific amplification, and DNA sequencing. CYP21A2 genotyping identified four duplicated CYP21A2 genes (1.53%) and 79 chimeric CYP21A1P/CYP21A2 genes (30.15%). Parental SB data were essential for determining the CYP21 haplotype in three cases, whereas PCR-based RFLP analysis was necessary for MLPA results to be accurately interpreted in the majority of cases. The comparison of different methods in detecting deletion and duplication showed that MLPA with PCR-based RFLP was comparable with SB analysis, with parental data of 100% sensitivity and specificity. DNA sequencing was required for the identification of 16 (6.1%) rare point mutations and determination of clinically significant chimera junction sites. MLPA with PCR-based RFLP analysis is an excellent substitute for SB analysis in detecting CYP21A2 deletion and duplication and a combination of MLPA, PCR-based RFLP, duplication-specific amplification, and DNA sequencing is a convenient and comprehensive strategy for mutation analysis of the CYP21A2 gene in patients with 21-OHD. PMID- 24071713 TI - A survey of handoff practices in emergency medicine. AB - This study aimed to assess practices in emergency department (ED) handoffs as perceived by emergency medicine (EM) residency program directors and other senior level faculty and to determine if there are deficits in resident handoff training. This cross-sectional survey study was guided by the Kern model for medical curriculum development. A 12-member Council of Emergency Medicine Residency Directors (CORD) Transitions in Care task force of EM physicians performed these steps and constructed a survey. The survey was distributed to the CORD listserv. There were 147 responses to the anonymous survey, which were collected using an online tool. At least 41% of the 158 American College of Graduate Medical Education EM residency programs were represented. More than half (56.6%) of responding EM physicians reported that their ED did not use a standardized handoff. There also exists a dearth of formal handoff training and handoff proficiency assessments for EM residents. PMID- 24071714 TI - Molecular diagnosis and immunotherapy. AB - PURPOSE OF REVIEW: To describe the recent insights of how molecular diagnosis can be useful to improve indication and selection of suitable allergens for specific immunotherapy and to increase its safety. RECENT FINDINGS: As specific allergen immunotherapy is allergen-specific, the identification of the disease-eliciting allergen is a prerequisite for accurate prescription of anti-allergic treatment. In areas of complex sensitization to aeroallergens or in hymenoptera venom allergy, the use of molecular diagnosis has demonstrated that it may change indication and selection of allergens for immunotherapy in a large proportion of patients when compared with the use of skin prick testing and/or specific IgE determination with commercial extracts. These changes in the prescription of immunotherapy after using molecular diagnosis have been demonstrated to be cost effective in some scenarios. Some patterns of sensitization to grass or olive pollen allergens may identify patients with higher risk of adverse reaction during immunotherapy. SUMMARY: Molecular diagnosis, together with other tools and patients' clinical history, can help clinicians better select the most appropriate patients and allergens for specific immunotherapy and, in some cases, predict the risk of adverse reactions. PMID- 24071712 TI - alpha-helical structures drive early stages of self-assembly of amyloidogenic amyloid polypeptide aggregate formation in membranes. AB - The human islet amyloid polypeptide (hIAPP) is the primary component in the toxic islet amyloid deposits in type-2 diabetes. hIAPP self-assembles to aggregates that permeabilize membranes and constitutes amyloid plaques. Uncovering the mechanisms of amyloid self-assembly is the key to understanding amyloid toxicity and treatment. Although structurally similar, hIAPP's rat counterpart, the rat islet amyloid polypeptide (rIAPP), is non-toxic. It has been a puzzle why these peptides behave so differently. We combined multiscale modelling and theory to explain the drastically different dynamics of hIAPP and rIAPP: The differences stem from electrostatic dipolar interactions. hIAPP forms pentameric aggregates with the hydrophobic residues facing the membrane core and stabilizing water conducting pores. We give predictions for pore sizes, the number of hIAPP peptides, and aggregate morphology. We show the importance of curvature-induced stress at the early stages of hIAPP assembly and the alpha-helical structures over beta-sheets. This agrees with recent fluorescence spectroscopy experiments. PMID- 24071715 TI - Facial and neck hematoma after carotid artery stenting: an uncommon misadventure in endovascular carotid revascularization. AB - The complication rates of carotid artery stenting (CAS) vary from 3.0% to 4.4%, and most commonly include ischemic stroke, intracranial hemorrhage, or groin complications. We present the rare complication of a patient who underwent CAS for a symptomatic 90% left internal carotid artery stenosis and developed an expanding cervical hematoma after the procedure with imminent respiratory compromise. After intubation, an arteriogram revealed perforation of the external carotid artery trunk, proximal to the origin of the internal maxillary artery. The artery was subsequently embolized and the hematoma resolved without further intervention. We present a potential catastrophic complication and suggest potential causes and treatment options available. PMID- 24071716 TI - A solid-phase extractant based on microemulsion modified date pits for toxic pollutants. AB - Application of microemulsion modified raw date pits as an inexpensive solid extractant for removing methylene blue (MB), copper ion (Cu(2+)) and cadmium ion (Cd(2+)) has been presented. The results summarised herein are also part of an investigation conducted to evaluate the adsorption capacity by taking into consideration the experimental parameters such as pH, particle size and initial solute concentration. The experimental data obtained from the adsorption isotherms studies were used to find pollutants distribution factors and modelled using both Langmuir and Freundlich equations. The modified adsorbent was more effective toward all pollutants with high removal capacities (50-350 mg/g) and with very large distribution values (9-235 L/g) which indicates the suitability of this new material for extraction organic and inorganic pollutants. After microemulsion modification, the FTIR scans of the samples show clear differences in the position and intensity the characteristics bands of the raw date pits (RDP). Three mechanisms of the MB, Cu(2+) and Cd(2+) adsorption onto MUE-MDP are possible: (i) adsorption by an electrostatic force of the anionic head group of the surfactant and the positive charge of the dye (MB+) or the metal ions (Cu(2+) or Cd(2+)), (ii) adsorption by tail groups of the surfactant and the hydrophobic character of the MB molecules. The MB is a basic dye and has basic characteristics and therefore is expected to interact strongly with the anionic head groups of the surfactants (RCOO-). In the contrary, the Cu(2+) and Cd(2+) ions are not expected to interact by the tail groups of the surfactant where the ionic radii of these ions may explain the differences between Cu(2+) (0.72 A) and Cd(2+) (0.99 A) adsorption capacities and (iii) filling the channel (pores) of the RDP by dissolving in the microemulsion micelles. PMID- 24071717 TI - Textile dyes removal from aqueous solution using Opuntia ficus-indica fruit waste as adsorbent and its characterization. AB - For this research, three different adsorbents, one untreated and two chemically activated, were prepared from Opuntia ficus-indica fruit waste. By the construction of adsorption isotherms, its adsorption capabilities and the viability of its use in the removal of textile basic and direct type dyes were determined. It was found that the adsorbent with the most adsorption capacity for basic dyes was the one activated with NaClO, and, for direct dyes, it was the one activated with NaOH. Langmuir and Freundlich equations isotherms were applied for the analysis of the experimental data. It was found that the Freundlich model best described the adsorption behavior. The adsorption capacity was improved when the pH of the dye solution had an acid value. The specific surface area of the adsorbents was calculated by means of methylene blue adsorption at 298 K to stay within a range between 348 and 643 m(2) g(-1). The FTIR spectroscopic characterization technique, the SEM, the point of zero charge, and the elemental analysis show the chemical and physical characteristics of the studied adsorbents, which confirm the adsorption results obtained. PMID- 24071718 TI - Understanding collision-induced dissociation of dofetilide: a case study in the application of density functional theory as an aid to mass spectral interpretation. AB - Fragmentation of molecules under collision-induced dissociation (CID) conditions is not well-understood. This may make interpretation of MSMS spectra difficult and limit the effectiveness of software tools intended to aid mass spectral interpretation. Density Functional Theory (DFT) has been successfully applied to explain the thermodynamics of fragmentation in the gas phase by the modelling the effect that protonation has on the bond lengths (and hence bond strengths). In this study, dofetilide and four methylated analogues were used to investigate further the potential for using DFT to understand and predict the CID fragmentation routes. The products ions present in the CID spectra of all five compounds were consistent with charge-directed fragmentation, with protonation adjacent to the cleavage site being required to initiate fragmentation. Protonation at the dissociative site may have occurred either directly or via proton migration. A correlation was observed between protonation-induced bond lengthening and the bonds which were observed to break in the CID spectra. This correlation was quantitative in that the bonds calculated to elongate to the greatest extent gave rise to the most abundant of the major product ions. Thus such quantum calculations may offer the potential for contributing to a predictive tool for aiding the accuracy and speed mass spectral interpretation by generating numerical data in the form of bond length increases to act as descriptors flagging potential bond cleavages. PMID- 24071719 TI - Forster resonance energy transfer and kinesin motor proteins. AB - Forster Resonance Energy Transfer (FRET) is the phenomenon of non-radiative transfer of electronic excitations from a donor fluorophore to an acceptor, mediated by electronic dipole-dipole coupling. The transfer rate and, as a consequence, efficiency depend non-linearly on the distance between the donor and the acceptor. FRET efficiency can thus be used as an effective and accurate reporter of distance between two fluorophores and changes thereof. Over the last 50 years or so, FRET has been used as a spectroscopic ruler to measure conformations and conformational changes of biomolecules. More recently, FRET has been combined with microscopy, ultimately allowing measurement of FRET between a single donor and a single acceptor pair. In this review, we will explain the physical foundations of FRET and how FRET can be applied to biomolecules. We will highlight the power of the different FRET approaches by focusing on its application to the motor protein kinesin, which undergoes several conformational changes driven by enzymatic action, that ultimately result in unidirectional motion along microtubule filaments, driving active transport in the cell. Single molecule and ensemble FRET studies of different aspects of kinesin have provided numerous insights into the complex chemomechanical mechanism of this fascinating protein. PMID- 24071721 TI - Electrostatic charging of jumping droplets. AB - With the broad interest in and development of superhydrophobic surfaces for self cleaning, condensation heat transfer enhancement and anti-icing applications, more detailed insights on droplet interactions on these surfaces have emerged. Specifically, when two droplets coalesce, they can spontaneously jump away from a superhydrophobic surface due to the release of excess surface energy. Here we show that jumping droplets gain a net positive charge that causes them to repel each other mid-flight. We used electric fields to quantify the charge on the droplets and identified the mechanism for the charge accumulation, which is associated with the formation of the electric double layer at the droplet-surface interface. The observation of droplet charge accumulation provides insight into jumping droplet physics as well as processes involving charged liquid droplets. Furthermore, this work is a starting point for more advanced approaches for enhancing jumping droplet surface performance by using external electric fields to control droplet jumping. PMID- 24071720 TI - Structural coupling of the EF hand and C-terminal GTPase domains in the mitochondrial protein Miro. AB - Miro is a highly conserved calcium-binding GTPase at the regulatory nexus of mitochondrial transport and autophagy. Here we present crystal structures comprising the tandem EF hand and carboxy terminal GTPase (cGTPase) domains of Drosophila Miro. The structures reveal two previously unidentified 'hidden' EF hands, each paired with a canonical EF hand. Each EF hand pair is bound to a helix that structurally mimics an EF hand ligand. A key nucleotide-sensing element and a Pink1 phosphorylation site both lie within an extensive EF hand cGTPase interface. Our results indicate structural mechanisms for calcium, nucleotide and phosphorylation-dependent regulation of mitochondrial function by Miro. PMID- 24071722 TI - An inherent instability of efficient markets. AB - Speculative markets are often described as "informationally efficient" such that predictable price changes are eliminated by traders exploiting them, leaving only residual unpredictable fluctuations. This classical view of markets operating close to an equilibrium is challenged by extreme price fluctuations which occur far more frequently than can be accounted for by external news. Here we show that speculative markets which absorb self-generated information can exhibit both: evolution towards efficient equilibrium states as well as their subsequent destabilisation. We introduce a minimal agent-based market model where the impacts of trading strategies naturally adapt according to their success. This implements a learning rule for the whole market minimising predictable price changes, and an extreme succeptibility at the point of perfect balance. The model quantitatively reproduces real heavy-tailed log return distributions and volatility clusters. Our results demonstrate that market instabilities can be a consequence of the very mechanisms that lead to market efficiency. PMID- 24071723 TI - Extremely stable all solution processed organic tandem solar cells with TiO2/GO recombination layer under continuous light illumination. AB - One approach to harvest a wide solar spectral solar energy is to stack two solar cells with different absorption characteristics in a tandem cell architecture. Herein, solution processed tandem solar cells, with highly transparent titanium oxide (TiO2) and graphene oxide (GO) as an efficient recombination layer, were designed, fabricated and characterized. We have adopted poly[(4,4'-bis(3 ethylhexyl)dithieno[3,2-b:''3'-d]silole)-2,6-diyl-alt-(2,5-(3-(2 ethylhexyl)thiophen-2-yl)thiazolo[5,4-d]thiazole]:indene-C60 bisadduct (PSEHTT:ICBA) and poly[(4,4'-bis(2-ethylhexyl)dithieno[3,2-b:2',3'-d]silole)-2,6 diyl-alt-(2,1,3-benzothiadiazole)-4,7-diyl]:[6,6]-phenyl-C70 butyric acid methyl ester (PSBTBT:PC70BM) as the active layers for the front and rear cells, respectively. The TiO2/GO serves as an electron and hole collecting and recombination layer. The tandem solar cells showed a high open circuit voltage (VOC) 1.62 V, a moderate short circuit current density (JSC) 8.23 mA cm(-2), fill factor (FF) 62.98%, leading to the power conversion efficiency of 8.40%. The obtained VOC value of tandem solar cells is ideal for the summation of VOCs attained from front and rear cells and it is evident that our tandem solar cells are well connected in series. Moreover, this tandem cell exhibits a 20% drop in conversion efficiency under continuous AM illumination for 2880 h. PMID- 24071724 TI - Mirror artifacts in obstetric ultrasound: case presentation of a ghost twin during the second-trimester ultrasound scan. AB - Mirror artifacts are produced by the reflection of ultrasound waves after they propagate through a structure and encounter a strong and smooth interface capable of acting as a mirror. Ultrasound waves bounce back and forth between the mirroring interface and the reflective object and then eventually return to the transducer. The typical display of the mirror artifact consists of two similar structures separated and at similar distances from the reflective interface. We report a mirror artifact in a patient with a singleton gestation at 18 weeks. The image was interpreted as consistent with a twin gestation using transabdominal and transvaginal ultrasound. The differential diagnosis consisted of an abdominal heterotopic pregnancy. The presence of synchronized but opposite movements of both fetuses, and the blurred image of the second fetus, suggested a mirror artifact. The reflective surface was created by the interface located between a distended rectosigmoid filled with gas and the posterior uterine wall. Mirror artifacts can lead to diagnostic errors. This case illustrates how a distended rectosigmoid colon can generate an image that simulates either a twin gestation or an abdominal heterotopic pregnancy. PMID- 24071725 TI - Identification of mycobacteria based on spectroscopic analyses of mycolic acid profiles. AB - This report examines lipophilic extracts containing mycolic acids isolated from tuberculosis (MTB) and non-tuberculosis (NTM) mycobacterial strains using chromatography, mass spectrometry (MS), nuclear magnetic resonance (NMR), and Raman spectroscopy. Gas chromatography-MS was used to identify major fatty acid mycolate components, while proton NMR confirmed the presence of characteristic cis- and trans-cyclopropane rings within different mycolic acid sub-types. Surface-enhanced Raman (SERS) spectra were obtained from the mycolic acids extracted from the bacterial cell envelopes of the MTB or NTM mycobacterial species. The Raman spectral profiles were used to develop a classification method based on chemometrics for identification of the mycobacterial species. Multivariate statistical analysis methods, including principal component analysis (PCA), hierarchical cluster analysis (HCA), and partial least squares discriminant analysis (PLS-DA) of the SERS spectra enabled differentiation of NTM mycobacteria from one another with 100% accuracy. These methods are also sensitive enough to differentiate clinically-isolated MTB strains that differed only by the presence or absence of a single extracytoplasmic sigma factor with 83 100% sensitivity and 80-100% specificity. The current work is the first report on discrimination of mycobacteria strains based on the SERS spectra of the constituent mycolic acids in lipophilic extracts. These results suggest that SERS can be used as an accurate and sensitive method for species and strain discrimination in mycobacteria. PMID- 24071726 TI - Effects of stock use and backpackers on water quality in wilderness in Sequoia and Kings Canyon National Parks, USA. AB - During 2010-2011, a study was conducted in Sequoia and Kings Canyon National Parks (SEKI) to evaluate the influence of pack animals (stock) and backpackers on water quality in wilderness lakes and streams. The study had three main components: (1) a synoptic survey of water quality in wilderness areas of the parks, (2) paired water quality sampling above and below several areas with differing types and amounts of visitor use, and (3) intensive monitoring at six sites to document temporal variations in water quality. Data from the synoptic water quality survey indicated that wilderness lakes and streams are dilute and have low nutrient and Escherichia coli concentrations. The synoptic survey sites were categorized as minimal use, backpacker-use, or mixed use (stock and backpackers), depending on the most prevalent type of use upstream from the sampling locations. Sites with mixed use tended to have higher concentrations of most constituents (including E. coli) than those categorized as minimal-use (P <= 0.05); concentrations at backpacker-use sites were intermediate. Data from paired site sampling indicated that E. coli, total coliform, and particulate phosphorus concentrations were greater in streams downstream from mixed-use areas than upstream from those areas (P <= 0.05). Paired-site data also indicated few statistically significant differences in nutrient, E. coli, or total coliform concentrations in streams upstream and downstream from backpacker-use areas. The intensive-monitoring data indicated that nutrient and E. coli concentrations normally were low, except during storms, when notable increases in concentrations of E. coli, nutrients, dissolved organic carbon, and turbidity occurred. In summary, results from this study indicate that water quality in SEKI wilderness generally is good, except during storms; and visitor use appears to have a small, but statistically significant influence on stream water quality. PMID- 24071727 TI - Exploring public perception of non-native species from a visions of nature perspective. AB - Not much is known about lay public perceptions of non-native species and their underlying values. Public awareness and engagement, however, are important aspects in invasive species management. In this study, we examined the relations between the lay public's visions of nature, their knowledge about non-native species, and their perceptions of non-native species and invasive species management with a survey administered in the Netherlands. Within this framework, we identified three measures for perception of non-native species: perceived risk, control and engagement. In general, respondents scored moderate values for perceived risk and personal engagement. However, in case of potential ecological or human health risks, control measures were supported. Respondents' images of the human-nature relationship proved to be relevant in engagement in problems caused by invasive species and in recognizing the need for control, while images of nature appeared to be most important in perceiving risks to the environment. We also found that eradication of non-native species was predominantly opposed for species with a high cuddliness factor such as mammals and bird species. We conclude that lay public perceptions of non-native species have to be put in a wider context of visions of nature, and we discuss the implications for public support for invasive species management. PMID- 24071728 TI - Can citizen science survey non-indigenous fish species in the eastern Mediterranean Sea? AB - Engaging non-scientists to survey ecosystems, a process known as citizen science has been adopted worldwide. For the first time, this was applied to monitor fish assemblages in the Kas Peninsula, Turkey, an area known for its important Lessepsian fish populations. For 3 years (2004, 2007 and 2010), fish assemblages were surveyed using underwater visual census by transect method. A total of 29 species was observed, seven of which were Lessepsian species. Results show a significant increase in the Lessepsian species over the study period. In 2004, they represented 34% of the total abundance, increasing to >61% in 2010. Differences were observed in the progression of populations between two invasive herbivores, Siganus rivulatus and Siganus luridus (Siganidae), and two native herbivores, Sparisoma cretense (Scaridae) and Sarpa salpa (Sparidae). The siganids were recorded each year in all sites, whereas S. cretense was regularly observed in fewer numbers, while S. salpa was rarely censused. Abundance of Siganus spp. increased threefold in 6 years while abundances of S. cretense and S. salpa remained stable. S. rivulatus was the most abundant among the four species. Its competitive superiority may be due to its greater adaptability to fluctuating environmental conditions and biological traits, e.g. rapid growth, earlier sexual maturity, high fecundity. Because siganids are herbivorous, their presence can strongly impact algal ecosystems. It is then important to follow their spreading at a large scale, but this can be challenging due to the limited number of scientists. Adopting citizen science can thus be a useful strategy to monitor the spread of invasive species in the Mediterranean. PMID- 24071729 TI - Emissive cyanide-bridged bimetallic compounds as building blocks for polymeric antennae. AB - A series of cyanide-bridged bimetallic compounds of the general formula [Ru(L)(bpy)(MU-NC)(M)](2-/-/2+) (L = tpy, 2,2'-6',2''-terpyridine, or tpm, tris(1 pyrazolyl)methane, bpy = 2,2'-bipyridine, M = Ru(II)(CN)5, Os(III)(CN)5, Os(II)(CN)5, Ru(II)(py)4(CN), py = pyridine) have been synthesized and fully characterized. Most of them present MLCT emission (lambda = 690-730 nm, Phi = 10( 3)-10(-4)) and their photophysical properties resemble the ones of the respective mononuclear Ru(L)(bpy) species. The exception is when M is Os(III)(CN)5, where an intramolecular electron transfer quenching mechanism is proposed. The conditions that should be met for avoiding the reductive or oxidative quenching of the excited state are also discussed. PMID- 24071730 TI - Screening for osteoporosis. AB - Determining which women should undergo dual-energy x-ray absorptiometry testing should be based on rational screening criteria. Screening tests should be simple to perform, readily available, and very sensitive. Clinical risk factors have been proposed by numerous professional societies as a way to screen women for further testing. There is significant variation between these societies' recommendations. There have also been attempts at developing predictive, screening algorithms such as questionnaires and, more recently, a fracture risk assessment calculator. One approach is to proceed with dual-energy x-ray absorptiometry testing when a woman's 10-year fracture risk meets that of a 65 year-old woman. PMID- 24071731 TI - Foreword: an evidence-based update with regard to the diagnosis and management of osteoporosis. PMID- 24071732 TI - Fetal surveillance and timing of delivery in pregnancy complicated by diabetes mellitus. AB - Diabetes concurrent with pregnancy is a high-risk condition associated with risks for adverse pregnancy outcomes. Historically, these risks were unacceptably high and a policy of late preterm delivery induction was the rule. With the advent of improved glycemic management and the introduction of antenatal fetal testing and surveillance, the perinatal risks have dropped significantly such that a healthy pregnancy is expected. Managing stable women with diabetes mellitus to 39 and 40 weeks is now commonplace as fetal surveillance tools such as nonstress testing and biophysical profiles have sufficiently low false-negative rates that providers can feel assured that expectantly managing these pregnancies close to term can be done with minimal risk. However, providers cannot become complacent, and the results of fetal surveillance, clinical characteristics of the pregnancy, and expected neonatal outcomes all need to be accounted when deciding the optimal gestational age to deliver a child. PMID- 24071733 TI - Medium optimization, molecular characterization, and bioactivity of exopolysaccharides from Pleurotus eryngii. AB - An optimal medium for exopolysaccharides (EPS) production was obtained through one-factor-at-a-time method and response surface methodology. Under optimal culture medium, the maximum EPS concentration in shake flask was 5.16 g/l. Two groups of EPSs (designated as Fr-I and Fr-II) were obtained from the culture filtrates by size exclusion chromatography/multiangle laser light scattering, and the weight average molar masses (M w) of Fr-I and Fr-II were determined to be 4.098 * 10(4) and 1.114 * 10(4) g/mol, respectively. The molecular confirmation of Fr-I was revealed to be a rigid rod form in aqueous solution. Moreover, monosaccharide composition and characteristic groups were investigated by GC and Fourier transform infrared, respectively. Finally, pharmacology experiment in vitro indicated EPS Fr-II of Pleurotus eryngii exhibited higher antioxidant and antitumor abilities than Fr-I, which might be attributed to the different molecular weights and chemical compositions in the EPS fraction. PMID- 24071734 TI - Differential interaction of neuroleptics with apomorphine-induced behavior in rats as a function of changing levels of dopamine receptor stimulation. AB - Twenty-two neuroleptic drugs were studied for interaction with the behavior induced by intravenous injection of apomorphine in rats. All compounds dose dependently shortened the duration of the apomorphine-induced agitation and-with the exception of clozapine-shortened the onset of the de-arousal grooming that typically occurs immediately after the agitation phase has been terminated. Progressively higher doses were required to antagonize higher levels of apomorphine at earlier time intervals after the intravenous injection. The compounds also decreased palpebral opening, and most of them suppressed grooming behavior at higher doses. Compounds differed considerably in dose increments required for: 1) suppression of grooming, from 0.33 for clozapine to >600 for remoxipride, raclopride, and droperidol; 2) blockade of agitation at 5 minutes after apomorphine, from 2.6 for pimozide to 165 for chlorprothixene and 254 for remoxipride; 3) mild decrease of palpebral opening, from 0.21 for sertindole to 191 for remoxipride; and 4) pronounced decrease of palpebral opening, from 10 for melperone to >820 for raclopride. Only four compounds were able to advance grooming to 15 minutes postapomorphine, but again dose increments varied considerably: droperidol (3.4), pimozide (9.1), raclopride (42), and remoxipride (383). Based on these results obtained in a single animal model, compounds were differentiated in terms of behavioral specificity, incisiveness (the power to counteract the effects of progressively higher apomorphine concentrations), and sedative side-effect liability. Possible explanations for the observed differences and clinical relevance are discussed. PMID- 24071735 TI - Atorvastatin-loaded hydrogel affects the smooth muscle cells of human veins. AB - Intimal hyperplasia (IH) is the major cause of stenosis of vein grafts. Drugs such as statins prevent stenosis, but their systemic administration has limited effects. We developed a hyaluronic acid hydrogel matrix, which ensures a controlled release of atorvastatin (ATV) at the site of injury. The release kinetics demonstrated that 100% of ATV was released over 10 hours, independent of the loading concentration of the hydrogel. We investigated the effects of such a delivery on primary vascular smooth muscle cells isolated from human veins. ATV decreased the proliferation, migration, and passage of human smooth muscle cells (HSMCs) across a matrix barrier in a similar dose-dependent (5-10 uM) and time dependent manner (24-72 hours), whether the drug was directly added to the culture medium or released from the hydrogel. Expression analysis of genes known to be involved in the development of IH demonstrated that the transcripts of both the gap junction protein connexin43 (Cx43) and plasminogen activator inhibitor-1 (PAI-1) were decreased after a 24-48-hour exposure to the hydrogel loaded with ATV, whereas the transcripts of the heme oxygenase (HO-1) and the inhibitor of tissue plasminogen activator were increased. At the protein level, Cx43, PAI-1, and metalloproteinase-9 expression were decreased, whereas HO-1 was upregulated in the presence of ATV. The data demonstrate that ATV released from a hydrogel has effects on HSMCs similar to the drug being freely dissolved in the environment. PMID- 24071736 TI - Application of bispecific antibody against antigen and hapten for immunodetection and immunopurification. AB - We present a bispecific antibody that recognizes an antigen and a hapten and can be applied to various biological assays, including immunoblotting and immunoprecipitation. In immunoblot analysis of serum, an anti-C5 * anti-cotinine bispecific tandem single-chain variable fragment (scFv)-Fc fusion protein and cotinine-conjugated horseradish peroxidase (HRP) generated a clean signal without the high background that was observed in a parallel experiment using HRP conjugated goat anti-rabbit immunoglobulin G (Fc-specific) antibody. In immunoprecipitation analysis of serum, use of the bispecific tandem scFv-Fc fusion protein and cotinine-crosslinked magnetic beads significantly reduced the amount of protein contaminants compared with a parallel experiment done with protein A agarose beads. In subsequent immunoblot analysis, use of cotinine-HRP as the secondary probe instead of HRP-conjugated goat anti-rabbit IgG (Fc specific) antibody successfully eliminated the band corresponding to the bispecific tandem scFv-Fc fusion protein. PMID- 24071737 TI - Constitutive stabilization of hypoxia-inducible factor alpha selectively promotes the self-renewal of mesenchymal progenitors and maintains mesenchymal stromal cells in an undifferentiated state. AB - With the increasing use of culture-expanded mesenchymal stromal cells (MSCs) for cell therapies, factors that regulate the cellular characteristics of MSCs have been of major interest. Oxygen concentration has been shown to influence the functions of MSCs, as well as other normal and malignant stem cells. However, the underlying mechanisms of hypoxic responses and the precise role of hypoxia inducible factor-1alpha (Hif-1alpha), the master regulatory protein of hypoxia, in MSCs remain unclear, due to the limited span of Hif-1alpha stabilization and the complex network of hypoxic responses. In this study, to further define the significance of Hif-1alpha in MSC function during their self-renewal and terminal differentiation, we established adult bone marrow (BM)-derived MSCs that are able to sustain high level expression of ubiquitin-resistant Hif-1alpha during such long-term biological processes. Using this model, we show that the stabilization of Hif-1alpha proteins exerts a selective influence on colony-forming mesenchymal progenitors promoting their self-renewal and proliferation, without affecting the proliferation of the MSC mass population. Moreover, Hif-1alpha stabilization in MSCs led to the induction of pluripotent genes (oct-4 and klf-4) and the inhibition of their terminal differentiation into osteogenic and adipogenic lineages. These results provide insights into the previously unrecognized roles of Hif-1alpha proteins in maintaining the primitive state of primary MSCs and on the cellular heterogeneities in hypoxic responses among MSC populations. PMID- 24071739 TI - Efficient n-doping of graphene films by APPE (aminophenyl propargyl ether): a substituent effect. AB - We report the synthesis and applications of APPE (aminophenyl propargyl ether) as a novel n-type dopant for graphene. The characteristics of APPE-doped graphene films were investigated using Raman spectroscopy as well as electron transport measurements. The Raman 2D/G peak ratio decreased by more than 40%, and the minimum conductivity voltage (Dirac voltage) was shifted to -133 V as the pristine graphene was doped with APPE, indicating that the graphene was strongly n-doped. We suppose that the electron donating property of the amine group (-NH2) is the origin of such an intense n-doping effect. In contrast, a similar molecule with an electron withdrawing nitro group (-NO2) (nitrophenyl propargyl ether, NPPE) showed a slight p-doping effect. Thus, we conclude that the doping effect of a molecular framework strongly depends on the functional substituents, which can be represented by the Hammett equation. We also confirmed that the sheet resistance of the APPE doped graphene film was reduced by ~70%, which is crucial to enhance the electrical conductivity of graphene for various electronic applications. In addition, the acetylene group of APPE appears promising to be utilized in "click chemistry" to further functionalize the pi-surface of graphene for sensors and bio applications. PMID- 24071738 TI - OTUB1 enhances TGFbeta signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3. AB - SMAD transcription factors are key intracellular transducers of TGFbeta cytokines. SMADs are tightly regulated to ensure balanced cellular responses to TGFbeta signals. Ubiquitylation has a key role in regulating SMAD stability and activity. Several E3 ubiquitin ligases that regulate the turnover of SMADs are known; however, proteins that prevent the ubiquitylation or cause deubiquitylation of active SMADs remain undefined. Here we demonstrate that OTUB1 is recruited to the active phospho-SMAD2/3 complex only on TGFbeta induction. Further, OTUB1 has a crucial role in TGFbeta-mediated gene transcription and cellular migration. OTUB1 inhibits the ubiquitylation of phospho-SMAD2/3 by binding to and inhibiting the E2 ubiquitin-conjugating enzymes independent of its catalytic activity. Consequently, depletion of OTUB1 in cells causes a rapid loss in levels of TGFbeta-induced phospho-SMAD2/3, which is rescued by the proteasomal inhibitor bortezomib. Our findings uncover a signal-induced phosphorylation dependent recruitment of OTUB1 to its target in the TGFbeta pathway. PMID- 24071741 TI - A prospective comparative pilot study comparing the urine collection pad with clean catch urine technique in non-toilet-trained children. AB - INTRODUCTION: There are many different methods for collecting urine from paediatric patients in emergency departments. Therefore, the aims of the study were to: METHODS: The three month study was a prospective non-randomised comparative paediatric pilot study. A purposeful sample of children, requiring a urine microscopy for clinical management, presenting to one district emergency department was enrolled in the study to compare two non-invasive techniques of urine collection. RESULTS: Thirty-three patients were enrolled and satisfactory samples were obtained from 22 patients. The heavy (mixed growth) contamination rate in the UCP group (n=2; 9.1%) versus the CCU group (n=1; 4.5%) was not statistically significant (p=0.50 by Fisher's exact test). The rate of agreement (n=20; 91%) in diagnosing or excluding urinary tract infection between the two groups was high. The median time to urine collection between the two groups (UCP method 30 min; CCU 107.5 min) was statistically significant (p<0.002, Mann Whitney U test). CONCLUSIONS: This study suggests that UCPs are practicable in Australasian Emergency Departments and may lead to faster diagnosis, disposition and reduced hospital stay. PMID- 24071743 TI - High-resolution summer precipitation variations in the western Chinese Loess Plateau during the last glacial. AB - We present a summer precipitation reconstruction for the last glacial (LG) on the western edge of the Chinese Loess Plateau (CLP) using a well-dated organic carbon isotopic dataset together with an independent modern process study results. Our results demonstrate that summer precipitation variations in the CLP during the LG were broadly correlated to the intensity of the Asian summer monsoon (ASM) as recorded by stalagmite oxygen isotopes from southern China. During the last deglaciation, the onset of the increase in temperatures at high latitudes in the Northern Hemisphere and decline in the intensity of the East Asia winter monsoon in mid latitudes was earlier than the increase in ASM intensity and our reconstructed summer precipitation in the western CLP. Quantitative reconstruction of a single paleoclimatic factor provides new insights and opportunities for further understanding of the paleoclimatic variations in monsoonal East Asia and their relation to the global climatic system. PMID- 24071742 TI - Effect of patient sex on triage for ischaemic heart disease and treatment onset times: A retrospective analysis of Australian emergency department data. AB - Time between emergency department (ED) presentation and treatment onset is an important, but little-researched phase within the revascularization process for ischaemic heart disease (IHD). OBJECTIVE: To determine if sex influences triage score allocation and treatment onset for patients with IHD in the ED. METHODS: Retrospective data for patients 18-85 years presenting to EDs from 2005 to 2010 for acute myocardial infarction (AMI), unstable and stable angina, and chest pain were analysed collectively and separately for AMI. RESULTS: Proportionately more men (61% of males) were triaged correctly for AMI than women (51.4% of females; P<0.001). Across all triage categories, average treatment time was faster for men than women with AMI (P<0.001). When incorrectly triaged for AMI, treatment time for men was faster than for women (P=0.04). When correctly triaged for AMI, there was no difference in mean treatment time between men and women (P=0.538). CONCLUSIONS: Substantial undertriage of AMI occurred for both sexes, but was worse in women. Incorrect triage led to prolonged treatment times for AMI, with women's treatment delays longer than men's. When triaged correctly, both sexes were treated early for AMI, emphasising the need for all patients to be accurately triaged for this time-sensitive disease. PMID- 24071744 TI - Jasmonic acid negatively regulates resistance to Tobacco mosaic virus in tobacco. AB - Nicotiana tabacum (tobacco) cultivars possessing the N resistance gene to Tobacco mosaic virus (TMV) induce a hypersensitive response, which is accompanied by the production of phytohormones such as salicylic acid (SA) and jasmonic acid (JA), to enclose the invaded virus at the initial site of infection, which inhibits viral multiplication and spread. SA functions as a positive regulator of TMV resistance. However, the role of JA in TMV resistance has not been fully elucidated. Exogenously applied methyl jasmonate, a methyl ester of JA, reduced local resistance to TMV and permitted systemic viral movement. Furthermore, in contrast to a previous finding, we demonstrated that silencing of CORONATINE INSENSITIVE 1 (COI1), a JA receptor, reduced viral accumulation in a tobacco cultivar possessing the N gene, as did that of allene oxide synthase, a JA biosynthetic enzyme. The reduction in viral accumulation in COI1-silenced tobacco plants was correlated with an increase in SA, and lowering SA levels by introducing an SA hydroxylase gene attenuated this reduction. Viral susceptibility did not change in a COI1-silenced tobacco cultivar lacking the N gene. These results suggest that JA signaling is not directly responsible for susceptibility to TMV, but is indirectly responsible for viral resistance through the partial inhibition of SA-mediated resistance conferred by the N gene, and that a balance between endogenous JA and SA levels is important for determining the degree of resistance. PMID- 24071745 TI - Main topics in transcultural psychiatric research in the Netherlands during the past decade. AB - The population of the Netherlands has become increasingly diverse in terms of ethnicity and religion, and anti-immigrant attitudes have become more apparent. At the same time, interest in issues linked to transcultural psychiatry has grown steadily. The purpose of this article is to describe the most important results in Dutch transcultural psychiatric research in the last decade and to discuss their relationship with relevant social and political developments in the Netherlands. All relevant PhD theses (N = 27) between 2000 and 2011 were selected. Screening of Dutch journals in the field of transcultural psychiatry and medical anthropology and a PubMed query yielded additional publications. Forensic and addiction psychiatry were excluded from this review. The results of the review indicate three main topics: (a) the prevalence of psychiatric disorders and their relation to migration issues as social defeat and ethnic density, showing considerable intra- and interethnic differences in predictors and prevalence rates, (b) the social position of refugees and asylum seekers, and its effect on mental health, showing especially high risk among asylum seekers, and (c) the patterns of health-seeking behaviour and use of mental health services, showing a differentiated picture among various migrant groups. Anthropological research brought additional knowledge on all the above topics. The overall conclusion is that transcultural psychiatric research in the Netherlands has made a giant leap since the turn of the century. The results are of international importance and invite redefinition of the relationship between migration and mental health, and reconsideration of its underlying mechanisms in multiethnic societies. PMID- 24071746 TI - Frigophobia: a case series from Sri Lanka. AB - Frigophobia is a condition in which patients report coldness of extremities leading to a morbid fear of death. It has been reported as a rare culture-related psychiatric syndrome in Chinese populations. An extensive survey of the literature yielded only six case reports. The present paper describes a series of 109 patients with frigophobia in Sri Lanka. The common clinical presentation was of patients initially examining their extremities for cold sensations, and then, with the onset of fear, covering themselves in layers of clothing, applying emollients, and staying near an open fire in an effort to ward off the cold. They avoided foods considered to be "cooling" and bathed only in the heat of the noonday sun. When the severity of the symptoms reached a peak, or when they felt death was imminent, Western medical aid was sought. The fear of dying is seen as the single most important aspect that drives these individuals to seek help. There was a preponderance of female patients, and a few had specific phobias as comorbid conditions. Management comprised primarily illness education, reassurance, and desensitisation by exposure to cold stimuli, with short-term anxiolytic medication use when necessary. PMID- 24071747 TI - An ultrasensitive electrochemical method for detection of Ag(+) based on cyclic amplification of exonuclease III activity on cytosine-Ag(+)-cytosine. AB - Ag(+) is known to bind very strongly with cytosine-cytosine (C-C) mismatches in DNA duplexes to form C-Ag(+)-C base pairs. Exonuclease III (Exo III) can catalyze the stepwise removal of mononucleotides of duplex DNA. In this work, we study Exo III activity on DNA hybrids containing C-Ag(+)-C base pairs. Our experiments show that Ag(+) ions could intentionally trigger the activity of Exo III towards a designed cytosine-rich DNA oligonucleotide (C-rich probe) by the conformational change of the probe. Our sensing strategy uses this conformation-dependent activity of Exo III, which is controlled through the cyclical shuffling of Ag(+) ions between the solid DNA hybrid and the solution phase. This interesting conversion has led to the development of an ultrasensitive detection platform for Ag(+) ions with a detection limit of 0.03 nM and a total assay time possible within minutes. This simple detection strategy could also be used for the detection of other metal ions which exhibit specific interactions with natural or synthetic bases. PMID- 24071748 TI - Self-injurious behaviour in children: A treatable catatonic syndrome. PMID- 24071749 TI - Demoralisation, deprofessionalisation, denial and detachment in medicine? PMID- 24071750 TI - [Nurses' experience of incivility in general hospitals]. AB - PURPOSE: This study was done to describe nurses' experience of incivility in hospitals and to consider nurses' work environment. METHODS: Data were collected through in-depth interviews and analyzed using Colaizzi' phenomenological analysis methodology. Participants were seven experienced clinical nurses working on a general ward (2 nurses), or in an intensive care unit (2 nurses), emergency room (2 nurses), or operating room (1 nurse). RESULTS: The incivility that nurses experienced was categorized as follows: 'being afflicted as a weak person', 'being treated as less than a professional', 'being overwhelmed by shock and anger', 'experiencing an untenable situation', 'struggling to survive', and 'pursuing professional growth'. CONCLUSION: Behavior guidelines should be developed to reduce incivility, and incivility cases should be continuously monitored by the nursing department. Also, to handle incivility problems in clinical nursing areas, a reporting and counseling system and education programs are needed. PMID- 24071751 TI - [Development and effects of a simulation-based education program for newborn emergency care]. AB - PURPOSE: This study was conducted to develop a simulation-based education program for newborn emergency care based on most needed topics found from the needs assessment. This study consisted of two phases: developing the program and evaluating its effectiveness. METHODS: The effectiveness of the program was tested in July, 2012, with 49 junior nursing students from C Nursing College in Seoul, who did not have any clinical experience in newborn care. The experimental group was given a three-hour lecture, three hours of clinical training, and a two hour simulation program, whereas the control group only had the three-hour lecture. RESULTS: There was significant improvement in knowledge in both groups, but no significant differences according to educational methods. The experiment group was more confident of their care (4.32+/-.29) than the control group (3.60+/-.29) with the difference being significant (t=8.85, p<.001), and the experimental group was also more satisfied with the program (chi2=4.60, p=.032). CONCLUSION: As the results indicate 'the neonatal emergency care program' increased learners' knowledge, confidence and satisfaction with the program, it should be integrated into clinical training in pediatric nursing curriculum and in-service programs for nurses. To increase generalization further verification studies with various learner groups are needed. PMID- 24071752 TI - [Development and effects of a health education program for North Korean preschool defectors]. AB - PURPOSE: This study was conducted to develop a health education program for preschoolers who have defected from North Korea with their mothers, and to evaluate the effects on health knowledge and behavior. METHODS: A non-equivalent control group pre-post test design was used with 58 preschoolers who were assigned to either the experimental or control group (29 for each group). The program was composed of five sessions in health education and contracts. To test the effectiveness of the intervention, health knowledge and behaviors, and total bacterial colony counts on hands were measured at one pretest and two post tests (1 week and 4 weeks after the intervention ended). Data were analyzed using the SAS program. RESULTS: Health knowledge and behavior in the experimental group increased significantly compared to the control group. The effects of the intervention were evident even at 4 weeks after the intervention ended. Total bacterial colony counts in the experimental group decreased significantly at the 1 and 4 week posttest intervention compared to the control group. CONCLUSION: Results indicate that this program is effective in improving health knowledge and behavior in these children and therefore can be utilized to ensure efficient management their health care. PMID- 24071753 TI - [Types of child rearing behavior of parents during early childhood: Q methodological approach]. AB - PURPOSE: The purpose of this study was to identify the awareness of child rearing among parents of children in early childhood and to provide fundamental data for parent education programs according to child rearing type. METHODS: Q-methodology which provides a method of analyzing the subjectivity of each item was used. Forty Q items which were derived from a literature review and interviews with nurturing mothers were classified into a normal distribution using a 9-point scale. Collected data were analyzed using the QUANAL PC Program. RESULTS: Four types of parents' child rearing were identified. Type I was named 'affection respect type', type II, 'concern-rule compliant type', type III, 'solicitude model type', and type IV, 'geniality-encouragement type'. CONCLUSION: For proper growth and development during early childhood, parents should have rational information and awareness of their child rearing type. Results of this study can be used as essential data to develop child rearing education programs according to parents' child rearing attitude. PMID- 24071754 TI - [Effects of a family education program for families of pathological gamblers]. AB - PURPOSE: This study was done to examine the intervention effects on the family of a family education program for pathological gamblers based on Community Reinforcement and Family Training (CRAFT). METHODS: A quasi-experimental, nonequivalent control group pretest-posttest design was used. The participants were 44 families of pathological gamblers from G center in Gyung-gi Province and 5 Gam-Anon groups in Seoul City and Gyung-gi Province. The experimental group (n=22) attended the 6 weekly 2 hour-long CRAFT family education program. The control group (n=22) attended the 12-step program of Gam-Anon. Data were collected from November, 2011 to May, 2012. RESULTS: Compared with the control group, the experimental group showed significant decrease in depression (p=.001) and state anger (p=.039). There were no significant differences between groups in the level of interpersonal communication, trait anger, the mode of anger expression and self-esteem. CONCLUSION: Findings from this study suggest that the CRAFT family education program is effective in decreasing depression and state anger in families of pathological gamblers. PMID- 24071755 TI - [Economic evaluation of a workplace occupational health nursing service: based on comparison with atmospheric environment managing engineer]. AB - PURPOSE: The purpose of this study was to use cost-benefit analysis of activity to clarify the economic effect of prepared nurses versus atmospheric environment managing engineers as healthcare managers. METHODS: For the study 111 workplaces were surveyed, workplaces in which nurses or atmospheric environment managing engineers were employed as healthcare managers. The survey content included annual gross salaries, participation in external job training, costs in joining association covered by the company, location and year of construction of the healthcare office, various kinds of healthcare expenditures, costs in operating healthcare office, health education, and activity performance in the work of environment management. RESULTS: In the case of the healthcare manager being a nurse, benefit was larger than input costs at a ratio of 2.31. On the other hand, in the case of healthcare manager being an atmospheric environment managing engineer, input costs were larger than benefits (benefit-cost ratio 0.88). CONCLUSION: Results indicate that nurses are an effective healthcare human resource and can offer good quality healthcare service. Therefore companies should hire nurses and actively promote the economic efficiency of nurses in workplace. PMID- 24071756 TI - [Effects of nurses' social capital on turnover intention: focused on the mediating effects organizational commitment and organizational cynicism]. AB - PURPOSE: The purpose of this study was to investigate the casual relationship between nurses' social capital and turnover intention and to verify the goodness of fit between a hypothetical model and actual data in order to suggest the best model. METHODS: This survey was conducted with 315 nurses working in general hospitals in Seoul. Data were collected from December 1 to December 30, 2011, and analyzed using SPSS Windows 18.0 and AMOS 16.0. RESULTS: Nurses' social capital was found to have a direct effect on reducting organization cynicism and increasing organizational commitment. Nurses' organizational cynicism and organizational commitment were found to have a direct effect on turnover intention, but social capital did not have a direct effect on turnover intention. However, social capital had a partial and indirect effect on turnover intention through mediating organizational cynicism and organizational commitment. CONCLUSION: Results of this study indicate that nurse managers should put increased effort in reducing nurses' organizational cynicism and improving their organizational commitment, two contrary parameters. At the same time managers need to develop plans to establish social capital more efficiently so that nurses have lower turnover intention. PMID- 24071757 TI - [Clinical nurses' knowledge and visual differentiation ability in pressure ulcer classification system and incontinence-associated dermatitis]. AB - PURPOSE: This study was done to compare clinical nurses' knowledge and visual differentiation diagnostic ability for the pressure ulcer classification system (PUCS) and incontinence-associated dermatitis (IAD). METHODS: A convenience sample of 602 nurses took the pressure ulcer classification system and incontinence-associated dermatitis knowledge test (PUCS & IAD KT) and completed the visual differentiation tool (VDT), consisting of 21 photographs with clinical information. RESULTS: The overall mean score for correct answers was 14.5 (+/ 3.2) in PUCS & IAD KT and 11.15 (+/-4.9) in PUCS & IAD VDT. Incorrect responses were most common for statements related to stage III, IAD for PUCS & IAD KT, and suspected deep tissue injury (SDTI), unstageable, and stage III for PUCS & IAD VDT. Significant correlations were found between PUCS & IAD KT and VDT (r=.48, p<.001). Factors affecting scores for PUCS & IAD VDT were PUCS & IAD KT, frequency of pressure ulcer, IAD management and participation in wound care education programs. CONCLUSION: Results indicate that nurses have an overall understanding of PUCS & IAD, but low visual differentiation ability regarding stage III, SDTI, and unstageable ulcers. Continuing education is needed to further improve knowledge and visual differentiation ability for PUCS & IAD. PMID- 24071758 TI - [A meta-analysis of the effect of walking exercise on lower limb muscle endurance, whole body endurance and upper body flexibility in elders]. AB - PURPOSE: The purpose of this study was to determine whether walking exercise improved physical function in elderly people using meta-analysis. METHODS: Medical and nursing literature databases were searched to identify the studies on the effectiveness of walking exercise on physical function. In the databases, there were 16 articles reporting 21 interventions. Overall effect sizes for three outcome variables, elders' physical function in lower limb muscle endurance, whole body endurance and upper body flexibility, were calculated. Effects of study characteristics on outcome variables were analyzed. RESULTS: The meta analysis showed that walking exercise generally had positive effects on CST (chair stand test), 6MW (6 min walking), and SRT (standing or sitting reach test) with overall weighted effect sizes of 1.06, 0.41 and 0.29 respectively. This study also showed that the chronic disease status of the elders, intervention methods, and type of residence had different effects on CST, 6MW and SRT. CONCLUSION: The results indicate that walking exercise improves physical function in elders. Walking exercise which can be done at any time and any location is indeed a very effective exercise for elderly people. PMID- 24071759 TI - [Effects of gout web based self-management program on knowledge related to disease, medication adherence, and self-management]. AB - PURPOSE: This study was conducted to examine the changing patterns of knowledge related to disease, medication adherence, and self-management and to determine if outcomes were more favorable in the experimental group than in the comparison group through 6 months after providing a web-based self-management intervention. METHODS: A non-equivalent control group quasi-experimental design was used and 65 patients with gout, 34 in experimental group and 31 in comparison group, were selected from the rheumatic clinics of two university hospitals. Data were collected four times, at baseline, at 1 month, 3 months, and 6 months after the intervention. RESULTS: According to the study results, the changing patterns of knowledge and self-management were more positive in the experimental group than in the control group, whereas difference in the changing pattern of medication adherence between two groups was not significant. CONCLUSION: The results indicate that the web-based self-management program has significant effect on improving knowledge and self-management for middle aged male patients with gout. However, in order to enhance medication adherence, the web-based intervention might not be sufficient and other strategies need to be added. PMID- 24071760 TI - [Effects of a smoking cessation program including telephone counseling and text messaging using stages of change for outpatients after a myocardial infarction]. AB - PURPOSE: This study was done to identify effects of a smoking cessation program including telephone counseling and text messaging using stages of change for outpatients who have had a myocardial infarction (MI). METHODS: This research was a quasi-experimental design with a nonequivalent control group pretest-posttest. The participants were 48 outpatients (experimental group=24, control group=24) recruited from one university hospital. They were randomly assigned to one of two groups: (a) an experimental group with telephone counseling (once a week) and text messaging (five times a week) using stages of change, and (b) a control group with traditional telephone counseling (once a month). Efficacy of the intervention was measured by comparing the two groups on smoking-related variables at 3 weeks and 12 weeks. RESULTS: At the 3-week and 12-week measurements, there were significant differences between the experimental and control groups on smoking cessation self-efficacy (p<.001), nicotine dependence (p<.001), CO levels (p<.001), and smoking cessation rates (p<.001). CONCLUSION: The results indicate that the smoking cessation program including telephone counseling and text messaging using stages of change is effective for outpatients after a MI. Further attention should be paid to the intensity of the smoking cessation program and periods for long-term follow-up. PMID- 24071761 TI - [Accessing factor structure and construct validity of the successful aging inventory]. AB - PURPOSE: The purpose of this study was to evaluate the reliability and validity of the Korean version of the Successful Aging Inventory (SAI-K) to determine its suitability for use with older Korean adults. METHODS: Exploratory and confirmatory factor analyses were utilized to assess the factor structure and the construct validity of the SAI-K. First- and second-order Confirmatory Factor Analysis (CFA) were conducted to identify the most adequate model. Cronbach's alpha was used to test the reliability. RESULTS: Using a second-order CFA, a four factor structure was validated (chi2=122.82, p<.001, GFI=.92, AGFI=.88, SRMR=.06 RMSEA=.07, 90% CI=.05-.09, CFI=.93). The four-factor SAI-K showed reliable internal consistency with a Cronbach's alpha for the total scale of .86. CONCLUSION: The four-factor, 13-item SAI-K showed satisfactory reliability and validity and, thus, has the potential to be an appropriate instrument for measuring successful aging in older Korean adults. PMID- 24071762 TI - Efficacy of the long-acting nitro vasodilator pentaerithrityl tetranitrate in patients with chronic stable angina pectoris receiving anti-anginal background therapy with beta-blockers: a 12-week, randomized, double-blind, placebo controlled trial. AB - BACKGROUND: The organic nitrate pentaerithrityl tetranitrate (PETN) has been shown to have ancillary properties that prevent the development of tolerance and endothelial dysfunction. This randomized, double-blind, placebo-controlled, multicentre study ('CLEOPATRA' study) was designed to investigate the anti ischaemic efficacy of PETN 80 mg b.i.d. (morning and mid-day) over placebo in patients with chronic stable angina pectoris. METHODS AND RESULTS: A total of 655 patients were evaluated in the intention-to-treat population, randomized to PETN (80 mg b.i.d., n = 328) or placebo (n = 327) and completed the study. Patients underwent treadmill exercise tests at randomization, after 6 and 12 weeks of treatment. Treatment with PETN over 12 weeks did not modify the primary endpoint total exercise duration (TED, P = 0.423). In a pre-specified sub-analysis of patients with reduced exercise capacity (TED at baseline <=9 min, n = 257), PETN appeared more effective than placebo treatment (P = 0.054). Superiority of PETN over placebo was evident in patients who were symptomatic at low exercise levels (n = 120; P = 0.017). Pentaerithrityl tetranitrate 80 mg b.i.d. was well tolerated, and the overall safety profile was comparable with placebo. CONCLUSION: Although providing no additional benefit in unselected patients with known coronary artery disease, PETN therapy, administered in addition to modern anti-ischaemic therapy, could increase exercise tolerance in symptomatic patients with reduced exercise capacity. PMID- 24071763 TI - Symptoms of angina pectoris increase the probability of disability pension and premature exit from the workforce even in the absence of obstructive coronary artery disease. AB - AIMS: To evaluate probabilities of disability pension (DP) and premature exit from the workforce (PEW) in patients with stable angina symptoms and no obstructive coronary artery disease (CAD) at angiography compared with obstructive CAD and asymptomatic reference individuals. METHODS AND RESULTS: We followed 4303 patients with no prior cardiovascular disease having a first-time coronary angiography (CAG) in 1998-2009 due to stable angina symptoms and 2772 reference individuals from the Copenhagen City Heart Study, all aged <65 years, through registry linkage until 2009 for DP and PEW. Five-year age-adjusted DP free survival probabilities for reference individuals, patients with angiographically normal coronary arteries, angiographically diffuse non obstructive CAD, 1 stenotic coronary vessel (1VD), 2VD, and 3VD, respectively, were 0.96, 0.88, 0.84, 0.82, 0.85, and 0.78 in women and 0.98, 0.90, 0.89, 0.89, 0.88, and 0.87 in men. Significant predictors of DP were higher age, angina symptoms, higher body mass index, diabetes, smoking, job status, non-marital status in men, lower income, lower educational level, and co-morbidity. Compared with the reference population, probabilities of DP and PEW were significantly increased in all patients with no gender difference (P > 0.2 for interaction). Thus, in pooled multivariable-adjusted analysis, patients referred to CAG for angina had a three-fold higher probability of DP and ~50% higher probability of PEW, with little difference between patients with angiographically normal coronary arteries, angiographically diffuse non-obstructive CAD, 1VD, 2VD, 3VD, the hazard ratios for DP being 2.7, 3.0, 3.3, 3.1, and 3.2 (all P < 0.001) and for PEW being 1.3, 1.4, 1.5, 1.6, and 1.6 (all P < 0.05). CONCLUSION: Patients with angina symptoms and angiographically normal coronary arteries, diffuse non obstructive CAD, or obstructive CAD at angiography have a three-fold increased probability of DP regardless of angiographic findings. PMID- 24071764 TI - Interface kinetic diffusion reaction leading to fast and continuous generation of AgCl nanocubes in NaCl solution. AB - It is found that the electrochemical corrosion of a silver sheet anode in NaCl solution gives rise to a fast and continuous way of generating AgCl nanocubes with good uniform morphology. We examined the factors affecting the size and morphologies of AgCl nanocubes, which include the applied voltage, the concentration of NaCl, and that of Na2SO4 added to enhance the conductivity of the NaCl solution as well as the physical ways of solution mixing and the placement of the Ag sheet anode with respect to the Pt cathode. Analysis of these factors indicates that the fast and continuous generation of AgCl nanocubes requires the presence of the interface reaction layer formed by the kinetic diffusion of Ag(+) and Cl(-) ions. The AgCl nanocubes possess {001} facets and uniform morphology, and the Ag@AgCl nanocubes have much higher photocatalytic activity than do the irregularly-shaped Ag@AgCl particles made from the conventional precipitation method. PMID- 24071769 TI - Karplus dependence of spin-spin coupling constants revisited theoretically. Part 1: second-order double perturbation theory. AB - A double perturbation theory (DPT) at the second order level of approximation formalism has been applied to examine the dihedral angle dependence of the Fermi contact (FC) contribution to nuclear spin-spin coupling constants. The unperturbed wave function of the ground state in DPT was approximated by the Hartree-Fock Slater determinant, while the excited states were treated as the single excited determinants. An analytical expression relating the FC term of vicinal proton-proton spin-spin coupling constants across the aliphatic single carbon-carbon bond to the dihedral angle describing inner rotation around the C-C bond in the ten-electron ten-orbital moiety H-C-C-H has been derived and analyzed. In particular, it has been shown that extrema of (3)J(H,H) are observed at phi = pin, n = 0, +/-1, +/-2,..., which provides a theoretical background of a well-known semiempirical Karplus equation. PMID- 24071771 TI - A comparative study of UV-induced cell signalling pathways in human keratinocyte derived cell lines. AB - Ultraviolet (UV) radiation can activate the p38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinase (JNK) and nuclear factor-kappaB (NFkappaB) pathways in skin cells. HaCaT cells are widely used as a primary keratinocyte substitute to study these pathways. However, like most squamous cell carcinomas (SCCs), it contains a dysfunctional p53. It is unclear if HaCaT cells activate these signalling pathways similarly to SCC cells (Colo16) or to primary human epidermal keratinocytes (HEK). In this study, the UV activation (UVA, UVB, UVA+B, UVB+A) of p38 MAPK, JNK and NFkappaB pathways, and TNFalpha secretion by HEK, HaCaT and Colo16 cells were investigated. The signalling pathway activation was UV-type and dose-dependent with UVB+A radiation inducing a high p38 and JNK activation. HaCaT cells exhibited 2- to 4-fold higher activity of the p38 (771% at 60 min) and JNK (794% at 30 min) pathways following UVB+A radiation than did HEK cells (p38: 367% at 15 min and JNK: 184% at 30 min). While both HaCaT and Colo16 cells did not activate the NFkappaB pathway, Colo16 cells had a lower p38 and higher JNK activity than HaCaT cells. Irradiated HaCaT cells produced less TNFalpha (UVB: 3.5 pg/ml), while HEK cells produced the most (UVB: 1,296 pg/ml). When co-exposed to IL1alpha, irradiated HaCaT had the greatest fold of TNFalpha release (UVB: 16.2-fold, UVA+B: 8.9-fold and UVB+A: 6.1-fold). The pattern of activation and TNFalpha secretion of HaCaT cells mirrored that of Colo16 cells. It is likely that the presence of molecular alterations in HaCaT cells may be responsible for its different responses to that seen for HEK cells. The results of this study suggest caution in using HaCaT cells as a substitute for normal keratinocytes in investigating UV-induced cells signalling pathways. PMID- 24071770 TI - Autologous transplantation of GDNF-expressing mesenchymal stem cells protects against MPTP-induced damage in cynomolgus monkeys. AB - Glial cell-derived neurotrophic factor (GDNF) has shown beneficial effects in models of Parkinson's disease. The mild results observed in the double-blind clinical trial by intraputamenal infusion of recombinant GDNF proteins warrant a search for alternative delivery methods. In this study, we investigated the function of autologous mesenchymal stem cells (MSCs) expressing GDNF (GDNF-MSCs) for protection against MPTP-induced injury in cynomolgus monkeys. MSCs were obtained from the bone marrow of individual monkeys and gene-modified to express GDNF. Following unilateral engraftment of GDNF-MSCs into the striatum and substantia nigra, the animals were challenged with MPTP to induce a stable systemic Parkinsonian state. The motor functions were spared in the contralateral limbs of monkeys receiving GDNF-MSCs, but not in those receiving MSCs alone. In the striatum of the grafted hemisphere, dopamine levels were higher and dopamine uptake was enhanced. The results suggest that autologous MSCs may be a safe vehicle to deliver GDNF for enhancing nigro-striatum functions. PMID- 24071772 TI - Morning and Evening Effects of Guanfacine Extended Release Adjunctive to Psychostimulants in Pediatric ADHD. AB - OBJECTIVE: To examine efficacy and safety of adjunctive guanfacine extended release (GXR) on morning and evening ADHD symptoms using the Conners' Global Index-Parent (CGI-P) and Before-School Functioning Questionnaire (BSFQ). METHOD: Participants 6 to 17 years with ADHD ( N = 461) and suboptimal psychostimulant response were maintained on current psychostimulants and randomized to dose optimized GXR (<=4 mg/d) in the morning (GXR AM) or evening (GXR PM), or placebo. RESULTS: CGI-P scores improved with GXR (morning assessment, GXR AM, placebo adjusted least squares [LS] mean = -1.7, GXR PM = -2.6; evening assessment, GXR AM = -2.4, GXR PM = -3.0; all ps < .01). Parent-rated BSFQ scores reflected improved morning functioning with GXR (GXR AM, placebo-adjusted LS mean = -5.1; GXR PM = -4.7; both ps < .01). Most adverse events were mild or moderate. CONCLUSION: Adjunctive GXR AM or GXR PM was associated with improvements in morning and evening ADHD symptoms in children and adolescents. PMID- 24071773 TI - Meta-analysis: parental interventions for preschool ADHD. AB - OBJECTIVE: Although psychostimulants are commonly utilized to treat preschoolers with ADHD, side effects and parental preferences limit their use in younger children. The current meta-analysis examines the efficacy of parent interventions for the treatment of ADHD in preschoolers. METHOD: We searched PubMed and the Cochrane Library for randomized, controlled trials comparing behavioral interventions for preschool children with ADHD. Our primary outcome measure was mean improvement in an ADHD rating scale compared with control conditions. RESULTS: Eight trials were included in the final analysis, totaling 399 participants. There was a significant benefit of parental behavioral interventions compared with control conditions (standardized mean difference [SMD] = 0.61, 95% confidence interval = [0.40, 0.83], z = 5.6, p < .001). CONCLUSION: The present meta-analysis provides preliminary evidence that parental interventions are an efficacious treatment for preschool ADHD. Future research is needed to compare the relative efficacy of parental interventions for ADHD with medication management and to determine if the combination of parental training and medication management is more effective than either condition alone. PMID- 24071775 TI - The Relation Between ADHD Symptoms and Alcohol Use in College Students. AB - OBJECTIVE: Although there is evidence to suggest an association between ADHD and alcohol use in college students, results are inconclusive primarily because studies have failed to control for related variables. Thus, this study was designed to systematically compare the relative contributions of inattention and hyperactivity/impulsivity to alcohol use and alcohol-related problems in a sample of college students while controlling for effects of antisocial behaviors. METHOD: A total of 192 undergraduate college students from a rural Midwestern university received class credit for participating in the study. They completed measures of alcohol use, ADHD symptoms, and antisocial behavior. RESULTS: Hierarchical regressions revealed inattention, but not hyperactivity/impulsivity, was related to alcohol-related problems even when controlling for antisocial behavior. However, neither inattention nor hyperactivity/impulsivity was related to alcohol use regardless of whether current antisocial behavior was controlled. CONCLUSION: Inattention may be an important factor related to alcohol-related problems in college students. PMID- 24071774 TI - Neurocognitive and Behavioral Predictors of Math Performance in Children With and Without ADHD. AB - OBJECTIVE: This study examined neurocognitive and behavioral predictors of math performance in children with and without ADHD. METHOD: Neurocognitive and behavioral variables were examined as predictors of (a) standardized mathematics achievement scores, (b) productivity on an analog math task, and (c) accuracy on an analog math task. RESULTS: Children with ADHD had lower achievement scores but did not significantly differ from controls on math productivity or accuracy. N back accuracy and parent-rated attention predicted math achievement. N-back accuracy and observed attention predicted math productivity. Alerting scores on the attentional network task predicted math accuracy. Mediation analyses indicated that n-back accuracy significantly mediated the relationship between diagnostic group and math achievement. CONCLUSION: Neurocognition, rather than behavior, may account for the deficits in math achievement exhibited by many children with ADHD. PMID- 24071776 TI - Development of a virtual reality training curriculum for phacoemulsification surgery. AB - PURPOSE: Training within a proficiency-based virtual reality (VR) curriculum may reduce errors during real surgical procedures. This study used a scientific methodology to develop a VR training curriculum for phacoemulsification surgery (PS). PATIENTS AND METHODS: Ten novice-(n) (performed <10 cataract operations), 10 intermediate-(i) (50-200), and 10 experienced-(e) (>500) surgeons were recruited. Construct validity was defined as the ability to differentiate between the three levels of experience, based on the simulator-derived metrics for two abstract modules (four tasks) and three procedural modules (five tasks) on a high fidelity VR simulator. Proficiency measures were based on the performance of experienced surgeons. RESULTS: Abstract modules demonstrated a 'ceiling effect' with construct validity established between groups (n) and (i) but not between groups (i) and (e)-Forceps 1 (46, 87, and 95; P<0.001). Increasing difficulty of task showed significantly reduced performance in (n) but minimal difference for (i) and (e)-Anti-tremor 4 (0, 51, and 59; P<0.001), Forceps 4 (11, 73, and 94; P<0.001). Procedural modules were found to be construct valid between groups (n) and (i) and between groups (i) and (e)-Lens-cracking (0, 22, and 51; P<0.05) and Phaco-quadrants (16, 53, and 87; P<0.05). This was also the case with Capsulorhexis (0, 19, and 63; P<0.05) with the performance decreasing in the (n) and (i) group but improving in the (e) group (0, 55, and 73; P<0.05) and (0, 48, and 76; P<0.05) as task difficulty increased. CONCLUSION: Experienced/intermediate benchmark skill levels are defined allowing the development of a proficiency-based VR training curriculum for PS for novices using a structured scientific methodology. PMID- 24071779 TI - Future for probiotic science in functional food and dietary supplement development. AB - PURPOSE OF REVIEW: The purpose of this study is to provide an update of probiotic science evolving from classical approaches to the development of next-generation probiotics, parallel to advances in the understanding of the complexity of the gut microbiome and its role in human health. RECENT FINDINGS: The probiotic concept is based on the notion that the gut ecosystem contributes to human physiology and, consequently, its modulation may help to maintain health and reduce disease risk. The understanding of the complexity of the gut microbiota and the specific components associated with progression from health to disease is rapidly increasing, thanks to the use of high-throughput and next-generation sequencing techniques in progressively better controlled epidemiological studies. Evidence on microbiome-mediated effects by intervention with classical probiotics on humans is, however, limited. The new information is helping to set a rationale for selection of a next generation of probiotics. Candidates include Clostridia clusters IV, XIVa and XVIII, Faecalibacterium prausnitzii, Akkermansia muciniphila and Bacteroides uniformis, the effects of which have been evaluated in preclinical trials with promising results for inflammatory and diet-related disorders. Yet, the extent to which new probiotic formulations consisting of nonconventional indigenous gut bacteria will be effective on humans at a population level or in personalized nutrition strategies remains to be explored. SUMMARY: Understanding the role that indigenous intestinal bacteria and their ecological interactions play in human health and disease based on epidemiological, intervention and mechanistic studies will provide a robust rationale for selection of probiotic strains and facilitate the optimization of integrated dietary strategies to efficiently modulate the human gut microbiome, leading to improvements in nutrition and clinical practice. PMID- 24071778 TI - The clinical and radiological status of contralateral ears in unilateral cholesteatoma patients. AB - PURPOSE: To evaluate the clinical and radiological features and the risk of middle ear disease in the contralateral ears of unilateral cholesteatoma with clinical and radiological assessment. METHODS: Fifty-two patients with unilateral cholesteatoma and 30 control subjects underwent otoscopic and audiologic examination. Temporal bone computed tomography was performed to evaluate the pneumatization of the temporal bones, the status of anterior epitympanic space and eustachian tube. Then, the parameters of the temporal bone pneumatization were calculated. RESULTS: 28% of the contralateral ears in the cholesteatoma patients showed abnormal tympanic membrane findings. In the audiologic examination, 10% of the contralateral ears showed moderate hearing loss and 3% showed severe hearing loss. Aeration areas were 1.81 +/- 1.01, 2.50 +/- 1.31 and 4.49 +/- 1.45 cm(2), aeration ratios were 24, 28 and 42%, in cholesteatoma, contralateral and control ears, respectively. Development of the anterior epitympanic space and eustachian tube patency was reduced in contralateral ears relative to control ears. CONCLUSIONS: The degree of temporal bone pneumatization, eustachian tube function, and development of the anterior epitympanic space are significantly decreased in the contralateral ears of unilateral cholesteatoma patients, and there is an increased risk of middle ear diseases. Continuous monitoring of the contralateral ear is crucial for early detection and optimal treatment of middle ear disease. PMID- 24071777 TI - CARMIL leading edge localization depends on a non-canonical PH domain and dimerization. AB - CARMIL is an approximately 1,370-amino-acid cytoskeletal scaffold that has crucial roles in cell motility and tissue development through interactions with cytoskeletal effectors and regulation of capping protein at the leading edge. However, the mechanism of CARMIL leading edge localization is unknown. Here we show that CARMIL interacts directly with the plasma membrane through its amino terminal region. The crystal structure of CARMIL1-668 reveals that this region harbours a non-canonical pleckstrin homology (PH) domain connected to a 16 leucine-rich repeat domain. Lipid binding is mediated by the PH domain, but is further enhanced by a central helical domain. Small-angle X-ray scattering reveals that the helical domain mediates antiparallel dimerization, properly positioning the PH domains for simultaneous membrane interaction. In cells, deletion of the PH domain impairs leading edge localization. The results support a direct membrane-binding mechanism for CARMIL localization at the leading edge, where it regulates cytoskeletal effectors and motility. PMID- 24071780 TI - Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection. AB - PURPOSE OF REVIEW: This review focuses upon the biology and metabolism of a trace component in foods called nicotinamide riboside. Nicotinamide riboside is a precursor of nicotinamide adenine dinucleotide (NAD), and is a source of Vitamin B3. Evidence indicates that nicotinamide riboside has unique properties as a Vitamin B3. We review knowledge of the metabolism of this substance, as well as recent work suggesting novel health benefits that might be associated with nicotinamide riboside taken in larger quantities than is found naturally in foods. RECENT FINDINGS: Recent work investigating the effects of nicotinamide riboside in yeast and mammals established that it is metabolized by at least two types of metabolic pathways. The first of these is degradative and produces nicotinamide. The second pathway involves kinases called nicotinamide riboside kinases (Nrk1 and Nrk2, in humans). The likely involvement of the kinase pathway is implicated in the unique effects of nicotinamide riboside in raising tissue NAD concentrations in rodents and for potent effects in eliciting insulin sensitivity, mitochondrial biogenesis, and enhancement of sirtuin functions. Additional studies with nicotinamide riboside in models of Alzheimer's disease indicate bioavailability to brain and protective effects, likely by stimulation of brain NAD synthesis. SUMMARY: Initial studies have clarified the potential for a lesser-known Vitamin B3 called nicotinamide riboside that is available in selected foods, and possibly available to humans by supplements. It has properties that are insulin sensitizing, enhancing to exercise, resisting to negative effects of high-fat diet, and neuroprotecting. PMID- 24071784 TI - Polar surface effects on the thermal conductivity of ZnO nanowires: a shell-like surface reconstruction-induced preserving mechanism. AB - We perform molecular dynamics (MD) simulations to investigate the effect of polar surfaces on the thermal transport in zinc oxide (ZnO) nanowires. We find that the thermal conductivity of nanowires with free polar (0001) surfaces is much higher than that of nanowires that have been stabilized with reduced charges on the polar (0001) surfaces, and also hexagonal nanowires without any transverse polar surface, where the reduced charge model has been proposed as a promising stabilization mechanism for the (0001) polar surfaces of ZnO nanowires. From normal mode analysis, we show that the higher thermal conductivity is due to the shell-like reconstruction that occurs for the free polar surfaces. This shell like reconstruction suppresses twisting motion in the nanowires such that the bending phonon modes are not scattered by the other phonon modes, and this leads to substantially higher thermal conductivity of the ZnO nanowires with free polar surfaces. Furthermore, the auto-correlation function of the normal mode coordinate is utilized to extract the phonon lifetime, which leads to a concise explanation for the higher thermal conductivity of ZnO nanowires with free polar surfaces. Our work demonstrates that ZnO nanowires without polar surfaces, which exhibit low thermal conductivity, are more promising candidates for thermoelectric applications than nanowires with polar surfaces (and also high thermal conductivity). PMID- 24071782 TI - Coffee and tea: perks for health and longevity? AB - PURPOSE OF REVIEW: Tea and coffee, after water, are the most commonly consumed beverages in the world and are the top sources of caffeine and antioxidant polyphenols in the American diet. The purpose of this review is to assess the health effects of chronic tea and/or coffee consumption. RECENT FINDINGS: Tea consumption, especially green tea, is associated with significantly reduced risks for stroke, diabetes and depression, and improved levels of glucose, cholesterol, abdominal obesity and blood pressure. Habitual coffee consumption in large epidemiological studies is associated with reduced mortality, both for all-cause and cardiovascular deaths. In addition, coffee intake is associated with risks of heart failure, stroke, diabetes mellitus and some cancers in an inverse dose dependent fashion. Surprisingly, coffee is associated with neutral to reduced risks for both atrial and ventricular arrhythmias. However, caffeine at high doses can increase anxiety, insomnia, calcium loss and possibly the risk of fractures. SUMMARY: Coffee and tea can generally be recommended as health promoting additions to an adult diet. Adequate dietary calcium intake may be particularly important for tea and coffee drinkers. PMID- 24071781 TI - Diet and cognition: interplay between cell metabolism and neuronal plasticity. AB - PURPOSE OF STUDY: To discuss studies in humans and animals revealing the ability of foods to benefit the brain: new information with regards to mechanisms of action and the treatment of neurological and psychiatric disorders. RECENT FINDINGS: Dietary factors exert their effects on the brain by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Energy metabolism influences neuronal function, neuronal signaling, and synaptic plasticity, ultimately affecting mental health. Epigenetic regulation of neuronal plasticity appears as an important mechanism by which foods can prolong their effects on long-term neuronal plasticity. SUMMARY: The prime focus of the discussion is to emphasize the role of cell metabolism as a mediator for the action of foods on the brain. Oxidative stress promotes damage to phospholipids present in the plasma membrane such as the omega-3 fatty acid docosahexenoic acid, disrupting neuronal signaling. Thus, dietary docosahexenoic acid seems crucial for supporting plasma membrane function, interneuronal signaling, and cognition. The dual action of brain-derived neurotrophic factor in neuronal metabolism and synaptic plasticity is crucial for activating signaling cascades under the action of diet and other environmental factors, using mechanisms of epigenetic regulation. PMID- 24071785 TI - Two three-dimensional porous frameworks built from metal-organic coordination polymer sheets pillared by polyoxometalate clusters. AB - Two new porous frameworks [Ni(bix)2][VW12O40].(H2bix).H2O (1) and [Co(bix)2][VW12O40].(H2bix).2H2O (2) (bix = 1,4-bis(imidazol-1-ylmethyl)-benzene) composed of Keggin polyoxometalates (POMs) and metal-organic coordination polymer sheets have been successfully obtained, and characterized by elemental analysis, IR spectra, thermal gravimetric analysis, and single crystal X-ray diffraction. Structural analysis reveals that the 2D metal-organic coordination polymer sheets in the two compounds are constructed from the transition-metal (TM) cations and the flexible N-donor ligand bix, which are further pillared by POM clusters into the 3D porous frameworks. Powder X-ray diffraction (PXRD) patterns of 1 indicate the structural integrity of the framework in aqueous solution with a wide pH range of 1 to 11, and in common organic solvents (methanol, ethanol and DMF). Photocatalytic studies indicate that compounds 1 and 2 are not only active photocatalysts for degradation of rhodamine B (RB), but very stable and easily separated from the photocatalytic system for reuse as well. PMID- 24071787 TI - Hexabromocyclododecane facilitates FSH activation of ERK1/2 and AKT through epidermal growth factor receptor in rat granulosa cells. AB - The toxicity of hexabromocyclododecane (HBCDD) has been extensively studied; however, the mechanism and the effects of HBCDD on female reproductive system have been less frequently reported. In this study, we exposed rat granulosa cells to HBCDD during in vitro follicle-stimulating hormone (FSH)-driven cell proliferation and differentiation. Here, we show that HBCDD affects the FSH driven signal transduction and ovulatory competence of granulosa cells. We found that HBCDD over-activates the FSH-stimulated extracellular-regulated kinase 1/2 (ERK1/2) and protein kinase B (PKB, also known as AKT). Inactivation of the epidermal growth factor receptor (EGFR) kinase activity with AG1478 and the mitogen-regulated kinase activity with U0126 completely prevented ERK1/2 activation in the FSH-stimulated and HBCDD-exposed granulosa cells. Moreover, AG1478 restored the HBCDD-induced AKT activation to the level observed in the FSH stimulated cells. Western blot shows that HBCDD potentiates FSH-stimulated EGFR phosphorylation in granulosa cells. Real-time PCR demonstrates that HBCDD decreases the FSH-induced luteinizing hormone receptor (Lhr) expression. Inadequate level of LHR in the HBCDD-exposed granulosa cells prevented human chorionic gonadotropin in stimulating expression of the ovulatory genes such as amphiregulin (Areg), epiregulin (Ereg), and progesterone receptor (Pgr). Addition of U0126 and AG1478 restored Lhr level in the FSH-stimulated and HBCDD-exposed granulosa cells. These results indicate a direct effect of HBCDD on EGFR activation, resulting in over-activation of ERK1/2 and AKT signal transduction pathways in the FSH-treated cells. Increased activity of the EGFR-ERK1/2 pathway above physiological level prevents sufficient acquisition of LHR in proliferating granulosa cells, thus compromising ovulation. PMID- 24071788 TI - Kinetic interactions of a neuropathy potentiator (phenylmethylsulfonyl fluoride) with the neuropathy target esterase and other membrane bound esterases. AB - Phenylmethylsulfonyl fluoride (PMSF) is a protease and esterase inhibitor that causes protection, or potentiation/"promotion," of organophosphorus delayed neuropathy (OPIDN), depending on whether it is dosed before or after an inducer of delayed neuropathy, such as mipafox. The molecular target of the potentiation/promotion of OPIDN has not yet been identified. The kinetic data of phenyl valerate esterase inhibition by PMSF were obtained with membrane chicken brain fractions, the animal model and tissue in which neuropathy target esterase (NTE) was first described. Data were analyzed using a kinetic model with a multienzymatic system in which inhibition, simultaneous chemical hydrolysis of the inhibitor and "ongoing inhibition" (inhibition during the substrate reaction) were considered. Three main esterase components were discriminated: two sensitive enzymatic entities representing 44 and 41 %, with I 50 (20 min) of 35 and 198 MUM at 37 degrees C, respectively, and a resistant fraction of 15 % of activity. The estimated constant of the chemical hydrolysis of PMSF was also calculated (kh = 0.28 min(-1)). Four esterase components were globally identified considering also previously data with paraoxon and mipafox: EPalpha (4-8 %), highly sensitive to paraoxon and mipafox, spontaneously reactivates after inhibition with paraoxon, and resistant to PMSF; EPbeta (38-41 %), sensitive to paraoxon and PMSF, but practically resistant to mipafox, this esterase component has the kinetic characteristics expected for the PMSF potentiator target, even though paraoxon cannot be a potentiator in vivo due to high AChE inhibition; EPgamma (NTE) (39-48 %), paraoxon-resistant and sensitive to the micromolar concentration of mipafox and PMSF; and EPdelta (10 %), resistant to all the inhibitors assayed. This kinetic characterization study is needed for further isolation and molecular characterization studies, and these PMSF phenyl valerate esterase components will have to be considered in further studies of OPIDN promotion. A simple test for monitoring the four esterase components is proposed. PMID- 24071789 TI - Development of coated-wire silver ion selective electrodes on paper using conductive films of silver nanoparticles. AB - Films of silver nanoparticles are used for the first time as an electrical conductor and ion-to-electron transducer to fabricate coated-wire ion selective electrodes (ISEs) on paper. The film of nano silver ink (nano silver film), synthesized from the reduction of AgNO3 by NaBH4, was screen printed on paper. Transmission electron microscopy showed that the synthesized silver nanoparticles (AgNPs) possessed a spherical shape with diameter ca. 5 nm. Energy-dispersive X ray spectroscopy supported the purity and good stability of the synthesized AgNPs. Nano silver films were sintered at room temperature, 100 degrees C and 200 degrees C. Upon increasing the sintering temperature, atomic force microscopy showed that the size of AgNPs of nano silver films increased, but the sheet resistivity decreased. Silver ISEs were then fabricated from nano silver films and o-NPOE-plasticized polymeric membranes containing benzothiazolyl calix[4]arene () as ionophore and KTpClPB as anionic site. The performance of the developed Ag-ISEs was investigated by potentiometric measurements, potentiometric water layer tests, current reversal chronopotentiometry and electrochemical impedance spectroscopy. The coated-wire electrode fabricated from the nano silver film sintering at room temperature showed the best characteristics of Ag-ISEs giving a near Nernstian response slope of 59.7 +/- 1.0 mV per decade, 10(-6) to 10(-2) M linear range, detection limit of 4.5 * 10(-7) M, long-term potential stability and good reversibility. PMID- 24071790 TI - Association of Psychosocial Factors and Heart Rate Variability in Heart Failure Patients. AB - The purpose of this study was to examine the association of psychosocial factors (depression, social support, and health-related quality of life) with heart rate variability (HRV) in patients with heart failure. The sample comprised 91 outpatients from a medical center. Data were collected using the Beck Depression Inventory-II, Medical Outcomes Study (MOS) Social Support Survey, and Minnesota Living With Heart Failure Questionnaire. HRV was measured in terms of time-domain parameters from a 24-hr ambulatory Holter electrocardiogram. After adjusting for demographic and clinical variables, quality of life and social support were significantly associated with HRV. HRV (time-domain measures) was significantly higher in patients who perceived better quality of life and more social support. Our findings suggest that nurses could screen early for patients' risk of adverse psychosocial conditions and suggest online or other social supportive interventions to help at-risk patients minimize the negative associations with HRV. PMID- 24071791 TI - Oxygen consumption rates in subseafloor basaltic crust derived from a reaction transport model. AB - Oceanic crust is the largest potential habitat for life on Earth and may contain a significant fraction of Earth's total microbial biomass; yet, empirical analysis of reaction rates in basaltic crust is lacking. Here we report the first assessment of oxygen consumption in young (~8 Ma) and cool (<25 degrees C) basaltic crust, which we calculate from modelling dissolved oxygen and strontium pore water gradients in basal sediments collected during Integrated Ocean Drilling Program Expedition 336 to 'North Pond' on the western flank of the Mid Atlantic Ridge. Dissolved oxygen is completely consumed within the upper to middle section of the sediment column, with an increase in concentration towards the sediment-basement interface, indicating an upward supply from oxic fluids circulating within the crust. A parametric reaction transport model of oxygen behaviour in upper basement suggests oxygen consumption rates of 1 nmol cm( 3)ROCK d(-1) or less in young and cool basaltic crust. PMID- 24071792 TI - Familial incidence and associated symptoms in a population of individuals with nonsyndromic craniosynostosis. AB - PURPOSE: Craniosynostosis is a common cranial malformation occurring in 1 per 2,000-2,500 births. Isolated defects (nonsyndromic) occur in ~75% of cases and are thought to have multifactorial etiology. It is believed that each suture synostosis is a distinct disease, with varying phenotypes and recurrence rates. METHODS: We analyzed family histories of 660 mutation-negative nonsyndromic craniosynostosis patients and symptoms in 189 of these patients. RESULTS: The incidence rate of craniosynostosis was highest for first-degree relatives of probands with metopic craniosynostosis (6.4%), followed by those with complex craniosynostosis (4.9%), sagittal craniosynostosis (3.8%), lambdoid craniosynostosis (3.9%), and coronal craniosynostosis (0.7%). Across all suture types, siblings had a greater craniosynostosis incidence rate than parents (7.5 vs. 2.3%). In phenotype comparisons, patients with complex craniosynostosis had the highest frequency of reported symptoms and those with sagittal craniosynostosis had the lowest. Ear infections, palate abnormalities, and hearing problems were more common in complex craniosynostosis patients. Visual problems were more common in coronal craniosynostosis, and metopic craniosynostosis patients noted increased frequency of chronic cough. CONCLUSION: Our data suggest that the genetic component of nonsyndromic craniosynostosis appears to be suture specific. The incidence rate of craniosynostosis among first degree relatives varies by suture and family member. Additionally, the phenotype of each suture synostosis shows both unique and shared features. PMID- 24071793 TI - ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. AB - Microarray methodologies, including array comparative genomic hybridization and single-nucleotide polymorphism-detecting arrays, are accepted as an appropriate first-tier test for the evaluation of imbalances associated with intellectual disability, autism, and multiple congenital anomalies. This technology also has applicability in prenatal specimens. To assist clinical laboratories in validation of microarray methodologies for constitutional applications, the American College of Medical Genetics and Genomics has produced the following revised professional standards and guidelines. PMID- 24071794 TI - A survey of informatics approaches to whole-exome and whole-genome clinical reporting in the electronic health record. AB - PURPOSE: Genome-scale clinical sequencing is being adopted more broadly in medical practice. The National Institutes of Health developed the Clinical Sequencing Exploratory Research (CSER) program to guide implementation and dissemination of best practices for the integration of sequencing into clinical care. This study describes and compares the state of the art of incorporating whole-exome and whole-genome sequencing results into the electronic health record, including approaches to decision support across the six current CSER sites. METHODS: The CSER Medical Record Working Group collaboratively developed and completed an in-depth survey to assess the communication of genome-scale data into the electronic health record. We summarized commonalities and divergent approaches. RESULTS: Despite common sequencing platform (Illumina) adoptions, there is a great diversity of approaches to annotation tools and workflow, as well as to report generation. At all sites, reports are human-readable structured documents available as passive decision support in the electronic health record. Active decision support is in early implementation at two sites. CONCLUSION: The parallel efforts across CSER sites in the creation of systems for report generation and integration of reports into the electronic health record, as well as the lack of standardized approaches to interfacing with variant databases to create active clinical decision support, create opportunities for cross-site and vendor collaborations. PMID- 24071795 TI - "Is a cure in my sight?" Multi-stakeholder perspectives on phase I choroideremia gene transfer clinical trials. AB - PURPOSE: Ocular gene transfer clinical trials are raising patient hopes for the treatment of choroideremia--a blinding degenerative retinopathy. Phase I choroideremia gene transfer trials necessitate communicating about the risks of harm and potential benefits with patients while avoiding the sensationalism that has historically undermined this field of translational medicine. METHODS: We conducted interviews between June 2011 and June 2012 with 6 choroideremia patient advocates, 20 patients, and 15 clinicians about their hopes for benefits, perceived risks of harm, and hopes for the time frame of clinical implementation of choroideremia gene transfer. RESULTS: Despite the safety focus of phase I trials, participants hoped for direct visual benefits with evident discrepancies between stakeholder perspectives about the degree of visual benefit. Clinicians and patient advocates were concerned by limited patient attention to risks of harm. Interviews revealed confusion about the time frames for the clinical implementation of choroideremia gene transfer and patient urgency to access gene transfer within a limited therapeutic window. CONCLUSION: Differences in stakeholder perspectives about choroideremia gene transfer necessitate strategies that promote responsible communications about choroideremia gene transfer and aid in its translation. Strategies should counter historical sensationalism associated with gene transfer, promote informed consent, and honor patient hope while grounding communications in current clinical realities. PMID- 24071796 TI - Factors affecting maternal participation in the genetic component of the National Birth Defects Prevention Study-United States, 1997-2007. AB - PURPOSE: As epidemiological studies expand to examine gene-environment interaction effects, it is important to identify factors associated with participation in genetic studies. The National Birth Defects Prevention Study is a multisite case-control study designed to investigate environmental and genetic risk factors for major birth defects. The National Birth Defects Prevention Study includes maternal telephone interviews and mailed buccal cell self-collection kits. Because subjects can participate in the interview, independent of buccal cell collection, detailed analysis of factors associated with participation in buccal cell collection was possible. METHODS: Multivariable logistic regression models were used to identify the factors associated with participation in the genetic component of the study. RESULTS: Buccal cell participation rates varied by race/ethnicity (non-Hispanic whites, 66.9%; Hispanics, 60.4%; and non-Hispanic blacks, 47.3%) and study site (50.2-74.2%). Additional monetary incentive following return of buccal cell kit and shorter interval between infant's estimated date of delivery and interview were associated with increased participation across all racial/ethnic groups. Higher education and delivering an infant with a birth defect were associated with increased participation among non Hispanic whites and Hispanics. CONCLUSION: Factors associated with participation varied by race/ethnicity. Improved understanding of factors associated with participation may facilitate strategies to increase participation, thereby improving generalizability of study findings. PMID- 24071797 TI - Recommendations from the EGAPP Working Group: does PCA3 testing for the diagnosis and management of prostate cancer improve patient health outcomes? AB - SUMMARY OF RECOMMENDATIONS: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found insufficient evidence to recommend prostate cancer antigen 3 (PCA3) testing to inform decisions for when to rebiopsy previously biopsy-negative patients for prostate cancer or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (e.g., previous elevated prostate-specific antigen test or suspicious digital rectal examination).The EGAPP Working Group found insufficient evidence to recommend PCA3 testing in men with cancer-positive biopsies to determine if the disease is indolent or aggressive in order to develop an optimal treatment plan.Based on the available evidence, the overall certainty of clinical validity to predict the diagnosis of prostate cancer using PCA3 is deemed "low." The EGAPP Working Group discourages clinical use for diagnosis unless further evidence supports improved clinical validity.Based on the available evidence, the overall certainty of net health benefit is deemed "low." The EGAPP Working Group discourages clinical use unless further evidence supports improved clinical outcomes. RATIONALE: It has been suggested that PCA3 testing in the general male population might lead to earlier diagnosis and management changes (e.g., earlier detection and earlier initiation or higher rates of medical interventions) that improve outcomes. EGAPP Working Group found no direct evidence to support this possibility, so we sought indirect evidence aimed at documenting the extent to which PCA3 testing alters prostate cancer diagnosis or management, alone and in combination with traditional clinical management factors, and the extent to which this testing improves health outcomes. ANALYTIC VALIDITY: Assay-related evidence was deemed adequate for the PROGENSA PCA3 assay approved by the US Food and Drug Administration, available from Gen-Probe. Very few studies were available that investigated preanalytical effects, analytical performance, and diagnostic accuracy of other quantitative assays for PCA3. CLINICAL VALIDITY: Evidence on clinical validity was rated inadequate to derive any conclusions about performance of PCA3 testing to inform decisions for when to rebiopsy previously biopsy-negative patients for prostate cancer, or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (e.g., previous elevated prostate-specific antigen test or suspicious digital rectal examination). Furthermore, there was little evidence to derive any conclusions about performance of PCA3 testing in men with cancer-positive biopsies to determine if the disease is indolent or aggressive in order to develop an optimal treatment plan. CLINICAL UTILITY: No studies were available to provide direct evidence on the balance of benefits and harms related to PCA3 testing for diagnosis and management in the general male population. Evidence for other populations (e.g., high risk) was not evaluated in the review. CONTEXTUAL ISSUES: Early diagnosis of prostate cancer is central to minimizing morbidity and mortality. Prevention of prostate cancer mortality is a public health priority. Improvements in outcomes associated with PCA3 testing could have important impacts. PMID- 24071798 TI - Practical challenges in integrating genomic data into the electronic health record. AB - Genetic testing has had limited impact on routine clinical care. Widespread adoption of electronic health records presents a promising means of disseminating genetic testing into diverse care settings. Practical challenges to integration of genomic data into electronic health records include size and complexity of genetic test results, inadequate use of standards for clinical and genetic data, and limitations in electronic health record capacity to store and analyze genetic data. Related challenges include uncertainty in the interpretation of regulatory requirements for return of results, and privacy concerns specific to genetic testing. Successful integration of genomic data may require significant redesign of existing electronic health record systems. PMID- 24071800 TI - Personalized medicine and genetic malpractice. PMID- 24071799 TI - The undiscovered country: the future of integrating genomic information into the EHR. PMID- 24071801 TI - Processes and factors involved in decisions regarding return of incidental genomic findings in research. AB - PURPOSE: Studies have begun exploring whether researchers should return incidental findings in genomic studies, and if so, which findings should be returned; however, how researchers make these decisions-the processes and factors involved-has remained largely unexplored. METHODS: We interviewed 28 genomics researchers in-depth about their experiences and views concerning the return of incidental findings. RESULTS: Researchers often struggle with questions concerning which incidental findings to return and how to make those decisions. Multiple factors shape their views, including information about the gene variant (e.g., pathogenicity and disease characteristics), concerns about participants' well-being and researcher responsibility, and input from external entities. Researchers weigh the evidence, yet they face conflicting pressures, with relevant data frequently being unavailable. Researchers vary in who they believe should decide: participants, principal investigators, institutional review boards, and/or professional organizations. Contextual factors can influence these decisions, including policies governing return of results by institutions and biobanks and the study design. Researchers vary in desires for: guidance from institutions and professional organizations, changes to current institutional processes, and community-wide genetics education. CONCLUSION: These data, the first to examine the processes by which researchers make decisions regarding the return of genetic incidental findings, highlight several complexities involved and have important implications for future genetics research, policy, and examinations of these issues. PMID- 24071802 TI - Effects of different metal ions on the fluorescence of CdSe/ZnS quantum dots capped with various thiolate ligands. AB - In this report, we systematically studied the effects of different metal ions on the fluorescence of common thiolate ligand capped quantum dots. Generally, heavy metal ions exhibited much more significant fluorescence quenching. Also, the coordination capability and steric hindrance of the ligand jointly affect the quenching efficiency. PMID- 24071803 TI - Stable bending performance of flexible organic light-emitting diodes using IZO anodes. AB - We report luminescent characteristics and mechanical stability of a flexible organic light-emitting diode (FOLED) using an amorphous ZnO-doped In2O3 (a-IZO) anode with a low sheet resistance of and a high optical transparency of 86%. The FOLED consisting of a-IZO/poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS)/poly[(9,9-di-n-octylfluorenyl-2,7-diyl)-alt-(benzo[2,1,3]thiadiazol 4, 8-diyl)] (F8BT)/LiF/Al exhibits the efficient luminescent characteristics, which are nearly identical with the photoluminescence spectrum of the organic emitting material in our FOLED. This observation clearly indicates that the luminescent characteristics of the FOLED are solely ascribed to molecular exciton formation within the F8BT layer, since exciplex and charge transfer exciton formation are strictly suppressed by both tunneling/thermionic injection of holes at the PEDOT:PSS/F8BT interface and enhanced hole transport. Furthermore, the use of the considerably flexible a-IZO anode and PEDOT:PSS acting as a strain-relief buffering material enables good retention of the efficient luminescent characteristics of the FOLED even after continuous bending of up to 1000 times. PMID- 24071804 TI - The versatile behaviour of a novel Janus scorpionate ligand towards sodium, potassium and bismuth(III) ions. AB - Alkali metal salts of a novel Janus scorpionate ligand [(Tr(Me))](-) with hard and soft donor sites (N, S) were synthesized by the reaction of 3-mercapto-4 methyl-1,2,4-triazole (L) with NaBH4 and KBH4, respectively, via Trofimenko's protocol. The resulting compounds were the sodium and potassium complexes [Na(Tr(Me))] (1), [K(Tr(Me))] (2) and the mixed ion compound [KNa(Tr(Me))] (3). [K(Tr(Me))] (2) was reacted with bismuth(III) chloride to afford the complexes [Bi(Tr(Me))(Cl)(MU-Cl)2]2 (5) and [Bi(Tr(Me))(Cl)2(MU-Cl)]n (6). Compound 5 was formed when 2 was applied to BiCl3 in a molar ratio 2:1, while 6 was achieved when a ratio of 1:1 was used. The reaction of 3-mercapto-4-methyl-1,2,4-triazole (L) with BiCl3 led to the formation of the complex [Bi(L)4(Cl)2]Cl (7). The products were characterized by NMR and IR spectroscopy, elemental analyses and mass spectrometry. Solid state structures were determined by X-ray diffraction of single crystals of 1, 3, 3a, 5, 6 and 7. The alkali metal scorpionates 1-3 are coordination polymers with alternating orientation of the ligands. They dissociate in solution as observed in NMR measurements. Negative mode ESI-MS data also indicate the presence of monomers. The bismuth complex 5 is dimeric and 6 is polymeric, and both are bridged via chloro ligands. The three bismuth complexes 5, 6 and 7 have highly distorted octahedral coordination geometries. The influence of the stereochemically active lone pair was found to be most pronounced in the dimeric complex 5. The ligand Tr(Me) and all bismuth complexes were also screened for their photo-luminescence activity. Whereas solutions of Tr(Me) exhibit no luminescence, 7 is only emissive at 77 K, and 5 is emissive both at r.t. and 77 K. PMID- 24071805 TI - Preoperative graft thickness measurements do not influence final BSCVA or speed of vision recovery after descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To evaluate the influence of preoperative graft thickness (GT) on final visual acuity and speed of vision recovery after Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: The best spectacle-corrected acuity (BSCVA) was measured after DSAEK was performed at 1, 3, 6, 12, and 24 months. A regression analysis was performed to determine whether GT predicted the BSCVA across each time gate. The time to achieve the "1-year maximum BSCVA" was determined to assess the "speed" of recovery for all eyes that had data at 1, 3, 6, and 12 months. Additionally, the final BSCVA was compared between 2 distinct groups of "thin" (<125-MUm) versus "thick" (>165-MUm) tissue. RESULTS: There were 144 eyes evaluated. No significant correlations were found between the GT and the BSCVA at any of the time gates: 1, 3, 6, 12, or 24 months. Speed of vision recovery was not affected by the GT. The average GT values of the eyes that achieved BSCVA by 1, 3, 6 months and 1 year were not significantly different and were 154.7, 141.3, 149, and 150.1 MUm, respectively. No difference was found between the BSCVA of "thick" versus "thin" tissues at any of the time gates: 1, 3, 6, or 12 months. CONCLUSIONS: Preoperative GT measurements were not correlated with the BSCVA after the DSAEK was performed at 1, 6, 12, or 24 months postoperatively and do not determine the speed of vision recovery. Additionally, no difference was found in postoperative vision outcomes when directly comparing tissues at either end of the GT spectrum of this study. PMID- 24071806 TI - Better surgical method for removing perfluorocarbon liquids from the anterior chamber. AB - PURPOSE: To describe a surgical method for removing perfluorocarbon liquids from the anterior chamber. METHODS: Perfluorodecalin was noted in the anterior chamber in 2 patients after a vitreoretinal surgery was performed. We removed the perfluorodecalin by using a Rycroft cannula mounted on the tip of a tuberculin syringe with continued irrigation by means of an anterior chamber maintainer. RESULTS: The perfluorodecalin was removed using a single intervention. We did not observe any perfluorodecalin residue in subsequent postoperative examinations in either patient. CONCLUSIONS: The method is simple and safe, and it allows the complete removal of perfluorocarbon liquids from the anterior chamber using a single intervention. PMID- 24071807 TI - Oral buccal mucous membrane allograft with a corneal lamellar graft for the repair of Boston type 1 keratoprosthesis stromal melts. AB - PURPOSE: To describe a surgical technique to repair Boston type 1 keratoprosthesis (KPro)-related corneal melts. METHODS: Technique description and review of 3 representative cases. RESULTS: After harvesting the buccal mucosa from the patient's inner lower lip, the exposed area of the KPro back plate is prepared for repair by adequate exposure and removal of necrotic tissue. The area is then covered with a lamellar patch of cornea secured in place with interrupted 10-0 nylon sutures, followed by a thin layer of buccal mucosa secured in place with interrupted 8-0 vicryl sutures. CONCLUSIONS: This technique provides surgeons with a method to repair KPro-related corneal melts when there is a conjunctival deficiency. PMID- 24071808 TI - Use of accidentally torn descemet membrane to successfully complete descemet membrane endothelial keratoplasty. AB - PURPOSE: To describe the use of an accidentally torn Descemet membrane (DM) to successfully complete Descemet membrane endothelial keratoplasty (DMEK) surgery. METHODS: Retrospective, observational case series of 3 eyes of 3 patients undergoing DMEK with a DM accidentally torn into 2 pieces during graft preparation. The mean outcome measures included best-corrected visual acuity, endothelial cell density, and central corneal thickness, before and at 1, 3, and 6 months after the DMEK surgery was performed. RESULTS: During graft preparation, immediately before transplantation, a large tear within the 8.0-mm marking line of the DM occurred, resulting in a DM torn into 2 pieces. In all the eyes, both pieces were successfully implanted into the anterior chamber, unfolded and attached to the posterior corneal stroma, one after the other. Six months after the surgery was performed, the best-corrected visual acuity ranged between 20/30 and 20/25. Endothelial cell loss was about 30% (range 28%-32%) 6 months after the surgery. Pachymetry findings showed normal corneal thickness 6 months after the surgery. All corneas remained clear without any signs of graft failure within 6 months of follow-up. CONCLUSIONS: DMEK surgery can be successfully completed despite the accidental tearing of donor DMs during the preparation of DMEK grafts by the sequential implantation of both DM pieces. PMID- 24071809 TI - Mapping corneal thickness using dual-scheimpflug imaging at different stages of keratoconus. AB - PURPOSE: To map the thickness of the entire cornea using dual-Scheimpflug imaging and to evaluate the changes in the corneal thickness over the entire cornea at different stages of keratoconus. METHODS: Corneal pachymetry was performed using the Galilei dual-Scheimpflug analyzer. The thinnest (TCT), central (CCT), paracentral (PaCT), and peripheral corneal thicknesses (PeCT) were also analyzed. The study examined 150 eyes of 150 patients who had myopia or myopic astigmatism and 107 eyes of 75 patients with keratoconus. Of these 107 eyes, 48 were evaluated at stage I keratoconus, 32 at stage II, 12 at stage III, and 15 at stage IV keratoconus. The level of severity of the keratoconus was based on the Amsler-Krumeich classification. RESULTS: There were significant decreases in the thickness values of the entire corneas at all the different stages of progression defined in the Amsler-Krumeich classification. Analysis of the receiver operating characteristic curve showed that the TCT provided a better parameter than did the CCT, PaCT, and PeCT for distinguishing between keratoconus at its different stages and myopic eyes. Although the TCT and CCT parameters provided an effective distinction of eyes with stage II, III, and IV keratoconus from normal eyes, they were not effective for discriminating eyes with stage I keratoconus from eyes with myopia. But, PaCT and PeCT parameters enabled the effective discrimination between eyes with stage IV keratoconus and those with myopia only. CONCLUSIONS: The data obtained by dual-Scheimpflug imaging for the corneal thicknesses of the entire cornea provide useful information for grading the severity of keratoconus. PMID- 24071810 TI - Intracorneal ring segment explantation after intracorneal ring segment implantation combined with same-day corneal collagen crosslinking in keratoconus. AB - PURPOSE: To report the outcome and the reversibility of refractive outcomes after intrastromal corneal ring segment (ICRS) explantation in patients with keratoconus treated with ICRS implantation and same-day collagen crosslinking (CXL). METHODS: This is a retrospective review of ICRS explantation in 3 eyes of 3 patients with keratoconus that had undergone femtosecond laser-enabled placement of paired ICRS (Intacs) with same-day CXL by a single surgeon between 2008 and 2011. The main outcome measures included baseline/preexplantation/postexplantation visual acuity, refractive error, keratometry, and higher order aberrations. RESULTS: None of the patients lost best-corrected distance visual acuity lines. ICRS can be safely and easily explanted from keratoconic eyes with previous CXL. Some of the topographic benefits gained from ICRS implantation may persist after explantation. CONCLUSIONS: Despite the reversal of refractive outcomes, the preservation of topographic changes may occur in some cases after the explantation of 1 or both the segments in patients with keratoconus treated with ICRS implantation with same-day CXL. PMID- 24071811 TI - Decoding the language of epigenetics during neural development is key for understanding development as well as developmental neurotoxicity. AB - Neural development is a delicate process that can be disrupted by pollution that exerts detrimental impact on neural signaling. This commentary highlights recent discoveries in the arena of research at the interface of environmental toxicology and developmental neuroscience relating to toxicity mechanisms of bisphenol A (BPA), a ubiquitous chemical used in manufacturing of plastics and epoxy resins that is known to bind to and interfere with estrogen receptors, estrogen-receptor related receptors and other receptors for gonadal steroids. It was recently observed that BPA disrupts the perinatal chloride shift, a key neurodevelopmental mechanism that brings down neuronal chloride from ~100 mM to ~20 mM within weeks. The chloride shift happens in all central nervous systems of vertebrates around parturition. High neuronal chloride supports neuron precursors' migrations, low neuronal chloride is the prerequisite for inhibitory action of neurotransmitters GABA and glycine, and thus an absolute requisite for normal functioning of the mature CNS. One critical contributor to the neuronal chloride shift is the concomitant upregulation of expression of the chloride-extruding transporter molecule, KCC2. We highlight recent findings including our discovery that BPA disrupts the chloride shift in a sex-specific manner by recruiting epigenetics mechanisms. These could be relevant for childhood neuropsychiatric disorders as well as for liability to develop chronic neuropsychiatric diseases later in life. PMID- 24071812 TI - Morphological and molecular analysis calls for a reappraisal of the red rain cells of Kerala. AB - Early studies on the coloured particles that fell as red rain over southern India identified them as unicellular eukaryotes such as members of the red algae or fungi; however, the results of the present investigation are not consistent with this designation. Using transmission electron microscopy, we have demonstrated significant differences in the ultrastructure when compared with representative species from these other groups. Most notably, the red rain cells show no evidence of typical eukaryotic internal structures such as mitochondria or endoplasmic reticulum. Furthermore, comparisons based on elemental composition using energy-dispersive X-ray analysis, as well as Raman spectral signatures demonstrate significant dissimilarities in their molecular composition. The identity and origins of the red rain cells remain an enigma; however, our findings are more consistent with an unidentified prokaryote, and thus suggest that previous attempts at their identification should be reappraised. PMID- 24071814 TI - Application of sweat patch screening for 16 drugs and metabolites using a fast and highly selective LC-MS/MS method. AB - BACKGROUND: To facilitate the monitoring of drug abuse by patients, a method was developed and validated for fast and highly selective screening for amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, methylenedioxyamphetamine, methylenedioxyethylamphetamine, methylphenidate, cocaine, benzoylecgonine, morphine, codeine, heroin, 6-monoacteylmorphine, methadone, 2-ethylidene-1,5 dimethyl-3,3-diphenylpyrrolidine, nicotine, and cotinine in PharmCheck sweat patches. The analysis of sweat patches would provide a noninvasive alternative matrix to urine or blood samples. METHODS: The sweat patches were extracted during vigorous shaking for 10 minutes with 1.5 mL of 20 mmol/L ammonium formate, pH 7, and methanol (50%:50% vol/vol). The extracts were cleaned up by filtering through Whatman mini-Uniprep syringeless filter vials before injection. The method uses a single injection to detect and confirm all 16 drugs and metabolites within 9.6 minutes. RESULTS: The validated substances have a linear range of 3.0 300 nanograms per patch, except for nicotine which has a linear range of 30-3750 nanograms per patch. Stabilities of all substances in worn sweat patches were validated at room temperature for 7 days and as a processed sample in the autosampler at 10 degrees C for 5 days. Only heroin was unstable, with high individual variability and reported bias and coefficient of variation of, respectively, -30.6% and 22.1% in worn sweat patches at room temperature. The monitoring of ion ratios was added to the validation criteria. This resulted in analytical cutoff concentrations of 3.0 and 60 nanograms per patch for nicotine with validated qualifier/quantifier ratios. All analytical cutoff concentrations were lower than the cutoff concentrations proposed by the Substance Abuse and Mental Health Services Administration. CONCLUSIONS: The method uses validated cutoff concentrations, qualifier/quantifier ratios, and a simple extraction without extensive sample treatment for the analysis of 16 drugs and metabolites with a runtime of 9.6 minutes. This method was successfully applied for the analysis of 96 worn sweat patches to monitor patients for drug abuse. The results provided the physician or health-care professional with information about drug abuse and could be used to improve patient care with patient-specific therapy. PMID- 24071813 TI - FLZ inhibited gamma-secretase selectively and decreased Abeta mitochondrial production in APP-SH-SY5Y cells. AB - Amyloid precursor protein (APP) metabolism is a key factor in the pathogenesis of Alzheimer's disease (AD). Amyloid-beta (Abeta) in mitochondria comes from APP mitochondrial metabolism or from the uptake Abeta from outside of mitochondria. It has been recently proposed that mitochondria are involved in the biochemical pathways through which Abeta causes neuronal dysfunction. The accumulated Abeta in mitochondria decreases the level of cytochrome c oxidase (COX IV) and attenuates the ATP production consequently. FLZ is a synthetic cyclic derivative of squamosamide from Annona glabra. In this study, the effect of FLZ on APP processing in mitochondria was investigated in SH-SY5Y cells over-expressing APP695 (wt/Swe). FLZ treatment attenuated APP processing and decreased Abeta production in mitochondria. The mitochondrial function was increased with the upregulation of COX IV both at protein and activity levels. ATP production was also increased after FLZ treatment. The mechanistic study showed that FLZ inhibited gamma-secretase activity by decreasing C-terminal fragment protein level of presenilin, the active center of gamma-secretase. The effect of FLZ differs from DAPT (a non-selective gamma-secretase inhibitor), suggesting FLZ is a selective gamma-secretase inhibitor. FLZ selectively inhibited gamma-secretase in the cleavage of recombinant C terminus of APP in vitro, without specifically modulating the processing of recombinant Notch intracellular domain. These results indicate that FLZ decreases Abeta accumulation in mitochondria by selectively inhibiting gamma-secretase. We propose that FLZ is a potential anti AD drug candidate, and its mechanism may be improving mitochondrial function by reducing the Abeta burden in mitochondria. PMID- 24071815 TI - Fast and highly selective LC-MS/MS screening for THC and 16 other abused drugs and metabolites in human hair to monitor patients for drug abuse. AB - BACKGROUND: To facilitate the monitoring of drug abuse by patients, a method was developed and validated for the analysis of amphetamine, methamphetamine, 3,4 methylenedioxymethamphetamine, methylenedioxyamphetamine, methylenedioxyethylamphetamine, methylphenidate, cocaine, benzoylecgonine, morphine, codeine, heroin, 6-monoacteylmorphine, methadone, 2-ethylidene-1,5 dimethyl-3,3-diphenylpyrrolidine (EDDP), delta-9-tetrahydrocannabinol (THC), nicotine, and cotinine in human hair. METHODS: The hair preparation method contains a 3-step wash procedure with dichloromethane followed by a simultaneous hair pulverization and extraction procedure with disposable metal balls. The developed liquid chromatography tandem mass spectrometry method uses a single injection to detect and confirm all 17 abused drugs, including THC, within 4.8 minutes. RESULTS: Nicotine was validated with a linear range of 800-25,000 pg/mg hair, and all other substances were validated with a linear range of 30.0-2500 pg/mg hair. For inaccuracy and imprecision, the overall bias did not exceed -8.2% and the overall coefficient of variation did not exceed 17.7%. Autosampler stability was proven for 48 hours at 10 degrees C for all substances. Analytical cutoff concentrations were defined for each substance at the lowest validated inaccuracy and imprecision concentration with a bias and coefficient of variation within 15% and qualifier/quantifier ratios within 20% of the set ratio. The analytical cutoff concentrations were 200 pg/mg for codeine and 80.0 pg/mg for 6 MAM, heroin, EDDP, and THC. The analytical cutoff concentration for nicotine was 800 pg/mg and for all other validated substances 30.0 pg/mg. This method was successfully applied to analyze hair samples from patients who were monitored for drug abuse. Hair samples of 47 subjects (segmented into 129 samples) showed 3,4 methylenedioxymethamphetamine, methylphenidate, cocaine, benzoylecgonine, codeine, methadone, EDDP, THC, nicotine, and cotinine above the analytical cutoff. CONCLUSIONS: The method was fully validated, including the validation of the qualifier/quantifier ratios. The analysis of real hair samples proved the efficacy of the developed method for monitoring drug abuse. The results obtained by this method provide the physician or health-care professional with extensive information about actual drug abuse or relapse and can be used for patient specific therapy. PMID- 24071816 TI - Phytochemical analyses of Ziziphus jujuba Mill. var. spinosa seed by ultrahigh performance liquid chromatography-tandem mass spectrometry and gas chromatography mass spectrometry. AB - Ziziphus jujuba Mill. var. spinosa (Z. jujuba) seeds have attracted much attention within the field of medicine due to their significant effects against disturbances of the central nervous system. Secondary metabolites composition is key to the influence of the pharmaceutical and commercial qualities of this plant. In this work, the phytochemical profile of Z. jujuba seeds was analysed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and gas chromatography-mass spectrometry (GC-MS). The UPLC-MS/MS information identified the main secondary metabolites in Z. jujuba seeds, including flavonoid C-glycosides, triterpene acids and unsaturated fatty acids. The leading chemical identified by UPLC-MS/MS was betulinic acid, and oleic acid was the leading volatile from the GC-MS results. All the samples tested showed similar phytochemical profiles, but levels of the chemical compounds varied. Principal component analysis revealed the principal secondary metabolites that could define the differences in quality. It was confirmed that the combination of UPLC-MS/MS and GC-MS was an effective technique to demonstrate the pharmaceutical quality of Z. jujuba seeds. PMID- 24071818 TI - Hierarchical LiFePO4 with a controllable growth of the (010) facet for lithium ion batteries. AB - Hierarchically structured LiFePO4 was successfully synthesized by ionic liquid solvothermal method. These hierarchically structured LiFePO4 samples were constructed from nanostructured platelets with their (010) facets mainly exposed. To the best of our knowledge, facet control of a hierarchical LiFePO4 crystal has not been reported yet. Based on a series of experimental results, a tentative mechanism for the formation of these hierarchical structures was proposed. After these hierarchically structured LiFePO4 samples were coated with a thin carbon layer and used as cathode materials for lithium-ion batteries, they exhibited excellent high-rate discharge capability and cycling stability. For instance, a capacity of 95% can be maintained for the LiFePO4 sample at a rate as high as 20 C, even after 1000 cycles. PMID- 24071819 TI - Retrospective analysis on the efficacy of corticosteroid prophylaxis prior to elective caesarean section to reduce neonatal respiratory complications at term of pregnancy: review of literature. AB - PURPOSE: Our purpose was to conduct a systematic review of the literature to determine whether synthetic pharmaceutical glucocorticoids (betamethasone and dexamethasone) are safe as well as effective in reducing neonatal respiratory morbidity at term of pregnancy prior to elective caesarean section. The overall incidence of respiratory disorders is estimated at 2.8%, and the main risk factors are gestational age and mode of delivery. Newborns delivered by elective caesarean section (CS after 37 weeks) are more susceptible to serious respiratory complications than babies born by vaginal delivery. Neonatal respiratory morbidity at term of pregnancy is low but not negligible. Further, it is increasing due to a drastic decline in trial of labour in those pregnant women who underwent a caesarean section in the past. Because prophylaxis is inexpensive, easy to administer, and safe, other studies should be conducted to confirm its effectiveness. METHODS: We conducted a systematic review of literature since 1965 on the discovery of action mechanisms, pharmaceutical development, proper dosage, and potential side effects of corticosteroids on the mother and offspring to extrapolate their efficacy as no clinical trial has directly demonstrated it. RESULTS: We extrapolated no negative effects on mother and foetus behaviour. CONCLUSIONS: Human studies suggest that corticosteroid administration may become a proper clinical indication prior to caesarean section in the reduction of neonatal respiratory problems. PMID- 24071820 TI - Comparing the efficacy of intrauterine lidocaine and paracervical block in decreasing the pain associated with endometrial biopsy: a randomised trial. AB - PURPOSE: Almost 50% of the patients experience moderate-to-severe pain during endometrial biopsy. The study aimed to examine the effectiveness of intrauterine lidocaine for relieving pain during endometrial biopsy. METHODS: A randomised trial was conducted in 120 patients undergoing endometrial biopsy. Sixty-seven women were assigned to the paracervical block group and 53 were assigned to the intrauterine lidocaine group. The main outcome measure was pain intensity, measured using the visual analogue scale, during and after the procedure. RESULTS: The groups were similar with regard to age, body mass index, gravidity, total number of previous vaginal deliveries, menopausal status, and uterine depth. The pain scores immediately after the procedure were similar in the groups (p = 0.079). However, the pain scores 30 min after the procedure were significantly lower in the intrauterine group than in the paracervical group (p = 0.0001). CONCLUSIONS: Compared to paracervical block, intrauterine lidocaine may be the preferred anaesthesia for endometrial biopsy, and it does not cause any serious complications. PMID- 24071821 TI - Clinical translation of the research article titled "the influence of early drinking contexts on current drinking among adult lesbian and bisexual women". PMID- 24071823 TI - A mechanistic understanding of plagioclase dissolution based on Al occupancy and T-O bond length: from geologic carbon sequestration to ambient conditions. AB - A quantitative description of how the bulk properties of aluminosilicates affect their dissolution kinetics is important in helping people understand the regulation of atmospheric CO2 concentration by silicate weathering and predict the fate and transport of geologically sequestered CO2 through brine-rock interactions. In this study, we employed a structure model based on the C1 space group to illustrate how differences in crystallographic properties of aluminosilicates, such as T-O (Tetrahedral site-Oxygen) bond length and Al/Si ordering, can result in quantifiable variations in mineral dissolution rates. The dissolution rates of plagioclases were measured under representative geologic carbon sequestration (GCS) conditions (90 degrees C, 100 atm of CO2, 1.0 M NaCl, and pH ~ 3.1), and used to validate the model. We found that the logarithm of the characteristic time of the breakdown of Al-O-Si linkages in plagioclases follows a good linear relation with the mineral's aluminum content (nAl). The Si release rates of plagioclases can be calculated based on an assumption of dissolution congruency or on the regularity of Al/Si distribution in the constituent tetrahedra of the mineral. We further extended the application of our approach to scenarios where dissolution incongruency arises because of different linkage reactivities in the solid matrix, and compared the model predictions with published data. The application of our results enables a significant reduction of experimental work for determining the dissolution rates of structurally related aluminosilicates, given a reaction environment. PMID- 24071824 TI - Direct measurement of the absolute absorption spectrum of individual semiconducting single-wall carbon nanotubes. AB - The optical properties of single-wall carbon nanotubes are very promising for developing novel opto-electronic components and sensors with applications in many fields. Despite numerous studies performed using photoluminescence or Raman and Rayleigh scattering, knowledge of their optical response is still partial. Here we determine using spatial modulation spectroscopy, over a broad optical spectral range, the spectrum and amplitude of the absorption cross-section of individual semiconducting single-wall carbon nanotubes. These quantitative measurements permit determination of the oscillator strength of the different excitonic resonances and their dependencies on the excitonic transition and type of semiconducting nanotube. A non-resonant background is also identified and its cross-section comparable to the ideal graphene optical absorbance. Furthermore, investigation of the same single-wall nanotube either free standing or lying on a substrate shows large broadening of the excitonic resonances with increase of oscillator strength, as well as stark weakening of polarization-dependent antenna effects, due to nanotube-substrate interaction. PMID- 24071822 TI - The relationships of sexual identity, hazardous drinking, and drinking expectancies with risky sexual behaviors in a community sample of lesbian and bisexual women. AB - This study examined the influence of demographic characteristics, sexual identity, hazardous drinking, and sexuality/intimacy enhancement alcohol expectancies on rates of risky sexual behaviors in a community sample of women who self-identified as lesbian, mostly lesbian, and bisexual (N = 349). Structured interview data were collected as part of a larger longitudinal study of sexual minority women's health, the Chicago Health and Life Experiences of Women study. We used structural equation modeling, controlling for demographic characteristics, to evaluate the influence of sexual identity, hazardous drinking, and alcohol-related sexuality/intimacy enhancement expectancies on sexual risk behaviors. Controlling for demographic characteristics and for sexual identity, higher levels of both hazardous drinking and sexuality/intimacy enhancement alcohol expectancies were associated with higher sexual risk scores. The final model predicted 36% of the variance in risky sexual behavior scores. Our findings regarding the central role of alcohol use and sexuality/intimacy enhancement expectancies in sexual risk behaviors among sexual minority women are consistent with previous research focusing on predominantly heterosexual women. Future efforts at sexual risk reduction in sexual minority women will need to address the influences of alcohol use and drinking-related expectancies on sexual behaviors and decision making. PMID- 24071825 TI - SBA-15 confined synthesis of TiNb2O7 nanoparticles for lithium-ion batteries. AB - Unlike most conventional anode materials, the newly developed TiNb2O7 (TNO) does not form a solid electrolyte interface (SEI) layer, which makes it safe for high power requiring lithium-ion batteries. In this paper, we demonstrated an SBA-15 confined synthetic approach to prepare TNO nanoparticles (S-TNO) with a small particle size around 10 nm and a large BET surface area of 79.5 m(2) g(-1). It is worth mentioning that this is the smallest size reported so far for TNO. In contrast, the TNO (L-TNO) synthesized without SBA-15 has a particle size above 100 nm and a BET surface area of only 4.3 m(2) g(-1). The S-TNO shows better lithium-ion storage properties than L-TNO. The excellent electrochemical performance of S-TNO is attributed to its small crystalline size, which not only provides a larger effective area for better contact between the electrode material and the electrolyte, but also reduces the rate-limiting Li diffusion path. Moreover, S-TNO shows a high Coulombic efficiency (above 98% over 300 cycles) and negligible increase of impedance after cycling, which confirms no SEI layer formation in the operational voltage (1-3 V) of TNO. PMID- 24071827 TI - Group IV complexes containing the benzotriazole phenoxide ligand as catalysts for the ring-opening polymerization of lactides, epoxides and as precatalysts for the polymerization of ethylene. AB - A series of Ti(IV), Zr(IV) and Hf(IV) benzotriazole phenoxide (BTP) complexes were synthesized and characterized by various spectroscopic techniques, elemental analysis and X-ray crystallography. The monosubstituted Zr(IV) BTP complexes [(MU L)Zr(O(i)Pr)3]2 1-3 [L = (C1)BTP-H (1), (TCl)BTP-H (2), (pent)BTP-H (3)] and tetrasubstituted Zr(IV), Hf(IV) complexes ZrL4 4-6 [L = (C1)BTP-H (4), (TCl)BTP-H (5), (pent)BTP-H (6)] and HfL4 7-9 [L = (C1)BTP-H (7), (TCl)BTP-H (8), (pent)BTP H (9)] were prepared by the reaction of Zr(O(i)Pr)4.((i)PrOH) and Hf(O(t)Bu)4 in toluene with the respective ligands in different stoichiometric proportions. The reaction between BTP and TiCl4 and ZrCl4 and HfCl4 in a 2 : 1 stoichiometric reaction resulted in the formation of disubstituted group IV chloride complexes L2MCl2 10-12 [L = (C1)BTP-H, M = Ti, Zr and Hf]. The molecular structures of complexes 1, 4, 7, 10, 11, and 12 were determined by single-crystal X-ray studies. The X-ray structure of 1 reveals a dimeric Zr(IV) complex containing a Zr2O2 core bridged through the oxygen atoms of the phenoxide groups. Each Zr atom is distorted from an octahedral symmetry. These complexes were found to be active towards the ring-opening polymerization (ROP) of L-lactide (L-LA) and rac-lactide (rac-LA). Complex 1 produced highly heterotactic poly(lactic acid) (PLA) from rac LA under melt conditions with narrow molecular weight distributions (MWDs) and well controlled number average molecular weights (M(n)). Additionally, epoxide polymerizations using rac-cyclohexene oxide (CHO), rac-propylene oxide (PO), and rac-styrene oxide (SO) were also carried out with these complexes. The yield and molecular weight of the polymer was found to increase with the extension of reaction time. Compounds 1-12 were activated by methylaluminoxane (MAO) and show good activity for ethylene polymerization and produced high molecular weight polyethylene. PMID- 24071828 TI - Analysis of microRNA expression profile by small RNA sequencing in Down syndrome fetuses. AB - Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21) and is associated with numerous deleterious phenotypes, including cognitive impairment, childhood leukemia and immune defects. Five Hsa21-derived microRNAs (i.e., hsa miR-99a, let-7c, miR-125b-2, miR-155 and miR-802) are involved in variable phenotypes of DS. However, the changes involved in the genome-wide microRNA expression of DS fetuses under the influence of trisomy 21 have yet to be determined. To investigate the expression characteristic of microRNAs during the development of DS fetuses and identify whether another microRNA gene resides in the Hsa21, Illumina high-throughput sequencing technology was employed to comprehensively characterize the microRNA expression profiles of the DS and normal fetal cord blood mononuclear cells (CBMCs). In total, 149 of 395 identified microRNAs were significantly differentially expressed (fold change >2.0 and P<0.001) and 2 of 181 candidate novel microRNAs were identified as residing within the DS critical region of human chromosome 21 (chr21q22.2-22.3). Additionally, 7 of 14 Hsa21-derived microRNAs were detected, although not all seven were overexpressed in DS CBMCs compared with the control. Gene ontology enrichment analyses revealed that a set of abnormally expressed microRNAs were involved in the regulation of transcription, gene expression, cellular biosynthetic process and nucleic acid metabolic process. Significantly, most of the mRNA targets in these categories were associated with immune modulation (i.e., SOD1, MXD4, PBX1, BCLAF1 and FOXO1). Findings of the present study provided a considerable insight into understanding the expression characteristic of microRNAs in the DS fetal CBMCs. To the best of our knowledge, this is the first study to examine genome-wide microRNA expression profiles in the DS fetus. Differentially expressed microRNAs may be involved in hemopoietic abnormalities and the immune defects of DS fetuses and newborns. PMID- 24071830 TI - Investigation of solute-solvent interactions in phenol compounds: accurate ab initio calculations of solvent effects on 1H NMR chemical shifts. AB - Accurate (1)H chemical shifts of the -OH groups of polyphenol compounds can be calculated, compared to experimental values, using a combination of DFT, polarizable continuum model (PCM) and discrete solute-solvent hydrogen bond interactions. The study focuses on three molecular solutes: phenol, 4 methylcatechol and the natural product genkwanin in DMSO, acetone, acetonitrile, and chloroform. Excellent linear correlation between experimental and computed chemical shifts (with the GIAO method at the DFT/B3LYP/6-311++G(2d,p) level) was obtained with minimization of the solvation complexes at the DFT/B3LYP/6-31+G(d) and DFT/B3LYP/6-311++G(d,p) level of theory with a correlation coefficient of 0.991. The use of the DFT/B3LYP/6-31+G(d) level of theory for minimization could provide an excellent means for the accurate prediction of the experimental OH chemical shift range of over 8 ppm due to: (i) strong intramolecular and solute solvent intermolecular hydrogen bonds, (ii) flip-flop intramolecular hydrogen bonds, and (iii) conformational effects of substituents of genkwanin. The combined use of ab initio calculations and experimental (1)H chemical shifts of phenol -OH groups provides a method of primary interest in order to obtain detailed structural, conformation and electronic description of solute-solvent interactions at a molecular level. PMID- 24071831 TI - Interprofessional collaboration in palliative care: rhetoric or reality? PMID- 24071829 TI - The cellular ratio of immune tolerance (immunoCRIT) is a definite marker for aggressiveness of solid tumors and may explain tumor dissemination patterns. AB - The adaptive immune system is involved in tumor establishment and aggressiveness. Tumors of the ovaries, an immune-privileged organ, spread via transceolomic routes and rarely to distant organs. This is contrary to tumors of non-immune privileged organs, which often disseminate hematogenously to distant organs. Epigenetics-based immune cell quantification allows direct comparison of the immune status in benign and malignant tissues and in blood. Here, we introduce the "cellular ratio of immune tolerance" (immunoCRIT) as defined by the ratio of regulatory T cells to total T lymphocytes. The immunoCRIT was analyzed on 273 benign tissue samples of colorectal, bronchial, renal and ovarian origin as well as in 808 samples from primary colorectal, bronchial, mammary and ovarian cancers. ImmunoCRIT is strongly increased in all cancerous tissues and gradually augmented strictly dependent on tumor aggressiveness. In peripheral blood of ovarian cancer patients, immunoCRIT incrementally increases from primary diagnosis to disease recurrence, at which distant metastases frequently occur. We postulate that non-pathological immunoCRIT values observed in peripheral blood of immune privileged ovarian tumor patients are sufficient to prevent hematogenous spread at primary diagnosis. Contrarily, non-immune privileged tumors establish high immunoCRIT in an immunological environment equivalent to the bloodstream and thus spread hematogenously to distant organs. In summary, our data suggest that the immunoCRIT is a powerful marker for tumor aggressiveness and disease dissemination. PMID- 24071832 TI - Panel discussion summary: when is palliative care everyone's business and when are specialists needed? PMID- 24071833 TI - Experiences and perceptions of nurses caring for dying patients and families in the acute medical admission setting. AB - AIM: This study aimed to explore the experiences and perceptions of nurses caring for dying patients and their families in the acute medical admission setting. METHODS: A qualitative interpretive descriptive methodology was used to explore the experiences and perceptions of 15 nurses recruited via purposive sampling from three acute medical wards of a hospital in Hong Kong. RESULTS: The nurses perceived insufficiency and experienced great mental and physiological strain regarding their caring roles in this setting. Four themes were derived from the findings: lack of preparedness for patients' deaths, reflecting on their own nursing roles for dying patients, reflecting on the meaning of death and their personal experiences of the death of their own family members, and coping with caring for dying patients. CONCLUSIONS: There are similarities between these experiences and those of nurses in similar settings in different cultures. There is a need for further research into and educational preparation of nurses in bereavement care and means of coping with somatic, cognitive, behavioural, and emotional responses in an environment where the emphasis is on curing people who are dying rather than caring for them. PMID- 24071834 TI - Integrating palliative care in lung cancer: an early feasibility study. AB - AIM: The aim of this preliminary study was to evaluate the feasibility of conducting an effectiveness trial of early access to palliative care services for people with lung cancer through use of an integrated outpatient model. METHODS: Newly diagnosed patients with lung cancer receiving palliative-intent treatment or best supportive care treatment were recruited over a 5-month period from one out-patient clinic in Scotland. Patients were offered a clinical review appointment with a palliative medicine consultant at two time points: baseline and 12 weeks later. Prior to each appointment patients completed three outcome measures addressing symptom severity, wellbeing, and health-care needs. One-to one interviews were also conducted to explore patients' experiences of being involved in the study. RESULTS: Three patients participated in the study. The main reasons for low recruitment were patients' deteriorating condition and unwillingness to undertake extra hospital visits. However, qualitative data indicated that the participants found this extra layer of supportive care useful in identifying and managing their needs, as well as enabling future planning. CONCLUSION: Further testing is needed to ascertain the feasibility of conducting a trial of integrating early access to palliative care services into routine practice for people with lung cancer. PMID- 24071835 TI - WHOQOL Pain and Discomfort Module: development and validity testing of the Italian version. AB - BACKGROUND: The World Health Organization Quality of Life scale Pain and Discomfort Module (WHOQOL PDM) was designed to assess quality of life (QoL) in adults with chronic pain. It comprises 16 items covering four facets of pain: relief, anger/frustration, vulnerability/fear/worry, and uncertainty. AIM: The purpose of this study was to validate the Italian version of the WHOQOL PDM. METHODS: Chronic pain was assessed in 400 patients using the WHOQOL PDM and other pain scales, together with scales measuring associated symptoms, depression, anxiety, and QoL. RESULTS: The WHOQOL PDM shows good internal consistency, concurrent validity (it was significantly associated with all the WHOQOL BREF domains), construct validity (it was significantly associated with other pain scales), and discriminant validity (there were significant differences among different groups of patients). CONCLUSIONS: The Italian version of the WHOQOL PDM is a brief, useful, and valid tool for assessing chronic pain and its impact on patients' QoL. PMID- 24071826 TI - Neurosteroid interactions with synaptic and extrasynaptic GABA(A) receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability. AB - RATIONALE: Neurosteroids are steroids synthesized within the brain with rapid effects on neuronal excitability. Allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are three widely explored prototype endogenous neurosteroids. They have very different targets and functions compared to conventional steroid hormones. Neuronal gamma-aminobutyric acid (GABA) type A (GABA(A)) receptors are one of the prime molecular targets of neurosteroids. OBJECTIVE: This review provides a critical appraisal of recent advances in the pharmacology of endogenous neurosteroids that interact with GABA(A) receptors in the brain. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance of the neuron, mainly via potentiation of GABA(A) receptors at low concentrations and direct activation of receptor chloride channel at higher concentrations. The GABA(A) receptor mediates two types of inhibition, now characterized as synaptic (phasic) and extrasynaptic (tonic) inhibition. Synaptic release of GABA results in the activation of low-affinity gamma2-containing synaptic receptors, while high affinity delta-containing extrasynaptic receptors are persistently activated by the ambient GABA present in the extracellular fluid. Neurosteroids are potent positive allosteric modulators of synaptic and extrasynaptic GABA(A) receptors and therefore enhance both phasic and tonic inhibition. Tonic inhibition is specifically more sensitive to neurosteroids. The resulting tonic conductance generates a form of shunting inhibition that controls neuronal network excitability, seizure susceptibility, and behavior. CONCLUSION: The growing understanding of the mechanisms of neurosteroid regulation of the structure and function of the synaptic and extrasynaptic GABA(A) receptors provides many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions. PMID- 24071836 TI - Managing urinary incontinence at the end of life: an examination of the evidence that informs practice. AB - To achieve a 'good' death, management of urinary incontinence at the end of life arguably should be as much a priority for nursing attention as managing symptoms such as pain and nausea. To understand how contemporary best practice is described and the nature of interventions prescribed for managing this issue, this article reviews the content of 16 seminal palliative care textbooks and 10 journal articles (retrieved through systematic search techniques) that discuss the management of urinary incontinence for patients at the end of life. The findings depict an area of nursing that has been governed by 'common sense' and precedent rather than evidence-based research, particularly regarding the use of indwelling urinary catheters. There is very little robust research evidence on this topic. Further research is required to ascertain the current state of practice in settings where patients who are approaching the end of life are cared for and the needs and preferences of patients and families. PMID- 24071837 TI - Managing complex palliative wounds: an interactive educational approach for district nurses. AB - Complex palliative wounds, although uncommon, are extremely distressing for patients because of their associated symptoms. Managing these symptoms presents significant challenges to clinicians. As the majority of these patients will be managed at home, district nurses will be the main providers of care. The quality of the literature in this field is limited due to the small number of patients presenting with these wounds and the difficulties associated with researching issues within palliative care. However, the literature available identifies that community nurses would value greater education in managing these wounds because the accepted wound healing theories and management strategies do not apply. This underpins the rationale for developing an educational resource to provide district nurses with current, evidence-based information to support their wound management decisions in caring for this patient group. This paper reports the development, through an action research work-based project, of such an interactive educational package. PMID- 24071840 TI - Targeting molecular tumor types. PMID- 24071841 TI - Germline PAX5 mutations and B cell leukemia. AB - The transcription factor PAX5 is required for normal B cell development and is frequently mutated or deleted in B cell precursor acute lymphoblastic leukemia (B ALL). A new study demonstrates that germline hypomorphic mutations of PAX5 are associated with susceptibility to B-ALL, implicating PAX5 in a growing list of hematopoietic transcription factors mutated in familial leukemia predisposition syndromes. PMID- 24071842 TI - Genomics informs glioblastoma biology. AB - Identifying genomic alterations in cancer does not guarantee therapeutic benefit. A new study combining DNA and RNA sequencing with functional validation uncovers new genetic driver alterations in glioblastoma with potential for clinical translation. PMID- 24071843 TI - Complex genetics of drug resistance in Mycobacterium tuberculosis. AB - Three new studies have used whole-genome sequencing of M. tuberculosis to demonstrate unexpected complexity in the modern evolution of drug-resistant tuberculosis, and a fourth study suggests a close evolutionary relationship between the pathogen and its human host over a period of 70,000 years. Collectively, the observations in these studies suggest that future strategies to tackle drug-resistant tuberculosis must integrate host genetics with detailed strain epidemiology. PMID- 24071850 TI - Enabling transparent and collaborative computational analysis of 12 tumor types within The Cancer Genome Atlas. AB - The Cancer Genome Atlas Pan-Cancer Analysis Working Group collaborated on the Synapse software platform to share and evolve data, results and methodologies while performing integrative analysis of molecular profiling data from 12 tumor types. The group's work serves as a pilot case study that provides (i) a template for future large collaborative studies; (ii) a system to support collaborative projects; and (iii) a public resource of highly curated data, results and automated systems for the evaluation of community-developed models. PMID- 24071851 TI - Emerging landscape of oncogenic signatures across human cancers. AB - Cancer therapy is challenged by the diversity of molecular implementations of oncogenic processes and by the resulting variation in therapeutic responses. Projects such as The Cancer Genome Atlas (TCGA) provide molecular tumor maps in unprecedented detail. The interpretation of these maps remains a major challenge. Here we distilled thousands of genetic and epigenetic features altered in cancers to ~500 selected functional events (SFEs). Using this simplified description, we derived a hierarchical classification of 3,299 TCGA tumors from 12 cancer types. The top classes are dominated by either mutations (M class) or copy number changes (C class). This distinction is clearest at the extremes of genomic instability, indicating the presence of different oncogenic processes. The full hierarchy shows functional event patterns characteristic of multiple cross-tissue groups of tumors, termed oncogenic signature classes. Targetable functional events in a tumor class are suggestive of class-specific combination therapy. These results may assist in the definition of clinical trials to match actionable oncogenic signatures with personalized therapies. PMID- 24071852 TI - Pan-cancer patterns of somatic copy number alteration. AB - Determining how somatic copy number alterations (SCNAs) promote cancer is an important goal. We characterized SCNA patterns in 4,934 cancers from The Cancer Genome Atlas Pan-Cancer data set. Whole-genome doubling, observed in 37% of cancers, was associated with higher rates of every other type of SCNA, TP53 mutations, CCNE1 amplifications and alterations of the PPP2R complex. SCNAs that were internal to chromosomes tended to be shorter than telomere-bounded SCNAs, suggesting different mechanisms underlying their generation. Significantly recurrent focal SCNAs were observed in 140 regions, including 102 without known oncogene or tumor suppressor gene targets and 50 with significantly mutated genes. Amplified regions without known oncogenes were enriched for genes involved in epigenetic regulation. When levels of genomic disruption were accounted for, 7% of region pairs were anticorrelated, and these regions tended to encompass genes whose proteins physically interact, suggesting related functions. These results provide insights into mechanisms of generation and functional consequences of cancer-related SCNAs. PMID- 24071856 TI - The impact and prospect of traumatic brain injury on olfactory function: a cross sectional and prospective study. AB - Traumatic brain injury (TBI) can cause olfactory loss. The aim of this cross sectional and prospective study was to determine the prevalence of olfactory loss among 110 patients with TBI within 3 months after the trauma. In 81 patients ("cross-sectional"-group), olfactory function could be measured using the validated "Sniffin' Sticks" test for odor threshold and odor identification. In addition, the prospective change of olfactory function was studied in 36 patients ("follow-up"-group) by means of a validated odor threshold, discrimination and identification test. Olfactory function was significantly better in patients with TBI I degrees compared to individuals with TBI II degrees and III degrees . Clinically significant improvement of olfactory function was found in 36% of the patients, most frequently during the first 6 months after the injury, in a median follow-up interval of 21 months. TBI I degrees has in general no major effect on olfaction. In contrast, patients with TBI II degrees and III degrees exhibit smell loss in 57%. Chances for olfactory recovery were highest within the first 6 months after the trauma. PMID- 24071857 TI - Prophylactic percutaneous endoscopic gastrostomy in head and neck cancer patients: results of tertiary institute. AB - To evaluate the use and complications of a prophylactic percutaneous endoscopic gastrostomy (PEG) in head and cancer patients in our institute. A retrospective study of 194 consecutive patients with a newly diagnosed upper aero digestive tract malignancy who underwent mainly prophylactic PEG tube placement. The procedure is relatively safe: 15 (7.7%) of the complications were considered serious; no deaths occurred. Of the patients 23 (12.5%) did not use the PEG tube at all, but it was not possible to single out a group of patients in which this could be predicted. The majority of the patients were considered to benefit from the prophylactic PEG insertion. PMID- 24071855 TI - Investigation of MGMT and DAPK1 methylation patterns in diffuse large B-cell lymphoma using allelic MSP-pyrosequencing. AB - The tumor suppressor genes MGMT and DAPK1 become methylated in several cancers including diffuse large B-cell lymphoma (DLBCL). However, allelic methylation patterns have not been investigated in DLBCL. We developed a fast and cost efficient method for the analysis of allelic methylation based on pyrosequencing of methylation specific PCR (MSP) products including a SNP. Allelic methylation patterns were reliably analyzed in standards of known allelic methylation status even when diluted in unmethylated DNA to below 1% methylation. When studying 148 DLBCL patients MGMT and DAPK1 methylation was observed in 19% and 89%, respectively, and among methylated and heterozygous patients 29% and 55%, respectively, were biallelically methylated. An association between the T-allele of the rs16906252 SNP and MGMT methylation was observed (p-value=0.04), and DAPK1 methylation of the A-allele was associated with shorter overall survival (p value=0.006). In future cancer research allelic MSP-pyrosequencing may be used to study a wide range of other loci. PMID- 24071858 TI - Tumor thickness as an independent risk factor of early recurrence in oral cavity squamous cell carcinoma. AB - The aim is to determine if tumor thickness is a risk factor related to the development of early recurrences in surgically treated oral cavity squamous cell carcinoma (SCC). Retrospective cohort study conducted at Instituto do Cancer do Estado de Sao Paulo (ICESP). Fifty-seven patients with oral cavity SCC (excluding lip tumors and patients previously submitted to any treatment) were analyzed regarding the occurrence of an early disease progression (locoregional or distant metastasis) within the first 12 months after initial treatment. Tumor thickness and other histological characteristics related to the development of recurrence up to 1 year after treatment were tested. Results demonstrated that tumor thickness greater than 10 mm (P = 0.034), as well as angiolymphatic invasion (P = 0.001), perineural invasion (P = 0.041) and lymph-node metastasis (P = 0.021) was associated with a worse 12-month disease-free survival (Log-Rank test). In multivariate analysis, tumor thickness greater than 10 mm emerged as an independent risk factor for early recurrence in oral cavity tumors (HR = 3.4, 95% CI: 1.005-11.690; P = 0.049--Cox regression). Post-operative radiotherapy seems to be a protective factor for early recurrences in patients with tumor thickness greater than 10 mm (P = 0.017--Log-Rank test; HR = 0.32, 95% CI: 0.12-0.87, P = 0.026--Cox regression). The results of the present research suggest that tumor thickness greater than 10 mm may be an independent adverse factor for early progression of surgically treated oral cavity SCC. Adjuvant therapies, in particular post-operative radiotherapy, should be advocated in this group of patients, regardless of the co-existence of other well-described histological risk factors. PMID- 24071849 TI - The Cancer Genome Atlas Pan-Cancer analysis project. AB - The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. PMID- 24071859 TI - Differences in clinical characteristics of fallopian canal dehiscence associated with pars flaccida and pars tensa cholesteatomas. AB - This study investigated the difference in clinical characteristics of fallopian canal dehiscence associated with pars flaccida and pars tensa cholesteatomas for the purpose of increasing the preoperative detectability of dehiscence. A total of 189 ears of patients 7-80 years of age (mean 42 years) with pars flaccida cholesteatoma and 63 ears of patients 9-84 years of age (mean 50 years) with pars tensa cholesteatoma were studied. All patients had undergone prior surgical management at our institution from January 2006 to April 2012. The incidence of fallopian canal dehiscence and its location were compared between pars flaccida and pars tensa cholesteatomas. Intraoperative findings of coexistent pathologies, including destruction of the stapes superstructure, labyrinthine fistula, and dural exposure, were compared between the dehiscence and no-dehiscence groups for the two types of cholesteatomas. The incidence of dehiscence was significantly higher in patients with pars tensa cholesteatoma (55.6 %) than in patients with pars flaccida cholesteatoma (26.5 %). Dehiscence located posterior to the cochleariform process occurred slightly more frequently in patients with pars tensa cholesteatoma than in those with pars flaccida cholesteatoma. In patients with pars flaccida cholesteatoma, labyrinthine fistulas and dural exposure were significantly more frequent in the dehiscence group than in the no-dehiscence group. Fallopian canal dehiscence is more frequent in patients with pars tensa cholesteatoma than in those with pars flaccida cholesteatoma. Especially in patients with pars flaccida cholesteatoma, paying special attention to these coexisting pathologies is important to increase preoperative detectability of dehiscence. PMID- 24071860 TI - Depression, Anxiety and Stress Scale in patients with tinnitus and hearing loss. AB - The study was proposed to evaluate co-morbid depression, anxiety and stress associated with tinnitus patients. The study was done on 196 subjects: 100 patients suffering from subjective tinnitus associated with hearing loss (tinnitus group), 45 patients suffering from hearing loss only (hearing loss group) and 50 healthy subjects not suffering from tinnitus or hearing loss (control group); the age ranges from 20 to 60 years old. The studied sample was subjected to full ear, nose and throat examinations and audiological evaluation. Depression, Anxiety and Stress Scale (DASS) was developed by Levibond H and Levibond F to assess three self-report scales designed to measure the negative emotional status of depression, anxiety and stress. All patients and control group were evaluated by DASS. (1) Depression: males were affected more than females. All patients over 60 years were affected by depression. The duration of tinnitus seems correlating with the severity of depression. Only 2 patients (4.3 %) of the hearing loss group suffer from depression. (2) Anxiety: 90 % of males suffer from anxiety as compared to 83.3 % females. The age group 20-29 years old suffers more than other age groups. Only 4 patients (8.7 %) of hearing loss group suffer from anxiety. (3) Stress: females seem to be affected by the stress (76.7 %) more than males (67.5). Patients in age group 30-39 suffer the most from the disease. There is a direct correlation between duration of tinnitus and severity of stress. No one of the hearing loss group suffers from stress. In conclusion, depression, anxiety and stress should be taken into consideration in the treatment of patients suffering from tinnitus. PMID- 24071861 TI - Perioperative bleeding control in functional endoscopic sinus surgery. PMID- 24071862 TI - Integrated analysis of genome-wide genetic and epigenetic association data for identification of disease mechanisms. AB - Many human diseases are multifactorial, involving multiple genetic and environmental factors impacting on one or more biological pathways. Much of the environmental effect is believed to be mediated through epigenetic changes. Although many genome-wide genetic and epigenetic association studies have been conducted for different diseases and traits, it is still far from clear to what extent the genomic loci and biological pathways identified in the genetic and epigenetic studies are shared. There is also a lack of statistical tools to assess these important aspects of disease mechanisms. In the present study, we describe a protocol for the integrated analysis of genome-wide genetic and epigenetic data based on permutation of a sum statistic for the combined effects in a locus or pathway. The method was then applied to published type 1 diabetes (T1D) genome-wide- and epigenome-wide-association studies data to identify genomic loci and biological pathways that are associated with T1D genetically and epigenetically. Through combined analysis, novel loci and pathways were also identified, which could add to our understanding of disease mechanisms of T1D as well as complex diseases in general. PMID- 24071863 TI - Mid-term results of elective repair of extensive thoracic aortic pathology by the Evita Open Plus hybrid endoprosthesis only. AB - OBJECTIVES: To describe the early and mid-term clinical and instrumental results of the frozen elephant trunk (FET) procedure using the recent Evita Open Plus hybrid endoprosthesis for elective one-stage treatment of extensive thoracic aortic disease. METHODS: We reviewed 16 patients undergoing FET for post dissection aneurysm (50%), true aneurysm (31%) or other aetiologies (19%), through median sternotomy and hypothermic circulatory arrest. An average 14 +/- 7.6-month follow-up with regular contrast-enhanced control computed tomography scans was available. Four patients received preliminary carotid-subclavian bypass to improve spinal cord protection. Distal extension through endovascular deployment of stent-grafts into the descending aorta was performed during the same procedure in 3 patients. Concomitant procedures on the ascending aorta/root were done in 25% of cases. RESULTS: There were no cases of operative mortality. Cases of neither cerebral stroke nor postoperative paraplegia were observed. Two cases of transient paraparesis and 1 case of Brown-Sequard syndrome occurred. At follow-up, there were no cases of endoleak or endotension. One patient was reoperated for distal completion (thoracoabdominal aortic replacement). CONCLUSIONS: The FET using the Evita Open Plus device is a reliable and versatile treatment for one-step management of extensive disease of the aortic arch and the descending aorta. This strategy should be reserved for patients having limited preoperative comorbidities and good functional status. PMID- 24071864 TI - A technical review of the United Kingdom National Adult Cardiac Surgery Governance Analysis 2008-11. AB - The Society for Cardiothoracic Surgery in Great Britain and Ireland (SCTS) has published named mortality data since 2001. The importance of accurate and robust clinical outcome reporting has been emphasized by a number of high-profile cases in England. In this article, we give a technical review of the United Kingdom National Adult Cardiac Surgery Governance Analysis 2008-11. The statistical and analytical assumptions and methods are discussed in order to add an additional layer of transparency to the clinical governance process and precipitate scrutiny with the aim of optimizing future analyses. PMID- 24071865 TI - Adult coarctation of the aorta repaired with a prosthetic bypass and its long term follow-up. PMID- 24071866 TI - [Identification of fungal pathogens in tissue samples using fluorescence in situ hybridization]. AB - Deep fungal infections are associated with significant mortality despite the availability of new antifungal agents. The identification of causative fungi is important to define successful antifungal therapies as agents differ in the in vitro susceptibility. Characterization of tissue morphology and cultivation from tissue provide important clues to patient management. Molecular techniques such as PCR-based assays are increasingly being used to identify agents of invasive fungal infections. However, potential contamination limits the use when ubiquitous fungi are targeted. Hybridization with fluorescently labeled probes targeting the ribosomal RNA of fungi is emerging as an alternative identification strategy. Using conserved or variable regions of the rRNA as targets, group or species-specific probes can be synthesized to identify fungal pathogens and localize them in the infectious process. These techniques have been successfully applied to deep fungal infections due to different agents in various organ samples. PMID- 24071867 TI - Stage II to IV low-grade serous carcinoma of the ovary is associated with a poor prognosis: a clinicopathologic study of 32 patients from a population-based tumor registry. AB - Low-grade serous carcinoma (LGSC) of the ovary has only recently been recognized as a disease entity distinct from the more common high-grade serous carcinoma (HGSC). When confined to the ovary, LGSC is associated with a very favorable prognosis, and chemotherapy is typically not recommended. There is little available information on the prognosis of patients with LGSC with extraovarian spread, from population-based tumor registries where there has been full pathology review. Thirty-two cases of Stage II to IV ovarian LGSC were identified in the Cheryl Brown Ovarian Cancer Outcomes Unit (1984-2000). In 19 cases, blocks were available and immunostaining for p53, p16, Ki-67, WT1, and E-cadherin was performed. Expression of these markers was then compared with a series of >400 cases of HGSC from the outcomes unit. LGSCs presented at Stage II in 10/32 cases, Stage III in 21/32 cases, and Stage IV in 1/32 cases. On follow-up, most patients died of disease, with <30% survival at 10 years. Compared with HGSCs, the LGSCs were significantly less likely to express p16 at high levels, or to show abnormal p53 expression (P=0.049 and <0.0001, respectively). Ki-67 staining indices were lower in the LGSCs (P<0.0001). There were no significant differences between LGSCs and HGSCs with respect to expression of WT1 and E-cadherin (P=0.27 and 0.62, respectively). This population-based series of LGSC with extraovarian spread at presentation had an unfavorable prognosis, similar to that of HGSC. As previously reported, LGSC shows lower tumor proliferation and fewer p53 abnormalities than in HGSC. PMID- 24071868 TI - Developmentally restricted differentiation antigens are targets for immunotherapy in epithelial ovarian carcinoma. AB - Developmentally restricted differentiation antigens or cancer-placental antigens, tastin and bystin, are components of an adhesion molecule that plays a critical role in the implantation of the embryo to the uterus. Cell adhesion molecules have been implicated in the metastasis of carcinomas and could be critical targets for immunotherapy in epithelial ovarian carcinomas (EOCs). Our objectives were to define the expression of tastin and bystin proteins in EOCs. Expression of tastin and bystin mRNA in a panel of human tissues and 70 EOC specimens was investigated using qualitative polymerase chain reaction. Amplification products were confirmed by sequencing. Validation of results was performed using immunohistochemical analysis of tastin and bystin applied on a tissue microarray of 202 EOC tissues. The distribution of tastin and bystin expression and clinicopathologic variables were analyzed. Survival probabilities were estimated using the Kaplan-Meier method and statistical significance was determined by performing the logrank test. Expression of tastin and bystin was restricted to placental and testis tissue by qualitative polymerase chain reaction. Of the 70 EOC specimens tested with polymerase chain reaction, 89% and 94% expressed tastin and bystin, respectively. Immunoexpressions of tastin and bystin protein were observed in 69% and 80 % of the ovarian tumors, respectively. Tastin and bystin expression in Stage I/II disease were 66% and 67% compared with 69% and 81% in Stage III/IV disease, respectively. The tissue-restricted expression of tastin and bystin and their abundant expression in EOCs and advanced-stage disease make these developmentally restricted antigens attractive targets for antigen-specific immunotherapy in EOCs. PMID- 24071869 TI - HNF-1beta in ovarian carcinomas with serous and clear cell change. AB - Many ovarian tumors, including high-grade serous carcinoma (HGSC), show clear cell change. Accurate diagnosis is important, however, as ovarian clear cell carcinoma (OCCC) is known to be less responsive to traditional types of ovarian cancer chemotherapies. In a previous study, the clinical, morphologic, and immunohistochemical features of 32 ovarian carcinomas, which had been previously diagnosed as pure OCCC (n=11), pure HGSC (n=11), and mixed serous and clear cell (MSC) (n=10), were analyzed. The immunoreactivities of WT1, ER, and p53, as well as the mitotic indices and stages of presentation of the MSC, were similar to those of HGSC. It was consequently concluded that MSC represented HGSC with clear cell change. Hepatocyte nuclear factor-1beta (HNF-1beta) is a relatively new immunohistochemical marker that has been shown to be rather sensitive and specific for OCCC. We thus sought to evaluate this marker in this specific group of tumors. One block each of pure HGSC and pure OCCC were stained with HNF-1beta. In the cases of MSC, 2 blocks were stained when the serous and clear cell components were not present on the same slide. None (0/11) of the pure HGSC showed immunoreactivity for HNF-1beta, whereas all (11/11) of the pure OCCC were positive. In the cases of MSC, both the serous and clear cell components were negative for HNF-1beta. HNF-1beta seems to be a sensitive and specific marker for OCCC and is not expressed in HGSC with clear cell change. The pattern of immunoreactivity of HNF-1beta in tumors with both serous and clear cell change supports the conclusion that MSC are HGSC with clear cells. PMID- 24071870 TI - Precursor lesions and prognostic factors in primary peritoneal serous carcinoma. AB - Primary peritoneal serous carcinoma (PPSC) is uncommon and precursor lesions and prognostic factors are incompletely understood or described. Charts of 22 women with PPSC were reviewed for clinical and pathology data. Glass slides were reviewed for areas of PPSC, ovarian surface epithelium (OSE), ovarian cortical inclusion cysts (OCICs), tubal epithelial atypia (TEA), and serous tubal intraepithelial carcinoma (STIC). p53 and p16 immunohistochemical staining was scored and expression between the sites was compared. PPSC outcome was correlated with biomarker expression and clinicopathologic variables. p53 and p16 scores were significantly higher among PPSC and tubes than OSE and OCICs. Approximately 64% of PPSC, 46% of fallopian tubes, and none of the OSE overexpressed both biomarkers. OCICs were more frequently negative. Tubal pathologies of STIC, TEA and/or p53 signatures were present in approximately 46% of PPSC cases and the association with tubal p53 overexpression was significant. Statistically significant associations between tubal pathologies, OSE and OCICs biomarker expression profiles and their PPSC expression profiles did not occur. The median overall survival was 53 months and low-grade tumors had a better prognosis (P=0.02). A role for p53 and p16 overexpression in the formation of some PPSC, and p53 overexpression in the generation of precursor tubal pathology was identified. The high frequency of tubal pathology overexpressing p53 and low frequency of OSE and OCICs expressing either biomarker highlights a possible precursor role for the tube in some PPSC. Tumor grade was the only significant prognostic factor. PMID- 24071871 TI - Ovarian tumors with functioning stroma: a clinicopathologic study with special reference to serum estrogen level, stromal morphology, and aromatase expression. AB - Ovarian tumors with functioning stroma often show estrogenic manifestations. The range of serum estrogen level, however, has not been analyzed, nor the correlation with the stromal morphology. We reviewed the preoperative serum level of estradiol (E2) in 20 postmenopausal ovarian tumors that contained lutein- or theca-like cells in the stroma. Tumor histology included mucinous (n=7), endometrioid (n=4), clear (n=4), or Brenner tumor (n=2), carcinosarcoma (n=2), and Krukenberg tumor (n=1). Overall, the preoperative serum level of E2 ranged widely from 12.1 to 162.4 pg/mL (reference range, 10-30 pg/mL). The range of serum E2 was 24.9 to 162.4 pg/mL (mean, 58.0 pg/mL) in 7 tumors containing lutein like cells, and 12.1 to 157.8 pg/mL (mean, 57.0 pg/mL) in 13 tumors containing theca-like cells alone. There was no significant difference in the serum E2 level between the 2 groups. To determine whether the functioning stroma is capable of final conversion of androgens to estrogens, the expression of P450 aromatase was examined immunohistochemically. P450 aromatase was exclusively expressed in the stromal cells, both lutein- and theca-like cells, in 16 tumors. In all tumors, however, it was focally or sparsely distributed, and there was no correlation between the immunoreactivity for P450 aromatase and the serum E2 level. These findings indicate that the functioning stroma, regardless of cell morphology, has a capacity for converting androgens to estrogens, but a significant amount of serum estrogens is finally qualified in the aromatase-rich peripheral tissues. PMID- 24071872 TI - Metastatic cholangiocarcinoma to the ovary: a case series. AB - Metastases to the ovary can be a challenging diagnostic dilemma as they often present similarly to a primary ovarian cancer, and there are many potential sites of origin. We present a case series of 5 patients with known cholangiocarcinoma recurrent in the ovary after completion of initial multimodality therapy including surgical resection of the primary tumor followed by adjuvant chemotherapy. PMID- 24071873 TI - Primary squamous cell carcinoma of the endometrium: clinicopathologic and molecular characteristics. AB - Molecular alterations leading to cell cycle dysregulation in primary squamous cell carcinoma of the endometrium (PSCCE) and correlation with clinical outcome are incompletely described. Molecular variables of 5 cases of PSCCE were compared with 8 controls of endometrial endometrioid adenocarcinoma and correlated with overall survival. Immunohistochemical expression of pRB, p18, p19, CDK4, CDK6, Cyclin D1, p16, HPVE7, pTEN, ER, PR, and p53 was independently scored (intensity: 0-3 and proportion: 0-5) twice by 2 reviewers. Scores were averaged and expression was categorized as positive or negative. Human papillomavirus (HPV) DNA amplification and Braf and Kras mutations were assessed by polymerase chain reaction. Distribution differences between cases and controls were tested for significance using chi/Fisher exact tests. Differences in overall survival and correlation with variables were calculated using Kaplan-Meier and tested for significance using log rank tests. All cases and controls were mostly positive for pRB, p19, CDK6, and Cyclin D1 and mostly negative for p16, p18, CDK4, HPVE7, pTEN, and p53. Cases were mostly negative for ER and PR, whereas controls were mostly positive. All were negative for HPV DNA amplification and Braf mutations. One case and 2 controls had a Kras mutation. Only the ER and PR distribution difference was significant (P=0.03 and 0.02, respectively) and differences in overall survival did not correlate with any variable. PSCCE has molecular alterations involving the pRB-Cyclin D1-CDK4/6-p16 pathway, and pTEN. In contrast to the type I EACC, PSCCE is not hormonally sensitive, suggesting a unique pathogenesis. PMID- 24071874 TI - Infiltration of tumor-associated macrophages is increased in the epithelial and stromal compartments of endometrial carcinomas. AB - Tumor-associated macrophages (TAMs) are derived from monocytes and recruited to the tumor microenvironment, where they play an important role in the progression of cancer. There is strong evidence for an inverse relationship between TAM density and clinical prognosis in solid tumors of the breast, prostate, ovary, and cervix. However, the role of TAMs in endometrial cancer is not well described. The objectives of this study were to determine whether macrophage distribution or density differed among normal endometrial tissue, hyperplasia, Type I, and II endometrial adenocarcinomas. In addition, we looked for a correlation among TAM density, known histopathologic prognostic indicators, and endometrial cancer progression. The pathologic specimens of women who underwent hysterectomy for benign disorders, endometrial hyperplasia, Type I, or Type II cancers were sectioned and stained with anti-CD68 antibody. The density of CD68 macrophages was quantified and stratified according to their epithelial or stromal location. Type I and II endometrial carcinomas had significantly higher macrophage density in both epithelial and stromal compartments than benign endometrium. In both benign and neoplastic specimens, the numbers of macrophages were significantly higher in the stroma compared with the epithelium. Although there were important trends in the density of TAMs with regard to several histopathologic prognostic indicators of endometrial cancer, none were statistically significant and the patients' cancer progression did not correlate significantly with the number of TAMs. PMID- 24071875 TI - Myometrial hyperplasia mimics the clinical presentation of uterine fibroids: a report of 3 cases. AB - The clinical diagnosis of fibroid uterus is based on physical examination findings and/or ultrasound. However, it is not uncommon for routine pathology examination to report no significant fibroids in such cases. Myometrial hyperplasia (MMH) is a structural variation with irregular zones of hypercellularity and increased nucleus/cell ratio that appears in adolescence, can progress during the childbearing years, and can sometimes cause grossly detectable bulges on pathologic examination. MMH can be inframucosal, intramural (microscopic), or subserosal. Three premenopausal women with a preoperative diagnosis of fibroids on pelvic examination, and/or sonograms, underwent hysterectomies. In all the 3 cases, the Myoma Index (number of fibroids*size of largest fibroid) indicated insignificant fibroids. The pathology simulating fibroids was firm, bulging inframucosal MMH. Firm, bulging MMH can mimic uterine fibroids on ultrasound and physical examination. In hysterectomies for fibroid uterus with a Myoma Index <3.7, it is recommended that pathologists evaluate for MMH as the possible explanation for the findings on physical examination and/or ultrasound. PMID- 24071876 TI - Invasive endocervical adenocarcinoma: proposal for a new pattern-based classification system with significant clinical implications: a multi institutional study. AB - The management of endocervical adenocarcinoma is largely based on tumor size and depth of invasion (DOI); however, DOI is difficult to measure accurately. The surgical treatment includes resection of regional lymph nodes, even though most lymph nodes are negative and lymphadenectomies can cause significant morbidity. We have investigated alternative parameters to better identify patients at risk of node metastases. Cases of invasive endocervical adenocarcinoma from 12 institutions were reviewed, and clinical/pathologic features assessed: patients' age, tumor size, DOI, differentiation, lymph-vascular invasion, lymph node metastases, recurrences, and stage. Cases were classified according to a new pattern-based system into Pattern A (well-demarcated glands), B (early destructive stromal invasion arising from well-demarcated glands), and C (diffuse destructive invasion). In total, 352 cases (FIGO Stages I-IV) were identified. Patients' age ranged from 20 to 83 years (mean 45), DOI ranged from 0.2 to 27 mm (mean 6.73), and lymph-vascular invasion was present in 141 cases. Forty-nine (13.9%) demonstrated lymph node metastases. Using this new system, 73 patients (20.7%) with Pattern A tumors (all Stage I) were identified. None had lymph node metastases and/or recurrences. Ninety patients (25.6%) had Pattern B tumors, of which 4 (4.4%) had positive nodes; whereas 189 (53.7%) had Pattern C tumors, of which 45 (23.8%) had metastatic nodes. The proposed classification system can spare 20.7% of patients (Pattern A) of unnecessary lymphadenectomy. Patients with Pattern B rarely present with positive nodes. An aggressive approach is justified in patients with Pattern C. This classification system is simple, easy to apply, and clinically significant. PMID- 24071877 TI - Ectodermal structures within the uterine cervix and vagina: report of a series of cases. AB - Ectodermal structures, in the form of sebaceous glands and hair follicles, are extremely rare within the cervix and vagina. We describe the clinicopathologic findings in 11 cases (10 cervix, 1 vagina) with a view to exploring the histogenesis of this unusual phenomenon. The cases occurred in patients aged 33 to 71. In 10 of the cases, sebaceous glands were present that were associated with hair follicle-like structures in 3 cases forming pilosebaceous units. In the other case, hair follicle- and sweat gland-like structures were present; the latter have not been previously described in the cervix. The ectodermal structures were usually either attached to the basal layer of the surface squamous epithelium or lay "free" within the superficial stroma, although in 1 case sebaceous glands were located within the squamous epithelium. The squamous epithelium overlying the ectodermal structures typically exhibited hyperkeratosis. Although we were unable to definitively resolve the debate as to whether ectodermal structures within the cervix and vagina represent misplaced embryonal tissue and a true heterotopia or a "metaplastic" process, we favor the latter as a response to prolonged irritation or chronic injury. PMID- 24071878 TI - Adenocarcinoma arising from vaginal stump: unusual vaginal carcinogenesis 7 years after hysterectomy due to cervical intraepithelial neoplasia. AB - Primary vaginal adenocarcinomas are one of the rarest malignant neoplasms, which develop in the female genital tract. Because of the extremely low incidence, their clinical and pathologic characteristics are still obscure. Recently, we experienced a case of vaginal adenocarcinoma that appeared 7 yr after hysterectomy because of cervical intraepithelial neoplasia. The patient, a 65-yr old obese woman, was diagnosed as having adenocarcinoma in the vaginal stump and was treated by simple tumor excision and radiation. Immunohistochemical and molecular biologic examinations indicated a potential association with human papilloma virus infection in the development of the vaginal adenocarcinoma. There has been no evidence of recurrence for 3 yr after the operation. PMID- 24071880 TI - Sarcoidosis on tattoos: a review of the literature from 1939 to 2011. AB - Sarcoidosis is an autoimmune disease of unknown etiology characterized by the presence of non-caseating epithelioid cell granulomas in multiple organs. Cutaneous sarcoidosis occurs in approximately 25% of the cases. Sarcoid reactions on old scars, traumatized skin sites and around embedded foreign material have long been observed. For the past 70 years, sarcoidal granulomas on tattoos and permanent make-up have also been documented. Granulomatous and sarcoidal tattoo reactions may be the first and sometimes only cutaneous manifestation of systemic sarcoidosis. This review summarizes the currently available data on this topic and discusses the issues related to the diagnosis, management and physiopathogeny of sarcoidal reactions on tattoos. PMID- 24071881 TI - Clinical course and outcome of rheumatoid arthritis-related usual interstitial pneumonia. AB - BACKGROUND: Although the prognosis of interstitial pneumonia in connective tissue disorders is better than that of idiopathic pulmonary fibrosis (IPF), the prognosis of rheumatoid arthritis (RA) related usual interstitial pneumonia (UIP) is controversial. OBJECTIVES: To determine prognosis, clinical course and prognostic factors of the patients with RA-UIP and compare them to IPF. DESIGN: Retrospective review of 84 patients with RA-UIP (biopsy-proven: 30) from two tertiary referral centers. RESULTS: The median follow-up period was 33 months. One half of the patients were stable, one third progressed, 17% had acute exacerbation and 6% improved. TLC % predicted was the only significant predictor for the stable group. Among non-AEx patients, 41% was treated due to poor initial lung function or progression of the disease and one half of them improved or had stable lung function. Despite of worse initial lung function, the survival of treated group was similar to untreated group. Age, FVC and change in DLco during 6 months were significant predictors for mortality. The prognosis of RA-UIP was significantly better than that of IPF matched with age, sex, smoking and baseline lung function (median survival, 53 vs. 41 months respectively, p = 0.015). CONCLUSIONS: In spite of variable clinical course of RA-UIP, overall prognosis of RA-UIP was significantly better compared to IPF. Our data supported the treatment of the patients with significant functional impairments or progression. PMID- 24071882 TI - Calcium and vitamin D metabolism in sarcoidosis. AB - BACKGROUND: Sarcoidosis associated hypercalcemia (SAHC) may be secondary to excessive levels of 1,25-(OH)2 vitamin D3 produced by autonomous 1-alpha hydroxylase activity within the granulomas. The frequency, treatment, and consequences of hypercalcemia remain unclear. STUDY DESIGN AND METHODS: Two patient cohorts were studied. In Cohort 1, the prevalence of hypercalcemia in 1606 sarcoidosis patients seen during a six year period was analyzed along with treatment and outcome. Cohort 2 consisted of 261 sarcoidosis patients with measured 25-(OH) vitamin D3 and 1,25-(OH) vitamin D3 levels. In forty patients, serial levels of 25-(OH) vitamin D3 and 1,25-(OH) vitamin D3 were measured at least three months apart without change in therapy. RESULTS: SAHC was identified in 97 of 1606 (6%) of patients studied and additional nine (0.6%) patients had primary hyperparathyroidism. Post treatment follow up was available in 86 SAHC patients. Hypercalcemia improved in >90% of patients, including eight patients treated solely with vitamin D supplement withdrawal. Renal insufficiency, documented in 41 (42%) of SAHC patients, improved with hypercalcemia treatment. In 80% of Cohort 2 patients low 25-(OH) vitamin D3 levels were measured with only one patient having a low 1,25(OH)2 vitamin D3 level. Elevated 1,25(OH)2 vitamin D3 levels, which were measured in 11% of patients, were higher for those with a history of hypercalcemia. CONCLUSION: Sarcoidosis associated hypercalcemia, which is often accompanied by renal insufficiency, responds to treatment of sarcoidosis and withdrawal of vitamin D supplementation. Measurement of serum vitamin 1,25(OH)2 vitamin D3 appears to best evaluate vitamin D status in sarcoidosis patients. PMID- 24071883 TI - The effect of anticoagulant therapy for idiopathic pulmonary fibrosis in real life practice. AB - BACKGROUND: IPF is a common form of interstitial lung disease for which there is no effective therapy and usually results in death. Two previous contradictory studies showed anticoagulant therapy to be associated with both improved and worsened survival, respectively. OBJECTIVE: The objective of this retrospective cohort study was to evaluate the effect of anticoagulant therapy on the survival and disease progression of patients with idiopathic pulmonary fibrosis (IPF) in real clinical practice. METHODS: We compared the clinical characteristics, time to disease progression, incidence of acute exacerbation, and survival of 25 (20%) IPF patients receiving anticoagulant therapy to the remaining 97 IPF patients not receiving anticoagulant therapy. In addition we conducted a sensitivity analysis using as comparator a group of 25 patients matched by age, sex, functional impairment, cardiac comorbidities and pulmonary hypertension. RESULTS: Patients on anticoagulant therapy had a worse 1- and 3-year survival (84% and 53% versus 89% and 64% in the non-anticoagulant group, respectively), a difference that persisted after adjusting for age and comorbidities (hazard ratio 3.1 - 95% confidence interval, 1.4 to 7.0; p=0.006) and after comparison with the matched group (adjusted HR=4.8, 95% CI: 1.8-12.8; p=0.002). IPF patients on anticoagulant therapy had a shorter interval to disease progression ( 0.7 years versus 1.6 years, adjusted HR 2.2 -95% CI, 0.96 to 5.1; p=0.063) confirmed also in the analysis with matched subgroups (HR=2.7 (95% CI: 1.2-6.5); p=0.023). The incidence of acute exacerbations did not differ in the two groups (22% versus 23%). Two patients (8%) experienced anticoagulant treatment related complications and included an episode of hemorrhagic shock. CONCLUSION: In this retrospective study patients treated with anticoagulants had a worse survival and a shorter interval to disease progression. This support the recent finding that warfarin worsen the respiratory status and survival of IPF patients. PMID- 24071884 TI - Mortality among African American women with sarcoidosis: data from the Black Women's Health Study. AB - BACKGROUND: Sarcoidosis is a chronic systemic granulomatous disease of unknown etiology that disproportionately affects black females. Few studies have specifically addressed causes of death in this population. OBJECTIVES: To assess rates and causes of death among women with sarcoidosis in a prospective cohort study of U.S. black women. DESIGN: The Black Women's Health Study is a follow-up study of 59,000 U.S. black women aged 21-69 (median age 38) at entry in 1995. Data on demographic and lifestyle factors and medical conditions, including sarcoidosis, were obtained through biennial questionnaires. Deaths and causes of death from 1995 through 2009 among study subjects were identified from National Death Index data. We assessed mortality rates among women with and without a history of sarcoidosis. Poisson regression models were used to estimate age adjusted mortality rates. Cox proportional-hazards models were used to estimate hazard ratios for mortality and 95% confidence intervals. RESULTS: A total of 121 deaths occurred among 1,192 women with a history of sarcoidosis and 2813 deaths among women without sarcoidosis. Mortality was greater at every age among women with sarcoidosis and the overall multivariable-adjusted hazard ratio was 2.44 (95% CI 2.03-2.93, p<0.0001). Of the deaths among women with sarcoidosis, 24.7% were directly attributable to sarcoidosis. CONCLUSIONS: In the Black Women's Health Study, women with sarcoidosis were more than twice as likely to die as women without the disease, with many of the deaths directly attributable to sarcoidosis. Sarcoidosis is an important cause of premature death among black women with the disease. PMID- 24071885 TI - Outcome of patients with interstitial lung disease admitted to the intensive care unit. AB - INTRODUCTION: The outcome of acute respiratory failure (ARF) affecting patients with various interstitial lung diseases (ILD) is poorly defined particularly in those with drug-induced ILD (DI-ILD). We investigated this issue focusing on fibrosing idiopathic interstitial pneumonitis (FIIP) and DI-ILD. METHODS: We carried out a retrospective study of patients with ILD admitted in a single center ICU. The primary end-point was in-hospital mortality. RESULTS: We included 72 subjects who fell into 3 diagnostic groups: DI-ILD (n=20), FIIP (n=28) and miscellaneous (M-ILD) (n=24). In-hospital mortality rates were 40% (n=8/20), 68% (n=19/28), and 25% (n=6/24) for DI-ILD, FIIP and M-ILD, respectively, (p=0.006). It reached, 64% (n=7/11), 100% (n=17/17) and 60% (n=6/10), respectively, in subjects on mechanical ventilation (p=0.007). In multivariate analysis, the need for mechanical ventilation (OR= 35; [95% CI, 5-255]), the type of ILD (FIIP vs miscellaneous) (OR=22; [95% CI, 3-147]) and high-dose steroids during ICU stay (OR=0.19; [95% CI, 0.04-0.99]) were independent determinants of in-hospital mortality. CONCLUSION: This study, while confirming the poor prognosis of FIIP patients in ICU, highlights the better prognosis of DI-ILD and M-ILD even though severity criteria on admission are similar in these 3 groups. These data impact on the management of these patients in ICU in whom a proper diagnostic of the underlying condition is crucial. PMID- 24071886 TI - Detection of sarcoidosis associated fasciitis by uptake on a FDG PET scan: a novel finding. AB - We report a case of a sarcoidosis patient with bilateral calf and thigh stiffness who was noted to ha ve intense linear FDG uptake on a PET scan that localized to the fascia of his calves and theighs. His serum creatine kinase level was normal. Fasciitis has rarely been reported to be detected on FDG PET scans, and, to our knowledge, never in a sarcoidosis patient. FDG PET may have a role in identifying fasciitis or myositis when a patient has muscular complaints and no clinical or laboratory evidence of muscle injury. PMID- 24071887 TI - First presentation of sarcoidosis with severe obstructive sleep apnoea and epiglottic involvement. AB - Sarcoidosis of the upper respiratory tract (SURT) is rare but well documented. We present a patient whose first presentation with sarcoidosis was with dysphonia, upper airways obstruction and severe obstructive sleep apnoea (OSA) . Systemic steroids and hydroxycholoroquine led to improvement in phonation, endoscopic appearance and upper airway obstruction with significant improvement in Apnoea Hypopnoea Index (AHI) on polysomnography. PMID- 24071888 TI - Massive splenomegaly and pancytopenia reuealing sarcoidosis in a child. AB - Clinical presentation of sarcoidosis in children is very variable and dependant upon age. Herein, we report the first association of massive splenomegaly and pancytopenia as the revealing mode of sarcoidosis in an 8-year-old girl who, despite bone marrow involvement, had a remarkable good outcome following steroid therapy. PMID- 24071889 TI - Neurosarcoidosis presenting as trigeminal nevralgia: a case report and review of the literature. AB - Sarcoidosis is a granulomatous disease that can present systemically, but primarily has pulmonary manifestations. It is reported across all races, but has a higher incidence among African Americans. Neurological involvement in sarcoidosis is rare, with cranial nerve seven being the most commonly reported neurological finding. Trigeminal neuralgia, as presented in this case, is very rare. A 38-year-old African American female, with history of refractory trigeminal neuralgia, cutaneous sarcoidosis, and an extensive psychiatric history, presented to the hospital for fifth cranial nerve decompression. She had failed medical therapy and gamma knife therapy. Prior to surgery, magnetic resonance imaging (MRI) revealed a mass of 1.5 cm x 0.6 cm x 1.1 cm in the left Meckel's cave, which, when compared with prior imaging, was not present. A partial craniotomy was done to excise the mass. Frozen pathological sections showed granulomatous inflammation consistent with sarcoidosis. Stains for acid fast bacilli and fungi remained negative. Quantiferon Gold and HIV serum studies were negative. High resolution computed tomography (CT) scan the chest showed patchy infiltrates in the lungs that presented as chronic interstitial lung disease. The patient's neurological symptoms resolved after surgical resection. She was dismissed home on a tapering dose of dexamethasone and follow-up with a rheumatologist. This case illustrates that when a patient with sarcoidosis presents with neurological symptoms, neurosarcoid should be considered. Most cases are diagnosed during autopsies. Recognizing and correctly diagnosing neurosarcoid leads to proper treatment and decreased morbidity in patients. PMID- 24071890 TI - TLR7 Gln11Leu single nucleotide polymorphism in patients with sarcoidosis. AB - Sarcoidosis is a multi-factorial systemic disease with increased activity of the cellular immune components which is responsible of the formation of non-caseating granulomas in involved organs. Recent views on the etiology indicate interactions between inherited susceptibility and environmental or lifestyle factors. Concerning genes that may influence susceptibility to sarcoidosis Toll-like receptors (TLRs) may represent plausible candidates. In this present study, we investigated the X-linked TLR7 rs179008/Gln11Leu polymorphism situated on exon 3. SNP genotyping of the TLR7 exon polymorphism was performed by TaqMan allelic discrimination using the StepOnePlusTM Real-Time PCR System (Applied Biosystems). In females, the incidence of the AT genotypes of the polymorphism was significantly lower in sarcoidosis patients compared to control subjects (P=0.0001). We could observe in control subjects a significant preponderance of the T allele of the TLR7 rs179008/Gln11Leu polymorphism compared to sarcoidosis female patients (P=0.008). In males, no significant differences between patients and controls emerged in allele frequencies of the TLR7 rs179008/Gln11Leu polymorphism. The presence of the TLR7 rs179008/Gln11Leu polymorphism in sarcoidosis may determine an alteration of TLR7 function hampering the signaling pathway involved in the onset of both cellular and humoral autoimmunity. This is consistent with the view that in some circumstances genetic mutations affecting components of the immune system can prevent systemic autoimmunity. PMID- 24071892 TI - Reactivity of Ir(III) carbonyl complexes with water: alternative by-product formation pathways in catalytic methanol carbonylation. AB - The reactions of water with a number of iridium(III) complexes relevant to the mechanism for catalytic methanol carbonylation are reported. The iridium acetyl, [Ir(CO)2I3(COMe)](-), reacts with water under mild conditions to release CO2 and CH4, rather than the expected acetic acid. Isotopic labeling and kinetic experiments are consistent with a mechanism involving nucleophilic attack by water on a terminal CO ligand of [Ir(CO)2I3(COMe)](-) to give an (undetected) hydroxycarbonyl species. Subsequent decarboxylation and elimination of methane gives [Ir(CO)2I2](-). Similar reactions with water are observed for [Ir(CO)2I3Me](-), [Ir(CO)2(NCMe)I2(COMe)] and [Ir(CO)3I2Me] with the neutral complexes exhibiting markedly higher rates. The results demonstrate that CO2 formation during methanol carbonylation is not restricted to the conventional water gas shift mechanism mediated by [Ir(CO)2I4](-) or [Ir(CO)3I3], but can arise directly from key organo-iridium(III) intermediates in the carbonylation cycle. An alternative pathway for methane formation not involving the intermediacy of H2 is also suggested. A mechanism is proposed for the conversion MeOH + CO -> CO2 + CH4, which may account for the similar rates of formation of the two gaseous by-products during iridium-catalysed methanol carbonylation. PMID- 24071893 TI - A highly luminescent spiro-anthracenone-based organic light-emitting diode exhibiting thermally activated delayed fluorescence. AB - Efficient thermally activated delayed fluorescence was observed from a spiro anthracenone derivative (ACRSA). An organic light-emitting diode containing ACRSA exhibited blue-greenish electroluminescence with a maximum external quantum efficiency of 16.5%. PMID- 24071894 TI - Morpho-spectral imaging in the biosciences. PMID- 24071895 TI - Dispersive liquid-liquid microextraction in food analysis. A critical review. AB - An extensive critical evaluation of the application of dispersive liquid-liquid microextraction (DLLME) combined with chromatographic and atomic-spectroscopic methods for the determination of organic and inorganic compounds is presented. The review emphasizes the procedures used for the prior treatment of food samples, which are very different from the DLLME procedures generally proposed for water samples. The main contribution of this work in the field of DLLME reviews is its critical review of the abundant literature showing the increasing interest and practical advantages of using DLLME and closely related microextraction techniques for food analysis. PMID- 24071896 TI - Structural insights into calmodulin/adenylyl cyclase 8 interaction. AB - Calmodulin (CaM) is a highly conserved intracellular Ca(2+)-binding protein that exerts important functions in many cellular processes. Prominent examples of CaM regulated proteins are adenylyl cyclases (ACs), which synthesize cAMP as a central second messenger. The interaction of ACs with CaM represents the link between Ca(2+)-signaling and cAMP-signaling pathways. Thereby, different AC isoforms stimulated by CaM, comprise diverse mechanisms of regulation by the Ca(2+) sensor. To extend the structural information about the detailed mechanisms underlying the regulation of AC8 by CaM, we employed an integrated approach combining chemical cross-linking and mass spectrometry with two peptides representing the CaM-binding regions of AC8. These experiments reveal that the structures of CaM/AC8 peptide complexes are similar to that of the CaM/skeletal muscle myosin light chain kinase peptide complex where CaM is collapsed around the target peptide that binds to CaM in an antiparallel orientation. Cross linking experiments were complemented by investigating the binding of AC8 peptides to CaM thermodynamically with isothermal titration calorimetry. There were no hints on a complex, in which both AC8 peptides bind simultaneously to CaM, refining our current understanding of the interaction between CaM and AC8. PMID- 24071898 TI - Single cycle and transient force measurements in dynamic atomic force microscopy. AB - The monitoring of the deflection of a micro-cantilever, as the end of a sharp probe mounted at its end, i.e. the tip, interacts with a surface, forms the foundation of atomic force microscopy AFM. In a nutshell, developments in the field are driven by the requirement of obtaining ever increasing throughput and sensitivity, and enhancing the versatility of the instrument to simultaneously map the topography and quantify nanoscale processes and properties. In the most common dynamic mode of operation, the motion of the driven cantilever is monitored at a single point on its longitudinal axis. Here, we show that from this single point a waveform is obtained that contains all the details about conservative and dissipative interactions. Then a formalism that accounts for multiple arbitrary flexural modes is developed for an indirectly driven cantilever. The formalism is shown to allow recovery of the details of the interaction even in the presence of complex and relevant hysteretic forces when the cantilever oscillates in the steady state. In a different approach, we develop a formalism that monitors the wave profile of the cantilever, i.e. the waveform at five different points on its longitudinal axis. With this formalism the interaction can be reconstructed during a single oscillation cycle even in the transient state of oscillation. Finally, we discuss the potential and advantages of the proposed methods and future technical challenges. Other standard and state of the art techniques and methods are also discussed and compared with the ones presented here. This work should also provide insight into the current high throughput-high sensitivity developments dealing with multifrequency dynamic AFM where information is recovered from multiple eigenmodes. PMID- 24071899 TI - Cu-catalyzed tandem reactions of fluorinated alkynes with sulfonyl azides en route to 2-trifluoromethylquinolines. AB - A novel method for the synthesis of 2-trifluoromethylquinolines via Cu-catalyzed tandem reactions was reported. A strong electronic effect was observed, but the steric effect was negligible. PMID- 24071900 TI - Topological phase transition without gap closing. AB - Topological phase transition is accompanied with a change of topological numbers. According to the bulk-edge correspondence, the gap closing and the breakdown of the adiabaticity are necessary at the phase transition point to make the topological number ill-defined. However, the gap closing is not always needed. In this paper, we show that two topological distinct phases can be continuously connected without gap closing, provided the symmetry of the system changes during the process. Here we propose the generic principles how this is possible by demonstrating various examples such as 1D polyacetylene with the charge-density wave order, 2D silicene with the antiferromagnetic order, 2D silicene or quantum well made of HgTe with superconducting proximity effects and 3D superconductor Cu doped Bi2Se3. It is argued that such an unusual phenomenon can occur when we detour around the gap closing point provided the connection of the topological numbers is lost along the detour path. PMID- 24071897 TI - Development and pathologies of the arterial wall. AB - Arteries consist of an inner single layer of endothelial cells surrounded by layers of smooth muscle and an outer adventitia. The majority of vascular developmental studies focus on the construction of endothelial networks through the process of angiogenesis. Although many devastating vascular diseases involve abnormalities in components of the smooth muscle and adventitia (i.e., the vascular wall), the morphogenesis of these layers has received relatively less attention. Here, we briefly review key elements underlying endothelial layer formation and then focus on vascular wall development, specifically on smooth muscle cell origins and differentiation, patterning of the vascular wall, and the role of extracellular matrix and adventitial progenitor cells. Finally, we discuss select human diseases characterized by marked vascular wall abnormalities. We propose that continuing to apply approaches from developmental biology to the study of vascular disease will stimulate important advancements in elucidating disease mechanism and devising novel therapeutic strategies. PMID- 24071901 TI - Mitochondrial genome of the basidiomycetous yeast Jaminaea angkorensis. AB - Jaminaea angkorensis is an anamorphic basidiomycetous yeast species originally isolated from decaying leaves in Cambodia. Taxonomically, J. angkorensis is affiliated with Microstromatales (Exobasidiomycetes, Ustilaginomycotina, Basidiomycota) and represents a basal phylogenetic lineage of this fungal order. To perform a comparative analysis of J. angkorensis with other basidiomycetes, we determined and analyzed its complete mitochondrial DNA sequence. The mitochondrial genome is represented by 29,999 base pairs long, circular DNA containing 32 % guanine and cytosine residues. Its genetic organization is relatively compact and comprises typical genes for 15 conserved proteins involved in oxidative phosphorylation (atp6, 8, and 9; cob; cox1, 2, and 3; and nad1, 2, 3, 4, 4L, 5, and 6) and translation (rps3), two ribosomal RNAs (rnl and rns) and twenty-two transfer RNAs (trnA-Y). Although the gene content is similar to other basidiomycetes, the gene orders in the examined species exhibit only a limited synteny, reflecting their phylogenetic distances and extensive genome rearrangements. In addition, a comparative analysis of basidiomycete mitochondrial genomes indicates that stop-to-tryptophan reassignment of the UGA codon was accompanied by structural alterations of tRNA-Trp(CCA). These results provide an insight into the evolution of the genetic code in fungal mitochondria. PMID- 24071902 TI - Use of atomic force microscopy (AFM) to explore cell wall properties and response to stress in the yeast Saccharomyces cerevisiae. AB - Over the past 20 years, the yeast cell wall has been thoroughly investigated by genetic and biochemical methods, leading to remarkable advances in the understanding of its biogenesis and molecular architecture as well as to the mechanisms by which this organelle is remodeled in response to environmental stresses. Being a dynamic structure that constitutes the frontier between the cell interior and its immediate surroundings, imaging cell surface, measuring mechanical properties of cell wall or probing cell surface proteins for localization or interaction with external biomolecules are among the most burning questions that biologists wished to address in order to better understand the structure-function relationships of yeast cell wall in adhesion, flocculation, aggregation, biofilm formation, interaction with antifungal drugs or toxins, as well as response to environmental stresses, such as temperature changes, osmotic pressure, shearing stress, etc. The atomic force microscopy (AFM) is nowadays the most qualified and developed technique that offers the possibilities to address these questions since it allows working directly on living cells to explore and manipulate cell surface properties at nanometer resolution and to analyze cell wall proteins at the single molecule level. In this minireview, we will summarize the most recent contributions made by AFM in the analysis of the biomechanical and biochemical properties of the yeast cell wall and illustrate the power of this tool to unravel unexpected effects caused by environmental stresses and antifungal agents on the surface of living yeast cells. PMID- 24071904 TI - Temporal quantification of oxygen saturation ranges: an effort to reduce hyperoxia in the neonatal intensive care unit. AB - OBJECTIVE: To reduce exposure to hyperoxia and its associated morbidities in preterm neonates. STUDY DESIGN: A multidisciplinary group was established to evaluate oxygen exposure in our neonatal intensive care unit. Infants were assigned target saturation ranges and signal extraction technology implemented to temporally quantify achievement of these ranges. The outcomes bronchopulmonary dysplasia/death, retinopathy of prematurity (ROP)/death, severe ROP and ROP requiring surgery were compared in a pre- versus post-intervention evaluation using multivariate analyses. RESULT: A total of 304 very low birth weight pre initiative infants were compared with 396 post-initiative infants. Multivariate analyses revealed decreased odds of severe ROP (adjusted odds ratio (OR): 0.41; 95% confidence interval (CI): 0.24-0.72) and ROP requiring surgery (adjusted OR 0.31; 95% CI: 0.17-0.59) post-initiative. No differences in death were observed. CONCLUSION: Significant reductions in severe ROP and ROP requiring surgery were observed after staff education and implementation of new technology to quantify success in achieving targeted saturations and reinforce principles and practices. PMID- 24071905 TI - Work of breathing indices in infants with respiratory insufficiency receiving high-flow nasal cannula and nasal continuous positive airway pressure. AB - OBJECTIVE: To compare work of breathing (WOB) indices between two nCPAP settings and two levels of HFNC in a crossover study. STUDY DESIGN: Infants with a CGA 28 40 weeks, baseline of HFNC 3-5 lpm or nCPAP 5-6 cmH2O and fraction of inspired oxygen <=40% were eligible. WOB was analyzed using respiratory inductive plethysmography (RIP) for each of the four modalities: HFNC 3 and 5 lpm, nCPAP 5 and 6 cmH2O. N=20; Study weight 1516 g (+/-40 g). RESULT: Approximately 12,000 breaths were analyzed indicating a high degree of asynchronous breathing and elevated WOB indices at all four levels of support. Phase angle values (means) (P<0.01): HFNC 3 lpm (114.7 degrees ), HFNC 5 lpm (96.7 degrees ), nCPAP 5 cmH2O (87.2 degrees ), nCPAP 6 cmH2O (80.5 degrees ). The mean phase relation of total breath (PhRTB) (means) (P<0.01): HFNC 3 lpm (63.2%), HFNC 5 lpm (55.3%), nCPAP 5 cmH2O (49.3%), nCPAP 6 cmH2O (48.0%). The relative labored breathing index (LBI) (means) (P<=0.001): HFNC 3 lpm (1.39), HFNC 5 lpm (1.31), nCPAP 5 cmH2O (1.29), nCPAP 6 cmH2O (1.26). Eighty-two percent of the study subjects-respiratory mode combinations displayed clustering, in which a proportion of breaths either occurred predominantly out-of-phase (relative asynchrony) or in-phase (relative synchrony). CONCLUSION: In this study, WOB indices were statistically different, yet clinically similar in that they were elevated with respect to normal values. These infants with mild-to-moderate respiratory insufficiency demonstrate a meaningful elevation in WOB indices and continue to require non-invasive respiratory support. Patient variability exists with regard to biphasic clustered breathing patterns and the level of supplemental fraction of inspired oxygen <=40% alone does not provide guidance to the optimal matching of WOB indices and non-invasive respiratory support. PMID- 24071907 TI - Estimating the quality of neonatal transport in California. AB - OBJECTIVE: To develop a strategy to assess the quality of neonatal transport based on change in neonatal condition during transport. STUDY DESIGN: The Canadian Transport Risk Index of Physiologic Stability (TRIPS) score was optimized for a California (Ca) population using data collected on 21 279 acute neonatal transports, 2007 to 2009, using models predicting (2/3) and validating (1/3) mortality within 7 days of transport. Quality Change Point 10th percentile (QCP10), a benchmark of the greatest deterioration seen in 10% of the transports by top-performing teams, was established. RESULT: Compared with perinatal variables (0.79), the Ca-TRIPS had a validation receiver operator characteristic area for prediction of death of 0.88 in all infants and 0.86 in infants transported after day 7. The risk of death increased 2.4-fold in infants whose deterioration exceeded the QCP10. CONCLUSION: We present a practical, benchmarked, risk-adjusted, estimate of the quality of neonatal transport. PMID- 24071906 TI - N-terminal pro-brain natriuretic peptide levels in monochorionic diamniotic twins with selective intrauterine growth restriction. AB - OBJECTIVE: To compare serum N-terminal pro-brain natriuretic peptide levels at birth between monochorionic diamniotic twins with and without selective intrauterine growth restriction. STUDY DESIGN: Blood samples were collected from 73 monochorionic diamniotic twins without twin-to-twin transfusion syndrome. Two groups were studied on the basis of fetal ultrasonographic findings: 16 twins with and 57 twins without selective intrauterine growth restriction. Selective intrauterine growth restriction was defined as an estimated fetal weight below the 10th percentile in one twin at 18 to 26 weeks of gestation. Serum N-terminal pro-brain natriuretic peptide levels were measured. RESULT: Serum N-terminal pro brain natriuretic peptide levels in monochorionic diamniotic twins with selective intrauterine growth restriction were significantly higher than in those without selective intrauterine growth restriction. Selective intrauterine growth restriction was independently associated with increased N-terminal pro-brain natriuretic peptide levels. CONCLUSION: N-terminal pro-brain natriuretic peptide levels at birth are elevated in monochorionic diamniotic twins with selective intrauterine growth restriction. PMID- 24071908 TI - Tagmentation-based whole-genome bisulfite sequencing. AB - Epigenetic modifications such as carbon 5 methylation of the cytosine base in a CpG dinucleotide context are involved in the onset and progression of human diseases. A comprehensive understanding of the role of genome-wide DNA methylation patterns, the methylome, requires quantitative determination of the methylation states of all CpG sites in a genome. So far, analyses of the complete methylome by whole-genome bisulfite sequencing (WGBS) are rare because of the required large DNA quantities, substantial bioinformatic resources and high sequencing costs. Here we describe a detailed protocol for tagmentation-based WGBS (T-WGBS) and demonstrate its reliability in comparison with conventional WGBS. In T-WGBS, a hyperactive Tn5 transposase fragments the DNA and appends sequencing adapters in a single step. T-WGBS requires not more than 20 ng of input DNA; hence, the protocol allows the comprehensive methylome analysis of limited amounts of DNA isolated from precious biological specimens. The T-WGBS library preparation takes 2 d. PMID- 24071909 TI - Upconversion luminescence imaging of cells and small animals. AB - Upconversion luminescence (UCL) is an anti-Stokes process whereby low-energy photons are converted to higher-energy ones. UCL imaging for cells and animal tissues has attracted substantial attention in recent years because of the unique abilities of upconversion materials, which can minimize the background interference from the autofluorescence of biosamples and enhance tissue penetration. This protocol describes a step-by-step guide for the fabrication of UCL probes, including lanthanide-based upconversion nanoparticles (Ln-UCNPs) with a particle size of ~20 nm (NaYF4/NaLuF4: Yb, Er/Tm) and triplet-triplet annihilation-based UCNPs (TTA-UCNPs) with a particle size of ~10 nm (palladium octaethylporphyrin as sensitizer and 9,10-diphenylanthracene as annihilator). We also describe the characterization of the UCL nanoprobes (via transmission electron microscopy and UCL emission spectroscopy) and functionalization (via silica coating and ligand exchange), as well as applications for UCL bioimaging of living cells (HeLa cells) and small animals (nude mice and Kunming mice). The setup of a laser-scanning UCL microscope and a UCL imaging system is also presented. Compared with a normal imaging setup, we adopted longer-wavelength excitation lasers and short-pass filters. The synthesis of hydrophilic UCNP for application in UCL bioimaging requires ~15 d. PMID- 24071910 TI - Real-time single-molecule coimmunoprecipitation of weak protein-protein interactions. AB - Coimmunoprecipitation (co-IP) analysis is a useful method for studying protein protein interactions. It currently involves electrophoresis and western blotting, which are not optimized for detecting weak and transient interactions. In this protocol we describe an advanced version of co-IP analysis that uses real-time, single-molecule fluorescence imaging as its detection scheme. Bait proteins are pulled down onto the imaging plane of a total internal reflection (TIR) microscope. With unpurified cells or tissue extracts kept in reaction chambers, we observe single protein-protein interactions between the surface-immobilized bait and the fluorescent protein-labeled prey proteins in real time. Such direct recording provides an improvement of five orders of magnitude in the time resolution of co-IP analysis. With the single-molecule sensitivity and millisecond time resolution, which distinguish our method from other methods for measuring weak protein-protein interactions, it is possible to quantify the interaction kinetics and active fraction of native, unlabeled bait proteins. Real time single-molecule co-IP analysis, which takes ~4 h to complete from lysate preparation to kinetic analysis, provides a general avenue for revealing the rich kinetic picture of target protein-protein interactions, and it can be used, for example, to investigate the molecular lesions that drive individual cancers at the level of protein-protein interactions. PMID- 24071912 TI - Hydrogen-fluorine exchange in NaBH4-NaBF4. AB - Hydrogen-fluorine exchange in the NaBH4-NaBF4 system is investigated using a range of experimental methods combined with DFT calculations and a possible mechanism for the reactions is proposed. Fluorine substitution is observed using in situ synchrotron radiation powder X-ray diffraction (SR-PXD) as a new Rock salt type compound with idealized composition NaBF2H2 in the temperature range T = 200 to 215 degrees C. Combined use of solid-state (19)F MAS NMR, FT-IR and DFT calculations supports the formation of a BF2H2(-) complex ion, reproducing the observation of a (19)F chemical shift at -144.2 ppm, which is different from that of NaBF4 at -159.2 ppm, along with the new absorption bands observed in the IR spectra. After further heating, the fluorine substituted compound becomes X-ray amorphous and decomposes to NaF at ~310 degrees C. This work shows that fluorine substituted borohydrides tend to decompose to more stable compounds, e.g. NaF and BF3 or amorphous products such as closo-boranes, e.g. Na2B12H12. The NaBH4-NaBF4 composite decomposes at lower temperatures (300 degrees C) compared to NaBH4 (476 degrees C), as observed by thermogravimetric analysis. NaBH4-NaBF4 (1:0.5) preserves 30% of the hydrogen storage capacity after three hydrogen release and uptake cycles compared to 8% for NaBH4 as measured using Sievert's method under identical conditions, but more than 50% using prolonged hydrogen absorption time. The reversible hydrogen storage capacity tends to decrease possibly due to the formation of NaF and Na2B12H12. On the other hand, the additive sodium fluoride appears to facilitate hydrogen uptake, prevent foaming, phase segregation and loss of material from the sample container for samples of NaBH4-NaF. PMID- 24071911 TI - Seamless genome editing in human pluripotent stem cells using custom endonuclease based gene targeting and the piggyBac transposon. AB - I report here a detailed protocol for seamless genome editing using the piggyBac transposon in human pluripotent stem cells (hPSCs). Recent advances in custom endonucleases have enabled us to routinely perform genome editing in hPSCs. Conventional approaches use the Cre/loxP system that leaves behind residual sequences in the targeted genome. I used the piggyBac transposon to seamlessly remove a drug selection cassette and demonstrated safe genetic correction of a mutation causing alpha-1 antitrypsin deficiency in patient-derived hPSCs. An alternative approach to using the piggyBac transposon to correct mutations involves using single-stranded oligonucleotides, which is a faster process to complete. However, this experimental procedure is rather complicated and it may be hard to achieve homozygous modifications. In contrast, using the piggyBac transposon with drug selection-based enrichment of genetic modifications, as described here, is simple and can yield multiple correctly targeted clones, including homozygotes. Although two rounds of genetic manipulation are required to achieve homozygote modifications, the entire process takes ~3 months to complete. PMID- 24071913 TI - Longitudinal task-negative network analyses in preclinical Huntington's disease. AB - Functional neuroimaging studies have reported task-related brain activation changes in preclinical individuals carrying the Huntington's disease (HD) gene mutation (preHD). Little is known about "task-negative" activity, i.e., patterns of task-related deactivation in preHD, and about the stability of any deactivation changes over the course of the disease. Here, we explored task related deactivation and functional connectivity of "task-negative" networks (TNNs) in preHD followed over a time period of 2 years. Thirteen far-from-onset preHD (mean time to estimated motor onset = 19.5 years) and thirteen healthy controls were investigated. We used functional magnetic resonance imaging (fMRI), a verbal working memory task, and uni- and multivariate analysis techniques for fMRI data. Behavior was similar in preHD and controls at baseline and did not change 2 years later. At both time points, deactivation was similar in preHD and controls. Within two spatio-temporally distinct TNNs, preHD had lower functional connectivity in the posterior cingulate cortex and higher functional connectivity in the left anterior prefrontal cortex compared to controls (p < 0.05, cluster corrected). These findings remained stable at follow-up. Anterior prefrontal connectivity correlated with disease burden scores both at baseline and at follow up. Over time, preHD exhibited higher connectivity in a dorsal cingulate region. Functional connectivity differences within this region were inversely associated with changes of motor function. These data provide first evidence for TNN connectivity changes in preHD followed over a period of 2 years. The relationship between dorsal cingulate connectivity and motor function suggests that "task negative" activity may capture time-sensitive neural and functional processes in preHD. PMID- 24071914 TI - Genetics of psychiatric disorders in the GWAS era: an update on schizophrenia. AB - The influence of genetic factors in the development of schizophrenia has been convincingly demonstrated by family, twin, and adoption studies. The statistical construct of heritability is generally used for estimating the liability due to genetic factors. Heritability estimates for schizophrenia are reported to be between 60 and 80 %. Due to the technical achievements in whole genome-wide association studies, dissection of the underlying genetic factors was intensified recently, resulting in the conclusion that schizophrenia is essentially a polygenic, complex disorder. Most likely more than 100 genes, each with small effect size, contribute to disease risk. A most recent multi-stage genome-wide association study (Ripke et al. in Nat Genet 2013) identified 22 risk loci and estimated that 8,300 independent single-nucleotide polymorphisms contributed to the risk accounting collectively for 32 % in liability. In addition to this polygenic, complex inheritance, there is also strong indication that in some patients a deletion or insertion of a larger chromosomal region [so-called copy number variation (CNV)] might play a crucial role in pathogenesis. This could be specifically important in sporadic cases with schizophrenia, since a higher frequency of de novo mutations has been associated with these CNVs. Further studies, combining much larger sample sizes as well as application of newer technology, such as deep sequencing technologies will be necessary in order to obtain a more comprehensive understanding of the genetic foundations of schizophrenia. PMID- 24071915 TI - An interaction between oxytocin and a genetic variation of the oxytocin receptor modulates amygdala activity toward direct gaze: evidence from a pharmacological imaging genetics study. AB - The neuropeptide oxytocin plays an important role in social cognition. One valuable tool to study social cognition in healthy and autistic humans in a neuroscientific context is the investigation of gaze toward another person. Of importance, it has been demonstrated that pronounced amygdala activation could be observed, when participants are confronted with direct gaze pictures in an fMRI setting, an effect that can be particularly observed in autistic individuals. In the present study, a combined pharmacological imaging genetics study has been conducted to further investigate the biological basis of direct gaze processing. N = 55 healthy males were invited to an oxytocin challenge study administered while watching direct vs. averted gaze pictures in an fMRI setting. In addition, the promoter region of the oxytocin receptor (OXTR) gene of the participants was investigated to search for individual differences in the recorded BOLD signal. The main result revealed that a genetic variation of the OXTR gene (rs401015) modulated the right amygdala activity for the fMRI contrast "direct > averted gaze" under the influence of the neuropeptide oxytocin. Here, carriers of the heterozygous CT variant showed higher activity compared to the TT group. The present study highlights the role of individual differences in a genetic variant of the OXTR gene for amygdala activation during processing of direct gaze pictures after intranasal oxytocin administration. In sum, the study shows the importance of combining a pharmacological challenge with genetic imaging to better understand the biological basis of social cognition. PMID- 24071916 TI - A fluorescent peroxidase probe increases the sensitivity of commercial ELISAs by two orders of magnitude. AB - The low detection sensitivity of enzyme linked immunosorbent assays (ELISAs) is a central problem in science and limits progress in multiple areas of biology and medicine. In this report we demonstrate that the hydrocyanines, a family of fluorescent reactive oxygen species (ROS) probes, can act as turn on fluorescent horseradish peroxidase (HRP) probes and thereby increase the sensitivity of conventional ELISAs by two orders of magnitude. PMID- 24071917 TI - Phenotypic screening with human iPS cell-derived cardiomyocytes: HTS-compatible assays for interrogating cardiac hypertrophy. AB - A major hurdle for cardiovascular disease researchers has been the lack of robust and physiologically relevant cell-based assays for drug discovery. Derivation of cardiomyocytes from human-induced pluripotent stem (iPS) cells at high purity, quality, and quantity enables the development of relevant models of human cardiac disease with source material that meets the demands of high-throughput screening (HTS). Here we demonstrate the utility of iPS cell-derived cardiomyocytes as an in vitro model of cardiac hypertrophy. Exposure of cardiomyocytes to endothelin 1 (ET-1) leads to reactivation of fetal genes, increased cell size, and robust expression of B-type natriuretic peptide (BNP). Using this system, we developed a suite of assays focused on BNP detection, most notably a high-content imaging based assay designed for phenotypic screening. Miniaturization of this assay to a 384-well format enabled the profiling of a small set of tool compounds known to modulate the hypertrophic response. The assays described here provide consistent and reliable results and have the potential to increase our understanding of the many mechanisms underlying this complex cardiac condition. Moreover, the HTS compatible workflow allows for the incorporation of human biology into early phases of drug discovery and development. PMID- 24071918 TI - Significant interaction between activated charcoal and antiretroviral therapy leading to subtherapeutic drug concentrations, virological breakthrough and development of resistance. AB - A 42-year-old, treatment-experienced woman, virologically suppressed on tenofovir/emtricitabine and boosted atazanavir, experienced virological breakthrough, drop in CD4(+) T-cell count and undetectable drug concentrations. Adherence to treatment was confirmed, but repeat testing yielded similar results. After 2 months, the patient stated that she had been taking activated charcoal to manage gastrointestinal symptoms associated with her combination antiretroviral therapy, but she had recently discontinued the charcoal. Atazanavir concentrations were therapeutic but the patient's viral load rebounded and genotype testing revealed new reverse transcriptase mutations. The patient was changed to zidovudine, lamivudine, and boosted darunavir and achieved viral suppression. At 1 year follow-up, her viral load remained <40 copies/ml. According to the drug interaction probability scale, our patient experienced a probable drug interaction between activated charcoal and atazanavir/ritonavir leading to virological breakthrough and development of resistance. PMID- 24071921 TI - Associations of workplace bullying and harassment with pain. AB - The aim of this study was to investigate associations of workplace bullying and harassment with headache, stiffness of the neck or shoulders, lumbago, and pain of two or more joints. The subjects in this cross-sectional study were recruited from workers (n = 1,913) at 35 healthcare or welfare facilities in Japan. Because of non-participation or missing data, the number of subjects included in the analysis varied (response rate >= 77.1%). Workplace bullying and harassment were assessed using the Negative Acts Questionnaire. Depression was assessed using the Brief Job Stress Questionnaire. The frequency of pain experienced by workers in the previous month was evaluated using a four-point scale. Many of the associations of person-related bullying, work-related bullying, and sexual harassment with headache, stiffness of the neck or shoulders, lumbago, and pain of two or more joints were positive and significant (p < 0.05). Even after adjustment for depression, some of the associations remained significant (p < 0.05). For example, changes in the prevalence ratio for headache associated with a 1-point increase in the work-related bullying score were 1.05 (95% confidence interval (CI) 1.01 to 1.09) in men and 1.03 (95% CI 1.01 to 1.05) in women after adjustment for age, marital status, employment status, work shift, and depression. PMID- 24071920 TI - Can probiotics improve the environmental microbiome and resistome of commercial poultry production? AB - Food animal production systems have become more consolidated and integrated, producing large, concentrated animal populations and significant amounts of fecal waste. Increasing use of manure and litter as a more "natural" and affordable source of fertilizer may be contributing to contamination of fruits and vegetables with foodborne pathogens. In addition, human and animal manure have been identified as a significant source of antibiotic resistance genes thereby serving as a disseminator of resistance to soil and waterways. Therefore, identifying methods to remediate human and animal waste is critical in developing strategies to improve food safety and minimize the dissemination of antibiotic resistant bacteria. In this study, we sought to determine whether withdrawing antibiotic growth promoters or using alternatives to antibiotics would reduce the abundance of antibiotic resistance genes or prevalence of pathogens in poultry litter. Terminal restriction fragment length polymorphism (T-RFLP) paired with high throughput sequencing was used to evaluate the bacterial community composition of litter from broiler chickens that were treated with streptogramin growth-promoting antibiotics, probiotics, or prebiotics. The prevalence of resistance genes and pathogens was determined from sequencing results or PCR screens of litter community DNA. Streptogramin antibiotic usage did not elicit statistically significant differences in Shannon diversity indices or correlation coefficients among the flocks. However, T-RFLP revealed that there were inter farm differences in the litter composition that was independent of antibiotic usage. The litter from all farms, regardless of antibiotic usage, contained streptogramin resistance genes (vatA, vatB, and vatE), macrolide-lincosamide streptogramin B resistance genes (ermA and ermB), the tetracycline resistance gene tetM and class 1 integrons. There was inter-farm variability in the distribution of vatA and vatE with no statistically significant differences with regards to usage. Bacterial diversity was higher in litter when probiotics or prebiotics were administered to flocks but as the litter aged, diversity decreased. No statistically significant differences were detected in the abundance of class 1 integrons where 3%-5% of the community was estimated to harbor a copy. Abundance of pathogenic Clostridium species increased in aging litter despite the treatment while the abundance of tetracycline-resistant coliforms was unaffected by treatment. However some treatments decreased the prevalence of Salmonella. These findings suggest that withdrawing antibiotics or administering alternatives to antibiotics can change the litter bacterial community and reduce the prevalence of some pathogenic bacteria, but may not immediately impact the prevalence of antibiotic resistance. PMID- 24071919 TI - Hepatitis E virus: foodborne, waterborne and zoonotic transmission. AB - Hepatitis E virus (HEV) is responsible for epidemics and endemics of acute hepatitis in humans, mainly through waterborne, foodborne, and zoonotic transmission routes. HEV is a single-stranded, positive-sense RNA virus classified in the family Hepeviridae and encompasses four known Genotypes (1-4), at least two new putative genotypes of mammalian HEV, and one floating genus of avian HEV. Genotypes 1 and 2 HEVs only affect humans, while Genotypes 3 and 4 are zoonotic and responsible for sporadic and autochthonous infections in both humans and several other animal species worldwide. HEV has an ever-expanding host range and has been identified in numerous animal species. Swine serve as a reservoir species for HEV transmission to humans; however, it is likely that other animal species may also act as reservoirs. HEV poses an important public health concern with cases of the disease definitively linked to handling of infected pigs, consumption of raw and undercooked animal meats, and animal manure contamination of drinking or irrigation water. Infectious HEV has been identified in numerous sources of concern including animal feces, sewage water, inadequately-treated water, contaminated shellfish and produce, as well as animal meats. Many aspects of HEV pathogenesis, replication, and immunological responses remain unknown, as HEV is an extremely understudied but important human pathogen. This article reviews the current understanding of HEV transmission routes with emphasis on food and environmental sources and the prevalence of HEV in animal species with zoonotic potential in humans. PMID- 24071922 TI - Disparities and menthol marketing: additional evidence in support of point of sale policies. AB - This study examined factors associated with point-of-sale tobacco marketing in St. Louis, an urban city in the United States. Using spatial analysis, descriptive statistics, and multilevel modeling, we examined point-of-sale data and the proportion of mentholated cigarette and total cigarette marketing from 342 individual tobacco retail stores within St. Louis census tracts characterized by the percent of black adults and children. Menthol and total tobacco product marketing was highest in areas with the highest percentages of black residents. When examining menthol marketing to children, we did not find as strong of a relationship, however results of multilevel modeling indicate that as the proportion of black children in a census tract increased, the proportion of menthol marketing near candy also increased. These results indicate the need for communities globally to counter this targeted marketing by taking policy action specifically through the enactment of marketing restrictions provided by the 2009 Family Smoking Prevention and Tobacco Control Act and the Framework Convention of Tobacco Control. PMID- 24071923 TI - Toluene-assisted synthesis of RHO-type zeolitic imidazolate frameworks: synthesis and formation mechanism of ZIF-11 and ZIF-12. AB - Toluene was discovered as the structure template for the synthesis of large-cage RHO-type zeolitic imidazolate frameworks (ZIF-11 and ZIF-12) in an alcohol-based solution where benzimidazole-toluene interactions play a decisive structure directing role; otherwise it leads to small-cage SOD-type ZIF-7 and ZIF-9 without toluene. The specific pi-pi interactions make toluene molecules adopt a specific and oriented arrangement in the unit cell. XRD intensity of the (100) plane is strongly dependent on the amount of toluene: apparent intensity degradation is observed after removing toluene by solvent exchange or thermal treatment, and the peak intensity is recoverable by filling of the pores with toluene vapor. More polar methanol as compared to ethanol is favorable for the formation of RHO-type ZIFs due to the enhanced interactions between toluene and imidazolate linkers. PMID- 24071924 TI - Observation of own exploration movements impairs haptic spatial perception. AB - The present study was designed to assess whether the visibility of ones' own exploratory movements impairs or enhances perceptual speed and precision of haptic stimuli with varying complexity. Previous studies have shown that noninformative vision of steady surroundings improves haptic spatial perception. However, due to the serial nature of haptic processing and limited capacity of working memory resources, we hypothesized that noninformative vision of limb movements may impair haptic perception. The study sample consisted of ninety eight healthy adults who were randomized into two groups, matched for sex and age. Participants were required to explore two-dimensional haptic stimuli with varying complexity and to recognize them visually. The difference between the two experimental groups was a screen that would prevent the participants from viewing their hands during exploration in the nonobservation condition (NonOb). The other half of participants were able to see their hands in the manual movement observation condition (MovOb) thanks to the special design of the stimuli. As hypothesized, the persons in the MovOb condition made significantly more errors. The difference in error frequency between participants of the MovOb and NonOb condition was greater for complex stimuli than for simple ones. These results suggest that incoming visual information about own manual exploration movements increases competitive pressure for limited working memory resources, and therefore, more recognition errors are made. Covering the hands during exploration may constitute a helpful simplification of the task's demands by supporting the maintenance of information in working memory. Additionally, the relation of haptic complexity and stimulus characteristics was analyzed. PMID- 24071925 TI - Balance affects prism adaptation: evidence from the latent aftereffect. AB - In prism adaptation experiments, the effect on throwing to a target is reduced (primary aftereffect is smaller) when the throwing condition with prisms removed (first test phase) is different from the throwing condition with prisms (the training phase). The missing adaptation, however, can be revealed through further testing (second test phase) in which the throwing condition during training is fully reinstated. We studied throwing underhand to a target flush with the floor. During training, participants wore left-shifting prism glasses while standing on the floor (Group 1) or on a balance board (Groups 2 and 3). Tests 1 and 2 following training involved the same underhand throwing. For Group 2, Test 1 was on the balance board and Test 2 on the ground; for Group 3, the order was reversed; and for Group 1, both tests were on the ground. The Group 3 Test 1 aftereffect was smaller, and the Test 2 aftereffect was larger than the respective tests for Groups 1 and 2, with the aftereffect sum the same for all three groups. A parallel was noted between prism adaptation and implicit memory: whether given training (study) conditions lead to better or poorer persistence of adaptation (memory performance) at test depends on the fit between the conditions at test relative to the conditions at training (study). In the general memory case, those conditions will involve nonobvious contributors to memory performance, analogous to the support for upright standing in the adaptation of the visual system to prismatic distortion investigated in the present research. PMID- 24071926 TI - Synthesis of hierarchical TiO2 nanowires with densely-packed and omnidirectional branches. AB - In this study, a hierarchical TiO2 nanostructure with densely-packed and omnidirectional branches grown by a hydrothermal method is introduced. This morphology is achieved via high-concentration TiCl4 treatment of upright backbone nanowires (NWs) followed by hydrothermal growth. Secondary nanobranches grow in all directions from densely distributed, needle-like seeds on the jagged round surface of the backbone NWs. In addition, hierarchical, flower-like branches grow on the top surface of each NW, greatly increasing the surface area. For dye sensitized solar cell (DSSC) applications, the TiO2 nanostructure demonstrated a photoconversion efficiency of up to 6.2%. A parametric study of the DSSC efficiency showed that branched TiO2 DSSCs can achieve nearly four times the efficiency of non-branched TiO2 nanowire DSSCs, and up to 170% the efficiency of previously-reported sparsely-branched TiO2 NW DSSCs. PMID- 24071928 TI - A facile fabrication process for polystyrene nanoring arrays. AB - Polystyrene nanoring arrays with outer diameters ranging from 130 to 230 nm were fabricated using low cost and simple fabrication techniques, including nanosphere lithography, argon plasma treatment, immersion in organic solvents and sonication. These nanorings were developed from polystyrene nanospheres pre assembled on substrates. Scanning electron microscopy revealed that the argon plasma treatment transformed polystyrene nanospheres into hollow cone-shaped nanostructures. X-ray photoelectron and Raman spectroscopy found that the argon plasma changed the composition of the polystyrene nanospheres by forming graphitic materials. The nanoring formation mechanism was discussed based on the instrument analyses. PMID- 24071929 TI - Improved photoresponse with enhanced photoelectric contribution in fully suspended graphene photodetectors. AB - Graphene's unique optoelectronic properties are promising to realize photodetectors with ultrafast photoresponse over a wide spectral range from far infrared to ultraviolet radiation. The underlying mechanism of the photoresponse has been a particular focus of recent work and was found to be either photoelectric or photo-thermoelectric in nature and enhanced by hot carrier effects. Graphene supported by a substrate was found to be dominated by the photo thermoelectric effect, which is known to be an order of magnitude slower than the photoelectric effect. Here we demonstrate fully-suspended chemical vapor deposition grown graphene microribbon arrays that are dominated by the faster photoelectric effect. Substrate removal was found to enhance the photoresponse by four-fold compared to substrate-supported microribbons. Furthermore, we show that the light-current input/output curves give valuable information about the underlying photophysical process responsible for the generated photocurrent. These findings are promising towards wafer-scale fabrication of graphene photodetectors approaching THz cut-off frequencies. PMID- 24071927 TI - Ribosome-inactivating proteins: potent poisons and molecular tools. AB - Ribosome-inactivating proteins (RIPs) were first isolated over a century ago and have been shown to be catalytic toxins that irreversibly inactivate protein synthesis. Elucidation of atomic structures and molecular mechanism has revealed these proteins to be a diverse group subdivided into two classes. RIPs have been shown to exhibit RNA N-glycosidase activity and depurinate the 28S rRNA of the eukaryotic 60S ribosomal subunit. In this review, we compare archetypal RIP family members with other potent toxins that abolish protein synthesis: the fungal ribotoxins which directly cleave the 28S rRNA and the newly discovered Burkholderia lethal factor 1 (BLF1). BLF1 presents additional challenges to the current classification system since, like the ribotoxins, it does not possess RNA N-glycosidase activity but does irreversibly inactivate ribosomes. We further discuss whether the RIP classification should be broadened to include toxins achieving irreversible ribosome inactivation with similar turnovers to RIPs, but through different enzymatic mechanisms. PMID- 24071930 TI - Transbronchial cryobiopsy in immunocompromised patients with pulmonary infiltrates: a pilot study. AB - BACKGROUND: In immunocompromised patients with pulmonary infiltrates, transbronchial lung biopsies (TBB) obtained by forceps has been shown to increase the diagnostic yield over simple bronchoalveolar lavage. Cryo-TBB is a novel modality for obtaining lung biopsies. We aimed to evaluate for the first time the efficacy and safety of cryo-TBB in immunocompromised patients. METHODS: Fifteen immunocompromised patients with pulmonary infiltrates underwent cryo-TBB. During the procedure two to three biopsy samples were taken. Procedure characteristics, complications, and the diagnostic yield were retrospectively evaluated. RESULTS: Most patients (n = 11) were immunocompromised due to hematological malignancies. The remaining four patients were receiving chronic immunosuppressive treatment due to previous solid-organ transplantation (n = 2) or collagen-vascular disease (n = 2). No major complications occurred in the cryo-TBB group. The mean surface area of the specimen taken by cryo-TBB was 9 mm(2). The increase in surface area and quality of biopsy samples translated to a high percentage of alveolated tissue (70 %) that enabled a clear histological detection of the following diagnoses: noncaseating granulomatous inflammation (n = 2), acute interstitial pneumonitis consistent with drug reaction (n = 5), nonspecific interstitial pneumonia fibrotic variant (n = 1), diffuse alveolar damage (n = 3), organizing pneumonia (n = 3), and pulmonary cryptococcal pneumonia (n = 1). Diagnostic information obtained by cryo-TBB led to change in the management of 12 patients (80 %). CONCLUSION: Cryo-TBB in immunocompromised patients with pulmonary infiltrates provides clinically important diagnostic data with a low complication rate. These advantages should be further compared with traditional forceps TBB in a prospective randomized trial. PMID- 24071932 TI - The MEFV mutations and their clinical correlations in children with familial Mediterranean fever in southeast Turkey. AB - The aim of this study was to determine the Mediterranean fever (MEFV) gene mutations and their clinical correlations in children with familial Mediterranean fever (FMF) in southeast Turkey. Clinical and laboratory characteristics of 147 (65 males, 82 females) consecutive children with FMF having a positive MEFV gene mutation were prospectively investigated. Patients with negative MEFV gene mutations or atypical FMF presentations and those from other regions of the country were excluded. Clinical manifestations and disease severity scores were recorded. The six most frequent MEFV mutations including M694V, V726A, R726H, P369S, E148Q and P369S were investigated by a reverse hybridization test method. The median age of study group was 9.0 years, median age at diagnosis was 7.8 years, median age at disease onset was 5.0 years, and median follow-up duration was 4.0 years. A positive family history of FMF and parent-to-offspring transmission was found in 58.5 and 42.2 % of families, respectively. The frequencies of independent alleles, with decreasing order, were E148Q (30.7 %), M694V (26.0 %), R761H (13.5 %), V726A (13.0 %), P369S (10.5 %) and M680I (6.3 %) in FMF patients. The M694V subgroup had higher mean disease severity score and longer attack duration compared with E148Q and other mutations subgroups (p < 0.05). Two patients with amyloidosis had the M694V homozygote genotype. In conclusion contrast to other regions and many other ethnicities of the world, the most frequent MEFV gene mutation was E148Q in southeast Turkey. The M694V mutation frequency was lower, and disease severity was relatively mild in FMF children of this region. PMID- 24071931 TI - Negative affect in systemic sclerosis. AB - Negative affect appears frequently in rheumatic diseases, but studies about their importance and prevalence in systemic sclerosis patients are scarce, and the results are inconclusive separately. We conducted a comprehensive search on April 2013 of PubMed, Medline, and PsycINFO databases to identify original research studies published. A total of 48 studies were included in this systematic review. We found negative emotions have very high levels in these patients, compared to both healthy population other chronic rheumatic patients assessed with the same instruments and cutoffs. Depression has been, of the three negative emotions that we approach to in this review, the most widely studied in systemic sclerosis, followed by anxiety. Despite the fact that anger is a common emotion in these diseases is poorly studied. Methodologic issues limited the ability to draw strong conclusions from studies of predictors. Disease-specific symptoms (swollen joints, gastrointestinal and respiratory symptoms and digital ulcers) and factors related to physical appearance were associated with negative emotions. Interdisciplinary care and biopsychosocial approach would have a great benefit in the clinical management of these patients. PMID- 24071933 TI - Improvement of plasma endothelin-1 and nitric oxide in patients with systemic sclerosis by bosentan therapy. AB - The aim of this study was to evaluate the effects of bosentan on plasma endothelin-1 (ET-1) and nitric oxide (NO) as pulmonary hypertension (PH) associated biochemical markers in patients with systemic sclerosis (SSc). Twenty four SSc patients receiving bosentan for 24 weeks were registered in this prospective observational study. Ten patients were complicated with clinically suspected PH. Plasma levels of ET-1 and NO were assessed at baseline and after 24 weeks of treatment in SSc patients and in 15 healthy controls. Plasma levels of ET-1 and NO at baseline were significantly higher in SSc patients than in healthy controls (p < 0.000), and they were also significantly higher in SSc patients with PH than in those without PH (p < 0.01). Plasma ET-1 levels were significantly decreased after 24 weeks of bosentan therapy (p < 0.0001), and ET-1 levels of SSc patients with PH decreased to a level comparable to that in patients without PH. In the 10 SSc patients with PH, changes in plasma ET-1 levels during the 24 weeks of the study were significantly larger in the 5 patients whose functional class (FC) improved than in the 5 patients whose FC was unchanged (p < 0.05). Plasma NO levels were also slightly decreased in SSc patients after 24 weeks of bosentan therapy. Plasma ET-1 levels could reflect the presence and severity of PH in SSc patients. Additionally, changes in plasma ET-1 levels may indicate the response to bosentan therapy in SSc patients with PH. PMID- 24071934 TI - Clinical implementation of musculoskeletal ultrasound in rheumatology in Austria. AB - The aim of the study is to assess the clinical implementation of musculoskeletal ultrasound (MSUS) in rheumatology in Austria. A survey was conducted among Austrian rheumatologists and physicians of other specialties with a focus on rheumatology. The questionnaire was designed by the members of the Austrian Radiology-Rheumatology Initiative for Musculoskeletal UltraSound including the following items: demographics, access to MSUS and MSUS training, application of MSUS to support diagnosis, monitoring and treatment decisions, and obstacles for the routine performance of MSUS. Eighty-eight (21.9 %) out of the 402 surveyed physicians responded. No access to MSUS and/or inadequate training in the technique was more commonly reported by senior (>50 years; 64.3 and 67.7 %, respectively) than by younger physicians (16.7 %, p = 0.01 and 18.5 %, p < 0.001, respectively). The lowest availability of sonography was found among senior rheumatologists (25.0 %, p = 0.001 compared to the total group). MSUS is routinely used for diagnosis and/or monitoring purposes by 12.5 % of physicians and 20.5 % perform sonography in clinically unclear cases. A limited number of physicians apply the method to support treatment decisions and/or to evaluate treatment success. The most important obstacles for routine application of MSUS in rheumatology are limited access to ultrasound machines, lack of training/education in the technique, and time constraints in daily routine. Low access to high-end ultrasound devices, lack of training, and time constraints may explain the low appreciation of MSUS among Austrian physicians evaluating patients with rheumatic diseases. PMID- 24071935 TI - Effects of Pilates, McKenzie and Heckscher training on disease activity, spinal motility and pulmonary function in patients with ankylosing spondylitis: a randomized controlled trial. AB - The optimal management of ankylosis spondylitis (AS) involves a combination of nonpharmacologic and pharmacologic treatment aiming to maximize health-related quality of life. The primary objective of our study was to demonstrate the benefits of an original multimodal exercise program combining Pilates, McKenzie and Heckscher techniques on pulmonary function in patients with AS, while secondary objectives were to demonstrate the benefits of the same program on function and disease activity. This is a randomized controlled study on ninety six consecutive patients with AS (axial disease subset), assigned on a 1:1 rationale into two groups based on their participation in the Pilates, McKenzie and Heckscher (group I) or in the classical kinetic program (group II). The exercise program consisted of 50-min sessions performed 3 times weekly for 48 weeks. Standard assessments were done at week 0 and 48 and included pain, modified Schober test (mST) and finger-floor distance (FFD), chest expansion (CE) and vital capacity (VC), as well as disease activity Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), functional Bath Ankylosing Spondylitis Functional Index (BASFI) and metrology index Bath Ankylosing Spondylitis Metrology Index (BASMI). Groups were comparable at baseline; we demonstrated significant improvement between baseline and after 48 weeks of regular kinetic training for all AS-related parameters in both groups. However, significant improvement was found in pain, lumbar spine motility (mST, FFD), BASFI, BASDAI and BASMI in AS performing the specific multimodal exercise program at the end of study (p = 0.001). Although there were significant improvements in CE in both groups as compared to baseline (group I, p = 0.001; group II, p = 0.002), this parameter increased significantly only in group I (p = 0.001). VC measurements were not significantly changed at the end of the study (group I, p = 0.127; group II, p = 0.997), but we found significant differences within groups (p = 0.011). A multimodal training combining Pilates, McKenzie and Heckscher exercises performed regularly should be included in the routine management of patients with AS for better control of function, disease activity and pulmonary function. PMID- 24071936 TI - Associates of school impairment in Egyptian patients with juvenile idiopathic arthritis: Sharkia Governorate. AB - The aim of this study was to investigate the factors associated with school absenteeism and poor school functioning in Egyptian children and adolescents with juvenile idiopathic arthritis (JIA). We studied 52 consecutive patients of JIA with age >= 7 years and duration of disease >= 1 year. All of the patients underwent assessment of socioeconomic and demographic characteristics, disease activity (JIDAS-27), functional ability (CHAQ), depressive symptoms (CDI score), and school functioning (PedsQLTM 4.0). Multivariate modeling was applied to determine the factors that associated with school absenteeism and poor school functioning. A total of 69% of the sample missed 3 weeks or more of school during past academic year. The mean percentage of missed school days was 12.5% (equivalent to 25 absent days). A total of 46% of the patients had poor school functioning (school functioning subscale score of HRQOL >= 1 SD below the mean of healthy children). In multiple regression analyses, high CHAQ scores, disease activity, and depressive symptoms were independent predictors for both of school absenteeism and of poor school functioning. However, living in rural regions was independently associated only with high school absenteeism in patients with JIA. Disease activity, functional disability, and high depressive symptoms are predictors of school absenteeism and poor school functioning. These findings underscore the critical need for treatment strategies that have the ability to better control disease activity, to minimize functional disability, and depressive symptoms. More attention should be given to JIA patients who live in rural regions. PMID- 24071937 TI - E2F1: a potential therapeutic target for systematic lupus erythematosus. AB - E2F1 is a transcriptional activator, which binds to DNA, and regulates the expression of genes involved in the cell cycle progression. Many elegant studies have revealed that E2F1 plays a crucial role in regulating the apoptosis process of DC and T cells. In addition, the pathogenesis of SLE involves marked immune dysfunction, and in particular, the function of immunosuppressive elements of the immune system is impaired, including regulatory T cell function and DC. Thus, therapeutic agents targeting E2F1 might result in important innovative therapies for SLE. PMID- 24071939 TI - Keratin k15 as a biomarker of epidermal stem cells. AB - Keratin 15 (K15) is type I keratin protein co-expressed with the K5/K14 pair present in the basal keratinocytes of all stratified epithelia. Although it is a minor component of the cytoskeleton with a variable expression pattern, nonetheless its expression has been reported as a stem cell marker in the bulge of hair follicles. Conversely, suprabasal expression of K15 has also been reported in both normal and diseased tissues, which is inconsistent with its role as a stem cell marker. Our recently published work has given evidence of the molecular pathways that seem to control the expression of K15 in undifferentiated and differentiated cells. In this article, we have critically reviewed the published work to establish the reliability of K15 as an epidermal stem cell marker. PMID- 24071938 TI - EGFR-ras-raf signaling in epidermal stem cells: roles in hair follicle development, regeneration, tissue remodeling and epidermal cancers. AB - The mammalian skin is the largest organ of the body and its outermost layer, the epidermis, undergoes dynamic lifetime renewal through the activity of somatic stem cell populations. The EGFR-Ras-Raf pathway has a well-described role in skin development and tumor formation. While research mainly focuses on its role in cutaneous tumor initiation and maintenance, much less is known about Ras signaling in the epidermal stem cells, which are the main targets of skin carcinogenesis. In this review, we briefly discuss the properties of the epidermal stem cells and review the role of EGFR-Ras-Raf signaling in keratinocyte stem cells during homeostatic and pathological conditions. PMID- 24071940 TI - Inhibition of oxidative stress by low-molecular-weight polysaccharides with various functional groups in skin fibroblasts. AB - The aim of this study was to evaluate the in cellulo inhibition of hydrogen peroxide-induced oxidative stress in skin fibroblasts using different low molecular-weight polysaccharides (LMPS) prepared from agar (LMAG), chitosan (LMCH) and starch (LMST), which contain various different functional groups (i.e., sulfate, amine, and hydroxyl groups). The following parameters were evaluated: cell viability, intracellular oxidant production, lipid peroxidation, and DNA damage. Trolox was used as a positive control in order to allow comparison of the antioxidant efficacies of the various LMPS. The experimentally determined attenuation of oxidative stress by LMPS in skin fibroblasts was: LMCH > LMAG > LMST. The different protection levels of these LMPS may be due to the physic-chemical properties of the LMPS' functional groups, including electron transfer ability, metal ion chelating capacities, radical stabilizing capacity, and the hydrophobicity of the constituent sugars. The results suggest that LMCH might constitute a novel and potential dermal therapeutic and sun-protective agent. PMID- 24071943 TI - Mixtures of L-amino acids as reaction medium for formation of iron nanoparticles: the order of addition into a ferrous salt solution matters. AB - Owing to Mossbauer spectroscopy, an advanced characterization technique for iron containing materials, the present study reveals previously unknown possibilities using l-amino acids for the generation of magnetic particles. Based on our results, a simple choice of the order of l-amino acids addition into a reaction mixture containing ferrous ions leads to either superparamagnetic ferric oxide/oxyhydroxide particles, or magnetically strong Fe0-Fe2O3/FeOOH core-shell particles after chemical reduction. Conversely, when ferric salts are employed with the addition of selected l-amino acids, only Fe0-Fe2O3/FeOOH core-shell particles are observed, regardless of the addition order. We explain this phenomenon by a specific transient/intermediate complex formation between Fe2+ and l-glutamic acid. This type of complexation prevents ferrous ions from spontaneous oxidation in solutions with full air access. Moreover, due to surface enhanced Raman scattering spectroscopy we show that the functional groups of l amino acids are not destroyed during the borohydride-induced reduction. These functionalities can be further exploited for (i) attachment of l-amino acids to the as-prepared magnetic particles, and (ii) for targeted bio- and/or environmental applications where the surface chemistry needs to be tailored and directed toward biocompatible species. PMID- 24071942 TI - Systematic exploration of natural and synthetic flavonoids for the inhibition of Staphylococcus aureus biofilms. AB - When single-cell (or suspended) bacteria switch into the biofilm lifestyle, they become less susceptible to antimicrobials, imposing the need for anti-biofilms research. Flavonoids are among the most extensively studied natural compounds with an unprecedented amount of bioactivity claims. Most studies focus on the antibacterial effects against suspended cells; fewer reports have researched their anti-biofilm properties. Here, a high throughput phenotypic platform was utilized to screen for the inhibitory activity of 500 flavonoids, including natural and synthetic derivatives, against Staphylococcus aureus biofilms. Since discrepancies among results from earlier antibacterial studies on flavonoids had been noted, the current study aimed to minimize sources of variations. After the first screen, flavonoids were classified as inactive (443), moderately active (47) or highly active (10). Further, exclusion criteria combining bioactivity and selectivity identified two synthetic flavans as the most promising. The body of data reported here serves three main purposes. First, it offers an improved methodological workflow for anti-biofilm screens of chemical libraries taking into account the (many times ignored) connections between anti-biofilm and antibacterial properties. This is particularly relevant for the study of flavonoids and other natural products. Second, it provides a large and freely available anti-biofilm bioactivity dataset that expands the knowledge on flavonoids and paves the way for future structure-activity relationship studies and structural optimizations. Finally, it identifies two new flavans that can successfully act on biofilms, as well as on suspended bacteria and represent more feasible antibacterial candidates. PMID- 24071941 TI - Mechanisms of chemical carcinogenesis in the kidneys. AB - Chemical carcinogens are substances which induce malignant tumours, increase their incidence or decrease the time taken for tumour formation. Often, exposure to chemical carcinogens results in tissue specific patterns of tumorigenicity. The very same anatomical, biochemical and physiological specialisations which permit the kidney to perform its vital roles in maintaining tissue homeostasis may in fact increase the risk of carcinogen exposure and contribute to the organ specific carcinogenicity observed with numerous kidney carcinogens. This review will address the numerous mechanisms which play a role in the concentration, bioactivation, and uptake of substances from both the urine and blood which significantly increase the risk of cancer in the kidney. PMID- 24071944 TI - Parts per trillion detection of 7-aminonitrazepam by nano-enhanced ELISA. AB - It is challenging to detect 7-aminonitrazepam (7-ANZP) residue in animal tissues simply and sensitively by the enzyme-linked sorbent immunoassay (ELISA) method. This paper demonstrates that utilizing a bioconjugate of gold nanoparticles and enzyme-labeled antibody as a signal probe increases the sensitivity of a traditional ELISA for 7-ANZP by nearly 20 times. The sensitivity of this ELISA for 7-ANZP was 5.6 pg/mL in buffer, and the limit of detection (LOD) of 0.18 ug/kg for 7-ANZP in urine could be achieved after the urine samples were simply hydrolyzed and diluted by buffer. This simple and sensitive method has potential application for improving the sensitivity of ELISA methods against various small molecules. PMID- 24071945 TI - Controlling magnetism of MoS2 sheets by embedding transition-metal atoms and applying strain. AB - Prompted by recent experimental achievement of transition metal (TM) atoms substituted in MoS2 nanostructures during growth or saturating existing vacancies (Sun et al., ACS Nano, 2013, 7, 3506; Deepak et al., J. Am. Chem. Soc., 2007, 129, 12549), we explored, via density functional theory, the magnetic properties of a series of 3d TM atoms substituted in a MoS2 sheet, and found that Mn, Fe, Co, Ni, Cu and Zn substitutions can induce magnetism in the MoS2 sheet. The localizing unpaired 3d electrons of TM atoms respond to the introduction of a magnetic moment. Depending on the species of TM atoms, the substituted MoS2 sheet can be a metal, semiconductor or half-metal. Remarkably, the applied elastic strain can be used to control the strength of the spin-splitting of TM-3d orbitals, leading to an effective manipulation of the magnetism of the TM substituted MoS2 sheet. We found that the magnetic moment of the Mn- and Fe substituted MoS2 sheets can monotonously increase with the increase of tensile strain, while the magnetic moment of Co-, Ni-, Cu- and Zn-substituted MoS2 sheets initially increases and then decreases with the increase of tensile strain. An instructive mechanism was proposed to qualitatively explain the variation of magnetism with elastic strain. The finding of the magnetoelastic effect here is technologically important for the fabrication of strain-driven spin devices on MoS2 nanostructures, which allows us to go beyond the current scope limited to the spin devices within graphene and BN-based nanostructures. PMID- 24071946 TI - Hoagland sign. PMID- 24071947 TI - Is the ATLS classification of hypovolaemic shock appreciated in daily trauma care? An online-survey among 383 ATLS course directors and instructors. AB - OBJECTIVE: For the early recognition and management of hypovolaemic shock, ATLS suggests four shock classes based upon an estimated blood loss in percent. The aim of this study was to assess the confidence and acceptance of the ATLS classification of hypovolaemic shock among ATLS course directors and instructors in daily trauma care. METHODS: During a 2-month period, ATLS course directors and instructors from the ATLS region XV (Europe) were invited to participate in an online survey comprising 15 questions. RESULTS: A total of 383 responses were received. Ninety-eight percent declared that they would follow the 'A, B, C, D, E' approach by ATLS in daily trauma care. However, only 48% assessed 'C Circulation' according to the ATLS classification of hypovolaemic shock. One out of four respondents estimated that in daily clinical routine, less than 50% of all trauma patients can be classified according to the current ATLS classification of hypovolaemic shock. Additionally, only 10.9% considered the ATLS classification of hypovolaemic shock as a 'good guide' for fluid resuscitation and blood product transfusion, whereas 45.1% stated that this classification only 'may help' or has 'no impact' to guide resuscitation strategies. CONCLUSIONS: Although the 'A, B, C, D, E' approach according to ATLS is widely implemented in daily trauma care, the use of the ATLS classification of hypovolaemic shock in daily practice is limited. Together with previous analyses, this study supports the need for a critical reassessment of the current ATLS classification of hypovolaemic shock. PMID- 24071948 TI - Diagnosing paediatric myocarditis: what really matters. AB - OBJECTIVE: Paediatric myocarditis has remained a diagnostic challenge. We aim to identify distinct characteristics and derive a scoring system that will trigger further investigations to be performed among paediatric patients presenting to the emergency department (ED) with clinically suspected myocarditis. DESIGN: We performed an age-matched case-control study of children seen in a large tertiary institution. Cases and controls were patients less than 16 years' old who presented to the ED over a 10-year period from Jan 2001 to Dec 2010. Cases were identified with a final discharge or postmortem diagnosis of acute myocarditis. Controls were those who presented to the ED in the same period and were initially diagnosed with acute myocarditis, but who were later found to have other diagnoses. We compared their vital signs, presenting symptoms, physical examination findings, electrocardiogram and chest radiograph findings. RESULTS: Based on domain-specific stepwise conditional logistic regression analyses, five characteristics were found to be potentially discriminating: respiratory distress, poor perfusion, hypotension, an abnormal chest radiograph and any electrocardiogram abnormalities. Satisfactory discrimination was attained using these five parameters. The estimated area under receiver operating characteristic curve was 90% (95% CI 0.83 to 0.97). A cut-off score of 3 would give a positive likelihood ratio of 13 (95% CI 3.31 to 51.06) and a negative likelihood ratio of 0.35 (95% CI 0.22 to 0.55). CONCLUSIONS: A cut-off risk score of 3, though not yet validated, may be potentially useful in future to trigger further investigations for children with suspected myocarditis. It allows for the appropriate use of resources, while minimising on misdiagnosis. PMID- 24071949 TI - Critical care paramedics: where is the evidence? A systematic review. AB - OBJECTIVES: Paramedic-delivered prehospital critical care is an established concept in a number of emergency medical services around the world and, more recently, has been introduced to the UK. This review identifies and describes the available evidence relating to paramedics who routinely provide prehospital critical care as primary scene response (critical care paramedics, or CCP). METHODS: A systematic search of electronic databases was performed: CENTRAL, EMBASE, MEDLINE (through EMBASE and Web of Knowledge) and Web of Science (through Web of Knowledge). RESULTS: The search identified 12 relevant publications, one of which was a randomised controlled trial. The remaining 11 were retrospective studies. Five studies compared CCPs with physician-led care. Three of these publications demonstrated improved outcomes with physician care, while two showed no difference. Four further publications examined CCPs versus non-physician-led care and found improved outcomes (two studies), mixed effects (one study) and no difference (one study) for CCPs. Finally, three publications addressed the addition of skills to CCP competencies. A randomised controlled trial of CCP rapid sequence induction (RSI) and tracheal intubation demonstrated improved neurologic outcomes. CCP tube thoracostomy was shown to have similar complication rates to the same procedure performed in the emergency department, while addition of a non-invasive ventilation protocol to CCP practice had no effect on long-term mortality. CONCLUSIONS: There is limited evidence to support the concept of paramedic-delivered prehospital critical care. The best available evidence suggests a benefit from prehospital RSI carried out by CCPs in patients with severe traumatic brain injury, but the impact of CCPs remains unclear for many conditions. Further high-quality research in this area would be welcome. PMID- 24071950 TI - Enantiospecific photochemical 6pi-ring closure of alpha-substituted atropisomeric acrylanilides--role of alkali metal ions. AB - Direct irradiation of atropisomeric alpha-substituted acrylanilides in the presence of alkali metal ions gave high ee values in the 3,4-dihydro-2-quinolin-2 one photoproduct, while in the absence of alkali metal ions, racemic photoproduct was observed. The heavy atom effect leading to enhanced triplet yields alters the reactive pathway leading to the observed enantioselectivity in the photoproduct. PMID- 24071952 TI - Heritability of lenticular myopia in English Springer spaniels. AB - PURPOSE: We determined whether naturally-occurring lenticular myopia in English Springer spaniels (ESS) has a genetic component. METHODS: Streak retinoscopy was performed on 226 related ESS 30 minutes after the onset of pharmacologic mydriasis and cycloplegia. A pedigree was constructed to determine relationships between affected offspring and parents. Estimation of heritability was done in a Bayesian analysis (facilitated by the MCMCglmm package of R) of refractive error in a model, including terms for sex and coat color. Myopia was defined as <=-0.5 diopters (D) spherical equivalent. RESULTS: The median refractive error for ESS was 0.25 D (range, -3.5 to +4.5 D). Median age was 0.2 years (range, 0.1-15 years). The prevalence of myopia in related ESS was 19% (42/226). The ESS had a strong correlation (r = 0.95) for refractive error between the two eyes. Moderate heritability was present for refractive error with a mean value of 0.29 (95% highest probability density, 0.07-0.50). CONCLUSIONS: The distribution of refractive error, and subsequently lenticular myopia, has a moderate genetic component in ESS. Further investigation of genes responsible for regulation of the development of refractive ocular components in canines is warranted. PMID- 24071953 TI - Retinal function and neural conduction along the visual pathways in affected and unaffected carriers with Leber's hereditary optic neuropathy. AB - PURPOSE: We assessed retinal ganglion cell (RGC) function, and established a correlation between the neural conduction along the visual pathways and the retinal involvement in Leber's hereditary optic neuropathy (LHON). METHODS: A total of 39 individuals carrying a LHON mutation (mean age, 33.35 +/- 8.4 years), LHON-unaffected (LU, 22 eyes) or LHON-affected (LA, 17 eyes), underwent visual acuity and visual field examinations. A total of 22 age-similar normal subjects (mean age, 38.2 +/- 6.0 years) served as controls. In all subjects, simultaneous pattern electroretinograms (PERGs) and visual evoked potentials (VEPs) were recorded in response to 60-minute (60') and 15-minute (15') checkerboard stimuli. RESULTS: When compared to controls, LU eyes did not show any statistically significant difference in 60' and 15' VEP P100 implicit times (ITs), VEP N75-P100 amplitudes, and 60' PERG P50 ITs, whereas 15' PERG P50-N95 amplitudes were significantly (P < 0.01) reduced. When compared to control and LU eyes, LA eyes showed significant differences in PERG and VEP ITs, and amplitudes with both stimulations (60' and 15' checks). No significant correlations between PERG and VEP parameters were found in LU eyes, while in LA eyes, PERG P50 and VEP P100 ITs correlated significantly only when using 60' checks. CONCLUSIONS: The LHON unaffected eyes showed a retinal dysfunction detected by abnormal PERG responses that was not associated with changes along the visual pathways assessed by normal VEP responses. In LA eyes, the impaired neural conduction recorded by VEPs in response to larger (60' VEP responses) and smaller (15' VEP responses) checks were associated and not associated, respectively, with the detected retinal dysfunction. PMID- 24071954 TI - Morphologic characteristics and proliferation of rabbit corneal stromal cells onto complexes of collagen-chitosan-sodium hyaluronate under simulated microgravity. AB - PURPOSE: We investigated the morphologic characteristics and proliferation of rabbit corneal stromal cells (CSCs) onto scaffolds under simulated microgravity. METHODS: Rabbit CSCs were cultured under simulated microgravity (SMG) and static condition. Complexes of collagen-chitosan-sodium hyaluronate with pores were used as scaffolds. Rotational speed was set at 15, 20, and 30 rpm in the first, second, and third weeks of culture, respectively. Histology, immunofluorescence staining, atomic force microscope (AFM), and scanning electron microscope (SEM) examinations were performed. The cell proliferation was analyzed by cell counting kit-8 (CCK-8) assay. RESULTS: In the SMG group, more CSCs adhered to the carriers in 24 hours. Confocal microscopic evaluation showed aggregated cells positively immunostained with vimentin. The SEM displayed the complex network of triangular or polygonal dendritic morphology of the cell bodies with many fine and long processes, which adhered to the scaffolds tightly. After 18 days of SMG culture, keratocyte-like CSCs with rich cell interconnections not only grew on the surface, but also into the interior of scaffolds. There were degradation phenomena in scaffolds in the SMG condition. Under static condition, cells just grew on scaffolds forming a monolayer. Cells showed elongating spindle shape and developed less processes. The absorbance values of the CCK-8 assay in the SMG group were significantly higher (P < 0.01) than in the conventional group. CONCLUSIONS: The condition of SMG and porous collagen-chitosan-sodium hyaluronate scaffolds facilitate the proliferation of CSCs. Cells showed robust growing characteristics and morphologic properties of keratocytes. The techniques for microgravity culture of keratocyte-like CSCs on scaffolds can yield cell aggregates or cell sheets that are favorable to the reconstruction of tissue engineering of the corneal stromal layer. PMID- 24071956 TI - The effects of blur and eccentric viewing on adult acuity for pediatric tests: implications for amblyopia detection. AB - PURPOSE: The detection of amblyopia in children relies on an accurate assessment of visual acuity. Visual deficits in anisometropic and strabismic amblyopia are different, but the influence of chart design, in particular position, and type of crowding features on visual acuity in the two types of amblyopia, is not clear. Certain aspects of amblyopic spatial vision are mimicked in healthy individuals by imposing increasing levels of blur and retinal eccentricity. We measured the effects of these conditions on visual acuity in healthy adults, with crowded and uncrowded vision tests. METHODS: Visual acuity was measured under conditions of blur (0-4 D) and eccentric viewing (0-5 degrees) using high-contrast optotypes derived from common children's acuity charts. Optotypes were presented in isolation, in commercially available crowded configurations, and in configurations with closer target-flanker separations than those currently available. RESULTS: Dioptric blur had similar degradative effects on crowded and isolated visual acuity (P > 0.05), whereas eccentric viewing resulted in a larger deterioration of visual acuity for crowded tests (E2 of 0.86-1.06) than for isolated optotypes (E2 of 1.57-1.72) (P < 0.05). Maximum crowding effects occurred for closer target-flanker separations than those currently used commercially. CONCLUSIONS: In so far as blur and eccentric viewing mimic spatial acuity deficits in amblyopia, the results suggest that crowded tests might be of limited value in the detection of anisometropic amblyopia, but should be valuable in the detection of strabismic amblyopia. Crowding effects would be greater if flanking features were placed closer to the target than they currently are in commercially available charts. PMID- 24071955 TI - Imaging of vascular wall fine structure in the human retina using adaptive optics scanning laser ophthalmoscopy. AB - PURPOSE: To improve the ability to image the vascular walls in the living human retina using multiply-scattered light imaging with an adaptive optics scanning laser ophthalmoscope (AOSLO). METHODS: In vivo arteriolar wall imaging was performed on eight healthy subjects using the Indiana AOSLO. Noninvasive imaging of vascular mural cells and wall structure were performed using systematic control of the position of a 10* Airy disk confocal aperture. Retinal arteries and arterioles were divided into four groups based on their lumen diameters (group 1: >=100 MUm; group 2: 50-99 MUm; group 3: 10-49 MUm; group 4: <10 MUm). RESULTS: Fine structure of retinal vasculature and scattering behavior of erythrocytes were clearly visualized in all eight subjects. In group 1 vessels the mural cells were flatter and formed the outer layer of regularly spaced cells of a two (or more) layered vascular wall. In the vessels of groups 2 and 3, mural cells were visualized as distinct cells lying along the lumen of the blood vessel, resulting in a wall of irregular thickness. Vascular wall components were not readily identified in group 4 vessels. CONCLUSIONS: Our results show that retinal vascular mural cells and wall structure can be readily resolved in healthy subjects using AOSLO with multiply scattered light imaging for retinal vessels with a lumen diameter greater than or equal to 10 MUm. Our noninvasive imaging approach allows direct assessment of the cellular structure of the vascular wall in vivo with potential applications in retinal vascular diseases such as diabetes and hypertension. PMID- 24071957 TI - Distinct characteristics of inferonasal fundus autofluorescence patterns in stargardt disease and retinitis pigmentosa. AB - PURPOSE: To report distinct characteristics of fundus autofluorescence (AF) patterns inferior to the optic disc in recessive Stargardt disease (STGD1) and retinitis pigmentosa (RP). METHODS: Short-wavelength (SW) and near-infrared (NIR) AF images were acquired from patients with STGD1 and RP. In SW- and NIR-AF images of STGD1 patients, gray levels (GL) on both sides of the demarcation line were measured. RESULTS: In STGD1, a demarcation line, which has been assigned to the closed optic fissure, was visible on SW-AF and NIR-AF inferior to the optic disc. In healthy subjects, this demarcation line is only visible by SW-AF. At 20 degrees inferior to the disc center, AF levels on the nasal side were 25% (+/ 11%) lower than on the temporal side in SW-AF images and 18% (+/-11%) lower in NIR-AF images. For both STGD1 and RP, the inferonasal quadrant exhibited distinct SW- and NIR-AF patterns compared with other fundus areas. Disease-related AF changes, such as flecks, appeared to respect the demarcation line as a boundary. CONCLUSIONS: Disease-related AF patterns originating in RPE in STGD1 and RP appear to respect the demarcation line in the inferonasal quadrant of the fundus as a border. The visibility of the inferonasal demarcation line by NIR-AF in STGD1 but not in healthy eyes may indicate that increased levels of RPE lipofuscin modulate the melanin-related NIR-AF signal. This feature of NIR-AF images may aid in the diagnosis of STGD1 patients. PMID- 24071958 TI - Reticular pseudodrusen in early age-related macular degeneration are associated with choroidal thinning. AB - PURPOSE: To compare choroidal thickness (CT) measurements in early AMD between patients with and without reticular pseudodrusen (RPD) using spectral-domain optical coherence tomography (SD-OCT). METHODS: This cross-sectional study examined 84 age- and sex-matched AMD patients (40 RPD [63 eyes], 44 non-RPD [75 eyes]). Fundus photographs and scanning laser ophthalmoscopy images were graded to identify RPD and non-RPD groups by three retinal specialists (MO, SY, SB) who were masked to corresponding SD-OCTs. CT at the fovea and 2400 to 3000 MUm superior and inferior to the fovea was measured on SD-OCT by a grader (AG) and reviewed by a retinal specialist (SB). Only images with a clear posterior choroidal margin were analyzed (six eyes excluded due to poor image quality), and enhanced depth imaging SD-OCT was used when available (20 of 138 eyes). Greatest retinal thickness (RT) on horizontal foveal SD-OCT was also recorded. RESULTS: Mean CTs in the superior, foveal, and inferior macula in RPD (191.3 MUm +/- 57.9 SD, 176.3 MUm +/- 60.5 SD, 179.7 MUm +/- 56.24 SD) were significantly less than that of non-RPD (228.0 MUm +/- 66.1 SD, 216.5 MUm +/- 70.3 SD, 224.4 MUm +/- 71.9 SD; P = 0.0010, P = 0.0005, P = 0.0001, respectively), as was greatest RT (P = 0.0301). CONCLUSIONS: CT was thinner throughout the macula in the RPD group as compared with the non-RPD group. The current analysis supports an association between RPD and a thinned choroidal layer and is consistent with a choroidal etiology of RPD. CT may be integral to understanding RPD, and may be helpful in stratifying AMD progression risk. PMID- 24071960 TI - Drug-drug interactions in HIV therapy: is it all clear? AB - Drug-drug interactions in HIV therapy have been known to the clinic from earliest days of HIV treatment. Hundreds of well-designed pharmacokinetic studies have been performed in either HIV-infected patients or, mostly, in healthy volunteers. Case reports generally are graded lower in terms of evidence-based medicine but sometimes provide valuable information. In this issue of Antiviral Therapy a case of virological failure on an atazanavir-containing regimen was explained by an interaction with charcoal that was used as self-medication for diarrhoea. Clinicians are invited to continue submitting well-documented case reports to increase knowledge on drug-drug interactions in HIV therapy even further. PMID- 24071959 TI - Importance of hematocrit for a tacrolimus target concentration strategy. AB - PURPOSE: To identify patient characteristics that influence tacrolimus individual dose requirement in kidney transplant recipients. METHODS: Data on forty-four 12 h pharmacokinetic profiles from 29 patients and trough concentrations in 44 patients measured during the first 70 days after transplantation (1,546 tacrolimus whole blood concentrations) were analyzed. Population pharmacokinetic modeling was performed using NONMEM 7.2(r). RESULTS: Standardization of tacrolimus whole blood concentrations to a hematocrit value of 45 % improved the model fit significantly (p<0.001). Fat-free mass was the best body size metric to predict tacrolimus clearance and volume of distribution. Bioavailability was 49 % lower in expressers of cytochrome P450 3A5 (CYP3A5) than in CYP3A5 nonexpressers. Younger females (<40 years) showed a 35 % lower bioavailability than younger males. Bioavailability increased with age for both males and females towards a common value at age >55 years that was 47 % higher than the male value at age <40 years. Bioavailability was highest immediately after transplantation, decreasing steeply thereafter to reach its nadir at day 5, following which it increased during the next 55 days towards an asymptotic value that was 28 % higher than that on day 5. CONCLUSIONS: Hematocrit predicts variability in tacrolimus whole blood concentrations but is not expected to influence unbound (therapeutically active) concentrations. Fat-free mass, CYP3A5 genotype, sex, age and time after transplant influence the tacrolimus individual dose requirement. Because hematocrit is highly variable in kidney transplant patients and increases substantially after kidney transplantation, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations. PMID- 24071961 TI - TLRs, SNPs and VLBWs: oh my! PMID- 24071962 TI - Non-immune hydrops fetalis caused by herpes simplex virus type 2 in the setting of recurrent maternal infection. AB - We report a case of non-immune hydrops fetalis (NIHF) caused by herpes simplex virus type 2 (HSV-2) in an infant whose mother had recurrent HSV-2 infection. In spite of prematurity, severe disseminated infection and hydrops, the infant survived and was neurologically intact. HSV-2-induced NIHF is extremely rare, particularly in the setting of recurrent maternal infection, and this case is, to our knowledge, the first report of a surviving infant. HSV-2 should be considered in the differential diagnosis of NIHF and early initiation of empiric acyclovir therapy is recommended in this setting, pending the results of virologic diagnostic tests. PMID- 24071963 TI - ARC syndrome in preterm baby. AB - A preterm female infant born of 32 weeks gestational age was presenting with musculoskeletal abnormalities, and cholestasis that later on resolved. Later on, she developed renal tubular acidosis (RTA), poor weight gain, unexplained intermittent fever and recurrent spontaneous bleeding episodes. ARC is an acronym that stands for arthrogryposis, renal dysfunction and cholestasis. ARC syndrome is a rare disorder that is difficult to diagnose and is associated with poor outcomes. We present a case of ARC syndrome in an infant with a history of failure to thrive, early cholestasis and RTA. There are many unique features about this case that should add to our understanding of this genetic condition. To our knowledge this is the first identified case of ARC syndrome in a preterm infant. Although the specific mutation found in our patient has not been reported previously, the type and location of this mutation is consistent with our genetic understanding of this disorder. PMID- 24071964 TI - Reply to Stokes and Watson. PMID- 24071965 TI - Reply to Govande et al. Prenatal counseling beyond the threshold of viability. PMID- 24071966 TI - Newborn intensive care units and perinatal healthcare: on light's imprinting role on circadian system stability for research and prevention. PMID- 24071967 TI - Aryl pyrazaboles: a new class of tunable and highly fluorescent materials. AB - Novel aryl substituted pyrazaboles 2-9 with direct and acetylenic linkages were synthesized by Pd-catalyzed Suzuki or Sonogashira cross-coupling reactions. Their structural, thermal, and photonic properties were investigated. The results show that the aryl pyrazaboles 2-9 exhibit good thermal stability, high fluorescence quantum yield, and tunable photophysical properties. The aryl substituted acetylenic pyrazaboles 6-9 exhibit red shifted absorption, small Stokes shifts, and high quantum yields as compared to directly linked aryl pyrazaboles 2-5. The X-ray structures of the pyrazaboles 2, 5, and 7 are discussed. The computational studies were used to calculate the relative energy levels, and band gap in the pyrazaboles. The computational results show good agreement with the experimental results. PMID- 24071968 TI - Chemistry and temperature-assisted dehydrogenation of C60H30 molecules on TiO2(110) surfaces. AB - The thermal induced on-surface chemistry of large polycyclic aromatic hydrocarbons (PAHs) deposited on dielectric substrates is very rich and complex. We evidence temperature-assisted (cyclo)dehydrogenation reactions for C60H30 molecules and the subsequent bottom-up formation of assembled nanostructures, such as nanodomes, on the TiO2(110) surface. To this aim we have deposited, under ultra-high vacuum, a submonolayer coverage of C60H30 and studied, by a combination of experimental techniques (STM, XPS and NEXAFS) and theoretical methods, the different chemical on-surface interaction stages induced by the increasing temperature. We show that room temperature adsorbed molecules exhibit a weak interaction and freely diffuse on the surface, as previously reported for other aromatics. Nevertheless, a slight annealing induces a transition from this (meta)stable configuration into chemisorbed molecules. This adsorbate-surface interaction deforms the C60H30 molecular structure and quenches surface diffusion. Higher annealing temperatures lead to partial dehydrogenation, in which the molecule loses some of the hydrogen atoms and LUMO levels spread in the gap inducing a net total energy gain. Further annealing, up to around 750 K, leads to complete dehydrogenation. At these temperatures the fully dehydrogenated molecules link between them in a bottom-up coupling, forming nanodomes or fullerene-like monodisperse species readily on the dielectric surface. This work opens the door to the use of on-surface chemistry to generate new bottom-up tailored structures directly on high-K dielectric surfaces. PMID- 24071969 TI - Intracerebral hemorrhage following multiple bee stings. PMID- 24071970 TI - Late effects of local irradiation on the expression of inflammatory markers in the Arteria saphena of C57BL/6 wild-type and ApoE-knockout mice. AB - Combined action of irradiation (IR), shear stress, and high blood pressure is well recognized to induce damage to vasculature, while data on pathological effects of IR in large peripheral vessels with low blood pressure are scarce. The purpose of the present study was hence to investigate time- and dose-dependent effects of local IR on inflammatory and prothrombotic processes in the Arteria (A.) saphena of C57BL/6 wild-type and apolipoprotein E (ApoE)-knockout mice. Single doses of 2, 5, 8, 10, or 16 Gy were locally delivered to the A. saphena of the left leg of the animals. The expression of CD31, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), and thrombomodulin (TM) was quantified by semiautomatic TissueFax fluorescence analysis in frozen arterial sections. Follow-up periods were 3, 6, 9, 12, or 18 months. Protein expression in the arterial wall displayed dose-dependent changes. Proinflammatory reactions were observed for CD31, E-selectin, ICAM, and VCAM already at doses of 2 Gy. Anti inflammatory changes were detected for MCP-1 and TM. The effects were more pronounced in wild-type versus ApoE(-/-) mice. Changes remain mostly transient up to 16 Gy. Dose- and time-dependent changes in inflammatory and thrombotic mediators in the wall of the A. saphena were found after local IR but did not transform into histopathological consequences. PMID- 24071971 TI - Highly efficient bienzyme functionalized nanocomposite-based microfluidics biosensor platform for biomedical application. AB - This report describes the fabrication of a novel microfluidics nanobiochip based on a composite comprising of nickel oxide nanoparticles (nNiO) and multiwalled carbon nanotubes (MWCNTs), as well as the chip's use in a biomedical application. This nanocomposite was integrated with polydimethylsiloxane (PDMS) microchannels, which were constructed using the photolithographic technique. A structural and morphological characterization of the fabricated microfluidics chip, which was functionalized with a bienzyme containing cholesterol oxidase (ChOx) and cholesterol esterase (ChEt), was accomplished using X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy. The XPS studies revealed that 9.3% of the carboxyl (COOH) groups present in the nNiO-MWCNT composite are used to form amide bonds with the NH2 groups of the bienzyme. The response studies on this nanobiochip reveal good reproducibility and selectivity, and a high sensitivity of 2.2 mA/mM/cm2. This integrated microfluidics biochip provides a promising low-cost platform for the rapid detection of biomolecules using minute samples. PMID- 24071972 TI - Efficient asymmetric synthesis of lamivudine via enzymatic dynamic kinetic resolution. AB - The anti-HIV nucleoside lamivudine was asymmetrically synthesized in only three steps via a novel surfactant-treated subtilisin Carlsberg-catalyzed dynamic kinetic resolution protocol. The enantiomer of lamivudine could also be accessed using the same protocol catalyzed by Candida antarctica lipase B. PMID- 24071973 TI - [Surgery and organ transplantation]. AB - Liver and kidney transplantations have been performed for almost 50 years and is nowadays a routine procedure for the treatment of terminal liver failure and terminal-stage renal failure. Under given optimal conditions and increasing experience good results can be achieved. Improvements in surgical techniques have led to a decrease in the incidence of surgical complications after transplantation. Nevertheless after liver and kidney transplantation complications can occur and increase the morbidity and mortality. There are a number of possible complications which range from harmless wound healing disorders to severe vascular, biliary or urinary complications that can be associated with graft dysfunction and lead to graft loss. In order to identify risk factors preoperatively and achieve good outcome after transplantation a good preparation of the recipients is necessary. Furthermore, a good interdisciplinary cooperation is necessary both to recognize complications early and to treat these adequately. PMID- 24071974 TI - [Selection of wrap type and indications for antireflux surgery]. PMID- 24071975 TI - [Influence of gastrojejunal reconstruction after pancreaticoduodenectomy on gastric emptying]. PMID- 24071977 TI - The clip-segment of the von Willebrand domain 1 of the BMP modulator protein Crossveinless 2 is preformed. AB - Bone Morphogenetic Proteins (BMPs) are secreted protein hormones that act as morphogens and exert essential roles during embryonic development of tissues and organs. Signaling by BMPs occurs via hetero-oligomerization of two types of serine/threonine kinase transmembrane receptors. Due to the small number of available receptors for a large number of BMP ligands ligand-receptor promiscuity presents an evident problem requiring additional regulatory mechanisms for ligand specific signaling. Such additional regulation is achieved through a plethora of extracellular antagonists, among them members of the Chordin superfamily, that modulate BMP signaling activity by binding. The key-element in Chordin-related antagonists for interacting with BMPs is the von Willebrand type C (VWC) module, which is a small domain of about 50 to 60 residues occurring in many different proteins. Although a structure of the VWC domain of the Chordin-member Crossveinless 2 (CV2) bound to BMP-2 has been determined by X-ray crystallography, the molecular mechanism by which the VWC domain binds BMPs has remained unclear. Here we present the NMR structure of the Danio rerio CV2 VWC1 domain in its unbound state showing that the key features for high affinity binding to BMP-2 is a pre-oriented peptide loop. PMID- 24071978 TI - Characterization of amide bond conformers for a novel heterocyclic template of N acylhydrazone derivatives. AB - Herein we describe NMR experiments and structural modifications of 4-methyl-2 phenylpyrimidine-N-acylhydrazone compounds (aryl-NAH) in order to discover if duplication of some signals in their 1H- and 13C-NMR spectra was related to a mixture of imine double bond stereoisomers (E/Z) or CO-NH bond conformers (syn and anti-periplanar). NMR data from NOEdiff, 2D-NOESY and 1H-NMR spectra at different temperatures, and also the synthesis of isopropylidene hydrazone revealed the nature of duplicated signals of a 4-methyl-2-phenylpyrimidine-N acylhydrazone derivative as a mixture of two conformers in solution. Further we investigated the stereoelectronic influence of substituents at the ortho position on the pyrimidine ring with respect to the carbonyl group, as well as the electronic effects of pyrimidine by changing it to phenyl. The conformer equilibrium was attributed to the decoplanarization of the aromatic ring and carbonyl group (generated by an ortho-alkyl group) and/or the electron withdrawing character of the pyrimidine ring. Both effects increased the rotational barrier of the C-N amide bond, as verified by the DG(?) values calculated from dynamic NMR. As far as we know, it is the first description of aryl-NAH compounds presenting two CO-NH bond- related conformations. PMID- 24071979 TI - Modes of neighbouring group participation by the methyl selenyl substituent in beta-methylselenylmethyl-substituted 1-phenylethyl carbenium ions. AB - Selenium substituents which are disposed beta to an electron deficient centre, such as a carbocation p-orbital, or the pi* orbital of an electron deficient p system, interact in a stabilising way by a combination of C-Se hyperconjugation (sigma(Se-C)-pi* interaction), and a through-space homoconjugative n(Se)-pi* interaction. The relative importance of these two modes of interaction is dependant on the electron demand of the cation, with hyperconjugation predominating for low electron demand systems, and the n(Se)-pi* interaction predominating for high electron demand cations. PMID- 24071980 TI - A commonly used Chinese herbal formula, Shu-Jing-Hwo-Shiee-Tang, potentiates anticoagulant activity of warfarin in a rabbit model. AB - BACKGROUND: Drug interactions between traditional Chinese herbal medicines and the anticoagulant warfarin may cause patient harm and are, therefore, important in clinical practice. Our experience in daily practice suggests that prothrombin time (PT) is prolonged when warfarin is used in combination with the Chinese herbal formula Shu-Jing-Hwo-Shiee-Tang (SJHST) commonly used by patients with osteoarthritis. OBJECTIVE: We conducted animal experiments to confirm the effect of SJHST and warfarin on anticoagulant activity. METHODS: Forty-eight male New Zealand white rabbits were randomized into eight groups of six rabbits. Group A (Control group) was administered normal saline. Group B (Western Medicine group) was administered warfarin 1.5 mg/kg/day. Groups C, D, and E [Traditional Chinese Medicine (TCM) groups] were administered different doses of SJHST (0.5 mg/kg/day, 1 mg/kg/day, and 2 mg/kg/day, respectively). Groups F, G, and H (Combination Therapy groups) were administered warfarin 1.5 mg/kg/day and different doses of SJHST (0.5 mg/kg/day, 1 mg/kg/day, and 2 mg/kg/day, respectively). The total duration of treatment was 14 days. Blood samples were obtained prior to beginning the experiments (day 0) and on day 7, day 14, and day 17 (3 days after discontinuation of the medications). The activated partial thromboplastin time (APTT), PT, and thrombin time (TT) were calculated and compared among the different groups. RESULTS: No significant changes were noted in APTT, PT or TT between the control and SJHST-only groups. Significant prolongations of APTT and PTT, but not TT, were observed in the combination groups compared to the warfarin only group. The enhanced anticoagulant effects returned to normal three days after discontinuation of SJHST treatment. CONCLUSIONS: We confirmed that the Chinese herb SJHST enhances the anticoagulant effect of warfarin. Although the exact mechanisms of the interaction are unknown, physicians should be aware of the possibility of drug interactions between warfarin and Chinese herbal medicines owing to the increased risk of bleeding. PMID- 24071981 TI - Metabolomics and fetal-neonatal nutrition: between "not enough" and "too much". AB - Metabolomics is a new analytical technique defined as the study of the complex system of metabolites that is capable of describing the biochemical phenotype of a biological system. In recent years the literature has shown an increasing interest in paediatric obesity and the onset of diabetes and the metabolic syndrome in adulthood. Some studies show that fetal malnutrition, both excessive and insufficient, may permanently alter the metabolic processes of the fetus and increase the risk of future chronic pathologies. At present then, attention is being focused mainly on the formulation of new hypotheses, by means of metabolomics, concerning the biological mechanisms to departure from fetal neonatal life that may predispose to the development of these diseases. PMID- 24071983 TI - A highly sensitive telomerase activity assay that eliminates false-negative results caused by PCR inhibitors. AB - An assay for telomerase activity based on asymmetric polymerase chain reaction (A PCR) on magnetic beads (MBs) and subsequent application of cycling probe technology (CPT) is described. In this assay, the telomerase reaction products are immobilized on MBs, which are then washed to remove PCR inhibitors that are commonly found in clinical samples. The guanine-rich sequences (5'-(TTAGGG)n-3') of the telomerase reaction products are then preferentially amplified by A-PCR, and the amplified products are subsequently detected via CPT, where a probe RNA with a fluorophore at the 5' end and a quencher at the 3' end is hydrolyzed by RNase H in the presence of the target DNA. The catalyst-mediated cleavage of the probe RNA enhances fluorescence from the 5' end of the probe. The assay allowed us to successfully detect HeLa cells selectively over normal human dermal fibroblast (NHDF) cells. Importantly, this selectivity produced identical results with regard to detection of HeLa cells in the absence and presence of excess NHDF cells; therefore, this assay can be used for practical clinical applications. The lower limit of detection for HeLa cells was 50 cells, which is lower than that achieved with a conventional telomeric repeat amplification protocol assay. Our assay also eliminated false-negative results caused by PCR inhibitors. Furthermore, we show that this assay is appropriate for screening among G quadruplex ligands to find those that inhibit telomerase activity. PMID- 24071982 TI - Impact of origin and biological source on chemical composition, anticholinesterase and antioxidant properties of some St. John's wort species (Hypericum spp., Hypericaceae) from the Central Balkans. AB - The study shows the influence of the origin of plant material and biological source on the in vitro antioxidant (neutralization of DPPH and OH radical, nitric oxide, and inhibition of lipid peroxidation) and anticholinesterase activity of chemically characterized and quantified ethanol extracts of ten St. John's wort samples. The investigated samples were: five Hypericum perforatum species representatives collected at different localities, one commercial sample of Hyperici herba purchased at a local market and four Hypericum species autochtonous to the Balkan Peninsula (H. maculatum subsp. immaculatum, H. olympicum, H. richeri subsp. grisebachii and H. barbatum). All the examined extracts exhibited notable antioxidant potential, but in most of the cases indigenous Hypericum species expressed stronger effects compared to the original source of the drug, H. perforatum. The changes in the content of phenolic compounds, especially flavonoids, hyperforin and hypericin, related to the source of the drug affected the investigated activities. Since all of the investigated species have shown prominent inhibition of acetylcholinesterase in vitro activity, they could be further investigated as potential substances in preventing of Alzheimer's disease. PMID- 24071984 TI - Lipid classes and fatty acid regiodistribution in triacylglycerols of seed oils of two Sambucus species (S. nigra L. and S. ebulus L.). AB - The oil content and fatty acid composition of total lipids (TLs) and main lipid classes (NLs- neutral and PLs- polar lipids) in seeds of two wild Sambucus species (S. nigra and S. ebulus) from Transylvania (Romania) were determined by capillary gas chromatography (GC-MS). In addition, the positional distribution of fatty acids in seed triacylglycerols (TAGs) was determined by hydrolysis with pancreatic lipase. The seeds were found to be rich in fat (22.40-24.90 g/100g) with high amounts of polyunsaturated fatty acids (PUFAs) ranging from 68.96% (S. ebulus) to 75.15% (S. nigra). High ratios of PUFAs/SFAs (saturated fatty acids), ranging from 7.06 (S. nigra) to 7.64 (S. ebulus), and low ratios of n-6/n-3, ranging from 0.84 (S. nigra) to 1.51 (S. ebulus), were determined in both oils. The lipid classes/subclasses analyzed (PLs, MAGs--monoacylglycerols, DAGs- diacylglycerols, FFAs--free fatty acids, TAGs and SEs--sterol esters) were separated and identified using thin-layer chromatography. The fatty acid compositions of the TAG fractions were practically identical to the profiles of TLs, with the same dominating fatty acids in both analyzed species. SEs and FFAs, were characterized by high proportions of SFAs. The sn-2 position of TAGs was esterified predominantly with linoleic acid (43.56% for S. nigra and 50.41% for S. ebulus). PMID- 24071985 TI - Design and synthesis of a biotinylated chemical probe for detecting the molecular targets of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin. AB - Pseudomonas aeruginosa is a human pathogen associated with a variety of life threatening nosocomial infections. This organism produces a range of virulence factors which actively cause damage to host tissues. One such virulence factor is pyocyanin, known to play a crucial role in the pathogenesis of P. aeruginosa infections. Previous studies had identified a novel compound capable of strongly inhibiting the production of pyocyanin. It was postulated that this inhibition results from modulation of an intercellular communication system termed quorum sensing, via direct binding of the compound with the LasR protein receptor. This raised the possibility that the compound could be an antagonist of quorum sensing in P. aeruginosa, which could have important implications as this intercellular signaling mechanism is known to regulate many additional facets of P. aeruginosa pathogenicity. However, there was no direct evidence for the binding of the active compound to LasR (or any other targets). Herein we describe the design and synthesis of a biotin-tagged version of the active compound. This could potentially be used as an affinity-based chemical probe to ascertain, in a direct fashion, the active compound's macromolecular biological targets, and thus better delineate the mechanism by which it reduces the level of pyocyanin production. PMID- 24071986 TI - Optical characterization of oligonucleotide DNA influenced by magnetic fields. AB - UV-VIS spectroscopic analysis of oligonucleotide DNA exposed to different magnetic fields was performed in order to investigate the relationship between DNA extinction coefficients and optical parameters according to magnetic-field strength. The results with the oligonucleotides adenine-thymine 100 mer (AT-100 DNA) and cytosine-guanine 100 mer (CG-100 DNA) indicate that the magnetic field influences DNA molar extinction coefficients and refractive indexes. The imaginary parts of the refractive index and molar extinction coefficients of the AT-100 and CG-100 DNA decreased after exposure to a magnetic field of 750 mT due to cleavage of the DNA oligonucleotides into smaller segments. PMID- 24071987 TI - A comparative analysis of the influence of human salivary enzymes on odorant concentration in three palm wines. AB - The influence of human salivary enzymes on palm wines' odorant concentrations were investigated by the application of aroma extracts dilution analysis (AEDA) and by the calculation of odour activity values (OAVs), respectively. The odorants were quantified by means of stable isotope dilution assays (SIDA), and the degradation profiles of odorants by human saliva were also studied. Results revealed 46 odour-active compounds in the flavour dilution (FD) factor range of 4 256, and all were subsequently identified. Of the 46 odorants, 41 were identified in the Elaeis guineensis wine, 36 in Raphia hookeri wine and 29 in Borassus flabellifer wine. Among the odorants, the highest FD-factors were obtained from acetoin, 2-acetyl-1-pyrroline and 3-isobutyl-2-methoxypyrazine. Among the 13 potent odorants identified, five aroma compounds are reported here as important contributors to palm wine aroma, namely 3-isobutyl-2-methoxy-pyrazine, acetoin, 2 acetyl-1-pyrroline, 3-methylbutylacetate and ethyl hexanoate. Meanwhile, salivary enzymic degradation of odorants was more pronounced among the aldehydes, esters and thiols. PMID- 24071988 TI - Improved quality control method for prescriptions of Polygonum capitatum through simultaneous determination of nine major constituents by HPLC coupled with triple quadruple mass spectrometry. AB - As a traditional Miao-nationality medicinal plant, Polygonum capitatum has been used in clinical practice for several thousand years. Its prescriptions, including three dosage forms: granules, capsule and tablet are known by the brand name Relinqing(r) and have played an indispensable role in the treatment of urinary system infection, pyelonephritis and kidney stones. However, no study about the comprehensive quality evaluation of Relinqing(r) has been reported. In the present paper, a method for the simultaneous determination of nine major compounds in three dosage forms of Relinqing(r) using HPLC coupled with triple quadrupole mass spectrometry (HPLC-QQQ MS) was established to comprehensively evaluate their quality. The nine compounds, including four phenolic acids, four flavonoids and a lignin, were analyzed with acceptable linear regression relationship (r2, 0.9923-0.9992), precision (RSD, 1.25%-2.78%), repeatability (RSD, 2.05%%-3.47%), stability (RSD, 1.84%-3.72%) and recovery (93.60%-108.54%, RSD <= 3.67%). The present study fills the gap in the multivariate quality control of Relinqing(r) and provides a valuable reference for quality standards and dosage reforming of this traditional Chinese medicine. PMID- 24071989 TI - The effect of butanolides from Cinnamomum tenuifolium on platelet aggregation. AB - This study investigated the effects of isotenuifolide and tenuifolide B from the stems of Cinnamomum tenuifolium on adenosine diphosphate (ADP)-induced human platelet aggregation. Treatment of human platelet-rich plasma with isotenuifolide (1 and 2 MUg/MUL) and tenuifolide B (1, 2 and 4 MUg/MUL) did not have any significant effect on human platelet aggregation in vitro, however, treatment of human platelet-rich plasma with isotenuifolide (4 MUg/MUL) resulted in an inhibitory effect on platelet aggregation, suggesting the potential of this compound as an anti-atherosclerogenic agent in humans. Isotenuifolide is a new butanolide compound, whose structure was characterized by spectral analyses. PMID- 24071990 TI - In vitro and in vivo studies of the inhibitory effects of emodin isolated from Polygonum cuspidatum on Coxsakievirus B4. AB - The lack of effective therapeutics for Coxsackievirus B4 (CVB4) infection underscores the importance of finding novel antiviral compounds. Emodin (1,3,8 trihydroxy-6-methylanthraquinone) is one of the natural anthraquinone derivatives obtained from the root and rhizome of Polygonum cuspidatum. In the present study, the possibility of using emodin as a potential antiviral to treat CVB4 infection was explored in vitro and in mice. Emodin reduced CVB4 entry and replication on Hep-2 cells in a concentration- and time-dependent manner, with a 50% effective concentration (EC50) of 12.06 MUM and selectivity index (SI) of 5.08, respectively. The inhibitory effect of emodin for CVB4 entry and replication was further confirmed by a quantitative real time PCR (qPCR) assay. The results further showed that the mice orally treated with different dosages of emodin displayed a dose dependent increase of survival rate, body weight and prolonged mean time of death (MTD), accompanied by significantly decreased myocardial virus titers and pathologic scores/lesions. Moreover, emodin could inhibit CVB4-induced apoptosis in vitro and in vivo. Our results indicated that emodin could be used as potential antiviral in the post-exposure prophylaxis for CVB4 infection. PMID- 24071991 TI - Chemical constituents from the roots of Ranunculus ternatus and their inhibitory effects on Mycobacterium tuberculosis. AB - Two new benzophenones, methyl (R)-3-[2-(3,4-dihydroxybenzoyl)-4,5 dihydroxyphenyl]-2-hydroxypropanoate (1) and n-butyl (R)-3-[2-(3,4 dihydroxybenzoyl)-4,5-dihydroxyphenyl]-2-hydroxypropanoate (2), were isolated from the roots of Ranunculus ternatus along with the two known compounds vanillic acid (3) and gallic acid (4). Their structures were elucidated by physical and spectroscopic analysis. In addition, compound 1 exhibited obvious activity against tuberculosis, while the activity of a 1:1 mixture of compound 1 plus 4 is better than that of 1 alone. PMID- 24071993 TI - Toward the creation of stable, functionalized metal clusters. AB - Nanomaterials which exhibit both stability and functionality are currently considered to hold the most promise as components of nanotechnology devices. Thiolate (RS)-protected gold nanoclusters (Aun(SR)m) have attracted significant attention in this regard and, among these, the magic clusters are believed to be the best candidates since they are the most stable. We have investigated the effects of heteroatom doping, protection by selenolate ligands and protection by photoresponsive thiolates on the stability and physical/chemical properties of these clusters. Through such studies, we have attempted to establish methods of modifying magic Aun(SR)m clusters as a means of creating metal clusters that are both robust and functional. This paper summarizes our studies towards this goal and the obtained results. PMID- 24071992 TI - Upright cone CT of the hindfoot: comparison of the non-weight-bearing with the upright weight-bearing position. AB - OBJECTIVES: To prospectively compare computed tomography (CT) of the hindfoot in the supine non-weight-bearing position (NWBCT) with upright weight-bearing position (WBCT). METHODS: Institutional review board approval and informed consent of all patients were obtained. NWBCT and WBCT scans of the ankle were obtained in 22 patients (mean age, 46.0 +/- 17.1 years; range 19-75 years) using a conventional 64-row CT for NWBCT and a novel cone-beam CT for WBCT. Two musculoskeletal radiologists independently performed the following measurements: the hindfoot alignment angle, fibulocalcaneal and tibiocalcaneal distances, lateral talocalcaneal joint space width, talocalcaneal overlap and naviculocalcaneal distance. Significant changes between NWBCT and WBCT were sought using Wilcoxon signed-rank test. P values <0.05 were considered statistically significant. RESULTS: Significant differences were found for all measurements except the hindfoot alignment angle and tibiocalcaneal distance. Significant measurement results were as follows (NWBCT/WBCT reader 1; NWBCT/WBCT reader 2, mean +/- standard deviation): fibulocalcaneal distance 3.6 mm +/- 5.2/0.3 mm +/- 6.0 (P = 0.006); 1.4 mm +/- 6.3/-1.1 mm +/- 6.3 (P = 0.002), lateral talocalcaneal joint space width 2.9 mm +/- 1.7/2.2 mm +/- 1.1 (P = 0.005); 3.4 mm +/- 1.9/2.4 mm +/- 1.3 (P = 0.001), talocalcaneal overlap 4.1 mm +/- 3.9/1.4 mm +/- 3.9 (P = 0.001); 4.5 mm +/- 4.3/1.4 mm +/- 3.7 (P < 0.001) and naviculocalcaneal distance 13.5 mm +/- 4.0/15.3 mm +/- 4.7 (P = 0.037); 14.0 mm +/- 4.4/15.7 mm +/- 6.2 (P = 0.100). Interreader agreement was good to excellent (ICC 0.48-0.94). CONCLUSION: Alignment of the hindfoot significantly changes in the upright weight-bearing CT position. Differences can be visualised and measured using WBCT. KEY POINTS: * Cone-beam computed tomography (CBCT) offers new opportunities for musculoskeletal problems * Visualization and quantification of hindfoot alignment are possible in upright weight-bearing CBCT * Hindfoot alignment changes significantly from non-weight-bearing to weight-bearing CT * The weight-bearing position leads to a decrease in the fibulocalcaneal distance and talocalcaneal overlap * The naviculocalcaneal distance is increased in the weight-bearing position. PMID- 24071994 TI - Platelet function testing to time surgery in patients on dual antiplatelet therapy? AB - In patients pretreated with P2Y12 receptor inhibitors who need to undergo non emergent cardiac or major non-cardiac surgery, current guidelines of the European Society of Cardiology recommend postponing surgery for at least five days after last intake of clopidogrel or ticagrelor, and for seven days after last intake of prasugrel, unless there is high risk of ischemic events. However, a fixed five to seven days preoperative waiting period may be challenged, in the presence of inter-individual variability in on-treatment platelet reactivity. Therefore, Society of Thoracic Surgeons guidelines suggest to base decisions about a surgical delay on platelet function although both, the optimal platelet function assay and a bleeding cutoff have not yet been defined by large scale multicenter trials. This review aims to provide an overview on current knowledge of P2Y12 receptor induced platelet inhibition and surgery related bleeding and the potential role of platelet function analysis to time surgery. PMID- 24071995 TI - A novel narrow-line red emitting Na2Y2B2O7:Ce(3+),Tb(3+),Eu(3+) phosphor with high efficiency activated by terbium chain for near-UV white LEDs. AB - The application of white LEDs is hindered by the low efficiency of commercial red phosphors. Here, a novel narrow-line red phosphor is produced by a terbium chain in the form of Ce(3+)-(Tb(3+))n-Eu(3+) in the Na2Y2B2O7 host and is characterized with X-ray diffraction, photoluminescence (PL), PL excitation (PLE), and fluorescence lifetime, and the energy transfer (ET) processes between rare-earth ions in the host are discussed. The formation of terbium chain with a quite low content of Tb(3+) in Na2Y2B2O7 is realized by the ET processes of Ce(3+)-Tb(3+) and Tb(3+)-Eu(3+), and a new concept of saturation distance is put forward as an explanation for the first time. An energy level diagram is proposed to explain the ET processes in the phosphor of Na2Y2B2O7:Ce(3+),Tb(3+),Eu(3+). The emitting colour of the phosphor can be tuned from blue to green or yellow and finally to the orange-red region with increasing the content of Tb(3+). The quantum efficiency of the phosphor with an optimized ratio of rare-earth ions, Na2Y2B2O7:0.5% Ce(3+),60% Tb(3+),0.5% Eu(3+), is up to 77% under the excitation of 365 nm, which indicates that the as-synthesized phosphor is applicable to near UV white LEDs. PMID- 24071996 TI - Self-organizing properties of triethylsilylethynyl-anthradithiophene on monolayer graphene electrodes in solution-processed transistors. AB - Graphene has shown great potential as an electrode material for organic electronic devices such as organic field-effect transistors (FETs) because of its high conductivity, thinness, and good compatibility with organic semiconductor materials. To achieve high performance in graphene-based organic FETs, favorable molecular orientation and good crystallinity of organic semiconductors on graphene are desired. This strongly depends on the surface properties of graphene. Here, we investigate the effects of polymer residues that remain on graphene source/drain electrodes after the transfer/patterning processes on the self-organizing properties and field-effect characteristics of the overlying solution-processed triethylsilylethynyl-anthradithiophene (TES-ADT). A solvent assisted polymer residue removal process was introduced to effectively remove residues or impurities on the graphene surface. Unlike vacuum-deposited small molecules, TES-ADT displayed a standing-up molecular assembly, which facilitates lateral charge transport, on both the residue-removed clean graphene and as transferred graphene with polymer residues. However, TES-ADT films grown on the cleaned graphene showed a higher crystallinity and larger grain size than those on the as-transferred graphene. The resulting TES-ADT FETs using cleaned graphene source/drain electrodes therefore exhibited a superior device performance compared to devices using as-transferred graphene electrodes, with mobilities as high as 1.38 cm(2) V(-1) s(-1). PMID- 24071997 TI - Accessible mutational trajectories for the evolution of pyrimethamine resistance in the malaria parasite Plasmodium vivax. AB - Antifolate antimalarials, such as pyrimethamine, have experienced a dramatic reduction in therapeutic efficacy as resistance has evolved in multiple malaria species. We present evidence from one such species, Plasmodium vivax, which has experienced sustained selection for pyrimethamine resistance at the dihydrofolate reductase (DHFR) locus since the 1970s. Using a transgenic Saccharomyces cerevisiae model expressing the P. vivax DHFR enzyme, we assayed growth rate and resistance of all 16 combinations of four DHFR amino acid substitutions. These substitutions were selected based on their known association with drug resistance, both in natural isolates and in laboratory settings, in the related malaria species P. falciparum. We observed a strong correlation between the resistance phenotypes for these 16 P. vivax alleles and previously observed resistance data for P. falciparum, which was surprising since nucleotide diversity levels and common polymorphic variants of DHFR differ between the two species. Similar results were observed when we expressed the P. vivax alleles in a transgenic bacterial system. This suggests common constraints on enzyme evolution in the orthologous DHFR proteins. The interplay of negative trade-offs between the evolution of novel resistance and compromised endogenous function varies at different drug dosages, and so too do the major trajectories for DHFR evolution. In simulations, it is only at very high drug dosages that the most resistant quadruple mutant DHFR allele is favored by selection. This is in agreement with common polymorphic DHFR data in P. vivax, from which this quadruple mutant is missing. We propose that clinical dosages of pyrimethamine may have historically been too low to select for the most resistant allele, or that the fitness cost of the most resistant allele was untenable without a compensatory mutation elsewhere in the genome. PMID- 24071998 TI - Lineage-specific duplications of Muroidea Faim and Spag6 genes and atypical accelerated evolution of the parental Spag6 gene. AB - Gene duplications restricted to single lineage combined with an asymmetric evolution of the resulting genes may play particularly important roles in this lineage's biology. We searched and identified asymmetrical evolution in nine gene families that duplicated exclusively in rodents and are present as single-copies in human, dog, cow, elephant, opossum, chicken, lizard, and Western clawed frog. Among those nine gene families are Fas apoptosis inhibitory molecule (Faim), implicated in apoptosis, and Sperm antigen 6 (Spag6), implicated in sperm mobility. Both genes were duplicated in or before the Muroidea ancestor. Due to the highly asymmetric evolution of the resulting paralogs, the existence of these duplications had been previously overlooked. Interestingly, Spag6, previously regarded and characterized as a single-copy ortholog of human Spag6, turns out to be a Muroidea-specific paralog. Conversely, the newly identified, highly divergent Spag6-BC061194 is in fact the parental gene. In consequence, this gene represents a rare exception from the general rule of rapid evolution of derived rather than parental genes following gene duplication. Unusual genes such as murine Spag6 may help to understand which mechanisms are responsible for this rule. PMID- 24071999 TI - [Unclear clinical change on the glans penis leads to different dermoscopic diagnoses]. PMID- 24072000 TI - IL-1alpha, IL-1beta, IL-6, and IL-8 secretion of human keratocytes following photodynamic inactivation (PDI) in vitro. AB - PURPOSE: With increasing resistance of microorganisms to antibiotics, photodynamic inactivation (PDI) may also be a potential therapeutic option in infectious keratitis. As part of the inflammatory response in infectious keratitis, keratocytes produce various interleukins. The purpose of this study was to evaluate the potential anti-inflammatory effect of PDI, analyzing interleukin-1 alpha (IL-1alpha), interleukine-1 beta (IL-1beta), interleukin-6 (IL-6), and interleukin-8 (IL-8) secretion of human keratocytes following PDI, in vitro. METHODS: Primary human keratocytes were isolated by digestion in collagenase A (1.0 mg/ml) from human corneal buttons, and cultured in DMEM/Ham's F12 medium supplemented with 10% FCS. Keratocyte cell cultures underwent illumination using red (670 nm) light for 13 min following exposure to 100 nM concentration of the photosensitizer chlorin e6 (Ce6) in the culture medium. Five and 24 hours after PDI, secretion of IL-1alpha, IL-1beta, IL-6, and IL-8 was measured by enzyme-linked immunoabsorbent assay (ELISA). RESULTS: The secretion of IL-1alpha was under the measurement limit in treated and untreated cell cultures 5 and 24 h after PDI. Compared to untreated controls, IL-6 and IL-8 secretion of keratocytes decreased (p < 0.05 and 0.0001) significantly 5 hours after PDI, whereas IL-1beta secretion remained unchanged. Twenty-four hours after PDI, secretion of IL-1beta, IL-6, and IL-8 did not differ significantly from untreated controls. CONCLUSIONS: In the short term, PDI does not have an impact on IL-1alpha and IL-1beta secretion of keratocytes, in vitro. Photodynamic inactivation inhibits IL-6 and IL-8 secretion of keratocytes transiently (5 h), which normalizes 24 h following treatment. Through the short-term impact of chlorine e6-PDI on IL-6 and IL-8 secretion, PDI may inhibit the inflammatory cascade in at least keratocyte cultures. PMID- 24072001 TI - Oxidative stress interferes with white matter renewal after prolonged cerebral hypoperfusion in mice. AB - BACKGROUND AND PURPOSE: White matter injury caused by cerebral hypoperfusion may contribute to the pathophysiology of vascular dementia and stroke, but the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that oxidative stress interferes with endogenous white matter repair by disrupting renewal processes mediated by oligodendrocyte precursor cells (OPCs). METHODS: In vitro, primary rat OPCs were exposed to sublethal CoCl2 for 7 days to induce prolonged chemical hypoxic stress. Then, OPC proliferation/differentiation was assessed. In vivo, prolonged cerebral hypoperfusion was induced by bilateral common carotid artery stenosis in mice. Then, reactive oxygen species production, myelin density, oligodendrocyte versus OPC counts, and cognitive function were evaluated. To block oxidative stress, OPCs and mice were treated with the radical scavenger edaravone. RESULTS: Prolonged chemical hypoxic stress suppressed OPC differentiation in vitro. Radical scavenging with edaravone ameliorated these effects. After 28 days of cerebral hypoperfusion in vivo, reactive oxygen species levels were increased in damaged white matter, along with the suppression of OPC to-oligodendrocyte differentiation and loss of myelin staining. Concomitantly, mice showed functional deficits in working memory. Radical scavenging with edaravone rescued OPC differentiation, ameliorated myelin loss, and restored working memory function. CONCLUSIONS: Our proof-of-concept study demonstrates that after prolonged cerebral hypoperfusion, oxidative stress interferes with white matter repair by disrupting OPC renewal mechanisms. Radical scavengers may provide a potential therapeutic approach for white matter injury in vascular dementia and stroke. PMID- 24072002 TI - Imaging characteristics of ischemic strokes related to patent foramen ovale. AB - BACKGROUND AND PURPOSE: Subclinical atrial fibrillation (AF) and patent foramen ovale (PFO) are the major causes of cryptogenic stroke, and neuroimaging may help distinguish the cause. We compared the imaging characteristics of ischemic stroke caused by PFO (PFO-stroke) and AF (AF-stroke). METHODS: We recruited 117 patients with PFO-stroke and 358 patients with AF-stroke after excluding other causes. The lesion patterns were classified according to number, location, size, and pertinent vascular territory and were compared between the 2 groups. Occlusion of the corresponding artery and its recanalization rate were also investigated. RESULTS: The lesion pattern of a PFO-stroke was more frequently observed as a single cortical infarction (34.2% versus 3.1%; P<0.001) or multiple small (<15 mm) scattered lesions (23.1% versus 5.9%; P<0.001) and in the vertebrobasilar artery territory (44.4% versus 22.9%; P<0.001). By contrast, AF-stroke was more frequently observed as a large cortico-subcortical infarction or confluent lesion (>15 mm) with additional lesions in multicirculatory territories. For a PFO stroke, occlusion of the corresponding vessel on angiography was less frequent (34.2% versus 71.5%; P<0.001), and the neurological deficit evaluated by the National Institutes of Health Stroke Scale was mild (3.48+/-4.16 versus 9.15+/ 7.35; P<0.001). The recanalization rate was also lower (57.1% versus 78.3%; P=0.007). CONCLUSIONS: A PFO-stroke usually appears as a single cortical or multiple small ischemic lesions in the vertebrobasilar circulation without any visible vessel occlusion on angiography. The recanalization rate is significantly lower than in AF-stroke. These imaging characteristics of PFO-stroke may help to diagnose the mechanism and determine the treatment strategy. PMID- 24072003 TI - THRIVE score predicts outcomes with a third-generation endovascular stroke treatment device in the TREVO-2 trial. AB - BACKGROUND AND PURPOSE: Several outcome prediction scores have been tested in patients receiving acute stroke treatment with previous generations of endovascular stroke treatment devices. The TREVO-2 trial was a randomized controlled trial comparing a novel endovascular stroke treatment device (the Trevo device) to a previous-generation endovascular stroke treatment device (the Merci device). METHODS: We used data from the TREVO-2 trial to validate the Totaled Health Risks in Vascular Events (THRIVE) score in patients receiving treatment with a third-generation endovascular stroke treatment device and to compare THRIVE to other predictive scores. We used logistic regression to model outcomes and compared score performance with receiver operating characteristic curve analysis. RESULTS: In the TREVO-2 trial, the THRIVE score strongly predicts clinical outcome and mortality. The relationship between THRIVE score and outcome is not influenced by either success of recanalization or the type of device used (Trevo versus Merci). The superiority of the Trevo device to the Merci device is evident particularly among patients with a low-to-moderate THRIVE score (0-5; 53.8% good outcome with Trevo versus 27.5% good outcome with Merci). In receiver operating characteristic curve analysis, the THRIVE score was comparable or superior to several other outcome prediction scores (HIAT, HIAT-2, SPAN-100, and iScore). CONCLUSIONS: The THRIVE score strongly predicts clinical outcome and mortality in the TREVO-2 trial. Taken together with THRIVE validation data from patients receiving intravenous tissue-type plasminogen activator or no acute treatment, the THRIVE score has broad predictive power in patients with acute ischemic stroke, which is likely because THRIVE reflects a set of strong nonmodifiable predictors of stroke outcome. A free Web calculator for the THRIVE score is available at http://www.thrivescore.org. PMID- 24072004 TI - THRIVE score predicts ischemic stroke outcomes and thrombolytic hemorrhage risk in VISTA. AB - BACKGROUND AND PURPOSE: In previous studies, the Totaled Health Risks in Vascular Events (THRIVE) score has shown broad utility, allowing prediction of clinical outcome, death, and risk of hemorrhage after tissue-type plasminogen activator (tPA) treatment, irrespective of the type of acute stroke therapy applied to the patient. METHODS: We used data from the Virtual International Stroke Trials Archive to further validate the THRIVE score in a large cohort of patients receiving tPA or no acute treatment, to confirm the relationship between THRIVE and hemorrhage after tPA, and to compare the THRIVE score with several other available outcome prediction scores. RESULTS: The THRIVE score strongly predicts clinical outcome (odds ratio, 0.55 for good outcome [95% CI, 0.53-0.57]; P<0.001), mortality (odds ratio, 1.57 [95% confidence interval, 1.50-1.64]; P<0.001), and risk of intracerebral hemorrhage after tPA (odds ratio, 1.34 [95% confidence interval, 1.22-1.46]; P<0.001). The relationship between THRIVE score and outcome is not influenced by the independent relationship of tPA administration and outcome. In receiver operator characteristic curve analysis, the THRIVE score was superior to several other available outcome prediction scores in the prediction of clinical outcome and mortality. CONCLUSIONS: The THRIVE score is a simple-to-use tool to predict clinical outcome, mortality, and risk of hemorrhage after thrombolysis in patients with ischemic stroke. Despite its simplicity, the THRIVE score performs better than several other outcome prediction tools. A free Web calculator for the THRIVE score is available at http://www.thrivescore.org. PMID- 24072005 TI - Current state of acute stroke imaging. PMID- 24072006 TI - Does use of the recognition of stroke in the emergency room stroke assessment tool enhance stroke recognition by ambulance clinicians? AB - BACKGROUND AND PURPOSE: U.K ambulance services assess patients with suspected stroke using the Face Arm Speech Test (FAST). The Recognition Of Stroke In the Emergency Room (ROSIER) tool has been shown superior to the FAST in identifying strokes in emergency departments but has not previously been tested in the ambulance setting. We investigated whether ROSIER use by ambulance clinicians can improve stroke recognition. METHODS: Ambulance clinicians used the ROSIER in place of the FAST to assess patients with suspected stroke. As the ROSIER includes all FAST elements, we calculated a FAST score from the ROSIER to enable comparisons between the two tools. Ambulance clinicians' provisional stroke diagnoses using the ROSIER and calculated FAST were compared with stroke consultants' diagnosis. We used stepwise logistic regression to compare the contribution of individual ROSIER and FAST items and patient demographics to the prediction of consultants' diagnoses. RESULTS: Sixty-four percent of strokes and 78% of nonstrokes identified by ambulance clinicians using the ROSIER were subsequently confirmed by a stroke consultant. There was no difference in the proportion of strokes correctly detected by the ROSIER or FAST with both displaying excellent levels of sensitivity. The ROSIER detected marginally more nonstroke cases than the FAST, but both demonstrated poor specificity. Facial weakness, arm weakness, seizure activity, age, and sex predicted consultants' diagnosis of stroke. CONCLUSIONS: The ROSIER was not better than the FAST for prehospital recognition of stroke. A revised version of the FAST incorporating assessment of seizure activity may improve stroke identification and decision making by ambulance clinicians. PMID- 24072007 TI - Nox2-derived superoxide contributes to cerebral vascular dysfunction in diet induced obesity. AB - BACKGROUND AND PURPOSE: Obesity is an increasing epidemic worldwide; however, little is known about effects of obesity produced by high-fat diet (HFD) on the cerebral circulation. The purpose of this study was to examine the functional and temporal effects of a HFD on carotid and cerebral vascular function and to identify mechanisms that contribute to such functional alterations. METHODS: Responses of cerebral arterioles (in vivo) and carotid arteries (in vitro) were examined in C57Bl/6 (wild-type) and Nox2-deficient (Nox2(-/-)) mice fed a control (10%) or a HFD (45% or 60% kcal of fat) for 8, 12, 30, or 36 weeks. RESULTS: In wild-type mice, a HFD produced obesity and endothelial dysfunction by 12 and 36 weeks in cerebral arterioles and carotid arteries, respectively. Endothelial function could be significantly improved with Tempol (a superoxide scavenger) treatment in wild-type mice fed a HFD. Despite producing a similar degree of obesity in both wild-type and Nox2(-/-) mice, endothelial dysfunction was observed only in wild-type, but not in Nox2(-/-), mice fed a HFD. CONCLUSIONS: Endothelial dysfunction produced by a HFD occurs in a temporal manner and appears much earlier in cerebral arterioles than in carotid arteries. Genetic studies revealed that Nox2-derived superoxide plays a major role in endothelial dysfunction produced by a HFD. Such functional changes may serve to predispose blood vessels to reduced vasodilator responses and thus may contribute to alterations in cerebral blood flow associated with obesity. PMID- 24072008 TI - Mapping spread and risk of avian influenza A (H7N9) in China. AB - The outbreak of human infections with an emerging avian influenza A (H7N9) virus occurred in China in early 2013. It remains unknown what and how the underlying risk factors were involved in the bird-to-human cross-species transmission. To illustrate the dynamics of viral spread, we created a thematic map displaying the distribution of affected counties and plotted epidemic curves for the three most affected provinces and the whole country. We then collected data of agro ecological, environmental and meteorological factors at the county level, and used boosted regression tree (BRT) models to examine the relative contribution of each factor and map the probability of occurrence of human H7N9 infection. We found that live poultry markets, human population density, irrigated croplands, built-up land, relative humidity and temperature significantly contributed to the occurrence of human infection with H7N9 virus. The discriminatory ability of the model was up to 97.4%. A map showing the areas with high risk for human H7N9 infection was created based on the model. These findings could be used to inform targeted surveillance and control efforts in both human and animal populations to reduce the risk of future human infections. PMID- 24072009 TI - Assessment of the learning curves for photoselective vaporization of the prostate using GreenLightTM 180-Watt-XPS laser therapy: defining the intra-operative parameters within a prospective cohort. AB - PURPOSE: To assess the learning curves for the intra-operative parameters of the GreenLightTM 180-W XPS for photoselective vaporization of the prostate (PVP). METHODS: A prospective study was conducted on 200 men who underwent PVP using the GreenLightTM 180-W XPS over 20 months. The population was divided into four consecutive equal groups. Evolution of lasing parameters was the main endpoint to reach an average energy of 5 kJ per prostate volume and to reach a lasing time/operative time (LT/OT) ratio of 66-80 %. Changes in the IPSS and prostate volume were also evaluated 12 weeks later. RESULTS: Total energy delivered (energy/ml of prostate) and the LT/OT ratio significantly increased over time (p < 0.05). Urinary function significantly improved from baseline in all groups. The first lasing parameter endpoint was reached after the 75th patient (group 1) and the second endpoint (LT/OT ratio) after the 125th patient (group 3). Only the PSA level (p = 0.04) and prostate volume (p < 0.0001) decreased significantly in the 3rd and the 4th group. Post-operative complications occurred in 20 % of patients, which were primarily Clavien-Dindo grades 1 and 2, though there were no statistical differences between the four groups (p = 0.62). In-hospital stay and time to catheter removal were significantly shorter in the 3rd and 4th group. CONCLUSIONS: The current study assessed the PVP learning curves within multiple intra-operative parameters. The PVP learning curves required at least 120 procedures until it met all intra-operative parameters of experts in this field. PMID- 24072010 TI - Predictors of admission in patients presenting to the emergency department with urinary tract infection. AB - PURPOSE: Previous studies examining the management of urinary tract infections (UTI) showed marked variability in the economical burden of care, with a tenfold increase in costs when patients require admission to the hospital. We sought to examine the patient and emergency department (ED) characteristics associated with hospitalization in patients presenting to the ED with UTI. METHODS: An estimate of 10,798,343 patients with a primary diagnosis of UTI was presented to the ED from 2006 to 2009 and was abstracted from the Nationwide Emergency Department Sample. Univariable and multivariable analyses examined patient and hospital characteristics of those admitted with UTI. RESULTS: Between 2006 and 2009, 10.8 million patients presented to the ED in the United States for the treatment of UTI and 1.8 million patients (16.7 %) were admitted to the hospital for further management. Admitted patients were older, and a higher proportion had pyelonephritis, was male, and had Medicare. Admitted patients were also more likely to be seen at urban teaching hospitals, and/or treated at zip codes with higher median incomes. Following multivariable analysis, the independent predictors of admission included pyelonephritis (OR 5.29, 95 % CI 5.23-5.35), male gender (OR 1.58, 95 % CI 1.56-1.59), and advancing age (OR 1.037, 95 % CI 1.037-1.037). CONCLUSIONS: Expansion in ED utilization for the management of UTI has exceeded previous estimates. While the preponderance of patients presenting to the ED for UTI is discharged home, 16.7 % are admitted for further management. Predictors of inpatient admission on multivariable analyses included pyelonephritis, advancing age, and male gender. PMID- 24072017 TI - Highly durable non-sticky silver film with a microball-nanosheet hierarchical structure prepared by chemical deposition. AB - Non-sticky and highly adhesive superhydrophobic microball-nanosheet hierarchically structured silver films were obtained after surface modification and storage respectively. PMID- 24072011 TI - Selective angioembolization for traumatic renal injuries: a survey on clinician practice. AB - PURPOSE: A variety of clinical and imaging findings are used by clinicians to determine utility of renal angioembolization (AE) in managing renal trauma. Our purpose was to investigate specific criteria that clinicians who manage high grade renal trauma (HGRT) utilize in decision-making for primary or delayed AE. METHODS: A total of 413 urologists and interventional radiologists (IRs) who practice at level 1 or 2 trauma centers within the United States were provided an original survey via email on experience and opinions regarding the utility of AE for HGRT. We described overall practice patterns and assessed differences by clinician type, using the Fisher's exact test. RESULTS: A total of 79 (20 %) clinicians completed the survey. All clinicians had AE capability for HGRT management. A higher proportion of IRs reported using AE for grade I-II (33 vs. 3 %, p = 0.002), grade III (65 vs. 26 %, p = 0.001), and penetrating injuries (83 vs. 58 %, p = 0.02). A greater proportion of urologists reported using AE for grade V injuries (81 vs. 56 %, p = 0.03). Clinicians most commonly cited computed tomography evidence of active arterial bleeding (97 %), or arteriovenous fistula/pseudoaneurysm (94 %) as indications for primary AE, and 62 % identified concurrent visceral injury as factor that would necessitate surgical intervention. CONCLUSION: In a survey of clinicians, we report that IRs and urologists utilize AE differently when managing HGRT, as a higher proportion of IRs use AE to manage lower grade as well as penetrating injuries. Validation studies are needed to establish algorithms to identify patients with HGRT who would benefit from selective renal AE. PMID- 24072018 TI - Neurologic complications of influenza. AB - We report on a child with mild encephalopathy with reversible splenial lesion (MERS) associated with influenza infection and present a case series of neurological complications associated with influenza infections in children who presented to a tertiary children's hospital in Australia over a period of one year. PMID- 24072019 TI - Therapeutic hypothermia with the use of intracranial pressure monitoring for acute disseminated encephalomyelitis with brainstem lesion: a case report. AB - Acute disseminated encephalomyelitis confined to the brainstem is associated with poor prognosis. We describe a case of a 10-year-old boy with acute disseminated encephalomyelitis in the brainstem that developed after influenza A infection. A 10-year-old boy presented with fever and prolonged disturbance of consciousness and was admitted to our hospital. Magnetic resonance imaging (MRI) of the midbrain, with T2-weighted and fluid-attenuated inversion recovery images, suggested acute disseminated encephalomyelitis accompanied by a brainstem lesion. Lumbar puncture showed pleocytosis and increased protein content, including myelin basic protein, interleukin-6, and immunoglobulin G, all suggestive of acute disseminated encephalomyelitis. Treatments such as methylprednisolone pulse therapy, intravenous immunoglobulin, and therapeutic hypothermia were performed. Although the patient presented with anisocoria with increased intracranial pressure monitoring during hypothermia, prompt therapy with d-mannitol and dopamine was effective. Our case results suggest that hypothermia could be included in the choice of therapy for acute disseminated encephalomyelitis with brainstem lesions. PMID- 24072020 TI - Lacunar stroke in a teenager after minor head trauma: case report and literature review. AB - Ischemic strokes in children and young adults are fortunately rare. Contrasted with adult ischemic strokes, pediatric stroke etiologies vary greatly and are often unknown. Childhood lacunar strokes and trauma-induced strokes represent particularly uncommon subsets and have been reported infrequently in the literature. It is unique to find a combination of the 2-a lacunar stroke induced by trauma. Underreporting of these trauma-induced ischemic strokes could be responsible for perpetuating the lack of recognition. Here we present a lacunar stroke in a young woman associated with a water sport accident and explore relevant literature encircling deep brain ischemia coinciding with trauma. PMID- 24072022 TI - Micro ethanol sensors with a heater fabricated using the commercial 0.18 MUm CMOS process. AB - The study investigates the fabrication and characterization of an ethanol microsensor equipped with a heater. The ethanol sensor is manufactured using the commercial 0.18 um complementary metal oxide semiconductor (CMOS) process. The sensor consists of a sensitive film, a heater and interdigitated electrodes. The sensitive film is zinc oxide prepared by the sol-gel method, and it is coated on the interdigitated electrodes. The heater is located under the interdigitated electrodes, and it is used to supply a working temperature to the sensitive film. The sensor needs a post-processing step to remove the sacrificial oxide layer, and to coat zinc oxide on the interdigitated electrodes. When the sensitive film senses ethanol gas, the resistance of the sensor generates a change. An inverting amplifier circuit is utilized to convert the resistance variation of the sensor into the output voltage. Experiments show that the sensitivity of the ethanol sensor is 0.35 mV/ppm. PMID- 24072021 TI - Tip-enhanced Raman imaging and nano spectroscopy of etched silicon nanowires. AB - Tip-enhanced Raman spectroscopy (TERS) is used to investigate the influence of strains in isolated and overlapping silicon nanowires prepared by chemical etching of a (100) silicon wafer. An atomic force microscopy tip made of nanocrystalline diamond coated with a thin layer of silver is used in conjunction with an excitation wavelength of 532 nm in order to probe the first order optical phonon mode of the [100] silicon nanowires. The frequency shift and the broadening of the silicon first order phonon are analyzed and compared to the topographical measurements for distinct configuration of nanowires that are disposed in straight, bent or overlapping configuration over a microscope coverslip. The TERS spatial resolution is close to the topography provided by the nanocrystalline diamond tip and subtle spectral changes are observed for different nanowire configurations. PMID- 24072023 TI - Satellite angular velocity estimation based on star images and optical flow techniques. AB - An optical flow-based technique is proposed to estimate spacecraft angular velocity based on sequences of star-field images. It does not require star identification and can be thus used to also deliver angular rate information when attitude determination is not possible, as during platform de tumbling or slewing. Region-based optical flow calculation is carried out on successive star images preprocessed to remove background. Sensor calibration parameters, Poisson equation, and a least-squares method are then used to estimate the angular velocity vector components in the sensor rotating frame. A theoretical error budget is developed to estimate the expected angular rate accuracy as a function of camera parameters and star distribution in the field of view. The effectiveness of the proposed technique is tested by using star field scenes generated by a hardware-in-the-loop testing facility and acquired by a commercial off-the shelf camera sensor. Simulated cases comprise rotations at different rates. Experimental results are presented which are consistent with theoretical estimates. In particular, very accurate angular velocity estimates are generated at lower slew rates, while in all cases the achievable accuracy in the estimation of the angular velocity component along boresight is about one order of magnitude worse than the other two components. PMID- 24072024 TI - A gold nanoparticles enhanced surface plasmon resonance immunosensor for highly sensitive detection of ischemia-modified albumin. AB - In this study a novel sensitive nanogold particle sensor enhancement based on mixed self-assembled monolayers was explored and used to construct a Surface Plasmon Resonance (SPR) immunosensor to detect Ischemia Modified Albumin (IMA). Compared with a direct binding SPR assay at a limit of detection (LOD) of 100 ng/L, gold nanoparticles (AuNPs) of 10 nm dramatically improved the LOD of IMA to 10 ng/L. Meanwhile, no interfering substance that may lead to false positive results was identified. These results suggested that the SPR biosensor presented superior properties, and provided a simple label-free strategy to increase assay sensitivity for further acute coronary syndrome (ACS) diagnosis. PMID- 24072025 TI - 3D multi-spectrum sensor system with face recognition. AB - This paper presents a novel three-dimensional (3D) multi-spectrum sensor system, which combines a 3D depth sensor and multiple optical sensors for different wavelengths. Various image sensors, such as visible, infrared (IR) and 3D sensors, have been introduced into the commercial market. Since each sensor has its own advantages under various environmental conditions, the performance of an application depends highly on selecting the correct sensor or combination of sensors. In this paper, a sensor system, which we will refer to as a 3D multi spectrum sensor system, which comprises three types of sensors, visible, thermal IR and time-of-flight (ToF), is proposed. Since the proposed system integrates information from each sensor into one calibrated framework, the optimal sensor combination for an application can be easily selected, taking into account all combinations of sensors information. To demonstrate the effectiveness of the proposed system, a face recognition system with light and pose variation is designed. With the proposed sensor system, the optimal sensor combination, which provides new effectively fused features for a face recognition system, is obtained. PMID- 24072026 TI - Best basis selection method using learning weights for face recognition. AB - In the face recognition field, principal component analysis is essential to the reduction of the image dimension. In spite of frequent use of this analysis, it is commonly believed that the basis faces with large eigenvalues are chosen as the best subset in the nearest neighbor classifiers. We propose an alternative that can predict the classification error during the training steps and find the useful basis faces for the similarity metrics of the classical pattern algorithms. In addition, we also show the need for the eye-aligned dataset to have the pure face. The experiments using face images verify that our method reduces the negative effect on the misaligned face images and decreases the weights of the useful basis faces in order to improve the classification accuracy. PMID- 24072027 TI - Real-time human ambulation, activity, and physiological monitoring: taxonomy of issues, techniques, applications, challenges and limitations. AB - Automated methods of real-time, unobtrusive, human ambulation, activity, and wellness monitoring and data analysis using various algorithmic techniques have been subjects of intense research. The general aim is to devise effective means of addressing the demands of assisted living, rehabilitation, and clinical observation and assessment through sensor-based monitoring. The research studies have resulted in a large amount of literature. This paper presents a holistic articulation of the research studies and offers comprehensive insights along four main axes: distribution of existing studies; monitoring device framework and sensor types; data collection, processing and analysis; and applications, limitations and challenges. The aim is to present a systematic and most complete study of literature in the area in order to identify research gaps and prioritize future research directions. PMID- 24072028 TI - Cooperation among wirelessly connected static and mobile sensor nodes for surveillance applications. AB - This paper presents a bio-inspired networking strategy to support the cooperation between static sensors on the ground and mobile sensors in the air to perform surveillance missions in large areas. The goal of the proposal is to provide low overhead in the communication among sensor nodes, while allocating the mobile sensors to perform sensing activities requested by the static ones. Simulations have shown that the strategy is efficient in maintaining low overhead and achieving the desired coordination. PMID- 24072029 TI - Automatic detection and recognition of pig wasting diseases using sound data in audio surveillance systems. AB - Automatic detection of pig wasting diseases is an important issue in the management of group-housed pigs. Further, respiratory diseases are one of the main causes of mortality among pigs and loss of productivity in intensive pig farming. In this study, we propose an efficient data mining solution for the detection and recognition of pig wasting diseases using sound data in audio surveillance systems. In this method, we extract the Mel Frequency Cepstrum Coefficients (MFCC) from sound data with an automatic pig sound acquisition process, and use a hierarchical two-level structure: the Support Vector Data Description (SVDD) and the Sparse Representation Classifier (SRC) as an early anomaly detector and a respiratory disease classifier, respectively. Our experimental results show that this new method can be used to detect pig wasting diseases both economically (even a cheap microphone can be used) and accurately (94% detection and 91% classification accuracy), either as a standalone solution or to complement known methods to obtain a more accurate solution. PMID- 24072030 TI - Degradation of bacterial quorum sensing signaling molecules by the microscopic yeast Trichosporon loubieri isolated from tropical wetland waters. AB - Proteobacteria produce N-acylhomoserine lactones as signaling molecules, which will bind to their cognate receptor and activate quorum sensing-mediated phenotypes in a population-dependent manner. Although quorum sensing signaling molecules can be degraded by bacteria or fungi, there is no reported work on the degradation of such molecules by basidiomycetous yeast. By using a minimal growth medium containing N-3-oxohexanoylhomoserine lactone as the sole source of carbon, a wetland water sample from Malaysia was enriched for microbial strains that can degrade N-acylhomoserine lactones, and consequently, a basidiomycetous yeast strain WW1C was isolated. Morphological phenotype and molecular analyses confirmed that WW1C was a strain of Trichosporon loubieri. We showed that WW1C degraded AHLs with N-acyl side chains ranging from 4 to 10 carbons in length, with or without oxo group substitutions at the C3 position. Re-lactonisation bioassays revealed that WW1C degraded AHLs via a lactonase activity. To the best of our knowledge, this is the first report of degradation of N-acyl-homoserine lactones and utilization of N-3-oxohexanoylhomoserine as carbon and nitrogen source for growth by basidiomycetous yeast from tropical wetland water; and the degradation of bacterial quorum sensing molecules by an eukaryotic yeast. PMID- 24072031 TI - Kink turn sRNA folding upon L7Ae binding using molecular dynamics simulations. AB - The kink-turn sRNA motif in archaea, whose combination with protein L7Ae initializes the assembly of small ribonucleoprotein particles (sRNPs), plays a key role in ribosome maturation and the translation process. Although many studies have been reported on this motif, the mechanism of sRNA folding coupled with protein binding is still poorly understood. Here, room and high temperature molecular dynamics (MD) simulations were performed on the complex of 25-nt kink turn sRNA and L7Ae. The average RMSD values between the bound and corresponding apo structures and Kolmogorov-Smirnov P test analysis indicate that sRNA may follow an induced fit mechanism upon binding with L7Ae, both locally and globally. These conclusions are further supported by high-temperature unfolding kinetic analysis. Principal component analysis (PCA) found both closing and opening motions of the kink-turn sRNA. This might play a key role in the sRNP assembly and methylation catalysis. These combined computational methods can be used to study the specific recognition of other sRNAs and proteins. PMID- 24072032 TI - Nanogap based graphene coated AFM tips with high spatial resolution, conductivity and durability. AB - After one decade of analyzing the intrinsic properties of graphene, interest into the development of graphene-based devices and micro electromechanical systems is increasing. Here, we fabricate graphene-coated atomic force microscope tips by growing the graphene on copper foil and transferring it onto the apex of a commercially available AFM tip. The resulting tip exhibits surprising enhanced resolution in nanoscale electrical measurements. By means of topographic AFM maps and statistical analyses we determine that this superior performance may be related to the presence of a nanogap between the graphene and the tip apex, which reduces the tip radius and tip-sample contact area. In addition, the graphene coated tips show a low tip-sample interaction, high conductivity and long life times. The novel fabrication-friendly tip could improve the quality and reliability of AFM experiments, while reducing the cost of AFM-based research. PMID- 24072033 TI - Effects of surface instability on neuromuscular performance during drop jumps and landings. AB - PURPOSE: The purpose of this study was to investigate the effects of surface instability on measures of performance and activity of leg and trunk muscles during drop jumps and landings. METHODS: Drop jumps and landings were assessed on a force plate under stable and unstable (balance pad on top of the force plate) conditions. Performance measures (contact time, jump height, peak ground reaction force) and electromyographic (EMG) activity of leg and trunk muscles were tested in 27 subjects (age 23 +/- 3 years) during different time intervals (preactivation phase, braking phase, push-off phase). RESULTS: The performance of drop jumps under unstable compared to stable conditions produced a decrease in jump height (9 %, p < 0.001, f = 0.92) and an increase in peak ground reaction force (5 %, p = 0.022, f = 0.72), and time for braking phase (12 %, p < 0.001, f = 1.25). When performing drop jumps on unstable compared to stable surfaces, muscle activity was reduced in the lower extremities during the preactivation, braking and push-off phases (11-25 %, p < 0.05, 0.48 <= f <= 1.23). Additionally, when landing on unstable compared to stable conditions, reduced lower limb muscle activities were observed during the preactivation phase (7-60 %, p < 0.05, 0.50 <= f <= 3.62). Trunk muscle activity did not significantly differ between the test conditions for both jumping and landing tasks. CONCLUSION: The present findings indicate that modified feedforward mechanisms in terms of lower leg muscle activities during the preactivation phase and/or possible alterations in leg muscle activity shortly after ground contact (i.e., braking phase) are responsible for performance decrements during jumping on unstable surfaces. PMID- 24072035 TI - Oxidation state and covalency in f-element metallocenes (M = Ce, Th, Pu): a combined CASSCF and topological study. AB - CASSCF calculated wavefunctions are presented for three f-element metallocenes, MCOT2 (M = Ce, Th, Pu; COT = eta(8)-C8H8). The configurational admixture of these systems is investigated and, where the ThCOT2 ground state is well-defined as a monodeterminantal Th(IV) state, the cerocene ground state is found to be strong multiconfigurational and to bear strong similarities to that of plutonocene. Associated electronic densities are studied using QTAIM topological analysis and compared to CASSCF-derived densities of the aromatic systems benzene and the COT dianion. This analysis provides evidence of enhanced covalent character in plutonocene, supporting structural data calculated previously. Evidence of charge localisation in found in cerocene, this being most pronounced in its excited state of A(g) symmetry. QTAIM analysis reveals that the ligand electronic structure is very similar in all metallocenes, and density differences show little variation in the ligand between the cerocene ground and excited state. Orbital contributions to integrated QTAIM properties are considered, and excellent agreement with experimentally determined f-orbital occupation is obtained. All methods of analysis support a Ce(IV) or mixed valence assignment of the cerocene ground state, whereas the A(g) excited state is best described as a Ce(III) state. PMID- 24072034 TI - Effect of adiposity on insulin action after acute and chronic resistance exercise in non-diabetic women. AB - PURPOSE: Obesity may attenuate metabolic health improvements following lifestyle interventions. However, the effect of adiposity on insulin action following resistance exercise in young non-diabetic women is unknown. The purpose of this study was to test the hypothesis that adiposity attenuates improvements in insulin sensitivity and glucose-stimulated insulin secretion (INS0-60/GLC0-60) after both acute resistance exercise (ARE) and progressive training (PRT). METHODS: Twenty-six young non-diabetic women (21.2 +/- 0.7 years) were randomly assigned to control (C; n = 7; BF 40.1 +/- 2.1 %) or exercise groups: normal body fat (NBF; n = 8; BF 29.9 +/- 2.3 %) and high body fat (HBF; n = 12; BF 48.2 +/- 1.4 %). Acute whole-body exercises were performed at 60 % of 1-RM for three sets of 8-12 repetitions, and PRT was performed 3 days/week for 7 weeks. A 75 g OGTT was conducted before and after ARE and PRT to estimate insulin sensitivity (Matsuda index) and INS0-60/GLC0-60. Insulin area under the curve (AUC) was calculated using the trapezoidal model. RESULTS: ARE had no statistical effect on insulin action across groups. Strength and fat-free mass (via DXA) increased after PRT in both NBF and HBF (p < 0.05), but only HBF women decreased BF (p < 0.01). HBF women were less insulin sensitive at baseline compared to NBF women (p < 0.05). Insulin sensitivity increased 95 % and INS0-60/GLC0-60 decreased 32 % following PRT in NBF, but not HBF or C (p < 0.05). After training, enhanced insulin sensitivity was inversely related to decreased INS0-60/GLC0-60 (r = 0.71, p < 0.001), fasting insulin (r = -0.71, p < 0.001), and insulin AUC (r = 0.85, p < 0.001). CONCLUSION: Seven weeks of PRT increases insulin sensitivity and reduces glucose-stimulated insulin secretion in NBF, but not HBF women. Obesity attenuates exercise-induced improvements in glucose regulation in young non-diabetic women. PMID- 24072036 TI - Rare e14a3 (b3a3) BCR-ABL fusion in chronic myeloid leukemia in India: the threats and challenges in monitoring minimal residual disease (MRD). AB - OBJECTIVE: The primary objective of this work was to confirm the occurrence of rare BCR ABL fusion variant involving the a3 region of the ABL gene in a patient positive for t(9;22) translocation but negative for common major and minor breakpoint cluster regions and the challenges and threats that it poses in a routine laboratory setting which use commercial kits for monitoring the minimal residual disease. METHODS: A patient with elevated white blood cell count was subjected to classical cytogenetics, FISH as well as RT-PCR testing using commercial kits as well as published primers and in house testing protocol. PCR amplicon generated from in the process was sequenced and analyzed. RESULTS: The translocation event in chromosome 9 and 22 could be successfully detected. BCR/ABL dual color, dual fusion probe generated a classical balanced translocation scenario within the nucleus of affected cells and presented a '1O1G2F' signal pattern. RT-PCR with probes from commercial kit designed to detect common breakpoints within the M- and m-BCR regions involving e13a2, e14a2 and e1a2 fusion variants respectively failed to generate any signal. Further investigation revealed presence of the rare e14a3 (b3a3) fusion. DISCUSSION: This is the first report of rare e14a3 fusion in the BCR ABL gene in a CML patient from India. The observation indicates the need for interrogating rare BCR ABL fusions when common breakpoint cluster regions are absent such that minimal residual disease (MRD), critical for disease monitoring, can be performed and false positive remission cases can be avoided. It also emphasizes the utility and significance of cytogenetics and FISH techniques in primary diagnosis of CML and use of RT-PCR based assays only for generating secondary information within special reference to MRD. CONCLUSION: The rare e14a3 (b3a3) fusion of the BCR ABL gene is present in Indian population as demonstrated from this first report and clinical laboratories using commercial kit that do not cover such rare fusions are likely to generate false result thereby declaring complete molecular remission in CML patients under therapy while conducting MRD assay using RT-PCR technology. PMID- 24072037 TI - Size and space controlled hexagonal arrays of superparamagnetic iron oxide nanodots: magnetic studies and application. AB - Highly dense hexagonally arranged iron oxide nanodots array were fabricated using PS-b-PEO self-assembled patterns. The copolymer molecular weight, composition and choice of annealing solvent/s allows dimensional and structural control of the nanopatterns at large scale. A mechanism is proposed to create scaffolds through degradation and/or modification of cylindrical domains. A methodology based on selective metal ion inclusion and subsequent processing was used to create iron oxide nanodots array. The nanodots have uniform size and shape and their placement mimics the original self-assembled nanopatterns. For the first time these precisely defined and size selective systems of ordered nanodots allow careful investigation of magnetic properties in dimensions from 50 nm to 10 nm, which delineate the nanodots are superparamagnetic, well-isolated and size monodispersed. This diameter/spacing controlled iron oxide nanodots systems were demonstrated as a resistant mask over silicon to fabricate densely packed, identical ordered, high aspect ratio silicon nanopillars and nanowire features. PMID- 24072038 TI - Direct intercalation of cisplatin into zirconium phosphate nanoplatelets for potential cancer nanotherapy. AB - We report the use of zirconium phosphate (ZrP) nanoplatelets for the encapsulation of the anticancer drug cisplatin and its delivery to tumor cells. Cisplatin was intercalated into ZrP by direct ion exchange and was tested in vitro for cytotoxicity in the human breast cancer (MCF-7) cell line. The structural characterization of the intercalated cisplatin in ZrP suggests that during the intercalation process, the chloride ligands of the cisplatin complex were substituted by phosphate groups within the layers. Consequently, a new phosphate phase with the platinum complex directly bound to ZrP (cisPt@ZrP) is produced with an interlayer distance of 9.3 A. The in vitro release profile of the intercalated drug upon a pH stimulus shows that at low pH under lysosomal conditions the platinum complex is released with simultaneous hydrolysis of the zirconium phosphate material, while at higher pH the complex is not released. Experiments with the MCF-7 cell line show that cisPt@ZrP reduced the cell viability up to 40%. The cisPt@ZrP intercalation product is envisioned as a future nanotherapy agent against cancer. Taking advantage of the shape and sizes of the ZrP particles and controlled release of the drug at low pH, it is intended to exploit the enhanced permeability and retention effect of tumors, as well as their intrinsic acidity, for the destruction of malignant cells. PMID- 24072039 TI - DPC in acute-phase inpatient hospital care. Visualization of amount of nursing care provided and accessibility to nursing care. AB - OBJECTIVE: The purpose of this study was to improve accessibility to nursing care by clarifying the relationship between patient characteristics and the amount of nursing care for the Diagnosis Procedure Combination system (DPC). METHOD: The subjects included 528 lung cancer patients; 170 gastric cancer patients; and 91 colon cancer patients, who were hospitalized from July 1, 2008, to March 31, 2010, at a university hospital. The patients were categorized into groups according to factors that could affect the amount of nursing care. Next, the relationship between the patient characteristics and the amount of nursing care was analyzed. Then the results from this study were used to classify patient characteristics according to the patient type and the amount nursing care required. RESULTS: The patient characteristics, which affected the amount of nursing care, varied according to each DPC code. The major factors affecting the amount of nursing care were whether the patient had received a surgical (under general anesthetics) treatment or a non-surgical treatment and the level of activities of daily living (ADL) of the hospitalized patients. For those who had received a surgical operation for colon cancer, the patient's age also affected the amount of nursing care. CONCLUSIONS: The findings show that the method for the visualization of the amount of nursing care based on the classification of patient characteristics can be implemented into the electronic health record system. This method can then be used as a management tool to assure appropriate distribution of nursing resources. PMID- 24072040 TI - Ultrathin self-assembled anionic polymer membranes for superfast size-selective separation. AB - Nanoporous membranes with superior separation performance have become more crucial with increasing concerns in functional nanomaterials. Here novel ultrahigh permeable nanoporous membranes have been fabricated on macroporous supports by self-assembly of anionic polymer on copper hydroxide nanostrand templates in organic solution. This facile approach has a great potential for the fabrication of ultrathin anionic polymer membranes as a general method. The as fabricated self-assembled membranes have a mean pore size of 5-12 nm and an adjustable thickness as low as 85 nm. They allow superfast permeation of water, and exhibit excellent size-selective separation properties and good fouling resistance for negatively-charged solutes during filtration. The 85 nm thick membrane has an ultrahigh water flux (3306 l m(-2) h(-1) bar(-1)) that is an order of magnitude larger than commercial membranes, and can highly efficiently separate 5 and 15 nm gold nanoparticles from their mixtures. The newly developed nanoporous membranes have a wide application in separation and purification of biomacromolecules and nanoparticles. PMID- 24072041 TI - Glucosamine hydrochloride exerts a protective effect against unilateral ureteral obstruction-induced renal fibrosis by attenuating TGF-beta signaling. AB - Renal fibrosis is a common consequence of unilateral ureteral obstruction, which provides a useful model to investigate the pathogenesis of obstructive nephropathy and progressive renal fibrosis. Transforming growth factor (TGF beta1) has been recognized as a key mediator in renal fibrosis by stimulating matrix-producing fibrogenic cells and promoting extracellular matrix deposition. Therefore, considerable efforts have been made to regulate TGF-beta signaling for antifibrotic therapy. Here, we investigated the mode of action of glucosamine hydrochloride (GS-HCl) on TGF-beta1-induced renal fibrosis. In the obstructed kidneys and TGF-beta1-treated renal cells, GS-HCl significantly decreased renal expression of alpha-smooth muscle actin, collagen I, and fibronectin. By investigating the inhibitory mechanism of GS-HCl on renal fibrosis, we found that GS-HCl suppressed TGF-beta signaling by inhibiting N-linked glycosylation of the type II TGF-beta receptor (TbetaRII), leading to an inefficient trafficking of TbetaRII to the membrane surface. Defective N-glycosylation of TbetaRII further suppressed the TGF-beta1-binding to TbetaRII, thereby decreasing TGF-beta signaling. Notably, GS-HCl treatment significantly reduced TGF-beta1-induced up regulation of Smad2/3 phosphorylation and transcriptional activity in vivo and in vitro. Taken together, GS-HCl-mediated regulation of TGF-beta signaling exerted an antifibrotic effect, thereby ameliorating renal fibrosis. Our study suggests that GS-HCl would be a promising agent for therapeutic intervention for preventing TGF-beta1-induced renal fibrosis in kidney diseases. KEY MESSAGE: Glucosamine-mediated attenuation of TGF-beta signaling ameliorates renal fibrosis in vivo TGF-beta1-induced fibrogenic action is reduced by glucosamine in vitro N glycosylation of the type II TGF-beta receptor is suppressed by glucosamine Glucosamine-induced defective N-glycosylation of TbetaRII decreases TGF-beta signaling. PMID- 24072043 TI - Comment on atorvastatin safety in kawasaki disease patients with coronary artery aneurysms. PMID- 24072042 TI - Tissue-specific differences in the regulation of KIBRA gene expression involve transcription factor TCF7L2 and a complex alternative promoter system. AB - KIBRA has been described as a key regulator of the Hippo signaling pathway, regulating organ size control, cell contact inhibition, cell growth, as well as tumorigenesis and cystogenesis. Since there is scarce information on KIBRA gene expression regulation, we analyzed the molecular basis of tissue-specific KIBRA expression in human kidney epithelial (IHKE, HPCT) and neuroblastoma (SH-SY5Y, SK SN-SH) cells. We detected four novel and differentially used transcription start sites, two of which positioned in the first intron, generating two novel alternative exons. We identified one constitutively active core promoter (P1a) and three alternative promoters (P1b, P2, and P3), which were exclusively active in kidney cells. Transcription factor 7-like 2 (TCF7L2) selectively activated KIBRA at P1a, P2, and P3 in kidney cells. The two genetic variants -580C>T (p < 0.05) and -1691C>T (p < 0.01) significantly affected the transcriptional activity of the KIBRA core promoter. We propose a novel functional structure of the KIBRA gene and provide detailed insight into molecular cell type-specific KIBRA transcriptional regulation by TCF7L2, the Yes-associated protein 1 and TEA domain family member. Our findings provide a potential basis for future studies on malfunctioning KIBRA regulation in pathophysiological conditions such as cancer development. KEY MESSAGE: KIBRA expression is regulated by three independent, cell type-specific promoters Two novel TSS were located within intron one resulting in two alternative exons TSS utilization is cell type-specific TCF7L2, YAP1, and TEAD are involved in the differential KIBRA expression regulation. PMID- 24072045 TI - [Acute encephalitis anti-ionotropic glutamate receptor activated N-methyl-D aspartate (NMDAR): analysis of eleven pediatric cases in Argentina (Benito Yelin Award)]. AB - Encephalitis are an inflammatory processes of various origin, among which include autoimmune origin. The identification of antibodies against the N-methyl-D- aspartate, allowed clinical immunological characterization of an entity susceptible to immunomodulatory therapy. Originally described in young women associated with ovarian teratoma, is now a recognized entity in children even in the absence of detectable tumors. The aim of the study was conducted through review of medical records, was to describe the clinical, developmental and findings in further studies of eleven children with confirmed diagnosis of this entity through identification of specific antibodies. All debuted with psychiatric symptoms in nine associating seizures, and two extrapyramidal movements. In the evolution of language all had commitment nine severe autonomic symptoms, one with hypoventilation and requirements of ARM. Brain MRI was abnormal in three. Eight had voltage EEG asymmetry and / or amplitude, three of them had spikes. Six had CSF pleocytosis and three of seven positive oligoclonal bands. Five IgM serology for mycoplasma were positive. CPK increase occurred in conjunction with antisychotics in five. With immunomodulatory treatment, five had complete recovery three behavioral disorders / cognitive deficits and one severe. A patient's clinical picture resolved without treatment. In any associated tumor was detected. We conclude that in front of a child with acute encephalopathy and clinical support this entity after infectious cause were ruled out, immunomodulatory therapy should be started early, avoid the use of antipsychotic drugs and search for possible hidden tumors. PMID- 24072044 TI - The novel CXCR4 antagonist POL5551 mobilizes hematopoietic stem and progenitor cells with greater efficiency than Plerixafor. AB - Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be corroborated in humans. PMID- 24072046 TI - [Autism spectrum disorder and specific language disorder. Are two different entities or a continuum of neuropsychological manifestations?]. AB - Follow-up of children with delayed language development underscores the fact that, in several cases, language difficulties coexist with other symptoms such as social behavior changes. Autism spectrum disorder (ASD) and language specific disorder (LSD) are developmental disorders that are defined differently, but have some common language and social behavior characteristics which impose diagnostic difficulties. For this reason it is believed that they may share not only symptomatic but also ethiological aspects. With that in mind, we performed a literature search of works that discussed and, with their results, clarified this issue. Although several studies have allowed clearer and frequent diagnosis of both ASD and LSD, many cases persist in which the question in this article's title cannot be clearly answered, especially in children younger than two years of age. PMID- 24072047 TI - [Follow up of patients with developmental delay and autistic spectrum disorders]. AB - The evolution of autism symptoms during life were revised, from childhood to adulthood. Little information is available. After a search in PubMed, no more than 40 publications address this issue. The review was divided into two parts: a) how change the three main symptoms of autism change; b) how change the other autism-associated symptoms. The three main symptoms, called "Triad of Wing" (communication problems, social skills deficits, and a restricted repertoire of interests) do not change significantly during lifetime. The diagnosis of autism remains stable during lifetime, and 80% of children continue with this diagnosis in adulthood. Furthermore, it is difficult to establish first diagnostic of autism in adults. In relation to the associated symptoms, one of the earliest are sleep disturbances and one of the most prevalent is both bipolar and anxiety disorders. Sleep disturbances are age-limited and disappear easily. Bipolar disorders are usually more severe in children with autism when compared to children without autism. The mood transitions are faster in autistic children. Anxiety is usually more intense in cognitive preserved autistic patients and tends to increase with age. The two main prognostic factors for autism in adults are: a) total IQ above 70. b) functional language before 6 years of age. PMID- 24072048 TI - [Autism and epigenetics. A model of explanation for the understanding of the genesis in autism spectrum disorders]. AB - Autism spectrum disorders are characterized by impairment of social integration and language development and restricted interests. Autism spectrum disorders manifest during childhood and may have a varying clinical expression over the years related to different therapeutic approaches, behavior-modifying drugs, and environmental factors, among others. So far, the genetic alterations identified are not sufficient to explain the genesis of all these processes, as many of the mutations found are also present in unaffected individuals. Findings on the underlying biological and pathophysiological mechanisms of entities strongly associated with autism spectrum disorders, such as Rett, fragile X, Angelman, and fetal alcohol syndromes, point to the role of epigenetic changes in disorders of neurodevelopment. Epigenetic phenomena are normal biological processes necessary for cell and thus human life, especially related to embryonic development. Different phenomena that affect epigenetic processes (changes that change operation or expression of a gene, without modifying the DNA structure) have also been shown to be important in the genesis of neurodevelopmental disorders. Alterations in the epigenetic mechanism may be reversible, which may explain the variation in the autism phenotype over time. Here we analyze the normal epigenetic mechanisms, autism spectrum disorders, their association with specific entities associated with altered epigenetic mechanisms, and possible therapeutic approaches targeting these alterations. PMID- 24072049 TI - [Acute cerebellar ataxia in childhood]. AB - Acute cerebellar ataxia of childhood is the most frequent neurological complication of chickenpox virus infection. Acute cerebellar ataxia is categorized within the group of acute postinfectious complications. The aims of this study were: (I) to evaluate the clinical presentation, management, and follow-up of children hospitalized due to acute cerebellar ataxia in a tertiary pediatric hospital, where immunization for chickenpox is not available, and (II) to describe the differential diagnosis of acute postinfectious cerebellitis. We evaluated 95 patients with acute cerebellar ataxia. The diagnostic criteria for acute ataxia were: Acute-onset loss of coordination or gait difficulties, with or without nystagmus, lasting less than 48 hours in a previously healthy child. All children met the inclusion criteria, except those with drug-induced ataxia in whom duration should be less than 24 hours for inclusion in the study. The data were recorded in a clinical pediatrics and neurological chart. Among immunosuppressed patients acute cerebellar ataxia was most frequently due to chickenpox. Most of the patients were male. Age at presentation ranged from preschool to 5 years of age. Time lapse between presentation of the rash and hospital admission ranged from 1 to 3 days. CSF study was performed in 59.5% of the cases. Brain magnetic resonance imaging and computed tomography scan showed edema in 33.3%. Intravenous acyclovir was used in 23 patients, however, no significant differences were found in clinical manifestations and follow-up between treated and untreated patients. Ataxia was the first clinical manifestation. Mean hospital stay ranged from 2 to 11 days with a mean of 4 days. PMID- 24072050 TI - [Chronic ataxia in childhood]. AB - Chronic ataxias are an heterogeneous group of disorders that affect the child at different ages. Thus, the congenital forms, generally non progressive are observed from first months of life and are expressed by hypotonia and motor delay long before the ataxia became evident. The cerebral magnetic resonance images (MRI) may be diagnostic in some pictures like Joubert syndrome. The group of progressive hereditary ataxias, usually begin after the infant period. The clinical signs are gait instability and ocular apraxia that can be associated with oculocutaneous telangiectasias (ataxia-telangiesctasia) or with sensory neuropathy (Friedreich ataxia). In this review are briefly described congenital ataxias and in more detailed form the progressive hereditary ataxias autosomal recessive, autosomal dominants and mitochondrials. The importance of genetic study is emphasized, because it is the key to obtain the diagnosis in the majority of these diseases. Although now there are no treatments for the majority of progressive hereditary ataxias, some they have like Refsum disease, vitamine E deficiency, Coenzyme Q10 deficiency and others, thus the diagnosis in these cases is even more important. At present the diagnosis of childhood hereditary ataxia not yet treatable is fundamental to obtain suitable handling, determine a precise outcome and to give to the family an opportune genetic counseling. PMID- 24072051 TI - [Therapeutic developments in chronic ataxias]. AB - Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederich's ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response. PMID- 24072052 TI - [Guidelines for detection of inborn errors of metabolism based on clinical exam, analytical studies and neuroimaging techniques]. AB - Neurometabolic disorders constitute an expanding and complex field in which it is difficult to diagnose and to acquire a specific education and training. This article tries to develop a practical orientation in the suspicion, clinical exam, biochemical studies and neuroimaging techniques for the detection of inborn errors of metabolism. It is very important for the neuropediatrician to suspect metabolic diseases depending on some of the most frequent unexplained neurological disturbances and symptoms as psychomotor delay, mental retardation, refractory epilepsy, dystonia, metabolic crisis or other extraneurological signs. It is important the diagnosis related to the new emergent therapeutic options, genetic counseling and prenatal diagnosis. PMID- 24072053 TI - [Simple febrile seizure, complex seizure, generalized epilepsy with febrile seizure plus, FIRES and new syndromes]. AB - Febrile seizures are the most common seizures in childhood. They have been observed in 2-5% of children before the age of 5, but in some populations this figure may increase to 15%. It is a common cause of pediatric hospital admissions and cause of anxiety for parents. Febrile seizures could be the first manifestation of epilepsy. About 13% of epileptic patients have a history of febrile seizure, and 30% have had recurrent febrile seizures. Their phenotypic characteristics allow, in the majority of cases, a classification of the seizure, an elaboration of a prognosis and to assume a specific therapeutic attitude. It is possible to describe a spectrum according to their severity, from the benign simple seizure to the more complex, febrile seizure plus, Dravet'syndrome, and FIRES. During the past decade, molecular genetic studies have contributed to the identification of genetic factors involved in febrile seizure and related disorders, making the necessity of a careful follow up of these patients in order to detect risk factors earlier. We have reviewed the medical literature to update current knowledge of febrile seizures, their prognosis and their relation to new epileptic syndromes. PMID- 24072054 TI - [Non-epileptic disorders in infancy and adolescence]. AB - Epilepsy affects 0.5% of the population. A 25% of the patients referred to epilepsy services have paroxysmal clinical events associated with motor activities, sensory or emotional alterations, or consciousness impairment, which are not epileptic seizures. The non-epileptic seizures can be classified as psychogenic, which do not have a medical cause, and are associated with primary or secondary psychological problems, and as of physiological origin. The non epileptic events are manifested by paroxysmal or repetitive behaviors that might be confused with epileptic seizures. The diagnosis is very important in order to avoid unnecessary tests and iatrogenic therapies. This study will present clinical cases and review of the main non-epileptic physiological events (sleep disorders, movement disorders, hypoxic-ischemic phenomena) and psychogenic events (somatoform disorders, fictitious disorders and anxiety disorder). PMID- 24072055 TI - [Status epilepticus in childhood]. AB - Status epilepticus is a medical emergency which presents seizures by 30 minutes or more of continuous activity, or two or more consecutive crises without full recovery of consciousness between them. Currently, it is considered that a seizure convulsive or not, that last more than 5 minutes should be considered a status epilepticus. Different drugs for the treatment of this disease have been used. There is a general consensus in an aggressive handling should be done to reduce their morbidity and mortality, without forgetting that the cause of status is important for its management, control, and its aftermath. PMID- 24072056 TI - [Viral encephalitis in children]. AB - Viral encephalitis is a severe illness that produces inflammation of the brain. CNS viral infections frequently occur as a complication of systemic viral infections. Over 100 viruses are implicated as causative agents, including herpes simplex virus type I which is the most common agent implied in non-epidemic encephalitis in all population groups in the world, and is responsible for the most severe cases in all ages. Many viruses, for which there are vaccines, may also cause encephalitis: measles, mumps, polio, rabies, rubella, and chickenpox. The virus causes an inflammation of the brain tissue, which may progress to destruction of nerve cells, cause bleeding and brain damage, leading to severe encephalitis, such as hemorrhagic or necrotizing encephalitis, with a worse prognosis, producing serious sequelae or death. The clinical evolution includes the presence of headache, fever and altered consciousness rapidly progressive. The outcome of viral encephalitis is variable, some cases are mild, with full recovery, but there are serious cases that can cause severe sequel in the brain. To diagnose this illness as soon as possible is essential, through laboratory tests (biochemistry, virus PCR, culture) and neuroimaging (CT, MRI) and above all, the establishment of early treatment to prevent the development of the process and possible complications. The prognosis worsens if the initiation of treatment is delayed. PMID- 24072057 TI - [Environmental toxic and its effect on neurodevelopment]. AB - Neurodevelopmental disorders are the result of a disturbance of brain function. They are frequent, with varied symptomatology, manifest themselves at different times of life and tend to be persistent with impact at the individual, family and social level. The association of these disorders with genetic entities is low. Although the research supports a mode of genetic inheritance, epigenetic factors and environmental factors can play an important role. In recent years there was a striking increase of these disorders especially attention deficit hyperactivity disorders and pervasive development disorder. Environmental factors such as the intoxication of the fetus by especially heavy metals lead and mercury are to blame in some children, of these disorders. Other substances of wide use, little degradation and maintenance in the food chain as pesticides, polychlorinated biphenyls and now the recycling of electronic waste put especially infants and children at risk, and even more so in the developing countries. PMID- 24072058 TI - Nanostructure-based optoelectronic sensing of vapor phase explosives--a promising but challenging method. AB - Optoelectronic sensing of gas phase hazardous chemicals is a newly explored field, which shows great advantages towards low concentration sensing when compared to normal gas sensing in the dark. Here, based on the recent progress on nanostructured vapor phase explosive gas sensors operated in dark conditions, the attractiveness of developing optoelectronic sensors for vapor phase explosive detection was highlighted. Furthermore, we try to propose some new insights to enhance optoelectronic sensing of vapor phase explosives. We suggest employing photocatalysis principles to enhance the sensitivity and employing a molecular imprinting technique (MIT) to enhance the selectivity. PMID- 24072060 TI - Fluorescent and radiolabeled triphenylphosphonium probes for imaging mitochondria. AB - Triphenylphosphonium-fluorochromes (TPP-fluorochromes) are a new class of spectrally variable, mitochondrially targeted probes, with an [(18)F] labeling option which, when enabled, allows imaging of a cardiac perfusion deficit using PET/CT. PMID- 24072063 TI - Computational design of concomitant type-I and type-II porphyrin sensitized solar cells. AB - Structures and electronic properties of porphyrins with various Donor (D) Acceptor (A) functionalization adsorbed on TiO2 (anatase) nanoparticles are studied using DFT calculations. Adsorption of porphyrin leads to a substantial loss of planarity (puckering) for the porphyrin rings due to the stabilization of the system by the interaction of the lone-pair of electrons of the N-atoms of porphyrin with the Ti-atoms of anatase. For free porphyrin, the mode of binding to anatase is from the top-site, while for the binding of D-A functionalized porphyrin, side-wise interactions are stabilized via anchoring groups on the A ( SO3H, -PO3H2 and -CO2H). Adsorption of porphyrin on TiO2 changes the relative ordering of HOMO and LUMO levels compared to that of the free molecule and bare TiO2 nanoparticles which critically effects their performance for dye sensitized solar cells (DSSCs). The relative energy differences between the LUMO of the free molecule and LUMO of molecule...TiO2 complex (epsilon2) and LUMO of molecule...TiO2 complex and CB (conduction band) of bare TiO2 (epsilon3) are proposed as two key parameters for determining the suitability of the material for functioning as a DSSC material. Coupling of the porphyrin ring with nanoparticles leads to the appearance of additional optically-active states due to dye -> TiO2 charge-transfer (CT) transitions. This leads to a possibility for these dyes to act as type-II DSSC materials as well. We suggest that there exists no such general rule that only different sets of molecules are suitable for type I and type-II DSSCs. Concentration dependent UV-Vis absorption spectra measurements can be a simple experimental test to detect a mechanistic switch over between type-I and type-II DSSC processes in dyes. PMID- 24072061 TI - Diagnosis of west nile virus human infections: overview and proposal of diagnostic protocols considering the results of external quality assessment studies. AB - West Nile virus, genus Flavivirus, is transmitted between birds and occasionally other animals by ornithophilic mosquitoes. This virus also infects humans causing asymptomatic infections in about 85% of cases and <1% of clinical cases progress to severe neuroinvasive disease. The virus also presents a threat since most infections remain unapparent. However, the virus contained in blood and organs from asymptomatically infected donors can be transmitted to recipients of these infectious tissues. This paper reviews the presently available methods to achieve the laboratory diagnosis of West Nile virus infections in humans, discussing the most prominent advantages and disadvantages of each in light of the results obtained during four different External Quality Assessment studies carried out by the European Network for 'Imported' Viral Diseases (ENIVD). PMID- 24072062 TI - Evolution of foamy viruses: the most ancient of all retroviruses. AB - Recent evidence indicates that foamy viruses (FVs) are the oldest retroviruses (RVs) that we know and coevolved with their hosts for several hundred million years. This coevolution may have contributed to the non-pathogenicity of FVs, an important factor in development of foamy viral vectors in gene therapy. However, various questions on the molecular evolution of FVs remain still unanswered. The analysis of the spectrum of animal species infected by exogenous FVs or harboring endogenous FV elements in their genome is pivotal. Furthermore, animal studies might reveal important issues, such as the identification of the FV in vivo target cells, which than require a detailed characterization, to resolve the molecular basis of the accuracy with which FVs copy their genome. The issues of the extent of FV viremia and of the nature of the virion genome (RNA vs. DNA) also need to be experimentally addressed. PMID- 24072065 TI - Solvent interaction analysis of intrinsically disordered proteins in aqueous two phase systems. AB - In an aqueous two-phase system (ATPS), the partitioning of a protein is defined by the differential interactions of the protein with aqueous media in the two phases. Our study shows that partitioning of proteins in a set of ATPSs of different ionic compositions can be used to quantify structural differences between alpha-synuclein, its variants and several globular proteins. Since application of ATPSs implies the use of high concentrations of two polymers in water when a certain threshold concentration of the polymers is exceeded, and since these levels of polymer concentrations are similar to those commonly used to mimic the effects of macromolecular crowding on proteins, we used circular dichroism spectroscopy to evaluate the structural consequences of placing proteins in solutions with high polymer concentrations and various ionic compositions. PMID- 24072064 TI - Biogenic amines are associated with worker task but not patriline in the leaf cutting ant Acromyrmex echinatior. AB - Division of labor among eusocial insect workers is a hallmark of advanced social organization, but its underlying neural mechanisms are not well understood. We investigated whether differences in whole-brain levels of the biogenic amines dopamine (DA), serotonin (5HT), and octopamine (OA) are associated with task specialization and genotype in similarly sized and aged workers of the leaf cutting ant Acromyrmex echinatior, a polyandrous species in which genotype correlates with worker task specialization. We compared amine levels of foragers and waste management workers to test for an association with worker task, and young in-nest workers across patrilines to test for a genetic influence on brain amine levels. Foragers had higher levels of DA and OA and a higher OA:5HT ratio than waste management workers. Patrilines did not significantly differ in amine levels or their ratios, although patriline affected worker body size, which correlated with amine levels despite the small size range sampled. Levels of all three amines were correlated within individuals in both studies. Among patrilines, mean levels of DA and OA, and OA and 5HT were also correlated. Our results suggest that differences in biogenic amines could regulate worker task specialization, but may be not be significantly affected by genotype. PMID- 24072066 TI - Functional and molecular characterization of the effect of amyloid-beta42 on an in vitro epithelial barrier model. AB - Recently, the blood-brain barrier (BBB) has been pointed to as an active player in neurodegenerative disorders, albeit the actual succession of pathogenic events remains to be elucidated. Amyloid-beta (Abeta) is an important pathogenic player in Alzheimer's disease, and it is cleared from the brain partly by transportation across the BBB. In this work we asked the question whether Abeta-induced alteration of tight junction (TJ) protein expression is a result of the complex in situ microenvironment of the BBB or if it can be replicated in an externalized environment, such as an in vitro epithelial barrier, where barrier property changes can be investigated without confounding factors. Therefore, we treated barrier forming MDCKI and II epithelial cells with Abeta42 and investigated TJ occludin and claudin-2 protein levels and cellular distribution through western blot and immunofluorescence. To assess barrier function, we measured transepithelial resistance (TEER) and studied cell polarity through atomic force microscopy (AFM). We found that Abeta42 cell treatment increased occludin expression and decreased claudin-2 expression. With TEER, an increase in paracellular resistance was noted, which started at 10 hours and peaked at 20 hours of Abeta42 treatment. AFM analysis demonstrated an associated morphological alteration of the cell monolayer. In conclusion, we demonstrated that Abeta42 is able to modify TJ protein expression and to functionally alter barrier properties in vitro and that this effect is not conditioned by other pathogenic Alzheimer's disease events taking place in the complex brain microenvironment. PMID- 24072067 TI - Titers of herpes simplex virus type 1 antibodies positively correlate with grey matter volumes in Alzheimer's disease. AB - HSV-1 infection of the central nervous system targets the same brain regions most affected in Alzheimer's disease (AD) and could play a pathogenic role in AD. HSV 1 serum IgG titers were analyzed in patients with mild AD (n = 83) and healthy controls (HC, n = 51); results were correlated with cortical grey matter (GM) volumes as analyzed by MRI. Seroprevalence and antibody (Ab) titers were comparable between AD and HC; elevated Ab titers (>75th percentile) were nevertheless significantly more frequent in AD and were positively correlated with cortical bilateral temporal and orbitofrontal GM volumes. HSV-1-specific-Ab could possibly play a protective role in the early stages of AD. PMID- 24072068 TI - In vitro amyloid-beta binding and inhibition of amyloid-beta self-association by therapeutic albumin. AB - BACKGROUND: A promising approach for treating Alzheimer's disease relies on the net efflux of the amyloid-beta (Abeta) peptide from the brain to peripheral plasma, as a result of plasma Abeta clearance promoted by plasma removal and therapeutic albumin replacement. OBJECTIVE: To assess the binding of therapeutic albumin (Albutein, Grifols) to monomeric and aggregated Abeta according to methods previously tested on the interactions between Abeta and research-grade albumin. METHODS: Albumin integrity and the interactions with albumin stabilizers (octanoic acid and N-Ac-Trp) were assessed through one-dimensional (1D) 1H-NMR and saturation transfer difference (STD) NMR spectra. The interactions between monomeric Abeta1-40 and albumin were probed by 2D 1H-15 N HSQC spectra of labeled Abeta1-40. The formation of cross-beta structured Abeta1-42 assemblies was monitored by ThT fluorescence. The interactions between self-assembled Abeta1-42 and albumin were probed by Trp fluorescence. RESULTS: NMR spectra indicated that both therapeutic and research-grade albumin are similarly well-folded proteins. No significant changes in either HSQC peak position or intensity were observed upon addition of albumin to 15N-labeled Abeta1-40, which rules out binding of albumin to monomeric Abeta with dissociation constant in the MUM or lower range. When aggregated Abeta1-42 was added to albumin, quenching of Trp fluorescence was observed, which indicates albumin binding to Abeta1-42 aggregates. The relative potency of therapeutic albumin as an Abeta self-association inhibitor was in the same order of magnitude as research-grade albumin. CONCLUSIONS: Albutein inhibited Abeta self-association by selectively binding Abeta aggregates rather than monomers and by preventing further growth of the Abeta assemblies. PMID- 24072069 TI - Meta-analysis of serum non-ceruloplasmin copper in Alzheimer's disease. AB - The fraction of copper not bound to ceruloplasmin seems altered in Alzheimer's disease (AD). We have addressed this notion evaluating all the studies carried out from 1996 until March 2013 by means of meta-analysis. We performed our analysis on diverse indices evaluating the relationship between copper and ceruloplasmin in general circulation, namely 'Non-Cp copper', '% Non-Cp copper', and 'Adjusted copper'. For Non-Cp copper and % Non-Cp copper, the correct stoichiometry between copper and ceruloplasmin (6-8 atoms of copper for each ceruloplasmin molecule) in healthy controls has been adopted as criterion for the study to be included in the meta-analysis evaluating data with the canonic Walshe's formula for Non-Cp copper. Copper to ceruloplasmin ratio (Cu:Cp), which is an internal quality control check for ceruloplasmin calibration, was used as an index of the actual stoichiometry in the specimens. Adjusted (Adj-Cp) copper, even though less reliable, was calculated, allowing the evaluation of all the studies selected. An additional meta-analysis of systemic total copper was re calculated accounting for all the studies carried out from 1983 to March 2013. Ten studies were analyzed in the meta-analysis for Non-Cp copper and % Non-Cp copper reaching a pooled total of 599 AD subjects and 867 controls. For Adj-Cp copper, 14 studies were analyzed with a pooled total of 879 AD and 1,712 controls. 27 studies were considered for systemic total copper meta-analysis, with a pooled total of 1,393 AD and 2,159 controls. All the copper indices analyzed were significantly higher in AD subjects compared to healthy controls. PMID- 24072070 TI - Early molecular changes in Alzheimer disease: can we catch the disease in its presymptomatic phase? AB - Alzheimer disease (AD) is the most common form of dementia and characterized by deposition of amyloid-beta (Abeta) plaques, neurofibrillary tangles consisting of hyperphosphorylated tau, atrophy, and progressive neurodegeneration. While the familial, early onset form of AD is known to be caused by specific mutations in genes encoding presenilin 1, presenilin 2, or amyloid-beta protein precursor, the underlying mechanisms leading to the development of sporadic AD are still not known. The major risk factors are, however, aging and APOE epsilon4. Here we review the latest evidence for the involvement of malfunctioning insulin signaling, dysfunction of mitochondria-associated membranes, cerebrovascular changes, increased oxidative stress and free radical formation, DNA damage, disturbed energy metabolism, and synaptic dysfunction in early stages of AD. We focus on whether the changes in these processes precede or succeed the earliest symptoms in AD patients, i.e., minimal cognitive impairment. Since changes in Abeta processing are probably a key event in AD we also highlight the relationship of the above mentioned processes with the formation, secretion, aggregation, and toxicity of Abeta. Based on our literature findings we propose a model in which insulin dysfunction, pathological cerebrovascular changes, dysfunction of mitochondria-associated membranes, and/or synaptic changes are likely to interact with each other, thereby initiating and facilitating the development of AD pathology by accelerating the production and deposition of Abeta. Increased oxidative stress and free radical formation, DNA damage, disturbed energy metabolism, and synaptic loss follow these events, but still occur very early in AD. PMID- 24072071 TI - Increased efflux of amyloid-beta peptides through the blood-brain barrier by muscarinic acetylcholine receptor inhibition reduces pathological phenotypes in mouse models of brain amyloidosis. AB - The formation and accumulation of toxic amyloid-beta peptides (Abeta) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Abeta homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Abeta or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose dependently reduced brain Abeta burden in AbetaPPPS1, hAbetaPPSL, and AbetaPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Abeta peptide clearance across the blood brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Abeta in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Abeta in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Abeta peptide in pre-plaque mhAbetaPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Abeta peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Abeta transport across the Blood Brain Brain (BBB). Thus increased Abeta clearance through the BBB may contribute to reduced Abeta burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects. PMID- 24072072 TI - Phonon transport assisted by inter-tube carbon displacements in carbon nanotube mats. AB - Thermal transport in carbon nanotube (CNT) mats, consisting of randomly networked multi-walled carbon nanotubes (MWNTs), is not as efficient as in an individual CNT because of the constrained tube-to-tube phonon transport. Through experiments and modeling, we discover that phonon transport in CNT mats is significantly improved by ion irradiation, which introduces inter-tube displacements, acting as stable point contacts between neighboring tubes. Inter-tube displacement-mediated phonon transport enhances conductivity, while inter-tube phonon-defect scattering reduces conductivity. At low ion irradiation fluence, inter-tube thermal transport enhancement leads to thermal conductivity increase by factor>5, while at high ion irradiation fluence point defects within tubes cause a decrease in thermal conductivity. Molecular dynamics simulations support the experimentally obtained results and the proposed mechanisms. Further conductivity enhancement in irradiated mats was obtained by post-irradiation heat treatment that removes majority of the defects within the tubes without affecting thermally stable inter tube displacements. PMID- 24072073 TI - Predictors of significant fibrosis in chronic hepatitis B patients with low viremia. AB - BACKGROUND AND AIM: The data on the prevalence and predictors of significant fibrosis (>=F2, METAVIR) in chronic hepatitis B virus (HBV) patients with low viremia are limited. We aimed to assess both the prevalence predictors of >=F2 fibrosis in hepatitis B envelope antigen-negative patients with HBV DNA <20,000 IU/mL. METHODS: Hepatitis B envelope antigen-negative patients (n=213) with mean HBV DNA <2000 IU/mL (n=97) and HBV DNA 2000 to 20,000 IU/mL (n=116) were included and all had liver biopsy. Variables significantly associated with >=F2 fibrosis on an univariate analysis were included in a multivariate logistic regression model. RESULTS: Overall, 40 (18.8%) patients had >=F2 fibrosis, with no difference between those with mean HBV DNA <2000 IU/mL (19.6%) compared with patients with HBV DNA of 2000 to 20,000 IU/mL (18.1%; P=0.782). Fibrosis >=F2 was similar in patients with HBV DNA <2000 versus 2000 to 20,000 IU/mL in relation to varying alanine aminotransferase thresholds (P>0.05), and was less frequent in persistently normal alanine aminotransferase patients (13.6%) when compared with those with elevated or fluctuating levels (25.3%, P=0.030). Fewer patients under 40 years of age had >=F2 fibrosis (12.5%) as compared with older ones (28.2%; P=0.004). Logistic regression analysis identified higher aspartate aminotransferase [odds ratio (OR), 6.21; 95% confidence interval (CI), 2.48 15.54; P<0.0001], lower albumin (OR, 0.86; 95% CI, 0.78-0.95; P=0.002), platelet count (OR, 0.99; 95% CI, 0.98-0.99; P=0.013), and age (OR, 1.05; 95% CI, 1.01 1.09; P=0.024) as independent predictors of significant fibrosis. CONCLUSIONS: A small but significant minority of HBV patients with low viremia harbor significant fibrosis, although its rate is not different in those with viremia above or below 2000 IU/mL. Our findings may guide in decisions regarding liver biopsy and treatment in this category of patients. PMID- 24072074 TI - Eosinophilic esophagitis: a paradigm shift for pathology. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is an increasingly recognized disease only reported in the adult literature since 1993. Our facility has the opportunity to evaluate steroid-naive EoE patients since 1988, allowing us to describe the evolution of the histologic diagnosis of EoE. METHODS: This retrospective study analyzed 95 patient charts with initial diagnosis of congenital esophageal stenosis/EoE from 1988 to 2012. Patients had dysphagia and met endoscopic criteria consistent with current EoE histologic criteria while on chronic proton-pump inhibitor therapy. Histologic slides were obtained for only 10 patients because of limited slide availability; and the slides were reviewed by a single pathologist. EoE is defined as >=1 biopsy specimens demonstrating >15 eosinophils/HPF. RESULTS: Following review of histologic analysis reports, pathologists in our 2 academic hospitals began recognizing EoE as separate disease entity starting in 2007, coincidental with first EoE guidelines. After 2007, there was a clear surge in histologic diagnosis of EoE. Slides from 10 patients from 1988 to 2012 were reviewed. Of 35 biopsy sets, 19 were previously interpreted as reflux esophagitis (RE) or acute/chronic inflammation, 3 as RE with eosinophils, 2 as normal, and 11 as EoE. Reevaluation revealed EoE in 79% specimens with RE/inflammation and 100% with RE and eosinophils; remaining specimens had confirmed original diagnosis. All 10 patients had at least one set of slides meeting current EoE histologic criteria. CONCLUSIONS: EoE as a disease has been present for at least 2 to 3 decades. This is the first report of a clearly demarcated time point reflecting a paradigm shift in the histologic diagnosis of EoE as a distinct entity resulting from a seminal consensus report. PMID- 24072075 TI - Does gluten intake influence the development of celiac disease-associated complications? AB - Celiac disease (CD) is regarded as the most common autoimmune enteropathy in western countries. Epidemiological studies indicate that approximately 1:100 individuals may present with histologically proven CD. CD develops in genetically predisposed subjects after gluten ingestion. It usually subsides after gluten is withdrawn from their diet. Gluten is the only known environmental factor that affects the progression/regression of the intestinal villous atrophy, which is the hallmark of this disease. CD generally follows a benign course after gluten elimination. However, it is also associated with the development of other autoimmune disorders or of intestinal malignancies. The issue of whether such complications, sometimes of significant clinical and prognostic impact, are or are not the result of ongoing gluten ingestion, is an important one that has been investigated over the recent years with conflicting results. In terms of practical implications, the presence of a positive correlation between gluten intake and the development of severe complications would lead to the need for early diagnosis and mass screening. The lack of such correlation would instead suggest a less aggressive diagnostic strategy. This review aims at critically summarizing the evidence supporting either hypothesis. PMID- 24072076 TI - An unusual cause of ascites: Strongyloides stercoralis. PMID- 24072077 TI - Changes in the soil bacterial communities in a cedar plantation invaded by moso bamboo. AB - Moso bamboo is fast-growing and negatively allelopathic to neighboring plants. However, there is little information on the effects of its establishment and expansion to adjacent forest soil communities. To better understand the impacts of bamboo invasion on soil communities, the phylogenetic structure and diversity of the soil bacterial communities in moso bamboo forest, adjacent Japanese cedar plantation, and bamboo-invaded transition zone were examined using a combination of 16S rRNA gene clone libraries and bar-coded pyrosequencing techniques. Based on the number of operational taxonomic units (OTUs), Shannon diversity index, Chao1 estimator, and rarefaction analysis of both techniques, the bamboo soil bacterial community was the most diverse, followed by the transition zone, with the cedar plantation possessing the lowest diversity. The results from both techniques revealed that the Acidobacteria and Proteobacteria predominated in the three communities, though the relative abundance was different. The 250 most abundant OTUs represented about 70% of the total sequences found by pyrosequencing. Most of these OTUs were found in all three soil communities, demonstrating the overall similarity among the bacterial communities. Nonmetric multidimensional scaling analysis showed further that the bamboo and transition soil communities were more similar with each other than the cedar soils. These results suggest that bamboo invasion to the adjacent cedar plantation gradually increased the bacterial diversity and changed the soil community. In addition, while the 10 most abundant OTUs were distributed worldwide, related sequences were not abundant in soils from outside the forest studied here. This result may be an indication of the uniqueness of this region. PMID- 24072079 TI - Patient empowerment by increasing the understanding of medical language for lay users. AB - BACKGROUND: Patient empowerment is important in order to increase the quality of medical care and the life quality of the patients. An important obstacle for empowering patients is the language barrier the lay patient encounter when accessing medical information. OBJECTIVES: To design and develop a service that will help increase the understanding of medical language for lay persons. METHODS: The service identifies and explains medical terminology from a given text by annotating the terms in the original text with the definition. It is based on an original terminology interpretation engine that uses a fuzzy matching dictionary. The service was implemented in two projects: a) into the server of a tele-care system (TELEASIS) with the purpose of adapting medical text assigned by medical personnel for the assisted patients. b) Into a dedicated web site that can adapt the medical language from raw text or from existing web pages. RESULT: The output of the service was evaluated by a group of persons, and the results indicate that such a system can increase the understanding of medical texts. Several design decisions were driven from the evaluation, and are being considered for future development. Other tests measuring accuracy and time performance for the fuzzy terminology recognition have been performed. Test results revealed good performance for accuracy and excellent results regarding time performance. CONCLUSION: The current version of the service increases the accessibility of medical language by explaining terminology with a good accuracy, while allowing the user to easily identify errors, in order to reduce the risk of incorrect terminology recognition. PMID- 24072078 TI - IL-17A potentiates TNFalpha-induced secretion from human endothelial cells and alters barrier functions controlling neutrophils rights of passage. AB - Interleukin-17A (IL-17A) is an important pro-inflammatory cytokine that regulates leukocyte mobilization and recruitment. To better understand how IL-17A controls leukocyte trafficking across capillaries in the peripheral blood circulation, we used primary human dermal microvascular endothelial cells (HDMEC) to investigate their secretory potential and barrier function when activated with IL-17A and TNFalpha. Activation by TNFalpha and IL-17A causes phosphorylation of p38 as well as IkappaBalpha whereby NFkappaB subsequently becomes phosphorylated, a mechanism that initiates transcription of adhesion molecules such as E-selectin. Members of the neutrophil-specific GRO-family chemokines were significantly up-regulated upon IL-17A stimulation on the mRNA and protein level, whereas all tested non neutrophil-specific chemokines remained unchanged in comparison. Moreover, a striking synergistic effect in the induction of granulocyte colony-stimulating factors (G-CSF) was elicited when IL-17A was used in combination with TNFalpha, and IL-17A was able to significantly augment the levels of TNFalpha-induced E selectin and ICAM-1. In accordance with this observation, IL-17A was able to markedly increase TNFalpha-induced neutrophil adherence to HDMEC monolayers in an in vitro adhesion assay. Using a trans-well migration assay with an HDMEC monolayer as a barrier, we here show that pre-stimulating the endothelial cells with TNFalpha and IL-17A together enhances the rate of neutrophil transmigration compared to TNFalpha or IL-17A alone. These results show that IL-17A and TNFalpha act in cooperation to facilitate neutrophil migration across the endothelial cell barrier. In addition, the synergistic actions of IL-17A with TNFalpha to secrete G-CSF appear to be important for mobilizing neutrophils from the bone marrow to the blood stream. PMID- 24072080 TI - Pubertal gynecomastia coincides with peak height velocity. AB - OBJECTIVE: Pubertal gynecomastia (PG) occurs in up to 65% of adolescent boys. In this study, we investigated the relationship between the ages at which PG and peak height velocity occur in pubertal boys. METHODS: This was a prospective study that was designed to detect PG within three months of its emergence. We examined one hundred and six boys who were followed for short stature and/or delayed puberty at three month intervals, and gynecomastia was observed in 43 of these boys (40.5%). RESULTS: PG occurred in the 43 boys within a year of their peak height velocity, and most of these boys were at Tanner stage 3 for pubic hair and had testicular volumes between 8-10 mL. CONCLUSION: It is recommended that evaluation of height growth be included in the diagnostic approach to PG in boys with short stature and/or delayed puberty. The coincidence of age of peak height velocity and PG suggests a causal relationship between the two events and a role of insulin-like growth factor-1. PMID- 24072081 TI - Microvascular complications in adolescents with type 1 diabetes mellitus. AB - OBJECTIVE: Screening of complications is an important part of diabetes care. The aim of this study was to investigate diabetic complications and related risk factors in adolescents with type 1 diabetes mellitus (T1DM). METHODS: This cross sectional study was conducted on type 1 diabetics who were over 11 years of age or had a diabetes duration of 2 years and included 155 adolescents with T1DM (67 male, 88 female). The mean age of the patients was 14.4+/-2.1 years. Mean diabetes duration was 6.3+/-2.9 years. The patients were screened for diabetic nephropathy, retinopathy and peripheral neuropathy. RESULTS: Mean glycosylated hemoglobin (HbA1c) level of the study group was 8.4%. The frequency of microalbuminuria and peripheral neuropathy were 16.1% and 0.6%, respectively. None of the patients had diabetic retinopathy. Dyslipidemia and hypertension rates were 30.3% and 12.3%, respectively. Risk factors associated with microalbuminuria were hypertension, higher HbA1c levels, longer diabetes duration and dyslipidemia. CONCLUSION: Early diagnosis and treatment of hypertension and dyslipidemia as well as achieving a better metabolic control are important in prevention or postponement of complications in patients with T1DM. Yearly screening for diabetic nephropathy should be started 2 years after the onset of the diabetes. PMID- 24072082 TI - Hyperinsulinemic hypoglycemia: experience in a series of 17 cases. AB - OBJECTIVE: Hyperinsulinemic hypoglycemia (HIH) is a genetically heterogeneous disorder with both familial and sporadic variants. Patients with HIH may present during the neonatal period, infancy, or childhood and may show transient, prolonged, and persistent features. In this study, we aimed to discuss our experience with HIH patients, based on a series of 17 patients. METHODS: We retrospectively analyzed the clinical and laboratory characteristics at the time of diagnosis and during treatment and evaluated the neurodevelopmental outcomes during follow-up in 17 HIH patients, who presented or were referred to the Pediatric Endocrinology Clinic of Dr. Sami Ulus Training and Research Children's Hospital between 1998 and 2011. The patients (7 male, 10 female) were aged between the first day of life and 7 years - 10 were in their first week of life, 6 in their infancy, and 1 in childhood. RESULTS: None of the mothers had gestational diabetes. Hypoglycemic seizure (76.5%) was the most common presenting symptom. Medical treatment failed in two patients, and was stopped in eight patients. Of two diazoxide-unresponsive patients, one underwent near-total pancreatectomy, but hypoglycaemic episodes continued after surgery. The parents of other patient refused surgery, the medical treatment was continued, nevertheless, severe motor and mental retardation developed. At follow-up, 23.5% of the patients were found to have mild or moderate psychomotor retardation, and 23.5% developed epilepsy. There was no marked difference in neurological results between cases with onset in the neonatal period or in infancy. CONCLUSIONS: Clinical course and treatment response in HIH cases are very heterogeneous. Long term careful monitoring is needed to detect and treat the complications. PMID- 24072083 TI - Relationship of epicardial adipose tissue thickness with early indicators of atherosclerosis and cardiac functional changes in obese adolescents with metabolic syndrome. AB - OBJECTIVE: Epicardial adipose tissue thickness (EATT) is suggested as a new cardiometabolic risk factor. Carotid intima-media thickness (IMT) is a potential indicator of subclinical atherosclerosis in patients with metabolic syndrome (MS). We investigated the association of EATT with carotid IMT and cardiac functional changes in obese adolescents with MS. METHODS: One hundred thirty eight obese adolescents and 63 lean subjects were enrolled in the study. The obese subjects were divided into two subgroups based on the presence or absence of MS (MS group and non-MS group). All subjects underwent transthoracic echocardiographic examination for determination of left ventricular (LV) function, LV mass index (LVMI), and myocardial performance index (MPI). EATT and carotid IMT were also measured during echocardiography. RESULTS: The average LVMI measurements were higher in both MS and non-MS obese patients in comparison with the lean children. The MS group had significantly higher LVMI measurements than the non-MS and lean groups (88.5+/-23.0, 67.5+/-24.8 g/m2, and 62.4+/-18.2 g/m2, respectively; p<0.01). Carotid IMT was higher in both the MS and non-MS obese patients in comparison with the lean group. The MS group had significantly higher carotid IMT measurements than the non-MS and lean groups (0.91+/-0.23, 0.78+/ 0.18, and 0.52+/-0.08 mm, respectively; p<0.01). The EATT was also increased significantly in patients with MS compared to lean adolescents (7.42+/-1.55 vs. 4.28+/-0.79mm; p=0.001). EATT was positively correlated with body mass index-SDS, waist circumference, fasting glucose, insulin, homeostasis model assessment insulin resistance, triglyceride levels, LV thickness, LVMI, and MPI in the MS obese group. EATT was the only independent predictor of carotid IMT in the multivariate analysis (beta= 0.69, p<0.001). CONCLUSION: The findings of the present study demonstrate a close relationship of EATT with carotid IMT and early cardiac dysfunction in obese adolescents with MS. Assessment of EATT and carotid IMT in routine echocardiographic examinations is suggested as a feasible and reliable method for the evaluation of obesity with MS and its related cardiovascular risks in children and adolescents. PMID- 24072084 TI - Effects of ACE inhibitors on insulin resistance and lipid profile in children with metabolic syndrome. AB - OBJECTIVE: The aim of this study was to evaluate the effects of using ACE inhibitors on insulin resistance, glucose metabolism, body fat composition, and lipid profile in children over 10 years of age with obesity-associated metabolic syndrome (MS). METHODS: A total of 53 children with MS, who had been followed for at least one year were included in the study. The sample was divided into two groups: Group 1-30 obese children (13 female, 17 male) who were not using an ACE inhibitor and Group 2-23 obese children (13 female, 10 male) who were using an ACE inhibitor. Anthropometric and laboratory data obtained at baseline and at the 3rd, 6th, and 12th months of follow-up were compared in the two groups. RESULTS: Comparison of the data in the two groups at 3rd, 6th, and 12th months revealed no statistically significant differences in terms of weight standard deviation score (SDS), body mass index SDS, weight for height percentile, body fat percentage, and very low-density lipoprotein (VLDL)values. However, there were statistically significant differences in mean glucose and insulin levels, homeostasis model assessment for insulin resistance, LDL and high-density lipoprotein values, and highly significant differences in mean triglyceride values. CONCLUSIONS: The positive effects of ACE inhibitor drugs, particularly on hypertriglyceridemia and insulin resistance, might bring them forth as first-line drugs in the treatment of obese and hypertensive children. Randomized, controlled, double-blind, and long-term studies are needed for a definitive conclusion. PMID- 24072085 TI - The role of initial clinical and laboratory findings in infants with hyperthyrotropinemia to predict transient or permanent hypothyroidism. AB - OBJECTIVE: Studies on the clinical course of children with hyperthyrotropinemia are scarce. We aimed to evaluate the role of presentation findings in such infants to predict eventual outcome. METHODS: Files of infants diagnosed as suspicious congenital hypothyroidism (CH) in the neonatal or early infancy period in the past ten years were analyzed retrospectively, and 37 patients (M/F: 20/17) with hyperthyrotropinemia diagnosed at a median age of 3.2 months were included in the study. Criteria for inclusion were: normal free thyroxine (fT4) levels and thyrotropin (TSH) levels between 10-20 MUIU/mL during the initial neonatal screening (or TSH<10MUIU/mL afterwards). Cases with permanent CH (Group 1) were compared to those with transient hyperthyrotropinemia (Group 2) regarding age at the time of diagnosis, sex, gestational age, birth weight, symptoms, ultrasonographic and scintigraphic findings, initial thyroid function tests, and state of mental and motor development. RESULTS: Of the total group, 20 patients (54%) were eventually diagnosed as permanent CH. T4 doses that maintained normal thyroid function tests were significantly higher at the end of the first and second years of life in this group. Age, TSH and fT4 levels at the time of diagnosis, sex, gestational age, birth weight, symptoms, ultrasonographic and scintigraphic findings, and the state of mental and motor development were similar in the two groups. CONCLUSIONS: T4 dose required to maintain a euthyroid state was the only parameter which distinguished between transient and permanent CH. PMID- 24072086 TI - Serum adiponectin and hsCRP levels and non-invasive radiological methods in the early diagnosis of cardiovascular system complications in children and adolescents with type 1 diabetes mellitus. AB - OBJECTIVE: Adiponectin and high-sensitivity C-reactive protein (hsCRP) can be used as early biochemical markers of cardiovascular diseases (CVDs). Radiologically, non-invasive flow-mediated dilation (FMD) of the brachial artery and carotid intima-media thickness (CIMT) measurements may be used as indicators in the early diagnosis of CVDs. To compare the biochemical markers of atherosclerosis with radiological markers of CVDs (CIMT, FMD, ventricular systolic and diastolic functions) and to assess the relationship of these parameters with metabolic control in diabetic children and adolescents. METHODS: A total of 55 patients with type 1 diabetes mellitus (T1DM) of at least 5-year duration and 30 healthy subjects were included in the study. Serum adiponectin, hsCRP, hemoglobin A1c (HbA1c), and lipid levels were evaluated in the patients and in the controls. CIMT, FMD, ventricular systolic and diastolic functions were assessed by echocardiography. RESULTS: Mean age of the patients with diabetes was 17.6 years; mean diabetes duration was 10.4 years. Mean serum hsCRP was elevated in children with diabetes (0.21+/-0.31 vs. 0.10+/-0.16 MUg/mL, p=0.00), while no significant difference from the controls was found in adiponectin levels. Mean CIMT was significantly higher in diabetic children compared to the control group (0.53+/-0.11 vs. 0.34+/-0.46 mm, p=0.00). Mean FMD of the diabetic children was significantly lower than that of the controls (6.86+/-2.85% vs. 12.13+/-1.99%, p=0.00). Diabetes duration was positively correlated with CIMT and negatively correlated with FMD. Right ventricular (RV) and left ventricular (LV) myocardial performance index (MPI) were higher in the patient group (p=0.00). CONCLUSIONS: Our data suggest that in addition to standard echocardiography, tissue Doppler echocardiography, FMD, and CIMT can be used as early-stage radiological markers and hsCRP as an early-stage biochemical marker of atherosclerosis in the routine follow-up of T1DM patients. PMID- 24072087 TI - Relationship between aspartate aminotransferase-to-platelet ratio index and carotid intima-media thickness in obese adolescents with non-alcoholic fatty liver disease. AB - OBJECTIVE: There is increasing evidence for an association between non-alcoholic fatty liver disease (NAFLD) and an increased risk of cardiovascular morbidity and mortality. The aim of this study was to investigate the association between aspartate aminotransferase-to-platelet ratio index (APRI) and carotid intima media thickness (IMT) in obese adolescents with NAFLD. METHODS: Seventy-six obese adolescents and 36 lean subjects were enrolled in this cross-sectional single centre study. The obese subjects were divided into two subgroups based on the presence or absence of fatty liver with high transaminase levels (NAFLD group and non-NAFLD group). Fasting blood samples were assayed for transaminase, glucose, and insulin levels. Insulin resistance was calculated by the homeostasis model assessment (HOMA-IR). RESULTS: APRI values were higher in both obese groups (NAFLD and non-NAFLD) in comparison with the lean group. The NAFLD group had significantly higher APRI values than the non-NAFLD obese group and the lean group. Carotid IMT was higher in both obese groups (NAFLD and non-NAFLD) in comparison with the lean group. The NAFLD group had significantly higher measurements of carotid IMT than the non-NAFLD group and the lean group. APRI was positively correlated with most of the metabolic parameters (total cholesterol, low-density lipoprotein cholesterol, glucose, insulin, HOMA-IR) and with carotid IMT in the NAFLD obese group. CONCLUSIONS: This study demonstrated that a significant relationship exists between APRI and carotid IMT in obese adolescents with NAFLD. We suggest that an increased APRI score in obese adolescents with NAFLD can possibly serve to predict a more adverse cardiovascular risk profile. PMID- 24072088 TI - Increased resistin serum concentrations in patientswith type 1 diabetes mellitus. AB - OBJECTIVE: Adiponectin, leptin, and resistin are adipokines which play a significant role in the regulation of lipid and carbohydrate metabolism in patients with type 2 diabetes, while little is known about their role in type 1 diabetes mellitus (T1DM). The aim of this study was to measure serum adiponectin, leptin, and resistin levels and to investigate their relationships with some parameters in patients with T1DM and healthy controls. METHODS: Fifty children and adolescents with T1DM (21 boys and 29 girls) and 33 healthy control subjects (18 boys and 15 girls) participated in the study. All subjects were patients followed in the Pediatric Endocrinology and Metabolism Unit of Gaziantep University Faculty of Medicine. None of the subjects had hypertension, obesity, hyperlipidemia, anemia, or infection. Adiponectin, leptin, and resistin levels were analyzed with ELISA. RESULTS: There were no statistically significant differences related with age, sex, pubertal status, or body mass index distribution between the diabetic and control groups. Resistin levels were significantly higher in the diabetic group compared to controls (5.26+/-3.15 ng/mL vs. 3.50+/-1.26 ng/mL; p<0.01). CONCLUSION: Of the three investigated adipokines, only resistin was associated with T1DM. Resistin may play a role in the process of inflammation and also in the pathophysiology of T1DM. PMID- 24072089 TI - Remission with cabergoline in adolescent boys with Cushing's disease. AB - Cabergoline is a long-acting dopamine receptor agonist used for treatment of patients with uncured Cushing's disease (CD) and, as a first-line treatment, was used in only limited numbers of patients. This report presents two adolescent boys with CD who were treated with cabergoline. Two adolescent boys with clinical and laboratory findings of CD are presented. No pituitary adenoma was detected by radiological investigation in either patient. Adrenocorticotropic hormone (ACTH) hypersecretion and lateralization was found by inferior petrosal sinus sampling in both patients. The initial cabergoline dose was 1mg/week and was adjusted up to 1.5 mg/week in the second patient, based on his urinary free cortisol (UFC) level. The patients responded to cabergoline treatment with normal UFC levels on the 4th and 6th months of treatment. The boys reached complete remission at the end of the 17th and 24th months, respectively. Cabergoline is effective in the control of cortisol secretion and can be considered as a first-line treatment in cases of CD. PMID- 24072090 TI - Novel mutation in the SLC19A2 gene in an Iranian family with thiamine-responsive megaloblastic anemia: a series of three cases. AB - Thiamine-responsive megaloblastic anemia (TRMA) is a clinical triad characterized by megaloblastic anemia, non-autoimmune diabetes mellitus, and sensory-neural hearing loss. Mutations in the thiamine transporter gene, solute carrier family 19, member 2 (SLC19A2), have been associated with TRMA. Three pediatric patients from a large consanguineous Iranian family with hyperglycemia, anemia, and hearing loss were clinically diagnosed with TRMA. In all three patients, TRMA was confirmed by direct sequencing of the SLC19A2 gene that revealed a novel missense homozygous mutation c.382 G>A (p.E128K). This mutation results in the substitution of glutamic acid to lysine at position 128 in exon 2 and was not detected in 200 control chromosomes. Thiamine therapy reversed the anemia and alleviated the hyperglycemia in all three patients. We recommend sequence analysis of the SLC19A2 gene in individuals with a clinical triad of diabetes mellitus, hearing loss, and anemia. The administration of thiamine ameliorates the megaloblastic anemia and the hyperglycemia in patients with TRMA. PMID- 24072091 TI - Long-term follow-up of Cushing's disease:a case report. AB - Cushing's disease is a condition in which hypercortisolism develops due to excessive hypophyseal adrenocorticotropic hormone production. It is rare in childhood. In this paper, we report the case of a 10-year-old male patient with hypophyseal microadenoma-related Cushing's disease who presented with obesity and was found to show poor height growth at follow-up. The diagnosis was confirmed with inferior petrosal sinus sampling, and the adenoma was successfully removed by transsphenoidal surgery. While adrenal axis suppression continued for approximately 1 year, clinical improvement was clearly observed after the third month following surgery. The findings in this patient demonstrate that decreased growth rate despite rapid weight gain in children can be early sign of Cushing's disease and emphasize the importance of monitoring of growth in obese children. PMID- 24072092 TI - Neonatal seizure as a manifestation of unrecognized maternal hyperparathyroidism. AB - Maternal hypercalcemia suppresses parathyroid activity in the fetus resulting in impaired parathyroid responsiveness to hypocalcemia after birth. Resultant hypocalcemia may be severe and prolonged and rarely may lead to convulsions. Here, we present a newborn infant admitted to the pediatric emergency department at age two weeks with recurrent tonic convulsions due to asymptomatic maternal hyperparathyroidism and vitamin D deficiency. Physicians should be aware that undiagnosed maternal hyperparathyroidism can cause severe hypocalcemia in the newborn. PMID- 24072093 TI - Multiple pituitary hormone deficiency due to gunshot injury in a 6-year-old girl. AB - Gunshot injuries (GSI) of the cranial area have an extremely high mortality rate. Herein, we present a girl who has been living with a bullet in the posterior sellar region. A 6-year-old girl was admitted with complaints of headache, polyuria and polydypsia, which started after a GSI. At the time of admission the patient's anthropometric, physical and neurological examinations were normal. Urine output was 5.5 L/m2/24h. A water deprivation test suggested central diabetes insipidus, which responded to treatment. Evaluation of other pituitary hormones revealed central hypothyroidism and growth hormone deficiency. Pituitary hormone deficiency must be kept in mind in patients injured by a gunshot to the sellar/parasellar region. PMID- 24072094 TI - Medical management of thyroid ectopia:report of three cases. AB - Thyroid ectopia (TE) is an embryological aberration of the thyroid gland migration most commonly observed in the lingual region followed by the sublingual, hyoid, and mediastinal regions. TE is often complicated by local compressive symptoms resulting in dysphagia, dysphonia, and dyspnea. Surgical removal of TE is frequently complicated by difficulties in intubation, increased perioperative bleeding, and severe primary hypothyroidism; on the other hand, I131 ablation is limited by high doses needed and the concern for long-term effects especially in children. We report three children with TE who all presented with compressive symptoms and were managed conservatively with levothyroxine resulting in resolution of compressive symptoms and favorable outcomes. Levothyroxine supplementation is effective and has an important role in managing TE, not only in correcting the associated hypothyroidism but also in resolving the associated compressive symptoms by reducing the size of the ectopic thyroid tissue. PMID- 24072096 TI - [Genetics of amyotrophic lateral sclerosis]. AB - Amyotrophic lateral sclerosis (ALS) is an aggressive rapidly progressing degeneration of both upper and lower motor neurons. Clinically, ALS is characterized by rapidly progressing atrophy and paresis of the muscles of the extremities. The genetics of ALS have become more complex in the last 5 years. The SOD gene is still very important; however, in recent years mutations in the genes for TDP-43 and FUS were discovered and also a most interesting intronic repeat expansion of the hexanucleotide repeat in C9ORF72 has been shown to be the most common in ALS. There are other quantitatively less relevant genes, which, however, are meaningful for pathogenetic aspects. It is also necessary to know that the phenotypes associated with ALS genetics have expanded. PMID- 24072097 TI - M180 amelogenin processed by MMP20 is sufficient for decussating murine enamel. AB - Amelogenin (AMELX) and matrix metalloproteinase-20 (MMP20) are essential for proper enamel development. Amelx and Mmp20 mutations cause amelogenesis imperfecta. MMP20, a protease secreted by ameloblasts, is responsible for processing enamel proteins, including AMELX, during the secretory stage of enamel formation. Of at least 16 different amelogenin splice products, the most abundant isoform found in murine ameloblasts and developing enamel is the M180 protein. To understand the role of MMP20 processing of M180 AMELX, we generated AmelxKO/Mmp20KO (DKO) mice with an amelogenin (M180Tg) transgene. We analyzed the enamel phenotype by SEM to determine enamel structure and thickness, uCT, and by nanoindentation to quantify enamel mechanical properties. M180Tg/DKO mouse enamel had 37% of the hardness of M180Tg/AmelxKO teeth and demonstrated a complete lack of normal prismatic architecture. Although molar enamel of M180Tg/AmelxKO mice was thinner than WT, it had similar mechanical properties and decussating enamel prisms, which were abolished by the loss of MMP20 in the M180Tg/DKO mice. Retention of the C-terminus or complete lack of this domain is unable to rescue amelogenin null enamel. We conclude that among amelogenins, M180 alone is sufficient for normal enamel mechanical properties and prism patterns, but that additional amelogenin splice products are required to restore enamel thickness. PMID- 24072098 TI - Dendrimer-folate-copper conjugates as bioprobes for synchrotron X-ray fluorescence imaging. AB - We present a bioprobe for synchrotron X-ray fluorescence imaging based on dendrimer-folate-copper conjugates. The metal nanoclusters within a dendrimer exhibit excellent FR-targeting properties in KB cells. It could be used as a new multifunction bioprobe for synchrotron X-ray fluorescence mapping. PMID- 24072099 TI - Cytogenetics and outcome of infants with acute lymphoblastic leukemia and absence of MLL rearrangements. PMID- 24072100 TI - Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment. PMID- 24072101 TI - MicroRNA expression at diagnosis adds relevant prognostic information to molecular categorization in patients with intermediate-risk cytogenetic acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous disease, and optimal treatment varies according to cytogenetic risk factors and molecular markers. Several studies have demonstrated the prognostic importance of microRNAs (miRNAs) in AML. Here we report a potential association between miRNA expression and clinical outcome in 238 intermediate-risk cytogenetic AML (IR-AML) patients from 16 institutions in the CETLAM cooperative group. We first profiled 670 miRNAs in a subset of 85 IR-AML patients from a single institution and identified 10 outcome related miRNAs. We then validated these 10 miRNAs by individual assays in the total cohort and confirmed the prognostic impact of 4 miRNAs. High levels of miR 196b and miR-644 were independently associated with shorter overall survival, and low levels of miR-135a and miR-409-3p with a higher risk of relapse. Interestingly, miR-135a and miR-409-3p maintained their independent prognostic value within the unfavorable molecular subcategory (wild-type NPM1 and CEBPA and/or FLT3-ITD), and miR-644 retained its value within the favorable molecular subcategory. miR-409-3p, miR-135a, miR-196b and mir-644 arose as prognostic markers for IR-AML, both overall and within specific molecular subgroups. PMID- 24072102 TI - ERG deletion is associated with CD2 and attenuates the negative impact of IKZF1 deletion in childhood acute lymphoblastic leukemia. PMID- 24072103 TI - Imaging the photodissociation dynamics of neutral metal clusters: copper dimer, Cu2, and copper oxide, CuO. AB - The spectroscopy and UV photodissociation dynamics of Cu2 and CuO have been studied using a combination of one- and two-colour excitation and velocity map imaging. Resonant excitation of Cu2 via the J <- X (1)Sigmag(+) transition leads to significant fragmentation which is interpreted in terms of a combination of direct dissociation of Cu2(+ 2)Pi produced in the resonant two-photon ionization process and dissociation of excited Cu2 states above the ionization threshold. By fitting of the kinetic energy release spectra obtained from the velocity map images, we determine a value for the dissociation energy of the cation of D0 (Cu2(+), X (2)Sigmag(+)) of 1.713 +/- 0.025 eV, which, when combined with known ionization energies, yields D0 (Cu2, X (1)Sigmag(+)) = 1.886 +/- 0.026 eV. In other experiments, resonant two colour (1 + 1') excitation of CuO via a range of excited states (C, D, F, H), yields unusually simple VMI images indicating fragmentation into a single dissociation channel which has been identified as Cu* (2)D3/2 + O* (1)D. Taken together, this data gives a CuO bond dissociation energy of 3.041 +/- 0.030 eV. Finally, the production of Cu2(+) with kinetic energy = 705 +/- 75 cm(-1) is tentatively interpreted as photolysis of Cu3 yielding Cu* + Cu2 X (1)Sigmag(+) from which a dissociation energy of Cu3 of 0.605 +/- 0.030 eV is deduced. PMID- 24072104 TI - The practicality of theory. AB - The study of medical education has broadened significantly over the past decade to include a wide variety of theoretical frameworks from multiple research domains. There remains a significant misconception, however, that learning theories (largely drawn from cognitive psychology and education) are practical and useful to educators, whereas other types of theory are not. The authors of this commentary reflect on a learning-theory-based model for developing master learners presented by Schumacher and colleagues in this issue of Academic Medicine. They suggest that bioscientific and sociocultural theories can enhance different aspects of that model and provide specific examples from neuropsychophysiology, Foucauldian discourse analysis, and critical theory. Bioscientific and sociocultural theories such as these present medical educators with an exciting array of new methodological and interpretive possibilities. The authors illustrate ways in which these theories can have important practical applications for, and impacts on, the practice of medical education. PMID- 24072105 TI - Educational objectives for international medical electives: a literature review. AB - PURPOSE: Although most medical schools and residency programs offer international medical electives (IMEs), little guidance on the educational objectives for these rotations exists; thus, the authors reviewed the literature to compile and categorize a comprehensive set of educational objectives for IMEs. METHOD: In February and July 2012, the authors searched SciVerse Scopus online, which includes the Embase and MEDLINE databases, using specified terms. From the articles that met their inclusion criteria, they extracted the educational objectives of IMEs and sorted them into preelective, intraelective, and postelective objectives. RESULTS: The authors identified and reviewed 255 articles, 11 (4%) of which described 22 educational objectives. Among those 22 objectives, 5 (23%), 15 (68%), and 2 (9%) were, respectively, preelective, intraelective, and postelective objectives. Among preelective objectives, only cultural awareness appeared in more than 2 articles (3/11; 27%). Among intraelective objectives, the most commonly defined were enhancing clinical skills and understanding different health care systems (9/11; 82%). Learning to manage diseases rarely seen at home and increasing cultural awareness appeared in nearly half (5/11; 45%) of all articles. Among postelective objectives, reflecting on experiences through a written project was most common (9/11; 82%). CONCLUSIONS: The authors identified 22 educational objectives for IMEs in the published literature, some of which were consistent across institutions. These consistencies, in conjunction with future research, can be used as a framework on which institutions can build their own IME curricula, ultimately helping to ensure that their medical trainees have a meaningful learning experience while abroad. PMID- 24072106 TI - Global health educational engagement - a tale of two models. AB - Global health learning experiences for medical students sit at the intersection of capacity building, ethics, and education. As interest in global health programs during medical school continues to rise, Northwestern University Alliance for International Development, a student-led and -run organization at Northwestern University Feinberg School of Medicine, has provided students with the opportunity to engage in two contrasting models of global health educational engagement.Eleven students, accompanied by two Northwestern physicians, participated in a one-week trip to Matagalpa, Nicaragua, in December 2010. This model allowed learning within a familiar Western framework, facilitated high volume care, and focused on hands-on experiences. This approach aimed to provide basic medical services to the local population.In July 2011, 10 other Feinberg students participated in a four-week program in Puerto Escondido, Mexico, which was coordinated by Child Family Health International, a nonprofit organization that partners with native health care providers. A longer duration, homestays, and daily language classes hallmarked this experience. An intermediary, third party organization served to bridge the cultural and ethical gap between visiting medical students and the local population. This program focused on providing a holistic cultural experience for rotating students.Establishing comprehensive global health curricula requires finding a balance between providing medical students with a fulfilling educational experience and honoring the integrity of populations that are medically underserved. This article provides a rich comparison between two global health educational models and aims to inform future efforts to standardize global health education curricula. PMID- 24072107 TI - Developing the master learner: applying learning theory to the learner, the teacher, and the learning environment. AB - As a result of the paradigm shift to a competency-based framework, both self directed lifelong learning and learner-centeredness have become essential tenets of medical education. In the competency-based framework, learners drive their own educational process, and both learners and teachers share the responsibility for the path and content of learning. This learner-centered emphasis requires each physician to develop and maintain lifelong learning skills, which the authors propose culminate in becoming a "master leaner." To better understand the development of these skills and the attainment of that goal, the authors explore how learning theories inform the development of master learners and how to translate these theories into practical strategies for the learner, the teacher, and the learning environment so as to optimize this development.The authors begin by exploring self-determination theory, which lays the groundwork for understanding the motivation to learn. They next consider the theories of cognitive load and situated cognition, which inform the optimal context and environment for learning. Building from this foundation, the authors consider key educational theories that affect learners' abilities to serve as primary drivers of their learning, including self-directed learning (SDL); the self-assessment skills necessary for SDL; factors affecting self-assessment (self-concept, self efficacy, illusory superiority, gap filling); and ways to mitigate the inaccuracies of self-assessment (reflection, self-monitoring, external information seeking, and self-directed assessment seeking).For each theory, they suggest practical action steps for the learner, the teacher, and the learning environment in an effort to provide a road map for developing master learners. PMID- 24072108 TI - Medical student in global health-just one part of a larger commitment. AB - Across U.S. medical schools, the interest in global health is rapidly growing. Medical schools are challenged by the sheer numbers of students requesting or independently arranging educational experiences in the developing world. The logistics, legalities, and ethical issues have led to the development of a variety of models that enable student participation in safe and educationally enriching experiences. A major challenge is providing for the educational needs of the students within the medical and cultural environment of the host country without being culturally insensitive or disruptive. While not all of these programs will be successful, some models, like those described in this issue of Academic Medicine, are instructive. The educational experience of the U.S. medical students should not be the only measured outcome however. In exchange for the educational opportunities provided to medical students, U.S. medical schools should commit to sustained involvement in these countries, ensuring a meaningful experience for students and value added to the host countries. PMID- 24072109 TI - Gender differences in salary in a recent cohort of early-career physician researchers. AB - PURPOSE: Studies have suggested that male physicians earn more than their female counterparts. The authors examined whether this disparity exists in a recently hired cohort. METHOD: In 2010-2011, the authors surveyed recent recipients of National Institutes of Health (NIH) mentored career development (i.e., K08 or K23) awards, receiving responses from 1,275 (75% response rate). For the 1,012 physicians with academic positions in clinical specialties who reported salary, they constructed linear regression models of salary considering gender, age, race, marital status, parental status, additional doctoral degree, academic rank, years on faculty, specialty, institution type, region, institution NIH funding rank, K award type, K award funding institute, K award year, work hours, and research time. They evaluated the explanatory value of spousal employment status using Peters-Belson regression. RESULTS: Mean salary was $141,325 (95% confidence interval [CI] 135,607-147,043) for women and $172,164 (95% CI 167,357-176,971) for men. Male gender remained an independent, significant predictor of salary (+$10,921, P < .001) even after adjusting for specialty, academic rank, work hours, research time, and other factors. Peters-Belson analysis indicated that 17% of the overall disparity in the full sample was unexplained by the measured covariates. In the married subset, after accounting for spousal employment status, 10% remained unexplained. CONCLUSIONS: The authors observed, in this recent cohort of elite, early-career physician-researchers, a gender difference in salary that was not fully explained by specialty, academic rank, work hours, or even spousal employment. Creating more equitable procedures for establishing salary is important. PMID- 24072110 TI - The Doris Duke Clinical Scientist Development Award: implications for early career physician scientists. AB - PURPOSE: The Doris Duke Charitable Foundation Clinical Scientist Development Award (CSDA) supports early-career physician scientists in their transition to independent research funding. The authors aimed to analyze the characteristics associated with success in CSDA competitions, determine whether attainment of a CSDA is associated with receiving subsequent research funding, and assess whether alumni remain in research. METHOD: In 2011, the authors tested for associations between gender, age, race/ethnicity, academic degree, National Institutes of Health (NIH) funding rank of the applicant's institution, and success in CSDA competitions. They compared NIH R01 grant attainment, defined as the percentage of individuals who received at least one R01 grant, between CSDA alumni and highly ranked but unsuccessful CSDA applicants (1998-2007). Finally, the authors surveyed alumni to learn more about their professional activities. RESULTS: Demographic factors were not predictors of success in CSDA competitions; academic degree and funding rank of the applicant's institution, however, were. A greater percentage of CSDA alumni than nonalumni received at least one R01 grant (62% [74/120] versus 42% [44/105]). For CSDA alumni who were 10 or more years from the start of their award, their median percent effort toward research activities was 68%. CONCLUSIONS: The factors associated with success in a CSDA competition included a combined clinical and doctoral research degree and affiliation with a well-funded institution. More alumni received NIH independent research funding than those who applied but did not receive the award. Thus, the CSDA is associated with physicians establishing independent and recognized research careers. PMID- 24072111 TI - The social and learning environments experienced by underrepresented minority medical students: a narrative review. AB - PURPOSE: To review the literature on the social and learning environments experienced by underrepresented minority (URM) medical students to determine what type of interventions are needed to eliminate potential barriers to enrolling and retaining URM students. METHOD: The authors searched MEDLINE, PubMed, Ovid HealthStar, and Web of Science, and the reference lists of included studies, published between January 1, 1980, and September 15, 2012. Studies of the learning and social environments and of students' satisfaction, experiences with discrimination or unfair practices, and academic performance or progress, as well as assessments of programs or interventions to improve URM students' academic performance, were eligible for inclusion. RESULTS: The authors identified 28 studies (27 unique data sets) meeting the inclusion criteria. The results of the included studies indicated that URM students experienced less supportive social and less positive learning environments, were subjected to discrimination and racial harassment, and were more likely to see their race as having a negative impact on their medical school experiences than non-URM students. Academic performance on standardized exams was worse, progress less timely, and attrition higher for URM students as well. CONCLUSIONS: For URM students, an adverse climate may be decreasing the attractiveness of careers in medicine, impairing their academic performance, and increasing attrition. Improvements to the social and learning environments experienced by URM students are needed to make medicine a more inclusive profession. The current environment of health care reform creates an opportunity for institutions to implement strategies to achieve this goal. PMID- 24072112 TI - Bridging care transitions: findings from a resident-staffed early postdischarge program. AB - PROBLEM: Academic medical centers face unique challenges to ensuring patient safety after a hospital discharge, including those related to providing patient follow-up care in practices staffed by residents who are not comfortable managing care transitions. APPROACH: In 2011, the authors designed a quality improvement program for early postdischarge follow-up (bridge visits) at a resident primary care outpatient practice, using existing resources. The authors added a unique appointment template to the outpatient electronic health record to guide residents during the visit. Residents completed both postvisit and postprogram surveys regarding their experience with the program, and patients completed postvisit phone surveys regarding their satisfaction with the program. OUTCOMES: Fifty-eight residents completed postvisit surveys, of which 31.0% (18/58) reported problems with medication reconciliation and 25.9% (15/58) with adherence to discharge medications. Of those residents who completed postprogram surveys, almost half (18/38; 47.4%) agreed that their experience changed the way they discharge patients. Nearly all patients who responded to the postvisit phone surveys reported that the program reinforced their discharge and medication instructions (44/46; 95.7%); 81.8% (18/22) of patients with established providers did not mind seeing an interim physician for expedited postdischarge care. NEXT STEPS: An early postdischarge program at a resident outpatient primary care practice is valuable both in ensuring patient safety and as a model to promote experiential learning in medical education. Findings from this study will be used to develop a formal curriculum in care transitions for all residents. PMID- 24072113 TI - Advancing the university mission through partnerships with state Medicaid programs. AB - State Medicaid programs are playing an increasingly important role in the U.S. health care system and represent a major expenditure as well as a major source of revenue for state budgets. The size and complexity of these programs will only increase with the implementation of the Patient Protection and Affordable Care Act. Yet, many state Medicaid programs lack the resources and breadth of expertise to maximize the value of their programs not only for their beneficiaries but also for all those served by the health care system.Universities, especially those with medical schools and other health science programs, can serve as valuable partners in helping state Medicaid programs achieve higher levels of performance, including designing and implementing new approaches for monitoring the effectiveness and outcomes of health services and developing and sharing knowledge about program outcomes. In turn, universities can expand their role in public policy decision making while taking advantage of opportunities for additional research, training, and funding. As of 2013, approximately a dozen universities have developed formal agreements to provide faculty and care delivery resources to support their state Medicaid programs. These examples offer a road map for how others might approach developing similar, mutually beneficial partnerships. PMID- 24072114 TI - Attitude adjustment: shaping medical students' perceptions of older patients with a geriatrics curriculum. AB - For more than half a century, scientific research has documented widespread avoidance and even denial of aging. Though nothing new, aversive reactions to the elderly are not only unfortunate but dangerous today, as increasing life expectancy and consequent demand for specialized geriatric medical care vastly outpace the supply of qualified clinicians equipped to provide it. This discrepancy has led to a crisis that is not easily resolved. At the same time, geriatrics reports the highest level of physician satisfaction among medical specialties. How can this apparent disconnect be explained, and what can be done about it? Citing evidence from medicine and other health care disciplines, the authors address these questions by emphasizing the role of aging-related attitudes, a complex but theoretically modifiable construct. Successful educational interventions are described, including the authors' experience at the helm of a monthlong geriatrics clerkship for fourth-year medical students. Novel suggestions are provided to combat the daunting challenges to achieving a workforce that is sufficient both in number and training to effectively meet the needs of the fastest-growing segment of the U.S. population. As patients continue to age across most medical specialties, the importance of geriatric curricula, particularly those sensitizing learners to the need for a systems-based, biopsychosocial (i.e., interdisciplinary) model of care, cannot be overemphasized. Such training, it is argued, should be a standard component of medical education, and future research should focus on identifying specific curricular content and teaching methods that most effectively achieve this end. PMID- 24072115 TI - The effect of medical students and residents on measures of efficiency and timeliness in an academic medical center emergency department. AB - PURPOSE: Research regarding the effect of trainees on emergency department (ED) operations has demonstrated mixed results. In this study, the authors evaluated the effect of trainees on ED length of stay (LOS), door to medical provider (DTMP) time, and door to disposition decision (DTDD) time while accounting for covariates known to influence ED efficiency and timeliness. METHOD: The authors used retrospective cohort data for ED visits to Maine Medical Center's mixed adult and pediatric ED for the calendar years 2005 through 2009. Each visit was coded indicating the type of provider conducting the visit (student-attending, resident-attending, midlevel provider, or attending group). Ordinary least squares regression analyses were performed to examine the relationships between provider groups and ED LOS, DTMP time, and DTDD time. Hierarchical regression models were constructed to control for the confounding effects of triage acuity, time of year, laboratory testing, radiographic testing, and patient characteristics. RESULTS: The analysis of 246,142 visits found significant intergroup differences across provider groups for each outcome (P < .001). Multiple regression modeling revealed that treatment by trainees was a significant predictor of longer LOS (medical students and residents), shorter DTMP time (residents), and longer DTDD time (medical students and residents), after controlling for covariates. CONCLUSIONS: Laboratory and radiographic testing accounted for a much larger proportion of variation in outcomes than did trainees. The small increases in LOS and DTDD time are balanced by the decrease in DTMP time and the intangible benefits of educating trainees. PMID- 24072116 TI - The evolving role of online virtual patients in internal medicine clerkship education nationally. AB - PURPOSE: Despite the significant resources required to develop and maintain virtual patient (VP) programs, little is known about why this innovation has been adopted and how it is implemented. Understanding needs and implementation strategies is important for effective curriculum planning. METHOD: In 2009 and 2011, surveys were offered to 110 U.S. internal medicine clerkship directors regarding their goals for adoption of Simulated Internal Medicine Patient Learning Experience VPs. In 2011, respondents were asked how they implemented VPs in their curricula. Results were analyzed using chi-square and Fisher exact test. RESULTS: Responses were obtained from 33 clerkship directors in 2009 and 45 in 2011. Comparing 2009 with 2011, improving students' knowledge (29/33 [88%] versus 40/45 [91%]), differential diagnoses (27/33 [82%] versus 38/45 [86%]), and ability to identify key findings (26/33 [79%] versus 38/45 [86%]) remained somewhat or very important reasons for adopting VPs. Meeting Liaison Committee on Medical Education ED-2 (31/33 [94%] versus 33/45 [73%], P = .011) and ED-8 requirements (25/33 [76%] versus 25/45 [56%], P = .004) declined in importance. Eight of 38 (21%) replaced a learning activity with VPs, 9/38 (24%) integrated VPs into other learning activities, and 21/38 (55%) simply added VPs onto their curricula. CONCLUSIONS: This large, multi-institutional study reports national trends in VP adoption and integration. Meeting cognitive learning objectives remained an important reason for adopting VPs, whereas meeting regulatory requirements decreased significantly in importance. Opportunities remain for m ore systematically integrating VPs into clerkship curricula. Clarifying the changing goals may help with this process. PMID- 24072117 TI - The influence of the residency application process on the online social networking behavior of medical students: a single institutional study. AB - PURPOSE: To evaluate medical students' behavior regarding online social networks (OSNs) in preparation for the residency matching process. The specific aims were to quantify the use of OSNs by students to determine whether and how these students were changing OSN profiles in preparation for the residency application process, and to determine attitudes toward residency directors using OSNs as a screening method to evaluate potential candidates. METHOD: An e-mail survey was sent to 618 third- and fourth-year medical students at Indiana University School of Medicine over a three-week period in 2012. Statistical analysis was completed using nonparametric statistical tests. RESULTS: Of the 30.1% (183/608) who responded to the survey, 98.9% (181/183) of students reported using OSNs. More than half, or 60.1% (110/183), reported that they would (or did) alter their OSN profile before residency matching. Respondents' opinions regarding the appropriateness of OSN screening by residency directors were mixed; however, most respondents did not feel that their online OSN profiles should be used in the residency application process. CONCLUSIONS: The majority of respondents planned to (or did) alter their OSN profile in preparation for the residency match process. The majority believed that residency directors are screening OSN profiles during the matching process, although most did not believe their OSN profiles should be used in the residency application process. This study implies that the more medical students perceive that residency directors use social media in application screening processes, the more they will alter their online profiles to adapt to protect their professional persona. PMID- 24072118 TI - Overwhelmed and uninspired by lack of coordinated care: a call to action for new physicians. AB - In this commentary, the author argues that medical students and residents often find themselves overwhelmed with the realities of facilitating coordinated care. He suggests that the difficulty in obtaining outside records for newly transferred patients leads to both unnecessary duplication of procedures and learned helplessness for new physicians. He provides examples of care coordination challenges by describing his five-hour attempt to obtain the medical records and brain biopsy slides for a transfer patient. He points out that practical solutions to these challenges have already been proposed but that their implementation remains a challenge given the many invested stakeholders. He calls on medical students and residents to join together with patients, community advocates, departmental leaders, and health system administrators to demand changes to the care coordination system that will ultimately provide patients with more efficient and appropriate medical care. PMID- 24072119 TI - Adopting an ethical approach to global health training: the evolution of the Botswana - University of Pennsylvania partnership. AB - Global health training opportunities for medical students and residents have proliferated in recent years. These short-term elective rotations allow trainees to learn about global health issues by participating in various aspects of education and health care in resource-limited settings. Recently published consensus-based ethical guidelines have suggested considerations for the design of international electives that address the activities of host and sending sites, visiting students and residents, and sponsors.The authors analyze the value of global health training opportunities for medical students, residents, faculty, host and sending institutions, and other stakeholders from the perspective of the Botswana-University of Pennsylvania Partnership, a program that has provided global health experiences for health care trainees for more than 10 years. Drawing from the Working Group on Ethics Guidelines for Global Health Training framework, they illustrate the ethical and logistical challenges faced by the program's organizers and the solutions that they implemented alongside their host site partners. They conclude with a summary of recommendations to guide implementation of ethically sound international health electives in resource limited settings. PMID- 24072120 TI - Geographic mobility advances careers: study of the Executive Leadership in Academic Medicine (ELAM) program for women. AB - PURPOSE: To explore whether geographic mobility is associated with career advancement of women in U.S. medical schools who are entering mid- to executive level positions. METHOD: Using an existing dataset of 351 participants in academic medicine who attended the Executive Leadership in Academic Medicine (ELAM) Program for Women (1996-2005) (adjusted to 345 participants in some analyses because data on initial faculty rank were missing), the authors conducted a quantitative study in 2009 to determine whether geographic mobility was associated with administrative promotion for those who relocated geographically (from employer while attending ELAM to employer at last job of record). RESULTS: Twenty-four percent of women (83/345) relocated geographically (movers) after attending ELAM. Moving had a positive association with career advancement (P = .001); odds for promotion were 168% higher for movers than for stayers [odds ratio Exp(beta) = 2.684]. Movers attained higher administrative positions (P = .003), and more movers (60%) were promoted at the most recent job compared with stayers (40%) (P = .0001). Few movers changed city size; 70% already resided in large or urban cities where most medical schools are located. Age was not a barrier to mobility. Career advancement was not related to research reputation (National Institutes of Health grant award ranking) of participants' schools (either at time of attending ELAM or post-ELAM). CONCLUSIONS: Similar to findings outside academic medicine, 24% of women classified as geographic "movers" among midcareer faculty in medical schools attained career advantages. Psychosocial and socioeconomic factors underlying women's relocation decisions require additional study. PMID- 24072121 TI - Career outcomes of the graduates of the American Board of Internal Medicine Research Pathway, 1995-2007. AB - PURPOSE: In 1995, the American Board of Internal Medicine (ABIM) formalized an integrated residency curriculum including both clinical and research training (the Research Pathway), designed to develop careers of physician-scientists. Individuals who completed Pathway training between 1995 and 2007 were surveyed to determine the extent to which graduates established research-oriented careers. METHOD: In 2012, the authors used a Web-based, 56-question, multiple-choice electronic survey of 813 participants in Research Pathway programs who completed their residency training between the years of 1995 and 2007. Survey questions addressed source and type of funding, research productivity, and job title/content. Descriptive and inferential analyses were performed. RESULTS: Forty-seven percent of solicited Pathway graduates participated in the survey. Ninety-seven percent of the respondents completed Pathway training. Ninety-one percent reported some research effort, with a group average of 58.6% of total professional effort spent in research. Seventy-two percent currently hold positions in academic medicine; 8.6% in the biomedical industry; and 2.1% in government medical service. Over 85% reported extramural research funding, with 81.4% receiving research support from federal sources. Among the variables positively correlated with the highest level of research engagement were previous graduate-level research training, any first-author publications arising from the Pathway research experience, and the receipt of extramural career development funding supporting the Pathway research. CONCLUSIONS: On the basis of a very high level of active research engagement reported by 385 ABIM Research Pathway graduates, this special research training track appears to be effectively meeting its goal of training biomedical scientists. PMID- 24072122 TI - Enhancement of the assessment of physician-patient communication skills in the United States Medical Licensing Examination. AB - The National Board of Medical Examiners (NBME) reviewed all components of the United States Medical Licensing Examination as part of a strategic planning activity. One recommendation generated from the review called for enhancements of the communication skills component of the Step 2 Clinical Skills (Step 2 CS) examination. To address this recommendation, the NBME created a multidisciplinary team that comprised experts in communication content, communication measurement, and implementation of standardized patient (SP)-based examinations. From 2007 through 2012, the team reviewed literature in physician-patient communication, examined performance characteristics of the Step 2 CS exam, observed case development and quality assurance processes, interviewed SPs and their trainers, and reviewed video recordings of examinee-SP interactions. The authors describe perspectives gained by their team from the review process and outline the resulting enhancements to the Step 2 CS exam, some of which were rolled out in June 2012. PMID- 24072123 TI - Making equity a value in value-based health care. AB - Equity in health and health care in America continues to be a goal unmet. Certain demographic groups in the United States-including racial and ethnic minorities and individuals with lower socioeconomic status-have poorer health outcomes across a wide array of diseases, and have higher all-cause mortality. Yet despite growing understanding of how social-, structural-, and individual-level factors maintain and create inequities, solutions to reduce or eliminate them have been elusive. In this article, the authors envision how disparities-related provisions in the Affordable Care Act and other recent legislation could be linked with new value-based health care requirements and payment models to create incentives for narrowing health care disparities and move the nation toward equity.Specifically, the authors explore how recent legislative actions regarding payment reform, health information technology, community health needs assessments, and expanding health equity research could be woven together to build an evidence base for solutions to health care inequities. Although policy interventions at the clinical and payer levels alone will not eliminate disparities, given the significant role the social determinants of health play in the etiology and maintenance of inequity, such policies can allow the health care system to better identify and leverage community assets; provide high-quality, more equitable care; and demonstrate that equity is a value in health. PMID- 24072124 TI - Developing physicians as catalysts for change. AB - Failures in care coordination are a reflection of larger systemic shortcomings in communication and in physician engagement in shared team leadership. Traditional medical care and medical education neither focus on nor inspire responses to the challenges of coordinating care across episodes and sites. The authors suggest that the absence of attention to gaps in the continuum of care has led physicians to attempt to function as the glue that holds the health care system together. Further, medical students and residents have little opportunity to provide feedback on care processes and rarely receive the training and support they need to assess and suggest possible improvements.The authors argue that this absence of opportunity has driven cynicism, apathy, and burnout among physicians. They support a shift in culture and medical education such that students and residents are trained and inspired to act as catalysts who initiate and expedite positive changes. To become catalyst physicians, trainees require tools to partner with patients, staff, and faculty; training in implementing change; and the perception of this work as inherent to the role of the physician.The authors recommend that medical schools consider interprofessional training to be a necessary component of medical education and that future physicians be encouraged to grow in areas outside the "purely clinical" realm. They conclude that both physician catalysts and teamwork are essential for improving care coordination, reducing apathy and burnout, and supporting optimal patient outcomes. PMID- 24072125 TI - Lessons learned about coordinating academic partnerships from an international network for health education. AB - There is a growing trend of academic partnerships between U.S., Canadian, and European health science institutions and academic health centers in low- and middle-income countries. These partnerships often encounter challenges such as resource disparities and power differentials, which affect the motivations, expectations, balance of benefits, and results of the joint projects. Little has been discussed in previous literature regarding the communication and project management processes that affect the success of such partnerships. To fill the gap in the literature, the authors present lessons learned from the African Health Open Educational Resources Network, a multicountry, multiorganizational partnership established in May 2008. The authors introduce the history of the network, then discuss actively engaging stakeholders throughout the project's life cycle (design, planning, execution, and closure) through professional development, relationship building, and assessment activities. They focus on communication and management practices used to identify mutually beneficial project goals, ensure timely completion of deliverables, and develop sustainable sociotechnical infrastructure for future collaborative projects. These activities yielded an interactive process of action, assessment, and reflection to ensure that project goals and values were aligned with implementation. The authors conclude with a discussion of lessons learned and how the partnership project may serve as a model for other universities and academic health centers in high income countries and low- and middle-income countries that are interested in or currently pursuing international academic partnerships. PMID- 24072126 TI - The challenge of promoting professionalism through medical ethics and humanities education. AB - Given recent emphasis on professionalism training in medical schools by accrediting organizations, medical ethics and humanities educators need to develop a comprehensive understanding of this emphasis. To achieve this, the Project to Rebalance and Integrate Medical Education (PRIME) II Workshop (May 2011) enlisted representatives of the three major accreditation organizations to join with a national expert panel of medical educators in ethics, history, literature, and the visual arts. PRIME II faculty engaged in a dialogue on the future of professionalism in medical education. The authors present three overarching themes that resulted from the PRIME II discussions: transformation, question everything, and unity of vision and purpose.The first theme highlights that education toward professionalism requires transformational change, whereby medical ethics and humanities educators would make explicit the centrality of professionalism to the formation of physicians. The second theme emphasizes that the flourishing of professionalism must be based on first addressing the dysfunctional aspects of the current system of health care delivery and financing that undermine the goals of medical education. The third theme focuses on how ethics and humanities educators must have unity of vision and purpose in order to collaborate and identify how their disciplines advance professionalism. These themes should help shape discussions of the future of medical ethics and humanities teaching.The authors argue that improvement of the ethics and humanities-based knowledge, skills, and conduct that fosters professionalism should enhance patient care and be evaluated for its distinctive contributions to educational processes aimed at producing this outcome. PMID- 24072127 TI - Ultimate publication rate of unpublished manuscripts listed on radiology residency applications at one institution. AB - PURPOSE: This study was designed to assess the ultimate publication rate of unpublished manuscripts listed on radiology residency applications. METHOD: A retrospective review was performed on all 628 Electronic Residency Application Service applications submitted to a single-institution radiology residency program in 2010. Publication status of unpublished manuscripts listed as "accepted," "in press," "provisional accepted," or "submitted" was assessed two years later by searching PubMed, Google Scholar, and journal- or conference specific Web sites. Manuscripts were considered "published" if they appeared in a peer-reviewed journal with the applicant as an author. Impact factors of proposed and publishing journals were compared. RESULTS: Five hundred fourteen (81.8%) of the 628 applicants listed a total of 1,431 manuscripts: 952 (66.5%) "published," 64 (4.5%) "in press," 95 (6.6%) "accepted," 27 (1.9%) "provisional accepted," and 293 (20.5%) "submitted." After two years, 81.3% (52/64) of "in press," 58.9% (56/95) of "accepted," 70.4% (19/27) of "provisional accepted," and 43.7% (128/293) of "submitted" manuscripts were published (P < .01). The proposed and publishing journal matched in 50.8% (65/128) of "submitted" manuscripts (P < .01). The impact factor of the proposed versus publishing journal was 4.189 versus 2.898 (P < .01) for "submitted" manuscripts. CONCLUSIONS: One-third of manuscripts listed on radiology residency applications were unpublished at the time of application. More than half of those listed as "submitted," and approximately one-third of those listed as "accepted," "in press," or "provisional accepted," remained unpublished after two years. Residency selection committees should consider these publication rates when assessing applicants. PMID- 24072128 TI - Ethical dilemmas in clerkship rotations. AB - A sound clinical education should include the opportunity for medical students to engage in a spirited and informed discussion with faculty about the ethical challenges they will undoubtedly face. Unfortunately, in many medical schools today this goal is thwarted by many factors, including denial that a problem exists, relentless system overload, unprofessional behavior, breakdown in communication, and inertia. What is worse is that this problem is not new, and the fallout is not insignificant. Another potential contributing factor is burnout, which is well documented in a high percentage of medical students, residents, and faculty, and two of its most serious consequences are patient dissatisfaction and medical error.The authors draw on hundreds of student reflections on ethical dilemmas submitted during classroom exercises to examine persistent themes. They posit that classroom and didactic teaching is not enough to enable students to face ethical dilemmas. The authors call for a major culture change in medical education: "buy in" from top administration, especially the dean (and associate/assistant deans), chairs of all departments, and clerkship and residency training directors; the appointing of an ombudsperson and/or ethicist to oversee and resolve issues as they arise; instructional workshops and materials to enhance and impart skills for all teachers; remediation or retiring of errant faculty; and ongoing research and dialogue between and among medical centers about novel solutions. PMID- 24072129 TI - Academic integrity: "accepted," "in press," or unacceptable? AB - In this issue, Grimm and Maxfield report the results of an analysis of the outcomes of manuscripts listed as "provisionally accepted," "accepted," "in press," and "submitted" on applications to a university radiology residency program. Their surprising finding that one-third of manuscripts listed as "accepted" or "in press" were not published two years after being included on an application raises questions about the reasons for these discrepancies.The authors of this commentary argue that one explanation for these findings is that some applicants deliberately misrepresented facts in order to be seen as more attractive candidates. After examining the professionalism implications of the study by Grimm and Maxfield, the authors offer recommendations for addressing lapses in students' professionalism early on. They recommend that medical school admissions and teaching faculty establish clear and unshakable expectations that untruths will not be tolerated regardless of the difficult administrative challenges that may ensue. Further, medical school admissions committees should select entrance criteria that reward collaborative behaviors and honesty in addition to academic achievement. The authors encourage more longitudinal, systematic analyses of potential fabrications in residency applications, with the goal of fostering a culture of trust in medicine. PMID- 24072130 TI - A framework for analysis of sentinel events in medical student education. AB - PROBLEM: Although previous studies have addressed student factors contributing to dismissal or withdrawal from medical school for academic reasons, little information is available regarding institutional factors that may hinder student progress. APPROACH: The authors describe the development and application of a framework for sentinel event (SE) root cause analysis to evaluate cases in which students are dismissed or withdraw because of failure to progress in the medical school curriculum. The SE in medical student education (MSE) framework was piloted at the Ohio State University College of Medicine (OSUCOM) during 2010 2012. Faculty presented cases using the framework during academic oversight committee discussions. OUTCOMES: Nine SEs in MSE were presented using the framework. Major institution-level findings included the need for improved communication, documentation of cognitive and noncognitive (e.g., mental health) issues, clarification of requirements for remediation and fitness for duty, and additional psychological services. Challenges related to alternative and combined programs were identified as well. The OSUCOM undertook system changes based on the action plans developed through the discussions of these SEs. NEXT STEPS: An SE analysis process appears to be a useful method for making system changes in response to institutional issues identified in evaluation of cases in which students fail to progress in the medical school curriculum. The authors plan to continue to refine the SE in MSE framework and analysis process. Next steps include assessing whether analysis using this framework yields improved student outcomes with universal applications for other institutions. PMID- 24072131 TI - Career Benchmarks From the Burroughs Wellcome Fund's Early Faculty Career Development Awards. AB - PURPOSE: Documenting the career characteristics of a highly selective group of researchers provides some insight into how a successful career begins. This knowledge is of value to early-career faculty and those who evaluate them, as well as trainees who aspire to the professoriate and those who educate them. METHOD: In 2010, the authors extracted information by hand from the curricula vitae of 196 basic scientists who have been supported by the Burroughs Wellcome Fund's early faculty career development programs from 1982 to 2010. Data were collected on awardees' education, awards and honors, funding, promotion, publication, service, and training activities. The end point for data was December 2010. Analyses quantified participants' time to terminal degree, faculty appointment, and first R01; determined their publication productivity; and calculated their rates of training graduate students and postdoctoral fellows. RESULTS: This group moved into jobs and gained first R01s faster than average. Surprisingly, those who train the most students and fellows do not publish the most. Women and men trained different numbers of undergraduates, PhDs, and postdocs. Women awardees had fewer publications on average than men. CONCLUSIONS: Researchers who are highly competitive at the early faculty career stage have generally been both timely in their arrival at important benchmarks and productive in terms of their scientific output. Newly trained researchers and the people and institutions that train them share responsibility for attaining expeditious progress, developing a substantial track record, and staking out fertile intellectual ground from which to grow an independent faculty career. PMID- 24072132 TI - Applying the milestones in an internal medicine residency program curriculum: a foundation for outcomes-based learner assessment under the next accreditation system. AB - In 2010, University of Kansas Medical Center internal medicine residency program leaders concluded that their competency-based curriculum and evaluation system was not sufficient to promote accurate assessment of learners' performance and needed revision to meet the requirements of the Accreditation Council for Graduate Medical Education (ACGME) Next Accreditation System (NAS). Evaluations of learners seldom referenced existing curricular goals and objectives and reflected an "everyone is exceptional, no one is satisfactory" view.The authors identified the American Board of Internal Medicine and ACGME's Developmental Milestones for Internal Medicine Residency Training as a published standard for resident development. They incorporated the milestones into templates, a format that could be modified for individual rotations. A milestones-based curriculum for each postgraduate year of training and every rotation was then created, with input from educational leaders within each division in the Department of Internal Medicine and with the support of the graduate medical education office.In this article, the authors share their implementation process, which took approximately one year, and discuss their current work to create a documentation system for direct observation of entrustable professional activities, with the aim of providing guidance to other programs challenged with developing an outcomes-based curriculum and assessment system within the time frame of the NAS. PMID- 24072133 TI - Does medical training promote or deter self-directed learning? A longitudinal mixed-methods study. AB - PURPOSE: The School of Medicine, University of Saskatchewan curriculum promotes self-direction as one of its learning philosophies. The authors sought to identify changes in self-directed learning (SDL) readiness during training. METHOD: Guglielmino's SDL Readiness Scale (SDLRS) was administered to five student cohorts (N = 375) at admission and the end of every year of training, 2006 to 2010. Scores were analyzed using repeated-measurement analysis. A focus group and interviews captured students' and instructors' perceptions of self direction. RESULTS: Overall, the mean SDLRS score was 230.6; men (n = 168) 229.5; women (n = 197) 232.3, higher than in the average adult population. However, the authors were able to follow only 275 students through later years of medical education. There were no significant effects of gender, years of premedical training, and Medical College Admission Test scores on SDLRS scores. Older students were more self-directed. There was a significant drop in scores at the end of year one for each of the cohorts (P < .001), and no significant change to these SDLRS scores as students progressed through medical school. Students and faculty defined SDL narrowly and had similar perceptions of curricular factors affecting SDL. CONCLUSIONS: The initial scores indicate high self-direction. The drop in scores one year after admission, and the lack of change with increased training, show that the current educational interventions may require reexamination and alteration to ones that promote SDL. Comparison with schools using a different curricular approach may bring to light the impact of curriculum on SDL. PMID- 24072134 TI - Bimetallic ruthenium-copper nanoparticles embedded in mesoporous carbon as an effective hydrogenation catalyst. AB - Bimetallic ruthenium-copper nanoparticles embedded in the pore walls of mesoporous carbon were prepared via a template route and evaluated in terms of catalytic properties in D-glucose hydrogenation. The existence of bimetallic entities was supported by Ru L3-edge and Cu K-edge X-ray absorption results. The hydrogen spillover effect of the bimetallic catalyst on the hydrogenation reaction was evidenced by the results of both hydrogen and carbon monoxide chemisorptions. The bimetallic catalyst displayed a higher catalytic activity than the single-metal catalysts prepared using the same approach, namely ruthenium or copper nanoparticles embedded in the pore walls of mesoporous carbon. This improvement was due to the changes in the geometric and electronic structures of the bimetallic catalyst because of the presence of the second metal. PMID- 24072135 TI - Can calcium dobesilate be used safely for peripheral microvasculopathies that require neoangiogenesis? AB - BACKGROUND: Calcium dobesilate (CaD) is a member of the synthetic veno-active drug family. Only a small number of reports are available that describe the micro angiogenic effects of CaD in the current literature. MATERIAL AND METHODS: The antiangiogenic potential of CaD was compared with bevacizumab (Bb), which is a potent angiogenesis inhibitor, in a chick chorioallantoic membrane model. Four different concentrations (10-7, 10-6, 10-5, and 10-4 M) of drug pellet were prepared for each drug. Changes in vessel formation were scored and compared for each drug according to the previous literature. RESULTS: The antiangiogenic behavior of CaD was lower than Bb, despite the significant dose-dependent manner of escalation. The anti-angiogenic scores of CaD were determined as 0.20, 0.47, 0.66, 1.0 in 10-7, 10-6, 10-5, and 10-4 M concentrations, respectively (average score >0.5 was significant). CONCLUSIONS: According to the data obtained, this agent should be used carefully for cases in which angiogenesis plays an important role in healing. PMID- 24072136 TI - Contrast between innovator drug- and generic drug-induced renal dysfunction on coronary angiography (CONTRAST study). AB - Contrast-induced nephropathy (CIN) has gained increasing attention in clinical practice, particularly during coronary angiography (CAG). However, some "bioequivalent" generic (GE) drugs are less effective than the innovator (IN) drug. Therefore, the aim of this study was to compare contrast media (IN drug) induced renal dysfunction with contrast media (GE drug)-induced dysfunction. We enrolled 44 patients who underwent elective CAG or percutaneous coronary intervention (PCI) and randomly divided them into two groups that received contrast media (Iohexol, nonionic and low-osmolality contrast agent) containing either IN drug (Omnipaque) or GE drug (Iopaque). Blood and urine sampling were performed before and after (24 and 48 h) CAG or PCI. Biochemical parameters in blood (serum creatinine, cystatin C, high-sensitivity C-reactive protein, and pentraxin-3) and urine (urinary albumin/Cr and liver-type fatty acid binding protein/Cr) were measured. There were no significant differences in the biochemical parameters at baseline between the groups. In addition, there were no differences in changes in biochemical parameters in blood and urine before and after CAG or PCI between the groups, although one patient in the GE group had CIN. The degree of contrast in Iopaque-induced renal dysfunction was comparable with that in Omnipaque-induced dysfunction. PMID- 24072137 TI - Prognostic implications of left ventricular regional function heterogeneity assessed with two-dimensional speckle tracking in patients with ST-segment elevation myocardial infarction and depressed left ventricular ejection fraction. AB - The aim of the current study was to evaluate the prognostic implications of myocardial tissue heterogeneity assessed with two-dimensional speckle-tracking echocardiography in patients three months after first ST-segment elevation myocardial infarction (STEMI) with left ventricular ejection fraction (LVEF) <=35 %. For this purpose, a total of 79 patients with first STEMI and LVEF <=35 % at three months postinfarction were evaluated. Based on left ventricular (LV) speckle-tracking longitudinal strain echocardiography, the infarct core, border zone, and remote zone at baseline and three months' follow-up were defined. Patients were followed for the occurrence of the composite end point of appropriate implantable cardioverter-defibrillator (ICD) therapy and/or cardiac mortality. During a median follow-up of 46 months, 13 patients (17 %) reached the composite end point. At baseline, patients with and without events showed comparable values of LV longitudinal strain at the infarct, border, and remote zones. However, at three months' follow-up, patients with events showed significantly more impaired longitudinal strain at the border zone (-6.8 +/- 3.1 % vs. -10.5 +/- 4.9 %, P = 0.002), whereas LVEF was comparable (28 +/- 6 % vs. 31 +/- 4 %, P = 0.09). The median three-month LV longitudinal strain at the border zone was -9.4 %. Multivariate Cox regression analysis demonstrated that three month longitudinal strain >-9.4 % at the border zone was independently associated with the composite end point (hazard ratio 3.94, 95 % confidence interval 1.05 14.70; P = 0.04). In conclusion, regional longitudinal strain at the border zone three months post-STEMI is associated with appropriate ICD therapy and cardiac mortality. PMID- 24072138 TI - Gp10 based-thioetherification (10BASE(d)-T) on a displaying library peptide of bacteriophage T7. AB - The site-specific introduction of a haloacetamide derivative into a designated cysteine on a displaying peptide on a capsid protein (gp10) of bacteriophage T7 has been achieved. This easiest gp10-based thioetherification (10BASEd-T) is carried out in one-pot without side reactions or loss of phage infectivity. PMID- 24072139 TI - Generation of diffraction-free optical beams using wrinkled membranes. AB - Wrinkling has become a well developed bottom-up technique to make artificial surface textures in about the last decade. However, application of the optical properties of long range ordered wrinkles has been limited to one dimensional gratings to date. We report the demonstration of macroscopic optical focusing using wrinkled membranes, in which concentric wrinkle rings on a gold-PDMS bilayer membrane convert collimated illuminations to diffraction-free focused beams. Beam diameters of 300-400 MUm have been observed in the visible range, which are dominantly limited by the eccentricity of the current devices. Based upon agreement between theoretical and experimental results on eccentricity effects, we predict a decrease of the beam diameter to no more than around 50 MUm, if eccentricity is eliminated. PMID- 24072140 TI - Gene mutations and steroid-resistant nephrotic syndrome. PMID- 24072141 TI - Voiding dysfunction in children with chronic functional constipation. PMID- 24072142 TI - Hepatitis B virus complications of pregnancy after kidney transplantation. PMID- 24072143 TI - Atypical hemolytic-uremic syndrome: the interplay between complements and the coagulation system. AB - Hemolytic-uremic syndrome (HUS) is a rare life-threatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and impaired renal function. A thrombotic microangiopathy underlies the clinical features of HUS. In the majority of cases, HUS follows an infection with toxin-producing bacteria such as verotoxin-producing Escherichia coli. In some cases, HUS is not preceded by a clinically apparent infection, and therefore, is named atypical HUS. The prognosis of atypical HUS is poor. While mortality approaches 25% during the acute phase, end-stage renal disease develops in nearly half of patients within a year. Evidence is accumulating that complement activation through the alternative pathway is at the heart of the pathophysiology leading to atypical HUS. Genetic abnormalities involving complement regulatory proteins and complement components form the molecular basis for complement activation. Since microvascular thrombosis is a quintessential feature of atypical HUS, complements and the coagulation system must work in tandem to give rise to the pathologic alterations observed in this condition. Here, a brief discussion of clinical and morphologic features of atypical HUS is followed by a concise presentation of the complement and coagulation systems. The interplay between complements and the coagulation system is graphically highlighted. Last but not least, conventional and emerging therapies for atypical HUS are outlined. PMID- 24072144 TI - NF-E2-related factor 2 and its role in diabetic nephropathy. AB - Diabetic nephropathy is the leading cause of chronic kidney disease and end-stage renal disease. Oxidative stress has been recognized as a major contributor to its pathogenesis. Defensive mechanisms have also widely been studied. One of them, the NF-E2-Related Factor 2, is reviewed in this article. PMID- 24072145 TI - Acute page kidney complicating kidney transplant artery stenting: presentation of a case and novel management. AB - We present a rare complication of transplant renal artery stenting in a patient who developed subcapsular hematoma and presented as acute page kidney. We discuss possible mechanisms and successful novel management using radiological-assisted decompression. We propose considering this alternative option before proceeding with surgical exploration and renal capsulotomy. PMID- 24072146 TI - Podocyte injury in segmental garland-pattern poststreptococcal glomerulonephritis. PMID- 24072147 TI - NPHS2 gene in steroid-resistant nephrotic syndrome: prevalence, clinical course, and mutational spectrum in South-West Iranian children. AB - INTRODUCTION: Mutations in podocin (NPHS2) gene have the key role in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS) in children, but data is scarce regarding their prevalence and natural course among different all ethnic groups. This study was aimed to demonstrate the spectrum of NPHS2 mutations in children with SRNS and to compare the clinical course of disease in patients with and without mutation. MATERIALS AND METHODS: All 8 exons of NPHS2 were sequenced in 99 children, including 49 with SRNS and 50 with steroid sensitive nephrotic syndrome (control group) by DNA sequencing. RESULTS: The prevalence rates of NPHS2 gene mutation among children with SRNS and SSNS were 31% and 4%, respectively. The prevalence rates of mutation among familial and sporadic forms were 57% and 26%, respectively. Thirty-three percent of the children experienced recurrence of primary disease after kidney transplantation, none of whom had a mutation. The clinical response to treatment was poorer in children with mutation in comparison with patients without mutation (12% versus 32%, respectively; odds ratio, 3.29, 95% confidence interval, 0.40 to 25.64). Patients with and without mutation could not be differentiated by demographic and histological features, glomerular filtration rate at onset, hypertension, progression to end-stage renal disease, and proteinuria. CONCLUSIONS: Mutations of NPHS2 gene are frequent among Iranian children with SRNS. Regarding similar clinical features in patients with and without mutation and poor response to pharmacotherapy in patients with mutation, a molecular approach might be necessary for different treatment plans and prediction of prognosis. PMID- 24072148 TI - Urinary tract infection and enuresis in children with chronic functional constipation. AB - INTRODUCTION: There is still controversy regarding the possible role of chronic functional constipation in disorders of the urinary tract, specifically urinary tract infection (UTI) and enuresis. The aim of this study was to investigate the frequency of (UTI) and enuresis in children with chronic functional constipation. MATERIALS AND METHODS: We included 120 children (60.8% girls) with chronic functional constipation based on the Rome III criteria. Detailed history of UTI and enuresis or symptoms pointing to these diagnoses was obtained. Urinalysis, urine culture, and abdominal ultrasonography were performed for all of the participants. RESULTS: The mean age of the patients was 7.4 +/- 3.2 years. Seventy-five percent of the patients had constipation for more than 1 year. The most common urinary symptoms were dysuria (16.7%), urinary frequency (12.5%), and dribbling (4.2%). The frequencies of nocturnal and daytime enuresis were 22.5% and 3.3%, respectively. Pyuria was seen in 10 girls (8.3%). Overall, 7 patients (5.8 %) had a positive urine culture, of whom all were girls and 6 had pyuria. Urinary tract ultrasonography was normal in these patients. CONCLUSIONS: Urinary symptoms, especially nocturnal enuresis, were found in a significant number of children who had chronic functional constipation, but UTI was not so common in the present study. Therefore, we suggest that nocturnal enuresis be considered in children with chronic functional constipation, but screening for UTI is not recommended in these patients. PMID- 24072149 TI - Oral administration of the aqueous extract of Rosmarinus officinalis in rats before renal reperfusion injury. AB - INTRODUCTION: Reperfusion injury leads to damage to the hemodynamic and functional parameters of the kidney. This study investigated the effects of oral administration of the aqueous extract of rosemary on improvement of changes induced by ischemia-reperfusion in rats. MATERIALS AND METHODS: Fourty male Sprague-Dawley rats were divided into 4 groups. One group was the control, rates in another group underwent sham operation, and 2 groups were exposed to reperfusion injury. Rats in one of the reperfusion groups was treated with 8% oral aqueous extract of rosemary (10 mL/kg/d) for 1 week (rosemary group), and the other received normal saline for the same period of time (reperfusion group). Reperfusion injury was induced by bilateral occlusion of the renal artery and vein for 30 minutes and reperfusion for 24 hours. Examination of oxidative stress was done, including measurement of malondialdehyde and ferric reducing antioxidant power in urine and blood samples. Histological studies were performed on excised kidneys. RESULTS: The comparison between the rosemary and reperfusion groups indicated significant reductions in the levels of plasma creatinine, blood urea nitrogen, and absolute urinary excretion of sodium in the rosemary group. Similarly, the rosemary group presented a significant decrease in malondialdehyde and a significant increase in ferric-reducing antioxidant power. Histopathological examinations showed significant reductions in vascular congestion and cells exfoliation in the rosemary group, in comparison with the reperfusion group. CONCLUSIONS: Oral administration of the aqueous extract of rosemary prior to ischemia-reperfusion is effective in reducing functional and histopathological complications associated with acute kidney failure. PMID- 24072150 TI - Ethanolic extract of garlic for attenuation of gentamicin-induced nephrotoxicity in Wistar rats. AB - INTRODUCTION: Nephrotoxicity is a serious side effect of gentamicin and is believed to be related to reactive oxygen species in the kidney. This study was aimed to find out whether garlic preparation (Allium sativum L) has ameliorative effects on gentamicin nephrotoxicity. MATERIALS AND METHODS: Fifty male Wistar rats were divided into 5 groups of 10 as follows: group 1, sham group (control); group 2 (positive control group), gentamicin for 10 days; group 3, garlic and gentamicin for 10 days; group 4, gentamicin for 10 days followed by garlic for 10 days; and group 5, gentamicin for 10 days followed by saline solution for 10 days. Gentamicin, 10 mg/kg, and garlic extract, 20 mg/kg, were administered intraperitoneally. Serum creatinine and concentrations were measured and the kidneys were processed for histopathological examinations. All specimens were examined for morphologic parameters involving tubular cells. RESULTS: Serum creatinine and BUN levels were significantly high in the gentamicin group (group 2) after the experiment. However, the levels of these parameters in group 3 (co treatment with gentamicin and garlic) were significantly lower than those in group 2. These parameters were also lower in group 4 (consecutive treatment with gentamicin and garlic), when compared with group 5 (gentamicin and saline). The pathology damage score was high for the gentamicin group. Postadministration of garlic after gentamicin treatment (group 4) or co-administration of garlic and gentamicin (group 3) significantly attenuated the damage score. CONCLUSIONS: Garlic has regenerative potential after tubular injury induced by gentamicin in animal models. PMID- 24072151 TI - Sex differences in protective effect of recombinant human erythropoietin against cisplatin-induced nephrotoxicity in rats. AB - INTRODUCTION: The protective role of recombinant human erythropoietin (RHE) against cisplatin-induced nephrotoxicity has been reported, but the role of sex differences is not clearly known. The aim of this study was to determine the sex based difference in the protective effect of RHE against cisplatin-induced nephrotoxicity. MATERIALS AND METHODS: Thirty-three Wistar rats were divided into 6 groups. According to protocol l, male and female rats were treated with RHE (100 IU/kg/d) for 3 days and then received a single dose of cisplatin (7 mg/kg). According to protocol 2, the rats received the same single dose of cisplatin and then were treated with RHE for 7 days. Two other groups of male and female rats received a similar regimen of protocol 2 except for saline instead of RHE. All the animals were sacrificed 1 week after cisplatin administration. RESULTS: All of the experimental animals experienced weight loss. The percentage change of weight in male rats with protocol 1 was significantly less than that in male rats in protocol 2 and control groups. However, in female groups, the percentage of change in weights was slightly higher with protocol 2 than with protocol 1 and control treatment. Administration of RHE significantly decreased changes in serum creatinine, BUN, and malondialdehyde levels in male rats, but not in females. No significant difference was observed in serum nitrite level, kidney weight, and kidney damage score between the groups. CONCLUSIONS: This study suggested that erythropoietin may lead to different responses against cisplatin-induced nephrotoxicity in male and female rats. PMID- 24072152 TI - Modulatory effect of Chandraprabha Vati on antimicrobial peptides and inflammatory markers in kidneys of mice with urinary tract infection. AB - INTRODUCTION: Chandraprabha Vati (CV) is an Indian polyherbal Siddha drug, traditionally used as an anti-inflammatory agent for arthritis and urinary ailments. This study explores its effect on mice with urinary tract infection. MATERIALS AND METHODS: The in-organic constituents of CV were determined by atomic absorption spectroscopy and phytochemical analysis was carried out. The supplementing dose of CV to infected experimental mice was determined by in vitro antimicrobial assay. Transurethrally infected animals were supplemented with CV extract for 20 days after confirmation of UTI. The animals were euthanized as per the guidelines and the tissues were harvested from the control and infected mice for histopathological examination the antimicrobial peptide Tamm-Horsfall protein (THP) and inflammatory markers (tumor necrosis factor-alpha and nuclear factor kappa-light-chain-enhancer of activated B cells) to ascertain the modulatory effects of CV. Indicators for oxidative stress and protein levels were also quantified to validate the efficacy of CV. RESULTS: Terpenoids and flavanoids were majorly found to constitute CV along with zinc and iron as in-organic content. Histological and immunohistochemical studies confirmed the pronounced infection in the kidney of the uropathogenic Escherichia coli-infected animals. Supplementation of CV significantly restored the increased levels of the antimicrobial proteins, THP, and inflammatory markers. CONCLUSIONS: This study explored the efficacy of the aqueous extract of CV as an alternative medication for the synthetic analogues administered for UTI. This study also provides information on the possible role of THP as an antimicrobial protein in the kidney in preventing infection due to uropathogenic E coli. PMID- 24072153 TI - R229Q polymorphism of NPHS2 gene in patients with late-onset steroid-resistance nephrotic syndrome: a preliminary study. AB - INTRODUCTION: Depending on the response to standard steroid therapy, nephrotic syndrome it is classified to steroid-sensitive and steroid-resistant nephrotic syndrome (SRNS). Mutations in several genes including NPHS2 have been implicated in SRNS. Gene R229Q polymorphism (p.R229Q) of NPHS2 is associated with adolescent or adult-onset SRNS in European and South American populations. We investigated this polymorphism among a group of Iranian-Azeri patients with primary SRNS. MATERIALS AND METHODS: All participants had the primary late-onset form of focal segmental glomerulosclerosis (FSGS) and their clinical feature was steroid unresponsiveness. They were compared with a group of age- and sex-matched individuals without any renal disease for NPHS2 gene as controls. The R229Q polymorphism (p.R229Q) was investigated in the case and control groups. RESULTS: A total of 25 patients (mean age, 26.6 +/- 8.0 years) with primary FSGS and 35 controls (mean age, 26.0 +/- 8.7 years) were studied. Serum creatinine of patients and their 24-hour protein excretion at the time of study were 2.4 +/- 1.94 mg/dL and 2830 +/- 981 mg/dL, respectively. Molecular study showed no p.R229Q polymorphism, neither in patients nor in controls. CONCLUSIONS: In this preliminary study, we showed that NPHS2 gene p.R229Q polymorphism does not present in Iranian-Azeri population with SRNS. Larger studies are needed to confirm our results and other mutated genes should also be considered in these patients. PMID- 24072154 TI - Pneumococcal sepsis, peritonitis, and cellulitis at the first episode of nephrotic syndrome. AB - Bacterial infections are common in patients with nephrotic syndrome, including peritonitis, sepsis, meningitis, urinary tract infection, and cellulitis. An 8 year-old boy presented with colicky abdominal pain, vomiting, swollen and painful erythematous lesions around the umbilicus and in anterior surface of left thigh (cellulitis), mild generalized edema, and ascites. The microorganism isolated from peritoneal fluid and blood cultures was Pneumococcus. Association of pneumococcal sepsis, peritonitis, and cellulitis has been rarely reported in nephrotic syndrome. PMID- 24072155 TI - Successful pregnancy in a kidney transplant recipient with chronic hepatitis B virus infection. AB - Overall success rate of pregnancies in kidney transplant recipients is higher than 90% if pregnancy goes beyond the 1st trimester. Risks to mother include hypertension, preeclampsia, infections, and worsening proteinuria, and those to the fetus are prematurity, intrauterine growth retardation, and low birth weight. Hepatitis B infection is associated with progressive liver disease and diminished survival in kidney transplant recipients. A 32-year-old woman had undergone living unrelated donor kidney transplant. Two years after transplantation, she presented with live gestation of 6 weeks. She was also found positive for hepatitis B surface antigen and extracellular antigen. Liver enzymes were normal and ultrasonography findings were normal. Cyclosporine dose was reduced and lamivudine was started. She was monitored closely until 33 weeks, when she gave birth to a healthy female baby through spontaneous vaginal delivery. The newborn received vaccination and immunoglobulins for hepatitis B virus. Mother's kidney allograft function remained stable throughout pregnancy. PMID- 24072156 TI - Re: ambulatory blood pressure monitoring for children with beta-thalassemia major: a preliminary report. PMID- 24072157 TI - Re: effect of silymarin on streptozotocin-nicotinamide-induced type 2 diabetic nephropathy in rats. PMID- 24072158 TI - Re: correlation between ankle-brachial index and microalbuminuria in type 2 diabetes mellitus. PMID- 24072159 TI - Promoter analysis and transcription regulation of fus gene cluster responsible for fusaricidin synthesis of Paenibacillus polymyxa SQR-21. AB - Fusaricidins produced by Paenibacillus polymyxa are lipopeptide antibiotics with outstanding antifungal activity. In this study, the whole gene cluster responsible for fusaricidin biosynthesis (fusA) was isolated and identified from the cDNA library of one biocontrol agent P. polymyxa SQR-21 (SQR-21). MALDI-TOF MS analysis confirmed that SQR-21 could produce four kinds of fusaricidins: A, B, C, and D. A central promoter that drove the transcription of fusGFEDCBA was revealed by mapping of the fus promoter region by 5' deletions. The disruption of fusA in SQR-21 led to the abolishment of fusaricidin production and antifungal activity. The direct interaction between a potential regulator, AbrB, and the promoter region of fus gene cluster was confirmed by electrophoretic mobility shift assays. One abrB disruption mutant showed significantly higher antifungal activity compared with the wild type. These results revealed a pathway for the transcriptional regulation of the fus gene cluster in P. polymyxa. PMID- 24072160 TI - Comparison of microbial communities in sequencing batch reactors (SBRs) exposed to trace erythromycin and erythromycin-H2O. AB - Wastewater treatment plants (WWTPs) are major collection pools of antibiotics of which low concentrations may induce antibiotic resistance in their microbial communities and pose threat to human health. However, information is still limited on the microbial community alteration in WWTPs upon exposure to low-dose antibiotics due to absence of negative control systems without input of resistant bacteria and resistance genes. Here we report the impact of trace erythromycin (ERY) and dehydrated erythromycin (ERY-H2O) on microbial community dynamics in three long-term (1 year) running sequencing batch reactors (SBRs), R1 (ERY-H2O), R2 (ERY), and negative control R3. The PhyloChip microarray analysis showed that ERY-H2O and ERY significantly altered their microbial communities based on bacterial richness (e.g., 825 operational taxonomic units (OTUs) in R1, 699 OTUs in R2, and 920 OTUs in R3) and population abundance (15 and 48 subfamilies with >80 % abundance decrease in R1 and R2, respectively). ERY-H2O and ERY have broad but distinct antimicrobial spectrums. For example, bacteria of all the major phyla (i.e., Proteobacteria, Actinobacteria, Bacteroidetes, and Chloroflexi) present in SBRs were severely inhibited by ERY-H2O and ERY, but bacteria of Acidobacteria, Chlorobi, Firmicutes, Nitrospira and OP10 phyla were only inhibited by ERY. Very limited bacterial groups showed antibiotic resistance to ERY-H2O or ERY through forming biofilms (e.g., Zoogloea) or synthesizing resistant proteins (e.g., Thauera, Candidatus Accumulibacter, Candidatus Competibacter, and Dechloromonas) in the SBRs. Inhibition was observed to be the main effect of ERY-H2O and ERY on microbial communities in the reactors. The results would broaden our knowledge of effects of low-dose antibiotics on microbial communities in WWTPs. PMID- 24072161 TI - Effect of temperature and sorbitol in improving the solubility of carboxylesterases protein CpCE-1 from Cydia pomonella and biochemical characterization. AB - Carboxylesterases (CEs) are enzymes responsible for the detoxification of insecticides in insects. In the Cydia pomonella, CEs are involved in synthetic pyrethroid, neonicotinoid, carbamate, and organophosphate detoxification. However, functional overexpression of CEs proteins in Escherichia coli systems often results in insoluble proteins. In this study, we expressed the fusion protein CpCE-1 in E. coli BL21 (DE3). This recombinant protein was overexpressed as inclusion bodies at 37 degrees C whereas it produced a higher percentage of soluble protein at lower growth temperatures. Production of soluble proteins and enzyme activity increased in the presence of sorbitol in the growth medium. The fusion protein was purified from the lysate supernatant using a Ni(2+)-NTA agarose gel column. The enzyme exhibited a higher affinity and substrate specificity for alpha-naphthyl acetate (alpha-NA), with k cat/K m of 100 s(-1) MUM(-1) for alpha-NA, and the value is 29.78 s(-1) MUM(-1) for beta-naphthyl acetate. The V max and K m were also determined to be 12.9 MUmol/min/mg protein and 13.4 MUM using substrate alpha-NA. The optimum pH was 7.0 and temperature was 25 degrees C. An enzyme inhibition assay shows that PMSF and DEPC strongly inhibit the enzyme activity, while the metal ions Cu(2+) and Mg(2+) significantly activated the activity. More importantly, cypermethrin, methomyl, and acephate were found to suppress enzyme activity. The data demonstrated here provide information for heterologous expression of soluble protein and further study on insecticide metabolism in C. pomonella in vitro. This is the first report of the characterization of CEs protein from C. pomonella. PMID- 24072162 TI - Comparison of (stereotactic) parcellations in mouse prefrontal cortex. AB - This study compares the cytoarchitectonic parcellation of the prefrontal cortex (PFC) in the mouse as presented in publications that are commonly used for identifying brain areas. Agreement was found to be greater for boundaries in the medial PFC than in the lateral PFC and lowest for those in the orbital areas of the PFC. In this review, we explain and illustrate in a selected series of photographs and stereotactic pictures the differences in location and terminology of the different prefrontal cortical areas. The significance of cytoarchitectonic parcellation is discussed. PMID- 24072163 TI - MRI anatomical variants of mammillary bodies. AB - The mammillary bodies (MBs) are classically defined as a pair of small round structures located on the undersurface of the diencephalon. The systematic observation of MR brain images of patients with neurological diseases, but also of healthy subjects enrolled in research protocols, reveals, however, a greater anatomical variability. The aim of the present study was to define the spectrum of such variability using spatial normalized 3D TFE T1-weighted MR images in a group of 151 healthy right-handed young subjects (78 females, age range 16-39 years). The MBs were identified on reformatted coronal and axial images and classified according to morphological, positional and numerical criteria. On the basis of coronal images, MBs were first divided into symmetrical (86.1 %) and asymmetrical (13.9 %), depending on their respective height. Symmetrical MBs were further subdivided into three variants [type A (2.7 %), B (76.2 %), C (7.3 %)] according to the depth of the intermammillary sulcus. Two morphological variants were defined on axial images, depending on whether the MBs were circular (63.6 %) or elliptic (36.4 %). This latter group was further divided in two subgroups, depending on whether the MBs were parallel (21.9 %) or convergent (14.6 %). Finally, two subjects (1.3 %) presented a supernumeral MB. The transverse size of the third ventricle was greater in the type A compared to the type B and C groups. Gender did not significantly affect the frequency of MBs variants, except for the three symmetrical subgroups in which the variants A and C were more frequent in males than in females. These findings suggest the presence of an anatomical variability of the MBs, in contrast to their classical definition. Therefore, atypical presentation of MBs can be the expression of this variability rather than a marker of neurological disorders (i.e. cerebral malformation, mesial temporal sclerosis, Wernicke-Korsakoff syndrome). PMID- 24072164 TI - Multivariate classification of social anxiety disorder using whole brain functional connectivity. AB - Recent research has shown that social anxiety disorder (SAD) is accompanied by abnormalities in brain functional connections. However, these findings are based on group comparisons, and, therefore, little is known about whether functional connections could be used in the diagnosis of an individual patient with SAD. Here, we explored the potential of the functional connectivity to be used for SAD diagnosis. Twenty patients with SAD and 20 healthy controls were scanned using resting-state functional magnetic resonance imaging. The whole brain was divided into 116 regions based on automated anatomical labeling atlas. The functional connectivity between each pair of regions was computed using Pearson's correlation coefficient and used as classification feature. Multivariate pattern analysis was then used to classify patients from healthy controls. The pattern classifier was designed using linear support vector machine. Experimental results showed a correct classification rate of 82.5 % (p < 0.001) with sensitivity of 85.0 % and specificity of 80.0 %, using a leave-one-out cross-validation method. It was found that the consensus connections used to distinguish SAD were largely located within or across the default mode network, visual network, sensory-motor network, affective network, and cerebellar regions. Specifically, the right orbitofrontal region exhibited the highest weight in classification. The current study demonstrated that functional connectivity had good diagnostic potential for SAD, thus providing evidence for the possible use of whole brain functional connectivity as a complementary tool in clinical diagnosis. In addition, this study confirmed previous work and described novel pathophysiological mechanisms of SAD. PMID- 24072165 TI - Obesity and vascular disease: from bench to bedside. PMID- 24072166 TI - Simultaneous measurement of thrombin and plasmin generation to assess the interplay between coagulation and fibrinolysis. AB - Normal haemostasis is maintained by a controlled balance between coagulation and fibrinolysis, involving thrombin and plasmin the respective key enzymes. Simultaneous evaluation of both enzymes facilitates, therefore, an overall understanding of normal and pathological haemostasis. Combined thrombin and plasmin generation (T/P-G) assays have been recently described, and we have adapted the technique to investigate the interplay between coagulation and fibrinolysis in patients with various haemostatic disorders. Our modified T/P-G was initiated by the addition of a mixture of optimised lower concentrations of tissue factor and tissue-type plasminogen activator. Thrombin generation (TG) and plasmin generation (PG) were monitored simultaneously using individual fluorescent substrates in separate microtitre wells. The relationship between coagulation and fibrinolysis was demonstrated by analysing the effects of thrombin inhibitors, activated protein C and thrombomodulin. The most evident impairments in TG were observed with plasma samples deficient of coagulation factors participating in the prothrombinase complex. Defects in PG were observed with deficiencies of factor (F)V, FX, fibrinogen, and plasminogen. TG appeared to be a prerequisite for the initiation of PG, and overall PG was governed by fibrinogen concentration. TG in patients with haemophilia A correlated with levels of FVIII activity, but there was no significant relationship between PG and FVIII:C, confirming that the abnormal haemostasis in haemophilia A results in a severe imbalance between coagulation and fibrinolysis. The findings demonstrate that global haemostasis depends on a sensitive balance between coagulation and fibrinolysis, and that the modified T/P-G assay could provide an enhanced understanding of haemorrhage and thrombosis in clinical practice. PMID- 24072167 TI - Oral antibiotic treatment of staphylococcal bone and joint infections in adults. AB - Bone and joint infections, especially implant-associated infections, are difficult to cure. Long-term antibiotic therapy, combined with appropriate surgery and the removal of prostheses, is required. The most common causative organisms in bone and joint infections are staphylococci. Oral agents are often used after an initial course of parenteral antibiotic treatment. However, it is unclear which oral regimens are most effective in staphylococcal bone and joint infections. We review various oral antibiotic regimens and discuss which regimens are effective for this indication. PMID- 24072168 TI - INQ-1, a chromosome-encoded AmpC beta-lactamase from Inquilinus limosus. PMID- 24072169 TI - Mutation rate and the emergence of drug resistance in Mycobacterium tuberculosis. AB - The emergence and spread of multidrug-resistant strains of Mycobacterium tuberculosis remains a major concern of tuberculosis control programmes worldwide, as treatment depends on low-efficacy, toxic compounds that often lead to poor outcomes. M. tuberculosis develops drug resistance exclusively through chromosomal mutations, in particular single-nucleotide polymorphisms. Moreover, in laboratory assays the organism exhibits a spontaneous mutation rate that is at the lower end of the bacterial spectrum. Despite this, whole-genome sequencing technology has identified unexpected genetic diversity among clinical M. tuberculosis populations. This suggests that the mycobacterial mutation rate may be modulated within the host and, in turn, implies a potential role for constitutive and/or transient mutator strains in adaptive evolution. It also raises the possibility that environmental factors might act as key mutagens during M. tuberculosis infection. Here we consider the elements that might influence the mycobacterial mutation rate in vivo and evaluate the potential roles of constitutive and transient mutator states in the generation of drug resistance mutations. In addition, we identify key research questions that will influence future efforts to develop novel therapeutic strategies for a disease that continues to impose a significant global health burden. PMID- 24072170 TI - Persister populations of Mycobacterium tuberculosis in sputum that grow in liquid but not on solid culture media. AB - OBJECTIVES: Can the characteristics of persisters in cultures of Mycobacterium tuberculosis also be found in bacilli from the sputum of pulmonary tuberculosis patients? The objective of this study was to explore whether the ability of persisters to grow in liquid but not on solid culture media, as in 100 day static cultures, can also be found in bacilli in sputum. METHODS: Serial dilutions of homogenized sputum obtained from patients before or during the first week of treatment were inoculated into broths to estimate the probable number of organisms and onto plates to give colony counts. RESULTS: Cultures in broths grew slowly to reach a maximal count at 12 weeks of probable numbers about 10-fold higher than the colony counts on plates, which did not grow beyond the initial count at 3-4 weeks. No such excess growth in liquid medium was found with control log-phase cultures. CONCLUSIONS: About 90% of the bacilli in sputum are persisters that can grow in liquid media but not on solid plates. PMID- 24072171 TI - Emergence of extended-spectrum beta-lactamase (ESBL) CTX-M-8 in Germany. PMID- 24072172 TI - High genetic diversity of methicillin-susceptible Staphylococcus aureus (MSSA) from humans and animals on livestock farms and presence of SCCmec remnant DNA in MSSA CC398. AB - OBJECTIVES: To investigate the genetic diversity of methicillin-susceptible Staphylococcus aureus (MSSA) carriage isolates from animals and humans on pig, veal, dairy, beef and broiler farms. METHODS: S. aureus isolates were genotyped using spa typing and multilocus sequence typing (MLST). Antimicrobial susceptibility phenotypes and genotypes were determined. The presence of staphylococcal cassette chromosome mec (SCCmec)-associated DNA was characterized by PCR and sequencing among isolates of clonal complex (CC) 398. RESULTS: Overall, 41 MSSA isolates in humans and 141 in animals were found, originating from all farm types. These MSSA were mainly assigned to CC398, CC1, CC5, CC9, CC30, CC97, CC133 and CC705/151. MSSA CC398 showed resistance to tetracycline, trimethoprim, macrolides and/or lincosamides, aminoglycosides, ciprofloxacin, spectinomycin and quinupristin/dalfopristin, whereas non-CC398 MSSA showed considerably less resistance. Three porcine MSSA CC398-t011 isolates harboured remnant DNA of a composite SCCmec V(5C2&5)c element that lacked the mec gene complex. This resulted from an MRSA-to-MSSA conversion due to recombination between the ccrC genes flanking the mec gene complex. The SCC remnant still contained an intact J1 region harbouring czrC and tet(K), encoding zinc and tetracycline resistance, respectively, thereby illustrating the capacity of S. aureus CC398 to adapt to different antibiotic selection pressures in the farming environment. Processes such as mec gene complex deletion probably contribute to the enormous diversity of SCC(mec) elements observed in staphylococci. CONCLUSIONS: MSSA CC398 precursors from which MRSA CC398 might (re)emerge were present on pig, veal and broiler farms, all of which are livestock sectors commonly known to be affected by MRSA CC398. The multiresistance phenotype of S. aureus CC398 appears to be independent of methicillin resistance. PMID- 24072173 TI - Independent predictors of bleeding complications in patients undergoing PCI with concomitant treatment with bivalirudin in clinical practice results from the ImproveR registry. AB - BACKGROUND: Bleeding complications are associated with an adverse outcome after a percutaneous coronary intervention (PCI) is performed. Traditional risk factors for bleeding complications are age, gender, underweight, hypertension, and renal impairment. The aim of our study was to identify the independent predictors of bleeding complications in patients undergoing a PCI with concomitant treatment with bivalirudin. METHODS: Between January 2005 and June 2006, a total of 3799 patients, undergoing a planned or urgent PCI with concomitant bivalirudin treatment, were prospectively enrolled in the ImproveR registry. One hundred two centers out of 12 European countries participated in the ImproveR registry. In this analysis, we report the incidence of bleeding complications in subgroups to be at a high risk for developing bleeding complications. A multivariate logistic regression model was performed to identify the independent predictors of bleeding complications. RESULTS: Major bleeding complications occurred in 1.7% of the patients. The highest incidence of major bleeding complications was observed in the subgroup with a sheath size >=7F (4.3%), heparin use after the PCI (3.5%), and additional use of GP IIb/IIIa inhibitors (3.3%). The multivariate regression analysis revealed female gender [odds ratio (OR), 2.3; 95% confidence interval (CI), 1.4-3.8], heparin after the PCI (OR, 3.1; 95% CI, 1.9-5.1), and sheath size >=7F (OR, 3.1; 95% CI, 1.8-5.4) as the independent predictors of bleeding. CONCLUSIONS: The rate of occurrence of bleeding complications in patients undergoing a PCI with concomitant use of bivalirudin is low in clinical practice. Female gender and procedural factors, such as sheath size and heparin after PCI, were associated with an increase in bleeding complications, whereas other traditional risk factors associated with bleeding, such as age, diabetes mellitus, and renal impairment, had no impact. PMID- 24072175 TI - Salidroside improves doxorubicin-induced cardiac dysfunction by suppression of excessive oxidative stress and cardiomyocyte apoptosis. AB - Doxorubicin (DOX) is a potent available antitumor drug; however, its clinical use is limited by the cardiotoxicity. Salidroside (SLD), with strong antioxidative and cytoprotective actions, is of particular interest in the development of antioxidative therapies for oxidative injury in cardiac diseases. Now, the protection and underlying mechanisms of SLD against DOX-induced cardiotoxicity are still unknown. In the present study, we revealed both antioxidative mechanism and Bcl2-dependent survival signaling involved in SLD's protection. We observed that DOX exposure induced mortality elevation, body weight loss, and cardiac dysfunction in mice, increased lactate dehydrogenase leakage and cardiomyocyte apoptosis, but decreased cell viability and size in cardiac tissues and cultured H9c2 cells, respectively, which were effectively antagonized by SLD supplement. We further observed that SLD significantly reduced the intercellular oxidative stress level, partly by inhibiting NOX1 expression and augmenting the expression and activities of the endogenous antioxidative enzymes, catalase, and manganese superoxide dismutase. In addition, SLD treatment upregulated the antiapoptotic Bcl2 and downregulated the proapoptotic Bax and inhibited a downstream pathway of Bcl2/Bax and caspase-3 activity. Our results indicated that SLD effectively protected the cardiomyocytes against DOX-induced cardiotoxicity by suppressing the excessive oxidative stress and activating a Bcl2-mediated survival signaling pathway. PMID- 24072174 TI - The immune system and the remodeling infarcted heart: cell biological insights and therapeutic opportunities. AB - Extensive necrosis of ischemic cardiomyocytes in the infarcted myocardium activates the innate immune response triggering an intense inflammatory reaction. Release of danger signals from dying cells and damaged matrix activates the complement cascade and stimulates Toll-like receptor/interleukin-1 signaling, resulting in the activation of the nuclear factor-kappaB system and induction of chemokines, cytokines, and adhesion molecules. Subsequent infiltration of the infarct with neutrophils and mononuclear cells serves to clear the wound from dead cells and matrix debris, while stimulating reparative pathways. In addition to its role in repair of the infarcted heart and formation of a scar, the immune system is also involved in adverse remodeling of the infarcted ventricle. Overactive immune responses and defects in suppression, containment, and resolution of the postinfarction inflammatory reaction accentuate dilative remodeling in experimental models and may be associated with chamber dilation, systolic dysfunction, and heart failure in patients surviving a myocardial infarction. Interventions targeting the inflammatory response to attenuate adverse remodeling may hold promise in patients with myocardial infarction that exhibit accentuated, prolonged, or dysregulated immune responses to the acute injury. PMID- 24072176 TI - Research progress of warfarin-associated vascular calcification and its possible therapy. AB - Vascular calcification is a common comorbidity in elderly patients with diabetes mellitus or renal insufficiency. A large number of studies have shown that vascular calcification can be induced and accelerated in patients undergoing long term treatment with warfarin, leading to some severe complications, such as hypertension, atherosclerosis, valvular calcification, and coronary calcification, especially in the population with atrial fibrillation, hemodialysis, and chronic kidney disease. Warfarin inhibits the activation of vitamin K-dependent coagulation factors and affects the function of vitamin K dependent proteins via interference of the vitamin K cycle by antagonizing vitamin K. One of its consequences is adverse effects on the expression and function of matrix Gla protein, one of the important vitamin K-dependent proteins. Matrix Gla protein acts as an inhibitor of vascular calcification by blocking bone morphogenetic protein signaling or promoting the phagocytosis of apoptotic bodies; moreover, it restrains the formation of calcification directly resulting in the promotion of vascular calcification. This article also discusses the various treatments for vascular calcification caused by warfarin. PMID- 24072178 TI - Discharge use of carvedilol is associated with higher survival in Japanese elderly patients with heart failure regardless of left ventricular ejection fraction. AB - Previous clinical trials have proven beneficial effects of beta-blockers in patients with heart failure (HF) with reduced ejection fraction (EF). However, those studies excluded elderly patients from the subjects or included only a small number of them. We assessed whether beta-blocker treatment with carvedilol improves survival in elderly patients with HF regardless of left ventricular EF (LVEF). We retrospectively analyzed a total of 189 patients older than 75 years who were hospitalized with HF from January 2004 to December 2010. Of these, 84 patients (44%) had been treated with carvedilol at discharge. Patients treated with carvedilol were younger, were less likely to have chronic obstructive pulmonary disease, and had lower LVEF compared with those without carvedilol (all P < 0.05). During the median follow-up of 2.5 years after discharge, 92 patients died. Cox hazard analysis showed that, even after adjustment for covariates, carvedilol significantly decreased all-cause mortality in this cohort (P < 0.01). Furthermore, a beneficial effect on outcome was found in patients with reduced (LVEF <= 40%) and preserved (LVEF > 40%) EF (all P < 0.05). In conclusion, Beta blockers may provide beneficial effects on Japanese elderly patients with HF regardless of LVEF. PMID- 24072177 TI - Cardiac titin and heart disease. AB - The giant sarcomeric protein titin is a key determinant of myocardial passive stiffness and stress-sensitive signaling. Titin stiffness is modulated by isoform variation, phosphorylation by protein kinases, and, possibly, oxidative stress through disulfide bond formation. Titin has also emerged as an important human disease gene. Early studies in patients with dilated cardiomyopathy (DCM) revealed shifts toward more compliant isoforms, an adaptation that offsets increases in passive stiffness based on the extracellular matrix. Similar shifts are observed in heart failure with preserved ejection fraction. In contrast, hypophosphorylation of PKA/G sites contributes to a net increase in cardiomyocyte resting tension in heart failure with preserved ejection fraction. More recently, titin mutations have been recognized as the most common etiology of inherited DCM. In addition, some DCM-causing mutations affect RBM20, a titin splice factor. Titin mutations are a rare cause of hypertrophic cardiomyopathy and also underlie some cases of arrhythmogenic right ventricular dysplasia. Finally, mutations of genes encoding proteins that interact with and/or bind to titin are responsible for both DCM and hypertrophic cardiomyopathy. Targeting titin as a therapeutic strategy is in its infancy, but it could potentially involve manipulation of isoforms, posttranslational modifications, and upregulation of normal protein in patients with disease-causing mutations. PMID- 24072179 TI - Pharmacological modulation of small GTPases in cardiovascular diseases: from statins to selective inhibitors. PMID- 24072180 TI - A novel protecting group methodology for syntheses using nitroxides. AB - The methoxyamine group represents an ideal protecting group for the nitroxide moiety. It can be easily and selectively introduced in high yield (typically >90%) to a range of functionalised nitroxides using FeSO4.7H2O and H2O2 in DMSO. Its removal is readily achieved under mild conditions in high yield (70-90%) using mCPBA in a Cope-type elimination process. PMID- 24072181 TI - Characterization of gene expression and activated signaling pathways in solid pseudopapillary neoplasm of pancreas. AB - Solid-pseudopapillary neoplasm is an uncommon pancreatic tumor with distinct clinicopathologic features. Solid-pseudopapillary neoplasms are characterized by mutations in exon 3 of CTNNB1. However, little is known about the gene and microRNA expression profiles of solid-pseudopapillary neoplasms. Thus, we sought to characterize solid-pseudopapillary neoplasm-specific gene expression and identify the signaling pathways activated in these tumors. Comparisons of gene expression in solid-pseudopapillary neoplasm to pancreatic ductal carcinomas, neuroendocrine tumors, and non-neoplastic pancreatic tissues identified solid pseudopapillary neoplasm-specific mRNA and microRNA profiles. By analyzing 1686 (1119 upregulated and 567 downregulated) genes differentially expressed in solid pseudopapillary neoplasm, we found that the Wnt/beta-catenin, Hedgehog, and androgen receptor signaling pathways, as well as genes involved in epithelial mesenchymal transition, are activated in solid-pseudopapillary neoplasms. We validated these results experimentally by assessing the expression of beta catenin, WIF-1, GLI2, androgen receptor, and epithelial-mesenchymal transition related markers with western blotting and immunohistochemistry. Our analysis also revealed 17 microRNAs, especially the miR-200 family and miR-192/215, closely associated with the upregulated genes associated with the three pathways activated in solid-pseudopapillary neoplasm and epithelial mesenchymal transition. Our results provide insight into the molecular mechanisms underlying solid-pseudopapillary neoplasm tumorigenesis and its characteristic less epithelial cell differentiation than the other common pancreatic tumors. PMID- 24072182 TI - Targeted development of specific biomarkers of endometrial stromal cell differentiation using bioinformatics: the IFITM1 model. AB - When classifying cellular uterine mesenchymal neoplasms, histological distinction of endometrial stromal from smooth muscle neoplasms can be difficult. The only widely established marker of endometrial stromal differentiation, CD10, has marginal specificity. We took a bioinformatics approach to identify more specific markers of endometrial stromal differentiation by searching the Human Protein Atlas, a public database of protein expression profiles. After screening the database using different methods, interferon-induced transmembrane protein 1 (IFITM1) was selected for further analysis. Immunohistochemistry for IFITM1 was performed using tissue sections from the selected cases of proliferative endometrium (22), secretory endometrium (6), inactive endometrium (19), adenomyosis (10), conventional leiomyoma (11), cellular leiomyoma (16), endometrial stromal nodule (2), low-grade endometrial stromal sarcoma (16), high grade endometrial stromal sarcoma (2) and undifferentiated uterine sarcoma (2). Stained slides were scored in terms of intensity and distribution. Normal endometrial samples uniformly showed diffuse and strong IFITM1 staining. Endometrial stromal neoplasms, particularly low-grade endometrial stromal sarcoma, showed higher IFITM1 expression compared with smooth muscle neoplasms (P<0.0001). IFITM1 immunohistochemistry has high sensitivity and specificity, particularly in the distinction between low-grade endometrial stromal sarcoma and leiomyoma (81.2 and 86.7%, respectively). Our results indicate that IFITM1 is a sensitive and specific marker of endometrial stromal differentiation across the spectrum from proliferative endometrium to metastatic stromal sarcoma. IFITM1 is a potential valuable addition to immunohistochemical panels used in the diagnosis of cellular mesenchymal uterine tumors. Further studies with larger number of cases are necessary to corroborate this impression and determine the utility of IFITM1 in routine practice. This study is a clear example of how bioinformatics, particularly tools for mining genomic and proteomic databases, can enhance and accelerate biomarker development in diagnostic pathology. PMID- 24072183 TI - ERG and FLI1 protein expression in epithelioid sarcoma. AB - Epithelioid sarcoma is a rare, aggressive keratin-positive sarcoma that co expresses CD34 in 50% of cases and may mimic an angiosarcoma. Recently, we have observed one case of epithelioid sarcoma that labeled for ERG, an ETS family regulatory transcription factor, which is considered to be a reliable marker for vascular differentiation. We investigated the prevalence of nuclear expression of ERG and FLI1, a homologous transcription factor, in these tumors. A formalin fixed paraffin-embedded tissue microarray of 37 epithelioid sarcomas was examined. Immunohistochemistry was performed using anti-ERG monoclonal antibody to the N-terminus, anti-ERG monoclonal antibody to the C-terminus and anti-FLI1 monoclonal antibody. Comparison was made with CD34, CD31, and D2-40 labeling. The extent of immunoreactivity was graded according to the percentage of positive tumor cell nuclei (0: no staining; 1+: <5%; 2+: 5-25%; 3+: 26-50%; 4+: 51-75%; and 5+: 76-100%), and the intensity of staining was graded as weak, moderate, or strong. Nuclear staining for the N-terminus of ERG was seen in 19 out of 28 cases: 10 with diffuse(4 to 5+) strong/moderate labeling; 1 with 2+ moderate labeling and 8 with weak labeling (1 to 4+, 2 each). Focal staining for the C terminus of ERG was seen in only 1 out of 29 cases (2+ moderate). FLI1 labeling was seen in nearly all (28 out of 30) cases: 16 with diffuse (5+) predominantly moderate labeling, and 8 cases with diffuse(5+) weak labeling. The remainder had variable moderate (1 to 3+) or weak (1 to 4+) FLI1 staining. CD34 was positive in 22 out of 30 cases and D2-40 was found to be positive in 22 out of 31 cases. All cases were negative for CD31 (0 out of 30). Epithelioid sarcoma can label with antibodies to the N-terminus of ERG, FLI1, and D2-40, which may cause diagnostic confusion for a vascular tumor. A panel of other antibodies including SMARCB1 and CD31 should be used in evaluating these tumors. ERG antibody selection is also critical, as those directed against the C-terminus are less likely to label epithelioid sarcoma. PMID- 24072185 TI - Volume shrinkage of a metal-organic framework host induced by the dispersive attraction of guest gas molecules. AB - Using a density functional theory calculation including van der Waals (vdW) corrections, we report that H2 adsorption in a cubic-crystalline microporous metal-organic framework (MOF-5) leads to volume shrinkage, which is in contrast to the intuition that gas adsorption in a confined system (e.g., pores in a material) increases the internal pressure and then leads to volumetric expansion. This extraordinary phenomenon is closely related to the vdW interactions between MOF and H2 along with the H2-H2 interaction, rather than the Madelung-type electrostatic interaction. At low temperatures, H2 molecules adsorbed in the MOF 5 form highly symmetrical interlinked nanocages that change from a cube-like shape to a sphere-like shape with H2 loading, helping to exert centrosymmetric forces and hydrostatic (volumetric) stresses from the collection of dispersive interactions. The generated internal negative stress is sufficient to overcome the stiffness of the MOF-5 which is a soft material with a low bulk modulus (15.54 GPa). PMID- 24072186 TI - Angular dependence of the magnetoresistance in nanoparticle arrays. AB - The interplay between the ferromagnetism and the charging effects strongly affects the electron transport through nanoparticle arrays when they are placed between two ferromagnetic electrodes with collinear magnetizations. There are oscillations in the current for the parallel orientation of magnetizations, and large values of the tunneling magnetoresistance (TMR). We analyze the transport properties in nanoparticle arrays for the case of noncollinear magnetizations. We show that the I-V and TMR curves strongly depend on the angle theta between the magnetization orientations of both electrodes. Large values of TMR are obtained for several values of theta. PMID- 24072184 TI - Evaluation of tissue PCA3 expression in prostate cancer by RNA in situ hybridization--a correlative study with urine PCA3 and TMPRSS2-ERG. AB - PCA3 is a prostate-specific non-coding RNA, with utility as a urine-based early detection biomarker. Here, we report the evaluation of tissue PCA3 expression by RNA in situ hybridization in a cohort of 41 mapped prostatectomy specimens. We compared tissue PCA3 expression with tissue level ERG expression and matched pre prostatectomy urine PCA3 and TMPRSS2-ERG levels. Across 136 slides containing 138 foci of prostate cancer, PCA3 was expressed in 55% of cancer foci and 71% of high grade prostatic intraepithelial neoplasia foci. Overall, the specificity of tissue PCA3 was >90% for prostate cancer and high-grade prostatic intraepithelial neoplasia combined. Tissue PCA3 cancer expression was not significantly associated with urine PCA3 expression. PCA3 and ERG positivity in cancer foci was positively associated (P<0.01). We report the first comprehensive assessment of PCA3 expression in prostatectomy specimens, and find limited correlation between tissue PCA3 and matched urine in prostate cancer. PMID- 24072187 TI - How a disaster preparedness rotation helps teach the seven NAVMEC professional competencies: the Texas A&M University Experience. AB - Changing societal expectations provide new challenges and opportunities for the veterinary medical profession. These changing expectations and approaches to the education of veterinary students in the future are reflected in the North American Veterinary Medical Education Consortium's report "Roadmap for Veterinary Medical Education in the 21st Century: Responsive, Collaborative, Flexible." They are also reflected in the expectations of the populace, who no longer find it acceptable that animals are not included in both planning for and responding to natural or manmade disasters. In response to the changing needs of society and the veterinary profession, Texas A&M University College of Veterinary Medicine has developed a required rotation in the fourth-year curriculum on emergency planning and response. The unique requirements of emergency preparedness and response and the design of the rotation provide an ideal platform for providing this valued public service while simultaneously addressing the seven professional competencies outlined in the NAVMEC roadmap. This article describes an overview of the rotation and its content and identifies opportunities for students to practice these important professional competencies using the tools introduced in this new rotation. PMID- 24072188 TI - Benefits and limitations of an employer-led, structured logbook to promote self directed learning in the clinical workplace. AB - A structured logbook, consisting of a competency log and a learning contract, was designed and implemented as part of a two-week structured work placement for final-year veterinary students to help them become more self-directed in the workplace. The competency log encompassed 48 core skills and, along with the learning contract, was reviewed at the start and end of the placement. To assess their perceptions of the logbook in promoting self-directed learning, students and supervisors were asked to complete a questionnaire pre- and post-placement and to participate in focus groups (students) and interviews (supervisors) after the placement. The study found significant increases pre- to post-placement in students' perceived levels of competence in all 48 skills and their confidence in being self-directed. However, student attitudes toward the logbook significantly decreased in terms of it encouraging supervisors to take a clearly designed role in structuring learning and facilitating alignment of employer and student expectations. Although supervisors were generally positive about the logbook, some had not been able to review it with their students, which affected students' perceptions of the logbook's usefulness. Some supervisors felt they had not received enough training, and most, erroneously, believed the logbook to be an external research initiative rather than having been designed by the head of their own organization. This study demonstrated that a structured logbook may be useful in helping students become more self-directed; however, supervisor support for the logbook is critical. To facilitate this, supervisors require training and support from senior management. PMID- 24072189 TI - The impact of using a veterinary medicine activity book in the classroom on fifth and sixth-grade students' depictions of veterinarians. AB - Efforts to develop a diverse, future veterinary workforce must start as early as elementary school, when children begin to form perceptions about careers. The objective of the current project was to determine the impact of the Veterinary Medicine Activity Book: Grade 5 on fifth- and sixth-grade students' depictions of veterinarians. The book was delivered as part of the curriculum in four classrooms. Students were asked to draw a veterinarian and describe the veterinarian's activities before and after being exposed to the book. Drawings were evaluated for the gender and race/ethnicity of the illustrated veterinarian, the description of the veterinarian's activity, and animals portrayed. Significant differences were detected within three of four classrooms. In one class, after exposure to the activity book, more students drew male veterinarians and veterinarians performing an activity specifically mentioned in the book. In a second class, more students drew large animals after exposure to the activity book. In a third class, after exposure to the activity book, more students drew large animals and veterinarians performing an activity specifically mentioned in the book. Results provide preliminary evidence that children's depictions of veterinarians can be altered through use of educational materials delivered in classrooms through teacher-led discussion or formal lesson plans. PMID- 24072190 TI - Curriculum asset mapping for One Health education. AB - The major premise of One Health is engagement of multiple disciplines to address shared problems spanning human, animal, and ecosystem health. The current model of academic specialization encourages development of isolated disciplines within the university setting, thereby creating barriers to resource sharing and academic collaboration. The aim of this project was to develop a systematic approach to mapping university assets that could be harnessed to advance One Health education. Asset in this context was defined as a course, program, or faculty expertise relevant to a particular One Health problem. The approach adopted comprised the following steps: (1) identify a current problem that would benefit from an integrated, interdisciplinary perspective (e.g., EIDs [emerging infectious diseases]); (2) identify individual disciplinary teaching areas pertinent to the problem (e.g., health communication, wildlife ecology); (3) identify competencies expected to be attained by graduates who will address the problem (e.g., respond to outbreaks); (4) survey faculty members on their teaching areas and curricular offerings that address these competencies; and (5) compile responses in a database that is searchable by teaching area and competency. We discuss our recent experiences mapping the assets at Tufts University that are relevant to the problem of EIDs with emphasis on zoonotic disease surveillance, outbreak investigation, and outbreak response. Using 13 teaching areas and 16 competencies relevant to applied epidemiology, we identified and characterized previously untapped resources across the university. Asset mapping is thus a useful tool for identifying university resources and opportunities that can be leveraged to support interdisciplinary education for One Health. PMID- 24072191 TI - A new educational resource to improve veterinary students' animal welfare learning experience. AB - A computer-aided learning (CAL) educational resource based on experiential learning principles has been developed. Its aim is to improve veterinary students' ability to critically review the effect on welfare of husbandry systems observed during their work placement on sheep farms. The CAL consisted of lectures, multiple-choice questions, video recordings of animals in various husbandry conditions, open questions, and concept maps. An intervention group of first-year veterinary students (N=31) was selected randomly to access the CAL before their sheep farm placement, and a control group (N=50) received CAL training after placement. Assessment criteria for the categories remember, understand, apply, analyze, evaluate, and create, based on Bloom's revised taxonomy, were used to evaluate farm reports submitted by all students after their 2-week placement. Students in the intervention group were more likely than their untrained colleagues (p<.05) to remember and understand animal-based measurements relating to the freedom from hunger and thirst; the freedom from discomfort; and the freedom from pain, injury, or disease. Intervention group students were also more likely to analyze the freedom from pain, injury, or disease and the freedom to exhibit normal behavior and to evaluate the freedom from fear and distress. Relatively few students in each group exhibited creativity in their reports. These findings indicate that use of CAL before farm placement improved students' ability to assess and report animal welfare as part of their extramural work experience. PMID- 24072192 TI - Cryopreservation of arbuscular mycorrhizal fungi from root organ and plant cultures. AB - Long-term maintenance of arbuscular mycorrhizal fungi (AMF) by in vitro or in vivo subcultivation is often expensive and time-consuming and could present the risk of contaminations and possibly morphological, physiological, and genetic variations over time. Recently, in vitro produced AMF isolates belonging to the genus Rhizophagus were successfully cryopreserved at -130 degrees C following encapsulation-drying. Here, this method was tested on 12 single species cultures belonging to six different genera (i.e., Rhizophagus, Glomus, Claroideoglomus, Septoglomus, Paraglomus, and Gigaspora) produced in vitro or in vivo. Their viability was estimated, after 1 month of cryopreservation at -130 degrees C, by the percentage of potentially infective beads (i.e., the percentage of beads that contained at least one germinated propagule) for the in vitro produced species and the percentage of infective beads (i.e., the percentage of beads that contained at least one propagule able to colonize a new host plant in pot culture) for the in vivo produced species. With the exception of Gigaspora sp. MUCL 52331 and Septoglomus constrictus PER 7.2, no significant differences were observed in the viability of the single species cultures before and after cryopreservation. These results, thus, demonstrated the suitability of the cryopreservation method by encapsulation-drying for AMF species belonging to different genera and produced in vitro or in vivo. This method opens the door to the long-term preservation at ultra-low temperature of a large number of AMF species and for the preservation of species that are still recalcitrant to in vitro cultivation. PMID- 24072193 TI - The arbuscular mycorrhizal symbiosis attenuates symptom severity and reduces virus concentration in tomato infected by Tomato yellow leaf curl Sardinia virus (TYLCSV). AB - The arbuscular mycorrhizal (AM) symbiosis is considered a natural instrument to improve plant health and productivity since mycorrhizal plants often show higher tolerance to abiotic and biotic stresses. However, the impact of the AM symbiosis on infection by viral pathogens is still largely uncertain and little explored. In the present study, tomato plants were grown under controlled conditions and inoculated with the AM fungus Funneliformis mosseae. Once the mycorrhizal colonization had developed, plants were inoculated with the Tomato yellow leaf curl Sardinia virus (TYLCSV), a geminivirus causing one of the most serious viral diseases of tomatoes in Mediterranean areas. Biological conditions consisted of control plants (C), TYLCSV-infected plants (V), mycorrhizal plants (M), and TYLCSV-infected mycorrhizal plants (MV). At the time of analysis, the level of mycorrhiza development and the expression profiles of mycorrhiza-responsive selected genes were not significantly modified by virus infection, thus indicating that the AM symbiosis was unaffected by the presence and spread of the virus. Viral symptoms were milder, and both shoot and root concentrations of viral DNA were lower in MV plants than in V plants. Overall F. mosseae colonization appears to exert a beneficial effect on tomato plants in attenuating the disease caused by TYLCSV. PMID- 24072194 TI - High rates of anal dysplasia in HIV-infected men who have sex with men, women, and heterosexual men. AB - OBJECTIVE: To determine rates of anal dysplasia in a cohort of HIV-infected men who have sex with men (MSM), women, and heterosexual men with abnormal anal cytology. DESIGN/METHODS: We evaluated histologic findings in 728 HIV-infected MSM, women, and heterosexual men referred for high-resolution anoscopy (HRA) after abnormal anal cytology in a single-center cohort study. Using multivariable logistic regression, we evaluated predictors of high-grade squamous intraepithelial lesion (HSIL) histology or invasive carcinoma including age, sexual behavior, receptive anal intercourse (RAI), anogenital warts, smoking status, antiretroviral therapy, CD4 T-cell count, and HIV-1 plasma viral load. RESULTS: A total of 2075 HIV-positive patients were screened with anal cytology and 62% of MSM, 42% of women, and 29% of heterosexual men had abnormal findings (P <0.001). Of the 728 HIV-infected patients with abnormal anal cytology who underwent HRA, 71% were MSM, 23% women, and 6% heterosexual men. HSIL/cancer was found in 32% of MSM, 26% of women, and 23% of heterosexual men (P = 0.3). There were five cases of anal squamous cell carcinoma (0.7%), four in MSM and one in a heterosexual man. In a multivariable adjusted analysis, biopsy-proven HSIL/cancer was associated with RAI [odds ratio (OR) 2.2; 95% confidence interval (CI) 1.3 3.7]. CD4 T-cell counts more than 500/MUl conferred a lower risk of HSIL/cancer (OR 0.5; 95% CI 0.3-0.9). CONCLUSION: Rates of anal HSIL histology are high in HIV-infected patients of all sexual risk groups with abnormal anal cytology. Consequently, all HIV-infected patients may warrant anal cancer screening. PMID- 24072195 TI - Antiretroviral therapy increases thymic output in children with HIV. AB - OBJECTIVE: Disease progression and response to antiretroviral therapy (ART) in HIV-infected children is different to that of adults. Immune reconstitution in adults is mainly from memory T cells, whereas in children it occurs predominantly from the naive T-cell pool. It is unclear however what proportion of reconstituted CD4 T cells comes from thymic export and homeostatic proliferation in the periphery. Thymic output is often estimated by measuring T-cell receptor excision circles and markers such as CD31 expressed on recent thymic emigrants but these are confounded by peripheral T-cell division and cannot in themselves be used as quantitative estimates of thymic output. DESIGN: To compare thymic output in HIV-infected children on ART, HIV-infected children not on ART and uninfected children of different ages. METHOD: Combined T-cell receptor excision circle (TREC) and proliferation data are used with a recently described mathematical model to give explicit measures of thymic output. RESULTS: We found that age-adjusted thymic output is reduced in untreated children with HIV, which increases significantly with length of time on ART. CONCLUSION: Our results suggest that a highly active thymus in early childhood may contribute to better immune reconstitution if ART is initiated early in life. PMID- 24072196 TI - Lower peak bone mass and abnormal trabecular and cortical microarchitecture in young men infected with HIV early in life. AB - INTRODUCTION: HIV infection and antiretroviral therapy (ART) early in life may interfere with acquisition of peak bone mass, thereby increasing fracture risk in adulthood. METHODS: We conducted a cross-sectional study of dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) in 30 HIV-infected African-American or Hispanic Tanner stage 5 men aged 20-25 on ART (15 perinatally infected and 15 infected during adolescence) and 15 HIV-uninfected controls. RESULTS: HIV-infected men were similar in age and BMI, but were more likely to be African-American (P = 0.01) than uninfected men. DXA-derived areal bone mineral density (aBMD) Z-scores were 0.4-1.2 lower in HIV-infected men at the spine, hip, and radius (all P < 0.05). At the radius and tibia, total and trabecular volumetric BMD (vBMD), and cortical and trabecular thickness were between 6 and 19% lower in HIV-infected than uninfected men (P <0.05). HIV-infected men had dramatic deficiencies in plate related parameters by individual trabeculae segmentation (ITS) analyses and 14 17% lower bone stiffness by finite element analysis. Differences in most HR-pQCT parameters remained significant after adjustment for race/ethnicity. No DXA or HR pQCT parameters differed between men infected perinatally or during adolescence. CONCLUSION: At an age by which young men have typically acquired peak bone mass, HIV-infected men on ART have lower BMD, markedly abnormal trabecular plate and cortical microarchitecture, and decreased whole bone stiffness, whether infected perinatally or during adolescence. Reduced bone strength in young adults infected with HIV early in life may place them at higher risk for fractures as they age. PMID- 24072198 TI - IFNL4 ss469415590 variant is a better predictor than rs12979860 of pegylated interferon-alpha/ribavirin therapy failure in hepatitis C virus/HIV-1 coinfected patients. AB - A new transiently induced region (interferon-lambda 4 protein; IFNL4) harbouring a dinucleotide variant ss469415590 (TT or DeltaG), upstream of IFNL3 (IL28B), was recently found to be associated with hepatitis C virus (HCV) clearance. To determine the effect of IFLN4 ss469415590 variation on the HCV response to IFN based therapy in HCV/HIV-1 coinfected patients, ss469415590 was genotyped in a cohort of 207 patients from our clinic. Treatment failure occurred in 77% of minor DeltaG-allele carriers versus 48% of noncarriers, indicating that the DeltaG allele was strongly associated with treatment failure. Importantly, multivariate logistic analysis revealed that ss469415590 genotype was a better predictor of treatment failure than rs12979860. PMID- 24072197 TI - The effect of tuberculosis treatment on virologic and CD4+ cell count response to combination antiretroviral therapy: a systematic review. AB - OBJECTIVE: To determine the impact of tuberculosis (TB) treatment at the time of combination antiretroviral therapy (cART) initiation on virologic and CD4 cell count response to cART. METHODS: Systematic review and meta-analysis of studies reporting HIV RNA and CD4 cell count response, stratified by TB treatment status at cART initiation. Stratified random-effects and meta-regression analyses were used when possible. RESULTS: Twenty-five eligible cohort studies reported data on 49 578 (range 42-15 646) adults, of whom 8826 (18%) were receiving TB treatment at cART initiation. Seventeen studies reported virologic response; 21 reported CD4 cell count response. The summarized random-effects relative risk (RRRE) of virologic suppression in those receiving vs. not receiving TB treatment at different time points following cART initiation was 1.06 (0.86-1.29) at 1-4 months, 0.91 (0.83-1.00) at 6 months, 0.99 (0.94-1.05) at 11-12 months, and 0.99 (0.77-1.28) at 18-48 months. The overall RRRE at 1-48 months was 0.97 (95% confidence interval 0.92-1.03). Available data regarding the effect of TB treatment on virologic failure were heterogeneous and inconclusive (13 estimates). Differences in median CD4 cell count gain between those receiving vs. not receiving TB treatment ranged from -10 to 60 cells/MUl (median 27) by 6 months (seven estimates) and -10 to 29 (median 6) by 11-12 months (five estimates), although the heterogeneity of the response measures did not support meta-analysis. CONCLUSION: Patients receiving TB treatment at cART initiation experience similar virologic suppression and CD4 cell count reconstitution as those not receiving TB treatment, reinforcing the need to start cART during TB treatment and allowing more confidence in clinical decision-making. PMID- 24072199 TI - Unifying model of carpal mechanics based on computationally derived isometric constraints and rules-based motion - the stable central column theory. AB - This study was part of a larger project to develop a (kinetic) theory of carpal motion based on computationally derived isometric constraints. Three-dimensional models were created from computed tomography scans of the wrists of ten normal subjects and carpal spatial relationships at physiological motion extremes were assessed. Specific points on the surface of the various carpal bones and the radius that remained isometric through range of movement were identified. Analysis of the isometric constraints and intercarpal motion suggests that the carpus functions as a stable central column (lunate-capitate-hamate-trapezoid trapezium) with a supporting lateral column (scaphoid), which behaves as a 'two gear four bar linkage'. The triquetrum functions as an ulnar translation restraint, as well as controlling lunate flexion. The 'trapezoid'-shaped trapezoid places the trapezium anterior to the transverse plane of the radius and ulna, and thus rotates the principal axis of the central column to correspond to that used in the 'dart thrower's motion'. This study presents a forward kinematic analysis of the carpus that provides the basis for the development of a unifying kinetic theory of wrist motion based on isometric constraints and rules-based motion. PMID- 24072200 TI - Effects of endostatin and a new drug terpestacin against human neuroblastoma xenograft and cell lines. AB - New development in the vascular network is a significant process for the proliferation, as well as metastatic expand, of cancer cells that depends on a sufficient provider of oxygen and nutrients and the removal of waste products. New blood and lymphatic vessels form via step called angiogenesis and lymphangiogenesis. Angiogenesis is controlled by activator and inhibitor of some molecules. So many different proteins have been established as angiogenic activators and inhibitors. Grades of expression of angiogenic factors demonstrate the forcefulness of tumor cells. The advance of angiogenic inhibitors should help to decrease both mortality and morbidity from carcinomas. So many patients have received anti-angiogenic therapy to date. Nevertheless, their notional efficacy and anti-angiogenic treatments have not demonstrated to be useful in terms of long-term survival. There is a crucial need for a new close treatment plan combining anti-angiogenic agents with standard cyto-reductive treatments in the regulation of cancer. PMID- 24072201 TI - Single-stage surgical approach in complicated paediatric ureteral duplication: surgical and functional outcome. AB - PURPOSE: Surgical approach to children with complicated ureteral duplication is discussed controversially. Our aim was to determine the outcome of children with complicated renal duplication undergoing a single-stage surgical approach with laparoscopic partial nephrectomy and open bladder reconstruction. METHODS: Data of patients from 2004 to 2008 were investigated retrospectively. Outcome was analyzed in terms of postoperative course, renal function, urinary tract infection and functional voiding. RESULTS: Thirteen patients were treated with laparoscopic partial nephrectomy and reconstruction of the lower urinary tract in a single-stage approach. Median age at operation was 15 months (2-63 m). One girl had a renal triplication. 7/13 patients presented with an ectopic ureterocele, two with an ectopic ureter, severe vesicoureteral reflux occurred in 6 patients. All patients had non-functioning renal moieties. Mean operative time was 239 min (129-309; SD 50). One re-operation was necessary 4 years after primary surgery due to a pole remnant. All patients had uneventful recoveries without evidence of recurrent UTI. Postoperative 99mTc-MAG3 scans showed no significant reduction of partial renal function (p = 0.4), and no signs of obstruction (p = 0.188). During a median follow-up of 60 months (49-86), dysfunctional voiding occurred in one patient. CONCLUSIONS: In children with complicated ureteral duplication a definitive single-stage procedure is feasible and shows excellent functional results. PMID- 24072202 TI - Beneficial effects of Etanercept on experimental necrotizing enterocolitis. AB - PURPOSE: Tissue damage in necrotizing enterocolitis (NEC) of infants occurs as a result of an uncontrolled inflammatory response. The aim of this study was to investigate any potential anti-inflammatory effects that Etanercept may have on the inflammatory response in an experimental NEC model in newborn rats. METHODS: Newborn pups were randomized into three groups immediately after birth (Control, NEC + Placebo and NEC + Etanercept). Pups in the NEC + Placebo and NEC + Etanercept groups were subjected to an NEC-inducing protocol (hypercarbia, hypothermia and hyperoxia) twice a day for 3 days. Pups in the NEC + Etanercept group were given an intraperitoneal injection of Etanercept. Rats were harvested for biochemical and histopathological examinations. RESULTS: The histopathological injury score of rats in the NEC + Placebo group was significantly higher compared to the NEC + Etanercept and Control groups (p < 0.05 for both comparisons). Tissue levels of tumor necrosis factor-alpha, interleukin-1beta, and malondialdehyde were higher in the placebo group compared to the Etanercept group. CONCLUSION: Our results suggest that Etanercept attenuates intestinal tissue damage in NEC by reducing inflammation and blocking the production of free-oxygen radicals, while also reducing tissue levels of tumor necrosis factor-alpha and interleukin-1beta. PMID- 24072203 TI - Patency of neck veins following ultrasound-guided percutaneous Hickman line insertion. AB - PURPOSE: Venous occlusion following permanent central venous catheter (CVC) insertion by open cutdown or the landmark percutaneous technique has been reported between up to 25 %. However, there are no published data on the equivalent rate following ultrasound-guided percutaneous CVC insertion. The purpose of this study was to document the rate of venous occlusion associated with ultrasound-guided percutaneous CVC insertion in children. METHOD: From 1 April 2010 to 1 December 2011, all children having elective or emergency removal of a Hickman line by the vascular access team had a Doppler ultrasound of their neck veins. Only Hickman lines inserted by the ultrasound-guided percutaneous route were included. Internal jugular, innominate and subclavian veins were scanned and recorded as patent, reduced or absent. RESULTS: We identified 100 consecutive children. Median age was 6 years (range 21 days to 16 years). Indication for insertion was chemotherapy (60), parenteral nutrition (15), blood products (12), renal replacement (3) and other indications (10). Three children had absent flow at the time of line removal (median age 4 months, range 3-6 months), with 2 out of 3 requiring removal for infection. The venous occlusion rate following ultrasound-guided insertion of CVC is 3 % in our study. CONCLUSIONS: We conclude that (1) complete venous occlusion is associated with younger age and CVC infection. (2) In our study, the venous occlusion rate of 3 % is significantly lower than the published series of either open cutdown or the landmark technique. PMID- 24072204 TI - Mineral-coated polymer membranes with superhydrophilicity and underwater superoleophobicity for effective oil/water separation. AB - Oil-polluted water is a worldwide problem due to the increasing industrial oily wastewater and the frequent oil spill accidents. Here, we report a novel kind of superhydrophilic hybrid membranes for effective oil/water separation. They were prepared by depositing CaCO3-based mineral coating on PAA-grafted polypropylene microfiltration membranes. The rigid mineral-coating traps abundant water in aqueous environment and forms a robust hydrated layer on the membrane pore surface, thus endowing the membranes with underwater superoleophobicity. Under the drive of either gravity or external pressure, the hybrid membranes separate a range of oil/water mixtures effectively with high water flux (>2000 L m(-2) h( 1)), perfect oil/water separation efficiency (>99%), high oil breakthrough pressure (>140 kPa) and low oil fouling. The oil/water mixtures include not only free mixtures but also oil-in-water emulsions. Therefore, the mineral-coated membrane enables an efficient and energy-saving separation for various oil/water mixtures, showing attractive potential for practical oil/water separation. PMID- 24072205 TI - Association between line per se and testcross performance for eight agronomic and quality traits in winter rye. AB - KEY MESSAGE: We investigated associations between line per se and testcross performance in rye and suggested that selection for per se performance is valuable for several traits in multi-stage selection programs. Genotypic correlation between line per se and testcross performance is an important quantitative-genetic parameter for optimizing hybrid breeding programs. The main goal of this survey was to study the association of line per se and testcross performance at the phenotypic level. We used experimental data from the line per se and testcross performance of two segregating winter rye populations (A, B) with each of 220 progenies tested in six environments for eight agronomic and quality traits. Genotypic variances were considerably larger for per se than for testcross performance of all investigated traits resulting in higher heritabilities of the former in most instances. Genotypic correlations (r g) between testcross and line per se performance decreased with increasing complexity of the trait as shown by the respective heritabilities. They were highest (r g >= 0.7) for plant height and test weight in population B, and thousand-kernel weight, falling number and starch content in both populations. A selection of these traits for line per se performance in early generations will save field plots in further testing testcross performance and increase efficiency of hybrid breeding. PMID- 24072206 TI - Inheritance of soybean aphid resistance in 21 soybean plant introductions. AB - KEY MESSAGE: The Rag2 region was frequently identified among 21 F 2 populations evaluated for soybean aphid resistance, and dominant gene action and single-gene resistance were also commonly identified. The soybean aphid [Aphis glycines Matsumura (Hemiptera: Aphididae)] is one of the most important insect pests of soybean [Glycine max (L.) Merr] in the northern USA and southern Canada, and four resistance loci (Rag1-rag4) have been discovered since the pest was identified in the USA in 2000. The objective of this research was to determine whether resistance expression in recently identified soybean aphid-resistant plant introductions (PIs) was associated with the four Rag loci using a collection of 21 F2 populations. The F2 populations were phenotyped with soybean aphid biotype 1, which is avirulent on plants having any of the currently identified Rag genes, using choice tests in the greenhouse and were tested with genetic markers linked to the four Rag loci. The phenotyping results indicate that soybean aphid resistance is controlled by a single dominant gene in 14 PIs, by two genes in three PIs, and four PIs had no clear Mendelian inheritance patterns. Genetic markers flanking Rag2 were significantly associated with aphid resistance in 20 PIs, the Rag1 region was significantly identified in five PIs, and the Rag3 region was identified in one PI. These results show that single dominant gene action at the Rag2 region may be a major source for aphid resistance in the USDA soybean germplasm collection. PMID- 24072207 TI - Mapping QTLs for yield and nitrogen-related traits in wheat: influence of nitrogen and phosphorus fertilization on QTL expression. AB - KEY MESSAGE: The present study identified some new important genomic regions and demonstrated the availability of conditional analysis in dissecting QTLs induced by environmental factors. The high input and low use efficiency of nutrient fertilizers require knowledge of the genetic control of crop reaction to nutrient supplements. In this study, 14 morphological and 8 physiological traits of a set of 182 wheat (Triticum aestivum L.) recombinant inbred lines (Xiaoyan 54 * Jing 411) were investigated in six environments to map quantitative trait loci (QTLs). The influence of nitrogen (N) and phosphorus (P) fertilization on QTL expression was studied by unconditional and conditional analysis. A total of 117 and 30 QTLs were detected by unconditional and conditional analysis, respectively, among which 21 were common for both methods. Thirty-four QTL clusters were identified. Eighteen conserved QTLs (15.4 % of the 117 QTLs) between years, but within nutritional treatment were found. The three major QTLs on chromosomes 2D, 4B and 6A were coincident with Rht8, Rht-B1b and TaGW2, respectively. The other two important intervals on chromosomes 4B and 7A for yield component traits were newly detected QTLs that warrant further study. By conditional analysis, spikelet number per spike was found to be induced by P fertilization mostly, whereas N fertilization had more effects on the expression of the QTLs for nitrogen concentration and utilization efficiency traits. QTLs that respond to N and P interactions were also detected. The results are helpful for understanding the genetic basis of N utilization efficiency in wheat under different N and P supplement environments and provide evidence for the availability of conditional analysis in dissecting QTLs induced by environmental factors. PMID- 24072208 TI - Grapevine powdery mildew resistance and susceptibility loci identified on a high resolution SNP map. AB - Improved efficacy and durability of powdery mildew resistance can be enhanced via knowledge of the genetics of resistance and susceptibility coupled with the development of high-resolution maps to facilitate the stacking of multiple resistance genes and other desirable traits. We studied the inheritance of powdery mildew (Erysiphe necator) resistance and susceptibility of wild Vitis rupestris B38 and cultivated V. vinifera 'Chardonnay', finding evidence for quantitative variation. Molecular markers were identified using genotyping-by sequencing, resulting in 16,833 single nucleotide polymorphisms (SNPs) based on alignment to the V. vinifera 'PN40024' reference genome sequence. With an average density of 36 SNPs/Mbp and uniform coverage of the genome, this 17K set was used to identify 11 SNPs on chromosome 7 associated with a resistance locus from V. rupestris B38 and ten SNPs on chromosome 9 associated with a locus for susceptibility from 'Chardonnay' using single marker association and linkage disequilibrium analysis. Linkage maps for V. rupestris B38 (1,146 SNPs) and 'Chardonnay' (1,215 SNPs) were constructed and used to corroborate the 'Chardonnay' locus named Sen1 (Susceptibility to Erysiphe necator 1), providing the first insight into the genetics of susceptibility to powdery mildew from V. vinifera. The identification of markers associated with a susceptibility locus in a V. vinifera background can be used for negative selection among breeding progenies. This work improves our understanding of the nature of powdery mildew resistance in V. rupestris B38 and 'Chardonnay', while applying next-generation sequencing tools to advance grapevine genomics and breeding. PMID- 24072209 TI - Immune thrombocytopenia: serum cytokine levels in children and adults. AB - BACKGROUND: Immune thrombocytopenia (ITP) is an immune-mediated platelet disorder in which autoantibody-coated platelets are removed from the blood by monocytic phagocytes and there is impaired platelet production. There is a delicate balance of specific cytokine levels, which has an important role in the immune system and is known to be deregulated in autoimmune diseases. This study was designed to investigate the differences in Th cytokine levels between children and adults with newly diagnosed ITP and to compare these profiles to those found in healthy, age-matched controls. MATERIAL/METHODS: The concentration of IL-1alpha, IL-2, IL 3, IL-4, IL-6, IL-10, TNF-alpha, IFN-alpha, and IFN-alpha in serum specimens was analyzed by enzyme-linked immunosorbent assay. RESULTS: At the time of ITP diagnosis, children showed significantly lower serum levels of interleukin IL-2 and tumor necrosis factor TNF-alpha and higher serum level of IL-3 than healthy controls. Serum level of IL-4 in adult ITP patients was higher than those in control subjects. When compared with adults, children with ITP had lower serum level of IL-4, IL-6 and IFN-alpha, and higher level of IFN-alpha. CONCLUSIONS: Significant differences in serum cytokine levels between pediatric patients and healthy controls indicate that cytokine disturbances--especially changes in IL-2, IL-3 and TNF-alpha--might be involved in the pathogenesis of newly diagnosed ITP. TNF-alpha is the most informative variable for discrimination between healthy children and those with ITP. PMID- 24072210 TI - Longitudinal assessment in COPD patients: multidimensional variability and outcomes. AB - The value and timing of multidimensional assessments in chronic obstructive pulmonary disease (COPD) remains unclear because there is little information about their variability and relationship to outcome. The aim of this study was to determine the progression of COPD using clinical and spirometric variability over time with mortality as the outcome. We determined the annual intra-individual variability of forced expiratory volume in 1 s (FEV1) and BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index in 403 patients with at least five measurements. The pattern was defined as "stable" if the annual change remained constant in >=66% of the observations and "unstable" if it did not meet that threshold. We explored the minimum number of yearly observations that related to mortality in the 704 patients of the cohort. The "unstable" pattern of FEV1 was seen in 53% and 40% of patients using a threshold of 40 mL.year(-1) and 100 mL.year(-1), respectively. There was a slightly more "stable" pattern in the BODE index (62% for 1 point). A profile associated with mortality was defined by a baseline measurement followed by annual measurements for 2 years of the BODE index, but not its individual components, including FEV1 (p<0.001). Progression of COPD measured using FEV1 is inconsistent and relates poorly to outcome. Monitoring the more stable BODE index better assesses disease progression. PMID- 24072211 TI - Measurement of FEF25-75% and FEF75% does not contribute to clinical decision making. AB - The aim of this study was to determine the added value of measuring the forced expiratory flow at 25-75% of forced vital capacity (FVC) (FEF25-75%) and flow when 75% of FVC has been exhaled (FEF75%) over and above the measurement of the forced expiratory volume in 1 s (FEV1), FVC and FEV1/FVC ratio. We used spirometric measurements of FEV1, FVC and FEF25-75% from 11 654 white males and 11 113 white females, aged 3-94 years, routinely tested in the pulmonary function laboratories of four tertiary hospitals. FEF75% was available in 8254 males and 7407 females. Predicted values and lower limits of normal, defined as the fifth percentile, were calculated for FEV1, FVC, FEV1/FVC ratio, FEF25-75% and FEF75% using prediction equations from the Global Lung Function Initiative. There was very little discordance in classifying test results. FEF25-75% and FEF75% were below the normal range in only 2.75% and 1.29% of cases, respectively, whereas FEV1, FVC and FEV1/FVC ratio were within normal limits. Airways obstruction went undetected by FEF25-75% in 2.9% of cases and by FEF75% in 12.3% of cases. Maximum mid-expiratory flow and flow towards the end of the forced expiratory manoeuvre do not contribute usefully to clinical decision making over and above information from FEV1, FVC and FEV1/FVC ratio. PMID- 24072212 TI - Visceral white fat remodelling contributes to intermittent hypoxia-induced atherogenesis. AB - Obstructive sleep apnoea is a highly prevalent disease characterised by repetitive upper airway collapse during sleep leading to intermittent hypoxia. Cardiometabolic complications of sleep apnoea have been mostly attributed to intermittent hypoxia. These consequences could be mediated through intermittent hypoxia-related alterations of the visceral white fat, as it is recognised for playing an important role in inflammation, atherogenesis and insulin resistance. Epididymal adipose tissue alterations were investigated in 20-week-old nonobese male apolipoprotein E-deficient mice exposed to intermittent hypoxia (inspiratory oxygen fraction 5-21%, 60-s cycle, 8 h . day(-1)) or air for 6 weeks. These adipose tissue alterations, as well as metabolic alterations and aortic atherosclerosis, were then assessed in lipectomised or sham-operated mice exposed to intermittent hypoxia or air for 6 weeks. Intermittent hypoxia induced morphological (shrunken adipocytes), functional (increased uncoupling protein-1 expression) and inflammatory (increased macrophage recruitment and secretion of interleukin-6 and tumour necrosis factor-alpha) remodelling of epididymal adipose tissue. Hypoxic mice presented more severe dyslipidaemia and atherosclerosis lesions and developed insulin resistance. Epididymal lipectomy attenuated both intermittent hypoxia-induced dyslipidaemia and atherogenesis, but did not improve insulin sensitivity. Our results confirmed that the dyslipidaemic and proatherogenic effects of intermittent hypoxia are partly mediated through morphological, functional and inflammatory remodelling of visceral white fat, regardless of obesity. PMID- 24072213 TI - ERS/WHO tuberculosis consilium: reporting of the initial 10 cases. PMID- 24072214 TI - Pneumomediastinum and hyponatraemic dehydration as presenting features of cystic fibrosis. PMID- 24072215 TI - Impact of cigarette smoking on latent tuberculosis infection: does age matter? PMID- 24072216 TI - Pulmonary fibrosis in dyskeratosis congenita with TINF2 gene mutation. PMID- 24072217 TI - Bevacizumab for advanced breast cancer: hope, hype, and hundreds of headlines. AB - On February 22, 2008, the Food and Drug Administration granted accelerated approval for the use of bevacizumab (Avastin) in metastatic breast cancer. Based on subsequent clinical trials, this approval was revoked on November 18, 2011. In this study, we categorize and analyze the newspaper reports related to bevacizumab's use in advanced breast cancer. Methods. Using the Factiva media database, we reviewed all newspaper reports published in North America from January 4, 2002, to January 4, 2013, containing the words "breast cancer" and "Avastin," or "bevacizumab." Articles were classified as pre-approval (January 4, 2002-February 21, 2008), approval (February 22, 2008-November 17, 2011), or post approval loss (November 18, 2011-January 4, 2013). Information regarding benefits, side effects, costs, interviewees, and article tone and theme were abstracted from each article by two independent reviewers. Differences among the three study phases were compared using the chi square analysis. Results. A total of 359 articles met study inclusion criteria. The number of reports having a positive headline tone and/or positive article tone declined with each study period. The proportion of articles discussing side effects and financial costs increased, whereas those discussing efficacy decreased with each study period. Drug representatives were most likely to be quoted in newspaper articles prior to bevacizumab's approval. Conclusion. Media reports are a common source of medical information for patients, practitioners, and policy makers. We observed substantial fluidity of media reports over time. PMID- 24072218 TI - Phase II study of dasatinib (BMS-354825) in patients with metastatic adenocarcinoma of the pancreas. AB - BACKGROUND: Src, EphA2, and platelet-derived growth factor receptors alpha and beta are dysregulated in pancreatic ductal adenocarcinoma (PDAC). METHODS: Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, platelet-derived growth factor receptor beta, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC. METHODS: Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected. RESULTS: Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8-6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6-3.2 months). In 34 evaluable patients, the best response achieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival. CONCLUSION: Single-agent dasatinib does not have clinical activity in metastatic PDAC. PMID- 24072219 TI - DNA repair gene patterns as prognostic and predictive factors in molecular breast cancer subtypes. AB - DNA repair pathways can enable tumor cells to survive DNA damage induced by chemotherapy and thus provide prognostic and/or predictive value. We evaluated Affymetrix gene expression profiles for 145 DNA repair genes in untreated breast cancer (BC) patients (n = 684) and BC patients treated with regimens containing neoadjuvant taxane/anthracycline (n = 294) or anthracycline (n = 210). We independently assessed estrogen receptor (ER)-positive/HER2-negative, HER2 positive, and ER-negative/HER2-negative subgroups for differential expression, bimodal distribution, and the prognostic and predictive value of DNA repair gene expression. Twenty-two genes were consistently overexpressed in ER-negative tumors, and five genes were overexpressed in ER-positive tumors, but no differences in expression were associated with HER2 status. In ER-positive/HER2 negative tumors, the expression of nine genes (BUB1, FANCI, MNAT1, PARP2, PCNA, POLQ, RPA3, TOP2A, and UBE2V2) was associated with poor prognosis, and the expression of one gene (ATM) was associated with good prognosis. Furthermore, the prognostic value of specific genes did not correlate with proliferation. A few genes were associated with chemotherapy response in BC subtypes and treatment specific manner. In ER-negative/HER2-negative tumors, the MSH2, MSH6, and FAN1 (previously MTMR15) genes were associated with pathological complete response and residual invasive cancer in taxane/anthracycline-treated patients. Conversely, PMS2 expression was associated with residual invasive cancer in treatments using anthracycline as a single agent. In HER2-positive tumors, TOP2A was associated with patient response to anthracyclines but not to taxane/anthracycline regimens. In genes expressed in a bimodal fashion, RECQL4 was significantly associated with clinical outcome. In vitro studies showed that defects in RECQL4 impair homologous recombination, sensitizing BC cells to DNA-damaging agents. PMID- 24072221 TI - Family socioeconomic status and the provision of motor affordances in the home. AB - BACKGROUND: Socioeconomic status (SES) and stimulation provided in the home environment are influential factors in aspects of child well-being including motor development. Little is known regarding the influence of SES on specific aspects of the home environment. OBJECTIVE: To evaluate the availability of affordances in the home to promote infant motor development and family SES. METHOD: The sample consisted of 300 families with infants aged 3 to 18 months. SES was assessed according to family socioeconomic class, income and parental level of education. To evaluate motor affordances found at home, the Affordances in the Home Environment for Motor Development-Infant Scale (AHEMD-IS) was used. The AHEMD-IS was designed to assess dimensions of the home environment including Physical Space (outside and inside space), Daily Activities and Play Materials (fine-motor and gross-motor toys). RESULTS: SES indicators significantly influenced the availability of Physical Space and Play Materials. The Physical Space dimension was influenced by family economic class and income. The Play Materials dimension was influenced by all SES indicators. Daily Activities were not influenced by any of the SES indicators. Daily activities and play material were influenced by the infant's age. CONCLUSIONS: This study suggests that SES indicators are influential with regard to the provision of motor affordances in the home environment for infants. However, daily activities, which represent an aspect of the environment that is highly dependent on parental generation of situations that are conducive to motor skill development, are independent of family SES. PMID- 24072220 TI - Chemotherapy with Erlotinib or chemotherapy alone in advanced non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitors. AB - Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer has an oncogene-addicted biology that confers sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Published data suggest that EGFR addiction persists after development of TKI acquired resistance, leading many clinicians to continue TKI with subsequent chemotherapy; however, this strategy has not been formally evaluated. Methods. We retrospectively reviewed an institutional database to identify patients with advanced EGFR mutation with acquired resistance who subsequently received chemotherapy. Patients were classified as receiving chemotherapy with continued erlotinib or chemotherapy alone. We assessed differences in outcomes between the two strategies. Results. Seventy-eight patients were included, 34 treated with chemotherapy and erlotinib and 44 treated with chemotherapy alone. Objective response rate was evaluable in 57 patients and was 41% for those treated with chemotherapy and erlotinib and 18% for those treated with chemotherapy alone. After adjusting for chemotherapy regimen and length of initial TKI course, the odds ratio for the response rate was 0.20 (95% confidence interval: 0.05-0.78; p = .02) favoring treatment with chemotherapy and erlotinib. The median progression-free survival was 4.4 months on chemotherapy and erlotinib and 4.2 months on chemotherapy alone (adjusted hazard ratio = 0.79; 95% confidence interval: 0.48-1.29; p = .34). There was no difference in overall survival. Conclusion. This is the first study, to our knowledge, to demonstrate that continuation of EGFR TKI with chemotherapy in patients with acquired resistance improves outcomes compared with chemotherapy alone. We observed an improved response rate but no difference in progression-free survival or overall survival. A larger prospective clinical trial is needed to evaluate this promising strategy further. PMID- 24072222 TI - Analysis of the user satisfaction level in a public physical therapy service. AB - BACKGROUND: The concepts of quality management have increasingly been introduced into the health sector. Methods to measure satisfaction and quality are examples of this trend. OBJECTIVE: This study aimed to identify the level of customer satisfaction in a physical therapy department involved in the public area and to analyze the key variables that impact the usersa?(tm) perceived quality. METHOD: A cross-sectional observational study was conducted, and 95 patients from the physical therapy department of the Hospital Universitario Gaffree e Guinle - Universidade Federal do Estado do Rio de Janeiro (HUGG/UNIRIO) - Rio de Janeiro, Brazil, were evaluated by the SERVQUAL questionnaire. A brief questionnaire to identify the sociocultural profile of the patients was also performed. RESULTS: Patients from this health service presented a satisfied status with the treatment, and the population final average value in the questionnaire was 0.057 (a positive value indicates satisfaction). There was an influence of the educational level on the satisfaction status (chi2=17,149; p=0.002). A correlation was found between satisfaction and the dimensions of tangibility (rho=0.56, p=0.05) and empathy (rho=0.46, p=0.01) for the Unsatisfied group. Among the Satisfied group, the dimension that was correlated with the final value of the SERVQUAL was responsiveness (rho=0.44, p=0.01). CONCLUSIONS: The final values of the GGUH physical therapy department showed that patients can be satisfied even in a public health service. Satisfaction measures must have a multidimensional approach, and we found that people with more years of study showed lower values of satisfaction. PMID- 24072223 TI - The development and psychometric evaluation of a self-efficacy scale for practicing pelvic floor exercises. AB - BACKGROUND: Self-efficacy has been shown to be a predictor of many health-related behaviors, including the practice of pelvic floor exercises with a focus on prevention or cure. OBJECTIVES: To describe the process of construction and the psychometric properties of the scale of self-efficacy for the practice of pelvic floor exercises (EAPEAP). METHOD: A cross-sectional study of validation was carried out with 81 from community and 96 postpartum women, 54.8% of them complained of urinary leakage. An exploratory factor analysis and internal consistency analysis was performed. To check predictive capacity, we analyzed the adherence at 3 months post - intervention and compared the scores of self efficacy between adherent and non-adherent women. Reliability was analyzed by split half procedure. RESULTS: The instrument showed alpha=0.923, and revealed three factors: performance expectation considering the action, performance expectation considering the preparation for action and outcome expectations. These factors accounted for 65.32% of the total variance. The instrument was able to differentiate between women who adhere and have not adhered to the exercises (U=352, p=0.013) and there was strong correlation between the two halves of the instrument (rho=0.889, p<0.001). CONCLUSION: The scale is a valid and reliable tool to measure self-efficacy to practice pelvic floor exercises. PMID- 24072224 TI - Patients hospitalized for community-acquired pneumonia present reduced functional performance. AB - BACKGROUND: Symptoms of fatigue and dyspnea, treatment with oral corticosteroids, high circulating levels of cytokines, and oxidant/antioxidant imbalance in patients hospitalized with community-acquired pneumonia (CAP) could affect the patients' exercise tolerance and peripheral muscle strength (PMS). OBJECTIVE: To evaluate the functional capacity (FC) of patients hospitalized for CAP and to correlate the FC with length of hospital stay. METHOD: We prospectively evaluated 45 patients (49+/-16 years; CAP group) and 20 healthy subjects (53+/-17 years; control group). They were randomized to perform, on separate days, a 6-minute walk test (6MWT), a test of PMS, and the Glittre test (GT). Additionally, the SF 36 questionnaire and the MRC scale were completed and evaluated. RESULTS: There were significant differences between the groups (CAP and controls) for the 6MWT (381.3+/-108 vs. 587.1+/-86.8 m) and GT (272.8+/-104.3 vs. 174+/-39 sec). The CAP group also presented worse health-related quality of life (HRQoL) scores, reduced strength (quadriceps and biceps), and higher scores of dyspnea. The time required to perform the GT correlated with the length of hospital stay (r=0.35, P=0.02) and dyspnea (r=0.36, P=0.02). Significant correlations were observed between GT and 6MWT (r=-0.66, P=0.0001) and between GT with the physical functioning domain of SF-36 (r=-0.51, P=0.0001). CONCLUSIONS: Patients hospitalized for CAP presented with reduced FC, PMS, and HRQoL during hospitalization. In addition, GT performance was related to the length of hospital stay. PMID- 24072225 TI - Assessment of gait in toddlers with normal motor development and in hemiplegic children with mild motor impairment: a validity study. AB - BACKGROUND: The optimization of gait performance is an important goal in the rehabilitation of children with cerebral palsy (CP) who present a prognosis associated with locomotion. Gait analysis using videos captured by digital cameras requires validation. OBJECTIVE: To evaluate the validity of a method that involves the analysis of videos captured using a digital camera for quantifying the temporal parameters of gait in toddlers with normal motor development and children with CP. METHOD: Eleven toddlers with normal motor development and eight children with spastic hemiplegia who were able to walk without assistive devices were asked to walk through a space contained in the visual field of two instruments: a digital camera and a three-dimensional motion analysis system, Qualisys Pro-Reflex. The duration of the stance and swing phases of gait and of the entire gait cycle were calculated by analyzing videos captured by a digital camera and compared to those obtained by Qualisys Pro-Reflex, which is considered a highly accurate system. RESULTS: The Intraclass Correlation Coefficient (ICC) demonstrated excellent agreement (ICC>0.90) between the two procedures for all measurements, except for the swing phase of the normal toddlers (ICC=0.35). The standard error of measurement was less than 0.02 seconds for all measures. CONCLUSIONS: The results reveal similarities between the two instruments, suggesting that digital cameras can be valid instruments for quantifying two temporal parameters of gait. This congruence is of clinical and scientific relevance and validates the use of digital cameras as a resource for helping the assessment and documentation of the therapeutic effects of interventions targeted at the gait of children with CP. PMID- 24072226 TI - The perceptions of Unified Health System (Sistema Unico de Saude) users about including undergraduate students in Family Health Units (Unidades de Saude da Familia). AB - BACKGROUND: Curriculum guidelines for health professionals in training recommend including health students in different levels of service in the Unified Health System (Sistema Unico de Saude - SUS). Thus, there is a need to investigate the perceptions of SUS users with regard to the students' participation. OBJECTIVE: To evaluate the perceptions of SUS users about the participation of health students in Family Health Units (Unidades de Saude da Familia - USF). METHOD: A total of 518 people were interviewed in the waiting room of eight USFs in Sao Carlos/Sao Paulo. The interviews were conducted by students using a semi structured questionnaire, and the data were analyzed descriptively. RESULTS: A total of 391 (75.5%) women and 127 (24.5%) men, with a mean age of 42.0+/-17.5 years, were interviewed. Among these users, 33.1% had encountered students in the USF, mainly while receiving clinical care (52.1%) or during home visits (20.1%); 55.3% considered the student's performance very good, and 0.6% considered it very bad. Most of the interviewees (58.2%) evaluated the activity performed by the student as effective, whereas 8.2% considered it ineffective. CONCLUSIONS: The students were included primarily in individual assistance activities, and the care provided by the students was well accepted. Both the users' satisfaction scores and their reported expectations were positive. PMID- 24072227 TI - The work ability index and functional capacity among older workers. AB - BACKGROUND: Decreases in functional ability due to aging can impair work capacity and productivity among older workers. OBJECTIVE: This study compares the sociodemographics, health conditions, and physical functioning abilities of young and old workers as well as correlates of physical functioning capacity with the work ability index (WAI). METHOD: This exploratory, cross-sectional study examined employees of a higher education institution (HEI) and those of a metallurgical industry. Older workers (50 years old or above) were matched for gender and occupation type with younger workers (less than 50 years old). The following evaluations were applied: the multidimensional assessment questionnaire (which included sociodemographic, clinical, health perception, and physical health indices), the WAI, and a battery of physical functional tests. RESULTS: Diseases and regularly used medications were more common among the group of aging workers. The WAI did not differ between groups (p=0.237). Both groups showed similar physical functional capacity performances with regard to walking speed, muscle strength, and lower limb physical functioning. Aging workers showed a poorer performance on a test of right-leg support (p=0.004). The WAI was moderately correlated with the sit-to-stand test among older female workers (r=0.573, p=0.051). CONCLUSIONS: Unfavorable general health conditions did not affect the assessment of work ability or most of the tests of physical functional capacity in the aging group. PMID- 24072229 TI - Gene regulation and priming by topoisomerase IIalpha in embryonic stem cells. AB - Topoisomerases resolve torsional stress, while their function in gene regulation, especially during cellular differentiation, remains unknown. Here we find that the expression of topo II isoforms, topoisomerase IIalpha and topoisomerase IIbeta, is the characteristic of dividing and postmitotic tissues, respectively. In embryonic stem cells, topoisomerase IIalpha preferentially occupies active gene promoters. Topoisomerase IIalpha inhibition compromises genomic integrity, which results in epigenetic changes, altered kinetics of RNA Pol II at target promoters and misregulated gene expression. Common targets of topoisomerase IIalpha and topoisomerase IIbeta are housekeeping genes, while unique targets are involved in proliferation/pluripotency and neurogenesis, respectively. Topoisomerase IIalpha targets exhibiting bivalent chromatin resolve upon differentiation, concomitant with their activation and occupancy by topoisomerase IIbeta, features further observed for long genes. These long silent genes display accessible chromatin in embryonic stem cells that relies on topoisomerase IIalpha activity. These findings suggest that topoisomerase IIalpha not only contributes to stem-cell transcriptome regulation but also primes developmental genes for subsequent activation upon differentiation. PMID- 24072228 TI - Influence of specific training on spatio-temporal parameters at the onset of goal directed reaching in infants. AB - BACKGROUND: There is evidence that long-term experience can promote functional changes in infants. However, much remains unknown about how a short-term experience affects performance of a task. OBJECTIVE: This study aims to investigate the influence of a single training session at the onset of goal directed reaching on the spatio-temporal parameters of reaching and whether there are differences in the effects of training across different reaching positions. METHOD: Thirty-three infants were divided into three groups: 1) a control group; 2) a group that was reach trained in a reclined position; and 3) a group trained in the supine position. The infants were submitted to two assessments (pre- and post-training) in two testing positions (supine and reclined at 45 degrees ). RESULTS: The short-duration training sessions were effective in promoting shorter reaches in the specific position in which the training was conducted. Training in the reclined position was associated with shorter and faster reaches upon assessment in the reclined position. CONCLUSIONS: A few minutes of reach training are effective in facilitating reaching behavior in infants at the onset of reaching. The improvements in reaching were specific to the position in which the infants were trained. PMID- 24072230 TI - Scaling adult dose and schedule of anticancer agents to children. AB - PURPOSE: Objective of this work was to extend pharmacokinetic scaling theory of the writer for bolus dosing to include the case of constant-rate i.v. dosing over fixed interval so as to allow projection of adult dose and schedule of typically administered anticancer agents to children. METHODS: The basis for the scaling is the requirement of time-scaled likeness of the plasma concentrations of an agent for adult and child. Algebraic expressions are established for describing the time history of the concentrations, and formulas for dose and dosing interval are determined so as to ensure the requirement on concentrations. RESULTS: Scaling results for simple drug behavior are illustrated using clinical data for the anticancer agent carboplatin. Basic aspects of the theory are confirmed for dose and dosing interval of adult and 4-year-old child. The theory is also shown to describe tolerable doses for children when scaled from adult dosing requirements and to have application in determining dosing conditions for children requiring individualized dosing because of renal impairment. Scaling with more complex drug behavior is illustrated using preclinical and clinical data for the anticancer agent docetaxel. Adult-to-child scaling is demonstrated and shown to be consistent with previously reported clinical data. Additional consideration is given to the anticancer agents etoposide and melphalan, as widely used in pediatric chemotherapy, and also to the modern practice of combination chemotherapy. CONCLUSIONS: Basic theory for scaling adult dose and schedule of anticancer agents to children is presented and demonstrated to be plausible in providing insight into existing and proposed pediatric treatment protocols. PMID- 24072231 TI - Modulation of peripheral immune responses by paclitaxel-ifosfamide-cisplatin chemotherapy in advanced non-small-cell lung cancer. AB - PURPOSE: The aim of this study was to assess systemic immunological responses in non-small-cell lung cancer (NSCLC) patients with stage III/IV disease during treatment with paclitaxel-ifosfamide-cisplatin (TIP) chemotherapy. METHODS: Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (HD) (n = 20) and chemotherapy-naive NSCLC patients treated with TIP (n = 32) were tested for production of IL-1, TNF-alpha, TNF-beta, IL-6, IL-8, IL-10, IL-12 and IL-2 upon polyclonal stimulation with anti-CD3 mAb. They were further assessed over a treatment period of twelve weeks (i.e., four treatment cycles). RESULTS: PBMCs from NSCLC patients produced higher IL-1, TNF-alpha, TNF-beta, IL-6, IL-8, IL-10 and IL-12 levels, whereas IL-2 exhibited lower values compared to HD (p < 0.001 for all parameters). Of interest, patients who responded to treatment had significantly higher increases in IL-2 (p < 0.001) and significantly higher decreases in IL-1 (p < 0.001), TNF-alpha (p < 0.001), TNF-beta (p < 0.001), IL-6 (p = 0.02), IL-8 (p < 0.001), IL-10 (p < 0.001) and IL-12 (p < 0.001) levels. Non responders revealed post-therapeutically a significantly higher increase in IL-1, TNF-alpha, TNF-beta, IL-6, IL-8, IL-10 and IL-12 secretion and a significantly higher decrease in IL-2 levels (p < 0.001 for all parameters). Patients who responded to treatment and had a significantly higher increase in IL-2 showed a significantly longer median survival (p value < 0.001, 26 vs. 7.5 months). CONCLUSION: Our study indicates that monitoring cytokine dynamics in patients with advanced NSCLC and especially those of IL-2 in peripheral blood components in vitro could be used as a predictor of treatment-related outcome and overall survival in NSCLC. PMID- 24072232 TI - Everolimus as treatment for breast cancer patients with bone metastases only: results of the phase II RADAR study. AB - PURPOSE: Everolimus has shown to stop formation and activity of osteoclasts. Breast cancer patients with bone metastases only are candidates for effective but low toxic treatment. PATIENTS AND METHODS: We evaluated everolimus in a double blind, placebo-controlled, phase II, randomized discontinuation study in breast cancer patients with HER2 negative breast cancer patients with bone metastases only. After being stable on 8 weeks of everolimus 10 mg/day, patients were randomized to everolimus-continuation or placebo. Primary outcome was time (from randomization) to progression (TTP). Seventy-six patients would have had to be randomized to show a hazard ration (HR) of 0.5 for everolimus-continuation. RESULTS: Eighty-nine patients were enrolled in 4 years. Thirty-nine patients with SD after 8 weeks on everolimus were randomized to everolimus-continuation or placebo. TTP in patients with everolimus-continuation was 37.0 (95 % CI 16.7 40.3) versus 12.6 weeks (95 % CI 7.1-17.9) with placebo [HR 0.554 (95 % CI 0.282 1.09) p = 0.0818], adjusted for endocrine therapy [HR 0.464 (95 % CI 0.226-0.954) p = 0.037]. TTP in everolimus responders (n = 6) was 86 weeks. CONCLUSION: The RADAR study is mainly hypothesis generating. It suggests that everolimus has single-agent activity, and patients with bone metastases only may retrieve long term benefit from everolimus if they do not progress within 8 weeks of treatment. PMID- 24072233 TI - The relationship between genetic profiling, clinicopathological factors and survival in patients undergoing surgery for node-negative colorectal cancer: 10 year follow-up. AB - PURPOSE: The introduction of the bowel cancer screening programme has resulted in increasing numbers of patients being diagnosed with node-negative disease. Unfortunately, approximately 30 % will develop recurrence following surgery. Given the toxicity associated with adjuvant chemotherapy, it is important to identify high-risk patients who may benefit from adjuvant therapy. This study aims to identify which clinicopathological factors and genetic profiling markers predict outcome in node-negative disease. METHODS: Forty-nine microsatellite stable (MSS) patients undergoing curative resection between 1991 and 1993 were included. Local immune response was assessed by Klintrup criteria and vascular invasion status assessed through Miller's elastin staining. Comparative genomic hybridisation (CGH) on a range of loci provided data on allelic imbalance. Analysis of survival included clinicopathological and CGH data in a multivariate (Cox) model. RESULTS: On binary logistical regression analysis, 4p deletion was independently associated with low Klintrup score (HR 0.16; 95 % CI (0.03-0.96); P = 0.045), venous invasion (HR 4.19; 95 % CI (1.08-16.29); P = 0.039) and higher Dukes' stage (HR 6.43; 95 % CI (1.22-33.97); P = 0.028). Minimum follow-up was 109 months and there were 24 cancer deaths. On multivariate analysis, high Klintrup score (HR 0.33; 95 % CI (0.12-0.93); P = 0.036), 4p- (HR 4.01; 95 % CI (1.58-10.21); P = 0.004) and 5q- (HR 3.81; 95 % CI (1.54-9.47); P = 0.004) were significantly associated with survival. CONCLUSION: 4p-, 5q- and low Klintrup score were independently associated with poor cancer-specific survival in node negative MSS colorectal cancer. Confirmatory work in a larger cohort is needed to determine whether these markers may be used to identify patients who may benefit from adjuvant chemotherapy. PMID- 24072234 TI - Intrapleural hyperthermic perfusion using distilled water at 48 degrees C for malignant pleural effusion. AB - BACKGROUND: To evaluate the feasibility, safety and preliminary efficacy of B ultrasound-guided continuous circulatory intrapleural hyperthermic perfusion (IHP) with distilled water (DW) at 48 degrees C, for the treatment of malignant pleural effusion (MPE). METHODS: Prospective, randomized interventional study in China (from December 2008 to December 2011) in adults with MPE originating from disseminated pleural tumor. EXCLUSION CRITERIA: thoracotomy or surgical resection, limited encapsulated pleural effusion or extensive pleural adhesions. Patients were randomly divided into DW (12 patients; B-ultrasound-guided IHP with 48 degrees C DW) and PSS-C (11 patients; B-ultrasound-guided IHP with 45 degrees C physiological saline solution and cisplatin) groups. Patients were followed up for assessment of objective MPE remission rate, Karnofsky performance scale (KPS) scores and survival duration. RESULTS: Pleural effusion was controlled in 100 % of patients, and mean KPS score was increased by 40 % after therapy. Patients' median survival times in the DW and PSS-C groups were 13.0 and 12.9 months, respectively. No serious clinical complications were observed. There were no significant differences between groups in the total objective MPE remission rate, mean KPS score change or median survival time, demonstrating the achievement of significant clinical efficacy with our modified IHP. CONCLUSION: Intrapleural hyperthermic perfusion with 48 degrees C DW is feasible, easy to perform and relatively safe. This method may offer excellent local control for patients with MPE secondary to disseminated pleural lesions. PMID- 24072236 TI - Long-term parvovirus B19 infections with genetic drift after cord blood transplantation complicated by persistent CD4+ lymphocytopenia. AB - A 5-month-old girl was diagnosed with Langerhans cell histiocytosis and received unrelated umbilical cord blood transplantation at the age of 14 months. After cord blood transplantation, CD4(+) lymphocytopenia from unknown causes was observed, and persistent infections with human parvovirus B19 (B19) occurred. We performed repeated longitudinal genetic analysis for B19, which revealed 6 nucleotide mutations in B19 nonstructural protein regions in the patient. The resulting changes of the nonstructural 1 structure may have altered antigenicity of the virus and could play a role in the pathogenesis of persistent infection under immunocompromised conditions. PMID- 24072235 TI - Percutaneous ablation therapy versus surgical resection in the treatment for early-stage hepatocellular carcinoma: a meta-analysis of 21,494 patients. AB - PURPOSE: To compare comprehensively the benefits of radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) with those of surgical resection (SR) in early-stage hepatocellular carcinoma (HCC). METHODS: The potentially relevant studies comparing the efficacy and safety of RFA and/or PEI with those of SR were searched using the databases such as PubMed, MEDLINE, Embase and Chinese databases (CNKI and Wanfang data). Overall survival rate, recurrence-free survival rate and complications were compared and analyzed. Pooled odds ratios with 95 % confidence intervals (95 % CIs) were calculated using either the fixed effects model or random-effects model. All statistic analyses were conducted using the Review Manager (version 5.1.) from the Cochrane Collaboration. RESULTS: Our analysis showed that the overall survival rate in patients treated with SR was significantly higher than that of percutaneous ablation therapy (PAT) [SR vs. PAT: 95 % confidence interval (95 % CI)2-year 0.46-0.89, P = 0.009; 95 % CI3-year 0.57-0.83, P < 0.0001; 95 % CI5-year 0.45-0.46, P < 0.0001]. SR was associated with significantly higher recurrence-free survival rate compared with PAT (SR vs. PAT: 95 % CI1-year 0.51-0.90, P = 0.008; 95 % CI2-year 0.41-0.78, P = 0.0004; 95 % CI3-year 0.38-0.77, P = 0.0006; 95 % CI5-year 0.33-0.61, P < 0.0001). SR resulted in longer survival than PAT in HCCs no larger than 3 cm. PAT was associated with less complications compared with SR (PAT vs. SR: 95 % CI 0.14 0.76, P = 0.01). CONCLUSIONS: Although SR was associated with more complications, SR was superior to RFA and PEI for treatment of patients with early-stage HCC. PMID- 24072237 TI - Follicular variant of papillary carcinoma presenting as a hyperfunctioning thyroid nodule. AB - In this study, we describe a case of papillary carcinoma in a 15-year-old girl who presented with a hyperfunctioning (hot) thyroid nodule and discuss it in the context of current management guidelines for patients with thyroid nodules. In adults, hot nodules rarely require cytologic or histologic evaluation, and hyperthyroidism is often treated with radioiodine (131I). However, in children and adolescents, the malignancy rate for nodules (both cold and hot) is higher and surgery is often necessary. Surgery may serve as a therapy, as well as a diagnostic tool, to treat hot nodules in children and adolescents. PMID- 24072238 TI - A rare case of congenital Ewing sarcoma/PNET of the scapula. AB - Ewing sarcoma (ES)/primitive neuroectodermal tumors (PNET) are known to occur at both central and peripheral locations, as well as at skeletal and extraskeletal sites. They most commonly occur in the first 2 decades of life. We report a rare case of congenital Ewing sarcoma/primitive neuroectodermal tumor arising from the scapula. PMID- 24072239 TI - Chediak-Higashi syndrome: novel mutation of the CHS1/LYST gene in 3 Omani patients. AB - BACKGROUND: Chediak-Higashi syndrome (CHS) is a rare, autosomal, recessive lysosomal disorder with hematological and immunologic abnormalities; however, stem-cell transplantation from a matched or related donor may be curative. Many mutations of the CHS1/LYST gene have been reported to date. We report a novel nonsense mutation of the CHS1/LYST gene in 3 Omani patients. METHODS AND RESULTS: Three patients from 2 different families presented with clinical and laboratory features of CHS and a history of death of a previous sibling because of a severe illness, suggestive of the accelerated phase of CHS. Giant granules were present in the myeloid cell lines. Before the stem-cell transplant, the first patient underwent gene sequencing of all exons of the lysosome trafficking regulator (CHS1/LYST) gene and revealed a nonsense mutation in exon 5 (c.925C>T, p.R309X). Subsequently, upon presentation, the second and third patients' direct gene sequencing of exon 5 revealed the same mutation. CONCLUSIONS: We report a nonsense mutation in exon 5 (c.925C>T, p.R309X). This supports the allelic heterogeneity of CHS and is in line with most reported mutation types that lead to a truncated protein. Identification of the mutation type will facilitate timely diagnosis, management, and family counseling for those with affected children in Oman. PMID- 24072240 TI - Open-label bendamustine monotherapy for pediatric patients with relapsed or refractory acute leukemia: efficacy and tolerability. AB - This open-label, single-arm, phase I/II, dose-escalation study was designed to determine the recommended phase II dose (RP2D), pharmacokinetics, tolerability, and efficacy of bendamustine in pediatric patients (age ranging from 1 to 20 y) with histologically proven relapsed/refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Patients (27 with ALL, 16 with AML) received intravenous bendamustine on days 1 and 2 of each treatment cycle. Phase I involved planned dose escalation of bendamustine to establish the RP2D for phase II. Objectives included overall response rate, duration of response, and tolerability. Eleven patients were treated in phase I, and the RP2D was 120 mg/m. In phase II, 32 patients received bendamustine 120 mg/m. Two patients with ALL (bendamustine 90 mg/m) experienced complete response (CR). Among patients who received bendamustine 120 mg/m, 2 experienced partial response (PR); 7 had stable disease. The overall response rate (CR+CR without platelet recovery [CRp]) was 4.7% and biological activity rate (CR+CRp+PR) was 9.3%. No AML patients responded. The most common adverse events were anemia, neutropenia, thrombocytopenia, pyrexia, nausea, vomiting, and diarrhea. Bendamustine monotherapy has acceptable tolerability in heavily pretreated children with relapsed/refractory ALL or AML and appears to have some activity in ALL, warranting further studies in combination trials. PMID- 24072241 TI - Acute lymphoblastic leukemia developing in a patient with Noonan syndrome harboring a PTPN11 germline mutation. AB - Noonan syndrome (NS) is a congenital genetic disorder characterized by certain facial features, short stature, and congenital heart disease. The disorder is caused by genetic alterations in the RAS/MAPK signal pathway. NS patients show a predisposition to malignancy; however, acute lymphoblastic leukemia (ALL) is rarely reported. Here, we describe a NS patient with B-cell precursor ALL (BCP ALL) harboring a hyperdiploid karyotype and a PTPN11 germline mutation (c.922A>G; p.N308D). We also discuss the relationship between the hyperdiploid karyotype and genetic alterations in the RAS/MAPK pathway in BCP-ALL. PMID- 24072242 TI - Homozygous antithrombin deficiency in adolescents presenting with lower extremity thrombosis and renal complications: two case reports from Turkey. AB - We present 2 cases of lower extremity deep venous thrombosis in 2 gypsy adolescents from related families. The patients had low antithrombin activity levels and inherited homozygous antithrombin deficiency was confirmed by molecular analysis (Leu131Phe mutation). One patient had a history of nephrectomy at the age of 9 due to nonfunctioning kidney and 2 siblings died at 4 months of age. His mother had 3 fetal losses in the third trimester. The other propositus had an elder sister who suffered from postpartum deep vein thrombosis and pulmonary embolism. Heterozygous mutation was demonstrated in both parents. PMID- 24072243 TI - Hemophagocytic lymphohistiocytosis associated with parechovirus 3 infection. AB - Hemophagocytic lymphohistiocytosis (HLH) denotes the common final pathway of a potentially fatal hyperinflammatory condition of diverse etiologies. We describe the first case of documented HLH associated with human parechovirus 3. A monoallelic Ala91Val mutation was found in the PRF1 gene, but the contribution of this mutation to HLH remains controversial. The diagnosis, based on accepted criteria, was established early in the course of the disease and led to successful treatment and complete recovery. The awareness of this new association is clinically important in facilitating early treatment, preventing organ damage, and increasing the likelihood of complete recovery. PMID- 24072244 TI - Inflammatory myofibroblastic tumor: an unusual mimicker of childhood intrathoracic tuberculosis. AB - Inflammatory myofibroblastic tumors are rare lesions of uncertain etiology that are often difficult to diagnose because of their myriad clinical presentations. Not uncommon, they mimic persistent pneumonia. We report a 4-year-old girl who presented with prolonged pyrexia, weight loss, severe anemia, hepatosplenomegaly, and nonresolving pneumonia. Initial investigations including flexible bronchoscopy and bronchial washing for usual causes of persistent pneumonia, such as tuberculosis and other infections, were negative. Chest computed tomography revealed a well-defined lesion involving the lingula and left upper lobe with extension into the subpleural space. Pleural tap and biopsy was also noncontributory. Thoracoscopic biopsy was suggestive of an inflammatory myofibroblastic tumor. As the lesion was encasing the major vessels, it was considered inoperable. The patient did not respond to steroid therapy and etoricoxib and later succumbed to the illness. This uncommon tumor should be considered in the differential diagnosis of children who presented with unresolving consolidation with pyrexia. PMID- 24072245 TI - Golden bullet-denosumab: early rapid response of metastatic giant cell tumor of the bone. AB - Giant cell tumor of the bone (GCTB) is usually a benign, locally aggressive tumor with metastatic potential. Histogenesis of GCTB is unknown and a correlation has not been found between histologic and clinical course. For this reason, many authors consider its prognosis unpredictable. Lung metastasis after GCTB treatment is well known and generally has unfavorable outcome, despite varied chemotherapy regimens. Denosumab, which inhibits RANK-RANKL interaction, is a new, promising actor among targeted therapeutic agents for GCTB. In this report, we emphasize on early rapid response to denosumab in metastatic GCTB. PMID- 24072246 TI - Cisplatin-induced hearing loss: the need for a long-term evaluating system. AB - Cisplatin is an effective chemotherapeutic agent against pediatric cancers; however, ototoxicity is a concern. This study describes the frequency, severity, and clinical course of hearing loss in Japanese pediatric patients treated with cisplatin-based multimodal therapy. A total of 55 children who received cisplatin based therapy from 1983 to 2012 underwent audiologic evaluations. Data were analyzed to determine the onset, time-to-progression, and severity of hearing loss. Thirty-five patients, 12 of 16 older patients (4 y or older), and 23 of 39 younger patients (under 4 y), including 7 of 8 patients treated with cisplatin, carboplatin, and radiotherapy, developed hearing loss. Ten of 18 patients who received a cumulative cisplatin dose of <360 mg/m developed hearing loss at a minimum dose of 200 mg/m. Median time to onset after the last cisplatin dose was 71 days; 6 patients developed hearing loss after >=2 years. Four patients required hearing aids, 6 patients developed progressive hearing loss with time, and 4 patients exhibited persistent hearing failure at low frequencies. Risk factors for acquired hearing loss and its severity may be associated with a combination of factors such as cisplatin and carboplatin therapy, radiotherapy, age at diagnosis, and genetic background. Our results suggested that all pediatric patients treated with cisplatin would have their hearing evaluated regularly, irrespective of the cumulative cisplatin dose as a suggestion, and that further prospective studies regarding ototoxicity including genetic polymorphisms analysis were required. PMID- 24072247 TI - Infantile extrapancreatic pancreatoblastoma: a report on a rare infantile abdominal mass. AB - Pancreatoblastoma is an extremely rare tumor in children, especially under 3 months of age. This tumor may arise from any portion of the pancreas, but in more rare cases the ectopic pancreas is the origin. We are reporting a 3-month-old boy who was presented with an abdominal mass. Computed tomography images revealed a huge lobulated mass anterior to the kidneys, with internal calcification and enhancement after intravenous contrast media injection. He underwent a complete surgical resection of the mass that was located in the transverse mesocolon without any connection with the pancreas. Pathologic studies specified that the disease was pancreatoblastoma. His parents refused any chemotherapeutic regimen but continued postsurgical follow-ups. PMID- 24072248 TI - Ectopic production of beta-hCG by osteosarcoma: a case report and review of the literature. AB - Ectopic production of beta-human chorionic gonadotropin (beta-hCG) by nontrophoblastic tumors has been reported but mostly in carcinomas. We report a case of an adolescent female patient with a epithelioid osteosarcoma that was discovered to secrete beta-hCG after routine pregnancy testing. Immunohistochemical staining of her primary tumor biopsy demonstrated immunoreactivity for beta-hCG. Levels of serum beta-hCG were monitored throughout her therapy and demonstrated normalization with effective systemic therapy and local control. She remains disease free 6 months off therapy, with undetectable hormone levels. A review of the available literature on beta-hCG production by sarcomas is also presented. PMID- 24072249 TI - A retrospective study to assess the utility of frequent laboratory monitoring of pediatric patients with sickle cell disease on hydroxyurea. AB - Hydroxyurea (hydroxycarbamide, HU) is currently the only FDA-approved disease modifying agent for individuals with sickle cell disease. Despite its efficacy in multicentered, randomized, placebo-controlled studies, HU remains highly underutilized among the sickle cell population. Several barriers to the use of HU have been identified including the need for frequent laboratory monitoring and physician visits. This study aimed to better assess the stability of patients' hematologic parameters when compliant with HU therapy to better determine the necessity of frequent routine laboratory monitoring. We conducted a retrospective review of 20 patients taking HU with record of good compliance. The within subject coefficient of variation was computed as a measure of subject variability to better assess the stability of individual patients' blood counts to evaluate potential hematologic toxicity in subjects taking HU. Results demonstrated that during routine laboratory appointments, individuals' variability was very consistent; therefore assessment of significant change may be more accurately detected by individual symptomatology. Decreasing the stringency of the requirements for routine laboratory monitoring for patients on HU is unlikely to cause physicians to miss critical nadirs in absolute neutrophil count (or other laboratory values) and may lead to improved acceptance and use of this disease modifying therapy in sickle cell disease. PMID- 24072250 TI - Basal ganglia germinoma: MRI classification correlates well with neurological and cognitive outcome. AB - Basal ganglia germinomas (BGG) are often associated with delayed diagnosis because of their nonspecific clinical presentation and subtle abnormalities on initial neuroimaging. Despite excellent survival, the prognostic indicators still remained unclear. From our case series, we demonstrated that the MRI classification scheme devised by Phi and colleagues is useful in predicting neurological and cognitive outcomes for patients with unilateral BGG. Subtle lesions with faint or no contrast enhancement are associated with early cerebral atrophy with progressive neurological deficits and poor cognitive outcomes. BGG along with bilateral involvement, regardless of the types of lesion, are also associated with poor neurological and cognitive outcomes. PMID- 24072251 TI - Magnetic resonance imaging spectroscopy in pediatric atypical teratoid rhabdoid tumors of the brain. AB - BACKGROUND: Pediatric central nervous system (CNS) atypical teratoid rhabdoid tumors (ATRT) are highly malignant tumors characterized by SMARCB1 gene abnormalities. Despite chemoradiation responsiveness, most children die of disease. No imaging findings distinguish ATRT from other malignant brain tumors. This study sought to describe magnetic resonance spectroscopy (MRS) of childhood CNS ATRT and identify metabolite patterns for diagnosis and disease status monitoring. METHODS: Data from 7 children diagnosed with CNS ATRT from 2007 to 2010, whose imaging included MRS, were retrospectively reviewed. RESULTS: Age at diagnosis ranged from 2.5 to 54 months. Tumors were large with calcium and cysts and avid gadolinium enhancement. All were isointense on T1-weighted imaging and mildly hyperintense on T2-weighted imaging. Short-TE MRS showed prominent lactate+lipid and choline, minimal N-acetyl acetate (NAA), and rarely minimal myoinositol and low creatine peaks. Long TE showed prominent choline, minimal NAA, and rarely low lactate peaks. CONCLUSIONS: The combination of prominent choline and lactate+lipids peaks, and generally absent NAA and myoinositol peaks by MRS in this panel of ATRT expands existing information and provides a potentially distinct metabolite profile from other malignant pediatric brain tumors, including medulloblastoma. Prospective, comparative quantitative MRS of ATRT with other pediatric CNS tumors is warranted. PMID- 24072252 TI - Severe leukemoid reaction in a preterm infant with congenital cytomegalovirus infection. AB - Leukemoid reaction, defined as a total leukocyte count of >50,000/mm, is most commonly related to antenatal administration of steroids, infections, and transient myeloproliferative disorder of Down syndrome in newborns. Atypical presentations of viral infections can be a diagnostic challenge in the newborn period. Cytomegalovirus (CMV) infection causes a multisystem disease, and symptomatic infants generally present with intrauterine growth restriction, hepatosplenomegaly, cholestasis, rash, thrombocytopenia, and microcephaly. We present a case of a preterm infant with severe myeloid leukemoid reaction (leukocyte count >100,000/mm) at birth who was diagnosed with congenital CMV infection on the basis of CMV polymerase chain reaction results after the appearance of cholestasis, blueberry muffin rash, and hepatosplenomegaly. PMID- 24072253 TI - The role of whole-body MRI in pediatric oncology. AB - Pediatric whole-body (WB) magnetic resonance imaging (MRI) is an established technique that, with improved accessibility and advances in technology, is being used with increasing frequency for a wide variety of applications. The advantages of WB MRI (over other imaging modalities), particularly its lack of ionizing radiation (of particular concern in pediatric imaging due to children's increased sensitivity to ionizing radiation) and the ability of MRI to image the bone marrow, solid organs, and soft tissues with superior soft-tissue contrast resolution to other techniques, promise that WB MRI has great potential in conditions that are diffuse or multifocal. There is particular interest in its role in the field of pediatric oncology (eg, lymphoma, neuroblastoma, sarcoma, and Langerhans cell histiocytosis). The main disadvantages of WB MRI are its relatively long scanning times, artifacts from motion (requiring patient cooperation or general anesthesia), and limited specificity. However, advances in hardware and imaging techniques, including additional sequences (out-of-phase imaging, diffusion-weighted imaging, and contrast enhancement) are reducing the impact of some of these challenges. PMID- 24072254 TI - Langer-Giedion syndrome: the evolving imaging features in hands and beyond. AB - Trichorhinophalangeal syndrome (TRP) is a group of rare genetic disorders with characteristic clinical and radiological features. In this case report we discuss the evolution of imaging features in hands in a Chinese boy diagnosed with TRP II (Langer-Giedion syndrome, LGS). This article ramifies the diagnostic value of serial hand radiograph in clinically suspected cases of TRP. PMID- 24072255 TI - Radiographic findings in Waldenstrom's macroglobulinemia resembling fibrogenesis imperfecta ossium (FIO): a case report. AB - A case of Waldenstrom's macroglobulinemia with radiographic features of fibrogenesis imperfecta ossium is presented. The case raises the possibility that these radiographic findings might be more common in Waldenstrom's macroglobulinemia than previously appreciated, and illustrates the need for bone biopsy to establish a definitive diagnosis of fibrogenesis imperfecta ossium. PMID- 24072256 TI - Comprehensive characterizations of nanoparticle biodistribution following systemic injection in mice. AB - Various nanoparticle (NP) properties such as shape and surface charge have been studied in an attempt to enhance the efficacy of NPs in biomedical applications. When trying to undermine the precise biodistribution of NPs within the target organs, the analytical method becomes the determining factor in measuring the precise quantity of distributed NPs. High performance liquid chromatography (HPLC) represents a more powerful tool in quantifying NP biodistribution compared to conventional analytical methods such as an in vivo imaging system (IVIS). This, in part, is due to better curve linearity offered by HPLC than IVIS. Furthermore, HPLC enables us to fully analyze each gram of NPs present in the organs without compromising the signals and the depth-related sensitivity as is the case in IVIS measurements. In addition, we found that changing physiological conditions improved large NP (200-500 nm) distribution in brain tissue. These results reveal the importance of selecting analytic tools and physiological environment when characterizing NP biodistribution for future nanoscale toxicology, therapeutics and diagnostics. PMID- 24072257 TI - Coinage metal exciplexes with helium atoms: a theoretical study of M*(2L)He(n) (M = Cu, Ag, Au; L = P,D). AB - The structure and energetics of exciplexes M*((2)L)He(n) (M = Cu, Ag and Au; L = P and D) in their vibrational ground state are studied by employing diffusion Monte Carlo (DMC). Interaction potentials between the excited coinage metals and He atoms are built using the Diatomics-in-Molecule (DIM) approach and ab initio potential curves for the M((2)L)-He dimers. Extending our previous work [Cargnoni et al., J. Phys. Chem. A, 2011, 115, 7141], we computed the dimer potential for Au in the (2)P and (2)D states, as well for Cu and Ag in the (2)D state, employing basis set superposition error-corrected Configuration Interaction calculations. We found that the (2)Pi potential correlating with the (2)P state of Au is substantially less binding than for Ag and Cu, a trend well supported by the M(+) ionic radiuses. Conversely, the interaction potentials between a (n - 1)d(9)ns(2 2)D metal and He present a very weak dependency on M itself or the projection of the angular momentum along the dimer axis. This is due to the screening exerted by the ns(2) electrons on the hole in the (n - 1)d shell. Including the spin-orbit coupling perturbatively in the DIM energy matrix has a major effect on the lowest potential energy surface of the (2)P manifold, the one for Cu allowing the formation of a "belt" of five He atoms while the one for Au being completely repulsive. Conversely, spin-orbit coupling has only a weak effect on the (2)D manifold due to the nearly degenerate nature of the diatomic potentials. Structural and energetic results from DMC have been used to support experimental indications for the formation of metastable exciplexes or the opening of non-radiative depopulation channels in bulk and cold gaseous He. PMID- 24072258 TI - CO oxidation on stepped-Pt(111) under electrochemical conditions: insights from theory and experiment. AB - The co-adsorption of CO and OH on two Pt stepped surfaces vicinal to the (111) orientation has been evaluated by means of density functional theory (DFT) calculations. Focusing on Pt(533) and Pt(221), which contain (100) and (111) steps, respectively, we find that (111)-steps should be more reactive towards CO oxidation than surfaces containing (100)-steps. The DFT results are compared with electrochemical experiments on the CO adsorption and oxidation on these vicinal surfaces. PMID- 24072259 TI - Removal of fluoride from contaminated ground water using raw and modified bauxite. AB - Endemic fluorosis affects millions of people worldwide. Fluorosis arises from the consumption of fluorine (F) contaminated water and was observed also in some parts of Turkey with volcanic rocks and geothermal resources. In the present study the removal of F from drinking water by raw and modified bauxite at the laboratory scale was investigated using a batch mode. Modified bauxite was prepared by using Na and Mg incorporated (B-Na, B-Mg) bauxite and calcination of Mg incorporated bauxite at 500 degrees C (B-Mg-500). The equilibration time for F between bauxite and water was identified to be 3 h. Adsorption of F increased with increasing adsorbent dose. Moreover, F adsorption isotherms fitted well with the Freundlich model. Low F adsorption was obtained onto the raw and incorporated bauxite. In contrast, maximum F adsorption was found for B-Mg-500, with Kf value of 0.247. This observation may be explained by the meaningfully stabilized and elevated number of positively charged sites in B-Mg-500. PMID- 24072260 TI - Ecotoxicity assessment of artificial groundwater recharge with reclaimed water: a pilot-scale study. AB - A demonstration of artificial groundwater recharge with tertiary effluent was evaluated using a set of bioassays (acute toxicity to Daphnia, genotoxicity, estrogenic and antiestrogenic toxicity). Around 95 % genotoxicity and 53 % antiestrogenicity were removed from the feed water by ozonation, whereas significant reduction of acute toxicity to Daphnia magna was achieved during a 3 days vadose soil treatment. The toxicity was further removed to the same level as the local groundwater during a 20 days aquifer soil treatment. The pilot study has shown that ozonation and soil treatments can improve the quality of municipal wastewater treatment plant effluents for possible groundwater recharge purposes. PMID- 24072261 TI - Selected heavy metals and selenium in the blood of black sea turtle (Chelonia mydas agasiizzi) from Sonora, Mexico. AB - The concentration of heavy metals (Zn, Cd, Ni, Cu, Mn) and selenium (Se) was analyzed in blood collected from 12 black turtles (Chelonia mydas agasiizzi) captured in Canal del Infiernillo, Punta Chueca, Mexico. The most abundant metals were Zn (63.58 MUg g(-1)) and Se (7.66 MUg g(-1)), and Cd was the lower (0.99 MUg g(-1)). The sequential concentrations of trace metals were Zn > Se > Cu > Mn > Ni > Cd. In conclusion, this information is important as a baseline when using blood as tissue analysis of heavy metals; however, these levels could represent recent exposure in foraging grounds of black turtles in the Sea of Cortez. PMID- 24072262 TI - Effects of antigen-expressing immunostimulatory liposomes on chemotaxis and maturation of dendritic cells in vitro and in human skin explants. AB - PURPOSE: Antigen-Expressing Immunostimulatory Liposomes (AnExILs) represent a novel DNA vaccination platform based on the production of protein antigens from DNA templates inside liposomes mediated by an in vitro transcription and translation (IVTT) mix. The aim of this study was to analyze the effects of AnExILs on different dendritic cells (DCs) models and to better understand the role of the different components of this formulation on its adjuvanticity. METHODS: The effect of beta-galactosidase-expressing AnExILs on maturation and particle uptake by murine DC cell line, fresh human monocyte-derived DCs or human dermal DCs in skin explants was investigated and compared to the effects of either plain liposomes or IVTT mix alone. RESULTS: AnExILs induced efficient DC chemotaxis and promoted up-regulation of maturation markers on murine DCs, due to the presence of IVTT in the formulation. Furthermore, the amount of active betaGal associated with DCs was higher for AnExILs than for free betaGal expressed in IVTT or betaGal encapsulated into non-adjuvanted liposomes. Most interestingly, the same trend was observed with human DCs. CONCLUSIONS: Both IVTT mix and liposomal vehicles were shown to be key components of the AnExIL formulation responsible for its adjuvanticity. AnExILs combine antigen production, adjuvanticity and delivery in one system, and can efficiently activate both murine and human DCs. PMID- 24072264 TI - The use of ROC analysis for the qualitative prediction of human oral bioavailability from animal data. AB - PURPOSE: To develop and evaluate a tool for the qualitative prediction of human oral bioavailability (Fhuman) from animal oral bioavailability (Fanimal) data employing ROC analysis and to identify the optimal thresholds for such predictions. METHODS: A dataset of 184 compounds with known Fhuman and Fanimal in at least one species (mouse, rat, dog and non-human primates (NHP)) was employed. A binary classification model for Fhuman was built by setting a threshold for high/low Fhuman at 50%. The thresholds for high/low Fanimal were varied from 0 to 100 to generate the ROC curves. Optimal thresholds were derived from 'cost analysis' and the outcomes with respect to false negative and false positive predictions were analyzed against the BDDCS class distributions. RESULTS: We successfully built ROC curves for the combined dataset and per individual species. Optimal Fanimal thresholds were found to be 67% (mouse), 22% (rat), 58% (dog), 35% (NHP) and 47% (combined dataset). No significant trends were observed when sub-categorizing the outcomes by the BDDCS. CONCLUSIONS: Fanimal can predict high/low Fhuman with adequate sensitivity and specificity. This methodology and associated thresholds can be employed as part of decisions related to planning necessary studies during development of new drug candidates and lead selection. PMID- 24072263 TI - A novel rapamycin-polymer conjugate based on a new poly(ethylene glycol) multiblock copolymer. AB - PURPOSE: Rapamycin has demonstrated potent anti-tumor activity in preclinical and clinical studies. However, the clinical development of its formulations was hampered due to its poor solubility and undesirable distribution in vivo. Chemical modification of rapamycin presents an opportunity for overcoming the obstacles and improving its therapeutic index. The objective of this study is to develop a drug-polymer conjugate to increase the solubility and cellular uptake of rapamycin. METHODS: We developed the rapamycin-polymer conjugate using a novel, linear, poly(ethylene glycol) (PEG) based multiblock copolymer. Cytotoxicity and cellular uptake of the rapamycin-polymer conjugate were evaluated in various cancer cells. RESULTS: The rapamycin-polymer conjugate provides enhanced solubility in water compared with free rapamycin and shows profound activity against a panel of human cancer cell lines. The rapamycin polymer conjugate also presents high drug loading capacity (wt% ~ 26%) when GlyGlyGly is used as a linker. Cellular uptake of the conjugate was confirmed by confocal microscopic examination of PC-3 cells that were cultured in the presence of FITC-labled polymer (FITC-polymer). CONCLUSION: This study suggests that the rapamycin-polymer conjugate is a novel anti-cancer agent that may provide an attractive strategy for treatment of a wide variety of tumors. PMID- 24072265 TI - Mechanisms controlling theophylline release from ethanol-resistant coated pellets. AB - PURPOSE: To elucidate the mass transport mechanisms controlling drug release from recently proposed, ethanol-resistant, polymeric film coatings. METHODS: Theophylline matrix pellets were coated with ethylcellulose: guar gum blends. Drug release from single pellets and ensembles of pellets was measured in various release media. Changes in the systems' morphology, composition and mechanical properties were monitored using SEM, gravimetrical analysis and a texture analyzer. Based on the obtained experimental results a mechanistically realistic mathematical model was identified and used to quantitatively predict drug release from coated pellets in ethanol-free and ethanol-containing bulk fluids. RESULTS: Drug diffusion though the intact polymeric film coatings is likely to be the dominant mass transport mechanism in the investigated systems, irrespective of the ethanol content in the surrounding environment. An appropriate solution of Fick's law could be used to quantitatively predict theophylline release from pellets coated with different ethylcellulose:guar gum blends at different coating levels. Importantly, independent experiments confirmed the theoretical predictions. CONCLUSIONS: In silico simulations can help facilitating the optimization of the novel ethanol-resistant polymeric film coatings, avoiding time-consuming and cost-intensive series of trial-and-error experiments. The presence/absence of ethanol does not affect the underlying drug release mechanisms. PMID- 24072268 TI - Clinical characteristics of breast cancer in patients with an NBS1 mutation. AB - To identify characteristic features of breast cancers associated with an NBS1 mutation. To estimate and to compare 10-year survival rates for patients with early-onset breast cancer, with and without an NBS1 mutation. 4,566 women with stage I to stage III breast cancer, diagnosed at or below age 50, were tested for a founder mutation in the NBS1 gene. Information on tumor characteristics and on treatments received was retrieved from medical records. Dates of death were obtained from the Poland vital statistics registry. Survival curves for the mutation-positive and negative sub-cohorts were generated and were compared and the effect of an NBS1 mutation on survival was determined using the Cox proportional hazards model. 4566 patients were enrolled in the study, of whom 53 (1.2 %) carried a NBS1 mutation. Mutation carriers were similar to non-carriers in terms of tumor receptor status, grade, and lymph node status. The 10-year survival for NBS1 mutation carriers was 81.2 % (95 % CI 70.1-94.1 %) and for non carriers was 79.4 % (95 % CI 78.0-80.9 %). The presence of an NBS1 mutation is not associated with prognosis (HR = 1.21; 95 % 0.67-2.19). The survival of women with breast cancer and a NBS1 mutation is similar to that of patients without a NBS1 mutation. PMID- 24072269 TI - Post-surgical highly sensitive C-reactive protein and prognosis in early-stage breast cancer. AB - Obesity, associated with inflammation, has been linked to poor prognosis in breast cancer. Research investigating the potential role of C-reactive protein (CRP), an obesity-associated systemic marker of inflammation, as a mediator of adverse prognostic effects of obesity has yielded inconsistent results. We examined the association of highly sensitive CRP (hsCRP) with obesity-related factors and breast cancer outcome. A cohort of 535 non-diabetic women diagnosed with T1-3, N0-1, M0 breast cancer, was assembled between 1989 and 1996 and followed prospectively. Circulating levels of hsCRP were analyzed on blood obtained postoperatively, prior to systemic therapy, in 501 women. Correlations and prognostic associations were analyzed using one-way analysis of variance, Spearman's rank correlation coefficients (r) and Cox models. hsCRP was significantly correlated with body mass index (r = 0.60), insulin (r = 0.44), leptin (r = 0.54), and lipids, but not T or N stage, grade or estrogen receptor/progesterone receptor. At a median follow-up of 12 years, hsCRP was not associated with distant disease-free survival or overall survival in univariable [Q4 vs. Q1 hazard ratio (HR) 1.03, 95 % confidence interval (CI) 0.69-1.52, P = 0.9 and HR 1.27, 95 % CI 0.86-1.86, P = 0.24, respectively] or multivariable [Q4 vs Q1 HR 1.02, 95 % CI 0.66-1.59, P = 0.93 and HR 1.17, 95 % CI 0.76-1.81, P = 0.48 respectively] analyses. hsCRP was associated with age, comorbidities, and the insulin resistance syndrome but not with breast cancer outcome. PMID- 24072267 TI - Human and non-human primate intestinal FcRn expression and immunoglobulin G transcytosis. AB - PURPOSE: To evaluate transcytosis of immunoglobulin G (IgG) by the neonatal Fc receptor (FcRn) in adult primate intestine to determine whether this is a means for oral delivery of monoclonal antibodies (mAbs). METHODS: Relative regional expression of FcRn and localization in human intestinal mucosa by RT-PCR, ELISA & immunohistochemistry. Transcytosis of full-length mAbs (sandwich ELISA-based detection) across human intestinal segments mounted in Ussing-type chambers, human intestinal (caco-2) cell monolayers grown in transwells, and serum levels after regional intestinal delivery in isoflurane-anesthetized cynomolgus monkeys. RESULTS: In human intestine, there was an increasing proximal-distal gradient of mucosal FcRn mRNA and protein expression. In cynomolgus, serum mAb levels were greater after ileum-proximal colon infusion than after administration to stomach or proximal small intestine (1-5 mg/kg). Serum levels of wild-type mAb dosed into ileum/proximal colon (2 mg/kg) were 124 +/- 104 ng/ml (n = 3) compared to 48 +/- 48 ng/ml (n = 2) after a non-FcRn binding variant. In vitro, mAb transcytosis in polarized caco-2 cell monolayers and was not enhanced by increased apical cell surface IgG binding to FcRn. An unexpected finding in primate small intestine, was intense FcRn expression in enteroendocrine cells (chromagranin A, GLP-1 and GLP-2 containing). CONCLUSIONS: In adult primates, FcRn is expressed more highly in distal intestinal epithelial cells. However, mAb delivery to that region results in low serum levels, in part because apical surface FcRn binding does not influence mAb transcytosis. High FcRn expression in enteroendocrine cells could provide a novel means to target mAbs for metabolic diseases after systemic administration. PMID- 24072270 TI - Elevated levels of serum tumor markers CA 15-3 and CEA are prognostic factors for diagnosis of metastatic breast cancers. AB - To investigate the prognostic value of tumor markers, cancer antigen 15-3 (CA 15 3) and carcinoembryonic antigen (CEA) levels at diagnosis of systemic recurrence. After primary treatments of locoregional breast cancers, serum CA 15-3 and/or CEA concentrations were regularly measured, and systemic recurrences were identified in 351 patients between January 1999 and December 2009. The association between tumor marker levels at systemic recurrence and survival were investigated by univariate and multivariate analyses. Elevated CA 15-3 and CEA levels were identified in 194 of 349 (55.6 %) and 111 of 308 (36.0 %) patients, respectively, at diagnosis of systemic recurrence. Elevated levels of CA 15-3 and CEA were correlated with visceral or multiple recurrences and elevated preoperative levels. Elevation of CA 15-3 was more prominent in younger patients and in primary node-positive tumors, while CEA was elevated in older patients at diagnosis and in estrogen receptor (ER)-positive tumors. Elevated tumor markers as well as ER negativity, short disease-free interval, and advanced stage at initial diagnosis showed independent prognostic significance on multivariate analysis. Among 306 patients for whom levels of both tumor markers at recurrence were available, 106 patients without elevation of either marker showed significantly better overall survival than those with elevated levels of either one or both markers, and the significance persisted in multivariate analysis. Elevated serum CA 15-3 and CEA levels at recurrence suggest increased tumor burden and may be prognostic for survival for metastatic breast cancer patients. PMID- 24072272 TI - On the mend. PMID- 24072273 TI - Rule for cancer diagnosis. PMID- 24072271 TI - Gene-based GWAS and biological pathway analysis of the resilience of executive functioning. AB - Resilience in executive functioning (EF) is characterized by high EF measured by neuropsychological test performance despite structural brain damage from neurodegenerative conditions. We previously reported single nucleotide polymorphism (SNP) genome-wide association study (GWAS) results for EF resilience. Here, we report gene- and pathway-based analyses of the same resilience phenotype, using an optimal SNP-set (Sequence) Kernel Association Test (SKAT) for gene-based analyses (conservative threshold for genome-wide significance = 0.05/18,123 = 2.8 * 10(-6)) and the gene-set enrichment package GSA-SNP for biological pathway analyses (False discovery rate (FDR) < 0.05). Gene based analyses found a genome-wide significant association between RNASE13 and EF resilience (p = 1.33 * 10(-7)). Genetic pathways involved with dendritic/neuron spine, presynaptic membrane, postsynaptic density, etc., were enriched with association to EF resilience. Although replication of these results is necessary, our findings indicate the potential value of gene- and pathway-based analyses in research on determinants of cognitive resilience. PMID- 24072274 TI - Fundamental misunderstandings. PMID- 24072276 TI - Radiographic necessity. PMID- 24072278 TI - Vine withered dentistry. PMID- 24072279 TI - Better late than never. PMID- 24072280 TI - What will it take. PMID- 24072281 TI - Cojoined cementoma. PMID- 24072282 TI - Events provide direct access to answers. PMID- 24072283 TI - First aesthetic orthodontics society to hold conference. PMID- 24072287 TI - HPV linked to a third of throat cancer cases. PMID- 24072291 TI - Non-surgical periodontal therapy safe in pregnancy. PMID- 24072293 TI - Missing a tooth? Urine luck. PMID- 24072295 TI - 'A bridge too far'--the negative impact of a bridge prosthesis on gingival health and its conservative management. AB - Bridges are commonly used to replace missing teeth. Periodontal health may, however, be compromised by ill-fitting margins and excess cement. This case report describes the conservative management of chronic gingival inflammation adjacent to the resin-bonded retainers of an anterior bridge by gingival remodelling via a removable prosthesis. This avoided the need for surgical intervention and re-established a suitable gingival profile before placement of a definitive cantilever resin-bonded bridge. PMID- 24072296 TI - Oral surgery: part 2. Endodontic surgery. AB - In the past, the interaction between dentoalveolar surgery and restorative dentistry has been limited to the removal of teeth with pulp and/or periradicular disease or those that were unrestorable. However, with the increasing dental awareness of the population and the retention of teeth into later life, the interaction between dentoalveolar surgery and restorative dentistry is becoming a fundamental aspect of clinical practice. Indeed, endodontic and implant surgery are core activities that facilitate the retention of a functional dentition. PMID- 24072301 TI - Summary of: A retrospective, practice-based,clinical evaluation of Fuji IX restorations aged over five years placed in load-bearing cavities. PMID- 24072302 TI - Summary of: Why individuals with HIV or diabetes do not disclose their medical history to the dentist: a qualitative analysis. PMID- 24072303 TI - The role of teeth in human evolution. AB - A review of recent insights into palaeodiets provided by new dating techniques, spectroscopy and attritional wear of enamel in ancient and recent human fossils. Fossilised dental plaque reveals changing dietary content and varying oral microbiota between Neolithic and Industrial era populations. DNA analysis of ancient dental pulpal tissue provides evidence of contemporary hereditary relationships and gene flow of human populations. PMID- 24072324 TI - Why individuals with HIV or diabetes do not disclose their medical history to the dentist: a qualitative analysis. AB - INTRODUCTION: Evidence shows that some individuals with HIV or diabetes do not report their medical history to the dentist. Disclosure is important because these individuals can be at greater risk of oral disease. AIMS AND OBJECTIVES: The aim of this study is to provide greater understanding of why some individuals do not disclose HIV or diabetes to the dentist.Methods In-depth interviews were conducted with 20 participants (10 HIV & 10 diabetes) based around the participant's diagnosis and disclosure history. Data were analysed using framework analysis. RESULTS: While a lack of disclosure can be found among those with a diagnosis of HIV and diabetes, it appears that the reasons behind disclosure, or lack thereof, are different for each. The reasons are based around: differences in age, understanding of diagnosis, experience of stigma, past disclosure behaviour, trust in dentists and experience of healthcare. Few individuals had discussed the effects of their diagnosis with their dentist or were advised on the importance of seeing a dentist. DISCUSSION: Individuals with chronic illness should be advised why it is important for the dentist to know their medical history and should be made to feel comfortable to disclose. PMID- 24072325 TI - A retrospective, practice-based, clinical evaluation of Fuji IX restorations aged over five years placed in load-bearing cavities. AB - OBJECTIVE: To evaluate reinforced glass-ionomer restorations which had been placed in a general dental practice more than five years previously. METHOD: Patients who were identified as having received reinforced one or more reinforced glass-ionomer restorations were invited to attend for an examination of their restorations using scientific evaluation criteria, by one independent examiner and the dentist who owned the practice. RESULTS: Forty-two restorations were assessed, their mean age being 7 years and 9 months, in patients of mean age 57 years: 86% achieved an A rating for anatomic form, 69% A for marginal integrity, 81% A for surface roughness and 2% A for colour match. CONCLUSIONS: The restorations which were assessed were found to be performing satisfactorily at periods of over five years. However, the proportion of the total number of reinforced glass-ionomer restorations placed in the participating dental practice which this represents is not known. PMID- 24072326 TI - A double SORLIP1 element is required for high light induction of ELIP genes in Arabidopsis thaliana. AB - Promoter elements that contribute to high light (HL) induction of the Arabidopsis ELIP1 gene were defined using a transgenic promoter-reporter system. Two adjacent SORLIP1 elements (double SORLIP1, dSL) were found to be essential for HL induction of a GUS reporter gene. The dSL element was also found to be essential for HL induction conferred by the ELIP2 promoter. SORLIP1 elements were enriched in ELIP promoters throughout the plant kingdom, and showed a clade-specific pattern of gain or loss that suggested functionality. In addition, two G-box elements were found to redundantly contribute to HL induction conferred by the ELIP1 promoter. PMID- 24072328 TI - Re: Mean systemic filling pressure: we can now estimate it but for what? PMID- 24072327 TI - Linkage mapping, molecular cloning and functional analysis of soybean gene Fg2 encoding flavonol 3-O-glucoside (1 -> 6) rhamnosyltransferase. AB - There are substantial genotypic differences in the levels of flavonol glycosides (FGs) in soybean leaves. The first objective of this study was to identify and locate genes responsible for FG biosynthesis in the soybean genome. The second objective was to clone and verify the function of these candidate genes. Recombinant inbred lines (RILs) were developed by crossing the Kitakomachi and Koganejiro cultivars. The FGs were separated by high performance liquid chromatography (HPLC) and identified. The FGs of Koganejiro had rhamnose at the 6"-position of the glucose or galactose bound to the 3-position of kaempferol, whereas FGs of Kitakomachi were devoid of rhamnose. Among the 94 RILs, 53 RILs had HPLC peaks classified as Koganejiro type, and 41 RILs had peaks classified as Kitakomachi type. The segregation fitted a 1:1 ratio, suggesting that a single gene controls FG composition. SSR analysis, linkage mapping and genome database survey revealed a candidate gene in the molecular linkage group O (chromosome 10). The coding region of the gene from Koganejiro, designated as GmF3G6"Rt-a, is 1,392 bp long and encodes 464 amino acids, whereas the gene of Kitakomachi, GmF3G6"Rt-b, has a two-base deletion resulting in a truncated polypeptide consisting of 314 amino acids. The recombinant GmF3G6"Rt-a protein converted kaempferol 3-O-glucoside to kaempferol 3-O-rutinoside and utilized 3-O glucosylated/galactosylated flavonols and UDP-rhamnose as substrates. GmF3G6"Rt-b protein had no activity. These results indicate that GmF3G6"Rt encodes a flavonol 3-O-glucoside (1 -> 6) rhamnosyltransferase and it probably corresponds to the Fg2 gene. GmF3G6"Rt was designated as UGT79A6 by the UGT Nomenclature Committee. PMID- 24072329 TI - Persuading bereaved families to permit organ donation. PMID- 24072330 TI - Procalcitonin kinetics: a reliable tool for diagnosis and monitoring of the course of bacterial infection in critically ill patients with autoimmune diseases. PMID- 24072331 TI - Mean systemic filling pressure: we can now estimate it, but for what? Response to comment by Parkin. PMID- 24072332 TI - Acute iron intoxication: change in urine color during chelation therapy with deferoxamine. PMID- 24072333 TI - Artificial photosynthetic hydrogen evolution over g-C3N4 nanosheets coupled with cobaloxime. AB - We report an economic and noble-metal-free artificial photosynthetic system, consisting of g-C3N4 as a photosensitizer and a photocatalyst, and cobaloxime as a co-catalyst, for H2 generation. This system allows for effective electron transfer from excited g-C3N4 to Co(III)(dmgH)2pyCl to generate reduced cobaloxime intermediate species for efficient H2 evolution. Transient fluorescence studies reveal that the presence of cobaloxime and TEOA promotes the population of excited electrons to transfer from g-C3N4, which is responsible for the high photocatalytic activity of this g-C3N4-cobaloxime conjugation system. PMID- 24072334 TI - Intestinal parasites of the gopher tortoise (Gopherus polyphemus) from eight populations in Georgia. AB - The gopher tortoise (Gopherus polyphemus), one of five tortoise species endemic in the USA, was recently classified as a candidate for federal listing as a threatened species. Fecal samples collected from 117 tortoises from eight sites in Georgia were examined for endoparasites using a combination of sedimentation and flotation. Samples from an island population were examined for parasitic oocysts and ova only by flotation, protozoan cysts by trichrome-stained direct smear, and Cryptosporidium by direct immunofluorescence assay and ProSpecT rapid assay. A total of 99 tortoises (85, range 0-100%) was infected with pinworms (Alaeuris spp.), 47 (40, 0-86%) with cestodes (Oochorstica sp.), 34 (41, 0-74%) with Chapiniella spp., 2 (3, 0-33%) with Eimeria paynei, and a single tortoise each with a capillarid and ascarid (1%). On the island, Entamoeba was detected in one tortoise (2%) while Cryptosporidium oocysts were detected in eight (17%). In conclusion, at least eight species of parasites were detected including Cryptosporidium, a possible pathogen of tortoises. Interestingly, we detected spatial variation in the distribution of several parasites among populations suggesting additional work should be conducted across a gradient of tortoise densities, land use, and habitat characteristics. PMID- 24072335 TI - Online access to doctors' notes: patient concerns about privacy. AB - BACKGROUND: Offering patients online access to medical records, including doctors' visit notes, holds considerable potential to improve care. However, patients may worry about loss of privacy when accessing personal health information through Internet-based patient portals. The OpenNotes study provided patients at three US health care institutions with online access to their primary care doctors' notes and then collected survey data about their experiences, including their concerns about privacy before and after participation in the intervention. OBJECTIVE: To identify patients' attitudes toward privacy when given electronic access to their medical records, including visit notes. METHODS: The design used a nested cohort study of patients surveyed at baseline and after a 1-year period during which they were invited to read their visit notes through secure patient portals. Participants consisted of 3874 primary care patients from Beth Israel Deaconess Medical Center (Boston, MA), Geisinger Health System (Danville, PA), and Harborview Medical Center (Seattle, WA) who completed surveys before and after the OpenNotes intervention. The measures were patient-reported levels of concern regarding privacy associated with online access to visit notes. RESULTS: 32.91% of patients (1275/3874 respondents) reported concerns about privacy at baseline versus 36.63% (1419/3874 respondents) post-intervention. Baseline concerns were associated with non-white race/ethnicity and lower confidence in communicating with doctors, but were not associated with choosing to read notes or desire for continued online access post-intervention (nearly all patients with notes available chose to read them and wanted continued access). While the level of concern among most participants did not change during the intervention, 15.54% (602/3874 respondents, excluding participants who responded "don't know") reported more concern post-intervention, and 12.73% (493/3874 respondents, excluding participants who responded "don't know") reported less concern. CONCLUSIONS: When considering online access to visit notes, approximately one-third of patients had concerns about privacy at baseline and post-intervention. These perceptions did not deter participants from accessing their notes, suggesting that the benefits of online access to medical records may outweigh patients' perceived risks to privacy. PMID- 24072336 TI - Abundance, activity, and diversity of archaeal and bacterial communities in both uncontaminated and highly copper-contaminated marine sediments. AB - We analyzed the impact of copper mine tailing discharges on benthic Archaea and Bacteria around the city of Chanaral in northern Chile. Quantitative PCR (Q-PCR) showed that the bacteria dominated the prokaryotic community at both sites, but only the bacteria showed a decrease in abundance in the copper-contaminated site. Q-PCR on reverse transcripts indicated a higher activity of both bacterial and archaeal communities in the contaminated site, suggesting an adaptation of the two communities to copper. This hypothesis was reinforced by the concomitant augmentation of the copper-resistant copA gene coding for a P-type ATP-ase pump in the contaminated site. The metabolically active bacterial community of the contaminated site was dominated by Gammaproteobacteria related to Ectothiorhodospiraceae and Chromatiaceae and by Alphaproteobacteria phylum related to Rhodobacteraceae. The metabolically active archaeal community was dominated by one lineage belonging to unclassified Euryarchaeota and to methanogenic Archaea. PMID- 24072337 TI - Rationale and design of the EPISTEME trial: efficacy of post-stroke intensive rosuvastatin treatment for aortogenic embolic stroke. AB - BACKGROUND: Large atheromatous aortic plaques (AAPs) are associated with stroke recurrence. Rosuvastatin is a potent lipid-lowering agent and suppresses carotid and coronary artery atherosclerosis. It is unclear whether rosuvastatin has anti atherogenic effects against AAPs in stroke patients. We designed a clinical trial in stroke patients to analyze changes in AAPs after rosuvastatin treatment using repeated transesophageal echocardiography (TEE). METHODS: This trial is a prospective randomized open label study. Inclusion criteria were patients were ischemic stroke with hypercholesterolemia and AAPs >= 4 mm in thickness. The patients are randomly assigned to either a group treated with 5 mg/day rosuvastatin or a control group. Primary endpoint is the changes in volume and composition of AAPs after 6 months using transesophageal echocardiography (TEE). Biochemical findings are analyzed. By using repeated TEE and binary image analysis, we will be able to compare the dynamic changes in plaque composition of AAPs before and after therapy in the two groups. CONCLUSIONS: The EPISTEME trial will provide information on the changes in plaque volume and composition achieved by improvement of lipid profiles with rosuvastatin therapy in stroke patients with aortic atherosclerosis. The results of the study may provide evidence for a therapeutic strategy for aortogenic brain embolism. This study is registered with UMIN-CTR (UMIN000010548). PMID- 24072338 TI - Anterior cervical fusion for radicular-disc conflict performed by three different procedures: clinical and radiographic analysis at long-term follow-up. AB - PURPOSE: Purpose of the study was to analyze in a retrospective way the clinical and radiographic outcome of three different surgical techniques in patients who underwent anterior cervical fusion. METHODS: Eighty-six patients affected by symptomatic cervical disc herniation or spondylosis underwent cervical anterior fusion. Patients were divided in three groups considering the surgical technique. Clinical outcomes were evaluated by Visual Analog Scale, Odom's criteria, Neck Disability Index. Radiographic evaluation included standard and functional X rays. RESULTS: At 7 years mean follow-up, a comparable improvement in clinical symptoms was observed in all groups. Radiographic findings showed a solid fusion in all patients but seven cases in group 2 showed a subsidence of the cage. CONCLUSIONS: As shown by the obtained clinical and radiographic results, the anterior interbody fusion with stand-alone peek cage containing beta-tricalcium phosphate could be considered an effective and reliable procedure. PMID- 24072339 TI - Standing lateral lumbar spine and pelvis (SLLP) radiograph: a screening, reduced radiation method, for sagittal imbalance. AB - INTRODUCTION: Sagittal imbalance is a predictor of failure after surgery for lumbar degenerative pathology. For this reason, specialists advocate correction of sagittal deformity and systematically perform preoperative standing whole spine films. Such diagnostic investigations expose patients to significant doses of radiation. The authors propose an easier radiographic investigation helpful as a screening test to identify patients likely to have sagittal imbalance. METHODS: Fifteen whole spine lateral films were evaluated, classifying subjects into three categories: balanced, compensating imbalanced or imbalanced. A second specialist evaluated the reduced SLLP versions of the film (from L1 to proximal femora), measuring spinopelvic parameters. RESULTS: In the SLLP film, the combination of two parameters (femoral inclination >10 degrees , pelvic tilt >1/3 pelvic incidence +5 degrees ) identified 94 % of patients with altered sagittal balance. CONCLUSIONS: This study preliminarily suggests that the SLLP film can be a useful screening test for sagittal balance abnormalities. PMID- 24072340 TI - Answer to the letter to the editor of Dr. Yusuf Izci entitled "anular closure device: Is it necessary after discectomy?" concerning "the high-risk discectomy patient: prevention of reherniation in patients with large anular defects using an anular closure device" by G. J. Bouma, M. Barth, D. Ledic, M. Vilendecic (2013) Eur Spine J; 22(5):1030-1036. PMID- 24072341 TI - Innovations in studying in vivo cell behavior and pharmacology in complex tissues -microvascular endothelial cells in the spotlight. AB - Many studies on the molecular control underlying normal cell behavior and cellular responses to disease stimuli and pharmacological intervention are conducted in single-cell culture systems, while the read-out of cellular engagement in disease and responsiveness to drugs in vivo is often based on overall tissue responses. As the majority of drugs under development aim to specifically interact with molecular targets in subsets of cells in complex tissues, this approach poses a major experimental discrepancy that prevents successful development of new therapeutics. In this review, we address the shortcomings of the use of artificial (single) cell systems and of whole tissue analyses in creating a better understanding of cell engagement in disease and of the true effects of drugs. We focus on microvascular endothelial cells that actively engage in a wide range of physiological and pathological processes. We propose a new strategy in which in vivo molecular control of cells is studied directly in the diseased endothelium instead of at a (far) distance from the site where drugs have to act, thereby accounting for tissue-controlled cell responses. The strategy uses laser microdissection-based enrichment of microvascular endothelium which, when combined with transcriptome and (phospho)proteome analyses, provides a factual view on their status in their complex microenvironment. Combining this with miniaturized sample handling using microfluidic devices enables handling the minute sample input that results from this strategy. The multidisciplinary approach proposed will enable compartmentalized analysis of cell behavior and drug effects in complex tissue to become widely implemented in daily biomedical research and drug development practice. PMID- 24072342 TI - Anteroposterior translation of the glenohumeral joint in various pathologies: differences between shoulder MRI in the adducted neutral rotation and abducted externally rotated positions. AB - PURPOSE: The present study was performed to determine the translation of the glenohumeral joint in patients with and without shoulder lesions by comparing the magnetic resonance images obtained in the conventional adducted neutral rotation position with those obtained in the abducted externally rotated position. METHODS: Two hundred and eighty-five consecutive shoulders without rotator cuff tears that had been subjected to magnetic resonance imaging (MRI) without arthrography in the abducted externally rotated position were reviewed retrospectively. Among them, 50 shoulders without pathology were selected at random to be compared with three shoulder pathology groups, comprising shoulders with superior labrum, anterior-to-posterior (SLAP) lesions without range of motion (ROM) limitation (group I, 47 shoulders), with massive rotator cuff tears without ROM limitation (group II, 20 shoulders), and with full-thickness subscapularis tendon tears without ROM limitation (group III, 20 shoulders). Glenohumeral translation in the anterior-to-posterior direction relative to the glenoid face was evaluated using a method based on the glenohumeral contact point (CP) and humeral head centre (HHC) in the adducted neutral rotation and abducted externally rotated views, which were measured by three orthopaedic surgeons. For each shoulder, the differences in translation for the glenohumeral CP and HHC between the adducted neutral rotation and abducted externally rotated views were calculated as relative posterior translation in millimetres. RESULTS: The differences in DeltaCP and DeltaHHC between group I and the normal control group were not statistically significant. The differences in DeltaCP (P = 0.001) and DeltaHHC (P = 0.001) between group II and the normal control group were statistically significant. Additionally, the differences in DeltaCP and DeltaHHC between group III and the normal control group were not statistically significant. CONCLUSIONS: The MRI in abducted externally rotated view in patients with SLAP lesions or full-thickness subscapularis tendon tears diagnosed by conventional MRI alone showed no significant glenohumeral posterior translation relative to the adducted neutral rotation view in the present study. However, the abducted externally rotated view in patients with massive rotator cuff tears showed significant glenohumeral anterior translation relative to the adducted neutral rotation view. PMID- 24072343 TI - Flexion and extension gaps created by the navigation-assisted gap technique show small acceptable mismatches and close mutual correlations. AB - PURPOSE: The aim of this study was to investigate the mechanism underlying the development of gap differences in total knee arthroplasty using the navigation assisted gap technique and to assess whether these gap differences have statistical significance. METHODS: Ninety-two patients (105 knees) implanted with cruciate-retaining prostheses using the navigation-assisted gap balancing technique were prospectively analysed. Medial extension and flexion gaps and lateral extension and flexion gaps were measured at full extension and at 90 degrees of flexion. Repeated measures analysis of variance was used to compare the mean values of these four gaps. The correlation coefficient between each pair of gaps was assessed using Pearson's correlation analysis. RESULTS: Mean intra operative medial and lateral extension gaps were 20.6 +/- 2.1 and 21.7 +/- 2.2 mm, respectively, and mean intra-operative medial and lateral flexion gaps were 21.6 +/- 2.7 and 22.1 +/- 2.5 mm, respectively. The pairs of gaps differed significantly (P < 0.05 each), except for the difference between the medial flexion and lateral extension gaps (n.s.). All four gaps were significantly correlated with each other, with the highest correlation between the medial and lateral flexion gaps (r = 0.890, P < 0.001) and the lowest between the medial flexion and lateral extension gaps (r = 0.701, P < 0.001). CONCLUSION: Medial and lateral flexion and extension gaps created using the navigation-assisted gap technique differed significantly, although the differences between them were <2 mm, and the gaps were closely correlated. CLINICAL RELEVANCE: These narrow ranges of statistically acceptable gap differences and the strong correlations between gaps should be considered by surgeons, as should the risks of soft tissue over release or unintentional increases in extension or flexion gap after preparation of the other gap. PMID- 24072344 TI - Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline based PET/CT for the diagnosis of recurrent prostate cancer. AB - PURPOSE: Positron emission tomography (PET) with choline tracers has found widespread use for the diagnosis of prostate cancer (PC). However, choline metabolism is not increased in a considerable number of cases, whereas prostate specific membrane antigen (PSMA) is overexpressed in most PCs. Therefore, a (68)Ga-labelled PSMA ligand could be superior to choline tracers by obtaining a high contrast. The aim of this study was to compare such a novel tracer with standard choline-based PET/CT. METHODS: Thirty-seven patients with biochemical relapse of PC [mean prostate-specific antigen (PSA) 11.1 +/- 24.1 ng/ml, range 0.01-116] were retrospectively analysed after (18)F-fluoromethylcholine and (68)Ga-PSMA PET/CT within a time window of 30 days. Radiotracer uptake that was visually considered as PC was semi-quantitatively analysed by measuring the maximum standardized uptake values (SUVmax) of the scans acquired 1 h after injection of (68)Ga-PSMA complex solution (median 132 MBq, range 59-263 MBq) and (18)F-fluoromethylcholine (median 237 MBq, range 114-374 MBq), respectively. In addition, tumour to background ratios were calculated. RESULTS: A total of 78 lesions characteristic for PC were detected in 32 patients using (68)Ga-PSMA PET/CT and 56 lesions were detected in 26 patients using choline PET/CT. The higher detection rate in (68)Ga-PSMA PET/CT was statistically significant (p=0.04). In five patients no lesion was found with both methods. All lesions detected by (18)F-fluoromethylcholine PET/CT were also seen by (68)Ga-PSMA PET/CT. In (68)Ga-PSMA PET/CT SUVmax was clearly (>10 %) higher in 62 of 78 lesions (79.1 %) and the tumour to background ratio was clearly (>10 %) higher in 74 of 78 lesions (94.9 %) when compared to (18)F-fluoromethylcholine PET/CT. CONCLUSION: (68)Ga-PSMA PET/CT can detect lesions characteristic for PC with improved contrast when compared to standard (18)F-fluoromethylcholine PET/CT, especially at low PSA levels. PMID- 24072345 TI - A retrospective comparison between 68Ga-DOTA-TOC PET/CT and 18F-DOPA PET/CT in patients with extra-adrenal paraganglioma. AB - PURPOSE: (18)F-Fluoro-L-dihydroxyphenylalanine ((18)F-DOPA) PET offers high sensitivity and specificity in the imaging of nonmetastatic extra-adrenal paragangliomas (PGL) but lower sensitivity in metastatic or multifocal disease. These tumours are of neuroendocrine origin and can be detected by (68)Ga-DOTA Tyr(3)-octreotide ((68)Ga-DOTA-TOC) PET. Therefore, we compared (68)Ga-DOTA-TOC and (18)F-DOPA as radiolabels for PET/CT imaging for the diagnosis and staging of extra-adrenal PGL. Combined cross-sectional imaging was the reference standard. METHODS: A total of 5 men and 15 women (age range 22 to 73 years) with anatomical and/or histologically proven extra-adrenal PGL were included in this study. Of these patients, 5 had metastatic or multifocal lesions and 15 had single sites of disease. Comparative evaluation included morphological imaging with CT and functional imaging with (68)Ga-DOTA-TOC PET and (18)F-DOPA PET. The imaging results were analysed on a per-patient and a per-lesion basis. The maximum standardized uptake value (SUVmax) of each functional imaging modality in concordant tumour lesions was measured. RESULTS: Compared with anatomical imaging, (68)Ga-DOTA-TOC PET and (18)F-DOPA PET each had a per-patient and per lesion detection rate of 100% in nonmetastatic extra-adrenal PGL. However, in metastatic or multifocal disease, the per-lesion detection rate of (68)Ga-DOTA TOC was 100% and that of (18)F-DOPA PET was 56.0%. Overall, (68)Ga-DOTA-TOC PET identified 45 lesions; anatomical imaging identified 43 lesions, and (18)F-DOPA PET identified 32 lesions. The overall per-lesion detection rate of (68)Ga-DOTA TOC PET was 100% (McNemar, P < 0.5), and that of (18)F-DOPA PET was 71.1% (McNemar, P < 0.001). The SUVmax (mean +/- SD) of all 32 concordant lesions was 67.9 +/- 61.5 for (68)Ga-DOTA-TOC PET and 11.8 +/- 7.9 for (18)F-DOPA PET (Mann Whitney U test, P < 0.0001). CONCLUSION: (68)Ga-DOTA-TOC PET may be superior to (18)F-DOPA PET and diagnostic CT in providing valuable information for pretherapeutic staging of extra-adrenal PGL, particularly in surgically inoperable tumours and metastatic or multifocal disease. PMID- 24072347 TI - Diet and 18F bone imaging. PMID- 24072346 TI - Five-year follow-up of 11C-PIB uptake in Alzheimer's disease and MCI. AB - PURPOSE: The aim of this study was to evaluate the longitudinal changes in [(11)C]PIB uptake in mild cognitive impairment (MCI) and Alzheimer's disease (AD) over a long-term follow-up. METHODS: Six AD patients, ten MCI patients and eight healthy subjects underwent a [(11)C]PIB PET scan at baseline and at 2 and 5 years. The clinical status of the MCI patients was evaluated every 6 months. RESULTS: The MCI group showed a significant increase in [(11)C]PIB uptake over time (p < 0.001), with a similar increase from baseline to 2 years (4.7% per year) and from 2 to 5 years (5.0% per year). Eight MCI patients (80%) converted to AD, and two of these patients showed a normal [(11)C]PIB scan at baseline but increased uptake later. There was an increase in [(11)C]PIB uptake with time in the AD group (p = 0.02), but this did not significantly differ from the change in the control group. CONCLUSION: Our results revealed a significant increase in amyloid load even at the time of AD diagnosis in some of the MCI patients who converted. A positive [(11)C]PIB scan at baseline in MCI patients strongly predicted future conversion to AD but a negative PIB scan in MCI patients did not exclude future conversion. The results suggest that there is wide individual variation in the brain amyloid load in MCI, and in the course of amyloid accumulation in relation to the clinical diagnosis of AD. PMID- 24072348 TI - Could 68Ga-somatostatin analogues replace other PET tracers in evaluating extra adrenal paragangliomas? PMID- 24072349 TI - Writing PET into existence. PMID- 24072350 TI - Associations between supportive leadership and employees self-rated health in an occupational sample. AB - BACKGROUND: Protecting the health of the work force has become an important issue in public health research. PURPOSE: This study aims to explore potential associations between supportive leadership style (SLS), an aspect of leadership behavior, and self-rated health (SRH) among employees. METHOD: We drew on cross sectional data from a cohort of industrial workers (n = 3,331), collected in 2009. We assessed employees' ratings of supportive, employee-oriented leadership behavior at their job, their SRH, and work stress as measured by the effort reward model and scales measuring demands, control, and social support. Logistic regression estimated odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) for the association between the perception of poor SLS and poor SRH controlling for work-related stress and other confounders. Sensitivity analyses stratified models by sex, age, and managerial position to test the robustness of associations. RESULTS: Perception of poor SLS was associated with poor SRH [OR 2.39 (95 % CI 1.95-2.92)]. Although attenuated following adjustment for measures of work-related stress and other confounders [OR 1.60 (95 % CI 1.26 2.04)], the magnitude, direction, and significance of this association remained robust in stratified models in most subgroups. CONCLUSION: SLS appears to be relevant to health in the workplace. Leadership behavior may represent a promising area for future research with potential for promoting better health in a large segment of the adult population. PMID- 24072351 TI - Morality, responsibility and risk: the importance of alternative perspectives in vaccination research. AB - BACKGROUND: The four papers presented in this special section together provide a striking example of the importance of eliciting people's understandings and meanings of vaccinations, from parents and children to health and medical professionals. PURPOSE: This commentary reflects on the findings of the papers in this special section and considers them within a broader sociocultural view on vaccination research. METHODS: The four papers in the special section were integrated with previous research and scholarship on public health and vaccinations. RESULTS: The studies demonstrate how both uptake of vaccinations and their meanings vary by cultural context, most notably across Eastern and Western Europe, and the fundamental role that political, economic and healthcare systems play. Nevertheless, there are many similarities across seemingly diverse contexts. Three specific tensions are apparent across the findings (and within other vaccination research). These tensions revolve around (1) responsible citizen versus responsible individual, (2) scientific knowledge versus lay understandings and (3) uncertainty and risk versus certainty and trust. CONCLUSION: Threaded through these tensions are discourses around citizenship, trust, morality, gender and power that are important to consider in research on vaccinations. PMID- 24072352 TI - Type D personality is associated with social anxiety in the general population. AB - BACKGROUND: Research on the emotional processes associated with Type D personality is important for its further conceptualization. We examined the associations of Type D personality with social and general anxiety symptoms in a large community sample. PURPOSE: The aim of the current study was to disentangle the associations of Type D personality and its components with social anxiety and general anxiety in a large sample from the general population. METHODS: A random sample of 2,475 adults from the general population filled out questionnaires to assess Type D personality (DS-14), social anxiety (SIAS(10), SPS(11), BFNE-II), and general anxiety (HADS-A, GAD-7). RESULTS: Type D individuals were characterized by increased levels of both social and general anxiety. The social inhibition (SI) component of Type D personality was most strongly associated with social interaction anxiety (r = .63), while negative affectivity (NA) was strongly associated with general anxiety (GAD-7: r = .70; HADS-A: r = .66). Within social anxiety, SI was more strongly associated with facets of social interaction anxiety than with social phobia. Multiple regression analysis showed that the synergistic interaction of NA and SI was a predictor of social anxiety (SIAS(10): beta = .32, p < .0005; SPS(11): beta = .27, p < .0005; BFNE-II: beta = .11, p = .007) independent of demographics and the scores on the individual Type D components. This interaction was not a significant predictor of general anxiety. Logistic regression using the dichotomous Type D classification demonstrated a 9.1-fold (95%CI, 7.0-11.8) increased odds of a score in the highest quartile of social interaction anxiety and a 7.6-fold (95%CI, 5.8-9.8) increased odds of high social phobia. Odds ratios for clinically relevant levels of general anxiety were 8.3 (95%CI, 5.5-12.5) for GAD-7 and 6.5 (95%CI, 3.4-12.6) for HADS-A. CONCLUSION: In the general population, Type D individuals were characterized by both social and general anxiety. The SI component of Type D is strongly associated with social interaction anxiety and the synergistic interaction of NA and SI was associated with high social anxiety, above and beyond the main NA and SI effects. PMID- 24072353 TI - Combination of periaortic elastase incubation and cholesterol-rich diet: a novel model of atherosclerosis in rabbit abdominal aorta. AB - Atherosclerosis, the leading cause of most cardiovascular disease, is a progressive multifaceted inflammatory disease characterized by extracellular matrix degradation and extensive remodeling of artery wall. However, its mechanism has not been completely understood, and animal models are useful to study its pathogenetic process. An analysis of literature on the nature of atherosclerosis indicates that focal accumulation of smooth muscle cells (SMCs) into the intima by plasma factors is fundamental to the entire process of plaque growth. In our previous study, vascular SMCs proliferation was obvious in elastase-induced aorta by day 15, which led to intimal hyperplasia and regression of rabbit aneurysm. Model induced by combination of balloon injury and an atherogenic diet in rabbits is the conventional, but most largely used experimental model of atherosclerosis. Since proliferation and accumulation of intimal SMCs are found in elastase-induced aorta, and hypercholesterolemia is usually induced by cholesterol-rich diets in rabbits, a novel atherosclerosis model may be induced by combination periaortic elastase incubation and cholesterol-rich diet. PMID- 24072354 TI - The effect of obesity on clinical outcomes in presumed sepsis: a retrospective cohort study. AB - Sepsis is a major cause of hospital admissions and mortality. Nevertheless, there are significant gaps in our knowledge of the epidemiology of sepsis in obese people, who now represent more than one-third of the population in the United States. The objective of this study was to measure the association between obesity and mortality from presumed sepsis. A retrospective cohort study was used of 1,779 adult inpatients with presumed sepsis at a Tertiary Care Academic Institution from March 1, 2007 to June 30, 2011. Cases of sepsis were identified using a standardized algorithm for sepsis antibiotic treatment. Exposure (i.e., obesity) was defined as a body mass index >=30 kg/m(2). Multivariable logistic regression was used to assess the adjusted association between obesity and mortality. Patients with presumed sepsis were of a median age of 60.9 years (interquartile range 49.7-71) and 41.1 % were women. A total of 393 patients died, resulting in a 28-day in-hospital mortality of 22.1 %. In adjusted analysis, obesity was not significantly associated with increased mortality (odds ratio 1.11, 95 % CI 0.85-1.41, P = 0.47). There was also no difference in the in hospital length of stay (P = 0.45) or maximum percent change in serum creatinine (P = 0.32) between obese and non-obese patients. Finally, there was no difference in the proportion of initial inadequate vancomycin levels (P = 0.1) after presumed sepsis. Obesity was not associated with increased mortality in patients with presumed sepsis. Further research is needed to determine how excess adiposity modulates inflammation from sepsis. PMID- 24072355 TI - Bone-targeted therapies for elderly patients with renal cell carcinoma: current and future directions. AB - Bone metastases are very common in advanced renal cell carcinoma (RCC) and can have a huge impact on quality of life by leading to skeletal-related events (SREs), including pain, pathologic fractures and spinal cord compression with need for surgery or radiotherapy. Because of their osteolytic aspect and biologic behaviour, these SREs are more common in patients with bone metastases from RCC than from other malignancies. As overall survival is increased by new anti angiogenic drugs like tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors, the incidence of SREs is rising, making the clinical management of bone metastases in RCC ever more important, especially in the more vulnerable elderly patient. In this review we discuss the current advances and future directions in bone-targeted therapies in patients with RCC with a special focus on the elderly population. Recently, two bone-targeted agents have been approved in the prevention of SREs in advanced RCC: zoledronic acid and denosumab. To date, there is no specific data on the use of bisphosphonates or denosumab in the elderly and specific studies in this setting are warranted. We compare the available evidence for the use and implications of both agents in the elderly patient and give general information on safety concerns that could be more important in these patients. PMID- 24072357 TI - Band structure engineering of TiO2 nanowires by n-p codoping for enhanced visible light photoelectrochemical water-splitting. AB - The advantages of one-dimensional nanostructures, such as excellent charge separation and charge transport, low charge carrier recombination losses and so on, render them the photocatalysts of choice for many applications that exploit solar energy. In this work, based on very recently synthesized ultrathin anatase TiO2 nanowires, we explore the possibility of these wires as photocatalysts for photoelectrochemical water-splitting via the mono-doping (C, N, V, and Cr) and n p codoping (C&V, C&Cr, N&V, and N&Cr) schemes. Our first-principles calculations predict that the C&Cr and C&V codoped ANWs may be strong candidates for photoelectrochemical water-splitting, because they have a substantially reduced band gap of 2.49 eV, appropriate band edge positions, no carrier recombination centers, and enhanced optical absorption in the visible light region. PMID- 24072356 TI - Lead optimization mapper: automating free energy calculations for lead optimization. AB - Alchemical free energy calculations hold increasing promise as an aid to drug discovery efforts. However, applications of these techniques in discovery projects have been relatively few, partly because of the difficulty of planning and setting up calculations. Here, we introduce lead optimization mapper, LOMAP, an automated algorithm to plan efficient relative free energy calculations between potential ligands within a substantial library of perhaps hundreds of compounds. In this approach, ligands are first grouped by structural similarity primarily based on the size of a (loosely defined) maximal common substructure, and then calculations are planned within and between sets of structurally related compounds. An emphasis is placed on ensuring that relative free energies can be obtained between any pair of compounds without combining the results of too many different relative free energy calculations (to avoid accumulation of error) and by providing some redundancy to allow for the possibility of error and consistency checking and provide some insight into when results can be expected to be unreliable. The algorithm is discussed in detail and a Python implementation, based on both Schrodinger's and OpenEye's APIs, has been made available freely under the BSD license. PMID- 24072358 TI - Evolution of lung function during the first year of life in newborn screened cystic fibrosis infants. AB - RATIONALE: Newborn screening (NBS) for cystic fibrosis (CF) allows early intervention. Design of randomised controlled trials (RCT) is currently impeded by uncertainty regarding evolution of lung function, an important trial end point in such infants. OBJECTIVE: To assess changes in pulmonary function during the first year of life in CF NBS infants. METHODS: Observational longitudinal study. CF NBS infants and healthy controls were recruited between 2009 and 2011. Lung Clearance Index (LCI), plethysmographic lung volume (plethysmographic functional residual capacity (FRCpleth)) and forced expired volume (FEV0.5) were measured at 3 months and 1 year of age. MAIN RESULTS: Paired measurements were obtained from 72 CF infants and 44 controls. At 3 months, CF infants had significantly worse lung function for all tests. FEV0.5 improved significantly (0.59 (95% CI 0.18 to 0.99) z-scores; p<0.01) in CF infants between 3 months and 1 year, and by 1 year, FEV0.5 was only 0.52 (0.89 to 0.15) z-scores less than in controls. LCI and FRCpleth remained stable throughout the first year of life, being on average 0.8 z-scores higher in infants with CF. Pulmonary function at 1 year was predicted by that at 3 months. Among the 45 CF infants with entirely normal LCI and FEV0.5 at 3 months, 80% remained so at 1 year, while 74% of those with early abnormalities remained abnormal at 1 year. CONCLUSIONS: This is the first study reporting improvements in FEV0.5 over time in stable NBS CF infants treated with standard therapy. Milder changes in lung function occurred by 1 year than previously reported. Lung function at 3 months predicts a high-risk group, who should be considered for intensification of treatment and enrolment into RCTs. PMID- 24072359 TI - Allogeneic materials in complications associated with pre-implantation restoration of maxillary and mandibular alveolar processes. A four case report. AB - There are numerous types of bone replacement materials used to regenerate atrophic alveolar processes before the elective intraosseous implantation. Properties of these materials differ one from another, therefore the choice of material should be thoroughly analysed as well as its type and texture in regard of intraoral conditions and the objective to be achieved. The study involved reconstruction of atrophic alveolar processes with allogeneic bone following unsuccessful use of synthetic and animal materials. The procedure of bone regeneration was performed with frozen bone block (case 1) and allogeneic bone granulate (cases 2, 3, 4) radiation-sterilised with 35 kGy prepared by the Tissue Bank. In all of the presented cases after 3-month implant reorganisation optimal width of the process was obtained, which allowed implant embedment (case 1) or correct implant submergence in the osseous tissue, when implantation took place at the same time (case 2, 3, 4). Allogeneic bone material both, in the form of a block as well as granulate, seems to be an adequate alternative for other materials used in order to widen the bone of the alveolar process, particularly in difficult, complicated cases, where the first regeneration procedure was not successful. PMID- 24072360 TI - Musculoskeletal: what is different in children? Pushed off of bed: shoulder pain. PMID- 24072361 TI - Reliability and relevance of radiographic measures of metatarsus primus elevatus and arch alignment in individuals with midfoot arthritis and controls. AB - BACKGROUND: Low arch alignment and metatarsus primus elevatus (MPE) have been postulated to increase dorsal compressive stresses in the joints of the medial column of the foot and to contribute to the development of degenerative changes. The primary purposes of this study were (1) to examine the relationship between radiographic measures of arch alignment and MPE and (2) to assess arch alignment and MPE in individuals with midfoot arthritis and in asymptomatic controls. The secondary aim was to examine the reliability of radiographic measures of arch alignment and MPE. METHODS: Radiographic measures of arch height and MPE were quantified on 28 individuals with midfoot arthritis and 22 individuals in a control group. Reliability was assessed using the intraclass correlation coefficient (ICC). The Pearson product moment correlation (r) was used to assess the relationship between arch alignment and MPE. Between-group differences were assessed using a two-sample t test (alpha = 0.05). RESULTS: Good to excellent reliability was noted for measures of arch height (ICC[2,3] = 0.919-0.994) as well as MPE (ICC[2,3] = 0.891-0.882). A modest positive association was noted between normalized cortical elevation and normalized navicular height (r = 0.274, P = .030) and calcaneal inclination angle (r = 0.263, P = .035). Individuals with midfoot arthritis demonstrated lower arch alignment, reflected in a significantly higher calcaneal-first metatarsal angle (P = .002), lower calcaneal inclination angle (P = .004), and lower normalized navicular height (P < .001) compared with controls. No evidence was found to support between-group differences in lateral intermetatarsal angle (P = .495) and normalized cortical elevation (P = .146). CONCLUSIONS: These findings provide objective data establishing the reliability of measures of MPE and arch alignment and their potential clinical significance. PMID- 24072362 TI - Demographic characteristics of individuals with diabetes mellitus and peripheral neuropathy. AB - BACKGROUND: Studies have established a positive association between peripheral neuropathy and diabetes mellitus. The purpose of the present investigation is to determine the predictor variables for demographic characteristics of individuals with diabetes mellitus and peripheral neuropathy. METHODS: Frequency and chi2 statistic analyses were conducted on the data to determine significance of predictor variables. RESULTS: Among individuals with and without diabetes mellitus, men are more at risk to develop complications related to peripheral neuropathy, such as foot insensate areas and numbness in extremities. Diabetic individuals older than 61 years are at higher risk than other age groups. Among diabetic patients with peripheral neuropathy, women are more likely to have emotional disorders such as panic, anxiety disorder, and depression than men of the same age or younger. CONCLUSIONS: Predictor variables will assist clinicians in better diagnosing peripheral neuropathy, contributing to more effective treatments and shortening of healing time. Diagnostic measures to be taken into consideration include race, age, education, marital status, duration of diabetes mellitus, numbness in hands or feet, participation in moderate physical activity, and use of tobacco. PMID- 24072363 TI - Sever's injury: a clinical diagnosis. AB - BACKGROUND: The diagnosis of Sever's injury (apophysitis calcanei) has previously been partly based on radiographic findings in the calcaneal apophysis. Sclerosis and fragmentation have been supposed to represent signs of inflammation due to tractions from the Achilles tendon. The clinical findings, diagnostic criteria, and studied population are often poorly defined. We sought to define diagnostic criteria by analyzing clinical and radiographic characteristics in a population with Sever's injury and to compare the findings with those of a control group of matched, symptom-free children. METHODS: We assessed 30 consecutive children with Sever's injury with high levels of pain but high physical activity levels in sports activities and 15 pain-free matched controls. RESULTS: One-leg heel standing showed 100% sensitivity; the squeeze test, 97%; and the palpation test, 80%. All three tests showed 100% specificity. All of the patients and controls showed increased density of the apophysis. Half of the pain-free controls showed fragmentation versus almost 90% of children with heel pain. CONCLUSIONS: The diagnosis of Sever's injury is clinical, not radiologic. Radiologic findings of increased density and fragmentation are found also in pain-free controls with high levels of physical activity and may, therefore, represent normal growth and development. We suggest that the diagnosis of Sever's injury should be based on patient history and the results of two specific clinical tests. PMID- 24072364 TI - Prevalence of flatfoot and anthropometric comparison between flat and normal feet in the Hausa ethnic group of Nigeria. AB - BACKGROUND: Flat arches in children usually become proper arches and high arches as the child progresses through adolescence and into adulthood. Only if the deformity persists or presents in adolescence or adulthood is it considered abnormal. We sought to determine the incidence of flatfoot in schoolchildren and to make an anthropometric comparison between flat and normal feet with respect to age and sex in the Hausa ethnic group of Nigeria. METHODS: Two hundred 9- to 14 year-old students (100 boys and 100 girls) were studied. Navicular height, medial malleolar height, lateral malleolar height, foot length, and transverse arch length were measured with a ruler, marker, and measuring tape. Statistical analysis was conducted using analysis of variance and independent-samples t tests (P < .05). RESULTS: The overall prevalence of flatfoot was 10% (n = 20) (7% in boys [n = 7] and 13% in girls [n = 13]). Statistically significant differences were found in all of the measured parameters except foot length. This study showed that flatfoot has a higher incidence in girls than in boys in the Hausa ethnic group, with the incidence decreasing with age. CONCLUSIONS: Girls had a higher incidence of flatfoot than boys, and it was also influenced by age. PMID- 24072365 TI - Foot and ankle characteristics of children with an idiopathic toe-walking gait. AB - BACKGROUND: Idiopathic toe-walking (ITW) in children has been associated with ankle equinus. Although equinus has been linked to foot deformity in adults, there has been limited investigation of the impact of equinus on structural foot change in children. We used the weightbearing lunge test and the six-item version of the Foot Posture Index (FPI-6) to evaluate the weightbearing foot and ankle measures of children with an ITW gait and to compare these with their age-matched peers. METHODS: Sixty 4-to 6-year-old children were grouped into ITW (n = 30) and non-toe-walking (n = 30) cohorts using a validated ITW tool. Ankle range of motion was determined with weightbearing lunge tests. The FPI-6 was calculated during weightbearing stance. RESULTS: There was a highly significant difference in the weightbearing lunge test measures between the ITW cohort and the non-toe walking cohort. The FPI-6 comparison was not significant. The straight-leg lunge test had a statistically significant relationship with the FPI-6 in the ITW cohort. CONCLUSION: Children with an ITW gait demonstrated reduced flexibility at the ankle joint but similar weightbearing foot posture compared with non-toe walking children, showing that for children 4 to 8 years old, an ITW gait affects the available ankle dorsiflexion but seems to have a limited effect on weightbearing foot posture as measured by the FPI-6. PMID- 24072366 TI - Low long-term risk of foot ulcer recurrence after nerve decompression in a diabetes neuropathy cohort. AB - BACKGROUND: Use of nerve decompression in diabetic sensorimotor polyneuropathy is a controversial treatment characterized as being of unknown scientific effectiveness owing to lack of level I scientific studies. METHODS: Herein, long term follow-up data have been assembled on 65 diabetic patients with 75 legs having previous neuropathic foot ulcer and subsequent operative decompression of the common peroneal and tibial nerve branches in the anatomical fibro-osseous tunnels. RESULTS: The cohort's previously reported low recurrence risk of less than 5% annually at a mean of 2.49 years of follow-up has persisted for an additional 3 years, and cumulative risk is now 2.6% per patient-year. Nine of 75 operated legs (12%) have developed an ulcer in 4,218 months (351 patient-years) of follow-up. Of the 53 contralateral legs without decompression, 16 (30%) have ulcerated, of which three have undergone an amputation. Fifty-nine percent of patients are known to be alive with intact feet a mean of 60 months after decompression. CONCLUSIONS: The prospective, objective, statistically significant finding of a large, long-term diminution of diabetic foot ulcer recurrence risk after operative nerve decompression compares very favorably with the historical literature and the contralateral legs of this cohort, which had no decompression. This finding invites prospective randomized controlled studies for validation testing and reconsideration of the frequency and contribution of unrecognized nerve entrapments in diabetic sensorimotor polyneuropathy and diabetic foot complications. PMID- 24072367 TI - A chemical application method with underwater dissection to improve anatomic identification of cadaveric foot and ankle structures in podiatric education. AB - BACKGROUND: Many cadaver-based anatomy courses and surgical workshops use prosections to help podiatry students and residents learn clinically relevant anatomy. The quality of these prosections is variable and dependent upon the methods used to prepare them. These methods have not been adequately described in the literature, and few studies describe the use of chemicals to prepare prosections of the cadaveric foot and ankle. Recognizing the need for better teaching prosections in podiatric education, we developed a chemical application method with underwater dissection to better preserve anatomic structures of the cadaveric foot and ankle. METHODS: We used inexpensive chemicals before, during, and after each step, which ultimately resulted in high-quality prosections that improved identification of anatomic structures relevant to the practice of podiatric medicine. RESULTS: Careful preservation of clinically important nerves, vessels, muscles, ligaments, and joints was achieved with these prosections. CONCLUSIONS: Although this method required additional preparation time, the resultant prosections have been repeatedly used for several years to facilitate learning among podiatry students and residents, and they have held up well. This method can be used by educators to teach podiatry students throughout their medical training and even into residency. PMID- 24072368 TI - Sagittal plane kinematics of passive dorsiflexion of the foot in adolescent athletes. AB - BACKGROUND: Although assessment of passive maximum foot dorsiflexion angle is performed routinely, there is a paucity of information regarding adolescents' foot and foot segment motion during this procedure. There are currently no trials investigating the kinematics of the adolescent foot during passive foot dorsiflexion. METHODS: A six-camera optoelectronic motion capture system was used to collect kinematic data using the Oxford Foot Model. Eight female amateur gymnasts 11 to 16 years old (mean age, 13.2 years; mean height, 1.5 m) participated in the study. A dorsiflexing force was applied to the forefoot until reaching maximum resistance with the foot placed in the neutral, pronated, and supinated positions in random order. The maximum foot dorsiflexion angle and the range of movement of the forefoot to hindfoot, tibia to forefoot, and tibia to hindfoot angles were computed. RESULTS: Mean +/- SD maximum foot dorsiflexion angles were 36.3 degrees +/- 7.2 degrees for pronated, 36.9 degrees +/- 4.0 degrees for neutral, and 33.0 degrees +/- 4.9 degrees for supinated postures. One-way repeated-measures analysis of variance results were nonsignificant among the 3 groups (P = .70), as were the forefoot to tibia angle and hindfoot to tibia angle variations (P = .091 and P = .188, respectively). Forefoot to hindfoot angle increased with the application of force, indicating that in adolescents, the forefoot does not lock at any particular posture as portrayed by the traditional Rootian paradigm. CONCLUSIONS: Participants had very flexible foot dorsiflexion, unlike those in another study assessing adolescent athletes. This finding, together with nonsignificant statistical results, implies that foot dorsiflexion measurement may be performed at any foot posture without notably affecting results. PMID- 24072369 TI - The foot posture index: anthropometric determinants and influence of sex. AB - BACKGROUND: The Foot Posture Index (FPI) quantifies foot posture on the basis of six criteria. Although the male foot is longer and broader than the female foot, limited evidence exists about the differences in foot posture between the sexes and which are its biological and anthropometric determinants. We sought to evaluate possible sex differences in the FPI and the determinants influencing foot posture. METHODS: In 400 individuals (201 men and 199 women), the FPI was determined in the static bipedal stance and relaxed position. The FPI was obtained as the sum of the scores (-2, -1, 0, 1, or 2) given to each of six criteria. A multiple regression model was constructed of the overall FPI against age, weight, height, body mass index, and foot size. RESULTS: The mean +/- SD FPI was 2.0 +/- 4.3 overall, 1.6 +/- 4.5 for men, and 2.4 +/- 4.1 for women, with the difference being nonsignificant (P = .142). The neutral posture was the most frequent (57.3%). A greater proportion of women had neutral and pronated feet, and a greater proportion of men had supinated and highly supinated feet, with the differences being nonsignificant (P = .143). Foot size, height, and body mass index together explained 10.1% of the overall FPI value (P < .001). CONCLUSIONS: The most frequent posture was neutral with a certain degree of pronation, with no differences in FPI values between men and women. Participants with larger foot sizes had higher FPI values, whereas taller and heavier participants had lower FPI values. PMID- 24072370 TI - A quick and reliable procedure for assessing foot alignment in athletes. AB - BACKGROUND: Quick procedures with proper psychometric properties that can capture the combined alignment of the foot-ankle complex in a position that may be more representative of the status of the lower limb during ground contact are essential for assessing a large group of athletes. METHODS: The assessed lower limb was positioned with the calcaneus surface facing upward in a way that all of the marks could be seen at the center of the camera display. After guaranteeing maintenance of the foot at 90 degrees of dorsiflexion actively sustained by the athlete, the examiner took the picture of the foot-ankle alignment. RESULTS: Intraclass correlation coefficients ranging from 0.82 to 0.93 demonstrated excellent intratester and intertester reliability for the proposed measurements of forefoot, rearfoot, and shank-forefoot alignments. The intraclass correlation coefficient between the shank-forefoot measures and the sum of the rearfoot and forefoot measures was 0.98, suggesting that the shank-forefoot alignment measures can represent the combined rearfoot and forefoot alignments. CONCLUSIONS: This study describes a reliable and practical measurement procedure for rearfoot, forefoot, and shank-forefoot alignments that can be applied to clinical and research situations as a screening procedure for risk factors for lower-limb injuries in athletes. PMID- 24072371 TI - Design of a first metatarsophalangeal joint simulator. AB - BACKGROUND: The use of total first metatarsophalangeal joint (MPJ) arthroplasty to treat patients in which the pain, due to a pathological joint, has not been relieved with a conservative method or for which the disease or disorder is at an advanced stage, is popular. Although meta-analysis of clinical results indicates that this surgical option is efficacious, there are problems with implant failure due to wear of the components. Although there is a plethora of designs of this type of implant in clinical use, there are no literature reports on total first MPJ simulators, which may be used to evaluate, for example, the wear rate of a total first MPJ implant. METHODS: We designed such a simulator, guided by the biomechanics of the joint. Thus, for example, the implant under test will be articulated at least 40 degrees dorsiflexion, under a 600 N loading, at 1 Hz. Furthermore, the testing stations will be configured to allow testing of any type of first MPJ implant. We also performed a finite element analysis (FEA) study of a model of an articulating station, subjected to a quasi-static load of 1200 N. RESULTS: For an articulating station, (1) the highest von Mises stress occurred at the implant-fixture interface; and (2), for the other parts, the minimum factor of safety, against elastic failure, is approximately 9. CONCLUSIONS: The designed joint simulator is mechanically sound and may be used for wear testing of any type of first MPJ implant. PMID- 24072372 TI - Use of primary corticosteroid injection in the management of plantar fasciopathy: is it time to challenge existing practice? AB - Plantar fasciopathy (PF) is characterized by degeneration of the fascia at the calcaneal enthesis. It is a common cause of foot pain, accounting for 90% of clinical presentations of heel pathology. In 2009-2010, 9.3 million working days were lost in England due to musculoskeletal disorders, with 2.4 million of those attributable to lower-limb disorders, averaging 16.3 lost working days per case. Numerous studies have attempted to establish the short- and long-term clinical efficacy of corticosteroid injections in the management of PF. Earlier studies have not informed clinical practice. As the research base has developed, evidence has emerged supporting clinical efficacy. With diverse opinions surrounding the etiology and efficacy debate, there does not seem to be a consensus of opinion on a common treatment pathway. For example, in England, the National Institute for Clinical Health and Excellence does not publish strategic guidance for clinical practice. Herein, we review and evaluate core literature that examines the clinical efficacy of corticosteroid injection as a treatment for PF. Outcome measures were wide ranging but largely yielded results supportive of the short- and long-term benefits of this modality. The analysis also looked to establish, where possible, "proof of concept." This article provides evidence supporting the clinical efficacy of corticosteroid injections, in particular those guided by imaging technology. The evidence challenges existing orthodoxy, which marginalizes this treatment as a secondary option. This challenge is supported by recently revised guidelines published by the American College of Foot and Ankle Surgeons advocating corticosteroid injection as a primary treatment option. PMID- 24072373 TI - Single longitudinal dorsal incision approach to transfer the flexor digitorum longus tendon between the flexor digitorum brevis hemitendons: a cadaveric study. AB - Transposition of the flexor digitorum longus tendon has been widely reported for the correction of flexible claw and hammertoe deformities. The most common technique uses two cutaneous incisions, one plantar and another dorsal. We performed a cadaveric study to determine whether the flexor digitorum longus tendon could be transferred to the dorsum of the proximal phalanx of the toe from its lateral or medial aspect through a unique single longitudinal central dorsal incision. The rationale for this novel approach was to minimize the risk of vascular compromise to the digit associated with the two-incision approach. Transposition of the flexor digitorum longus tendon was attempted in 120 toes of cadaveric feet (60 each second and third digits) through a central longitudinal dorsal incision. The flexor digitorum longus tendon segment was long enough to be successfully transposed between the flexor digitorum brevis hemitendons of the second and third toes in 100% of the cases using the central longitudinal dorsal incision approach, with a resection arthroplasty at the proximal interphalangeal joint. Transfer of the flexor digitorum longus tendon to the dorsum of the proximal phalanx can be performed for the correction of claw and hammertoe deformities in the second and third digits. The meticulous longitudinal incision of the flexor tendon sheath to expose the flexor digitorum brevis tendon and its longitudinal incision are essential to the successful transfer of the flexor digitorum longus tendon between the flexor digitorum brevis hemitendons. PMID- 24072374 TI - Adenoid cystic carcinoma of the leg: a case study. AB - Adenoid cystic carcinoma is a malignant tumor commonly located in the parotid and submandibular glands. There is no literature to date that discusses its incidence in the lower extremity. This article presents a case of adenoid cystic carcinoma presenting in the leg. PMID- 24072375 TI - Traumatic digital amputations of the foot inflicted by pet cat upon individual with diabetic peripheral neuropathy. AB - Diabetic peripheral neuropathy (DPN) is a common cause of many lower-extremity complications. This case study illustrates the potential perils of pet ownership associated with diabetes and neuropathy. The case describes an incident resulting in traumatic digital amputations inflicted by a patient's pet feline while she was sleeping. In presenting this case, the potential risks of pet ownership for patients with DPN are discussed along with a review of the relevant literature. PMID- 24072377 TI - Congenital onychoheterotopia involving multiple toe nails. AB - Onychoheterotopia is an uncommon condition in which nail tissue is found beyond the common nail unit of the digits of the hands and feet, most often on the fifth digit of the hand. It represents an extra and independent nail that can be present either congenitally, or more commonly, acquired following trauma. The exact pathogenesis of the congenital type is undetermined. We report a 25-year old male with multiple congenital ectopic nails of the toes since birth, which has not been reported before. PMID- 24072378 TI - Pedal pathology potentiated by personal pedicure procedures in the presence of painless peripheral neuropathy. AB - Although the literature is replete with recommendations for people with diabetes particularly those with neuropathy, ischemia, or both-to avoid caring for corns and calluses on their own feet, there are virtually no reports of damage associated with this care. The purpose of this article is to report on the potential perils of personal pedicures in the presence of peripheral neuropathy by using a case-based example. In this article, we report on the inappropriate use of a Ped Egg personal pedicure device that led to limb-threatening lesions in a gentleman with diabetic peripheral sensory neuropathy. PMID- 24072379 TI - A field test of Web-based screening for dry eye disease to enhance awareness of eye problems among general Internet users: a latent strategy to promote health. AB - BACKGROUND: A Web-based self-check system including a brief questionnaire would seem to be a suitable tool for rapid disease screening. OBJECTIVE: The purpose of this preliminary study was to test a Web-based self-screening questionnaire for drawing attention to dry eye disease among general Internet users and identifying those with a higher risk of developing the condition. METHODS: A survey website was launched and used to recruit participants from general Internet users. In the first phase, volunteers were asked to complete a Web-based self-screening questionnaire containing 12 questions on dry eye symptoms. The second phase focused on the respondents who reported five or more dry eye symptoms and expressed their intention to seek medical attention. These participants performed the Schirmer test, for evaluating tear production, and completed a paper-based lifestyle questionnaire to provide relevant background data. RESULTS: Of the 1689 visitors to the website, 980 (58.0%) volunteers completed the Web-based self screening questionnaire. Among these, 355 (36.2%) respondents reported five or more dry eye symptoms. Then, 99 (27.9%) of the symptomatic participants performed the Schirmer test and completed the paper-based lifestyle questionnaire. Out of these, 32 (32.2%) had abnormal tear production (<=5 mm). CONCLUSIONS: The proposed Web-based self-screening questionnaire seems to be a promising tool for raising awareness of dry eye disease among general Internet users and identifying those with a higher risk of developing the condition, although further research is needed to validate its effectiveness. PMID- 24072381 TI - MRI of anal cancer: assessing response to definitive chemoradiotherapy. AB - Anal cancer is an uncommon malignancy of the gastrointestinal tract but has a relatively good prognosis with an 80% 5-year overall survival. In this article, we review the role of MRI for assessing treatment response in anal cancer after completion of definitive chemoradiotherapy. New generation MRI scanners with optimal-phased array body coils, resulting in better signal to noise and improved contrast and spatial resolution, have contributed to high-resolution imaging in clinical practice enabling visualization of relevant anatomy including the sphincter complex, adjacent structures, mesorectal and pelvic lymph nodes with a diameter down to 2 mm. Multiplanar, high-resolution T2-weighted and diffusion weighted sequences have a role in initial locoregional staging of anal SCC, assisting radiotherapy planning, as well as in assessing response to treatment and treatment-related complications. PMID- 24072380 TI - Hemoglobin A1c as a marker for identifying diabetes and cardiovascular risk factors: the China Health and Nutrition Survey 2009. AB - Hemoglobin A1c (HbA1c) has been recommended as an optional method for diagnosing diabetes. The impact of HbA1c on the diagnosis of diabetes has not been evaluated in China, a country with the greatest number of people with diabetes in the world. Hence, we aim to examine how well HbA1c performs as compared with fasting plasma glucose (FPG) for diagnosing diabetes in Chinese population. We conducted a cross-sectional analysis of 7,641 Chinese men and women aged >=18 years using data from the China Health and Nutrition Survey 2009 in which FPG and standardized HbA1c were measured. HbA1c was measured with high-performance liquid chromatography system. Diabetes is defined as having FPG >=7 mmol/l or HbA1c >=6.5 %. Overall, 5.0 and 5.8 % had undiagnosed diabetes by FPG >=7 mmol/l and HbA1c >=6.5 %, respectively. Overlap between HbA1c- and FPG-based diagnosis of diabetes was limited (n = 214, 34.9 %). Similar trends were noted in both genders, all age groups, urban/rural settings, regions, body mass index (BMI) categories, waist circumference (WC) groups, and blood pressure status. Solely HbA1c-defined individuals exhibited higher levels of BMI, WC, total cholesterol, and hypersensitive C-reactive protein and lower levels of homeostasis model assessment of insulin resistance. We note limited overlap between FPG- and HbA1c based diagnosis of diabetes. The limited overlap between FPG- and HbA1c-based diagnosis of diabetes persisted in each evaluated subgroup. HbA1c criterion for the diagnosis of diabetes identifies individuals with a worse cardiovascular risk profile compared with FPG. PMID- 24072382 TI - Dual-energy CT of the abdomen. AB - Although conceived of in the 1970s, practical use of dual-energy CT in the clinical setting did not come to fruition until 2006, and since that time an ever expanding exploration of the technology has been underway. This article will discuss technical aspects of the two commercially available CT scanners, review the recent literature, and provide an organ-based description of abdominal dual energy CT applications for the practicing radiologist. PMID- 24072383 TI - Diffusion-weighted MRI in bladder carcinoma: the differentiation between tumor recurrence and benign changes after resection. AB - PURPOSE: To investigate the efficacy of diffusion-weighted MRI (DWI) in differentiating recurrent tumor from chronic inflammation and fibrosis after cystectomy or transurethral resection of bladder cancer. METHODS: Eleven patients with suspected tumor recurrence underwent pelvic DWI and dynamic contrast enhanced (DCE) MRI at 3 months to 7 years following bladder cancer resection. The diagnosis was histologically confirmed in all patients by transurethral or cystoscopic resection of 27 lesions within 2 weeks of MR examinations. RESULTS: The accuracies, sensitivities, specificities, and positive predict values of DWI (92.6%, 100%, 81.8%, and 88.9%) were higher than those of DCE MRI (59.3%, 81.3%, 27.3%, and 54.2%) for detecting recurrent tumors. Using receiver operating characteristic analysis, the accuracy of DWI was significantly higher than that of DCE MRI (P < 0.05). There was no significant difference between DWI diagnosis and histopathology (P > 0.05), whereas the difference between diagnosis of DCE MRI and histopathology was significant (P < 0.05). The normalized apparent diffusion coefficients of recurrent tumors (0.697 +/- 0.219) were significantly (P < 0.05) lower than those of postoperative inflammation or fibrosis (1.019 +/- 0.143). CONCLUSIONS: DWI is superior to DCE MRI for differentiating recurrent bladder tumors from postoperative inflammation or fibrosis. DWI can be included in the follow-up MRI protocol after bladder cancer surgery. PMID- 24072384 TI - Imaging female infertility. AB - The purpose of this pictorial review is to discuss causes of female infertility, in particular, those etiologies in which imaging plays a key role in detection. Included are disorders of cervical, ovarian, fallopian tube, and uterine origin. We also discuss the role of various imaging modalities including hysterosalpingography, pelvic ultrasonography, hysterosonography, and pelvic MR imaging in elucidating the cause of female infertility. Radiologists need to know the conditions to be aware of when these patients are sent for diagnostic imaging, as well as how to direct further management, if necessary, should an abnormality be detected. PMID- 24072385 TI - "Munster correlation" in temporal bone: surgical relevance of an anatomical study. AB - Resection of the temporal bone to various degrees provides different levels of access to lesions of the posterior fossa. However, precise distances to the petrosal bone are still not clearly described. We evaluated the different distances of temporal bone landmarks in order to assess their variations and the possible correlations between them. We also evaluated the surgical relevance of the possible correlations. An anatomical study was performed on 60 temporal bones from 60 human cadavers. All bones contained an adequate portion of the petrous apex and attached fossa dura. We analyzed the variation in different distances between landmarks and also the correlations between different measured distances. There was a statistically significant correlation between the distance between the inferior axial plane of the posterior semicircular canal to the superior plane of jugular bulb and the thickness of the mastoid cortex at the M point (M point was defined by the authors). This correlation is important for estimating the height of the jugular bulb during a lateral suboccipital craniotomy in cerebellopontine angle surgery. The Munster correlation is an easy and safe method for estimating the height of the jugular bulb in cerebellopontine angle surgery. PMID- 24072386 TI - Abstracts of the 20th Annual Conference of the International Society for Quality of Life Research. October 10, 2013. PMID- 24072388 TI - Identification of patients with nasopharyngeal carcinoma by serum protein profiling using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. AB - BACKGROUND: As diagnosis of nasopharyngeal carcinoma at an early disease stage is important, we attempted to distinguish between patients with nasopharyngeal carcinoma and noncancer controls by using serum protein profiles. METHODS: Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry and CM10 protein chip were used to detect the serum proteomic patterns of 65 patients with nasopharyngeal carcinoma before radiotherapy and 93 noncancer controls. Proteomic spectra of serum samples from 50 nasopharyngeal carcinoma patients and 60 noncancer controls were used as a training set. The validity of the classification tree was then challenged with a blind test set which included another 15 patients with nasopharyngeal carcinoma and 33 noncancer controls. Biomarker Wizard 3.01 and Biomarker Pattern 5.01 were used in combination to analyze the data and to develop diagnostic models. RESULTS: 21 protein peaks were significantly different between nasopharyngeal carcinoma and controls. 4 mass peaks (M4182, M5343, M5913 and M8702 mass/charge ratio) were chosen automatically to construct a classification tree. The classification tree correctly determined 93.8 % (45/48) of the test samples with 93.3 % (14/15) of the nasopharyngeal carcinoma samples and 93.9 % (31/33) of the noncancer samples. Using a combination of serum protein profiles and Epstein-Barr viral capsid antigen immunoglobulin A antibody tests, the diagnostic sensitivity and specificity were increased to 100 and 97 %, respectively. CONCLUSIONS: Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry could correctly distinguish nasopharyngeal carcinoma from noncancer individuals and showed great potential for the development of a screening test for the detection of nasopharyngeal carcinoma. PMID- 24072389 TI - Molecular basis of active copper resistance mechanisms in Gram-negative bacteria. AB - Copper is a metallic element that is crucial for cell metabolism; however, in extended concentrations, it is toxic for all living organisms. The dual nature of copper has forced organisms, including bacteria, to keep a tight hold on cellular copper content. This challenge has led to the evolution of complex mechanisms that on one hand enable them to deliver the essential element and on the other to protect cells against its toxicity. Such mechanisms have been found in both eukaryotic and prokaryotic cells. In bacteria a number of different systems such as extra- and intracellular sequestration, enzymatic detoxification, and metal removal from the cell enabling them to survive in the presence of high concentration of copper have been identified. Gram-negative bacteria, due to their additional compartment, need to deal with both cytoplasmic and periplasmic copper. Therefore, these bacteria have evolved intricate and precisely regulated systems which interact with each other. In this review the active mechanisms of copper resistance at their molecular level are discussed. PMID- 24072390 TI - The effect of tenocyte/hyaluronic acid therapy on the early recovery of healing Achilles tendon in rats. AB - The aim of this study was to explore the potential for a better recovery outcome for the Achilles tendon at an early healing stage when a mixed biomaterial tenocyte injection is used. The experimental animals underwent single limb Achilles tendon transection followed by suturing repair. A solution of either hyaluronic acid with or without tenocytes or normal saline was randomly chosen to be injected around the injury site after surgery. To obtain the comprehensive recovery condition of the rats on different management protocols, the animals were evaluated histologically, mechanically, and functionally. A significant difference in the recovery condition was found in the injured tendon injected with the hyaluronic acid solution with tenocytes compared with the other groups. Tendon stiffness and the locomotion abilities of the rats with healing Achilles tendons were improved in the hyaluronic acid with tenocyte transplantation group. The acceleration of the inflammatory phase in rats with the hyaluronic acid with tenocyte injections might be the major reason for the better functional outcomes. PMID- 24072391 TI - Dielectric study of the adhesion of mesenchymal stem cells from human umbilical cord on a sugarcane biopolymer. AB - It is of current interest the identification of appropriate matrices for growing mesenchymal stem cells (MSC). These cells are able not only to regenerate themselves but also to differentiate into other type of functional cells, and so they have been extensively used in tissue engineering. In this work, we have evaluated the use of electric impedance spectroscopy (EIS) to follow the adhesion of MSC from Wharton's jelly of the human umbilical cord (hWJMSC) on sugarcane biopolymers (SCB). Impedance spectra of the systems were obtained in the frequency range of 10(2)-10(5) Hz. An EIS investigation showed that when deposited on a metallic electrode SCB films prevent the passage of electrons between the solution and the metallic interface. The impedance spectra of hWJMSCs adhered on SCB revealed that there is a significant increase in the magnitude of the impedance when compared to that of pure SCB. The corresponding resistance (real part of the impedance) was even higher for the SCB-hWJMSC system than for SCB without cells on their surface, in an indication of an increased blockage to the electron transfers. The resistance charge transfer is extracted by curve fitting the impedance spectra to an equivalent circuit model. Also, a shift of the phase angle to higher frequencies was obtained for SCB-hWJMSC system as a result from hWJMSC adhesion. Our study demonstrates that EIS is an appropriate method to evaluate the adhesion of MSC. SCB can be considered as a promising biomaterial for tissue engineering. PMID- 24072392 TI - What will it take to get to under 5% smoking prevalence by 2025? Modelling in a country with a smokefree goal. AB - BACKGROUND: New Zealand has a goal of becoming a smokefree nation by the year 2025. Smoking prevalence in 2012 was 17%, but is over 40% for Maori (indigenous New Zealanders). We forecast the prevalence in 2025 under a business-as-usual (BAU) scenario, and determined what the initiation and cessation rates would have to be to achieve a <5% prevalence. METHODS: A dynamic model was developed using Census and Health Survey data from 1981 to 2012 to calculate changes in initiation by age 20 years, and net annual cessation rates, by sex, age, ethnic group and time period. Similar parameters were also calculated from a panel study for sensitivity analyses. 'Forecasts' used these parameters, and other scenarios, applied to the 2011-2012 prevalence. FINDINGS: Since 2002-2003, prevalence at age 20 years has decreased annually by 3.1% (95% uncertainty interval 0.8% to 5.7%) and 1.1% (-1.2% to 3.2%) for non-Maori males and females, and by 4.7% (2.2% to 7.1%) and 0.0% (-2.2% to 1.8%) for Maori, respectively. Annual net cessation rates from the dynamic model ranged from -3.0% to 6.1% across demographic groups, and from 3.0% to 6.0% in the panel study. Under BAU, smoking prevalence is forecast to be 11% and 9% for non-Maori males and females by 2025, and 30% and 37% for Maori, respectively. Achieving <5% by 2025 requires net cessation rates to increase to 10% for non-Maori and 20% for Maori, accompanied by halving or quartering of initiation rates. CONCLUSIONS: The smokefree goal of <5% prevalence is only feasible with large increases in cessation rates. PMID- 24072393 TI - Reprogramming of pig dermal fibroblast into insulin secreting cells by a brief exposure to 5-aza-cytidine. AB - Large animal models provide useful data for pre-clinical research including regenerative medicine. However whereas the derivation of tissue specific stem cells has been successful. pluripotent stem cells so far have been difficult to obtain in these species. A possible alternative could be direct reprogramming but this has only been described in mouse and human. We have recently described an alternative method for reprogramming human somatic cells based on a brief demethylation step immediately followed by an induction protocol. Aim of the present paper was to determine whether this method is applicable to pig in the attempt to achieve cell reprogramming in a large animal model for the first time. Pig dermal fibroblasts were exposed to DNA methyltransferase inhibitor 5-aza cytidine (5-aza-CR) for 18 h. After a brief recovery period, fibroblast were subjected to a three-step protocol for the induction of endocrine pancreatic differentiation that was completed after 42 days. During the process pig fibroblast rapidly lost their typical elongated form and gradually became organized in a reticular pattern that evolved into distinct cell aggregates. After a brief expression of some pluripotency genes, cells expression pattern mimicked the transition from primitive endoderm to endocrine pancreas. Not only converted cells expressed insulin but were able to release it in response to a physiological glucose challenge in vitro. Finally they were able to protect recipient mice against streptozotocin-induced diabetes. This work shows, that the conversion of a somatic cell into another, even if belonging to a different germ layer, is possible also in pig. PMID- 24072394 TI - Germline mutation and protein expression analysis of mismatch repair genes MSH6 and PMS2 in Malaysian Lynch syndrome patients. PMID- 24072395 TI - An insight into pelvic floor status in nulliparous women. AB - INTRODUCTION AND HYPOTHESIS: Few studies have comprehensively investigated the prevalence of various types of pelvic floor Dysfunction (PFD) in women before their first pregnancy. However, no previous studies have investigated in detail all four compartments of PFD and the correlation between them. METHODS: This was a cross-sectional study nested within a parent prospective study Screening for Pregnancy Endpoints (SCOPE) performed in a tertiary referral teaching hospital with approximately 9,000 deliveries per annum. Nulliparous women completed the validated Australian Pelvic Floor Questionnaire at 15 weeks' gestation, at the time of recruitment to the SCOPE study. The questionnaire contained four sections, with questions about urinary, faecal, prolapse and sexual dysfunction in the prepregnancy period. RESULTS: A total of 1,484 participants completed the prenatal questionnaire. Urinary dysfunction was present in 61 % of participants, faecal in 41 %, prolapse in 5 % and sexual in 41 %; in 37 %, dysfunction was perceived as bothersome . At least one clinically significant symptom, defined as severity grade 2 or 3, or grade 1 associated with being bothersome, was reported by 58.2 % of participants. More than one type of PFD was present in 57.6 % of cases. The severity score of each symptom within a PFD section was associated with total section score. CONCLUSIONS: We confirmed a high rate of PFD in nulliparous women. Clinically significant symptoms and associated bother were very common among symptomatic participants. The majority of affected women had more than one type of PFD. Postnatal follow-up is needed in order to elucidate the role of prepregnancy symptoms in the aetiology of postnatal pelvic floor pathology. PMID- 24072397 TI - Biomarker tests for risk assessment in coronary artery disease: will they change clinical practice? AB - The clinical significance and economic impact of coronary artery disease has triggered major research efforts into the discovery of novel biomarkers for risk stratification in primary and secondary prevention and then the development of assays suitable for routine measurement. Nevertheless, the clinical impact of these novel biomarkers for risk stratification is still limited because they do not add substantially to traditional risk factors and they only modestly-even with a multimarker approach-improve risk stratification and patient reclassification. The most useful markers appear to be high-sensitivity C reactive protein, natriuretic peptides, and, eventually, high-sensitivity cardiac troponins. Further research is clearly needed. PMID- 24072398 TI - A single neurotoxic dose of methamphetamine induces a long-lasting depressive like behaviour in mice. AB - Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and HVA, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis. PMID- 24072399 TI - Outcome of sentinel lymph node biopsy in breast cancer using dye alone: a single center review with a median follow-up of 5 years. AB - PURPOSE: Various techniques are used for sentinel lymph node biopsy (SLNB) in breast cancer. While subareolar injection with dye alone is a relatively easy method, few studies have reported the outcome with a follow-up period. This study presents our results of SLNB using dye alone. METHODS: Between November 2002 and December 2010, 701 patients with breast cancer underwent SLNB using subareolar injection of indocyanine green or indigo carmine. Sentinel lymph node (SLN) negative patients were followed without axillary lymph node dissection (ALND). RESULTS: SLNs were detected in 654 of 701 patients (93.3%), and the rate increased to 98.1% over the course of the study. The mean number of SLNs removed was 1.5. There was no significant difference in the detection rate between two dyes. No adverse events resulted from the injection of dyes. Of the 654 patients, 136 (20.8%) had SLN metastasis. Five hundred patients were followed without ALND. Thirty-six patients experienced disease relapse during a median follow-up of 60 months. Thirteen patients (2.6%) had regional lymph node relapse, and eight of them could undergo salvage lymph node dissection. The 5-year disease-free and overall survival rates were 92.4 and 96.1 %, respectively. CONCLUSION: SLNB using subareolar injection with dye alone was safe and feasible even after a long follow-up. PMID- 24072400 TI - A study on the influence of different promoter and 5'UTR (URM) cassettes from Arabidopsis thaliana on the expression level of the reporter gene beta glucuronidase in tobacco and cotton. AB - Several reports of promoters from plants, viral and artificial origin that confer high constitutive expression are known. Among these the CaMV 35S promoter is used extensively for transgene expression in plants. We identified candidate promoters from Arabidopsis based on their transcript levels (meta-analysis of available microarray control datasets) to test their activity in comparison to the CaMV 35S promoter. A set of 11 candidate genes were identified which showed high transcript levels in the aerial tissue (i.e. leaf, shoot, flower and stem). In the initial part of the study binary vectors were developed wherein the promoter and 5'UTR region of these candidate genes (Upstream Regulatory Module, URM) were cloned upstream to the reporter gene beta glucuronidase (gus). The promoter strengths were tested in transformed callus of Nicotiana tabacum and Gossypium hirsutum. On the basis of the results obtained from the callus, the influence of the URM cassettes on transgene expression was tested in transgenic tobacco. The URM regions of the genes encoding a subunit of photosystem I (PHOTO) and geranyl geranyl reductase (GGR) in A. thaliana genome showed significantly high levels of GUS activity in comparison to the CaMV 35S promoter. Further, when the 5'UTRs of both the genes were placed downstream to the CaMV 35S promoter it led to a substantial increase in GUS activity in transgenic tobacco lines and cotton callus. The enhancement observed was even higher to that observed with the viral leader sequences like Omega and AMV, known translational enhancers. Our results indicate that the two URM cassettes or the 5'UTR regions of PHOTO and GGR when placed downstream to the CaMV 35S promoter can be used to drive high levels of transgene expression in dicotyledons. PMID- 24072401 TI - Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients. AB - Myeloid-derived suppressor cells are increased in the peripheral blood of advanced-stage cancer patients; however, no studies have shown a correlation of these immunosuppressive cells with clinical outcomes in melanoma patients. We characterized the frequency and suppressive function of multiple subsets of myeloid-derived suppressor cells in the peripheral blood of 34 patients with Stage IV melanoma, 20 patients with Stage I melanoma, and 15 healthy donors. The frequency of CD14+ MDSCs (Lin- CD11b+ HLA-DR- CD14+ CD33+) and CD14- MDSCs (Lin- CD11b+ HLA-DR- CD14- CD33+) was increased in the peripheral blood of Stage IV melanoma patients relative to healthy donors. The frequency of CD14+ and CD14- MDSCs correlated with each other and with the increased frequency of regulatory T cells, but not with classically defined monocytes. CD14- MDSCs isolated from the peripheral blood of Stage IV melanoma patients suppressed T cell activation more than those isolated from healthy donors, and the frequency of these cells correlated with disease progression and decreased overall survival. Our study provides the first evidence that the frequency of CD14- MDSCs negatively correlates with clinical outcomes in advanced-stage melanoma patients. These data indicate that suppressive MDSCs should be considered as targets for future immunotherapies. PMID- 24072402 TI - Non-genomic events determining the sensitivity of hemopoietic malignancies to glucocorticoid-induced apoptosis. AB - Glucocorticoid (GC) hormones have been introduced as therapeutic agents in blood cancers six decades ago. The effectiveness of GC treatment stems from its ability to induce apoptotic death of hemopoietic cells. A major impediment in GC therapy is the acquisition of resistance to the drug upon repeated treatment. In addition, some blood cancers are a priori resistant to GC therapy. Usually, resistance to GC correlates with poor prognosis. Albeit the wide use of GC in clinical practice, their mode of action is not fully understood. The cellular response to GC is initiated by its binding to the cytosolic GC receptor (GR) that translocates to the nucleus and modulates gene expression. However, nuclear activities of GR occur in both apoptosis-sensitive and apoptosis-resistant cells. These apparent controversies can be resolved by deciphering non-genomic effects of GCs and the mode by which they modulate the apoptotic response. We suggest that non-genomic consequences of GC stimulation determine the cell fate toward survival or death. Understanding the cellular mechanisms of GC apoptotic sensitivity contributes to the development of new modalities for overcoming GC resistance. PMID- 24072403 TI - Comparative analysis of some aspects of mitochondrial metabolism in differentiated and undifferentiated neuroblastoma cells. AB - The aim of the present study is to clarify some aspects of the mechanisms of regulation of mitochondrial metabolism in neuroblastoma (NB) cells. Experiments were performed on murine Neuro-2a (N2a) cell line, and the same cells differentiated by all-trans-retinoic acid (dN2a) served as in vitro model of normal neurons. Oxygraphy and Metabolic Control Analysis (MCA) were applied to characterize the function of mitochondrial oxidative phosphorylation (OXPHOS) in NB cells. Flux control coefficients (FCCs) for components of the OXPHOS system were determined using titration studies with specific non-competitive inhibitors in the presence of exogenously added ADP. Respiration rates of undifferentiated Neuro-2a cells (uN2a) and the FCC of Complex-II in these cells were found to be considerably lower than those in dN2a cells. Our results show that NB is not an exclusively glycolytic tumor and could produce a considerable part of ATP via OXPHOS. Two important enzymes - hexokinase-2 and adenylate kinase-2 can play a role in the generation of ATP in NB cells. MCA has shown that in uN2a cells the key sites in the regulation of OXPHOS are complexes I, II and IV, whereas in dN2a cells complexes II and IV. Results obtained for the phosphate and adenine nucleotide carriers showed that in dN2a cells these carriers exerted lower control over the OXPHOS than in undifferentiated cells. The sum of FCCs for both types of NB cells was found to exceed significantly that for normal cells suggesting that in these cells the respiratory chain was somehow reorganized or assembled into large supercomplexes. PMID- 24072405 TI - Indirect costs account for half of the total costs of an osteoporotic fracture: a prospective evaluation. AB - Data on direct and indirect costs of clinical fractures in 116 osteoporotic patients 50 years and older were prospectively collected using cost diaries. Indirect costs accounted for roughly half of the total costs, with a contribution of at least 81% of these costs in employed patients. INTRODUCTION: The aim of this prospective study was to gain insight into the current total costs of clinical fractures in osteoporotic patients aged 50 years and older. METHODS: In a study in the Netherlands, patients prospectively filled out cost diaries every 3 months, during 1 year after a clinical fracture. Primary analyses were performed on those patients with all four cost diaries returned. In-depth analyses of indirect costs were performed, dividing results for employed and unemployed patients. Sensitivity analyses using imputation techniques were performed on patients who returned two or three diaries RESULTS: Of the 116 included patients, 69 completed all four diaries, 24 only two or three, and 23 patient completed one or no diaries. For all fractures, approximately 50% of the total costs were due to indirect costs; employed patients contributed for at least 81% of the indirect cost. Humerus fractures were most expensive with a total 1-year cost of ?16.841 per patient. Indirect costs in the group with clinical spine fractures were highest (12.522), accounting for 89.1% of the total costs for this fracture. CONCLUSION: Indirect costs account for roughly half of the total costs of clinical fractures, which are largely related to sick leave. When performing cost analyses in fracture patients, we advise a societal perspective in which indirect costs are also considered, and to apply a patient derived prospective data collection method to get a 'true' and complete image of the total costs due to clinical fractures. PMID- 24072406 TI - Impact of reduced daily physical activity on conduit artery flow-mediated dilation and circulating endothelial microparticles. AB - Physical inactivity promotes the development of cardiovascular diseases. However, few data exist examining the vascular consequences of short-term reductions in daily physical activity. Thus we tested the hypothesis that popliteal and brachial artery flow-mediated dilation (FMD) would be reduced and concentrations of endothelial microparticles (EMPs) would be elevated following reduced daily physical activity. To examine this, popliteal and brachial artery FMD and plasma levels of EMPs suggestive of apoptotic and activated endothelial cells (CD31(+)/CD42b(-) and CD62E(+) EMPs, respectively) were measured at baseline and during days 1, 3, and 5 of reduced daily physical activity in 11 recreationally active men (25 +/- 2 yr). Subjects were instructed to reduce daily physical activity by taking <5,000 steps/day and refraining from planned exercise. Popliteal artery FMD decreased with reduced activity (baseline: 4.7 +/- 0.98%, reduced activity day 5: 1.72 +/- 0.68%, P < 0.05), whereas brachial artery FMD was unchanged. In contrast, baseline (pre-FMD) popliteal artery diameter did not change, whereas brachial artery diameter decreased (baseline: 4.35 +/- 0.12, reduced activity day 5: 4.12 +/- 0.11 P < 0.05) following 5 days of reduced daily physical activity. CD31(+)/CD42b(-) EMPs were significantly elevated with reduced activity (baseline: 17.6 +/- 9.4, reduced activity day 5: 104.1 +/- 43.1 per MUl plasma, P < 0.05), whereas CD62E(+) EMPs were unaltered. Collectively, our results provide evidence for the early and robust deleterious impact of reduced daily activity on vascular function and highlight the vulnerability of the vasculature to a sedentary lifestyle. PMID- 24072407 TI - Rho-kinase mediated cytoskeletal stiffness in skinned smooth muscle. AB - The structurally dynamic cytoskeleton is important in many cell functions. Large gaps still exist in our knowledge regarding what regulates cytoskeletal dynamics and what underlies the structural plasticity. Because Rho-kinase is an upstream regulator of signaling events leading to phosphorylation of many cytoskeletal proteins in many cell types, we have chosen this kinase as the focus of the present study. In detergent skinned tracheal smooth muscle preparations, we quantified the proteins eluted from the muscle cells over time and monitored the muscle's ability to respond to acetylcholine (ACh) stimulation to produce force and stiffness. In a partially skinned preparation not able to generate active force but could still stiffen upon ACh stimulation, we found that the ACh-induced stiffness was independent of calcium and myosin light chain phosphorylation. This indicates that the myosin light chain-dependent actively cycling crossbridges are not likely the source of the stiffness. The results also indicate that Rho-kinase is central to the ACh-induced stiffness, because inhibition of the kinase by H1152 (1 MUM) abolished the stiffening. Furthermore, the rate of relaxation of calcium-induced stiffness in the skinned preparation was faster than that of ACh induced stiffness, with or without calcium, suggesting that different signaling pathways lead to different means of maintenance of stiffness in the skinned preparation. PMID- 24072408 TI - Drinking-induced bradyarrhythmias and cerebral injury in Dahl salt-sensitive rats with sinoaortic denervation. AB - We have demonstrated that a drinking-induced pressor response was larger if the baroreflex did not operate, and the mean arterial pressure reached 163 mmHg in conscious rats with sinoaortic denervation (SAD). Thus we hypothesized that a drinking behavior became a cardiovascular risk factor if a basal arterial pressure was high. To clarify this, we analyzed the occurrence of arrhythmias and the accumulation of microglia in Dahl salt-sensitive rats (Dahl S) with SAD. We maintained Dahl S and Dahl salt-resistant rats (Dahl R) with a high-sodium diet for 5 weeks. After SAD surgery, we measured arterial pressure and electrocardiogram during water-drinking behavior in all rats. Furthermore, we measured tumor necrosis factor-alpha concentration in the cerebrospinal fluid (CSF) and microglial accumulations around the third and fourth ventricles in rats with programmed drinking at a rapid or slow rate for 7 days. Incidences of drinking-induced bradyarrhythmias and premature ventricular contractions (PVCs) were significantly larger in Dahl S than Dahl R rats. Both bradyarrhythmias and PVCs were completely abolished by atropine administration. Accumulations of microglia around the third ventricle and increases in TNF-alpha in the CSF were observed in rats that drank water at a rapid rate; these were not seen in rats that drank water slowly. In conclusion, both cardiovascular events and cerebral injury may be increased by drinking in Dahl S rats with SAD. These risks are reduced by modifying drinking behavior such as slowing the drinking rate. PMID- 24072410 TI - Long-term levosimendan treatment improves systolic function and myocardial relaxation in mice with cardiomyocyte-specific disruption of the Serca2 gene. AB - In human heart failure (HF), reduced cardiac function has, at least partly, been ascribed to altered calcium homeostasis in cardiomyocytes. The effects of the calcium sensitizer levosimendan on diastolic dysfunction caused by reduced removal of calcium from cytosol in early diastole are not well known. In this study, we investigated the effect of long-term levosimendan treatment in a murine model of HF where the sarco(endo)plasmatic reticulum ATPase (Serca) gene is specifically disrupted in the cardiomyocytes, leading to reduced removal of cytosolic calcium. After induction of Serca2 gene disruption, these mice develop marked diastolic dysfunction as well as impaired contractility. SERCA2 knockout (SERCA2KO) mice were treated with levosimendan or vehicle from the time of KO induction. At the 7-wk end point, cardiac function was assessed by echocardiography and pressure measurements. Vehicle-treated SERCA2KO mice showed significantly diminished left-ventricular (LV) contractility, as shown by decreased ejection fraction, stroke volume, and cardiac output. LV pressure measurements revealed a marked increase in the time constant (tau) of isovolumetric pressure decay, showing impaired relaxation. Levosimendan treatment significantly improved all three systolic parameters. Moreover, a significant reduction in tau toward normalization indicated improved relaxation. Gene expression analysis, however, revealed an increase in genes related to production of the ECM in animals treated with levosimendan. In conclusion, long-term levosimendan treatment improves both contractility and relaxation in a heart failure model with marked diastolic dysfunction due to reduced calcium transients. However, altered gene expression related to fibrosis was observed. PMID- 24072411 TI - Evidence of cell damages caused by circulating bubbles: high level of free mitochondrial DNA in plasma of rats. AB - Bubble formation can occur in the vascular system after diving, leading to decompression sickness (DCS). DCS signs and symptoms range from minor to death. Too often, patients are admitted to a hyperbaric center with atypical symptoms, as bubbles cannot be detected anymore. In the absence of a relevant biomarker for humans, the therapeutic management remains difficult. As circulating DNA was found in the blood of healthy humans and animals, our study was made to correlate the extracellular mitochondrial DNA (mDNA) concentration with the occurrence of clinical DCS symptoms resulting from initial bubble-induced damages. Therefore, 109 rats were subjected to decompression from a simulated 90-m sea water dive, after which, 78 rats survived (71.6%). Among the survivors, 15.6% exhibited typical DCS symptoms (DCS group), whereas the remaining 56% showed no detectable symptoms (noDCS group). Here, we report that the symptomatic rats displayed both a circulating mDNA level (DNADCS -> 2.99 +/- 2.62) and a bubble grade (median Spencer score = 3) higher than rats from the noDCS group (DNAnoDCS -> 1.49 +/- 1.27; Spencer score = 1). These higher levels could be correlated with the platelet and leukocyte consumption induced by the pathogenic decompression. Rats with no detectable bubble had lower circulating mDNA than those with higher bubble scores. We determined that in rats, a level of circulating mDNA >1.91 was highly predictive of DCS with a positive-predictive value of 87.3% and an odds ratio of 4.57. Thus circulating mDNA could become a relevant biomarker to diagnose DCS and should be investigated further to confirm its potential application in humans. PMID- 24072412 TI - A 3-D mathematical model to identify organ-specific risks in rats during thermal stress. AB - Early prediction of the adverse outcomes associated with heat stress is critical for effective management and mitigation of injury, which may sometimes lead to extreme undesirable clinical conditions, such as multiorgan dysfunction syndrome and death. Here, we developed a computational model to predict the spatiotemporal temperature distribution in a rat exposed to heat stress in an attempt to understand the correlation between heat load and differential organ dysfunction. The model includes a three-dimensional representation of the rat anatomy obtained from medical imaging and incorporates the key mechanisms of heat transfer during thermoregulation. We formulated a novel approach to estimate blood temperature by accounting for blood mixing from the different organs and to estimate the effects of the circadian rhythm in body temperature by considering day-night variations in metabolic heat generation and blood perfusion. We validated the model using in vivo core temperature measurements in control and heat-stressed rats and other published experimental data. The model predictions were within 1 SD of the measured data. The liver demonstrated the greatest susceptibility to heat stress, with the maximum temperature reaching 2 degrees C higher than the measured core temperature and 95% of its volume exceeding the targeted experimental core temperature. Other organs also attained temperatures greater than the core temperature, illustrating the need to monitor multiple organs during heat stress. The model facilitates the identification of organ-specific risks during heat stress and has the potential to aid in the development of improved clinical strategies for thermal-injury prevention and management. PMID- 24072409 TI - Individuals with medial knee osteoarthritis show neuromuscular adaptation when perturbed during walking despite functional and structural impairments. AB - Neuromuscular control relies on sensory feedback that influences responses to changing external demands, and the normal response is for movement and muscle activation patterns to adapt to repeated perturbations. People with knee osteoarthritis (OA) are known to have pain, quadriceps weakness, and neuromotor deficits that could affect adaption to external perturbations. The aim of this study was to analyze neuromotor adaptation during walking in people with knee OA (n = 38) and controls (n = 23). Disability, quadriceps strength, joint space width, malalignment, and proprioception were assessed. Kinematic and EMG data were collected during undisturbed walking and during perturbations that caused lateral translation of the foot at initial contact. Knee excursions and EMG magnitudes were analyzed. Subjects with OA walked with less knee motion and higher muscle activation and had greater pain, limitations in function, quadriceps weakness, and malalignment, but no difference was observed in proprioception. Both groups showed increased EMG and decreased knee motion in response to the first perturbation, followed by progressively decreased EMG activity and increased knee motion during midstance over the first five perturbations, but no group differences were observed. Over 30 trials, EMG levels returned to those of normal walking. The results illustrate that people with knee OA respond similarly to healthy individuals when exposed to challenging perturbations during functional weight-bearing activities despite structural, functional, and neuromotor impairments. Mechanisms underlying the adaptive response in people with knee OA need further study. PMID- 24072413 TI - Prevalence of chronic illnesses and characteristics of chronically ill informal caregivers of persons with dementia. AB - OBJECTIVES: to examine the prevalence of and the link of chronic illnesses (CIs) to informal caregivers of persons with dementia (PWDs), as well as to identify characteristics of caregivers with CIs. METHODS: the sample included 124 caregivers of PWDs from a caregiver programme of research. Sociodemographic information and caregivers CIs were collected by an in-person interview. Descriptive statistics, t-tests, chi-square analysis and binary logistic regressions were performed for data analysis. RESULTS: approximately 81.5% (n = 101) of caregivers reported having at least one CI, 60.5% (n = 75) reported two or more CIs. Caregivers with CIs were more likely to be older and unemployed; advanced age and female gender were risk factors for CIs. The link of CIs to caregivers was stronger in younger caregivers but weaker in older caregivers when compared with the general population. CONCLUSION: targeted interventions based on this study need to be developed to improve the health of caregivers of PWDs. PMID- 24072404 TI - The societal costs of femoral neck fracture patients treated with internal fixation. AB - SUMMARY: The study rationale was to provide a detailed overview of the costs for femoral neck fracture treatment with internal fixation in the Netherlands. Mean total costs per patient at 2-years follow-up were 19,425. Costs were higher for older, less healthy patients. Results are comparable to internationally published costs. INTRODUCTION: The aim of this study was to provide a detailed overview of the cost and healthcare consumption of patients treated for a hip fracture with internal fixation. A secondary aim was to compare costs of patients who underwent a revision surgery with patients who did not. METHODS: The study was performed alongside the Dutch sample of an international randomized controlled trial, concerning femoral neck fracture patients treated with internal fixation. Patient characteristics and healthcare consumption were collected. Total follow-up was 2 years. A societal perspective was adopted. Costs included hospital costs during primary stay and follow-up, and costs related to rehabilitation and changes in living situation. Costs were compared between non revision surgery patients, implant removal patients, and revision arthroplasty patients. RESULTS: A total of 248 patients were included (mean age 71 years). Mean total costs per patient at 2-years follow-up were 19,425. In the non revision surgery patients total costs were 17,405 (N = 137), in the implant removal patients 10,066 (N = 38), and in the revision arthroplasty patients 26,733 (N = 67). The main contributing costs were related to the primary surgery, admission days, physical therapy, and revision surgeries. CONCLUSIONS: The main determinant was the costs of admission to a rehabilitation center/nursing home. Costs were specifically high in elderly with comorbidity, who were less independent pre-fracture, and have a longer admission to the hospital and/or a nursing home. Costs were also higher in revision surgery patients. The 2-years follow-up costs in our study were comparable to published costs in other Western societies. PMID- 24072414 TI - Proposal of anti-moesin as a novel biomarker for ANCA-associated vasculitis. AB - Myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibody (ANCA) is associated with rapidly progressive glomerulonephritis (RPGN) in microscopic polyangiitis (MPA). MPO-ANCA activates neutrophils by binding to cell surface MPO expressed on tumor necrosis factor-alpha (TNF-alpha)-primed neutrophils and induces neutrophil degranulation and production of reactive oxygen species, consequently resulting in glomerular endothelial damage. Recently, anti-MPO antibody has been found to activate glomerular endothelial cells, leading to an upregulation of adhesion molecules. MPO-ANCA, however, is not always correlated with disease activity in MPA. Accordingly, the molecule(s) responsible for the anti-MPO antibody have been explored on mouse glomerular endothelial cells. The molecule was identified as moesin, which is a heparin-binding protein and belongs to the ezrin/radixin/moesin family of proteins distributed in the plasma membrane in the cellular cortex. Interestingly, anti-moesin is observed in sera of SCG/Kj mice, which spontaneously develop MPO-ANCA-associated RPGN, and of patients with MPO-AAV. The activation of glomerular endothelial cells by the anti-MPO antibody appears to be associated with signaling through moesin. PMID- 24072415 TI - The role of lipids and uremic toxins in cardiovascular disease in CKD. AB - Lipid abnormalities and uremic toxins are features of chronic kidney disease (CKD) and may influence cardiovascular outcomes in CKD patients. Recent data suggest that uremic toxins may modulate lipoprotein levels and composition (e.g., oxidation or carbamylation) and enhance the cardiovascular toxicity of lipoproteins in CKD patients. PMID- 24072416 TI - Overview of the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. AB - The nomenclature and classification of vasculitis has been difficult and controversial for many decades. This is problematic both for research on vasculitis as well as clinical care of patients with vasculitis. The first (1994) International Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitides (CHCC) proposed names and definitions for the most common forms of vasculitis. Since then, there have been substantial advances in our understanding of vasculitis and changes in medical terminology. In addition, CHCC 1994 did not propose a nomenclature for some relatively common forms of vasculitis, such as vasculitis secondary to other diseases. To address these issues, a second International Chapel Hill Consensus Conference was held in 2012. The goals were to change names and definitions as appropriate, and add important categories of vasculitis not included in CHCC 1994. This overview summarizes the 2012 CHCC and points out the changes compared to the 1994 CHCC. Notable changes include the introduction of new terms such as granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and immunoglobulin A vasculitis and the inclusion of categories for variable vessel vasculitis and secondary forms of vasculitis. PMID- 24072417 TI - Serum lipids and prevention of atherosclerotic cardiovascular events in hemodialysis patients. AB - This article reviews the relationship between serum lipids and cardiovascular disease (CVD) in hemodialysis patients. Epidemiologic studies showed a cholesterol paradox in hemodialysis patients, but it can be solved by taking protein-energy wasting and inflammation into consideration. Wasting and inflammation are the risk factors of fatality after incident CVD. Randomized controlled trials showed neutral effects of statins and statin-ezetimibe combination on CVD outcomes in dialysis patients. Current guidelines in Japan recommend that low-density lipoprotein cholesterol (LDL-C) be <120 mg/dL, or non high-density lipoprotein cholesterol (non-HDL-C) be <150 mg/dL as an alternative target in patients with chronic kidney disease (CKD), whereas Kidney Disease: Improving Global Outcome (KDIGO) guidelines do not recommend any target lipid levels. In addition to "treat to target" and "fire and forget" guidelines, it is possible to recommend that lipid-lowering medication be initiated in certain subgroups of CKD patients. New directions of lipid research in CKD include cholesterol metabolism markers, omega-3 polyunsaturated fatty acids, and modifications of lipoproteins. PMID- 24072418 TI - Compassionate use of a paclitaxel coated balloon in patients with refractory recurrent coronary in-stent restenosis. AB - OBJECTIVE: Treatment of coronary in-stent restenosis (ISR) remains a challenge in interventional cardiology, especially after drug eluting stent (DES)-ISR. Drug coated balloons (DCB) provide a new therapeutic option in the treatment of ISR. In patients with multiple layers of stents due to refractory ISR and exclusion criteria for revascularization by coronary artery bypass grafting, DCB may be a last therapy option. This paper presents DCB therapy as compassionate use treatment before the balloons were available in Europe. PATIENTS: Compassionate use of DCB was approved by the local ethical committee. Fifteen patients with refractory ISR in 28 lesions were prospectively enrolled between 12/2006 and 04/2009. The frequency of prior ISR was 3.0 +/- 1.1. Nine patients presented with coronary three-vessel disease and six patients with one- or two-vessel disease. Thirteen patients had DES-ISR, two patients with contraindication for prolonged dual anti-platelet therapy repeated BMS-ISR. Two or three layers of metal were present in eleven patients. Four patients had prior coronary artery bypass grafting. RESULTS: All lesions were treated with DCB (SeQuentTM Please, B.Braun, Germany). Angiographic follow-up was obtained in 14 patients. Clinical follow-up was available in all patients after 3.2 +/- 0.8 years (maximum 4.8 years). Target lesion revascularization was done in 2 of 28 lesions (7.1 %), one patient with ischemic cardiomyopathy died after 1.5 years. No further MACE occurred. CONCLUSION: DCB appear to be safe and clinically useful in the treatment of ISR. DCB is a new promising option for high-risk patients with refractory ISR. PMID- 24072419 TI - Morphine and breast tumor metastasis: the role of matrix-degrading enzymes. AB - Opioids including morphine are commonly used in pain management during and after cancer surgery but have been linked to a variety of pro- and anti-tumor effects. In the present study the effect of morphine administration on the localization and growth of breast tumor cells in lungs and the level of extracellular matrix (ECM) proteases were investigated. In a mouse syngeneic model of intravenously inoculated breast cancer cells, morphine administration led to a reduction in the localization and growth of tumors in the lungs and a reduction in circulating matrix metalloproteinase-9 (MMP-9) and urokinase-like plasminogen activator (uPA). To model the involvement of non-malignant cells of the tumor microenvironment in the changes we observed in the level of proteases, we co cultured breast cancer cells with macrophages, endothelial cells and fibroblasts. We found a significant elevation of matrix proteases as well as matrix protease inhibitors in co-cultures of breast cancer cells with macrophages or endothelial cells. Interestingly, morphine treatment of these co-cultures reduced the level of MMP-9 and increased its endogenous inhibitor, TIMP-1, thereby altering the proteolytic profile. Morphine affected the level of enzymes in co-cultures but not in cells grown individually. This suggests that anti-tumor effects of morphine observed in our in vivo model could be mediated at least in part through modulation of paracrine communication between cancer cells and non-malignant cells in the tumor microenvironment. PMID- 24072420 TI - [Using the capture-mark-recapture method for quantitative assessment of populations of molluscs in two sites in Lampsar (Valley of the Senegal River)]. AB - The authors have made an estimate of the number of mollusc by the capture-mark recapture method at two sites in the Valley of the Senegal River. This quantification is necessary to track the effect of the introduction in one of the sites of a native shrimp Machrobrachium vollenhovenii, predator of mollusc. The populations of two study sites were approximately 1,800 and 1,500 individuals with coefficients of variation of about 30%. PMID- 24072421 TI - [Health staff workload in a context of user fees exemption policy for health care in Burkina Faso and Niger]. AB - User fees exemption policy supported by NGOs in Burkina Faso and Niger resulted in a higher utilization of health services in primary health care facilities. We conducted a survey in 2 health districts in Burkina Faso and Niger in 2011. The study objective was to assess whether the higher utilization associated with the user fees exemption policy, may result in an overload for health staff at the front line in health facilities. The WHO's recommended WISN method was used to compute a ratio of actual/required staff using a comparative study with 4 control facilities and 4 intervention sites where the user fees exemption policy was provided by local NGOs in both countries. Overall, 8 primary health facilities both in Burkina Faso and Niger were involved. In Burkina Faso, the ratio was >=1 in all facilities both control and intervention, i.e. a sufficient staff in facilities. In Niger, 3 out of the 4 intervention facilities in Keita district were found to have a ratio <=1, i.e. understaffed. In the 4 control facilities, the staff was sufficient with a ratio >=1. In Burkina Faso, the actual number of staff in facilities appeared enough to face the higher utilization of health services that may follow the user fees exemption policy supported by local NGOs unlike Niger where we found that the actual number of staff was insufficient to face a possible higher utilization resulting from the same policy in intervention facilities. PMID- 24072422 TI - [Marine envenomation by box-jellyfish in a tourist in Cambodia]. AB - We report a case of box-jellyfish related envenomation in a 40 year old tourist that occurred in Sihanoukville, Cambodia, in the Gulf of Thailand. Symptoms that appeared within a few minutes associated intense pain, hand edema and large edematous and erythematous flagellations in the stung skin areas. Antibiotics and corticosteroids were delivered. Inflammatory signs and skin lesions disappeared within 15 days followed by crusts then scars. Jellyfish at risk for humans are generally found in tropical seas and their geographic distribution seems to spread. As it is difficult to prevent this kind of accident, travelers should be aware of the first acts to perform, such as appropriate cleaning of the wound, the interest of vinegar usage, the administration of analgesics and corticosteroids in case of significant inflammatory signs. PMID- 24072423 TI - The effects of fruit smoothies on enamel erosion. AB - OBJECTIVES: This prospective, randomised in vitro study was to investigate the pH and titratable acidity of fruit smoothie drinks and to assess the effect of these drinks on enamel erosion. METHOD: Fifty enamel slabs were divided into five groups which were allocated to the sample solutions groups: Innocent((r)) smoothie strawberries and bananas (SB), Innocent((r)) smoothie mangoes and passion fruit (MP) and Diet Coke. Distilled deionised water (DD) was used as negative control and citric acid 0.3% as positive control. All the slabs were subjected to a 21-day pH cycling regime involving 2 min of immersions, five times a day with appropriate remineralization periods in between. Measurement of surface loss was assessed using profilometry. Independent sample t tests were used to compare mean. RESULTS: The titratable acidity for both test smoothies were 3.5-4 times more than that needed to neutralise Diet Coke and citric acid 0.3%. The pH of SB, MP smoothie and Diet Coke was found to be 3.73, 3.59 and 2.95, respectively. MP smoothie caused the greatest amount of surface loss followed by Diet Coke. Both smoothies were found to cause significant surface loss. MP smoothie resulted in significantly higher surface loss compared with MB smoothie and citric acid 3 %. CONCLUSION: The smoothies tested were acidic and had high titratable acidity. They produced a significant erosion of enamel in vitro. The results of this study suggest that there should be increased awareness of the erosive effects of smoothies especially as their consumption seems to be on the increase. PMID- 24072424 TI - Risk factors for early childhood caries: a case-control study. AB - AIM: To investigate the risk factors for early childhood caries (ECC) among Indian preschool children. METHODS: This case control study recruited 380 children who were divided into two groups based on their def scores. The study group (cases) included children who were diagnosed with ECC (def > 0). The cases were compared with the control group which included children who were caries free (def = 0). Data were statistically analysed using chi (2) test and multiple logistic regression analysis. RESULTS: Risk factors specific to the ECC group were first born child (OR 4.18, 95 % CI 1.98-8.80), snacking more than thrice per day (OR 2.78, 95 % CI 1.41-5.47), bottled drinking water (OR 4.58, 95 % CI 2.13 9.86), use of more than a smear amount of toothpaste (OR 4.99, 95 % CI 2.54 9.81), mother unemployed (OR 3.45, 95 % CI 1.70-6.99) and day care person of the child (OR 8.49, 95 % CI 3.98-18.10). CONCLUSIONS: Most common risk factors were order of birth, snacking more than thrice per day, source of drinking water, use of more than a smear amount of toothpaste, mother's work status and day care person of the child. PMID- 24072425 TI - Role of intraoperative neurophysiological monitoring during fluorescence-guided resection surgery. AB - BACKGROUND: Fluorescence-guided resection (FGR) using 5-aminolevulinic acid (5 ALA) exhibits a potential risk of permanent neurological deficits that can be minimized using intraoperative neurophysiological monitoring (IONM). We assessed the role of IONM in FGR surgery in patients harboring tumors in or near eloquent areas. METHODS: IONM and FGR surgeries were performed on 34 patients (49.8 +/- 2.4 years) harbored malignant primary gliomas near eloquent cortical areas or semioval center. Different combinations of neurophysiological techniques were used depending on each patient. RESULTS: Gross total resection (GTR) was achieved in 66.7 % of the patients, mean 90.4 +/- 3.7 % without neurological deficits. Resection in four patients was stopped by the occurrence of severe warning criteria despite the presence of fluorescence. Hemispheric transcranial electrical stimulation was safe and confident even in cortical surgery. Notably, a significant percentage of patients exhibited clinical improvement after the surgery. One week after surgery, only one patient worsened, and seven patients improved. At 3 months, 27.8 % of the patients improved, and the other patients maintained a similar status to their pre-surgery condition. Warning common criteria (amplitude reduction and/or latency increase) appeared in 68.2 and 50.0 % of patients during cortical or semioval surgery, respectively, with neither a false-negative nor a false-positive clinical outcome. Although 5-ALA exhibits phototoxicity, VEP did not induce any secondary effects in the visual system, including eyelids. CONCLUSIONS: IONM can be helpful during surgery to maximize the tumor resection, meanwhile help to avoid neurological deficits and, therefore, to improve the quality of life of these patients. PMID- 24072426 TI - Percutaneous dorsal root ganglion lysis with phenol for the treatment of pain associated with thoracic compression fracture. AB - BACKGROUND: Symptomatic thoracic compression fracture is one of the most common causes of back pain in elderly. Although vertebroplasty is widely utilized in patients when conservative treatment fails, we introduced an alternative percutaneous technique for the treatment of thoracic compression pain. METHODS: This in a retrospective study. The analysis was performed on 28 consecutive patients who underwent undergoing percutaneous dorsal root ganglion lysis with phenol for the treatment of pain associated with thoracic compression fracture. An acceptable treatment outcome was operationally defined as a pain intensity numerical rating scale (NRS) score of 3 or lower or EQ-5D index of 0.672 or higher. The primary outcome was pain relief and acceptable treatment outcome at 1 day, 1 week, 1 month, and 1 year. RESULTS: Of the 28 cases treated with our procedures, the change in mean NRS score between baseline and one day was -2.5 (95 % CI -1.6 ~ -3.4, p < 0.001), between baseline and one week was -4.7 (-4.1 to -5.3, p < 0.001), between baseline and one month was -5.8 (-5.2 to -6.5, p < 0.001), and between baseline and one year was -6.3 (-5.6 to -7.1, p < 0.001). An acceptable treatment outcome was 14 % one day after the procedure, 46 % at one week, 72 % at one month, and 84 % at one year. Complication rate was 3.6 %. CONCLUSIONS: For thoracic compression fracture patients, percutaneous dorsal root ganglion lysis with phenol is an effective, and safe alternative treatment method worth considering. Pain relief is fast and persists for one year. PMID- 24072427 TI - Effect of micronutrient supplementation on the immune function of crossbred dairy cows under semi-arid tropical environment. AB - This study assessed the effect of micronutrient supplementation around peripartum period on immune function, reproductive performance, milk yield and milk quality of crossbred cows. Thirty pregnant crossbred cows in their late gestation were selected and randomly divided into five groups for study. Six cows in each group were supplemented with vitamin E (VE) (2000 IU/cow/day), vitamin A (VA) (100,000 IU/cow/day), copper (Cu) (20 ppm/cow/day), zinc (Zn) (80 ppm/cow/day) individually from 45 days pre-calving to 45 days post-calving and one group without any supplementation served as control. Immune function was studied by in vitro phagocytic activity (PA) of blood neutrophils, lymphocyte proliferation response (LPR) and plasma interleukin-8 (IL-8) concentration. Supplementation of VA significantly (P < 0.05) increased the in vitro PA of blood neutrophils and decreased milk somatic cell counts (SCC). Zn supplementation significantly (P < 0.05) increased the T lymphocyte proliferation response, whereas B lymphocyte LPR was significantly (P < 0.05) increased with both VA and Zn supplementation as compared to the control cows. Plasma IL-8 concentration was significantly (P < 0.05) higher in all supplemented cows. Supplementation of VE, VA and Zn significantly (P < 0.05) reduces days open, whereas VA significantly (P < 0.05) reduced the service per conception. In this study, it is concluded that VE, VA and Zn supplementation around peripartum period can boost the immunity and improve the reproductive performance of crossbred cows in a semi-arid tropical environment. PMID- 24072429 TI - Cognitive and personality factors in the prediction of health behaviors: an examination of total, direct and indirect effects. AB - Conscientiousness reliably predicts health behavioral patterns, and the same is true of executive function. However, few investigations have examined their relative predictive power, or probed for possible indirect effects and age moderated effects. In the current study, we examined the predictive validity of all Big Five personality traits, executive function and IQ in relation to an index of health behaviors in an age-stratified community sample. Results indicated that conscientiousness, neuroticism and executive function were significant predictors of health behavior in age-corrected regression analyses. Using bootstrapping methods, we found that executive function partially explains the relationship between both personality dimensions and health behavior. Moderational analyses revealed that effects of personality traits on health behavior were uniformly modest across the age span, whereas the predictive power of executive function became more amplified with increasing age. Both conscientiousness and neuroticism predict health behavior patterns, though their magnitude of association is significantly weaker than executive function and some of their effects are explained by executive function. PMID- 24072430 TI - Association of cancer worry and perceived risk with doctor avoidance: an analysis of information avoidance in a nationally representative US sample. AB - Fear of receiving bad news about one's health can lead people to avoid seeking out health information that, ironically, may be crucial for health maintenance. Using a nationally representative US sample, the present study examined whether perceived likelihood of developing cancer and worry about cancer were associated with reports of avoiding visits to one's doctor, in respondents under and over age 50. Cancer worry, but not perceived risk of cancer, predicted doctor avoidance in respondents aged 50 and older, whereas the opposite pattern held for respondents under age 50. Moreover, in respondents aged 50 and older, cancer worry and perceived cancer risk interacted such that cancer worry was linked to doctor avoidance only when respondents also perceived a high likelihood of cancer. The latter result is consistent with the notion that worry may motivate information seeking when people expect information to dispel worry and information avoidance when the information is seen as highly likely to confirm one's fears. Findings suggest a need for communication strategies that can influence worry and perceived risk differentially. Research should also assess the effectiveness of other behavioral strategies (e.g., automatic scheduling of appointments) as a means for reducing doctor avoidance. PMID- 24072428 TI - Tumor necrosis factor-alpha-converting enzyme activities and tumor-associated macrophages in breast cancer. AB - The role of the tumor microenvironment especially of tumor-associated macrophages (TAMs) in the progression and metastatic spread of breast cancer is well established. TAMs have primarily a M2 (wound-healing) phenotype with minimal cytotoxic activities. The mechanisms by which tumor cells influence TAMs to display a pro-tumor phenotype are still debated although the key roles of immunomodulatory cytokines released by tumor cells, including colony-stimulating factor 1, tumor necrosis factor (TNF) and soluble TNF receptors 1/2, soluble vascular cell adhesion molecule 1, soluble interleukin 6 receptor and amphiregulin, have been demonstrated. Importantly, these factors are released through ectodomain shedding by the activities of the tumor necrosis factor-alpha converting enzyme (TACE/ADAM17). The role of TACE activation leading to autocrine effects on tumor progression has been extensively studied. In contrast, limited information is available on the role of tumor cell TACE activities on TAMs in breast cancer. TACE inhibitors, currently in clinical trials, will certainly affect TAMs and subsequently treatment outcomes based on the substrates it releases. Furthermore, whether targeting a subset of the molecules shed by TACE, specifically those leading to TAMs with altered functions and phenotype, holds greater therapeutic promises than past clinical trials of TACE antagonists' remains to be determined. Here, the potential roles of TACE ectodomain shedding in the breast tumor microenvironment are reviewed with a focus on the release of tumor-derived immunomodulatory factors shed by TACE that directs TAM phenotypes and functions. PMID- 24072431 TI - Worry about skin cancer mediates the relation of perceived cancer risk and sunscreen use. AB - Preventive health behaviors are believed to be motivated in part by a person's perception of risk for a particular health problem. Risk contains a cognitive component, beliefs about the chances of a health problem occurring, and an affective component, fear or worry about the health problem. Although both have been shown to influence behavior, the nature of their interrelation as an influence on behavior has not been examined. Data from the 2005 Health Information National Trends Survey, a US nationally-representative telephone survey was analyzed. Participants reported perceived absolute and comparative risk for skin cancer, feelings of worry about skin cancer, and sunscreen use behavior. Analyses examined main effects models for the relation between perceived risk, worry, and sunscreen use, as well as both moderated and mediated models. For both absolute and comparative risk, the relation between cognitively based perceived risk for skin cancer and sunscreen use was fully mediated by feelings of worry, as evidenced by significant direct effects of worry (bs > 0.046, ps < 0.01) and indirect effects of risk through worry (bs > 0.19, ps < 0.01). When worry was included in the models, direct effects of risk perceptions were non-significant (bs < 0.11, ps < 0.10). No evidence was found for moderated effects of worry on the relation between risk and behavior. While cognitive risk appraisals do influence decision making and may be addressed by interventions, these findings demonstrate that affectively-based risk components play a key role in behavior regulation. Affectively-based risk might be an effective target for interventions and should be incorporated more fully in decision-making models. PMID- 24072432 TI - Publication rates of presentations at the Irish Orthopaedic Association annual meeting. AB - BACKGROUND: Presentation of scientific research at national and international meetings is an important forum for the dissemination of knowledge. Subsequent publication of a full-text paper in a peer-reviewed journal is the expected outcome of such presentations. The publication rate from these meetings is highly variable. AIMS: To determine the publication rate of abstracts presented at the Irish Orthopaedic Association's Annual Conference and to determine which factors are associated with progression to full-text publication. METHODS: We reviewed the proceedings from the Irish Orthopaedic Association's National Meeting over a 4 year period. We searched the Pubmed database using author names, institution names, and keywords from each abstract's title, to determine how many presented articles progressed to full-text publication. RESULTS: Sixty-six of 203 were published, 97 % within 5 years of presentation. Laboratory based studies presenting novel or innovative findings were more likely to be published than clinical studies. Clinical studies were more likely to be published if they were prospective and had a longer period of follow-up. Retrospective audits were less likely to be published, even with a large cohort size. Changes in authorship of presented papers were related to a longer delay in time to full-text publication. CONCLUSIONS: Thorough planning of research studies is essential to ensure a timely progression to full-text publication in a peer-reviewed journal. Most studies will be published within 5 years of initial presentation. PMID- 24072433 TI - The number of tPSA tests continues to rise and variation in testing practices persists: a survey of laboratory services in Ireland 2008-2010. AB - BACKGROUND: Ireland had the highest incidence of prostate cancer in Europe in 2008, due to widespread prostate specific antigen (PSA) testing. AIMS: To investigate practices and costs of PSA testing in Ireland, 2008-2010. METHODS: Postal laboratory questionnaire. Results were compared with 2006 and 2007 surveys. RESULTS: Response rate was 95 % (42/44). In 2010, 37 laboratories measured total PSA (tPSA); 10 measured free PSA (fPSA). Eight assays were used and cut-offs to define 'normal' tPSA varied widely. There was a 9.9 % annual increase in the number of tPSA tests and a -31 % annual decrease in the number of fPSA, 2006-2010. A 100-fold difference in tPSA workload was observed across laboratories. In 2010, the estimated cost of PSA testing was 3,649,984 (95 % CI 2,532,745-4,767,222). CONCLUSIONS: Health service costs of PSA testing are significant. The number of tPSA tests continues to rise; fPSA use fell by almost one-third. Inter-laboratory variation in testing practices persists. These have potentially important clinical consequences for men and need to be addressed. PMID- 24072434 TI - Anti-inflammatory and pro-angiogenic effects of beta blockers in a canine model of chronic ischemic cardiomyopathy: comparison between carvedilol and metoprolol. AB - There is controversy regarding the superiority of carvedilol (C) over metoprolol (M) in congestive heart failure. We hypothesized that C is superior to M in chronic ischemic cardiomyopathy because of its better anti-inflammatory and pro angiogenic effects. In order to test our hypothesis we used a chronic canine model of multivessel ischemic cardiomyopathy where myocardial microcatheters were placed from which interstitial fluid was collected over time to measure leukocyte count and cytokine levels. After development of left ventricular dysfunction, the animals were randomized into four groups: sham (n = 7), placebo (n = 8), M (n = 11), and C (n = 10), and followed for 3 months after treatment initiation. Tissue was examined for immunohistochemistry, oxidative stress, and capillary density. At 3 months both rest and stress wall thickening were better in C compared to the other groups. At the end of 3 months of treatment end-systolic wall stress also decreased the most in C. Similarly resting myocardial blood flow (MBF) improved the most in C as did the stress endocardial/epicardial MBF. Myocardial interstitial fluid showed greater attenuation of leukocytosis with C compared to M, which was associated with less fibrosis and oxidative stress. C also had higher IL-10 level and capillary density. In conclusion, in a chronic canine model of multivessel ischemic cardiomyopathy we found 3 months of C treatment resulted in better resting global and regional function as well as better regional function at stress compared to M. These changes were associated with higher myocardial levels of the anti-inflammatory cytokine IL-10 and less myocardial oxidative stress, leukocytosis, and fibrosis. Capillary density and MBF were almost normalized. Thus in the doses used in this study, C appears to be superior to M in a chronic canine model of ischemic cardiomyopathy from beneficial effects on inflammation and angiogenesis. Further studies are required for comparing additional doses of these drugs. PMID- 24072435 TI - Ketoprofen-loaded polymeric nanocapsules selectively inhibit cancer cell growth in vitro and in preclinical model of glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the worst and most common brain tumor, characterized by high proliferation and invasion rates. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted interest in recent years since they provide targeted delivery and may overcame the obstacle imposed by blood-brain barrier. Here we investigated the antitumoral effect of ketoprofen-loaded nanocapsules (Keto-NC) treatment on in vitro and in vivo glioma progression. We observed that Keto-NC treatment decreased selectively the cell viability of a panel of glioma cell lines, while did not exhibited toxicity to astrocytes. We further demonstrate that the treatment with sub-therapeutic dose of Keto-NC reduced the in vivo glioma growth as well as reduced the malignity characteristics of implanted tumors. Keto-NC treatment improved the weight, the locomotion/exploration behavior of glioma-bearing rats. Importantly, Keto-NC treatment neither induced mortality or peripheral damage. Finally, Ketoprofen also altered the extracellular nucleotide metabolism of peripheral lymphocytes, suggesting that antiinflammatory effects of ketoprofen could also be associated with the modulation of the adenine nucleotide metabolism in lymphocytes. Data indicate at first time the potential of Keto-NC as a promising therapeutic alterative to GBM treatment. PMID- 24072436 TI - NCIC CTG IND.181: phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies. AB - PURPOSE: AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283. PATIENTS AND METHODS: Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D). RESULTS: 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months). CONCLUSION: In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers. PMID- 24072437 TI - Climate, social factors and research disturbance influence population dynamics in a declining sociable weaver metapopulation. AB - Population trends are determined by gains through reproduction and immigration, and losses through mortality and emigration. These demographic quantities and resulting population dynamics are affected by different external and internal drivers. We examined how these demographic quantities were affected by weather, research-induced disturbance, local density, colony site and year in a metapopulation of 17 sociable weaver (Philetairus socius) colonies over 17 years of study (4 years for reproduction). Most colonies declined, but at different rates. The four demographic quantities were related to different drivers. Survival strongly varied among years and colonies and was positively related to rainfall and negatively related to extreme temperature (together explaining 30% of variation) and disturbance (measured as number of captures conducted at a colony; 7%). There was a trend for a positive relationship between reproduction and rainfall (50%). Movement was mainly related to local density: individuals were more likely to emigrate from small to large colonies and from colonies that were either well below or above their long-term mean. They were more likely to immigrate into colonies that were nearby, and below their mean size. We then quantified the effects of these relationships on metapopulation dynamics using a multi-site matrix projection model. Rainfall was potentially a strong driver of metapopulation dynamics. In addition, field-work disturbance might have contributed to the decline of this metapopulation but could not explain its full magnitude. Hence, through a combination of analytical methods we were able to obtain information on the main drivers affecting dynamics in a declining metapopulation. PMID- 24072438 TI - Herbivores differentially limit the seedling growth and sapling recruitment of two dominant rain forest trees. AB - Resource heterogeneity may influence how plants are attacked and respond to consumers in multiple ways. Perhaps a better understanding of how this interaction might limit sapling recruitment in tree populations may be achieved by examining species' functional responses to herbivores on a continuum of resource availability. Here, we experimentally reduced herbivore pressure on newly established seedlings of two dominant masting trees in 40 canopy gaps, across c. 80 ha of tropical rain forest in central Africa (Korup, Cameroon). Mesh cages were built to protect individual seedlings, and their leaf production and changes in height were followed for 22 months. With more light, herbivores increasingly prevented the less shade-tolerant Microberlinia bisulcata from growing as tall as it could and producing more leaves, indicating an undercompensation. The more shade-tolerant Tetraberlinia bifoliolata was much less affected by herbivores, showing instead near to full compensation for leaf numbers, and a negligible to weak impact of herbivores on its height growth. A stage-matrix model that compared control and caged populations lent evidence for a stronger impact of herbivores on the long-term population dynamics of M. bisulcata than T. bifoliolata. Our results suggest that insect herbivores can contribute to the local coexistence of two abundant tree species at Korup by disproportionately suppressing sapling recruitment of the faster-growing dominant via undercompensation across the light gradient created by canopy disturbances. The functional patterns we have documented here are consistent with current theory, and, because gap formations are integral to forest regeneration, they may be more widely applicable in other tropical forest communities. If so, the interaction between life-history and herbivore impact across light gradients may play a substantial role in tree species coexistence. PMID- 24072439 TI - Radish introduction affects soil biota and has a positive impact on the growth of a native plant. AB - Introduced plants may out-compete natives by belowground allelopathic effects on soil communities including the symbionts of native plants. We tested for an allelopathic effect of an introduced crucifer, Raphanus sativus, on a common neighboring legume, Lupinus nanus, on the legume's rhizobium affiliates, and on the broader soil community. In both field observations and a greenhouse experiment, we found that R. sativus decreased the density of nodules on L. nanus roots. However, in the greenhouse experiment, R. sativus soils only decreased the density of small, likely non-beneficial rhizobium nodules. In the same experiment, R. sativus soils decreased fungivorous nematode abundance, though there was no effect of R. sativus introduction on fungal density. In the greenhouse experiment, R. sativus soils had a net positive effect on L. nanus biomass. One explanation of this effect is that R. sativus introduction might alter the mutualistic/parasitic relationship between L. nanus and its rhizobial associates with a net benefit to L. nanus. Our results suggest that introduced brassicas can quickly alter belowground communities, but that the net effect of this on neighboring plants is not necessarily negative. PMID- 24072440 TI - Preventing overexploitation in a mutualism: partner regulation in the crayfish branchiobdellid symbiosis. AB - For a symbiosis to be a mutualism, benefits received must exceed costs incurred for both partners. Partners can prevent costly overexploitation through behaviors that moderate interactions with the other symbiont. In a symbiosis between crayfish and branchiobdellidan annelids, the worms can increase crayfish survival and growth by removing fouling material from the gills. However, overexploitation by the worms is possible and results in damage to host gills. We used behavioral observations to assess the degree to which two species of crayfish (Cambarus chasmodactylus and Orconectes cristavarius) use grooming to moderate their interaction with branchiobdellids. We found that grooming could effectively reduce worm numbers, and the proportion of total grooming directed at worms differed between crayfish species and as a function of worm number. O. cristavarius increased grooming in response to the addition of a single worm, while C. chasmodactylus only increased grooming in response to ten worms. These differences in the number of worms that trigger grooming behavior reflect differences between crayfish species in field settings. We also assessed whether antibacterial compounds in circulating crayfish hemolymph could limit bacterial gill fouling. O. cristavarius hemolymph inhibited some test bacteria more effectively than C. chasmodactylus did. Differences in the antibacterial properties of crayfish hemolymph may therefore help explain differences in both worm-directed grooming and worm loads in the field. We conclude that crayfish can use grooming to reduce worm numbers, which could lower the potential for gill damage, and that the level of grooming varies between crayfish species. PMID- 24072441 TI - Light use efficiency of California redwood forest understory plants along a moisture gradient. AB - We investigated photosynthesis of five plant species growing in the understory at three sites (1,170-, 1,600- and 2,100-mm annual moisture inputs), along the geographical range of coastal California redwood forest, to determine whether greater inputs of rain and fog at northern sites enhance photosynthetic utilization of fluctuating light. Measurements of understory light environment and gas exchange were carried out to determine steady state and dynamic photosynthetic responses to light. Leaf area index ranged from 4.84 at the 2,100 mm site to 5.98 at the 1,170-mm site. Maximum rates of net photosynthesis and stomatal conductance (g) did not vary appreciably within species across sites. Photosynthetic induction after a change from low to high light was significantly greater in plants growing in lower light conditions regardless of site. Photosynthetic induction also increased with the rate of g in diffuse light, prior to the increase to saturating light levels. Post-illumination CO2 assimilation was the largest factor contributing to variation in C gain during simulated lightflecks. The duration of post-illumination photosynthetic activity, total CO2 assimilation per light received, and light use efficiency during simulated lightflecks increased significantly with moisture inputs in four out of five species. Increasing leaf N concentration with increasing moisture inputs in three out of five species, coupled with changes in leaf N isotopic composition with the onset of the summer fog season suggest that natural N deposition increases with rain and fog inputs and contributes to greater utilization of fluctuating light availability in coastal California redwood forests. PMID- 24072442 TI - The reaction of European lobster larvae (Homarus gammarus) to different quality food: effects of ontogenetic shifts and pre-feeding history. AB - Young larval stages of many organisms represent bottlenecks in the life-history of many species. The high mortality commonly observed in, for example, decapod larvae has often been linked to poor nutrition, with most studies focussing on food quantity. Here, we focus instead on the effects of quality and have investigated its effects on the nutritional condition of lobster larvae. We established a tri-trophic food chain consisting of the cryptophyte Rhodomonas salina, the calanoid copepod Acartia tonsa and larvae of the European lobster Homarus gammarus. In a set of experiments, we manipulated the C:N:P stoichiometry of the primary producers, and accordingly those of the primary consumer. In a first experiment, R. salina was grown under N- and P-limitation and the nutrient content of the algae was manipulated by addition of the limiting nutrient to create a food quality gradient. In a second experiment, the effect on lobster larvae of long- and short-term exposure to food of varying quality during ontogenetic development was investigated. The condition of the lobster larvae was negatively affected even by subtle N- and P-nutrient limitations of the algae. Furthermore, younger lobster larvae were more vulnerable to nutrient limitation than older ones, suggesting an ontogenetic shift in the capacity of lobster larvae to cope with low quality food. The results presented here might have substantial consequences for the survival of lobster larvae in the field, as, in the light of future climate change and re-oligotrophication of the North Sea, lobster larvae might face marked changes in temperature and nutrient conditions, thus significantly altering their condition and growth. PMID- 24072444 TI - From monitoring to vigilance about patient adherence to new oral anticoagulants. PMID- 24072443 TI - Modified phased radiofrequency ablation of atrial fibrillation reduces the number of cerebral microembolic signals. AB - AIMS: Phased radiofrequency (RF) ablation for atrial fibrillation is associated with an increased number of silent cerebral lesions on magnetic resonance imaging and cerebral microembolic signals (MESs) on transcranial Doppler ultrasound imaging compared with irrigated RF. The increased rate of embolic events may be due to a specific electrical interference of ablation electrodes attributed to the catheter design. The purpose of this study was to elucidate the effect of deactivating the culprit electrodes on cerebral MESs. METHODS AND RESULTS: Twenty nine consecutive patients (60 +/- 11 years, 10 female) underwent their first pulmonary vein isolation using phased RF energy. Electrode pairs 1 or 5 were deactivated to avoid electrical interference between electrodes 1 and 10 ('modified'). Detection of MESs by transcranial Doppler ultrasound was performed throughout the procedure to assess cerebral microembolism. Results were compared with the numbers of MESs in 31 patients ablated using all available electrodes ('conventional') and to 30 patients undergoing irrigated RF ablation of a previous randomized study. Ablation with 'modified' phased RF was associated with a marked decrease in MESs when compared with 'conventional' phased RF (566 +/- 332 vs. 1530 +/- 980; P < 0.001). This difference was mainly triggered by the reduction of MES during delivery of phased RF energy, resulting in MES numbers comparable to irrigated RF ablation (646 +/- 449; P = 0.7). Total procedure duration as well as time of RF delivery was comparable between phased RF groups. Both times, however, were significantly shorter compared with the irrigated RF group (123 +/- 28 vs. 195 +/- 38; 15 +/- 4 vs. 30 +/- 9; P < 0.001, respectively). CONCLUSION: Pulmonary vein isolation with 'modified' phased RF is associated with a decreased number of cerebral microembolism especially during the delivery of ablation impulses, supporting the significance of electrical interference between ablation electrodes 1 and 10. Deactivation of electrode pairs 1 or 5 might increase the safety of this approach without an increase in procedure duration or RF delivery time. PMID- 24072445 TI - A pacing lead repositioned without incising the skin: a simplified approach. PMID- 24072446 TI - Simple and non-invasive diagnostics of a broad complex tachycardia in a device patient. PMID- 24072447 TI - Common SCN10A variants modulate PR interval and heart rate response during atrial fibrillation. AB - AIMS: SCN10A encodes the sodium channel Nav1.8 implicated by genome-wide association studies as a modulator of atrioventricular conduction (PR interval). In a cohort of patients with atrial fibrillation (AF), we examined whether there was an association between common variants in SCN10A and both the PR interval during normal sinus rhythm and the heart rate response during AF. METHODS AND RESULTS: Patients prospectively enrolled in the Vanderbilt AF registry with electrocardiograms in normal sinus rhythm and/or AF within 1 year of enrollment were genotyped for two common SCN10A variants rs6795970 and rs12632942. Both variants were associated with the PR interval duration in a gene-dose effect on unadjusted analysis; after adjustment for the covariates age, gender, body mass index, hypertension, congestive heart failure, and medication usage, the association remained for rs6795970 only (P = 0.012, partial R(2) = 0.0139). On unadjusted analysis, heart rate response during AF was associated with rs6795970 (P = 0.035, partial R(2) = 0.015), but not with rs12632942 (P = 0.89), and neither association was significant after adjustment for covariates. CONCLUSION: The common variant rs6795970 in SCN10A is associated with the PR interval duration among healthy patients and those with AF. In addition, this single nucleotide polymorphism trended towards an association with heart rate response during AF indicating the importance of this common SCN10A polymorphism as a marker of atrioventricular conduction. PMID- 24072448 TI - Left ventricular lead stabilization to retain cardiac resynchronization therapy at long term: when is it advisable? AB - AIMS: Left ventricular (LV) lead dislodgement occurs in about 10.6% of patients in the first 12 months after cardiac resynchronization therapy defibrillator implantation, and causes lack of clinical improvement, repeated surgery, and predisposes to infective complications and death. To understand the factors predictive of lead dislodgement, and to investigate whether bipolar LV lead stabilization can reduce the dislodgement rate and improve the clinical outcome. METHODS AND RESULTS: Predisposing coronary vein anatomy was identified on a retrospective series of 218 patients implanted before August 2009. Lead stabilization guided by vein anatomy was prospectively tested on consecutive patients from October 2009 to December 2010. Among 84 patients, lead stabilization based on vein anatomy was recommended in 19 patients, of which 16 agreed and 3 refused. Two of these latter had lead dislodgement within 1 month, whereas none of the former had adverse events during 23.8 +/- 3.1 months follow up. Only 1 of 58 patients deemed at low risk had lead dislodgement. Seven patients required lead stabilization for severe phrenic stimulation issues that dictated lead placement at specific sites. Patients with stabilized LV leads were more likely to be cardiac resynchronization therapy (CRT) responders than the others: 19 of 26 (73%) vs. 34 of 58 (59%, P= NS), and had a significantly higher proportion of super-responders: 12 of 26 (46%) vs. 12 of 58 (21%, P< 0.005). CONCLUSION: Coronary vein anatomy may assist decision making about the need for LV lead stabilization, and the choice of tools during the implanting procedure to ensure effective CRT delivery at long term. PMID- 24072449 TI - Authors' response: from monitoring to vigilance about patient adherence to new oral anticoagulants. PMID- 24072450 TI - Ivabradine in treatment of sinus tachycardia mediated vasovagal syncope. AB - AIMS: Ivabradine, an I(f) current blocker, has shown promising results in treatment of postural orthostatic tachycardia syndrome (POTS). There is a subgroup of vasovagal syncope (VVS) patients, who demonstrate sinus tachycardia before collapse on tilt testing mimicking some features of POTS. These patients may also respond to ivabradine therapy. University Hospital Syncope Clinic where ivabradine was prescribed in a prospective fashion on humanitarian grounds between October 2008 and December 2011. METHODS AND RESULTS: Twenty-five patients of mean age 33+/-years presenting syncope in all and palpitation in 23, duration 9+/-years underwent tilt testing with reproduction of usual symptoms including tachycardia preceding collapse. Ivabradine was prescribed in doses of 5-20 mg/day, mean 10.7 mg, as once or twice daily medication. The response to treatment was classified as deterioration in none, no change in 5, improvement in 10, and symptoms abolished in 8 patients. Side effects were minimal; one patient required discontinuation. CONCLUSION: In this pilot study of ivabradine, in patients with VVS, of patients who demonstrated sinus tachycardia before collapse on tilt, 72% reported a marked benefit or complete resolution of symptoms. The drug was well tolerated. A randomized controlled trial against placebo is justified. PMID- 24072451 TI - Effect of dronedarone on clinical end points in patients with atrial fibrillation and coronary heart disease: insights from the ATHENA trial. AB - AIMS: This study aimed to assess safety and cardiovascular outcomes of dronedarone in patients with paroxysmal or persistent atrial fibrillation (AF) with coronary heart disease (CHD). Coronary heart disease is prevalent among AF patients and limits antiarrhythmic drug use because of their potentially life threatening ventricular proarrhythmic effects. METHODS AND RESULTS: This post hoc analysis evaluated 1405 patients with paroxysmal or persistent AF and CHD from the ATHENA trial. Follow-up lasted 2.5 years, during which patients received either dronedarone (400 mg twice daily) or a double-blind matching placebo. Primary outcome was time to first cardiovascular hospitalization or death due to any cause. Secondary end points included first hospitalization due to cardiovascular events. The primary outcome occurred in 350 of 737 (47%) placebo patients vs. 252 of 668 (38%) dronedarone patients [hazard ratio (HR) = 0.73; 95% confidence interval (CI) = 0.62-0.86; P = 0.0002] without a significant increase in number of adverse events. In addition, 42 of 668 patients receiving dronedarone suffered from a first acute coronary syndrome compared with 67 of 737 patients from the placebo group (HR = 0.67; 95% CI = 0.46-0.99; P = 0.04). CONCLUSION: In this post hoc analysis, dronedarone on top of standard care in AF patients with CHD reduced cardiovascular hospitalization or death similar to that in the overall ATHENA population, and reduced a first acute coronary syndrome. Importantly, the safety profile in this subpopulation was also similar to that of the overall ATHENA population, with no excess in proarrhythmias. The mechanism of the cardiovascular protective effects is unclear and warrants further investigation. PMID- 24072453 TI - Predictive factors for the development of chronic renal insufficiency after renal surgery: a multicenter study. AB - PURPOSE: To evaluate which factors affecting changes in postoperative renal function after conducting radical nephrectomy or partial nephrectomy. METHODS: Data on patients who underwent operations for renal cell carcinoma between 2000 and 2010 at multiple institutions were collected. Patient characteristics including preoperative estimated glomerular filtration rate (EGFR) were investigated, and types of surgery and postoperative results were evaluated. Renal insufficiency was defined as an EGFR <60 ml/min/1.73 m(2). Cox proportional hazard regression analysis was used to investigate which factors were associated with chronic renal insufficiency after surgery. RESULTS: A total of 2,454 patients were included for evaluation; 1,502 patients underwent radical nephrectomy, whereas 952 patients underwent partial nephrectomy. The mean follow up period was 44.48 +/- 27.04 months (range, 12-120 months). Factors affecting EGFR were age, diabetes, hypertension, surgical procedure, and preoperative creatinine level (p < 0.001). Factors affecting postoperative renal insufficiency were age, surgical procedure, serum creatinine level, and EGFR. CONCLUSION: The risk for developing post-nephrectomy renal insufficiency in patients who underwent radical nephrectomy was higher than those who underwent partial nephrectomy. Factors affecting post-nephrectomy renal insufficiency were age, preoperative serum creatinine level, and preoperative EGFR. In addition to radical nephrectomy, patient >58 years with a preoperative serum creatinine >1.03 mg/ml, and EGFR <73 ml/min/1.73 m(2) had a higher probability of developing post nephrectomy chronic renal insufficiency. PMID- 24072452 TI - Unilateral ureteral obstruction: beyond obstruction. AB - Unilateral ureteral obstruction is a popular experimental model of renal injury. However, the study of the kidney response to urinary tract obstruction is only one of several advantages of this model. Unilateral ureteral obstruction causes subacute renal injury characterized by tubular cell injury, interstitial inflammation and fibrosis. For this reason, it serves as a model both of irreversible acute kidney injury and of events taking place during human chronic kidney disease. Being a unilateral disease, it is not useful to study changes in global kidney function, but has the advantage of a low mortality and the availability of an internal control (the non-obstructed kidney). Experimental unilateral ureteral obstruction has illustrated the molecular mechanisms of apoptosis, inflammation and fibrosis, all three key processes in kidney injury of any cause, thus providing information beyond obstruction. Recently this model has supported key concepts on the role in kidney fibrosis of epithelial-mesenchymal transition, tubular epithelial cell G2/M arrest, the anti-aging hormone Klotho and renal innervation. We now review the experimental model and its contribution to identifying novel therapeutic targets in kidney injury and fibrosis, independently of the noxa. PMID- 24072454 TI - A population-based study on the prevalence and incidence of chronic kidney disease in the Netherlands. AB - PURPOSE: Because most population-based studies on the epidemiology of chronic kidney disease (CKD) are cross-sectional, there is, except for end-stage renal disease, hardly any information on incidence rates. METHODS: We conducted a retrospective cohort study in a dynamic population, using data of 784,563 adult participants retrieved from the Integrated Primary Care Information database, a primary care database containing the complete electronic longitudinal medical records. CKD (both incidence and prevalence) was based on (1) an increased urine albumin-to-creatinine ratio, (2) a decreased estimated glomerular filtration rate, or (3) explicit statement in the medical record. Results were stratified by age according to the WHO standard population, sex, and diabetes mellitus. RESULTS: Based on a single measurement only, the incidence rate of CKD in adults was 1,213 per 100,000 person-years, and 6.7 percent of the adult population had a prevalent diagnosis of CKD. The incidence rate increased by age and was the highest in participants with diabetes with an incidence of 25,000 per 100,000 person-years, affecting over 75 percent of participants with diabetes. CONCLUSIONS: This is the first study to report the incidence rates of all stages of CKD for the entire adult population, stratified by sex, 5-year age groups, and diabetes. Our data demonstrate that the incidence of CKD increases with age and is the highest in participants with diabetes mellitus. PMID- 24072455 TI - Traditional Chinese medicine use among Chinese immigrant cancer patients. AB - Traditional Chinese Medicine (TCM) includes both herbal remedies and non-herbal practices. Chinese cancer patients are particularly at high risk for herb-drug interactions. Providers, both primary care physicians and oncologists, frequently do not ask patients about TCM use, which has potentially dangerous consequences. This study describes an assessment of TCM use while undergoing conventional cancer treatment, among a cohort of Chinese immigrant cancer patients in New York City. The Immigrant Health and Cancer Disparities Service at Memorial Sloan Kettering Cancer Center assists underserved cancer patients through a patient navigation program, the Cancer Portal Project. Six questions related to TCM are included in the existing Portal Needs Assessment Intake. Mandarin- or Cantonese speaking Portal patients enrolled between January 2010 and May 2012 were surveyed. One hundred nine Chinese-speaking patients were enrolled in the Portal Project during the study period. Forty-six completed the TCM questions. Ninety six percent preferred to speak Mandarin, Cantonese, or Fujianese in the healthcare setting. Thirty-nine percent (n = 18) of the 46 participants reported using TCM since being diagnosed with cancer. Nearly all (n = 16) who used TCM reported using herbal medicines. Ten TCM users did not describe sharing their use with Western doctors. Eight (44%) of TCM users reported concurrently using TCM and conventional cancer treatment. Larger scale studies should further explore the concurrent use of TCM and conventional cancer treatment in this unique population. Future research should also address patient-provider communication related to the concurrent use of TCM and cancer treatment. This is also an important area of education for both patients and providers. PMID- 24072456 TI - Bringing the real world to psychometric evaluation of cervical cancer literacy assessments with Black, Latina, and Arab women in real-world settings. AB - This research describes the development and evaluation of a new scale for assessing functional cervical cancer health literacy, the Cervical Cancer Literacy Assessment Tool (C-CLAT). In phase 1, 35 items in English, Spanish, and Arabic for C-CLAT were generated, taking into account three content domains Awareness, Knowledge, and Prevention/Control. After content validation, 24 items were retained for psychometric evaluation. In phase 2, the 24-item C-CLAT was evaluated in three racial/ethnic populations of urban women (N = 543). Psychometric methods included item analysis, multifactor item response theory modeling, and concurrent correlations. The final C-CLAT consisted of 16 items, with an internal consistency reliability of 0.72. C-CLAT reliabilities in Black, Latina, and Arab women were 0.73, 0.76, and 0.60, respectively. The rank order correlations of item difficulties across racial/ethnic groups was high (r's = 0.97 to 0.98). The C-CLAT was positively related to educational level, and Arab women scored significantly higher than the Black and Latina participants. This study presents a psychometrically sound instrument that measures health literacy related to cervical cancer. The C-CLAT is a tool that can be orally administered by a lay person and used in a community-based health promotion intervention. PMID- 24072457 TI - Cerebral microdialysis in traumatic brain injury and subarachnoid hemorrhage: state of the art. AB - Cerebral microdialysis (CMD) is a laboratory tool that provides on-line analysis of brain biochemistry via a thin, fenestrated, double-lumen dialysis catheter that is inserted into the interstitium of the brain. A solute is slowly infused into the catheter at a constant velocity. The fenestrated membranes at the tip of the catheter permit free diffusion of molecules between the brain interstitium and the perfusate, which is subsequently collected for laboratory analysis. The major molecules studied using this method are glucose, lactate, pyruvate, glutamate, and glycerol. The collected substances provide insight into the neurochemical features of secondary injury following traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) and valuable information about changes in brain metabolism within a short time frame. In this review, the authors detail the CMD technique and its associated markers and then describe pertinent findings from the literature about the clinical application of CMD in TBI and SAH. PMID- 24072458 TI - Hypothermia at 35 degrees C reduces the time-dependent microglial production of pro-inflammatory and anti-inflammatory factors that mediate neuronal cell death. AB - BACKGROUND: Therapeutic hypothermia protects neurons after severe brain damage. This effect has been mainly achieved at the core temperatures of 32-34 degrees C; however, the optimum temperature of therapeutic hypothermia is not fully defined. Here we studied whether hypothermic culture at 35 degrees C had the same effects on the decrease of time-dependent expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, and nitric oxide (NO) by stimuli activated microglia as that at 33 degrees C, as determined in our previous reports, and whether these factors directly induced neuronal cell death. METHODS: We determined the levels of cytokines and NO produced by microglia cultured with adenosine triphosphate (ATP), a toll-like receptor (TLR)2 agonist (N-palmitoyl-S (2,3-bis(palmitoyloxy)-(2R,S)-propyl)-(R)-cysteinyl-seryl-(lysyl)3-lysine, Pam(3)CSK(4)), or a TLR4 agonist (lipopolysaccharide) under mild hypothermic (33 degrees C), minimal hypothermic (35 degrees C), and normothermic (37 degrees C) conditions. We also determined the viability of rat neuronal pheochromocytoma PC12 cells treated with recombinant TNF-alpha or IL-10 or (+/-)-(E)-4-ethyl-2 [(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3, an NO donor). RESULTS: Production of TNF-alpha, as well as that of IL-10 and NO were decreased by minimal hypothermia at 1.5-6, and 24-48 h, respectively, compared with normothermia, although some effects were diminished as compared with those by mild hypothermia. Exposure to TNF-alpha, IL-10, and NOR3 caused the death of PC12 cells in a concentration-dependent manner after 24 h. CONCLUSION: Hypothermic culture at 35 degrees C decreased the production of early-phase TNF-alpha and late-phase IL-10 and NO from ATP- and TLR-activated microglia as observed at 33 degrees C, albeit with diminished effects. Moreover, these factors caused the death of neuronal cells in a concentration-dependent manner. These results suggest that the attenuation of microglial production of TNF-alpha, IL-10, and NO by therapeutic hypothermia leads to the inhibition of neuronal cell death. Minimal hypothermia at 35 degrees C may be sufficient to elicit neuroprotective effect. PMID- 24072459 TI - Glyburide is associated with attenuated vasogenic edema in stroke patients. AB - BACKGROUND: Brain edema is a serious complication of ischemic stroke that can lead to secondary neurological deterioration and death. Glyburide is reported to prevent brain swelling in preclinical rodent models of ischemic stroke through inhibition of a non-selective channel composed of sulfonylurea receptor 1 and transient receptor potential cation channel subfamily M member 4. However, the relevance of this pathway to the development of cerebral edema in stroke patients is not known. METHODS: Using a case-control design, we retrospectively assessed neuroimaging and blood markers of cytotoxic and vasogenic edema in subjects who were enrolled in the glyburide advantage in malignant edema and stroke-pilot (GAMES-Pilot) trial. We compared serial brain magnetic resonance images (MRIs) to a cohort with similar large volume infarctions. We also compared matrix metalloproteinase-9 (MMP-9) plasma level in large hemispheric stroke. RESULTS: We report that IV glyburide was associated with T2 fluid-attenuated inversion recovery signal intensity ratio on brain MRI, diminished the lesional water diffusivity between days 1 and 2 (pseudo-normalization), and reduced blood MMP-9 level. CONCLUSIONS: Several surrogate markers of vasogenic edema appear to be reduced in the setting of IV glyburide treatment in human stroke. Verification of these potential imaging and blood biomarkers is warranted in the context of a randomized, placebo-controlled trial. PMID- 24072460 TI - Pressures, flow, and brain oxygenation during plateau waves of intracranial pressure. AB - BACKGROUND: Plateau waves are common in traumatic brain injury. They constitute abrupt increases of intracranial pressure (ICP) above 40 mmHg associated with a decrease in cerebral perfusion pressure (CPP). The aim of this study was to describe plateau waves characteristics with multimodal brain monitoring in head injured patients admitted in neurocritical care. METHODS: Prospective observational study in 18 multiple trauma patients with head injury admitted to Neurocritical Care Unit of Hospital Sao Joao in Porto. Multimodal systemic and brain monitoring of primary variables [heart rate, arterial blood pressure, ICP, CPP, pulse amplitude, end tidal CO2, brain temperature, brain tissue oxygenation pressure, cerebral oximetry (CO) with transcutaneous near-infrared spectroscopy and cerebral blood flow (CBF)] and secondary variables related to cerebral compensatory reserve and cerebrovascular reactivity were supported by dedicated software ICM+ ( www.neurosurg.cam.ac.uk/icmplus) . The compiled data were analyzed in patients who developed plateau waves. RESULTS: In this study we identified 59 plateau waves that occurred in 44% of the patients (8/18). During plateau waves CBF, cerebrovascular resistance, CO, and brain tissue oxygenation decreased. The duration and magnitude of plateau waves were greater in patients with working cerebrovascular reactivity. After the end of plateau wave, a hyperemic response was recorded in 64% of cases with increase in CBF and brain oxygenation. The magnitude of hyperemia was associated with better autoregulation status and low oxygenation levels at baseline. CONCLUSIONS: Multimodal brain monitoring facilitates identification and understanding of intrinsic vascular brain phenomenon, such as plateau waves, and may help the adequate management of acute head injury at bed side. PMID- 24072461 TI - Toxicokinetic, toxicodynamic, and toxicoproteomic aspects of short-term exposure to trenbolone in female fish. AB - The toxicokinetics of trenbolone was characterized during 500 ng/l water exposures in female rainbow trout (Oncorhynchus mykiss) and fathead minnows (Pimephales promelas). Related experiments measured various toxicodynamic effects of exposure. In both species, trenbolone was rapidly absorbed from the water and reached peak plasma levels within 8h of exposure. Afterwards, trenbolone concentrations in trout (66-95 ng/ml) were 2-6 times higher compared with minnows (15-29 ng/ml), which was attributable to greater plasma binding in trout. During water exposures, circulating levels of estradiol (E2) rapidly decreased in both species to a concentration that was 25%-40% of control values by 8-24h of exposure and then remained relatively unchanged for the subsequent 6 days of exposure. In trout, changes in circulating levels of follicle-stimulating hormone were also significantly greater after trenbolone exposure, relative to controls. In both species, the pharmacokinetics of injected E2-d3 was altered by trenbolone exposure with an increase in total body clearance and a corresponding decrease in elimination half-life. The unbound percentage of E2 in trout plasma was 0.25%, which was similar in pre- or postvitellogenic female trout. Subsequent incubation with trenbolone caused the unbound percentage to significantly increase to 2.4% in the previtellogenic trout plasma. iTRAQ-based toxicoproteomic studies in minnows exposed to 5, 50, and 500 ng/l trenbolone identified a total of 148 proteins with 19 downregulated including vitellogenin and 18 upregulated. Other downregulated proteins were fibrinogens, alpha-2-macroglobulin, and transferrin. Upregulated proteins included amine oxidase, apolipoproteins, parvalbumin, complement system proteins, and several uncharacterized proteins. The results indicate trenbolone exposure is a highly dynamic process in female fish with uptake and tissue equilibrium quickly established, leading to both rapid and delayed toxicodynamic effects. PMID- 24072462 TI - Chemoinformatics profiling of ionic liquids--uncovering structure-cytotoxicity relationships with network-like similarity graphs. AB - Ionic liquids (ILs) constitute one of the hottest areas in chemistry since they have become increasingly popular as reaction and extraction media. Their almost limitless structural possibilities, as opposed to limited structural variations within molecular solvents, make ILs "designer solvents." They also have been widely promoted as "green solvents" although their claimed relative nontoxicity has been frequently questioned. The Thinking in Structure-Activity Relationships (T-SAR) approach has proved to be an efficient method to gather relevant toxicological information of analog series of ILs. However, when data sets significantly grow in size and structural diversity, the use of computational models becomes essential. We provided such a computational solution in a previous work by introducing a reliable, predictive, simple, and chemically interpretable Classification and Regression Tree (CART) classifier enabling the prioritization of ILs with a favorable cytotoxicity profile. Even so, an efficient and exhaustive mining of SAR information goes beyond analog compound series and the applicability domain of quantitative SAR modeling. So, we decided to complement our previous findings based on the use of the CART classifier by applying the network-like similarity graph (NSG) approach to the mining of relevant structure cytotoxicity relationship (SCR) trends. Finally, the SCR information concurrently gathered by both, quantitative (CART classifier) and qualitative (NSG) approaches was used to design a focused combinatorial library enriched with potentially safe ILs. PMID- 24072464 TI - Optimisations and evolution of the mammalian respiratory system : A suggestion of possible gene sharing in evolution. AB - The respiratory system of mammalians is made of two successive branched structures with different physiological functions. The upper structure, or bronchial tree, is a fluid transportation system made of approximately 15 generations of bifurcations leading to the order of about 2(15) = 30, 000 terminal bronchioles with a diameter of approximately 0.5mm in the human lung. The branching pattern continues up to generation 23 but the structure and function of each of the subsequent structures, called acini, is different. Each acinus consists in a branched system of ducts surrounded by alveoli and plays the role of a diffusion cell where oxygen and carbon dioxide are exchanged with blood across the alveolar membrane. We show here that the bronchial tree simultaneously presents several different optimal properties. It is first energy efficient, second, it is space filling and third it is also "rapid". This physically based multi-optimality suggests that, in the course of evolution, an organ selected against one criterion could have been used later for a totally different purpose. For example, once selected for its energetic efficiency for the transport of a viscous fluid like blood, the same genetic material could have been used for its optimized rapidity. This would have allowed the emergence of atmospheric respiration made of inspiration-expiration cycles. For this phenomenon to exist, rapidity is essential as fresh air has to reach the gas exchange organs, the pulmonary acini, before the beginning of expiration. We finally show that the pulmonary acinus is optimized in the sense that the acinus morphology is directly related to the notion of a "best possible" extraction of entropic energy by a diffusion exchanger that has to feed oxygen efficiently from air to blood across a membrane of finite permeability. PMID- 24072465 TI - Controlled block copolymer micelle formation for encapsulation of hydrophobic ingredients. AB - We report on the formation of polymeric micelles in water using triblock copolymers with a polyethylene glycol middle block and various hydrophobic outer blocks prepared with the precipitation method. We form micelles in a reproducible manner with a narrow size distribution. This suggests that during the formation of the micelles the system had time to form micelles under close-to-thermodynamic control. This may explain why it is possible to use an equilibrium self consistent field theory to predict the hydrodynamic size and the loading capacity of the micelles in accordance with experimental finding. Yet, the micelles are structurally quenched as concluded from the observation of size stability in time. We demonstrate that our approach enables to prepare rather hydrophobic block copolymer micelles with tunable size and loading. PMID- 24072463 TI - An F1-extended one-generation reproductive toxicity study in Crl:CD(SD) rats with 2,4-dichlorophenoxyacetic acid. AB - 2,4-Dichlorophenoxyacetic acid (2,4-D) was assessed for systemic toxicity, reproductive toxicity, developmental neurotoxicity (DNT), developmental immunotoxicity (DIT), and endocrine toxicity. CD rats (27/sex/dose) were exposed to 0, 100, 300, 600 (female), or 800 (male) ppm 2,4-D in diet. Nonlinear toxicokinetic behavior was shown at high doses; the renal clearance saturation threshold for 2,4-D was exceeded markedly in females and slightly exceeded in males. Exposure was 4 weeks premating, 7 weeks postmating for P1 males and through lactation for P1 females. F1 offspring were examined for survival and development, and at weaning, pups were divided in cohorts, by sex and dose, and by systemic toxicity (10), DNT (10), DIT (20), and reproductive toxicity (>= 23). Remaining weanlings were evaluated for systemic toxicity and neuropathology (10 12). Body weight decreased during lactation in high-dose P1 females and in F1 pups. Kidney was the primary target organ, with slight degeneration of proximal convoluted tubules observed in high-dose P1 males and in high-dose F1 males and females. A slight intergenerational difference in kidney toxicity was attributed to increased intake of 2,4-D in F1 offspring. Decreased weanling testes weights and delayed preputial separation in F1 males were attributed to decreased body weights. Endocrine-related effects were limited to slight thyroid hormone changes and adaptive histopathology in high-dose GD 17 dams seen only at a nonlinear toxicokinetic dose. 2,4-D did not cause reproductive toxicity, DNT, or DIT. The "No Observed Adverse Effect Level" for systemic toxicity was 300 ppm in both males (16.6 mg/kg/day) and females (20.6 mg/kg/day), which is approximately 6700- to 93 000-fold higher than that reported for 2,4-D exposures in human biomonitoring studies. PMID- 24072466 TI - Kinetic modelling and bifurcation analysis of chemomechanically miniaturized gels under mechanical load. AB - Chemomechanically responsive gels, with great potential applications in the fields of smart structures and biomedicines, present autonomously oscillatory deformation driven by the Belousov-Zhabotinsky chemical reaction. The dynamic behavior of the responsive gels is obviously affected by the external mechanical load. This approach proposed a kinetic model with an ordinary differential equation to describe the oscillatory deformation of the gels under the mechanical load. Then the periodic solutions and phase diagrams of the oscillation are obtained using the improved Runge-Kutta and shooting methods. The results demonstrated that bifurcations are typically existent in the system and the characters of the oscillatory deformation regularly depend on the mechanical load as well as the concentration of reactants and the stoichiometric coefficient of chemical reaction. This development is supposed to promote the practical applications of the chemomechanically responsive gels. PMID- 24072467 TI - Dipoles in thin sheets. AB - A flat elastic sheet may contain pointlike conical singularities that carry a metrical "charge" of Gaussian curvature. Adding such elementary defects to a sheet allows one to make many shapes, in a manner broadly analogous to the familiar multipole construction in electrostatics. However, here the underlying field theory is non-linear, and superposition of intrinsic defects is non-trivial as it must respect the immersion of the resulting surface in three dimensions. We consider a "charge-neutral" dipole composed of two conical singularities of opposite sign. Unlike the relatively simple electrostatic case, here there are two distinct stable minima and an infinity of unstable equilibria. We determine the shapes of the minima and evaluate their energies in the thin-sheet regime where bending dominates over stretching. Our predictions are in surprisingly good agreement with experiments on paper sheets. PMID- 24072468 TI - Is superhydrophobicity robust with respect to disorder? AB - We consider theoretically the Cassie-Baxter and Wenzel states describing the wetting contact angles for rough substrates. More precisely, we consider different types of periodic geometries such as square protrusions and disks in 2D, grooves and nanoparticles in 3D and derive explicitly the contact angle formulas. We also show how to introduce the concept of surface disorder within the problem and, inspired by biomimetism, study its effect on superhydrophobicity. Our results, quite generally, prove that introducing disorder, at fixed given roughness, will lower the contact angle: a disordered substrate will have a lower contact angle than a corresponding periodic substrate. We also show that there are some choices of disorder for which the loss of superhydrophobicity can be made small, making superhydrophobicity robust. PMID- 24072470 TI - The controversial paper. PMID- 24072471 TI - Individualizing propofol dosage: a multivariate linear model approach. AB - In the last decades propofol became established as an intravenous agent for the induction and maintenance of both sedation and general anesthesia procedures. In order to achieve the desired clinical effects appropriate infusion rate strategies must be designed. Moreover, it is important to avoid or minimize associated side effects namely adverse cardiorespiratory effects and delayed recovery. Nowadays, to attain these purposes the continuous propofol delivery is usually performed through target-controlled infusion (TCI) systems whose algorithms rely on pharmacokinetic and pharmacodynamic models. This work presents statistical models to estimate both the infusion rate and the bolus administration. The modeling strategy relies on multivariate linear models, based on patient characteristics such as age, height, weight and gender along with the desired target concentration. A clinical database collected with a RugLoopII device on 84 patients undergoing ultrasonographic endoscopy under sedation analgesia with propofol and remifentanil is used to estimate the models (training set with 74 cases) and assess their performance (test set with 10 cases). The results obtained in the test set comprising a broad range of characteristics are satisfactory since the models are able to predict bolus, infusion rates and the effect-site concentrations comparable to those of TCI. Furthermore, comparisons of the effect-site concentrations for dosages predicted by the proposed Linear model and the Marsh model for the same target concentration is achieved using Schnider model and a factorial design on the factors (patients characteristics). The results indicate that the Linear model predicts a dosage profile that is faster in leading to an effect-site concentration closer to the desired target concentration. PMID- 24072472 TI - A giant Pseudomonas phage from Poland. AB - A novel giant phage of the family Myoviridae is described. Pseudomonas phage PA5oct was isolated from a sewage sample from an irrigated field near Wroclaw, Poland. The virion morphology indicates that PA5oct differs from known giant phages. The phage has a head of about 131 nm in diameter and a tail of 136 * 19 nm. Phage PA5oct contains a genome of approximately 375 kbp and differs in size from any tailed phages known. PA5oct was further characterized by determination of its latent period and burst size and its sensitivity to heating, chloroform, and pH. PMID- 24072473 TI - Intensive care unit mortality in solid tumor patients: is this predictable and preventable? PMID- 24072474 TI - Comparison of two chemotherapy-induced peripheral neuropathy measurement approaches in children. AB - PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment in children; however, measurement of CIPN has been hampered by limitations in available tools, which may impact prevalence estimates. The purpose of this study was to assess the relative ability of the Common Terminology Criteria (CTCAE) rating process to detect sensory and motor neuropathy as compared to administration of the pediatric modified Total Neuropathy Score (peds-mTNS). METHODS: The ped-mTNS was administered to 60 children/adolescents ages 5-18 undergoing treatment for acute lymphocytic leukemia, lymphoma, or non-CNS solid tumors. CTCAE v3.0 scores for the same time point were abstracted from the medical record by a separate trained rater. Comparisons were made between scores using descriptive statistics, correlations, and specificity and sensitivity calculations. RESULTS: The median ped-mTNS score was 9 (32 possible), while the median sensory and motor CTCAE ratings were 0 and 2, respectively (4 and 5 possible, respectively). There was no correlation between ped-mTNS and combined sensory and motor CTCAE scores. The only ped-mTNS item with significant correlation to CTCAE scoring was strength testing. Medical record abstraction of CTCAE scores failed to identify sensory neuropathy in 40 % and significant motor neuropathy (manual muscle test grade 3 or worse) in 15 % of subjects. CONCLUSIONS: Prospective measures of CIPN using the ped-mTNS identified a far greater proportion of subjects with peripheral neurotoxicity as compared to CTCAE v3.0 sensory and motor neuropathy ratings, and thus we recommend the use of a specific measure of CIPN such as the ped-mTNS. PMID- 24072476 TI - "I'm just waiting...": an exploration of the experience of living and dying with primary malignant glioma. AB - PURPOSE: Referral to supportive and palliative care services for people with high grade primary malignant glioma (PMG) often occurs late in the illness course, despite significant care needs and overall poor prognosis. This study aimed to understand patient experience at the end of life and document supportive and palliative care needs. METHODS: A qualitative study was conducted involving ten PMG patients who were at different stages in the illness course including the end of life and had varying levels of physical and cognitive function. Consecutive, eligible patients attending neurosurgery, oncology, and palliative care services of two metropolitan hospitals were recruited. In-depth interviews explored supportive and palliative care needs across the disease trajectory. Interviews were analysed independently by three investigators consistent with a grounded theory approach, and emerging ideas were compared and refined to define key patient experiences. RESULTS: Despite the medical treatment and supportive care available, there remains a gap in services addressing complex existential and psychosocial needs that were markedly valued by patients. Patient experience was characterised by a pervasive loss of all that encompassed their former sense of self and a focus on immediate needs. CONCLUSIONS: Patients in this study had substantial needs, which were often not shared and not addressed by the current medical system of care. An improved multidisciplinary care model is indicated, which proactively (1) engages care coordination and advocacy; (2) minimises patients' sense of waiting and uncertainty through mapping out a plan, including involvement of palliative care in a timely fashion; and (3) actively invites discussion around goals and preferences for care to promote patients' sense of self. PMID- 24072477 TI - Impact of behavioral interventions in the management of adults with type 2 diabetes mellitus. AB - Research on the role of behavior change as an efficacious intervention for adults with type 2 diabetes is evolving. Searching PubMed and Ovid Medline, we identified and reviewed primarily randomized controlled trials from 2010 to 2013 of adults managing type 2 diabetes without insulin. All studies are evaluated in terms of the rigor of their design and their impact on glycosylated hemoglobin. The most efficacious interventions appear to be low-carbohydrate/glycemic load diets, combined aerobic and resistance training, and self-monitoring of blood glucose, which educates patients about the impact of their food selections and physical activity on their blood glucose. PMID- 24072478 TI - The growing prevalence of type 2 diabetes: increased incidence or improved survival? AB - Approximately 347 million persons were estimated to have diabetes worldwide in 2008, an increase of 194 million cases from 1980. Diabetes now affects both high- and low-income countries, with low-income countries bearing the majority of the burden. The epidemiologic transition from traditional health risks, such as poor hygiene, to modern health risks, such as sedentary lifestyle, has facilitated the increase in incidence in diabetes, especially in developing countries. The effect of these risk factors may be especially pronounced in some racial and ethnic populations. Increased surveillance for diabetes has contributed to increased diabetes prevalence in higher-income countries. Survival with and some risk factors for diabetes have improved in developed countries, but global diabetes mortality has increased by 20 % since 1990. Population growth and aging will only increase the burden of diabetes, and public health interventions are needed to address diabetes risk factors to stem the tide of this epidemic. PMID- 24072479 TI - The emerging global epidemic of type 1 diabetes. AB - Type 1 diabetes mellitus (T1D) can occur at any age, with a peak in incidence around puberty. Classification between T1D and type 2 diabetes becomes more challenging with increasing age of onset of T1D over time develops in genetically predisposed individuals. The main susceptibility is conferred with human leukocyte antigen (HLA) genes. Some of the geographic variation in incidence and familial aggregation is explained by differences in HLA haplotypes. In many populations, the incidence is somewhat higher in males than in females, and a 1.3 to 2.0-fold male excess in incidence after about 15 years of age exists in most populations. The incidence of childhood-onset T1D varies markedly among countries. East Asian and native American populations have low incidences (approximately 0.1-8 per 100 000/year), while the highest rates are found in Finland (>60 per 100 000/year), Sardinia (40 per 100 000/year), and Sweden (47 per 100 000/year). The risk is highest in European-derived populations. About 10 %-20 % of newly diagnosed childhood cases of T1D have an affected first-degree relative. Those with an affected sibling or parent have a cumulative risk of 3 % 7 % up to about 20 years of age, as compared with <1 % in the general population. The cumulative incidence among the monozygotic co-twins of persons with T1D is less than 50 %. Thus, the majority of genetically predisposed people do not develop T1D. Studies assessing temporal trends have shown that the incidence of childhood-onset T1D has increased in all parts of the world. The average relative increase is 3 %-4 % per calendar year. For instance, in Finland, the incidence today is 5 times higher than 60 years ago. At the same time, the age at onset of T1D in children has become younger. It is strongly believed that nongenetic factors are important for the development of T1D and its increase, but the causative evidence is missing. The causes for this increasing trend and current epidemic still remain unknown. PMID- 24072480 TI - Basic fibroblast growth factor (bFGF) facilitates differentiation of adult dorsal root ganglia-derived neural stem cells toward Schwann cells by binding to FGFR-1 through MAPK/ERK activation. AB - Considerable research has been devoted to unraveling the regulation of neural stem cell (NSC) differentiation. The responses of NSCs to various differentiation inducing stimuli, however, are still difficult to estimate. In this study, we aimed to search for a potent growth factor that was able to effectively induce differentiation of NSCs toward Schwann cells. NSCs were isolated from dorsal root ganglia (DRGs) of adult rats and identified by immunostaining. Three different growth factors were used to stimulate the differentiation of DRG-derived NSCs (DRG-NSCs). We found that among these three growth factors, bFGF was the strongest inducer for the glial differentiation of DRG-NSCs, and bFGF induced the generation of an increased number of Schwann cell-like cells as compared to nerve growth factor (NGF) and neuregulin1-beta (NRG). These Schwann cell-like cells demonstrated the same characteristics as those of primary Schwann cells. Furthermore, we noted that bFGF-induced differentiation of DRG-NSCs toward Schwann cells might be mediated by binding to fibroblast growth factor receptor-1 (FGFR-1) through activation of MAPK/ERK signal pathway. PMID- 24072481 TI - Amyloid beta suppresses protein C activation through inhibition of the endothelial protein C receptor (EPCR). AB - Alzheimer's disease (AD) is known to be associated with microcirculatory injury, capillary blockage, and disruption of the blood-brain barrier. Endothelial dysfunction has also been reported to be associated with AD, but the underlying mechanisms remain to be elucidated. Endothelial protein C receptor (EPCR) is an N glycosylated type I membrane protein that enhances the activation of protein C. However, the effects of EPCR and protein C in AD are still unknown. In this study, we found that the expression of EPCR was reduced in the brains of beta amyloid precursor protein overexpressing Tg2576 transgenic mice at both the mRNA level and the protein level. However, levels of thrombomodulin (TM) did not undergo any changes. An in vitro study displayed that beta-amyloid (Abeta) treatment led to suppression of EPCR along with reduction of protein C activation in mouse primary endothelial cells. Further study revealed that the induction of the c-Jun N-terminal kinase (JNK)/c-Jun pathway plays a causal role in the inhibitory effects of Abeta1-42 on the expression of EPCR. As a transcriptional factor, c-Jun was able to transinactivate the EPCR promoter. Finally, we found that c-Jun silencing or the use of a JNK inhibitor could attenuate the effects of Abeta1-42 in the activation of protein C. PMID- 24072482 TI - Activating transcription factor 4 modulates BDNF release from microglial cells. AB - Pathogenic pain is a common sign of many diseases. The mechanism is unclear. Activating transcription factor 4 (ATF4) plays a critical role in cell activation. Brain-derived neurotrophic factor (BDNF) is an important molecule in pathogenic pain. This study aims to investigate the role of ATF4 in inducing BDNF release from microglial cells. In this study, mouse microglial cells were cultured. The levels of BDNF in the culture medium were determined by enzyme linked immunosorbent assay. Overexpression of ATF4 in microglial cells was performed by gene transfection. The apoptosis of microglial cells was assessed by flow cytometry. The results showed that microglial cells expressed ATF4 and protease-activated receptor-2 (PAR2). BDNF was detectable in the culture medium of microglial cells, which was significantly increased in the ATF4-overexpressing microglial cells. The ATF4-overexpressing microglial cells showed a high frequency of apoptotic cells, which could be inhibited by exposure to the PAR2 agonist tryptase in the culture. The tryptase-treated ATF4-overexpressing microglial cells kept higher secretion of BDNF. We conclude that the activation of ATF4 can increase BDNF release from microglial cells. PMID- 24072483 TI - Brain editorial. PMID- 24072484 TI - Defining and treating leucine-rich glioma inactivated 1 antibody associated autoimmunity. PMID- 24072485 TI - Off to never-never land: losing consciousness to gain thought. PMID- 24072487 TI - Comparative assessment of effectiveness of ketoprofen and ketoprofen/beta cyclodextrin complex in two experimental models of inflammation in rats. AB - Oral administration of non-steroidal anti-inflammatory drugs (NSAIDs) can lead to adverse effects such as gastrointestinal distress. The complexation of different groups of active substances with beta-cyclodextrin (beta-CD) has drawn considerable interest over recent years. The purpose of this study was to analyze the ketoprofen/beta-cyclodextrin (K/beta-CD) conjugate complex as well as to assess its anti-inflammatory effect after oral administration (doses of 30 mg/m(2) and 15 mg/m(2) of body surface), compared with ketoprofen. The studies were done on two models of experimentally-induced acute inflammation in rats (n = 48, 6/group), by means of intraplantar administration of a 10% aqueous kaolin suspension and intraperitoneal administration of a 1% sodium thioglycolate solution. The dynamics of the acute inflammatory process and the anti inflammatory effects were monitored using plethysmometric determinations after 3, 6, 9, 12, 24 and 48 h (plantar inflammation), and the absorbance of the exudates (spectrophotometrically read) and nucleated cell counts after 24 h (peritoneal inflammation). The coupling of ketoprofen with beta-CD resulted in increased solubility (100% in 60 min) of the newly-formed product, which further resulted in a higher bioavailability compared with ketoprofen (<40% in 120 min). In both models of experimentally-induced inflammation, the K/beta-CD complex had a higher anti-inflammatory activity than ketoprofen. PMID- 24072486 TI - Anterior temporal lobe degeneration produces widespread network-driven dysfunction. AB - The neural organization of semantic memory remains much debated. A 'distributed only' view contends that semantic knowledge is represented within spatially distant, modality-selective primary and association cortices. Observations in semantic variant primary progressive aphasia have inspired an alternative model featuring the anterior temporal lobe as an amodal hub that supports semantic knowledge by linking distributed modality-selective regions. Direct evidence has been lacking, however, to support intrinsic functional interactions between an anterior temporal lobe hub and upstream sensory regions in humans. Here, we examined the neural networks supporting semantic knowledge by performing a multimodal brain imaging study in healthy subjects and patients with semantic variant primary progressive aphasia. In healthy subjects, the anterior temporal lobe showed intrinsic connectivity to an array of modality-selective primary and association cortices. Patients showed focal anterior temporal lobe degeneration but also reduced physiological integrity throughout distributed modality selective regions connected with the anterior temporal lobe in healthy controls. Physiological deficits outside the anterior temporal lobe correlated with scores on semantic tasks and with anterior temporal subregion atrophy, following domain specific and connectivity-based predictions. The findings provide a neurophysiological basis for the theory that semantic processing is orchestrated through interactions between a critical anterior temporal lobe hub and modality selective processing nodes. PMID- 24072488 TI - Evaluation of a new side-stream, low dead space, end-tidal carbon dioxide monitoring system in rats. AB - The aim of this study was to evaluate a newly developed infrared side-stream capnograph with minimal sample volume for the continuous measurement of end-tidal carbon dioxide (CO2) concentrations in small rodents. Thirty-four male Wistar rats (weight 345 +/- 70 g) were treated in accordance with the National Institutes of Health (NIH) guidelines for animal care. All experiments were performed with approval of the local animal care and use committee. Sepsis was induced by implanting an 18 gauge stent into the colon 24 h prior to the experiments, allowing a constant fecal leakage into the peritoneal cavity (25 septic and nine control animals). Hemodynamic variables and end-tidal CO2 were recorded continuously and arterial blood (5 * 120 uL) was sampled periodically for arterial blood gas analysis. After baseline controlled mechanical ventilation was randomized and titrated to either normocapnia (35-45 mmHg) or hypercapnia (65 75 mmHg) with exogenous application of CO2. A total of 155 paired CO2 measurements comparing end-tidal and arterial partial pressure were conducted. Side-stream capnography underestimated the CO2 partial pressure with a bias of 6.1 mmHg and a 95% limit of agreement from 6.7 to -19.1 mmHg. Our results suggest that side-stream end-tidal CO2 monitoring with a low dead space could be utilized in rats as a surrogate for the arterial CO2 measurement over a wide range of partial pressures in normal and septic animals. PMID- 24072489 TI - Mitral valve repair using ePTFE sutures for ruptured mitral chordae tendineae: a computational simulation study. AB - Mitral valve (MV) repair using expanded polytetrafluoroethylene sutures is an established and preferred interventional method to resolve the complex pathophysiologic problems associated with chordal rupture. We developed a novel computational evaluation protocol to determine the effect of the artificial sutures on restoring MV function following valve repair. A virtual MV was created using three-dimensional echocardiographic data in a patient with ruptured mitral chordae tendineae (RMCT). Virtual repairs were designed by adding artificial sutures between the papillary muscles and the posterior leaflet where the native chordae were ruptured. Dynamic finite element simulations were performed to evaluate pre- and post-repair MV function. Abnormal posterior leaflet prolapse and mitral regurgitation was clearly demonstrated in the MV with ruptured chordae. Following virtual repair to reconstruct ruptured chordae, the severity of the posterior leaflet prolapse decreased and stress concentration was markedly reduced both in the leaflet tissue and the intact native chordae. Complete leaflet coaptation was restored when four or six sutures were utilized. Computational simulations provided quantitative information of functional improvement following MV repair. This novel simulation strategy may provide a powerful tool for evaluation and prediction of interventional treatment for RMCT. PMID- 24072490 TI - The tendon injury response is influenced by decorin and biglycan. AB - Defining the constituent regulatory molecules in tendon is critical to understanding the process of tendon repair and instructive to the development of novel treatment modalities. The purpose of this study is to define the structural, expressional, and mechanical changes in the tendon injury response, and elucidate the roles of two class I small leucine-rich proteoglycans (SLRPs). We utilized biglycan-null, decorin-null and wild type mice with an established patellar tendon injury model. Mechanical testing demonstrated functional changes associated with injury and the incomplete recapitulation of mechanical properties after 6 weeks. In addition, SLRP deficiency influenced the mechanical properties with a marked lack of improvement between 3 and 6 weeks in decorin-null tendons. Morphological analyses of the injury response and role of SLRPs demonstrated alterations in cell density and shape as well as collagen alignment and fibril structure resulting from injury. SLRP gene expression was studied using RT-qPCR with alterations in expression associated with the injured tendons. Our results show that in the absence of biglycan initial healing may be impaired while in the absence of decorin later healing is clearly diminished. This suggests that biglycan and decorin may have sequential roles in the tendon response to injury. PMID- 24072491 TI - COL1A1 polymorphism is associated with risks of osteosarcoma susceptibility and death. AB - Osteosarcoma is a life-threatening malignancy that often occurs in teenagers. Collagen type I alpha 1 (COL1A1) polymorphism is reportedly associated with the occurrence of several human diseases. However, the relationship between COL1A1 and osteosarcoma occurrence remains unknown, and there is no report about the prevalence of COL1A1 in osteosarcoma. The purpose of this study is to investigate the associations of COL1A1 polymorphism with the susceptibility and survival of osteosarcoma. The relative risk to develop osteosarcomas and the overall survival associated to COL1A1 polymorphism were investigated in a homogeneous group of 189 osteosarcomas patients. Correlations with overall survival and hazard ratios (HR) were also analyzed. CT genotype and C allele of COL1A1 at rs1061970, and CG genotype and G allele of COL1A1 at rs2075559 are associated with decreased susceptibility to osteosarcoma in the Chinese population. CC genotype and C allele of COL1A1 at rs1061970 are associated with nonmetastasis in patients. CC genotype and CT genotype of COL1A1 at rs1061970 are associated with lower risk of death. Metastasis was found to be an independent prognostic factor for survival. This study provides the first evidence for the association between COL1A1 polymorphism and osteosarcoma risk in Chinese and shows that COL1A1 polymorphism at rs1061970 has a prognostic value for overall survival in osteosarcoma patients. PMID- 24072492 TI - ILEI drives epithelial to mesenchymal transition and metastatic progression in the lung cancer cell line A549. AB - Transforming growth factor beta (TGF-beta) induces epithelial-mesenchymal transition (EMT) accompanied by cellular differentiation and migration. Despite extensive transcriptomic profiling, identification of TGF-beta-inducible, EMT specific genes during metastatic progression of lung cancer remains elusive. Here, we functionally validate a previously described post-transcriptional pathway by which TGF-beta modulates expression of interleukin-like EMT inducer (ILEI), and EMT itself. We show that poly r(C)-binding protein 1 (PCBP1) binds ILEI transcript and repress its translation. TGF-beta activation leads to phosphorylation at serine-43 of PCBP1 by protein kinase Bbeta/Akt2, inducing its release from the ILEI transcript and translational activation. Modulation of hnRNP E1 expression modification altered TGF-beta-mediated reversal of translational silencing of ILEI transcripts and EMT. Furthermore, ILEI could induce, as well as maintain, CD24(low)CD44(high) subpopulation in A549 cells treated with TGF-beta, which might explain its capability to induce metastatic progression. These results thus validate the existence of an evolutionary conserved TGF-beta-inducible post-transcriptional regulon that controls EMT and subsequent metastatic progression of lung cancer. PMID- 24072493 TI - Inhibition of gastric cancer cell growth and invasion through siRNA-mediated knockdown of guanine nucleotide exchange factor Vav3. AB - Vav3, a Rho GTPase guanine nucleotide exchange factor, is associated with tumor growth, apoptosis, invasion and metastasis, and angiogenesis. However, the role of Vav3 in gastric cancer remains unclear. In this study, Vav3 expression was blocked by specific siRNA in gastric cancer cell line MGC803. MTT was used to assay cell proliferation activity; wound healing assay and transwell assay were applied to detect cell migration and invasion ability; and qRT-PCR and Western blot were employed to detect expression levels of Vav3 as well as proliferation, migration, and invasion-related genes. The results showed that Vav3 expression in gastric cancer tissues and cell lines was significantly upregulated and was higher than that in adjacent tissues of cancer and normal gastric mucosal cell lines. Vav3 knockdown inhibited proliferation, migration, and invasion of MGC803 gastric cancer cells. The expression of P21, P27, TIMP-1, and TIMP-2 was upregulated, while proliferating cell nuclear antigen, cyclin E1, matrix metalloproteinase (MMP)-2, and MMP-7 were downregulated by Vav3 knockdown in MGC803 gastric cells. In conclusion, Vav3 is involved in the proliferation, migration, and invasion of gastric cancer cell as a tumor oncogene. PMID- 24072494 TI - Quantitative assessment of the influence of tumor necrosis factor alpha polymorphism with gastritis and gastric cancer risk. AB - Tumor necrosis factor alpha (TNFA) is an important molecule in inflammatory, infectious, and tumoral processes. Inflammation is one of the early phases in the development of gastric cancer (GC). Therefore, several studies have examined the association of polymorphism in TNFA with gastritis and GC risk. A functional polymorphism, -308G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-alpha and influence cancer risk. To date, a number of studies have been carried out to investigate the relationship between the polymorphism and gastritis or GC susceptibility, but the results were conflicting. To investigate this inconsistency, we performed a meta analysis of 36 studies for TNFA -308G>A polymorphism to evaluate the effect of TNFA on genetic susceptibility for gastritis and GC. An overall random-effects per-allele odds ratio of 1.16 (95 % confidence interval 1.04-1.29, P = 0.008) was found for the polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians, whereas no significant associations were found among East Asians and other ethnic populations. No associations between the polymorphism and gastritis were observed. In addition, our data indicate that TNFA is involved in GC susceptibility and confers its effect primarily in diffuse type of tumors. Besides, -308G>A polymorphism was found to be significantly associated with both cardiac and noncardiac tumors. This meta-analysis demonstrated that the TNFA -308G>A polymorphism is a risk factor for developing GC, but the associations vary in different ethnic populations. PMID- 24072495 TI - Association between IL-4 -590C>T polymorphism and gastric cancer risk. AB - Published studies on the association between interleukin-4 (IL-4) -590C>T polymorphism and gastric cancer risk have yielded conflicting results. Thus, a meta-analysis of published studies was performed to assess the possible association. All eligible studies of -590C>T polymorphism and gastric cancer risk were collected from the PubMed, the Cochrane Library, and the Embase electronic databases. Statistical analyses were performed by Review Manager 5.0 and Stata 11.0. When all groups were pooled, we did not detect a significant association of -590C>T polymorphism with gastric cancer risk. When stratifying for race, there was a significant association between -590C>T polymorphism and decreased gastric cancer risk under dominant model and allelic model in the subgroup of Caucasians. However, significant association was absent in Asians. Based on our meta analysis, -590C>T polymorphism was associated with a lower gastric cancer risk under dominant model and allelic model in Caucasians. Nevertheless, we suggest that further studies should be made to confirm these findings. PMID- 24072496 TI - Diagnostic value of pleural interleukin 17 and carcinoembryonic antigen in lung cancer patients with malignant pleural effusions. AB - Interleukin 17 (IL-17) has been found to be increased in some human cancers; however, the possible implication of IL-17 in regulating antitumor responses in lung cancer patients with malignant pleural effusions (MPE) remains to be elucidated. This study aimed to investigate the diagnostic value of pleural IL-17 and carcinoembryonic antigen (CEA) in MPE and benign pleural effusions (BPE). Pleural effusion samples from 108 patients were classified on the basis of diagnosis as MPE (n = 56) and BPE (n = 52). The concentration of IL-17 was determined by enzyme-linked immunosorbent assay (ELISA). The CEA levels were also determined in all patients. A significant difference was observed in the levels of CEA (P < 0.01) between MPE and BPE. The concentration of IL-17 in MPE was significantly higher compared to that in BPE (P < 0.01). With a cutoff point of 15.7 pg/ml, IL-17 had a sensitivity of 76.8 % and a specificity of 80.8 % for differential diagnosis. The combined detection of IL-17 and CEA had a sensitivity of 96.4 % and a specificity of 92.3 % to distinguish MPE from BPE. The combined detection of IL-17 and CEA may be more valuable in the differential diagnosis between MPE and BPE. PMID- 24072497 TI - Rapid detection of resistance in Staphylococcus aureus by using Quicolor ES. AB - Traditional microbiological methods are dependent on the growth of microorganisms, and hence require prolonged periods. The methods used to detect resistance in Staphylococcus aureus should have high sensitivity and specificity, yet provide results in a timely manner. The aim of this study was to evaluate the use of Quicolor (QC) ES((r)) agar for the rapid detection of resistance in S. aureus. We evaluated 100 clinical S. aureus isolates. Resistance detection was performed using traditional microbiological methods. Methicillin resistance detection was evaluated using traditional and molecular microbiological methods. Traditional antibiotic susceptibility testing methods, such as disc diffusion, were conducted using QC ES and Mueller-Hinton (MH) media. The plates were incubated at 36 degrees C for 5, 6 and 24 h. Rapid results obtained using QC ES agar after 5 h of incubation were consistent with those using the overnight procedure with MH agar for 83 of the 100 S. aureus (including methicillin susceptible S. aureus) strains. However, the correlation for oxacillin between MH (24 h) and QC ES (5 h) was not satisfactory (r = 0.770). The total agreement between QC ES and MH agar was 83% after 5 h, 89% after 6 h, and 94% after 24 h. The accurate and rapid detection of resistance in S. aureus is critical due to the associated therapeutic problems and infection control measures. We believe that the use of QC ES for S. aureus will reduce the delay in resistance detection, thus providing physicians and infection control practitioners with early information for better management. PMID- 24072498 TI - Molecular characterization and identification of plant growth promoting endophytic bacteria isolated from the root nodules of pea (Pisum sativum L.). AB - Root nodule accommodates various non-nodulating bacteria at varying densities. Present study was planned to identify and characterize the non-nodulating bacteria from the pea plant. Ten fast growing bacteria were isolated from the root nodules of cultivated pea plants. These bacterial isolates were unable to nodulate pea plants in nodulation assay, which indicate the non-rhizobial nature of these bacteria. Bacterial isolates were tested in vitro for plant growth promoting properties including indole acetic acid (IAA) production, nitrogen fixation, phosphate solubilization, root colonization and biofilm formation. Six isolates were able to produce IAA at varying level from 0.86 to 16.16 MUg ml(-1), with the isolate MSP9 being most efficient. Only two isolates, MSP2 and MSP10, were able to fix nitrogen. All isolates were able to solubilize inorganic phosphorus ranging from 5.57 to 11.73 MUg ml(-1), except MSP4. Bacterial isolates showed considerably better potential for colonization on pea roots. Isolates MSP9 and MSP10 were most efficient in biofilm formation on polyvinyl chloride, which indicated their potential to withstand various biotic and abiotic stresses, whereas the remaining isolates showed a very poor biofilm formation ability. The most efficient plant growth promoting agents, MSP9 and MSP10, were phylogenetically identified by 16S rRNA gene sequence analysis as Ochrobactrum and Enterobacter, respectively, with 99% similarity. It is suggested the potential endophytic bacterial strains, Ochrobactrum sp. MSP9 and Enterobacter sp. MSP10, can be used as biofertilizers for various legume and non-legume crops after studying their interaction with the host crop and field evaluation. PMID- 24072499 TI - Urea based dipodal fluorescence receptor for sensing of Fe3+ ion in semi-aqueous medium. AB - Urea based fluorescent chemosensor 1 was synthesized. Receptor 1 shows unique selectivity for the Fe(3+)ion and no such significant response was noticed with other metal ions (Cr(3+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+), Pb(2+) and Bi(3+)) in DMSO/H2O (50:50,v/v) semi-aqueous solution. The binding features have been established by absorption and fluorescence spectroscopic methods. The binding constant (K) values obtained from Benesi-Hildebrand, Scatchard and Connor plot for receptor 1 is (8.3 +/- 0.3) * 10(3) M(-1) and has good detection limit 0.7 MUM. The stoichiometry of 1.Fe(3+) complex was confirmed by mass spectroscopy and Job's plot. PMID- 24072500 TI - Two new flavonol glycosides and a metabolite profile of Bryophyllum pinnatum, a phytotherapeutic used in obstetrics and gynaecology. AB - Bryophyllum pinnatum is a succulent perennial plant native to Madagascar which is used in anthroposophical medicine to treat psychiatric disorders and as a tocolytic agent to prevent premature labour. We performed a metabolite profiling study in order to obtain a comprehensive picture of the constituents in B. pinnatum leaves and to identify chromatographic markers for quality control and safety assessment of medicinal preparations. Preliminary HPLC-PDA-ESIMS analyses revealed that flavonoid glycosides were the main UV-absorbing constituents in the MeOH extract of B. pinnatum. Two phenolic glucosides, syringic acid beta-D glucopyranosyl ester (1) and 4'-O-beta-D-glucopyranosyl-cis-p-coumaric acid (2), as well as nine flavonoids (3-11) including kaempferol, quercetin, myricetin, acacetin, and diosmetin glycosides were unambiguously identified by 1H and 2D NMR analysis after isolation from a MeOH extract. The flavonol glycosides quercetin 3 O-alpha-L-arabinopyranosyl-(1 -> 2)-alpha-L-rhamnopyranoside 7-O-beta-D glucopyranoside (3) and myricetin 3-O-alpha-L-arabinopyranosyl-(1 -> 2)-alpha-L rhamnopyranoside (4) were new natural products. With the aid of HPLC-PDA-APCIMS and authentic references isolated from the related species B. daigremontianum, the presence of four bufadienolides, bersaldegenin-1-acetate (12), bryophyllin A (13), bersaldegenin-3-acetate (14), and bersaldegenin-1,3,5-orthoacetate (15) was detected in B. pinnatum. PMID- 24072501 TI - The mechanisms of in vitro cytotoxicity of mountain tea, Sideritis scardica, against the C6 glioma cell line. AB - Sideritis scardica (mountain tea) is an endemic plant on the Balkan Peninsula traditionally used for treating different conditions, mainly of inflammatory nature. This study was aimed to examine the cytotoxic activity of different S. scardica extracts against the rat glioma C6 line and rat astrocytes in primary culture. The obtained data revealed that diethyl ether (extract 2) and ethyl acetate (extract 3) extracts of S. scardica exerted a cytotoxic effect on C6 rat glioma cells. Diethyl ether extract induced an increase in reactive oxygen species production, leading to apoptotic and autophagic cell death. Ethyl acetate extract induced G2 M cell cycle arrest and autophagy. None of the tested extracts was cytotoxic to rat astrocytes in primary culture. Cytotoxic effects of S. scardica extracts were, at least in part, mediated by their flavonoid constituents apigenin and luteolin that, when applied alone, induced cell cycle arrest, apoptosis, and autophagy. PMID- 24072502 TI - From olive drupes to olive oil. An HPLC-orbitrap-based qualitative and quantitative exploration of olive key metabolites. AB - The aim of the current study was the qualitative exploration and quantitative monitoring of key olive secondary metabolites in different production steps (drupes, paste, first and final oil) throughout a virgin olive oil production line. The Greek variety Koroneiki was selected as one of the most representative olives, which is rich in biological active compounds. For the first time, an HPLC Orbitrap platform was employed for both qualitative and quantitative purposes. Fifty-two components belonging to phenyl alcohols, secoiridoids, flavonoids, triterpenes, and lactones were identified based on HRMS and HRMS/MS data. Nine biologically and chemically significant metabolites were quantitatively determined throughout the four production steps. Drupes and paste were found to be rich in several components, which are not present in the final oil. The current study discloses the chemical nature of different olive materials in a successive and integrated way and reveals new sources of high added value constituents of olives. PMID- 24072503 TI - Icariin induces osteoblast differentiation and mineralization without dexamethasone in vitro. AB - An effective method for preventing bone loss is by promoting osteoblast differentiation and bone formation. While dexamethasone has been routinely used as a classical inducer for osteoblast differentiation, limitations have been observed with its usage, including its varied effects on expression of osteoblast genes in different species and its potentials in suppressing osteoblastic differentiation and mineralization. In this study, we assessed the ability of flavonoid icariin in enhancing differentiation and mineralization of cultured rat primary osteoblasts in the absence of dexamethasone. It was found that, compared to the non-stimulated control, icariin at 10(-5) M produced a higher alkaline phosphatase activity, more and larger areas of alkaline phosphatase-positive colonies (CFU-FALP) and mineralized nodules, more osteocalcin secretion and calcium deposition, higher levels of mRNA expression of alkaline phosphatase, osteoblastic transcription factors osterix and runt-related transcription factor 2, and collagen 1alpha, higher levels of protein expression of collagen 1alpha, alkaline phosphatese, osterix, and runt-related transcription factor 2. In addition, icariin at 10(-5) M was always more potent than dexamethasone at its optimal concentration of 10(-8) M on the above osteoblast differentiation and mineralization markers. Taken together, our studies demonstrated that icariin has a pronounced ability in promoting osteoblast differentiation in vitro in the absence of dexamethasone. PMID- 24072504 TI - Influence of acute tryptophan depletion on verbal declarative episodic memory in young adult females. AB - Diminished synthesis of the neurotransmitter serotonin (5-HT) in the brain has been linked to disturbed memory processes. The present study investigated the effects of diminished central nervous 5-HT synthesis as achieved by an acute dietary tryptophan depletion (ATD) on verbal declarative episodic memory in young women while controlling for the effects of female sex hormones. Eighteen healthy females (aged 20-31 years) participated in a within-subject repeated measures study, with two separate days of assessment spaced at least one individual menstrual cycle apart. On one day, participants were subjected to ATD, thus lowering central nervous 5-HT synthesis. The other day participants received a tryptophan-balanced amino acid load (BAL = control condition). The study was randomized, counterbalanced and double blind in terms of ATD/BAL administration. Measurements took place in the early follicular phase of the participants' menstrual cycle. Estrogen, FSH and LH levels were assessed at baseline. Verbal declarative episodic memory was assessed using a structured word-learning task. Short-term memory, as indexed by immediate recall, was reduced after ATD intake, whereas delayed recall and recognition after a 25-min delay did not show any differences after intake of ATD or BAL. In young women, verbal short-term memory function was more vulnerable to ATD than consolidation processes. In light of the possible interplay between female sex hormones and 5-HT, further studies comparing different menstrual cycle phases are needed. PMID- 24072505 TI - Enantiomer-specific selection of amino acids. AB - Dietary intake of L-amino acids impacts on several physiological functions, including the control of gastrointestinal motility, pancreatic secretion, and appetite. However, the biological mechanisms regulating behavioral predilections for certain amino acid types remain poorly understood. We tested the hypothesis that, in mice, the potency with which a given glucogenic amino acid increases glucose utilization reflects its rewarding properties. We have found that: (1) during long-, but not short-, term preference tests, L-alanine and L-serine were preferred over their D-enantiomer counterparts, while no such effect was observed for L-threonine vs. D-threonine; (2) these behavioral patterns were closely associated with the ability of L-amino acids to promote increases in respiratory exchange ratios such that those, and only those, L-amino acids able to promote increases in respiratory exchange ratios were preferred over their D-isomers; (3) these behavioral preferences were independent of gustatory influences, since taste-deficient Trpm5 knockout mice displayed ingestive responses very similar to those of their wild-type counterparts. We conclude that the ability to promote increases in respiratory exchange ratios enhances the reward value of nutritionally relevant amino acids and suggest a mechanistic link between substrate utilization and amino acid preferences. PMID- 24072506 TI - Human baby hair amino acid natural abundance 15N-isotope values are not related to the 15N-isotope values of amino acids in mother's breast milk protein. AB - Since exclusively breast-suckled infants obtain their nutrient only from their mother's milk, it might be anticipated that a correlation will exist between the (15)N/(14)N isotope ratios of amino acids of protein of young infants and those supplied by their mother. The work presented here aimed to determine whether amino nitrogen transfer from human milk to infant hair protein synthesized within the first month of life conserves the maternal isotopic signature or whether post ingestion fractionation dominates the nitrogen isotope spectrum. The study was conducted at 1 month post-birth on 100 mother-infant pairs. Isotope ratios (15)N/(14)N and (13)C/(12)C were measured using isotope ratio measurement by Mass Spectrometry (irm-MS) for whole maternal milk, and infant hair and (15)N/(14)N ratios were also measured by GC-irm-MS for the N-pivaloyl-O-isopropyl esters of amino acids obtained from the hydrolysis of milk and hair proteins. The delta(15)N and delta(13)C (0/00) were found to be significantly higher in infant hair than in breast milk (delta(15)N, P < 0.001; delta(13)C, P < 0.001). Furthermore, the delta(15)N (0/00) of individual amino acids in infant hair was also significantly higher than that in maternal milk (P < 0.001). By calculation, the observed shift in isotope ratio was shown not to be accounted for by the amino acid composition of hair and milk proteins, indicating that it is not simply due to differences in the composition in the proteins present. Rather, it would appear that each pool-mother and infant-turns over independently, and that fractionation in infant N-metabolism even in the first month of life dominates over the nutrient N-content. PMID- 24072507 TI - Long-term mortality risk by cause of death in newly diagnosed patients with epilepsy in Finland: a nationwide register-based study. AB - To estimate long-term mortality by cause of death in a nationwide, register-based cohort of newly diagnosed patients with epilepsy (PWE). All noninstitutionalized Finnish PWE aged 10-74 years (n = 10,818) eligible for reimbursement for antiepileptic medication for the first time between 1990 and 1994 were identified in the database of Social Insurance Institution of Finland. Mortality was compared against a population-based reference cohort (n = 43,894). Hazard ratios (HR) and their 95 % confidence intervals (95 % CI) during a follow-up of 18 years were estimated using proportional hazards modeling. Potential years of life lost (PYLL) and excess fraction of causes of death attributable to epilepsy were estimated. PWE contributed 137,610 person-years of observation and there were 3,558 deaths. Mortality remained elevated up to 18 years post-diagnosis (HR 3.21, 95 % CI 3.07-3.35). Ischemic heart disease mortality in PWE was two-fold (HR 2.31, 95 % CI 2.09-2.54), and remained constantly elevated during entire follow up in both men and women. Most premature mortality in terms of PYLL was attributable to brain cancer (17 %), other cancers (15 %), ischemic heart disease (11 %), as well as cerebrovascular diseases (10 %). The percentage of deaths in PWE statistically attributable to epilepsy was 3.9 % for accidents, 3.4 % for alcohol-related diseases, and 1.6 % for suicides. PWE had substantial excess mortality from non-communicable diseases, which did not disappear by 18 years. Diseases of the circulatory system and cancers, especially brain cancer, were the most important causes of death almost regardless of the mortality indicator. PMID- 24072508 TI - Cerebral microbleeds and the risk of mortality in the general population. AB - Presence of cerebral microbleeds indicates underlying vascular brain disease and has been implicated in lobar hemorrhages and dementia. However, it remains unknown whether microbleeds also reflect more systemic vascular burden. We investigated the association of microbleeds with all-cause and cardiovascular related mortality in the general population. We rated the brain magnetic resonance imaging scans of 3979 Rotterdam Scan Study participants to determine presence, number, and location of microbleeds. Cox proportional hazards models, adjusted for age, sex, subcohort, vascular risk factors, and other MRI markers of cerebral vascular disease, were applied to quantify the association of microbleeds with mortality. After a mean follow up of 5.2 (+/-1.1) years, 172 (4.3 %) people had died. Presence of microbleeds, and particularly deep or infratentorial microbleeds, was significantly associated with an increased risk of all-cause mortality [sex-, age-, subcohort adjusted hazard ratio (HR) 2.27; CI 1.50-3.45], independent of vascular risk factors (HR 1.87; 95 % CI 1.20-2.92). The presence of deep or infratentorial microbleeds strongly associated with the risk of cardiovascular related mortality (HR 4.08; CI 1.78-9.39). Mortality risk increased with increasing number of microbleeds. The presence of microbleeds, particularly multiple microbleeds and those in deep or infratentorial regions, indicates an increased risk of mortality, independent of other MRI markers of cerebral vascular disease. Our data suggest that microbleeds may mark severe underlying vascular pathology associated with poorer survival. PMID- 24072509 TI - High expression level of TMPRSS4 predicts adverse outcomes of colorectal cancer patients. AB - Transmembrane protease/serine 4 (TMPRSS4), a member of the type II transmembrane serine protease family, is highly expressed in some human cancers and involved in the EMT regulation of cancer cells. The prognostic value of TMPRSS4 in colorectal cancer (CRC) has not been discussed. This study aims to evaluate the association between TMPRSS4 expressions and survival in CRC patients. Immunohistochemistry revealed high expression of TMPRSS4 in 69/122 CRC samples, compared with 14/47 in normal tissues (P < 0.01). Correlation analysis showed high expression of TMPRSS4 was significantly associated with advanced TNM stage (P = 0.011), pT (P = 0.019), pN (P = 0.035), and pM status (P = 0.004). Higher TMPRSS4 predicted shorter overall survival (OS) and disease-free survival (DFS) in CRC patients (P < 0.01, both). Moreover, both TMPRSS4 expression and TNM stage were independent predictive factors of OS and DFS in Cox regression analysis. The findings in our study demonstrated the potential value of TMPRSS4 expression level as a prognostic biomarker for CRC patients. PMID- 24072510 TI - The STYRO 2011 project: a survey on perceived quality of training among young Italian radiation oncologists. AB - In order to evaluate the perceived quality of training and education among young Italian radiation oncologists (age <40), AIRO Giovani (Italian Association of Radiation Oncology-Young Members Working Group) carried out a nationwide online survey in 2011, employing a 63-item-based questionnaire, addressed to physician's self-perception of personal training experience (during decade 2001-2011). Issues explored investigated demographics data, duration/organization/content/characteristics of residency programs, the quality of education in clinical oncology, radiation oncology, management and communication attitudes. A total of 382 questionnaires were sent out to physicians and 217 (56.8%) were returned with 197 (51.6%) appropriately filled in and considered for the analysis. The general perception of education and training is positive in most of the explored fields, however some specific contexts and skills still require optimization (combination therapy, peculiar clinical scenarios, particular radiotherapy technical issues, structural organization of residency programs). The present report is expected to be useful for residents, program directors and scientific societies (such as AIRO), to further continue the effort in the improvement of training in radiation oncology. PMID- 24072511 TI - Status of antioxidant enzyme: glutathione peroxidase and total polyphenol level in plasma of Tunisian patients suffering from colorectal and gastric cancer: interaction with clinical outcome. AB - In our case-control study, we measure the antioxidant status by dosing enzymes involved in oxidant stress in plasma of patients with colorectal and gastric cancer, and in the second step, we investigate the impact of chemotherapy before and after surgery on plasma antioxidant status and polyphenols in patients. Blood serum was collected from patients with stomach and colorectal cancer before conventional treatment, and glutathione peroxidase (GSHPX) enzyme activities and total polyphenols were determined by spectrophotometric methods. In our study, we found a significant decrease in glutathione peroxidase activity in plasma of patients compared with controls (P = 0.02), although we did not find a significant association between total polyphenols and 2,2'-azino-bis-(3 ethylbenzothiazoline-6-sulfonic acid) or ABTS in plasma of colorectal and stomach cancer compared with control; furthermore, we observed no significant difference in the average plasma polyphenols in patients treated with chemotherapy before and after surgery. We have shown the decrease in GSHPX activity in plasma of cases with colorectal and gastric cancer, and this decrease reflects that the oxidative stress is associated with tumor tract and related to oxidative metabolism; however, no association was found between total polyphenols and ABTS in our study. PMID- 24072512 TI - Critical appraisal of costly therapy modalities for heart failure in a developing country. AB - Contemporaneous challenges in heart failure management include strategies to rationally use health economic resources and relative donor shortage to adequately offer electric devices (cardiac resynchronization therapy [CRT] and implantable cardioverter defibrillators [ICD]), ventricular assist devices (VADs) and heart transplant, respectively. These issues are particularly important in countries with middle-income rates and limited structured heart transplant centers, such as Brazil. Use of CRT and ICDs need to follow strict guidelines, further customized to public financial health conditions. Experience with VADs in is the early days in Brazil and will require extreme caution to allocate health public resources to develop VAD programs in highly selected centers. Chagas' disease is epidemiologically important in Brazil; outcomes of patients with Chagas' on electric devices are unclear while these patients fare better post transplant than non-Chagas' patients. Thus, heart transplant remains an attractive option regarding both favorable outcomes and resource allocation for advanced heart failure patients in Brazil. PMID- 24072513 TI - Stigma against people with HIV/AIDS in rural Ethiopia, 2005 to 2011: signs and predictors of improvement. AB - This study sought to determine trends in and factors associated with stigma against people with HIV/AIDS in Ethiopia. Rural data from the 2005 and 2011 Demographic and Health Surveys were analyzed. HIV testing rates among males increased dramatically from 2005 to 2011 (8-35 %). Among females, testing rates dropped 10 % during the same period. HIV knowledge was associated with stigma, shown by a negative correlation in both data waves, but groups with higher knowledge tended to have lower stigma. Lower levels of knowledge were uniformly associated with higher levels of stigma, but higher levels of knowledge, combined with higher levels of education, were associated with lower levels of stigma in a multiplicative way. Improvements in knowledge can serve as an important intermediate process to behavior change. The found interaction suggests improvements in either education or knowledge can reduce stigma, and when both are improved, stigma reduction will be more dramatic. PMID- 24072515 TI - Fatalism and health promoting behaviors in Chinese and Korean immigrants and Caucasians. AB - Fatalism has been associated with non-adherence to health behavior in the past. This study compared fatalism of Chinese and Korean immigrants with native-born Caucasians (N = 309) and examined whether the relationship between fatalism and exercise, nutrition and medical screening would be moderated by ethnicity. Chinese reported higher fatalism than Caucasians and Koreans. Higher fatalism was associated with greater exercise among Chinese and Koreans, but less reported exercise among Caucasians. Caucasian participants had higher scores for nutrition and medical screening compared with Chinese and Korean immigrants. These findings indicate that fatalism is more prevalent among Chinese immigrants; however, there is no evidence of a detrimental effect of fatalism on exercise, nutrition or medical screening among the Asian immigrants. Caucasians with higher fatalism may be at greater risk of future illnesses, given the association between fatalism and sedentary behavior in this group. Differences between cultural groups in the adoption of health behavior justify the development and assessment of targeted interventions to optimize health promoting behaviors. PMID- 24072516 TI - [Basic standards for a department of cardiac surgery. Quality requirements for the care of cardiac patients in connection with operations on the heart, the heart vessels and thoracic organ transplantation]. AB - Current evolutions and substantial amendments of the German health care system in combination with distinguished progress in cardiac surgery over the past years require both a reflection of principles in patient-centered care and an update of basic standard requirements for a department of cardiac surgery in Germany. In due consideration of the data from the voluntary registry of the German Society for Thoracic and Cardiovascular Surgery, this article accurately defines core requirements for a cardiac surgical department (cardiac surgery on-site), subdivided into facilities, staff and processes. If based on these standards, one may anticipate that cardiac surgical care is performed under appropriate conditions leading to an intrinsic benefit for patients. PMID- 24072514 TI - Chromatin modifications associated with DNA double-strand breaks repair as potential targets for neurological diseases. AB - The integrity of the genome is continuously challenged by both endogenous and exogenous DNA damaging agents. Neurons, due to their post-mitotic state, high metabolism, and longevity are particularly prone to the accumulation of DNA lesions. Indeed, DNA damage has been suggested as a major contributor to both age associated neurodegenerative diseases and acute neurological injury. The DNA damage response is a key factor in maintaining genome integrity. It relies on highly dynamic posttranslational modifications of the chromatin and DNA repair proteins to allow signaling, access, and repair of the lesion. Drugs that modulate the activity of the enzymes responsible for these modifications have emerged as attractive therapeutic compounds to treat neurodegeneration. In this review, we discuss the role of DNA double-strand breaks and abnormal chromatin modification patterns in a range of neurodegenerative conditions, and the chromatin modifiers that might ameliorate them. Finally, we suggest that understanding the epigenetic modifications specific to neuronal DNA repair is crucial for the development of efficient neurotherapeutic strategies. PMID- 24072517 TI - Molecular cloning and functional analysis of the Populus deltoides remorin gene PdREM. AB - Remorins play vital roles in signal transduction, energy transformation, ion flow and transport in plants. Upregulation of remorins correlates with dehiscence and cell maturation; however, no studies have been performed to elucidate the function of remorins in tree species. In this study, a Populus deltoides (Marsh.) plasma membrane-binding protein remorin gene (PdREM) was cloned and characterized by investigating its expression pattern and creating transgenic hybrid poplar (P. davidiana Dode * P. bolleana Lauche) lines expressing sense or antisense PdREM. PdREM was specifically expressed in leaf buds, and immature and mature phloem in P. deltoides. Downregulation of PdREM increased plant height, stem diameter, number of leaves, size of the xylem and phloem zones and induced expression of cell wall biosynthesis- and microfibril angle (MFA)-related genes. Overexpression of PdREM retarded vegetative growth. PdREM may negatively regulate vascular growth by inhibiting secondary cell wall expansion in poplar. In addition, antisense PdREM transgenic poplar had a lower MFA, suggesting that PdREM might contribute to sheet strength and wood properties in poplar. This study sheds light on the molecular mechanism of PdREM in P. deltoides growth and development, and lays the foundation for future functional genomics research into wood formation and the genetic engineering of forest trees with improved wood quality traits. PMID- 24072518 TI - Scaling Erica arborea transpiration from trees up to the stand using auxiliary micrometeorological information in a wax myrtle-tree heath cloud forest (La Gomera, Canary Islands). AB - We investigate evapotranspiration, sap flow and top soil water content variations in a wax myrtle-tree heath ('fayal-brezal' in Spanish) cloud forest in the Garajonay National Park (La Gomera, Canary Islands) over a 1-year period. We provide transpiration estimates for one of the representative species, the shrubby needle-like Erica arborea L., present in this relict subtropical forest. An ad hoc tree up to the stand scaling method that combines the sap flow and auxiliary reference evapotranspiration data is illustrated, showing to be useful when sap flow in a limited number of trees has been monitored. Individual daily based scaling curves of the Gompertz type were necessary to explain the observed sap flow variability in E. arborea during the 1-year period investigated (r(2) >= 0.953 with mode of r(2) = 0.9999). The mean daily sap flow of an E. arborea individual amounted to 8.37 +/- 5.65 kg day(-1) tree(-1), with a maximum of 20.48 kg day(-1) tree(-1), yielding an annual total of 3052.89 kg tree(-1). A comparison of the computed daily transpiration with the continuous micrometeorological time series monitored in the studied plot suggested that solar radiation was the main driving force of transpiration in E. arborea (cross correlation index = 0.94). Fog may also affect tree transpiration via its reduction of radiation and temperature, such that during foggy periods the mean daily water loss estimate of E. arborea was 5.35 +/- 4.30 kg day(-1) tree(-1), which sharply contrasted with the 2.4-fold average transpiration values obtained for fog-free days, i.e., 12.81 +/- 4.33 kg day(-1) tree(-1). The annual water balance rendered a 288 mm year(-1) water input to the forest and evidenced the need for accurately quantifying the contribution of fog water dripping from the canopy. PMID- 24072519 TI - Information to women invited to mammography screening. PMID- 24072520 TI - Equipoise abandoned? Randomization and clinical trials. PMID- 24072523 TI - Effectiveness of preventive support groups for children of mentally ill or addicted parents: a randomized controlled trial. AB - In various countries preventive support groups are offered to children of mentally ill and/or addicted parents to reduce the risk that they will develop problems themselves. This study assessed the effectiveness of Dutch support groups for children aged 8-12 years old in terms of reducing negative cognitions; improving social support, competence, and parent-child interaction (direct intervention goals); and reducing emotional and behavioural problems (ultimate intervention aim). Children from 254 families were randomly assigned to the intervention or a control condition. Parents and children completed questionnaires at baseline and 3 and 6 months later. Emotional and behavioural problems of intervention group children were also assessed 1 year after the start. Univariate analyses of variance showed that children in the intervention group experienced a greater decrease in negative cognitions and sought more social support, immediately after participation and 3 months later, as compared to control group children. They also remained stable in their feelings of social acceptance (competence aspect) immediately after the intervention, whereas these feelings declined in control group children. The intervention and control groups both improved over time in terms of cognitions, competence, parent-child interaction and emotional and behavioural problem scores. Additional improvement in terms of problem scores was found in the intervention group 1 year after baseline. Further enhancement of effectiveness requires re-consideration of the support group goals; it should be studied whether the goals reflect the most important and influential risk and protective factors for this specific population. Besides, effects should be studied over a longer period. PMID- 24072524 TI - CDOM fluorescence as a proxy of DOC concentration in natural waters: a comparison of four contrasting tropical systems. AB - Chromophoric dissolved organic matter (CDOM) fluorescence or absorption is often proposed as a rapid alternative to chemical methods for the estimation of bulk dissolved organic carbon (DOC) concentration in natural waters. However, the robustness of this method across a wide range of systems remains to be shown. We measured CDOM fluorescence and DOC concentration in four tropical freshwater and coastal environments (estuary and coastal, tropical shallow lakes, water from the freshwater lens of two small islands, and soil leachates). We found that although this method can provide an estimation of DOC concentration in sites with low variability in DOC and CDOM sources in systems where the variability of DOC and CDOM sources are high, this method should not be used as it will lead to errors in the estimation of the bulk DOC concentration. PMID- 24072525 TI - Effects of changing forest land definitions on forest inventory on the West Coast, USA. AB - A key function of forest inventory is to detect changes in the area of forest land over time, yet different definitions of forest land are used in different regions of the world. Changes in the definition of forest intended to improve international consistency can affect the ability to quantify true changes over time. The objective of this study was to evaluate the effects of a definitional change from relative stocking to canopy cover on the area classified as forest land and its relationship to species and forest density in California, Oregon, and Washington. Both western Juniper and ponderosa pine will yield higher estimates of forest land area using a canopy cover definition in comparison to a stocking-based definition, with the difference being most pronounced where land is marginally forested. The change in definition may result in an additional 146,000 ha of forest land identified on the West Coast. Measuring marginal forest lands with both metrics for the first cycle after implementation should make it possible to distinguish real change from definitional change. PMID- 24072526 TI - The effects of railway transportation on the enrichment of heavy metals in the artificial soil on railway cut slopes. AB - Heavy metal contamination in the artificial soils on the railway cut slopes may have great influence on the revegetation of the cut slopes. The purpose of this study was to assess the variation of heavy metal contamination levels with railway operation time and analyze their possible resources. A total of 100 soil samples from four cut slopes, which were affected by railway transportation for different years, were analyzed for metal pollution (Cd, Pb, Cr, Cu, Zn, Fe). The concentrations of Cd, Pb showed increasing trend with increasing operation time of railways, while such trend was not found in Cr, Cu, Zn, Fe. According to the soil quality standard of China, Cd was considered to have considerable contamination, while Pb has less, but Cr, Cu, Zn, Fe have none. Moreover, cadmium exhibited remarkably higher levels rather than those reported in other studies. Enrichment factors and ecological index showed that Cd and Pb showed a moderate enrichment and a considerable ecological risk in most of the soil samples. The results of descriptive statistic, principal component analysis, cluster analysis and correlation analysis were totally consistent with each other. Their results revealed that Cr, Cu, Zn and Fe had common origins, and they may come from natural resources. While Cd and Pb were significantly influenced by railway transportation, leaked cargos, fuel combustion, the use of lubricate oils and sleeper impregnation oils during railway transportation may be their main resources. PMID- 24072527 TI - Health risk assessment of mercury and arsenic associated with consumption of fish from the Persian Gulf. AB - Concentrations of mercury and arsenic in fish from the Persian Gulf were determined by graphite furnace atomic absorption spectrometry. Concentrations of the metals in muscle samples were 0.049-0.402 MUg g(-1) for mercury and 0.168 0.479 MUg g(-1) for arsenic, with means of 0.133 and 0.312 MUg g(-1), respectively. The maximum daily consumption rate (grams per day) and meal consumption limit (meals per month) was calculated to estimate health risks associated with fish consumption. According to the results, the maximum allowable consumption rate varies between 8-56 and 15-96 g/day base on mercury and arsenic content, respectively. The results of this study indicate that the concentration of mercury and arsenic is well below the maximum permissible levels for mercury (0.5 MUg g(-1)) and arsenic (6 MUg g(-1)) according to international standards. PMID- 24072528 TI - Retraction Note: Meyl, K., 2012: Task of the introns, cell communication explained by field physics, Journal of Cell Communication and Signaling 6 (1), 53 58. PMID- 24072529 TI - Portfolio of clinical research in adult cardiovascular disease as reflected in ClinicalTrials.gov. AB - BACKGROUND: Cardiovascular medicine is widely regarded as a vanguard for evidence based drug and technology development. Our goal was to describe the cardiovascular clinical research portfolio from ClinicalTrials.gov. METHODS AND RESULTS: We identified 40 970 clinical research studies registered between 2007 and 2010 in which patients received diagnostic, therapeutic, or other interventions per protocol. By annotating 18 491 descriptors from the National Library of Medicine's Medical Subject Heading thesaurus and 1220 free-text terms to select those relevant to cardiovascular disease, we identified studies that related to the diagnosis, treatment, or prevention of diseases of the heart and peripheral arteries in adults (n = 2325 [66%] included from review of 3503 potential studies). The study intervention involved a drug in 44.6%, a device or procedure in 39.3%, behavioral intervention in 8.1%, and biological or genetic interventions in 3.0% of the trials. More than half of the trials were postmarket approval (phase 4, 25.6%) or not part of drug development (no phase, 34.5%). Nearly half of all studies (46.3%) anticipated enrolling 100 patients or fewer. The majority of studies assessed biomarkers or surrogate outcomes, with just 31.8% reporting a clinical event as a primary outcome. CONCLUSIONS: Cardiovascular studies registered on ClinicalTrials.gov span a range of study designs. Data have limited verification or standardization and require manual processes to describe and categorize studies. The preponderance of small and late phase studies raises questions regarding the strength of evidence likely to be generated by the current portfolio and the potential efficiency to be gained by more research consolidation. PMID- 24072530 TI - Racial differences in the prevalence and outcomes of atrial fibrillation among patients hospitalized with heart failure. AB - BACKGROUND: The intersection of heart failure (HF) and atrial fibrillation (AF) is common, but the burden of AF among black patients with HF is poorly characterized. We sought to determine the prevalence of AF, characteristics, in hospital outcomes, and warfarin use associated with AF in patients hospitalized with HF as a function of race. METHODS AND RESULTS: We analyzed data on 135 494 hospitalizations from January 2006 through January 2012 at 276 hospitals participating in the American Heart Association's Get With The Guidelines HF Program. Multivariable logistic regression models using generalized estimating equations approach for risk-adjusted comparison of AF prevalence, in-hospital outcomes, and warfarin use. In this HF population, 53 389 (39.4%) had AF. Black patients had markedly less AF than white patients (20.8% versus 44.8%, P < 0.001). Adjusting for risk factors and hospital characteristics, black race was associated with significantly lower odds of AF (adjusted odds ratio 0.52, 95% CI 0.48 to 0.55, P < 0.0001). There were no racial differences in in-hospital mortality; however, black patients had a longer length of stay relative to white patients. Black patients compared with white patients with AF were less likely to be discharged on warfarin (adjusted odds ratio 0.76, 95% CI 0.69 to 0.85, P < 0.001). CONCLUSIONS: Despite having many risk factors for AF, black patients, relative to white patients hospitalized for HF, had a lower prevalence of AF and lower prescription of guideline-recommended warfarin therapy. PMID- 24072531 TI - Loss of cellular inhibitor of apoptosis protein 2 reduces atherosclerosis in atherogenic apoE-/- C57BL/6 mice on high-fat diet. AB - BACKGROUND: Cellular inhibitor of apoptosis protein 2 (cIAP2) is predicted to participate in atherosclerosis; however, its direct role in atherosclerosis development has not been investigated. We aimed to examine and assess the loss of cIAP2 on atherosclerosis lesion development. METHODS AND RESULTS: We used apoE-/- C57BL/6 male mice, either cIAP2-/- or cIAP2+/+. At 8 weeks, mice were fed a high fat diet (HFD) for 4 and 12 weeks. Aortic root was serially sectioned and stained with Sudan IV, CD68, alpha-actin, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). cIAP2-/- mice displayed a significant decrease in atherosclerotic lesion's macrophage number after 4 weeks of HFD. Similarly, decrease in lesion area at 4 and 12 weeks HFD was detected by use of en face analysis (cIAP2-/- 0.58 +/- 0.37% versus cIAP2+/+ 1.51 +/- 0.79% [P = 0.0056]); (cIAP2-/- 9.34 +/- 4.88% versus cIAP2+/+ 17.65 +/- 6.24% [P = 0.0019]). Aortic root lesion area after 4 and 12 weeks of HFD also decreased (cIAP2-/- 0.0328 +/- 0.014 mm2 versus cIAP2+/+ 0.0515 +/- 0.021 mm2 [P = 0.022]); (cIAP2-/- 0.3614 +/- 0.1157 mm2 versus cIAP2+/+ 0.4901 +/- 0.125 mm2 [P = 0.065]). TUNEL analysis after 4 and 12 weeks of HFD showed a 2.5-fold increase in TUNEL+ cells (cIAP2-/- 4.47 +/- 2.26% versus cIAP2+/+ 1.74 +/- 0.98% [P = 0.036]); (cIAP2-/- 2.39 +/- 0.75% versus cIAP2+/+ 1.29 +/- 0.47% [P = 0.032]). Smooth muscle cell content in cIAP2-/- mice was 3.075 +/- 3.3% compared with cIAP2+/+ with 0.085 +/- 0.1% (P = 0.0071). CONCLUSIONS: Results uncover a key role for cIAP2 in atherosclerotic lesion development, and targeting it may represent a novel therapeutic strategy. PMID- 24072532 TI - Clopidogrel use is associated with an increased prevalence of cerebral microbleeds in a stroke-free population: the Rotterdam study. AB - BACKGROUND: Although clopidogrel reduces the incidence of atherothrombotic events, its use is associated with an increased risk of major bleeding. Cerebral microbleeds (CMBs) are indicative of subclinical microangiopathy in the brain and may prelude symptomatic intracerebral hemorrhage. We examined the association between use of clopidogrel and CMBs in persons without a history of stroke. METHODS AND RESULTS: We performed a cross-sectional analysis using data from the Rotterdam Study, a prospective population-based cohort of persons aged 45 years and older. Among 4408 stroke-free individuals who underwent brain magnetic resonance imaging for the detection of CMBs, we identified 121 ever-users and 4287 never-users of clopidogrel before magnetic resonance imaging. We used multiple logistic regression to analyze the association between clopidogrel and CMBs with adjustment for age, sex, cardiovascular risk factors, and common cardiovascular medication. Users of clopidogrel had a higher prevalence of CMBs (odd ratio 1.55, 95% CI 1.01 to 2.37) than nonusers and more often had a high number (> 4) of CMBs (odds ratio 3.19, 95% CI 1.52 to 6.72). Clopidogrel use was associated with a significantly higher prevalence of deep or infratentorial CMBs (odd ratio 1.90, 95% CI 1.05 to 3.45). Among clopidogrel users, we were unable to demonstrate differences in the prevalence of CMBs by indication of prescription, history of coronary heart disease, or common genetic variants in CYP2C19. CONCLUSIONS: In stroke-free individuals, clopidogrel use was associated with a higher prevalence and higher number of CMBs. Whether this association is causal requires confirmation in prospective studies, especially given the small number of participants taking clopidogrel and the possibility of residual confounding in this study. PMID- 24072533 TI - Noninvasive MRI monitoring of the effect of interventions on endothelial permeability in murine atherosclerosis using an albumin-binding contrast agent. AB - BACKGROUND: Endothelial dysfunction promotes atherosclerosis. We investigated whether in vivo magnetic resonance imaging (MRI) using an albumin-binding contrast agent, gadofosveset, could monitor the efficacy of minocycline and ebselen in reducing endothelial permeability and atherosclerotic burden in the brachiocephalic artery of high-fat diet (HFD)-fed ApoE-/- mice. METHODS AND RESULTS: ApoE-/- mice were scanned 12 weeks after commencement of either a normal diet (controls) or an HFD. HFD-fed ApoE-/- mice were either untreated or treated with minocycline or ebselen for 12 weeks. Delayed-enhancement MRI and T1 mapping of the brachiocephalic artery, 30 minutes after injection of gadofosveset, showed increased vessel wall enhancement and relaxation rate (R1, s(-1)) in untreated HFD-fed ApoE-/- mice (R1 = 3.8 +/- 0.52 s(-1)) compared with controls (R1 = 2.15 +/- 0.34 s(-1), P < 0.001). Conversely, minocycline-treated (R1 = 2.7 +/- 0.17 s( 1), P < 0.001) and ebselen-treated (R1 = 2.7 +/- 0.23 s(-1), P < 0.001) ApoE-/- mice showed less vessel wall enhancement compared with untreated HFD-fed ApoE-/- mice. Mass spectroscopy showed a lower gadolinium concentration in the brachiocephalic artery of treated (minocycline = 28.5 +/- 3 MUmol/L, ebselen = 32.4 +/- 4 MUmol/L) compared with untreated HFD-fed ApoE-/- mice (191 +/- 4.8 MUmol/L) (P < 0.02). Both interventions resulted in a lower plaque burden as measured by delayed-enhancement MRI (minocycline = 0.14 +/- 0.02 mm2, ebselen= 0.20 +/- 0.09 mm2), untreated = 0.44 +/- 0.01 mm2; P < 0.001) and histology (minocycline = 0.13 +/- 0.05 mm2, ebselen = 0.18 +/- 0.02 mm2, untreated = 0.32 +/- 0.04 mm2; P < 0.002). Endothelium cells displayed fewer structural changes and smaller gap junction width in treated compared with untreated animals as seen by electron microscopy (minocycline=42.3 +/- 8.4 nm, ebselen = 56.5 +/- 17 nm, untreated = 2400 +/- 39 nm; P < 0.001). Tissue flow cytometry of the brachiocephalic artery showed lower monocyte/macrophage content in both ebselen- and minocycline-treated mice (8.06 +/- 3.2% and 7.62 +/- 1.73%, respectively) compared with untreated animals (20.1 +/- 2.2%) (P = 0.03), with significant attenuation of the proinflammatory Ly6Chigh subtype (untreated mice, 42.64 +/- 6.1% of total monocytes; ebselen, 14.07 +/- 9.5% of total monocytes; minocycline, 26.42 +/- 0.6% of total monocytes). CONCLUSIONS: We demonstrate that contrast enhanced MRI with an albumin-binding contrast agent can be used to noninvasively monitor the effect of interventions on endothelial permeability and plaque burden. Blood albumin leakage could be a surrogate marker for the in vivo evaluation of interventions that aim at restoring endothelial integrity. PMID- 24072534 TI - Validity of cognitive screens for HIV-associated neurocognitive disorder: a systematic review and an informed screen selection guide. AB - Various screening tools have been proposed to identify HIV-Associated Neurocognitive Disorder (HAND). However, there has been no systematic review of their strengths and weaknesses in detecting HAND when compared to gold standard neuropsychological testing. Thirty-five studies assessing HAND screens that were conducted in the era of combination antiretroviral therapy were retrieved using standard search procedures. Of those, 19 (54 %) compared their screen to standard neuropsychological testing. Studies were characterised by a wide variation in criterion validity primarily due to non-standard definition of neurocognitive impairment, and to the demographic and clinical heterogeneity of samples. Assessment of construct validity was lacking, and longitudinal useability was not established. To address these limitations, the current review proposed a summary of the most sensitive and specific studies (>70 %), as well as providing explicit caution regarding their weaknesses, and recommendations for their use in HIV primary care settings. PMID- 24072535 TI - Cardiovascular risk factors in seamen and fishermen: review of literature. AB - BACKGROUND AND AIM: The aim of this study was to evaluate the prevalence of risk factors for cardiovascular disease among sailors and their evolution over time. MATERIALS AND METHODS: This study is a review of the literature from Medline(r) database and the Medicina Maritima journal. With prevalence studies, the overall prevalence was calculated; 2 groups were created according to the study period (1990s vs. 2000s) and compared by c2 test with Mantel-Haenszel correction. RESULTS: Eighteen articles were selected (total: 57,473 European sailors and 327 non-European sailors). Smoking prevalence varied between 37.3 and 72.3%; overweight prevalence between 27.9 and 66.5%; hypertension was between 8.2 and 49.7%; hypercholesterolaemia ("high blood level of cholesterol") variedbetween 25.1 and 42% of the populations studied; between 3.3 and 9.3% of the populations studied suffered from diabetes. Two studies showed a 10-year cardiovascular risk comparable to that of the general population. After calculating with similar studies, the prevalences were 61.4% for smoking, 60.9% for overweight, 30.1% for hypertension, 34.6% for high cholesterol, and 3.6% for diabetes. Smoking prevalence was significantly lower in 2000s (45.4% vs. 61.3%, p < 0.01), those of overweight, hypertension and hypercholesterolaemia were higher (64.1% vs. 47.1%, p < 0.01, and 42.1% vs. 14.8%, p < 0.01, 42.0%vs. 33.9%, p = 0.02). CONCLUSIONS: Modifiable risk factors are the most studied. Smoking tended to decrease in the 2000s. PMID- 24072536 TI - The influence of ship movements on the energy expenditure of fishermen. A study during a North Sea voyage in calm weather. AB - BACKGROUND: Former studies of professional fishing activities have indicated that movements of a ship, in itself, may increase the energy expenditure in addition to the traditional work carried out by fishermen. We have studied the effects of exposure to the ships movement during calm weather by examining the crude relation between the ship movement and the energy expenditure of the fishermen, thus ignoringthe various tasks undertaken on board. MATERIALS AND METHODS: We have recruited 4 fishermen on 2 contemporary steel trawlers who participatedduring the whole study period. Each of 4 participants recorded his activities and health conditions oncean hour in a registration scheme for 4 days. Estimations of energy expenditure were done with a bodymonitoring system (SenseWear Pro 3) carried as an armband, placed at the surface on the right upper arm. Measurements of sea movements were obtained by a gyroscope placed in the vessels wheelhouse during fishing expeditions in the North Sea off the coast of Bergen. Data were analysed by linear regression. RESULTS: The exposure monitored in calm weather conditions was small for all measurements of heelingand pitch being less than 10o for both vessels. However, the fishermen's energy expenditure was influenced by these minor sea motions. Trends were seen in the individual graphs with increasing energy expenditureat higher exposures. CONCLUSIONS: Our data suggest that even the heel and pitch in calm weather have an impact on the fishermen by increasing their energy consumption, but without any observation of discomfort or negative health outcomes. This study has demonstrated the feasibility of the applied methods, which should be repeated with larger samples and in rough weather. PMID- 24072537 TI - Association between nationality and occupational injury risk on Danish non passenger merchant ships. AB - BACKGROUND: Maritime occupational accidents can be determined by several factors, among which human characteristics play a crucial role. Worker's safety behaviour depends on individual physical and mental characteristics as well as on his/her social and cultural background. The aim of this study is to investigate the frequency of workplace injuries in the Danish merchant fleet in the period 2010 2012, and to characterise its nationality dependence. MATERIALS AND METHODS: Occupational injuries data reported from ships registered in the Danish International Ship Register to the Danish Maritime Authority were collected. Publicly available employment data were used to calculate the cumulative incidence rates for Danish, non-Danish European Union (EU) and non-EU employees working on non-passenger ships. Crude injury rates and rates adjusted for occupational status were statistically compared. RESULTS: The majority of accidents happened to Danish and non-EU workers on non-passenger ships. The injury rate varied around 70 per 1000 among Danish seafarers, while the rate for non-Danish employees was about 30 per 1000. Crude and adjusted relative risk was found significantly lower for EU (0.33-0.46;0.26-0.39) and for non-EU (0.41-0.53; 0.54-0.65) workers compared to Danish seafarers. The difference decreased, but remained significant in most cases for serious injuries. CONCLUSIONS: Occupational injury rates show considerable nationality differences as reported from non-passenger ships registered under the Danish flag. The differences can only be partly explained by varying reporting practices. The findings confirm the results of previous studies and point out the need for effective interventions in the high-risk groups. PMID- 24072538 TI - Skin infection by Staphylococcus aureus in a fisherman: difficulty in continuing work on board. AB - BACKGROUND AND AIM: The aim of this study was to understand why an infectious skin disease due to colonisation by Staphylococcus aureus methi-S led to disembarkation of a fisherman for treatment and follow-up. MATERIALS AND METHODS: While discussing this case we have analysed different reasons why the studied fisherman could not be successfully treated on board. RESULTS: A 42-year-old fisherman was first presented with skin lesions while fishing for hake. When the fisherman had developed a fever and exfoliative skin lesions on both hands, the ship's captain called the radio-medical centre for the maritime consultation in Toulouse and for the advice on treatment. After 3 days on penicillin, the fever decreased, but the dermatitis became incapacitating. On his return to shore, the fisherman was hospitalised. Bacteriological swabs of the skin lesion showed colonisation with Staphylococcus aureus methi-S with presence of Panton Valentine leukocidin. Seven-day treatment witha follow-up of antibioticotherapy was necessary to resolve the skin eruption and obtain definitive apyrexia. Treatment ashore was advised because of difficulty in continuing manual work on board whilst suffering from significant skin lesions and also due to fear of contagion. CONCLUSIONS: Skin infection with Staphylococcus aureus methi-S with presence of Panton Valentine leukocidinis difficult to treat on board because of difficulty in carrying out manual work when hands are affected, and also due to slow improvement of dermatitis even when appropriate treatment is undergone. The maritime environment is also a risk factor for skin abrasion, which can lead to secondary colonisation of pathogenic bacteria. PMID- 24072539 TI - The business case for telemedicine. AB - BACKGROUND AND AIM: Following the coming into force of the International Labour Organisation Maritime Labour Convention (ILO/MLC) and International Maritime Organisation Standards for Training, Certification and Watchkeeping, Manila 2010 (IMO/STCW) amendments, the objective of this article is to provide the shipping community with an initial assessment of the economic reasons and business case, in support of both publicly financed and private telemedicine being implemented on board commercial vessels. MATERIALS AND METHODS: It provides the global scale of the requirement, the number of Telemedicine Assistance Services (TMAS) calls handled by participating TMAS, the average direct and indirect costs incurred by both TMAS and ship operators, responding to medical emergencies, and also provides a calculation of the market size of about 760 million Euro/year. It estimates a return on investment per ship, of implementing telemedicine on board to meet the MLC and STCW requirements at less than 1 year. RESULTS AND CONCLUSIONS: 1. There are both financial and soft benefits, such as crew retention and being perceived as a quality employer offering a telemedicine service on board. 2. It is quite possible to obtain a 20% savings to the industry of perhaps 152 million Euro/year from the deployment of telemedicine on board. 3. The deployment of a telemedical service on ships is an opportunity to encourage further cooperation between TMAS and also with the private TMAS sector. 4. There is clearly a great need, on a global basis, for more cooperation, particularly in standardisation of pre-boarding medical files available, the equipmentrequired on board at a minimum, and level of service quality provided. 5. A collection of a common TMAS annual set of normalised statistics from the stakeholders in the maritime industry is needed. Should someone not be tasked with collecting this? 6. Open registries and countries where the private sector only providestele medicine, should be encouraged to work with the global public TMAS system and contribute to its costs? PMID- 24072540 TI - Psychological consequences in victims of maritime piracy: the Italian experience. AB - BACKGROUND AND AIM: Maritime piracy is a worrying phenomenon. Its recurrence in the last few years iscausing several problems to the safety of maritime routes. In spite of the number of seafarers kidnappedand maintained in captivity, psychological/mental disorders developed in victims of these criminal actshave not been investigated. This study has assessed psychological consequences of kidnapping in a groupof Italian seafarers held in captivity from 7 to 10 months. MATERIALS AND METHODS: Four Italian seafarers were examined at the 5th month after release. An initial, semi-structured interview was followed by 2 structured clinical evaluations for assessing the possible presence of psychopathological disorders. Instruments used were the Cognitive Behavioural Assessment (CBA 2.0) and the Clinician-Administered Post Traumatic Stress Disorder (PTSD) Scale (CAPS DX). RESULTS: All victims showed high scores of state anxiety (56.00 +/- 3.36) and social adjustment disorder (12.75 +/- 2.21) to CBA 2.0. Moreover, 3 of them revealed traits of anxiety (58.75 +/- 8.50) and emotionalinstability (8.25 +/- 2.50). Two of them had somatic disorders (63.25 +/- 15.94), depression (17.25 +/- 4.78) and phobic problems (91.00 +/- 7.02). In 3 of 4 victims examined, a PTSD diagnosis was made. Symptomsof recall resulted in higher CAPS-DX (13.00 +/- 4.05) scores. CONCLUSIONS: Traumatic experiences such as being kept in captivity by pirates could entail relevant psychopathological disorders in victims and their families. Quality care interventions, aimed to develop paradigms for resilience training, represent a priority. An international partnerships and collaboration between institutions, clinicians and seafarer organisations can be useful to evaluate psychological conditions of these workers. PMID- 24072541 TI - Prevalence and causes of loss of consciousness in former North Sea occupational divers. AB - BACKGROUND: Loss of consciousness (LOC) is a serious event during diving. The purpose of this study wasto estimate the prevalence and causes of LOC during diving in former North Sea divers, and the impacton health-related quality of life. MATERIALS AND METHODS: Up to 1990 a total of 373 Norwegian offshore divers worked in the North Sea. From 2000 to 2011, 221 of these were referred to the Department of Occupational Medicine at Haukeland University Hospital for examination due to health complaints. They filled in a questionnaire for registration of diving experience and health complaints, including the SF-36 version 1 for the assessment of quality oflife. The questionnaire and the hospital records were systematically reviewed by 2 independent observers. Episodes of LOC during diving and the causes were registered. All participants underwent a clinical neurological examination. Electroencephalogram (EEG) and the event-related brain potential (P300) were recorded. RESULTS: One or more episodes of LOC were reported by 58 of 219 divers. LOC due to gas cut was reportedby 27 of these. Divers having experienced LOC due to gas cut had lower SF-36 sub-scores then the rest of the diving population. EEG and P300 recordings did not differ between the groups. CONCLUSIONS: A high proportion of former Norwegian North Sea divers reported episodes of LOC, for whichgas cut was the most common cause. Both hypoxia and peritraumatic stress associated with the episodecould have a long term impact on the quality of life. Neurophysiological functions, however, did not differbetween the groups. PMID- 24072542 TI - Knowledge and attitudes of Senegalese sailors about HIV/AIDS. AB - BACKGROUND: In West Africa there is little information on the behavior of sailors with respect to HIV/AIDS. AIM: The objective of this study was to assess the knowledge and attitudes on HIV/AIDS and their risk factors. MATERIALS AND METHODS: This was a cross-sectional study on a sample of 400 sailors. Information was collected on knowledge and attitudes. Multiple logistic regression was performed to analyse the factors related to knowledge and attitudes. RESULTS: The mean age was 38.1 +/- 9.8 years. Among sailors, 7.5% knew the 3 main modes of HIV transmissionand 48.3% did not sail with a crew member infected with HIV. Knowledge was related to occupationalcategory (OR = 14.07 [5.40-36.65]). Stigmatisation was related to education (OR = 0.45 [0.27-0.74]) and fear (0.19 [0.09-0.41]). CONCLUSIONS: Sailors have a low level of knowledge and negative attitudes towards people living with HIV. Intervention simplemented must take into account the low level of knowledge and the mobility of the target population. PMID- 24072543 TI - Recommendations for assessing water quality and safety on board merchant ships. AB - INTRODUCTION: Health and diseases on board ships may depend on water. Interventions to improve the quality of water may bring to significant benefits to health and water stores/supply and should be controlledto protect health. This paper has reviewed the main regulations for the control of water safety and qualityon board ships and presents some practical recommendations for keeping water healthy and safe in passenger and cargo merchant ships. METHODOLOGY: The main international regulations and guidelines on the topic were analysed. Guidelines forWater Quality on Board Merchant Ships Including Passenger Vessels of Health Protection Agency, World Health Organisation (WHO) Guide to Ship Sanitation, WHO Guidelines for Drinking Water Quality, WHO Water Safety Plan and the United States Center for Disease Control and Prevention Vessel Sanitation Program were examined. Recommendations for passenger and, if available, for cargo ships were collected and compared. Recommended questionnaire: A questionnaire summarising the main information to collect for assessingthe enough quality of water for the purposes it should be used on board is proposed. The need of havinga crew member with water assessment duties on board, trained for performing these activities properlyis discussed. CONCLUSIONS: Water quality on board ships should be monitored routinely. Monitoring should be directedto chemical and microbiological parameters for identifying possible contamination sources, using specifickits by a designed crew member. More detailed periodic assessments should be under the responsibility ofspecialised personnel/laboratories and should be based on sample collection from all tanks and sites of waterdistribution. It is important to select a properly trained crew member on board for monitoring water quality. PMID- 24072544 TI - Survey on food hygiene knowledge on board ships. AB - BACKGROUND AND AIM: The aim of the study was to evaluate the knowledge and attitudes on food hygiene in seafarers. MATERIALS AND METHODS: The study was conducted using an anonymous questionnaire presented to the workers of 7 tankers of an Italian shipping company (Finaval S.p.A.). As a reference, the analysis was extended to office employees of the same firm. Data were divided according to the rank of seafarers to assess possible differences in perceiving the risk. RESULTS: Overall knowledge on food safety concept was not high among seafarers. In general, galley and catering workers group provided a lower percentage of correct answers than other crew members. Foodservices staff revealed little awareness of the risks linked with handling food and their perception of risk of disease transmission through food was low. Answers about risk related to specific food (eggs and fish) showed that knowledge about these problems was less than satisfactory. Moreover, the percentage of 'I don't know' answers was high. These findings suggest that this personnel is aware of the right stepsof health protection in terms of food hygiene, but does not understand why it is necessary. CONCLUSIONS: Galley and catering group workers were not the most informed about food hygiene problems.This highlights the need to hire qualified personnel of the food industry on board ships. All those working inthe food service area should be properly trained on food hygiene. Seafarers should be the target of specificinformative campaigns about health risks linked with aliments, possible consequences of it and also oneson how to minimise the exposure to potentially dangerous agents/behaviours during travel/life at sea. PMID- 24072545 TI - MENHOB - Mental Health on Board 12th International Symposium on Maritime Health Brest, France, June 6, 2013. PMID- 24072546 TI - Response to letter to the editor by Westerweel et al., entitled 'aspirin in the treatment of decompression sickness: what can we learn from French experience?' [Int Marit Health 2013; 64, 1: 51]. PMID- 24072548 TI - Exercise and the brain: a slap on the HAND. PMID- 24072550 TI - Prevalence of signs and symptoms suggestive of obstructive sleep apnea syndrome in Guangxi, China. AB - BACKGROUND: The prevalence, profiles, and potential risk factors of snoring and obstructive sleep apnea-hypopnea syndrome (OSAHS) in China are largely unknown. OBJECTIVES: This study aims to investigate the prevalence, profiles, and potential risk factors for snoring and OSAHS in Guangxi, China, and the association between OSAHS and ethnicity. METHODS: Urban and rural population based cluster samples were randomly selected in each of eight counties/cities. All residents aged 14 years or older in the selected clusters were interviewed using a standardized questionnaire. A subject was considered to have clinically diagnosed OSAHS if snoring was loud and habitual, breathing pauses were observed, and the subject experienced excessive daytime sleepiness. RESULTS: Among 12,742 sampled subjects, 10,819 completed the questionnaire (response rate = 84.9%). The overall OSAHS prevalence was 4.1% (men, 5.7% (5.1-6.3%); women, 2.4% (2.0-2.9%); Zhuang people, 3.2% (2.8-3.7%); Han people 6.0% (5.2-6.8%).The overall rate of habitual snoring was 11.5 % (men, 17.1% (16.1-18.1%); women, 5.6% (5.0-6.2%)). Univariate analysis showed that the OSAHS prevalence was significantly higher among the following groups: urban residents, elderly individuals, smokers, drinkers, those with higher body mass indexes (BMI), those with more years of schooling, those with nasal problems, those whose parents are Han, and those who usually sleep in prone position. However, multiple logistic regression analysis revealed that only urban residency, age, smoking status, drinking status, and BMI were the risk factors for OSAHS. CONCLUSIONS: OSAHS is prevalent in individuals aged 14 years or older in Guangxi, China. Han and Zhuang people differ significantly in their obstructive sleep apnea (OSA) prevalence, but this difference is explained by the combination of classic OSA risk factors. PMID- 24072551 TI - Tracheal intubation in patients with odentogenous abscesses and reduced mouth opening. AB - BACKGROUND: Odentogenous abscesses with involvement of the facial or cervical spaces can be life-threatening and often have to be drained under general anaesthesia. Trismus and swelling can make intubation with a Macintosh laryngoscope difficult or even impossible. However, indirect laryngoscopy has been successful when conventional direct laryngoscopy has failed. Therefore, we evaluated the efficacy of the Glidescope laryngoscope in patients with odentogenous abscesses and the improvement in mouth opening after neuromuscular block. METHODS: After approval of the ethics committee, 100 patients with odentogenous abscesses were randomized to undergo tracheal intubation with the Glidescope or Macintosh laryngoscope. Success rate, visualization of the glottis, intubation duration, and need for supporting manoeuvres were evaluated. RESULTS: Intubation with the Glidescope was always successful, while conventional intubation failed in 17 out of 50 patients (P<0.0001). In all patients in whom conventional tracheal intubation failed, a subsequent attempt with the Glidescope was successful. The view at the glottis (according to Cormack and Lehane; P<0.0001), intubation duration [34 s (CI 27-41) vs 67 s (CI 52-82), mean (95% confidence interval); P=0.0001], and need for supporting manoeuvres (P<0.0001) were significantly different. The inter-incisor distance improved overall with induction of anaesthesia from 2.0 cm (CI 1.8-2.2) to 2.6 cm (CI 2.3-2.9; P<0.0001) and was correlated with the duration of symptoms. CONCLUSIONS: In patients with odentogenous abscesses, the use of a Glidescope laryngoscope was associated with significantly faster tracheal intubation, with a better view, fewer supporting manoeuvres, and a higher success rate than with a conventional laryngoscope. Improvement of the inter-incisor distance after induction of anaesthesia correlated with the duration of symptoms. PMID- 24072552 TI - Birt-Hogg-Dube syndrome. PMID- 24072553 TI - Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes. AB - Preimplantation genetic diagnosis (PGD) allows couples to avoid having a child with an inherited condition, potentially reducing cancer burden in families with a hereditary cancer predisposition. This study investigated and compared awareness and acceptance of PGD among patients with different hereditary cancer syndromes. Questionnaires were mailed to 984 adults with hereditary breast and ovarian cancer, Lynch syndrome, familial adenomatous polyposis, or multiple endocrine neoplasia type 1 or 2. Associations between clinical, demographic, and psychosocial factors and awareness and acceptance of PGD were examined. Of 370 respondents (38 % return rate), 28 % felt their syndrome impacted family planning, 24 % were aware of PGD, 72 % felt that PGD should be offered, 43 % would consider using PGD, and 29 % were uncertain. Family experience and syndrome specific characteristics, such as disease severity, quality of life and availability of medical interventions as well as gender, family planning stage, and religiosity impact perceptions of the acceptability of PGD, though a high level of uncertainty exists. Hereditary cancer patients lack awareness of PGD despite feeling that PGD should be offered, highlighting the need for education on this topic. While we found attitudes about the acceptability of PGD to be generally similar to those reported in the literature and of genetics and ethics experts, we observed similarities and differences between syndromes that provide insight into why some hereditary cancer patients may find PGD more acceptable than others. PMID- 24072549 TI - Drastic changes in aquatic bacterial populations from the Cuatro Cienegas Basin (Mexico) in response to long-term environmental stress. AB - Understanding the changes of aquatic microbial community composition in response to changes in temperature and ultraviolet irradiation is relevant for predicting biogeochemical modifications in the functioning of natural microbial communities under global climate change scenarios. Herein we investigate shifts in the bacterioplankton composition in response to long-term changes in temperature and UV radiation. For this purpose, 15 mesocosms were seeded with composite aquatic microbial communities from natural pools within the Cuatro Cienegas Basin (Mexican Chihuahuan desert) and were subject to different temperatures and UV conditions. 16S rRNA gene clone libraries were obtained from water samples at the mid-point (4 months) and the end of the experiment (8 months). An increase in bacterial diversity over time was found in the treatment of constant temperature and UV protection, which suggests that stable environments promote the establishment of complex and diverse bacterial community. Drastic changes in the phylogenetic bacterioplankton composition and structure were observed in response to fluctuating temperature and increasing UV radiation and temperature. Fluctuating temperature induced the largest decrease of bacterial richness during the experiment, indicating that frequent temperature changes drive the reduction in abundance of several species, most notably autotrophs. The long-term impact of these environmental stresses reduced diversity and selected for generalist aquatic bacterial populations, such as Porphyrobacter. These changes at the community level occur at an ecological time scale, suggesting that under global warming scenarios cascade effects on the food web are possible if the microbial diversity is modified. PMID- 24072556 TI - High reliability in respiratory rate assessment in children with respiratory symptomatology in a rural area in Mozambique. AB - Early recognition of severe medical conditions is often based on clinical scores and vital sign measurements such as the respiratory rate (RR) count. We designed this study to determine the reliability of RR assessment counted three times during a full minute by independent observers in children in a developing country setting. A total of 55 participants were enrolled in the study. Participant ages ranged from 10 days to 7 years (median 22 months). Agreement for RR count was high (intraclass correlation coefficient of 0.95; 95% confidence interval: 0.93 0.97). Agreement for presence of tachypnea was also high (Kappa coefficient of 0.83, p < 0.001). However, a single reading would have misclassified 5-11% of the participants as non-tachypneic. Repeated RR counts offer reliable results if done during a full minute. Patients not fulfilling tachypnea criterion but with a high RR count should have the measurement repeated. PMID- 24072555 TI - Paricalcitol downregulates myocardial renin-angiotensin and fibroblast growth factor expression and attenuates cardiac hypertrophy in uremic rats. AB - BACKGROUND: Vitamin D attenuates uremic cardiac hypertrophy, possibly by suppressing the myocardial renin-angiotensin system (RAS) and fibroblast growth factors (FGFs). We compared the suppression of cardiac hypertrophy and myocardial expression of RAS and FGF receptor genes offered by the vitamin D analog paricalcitol (Pc) or the angiotensin-converting enzyme inhibitor enalapril (E) in experimental uremia. METHODS: Rats with 5/6 nephrectomy received Pc or E for 8 weeks. Renal function, systolic blood pressure, and cardiac hypertrophy were evaluated. Myocardial expression of RAS genes, brain natriuretic peptide (BNP), and FGF receptor-1 (FGFR-1) were determined using quantitative reverse transcription (pRT)-PCR. RESULTS: Blood pressure, proteinuria, and serum creatinine were significantly higher in untreated uremic animals. Hypertension was significantly reduced by E but only modestly by Pc; however, cardiac hypertrophy in the untreated group was similarly attenuated by Pc or E. Upregulation of myocardial expressions of renin, angiotensinogen, FGFR-1, and BNP in untreated uremic animals was reduced similarly by Pc and E, while the angiotensin II type 1 receptor was downregulated only by E. CONCLUSIONS: Uremic cardiac hypertrophy is associated with activation of the myocardial RAS and the FGFR-1. Downregulation of these genes induced by Pc and E results in similar amelioration of left ventricular hypertrophy despite the different antihypertensive effects of these drugs. PMID- 24072554 TI - A knowledge-based halogen bonding scoring function for predicting protein-ligand interactions. AB - Halogen bonding, a non-covalent interaction between the halogen sigma-hole and Lewis bases, could not be properly characterized by majority of current scoring functions. In this study, a knowledge-based halogen bonding scoring function, termed XBPMF, was developed by an iterative method for predicting protein-ligand interactions. Three sets of pairwise potentials were derived from two training sets of protein-ligand complexes from the Protein Data Bank. It was found that two-dimensional pairwise potentials could characterize appropriately the distance and angle profiles of halogen bonding, which is superior to one-dimensional pairwise potentials. With comparison to six widely used scoring functions, XBPMF was evaluated to have moderate power for predicting protein-ligand interactions in terms of "docking power", "ranking power" and "scoring power". Especially, it has a rather satisfactory performance for the systems with typical halogen bonds. To the best of our knowledge, XBPMF is the first halogen bonding scoring function that is not dependent on any dummy atom, and is practical for high-throughput virtual screening. Therefore, this scoring function should be useful for the study and application of halogen bonding interactions like molecular docking and lead optimization. PMID- 24072557 TI - Are preterm infants at high altitude at greater risk for the development of bronchopulmonary dysplasia? AB - OBJECTIVES: To assess the association between altitudes of neonatal intensive care units (NICUs) and the incidence of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: Data from infants born at <32 weeks' gestation admitted to NICUs at high altitude (2200 m above sea level) between 2002 and 2011 were analyzed and compared with the data from a lower altitude NICU in Saudi Arabia. RESULTS: Of 942 preterm infants admitted to the high altitude NICUs, 266 (28.2%) infants developed BPD. The incidence of BPD was significantly higher in infants admitted to the NICU at high altitude than in those at lower altitude (28.2 vs. 17.7%, respectively, p = 0.003). In multivariable analysis, high altitude was significantly associated with a higher risk of BPD (odds ratio: 0.54, 95% confidence interval: 0.36-0.81). CONCLUSION: Findings suggest that high altitude may increase the risk of BPD development among preterm infants. PMID- 24072558 TI - Progress and future aspects in genetics of human hypertension. AB - Hypertension has become a major global health burden due to its high prevalence and associated increase in risk of cardiovascular disease and premature death. It is well established that hypertension is determined by both genetic and environmental factors and their complex interactions. Recent large-scale meta analyses of genome-wide association studies (GWAS) have successfully identified a total of 38 loci which achieved genome-wide significance (P < 5 * 10(-8)) for their association with blood pressure (BP). Although the heritability of BP explained by these loci is very limited, GWAS meta-analyses have elicited renewed optimism in hypertension genomics research, highlighting novel pathways influencing BP and elucidating genetic mechanisms underlying BP regulation. This review summarizes evolving progress in the rapidly moving field of hypertension genetics and highlights several promising approaches for dissecting the remaining heritability of BP. It also discusses the future translation of genetic findings to hypertension treatment and prevention. PMID- 24072559 TI - Uric acid, hypertension, and cardiovascular and renal complications. AB - Over the last decade, the biologic interference of uric acid with the cardiovascular (CV) system and the kidney has been intensively investigated, and several experimental studies in animal models and in vitro documented that hyperuricemia may trigger hypertension and incite endothelial dysfunction, vascular damage and renal disease. A substantial proportion of epidemiological studies are compatible with the hypothesis that hyperuricemia may be noxious to the CV system and the kidney as well. However, there are still no well-powered trials testing whether uric acid-lowering interventions may reduce BP or attenuate the risk for adverse CV and renal outcomes. Evidence still remains largely insufficient to recommend changes in the current policy of not prescribing uric acid-lowering drugs to individuals with asymptomatic hyperuricemia. PMID- 24072560 TI - Adapting collaborative depression care for public community long-term care: using research-practice partnerships. AB - This manuscript details potential benefits for using a research-practice partnership to adapt collaborative depression care for public community long-term care agencies serving older adults. We used sequential, multi-phase, and mixed methods approaches for documenting the process of adaptation within a case study. Systematic adaptation strategies are described, such as leveraging long-term research-practice collaborations, consulting with multiple stakeholders across all levels and disciplines, and balancing demands to monitor treatment fidelity, clinical outcomes, and implementation results. These examples demonstrate that researchers interested in implementation science need skills to negotiate the competing demands that arise from both the research and practice settings. PMID- 24072562 TI - Proposal for a new nomenclature of disease-modifying antirheumatic drugs. AB - In light of the recent emergence of new therapeutics for rheumatoid arthritis, such as kinase inhibitors and biosimilars, a new nomenclature for disease modifying antirheumatic drugs (DMARDs), which are currently often classified as synthetic (or chemical) DMARDs (sDMARDS) and biological DMARDs (bDMARDs), may be needed. We propose to divide the latter into biological original and biosimilar DMARDs (boDMARDs and bsDMARDs, respectively, such as abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab or tocilizumab, but also emerging ones like clazakizumab, ixekizumab, sarilumab, secukinumab or sirukumab) and the former into conventional synthetic and targeted synthetic DMARDs (csDMARDs and tsDMARDs, respectively). tsDMARDs would then constitute only those that were specifically developed to target a particular molecular structure (such as tofacitinib, fostamatinib, baricitinib or apremilast, or agents not focused primarily on rheumatic diseases, such as imatinib or ibrutinib), while csDMARDs would comprise the traditional drugs (such as methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, gold salts and others). The proposed nomenclature may provide means to group and distinguish the different types of DMARDs in clinical studies and review articles. PMID- 24072561 TI - Tackling gliomas with nanoformulated antineoplastic drugs: suitability of hyaluronic acid nanoparticles. PMID- 24072563 TI - Temperature has a reduced effect on routine metabolic rates of juvenile shortnose sturgeon (Acipenser brevirostrum). AB - This study examined the effects of acclimation temperature (10, 15, 20, or 25 degrees C) and an acute exposure to various temperatures on the routine metabolism of juvenile (~11 g) shortnose sturgeon (Acipenser brevirostrum). For the acclimation experiment, the minimum, mean, and maximum routine metabolic rates were established for sturgeon at each temperature. Mean routine metabolic rates for 10, 15, 20, and 25 degrees C were 134, 277, 313, and 309 mg O2 kg(-1) h(-1), respectively, with significant differences occurring between 10 and 15, 10 and 20, and 10 and 25 degrees C. For the acute exposure, similar patterns and significant differences were observed. Temperature quotient (Q 10) values indicate that the greatest effect of temperature occurred between 10 and 15 degrees C for both the acclimation and acute temperature experiments. In addition, the effect of temperature on the metabolic rate of sturgeon was nearly negligible between 15 and 25 degrees C. These results suggest that juvenile shortnose sturgeon are sensitive to temperature changes at the lower end of the range, and less sensitive in the mid-to-upper temperature range. PMID- 24072564 TI - Parent-child relationships, parental psychological control, and aggression: maternal and paternal relationships. AB - Few studies have examined both maternal and paternal parenting practices in the prediction of child outcomes despite evidence that underscores the salience of fathers throughout their children's development. This study examined the role of the quality of mother-child and father-child relationships in buffering the influence of ineffective parenting practices on subsequent adolescent aggression. Measures of parental psychological control, the quality of the parent-child relationship, and youth aggressive behavior were completed by 163 (49 % female) mostly White and Asian adolescents and their parents during the eighth and ninth grades. Paternal psychological control predicted aggression when adolescents perceived low-quality relationships with their mothers. Similarly, maternal psychological control predicted aggression when adolescents perceived low-quality relationships with their fathers. Maternal psychological control was also associated with lower levels of aggression among adolescent males who reported a high-quality relationship with their father. These findings indicate that, when one parent exerts psychological control, the low-quality relationship the adolescent shares with the opposite gender parent increases risk for adolescent aggression. The findings also suggest that, as mothers exert psychological control, the high-quality parent-child relationship a son shares with his father decreases risk for adolescent aggression. PMID- 24072566 TI - Contextualising the biology of psychiatry within its social environment. PMID- 24072565 TI - Inhibition of ubiquitin conjugating enzyme UBE2C reduces proliferation and sensitizes breast cancer cells to radiation, doxorubicin, tamoxifen and letrozole. AB - PURPOSE: The objective of this study was to determine radiation, doxorubicin, tamoxifen and letrozole sensitivity of breast cancer cells in response to functional inhibition of the ubiquitin conjugating enzyme UBE2C. METHODS: Taqman Real time PCR was performed to measure UBE2C levels in breast cancer cell lines and control HBL100 and HEK293T cells. A dominant negative form of UBE2C (DN UBE2C) was used to functionally inhibit wild type UBE2C. Cell proliferation and anchorage independent growth were measured by colorimetric and soft agar assays, respectively. Radiation, doxorubicin, tamoxifen and letrozole responses of the cell lines were assessed by colorimetric and clonogenic assays. RESULTS: Overexpression of UBE2C was observed in all breast cancer cell lines tested using quantitative real time PCR. UBE2C expression was found to be highest in MDAMB231 and relatively lowest in MCF7 cells, compared to control cells. Both the growth rate and the anchorage independent growth of MCF7 and MDAMB231 cells transfected with DN-UBE2C were significantly reduced compared to cells transfected with vector alone. MCF7 and MDAMB231 cells expressing DN-UBE2C were significantly more sensitive to different doses of radiation and doxorubicin compared to both wild type and vector alone transfected cells. In addition, DN-UBE2C transfected MCF7 cells were more sensitive to inhibition by tamoxifen and letrozole compared to wild type and vector alone transfected cells. CONCLUSIONS: Our results show that inhibition of UBE2C sensitizes breast cancer cells to radiation, doxorubicin and hormone blocking agents. UBE2C may, therefore, serve as a potential therapeutic target aimed at inducing radiation and chemo sensitization. PMID- 24072567 TI - Making up schizoaffective disorder: cosmetic changes to a sad creation? PMID- 24072568 TI - Will DSM-5 make us feel dysphoric? Conceptualisation(s) of dysphoria in the most recent classification of mental disorders. PMID- 24072570 TI - A qualitative and quantitative study of mites in similar alfalfa fields in Greece. AB - The present study investigated the mite fauna and the relative abundance of mites present in foliage and litter of two adjacent and similar alfalfa fields, differing only in the number of cuttings, in Kopais Valley (Central Greece) through 2008-2010. We also examined the relationship between assemblage patterns of Mesostigmata, Oribatida and Prostigmata by comparing their population fluctuation, population density, species richness and diversity. Spatial distribution of common dominant and influent mite species was also estimated. Our results showed that both fields supported a very rich and similar mite fauna with eight new species records for alfalfa of Greece, although these species have been previously reported from other habitats in Greece. The pattern of population fluctuation in foliage was similar in both fields, unlike the fluctuation in litter. Population density significantly differed between fields, being higher in the less harvested field, except Prostigmata. Species richness in litter was higher in the less harvested field, whereas it was higher in the foliage of the more harvested field, apart from that of prostigmatic mites in litter, which was higher in the more harvested field, and that of oribatid mites in foliage, which was higher in the less harvested field. The diversity of mites was higher in the more harvested field, with the exception of prostigmatic mites. The spatial distribution of mites in foliage and litter was aggregated in both fields. Our results indicate that despite the considerable similarity of the study fields, the different harvesting frequency might have disturbed differently the mite communities hosted in foliage and litter. PMID- 24072569 TI - Infectious complications of immune modulatory agents. AB - Immune modulatory agents used in solid organ transplantation and other disciplines have various mechanisms of action and differences in the duration and intensity of immunosuppression. While newer agents have improved patient outcomes, an important result of these immune modulatory agents is associated infections, caused by organisms such as cytomegalovirus, BK polyomavirus, Epstein Barr virus and tuberculosis. Herein, we review the infectious complications of several newer immune modulatory drugs-belatacept, alemtuzumab, and rituximab-and focus on their use in solid organ transplantation. New immune modulatory agents can potentially modify the landscape of allograft rejection and noninfectious and infectious complications. Health-care practitioners should remain familiar with these agents and their potential infectious complications to help ensure optimal patient outcomes. PMID- 24072571 TI - Point of care testing: evolving scenarios and innovative perspectives. PMID- 24072572 TI - Stabilization of glucose in blood samples: out with the old, in with the new. PMID- 24072573 TI - Sampling and storage conditions influencing the measurement of parathyroid hormone in blood samples: a systematic review. AB - Parathyroid hormone (PTH) is relatively unstable: optimisation of pre-analytical conditions, including specimen type, sampling time and storage conditions, is essential. We have undertaken a systematic review of these pre-analytical conditions. An electronic search of the PubMed, Embase, Cochrane, Centre for Research and Dissemination and Bandolier databases was undertaken. Of 5511 papers identified, 96 underwent full text review, of which 83 were finally included. At room temperature PTH was stable in ethylenediaminetetraacetic acid (EDTA) preserved whole blood for at least 24 h and in EDTA plasma for at least 48 h after venepuncture. Losses were observed in clotted blood samples after 3 h and in serum after 2 h. At 4 degrees C PTH was more stable in EDTA plasma (at least 72 h) than serum (at least 24 h). Central venous PTH concentrations were higher than peripheral venous concentrations. In the northern hemisphere, PTH concentrations were higher in winter than summer. PTH has a circadian rhythm characterised by a nocturnal acrophase and mid-morning nadir. Data related to frozen storage of PTH (-20 degrees C and -80 degrees C) were limited and contradictory. We recommend that blood samples for PTH measurement should be taken into tubes containing EDTA, ideally between 10:00 and 16:00, and plasma separated within 24 h of venepuncture. Plasma samples should be stored at 4 degrees C and analysed within 72 h of venepuncture. Particular regard must be paid to the venepuncture site when interpreting PTH concentration. Further research is required to clarify the suitability of freezing samples prior to PTH measurement. PMID- 24072574 TI - A systematic review of data on biological variation for alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase. AB - BACKGROUND: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) are enzymes measured in serum or plasma to investigate liver disease. The aim of this work is to assess the validity of published biological variation (BV) data currently available for these enzymes. METHODS: Publications containing BV data for ALT, AST and GGT were identified by searching PubMed using the following keywords: biological varia*, RCV, CV(w), CV(i), CV(b), and CV(g). The 95% confidence intervals for the within- and between subject coefficients of variation were calculated using the analytical imprecision, the number of subjects, samples and replicates. RESULTS: The searches identified 10 publications with ALT, 14 with AST and nine with GGT data. The protocols presented in those publications as used were varied. The ranges of within-subject variation reported were: ALT: 11.1%-58.1%, AST: 3.0%-32.3% and for GGT: 3.9%-14.5%. The median values (ALT: 18.0%, AST: 11.9% and GGT: 13.8%) were similar to those listed in a BV database commonly used as a reference source. CONCLUSIONS: Published BV data for ALT, AST and GGT demonstrate a wide range of values derived from inconsistent protocols. The quality of the presentations of the data is variable. These findings raise concerns around the utility of the data currently available and highlight the need for critical appraisal of such publications. The working group on BV of the European Federation of Clinical Chemistry and Laboratory Medicine is undertaking work to develop a critical appraisal checklist for the production and publication of reliable BV data. PMID- 24072575 TI - IDS iSYS automated intact procollagen-1-N-terminus pro-peptide assay: method evaluation and reference intervals in adults and children. AB - BACKGROUND: We carried out a technical evaluation of the Immunodiagnostic Systems (IDS) automated intact procollagen-I N-terminus propeptide (PINP) assay on the iSYS platform, and established reference intervals for PINP in both adults and children. METHODS: Assay imprecision, recovery and interference were studied. Serum and plasma values were compared, and PINP stability was assessed. Using 828 specimens, IDS iSYS intact PINP and Roche E170 total PINP values were compared. Specimens from 597 adults and 485 children and adolescents were used to establish reference intervals for intact PINP. RESULTS: The method demonstrated good recovery and acceptable imprecision. The assay was unaffected by icterus and lipaemia, but haemolysis decreased measured PINP. Serum and plasma values were comparable. There was a non-linear relation between IDS intact and Roche total PINP values. Pre- and post-menopausal women had comparable PINP values, but there was a difference between women of different age groups. Serum PINP in men showed a decline in young age up to 45 years, but remained steady thereafter. Separate reference intervals were established for four age groups in women and for two age groups in men. Data for children were partitioned into four-year age groups, and these showed PINP to be high with no major gender differences until 12 years of age. Thereafter, values in females decreased in 13-16 years age groups and further in 17-20 years age groups, whereas PINP increased in boys of 13-16 years of age with a subsequent decline at 17-20 years. CONCLUSIONS: The IDS iSYS PINP intact assay appears to be reliable. We have established gender- and age-related reference intervals for children and adults based on a relatively large healthy North European population. PMID- 24072576 TI - High-sensitivity cardiac troponin T and N-terminal pro-B-type natriuretic peptide predict mortality in stable coronary artery disease: results from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. AB - BACKGROUND: The simultaneous assessment of high-sensitivity cardiac troponin T (hscTnT) and NT-proBNP for predicting death in stable coronary artery disease (CAD) has yet not been examined. We investigated the additional contribution of hscTnT to the risk of mortality prediction of NT-proBNP in patients with stable CAD. METHODS: We studied 1469 patients with stable CAD enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC). hscTnT and NT-proBNP were measured in baseline samples using immunoassays (Roche Diagnostics, Germany). RESULTS: Thirty-five percent (n=525) of the patients died during a median follow-up of 7 and a half years. In total 59.0% of the non-survivors and 25.2% of the survivors exhibited concentrations of hscTnT>=14 ng/L. Logistic regression analysis identified hscTnT and NT-proBNP as independent risk markers for short-term (1-year follow-up) and long-term (9-years follow-up) mortality. ROC curve analysis determined optimal univariate cut-offs at 14 ng/L and 443 ug/L for hscTnT (AUC 0.725, p<0.0001) and NT-proBNP (AUC 0.742, p<0.0001), respectively. Kaplan-Meier survival analysis based on optimized cut-offs for the simultaneous determination of both biomarkers confirmed the usefulness of additive hscTnT especially in prediction of short-term mortality. The prognostic benefit of the combined assessment of hscTnT and NT-proBNP could be confirmed by a significantly increased reclassification index (NRI) of 24.2%. CONCLUSIONS: The majority of non-survivors exhibited increased hscTnT concentrations above 14 ng/L. The simultaneous determination of NT-proBNP and hscTnT was superior for risk stratification compared to determining either marker alone. Especially the prediction of the clinically important 1-year mortality was significantly improved by addition of hscTnT to NT-proBNP. PMID- 24072579 TI - Autoimmune hypothyroidism presenting as pituitary hyperplasia. AB - Pituitary hyperplasia with hyperprolactinemia has been described as a rare presentation of primary hypothyroidism. A 12-y-old child presented with intermittent headache, easy fatigability, coarseness of facial features, and hoarseness of voice for 6 mo duration. Brain imaging findings showed pituitary hyperplasia; hormonal assessment revealed primary hypothyroidism and hyperprolactinemia. Pituitary hyperplasia regressed with thyroid hormone replacement therapy. This report describes an unusual case of pituitary hyperplasia with hyperprolactinemia secondary to primary hypothyroidism. PMID- 24072581 TI - Phloem transport velocity varies over time and among vascular bundles during early cucumber seedling development. AB - We use a novel dye-tracing technique to measure in vivo phloem transport velocity in cucumber (Cucumis sativus) plants during early seedling development. We focus on seedlings because of their importance in plant establishment and because they provide a simple source and sink model of phloem transport. The dye-tracing method uses a photodiode to track the movement of a bleach front of fluorescent dye traveling in the phloem from the cotyledons (source) to the roots (sink). During early seedling development, phloem transport velocity in this direction can change 2-fold depending on vascular connectivity and the number of actively growing sinks. Prior to leaf expansion, vascular bundles attached to the first developing leaf demonstrate a decline in basipetal phloem transport that can be alleviated by the leaf's removal. At this stage, seedlings appear carbon limited and phloem transport velocity is correlated with cotyledon area, a pattern that is apparent both during cotyledon expansion and after source area manipulation. When the first leaf transitions to a carbon source, seedling growth rate increases and basipetal phloem transport velocity becomes more stable. Because bundles appear to operate autonomously, transport velocity can differ among vascular bundles. Together, these results demonstrate the dynamic and heterogeneous nature of phloem transport and underline the need for a better understanding of how changes in phloem physiology impact growth and allocation at this critical stage of development. PMID- 24072580 TI - Kawasaki disease and the emerging coronary artery disease epidemic in India: is there a correlation? AB - Although Kawasaki disease (KD) is now being increasingly reported from India, the vast majority of children with KD are still not being diagnosed and treated. A recent study from Chandigarh has shown that the incidence of KD is at least 4.54/100,000 children below 15 y of age. Extrapolations of this figure suggest that a minimum of 17,417 new cases of KD would be occurring every year in our country. A significant proportion of these children may develop coronary artery abnormalities. These children would then be at risk of developing myocardial ischemia as young adults. It is authors' contention that (undiagnosed) KD in childhood may be contributing to the growing pool of coronary artery disease (CAD) in India. Similarly, a missed diagnosis of KD in childhood should be considered as a possibility while evaluating adults with CAD, especially when there are no overt risk factors and no family history of the disease. PMID- 24072583 TI - Nonparametric estimation with recurrent competing risks data. AB - Nonparametric estimators of component and system life distributions are developed and presented for situations where recurrent competing risks data from series systems are available. The use of recurrences of components' failures leads to improved efficiencies in statistical inference, thereby leading to resource efficient experimental or study designs or improved inferences about the distributions governing the event times. Finite and asymptotic properties of the estimators are obtained through simulation studies and analytically. The detrimental impact of parametric model misspecification is also vividly demonstrated, lending credence to the virtue of adopting nonparametric or semiparametric models, especially in biomedical settings. The estimators are illustrated by applying them to a data set pertaining to car repairs for vehicles that were under warranty. PMID- 24072582 TI - A mathematical model for the coreceptors SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE1 and SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE3 in BRASSINOSTEROID INSENSITIVE1-mediated signaling. AB - Brassinosteroids (BRs) are key regulators in plant growth and development. The main BR-perceiving receptor in Arabidopsis (Arabidopsis thaliana) is BRASSINOSTEROID INSENSITIVE1 (BRI1). Seedling root growth and hypocotyl elongation can be accurately predicted using a model for BRI1 receptor activity. Genetic evidence shows that non-ligand-binding coreceptors of the SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) family are essential for BRI1 signal transduction. A relatively simple biochemical model based on the properties of SERK loss-of-function alleles explains complex physiological responses of the BRI1-mediated BR pathway. The model uses BRI1-BR occupancy as the central estimated parameter and includes BRI1-SERK interaction based on mass action kinetics and accurately describes wild-type root growth and hypocotyl elongation. Simulation studies suggest that the SERK coreceptors primarily act to increase the magnitude of the BRI1 signal. The model predicts that only a small number of active BRI1-SERK complexes are required to carry out BR signaling at physiological ligand concentration. Finally, when calibrated with single mutants, the model predicts that roots of the serk1serk3 double mutant are almost completely brassinolide (BL) insensitive, while the double mutant hypocotyls remain sensitive. This points to residual BRI1 signaling or to a different coreceptor requirement in shoots. PMID- 24072584 TI - Simple estimation procedures for regression analysis of interval-censored failure time data under the proportional hazards model. AB - Interval-censored failure time data occur in many fields including epidemiological and medical studies as well as financial and sociological studies, and many authors have investigated their analysis (Sun, The statistical analysis of interval-censored failure time data, 2006; Zhang, Stat Modeling 9:321 343, 2009). In particular, a number of procedures have been developed for regression analysis of interval-censored data arising from the proportional hazards model (Finkelstein, Biometrics 42:845-854, 1986; Huang, Ann Stat 24:540 568, 1996; Pan, Biometrics 56:199-203, 2000). For most of these procedures, however, one drawback is that they involve estimation of both regression parameters and baseline cumulative hazard function. In this paper, we propose two simple estimation approaches that do not need estimation of the baseline cumulative hazard function. The asymptotic properties of the resulting estimates are given, and an extensive simulation study is conducted and indicates that they work well for practical situations. PMID- 24072585 TI - G2/M cell cycle arrest by an N-acetyl-D-glucosamine specific lectin from Psathyrella asperospora. AB - A new N-acetyl-D-glucosamine (GlcNAc) specific lectin was identified and purified from the fruiting body of the Australian indigenous mushroom Psathyrella asperospora. The functional lectin, named PAL, showed hemagglutination activity against neuraminidase treated rabbit and human blood types A, B and O, and exhibited high binding specificity towards GlcNAc, as well as mucin and fetuin, but not against asialofetuin. PAL purified to homogeneity by a combination of ammonium sulfate precipitation, chitin affinity chromatography and size exclusion chromatography, was monomeric with a molecular mass of 41.8 kDa, was stable at temperatures up to 55 degrees C and between pH 6-10, and did not require divalent cations for optimal activity. De novo sequencing of PAL using LC-MS/MS, identified 10 tryptic peptides that revealed substantial sequence similarity to the GlcNAc recognizing lectins from Psathyrella velutina (PVL) and Agrocybe aegerita (AAL-II) in both the carbohydrate binding and calcium binding sites. Significantly, PAL was also found to exert a potent anti-proliferative effect on HT29 cells (IC50 0.48 MUM) that was approximately 3-fold greater than that observed on VERO cells; a difference found to be due to the differential expression of cell surface GlcNAc on HT29 and VERO cells. Further characterization of this activity using propidium iodine staining revealed that PAL induced cell cycle arrest at G2/M phase in a manner dependent on its ability to bind GlcNAc. PMID- 24072586 TI - Carbon nanotubes in tissue engineering. AB - As a result of their peculiar features, carbon nanotubes (CNTs) are emerging in many areas of nanotechnology applications. CNT-based technology has been increasingly proposed for biomedical applications, to develop biomolecule nanocarriers, bionanosensors and smart material for tissue engineering purposes. In the following chapter this latter application will be explored, describing why CNTs can be considered an ideal material able to support and boost the growth and the proliferation of many kinds of tissues. PMID- 24072587 TI - Protein-protein interactions and multi-component complexes of aminoacyl-tRNA synthetases. AB - Protein-protein interaction occurs transiently or stably when two or more proteins bind together to mediate a wide range of cellular processes such as protein modification, signal transduction, protein trafficking, and structural folding. The macromolecules involved in protein biosynthesis such as aminoacyl tRNA synthetase (ARS) have a number of protein-protein interactions. The mammalian multi-tRNA synthetase complex (MSC) consists of eight different enzymes: EPRS, IRS, LRS, QRS, MRS, KRS, RRS, and DRS, and three auxiliary proteins: AIMP1/p43, AIMP2/p38, and AIMP/p18. The distinct ARS proteins are also connected to diverse protein networks to carry out biological functions. In this chapter we first show the protein networks of the entire MSC and explain how MSC components interact with or can regulate other proteins. Finally, it is pointed out that the understanding of protein-protein interaction mechanism will provide insight to potential therapeutic application for diseases related to the MSC network. PMID- 24072588 TI - Semantic significance: a new measure of feature salience. AB - According to the feature-based model of semantic memory, concepts are described by a set of semantic features that contribute, with different weights, to the meaning of a concept. Interestingly, this theoretical framework has introduced numerous dimensions to describe semantic features. Recently, we proposed a new parameter to measure the importance of a semantic feature for the conceptual representation-that is, semantic significance. Here, with speeded verification tasks, we tested the predictive value of our index and investigated the relative roles of conceptual and featural dimensions on the participants' performance. The results showed that semantic significance is a good predictor of participants' verification latencies and suggested that it efficiently captures the salience of a feature for the computation of the meaning of a given concept. Therefore, we suggest that semantic significance can be considered an effective index of the importance of a feature in a given conceptual representation. Moreover, we propose that it may have straightforward implications for feature-based models of semantic memory, as an important additional factor for understanding conceptual representation. PMID- 24072589 TI - Extraskeletal Ewing's sarcoma arising in the larynx. AB - Extraskeletal Ewing's sarcoma (EES), or primitive neuroectodermal tumor, is an uncommon neoplasm with low incidence in the head and neck. Occurrences in the larynx are even more exceptional with only two previous reported cases of EES arising from the larynx. We report the case of a 45-year-old woman with a laryngeal Ewing's sarcoma treated with chemotherapy with radiotherapy to follow. Here we describe the histology, molecular diagnosis and treatment of this unusual tumor. PMID- 24072590 TI - The putative BH3 mimetic S1 sensitizes leukemia to ABT-737 by increasing reactive oxygen species, inducing endoplasmic reticulum stress, and upregulating the BH3 only protein NOXA. AB - S1 is a putative BH3 mimetic proposed to inhibit BCL2 and MCL1 based on cell-free assays. However, we previously demonstrated that it failed to inhibit BCL2 or induce apoptosis in chronic lymphocytic leukemia (CLL) cells, which are dependent on BCL2 for survival. In contrast, we show here that S1 rapidly increases reactive oxygen species, initiates endoplasmic reticulum stress, and upregulates the BH3-only protein NOXA. The BCL2 inhibitors, ABT-737, ABT-263, and ABT-199, have demonstrated pro-apoptotic efficacy in cell lines, while ABT-263 and ABT-199 have demonstrated efficacy in early clinical trials. Resistance to these inhibitors arises from the upregulation of anti-apoptotic factors, such as MCL1, BFL1, and BCLXL. This resistance can be induced by co-culturing CLL cells on a stromal cell line that mimics the microenvironment found in patients. Since NOXA can inhibit MCL1, BFL1, and BCLXL, we hypothesized that S1 may overcome resistance to ABT-737. Here we demonstrate that S1 induces NOXA-dependent sensitization to ABT-737 in a human promyelocytic leukemia cell line (NB4). Furthermore, S1 sensitized CLL cells to ABT-737 ex vivo, and overcame resistance to ABT-737 induced by co-culturing CLL cells with stroma. PMID- 24072591 TI - Myostatin--the holy grail for muscle, bone, and fat? AB - Myostatin, a member of the transforming growth factor beta (TGF-beta) superfamily, was first described in 1997. Since then, myostatin has gained growing attention because of the discovery that myostatin inhibition leads to muscle mass accrual. Myostatin not only plays a key role in muscle homeostasis, but also affects fat and bone. This review will focus on the impact of myostatin and its inhibition on muscle mass/function, adipose tissue and bone density/geometry in humans. Although existing data are sparse, myostatin inhibition leads to increased lean mass and 1 study found a decrease in fat mass and increase in bone formation. In addition, myostatin levels are increased in sarcopenia, cachexia and bed rest whereas they are increased after resistance training, suggesting physiological regulatory of myostatin. Increased myostatin levels have also been found in obesity and levels decrease after weight loss from caloric restriction. Knowledge on the relationship of myostatin with bone is largely based on animal data where elevated myostatin levels lead to decreased BMD and myostatin inhibition improved BMD. In summary, myostatin appears to be a key factor in the integrated physiology of muscle, fat, and bone. It is unclear whether myostatin directly affects fat and bone, or indirectly via muscle. Whether via direct or indirect effects, myostatin inhibition appears to increase muscle and bone mass and decrease fat tissue-a combination that truly appears to be a holy grail. However, at this time, human data for both efficacy and safety are extremely limited. Moreover, whether increased muscle mass also leads to improved function remains to be determined. Ultimately potential beneficial effects of myostatin inhibition will need to be determined based on hard outcomes such as falls and fractures. PMID- 24072594 TI - Rethinking trait conceptions of social desirability scales: impression management as an expression of honesty-humility. AB - Numerous researchers have noted that, instead of response sets or styles, most social desirability scales seem to measure personality traits instead. In two studies, we investigated the substantive interpretation of the Balanced Inventory of Desirable Responding in terms of the HEXACO model of personality. Because of its focus on honesty and integrity, the Impression Management (IM) scale was hypothesized to be mainly related to HEXACO Honesty-Humility. In the main study among 1,106 students and well-acquainted others (friends, family, or partners), positive self-other agreement correlations were found for both IM (r = .45) and Self-Deceptive Enhancement (SDE; r = .34), supporting a trait conception of IM and SDE. In both self- and other ratings, the most important predictors of SDE were (low) Emotionality, Extraversion, and Conscientiousness. IM was associated with Conscientiousness and Agreeableness, but Honesty-Humility was by far its most important predictor. In a subsample (n = 465), Honesty-Humility and IM were unrelated to GPA. PMID- 24072592 TI - The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design. AB - The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases. PMID- 24072595 TI - Domain familiarity as a cue for judgments of learning. AB - Students differ in how much they already know about topics within and across their courses. Few studies, however, have examined the relationship between participants' levels of knowledge across topics (i.e., their "domain familiarity") and their learning of information from those topics, their study choices related to those topics, and their subjective self-assessments of their learning about the topics. As such, in two studies we had participants (Study 1, college students; Study 2, Mturk workers) rank their domain familiarity for several to-be-studied domains (e.g., chemistry, history), rate their efficacy and interest in those domains, study and make judgments of learning (JOLs) for facts from each domain, and finally complete a short-answer test over those facts. Participants' efficacy and interest ratings for the topics were linearly related to their topic rankings, as were their recall of and JOLs for facts from those domains. Although the JOLs were consistently overconfident, they were more overconfident for better-known than for lesser-known topics. Participants' study times were not related to their topic rankings (Studies 1 and 2), but participants did use domain familiarity to strategically decide which domains to restudy before the test (Study 2). Participants typically chose to restudy their least-familiar topics, but chose to restudy their best-known topic under extremely limited restudy conditions. As a whole, the results suggest that participants effectively use their domain familiarity as a basis for their JOLs and restudy choices, but to some extent overuse this factor to assess their learning, and underuse it to guide initial study. PMID- 24072593 TI - Atrial fibrillation and heart failure: intersecting populations, morbidities, and mortality. AB - Heart failure (HF) and atrial fibrillation (AF) are the only two cardiovascular disorders that continue to increase in magnitude in the United States. The purpose of this brief overview is to provide a description of these two cardiovascular epidemics of HF and AF as they interact, and to provide additional information regarding the emerging influence of genetics and environment in the development of AF in the HF setting. These two modern epidemics are highly interactive and highly age-dependent. The development of new AF in a patient with either HF with preserved ejection fraction or HF with reduced ejection fraction possesses challenging management issues for practicing physicians. Control of heart rate is always prudent though still not precisely defined. The need to restore normal sinus rhythm is highly patient-dependent and strategies will vary. Elderly patients derive the most benefit from anticoagulation, but are also more prone to falls and bleeding complications. Today, we know much more about AF and HF and how they interact. The extent of AF/HF challenge is now widely recognized. It is inevitable that as people age, they will develop structural and functional changes in the cardiovascular system, some of which will predispose to the development of HF and AF. Not every case of HF or AF is preventable. Nevertheless, it is only throughout careful observations and further studies that we will be able to better manage these two Goliaths. PMID- 24072596 TI - Decision deadlines and uncertainty monitoring: the effect of time constraints on uncertainty and perceptual responses. AB - The behavioral uncertainty response has grounded the study of animal metacognition and influenced the study of human psychophysics. However, the interpretation of this response is debated--especially whether it is a behavioral index of metacognition. The authors advanced this interpretation using the dissociative technique of response deadlines. Uncertainty responding, if it is higher level or metacognitive, should depend on a slower, more controlled decisional process and be more vulnerable to time constraints. Humans performed sparse-uncertain-dense or sparse-middle-dense discriminations in which, respectively, they could decline difficult trials or positively identify middle stimuli. Uncertainty responses were sharply and selectively reduced under a decision deadline, as compared to primary perceptual responses (i.e., "sparse," "middle," and "dense" responses). This dissociation suggests that the uncertainty response does reflect a higher-level, decisional response. It grants the uncertainty response a distinctive psychological role in its task and encourages an interpretation of this response as an elemental behavioral index of uncertainty that deserves continuing research. PMID- 24072597 TI - Positive childbirth experiences in U.S. hospitals: a mixed methods analysis. AB - Research on maternity care quality in the US often focuses on avoiding adverse events. Positive birth experiences receive less attention. This analysis used a mixed methods approach to identify factors associated with confidence and positive experiences during birth among a national sample of U.S. mothers. Data are from a nationally representative survey of women who delivered a singleton baby in a US hospital in 2005 (N = 1,573). We explored the relationship between confidence, positive birth experiences and socio-demographic characteristics as well as factors related to the clinical encounter and health systems, including common obstetric procedures and interventions. Self-reported confidence during birth was the outcome in quantitative analyses. We used logistic regression analysis and qualitative analysis of open-ended survey responses. Approximately 42% of mothers reported feeling confident during birth. Confidence going into labor was the strongest predictor of confidence during birth (adjusted odds ratio 12.88 for nulliparous women, 8.54 for parous women). Black and Hispanic race/ethnicity (compared to white) and having partner support were positively associated with confidence during birth for nulliparous women. Qualitative analyses revealed that positive experiences were related to previous birth experiences, communication between women and their clinicians, perceptions of shared decision-making, and communication among clinicians related to the timing and logistics of managing complications and coordinating care. For clinicians who care for women during pregnancy and childbirth, thoughtful, deliberate attention to factors promoting positive birth experiences may help create circumstances amenable to enhancing the quality of obstetric care and improving outcomes for mothers and infants. PMID- 24072598 TI - A twin-sibling study on the relationship between exercise attitudes and exercise behavior. AB - Social cognitive models of health behavior propose that individual differences in leisure time exercise behavior are influenced by the attitudes towards exercise. At the same time, large scale twin-family studies show a significant influence of genetic factors on regular exercise behavior. This twin-sibling study aimed to unite these findings by demonstrating that exercise attitudes can be heritable themselves. Secondly, the genetic and environmental cross-trait correlations and the monozygotic (MZ) twin intrapair differences model were used to test whether the association between exercise attitudes and exercise behavior can be causal. Survey data were obtained from 5,095 twins and siblings (18-50 years). A genetic contribution was found for exercise behavior (50 % in males, 43 % in females) and for the six exercise attitude components derived from principal component analysis: perceived benefits (21, 27 %), lack of skills, support and/or resources (45, 48 %), time constraints (25, 30 %), lack of energy (34, 44 %), lack of enjoyment (47, 44 %), and embarrassment (42, 49 %). These components were predictive of leisure time exercise behavior (R(2) = 28 %). Bivariate modeling further showed that all the genetic (0.36 < |rA| < 0.80) and all but two unique environmental (0.00 < |rE| < 0.27) correlations between exercise attitudes and exercise behavior were significantly different from zero, which is a necessary condition for the existence of a causal effect driving the association. The correlations between the MZ twins' difference scores were in line with this finding. It is concluded that exercise attitudes and exercise behavior are heritable, that attitudes and behavior are partly correlated through pleiotropic genetic effects, but that the data are compatible with a causal association between exercise attitudes and behavior. PMID- 24072599 TI - Homozygous truncating mutation of the KBP gene, encoding a KIF1B-binding protein, in a familial case of fetal polymicrogyria. AB - Polymicrogyria (PMG) is a clinically heterogeneous malformation of cortical development, characterized by a loss of the normal gyral pattern that is replaced by many small and infolded gyri separated by shallow sulci that are partly fused in their depths. Causes of PMG are heterogeneous and include acquired and genetic causes. There are more than 100 syndromes possibly associated with PMG but mutations in specific genes such as SRPX2, GPR56, TUBB2B, TUBB3, NHEJ1, TUBA1A, TUBA8, and WDR62 have been reported only in a minority of patients. PMID- 24072600 TI - Altered glycosylation of MUC1 influences its association with CIN85: the role of this novel complex in cancer cell invasion and migration. AB - MUC1 is a transmembrane glycoprotein abnormally expressed in human adenocarcinomas. The extracellular domain of MUC1 contains a variable number of tandem repeats (VNTR) region that is extensively O-glycosylated in normal epithelia and underglycosylated in tumor cells. This change in posttranslational modification of MUC1 leads to changes in its normal functions including, we hypothesized, its interaction with other molecules. We identified CIN85, an adaptor protein involved in multiple cellular processes including signal transduction, cytoskeletal remodeling and cancer cell invasion, as one of several proteins that associate with MUC1 in tumor cells. CIN85 associates with both the cytosolic tail and the extracellular VNTR of MUC1. Co-immunoprecipitation and confocal immunofluorescence confirmed that MUC1 and CIN85 co-localize primarily at the plasma membrane but the complex can be found also in the cytosol and on the cytoskeleton. MUC1 and CIN85 are both over-expressed in early as well as advanced clinical stages of breast cancer and co-localize on invadopodia-like structures implicated in cell invasion. siRNA-mediated silencing of CIN85 and/or MUC1 revealed that MUC1 enhances CIN85-dependent breast cancer cell migration and invasion in vitro. However, ectopic expression of MUC1 enhances the motility induced by CIN85. When tested in vivo in a tumor metastasis model of B16 melanoma, mice injected with CIN85-depleted melanoma cells exhibited few or no lung metastasis and, similarly to the in vitro results, overexpression of MUC1 recovered the shCIN85-reduced metastatic process. Our findings implicate this newly identified CIN85/MUC1 complex associated with invadopodia-related molecules in promoting the invasive and metastatic potential of breast cancer. PMID- 24072601 TI - Outcome assessments in rheumatoid arthritis. AB - Increasing evidence suggests low disease activity or remission is achievable in rheumatoid arthritis (RA). Using a treat to target strategy (T2T) has been shown to achieve these targets of remission or low disease activity in RA. In order to successfully treat to target, rheumatologists need reliable measures of disease activity to switch and/or escalate therapy to achieve or maintain therapeutic targets. Multiple disease-activity measures have been developed for both research and clinical practice. For clinical practice, the American College of Rheumatology (ACR) has recommended the PAS, PAS II, RAPID 3, CDAI, DAS 28, and SDAI for measuring disease activity in rheumatoid arthritis. Each of these measures has strengths and limitations, but they all accurately reflect disease activity, discriminate well between disease states, and are feasible to perform in the clinical setting. Implementation in the clinical setting can be optimized through leveraging technology and systems redesign. Tools such as web-based and smartphone applications have been developed to increase the ease with which these measures can be deployed. Disease-activity measurement in rheumatoid arthritis is included in the rheumatoid arthritis quality measures group in the Centers for Medicare and Medicaid Services' incentive-based Physician Quality Reporting System. PMID- 24072602 TI - Epigenetics in rheumatoid arthritis: a primer for rheumatologists. AB - Epigenetic anomalies are emerging as key pathogenic features of rheumatoid arthritis (RA). The effect of epigenetics in RA ranges from contributing to complex disease mechanisms to identifying biomarkers for early diagnosis and response to therapy. This review focuses on three key epigenetic areas in RA, namely DNA methylation, histone modification, and expression and/or function of microRNAs. Epigenomics studies of DNA methylation have identified alterations of genome-wide DNA methylation in cells from patients with rheumatoid arthritis. Histone modification studies have focused on histone acetylation, which tends to be increased in RA. Preclinical studies show that inhibitors of histone deacetylases are effective in cellular and animal models of RA. Genome-wide and candidate microRNA surveys identified increased or reduced expression of selected microRNAs in rheumatoid arthritis. These microRNA are either pro or anti inflammatory in multiple cell types or affect osteoclast physiology and the pathogenesis of bone erosion. Defining epigenetic contributions to the pathogenesis of RA, especially in combination with understanding genetic associations, could lead to novel therapy and a clearer understanding of disease risk. PMID- 24072603 TI - Measuring bone quality. AB - Osteoporosis is defined as a reduction in bone mass and impairment of bone quality that lead to bone fragility and fracture risk. Bone quality includes a hierarchy of properties from macroscopic to nanoscale level. Several techniques have been developed in an attempt to measure these non-density properties. Densitometry, high-resolution images (radiography, CT scan), and MRI can measure the geometry and microarchitecture of bone. Tissue mineralization and composition can be assessed by use of microradiography, Fourier-transform infrared spectroscopy, or Raman microspectroscopy. Finite-element analysis is an image based method that enables calculation of bone strength. More recently, microindentation has enabled direct estimation of bone material strength, measured in the cortical bone of the tibia. Most of these techniques are of limited use to clinics, although finite-element analysis and microindentation have high potential for clinical use and can enable more comprehensive and accurate evaluation of bone fragility and fracture susceptibility. PMID- 24072605 TI - Mechanistic insights from animal models of psoriasis and psoriatic arthritis. AB - Psoriasis and psoriatic arthritis are common chronic inflammatory conditions associated with substantial local and systemic morbidity. The genetic and phenotypic heterogeneity of these disorders presents great challenges to investigators of disease mechanisms. Valid and reliable animal models that combine the main elements of human skin and joint disease have not been developed, and this has hindered our ability to understand the complex immunopathology and develop treatments. Recently, novel animal models have been developed with the potential to greatly increase our knowledge of important mechanisms that underlie psoriatic skin and joint inflammation and bone remodeling. Herein, we discuss how recent models generated by use of promising new technologies are revealing novel inflammatory pathways that have promising therapeutic potential. PMID- 24072606 TI - Clinical outcome prediction of percutaneous cementoplasty for metastatic bone tumor using (18)F-FDG PET-CT. AB - OBJECTIVES: Percutaneous cementoplasty (PC) is used for metastatic bone tumor. Bone metastases patients who are unable to avail regular surgery, because of their poor general condition, undergo PC to gain mechanical stability and pain relief. We evaluated the effect of PC using (18)F-FDG PET-CT and investigated the correlation and predictability between quantitative parameters of (18)F-FDG PET CT and pain status after PC. METHODS: Subjects comprised 18 patients (total 32 sites) who had undergone PC for the metastatic bone tumors. Pain degree of the patients was obtained by visual analog scale (VAS) in the pre-PC, immediate post PC, and follow-up post-PC state. As PET-CT parameters, maximum and mean standardized uptake value (MaxSUV and MeanSUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured. Receiver operator characteristic curve analysis was performed for pre-PC, post-PC PET-CT, and delta (Delta) values of PET-CT parameters to correlate and predict the good pain improvement (VAS pain <=2) after the PC procedure. RESULTS: Patients' pain status improved significantly in immediate post-PC and follow-up post-PC pain (all p < 0.001). Among PET-CT parameters, MaxSUV (p = 0.004) and MeanSUV (p = 0.007) showed significant interval decrease after PC procedure. All of the post-PC PET-CT and DeltaPET-CT values showed significant prediction of pain improvement for follow up post-PC pain, especially DeltaTLG (AUC = 0.804, p = 0.0003) and DeltaMTV (AUC = 0.804, p = 0.0004). CONCLUSIONS: There was significant reduction of patients' pain after PC, and DeltaTLG and DeltaMTV of PET-CT parameters showed best predictability for follow-up post-PC pain improvement. PET-CT can be the useful parameter to predict treatment response of PC. PMID- 24072604 TI - Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis. AB - Osteoarthritis (OA) is a whole joint disease, in which thinning and disappearance of cartilage is a critical determinant in OA progression. The rupture of cartilage homeostasis whatever its cause (aging, genetic predisposition, trauma or metabolic disorder) induces profound phenotypic modifications of chondrocytes, which then promote the synthesis of a subset of factors that induce cartilage damage and target other joint tissues. Interestingly, among these factors are numerous components of the inflammatory pathways. Chondrocytes produce cytokines, chemokines, alarmins, prostanoids, and adipokines and express numerous cell surface receptors for cytokines and chemokines, as well as Toll-like receptors. These receptors activate intracellular signaling pathways involved in inflammatory and stress responses of chondrocytes in OA joints. This review focuses on mechanisms responsible for the maintenance of cartilage homeostasis and highlights the role of inflammatory processes in OA progression. PMID- 24072607 TI - Interleukin 6(-174G/C) variant and its circulating levels in coronary artery disease patients and their first degree relatives. AB - Interleukin-6 (IL-6) a pleiotropic cytokine is a central mediator of inflammation in the pathogenesis of coronary artery disease (CAD). Our aim is to evaluate the serum levels of IL-6 and C-reactive protein (CRP) and to analyze the IL-6 polymorphism in CAD patients and to identify the first-degree relatives (FDRs) at risk of the disease in comparison with healthy controls. Estimation of IL-6 levels by enzyme-linked immunosorbent assay (ELISA) and CRP by latex reagent kit method, and genotyping of IL6 gene variants -174 (G>C) was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 600 subjects. IL-6 and CRP levels were significantly high in patients followed by FDRs compared to controls. The frequency of the IL-6 genotype was significantly different between cases, FDRs and controls and association of serum IL-6 levels with genotype found to be significant in CC genotype compared to GC and GG at p < 0.01 in CAD patients and FDRs, while there is no significant difference observed in controls. The study shows the importance of inflammation in the pathogenesis of CAD and predicts the risk of future coronary events in healthy asymptomatic FDRs. PMID- 24072608 TI - Growing up together: cohort composition and child investment. AB - In sub-Saharan Africa, 60 % of child deaths are preventable by investments in child health as simple as immunizations, bed nets, or water purification. This article investigates how a household's decisions regarding such investments are affected by the size and gender composition of a child's cohort. I focus on a previously overlooked type of investment: nonrival, child-specific goods (club goods). I empirically estimate the response of immunization status to cohort characteristics. I carefully address the problem of endogenous fertility, which is common in cohort studies. Because most rural Senegalese households are composed of multiple nuclear families, a child's cohort is composed of both siblings and nonsibling children. Estimating within households, I instrument cohort characteristics with those of the nonsibling (exogenous) portion. I find that children with larger (or more predominantly male) cohorts of vaccine eligible age are significantly more likely to receive immunization. These findings suggest that children with larger cohorts may be better off in terms of club investments; this is a significant finding for child health given that many illness prevention methods are of a club good nature. PMID- 24072609 TI - Cohort trends in premarital first births: what role for the retreat from marriage? AB - We examine cohort trends in premarital first births for U.S. women born between 1920 and 1964. The rise in premarital first births is often argued to be a consequence of the retreat from marriage, with later ages at first marriage resulting in more years of exposure to the risk of a premarital first birth. However, cohort trends in premarital first births may also reflect trends in premarital sexual activity, premarital conceptions, and how premarital conceptions are resolved. We decompose observed cohort trends in premarital first births into components reflecting cohort trends in (1) the age-specific risk of a premarital conception taken to term; (2) the age-specific risk of first marriages not preceded by such a conception, which will influence women's years of exposure to the risk of a premarital conception; and (3) whether a premarital conception is resolved by entering a first marriage before the resulting first birth (a "shotgun marriage"). For women born between 1920-1924 and 1945-1949, increases in premarital first births were primarily attributable to increases in premarital conceptions. For women born between 1945-1949 and 1960-1964, increases in premarital first births were primarily attributable to declines in responding to premarital conceptions by marrying before the birth. Trends in premarital first births were affected only modestly by the retreat from marriages not preceded by conceptions-a finding that holds for both whites and blacks. These results cast doubt on hypotheses concerning "marriageable" men and instead suggest that increases in premarital first births resulted initially from increases in premarital sex and then later from decreases in responding to a conception by marrying before a first birth. PMID- 24072610 TI - Assessing validity and application scope of the intrinsic estimator approach to the age-period-cohort problem. AB - In many different fields, social scientists desire to understand temporal variation associated with age, time period, and cohort membership. Among methods proposed to address the identification problem in age-period-cohort analysis, the intrinsic estimator (IE) is reputed to impose few assumptions and to yield good estimates of the independent effects of age, period, and cohort groups. This article assesses the validity and application scope of IE theoretically and illustrates its properties with simulations. It shows that IE implicitly assumes a constraint on the linear age, period, and cohort effects. This constraint not only depends on the number of age, period, and cohort categories but also has nontrivial implications for estimation. Because this assumption is extremely difficult, if not impossible, to verify in empirical research, IE cannot and should not be used to estimate age, period, and cohort effects. PMID- 24072611 TI - Broadening engineering education: bringing the community in : commentary on "social responsibility in French engineering education: a historical and sociological analysis". AB - Two issues of particular interest in the Irish context are (1) the motivation for broadening engineering education to include the humanities, and an emphasis on social responsibility and (2) the process by which broadening can take place. Greater community engagement, arising from a socially-driven model of engineering education, is necessary if engineering practice is to move beyond its present captivity by corporate interests. PMID- 24072612 TI - Education for life scientists on the dual-use implications of their research : commentary on "implementing biosecurity education: approaches, resources and programmes". AB - Advances in the life sciences are occurring with extreme rapidity and accumulating a great deal of knowledge about life's vital processes. While this knowledge is essential for fighting disease in a more effective way, it can also be misused either intentionally or inadvertently to develop novel and more effective biological weapons. For nearly a decade civil-academic society as well as States Parties to the Biological and Toxin Weapons Convention have recognised the importance of dual-use biosecurity education for life scientists as a means to foster a culture of responsibility and prevent the potential misuse of advances in the life sciences for non-peaceful purposes. Nevertheless, the implementation of dual-use biosecurity education for life scientists has made little progress in institutions of higher learning. Professional societies and academic organizations have worked from the bottom-up in developing online dual use biosecurity education modules that can be used for instruction. However, top down help is needed from goverments if further progress is to be made in implementing biosecurity education for life scientists. PMID- 24072613 TI - Regulation of carbohydrate metabolism by indole-3-carbinol and its metabolite 3,3'-diindolylmethane in high-fat diet-induced C57BL/6J mice. AB - Indole glucosinolates, present in cruciferous vegetables have been investigated for their putative pharmacological properties. The current study was designed to analyse whether the treatment of the indole glucosinolates-indole-3-carbinol (I3C) and its metabolite 3,3'-diindolylmethane (DIM) could alter the carbohydrate metabolism in high-fat diet (HFD)-induced C57BL/6J mice. The plasma glucose, insulin, haemoglobin (Hb), glycosylated haemoglobin (HbA1c), glycogen and the activities of glycolytic enzyme (hexokinase), hepatic shunt enzyme (glucose-6 phosphate dehydrogenase), gluconeogenic enzymes (glucose-6-phosphatase and fructose-1,6-bisphosphatase) were analysed in liver and kidney of the treated and HFD mice. Histopathological examination of liver and pancreases were also carried out. The HFD mice show increased glucose, insulin and HbA1c and decreased Hb and glycogen levels. The elevated activity of glucose-6-phosphatase and fructose-1,6 bisphosphatase and subsequent decline in the activity of glucokinase and glucose 6-phosphate dehydrogenase were seen in HFD mice. Among treatment groups, the mice administered with I3C and DIM, DIM shows decreased glucose, insulin and HbA1c and increased Hb and glycogen content in liver when compared to I3C, which was comparable with the standard drug metformin. The similar result was also obtained in case of carbohydrate metabolism enzymes; treatment with DIM positively regulates carbohydrate metabolic enzymes by inducing the activity of glucokinase and glucose-6-phosphate dehydrogenase and suppressing the activity of glucose-6 phosphatase and fructose-1,6-bisphosphatase when compared to I3C, which were also supported by our histopathological observations. PMID- 24072614 TI - LY294002 and Rapamycin promote coxsackievirus-induced cytopathic effect and apoptosis via inhibition of PI3K/AKT/mTOR signaling pathway. AB - Coxsackievirus B3 (CVB3) is a common human pathogen for acute myocarditis, pancreatitis, non-septic meningitis, and encephalitis; it induces a direct cytopathic effect (CPE) and apoptosis on infected cells. The Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT/PKB)/mammalian target of Rapamycin (mTOR) signaling pathway regulates several cellular processes and it is one of the most important pathways in human networks. However, the effect and mechanism of PI3K/AKT/mTOR signaling pathway in CVB3 infected cells are poorly understood. In this study, we demonstrate that inhibition of PI3K/AKT/mTOR signaling pathway increased CVB3-induced CPE and apoptosis in HeLa cells. The activity of downstream targets of PI3K and mTOR is attenuated after CVB3 infection and inhibitors of PI3K and mTOR made their activity to decrease more significantly. We further show that LY294002 and Rapamycin, the inhibitor of PI3K and mTOR respectively, promote CVB3-induced CPE and apoptosis. Taken together, these data illustrate a new and imperative role for PI3K/AKT/mTOR signaling in CVB3 infection in HeLa cells and suggest an useful approach for the therapy of CVB3 infection. PMID- 24072615 TI - Paracetamol (acetaminophen): a blessing or a hidden curse? AB - This Journal has recently published a splendid review of all you need to know about paracetamol (Graham et al. 2013), an analgesic widely used in the long-term management of arthritis. It clearly presents the science and hard facts. This commentary, by contrast, discusses some aspects of the metapharmacology of paracetamol; particularly by asking questions of how we might extract more benefit and suffer less adverse reactions when using this analgesic in the context of non-transient inflammation. As both a drug and a toxin, paracetamol exemplifies how beneficial and/or deleterious responses may be conditioned by circumstances (disease stress, nutritional status, fasting, etc.). PMID- 24072616 TI - ceRNA cross-talk in cancer: when ce-bling rivalries go awry. AB - The cancer transcriptome is characterized by aberrant expression of both protein coding and noncoding transcripts. Similar to mRNAs, a significant portion of the noncoding transcriptome, including long noncoding RNAs and pseudogenes, harbors microRNA (miRNA)-response elements (MRE). The recent discovery of competitive endogenous RNAs (ceRNA), natural decoys that compete for a common pool of miRNAs, provides a framework to systematically functionalize MRE-harboring noncoding RNAs and integrate them with the protein-coding RNA dimension in complex ceRNA networks. Functional interactions in ceRNA networks aid in coordinating a number of biologic processes and, when perturbed, contribute to disease pathogenesis. In this review, we discuss recent discoveries that implicate natural miRNA decoys in the development of cancer. SIGNIFICANCE: Cross-talk between ceRNAs through shared miRNAs represents a novel layer of gene regulation that plays important roles in the physiology and development of diseases such as cancer. As cross-talk can be predicted on the basis of the overlap of miRNA-binding sites, we are now one step closer to a complete functionalization of the human transcriptome, especially the noncoding space. PMID- 24072617 TI - Neuromodulation for treatment resistant depression: state of the art and recommendations for clinical and scientific conduct. AB - Research of Deep Brain Stimulation as a putative treatment for resistant psychiatric disorders might very well lead to the most significant development in clinical psychiatry of the last 40 years-possibly offering a rise of hope for patients to whom medicine had hitherto little to offer. Furthermore, translational research on neuromodulation will allow us to glean something about the underlying cause of patient's illnesses before figuring out a treatment that addresses the source of the problem. Major depression offers perhaps the best example of the rapid progress being made in understanding the biology of mental illness. Studies on the underlying neurobiology of major depression have typically focused on the description of biological differences between patients and healthy subjects such as alterations of monoaminergic or endocrine systems. Psychotropic drugs work by altering neurochemistry to a large extent in widespread regions of the brain, many of which may be unrelated to depression. We believe that more focused, targeted treatment approaches that modulate specific networks in the brain will prove a more effective approach to help treatment resistant patients. In other words, whereas existing depression treatments approach this disease as a general brain dysfunction, a more complete and appropriate treatment will arise from thinking of depression as a dysfunction of specific brain networks that mediate mood and reward signals (Berton and Nestler, Nat Rev Neurosci 7 (2):137-151, 2006; Krishnan and Nestler, Nature 455(7215):894 902, 2008). A better understanding of defined dysfunctions in these networks will invariably lead to a better understanding of patients afflicted with depression and perhaps contribute to a de-stigmatization of psychiatric patients and the medical specialty treating them. PMID- 24072618 TI - The role of health behaviours across the life course in the socioeconomic patterning of all-cause mortality: the west of Scotland twenty-07 prospective cohort study. AB - BACKGROUND: Socioeconomic differentials in mortality are increasing in many industrialised countries. PURPOSE: This study aims to examine the role of behaviours (smoking, alcohol, exercise, and diet) in explaining socioeconomic differentials in mortality and whether this varies over the life course, between cohorts and by gender. METHODS: Analysis of two representative population cohorts of men and women, born in the 1950s and 1930s, were performed. Health behaviours were assessed on five occasions over 20 years. RESULTS: Health behaviours explained a substantial part of the socioeconomic differentials in mortality. Cumulative behaviours and those that were more strongly associated with socioeconomic status had the greatest impact. For example, in the 1950s cohort, the age-sex adjusted hazard ratio comparing respondents with manual versus non manual occupational status was 1.80 (1.25, 2.58); adjustment for cumulative smoking over 20 years attenuated the association by 49 %, diet by 43 %, drinking by 13 % and inactivity by only 1%. CONCLUSIONS: Health behaviours have an important role in explaining socioeconomic differentials in mortality. PMID- 24072619 TI - "Thinking healthy" in pregnancy: a comment on Christian et al. PMID- 24072620 TI - Endovascular treatment of middle cerebral artery aneurysms with flow modification with the use of the pipeline embolization device. AB - BACKGROUND AND PURPOSE: The Pipeline Embolization Device was reported to be safe and effective in the treatment of sidewall aneurysms, preserving the patency of the vessels covered by the construct. However, to date, the safety and efficacy of this device in treating bifurcation aneurysms remains unknown. We report our preliminary experience with the use of the Pipeline Embolization Device in the management of MCA aneurysms located at the bifurcations, including mid- and long term follow-up data. MATERIALS AND METHODS: Wide-neck MCA aneurysms, which give rise to a bifurcating or distal branch in which other endovascular techniques are thought to be unfeasible or more risky, were included. Data including demographics, aneurysm features, antiplatelet therapy, complications, and angiographic follow-up results for up to 30 months were recorded. RESULTS: Twenty five aneurysms located at the MCA bifurcation (n = 21) or distal (n = 4) were treated. Of these, 22 were small and 3 were large. A single device was used in all but 2. No deaths occurred in the series. All patients had at least 1 control angiographic study, 21 of which were DSA (3-30 months), which showed that 12 of the rising branches were patent whereas 6 were filling in reduced caliber and 3 were occluded asymptomatically. According to the last angiographic follow-up, complete occlusion was revealed in 21 of 25 aneurysms (84%). CONCLUSIONS: The Pipeline Embolization Device provides a safe and effective treatment alternative for wide-neck MCA aneurysms that give rise to a bifurcating or distal branch when other endovascular techniques are thought to be unfeasible or more risky. PMID- 24072621 TI - White matter microstructural abnormality in children with hydrocephalus detected by probabilistic diffusion tractography. AB - BACKGROUND AND PURPOSE: Hydrocephalus is a severe pathologic condition in which WM damage is a major factor associated with poor outcomes. The goal of the study was to investigate tract-based WM connectivity and DTI measurements in children with hydrocephalus by using the probabilistic diffusion tractography method. MATERIALS AND METHODS: Twelve children with hydrocephalus and 16 age-matched controls were included in the study. Probabilistic diffusion tractography was conducted to generate tract-based connectivity distribution and DTI measures for the genu of the corpus callosum and the connectivity index. Tract-based summary measurements, including the connectivity index and DTI measures (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity), were calculated and compared between the 2 study groups. RESULTS: Tract-based summary measurement showed a higher percentage of voxels with lower normalized connectivity index values in the WM tracts in children with hydrocephalus. In the genu of the corpus callosum, the left midsegment of the corticospinal tract, and the right midsegment of the corticospinal tract, the normalized connectivity index value in children with hydrocephalus was found to be significantly lower (P < .05, corrected). The tract-based DTI measures showed that the children with hydrocephalus had significantly higher mean diffusivity, axial diffusivity, and radial diffusivity in the genu of the corpus callosum, left midsegment of the corticospinal tract, and right midsegment of corticospinal tract and lower fractional anisotropy in the genu of the corpus callosum (P < .05, corrected). CONCLUSIONS: The analysis of WM connectivity showed that the probabilistic diffusion tractography method is a sensitive tool to detect the decreased continuity in WM tracts that are under the direct influence of mechanical distortion and increased intracranial pressure in hydrocephalus. This voxel-based connectivity method can provide quantitative information complementary to the standard DTI summary measures. PMID- 24072622 TI - Variable porosity of the pipeline embolization device in straight and curved vessels: a guide for optimal deployment strategy. AB - BACKGROUND AND PURPOSE: Low-porosity endoluminal devices for the treatment of intracranial aneurysms, also known as flow diverters, have been in experimental and clinical use for close to 10 years. Despite rigorous evidence of their safety and efficacy in well-controlled trials, a number of key factors concerning their use remain poorly defined. Among these, none has received more attention to date than the debate on how many devices are optimally required to achieve a safe, effective, and economical outcome. Additional, related questions concern device sizing relative to the parent artery and optimal method of deployment of the devices. While some or all of these issues may be ultimately answered on an empiric basis via subgroup analysis of growing treatment cohorts, we believe that careful in vitro examination of relevant device properties can also help guide its in vivo use. MATERIALS AND METHODS: We conducted a number of benchtop experiments to investigate the varied porosity of Pipeline Embolization Devices deployed in a simulated range of parent vessel diameters and applied these results toward conceptualizing optimal treatment strategies of fusiform and wide neck aneurysms. RESULTS: The results of our studies confirm a predictable parabolic variability in device porosity based on the respective comparative sizes of the device and recipient artery, as well as device curvature. Even modest oversizing leads to a significant increase in porosity. CONCLUSIONS: The experiments demonstrate various deleterious effects of device oversizing relative to the parent artery and provide strategies for addressing size mismatches when they are unavoidable. PMID- 24072623 TI - Manual hippocampal volumetry is a better detector of hippocampal sclerosis than current automated hippocampal volumetric methods. PMID- 24072625 TI - Symposium: ABJS Carl T. Brighton Workshop on outcome measures. PMID- 24072624 TI - Stakeholders in outcome measures: review from a clinical perspective. AB - BACKGROUND: Modern interest in patient-reported outcomes measures (PROMs) in orthopaedics dates back to the mid-1980s. While gradual growth of activity in this area has occurred over the past 25 years, the extent to which this research methodology is applied in clinical practice to improve patient care is unclear. WHERE ARE WE NOW?: Historically, clinical research in orthopaedics has focused on the technical success of treatment, and objective indicators such as mortality, morbidity, and complications. By contrast, the PROMs framework focuses on effects of treatment described in terms of relief of symptoms, restoring functional ability, and improving quality of life. PROMs can be used to study the relative effects of disease, injury, and treatment across different health conditions. WHERE DO WE NEED TO GO?: All clinical research should begin with identifying clear and meaningful research questions so that the resources and efforts required for data collection result in useful data. Different consumers of research data have different perspectives on what comprises meaningful information. Involving stakeholders such as patients, providers, payers, and policy-makers when defining priorities in the larger research endeavor is one way to inform what type of data should be collected in a particular study. HOW DO WE GET THERE?: Widespread collection of outcomes data would potentially aid these stakeholders by identifying best practices, benefits and costs, and important patient or practice characteristics related to outcomes. Several initiatives currently underway may help systematic collection of PROMs, create efficient systems, and foster collaborations to provide support and resources to minimize costs. PMID- 24072626 TI - Art in science: orthopaedics through philatelic material. PMID- 24072627 TI - CORR Insights (r): Randomized trial of hemiarthroplasty versus internal fixation for femoral neck fractures: no differences at 6 years. PMID- 24072628 TI - Editor's Spotlight/Take 5: CT pulmonary angiography after total joint arthroplasty: overdiagnosis and iatrogenic harm? PMID- 24072629 TI - Editor's Spotlight/Take 5: CT pulmonary angiography after total joint arthroplasty: overdiagnosis and iatrogenic harm? PMID- 24072630 TI - CORR Insights (r): Loss of cement-bone interlock in retrieved tibial components from total knee arthroplasties. PMID- 24072632 TI - Male preference for younger women explains today's menopausal age. PMID- 24072634 TI - A randomised controlled trial comparing the effects of micronized progesterone to medroxyprogesterone acetate on cardiovascular health, lipid metabolism and the coagulation cascade in women with premature ovarian insufficiency: study protocol and review of the literature. AB - Premature ovarian insufficiency (POI) can have significant health implications for the affected patient population, but remains a largely under researched area. There is lack of evidence from randomised controlled trials to guide clinical practice, regarding the optimal hormone replacement therapy regimens, dose and route of administration. Furthermore, little research has addressed the effect of the various progestogens used on health parameters in women with POI. Here we describe an ongoing randomised clinical trial looking at the effects of micronized progesterone and medroxyprogesterone acetate, both used in combination with transdermal oestradiol on the cardiovascular system, lipid profile and coagulation cascade in women with POI as a step towards better understanding of the implications of hormone treatment in this cohort of women. PMID- 24072635 TI - Red clover causing symptoms suggestive of methotrexate toxicity in a patient on high-dose methotrexate. AB - The case report discusses a very serious interaction between red clover and methotrexate not previously documented. It highlights the potential pitfalls of concomitant use of herbal remedies and conventionally prescribed drugs and the importance of advising our patients about OTC drugs. A 52-year-old woman attended her general practitioner for advice on menopausal flushing. She was on methotrexate weekly injections for severe psoriasis and was not keen to consider anything that would possibly affect her skin. Alternative therapies were discussed and red clover was suggested. This was bought OTC. After the third day of taking red clover capsules (430 mg), the patient developed severe vomiting and epigastric pain. She contacted the dermatology clinic that administers the methotrexate injection and was thought to have symptoms suggestive of methotrexate toxicity even though her liver function tests remained within normal levels. She had been receiving methotrexate injections for nearly two years with no adverse effects. The only new drug that had been started was red clover and this was thought to be the probable cause of the toxicity. It was withdrawn. The patient made a full recovery and received her next injection of methotrexate with no adverse effects. The interaction was reported to the MHRA with a yellow card. PMID- 24072636 TI - Practice observed. PMID- 24072638 TI - Authenticity and psychiatric disorder: does autonomy of personal preferences matter? AB - In healthcare ethics there is a discussion regarding whether autonomy of personal preferences, what sometimes is referred to as authenticity, is necessary for autonomous decision-making. It has been argued that patients' decisions that lack sufficient authenticity could be deemed as non-autonomous and be justifiably overruled by healthcare staff. The present paper discusses this issue in relation certain psychiatric disorders. It takes its starting point in recent qualitative studies of the experiences and thoughts of patients' with anorexia nervosa where issues related to authenticity seem particularly relevant. The paper examines different interpretations of authenticity relevant for autonomy and concludes that the concept, as it has been elaborated in recent debate, is highly problematic to use as a criterion for autonomous decision-making in healthcare. PMID- 24072640 TI - Mar Piccolo of Taranto: Vibrio biodiversity in ecotoxicology approach. AB - Microorganisms play an indispensable role in the ecological functioning of marine environment. Some species are sensitive while others are insensitive for a specific pollutant. The aim of this work is a preliminary study of the quantitative and qualitative distribution of cultivable vibrios in sediments and water samples characterized by different toxicity levels. For 1 year, in three suitably selected sampling stations of Mar Piccolo in Taranto (Ionian Sea, Italy), we have evaluated the toxicity level by Microtox(r) system, vibrios, total, and fecal coliform densities. The results of the Microtox(r) tests showed sediments characterized by an elevated level of toxicity, while the interstitial water of the same sites always showed biostimulatory phenomenon. The quantitative results show that vibrios and coliforms are more abundant in water than in sediment samples. The most often isolated strains were: Vibrio alginolyticus, Vibrio mediterranei, Vibrio metschinkovii, and Vibrio splendidus II. This work is the first example of study on the distribution of Vibrio species related to toxicity evaluation conducted by the Microtox(r) bioassay. The results show the different distribution of Vibrionaceae in two environmental matrices analyzed and characterized by different levels of toxicity. PMID- 24072639 TI - Attenuated auditory event-related potentials and associations with atypical sensory response patterns in children with autism. AB - Neurobiological underpinnings of unusual sensory features in individuals with autism are unknown. Event-related potentials elicited by task-irrelevant sounds were used to elucidate neural correlates of auditory processing and associations with three common sensory response patterns (hyperresponsiveness; hyporesponsiveness; sensory seeking). Twenty-eight children with autism and 39 typically developing children (4-12 year-olds) completed an auditory oddball paradigm. Results revealed marginally attenuated P1 and N2 to standard tones and attenuated P3a to novel sounds in autism versus controls. Exploratory analyses suggested that within the autism group, attenuated N2 and P3a amplitudes were associated with greater sensory seeking behaviors for specific ranges of P1 responses. Findings suggest that attenuated early sensory as well as later attention-orienting neural responses to stimuli may underlie selective sensory features via complex mechanisms. PMID- 24072641 TI - Treatment process and toxicities assessment of wastewater issued from anaerobic digestion of household wastes. AB - Modern society grapples with large amounts of household waste. The anaerobic digestion of this waste offers a promising source for energy-rich biogas production but generates high toxic effluents that require treatment before reuse or disposal into the environment. This study aimed to investigate three techniques, namely coagulation/flocculation, electro-coagulation, and activated sludge, in terms of efficiency in the treatment of these effluents. It also aimed to assess their toxicity effects on the germination and growth of durum wheat Triticum aestivum L. seeds before and after 6 days of treatment. Activated sludge was most efficient in reducing chemical oxygen demand, turbidity, and conductivity (95.7 %, 15.8 %, and 37.5 %, respectively). The effluent treated with this technique induced a marked delay in germination (low mean time of germination) and a significant reduction in the percentages of seed germination and root and leaf growths. It was also noted to strongly induce lipid peroxidation in roots and leaves, which presumably explained the germination/growth inhibition of the wheat seeds. The effluent also induced marked lipid peroxidation effects and strongly inhibited the activities of butyrylcholinesterase in mice bone marrows. The effluent shows a high ability to inhibit the growth of three microalgae; these endpoints are useful tools to biomonitor the physico-chemical quality of this wastewater. Overall, while no significant alterations were observed in terms of animal and vegetable toxicities when the effluent was treated by coagulation/flocculation, activated sludge treatment proved efficient in reducing the toxicities induced by the untreated effluents. The results indicate that the application of this technique is promising with regards to attaining efficient, eco-friendly, and cost-effective strategies for the management and treatment of household waste. PMID- 24072642 TI - Self-potential monitoring of a crude oil-contaminated site (Trecate, Italy). AB - We present a multidisciplinary approach for characterization of a crude oil contaminated site (Trecate, Italy), integrating geophysical data, such as subsoil electrical potential (in millivolts) and electrical resistivity (in ohm meters) distribution, with hydrogeological and bio-chemical data. Self-potential measurements have been evaluated together with active geoelectrical measurements and hydrological information, to provide spatial and temporal information about the self-potential sources and their possible correlations with the contamination state of the subsoil. Three self-potential surveys (March 2010, October 2010, and March 2011) were conducted at the site, both in the contaminated and uncontaminated regions. The obtained self-potential maps show large time-lapse differences in correspondence of the contaminated area, with positive electrical potential values (up to 50 mV) in spring surveys and an electrical potential dipolar distribution in October (2010) survey (amplitude from -15 to 25 mV). To understand the origin of the measured self-potential signals, a model using vertical dipolar electrical sources was built, taking into account the electrical resistivity distribution deduced from electrical resistivity tomography. The self potential source identification allows the Trecate contamination state to be better delineated. In particular, two self-potential contributions are superimposed: the electrokinetic mechanism is predominant in spring, while the redox mechanism represents the most important contribution in autumn. PMID- 24072643 TI - Verification of responses of Japanese medaka (Oryzias latipes) to anti-androgens, vinclozolin and flutamide, in short-term assays. AB - Various testing methods for the detection of the endocrine disruptive activities of chemicals have been developed in freshwater fish species. However, a few relatively easier specific methods for detecting anti-androgenic activities are available for fish. The aim of this study was to verify the papillary process in Japanese medaka (Oryzias latipes) as an indicator of the anti-androgenic activity of chemicals. Japanese medaka were exposed to two types of anti-androgenic compounds, vinclozolin and flutamide, using two short-term assays; one was conformed to the existing short-term reproduction assay using adult fish (adult test) and the other was a test based on the same methods but using juvenile fish at the beginning of exposure (juvenile test). Significant decreases in male papillary processes were observed in the juvenile test treated with the highest concentration of both antiandrogens (640 ug l(-1) vinclozolin and 1000 ug l(-1) flutamide); however, no significant effects were observed in the adult test. Consequently, our results indicate that papillary processes in Japanese medaka can be used as the end-point for screening the anti-androgenic activity of chemicals using juvenile fish for a specific period based on the existing short term reproduction assay. PMID- 24072644 TI - The ability to recognize objects from bottlenose dolphin (Tursiops truncatus) echoes generalizes across multiple orientations in humans and neural networks. AB - Object constancy, the ability to recognize objects despite changes in orientation, has not been well studied in the auditory modality. Dolphins use echolocation for object recognition, and objects ensonified by dolphins produce echoes that can vary significantly as a function of orientation. In this experiment, human listeners had to classify echoes from objects varying in material, shape, and size that were ensonified with dolphin signals. Participants were trained to discriminate among the objects using an 18-echo stimulus from a 10 degrees range of aspect angles, then tested with novel aspect angles across a 60 degrees range. Participants were typically successful recognizing the objects at all angles (M = 78 %). Artificial neural networks were trained and tested with the same stimuli with the purpose of identifying acoustic cues that enable object recognition. A multilayer perceptron performed similarly to the humans and revealed that recognition was enabled by both the amplitude and frequency of echoes, as well as the temporal dynamics of these features over the course of echo trains. These results provide insight into representational processes underlying echoic recognition in dolphins and suggest that object constancy perceived through the auditory modality is likely to parallel what has been found in the visual domain in studies with both humans and animals. PMID- 24072645 TI - Emergence of Enterococcus species in the infectious microorganisms cultured from patients with endophthalmitis in South Korea. AB - PURPOSE: To investigate the microorganisms in culture-proven endophthalmitis and their susceptibilities to antimicrobial agents commonly used in South Korea. METHODS: Medical records of consecutive patients with culture-proven endophthalmitis at eight institutions between 1 January 2004 and 31 July 31 2010 were reviewed. Four categories of endophthalmitis were studied: postoperative, posttraumatic, endogenous, and unspecified. Outcome measures were culture-proven infectious organisms, antimicrobial susceptibilities, and final visual acuity in the patients. RESULTS: A total of 93 microorganisms were identified from 103 patients during the study period. The positive culture rate was 59.2 % (103/174). The most common organisms identified were Enterococcus faecalis (in 20.8 % of patients, 20/96), Staphylococcus epidermidis (18.8 %, 18/96), other coagulase negative staphylococci (10.4 %, 10/96), Pseudomonas aeruginosa (6.3 %, 6/96), and Klebsiella pneumoniae (6.3 %, 6/96). Two cases of Enterococcus faecium (2.1 %) were recognized. Overall, 70 of 96 (73.0 %) isolates were Gram-positive bacteria, 22 (23.0 %) were Gram-negative bacteria, and 4 (4.2 %) were fungi. The most common organisms resulting in reduced light perception were E. faecalis and K. pneumoniae. CONCLUSIONS: The emergence of E. faecalis in endophthalmitis is mainly caused by the high incidence of E. faecalis in postoperative endophthalmitis. This increase also impacts the final visual acuity of the patients. PMID- 24072646 TI - More evidence for anthropogenic influence on climate change. PMID- 24072647 TI - RNA does the folding dance of twist, turn, stack. PMID- 24072648 TI - Integrated assessments of payments for ecosystem services programs. PMID- 24072649 TI - Silencing synuclein at the synapse with PLK2. PMID- 24072652 TI - A meta-analysis of the relationship between glutathione S-transferase T1 null/presence gene polymorphism and the risk of lung cancer including 31802 subjects. AB - The relationship between glutathione S-transferase T1 (GSTT1) null/presence gene polymorphism and the risk of lung cancer from the published reports are still conflicting. This study was conducted to evaluate the relationship between GSTT1 null/presence gene polymorphism and the risk of lung cancer using meta-analysis method. The association studies were identified from PubMed, and Cochrane Library on July 1, 2012, and eligible investigations were included and synthesized using meta-analysis method. 51 reports were recruited into this meta-analysis for the association of null genotype of GSTT1 with lung cancer susceptibility, consisting of 15,140 patients with lung cancer and 16,662 controls. There was a marked association between GSTT1 null genotype and lung cancer risk in overall populations (OR = 1.15, 95 % CI 1.04-1.27, P = 0.007). Furthermore, GSTT1 null genotype was associated with the lung cancer risk in Asians (OR = 1.47, 95 % CI 1.23-1.76, P < 0.0001). However, GSTT1 null genotype was not associated with the risk of lung cancer in Caucasians, Brazilian population and Africans. In conclusion, GSTT1 null genotype is associated with the lung cancer in overall populations and in Asians. PMID- 24072653 TI - Functional polymorphism rs4072037 in MUC1 gene contributes to the susceptibility to gastric cancer: evidence from pooled 6,580 cases and 10,324 controls. AB - Genome-wide association studies have reported a promising association of rs4072037 with gastric cancer (GC). This variant was associated with altered physiological function of MUC1 possibly by modulating promoter activity and alternative splicing of MUC1. However, the association results were inconclusive and estimate of the effect of this variant was not well evaluated. A meta analysis by systematically reviewing relevant reports may facilitate to address these concerns. Association studies involving MUC1 rs4072037 polymorphism and GC risk were identified up to June 30, 2012. Odds ratio (OR) and 95 % confidence interval (CI) in additive model were estimated or extracted from each study. The pooled effect size was quantitatively synthesized using meta-analysis. Heterogeneity between studies was measured by the Q test and I (2) statistic, and publication bias was evaluated by a funnel plot and the Egger's test. A total of 10 independent case-control studies including 6,580 GC cases and 10,324 controls were included in this meta-analysis. Eight of the ten studies were Asian ethnicity and two European. The G allele of MUC1 rs4072037 was significantly associated with a decreased risk of GC (OR = 0.72, 95 % CI 0.68-0.77; P = 7.82 * 10(-25)), as compared with A allele. Stratification for different ethnicity, tumor localization or type showed similar results. These findings represent important evidence for association of MUC1 rs4072037 variant with GC risk, and also provide a relatively reliable estimate of effect size. MUC1 is a strong candidate as a susceptibility gene of GC. PMID- 24072654 TI - Influence of interleukin gene polymorphisms on development of acute pancreatitis: a systematic review and meta-analysis. AB - Several epidemiological studies have assessed the associations of interleukin (IL) gene polymorphisms with acute pancreatitis (AP) in different populations. However, the results were inconclusive. Therefore, we performed the present study to comprehensively evaluate the associations of IL gene polymorphisms and susceptibility to AP. Systematic searches of the PubMed, Web of Science, Embase, CNKI, CBMdisc and Google Scholar until February 27, 2013, as well as hand searching of the references of identified articles were performed. Data were extracted using standardized forms and odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. All statistical analyses were performed using Stata 11.0. Ten studies were included in our final combined analysis, covering a total of 1,220 AP cases and 1,351 controls. The results showed evidence for significant association between IL-8 -251 T/A (rs4073) polymorphism and AP risk, suggesting that IL-8 -251 A allele was associated with an increased risk of AP (for A allele vs. T allele: OR = 1.36, 95 % CI 1.05-1.76, p = 0.02; for A/A vs. T/T: OR = 2.28, 95 % CI 1.08-4.81, p = 0.03; for A/A+T/A vs. T/T: OR = 1.40, 95 % CI 1.11-1.77, p = 0.005). However, there were no significant associations between IL-1beta (IL-1beta +3954 C/T (rs1143634) and IL-1beta -511 C/T (rs16944)), IL-6 (IL-6 -174 G/C (rs1800795) and IL-6 -634 C/G (rs1800796)) and IL-10 (IL-10 -1082 A/G (rs1800896), IL-10 -819 C/T (rs1800871) and IL-10 -592 C/A (rs1800872)) gene polymorphisms and AP risk. In summary, the current study suggests that the IL-8 -251 T/A polymorphism is associated with an increased risk of AP. In addition, there were no significant associations between IL-1beta, IL-6 and IL-10 gene polymorphisms and AP risk. PMID- 24072655 TI - Molecular classification of Pakistani collared dove through DNA barcoding. AB - Pakistan is bestowed by a diversified array of wild bird species including collared doves of which the taxonomy has been least studied and reported. DNA barcoding is a geno-taxonomic tool that has been used for characterization of bird species using mitochondrial cytochrome c oxidase I gene (COI). This study aimed to identify taxonomic order of Pakistani collared dove using DNA barcoding. Purposely herein, we present a phylogenetic analysis of Pakistani collared dove based on 650 base pairs of COI gene sequences. Analysis of phylogenetic tree revealed that Pakistani collared dove shared a common clade with Eurasian collared dove (Streptopelia decaocto) and African collared dove (Streptopelia roseogrisea) which indicated a super-species group in Streptopelia genus. This is the first report of molecular classification of Pakistani collared dove using DNA barcoding. PMID- 24072656 TI - Characterization of polymorphic microsatellite markers and genetic diversity in wild bronze featherback, Notopterus notopterus (Pallas, 1769). AB - Six polymorphic microsatellite DNA loci were identified in the primitive fish, bronze featherback, Notopterus notopterus for the first time and demonstrated significant population genetic structure. Out of the six primers, one primer (NN90) was specific to N. notopterus (microsatellite sequence within the RAG1 gene) and five primers were product of successful cross-species amplification. Sixty-four primers available from 3 fish species of order Osteoglossiformes and families Notopteridae and Osteoglossidae were tested to amplify homologous microsatellite loci in N. notopterus. Fifteen primer pairs exhibited successful cross-priming PCR product. However, polymorphism was detected only at five loci. To assess the significance of these six loci (including NN90) in population genetic study, 215 samples of N. notopterus from five rivers, viz Satluj, Gomti, Yamuna, Brahmaputra and Mahanadi were analyzed. The five sample sets displayed different diversity levels and observed heterozygosity ranged from 0.6036 to 0.7373. Significant genotype heterogeneity (P < 0.0001) and high FST (0.2205) over all loci indicated that the samples are not drawn from the same genepool. The identified microsatellite loci are promising for use in fine-scale population structure analysis of N. notopterus. PMID- 24072657 TI - The effect of haplotype variation in the bovine PAX6 gene. AB - The transcription factor paired box 6 gene (PAX6) plays a key role during the early development of various organs. In this study, three single nucleotide polymorphisms (SNPs) have been identified in the introns 2, 8 and 11 of the bovine PAX6 gene. 8 haplotypes and 13 diplotypes were revealed and the linkage disequilibrium (LD) was assessed in 817 cows representing four main cattle breeds from China (Nanyang, NY; Qinchuan, QC; Jiaxian, JX; Chinese Holstein, CH). The LD analysis revealed that the additional three SNPs were not in strong LD, the wild haplotype (Hap 1: CTT) and mutant haplotype (Hap 8: TCC) have a frequency of 9.36, 35.61, 18.32, 57.15 % and 15.60, 14.19, 0.83, 0 % in the four cattle populations. The statistical analyses indicated that the SNP2 and 3 are associated with the body weight at birth, 6 and 12 months in NY and JX cattle population (P < 0.01 or P < 0.05); and significant association was detected between 19 (NY) or 13 (JX) diplotype (combined genotypes) and body weight at different ages (birth, 6 and 12 months). Our results provide evidence that some polymorphisms in PAX6 are associated with growth traits at some ages, and may be used as candidates for marker-assisted selection in beef cattle breeding program. PMID- 24072658 TI - Anxiety state affects information processing speed in patients with multiple sclerosis. AB - The aim of this study was to investigate the impact of anxiety on the cognitive performance of a clinical sample of relapsing-remitting (RR) MS patients. One hundred ninety patients (140 females) were included in the study and assessed through the beck depression inventory, the state-trait anxiety inventory and the Rao's brief repeatable battery which assesses cognitive domains most frequently impaired in MS. As for neuropsychological performance, a total of 76 (40%) subjects fulfilled our criterion for cognitive impairment. Tests most frequently failed by cognitive impairment (CI) patients were those assessing complex attention and information processing speed [Simbol Digit Modalities Test (SDMT), Paced Auditory Serial Auditory Test (PASAT) 3 and 2] and verbal memory. In the univariate analysis, state anxiety was related to failure on the SDMT (p = 0.042), and marginally, to failure on the PASAT-3 (p = 0.068), and to the presence of CI (p = 0.082). Moderate/severe depression was detected in 38 (20%) patients and fatigue in 109 (57%). Higher depression scores were related to impairment on the ST (OR = 1.05; 95% CI 1.01-1.10; p = 0.029). PMID- 24072659 TI - Reaction-diffusion patterns in plant tip morphogenesis: bifurcations on spherical caps. AB - We study a chemical reaction-diffusion model (the Brusselator) for pattern formation on developing plant tips. A family of spherical cap domains is used to represent tip flattening during development. Applied to conifer embryos, we model the chemical prepatterning underlying cotyledon ("seed leaf") formation, and demonstrate the dependence of patterns on tip flatness, radius, and precursor concentrations. Parameters for the Brusselator in spherical cap domains can be chosen to give supercritical pitchfork bifurcations of patterned solutions of the nonlinear reaction-diffusion system that correspond to the cotyledon patterns that appear on the flattening tips of conifer embryos. PMID- 24072660 TI - A phase-field model for articular cartilage regeneration in degradable scaffolds. AB - Degradable scaffolds represent a promising solution for tissue engineering of damaged or degenerated articular cartilage which due to its avascular nature, is characterized by a low self-repair capacity. To estimate the articular cartilage regeneration process employing degradable scaffolds, we propose a mathematical model as the extension of Olson and Haider's work (Int. J. Pure Appl. Math. 53:333-353, 2009). The simulated tissue engineering procedure consists in (i) the explant of a cylindrical sample, (ii) the removal of the inner core region, and (iii) the filling of the inner region with hydrogels, degradable scaffolds enriched with nutrients, such as oxygen and glucose. The phase-field model simulates the cartilage regeneration process at the scaffold-cartilage interface. It embeds reaction-diffusion equations, which are used to model the nutrient and regenerated extracellular matrix. The equations are solved using an unconditionally stable hybrid numerical scheme. Cartilage repair processes with full-thickness defects, which are controlled by properties of hydrogel materials and cartilage explant culture based on biological interest are observed. The implemented mathematical model shows the capability to simulate cartilage repairing processes, which can be virtually controlled evaluating hydrogel and cartilage material properties including nutrient supply and defected magnitude. In particular, the adopted methodology is able to explain the regeneration time of cartilage within hydrogel environments. With the numerical scheme, the numerical simulations are demonstrated for the potential improvement of hydrogel structures. PMID- 24072661 TI - The presence of migraines and its association with sensory hyperreactivity and anxiety symptomatology in children with autism spectrum disorder. AB - Migraine headaches are associated with sensory hyperreactivity and anxiety in the general population, but it is unknown whether this is also the case in autism spectrum disorders. This pilot study asked parents of 81 children (aged 7-17 years) with autism spectrum disorders to report their child's migraine occurrence, sensory hyperreactivity (Sensory Over-Responsivity Inventory), and anxiety symptoms (Spence Child Anxiety Scale). Children with autism spectrum disorders who experienced migraine headaches showed greater sensory hyperreactivity and anxiety symptomatology (p < 0.01; medium effect size for both) than those without migraines. Sensory hyperreactivity and anxiety symptomatology were additionally correlated (rho = 0.31, p = 0.005). This study provides preliminary evidence for a link between migraine headaches, sensory hyperreactivity, and anxiety symptomatology in autism spectrum disorders, which may suggest strategies for subtyping and exploring a common pathogenesis. PMID- 24072662 TI - The relation of parent-child interaction qualities to social skills in children with and without autism spectrum disorders. AB - This study examined associations between parent-child interactions and the development of social skills in 42 children (21 typically developing and 21 with autism spectrum disorders) between the ages of 3 years, 0 months and 6 years, 11 months. We expected that positive parent-child interaction qualities would be related to children's social skills and would mediate the negative relation between children's developmental status (typical development vs autism spectrum disorders) and social skills. Videotapes of parents and children during a 5-min wordless book task were coded for parent positive affect and emotional support as well as parent-child cohesiveness. Emotional support and cohesiveness were significantly related to children's social skills, such that higher emotional support and cohesiveness were associated with higher social skills, R (2) = .29, p = .02, and R (2) = .38, p = .002, respectively. Additionally, cohesiveness mediated the relation between children's developmental status and social skills. These findings suggest that parent emotional support and cohesiveness between parents and children positively influence children's social skills. Parent positive affect was unrelated to social skills. Implications of these findings for social skills interventions are discussed, particularly for young children with autism spectrum disorders. PMID- 24072663 TI - Goal-directed action control in children with autism spectrum disorders. AB - Repetitive behavior is a key characteristic of autism spectrum disorders. Our aim was to investigate the hypothesis that this abnormal behavioral repetition results from a tendency to over-rely on habits at the expense of flexible, goal directed action. Twenty-four children with autism spectrum disorders and 24 age- and gender-matched controls (8-12 years) initially learned to give specific responses to different pictorial stimuli in order to gain valuable outcomes. Subsequently, in the "slips-of-action" test, some of these outcomes were no longer valuable. Children needed to refrain from responding when stimuli were shown that signaled the availability of those outcomes while continuing to respond for the still-valuable outcomes. Reliance on habits should lead to "slips of action" toward no longer valuable outcomes. Therefore, the children's ability to respond selectively for still-valuable outcomes provides a measure of relative habitual versus goal-directed control. Two additional tasks were included to control for general task characteristics (i.e. working memory and inhibition). Children with autism spectrum disorders learned equally well as controls and were not impaired at flexibly adjusting their behavior to devaluation of the outcomes or stimuli. We found no evidence for a disruption in the balance between goal directed and habitual behavioral control in children with autism spectrum disorders. PMID- 24072664 TI - An investigation of the security of caregiver attachment during middle childhood in children with high-functioning autistic disorder. AB - Previous research has investigated caregiver attachment relationships in children with autism during early childhood, with few differences found from matched control groups. However, little is known of this relationship during middle childhood (ages 8-12 years). In this study, the aim was to establish whether there are differences in the security of attachment in children with high functioning autism compared to typically developing children. A secondary aim was to establish whether caregivers' perceptions of their child's attachment to them accorded with the children's own reports. Twenty-one children with high functioning autism and 17 typically developing children were administered the Kerns Security Scale and the Inventory of Parent and Peer Attachment-Revised, and caregivers completed the same questionnaires from the viewpoint of their child. There were no differences between the groups in the children's and parents' reports of attachment security. Parents' and children's reports were moderately correlated on the Kerns Security Scale but were not correlated on the Inventory of Parent and Peer Attachment-Revised. The results indicate that levels of attachment security in children with high-functioning autism are not different from those in typically developing children. PMID- 24072665 TI - OnabotulinumtoxinA is effective in patients with urinary incontinence due to neurogenic detrusor overactivity [corrected] regardless of concomitant anticholinergic use or neurologic etiology. AB - INTRODUCTION: To evaluate the efficacy and safety of onabotulinumtoxinA for the treatment of neurogenic detrusor overactivity (NDO) in subpopulations of etiology (multiple sclerosis [MS] or spinal cord injury [SCI]) and concomitant anticholinergics (use/non-use). METHODS: Data were pooled from two double-blind, placebo-controlled, pivotal, phase 3 studies including a total of 691 patients with >= 14 urinary incontinence (UI) episodes/week due to MS (n = 381) or SCI (n = 310). Patients received intradetrusor injections of onabotulinumtoxinA 200U (n = 227), 300U (n = 223), or placebo (n = 241). Change from baseline at week 6 in UI episodes/week (primary endpoint), urodynamics, quality of life (QOL), and adverse events (AEs) were assessed. RESULTS: Significant and similar reductions in UI episodes were observed regardless of etiology or anticholinergic use: at week 6, mean weekly decreases of -22.6 and -19.6 were seen in MS and SCI patients, respectively, and -20.3 and -22.5 in anticholinergic users and non users, respectively, treated with onabotulinumtoxinA 200U. The 300U dose did not add to the clinical efficacy in any subpopulation. Similar proportions of patients achieved >= 50% or 100% reductions in UI episodes in all subgroups. Improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and QOL were significant in both etiologies and were independent of anticholinergic use. The most common AEs in all groups were urinary tract infection and urinary retention. CONCLUSION: Regardless of concomitant anticholinergic use or etiology, onabotulinumtoxinA significantly improved UI symptoms, urodynamics, and QOL in patients with UI due to NDO. OnabotulinumtoxinA was well tolerated in all groups. PMID- 24072666 TI - Interactive E-learning module in pharmacology: a pilot project at a rural medical college in India. AB - Many medical educators are experimenting with innovative ways of E-learning. E learning provides opportunities to students for self-directed learning in addition to other advantages. In this study, we designed and evaluated an interactive E-learning module in pharmacology for effectiveness, acceptability and feasibility, with the aim of promoting active learning in this fact-filled subject. A quasi-experimental single-group pre-test/post-test study was conducted with fourth-semester students of the second professionals course (II MBBS), selected using non-probability convenience sampling method. An E-learning module in endocrine pharmacology was designed to comprise three units of interactive PowerPoint presentations. The pre-validated presentations were uploaded on the website according to a predefined schedule and the 42 registered students were encouraged to self-learning using these interactive presentations. Cognitive gain was assessed using an online pre- and post-test for each unit. Students' perceptions were recorded using an online feedback questionnaire on a 5-point Likert scale. Finally, focused group discussion was conducted to further explore students' views on E-learning activity. Significant attrition was observed during the E-learning activity. Of the 42 registered students, only 16 students completed the entire E-learning module. The summed average score of all three units (entire module) was increased significantly from 38.42 % (summed average pre-test score: 11.56/30 +/- 2.90) to 66.46 % (summed average post-test score: 19.94/30 +/- 6.13). The class-average normalized gain for the entire module was 0.4542 (45.42). The students accepted this E-learning activity well as they perceived it to be innovative, convenient, flexible and useful. The average rating was between 4 (agree) and 5 (strongly agree). The interactive E-learning module in pharmacology was moderately effective and well perceived by the students. The simple, cost-effective and readily available Microsoft PowerPoint tool appealed to medical educators to use this kind of simple E-learning technology blended with traditional teaching to encourage active learning among students especially in a rural setup is attractive. PMID- 24072667 TI - Problem-based learning and undergraduate research: another student's perspective. PMID- 24072669 TI - Speciation, distribution, and bioavailability of soil selenium in the Tibetan Plateau Kashin-beck disease area-a case study in Songpan County, Sichuan Province, China. AB - To clarify the relationship between the soil selenium distribution and its bioavailability with the distribution of Kashin-Beck disease (KBD) endemic areas on the eastern edge of the Tibetan Plateau, samples of natural soil (0-20 cm), cultivated topsoil, and main crops of the region (highland barley) were collected at different altitudes according to topographical and geomorphological features in both KBD and non-KBD areas of Songpan County. These samples were used for determination and analysis of total selenium content in soil and highland barley and available selenium that can be absorbed and utilized by plants. The results showed that the average total selenium content of natural and cultivated topsoil in KBD areas was lower than that in non-KBD areas (natural soil, P = 0.061; cultivated soil, P = 0.002), which is in agreement with the geographical distributions of selenium in other KBD-affected areas. However, the total soil selenium content exhibits certain micro-spatial distribution features, namely, the total selenium content in some endemic areas was significantly higher than that of non-KBD areas. This result was contrary to the general distribution that total selenium content in a KBD-affected area is lower than that in a non-KBD area. We further studied the extraction rate and content of soil selenium in six different fractions. The results indicated that the content and extraction rate of available selenium in KBD-affected areas were significantly lower than those in non-KBD areas. There is a distinct positive correlation between plant available selenium and highland barley selenium (r = 0.875, P = 0.001) and a distinct negative correlation with altitude (r = -0.801, P = 0.010). Therefore, in KBD endemic areas, the selenium content in crops decreases as the available selenium content in soil decreases and is closely related to the geographical environment features (such as altitude and precipitation). These results suggest that the soil available selenium and ecological features are important factors that restrict the dietary selenium flux for residents in KBD endemic areas of the Tibetan Plateau, providing a theoretical and experimental basis for implementing agricultural measures to regulate the ecological cycle of the selenium flux in the KBD endemic area. PMID- 24072668 TI - Lithium in the public water supply and suicide mortality in Greece. AB - The purpose of the present study was to evaluate the association between lithium levels in the public water supply and prefecture-based suicide rates in Greece. Analyses were conducted with respect to lithium levels in 149 samples from 34 prefectures of Greece. The average lithium level was 11.10 MUg/l (range 0.1 to 121 MUg/l). The results indicate that there is a tendency for lower suicide rates in the prefectures with high levels of lithium in drinking water. Ecological studies explained by researchers Schrauzer and Shrestha have revealed the existence of statistically significant inverse associations between the lithium levels in drinking water and the incidence of suicides, homicides, rapes, possession of narcotic drugs, and in juveniles, the rates of runaway from home. Such a result of inverse relationship was not proven by Kabacs et al., most likely because the differences of the lithium levels in the selection of their case-control samples were not large enough. In addition, probably the selection of random regions in Japan and East England might have been biased. Thus, the addition of small amounts of lithium to the drinking water could provide an effective means to lower the incidence of these conditions in the general population. Furthermore, the nutritional importance of lithium in the form of the carbonate named lithium carbonate (Li2CO3) is currently still viewed primarily as a pharmacological agent. The study by Al-Chalabi et al. state that the therapeutic activity of lithium in amyotrophic lateral sclerosis (ALS) is worth investigating. Any drug that can be shown to slow the course of ALS in a clinically significant way and to be safe and well tolerated will be an important advance for patients with this disease. PMID- 24072670 TI - The effect of deposition Se on the mRNA expression levels of GPxs in goats from a Se-enriched county of China. AB - Previous studies revealed that Se was an important regulatory factor for glutathione peroxidase (GPx) genes. However, the relationship between Se concentrations and mRNA expression levels of GPxs were unclear in goats, especially the goats living in natural Se-enriched area. Thus, the aim of this study was to determine the Se concentrations and the mRNA expression levels of GPx-1, GPx-2, GPx-3, and GPx-4 in goats from Ziyang County (ZY-H and ZY-L goats) and Baoji City (BJ-P goats), which were Se-rich region and Se-poor region in China, respectively. Atomic fluorescence spectrometry was used as an essential method to determine the Se concentrations in heart, liver, spleen, lung, kidney, longissimus, biceps femoris, and serum, and the gene expressions were quantified in mRNA samples extracted from the above tissues by real-time quantitative reverse transcription-polymerase chain reaction. We found that the Se concentrations in ZY-H and ZY-L goats were higher than that in BJ-P goats significantly (P < 0.05), and the pertinence relations of Se levels between serum and heart, liver, spleen, and kidney were significant (P < 0.05). The mRNA levels of GPx-1 in ZY-H and ZY-L goats were higher than that in BJ-P goats very significantly (P < 0.01) except for longissimus (P < 0.05). Our results indicated a significant trend for GPx-2 in the direction of increasing mRNA levels with increasing Se concentrations in goats but had no statistical significance (P > 0.05) in our experimental conditions. As to GPx-3, its mRNA expression in spleen, lung, and kidney (P < 0.05) were upregulated and were consensual to high Se contents in ZY-H goats, but no significant effects were observed in heart, liver, longissimus, and biceps femoris among our three groups (P > 0.05). The mRNA levels of GPx-4 in heart, liver, lung, and kidney of ZY-H and ZY-L goats were higher than that of BJ-P goats (P < 0.05), and the difference was very significant in lung especially (P < 0.01), but no change in spleen, longissimus, and biceps femoris (P > 0.05). In summary, these data suggested that the goats living in Ziyang County were rich in Se, and the deposition Se played important roles in the mRNA expression of GPx-1, GPx-3, and GPx-4 in certain tissues of goats differentially. PMID- 24072671 TI - Roles of changes in active glutamine transport in brain edema development during hepatic encephalopathy: an emerging concept. AB - Excessive glutamine (Gln) synthesis in ammonia-overloaded astrocytes contributes to astrocytic swelling and brain edema, the major complication of hepatic encephalopathy (HE). Much of the newly formed Gln is believed to enter mitochondria, where it is recycled to ammonia, which causes mitochondrial dysfunction (a "Trojan horse" mode of action). A portion of Gln may increase osmotic pressure in astrocytes and the interstitial space, directly and independently contributing to brain tissue swelling. Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis. Accumulation of excess Gln in mitochondria involves a carrier-mediated transport which is activated by ammonia. Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects. HE lowered the expression of SN1 at the RNA and protein level in the cerebral cortex (cc) in the thioacetamide (TAA) model of HE and the effect paralleled induction of cerebral cortical edema. Neither SN1 nor SN2 expression was affected by simple hyperammonemia, which produces no cc edema. TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons. Taken together, changes in the expression of Gln transporters during HE appear to favor retention of Gln in astrocytes and/or the interstitial space of the brain. HE may also affect arginine (Arg)/Gln exchange across the astrocytic cell membrane due to changes in the expression of the hybrid Arg/Gln transporter y(+)LAT2. Gln export from brain across the blood brain barrier may be stimulated by HE via its increased exchange with peripheral tryptophan. PMID- 24072672 TI - Unexpected Properties of delta-Containing GABAA Receptors in Response to Ligands Interacting with the alpha+ beta- Site. AB - GABAA receptors are the major inhibitory neurotransmitter receptors in the central nervous system and are the targets of many clinically important drugs, which modulate GABA induced chloride flux by interacting with separate and distinct allosteric binding sites. Recently, we described an allosteric modulation occurring upon binding of pyrazoloquinolinones to a novel binding site at the extracellular alpha+ beta- interface. Here, we investigated the effect of 4-(8-methoxy-3-oxo-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzonitrile (the pyrazoloquinolinone LAU 177) at several alphabeta, alphabetagamma and alphabetadelta receptor subtypes. LAU 177 enhanced GABA-induced currents at all receptors investigated, and the extent of modulation depended on the type of alpha and beta subunits present within the receptors. Whereas the presence of a gamma2 subunit within alphabetagamma2 receptors did not dramatically change LAU 177 induced modulation of GABA currents compared to alphabeta receptors, we observed an unexpected threefold increase in modulatory efficacy of this compound at alpha1beta2,3delta receptors. Steric hindrance experiments as well as inhibition by the functional alpha+ beta- site antagonist LAU 157 indicated that the effects of LAU 177 at all receptors investigated were mediated via the alpha+ beta- interface. The stronger enhancement of GABA-induced currents by LAU 177 at alpha1beta3delta receptors was not observed at alpha4,6beta3delta receptors. Other experiments indicated that this enhancement of modulatory efficacy at alpha1beta3delta receptors was not observed with another alpha+ beta- modulator, and that the efficacy of modulation by alpha+ beta- ligands is influenced by all subunits present in the receptor complex and by structural details of the respective ligand. PMID- 24072673 TI - Changes in levels of hypoxia-induced mediators in rat hippocampus during chronic cerebral hypoperfusion. AB - The hypoxia-inducible factor (HIF)-mediated signaling pathway is an adaptive and protective mechanism that is triggered by hypoxia, ischemia, and other pathophysiological conditions. The expression of HIF-1alpha and downstream genes, some of which are pro-apoptotic whereas others are pro-survival, is up-regulated in ischemic stroke. Interestingly, however, the effects of HIF-1alpha activation are different in the early and late stages of acute cerebral ischemia, and these differences may depend on the duration and severity of hypoxia. Therefore, in the present study, we investigated the effect of HIF-1alpha activation in chronic cerebral hypoperfusion, which plays an important role in the development of dementia. Permanent bilateral common carotid artery occlusion (2VO) was used to induce chronic global cerebral hypoperfusion in rats. The expression of HIF 1alpha protein and the transcription of downstream genes were measured at different time points, including 0 h, 12 h, 24 h, 3 days, 7 days, 14 days, 28 days, 42 days, and 56 days after 2VO. HIF-1alpha increased as early as 12 h after the occlusion and remained high for at least 56 days. Interestingly, mRNA levels of both pro-apoptotic (Bcl-2/adenovirus EIB 19 kDa-interacting protein 3, NADPH oxidase activator 1, and NIP3-like protein X) and pro-survival (vascular endothelial growth factor, glucose transporter-1) genes were up-regulated at the early stage after 2VO, followed by a gradual decline to baseline/control levels. Thus, HIF-1alpha increased consistently during chronic cerebral hypoperfusion, whereas both pro-apoptotic and pro-survival downstream genes were up-regulated only early after 2VO. This mismatch in gene expression may contribute to the lack of a protective effect of highly expressed HIF-1alpha during the chronic stage of cerebral hypoperfusion. PMID- 24072674 TI - Class I histone deacetylase inhibitor valproic acid reverses cognitive deficits in a mouse model of septic encephalopathy. AB - Accumulating evidence suggests that histone deacetylase inhibitor exert neuroprotective effects in animal models of neurological diseases. We investigated for the first time whether class I histone deacetylase inhibitor valproic acid (VPA) can reverse cognitive deficits in a mouse model of sepsis associated encephalopathy (SAE). Moreover, the possible mechanisms of protection were also explored. A mouse model of SAE was induced in adult male mice by cecal ligation and puncture (CLP). Mice received an administration of saline or VPA (100 mg/kg) once daily for 14 consecutive days starting either immediately or 2 weeks after operation. Furthermore, the TrkB antagonist K252a was used in another group of experiment to investigate whether brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway is involved in the protection of VPA. Our data suggested that CLP resulted in significant cognitive impairments accompanied by increased expressions in interleukin-1beta and caspase-3, and decreased expressions in BDNF, phospho-TrkB (pTrkB), postsynaptic density 95, and synapses, which were reversed by VPA. However, TrkB antagonist K252a abolished the beneficial effects of VPA with regard to cognition and decreased pTrkB expression and synapses in the hippocampus. Taken together, the findings of the present study suggested chronic treatment with VPA reverses cognitive deficits through mechanisms probably via a reduction in inflammation and apoptosis in the brain, as well as the activation of the BDNF-TrkB signaling pathway in a mouse model of SAE. PMID- 24072675 TI - Combination of chemopreventive agents in nanoparticles for cancer prevention. AB - Carcinogenesis involves multiple genetic and epigenetic alterations, and a single chemopreventive agent may not be sufficient to prevent these events. Therefore, the use of a combination of agents is an attractive approach for cancer chemoprevention. In this issue of the journal, Prabhu and colleagues examined a combination of aspirin, curcumin, and sulforaphane for the prevention of pancreatic cancer in hamsters (beginning page 1015). The novelty of this work is that when aspirin and curcumin were incorporated in nanoparticles and administered orally, in combination with sulforaphane, the effective dosages were decreased by 10-fold in comparison with the free form mixture. In this commentary, the possible mechanisms of synergistic action among multiple chemopreventive agents and the use of stable nanoparticles for oral delivery are discussed. Also discussed is the importance of measuring tissue levels of the chemopreventive agents to understand the mode of action of these nanoparticles and to avoid toxicity. PMID- 24072677 TI - Big punches come in nanosizes for chemoprevention. AB - Literature to support the chemopreventive potential of several bioactive molecules has been prolific and convincing, but the clinical development of these agents has been slow. Major hurdles for development of bioactive chemoprevention approaches include low potency, lack of reliable formulations with high bioavailability that are suitable for oral administration, and relevant preclinical primary prevention models that use meaningful doses that can be translated to humans. The paper presented in this issue (Grandhi and colleagues) is an important step forward in this direction. It shows the efficacy of an oral, low dose, solid-lipid nanoparticles encapsulated curcumin and aspirin combined with free sulforaphane for long-term chemoprevention of pancreatic cancer in a carcinogen-induced hamster model. Reproducing this benefit in multiple cancer models, accompanied by development of intermediate markers of response will allow rapid translation of these findings. It will constitute the first successful multipronged attack at key pathways known to initiate and promote carcinogenesis. PMID- 24072676 TI - A novel combinatorial nanotechnology-based oral chemopreventive regimen demonstrates significant suppression of pancreatic cancer neoplastic lesions. AB - Pancreatic cancer is a deadly disease killing 37,000 Americans each year. Despite two decades of research on treatment options, the chances of survival are still less than 5% upon diagnosis. Recently, chemopreventive strategies have gained considerable attention as an alternative to treatment. We have previously shown significant in vitro chemopreventive effects with low-dose combinations of aspirin, curcumin, and sulforaphane (ACS) on pancreatic cancer cell lines. Here, we report the results of 24-week chemopreventive study with the oral administration of ACS combinations on the N-nitrosobis (2-oxopropyl) amine (BOP) treated Syrian golden hamster model to suppress the progression of pancreatic intraepithelial neoplasms (PanIN) using unmodified (free drug) combinations of ACS, and nanoencapsulated (solid lipid nanoparticles; SLN) combinations of aspirin, curcumin, and free sulforaphane. The use of three different doses (low, medium, and high) of unmodified ACS combinations exhibited reduction in tumor incidence by 18%, 50%, and 68.7% respectively; whereas the modified nanoencapsulated ACS regimens reduced tumor incidence by 33%, 67%, and 75%, respectively, at 10 times lower dose compared with the free drug combinations. Similarly, although the unmodified free ACS showed a notable reduction in cell proliferation, the SLN encapsulated ACS regimens showed significant reduction in cell proliferation at 6.3%, 58.6%, and 72.8% as evidenced by proliferating cell nuclear antigen expression. Cell apoptotic indices were also upregulated by 1.5, 2.8, and 3.2 times, respectively, compared with BOP control. These studies provide a proof-of-concept for the use of an oral, low-dose, nanotechnology-based combinatorial regimen for the long-term chemoprevention of pancreatic cancer. PMID- 24072678 TI - Resolvin D1 improves survival in experimental sepsis through reducing bacterial load and preventing excessive activation of inflammatory response. AB - Sepsis is characterized as an uncontrolled inflammatory response. Spite et al. (Nature 461(7268):1287-1291, 2009) had demonstrated that resolvin D2, which is derived from docosahexaenoic acid (DHA), improves survival in cecal ligation and puncture (CLP)-initiated sepsis and enhances bacterial clearance without immune suppression. Resolvin D1, which is also derived from DHA and homologous with resolvin D2, is an endogenous anti-inflammatory and proresolving lipid molecule. We sought to investigate the effects of resolvin D1 on sepsis and to explore the mechanism of action. Six-to-eight-week-old male C57BL/6 mice were randomly divided into three groups: the sham group underwent the sham operation followed by tail vein injection of vehicle (0.1 % ethanol); the CLP group received vehicle (0.1 % ethanol) after CLP; the resolvin D1 group received resolvin D1 (100 ng) after CLP. Blood, peritoneal lavage fluid, and organs of mice were harvested 24 h after treatment for cytokine analysis, cell counts, bacterial cultures, histopathological studies, and apoptosis quantification. Compared with the vehicle control group, the survival rate and bacterial clearance of mice with sepsis induced by CLP were improved after resolvin D1 treatment, but the numbers of neutrophils in peritoneal lavage fluid, the inflammatory cytokines, the phosphorylation of the nuclear factor-kappaB (NF-kappaB) (P65) pathway, and the apoptosis rate of CD3(+) T lymphocytes of the thymus were suppressed. Resolvin D1 treatment improved survival in mice with sepsis induced by CLP, enhanced organism bacterial clearance, suppressed the increase of the numbers of neutrophils in peritoneal lavage fluid, reduced the release of inflammatory cytokines, and decreased the apoptosis rate of CD3(+) T lymphocytes of the thymus. These results suggest that resolvin D1 may attenuate the degree of inflammatory reaction in sepsis caused by CLP, without harming the host defense response. PMID- 24072679 TI - Development of a multilocus sequence typing scheme for Ureaplasma. AB - Ureaplasma is a commensal of the human urogenital tract but is always associated with invasive diseases such as non-gonococcal urethritis and infertility adverse pregnancy outcomes. To better understand the molecular epidemiology and population structure of Ureaplasma, a multilocus sequence typing (MLST) scheme based on four housekeeping genes (ftsH, rpL22, valS, thrS) was developed and validated using 283 isolates, including 14 serovars of reference strains and 269 strains obtained from clinical patients. A total of 99 sequence types (STs) were revealed: the 14 type strains of the Ureaplasma serovars were assigned to 12 STs, and 87 novel and special STs appeared among the clinical isolates. ST1 and ST22 were the predominant STs, which contained 68 and 70 isolates, respectively. Two clonal lineages (CC1 and CC2) were shown by eBURST analysis, and linkage disequilibrium was revealed through a standardized index of association (I A (S)). The neighbor-joining tree results of 14 Ureaplasma serovars showed two genetically significantly distant clusters, which was highly congruent with the species taxonomy of ureaplasmas [Ureaplasma parvum (UPA) and Ureaplasma urealyticum (UUR)]. Analysis of the biotypes of 269 clinical isolates revealed that all the isolates of CC1 were UPA and those of CC2 were UUR. Additionally, CC2 was found more often in symptomatic patients with vaginitis, tubal obstruction, and cervicitis. In conclusion, this MLST scheme is adequate for investigations of molecular epidemiology and population structure with highly discriminating capacity. PMID- 24072681 TI - Digestion of epithelial tight junction proteins by the commensal Clostridium perfringens. AB - The enteric microbiota contributes to the pathogenesis of inflammatory bowel disease, but the pathways involved and bacterial participants may vary in different hosts. We previously reported that some components of the human commensal microbiota, particularly Clostridium perfringens (C. perfringens), have the proteolytic capacity for host matrix degradation and reduce transepithelial resistance. Here, we examined the C. perfringens-derived proteolytic activity against epithelial tight junction proteins using human intestinal epithelial cell lines. We showed that the protein levels of E-cadherin, occludin, and junctional adhesion molecule 1 decrease in colonic cells treated with C. perfringens culture supernatant. E-cadherin ectodomain shedding in C. perfringens-stimulated intestinal epithelial cells was detected with antibodies against the extracellular domain of E-cadherin, and we demonstrate that this process occurs in a time- and dose-dependent manner. In addition, we showed that the filtered sterile culture supernatant of C. perfringens has no cytotoxic activity on the human intestinal cells at the concentrations used in this study. The direct cleavage of E-cadherin by the proteases from the C. perfringens culture supernatant was confirmed by C. perfringens supernatant-induced in vitro degradation of the human recombinant E-cadherin. We conclude that C. perfringens culture supernatant mediates digestion of epithelial cell junctional proteins, which is likely to enable access to the extracellular matrix components by the paracellular pathway. PMID- 24072680 TI - Loss of NHE3 alters gut microbiota composition and influences Bacteroides thetaiotaomicron growth. AB - Changes in the intestinal microbiota have been linked to diabetes, obesity, inflammatory bowel disease, and Clostridium difficile (C. difficile)-associated disease. Despite this, it remains unclear how the intestinal environment, set by ion transport, affects luminal and mucosa-associated bacterial composition. Na(+)/H(+)-exchanger isoform 3 (NHE3), a target of C. difficile toxin B, plays an integral role in intestinal Na(+) absorption. Thus the NHE3-deficient mouse model was chosen to examine the effect of pH and ion composition on bacterial growth. We hypothesized that ion transport-induced change in the intestinal environment would lead to alteration of the microbiota. Region-specific changes in ion composition and pH correlated with region-specific alteration of luminal and mucosal-associated bacteria with general decreases in Firmicutes and increases in Bacteroidetes members. Bacteroides thetaiotaomicron (B. thetaiotaomicron) increased in NHE3(-/-) terminal ileum and was examined in vitro to determine whether altered Na(+) was sufficient to affect growth. Increased in vitro growth of B. thetaiotaomicron occurred in 43 mM Na(+) correlating with the NHE3(-/-) mouse terminal ileum [Na(+)]. NHE3(-/-) terminal ileum displayed increased fut2 mRNA and fucosylation correlating with B. thetaiotaomicron growth. Inoculation of B. thetaiotaomicron in wild-type and NHE3(-/-) terminal ileum organoids displayed increased fut2 and fucosylation, indicating that B. thetaiotaomicron alone is sufficient for the increased fucosylation seen in vivo. These data demonstrate that loss of NHE3 alters the intestinal environment, leading to region-specific changes in bacteria, and shed light on the growth requirements of some gut microbiota members, which is vital for creating better treatments of complex diseases with an altered gut microbiota. PMID- 24072682 TI - Glucose-dependent insulinotropic polypeptide regulates dipeptide absorption in mouse jejunum. AB - Glucose-dependent insulinotropic polypeptide (GIP) secreted from jejunal mucosal K cells augments insulin secretion and plays a critical role in the pathogenesis of obesity and Type 2 diabetes mellitus. In recent studies, we have shown GIP directly activates Na-glucose cotransporter-1 (SGLT1) and enhances glucose absorption in mouse jejunum. It is not known whether GIP would also regulate other intestinal nutrient absorptive processes. The present study investigated the effect of GIP on proton-peptide cotransporter-1 (PepT1) that mediates di- and tripeptide absorption as well as peptidomimetic drugs. Immunohistochemistry studies localized both GIP receptor (GIPR) and PepT1 proteins on the basolateral and apical membranes of normal mouse jejunum, respectively. Anti-GIPR antibody detected 50-, 55-, 65-, and 70-kDa proteins, whereas anti-PepT1 detected a 70-kDa proteins in mucosal homogenates of mouse jejunum. RT-PCR analyses established the expression of GIPR- and PepT1-specific mRNA in mucosal cells of mouse jejunum. Absorption of Gly-Sar (a nondigestible dipeptide) measured under voltage-clamp conditions revealed that the imposed mucosal H(+) gradient-enhanced Gly-Sar absorption as an evidence for the presence of PepT1-mediated H(+):Gly-Sar cotransport on the apical membranes of mouse jejunum. H(+):Gly-Sar absorption was completely inhibited by cephalexin (a competitive inhibitor of PepT1) and was activated by GIP. The GIP-activated Gly-Sar absorption was completely inhibited by RP-cAMP (a cAMP antagonist). In contrast to GIP, the ileal L cell secreting glucagon-like peptide-1 (GLP-1) did not affect the H(+):Gly-Sar absorption in mouse jejunum. We conclude from these observations that GIP, but not GLP-1, directly activates PepT1 activity by a cAMP-dependent signaling pathway in jejunum. PMID- 24072683 TI - Impact of hospital teaching status on length of stay and mortality among patients undergoing complex hepatopancreaticobiliary surgery in the USA. AB - OBJECTIVE: To define the impact of hospital teaching status on length of stay and mortality for patients undergoing complex hepatopancreaticobiliary (HPB) surgery in the USA. METHODS: Using the Nationwide Inpatient Sample, we identified 285,442 patient records that involved a liver resection, pancreatoduodenectomy, other pancreatic resection, or hepaticojejunostomy between years 2000 and 2010. Year wise distribution of procedures at teaching and non-teaching hospitals was described. The impact of teaching status on in-hospital mortality for operations performed at hospitals in the top tertile of procedure volume was determined using multivariate logistic regression analysis. RESULTS: A majority of patients were under 65 years of age (59.6 %), white (74.0 %), admitted on an elective basis (77.3 %), and had a low comorbidity burden (70.5 %). Ninety percent were operated upon at hospitals in the top tertile of yearly procedure volume. Among patients undergoing an operation at a hospital in the top tertile of procedure volume (>25/year), non-teaching status was associated with an increased risk of in-hospital death (OR 1.47 [1.3, 1.7]). Other factors associated with increased risk of mortality were older patient age (OR 2.52 [2.3, 2.8]), male gender (OR 1.73 [1.6, 1.9]), higher comorbidity burden (OR 1.49 [1.3, 1.7]), non-elective admission (OR 3.32 [2.9, 4.0]), and having a complication during in-hospital stay (OR 2.53 [2.2, 3.0]), while individuals with private insurance had a lower risk of in-hospital mortality (OR 0.45 [0.4, 0.5]). After controlling for other covariates, undergoing complex HPB surgery at a non-teaching hospital remained independently associated with 32 % increased odds of death as (OR 1.32, 95 % CI 1.11-1.58; P < 0.001). CONCLUSIONS: Even among high-volume hospitals, patients undergoing complex HPB have better outcomes at teaching vs. non-teaching hospitals. While procedural volume is an established factor associated with surgical outcomes among patients undergoing complex HPB procedures, other hospital-level factors such as teaching status have an important impact on peri operative outcomes. PMID- 24072684 TI - Colorectal emergencies: perforated diverticulitis (operative and nonoperative management). PMID- 24072685 TI - Proximity ligation assay for high-content profiling of cell signaling pathways on a microfluidic chip. AB - Here, we present the full integration of a proximity ligation assay (PLA) on a microfluidic chip for systematic cell signaling studies. PLA is an in situ technology for the detection of protein interaction, post-translational modification, concentration, and cellular location with single-molecule resolution. Analytical performance advances on chip are achieved, including full automation of the biochemical PLA steps, target multiplexing, and reduction of antibody consumption by 2 orders of magnitude relative to standard procedures. In combination with a microfluidic cell-culturing platform, this technology allows one to gain control over 128 cell culture microenvironments. We demonstrate the use of the combined cell culture and protein analytic assay on chip by characterizing the Akt signaling pathway upon PDGF stimulation. Signal transduction is detected by monitoring the phosphorylation states of Akt, GSK 3beta, p70S6K, S6, Erk1/2, and mTOR and the cellular location of FoxO3a in parallel with the PLA. Single-cell PLA results revealed for Akt and direct targets of Akt a maximum activation time of 4 to 8 min upon PDGF stimulation. Activation times for phosphorylation events downward in the Akt signaling pathway including the phosphorylation of S6, p70S6K, and mTOR are delayed by 8 to 10 min or exhibit a response time of at least 1 h. Quantitative confirmation of the Akt phosphorylation signal was determined with the help of a mouse embryonic fibroblast cell line deficient for rictor. In sum, this work with a miniaturized PLA chip establishes a biotechnological tool for general cell signaling studies and their dynamics relevant for a broad range of biological inquiry. PMID- 24072686 TI - Fostering diffusion of scientific contents of National Society Cardiovascular Journals:the new ESC search engine. AB - European Society of Cardiology (ESC) National Society Cardiovascular Journals (NSCJs) are high-quality biomedical journals focused on cardiovascular diseases. The Editors' Network of the ESC devises editorial initiatives aimed at improving the scientific quality and diffusion of NSCJ. In this article we will discuss on the importance of the Internet, electronic editions and open access strategies on scientific publishing. Finally, we will propose a new editorial initiative based on a novel electronic tool on the ESC web-page that may further help to increase the dissemination of contents and visibility of NSCJs. PMID- 24072687 TI - What do cardiologists know about the effects of cardiovascular agents on sexual function? A survey among Dutch cardiologists. Part I. AB - INTRODUCTION: Several cardiovascular agents, such as diuretics and beta-blockers, can negatively affect sexual function, leading to noncompliance with therapy. Others such as angiotensin II receptor blockers (ARBs) can improve patients' sexual function. AIMS: We aimed to gain insight into cardiologists' knowledge about the effects of cardiovascular drugs on sexual function and whether they take this knowledge into account when prescribing drugs. METHODS: An anonymous questionnaire was mailed to 980 members of the Netherlands Society of Cardiologists (cardiologists and residents in training). RESULTS: Almost 54 % of Dutch cardiologists responded; 414 questionnaires were analysed. Forty-five percent of cardiologists were aware that diuretics can negatively affect sexual function, 93.1 % knew about the negative effects beta-blockers can have, but only 9.2 % were aware that ARBs can have positive effects on sexual health. Almost half of respondents (48.2 %) stated they change medication regularly in an attempt to improve sexual function. Experienced cardiologists said they do this significantly more often than less experienced ones. CONCLUSIONS: Cardiologists' knowledge about the effects of cardiovascular drugs on sexual health appears to be insufficient. Sexual dysfunction is not routinely taken into account when cardiologists prescribe drugs. PMID- 24072688 TI - Adoption of prasugrel into routine practice: rationale and design of the Rijnmond Collective Cardiology Research (CCR) study in percutaneous coronary intervention for acute coronary syndromes. AB - BACKGROUND: Platelet inhibition is crucial in reducing both short- and long-term atherothrombotic risks in patients with acute coronary syndromes (ACS) managed with percutaneous coronary intervention (PCI). Based on randomised trials, recent recommendations in the current guidelines include the endorsement of prasugrel as a first-choice adenosine diphosphate receptor inhibitor. Yet, there is limited experience with the use of prasugrel in routine practice. METHODS: The Rijnmond Collective Cardiology Research (CCR) registry is a prospective, observational study that will follow-up 4000 PCI-treated ACS patients in the larger region of Rotterdam, the Netherlands. Based on recently implemented hospital protocols, all patients will receive prasugrel as first-choice antiplatelet agent, unless contraindicated, in accordance with European guidelines, and will be followed for up to 1 year post-discharge for longitudinal assessment of outcomes and bleeding events. This registry exemplifies a collaborative study design that employs a regional PCI registry platform and provides feedback to participating sites regarding their practice patterns, thereby supporting and promoting improvement of quality of care. CONCLUSION: The CCR registry will evaluate the adoption of prasugrel into routine clinical practice and thus, will provide important evidence with regard to the benefits and risks of real-world utilisation of prasugrel as antiplatelet therapy in PCI-treated ACS patients. PMID- 24072689 TI - The new oral anticoagulants in atrial fibrillation: an update. AB - In patients with nonvalvular atrial fibrillation, oral anticoagulation with the vitamin K antagonists acenocoumarol, phenprocoumon and warfarin reduces the risk of stroke by more than 60 %, whereas single or double antiplatelet therapy is much less effective and sometimes associated with a similar bleeding risk as vitamin K antagonists. Besides bleeding, and intracranial haemorrhage in particular, INR monitoring remains the largest drawback of vitamin K antagonists. In the last decade oral agents have been developed that directly block the activity of thrombin (factor IIa), as well as drugs that directly inhibit activated factor X (Xa), which is the first compound in the final common pathway to the activation of thrombin. These agents have been approved for stroke prevention in atrial fibrillation and are now reimbursed under a national guideline for their safe use. They have advantages in that they do not need monitoring and have a fast onset and offset of action, but lack an established specific antidote. This survey addresses the role of modern anticoagulation for stroke prevention in atrial fibrillation. PMID- 24072690 TI - Internal anatomy of Haliclystus antarcticus (Cnidaria, Staurozoa) with a discussion on histological features used in Staurozoan taxonomy. AB - Stauromedusae have relatively few macromorphological characters, making both their taxonomy and identification difficult. For this reason, histological characters are also employed in the taxonomy of the group. This study presents a detailed description of the histomorphology of Haliclystus antarcticus Pfeffer, 1889 (Cnidaria, Staurozoa). We make new observations for the species and for the class, and address functional, taxonomical, and evolutionary aspects of staurozoan histo-anatomy. A complete reconstruction of H. antarcticus body plan is used to guide a more detailed observation, based on light microscopy, of structures rarely cited in the literature, such as the intertentacular lobules, the ostia between adjacent perradial pockets, and the male and female gonadal vesicles. Two possible regions of nematocyst formation are hypothesized and discussed. We also provide a review of the current use of histological characters in the taxonomy of the group. Understanding the body plan of stauromedusae is a challenge, because each single individual presents characters found in medusae and in polyps of other medusozoans. Comprehensive histological descriptions are important to establish relations of homology within Staurozoa and Cnidaria, providing crucial data on their evolution. PMID- 24072691 TI - Serum 25-hydroxyvitamin D concentration in subclinical carotid atherosclerosis. AB - OBJECTIVE: Vitamin D deficiency has been implicated in cardiovascular disease and is associated with multiple cardiovascular risk factors. We investigated the serum 25-hydroxyvitamin D (25(OH)D) concentration in relation to latitude, baseline carotid intima-media thickness (IMT), and IMT progression, the carotid IMT measures being surrogate markers of subclinical atherosclerosis and cardiovascular disease risk. APPROACH AND RESULTS: Serum 25(OH)D concentration was related to high-resolution carotid IMT measures in 3430 middle-aged and elderly subjects with high cardiovascular risk but no prevalent disease, who were recruited at 7 centers in Finland, Sweden, The Netherlands, France, and Italy. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30 after entry into the study, whereas blood samples, clinical data, and information about lifestyle were collected at baseline. Serum 25(OH)D levels were positively associated with latitude (Jonckheere-Terpstra chi=166.643; P<0.001) and, as previously reported, associated with a range of cardiovascular risk factors. There were no independent relationships between 25(OH)D and segment specific or composite IMT measures in the entire cohort. In analyses stratified by sex, diabetes mellitus, and statin treatment, weak associations with some baseline and progression measures of carotid IMT were observed in males, diabetics, and nonstatin-treated individuals. CONCLUSIONS: Levels of 25(OH)D differed across Europe, were highest in the North, showed multiple associations with established and emerging cardiovascular risk factors but were not consistently, independently related to measures of carotid IMT. This argues against a protective role of vitamin D against subclinical atherosclerosis in high-risk individuals. PMID- 24072692 TI - Soluble JAGGED1 inhibits pulmonary hypertension by attenuating notch signaling. AB - OBJECTIVE: Notch signaling has been implicated in the development of pulmonary arterial hypertension (PH) as reflected by increased expression of Notch member proteins that induce the proliferation of pulmonary arterial smooth muscle cells (PASMCs). Soluble Jagged1 (sJag1) has been shown to inhibit Notch signaling in vitro and in vivo; however, its capacity to suppress PH remains unknown. APPROACH AND RESULTS: Notch1, Notch3, Jagged1, and Herp2 protein were highly expressed in both the mouse model of hypoxia-induced PH and the rat model of monocrotaline induced PH. By attenuation and reversal of multiple pathological processes that were associated with PH, adenoviral sJag1 transfection significantly reduced the proliferation and enhanced the apoptosis of PASMCs in PH, whereas vehicle had no effect. The sJag1 inhibitory effect on Notch activation is likely related to its interference with ligand-induced signaling. Importantly, the administration with adenoviral sJag1 improved the survival rate of PH rats. Furthermore, sJag1 can restore the PH-PASMCs phenotype from the dedifferentiated to the differentiated state, by giving a positive effect on the physical binding of myocardin to the CC(A/T)nGG (CArG)-containing regions of vascular smooth muscle cells-specific promoters. CONCLUSIONS: Our results demonstrated that the potential therapeutic use of the sJag1 may not only inhibit the proliferation of PASMCs but also restore the PH-PASMCs phenotype from the dedifferentiated to the differentiated state through interference with Notch-Herp2 signaling. PMID- 24072693 TI - Hypoxia induces metalloproteinase-9 activation and human vascular smooth muscle cell migration through low-density lipoprotein receptor-related protein 1 mediated Pyk2 phosphorylation. AB - OBJECTIVE: Hypoxia disturbs vascular function by promoting extracellular matrix remodeling. Extracellular matrix integrity and composition are modulated by metalloproteinases (MMPs). Our aim was to investigate the role of low-density lipoprotein receptor-related protein 1 (LRP1) in regulating MMP-9/MMP-2 activation and vascular smooth muscle cells (VSMCs) migration in response to hypoxia, and to elucidate the LRP1-signaling pathways involved in this process. APPROACH AND RESULTS: Western blot analysis showed that hypoxia induced a sustained phosphorylation of proline-rich tyrosine kinase 2 concomitantly with LRP1 overexpression in human VSMCs (hVSMCs). Deletion of LRP1 using small interfering RNA technology or treatment of hVSMCs with the Src family kinase inhibitor PP2 impaired hypoxia-induced phosphorylation of proline-rich tyrosine kinase 2 levels. Coimmunoprecipitation experiments showed that the higher amounts of phosphorylation of proline-rich tyrosine kinase 2/LRP1beta immunoprecipitates in hypoxic hVSMCs were abolished in PP2-treated hVSMCs. Both LRP1 silencing and PP2 treatment were highly effective in the prevention of hypoxia-induced MMP-9 activation and hVSMC migration. Cellular subfractionation experiments revealed that PP2 effects may be caused by impairment of hypoxia-induced nuclear factor kappabeta translocation to the nucleus. ELISA measurements showed that LRP1 silencing but not PP2 treatment increased interleukin-1beta, interleukin-6, and monocyte chemoattractant protein-1 secretion by hypoxic hVSMCs. CONCLUSIONS: Our findings determine a crucial role of LRP1-mediated Pyk2 phosphorylation on hypoxia-induced MMP-9 activation and hVSMC migration and therefore in hypoxia induced vascular remodeling. Both LRP1 silencing and PP2 treatments also influence hypoxia-induced proinflammatory effects in hVSMCs. Therefore, further studies are required to establish therapeutical strategies that efficiently modulate vascular remodeling and inflammation associated with hypoxia-vascular diseases. PMID- 24072695 TI - C-reactive protein, fatal and nonfatal coronary artery disease, stroke, and peripheral artery disease in the prospective EPIC-Norfolk cohort study. AB - OBJECTIVE: Circulating levels of C-reactive protein (CRP) are associated with an increased risk of coronary artery disease (CAD), stroke, and peripheral artery disease (PAD). Observational and experimental evidence suggest that CRP might differentially predict fatal and nonfatal cardiovascular events. Here, we sought to determine the predictive value of CRP for fatal and nonfatal CAD, stroke, or PAD. APPROACH AND RESULTS: CRP levels were measured in 18 450 apparently healthy participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. Cox proportional hazards models were used to quantify the association between CRP levels and fatal and nonfatal CAD events, strokes, and PAD events. Bootstrapping was applied to test for significant differences between the risk of fatal and nonfatal events. During 208 485 person-years at risk, 2915 CAD events, 361 strokes, and 657 PAD events occurred. CRP was associated with fatal and nonfatal CAD events and nonfatal PAD events. When adding CRP to predictive risk models for fatal and nonfatal events corrected for known cardiovascular risk factors, the net reclassification index was 2.1% for fatal and 1.9% for nonfatal events. Multivariate adjusted hazard ratios for fatal CAD events (hazard ratio, 1.36; 95% confidence interval, 1.27-1.46) differed significantly (mean difference, 13%; 95% confidence interval, 5.1%-21.9%; P<0.001) from the multivariate adjusted hazard ratio for nonfatal CAD events (hazard ratio, 1.21; 95% confidence interval, 1.15-1.26). CONCLUSIONS: In the EPIC-Norfolk cohort, CRP was associated with fatal and nonfatal CAD events, as well as nonfatal PAD events. Adding CRP to risk stratification models resulted in a small improvement in classification for both fatal and nonfatal events. Importantly, CRP was significantly more strongly associated with fatal CAD events than with nonfatal CAD events. PMID- 24072694 TI - Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia. AB - OBJECTIVE: Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular pathogenesis of autosomal recessive hypercholesterolemia in this family. APPROACH AND RESULTS: We used exome sequencing to assess all protein-coding regions of the genome in 3 family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Because homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease, we performed directed follow-up phenotyping by noninvasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of cholesterol ester storage disease. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27 000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance. CONCLUSIONS: By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent cholesterol ester storage disease in the affected individuals from this kindred and addressed an outstanding question about risk of cardiovascular disease in LIPA E8SJM heterozygous carriers. PMID- 24072696 TI - Angiogenic impairment of the vascular endothelium: a novel mechanism and potential therapeutic target in muscular dystrophy. AB - OBJECTIVE: Dystrophin, the missing or defective protein in Duchenne muscular dystrophy, is expressed not only in muscle cells but also in vascular endothelial cells (ECs). In this study, we assessed the effects of dystrophin deficiency on the angiogenic capacities of ECs. APPROACH AND RESULTS: We isolated vascular ECs from mdx mice, the murine equivalent of Duchenne muscular dystrophy in humans, and wild-type controls, and we found that mdx-derived ECs have impaired angiogenic properties, in terms of migration, proliferation, and tube formation. They also undergo increased apoptosis in vitro compared with wild-type cells and have increased senescence-associated beta-galactosidase activity. Mdx-derived ECs also display reduced ability to support myoblast proliferation when cocultured with satellite cell-derived primary myoblasts. These endothelial defects are mirrored by systemic impairment of angiogenesis in vivo, both on induction of ischemia, stimulation with growth factors in the corneal model and matrigel plug assays, and tumor growth. We also found that dystrophin forms a complex with endothelial NO synthase and caveolin-1 in ECs, and that NO production and cGMP formation are compromised in ECs isolated from mdx mice. Interestingly, treatment with aspirin enhances production of both cGMP and NO in dystrophic ECs, whereas low-dose aspirin improves the dystrophic phenotype of mdx mice in vivo, in terms of resistance to physical exercise, muscle fiber permeability, and capillary density. CONCLUSIONS: These findings demonstrate that impaired angiogenesis is a novel player and potential therapeutic target in Duchenne muscular dystrophy. PMID- 24072697 TI - Transforming growth factor-beta-activated kinase 1 regulates angiogenesis via AMP activated protein kinase-alpha1 and redox balance in endothelial cells. AB - OBJECTIVE: Transforming growth factor-beta-activated kinase 1 (TAK1) is a mitogen activated protein 3-kinase and an AMP-activated protein kinase (AMPK) kinase in some cell types. Although TAK1(-/-) mice display defects in developmental vasculogenesis, the role of TAK1 in endothelial cells has not been investigated in detail. APPROACH AND RESULTS: TAK1 downregulation (small interfering RNA) in human endothelial cells attenuated proliferation without inducing apoptosis and diminished endothelial cell migration, as well as tube formation. Cytokine- and vascular endothelial growth factor (VEGF)-induced endothelial cell sprouting in a modified spheroid assay were abrogated by TAK1 downregulation. Moreover, VEGF induced endothelial sprouting was impaired in aortic rings from mice lacking TAK1 in endothelial cells (TAK(DeltaEC)). TAK1 inhibition and downregulation also inhibited VEGF-stimulated phosphorylation of several kinases, including AMPK. Proteomic analyses revealed that superoxide dismutase 2 (SOD2) expression was reduced in TAK1-deficient endothelial cells, resulting in attenuated hydrogen peroxide production but increased mitochondrial superoxide production. Endothelial cell SOD2 expression was also attenuated by AMPK inhibition and in endothelial cells from AMPKalpha1(-/-) mice but was unaffected by inhibitors of c Jun N-terminal kinase, p38, extracellular signal-regulated kinase 1/2, or phosphatidylinositol 3-kinase/Akt. Moreover, the impaired endothelial sprouting from TAK(DeltaEC) aortic rings was abrogated in the presence of polyethylene glycol-SOD, and tube formation was normalized by the overexpression of SOD2. A similar rescue of angiogenesis was observed in polyethylene glycol-SOD-treated aortic rings from mice with endothelial cell-specific deletion of the AMPKalpha1. CONCLUSIONS: These results establish TAK1 as an AMPKalpha1 kinase that regulates vascular endothelial growth factor-induced and cytokine-induced angiogenesis by modulating SOD2 expression and the superoxide anion:hydrogen peroxide balance. PMID- 24072698 TI - Bone morphogenetic proteins protect pulmonary microvascular endothelial cells from apoptosis by upregulating alpha-B-crystallin. AB - OBJECTIVE: To investigate the role of bone morphogenetic proteins (BMPs) on alpha B-crystallin (CRYAB) expression and its physiological consequences on endothelial cells (ECs). APPROACH AND RESULTS: We report that the gene encoding for the small heat shock protein, CRYAB, is a transcriptional target of the BMP signaling pathway. We demonstrate that CRYAB expression is upregulated strongly by BMPs in an EC line and in human lung microvascular ECs and human umbilical vein ECs. We show that BMP signals through the BMPR2-ALK1 pathway to upregulate CRYAB expression through a transcriptional indirect mechanism involving Id1. We observed that the known antiapoptotic effect of the BMPs is, in part, because of the upregulation of CRYAB expression in EC. We also show that cryab is downregulated in vivo, in a mouse model of pulmonary arterial hypertension induced by chronic hypoxia where the BMP pathway is downregulated. CONCLUSIONS: We demonstrate a cross-talk between BMPs and CRYAB and a major effect of this regulatory interaction on resistance to apoptosis. PMID- 24072699 TI - High-dose resveratrol treatment for 2 weeks inhibits intestinal and hepatic lipoprotein production in overweight/obese men. AB - OBJECTIVE: Overproduction of hepatic apolipoprotein B (apoB)-100 containing very low-density lipoprotein particles and intestinal apoB-48 containing chylomicrons contributes to hypertriglyceridemia seen in conditions such as obesity and insulin resistance. Some, but not all, preclinical and clinical studies have demonstrated that the polyphenol resveratrol ameliorates insulin resistance and hypertriglyceridemia. Here, we assessed intestinal and hepatic lipoprotein turnover, in humans, after 2 weeks of treatment with resveratrol (1000 mg daily for week 1 followed by 2000 mg daily for week 2) or placebo. APPROACH AND RESULTS: Eight overweight or obese individuals with mild hypertriglyceridemia were studied on 2 occasions, 4 to 6 weeks apart, after treatment with resveratrol or placebo in a randomized, double-blinded, crossover study. Steady-state lipoprotein kinetics was assessed in a constant fed state with a primed, constant infusion of deuterated leucine. Resveratrol treatment did not significantly affect insulin sensitivity (homeostasis model of assessment of insulin resistance), fasting or fed plasma triglyceride concentration. Resveratrol reduced apoB-48 production rate by 22% (P=0.007) with no significant effect on fractional catabolic rate. Resveratrol reduced apoB-100 production rate by 27% (P=0.02) and fractional catabolic rate by 26% (P=0.04). CONCLUSIONS: These results indicate that 2 weeks of high-dose resveratrol reduces intestinal and hepatic lipoprotein particle production. Long-term studies are needed to evaluate the potential clinical benefits of resveratrol in patients with hypertriglyceridemia, who have increased concentrations of triglyceride-rich lipoprotein apoB-100 and apoB-48. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT01451918. PMID- 24072700 TI - Working to establish 'normality' post-transplant: a qualitative study of kidney transplant patients. AB - OBJECTIVES: To explore patients' perceptions and experiences of 'normality' and the influences on this at three time points post-transplant. METHODS: In-depth interviews with 25 patients at three months, one year and more than three years following kidney transplant. Patients' accounts were compared with Sanderson et al.'s typology of types of normality. FINDINGS: Post-transplant, patients worked hard to re-establish normality, albeit in a 'reset' form. This normality was a very personal construct, shaped by a wide range of factors including age, gender and personal circumstances. Some patients encountered significant challenges in regaining normality, both at three months for those experiencing acute and distressing side effects, and later relating to the long-term side effects of transplant medication and co-morbidities. However, the most dramatic threat to normality (disrupted normality) came from episodes of rejection and transplant failure. CONCLUSIONS: The main types of normality achieved vary for different conditions. Moreover, despite improvements in health post-transplant and opportunities to build a new, reset normality, the participants recognised the need to pay careful attention to the spectre of future ill health and transplant failure. Transplant failure was therefore a source of disruption that was central to their illness narratives and perceived as an ever present risk. PMID- 24072701 TI - Regulation of the microRNA 200b (miRNA-200b) by transcriptional regulators PEA3 and ELK-1 protein affects expression of Pin1 protein to control anoikis. AB - MicroRNA (miRNA) 200s regulate E-cadherin by directly targeting ZEB1/ZEB2, which are transcriptional repressors of E-cadherin. Decreased expression of E-cadherin results in cancer cells losing interaction with the extracellular matrix and detaching from the primary tumor. Normally, cells will undergo anoikis after losing interaction with the extracellular matrix. Cancer cells must, therefore, possess the ability to resist anoikis during the process of metastasis. Here we show that miRNA-200b regulates anoikis by directly targeting the 3' UTR of Pin1 mRNA and regulating Pin1 expression at the translational level. We found that down-regulation of miRNA-200b promotes cancer cells survival during metastasis, and the homeless state of these cells resulted in decreased expression of miRNA 200b in the MCF-7 cell line. We also found that expression of miRNA-200b is down regulated in human breast cancer during lymph node metastasis, which has a significant negative correlation with Pin1 expression. Two members of the ETS (E 26) family (PEA3 and ELK-1) regulate the expression of miRNA-200b. PEA3 promotes the expression of miRNA-200b, and ELK-1 is a transcriptional repressor of miRNA 200b. In addition, miRNA-200b regulates the activity of PEA3 and ELK-1 via the Pin1-pERK pathway and forms self-regulated feedback loops. This study characterizes the role of miRNA-200b in the regulation of anoikis and demonstrates the regulation of its own expression in the process of metastasis. PMID- 24072702 TI - Arabidopsis CROLIN1, a novel plant actin-binding protein, functions in cross linking and stabilizing actin filaments. AB - Higher order actin filament structures are necessary for cytoplasmic streaming, organelle movement, and other physiological processes. However, the mechanism by which the higher order cytoskeleton is formed in plants remains unknown. In this study, we identified a novel actin-cross-linking protein family (named CROLIN) that is well conserved only in the plant kingdom. There are six isovariants of CROLIN in the Arabidopsis genome, with CROLIN1 specifically expressed in pollen. In vitro biochemical analyses showed that CROLIN1 is a novel actin-cross-linking protein with binding and stabilizing activities. Remarkably, CROLIN1 can cross link actin bundles into actin networks. CROLIN1 loss of function induces pollen germination and pollen tube growth hypersensitive to latrunculin B. All of these results demonstrate that CROLIN1 may play an important role in stabilizing and remodeling actin filaments by binding to and cross-linking actin filaments. PMID- 24072703 TI - Structural determinants of Tau aggregation inhibitor potency. AB - Small-molecule Tau aggregation inhibitors are under investigation as potential therapeutic agents against Alzheimer disease. Many such inhibitors have been identified in vitro, but their potency-driving features, and their molecular targets in the Tau aggregation pathway, have resisted identification. Previously we proposed ligand polarizability, a measure of electron delocalization, as a candidate descriptor of inhibitor potency. Here we tested this hypothesis by correlating the ground state polarizabilities of cyanine, phenothiazine, and arylmethine derivatives calculated using ab initio quantum methods with inhibitory potency values determined in the presence of octadecyl sulfate inducer under reducing conditions. A series of rhodanine analogs was analyzed as well using potency values disclosed in the literature. Results showed that polarizability and inhibitory potency directly correlated within all four series. To identify putative binding targets, representative members of the four chemotypes were added to aggregation reactions, where they were found to stabilize soluble, but SDS-resistant Tau species at the expense of filamentous aggregates. Using SDS resistance as a secondary assay, and a library of Tau deletion and missense mutants as targets, interaction with cyanine was localized to the microtubule binding repeat region. Moreover, the SDS-resistant phenotype was completely dependent on the presence of octadecyl sulfate inducer, but not intact PHF6/PH6* hexapeptide motifs, indicating that cyanine interacted with a species in the aggregation pathway prior to nucleus formation. Together the data suggest that flat, highly polarizable ligands inhibit Tau aggregation by interacting with folded species in the aggregation pathway and driving their assembly into soluble but highly stable Tau oligomers. PMID- 24072704 TI - Role of Ser-257 in the sliding mechanism of NADP(H) in the reaction catalyzed by the Aspergillus fumigatus flavin-dependent ornithine N5-monooxygenase SidA. AB - SidA (siderophore A) is a flavin-dependent N-hydroxylating monooxygenase that is essential for virulence in Aspergillus fumigatus. SidA catalyzes the NADPH- and oxygen-dependent formation of N(5)-hydroxyornithine. In this reaction, NADPH reduces the flavin, and the resulting NADP(+) is the last product to be released. The presence of NADP(+) is essential for activity, as it is required for stabilization of the C4a-hydroperoxyflavin, which is the hydroxylating species. As part of our efforts to determine the molecular details of the role of NADP(H) in catalysis, we targeted Ser-257 for site-directed mutagenesis and performed extensive characterization of the S257A enzyme. Using a combination of steady state and stopped-flow kinetic experiments, substrate analogs, and primary kinetic isotope effects, we show that the interaction between Ser-257 and NADP(H) is essential for stabilization of the C4a-hydroperoxyflavin. Molecular dynamics simulation results suggest that Ser-257 functions as a pivot point, allowing the nicotinamide of NADP(+) to slide into position for stabilization of the C4a hydroperoxyflavin. PMID- 24072705 TI - A nondiscriminating glutamyl-tRNA synthetase in the plasmodium apicoplast: the first enzyme in an indirect aminoacylation pathway. AB - The malaria parasite Plasmodium falciparum and related organisms possess a relict plastid known as the apicoplast. Apicoplast protein synthesis is a validated drug target in malaria because antibiotics that inhibit translation in prokaryotes also inhibit apicoplast protein synthesis and are sometimes used for malaria prophylaxis or treatment. We identified components of an indirect aminoacylation pathway for Gln-tRNA(Gln) biosynthesis in Plasmodium that we hypothesized would be essential for apicoplast protein synthesis. Here, we report our characterization of the first enzyme in this pathway, the apicoplast glutamyl tRNA synthetase (GluRS). We expressed the recombinant P. falciparum enzyme in Escherichia coli, showed that it is nondiscriminating because it glutamylates both apicoplast tRNA(Glu) and tRNA(Gln), determined its kinetic parameters, and demonstrated its inhibition by a known bacterial GluRS inhibitor. We also localized the Plasmodium berghei ortholog to the apicoplast in blood stage parasites but could not delete the PbGluRS gene. These data show that Gln tRNA(Gln) biosynthesis in the Plasmodium apicoplast proceeds via an essential indirect aminoacylation pathway that is reminiscent of bacteria and plastids. PMID- 24072706 TI - Interaction of nascent chains with the ribosomal tunnel proteins Rpl4, Rpl17, and Rpl39 of Saccharomyces cerevisiae. AB - As translation proceeds, nascent polypeptides pass through an exit tunnel that traverses the large ribosomal subunit. Three ribosomal proteins, termed Rpl4, Rpl17, and Rpl39 expose domains to the interior of the exit tunnel of eukaryotic ribosomes. Here we generated ribosome-bound nascent chains in a homologous yeast translation system to analyze contacts between the tunnel proteins and nascent chains. As model proteins we employed Dap2, which contains a hydrophobic signal anchor (SA) segment, and the chimera Dap2alpha, in which the SA was replaced with a hydrophilic segment, with the propensity to form an alpha-helix. Employing a newly developed FLAG exposure assay, we find that the nascent SA segment but not the hydrophilic segment adopted a stable, alpha-helical structure within the tunnel when the most C-terminal SA residue was separated by 14 residues from the peptidyl transferase center. Using UV cross-linking, antibodies specifically recognizing Rpl17 or Rpl39, and a His6-tagged version of Rpl4, we established that all three tunnel proteins of yeast contact the SA, whereas only Rpl4 and Rpl39 also contact the hydrophilic segment. Consistent with the localization of the tunnel exposed domains of Rpl17 and Rpl39, the SA was in contact with Rpl17 in the middle region and with Rpl39 in the exit region of the tunnel. In contrast, Rpl4 was in contact with nascent chain residues throughout the ribosomal tunnel. PMID- 24072707 TI - The function of vacuolar ATPase (V-ATPase) a subunit isoforms in invasiveness of MCF10a and MCF10CA1a human breast cancer cells. AB - The vacuolar H(+) ATPases (V-ATPases) are ATP-driven proton pumps that transport protons across both intracellular and plasma membranes. Previous studies have implicated V-ATPases in the invasiveness of various cancer cell lines. In this study, we evaluated the role of V-ATPases in the invasiveness of two closely matched human breast cancer lines. MCF10a cells are a non-invasive, immortalized breast epithelial cell line, and MCF10CA1a cells are a highly invasive, H-Ras transformed derivative of MCF10a cells selected for their metastatic potential. Using an in vitro Matrigel assay, MCF10CA1a cells showed a much higher invasion than the parental MCF10a cells. Moreover, this increased invasion was completely sensitive to the specific V-ATPase inhibitor concanamycin. MCF10CA1a cells expressed much higher levels of both a1 and a3 subunit isoforms relative to the parental line. Isoforms of subunit a are responsible for subcellular localization of V-ATPases, with a3 and a4 targeting V-ATPases to the plasma membrane of specialized cells. Knockdown of either a3 alone or a3 and a4 together using isoform-specific siRNAs inhibited invasion by MCF10CA1a cells. Importantly, overexpression of a3 but not the other a subunit isoforms greatly increased the invasiveness of the parental MCF10a cells. Similarly, overexpression of a3 significantly increased expression of V-ATPases at the plasma membrane. These studies suggest that breast tumor cells employ particular a subunit isoforms to target V-ATPases to the plasma membrane, where they function in tumor cell invasion. PMID- 24072708 TI - Thioesterase superfamily member 2/Acyl-CoA thioesterase 13 (Them2/Acot13) regulates adaptive thermogenesis in mice. AB - Members of the acyl-CoA thioesterase (Acot) gene family hydrolyze fatty acyl CoAs, but their biological functions remain incompletely understood. Thioesterase superfamily member 2 (Them2; synonym Acot13) is enriched in oxidative tissues, associated with mitochondria, and relatively specific for long chain fatty acyl CoA substrates. Using Them2(-/-) mice, we have demonstrated key roles for Them2 in regulating hepatic glucose and lipid metabolism. However, reduced body weights and decreased adiposity in Them2(-/-) mice observed despite increased food consumption were not well explained. To explore a role in thermogenesis, mice were exposed to ambient temperatures ranging from thermoneutrality (30 degrees C) to cold (4 degrees C). In response to short term (24-h) exposures to decreasing ambient temperatures, Them2(-/-) mice exhibited increased adaptive responses in physical activity, food consumption, and energy expenditure when compared with Them2(+/+) mice. By contrast, genotype-dependent differences were not observed in mice that were equilibrated (96 h) at each ambient temperature. In brown adipose tissue, the absence of Them2 was associated with reduced lipid droplets, alterations in the ultrastructure of mitochondria, and increased expression of thermogenic genes. Indicative of a direct regulatory role for Them2 in heat production, cultured primary brown adipocytes from Them2(-/-) mice exhibited increased norepinephrine-mediated triglyceride hydrolysis and increased rates of O2 consumption, together with elevated expression of thermogenic genes. At least in part by regulating intracellular fatty acid channeling, Them2 functions in brown adipose tissue to suppress adaptive increases in energy expenditure. PMID- 24072709 TI - Crystal structure and pharmacological characterization of a novel N-methyl-D aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site. AB - NMDA receptors are ligand-gated ion channels that mediate excitatory neurotransmission in the brain. They are tetrameric complexes composed of glycine binding GluN1 and GluN3 subunits together with glutamate-binding GluN2 subunits. Subunit-selective antagonists that discriminate between the glycine sites of GluN1 and GluN3 subunits would be valuable pharmacological tools for studies on the function and physiological roles of NMDA receptor subtypes. In a virtual screening for antagonists that exploit differences in the orthosteric binding site of GluN1 and GluN3 subunits, we identified a novel glycine site antagonist, 1-thioxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (TK40). Here, we show by Schild analysis that TK40 is a potent competitive antagonist with Kb values of 21-63 nM at the GluN1 glycine-binding site of the four recombinant GluN1/N2A-D receptors. In addition, TK40 displayed >100-fold selectivity for GluN1/N2 NMDA receptors over GluN3A- and GluN3B-containing NMDA receptors and no appreciable effects at AMPA receptors. Binding experiments on rat brain membranes and the purified GluN1 ligand-binding domain using glycine site GluN1 radioligands further confirmed the competitive interaction and high potency. To delineate the binding mechanism, we have solved the crystal structure of the GluN1 ligand-binding domain in complex with TK40 and show that TK40 binds to the orthosteric binding site of the GluN1 subunit with a binding mode that was also predicted by virtual screening. Furthermore, the structure reveals that the imino acetamido group of TK40 acts as an alpha-amino acid bioisostere, which could be of importance in bioisosteric replacement strategies for future ligand design. PMID- 24072710 TI - Stabilization of speckle-type POZ protein (Spop) by Daz interacting protein 1 (Dzip1) is essential for Gli turnover and the proper output of Hedgehog signaling. AB - The Hedgehog (Hh) pathway is essential for embryonic development and adult tissue homeostasis. The Gli/Cubitus interruptus (Ci) family of transcription factors acts at the downstream end of the pathway to mediate Hh signaling. Both Hh dependent and -independent Gli regulatory mechanisms are important for the output of Hh signaling. Daz interacting protein 1 (Dzip1) has bipartite positive and negative functions in the Hh pathway. The positive Hh regulatory function appears to be attributed to a requirement for Dzip1 during ciliogenesis. The mechanism by which Dzip1 inhibits Hh signaling, however, remains largely unclear. We recently found that Dzip1 is required for Gli turnover, which may account for its inhibitory function in Hh signaling. Here, we report that Dzip1 regulates Gli/Ci turnover by preventing degradation of speckle-type POZ protein (Spop), a protein that promotes proteasome-dependent turnover of Gli proteins. We provide evidence that Dzip1 regulates the stability of Spop independent of its function in ciliogenesis. Partial knockdown of Dzip1 to levels insufficient for perturbing ciliogenesis, sensitized Xenopus embryos to Hh signaling, leading to phenotypes that resemble activation of Hh signaling. Importantly, overexpression of Spop was able to restore proper Gli protein turnover and rescue phenotypes in Dzip1 depleted embryos. Consistently, depletion of Dzip1 in Drosophila S2 cells destabilized Hh-induced BTB protein (HIB), the Drosophila homolog of Spop, and increased the level of Ci. Thus, Dzip1-dependent stabilization of Spop/HIB is evolutionarily conserved and essential for proper regulation of Gli/Ci proteins in the Hh pathway. PMID- 24072711 TI - The SUMO1-E67 interacting loop peptide is an allosteric inhibitor of the dipeptidyl peptidases 8 and 9. AB - The intracellular peptidases dipeptidyl peptidase (DPP) 8 and DPP9 are involved in multiple cellular pathways including antigen maturation, cellular homeostasis, energy metabolism, and cell viability. Previously we showed that the small ubiquitin-like protein modifier SUMO1 interacts with an armlike structure in DPP9, leading to allosteric activation of the peptidase. Here we demonstrate that the E67-interacting loop (EIL) peptide, which corresponds to the interaction surface of SUMO1 with DPP9, acts as a noncompetitive inhibitor of DPP9. Moreover, by analyzing the sensitivity of DPP9 arm mutants to the EIL peptide, we mapped specific residues in the arm that are important for inhibition by the EIL, suggesting that the peptide acts as an allosteric inhibitor of DPP9. By modifying the EIL peptide, we constructed peptide variants with more than a 1,000-fold selectivity toward DPP8 (147 nM) and DPP9 (170 nM) over DPPIV (200 MUM). Furthermore, application of these peptides to cells leads to a clear inhibition of cellular prolyl peptidase activity. Importantly, in line with previous publications, inhibition of DPP9 with these novel allosteric peptide inhibitors leads to an increase in EGF-mediated phosphorylation of Akt. This work highlights the potential use of peptides that mimic interaction surfaces for modulating enzyme activity. PMID- 24072713 TI - Characterization of the translocation-competent complex between the Helicobacter pylori oncogenic protein CagA and the accessory protein CagF. AB - CagA is a virulence factor that Helicobacter pylori inject into gastric epithelial cells through a type IV secretion system where it can cause gastric adenocarcinoma. Translocation is dependent on the presence of secretion signals found in both the N- and C-terminal domains of CagA and an interaction with the accessory protein CagF. However, the molecular basis of this essential protein protein interaction is not fully understood. Herein we report, using isothermal titration calorimetry, that CagA forms a 1:1 complex with a monomer of CagF with nM affinity. Peptide arrays and isothermal titration calorimetry both show that CagF binds to all five domains of CagA, each with MUM affinity. More specifically, a coiled coil domain and a C-terminal helix within CagF contacts domains II-III and domain IV of CagA, respectively. In vivo complementation assays of H. pylori with a double mutant, L36A/I39A, in the coiled coil region of CagF showed a severe weakening of the CagA-CagF interaction to such an extent that it was nearly undetectable. However, it had no apparent effect on CagA translocation. Deletion of the C-terminal helix of CagF also weakened the interaction with CagA but likewise had no effect on translocation. These results indicate that the CagA-CagF interface is distributed broadly across the molecular surfaces of these two proteins to provide maximal protection of the highly labile effector protein CagA. PMID- 24072712 TI - Herpesvirus-associated ubiquitin-specific protease (HAUSP) modulates peroxisome proliferator-activated receptor gamma (PPARgamma) stability through its deubiquitinating activity. AB - The peroxisome proliferator-activated receptor gamma (PPARgamma) is a central regulator of adipogenesis and modulates glucose and lipid metabolism. In this study, herpesvirus-associated ubiquitin-specific protease (HAUSP) was isolated as a binding partner of PPARgamma. Both endogenous and exogenous PPARgamma associated with HAUSP in co-immunoprecipitation analysis. HAUSP, but not the catalytically inactive HAUSP C223S mutant, increased the stability of both endogenous and exogenous PPARgamma through its deubiquitinating activity. Site directed mutagenesis experiments showed that the Lys(462) residue of PPARgamma is critical for ubiquitination. HBX 41,108, a specific inhibitor of HAUSP, abolished the increase in PPARgamma stability induced by HAUSP. In addition, knockdown of endogenous HAUSP using siRNA decreased PPARgamma protein levels. HAUSP enhanced the transcriptional activity of both exogenous and endogenous PPARgamma in luciferase activity assays. Quantitative RT-PCR analysis showed that HAUSP increased the transcript levels of PPARgamma target genes in HepG2 cells, resulting in the enhanced uptake of glucose and fatty acids, and vice versa, upon siRNA knockdown of HAUSP. In vivo analysis using adenoviruses confirmed that HAUSP, but not the HAUSP C223S mutant, decreased blood glucose and triglyceride levels, which are associated with the increased expression of endogenous PPARgamma and lipid accumulation in the liver. Our results demonstrate that the stability and activity of PPARgamma are modulated by the deubiquitinating activity of HAUSP, which may be a target for the development of anti-diabetic drugs. PMID- 24072714 TI - Intermediates in the guanine nucleotide exchange reaction of Rab8 protein catalyzed by guanine nucleotide exchange factors Rabin8 and GRAB. AB - Small G-proteins of the Ras superfamily control the temporal and spatial coordination of intracellular signaling networks by acting as molecular on/off switches. Guanine nucleotide exchange factors (GEFs) regulate the activation of these G-proteins through catalytic replacement of GDP by GTP. During nucleotide exchange, three distinct substrate.enzyme complexes occur: a ternary complex with GDP at the start of the reaction (G-protein.GEF.GDP), an intermediary nucleotide free binary complex (G-protein.GEF), and a ternary GTP complex after productive G protein activation (G-protein.GEF.GTP). Here, we show structural snapshots of the full nucleotide exchange reaction sequence together with the G-protein substrates and products using Rabin8/GRAB (GEF) and Rab8 (G-protein) as a model system. Together with a thorough enzymatic characterization, our data provide a detailed view into the mechanism of Rabin8/GRAB-mediated nucleotide exchange. PMID- 24072715 TI - Motor domain phosphorylation modulates kinesin-1 transport. AB - Disruptions in microtubule motor transport are associated with a variety of neurodegenerative diseases. Post-translational modification of the cargo-binding domain of the light and heavy chains of kinesin has been shown to regulate transport, but less is known about how modifications of the motor domain affect transport. Here we report on the effects of phosphorylation of a mammalian kinesin motor domain by the kinase JNK3 at a conserved serine residue (Ser-175 in the B isoform and Ser-176 in the A and C isoforms). Phosphorylation of this residue has been implicated in Huntington disease, but the mechanism by which Ser 175 phosphorylation affects transport is unclear. The ATPase, microtubule-binding affinity, and processivity are unchanged between a phosphomimetic S175D and a nonphosphorylatable S175A construct. However, we find that application of force differentiates between the two. Placement of negative charge at Ser-175, through phosphorylation or mutation, leads to a lower stall force and decreased velocity under a load of 1 piconewton or greater. Sedimentation velocity experiments also show that addition of a negative charge at Ser-175 favors the autoinhibited conformation of kinesin. These observations imply that when cargo is transported by both dynein and phosphorylated kinesin, a common occurrence in the cell, there may be a bias that favors motion toward the minus-end of microtubules. Such bias could be used to tune transport in healthy cells when properly regulated but contribute to a disease state when misregulated. PMID- 24072716 TI - Characterization of three full-length human nonmuscle myosin II paralogs. AB - Nonmuscle myosin IIs (NM IIs) are a group of molecular motors involved in a wide variety of cellular processes including cytokinesis, migration, and control of cell morphology. There are three paralogs of the NM II heavy chain in humans (IIA, IIB, and IIC), each encoded by a separate gene. These paralogs are expressed at different levels according to cell type and have different roles and intracellular distributions in vivo. Most previous studies on NM II used tissue purified protein or expressed fragments of the molecule, which presents potential drawbacks for characterizing individual paralogs of the intact protein in vitro. To circumvent current limitations and approach their native properties, we have successfully expressed and purified the three full-length human NM II proteins with their light chains, using the baculovirus/Sf9 system. The enzymatic and structural properties of the three paralogs were characterized. Although each NM II is capable of forming bipolar filaments, those formed by IIC tend to contain fewer constituent molecules than those of IIA and IIB. All paralogs adopt the compact conformation in the presence of ATP. Phosphorylation of the regulatory light chain leads to assembly into filaments, which bind to actin in the presence of ATP. The nature of interactions with actin filaments is shown with different paralogs exhibiting different actin binding behaviors under equivalent conditions. The data show that although NM IIA and IIB form filaments with similar properties, NM IIC forms filaments that are less well suited to roles such as tension maintenance within the cell. PMID- 24072717 TI - Direct regulation of microtubule dynamics by KIF17 motor and tail domains. AB - KIF17 is a kinesin-2 family motor that interacts with EB1 at microtubule (MT) plus-ends and contributes to MT stabilization in epithelial cells. The mechanism by which KIF17 affects MTs and how its activity is regulated are not yet known. Here, we show that EB1 and the KIF17 autoinhibitory tail domain (KIF17-Tail) interacted competitively with the KIF17 catalytic motor domain (K370). Both EB1 and KIF17-Tail decreased the K0.5MT of K370, with opposing effects on MT stimulated ATPase activity. Importantly, K370 had independent effects on MT dynamic instability, resulting in formation of long MTs without affecting polymerization rate or total polymer mass. K370 also inhibited MT depolymerization induced by dilution in vitro and by nocodazole in cells, suggesting that it acts by protecting MT plus-ends. Interestingly, KIF17-Tail bound MTs and tubulin dimers, delaying initial MT polymerization in vitro and MT regrowth in cells. However, neither EB1 nor KIF17-Tail affected K370-mediated MT polymerization or stabilization significantly in vitro, and EB1 was dispensable for MT stabilization by K370 in cells. Thus, although EB1 and KIF17-Tail may coordinate KIF17 catalytic activity, our data reveal a novel and direct role for KIF17 in regulating MT dynamics. PMID- 24072718 TI - Does improved continuity of primary care affect clinician-patient communication in VA? AB - BACKGROUND: Recent changes in health care delivery may reduce continuity with the patient's primary care provider (PCP). Little is known about the association between continuity and quality of communication during ongoing efforts to redesign primary care in the Veterans Administration (VA). OBJECTIVE: To evaluate the association between longitudinal continuity of care (COC) with the same PCP and ratings of patient-provider communication during the Patient Aligned Care Team (PACT) initiative. DESIGN: Cross-sectional survey. PARTICIPANTS: Four thousand three hundred ninety-three VA outpatients who were assigned to a PCP, had at least three primary care visits to physicians or physician extenders during Fiscal Years 2009 and 2010 (combined), and who completed the Survey of Healthcare Experiences of Patients (SHEP) following a primary care visit in Fiscal Year (FY)2011. MAIN MEASURES: Usual Provider of Continuity (UPC), Modified Modified Continuity Index (MMCI), and duration of PCP care were calculated for each primary care patient. UPC and MMCI values were categorized as follows: 1.0 (perfect), 0.75-0.99 (high), 0.50-0.74 (intermediate), and < 0.50 (low). Quality of communication was measured using the four-item Consumer Assessment of Healthcare Providers and Systems-Health Plan program (CAHPS-HP) communication subscale and a two-item measure of shared decision-making (SDM). Excellent care was defined using an "all-or-none" scoring strategy (i.e., when all items within a scale were rated "always"). KEY RESULTS: UPC and MMCI continuity remained high (0.81) during the early phase of PACT implementation. In multivariable models, low MMCI continuity was associated with decreased odds of excellent communication (OR = 0.74, 95 % CI = 0.58-0.95) and SDM (OR = 0.70, 95 % CI = 0.49, 0.99). Abbreviated duration of PCP care (< 1 year) was also associated with decreased odds of excellent communication (OR = 0.35, 95 % CI = 0.18, 0.71). CONCLUSIONS: Reduced PCP continuity may significantly decrease the quality of patient-provider communication in VA primary care. By improving longitudinal continuity with the assigned PCP, while redesigning team-based roles, the PACT initiative has the potential to improve patient-provider communication. PMID- 24072719 TI - Identifying axial spondyloarthritis in Dutch primary care patients, ages 20-45 years, with chronic low back pain. AB - OBJECTIVE: To identify axial spondyloarthritis (SpA) in Dutch primary care patients with chronic low back pain (CLBP), and to design a simple referral model for general practitioners (GPs) that would identify patients at risk for axial SpA. METHODS: Patients (ages 20-45 years) with CLBP were identified from GP records. Assessments included inflammatory back pain questionnaires, medical interviews, physical examinations, HLA-B27, C-reactive protein level, conventional radiography, and magnetic resonance imaging. The outcome measure was axial SpA defined by the Assessment of SpondyloArthritis international Society (ASAS) criteria. Multivariable regression analysis with bootstrapping was used to develop the referral model. RESULTS: A total of 364 patients (mean +/- SD age 36.3 +/- 6.8 years) was recruited with a median symptom duration of 9.0 years. Eighty-six patients (24%) fulfilled the ASAS criteria for axial SpA. Of all potential determinants, the ASAS inflammatory back pain questionnaire, good response to nonsteroidal antiinflammatory drugs, family history of SpA, and symptom duration were identified as most relevant for diagnosing axial SpA by multivariable regression analysis related to axial SpA. The shrunken regression coefficients were, respectively, 1.04, 0.83, 0.73, and 0.23. The combination of these 4 items proved a useful area under the receiver operating characteristic curve of 0.75 (SE 0.03). In a simplified score model, at the suggested cutoff value of 1.5, the sensitivity was 83% and specificity was 59%. CONCLUSION: This study shows that 1 of 4 primary care patients with CLBP was classified as having axial SpA. A preselection in primary care based on a combination of clinical items may be useful to facilitate the identification of patients at risk of axial SpA. PMID- 24072720 TI - Accounting for personhood in palliative sedation: the Ring Theory of Personhood. AB - Application of sedation at the end of life has been fraught with ethical and clinical concerns, primarily focused on its potential to hasten death. However, in the face of clinical data that assuage most of these concerns, a new threat to this treatment of last resort has arisen. Concern now pivots on its effects on the personhood of the patient, underpinned by the manner in which personhood has been conceptualised. For many authors, it is consciousness that is seen to be the seat of personhood, thus its loss is seen to rob a patient of their moral and ethical worth, leaving them in a state that cannot ethically be differentiated from death. Here I proffer a clinically based alternative to this view, the Ring Theory of Personhood, which dispels these concerns about sedation at the end of life. The Ring Theory envisages personhood as a coadunation of three domains of concern: the innate, the individual and the relational elements of personhood. The innate element of personhood is held to be present among all humans by virtue of their links with the Divine and or their human characteristics. The individual elements of personhood pivot on the presence of consciousness-dependent features such as self-awareness, self-determination and personality traits. The relational component of personhood envisages an individual as being 'socially embedded' replete with social and familial ties. It is these three equally important inter related domains that define personhood. PMID- 24072721 TI - Psychiatric diagnoses and cognitive impairment in pediatric multiple sclerosis. AB - BACKGROUND: Pediatric multiple sclerosis (MS) represents approximately 5% of the MS population; information regarding clinical features is slowly accumulating. Cognitive and psychiatric impairments frequently occur, but remain poorly understood. OBJECTIVES: To describe psychiatric diagnoses among children with MS referred for psychiatric assessment and their relation to cognitive impairment. METHODS: Forty-five pediatric MS patients (aged 8 to 17 years) were referred for outpatient psychiatric evaluation including a psychiatric interview (K-SADS), a clinician-based global assessment of functioning (Children's Global Assessment Scale, CGAS), a neurologic examination including the Expanded Disability Status Scale (EDSS), and a neuropsychological test battery. RESULTS: The most common categories of psychiatric diagnoses were anxiety disorders (n=15), attention deficit hyperactivity disorder (ADHD, n=12), and mood disorders (n=11). Cognitive impairment was classified in 20/25 (80%) of patients meeting criteria for a psychiatric disorder versus 11/20 (55%) of those without psychiatric disorder (p=0.08). Those diagnosed with anxiety or mood disorder had the highest frequency of cognitive impairment, with a significantly higher rate when compared with those with psychiatric diagnoses in other categories (p=0.05). CONCLUSIONS: A variety of psychiatric diagnoses can occur in children with pediatric MS. Many of these children also had cognitive impairment, particularly those in the mood and anxiety groups. PMID- 24072723 TI - Season of infectious mononucleosis and risk of multiple sclerosis at different latitudes; the EnvIMS Study. AB - BACKGROUND: Seasonal fluctuations in solar radiation and vitamin D levels could modulate the immune response against Epstein-Barr virus (EBV) infection and influence the subsequent risk of multiple sclerosis (MS). METHODS: Altogether 1660 MS patients and 3050 controls from Norway and Italy participating in the multinational case-control study of Environmental Factors In Multiple Sclerosis (EnvIMS) reported season of past infectious mononucleosis (IM). RESULTS: IM was generally reported more frequently in Norway (p=0.002), but was associated with MS to a similar degree in Norway (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.64-2.73) and Italy (OR 1.72, 95% CI 1.17-2.52). For all participants, there was a higher reported frequency of IM during spring compared to fall (p<0.0005). Stratified by season of IM, the ORs for MS were 1.58 in spring (95% CI 1.08-2.31), 2.26 in summer (95% CI 1.46-3.51), 2.86 in fall (95% CI 1.69-4.85) and 2.30 in winter (95% CI 1.45-3.66). CONCLUSIONS: IM is associated with MS independently of season, and the association is not stronger for IM during spring, when vitamin D levels reach nadir. The distribution of IM may point towards a correlation with solar radiation or other factors with a similar latitudinal and seasonal variation. PMID- 24072722 TI - JC-virus seroconversion in multiple sclerosis patients receiving natalizumab. AB - AIM: The objectives of this study were to evaluate the rate of JC virus (JCV) seroconversion/seroreversion in a French cohort of multiple sclerosis (MS) patients receiving natalizumab (NTZ), describe the characteristics of this population, identify risk factors for JCV seropositivity and analyse the additional value of quantitative JCV serology results in this context. METHODS: MS patients from two French MS centres, whose JCV serological status in 2011 while receiving NTZ was known (n=357; first-generation enzyme-linked immunosorbent assay (ELISA) test (Gen1)), were proposed for inclusion in this study. We evaluated the rate of JCV seroconversion over a period of one year with a second-generation ELISA test (Gen2; n=303) and analysed the quantitative results. Multivariate analysis was performed to identify risk factors for JCV seropositivity. RESULTS: Among the patients with Gen2 JCV serology (n=303) that had been JCV-seronegative one year before (n=165), the rate of JCV seroconversion was 26.67% (44/165). We observed a higher proportion of anti-JCV antibody seroconverters (14.5%) than expected (<=3%) but also increasing index values of anti-JCV antibody over time. CONCLUSION: Our data suggest that JCV reactivation occurs during NTZ therapy and leads to an increase in the anti-JCV antibodies titre, thus making them more easily detectable by the second-generation ELISA test. PMID- 24072724 TI - Changes of brain resting state functional connectivity predict the persistence of cognitive rehabilitation effects in patients with multiple sclerosis. AB - OBJECTIVE: We investigated whether the efficacy of 12-week cognitive rehabilitation in MS patients persists six months after treatment termination and, together with resting state (RS) functional connectivity (FC), changes on neuropsychological performance at follow-up. METHODS: Eighteen MS patients with cognitive deficits, assigned randomly either to undergo treatment (n=9) or not (n=9), underwent neuropsychological evaluation at baseline (t0), after 12 weeks of rehabilitation (t1) and at six-month follow-up (t2). RS fMRI was obtained at t0 and t1. Changes in neuropsychological performance and their correlations with RS FC modifications were assessed using longitudinal linear models. RESULTS: At t2 vs. t0, compared with the control group, treated group patients improved in tests of attention, executive function, depression and quality of life (QoL). Neuropsychological scores in these tests at t2 were significantly correlated with RS FC changes in cognitive-related networks and RS FC of the anterior cingulum. RS FC changes in the default mode network predicted cognitive performance and less severe depression, whereas RS FC changes of the executive network predicted better QoL. DISCUSSION: Changes in RS FC of cognitive-related networks helps to explain the persistence of the effects of cognitive rehabilitation after several months in relapsing-remitting multiple sclerosis patients and their improvement on depression and QoL scales. PMID- 24072725 TI - Childhood obesity is a risk factor for multiple sclerosis. PMID- 24072726 TI - The usefulness of brain MRI at onset in the differentiation of multiple sclerosis and seropositive neuromyelitis optica spectrum disorders. AB - BACKGROUND: Although neuromyelitis optica (NMO) is a central nervous system (CNS) autoimmune disease distinct from multiple sclerosis (MS). NMO and NMO spectrum disorder (NMOSD) sometimes show asymptomatic lesions on brain magnetic resonance imaging (MRI) at onset, and even present with symptomatic brain involvement. OBJECTIVES: We investigated whether brain MRI at onset can be helpful for the differentiation of MS and NMOSD. METHODS: We retrospectively analyzed initial brain MRIs, performed within three months of onset, in patients with MS (n = 51) and anti-aquaporin4-antibody-positive patients with NMOSD (n = 67). RESULTS: NMOSD patients met the Paty (37%) and Barkhof (13%) criteria, and the criteria of the European Magnetic Imaging in MS (MAGNIMS) study group (9%), for MS. Ovoid lesions perpendicular to the lateral ventricle, isolated juxtacortical lesions in U-fibers and isolated ovoid/round cortical lesions were found only in MS patients, whereas longitudinal corticospinal tract lesions, extensive hemispheric lesions, periependymal lesions surrounding the lateral ventricle and cervicomedullary lesions were found only in NMOSD patients. CONCLUSIONS: Our study suggests that it is difficult to differentiate MS from NMOSD by the fulfillment of the MRI criteria for MS on brain MRI at onset; however, the characteristic morphology of brain lesions is highly useful for the early differentiation of the two disorders. PMID- 24072727 TI - Examining the impact of reimbursement on referral to bone density testing for older adults: 8 years of data from the Barwon Statistical Division, Australia. AB - In 2007, Medicare Australia revised rei:mbursement guidelines for dual energy X ray absorptiometry (DXA) for Australians aged >=70 years; we examined whether these changes increased DXA referrals in older adults. Proportions of DXA referrals doubled for men and tripled for women from 2003 to 2010; however, rates of utilization remained low. INTRODUCTION: On April 1, 2007 Medicare Australia revised reimbursement guidelines for DXA for Australians aged >=70 year; changes that were intended to increase the proportion of older adults being tested. We examined whether changes to reimbursement increased DXA referrals in older adults, and whether any sex differences in referrals were observed in the Barwon Statistical Division. METHODS: Proportions of DXA referrals 2003-2010 based on the population at risk ascertained from Australian Census data and annual referral rates and rate ratios stratified by sex, year of DXA, and 5-year age groups. Persons aged >=70 years referred to the major public health service provider for DXA clinical purposes (n = 6,096; 21 % men). RESULTS: DXA referrals. Proportions of DXA referrals for men doubled from 0.8 % (2003) to 1.8 % (2010) and tripled from 2.0 to 6.3 % for women (all p < 0.001). For 2003-2006, referral ratios of men/women ranged between 1:1.9 and 1:3.0 and for 2007-2010 were 1:2.3 to 1:3.4. Referral ratios <2007:>=2007 were 1:1.7 for men aged 70-79 years (p < 0.001), 1:1.2 for men aged 80-84 years (p = 0.06), and 1:1.3 for men 85+ years (p = 0.16). For women, the ratios <2007:>=2007 were 1:2.1 (70-79 years), 1.1.5 (80 84 years), and 1:1.4 (85+ years) (all p < 0.001). CONCLUSIONS: DXA referral ratios were 1:1.6 (men) and 1:1.8 (women) for 2007-2010 vs. 2003-2006; proportions of referrals doubled for men and tripled for women from 2003 to 2010. Overall, rates of DXA utilization remained low. Policy changes may have had minimal influence on referral; thus, ongoing evaluation over time is warranted. PMID- 24072728 TI - Patients' perspectives on the educational preparation of cardiac nurses. AB - BACKGROUND: Over the last two decades the UK health service has endeavoured to place patient and public involvement at the heart of its modernisation agenda. Despite these aspirations the role of patients in the development of nursing curricula remains limited. AIM: A descriptive qualitative design was used to explore the views of cardiac patients about the educational preparation of cardiac nurses. METHOD: Eight participants attending an annual conference of a patient and carer support group were recruited to the study. A focus group was conducted to explore their views on how the educational preparation of cardiac nurses in the UK should develop. Tape-recorded data were transcribed and a thematic analysis was undertaken. FINDINGS: Four themes were identified: contradictions around practice and education; demonstrating compassion; delivering rehabilitation expertise; leadership in practice. Participants perceived that they had a valuable role in the educational development of nurses, enhancing nurses' understanding of how individuals live and adjust to living with cardiovascular disease. CONCLUSION: Cardiac patients believe that the education of cardiac nurses should be driven by experiences in practice, nevertheless they want nurses to be equipped to deliver care that is underpinned by a strong knowledge base and skills combined with an ability to engage, educate and deliver high quality care that is both compassionate and individualised. PMID- 24072729 TI - Nature and determinants of the course of chronic low back pain over a 12-month period: a cluster analysis. AB - BACKGROUND: It has been suggested that low back pain (LBP) is a condition with an unpredictable pattern of exacerbation, remission, and recurrence. However, there is an incomplete understanding of the course of LBP and the determinants of the course. OBJECTIVE: The purposes of this study were: (1) to identify clusters of LBP patients with similar fluctuating pain patterns over time and (2) to investigate whether demographic and clinical characteristics can distinguish these clusters. DESIGN: This study was a secondary analysis of data extracted from a randomized controlled trial. METHODS: Pain scores were collected from 155 participants with chronic nonspecific LBP. Pain intensity was measured monthly over a 1-year period by mobile phone short message service. Cluster analysis was used to identify participants with similar fluctuating patterns of pain based on the pain measures collected over a year, and t tests were used to evaluate if the clusters differed in terms of baseline characteristics. RESULTS: The cluster analysis revealed the presence of 3 main clusters. Pain was of fluctuating nature within 2 of the clusters. Out of the 155 participants, 21 (13.5%) had fluctuating pain. Baseline disability (measured with the Roland-Morris Disability Questionnaire) and treatment groups (from the initial randomized controlled trial) were significantly different in the clusters of patients with fluctuating pain when compared with the cluster of patients without fluctuating pain. LIMITATIONS: A limitation of this study was the fact that participants were undergoing treatment that may have been responsible for the rather positive prognosis observed. CONCLUSIONS: A small number of patients with fluctuating patterns of pain over time were identified. This number could increase if individuals with episodic pain are included in this fluctuating group. PMID- 24072730 TI - p53 and hepatoma-derived growth factor expression and their clinicopathological association with Ewing family tumour. AB - PURPOSE: To investigate p53 and hepatoma-derived growth factor (HDGF) expression and their association with clinicopathological features of Ewing family tumour (EFT). EXPERIMENTAL DESIGN: A total of 108 cases of EFT were retrospectively analysed. p53 and HDGF expression were detected using immunohistochemistry, and the relationships between p53 expression and HDGF expression and clinicopathological features of EFT were analysed. Kaplan-Meier curves were applied to estimate overall survival, log-rank test was used to assess prognostic relevance of p53 expression with overall survival and Cox regression model was performed to evaluate HRs. RESULTS: p53 expression and high HDGF expression was found in 17 (15.7%) and 55 (50.9%) patients, respectively. p53 expression was significantly associated with metastatic stage at initial diagnosis (p=0.007) and tumour venous/nerve invasion (p=0.023). A significant positive correlation was found between p53 expression and HDGF expression in EFT (p=0.022). p53 expression was an independent prognostic factor for overall survival of patients with EFT (p<0.001). Patients with p53-positive/high HDGF expression had a significantly shorter overall survival than those with p53-positive/low HDGF expression or p53 negative/high HDGF expression or p53-negative/low HDGF expression. We first constructed a novel molecular staging system by combining p53 expression and HDGF expression, which significantly improved prognostic stratification for patients with EFT. CONCLUSIONS: p53 expression was an independent prognostic factor for patients with EFT. Combining p53 expression and HDGF expression significantly improved prognostic stratification for patients with EFT. PMID- 24072731 TI - Internal quality control: best practice. AB - There is a wide variation in laboratory practice with regard to implementation and review of internal quality control (IQC). A poor approach can lead to a spectrum of scenarios from validation of incorrect patient results to over investigation of falsely rejected analytical runs. This article will provide a practical approach for the routine clinical biochemistry laboratory to introduce an efficient quality control system that will optimise error detection and reduce the rate of false rejection. Each stage of the IQC system is considered, from selection of IQC material to selection of IQC rules, and finally the appropriate action to follow when a rejection signal has been obtained. The main objective of IQC is to ensure day-to-day consistency of an analytical process and thus help to determine whether patient results are reliable enough to be released. The required quality and assay performance varies between analytes as does the definition of a clinically significant error. Unfortunately many laboratories currently decide what is clinically significant at the troubleshooting stage. Assay-specific IQC systems will reduce the number of inappropriate sample-run rejections compared with the blanket use of one IQC rule. In practice, only three or four different IQC rules are required for the whole of the routine biochemistry repertoire as assays are assigned into groups based on performance. The tools to categorise performance and assign IQC rules based on that performance are presented. Although significant investment of time and education is required prior to implementation, laboratories have shown that such systems achieve considerable reductions in cost and labour. PMID- 24072732 TI - WebGLORE: a web service for Grid LOgistic REgression. AB - WebGLORE is a free web service that enables privacy-preserving construction of a global logistic regression model from distributed datasets that are sensitive. It only transfers aggregated local statistics (from participants) through Hypertext Transfer Protocol Secure to a trusted server, where the global model is synthesized. WebGLORE seamlessly integrates AJAX, JAVA Applet/Servlet and PHP technologies to provide an easy-to-use web service for biomedical researchers to break down policy barriers during information exchange. AVAILABILITY AND IMPLEMENTATION: http://dbmi-engine.ucsd.edu/webglore3/. WebGLORE can be used under the terms of GNU general public license as published by the Free Software Foundation. PMID- 24072733 TI - MATE-CLEVER: Mendelian-inheritance-aware discovery and genotyping of midsize and long indels. AB - MOTIVATION: Accurately predicting and genotyping indels longer than 30 bp has remained a central challenge in next-generation sequencing (NGS) studies. While indels of up to 30 bp are reliably processed by standard read aligners and the Genome Analysis Toolkit (GATK), longer indels have still resisted proper treatment. Also, discovering and genotyping longer indels has become particularly relevant owing to the increasing attention in globally concerted projects. RESULTS: We present MATE-CLEVER (Mendelian-inheritance-AtTEntive CLique Enumerating Variant findER) as an approach that accurately discovers and genotypes indels longer than 30 bp from contemporary NGS reads with a special focus on family data. For enhanced quality of indel calls in family trios or quartets, MATE-CLEVER integrates statistics that reflect the laws of Mendelian inheritance. MATE-CLEVER's performance rates for indels longer than 30 bp are on a par with those of the GATK for indels shorter than 30 bp, achieving up to 90% precision overall, with >80% of calls correctly typed. In predicting de novo indels longer than 30 bp in family contexts, MATE-CLEVER even raises the standards of the GATK. MATE-CLEVER achieves precision and recall of ~63% on indels of 30 bp and longer versus 55% in both categories for the GATK on indels of 10-29 bp. A special version of MATE-CLEVER has contributed to indel discovery, in particular for indels of 30-100 bp, the 'NGS twilight zone of indels', in the Genome of the Netherlands Project. AVAILABILITY AND IMPLEMENTATION: http://clever-sv.googlecode.com/ PMID- 24072734 TI - Misconception: human papillomavirus vaccine and infertility. AB - BACKGROUND: This study sought to determine if parents of males express concerns about vaccine-associated infertility (VAI) with the human papillomavirus (HPV) vaccine and to understand the impact of those concerns. METHODS: Parents of sons were surveyed to determine VAI concerns. Logistic regression was used to find if parents worried about VAI had lower knowledge of HPV disease, more concern for side effects, lacked information about vaccination, or had lower intention to vaccinate. RESULTS: In all, 39% of parents were worried about VAI. Parents worried about VAI had similar knowledge of HPV compared with other parents. Parents worried about VAI had twice the odds of agreeing the vaccine may cause side effects and agreeing they did not have enough information compared to their counterparts. Parents worried about VAI less often intended to vaccinate sons than other parents. CONCLUSIONS: These findings suggest many parents worry about VAI in sons with HPV vaccine. PMID- 24072735 TI - Developmental screening in rural primary care: real-world application. PMID- 24072736 TI - No signs of ventilatory inefficiency in patients with heart failure with preserved ejection fraction and very low oxygen consumption: how is this possible? PMID- 24072737 TI - Malnutrition at diagnosis predicts mortality in patients with systemic immunoglobulin light-chain amyloidosis independently of cardiac stage and response to treatment. AB - BACKGROUND: Nutrition status was shown to be a prognostic factor in patients with immunoglobulin light-chain amyloidosis (AL). However, malnutrition was associated with cardiac involvement, thus suggesting potential interactions. This study aim was to clarify the association among nutrition status, cardiac stage, and mortality in AL. METHODS: One hundred twenty-eight consecutive newly diagnosed, treatment-naive patients with histologically confirmed AL were enrolled. Anthropometric, biochemical, and clinical variables were assessed. RESULTS: At multivariable Cox proportional hazard analysis, body mass index (BMI) < 22 kg/m(2) (HR = 1.98, 95% CI = 1.09-3.56) and unintentional 6-month weight loss (WL) >= 10% (HR = 1.94, 95% CI = 1.00-3.74) resulted in independent predictors of survival after controlling for hematologic response to treatment (HR = 0.27, 95% CI = 0.14-0.53) and cardiac stage (Mayo Clinic stage III, HR = 4.42, 95% CI = 2.61-7.51). There was no effect modification of malnutrition on mortality by cardiac stage (P for interaction = .27). Moderate and severe malnutrition (prevalence: 21.9% and 7.8%, respectively) similarly increased the risk of death (HR = 3.09, 95% CI = 1.75-5.46; 2.88, 95% CI = 1.23-6.72, respectively). CONCLUSIONS: In AL, malnutrition at diagnosis is a frequent comorbidity that affects the prognosis independently of hematologic response to treatment and cardiac stage. Nutrition status should be systematically considered in future intervention trials in AL. Nutrition support trials are warranted. PMID- 24072738 TI - Protocol-driven enteral nutrition in critically ill children: a systematic review. AB - Enteral nutrition (EN) protocols are thought to improve clinical outcomes in the pediatric intensive care unit (PICU); however, critical evaluation of their efficacy is limited. We conducted a systematic review with the aim of assessing the effect of EN protocols on important clinical outcomes in these children. We searched MEDLINE, Cochrane Database for Reviews, Embase, and CINAHL using predetermined keywords and MESH terms. We included randomized controlled trials (RCTs) and observational studies that involved EN protocols in children admitted to the PICU for >24 hours. We included studies that reported at least 1 of our outcomes of interest. Studies that exclusively studied premature neonates or adults were excluded. Primary outcomes were PICU or hospital mortality, PICU or hospital length of stay (LOS), duration of mechanical ventilation, gastrointestinal (GI) complications, and infective complications. Secondary outcomes were time to initiate feeds and time to achieve goal feeds. In total, we included 9 studies (total 1564 children) in our systematic review (1 RCT, 4 before-and-after studies, 1 single-arm cohort study, 1 prospective descriptive study, and 2 audits). There is low-level evidence that the use of EN protocols is associated with a reduction in GI and infective complications and improved timeliness of feed initiation and achievement of goal feeds. Current medical literature does not have compelling data on the effects of an EN protocol on clinical outcomes among critically ill children. Future clinical trials should look into using standardized interventions and outcome measures to strengthen the existing evidence. PMID- 24072739 TI - Hypothyroidism and iodine deficiency in an infant requiring total parenteral nutrition. AB - While iodine deficiency remains a relatively rare cause of thyroid dysfunction in the United States, little is known about iodine status and deficiency in children requiring parenteral nutrition (PN). This population may be at an elevated risk of thyroid dysregulation and neurodevelopmental sequelae due to low concentrations in typical PN formulations. Furthermore, with the widespread practice of switching from iodine-based antiseptics to chlorhexadine, previous inadvertent sources of iodine are being eliminated as well. PMID- 24072740 TI - Elderly persons with ICU-acquired weakness: the potential role for beta-hydroxy beta-methylbutyrate (HMB) supplementation? AB - Intensive care unit (ICU)-acquired weakness is common and characterized by muscle loss, weakness, and paralysis. It is associated with poor short-term outcomes, including increased mortality, but the consequences of reduced long-term outcomes, including decreased physical function and quality of life, can be just as devastating. ICU-acquired weakness is particularly relevant to elderly patients who are increasingly consuming ICU resources and are at increased risk for ICU-acquired weakness and complications, including mortality. Elderly patients often enter critical illness with reduced muscle mass and function and are also at increased risk for accelerated disuse atrophy with acute illness. Increasingly, intensivists and researchers are focusing on strategies and therapies aimed at improving long-term neuromuscular function. beta-Hydroxy-beta methylbutyrate (HMB), an ergogenic supplement, has shown efficacy in elderly patients and certain clinical populations in counteracting muscle loss. The present review discusses ICU-acquired weakness, as well as the unique physiology of muscle loss and skeletal muscle function in elderly patients, and then summarizes the evidence for HMB in elderly patients and in clinical populations. We subsequently postulate on the potential role and strategies in studying HMB in elderly ICU patients to improve muscle mass and function. PMID- 24072741 TI - Epidemiology and risk factors for bloodstream infections in a home parenteral nutrition program. AB - BACKGROUND: An increasing number of patients with intestinal failure are receiving home parenteral nutrition (HPN). Associated complications include bloodstream infections (BSIs), but data on rates and risk factors for HPN-related BSIs are scarce. METHODS: A retrospective review was conducted of patients enrolled in the regional HPN program between 2001 and 2008. Demographic information and data on indication for HPN, duration of PN therapy, type and date of insertion of central venous access device, and blood culture results were recorded. RESULTS: In total, 155 patients (165 courses of HPN) were included for a total of 45,876 catheter days. The mean patient age was 49 years, and 105 (64%) patients were female. A total of 105 organisms were cultured from 93 distinct episodes of BSIs. The rate of BSI was found to be 2.0 per 1000 catheter days, but excluding BSIs with a single positive culture of coagulase-negative staphylococcus and diphtheroid bacilli, the rate of infection was 1.4 per 1000 catheter days. Male sex and underlying malignancy were significant predictors of BSI, with hazard ratios of 1.69 (95% confidence interval [CI], 1.14-2.60; P = .009) and 2.38 (95% CI, 1.53-3.50; P < .001). CONCLUSION: In a large heterogeneous group of HPN patients, the BSI rate ranged between 1.4 and 2.0 infections per 1000 catheter days. Isolated organisms were similar to those found in hospitalized patients. Male sex and underlying malignancy were significant risk factors for BSI. These high-risk patients are likely to benefit from interventions aimed at reducing BSIs. PMID- 24072742 TI - Initial non-participation and loss to follow-up in a Danish youth cohort: implications for relative risk estimates. AB - BACKGROUND: Initial non-participation and loss to follow-up in the Danish youth cohort Vestliv could introduce selection bias of the measured risk estimates. OBJECTIVE: To investigate the impact of initial non-participation and loss to follow-up on the validity of descriptive measures and selected estimates of relative risk. METHODS: Of the 3681 young people defining the source population, 83% answered a questionnaire at baseline in 2004. At follow-up waves in 2007 and 2010, the response rates were 71% and 64%, respectively. Relative ORs (RORs) were used to examine the impact of initial non-participation and loss to follow-up on the association between socioeconomic or personal risk factors at age 14/15 and educational attainment at age 20/21. RORs were calculated as OR (baseline population)/OR (source population) or OR (follow-up population)/OR (baseline population). RESULTS: The participants had slightly better school abilities and came more often from homes with two adults, higher income or higher educational level. These differences increased at subsequent follow-ups. The effect of initial non-participation on the ORs was modest with most RORs being close to one. Loss to follow-up led to larger variations in the RORs ranging from 0.77 to 1.62 although for most estimates, the bias was minor. None of the measured RORs were statistically different from one indicating no significant bias. CONCLUSIONS: Although certain characteristics were related to those who initially chose to participate and especially to those who participated at follow-ups, it did not have any large influence on the relative risk estimates measured in the study. PMID- 24072743 TI - Pregnancy e-health: a multicenter Italian cross-sectional study on Internet use and decision-making among pregnant women. AB - BACKGROUND: Our study aimed to estimate the prevalence of pregnancy e-health seekers in a large Italian sample; to explore the factors influencing the choices of the childbearing women regarding their lifestyles after internet consultation; and finally to investigate potential differences between primiparous and multiparous women in internet use to find information about pregnancy. METHODS: A multicentre survey was carried out in seven Italian cities. Data were collected through a validated questionnaire administered in waiting rooms of outpatient departments by medical doctors. Respondents were questioned about their sociodemographic status, their use of the internet to seek pregnancy information and their consequent choices to modify their lifestyles. Data were analysed using descriptive statistics and logistic regression. RESULTS: Almost all women were pregnancy e-health seekers (95%), including those who also received information from healthcare professionals. Indeed, the main reason for searching the web was the need of further knowledge on pregnancy-related topic, over and beyond other key advantages of the net such as anonymity, simplicity and rapidity. A higher likelihood of changing lifestyle after pregnancy e-health was observed among the women who searched institutional websites; declared more confidence in the information retrieved; participated into pregnancy-centred forum online; and were residents in Italy. CONCLUSIONS: To reduce the likelihood for women of both finding erroneous information or misinterpreting correct ones, healthcare professionals should commit to fill the information gap and guide pregnant women in the online searches. Also, future studies are strongly needed to analyse the quality and accuracy of health information found on the web. PMID- 24072744 TI - Neighbourhood economic deprivation explains racial/ethnic disparities in overweight and obesity among children and adolescents in the U.S.A. AB - BACKGROUND: Low-income and some racial and ethnic subpopulations are more likely to suffer from obesity. Inequities in the physical and social environment may contribute to disparities in paediatric obesity, but there is little empirical evidence to date. This study explored whether neighbourhood-level socioeconomic factors attenuate racial and ethnic disparities in obesity among youth in the U.S.A. and whether individual-level socioeconomic status (SES) interacts with neighbourhood deprivation. METHODS: This analysis used data from 17,100 youth ages 2-18 years participating in the 2001-2010 National Health and Nutrition Examination Survey linked to census tract-level socioeconomic characteristics. Multilevel logistic regression models were used to examine neighbourhood deprivation in association with odds of obesity (age-specific and sex-specific body mass index percentile >=95). RESULTS: The unadjusted prevalence of obesity was 15% among non-Hispanic white children and 21% among non-Hispanic black and Mexican-American children. Adjustment for individual-level SES neighbourhood deprivation and the interaction between these two factors resulted in a 74% attenuation of the disparity in obesity between non-Hispanic black and non Hispanic white children and a 49% attenuation of the disparity between Mexican American and non-Hispanic white children. There was a significant interaction between individual-level SES and neighbourhood deprivation where higher individual-level income was protective for children living in low-deprivation neighbourhoods, but not for children who lived in high-deprivation areas. Conversely, area deprivation was associated with higher odds of obesity, but only among children who were above the poverty threshold. CONCLUSIONS: Future research on disparities in obesity and other health outcomes should examine broader contextual factors and social determinants of inequities. PMID- 24072745 TI - CD95L cell surface cleavage triggers a prometastatic signaling pathway in triple negative breast cancer. AB - Triple-negative breast cancers (TNBC) lacking estrogen and progesterone receptors and HER2 amplification have a relatively high risk of metastatic dissemination, but the mechanistic basis for this risk is not understood. Here, we report that serum levels of CD95 ligand (CD95L) are higher in patients with TNBC than in other patients with breast cancer. Metalloprotease-mediated cleavage of CD95L expressed by endothelial cells surrounding tumors generates a gradient that promotes cell motility due to the formation of an unconventional CD95-containing receptosome called the motility-inducing signaling complex. The formation of this complex was instrumental for Nox3-driven reactive oxygen species generation. Mechanistic investigations revealed a Yes-Orai1-EGFR-PI3K pathway that triggered migration of TNBC cells exposed to CD95L. Our findings establish a prometastatic function for metalloprotease-cleaved CD95L in TNBCs, revisiting its role in carcinogenesis. PMID- 24072746 TI - Parathyroid hormone-related protein drives a CD11b+Gr1+ cell-mediated positive feedback loop to support prostate cancer growth. AB - In the tumor microenvironment, CD11b(+)Gr1(+) bone marrow-derived cells are a predominant source of protumorigenic factors such as matrix metalloproteinases (MMP), but how distal tumors regulate these cells in the bone marrow is unclear. Here we addressed the hypothesis that the parathyroid hormone-related protein (PTHrP) potentiates CD11b(+)Gr1(+) cells in the bone marrow of prostate tumor hosts. In two xenograft models of prostate cancer, levels of tumor-derived PTHrP correlated with CD11b(+)Gr1(+) cell recruitment and microvessel density in the tumor tissue, with evidence for mediation of CD11b(+)Gr1(+) cell-derived MMP-9 but not tumor-derived VEGF-A. CD11b(+)Gr1(+) cells isolated from mice with PTHrP overexpressing tumors exhibited relatively increased proangiogenic potential, suggesting that prostate tumor-derived PTHrP potentiates this activity of CD11b(+)Gr1(+) cells. Administration of neutralizing PTHrP monoclonal antibody reduced CD11b(+)Gr1(+) cells and MMP-9 in the tumors. Mechanistic investigations in vivo revealed that PTHrP elevated Y418 phosphorylation levels in Src family kinases in CD11b(+)Gr1(+) cells via osteoblast-derived interleukin-6 and VEGF-A, thereby upregulating MMP-9. Taken together, our results showed that prostate cancer-derived PTHrP acts in the bone marrow to potentiate CD11b(+)Gr1(+) cells, which are recruited to tumor tissue where they contribute to tumor angiogenesis and growth. PMID- 24072747 TI - Chk1 targeting reactivates PP2A tumor suppressor activity in cancer cells. AB - Checkpoint kinase Chk1 is constitutively active in many cancer cell types and new generation Chk1 inhibitors show marked antitumor activity as single agents. Here we present a hitherto unrecognized mechanism that contributes to the response of cancer cells to Chk1-targeted therapy. Inhibiting chronic Chk1 activity in cancer cells induced the tumor suppressor activity of protein phosphatase protein phosphatase 2A (PP2A), which by dephosphorylating MYC serine 62, inhibited MYC activity and impaired cancer cell survival. Mechanistic investigations revealed that Chk1 inhibition activated PP2A by decreasing the transcription of cancerous inhibitor of PP2A (CIP2A), a chief inhibitor of PP2A activity. Inhibition of cancer cell clonogenicity by Chk1 inhibition could be rescued in vitro either by exogenous expression of CIP2A or by blocking the CIP2A-regulated PP2A complex. Chk1-mediated CIP2A regulation was extended in tumor models dependent on either Chk1 or CIP2A. The clinical relevance of CIP2A as a Chk1 effector protein was validated in several human cancer types, including neuroblastoma, where CIP2A was identified as an NMYC-independent prognostic factor. Because the Chk1-CIP2A-PP2A pathway is driven by DNA-PK activity, functioning regardless of p53 or ATM/ATR status, our results offer explanative power for understanding how Chk1 inhibitors mediate single-agent anticancer efficacy. Furthermore, they define CIP2A-PP2A status in cancer cells as a pharmacodynamic marker for their response to Chk1 targeted therapy. PMID- 24072748 TI - A small-molecule blocking ribonucleotide reductase holoenzyme formation inhibits cancer cell growth and overcomes drug resistance. AB - Ribonucleotide reductase (RNR) is an attractive target for anticancer agents given its central function in DNA synthesis, growth, metastasis, and drug resistance of cancer cells. The current clinically established RNR inhibitors have the shortcomings of short half-life, drug resistance, and iron chelation. Here, we report the development of a novel class of effective RNR inhibitors addressing these issues. A novel ligand-binding pocket on the RNR small subunit (RRM2) near the C-terminal tail was proposed by computer modeling and verified by site-directed mutagenesis and nuclear magnetic resonance (NMR) techniques. A compound targeting this pocket was identified by virtual screening of the National Cancer Institute (NCI) diverse small-molecule database. By lead optimization, we developed the novel RNR inhibitor COH29 that acted as a potent inhibitor of both recombinant and cellular human RNR enzymes. COH29 overcame hydroxyurea and gemcitabine resistance in cancer cells. It effectively inhibited proliferation of most cell lines in the NCI 60 human cancer panel, most notably ovarian cancer and leukemia, but exerted little effect on normal fibroblasts or endothelial cells. In mouse xenograft models of human cancer, COH29 treatment reduced tumor growth compared with vehicle. Site-directed mutagenesis, NMR, and surface plasmon resonance biosensor studies confirmed COH29 binding to the proposed ligand-binding pocket and offered evidence for assembly blockade of the RRM1-RRM2 quaternary structure. Our findings offer preclinical validation of COH29 as a promising new class of RNR inhibitors with a new mechanism of inhibition, with broad potential for improved treatment of human cancer. PMID- 24072750 TI - Obesity in Bulgarian patients with chronic obstructive pulmonary disease. AB - It has been well defined that obesity is strongly linked with several respiratory symptoms and diseases, but no convincing evidence has been provided for chronic obstructive pulmonary disease (COPD). In the current study, we aim to assess the possible prevalence of obesity in patients with COPD in a cross-sectional case control study of individuals from the region of Stara Zagora, Bulgaria, and to explore whether the body mass has some effect on the lung function of COPD patients. The study included 158 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) II, III, and IV stages) and 123 individuals unaffected by the disease (control). A higher frequency of obesity compared to the controls (20.3%) was observed in patients with COPD (29.1%, p=0.093), especially in those with GOLD II stage (37.7%, p=0.009). Prevalence of obesity was highest in COPD GOLD II, followed by GOLD III and IV stages (p=0.068). When diabetes was considered as confounding factor, we found a significant prevalence of obesity in COPD patients than the controls with diabetes (p=0.031). Interestingly, there was a statistically significant moderate positive correlation between the body mass index and forced expiratory volume in one second as a percentage of predicted value in the whole patients' group (R=0.295, p=0.0002) as well as in the subgroups of GOLD II (R=0.257, p=0.024) and GOLD III COPD (R=0.259, p=0.031).The results of our study propose that the increased body mass, particularly obesity is frequent comorbidity to COPD, especially to less severe diseases. Moreover, the results suggest that the higher body weight may provide some protection against the impairment of lung functions in patients with stable COPD. PMID- 24072749 TI - Photodynamic therapy of murine mastocytoma induces specific immune responses against the cancer/testis antigen P1A. AB - Photodynamic therapy (PDT) involves the intravenous administration of photosensitizers followed by illumination of the tumor with visible light, leading to local production of reactive oxygen species that cause vascular shutdown and tumor cell death. Antitumor immunity is stimulated after PDT because of the acute inflammatory response that involves activation of the innate immune system, leading to stimulation of adaptive immunity. We carried out PDT using benzoporphyrin derivative and 690-nm light after 15 minutes, in DBA/2 mice bearing either the mastocytoma, P815, which expresses the naturally occurring cancer/testis antigen P1A, or the corresponding tumor P1.204 that lacks P1A expression. Tumor cures, significantly higher survival, and rejection of tumor rechallenge were obtained with P815, which were not seen with P1.204 or seen with P815 growing in nude mice. Both CD4 and CD8 T cells had higher levels of intracellular cytokines when isolated from mice receiving PDT of P815 tumors than P1.204 tumors and CD8 T cells from P815-cured mice recognized the peptide epitope of the P1A antigen (LPYLGWLVF) using pentamer staining. Taken together, these findings show that PDT can induce a potent antigen- and epitope-specific immune response against a naturally occurring mouse tumor antigen. PMID- 24072751 TI - Catheter-directed foam sclerotherapy for chronic venous leg ulcers. AB - OBJECTIVES: This study presents the results of catheter-directed foam sclerotherapy (CDS) for chronic venous ulcer refractory to compression treatment, four weeks and one year after treatment. METHODS: In sum, 31 patients (32 limbs) with refractory chronic venous ulcer and duplex-verified superficial insufficiency were offered CDS. CDS was conducted with 10 ml of sclerosant foam of 3% polidocanol. Four weeks and one year after treatment, the patients were evaluated regarding ulcer healing and ultrasound appearance of the saphenous trunk. RESULTS: CDS was successfully performed in all patients. After one year, 65% of the ulcers were healed. Only two (6%) recurred. 86% of the treated saphenous trunk were completely occluded, 3% was partly occluded and 10% were recanalised. No serious side effects occurred. CONCLUSIONS: CDS is one alternative of eliminating superficial venous reflux when treating refractory venous leg ulcers. This study suggests that the treatment is safe and induce a quick ulcer healing. PMID- 24072752 TI - A prospective study of risk factors for foot ulceration: the West of Ireland Diabetes Foot Study. AB - BACKGROUND: This is the first study to examine risk factors for diabetic foot ulceration in Irish general practice. AIM: To determine the prevalence of established risk factors for foot ulceration in a community-based cohort, and to explore the potential for estimated glomerular filtration rate (eGFR) to act as a novel risk factor. DESIGN: A prospective observational study. METHODS: Patients with diabetes attending 12 (of 17) invited general practices were invited for foot screening. Validated clinical tests were carried out at baseline to assess for vascular and sensory impairment and foot deformity. Ulcer incidence was ascertained by patient self-report and medical record. Patients were re-assessed 18 months later. RESULTS: Of 828 invitees, 563 (68%) attended screening. On examination 23-25% had sensory dysfunction and 18-39% had evidence of vascular impairment. Using the Scottish Intercollegiate Guidelines Network risk stratification system we found the proportion at moderate and high risk of future ulceration to be 25% and 11%, respectively. At follow-up 16/383 patients (4.2%) developed a new foot ulcer (annual incidence rate of 2.6%). We observed an increasing probability of abnormal vascular and sensory test results (pedal pulse palpation, doppler waveform assessment, 10 g monofilament, vibration perception and neuropathy disability score) with declining eGFR levels. We were unable to show an independent association between new ulceration and reduced eGFR [Odds ratio 1.01; P = 0.64]. CONCLUSION: Our data show the extent of foot complications in a representative sample of diabetes patients in Ireland. Use of eGFR did not improve identification of patients at risk of foot ulceration. PMID- 24072753 TI - The key ingredients of personality traits: situations, behaviors, and explanations. AB - The trait and social cognitive perspectives are considered disparate approaches to understanding personality. We suggest an integrative view in which three elements derived from the social cognitive perspective (i.e., situations, behaviors, and explanations [SBEs]) form the basis of personality traits. Study 1 demonstrated strong associations between traits and SBEs across the Big Five dimensions. Studies 2 through 7 tested the discriminative validity, internal structure, and unique contributions of the individual components of SBEs. Studies 8 and 9 demonstrated that the strong associations between traits and SBEs generalize to different cultures. The present work suggests that SBEs may be a universal folk psychological mechanism underlying personality traits. PMID- 24072754 TI - Feasibility of a supported self-management intervention for relatives of people with recent-onset psychosis: REACT study. AB - BACKGROUND: Relatives of people with psychosis experience high levels of distress and require support. Family interventions have been shown to be effective in improving outcomes but are difficult to access and not suitable for all relatives. AIMS: To assess the feasibility and effectiveness of a supported self management package for relatives of people with recent-onset psychosis. METHOD: A randomised controlled trial (n = 103) comparing treatment as usual (TAU) in early intervention services with TAU plus the Relatives' Education And Coping Toolkit (REACT) intervention (trial identifier: ISRCTN69299093). RESULTS: Compared with TAU only, those receiving the additional REACT intervention showed reduced distress and increased perceived support and perceived ability to cope at 6-month follow-up. CONCLUSIONS: The toolkit is a feasible and potentially effective intervention to improve outcomes for relatives. A larger trial is needed to reliably assess the clinical and cost-effectiveness of REACT, and its impact on longer-term outcomes. PMID- 24072755 TI - Decision aid on disclosure of mental health status to an employer: feasibility and outcomes of a randomised controlled trial. AB - BACKGROUND: Many mental health service users delay or avoid disclosing their condition to employers because of experience, or anticipation, of discrimination. However, non-disclosure precludes the ability to request 'reasonable adjustments'. There have been no intervention studies to support decision-making about disclosure to an employer. AIMS: To determine whether the decision aid has an effect that is sustained beyond its immediate impact; to determine whether a large-scale trial is feasible; and to optimise the designs of a larger trial and of the decision aid. METHOD: In this exploratory randomised controlled trial (RCT) in London, participants were randomly assigned to use of a decision aid plus usual care or usual care alone. Follow-up was at 3 months. Primary outcomes were: (a) stage of decision-making; (b) decisional conflict; and (c) employment related outcomes (trial registration number: NCT01379014). RESULTS: We recruited 80 participants and interventions were completed for 36 out of 40 in the intervention group; in total 71 participants were followed up. Intention-to-treat analysis showed that reduction in decisional conflict was significantly greater in the intervention group than among controls (mean improvement -22.7 (s.d. = 15.2) v. -11.2 (s.d. = 18.1), P = 0.005). More of the intervention group than controls were in full-time employment at follow-up (P = 0.03). CONCLUSIONS: The observed reduction in decisional conflict regarding disclosure has a number of potential benefits which next need to be tested in a definitive trial. PMID- 24072757 TI - Predicting future violence among individuals with psychopathy. AB - Structured risk assessment aims to help clinicians classify offenders according to likelihood of future violent and criminal behaviour. We investigated how confident clinicians can be using three commonly used instruments (HCR-20, VRAG, OGRS-II) in individuals with different diagnoses. Moderate to good predictive accuracy for future violence was achieved for released prisoners with no mental disorder, low to moderate for clinical syndromes and personality disorder, but accuracy was no better than chance for individuals with psychopathy. Comprehensive diagnostic assessment should precede an assessment of risk. Risk assessment instruments cannot be relied upon when managing public risk from individuals with psychopathy. PMID- 24072756 TI - Total somatic symptom score as a predictor of health outcome in somatic symptom disorders. AB - BACKGROUND: The diagnosis of somatisation disorder in DSM-IV was based on 'medically unexplained' symptoms, which is unsatisfactory. AIMS: To determine the value of a total somatic symptom score as a predictor of health status and healthcare use after adjustment for anxiety, depression and general medical illness. METHOD: Data from nine population-based studies (total n = 28 377) were analysed. RESULTS: In all cross-sectional analyses total somatic symptom score was associated with health status and healthcare use after adjustment for confounders. In two prospective studies total somatic symptom score predicted subsequent health status. This association appeared stronger than that for medically unexplained symptoms. CONCLUSIONS: Total somatic symptom score provides a predictor of health status and healthcare use over and above the effects of anxiety, depression and general medical illnesses. PMID- 24072758 TI - Alcohol assessment and feedback by email for university students: main findings from a randomised controlled trial. AB - BACKGROUND: Brief interventions can be efficacious in changing alcohol consumption and increasingly take advantage of the internet to reach high-risk populations such as students. AIMS: To evaluate the effectiveness of a brief online intervention, controlling for the possible effects of the research process. METHOD: A three-arm parallel groups design was used to explore the magnitude of the feedback and assessment component effects. The three groups were: alcohol assessment and feedback (group 1); alcohol assessment only without feedback (group 2); and no contact, and thus neither assessment nor feedback (group 3). Outcomes were evaluated after 3 months via an invitation to participate in a brief cross-sectional lifestyle survey. The study was undertaken in two universities randomising the email addresses of all 14 910 students (the AMADEUS-1 study, trial registration: ISRCTN28328154). RESULTS: Overall, 52% (n = 7809) of students completed follow-up, with small differences in attrition between the three groups. For each of the two primary outcomes, there was one statistically significant difference between groups, with group 1 having 3.7% fewer risky drinkers at follow-up than group 3 (P = 0.006) and group 2 scoring 0.16 points lower than group 3 on the three alcohol consumption questions from the Alcohol Use Disorders Identification Test (AUDIT-C) (P = 0.039). CONCLUSIONS: This study provides some evidence of population-level benefit attained through intervening with individual students. PMID- 24072759 TI - Administration of kefir-fermented milk protects mice against Giardia intestinalis infection. AB - Giardiasis, caused by the protozoan Giardia intestinalis, is one of the most common intestinal diseases worldwide and constitutes an important problem for the public health systems of various countries. Kefir is a probiotic drink obtained by fermenting milk with 'kefir grains', which consist mainly of bacteria and yeasts that coexist in a complex symbiotic association. In this work, we studied the ability of kefir to protect mice from G. intestinalis infection, and characterized the host immune response to this probiotic in the context of the intestinal infection. Six- to 8-week-old C75BL/6 mice were separated into four groups: controls, kefir mice (receiving 1 : 100 dilution of kefir in drinking water for 14 days), Giardia mice (infected orally with 4*10(7) trophozoites of G. intestinalis at day 7) and Giardia-kefir mice (kefir-treated G. intestinalis infected mice), and killed at 2 or 7 days post-infection. Kefir administration was able to significantly reduce the intensity of Giardia infection at 7 days post-infection. An increase in the percentage of CD4(+) T cells at 2 days post infection was observed in the Peyer's patches (PP) of mice belonging to the Giardia group compared with the control and kefir groups, while the percentage of CD4(+) T cells in PP in the Giardia-kefir group was similar to that of controls. At 2 days post-infection, a reduction in the percentage of B220-positive major histocompatibility complex class II medium cells in PP was observed in infected mice compared with the other groups. At 7 days post-infection, Giardia-infected mice showed a reduction in RcFcepsilon-positive cells compared with the control group, suggesting a downregulation of the inflammatory response. However, the percentages of RcFcepsilon-positive cells did not differ from controls in the kefir and Giardia-kefir groups. An increase in IgA-positive cells was observed in the lamina propria of the kefir group compared with controls at 2 days post infection. Interestingly, the diminished number of IgA-positive cells registered in the Giardia group at 7 days post-infection was restored by kefir feeding, although the increase in IgA-positive cells was no longer observed in the kefir group at that time. No significant differences in CXCL10 expression were registered between groups, in concordance with the absence of inflammation in small-intestinal tissue. Interestingly, a slight reduction in CCL20 expression was observed in the Giardia group, suggesting that G. intestinalis might downregulate its expression as a way of evading the inflammatory immune response. On the other hand, a trend towards an increase in TNF-alpha expression was observed in the kefir group, while the Giardia-kefir group showed a significant increase in TNF-alpha expression. Moreover, kefir-receiving mice (kefir and Giardia-kefir groups) showed an increase in the expression of IFN-gamma, the most relevant Th1 cytokine, at 2 days post-infection. Our results demonstrate that feeding mice with kefir reduces G. intestinalis infection and promotes the activation of different mechanisms of humoral and cellular immunity that are downregulated by parasitic infection, thus contributing to protection. PMID- 24072760 TI - Brucellae growing on Thayer-Martin medium: a source of inadvertent exposure for laboratory personnel in endemic areas. PMID- 24072761 TI - Microbiological investigation in male infertility: a practical overview. AB - The roles of inflammation and/or infection of the male accessory sex glands are very important for the potential effects that these conditions may have on male fertility. The clinical andrologist should be aware of the pathophysiological role of the main determinants of sperm damage when these conditions occur, in particular, seminal leukocytes, oxidative stress and cytokines. In addition, it is important to have a good knowledge of the methodologies to be used in clinical practice. This article summarizes the methods used to look for and to identify the micro-organisms responsible for male urogenital tract infections. These include sperm culture, urine culture, urethral swabbing, the Meares-Stamey test and balanopreputial swabbing. Finally, we discuss the role of human papilloma virus infection in male infertility. PMID- 24072762 TI - Meningoencephalitis due to Gemella haemolysans. AB - Gemella haemolysans is an uncommon but described cause of invasive disease in humans. We report a case of meningitis due to G. haemolysans that did not grow in cerebrospinal fluid culture, demonstrating a potential role for direct 16S rRNA gene PCR and sequencing in culture-negative cerebrospinal fluid when bacterial meningitis is suspected. PMID- 24072763 TI - Bacteraemia due to meticillin-resistant Staphylococcus aureus carrying the mecC gene in a patient with urothelial carcinoma. AB - We present a case of bacteraemia due to meticillin-resistant Staphylococcus aureus (MRSA) carrying the mecC gene. The susceptibility to meticillin of Staphylococcus aureus was investigated directly from one blood culture bottle using GenomEra MRSA/SA (Abacus Diagnostica Oy) test. This test identified S. aureus but the presence of the mecA gene result was negative, and the isolate was reported as meticillin-sensitive Staphylococcus aureus (MSSA). Susceptibility studies were done using VITEK 2 AST-P588 susceptibility cards (bioMerieux). The strain was identified as MRSA by the VITEK 2 system, although oxacillin MIC was low (0.5 ug ml(-1)). In view of these results, the isolate was tested for the presence of the mecC gene by a specific PCR and was verified as MRSA carrying mecC. The emergence of this new mecA homologue could have important consequences for the detection of MRSA when routine PCR methods are used as an identification method or provisional detection of MRSA, as in the case reported in this article, because S. aureus carrying the mecC gene will be wrongly diagnosed as meticillin susceptible. Negative results must be interpreted with caution and should be followed by conventional culture, and antimicrobial susceptibility testing or detection of mecC gene by a specific PCR. PMID- 24072764 TI - Synergistic antibacterial efficacies of the combination of bovine lactoferrin or its hydrolysate with probiotic secretion in curbing the growth of meticillin resistant Staphylococcus aureus. AB - The occurrence of multidrug-resistant or meticillin-resistant Staphylococcus aureus (MRSA) has become an important issue in clinics. This study evaluated a combinatorial treatment approach by using the well-documented antibacterial protein apo-bovine lactoferrin (apo-bLf) or its hydrolysate and specific probiotic supernatants for controlling MRSA infection. Clinical MRSA strains were isolated from different patient specimens. Apo-bLf-hydrolysate possessed stronger anti-MRSA activity than complete bLf in that it inhibited the growth of most MRSA strains tested in vitro. Otherwise, the supernatants produced by Lactobacillus fermentum (ATCC 11739), Bifidobacterium longum subsp. longum (ATCC 15707) and Bifidobacterium animalis subsp. lactis (BCRC 17394) inhibited the growth of various MRSA strains. Further, L. fermentum or B. animalis subsp. lactis supernatant plus apo-bLf or bLf-hydrolysate led to partially synergistic to synergistic growth-inhibitory activity against MRSA strains. However, L. fermentum and not B. animalis subsp. lactis or B. longum subsp. longum was observed to resist the antibacterial activity of both apo-Lf and bLf-hydrolysate. Therefore, it is suggested that L. fermentum could be the best candidate to be used with apo-bLf or bLf-hydrolysate as a live supplement against MRSA infections. PMID- 24072765 TI - First isolation of oleate-dependent Enterococcus faecalis small-colony variants from the umbilical exudate of a paediatric patient with omphalitis. AB - An oleate-dependent Enterococcus faecalis isolate representing small-colony variants (SCVs) was isolated from the umbilical exudate of a 31-month-old Japanese male patient in Nagano Children's Hospital, Azumino, Japan. The patient had been suffering from recurrent omphalitis since early infancy. The initial E. faecalis SCV isolate formed small colonies on sheep blood agar plates and tiny colonies on chocolate and modified Drigalski agar, although no visible growth was observed in HK-semi solid medium after 48 h incubation in ambient air. Moreover, the SCV isolate, the colonial morphology of which was reminiscent of Streptococcus species, could not be identified using the MicroScan WalkAway-40 and API 20 Strep systems, both of which yielded profile numbers that did not correspond to any bacterial species, probably as a result of insufficient growth of the isolate. The SCV isolate was subsequently identified as E. faecalis based on its morphological, cultural and biochemical properties, and this was confirmed by sequencing the 16S rRNA gene of the organism. Investigations revealed that the addition of oleate, an unsaturated fatty acid, enabled the isolate to grow on every medium with normal-sized colony morphology. Although it has long been known that long-chain fatty acids, especially unsaturated oleic acid, have a major inhibitory effect on the growth of a variety of microorganisms, including not only mycobacteria but also streptococci, this is, to the best of our knowledge, the first clinical isolation of an oleate-dependent E. faecalis SCV isolate. In addition, oleic acid might be considered to affect the cell membrane permeability of carbohydrates or antimicrobial agents such as beta-lactams. PMID- 24072766 TI - Diagnostic accuracy and comparison of two assays for Borrelia-specific IgG and IgM antibodies: proposals for statistical evaluation methods, cut-off values and standardization. AB - Two assays (Liaison, Diasorin; IDEIA, Oxoid) for detection of Borrelia-specific antibodies were compared. A case-control design using patients with neuroborreliosis (n = 48), laboratory defined by a positive Borrelia-specific antibody index in the spinal fluid, was available and was intended to represent the serological response of disseminated early Lyme borreliosis in general. Serum samples were obtained from 216 Danish blood donors as controls. By comparing sensitivity and specificity using pre-specified cut-off values, significant differences were found. However, using receiver operating characteristic (ROC) curves to optimize and standardize test interpretation, it was shown that testing with both IDEIA IgG and IgM was comparable to testing with Liaison IgG alone by comparing the area under the curve of the diagnostically relevant 25 % partial ROC curve (P = 0.1). When using the Liaison OspC/VlsE IgM assay, the specificity was decreased without a gain in sensitivity. This study proposes standardizing of reporting by using a control population as the reference and choosing decision thresholds guided by the risk of false-positive results at 2 and 8 %. The sensitivities for IDEIA (IgG and IgM combined) were 85 and 95 % and for the Liaison (VlsE IgG) method were 67 and 96 %, respectively. Methods for test evaluation, test interpretation and statistical testing are presented and discussed. In conclusion, Liaison VlsE IgG alone and IDEIA IgG/IgM combined showed a high and comparable discriminatory ability to distinguish serum samples from patients with neuroborreliosis from blood donor controls. However, cut-off values should be adjusted for a proper comparison. PMID- 24072767 TI - Differentiation of Yersinia enterocolitica biotype 1A from pathogenic Yersinia enterocolitica biotypes by detection of beta-glucosidase activity: comparison of two chromogenic culture media and Vitek2. AB - Aesculin hydrolysis (ESC) is one of the key reactions in differentiating pathogenic Yersinia enterocolitica biotypes 1B, 2, 3, 4 and 5 from the less pathogenic biotype 1A. Because the ESC reaction is caused by beta-glucosidase (betaGLU) activity of the bacteria, we studied whether two commonly used methods (BBL CHROMagar Orientation and Vitek2 Gram-negative identification card) could be used in assessing betaGLU activity of 74 Yersinia strains. Both methods were sensitive (100 % and 97 %) and specific (100 % and 100 %) in differentiating betaGLU-positive YE BT1A from betaGLU-negative Y. enterocolitica biotypes. For a subset of strains (n = 69), a new selective CHROMagar Yersinia showed excellent agreement with the strains' betaGLU activity. Thus all the methods evaluated in this study may be used to differentiate between YE BT1A and other Y. enterocolitica biotypes. PMID- 24072768 TI - Native valve endocarditis caused by Erysipelothrix rhusiopathiae in an immunocompetent individual. AB - Infective endocarditis is a very rare clinical form caused by Erysipelothrix rhusiopathiae. It is rarely seen in immunocompetent individuals. Even after surgery it may entail mortality rates as high as 30-40 %. This report describes a case of native valve endocarditis caused by E. rhusiopathiae and cured with crystallized penicillin G and surgery. PMID- 24072769 TI - Peri-ablation warfarin vs. dabigatran: different but the same. PMID- 24072770 TI - Novel oral anticoagulants for stroke prevention in atrial fibrillation: results of the European Heart Rhythm Association survey. AB - The purpose of this European Heart Rhythm Association (EHRA) survey was to assess clinical practice in relation to stroke prevention in atrial fibrillation (AF), particularly into the use of novel oral anticoagulants (NOACs) for stroke prevention, among members of the EHRA electrophysiology (EP) research network. In this EP Wire survey, we have provided some insights into current practice in Europe for the use of NOACs for stroke prevention in AF. There were clear practice differences evident, and also the need for greater adherence to the guidelines, especially since guideline adherent management results in better outcomes in AF. PMID- 24072771 TI - Oral administration of naturally occurring chitosan-based nanoformulated green tea polyphenol EGCG effectively inhibits prostate cancer cell growth in a xenograft model. AB - In preclinical animal models, several phytochemicals have shown excellent potential to be used as effective agents in preventing and treating many cancers. However, the limited bioavailability of active agents could be one reason for their restricted usefulness for human consumption. To overcome this limitation, we recently introduced the concept of nanochemoprevention by encapsulating useful bioactive food components for their slow and sustained release. Here, we report the synthesis, characterization and efficacy assessment of a nanotechnology-based oral formulation of chitosan nanoparticles encapsulating epigallocatechin-3 gallate (Chit-nanoEGCG) for the treatment of prostate cancer (PCa) in a preclinical setting. Chit-nanoEGCG with a size of <200nm diameter and encapsulating EGCG as determined by dynamic light scattering and transmission electron microscope showed slow release of EGCG in simulated gastric juice acidic pH and faster release in simulated intestinal fluid. The antitumor efficacy of Chit-nanoEGCG was assessed in subcutaneously implanted 22Rnu1 tumor xenografts in athymic nude mice. Treatment with Chit-nanoEGCG resulted in significant inhibition of tumor growth and secreted prostate-specific antigen levels compared with EGCG and control groups. In tumor tissues of mice treated with Chit nanoEGCG, compared with groups treated with EGCG and controls, there was significant (i) induction of poly (ADP-ribose) polymerases cleavage, (ii) increase in the protein expression of Bax with concomitant decrease in Bcl-2, (iii) activation of caspases and (iv) reduction in Ki-67 and proliferating cell nuclear antigen. Through this study, we propose a novel preventive and therapeutic modality for PCa using EGCG that addresses issues related to bioavailability. PMID- 24072772 TI - JWA suppresses tumor angiogenesis via Sp1-activated matrix metalloproteinase-2 and its prognostic significance in human gastric cancer. AB - JWA, a multifunctional microtubule-binding protein, plays an important role in regulating tumor metastasis via inhibition of matrix metalloproteinase-2 (MMP-2). Recent investigations suggest that MMP-2 is an angiogenesis-associated molecule. In this study, we provide novel evidence that JWA inhibits tumor angiogenesis in gastric cancer (GC). In two independent retrospective GC cohorts, we found that the expression of JWA was downregulated and that of MMP-2 was upregulated in GC tissues compared with the same in normal gastric mucosa. For patients treated with surgery alone, a strong and independent negative prognostic value was shown for low JWA and high MMP-2 expressions separately, which was even stronger when combined (hazard ratio = 7.75, P < 0.001, in the training cohort; hazard ratio = 2.31, P < 0.001, in the validation cohort). Moreover, we found that loss of JWA expression was strongly correlated with increased GC angiogenesis. In vitro, JWA inhibited MMP-2 at both messenger RNA and protein levels by modulating Sp1 activity. Knockdown of endogenous JWA resulted in enhanced human umbilical vein endothelial cell tube formation and MMP-2 expression. Furthermore, JWA was found to inhibit Sp1 activity via an ubiquitin-proteasome-dependent mechanism and to downregulate the expression of the proangiogenic MMP-2. Our findings imply that JWA and MMP-2 may serve as promising prognostic markers in resectable GC, with JWA as a useful biomarker of angiogenesis in GC and a potential therapeutic target by MMP-2 modulation. PMID- 24072774 TI - Cardiac MR imaging to measure myocardial blood flow response to the cold pressor test in healthy smokers and nonsmokers. AB - PURPOSE: To determine if myocardial perfusion cardiac magnetic resonance (MR) imaging can show changes in myocardial blood flow (MBF) during the cold pressor test (CPT) and can allow identification of the differing endothelial function of smokers and nonsmokers when compared during adenosine stress. MATERIALS AND METHODS: The study was approved by the institutional ethics review board and all participants gave informed written consent. Twenty-nine healthy volunteers (19 nonsmokers, 10 smokers; mean age +/- standard deviation, 22 years +/- 4) underwent 1.5-T MR imaging and analysis. Myocardial perfusion was assessed during rest, peak CPT, and adenosine hyperemia with a saturation-recovery gradient-echo pulse sequence (spatial resolution, 2.4 * 2.4 * 10 mm). Global, endocardial, and epicardial MBF were calculated by using Fermi-constrained deconvolution. Paired and independent t test statistical analyses were used to compare the responses between tests and groups. Regression analysis was performed to identify predictors of MBF change. RESULTS: MBF at rest was similar between the nonsmoking and smoking groups (0.97 mL/g/min +/- 0.4 vs 0.96 mL/g/min +/- 0.3, respectively; P = .96). Nonsmokers responded to CPT with a 47% increase in MBF (1.43 mL/g/min +/- 0.5) and smokers responded with a 27% increase (1.22 mL/g/min +/- 0.4; P < .001). An endocardial-to-epicardial gradient existed at rest (nonsmokers, 1.10 [P = .002]; smokers, 1.30 [P = .01]) and CPT (nonsmokers, 1.19 [P < .001] smokers, 1.28 [P = .04]) but reversed during adenosine stress (nonsmokers, 0.89 [P = .03]; smokers, 0.92 [P = .42]). CONCLUSION: Myocardial perfusion cardiac MR imaging during CPT can allow assessment of changes in MBF globally and in the separate myocardial layers in healthy smokers and nonsmokers. This allows the combined assessment of endothelium-dependent (CPT) and endothelium-independent (adenosine stress test) MBF reserve in a single study. PMID- 24072773 TI - Regulation of polarized morphogenesis by protein kinase C iota in oncogenic epithelial spheroids. AB - Protein kinase C iota (PKCiota), a serine/threonine kinase required for cell polarity, proliferation and migration, is commonly up- or downregulated in cancer. PKCiota is a human oncogene but whether this is related to its role in cell polarity and what repertoire of oncogenes acts in concert with PKCiota is not known. We developed a panel of candidate oncogene expressing Madin-Darby canine kidney (MDCK) cells and demonstrated that H-Ras, ErbB2 and phosphatidylinositol 3-kinase transformation led to non-polar spheroid morphogenesis (dysplasia), whereas MDCK spheroids expressing c-Raf or v-Src were largely polarized. We show that small interfering RNA (siRNA)-targeting PKCiota decreased the size of all spheroids tested and partially reversed the aberrant polarity phenotype in H-Ras and ErbB2 spheroids only. This indicates distinct requirements for PKCiota and moreover that different thresholds of PKCiota activity are required for these phenotypes. By manipulating PKCiota function using mutant constructs, siRNA depletion or chemical inhibition, we have demonstrated that PKCiota is required for polarization of parental MDCK epithelial cysts in a 3D matrix and that there is a threshold of PKCiota activity above and below which, disorganized epithelial morphogenesis results. Furthermore, treatment with a novel PKCiota inhibitor, CRT0066854, was able to restore polarized morphogenesis in the dysplastic H-Ras spheroids. These results show that tightly regulated PKCiota is required for normal-polarized morphogenesis in mammalian cells and that H-Ras and ErbB2 cooperate with PKCiota for loss of polarization and dysplasia. The identification of a PKCiota inhibitor that can restore polarized morphogenesis has implications for the treatment of Ras and ErbB2 driven malignancies. PMID- 24072775 TI - Simple cyst-appearing renal masses at unenhanced CT: can they be presumed to be benign? AB - PURPOSE: To determine renal cancer incidence in simple cyst-appearing renal masses detected at unenhanced computed tomography (CT). MATERIALS AND METHODS: Institutional review board approval and an informed consent waiver for this retrospective HIPAA-compliant study were obtained. Patients who had renal masses with homogeneous water attenuation, hairline-thin smooth walls, and no calcifications or septations were identified by applying a validated natural language processing algorithm to radiology reports for 15 695 unique patients who underwent unenhanced abdominal CT at our institution between 2000 and 2005. Reports that included renal masses were selected, then categorized through manual report review as pertaining to simple cyst-appearing renal masses, nonsimple or solid renal masses, or no renal masses. Medical records were reviewed for subsequent renal cancer diagnoses. Patients without renal cancer were evaluated for a minimum of 5 years (mean, 8 years; range, 5-12 years). The Cox proportional hazards regression model was used to compare renal cancer incidence for patients who had simple cyst-appearing renal masses with those who had nonsimple cystic or solid renal masses and those who had no renal masses. RESULTS: Simple cyst appearing renal masses were identified in 2669 patients (17%), no renal masses in 11844 (75%), and nonsimple cystic or solid renal masses in 1182 (8%). Of 1159 patients with simple cyst-appearing renal masses and a minimum of 5 years of follow-up, six (0.52%) subsequently developed renal cancers, all of which were separate from the simple cyst-appearing renal mass, rather than within it. Of 446 patients with nonsimple or solid renal masses and sufficient follow-up, 50 (11%) developed renal cancer. There was no difference in renal cancer incidence in patients with simple cyst-appearing renal masses versus those without renal masses (P = .54). The incidence of renal cancer was significantly lower in patients with simple cyst-appearing renal masses than that in nonsimple cystic or solid renal masses (P < .0001). CONCLUSION: Simple cyst-appearing renal masses are unlikely to be malignant. These data support foregoing further imaging evaluation of these common masses. PMID- 24072776 TI - Metastatic melanoma: lactate dehydrogenase levels and CT imaging findings of tumor devascularization allow accurate prediction of survival in patients treated with bevacizumab. AB - PURPOSE: To predict survival in patients with metastatic melanoma by evaluating a combination of serum lactate dehydrogenase (LDH) level and initial computed tomographic (CT) findings of tumor devascularization after antiangiogenic therapy. MATERIALS AND METHODS: Consent was waived for this institutional review board-approved, retrospective, secondary analysis. Forty-four patients with metastatic melanoma received bevacizumab therapy in a randomized prospective phase II trial. Target lesions on the initial posttherapy CT images were evaluated by using Response Evaluation Criteria in Solid Tumors, the Choi criteria, and Morphology, Attenuation, Size, and Structure (MASS) criteria. Cox proportional hazards models were used to assess the association of baseline clinical variables including serum LDH and imaging findings with progression-free and overall survival. The receiver operating characteristic curve with area under the curve (AUC) was used to evaluate accuracy. RESULTS: In multivariate analysis, a high baseline serum LDH level was associated with decreased progression-free survival (hazard ratio = 1.29 for each increase of 100 IU/L; P = .002) and overall survival (hazard ratio = 1.44 for each increase of 100 IU/L; P = .001). Evaluation with MASS criteria of the first CT examination after therapy strongly predicted progression-free (P < .001) and overall (P < .001) survival. Baseline serum LDH level was moderately accurate for predicting progression-free survival at 9 months (AUC = 0.793) and overall survival at 18 months (AUC = 0.689). The combination of baseline serum LDH levels and evaluation with MASS criteria at the first CT examination after therapy had significantly higher accuracy for predicting progression-free survival at 9 months (AUC = 0.969) and overall survival at 18 months (AUC = 0.813) than did baseline serum LDH levels alone for prediction of progression-free survival (P = .020). CONCLUSION: A combination of baseline serum LDH levels and evaluation with MASS criteria at the first CT examination after bevacizumab therapy had the highest accuracy for predicting survival in patients with metastatic melanoma. PMID- 24072777 TI - Cerebral hemodynamic impairment: assessment with resting-state functional MR imaging. AB - PURPOSE: To test the feasibility of noninvasive global assessment of cerebral hemodynamic impairment with use of resting-state blood oxygenation level dependent functional magnetic resonance (MR) imaging. MATERIALS AND METHODS: In this institutional review board-approved study, five patients with chronic hypoperfusion without neurologic impairment and six patients with acute stroke underwent 10-minute resting-state functional MR imaging and dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging, which was considered the standard of reference. All patients gave informed consent. The temporal shift of low-frequency signal fluctuations in each voxel compared with the averaged whole brain or global mean signal at resting-state functional MR imaging and the delay in time to peak at dynamic susceptibility-weighted contrast enhanced perfusion imaging were computed with voxel-wise analysis. The similarity of the temporal delay maps obtained with resting-state functional MR imaging and perfusion data, as well as the stability of the resting-state functional MR imaging measurement, were evaluated with the Dice similarity coefficient (DSC) and the two-tailed t test (random-effect analysis). RESULTS: The brain tissue with normal perfusion at dynamic susceptibility-weighted contrast-enhanced imaging showed no delay to global mean signal at resting-state functional MR imaging, whereas areas of abnormal perfusion with delayed time to peak (3.4 seconds +/- 2.1) showed a delay at resting-state functional MR imaging that was similar to the time to peak at dynamic susceptibility-weighted contrast-enhanced perfusion imaging, both in spatial coverage (mean DSC, 0.57 +/- 0.16) and tendency (t = 5.1, P < .001). Resting-state functional MR imaging measurements were highly stable (mean DSC, 0.83 +/- 0.12). CONCLUSION: Resting-state functional MR imaging temporal-shift analysis can noninvasively demonstrate the extent and degree of perfusion delay in patients with hypoperfusion both with and without neurologic deficit. PMID- 24072778 TI - Registry-based study of trends in breast cancer screening mammography before and after the 2009 U.S. Preventive Services Task Force recommendations. AB - PURPOSE: To determine whether the 2009 U.S. Preventive Services Task Force (USPSTF) guidelines for breast cancer mammography screening were followed by changes in screening utilization in the state of Vermont. MATERIALS AND METHODS: This retrospective study was HIPAA compliant and approved by the institutional review board, with waiver of informed consent. Trends in screening mammography utilization during 1997-2011 were examined among approximately 150,000 women aged 40 years and older in the state of Vermont using statewide mammography registry data. RESULTS: The percentage of Vermont women aged 40 years and older screened in the past year declined from 45.3% in 2009% to 41.6% in 2011 (an absolute decrease of -3.7 percentage points; 95% confidence interval [CI]: -3.3, -4.1). The largest decline in utilization was among women aged 40-49 years (-4.8 percentage points; 95% CI: -4.1, -5.4), although substantial declines were also observed among women aged 50-74 years (-3.0 percentage points; 95% CI: -2.6, 3.5) and women aged 75 years and older (-3.1 percentage points; 95% CI: -2.3, 4.0). The percentage of women aged 50-74 years screened within the past 2 years declined by -3.4 percentage points (95% CI: -3.0, -3.9) from 65.4% in 2009 to 61.9% in 2011. CONCLUSION: After years of increasing screening mammography utilization in Vermont, there was a decline in screening, which coincided with the release of the 2009 USPSTF recommendations. The age-specific patterns in utilization were generally consistent with the USPSTF recommendations, although there was also evidence that the percentage of women aged 50-74 years screened in the past 2 years declined since 2009. PMID- 24072779 TI - Uterine fibroids: postsonication temperature decay rate enables prediction of therapeutic responses to MR imaging-guided high-intensity focused ultrasound ablation. AB - PURPOSE: To determine whether intraprocedural thermal parameters as measured with magnetic resonance (MR) thermometry can be used to predict immediate or delayed therapeutic response after MR-guided high-intensity focused ultrasound (HIFU) ablation of uterine fibroids. MATERIALS AND METHODS: Institutional review board approval and subject informed consent were obtained. A total of 105 symptomatic uterine fibroids (mean diameter, 8.0 cm; mean volume, 251.8 mL) in 71 women (mean age, 43.3 years; age range, 25-52 years) who underwent volumetric MR HIFU ablation were analyzed. Correlations between tumor-averaged intraprocedural thermal parameters (peak temperature, thermal dose efficiency [estimated volume of 240 equivalent minutes at 43 degrees C divided by volume of treatment cells], and temperature decay rate after sonication) and the immediate ablation efficiency (ratio of nonperfused volume [NPV] at immediate follow-up to treatment cell volume) or ablation sustainability (ratio of NPV at 3-month follow-up to NPV at immediate follow-up) were assessed with linear regression analysis. RESULTS: A total of 2818 therapeutic sonications were analyzed. At immediate follow-up with MR imaging (n = 105), mean NPV-to-fibroid volume ratio and ablation efficiency were 0.68 +/- 0.26 (standard deviation) and 1.35 +/- 0.75, respectively. A greater thermal dose efficiency (B = 1.894, P < .001) and slower temperature decay rate (B = -1.589, P = .044) were independently significant factors that indicated better immediate ablation efficiency. At 3-month follow-up (n = 81), NPV had decreased to 43.1% +/- 21.0 of the original volume, and only slower temperature decay rate was significantly associated with better ablation sustainability (B = -0.826, P = .041). CONCLUSION: The postsonication temperature decay rate enables prediction of both immediate and delayed therapeutic responses, whereas thermal dose efficiency enables prediction of immediate therapeutic response to MR HIFU ablation of uterine fibroids. PMID- 24072780 TI - Inhibition of protein translation as a novel mechanism for prostaglandin E2 regulation of cell functions. AB - Prostaglandin E2 (PGE2) regulates numerous biological processes by modulating transcriptional activation, epigenetic control, proteolysis, and secretion of various proteins. Scar formation depends on fibroblast elaboration of matrix proteins such as collagen, and this process is strongly suppressed by PGE2 through activation of cAMP-dependent protein kinase A (PKA). However, the actual mechanism by which PGE2-PKA signaling inhibits collagen expression in fibroblasts has never been delineated, and that was the objective of this study. PGE2 unexpectedly induced a rapid reduction in procollagen I protein expression in adult lung fibroblasts, with a half-maximum effect at 1.5 h. This effect reflected its inhibition of translation rather than transcription. Global protein synthesis was also inhibited by PGE2. This action was mediated by PKA and involved both activation of ribosomal protein (rpS6) and suppression of mammalian target of rapamycin (mTOR). Similar effects of PGE2 were demonstrated in mouse peritoneal macrophages (PMs). These findings identify inhibition of translation as a new mechanism by which PGE2 regulates cellular function and a novel example of translational inhibition mediated by opposing actions on two distinct translational control pathways. Translational inhibition would be expected to contribute to dynamic alterations in cell function that accompany the changing PGE2 levels observed in disease states and with various pharmacotherapies. PMID- 24072781 TI - Generation of an efficiently secreted, cell penetrating NF-kappaB inhibitor. AB - Gene therapy is a powerful approach to treat disease locally. However, if the therapeutic target is intracellular, the therapeutic will be effective only in the cells where the therapeutic gene is delivered. We have engineered a fusion protein containing an intracellular inhibitor of the transcription factor NF kappaB pathway that can be effectively secreted from producing cells. This fusion protein is cleaved extracellularly by metalloproteinases allowing release of a protein transduction domain (PTD) linked to the NF-kappaB inhibitor for translocation into neighboring cells. We show that engineered molecules can be efficiently secreted (>80%); are cleaved with matrix metalloprotease-1; inhibit NF-kappaB driven transcription in a biological assay with a human reporter cell line; and display significant inhibition in mouse paw inflammation models when delivered by lentivirus or secreting cells. No inhibition of NF-kappaB transcription or therapeutic effect was seen using molecules devoid of the PTD and NF-kappaB inhibitory domains. By creating a fusion protein with an endogenous secretion partner, we demonstrate a novel approach to efficiently secrete PTD containing protein domains, overcoming previous limitations, and allowing for potent paracrine effects. PMID- 24072782 TI - Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2). AB - The mechanistic target of rapamycin (mTOR) exists in two complexes that regulate diverse cellular processes. mTOR complex 1 (mTORC1), the canonical target of rapamycin, has been well studied, whereas the physiological role of mTORC2 remains relatively uncharacterized. In mice in which the mTORC2 component Rictor is deleted in liver [Rictor-knockout (RKO) mice], we used genomic and phosphoproteomic analyses to characterize the role of hepatic mTORC2 in vivo. Overnight food withdrawal followed by refeeding was used to activate mTOR signaling. Rapamycin was administered before refeeding to specify mTORC2-mediated events. Hepatic mTORC2 regulated a complex gene expression and post-translational network that affects intermediary metabolism, ribosomal biogenesis, and proteasomal biogenesis. Nearly all changes in genes related to intermediary metabolic regulation were replicated in cultured fetal hepatocytes, indicating a cell-autonomous effect of mTORC2 signaling. Phosphoproteomic profiling identified mTORC2-related signaling to 144 proteins, among which were metabolic enzymes and regulators. A reduction of p38 MAPK signaling in the RKO mice represents a link between our phosphoproteomic and gene expression results. We conclude that hepatic mTORC2 exerts a broad spectrum of biological effects under physiological conditions. Our findings provide a context for the development of targeted therapies to modulate mTORC2 signaling. PMID- 24072783 TI - Pointed-end capping by tropomodulin modulates actomyosin crossbridge formation in skeletal muscle fibers. AB - In skeletal muscle, thick and thin filaments are arranged in a myofibrillar lattice. Tropomodulin 1 (Tmod1) is a pointed-end capping and tropomyosin-binding protein that controls thin-filament assembly, stability, and lengths. It remains unknown whether Tmods have other functional roles, such as regulating muscle contractility. To investigate this, we recorded and analyzed the mechanical properties and X-ray diffraction patterns of single membrane-permeabilized skeletal muscle fibers from mice lacking Tmod1. Results show that absence of Tmod1 and its replacement by Tmod3 and Tmod4 may impair initial tropomyosin movement over actin subunits during thin-filament activation, thus reducing both the fraction of actomyosin crossbridges in the strongly bound state (-29%) and fiber force-generating capacity (-31%). Therefore, Tmods are novel regulators of actomyosin crossbridge formation and muscle contractility, and future investigations and models of skeletal muscle force production must incorporate Tmods. PMID- 24072784 TI - Burt Sobel: a farewell to a friend, mentor, and dedicative leader of SEBM and EBM. PMID- 24072785 TI - In memoriam: Burton E. Sobel a tribute from family, friends and colleagues October 21, 1937 - May 3, 2013. PMID- 24072786 TI - Development and Psychometric Evaluation of a German Version of the PROMIS(r) Item Banks for Satisfaction With Participation. AB - The Patient Reported Outcomes Measurement Information System (PROMIS) initiative aims to provide reliable and precise item banks measuring patient-reported outcomes in different health domains. The aim of the present work was to provide a German translation of the PROMIS item banks for satisfaction with participation and to psychometrically test these German versions. Cognitive interviews followed a forward-backward translation. Distribution characteristics, unidimensionality, Rasch model fit, reliability, construct validity, and internal responsiveness were tested in 262 patients with chronic low back pain undergoing rehabilitation. Results for the final 13- and 10-item German static scales (Satisfaction with Participation in Social Roles-German version [PSR-G] and Satisfaction for Participation in Discretionary Social Activities-German version [PSA-G]) regarding unidimensionality were satisfactory. The scales are reliable and show good Rasch model fit and distribution characteristics. Both scales are sensitive to small to moderate clinical changes, and we observed initial proof of construct validity. These German versions of the Satisfaction with Participation scales can be recommended to assess participation in a clinical context. The scales' applicability in other contexts should be examined. PMID- 24072787 TI - Effect of barley flour on rheological characteristics of dough, organoleptic, nutritional and storage characteristics of south Indian parotta. AB - Barley (Hordeum sativum) is a good source of dietary fibre, particularly beta glucan. Effect of 10, 20, 30 and 40% barley flour on the rheological characteristics of dough and quality characteristics of south Indian parotta was studied. Use of increasing amount of barley flour from 0 to 40% increased farinograph water absorption and decreased stability, increased extensograph resistance to extension and decreased extensibility, decreased amylograph set back and increased peak viscosity values. Sensory analysis showed that use of barley flour above 30% brought about adverse effect on the quality of parotta. Addition of combination of 2% dry gluten powder and 0.001% xylanase enzyme, XY (combination of improvers) decreased elasticity, increased extensibility of the dough and quality of parotta with 30% BF. During 48 h of storage, parottas with 30% barley flour remained softer than control parotta. The total dietary fibre and beta-glucan contents of parotta with 30% BF were 2.0 and 10.5 times higher than the control parotta. PMID- 24072788 TI - Effect of protein and glycerol concentration on the mechanical, optical, and water vapor barrier properties of canola protein isolate-based edible films. AB - Biodegradable edible films prepared using proteins are both economically and environmentally important to the food packaging industry relative to traditional petroleum-derived synthetic materials. In the present study, the mechanical and water vapor barrier properties of casted canola protein isolate edible films were investigated as a function of protein (5.0% and 7.5%) and glycerol (30%, 35%, 40%, 45%, and 50%) content. Specifically, tensile strength and elongation, elastic modulus, puncture strength and deformation, opacity, and water vapor permeability were measured. Results indicated that tensile strength, puncture strength, and elastic modulus decreased, while tensile elongation and puncture deformation values increased as glycerol concentration increased for both 5.0% and 7.5% canola protein isolate films. Furthermore, tensile strength, puncture strength, and elastic modulus values were found to increase at higher protein concentrations within the canola protein isolate films, whereas puncture deformation values decreased. Tensile elongation was found to be similar for both canola protein isolate protein levels. Canola protein isolate films became more transparent with increasing of glycerol concentration and decreasing of canola protein isolate concentration. Water vapor permeability value was also found to increase with increasing glycerol and protein contents. Overall, results indicated that canola protein isolate films were less brittle, more malleable and transparent, and had greater water vapor permeability at higher glycerol levels. However, as protein level increased, canola protein isolate films were more brittle, less malleable and more opaque, and also had increased water vapor permeability. PMID- 24072789 TI - Structure, material characteristics and function of the upper respiratory tract of the pygmy sperm whale. AB - Cetaceans are neckless, so the trachea is very short. The upper respiratory tract is separate from the mouth and pharynx, and the dorsal blowhole connects, via the vestibular and nasopalatine cavities, directly to the larynx. Toothed cetaceans (Odontoceti) are capable of producing sounds at depth, either for locating prey or for communication. It has been suggested that during dives, air from the lungs and upper respiratory tract can be moved to the vestibular and nasal cavities to permit sound generation to continue when air volume within these cavities decreases as ambient pressure rises. The pygmy sperm whale, Kogia breviceps, is a deep diver (500-1000 m) that is known to produce hunting clicks. Our study of an immature female shows that the upper respiratory tract is highly asymmetrical: the trachea and bronchi are extremely compressible, whereas the larynx is much more rigid. Laryngeal and tracheal volumes were established. Calculations based on Boyle's Law imply that all air from the lungs and bronchi would be transferred to the larynx and trachea by a depth of 270 m and that the larynx itself could not accommodate all respiratory air mass at a depth of 1000 m. This suggests that no respiratory air would be available for vocalisation. However, the bronchi, trachea and part of the larynx have a thick vascular lining featuring large, thin walled vessels. We propose that these vessels may become dilated during dives to reduce the volume of the upper respiratory tract, permitting forward transfer of air through the larynx. PMID- 24072790 TI - Tilapia (Oreochromis mossambicus) brain cells respond to hyperosmotic challenge by inducing myo-inositol biosynthesis. AB - This study aimed to determine the regulation of the de novo myo-inositol biosynthetic (MIB) pathway in Mozambique tilapia (Oreochromis mossambicus) brain following acute (25 ppt) and chronic (30, 60 and 90 ppt) salinity acclimations. The MIB pathway plays an important role in accumulating the compatible osmolyte, myo-inositol, in cells in response to hyperosmotic challenge and consists of two enzymes, myo-inositol phosphate synthase and inositol monophosphatase. In tilapia brain, MIB enzyme transcriptional regulation was found to robustly increase in a time (acute acclimation) or dose (chronic acclimation) dependent manner. Blood plasma osmolality and Na(+) and Cl(-) concentrations were also measured and significantly increased in response to both acute and chronic salinity challenges. Interestingly, highly significant positive correlations were found between MIB enzyme mRNA and blood plasma osmolality in both acute and chronic salinity acclimations. Additionally, a mass spectrometry assay was established and used to quantify total myo-inositol concentration in tilapia brain, which closely mirrored the hyperosmotic MIB pathway induction. Thus, myo-inositol is a major compatible osmolyte that is accumulated in brain cells when exposed to acute and chronic hyperosmotic challenge. These data show that the MIB pathway is highly induced in response to environmental salinity challenge in tilapia brain and that this induction is likely prompted by increases in blood plasma osmolality. Because the MIB pathway uses glucose-6-phosphate as a substrate and large amounts of myo-inositol are being synthesized, our data also illustrate that the MIB pathway likely contributes to the high energetic demand posed by salinity challenge. PMID- 24072792 TI - Stress-induced plastic responses in Drosophila simulans following exposure to combinations of temperature and humidity levels. AB - Plastic responses to heat and desiccation stress in insects have been studied in many laboratory experiments on Drosophila. However, in these studies the possible interaction between the corresponding stress factors in natural environments has not been taken into consideration. We investigated changes in heat and desiccation resistance of adult Drosophila simulans after short-term exposures to different temperatures (35, 31 and 18 degrees C) in combination with high and low relative humidity (ca. 90 and 20%, respectively). Hardening under extreme conditions (35 or 31 degrees C and low relative humidity) commonly resulted in higher resistance to heat and desiccation as compared with other less stressful combinations of temperature and humidity levels. The concentration of the heat shock protein Hsp70 in the experimental flies increased following almost all applied treatments. Life span of the hardened flies under non-stressful conditions was reduced irrespective of the stress dose, indicating a fitness cost for the plastic responses. The results of the study show that hardening using combined heat and desiccation stress can be very efficient with regard to induction of plastic responses improving tolerance to both types of stress. This may favour adaptation to hot and dry climatic conditions, though the negative effects on fitness are likely to constrain evolution of such plastic responses. PMID- 24072791 TI - Salinity-induced regulation of the myo-inositol biosynthesis pathway in tilapia gill epithelium. AB - The myo-inositol biosynthesis (MIB) pathway converts glucose-6-phosphate to the compatible osmolyte myo-inositol that protects cells from osmotic stress. Using proteomics, the enzymes that constitute the MIB pathway, myo-inositol phosphate synthase (MIPS) and inositol monophosphatase 1 (IMPA1), are identified in tilapia (Oreochromis mossambicus) gill epithelium. Targeted, quantitative, label-free proteomics reveals that they are both upregulated during salinity stress. Upregulation is stronger when fish are exposed to severe (34 ppt acute and 90 ppt gradual) relative to moderate (70 ppt gradual) salinity stress. IMPA1 always responds more strongly than MIPS, suggesting that MIPS is more stable during salinity stress. MIPS is N-terminally acetylated and the corresponding peptide increases proportionally to MIPS protein, while non-acetylated N-terminal peptide is not detectable, indicating that MIPS acetylation is constitutive and may serve to stabilize the protein. Hyperosmotic induction of MIPS and IMPA1 is confirmed using western blot and real-time qPCR and is much higher at the mRNA than at the protein level. Two distinct MIPS mRNA variants are expressed in the gill, but one is more strongly regulated by salinity than the other. A single MIPS gene is encoded in the tilapia genome whereas the zebrafish genome lacks MIPS entirely. The genome of euryhaline tilapia contains four IMPA genes, two of which are expressed, but only one is salinity regulated in gill epithelium. The genome of stenohaline zebrafish contains a single IMPA gene. We conclude that the MIB pathway represents a major salinity stress coping mechanism that is regulated at multiple levels in euryhaline fish but absent in stenohaline zebrafish. PMID- 24072793 TI - A simple and affordable calorespirometer for assessing the metabolic rates of fishes. AB - Calorimetry is the measurement of the heat liberated during energy transformations in chemical reactions. When applied to living organisms, it measures the heat released due to the energy transformations associated with metabolism under both aerobic and anaerobic conditions. This is in contrast to the often-used respirometric techniques for assessing energy turnover, which can only be used under fully aerobic conditions. Accordingly, calorimetry is considered the 'gold standard' for quantifying metabolic rate, yet despite this, it remains a seldom-used technique among comparative physiologists. The reasons for this are related to the expense and perceived difficulty of the technique. We have designed and constructed an inexpensive flow-through calorespirometer capable of detecting rates of metabolic heat loss and oxygen consumption (O2) in fish under a variety of environmental conditions over long-term experiments. The metabolic heat of the fish is detected as a voltage by a collection of Peltier units wired in series, while oxygen optodes placed on the inflowing and outflowing water lines are used for the calculation of O2. The apparatus is constructed in a differential fashion to account for ambient temperature fluctuations. This paper describes the design and construction of the calorespirometer for ~$1300 CDN. Using the goldfish (Carassius auratus auratus), we show that the calorespirometer is sensitive to changes in metabolic rate brought about by pharmacological manipulation and severe hypoxia exposures. PMID- 24072794 TI - Hawkmoth flight stability in turbulent vortex streets. AB - Shedding of vortices is a common phenomenon in the atmosphere over a wide range of spatial and temporal scales. However, it is unclear how these vortices of varying scales affect the flight performance of flying animals. In order to examine these interactions, we trained seven hawkmoths (Manduca sexta) (wingspan ~9 cm) to fly and feed in a wind tunnel under steady flow (controls) and in the von Karman vortex street of vertically oriented cylinders (two different cylinders with diameters of 10 and 5 cm) at speeds of 0.5, 1 and 2 m s(-1). Cylinders were placed at distances of 5, 25 and 100 cm upstream of the moths. Moths exhibited large amplitude yaw oscillations coupled with modest oscillations in roll and pitch, and slight increases in wingbeat frequency when flying in both the near (recirculating) and middle (vortex dominated) wake regions. Wingbeat amplitude did not vary among treatments, except at 1 m s(-1) for the large cylinder. Yaw and roll oscillations were synchronized with the vortex shedding frequencies in moths flying in the wake of the large cylinder at all speeds. In contrast, yaw and pitch were synchronized with the shedding frequency of small vortices at speeds <=1 m s(-1). Oscillations in body orientation were also substantially smaller in the small cylinder treatment when compared with the large cylinder, regardless of temporal or non-dimensional spatial scale. Moths flying in steady conditions reached a higher air speed than those flying into cylinder wakes. In general, flight effects produced by the cylinder wakes were qualitatively similar among the recirculating and vortex-dominated wake regions; the magnitude of those effects, however, declined gradually with downstream distance. PMID- 24072795 TI - Isotope turnover rates and diet-tissue discrimination in skin of ex situ bottlenose dolphins (Tursiops truncatus). AB - Diet-tissue discrimination factors (Delta(15)N or Delta(13)C) and turnover times are thought to be influenced by a wide range of variables including metabolic rate, age, dietary quality, tissue sampled and the taxon being investigated. In the present study, skin samples were collected from ex situ dolphins that had consumed diets of known isotopic composition for a minimum of 8 weeks. Adult dolphins consuming a diet of low fat (5-6%) and high delta(15)N value had significantly lower Delta(15)N values than animals consuming a diet with high fat (13.9%) and low delta(15)N value. Juvenile dolphins consuming a diet with low fat and an intermediate delta(15)N value had significantly higher Delta(15)N values than adults consuming the same diet. Calculated half-lives for delta(15)N ranged from 14 to 23 days (17.2 +/- 1.3 days). Half-lives for delta(13)C ranged from 11 to 23 days with a significant difference between low fat (13.9 +/- 4.8 days) and high fat diets (22.0 +/- 0.5 days). Overall, our results indicate that while assuming a Delta(13)C value of 10/00 may be appropriate for cetaceans, Delta(15)N values may be closer to 1.50/00 rather than the commonly assumed 30/00. Our data also suggest that understanding seasonal variability in prey composition is another significant consideration when applying discrimination factors or turnover times to field studies focused on feeding habits. Isotope retention times of only a few weeks suggest that, in addition, these isotope data could play an important role in interpreting recent fine-scale habitat utilization and residency patterns. PMID- 24072797 TI - Color-dependent learning in restrained Africanized honey bees. AB - Associative color learning has been demonstrated to be very poor using restrained European honey bees unless the antennae are amputated. Consequently, our understanding of proximate mechanisms in visual information processing is handicapped. Here we test learning performance of Africanized honey bees under restrained conditions with visual and olfactory stimulation using the proboscis extension response (PER) protocol. Restrained individuals were trained to learn an association between a color stimulus and a sugar-water reward. We evaluated performance for 'absolute' learning (learned association between a stimulus and a reward) and 'discriminant' learning (discrimination between two stimuli). Restrained Africanized honey bees (AHBs) readily learned the association of color stimulus for both blue and green LED stimuli in absolute and discriminatory learning tasks within seven presentations, but not with violet as the rewarded color. Additionally, 24-h memory improved considerably during the discrimination task, compared with absolute association (15-55%). We found that antennal amputation was unnecessary and reduced performance in AHBs. Thus color learning can now be studied using the PER protocol with intact AHBs. This finding opens the way towards investigating visual and multimodal learning with application of neural techniques commonly used in restrained honey bees. PMID- 24072796 TI - Increase in cardiac myosin heavy-chain (MyHC) alpha protein isoform in hibernating ground squirrels, with echocardiographic visualization of ventricular wall hypertrophy and prolonged contraction. AB - Deep hibernators such as golden-mantled ground squirrels (Callospermophilus lateralis) have multiple challenges to cardiac function during low temperature torpor and subsequent arousals. As heart rates fall from over 300 beats min(-1) to less than 10, chamber dilation and reduced cardiac output could lead to congestive myopathy. We performed echocardiography on a cohort of individuals prior to and after several months of hibernation. The left ventricular chamber exhibited eccentric and concentric hypertrophy during hibernation and thus calculated ventricular mass was ~30% greater. Ventricular ejection fraction was mildly reduced during hibernation but stroke volumes were greater due to the eccentric hypertrophy and dramatically increased diastolic filling volumes. Globally, the systolic phase in hibernation was ~9.5 times longer, and the diastolic phase was 28* longer. Left atrial ejection generally was not observed during hibernation. Atrial ejection returned weakly during early arousal. Strain echocardiography assessed the velocity and total movement distance of contraction and relaxation for regional ventricular segments in active and early arousal states. Myocardial systolic strain during early arousal was significantly greater than the active state, indicating greater total contractile movement. This mirrored the increased ventricular ejection fraction noted with early arousal. However, strain rates were slower during early arousal than during the active period, particularly systolic strain, which was 33% of active, compared with the rate of diastolic strain, which was 67% of active. As heart rate rose during the arousal period, myocardial velocities and strain rates also increased; this was matched closely by cardiac output. Curiously, though heart rates were only 26% of active heart rates during early arousal, the cardiac output was nearly 40% of the active state, suggesting an efficient pumping system. We further analyzed proportions of cardiac myosin heavy-chain (MyHC) isoforms in a separate cohort of squirrels over 5 months, including time points before hibernation, during hibernation and just prior to emergence. Hibernating individuals were maintained in both a 4 degrees C cold room and a 20 degrees C warm room. Measured by SDS PAGE, relative percentages of cardiac MyHC alpha were increased during hibernation, at both hibernacula temperatures. A potential increase in contractile speed, and power, from more abundant MyHC alpha may aid force generation at low temperature and at low heart rates. Unlike many models of cardiomyopathies where the alpha isoform is replaced by the beta isoform in order to reduce oxygen consumption, ground squirrels demonstrate a potential cardioprotective mechanism to maintain cardiac output during torpor. PMID- 24072798 TI - The variability and interdependence of spider viscid line tensile properties. AB - True stress-true strain curves of naturally spun viscid line fibres retrieved directly from the spiral of orb-webs built by Argiope trifasciata spiders were measured using a novel methodology. This new procedure combines a method for removing the aqueous coating of the fibres and a technique that allows the accurate measurement of their cross-sectional area. Comparison of the tensile behaviour of different samples indicated that naturally spun viscid lines show a large variability, comparable to that of other silks, such as major ampullate gland silk and silkworm silk. Nevertheless, application of a statistical analysis allowed the identification of two independent parameters that underlie the variability and characterize the observed range of true stress-true strain curves. The combination of this result with previous mechanical and microstructural data suggested the assignment of these two independent effects to the degree of alignment of the protein chains and to the local relative humidity, which, in turn, depends on the composition of the viscous coating and on the external environmental conditions. PMID- 24072799 TI - Undulating fins produce off-axis thrust and flow structures. AB - While wake structures of many forms of swimming and flying are well characterized, the wake generated by a freely swimming undulating fin has not yet been analyzed. These elongated fins allow fish to achieve enhanced agility exemplified by the forward, backward and vertical swimming capabilities of knifefish, and also have potential applications in the design of more maneuverable underwater vehicles. We present the flow structure of an undulating robotic fin model using particle image velocimetry to measure fluid velocity fields in the wake. We supplement the experimental robotic work with high fidelity computational fluid dynamics, simulating the hydrodynamics of both a virtual fish, whose fin kinematics and fin plus body morphology are measured from a freely swimming knifefish, and a virtual rendering of our robot. Our results indicate that a series of linked vortex tubes is shed off the long edge of the fin as the undulatory wave travels lengthwise along the fin. A jet at an oblique angle to the fin is associated with the successive vortex tubes, propelling the fish forward. The vortex structure bears similarity to the linked vortex ring structure trailing the oscillating caudal fin of a carangiform swimmer, though the vortex rings are distorted because of the undulatory kinematics of the elongated fin. PMID- 24072800 TI - Functional implications of ontogenetically and sexually dimorphic dentition in the eastern shovelnose ray, Aptychotrema rostrata. AB - Unlike other elasmobranchs, batoids exhibit sexually dimorphic dentition. The functional implications of such dentition, however, remain understudied. For the present study, ontogenetic and sexual dimorphism in tooth and jaw structure, together with the functional implications of this dimorphism, were determined in the eastern shovelnose ray, Aptychotrema rostrata. Sexually dimorphic dentition and jaw structure was first observed in sub-adult age classes, with males developing a pronounced lower jaw at the symphysis. Monognathic heterodonty was prominent in mature males, with teeth in the symphyseal region developing significantly greater heights and sharpness ratios in comparison to females. Ex vivo mechanical grip strength tests were used to determine simulated bite-grip tenacity. The mean peak pull-out forces required to withdraw a section of a dissected pectoral fin from between jaws closed with a constant occlusal force was highest for mature males, intermediate for mature females and lowest for immature females and males. Although the species exhibits ontogenetic variations in diet, these were unrelated to sex. Rather, the larger and highly cuspidate teeth of mature males increased the bite-grip tenacity, which likely aids in copulation. PMID- 24072801 TI - Seasonal changes in the behaviour and respiration physiology of the freshwater duck mussel, Anodonta anatina. AB - For low-energy organisms such as bivalves, the costs of thermal compensation of biological rates (synonymous with acclimation or acclimatization) may be higher than the benefits. We therefore conducted two experiments to examine the effect of seasonal temperature changes on behaviour and oxygen consumption. In the first experiment, we examined the effects of seasonal temperature changes on the freshwater bivalve Anodonta anatina, taking measurements each month for a year at the corresponding temperature for that time of year. There was no evidence for compensation of burrowing valve closure duration or frequency, or locomotory speed. In the second experiment, we compared A. anatina at summer and winter temperatures (24 and 4 degrees C, respectively) and found no evidence for compensation of the burrowing rate, valve closure duration or frequency, or oxygen consumption rates during burrowing, immediately after valve closure or at rest. Within the experimental limits of this study, the evidence suggests that thermal compensation of biological rates is not a strategy employed by A. anatina. We argue that this is due to either a lack of evolutionary pressure to acclimatize, or evolutionary pressure to not acclimatize. Firstly, there is little incentive to increase metabolic rate to enhance predatory ability given that these are filter feeders. Secondly, maintained low energetic demand, enhanced at winter temperatures, is essential for predator avoidance, i.e. valve closure. Thus, we suggest that the costs of acclimatization outweigh the benefits in A. anatina. PMID- 24072802 TI - Interactions between hypoxia tolerance and food deprivation in Amazonian oscars, Astronotus ocellatus. AB - Oscars are often subjected to a combination of low levels of oxygen and fasting during nest-guarding on Amazonian floodplains. We questioned whether this anorexia would aggravate the osmo-respiratory compromise. We compared fed and fasted oscars (10-14 days) in both normoxia and hypoxia (10-20 Torr, 4 h). Routine oxygen consumption rates (O2) were increased by 75% in fasted fish, reflecting behavioural differences, whereas fasting improved hypoxia resistance and critical oxygen tensions (Pcrit) lowered from 54 Torr in fed fish to 34 Torr when fasting. In fed fish, hypoxia reduced liver lipid stores by approximately 50% and total liver energy content by 30%. Fasted fish had a 50% lower hepatosomatic index, resulting in lower total liver protein, glycogen and lipid energy stores under normoxia. Compared with hypoxic fed fish, hypoxic fasted fish only showed reduced liver protein levels and even gained glycogen (+50%) on a per gram basis. This confirms the hypothesis that hypoxia-tolerant fish protect their glycogen stores as much as possible as a safeguard for more prolonged hypoxic events. In general, fasted fish showed lower hydroxyacylCoA dehydrogenase activities compared with fed fish, although this effect was only significant in hypoxic fasted fish. Energy stores and activities of enzymes related to energy metabolism in muscle or gills were not affected. Branchial Na(+) uptake rates were more than two times lower in fed fish, whereas Na(+) efflux was similar. Fed and fasted fish quickly reduced Na(+) uptake and efflux during hypoxia, with fasting fish responding more rapidly. Ammonia excretion and K(+) efflux were reduced under hypoxia, indicating decreased transcellular permeability. Fasted fish had more mitochondria-rich cells (MRC), with larger crypts, indicating the increased importance of the branchial uptake route when feeding is limited. Gill MRC density and surface area were greatly reduced under hypoxia, possibly to reduce ion uptake and efflux rates. Density of mucous cells of normoxic fasted fish was approximately fourfold of that in fed fish. Overall, a 10-14 day fasting period had no negative effects on hypoxia tolerance in oscars, as fasted fish were able to respond more quickly to lower oxygen levels, and reduced branchial permeability effectively. PMID- 24072803 TI - Comparison of rotator cuff muscle architecture between humans and other selected vertebrate species. AB - In this study, we compare rotator cuff muscle architecture of typically used animal models with that of humans and quantify the scaling relationships of these muscles across mammals. The four muscles that correspond to the human rotator cuff - supraspinatus, infraspinatus, subscapularis and teres minor - of 10 commonly studied animals were excised and subjected to a series of comparative measurements. When body mass among animals was regressed against physiological cross-sectional area, muscle mass and normalized fiber length, the confidence intervals suggested geometric scaling but did not exclude other scaling relationships. Based on the architectural difference index (ADI), a combined measure of fiber length-to-moment arm ratio, fiber length-to-muscle length ratio and the fraction of the total rotator cuff physiological cross-sectional area contributed by each muscle, chimpanzees were found to be the most similar to humans (ADI=2.15), followed closely by capuchins (ADI=2.16). Interestingly, of the eight non-primates studied, smaller mammals such as mice, rats and dogs were more similar to humans in architectural parameters compared with larger mammals such as sheep, pigs or cows. The force production versus velocity trade-off (indicated by fiber length-to-moment arm ratio) and the excursion ability (indicated by fiber length-to-muscle length ratio) of humans were also most similar to those of primates, followed by the small mammals. Overall, primates provide the best architectural representation of human muscle architecture. However, based on the muscle architectural parameters of non-primates, smaller rather than larger mammals may be better models for studying muscles related to the human rotator cuff. PMID- 24072804 TI - Acute heat tolerance of cardiac excitation in the brown trout (Salmo trutta fario). AB - The upper thermal tolerance and mechanisms of heat-induced cardiac failure in the brown trout (Salmo trutta fario) was examined. The point above which ion channel function and sinoatrial contractility in vitro, and electrocardiogram (ECG) in vivo, started to fail (break point temperature, BPT) was determined by acute temperature increases. In general, electrical excitation of the heart was most sensitive to heat in the intact animal (electrocardiogram, ECG) and least sensitive in isolated cardiac myocytes (ion currents). BPTs of Ca(2+) and K(+) currents of cardiac myocytes were much higher (>28 degrees C) than BPT of in vivo heart rate (23.5 +/- 0.6 degrees C) (P<0.05). A striking exception among sarcolemmal ion conductances was the Na(+) current (INa), which was the most heat sensitive molecular function, with a BPT of 20.9 +/- 0.5 degrees C. The low heat tolerance of INa was reflected as a low BPT for the rate of action potential upstroke in vitro (21.7 +/- 1.2 degrees C) and the velocity of impulse transmission in vivo (21.9 +/- 2.2 degrees C). These findings from different levels of biological organization strongly suggest that heat-dependent deterioration of Na(+) channel function disturbs normal spread of electrical excitation over the heart, leading to progressive variability of cardiac rhythmicity (missed beats, bursts of fast beating), reduction of heart rate and finally cessation of the normal heartbeat. Among the cardiac ion currents INa is 'the weakest link' and possibly a limiting factor for upper thermal tolerance of electrical excitation in the brown trout heart. Heat sensitivity of INa may result from functional requirements for very high flux rates and fast gating kinetics of the Na(+) channels, i.e. a trade-off between high catalytic activity and thermal stability. PMID- 24072805 TI - Adapting social neuroscience measures for schizophrenia clinical trials, Part 2: trolling the depths of psychometric properties. AB - The psychometric properties of 4 paradigms adapted from the social neuroscience literature were evaluated to determine their suitability for use in clinical trials of schizophrenia. This 2-site study (University of California, Los Angeles and University of North Carolina) included 173 clinically stable schizophrenia outpatients and 88 healthy controls. The social cognition battery was administered twice to the schizophrenia group (baseline, 4-week retest) and once to the control group. The 4 paradigms included 2 that assess perception of nonverbal social and action cues (basic biological motion and emotion in biological motion) and 2 that involve higher level inferences about self and others' mental states (self-referential memory and empathic accuracy). Each paradigm was evaluated on (1) patient vs healthy control group differences, (2) test-retest reliability, (3) utility as a repeated measure, and (4) tolerability. Of the 4 paradigms, empathic accuracy demonstrated the strongest characteristics, including large between-group differences, adequate test-retest reliability (.72), negligible practice effects, and good tolerability ratings. The other paradigms showed weaker psychometric characteristics in their current forms. These findings highlight challenges in adapting social neuroscience paradigms for use in clinical trials. PMID- 24072807 TI - Fluphenazine (oral) versus placebo for schizophrenia. AB - Fluphenazine, a phenothiazine derivative, was one of the first drugs to be classed as an "antipsychotic" and was approved by the Food and Drug Administration in 1959. In Britain, it was first used for the relief of anxiety. The American reports, however, were the first to indicate its value in psychotic illness. Fluphenazine is an inexpensive and widely accessible antipsychotic drug that has been available to treat people with schizophrenia for five decades. We updated our original search (from September 2006) using The Cochrane Schizophrenia Group Trials register (May 2012); we found no new relevant studies. Seven randomized controlled trials (RCTs) were included with a total of N = 439 participants. Results, based on this small selection of studies, suggested that there was no significant difference between oral fluphenazine and placebo for most outcomes, including global state and leaving the study early. Results did suggest a statistically significant effect favoring oral fluphenazine in the short term for levels of relapse (n = 38, 1 RCT, RR 0.25 CI 0.06-1.03) with levels of extrapyramidal adverse effects more frequent with oral fluphenazine. The findings in this review confirm much that clinicians and recipients of care already know, but they provide quantification to support clinical impression. In this review, for perhaps the first time, we objectively quantified the effects of oral administration of fluphenazine in comparison with placebo. It is indeed a potent antipsychotic but with considerable adverse effects. Other drugs may well be preferable. PMID- 24072806 TI - Adapting social neuroscience measures for schizophrenia clinical trials, part 3: fathoming external validity. AB - It is unknown whether measures adapted from social neuroscience linked to specific neural systems will demonstrate relationships to external variables. Four paradigms adapted from social neuroscience were administered to 173 clinically stable outpatients with schizophrenia to determine their relationships to functionally meaningful variables and to investigate their incremental validity beyond standard measures of social and nonsocial cognition. The 4 paradigms included 2 that assess perception of nonverbal social and action cues (basic biological motion and emotion in biological motion) and 2 that involve higher level inferences about self and others' mental states (self-referential memory and empathic accuracy). Overall, social neuroscience paradigms showed significant relationships to functional capacity but weak relationships to community functioning; the paradigms also showed weak correlations to clinical symptoms. Evidence for incremental validity beyond standard measures of social and nonsocial cognition was mixed with additional predictive power shown for functional capacity but not community functioning. Of the newly adapted paradigms, the empathic accuracy task had the broadest external validity. These results underscore the difficulty of translating developments from neuroscience into clinically useful tasks with functional significance. PMID- 24072808 TI - The effect of motivational interviewing on medication adherence and hospitalization rates in nonadherent patients with multi-episode schizophrenia. AB - BACKGROUND: Medication nonadherence in patients with schizophrenia presents a serious clinical problem. Research on interventions incorporating motivational interviewing (MI) to improve adherence have shown mixed results. AIMS: Primary aim is to determine the effectiveness of a MI intervention on adherence and hospitalization rates in patients, with multi-episode schizophrenia or schizoaffective disorder, who have experienced a psychotic relapse following medication nonadherence. Secondary aim is to evaluate whether MI is more effective in specific subgroups. METHODS: We performed a randomized controlled study including 114 patients who experienced a psychotic relapse due to medication nonadherence in the past year. Participants received an adapted form of MI or an active control intervention, health education (HE). Both interventions consisted of 5-8 sessions, which patients received in adjunction to the care as usual. Patients were assessed at baseline and at 6 and 12 months follow-up. RESULTS: Our results show that MI did not improve medication adherence in previously nonadherent patients who experienced a psychotic relapse. Neither were there significant differences in hospitalization rates at follow-up between MI and HE (27% vs 40%, P = .187). However, MI resulted in reduced hospitalization rates for female patients (9% vs 63%, P = .041), non-cannabis users (20% vs 53%, P = .041), younger patients (14% vs 50%, P = .012), and patients with shorter illness duration (14% vs 42%, P = .040). CONCLUSIONS: Targeted use of MI may be of benefit for improving medication adherence in certain groups of patients, although this needs further examination. PMID- 24072809 TI - Spontaneous parkinsonism is associated with cognitive impairment in antipsychotic naive patients with first-episode psychosis: a 6-month follow-up study. AB - There is now growing evidence that parkinsonism and other extrapyramidal signs are highly prevalent in patients with first-episode psychosis who have never been exposed to antipsychotic drugs. However, the neurocognitive correlates of parkinsonism in this population remained to be clarified. A sample comprising 100 consecutive drug-naive patients with first-episode psychosis were enrolled on the study and followed up for 6 months. Seventy-seven completed assessments at 3 time points (baseline, 1 mo, and 6 mo), involving clinical and cognitive examinations and a specific assessment of motor abnormalities. The Simpson-Angus Scale (SAS) was used for the assessment of extrapyramidal signs, and each motor domain was evaluated with a standard assessment scale. Linear mixed models were built to explore the longitudinal relationships between parkinsonism scores and cognitive impairment. Parkinsonism scores showed significant strong longitudinal associations with deficits in memory, executive functioning, and attention. Spontaneous parkinsonism (total SAS score and hypokinesia and rigidity subscores at baseline) showed high 6-month predictive values for cognitive impairment. In addition, they also had high predictive values for neurologic soft-sign abnormalities but not for dyskinesia, akathisia, and pure catatonic abnormalities. No predictive value was found for glabella-salivation or tremor subscores on the SAS scale. These results emphasize the relevance of the assessment of parkinsonism signs prior to starting to administer antipsychotic drugs, as core manifestations of psychotic illness with a high predictive value for cognitive impairment. PMID- 24072810 TI - Going from social neuroscience to schizophrenia clinical trials. AB - The goals of the project Social Cognition and Functioning in Schizophrenia (SCAF) were to (1) identify the domains to target from social neuroscience for translation to clinical schizophrenia research, (2) identify the paradigms that represent these domains for which the neural substrates are well documented, (3) adapt these paradigms for use in schizophrenia clinical trials, (4) assess the psychometric properties of these measures, and (5) assess the external validity of these measures. The articles in this theme section present the initial findings from the SCAF project. As more training and psychopharmacological studies evaluate interventions for social cognition, the articles in this theme section are intended to serve as a guide for informed design decisions about possible endpoints in clinical trials. PMID- 24072812 TI - Inflammation and schizophrenia. PMID- 24072811 TI - Adapting social neuroscience measures for schizophrenia clinical trials, Part 1: ferrying paradigms across perilous waters. AB - Social cognitive impairment is prominent in schizophrenia, and it is closely related to functional outcome. Partly for these reasons, it has rapidly become a target for both training and psychopharmacological interventions. However, there is a paucity of reliable and valid social cognitive endpoints that can be used to evaluate treatment response in clinical trials. Also, clinical studies in schizophrenia have benefited rather little from the surge of activity and knowledge in nonclinical social neuroscience. The National Institute of Mental Health-sponsored study, "Social Cognition and Functioning in Schizophrenia" (SCAF), attempted to address this translational challenge by selecting paradigms from social neuroscience that could be adapted for use in schizophrenia. The project also evaluated the psychometric properties and external validity of the tasks to determine their suitability for multisite clinical trials. This first article in the theme section presents the goals, conceptual background, and rationale for the SCAF project. PMID- 24072813 TI - Dichotomous roles of leptin and adiponectin as enforcers against lipotoxicity during feast and famine. AB - Science is marked by the death of dogmas; the discovery that adipocytes are more than just lipid-storing cells but rather produce potent hormones is one such example that caught physiologists by surprise and reshaped our views of metabolism. While we once considered the adipocyte as a passive storage organ for efficient storage of long-term energy reserves in the form of triglyceride, we now appreciate the general idea (once a radical one) that adipocytes are sophisticated enough to have potent endocrine functions. Over the past two decades, the discoveries of these adipose-derived factors ("adipokines") and their mechanistic actions have left us marveling at and struggling to understand the role these factors serve in physiology and the pathophysiology of obesity and diabetes. These hormones may serve an integral role in protecting nonadipose tissues from lipid-induced damage during nutrient-deprived or replete states. As such, adipocytes deliver not only potentially cytotoxic free fatty acids but, along with these lipids, antilipotoxic adipokines such as leptin, adiponectin, and fibroblast growth factor 21 that potently eliminate excessive local accumulation of these lipids or their conversion to unfavorable sphingolipid intermediates. PMID- 24072814 TI - Presence-absence variation in A. thaliana is primarily associated with genomic signatures consistent with relaxed selective constraints. AB - The sequencing of multiple genomes of the same plant species has revealed polymorphic gene and exon loss. Genes associated with disease resistance are overrepresented among those showing structural variations, suggesting an adaptive role for gene and exon presence-absence variation (PAV). To shed light on the possible functional relevance of polymorphic coding region loss and the mechanisms driving this process, we characterized genes that have lost entire exons or their whole coding regions in 17 fully sequenced Arabidopsis thaliana accessions. We found that although a significant enrichment in genes associated with certain functional categories is observed, PAV events are largely restricted to genes with signatures of reduced essentiality: PAV genes tend to be newer additions to the genome, tissue specific, and lowly expressed. In addition, PAV genes are located in regions of lower gene density and higher transposable element density. Partial coding region PAV events were associated with only a marginal reduction in gene expression level in the affected accession and occurred in genes with higher levels of alternative splicing in the Col-0 accession. Together, these results suggest that although adaptive scenarios cannot be ruled out, PAV events can be explained without invoking them. PMID- 24072815 TI - Impact on hospital performance of introducing routine patient reported outcome measures in surgery. AB - OBJECTIVES: To determine the impact of introducing patient reported outcome measures (PROMs) on the selection of patients for surgery and on outcome for four elective operations (hip replacement, knee replacement, varicose vein surgery and groin hernia repair). METHODS: Patient-level data from the National PROMs programme for England from April 2009 to March 2012 were analysed to determine the extent of change in mean preoperative scores and mean adjusted postoperative scores using disease-specific and generic PROMs assessed using standardized effect sizes (SESs). Variation between providers was determined by intra-class correlation coefficients for each time period. Consistency in outlier ratings was tested using weighted Kappa statistics. RESULTS: There was little apparent impact. Preoperative severity increased slightly for two procedures only: varicose vein surgery (SES disease-specific PROM 0.10; generic PROM -0.07) and to a lesser extent for hip replacement (SES disease-specific PROM -0.03). There was little inter-provider variation and it did not change significantly over time. There were also slight improvements in outcomes for hip and knee replacement (SES for disease-specific and generic PROMs 0.03) though not for hernia repair and a slight worsening for varicose vein surgery. The extent of variation in performance between providers was unchanged. The proportion of providers deemed to be outliers did not change over time. There was only moderate consistency in those providers deemed to be outliers for hip and knee replacement (Kappa 0.31 0.47) and it was even weaker for the other two procedures. Although 35% of providers of hip replacement were outliers in at least one year, only 6% were consistently outliers. Such inconsistency may be partly due to regression to the mean. CONCLUSIONS: The minimal impact that the routine use and feedback of PROMs had on provider behaviour during the initial years suggests that more attention needs to be paid to how results are communicated and to the provision of advice as to what action may be taken. PMID- 24072816 TI - Approaches for assessing and discovering protein interactions in cancer. AB - Significant insight into the function of proteins can be delineated by discovering and characterizing interacting proteins. There are numerous methods for the discovery of unknown associated protein networks, with purification of the bait (the protein of interest) followed by mass spectrometry as a common theme. In recent years, advances have permitted the purification of endogenous proteins and methods for scaling down starting material. As such, approaches for rapid, unbiased identification of protein interactomes are becoming a standard tool in the researchers toolbox, rather than a technique that is only available to specialists. This review will highlight some of the recent technical advances in proteomic-based discovery approaches, the pros and cons of various methods and some of the key findings in cancer-related systems. PMID- 24072817 TI - Resveratrol and P-glycoprotein inhibitors enhance the anti-skin cancer effects of ursolic acid. AB - Ursolic acid, present in apples, rosemary, and other sources, is known to inhibit tumor formation and tumor cell viability in multiple systems, including skin. However, various cancers are resistant to ursolic acid treatment. Herein, skin carcinoma cells (Ca3/7) as compared with skin papilloma cells (MT1/2) displayed more resistance to ursolic acid-induced cytotoxicity. Interestingly, Ca3/7 cells had elevated levels of P-glycoprotein (P-gp), an ATP-dependent efflux pump that mediates resistance to chemotherapy in preclinical and clinical settings, and not only accumulated less but also more rapidly expelled the P-gp substrate rhodamine 123 (Rh123) indicating ursolic acid is transported by P-gp. To determine whether P-gp inhibition can enhance ursolic acid-mediated cytotoxicity, cells were challenged with P-gp inhibitors verapamil or cyclosporin A. Alternatively, cells were pretreated with the natural compound resveratrol, a known chemotherapy sensitizer. Verapamil and resveratrol enhanced the effects of ursolic acid in both cell lines, whereas cyclosporin A only did so in Ca3/7 cells. Similarly, verapamil inhibited Rh123 efflux in both lines, whereas cyclosporin A only inhibited Rh123 efflux in Ca3/7 cells. Resveratrol did not inhibit Rh123 efflux in either line, indicating the synergistic effects of resveratrol and ursolic acid are not manifest by inhibition of P-gp-mediated efflux of ursolic acid. These results indicate that the anti-skin cancer effects of ursolic acid are enhanced with P-gp inhibitors. In addition, resveratrol and ursolic acid interact synergistically, but not through inhibition of P-gp. IMPLICATIONS: Resveratrol and/or p-glycoprotein inhibitors in combination with ursolic acid are an effective anti-skin cancer regimen. PMID- 24072819 TI - Real-space identification of intermolecular bonding with atomic force microscopy. AB - We report a real-space visualization of the formation of hydrogen bonding in 8 hydroxyquinoline (8-hq) molecular assemblies on a Cu(111) substrate, using noncontact atomic force microscopy (NC-AFM). The atomically resolved molecular structures enable a precise determination of the characteristics of hydrogen bonding networks, including the bonding sites, orientations, and lengths. The observation of bond contrast was interpreted by ab initio density functional calculations, which indicated the electron density contribution from the hybridized electronic state of the hydrogen bond. Intermolecular coordination between the dehydrogenated 8-hq and Cu adatoms was also revealed by the submolecular resolution AFM characterization. The direct identification of local bonding configurations by NC-AFM would facilitate detailed investigations of intermolecular interactions in complex molecules with multiple active sites. PMID- 24072818 TI - Product-to-parent reversion of trenbolone: unrecognized risks for endocrine disruption. AB - Trenbolone acetate (TBA) is a high-value steroidal growth promoter often administered to beef cattle, whose metabolites are potent endocrine-disrupting compounds. We performed laboratory and field phototransformation experiments to assess the fate of TBA metabolites and their photoproducts. Unexpectedly, we observed that the rapid photohydration of TBA metabolites is reversible under conditions representative of those in surface waters (pH 7, 25 degrees C). This product-to-parent reversion mechanism results in diurnal cycling and substantial regeneration of TBA metabolites at rates that are strongly temperature- and pH dependent. Photoproducts can also react to produce structural analogs of TBA metabolites. These reactions also occur in structurally similar steroids, including human pharmaceuticals, which suggests that predictive fate models and regulatory risk assessment paradigms must account for transformation products of high-risk environmental contaminants such as endocrine-disrupting steroids. PMID- 24072820 TI - Architecture of an RNA polymerase II transcription pre-initiation complex. AB - The protein density and arrangement of subunits of a complete, 32-protein, RNA polymerase II (pol II) transcription pre-initiation complex (PIC) were determined by means of cryogenic electron microscopy and a combination of chemical cross linking and mass spectrometry. The PIC showed a marked division in two parts, one containing all the general transcription factors (GTFs) and the other pol II. Promoter DNA was associated only with the GTFs, suspended above the pol II cleft and not in contact with pol II. This structural principle of the PIC underlies its conversion to a transcriptionally active state; the PIC is poised for the formation of a transcription bubble and descent of the DNA into the pol II cleft. PMID- 24072821 TI - Deterministically encoding quantum information using 100-photon Schrodinger cat states. AB - In contrast to a single quantum bit, an oscillator can store multiple excitations and coherences provided one has the ability to generate and manipulate complex multiphoton states. We demonstrate multiphoton control by using a superconducting transmon qubit coupled to a waveguide cavity resonator with a highly ideal off resonant coupling. This dispersive interaction is much greater than decoherence rates and higher-order nonlinearities to allow simultaneous manipulation of hundreds of photons. With a tool set of conditional qubit-photon logic, we mapped an arbitrary qubit state to a superposition of coherent states, known as a "cat state." We created cat states as large as 111 photons and extended this protocol to create superpositions of up to four coherent states. This control creates a powerful interface between discrete and continuous variable quantum computation and could enable applications in metrology and quantum information processing. PMID- 24072823 TI - Causes and effects of N-terminal codon bias in bacterial genes. AB - Most amino acids are encoded by multiple codons, and codon choice has strong effects on protein expression. Rare codons are enriched at the N terminus of genes in most organisms, although the causes and effects of this bias are unclear. Here, we measure expression from >14,000 synthetic reporters in Escherichia coli and show that using N-terminal rare codons instead of common ones increases expression by ~14-fold (median 4-fold). We quantify how individual N-terminal codons affect expression and show that these effects shape the sequence of natural genes. Finally, we demonstrate that reduced RNA structure and not codon rarity itself is responsible for expression increases. Our observations resolve controversies over the roles of N-terminal codon bias and suggest a straightforward method for optimizing heterologous gene expression in bacteria. PMID- 24072824 TI - Reactive perforating collagenosis in two siblings. PMID- 24072822 TI - Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. AB - A dense mucus layer in the large intestine prevents inflammation by shielding the underlying epithelium from luminal bacteria and food antigens. This mucus barrier is organized around the hyperglycosylated mucin MUC2. Here we show that the small intestine has a porous mucus layer, which permitted the uptake of MUC2 by antigen sampling dendritic cells (DCs). Glycans associated with MUC2 imprinted DCs with anti-inflammatory properties by assembling a galectin-3-Dectin-1-FcgammaRIIB receptor complex that activated beta-catenin. This transcription factor interfered with DC expression of inflammatory but not tolerogenic cytokines by inhibiting gene transcription through nuclear factor kappaB. MUC2 induced additional conditioning signals in intestinal epithelial cells. Thus, mucus does not merely form a nonspecific physical barrier, but also constrains the immunogenicity of gut antigens by delivering tolerogenic signals. PMID- 24072825 TI - Two similar cases of internal hernia after laparoscopic Roux-en-Y gastric bypass surgery. AB - Internal hernia after laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery can lead to acute small bowel obstruction or chronic recurrent abdominal pain. We present two cases of internal hernias after antecolic antegastric LRYGB. Both patients presented to the emergency room with acute diffuse abdominal pain. Other than that, a physical examination and routine laboratory workup did not reveal any pathological finding. An abdominal CT was performed in both cases. It showed mesenteric torsion as a sign of internal hernia in one case, but remained inconclusive in the other patient. Immediate diagnostic laparoscopy was performed in both cases. Intraoperatively, both patients revealed an internal hernia, where the common channel herniated through the mesojejunal space. The conversion to upper median minilaparotomy was necessary for hernia reduction in both cases. No bowel resection was required and both patients recovered fully. PMID- 24072826 TI - A comorbid case of multicentric Castleman's disease and pulmonary hyalinising granuloma successfully treated with tocilizumab and corticosteroid. AB - A 49-year-old man with superficial lymphadenopathy presented with symptoms of low grade fever, general fatigue and weight loss. On examination, multiple superficial lymphadenopathies and brown macules were observed on the trunk. Laboratory studies revealed an elevation of serum C reactive protein and interleukin 6 (IL-6) in addition to polyclonal hyperimmunoglobulinaemia. High resolution CT of the chest showed bilateral multiple nodules and patchy ground glass opacities with interstitial thickening. Biopsy of the cervical lymph node and skin biopsy showed numerous perivascular plasma cells, which were characteristic of the plasma cell type of Castleman's disease. Surgical lung biopsy showed hyalinising granuloma, which are hyalinous nodular lesions surrounded by lymphoid cells. He was diagnosed with multicentric Castleman's disease complicated by pulmonary hyalinising granulomas; his symptoms improved by treatment with tocilizumab, which is a humanised antihuman IL-6 receptor monoclonal antibody and corticosteroid. This is the first report of a comorbid case successfully treated with tocilizumab and corticosteroid. PMID- 24072827 TI - Pain and fracture after anterior cruciate ligament reconstruction caused by giant cell tumour of the distal femur. AB - The causes of pain after an anterior cruciate ligament (ACL) reconstruction are numerous and may have complex origins. We present an unusual case in which pain after an ACL reconstruction developed secondary to a giant cell tumour of the bone occurring around a fixation screw in the distal femur, with an associated fracture through the femoral tunnel of a previously well-functioning reconstruction. We discuss the aetiology and the treatment of a complex clinical scenario. PMID- 24072828 TI - Tuberculous gumma: a forgotten entity in the UK. AB - A 24-year-old immunocompetent Pakistani man presented with multiple subcutaneous abscesses that had developed and persisted over 2 months. After surgical incision and drainage, Mycobacterium tuberculosis was isolated (MTB). Further investigation yielded positive sputum cultures confirming pulmonary tuberculosis (TB) too. The patient was started on standard quadruple therapy for disseminated haematogenous TB in the form of tuberculous gumma and pulmonary TB. PMID- 24072829 TI - An unusual case of peripartum pulmonary oedema. AB - A previously healthy woman in her early 20s presented in week 38 of pregnancy with a 2-week history of haemoptysis, positional dyspnoea and an examination suggestive of pulmonary oedema. A chest CT showed a left lower lobe lung mass invading through the inferior pulmonary vein into the left atrium and abutting the posterior mitral leaflet. Pulmonary oedema consequent on left inferior pulmonary vein occlusion was initially restricted to the left lower lobe, but progressed to involve the contralateral lung following extension of the mass to the mitral orifice, resulting in functional mitral stenosis. A biopsy was positive for poorly differentiated spindle cell neoplasm. This is the first reported case of a pregnant patient with spindle cell neoplasm of lung and of a spindle neoplasm causing mitral stenosis, as well as the youngest known case of this disease. PMID- 24072830 TI - Just another negative DVT? AB - A 69-year-old woman presented to the emergency department (ED) with a swollen left thigh and leg. D-dimer test was positive, a radiology department ultrasound showed no direct evidence of a deep venous thrombosis but a lack of respiratory modulation was seen. ED ultrasound showed large groin lymph nodes and this, together with low haemoglobin, prompted a CT scan which led to the diagnosis of metastatic carcinoma. PMID- 24072831 TI - Vein of Galen malformation presenting as persistent pulmonary hypertension of newborn (PPHN). AB - Arteriovenous malformation is a recognised cause of persistent pulmonary hypertension in a newborn (PPHN). Vein of Galen malformation (VOGM) is a rare vascular malformation which can be life-threatening if not diagnosed and treated early. We describe a case of a term baby who presented at day 4 of life with PPHN secondary to VOGM. The neonate underwent two transarterial interventional embolisation procedures on day 9 and then another one due to developing ventricular dilation on day 44. He remains stable since and was doing well at clinical review at 10 weeks and 4 months of age. VOGM usually presents in the neonatal period with high-output cardiac failure. In a baby who presents atypically with pulmonary hypertension, a cranial ultrasound scan should be considered to look for extracardiac shunting in the brain, especially, VOGM. PMID- 24072832 TI - Perianal Paget's disease: a diagnostic dilemma. AB - Perianal Paget's disease (PPD) is part of the spectrum of pagetoid skin lesions occurring outside the region of the nipple/areolar complex that are collectively referred to as extramammary Paget's disease (EMPD). However, unlike Paget's disease of the breast, which in the vast majority of cases is invariably associated with an underlying ductal carcinoma, most cases of EMPD occur as either insitu or invasive adenocarcinomas with visceral malignancy being a rare entity. We present a case of a 50-year-old man who was referred to us with PPD. This case highlights the difficulties associated with making a clinical diagnosis of this condition. Furthermore, investigative workup to exclude possible malignancy with associated metastatic spread as well as the treatment options available are also discussed. In addition, this case highlights the need for a multidisciplinary team approach when dealing with this difficult problem. PMID- 24072833 TI - Peliosis hepatis: a complicating finding in a case of biliary colic. AB - A 33-year-old woman was referred for an ultrasound of the abdomen because of biliary colic. The symptoms had started 2 months after giving birth to her first child. The ultrasound showed gallstones, but it also revealed multiple focal liver lesions that were initially thought to be malignant. The examination was supplemented with a CT scan, contrast-enhanced ultrasound (CEUS) and MRI. The lesions were suspected to be peliosis hepatis-a rare morphological entity characterised by multiple blood-filled cavities in the liver. Because of uncertainty as to the aetiology of the lesions demonstrated at CEUS and MRI, the diagnosis was definitively confirmed by large-size needle biopsies. Regular size biopsies were initially insufficient for diagnosis. The use of oral contraceptives for several years or the recent pregnancy may have been the cause of peliosis hepatis in this patient. PMID- 24072834 TI - Bilateral Malphigian bulge or pseudohernia simulating inguinal hernias in a case of spontaneous descent of bilateral undescended testis. PMID- 24072835 TI - Ataxia: a diagnostic perplexity and management dilemma. AB - A 79-year-old woman presented with lower extremity weakness and unsteadiness for 2 weeks. She was recently diagnosed with refractory atrial flutter and was prescribed amiodarone. Physical examination revealed signs of cerebellar dysfunction. Neuroimaging including CT and MRI were unremarkable. Her hospital course included the development of ventricular tachycardia necessitating increment in amiodarone dose. Laboratory studies were unremarkable except mild transaminitis. Other workup including the one for paraneoplastic neurological involvement was negative. The patient experienced worsening of ataxia requiring assistance with ambulation. In view of comprehensive routine negative work-up for ataxia, recent use of amiodarone and worsening of symptomatology with increase in its dosing, drug-induced neurotoxicity from amiodarone was suspected. Amiodarone dose was subsequently reduced and mexilitine was introduced as an additive antiarrhythmic therapy for ventricular tachycardia. In follow-up, the patient experienced significant improvement in her symptoms and was able to ambulate independently. She was subsequently discharged to short-term rehabilitation. PMID- 24072836 TI - Is this an exacerbation of asthma? A cautionary tale. AB - Asthma exacerbations are a fairly common presentation to emergency departments. However, a careful history, clinical examination and interpretation of investigations may uncover a more serious pathology. We present an interesting case of a 44-year-old man with symptoms suggestive of an asthma exacerbation, who was found to have Churg-Strauss vasculitis/eosinophilic granulomatosis with polyangitis. He had clinical features of a vasculitis, ECG changes and a troponin T level of 7562 ng/L. Renal biopsy confirmed Churg-Strauss vasculitis. Cardiac involvement in Churg-Strauss Syndrome (CSS) is one of the leading causes of mortality. We describe the successful diagnosis and management of a patient with CSS. PMID- 24072837 TI - Paradoxical air embolism following central venous catheter removal. AB - Central venous catheters are commonly used in the management of critically ill patients. This case report described a rare but potentially fatal complication of central venous catheter use. A 52-year-old man underwent mechanical aortic valve replacement for infective endocarditis. On day 8 postoperatively he accidentally removed his catheter and collapsed with symptoms and signs suggestive of a cerebral air embolism. A transthoracic echocardiogram showed air bubbles in both the right and left ventricles of the heart confirming the presence of a paradoxical air embolism. PMID- 24072838 TI - Spinal epidural abscess in brucellosis. AB - Involvement of the skeletal system is a common complication of brucellosis. However, muscle involvement or paraspinal abscess formation are rare complications. Paraspinal abscess usually develops secondary to spondylitis. A case is reported here of a 33-year-old woman with symptoms of night sweats, fever and low back pain. Rose-Bengal test for brucellosis was positive and Brucella standard tube agglutination test was positive at a titre of 1/160. The diagnosis was made on MRI. The patient was treated with doxycycline and rifampin daily for 16 weeks. On day 14 of treatment, decline was observed in the patient's symptoms. In the presence of inflammatory lower back pain and fever, brucellosis should be considered particularly in the endemic areas. Furthermore, tuberculosis should be remembered in the differential diagnosis when a spinal epidural abscess is determined. PMID- 24072839 TI - Acute liver injury secondary to sertraline. AB - Sertraline is widely prescribed to treat depression and anxiety disorders. However, hepatitis secondary to its use is a rare entity. We report the case of a 26-year-old woman in her 20th week of pregnancy presented with nausea, vomiting, malaise and dark urine. This occurred 6 months after sertraline 50 mg daily was started for the treatment of depression. Three weeks prior to her presentation, the dose of sertraline was increased to 100 mg daily. The patient's liver biochemical profile demonstrated increased transaminases. The biopsy of the liver showed lobular hepatitis, with a mild prominence of eosinophils, suggestive of a drug-induced or toxin-induced aetiology. Extensive biochemical work-up failed to show any other pathology to account for her hepatitis. Liver function tests normalised after cessation of sertraline, indicating a probable association between sertraline use and acute hepatocellular injury in our patient. PMID- 24072840 TI - Rare causes of persistent wheeze that mimic poorly controlled asthma. AB - Upper airway obstruction can present with stridor or expiratory or inspiratory wheeze and is commonly misdiagnosed as asthma. As asthma is common, such cases can remain hidden among patients with lower airway obstruction who attend primary care or respiratory clinics. We describe four causes of upper airway obstruction (paradoxical vocal cord movement, subglottic stenosis, retrosternal goitre and double aortic arch) which were misdiagnosed as 'poorly controlled asthma'. PMID- 24072841 TI - Congenital anterior mediastinal teratoma causing severe airway compression in a neonate. PMID- 24072842 TI - Devastating complication of silver nitrate instillation for the treatment of chyluria. AB - The passage of milky white urine (chyluria) is an alarming sign. Safety and efficacy of silver nitrate instillation therapy for chyluria has been demonstrated in various studies in literature. Inspite of these, various serious complications following silver nitrate therapy have been reported from the regions where the pathology is prevalent. Even today, no protocol has been standardised for instillation therapy for chyluria about the ideal agent used, exact concentration or amount to be instilled, total number of instillations and doses per instillation to be administered. We presented a devastating complication of silver nitrate instillation therapy resulted in acute renal failure followed by later formation of long ureteric stricture in a patient resulting in long-term morbidity to the patient. There is a need for more vigilant approach and standardisation of protocol for silver nitrate instillation for treatment of chyluria. PMID- 24072843 TI - Diltiazem-induced palmar desquamation and oral erosions. PMID- 24072844 TI - Influenza A virus exacerbates Staphylococcus aureus pneumonia in mice by attenuating antimicrobial peptide production. AB - Influenza A represents a significant cause of morbidity and mortality worldwide. Bacterial complications of influenza A confer the greatest risk to patients. TH17 pathway inhibition has been implicated as a mechanism by which influenza A alters bacterial host defense. Here we show that preceding influenza causes persistent Staphylococcus aureus infection and suppression of TH17 pathway activation in mice. Influenza does not inhibit S. aureus binding and uptake by phagocytic cells but instead attenuates S. aureus induced TH17 related antimicrobial peptides necessary for bacterial clearance in the lung. Importantly, exogenous lipocalin 2 rescued viral exacerbation of S. aureus infection and decreased free iron levels in the bronchoalveolar lavage from mice coinfected with S. aureus and influenza. These findings indicate a novel mechanism by which influenza A inhibits TH17 immunity and increases susceptibility to secondary bacterial pneumonia. Identification of new mechanisms in the pathogenesis of bacterial pneumonia could lead to future therapeutic targets. PMID- 24072845 TI - Protective role of the lymphatics from sepsis. PMID- 24072846 TI - New insights into HIV impact on hematopoiesis. PMID- 24072847 TI - Shaping oncogenic NF-kappaB activity in the nucleus. PMID- 24072848 TI - Maraviroc-induced decrease in circulating bacterial products is not linked to an increase in immune activation in HIV-infected individuals. PMID- 24072849 TI - Response: Maraviroc intensification and microbial translocation. PMID- 24072850 TI - MYD88 (L265P) mutation is an independent risk factor for progression in patients with IgM monoclonal gammopathy of undetermined significance. PMID- 24072851 TI - Can the revised IPSS predict response to erythropoietic-stimulating agents in patients with classical IPSS low or intermediate-1 MDS? PMID- 24072852 TI - Impact of lead intoxication in children with iron deficiency anemia in low- and middle-income countries. PMID- 24072853 TI - Iron deficiency anemia in low- and middle-income countries. PMID- 24072854 TI - Locoregional control after intensity-modulated radiotherapy for nasopharyngeal carcinoma with an anatomy-based target definition. AB - OBJECTIVE: The objective of the study was to evaluate locoregional control after intensity-modulated radiotherapy for nasopharyngeal cancer using a target definition along with anatomical boundaries. METHODS: Forty patients with biopsy proven squamous cell or non-keratinizing carcinoma of the nasopharynx who underwent intensity-modulated radiotherapy between April 2006 and November 2009 were reviewed. There were 10 females and 30 males with a median age of 48 years (range, 17-74 years). More than half of the patients had T3/4 (n = 21) and/or N2/3 (n = 24) disease. Intensity-modulated radiotherapy was administered as 70 Gy/33 fractions with or without concomitant chemotherapy. The clinical target volume was contoured along with muscular fascia or periosteum, and the prescribed radiotherapy dose was determined for each anatomical compartment and lymph node level in the head and neck. RESULTS: One local recurrence was observed at Meckel's cave on the periphery of the high-risk clinical target volume receiving a total dose of <63 Gy. Otherwise, six locoregional failures were observed within irradiated volume receiving 70 Gy. Local and nodal control rates at 3 years were 91 and 89%, respectively. Adverse events were acceptable, and 25 (81%) of 31 patients who were alive without recurrence at 2 years had xerostomia of <=Grade 1. The overall survival rate at 3 years was 87%. CONCLUSIONS: Target definition along with anatomically defined boundaries was feasible without compromise of the therapeutic ratio. It is worth testing this method further to minimize the unnecessary irradiated volume and to standardize the target definition in intensity-modulated radiotherapy for nasopharyngeal cancer. PMID- 24072855 TI - Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile. AB - Circulating myeloma tumor cells (CTCs) as defined by the presence of peripheral blood (PB) clonal plasma cells (PCs) are a powerful prognostic marker in multiple myeloma (MM). However, the biological features of CTCs and their pathophysiological role in MM remains unexplored. Here, we investigate the phenotypic, cytogenetic, and functional characteristics as well as the circadian distribution of CTCs vs paired bone marrow (BM) clonal PCs from MM patients. Our results show that CTCs typically represent a unique subpopulation of all BM clonal PCs, characterized by downregulation (P < .05) of integrins (CD11a/CD11c/CD29/CD49d/CD49e), adhesion (CD33/CD56/CD117/CD138), and activation molecules (CD28/CD38/CD81). Fluorescence in situ hybridization analysis of fluorescence-activated cell sorter-sorted CTCs also unraveled different cytogenetic profiles vs paired BM clonal PCs. Moreover, CTCs were mostly quiescent and associated with higher clonogenic potential when cocultured with BM stromal cells. Most interestingly, CTCs showed a circadian distribution which fluctuates in a similar pattern to that of CD34(+) cells, and opposite to stromal cell-derived factor 1 plasma levels and corresponding surface expression of CXC chemokine receptor 4 on clonal PCs, suggesting that in MM, CTCs may egress to PB to colonize/metastasize other sites in the BM during the patients' resting period. PMID- 24072856 TI - Whole-Genome Sequences of Staphylococcus aureus ST398 Strains of Animal Origin. AB - Staphylococcus aureus sequence type 398 (ST398) was originally associated with animal infections. We announce the complete genome sequences of two ST398 methicillin-susceptible S. aureus strains from the livestock environment. These genome sequences assist in the characterization of interesting ST398 features relying on host tropism and epidemiological settings. PMID- 24072857 TI - Complete Genome Sequence of a Cytomegalovirus Towne-BAC (Bacterial Artificial Chromosome) Isolate Maintained in Escherichia coli for 10 Years and Then Serially Passaged in Human Fibroblasts. AB - Here, we present the complete genome sequence of a cytomegalovirus, the Towne-BAC (bacterial artificial chromosome) isolate, which was maintained in bacterial cells for 10 years and then serially passaged in human fibroblasts for 10 passages. A total of 132 nucleotide differences were discovered in the Towne sequence compared to the reference sequence (GenBank accession no. AC146851). PMID- 24072858 TI - Complete genome sequence of a novel feline astrovirus from a domestic cat in Hong Kong. AB - We report the first complete genome sequence of a feline astrovirus (FAstV), FAstV2 strain 1637F, identified from a domestic cat. The genome is 6,779 nucleotides (nt) in length and consists of three overlapping open reading frames (ORF1a-ORF1b-ORF2). Sequence analysis suggests that FAstV2 represents a new FAstV genotype that is closely related to human astroviruses. PMID- 24072859 TI - Draft Genome Sequence of Vancomycin-Heteroresistant Staphylococcus epidermidis Strain UC7032, Isolated from Food. AB - Staphylococcus epidermidis strain UC7032 was isolated from ready-to-eat cured meat and is heteroresistant to glycopeptide antibiotics. The draft whole-genome analysis revealed that this strain shows common characteristics typical of strains that are involved in nosocomial infections. PMID- 24072860 TI - Genome Sequences of Three hpAfrica2 Strains of Helicobacter pylori. AB - We present the genome sequences of three hpAfrica2 strains of Helicobacter pylori, which are postulated to have evolved in isolation for many millennia in people of San ethnicity. Although previously considered to be ancestral to Helicobacter acinonychis, the hpAfrica2 strains differ markedly from H. acinonychis in their gene arrangement. These data provide new insights into Helicobacter evolution. PMID- 24072861 TI - First Whole-Genome Sequence of Mycobacterium iranicum, a Newly Reported Mycobacterial Species. AB - Mycobacterium iranicum is a new species of nontuberculous mycobacterium reported in 2013. Here, we describe the first whole-genome sequence of this species, that of M. iranicum strain UM_TJL, isolated from a patient in Malaysia. PMID- 24072862 TI - Complete Genome Sequence of the Probiotic Strain Lactobacillus casei (Formerly Lactobacillus paracasei) LOCK919. AB - Lactobacillus casei is usually regarded as a bacterium that lives naturally in the human intestinal tract, where it can contribute to host health and well being. We describe here the complete genome sequence of L. casei LOCK919, a strain with probiotic properties isolated from child feces. The genome consists of a 3.11-Mb chromosome and a 29,768-bp plasmid. PMID- 24072864 TI - Draft Genome Sequence of Cryptococcus flavescens Strain OH182.9_3C, a Biocontrol Agent against Fusarium Head Blight of Wheat. AB - Cryptococcus flavescens strain OH182.9_3C (3C) is a novel biopesticidal agent that can be used to control fusarium head blight of wheat. Here we present the draft genome sequence for 3C, the first for the species C. flavescens. Additionally, several genes that may contribute to the biocontrol activities of 3C were identified in silico. PMID- 24072863 TI - Complete Genome Sequence of Micromonospora Strain L5, a Potential Plant-Growth Regulating Actinomycete, Originally Isolated from Casuarina equisetifolia Root Nodules. AB - Micromonospora species live in diverse environments and exhibit a broad range of functions, including antibiotic production, biocontrol, and degradation of complex polysaccharides. To learn more about these versatile actinomycetes, we sequenced the genome of strain L5, originally isolated from root nodules of an actinorhizal plant growing in Mexico. PMID- 24072865 TI - Whole-Genome Shotgun Sequencing of Rhodococcus erythropolis Strain P27, a Highly Radiation-Resistant Actinomycete from Antarctica. AB - Here, we report the draft genome sequence of radiation-resistant Rhodococcus erythropolis strain P27, isolated from leaves of Deschampsia antarctica Desv. (Poaceae) in the Admiralty Bay area, Antarctica. PMID- 24072866 TI - Draft Genome Sequence of Bacillus subtilis Strain S1-4, Which Degrades Feathers Efficiently. AB - Bacillus subtilis strain S1-4, with the capacity to efficiently degrade feathers, was isolated from chicken feathers. Sequencing showed that the genome of strain S1-4 differs from that of other B. subtilis strains, with limited insertions and deletions. The genome encodes multiple extracellular proteases and keratinases. PMID- 24072867 TI - Complete Genome Sequence of Vibrio anguillarum M3, a Serotype O1 Strain Isolated from Japanese Flounder in China. AB - Vibrio anguillarum is an important bacterial pathogen that causes vibriosis in marine fish. We present the complete genome sequence of V. anguillarum M3, a serotype O1 clinical strain isolated from Japanese flounder (Paralichthys olivaceus) in Shandong, China. PMID- 24072868 TI - Genome Sequence of Lactobacillus fermentum Strain MTCC 8711, a Probiotic Bacterium Isolated from Yogurt. AB - Lactobacillus fermentum strain MTCC 8711 is a lactic acid bacterium isolated from yogurt. Here, we describe the draft genome sequence and annotation of this strain. The 2,566,297-bp-long genome consisted of a single chromosome and seven plasmids. The genome contains 2,609 protein-coding and 74 RNA genes. PMID- 24072869 TI - Draft Genome Sequence of Exopolysaccharide-Producing Thermophilic Bacterium Brevibacillus thermoruber Strain 423. AB - Brevibacillus thermoruber strain 423 is a Gram-positive, spore-forming, aerobic, and thermophilic bacterium that produces mannogalactoglucan exopolysaccharide (EPS). We report the draft genome sequence of B. thermoruber 423, which will accelerate research on the cellular organization of thermophilic bacteria, as well as the rational design and optimization of EPS production. PMID- 24072870 TI - Complete Genome Sequence of Staphylococcus aureus 6850, a Highly Cytotoxic and Clinically Virulent Methicillin-Sensitive Strain with Distant Relatedness to Prototype Strains. AB - Staphylococcus aureus is a frequent human commensal bacterium and pathogen. Here we report the complete genome sequence of strain 6850 (spa type t185; sequence type 50 [ST50]), a highly cytotoxic and clinically virulent methicillin-sensitive strain from a patient with complicated S. aureus bacteremia associated with osteomyelitis and septic arthritis. PMID- 24072871 TI - Draft Genome Sequence of the Earliest Cronobacter sakazakii Sequence Type 4 Strain, NCIMB 8272. AB - The Cronobacter sakazakii clonal lineage defined as sequence type 4 (ST4) is associated with severe cases of neonatal meningitis and persistence in powdered infant formula. For genome sequencing of the earliest deposited culture collection strain of Cronobacter sakazakii ST4, we used the strain NCIMB 8272, originally isolated from milk powder in 1950. PMID- 24072872 TI - Draft Genome Sequences of Three Newly Identified Species in the Genus Cronobacter, C. helveticus LMG23732T, C. pulveris LMG24059, and C. zurichensis LMG23730T. AB - Cronobacter helveticus, Cronobacter pulveris, and Cronobacter zurichensis are newly described species in the Cronobacter genus, which is associated with serious infections of neonates. This is the first report of draft genome sequences for these species. PMID- 24072874 TI - Study raises concerns over racial discrimination in MRCGP exam. PMID- 24072875 TI - FDA will not regulate most mobile medical apps. PMID- 24072873 TI - 3' UTR-isoform choice has limited influence on the stability and translational efficiency of most mRNAs in mouse fibroblasts. AB - Variation in protein output across the genome is controlled at several levels, but the relative contributions of different regulatory mechanisms remain poorly understood. Here, we obtained global measurements of decay and translation rates for mRNAs with alternative 3' untranslated regions (3' UTRs) in murine 3T3 cells. Distal tandem isoforms had slightly but significantly lower mRNA stability and greater translational efficiency than proximal isoforms on average. The diversity of alternative 3' UTRs also enabled inference and evaluation of both positively and negatively acting cis-regulatory elements. The 3' UTR elements with the greatest implied influence were microRNA complementary sites, which were associated with repression of 32% and 4% at the stability and translational levels, respectively. Nonetheless, both the decay and translation rates were highly correlated for proximal and distal 3' UTR isoforms from the same genes, implying that in 3T3 cells, alternative 3' UTR sequences play a surprisingly small regulatory role compared to other mRNA regions. PMID- 24072876 TI - Hospitals have more negotiating power than commissioning groups, Monitor says. PMID- 24072878 TI - Jak/STAT and PI3K signaling pathways have both common and distinct roles in IL-7 mediated activities in human CD8+ T cells. AB - IL-7 plays an important role in T cell survival, function, and memory cell development, yet the role of cytokine signaling pathways in these processes has not been fully elucidated. Moreover, the underlying mechanisms for the observed impairment of IL-7 activity in diseases, such as HIV infection, breast cancer, and autoimmunity, are not well understood. It was therefore hypothesized that IL 7-induced signaling molecules could be linked with distinct IL-7-associated activities. To address this, the activation and functional associations of IL-7 induced signaling pathways, specifically antigen-independent activities that are relevant to T cell homeostasis, were examined. Low concentrations of IL-7 (100 pg/ml) are capable of activating the Jak-STAT and PI3K signaling pathways, whereas higher concentrations (500-1000 pg/ml) were required to induce Bcl-2 production and glucose uptake. Even higher concentrations of IL-7 (10,000 pg/ml) were needed to induce cell proliferation and intracellular accumulation of perforin. Inhibition of Jak activation reduced IL-7-induced Bcl-2 and perforin production, whereas inhibition of Jak/STAT or PI3K pathways reduced glucose uptake and proliferation. This study suggests a complex control of IL-7 associated activities in the absence of antigen stimulation. These data may provide insights into mechanisms of impaired IL-7 signaling and function in disease and could be relevant for the study of IL-7-based immunotherapeutics. Specifically, this study has linked STAT5 and PI3K activation to shared and distinct IL-7-associated activities in human CD8+ T cells. PMID- 24072877 TI - Inhibition of caspase-8 activity promotes protective Th1- and Th2-mediated immunity to Leishmania major infection. AB - We investigated how apoptosis pathways mediated by death receptors and caspase-8 affect cytokine responses and immunity to Leishmania major parasites. Splenic CD4 T cells undergo activation-induced apoptosis, and blockade of FasL-Fas interaction increased IFN-gamma and IL-4 cytokine responses to L. major antigens. To block death receptor-induced death, we used mice expressing a T cell restricted transgene for vFLIP. Inhibition of caspase-8 activation in vFLIP mice enhanced Th1 and Th2 cytokine responses to L. major infection, even in the Th1 prone B6 background. We also observed increased NO production by splenocytes from vFLIP mice upon T cell activation. Despite an exacerbated Th2 response, vFLIP mice controlled better L. major infection, with reduced lesions and lower parasite loads compared with WT mice. Moreover, injection of anti-IL-4 mAb in infected vFLIP mice disrupted control of parasite infection. Therefore, blockade of caspase-8 activity in T cells improves immunity to L. major infection by promoting increased Th1 and Th2 responses. PMID- 24072880 TI - GCN5 is essential for IRF-4 gene expression followed by transcriptional activation of Blimp-1 in immature B cells. AB - During B-cell differentiation, the gene expression of B-cell differentiation related transcription factors must be strictly controlled by epigenetic mechanisms including histone acetylation and deacetylation, to complete the differentiation pathway. GCN5, one of the most important histone acetyltransferases, is involved in epigenetic events for transcriptional regulation through alterations in the chromatin structure. In this study, by analyzing the homozygous DT40 mutants GCN5(-/-), generated with gene targeting techniques, we found that GCN5 was necessary for transcriptional activation of IRF-4, an essential transcription factor for plasma cell differentiation. GCN5 deficiency caused drastic decreases in both the mRNA and the protein levels of Blimp-1 and IRF-4. The ectopic expression of Blimp-1 and IRF-4 suggests that IRF 4, but not Blimp-1, is the target gene of GCN5 in immature B cells. Moreover, a chromatin immunoprecipitation assay showed that GCN5 bound to the IRF-4 gene around its 5'-flanking region and acetylated H3K9 residues within chromatin surrounding the region in vivo, suggesting that gene expression of IRF-4 is certainly regulated by GCN5. These results reveal that GCN5 is essential for IRF 4 gene expression, followed by transcriptional activation of Blimp-1, and plays a key role in epigenetic regulation of B-cell differentiation. PMID- 24072881 TI - Global health in foreign policy--and foreign policy in health? Evidence from the BRICS. AB - Amidst the growing literature on global health, much has been written recently about the Brazil, Russia, India, China, South Africa (BRICS) countries and their involvement and potential impact in global health, particularly in relation to development assistance. Rather less has been said about countries' motivations for involvement in global health negotiations, and there is a notable absence of evidence when their motivations are speculated on. This article uses an existing framework linking engagement in global health to foreign policy to explore differing levels of engagement by BRICS countries in the global health arena, with a particular focus on access to medicines. It concludes that countries' differing and complex motivations reinforce the need for realistic, pragmatic approaches to global health debates and their analysis. It also underlines that these analyses should be informed by analysis from other areas of foreign policy. PMID- 24072879 TI - TNF-alpha and IFN-gamma promote lymphocyte adhesion to endothelial junctional regions facilitating transendothelial migration. AB - Inflammatory conditions induce redistribution of junctional adhesion receptors toward the apical regions of endothelial cells promoting lymphocyte TEM. Much of the molecular structures of TEM have been revealed; however, the biophysical mechanisms underlying this process remain to be fully elucidated. Here, we used immunofluorescence microscopy and AFM to study endothelial distribution of adhesion molecules upon lymphocyte activation and transmigration. Our immunofluorescence results revealed redistribution of JAM-A and PECAM-1 but not ICAM-1 or VCAM-1 toward the apical junctional regions of HUVECs following a 6-h stimulation with TNF-alpha and IFN-gamma. Consistently, our SCFS studies revealed that Jurkat cell adhesion to stimulated HUVEC monolayers was significantly greater in junctional regions. Enhanced adhesion was mediated mostly by JAM-A receptors. Further AFM adhesion mapping of the homophilic JAM-A/JAM-A interaction on the surfaces of HUVECs revealed a greater number of JAM-A receptors available for binding along junctional regions after TNF-alpha and IFN-gamma stimulation. Our data reveal for the first time that adhesion "hot spots" of JAM-A receptors are involved in initiating lymphocyte TEM under inflammatory conditions. PMID- 24072882 TI - Academic performance of ethnic minority candidates and discrimination in the MRCGP examinations between 2010 and 2012: analysis of data. AB - OBJECTIVE: To determine the difference in failure rates in the postgraduate examination of the Royal College of General Practitioners (MRCGP) by ethnic or national background, and to identify factors associated with pass rates in the clinical skills assessment component of the examination. DESIGN: Analysis of data provided by the Royal College of General Practitioners and the General Medical Council. PARTICIPANTS: Cohort of 5095 candidates sitting the applied knowledge test and clinical skills assessment components of the MRCGP examination between November 2010 and November 2012. A further analysis was carried out on 1175 candidates not trained in the United Kingdom, who sat an English language capability test (IELTS) and the Professional and Linguistic Assessment Board (PLAB) examination (as required for full medical registration), controlling for scores on these examinations and relating them to pass rates of the clinical skills assessment. SETTING: United Kingdom. RESULTS: After controlling for age, sex, and performance in the applied knowledge test, significant differences persisted between white UK graduates and other candidate groups. Black and minority ethnic graduates trained in the UK were more likely to fail the clinical skills assessment at their first attempt than their white UK colleagues (odds ratio 3.536 (95% confidence interval 2.701 to 4.629), P<0.001; failure rate 17% v 4.5%). Black and minority ethnic candidates who trained abroad were also more likely to fail the clinical skills assessment than white UK candidates (14.741 (11.397 to 19.065), P<0.001; 65% v 4.5%). For candidates not trained in the UK, black or minority ethnic candidates were more likely to fail than white candidates, but this difference was no longer significant after controlling for scores in the applied knowledge test, IELTS, and PLAB examinations (adjusted odds ratio 1.580 (95% confidence interval 0.878 to 2.845), P=0.127). CONCLUSIONS: Subjective bias due to racial discrimination in the clinical skills assessment may be a cause of failure for UK trained candidates and international medical graduates. The difference between British black and minority ethnic candidates and British white candidates in the pass rates of the clinical skills assessment, despite controlling for prior attainment, suggests that subjective bias could also be a factor. Changes to the clinical skills assessment could improve the perception of the examination as being biased against black and minority ethnic candidates. The difference in training experience and other cultural factors between candidates trained in the UK and abroad could affect outcomes. Consideration should be given to strengthening postgraduate training for international medical graduates. PMID- 24072883 TI - Targeting plasminogen activator inhibitor-1 inhibits angiogenesis and tumor growth in a human cancer xenograft model. AB - Cancers of the urinary bladder result in aggressive and highly angiogenic tumors for which standard treatments have only limited success. Patients with advanced disease have a 5-year survival rate of less than 20%, and no new anticancer agent has been successfully introduced into the clinic armamentarium for the treatment of bladder cancer in more than 20 years. Investigations have identified plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, as being highly expressed in several malignancies, including bladder cancer, in which high expression is associated with a poor prognosis. In this study, we evaluated PAI-1 as a potential therapeutic target for bladder cancer. PAI-1 expression was manipulated in a panel of cell lines and functional inhibition was achieved using the small molecule tiplaxtinin. Reduction or inhibition of PAI-1 resulted in the reduction of cellular proliferation, cell adhesion, and colony formation, and the induction of apoptosis and anoikis in vitro. Treatment of T24 xenografts with tiplaxtinin resulted in inhibition of angiogenesis and induction of apoptosis, leading to a significant reduction in tumor growth. Similar results were obtained through evaluation of the human cervical cancer HeLa cell line, showing that PAI 1-mediated effects are not restricted to tumor cells of bladder origin. Collectively, these data show that targeting PAI-1 may be beneficial and support the notion that novel drugs such as tiplaxtinin could be investigated as anticancer agents. PMID- 24072885 TI - Apropos "seroprevalence of antipolio antibodies among children <15 years of age in border provinces in China". PMID- 24072884 TI - RAC1: an emerging therapeutic option for targeting cancer angiogenesis and metastasis. AB - Angiogenesis and metastasis are well recognized as processes fundamental to the development of malignancy. Both processes involve the coordination of multiple cellular and chemical activities through myriad signaling networks, providing a mass of potential targets for therapeutic intervention. This review will focus on one master regulator of cell motility, RAC1, and the existing data with regard to its role in cell motility, including particular roles for tumor angiogenesis and invasion/metastasis. We also emphasize the preclinical investigations carried out with RAC1 inhibitors to evaluate the therapeutic potential of this target. Herein, we explore potential future directions as well as the challenges of targeting RAC1 in the treatment of cancer. Recent insights at the molecular and cellular levels are paving the way for a more directed and detailed approach to target mechanisms of RAC1 regulating angiogenesis and metastasis. Understanding these mechanisms may provide insight into RAC1 signaling components as alternative therapeutic targets for tumor angiogenesis and metastasis. PMID- 24072886 TI - Reply to 'apropos "seroprevalence of antipolio antibodies among children <15 years of age in border provinces in China"'. PMID- 24072888 TI - Sleep and cortisol interact to support memory consolidation. AB - Separate lines of research have demonstrated that rises in cortisol can benefit memory consolidation, as can the occurrence of sleep soon after encoding. For the first time, we demonstrate that pre-learning cortisol interacts with sleep to benefit memory consolidation, particularly for negative arousing items. Resting cortisol levels during encoding were positively correlated with subsequent memory, but only following a period of sleep. There was no such relation following a period of wakefulness. Using eye tracking, we further reveal that for negative stimuli, this facilitative effect may arise because cortisol strengthens the relationship between looking time at encoding and subsequent memory. We suggest that elevated cortisol may "tag" attended information as important to remember at the time of encoding, thus enabling sleep-based processes to optimally consolidate salient information in a selective manner. Neuroimaging data suggest that this optimized consolidation leads to a refinement of the neural processes recruited for successful retrieval of negative stimuli, with the retrieval of items attended in the presence of elevated cortisol and consolidated over a night of sleep associated with activity in the amygdala and vmPFC. PMID- 24072890 TI - Mercury and health. PMID- 24072889 TI - The neuroanatomical correlates of training-related perceptuo-reflex uncoupling in dancers. AB - Sensory input evokes low-order reflexes and higher-order perceptual responses. Vestibular stimulation elicits vestibular-ocular reflex (VOR) and self-motion perception (e.g., vertigo) whose response durations are normally equal. Adaptation to repeated whole-body rotations, for example, ballet training, is known to reduce vestibular responses. We investigated the neuroanatomical correlates of vestibular perceptuo-reflex adaptation in ballet dancers and controls. Dancers' vestibular-reflex and perceptual responses to whole-body yaw plane step rotations were: (1) Briefer and (2) uncorrelated (controls' reflex and perception were correlated). Voxel-based morphometry showed a selective gray matter (GM) reduction in dancers' vestibular cerebellum correlating with ballet experience. Dancers' vestibular cerebellar GM density reduction was related to shorter perceptual responses (i.e. positively correlated) but longer VOR duration (negatively correlated). Contrastingly, controls' vestibular cerebellar GM density negatively correlated with perception and VOR. Diffusion-tensor imaging showed that cerebral cortex white matter (WM) microstructure correlated with vestibular perception but only in controls. In summary, dancers display vestibular perceptuo-reflex dissociation with the neuronatomical correlate localized to the vestibular cerebellum. Controls' robust vestibular perception correlated with a cortical WM network conspicuously absent in dancers. Since primary vestibular afferents synapse in the vestibular cerebellum, we speculate that a cerebellar gating of perceptual signals to cortical regions mediates the training-related attenuation of vestibular perception and perceptuo-reflex uncoupling. PMID- 24072895 TI - U.S. research spending. Sequester takes uneven bite from agency budgets. PMID- 24072896 TI - Climate policy. U.S. carbon plan relies on uncertain capture technology. PMID- 24072897 TI - Australia. Will new government overcome 'symbolically challenged' start? PMID- 24072898 TI - Infectious diseases. DNA sleuths track C. difficile infection routes. PMID- 24072899 TI - Ecology. Zombie endocrine disruptors may threaten aquatic life. PMID- 24072900 TI - Mercury pollution. Taming a mercurial element. PMID- 24072901 TI - Mercury pollution. With pact's completion, the real work begins. PMID- 24072902 TI - Mercury pollution. In Minamata, mercury still divides. PMID- 24072903 TI - Mercury pollution. Gold's dark side. PMID- 24072904 TI - L'Aquila's aftershocks shake scientists. PMID- 24072905 TI - Low marks for education funding priorities. PMID- 24072906 TI - Bayes' confidence. PMID- 24072907 TI - Research funders should take the field. PMID- 24072909 TI - Science education. Increasing persistence of college students in STEM. PMID- 24072910 TI - Environmental science. Global change and mercury. PMID- 24072911 TI - Materials science. A coat of many functions. PMID- 24072912 TI - Materials science. A new route for growing large grains in metals. PMID- 24072913 TI - Immunology. Some monocytes got rhythm. PMID- 24072914 TI - Materials science. Small volumes create super(elastic) effects. PMID- 24072915 TI - IBI series winner. Students propose genetic solutions to societal problems. PMID- 24072916 TI - Analysis of surface materials by the Curiosity Mars rover. PMID- 24072917 TI - Electromagnetic energy conversion at reconnection fronts. AB - Earth's magnetotail contains magnetic energy derived from the kinetic energy of the solar wind. Conversion of that energy back to particle energy ultimately powers Earth's auroras, heats the magnetospheric plasma, and energizes the Van Allen radiation belts. Where and how such electromagnetic energy conversion occurs has been unclear. Using a conjunction between eight spacecraft, we show that this conversion takes place within fronts of recently reconnected magnetic flux, predominantly at 1- to 10-electron inertial length scale, intense electrical current sheets (tens to hundreds of nanoamperes per square meter). Launched continually during intervals of geomagnetic activity, these reconnection outflow flux fronts convert ~10 to 100 gigawatts per square Earth radius of power, consistent with local magnetic flux transport, and a few times 10(15) joules of magnetic energy, consistent with global magnetotail flux reduction. PMID- 24072918 TI - Abnormal grain growth induced by cyclic heat treatment. AB - In polycrystalline materials, grain growth occurs at elevated temperatures to reduce the total area of grain boundaries with high energy. The grain growth rate usually slows down with annealing time, making it hard to obtain grains larger than a millimeter in size. We report a crystal growth method that employs only a cyclic heat treatment to obtain a single crystal of more than several centimeters in a copper-based shape-memory alloy. This abnormal grain growth phenomenon results from the formation of a subgrain structure introduced through phase transformation. These findings provide a method of fabricating a single-crystal or large-grain structure important for shape-memory properties, magnetic properties, and creep properties, among others. PMID- 24072919 TI - Cation intercalation and high volumetric capacitance of two-dimensional titanium carbide. AB - The intercalation of ions into layered compounds has long been exploited in energy storage devices such as batteries and electrochemical capacitors. However, few host materials are known for ions much larger than lithium. We demonstrate the spontaneous intercalation of cations from aqueous salt solutions between two dimensional (2D) Ti3C2 MXene layers. MXenes combine 2D conductive carbide layers with a hydrophilic, primarily hydroxyl-terminated surface. A variety of cations, including Na(+), K(+), NH4(+), Mg(2+), and Al(3+), can also be intercalated electrochemically, offering capacitance in excess of 300 farads per cubic centimeter (much higher than that of porous carbons). This study provides a basis for exploring a large family of 2D carbides and carbonitrides in electrochemical energy storage applications using single- and multivalent ions. PMID- 24072920 TI - Shape memory and superelastic ceramics at small scales. AB - Shape memory materials are a class of smart materials able to convert heat into mechanical strain (or strain into heat) by virtue of a martensitic phase transformation. Some brittle materials such as intermetallics and ceramics exhibit a martensitic transformation but fail by cracking at low strains and after only a few applied strain cycles. Here we show that such failure can be suppressed in normally brittle martensitic ceramics by providing a fine-scale structure with few crystal grains. Such oligocrystalline structures reduce internal mismatch stresses during the martensitic transformation and lead to robust shape memory ceramics that are capable of many superelastic cycles up to large strains; here we describe samples cycled as many as 50 times and samples that can withstand strains over 7%. Shape memory ceramics with these properties represent a new class of actuators or smart materials with a set of properties that include high energy output, high energy damping, and high-temperature usage. PMID- 24072921 TI - Near-complete extinction of native small mammal fauna 25 years after forest fragmentation. AB - Tropical forests continue to be felled and fragmented around the world. A key question is how rapidly species disappear from forest fragments and how quickly humans must restore forest connectivity to minimize extinctions. We surveyed small mammals on forest islands in Chiew Larn Reservoir in Thailand 5 to 7 and 25 to 26 years after isolation and observed the near-total loss of native small mammals within 5 years from <10-hectare (ha) fragments and within 25 years from 10- to 56-ha fragments. Based on our results, we developed an island biogeographic model and estimated mean extinction half-life (50% of resident species disappearing) to be 13.9 years. These catastrophic extinctions were probably partly driven by an invasive rat species; such biotic invasions are becoming increasingly common in human-modified landscapes. Our results are thus particularly relevant to other fragmented forest landscapes and suggest that small fragments are potentially even more vulnerable to biodiversity loss than previously thought. PMID- 24072922 TI - The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. AB - The growing prevalence of overeating disorders is a key contributor to the worldwide obesity epidemic. Dysfunction of particular neural circuits may trigger deviations from adaptive feeding behaviors. The lateral hypothalamus (LH) is a crucial neural substrate for motivated behavior, including feeding, but the precise functional neurocircuitry that controls LH neuronal activity to engage feeding has not been defined. We observed that inhibitory synaptic inputs from the extended amygdala preferentially innervate and suppress the activity of LH glutamatergic neurons to control food intake. These findings help explain how dysregulated activity at a number of unique nodes can result in a cascading failure within a defined brain network to produce maladaptive feeding. PMID- 24072923 TI - Cocaine disinhibits dopamine neurons by potentiation of GABA transmission in the ventral tegmental area. AB - Drug-evoked synaptic plasticity in the mesolimbic system reshapes circuit function and drives drug-adaptive behavior. Much research has focused on excitatory transmission in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). How drug-evoked synaptic plasticity of inhibitory transmission affects circuit adaptations remains unknown. We found that medium spiny neurons expressing dopamine (DA) receptor type 1 (D1R-MSNs) of the NAc project to the VTA, strongly preferring the GABA neurons of the VTA. Repeated in vivo exposure to cocaine evoked synaptic potentiation at this synapse, occluding homosynaptic inhibitory long-term potentiation. The activity of the VTA GABA neurons was thus reduced and DA neurons were disinhibited. Cocaine-evoked potentiation of GABA release from D1R-MSNs affected drug-adaptive behavior, which identifies these neurons as a promising target for novel addiction treatments. PMID- 24072929 TI - An LC-MS method for determination of milbemycin oxime in dog plasma. AB - An HPLC-MS method has been developed and validated for the quantitative determination of milbemycin oxime (MBO) in dog plasma. The developed method has been then applied in in vivo clinical studies to obtain pharmacokinetics of MBO in blood after its oral administration. Samples were extracted using solid-phase extraction (SPE). Sample proteins were precipitated with acetonitrile (ACN) and sodium chloride (NaCl) and then diluted with methanol and water. Calibration standards were prepared by using plasma matrix and following the same SPE procedure. Chromatographic separation was performed on a Waters C18 packed column (3.5 MUm particles diameter; 3 * 100 mm) with a C18 guard column (3.5 MUm particles diameter; 3 * 20 mm). The mobile phase was an 85:15 (v/v) mixed solution of ACN and 5 mM ammonium acetate. The calibration curve was linear over a concentration range of 2.0-500 ng/mL with a limit of quantitation of 2.0 ng/mL. The oral administration of a pellet of 2.5 mg MBO produced blood concentrations ranging from 6.10 +/- 0.92 to 78.81 +/- 4.38 ng/mL within 6 h, with a terminal half-time of 11.66 +/- 0.93 h. This study determined the suitability of the herein proposed method to investigate the pharmacokinetics of MBO after oral administration. PMID- 24072930 TI - Contribution of sexual practices (other than anal sex) to bacterial sexually transmitted infection transmission in men who have sex with men: a cross sectional analysis using electronic health records. AB - OBJECTIVE: We quantified the proportion of cases and risk of primary syphilis (PS), urethral chlamydia (UCT) and urethral gonorrhoea (UGC) attributable to sexual practices other than anal sex. METHODS: In this cross-sectional study, electronic records for men who have sex with men (MSM) who attended the Melbourne Sexual Health Centre between July 2002 (for PS) or January 2006 (for UCT and UGC) and October 2012, inclusive, were examined. RESULTS: There were 37 533 eligible consultations; 2374 (6%) of these reported no anal sex. There were 204 PS diagnoses, 673 UCT diagnoses, and 618 UGC diagnoses; 12 (6%), 16 (2%) and 44 (7%) cases, respectively, occurred in consultations where no anal sex was reported in the previous 3 months (PS, UGC) or twelve months (UCT). Among MSM reporting no anal sex, PS was diagnosed in 0.5 cases/100 consultations, UCT was diagnosed in 1.5 cases/100 tests for UCT and UGC was diagnosed in 14 cases/100 tests for UGC. UCT was significantly more common in MSM reporting anal sex (OR 2.18, 95% CI 1.32 to 3.59, p=0.002), but PS (OR 1.07 95% CI 0.6 to 1.93, p=0.82) and UGC (OR 1.28 95% CI 0.92 to 1.79. p=0.14) were not. For MSM reporting anal sex, condom use was protective for all three infections (all p<=0.03). CONCLUSIONS: Our findings suggest that UCT uncommonly occurs from sexual practices other than anal sex; however, these practices contribute significantly to PS and UGC. Successful programmes to control PS and UGC will need strategies, such as frequent testing, in addition to promoting condom use. PMID- 24072924 TI - Soil diversity and hydration as observed by ChemCam at Gale crater, Mars. AB - The ChemCam instrument, which provides insight into martian soil chemistry at the submillimeter scale, identified two principal soil types along the Curiosity rover traverse: a fine-grained mafic type and a locally derived, coarse-grained felsic type. The mafic soil component is representative of widespread martian soils and is similar in composition to the martian dust. It possesses a ubiquitous hydrogen signature in ChemCam spectra, corresponding to the hydration of the amorphous phases found in the soil by the CheMin instrument. This hydration likely accounts for an important fraction of the global hydration of the surface seen by previous orbital measurements. ChemCam analyses did not reveal any significant exchange of water vapor between the regolith and the atmosphere. These observations provide constraints on the nature of the amorphous phases and their hydration. PMID- 24072931 TI - Infectious diseases specialty intervention is associated with decreased mortality and lower healthcare costs. AB - BACKGROUND: Previous studies, largely based on chart reviews with small sample sizes, have demonstrated that infectious diseases (ID) specialists positively impact patient outcomes. We investigated how ID specialists impact mortality, utilization, and costs using a large claims dataset. METHODS: We used administrative fee-for-service Medicare claims to identify beneficiaries hospitalized from 2008 to 2009 with at least 1 of 11 infections. There were 101 991 stays with and 170 336 stays without ID interventions. Cohorts were propensity score matched for patient demographics, comorbidities, and hospital characteristics. Regression models compared ID versus non-ID intervention and early versus late ID intervention. Risk-adjusted outcomes included hospital and intensive care unit (ICU) length of stay (LOS), mortality, readmissions, hospital charges, and Medicare payments. RESULTS: The ID intervention cohort demonstrated significantly lower mortality (odds ratio [OR], 0.87; 95% confidence interval [CI], .83 to .91) and readmissions (OR, 0.96; 95% CI, .93 to .99) than the non-ID intervention cohort. Medicare charges and payments were not significantly different; the ID intervention cohort ICU LOS was 3.7% shorter (95% CI, -5.5% to 1.9%). Patients receiving ID intervention within 2 days of admission had significantly lower 30-day mortality and readmission, hospital and ICU length of stay, and Medicare charges and payments compared with patients receiving later ID interventions. CONCLUSIONS: ID interventions are associated with improved patient outcomes. Early ID interventions are also associated with reduced costs for Medicare beneficiaries with select infections. PMID- 24072932 TI - Analysis of Biological Samples Using Paper Spray Mass Spectrometry: An Investigation of Impacts by the Substrates, Solvents and Elution Methods. AB - Paper spray has been developed as a fast sampling ionization method for direct analysis of raw biological and chemical samples using mass spectrometry (MS). Quantitation of therapeutic drugs in blood samples at high accuracy has also been achieved using paper spray MS without traditional sample preparation or chromatographic separation. The paper spray ionization is a process integrated with a fast extraction of the analyte from the raw sample by a solvent, the transport of the extracted analytes on the paper, and a spray ionization at the tip of the paper substrate with a high voltage applied. In this study, the influence on the analytical performance by the solvent-substrate systems and the selection of the elution methods was investigated. The protein hemoglobin could be observed from fresh blood samples on silanized paper or from dried blood spots on silica-coated paper. The on-paper separation of the chemicals during the paper spray was characterized through the analysis of a mixture of the methyl violet 2B and methylene blue. The mode of applying the spray solvent was found to have a significant impact on the separation. The results in this study led to a better understanding of the analyte elution, on-paper separation, as well as the ionization processes of the paper spray. This study also help to establish a guideline for optimizing the analytical performance of paper spray for direct analysis of target analytes using mass spectrometry. PMID- 24072925 TI - X-ray diffraction results from Mars Science Laboratory: mineralogy of Rocknest at Gale crater. AB - The Mars Science Laboratory rover Curiosity scooped samples of soil from the Rocknest aeolian bedform in Gale crater. Analysis of the soil with the Chemistry and Mineralogy (CheMin) x-ray diffraction (XRD) instrument revealed plagioclase (~An57), forsteritic olivine (~Fo62), augite, and pigeonite, with minor K feldspar, magnetite, quartz, anhydrite, hematite, and ilmenite. The minor phases are present at, or near, detection limits. The soil also contains 27 +/- 14 weight percent x-ray amorphous material, likely containing multiple Fe(3+)- and volatile-bearing phases, including possibly a substance resembling hisingerite. The crystalline component is similar to the normative mineralogy of certain basaltic rocks from Gusev crater on Mars and of martian basaltic meteorites. The amorphous component is similar to that found on Earth in places such as soils on the Mauna Kea volcano, Hawaii. PMID- 24072933 TI - Protestant Clergy and the Culture Wats: An Empirical Test of Hunter's Thesis. AB - This study instead focuses on culture wars among religious elites-clergy-and tests three aspects of the culture wars thesis: (1) whether cultural wars exist at all among religious elites, (2) whether clergy attitudes are polarized on these issues, and (3) whether religious authority or religious affiliation is more salient in creating culture wars cleavages. Using data from a large random sample of Protestant clergy, we find a substantial amount of engagement in culture wars by all types of Protestant clergy. The amount of polarization is more attributable to views of religious authority (i.e., biblical inerrancy) than to religious tradition. Moreover, polarization among clergy is somewhat more evident on culture wars issues than on other social and political issues. These findings are generally supportive of the culture wars thesis and should help return examinations of culture wars back to where they were originally theorized to be waged: among elites. PMID- 24072926 TI - Volatile, isotope, and organic analysis of martian fines with the Mars Curiosity rover. AB - Samples from the Rocknest aeolian deposit were heated to ~835 degrees C under helium flow and evolved gases analyzed by Curiosity's Sample Analysis at Mars instrument suite. H2O, SO2, CO2, and O2 were the major gases released. Water abundance (1.5 to 3 weight percent) and release temperature suggest that H2O is bound within an amorphous component of the sample. Decomposition of fine-grained Fe or Mg carbonate is the likely source of much of the evolved CO2. Evolved O2 is coincident with the release of Cl, suggesting that oxygen is produced from thermal decomposition of an oxychloride compound. Elevated deltaD values are consistent with recent atmospheric exchange. Carbon isotopes indicate multiple carbon sources in the fines. Several simple organic compounds were detected, but they are not definitively martian in origin. PMID- 24072934 TI - The Role Of The Self-Fulfilling Prophecy In Young Adolescents' Responsiveness To A Substance Use Prevention Program. AB - This research examined whether naturally-occurring self-fulfilling prophecies influenced adolescents' responsiveness to a substance use prevention program. The authors addressed this issue with a unique methodological approach that was designed to enhance the internal validity of research on naturally-occurring self fulfilling prophecies by experimentally controlling for prediction without influence. Participants were 321 families who were assigned to an adolescent substance use prevention program that either did or did not systematically involve parents. Results showed that parents' perceptions about the value of involving parents in adolescent substance use prevention predicted adolescents' alcohol use more strongly among families assigned to the prevention program that systematically involved parents than to the one that did not. The theoretical and practical implications of these findings are discussed. PMID- 24072935 TI - WEAK GALERKIN METHODS FOR SECOND ORDER ELLIPTIC INTERFACE PROBLEMS. AB - Weak Galerkin methods refer to general finite element methods for partial differential equations (PDEs) in which differential operators are approximated by their weak forms as distributions. Such weak forms give rise to desirable flexibilities in enforcing boundary and interface conditions. A weak Galerkin finite element method (WG-FEM) is developed in this paper for solving elliptic PDEs with discontinuous coefficients and interfaces. Theoretically, it is proved that high order numerical schemes can be designed by using the WG-FEM with polynomials of high order on each element. Extensive numerical experiments have been carried to validate the WG-FEM for solving second order elliptic interface problems. High order of convergence is numerically confirmed in both L2 and Linfinity norms for the piecewise linear WG-FEM. Special attention is paid to solve many interface problems, in which the solution possesses a certain singularity due to the nonsmoothness of the interface. A challenge in research is to design nearly second order numerical methods that work well for problems with low regularity in the solution. The best known numerical scheme in the literature is of order [Formula: see text] to [Formula: see text] for the solution itself in Linfinity norm. It is demonstrated that the WG-FEM of the lowest order, i.e., the piecewise constant WG-FEM, is capable of delivering numerical approximations that are of order [Formula: see text] to [Formula: see text] in the Linfinity norm for C1 or Lipschitz continuous interfaces associated with a C1 or H2 continuous solution. PMID- 24072937 TI - Fabrication of core-shell nanoparticles via controlled aggregation of semi flexible conjugated polymer and hyaluronic acid. AB - Core-shell conjugated polymer nanoparticles (CPNs) were fabricated by complexing a semi-flexible, primary amine-containing conjugated polymer (CP) with hyaluronic acid (HA). Flexibility introduced in the rigid rod conjugated backbone allows backbone reorganization to increase pi-pi interaction under ionic complexation, resulting in core-shell nanoparticles with a hydrophobic CP core wrapped with a HA shell. The core-shell nanoparticles exhibited no cellular toxicity and high cancer cell specificity with minimal binding to normal cells. PMID- 24072936 TI - What No Child Left Behind Leaves Behind: The Roles of IQ and Self-Control in Predicting Standardized Achievement Test Scores and Report Card Grades. AB - The increasing prominence of standardized testing to assess student learning motivated the current investigation. We propose that standardized achievement test scores assess competencies determined more by intelligence than by self control, whereas report card grades assess competencies determined more by self control than by intelligence. In particular, we suggest that intelligence helps students learn and solve problems independent of formal instruction, whereas self control helps students study, complete homework, and behave positively in the classroom. Two longitudinal, prospective studies of middle school students support predictions from this model. In both samples, IQ predicted changes in standardized achievement test scores over time better than did self-control, whereas self-control predicted changes in report card grades over time better than did IQ. As expected, the effect of self-control on changes in report card grades was mediated in Study 2 by teacher ratings of homework completion and classroom conduct. In a third study, ratings of middle school teachers about the content and purpose of standardized achievement tests and report card grades were consistent with the proposed model. Implications for pedagogy and public policy are discussed. PMID- 24072927 TI - The petrochemistry of Jake_M: a martian mugearite. AB - "Jake_M," the first rock analyzed by the Alpha Particle X-ray Spectrometer instrument on the Curiosity rover, differs substantially in chemical composition from other known martian igneous rocks: It is alkaline (>15% normative nepheline) and relatively fractionated. Jake_M is compositionally similar to terrestrial mugearites, a rock type typically found at ocean islands and continental rifts. By analogy with these comparable terrestrial rocks, Jake_M could have been produced by extensive fractional crystallization of a primary alkaline or transitional magma at elevated pressure, with or without elevated water contents. The discovery of Jake_M suggests that alkaline magmas may be more abundant on Mars than on Earth and that Curiosity could encounter even more fractionated alkaline rocks (for example, phonolites and trachytes). PMID- 24072938 TI - Stabilities of Uracil and Pyridone-Based Carbanions: A Systematic Study in the Gas Phase and Solution and Implications for the Mechanism of Orotidine-5' Monophosphate Decarboxylase. AB - The stabilities of the C6-centered carbanions derived from 1,3-dimethyluracil, N methyl-2-pyridone, and N-methyl-4-pyridone were systematically investigated in the gas phase and in DMSO and water solutions. The stabilities of the carbanions in the gas phase and DMSO were directly measured through their reactions with carbon acids with known proton affinity or pKa values. The stabilities of the carbanions in DMSO were also probed through their kinetic isotope effects of protonation over deuteriation using acids with different acidity. The stabilities of the carbanions in water were determined through the rates of hydrogen deuterium exchange reactions of the corresponding conjugate acids. The carbanions derived from the two pyridones were found to have the same stability, whereas the carbanion derived from 1,3-dimethyluracil was more stable. The order of the stability of the carbanions showed no correlation with the decarboxylation rates of their corresponding carboxylic acids. The implications of the results for the mechanism of orotidine-5'-monophosphate decarboxylase (ODCase) are discussed. PMID- 24072939 TI - Asymmetric Formal Total Synthesis of the Stemofoline Alkaloids: The Evolution, Development and Application of a Catalytic Dipolar Cycloaddition Cascade. AB - A formal synthesis of didehydrostemofoline and isodidehydrostemofoline has been accomplished by preparing an intermediate in the Overman synthesis of these alkaloids from commercially available 2-deoxy-D-ribose. The work presented in this account chronicles the evolution of our explorations to identify the optimal steric and electronic control elements necessary to generate the tricyclic core structure of these alkaloids in a single operation from an acyclic precursor. The key step in the synthesis is a novel dipolar cycloaddition cascade sequence that is initiated by cyclization of a rhodium-derived carbene onto the nitrogen atom of a proximal imine group to generate an azomethine ylide that then undergoes spontaneous cyclization via dipolar cycloaddition. The synthesis features several other interesting reactions, including a Boord elimination to prepare a chiral allylic alcohol, a highly diastereoselective Hirama-Ito cyclization, and a useful modification of the Barton decarboxylation protocol. PMID- 24072928 TI - Curiosity at Gale crater, Mars: characterization and analysis of the Rocknest sand shadow. AB - The Rocknest aeolian deposit is similar to aeolian features analyzed by the Mars Exploration Rovers (MERs) Spirit and Opportunity. The fraction of sand <150 micrometers in size contains ~55% crystalline material consistent with a basaltic heritage and ~45% x-ray amorphous material. The amorphous component of Rocknest is iron-rich and silicon-poor and is the host of the volatiles (water, oxygen, sulfur dioxide, carbon dioxide, and chlorine) detected by the Sample Analysis at Mars instrument and of the fine-grained nanophase oxide component first described from basaltic soils analyzed by MERs. The similarity between soils and aeolian materials analyzed at Gusev Crater, Meridiani Planum, and Gale Crater implies locally sourced, globally similar basaltic materials or globally and regionally sourced basaltic components deposited locally at all three locations. PMID- 24072940 TI - Indoxacarb, Metaflumizone, and Other Sodium Channel Inhibitor Insecticides: Mechanism and Site of Action on Mammalian Voltage-Gated Sodium Channels. AB - Sodium channel inhibitor (SCI) insecticides were discovered almost four decades ago but have only recently yielded important commercial products (eg., indoxacarb and metaflumizone). SCI insecticides inhibit sodium channel function by binding selectively to slow-inactivated (non-conducting) sodium channel states. Characterization of the action of SCI insecticides on mammalian sodium channels using both biochemical and electrophysiological approaches demonstrates that they bind at or near a drug receptor site, the "local anesthetic (LA) receptor." This mechanism and site of action on sodium channels differentiates SCI insecticides from other insecticidal agents that act on sodium channels. However, SCI insecticides share a common mode of action with drugs currently under investigation as anticonvulsants and treatments for neuropathic pain. In this paper we summarize the development of the SCI insecticide class and the evidence that this structurally diverse group of compounds have a common mode of action on sodium channels. We then review research that has used site-directed mutagenesis and heterologous expression of cloned mammalian sodium channels in Xenopus laevis oocytes to further elucidate the site and mechanism of action of SCI insecticides. The results of these studies provide new insight into the mechanism of action of SCI insecticides on voltage-gated sodium channels, the location of the SCI insecticide receptor, and its relationship to the LA receptor that binds therapeutic SCI agents. PMID- 24072941 TI - UNIVERSITY TRUSTEES AS CHANNELS BETWEEN ACADEME AND INDUSTRY: TOWARD AN UNDERSTANDING OF THE EXECUTIVE SCIENCE NETWORK. PMID- 24072943 TI - Is carotid ultrasound necessary in the clinical evaluation of the asymptomatic Hollenhorst plaque? (An American Ophthalmological Society thesis). AB - PURPOSE: To evaluate the utility of carotid ultrasound in patients with asymptomatic Hollenhorst plaques. METHODS: Retrospective chart review of 237 patients diagnosed with Hollenhorst plaques between 1996 and 2004. The baseline cardiovascular risk profile, medications, and carotid ultrasound findings were documented. Retinal ischemia, myocardial ischemia, and cerebrovascular events during follow-up were noted. RESULTS: There was no statistically significant difference in the proportion of patients with carotid stenosis >40% between symptomatic (n=60) and asymptomatic (n=177) patients (32.7% vs 22.7%; P=.192, one way ANOVA). However, symptomatic patients were statistically more likely to have stenosis >69% (25% compared with 9.2% in the asymptomatic group; P=.008, one-way ANOVA). Among asymptomatic patients, those with carotid bruit (27.1%) were more likely to have moderate carotid stenosis >40% (55.6% vs 18.6% in patients without bruit; P=.0008, one-way ANOVA) and significant stenosis >69% (37% vs 4.3% in patients without bruit; P=.0001, one-way ANOVA). Follow-up data was obtained from 32 symptomatic patients (39.6 +/- 22.9 months) and 100 asymptomatic patients (41.3 +/- 21.8 months). Vascular and neurologic event rates were similar between the two groups. CONCLUSIONS: Hollenhorst plaques are a marker of significant carotid disease irrespective of retinal symptoms. Carotid auscultation remains important in the examination of patients with Hollenhorst plaques and increases the yield of asymptomatic patients diagnosed with carotid stenosis. The presence of visual symptoms on presentation did not correlate with an increased risk of death or stroke compared to asymptomatic patients during follow-up. Therefore all patients with asymptomatic plaques should have a medical workup, including carotid ultrasonography. PMID- 24072942 TI - Psychometrics of a new questionnaire to assess glaucoma adherence: the Glaucoma Treatment Compliance Assessment Tool (an American Ophthalmological Society thesis). AB - PURPOSE: To report the psychometrics of the Glaucoma Treatment Compliance Assessment Tool (GTCAT), a new questionnaire designed to assess adherence with glaucoma therapy. METHODS: We developed the questionnaire according to the constructs of the Health Belief Model. We evaluated the questionnaire using data from a cross-sectional study with focus groups (n = 20) and a prospective observational case series (n=58). Principal components analysis provided assessment of construct validity. We repeated the questionnaire after 3 months for test-retest reliability. We evaluated predictive validity using an electronic dosing monitor as an objective measure of adherence. RESULTS: Focus group participants provided 931 statements related to adherence, of which 88.7% (826/931) could be categorized into the constructs of the Health Belief Model. Perceived barriers accounted for 31% (288/931) of statements, cues-to-action 14% (131/931), susceptibility 12% (116/931), benefits 12% (115/931), severity 10% (91/931), and self-efficacy 9% (85/931). The principal components analysis explained 77% of the variance with five components representing Health Belief Model constructs. Reliability analyses showed acceptable Cronbach's alphas (>.70) for four of the seven components (severity, susceptibility, barriers [eye drop administration], and barriers [discomfort]). Predictive validity was high, with several Health Belief Model questions significantly associated (P <.05) with adherence and a correlation coefficient (R (2)) of .40. Test-retest reliability was 90%. CONCLUSION: The GTCAT shows excellent repeatability, content, construct, and predictive validity for glaucoma adherence. A multisite trial is needed to determine whether the results can be generalized and whether the questionnaire accurately measures the effect of interventions to increase adherence. PMID- 24072944 TI - Development of a new valid, reliable, and internationally applicable assessment tool of residents' competence in ophthalmic surgery (an American Ophthalmological Society thesis). AB - PURPOSE: To test the validity and reliability of a new tool for assessing residents' competence in ophthalmic surgery. Changing paradigms of ophthalmic education in the United States have influenced worldwide ophthalmic education and necessitated new methods of assessing resident competence. Accordingly, a new tool for assessing residents' competence in ophthalmic surgery (phacoemulsification) that could be applicable internationally was developed. We hypothesize that this instrument is valid and reliable. METHODS: A panel of six international content experts adapted a previously published tool for assessing phacoemulsification. The tool (called the International Council of Ophthalmology's Ophthalmology Surgical Competency Assessment Rubric, or ICO OSCAR:phaco) was reviewed by 12 international content experts for their constructive comments, which were incorporated to ensure content validity. Ten expert cataract surgery teachers then graded six recorded phacoemulsification surgeries with the ICO-OSCAR:phaco to investigate inter-rater reliability. RESULTS: The coefficient alpha statistic (a measure of reliability/internal consistency) for the ICO-OSCAR:phaco as a whole was 0.92, and 17 of its 20 dimensions had alpha coefficients greater than 0.70. CONCLUSIONS: The ICO OSCAR:phaco is a valid and reliable assessment tool that could be applied internationally to satisfy the global need of new instruments to comply with emerging trends in ophthalmic education. A toolbox of similar surgical competency assessment tools is being developed. PMID- 24072945 TI - Within-person Covariation of Agentic and Communal Perceptions: Implications for Interpersonal Theory and Assessment. AB - Interpersonal theory identifies agency and communion as uncorrelated (orthogonal) dimensions, largely evidenced by research examining between-person analyses of single-occasion measures. However, longitudinal studies of interpersonal behavior demonstrated the within-person association of agency and communion is not orthogonal for many individuals, and between-person differences in these associations relate to adjustment. We applied a similar approach to investigate the association of interpersonal perceptions. 184 university students completed a 7-day event-contingent study of their interpersonal experiences. Using multilevel regression models, we demonstrated that agentic and communal perceptions were positively associated, and the strength of this within-person association was moderated by between-person scores of dependency and narcissism. We discuss the benefits of incorporating within-person interpersonal associations (termed interpersonal covariation) into interpersonal theory and assessment. PMID- 24072946 TI - Reliability, Validity, and Predictive Utility of the 25-Item Criminogenic Cognitions Scale (CCS). AB - Theory, research, and clinical reports suggest that moral cognitions play a role in initiating and sustaining criminal behavior. The 25 item Criminogenic Cognitions Scale (CCS) was designed to tap 5 dimensions: Notions of entitlement; Failure to Accept Responsibility; Short-Term Orientation; Insensitivity to Impact of Crime; and Negative Attitudes Toward Authority. Results from 552 jail inmates support the reliability, validity, and predictive utility of the measure. The CCS was linked to criminal justice system involvement, self-report measures of aggression, impulsivity, and lack of empathy. Additionally, the CCS was associated with violent criminal history, antisocial personality, and clinicians' ratings of risk for future violence and psychopathy (PCL:SV). Furthermore, criminogenic thinking upon incarceration predicted subsequent official reports of inmate misconduct during incarceration. CCS scores varied somewhat by gender and race. Research and applied uses of CCS are discussed. PMID- 24072947 TI - Moment Adjusted Imputation for Multivariate Measurement Error Data with Applications to Logistic Regression. AB - In clinical studies, covariates are often measured with error due to biological fluctuations, device error and other sources. Summary statistics and regression models that are based on mismeasured data will differ from the corresponding analysis based on the "true" covariate. Statistical analysis can be adjusted for measurement error, however various methods exhibit a tradeo between convenience and performance. Moment Adjusted Imputation (MAI) is method for measurement error in a scalar latent variable that is easy to implement and performs well in a variety of settings. In practice, multiple covariates may be similarly influenced by biological fluctuastions, inducing correlated multivariate measurement error. The extension of MAI to the setting of multivariate latent variables involves unique challenges. Alternative strategies are described, including a computationally feasible option that is shown to perform well. PMID- 24072948 TI - A Population-Based Inquiry of Homeless Episode Characteristics and Early Educational Well-Being. AB - Child homelessness and educational well-being is an area of national research that requires more precise investigation to address mixed findings. The aim of this study was to extend the investigation of the relations between homelessness and educational well-being by determining if timing and frequency of homeless episodes are differentially associated with children's academic and classroom engagement outcomes. This investigation used a comprehensive research model to study the effects of these homeless episode characteristics within a large urban student cohort. Additionally, this study accounted for co-occurring early risk factors. Findings indicated that having a first homeless episode in early childhood was associated with non-proficiency in mathematics and academic engagement problems. Also more frequent homeless episodes were related to truancy in third grade. These results stress the importance of early intervention for homeless children and underscore the need to further understand the variation in young children's homeless experiences. PMID- 24072949 TI - Dissolving Borders: Reframing Risk, Delinquent Peers, and Youth Violence. AB - Although "association with delinquent peers" is commonly identified as "a risk factor for youth violence," this framework leads us to blame individuals and ignore the complex lives of youth who face state, symbolic, and interpersonal violence. This study is based on interviews with young adults about their adolescence in a low-income immigrant gateway neighborhood of Oakland, California. Most of the interviewees have peer networks that are racially/ethnically diverse and also include both delinquent and conforming peers. We show that having these "doubly diverse" friendship networks helps youth move through their neighborhood safely and feel anchored to their community even when they leave to attend college. Even successful youth in our study do not erect borders between themselves and "delinquent peers." It is easy to assign blame to youth for their friendships, their violent behavior, their lack of education, their unstable and low-paying jobs, but this calculus ignores both the structural factors that constrain youth choices and the benefits that seem to be linked to diverse friendships, even with delinquent peers. Growing up in a site of global capital accumulation and disinvestment in the era of neoliberalism, our interviewees challenge us to reframe risk. PMID- 24072950 TI - Evaluating the Iowa Gambling Task as a Direct Assessment of Impulsivity with Low Income Children. AB - This study examined performance on the Iowa Gambling Task (IGT; Bechara, Damasio, Damasio, & Anderson, 1994) as a measure of low-income school-aged children's affective decision-making and considered its utility as a direct indicator of impulsivity. One hundred and ninety-three 8-11 year olds performed a computerized version of the Iowa Gambling Task, a validated measure of decision-making. Multi level modeling was used to examine children's performance over the course of the task, with age, gender, and teachers' ratings of child impulsivity (BIS-11; Patton, Stanford, & Barratt, 1995) used to predict children's Iowa Gambling performance. Higher impulsivity scores predicted a decrease in slope of Iowa Gambling performance, indicating students rated higher on impulsivity chose more disadvantageously across the task blocks. Results support evidence of the validity of the Iowa Gambling Task as a measure of impulsivity in low-income minority children. PMID- 24072951 TI - The Paradox of Probation: Community Supervision in the Age of Mass Incarceration. AB - After four decades of steady growth, U.S. states' prison populations finally appear to be declining, driven by a range of sentencing and policy reforms. One of the most popular reform suggestions is to expand probation supervision in lieu of incarceration. However, the classic socio-legal literature suggests that expansions of probation instead widen the net of penal control and lead to higher incarceration rates. This article reconsiders probation in the era of mass incarceration, providing the first comprehensive evaluation of the role of probation in the build-up of the criminal justice system. The results suggest that probation was not the primary driver of mass incarceration in most states, nor is it likely to be a simple panacea to mass incarceration. Rather, probation serves both capacities, acting as an alternative and as a net-widener, to varying degrees across time and place. Moving beyond the question of diversion versus net widening, this article presents a new theoretical model of the probation-prison link that examines the mechanisms underlying this dynamic. Using regression models and case studies, I analyze how states can modify the relationship between probation and imprisonment by changing sentencing outcomes and the practices of probation supervision. When combined with other key efforts, reforms to probation can be part of the movement to reverse mass incarceration. PMID- 24072952 TI - Structural Analysis of Cubane-Type Iron Clusters. AB - The generalized cluster type [M4(MU3-Q)4L n ] x contains the cubane-type [M4Q4] z core unit that can approach, but typically deviates from, perfect Td symmetry. The geometric properties of this structure have been analyzed with reference to Td symmetry by a new protocol. Using coordinates of M and Q atoms, expressions have been derived for interatomic separations, bond angles, and volumes of tetrahedral core units (M4, Q4) and the total [M4Q4] core (as a tetracapped M4 tetrahedron). Values for structural parameters have been calculated from observed average values for a given cluster type. Comparison of calculated and observed values measures the extent of deviation of a given parameter from that required in an exact tetrahedral structure. The procedure has been applied to the structures of over 130 clusters containing [Fe4Q4] (Q = S2-, Se2-, Te2-, [NPR3]-, [NR]2-) units, of which synthetic and biological sulfide-bridged clusters constitute the largest subset. General structural features and trends in structural parameters are identified and summarized. An extensive database of structural properties (distances, angles, volumes) has been compiled in Supporting Information. PMID- 24072953 TI - Event Structure Influences Language Production: Evidence from Structural Priming in Motion Event Description. AB - This priming study investigates the role of conceptual structure during language production, probing whether English speakers are sensitive to the structure of the event encoded by a prime sentence. In two experiments, participants read prime sentences aloud before describing motion events. Primes differed in 1) syntactic frame, 2) degree of lexical and conceptual overlap with target events, and 3) distribution of event components within frames. Results demonstrate that conceptual overlap between primes and targets led to priming of (a) the information that speakers chose to include in their descriptions of target events, (b) the way that information was mapped to linguistic elements, and (c) the syntactic structures that were built to communicate that information. When there was no conceptual overlap between primes and targets, priming was not successful. We conclude that conceptual structure is a level of representation activated during priming, and that it has implications for both Message Planning and Linguistic Formulation. PMID- 24072954 TI - Reactions to Dating Violence Research: Do Difficulties with Distress Tolerance Increase Negative Reactions? AB - Recent research has begun to examine whether participants in dating violence studies perceive any benefit from the research and/or experience emotional distress as a result of having participated. Such information is important for Institutional Review Boards (IRBs) and researchers in determining ethical and appropriate protections for participants. In the current study, we examined participants' reactions to answering questions on dating violence victimization and perpetration utilizing a sample of female college students (N = 282). We also examined whether distress tolerance was associated with research reactions and moderated the relation between reports of victimization/perpetration and negative emotional reactions to the research. Findings demonstrated that negative emotional reactions to the research did not differ between individuals with or without previous dating violence. Further, distress tolerance had a main effect, but not a moderating effect, on negative emotional reactions to research participation. Implications of these findings for future research and IRBs are discussed. PMID- 24072955 TI - Intraportal versus Systemic Pentoxifylline Infusion after Normothermic Liver Ischemia: Effects on Regional Blood Flow Redistribution and Hepatic Ischemia Reperfusion Injury. AB - Pentoxifylline (PTX) has been shown to have beneficial effects on microcirculatory blood flow. In this study we evaluate the potential hemodynamic and metabolic benefits of PTX during hepatic ischemia. We also test the hypothesis that portal PTX infusion can minimize the I/R injury when compared to systemic infusion. Methods. Twenty-four dogs (18.1 +/- 0.7 kg) were subjected to portal triad occlusion (PTO) for 45 min. The animals were assigned to 3 groups: CT (control, PTO, n = 8), PTX-syst (PTO + 25 mg/Kg of PTX IV, n = 8), and PTX-pv (PTO + 25 mg/Kg of PTX in the portal vein, n = 8). Animals were followed for 120 min. Systemic hemodynamics, gastrointestinal tract perfusion, oxygen-derived variables, and liver enzymes were evaluated throughout the experiment. Results. Animals treated with PTX presented significantly higher CO in the first hour after reperfusion, when compared to the CT (~3.7 vs. 2.1 L/min, P < 0.05). Alanine aminotransferase (ALT) was similar in the PTX groups two hours after reperfusion but significantly higher in the CT (227 vs. ~64 U/L, P < 0.05). Conclusion. PTX infusion was associated with hemodynamic benefits and was able to minimize liver injury during normothermic hepatic I/R. However, local PTX infusion was not associated with any significant advantage over systemic route. PMID- 24072956 TI - Nipple Reconstruction: Risk Factors and Complications after 189 Procedures. AB - BACKGROUND: A multitude of different approaches have been proposed for achieving optimal aesthetic results after nipple reconstruction. In contrast, however, only a few studies focus on the morbidity associated with this procedure, particularly after implant-based breast reconstruction. METHODS: Using a cross-sectional study design all patients who underwent implant-based breast reconstruction with subsequent nipple reconstruction between 2000 and 2010 at Stanford University Medical Center were identified. The aim of the study was to analyze the impact of the following parameters on the occurrence of postoperative complications: age, final implant volume, time interval from placement of final implant to nipple reconstruction, and history of radiotherapy. RESULTS: A total of 139 patients with a mean age of 47.5 years (range, 29 to 75 years) underwent 189 nipple reconstructions. The overall complication rate was 13.2 percent (N = 25 nipple reconstructions). No association was observed between age (p = 0.43) or implant volume (p = 0.47) and the occurrence of complications. A trend towards higher complication rates in patients in whom the time interval between final implant placement and nipple reconstruction was greater than 8.5 months was seen (p = 0.07). Radiotherapy was the only parameter that was associated with a statistically significant increase in postoperative complication rate (51.7 percent vs. 6.25 percent; p < 0.00001). CONCLUSION: While nipple reconstruction is a safe procedure after implant-based breast reconstruction in patients without a history of radiotherapy, the presence of an irradiated field converts it to a high-risk one with a significant increase in postoperative complication rate. Patients with a history of radiotherapy should be informed about their risk profile and as a result may choose autologous reconstruction instead. LEVEL OF EVIDENCE: IV. PMID- 24072957 TI - Characterization of freestanding photoresist films for biological and MEMS applications. AB - Photoresists are light-sensitive resins used in a variety of technological applications. In most applications, however, photoresists are generally used as sacrificial layers or a structural layer that remains on the fabrication substrate. Thin layers of patterned 1002F photoresist were fabricated and released to form a freestanding film. Films of thickness in the range of 4.5-250 MUm were patterned with through-holes to a resolution of 5 MUm and an aspect ratio of up to 6:1. Photoresist films could be reliably released from the substrate after a 12-hour immersion in water. The Young's modulus of a 50 MUm thick film was 1.43 +/- 0.20 GPa. Use of the films as stencils for patterning sputtered metal onto a surface was demonstrated. These 1002F stencils were used multiple times without deterioration in feature quality. Furthermore, the films provided biocompatible, transparent surfaces of low autofluorescence on which cells could be grown. Culture of cells on a film with an isolated small pore enabled a single cell to be accessed through the underlying channel and loaded with exogenous molecules independently of nearby cells. Thus 1002F photoresist was patterned into thin, flexible, free-standing films that will have numerous applications in the biological and MEMS fields. PMID- 24072958 TI - JNK and NADPH oxidase involved in fluoride-induced oxidative stress in BV-2 microglia cells. AB - Excessive fluoride may cause central nervous system (CNS) dysfunction, and oxidative stress is a recognized mode of action of fluoride toxicity. In CNS, activated microglial cells can release more reactive oxygen species (ROS), and NADPH oxidase (NOX) is the major enzyme for the production of extracellular superoxide in microglia. ROS have been characterized as an important secondary messenger and modulator for various mammalian intracellular signaling pathways, including the MAPK pathways. In this study we examined ROS production and TNF- alpha , IL-1 beta inflammatory cytokines releasing, and the expression of MAPKs in BV-2 microglia cells treated with fluoride. We found that fluoride increased JNK phosphorylation level of BV-2 cells and pretreatment with JNK inhibitor SP600125 markedly reduced the levels of intracellular O2(.-) and NO. NOX inhibitor apocynin and iNOS inhibitor SMT dramatically decreased NaF-induced ROS and NO generations, respectively. Antioxidant melatonin (MEL) resulted in a reduction in JNK phosphorylation in fluoride-stimulated BV-2 microglia. The results confirmed that NOX and iNOS played an important role in fluoride inducing oxidative stress and NO production and JNK took part in the oxidative stress induced by fluoride and meanwhile also could be activated by ROS in fluoride treated BV-2 cells. PMID- 24072959 TI - Dissemination and Implementation of Evidence-Based Practices: Training and Consultation as Implementation Strategies. AB - To provide effective treatment for individuals with mental health needs, there is a movement to deploy evidence-based practices (EBPs) developed in research settings into community settings. Training clinicians in EBPs is often used as the primary implementation strategy in these efforts, despite evidence suggesting that training alone does not change therapist behavior. A promising implementation strategy that can be combined with training is consultation, or ongoing support. This paper reviews the literature on consultation following initial training. A model of consultation is presented as well as preliminary findings regarding effective consultation techniques. Future directions are offered. PMID- 24072960 TI - New and Emerging Techniques in Cartilage Repair: MACI. AB - The management of full thickness articular cartilage defects is a challenging problem for orthopaedic surgeons. It has limited potential for healing and can be a significant source of pain and loss of function. Multiple cartilage repair strategies have been attempted. Matrix-induced Autologous Chondrocyte Implantation (MACI) has been shown to produce hyaline-like cartilage into chondral defects. The goal of this review is to provide the current principles and technique of the MACI procedure along with reported clinical outcomes with its use. PMID- 24072961 TI - The Mediated Effect of Contextual Risk Factors on Trajectories of Violence: Results from a Nationally Representative, Longitudinal Sample of Hispanic Adolescents. AB - The current study sought to estimate trajectories of violent behavior and evaluate the direct and indirect effects of contextual factors among Hispanics, stratified by gender. Relying on data from 3,719 Hispanic adolescents surveyed as a part of the National Longitudinal Study of Adolescent Health (Add Health), violence trajectories were estimated using group-based trajectory modeling. The results identified three groups of violence trajectories for both males and females (non-violent, desistors, and escalators) and there were considerable gender differences in the direct and indirect effects of risk and protective factors on violent behavior. Study limitations and policy implications are also discussed. PMID- 24072962 TI - Evolved priors for ethnolinguistic categorization: A case study from the Quechua Aymara boundary in the Peruvian Altiplano. AB - Ethnic categories uniquely structure human social worlds. People readily form stereotypes about these, and other social categories, but it is unclear whether certain dimensions are privileged for making predictions about strangers when information is limited. If humans have been living in culturally-structured groups for much of their evolutionary history, we might expect them to have adaptations for prioritizing ethno-linguistic cues as a basis for making predictions about others. We provide a strong test of this possibility through a series of studies in a field context along the Quechua-Aymara linguistic boundary in the Peruvian Altiplano where the language boundary is not particularly socially meaningful. We find evidence of such psychological priors among children and adults at this site by showing that their age, and the social categories' novelty affect participants' reliance on ethno-linguistic inductive inferences (i.e. one-to-many predictions). Studies 1-3 show that participants make more ethno-linguistic inferences when the social categories are more removed from their real-world context. Additionally, in Study 4 when the category is marked with acoustic cues of language use, young children rely heavily on ethno linguistic predictions, even though adults do not. PMID- 24072963 TI - A case of orbital sebaceous gland carcinoma developing in an anophthalmic socket 65 years after enucleation. AB - Although conjunctival squamous cell carcinoma is known to develop as a result of chronic irritation from wearing an ocular prosthesis, orbital sebaceous gland carcinoma arising in an anophthalmic pocket is extremely rare. We report a 68 year-old female who developed a sebaceous gland carcinoma 65 years after her right eye was enucleated (at the age of three years) due to congenital glaucoma. The patient had noticed increasing discharge and swelling of her right eyelid. Incisional biopsies of an underlying orbital mass revealed poorly differentiated sebaceous gland carcinoma. The sebaceous gland carcinoma in this case could have been caused by chronic irritation as a result of long-standing use of a poorly fitted ocular prosthesis. The current case of a malignant tumor occurring 65 years after enucleation emphasizes the importance of long-term clinical surveillance to monitor for tumor formation. Careful examination of the anophthalmic socket should be part of the physical examination. PMID- 24072964 TI - Impact of beta2-agonists, beta-blockers, and their combination on cardiac function in elderly male patients with chronic obstructive pulmonary disease. AB - PURPOSE: This study was undertaken to determine the association between cardiac function and therapy with beta2-adrenoceptor agonists (beta2-agonists), beta blockers, or beta-blocker-beta-agonist combination therapy in elderly male patients with chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: This was a retrospective cohort study of 220 elderly male COPD patients (mean age 84.1 +/- 6.9 years). The patients were divided into four groups on the basis of the use of beta-blockers and beta2-agonists. N-terminal fragment pro-B-type natriuretic peptide (NT pro-BNP), left ventricular ejection fraction (LVEF), and other relevant parameters were measured and recorded. At follow-up, the primary end point was all-cause mortality. RESULTS: Multiple linear regression analysis revealed no significant associations between NT pro-BNP and the use of beta2 agonists (beta = 35.502, P = 0.905), beta-blockers (beta = 3.533, P = 0.989), or combination therapy (beta = 298.635, P = 0.325). LVEF was not significantly associated with the use of beta2-agonists (beta = -0.360, P = 0.475), beta blockers (beta = -0.411, P = 0.284), or combination therapy (beta = -0.397, P = 0.435). Over the follow-up period, 52 patients died, but there was no significant difference in mortality among the four groups (P = 0.357). Kaplan-Meier analysis showed no significant difference among the study groups (log-rank test, P = 0.362). After further multivariate adjustment, use of beta2-agonists (hazard ratio [HR] 0.711, 95% confidence interval [CI] 0.287-1.759; P = 0.460), beta blockers (HR 0.962, 95% CI 0.405-2.285; P = 0.930), or combination therapy (HR 0.638, 95% CI 0.241-1.689; P < 0.366) were likewise not correlated with mortality. CONCLUSION: There was no association between the use of beta2 agonists, beta-blockers, or beta-blocker-beta2-agonist combination therapy with cardiac function and all-cause mortality in elderly male COPD patients, which indicated that they may be used safely in this population. PMID- 24072965 TI - Telephone-delivered psychoeducational intervention for Hong Kong Chinese dementia caregivers: a single-blinded randomized controlled trial. AB - PURPOSE: Many family caregivers of persons with dementia (PWD) are unable to participate in community center-based caregiver support services because of logistical constraints. This study evaluated the effectiveness of a telephone delivered psychoeducational intervention for family caregivers of PWD in alleviating caregiver burden and enhancing caregiving self-efficacy. SUBJECTS AND METHODS: In a single-blinded randomized controlled trial, 38 family caregivers of PWD were randomly allocated into an intervention group or a control group. The intervention group received psychoeducation from a registered social worker over the phone for 12 sessions. Caregivers in the control group were given a DVD containing educational information about dementia caregiving. Outcomes of the intervention were measured by the Chinese versions of the Zarit Burden Interview and the Revised Scale for Caregiving Self-efficacy. Mann-Whitney U tests were used to compare the differences between the intervention and control groups. RESULTS: The level of burden of caregivers in the intervention group reduced significantly compared with caregivers in the control group. Caregivers in the intervention group also reported significantly more gain in self-efficacy in obtaining respite than the control group. CONCLUSION: A structured telephone intervention can benefit dementia caregivers in terms of self-efficacy and caregiving burden. The limitations of the research and recommendations for intervention are discussed. PMID- 24072966 TI - The relationship between Elder Risk Assessment (ERA) scores and cardiac revascularization: a cohort study in Olmsted County, Minnesota, USA. AB - PURPOSE: The aging population is predisposed to cardiovascular disease. Our goal was to determine the relationship between a higher Elder Risk Assessment (ERA) score and coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI), in adults over 60 years. METHODS: This was a retrospective cohort study in a primary care internal medicine practice. Patients included community-dwelling individuals aged 60 years or older on January 1, 2005. The primary outcome was a combined outcome of CABG and PCI in 2 years. The secondary outcome was mortality 5 years after CABG or PCI. The primary predictor variable was the score on the ERA Index, an instrument that predicts emergency room visits and hospitalization. The outcomes were obtained using administrative data from electronic medical records. The analysis included logistic regression, with odds ratios for the primary outcome and time-to-event analysis for mortality. RESULTS: The records of 12,650 patients were studied. A total of 902 patients (7.1%) had either CABG or PCI, with an average age of 74.5 years (+/-8.3 years). There were 205 patients (23%) who experienced CABG or PCI in the highest-score group (top 10%) compared with 29 patients (3%) in the lowest score group, for an odds ratio of 15.4; 95% confidence interval, 10.1-23.5. There was a greater association of revascularization events by increasing score group. We noted increased mortality by increasing ERA score, in patients undergoing CABG or PCI. The patients in the highest-scoring group had a 50% 5-year survival rate compared with a 97% 5-year survival rate in the lowest-scoring group (P < 0.001). CONCLUSION: Older adults in the highest-ERA-scoring group had the highest utilization of CABG or PCI. Patients with high ERA scores undergoing coronary revascularization were also at the highest risk of mortality. Providers should be aware that higher ERA scores can potentially predict outcomes in high-risk patients. PMID- 24072967 TI - Sixteen weeks of resistance training can decrease the risk of metabolic syndrome in healthy postmenopausal women. AB - BACKGROUND: The postmenopausal phase has been considered an aggravating factor for developing metabolic syndrome. Notwithstanding, no studies have as yet investigated the effects of resistance training on metabolic syndrome in postmenopausal women. Thus, the purpose of this study was to verify whether resistance training could reduce the risk of metabolic syndrome in postmenopausal women. METHODS: Twenty postmenopausal women were randomly assigned to a resistance training protocol (n = 10, 53.40 +/- 3.95 years, 64.58 +/- 9.22 kg) or a control group (n = 10, 53.0 +/- 5.7 years, 64.03 +/- 5.03 kg). In the resistance training protocol, ten exercises were performed, with 3 * 8-10 maximal repetitions three times per week, and the load was increased every week. Two-way analysis of variance was used to evaluate specific metabolic syndrome Z-score, high density lipoprotein cholesterol, fasting blood glucose, triglycerides, waist circumference, blood pressure, strength, and body composition. The level of statistical significance was set at P < 0.05. RESULTS: The main results demonstrated a significant decrease of metabolic syndrome Z-score when the postmenopausal women performed resistance training (P = 0.0162). Moreover, we observed decreases in fasting blood glucose for the resistance training group (P = 0.001), and also significant improvements in lean body mass (P = 0.042, 2.46%), reduction of body fat percentage (P = 0.001, -6.75%) and noticeable increases in muscle strength after resistance training to leg press (P = 0.004, 41.29%) and bench press (P = 0.0001, 27.23%). CONCLUSION: It was concluded that resistance training performed three times a week may reduce the metabolic syndrome Z-score with concomitant decreases in fasting blood glucose, improvements in body composition, and muscle strength in postmenopausal women. PMID- 24072968 TI - Management of mantle cell lymphoma in the elderly patient. AB - Mantle cell lymphoma is a relatively rare B-cell lymphoma with a specific genetic lesion and a typical immunophenotypic profile. The median age is 65 years. There is no curative treatment, except allogeneic stem cell transplantation for a selected group of patients. For the majority of patients, especially the elderly, the aim of therapy should therefore be a long progression-free survival. Age and comorbidity may hamper the use of the most active treatment regimen, such as high dose cytarabine and autologous stem cell transplantation. Therefore, it is a challenge to select the most appropriate therapy for an elderly patient. Studies specifically designed for elderly patients are rare. A recently performed large randomized study for elderly patients, however, has shown that R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy followed by maintenance rituximab can result in a long progression-free survival. For patients too frail for R-CHOP chemotherapy, a treatment should be offered that benefits the patient in reducing the symptoms of the disease without causing too many side effects. Progression or relapse will occur in all patients sooner or later. Second-line treatment should again be carefully selected. Several options are mentioned. New drugs are being developed, and new combinations are investigated. Further improvement in the outcome of patients with mantle cell lymphoma is expected. Participation in well-designed clinical trials, also by elderly patients, is important to find the real benefit that can be achieved, and to get information on the tolerability of these treatments in this age group. PMID- 24072969 TI - Postural stability and quality of life after guided and self-training among older adults residing in an institutional setting. AB - PURPOSE: To evaluate whether rehabilitation of muscle force or balance improves postural stability and quality of life (QoL), and whether self-administered training is comparable with guided training among older adults residing in an institutional setting. PATIENTS AND METHODS: A randomized, prospective intervention study was undertaken among 55 elderly patients. Three intervention groups were evaluated: a muscle force training group; a balance and muscle force training group; and a self-administered training group. Each group underwent 1 hour-long training sessions, twice a week, for 3 months. Postural stability was measured at onset, after 3 months, and after 6 months. Time-domain-dependent body sway variables were calculated. The fall rate was evaluated for 3 years. General health related quality of life (HRQoL) was measured with a 15D instrument. Postural stability was used as a primary outcome, with QoL and falls used as secondary outcomes. RESULTS: Muscle force trainees were able to undertake training, progressing towards more strenuous exercises. In posturography, the number of spiky oscillations was reduced after training, and stationary fields of torque moments of the ankle increased, providing better postural stability in all groups; in particular, the zero crossing rate of weight signal and the number of low variability episodes in the stabilogram were improved after training. While no difference was found between different training groups in posturography outcomes, a reduction of fall rate was significant in only the guided training groups. A significant part of the variability of the QoL could be explained by the posturography outcome (46%). However, the outcome of training was associated with a reduced QoL. CONCLUSION: Even moderate or severely demented residents could do exercises in five-person groups under the supervision of a physiotherapist. An improvement in postural stability was observed in all training groups, indicating that even self-administered training could be beneficial. Posturography outcome indicated that training alters the postural strategy by reducing the oscillatory fluctuations of body sway signal. However, only guided training tended to reduce falls. Short training intervention programs may decrease QoL by changing the elderly's daily routine and making it more active and exhausting. PMID- 24072970 TI - Treating relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: liposome-encapsulated vincristine. AB - Acute lymphoblastic leukemia (ALL) remains a disease with poor outcomes in adults. While induction chemotherapy achieves a complete remission in almost 90% of patients, the majority will relapse and die of their disease. Relapsed ALL is associated with a high reinduction mortality and chemotherapy resistance, with allogeneic hematopoietic stem cell transplantation offering the only therapy with curative potential. However, there is no efficacious and well tolerated standard regimen accepted as a "bridge" to allogeneic stem cell transplantation or as definitive treatment for patients who are not transplant candidates. Vincristine is an active drug in patients with ALL, but its dose intensity is limited by neurotoxicity, and its full potential as an anticancer drug is thus not realized. Encapsulation of vincristine into sphingomyelin and cholesterol nanoparticle liposomes facilitates dose-intensification and densification to enhanced target tissues with reduced potential for toxicity. Vincristine sulfate liposome injection (VSLI) is associated with significant responses in clinically advanced ALL, and has recently been approved by the US Food and Drug Administration for treatment of relapsed and clinically advanced Philadelphia chromosome-negative ALL. This review provides an overview of the preclinical and clinical studies leading to the approval of VSLI for the treatment of relapsed and refractory ALL, and suggests potential areas of future clinical development. PMID- 24072971 TI - Review of the pharmacoeconomics of early treatment of multiple sclerosis using interferon beta. AB - Multiple sclerosis (MS) is a common neurological disease with increasing incidence and prevalence. Onset of disease is most frequently in young adulthood when productivity is usually highest; it is of chronic nature and, in the majority of patients, it will result in accumulation of disability. Due to loss of productivity in patients and caregivers as well as high expenses for medical treatment, MS is considered a disease with high economic burden for patients and society. Several drugs have been approved for treatment of MS. While treatment ameliorates the course of the disease, it is very costly; therefore, pharmacoeconomics, evaluating costs and effects of disease-modifying treatment in MS, has become an important issue. Here, we review the economic impact and treatment strategies of MS and discuss recent studies on pharmacoeconomics of early treatment with interferon beta. PMID- 24072972 TI - Treatment of neurolept-induced tardive dyskinesia. AB - Tardive dyskinesia (TDK) includes orobuccolingual movements and "piano-playing" movements of the limbs. It is a movement disorder of delayed onset that can occur in the setting of neuroleptic treatment as well as in other diseases and following treatment with other drugs. The specific pathophysiology resulting in TDK is still not completely understood but possible mechanisms include postsynaptic dopamine receptor hypersensitivity, abnormalities of striatal gamma aminobutyric acid (GABA) neurons, and degeneration of striatal cholinergic interneurons. More recently, the theory of synaptic plasticity has been proposed. Considering these proposed mechanisms of disease, therapeutic interventions have attempted to manipulate dopamine, GABA, acetylcholine, norepinephrine and serotonin pathways and receptors. The data for the effectiveness of each class of drugs and the side effects were considered in turn. PMID- 24072974 TI - Radiographic evaluation of third molar genesis in Greek orthodontic patients. AB - OBJECTIVES: The study reported here investigated the first radiographic evidence of third molar (M3) formation, their incidence and distribution as well as their congenital absence on the right or the left side in either the maxilla or the mandible, in both male and female Greek orthodontic patients. MATERIALS AND METHODS: A total of 618 panoramic radiographs were initially examined. After the application of inclusion/exclusion criteria, the group finally selected consisted of 428 patients (mean age 11.64 years, range 5-18): 179 males (mean age 11.73 +/- 2.46) and 249 females (mean age 11.57 +/- 2.45). The collected data were analyzed using SPSS software (IBM, Armonk, New York, NY, USA). The level of significance for all analyses was set to p = 0.05. The chi-square (chi(2)) test was used to assess the relationships between variables. The Wilcoxon's signed-rank test and the Mann-Whitney U test were also used for comparisons as well as the Spearman's rho test for correlations. RESULTS: M3s were first detected in females at the age of 7 years whereas males followed one year later at the age of 8 years. A strong correlation between age and M3 development was revealed for both sexes (Spearman's rho = 0.177, p = 0.05). Presence of all four M3s was the most common incidence (present in 70.8% of study subjects), followed by the agenesis of two (12.1%), agenesis of all four (8.4%), one (6.8%), and three (1.9%) M3s. Congenitally missing M3s in all subjects showed a significantly greater predilection for the maxilla over the mandible (19.6% and 15.5%, respectively) (Wilcoxon signed-rank test Z = -2.404, p = 0.016). However, the distribution was found equal between the two sides of the jaws. The difference between the absent frequencies of M3s in the mandible and the maxilla was found statistically significant for the total sample (McNemar's test, p < 0.001) and for males (p = 0.041) as well. CONCLUSION: The study data may provide a reference for the M3 genesis in Greeks. PMID- 24072973 TI - Saccadic eye movement applications for psychiatric disorders. AB - OBJECTIVE: The study presented here analyzed the patterns of relationship between oculomotor performance and psychopathology, focusing on depression, bipolar disorder, schizophrenia, attention-deficit hyperactivity disorder, and anxiety disorder. METHODS: Scientific articles published from 1967 to 2013 in the PubMed/Medline, ISI Web of Knowledge, Cochrane, and SciELO databases were reviewed. RESULTS: Saccadic eye movement appears to be heavily involved in psychiatric diseases covered in this review via a direct mechanism. The changes seen in the execution of eye movement tasks in patients with psychopathologies of various studies confirm that eye movement is associated with the cognitive and motor system. CONCLUSION: Saccadic eye movement changes appear to be heavily involved in the psychiatric disorders covered in this review and may be considered a possible marker of some disorders. The few existing studies that approach the topic demonstrate a need to improve the experimental paradigms, as well as the methods of analysis. Most of them report behavioral variables (latency/reaction time), though electrophysiological measures are absent. PMID- 24072975 TI - Efficacy of musculoskeletal injections given by primary care providers in the office. PMID- 24072976 TI - Smears and cultures for diagnosis of pulmonary tuberculosis in an asymptomatic immigrant population. AB - BACKGROUND: The World Health Organization estimated in 2010 that 8.8 million new tuberculosis (TB) cases. About one-third of the world's population is infected and 10% will develop active TB disease. While cultures remain the international gold standard for diagnosing TB disease, in many other low-income countries, sputum smears remain the only and most accessible tool with which to diagnose active TB disease. As a consequence, in patients with TB who have negative smears, their TB remains undetected. AIM: The objective of the study reported here was to demonstrate the proportion of smear-positive/culture-positive cases compared with smear-negative/culture-positive TB cases in Mexican immigrants bound for the USA. METHODS: A retrospective study was undertaken of the medical records of 122 active TB cases diagnosed at a clinic in Ciudad Juarez, Mexico, from 2009 to 2012. All cases were confirmed by culture, regardless of the sputum smear results. RESULTS: Of the cases, 80% (97 active TB cases) had negative sputum smears, while only 25 cases (20%) had at least one positive smear. All of the cultures were confirmed as positive for Mycobacterium tuberculosis complex. CONCLUSION: The fact that 80% of the TB cases were smear negative and 20% smear positive shows that there is a clear gap between the actual state of active TB disease within patients under screening conditions, meaning that eight out of ten actual cases are being missed when sputum smear is the only diagnostic tool in asymptomatic patients with abnormal chest X-rays. Based on these results, it is highly recommended that countries that have not standardized culturing as the gold standard for the diagnosis of active TB do so, so that TB cases - which may endanger global public health - are not missed. It is also recommended that further studies be undertaken to determine the clinical background of the patients diagnosed by smear and culture to identify a direct relationship between clinical signs and symptoms and the smear result. PMID- 24072977 TI - Persistent pain after total knee or hip arthroplasty: differential study of prevalence, nature, and impact. AB - This study compares the incidence, nature, and impact of persistent post-surgical pain after total knee arthroplasty (TKA) and total hip arthroplasty (THA) and investigates differences between these procedures, with the focus on potential presurgical and post-surgical issues that could be related to the distinct persistent post-surgical pain outcomes between these two groups. A consecutive sample of 92 patients was assessed prospectively 24 hours before, 48 hours, and 4 6 months after surgery. The data show that TKA patients had a higher likelihood of developing persistent post-surgical pain, of reporting higher pain levels, and of using more neuropathic descriptors when classifying their pain. In addition, TKA patients more often reported interference from pain on functional domains, including general activity, walking ability, and normal work. Demographic factors, like gender and age, along with presurgical clinical factors like disease onset, existence of medical comorbidities, and other pain problems, may have contributed to these differences, whereas baseline psychologic factors and functionality levels did not seem to exert an influence. Heightened acute post surgical pain experience among TKA patients could also be related to distinct outcomes for persistent post-surgical pain. Future prospective studies should therefore collect TKA and THA samples wherein patients are homogeneous for demographic and presurgical clinical issues. Overall, these findings contribute to a small but growing body of literature documenting persistent post-surgical pain after major arthroplasty, conducted in different countries and across different health care settings. PMID- 24072978 TI - Tissue effects in vessel sealing and transection from an ultrasonic device with more intelligent control of energy delivery. AB - BACKGROUND: Ultrasonic surgical devices have been demonstrated to provide excellent hemostasis, efficient transection, minimal lateral thermal damage, low smoke generation, and no risk of electrical current passage to the patient. These benefits originate from the inherent characteristics of the ultrasonic mechanism, but further improvements were thought possible through optimization of the energy delivery during application. The study reported here compared a new ultrasonic device, Harmonic ACE(r)+ Shears with Adaptive Tissue Technology, with a commercial predicate device, Harmonic ACE(r) Shears (both Ethicon Endo-Surgery, Inc., Cincinnati, OH, USA). METHODS: Devices were evaluated in an in vivo porcine model intraoperatively and after a 30-day survival period. Both devices were used to seal a variety of vessels 1-5 mm in diameter, and compared for hemostasis, histological thermal damage, and adhesion formation. Sealed vessels were evaluated ex vivo for burst pressure, and visual obstruction caused by plumage from device application was assessed quantitatively. RESULTS: ACE+ produced significantly less thermal damage, had fewer adhesions, offered faster transection, involved less visual obstruction, and had higher burst pressures than the predicate device. All vessel seals, evaluated over the course of a 30 day survival period in pigs, remained intact. CONCLUSION: The new Adaptive Tissue Technology algorithm assists the surgeon in achieving better control of energy delivery to the tissue, sealing vessels with supra-physiological burst pressures, and low thermal damage. These preclinical results with Harmonic ACE+ may translate into meaningful clinical benefits, providing greater precision along with more efficient and effective cutting and coagulation in open or laparoscopic procedures. PMID- 24072979 TI - Characterization of Anomalous Diffusion in Porous Biological Tissues Using Fractional Order Derivatives and Entropy. AB - In this high-resolution magnetic resonance imaging (MRI) study at 17.6 Tesla of a fixed rat brain, we used the continuous time random walk theory (CTRW) for Brownian motion to characterize anomalous diffusion. The complex mesoporus structure of biological tissues (membranes, organelles, and cells) perturbs the motion of the random walker (water molecules in proton MRI) introducing halts between steps (waiting times) and restrictions on step sizes (jump lengths). When such waiting times and jump lengths are scaled with probability distributions that follow simple inverse power laws (t-(1+alpha), |x|-(1+beta)) non-Gaussian motion gives rise to sub- and super- diffusion. In the CTRW approach, the Fourier transform yields a solution to the generalized diffusion equation that can be expressed by the Mittag-Leffler function (MLF), Ealpha (- Dalpha, beta|q|betaDeltaalpha). We interrogated both white and gray matter regions in a 1 mm slice of a fixed rat brain (190 MUm in plane resolution) with diffusion weighted MRI experiments using b-values up to 25,000 s/mm2, by independently varying q and Delta. When fitting these data to our model, the fractional order parameters, alpha and beta, and the entropy measure, [Formula: see text], were found to provide excellent contrast between white and gray matter and to give results that were sensitive to the type of diffusion experiment performed. PMID- 24072980 TI - Conservation of Protists: The Krauthugel Pond in Austria. AB - Although constituting more than 100,000 described species, protists are virtually ignored within the arena of biodiversity conservation. One reason is the widespread belief that the majority of protists have cosmopolitan distributions, in contrast to the highly hetereogenous biogeography of the "mega-Metazoa". However, modern research reveals that about one third of the known protists have restricted distributions, which endorses their conservation, at least in special cases. Here, we report what probably ranks as the first successful conservation intervention focused directly on known protist diversity. It is justified by unique species, type localities, and landscape maintenance as evidence for legislation. The protected habitat comprises an ephemeral pond, which is now a "Natural Monument" for ciliated protozoa. This wetland occupies a natural depression on the Krauthugel ("cabbage hill") south of the fortress of Salzburg City. When filled, the claviform pond has a size of ~30 * 15 m and a depth rarely surpassing 30 cm. Water is present only for some days or weeks, depending on heavy and/or prolonged rain. The pond occupied an agricultural field where root and leafy vegetables were cultivated for possibly more than 200 years. In the 1960s, this area became a grassland utilized as an autumn pasture, but was abandoned in the 1990s. Repeated sampling between 1982 and 2012 recovered a total of at least 150 ciliate taxa, of which 121 were identified to species level. Eight species were new to science, and an additional 10 poorly known species were reinvestigated and neotypified with populations from the Krauthugel pond. Both endemism and type localities justify the argument that the "integrative approach" in biodiversity and conservation issues should include protists and micro metazoans. We argue that Krauthugel holds a unique reference node for biodiversity inventories to obtain the baseline knowledge-which is the prerequisite to monitor ecosystem integrity-and detect and evaluate impacts of natural and anthropogenic disturbances. PMID- 24072981 TI - Death Penalty Decisions: Instruction Comprehension, Attitudes, and Decision Mediators. AB - A primary goal of this research was to empirically evaluate a set of assumptions, advanced in the Supreme Court's ruling in Buchanan v. Angelone (1998), about jury comprehension of death penalty instructions. Further, this research examined the use of evidence in capital punishment decision making by exploring underlying mediating factors upon which death penalty decisions may be based. Manipulated variables included the type of instructions and several variations of evidence. Study 1 was a paper and pencil study of 245 undergraduate mock jurors. The experimental design was an incomplete 4*2*2*2*2 factorial model resulting in 56 possible conditions. Manipulations included four different types of instructions, presence of a list of case-specific mitigators to accompany the instructions, and three variations in the case facts: age of the defendant, bad prior record, and defendant history of emotional abuse. Study 2 was a fully-crossed 2*2*2*2*2 experiment with four deliberating mock juries per cell. Manipulations included jury instructions (original or revised), presence of a list of case-specific mitigators, defendant history of emotional abuse, bad prior record, and heinousness of the crime. The sample of 735 jury-eligible participants included 130 individuals who identified themselves as students. Participants watched one of 32 stimulus videotapes based on a replication of a capital sentencing hearing. The present findings support previous research showing low comprehension of capital penalty instructions. Further, we found that higher instruction comprehension was associated with higher likelihood of issuing life sentence decisions. The importance of instruction comprehension is emphasized in a social cognitive model of jury decision making at the sentencing phase of capital cases. PMID- 24072982 TI - Raman spectra of high- kappa dielectric layers investigated with micro-Raman spectroscopy comparison with silicon dioxide. AB - Three samples with dielectric layers from high- kappa dielectrics, hafnium oxide, gadolinium-silicon oxide, and lanthanum-lutetium oxide on silicon substrate were studied by Raman spectroscopy. The results obtained for high- kappa dielectrics were compared with spectra recorded for silicon dioxide. Raman spectra suggest the similarity of gadolinium-silicon oxide and lanthanum-lutetium oxide to the bulk nondensified silicon dioxide. The temperature treatment of hafnium oxide shows the evolution of the structure of this material. Raman spectra recorded for as-deposited hafnium oxide are similar to the results obtained for silicon dioxide layer. After thermal treatment especially at higher temperatures (600 degrees C and above), the structure of hafnium oxide becomes similar to the bulk non-densified silicon dioxide. PMID- 24072983 TI - Discrete particle swarm optimization with scout particles for library materials acquisition. AB - Materials acquisition is one of the critical challenges faced by academic libraries. This paper presents an integer programming model of the studied problem by considering how to select materials in order to maximize the average preference and the budget execution rate under some practical restrictions including departmental budget, limitation of the number of materials in each category and each language. To tackle the constrained problem, we propose a discrete particle swarm optimization (DPSO) with scout particles, where each particle, represented as a binary matrix, corresponds to a candidate solution to the problem. An initialization algorithm and a penalty function are designed to cope with the constraints, and the scout particles are employed to enhance the exploration within the solution space. To demonstrate the effectiveness and efficiency of the proposed DPSO, a series of computational experiments are designed and conducted. The results are statistically analyzed, and it is evinced that the proposed DPSO is an effective approach for the studied problem. PMID- 24072984 TI - On the normed space of equivalence classes of fuzzy numbers. AB - We study the norm induced by the supremum metric on the space of fuzzy numbers. And then we propose a method for constructing a norm on the quotient space of fuzzy numbers. This norm is very natural and works well with the induced metric on the quotient space. PMID- 24072985 TI - A preliminary study on the synthesis and characterization of multilayered Ag/Co magnetic nanowires fabricated via the electrodeposition method. AB - A single-bath electrodeposition method was developed to integrate multilayer Ag/Co nanowires with a commercial anodic alumina oxide (AAO) template with a pore diameter of 100-200 nm. An electrolyte system containing silver nitride and cobalt sulfide was studied using cyclic voltammetry, and the electrodeposition rate was varied to optimize the electrodeposition conditions. A constant stepwise potential and a variable cation ratio of [Co2+]/[Ag+] were used during electrodeposition. After the dissolution of the template in aqueous NaOH solution, multilayered Ag/Co nanowires were obtained with a composition of [Co]/[Ag80Co20], as identified by XRD and TEM, when [Co2+]/[Ag+] = 150. By annealing at 200 degrees C for 1 h, uniformly structured (Co99.57/Ag100) nanowires were obtained. Compared with pure Co nanowires, the magnetic hysteresis loops showed a greater magnetic anisotropy for (Co99.57/Ag100) nanowires than for pure Co nanowires, corresponding to a change in the easy axis upon magnetization. PMID- 24072986 TI - Risk and Protective Factors for Trajectories of Violent Delinquency Among a Nationally Representative Sample of Early Adolescents. AB - To estimate trajectories of violence using a longitudinal sample of adolescents, considering the effects of multiple domains of influences as differentiators between profiles of violent behavior. A nationally representative sample of 9,421 adolescents ages 15-26. Trajectories were estimated, and multinomial regression procedures were used to evaluate factors predicting membership in high-violence trajectory groups. Mediation analyses were conducted to evaluate the mediated effect of distal influences on violence. Three groups of violence trajectories were identified: (a) nonviolent (73.1%); (b) escalators (14.6%); and (c) desistors (12.3%). Peer alcohol use predicted both escalation and desistance; however, these effects were mediated through individual-level variables. Aside from baseline violence, no other risk factor predicted membership in the "escalator" group. The lack of significance in predicting escalation highlights the need for further study on the etiology of late onset violence. Implications for violence prevention are discussed. PMID- 24072987 TI - Cigarette Smoking and Health Characteristics in Individuals With Serious Mental Illness Enrolled in a Behavioral Weight Loss Trial. AB - Objective: Cigarette smoking is the most preventable cause of disease and death in the US. We examined the prevalence of smoking and the association between smoking status and health characteristics in persons with serious mental illness. Methods: A total of 291 overweight or obese adults with serious mental illness were enrolled in a behavioral weight loss trial. Cigarette smoking, co-occurring medical diagnoses, dietary intake, blood pressure, cardiovascular fitness, body mass index, quality of life, and psychiatric symptoms were assessed at baseline in 2008-2011. Fasting glucose and lipid markers were measured from blood samples. Cardiovascular risk profile was calculated based on the global Framingham Health Study Risk Equation. Results: A total of 128 (44%) of participants were current smokers or had smoked in the previous one year. The smokers had significantly higher diastolic blood pressure and blood triglyceride levels, and lower HDL cholesterol than the nonsmokers, adjusted for age, sex, education, and diagnosis. They were more likely to have a history of emphysema, and had a 10-year cardiovascular disease risk of 13.2%, significantly higher than the 7.4% in the nonsmokers. The smokers also had elevated ratings of psychopathology on the BASIS 24 scale. Smokers did not differ from nonsmokers in cardiovascular fitness, body mass index, depression, quality of life, or other comorbid medical diagnoses. There was no characteristic in which smokers appeared healthier than nonsmokers. Conclusions: The prevalence of smoking in this contemporary cohort of individuals with serious mental illness who were motivated to lose weight was more than twice that in the overall population. Smokers had more indicators of cardiovascular disease and poorer mental health than did nonsmokers. The high burden of comorbidity in smokers with serious mental illness indicates a need for broad health interventions. PMID- 24072988 TI - Measuring Organizational Capacity to Treat Co-Occurring Psychiatric and Substance Use Disorders. PMID- 24072990 TI - The Role of Genes in the Insomnia Phenotype. PMID- 24072991 TI - Bias Correction Methods for Misclassified Covariates in the Cox Model: comparison offive correction methods by simulation and data analysis. AB - Measurement error/misclassification is commonplace in research when variable(s) can notbe measured accurately. A number of statistical methods have been developed to tackle this problemin a variety of settings and contexts. However, relatively few methods are available to handlemisclassified categorical exposure variable(s) in the Cox proportional hazards regression model. Inthis paper, we aim to review and compare different methods to handle this problem - naivemethods, regression calibration, pooled estimation, multiple imputation, corrected score estimation,and MC-SIMEX - by simulation. These methods are also applied to a life course study with recalleddata and historical records. In practice, the issue of measurement error/misclassification should beaccounted for in design and analysis, whenever possible. Also, in the analysis, it could be moreideal to implement more than one correction method for estimation and inference, with properunderstanding of underlying assumptions. PMID- 24072989 TI - Insomnia with Short Sleep Duration: Nosological, Diagnostic, and Treatment Implications. AB - The diagnosis of insomnia is based solely on subjective complaints. This has contributed to the low reliability and validity of the current nosology of insomnia as well as to its lack of firm association with clinically relevant outcomes such as cardiometabolic and neurocognitive morbidity. We review evidence that insomnia with objective short sleep duration is associated with physiological hyperarousal, higher risk for hypertension, diabetes, neurocognitive impairment, and mortality as well as with a persistent course. It also appears that objective short sleep duration in poor sleepers is a biological marker of genetic predisposition to chronic insomnia. In contrast, insomnia with objective normal sleep duration is associated with cognitive-emotional and cortical arousal and sleep misperception but not with signs of physiological hyperarousal or medical complications. Thus, short sleep duration in insomnia may be a reliable marker of the biological severity and medical impact of the disorder. We propose that (a) objective measures of sleep be included in the diagnosis of insomnia and its subtypes, (b) objective measures of sleep obtained in the home environment of the patient would become part of the routine assessment and diagnosis of insomnia in a clinician's office setting, and (c) insomnia with short sleep duration may respond better to biological treatments, whereas insomnia with normal sleep duration may respond primarily to psychological therapies. PMID- 24072992 TI - Arylethyne Bromoboration-Negishi Coupling Route to E- or Z-Aryl-Substituted Trisubstituted Alkenes of >=98% IsomericPurity. New Horizon in the Highly Selective Synthesis of Trisubstituted Alkenes. AB - The hitherto unprecedented palladium-catalyzed cross-coupling of (Z)-beta-bromo beta-arylethenylboranes can be made to proceed satisfactorily through (1) the use of highly catalytically active bis(tri-tert-butylphosphine)palladium or dichloro[N,N-bis-(2,6-diisopropylphenyl)imidazol-2-yl](m-chloropyridine)palladium and (2) conversion of dibromoboryl group to (pinacol)boryl group. Thus, a wide variety of carbon groups can be used to substitute bromine in >=98% stereo- and regioselectivity, while suppressing the otherwise dominant beta-debromoboration. Together with the alkylethyne-based protocols, the alkyne bromoboration-Negishi coupling tandem process has emerged as the most widely applicable and highly selective route to trisubstituted alkenes including those that are otherwise difficult to access. PMID- 24072993 TI - Highly(>=98%) Stereo- and Regioselective Trisubstituted Alkene Synthesis of Wide Applicability via 1-Halo-1-alkyne Hydroboration-Tandem Negishi-Suzuki Coupling or Organoborate Migratory Insertion Protocol. AB - (Z)-1-Halo-1-alkenylboranes (7), preparable in 82-90% yields as >=98% isomerically pure compounds via hydroboration of 1-halo-1-alkynes, have been converted to a wide range of trisubstituted alkenes via three different routes in the tail-to-head (T-to-H) direction, i.e., (i) Palladium-catalyzed Negishi-Suzuki tandem alkenylation, (ii) treatment of 7 with organolithium or Grignard reagents to generate alpha-bromo-1-alkenylboronate complexes (10) that can undergo migratory insertion of a carbon group (R2) to form (E)-alkenylboranes (11) with inversion of alkene configuration (>=98% inversion), followed by fluoride promoted Suzuki alkenylation, and (iii) Negishi coupling to generate (Z) alkenylboranes (8) in >=98% retention of configuration, followed by treatment with organolithium or Grignard reagents to produce trisubstituted alkenes with reversed stereo configurations. The synthetic utility of the present methodology has been demonstrated in the highly selective synthesis of side chain (4) of scyphostatin in 28% yield over nine steps in the longest linear sequence from allyl alcohol. Thus, this new tandem protocol has been emerged as the most widely applicable and highly selective route to trisubstituted alkenes including those that are otherwise difficult to prepare. PMID- 24072994 TI - How fatigue is experienced and handled by female outpatients with inflammatory bowel disease. AB - Background. Fatigue is a significant aspect of everyday life for patients with inflammatory bowel disease (IBD), and it influences their health-related quality of life. Little is known about fatigue from the patient's perspective. Aim. To investigate how female IBD patients experience and handle fatigue. Methods. The study included 11 female outpatients. These patients were 40-59 years old and had IBD >= one year and a significantly increased fatigue score. Patients with severe active IBD, anaemia, comorbidity, or pregnancy were excluded. The included patients agreed to participate in a semistructured interview. The interviews were analysed using Malterud's principles of systematic text condensation. Results. The patients described physical and mental symptoms of fatigue that led to social , physical-, and work-related limitations with emotional consequences. To handle fatigue, the patients used planning, priority, acceptance, exercise, and support. Two of the eleven patients used exercise on a regular basis. Surprisingly, some patients indicated that they did not need to talk with professionals about their fatigue unless a cure was available. Conclusion. Fatigue in IBD includes physical and mental symptoms that limit the patients' social-, physical-, and work-related lives. Despite this, some patients expressed that they had chosen to accept their fatigue. PMID- 24072995 TI - Robotic Intracorporeal Ileal Conduit Formation: Initial Experience from a Single UK Centre. AB - Objectives. To describe our technique of robotic intracorporeal ileal conduit formation (RICIC) during robotic-assisted radical cystectomy (RARC). To report our initial results of this new procedure. Patients and Methods. Seven male and one female patients underwent RARC with RICIC over a six-month period. Demographic, operative, and outcome data was collected prospectively. Median patient age was 75 years (range 62-78 years). Median followup was 9 months (range 7-14 months). Results. RARC with RICIC was performed successfully in all eight patients. The median total operating time was 360 minutes (range 310-440 minutes) with a median blood loss of 225 mL (range 50-1000 mL). The median length of stay was nine days (range 6-34 days). Four patients (50%) were discharged within seven days. Four patients (50%) experienced one or more complications. This included two Clavien I complications, two Clavien II complications, and two Clavien III complications. Two patients (25%) required transfusion of two units each. To date, there have been no complications associated with the ileal conduit. Conclusion. Whilst being technically challenging, this procedure is safe, feasible, and reproducible. Patients who avoid complication show potential for rapid recovery and early discharge. PMID- 24072996 TI - Association between Sleep Disruption and Levels of Lipids in Caucasians with Type 2 Diabetes. AB - Aim. To investigate the association between sleep quality and duration with lipid and glycaemic control in Caucasian subjects with type 2 diabetes. Methods. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) in 114 type 2 diabetes (T2DM) subjects. Comparisons were made between subjects with different sleep quality and sleep duration. Hierarchical multiple regression analyses were used to determine contributors to metabolic parameters. Results. Subjects with poor sleep quality (PQ; PSQI >= 6) had higher systolic blood pressure, glycated haemoglobin, urine albumin : creatinine ratio (UAC), total cholesterol (TC), and triglycerides (TG) (P < 0.05 for all) compared to those with good sleep quality (GQ; PSQI <= 5). Long sleep duration (LSD) subjects had higher TC and short sleep duration (SSD) subjects had higher TG compared to those with medium sleep duration. Sleep duration and PSQI score were independent predictors of TC and low density lipoprotein cholesterol (LDL), contributing to 14.0% and 6.1% of the total variance, respectively. Conclusions. In this Caucasian T2DM population, PQ is associated with adverse cardiovascular risk markers, and long and short sleep disruptions have an independent negative impact on lipids. Sleep assessment should be included as part of a diabetes clinic review. PMID- 24072998 TI - Endoscopic submucosal dissection for large colorectal tumor in a Japanese general hospital. AB - Background and Aims. Endoscopic submucosal dissection (ESD) is not widely used in large colorectal lesions because of technical difficulty and possible complications. We aimed to examine the efficacy and safety of ESD for large colorectal neoplasms. Patients and Methods. During the past 5 years, 608 cases of colorectal neoplasm (?20 mm) were treated by ESD. They were divided into Group A (20-49 mm, 511 cases) and Group B (?50 mm, 97 cases). Results. The average age, lesion size, and procedure time were 67.4 years, 30.0 mm, and 60.0 min in Group A, and they were 67.1 years, 64.2 mm, and 119.6 min in Group B. En bloc resection rates were 99.2% and 99.0% (P = 0.80), and complication rates were 4.1% and 9.9% (P = 0.03). Complications in Group A consisted of perforation (2.7%), bleeding (1.2%), and ischemic colitis (0.2%). Those in Group B were perforation (8.2%) and bleeding (1.0%). Two cases in Group A and none in Group B required emergency surgery for perforation. Conclusions. There was no difference in efficacy between Groups A and B. Complications were more frequent in Group B, but all perforations in Group B were successfully managed conservatively. ESD can be effective and safe for large colorectal tumors. PMID- 24072997 TI - Endocannabinoids and endovanilloids: a possible balance in the regulation of the testicular GnRH signalling. AB - Reproductive functions are regulated both at central (brain) and gonadal levels. In this respect, the endocannabinoid system (eCS) has a very influential role. Interestingly, the characterization of eCS has taken many advantages from the usage of animal models different from mammals. Therefore, this review is oriented to summarize the main pieces of evidence regarding eCS coming from the anuran amphibian Rana esculenta, with particular interest to the morphofunctional relationship between eCS and gonadotropin releasing hormone (GnRH). Furthermore, a novel role for endovanilloids in the regulation of a testicular GnRH system will be also discussed. PMID- 24072999 TI - Breaking the Code of Amyloid-beta Oligomers. AB - Departing from the original postulates that defined various neurodegenerative disorders, accumulating evidence supports a major role for soluble forms of amyloid proteins as initiator toxins in Alzheimer's disease, Parkinson's disease, frontotemporal dementias, and prion diseases. Soluble multimeric assemblies of amyloid- beta , tau, alpha -synuclein, and the prion protein are generally englobed under the term oligomers. Due to their biophysical properties, soluble amyloid oligomers can adopt multiple conformations and sizes that potentially confer differential biological activities. Therein lies the problem: with sporadic knowledge and limited tools to identify, characterize, and study amyloid oligomers, how can we solve the enigma of their respective role(s) in the pathogenesis of neurodegenerative disorders? To further our understanding of these devastating diseases, the code of the amyloid oligomers must be broken. PMID- 24073000 TI - Short Interval Infield Sarcoma Development following Resection of Glioblastoma and Adjuvant Radiotherapy and Temozolomide. AB - Background. The development of 2 unassociated brain cancers in the same patient is a rare occurrence. Secondary cancers are generally thought to develop as an oncogenic consequence of the radiation therapy delivered to treat the primary cancers, always requiring a significant time interval between radiation treatment and secondary cancer development. Case Description. We report the development of an undifferentiated myxoid sarcoma only 13 months following radiation therapy for a glioblastoma. Conclusion. This case represents the shortest time interval reported between radiation therapy and secondary brain cancer development. PMID- 24073001 TI - Nonsurgical treatment of a massive substance loss. AB - Traumatic wounds are caused by severe trauma, resulting in lesions with extensive skin and subcutaneous tissue loss and damage to tissue viability. A "difficult wound" is a solution of continuity that does not heal spontaneously within three months. The factors that determine it may be as follows: a massive loss of substance, an infection, the presence of foreign bodies, or the clinical condition of the patient. We report a case of a 25-year-old man that presents a skin lesion on the anterior region of the left arm with extensive necrosis of skin and subcutaneous plants that involve the underlying muscle planes, caused by a trauma due to a car accident. In most of the lesions of such size and position, there is always a need for surgery. But in this case, considering the young age and the regenerative capacity of the patient, a quick and targeted antibiotic therapy was chosen, combined with debridement and worked with collagenase ointment. PMID- 24073002 TI - HIV Infection and Acute Stroke: A Case Report and a Review of the Literature. AB - Background. In the United States, ischemic stroke in HIV-infected patients has increased by 60%. However, unexpected cardiovascular events in relatively young patients have been observed. Clinical Vignette. A 31-year-old male who presented with a 5-hour history of sudden onset slurred speech and left hemiplegia. He has medical history of HIV infection for 2 years taking ARTs. On exam, a significant left hemiparesis was noticed. Brain MRI showed right anterior corona radiata and basal ganglia acute infarction. Discussion. Several mechanisms have been proposed for the relationship between HIV infection and cardiovascular risk. (i) HIV associated dyslipidemia: HIV-infected patients tend to develop decrease in HDL-c and LDL-c levels. ART was associated with an increase in LDL-c but little change in HDL-c. (ii) Endothelial dysfunction: certain antiretroviral agents may independently contribute to endothelial damage. (iii) Hypertension: systolic blood pressure is higher in those using ART for greater than five years. (iv) Insulin resistance and diabetes have been noticed with ART. (v) Chronic inflammation. (vi) Hypercoagulability: decrease in proteins C and S was associated with HIV infection. Conclusion. Poorly controlled HIV infection and/or the introduction of ATR might be risk factors for cardiovascular events. More studies needed to address this medical dilemma. PMID- 24073003 TI - Late-onset ornithine carbamoyltransferase deficiency accompanying acute pancreatitis and hyperammonemia. AB - Hyperammonemia related to urea cycle disorders is a rare cause of potentially fatal encephalopathy that is encountered in intensive care units (ICUs). Left undiagnosed, this condition may manifest irreversible neuronal damage. However, timely diagnosis and treatment initiation can be facilitated simply by increased awareness of the ICU staff. Here, we describe a patient with acute severe pancreatitis who developed hyperammonemia and encephalopathy without liver disease. Urea cycle disorder was suspected and hemodialysis was initiated. Following reduction of ammonia levels, subsequent treatment included protein restriction and administration of arginine and sodium benzoate. The patient was discharged to home after 47 days with plasma ammonia within normal range and without neurological symptoms. In clinical care settings, patients with neurological symptoms unexplained by the present illness should be assessed for serum ammonia levels to disclose any urea cycle disorders to initiate timely treatment and improve outcome. PMID- 24073004 TI - Tongguan Capsule Protects against Myocardial Ischemia and Reperfusion Injury in Mice. AB - Myocardial ischemia/reperfusion (I/R) can induce lethal ventricular arrhythmia and myocardial infarction. One of the clinical strategies for managing patients with high risk of myocardial I/R is to prevent the occurrence of arrhythmias and limit the size of infarction following a coronary episode. Tongguan Capsule (TGC) is one of the popular herbal remedies in treating coronary artery disease in the clinics of Chinese medicine. However, the potential roles and mechanisms of TGC in reducing I/R injury are still unclear. The present study statistically assessed the effectiveness of TGC in reducing I/R injury by comparing the infarct size (IS), risk region (RR), and arrhythmia (in electrocardiogram) among four groups of surgically created mice models of myocardial I/R: SHAM, I/R, VER (I/R with verapamil 20 mg/kg pretreatment), and TGC (I/R with TGC 5 g/kg/d pretreatment). We found that IS was significantly smaller in the TGC and VER groups than I/R group, and the incidence of arrhythmias was reduced in the TGC group compared with I/R group, although there were no differences in RR among the four groups. We conclude that TGC is effective in reducing I/R injury in mice. These results provided an experimental basis for clinical application of TGC in reducing I/R injury. PMID- 24073005 TI - Dissection of Biological Property of Chinese Acupuncture Point Zusanli Based on Long-Term Treatment via Modulating Multiple Metabolic Pathways. AB - Acupuncture has a history of over 3000 years and is a traditional Chinese medical therapy that uses hair-thin metal needles to puncture the skin at specific points on the body to promote wellbeing, while its molecular mechanism and ideal biological pathways are still not clear. High-throughput metabolomics is the global assessment of endogenous metabolites within a biologic system and can potentially provide a more accurate snap shot of the actual physiological state. We hypothesize that acupuncture-treated human would produce unique characterization of metabolic phenotypes. In this study, UPLC/ESI-HDMS coupled with pattern recognition methods and system analysis were carried out to investigate the mechanism and metabolite biomarkers for acupuncture treatment at "Zusanli" acupoint (ST-36) as a case study. The top 5 canonical pathways including alpha-linolenic acid metabolism, d-glutamine and d-glutamate metabolism, citrate cycle, alanine, aspartate, and glutamate metabolism, and vitamin B6 metabolism pathways were acutely perturbed, and 53 differential metabolites were identified by chemical profiling and may be useful to clarify the physiological basis and mechanism of ST-36. More importantly, network construction has led to the integration of metabolites associated with the multiple perturbation pathways. Urine metabolic profiling might be a promising method to investigate the molecular mechanism of acupuncture. PMID- 24073006 TI - The Effectiveness and Mechanism of Toona sinensis Extract Inhibit Attachment of Pandemic Influenza A (H1N1) Virus. AB - TSL-1 is a fraction of the aqueous extract from the tender leaf of Toona sinensis Roem, a nutritious vegetable. The pandemic influenza A (H1N1) virus is a recently described, rapidly contagious respiratory pathogen which can cause acute respiratory distress syndrome (ARDS) and poses a major public health threat. In this study, we found that TSL-1 inhibited viral yields on MDCK plaque formation by pandemic influenza A (H1N1) virus on infected A549 cells with high selectivity index. Meanwhile, TSL-1 also suppressed viral genome loads in infected A549 cells, quantified by qRT-PCR. This study further demonstrated that TSL-1 inhibited pandemic influenza A (H1N1) virus activity through preventing attachment of A549 cells but not penetration. TSL-1 inhibited viral attachment through significant downregulation of adhesion molecules and chemokines (VCAM-1, ICAM-1, E-selectin, IL-8, and fractalkine) compared to Amantadine. Our results suggest that TSL-1 may be used as an alternative treatment and prophylaxis against pandemic influenza A (H1N1) virus. PMID- 24073007 TI - Interaction of Veratrum nigrum with Panax ginseng against Obesity: A Sang-ban Relationship. AB - Obesity has become a major health threat in developed countries. However, current medications for obesity are limited because of their adverse effects. Interest in natural products for the treatment of obesity is thus rapidly growing. Korean Medicine (KM) is characterized by the wide use of herbal formulas. However, the combination rule of herbal formulas in KM lacks experimental evidence. According to Shennong's Classic of Materia Medica, the earliest book of herbal medicine, Veratrum nigrum (VN) has antagonistic features against Panax ginseng (PG), and the PG-VN pair is strictly forbidden. In this study, we have shown the effects of PG, VN, and their combination on obesity in high-fat (HF) diet-induced obese mice and in 3T3-L1 cells. PG, VN, and PG-VN combination significantly reduced weight gain and the fat pad weight in HF diet-induced obese mice. They also significantly decreased lipid accumulation and the expressions of two major adipogenesis factors, PPAR gamma and C/EBP alpha , in 3T3-L1 cells. In addition, the PG-VN combination had synergistic effects compared with the mixture of extracts of PG and VN on inhibition of PPAR gamma and C/EBP alpha expressions at lower doses. These results indicate a new potential anti-obese pharmacotherapy and also provide scientific evidence supporting the usage of herbal combinations instead of mixtures in KM. PMID- 24073008 TI - Additive Complex Ayurvedic Treatment in Patients with Fibromyalgia Syndrome Compared to Conventional Standard Care Alone: A Nonrandomized Controlled Clinical Pilot Study (KAFA Trial). AB - Background. Fibromyalgia (FMS) is a challenging condition for health care systems worldwide. Only limited trial data is available for FMS for outcomes of complex treatment interventions of complementary and integrative (CIM) approaches. Methods. We conducted a controlled, nonrandomized feasibility study that compared outcomes in 21 patients treated with Ayurveda with those of 11 patients treated with a conventional approach at the end of a two-week inpatient hospital stay. Primary outcome was the impact of fibromyalgia on patients as assessed by the FIQ. Secondary outcomes included scores of pain intensity, pain perception, depression, anxiety, and quality of sleep. Follow-up assessments were done after 6 months. Results. At 2 weeks, there were comparable and significant improvements in the FIQ and for most of secondary outcomes in both groups with no significant in-between-group differences. The beneficial effects for both treatment groups were partly maintained for the main outcome and a number of secondary outcomes at the 6-month followup, again with no significant in-between-group differences. Discussion. The findings of this feasibility study suggest that Ayurvedic therapy is noninferior to conventional treatment in patients with severe FMS. Since Ayurveda was only used as add-on treatment, RCTs on Ayurveda alone are warranted to increase model validity. This trial is registered with NCT01389336. PMID- 24073011 TI - Antihyperglycemic effects of short term resveratrol supplementation in type 2 diabetic patients. AB - The objective of this study was to examine the effectiveness of resveratrol in lowering blood glucose in the presence of standard antidiabetic treatment in patients with type 2 diabetes, in a randomized placebo-controlled double-blinded parallel clinical trial. A total of 66 subjects with type 2 diabetes were enrolled in this study and randomly assigned to intervention group which was supplemented with resveratrol at a dose 1 g/day for 45 days and control group which received placebo tablets. Body weight, blood pressure, fasting blood glucose, haemoglobin A1c, insulin, homeostatic assessments for insulin resistance, triglycerides, total cholesterol, low density lipoprotein, high density lipoprotein, and markers of liver and kidney damage were measured at baseline and after 45 days of resveratrol or placebo supplementation. Resveratrol treatment significantly decreased systolic blood pressure, fasting blood glucose, haemoglobin A1c, insulin, and insulin resistance, while HDL was significantly increased, when compared to their baseline levels. On the other hand, the placebo group had slightly increased fasting glucose and LDL when compared to their baseline levels. Liver and kidney function markers were unchanged in the intervention group. Overall, this study showed that resveratrol supplementation exerted strong antidiabetic effects in patients with type 2 diabetes. PMID- 24073009 TI - Polycystic ovary syndrome: effect and mechanisms of acupuncture for ovulation induction. AB - Polycystic ovary syndrome (PCOS), the most common endocrine disorder among women of reproductive age, is characterized by the coexistence of hyperandrogenism, ovulatory dysfunction, and polycystic ovaries (PCO). PCOS also represents the largest part of female oligoovulatory infertility, and the management of ovulatory and menstrual dysfunction, comprises a third of the high costs of PCOS treatment. Current pharmacological and surgical treatments for reproductive symptoms are effective, however, associated with negative side effects, such as cardiovascular complications and multiple pregnancies. For menstrual irregularities and ovulation induction in women with PCOS, acupuncture has indicated beneficial effects. This review will focus on the results from randomized controlled acupuncture trials for regulation of menstrual dysfunction and for inducing ovulation in women with PCOS although there are uncontrolled trials with nonetheless interesting results. Animal experimental studies will be further discussed when they can provide a more mechanistic explanatory view. PMID- 24073010 TI - Norcantharidin, derivative of cantharidin, for cancer stem cells. AB - Cancer stem cells (CSCs) existing in human cancers have been demonstrated to be a major cause of cancer treatment resistance, invasion, metastasis, and relapse. Self-renewal pathways, Wnt/ beta -catenin, Sonic hedgehog (Shh), and the Notch signaling pathway play critical roles in developing CSCs and lead to angiogenesis, migration, invasion, and metastasis. Multidrug resistance (MDR) is an unfavorable factor causing the failure of treatments against cancer cells. The most important and thoroughly studied mechanism involved in MDR is the active efflux of chemotherapeutic agents through membrane drug transporters. There is growing evidence that Norcantharidin (NCTD), a water-soluble synthetic small molecule derivative of naturally occurring cantharidin from the medicinal insect blister beetle (Mylabris phalerata Pallas), is capable of chemoprevention and tumor inhibition. We summarize investigations into the modulation of self-renewal pathways and MDR in CSCs by NCTD. This review may aid in further investigation of using NCTD to develop more effective strategies for cancer treatment to reduce resistance and recurrence. PMID- 24073012 TI - Advances in neuroprotective ingredients of medicinal herbs by using cellular and animal models of Parkinson's disease. AB - Parkinson's disease (PD) is a multifactorial disorder, which is neuropathologically identified by age-dependent neurodegeneration of dopaminergic neurons in the substantia nigra. Development of symptomatic treatments has been partly successful for PD research, but there remain a number of inadequacies in therapeutic strategies for the disease. The pathogenesis of PD remains intricate, and the present anti-PD treatments appears to be clinically insufficient. Comprehensive research on discovery of novel drug candidates has demonstrated that natural products, such as medicinal herbs, plant extracts, and their secondary metabolites, have great potential as therapeutics with neuroprotective activity in PD. Recent preclinical studies suggest that a number of herbal medicines and their bioactive ingredients can be developed into optimum pharmaceuticals for treating PD. In many countries, traditional herbal medicines are used to prevent or treat neurodegenerative disorders, and some have been developed as nutraceuticals or functional foods. Here we focus on recent advances of the evidence-linked neuroprotective activity of bioactive ingredients of herbal origin in cellular and animal models of PD research. PMID- 24073013 TI - Comparison of cardiac amyloidosis due to wild-type and V122I transthyretin in older adults referred to an academic medical center. AB - AIMS: In the USA, transthyretin cardiac amyloidosis usually results from 'wild type' transthyretin (senile cardiac amyloidosis [SCA]) or the V122I variant. PATIENTS & METHODS: We compared presentations and outcomes among SCA and V122I patients referred to the Center for Advanced Cardiac Care at Columbia University Medical Center (NY, USA) between 2001 and 2012. RESULTS: V122I patients were younger (mean: 71 years, standard deviation [SD]: 7) than SCA patients (mean: 77, SD: 6; p = 0.0002) and 96% were black compared with 3% of SCA patients (p < 0.0001). Average ejection fraction was lower among V122I patients (mean: 25% [SD: 12] vs mean: 47% [SD: 15]; p = 0.0001), as was mean cardiac index. Median time to death or orthotopic heart transplant was 36.4 months for V122I patients and 66.5 for SCA patients (p = 0.09). CONCLUSION: In this study of patients with transthyretin cardiac amyloidosis, V122I patients presented to a tertiary academic medical center at a younger age than SCA patients but had higher levels of cardiac dysfunction, despite genetic screening availability. There was a trend toward shorter time to orthotopic heart transplant or death among V122I patients. Whether this is a result of a different biologic progression or late diagnosis requires further study. PMID- 24073015 TI - Infants and Toddlers in Foster Care. AB - Young children involved in the child welfare system are susceptible to behavioral and physiological dysregulation. These children need nurturing care to develop organized attachments to caregivers; they need synchronous care to support their physiological and behavioral regulation; and they need stable caregivers who can commit to them, supporting their sense of self and behavioral regulation. Without intervention at the level of the parent and the system, most children involved with the child welfare system are unlikely to have these needs met. We present two models of intervention designed to enhance parents' synchrony and nurturance, and highlight aspects of the system that can enhance the stability and commitment of caregivers. PMID- 24073014 TI - Nanoelectronics-biology frontier: From nanoscopic probes for action potential recording in live cells to three-dimensional cyborg tissues. AB - Semiconductor nanowires configured as the active channels of field-effect transistors (FETs) have been used as detectors for high-resolution electrical recording from single live cells, cell networks, tissues and organs. Extracellular measurements with substrate supported silicon nanowire (SiNW) FETs, which have projected active areas orders of magnitude smaller than conventional microfabricated multielectrode arrays (MEAs) and planar FETs, recorded action potential and field potential signals with high signal-to-noise ratio and temporal resolution from cultured neurons, cultured cardiomyocytes, acute brain slices and whole animal hearts. Measurements made with modulation-doped nanoscale active channel SiNW FETs demonstrate that signals recorded from cardiomyocytes are highly localized and have improved time resolution compared to larger planar detectors. In addition, several novel three-dimensional (3D) transistor probes, which were realized using advanced nanowire synthesis methods, have been implemented for intracellular recording. These novel probes include (i) flexible 3D kinked nanowire FETs, (ii) branched intracellular nanotube SiNW FETs, and (iii) active silicon nanotube FETs. Following phospholipid modification of the probes to mimic the cell membrane, the kinked nanowire, branched intracellular nanotube and active silicon nanotube FET probes recorded full-amplitude intracellular action potentials from spontaneously firing cardiomyocytes. Moreover, these probes demonstrated the capability of reversible, stable, and long-term intracellular recording, thus indicating the minimal invasiveness of the new nanoscale structures and suggesting biomimetic internalization via the phospholipid modification. Simultaneous, multi-site intracellular recording from both single cells and cell networks were also readily achieved by interfacing independently addressable nanoprobe devices with cells. Finally, electronic and biological systems have been seamlessly merged in 3D for the first time using macroporous nanoelectronic scaffolds that are analogous to synthetic tissue scaffold and the extracellular matrix in tissue. Free-standing 3D nanoelectronic scaffolds were cultured with neurons, cardiomyocytes and smooth muscle cells to yield electronically-innervated synthetic or 'cyborg' tissues. Measurements demonstrate that innervated tissues exhibit similar cell viability as with conventional tissue scaffolds, and importantly, demonstrate that the real-time response to drugs and pH changes can be mapped in 3D through the tissues. These results open up a new field of research, wherein nanoelectronics are merged with biological systems in 3D thereby providing broad opportunities, ranging from a nanoelectronic/tissue platform for real-time pharmacological screening in 3D to implantable 'cyborg' tissues enabling closed-loop monitoring and treatment of diseases. Furthermore, the capability of high density scale-up of the above extra and intracellular nanoscopic probes for action potential recording provide important tools for large-scale high spatio-temporal resolution electrical neural activity mapping in both 2D and 3D, which promises to have a profound impact on many research areas, including the mapping of activity within the brain. PMID- 24073016 TI - Health outcomes in recipients of blood transfusion - observational studies versus randomized clinical trials. PMID- 24073017 TI - Transoral robotic surgery in the management of head and neck tumours. AB - The article reviews the use of robotic technology for head and neck tumours. The authors discuss the development of transoral robotic surgery (TORS), the current status of the technology, and the set-up in the operating room. The article provides a review of the literature, highlighting the applications, advantages, functional outcomes, and disadvantages of TORS for each anatomic subsite (oropharynx, hypopharynx, larynx, parapharyngeal space, and skull base). New challenges related to reconstruction are also presented. Overall early functional and oncologic outcome data are promising; further long-term prospective trials are still needed to confirm the oncological safety of TORS. PMID- 24073018 TI - Overview of Behavioral Genetics Research for Family Researchers. AB - This article provides an overview of the methods, assumptions, and key findings of behavioral genetics methodology for family researchers with a limited background. We discuss how family researchers can utilize and contribute to the behavioral genetics field, particularly in terms of conducting research that seeks to explain shared environmental effects. This can be done, in part, by theoretically controlling for genetic confounds in research that seeks to determine cause-and-effect relationships among family variables and individual outcomes. Gene-environment correlation and interaction are especially promising areas for the family researcher to address. Given the methodological advancements in the field, we also briefly comment on new methods in molecular genetics for studying psychological mental health disorders. PMID- 24073020 TI - MICROFLUIDIC DEVICE FOR EXAMINING DIRECTIONAL SENSING IN DENDRITIC CELL CHEMOTAXIS. AB - Dendritic cell chemotaxis is an important process involved in the acquisition of adaptive immunity. Despite several studies, our understanding of this process remains limited. One of the reasons for this is the lack of experimental models that give us real-time information on dendritic cell locomotion. Here, using tools in microfluidics, we have fabricated a microdevice that allows us to monitor dendritic cell migration in a chemokine gradient in real time. We successfully observed the migration of dendritic cells derived from a myeloid leukemia cell line (MUTZ-3) in a soluble chemokine (CCL-19) gradient. Our experiments suggest the utility of microdevices in monitoring dendritic cell chemotaxis in real time and getting important information regarding migration speeds and distances previously not available from conventional chemotaxis assays. This kind of data is useful for building mechanistic mathematical models of dendritic cell chemotaxis that may give us novel insights to the process of dendritic cell chemotaxis. PMID- 24073019 TI - Mental Health Evaluations for Adolescents Prior to Bariatric Surgery: A Review of Existing Practices and a Specific Example of Assessment Procedures. AB - OBJECTIVE: Best practice guidelines for adolescents considering bariatric surgery recommend a pre-operative mental health evaluation. However, only general information about these assessments appears in the literature, which makes consistency of administration challenging. This review proposes a specific empirically-derived format for pre-surgical mental health evaluations and summarizes currently available data on the psychiatric functioning of adolescents seeking bariatric surgery. DESIGN: Studies of mental health evaluations for adults preparing for bariatric surgery are reviewed, as is the limited literature relevant to adolescent evaluations. A specific and detailed example of an evaluation (clinical interview, self-report questionnaires, cognitive assessment) used for younger patients at a major metropolitan hospital center is presented, followed by data from an initial group of adolescents completing this evaluation. SUBJECTS: 200 adolescents (n=139 female; age: 14-18 y, BMI: 35.4-83.3 kg/m2) presenting for bariatric surgery. RESULTS: A notable subset of adolescents reported current Axis I conditions (31.5%) and current mental health treatment (29.5%), but reports of current illicit drug use (1.5%) and regular alcohol use (0.5%) were relatively rare. Procedures for using the completed evaluation and post-surgery monitoring of psychosocial issues are discussed. CONCLUSIONS: Adolescents considering weight loss surgery should receive comprehensive pre surgical mental health evaluations, but additional data are needed to develop specific recommendations the use of these evaluations in post-operative care. PMID- 24073022 TI - Translational Behavioral Medicine: a pathway to better health. PMID- 24073021 TI - Conditioned Media Downregulates Nuclear Expression of Nrf2. AB - Nuclear factor erythroid 2-related factor-2 (Nrf2) is a redox-sensitive transcription factor that activates several antioxidant and cytoprotective genes in response to oxidative stress. The role of Nrf2 activators and the intracellular regulation of Nrf2 have been studied extensively. In comparison, little is known about the self-regulation of Nrf2 due to experimental techniques commonly used to synchronize cellular signaling. Here we report that endogenous Nrf2 was downregulated in the nucleus of HeLa and MDA-MB-231 cells serum starved for 24hrs. Nrf2 expression was rescued by the addition of unconditioned media irrespective of its serum content. No concomitant change was observed in the expression of the primary inhibitor of Nrf2, Kelch-like ECH-associated protein-1 (Keap1). Nrf2 was upregulated by tert-butyl hydroquinone, although there was limited increase in Nrf2 in conditioned media-treated cells as compared to unconditioned media-treated cells. Decreasing the fraction of conditioned media in culture resulted in a dose-dependent increase in Nrf2 protein level. Taken together, our data suggests the existence of a complex self-regulatory mechanism for endogenous Nrf2 signaling. PMID- 24073023 TI - News from NIH: column no. 1. PMID- 24073024 TI - News from the CDC. PMID- 24073026 TI - Consumer health informatics: improving patient engagement. PMID- 24073025 TI - CALM technology-supported intervention: synopsis of evidence for an emerging class of practice tool. PMID- 24073027 TI - Guest editors' introduction to the special section on information technology and evidence implementation. AB - Healthcare is experiencing a transformation-perhaps as significant as the publication of the first randomized controlled trial-in the ways in which basic discovery is translated into effective practice. The change is being precipitated by efforts to undergird the healthcare industry with the same transformational capacities from information technology as is afforded to other sectors in the economy. Although the transformation has been slow in materializing, change is expected to accelerate under the stimulating influence of the Health Information Technology for Economic and Clinical Health Act of 2009 and the Patient Protection and Affordable Care Act of 2010. As the changes ripple throughout the healthcare sector, two aspects of medical care in the twenty-first century are expected to rise in importance: data and behavior. Each of the articles within this inaugural issue of Translational Behavioral Medicine has been selected to illustrate treatment of these two assets in one way or another. The editors hope this first issue will serve as a vanguard illustration for how behavioral scientists can be included as integral members of the design team in creating a new platform for evidence implementation in the USA and abroad. PMID- 24073028 TI - If we only knew what we know: principles for knowledge sharing across people, practices, and platforms. AB - The improvement of health outcomes for both individual patients and entire populations requires improvement in the array of structures that support decisions and activities by healthcare practitioners. Yet, many gaps remain in how even sophisticated healthcare organizations manage knowledge. Here we describe the value of a trans-institutional network for identifying and capturing how-to knowledge that contributes to improved outcomes. Organizing and sharing on the-job experience would concentrate and organize the activities of individual practitioners and subject their rapid cycle improvement testing and refinement to a form of collective intelligence for subsequent diffusion back through the network. We use the existing Cancer Research Network as an example of how a loosely structured consortium of healthcare delivery organizations could create and grow an implementation registry to foster innovation and implementation success by communicating what works, how, and which practitioners are using each innovation. We focus on the principles and parameters that could be used as a basis for infrastructure design. As experiential knowledge from across institutions builds within such a system, the system could ultimately motivate rapid learning and adoption of best practices. Implications for research about healthcare IT, invention, and organizational learning are discussed. PMID- 24073029 TI - True translational research: bridging the three phases of translation through data and behavior. AB - Translational medicine has yet to deliver on its vast potential. Obstacles, or "blocks," to translation at three phases of research have impeded the application of research findings to clinical needs and, subsequently, the implementation of newly developed interventions in patient care. Recent federal support for comparative effectiveness research focuses attention on the clinical relevance of already-developed diagnostic and therapeutic interventions and on translating interventions found to be effective into new population-level strategies for improving health-thereby overcoming blocks at one end of the translational continuum. At the other end, while there is a preponderance of federal funding underwriting basic science research, further improvement is warranted in translating results of basic research into clinical applications and in integrating the basic sciences into the translational continuum. With its focus on the human and interactional aspects of health, medical practice, and healthcare delivery systems, behavioral medicine, itself a component of translational medicine, can inform this process. PMID- 24073030 TI - An expanded opportunity to provide tobacco cessation services in primary care. AB - The Patient Protection and Affordable Care Act, and Centers for Medicare and Medicaid Services (CMS) decision on tobacco cessation counseling support the need for expanded cessation coverage. Primary care practices receiving CMS payments will soon be mandated to offer these services. This commentary discusses the salience of tobacco cessation policy in terms of opportunities for primary care, and anticipated issues in meeting healthcare reform requirements. Comments build upon recent federal policy and suggest areas to which primary care practices will need to attend when operationalizing tobacco cessation policies. Research supports efficacious tobacco cessation interventions delivered in a primary care context. To effectively implement tobacco cessation in primary care, practices will need to address coding and payment issues, define service offerings, identify reporting requirements, align with the medical home model, and increase provider buy-in. PMID- 24073031 TI - Behavioral medicine perspectives on the design of health information technology to improve decision-making, guideline adherence, and care coordination in chronic pain management. AB - Development of clinical decision support systems (CDSs) has tended to focus on facilitating medication management. An understanding of behavioral medicine perspectives on the usefulness of a CDS for patient care can expand CDSs to improve management of chronic disease. The purpose of this study is to explore feedback from behavioral medicine providers regarding the potential for CDSs to improve decision-making, care coordination, and guideline adherence in pain management. Qualitative methods were used to analyze semi-structured interview responses from behavioral medicine stakeholders following demonstration of an existing CDS for opioid prescribing, ATHENA-OT. Participants suggested that a CDS could assist with decision-making by educating providers, providing recommendations about behavioral therapy, facilitating risk assessment, and improving referral decisions. They suggested that a CDS could improve care coordination by facilitating division of workload, improving patient education, and increasing consideration and knowledge of options in other disciplines. Clinical decision support systems are promising tools for improving behavioral medicine care for chronic pain. PMID- 24073032 TI - Supporting implementation of evidence-based behavioral interventions: the role of data liquidity in facilitating translational behavioral medicine. AB - The advancement of translational behavioral medicine will require that we discover new methods of managing large volumes of data from disparate sources such as disease surveillance systems, public health systems, and health information systems containing patient-centered data informed by behavioral and social sciences. The term "liquidity," when applied to data, refers to its availability and free flow throughout human/computer interactions. In seeking to achieve liquidity, the focus is not on creating a single, comprehensive database or set of coordinated datasets, nor is it solely on developing the electronic health record as the "one-stop shopping" source of health-related data. Rather, attention is on ensuring the availability of secure data through the various methods of collecting and storing data currently existent or under development-so that these components of the health information infrastructure together support a liquid data system. The value of accessible, interoperable, high-volume, reliable, secure, and contextually appropriate data is becoming apparent in many areas of the healthcare system, and health information liquidity is currently viewed as an important component of a patient-centered healthcare system. The translation from research interventions to behavioral and psychosocial indicators challenges the designers of healthcare systems to include this new set of data in the correct context. With the intention of advancing translational behavioral medicine at the local level, "on the ground" in the clinical office and research institution, this commentary discusses data liquidity from the patient's and clinician's perspective, requirements for a liquid healthcare data system, and the ways in which data liquidity can support translational behavioral medicine. PMID- 24073033 TI - Consumer health informatics: results of a systematic evidence review and evidence based recommendations. AB - An increasing array of technology based tools are available for patient and consumer utilization which claim to facilitate health improvement. The efficacy of these Consumer Health Informatics tools has not previously been systematically reviewed. As such a systematic evidence review of the efficacy of consumer health informatics tools was conducted. This review also sought evidence of any barriers to future widespread utilization of these tools and evidence of economic impact of these tools on health care costs. The findings of this review indicate that while more work needs to be done, the available literature does suggest a positive impact of consumer health informatics tools on select health conditions and outcomes. Many barriers remain that must be overcome prior to widespread utilization of these tools. There was insufficient data regarding economic impact of consumer health informatics tools on healthcare costs. PMID- 24073034 TI - Potential benefits of health information technology for integrating physical and behavioral health care: perinatal depression as a case-in-point. AB - Depression among pregnant and postpartum women (i.e., perinatal depression) is the number one complication of childbirth. The Allegheny County Maternal Depression Initiative aimed to bridge gaps between physical and behavioral health care and improve the capacity of local systems of care for identifying and treating women at high risk for perinatal depression. To achieve these goals, the collaborative adopted a community-based model of systems change focused on women enrolled in the local Medicaid managed care system. Although the systems change protocol included a number of strategies for enhancing communication at all levels of care, variations in health information technology (HIT) capacities and/or capabilities across initiative partners frequently prevented optimal implementation of these strategies. Here, we present an overview of the results of the initiative, share insights from the collaborative regarding how HIT could have improved those results, and offer recommendations related to ways to effectively leverage HIT to integrate physical and behavioral health care. PMID- 24073035 TI - Adapting research-tested computerized tailored interventions for broader dissemination and implementation. AB - This paper focuses on the process for adapting existing legacy computerized tailored intervention (CTI) programs and implications for future development of CTI to ensure that interventions can be disseminated and implemented in different settings. A significant amount of work is required to adapt existing CTI for new research applications and public health interventions. Most new CTI are still developed from scratch, with minimal re-use of software or message content, even when there are considerable overlaps in functionality. This is largely a function of the substantial technical, organizational, and content-based barriers to adapting and disseminating CTI. CTI developers should thus consider dissemination and re-use early in the design phase of their systems. This is not intended to be a step-by-step guide on how to adopt or disseminate research-tested CTI, but rather a discussion that highlights issues to be considered for adapting and disseminating evidence-based CTI. PMID- 24073036 TI - Developing an electronic clinical decision support system to promote guideline adherence for healthy weight management and cardiovascular risk reduction in children: a progress update. AB - Overweight and obesity are common challenges facing pediatric clinicians. Electronic health records (EHRs) can impact clinician behavior through the presentation of relevant, patient-specific information during clinical encounters, potentially improving clinician recognition and management of overweight/obesity in children. Little research has been published evaluating the impact of EHR-facilitated decision support on the treatment of obesity in children. The main objectives of our community clinician-led project are: 1) to build customized, evidence-based decision support into an EHR; 2) To evaluate the impact of decision support on the identification and treatment of overweight and obese children; and 3) to improve behavior around screening for obesity-related comorbidities. Through a clinician-led consensus process, we customized end user templates in the commercially-available EHR at an urban community health center with a known high prevalence of childhood overweight and obesity. Evidence based decision support was build into the screens to prompt clinicians to identify and address overweight and obesity, as well as for related comorbidities. Pre/post measures will be used to evaluate the impact of these tactics on clinician behavior. The customized EHR templates took longer than anticipated to develop, but are now being used by pediatric clinicians at the health center. Feedback to date suggests that clinicians find the evidence based decision support useful at the point of care, especially around ordering recommended screening tests. Clinicians must be active participants in the design of decision support in order for it to impact their behavior. Off-the-shelf EHR products do not automatically come with comprehensive functionality to support evidence-based interventions around clinician behavior. Modifications are needed to achieve the full promise of health information technology as it relates to delivering high quality, patient-centered, for underserved populations. PMID- 24073037 TI - The public health need for patient-reported measures and health behaviors in electronic health records: a policy statement of the Society of Behavioral Medicine. PMID- 24073038 TI - Stakeholder perspectives on implementing the National Cancer Institute's patient reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). AB - The National Cancer Institute (NCI) is developing a patient-reported version of its Common Terminology Criteria for Adverse Events, called the "PRO-CTCAE." The PRO-CTCAE consists of a library of patient-reported items which can be administered in clinical trials to directly capture the patient experience of adverse events during cancer treatment, as well as a software platform for administering these items via computer or telephone. In order to better understand the impressions of stakeholders involved in cancer clinical research about the potential value of the PRO-CTCAE approach to capturing adverse event information in clinical research, as well as their perspectives about barriers and strategies for implementing the PRO-CTCAE in NCI-sponsored cancer trials, a survey was conducted. A survey including structured and open-ended questions was developed to elicit perceptions about the use of patient-reported outcomes (PROs) for adverse event reporting, and to explore logistical considerations for implementing the PRO-CTCAE in cancer trials. The survey was distributed electronically and by paper to a convenience sample of leadership and committee members in the NCI's cooperative group network, including principal investigators, clinical investigators, research nurses, data managers, patient advocates, and representatives of the NCI and Food and Drug Administration. Between October, 2008 through February, 2009, 727 surveys were collected. Most respondents (93%) agreed that patient reporting of adverse symptoms would be useful for improving understanding of the patient experience with treatment in cancer trials, and 88%, 80%, and 76%, respectively, endorsed that administration of PRO-CTCAE items in clinical trials would improve the completeness, accuracy, and efficiency of symptom data collection. More than three fourths believed that patient reports would be useful for informing treatment dose modifications and towards FDA regulatory evaluation of drugs. Eighty-eight percent felt that patients in clinical trials would be willing to self-report adverse symptoms at clinic visits via computer, and 68% felt patients would self-report weekly from home via the internet or an automated telephone system. Lack of computers and limited space and personnel were seen as potential barriers to in-clinic self reporting, but these were judged to be surmountable with adequate funding. The PRO-CTCAE items and software are viewed by a majority of survey respondents as a means to improve adverse event data quality and comprehensiveness, enhance clinical decision-making, and foster patient-clinician communication. Research is ongoing to assess the measurement properties and feasibility of implementing this measure in cancer clinical trials. PMID- 24073039 TI - Shared decision making: using health information technology to integrate patient choice into primary care. AB - Advances in shared decision making (SDM) have not successfully translated to practice. We describe our experience and lessons learned in translating an SDM process for primary care cardiovascular disease management. The SDM process operationalized recognized SDM elements using workflow modifications, a computerized patient questionnaire, an automated risk calculator to identify at risk patients, a web-based tool for patients to choose interventions, automated feedback on the personalized benefits of choices, and a web-based tool for providers to view patient risk, patient choice, and expert advice. Although medication was typically the intervention resulting in the greatest risk reduction, the majority of patients preferred dietary and other lifestyle changes. Patients generally favored the opportunity to make and communicate choices. However, providers only viewed patient choice data in 20% of the encounters. Translation of the SDM process was successful for patients and the difference between patient choice and optimal risk reduction points to the importance of engaging in an SDM process. Lack of engagement by providers may be due to "alert fatigue" or to the failure of the SDM process to improve efficiency in the office visit. PMID- 24073041 TI - News from NIH: Global Health. PMID- 24073042 TI - CDC's dissemination of evidence-based behavioral HIV prevention interventions. AB - The Division of HIV/AIDS Prevention at the National Center for HIV, Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention seeks to make evidence-based behavioral HIV prevention interventions (EBIs) accessible to HIV prevention providers through a systematic process of identification, packaging, and dissemination. This update synthesizes that process and describes recent efforts to expand the use of EBIs internationally through partnerships between the CDC's Global AIDS Program, academic research centers, and other international and US agencies. PMID- 24073040 TI - Evaluation of a self-management implementation intervention to improve hypertension control among patients in Medicaid. AB - Elevated blood pressure can lead to serious patient morbidity and mortality. The aim of the study was to evaluate the implementation of a tailored multifaceted program, administered by care managers in a Medicaid setting to improve hypertension medication adherence. The program enrolled 558 Medicaid patients. Patients had at least one phone call by care managers. The individually tailored program focused on improving lifestyle and medication adherence. The primary outcome was the medication possession ratio (MPR), calculated using fill history from pharmacy claims. We observed an improvement of medication possession from 55% 9-12 months prior to program enrollment to 77% 9-12 months post initiation of the program. We demonstrated 12 month sustainability and increased MPR. Personal interaction by phone allows the intervention to be tailored to participants' current concerns, health goals, and specific barriers to achieving these goals. PMID- 24073044 TI - Policies supporting urban physical activity promotion: lessons from Bogota, Colombia and Curitiba, Brazil. PMID- 24073043 TI - The DECISIONS study: synopsis of evidence for shared decision-making and quality patient-provider communication. AB - The second column on Evidence-Based Behavioral Medicine (EBBM) has two goals. First, we describe the importance of patient-provider communication and shared decision-making as integral components in EBBM. Second, we provide a synopsis of the DECISIONS study's findings on patient knowledge and prevalence of decision making in order to illustrate the role that patient involvement in health care decisions plays in quality health care. PMID- 24073045 TI - Sustainability of evidence-based community-based physical activity programs for older adults: lessons from Active for Life. AB - Program sustainability in community and healthcare settings is critical to realizing the translation of research into practice. The purpose of this study is to describe the implementation and assessment of an intervention to increase organizational maintenance of evidence-based physical activity programs and the factors that impede or facilitate sustainability. All organizations implemented a sustainability action plan that included identifying factors related to sustainability, examining resources available, identifying program modifications to enhance sustainability, and long-term action planning. A mixed methods approach was used. Organizational (n = 12 sites) ability to demonstrate program effectiveness, align priorities with the organizational mission, and integrate the program within the existing infrastructure were strengths related to sustainability. Sites were more optimistic about program sustainability when they had less reliance on internal financial, but more reliance on internal human resources to run the program post-funding. The study resulted in a number of tools that can help community organizations plan for sustainability of physical activity programs. PMID- 24073046 TI - Literacy and cultural adaptations for cognitive behavioral therapy in a rural pain population. AB - Low literacy and chronic pain have been identified as significant problems in the rural USA. Cognitive behavioral therapy (CBT) is a widely used efficacious psychosocial treatment for chronic pain; adaptations for low-literacy rural populations are lacking. This paper reports on preparatory steps implemented to address this deficit. Adapting an existing group, CBT patient workbook for rural adults with low literacy is described, and adaptations to reduce cognitive demand inherent in CBT are explained via cognitive load theory. Adhering to health literacy guidelines, the patient workbook readability was lowered to the fifth grade. Two key informant interviews and four focus groups provided the impetus for structural and procedural adaptations. Using health literacy guidelines and participant feedback, the patient workbook and treatment approach were adapted for implementation in low-literacy rural adult chronic pain populations, setting the stage for proceeding with a larger trial using the adapted materials. PMID- 24073047 TI - A community-based approach to translational research addressing breast cancer disparities. AB - Disparities in breast cancer survival rates suggest that biological processes contribute. Translational research addressing health disparities would benefit from using a community-based participatory approach (CBPR) to examine biological processes commonly seen as the proximal causes of illness as well as behavioral and social-ecological "causes of the causes" within an integrated conceptual framework. This paper describes a CBPR study that explored perceptions regarding breast cancer relevant behaviors, and the application of the study's results to develop translational research. Data from eight focus groups of African American (n = 29) and Caucasian women (n = 27) were analyzed, using the framework of the social-ecological model. Nutrition and physical activity were valued over screening and research participation. Treatment of illness was emphasized over prevention. Women's perspectives are presented within a framework that facilitated the collaborative development of translational research to examine associations among biological, behavioral, and societal processes contributing to disparities. PMID- 24073049 TI - Conceptual challenges in the translation of research into practice: it's not just a matter of "communication". AB - This paper identifies key barriers to the translation of science into practice and policy and makes recommendations for addressing them. It focuses on the challenges of translation within the field of tobacco control, but we argue that the insights are widely generalisable. Actor-Network Theory is used to frame an analysis, supplemented by focussed discussions with international tobacco control practitioners (service delivery and advocacy) and researchers. The central challenge to translation is that researchers and practitioners have different "practical ontologies". Researchers use findings from specific contexts to generalise to universal principles, while practitioners try to use these generalisations to inform their work in what are typically a somewhat different set of specific contexts. Neglecting the need to translate back from the general to the particular means research syntheses are not framed to meet practitioners' needs. Traditional knowledge broking roles need to be extended to better align the needs of researchers and practitioners. This may be facilitated by more creative use of "social computing" to enable real-time input into research syntheses from all interested parties, including input to the questions that research addresses. To do this systematically requires that we construct "generalisation gradients" to help practitioners apply general research conclusions to their particular situation and researchers to identify the relevance of their work. Disadvantaged communities in particular need help, since there is typically less research directly applicable to their contexts; thus, they need to generalise more. PMID- 24073048 TI - What are successful recruitment and retention strategies for underserved populations? Examining physical activity interventions in primary care and community settings. AB - The purposes of this review are to (1) describe recruitment and retention strategies for physical activity interventions focusing on underserved populations and (2) identify successful strategies which show the most promise for "best practices" recommendations to guide future research. The method used was systematic review. Data on recruitment and retention strategies were abstracted and analyzed according to participant characteristics, types of strategies used, and effectiveness using an ecological framework. Thirty-eight studies were identified. Populations included African American (n = 25), Hispanic (n = 8), or Asian (n = 3) groups. Successful recruitment strategies consisted of partnering with respected community stakeholders and organizations, well-trained study staff ethnically, linguistically, and culturally matched to the population of interest, and use of multiple advertising channels. Successful retention strategies included efficient administrative tracking of participants, persistence, skillful teamwork, and demonstrating a positive, caring attitude towards participants. Promising recruitment and retention strategies correspond to all levels of ecological influence: individual, interpersonal, organizational, and societal. PMID- 24073050 TI - The China Seven Cities Study (CSCS) consortium: adapting evidence-based prevention science from west to east. AB - Chronic, noncommunicable diseases (NCDs) have surpassed infectious diseases as the primary cause of death and disability in most developing nations. Nowhere is this more evident than in China where NCDs account for 80% of all deaths and skyrocketing medical costs. Driving the escalation of NCDs are high rates of tobacco use, longer life spans, and changes in the traditional Chinese diet and lifestyle bolstered by unprecedented economic growth and the new global culture. Despite the epidemic of NCDs, few evidence-based interventions either to prevent or retard their progression exist in China. We present a case for the development and adoption of such strategies as effective tools to combat China's greatest health threat. Finally, we offer an example of a collaborative network linking Chinese public health and academic institutions with US researchers to promote the translation of western evidence-based interventions that fully incorporate local knowledge, culture, and capacity. PMID- 24073052 TI - Insights on conducting research in low-resource settings: examples from Vietnam and Uganda. AB - This commentary describes key observations and strategies, based on the author's experiences in Vietnam and Uganda, for tailoring evidence-based behavioral medicine research in low-resource settings. PMID- 24073051 TI - Promoting culturally targeted chronic disease prevention research through an adapted participatory research approach: The Qassim-Stanford Universities project. AB - The Kingdom of Saudi Arabia (KSA), similar to other countries in the Eastern Mediterranean, has been experiencing a recent rapid increase in the prevalence of chronic diseases and associated risk factors. To begin to take advantage of the chronic disease prevention and health promotion (CDPHP) knowledge available from other nations, researchers at a newly established University in the Qassim Province of the KSA have partnered with Stanford University in the United States of America. To ensure that CDPHP research and interventions are culturally relevant and appropriate, a participatory research approach has been adopted where local researchers are the target "community." Contextual challenges of conducting CDPHP research in the KSA, at the individual, social/cultural, organizational and environmental/policy levels, are identified, as well as examples of CDPHP intervention strategies that may be culturally appropriate at each level. PMID- 24073053 TI - Adaptation and implementation of an evidence-based behavioral medicine program in diverse global settings: The Williams LifeSkills experience. AB - Epidemiological research has documented the health-damaging effects of psychosocial factors like hostility, depression, anxiety, job stress, social isolation and low socioeconomic status. Several studies suggest that behavioral interventions can reduce levels of these psychosocial factors. Herein we describe the translational process whereby the Williams LifeSkills(r) (WLS((r))) program and products for reducing psychosocial risk factors have been developed and tested in clinical trials in the U.S. and Canada and then adapted for other cultures and tested in clinical trials in other countries around the world. Evidence from published controlled and observational trials of WLS((r)) products in the U.S. and elsewhere shows that persons receiving coping skills training using WLS((r)) products have consistently reported reduced levels of psychosocial risk factors. In two controlled trials, one for caregivers of a relative with Alzheimer's Disease in the U.S. and one for coronary bypass surgery patients in Singapore, WLS((r)) training also produced clinically significant blood pressure reductions. In conclusion, WLS((r)) products have been shown in controlled and observational trials to produce reduced levels of both psychosocial and cardiovascular stress indices. Ongoing research has the potential to show that WLS((r)) products can be an effective vehicle for the delivery of stress reduction and mental health services in developing countries. PMID- 24073054 TI - Community trial of insecticide-treated bed net use promotion in southern Ghana: the Net Use Intervention study. AB - Insecticide-treated nets (ITNs) reduce malaria transmission and related morbidity and child mortality; however, incorrect and inconsistent use limits their protective factors. This community trial titled the Net Use Intervention study sought to bridge the gap between ITN ownership and use in southern (coastal) Ghana and to determine the best mix of communication tools to affect behavior of ITN owners to consistent use while maintaining optimal internal and external validity. This two-group, non-randomized experiment evaluated a multichannel, multisector intervention process over the course of 8 weeks. A longitudinal cohort was scientifically sampled from six intervention and six control communities for both baseline and posttest surveys. The posttest survey showed no change in knowledge of ITNs in the intervention or control. In terms of use the previous night, there was a strong and statistically significant intervention effect (OR = 1.67; p < .05) within the intervention communities. The overall increase in ITN coverage was approximately one person per night per every two households. The promotion efforts succeeded well beyond the planners' expectations, not only promoting usage but also dramatically increasing demand for new ITNs. PMID- 24073055 TI - Translating evidence to policy: urban interventions and physical activity promotion in Bogota, Colombia and Curitiba, Brazil. AB - The growing evidence of the influence of urban environment on physical activity (PA) underscore the need for novel policy solutions to address the inequality, lack of space, and limited PA resources in rapidly growing Latin American cities. This study aims to better understand the PA policy process by conducting two case studies of Bogota's Ciclovia and Curitiba's CuritibAtiva. Literature review of peer- and non-peer-reviewed documents and semi-structured interviews with stakeholders was conducted. In the cases of Ciclovia and CuritibAtiva, most policies conducive to program development and sustainability were developed outside the health sector in sports and recreation, urban planning, environment, and transportation. Both programs were developed by governments as initiatives to overcome inequalities and provide quality of life. In both programs, multisectoral policies mainly from recreation and urban planning created a window of opportunity for the development and sustainability of the programs and environments supportive of PA. PMID- 24073056 TI - Systems thinking: a different window on the world of implementation and global exchange of behavioral medicine evidence. PMID- 24073057 TI - News from NIH: obesity and diabetes. PMID- 24073058 TI - News from CDC (summer 2011)-translating knowledge to program action for nutrition, physical activity, and obesity interventions. AB - CDC's Division of Nutrition, Physical Activity, and Obesity (DNPAO) focuses on supporting healthy eating and active living through policy and environmental changes where Americans live, work, learn, and play. Within DNPAO, the Program Development and Translation Team (PDATT)-a cross-disciplinary team of behavioral scientists, epidemiologists, nutritionists, physical activity specialists, and public health educators-works to identify, synthesize, and disseminate evidence- and practice-based interventions to state-funded programs. In addition to the translation efforts of PDATT, DNPAO provides external funding to the Center for Training and Research Translation to translate and disseminate evidence-informed interventions and train practitioners to adapt and implement obesity-prevention interventions. PMID- 24073059 TI - Translating clinical evidence to the community: a synopsis and comment on "Community wide interventions for increasing physical activity". AB - The third column on Evidence-Based Behavioral Medicine is focused on the Baker et al. Cochrane Review entitled "Community wide interventions for increasing physical activity." We provide a synopsis of the review as well as a comment on the future direction of community-wide physical activity interventions. PMID- 24073060 TI - Diabetes prevention program: a lesson in translation. PMID- 24073061 TI - Suicide risk management: development and analysis of a telephone-based approach to patient safety. AB - Research-based queries about patients' experiences often uncover suicidal thoughts. Human subjects review requires suicide risk management (SRM) protocols to protect patients, yet minimal information exists to guide researchers' protocol development and implementation efforts. The purpose of this study was to examine the development and implementation of an SRM protocol employed during telephone-based screening and data collection interviews of depressed primary care patients. We describe an SRM protocol development process and employ qualitative analysis of de-identified documentation to characterize protocol driven interactions between research clinicians and patients. Protocol development required advance planning, training, and team building. Three percent of screened patients evidenced suicidal ideation; 12% of these met protocol standards for study clinician assessment/intervention. Risk reduction activities required teamwork and extensive collaboration. Research-based SRM protocols can facilitate patient safety by (1) identifying and verifying local clinical site approaches and resources and (2) integrating these features into prevention protocols and training for research teams. PMID- 24073062 TI - Programmatic influences on outcomes of an evidence-based fall prevention program for older adults: a translational assessment. AB - Investigating the implementation and dissemination of evidence-based health promotion programs to reach large numbers of diverse older adults is needed. The purpose of this study is to examine relationships between class size and session attendance and assess differences in intervention outcomes based on these community-based fall prevention program characteristics. Pre-post data were analyzed from 2,056 falls prevention program participants. PROC MIXED for repeated measures and ordinary least squares regressions were employed. Approximately 32% of participants enrolled in recommended class sizes (eight to 12 participants) and 76.4% of enrolled seniors attended more than five of eight sessions. Enrolling in smaller class sizes was associated with higher class attendance (X (2) = 43.43, p < 0.001). Recommended class sizes and those with 13 20 participants reported significant improvements in falls efficacy and physical activity. Perfect attendance was associated with improvements in falls efficacy (t = 2.52, p < 0.05) and activity limitation (t = -2.66, p < 0.01). Findings can inform fall prevention program developers and lay leader deliverers about ideal class sizes relative to maximum intervention benefits and cost efficiency. PMID- 24073063 TI - Proactive recruitment predicts participant retention to end of treatment in a secondhand smoke reduction trial with low-income maternal smokers. AB - Improving smoking intervention trial retention in underserved populations remains a public health priority. Low retention rates undermine clinical advancements that could reduce health disparities. To examine the effects of recruitment strategies on participant retention among 279 low-income, maternal smokers who initiated treatment in a 16-week behavioral counseling trial to reduce child secondhand smoke exposure (SHSe). Participants were recruited using either reactive strategies or methods that included proactive strategies. Logistic regression analysis was used to test associations among retention and recruitment method in the context of other psychosocial and sociodemographic factors known to relate to retention. Backwards stepwise procedures determined the most parsimonious solution. Ninety-four percent of participants recruited with proactive + reactive methods were retained through end of treatment compared to 74.7% of reactive-recruited participants. Retention likelihood was five times greater if participants were recruited with proactive + reactive strategies rather than reactive recruitment alone (odds ration [OR] = 5.36; confidence interval [CI], 2.31-12.45). Greater knowledge of SHS consequences (OR = 1.58; CI, 1.07-2.34) was another significant factor retained in the final LR model. Proactive recruitment may improve retention among underserved smokers in behavioral intervention trials. Identifying factors influencing retention may improve the success of recruitment strategies in future trials, in turn, enhancing the impact of smoking interventions. PMID- 24073066 TI - Translation of the diabetes prevention program into a community mental health organization for individuals with severe mental illness: a case study. AB - Individuals with severe mental illness (SMI) have significant health disparities. Wellness services embedded in community mental health organizations could lessen these disparities. This case study illustrates the integration of the Diabetes Prevention Program (DPP) lifestyle intervention into a community mental health organization. The Diffusion of Innovations Theory was used as a model for integration, which included a collaboration between researchers and the organization and qualitative work, culminating in a small pilot of the DPP led by peer specialists to test the feasibility of the DPP in this setting. Fourteen individuals with SMI participated in the 19-week intervention. Three dropped out, but the remaining 11 demonstrated 92% attendance. Weight loss was minimal, but the participants reported benefit and showed continued interest in the intervention. The use of a peer-led DPP in a community mental health organization is feasible and warrants further investigation to demonstrate efficacy. PMID- 24073065 TI - The current state of lifestyle intervention implementation research: where do we go next? PMID- 24073067 TI - A systematic review of the translational research on the Diabetes Prevention Program. AB - International clinical trials have demonstrated compelling evidence on the prevention or delay of type 2 diabetes (T2D) by lifestyle change programs. Numerous studies have translated the Diabetes Prevention Program (DPP) protocol to "real-world" settings. The purpose of this paper is to review the translational research of the DPP protocol in adults at-risk for T2D. This study is a systematic review based on the guidelines from the Cochrane Handbook for Systematic Reviews. There were 16 studies that translated the DPP protocol in four distinct settings: (a) hospital outpatient, (b) primary care, (c) community, and (d) work and church. Settings varied considerably in terms of reach, efficacy, adoption, implementation, and maintenance. There were strengths and limitations to each setting. Better understanding of program adaptation and mediators and moderators to program efficacy are indicated. Future research also needs to continue to explore mechanisms to improve access and long-term outcomes. PMID- 24073068 TI - The Society of Behavioral Medicine (SBM) and public policy advocacy: a call to action. AB - In 2010, the Society of Behavioral Medicine heightened its priority to take an even more active role in influencing health-related public policy. Here we discuss the importance of behavioral medicine presence in public policy initiatives, review a brief history of SBM's involvement in public policy, describe steps SBM is now taking to increase its involvement in health-related public policy, and finally, put forth a call to action for SBM members to increase their awareness of and become involved in public policy initiatives. PMID- 24073070 TI - News from NIH: using basic behavioral science to develop better behavioral interventions. PMID- 24073069 TI - Youth advocacy for obesity prevention: the next wave of social change for health. AB - Recommended obesity prevention interventions target multiple levels. Effective advocacy is needed to influence factors at individual, social, environmental, and policy levels. This paper describes the rationale for engaging youth in obesity prevention advocacy efforts targeting environment and policy changes to improve nutrition and physical activity. Advocacy involves education, skill development, and behavior and attitude changes, with the goal of persuading others or taking action. Youth advocacy has been successfully used in substance use prevention, but it is relatively new in obesity prevention. A model is presented to guide intervention and evaluation in youth advocacy for obesity prevention. With youth advocacy as a central construct, the model outlines inputs and outcomes of advocacy at individual, social environment, built environment, and policy levels. The model can be used and refined in youth advocacy evaluation projects. By involving youth in their communities, advocacy can produce ownership, engagement, and future involvement yielding sustainable changes. PMID- 24073071 TI - News from the CDC: Translating science into HCV infection screening recommendations. PMID- 24073072 TI - Quality care process in the VA: a synopsis and comment on "Comparison of the quality of medical care in veterans affairs and non-veterans affairs settings". AB - The fourth column on Evidence-Based Behavioral Medicine presents a synopsis of the systematic review by Trivedi et al. (2011) comparing the quality of medical care in veterans affairs (VA) and non-VA settings. Thirty-six studies were included in the synthesis. Each article was given a grade of A, B, or C based on the six elements of high-quality studies. Most studies assessing adherence to recommended processes of care showed that the VA performed better that non-VA sites. Similar rates were found for both groups in studies that assessed risk adjusted mortality. This implies that a greater adherence to evidence-based processes (e.g., preventive care, medication prescription, and referral) did not result in decreased morbidity and mortality. It is established that engaging in evidence-based practices and processes improves short-term intermediate endpoints (e.g., patient satisfaction). Future research is needed to test whether short term benefits of evidence-based care processes connect to mortality outcomes. PMID- 24073073 TI - National program for improvement of VA primary care: evaluating the PACT initiative in VA Ann Arbor healthcare system. PMID- 24073074 TI - Weight loss-there is an app for that! But does it adhere to evidence-informed practices? AB - Little is known about how much smartphone apps for weight control adhere to evidence-informed practices. The aim of this study was to review and summarize the content of available weight control apps. Information on content, user rating, and price was extracted from iTunes on September 25, 2009. Apps (n = 204) were coded for adherence to 13 evidence-informed practices for weight control. Latent class analysis was used to identify subgroups of apps based on endorsement practices. Only a small percentage of apps had five or more of the 13 practices (15%). Latent class analysis revealed three main types of apps: diet, physical activity, and weight journals (19%); dietary advice and journals (34%); and weight trackers (46%). User ratings were not associated with apps from these three classes. Many apps have insufficient evidence-informed content. Research is needed that seeks to develop, improve, and evaluate these apps. PMID- 24073075 TI - Translation of the diabetes prevention program lifestyle intervention for promoting postpartum weight loss among low-income women. AB - The Women Infants and Children (WIC) program is a promising venue in which to implement weight loss interventions for low-income postpartum women. The goals of this study were to describe formative steps to translate the DPP lifestyle intervention to be delivered to diverse low-income postpartum women who are served by the WIC program, and to present the results of a pilot trial of the intervention. The steps of intervention translation involved were the following: (1) building partnerships, (2) understanding the target setting, (3) understanding the target population, (4) re-designing the intervention, and (5) refining the intervention. The pilot trial was a single group pre/post test comparison among 27 overweight/obese postpartum WIC clients. The intervention resulted in an average weight loss of 4.6 lb at a 4-month follow-up (p = 0.004). A dose-response association between intervention attendance and weight loss was observed. This translation of the DPP for diverse low-income postpartum women has potential for widespread implementation. PMID- 24073076 TI - Exercise for breast cancer survivors: bridging the gap between evidence and practice. AB - Evidence supporting the benefits of exercise following the diagnosis of breast cancer is overwhelming and compelling. Exercise reduces the severity and number of treatment-related side effects, optimizes quality of life during and following treatment, and may optimize survival. Yet, exercise does not uniformly form part of the standards of care provided to women following a breast cancer diagnosis. This commentary summarizes the evidence in support of exercise as a form of adjuvant treatment and identifies and discusses potential issues preventing the formal integration of exercise into breast cancer care. Proposed within the commentary is a model of breast cancer care that incorporates exercise prescription as a key component but also integrates the need for surveillance and management for common breast cancer treatment-related morbidities, as well as education. While future research evaluating the potential cost savings through implementation of such a model is required, a committed, collaborative approach by clinicians, allied health professionals, and researchers will be instrumental in bridging the gap between research and practice. PMID- 24073077 TI - Behavioral medicine translation in the Veterans Health Administration: editorial to the special section on the Department of Veterans Affairs. PMID- 24073078 TI - Health services research is translational: lessons learned from VHA-funded research on cancer screening in older adults. PMID- 24073079 TI - RE-AIM evaluation of the Veterans Health Administration's MOVE! Weight Management Program. AB - Over one-third of patients treated in the Veterans Health Administration (VHA) are obese. VHA introduced the MOVE! Weight Management Program for Veterans in 2006 to provide comprehensive weight management services. An evolving, periodic evaluation using the RE-AIM framework (reach, effectiveness, adoption, implementation, and maintenance) has been conducted to gauge success and opportunities for improvement. Key metrics were identified in each RE-AIM dimension. Data were compiled over fiscal years (FY) 2006 through 2010 from a variety of sources including VHA administrative and clinical databases, electronic medical record reviews, and an annual, structured VHA facility self report. REACH: Screening for obesity and offering weight management treatment to eligible patients increased from 66% to 95% over the past 3 years. MOVE! is currently provided at every VHA hospital facility and at over one-half of VHA community-based outpatient clinics. The percent of eligible patients who participate in at least one weight management visit has doubled since implementation began but has stabilized at 10 to 12%. EFFECTIVENESS: About 18.6% of the 31,854 patients with available weight data who participated in at least two treatment visits between Jul 1, 2008 and Sep 30, 2009 had at least a 5% body weight loss by 6 months as did almost one-third of those who participated in more intense and sustained treatment. By contrast, only 12.5% of a comparison group of patients matched on age, gender, body mass index (BMI) class, and comorbidity status who were not treated with MOVE! had at least a 5% body weight loss. ADOPTION: The median full-time staff equivalent providing weight management services at each facility has increased over time and was 1.76 in FY 2010. IMPLEMENTATION: Staff from multiple disciplines typically provide MOVE!-related care although not all disciplines are involved with providing care at every facility. Group-based treatment has become increasingly utilized, and in FY 2010 it represented 72% of all MOVE!-related visits. Intensity of treatment has increased from an average of 3.6 visits per patient per year in FY 2007 to 4.6 in FY 2010, but more than half of patients have two visits or less. Almost all facilities now report the consistent use of key evidence-based behavioral strategies with patients. MAINTENANCE: While participation in MOVE! by patients continues to grow each year, facility self-reported program staffing and space/equipment challenges are potential barriers to long-term program maintenance. Evidence-based weight management treatment can be delivered at VHA medical centers and community-based outpatient clinics, but the REACH remains limited after several years of implementation. Intense and sustained treatment with MOVE! results in a modest positive impact on short-term weight loss outcomes, but a relatively small proportion of patients engage in this level of care. Increasing reach, improving effectiveness of care, and keeping patients engaged in treatment are areas for future policy, practice, and research. PMID- 24073080 TI - Implementation of a stroke self-management program: A randomized controlled pilot study of veterans with stroke. AB - Secondary stroke prevention is championed as guideline care; yet there are no systematic programs offered. We developed a stroke self-management program to address this gap and pilot test the program. We conducted a randomized controlled trial at two Veterans Administration (VA) hospital sites where we recruited patients with an acute stroke to receive either the stroke program or an attention-control protocol over a 12-week period following hospital discharge. The stroke program included six sessions that facilitated stroke self management focusing on increasing self-efficacy to recover from stroke and engage in secondary stroke risk factor management. We surveyed outcomes at baseline, 3 and 6 months. We conducted an intention to treat analysis comparing the intervention to the control group on changes of outcomes between baseline and follow-up modeled by a linear model with fixed effects for treatment, visit, and the treatment by visit interaction adjusting for baseline. We recruited 63 participants (33 control and 30 intervention) who were hospitalized with a primary diagnosis of ischemic stroke. We found trends in differences between groups on self-efficacy to communicate with physicians, weekly minutes spent in aerobic exercise, and on dimensions of stroke-specific quality of life. This pilot study demonstrated the feasibility of delivering a stroke self-management program to recent stroke survivors in a healthcare organization. The program also demonstrated improvements in patient self-efficacy, self-management behaviors, specific dimensions of stroke-specific quality of life compared to a group that received an attention placebo program. PMID- 24073081 TI - Implementing motivational interviewing in primary care: the role of provider characteristics. AB - Primary care is an optimal place to target modifiable health behavior problems that are linked to increased risk for mortality. The Veterans Administration (VA) has recognized the importance of coordinated, patient-centered care that increases access to health care services and has recently initiated efforts to implement Patient Aligned Care Teams within the primary care setting. To help support this initiative, administrative leaders at a large VA Health Care organization implemented a training program to teach all primary care staff motivational interviewing (MI) across its local facilities. Guided by the Consolidated Framework for Implementation Research, we examined the characteristics of providers working within this setting in an attempt to better understand the specific training needs of this group with the goal of optimizing the adoption of MI-related skills. Our findings show that providers vary on perspectives of lifestyle counseling, time commitment pressure, job-related burnout, and self-efficacy, which have important implication for the design and implementation of future trainings in MI and other evidence-based therapies. PMID- 24073082 TI - A computerized, tailored intervention to address behaviors associated with PTSD in veterans: rationale and design of STR(2)IVE. AB - Combat exposure among military personnel results in increased risk of posttraumatic stress disorder (PTSD), major depression, substance use, and related health risks. PTSD symptoms require innovative approaches to promote effective coping postdeployment. PTSD's nature and scope requires an approach capable of integrating multiple health risks while reaching large populations. This article provides the rationale and approach to adapt and evaluate a Pro Change computerized tailored intervention (CTI) targeted at behavioral sequelae (i.e., smoking, stress, and depression) for veterans with or at risk for PTSD. The three-phase approach includes: 1) focus groups to review and, subsequently, adapt content of the existing CTI programs; 2) usability testing; and 3) feasibility testing using a three-month pre-postdesign. Effective, theory-based, real-time, multiple behavior interventions targeting veterans' readiness to quit smoking, manage stress, and depression are warranted to provide potential health impact, opportunities for learning veteran-specific issues, and advance multiple health behavior change knowledge. PMID- 24073083 TI - Translating preoperative smoking cessation interventions into routine clinical care of veterans: provider beliefs. AB - Smoking among veterans undergoing surgery is estimated to be 36%. Smoking has been linked to postoperative surgical complications including ischemia and cardiac arrhythmias, pneumonia, deep venous thrombosis, pulmonary embolism, and surgical site infection. Preoperative smoking cessation interventions, in which smokers quit at least 6 weeks prior to surgery, have been shown to be effective both in smoking cessation and reduction of postoperative complications; however, little is known about physician beliefs regarding the optimal location and the responsible provider for intervention, or whether surgery should be postponed or delayed based on smoking status. Within the routine coordination from medical to surgical care, how should cessation interventions best be implemented? To better inform the translation of preoperative best practices for smoking cessation into clinical care in VA, a survey regarding preoperative smoking cessation beliefs and practices was administered to primary care physicians, surgeons, and anesthesia providers. Chi-square tests were used to examine differences in proportions by provider type. Most providers agreed that the primary care clinic is the best location for intervention, with preoperative and surgical clinics ranked by few as the optimal location (13% and 11%, respectively); most respondents (82%) reported that they would refuse or delay surgery in some cases based on smoking status. There were no differences in either beliefs on location or delay based on provider type. Primary care providers were most likely to advise (86.7%) and assess (80.0%) while anesthesia providers were least likely (59.1% and 22.7%, respectively). Taking time to counsel and the belief that dedicated resources would improve quit rates were associated with advising patients to quit smoking, while being uncomfortable with counseling, the belief that acute health takes precedence and the belief that there is not always time to counsel were identified as barriers to assessing patients for smoking cessation intervention. Primary care providers were more optimistic (100%) that patients would quit if counseled, more often (73.3%) reported having time to counsel, and were less likely to report that acute health takes precedence. Most providers believe that smoking cessation would reduce postoperative complications, with the ideal location for the intervention being the primary care clinic, and that some surgical cases should be delayed for this intervention. PMID- 24073084 TI - Enhancing entrance into PTSD treatment for post-deployment veterans through collaborative/integrative care. AB - High rates of posttraumatic stress disorder (PTSD) among post-deployment veterans and the associated long-term consequences highlight the importance of early identification and treatment. The Veterans Health Administration (VHA)'s Primary Care Mental Health Integration (PCMHI) program aims to increase identification and access to care for veterans with mental illness, decrease stigma, improve continuity of care, and the efficiency of healthcare utilization. This project examines PCMHI's progress towards these goals within the Operation Iraqi Freedom/Operation Enduring Freedom (OEF/OIF) population. We examined data from consults to the OEF/OIF PTSD clinic for 18 months. PCMHI placed 129 consults and 91 (70.5%) were completed. Veterans referred by PCMHI tended to have increased consult completion in specialty care, higher rates of confirmed PTSD, however, no significant differences in reported PTSD symptoms, or follow-up visits in the OEF/OIF PTSD clinic compared to Veterans referred from the hospital at large. PCMHI potentially preserve resources, increases continuity of care, and increases treatment access for OEF/OIF/OND veterans. PMID- 24073086 TI - The role of mental and behavioral health in the application of the patient centered medical home in the Department of Veterans Affairs. AB - The patient-centered medical home, which is termed the Patient Aligned Care Team (PACT) in the Department of Veterans Affairs (VA), is a transformational initiative with mental and behavioral health as integral components. Funding has been provided to VA medical facilities to assist with the transformation and process redesign of primary care into interdisciplinary teams focused on increased access, Veteran-centered care, and active incorporation of collaborative expertise from specialists within primary care. Primary care clinics are not simple machines that change by merely replacing parts or colocating additional resources. Rather, they are complex systems with a relationship infrastructure among members of the team that is critically important to the change process. Mental health professionals are integral, mandated members of the PACTs providing needed mental and behavioral health care to Veterans as an integrated component of primary care. They also work to catalyze a quality improvement process that encourages collaboration, innovation, and adoption of best practices that promote transformation based on patient centered principles of care. The purpose of this article is to describe the evolution of VA primary care settings toward interdisciplinary teams that provide patient-centered care in collaboration with Primary Care-Mental Health Integration providers and Health Promotion Disease Prevention team members. PMID- 24073085 TI - Improving chronic illness care for veterans within the framework of the Patient Centered Medical Home: experiences from the Ann Arbor Patient-Aligned Care Team Laboratory. AB - While key components of the Patient-Centered Medical Home (PCMH) have been described, improved patient outcomes and efficiencies have yet to be conclusively demonstrated. We describe the rationale, conceptual framework, and progress to date as part of the VA Ann Arbor Patient-Aligned Care Team (PACT) Demonstration Laboratory, a clinical care-research partnership designed to implement and evaluate PCMH programs. Evidence and experience underlying this initiative is presented. Key components of this innovation are: (a) a population-based registry; (b) a navigator system that matches veterans to programs; and (c) a menu of self-management support programs designed to improve between-visit support and leverage the assistance of patient-peers and informal caregivers. This approach integrates PCMH principles with novel implementation tools allowing patients, caregivers, and clinicians to improve disease management and self-care. Making changes within a complex organization and integrating programmatic and research goals represent unique opportunities and challenges for evidence-based healthcare improvements in the VA. PMID- 24073087 TI - MOVE! multidisciplinary programs: Challenges and resources for weight management treatment in VHA. AB - The MOVE! program has been a successful weight management and physical activity initiative from the Veteran's Health Administration. While it embraces a multicomponent approach to weight management, local facilities have primarily focused on the implementation of delivery of MOVE! educational materials to groups or individuals. We discuss additional MOVE!-related weight management efforts within VHA that reflect treatment strategies beyond delivery of these educational materials. First, we present a case study that highlights the special challenges associated with the Veteran overweight/obese population. Second, we describe the implementation of our local, multidisciplinary, individualized weight management clinic as an example of on-the-ground provision of a higher treatment intensity program as part of MOVE!'s multicomponent model. Third, we present program outcomes and consider challenges to program sustainability. PMID- 24073088 TI - Implementation of the veterans health administration national pain management strategy. AB - Since its introduction in 1998, the VHA National Pain Management Strategy has introduced and implemented a series of plans for promoting systems improvements in pain care. We present the milestones of VHA efforts in pain management as reflected by the work of the Strategy. This includes the development of the Strategy and its current structure as well as a review of important initiatives such as "pain as the fifth vital sign" and the stepped care model of pain management. PMID- 24073090 TI - News from NIH: pain management. PMID- 24073089 TI - Access to care for vulnerable veterans with hepatitis C: a hybrid conceptual framework and a case study to guide translation. AB - The Veterans Health Administration (VHA) is the largest single provider of medical care to people with hepatitis C (HCV) in the USA. Given the advent of promising new HCV therapies, the VHA is now faced with a large number of chronically HCV-infected veterans with concomitant psychiatric or substance use comorbid conditions who will need to either be retreated or newly treated for HCV or will require management for chronic liver disease. There is a critical need in the VHA for behavioral medicine and hepatology specialists, along with infectious disease and primary care providers with an interest in hepatitis C, to provide coordinated care for these complex patients. The VHA Health Services Research and Development Service has advocated for the application of strong implementation science theories and methods to translate new models of healthcare delivery in clinical practice. To inform the delivery and evaluation of integrated behavioral medicine and specialty care for vulnerable patient populations, we sought to develop an enriched framework which incorporates implementation science theory and strong conceptual models for access to care. In this paper, we present a hybrid conceptual framework that accomplishes this goal. To illustrate how this hybrid model could inform the translation of a novel method of healthcare delivery, we provide a case study of a VHA initiative to improve access to integrated behavioral medicine and specialty care among veterans with HCV. PMID- 24073091 TI - News from the CDC: Scaling up sustainable intervention delivery-lessons learned from the CDC arthritis program. AB - Expanding behavior change programs into widespread use with meaningful population impact is a public health challenge. This report described the CDC Arthritis Program's strategic approach to fostering widespread availability and sustainability of community-based self-management education and physical activity interventions, and reviews common errors observed in efforts to disseminate and implement these interventions. The Arthritis Program strategic approach focuses on embedding interventions in delivery systems to facilitate spread and sustainability. Minimizing common implementation errors, such as pay-to-play partnerships, unsustainable delivery models, non-strategic growth strategies, non selective training, imbalance between delivery and demand, infrequent interventions, and inadequate attention to data collection, can also enhance scaling up and sustaining behavior change interventions. PMID- 24073092 TI - The future of pain research, education, and treatment: a summary of the IOM report "Relieving pain in America: a blueprint for transforming prevention, care, education, and research". AB - The fifth column on Evidence-Based Behavioral Medicine is focused on the Institute of Medicine's (IOM) report entitled "Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research." The IOM has reported that chronic pain affects 116 million American adults, which is greater than the total of heart disease, cancer, and diabetes combined. It is recommended that data collection takes place at regular intervals using standardized questions, survey protocols, and electronic medical records with the aim of the identifying the following: subpopulations at risk; characteristics of acute and chronic pain; health consequences of pain, including death, disease, and disability; and longitudinal trends of pain. In addition, health education programs should be redesigned to include information about self-management, actions to prevent injuries at the individual and community level, advocacy for pain treatment, and support for improved prevention and control policies. Through teamwork between various professions, from physicians, nurses, and psychologists to physical therapists, pharmacists, and policy makers, advancements in pain awareness, education, research, and treatment should begin to materialize. PMID- 24073093 TI - Pain prevention and treatment using the Internet: possibilities and policy implications. PMID- 24073094 TI - Translational behavioral pain management: new directions and new opportunities. PMID- 24073095 TI - Is reduction in pain catastrophizing a therapeutic mechanism specific to cognitive-behavioral therapy for chronic pain? AB - Mechanisms underlying favorable outcomes of psychosocial interventions for chronic pain are unclear. Theory suggests changes in maladaptive cognitions represent therapeutic mechanisms specific to cognitive-behavioral therapy (CBT). We illustrate the importance of examining whether treatments work either uniquely via mechanisms specified by theory or via mechanisms common to different treatments. Secondary data analysis was conducted to examine the effects of reduction in pain catastrophizing on outcomes following CBT and Pain Education. Generally, reductions in pain catastrophizing were significantly related to outcome improvements irrespective of CBT or Pain Education condition. Results underscore the need to assess whether mechanisms presumed to operate specifically in one treatment do indeed predict outcomes and illustrate the importance of broadening the assessment of mechanisms beyond those specified by theory. Theory specific, competing, and common mechanisms must all be assessed to determine why our treatments work. PMID- 24073096 TI - Pain management in the context of workers compensation: a case study. AB - The clinical management of chronic pain is a biopsychosocial challenge in itself; however, when the pain occurs in the context of workers compensation, there is even greater clinical complexity. A review of the literature shows that patients being treated for chronic pain under workers compensation are generally more distressed and have poorer outcomes both clinically and vocationally than non compensated patients. A range of factors is identified to explain these differences, including operation of the system itself. However, a case study is presented involving a 49-year-old woman with chronic neck pain, whose clinical history illustrates how workers compensation can negatively influence outcomes, but where successful rehabilitation is also possible. PMID- 24073097 TI - Managing pain in high-risk patients within a patient-centered medical home. AB - Chronic pain remains a major healthcare problem despite noteworthy advancements in diagnostics, pharmacotherapy, and invasive and non-invasive interventions. The prevalence of chronic pain in the United States is staggering and continues to grow, and the personal and societal costs are not inconsequential. The etiology of pain is complex, and individuals suffering from chronic pain tend to have significant medical and psychiatric comorbidities such as depression, anxiety, and in some cases, substance use disorders. There is great concern regarding the burgeoning rate of prescription opioid misuse/abuse both for non-medical use and in pain patients receiving chronic opioid therapy. While there is ongoing debate about the "true" incidence of opioid abuse in the pain population, clearly, patients afflicted with both pain and substance use disorder are particularity challenging. The majority of patients with chronic pain including those with co occurring substance use disorders are managed in the primary care setting. Primary care practitioners have scant time, resources and training to effectively assess, treat and monitor these complicated cases. A number of evidence- and expert consensus-based treatment guidelines on opioid therapy and risk mitigation have been developed but they have been underutilized in both specialty and primary care clinics. This article will discuss the utilization of new technologies and delivery systems for risk stratification, intervention and monitoring of patients with pain receiving opioid. PMID- 24073098 TI - Measurement of adherence to clinical practice guidelines for opioid therapy for chronic pain. AB - The safe and effective prescribing of opioid therapy for chronic pain has become a significant health care priority over the last several years. Substantial research has focused on patient-oriented interventions toward preventing problematic use, but provider and system level factors may be more amenable to quality improvement approaches. Here, we outline administrative data-based metrics that are intended to assess adherence to key practices outlined in the 2010 Department of Veterans Affairs/Department of Defense Clinical Practice Guideline for management of opioid therapy for chronic pain. In addition to the metrics, we discuss their development process, which was done in consultation with experts on chronic opioid therapy. PMID- 24073099 TI - Neurophysiology of pain and hypnosis for chronic pain. AB - In the past decade there has been a dramatic increase in (1) understanding the neurophysiological components of the pain experiences, (2) randomized clinical trials testing the efficacy of hypnotic treatments on chronic pain, and (3) laboratory research examining the effects of hypnosis on the neurophysiological processes implicated in pain. Work done in these areas has not only demonstrated the efficacy of hypnosis for treating chronic pain but is beginning to shed light on neurophysiological processes that may play a role in its effectiveness. This paper reviews a selection of published studies from these areas of research, focusing on recent findings that have the most potential to inform both clinical work and research in this area. The paper concludes with research and clinical recommendations for maximizing treatment efficacy based on the research findings that are available. PMID- 24073100 TI - From the clinic to the lab (and back)-a call for laboratory research to optimize cognitive behavioural treatment of pain. AB - Cognitive behavioural therapy (CBT) is the dominant psychological treatment for chronic pain. CBT covers a mixture of aims and a broad range of techniques, including attentional control, modification of maladaptive beliefs and coping strategies and flexible goal setting and acceptance. Patients are exposed to varying selections of these strategies, and a major challenge for clinical practice is to determine what works for whom in which context. We propose that incorporating laboratory research into translational behaviour medicine is a critical developmental step that will help optimizing CBT and provide examples of representative experimental research programs. PMID- 24073102 TI - Musculoskeletal pain on the global stage: what next? AB - In this essay, we describe two recent developments in global public health efforts in the chronic pain field and use the example of musculoskeletal pain to explore some of the implications arising from these developments. The first is the recognition of chronic pain as a condition in its own right, which has been the impetus for several national and one recent international pain summits that have translated that into a call for recognition, rights and resources for people with pain. The other development is the first comprehensive attempt to measure the global burden of musculoskeletal conditions in the current round of the Global Burden of Diseases, Injuries and Risk Factors Study (GBD 2010). In essence, the task here has been to translate epidemiological data from all countries where data are available into standardised measures of the overall burden of musculoskeletal conditions to allow comparison of the burden relative to other conditions, and to identify the proportion of the burden that is attributable to a set of common risk factors. Past rounds of the GBD have been influential in priority setting and allocation of health funding by the World Health Organisation and national governments. The current GBD 2010 Study is occurring in the context of changes in thinking about how to fund health care in a global context. These changes are away from disease-specific programmes to more 'integrated' approaches, and thus represent a potential challenge to the calls to consider pain-focussed funding. We explore the strategic implications of both of these developments for translating our better understanding of the problem of musculoskeletal pain into effective policy action. PMID- 24073103 TI - News from NIH: translational research for an aging population. PMID- 24073101 TI - Interventional pain medicine: retreat from the biopsychosocial model of pain. AB - The field of pain medicine has shifted from multidisciplinary rehabilitation to procedure-focused interventional pain medicine (IPM). Considerable controversy exists regarding the efficacy of IPM and its more narrow focus on nociception as an exclusive target of pain treatment. This topical review aims to examine pain research and treatment outcome studies that support a biopsychosocial model of pain, and to critique the clinical practice of IPM given its departure from the premises of a biopsychosocial model. A modern definition of pain and findings from clinical and basic science studies indicate that pain-related psychological factors are integral to pain perception. The clinical viability of IPM is challenged based upon its biomedical view of peripheral nociception as a primary source of pain and the potential of this viewpoint to foster maladaptive pain attributions and discourage the use of pain coping strategies among chronic pain patients. IPM should adopt a biopsychosocial perspective on pain and operate within a framework of multidisciplinary pain rehabilitation to improve its effectiveness. PMID- 24073104 TI - News from the CDC: translating epilepsy self-management research to practice. PMID- 24073105 TI - Factors and predictors of cognitive impairment in the elderly: A synopsis and comment on "Systematic Review: Factors associated with risk for and possible prevention of cognitive decline in later life". AB - The sixth column on Evidence-Based Behavioral Medicine is focused on Plassman et al.'s (Ann Internal Med 153:182-193, 2010) systematic review on factors associated with risk for and prevention of cognitive decline among the elderly. A total of 250 studies were included in the final analyses. Cognitive training was most consistently and negatively associated with cognitive decline. Evidence was largely consistent across observational and randomized controlled trial (RCT) studies. Other factors, such as physical activity, some healthy nutritional patterns, and not smoking might also be protective against cognitive decline, but the available evidence is not adequate to draw conclusions about the strength of these relationships. Future research addressing these limitations should include well-designed RCTs that attempt to replicate the finding that cognitive training is protective, and well as high-quality observational and interventional studies that examine the impact of health behaviors on cognitive decline. PMID- 24073106 TI - Adapting heart disease prevention for older women with diabetes: evidence-based possibilities. PMID- 24073107 TI - A telephonic intervention for promoting occupational re-integration in work disabled individuals with musculoskeletal pain. AB - The purpose of the present research was to examine the feasibility of a telephonic occupational rehabilitation program. A sample of 23 individuals with chronic musculoskeletal pain was enrolled in the telephonic version of the Progressive Goal Attainment Program (PGAP-Tel). The PGAP-Tel is a risk-targeted intervention designed to reduce pain-related disability consequent to musculoskeletal injury. Treatment outcomes of PGAP-Tel were compared to a group of individuals with chronic musculoskeletal pain, who participated in the face-to face format of the PGAP. Results showed that PGAP-Tel was acceptable to the majority of participants (76%) to whom it was offered. There were indications that engagement and adherence issues were more problematic in PGAP-Tel than in the face-to-face intervention. Both groups showed comparable reductions in pain, depression, fear of symptom exacerbation, and self-reported disability. Participants in the face-to-face intervention showed greater reduction in catastrophic thinking than participants in PGAP-Tel. Finally, 26% of participants in PGAP-Tel had resumed some form of employment at treatment termination compared to 56% of the participants in the face-to-face intervention. Given the low cost of the PGAP-Tel intervention and the accessibility advantages of a telephonic delivery, this type of intervention might be an important resource for targeting occupational disability in rural or remote communities when face-to-face services are not available. PMID- 24073108 TI - Changing behavior throughout the life-course: Translating the success of aging research. PMID- 24073109 TI - A systematic review of single health behavior change interventions vs. multiple health behavior change interventions among older adults. AB - Multiple behavior change is widely used to reduce targeted health behaviors; however, its effect on behaviors such as physical activity, nutrition, and alcohol and tobacco use among older adults remains inconclusive. The primary purpose of this systematic review was to evaluate the effects of single health behavior change (SHBC) interventions vs. multiple health behavior change (MHBC) interventions among older age individuals. PubMed was searched for publications on health behavior interventions from 2006 to 2011. Twenty-one randomized clinical trials assessed the effects of health behavior change in older individuals. Results were reviewed by a number of health behaviors and effectiveness. Results revealed that within SHBC interventions, physical activity or exercise behavior revealed that interventions were the most common and showed the most promise in influencing positive outcomes in physical activity behavior among community-dwelling older adults. There were too few MHBC studies identified to allow confident comparison to SHBC interventions. The MHBC field is still at an early stage within the older adult literature, and more attention is recommended to investigate if the benefits of MHBC apply to this age group. PMID- 24073110 TI - Adapting and RE-AIMing a heart disease prevention program for older women with diabetes. AB - Coronary heart disease is a pervasive public health problem with a heavy burden among older women. There is a need for developing effective interventions for addressing this problem and for evaluating the dissemination potential of such interventions. A multiple-behavior-change program originally designed for men with heart disease was adapted for women at high risk of heart disease in two randomized clinical trials-the Mediterranean Lifestyle Program and !Viva Bien!. Results from these two trials, including readiness for dissemination, are evaluated using the RE-AIM framework in terms of Reach, Effectiveness, Adoption, Implementation, and Maintenance. Program adaptations produced relative high reach as well as consistent and replicated effectiveness and maintenance, and were adopted by a high percentage of primary care offices and clinicians approached. We discuss key findings, lessons learned, future directions for related research, and use of RE-AIM for program development, adaptation, scale-up, and evaluation. PMID- 24073111 TI - Personal and delivery site characteristics associated with intervention dosage in an evidence-based fall risk reduction program for older adults. AB - The objective of this study is to identify sociodemographics of older adults enrolled in a nationally disseminated evidence-based fall risk reduction program, describe different delivery sites, and examine personal and site characteristics associated with intervention adherence. Data were analyzed from 6,922 older adults enrolled in A Matter of Balance/Volunteer Lay Leader (AMOB/VLL) model between 2006 and 2009. Intervention dosage was measured by workshop attendance. Logistic regression analyses examined factors associated with attendance levels. Intervention dosage differed by sociodemographic and delivery site characteristics. Patterns of intervention dose significantly differed between Hispanic and non-Hispanic White participants. Those with less education and living in rural areas were more likely to receive adequate program doses. Although senior services agencies offered the most programs, intervention adherence was more likely in nonaging service sites. Findings may help program administrators better understand and minimize attrition issues within their AMOB/VLL workshops. PMID- 24073112 TI - Perceived versus actual factors associated with adoption and maintenance of an evidence-based physical activity program. AB - The public health burden of arthritis requires the dissemination of evidence based physical activity (PA) programs for arthritis. This study examined perceived vs. actual factors related to the adoption and maintenance of PA programs and Fit and Strong! Six focus groups (n = 46) were conducted in two states with potential Fit and Strong! providers. Key informant interviews (n = 18) were conducted with actual Fit and Strong! providers. Participant interest was a primary motivator for PA program adoption in both focus groups and key informant interviews. Fit and Strong's evidence base was a motivator for adoption among focus group participants. The primary perceived barrier to adopting Fit and Strong! among focus group participants was cost/resource limitations compared to scheduling among key informants. Evidence-based programs need to craft different messages to deal with barriers perceived and experienced by providers engaged in specific stages of the translation process. PMID- 24073113 TI - Implementing an evidence-based caregiver intervention within an integrated healthcare system. AB - The complexity of dementia care combined with the lack of care experience and external support systems creates unique burdens for the caregiver. This article describes the initial findings from the Scott & White Family Caregiver Program (FCP), the Resources for Enhancing Alzheimer's Caregiver Health (REACH II) intervention adapted for a healthcare setting. The FCP targeted one large hospital and one large ambulatory internal medicine primary care clinic within the Scott & White system. The 6-month program provided support and skills training tailored to the specific needs of caregivers based on their level of risk. At follow-up, the overall risk score, caregiver burden, and patient problem behaviors were significantly decreased and care recipient safety significantly increased. All caregivers reported that the information provided was helpful. This model successfully translated REACH II into an integrated healthcare setting and significantly reduced risks associated with dementia caregiving. PMID- 24073114 TI - Worksite wellness program implementation: a model of translational effectiveness. AB - Occupational health promotion programs with documented efficacy have not penetrated worksites. Establishing an implementation model would allow focusing on mediating aspects to enhance installation and use of evidence-based occupational wellness interventions. The purpose of the study was to implement an established wellness program in fire departments and define predictors of program exposure/dose to outcomes to define a cross-sectional model of translational effectiveness. The study is a prospective observational study among 12 NW fire departments. Data were collected before and following installation, and findings were used to conduct mediation analysis and develop a translational effectiveness model. Worker age was examined for its impact. Leadership, scheduling/competing demands, and tailoring were confirmed as model components, while organizational climate was not a factor. The established model fit data well (chi (2)(9) = 25.57, CFI = 0.99, RMSEA = 0.05, SRMR = 0.03). Older firefighters, nearing retirement, appeared to have influences that both enhanced and hindered participation. Findings can inform implementation of worksite wellness in fire departments, and the prioritized influences and translational model can be validated and manipulated in these and other settings to more efficiently move health promotion science to service. PMID- 24073115 TI - People reducing risk and improving strength through exercise, diet, and drug adherence (PRAISEDD): a case report on long-term single site adoption. AB - African-American and low-income older adults have heightened risk for cardiovascular disease (CVD). Culturally and socially congruent community-based programs can promote risk-reduction behaviors, including physical activity (PA), and can demonstrate durability. The purpose was to increase lifestyle PA and promote self-management of CVD risk factors in a sample of at-risk older adults and to sustain a PA program within low-income housing. Exercise and education sessions were conducted three times/week for 12 weeks. A community champion was trained to carry on the classes thereafter, with monthly inoculation visits by a nurse and exercise trainer. Outcome measures included attendance and CVD risk factor control. This ongoing community-based program, incorporating peer leadership, inoculation visits, and self-efficacy enhancement, has been sustained for over 3 years with classes one to two times per week and routine attendance of about 12-18 residents. PRAISEDD demonstrates that a community-based PA program can be maintained using within-community leadership, periodic involvement of health care experts, and social support and self-efficacy enhancement. PMID- 24073116 TI - The clinical practice guideline for falls and fall risk. AB - Falling is a significant cause of injury and death in frail older adults. Residents in long-term care (LTC) facilities fall for a variety of reasons and are more likely to endure injuries after a fall than those in the community The American Medical Directors Association (AMDA) Clinical Practice Guideline is written to give LTC staff an understanding of risk factors for falls and provide guidance for a systematic approach to patient assessment and selection of appropriate interventions. It is intended to help facilities establish processes for evaluating, managing, and preventing falls. AMDA guidelines are written specifically for the elder in the LTC setting. Facility teams systematically address each individual's risk factors for falls and fall risks and the adverse consequences on the patient's functioning and quality of life. AMDA guidelines emphasize key care processes and are organized for ready incorporation into facility-specific policies and procedures to guide staff and practitioner practices and performance. PMID- 24073117 TI - Beyond screening: tailoring physical activity options with the EASY tool. AB - The development and dissemination of the EASY tool provides a resource to facilitate access to information about physical activity for older adults, particularly with regard to specific physical activity recommendations for individuals with chronic medical conditions. Health care providers and older adults can use the EASY tool to provide a flexible, tailored approach to screening. This approach will better inform both older adults and their health care providers about safe physical activity programs with appropriate injury management strategies. The identification of a broad range of activities appropriate for different health circumstances and situations will enable a greater number of older adults to engage in physical activity/exercises that will improve their health and functioning. PMID- 24073118 TI - Neighborhood Eating and Activity Advocacy Teams (NEAAT): engaging older adults in policy activities to improve food and physical environments. AB - Local food and physical activity environments are known to impact health, and older adults are generally more vulnerable to health-related environmental impacts due to poorer physical function and mobility impairments. There is a need to develop cost-conscious, community-focused strategies that impact local food and physical activity environment policies. Engaging older adult community residents in assessment and advocacy activities is one avenue to address this need. We describe the Neighborhood Eating and Activity Advocacy Team project, a community-based participatory project in low-income communal housing settings in San Mateo County, CA, as one method for engaging older adults in food and physical activity environment and policy change. Methods and strategies used by the "community action teams" to generate relevant neighborhood environmental data, build coalitions, prioritize complex issues, and advocate for change are presented. Advocacy groups are feasible among older adults to improve food and physical activity environments. PMID- 24073119 TI - News from NIH: the patient-centered medical home. PMID- 24073120 TI - News from the CDC: Integrating Behavioral Health into the Patient-Centered Medical Home. PMID- 24073121 TI - Developing a patient-centered medical home: synopsis and comment on "Patient preferences for shared decisions: a systematic review". AB - The seventh column on Evidence-Based Behavioral Medicine synopsizes a systematic review by Chewning and colleagues (Pat Educ Couns 86:9-18, 2012) on patient preferences for shared decision-making regarding treatment and screening. A total of 115 studies were included in the final analyses. In 63 % of studies, a majority of patients preferred sharing decisions with their primary care physician, as opposed to delegating health decisions to their provider. A time trend appeared such that in studies published more recently, a greater percentage of patients, particularly cancer patients, preferred sharing decisions. Further research should seek to better understand how the decision making of specific patient populations is influenced by life course changes and secular trends. Longitudinal studies can help to elucidate how patient decision-making preferences evolve over the course of illness and health status changes in different medical conditions. PMID- 24073122 TI - Integrating behavioral health services within military health system: a model for opportunities and challenges. PMID- 24073123 TI - Development of StopAdvisor: A theory-based interactive internet-based smoking cessation intervention. AB - Reviews of internet-based behaviour-change interventions have shown that they can be effective but there is considerable heterogeneity and effect sizes are generally small. In order to advance science and technology in this area, it is essential to be able to build on principles and evidence of behaviour change in an incremental manner. We report the development of an interactive smoking cessation website, StopAdvisor, designed to be attractive and effective across the social spectrum. It was informed by a broad motivational theory (PRIME), empirical evidence, web-design expertise, and user-testing. The intervention was developed using an open-source web-development platform, 'LifeGuide', designed to facilitate optimisation and collaboration. We identified 19 theoretical propositions, 33 evidence- or theory-based behaviour change techniques, 26 web design principles and nine principles from user-testing. These were synthesised to create the website, 'StopAdvisor' (see http://www.lifeguideonline.org/player/play/stopadvisordemonstration). The systematic and transparent application of theory, evidence, web-design expertise and user-testing within an open-source development platform can provide a basis for multi-phase optimisation contributing to an 'incremental technology' of behaviour change. PMID- 24073124 TI - Successful dissemination of Fun 5 - a physical activity and nutrition program for children. AB - Examine the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE AIM) of an evidence-based physical activity and nutrition curriculum disseminated to after-school programs. Program components included nutrition, physical activity, and sustainability, adapted to after-school settings and disseminated across 4 years (2004-2008). The RE-AIM framework was used to evaluate dissemination quality through direct observations, surveys, and interviews. In the final year, the Fun 5 program was implemented in 90% (>22,000 students) of Hawai'i after-school sites. Despite substantial annual increases in program reach, implementation and adoption remained consistently effective, and students' physical activity levels during program activities peaked in the final year. Further, evaluations demonstrated strong long-term program sustainability potential. The Fun 5 program demonstrated promise for long-term maintenance with potential for a public health impact among Hawai'i after-school students. Future emphasis on wide-spread program dissemination is encouraged, bridging research and community efforts to improve our children's health and impact public health. PMID- 24073125 TI - Advocating widespread dissemination of physical activity programs in the afterschool setting: The need for more evidence. PMID- 24073126 TI - Authors' response. PMID- 24073127 TI - Sequential behavioral treatment of smoking and weight control in bipolar disorder. AB - People with severe mental illnesses like schizophrenia and bipolar disorder (BPAD) live significantly shorter lives than people in the general population and most commonly die of cardiovascular disease (CVD). CVD risk behaviors such as smoking are not routinely assessed or assertively treated among people with a severe mental illness. This article provides an illustrative case example of a woman with BPAD who is motivated to quit smoking, despite concerns about weight gain and relapse to depression. It outlines key considerations and describes the patient's experience of participating in a behavioral intervention focussing first on smoking, then diet and physical activity. Clinical challenges encountered during treatment are discussed in the context of relevant literature. These include motivational issues, relapse to depression, medication interactions, weight gain, addressing multiple health behavior change, focussing on a behavioral rather than cognitive approach, collaborating with other health care providers, and gender issues. PMID- 24073128 TI - Culturally tailoring patient education and communication skills training to empower African-Americans with diabetes. AB - New translational strategies are needed to improve diabetes outcomes among low income African-Americans. Our goal was to develop/pilot test a patient intervention combining culturally tailored diabetes education with shared decision-making training. This was an observational cohort study. Surveys and clinical data were collected at baseline, program completion, and 3 and 6 months. There were 21 participants; the mean age was 61 years. Eighty-six percent of participants attended >70 % of classes. There were improvements in diabetes self efficacy, self-care behaviors (i.e., following a "healthful eating plan" (mean score at baseline 3.4 vs. 5.2 at program's end; p = 0.002), self glucose monitoring (mean score at baseline 4.3 vs. 6.2 at program's end; p = 0.04), and foot care (mean score at baseline 4.1 vs. 6.0 at program's end; p = 0.001)), hemoglobin A1c (8.24 at baseline vs. 7.33 at 3-month follow-up, p = 0.02), and HDL cholesterol (51.2 at baseline vs. 61.8 at 6-month follow-up, p = 0.01). Combining tailored education with shared decision-making may be a promising strategy for empowering low-income African-Americans and improving health outcomes. PMID- 24073129 TI - SBM and SRNT urge increased funding of quitlines and research to maximize public health benefits of 1-800-QUIT-NOW on cigarette packs. PMID- 24073130 TI - The patient centered medical home: a great opportunity to move beyond brilliant and irrelevant. PMID- 24073131 TI - Linking internet-based diabetes self-management to primary care: lessons learned and implications for research translation and practice implementation. AB - There has been little discussion of or research on the key translational issue of how to integrate patient self-management programs across multiple primary care clinics within an HMO. The purpose of this study was to summarize our experiences and lessons learned in trying to integrate information from a web-based diabetes self-management program into primary care and the electronic health record (EHR). We describe plans, implementation, adaptations made, and data on patient and physician reactions to the My Path diabetes self-management program provided to 331 adult primary care patients. Mixed methods results revealed that, despite the availability of a state-of-the-art EHR, the intervention was not well integrated into primary care. Information from health-promotion and disease management programs, even within the same organization and with advanced EHR systems, is challenging to integrate into busy primary care. PMID- 24073132 TI - Collaboration between NCQA Patient-Centered Medical Homes and specialty behavioral health and medical services. AB - There is increased recognition that more mental health concerns are seen in primary care than any other healthcare setting. The Patient-Centered Medical Home (PCMH) is a significant redesign of primary care, and many of the principles of the PCMH appeal to the usage of a whole person mind-and-body treatment approach that is responsive to all the patient's needs. This study examined the level of collaboration between National Committee for Quality Assurance (NCQA)-recognized PCMH primary care practices and outpatient specialty behavioral health services (when compared to other medically oriented specialties). In 2010, a 20-item survey was sent to 238 NCQA PCMHs to learn what they were doing to address behavioral health needs in primary care. A sub-dataset from the survey was analyzed in order to look specifically at referrals, communication, and scheduling-support processes. These data were compared with how the practice responded to similar questions about endocrinology and cardiology. Results from the participating 123 practices revealed that very few practices address behavioral health conditions as they would other medical conditions. This is evidenced by the lack of routinized processes to assist with referrals, communication, and scheduling to outpatient behavioral health services. There appears to be significant opportunity to improve how behavioral health is addressed in the patient-centered medical home. PMID- 24073133 TI - Behavioral health referrals and treatment initiation rates in integrated primary care: a Collaborative Care Research Network study. AB - Although the benefits of integrating behavioral health (BH) services into primary care are well established (World Health Organization and World Organization of Family Doctors, 2012; Chiles et al. in Clin Psychol-Sci Pr 6:204-220, 1999; Cummings 1997; O'Donohue et al. 2003; Olfson et al. in Health Aff 18:79-93, 1999; Katon et al. in Ann Intern Med 124:917-925, 2001; Simon et al. in Arch Gen Psychiatry 52:850-856, 1995; Anderson et al. in Diabetes Care 24:1069-1078, 2001; Ciechanowski et al. in Arch Intern Med 160:3278-3285, 2000; Egede et al. in Diabetes Care 25:464-470, 2002), research has focused primarily on describing the types of interventions behavioral health providers (BHPs) employ rather than on reasons for referral, treatment initiation rates, or the patient characteristics that may impact them. This study presents the results of a multisite card study organized by The Collaborative Care Research Network, a subnetwork of the American Academy of Family Physicians' National Research Network devoted to conducting practice-based research focused on the provision of BH and health behavior services within primary care practices. The goals of the study included: (1) identifying the characteristics of patients referred for BH services; (2) codifying reasons for referral and whether patients were treated for the referral; (3) exploring any differences between patients who initiated BH contact and those who did not; and (4) assessing the types and frequency of BH services provided to patients who attended at least one appointment. Of the 200 patients referred to a BHP, 81 % had an initial contact, 71 % of which occurred on the same day. Men and women were equally likely to engage with a BHP although the time between appointments varied by gender. Depression and anxiety were the primary reasons for referral. Practice-based research is a viable strategy for advancing the knowledge about integrated primary care. PMID- 24073134 TI - Mental health, substance abuse, and health behavior intervention as part of the patient-centered medical home: a case study. AB - Currently integrating mental health, substance abuse, and health behavior into Patient-Centered Medical Homes (PCMH) is being advocated with increasing frequency. There are no current reports describing efforts to accomplish this. A theory-based project was developed to integrate mental health, substance abuse, and health behavior services into the fabric and culture of an NCQA-certified level-three PCMH using funding from the Vermont legislature. A mixed methods case report of data from the first 34 months reviews planning, development, implementation, care model, information technology (IT), and data collection, and reports results using the elements of a RE-AIM framework. Early accomplishment of most RE-AIM dimensions is observed. Implementation remains a struggle, specifically the questions of role responsibilities, form, and financing. This effort is a successful pilot implementation of the Primary Care Behavioral Health (PCBH) model in the PCMH with the potential for dissemination toward additional implementation and a model for a comparative effectiveness trial. PMID- 24073135 TI - Behavioral health in the Department of Defense Patient-Centered Medical Home: history, finance, policy, work force development, and evaluation. AB - Integrating behavioral health services into the patient-centered medical home (PCMH) is an important component for meeting the goals of easy access, whole person, coordinated, and integrated care. Unlike most PCMH initiatives, the Department of Defense's (DoD) Military Health System (MHS) launched its PCMH initiative with integrated behavioral health services. This integration facilitates the MHS's goal to meet its strategic imperatives under the "Quadruple Aim" of (1) maximizing readiness, (2) improving the health of the population, (3) enhancing the patient experience of care (including quality, access, and reliability), and (4) responsibly managing per capita cost of care. The MHS experience serves as a guide to other organizations. We discuss the historical underpinnings, funding, policy, and work force development strategies that contributed to integrated behavioral healthcare being a mandated component of the MHS's PCMH. PMID- 24073136 TI - Behavioral health integration: an essential element of population-based healthcare redesign. AB - The fundamental aim of healthcare reform is twofold: to provide health insurance coverage for most of the citizens currently uninsured, thereby granting them access to healthcare; and to redesign the overall healthcare system to provide better care and achieve the triple aim (better health for the population, better healthcare for individuals, and at less cost). The foundation for this improved system will rest on a redesigned (i.e., sufficiently comprehensive and integrated) system of primary care, with which all other providers, services, and sites of care are associated. The Patient-Centered Medical Home (PCMH) and its congeners are the best current examples of the kind of primary care that can achieve the triple aim, if they can become sufficiently comprehensive and can adequately integrate services. This means fully integrating behavioral healthcare into the PCMH, a difficult task under the most favorable circumstances. Creating functioning accountable care organizations is an even more daunting task: this requires new principles of collaborating and financing and the current prototypes have generally failed to incorporate behavioral healthcare sufficient to meet even the basic needs of the target population. This paper will discuss (1) the case for and the difficulties associated with integrating behavioral healthcare into primary care at three levels: the practice, the state, and the nation; and (2) how this looks clinically, operationally, and financially. PMID- 24073137 TI - News from NIH: resources for team-based research to more effectively address complex public health problems. PMID- 24073138 TI - News from the CDC: making evaluation findings actionable for suicide prevention practice. PMID- 24073139 TI - The impact of team science collaborations in health care: a synopsis and comment on "Interprofessional collaboration: effects of practice-based interventions on professional practice and healthcare outcomes". AB - The eighth column on evidence-based behavioral medicine is a synthesis of the study of Zwarenstein et al. (1). which examines the effects of practice-based interventions to improve interprofessional collaboration. Poor interprofessional collaboration may have deleterious effects on quality of care. The purpose of the systematic review was to investigate whether interventions aimed at improving interprofessional collaboration affect patient satisfaction and/or the effectiveness and efficiency of care. Five randomized controlled trials were reviewed, examining studies that differed across setting, interventions, and outcomes. Of the five studies reviewed, three showed improvements in patient care, one found no effect, and one had mixed findings. Findings indicate that interventions aimed at improving interprofessional care may improve outcomes, but interpretation of these findings is limited due to the small sample size and heterogeneity across studies reviewed. PMID- 24073140 TI - A model for transdisciplinary team-based research: implications for policy and research. PMID- 24073141 TI - The Society of Behavioral Medicine position statement on the CMS decision memo on intensive behavior therapy for obesity. AB - In 2011, the Centers for Medicare and Medicaid Services (CMS) issued a decision to cover intensive behavior therapy for obesity in the primary care setting. The Society of Behavioral Medicine (SBM) Public Policy Leadership Group reviewed the CMS decision and has issued a position statement. SBM is in support of the CMS decision to cover intensive behavior therapy for obesity but expresses significant concern that aspects of the decision will severely limit the impact of the decision. Concerns focus on the degree to which this care can be feasibly implemented in its current form given the limitations in providers who are covered and the short length of counseling visits relative to evidence-based protocols. SBM is in strong support of modifications that would include providers who have expertise in weight control (e.g., psychologists and dietitians) and to expand the treatment time to better match protocols with confirmed efficacy. PMID- 24073142 TI - Exploring dispositional tendencies to seek online information about direct-to consumer genetic testing. AB - Varying perspectives exist regarding the implications of genetic susceptibility testing for common disease, with some anticipating adverse effects and others expecting positive outcomes; however, little is known about the characteristics of people who are most likely to be interested in direct-to-consumer genetic testing. To that end, this study examines the association of individual dispositional differences with health risk perceptions and online information seeking related to a free genetic susceptibility test. Healthy adults enrolled in a large health maintenance organization were surveyed by telephone. Eligible participants (N = 1,959) were given access to a secure website that provided risk and benefit information about a genetic susceptibility test and given the option to be tested. Neuroticism was associated with increased perceptions of disease risk but not with logging on. Those scoring high in conscientiousness were more likely to log on. We found no evidence that neuroticism, a dispositional characteristic commonly linked to adverse emotional response, was predictive of online genetic information seeking in this sample of healthy adults. PMID- 24073143 TI - An emerging science and praxis for research and practice teams. PMID- 24073144 TI - A transdisciplinary approach to protocol development for tobacco control research: a case study. AB - The increasing complexity of scientific problems related to lifestyle risk factors has prompted substantial investments in transdisciplinary or team science initiatives at the biological, psychosocial, and population levels of analysis. To date, the actual process of conducting team science from the perspectives of investigators engaged in it has not been well documented. We describe the experience of developing and implementing data collection protocols using the principles of transdisciplinary science. The New England Family Study Transdisciplinary Tobacco Use Research Center was a 10-year collaboration involving more than 85 investigators and consultants from more than 20 disciplines as well as more than 50 research staff. We used a two-phase process in which all the study personnel participated in the developing and testing of 160 instruments. These instruments were used in 4,378 assessments with 3,501 participants. With substantial effort, it is possible to build a team of scientists from diverse backgrounds that can develop a set of instruments using a shared conceptual approach, despite limited or no experience working together previously. PMID- 24073145 TI - A commentary on the pluralistic goals, logics of action, and institutional contexts of translational team science. AB - Teams have emerged as a pivotal form for organizing science efforts. Team goals and issues such as goal alignment are generally considered to be essential to team success. However, given the interdisciplinary and pluralistic goals associated with translational science, team goals become a challenging area for studies that cannot be reconciled without attention to the broader institutional contexts of translational teams. In this commentary, we draw attention to how different goals in team science can be rooted in the broader institutional context and associated logics of action. For the science of team science (SciTS) to impact practice, it is imperative that we be clear about the logic of team goals and their relation to preferred patterns of organizing. We conclude with a reflection on how contextual issues should be at the foreground of SciTS along with the other important issues of team science. PMID- 24073146 TI - Influence of a National Cancer Institute transdisciplinary research and training initiative on trainees' transdisciplinary research competencies and scholarly productivity. AB - Over the past several decades, there has been burgeoning interest and investment in large transdisciplinary (TD) team science initiatives that aim to address complex societal problems. Despite this trend, TD training opportunities in the health sciences remain limited, and evaluations of these opportunities are even more uncommon due to funding constraints. We had the unique opportunity to conduct an exploratory study to examine the potential outcomes and impacts of TD training in a National Cancer Institute-supported initiative for TD research and training-the Transdisciplinary Research on Energetics and Cancer I (TREC I) initiative. This study used a retrospective mixed-methods approach leveraging secondary analysis of existing data sources to learn about TREC trainees' experiences with TREC training, TD research competencies, changes in scholarly productivity, and the associations among these domains. Results indicated that, on average, TREC trainees were satisfied with their TREC mentoring experiences and believed that TREC training processes were effective, in general. Participation in TREC training was associated with TD research competencies, including TD research orientation, positive general attitude toward TD training, development of scientific skills for TD research, and intrapersonal/interpersonal competencies for collaboration. There was also a significant increase in trainees' scholarly productivity from before to after starting in TREC training, as indicated by average annual number of publications and presentations and average number of coauthors per publication. Perceived effectiveness of TREC training was positively correlated with change in average annual number of research presentations from before to after starting in TREC training (r = 0.65, p < 0.05, N = 12), as well as TD research orientation (r = 0.36, p < 0.05), general attitude toward TD training (0.39, p < 0.05), scientific skills for TD research (r = 0.45-0.48, p < 0.05), and perceived collaborative productivity at one's TREC center (r = 0.47, p < 0.01). Finally, a significant positive correlation was observed between multi-mentoring experiences and both TD research orientation (r = 0.58, p < 0.05) and perceived collaborative productivity at one's TREC center (r = 0.44, p < 0.05). This exploratory study had methodological constraints including the absence of a comparison group and cross-sectional rather than longitudinal data related to TD research competencies. Despite these limitations, the study provided an opportunity to use existing data sources to explore potential outcomes and impacts of TD training and inform development of future rigorous evaluations of TD training. Overall, findings suggest that TD training in the context of a TD research initiative can provide satisfying training opportunities that support the development of TD research competencies and promote scholarly productivity. PMID- 24073147 TI - How to talk to strangers: facilitating knowledge sharing within translational health teams with the Toolbox dialogue method. AB - Translational behavioral medicine involves experts from different disciplines and professions interacting to solve complex problems. Coordinating this expertise can be frustrated by the partially tacit nature of expertise and by the various ways in which it manifests in different communities. We describe a method-the Toolbox dialogue method-for addressing these challenges by means of a structured dialogue among team members concerning their respective approaches to complex problems. The Toolbox dialogue method consists of a philosophically grounded questionnaire-the "Toolbox"-deployed in workshops by collaborators from different disciplines and professions. The Health Science Toolbox was modified from an extensively utilized questionnaire designed for Science-Technology-Engineering Mathematics (STEM) research and has been piloted with translational medicine teams. Eighty-five percent of participants in STEM workshops indicated a positive impact on awareness of the knowledge, opinions, or scientific approach of teammates. In the Health Science Toolbox, 35 % of questionnaire responses changed substantially from pre- to post-workshop, demonstrating impact of the workshops. The Toolbox dialogue method is a relatively brief workshop encounter that can have a positive impact on mutual understanding within translational medicine teams. PMID- 24073148 TI - Charting a course for collaboration: a multiteam perspective. AB - The translation of medical research from bench-to-bedside often requires integrated input from multiple expert teams. These collectives can best be understood through the lens of multiteam systems theory. Team charters are a practical tool thought to facilitate team performance through the creation of explicit shared norms for behavior. We extend the current literature on team charters to the multiteam context and make three practical recommendations for multiteam charter content that could facilitate effective communication and leadership processes between teams. PMID- 24073149 TI - Dear Doc: advice for collaborators. AB - Years ago, when Doc was a junior faculty member she became aware of a situation that changed her life. An extremely well-known senior scientist in her department took the data of a graduate student and published it in a very significant, oft cited paper without crediting the student in any way. That this action had the tacit approval of the department chair was confusing. Dismayed by this violation of trust and feeling powerless to intervene, she decided to become the Dear Abby of Science. Working in the lab during the day she was becoming a world-renowned researcher as well as a highly revered mentor to younger scientists. At night, disguised as Dr. Doc she began advising other researchers who were looking for help with their sticky situations. As word of mouth spread about Doc more and more researchers sought out her advice about a wide range of problems in their labs and in their collaborations. She is currently entertaining a proposal from a collaborative group of editors from high-impact journals to develop a web presence that would offer insightful advice to struggling scientific collaborators around the world. The following is a selection of letters from Doc's files focused on collaboration. The names and details in the letters have been changed to protect confidentiality. PMID- 24073150 TI - Helping fluid teams work: A research agenda for effective team adaptation in healthcare. AB - Although membership changes within teams are a common practice, research into this phenomenon is relatively nascent (Summers et al.; Acad Manag J 55:314-338, 2012). The small literature base, however, does provide insight into skills required for effective adaptation. The purpose of this effort is to provide a brief research synopsis, leading to research hypotheses about medical team training. By generalizing previous scientific findings regarding skills required for effective membership adaptation in different kinds of teams, we posit mechanisms whereby teamwork training might also support adaptation among medical teams (Burke et al.; Qual & Saf Health Care 13:i96-i104, 2004 and Salas et al.; Theor Issues Ergon Sci 8:381-394, 2007). We provide an overview of the membership change literature. Drawing upon literature from both within and outside of the medical domain, we suggest a framework and research propositions to aid in research efforts designed to determine the best content for helping to create adaptable medical teams through team training efforts. For effective adaptation, we suggest ad hoc teams should be trained on generalizable teamwork skills, to share just "enough" and the "right" information, to engage in shared leadership, and to shift from explicit to implicit coordination. Our overarching goal was to present what is known from the general research literature on successful team adaptation to membership changes, and to propose a research agenda to evaluate whether findings generalize to member changes in medical teams. PMID- 24073151 TI - Enhancing cross-system collaboration for caregivers at risk for depression. AB - In the United States, many health care systems function independently from one another. Increasing coordination across systems has the potential to vastly improve services and patient outcomes, yet implementing these changes can be challenging, requiring increased communication, interaction, and coordination across systems that typically function independently. Parental depression is one health issue that could benefit greatly from a comprehensive systems approach. The Helping Families Raise Healthy Children initiative is a cross-system quality improvement initiative aimed at improving identification and treatment of families faced with the dual challenge of caregiver depression and early childhood developmental delays. Four main techniques were used to foster and sustain cross-system collaboration and communication: cross-system trainings, regular meetings of collaborative partners, a cross-system learning collaborative for service providers, and two cross-system facilitators. The initiative achieved successful cross-system collaboration, suggesting that these methods may be used in other initiatives to foster similar types of collaboration across systems. PMID- 24073152 TI - A case study of a community-university multidisciplinary partnership approach to increasing physical activity participation among people with spinal cord injury. AB - Over the past decade, increasing emphasis has been placed on the importance of health behavior change research being conducted in partnership with the beneficiaries of the intended research outcomes. Although such an approach should enhance the relevance of the research and the uptake of findings, it raises challenges regarding how best to cultivate and sustain meaningful partnerships to accomplish these goals. In this paper, we provide a case study of SCI Action Canada-a multidisciplinary team partnership approach to increasing physical activity among adults with spinal cord injuries. The research and knowledge mobilization phases are described. In addition, preliminary indicators of partnership success and key informant interviews are presented to highlight the challenges and opportunities associated with using a community-university partnership approach to influence positive health behavior change. PMID- 24073153 TI - Confessions of a team science funder. PMID- 24073155 TI - News from NIH: effective behavioral treatments for patients with multiple chronic conditions. PMID- 24073157 TI - Preventing substance abuse and increasing energy balance in middle school students: What works? PMID- 24073156 TI - News from the CDC: collaborations to build capacity at the community level in cancer prevention and control. AB - The Cancer Prevention and Control Research Network (CPCRN) is a national network of ten academic centers funded by the Centers for Disease Control and Prevention and the National Cancer Institute, whose mission is to accelerate the adoption of evidence-based cancer prevention and control practices in communities through increased understanding of program dissemination and implementation. CPCRN researchers collaborate to raise awareness, provide education, guidance, and technical assistance to reduce cancer incidence and mortality rates in their communities. The CPCRN capacity building at the community level involves implementing evidence-based programs, policies, and strategies recommended by the Community Preventive Services Task Force to decrease obesity, increase physical activity, promote healthier behaviors, decrease tobacco use, and improve the appropriate use of cancer screening tests. These accomplishments demonstrate how the collaboration of federal, academic, and community-based organizations can be mutually beneficial by developing partnerships, research infrastructure, and community capacity that can catalyze behavior change. PMID- 24073154 TI - Translating patient self-management research into primary care: challenges and successes with group medical visits. AB - Essential to the implementation of a patient-centered medical home is use of evidence-based interventions by a well-coordinated team of providers in a cost effective manner. Group Medical Visits (GMVs), designed to increase self management behaviors in patients with chronic illness, have shown inconsistently to be efficacious. Despite the modest results reported thus far in the literature, GMVs have been promoted by the American Academy of Family Physicians as an important component in the patient-centered medical home. This paper describes the challenges of translating GMVs into clinical practice when research support is not available. A review of 5+ years experience in conducting GMVs in clinical practice, including the numerous barriers, is presented through a "three world view" model utilized by collaborative care leaders. This review is followed by a comparison of variables extracted from patients' electronic health records of those who participated in GMVs to similar patients who did not participate in GMVs. Results suggest that outcomes often reported in efficacy trials are not easily obtained in real clinical practice. Overcoming the operational and financial obstacles to offering GMVs is necessary before they can be promoted as essential elements in a patient-centered medical home. PMID- 24073158 TI - Erythema and ultraviolet indoor tanning: findings from a diary study. AB - The use of artificial ultraviolet (UV) indoor tanning (IT) beds increases the risk of skin cancer. The IT industry claims IT devices provide users with control over the amount of UV radiation exposure and thus reduces risks of sunburn (i.e., skin erythema) when tanning. This study aims to establish the prevalence and predictors of IT-related erythema using diary data. Six bimonthly diary surveys were administered to 198 female college IT users. Diaries assessed IT use and IT related erythema. Among participants who used IT, 66 % experienced at least one episode of erythema and nearly one in five IT sessions resulted in skin erythema. Those who reported the most frequent IT use prior to the study were less likely to experience an IT-related erythema on a given IT session compared to the least experienced IT users. Perceived susceptibility to burns from IT use was positively associated with risk of erythema. Erythema was a frequently reported experience among IT users. Implications for policy makers and behavioral medicine practitioners are discussed. PMID- 24073160 TI - The challenges of translating an efficacious smoking cessation program, Commit to Quit, to the community setting of YMCAs. AB - Commit to Quit (CTQ), a program that utilized vigorous intensity exercise as an adjunct to a cognitive-behavioral smoking cessation program, was shown to be effective for female smokers (Marcus et al., Prev Med 26(4):586-597, 1997; Marcus et al., Arch Intern Med 159(11):1229-1234, 1999). Adapting effective programs, such as CTQ, to community settings could lead to a large public health impact as the program could substantially increase its reach. This case study chronicles the steps taken by researchers to translate CTQ from the medical to the community setting of YMCAs (CTQY). Use of aspects of Diffusion Theory [3] such as identifying a champion of the program and attending to the characteristics of an innovation to enhance program adoption are discussed. Details regarding attending to the tensions between internal and external validity as the program was adapted to the community setting are also outlined. The challenges of conducting community trials are discussed. PMID- 24073161 TI - Advances in multiple health behavior change research. PMID- 24073164 TI - A disconnect between guidelines and practice: provider pharmacotherapy counseling for cancer survivors who smoke. PMID- 24073163 TI - Sociodemographic and social contextual predictors of multiple health behavior change: data from the Healthy Directions-Small Business study. AB - Multiple modifiable health behaviors contribute to the chronic diseases that are the leading causes of death in the USA. Disparities for meeting recommended health behavior guidelines exist across occupational classes and socioeconomic levels. The purpose of this paper was to investigate sociodemographic and social contextual predictors of multiple health behavior change in a worksite intervention. We analyzed data on four diet and exercise variables from an intervention trial with worksite-level randomization. Eight hundred forty-one employees had complete data from baseline (response rate = 84 %) and follow-up surveys (response rate = 77 %). Multilevel logistic regression estimated associations between least absolute shrinkage and selection operator-selected sociodemographic and social contextual predictor variables and the multiple health behavior change outcome (changing 2+ versus 0 behaviors). Gender, being married/partnered, and perceived discrimination were significantly associated with multiple health behavior change. Sociodemographic and social contextual factors predict multiple health behavior change and could inform the design and delivery of worksite interventions targeting multiple health behaviors. PMID- 24073159 TI - Providers' roles in enhancing patients' adherence to pain self management. AB - Practice guidelines and empirical research related to pain management encourage clinicians to take active roles in providing education about self management and promoting adoption of a self-management approach. The purpose of the study was to review the relevant literature, summarize aspects of the patient-provider interaction that influence patient engagement in self management for chronic pain, and outline practice recommendations in this area. Review of the literature on aspects of the patient-provider interaction that promote engagement in pain self-management was used. Findings are synthesized into recommendations for providers. Patients benefit from a biopsychosocial and patient-centered approach. Patients are more likely to fully disclose when providers respond empathically, which can improve conceptualization and treatment. Patient education and motivation play important roles in engaging patients in self management. Self management is influenced in part by the patient-provider communication process. Suggestions for communication strategies to facilitate patient engagement in self management techniques, including empathic discussion of barriers and motivation enhancement, are provided. PMID- 24073162 TI - Exploring opportunities for colorectal cancer screening and prevention in the context of diabetes self-management: an analysis of the 2010 National Health Interview Survey. AB - Because diabetes is associated with increased colorectal cancer (CRC) risk, it is important that people with diabetes receive CRC screenings according to guidelines. In addition, many diabetes self-care recommendations are associated with a reduced risk of CRC. This study aims to identify potential opportunities for enhancing CRC prevention within the context of diabetes management. Using data from 1,730 adults with diabetes aged 50-75 years who responded to the 2010 National Health Interview Survey, we calculated population estimates of behaviors consistent with US Preventive Services Task Force guidelines for CRC screening and American Diabetes Association recommendations for diabetes care. We examined bivariate associations between CRC screening and selected diabetes self-care behaviors associated with CRC risk. Results were stratified by demographic characteristics. Thirty-nine percent of adults with diagnosed diabetes were not up-to-date with CRC screenings. Sixteen percent smoked and 2 % exceeded alcohol intake recommendations. Among those capable of exercise, 69 and 90 % did not meet aerobic exercise and resistance training recommendations, respectively. CRC screening was generally not associated with diabetes self-care behaviors. Among some demographic groups, CRC screening was associated with adequate aerobic activity, not smoking, and being overweight or obese. Many adults with diabetes do not follow guidelines for CRC screening or recommendations for diabetes care that may also reduce CRC risk. Thus, opportunities may exist to jointly promote CRC screening and prevention and diabetes self-management among adults with diabetes. PMID- 24073165 TI - Process of diffusing cancer survivorship care into oncology practice. AB - The LIVESTRONG Centers of Excellence were funded to increase the effectiveness of survivorship care in oncology practice. This study describes the ongoing process of adopting and implementing survivorship care using the framework of the diffusion of innovation theory of change. Primary data collection included telephone interviews with 39 members from the eight centers and site visits. Organizational characteristics, overall progress, and challenges for implementation were collected from proposals and annual reports. Creating an awareness of cancer survivorship care was a major accomplishment (relative advantage). Adoption depended on the fit within the cancer center (compatibility), and changed over time based on trial and error (trialability). Implementing survivorship care within the existing culture of oncology and breaking down resistance to change was a lengthy process (complexity). Survivorship care became sustainable as it became reimbursed, and more new patients were seen (observability). Innovators and early adopters were crucial to success. Diffusion of innovation theory can provide a strategy to evaluate adoption and implementation of cancer survivorship programs into clinical practice. PMID- 24073167 TI - Evaluation of question-listing at the Cancer Support Community. AB - The Cancer Support Community (CSC) provides psychosocial support to people facing cancer in community settings. The purpose of this study was to evaluate the compatibility, effectiveness, and fidelity of the Situation-Choices-Objectives People-Evaluation-Decisions (SCOPED) question-listing intervention at three CSC sites. Between August 2008 and August 2011, the Program Director at each CSC site implemented question-listing, while measuring patient distress, anxiety, and self efficacy before and after each intervention. We analyzed the quantitative results using unadjusted statistical tests and reviewed qualitative comments by patients and the case notes of Program Directors to assess compatibility and fidelity. Program Directors implemented question-listing with 77 blood cancer patients. Patients reported decreased distress (p = 0.009) and anxiety (p = 0.005) and increased self-efficacy (p < 0.001). Patients and Program Directors endorsed the intervention as compatible with CSC's mission and approach and feasible to implement with high fidelity. CSC effectively translated SCOPED question-listing into practice in the context of its community-based psychosocial support services at three sites. PMID- 24073166 TI - Putting program evaluation to work: a framework for creating actionable knowledge for suicide prevention practice. AB - The economic and human cost of suicidal behavior to individuals, families, communities, and society makes suicide a serious public health concern, both in the US and around the world. As research and evaluation continue to identify strategies that have the potential to reduce or ultimately prevent suicidal behavior, the need for translating these findings into practice grows. The development of actionable knowledge is an emerging process for translating important research and evaluation findings into action to benefit practice settings. In an effort to apply evaluation findings to strengthen suicide prevention practice, the Centers for Disease Control and Prevention (CDC) and the Substance Abuse and Mental Health Services Administration (SAMHSA) supported the development of three actionable knowledge products that make key findings and lessons learned from youth suicide prevention program evaluations accessible and useable for action. This paper describes the actionable knowledge framework (adapted from the knowledge transfer literature), the three products that resulted, and recommendations for further research into this emerging method for translating research and evaluation findings and bridging the knowledge-action gap. PMID- 24073168 TI - Evaluating the uptake of Canada's new physical activity and sedentary behavior guidelines on service organizations' websites. AB - New evidence-based physical activity and sedentary behavior guidelines for Canadians were launched in 2011. As a consequence, service organizations that promote physical activity directly to the public needed to change their promotion materials to reflect the new guidelines. Little is known about the rate at which service organizations adopt and integrate new evidence-based guidelines and determinants of guideline adoption. In this natural observational study, we evaluated the rate of online adoption of the new guidelines among key service organizations that promote physical activity and examined participation in a booster webinar as a supplemental dissemination strategy. One hundred fifty nine service organization websites were coded by one of six raters prior to the release of the new guidelines as well as at 3, 6, and 9 months after the release. Online adoption of the guidelines increased during the coding period with 51 % of organizations posting the guidelines or related information on their websites. Organizations' engagement in a webinar was associated with their adoption of the guidelines. The release of new Canadian Physical Activity and Sedentary Behaviour Guidelines led to increased guideline adoption on service organizations' websites. However, adoption was not universal. In order for the uptake of the new guidelines to be successful, further efforts need to be taken to ensure that service organizations present physical activity guidelines on their websites. Comprehensive, active dissemination strategies tailored to address organizational barriers are needed to ensure online guideline adoption. PMID- 24073170 TI - News from the NIH: using mobile and wireless technologies to improve health. PMID- 24073169 TI - A staff training and management intervention in VA long-term care: impact on feeding assistance care quality. AB - Efforts to translate efficacious interventions into long-term care practice have had limited success due to the lack of consideration of key translational intervention components. A multi-faceted intervention was implemented in two veteran affairs facilities to improve feeding assistance care. There were three study phases: baseline, intervention, and follow-up. During each phase, trained research staff conducted standardized observations of 12 meals/participant to assess feeding assistance care quality. The staff received three initial training sessions followed by six consecutive weeks of feedback sessions wherein the observation-based care process measures were shared with the staff. There were significant, but modest, improvements in mealtime feeding assistance care processes, and most of the improvements were maintained during follow-up. A multi faceted intervention resulted in significant, but modest, improvements in mealtime feeding assistance care quality. Organizational (staff schedules, communication) and environmental (dining location) barriers were identified that interfered with improvement efforts. PMID- 24073171 TI - News from the CDC: using web-based training to translate evidence on the value of community health workers into public health action. PMID- 24073172 TI - Mobile technology: a synopsis and comment on "mobile phone-based interventions for smoking cessation". PMID- 24073173 TI - Are diabetes self-management apps based on evidence? PMID- 24073174 TI - Using findings in multimedia learning to inform technology-based behavioral health interventions. AB - Clinicians and researchers are increasingly using technology-based behavioral health interventions to improve intervention effectiveness and to reach underserved populations. However, these interventions are rarely informed by evidence-based findings of how technology can be optimized to promote acquisition of key skills and information. At the same time, experts in multimedia learning generally do not apply their findings to health education or conduct research in clinical contexts. This paper presents an overview of some key aspects of multimedia learning research that may allow those developing health interventions to apply informational technology with the same rigor as behavioral science content. We synthesized empirical multimedia learning literature from 1992 to 2011. We identified key findings and suggested a framework for integrating technology with educational and behavioral science theory. A scientific, evidence driven approach to developing technology-based interventions can yield greater effectiveness, improved fidelity, increased outcomes, and better client service. PMID- 24073175 TI - Electronic health records as a tool for recruitment of participants' clinical effectiveness research: lessons learned from tobacco cessation. AB - Translating tobacco dependence treatments that are effective in research settings into real-world clinical settings remains challenging. Electronic health record (EHR) technology can facilitate this process. This paper describes the accomplishments and lessons learned from a translational team science (clinic/research) approach to the development of an EHR tool for participant recruitment and clinic engagement in tobacco cessation research. All team stakeholders-research, clinical, and IT-were engaged in the design and planning of the project. Results over the first 17 months of the study showed that over one half of all smokers, coming in for any type of clinic appointment, were offered participation in the study, a very high level of adherent use of the EHR. Study recruitment over this period was 1,071 individuals, over 12 % of smokers in the participating clinics. PMID- 24073176 TI - Recruiting and engaging smokers in treatment in a primary care setting: developing a chronic care model implemented through a modified electronic health record. AB - Almost 35 million U.S. smokers visit primary care clinics annually, creating a need and opportunity to identify such smokers and engage them in evidence-based smoking treatment. The purpose of this study is to examine the feasibility and effectiveness of a chronic care model of treating tobacco dependence when it is integrated into primary care systems using electronic health records (EHRs). The EHR prompted primary care clinic staff to invite patients who smoked to participate in a tobacco treatment program. Patients who accepted and were eligible were offered smoking reduction or cessation treatment. More than 65 % of smokers were invited to participate, and 12.4 % of all smokers enrolled in treatment-30 % in smoking reduction and 70 % in cessation treatment. The chronic care model developed for treating tobacco dependence, integrated into the primary care system through the EHR, has the potential to engage up to 4.3 million smokers in treatment a year. PMID- 24073177 TI - Using research data to impact consumer protection legislation: lessons learned from CITY100 dissemination efforts. AB - The Correlates of Indoor Tanning in Youth (CITY100) project evaluated individual, built-environmental, and policy correlates of indoor tanning by adolescents in the 100 most populous US cities. After CITY100's completion, the research team obtained supplemental dissemination funding to strategically share data with stakeholders. The primary CITY100 dissemination message was to encourage state level banning of indoor tanning among youth. We created a user-friendly website to broadly share the most relevant CITY100 data. Journalists were a primary target audience, as were health organizations that would be well positioned to advocate for legislative change. CITY100 data were used to pass the first US state law to ban indoor tanning among those under 18 (CA, USA), as well as in other legislative advocacy activities. This paper concludes with lessons learned from CITY100 dissemination activities that we hope will encourage more health researchers to proactively address policy implications of their data and to design relevant, effective dissemination strategies. PMID- 24073178 TI - How behavioral science can advance digital health. AB - The field of behavioral science has produced myriad data on health behavior change strategies and leveraged such data into effective human-delivered interventions to improve health. Unfortunately, the impact of traditional health behavior change interventions has been heavily constrained by patient and provider burden, limited ability to measure and intervene upon behavior in real time, variable adherence, low rates of implementation, and poor third-party coverage. Digital health technologies, including mobile phones, sensors, and online social networks, by being available in real time, are being explored as tools to increase our understanding of health behavior and to enhance the impact of behavioral interventions. The recent explosion of industry attention to the development of novel health technologies is exciting but has far outpaced research. This Special Section of Translational Behavioral Medicine, Smartphones, Sensors, and Social Networks: A New Age of Health Behavior Change features a collection of studies that leverage health technologies to measure, change, and/or understand health behavior. We propose five key areas in which behavioral science can improve the impact of digital health technologies on public health. First, research is needed to identify which health technologies actually impact behavior and health outcomes. Second, we need to understand how online social networks can be leveraged to impact health behavior on a large scale. Third, a team science approach is needed in the developmental process of health technologies. Fourth, behavioral scientists should identify how a balance can be struck between the fast pace of innovation and the much slower pace of research. Fifth, behavioral scientists have an integral role in informing the development of health technologies and facilitating the movement of health technologies into the healthcare system. PMID- 24073179 TI - Adherence to evidence-based guidelines among diabetes self-management apps. AB - Smartphone apps can provide real-time, interactive self-management aid to individuals with diabetes. It is currently unclear whether existing diabetes self management apps follow evidence-based guidelines. The purpose of this study was to evaluate the extent to which existing diabetes self-management apps address the seven self-management behaviors recommended by the American Association of Diabetes Educators (the AADE7TM). The term "diabetes" identified relevant self management apps via the Apple App Store search engine in March 2012. Ratings were based on app descriptions and downloads. Chi-square analyses assessed differences in apps based on developer type. Apps promoted a median of two AADE7TM skills. Overall reliability between description and download ratings was good (kappa = .66). Reliability of individual skills was variable (kappa = .25 to .91). Most diabetes apps do not conform to evidence-based recommendations, and future app reviews would benefit from testing app performance. Future apps may also benefit from theory-based designs. PMID- 24073180 TI - Weight loss social support in 140 characters or less: use of an online social network in a remotely delivered weight loss intervention. AB - Little is known about how online social networking can help enhance weight loss. To examine the types of online social support utilized in a behavioral weight loss intervention and relationship of posting and weight loss. A sub-analysis of the content and number of posts to Twitter among participants (n = 47) randomized to a mobile, social network arm as part of a 6-month trial among overweight adults, examining weight loss, use of Twitter, and type of social support (informational, tangible assistance, esteem, network, and emotional support). A number of Twitter posts were related to % weight loss at 6 months (p < 0.001). Initial reported weight loss predicted engagement with Twitter (p < 0.01) but prior Twitter use or initial Twitter engagement did not. Most Twitter posts (total posts n = 2,630) were Informational support (n = 1,981; 75 %), with the predominant subtype of Teaching (n = 1,632; 62 %), mainly in the form of a status update (n = 1,319). Engagement with Twitter was related to weight loss and participants mainly used Twitter to provide Information support to one another through status updates. PMID- 24073181 TI - Implementation of an online pragmatic randomized controlled trial: a methodological case study. AB - Rigorous evaluation of eHealth interventions is acutely needed but can be challenging to execute in a cost- and time-efficient way. The purpose of this study is to describe a randomized controlled trial carried out as part of an approach that evaluates and informs product development throughout an intervention's life cycle. We present the methodological case of a pragmatic randomized controlled trial evaluating the effectiveness of the web-based intervention "Daily Challenge." We conducted the trial entirely online and leveraged existing resources to implement it quickly and within budget. One thousand five hundred three participants were recruited in 49 days (17.1 % of candidates assessed for eligibility). Then, 68.7 % of participants were reached for follow-up at 30 days and 62.5 % at 90 days. Data collection (baseline to 90 day follow-up) was completed within 5 months. Rigorous trials can be conducted efficiently and in a timely manner, enabling evaluation on a continuous basis. Development should include ongoing empirical input to inform product iterations. PMID- 24073182 TI - Twitter classification model: the ABC of two million fitness tweets. AB - The purpose of this project was to design and test data collection and management tools that can be used to study the use of mobile fitness applications and social networking within the context of physical activity. This project was conducted over a 6-month period and involved collecting publically shared Twitter data from five mobile fitness apps (Nike+, RunKeeper, MyFitnessPal, Endomondo, and dailymile). During that time, over 2.8 million tweets were collected, processed, and categorized using an online tweet collection application and a customized JavaScript. Using the grounded theory, a classification model was developed to categorize and understand the types of information being shared by application users. Our data show that by tracking mobile fitness app hashtags, a wealth of information can be gathered to include but not limited to daily use patterns, exercise frequency, location-based workouts, and overall workout sentiment. PMID- 24073183 TI - Actual versus perceived peer sexual risk behavior in online youth social networks. AB - Perception of peer behaviors is an important predictor of actual risk behaviors among youth. However, we lack understanding of peer influence through social media and of actual and perceived peer behavior concordance. The purpose of this research is to document the relationship between individual perception of and actual peer sexual risk behavior using online social networks. The data are a result of a secondary analysis of baseline self-reported and peer-reported sexual risk behavior from a cluster randomized trial including 1,029 persons from 162 virtual networks. Individuals (seeds) recruited up to three friends who then recruited additional friends, extending three waves from the seed. ANOVA models compared network means of actual participant behavior across categories of perceived behavior. Concordance varied between reported and perceived behavior, with higher concordance between perceived and reported condom use, multiple partners, concurrent partners, sexual pressure, and drug and alcohol use during sex. Individuals significantly over-reported risk and under-reported protective peer behaviors related to sex. PMID- 24073184 TI - Mobile apps for pediatric obesity prevention and treatment, healthy eating, and physical activity promotion: just fun and games? AB - Mobile applications (apps) offer a novel way to engage children in behavior change, but little is known about content of commercially available apps for this population. We analyzed the content of apps for iPhone/iPad for pediatric weight loss, healthy eating (HE), and physical activity (PA). Fifty-seven apps were downloaded and tested by two independent raters. Apps were coded for: inclusion of the Expert Committee for Pediatric Obesity Prevention's (ECPOP) eight recommended strategies (e.g., set goals) and seven behavioral targets (e.g., do >=1 h of PA per day), utilization of gaming elements, and general characteristics. Most apps lacked any expert recommendations (n = 35, 61.4 %). The mean number of recommendations among apps that used recommendations was 3.6 +/- 2.7 out of 15, 56.1 % (n = 32) apps were classified as games, and mean price per app was $1.05 +/- 1.66. Most apps reviewed lacked expert recommendations and could be strengthened by addition of comprehensive information about health behavior change and opportunities for goal setting. PMID- 24073185 TI - A microfluidic platform for real-time and in situ monitoring of virus infection process. AB - Microfluidic chip is a promising platform for studying virus behaviors at the cell level. However, only a few chip-based studies on virus infection have been reported. Here, a three-layer microfluidic chip with low shear stress was designed to monitor the infection process of a recombinant Pseudorabies virus (GFP-PrV) in real time and in situ, which could express green fluorescent protein during the genome replication. The infection and proliferation characteristics of GFP-PrV were measured by monitoring the fluorescence intensity of GFP and determining the one-step growth curve. It was found that the infection behaviors of GFP-PrV in the host cells could hardly be influenced by the microenvironment in the microfluidic chip. Furthermore, the results of drug inhibition assays on the microfluidic chip with a tree-like concentration gradient generator showed that one of the infection pathways of GFP-PrV in the host cells was microtubule dependent. This work established a promising microfluidic platform for the research on virus infection. PMID- 24073192 TI - The proline-rich motif of the proDer p 3 allergen propeptide is crucial for protease-protease interaction. AB - The majority of proteases are synthesized in an inactive form, termed zymogen, which consists of a propeptide and a protease domain. The propeptide is commonly involved in the correct folding and specific inhibition of the enzyme. The propeptide of the house dust mite allergen Der p 3, NPILPASPNAT, contains a proline-rich motif (PRM), which is unusual for a trypsin-like protease. By truncating the propeptide or replacing one or all of the prolines in the non glycosylated zymogen with alanine(s), we demonstrated that the full-length propeptide is not required for correct folding and thermal stability and that the PRM is important for the resistance of proDer p 3 to undesired proteolysis when the protein is expressed in Pichia pastoris. Additionally, we followed the maturation time course of proDer p 3 by coupling a quenched-flow assay to mass spectrometry analysis. This approach allowed to monitor the evolution of the different species and to determine the steady-state kinetic parameters for activation of the zymogen by the major allergen Der p 1. This experiment demonstrated that prolines 5 and 8 are crucial for proDer p 3-Der p 1 interaction and for activation of the zymogen. PMID- 24073193 TI - Highly pathogenic avian influenza virus nucleoprotein interacts with TREX complex adaptor protein Aly/REF. AB - We constructed a novel chicken (Gallus gallus) lung cDNA library fused inside yeast acting domain vector (pGADT7). Using yeast two-hybrid screening with highly pathogenic avian influenza (HPAI) nucleoprotein (NP) from the strain (A/chicken/Malaysia/5858/2004(H5N1)) as bait, and the Gallus gallus lung cDNA library as prey, a novel interaction between the Gallus gallus cellular RNA export adaptor protein Aly/REF and the viral NP was identified. This interaction was confirmed and validated with mammalian two hybrid studies and co immunoprecipitation assay. Cellular localization studies using confocal microscopy showed that NP and Aly/REF co-localize primarily in the nucleus. Further investigations by mammalian two hybrid studies into the binding of NP of other subtypes of influenza virus such as the swine A/New Jersey/1976/H1N1 and pandemic A/Malaysia/854/2009(H1N1) to human Aly/REF, also showed that the NP of these viruses interacts with human Aly/REF. Our findings are also supported by docking studies which showed tight and favorable binding between H5N1 NP and human Aly/REF, using crystal structures from Protein Data Bank. siRNA knockdown of Aly/REF had little effect on the export of HPAI NP and other viral RNA as it showed no significant reduction in virus titer. However, UAP56, another component of the TREX complex, which recruits Aly/REF to mRNA was found to interact even better with H5N1 NP through molecular docking studies. Both these proteins also co-localizes in the nucleus at early infection similar to Aly/REF. Intriguingly, knockdown of UAP56 in A549 infected cells shows significant reduction in viral titer (close to 10 fold reduction). Conclusively, our study have opened new avenues for research of other cellular RNA export adaptors crucial in aiding viral RNA export such as the SRSF3, 9G8 and ASF/SF2 that may play role in influenza virus RNA nucleocytoplasmic transport. PMID- 24073195 TI - Effects of a range-expanding sea urchin on behaviour of commercially fished abalone. AB - BACKGROUND: Global climate change has resulted in a southerly range expansion of the habitat modifying sea urchin Centrostephanus rodgersii to the east coast of Tasmania, Australia. Various studies have suggested that this urchin outcompetes black-lipped abalone (Haliotis rubra) for resources, but experiments elucidating the mechanisms are lacking. METHODOLOGY/PRINCIPAL FINDINGS: We outline a new framework involving experimental manipulations and Markov chain and Pareto modelling to examine the effects of interspecific competition between urchins and abalone and the effect of intraspecific competition in abalone, assessed as effects on behaviour. Manipulations of abalone densities had no detectable effect on urchin behavioural transitions, movement patterns or resightability through time. In contrast, additions of urchins resulted in abalone shifting microhabitats from exposed to sheltered positions, an increase in the proportion of mobile abalone, and declines in abalone resightability through time relative to controls without the urchins. Our results support the hypothesis of asymmetrical competitive interactions between urchins and abalone. CONCLUSIONS/SIGNIFICANCE: The introduction of urchins to intact algal beds causes abalone to flee and seek shelter in cryptic microhabitat which will negatively impact both their accessibility to such microhabitats, and productivity of the abalone fishery, and will potentially affect their growth and survival, while the presence of the abalone has no detectable effect on the urchin. Our approach involving field-based experiments and modelling could be used to test the effects of other invasive species on native species behaviour. PMID- 24073194 TI - Genetic characterization of the hemagglutinin genes of wild-type measles virus circulating in china, 1993-2009. AB - BACKGROUND: China experienced several large measles outbreaks in the past two decades, and a series of enhanced control measures were implemented to achieve the goal of measles elimination. Molecular epidemiologic surveillance of wild type measles viruses (MeV) provides valuable information about the viral transmission patterns. Since 1993, virologic surveillnace has confirmed that a single endemic genotype H1 viruses have been predominantly circulating in China. A component of molecular surveillance is to monitor the genetic characteristics of the hemagglutinin (H) gene of MeV, the major target for virus neutralizing antibodies. PRINCIPAL FINDINGS: Analysis of the sequences of the complete H gene from 56 representative wild-type MeV strains circulating in China during 1993 2009 showed that the H gene sequences were clustered into 2 groups, cluster 1 and cluster 2. Cluster1 strains were the most frequently detected cluster and had a widespread distribution in China after 2000. The predicted amino acid sequences of the H protein were relatively conserved at most of the functionally significant amino acid positions. However, most of the genotype H1 cluster1 viruses had an amino acid substitution (Ser240Asn), which removed a predicted N linked glycosylation site. In addition, the substitution of Pro397Leu in the hemagglutinin noose epitope (HNE) was identified in 23 of 56 strains. The evolutionary rate of the H gene of the genotype H1 viruses was estimated to be approximately 0.76*10(-3) substitutions per site per year, and the ratio of dN to dS (dN/dS) was <1 indicating the absence of selective pressure. CONCLUSIONS: Although H genes of the genotype H1 strains were conserved and not subjected to selective pressure, several amino acid substitutions were observed in functionally important positions. Therefore the antigenic and genetic properties of H genes of wild-type MeVs should be monitored as part of routine molecular surveillance for measles in China. PMID- 24073196 TI - Dopamine receptor autoantibodies correlate with symptoms in Sydenham's chorea. AB - BACKGROUND: Sydenham chorea (SC), a neuropsychiatric sequela of group-A streptococcal infection, is associated with basal ganglia autoantibodies. Although autoantibodies have been proposed in neuropsychiatric disorders, little evidence has been shown to link autoimmunity and clinical symptoms. We hypothesized that dopamine receptor-autoantibody interactions may be the basis of neuropsychiatric symptoms in SC. METHODS: Sera from 22 children with SC (age 10.7+/-4.5 years) and 22 age-matched controls were studied. Clinical neuropsychiatric symptoms were measured in SC at sample collection using the UFMG Sydenham's-Chorea-Rating-Scale (USCRS). Anti-dopamine D1 receptor (D1R) and anti dopamine D2 receptor (D2R) autoantibodies were measured by the enzyme linked immunosorbent assay (ELISA) and were correlated with clinical symptoms. RESULTS: Anti-D1R and anti-D2R autoantibodies were significantly higher in SC compared to controls (n = 44; p = 0.010 and p = 0.017, respectively). We found that the ratio (anti-D2R/D1R) of the two anti-dopaminergic receptor antibodies correlated with neuropsychiatric symptoms as determined by USCRS measurements (n = 18; r = 0.53, p = 0.024). In addition, anti-D2R titers correlated with antistreptolysin-O titers (n = 43; r = 0.49, p = 0.0008). INTERPRETATION: Our report linked, for the first time, autoimmunity with neuropsychiatric symptoms. The significant correlation was found using ratios of autoantibodies against dopamine receptors (anti-D2R/D1R) rather than the absolute elevated individual anti-D1R or anti-D2R titers. We suggest that autoantibodies may lead to a receptor imbalance and induce greater sensitivity to dopamine signaling potentially leading to neuropsychiatric symptoms in SC. Our novel findings suggesting altered balance in the dopaminergic system may provide a new approach in understanding autoimmune neuropsychiatric disorders with possible implications for diagnosis and treatment. PMID- 24073197 TI - Identification and expression profiling of odorant binding proteins and chemosensory proteins between two wingless morphs and a winged morph of the cotton aphid Aphis gossypii glover. AB - Insects interact with their environment and respond to the changes in host plant conditions using semiochemicals. Such ecological interactions are facilitated by the olfactory sensilla and the use of olfactory recognition proteins. The cotton aphid Aphis gossypii can change its phenotype in response to ecological conditions. They reproduce mainly as wingless asexual morphs but develop wings to find mates or new plant hosts under the influence of environmental factors such as temperature, plant nutrition and population density. Two groups of small soluble proteins, odorant binding proteins (OBPs) and chemosensory proteins (CSPs) are believed to be involved in the initial biochemical recognition steps in semiochemical perception. However, the exact molecular roles that these proteins play in insect olfaction remain to be discovered. In this study, we compared the transcriptomes of three asexual developmental stages (wingless spring and summer morphs and winged adults) and characterised 9 OBP and 9 CSP genes. The gene structure analysis showed that the number and length of introns in these genes are much higher and this appears to be unique feature of aphid OBP and CSP genes in general. Another unique feature in aphids is a higher abundance of CSP transcripts than OBP transcripts, suggesting an important role of CSPs in aphid physiology and ecology. We showed that some of the transcripts are overexpressed in the antennae in comparison to the bodies and highly expressed in the winged aphids compared to wingless morphs, suggesting a role in host location. We examined the differential expression of these olfactory genes in ten aphid species and compared the expression profile with the RNA-seq analyses of 25 pea aphid transcriptome libraries hosted on AphidBase. PMID- 24073198 TI - Oncolytic reovirus in canine mast cell tumor. AB - The usage of reovirus has reached phase II and III clinical trials in human cancers. However, this is the first study to report the oncolytic effects of reovirus in veterinary oncology, focusing on canine mast cell tumor (MCT), the most common cutaneous tumor in dogs. As human and canine cancers share many similarities, we hypothesized that the oncolytic effects of reovirus can be exploited in canine cancers. The objective of this study was to determine the oncolytic effects of reovirus in canine MCT in vitro, in vivo and ex vivo. We demonstrated that MCT cell lines were highly susceptible to reovirus as indicated by marked cell death, high production of progeny virus and virus replication. Reovirus induced apoptosis in the canine MCT cell lines with no correlation to their Ras activation status. In vivo studies were conducted using unilateral and bilateral subcutaneous MCT xenograft models with a single intratumoral reovirus treatment and apparent reduction of tumor mass was exhibited. Furthermore, cell death was induced by reovirus in primary canine MCT samples in vitro. However, canine and murine bone marrow-derived mast cells (BMCMC) were also susceptible to reovirus. The combination of these results supports the potential value of reovirus as a therapy in canine MCT but warrants further investigation on the determinants of reovirus susceptibility. PMID- 24073199 TI - Enterovirus 71 VP1 activates calmodulin-dependent protein kinase II and results in the rearrangement of vimentin in human astrocyte cells. AB - Enterovirus 71 (EV71) is one of the main causative agents of foot, hand and mouth disease. Its infection usually causes severe central nervous system diseases and complications in infected infants and young children. In the present study, we demonstrated that EV71 infection caused the rearrangement of vimentin in human astrocytoma cells. The rearranged vimentin, together with various EV71 components, formed aggresomes-like structures in the perinuclear region. Electron microscopy and viral RNA labeling indicated that the aggresomes were virus replication sites since most of the EV71 particles and the newly synthesized viral RNA were concentrated here. Further analysis revealed that the vimentin in the virus factories was serine-82 phosphorylated. More importantly, EV71 VP1 protein is responsible for the activation of calmodulin-dependent protein kinase II (CaMK-II) which phosphorylated the N-terminal domain of vimentin on serine 82. Phosphorylation of vimentin and the formation of aggresomes were required for the replication of EV71 since the latter was decreased markedly after phosphorylation was blocked by KN93, a CaMK-II inhibitor. Thus, as one of the consequences of CaMK-II activation, vimentin phosphorylation and rearrangement may support virus replication by playing a structural role for the formation of the replication factories. Collectively, this study identified the replication centers of EV71 in human astrocyte cells. This may help us understand the replication mechanism and pathogenesis of EV71 in human. PMID- 24073200 TI - Intraoperative ultrasound guidance is associated with clear lumpectomy margins for breast cancer: a systematic review and meta-analysis. AB - PURPOSE: Margin status is one of the most important predictors of local recurrence after breast conserving surgery (BCS). Intraoperative ultrasound guidance (IOUS) has the potential to improve surgical accuracy for breast cancer. The purpose of the present meta-analysis was to determine the efficacy of IOUS in breast cancer surgery and to compare the margin status to that of the more traditional Guide wire localization (GWL) or palpation-guidance. METHODS: We searched the database of PubMed for prospective and retrospective studies about the impact of IOUS on margin status of breast cancer, and a meta-analysis was conducted. RESULTS: Of the 13 studies included, 8 were eligible for the impact of IOUS on margin status of non-palpable breast cancers, 4 were eligible for palpable breast cancers, and 1 was for both non-palpable and palpable breast cancers. The rate of negative margins of breast cancers in IOUS group was significantly higher than that in control group without IOUS (risk ratio (RR) = 1.37, 95% confidence interval (CI) = 1.18-1.59 from 7 prospective studies, odds ratio (OR) = 2.75, 95% CI = 1.66-4.55 from 4 retrospective studies). For non palpable breast cancers, IOUS-guidance enabled a significantly higher rate of negative margins than that of GWL-guidance (RR = 1.26, 95% CI = 1.09-1.46 from 6 prospective studies; OR = 1.45, 95% CI = 0.86-2.43 from 2 retrospective studies). For palpable breast cancers, relative to control group without IOUS, the RR for IOUS associated negative margins was 2.36 (95% CI = 1.26-4.43) from 2 prospective studies, the OR was 2.71 (95% CI = 1.25-5.87) from 2 retrospective studies. CONCLUSION: This study strongly suggests that IOUS is an accurate method for localization of non-palpable and palpable breast cancers. It is an efficient method of obtaining high proportion of negative margins and optimum resection volumes in patients undergoing BCS. PMID- 24073202 TI - Quantitative receptor-based imaging of tumor proliferation with the sigma-2 ligand [(18)F]ISO-1. AB - The sigma-2 receptor is expressed in higher density in proliferating (P) tumor cells versus quiescent (Q) tumor cells, thus providing an attractive target for imaging the proliferative status (i.e., P:Q ratio) of solid tumors. Here we evaluate the utility of the sigma-2 receptor ligand 2-(2-[(18)F]fluoroethoxy)-N (4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl)-5-methyl-benzamide, [(18)F]ISO-1, in two different rodent models of breast cancer. In the first study, small animal Positron Emission Tomography (PET) imaging studies were conducted with [(18)F]ISO-1 and (18)FDG in xenografts of mouse mammary tumor 66 and tracer uptake was correlated with the in vivo P:Q ratio determined by flow cytometric measures of BrdU-labeled tumor cells. The second model utilized a chemically-induced (N-methyl-N-nitrosourea [MNU]) model of rat mammary carcinoma to correlate measures of [(18)F]ISO-1 and FDG uptake with MR-based volumetric measures of tumor growth. In addition, [(18)F]ISO-1 and FDG were used to assess the response of MNU-induced tumors to bexarotene and Vorozole therapy. In the mouse mammary 66 tumors, a strong linear correlation was observed between the [(18)F]ISO-1 tumor: background ratio and the proliferative status (P:Q ratio) of the tumor (R = 0.87). Similarly, measures of [(18)F]ISO-1 uptake in MNU-induced tumors significantly correlated (R = 0.68, P<0.003) with changes in tumor volume between consecutive MR imaging sessions. Our data suggest that PET studies of [(18)F]ISO-1 provide a measure of both the proliferative status and tumor growth rate, which would be valuable in designing an appropriate treatment strategy. PMID- 24073203 TI - Molecular evolution of enterovirus 68 detected in the Philippines. AB - BACKGROUND: Detection of Enterovirus 68 (EV68) has recently been increased. However, underlying evolutionary mechanism of this increasing trend is not fully understood. METHODS: Nasopharyngeal swabs were collected from 5,240 patients with acute respiratory infections in the Philippines from June 2009 to December 2011. EV68 was detected by polymerase chain reaction (PCR) targeting for 5' untranslated region (5'UTR), viral protein 1 (VP1), and VP4/VP2. Phylogenetic trees were generated using the obtained sequences. RESULTS: Of the 5,240 tested samples, 12 EV68 positive cases were detected between August and December in 2011 (detection rate, 0.23%). The detection rate was higher among inpatients than outpatients (p<0.0001). Among VP1 sequences detected from 7 patients in 2011, 5 in lineage 2 were diverged from those detected in the Philippines in 2008, however, 2 in lineage 3 were not diverged from strains detected in the Philippines in 2008 but closely associated with strains detected in the United States. Combined with our previous report, EV68 occurrences were observed twice in the Philippines within the last four years. CONCLUSIONS: EV68 detections might be occurring in cyclic patterns, and viruses might have been maintained in the community while some strains might have been newly introduced. PMID- 24073201 TI - The suppressor of AAC2 Lethality SAL1 modulates sensitivity of heterologously expressed artemia ADP/ATP carrier to bongkrekate in yeast. AB - The ADP/ATP carrier protein (AAC) expressed in Artemia franciscana is refractory to bongkrekate. We generated two strains of Saccharomyces cerevisiae where AAC1 and AAC3 were inactivated and the AAC2 isoform was replaced with Artemia AAC containing a hemagglutinin tag (ArAAC-HA). In one of the strains the suppressor of DeltaAAC2 lethality, SAL1, was also inactivated but a plasmid coding for yeast AAC2 was included, because the ArAACDeltasal1Delta strain was lethal. In both strains ArAAC-HA was expressed and correctly localized to the mitochondria. Peptide sequencing of ArAAC expressed in Artemia and that expressed in the modified yeasts revealed identical amino acid sequences. The isolated mitochondria from both modified strains developed 85% of the membrane potential attained by mitochondria of control strains, and addition of ADP yielded bongkrekate-sensitive depolarizations implying acquired sensitivity of ArAAC mediated adenine nucleotide exchange to this poison, independent from SAL1. However, growth of ArAAC-expressing yeasts in glycerol-containing media was arrested by bongkrekate only in the presence of SAL1. We conclude that the mitochondrial environment of yeasts relying on respiratory growth conferred sensitivity of ArAAC to bongkrekate in a SAL1-dependent manner. PMID- 24073204 TI - Coffee berry borer joins bark beetles in coffee klatch. AB - Unanswered key questions in bark beetle-plant interactions concern host finding in species attacking angiosperms in tropical zones and whether management strategies based on chemical signaling used for their conifer-attacking temperate relatives may also be applied in the tropics. We hypothesized that there should be a common link in chemical signaling mediating host location by these Scolytids. Using laboratory behavioral assays and chemical analysis we demonstrate that the yellow-orange exocarp stage of coffee berries, which attracts the coffee berry borer, releases relatively high amounts of volatiles including conophthorin, chalcogran, frontalin and sulcatone that are typically associated with Scolytinae chemical ecology. The green stage of the berry produces a much less complex bouquet containing small amounts of conophthorin but no other compounds known as bark beetle semiochemicals. In behavioral assays, the coffee berry borer was attracted to the spiroacetals conophthorin and chalcogran, but avoided the monoterpenes verbenone and alpha-pinene, demonstrating that, as in their conifer-attacking relatives in temperate zones, the use of host and non host volatiles is also critical in host finding by tropical species. We speculate that microorganisms formed a common basis for the establishment of crucial chemical signals comprising inter- and intraspecific communication systems in both temperate- and tropical-occurring bark beetles attacking gymnosperms and angiosperms. PMID- 24073205 TI - Organism-specific rRNA capture system for application in next-generation sequencing. AB - RNA-sequencing is a powerful tool in studying RNomics. However, the highly abundance of ribosomal RNAs (rRNA) and transfer RNA (tRNA) have predominated in the sequencing reads, thereby hindering the study of lowly expressed genes. Therefore, rRNA depletion prior to sequencing is often performed in order to preserve the subtle alteration in gene expression especially those at relatively low expression levels. One of the commercially available methods is to use DNA or RNA probes to hybridize to the target RNAs. However, there is always a concern with the non-specific binding and unintended removal of messenger RNA (mRNA) when the same set of probes is applied to different organisms. The degree of such unintended mRNA removal varies among organisms due to organism-specific genomic variation. We developed a computer-based method to design probes to deplete rRNA in an organism-specific manner. Based on the computation results, biotinylated RNA-probes were produced by in vitro transcription and were used to perform rRNA depletion with subtractive hybridization. We demonstrated that the designed probes of 16S rRNAs and 23S rRNAs can efficiently remove rRNAs from Mycobacterium smegmatis. In comparison with a commercial subtractive hybridization-based rRNA removal kit, using organism-specific probes is better in preserving the RNA integrity and abundance. We believe the computer-based design approach can be used as a generic method in preparing RNA of any organisms for next-generation sequencing, particularly for the transcriptome analysis of microbes. PMID- 24073206 TI - Development of methodology for disability-adjusted life years (DALYs) calculation based on real-life data. AB - BACKGROUND: Disability-Adjusted Life Years (DALYs) have the advantage that effects on total health instead of on a specific disease incidence or mortality can be estimated. Our aim was to address several methodological points related to the computation of DALYs at an individual level in a follow-up study. METHODS: DALYs were computed for 33,507 men and women aged 20-70 years when participating in the EPIC-NL study in 1993-7. DALYs are the sum of the Years Lost due to Disability (YLD) and the Years of Life Lost (YLL) due to premature mortality. Premature mortality was defined as death before the estimated date of individual Life Expectancy (LE). Different methods to compute LE were compared as well as the effect of different follow-up periods using a two-part model estimating the effect of smoking status on health as an example. RESULTS: During a mean follow up of 12.4 years, there were 69,245 DALYs due to years lived with a disease or premature death. Current-smokers had lost 1.28 healthy years of their life (1.28 DALYs 95%CI 1.10; 1.46) compared to never-smokers. The outcome varied depending on the method used for estimating LE, completeness of disease and mortality ascertainment and notably the percentage of extinction (duration of follow-up) of the cohort. CONCLUSION: We conclude that the use of DALYs in a cohort study is an appropriate way to assess total disease burden in relation to a determinant. The outcome is sensitive to the LE calculation method and the follow-up duration of the cohort. PMID- 24073207 TI - Metaphor interpretation using paraphrases extracted from the web. AB - Interpreting metaphor is a hard but important problem in natural language processing that has numerous applications. One way to address this task is by finding a paraphrase that can replace the metaphorically used word in a given context. This approach has been previously implemented only within supervised frameworks, relying on manually constructed lexical resources, such as WordNet. In contrast, we present a fully unsupervised metaphor interpretation method that extracts literal paraphrases for metaphorical expressions from the Web. It achieves a precision of [Formula: see text], which is high for an unsupervised paraphrasing approach. Moreover, the method significantly outperforms both the baseline and the selectional preference-based method of Shutova employed in an unsupervised setting. PMID- 24073208 TI - EMMPRIN promotes angiogenesis, proliferation, invasion and resistance to sunitinib in renal cell carcinoma, and its level predicts patient outcome. AB - PURPOSE: Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to play crucial roles, including in angiogenesis, in several carcinomas. However, the correlation between EMMPRIN levels and angiogenesis expression profile has not been reported, and the role of EMMPRIN in renal cell carcinoma (RCC) is unclear. In the present study, we evaluated the association of EMMPRIN with angiogenesis, its value in prognosis, and its roles in RCC. EXPERIMENTAL DESIGN: EMMPRIN expression was examined in 50 RCC patients treated with radical nephrectomy. Angiogenesis, proliferation, and invasion activity were evaluated using EMMPRIN knockdown RCC cell lines. The size of EMMPRIN-overexpressing xenografts was measured and the degree of angiogenesis was quantified. EMMPRIN expression was evaluated in RCC patients who received sunitinib therapy and in sunitinib-resistant cells. Further, the relation between EMMPRIN expression and sensitivity to sunitinib was examined. RESULTS: EMMPRIN score was significantly associated with clinicopathological parameters in RCC patients, as well as being significantly correlated with microvessel area (MVA) in immature vessels and with prognosis. Down-regulation of EMMPRIN by siRNA led to decreased VEGF and bFGF expression, cell proliferation, and invasive potential. EMMPRIN over-expressing xenografts showed accelerated growth and MVA of immature vessels. EMMPRIN expression was significantly increased in patients who received sunitinib therapy as well as in sunitinib-resistant 786-O cells (786-suni). EMMPRIN-overexpressing RCC cells were resistant to sunitinib. CONCLUSION: Our findings indicate that high expression of EMMPRIN in RCC plays important roles in tumor progression and sunitinib resistance. Therefore, EMMPRIN could be a novel target for the treatment of RCC. PMID- 24073209 TI - Rebelling for a reason: protein structural "outliers". AB - Analysis of structural variation in domain superfamilies can reveal constraints in protein evolution which aids protein structure prediction and classification. Structure-based sequence alignment of distantly related proteins, organized in PASS2 database, provides clues about structurally conserved regions among different functional families. Some superfamily members show large structural differences which are functionally relevant. This paper analyses the impact of structural divergence on function for multi-member superfamilies, selected from the PASS2 superfamily alignment database. Functional annotations within superfamilies, with structural outliers or 'rebels', are discussed in the context of structural variations. Overall, these data reinforce the idea that functional similarities cannot be extrapolated from mere structural conservation. The implication for fold-function prediction is that the functional annotations can only be inherited with very careful consideration, especially at low sequence identities. PMID- 24073210 TI - Wide host ranges of herbivorous beetles? Insights from DNA bar coding. AB - There are very few studies that have investigated host-specificity among tropical herbivorous insects. Indeed, most of the trophic interactions of herbivorous insects in Southeast Asian tropical rainforests remain unknown, and whether polyphagous feeding is common in the herbivores of this ecosystem has not been determined. The present study employed DNA bar coding to reveal the trophic associations of adult leaf-chewing chrysomelid beetles in a Bornean rainforest. Plant material ingested by the adults was retrieved from the bodies of the insects, and a portion of the chloroplast rbcL sequence was then amplified from this material. The plants were identified at the family level using an existing reference database of chloroplast DNA. Our DNA-based diet analysis of eleven chrysomelid species successfully identified their host plant families and indicated that five beetle species fed on more than two families within the angiosperms, and four species fed on several families of gymnosperms and/or ferns together with multiple angiosperm families. These findings suggest that generalist chrysomelid beetles associated with ecologically and taxonomically distant plants constitute a part of the plant-insect network of the Bornean rainforest. PMID- 24073212 TI - TCTP is a critical factor in shrimp immune response to virus infection. AB - The translationally controlled tumor protein (TCTP) is an abundant, ubiquitous, and conserved protein which plays important roles in a number of biological processes. In the present study, the TCTP in shrimp Litopenaeus vannamei was analyzed. The TCTP of L.vannamei, a 168-amino-acid polypeptide, shares a high degree of similarity with TCTPs from other species, having two TCTP protein signatures at the 45-55 aa and 123-145 aa motif. The mRNA and protein levels from different tissues were detected with the highest in muscle and the lowest in heart among all examined tissues. In addition, temporal TCTP expression was significantly up-regulated at 16 h and 48 h following infection with white spot syndrome virus (WSSV). Lastly, silencing of TCTP with dsRNA led to a significant increase of WSSV loads. These results provide new insights into the importance of TCTP as an evolutionarily conserved molecule for shrimp innate immunity against virus infection. PMID- 24073211 TI - Aureochrome 1a is involved in the photoacclimation of the diatom Phaeodactylum tricornutum. AB - Aureochromes constitute a family of blue light (BL) receptors which are found exclusively in heterokont algae such as diatoms (Bacillariophyceae) and yellow green algae (Xanthophyceae). Previous studies on the diatom Phaeodactylum tricornutum indicate that the formation of a high light acclimated phenotype is mediated by the absorption of BL and that aureochromes might play an important role in this process. P. tricornutum possesses four genes encoding aureochromes. In this study we confirm the nuclear localisation of the PtAUREO1a, 1b and 2 proteins. Furthermore we studied the physiology of light quality acclimation in genetically transformed P. tricornutum cell lines with reduced expression of the aureochrome 1a gene. The results demonstrate that the AUREO1a protein has a distinct function in light acclimation. However, rather unexpectedly AUREO1a seems to repress high light acclimation which resulted in a state of 'hyper' high light acclimation in aureo1a silenced strains. This was indicated by characteristic changes of several photosynthetic parameters, including increased maximum photosynthesis rates, decreased chlorophyll a contents per cell and increased values of non-photochemical quenching in AUREO1a silenced strains compared to wild type cultures. Strikingly, AUREO1a silenced strains exhibited phenotypic differences compared to wild type cells during cultivation under BL as well as under red light (RL) conditions. Therefore, AUREO1a might influence the RL signalling process, suggesting an interaction of AUREO1a with RL perception pathways. PMID- 24073213 TI - Observation of simple intransitive actions: the effect of familiarity. AB - INTRODUCTION: Humans are more familiar with index - thumb than with any other finger to thumb grasping. The effect of familiarity has been previously tested with complex, specialized and/or transitive movements, but not with simple intransitive ones. The aim of this study is to evaluate brain activity patterns during the observation of simple and intransitive finger movements with differing degrees of familiarity. METHODOLOGY: A functional Magnetic Resonance Imaging (fMRI) study was performed using a paradigm consisting of the observation of 4 videos showing a finger opposition task between the thumb and the other fingers (index, middle, ring and little) in a repetitive manner with a fixed frequency (1 Hz). This movement is considered as the pantomime of a precision grasping action. RESULTS: Significant activity was identified in the bilateral Inferior Parietal Lobule and premotor regions with the selected level of significance (FDR [False Discovery Rate] = 0.01). The extent of the activation in both regions tended to decrease when the finger that performed the action was further from the thumb. More specifically, this effect showed a linear trend (index>middle>ring>little) in the right parietal and premotor regions. CONCLUSIONS: The observation of less familiar simple intransitive movements produces less activation of parietal and premotor areas than familiar ones. The most important implication of this study is the identification of differences in brain activity during the observation of simple intransitive movements with different degrees of familiarity. PMID- 24073214 TI - HIV-1 Tat protein induces the production of IDO in human monocyte derived dendritic cells through a direct mechanism: effect on T cells proliferation. AB - During HIV-1 infection, an increase of indoleamine 2,3 dioxygenase (IDO) expression, and dendritic cells (DC) dysfunction were often associated with AIDS disease progression. In this work, we investigated the effect of HIV-1 Tat protein on the expression of IDO, in MoDCs. We show that Tat induces IDO protein expression and activity in a dose dependent manner by acting at the cell membrane. Using Tat-mutants, we show that the N-Terminal domain, Tat 1-45, but not the central region, Tat 30-72, is sufficient to induce the expression of active IDO. Tat protein is also able to induce several cytokines in MoDCs, including IFN-gamma, a strong inducer of IDO. In order to understand whether IDO is induced directly by Tat protein or indirectly following IFN-gamma production, complementary experiments were performed and showed that: i) at the kinetic level, Tat induced IDO expression before the production of IFN-gamma ii) treatment of MoDCs with Tat-conditioned medium was unable to stimulate IDO expression, iii) coculture of MoDCs in a transwell cell system did not allow IDO expression in MoDCs not previously treated by Tat, iv) direct contact between Tat treated and untreated MoDCs was not sufficient to induce IDO expression in a Tat independent manner, and v) treatment of MoDCs in the presence of IFN-gamma pathway inhibitors, Jak I and Ly294002, inhibited IFN-gamma-induced IDO but had no effect on Tat-induced IDO. At the functional level, our data showed that treatment of MoDCs with Tat led to the inhibition of their capacity to stimulate T cell proliferation. This impairement was totally abolished when the stimulation was performed in the presence of 1MT, an inhibitor of IDO activity, arguing for the implication of the kynurenine pathway. By inducing IDO, Tat protein may be considered, as a viral pathogenic factor, in the dysregulation of the DC functions during HIV-1 infection. PMID- 24073215 TI - HIV-infected adolescent mothers and their infants: low coverage of HIV services and high risk of HIV transmission in KwaZulu-Natal, South Africa. AB - OBJECTIVES: Rates of pregnancy and HIV infection are high among South African adolescents, yet little is known about rates of mother-to-child transmission of HIV (MTCT) in this group. We report a comparison of the characteristics of adolescent mothers and adult mothers, including HIV prevalence and MTCT rates. METHODS: We examined patterns of health service utilization during the antenatal and early postnatal period, HIV prevalence and MTCT amongst adolescent (<20-years old) and adult (20 to 39-years-old) mothers with infants aged <=16 weeks attending immunization clinics in six districts of KwaZulu-Natal between May 2008 and April 2009. FINDINGS: Interviews were conducted with 19,093 mothers aged between 12 and 39 years whose infants were aged <=16 weeks. Most mothers had attended antenatal care four or more times during their last pregnancy (80.3%), and reported having an HIV test (98.2%). A greater proportion of HIV-infected adult mothers, compared to adolescent mothers, reported themselves as HIV positive (41.2% vs. 15.9%, p<0.0001), reported having a CD4 count taken during their pregnancy (81.0% vs. 66.5%, p<0.0001), and having received the CD4 count result (84.4% vs. 75.7%, p<0.0001). Significantly fewer adolescent mothers received the recommended PMTCT regimen. HIV antibody was detected in 40.4% of 7,800 infants aged 4-8 weeks tested for HIV, indicating HIV exposure. This was higher among infants of adult mothers (47.4%) compared to adolescent mothers (17.9%, p<0.0001). The MTCT rate at 4-8 weeks of age was significantly higher amongst infants of adolescent mothers compared to adult mothers (35/325 [10.8%] vs. 185/2,800 [6.1%], OR 1.7, 95% CI 1.2-2.4). CONCLUSION: Despite high levels of antenatal clinic attendance among pregnant adolescents in KwaZulu-Natal, the MTCT risk is higher among infants of HIV-infected adolescent mothers compared to adult mothers. Access to adolescent-friendly family planning and PMTCT services should be prioritised for this vulnerable group. PMID- 24073216 TI - EEG-response consistency across subjects in an active oddball task. AB - The active oddball paradigm is a candidate task for voluntary brain activation. Previous research has focused on group effects, and has largely overlooked the potential problem of interindividual differences. Interindividual variance causes problems with the interpretation of group-level results. In this study we want to demonstrate the degree of consistency in the active oddball task across subjects, in order to answer the question of whether this task is able to reliably detect conscious target processing in unresponsive patients. We asked 18 subjects to count rare targets and to ignore frequent standards and rare distractors in an auditory active oddball task. Event-related-potentials (ERPs) and time-frequency data were analyzed with permutation-t-tests on a single subject level. We plotted the group-average ERPs and time-frequency data, and evaluated the numbers of subjects showing significant differences between targets and distractors in certain time-ranges. The distinction between targets/distractors and standards was found to be significant in the time-range of the P300 in all participants. In contrast, significant differences between targets and distractors in the time range of the P3a/b were found in 8 subjects, only. By including effects in the N1 and in a late negative component there remained 2 subjects who did not show a distinction between targets and distractors in the ERP. While time-frequency data showed prominent effects for target/distractor vs. standard, significant differences between targets and distractors were found in 2 subjects, only. The results suggest that time-frequency- and ERP-analysis of the active oddball task may not be sensitive enough to detect voluntary brain activation in unresponsive patients. In addition, we found that time-frequency analysis was even less informative than ERPs about the subject's task performance. Despite suggesting the use of more sensitive paradigms and/or analysis techniques, the present results give further evidence that electroencephalographic research should rely more strongly on single-subject analysis because interpretations of group-effects may be misleading. PMID- 24073217 TI - Body sodium overload modulates the firing rate and fos immunoreactivity of serotonergic cells of dorsal raphe nucleus. AB - In order to determine whether serotonergic (5HT) dorsal raphe nucleus (DRN) cells are involved in body sodium status regulation, the effect of a s.c. infusion of either 2 M or 0.15 M NaCl on 5HT DRN neuron firing was studied using single unit extracellular recordings. In separate groups of 2 M and 0.15 M NaCl-infused rats, water intake, oxytocin (OT) plasma concentration, urine and plasma sodium and protein concentrations were also measured. Also, to determine the involvement of particular brain nuclei and neurochemical systems in body sodium overload (SO), animals from both groups were perfused for brain immunohistochemical detection of Fos, Fos-OT and Fos-5HT expression. SO produced a significant increase in serotonergic DRN neuron firing rate compared to baseline and 0.15 M NaCl-infused rats. As expected, 2 M NaCl s.c. infusion also induced a significant increase of water intake, diuresis and natriuresis, plasma sodium concentration and osmolality, even though plasma volume did not increase as indicated by changes in plasma protein concentration. The distribution of neurons along the forebrain and brainstem expressing Fos after SO showed the participation of the lamina terminalis, extended amygdala, supraoptic and paraventricular hypothalamic nuclei in the neural network that controls osmoregulatory responses. Both Fos-OT immunoreactive and plasma OT concentration increased after s.c. hypertonic sodium infusion. Finally, matching the "in vivo" electrophysiological study, SO doubled the number of Fos-5HT immunolabeled cells within the DRN. In summary, the results characterize the behavioral, renal and endocrine responses after body sodium overload without volume expansion and specify the cerebral nuclei that participate at different CNS levels in the control of these responses. The electrophysiological approach also allows us to determine in an "in vivo" model that DRN 5HT neurons increase their firing frequency during an increase in systemic sodium concentration and osmolality, possibly to modulate sodium and water intake/excretion and avoid extracellular volume expansion. PMID- 24073218 TI - Structural, biochemical and genetic characterization of dissimilatory ATP sulfurylase from Allochromatium vinosum. AB - ATP sulfurylase (ATPS) catalyzes a key reaction in the global sulfur cycle by reversibly converting inorganic sulfate (SO4 (2-)) with ATP to adenosine 5' phosphosulfate (APS) and pyrophosphate (PPi). In this work we report on the sat encoded dissimilatory ATP sulfurylase from the sulfur-oxidizing purple sulfur bacterium Allochromatium vinosum. In this organism, the sat gene is located in one operon and co-transcribed with the aprMBA genes for membrane-bound APS reductase. Like APS reductase, Sat is dispensible for growth on reduced sulfur compounds due to the presence of an alternate, so far unidentified sulfite oxidizing pathway in A. vinosum. Sulfate assimilation also proceeds independently of Sat by a separate pathway involving a cysDN-encoded assimilatory ATP sulfurylase. We produced the purple bacterial sat-encoded ATP sulfurylase as a recombinant protein in E. coli, determined crucial kinetic parameters and obtained a crystal structure in an open state with a ligand-free active site. By comparison with several known structures of the ATPS-APS complex in the closed state a scenario about substrate-induced conformational changes was worked out. Despite different kinetic properties ATPS involved in sulfur-oxidizing and sulfate-reducing processes are not distinguishable on a structural level presumably due to the interference between functional and evolutionary processes. PMID- 24073219 TI - Down-regulation of claudin-18 is associated with the proliferative and invasive potential of gastric cancer at the invasive front. AB - BACKGROUND: Claudins are known as tight junction proteins, and their expression pattern in gastric cancer is still controversial. The relationship between the expression patterns of tight junction proteins and tumor proliferation in early gastric cancer is still far from clear. AIMS: To investigate the expression patterns of claudin-18 and Ki-67 in early gastric cancer at the invasive front and surrounding normal gastric mucosa and to investigate the biological function of claudin-18 in the proliferation and invasion of cancer cells. METHODS: Seventy five early gastric cancer lesions removed via endoscopic mucosal resection or endoscopic submucosal resection were evaluated. All gastric cancer lesions were diagnosed as differentiated adenocarcinoma using the Japanese Classification of Gastric Carcinoma. To assess epithelial proliferation, immunostaining with Ki-67 was performed, and the labeling index was calculated. To assess the expression of epithelial tight junction proteins, immunofluorescent staining of claudin-18 was performed. The immunoreactivity of claudin-18 was graded according to the number of stained cells. Correlation analysis was performed by Spearman's rank correlation coefficient. Transfection of claudin-18 small interfering RNA (siRNA) was accomplished in MKN74, a claudin-18-positive gastric cancer cell line, to investigate the effect of claudin-18 on proliferation and invasion of cancer cells. RESULTS: Claudin-18 was significantly down-regulated in gastric cancer compared to surrounding gastric normal mucosa or intestinal metaplasia. The Ki-67 labeling index of gastric cancer at the invasive front was inversely correlated with the claudin-18 level, but that at the mucosal lesion was not correlated. Claudin-18 knockdown significantly promoted the proliferation of MKN74 compared with control siRNA-transfected cells. MKN74 invasion increased significantly with claudin-18 siRNA transfection compared with control siRNA transfection. CONCLUSIONS: Down-regulation of claudin-18 is associated with the proliferative potential at the invasive front of gastric cancer, suggesting that it has a pivotal role in gastric cancer progression. PMID- 24073220 TI - Novel NR5A1 missense mutation in premature ovarian failure: detection in han chinese indicates causation in different ethnic groups. AB - BACKGROUND: The etiology of most premature ovarian failure (POF) cases is usually elusive. Although genetic causes clearly exist and a likely susceptible region of 8q22.3 has been discovered, no predominant explanation exists for POF. More recently, evidences have indicated that mutations in NR5A1 gene could be causative for POF. We therefore screened for mutations in the NR5A1 gene in a large cohort of Chinese women with non-syndromic POF. METHODS: Mutation screening of NR5A1 gene was performed in 400 Han Chinese women with well-defined 46,XX idiopathic non-syndromic POF and 400 controls. Subsequently, functional characterization of the novel mutation identified was evaluated in vitro. RESULTS: A novel heterozygous missense mutation [c.13T>G (p.Tyr5Asp)] in NR5A1 was identified in 1 of 384 patients (0.26%). This mutation impaired transcriptional activation on Amh, Inhibin-a, Cyp11a1 and Cyp19a1 gene, as shown by transactivation assays. However, no dominant negative effect was observed, nor was there impact on protein expression and nuclear localization. CONCLUSIONS: This novel mutation p.Tyr5Asp, in a novel non-domain region, is presumed to result in haploinsufficiency. Irrespectively, perturbation in NR5A1 is not a common explanation for POF in Chinese. PMID- 24073221 TI - Influence of vitamin D-related gene polymorphisms (CYP27B and VDR) on the response to interferon/ribavirin therapy in chronic hepatitis C. AB - BACKGROUND AND AIMS: Vitamin D exerts immunomodulatory effects on the host response against infection with hepatitis C virus (HCV). This study was performed to assess the putative influence of polymorphisms in vitamin D-related genes on the response to antiviral therapy in patients with chronic hepatitis C (CHC). METHODS: Single nucleotide polymorphisms (SNPs) in CYP27B-1260 gene promoter (rs10877012AC) and in vitamin D receptor (VDR) gene rs2228570TC, rs1544410CT, rs7975232AC and rs731236AT were analyzed in a cohort of 238 Caucasian CHC patients treated with pegylated interferon (Peg-IFN) plus ribavirin (RBV). Multivariate analyses were performed to exclude confounding effects of well-known baseline predictors of response to therapy (HCV genotype and load, IL28B genotype, age, and GGT and serum cholesterol). RESULTS: Three SNPs at the VDR gene (rs1544410, rs7975232 and rs731236) were in strong linkage disequilibrium, with the CCA haplotype predicting therapeutic failure [Odds ratio 2.743; (95% C.I. 1.313-5.731), p = 0.007]. The carrier state of the VDR rs2228570 T allele was inversely related to the probability of therapeutic failure [Odds ratio 0.438; 95 C.I. (0.204-0.882), p = 0.021]. No relation existed between CYP27B-1260 rs10877012 polymorphism and response to therapy. The area under the operating curve (AUROC) based on the model including all variables significantly related to the response to therapy was 0.846 (95% confidence interval = 0.793-0.899). CONCLUSION: VDR gene polymorphisms are independently related to the response to Peg-IFN+RBV therapy in chronic hepatitis C and could be used as complementary biomarkers of response when included in a prediction algorithm in association with demographic, virologic, biochemical and genetic traits. PMID- 24073222 TI - Reducing inequities in neonatal mortality through adequate supply of health workers: evidence from newborn health in Brazil. AB - INTRODUCTION: Progress towards the MDG targets on maternal and child mortality is hindered worldwide by large differentials between poor and rich populations. Using the case of Brazil, we investigate the extent to which policies and interventions seeking to increase the accessibility of health services among the poor have been effective in decreasing neonatal mortality. METHODS: With a panel data set for the 4,267 Minimum Comparable Areas (MCA) in Brazil in 1991 and 2000, we use a fixed effect regression model to evaluate the effect of the provision of physicians, nurse professionals, nurse associates and community health workers on neonatal mortality for poor and non-poor areas. We additionally forecasted the neonatal mortality rate in 2005. RESULTS: We find that the provision of health workers is particularly important for neonatal mortality in poor areas. Physicians and especially nurse professionals have been essential in decreasing neonatal mortality: an increase of one nurse professional per 1000 population is associated with a 3.8% reduction in neonatal mortality while an increase of one physician per 1000 population is associated with a 2.3% reduction in neonatal mortality. We also find that nurse associates are less important for neonatal mortality (estimated reduction effect of 1.2% ) and that community health workers are not important particularly among the poor. Differences in the provision of health workers explain a large proportion of neonatal mortality. DISCUSSION: In this paper, we show new evidence to inform decision making on maternal and newborn health. Reductions in neonatal mortality in Brazil have been hampered by the unequal distribution of health workers between poor and non-poor areas. Thus, special attention to a more equitable health system is required to allocate the resources in order to improve the health of poor and ensure equitable access to health services to the entire population. PMID- 24073223 TI - Isolation of a New Chlamydia species from the Feral Sacred Ibis (Threskiornis aethiopicus): Chlamydia ibidis. AB - Investigations conducted on feral African Sacred Ibises (Threskiornisaethiopicus) in western France led to the isolation of a strain with chlamydial genetic determinants. Ultrastructural analysis, comparative sequence analysis of the 16S rRNA gene, ompA, and of a concatenate of 31 highly conserved genes, as well as determination of the whole genome sequence confirmed the relatedness of the new isolate to members of the Chlamydiaceae, while, at the same time demonstrating a unique position outside the currently recognized species of this family. We propose to name this new chlamydial species Chlamydiaibidis . PMID- 24073224 TI - Secreted human adipose leptin decreases mitochondrial respiration in HCT116 colon cancer cells. AB - Obesity is a key risk factor for the development of colon cancer; however, the endocrine/paracrine/metabolic networks mediating this connection are poorly understood. Here we hypothesize that obesity results in secreted products from adipose tissue that induce malignancy-related metabolic alterations in colon cancer cells. Human HCT116 colon cancer cells, were exposed to conditioned media from cultured human adipose tissue fragments of obese vs. non-obese subjects. Oxygen consumption rate (OCR, mostly mitochondrial respiration) and extracellular acidification rate (ECAR, mostly lactate production via glycolysis) were examined vis-a-vis cell viability and expression of related genes and proteins. Our results show that conditioned media from obese (vs. non-obese) subjects decreased basal (40%, p<0.05) and maximal (50%, p<0.05) OCR and gene expression of mitochondrial proteins and Bax without affecting cell viability or expression of glycolytic enzymes. Similar changes could be recapitulated by incubating cells with leptin, whereas, leptin-receptor specific antagonist inhibited the reduced OCR induced by conditioned media from obese subjects. We conclude that secreted products from the adipose tissue of obese subjects inhibit mitochondrial respiration and function in HCT116 colon cancer cells, an effect that is at least partly mediated by leptin. These results highlight a putative novel mechanism for obesity-associated risk of gastrointestinal malignancies, and suggest potential new therapeutic avenues. PMID- 24073225 TI - Differential host response, rather than early viral replication efficiency, correlates with pathogenicity caused by influenza viruses. AB - Influenza viruses exhibit large, strain-dependent differences in pathogenicity in mammalian hosts. Although the characteristics of severe disease, including uncontrolled viral replication, infection of the lower airway, and highly inflammatory cytokine responses have been extensively documented, the specific virulence mechanisms that distinguish highly pathogenic strains remain elusive. In this study, we focused on the early events in influenza infection, measuring the growth rate of three strains of varying pathogenicity in the mouse airway epithelium and simultaneously examining the global host transcriptional response over the first 24 hours. Although all strains replicated equally rapidly over the first viral life-cycle, their growth rates in both lung and tracheal tissue strongly diverged at later times, resulting in nearly 10-fold differences in viral load by 24 hours following infection. We identified separate networks of genes in both the lung and tracheal tissues whose rapid up-regulation at early time points by specific strains correlated with a reduced viral replication rate of those strains. The set of early-induced genes in the lung that led to viral growth restriction is enriched for both NF-kappaB binding site motifs and members of the TREM1 and IL-17 signaling pathways, suggesting that rapid, NF-kappaB mediated activation of these pathways may contribute to control of viral replication. Because influenza infection extending into the lung generally results in severe disease, early activation of these pathways may be one factor distinguishing high- and low-pathogenicity strains. PMID- 24073226 TI - Neuroprotective effect of a new synthetic aspirin-decursinol adduct in experimental animal models of ischemic stroke. AB - Stroke is the second leading cause of death. Experimental animal models of cerebral ischemia are widely used for researching mechanisms of ischemic damage and developing new drugs for the prevention and treatment of stroke. The present study aimed to comparatively investigate neuroprotective effects of aspirin (ASA), decursinol (DA) and new synthetic aspirin-decursinol adduct (ASA-DA) against transient focal and global cerebral ischemic damage. We found that treatment with 20 mg/kg, not 10 mg/kg, ASA-DA protected against ischemia-induced neuronal death after transient focal and global ischemic damage, and its neuroprotective effect was much better than that of ASA or DA alone. In addition, 20 mg/kg ASA-DA treatment reduced the ischemia-induced gliosis and maintained antioxidants levels in the corresponding injury regions. In brief, ASA-DA, a new synthetic drug, dramatically protected neurons from ischemic damage, and neuroprotective effects of ASA-DA may be closely related to the attenuation of ischemia-induced gliosis and maintenance of antioxidants. PMID- 24073227 TI - A new method for extracting skin microbes allows metagenomic analysis of whole deep skin. AB - In the last decade, an extensive effort has been made to characterize the human microbiota, due to its clinical and economic interests. However, a metagenomic approach to the skin microbiota is hampered by the high proportion of host DNA that is recovered. In contrast with the burgeoning field of gut metagenomics, skin metagenomics has been hindered by the absence of an efficient method to avoid sequencing the host DNA. We present here a method for recovering microbial DNA from skin samples, based on a combination of molecular techniques. We have applied this method to mouse skin, and have validated it by standard, quantitative PCR and amplicon sequencing of 16S rRNA. The taxonomic diversity recovered was not altered by this new method, as proved by comparing the phylogenetic structure revealed by 16S rRNA sequencing in untreated vs. treated samples. As proof of concept, we also present the first two mouse skin metagenomes, which allowed discovering new taxa (not only prokaryotes but also viruses and eukaryots) not reachable by 16S rRNA sequencing, as well as to characterize the skin microbiome functional landscape. Our method paves the way for the development of skin metagenomics, which will allow a much deeper knowledge of the skin microbiome and its relationship with the host, both in a healthy state and in relation to disease. PMID- 24073228 TI - The genome-wide early temporal response of Saccharomyces cerevisiae to oxidative stress induced by cumene hydroperoxide. AB - Oxidative stress is a well-known biological process that occurs in all respiring cells and is involved in pathophysiological processes such as aging and apoptosis. Oxidative stress agents include peroxides such as hydrogen peroxide, cumene hydroperoxide, and linoleic acid hydroperoxide, the thiol oxidant diamide, and menadione, a generator of superoxide, amongst others. The present study analyzed the early temporal genome-wide transcriptional response of Saccharomyces cerevisiae to oxidative stress induced by the aromatic peroxide cumene hydroperoxide. The accurate dataset obtained, supported by the use of temporal controls, biological replicates and well controlled growth conditions, provided a detailed picture of the early dynamics of the process. We identified a set of genes previously not implicated in the oxidative stress response, including several transcriptional regulators showing a fast transient response, suggesting a coordinated process in the transcriptional reprogramming. We discuss the role of the glutathione, thioredoxin and reactive oxygen species-removing systems, the proteasome and the pentose phosphate pathway. A data-driven clustering of the expression patterns identified one specific cluster that mostly consisted of genes known to be regulated by the Yap1p and Skn7p transcription factors, emphasizing their mediator role in the transcriptional response to oxidants. Comparison of our results with data reported for hydrogen peroxide identified 664 genes that specifically respond to cumene hydroperoxide, suggesting distinct transcriptional responses to these two peroxides. Genes up-regulated only by cumene hydroperoxide are mainly related to the cell membrane and cell wall, and proteolysis process, while those down-regulated only by this aromatic peroxide are involved in mitochondrial function. PMID- 24073229 TI - Ectopic expression of nolz-1 in neural progenitors promotes cell cycle exit/premature neuronal differentiation accompanying with abnormal apoptosis in the developing mouse telencephalon. AB - Nolz-1, as a murine member of the NET zinc-finger protein family, is expressed in post-mitotic differentiating neurons of striatum during development. To explore the function of Nolz-1 in regulating the neurogenesis of forebrain, we studied the effects of ectopic expression of Nolz-1 in neural progenitors. We generated the Cre-loxP dependent conditional transgenic mice in which Nolz-1 was ectopically expressed in proliferative neural progenitors. Ectopic expression of Nolz-1 in neural progenitors by intercrossing the Nolz-1 conditional transgenic mice with the nestin-Cre mice resulted in hypoplasia of telencephalon in double transgenic mice. Decreased proliferation of neural progenitor cells were found in the telencephalon, as evidenced by the reduction of BrdU-, Ki67- and phospho histone 3-positive cells in E11.5-12.5 germinal zone of telencephalon. Transgenic Nolz-1 also promoted cell cycle exit and as a consequence might facilitate premature differentiation of progenitors, because TuJ1-positive neurons were ectopically found in the ventricular zone and there was a general increase of TuJ1 immunoreactivity in the telencephalon. Moreover, clusters of strong TuJ1 expressing neurons were present in E12.5 germinal zone. Some of these strong TuJ1 positive clusters, however, contained apoptotic condensed DNA, suggesting that inappropriate premature differentiation may lead to abnormal apoptosis in some progenitor cells. Consistent with the transgenic mouse analysis in vivo, similar effects of Nozl-1 over-expression in induction of apoptosis, inhibition of cell proliferation and promotion of neuronal differentiation were also observed in three different N18, ST14A and N2A neural cell lines in vitro. Taken together, our study indicates that ectopic expression of Nolz-1 in neural progenitors promotes cell cycle exit/premature neuronal differentiation and induces abnormal apoptosis in the developing telencephalon. PMID- 24073230 TI - 'How poor are you?' -- a comparison of four questionnaire delivery modes for assessing socio-economic position in rural zimbabwe. AB - BACKGROUND: Assessing socio-economic position can be difficult, particularly in developing countries. Collection of socio-economic data usually relies on interviewer-administered questionnaires, but there is little research exploring how questionnaire delivery mode (QDM) influences reporting of these indicators. This paper reports on results of a trial of four QDMs, and the effect of mode on poverty reporting. METHODS: This trial was nested within a community-randomised trial of an adolescent reproductive health intervention conducted in rural Zimbabwe. Participants were randomly allocated to one of four QDMs (three different self-administered modes and one interviewer-administered mode); a subset was randomly selected to complete the questionnaire twice. Questions covered three socio-economic domains: i) ownership of sellable and fixed assets; ii) ability to afford essential items; and iii) food sufficiency. Statistical analyses assessed the association between QDM and reporting of poverty, and compared the extent of response agreement between questionnaire rounds. RESULTS: 96% (n = 1483) of those eligible took part; 395 completed the questionnaire twice. Reported levels of poverty were high. Respondents using self-administered modes were more likely to report being unable to afford essential items and having insufficient food. Among those completing the questionnaire twice using different modes, higher levels of poverty and food insufficiency were reported when they completed the questionnaire using a self-administered mode. CONCLUSION: These data suggest that QDM plays a significant role in how different socio economic indicators are reported, and reminds us to consider the mode of collection when identifying indicators to determine socio-economic position. PMID- 24073231 TI - Desorption electrospray ionization mass spectrometry reveals lipid metabolism of individual oocytes and embryos. AB - Alteration of maternal lipid metabolism early in development has been shown to trigger obesity, insulin resistance, type 2 diabetes and cardiovascular diseases later in life in humans and animal models. Here, we set out to determine (i) lipid composition dynamics in single oocytes and preimplantation embryos by high mass resolution desorption electrospray ionization mass spectrometry (DESI-MS), using the bovine species as biological model, (ii) the metabolically most relevant lipid compounds by multivariate data analysis and (iii) lipid upstream metabolism by quantitative real-time PCR (qRT-PCR) analysis of several target genes (ACAT1, CPT 1b, FASN, SREBP1 and SCAP). Bovine oocytes and blastocysts were individually analyzed by DESI-MS in both positive and negative ion modes, without lipid extraction and under ambient conditions, and were profiled for free fatty acids (FFA), phospholipids (PL), cholesterol-related molecules, and triacylglycerols (TAG). Principal component analysis (PCA) and linear discriminant analysis (LDA), performed for the first time on DESI-MS fused data, allowed unequivocal discrimination between oocytes and blastocysts based on specific lipid profiles. This analytical approach resulted in broad and detailed lipid annotation of single oocytes and blastocysts. Results of DESI-MS and transcript regulation analysis demonstrate that blastocysts produced in vitro and their in vivo counterparts differed significantly in the homeostasis of cholesterol and FFA metabolism. These results should assist in the production of viable and healthy embryos by elucidating in vivo embryonic lipid metabolism. PMID- 24073232 TI - Doublecortin knockout mice show normal hippocampal-dependent memory despite CA3 lamination defects. AB - Mutations in the human X-linked doublecortin gene (DCX) cause major neocortical disorganization associated with severe intellectual disability and intractable epilepsy. Although Dcx knockout (KO) mice exhibit normal isocortical development and architecture, they show lamination defects of the hippocampal pyramidal cell layer largely restricted to the CA3 region. Dcx-KO mice also exhibit interneuron abnormalities. As well as the interest of testing their general neurocognitive profile, Dcx-KO mice also provide a relatively unique model to assess the effects of a disorganized CA3 region on learning and memory. Based on its prominent anatomical and physiological features, the CA3 region is believed to contribute to rapid encoding of novel information, formation and storage of arbitrary associations, novelty detection, and short-term memory. We report here that Dcx KO adult males exhibit remarkably preserved hippocampal- and CA3-dependant cognitive processes using a large battery of classical hippocampus related tests such as the Barnes maze, contextual fear conditioning, paired associate learning and object recognition. In addition, we show that hippocampal adult neurogenesis, in terms of proliferation, survival and differentiation of granule cells, is also remarkably preserved in Dcx-KO mice. In contrast, following social deprivation, Dcx-KO mice exhibit impaired social interaction and reduced aggressive behaviors. In addition, Dcx-KO mice show reduced behavioral lateralization. The Dcx-KO model thus reinforces the association of neuropsychiatric behavioral impairments with mouse models of intellectual disability. PMID- 24073233 TI - Orthopedia transcription factor otpa and otpb paralogous genes function during dopaminergic and neuroendocrine cell specification in larval zebrafish. AB - The homeodomain transcription factor Orthopedia (Otp) is an important regulator for specification of defined subsets of neuroendocrine cells and dopaminergic neurons in vertebrates. In zebrafish, two paralogous otp genes, otpa and otpb, are present in the genome. Neither complete loss of Otp activity nor differential contributions of Otpa and Otpb to specification of defined neuronal populations have been analyzed in detail. We characterized zebrafish embryos and early larvae mutant for null alleles of otpa, otpb, or both genes to determine their individual contributions to the specification of th expressing dopaminergic neuronal populations as well as of crh, oxt, avp, trh or sst1.1 expressing neuroendocrine cells. otpa mutant larvae show an almost complete reduction of ventral diencephalic dopaminergic neurons, as reported previously. A small reduction in the number of trh cells in the preoptic region is detectable in otpa mutants, but no significant loss of crh, oxt and avp preoptic neuroendocrine cells. otpb single mutant larvae do not display a reduction in dopaminergic neurons or neuroendocrine cells in the otp expressing regions. In contrast, in otpa and otpb double mutant larvae specific groups of dopaminergic neurons as well as of crh, oxt, avp, trh and sst1.1-expressing neuroendocrine cells are completely lost. These observations suggest that the requirement for otpa and otpb function during development of the larval diencephalon is partially redundant. During evolutionary diversification of the paralogous otp genes, otpa maintained the prominent role in ventral diencephalic dopaminergic and neuroendocrine cell specification and is capable of partially compensating otpb loss of function. In addition, we identified a role of Otp in the development of a domain of somatostatin1-expressing cells in the rostral hindbrain, a region with strong otp expression but so far uncharacterized Otp function. Otp may thus be crucial for defined neuronal cell types also in the hindbrain. PMID- 24073234 TI - Identification of the sites of tau hyperphosphorylation and activation of tau kinases in synucleinopathies and Alzheimer's diseases. AB - OBJECTIVE: Most neurodegenerative diseases contain hyperphosphorylated Tau [p Tau]. We examined for the first time epitopes at which Tau is hyperphosphorylated in Parkinson's disease, dementia with Lewy bodies and Alzheimer's disease, and also select Tau kinases. METHODS: Postmortem frontal cortex from Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease and striata from Parkinson's disease, were analyzed by immunoblots using commercially available antibodies against 20 different phospho-epitopes of Tau. Major Tau kinases were also screened. Results in diseased tissues were compared to nondiseased controls. RESULTS: In Alzheimer's disease, Tau was hyperphosphorylated at all the 20 epitopes of p-Tau. In dementia with Lewy bodies, p-Tau formation occurred at 6 sites sharing 30% overlap with Alzheimer's disease, while in Parkinson's frontal cortex, an area which does not degenerate, Tau hyperphosphorylation was seen at just 3 epitopes, indicating 15% overlap with Alzheimer's disease. In Parkinson's disease striatum, an area which undergoes considerable neurodegeneration, Tau was hyperphosphorylated at 10 epitopes, sharing 50% overlap with Alzheimer's disease. Between frontal cortex of Parkinson's disease and dementia with Lewy bodies, there were only two p-Tau epitopes in common. In striata of Parkinson's disease, there were 3 clusters of Tau hyperphosphorylated at 3 contiguous sites, while two such clusters were detected in dementia with Lewy bodies; such clusters disrupt axonal transport of mitochondria, cause microtubule remodeling and result in cell death. p-GSK-3beta, a major Tau kinase, was activated in all brain regions examined, except in dementia with Lewy bodies. Activation of other Tau kinases was seen in all brain regions, with no clear pattern of activation. INTERPRETATION: Our studies suggest that the three neurodegenerative diseases each have a signature-specific profile of p-Tau formation which may be useful in understanding the genesis of the diseases and for the development of a panel of specific biomarkers. PMID- 24073235 TI - A connectome-based comparison of diffusion MRI schemes. AB - Diffusion MRI has evolved towards an important clinical diagnostic and research tool. Though clinical routine is using mainly diffusion weighted and tensor imaging approaches, Q-ball imaging and diffusion spectrum imaging techniques have become more widely available. They are frequently used in research-oriented investigations in particular those aiming at measuring brain network connectivity. In this work, we aim at assessing the dependency of connectivity measurements on various diffusion encoding schemes in combination with appropriate data modeling. We process and compare the structural connection matrices computed from several diffusion encoding schemes, including diffusion tensor imaging, q-ball imaging and high angular resolution schemes, such as diffusion spectrum imaging with a publically available processing pipeline for data reconstruction, tracking and visualization of diffusion MR imaging. The results indicate that the high angular resolution schemes maximize the number of obtained connections when applying identical processing strategies to the different diffusion schemes. Compared to the conventional diffusion tensor imaging, the added connectivity is mainly found for pathways in the 50-100mm range, corresponding to neighboring association fibers and long-range associative, striatal and commissural fiber pathways. The analysis of the major associative fiber tracts of the brain reveals striking differences between the applied diffusion schemes. More complex data modeling techniques (beyond tensor model) are recommended 1) if the tracts of interest run through large fiber crossings such as the centrum semi-ovale, or 2) if non-dominant fiber populations, e.g. the neighboring association fibers are the subject of investigation. An important finding of the study is that since the ground truth sensitivity and specificity is not known, the comparability between results arising from different strategies in data reconstruction and/or tracking becomes implausible to understand. PMID- 24073236 TI - The B7-1 cytoplasmic tail enhances intracellular transport and mammalian cell surface display of chimeric proteins in the absence of a linear ER export motif. AB - Membrane-tethered proteins (mammalian surface display) are increasingly being used for novel therapeutic and biotechnology applications. Maximizing surface expression of chimeric proteins on mammalian cells is important for these applications. We show that the cytoplasmic domain from the B7-1 antigen, a commonly used element for mammalian surface display, can enhance the intracellular transport and surface display of chimeric proteins in a Sar1 and Rab1 dependent fashion. However, mutational, alanine scanning and deletion analysis demonstrate the absence of linear ER export motifs in the B7 cytoplasmic domain. Rather, efficient intracellular transport correlated with the presence of predicted secondary structure in the cytoplasmic tail. Examination of the cytoplasmic domains of 984 human and 782 mouse type I transmembrane proteins revealed that many previously identified ER export motifs are rarely found in the cytoplasmic tail of type I transmembrane proteins. Our results suggest that efficient intracellular transport of B7 chimeric proteins is associated with the structure rather than to the presence of a linear ER export motif in the cytoplasmic tail, and indicate that short (less than ~ 10-20 amino acids) and unstructured cytoplasmic tails should be avoided to express high levels of chimeric proteins on mammalian cells. PMID- 24073237 TI - Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. AB - OBJECTIVE: Neuronal damage is the morphological substrate of persisting neurological disability. Neurofilaments (Nf) are cytoskeletal proteins of neurons and their release into cerebrospinal fluid has shown encouraging results as a biomarker for neurodegeneration. This study aimed to validate the quantification of the Nf light chain (NfL) in blood samples, as a biofluid source easily accessible for longitudinal studies. METHODS: We developed and applied a highly sensitive electrochemiluminescence (ECL) based immunoassay for quantification of NfL in blood and CSF. RESULTS: Patients with Alzheimer's disease (AD) (30.8 pg/ml, n=20), Guillain-Barre-syndrome (GBS) (79.4 pg/ml, n=19) or amyotrophic lateral sclerosis (ALS) (95.4 pg/ml, n=46) had higher serum NfL values than a control group of neurological patients without evidence of structural CNS damage (control patients, CP) (4.4 pg/ml, n=68, p<0.0001 for each comparison, p=0.002 for AD patients) and healthy controls (HC) (3.3 pg/ml, n=67, p<0.0001). Similar differences were seen in corresponding CSF samples. CSF and serum levels correlated in AD (r=0.48, p=0.033), GBS (r=0.79, p<0.0001) and ALS (r=0.70, p<0.0001), but not in CP (r=0.11, p=0.3739). The sensitivity and specificity of serum NfL for separating ALS from healthy controls was 91.3% and 91.0%. CONCLUSIONS: We developed and validated a novel ECL based sandwich immunoassay for the NfL protein in serum (NfL(Umea47:3)); levels in ALS were more than 20 fold higher than in controls. Our data supports further longitudinal studies of serum NfL in neurodegenerative diseases as a potential biomarker of on-going disease progression, and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials. PMID- 24073238 TI - Suppression of DS1 phosphatidic acid phosphatase confirms resistance to Ralstonia solanacearum in Nicotiana benthamiana. AB - Nicotianabenthamiana is susceptible to Ralstonia solanacearum. To analyze molecular mechanisms for disease susceptibility, we screened a gene-silenced plant showing resistance to R. solanacearum, designated as DS1 (Disease suppression 1). The deduced amino acid sequence of DS1 cDNA encoded a phosphatidic acid phosphatase (PAP) 2. DS1 expression was induced by infection with a virulent strain of R. solanacearum in an hrp-gene-dependent manner. DS1 rescued growth defects of the temperature-sensitive ?lpp1?dpp1?pah1 mutant yeast. Recombinant DS1 protein showed Mg(2+)-independent PAP activity. DS1 plants showed reduced PAP activity and increased phosphatidic acid (PA) content. After inoculation with R. solanacearum, DS1 plants showed accelerated cell death, over accumulation of reactive oxygen species (ROS), and hyper-induction of PR-4 expression. In contrast, DS1-overexpressing tobacco plants showed reduced PA content, greater susceptibility to R. solanacearum, and reduced ROS production and PR-4 expression. The DS1 phenotype was partially compromised in the plants in which both DS1 and NbCoi1 or DS1 and NbrbohB were silenced. These results show that DS1 PAP may affect plant immune responses related to ROS and JA cascades via regulation of PA levels. Suppression of DS1 function or DS1 expression could rapidly activate plant defenses to achieve effective resistance against Ralstonia solanacearum. PMID- 24073239 TI - Differential growth and development of the upper and lower human thorax. AB - The difficulties in quantifying the 3D form and spatial relationships of the skeletal components of the ribcage present a barrier to studies of the growth of the thoracic skeleton. Thus, most studies to date have relied on traditional measurements such as distances and indices from single or few ribs. It is currently known that adult-like thoracic shape is achieved early, by the end of the second postnatal year, with the circular cross-section of the newborn thorax transforming into the ovoid shape of adults; and that the ribs become inclined such that their anterior borders come to lie inferior to their posterior. Here we present a study that revisits growth changes using geometric morphometrics applied to extensive landmark data taken from the ribcage. We digitized 402 (semi) landmarks on 3D reconstructions to assess growth changes in 27 computed tomography-scanned modern humans representing newborns to adults of both sexes. Our analyses show a curved ontogenetic trajectory, resulting from different ontogenetic growth allometries of upper and lower thoracic units. Adult thoracic morphology is achieved later than predicted, by diverse modifications in different anatomical regions during different ontogenetic stages. Besides a marked increase in antero-posterior dimensions, there is an increase in medio lateral dimensions of the upper thorax, relative to the lower thorax. This transforms the pyramidal infant thorax into the barrel-shaped one of adults. Rib descent is produced by complex changes in 3D curvature. Developmental differences between upper and lower thoracic regions relate to differential timings and rates of maturation of the respiratory and digestive systems, the spine and the locomotor system. Our findings are relevant to understanding how changes in the relative rates of growth of these systems and structures impacted on the development and evolution of modern human body shape. PMID- 24073240 TI - Resveratrol Inhibits CD4+ T cell activation by enhancing the expression and activity of Sirt1. AB - Resveratrol, a natural polyphenol compound, has broad effects on critical events, including inflammation, oxidation, cancer and aging. However, the function and molecular mechanisms of resveratrol on T cell activation are controversial. In the present study, we found that resveratrol significantly inhibits the activation and cytokine production of T cells in vitro and in vivo. Sirt1 expression was up-regulated in resveratrol-treated T cells. Once Sirt1 was down regulated in the T cells, the resveratrol-induced inhibition of T cell activation noticeably diminished. The acetylation of c-Jun decreased and its translocation was impeded in the resveratrol-treated T cells. The incidence and severity of collagen-induced arthritis in the resveratrol-treated mice were considerably reduced. PMID- 24073242 TI - Revisiting the genetic ancestry of Brazilians using autosomal AIM-Indels. AB - There are many different studies that contribute to the global picture of the ethnic heterogeneity in Brazilian populations. These studies use different types of genetic markers and are focused on the comparison of populations at different levels. In some of them, each geographical region is treated as a single homogeneous population, whereas other studies create different subdivisions: political (e.g., pooling populations by State), demographic (e.g., urban and rural), or ethnic (e.g., culture, self-declaration, or skin colour). In this study, we performed an enhanced reassessment of the genetic ancestry of ~ 1,300 Brazilians characterised for 46 autosomal Ancestry Informative Markers (AIMs). In addition, 798 individuals from twelve Brazilian populations representing the five geographical macro-regions of Brazil were newly genotyped, including a Native American community and a rural Amazonian community. Following an increasing North to South gradient, European ancestry was the most prevalent in all urban populations (with values up to 74%). The populations in the North consisted of a significant proportion of Native American ancestry that was about two times higher than the African contribution. Conversely, in the Northeast, Center-West and Southeast, African ancestry was the second most prevalent. At an intrapopulation level, all urban populations were highly admixed, and most of the variation in ancestry proportions was observed between individuals within each population rather than among population. Nevertheless, individuals with a high proportion of Native American ancestry are only found in the samples from Terena and Santa Isabel. Our results allowed us to further refine the genetic landscape of Brazilians while establishing the basis for the effective application of an autosomal AIM panel in forensic casework and clinical association studies within the highly admixed Brazilian populations. PMID- 24073241 TI - Global substrate profiling of proteases in human neutrophil extracellular traps reveals consensus motif predominantly contributed by elastase. AB - Neutrophil extracellular traps (NETs) consist of antimicrobial molecules embedded in a web of extracellular DNA. Formation of NETs is considered to be a defense mechanism utilized by neutrophils to ensnare and kill invading pathogens, and has been recently termed NETosis. Neutrophils can be stimulated to undergo NETosis ex vivo, and are predicted to contain high levels of serine proteases, such as neutrophil elastase (NE), cathepsin G (CG) and proteinase 3 (PR3). Serine proteases are important effectors of neutrophil-mediated immunity, which function directly by degrading pathogenic virulent factors and indirectly via proteolytic activation or deactivation of cytokines, chemokines and receptors. In this study, we utilized a diverse and unbiased peptide library to detect and profile protease activity associated with NETs induced by phorbol-12-myristate-13-acetate (PMA). We obtained a "proteolytic signature" from NETs derived from healthy donor neutrophils and used proteomics to assist in the identification of the source of this proteolytic activity. In addition, we profiled each neutrophil serine protease and included the newly identified enzyme, neutrophil serine protease 4 (NSP4). Each enzyme had overlapping yet distinct endopeptidase activities and often cleaved at unique sites within the same peptide substrate. The dominant proteolytic activity in NETs was attributed to NE; however, cleavage sites corresponding to CG and PR3 activity were evident. When NE was immunodepleted, the remaining activity was attributed to CG and to a lesser extent PR3 and NSP4. Our results suggest that blocking NE activity would abrogate the major protease activity associated with NETs. In addition, the newly identified substrate specificity signatures will guide the design of more specific probes and inhibitors that target NET-associated proteases. PMID- 24073243 TI - Alterations in regulatory T cells induced by specific oligosaccharides improve vaccine responsiveness in mice. AB - Prophylactic vaccinations are generally performed to protect naive individuals with or without suppressed immune responsiveness. In a mouse model for Influenza vaccinations the specific alterations of CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Tregs) in the immune modulation induced by orally supplied oligosaccharides containing scGOS/lcFOS/pAOS was assessed. This dietary intervention increased vaccine specific DTH responses. In addition, a significant increased percentage of T-bet(+) (Th1) activated CD69(+)CD4(+) T cells (p<0.001) and reduced percentage of Gata-3(+) (Th2) activated CD69(+)CD4(+)T cells (p<0.001) was detected in the mesenteric lymph nodes (MLN) of mice receiving scGOS/lcFOS/pAOS compared to control mice. Although no difference in the number or percentage of Tregs (CD4(+)Foxp3(+)) could be determined after scGOS/lcFOS/pAOS intervention, the percentage of CXCR3 (+) /T-bet(+) (Th1-Tregs) was significantly reduced (p<0.05) in mice receiving scGOS/lcFOS/pAOS as compared to mice receiving placebo diets. Moreover, although no absolute difference in suppressive capacity could be detected, an alteration in cytokine profile suggests a regulatory T cell shift towards a reducing Th1 suppression profile, supporting an improved vaccination response. IN CONCLUSION: These data are indicative for improved vaccine responsiveness due to reduced Th1 suppressive capacity in the Treg population of mice fed the oligosaccharide specific diet, showing compartmentalization within the Treg population. The modulation of Tregs to control immune responses provides an additional arm of intervention using alternative strategies possibly leading to the development of improved vaccines. PMID- 24073244 TI - Doxorubicin-induced vascular toxicity--targeting potential pathways may reduce procoagulant activity. AB - INTRODUCTION: Previous study in mice using real-time intravital imaging revealed an acute deleterious effect of doxorubicin (DXR) on the gonadal vasculature, as a prototype of an end-organ, manifested by a reduction in blood flow and disintegration of the vessel wall. We hypothesized that this pattern may represent the formation of microthrombi. We aimed to further characterize the effect of DXR on platelets' activity and interaction with endothelial cells (EC) and to examine potential protectants to reduce DXR acute effect on the blood flow. METHODS: The effect of DXR on platelet adhesion and aggregation were studied in vitro. For in vivo studies, mice were injected with either low molecular weight heparin (LMWH; Enoxaparin) or with eptifibatide (Integrilin((c))) prior to DXR treatment. Testicular arterial blood flow was examined in real-time by pulse wave Doppler ultrasound. RESULTS: Platelet treatment with DXR did not affect platelet adhesion to a thrombogenic surface but significantly decreased ADP-induced platelet aggregation by up to 40% (p<0.001). However, there was a significant increase in GPIIbIIIa-mediated platelet adhesion to DXR-exposed endothelial cells (EC; 5.7-fold; p<0.001) reflecting the toxic effect of DXR on EC. The testicular arterial blood flow was preserved in mice pre treated with LMWH or eptifibatide prior to DXR (P<0.01). CONCLUSIONS: DXR-induced acute vascular toxicity may involve increased platelet-EC adhesion leading to EC bound microthrombi formation resulting in compromised blood flow. Anti platelet/anti-coagulant agents are effective in reducing the detrimental effect of DXR on the vasculature and thus may serve as potential protectants to lessen this critical toxicity. PMID- 24073245 TI - T cell and dendritic cell abnormalities synergize to expand pro-inflammatory T cell subsets leading to fatal autoimmunity in B6.NZBc1 lupus-prone mice. AB - We have previously shown that B6 congenic mice with a New Zealand Black chromosome 1 (c1) 96-100 cM interval produce anti-nuclear Abs and that at least two additional genetic loci are required to convert this subclinical disease to fatal glomerulonephritis in mice with a c1 70-100 cM interval (c1(70-100)). Here we show that the number of T follicular helper and IL-21-, IFN-gamma-, and IL-17 secreting CD4(+) T cells parallels disease severity and the number of susceptibility loci in these mice. Immunization of pre-autoimmune mice with OVA recapitulated these differences. Differentiation of naive T cells in-vitro under polarizing conditions and in-vivo following adoptive transfer of OVA-specific TCR transgenic cells into c1(70-100) or B6 recipient mice, revealed T cell functional defects leading to increased differentiation of IFN-gamma- and IL-17-producing cells in the 96-100 cM and 88-96 cM intervals, respectively. However, in-vivo enhanced differentiation of pro-inflammatory T cell subsets was predominantly restricted to c1(70-100) recipient mice, which demonstrated altered dendritic cell function, with increased production of IL-6 and IL-12. The data provide support for the role of pro-inflammatory T cells in the conversion of subclinical disease to fatal autoimmunity and highlight the importance of synergistic interactions between individual susceptibility loci in this process. PMID- 24073246 TI - Detecting dissonance in clinical and research workflow for translational psychiatric registries. AB - BACKGROUND: The interplay between the workflow for clinical tasks and research data collection is often overlooked, ultimately making it ineffective. QUESTIONS/PURPOSES: To the best of our knowledge, no previous studies have developed standards that allow for the comparison of workflow models derived from clinical and research tasks toward the improvement of data collection processes. METHODS: In this study we used the term dissonance for the occurrences where there was a discord between clinical and research workflows. We developed workflow models for a translational research study in psychiatry and the clinic where its data collection was carried out. After identifying points of dissonance between clinical and research models we derived a corresponding classification system that ultimately enabled us to re-engineer the data collection workflow. We considered (1) the number of patients approached for enrollment and (2) the number of patients enrolled in the study as indicators of efficiency in research workflow. We also recorded the number of dissonances before and after the workflow modification. RESULTS: We identified 22 episodes of dissonance across 6 dissonance categories: actor, communication, information, artifact, time, and space. We were able to eliminate 18 episodes of dissonance and increase the number of patients approached and enrolled in research study trough workflow modification. CONCLUSION: The classification developed in this study is useful for guiding the identification of dissonances and reveal modifications required to align the workflow of data collection and the clinical setting. The methodology described in this study can be used by researchers to standardize data collection process. PMID- 24073247 TI - Preeclampsia and the risk of bronchopulmonary dysplasia in VLBW infants: a population based study. AB - BACKGROUND: Preeclampsia remains a leading cause of maternal mortality and preterm delivery. Both preeclampsia and bronchopulmonary dysplasia (BPD) of prematurity are associated with impaired angiogenesis. However, the relationship between maternal preeclampsia and BPD remains controversial. This study aims to test whether or not preeclampsia is associated with development of BPD in a cohort of premature infants. MATERIALS AND METHODS: We conducted a retrospective cohort study assessing the association between preeclampsia and the risk of developing BPD in very-low-birth-weight (VLBW) infants registered in the Premature Baby Foundation of Taiwan from 1997 through 2006. All 21 neonatal departments in Taiwan participated in the data collection. A total of 8,653 VLBW infants were registered in the database. The exclusion criteria included congenital anomalies, chromosome anomalies, infants that died before 36 weeks post-conceptual (PCA), and those whose BPD status were unavailable. BPD was defined as oxygen dependence at 36 weeks postmenstrual age. The association between maternal preeclampsia and BPD was assessed using a multivariate-adjusted logistic regression model. RESULTS: In the end, a total of 5,753 cases were enrolled in this study. The incidence of preeclampsia was 14.7% (n=847) and the overall incidence of BPD was 34.9%. Infants with maternal preeclampsia had a higher gestational age, higher incidence of cesarean section and being small for their gestational age, lower incidence of respiratory distress syndrome, patent ductus arteriosus, and sepsis. BPD occurred significantly less frequently in the maternal preeclampsia group (24.1% vs. 36.7%; adjusted odds ratio: 0.78; 95% confidence interval, 0.62-0.98). Subgroup analysis showed that the association between preeclampsia and BPD was significant only in those VLBW infants with a gestational age between 31-34 weeks. CONCLUSION: This data supports the association between fetal exposure to maternal preeclampsia and a reduced risk of BPD in relatively mature VLBW infants. PMID- 24073248 TI - Brachypodium sylvaticum, a model for perennial grasses: transformation and inbred line development. AB - Perennial species offer significant advantages as crops including reduced soil erosion, lower energy inputs after the first year, deeper root systems that access more soil moisture, and decreased fertilizer inputs due to the remobilization of nutrients at the end of the growing season. These advantages are particularly relevant for emerging biomass crops and it is projected that perennial grasses will be among the most important dedicated biomass crops. The advantages offered by perennial crops could also prove favorable for incorporation into annual grain crops like wheat, rice, sorghum and barley, especially under the dryer and more variable climate conditions projected for many grain-producing regions. Thus, it would be useful to have a perennial model system to test biotechnological approaches to crop improvement and for fundamental research. The perennial grass Brachypodiumsylvaticum is a candidate for such a model because it is diploid, has a small genome, is self-fertile, has a modest stature, and short generation time. Its close relationship to the annual model Brachypodiumdistachyon will facilitate comparative studies and allow researchers to leverage the resources developed for B. distachyon. Here we report on the development of two keystone resources that are essential for a model plant: high-efficiency transformation and inbred lines. Using Agrobacterium tumefaciens-mediated transformation we achieved an average transformation efficiency of 67%. We also surveyed the genetic diversity of 19 accessions from the National Plant Germplasm System using SSR markers and created 15 inbred lines. PMID- 24073249 TI - Elucidating the population dynamics of Japanese knotweed using integral projection models. AB - Plant demographic studies coupled with population modeling are crucial components of invasive plant management because they inform managers when in a plant's life cycle it is most susceptible to control efforts. Providing land managers with appropriate data can be especially challenging when there is limited data on potentially important transitions that occur belowground. For 2 years, we monitored 4 clonal Japanese knotweed (Polygonumcuspidatum) infestations for emergence, survival, shoot height until leaf senescence, dry shoot biomass after senescence, and rhizome connections for 424 shoots. We developed an integral projection model using both final autumn shoot height and shoot biomass as predictors of survival between years, growth from year to year, and number of rhizomes produced by a shoot (fecundity). Numbers of new shoots within an infestation (population growth rate lambda) were projected to increase 13-233% in a year, with the greatest increase at the most frequently disturbed site. Elasticity analysis revealed population growth at 3 of the 4 sites was primarily due to ramet survival between years and to year-to-year growth in shoot height and shoot biomass. Population growth at the fourth site, the most disturbed, was due to the large production of new rhizomes and associated shoots. In contrast to previous studies, our excavation revealed that most of the shoots were not interconnected, suggesting rhizome production may be limited by the size or age of the plants, resource availability, disturbance frequency, or other factors. Future integration of plant population models with more data on belowground growth structures will clarify the critical stages in Japanese knotweed life cycle and support land managers in their management decisions. PMID- 24073250 TI - Differential stability of cell-free circulating microRNAs: implications for their utilization as biomarkers. AB - BACKGROUND: MicroRNAs circulating in the blood, stabilized by complexation with proteins and/or additionally by encapsulation in lipid vesicles, are currently being evaluated as biomarkers. The consequences of their differential association with lipids/vesicles for their stability and use as biomarkers are largely unexplored and are subject of the present study. METHODS: The levels of a set of selected microRNAs were determined by quantitative reverse-transcription PCR after extraction from sera or vesicle- and non-vesicle fractions prepared from sera. The stability of these microRNAs after incubation with RNase A or RNase inhibitor, an inhibitor of RNase A family enzymes was studied. RESULTS: The levels of microRNA-1 and microRNA-122, but not those of microRNA-16, microRNA-21 and microRNA-142-3p, declined significantly during a 5-h incubation of the sera. RNase inhibitor prevented the loss of microRNAs in serum as well as the degradation of microRNA-122, a microRNA not expressed in blood cells, in whole blood. Stabilization of microRNA-122 was also achieved by hemolysis. Prolonged incubation of the sera led to enrichment of vesicle-associated relative to non vesicle-associated microRNAs. Vesicle-associated microRNAs were more resistant to RNase A treatment than the respective microRNAs not associated with vesicles. CONCLUSIONS: Serum microRNAs showed differential stability upon prolonged incubation. RNase inhibitor might be useful to robustly preserve the pattern of cell-free circulating microRNAs. In the case of microRNAs not expressed in blood cells this can also be achieved by hemolysis. Vesicle-associated microRNAs appeared to be more stable than those not associated with vesicles, which might be useful to disclose additional biomarker properties of miRNAs. PMID- 24073251 TI - Novel 3D co-culture model for epithelial-stromal cells interaction in prostate cancer. AB - Paracrine function is a major mechanism of cell-cell communication within tissue microenvironment in normal development and disease. In vitro cell culture models simulating tissue or tumor microenvironment are necessary tools to delineate epithelial-stromal interactions including paracrine function, yet an ideal three dimensional (3D) tumor model specifically studying paracrine function is currently lacking. In order to fill this void we developed a novel 3D co-culture model in double-layered alginate hydrogel microspheres, incorporating prostate cancer epithelial and stromal cells in separate compartments of the microspheres. The cells remained confined and viable within their respective spheres for over 30 days. As a proof of principle regarding paracrine function of the model, we measured shedded component of E-cadherin (sE-cad) in the conditioned media, a major membrane bound cell adhesive molecule that is highly dysregulated in cancers including prostate cancer. In addition to demonstrating that sE-cad can be reliably quantified in the conditioned media, the time course experiments also demonstrated that the amount of sE-cad is influenced by epithelial-stromal interaction. In conclusion, the study establishes a novel 3D in vitro co-culture model that can be used to study cell-cell paracrine interaction. PMID- 24073252 TI - Re-challenge with ovalbumin failed to induce bronchial asthma in mice with eosinophilic bronchitis. AB - OBJECTIVE: To investigate whether eosinophilic bronchitis without airway hyperresponsiveness will develop bronchial asthma in allergic mice. METHODS: Mice were sensitized with OVA on days 0, 7, and 14, challenged on days 21 to 23 (1(st) OVA challenge), and re-challenged on days 46 to 48 (2(nd) OVA challenge), intranasally with 10 (the EB group) and 200 (the AS group) MUg OVA. Lung resistance (RL) was assessed 24 h after each challenge and on day 45 followed by analysis of leukocyte distribution in the bronchoalveolar lavage (BAL) fluid and histological examination. RESULTS: Twenty-four hours after the 1(st) OVA challenge, aerosolized methacholine caused a dose-dependent increase in RL in all groups. At doses >=1.56 mg/mL, RL in the AS group was significantly higher than that of the NS-1 group (P<0.01 or 0.05) and at doses >=12.5 mg/mL, RL was markedly higher in the AS group than that of the EB group (P<0.01). The percentage of eosinophils in both the EB group and the AS group was markedly higher than that of the control group. Twenty-four hours after the 2(nd) OVA challenge, at doses <=12.5 mg/mL, there was no significant difference in RL among all groups (P>0.05). At doses >=12.5 mg/mL, RL in the AS group was significantly higher than that of the control group and EB group (P<0.01 or 0.05). The percentage of eosinophils in the AS group was noticeably higher than that of the EB group(P<0.05). Furthermore, there was apparent infiltration by inflammatory cells, predominantly eosinophils, into the sub-epithelial region of the bronchus and the bronchioles and around the vessels in the EB and AS group. CONCLUSION: Re challenge with low doses of ovalbumin did not increase airway reactivity and failed to induce bronchial asthma in mice with ovalbumin-induced EB. PMID- 24073253 TI - Diacylglycerol kinase zeta positively controls the development of iNKT-17 cells. AB - Invariant natural killer T (iNKT) cells play important roles in bridging innate and adaptive immunity via rapidly producing a variety of cytokines. A small subset of iNKT cells produces IL-17 and is generated in the thymus during iNKT cell ontogeny. The mechanisms that control the development of these IL-17 producing iNKT-17 cells (iNKT-17) are still not well defined. Diacylglycerol kinase zeta (DGKzeta) belongs to a family of enzymes that catalyze the phosphorylation and conversion of diacylglycerol to phosphatidic acid, two important second messengers involved in signaling from numerous receptors. We report here that DGKzeta plays an important role in iNKT-17 development. A deficiency of DGKzeta in mice causes a significant reduction of iNKT-17 cells, which is correlated with decreased RORgammat and IL-23 receptor expression. Interestingly, iNKT-17 defects caused by DGKzeta deficiency can be corrected in chimeric mice reconstituted with mixed wild-type and DGKzeta-deficient bone marrow cells. Taken together, our data identify DGKzeta as an important regulator of iNKT-17 development through iNKT-cell extrinsic mechanisms. PMID- 24073254 TI - High-incidence of human adenoviral co-infections in taiwan. AB - BACKGROUND: Respiratory infections caused by adenovirus (HAdV) are common year round. Recently, a significant increase of adenoviral infections was observed in Taiwan. OBJECTIVE: To understand the prevalence and molecular epidemiology of respiratory adenovirus circulating in Taiwan for the past decade. STUDY DESIGN: One hundred and twenty-six human adenoviruses, isolated between 2002 to 2011, were characterized via DNA sequencing of the hexon and fiber genes. The nucleotide sequences were then compared by phylogenetic analysis. RESULTS: HAdV B3 accounted for 64.3% (81/126) and peaked almost every year, whereas the sequences of hexon and fiber genes of HAdV-B3 were highly conserved in different years. A high incidence of co-infection of adenoviruses was observed (19.0%, 24/126); HAdV-B3 co-infected with HAdV-C2 was the most common combination (58.3%, 14/24). An additional interesting finding of repeated infection was noted in 10 children, all of whom showed first infection with adenovirus species HAdV-C, followed by species HAdV-B or HAdV-E. CONCLUSIONS: HAdV-B3 was the predominant type of respiratory adenovirus circulating in Taiwan over the past ten years. This merits further attention for vaccine development. Furthermore, the observed high-incidence of adenoviral co-infections along with repeated infections found in our study provides important epidemiological insights into adenovirus infections. PMID- 24073255 TI - Transcriptome profile of the green odorous frog (Odorrana margaretae). AB - Transcriptome profiles provide a practical and inexpensive alternative to explore genomic data in non-model organisms, particularly in amphibians where the genomes are very large and complex. The odorous frog Odorranamargaretae (Anura: Ranidae) is a dominant species in the mountain stream ecosystem of western China. Limited knowledge of its genetic background has hindered research on this species, despite its importance in the ecosystem and as biological resources. Here we report the transcriptome of O. margaretae in order to establish the foundation for genetic research. Using an Illumina sequencing platform, 62,321,166 raw reads were acquired. After a de novo assembly, 37,906 transcripts were obtained, and 18,933 transcripts were annotated to 14,628 genes. We functionally classified these transcripts by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). A total of 11,457 unique transcripts were assigned to 52 GO terms, and 1,438 transcripts were assigned to 128 KEGG pathways. Furthermore, we identified 27 potential antimicrobial peptides (AMPs), 50,351 single nucleotide polymorphism (SNP) sites, and 2,574 microsatellite DNA loci. The transcriptome profile of this species will shed more light on its genetic background and provide useful tools for future studies of this species, as well as other species in the genus Odorrana. It will also contribute to the accumulation of amphibian genomic data. PMID- 24073256 TI - Surface physicochemical properties at the micro and nano length scales: role on bacterial adhesion and Xylella fastidiosa biofilm development. AB - The phytopathogen Xylella fastidiosa grows as a biofilm causing vascular occlusion and consequently nutrient and water stress in different plant hosts by adhesion on xylem vessel surfaces composed of cellulose, hemicellulose, pectin and proteins. Understanding the factors which influence bacterial adhesion and biofilm development is a key issue in identifying mechanisms for preventing biofilm formation in infected plants. In this study, we show that X. fastidiosa biofilm development and architecture correlate well with physicochemical surface properties after interaction with the culture medium. Different biotic and abiotic substrates such as silicon (Si) and derivatized cellulose films were studied. Both biofilms and substrates were characterized at the micro- and nanoscale, which corresponds to the actual bacterial cell and membrane/ protein length scales, respectively. Our experimental results clearly indicate that the presence of surfaces with different chemical composition affect X. fastidiosa behavior from the point of view of gene expression and adhesion functionality. Bacterial adhesion is facilitated on more hydrophilic surfaces with higher surface potentials; XadA1 adhesin reveals different strengths of interaction on these surfaces. Nonetheless, despite different architectural biofilm geometries and rates of development, the colonization process occurs on all investigated surfaces. Our results univocally support the hypothesis that different adhesion mechanisms are active along the biofilm life cycle representing an adaptation mechanism for variations on the specific xylem vessel composition, which the bacterium encounters within the infected plant. PMID- 24073257 TI - Identification of therapeutic candidates for chronic lymphocytic leukemia from a library of approved drugs. AB - Chronic lymphocytic leukemia (CLL) is an adult lymphoid malignancy with a variable clinical course. There is considerable interest in the identification of new treatments, as most current approaches are not curative. While most patients respond to initial chemotherapy, relapsed disease is often resistant to the drugs commonly used in CLL and patients are left with limited therapeutic options. In this study, we used a luminescent cell viability assay based on ATP levels to find compounds that were potent and efficacious in killing CLL cells. We employed an in-house process of quantitative high throughput screening (qHTS) to assess 8 concentrations of each member of a 2,816 compound library (including FDA-approved drugs and those known to be bio-active from commercial suppliers). Using qHTS we generated potency values on each compound in lymphocytes donated from each of six individuals with CLL and five unaffected individuals. We found 102 compounds efficacious against cells from all six individuals with CLL ("consensus" drugs) with five of these showing low or no activity on lymphocytes from a majority of normal donors, suggesting some degree of specificity for the leukemic cells. To our knowledge, this is the first study to screen a drug library against primary CLL cells to identify candidate agents for anti-cancer therapy. The results presented here offer possibilities for the development of novel drug candidates for therapeutic uses to treat CLL and other diseases. PMID- 24073258 TI - Association between RASSF1A promoter methylation and prostate cancer: a systematic review and meta-analysis. AB - Prostate cancer (PCa) remains as one of the most common cause of cancer related death among men in the US. The widely used prostate specific antigen (PSA) screening is limited by low specificity. The diagnostic value of other biomarkers such as RAS association domain family protein 1 A (RASSF1A) promoter methylation in prostate cancer and the relationship between RASSF1A methylation and pathological features or tumor stage remains to be established. Therefore, a meta analysis of published studies was performed to understand the association between RASSF1A methylation and prostate cancer. In total, 16 studies involving 1431 cases and 565 controls were pooled with a random effect model in this investigation. The odds ratio (OR) of RASSF1A methylation in PCa case, compared to controls, was 14.73 with 95% CI = 7.58-28.61. Stratified analyses consistently showed a similar risk across different sample types and, methylation detection methods. In addition, RASSF1A methylation was associated with high Gleason score OR=2.35, 95% CI: 1.56-3.53. Furthermore, the pooled specificity for all included studies was 0.87 (95% CI: 0.72-0.94), and the pooled sensitivity was 0.76 (95% CI: 0.55-0.89). The specificity in each subgroup stratified by sample type remained above 0.84 and the sensitivity also remained above 0.60. These results suggested that RASSF1A promoter methylation would be a potential biomarker in PCa diagnosis and therapy. PMID- 24073259 TI - Evaluation of digital PCR for absolute RNA quantification. AB - Gene expression measurements detailing mRNA quantities are widely employed in molecular biology and are increasingly important in diagnostic fields. Reverse transcription (RT), necessary for generating complementary DNA, can be both inefficient and imprecise, but remains a quintessential RNA analysis tool using qPCR. This study developed a Transcriptomic Calibration Material and assessed the RT reaction using digital (d)PCR for RNA measurement. While many studies characterise dPCR capabilities for DNA quantification, less work has been performed investigating similar parameters using RT-dPCR for RNA analysis. RT dPCR measurement using three, one-step RT-qPCR kits was evaluated using single and multiplex formats when measuring endogenous and synthetic RNAs. The best performing kit was compared to UV quantification and sensitivity and technical reproducibility investigated. Our results demonstrate assay and kit dependent RT dPCR measurements differed significantly compared to UV quantification. Different values were reported by different kits for each target, despite evaluation of identical samples using the same instrument. RT-dPCR did not display the strong inter-assay agreement previously described when analysing DNA. This study demonstrates that, as with DNA measurement, RT-dPCR is capable of accurate quantification of low copy RNA targets, but the results are both kit and target dependent supporting the need for calibration controls. PMID- 24073260 TI - Non-secreted clusterin isoforms are translated in rare amounts from distinct human mRNA variants and do not affect Bax-mediated apoptosis or the NF-kappaB signaling pathway. AB - Clusterin, also known as apolipoprotein J, is expressed from a variety of tissues and implicated in pathological disorders such as neurodegenerative diseases, ischemia and cancer. In contrast to secretory clusterin (sCLU), which acts as an extracellular chaperone, the synthesis, subcellular localization and function(s) of intracellular CLU isoforms is currently a matter of intense discussion. By investigating human CLU mRNAs we here unravel mechanisms leading to the synthesis of distinct CLU protein isoforms and analyze their subcellular localization and their impact on apoptosis and on NF-kappaB-activity. Quantitative PCR-analyses revealed the expression of four different stress-inducible CLU mRNA variants in non-cancer and cancer cell lines. In all cell lines variant 1 represents the most abundant mRNA, whereas all other variants collectively account for no more than 0.34% of total CLU mRNA, even under stressed conditions. Overexpression of CLU cDNAs combined with in vitro mutagenesis revealed distinct translational start sites including a so far uncharacterized non-canonical CUG start codon. We show that all exon 2-containing mRNAs encode sCLU and at least three non-glycosylated intracellular isoforms, CLU1-449, CLU21-449 and CLU34-449, which all reside in the cytosol of unstressed and stressed HEK-293 cells. The latter is the only form expressed from an alternatively spliced mRNA variant lacking exon 2. Functional analysis revealed that none of these cytosolic CLU forms modulate caspase mediated intrinsic apoptosis or significantly affects TNF-alpha-induced NF-kappaB activity. Therefore our data challenge some of the current ideas regarding the physiological functions of CLU isoforms in pathologies. PMID- 24073261 TI - 4-ethylphenyl-cobalamin impairs tissue uptake of vitamin B12 and causes vitamin B12 deficiency in mice. AB - Cobeta-4-ethylphenyl-cob(III) alamin (EtPhCbl) is an organometallic analogue of vitamin B12 (CNCbl) which binds to transcobalamin (TC), a plasma protein that facilitates the cellular uptake of cobalamin (Cbl). In vitro assays with key enzymes do not convert EtPhCbl to the active coenzyme forms of Cbl suggesting that administration of EtPhCbl may cause cellular Cbl deficiency. Here, we investigate the in vivo effect of EtPhCbl in mice and its ability, if any, to induce Cbl deficiency. We show that EtPhCbl binds to mouse TC and we examined mice that received 3.5 nmol/24h EtPhCbl (n=6), 3.5 nmol/24h CNCbl (n=7) or NaCl (control group) (n=5) through osmotic mini-pumps for four weeks. We analyzed plasma, urine, liver, spleen, submaxillary glands and spinal cord for Cbl and markers of Cbl deficiency including methylmalonic acid (MMA) and homocysteine (tHcy). Plasma MMA (mean+/-SEM) was elevated in animals treated with EtPhCbl (1.01+/-0.12 umol/L) compared to controls (0.30+/-0.02 umol/L) and CNCbl (0.29+/ 0.01 umol/L) treated animals. The same pattern was observed for tHcy. Plasma total Cbl concentration was higher in animals treated with EtPhCbl (128.82+/-1.87 nmol/L) than in CNCbl treated animals (87.64+/-0.93 nmol/L). However, the organ levels of total Cbl were significantly lower in animals treated with EtPhCbl compared to CNCbl treated animals or controls, notably in the liver (157.07+/ 8.56 pmol/g vs. 603.85+/-20.02 pmol/g, and 443.09+/-12.32 pmol/g, respectively). Differences between the three groups was analysed using one-way ANOVA and, Bonferroni post-hoc test. EtPhCbl was present in all tissues, except the spinal cord, accounting for 35-90% of total Cbl. In conclusion, treatment with EtPhCbl induces biochemical evidence of Cbl deficiency. This may in part be caused by a compromised tissue accumulation of Cbl. PMID- 24073262 TI - Transcriptome sequencing and differential gene expression analysis of delayed gland morphogenesis in Gossypium australe during seed germination. AB - The genus Gossypium is a globally important crop that is used to produce textiles, oil and protein. However, gossypol, which is found in cultivated cottonseed, is toxic to humans and non-ruminant animals. Efforts have been made to breed improved cultivated cotton with lower gossypol content. The delayed gland morphogenesis trait possessed by some Australian wild cotton species may enable the widespread, direct usage of cottonseed. However, the mechanisms about the delayed gland morphogenesis are still unknown. Here, we sequenced the first Australian wild cotton species (Gossypiumaustrale) and a diploid cotton species (Gossypiumarboreum) using the Illumina Hiseq 2000 RNA-seq platform to help elucidate the mechanisms underlying gossypol synthesis and gland development. Paired-end Illumina short reads were de novo assembled into 226,184, 213,257 and 275,434 transcripts, clustering into 61,048, 47,908 and 72,985 individual clusters with N50 lengths of 1,710 bp, 1544 BP and 1,743 bp, respectively. The clustered Unigenes were searched against three public protein databases (TrEMBL, SwissProt and RefSeq) and the nucleotide and protein sequences of Gossypiumraimondii using BLASTx and BLASTn. A total of 21,987, 17,209 and 25,325 Unigenes were annotated. Of these, 18,766 (85.4%), 14,552 (84.6%) and 21,374 (84.4%) Unigenes could be assigned to GO-term classifications. We identified and analyzed 13,884 differentially expressed Unigenes by clustering and functional enrichment. Terpenoid-related biosynthesis pathways showed differentially regulated expression patterns between the two cotton species. Phylogenetic analysis of the terpene synthases family was also carried out to clarify the classifications of TPSs. RNA-seq data from two distinct cotton species provide comprehensive transcriptome annotation resources and global gene expression profiles during seed germination and gland and gossypol formation. These data may be used to further elucidate various mechanisms and help promote the usage of cottonseed. PMID- 24073263 TI - Selective feeding of bdelloid rotifers in river biofilms. AB - In situ pigment contents of biofilm-dwelling bdelloid rotifers of the Garonne River (France) were measured by high performance liquid chromatography (HPLC) and compared with pigment composition of surrounding biofilm microphytobenthic communities. Among pigments that were detected in rotifers, the presence of carotenoids fucoxanthin and myxoxanthophyll showed that the rotifers fed on diatoms and cyanobacteria. Unexpectedly, while diatoms strongly dominated microphytobenthic communities in terms of biomass, HPLC results hinted that rotifers selectively ingested benthic filamentous cyanobacteria. In doing so, rotifers could daily remove a substantial fraction (up to 28%) of this cyanobacterial biomass. The possibility that the rotifers hosted symbiotic myxoxanthophyll-containing cyanobacteria was examined by localisation of chlorophyll fluorescence within rotifers using confocal laser scanning microscopy (CLSM). CLSM results showed an even distribution of quasi-circular fluorescent objects (FO) throughout rotifer bodies, whereas myxoxanthophyll is a biomarker pigment of filamentous cyanobacteria, so the hypothesis was rejected. Our results also suggest that rotifers converted beta-carotene (provided by ingested algae) into echinenone, a photoprotective pigment. This study, which is the first one to detail in situ pigment contents of rotifers, clearly shows that the role of cyanobacteria as a food source for meiobenthic invertebrates has been underestimated so far, and deserves urgent consideration. PMID- 24073264 TI - Inhibition of Xenograft tumor growth by gold nanoparticle-DNA oligonucleotide conjugates-assisted delivery of BAX mRNA. AB - Use of non-biological agents for mRNA delivery into living systems in order to induce heterologous expression of functional proteins may provide more advantages than the use of DNA and/or biological vectors for delivery. However, the low efficiency of mRNA delivery into live animals, using non-biological systems, has hampered the use of mRNA as a therapeutic molecule. Here, we show that gold nanoparticle-DNA oligonucleotide (AuNP-DNA) conjugates can serve as universal vehicles for more efficient delivery of mRNA into human cells, as well as into xenograft tumors generated in mice. Injections of BAX mRNA loaded on AuNP-DNA conjugates into xenograft tumors resulted in highly efficient mRNA delivery. The delivered mRNA directed the efficient production of biologically functional BAX protein, a pro-apoptotic factor, consequently inhibiting tumor growth. These results demonstrate that mRNA delivery by AuNP-DNA conjugates can serve as a new platform for the development of safe and efficient gene therapy. PMID- 24073265 TI - Common genetic variations in Patched1 (PTCH1) gene and risk of hirschsprung disease in the Han Chinese population. AB - Hirschsprung disease (HSCR) is the most frequent genetic cause of congenital intestinal obstruction with an incidence of 1:5000 live births. In a pathway based epistasis analysis of data generated by genome-wide association study on HSCR, specific genotype of Patched 1 (PTCH1) has been linked to an increased risk for HSCR. The aim of the present study is to examine the contribution of genetic variants in PTCH1 to the susceptibility to HSCR in Han Chinese. Accordingly, we assessed 8 single nucleotide polymorphisms (SNPs) within PTCH1 gene in 104 subjects with sporadic HSCR and 151 normal controls of Han Chinese origin by the Sequenom MassArray technology (iPLEX GOLD). Two of the eight genetic markers were found to be significantly associated with Hirschsprung disease (rs357565, allele P = 0.005; rs2236405, allele P = 0.002, genotype P = 0.003). Both the C allele of rs357565 and the A allele of rs2236405 served as risk factors for HSCR. During haplotype analysis, one seven-SNP-based haplotype was the most significant, giving a global P = 0.0036. Our results firstly suggest common variations of PTCH1 may be involved in the altered risk for HSCR in the Han Chinese population, providing potential molecular markers for early diagnosis of Hirschsprung disease. PMID- 24073266 TI - Changes in the calcium-parathyroid hormone-vitamin d axis and prognosis for critically ill patients: a prospective observational study. AB - OBJECTIVE: Vitamin D deficiency is prevalent in critically ill patients and may contribute to suboptimal clinical outcomes, but little is known about alterations of the calcium-parathyroid hormone (PTH)-vitamin D axis and prognosis in these individuals. METHODS: A prospective observational study was conducted on 216 patients admitted to a university-affiliated, tertiary-care medical intensive care unit(MICU) between June 2011 and December 2012. Serum levels of 25 hydroxyvitamin D, ionised calcium and intact PTH were determined within 24 h of MICU admission. The primary end point was all-cause hospital mortality within 90 days of admission. RESULTS: 95 patients (44%) showed 25-hydroxyvitamin D deficiency. Patients deficient in vitamin D showed significantly higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score, rate of positive blood culture, incidence of multiple organ dysfunction syndrome, and 90-day mortality rate than did patients with vitamin D insufficiency or sufficiency (P<0.05), as well as lower levels of serum IgG. 25-Hydroxyvitamin D deficiency was identified as an independent risk factor for mortality (OR = 3.018, 95%CI 1.329-6.854, P = 0.008). Hypovitaminosis D in PTH-responders was associated with higher mortality than was the same condition in non-responders (P<0.05). CONCLUSIONS: These results suggest that vitamin D deficiency is prevalent among MICU patients, suggesting a significant derangement of the calcium-PTH-vitamin D axis in critically ill patients. Vitamin D deficiency is an independent risk factor for 90-day mortality, and hypovitaminosis D in PTH-responders is associated with higher mortality than is the same condition in non-responders. PMID- 24073268 TI - Joint modeling of transitional patterns of Alzheimer's disease. AB - While the experimental Alzheimer's drugs recently developed by pharmaceutical companies failed to stop the progression of Alzheimer's disease, clinicians strive to seek clues on how the patients would be when they visit back next year, based upon the patients' current clinical and neuropathologic diagnosis results. This is related to how to precisely identify the transitional patterns of Alzheimer's disease. Due to the complexities of the diagnosis of Alzheimer's disease, the condition of the disease is usually characterized by multiple clinical and neuropathologic measurements, including Clinical Dementia Rating (CDRGLOB), Mini-Mental State Examination (MMSE), a score derived from the clinician judgement on neuropsychological tests (COGSTAT), and Functional Activities Questionnaire (FAQ). In this research article, we investigate a class of novel joint random-effects transition models that are used to simultaneously analyze the transitional patterns of multiple primary measurements of Alzheimer's disease and, at the same time, account for the association between the measurements. The proposed methodology can avoid the bias introduced by ignoring the correlation between primary measurements and can predict subject-specific transitional patterns. PMID- 24073267 TI - Similar brain activation during false belief tasks in a large sample of adults with and without autism. AB - Reading about another person's beliefs engages 'Theory of Mind' processes and elicits highly reliable brain activation across individuals and experimental paradigms. Using functional magnetic resonance imaging, we examined activation during a story task designed to elicit Theory of Mind processing in a very large sample of neurotypical (N = 462) individuals, and a group of high-functioning individuals with autism spectrum disorders (N = 31), using both region-of interest and whole-brain analyses. This large sample allowed us to investigate group differences in brain activation to Theory of Mind tasks with unusually high sensitivity. There were no differences between neurotypical participants and those diagnosed with autism spectrum disorder. These results imply that the social cognitive impairments typical of autism spectrum disorder can occur without measurable changes in the size, location or response magnitude of activity during explicit Theory of Mind tasks administered to adults. PMID- 24073269 TI - Determining the true polarity and amplitude of synaptic currents underlying gamma oscillations of local field potentials. AB - Fluctuations in successive waves of oscillatory local field potentials (LFPs) reflect the ongoing processing of neuron populations. However, their amplitude, polarity and synaptic origin are uncertain due to the blending of electric fields produced by multiple converging inputs, and the lack of a baseline in standard AC coupled recordings. Consequently, the estimation of underlying currents by laminar analysis yields spurious sequences of inward and outward currents. We devised a combined analytical/experimental approach that is suitable to study laminated structures. The approach was essayed on an experimental oscillatory LFP as the Schaffer-CA1 gamma input in anesthetized rats, and it was verified by parallel processing of model LFPs obtained through a realistic CA1 aggregate of compartmental units. This approach requires laminar LFP recordings and the isolation of the oscillatory input from other converging pathways, which was achieved through an independent component analysis. It also allows the spatial and temporal components of pathway-specific LFPs to be separated. While reconstructed Schaffer-specific LFPs still show spurious inward/outward current sequences, these were clearly stratified into distinct subcellular domains. These spatial bands guided the localized delivery of neurotransmitter blockers in experiments. As expected, only Glutamate but not GABA blockers abolished Schaffer LFPs when applied to the active but not passive subcellular domains of pyramidal cells. The known chemical nature of the oscillatory LFP allowed an empirical offset of the temporal component of Schaffer LFPs, such that following reconstruction they yield only sinks or sources at the appropriate sites. In terms of number and polarity, some waves increased and others decreased proportional to the concomitant inputs in native multisynaptic LFPs. Interestingly, the processing also retrieved the initiation time for each wave, which can be used to discriminate afferent from postsynaptic cells in standard spike-phase correlations. The applicability of this approach to other pathways and structures is discussed. PMID- 24073270 TI - Early exposure to traumatic stressors impairs emotional brain circuitry. AB - Exposure to early life trauma (ELT) is known to have a profound impact on mental development, leading to a higher risk for depression and anxiety. Our aim was to use multiple structural imaging methods to systematically investigate how traumatic stressors early in life impact the emotional brain circuits, typically found impaired with clinical diagnosis of depression and anxiety, across the lifespan in an otherwise healthy cohort. MRI data and self-reported histories of ELT from 352 healthy individuals screened for no psychiatric disorders were analyzed in this study. The volume and cortical thickness of the limbic and cingulate regions were assessed for all participants. A large subset of the cohort also had diffusion tensor imaging data, which was used to quantify white matter structural integrity of these regions. We found a significantly smaller amygdala volume and cortical thickness in the rostral anterior cingulate cortex associated with higher ELT exposure only for the adolescence group. White matter integrity of these regions was not affected. These findings demonstrate that exposure to early life trauma is associated with alterations in the gray matter of cingulate-limbic regions during adolescence in an otherwise healthy sample. These findings are interesting in the context that the affected regions are central neuroanatomical components in the psychopathology of depression, and adolescence is a peak period for risk and onset of the disorder. PMID- 24073271 TI - Dissection of malonyl-coenzyme A reductase of Chloroflexus aurantiacus results in enzyme activity improvement. AB - The formation of fusion protein in biosynthetic pathways usually improves metabolic efficiency either channeling intermediates and/or colocalizing enzymes. In the metabolic engineering of biochemical pathways, generating unnatural protein fusions between sequential biosynthetic enzymes is a useful method to increase system efficiency and product yield. Here, we reported a special case. The malonyl-CoA reductase (MCR) of Chloroflexus aurantiacus catalyzes the conversion of malonyl-CoA to 3-hydroxypropionate (3HP), and is a key enzyme in microbial production of 3HP, an important platform chemical. Functional domain analysis revealed that the N-terminal region of MCR (MCR-N; amino acids 1-549) and the C-terminal region of MCR (MCR-C; amino acids 550-1219) were functionally distinct. The malonyl-CoA was reduced into free intermediate malonate semialdehyde with NADPH by MCR-C fragment, and further reduced to 3HP by MCR-N fragment. In this process, the initial reduction of malonyl-CoA was rate limiting. Site-directed mutagenesis demonstrated that the TGXXXG(A)X(1-2)G and YXXXK motifs were important for enzyme activities of both MCR-N and MCR-C fragments. Moreover, the enzyme activity increased when MCR was separated into two individual fragments. Kinetic analysis showed that MCR-C fragment had higher affinity for malonyl-CoA and 4-time higher K cat/K m value than MCR. Dissecting MCR into MCR-N and MCR-C fragments also had a positive effect on the 3HP production in a recombinant Escherichia coli strain. Our study showed the feasibility of protein dissection as a new strategy in biosynthetic systems. PMID- 24073272 TI - Polyunsaturated fatty acid metabolism signature in ischemia differs from reperfusion in mouse intestine. AB - Polyunsaturated fatty acid (PUFA) metabolites are bioactive autoacoids that play an important role in the pathogenesis of a vast number of pathologies, including gut diseases. The induction and the resolution of inflammation depend on PUFA metabolic pathways that are favored. Therefore, understanding the profile of n-6 (eicosanoids)/n-3 (docosanoids) PUFA-derived metabolites appear to be as important as gene or protein array approaches, to uncover the molecules potentially implicated in inflammatory diseases. Using high sensitivity liquid chromatography tandem mass spectrometry, we characterized the tissue profile of PUFA metabolites in an experimental model of murine intestinal ischemia reperfusion. We identified temporal and quantitative differences in PUFA metabolite production, which correlated with inflammatory damage. Analysis revealed that early ischemia induces both pro-inflammatory and anti-inflammatory eicosanoid production. Primarily, LOX- (5/15/12/8-HETE, LTB4, LxA4) and CYP- (5, 6-EET) metabolites were produced upon ischemia, but also PGE3, and PDx. This suggests that different lipids simultaneously play a role in the induction and counterbalance of ischemic inflammatory response from its onset. COX-derived metabolites were more present from 2 to 5 hours after reperfusion, fitting with the concomitant inflammatory peaks. All metabolites were decreased 48 hours post reperfusion except for to the pro-resolving RvE precursor 18-HEPE and the PPAR gammaalphaMUMUalpha agonist, 15d-PGJ2. Data obtained through the pharmacological blockade of transient receptor potential vanilloid-4, which can be activated by 5, 6-EET, revealed that the endogenous activation of this receptor modulates post ischemic intestinal inflammation. Altogether, these results demonstrate that different lipid pathways are involved in intestinal ischemia-reperfusion processes. Some metabolites, which expression is severely changed upon intestinal ischemia-reperfusion could provide novel targets and may facilitate the development of new pharmacological treatments. PMID- 24073273 TI - Cross-sectional study assessing HIV related knowledge, attitudes and behavior in Namibian public sector employees in capital and regional settings. AB - The study objective was to assess the current status of HIV knowledge, attitudes and behavior (KAB) among employees of Namibian ministries. As most HIV campaigning takes place in the capital of Windhoek, an additional aim was to compare Windhoek to four regions (Hardap, Erongo, Oshana, and Caprivi). Between January and March 2011 a cross-sectional survey was conducted in two Namibian ministries, with participants selected randomly from the workforce. Data collection was based on questionnaires. 832 participants were included in the study (51.6% male). Nearly 90% of participants reported to have been tested for HIV before. Knowledge about HIV transmission ranged from 67% to 95% of correct answers, with few differences between the capital and regions. However, a knowledge gap regarding HIV transmission and prevention was seen. In particular, we found significantly lower knowledge regarding transmission from mother-to child during pregnancy and higher rate of belief in a supernatural role in HIV transmission. In addition, despite many years of HIV prevention activities, a substantial proportion of employees had well-known HIV risk factors including multiple concurrent partnership rates (21%), intergenerational sex (19%), and lower testing rates for men (82% compared to women with 91%). PMID- 24073274 TI - Novel CD47: SIRPalpha dependent mechanism for the activation of STAT3 in antigen presenting cell. AB - Cell surface CD47 interacts with its receptor, signal-regulatory-protein alpha (SIRPalpha) that is expressed predominantly on macrophages, to inhibit phagocytosis of normal, healthy cells. This "don't eat me" signal is mediated through tyrosine phosphorylation of SIRPalpha at the cytoplasmic ITIM motifs and the recruitment of the phosphatase, SHP-1. We previously revealed a novel mechanism for the activation of the STAT3 pathway and the regulation of human APC maturation and function that is based on cell:cell interaction. In this study, we present evidence supporting the notion that CD47:SIRPalpha serves as a cell surface receptor: ligand pair involved in this contact-dependent STAT3 activation and regulation of APC maturation. We show that upon co-culturing APC with various primary and tumor cell lines STAT3 phosphorylation and IL-10 expression are induced, and such regulation could be suppressed by specific CD47 siRNAs and shRNAs. Significantly, >50% reduction in CD47 expression abolished the contact dependent inhibition of T cell activation. Furthermore, co-immunoprecipitation experiments revealed a physical association between SIRPalpha and STAT3. Thus, we suggest that in addition to signaling through the ITIM-SHP-1 complex that transmit an anti-phagocytotic, CD47:SIRPalpha also triggers STAT3 signaling that is linked to an immature APC phenotype and peripheral tolerance under steady state and pathological conditions. PMID- 24073275 TI - Cathepsin L plays a role in quinolinic acid-induced NF-Kappab activation and excitotoxicity in rat striatal neurons. AB - The present study seeks to investigate the role of cathepsin L in glutamate receptor-induced transcription factor nuclear factor-kappa B (NF-kappaB) activation and excitotoxicity in rats striatal neurons. Stereotaxic administration of the N-methyl-d-aspartate (NMDA) receptor agonist Quinolinic acid (QA) into the unilateral striatum was used to produce the in vivo excitotoxic model. Co-administration of QA and the cathepsin L inhibitor Z-FF-FMK or 1-Naphthalenesulfonyl-IW-CHO (NaphthaCHO) was used to assess the contribution of cathepsin L to QA-induced striatal neuron death. Western blot analysis and cathepsin L activity assay were used to assess the changes in the levels of cathepsin L after QA treatment. Western blot analysis was used to assess the changes in the protein levels of inhibitor of NF-kappaB alpha isoform (IkappaB alpha) and phospho-IkappaB alpha (p-IkappaBalpha) after QA treatment. Immunohistochemical analysis was used to detect the effects of Z-FF-FMK or NaphthaCHO on QA-induced NF-kappaB. Western blot analysis was used to detect the effects of Z-FF-FMK or NaphthaCHO on QA-induced IkappaB-alpha phosphorylation and degradation, changes in the levels of IKKalpha, p-IKKalpha, TP53, caspase-3, beclin1, p62, and LC3II/LC3I. The results show that QA-induced loss of striatal neurons were strongly inhibited by Z-FF-FMK or NaphthaCHO. QA-induced degradation of IkappaB-alpha, NF-kappaB nuclear translocation, up-regulation of NF-kappaB responsive gene TP53, and activation of caspase-3 was strongly inhibited by Z-FF FMK or NaphthaCHO. QA-induced increases in beclin 1, LC3II/LC3I, and down regulation of p62 were reduced by Z-FF-FMK or NaphthaCHO. These results suggest that cathepsin L is involved in glutamate receptor-induced NF-kappaB activation. Cathepsin L inhibitors have neuroprotective effects by inhibiting glutamate receptor-induced IkappaB-alpha degradation and NF-kappaB activation. PMID- 24073276 TI - Diversity dynamics of silurian-early carboniferous land plants in South china. AB - New megafossil and microfossil data indicate four episodes in the diversification of Silurian-Early Carboniferous land plants of South China, a relatively continuous regional record. Plant diversity increased throughout, but the rising curve was punctuated by three major falls. There were peaks of origination in the Ludlow-Pragian, Givetian, late Famennian and Visean and peaks of extinction in the Pragian-Emsian, Givetian and early Tournaisian. Speciation and extinction rates were highest in the Lochkovian-Pragian and became progressively lower in subsequent stages. High correlation coefficients indicate that these events are associated with the availability of land habitat contingent on eustatic variations and increasing numbers of cosmopolitan genera. Meanwhile, proportions of endemic genera declined gradually. Due to less endemism and more migrations, both speciation and species extinction rates reduced. The changes of diversity and the timing of the three extinctions of land plants in South China are similar to those known already from Laurussia. However, the largest events in the Lochkovian-Pragian and subsequent smaller ones have not been seen in the global pattern of plant evolution. These land plant events do not correspond well temporally with those affecting land vertebrates or marine invertebrates. In South China, the diversity curve of land plants is generally opposite to that of marine faunas, showing a strong effect of eustatic variations. The increasing diversity of both land vertebrates and plants was punctuated above the Devonian Carboniferous boundary, known as Romer's Gap, implying common underlying constraints on macroevolution of land animals and plants. PMID- 24073277 TI - Tuberculosis case finding: evaluation of a paper slip method to trace contacts. AB - SETTING: South Africa has the third highest tuberculosis (TB) burden in the world. Intensified case finding, recommended by WHO, is one way to control TB. OBJECTIVE: To evaluate the effectiveness and acceptability of a paper slip method for TB contact tracing. METHOD: TB patients were offered paper slips to give to their contacts, inviting them for TB screening. The number of contacts screened and the proportion diagnosed with TB was calculated. Contacts that returned to the clinic after receiving the slips were interviewed. A focus group discussion (FGD) with TB patients was held to determine their acceptability. RESULTS: From 718 paper slips issued, a 26% TB contact tracing rate was found, with a 12% case detection rate. The majority (68%) of contacts were screened within 2 weeks of receiving the slip. Age and gender were not significantly associated with time to screening. 16% of the contacts screened did not reside with the TB patients. 98% of the contacts said the method was acceptable. FGD findings show that this method is acceptable and may prevent stigma associated with TB/HIV. CONCLUSION: This simple, inexpensive method yields high contact tracing and case detection rates and potentially would yield additional benefits outside households. PMID- 24073278 TI - Adaptation to emotional conflict: evidence from a novel face emotion paradigm. AB - The preponderance of research on trial-by-trial recruitment of affective control (e.g., conflict adaptation) relies on stimuli wherein lexical word information conflicts with facial affective stimulus properties (e.g., the face-Stroop paradigm where an emotional word is overlaid on a facial expression). Several studies, however, indicate different neural time course and properties for processing of affective lexical stimuli versus affective facial stimuli. The current investigation used a novel task to examine control processes implemented following conflicting emotional stimuli with conflict-inducing affective face stimuli in the absence of affective words. Forty-one individuals completed a task wherein the affective-valence of the eyes and mouth were either congruent (happy eyes, happy mouth) or incongruent (happy eyes, angry mouth) while high-density event-related potentials (ERPs) were recorded. There was a significant congruency effect and significant conflict adaptation effects for error rates. Although response times (RTs) showed a significant congruency effect, the effect of previous-trial congruency on current-trial RTs was only present for current congruent trials. Temporospatial principal components analysis showed a P3-like ERP source localized using FieldTrip software to the medial cingulate gyrus that was smaller on incongruent than congruent trials and was significantly influenced by the recruitment of control processes following previous-trial emotional conflict (i.e., there was significant conflict adaptation in the ERPs). Results show that a face-only paradigm may be sufficient to elicit emotional conflict and suggest a system for rapidly detecting conflicting emotional stimuli and subsequently adjusting control resources, similar to cognitive conflict detection processes, when using conflicting facial expressions without words. PMID- 24073279 TI - Microtubules coordinate VEGFR2 signaling and sorting. AB - VEGF signaling is a key regulator of vessel formation and function. In vascular endothelial cells, this signaling is mediated through its cognate receptor VEGFR2, which is dynamically sorted in response to ligand. Little is known about the underlying mechanism of this intracellular sorting. Here we examined the role of different components of the cytoskeleton in this process. We found that VEGFR2 mainly associates with microtubule fibers and to a lesser extent with intermediate filaments and actin. Microtubule disruption leads to accumulation of VEGFR2 protein in the membrane and cytoplasm leading to defects in VEGF signaling. In contrast, inhibition of actin filaments results in no accumulation of VEGFR2 total protein or apparent changes in microtubule association. Instead, actin inhibition leads to a more global signaling disruption of the ERK1/2 pathway. This is the first report demonstrating that VEGFR2 associates closely with microtubules in modulating the subcellular sorting and signaling of VEGFR2. PMID- 24073280 TI - Matrix metalloproteinase-10/TIMP-2 structure and analyses define conserved core interactions and diverse exosite interactions in MMP/TIMP complexes. AB - Matrix metalloproteinases (MMPs) play central roles in vertebrate tissue development, remodeling, and repair. The endogenous tissue inhibitors of metalloproteinases (TIMPs) regulate proteolytic activity by binding tightly to the MMP active site. While each of the four TIMPs can inhibit most MMPs, binding data reveal tremendous heterogeneity in affinities of different TIMP/MMP pairs, and the structural features that differentiate stronger from weaker complexes are poorly understood. Here we report the crystal structure of the comparatively weakly bound human MMP-10/TIMP-2 complex at 2.1 A resolution. Comparison with previously reported structures of MMP-3/TIMP-1, MT1-MMP/TIMP-2, MMP-13/TIMP-2, and MMP-10/TIMP-1 complexes offers insights into the structural basis of binding selectivity. Our analyses identify a group of highly conserved contacts at the heart of MMP/TIMP complexes that define the conserved mechanism of inhibition, as well as a second category of diverse adventitious contacts at the periphery of the interfaces. The AB loop of the TIMP N-terminal domain and the contact loops of the TIMP C-terminal domain form highly variable peripheral contacts that can be considered as separate exosite interactions. In some complexes these exosite contacts are extensive, while in other complexes the AB loop or C-terminal domain contacts are greatly reduced and appear to contribute little to complex stability. Our data suggest that exosite interactions can enhance MMP/TIMP binding, although in the relatively weakly bound MMP-10/TIMP-2 complex they are not well optimized to do so. Formation of highly variable exosite interactions may provide a general mechanism by which TIMPs are fine-tuned for distinct regulatory roles in biology. PMID- 24073281 TI - Lipid metabolites enhance secretion acting on SNARE microdomains and altering the extent and kinetics of single release events in bovine adrenal chromaffin cells. AB - Lipid molecules such as arachidonic acid (AA) and sphingolipid metabolites have been implicated in modulation of neuronal and endocrine secretion. Here we compare the effects of these lipids on secretion from cultured bovine chromaffin cells. First, we demonstrate that exogenous sphingosine and AA interact with the secretory apparatus as confirmed by FRET experiments. Examination of plasma membrane SNARE microdomains and chromaffin granule dynamics using total internal reflection fluorescent microscopy (TIRFM) suggests that sphingosine production promotes granule tethering while arachidonic acid promotes full docking. Our analysis of single granule release kinetics by amperometry demonstrated that both sphingomyelinase and AA treatments enhanced drastically the amount of catecholamines released per individual event by either altering the onset phase of or by prolonging the off phase of single granule catecholamine release kinetics. Together these results demonstrate that the kinetics and extent of the exocytotic fusion pore formation can be modulated by specific signalling lipids through related functional mechanisms. PMID- 24073282 TI - Reduced sleep-like quiescence in both hyperactive and hypoactive mutants of the Galphaq Gene egl-30 during lethargus in Caenorhabditis elegans. AB - Sleep-like states are characterized by massively reduced behavioral activity. Little is known about genetic control of sleep-like behavior. It is also not clear how general activity levels during wake-like behavior influence activity levels during sleep-like behavior. Mutations that increase wake-like activity are generally believed to also increase activity during sleep-like behavior and mutations that decrease wake-like activity are believed to have decreased activity during sleep-like behavior. We studied sleep-like behavior during lethargus in larvae of Caenorhabditis elegans. We looked through a small set of known mutants with altered activity levels. As expected, mutants with increased activity levels typically showed less sleep-like behavior. Among these hyperactive mutants was a gain-of-function mutant of the conserved heterotrimeric G protein subunit Galphaq gene egl-30. We found, however, that an unusual semidominant hypoactive mutant of egl-30 also had reduced sleep-like behavior. While movement was severely reduced and impaired in the semidominant egl-30 mutant, sleep-like behavior was severely reduced: the semidominant egl-30 mutant lacked prolonged periods of complete immobility, reduced spontaneous neural activity less, and reduced responsiveness to stimulation less. egl-30 is a well known regulator of behavior. Our results suggest that egl-30 controls not only general activity levels, but also differences between wake-like and sleep-like behavior. PMID- 24073283 TI - Ethanol metabolism modifies hepatic protein acylation in mice. AB - Mitochondrial protein acetylation increases in response to chronic ethanol ingestion in mice, and is thought to reduce mitochondrial function and contribute to the pathogenesis of alcoholic liver disease. The mitochondrial deacetylase SIRT3 regulates the acetylation status of several mitochondrial proteins, including those involved in ethanol metabolism. The newly discovered desuccinylase activity of the mitochondrial sirtuin SIRT5 suggests that protein succinylation could be an important post-translational modification regulating mitochondrial metabolism. To assess the possible role of protein succinylation in ethanol metabolism, we surveyed hepatic sub-cellular protein fractions from mice fed a control or ethanol-supplemented diet for succinyl-lysine, as well as acetyl , propionyl-, and butyryl-lysine post-translational modifications. We found mitochondrial protein propionylation increases, similar to mitochondrial protein acetylation. In contrast, mitochondrial protein succinylation is reduced. These mitochondrial protein modifications appear to be primarily driven by ethanol metabolism, and not by changes in mitochondrial sirtuin levels. Similar trends in acyl modifications were observed in the nucleus. However, comparatively fewer acyl modifications were observed in the cytoplasmic or the microsomal compartments, and were generally unchanged by ethanol metabolism. Using a mass spectrometry proteomics approach, we identified several candidate acetylated, propionylated, and succinylated proteins, which were enriched using antibodies against each modification. Additionally, we identified several acetyl and propionyl lysine residues on the same sites for a number of proteins and supports the idea of the overlapping nature of lysine-specific acylation. Thus, we show that novel post-translational modifications are present in hepatic mitochondrial, nuclear, cytoplasmic, and microsomal compartments and ethanol ingestion, and its associated metabolism, induce specific changes in these acyl modifications. These data suggest that protein acylation, beyond protein acetylation, contributes to the overall metabolic regulatory network and could play an important role in the pathogenesis of alcoholic liver disease. PMID- 24073284 TI - Molecular expression and pharmacological evidence for a functional role of kv7 channel subtypes in Guinea pig urinary bladder smooth muscle. AB - Voltage-gated Kv7 (KCNQ) channels are emerging as essential regulators of smooth muscle excitability and contractility. However, their physiological role in detrusor smooth muscle (DSM) remains to be elucidated. Here, we explored the molecular expression and function of Kv7 channel subtypes in guinea pig DSM by RT PCR, qRT-PCR, immunohistochemistry, electrophysiology, and isometric tension recordings. In whole DSM tissue, mRNAs for all Kv7 channel subtypes were detected in a rank order: Kv7.1~Kv7.2Kv7.3~Kv7.5Kv7.4. In contrast, freshly-isolated DSM cells showed mRNA expression of: Kv7.1~Kv7.2Kv7.5Kv7.3~Kv7.4. Immunohistochemical confocal microscopy analyses of DSM, conducted by using co-labeling of Kv7 channel subtype-specific antibodies and alpha-smooth muscle actin, detected protein expression for all Kv7 channel subtypes, except for the Kv7.4, in DSM cells. L-364373 (R-L3), a Kv7.1 channel activator, and retigabine, a Kv7.2-7.5 channel activator, inhibited spontaneous phasic contractions and the 10-Hz electrical field stimulation (EFS)-induced contractions of DSM isolated strips. Linopiridine and XE991, two pan-Kv7 (effective at Kv7.1-Kv7.5 subtypes) channel inhibitors, had opposite effects increasing DSM spontaneous phasic and 10 Hz EFS induced contractions. EFS-induced DSM contractions generated by a wide range of stimulation frequencies were decreased by L-364373 (10 uM) or retigabine (10 uM), and increased by XE991 (10 uM). Retigabine (10 uM) induced hyperpolarization and inhibited spontaneous action potentials in freshly-isolated DSM cells. In summary, Kv7 channel subtypes are expressed at mRNA and protein levels in guinea pig DSM cells. Their pharmacological modulation can control DSM contractility and excitability; therefore, Kv7 channel subtypes provide potential novel therapeutic targets for urinary bladder dysfunction. PMID- 24073285 TI - Downregulation of DAB2IP promotes mesenchymal-to-neuroepithelial transition and neuronal differentiation of human mesenchymal stem cells. AB - The DOC-2/DAB2 interactive protein (DAB2IP) is a new member of the Ras GTPase activating protein family. Recent studies have shown that, in addition to its tumor suppressive role in various tumors, DAB2IP also plays an important role in regulating neuronal migration and positioning during brain development. In this study, we determined the roles of DAB2IP in the neuronal differentiation of human mesenchymal stem cells (hMSCs). We found that lentiviral short hairpin RNA (shRNA)-mediated knockdown of DAB2IP promoted the mesenchymal-to-neuroepithelial stem cell transition (MtNeST) and neuronal differentiation, which were accompanied by a reduction of cell proliferation but not apoptosis or cellular senescence. This suggests that DAB2IP plays an important role in the neuronal induction of hMSCs. Moreover, our finding that reduction of glycogen synthase kinase 3 beta (GSK3beta) activity upon LiCl pretreatment inhibited both the MtNeST and production of MAP2-positive cells upon DAB2IP knockdown suggests that this transition is most likely mediated by regulation of the GSK3beta signaling pathway. Our study demonstrates that DAB2IP participates in the first step of neuron induction of hMSCs, which implies a potentially important role for DAB2IP in the MtNeST during neurogenesis. PMID- 24073286 TI - Soluble HMGB1 is a novel adipokine stimulating IL-6 secretion through RAGE receptor in SW872 preadipocyte cell line: contribution to chronic inflammation in fat tissue. AB - Low-grade inflammation (LGI) is a central phenomenon in the genesis of obesity and insulin-resistance characterized by IL-6 in human serum. Whereas this LGI was initially thought to be mainly attributed to macrophage activation, it is now known that pre-adipocytes and adipocytes secrete several adipokines including IL 6 and participate to LGI and associated pathologies. In macrophages, HMGB1 is a nuclear yet secreted protein and acts as a cytokine to drive the production of inflammatory molecules through RAGE and TLR2/4. In this paper we tested the secretion of HMGB1 and the auto- and paracrine contribution to fat inflammation using the human preadipocyte cell line SW872 as a model. We showed that 1) human SW872 secreted actively HMGB1, 2) IL-6 production was positively linked to high levels of secreted HMGB1, 3) recombinant HMGB1 boosted IL-6 expression and this effect was mediated by the receptor RAGE and did not involve TLR2 or TLR4. These results suggest that HMGB1 is a major adipokine contributing to LGI implementation and maintenance, and can be considered as a target to develop news therapeutics in LGI associated pathologies such as obesity and type II diabetes. PMID- 24073287 TI - High-throughput RNA FISH analysis by imaging flow cytometry reveals that pioneer factor Foxa1 reduces transcriptional stochasticity. AB - Genes are regulated at the single-cell level. Here, we performed RNA FISH of thousands of cells by flow cytometry (flow-RNA FISH) to gain insight into transcriptional variability between individual cells. These experiments utilized the murine adenocarcinoma 3134 cell line with 200 copies of the MMTV-Ras reporter integrated at a single genomic locus. The MMTV array contains approximately 800 1200 binding sites for the glucocorticoid receptor (GR) and 600 binding sites for the pioneer factor Foxa1. Hormone activation of endogenous GR by dexamethasone treatment resulted in highly variable changes in the RNA FISH intensity (25-300 pixel intensity units) and size (1.25-15 um), indicative of probabilistic or stochastic mechanisms governing GR and cofactor activation of the MMTV promoter. Exogenous expression of the pioneer factor Foxa1 increased the FISH signal intensity and size as expected for a chromatin remodeler that enhances transcriptional competence through increased chromatin accessibility. In addition, specific analysis of Foxa1-enriched cell sub-populations showed that low and high Foxa1 levels substantially lowered the cell-to-cell variability in the FISH intensity as determined by a noise calculation termed the % coefficient of variation. These results suggest that an additional function of the pioneer factor Foxa1 may be to decrease transcriptional noise. PMID- 24073288 TI - A transmission model for the ecology of an avian blood parasite in a temperate ecosystem. AB - Most of our knowledge about avian haemosporidian parasites comes from the Hawaiian archipelago, where recently introduced Plasmodiumrelictum has contributed to the extinction of many endemic avian species. While the ecology of invasive malaria is reasonably understood, the ecology of endemic haemosporidian infection in mainland systems is poorly understood, even though it is the rule rather than the exception. We develop a mathematical model to explore and identify the ecological factors that most influence transmission of the common avian parasite, Leucocytozoonfringillinarum (Apicomplexa). The model was parameterized from White-crowned Sparrow (Zonotrichialeucophrys) and S. silvestre / craigi black fly populations breeding in an alpine ecosystem. We identify and examine the importance of altricial nestlings, the seasonal relapse of infected birds for parasite persistence across breeding seasons, and potential impacts of seasonal changes in black fly emergence on parasite prevalence in a high elevation temperate system. We also use the model to identify and estimate the parameters most influencing transmission dynamics. Our analysis found that relapse of adult birds and young of the year birds were crucial for parasite persistence across multiple seasons. However, distinguishing between nude nestlings and feathered young of the year was unnecessary. Finally, due to model sensitivity to many black fly parameters, parasite prevalence and sparrow recruitment may be most affected by seasonal changes in environmental temperature driving shifts in black fly emergence and gonotrophic cycles. PMID- 24073289 TI - Cell-intrinsic role for NF-kappa B-inducing kinase in peripheral maintenance but not thymic development of Foxp3+ regulatory T cells in mice. AB - NF-kappaB inducing kinase (NIK, MAP3K14) is a key signaling molecule in non canonical NF-kappaB activation, and NIK deficient mice have been instrumental in deciphering the immunologic role of this pathway. Global ablation of NIK prevents lymph node development, impairs thymic stromal development, and drastically reduces B cells. Despite altered thymic selection, T cell numbers are near normal in NIK deficient mice. The exception is CD4(+) regulatory T cells (Tregs), which are reduced in the thymus and periphery. Defects in thymic stroma are known to contribute to impaired Treg generation, but whether NIK also plays a cell intrinsic role in Tregs is unknown. Here, we compared intact mice with single and mixed BM chimeric mice to assess the intrinsic role of NIK in Treg generation and maintenance. We found that while NIK expression in stromal cells suffices for normal thymic Treg development, NIK is required cell-intrinsically to maintain peripheral Tregs. In addition, we unexpectedly discovered a cell-intrinsic role for NIK in memory phenotype conventional T cells that is masked in intact mice, but revealed in BM chimeras. These results demonstrate a novel role for NIK in peripheral regulatory and memory phenotype T cell homeostasis. PMID- 24073290 TI - Integrated analysis of mismatch repair system in malignant astrocytomas. AB - Malignant astrocytomas are the most aggressive primary brain tumors with a poor prognosis despite optimal treatment. Dysfunction of mismatch repair (MMR) system accelerates the accumulation of mutations throughout the genome causing uncontrolled cell growth. The aim of this study was to characterize the MMR system defects that could be involved in malignant astrocytoma pathogenesis. We analyzed protein expression and promoter methylation of MLH1, MSH2 and MSH6 as well as microsatellite instability (MSI) and MMR gene mutations in a set of 96 low- and high-grade astrocytomas. Forty-one astrocytomas failed to express at least one MMR protein. Loss of MSH2 expression was more frequent in low-grade astrocytomas. Loss of MLH1 expression was associated with MLH1 promoter hypermethylation and MLH1-93G>A promoter polymorphism. However, MSI was not related with MMR protein expression and only 5% of tumors were MSI-High. Furthermore, the incidence of tumors carrying germline mutations in MMR genes was low and only one glioblastoma was associated with Lynch syndrome. Interestingly, survival analysis identified that tumors lacking MSH6 expression presented longer overall survival in high-grade astrocytoma patients treated only with radiotherapy while MSH6 expression did not modify the prognosis of those patients treated with both radiotherapy and chemotherapy. Our findings suggest that MMR system alterations are a frequent event in malignant astrocytomas and might help to define a subgroup of patients with different outcome. PMID- 24073291 TI - Pax6 is required for normal cell-cycle exit and the differentiation kinetics of retinal progenitor cells. AB - The coupling between cell-cycle exit and onset of differentiation is a common feature throughout the developing nervous system, but the mechanisms that link these processes are mostly unknown. Although the transcription factor Pax6 has been implicated in both proliferation and differentiation of multiple regions within the central nervous system (CNS), its contribution to the transition between these successive states remains elusive. To gain insight into the role of Pax6 during the transition from proliferating progenitors to differentiating precursors, we investigated cell-cycle and transcriptomic changes occurring in Pax6 (-) retinal progenitor cells (RPCs). Our analyses revealed a unique cell cycle phenotype of the Pax6-deficient RPCs, which included a reduced number of cells in the S phase, an increased number of cells exiting the cell cycle, and delayed differentiation kinetics of Pax6 (-) precursors. These alterations were accompanied by coexpression of factors that promote (Ccnd1, Ccnd2, Ccnd3) and inhibit (P27 (kip1) and P27 (kip2) ) the cell cycle. Further characterization of the changes in transcription profile of the Pax6-deficient RPCs revealed abrogated expression of multiple factors which are known to be involved in regulating proliferation of RPCs, including the transcription factors Vsx2, Nr2e1, Plagl1 and Hedgehog signaling. These findings provide novel insight into the molecular mechanism mediating the pleiotropic activity of Pax6 in RPCs. The results further suggest that rather than conveying a linear effect on RPCs, such as promoting their proliferation and inhibiting their differentiation, Pax6 regulates multiple transcriptional networks that function simultaneously, thereby conferring the capacity to proliferate, assume multiple cell fates and execute the differentiation program into retinal lineages. PMID- 24073292 TI - Cellular localization and processing of primary transcripts of exonic microRNAs. AB - Processing of miRNAs occurs simultaneous with the transcription and splicing of their primary transcripts. For the small subset of exonic miRNAs it is unclear if the unspliced and/or spliced transcripts are used for miRNA biogenesis. We assessed endogenous levels and cellular location of primary transcripts of three exonic miRNAs. The ratio between unspliced and spliced transcripts varied markedly, i.e. >1 for BIC, <1 for pri-miR-146a and variable for pri-miR-22. Endogenous unspliced transcripts were located almost exclusively in the nucleus and thus available for miRNA processing for all three miRNAs. Endogenous spliced pri-miRNA transcripts were present both in the nucleus and in the cytoplasm and thus only partly available for miRNA processing. Overexpression of constructs containing the 5' upstream exonic or intronic sequence flanking pre-miR-155 resulted in strongly enhanced miR-155 levels, indicating that the flanking sequence does not affect processing efficiency. Exogenously overexpressed full length spliced BIC transcripts were present both in the nucleus and in the cytoplasm, were bound by the Microprocessor complex and resulted in enhanced miR 155 levels. We conclude that both unspliced and spliced transcripts of exonic miRNAs can be used for pre-miRNA cleavage. Splicing and cytoplasmic transport of spliced transcripts may present a mechanism to regulate levels of exonic microRNAs. PMID- 24073293 TI - The duration of Chlamydia muridarum genital tract infection and associated chronic pathological changes are reduced in IL-17 knockout mice but protection is not increased further by immunization. AB - IL-17 is believed to be important for protection against extracellular pathogens, where clearance is dependent on neutrophil recruitment and local activation of epithelial cell defences. However, the role of IL-17 in protection against intracellular pathogens such as Chlamydia is less clear. We have compared (i) the course of natural genital tract C. muridarum infection, (ii) the development of oviduct pathology and (iii) the development of vaccine-induced immunity against infection in wild type (WT) BALB/c and IL-17 knockout mice (IL-17-/-) to determine if IL-17-mediated immunity is implicated in the development of infection-induced pathology and/or protection. Both the magnitude and duration of genital infection was significantly reduced in IL-17-/- mice compared to BALB/c. Similarly, hydrosalpinx was also greatly reduced in IL-17-/- mice and this correlated with reduced neutrophil and macrophage infiltration of oviduct tissues. Matrix metalloproteinase (MMP) 9 and MMP2 were increased in WT oviducts compared to IL-17-/- animals at day 7 post-infection. In contrast, oviducts from IL-17-/- mice contained higher MMP9 and MMP2 at day 21. Infection also elicited higher levels of Chlamydia-neutralizing antibody in serum of IL-17-/- mice than WT mice. Following intranasal immunization with C. muridarumMajor Outer Membrane Protein (MOMP) and cholera toxin plus CpG adjuvants, significantly higher levels of chlamydial MOMP-specific IgG and IgA were found in serum and vaginal washes of IL-17-/- mice. T cell proliferation and IFNgamma production by splenocytes was greater in WT animals following in vitro re-stimulation, however vaccination was only effective at reducing infection in WT, not IL-17-/- mice. Intranasal or transcutaneous immunization protected WT but not IL-17-/- mice against hydrosalpinx development. Our data show that in the absence of IL-17, the severity of C. muridarum genital infection and associated oviduct pathology are significantly attenuated, however neither infection or pathology can be reduced further by vaccination protocols that effectively protect WT mice. PMID- 24073294 TI - Inhibition of ERK1/2 worsens intestinal ischemia/reperfusion injury. AB - BACKGROUND: The role of extracellular signal-regulated protein kinase (ERK) in intestinal ischemia/reperfusion (I/R) injury has not been well investigated. The aim of the current study was to examine the effect of inhibition of the ERK pathway in an in vitro and in vivo model of intestinal I/R injury. METHODS: ERK1/2 activity was inhibited using the specific inhibitor, U0126, in intestinal epithelial cells under hypoxia/reoxygenation conditions and in mice subjected to 1 hour of intestinal ischemia followed by 6 hours reperfusion. In vitro, cell proliferation was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, apoptosis by DNA fragmentation, and migration using an in vitro model of intestinal wound healing. Cells were also transfected with a p70S6K plasmid and the effects of overexpression similarly analyzed. In vivo, the effects of U0126 on intestinal cell proliferation and apoptosis, intestinal permeability, lung and intestinal neutrophil infiltration and injury, and plasma cytokine levels were measured. Survival was also assessed after U0126. Activity of p70S6 kinase (p70S6K) was measured by Western blot. RESULTS: In vitro, inhibition of ERK1/2 by U0126 significantly decreased cell proliferation and migration but enhanced cell apoptosis. Overexpression of p70S6K promoted cell proliferation and decreased cell apoptosis. In vivo, U0126 significantly increased cell apoptosis and decreased cell proliferation in the intestine, increased intestinal permeability, intestinal and lung neutrophil infiltration, and injury, as well as systemic pro-inflammatory cytokines, TNF-alpha, IL-6 and IL-1beta. Mortality was also significantly increased by U0126. Inhibition of ERK1/2 by U0126 also abolished activity of p70S6K both in vitro and in vivo models. CONCLUSION: Pharmacologic inhibition of ERK1/2 by U0126 worsens intestinal IR injury. The detrimental effects are mediated, at least in part, by inhibition of p70S6K, the major effector of mammalian target of rapamycin pathway. PMID- 24073295 TI - State of the Art in Cardiac Hybrid Technology: PET/MR. AB - Simultaneous PET/MRI is an emerging technique combining two powerful imaging modalities in a single device. The wide variety of available tracers for perfusion and metabolic studies and the high sensitivity of positron emission tomography (PET) combined with the high spatial resolution and soft tissue contrast of magnetic resonance imaging (MRI) in depicting cardiac morphology and function as well as MRI's absence of ionizing radiation makes PET/MRI very attractive to radiologists and clinicians. Nevertheless, PET/MR scientific and clinical promise is to be considered in the context of numerous technical challenges that hinder its use in the clinical setting. For example, in order for a PET system to work correctly within an MR field, major changes are required to the photon detection chain such as the elimination of photomultiplier tubes, etc. Another significant limitation of PET/MRI is the lack of an electron density map (as is the case with PET-CT) that can be readily obtained from MRI (the latter measures proton not electron density) and used to correct PET data for attenuation. Moreover, as with PET-CT, cardiac and respiratory motions cause image degradations that affect image quality and accuracy both in static and dynamic PET imaging. As a result, overcoming these (and other) technical limitations is a very active area of research both in academic institutions as well as industry. In this paper, we review recent literature on cardiac PET/MRI, present the state-of-the-art of this technology, and explore promising preclinical and clinical cardiac applications where PET/MRI could play a substantial role. PMID- 24073296 TI - Omega-3 fatty acids for the prevention of breast cancer: an update and state of the science. AB - The quantity and makeup of dietary fat intake are known to impact human health. Use of Omega-3 (omega-3) polyunsaturated fatty acid (PUFA) supplements has gained increasing attention for a variety of purported health benefits, including cancer prevention. Preclinical evidence has been encouraging and recent studies have expanded our understanding of the mechanisms by which omega-3 PUFAs may protect against breast cancer. However, epidemiologic studies have yielded mixed results. Recent population studies have attempted to delineate factors that may influence the effects of omega-3 PUFAs such as total fat intake and the ratio of omega-3 to omega-6 PUFA intake. Several clinical trials, including some currently ongoing, are investigating novel strategies that favorably alter endogenous fatty acid profiles in an effort to develop clinically feasible prevention methods. Identification of well-defined subpopulations that are most likely to benefit from a targeted prevention approach will likely be crucial in this effort. PMID- 24073297 TI - Current management of noninfectious hepatic cystic lesions: A review of the literature. AB - Nonparasitic hepatic cysts consist of a heterogeneous group of disorders, which differ in etiology, prevalence, and manifestations. With improving diagnostic techniques, hepatic cysts are becoming more common. Recent advancements in minimally invasive technology created a new Era in the management of hepatic cystic disease. Herein, the most current recommendations for management of noninfectious hepatic cysts are described, thereby discussing differential diagnosis, new therapeutic modalities and outcomes. PMID- 24073298 TI - Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is a common health problem with a high mortality burden due to its liver- and vascular-specific complications. It is associated with obesity, high-fat diet as well as with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). Impaired hepatic fatty acid (FA) turnover together with insulin resistance are key players in NAFLD pathogenesis. Peroxisome proliferator-activated receptors (PPARs) are involved in lipid and glucose metabolic pathways. The novel concept is that the activation of the PPARalpha subunit may protect from liver steatosis. Fenofibrate, by activating PPARalpha, effectively improves the atherogenic lipid profile associated with T2DM and MetS. Experimental evidence suggested various protective effects of the drug against liver steatosis. Namely, fenofibrate-related PPARalpha activation may enhance the expression of genes promoting hepatic FA beta-oxidation. Furthermore, fenofibrate reduces hepatic insulin resistance. It also inhibits the expression of inflammatory mediators involved in non-alcoholic steatohepatitis pathogenesis. These include tumor necrosis factor-alpha, intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Consequently, fenofibrate can limit hepatic macrophage infiltration. Other liver-protective effects include decreased oxidative stress and improved liver microvasculature function. Experimental studies showed that fenofibrate can limit liver steatosis associated with high-fat diet, T2DM and obesity-related insulin resistance. Few studies showed that these benefits are also relevant even in the clinical setting. However, these have certain limitations. Namely, these were uncontrolled, their sample size was small, fenofibrate was used as a part of multifactorial approach, while histological data were absent. In this context, there is a need for large prospective studies, including proper control groups and full assessment of liver histology. PMID- 24073299 TI - Hepatitis C virus infection, microRNA and liver disease progression. AB - Hepatitis C virus (HCV) is a global health problem with an estimated 170-200 million peoples (approximately 3% of world population) are chronically infected worldwide and new infections are predicted to be on rise in coming years. HCV infection remains categorized as a major risk factor for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. There has been considerable improvement in our understanding of virus life cycle since, the discovery of HCV two-decades ago. MicroRNAs (miRNAs) are important players in establishment of HCV infection and their propagation in infected hepatocytes. They target crucial host cellular factors needed for productive HCV replication and augmented cell growth. Very first anti-miRNA oligonucleotides, miravirsen has been tested in clinical trial and shown promising results as therapeutic agent in treatment against chronic HCV infection. Deregulated expression of miRNAs has been linked to the pathogenesis associated with HCV infection by controlling signaling pathways such as, proliferation, apoptosis and migration. Circulating miRNAs emerging as growing field in identification of biomarkers in disease progression and their potential as a means of communication between cells inside the liver is an exciting area of research in future. This review focuses on recent studies enforcing the contribution of miRNAs in HCV life cycle and coordinated regulation in HCV mediated liver disease progression. PMID- 24073300 TI - Pure laparoscopic hepatectomy for hepatocellular carcinoma with chronic liver disease. AB - Pure laparoscopic hepatectomy is a less invasive procedure than conventional open hepatectomy for the resection of hepatic lesions. Increases in experiences with the technique, in combination with advances in technology, have promoted the popularity of pure laparoscopic hepatectomy. However, indications for usage and potential contraindications of the procedure remain unresolved. The characteristics and specific advantages of the procedure, especially for hepatocellular carcinoma (HCC) patients with chronic liver diseases, are reviewed and discussed in this paper. For cirrhotic patients with liver tumors, pure laparoscopic hepatectomy minimizes destruction of the collateral blood and lymphatic flow from laparotomy and mobilization, and mesenchymal injury from compression. Therefore, pure laparoscopic hepatectomy has the specific advantage of minimal postoperative ascites production that leads to lowering the risk of disturbance in water or electrolyte balance and hypoproteinemia. It minimizes complications that routinely trigger postoperative serious liver failure. Under adequate patient positioning and port arrangement, the partial resection of the liver in the area of subphrenic space, peri-inferior vena cava area or next to the attachment of retro-peritoneum is facilitated in pure laparoscopic surgery by providing good vision and manipulation in the small operative field. Furthermore, the features of reduced post-operative adhesion, good vision, and manipulation within the small area between the adhesions make this procedure safer in the context of repeat hepatectomy procedures. These improved features are especially advantageous for patients with liver cirrhosis and multicentric and/or metachronous HCCs. PMID- 24073301 TI - Hepatitis C genotype 6: A concise review and response-guided therapy proposal. AB - Hepatitis C genotype 6 is endemic in Southeast Asia [prevalence varies between 10%-60% among all hepatitis C virus (HCV) infection], as well as also sporadically reported outside the area among immigrations. The diagnosis of HCV genotype can be inaccurate with earlier methods of genotyping due to identical 5' UTR between genotype 6 and 1b, hence the newer genotyping methods with core sequencing are preferred. Risk factors and clinical course of HCV genotype 6 do not differ considerably from other genotypes. Treatment outcome of HCV genotype 6 with a combination of pegylated interferon and ribavirin is superior to genotype 1, and nearly comparable to genotype 3, with expected sustained virological response (SVR) rates of 60%-90%. Emerging data suggests that a shorter course 24 wk treatment is equally effective as a standard 48-wk treatment, particularly for those patients who attained undetectable HCV RNA at week 4 (RVR). In addition, baseline and on-treatment predictors of response used for other HCV genotypes appear effective with genotype 6. Although some pan-genotypic direct-acting antivirals have completed phase II/III studies (sofosbuvir and simeprevir) with clinical benefit demonstrated in small number of patients with genotype 6, broad availability of these agents in Southeast Asia may not be expected in the near future. While awaiting the newer therapy, response-guided therapy seems appropriate for patients with HCV genotype 6. Patients with RVR (representing > 70% of patients) are suitable for 24-wk treatment with expected SVR rates > 80%. Patients without RVR and/or those with poor response predictors may benefit from 48 wk of therapy, and a detectable HCV RNA at week 12 (with no early virological response) serves as a stopping rule. This treatment scheme is likely to have a major economic impact on HCV therapy, particularly in Southeast Asia, wherein treatment can be truncated securely in the majority of patients with HCV genotype 6. PMID- 24073302 TI - Changes of liver fat content and transaminases in obese children after 12-mo nutritional intervention. AB - AIM: To assess a relationship between longitudinal changes in liver fat content and biochemical parameters in obese children after 1-year nutritional intervention. METHODS: Forty-six obese children, 21 males and 25 females, aged 6 14 years, underwent metabolic measurements, liver ultrasonography (US) and chemical-shift magnetic resonance imaging (MRI) examinations at baseline and after 1-year nutritional intervention. A child was defined obese if her/his body mass index (BMI) was above the age- and sex-adjusted BMI Cole's curve passing through the cut-off of 30 kg/m(2) at 18 years. BMI Z scores were calculated and adjusted for age and gender by using the Cole's LMS-method and Italian reference data. Biochemistry included serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Abdominal US and chemical-shift MRI were performed according to a randomized sequence. The same radiologist performed US by a GE Logiq 9 (General Electric Healthcare Medical Systems, Milwaukee, WI, United States) using a 3.5-MHz convex array transducer. Liver echogenicity was evaluated independently on videotape by 3 radiologists unaware of the child and MRI outcomes, and a consensus was established. Another experienced radiologist, unaware of the child and US data, performed the abdominal chemical-shift MRI with a 1-t system NT-Intera (Philips Medical Systems, Best, The Netherlands) and a phased-array coil. Liver fat fraction (FF) on MRI was judged elevated when greater than 9%. A FF > 18% was considered expressing more severe cases of fatty liver according to Fishbein. A nutritional-behavioral intervention was recommended to promote a normocaloric balanced diet and active lifestyle based on the Italian guidelines for treatment of childhood obesity. RESULTS: Compared to baseline, at the end of intervention children showed lower intakes of energy (mean +/- SD: 2549 +/- 1238 Kcal vs 1770 +/- 622 Kcal, P < 0.0001), total fat (90 +/- 47 g vs 52 +/- 23 g, P < 0.0001), carbohydrates (356 +/- 174 g vs 241 +/- 111 g, P = 0.001), and protein (99 +/- 48 g vs 75 +/- 23 g, P = 0.006) intakes. Prevalence of FF >= 9% declined from 34.8% to 8.7% (P < 0.01), with a mean reduction of 7.8% (95%CI: 5.0-10.6). At baseline, FF was associated with liver biochemical parameters (maximum P < 0.001). At the end of the intervention association was found with AST (P = 0.017). Change of FF was associated with change in AST (P = 0.027) and ALT (P = 0.024). Rate of increased liver echogenicity declined from 45.6% to 21.7% (P < 0.0001). Liver echogenicity was associated with ALT at baseline only (P < 0.001). An age- and sex- adjusted multiple regression analysis showed that FF change was independently associated with change in serum AST (adjusted regression coefficient 0.348, P = 0.048). CONCLUSION: The results suggest that in obese children longitudinal changes in liver fat content based on MRI may be associated with change in serum transaminases suggesting novelty in monitoring nonalcoholic fatty liver disease. PMID- 24073303 TI - Ciclosporin does not attenuate intracranial hypertension in rats with acute hyperammonaemia. AB - AIM: To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin-4 expression in a rat model with acute hyperammonaemia. METHODS: Twenty-four male Wistar rats with portacaval anastomosis were randomised into four groups receiving ciclosporin or vehicle and ammonia or saline infusion. Ciclosporin or vehicle was given intrathecally prior to the ammonia or saline infusion. The ammonia or saline infusion was given intravenously for 4 h, while intracranial pressure and arterial pressure was recorded. At the end of the experiment, cerebral cortex and cerebellar brain tissue was analysed for water and aquaporin-4 content. RESULTS: The following intracranial pressures were found at the end of the experiment: ammonia + ciclosporin: 10.0 +/- 1.7 mmHg, ammonia + vehicle: 6.8 +/- 1.0 mmHg, saline + ciclosporin: 3.1 +/- 0.5 mmHg, saline + vehicle: 3.3 +/- 0.6 mmHg. Ammonia infusion had a significant effect on intracranial pressure and brain water content, which both were higher in the groups receiving ammonia (P < 0.001, two-way analysis of variance). Treatment with ciclosporin resulted in relevant tissue concentrations of ciclosporin (> 0.2 micromolar) but did not reduce intracranial pressure after 4 h. Furthermore, ciclosporin did not attenuate the increase in cerebral water content, and did not affect aquaporin-4 expression. CONCLUSION: Intrathecal administration of ciclosporin does not attenuate intracranial hypertension or brain oedema in rats with portacaval anastomosis and 4 h of ammonia infusion. PMID- 24073304 TI - Spectroscopic Imaging of Deep Tissue through Photoacoustic Detection of Molecular Vibration. AB - The quantized vibration of chemical bonds provides a way of imaging target molecules in a complex tissue environment. Photoacoustic detection of harmonic vibrational transitions provides an approach to visualize tissue content beyond the ballistic photon regime. This method involves pulsed laser excitation of overtone transitions in target molecules inside a tissue. Fast relaxation of the vibrational energy into heat results in a local temperature rise on the order of mK and a subsequent generation of acoustic waves detectable with an ultrasonic transducer. In this perspective, we review recent advances that demonstrate the advantages of vibration-based photoacoustic imaging and illustrate its potential in diagnosing cardiovascular plaques. An outlook into future development of vibrational photoacoustic endoscopy and tomography is provided. PMID- 24073305 TI - Lack of Association between COX-2 Staining Level and Biochemical Recurrence Following Salvage Radiation Therapy for Recurrent Prostate Cancer. AB - OBJECTIVE: The ability to predict which men will experience biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer following radical prostatectomy has potential for improvement. Cyclooxygenase-2 (COX-2) overexpression has previously correlated with poor clinical outcomes following primary treatment for prostate cancer, however its predictive ability in the specific setting of SRT has not been examined to date. This study evaluated the association between COX-2 staining intensity and BCR following SRT for recurrent prostate cancer. METHODS: We utilized a cohort of 151 patients who underwent SRT between July 1987 and July 2003. COX-2 staining intensity in primary tumor samples was detected using monoclonal antibodies and quantified using a computer-assisted method. The association between COX-2 staining intensity and BCR was evaluated using multivariable Cox regression models. RESULTS: When examining COX-2 staining level as three-level categorical variable (low, moderate, high) based on approximate sample tertiles, there was no evidence of an association with BCR (P=0.18). More specifically, in comparison to patients with low staining intensity, there was no significant difference in risk of BCR for moderate (Relative risk [RR]: 1.17, P=0.56) or high (RR: 0.72, P=0.22) COX-2 staining intensity patients. This lack of association was also observed when considering COX-2 staining intensity as a continuous variable (RR: 0.83, P=0.15). CONCLUSION: Our results indicate that COX-2 staining intensity is likely of little use in discriminating prognosis of SRT. It appears that the search for prognostic factors associated with BCR should continue elsewhere in order to further enhance patient selection for SRT. PMID- 24073306 TI - Role of ghrelin in the pathophysiology of gastrointestinal disease. AB - Ghrelin is a 28-amino-acid peptide that plays multiple roles in humans and other mammals. The functions of ghrelin include food intake regulation, gastrointestinal (GI) motility, and acid secretion by the GI tract. Many GI disorders involving infection, inflammation, and malignancy are also correlated with altered ghrelin production and secretion. Although suppressed ghrelin responses have already been observed in various GI disorders, such as chronic gastritis, Helicobacter pylori infection, irritable bowel syndrome, functional dyspepsia, and cachexia, elevated ghrelin responses have also been reported in celiac disease and inflammatory bowel disease. Moreover, we recently reported that decreased fasting and postprandial ghrelin levels were observed in female patients with functional dyspepsia compared with healthy subjects. These alterations of ghrelin responses were significantly correlated with meal-related symptoms (bloating and early satiation) in female functional dyspepsia patients. We therefore support the notion that abnormal ghrelin responses may play important roles in various GI disorders. Furthermore, human clinical trials and animal studies involving the administration of ghrelin or its receptor agonists have shown promising improvements in gastroparesis, anorexia, and cancer. This review summarizes the impact of ghrelin, its family of peptides, and its receptors on GI diseases and proposes ghrelin modulation as a potential therapy. PMID- 24073307 TI - SOX9 Is Highly Expressed in Nonampullary Duodenal Adenoma and Adenocarcinoma in Humans. AB - BACKGROUND/AIMS: SOX9 is a marker for stem cells in the intestine, and overexpression of SOX9 is found in gastric and colon cancer; however, the expression of SOX9 in nonampullary duodenal adenoma and adenocarcinoma has not yet been evaluated. This study aimed to investigate SOX9 expression in nonampullary duodenal adenoma and adenocarcinoma by immunohistochemistry. METHODS: We evaluated SOX9 expression in 43 clinical samples (nonampullary duodenal adenoma in 22 lesions and nonampullary duodenal adenocarcinoma in 21 lesions) resected under endoscopic mucosal resection or endoscopic submucosal dissection. RESULTS: SOX9 was expressed in part of the base of the normal duodenal mucosa surrounding adenomas and adenocarcinomas. In contrast, SOX9 positive cells were found in more than half of the crypts from the bottom part of the crypt in all of the 43 samples. Moreover, in 15 adenoma samples (68.2%) and 19 carcinoma samples (90.5%), SOX9 was expressed in more than three-quarters of the crypts from the bottom part of the crypt. CONCLUSIONS: SOX9 is overexpressed in nonampullary duodenal adenoma and adenocarcinoma in humans. PMID- 24073308 TI - Association between Plasma Levels of Plasminogen Activator Inhibitor-1 and Colorectal Neoplasms. AB - BACKGROUND/AIMS: Plasminogen activator inhibitor-1 (PAI-1) is important for tumor growth, Invasion, and metastasis. In this study, we investigated the relationship between plasma levels of PAI-1 and colorectal adenomas. METHODS: We reviewed the medical records of 3,136 subjects who underwent colonoscopy as a screening exam. The subjects were classified into a case group with adenomas (n=990) and a control group (n=2,146). Plasma PAI-1 levels were categorized into three groups based on tertile. RESULTS: The plasma levels of PAI-1 were significantly higher in adenoma cases than in controls (p=0.023). The prevalence of colorectal adenomas increased significantly with increasing levels of PAI-1 (p=0.038). In the adenoma group, advanced pathologic features, size, and number of adenomas did not differ among the three groups based on tertiles for plasma PAI-1 levels. Using multivariate analysis, we found that plasma level of PAI-1 was not associated with the risk of colorectal adenomas (p=0.675). Adjusted odds ratios for colorectal adenomas according to increasing plasma levels of PAI-1 were 0.980 (95% confidence interval [CI], 0.768 to 1.251) for the second-highest plasma level and 1.091 (95% CI, 0.898 to 1.326) for the highest level, compared with the lowest levels. CONCLUSIONS: These results suggest that elevated plasma PAI-1 levels are not associated with the risk of colorectal neoplasms. PMID- 24073309 TI - Prevalence of proximal serrated polyps and conventional adenomas in an asymptomatic average-risk screening population. AB - BACKGROUND/AIMS: Detection of proximal serrated polyps (PSPs) is increasingly recognized as a new qualitative target for colonoscopy. The aims of this study were to assess the detected prevalence of PSPs and synchronous adenomas in an asymptomatic average-risk screening cohort and to evaluate potential factors associated with detection of PSPs. METHODS: The study included 1,375 asymptomatic average-risk Korean patients (aged 50 years or older) who underwent screening colonoscopy. In total, 1,710 polyps were evaluated pathologically. RESULTS: The overall PSP detection rate (PSPDR) was low at 3.1%, despite high polyp (54.0%) and adenoma detection rates (ADRs, 43.5%). ADR did not correlate with PSPDR, but it was strongly correlated with PDR (r=0.810; p<0.001). Patients with PSPs were more likely to have longer withdrawal time and more proximal colon adenomas than patients without PSPs (adjusted odds ratio [OR], 1.19; 95% confidence interval [CI], 1.09 to 1.31; p<0.001) (adjusted OR, 2.03; 95% CI, 1.06 to 3.88; p=0.031, respectively). CONCLUSIONS: The detected prevalence of PSPs was low (<5%) in an asymptomatic average-risk screening Korean population, despite the high prevalence of conventional adenomas. A longer mucosal inspection of the proximal colon may serve as a practical method to enhance detection of PSPs. PMID- 24073310 TI - Visceral obesity as a risk factor for left-sided diverticulitis in Japan: a multicenter retrospective study. AB - BACKGROUND/AIMS: Left-sided diverticulitis is increasing in Japan, and many studies report that left-sided diverticulitis is more likely to be severe. Therefore, it is important to identify the features and risk factors for left sided diverticulitis. We hypothesized that left-sided diverticulitis in Japan is related to obesity and conducted a study of the features and risk factors for this disorder in Japan. METHODS: Right-sided diverticulitis and left-sided diverticulitis patients (total of 215) were compared with respect to background, particularly obesity-related factors to identify risk factors for diverticulitis. RESULTS: There were 166 (77.2%) right-sided diverticulitis patients and 49 (22.8%) left-sided diverticulitis patients. The proportions of obese patients (body mass index >=25 kg/m(2), p=0.0349), viscerally obese patients (visceral fat area >=100 cm(2), p=0.0019), patients of mean age (p=0.0003), and elderly patients (age >=65 years, p=0.0177) were significantly higher in the left-sided diverticulitis group than in the right-sided-diverticulitis group. The proportion of viscerally obese patients was significantly higher in the left-sided diverticulitis group than in the left-sided-diverticulosis group (p=0.0390). CONCLUSIONS: This study showed that obesity, particularly visceral obesity, was a risk factor for left-sided diverticulitis in Japan. PMID- 24073311 TI - Prevalence of and risk factors for gastrointestinal diseases in korean americans and native koreans undergoing screening endoscopy. AB - BACKGROUND/AIMS: In South Korea, health check-ups are readily accessible to the public. We aimed to compare the prevalence of upper gastrointestinal (GI) and lower GI diseases in Korean Americans and native Koreans to determine differences and risk factors. METHODS: In total, 1,942 subjects who visited Gangnam Severance Hospital from July 2008 to November 2010 for a health check-up were enrolled. Basic characteristics and laboratory data for the subjects were collected. Esophagogastroduodenoscopy and colonoscopy were performed. In total, 940 Korean Americans (group 1) and 1,002 native Koreans (group 2) were enrolled. RESULTS: The overall prevalence of GI diseases for each group (group 1 vs group 2) were as follows: reflux esophagitis (RE) (9.65% vs 7.9%), gastric ulcer (2.8% vs 3.4%), duodenal ulcer (2.3% vs 3.6%), gastric cancer (0.4% vs 0.3%), colorectal polyp (35.9% vs 35.6%), colorectal cancer (0.5% vs 0.5%), and hemorrhoids (29.4% vs 21.3%). The prevalence of hemorrhoids was significantly higher in group 1 than in group 2 (p=0.001). In the multivariable analysis of group 1, male sex, age over 50 years, hypercholesterolemia and hypertriglyceridemia predicted colorectal polyps. Male sex and high fasting glucose levels were associated with RE. CONCLUSIONS: Our study showed that the prevalence of GI diseases (except hemorrhoids) in Korean Americans was similar to that observed in native Koreans. Therefore, the Korean guidelines for upper and lower screening endoscopy may be applicable to Korean Americans. PMID- 24073312 TI - Sequential Therapy for Helicobacter pylori Infection in Korea: Systematic Review and Meta-Analysis. AB - BACKGROUND/AIMS: Sequential therapy (ST) for Helicobacter pylori infection in countries other than Korea has shown higher eradication rates than triple therapy (TT). The aim of this study was to evaluate the efficacy of ST in Korea by performing a meta-analysis. METHODS: We performed a comprehensive literature search on the efficacy of ST as a first-line therapy. The odds ratios (ORs) of eradicating H. pylori infection after ST compared with TT were pooled. Pooled estimates of the eradication rates of ST and TT were also calculated. RESULTS: A total of six studies provided data on 1,759 adult patients. The ORs for the intention to treat (ITT) and the per-protocol (PP) eradication rate were 1.761 (95% confidence interval [CI], 1.403 to 2.209) and 1.966 (95% CI, 1.489 to 2.595). Pooled estimates of the ITT and PP eradication rate were 79.4% (95% CI, 76.3% to 82.2%) and 86.4% (95% CI, 83.5% to 88.8%), respectively, for the ST group, and 68.2% (95% CI, 62.1% to 73.8%) and 78.9% (95% CI, 68.9% to 81.7%), respectively, for the TT group. CONCLUSIONS: Although ST presented a higher eradication rate than TT in Korea, the pooled eradication rates were lower than expected. Further studies are needed to validate ST as a first-line treatment for H. pylori in Korea. PMID- 24073313 TI - The Effect of Helicobacter pylori on Epidermal Growth Factor Receptor-Induced Signal Transduction and the Preventive Effect of Celecoxib in Gastric Cancer Cells. AB - BACKGROUND/AIMS: Helicobacter pylori infection induces cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) overexpression, and these factors may engage in cross-talk. The aim of the present study was to evaluate the effect of H. pylori on EGFR signaling pathways and to determine whether celecoxib has an inhibitory effect on this pathway. METHODS: The AGS cell line was cocultured with H. pylori G27 and the isogenic cagE- mutant. The expression of COX-2, EGFR, heparin binding-epidermal growth factor (HB-EGF), and transforming growth factor beta (TGF-beta) was measured by real time-polymerase chain reaction (RT-PCR). Next, Western blot analyses of COX-2, EGFR, total Akt, phosphorylated Akt (pAkt), and phosphorylated glycogen synthase kinase-3beta (pGSK3beta) were performed after incubating H. pylori-treated AGS cells for 24 hours with various concentrations of celecoxib (0, 10, 20, and 30 umol/L). RESULTS: H. pylori infection upregulated the mRNA levels of COX-2, EGFR, HB-EGF, and TGF-beta, as detected by RT-PCR. However, AGS cells treated with cagE- mutants, which have a defective type IV secretion system, did not exhibit EGFR upregulation. Celecoxib had inhibitory effects on the H. pylori-induced overexpression of COX-2 (p=0.015), EGFR (p=0.025), pAkt (p=0.025), and pGSK3beta (p=0.029) by Western blot analysis. CONCLUSIONS: H. pylori with an intact type IV secretion system activated the COX-2 and EGFR-Akt pathways in the AGS cell line. As celecoxib exhibited inhibitory effects on the EGFR signaling pathway, the cross-talk of COX 2 and EGFR likely mediates H. pylori-induced gastric cancer. PMID- 24073314 TI - The Effect of Cochinchina momordica Seed Extract on Gastric Acid Secretion and Morphologic Change in Aged Rat Stomach. AB - BACKGROUND/AIMS: Cochinchina momordica seed extract (SK-MS10) has a gastric protective effect. We aimed to assess the effect of SK-MS10 on gastric acid secretion with morphologic changes in the aged rat. METHODS: Acid secretions were evaluated in the male F344 rats of four different ages (6-, 31-, 74-week, and 2 year). The 31-week-old rats were divided to three groups and continuously administered chow containing vehicle, SK-MS10 and lansoprazole, respectively. At the age of 74 weeks and 2 years, basal and stimulated acid was measured and the expression of mRNA and protein of H(+)-K(+)-ATPase were determined. The area of connective tissue of lamina propria was measured. RESULTS: Basal and stimulated gastric acid significantly decreased and connective tissue of lamina propria increased with age. The expression of mRNA and protein of H(+)-K(+)-ATPase significantly decreased with age. However, 74-week-old rats in the SK-MS10 group had higher stimulated gastric acid secretion than those in the vehicle and lansoprazole groups. In 2-year-old rats of SK-MS10 group, there was no increase of connective tissue. CONCLUSIONS: As SK-MS10 kept the capacity of acid secretion as well as connective tissue area to comparable to young rats, it might valuable to perform further research regarding mechanism of SK-MS10 as an antiaging agent in the stomach. PMID- 24073315 TI - Impact of Nucleotide Mutations at the HNF3- and HNF4-Binding Sites in Enhancer 1 on Viral Replication in Patients with Chronic Hepatitis B Virus Infection. AB - BACKGROUND/AIMS: The hepatitis B virus (HBV) genome contains binding sites for hepatocyte nuclear factors (HNF) 3 and 4 in the core domain of enhancer 1 (Enh1), and mutations in this domain have a strong impact on virus replication. We aimed to identify frequent base-mutation sites in the core domain of Enh1 and to examine the impact of these mutations on viral replication. METHODS: We studied virological characteristics and genetic sequences in 387 patients with chronic hepatitis B. We evaluated functional differences associated with specific mutations within the core domain of Enh1. RESULTS: Mutations in the core domain were found with significant frequency in C1126 (122/387 [31.5%], the binding site for HNF3) and in C1134 (106/387 [27.4%], the binding site for HNF4). A single mutation at nt 1126 (C1126) was identified in 17/123 (13.8%), and 105/123 (85.4%) had double mutations (C1126/1134). The level of HBV DNA (log10 copies/mL) was lower in single mutants (C1126, 5.81+/-1.25) than in wild (6.80+/-1.65) and double mutants (C1126/1134, 6.81+/-1.54). Similarly, the relative luciferase activity of C1126 and C1126/C1134 was 0.18 and 1.12 times that of the wild-type virus, respectively. CONCLUSIONS: Mutations in the HNF3 binding site inhibit viral replication, whereas mutations at the HNF4 binding site restore viral replication. PMID- 24073316 TI - What Is the Most Effective Drug Delivery System for Cisplatin during the Treatment of Hepatic Tumors with Single-Session Transcatheter Chemotherapy? A Pilot Study. AB - BACKGROUND/AIMS: The aim of this study was to determine the pharmacodynamics of cisplatin following three different treatment procedures for intrahepatic arterial infusion therapy for hepatocellular carcinoma (HCC). METHODS: We divided 13 HCC patients into the following three groups: group A, lone injection of cisplatin (n=3); group B, combined injection of cisplatin and lipiodol, with embolization using small gelatin cubes (GCs) (n=5); and group C, injection of suspended lipiodol with cisplatin powder, with embolization using small GCs (n=5). In each group, the free cisplatin concentration in the hepatic vein was measured at 0, 5, 10, and 30 minutes. RESULTS: The mean free cisplatin concentrations were as follows. For group A, the mean was 48.58 ug/mL at 0 minute, 7.31 ug/mL at 5 minutes, 5.70 ug/mL at 10 minutes, and 7.15 ug/mL at 30 minutes. For the same time points, for group B, the concentrations were 8.66, 4.23, 3.22, and 1.65 ug/mL, respectively, and for group C, the concentrations were 4.81, 2.61, 2.52, and 1.75 ug/mL, respectively. The mean area under the curve (AUC)0-infinity for the free cisplatin concentration was 7.80 in group A, 2.48 in group B, and 2.27 in group C. The AUC0-infinity for the free cisplatin concentration gradually decreased, from group A to group C. CONCLUSIONS: These results indicate that the combination of lipiodol and small GCs may be useful for delaying cisplatin drainage from the liver. PMID- 24073317 TI - Pegylated interferon and ribavirin in the retreatment of chronic hepatitis C in Korea. AB - BACKGROUND/AIMS: Pegylated interferon (peginterferon) and ribavirin is the current standard therapy for chronic hepatitis C. The aims of this study were to evaluate the efficacy of peginterferon and ribavirin and to identify predictors of a sustained virological response (SVR) to the retreatment of chronic hepatitis C in Korea. METHODS: The clinical records of 91 patients with chronic hepatitis C who were retreated with peginterferon and ribavirin were retrospectively analyzed. None of the patients had previously attained a SVR, and the patients were categorized according to their previous responses (nonresponder, relapser, or inadequate treatment) to conventional interferon/ribavirin. RESULTS: The overall SVR rate was 54.9%. Independent predictors of a SVR were genotypes 2 and 3, relapse, an adherence to peginterferon of over 80%, and an early virological response (EVR). For genotype 1 patients, an adherence to peginterferon of over 80% was an independent predictor of a SVR. CONCLUSIONS: Peginterferon and ribavirin therapy is effective for the retreatment of Korean chronic hepatitis C patients who have failed interferon/ribavirin, especially in patients with genotypes 2 and 3, relapse, an adherence to peginterferon over 80%, and an EVR. For genotype 1 patients, retreatment was effective in patients with an adherence to peginterferon over 80%. PMID- 24073318 TI - A Multicenter Phase II Trial of Gemcitabine Plus Oxaliplatin in Unresectable Gallbladder Cancer. AB - BACKGROUND/AIMS: No standard chemotherapy has been established for advanced gallbladder cancer. The authors studied the activity and tolerability of a gemcitabine and oxaliplatin (GEMOX) combination in unresectable gallbladder cancer (GBC). METHODS: Adult patients with pathologically confirmed unresectable GBC were prospectively recruited at three centers. No patient had received prior chemotherapy or radiotherapy. Patients received cycles of gemcitabine at 1,000 mg/m(2) on day 1, followed by oxaliplatin at 100 mg/m(2) on day 2, every 2 weeks. The primary study endpoint was time to progression. RESULTS: Forty patients with unresectable GBC were enrolled. The median age was 60 years (range, 38 to 79 years). All patients showed good performance status. Of the 33 analyzable patients, 12 achieved partial response (36%), 17 stable disease (52%), and four progressive disease (12%). No patient achieved a complete response. The tumor control rate was 88%. At a median follow-up of 6.8 months, the median time to progression was 5.3 months (95% confidence interval [CI], 3.7 to 6.9), and median overall survival was 6.8 months (95% CI, 6.1 to 7.5). Nine of the 40 patients (23%) experienced at least a grade-3 adverse event, but no patient experienced a grade-4 adverse event. CONCLUSIONS: GEMOX combination therapy is a feasible option and is well tolerated in unresectable GBC. PMID- 24073319 TI - Clinical role of contrast-enhanced harmonic endoscopic ultrasound in differentiating solid lesions of the pancreas: a single-center experience in Korea. AB - BACKGROUND/AIMS: The differential diagnosis of pancreatic solid lesions remains challenging. The aim of this study was to investigate the accuracy of contrast enhanced harmonic endoscopic ultrasound (CEH-EUS) in differentiating pancreatic cancer from benign lesions. METHODS: We prospectively evaluated 37 patients with pancreatic solid lesions. After intravenous injection of a contrast agent (SonoVue), CEH-EUS was performed using a radial echoendoscope. Pancreatic solid lesions were classified into three vascular patterns (hyperintense, isointense, and hypointense) on the basis of CEH-EUS imaging, and these patterns were compared to the histological diagnosis. RESULTS: The lesions were hypervascular (n=6), isovascular (n=3), or hypovascular (n=28). Histological diagnosis was confirmed by EUS-FNA in 26 patients (22 adenocarcinomas, two focal pancreatitis, one pancreatic neuroendocrine tumor [NET], and one pancreatic tuberculosis); by surgery in 10 patients (four adenocarcinomas, three pancreatic NETs, two invasive intraductal papillary mucinous neoplasms, and one acinar cell carcinoma); and by both methods in one patient. Among pancreatic carcinomas, 28 out of 30 lesions (93%) had persistent hypovascular signals in the early and late phase, which indicates a sensitivity and diagnostic accuracy of 93% and 92%, respectively for the diagnosis of pancreatic cancer. CONCLUSIONS: CEH-EUS was useful for characterization of pancreatic solid masses with high sensitivity and accuracy. PMID- 24073320 TI - Histology combined with cytology by endoscopic ultrasound-guided fine needle aspiration for the diagnosis of solid pancreatic mass and intra-abdominal lymphadenopathy. AB - BACKGROUND/AIMS: Small core biopsy samples can occasionally be obtained with conventional endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA). Although most studies have focused on the cytological analysis of specimens, data regarding histological assessment is scarce. The aim of this study was to determine whether core biopsies by conventional EUS-FNA could increase the accuracy of EUS-guided sampling when combined with cytology in the absence of an on-site cytopathologist. METHODS: In the 95 consecutive patients (98 lesions) undergoing EUS-FNA of solid pancreatic masses and intra-abdominal lymphadenopathy, tissue coils from the needle were harvested for histology, and residual tissue was examined by cytology. RESULTS: Adequate samples were obtained by EUS-FNA cytology, histology, and combined cytology-histology in 91.8%, 65.3%, and 94.8% of patients, respectively. From the pancreas (n=67), adequate samples for histology were obtained by EUS-FNA in 68.7% of cases, compared with 58.0% from non-pancreatic cases (n=31), respectively (p>0.05). The overall sensitivity and accuracy of EUS-FNA was 78.0% and 81.6% for cytology alone, 63.4% and 69.4% for histology alone, and 84.1% and 86.7% for combined cytology-histology, respectively. CONCLUSIONS: Combined cytology and histology analysis for diagnosing pancreatic masses and intra-abdominal lymphadenopathy may increase the diagnostic yield of conventional EUS-FNA without on-site cytology. PMID- 24073321 TI - Phase II Trial of Erlotinib Plus Gemcitabine Chemotherapy in Korean Patients with Advanced Pancreatic Cancer and Prognostic Factors for Chemotherapeutic Response. AB - BACKGROUND/AIMS: Erlotinib and gemcitabine combined chemotherapy is becoming the treatment of choice in advanced pancreatic cancer. We evaluated the effectiveness of treatment with erlotinib plus gemcitabine and the prognostic factors for chemotherapeutic response in Korean pancreatic cancer patients. METHODS: Sixty nine patients with advanced pancreatic cancer who were treated with daily erlotinib 100 mg orally and gemcitabine 1,000 mg/m(2)/30 min intravenous infusion on days 1, 8, and 15 of each 4-week cycle from 2006 to 2009 were included in this study. This study was a phase II single-center trial. RESULTS: All 69 patients with advanced pancreatic cancer were chemotherapy-naive. The objective response rate was 18.8%, and the overall tumor-stabilization rate was 49.2%. The median overall survival was 7.7 months (95% confidence interval [CI], 6.0 to 9.4 months). The median progression-free survival was 1.9 months (95% CI, 1.4 to 2.5 months). Prognostic factors for good chemotherapeutic response were good performance status and the presence of skin rash during chemotherapy. Patients with lower performance scores showed worse chemotherapeutic responses (odds ratio [OR], 7.6; 95% CI, 2.4 to 24.8). Poor responses were predicted by the absence of skin rash during chemotherapy (OR, 3.0; 95% CI, 1.4 to 6.3). CONCLUSIONS: Erlotinib and gemcitabine chemotherapy is a tolerable treatment regimen and has a favorable therapeutic effect in Korean patients with advanced pancreatic cancer. PMID- 24073322 TI - Immunoglobulin g4-related disease mimicking unresectable gallbladder cancer. AB - Immunoglobulin G4 (IgG4)-related disease is a novel disease entity that can involve diverse organs, causing specific diseases, including autoimmune pancreatitis, sclerosing cholangitis, cholecystitis, inflammatory aortic aneurysm, and inflammatory pseudotumor. IgG4-related disease is characterized by elevated serum IgG4 concentrations, abundant IgG4 lymphoplasmacytic infiltration, and dramatic steroid responses. It is clinically important to differentiate this rare disease from primary sclerosing cholangitis and cholangiocarcinoma, because the treatment and prognosis of these two diseases are completely different. However, the preoperative diagnosis is challenging, and the disease is frequently misdiagnosed. If the serum level of IgG4 is within the normal range, the diagnosis of IgG4-related disease is more difficult. This article reports on a 59 year-old man with IgG4-related disease mimicking unresectable gallbladder cancer with normal serum IgG4 concentrations. PMID- 24073323 TI - Unusual Multiorgan Immunoglobulin G4 (IgG4) Inflammation: Autoimmune Pancreatitis, Mikulicz Syndrome, and IgG4 Mastitis. AB - Autoimmune pancreatitis (AIP) type 1 is commonly associated with simultaneous involvement of extrapancreatic organs. Sclerosing cholangitis, sialadenitis, retroperitoneal fibrosis, Sjogren syndrome, and other extrapancreatic lesions are often observed concurrently with AIP. High levels of immunoglobulin G4 (IgG4) in the blood serum and affected tissues are typical of this diagnostic entity. We describe a case report of a 58-year-old female with findings of AIP (according to Asian criteria), IgG4-positive mastitis, and histologically verified Mikulicz syndrome. The effect of corticoid therapy supported the diagnosis of AIP and simultaneously led to the eradication of recurrent mastitis. To the best of our knowledge, this is the first reported case of concurrent findings of AIP and IgG4 mastitis. Our case report supports the concept of systemic IgG4 syndrome with multisystem involvement. Timely diagnosis and appropriate therapy can be effective in a high percentage of patients. PMID- 24073324 TI - Alteration of p62/SQSTM1 Expression Is Uncommon in Gastrointestinal and Prostate Cancer Tissues. PMID- 24073325 TI - Targeting of systemically-delivered magnetic nanoparticle hyperthermia using a noninvasive, static, external magnetic field. AB - One of the greatest challenges of nanoparticle cancer therapy is the delivery of adequate numbers of nanoparticles to the tumor site. Iron oxide nanoparticles (IONPs) have many favorable qualities, including their nontoxic composition, the wide range of diameters in which they can be produced, the cell-specific cytotoxic heating that results from their absorption of energy from a nontoxic, external alternating magnetic field (AMF), and the wide variety of functional coatings that can be applied. Although IONPs can be delivered via an intra tumoral injection to some tumors, the resulting tumor IONP distribution is generally inadequate; additionally, local tumor injections do not allow for the treatment of systemic or multifocal disease. Consequently, the ultimate success of nanoparticle based cancer therapy likely rests with successful systemic, tumor targeted IONP delivery. In this study, we used a surface-based, bilateral, noninvasive static magnetic field gradient produced by neodymium-boron-iron magnets (80 T/m to 130 T/m in central plane between magnets), a rabbit ear model, and systemically-delivered starch-coated 100 nm magnetic (iron oxide) nanoparticles to demonstrate a spatially-defined increase in the local tissue accumulation of IONPs. In this non-tumor model, the IONPs remained within the local vascular space. It is anticipated that this technique can be used to enhance IONP delivery significantly to the tumor parenchyma/cells. PMID- 24073326 TI - Development of new N-Arylbenzamides as STAT3 Dimerization Inhibitors. AB - The O-tosylsalicylamide S3I-201 (10) was used as a starting point for design and synthesis of novel STAT-3 dimerization inhibitors with improved drug-like qualities. The phosphonic acid 12d and salicylic acids 13f, 13g with a shorter amide linker lacking the O-tosyl group had improved STAT-3 inhibitory activity. The equivalent potencies observed by the replacement of phosphonic acid moiety of 12d with 5-amino-2-hydroxybenzoic acid group as in 13f further validates 5-amino 2-hydroxybenzoic acid as a phosphotyrosine mimic. The salicylic acid 13f displayed improved whole cell activity. The focused library of salicylic acids 13 with benzamide linker indicated that hydrophobic heptyl and cyclohexyl are the best tolerated R groups and a biphenyl ether (as the Ar group) significantly contributes to STAT3 inhibitory activity. Our docking studies indicated that the acidic groups of 12d, 13f and 13g interact in the p-Tyr-705 binding site in a broadly similar manner, while the phenoxybenzoyl group and the cyclohexylbenzyl group occupying pY+1 and pY-X hydrophobic pockets respectively. The in vitro and cell based potency of 13f warrants further development of this scaffold as STAT3 inhibitors. PMID- 24073327 TI - Bilingualism is not a categorical variable: Interaction between language proficiency and usage. AB - Bilingual experience is dynamic and poses a challenge for researchers to develop instruments that capture its relevant dimensions. The present study examined responses from a questionnaire administered to 110 heterogeneous bilingual young adults. These questions concern participants' language use, acquisition history and self-reported proficiency. The questionnaire responses and performances on standardized English proficiency measures were analyzed using factor analysis. In order to retain a realistic representation of bilingual experience, the factors were allowed to correlate with each other in the analysis. Two correlating factors were extracted, representing daily bilingual usage and English proficiency. These two factors were also related to self-rated proficiency in English and non-English language. Results were interpreted as supporting the notion that bilingual experience is composed of multiple related dimensions that will need to be considered in assessments of the consequences of bilingualism. PMID- 24073328 TI - Eye Movements while Reading Biased Homographs: Effects of Prior Encounter and Biasing Context on Reducing the Subordinate Bias Effect. AB - Readers experience processing difficulties when reading biased homographs preceded by subordinate-biasing contexts. Attempts to overcome this processing deficit have often failed to reduce the subordinate bias effect (SBE). In the present studies, we examined the processing of biased homographs preceded by single-sentence, subordinate-biasing contexts, and varied whether this preceding context contained a prior instance of the homograph or a control word/phrase. Having previously encountered the homograph earlier in the sentence reduced the SBE for the subsequent encounter, while simply instantiating the subordinate meaning produced processing difficulty. We compared these reductions in reading times to differences in processing time between dominant-biased repeated and non repeated conditions in order to verify that the reductions observed in the subordinate cases did not simply reflect a general repetition benefit. Our results indicate that a strong, subordinate-biasing context can interact during lexical access to overcome the activation from meaning frequency and reduce the SBE during reading. PMID- 24073329 TI - On the move. AB - Single-molecule experiments have shed new light on the mechanisms responsible for the movement of RNA polymerase along DNA during transcription. PMID- 24073330 TI - Does rebound tonometry probe misalignment modify intraocular pressure measurements in human eyes? AB - Purpose. To examine the influence of positional misalignments on intraocular pressure (IOP) measurement with a rebound tonometer. Methods. Using the iCare rebound tonometer, IOP readings were taken from the right eye of 36 healthy subjects at the central corneal apex (CC) and compared to IOP measures using the Goldmann applanation tonometer (GAT). Using a bespoke rig, iCare IOP readings were also taken 2 mm laterally from CC, both nasally and temporally, along with angular deviations of 5 and 10 degrees, both nasally and temporally to the visual axis. Results. Mean IOP +/- SD, as measured by GAT, was 14.7 +/- 2.5 mmHg versus iCare tonometer readings of 17.4 +/- 3.6 mmHg at CC, representing an iCare IOP overestimation of 2.7 +/- 2.8 mmHg (P < 0.001), which increased at higher average IOPs. IOP at CC using the iCare tonometer was not significantly different to values at lateral displacements. IOP was marginally underestimated with angular deviation of the probe but only reaching significance at 10 degrees nasally. Conclusions. As shown previously, the iCare tonometer overestimates IOP compared to GAT. However, IOP measurement in normal, healthy subjects using the iCare rebound tonometer appears insensitive to misalignments. An IOP underestimation of <1 mmHg with the probe deviated 10 degrees nasally reached statistical but not clinical significance levels. PMID- 24073331 TI - Correlation between Ocular Manifestations and Their Complications as Opposed to Visual Acuity and Treatment in Behcet's Disease. AB - The aim of this study was to analyze ocular manifestations, their complications, and treatment in a sample of 40 patients with confirmed Behcet's disease. Results. Serofibrinous iridocyclitis was the most common form of uveitis (60%). Retinal periphlebitis manifested in 92.5% of cases, and periphlebitis in conjunction with periarteritis was diagnosed in 72.5% of cases. Macular edema was the most frequent complication on the posterior segment (60%) and it correlated with periphlebitis (P = 0.45) and periphlebitis associated with periarteritis (P = 0.51). Cyclosporine A and corticosteroids were used in the majority of cases (67%). Following six months of therapy, a significant improvement of visual acuity occurred in patients with initial visual acuity >0.5 on both eyes. Level of visual acuity before and after treatment had a strong significant correlation coefficient with various ocular complications. Previously proven significant increase of visual acuity in patients with macular edema depicts effectiveness of treatment in these types of ocular manifestations of Behcet's disease. Conclusions. Significant improvement of visual acuity occurred in patients with initial visual acuity >0.5 on both eyes. The highest increase in visual acuity was achieved by laser photocoagulation in combination with triamcinolone acetonide P = 0.038 < 0.050. PMID- 24073332 TI - Obesity as a major risk factor for cancer. AB - The number of cancer cases caused by being obese is estimated to be 20% with the increased risk of malignancies being influenced by diet, weight change, and body fat distribution together with physical activity. Reports from the International Agency for Research into Cancer and the World Cancer Research Fund (WCRF) have shown that the strongest evidence exists for an association of obesity with the following cancer types: endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, and renal, whereas the less common malignancies are leukemia, non-Hodgkin's lymphoma, multiple myeloma, malignant melanoma, and thyroid tumours. To be able to develop novel methods in prevention and treatment, we first must understand the underlying processes which link cancer to obesity. Four main systems have been identified as potential producers of cancer in obesity: insulin, insulin-like growth factor-I, sex steroids, and adipokines. Various novel candidate mechanisms have been proposed: chronic inflammation, oxidative stress, crosstalk between tumour cells and surrounding adipocytes, migrating adipose stromal cells, obesity-induced hypoxia, shared genetic susceptibility, and the functional defeat of immune function. Herein, we review the major pathogenic links between obesity and susceptibility to cancer. PMID- 24073333 TI - Alterations in phosphorylated CREB expression in different brain regions following short- and long-term morphine exposure: relationship to food intake. AB - BACKGROUND: Activation of the cyclic adenosine monophosphate (cAMP)/phosphorylated CREB (P-CREB) system in different brain regions has been implicated in mediating opioid tolerance and dependence, while alteration of this system in the lateral hypothalamus (LH) has been suggested to have a role in food intake and body weight. METHODS: Given that opioids regulate food intake, we measured P-CREB in different brain regions in mice exposed to morphine treatments designed to induce different degrees of tolerance and dependence. RESULTS: We found that a single morphine injection or daily morphine injections for 8 days did not influence P-CREB levels, while the escalating dose of morphine regimen raised P-CREB levels only in the ventral tegmental area (VTA). Chronic morphine pellet implantation for 7 days raised P-CREB levels in the LH, VTA, and dorsomedial nucleus of the hypothalamus (DM) but not in the nucleus accumbens and amygdala. Increased P-CREB levels in LH, VTA, and DM following 7-day treatment with morphine pellets and increased P-CREB levels in the VTA following escalating doses of morphine were associated with decreased food intake and body weight. CONCLUSION: The morphine regulation of P-CREB may explain some of the physiological sequelae of opioid exposure including altered food intake and body weight. PMID- 24073336 TI - Focused Assessment with Sonography in Trauma and Abdominal Computed Tomography Utilization in Adult Trauma Patients: Trends over the Last Decade. AB - Objective. We sought to describe the trend in abdominal CT use in adult trauma patients after a point-of-care emergency ultrasound program was introduced. We hypothesized that abdominal CT use would decrease as FAST use increased. Methods. We performed a retrospective study of 19940 consecutive trauma patients over the age of 18 admitted to our level one trauma center from 2002 through 2011. Data was collected retrospectively and recorded in a trauma registry. We plotted the rate of FAST and abdominal CT utilization over time. Head CT was used as a surrogate for overall CT utilization rates during the study period. Results. Use of FAST increased by an average of 2.3% (95% CI 2.1 to 2.5, P < 0.01) while abdominal CT use decreased by the same rate annually. The percentage of patients who received FAST as the sole imaging modality for the abdomen rose from 2.0% to 21.9% while those who only received an abdominal CT dropped from 21.7% to 2.3%. Conclusions. Abdominal CT use in our cohort declined while FAST utilization grew in the last decade. The rising use of FAST may have played a role in the reduction of abdominal CT performed as decline in CT utilization appears contrary to overall trends. PMID- 24073334 TI - Developmental origins of chronic renal disease: an integrative hypothesis. AB - Cardiovascular diseases are one of the leading causes of mortality. Hypertension (HT) is one of the principal risk factors associated with death. Chronic kidney disease (CKD), which is probably underestimated, increases the risk and the severity of adverse cardiovascular events. It is now recognized that low birth weight is a risk factor for these diseases, and this relationship is amplified by a rapid catch-up growth or overfeeding during infancy or childhood. The pathophysiological and molecular mechanisms involved in the "early programming" of CKD are multiple and partially understood. It has been proposed that the developmental programming of arterial hypertension and chronic kidney disease is related to a reduced nephron endowment. However, this mechanism is still discussed. This review discusses the complex relationship between birth weight and nephron endowment and how early growth and nutrition influence long term HT and CKD. We hypothesize that fetal environment reduces moderately the nephron number which appears insufficient by itself to induce long term diseases. Reduced nephron number constitutes a "factor of vulnerability" when additional factors, in particular a rapid postnatal growth or overfeeding, promote the early onset of diseases through a complex combination of various pathophysiological pathways. PMID- 24073335 TI - Cell shape and cardiosphere differentiation: a revelation by proteomic profiling. AB - Stem cells (embryonic stem cells, somatic stem cells such as neural stem cells, and cardiac stem cells) and cancer cells are known to aggregate and form spheroid structures. This behavior is common in undifferentiated cells and may be necessary for adapting to certain conditions such as low-oxygen levels or to maintain undifferentiated status in microenvironments including stem cell niches. In order to decipher the meaning of this spheroid structure, we established a cardiosphere clone (CSC-21E) derived from the rat heart which can switch its morphology between spheroid and nonspheroid. Two forms, floating cardiospheres and dish-attached flat cells, could be switched reversibly by changing the cell culture condition. We performed differential proteome analysis studies and obtained protein profiles distinct between spherical forms and flat cells. From protein profiling analysis, we found upregulation of glycolytic enzymes in spheroids with some stress proteins switched in expression levels between these two forms. Evidence has been accumulating that certain chaperone/stress proteins are upregulated in concert with cellular changes including proliferation and differentiation. We would like to discuss the possible mechanism of how these aggregates affect cell differentiation and/or other cellular functions. PMID- 24073337 TI - Enhanced blood lymphocytes apoptosis in children with inflammatory bowel disease. AB - The aim of this work was to measure peripheral lymphocyte apoptosis during IBD flare and remission. Subjects and Methods. Flow-cytometric assessment of apoptosis of peripheral blood lymphocytes (PBL) was assessed in 30 children with IBD (16 with ulcerative colitis and 14 with Crohn's disease) compared to 22, age and sex matched, healthy children. This was carried out during a flare, whether in newly diagnosed or relapsing patients, and after achievement of remission. Clinical findings, complete blood count, liver transaminases, and kidney functions were assessed. Results. Early apoptotic and late apoptotic/necrotic lymphocytes were significantly higher during IBD flare compared to controls (P <= 0.01 and <0.01, resp., in ulcerative colitis and P <= 0.01 and <0.01, resp., in Crohn's disease patients). Remission values were significantly decreased but did not come back to the control levels. Early apoptotic values were significantly related to joint involvement in IBD patients (P < 0.0001). Conclusions. We can speculate a systemic nature of IBD as evident by enhanced peripheral lymphocyte apoptosis. This is related, to a great extent, to the disease process as it is more deranged in flare than in remission. Relation of this derangement to extraintestinal manifestations needs a special attention. PMID- 24073338 TI - Emptying of Intracellular Calcium Pool and Oxidative Stress Imbalance Are Associated with the Glyphosate-Induced Proliferation in Human Skin Keratinocytes HaCaT Cells. AB - We demonstrated that glyphosate possesses tumor promoting potential in mouse skin carcinogenesis and SOD 1, calcyclin (S100A6), and calgranulin B (S100A9) have been associated with this potential, although the mechanism is unclear. We aimed to clarify whether imbalance in between [Ca(2+)] i levels and oxidative stress is associated with glyphosate-induced proliferation in human keratinocytes HaCaT cells. The [Ca(2+)] i levels, ROS generation, and expressions of G1/S cyclins, IP3R1, S100A6, S100A9, and SOD 1, and apoptosis-related proteins were investigated upon glyphosate exposure in HaCaT cells. Glyphosate (0.1 mM) significantly induced proliferation, decreases [Ca(2+)] i , and increases ROS generation in HaCaT cells, whereas antioxidant N-acetyl-L-cysteine (NAC) pretreatment reverts these effects which directly indicated that glyphosate induced cell proliferation by lowering [Ca(2+)] i levels via ROS generation. Glyphosate also enhanced the expression of G1/S cyclins associated with a sharp decrease in G0/G1 and a corresponding increase in S-phases. Additionally, glyphosate also triggers S100A6/S100A9 expression and decreases IP3R1 and SOD 1 expressions in HaCaT cells. Notably, Ca(2+) suppression also prevented apoptotic related events including Bax/Bcl-2 ratio and caspases activation. This study highlights that glyphosate promotes proliferation in HaCaT cells probably by disrupting the balance in between [Ca(2+)] i levels and oxidative stress which in turn facilitated the downregulation of mitochondrial apoptotic signaling pathways. PMID- 24073340 TI - Effects of cardiopulmonary bypass surgery on auditory function: a preliminary study. AB - Hearing loss has been reported as a complication following cardiac surgery with extracorporeal circulation. Preoperative hearing testing is not commonly done in these procedures, so preoperative and postoperative hearing loss, if any, may occur unnoticed. 30 subjects in the age range of 50-70 with a mean age of 60.16 years with myocardial infarction and scheduled to undergo cardiopulmonary bypass surgery underwent detailed audiological assessment comprising of pure tone audiometry with extended high frequency audiometry, speech audiometry and otoacoustic emissions (OAE) testing. The audiological testing was done preoperatively and at 2 weeks after the surgery. On pure tone audiometry, the difference between pre- and postsurgery mean values for both ears at 10, 12, and 16 KHz showed highly significant differences (P < 0.0001). On OAE testing, a significant difference (P < 0.05) between pre- and postvalues of signal to noise ratio (SNR) was found. It is hypothesised that CPB surgery makes blood redistribution to other organs easy, deviating from internal ear, which is highly susceptible as it lacks collateral circulation and its cells have high energy metabolism. Epithelial damage on internal ear microcirculation causes reduction of the cochlear potentials and hence hearing loss. PMID- 24073339 TI - Sustained elevation of systemic oxidative stress and inflammation in exacerbation and remission of asthma. AB - Oxidative stress has been implicated in the pathogenesis of asthma. We aimed at investigating the biomarkers of oxidative stress, inflammation, and tissue damage in patients with asthma in acute exacerbation and remission. We recruited 18 asthmatics admitted to hospital with acute exacerbation and 18 healthy nonsmoking controls matched for age. We evaluated plasma levels of 8-isoprostane, C-reactive protein (CRP) and total matrix metalloproteinase- (MMP-) 9 by ELISA, and MMP-9 activity by zymographic analysis. Plasma levels of 8-isoprostane and CRP were significantly elevated in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls. The activities of pro MMP-9 were also significantly higher in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls in parallel to plasma levels of total MMP-9. These data suggest that overproduction of MMP-9 along with highly elevated levels of oxidative stress and inflammation is implicated in asthma exacerbation and that measurements of these biomarkers can be a valid index in its management. PMID- 24073341 TI - Completely resected n0 non-small cell lung cancer: prognostic factors affecting long-term survival. AB - Background. Although early stage non-small cell lung cancer (NSCLC) has an excellent outcome and correlated with good long-term survival, up to 15 percent of patients still relapse postoperatively and die. This study is conducted to identify prognostic factors that may affect the long-term survival in completely resected N0 NSCLC. Methods. Medical records of 124 patients with completely resected N0 NSCLC were retrospectively reviewed. Prognostic factors affecting long-term survival were analyzed by the Kaplan-Meier method and Cox proportional hazards analysis. Results. Overall five-year survival rate was 48 percent. Multivariable analysis revealed stage of disease, tumor necrosis, tumor recurrence, brain metastasis, adrenal metastases, and skin metastases as significant prognostic factors affecting long-term survival. The hazard ratio (HR) of tumor necrosis, tumor recurrence, brain metastasis, adrenal metastases, and skin metastases was 2.0, 2.3, 7.6, 4.1, and 8.3, respectively, and all P values were less than 0.001. Conclusions. Our study shows stage of disease, tumor necrosis, tumor recurrence, brain metastasis, adrenal metastasis, and skin metastasis as the independent prognostic factors of long-term survival in pathological N0 NSCLC. Early stage NSCLC patients without nodal involvement or presented with tumor necrosis should benefit from adjuvant chemotherapy, and sites of metastasis could predict the long-term survival as described. PMID- 24073342 TI - Cavernous hemangioma of the tongue. AB - Hemangioma is a benign tumor of dilated blood vessels. It is most commonly seen in the head and neck region and rarely in the oral cavity. Hemangiomas in the oral cavity are always of clinical importance and require appropriate treatment. We report here a case of a 34-year-old female patient with a swelling on the lateral surface of tongue which did not respond to the sclerosing agent and was finally confirmed as cavernous hemangioma on histological evaluation. PMID- 24073343 TI - A Dermal Piercing Complicated by Mycobacterium fortuitum. AB - Background. Dermal piercings have recently become a fashion symbol. Common complications include hypertrophic scarring, rejection, local infection, contact allergy, and traumatic tearing. We report a rare case of Mycobacterium fortuitum following a dermal piercing and discuss its medical implications and treatments. Case. A previously healthy 19-year-old woman presented complaining of erythema and edema at the site of a dermal piercing on the right fourth dorsal finger. She was treated with a 10-day course of trimethoprim-sulfamethoxazole and one course of cephalexin by her primary care physician with incomplete resolution. The patient stated that she had been swimming at a local water park daily. A punch biopsy around the dermal stud was performed, and cultures with sensitivities revealed Mycobacterium fortuitum. The patient was treated with clarithromycin and ciprofloxacin for two months receiving full resolution. Discussion. Mycobacterium fortuitum is an infrequent human pathogen. This organism is a Runyon group IV, rapidly growing nontuberculous mycobacteria, often found in water,soil, and dust. Treatment options vary due to the size of the lesion. Small lesions are typically excised, while larger lesions require treatment for 2-6 months with antibiotics. We recommend a high level of suspicion for atypical mycobacterial infections in a piercing resistant to other therapies. PMID- 24073344 TI - Association between Rash and a Positive Drug Response Associated with Vinorelbine in a Patient with Primary Peritoneal Carcinoma. AB - Vinorelbine (Navelbine, VRL) is commonly used for platinum-resistant ovarian cancer and has been shown to be effective in patients with recurrent primary peritoneal carcinoma. Of VRL's major side effects, skin rash is uncommon, and, if it does occur, it is usually localized to site of injection. In this case report, a 71-year-old Hispanic female with primary peritoneal carcinoma received single agent VRL as fourth-line regimen, which she tolerated very well except for a skin rash related to VRL. The rash continued to progress throughout 6 cycles of VRL, and follow-up CT/PET scan demonstrated complete metabolic and radiological responses. We, therefore, believe that this rash was linked to VRL administration and correlated with response to therapy. Rash has been recognized as a useful surrogate marker with targeted agents such as cetuximab and erlotinib; to the best of our knowledge, this case report describes the first patient with a possible drug rash and its association with a positive outcome. This case report incites interest in further investigation of similar cases to support this observation, since there is a lack of reports of skin rash with VRL therapy. PMID- 24073345 TI - Hemophagocytic Lymphohistiocytosis Complicating T-Cell Lymphoma in a Patient with HIV Infection. AB - Hemophagocytic lymphohistiocytosis (HLH), while uncommon, may be a devastating complication of lymphoma and/or human immunodeficiency virus (HIV) infection. While several of the diagnostic criteria for HLH are relatively nonspecific, particularly in the setting of a systemic inflammatory response, more diagnostic specificity may be achieved with marked elevations in serum ferritin (e.g., >100,000 ng/mL). Increased suspicion of HLH, particularly in the setting of persistent, unexplained fevers, pancytopenia, and transaminitis, should prompt consideration of HLH. Earlier diagnosis and initiation of therapy have the potential to alter the natural history and poor prognosis of this disorder. We present a patient with HIV infection who developed relapsed T-cell lymphoma complicated by hemophagocytic lymphohistiocytosis. PMID- 24073346 TI - Aggressive angiomyxoma of the vulva: a precis for primary care providers. AB - Vulvar aggressive angiomyxoma (AA) is a rare mesenchymal tumor of the vulva. Due to its slow-growing nature, it is often overlooked and misdiagnosed by primary care providers (PCPs). We describe a case report of vulvar AA in a 38-year-old woman who underwent complete surgical excision of the neoplasm with no evidence of recurrence on a 5-year followup. A literature review follows to provide PCPs with the clinical, radiologic, and pathologic features that this tumor displays. PMID- 24073347 TI - Generalized peritonitis secondary to spontaneous perforation of pyometra in a 63 year-old patient. AB - Spontaneous perforation of pyometra resulting in generalized diffuse peritonitis is extremely uncommon. Herein, we report the case of a 63-year-old woman who presented to emergency department with a 2-day history of severe diffuse abdominal pain, high-grade fever, nausea, and vomiting. Acute abdomen series was done, and upright plain chest radiograph showed free air under diaphragm. A noncontrast-enhanced computed tomography scan showed a significantly distended fluid-filled uterus measuring 10 * 7.8 * 10 cm, in addition to a single focus of perforation involving the uterine fundus and associated with presence of free air within the nondependant area. No evidence of ascites or pelvi-abdominal lymphadenopathy was identified. A preoperative diagnosis of generalized peritonitis secondary to spontaneous perforation of uterus was established. Subsequently, patient underwent urgent exploratory laparotomy which revealed pus filled uterus with perforated fundus. Diagnosis of generalized peritonitis secondary to spontaneous perforation of pyometra was established. Consequently, patient underwent total abdominal hysterectomy with bilateral salpingo oophorectomy, as well as thorough drainage and irrigation of pelvi-abdominal cavity. Postoperatively, patient was admitted to intensive care unit. Histopathological examination of uterus was negative for malignancy, and surgical culture grew Streptococcus constellatus. Patient had an uneventful recovery. Moreover, a brief literature review on pyometra is presented. PMID- 24073348 TI - Merkel cell carcinoma of the retroperitoneum with no identifiable primary site. AB - Merkel cell carcinoma (MCC) is an extremely rare primary neuroendocrine neoplasm of the skin that shows aggressive behavior and a poor prognosis. We report a case of a 67-year-old male with a Merkel cell carcinoma which initially presented itself as a large retroperitoneal mass. Pathological and immunohistochemical analysis revealed tissue consistent with neuroendocrine carcinoma. Despite complete medical workup, no other primary MCC could be detected. While being an atypical presentation, the tumor mass showed an excellent response to the combination of chemotherapy followed by radiotherapy. PMID- 24073349 TI - Posterior and anterior spinal fusion for the management of deformities in patients with Parkinson's disease. AB - Introduction. Spinal scoliosis and kyphosis in elderly people sometimes cause severe low back pain. Surgical methods such as osteotomy are useful for correcting the deformity. However, complications during and after surgery are associated with the osteotomy procedure. In particular, it is difficult to manage deformity correction surgery for patients with Parkinson's disease. Here, we present two cases of combined anterior and posterior surgery for deformity in patients with adult scoliosis and kyphosis due to Parkinson's disease. Case Presentation. Two 70-year-old women had spinal scoliosis and kyphosis due to Parkinson's disease. They had severe low back pain, and conservative treatment was not effective for the pain. Surgery was planned to correct the deformity in both patients. We performed combined posterior and anterior correction surgery. At first, posterior fusions were performed from T4 to the ilium using pedicle screws. Next, cages and autograft from the iliac crest were used in anterior lumbar surgery. The patients became symptom free after surgery. Bony fusion was observed 12 months after surgery. Conclusions. Combined posterior and anterior fusion surgery is effective for patients who show scoliosis and kyphosis deformity, and symptomatic low back pain due to Parkinson's disease. PMID- 24073350 TI - Delayed postoperative epidural hematoma presenting only with vesicorectal disturbance. AB - We present a rare case of delayed onset of epidural hematoma after lumbar surgery whose only presenting symptom was vesicorectal disturbance. A 68-year-old man with degenerative spinal stenosis underwent lumbar decompression and instrumented posterolateral spine fusion. The day after his discharge following an unremarkable postoperative course, he presented to the emergency room complaining of difficulty in urination. An MRI revealed an epidural fluid collection causing compression of the thecal sac. The fluid was evacuated, revealing a postoperative hematoma. After removal of the hematoma, his symptoms disappeared immediately, and his urinary function completely recovered. Most reports have characterized postoperative epidural hematoma as occurring early after operation and accompanied with neurological deficits. But it can happen even two weeks after spinal surgery with no pain. Surgeons thus may need to follow up patients for at least a few weeks because some complications, such as epidural hematomas, could take that long to manifest themselves. PMID- 24073351 TI - Gangliocytic paraganglioma of duodenum. AB - Gangliocytic paragangliomas are rare benign tumors which are usually encountered in the second portion of the duodenum. Histogenesis of these tumors is incompletely understood. Patients usually present with upper gastrointestinal bleeding. The endoscopic features of gangliocytic paraganglioma do not differ from those of other submucosal tumors. Therefore, they can be diagnosed histologically by the presence of epithelioid, spindle, and ganglion cells, which is similar to that observed for paraganglioma. We herein report a case of gangliocytic paraganglioma due to the rarity of the lesion and the characteristic histopathologic findings. PMID- 24073352 TI - Cold induced sweating syndrome with urinary system anomaly association. AB - Mutation in the cytokine receptor-like factor 1 and the cardiotrophin-like cytokine (CRLF1 or CLCF1 genes) phenotypically presents as cold induced sweating syndrome (CISS), which is a rare autosomal recessive disorder. The syndrome is characterized by paradoxical sweating in cold weather, dysmorphic facial features, musculoskeletal deformities, difficulty in feeding, and unexplained recurrent episodes of high-grade fever. We are presenting the first case of CISS with urinary system anomaly, which might relate to CRLF1/CLCF1 complex role in the embryonal nephrogenesis. PMID- 24073353 TI - Neuroimaging features of immune reconstitution inflammatory syndrome in a patient with AIDS successfully treated for neurocryptococcosis. AB - The use of highly active antiretroviral therapy (HAART) has significantly reduced the incidence and progression of HIV-associated cryptococcosis. However, an early complication of HAART is the immune reconstitution inflammatory syndrome (IRIS), which may affect the CNS. The authors report a patient successfully treated for cryptococcosis and HIV who presented a late manifestation of IRIS. Neuroimaging aspects and management of CNS-IRIS in this patient are discussed in this paper. PMID- 24073354 TI - The effect of curcumin and cotrimoxazole in salmonella typhimurium infection in vivo. AB - Typhoid fever is a disease caused by Salmonella Typhi and commonly treated by an antimicrobial agent such as cotrimoxazole. On the other hand, herbal usage has risen as an adjunctive therapy to treat many diseases. Curcuma (Curcuma domestica) is a commonly used herb which consists of curcumin as its major active compound. Curcumin has been known for its antimicrobial effect, but there is no proof regarding the usage of curcumin and cotrimoxazole together. This research was conducted by using typhoid fever model in mice infected by Salmonella Typhimurium. Each animal was treated with curcumin, cotrimoxazole, or both. Ileum, spleen, and liver of each animal were isolated and cultured. We found that curcumin-cotrimoxazole combination therapy lowered the antimicrobial effectivity of cotrimoxazole in both intraintestinal and extraintestinal organs. We conclude that curcumin-cotrimoxazole combination therapy in typhoid fever has to be reconsidered. PMID- 24073356 TI - Prospective Predictors of Technology-Based Sexual Coercion by College Males. AB - OBJECTIVE: Technology-based coercive behavior (TBC) represents an emerging public health problem. This study contributes to the literature by identifying prospective individual-, social-, and community-level predictors of TBC. METHOD: Data were collected from 800 males who participated in a prospective study on attitudes and behaviors regarding relationships with women. Variables across multiple ecological layers were used to predict TBC. RESULTS: Bivariate analyses indicated that 16 of the 17 risk variables significantly predicted TBC including anger, impulsivity, sexual compulsivity, hostility towards women, rape supportive beliefs, high-risk drinking, childhood sexual abuse, interparental conflict, peer pressure to engage in sex, peer approval of forced sex, number of sexual partners, perceived negative sanctions for sexual aggression, exposure to pornography, and participation in varsity sports, student government, and religious groups. Multivariate regression analyses indicated five variables uniquely accounted for TBC behaviors, including rape supportive beliefs, peer approval of forced sex, number of sexual partners, exposure to pornography, and participation in student government. CONCLUSIONS: Our findings that TBC can be prospectively predicted by these risk factors suggest that computer-based technology interventions focusing on these factors through social network ads that promote reflection on healthy social and romantic relationship behaviors and attitudes could help prevent and reduce TBC. PMID- 24073355 TI - Cholesterol and copper affect learning and memory in the rabbit. AB - A rabbit model of Alzheimer's disease based on feeding a cholesterol diet for eight weeks shows sixteen hallmarks of the disease including beta amyloid accumulation and learning and memory changes. Although we have shown that feeding 2% cholesterol and adding copper to the drinking water can retard learning, other studies have shown that feeding dietary cholesterol before learning can improve acquisition and feeding cholesterol after learning can degrade long-term memory. We explore the development of this model, the issues surrounding the role of copper, and the particular contributions of the late D. Larry Sparks. PMID- 24073357 TI - Physiological effects of nickel chloride on the freshwater cyanobacterium Synechococcus sp. IU 625. AB - Harmful algal blooms (HABs) are a serious environmental problem globally. The ability of cyanobacteria, one of the major causative agents of HABs, to grow in heavy metal polluted areas is proving a challenge to environmental restoration initiatives. Some cyanobacteria secrete toxins, such as microcystin, that are potentially dangerous to animals and humans. In this study, the physiology of a cyanobacterium was assessed to nickel chloride exposure. Cell growths were monitored throughout the study with various nickel chloride concentrations (0, 10, 25 or 50 mg/L). Morphological abnormalities were observed with microscopic image analyses. Inductively coupled plasma mass spectrometry (ICP-MS) was carried out to trace the distribution of nickel during the growth period. This study provides insight on potential nickel response mechanisms in freshwater cyanobacteria, which may lead to effective HAB prevention strategy development. PMID- 24073358 TI - Early Phase Clinical Trials: Referral Barriers and Promoters among Physicians. AB - BACKGROUND: Physician referral is among the most effective means of recruiting patients into cancer clinical trials. Therefore, to increase minority representation in early-phase clinical trials (EPCTs), specifically accrual of Latinos, it is first necessary to examine physicians' attitudes and practices regarding these studies and factors that influence physicians' referral decisions. METHODS: This study surveyed oncologists (N=111) from a Texas Medical Association mailing list to examine barriers and promoting factors associated with physician referral of patients to EPCTs and identify areas for intervention to increase accrual of Latinos and other minorities into clinical research. Exploratory factor analysis was conducted to identify underlying dimensions, and significant factors that promote or deter physicians from referring patients to EPCTs were assessed through multiple logistic regression. RESULTS: Burden of the clinical trial process was the only significant dimension associated with referring patients to EPCTs. Physicians who agreed with this set of logistical barriers-such as diverting time and resources away from their practice-were less likely to refer patients than physicians with opposing opinions (OR= 0.28, 95% CI= 0.08-0.94). CONCLUSION: This study, one of the first to identify physician barriers for referring patients to EPCTs in Texas, highlights potential focal areas for physician and community-based education and communication to promote clinical trial opportunities among both minority and non-minority patients. Given that Texas physicians deal with a large proportion of Latino patients, such efforts could also address ethnic disparities in clinical trial participation, which will become increasingly important as the Latino population continues to grow. PMID- 24073359 TI - Neuroblastoma-related inflammation: May small doses of aspirin be suitable for small cancer patients? AB - The daily intake of low-dose aspirin lowers the risk of several cancers among the adults. The continuous administration of low-dose aspirin to TH-MYCN mice (a model of pediatric neuroblastoma) delays tumor outgrowth and decreases tumor promoting inflammation by inhibiting regulatory cells of the innate immune system as well as immunosuppressive mediators such as transforming growth factor beta (TGFbeta) and thromboxane A2. These findings pave novel avenues for the clinical management of neuroblastoma. PMID- 24073360 TI - Bone marrow provides an environment that prevents suppression of therapeutic graft-vs.-tumor immunity by regulatory T cells. AB - Regulatory T cells (Tregs) can prevent graft-vs.-host disease as induced by the infusion of donor lymphocytes to cancer patients, but often they also suppress therapeutic antitumor immunity. We discuss an exception to this phenomenon, exemplifying how the milieu provided by the bone marrow may neutralize Tregs to allow local immune responses against cancer. PMID- 24073361 TI - The combination of TLR2 and TLR4 agonists promotes the immunogenicity of dendritic cell/cancer cell fusions. AB - The induction of antitumor immune responses by dendritic cell (DC)/tumor cell fusions can be modulated by their activation status. Our recent work reveals that the combination of Toll-like receptor 2 (TLR2) and TLR4 agonists promotes the immunogenicity of DC/tumor cell fusions, allowing them to overcome the immunosuppressive effects of transforming growth factor beta1. PMID- 24073362 TI - Reducing cell number improves the homing of dendritic cells to lymph nodes upon intradermal vaccination. AB - Dendritic cell (DC)-based vaccines require the cells to relocate to lymph nodes (LNs). Unfortunately, however, DC migration rates are typically very poor. We investigated strategies to increase the migration efficacy of DC-based vaccines. Surprisingly, a reduction in DC number, but not the conditioning of the injection site, improved LN targeting. PMID- 24073363 TI - Approaching untargetable tumor-associated antigens with antibodies. AB - Approved therapeutic antineoplastic antibodies have targeted extracellular or cell-surface molecules. ESK1 is the first fully human T-cell receptor-like antibody targeting an intracellular tumor-associated antigen, Wilm's tumor 1 (WT1). In murine xenograft models, ESK1 exhibits a high specificity and exert robust antineoplastic effects against human cancers that express WT1 epitopes on HLA-A201 molecules. PMID- 24073364 TI - High immunosuppressive burden in advanced hepatocellular carcinoma patients: Can effector functions be restored? AB - The accumulation of immunosuppressive cells and exhausted effector T cells highlight an important immune dysfunction in advanced stage hepatocellular carcinoma (HCC) patients. These cells significantly hamper the efficacy immunotherapies and facilitate HCC progression. We have recently demonstrated that the multipronged depletion of immunosuppressive cells potentially restores effector T-cell function in HCC. PMID- 24073365 TI - Tumor-infiltrating lymphocytes, breast cancer subtypes and therapeutic efficacy. AB - By analyzing over 2000 samples from a randomized clinical trial, we have recently associated high levels of tumor-infiltrating lymphocytes with an excellent prognosis among triple negative breast cancer patients as well with improved clinical responses to immunogenic chemotherapy among patients bearing HER2 over expression. These findings suggest that immunomodulation could represent a new approach to treat these aggressive breast cancer subtypes. PMID- 24073366 TI - Peptide-based anticancer vaccines: The making and unmaking of a T-cell graveyard. AB - Poorly biodegradable, incomplete Freund's adjuvant (IFA)-based anticancer vaccines primed CD8+ T cells that did not localize to the tumor site but to the persisting, antigen-rich vaccination site, which became a T-cell graveyard. Short lived, water-based formulations and the provision of immunostimulatory molecules overcame this issue, resulting in tumor suppression. Here, we discuss the implications of these findings for the development of therapeutic anticancer vaccines. PMID- 24073367 TI - B7x and myeloid-derived suppressor cells in the tumor microenvironment: A tale of two cities. AB - A new study demonstrates the tumorigenic functions of B7x and reveals a link between B7x and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment. We propose that the binding of B7x to a hitherto unidentified receptor on MDSCs may stimulate their proliferation and/or immunosuppressive functions, hence promoting tumor growth. PMID- 24073368 TI - Myeloid-derived suppressor cells, age and cancer. AB - We have recently discovered that the levels of circulating myeloid-derived suppressor cells, which are associated with an impaired T-cell proliferation and produce high amounts of reactive oxygen species, increase with age and are elevated in individuals in remission from cancer. Herein, potential mechanisms underpinning these observations are discussed. PMID- 24073370 TI - Vaccination of biliary tract cancer patients with four peptides derived from cancer-testis antigens. AB - In the context of a Phase I clinical trial, the long-term vaccination of advanced biliary tract cancer patients with peptides derived from four distinct cancer testis antigens resulted in remarkable disease stability and in the elicitation of antigen-specific T-cell responses. PMID- 24073371 TI - IgG4 antibodies and cancer-associated inflammation: Insights into a novel mechanism of immune escape. AB - The role of B cells and antibodies in cancer is insufficiently understood but is receiving increasing attention. We have recently identified IgG4 as an antibody subclass elicited by melanoma-associated interleukin-10-driven inflammation. In this setting, IgG4 exhibit inefficient immunostimulatory capacity and block the cytotoxic activities of other antibodies. These previously unappreciated mechanisms of immune escape may constitute promising targets for the development of novel anticancer immunotherapies. PMID- 24073369 TI - Trial Watch: Immunostimulatory cytokines. AB - During the past two decades, the notion that cancer would merely constitute a cell-intrinsic disease has gradually been complemented by a model postulating that the immune system plays a relevant role during all stages of oncogenesis and tumor progression. Along with this conceptual shift, several strategies have been devised to stimulate tumor-specific immune responses, including relatively unselective approaches such as the systemic administration of adjuvants or immunomodulatory cytokines. One year ago, in the July issue of OncoImmunology, we described the main biological features of this large group of proteins and discussed the progress of ongoing clinical studies evaluating their safety and therapeutic potential in cancer patients. Here, we summarize the latest developments in this area of clinical research, focusing on high impact studies that have been published during the last 13 mo and clinical trials launched in the same period to investigate which cytokines can be employed as safe and efficient immunostimulatory interventions against cancer. PMID- 24073372 TI - The human TLR4 variant D299G mediates inflammation-associated cancer progression in the intestinal epithelium. AB - Homeostatic TLR4 signaling protects the intestinal epithelium in health. Evidence suggests that perturbed TLR4 signaling is linked to carcinogenesis. We have recently demonstrated that the common human TLR4 variant D299G exerts pro inflammatory effects and drives malignant tumor progression in human colon cancer. PMID- 24073373 TI - Pancreatic cancer-associated stellate cells: A viable target for reducing immunosuppression in the tumor microenvironment. AB - Pancreatic cancer-associated stellate cells secrete soluble factors, such as interleukin-6 (IL-6), that promote the accumulation of myeloid-derived suppressor cells via a signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. Targeting components of the IL-6/JAK/STAT3 signaling axis within the tumor stroma could therefore inhibit local immunosuppression and improve the efficacy of immunotherapeutic regimens against pancreatic cancer. PMID- 24073374 TI - Organ-specific regulatory T cells of thymic origin are expanded in murine prostate tumors. AB - Little is known about the relative contributions of self-specific regulatory T cells (Tregs) of thymic origin and induced Tregs generated extrathymically to the pool of tumor-infiltrating Tregs. We have recently demonstrated that thymic derived Tregs reactive to a prostate-associated self antigen are highly and recurrently enriched within oncogene-driven murine prostate cancers. PMID- 24073375 TI - The emergence of WT1-specific T-cell responses following allogeneic T cell depleted hematopoietic stem cell transplantation and low-dose donor lymphocyte infusions is associated with a graft-vs.- myeloma effect. AB - The development of T-cell responses specific for myeloma-associated antigens correlates with improved clinical outcomes in multiple myeloma patients undergoing allogeneic T cell-depleted hematopoietic stem cell transplantation and donor lymphocyte infusions. Thus, immunotherapeutic strategies that further increase the frequency of Wilms tumor 1 (WT1)-specific T cells may provide clinical benefits to multiple myeloma patients. PMID- 24073376 TI - Development of interferon gamma-based immunocytokines targeting renal cancer. AB - Advanced renal cancer is an incurable malignancy in need of novel therapeutic avenues. We have generated interferon gamma (IFNgamma)-based fusion antibodies (immunocytokines) that target CD70, a putative biomarker of renal cancer. These immunocytokines efficiently labeled renal cancer cells, and, when combined with the proteasome inhibitor bortezomib, killed them by activating a RIP1-dependent necrotic pathway. PMID- 24073377 TI - Myeloid-derived suppressor cells in allogeneic hematopoietic stem cell transplantation: A double-edged sword? AB - Accumulating evidence suggests that myeloid-derived suppressor cells (MDSCs) underpin an immunological checkpoint that is activated during inflammation or "inflammatory-like" conditions like cancer. Here, we discuss the identification of MDSCs in patients receiving allogeneic hematopoietic stem cell transplantation and their potential as therapeutic targets or tools for improving the efficacy of this treatment. PMID- 24073378 TI - Boosting anticancer vaccines: Too much of a good thing? AB - Using both transplantable and oncogene-driven autochthonous tumor models challenged with dendritic cell-based vaccines, we have recently found that boosting provides a clear advantage in prophylactic settings, unless performed on an excessively tight schedule, which causes the loss of central memory T cells. In therapeutic settings, boosting turned out to be always detrimental. PMID- 24073379 TI - Injection site and regulatory T cells influence durable vaccine-induced tumor immunity to an over-expressed self tumor associated antigen. AB - Tumor protein D52 (D52) is constitutively expressed in healthy tissues and overexpressed in multiple cancers, including (but not limited to) breast, prostate and ovarian carcinomas. Although the normal functions of D52 are unknown, it is clear that increased D52 expression levels not only stimulate cell proliferation and metastasis, but also correlate with poor prognosis in a subset of breast cancer patients. The murine orthologs of D52 (mD52) shares 86% identity with its human counterpart (hD52) and mirrors hD52 expression patterns. The forced overexpression of mD52 induces anchorage-independent growth in vitro and promotes tumor formation as well as spontaneous metastasis in vivo. We have previously reported that the intramuscular administration of recombinant mD52 elicits immune responses capable of rejecting a challenge with tumor cells and preventing spontaneous metastasis only in 50% of mice. We hypothesized that mechanisms of peripheral tolerance dampen immune responses against mD52, thus limiting the protective effects of vaccination. To test this hypothesis, mice were depleted of CD25+ regulatory T cells (Tregs) and subcutaneously immunized with mD52 prior to a tumor challenge. The subcutaneous immunization failed to induce protective antitumor immunity unless accompanied by Treg depletion, which resulted in a rate of protection of 70% as compared with. PMID- 24073380 TI - SOX2-specific adaptive immunity and response to immunotherapy in non-small cell lung cancer. AB - Immunotherapeutic strategies including the blockade of programmed death 1 (PD-1) receptors hold promise for the treatment of various cancers including non-small cell lung carcinoma (NSCLC). Preclinical data suggest that pre-existing tumor immunity is important for disease regression upon checkpoint blockade-based therapies. However, the nature of antigen-specific T-cell responses that correlate with the clinical response to immunotherapy in NSCLC patients is not known. The embryonic stem cell gene SRY (sex determining region Y)-box 2 (SOX2) has recently emerged as a major oncogenic driver in NSCLC. Here, we show that nearly 50% of a cohort of NSCLC patients mounted both CD4+ and CD8+ T-cell responses against SOX2, which could be readily detected among peripheral blood mononuclear cells. T-cell responses against SOX2 were associated with NSCLC regression upon immunotherapy with anti-PD-1 monoclonal antibodies, whereas none of the patients lacking SOX2-specific T cells experienced disease regression following immune checkpoint blockade. Conversely, cellular and humoral responses against viral antigens or another tumor-associated antigen (NY-ESO-1) failed to correlate with the clinical response of NSCLC patients to immunotherapy. Of note, the administration of PD-1-blocking antibodies was associated with intramolecular epitope spread as well as with the amplification of SOX2-specific immune responses in vivo. These findings identify SOX2 as an important tumor-associated antigen in NSCLC and link the presence of SOX2-specific T cells with the clinical response of lung cancer patients to immunotherapy. PMID- 24073381 TI - High frequency of T cells specific for cryptic epitopes in melanoma patients. AB - A number of cytotoxic T-cell epitopes are cryptic epitopes generated from non conventional sources. These include epitopes that are encoded by alternative open reading frames or in generally non-coding genomic regions, such as introns. We have previously observed a frequent recognition of cryptic epitopes by tumor infiltrating lymphocytes isolated from melanoma patients. Here, we show that such cryptic epitopes are more frequently recognized than antigens of the same class encoded by canonical reading frames. Furthermore, we report the presence of T cells specific for three cryptic epitopes encoded in intronic sequences, as a result of incomplete splicing, in the circulation of melanoma patients. One of these epitopes derives from antigen isolated from immunoselected melanoma 2 (AIM2), while the two others are encoded in an alternative open reading frame of an incompletely spliced form of N-acetylglucosaminyl-transferase V (GNT-V) known as NA17-A. We have detected frequent T-cell responses against AIM2 and NA17-A epitopes in the blood of melanoma patients, both prior and after one round of in vitro peptide stimulation, but not in the circulation of healthy individuals and patients with breast or renal carcinoma. In summary, our findings indicate that the T-cell reactivity against AIM2 and NA17-A in the blood of melanoma patients is extensive, suggesting that-similar to melan A (also known as MART1)-these antigens might be used for immunomonitoring or as model antigens in several clinical and preclinical settings. PMID- 24073383 TI - Following up tumor-specific regulatory T cells in cancer patients. PMID- 24073382 TI - B cell-regulated immune responses in tumor models and cancer patients. AB - The essential role played by T cells in anticancer immunity is widely accepted. The immunosuppressive functions of regulatory T cells are central for tumor progression and have been endowed with a robust predictive value. Increasing evidence indicates that also B cells have a crucial part in the regulation of T cell responses against tumors. Although experiments reporting the production of natural antitumor antibodies and the induction of cytotoxic immune responses have revealed a tumor-protective function for B cells, other findings suggest that B cells may also exert tumor-promoting functions, resulting in a controversial picture. Here, we review recent evidence on the interactions between B and T cells in murine models and cancer patients and their implications for cancer immunology. PMID- 24073384 TI - A role for CCL2 in both tumor progression and immunosurveillance. AB - The chemokine CCL2, which is best known for its chemotactic functions, is expressed not only by immune cells, but also by several types of malignant and stromal cells. CCL2 has been shown to exert both pro- and anti-tumor effects. However, recent results demonstrate a main role for CCL2 in tumor progression and metastasis, suggesting that this chemokine may constitute a therapeutic target for anticancer drugs. Mammary carcinoma models, including models of implantable, transgenic, and chemically-induced tumors, were employed in the setting of Ccl2 or Ccr2 knockout mice or CCL2 neutralization with a monoclonal antibody to further investigate the role of the CCL2/CCR2 signaling axis in tumor progression and metastatic spread. In our implantable tumor models, an anti-CCL2 monoclonal antibody inhibited the growth of primary malignant lesions in a biphasic manner and reduced the number of metastases. However, in Ccl2-/- or Ccr2-/- mice developing implanted or transgenic tumors, the number of pulmonary metastases was increased despite a reduction in the growth rate of primary neoplasms. Transgenic Mtag.Ccl2-/- or Mtag.Ccr2-/- mice also exhibited a significantly earlier of disease onset. In a chemical carcinogenesis model, anti-CCL2 monoclonal antibody inhibited the growth of established lesions but was ineffective in the tumor induction phase. In contrast to previous studies indicating a role for CCL2 in the establishment of metastases, we have demonstrated that the absence of CCL2/CCR2-signaling results in increased metastatic disease. Thus, the CCL2/CCR2 signaling axis appears to play a dual role in mediating early tumor immunosurveillance and sustaining the growth and progression of established neoplasms. Our findings support the use of anti-CCL2 therapies for the treatment of established breast carcinoma, although the complete abrogation of the CCL2 signaling cascade may also limit immunosurveillance and support metastatic spread. PMID- 24073385 TI - Generation and immunosuppressive functions of p53-induced human adaptive regulatory T cells. AB - Inducible regulatory T cells (iTregs, also called Tr1 cells) are generated in the periphery (circulation or tissue) of cancer patients upon the encounter of naive CD4+ T cells with tumor-associated antigens. As p53 is often inactivated by genetic or epigenetic events during oncogenesis, p53-induced Tr1 cells might play a key role in establishing immunosuppressive networks in cancer patients. Tr1 cells were generated by co-culturing circulating CD4+CD25- T cells with autologous immature dendritic cells pulsed with a wild-type (WT) p53-derived peptide or an unrelated peptide derived from mucin 1 (MUC1). The Tr1 phenotype and the specificity for p53 of these cells were confirmed by multicolor flow cytometry. Moreover, the Tr1 cell-mediated suppression of T-cell proliferation was evaluated by CFSE-based flow cytometry, while their ability to alter the T cell cytokine profile by ELISA and Luminex assays. The capacity of p53-induced Tr1 cells to suppress the generation and function of cytotoxic T lymphcoytes (CTLs) was assessed by flow cytometry and ELISPOT. Of note, low doses of the p53 derived peptide (p53low) induced greater numbers of Tr1 cells than the same peptide employed at high doses (p53high). Moreover, Tr1/p53low cells not secreted higher levels of interleukin-10 and transforming growth factor beta1, but also mediated more robust suppressive effects on CTL proliferation than Tr1/p53high cells. Tr1/p53low cells, Tr1/p53high cells, as well as Tr1 cells generated with low doses of an unrelated MUC1-derived peptide were equally effective in suppressing the expansion and antitumor activity of p53-reactive CTLs. p53low induced the expansion of highly suppressive p53-reactive Tr1 cells. However, the capacity of these Tr1 cells to suppress the generation and function of p53 reactive CTLs was independent of their antigen-specificity. PMID- 24073386 TI - The endothelial glycocalyx: an important regulator of the pulmonary vascular barrier. AB - Once thought to be a structure of small size and uncertain significance, the endothelial glycocalyx is now known to be an important regulator of endothelial function. Studies of the systemic vasculature have demonstrated that the glycocalyx forms a substantial in vivo endothelial surface layer (ESL) critical to inflammation, barrier function, and mechanotransduction. The pulmonary ESL is significantly thicker than the systemic ESL, suggesting unique physiologic function. We have recently demonstrated that the pulmonary ESL regulates exposure of endothelial surface adhesion molecules, thereby serving as a barrier to neutrophil adhesion and extravasation. While the pulmonary ESL is not a critical structural component of the endothelial barrier to fluid and protein, it serves a major role in the mechanotransduction of vascular pressure, with impact on the active regulation of endothelial permeability. It is likely that the ESL serves numerous additional functions in vascular physiology, representing a fertile area for future investigation. PMID- 24073387 TI - P2X receptor channels in endocrine glands. AB - The endocrine system is the system of ductless glands and single cells that synthetize hormones and release them directly into the bloodstream. Regulation of endocrine system is very complex and ATP and its degradable products ADP and adenosine contribute to its regulation acting as extracellular messengers for purinergic receptors. These include P2X receptors, a family of ligand-gated ion channels which expression and roles in endocrine tissues are reviewed here. There are seven mammalian purinergic receptor subunits, denoted P2X1 through P2X7, and the majority of these subunits are also expressed in secretory and non-secretory cells of endocrine system. Functional channels have been identified in the neuroendocrine hypothalamus, the posterior and anterior pituitary, the thyroid gland, the adrenals, the endocrine pancreas, the gonads and the placenta. Native channels are capable of promoting calcium influx through its pore in both excitable and non-excitable cells, as well as of increasing electrical activity in excitable cells by membrane depolarization. This leads to generation of calcium transients and stimulation of hormone release. The pattern of expression and action of P2XRs in endocrine system suggests that locally produced ATP amplifies and synchronizes the secretory responses of individual cells. PMID- 24073388 TI - LRRKing up the right trees? On figuring out the effects of mutant LRRK2 and other Parkinson's disease-related genes. PMID- 24073389 TI - Ethanolic Extracts of California Mugwort (Artemisia douglasiana Besser) Are Cytotoxic against Normal and Cancerous Human Cells. AB - California mugwort (Artemisia douglasiana Besser) is used by many tribes throughout California to treat a variety of conditions, including colds, allergies, and pain. California mugwort is also utilized as women's medicine. Its use is on the rise outside of Native communities, often without the guidance of a traditional healer or experienced herbalist. Because it has been shown to have antiproliferative activity against plant and animal cells, we investigated whether California mugwort extracts have an effect on normal human cells as well as estrogen receptor positive (ER+) and estrogen receptor negative (ER-) human breast cancer cells. Ethanolic and aqueous extracts of A. douglasiana leaves were tested for cytotoxicity against unstimulated normal human peripheral blood mononuclear cells (hPBMC), as well as against an ER+ human breast cancer cell line (BT-474) and an ER- human breast cancer cell line (MDA-MB-231). An ethanolic leaf extract killed hPBMC, BT-474, and MDA-MB-231 cells with IC50 values of 23.6 +/- 0.3, 27 +/- 5, and 37 +/- 4 MUg/ml, respectively. An aqueous extract killed hPBMC with an IC50 value of 60 +/- 10 MUg/ml, but had no effect on the two cancer cell lines at concentrations up to 100 MUg/ml. The results of this study indicate that the cytotoxicity of California mugwort extends to normal human cells, as well as cancerous cells. Therefore, until further is known about the safety of this medicine, caution should be taken when consuming extracts of California mugwort, whether as a tincture or as a tea. PMID- 24073390 TI - Predictive Validity of Explicit and Implicit Threat Overestimation in Contamination Fear. AB - We examined the predictive validity of explicit and implicit measures of threat overestimation in relation to contamination-fear outcomes using structural equation modeling. Undergraduate students high in contamination fear (N = 56) completed explicit measures of contamination threat likelihood and severity, as well as looming vulnerability cognitions, in addition to an implicit measure of danger associations with potential contaminants. Participants also completed measures of contamination-fear symptoms, as well as subjective distress and avoidance during a behavioral avoidance task, and state looming vulnerability cognitions during an exposure task. The latent explicit (but not implicit) threat overestimation variable was a significant and unique predictor of contamination fear symptoms and self-reported affective and cognitive facets of contamination fear. On the contrary, the implicit (but not explicit) latent measure predicted behavioral avoidance (at the level of a trend). Results are discussed in terms of differential predictive validity of implicit versus explicit markers of threat processing and multiple fear response systems. PMID- 24073391 TI - Impaired and facilitated functional networks in temporal lobe epilepsy. AB - How epilepsy affects brain functional networks remains poorly understood. Here we investigated resting state functional connectivity of the temporal region in temporal lobe epilepsy. Thirty-two patients with unilateral temporal lobe epilepsy underwent resting state blood-oxygenation level dependent functional magnetic resonance imaging. We defined regions of interest a priori focusing on structures involved, either structurally or metabolically, in temporal lobe epilepsy. These structures were identified in each patient based on their individual anatomy. Our principal findings are decreased local and inter hemispheric functional connectivity and increased intra-hemispheric functional connectivity ipsilateral to the seizure focus compared to normal controls. Specifically, several regions in the affected temporal lobe showed increased functional coupling with the ipsilateral insula and immediately neighboring subcortical regions. Additionally there was significantly decreased functional connectivity between regions in the affected temporal lobe and their contralateral homologous counterparts. Intriguingly, decreased local and inter hemispheric connectivity was not limited or even maximal for the hippocampus or medial temporal region, which is the typical seizure onset region. Rather it also involved several regions in temporal neo-cortex, while also retaining specificity, with neighboring regions such as the amygdala remaining unaffected. These findings support a view of temporal lobe epilepsy as a disease of a complex functional network, with alterations that extend well beyond the seizure onset area, and the specificity of the observed connectivity changes suggests the possibility of a functional imaging biomarker for temporal lobe epilepsy. PMID- 24073392 TI - Effects of Cortisol Administered through Slow-Release Implants on Innate Immune Responses in Rainbow Trout (Oncorhynchus mykiss). AB - Cortisol is a key hormone in the fish stress response with a well-known ability to regulate several physiological functions, including energy metabolism and the immune system. However, data concerning cortisol effects on fish innate immune system using a more controlled increase in cortisol levels isolated from any other stress related signaling is scarce. The present study describes the effect of doses of cortisol corresponding to acute and chronic levels on the complement and lysozyme activity in plasma of the rainbow trout (Oncorhynchus mykiss). We also evaluated the effects of these cortisol levels (from intraperitoneally implanted hydrocortisone) on the mRNA levels quantified by RT-qPCR of selected key immune-related genes in the liver, head kidney, and spleen. For that purpose, 60 specimens of rainbow trout were divided in to two groups: a control group injected with a coconut oil implant and another group injected with the same implant and cortisol (50 MU g cortisol/g body weight). Our results demonstrate the role of cortisol as a modulator of the innate immune response without the direct contribution of other stress axes. Our results also show a relationship between the complement and lysozyme activity in plasma and mRNA levels in liver, supporting the important role of this organ in producing these immune system proteins after a rise of cortisol in the fish plasma. PMID- 24073394 TI - Development and characterization of novel polyurethane films impregnated with tolfenamic acid for therapeutic applications. AB - The present study deals with the preparation of polyurethane (PU) films impregnated with a nonsteroidal anti-inflammatory drug, tolfenamic acid (TA). Solvent evaporation technique has been employed for the preparation of TA-PU films in two different ratios of 1:2 and 1:5 in Tetrahydrofuran (THF) or THF ethanol mixtures. The prepared films were characterized using X-Ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and release studies. The results indicate transformation of crystalline TA to its amorphous form. The degree of crystallinity changes both by increasing the polymer concentration and solvent used for the film preparations. The release profiles of TA were also found to be affected, showing a decrease from approximately 50% to 25% from 1:2 to 1:5 ratios, respectively. PMID- 24073393 TI - Nonpharmacological management of gastroesophageal reflux in preterm infants. AB - Gastroesophageal reflux (GOR) is very common among preterm infants, due to several physiological mechanisms. Although GOR should not be usually considered a pathological condition, its therapeutic management still represents a controversial issue among neonatologists; pharmacological overtreatment, often unuseful and potentially harmful, is increasingly widespread. Hence, a stepwise approach, firstly promoting conservative strategies such as body positioning, milk thickening, or changes of feeding modalities, should be considered the most advisable choice in preterm infants with GOR. This review focuses on the conservative management of GOR in the preterm population, aiming to provide a complete overview, based on currently available evidence, on potential benefits and adverse effects of nonpharmacological measures. Nonpharmacological management of GOR might represent a useful tool for neonatologists to reduce the use of antireflux medications, which should be limited to selected cases of symptomatic babies. PMID- 24073395 TI - Primary immunodeficiency diseases at reference and high-specialty hospitals in the state of Guanajuato, Mexico. AB - BACKGROUND: In general, primary immunodeficiency diseases (PIDs) are underdiagnosed in most countries. The objective of this study was to describe the frequency and clinical spectrum of PID in the most important tertiary hospitals in our region. METHODS: An observational, cross-sectional, with retrospective chart, review study was conducted. A total of 26 patients were included and grouped according to the updated classification of PIDs. RESULTS: PIDs spectra were as follows: predominantly antibody deficiency diseases were the most common category (65.38%), followed by other well-defined immunodeficiency syndromes (11.55%), congenital defects of phagocyte number and/or function (7.69%), complement deficiencies (3.85%), combined T- and B-cell immunodeficiencies (3.85%), and defects in innate immunity (3.85%). The mean time elapsed from the onset of symptoms to the reference and diagnosis by a tertiary hospital was of 4.65 +/- 6.95 years. CONCLUSIONS: Predominant antibody deficiency disease was the most common group of PIDs, agreeing with international reports. Awareness of underdiagnosis by physicians is crucial for a prompt diagnosis and treatment, which in turn should improve the quality of life among patients with PIDs. PMID- 24073396 TI - Hyperthermia as adjunct to intravesical chemotherapy for bladder cancer. AB - Nonmuscle invasive bladder cancer remains a very costly cancer to manage because of high recurrence rates requiring long-term surveillance and treatment. Emerging evidence suggests that adjunct and concurrent use of hyperthermia with intravesical chemotherapy after transurethral resection of bladder tumor further reduces recurrence risk and progression to advanced disease. Hyperthermia has both direct and immune-mediated cytotoxic effect on tumor cells including tumor growth arrest and activation of antitumor immune system cells and pathways. Concurrent heat application also acts as a sensitizer to intravesical chemotherapy agents. As such the ability to deliver hyperthermia to the focus of tumor while minimizing damage to surrounding benign tissue is of utmost importance to optimize the benefit of hyperthermia treatment. Existing chemohyperthermia devices that allow for more localized heat delivery continue to pave the way in this effort. Current investigational methods involving heat activated drug delivery selectively to tumor cells using temperature-sensitive liposomes also offer promising ways to improve chemohyperthermia efficacy in bladder cancer while minimizing toxicity to benign tissue. This will hopefully allow more widespread use of chemohyperthermia to all bladder cancer patients, including metastatic bladder cancer. PMID- 24073397 TI - Digital microscopy assessment of angiogenesis in different breast cancer compartments. AB - BACKGROUND/AIM: Tumour angiogenesis defined by microvessel density (MVD) is generally accepted as a prognostic factor in breast cancer. However, due to variability of measurement systems and cutoffs, it is questionable to date whether it contributes to predictive outline. Our study aims to grade vascular heterogeneity by comparing clear-cut compartments: tumour associated stroma (TAS), tumour parenchyma, and tumour invasive front. MATERIAL AND METHODS: Computerized vessel area measurement was performed using a tissue cytometry system (TissueFAXS) on slides originated from 50 patients with breast cancer. Vessels were marked using immunohistochemistry with CD34. Regions of interest were manually defined for each tumour compartment. RESULTS: Tumour invasive front vascular endothelia area was 2.15 times higher than that in tumour parenchyma and 4.61 times higher than that in TAS (P < 0.002). Worth to mention that the lymph node negative subgroup of patients show a slight but constant increase of vessel index in all examined compartments of breast tumour. CONCLUSION: Whole slide digital examination and region of interest (ROI) analysis are a valuable tool in scoring angiogenesis markers and disclosing their prognostic capacity. Our study reveals compartments' variability of vessel density inside the tumour and highlights the propensity of invasive front to associate an active process of angiogenesis with potential implications in adjuvant therapy. PMID- 24073398 TI - The effect of silver nitrate pleurodesis after a failed thoracoscopic talc poudrage. AB - BACKGROUND: Chemical pleurodesis is the procedure of choice in the management of recurrent malignant pleural effusions (MPE). Talc is probably the most effective sclerosant, with a success rate of 80%. The aim of this study is to demonstrate the effectiveness of silver nitrate solution (SNS) pleurodesis after an unsuccessful thoracoscopic talc poudrage. METHODS: Between 2011 and 2013 one hundred and nine patients with unilateral MPE underwent thoracoscopic talc poudrage. Seventeen patients who did not obtain a successful pleurodesis via thoracoscopic procedure were considered for an SNS slurry. The pleural injectate consisted of 100 mL 1% SNS with 10 mL of lidocaine (100 mg/5 mL). The SNS procedure was undertaken once and repeated with the same dose in 5 patients. RESULTS: The duration of follow-up period was 30 days. Subjective pain was low and the same before and after SNS procedure (P value = NS). The mean daily fluid drainage was statistically different (P = 0.001) comparing values before (597.0 +/- 122.8 mL) and after SNS procedure (109.1 +/- 22.3 mL). After 30 days from SNS procedure recurrence of pleural effusion was observed in 2 patients (11%). CONCLUSIONS: The present study demonstrates that SNS is an effective agent for producing pleurodesis after a failed thoracoscopic talc poudrage. PMID- 24073399 TI - Protective effect of fermented soybean dried extracts against TPA-induced oxidative stress in hairless mice skin. AB - This study evaluated the chemical properties (polyphenol and genistein contents) of soybean extracts obtained by biotransformation and dried by spray dryer at different conditions and their in vivo ability to inhibit 12-O tetradecanoylphorbol-13-acetate- (TPA-) induced biochemical alterations in the skin of hairless mice. By comparing the obtained data with that of the well-known active soybean extract Isoflavin beta, we evaluated the influence of the fermentation and drying process in the extracts efficacy. The results demonstrated that inlet gas temperature and adjuvant concentration for the extract drying process have significantly affected the total polyphenol contents and, to a minor degree, the genistein contents. However, the effect of topical stimulus with TPA, an oxidative stress inducer, which caused significant depletion of reduced glutathione (GSH) and catalase, with increased levels of H2O2 and lipid peroxidation (MDA) in the skin of hairless mice, was significantly prevented by the soybean extracts treatment. These results indicate that the spray drying processing resulted in a product capable of limiting the oxidative stress with possible therapeutic applicability as an antioxidant in pharmaceutical forms. PMID- 24073400 TI - Performance study of chromium (VI) removal in presence of phenol in a continuous packed bed reactor by Escherichia coli isolated from East Calcutta Wetlands. AB - Organic pollutants, like phenol, along with heavy metals, like chromium, are present in various industrial effluents that pose serious health hazard to humans. The present study looked at removal of chromium (VI) in presence of phenol in a counter-current continuous packed bed reactor packed with E. coli cells immobilized on clay chips. The cells removed 85% of 500 mg/L of chromium (VI) from MS media containing glucose. Glucose was then replaced by 500 mg/L phenol. Temperature and pH of the MS media prior to addition of phenol were 30 degrees C and 7, respectively. Hydraulic retention times of phenol- and chromium (VI)-containing synthetic media and air flow rates were varied to study the removal efficiency of the reactor system. Then temperature conditions of the reactor system were varied from 10 degrees C to 50 degrees C, the optimum being 30 degrees C. The pH of the media was varied from pH 1 to pH 12, and the optimum pH was found to be 7. The maximum removal efficiency of 77.7% was achieved for synthetic media containing phenol and chromium (VI) in the continuous reactor system at optimized conditions, namely, hydraulic retention time at 4.44 hr, air flow rate at 2.5 lpm, temperature at 30 degrees C, and pH at 7. PMID- 24073401 TI - Molecular dynamic simulation and inhibitor prediction of cysteine synthase structured model as a potential drug target for trichomoniasis. AB - In our presented research, we made an attempt to predict the 3D model for cysteine synthase (A2GMG5_TRIVA) using homology-modeling approaches. To investigate deeper into the predicted structure, we further performed a molecular dynamics simulation for 10 ns and calculated several supporting analysis for structural properties such as RMSF, radius of gyration, and the total energy calculation to support the predicted structured model of cysteine synthase. The present findings led us to conclude that the proposed model is stereochemically stable. The overall PROCHECK G factor for the homology-modeled structure was 0.04. On the basis of the virtual screening for cysteine synthase against the NCI subset II molecule, we present the molecule 1-N, 4-N-bis [3-(1H-benzimidazol-2 yl) phenyl] benzene-1,4-dicarboxamide (ZINC01690699) having the minimum energy score (-13.0 Kcal/Mol) and a log P value of 6 as a potential inhibitory molecule used to inhibit the growth of T. vaginalis infection. PMID- 24073402 TI - Comparative plasma exposure and lung distribution of two human use commercial azithromycin formulations assessed in murine model: a preclinical study. AB - Azithromycin (AZM) therapeutic failure and relapses of patients treated with generic formulations have been observed in clinical practice. The main goal of this research was to compare in a preclinical study the serum exposure and lung tissue concentration of two commercial formulations AZM-based in murine model. The current study involved 264 healthy Balb-C. Mice were divided into two groups (n = 44): animals of Group A (reference formulation -R-) were orally treated with AZM suspension at 10 mg/kg of b.w. Experimental animals of Group B (generic formulation -G-) received identical treatment than Group A with a generic formulation AZM-based. The study was repeated twice as Phase II and III. Serum and lung tissue samples were taken 24 h post treatment. Validated microbiological assay was used to determine the serum pharmacokinetic and lung distribution of AZM. After the pharmacokinetic analysis was observed, a similar serum exposure for both formulations of AZM assayed. In contrast, statistical differences (P < 0.001) were obtained after comparing the concentrations of both formulations in lung tissue, being the values obtained for AUC and Cmax (AZM-R-) +1586 and 122%, respectively, than those obtained for AZM-G- in lung. These differences may indicate large differences on the distribution process of both formulations, which may explain the lack of efficacy/therapeutic failure observed on clinical practice. PMID- 24073403 TI - Network-based inference framework for identifying cancer genes from gene expression data. AB - Great efforts have been devoted to alleviate uncertainty of detected cancer genes as accurate identification of oncogenes is of tremendous significance and helps unravel the biological behavior of tumors. In this paper, we present a differential network-based framework to detect biologically meaningful cancer related genes. Firstly, a gene regulatory network construction algorithm is proposed, in which a boosting regression based on likelihood score and informative prior is employed for improving accuracy of identification. Secondly, with the algorithm, two gene regulatory networks are constructed from case and control samples independently. Thirdly, by subtracting the two networks, a differential-network model is obtained and then used to rank differentially expressed hub genes for identification of cancer biomarkers. Compared with two existing gene-based methods (t-test and lasso), the method has a significant improvement in accuracy both on synthetic datasets and two real breast cancer datasets. Furthermore, identified six genes (TSPYL5, CD55, CCNE2, DCK, BBC3, and MUC1) susceptible to breast cancer were verified through the literature mining, GO analysis, and pathway functional enrichment analysis. Among these oncogenes, TSPYL5 and CCNE2 have been already known as prognostic biomarkers in breast cancer, CD55 has been suspected of playing an important role in breast cancer prognosis from literature evidence, and other three genes are newly discovered breast cancer biomarkers. More generally, the differential-network schema can be extended to other complex diseases for detection of disease associated-genes. PMID- 24073404 TI - Prokaryotic phylogenies inferred from whole-genome sequence and annotation data. AB - Phylogenetic trees are used to represent the evolutionary relationship among various groups of species. In this paper, a novel method for inferring prokaryotic phylogenies using multiple genomic information is proposed. The method is called CGCPhy and based on the distance matrix of orthologous gene clusters between whole-genome pairs. CGCPhy comprises four main steps. First, orthologous genes are determined by sequence similarity, genomic function, and genomic structure information. Second, genes involving potential HGT events are eliminated, since such genes are considered to be the highly conserved genes across different species and the genes located on fragments with abnormal genome barcode. Third, we calculate the distance of the orthologous gene clusters between each genome pair in terms of the number of orthologous genes in conserved clusters. Finally, the neighbor-joining method is employed to construct phylogenetic trees across different species. CGCPhy has been examined on different datasets from 617 complete single-chromosome prokaryotic genomes and achieved applicative accuracies on different species sets in agreement with Bergey's taxonomy in quartet topologies. Simulation results show that CGCPhy achieves high average accuracy and has a low standard deviation on different datasets, so it has an applicative potential for phylogenetic analysis. PMID- 24073405 TI - Transcription regulation of plastid genes involved in sulfate transport in Viridiplantae. AB - This study considers transcription regulation of plastid genes involved in sulfate transport in the parasites of invertebrate (Helicosporidium sp.) and other species of the Viridiplantae. A one-box conserved motif with the consensus TAAWATGATT is found near promoters upstream the cysT and cysA genes in many species. In certain cases, the motif is repeated two or three times. PMID- 24073406 TI - Genetic and biochemical diversity of Paenibacillus larvae isolated from Tunisian infected honey bee broods. AB - Paenibacillus larvae is the causative agent of American foulbrood (AFB), a virulent disease of honeybee (Apis mellifera) larvae. In Tunisia, AFB has been detected in many beekeeping areas, where it causes important economic losses, but nothing is known about the diversity of the causing agent. Seventy-five isolates of P. larvae, identified by biochemical tests and 16S rRNA gene sequencing, were obtained from fifteen contaminated broods showing typical AFB symptoms, collected in different locations in the northern part of the country. Using BOX-PCR, a distinct profile of P. larvae with respect to related Paenibacillus species was detected which may be useful for its identification. Some P. larvae-specific bands represented novel potential molecular markers for the species. BOX-PCR fingerprints indicated a relatively high intraspecific diversity among the isolates not described previously with several molecular polymorphisms identifying six genotypes on polyacrylamide gel. Polymorphisms were also detected in several biochemical characters (indol production, nitrate reduction, and methyl red and oxidase tests). Contrary to the relatively high intraspecies molecular and phenotypic diversity, the in vivo virulence of three selected P. larvae genotypes did not differ significantly, suggesting that the genotypic/phenotypic differences are neutral or related to ecological aspects other than virulence. PMID- 24073407 TI - Effects of repeated central administration of endothelin type A receptor antagonist on the development of neuropathic pain in rats. AB - Endothelin-1 (ET-1) predominates in the endothelin family effectively in vascular tone control, mitogenesis, and neuromodulation. Its receptors are widespread in the central nervous system (CNS) associated with endogenous pain control, suggesting an important role of ET-1 in central pain processing. This study aimed to evaluate the effect of central ET-1 on the development of neuropathic pain behaviour by repeated intrathecal administration of endothelin type A receptor (ETAR) antagonist (BQ-123) in a sciatic nerve ligation (SNL) animal model. BQ-123 was administered intrathecally to rats at dosages 15 MUg, 20 MUg, 25 MUg, and 30 MUg, daily for 3 days. Mechanical allodynia was assessed daily 30 minutes before/after injection, 1 hour after injection of BQ-123 from post-SNL day 4 to day 6, and once on day 7 (without BQ-123 administration) before rats were sacrificed. Increasing trends of mechanical threshold were observed, and they reached significance at all dosages on post-SNL day 7 (P < 0.05 at dosage 15 MUg and P < 0.001 at dosages 20 MUg, 25 MUg, and 30 MUg) in comparison to control group. BQ-123 at dosage 30 MUg showed the most stable and significant mechanical threshold rise. Repeated central administration of BQ-123 alleviated mechanical allodynia after SNL. Our results provide insight into the therapeutic strategies, including timing, against neuropathic pain development with ETAR antagonist. PMID- 24073408 TI - Is health-related quality of life associated with upper and lower airway inflammation in asthmatics? AB - BACKGROUND: Allergic diseases impair health-related quality of life (HR-QoL). However, the relationship between airway inflammation and HR-QoL in patients with asthma and rhinitis has not been fully investigated. We explored whether the inflammation of upper and lower airways is associated with HR-QoL. METHODS: Twenty-two mild allergic asthmatics with concomitant rhinitis (10 males, 38 +/- 17 years) were recruited. The Rhinasthma was used to identify HR-QoL, and the Asthma Control Test (ACT) was used to assess asthma control. Subjects underwent lung function and exhaled nitric oxide (eNO) test, collection of exhaled breath condensate (EBC), and nasal wash. RESULTS: The Rhinasthma Global Summary score (GS) was 25 +/- 11. No relationships were found between GS and markers of nasal allergic inflammation (% eosinophils: r = 0.34, P = 0.24; ECP: r = 0.06, P = 0.87) or bronchial inflammation (pH of the EBC: r = 0.12, P = 0.44; bronchial NO: r = 0.27, P = 0.22; alveolar NO: r = 0.38, P = 0.10). The mean ACT score was 18. When subjects were divided into controlled (ACT >= 20) and uncontrolled (ACT < 20), the alveolar NO significantly correlated with GS in uncontrolled asthmatics (r = 0.60, P = 0.04). CONCLUSIONS: Upper and lower airways inflammation appears unrelated to HR-QoL associated with respiratory symptoms. These preliminary findings suggest that, in uncontrolled asthma, peripheral airway inflammation could be responsible for impaired HR-QoL. PMID- 24073409 TI - Mesenchymal stem cells and platelet gel improve bone deposition within CAD-CAM custom-made ceramic HA scaffolds for condyle substitution. AB - PURPOSE: This study evaluated the efficacy of a regenerative approach using mesenchymal stem cells (MSCs) and CAD-CAM customized pure and porous hydroxyapatite (HA) scaffolds to replace the temporomandibular joint (TMJ) condyle. METHODS: Pure HA scaffolds with a 70% total porosity volume were prototyped using CAD-CAM technology to replace the two temporomandibular condyles (left and right) of the same animal. MSCs were derived from the aspirated iliac crest bone marrow, and platelets were obtained from the venous blood of the sheep. Custom-made surgical guides were created by direct metal laser sintering and were used to export the virtual planning of the bone cut lines into the surgical environment. Sheep were sacrificed 4 months postoperatively. The HA scaffolds were explanted, histological specimens were prepared, and histomorphometric analysis was performed. RESULTS: Analysis of the porosity reduction for apposition of newly formed bone showed a statistically significant difference in bone formation between condyles loaded with MSC and condyles without (P < 0.05). The bone ingrowth (BI) relative values of split-mouth comparison (right versus left side) showed a significant difference between condyles with and without MSCs (P < 0.05). Analysis of the test and control sides in the same animal using a split-mouth study design was performed; the condyle with MSCs showed greater bone formation. CONCLUSION: The split-mouth design confirmed an increment of bone regeneration into the HA scaffold of up to 797% upon application of MSCs. PMID- 24073411 TI - Evaluation of a worksite cervical screening initiative to increase Pap smear uptake in Malaysia: a cluster randomized controlled trial. AB - BACKGROUND: Despite the significant burden of cervical cancer, Malaysia like many middle-income countries relies on opportunistic cervical screening as opposed to a more organized population-based program. The aim of this study was to ascertain the effectiveness of a worksite screening initiative upon Papanicolaou smear test (Pap test) uptake among educated working women in Malaysia. METHODS: 403 female teachers who never or infrequently attended for a Pap test from 40 public secondary schools in Kuala Lumpur were recruited into a cluster randomized trial conducted between January and November 2010. The intervention group participated in a worksite cervical screening initiative whilst the control group received usual care from the existing cervical screening program. Multivariate logistic regression was performed to determine the impact of the intervention program on Pap smear uptake after 24 weeks of followup. RESULTS: The proportion of women attending for a Pap test was significantly higher in the intervention than in the control group (18.1% versus 10.1%, P value < 0.05) with the worksite screening initiative doubling the Pap smear uptake, adjusted odds ratio 2.44 (95% CI: 1.29 4.62). CONCLUSION: Worksite health promotion interventions can effectively increase cervical smear uptake rates among eligible workers in middle-income countries. Policy makers and health care providers in these countries should include such interventions in strategies for reducing cervical cancer burden. This trial is registered with IRCT201103186088N1. PMID- 24073410 TI - Intracellular secretory leukoprotease inhibitor modulates inositol 1,4,5 triphosphate generation and exerts an anti-inflammatory effect on neutrophils of individuals with cystic fibrosis and chronic obstructive pulmonary disease. AB - Secretory leukoprotease inhibitor (SLPI) is an anti-inflammatory protein present in respiratory secretions. Whilst epithelial cell SLPI is extensively studied, neutrophil associated SLPI is poorly characterised. Neutrophil function including chemotaxis and degranulation of proteolytic enzymes involves changes in cytosolic calcium (Ca(2+)) levels which is mediated by production of inositol 1,4,5 triphosphate (IP3) in response to G-protein-coupled receptor (GPCR) stimuli. The aim of this study was to investigate the intracellular function of SLPI and the mechanism-based modulation of neutrophil function by this antiprotease. Neutrophils were isolated from healthy controls (n = 10), individuals with cystic fibrosis (CF) (n = 5) or chronic obstructive pulmonary disease (COPD) (n = 5). Recombinant human SLPI significantly inhibited fMet-Leu-Phe (fMLP) and interleukin(IL)-8 induced neutrophil chemotaxis (P < 0.05) and decreased degranulation of matrix metalloprotease-9 (MMP-9), hCAP-18, and myeloperoxidase (MPO) (P < 0.05). The mechanism of inhibition involved modulation of cytosolic IP3 production and downstream Ca(2+) flux. The described attenuation of Ca(2+) flux was overcome by inclusion of exogenous IP3 in electropermeabilized cells. Inhibition of IP3 generation and Ca(2+) flux by SLPI may represent a novel anti inflammatory mechanism, thus strengthening the attractiveness of SLPI as a potential therapeutic molecule in inflammatory airway disease associated with excessive neutrophil influx including CF, non-CF bronchiectasis, and COPD. PMID- 24073412 TI - Comparison between AmniSure placental alpha microglobulin-1 rapid immunoassay and standard diagnostic methods for detection of rupture of membranes. AB - Objective. To determine the diagnostic accuracy of placental alpha microglobulin 1 assay and standard diagnostic methods for detecting rupture of membrane. Study Design. Prospective diagnostic study, between June 2011 to November 2011 at a tertiary centre. Initial evaluation included both the standard diagnostic methods for rupture of membranes and placental alpha microglobulin-1 immunoassay. The actual rupture of membranes was diagnosed on review of the medical records after delivery (absence of membrane or a positive pad chart). Main Outcome Measures. Placental alpha microglobulin-1 immunoassay and standard diagnostic methods for diagnosis of rupture of membrane. Results. A total of 211 patients were recruited. At initial presentation, 187 patients (88.6%) had ruptured membranes, while 24 patients (11.4%) had intact membranes. Placental alpha microglobulin-1 immunoassay confirmed rupture of membranes at initial presentation with a sensitivity of 95.7% (179 of 187), specificity of 100% (24 of 24), positive predictive value of 100% (179 of 179), and negative predictive value of 75.0% (24 of 32). By comparison, the conventional standard diagnostic methods had a sensitivity of 78.1% (146 of 187), specificity of 100% (24 of 24), positive predictive value of 100% (146 of 146), and negative predictive value of 36.9% (24 of 65) in diagnosing rupture of membrane. Conclusion. Placental alpha microglobulin-1 immunoassay is a rapid and accurate method for confirming the diagnosis of rupture of membrane. It was superior to conventional standard diagnostic methods (pooling, nitrazine, and ferning), the nitrazine test alone or fern test alone. PMID- 24073414 TI - The Ehrlich tumor induces pain-like behavior in mice: a novel model of cancer pain for pathophysiological studies and pharmacological screening. AB - The Ehrlich tumor is a mammary adenocarcinoma of mice that can be developed in solid and ascitic forms depending on its administration in tissues or cavities, respectively. The present study investigates whether the subcutaneous plantar administration of the Ehrlich tumor cells induces pain-like behavior and initial pharmacological susceptibility characteristics. The Ehrlich tumor cells (1 * 10(4)-10(7) cells) induced dose-dependent mechanical hyperalgesia (electronic version of the von Frey filaments), paw edema/tumor growth (caliper), and flinches compared with the saline group between days 2 and 12. There was no difference between doses of cells regarding thermal hyperalgesia in the hot-plate test. Indomethacin (a cyclooxygenase inhibitor) and amitriptyline hydrochloride (a tricyclic antidepressant) treatments did not affect flinches or thermal and mechanical hyperalgesia. On the other hand, morphine (an opioid) inhibited the flinch behavior and the thermal and mechanical hyperalgesia. These effects of morphine on pain-like behavior were prevented by naloxone (an opioid receptor antagonist) treatment. None of the treatments affected paw edema/tumor growth. The results showed that, in addition to tumor growth, administration of the Ehrlich tumor cells may represent a novel model for the study of cancer pain, specially the pain that is susceptible to treatment with opioids, but not to cyclooxygenase inhibitor or to tricyclic antidepressant. PMID- 24073415 TI - Temperature and drug treatments in mevalonate kinase deficiency: an ex vivo study. AB - Mevalonate Kinase Deficiency (MKD) is a rare autosomal recessive inborn disorder of cholesterol biosynthesis caused by mutations in the mevalonate kinase (MK) gene, leading to MK enzyme decreased activity. The consequent shortage of mevalonate-derived isoprenoid compounds results in an inflammatory phenotype, caused by the activation of the NALP3 inflammasome that determines an increased caspase-1 activation and IL-1 beta release. In MKD, febrile temperature can further decrease the residual MK activity, leading to mevalonate pathway modulation and to possible disease worsening. We previously demonstrated that the administration of exogenous isoprenoids such as geraniol or the modulation of the enzymatic pathway with drugs, such as Tipifarnib, partially rescues the inflammatory phenotype associated with the defective mevalonic pathway. However, it has not been investigated yet how temperature can affect the success of these treatments. Thus, we investigated the effect of temperature on primary human monocytes from MKD patients. Furthermore the ability of geraniol and Tipifarnib to reduce the abnormal inflammatory response, already described at physiological temperature in MKD, was studied in a febrile condition. We evidenced the role of temperature in the modulation of the inflammatory events and suggested strongly considering this variable in future researches aimed at finding a treatment for MKD. PMID- 24073416 TI - What are the barriers which discourage 15-16 year-old girls from participating in team sports and how can we overcome them? AB - Given the clear benefits of regular physical activity (such as reduced risks of cardiovascular disease and obesity, as well as other benefits including those related to mental health), exploration of the reasons that adolescent girls give for not taking part in team sports may be particularly valuable for enhancing later rates of participation. We combined questionnaires (n = 60) and semistructured interviews (n = 6) to assess the barriers that prevent 15-16-year old girls from participating in extracurricular team games and what can be done to overcome these barriers and improve physical activity levels. Four barriers became prominent as to why girls in this sample do not participate: Internal Factors, Existing Stereotypes, Other Hobbies and Teachers. Methods to overcome these barriers were identified; changing teachers' attitudes and shifting the media's focus away from male sport. Following the successful summer Olympics and Paralympics in the UK, and the resulting positive focus on some of the nation's female athletes, a shift in focus may be possible. However, this needs to be maintained to allow girls more opportunities, role models and motivation to participate in sport. PMID- 24073413 TI - The measurement of maximal (anaerobic) power output on a cycle ergometer: a critical review. AB - The interests and limits of the different methods and protocols of maximal (anaerobic) power (Pmax) assessment are reviewed: single all-out tests versus force-velocity tests, isokinetic ergometers versus friction-loaded ergometers, measure of Pmax during the acceleration phase or at peak velocity. The effects of training, athletic practice, diet and pharmacological substances upon the production of maximal mechanical power are not discussed in this review mainly focused on the technical (ergometer, crank length, toe clips), methodological (protocols) and biological factors (muscle volume, muscle fiber type, age, gender, growth, temperature, chronobiology and fatigue) limiting Pmax in cycling. Although the validity of the Wingate test is questionable, a large part of the review is dedicated to this test which is currently the all-out cycling test the most often used. The biomechanical characteristics specific of maximal and high speed cycling, the bioenergetics of the all-out cycling exercises and the influence of biochemical factors (acidosis and alkalosis, phosphate ions...) are recalled at the beginning of the paper. The basic knowledge concerning the consequences of the force-velocity relationship upon power output, the biomechanics of sub-maximal cycling exercises and the study on the force-velocity relationship in cycling by Dickinson in 1928 are presented in Appendices. PMID- 24073417 TI - Structural changes in individual retinal layers in diabetic macular edema. AB - Optical coherence tomography (OCT) has enabled objective measurement of the total retinal thickness in diabetic macular edema (DME). The central retinal thickness is correlated modestly with visual impairment and changes paradoxically after treatments compared to the visual acuity. This suggests the clinical relevance of the central retinal thickness in DME and the presence of other factors that affect visual disturbance. Recent advances in spectral-domain (SD) OCT have provided better delineation of the structural changes and fine lesions in the individual retinal layers. Cystoid spaces in the inner nuclear layer and outer plexiform layer are related to quantitative and qualitative parameters in fluorescein angiography. OCT often shows vitreoretinal interface abnormalities in eyes with sponge-like retinal swelling. Serous retinal detachment is sometimes accompanied by hyperreflective foci in the subretinal fluid, which exacerbates the pathogenesis at the interface of the photoreceptors and retinal pigment epithelium. Photoreceptor damage at the fovea is thought to be represented by disruption of the external limiting membrane or the junction between the inner and outer segment lines and is correlated with visual impairment. Hyperreflective foci in the outer retinal layers on SD-OCT images, another marker of visual disturbance, are associated with foveal photoreceptor damage. PMID- 24073419 TI - Strategic planning for organizational effectiveness during dynamic change. AB - The leadership of a professional association is charged with developing a strategic plan to operationalize the organization's goals, tactics, and progress. Within the context of its values and goals, a strategic plan steers the organization toward its mission. While there are a variety of models and approaches used in strategic planning, the National Gerontological Nursing Association (NGNA) has historically used goal-based methodology. This method is congruent with the organization's leadership preferences, consistent with the mission-driven culture of the organization, and collaborative in its approach. In 2009 the NGNA Board of Directors initiated a plan for the organization's transformation to a more dynamic and member-driven association through a deliberate process. This article addresses the process used to arrive at the 2010 2011 NGNA strategic initiatives, including a discussion of pertinent data revealed in the 2011 needs assessment survey and NGNA's future initiatives focused on networking, communication, and membership benefits. This process is relevant for all organizations and groups seeking improvement in serving their constituents. PMID- 24073418 TI - Increased Rate of Sporadic and Recurrent Rare Genic Copy Number Variants in Parkinson's Disease Among Ashkenazi Jews. AB - To date, only one genome-wide study has assessed the contribution of CNVs to Parkinson's Disease (PD). We conducted a genome-wide scan for CNVs in a case control dataset of Ashkenazi Jewish (AJ) origin (268 PD cases and 178 controls). Using high-confidence CNVs, we examined the global genome wide burden of large (>=100Kb) and rare (<=1% in the dataset) CNVs between cases and controls. A total of 986 such CNVs were observed in our dataset of 432 subjects. Overall global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications or number of genes affected by CNVs. Overall deletions (total CNV size and >2x frequency) were found 1.4 times more often in cases than in controls (p=0.019). The large CNVs (>500kb) were also significantly associated with PD (p=0.046, 1.24-folder higher in cases than in controls). Global burden was elevated for rare CNV regions. Specifically, for OVOS2 on Chr12p11.21, CNVs were observed only in PD cases (n=7) but not in controls (p=0.028) and this was experimentally validated. A total of 81 PD cases carried a rare genic CNV that was absent in controls. Ingenuity pathway analysis (IPA) identified ATXN3, FBXW7, CHCHD3, HSF1, KLC1 and MBD3 in the same disease pathway with known PD genes. PMID- 24073420 TI - Two GNPs create and innovate in an independent house call practice. PMID- 24073422 TI - Communication and nursing: reflections of a broadcast journalist nurse. PMID- 24073421 TI - Practice brief: A hydration initiative in a long-term care facility. PMID- 24073423 TI - Reply to Wennerstrom et al.: Entropic forces on a confined membrane. PMID- 24073424 TI - Reply to Aze et al.: Distinguishing speciation modes based on multiple lines of evidence. PMID- 24073425 TI - Reply to Price and Bird: No inconsistency between the date of gene flow from India and the Australian archaeological record. PMID- 24073426 TI - Electrochemiluminescence of luminol at the titanate nanotubes modified glassy carbon electrode. AB - A new strategy for the construction of a sensitive and stable electrochemiluminescent platform based on titanate nanotubes (TNTs) and Nafion composite modified electrode for luminol is described, TNTs contained composite modified electrodes that showed some photocatalytic activity toward luminol electrochemiluminescence emission, and thus could dramatically enhance luminol light emission. This extremely sensitive and stable platform allowed a decrease of the experiment electrochemiluminescence luminol reagent. In addition, in luminol solution at low concentrations, we compared the capabilities of a bare glassy carbon electrode with the TNT composite modified electrode for hydrogen peroxide detection. The results indicated that compared with glassy carbon electrode this platform was extraordinarily sensitive to hydrogen peroxide. Therefore, by combining with an appropriate enzymatic reaction, this platform would be a sensitive matrix for many biomolecules. PMID- 24073427 TI - The Endocrine Society Laureate Awards. PMID- 24073428 TI - The Endocrine Society 2013 Laureate Awards. PMID- 24073429 TI - [Endovascular therapy after the intravenous administration of t-PA versus isolated t-PA in the treatment of ischemic ictus]. PMID- 24073430 TI - [Strategies for multivessel revascularization in diabetes mellitus patients]. PMID- 24073431 TI - Abstracts of the 27th Annual North American Cystic Fibrosis Conference. October 17-19, 2013. Salt Lake City, Utah, USA. PMID- 24073432 TI - Abstracts of the 26th International Conference on Yeast Genetics and Molecular Biology. Frankfurt/Main, Germany. August 29-September 3, 2013. PMID- 24073433 TI - [Long-term comparison between endovascular or open repair abdominal aortic aneurysms]. PMID- 24073434 TI - Abstracts of the 98th National Congress of the Italian Society of Orthopaedics and Traumatology. October 26-29, 2013. Genova, Italy. PMID- 24073438 TI - Blood-pressure lowering in acute intracerebral hemorrhage. PMID- 24073439 TI - Education: Financial burden. PMID- 24073437 TI - A healthier approach to clinical trials evaluating resveratrol for primary prevention of age-related diseases in healthy populations. AB - In recent years, the wealth of basic science research supporting resveratrol's potential to treat, delay, and even prevent age-related chronic diseases has led to a number of human clinical trials. While such translational research has yielded promising results in clinical populations, recently published conflicting results from studies evaluating resveratrol's potential for primary prevention of chronic disease in healthy / asymptomatic individuals have generated considerable controversy and do not initially appear consistent with findings from animal models. We argue that trials targeting healthy humans are often fundamentally flawed owing to inappropriate use of paradigms only applicable to populations with overt clinical disease and the consequent misleading (typically negative) results can severely retard advancement of drug development. To appropriately perform translational research centered on resveratrol as a primary prevention agent in non-clinical populations, it is critical to utilize study designs which can provide adequate information on clinically relevant outcome measures, avoid paradigms and assumptions from interventions which are specific to clinical populations, and maintain realistic expectations compared to interventions which provide the theoretical maximal response (e.g., caloric restriction and aerobic exercise training). PMID- 24073440 TI - Abstracts of the Annual Meeting of the Working Group for Rhythmology. October 10 12, 2013. Dresden, Germany. PMID- 24073441 TI - The authors reply. PMID- 24073442 TI - Two authors reply. PMID- 24073444 TI - Current world literature. Nutrition and the gastrointestinal tract. PMID- 24073443 TI - The authors reply. PMID- 24073445 TI - Counting the cost. PMID- 24073446 TI - Time for change. PMID- 24073447 TI - Homes for bones. PMID- 24073448 TI - Innovation: Bridging the market gap. PMID- 24073449 TI - Ecology: Gene tweaking for conservation. PMID- 24073450 TI - Correlating infarct size and patient prognosis: are cardiac biomarkers truly insufficient? Reply. PMID- 24073451 TI - [A role of polyamine metabolism in the functional activity of the normal and pathological brain]. PMID- 24073452 TI - [Donepezil in Alzheimer's disease and vascular dementia]. PMID- 24073453 TI - [Preventive/therapeutic correction of the development and progression of cognitive deficit in patients after stroke]. PMID- 24073454 TI - Are your ancillaries at risk? PMID- 24073455 TI - How will the ACA affect your practice? PMID- 24073456 TI - Internal and external testing for ICD-10. PMID- 24073457 TI - Budgeting for mother nature: a fresh perspective on risk management. PMID- 24073458 TI - Common ground. Dual facility boosts efficiency, cuts costs. PMID- 24073460 TI - Braving the blizzard of 2013: Connecticut nurses respond. PMID- 24073459 TI - Flu, 1918 and now: the importance of good nursing. PMID- 24073461 TI - Global programme to eliminate lymphatic filariasis: progress report for 2012. PMID- 24073462 TI - Radiolucency of anterior mandible. Calcifying cystic odontogenic tumor. PMID- 24073463 TI - Meeting of the WHO working group on polymerase chain reaction protocols for detecting subtype influenza A viruses - Geneva, July 2013. PMID- 24073464 TI - Assessing and mitigating the risks of wild poliovirus outbreaks in polio-free African countries, January 2012- July 2013. PMID- 24073465 TI - If the price is right, most uninsured--even young invincibles--likely to consider new health insurance marketplaces. AB - A key issue for the new insurance exchanges under national health reform is whether enough younger and healthier people will take advantage of new subsidized coverage on Jan. 1, 2014. Without enough good risks to offset older and sicker people who are likely to jump at the opportunity to gain more-affordable coverage, the exchanges risk significant adverse selection--attracting a sicker than-average population--that will drive up premiums. Key to persuading younger and healthier uninsured people to opt for cover-age will be convincing them that health insurance is a good deal, according to a new national study by the Center for Studying Health System Change (HSC). While most uninsured people believe health insurance is important, far fewer now believe coverage is affordable and worth the cost. However, new federal subsidies for lower-to-middle-income people may change the calculus of whether coverage is affordable. While uninsured people who are younger, have few or no health prob-lems, and are self-described risk takers are more likely to believe they can go without health insurance, even a majority of these so-called young invincibles believe health insurance is important. The findings indicate that most uninsured people are not inherently resistant to the idea of having health insurance. The main challenge will be to convince them that new coverage options under national health reform are affordable and offer enough protection to offset the medical and financial risks of going without health coverage. PMID- 24073466 TI - High and varying prices for privately insured patients underscore hospital market power. AB - Across 13 selected U.S. metropolitan areas, hospital prices for privately insured patients are much higher than Medicare payment rates and vary widely across and within markets, according to a study by the Center for Studying Health System Change (HSC) based on claims data for about 590,000 active and retired nonelderly autoworkers and their dependents. Across the 13 communities, aver-age hospital prices for privately insured patients are about one-and-a-half times Medicare rates for inpatient care and two times what Medicare pays for outpa-tient care. Within individual communities, prices vary widely, with the highest-priced hospital typically paid 60 percent more for inpatient services than the lowest priced hospital. The price gap within markets is even greater for hospital outpatient care, with the highest-priced hospital typically paid nearly double the lowest-priced hospital. In contrast to the wide variation in hospital prices for pri-vately insured patients across and within markets, prices for primary care physi-cian services generally are close to Medicare rates and vary little within markets. Prices for specialist physician services, however, are higher relative to Medicare and vary more across and within markets. Of the 13 markets, five are in Michigan, which has an unusually concentrated private insurance market, with one insurer commanding a 70-percent market share. Despite the presence of a dominant insurer, almost all Michigan hospi-tals command prices that are higher than Medicare, and some hospitals com-mand prices that are twice what Medicare pays. In the eight markets outside of Michigan, private insurers generally pay even higher hospital prices, with even wider gaps between high- and low-priced hospitals. The variation in hospital and specialist physician prices within communities underscores that some hospitals and physicians have significant market power to command high prices, even in markets with a dominant insurer. PMID- 24073467 TI - The surge in urgent care centers: emergency department alternative or costly convenience? AB - As the U.S. health care system grapples with strained hospital emergency department (ED) capacity in some areas, primary care clinician shortages and rising health care costs, urgent care centers have emerged as an alterna-tive care setting that may help improve access and contain costs. Growing to 9,000 locations in recent years, urgent care centers provide walk-in care for illnesses and injuries that need immediate attention but don't rise to the level of an emergency. Though their impact on overall health care access and costs remains unclear, hospitals and health plans are optimistic about the potential of urgent care centers to improve access and reduce ED visits, according to a new qualitative study by the Center for Studying Health System Change (HSC) for the National Institute for Health Care Reform. Across the six communities studied- Detroit; Jacksonville, Fla.; Minneapolis; Phoenix; Raleigh-Durham, N.C.; and San Francisco--respon-dents indicated that growth of urgent care centers is driven heavily by con-sumer demand for convenient access to care. At the same time, hospitals view urgent care centers as a way to gain patients, while health plans see opportu-nities to contain costs by steering patients away from costly emergency depart-ment visits. Although some providers believe urgent care centers disrupt coor-dination and continuity of care, others believe these concerns may be over-stated, given urgent care's focus on episodic and simple conditions rather than chronic and complex cases. Looking ahead, health coverage expansions under national health reform may lead to greater capacity strains on both primary and emergency care, spurring even more growth of urgent care centers. PMID- 24073468 TI - [Report on poisoning statistics in 2012 from the Japanese Poison Control Center]. PMID- 24073469 TI - [Molecular imaging of a targeted molecule in the process of drug design--from still imaging to moving imaging]. PMID- 24073470 TI - [Hypertension: new European guidelines have arrived! BP <140/90 mmHg for all]. PMID- 24073471 TI - [Impact of salt intake on health: beliefs of the Swiss population]. AB - Excessive salt intake increases the risk of developing hypertension and cardiovascular disease. Sodium intake remains high both in developed and emerging countries. The Swiss Federal Office of Public Health has ordered a national survey on the salt intake in Switzerland, realized in different centers. This article presents the results of the awareness of the Swiss population concerning the relationship between excessive salt intake and health. This survey reveals a lack of knowledge regarding the association between high salt intake and cardiovascular disease, the sodium content of usual food, and the recommended daily value of sodium intake. Strategies to reduce salt consumption need to be reinforced by collaborations between health authorities and health care professionals. PMID- 24073472 TI - [Orthostatic hypotension: what to think of it and what to do?]. AB - Orthostatic hypotension is encountered frequently in everyday practice. It is often very disabling because of its troublesome symptomalogy. Orthostatic hypotension may be due to several causes and can be easily diagnosed by measuring blood pressure and heart rate after 3 minutes in upright posture. Its treatment comprises in all cases non-pharmacological interventions which can be associated whenever required by medications, in particular midodrine and fludrocortisone. PMID- 24073473 TI - [Treatment of hypertension in obese patients]. AB - Prevalence of obesity and hypertension has increased these last decades. Around 60 to 70% of the incidence of hypertension is related to obesity. The relationship between obesity and hypertension is now well established. The sympathetic nervous system and the renin-angiotensin-aldosterone (RAA) system are activated in obese patients, mostly by insulin, and predispose the kidney to reabsorb sodium and water. In obese patients with hypertension, it is recommended to target a blood pressure < 140/90 mmHg. Lifestyle changes (weight loss, physical activity, low-salt diets) are useful to decrease blood pressure but are difficult to maintain in the long-term. When drugs are necessary, drugs that are metabolically neutral should be used, and often need to be combined to other drug classes in order to achieve blood pressure target. PMID- 24073474 TI - [Renovascular prognosis of preeclampsia on the mother and the child]. AB - Preeclampsia is a pregnancy-related disease that affects 2 to 8% of pregnancy worldwide. It is now a well-established risk factor for cardiovascular and renal diseases. Preeclampsia is a well-recognized risk factor for future cardiovascular, renal and neurological disorders for the mother. It predetermines the risk profile of the future child's health. A long-term follow-up aimed on prevention and screening should be offered. Further studies are needed to determine the modality of that follow-up as well as the prevention strategies specific for that population. This article proposes a non-exhaustive review of the cardiovascular, renal and neurological consequences of the disease on the mother and child's health. PMID- 24073475 TI - [Primary hyperaldosteronism with adrenal adenoma or hyperplasia: surgical case or not?]. AB - Primary hyperaldosteronism is one of the most frequent causes of secondary hypertension. Cardiovascular morbimortality is higher than in essential hypertonic and justifies diagnostic and specific treatment of this pathology. Therapeutic choice depends of health and desire of the patient. It is either medical with mineralocorticoid receptor antagonists, or surgical through adrenalectomy. In this case, a pre-surgery exam including a radiologic examination and a venous adrenal catheterism has to be done. Surgery allows a normalisation of kaliema and a blood pressure decrease in 50 to 88% of the patients. Beyond them, 30% are able to stop entirely their medication. Both therapeutic choices decrease cardiovascular risks equally if blood pressure is controlled. PMID- 24073476 TI - [New recommendations of the ESH/ESC: smooth changes for the hypertensive patient]. AB - The last recommendations of the European Society of Hypertension and the European Society of Cardiology made available deal with the diagnosis and the treatment of arterial hypertension. They point to the importance of both 24-hour ambulatory blood pressure monitoring and home blood pressure measurement. They also underscore the importance of stratifying cardiovascular risk and of controlling strictly blood pressure using hygienic measures and antihypertensive drugs, either as monotherapy or combination therapy. PMID- 24073477 TI - [Hypnosis integrated in burn care: impact on the healthcare team's stress]. AB - Hypnosis for burn care was introduced in 2004 in the CHUV burn center showing great benefit for burned patients. Whereas advantages of hypnosis for the patient are well established, the impact on the medical staff remains poorly assessed. This manuscrit reviews current attested benefits of hypnosis for patients, specially for burned patients. The results of a recent study assessing the impact of hypnosis on the staffs level of stress caused by burn treatment, will also be introduced. PMID- 24073478 TI - [Obesity: new perspectives, future progress]. PMID- 24073479 TI - [The necessary laws and the others...]. PMID- 24073480 TI - [HeLa: perpetual legacy of Ms Lacks (1920-1950)]. PMID- 24073482 TI - [Underneath the patient revolution]. PMID- 24073483 TI - An evolution of environmental health: NEHA adapts and embraces change. PMID- 24073484 TI - Examination of the association between announced inspections and inspection scores. AB - In 2010 the Salt Lake Valley Health Department conducted a pilot of an announced inspection program utilizing a randomized assignment of restaurants to an intervention group with announced inspections and a control group that remained on the usual schedule of unannounced inspections. After adjusting for food type, visible kitchen, outside quality assurance, season, and standardized inspector, significant reductions were found in the odds ratios of personal hygiene (adjusted odds ratios [aOR] = 0.11, p = .00) and equipment cleanliness (aOR = 0.19, p = .00) violations. In the models for the control group, none of the odds ratios were statistically different from one, indicating no change in the postintervention time period as compared to the preintervention period. PMID- 24073485 TI - Food safety training needs at evacuation shelters operated by faith-based organizations. AB - The authors conducted a survey to identify food safety training needs at evacuation shelters operated by faith-based organizations (FBOs) in four hurricane-prone states. Five thousand randomly selected FBO leaders were asked questions about their food safety attitudes and food handling practices at evacuation shelters. Descriptive statistics and multivariate analysis of variance were calculated to summarize and prioritize the responses. Results from 138 leaders revealed that on average, 590 +/- 4,787 evacuees were served for 36 +/- 72 days at FBO-operated shelters. Only 19.6% felt they were well prepared for the shelter. Only 5.8% had professional food preparation staff and many accepted hot (47.8%) and cold (37%) prepared food donations. Some lacked adequate refrigerator (18.8%) or freezer (16.7%) spaces, but 40% kept hot food leftovers for later use. The majority did not provide food safety training before opening the shelters (73.2%), yet 76.9% said they will provide food to evacuation shelters again. The results show a need for food safety training and specific strategies for training at FBOs. PMID- 24073486 TI - Promoting healthy school environments: a step-by-step framework to improve indoor air quality in Tangipahoa Parish, Louisiana. AB - Poor indoor air quality (IAQ) is highly correlated with asthma and other respiratory illnesses. As a chronic lung disease, asthma can have significant impacts on the respiratory system and other complications in large populations of the young, the elderly, and the infirm. This disease is associated with various environmental triggers in indoor environments including schools and homes. Reducing these sources of asthma triggers can lead to improved health outcomes in children. Environmental triggers of asthma and other respiratory illnesses can be reduced by systematically identifying and evaluating their sources and then developing a plan of action to prevent, control, and eliminate them. This article presents a step-by-step framework including easy-to-adopt strategies to support the development and implementation of an IAQ improvement and management plan for schools in semiurban environments with a focus on Tangipahoa Parish, Louisiana. The framework presented here encourages outreach, training, and consultations as key parameters for implementation of a sustainable IAQ program. PMID- 24073487 TI - Listeria monocytogenes strains isolated from dry milk samples in Mexico: occurrence and antibiotic sensitivity. AB - Dry milk is a particular concern in Mexico, as approximately 150,000 metric tons of dry milk are imported every year at a cost of around $250 million. Dry milk is used to make many products, most of which are dairy products widely distributed among the population covered by welfare programs. The purpose of the study described in this article was to determine the presence of Listeria spp. in imported dry milk samples in Mexico, and to determine the sensitivity of the Listeria monocytogenes isolates to different antimicrobial agents. Listeria isolates (7.8% of 550 bacterial isolates) were identified as L. monocytogenes (53.49%), L. innocua (30.23%), L. seeligeri (13.95%), and L. ivanovii (2.33%). L. monocytogenes strains isolated showed multiresistance to ampicillin, erythromycin, tetracycline, dicloxacillin, and trimethoprim-sulfamethoxazole (9% 14%). The results provide additional evidence of the emergence of multiresistant Listeria strains both in nature and in widely consumed dairy products, representing a potential threat to human health. PMID- 24073488 TI - The development of a standards-based national curriculum framework for regulatory food safety training in the United States. AB - In response to the recognized need for a training system to support an integrated food safety system in the U.S., the International Food Protection Training Institute (IFPTI) in Battle Creek, Michigan, designed a career-spanning curriculum framework. IFPTI collaborated with a national curriculum team consisting of regulatory officials and university academics. The curriculum framework encompasses and organizes existing professional development for the estimated 45,000 federal, state, and local food regulators in the U.S. into efficient, standards-driven learning paths. This article describes the development process leading to an integrated national food protection training curriculum framework. PMID- 24073489 TI - InFORM: an innovative, integrated food safety meeting. PMID- 24073490 TI - Hi, I'm a robot and I'm here to take your job. PMID- 24073491 TI - Food safety and the global supply chain. PMID- 24073492 TI - Pivoting toward a younger NEHA membership. PMID- 24073493 TI - Practice management predicament. PMID- 24073494 TI - Duty to be understood. PMID- 24073495 TI - Pediatric dentistry update. PMID- 24073496 TI - A review of pediatric radiology. AB - In most dental schools, the focus is on teaching students how to treat adults, with little emphasis placed on treating children. The goal of this article is to review some basic concepts in pediatric radiology to help general practitioners have a better understanding of when to take radiographs on children, which radiographs should be taken, what to look for when examining the radiographs and possible ways to treat the problems diagnosed from the radiographs. PMID- 24073497 TI - A review of pulp therapy for primary and immature permanent teeth. AB - The aim of pulp therapy in primary and young permanent teeth is to maintain a functional tooth so that arch integrity is preserved in a growing child. History, clinical evaluation and radiographic findings should be integrated to arrive at pulp diagnosis. Vital pulp therapy should be attempted whenever the pulp is diagnosed to be vital. Nonvital pulp therapy should be performed for strategically important primary teeth. Revascularization is an emerging technique for immature necrotic teeth. PMID- 24073498 TI - Communicating with parents and children in the dental office. AB - Providing dental care for children can be challenging. Successful treatment is often dependent upon the effectiveness of the communication between the dentist, parent and patient. Effective communication should be developed by establishing rapport and trust during the initial visit. Few parents realize the disadvantage of the dentist who is introduced to a child who is anxious, afraid or resistant. They undoubtedly expect the dentist to provide care regardless of the child's reaction. PMID- 24073499 TI - Sedation of the pediatric patient. AB - Children's behavior during dental treatment is often unpredictable. Many techniques for behavior management have been developed and include both pharmacologic and nonpharmacologic methods. Pharmacologic management with sedation has been shown to be an important adjunct in treating the fearful, uncooperative or precommunicative patient. This article reviews the definitions, levels, techniques and pharmacology of typical drugs used for sedation. The protocols for safe management of children before, during and after sedation are also discussed. PMID- 24073500 TI - Management of premature primary tooth loss in the child patient. AB - Premature loss of primary teeth can result in a loss of arch length and have a negative effect on occlusion and alignment, often increasing the need for orthodontic treatment. Use of space maintainers can reduce the severity of problems such as crowding, ectopic eruption, tooth impaction and poor molar relationship. This article presents a review of the consequences of premature tooth loss and discusses the appliances commonly used for space maintenance. PMID- 24073501 TI - Management of dental caries and esthetic issues in the pediatric patient. AB - Anterior pediatric restorations exhibit a unique treatment challenge. Factors to consider include the child's medical history, level of cooperation, dental age, caries risk, parental preferences and cultural norms regarding esthetics. The goal is to retain the anterior teeth with an esthetic result and allow natural exfoliation without the need to retreat. Anterior restorations are discussed. Rebonding traumatized fractured teeth, pediatric partial dentures, microabrasion, vital bleaching and enamel hypoplasia are also discussed. PMID- 24073502 TI - Word weary. PMID- 24073503 TI - Done in, fed up, burned out. Is burnout a terminal event or a dynamic? PMID- 24073504 TI - When no means maybe. Knowing when to push for transport is part of good medicine. PMID- 24073505 TI - Fight-picker. Small wounds can have big consequences. PMID- 24073506 TI - RETTmobil and the future of EMS safety. What can we learn from European ambulances and equipment? PMID- 24073507 TI - What is data good for? Better operations and patient care are scarcely possible without it. PMID- 24073508 TI - The evidence against backboards. Backboards often don't help and may hurt--why do they persist? PMID- 24073509 TI - Does spinal immobilization help patients? Growing evidence suggests it may actually cause harm. PMID- 24073510 TI - Acute anterior STEMI: a challenging diagnosis. Learn to differentiate between different STEMIs on the 12-lead ECG. PMID- 24073511 TI - Case studies in hypoglycemia. When is it safe to leave these patients at home? PMID- 24073512 TI - A cry for help. When a colleague is hurting, don't sit idly by. PMID- 24073514 TI - Spousal lifetime access trust. PMID- 24073513 TI - The spirit of cooperation. PMID- 24073515 TI - Employment strategies and the ACA. PMID- 24073516 TI - Are you thinking of taking your dental practice digital? PMID- 24073517 TI - Site inspections: a practical approach. PMID- 24073518 TI - 2013 William McKenna volunteer heroes. PMID- 24073519 TI - Hospital-based ED visits with dental conditions among geriatric patients. AB - OBJECTIVE: To provide nationally representative estimates of all hospital-based emergency department (ED) visits with dental caries, pulp and periapical lesions, gingival/periodontal lesions, and mouth cellulitis occurring among the older population groups (aged 60 years and above). METHODS: The 2008 Nationwide Emergency Department Sample of the Healthcare Cost and Utilization Project was used. This database provides weighted estimates of all ED visits in the United States (approximately 150 million). Hospital discharges with primary procedure ICD-9-CM codes for dental conditions in adults aged 60 and older were evaluated. All estimates obtained from the sample were projected to national levels. RESULTS: A total of 50,881 ED visits had a dental condition including dental caries (33.6%), pulpal lesions (10.4%), periapical abscess (36%), gingival conditions (11%), and cellulitis (6.7%). Close to 72.7% were discharged routinely and 25.1% were admitted as inpatients into the same hospitals. About 63.4% of ED visits were covered by Medicare. Close to 40% of all ED visits occurred in the southern regions. The mean charge per ED visit was $1,114, and the total charges across the entire United States were $44.8 million. CONCLUSIONS: In comparison to other age groups, older adults are hospitalized more frequently after ED visits for dental conditions. As the U.S. population ages, innovative programs are necessary to manage dental conditions in dental offices and reduce the number of ED visits and hospitalizations for dental complaints by older adults. PMID- 24073520 TI - Technique to incorporate mathematical principles into esthetic dentistry. AB - Space closure in the maxillary anterior segment using direct composite is one of the most challenging esthetic procedures. The challenge lies in determining and achieving the correct dimensions. Various mathematical principles that have been observed in esthetically pleasing smiles can be applied to simplify the procedure and achieve symmetry while treating spaced dentition. The aim was to devise a technique for simplifying the application of mathematical principles in esthetic dentistry and improve the predictability and accuracy of the procedure of space closure using direct composite. PMID- 24073521 TI - How to write an employment ad. PMID- 24073522 TI - A clinico-pathologic correlation. Diagnosis. Lateral periodontal cyst. PMID- 24073523 TI - Temporomandibular joint imaging: a summary. PMID- 24073524 TI - Localized juvenile spongiotic gingival hyperplasia. PMID- 24073525 TI - Endodontic involvement of a geminated tooth with talon cusp: a rare occurrence. PMID- 24073526 TI - Sidewalk sales. PMID- 24073527 TI - Beneficial effects of an arginine-calcium carbonate desensitizing paste for treatment of dentin hypersensitivity. AB - PURPOSE: To evaluate the clinical efficacy of a single professional application of a Pro-Relief desensitizing fluoride-free paste containing 8% arginine and calcium as compared to a fluoride-free prophylaxis paste on dentin hypersensitivity reduction in adults with a clinical diagnosis of dentin hypersensitivity. METHODS: This single-center, parallel group, double-blind and randomized clinical study conducted in Santo Domingo, Dominican Republic included 50 (25 per group) adult male and female subjects. Each study subject had two teeth hypersensitive to air blast stimuli when applied directly at its cervical surface (gingivo-facial 1/3). An air blast hypersensitivity score equal or greater to 2 (Schiff Cold Air Sensitivity Scale) was randomly assigned to one of two treatment groups (1) Pro-Relief in-office desensitizing fluoride-free paste containing 8% arginine and calcium carbonate (Test Paste group), and (2) a fluoride-free prophylaxis paste (Control Paste group). Prior to their baseline examination, subjects were instructed to return to the clinical facility having refrained from eating and drinking for 2 hours. An assessment of air blast hypersensitivity and examinations of oral soft and hard tissue were performed at the baseline. Subjects were provided a professional in-office prophylaxis with their assigned prophylaxis paste. A post hypersensitivity examination was performed immediately after the oral prophylaxis. RESULTS: All subjects completed the study. At the post-hypersensitivity examination, subjects assigned to the Test Paste group and Control Paste group both exhibited statistically significant (P = 0000) reductions (compared to baseline), to air blast hypersensitivity of 44.7% and 25.6%, respectively. At the post-hypersensitivity examination, subjects in the Test Paste group exhibited a statistically significant (P = 0.005) reduction of 24.4% in mean air blast hypersensitivity scores as compared to the Control Paste group. PMID- 24073528 TI - Plaque removal efficacy of oscillating-rotating power toothbrushes: review of six comparative clinical trials. AB - PURPOSE: This review of six clinical trials provides a comprehensive overview of the results of statistical analyses to explore between-brush differences, specifically in the lingual, gingival marginal, and approximal ("hard-to-clean") areas, in post-brushing plaque removal of oscillating-rotating (O-R) power toothbrushes compared to either a marketed sonic power toothbrush or a manual toothbrush control. METHODS: All studies were single-center, randomized and controlled, and examiner-blind. Four trials were four-period crossover design with replicate single-use brushing, while two studies were parallel group investigations (4 or 12 weeks) with multiple brushings and assessments at each visit. Generally healthy subjects were enrolled. Plaque evaluations were via the Turesky Modification of the Quigley-Hein Plaque Index (TMQHPI) or the Rustogi Modification of the Navy Plaque Index (RMNPI). At each evaluation visit, subjects brushed with either the randomly assigned O-R power brush [Oral-B Professional Care Series 4000 (Triumph) or Oral-B Vitality with Floss Action or Precision Clean brush head] or a control brush [Sonicare FlexCare with ProResults brush head (three trials) or an American Dental Association (ADA) reference manual toothbrush (three trials)]. ANCOVA and ANOVA analyses subsequently evaluated specifically the 'hard-to-clean' tooth surfaces for between-brush differences. RESULTS: In total, 462 subjects completed the trials and were evaluable. While all toothbrushes provided significant post-brushing versus baseline plaque removal efficacy, the magnitude of the reduction was consistently superior for the O-R brush compared to either the sonic power or manual brush control in all the 'hard-to-clean" region-specific analyses. Adjusted mean RMNPI or TMQHPI benefits favoring the O-R brush relative to the sonic brush control were collectively 18% to 34% greater on lingual surfaces (P < or = 0.044), 32% to 49% greater on lingual approximal surfaces (P < 0.001), and 32% and 31% greater in lingual mandibular and lingual mandibular anterior regions, respectively (P < or = 0.005). Post-brushing whole mouth adjusted mean reduction RMNPI or TMQHPI benefits favoring the O-R brush compared to the manual brush control were collectively 31% to 206% greater on lingual surfaces (P < or = 0.001), 29% to 217% greater on lingual approximal surfaces (P < or = 0.001), and 67% to 526% greater in lingual gingival margin regions, respectively (P < or = 0.001). All study toothbrushes were well-tolerated. PMID- 24073529 TI - Effect of low-fluoride dentifrices supplemented with calcium glycerophosphate on enamel demineralization in situ. AB - PURPOSE: To evaluate whether a low-fluoride dentifrice with calcium glycerophosphate (CaGP) reduced the demineralization process in situ. METHODS: A cross-over design with four treatment phases of 7 days each was used. Ten volunteers wore palatal devices containing four blocks of bovine dental enamel. The enamel was treated (ex-vivo) with a placebo, 500 microg-F/g (500), 500 microg F/g with 0.25%CaGP (500 CaGP), and 1,100 microg-F/g (1,100) dentifrices (twice a day/1 minute) under cariogenic challenge from sucrose solution. To evaluate mineral loss, surface and cross-sectional hardness were performed. The fluoride, calcium, and phosphorus ion concentrations from enamel and dental plaque were determined. The insoluble extracellular polysaccharide (EPS) concentrations were also analyzed. The data were submitted to ANOVA (1-way) followed by the Student Newman-Keuls test (P < 0.05). RESULTS: The mineral loss and EPS concentration were lowest in the 500 CaGP and 1,100 dentifrice groups. The use of the 500 CaGP and 1,100 dentifrices resulted in similar fluoride, calcium, and phosphorus concentrations in the enamel and in dental plaque (P > 0.05). The ionic activities of calcium phosphate phases for the 500 CaGP and 1,100 dentifrices were similar (P > or = 0.492). The low-fluoride dentifrice with 0.25%CaGP demonstrated efficacy similar to that of the positive control (1,100 dentifrice) with respect to in situ demineralization. PMID- 24073530 TI - In vitro caries lesion rehardening and enamel fluoride uptake from fluoride varnishes as a function of application mode. AB - PURPOSE: To study the laboratory predicted anticaries efficacy of five commercially available fluoride varnishes (FV) by determining their ability to reharden and to deliver fluoride to an early caries lesion when applied directly or in close vicinity to the lesion (halo effect). METHODS: Early caries lesions were created in 80 polished bovine enamel specimens. Specimens were allocated to five FV groups (n = 16) based on Knoop surface microhardness (KHN) after lesion creation. All tested FV claimed to contain 5% sodium fluoride and were: CavityShield, Enamel Pro, MI Varnish, Prevident and Vanish. FV were applied (10 +/- 2 mg per lesion) to eight specimens per FV group (direct application); the remaining eight specimens received no FV but were later exposed to fluoride released from specimens which received a FV treatment (indirect application). Specimens were paired again and placed into containers (one per FV). Artificial saliva was added and containers placed into an incubator (27 hours at 37 degrees C). Subsequently, FV was carefully removed using chloroform. Specimens were exposed to fresh artificial saliva again (67 hours at 37 degrees C). KHN was measured and differences to baseline values calculated. Enamel fluoride uptake (EFU) was determined using the acid etch technique. Data were analyzed using two way ANOVA. RESULTS: The two-way ANOVA highlighted significant interactions between FV vs. application mode, for both deltaKHN and EFU (P < 0.001). All FV were able to reharden and deliver fluoride to caries lesions, but to different degrees. Furthermore, considerable differences were found for both variables between FV when applied either directly or in close vicinity to the lesion: MI Varnish and Enamel Pro exhibited greater fluoride efficacy when applied in vicinity rather than directly to the lesion, whereas CavityShield and Vanish did not differ. Prevident exhibited a higher EFU when applied directly, but little difference in rehardening. PMID- 24073531 TI - The role of occlusal loading in the pathogenesis of non-carious cervical lesions. AB - PURPOSE: To evaluate the putative role of occlusal loading in the pathogenesis of non-carious cervical lesions (NCCLs) in subjects who exhibited mixed excursive guidance [i.e., immediate canine guidance on one side and group function (GF) on the other]. METHODS: 20 subjects with Angle Class 1 occlusion and having from 1 to 5 NCCLs on separate teeth were selected. Only subjects who displayed mixed excursive guidance were recruited so that they could serve as their own controls. Non-carious cervical lesions were recorded on casts mounted in semi-adjustable articulators. RESULTS: On the GF sides, 22.5% of all teeth that contacted in working excursions exhibited NCCLs; only 2.1% of the teeth on the canine guided sides exhibited NCCLs, which were found exclusively in canines. Although a case for the multifactorial etiology of NCCLs remains strong, our data, albeit limited, seems to support the dominant role of occlusion in lesion formation. PMID- 24073532 TI - A double-blind randomized clinical trial of a silorane-based resin composite in class 2 restorations: 18-month follow-up. AB - PURPOSE: To compare the clinical performance of a silorane-based with a methacrylate-based restorative system in class 2 restorations after an 18-month follow-up. METHODS: This randomized, double-blind and controlled study included 33 subjects receiving 100 direct resin composite restorations that were completely randomized to silorane-based group (Filtek P90/Silorane System Adhesive - 3M ESPE) or methacrylate-based group (Filtek P60/Adper SE Plus - 3M ESPE). The restorative system was determined by chance using a coin toss until 50 units for each group were completed. Each subject contributed with one to seven restorations. A single operator performed all of the restorative procedures. Two calibrated examiners (kw > or = 0.7) assessed the restorations at baseline and after 18 months according to modified United States Public Health System (USPHS) criteria. The data were analyzed with Mann-Whitney U-test, Wilcoxon signed rank and Kaplan-Meier survival curves (alpha = 0.05). RESULTS: After 18 months, 88 restorations were evaluated, and five unacceptable restorations were observed. Proximal contact loss was the main reason for failure (three) followed by composite fracture (two). The marginal integrity of the silorane-based group was significantly worse than that of the methacrylate-based group (P= 0.035). Comparing baseline to 18-month evaluations, the silorane-based group showed significant differences for marginal discoloration, marginal integrity and surface texture (P < 0.05); and the methacrylate-based group differed significantly for marginal discoloration and surface texture (P < 0.05). Combined survival rate for both groups together was 95%. No statistically significant difference was found between methacrylate-based (98%) and silorane-based (92%) overall survival rate (Log rank test; P = 0.185). PMID- 24073533 TI - Influence of selective enamel etching on the bonding effectiveness of a new "all in-one" adhesive. AB - PURPOSE: To evaluate in vitro the all-in-one adhesive G-Bond Plus/G-aenial Bond (GBP), used according to the selective enamel etching (SEE) technique, compared to Optibond FL, an etch-and-rinse adhesive tested as control (C). METHODS: 133 molars provided specimens for enamel and dentin shear bond strength (SBS) testing, microleakage measurements in class 5 restorations, and scanning electron microscope observations of demineralization patterns produced by GBP and 37% phosphoric acid (PA). RESULTS: On enamel: C displayed the highest SBS. PA etching significantly increased enamel SBS of GBP. No statistically significant difference in SBS was noted among the bonding procedures on dentin. On both substrates, C revealed the most satisfactory seal. PA pre-etching did not significantly affect the sealing ability of GBP on either substrate. PMID- 24073534 TI - Implant coatings: new modalities for increased osseointegration. AB - PURPOSE: To present new techniques for implant coatings, biological tissue response to them, and, if applicable, clinical outcome. METHODS: A search for publications was done in PubMed using search words such as coated dental implants, clinical outcome, dental implant coatings and combinations thereof. Further, a manual search was done. 216 papers were found; the selection was directed towards in vivo investigations. RESULTS: Several different coatings are described in the literature, many of them with the purpose to be bioactive. Such surface coatings include hydroxyapatite, bioglass, proteins, polysaccharides and drugs. The majority of the publications are evaluations in vitro; most of the in vivo studies are directed to implant incorporation in bone. Rather few exist that use a coat to promote soft tissue adhesion or prevention of infection. PMID- 24073535 TI - Three-dimensional facial architecture in normodivergent class I Caucasian subjects. AB - INTRODUCTION: The aims of this study were to (1) define facial architecture in Caucasian patients with normodivergent, skeletal and dental class I using Treil's cephalometric analysis, which is based on computed tomography (CT), and (2) develop a scheme to determine individual balance or normality in relation to linear, angular and volumetric parameters. MATERIAL AND METHODS: The CT data of 60 adult subjects were equally divided between both genders. Based on anatomical points located along the trigeminal neuro-matricial facial growth axes, a three dimensional maxillo-facial architecture was constructed. RESULTS: Volumetric and linear parameters were greater in males (0.000 < p < 0.044) except for the anterior and posterior mandibular width. Sexual dimorphism was not observed with angular parameters. There was no correlation between volumetric and angular parameters. The correlation tests showed that the total volume of the frame increases with infraorbital depth, supraorbital depth, posterior mandibular width and facial height (0.526 < r < 0.777), while it was not associated with the maxillo-orbital width (0.252 < r < 0.389). Total and orbital volumes were more correlated with posterior than with anterior mandibular width. Maxillo-mandibular volume of the frame was more cor-related with orbital depth (0.591 < r < 0.742) than the orbital volume (0.482 < r < 0.589). CONCLUSIONS: The results allowed us to establish three-dimensional cephalometric standards, and to replace the tenet of normality, which is a mean value of calculated parameters, by the concept of individual balance among volumetric entities. While sagittal and vertical dimensions affect volumetric changes of the frame, the transverse dimension does not. PMID- 24073536 TI - Maternal knowledge and awareness of factors affecting oral health in the paediatric population. AB - AIM: To assess expectant mothers on their knowledge and awareness of factors affecting paediatric oral health. METHOD: Seven hundred and six women in different stages of pregnancy were recruited from the antenatal clinic of the University of Port Harcourt Teaching Hospital over a period of four weeks. A self administered structured questionnaire on socio-demographic information, oral health knowledge and oral health behaviour was filled by the participants. Data was analyzed using SPSS version 17. RESULTS: The mean age of the subjects was 29.6 (SD + 4.4) years. Seventy percent of them had tertiary education and 63.9% were unemployed. A significant proportion (83.4%) of the women had medium to high score (> 50%) in the knowledge of causal and preventive factors in dental caries and gingivitis. Over seventy nine percent (79.2%) of them acknowledged that primary teeth are important, but 43.6% did not know whether primary teeth should be restored or not. Only 39.3% of the women knew that leaving a feeding bottle/breast in the mouth of a sleeping child could be harmful to the teeth. Knowledge of the role of bacteria in gingivitis (81.3%) and dental caries (86.6%) was high. Over 45% of participants agreed that mothers could transmit cariogenic bacteria to their children. Only 0.7% of the women had taken their children to the dental clinic for routine checkup. CONCLUSION: Most of the participants had medium to high knowledge of the factors that affect paediatric oral health, yet the participants did not demonstrate adequate and proper concomitant oral health practice. PMID- 24073537 TI - [Tooth decay in school environment at Brazzaville (Congo)]. AB - AIM: To determine the frequency of dental caries and habits that can be the cause of this disease in Brazzaville. METHODS: A prospective study was conducted in primary schools between February and May 2010. This study involved a sample of 307 students of both sexes, aged 4-15 years from school in the city of Brazzaville. RESULTS: Prevalence of dental caries was 53.4% and the index of DMFT 2.06. Use of toothbrush was 99.4%. Two children (0.7%) brushed their teeth three times a day. There was a statistical link between regularity of brushing and occurrence of caries. The prevalence of caries was of 53% in children who brushed once a day and 12.8% in those who brushed twice a day. No decay was noted in those who brushed three times a day (p = 0.001). The DMFT was 2.06 in children who used non-fluoridated toothpaste and 1.13 in those who used the fluoridated toothpaste (p = 0.002). CONCLUSION: To ensure students a better oral hygiene and healthier teeth, a module in oral health education in schools is one of the way to fight against this public health problem. PMID- 24073538 TI - Occupational stress among dental house officers and students in a tertiary healthcare centre. AB - OBJECTIVE: To assess occupational stress among dental house officers and students treating patients in a tertiary healthcare centre in Nigeria. MATERIALS AND METHODS: This questionnaire-based cross-sectional study of dental officers and final year dental students at the University of Benin Teaching Hospital, Benin City was conducted in the second half of 2010. The questionnaire utilized was a modified form of stress screening questionnaire of International Stress Management Association. RESULTS: Out of the 100 questionnaires distributed, 88 questionnaires were returned, giving a response rate of 88.0%. A total of 53 (60.2%) the respondents were male and 35 (39.8%) were females. Dental students constituted 54 (61.4%) of the respondents while the remaining 34 (38.6%) were house officers. Amongst the respondents, 9 (10.2%), 68 (77.8%) and 11 (12.5%) reported severe, moderate and mild occupational stress respectively. The reported stress was significantly associated with gender (P = 0.032) as more female reported severe stress and more male reported moderate stress. The mean stress level was significantly higher among dental students than house officers (P = 0.007). CONCLUSION: One in every ten respondent reported severe occupational stress with a significant gender difference. Development of stress reduction strategies for dental house officers and students with gender bias is imperative. PMID- 24073539 TI - Dental extraction as a risk factor for bisphosphonate related osteonecrosis of the jaw in cancer patients: an update. AB - Osteonecrosis of the jaw (ONJ) is a complication related to the use of bisphosphonates (BPs). Patients receiving BPs for the treatment of malignancies are at an increased risk of developing bisphosphonate-related ONJ (BRONJ) as compared to patients receiving BPs for the treatment of other disorders such as osteoporosis. Additionally, tooth extractions have been suggested to increase the risk of BRONJ in individuals taking BPs. OBJECTIVE: To review the role of dental extraction as a risk factor for BRONJ in cancer patients. MATERIALS AND METHODS: Databases were searched from January 1999 up to and including July 2012 using various combinations of the following keywords: "bisphosphonate", "osteonecrosis of the jaw", "cancer", "oral" and "dental extraction". RESULTS: Twenty two studies were included. Eighteen studies assessed the relationship between BRONJ and dental extractions in cancer patients, reporting the overall prevalence of BRONJ following extraction in this group as 3.25 +/- 2.23%. Four studies did not report a correlation between BRONJ and extractions, and recommended protocols to avoid the complication. CONCLUSION: There is a plausible relationship between dental extractions and the development of BRONJ in cancer patients. Written informed consent must be obtained prior to dental procedures in patients at risk for developing BRONJ. PMID- 24073540 TI - Adult non-cardiac ECMO for the treatment of ARDS--the Mississippi experience. AB - The University of Mississippi Medical Center (UMMC) has become a center for ECMO (Extracorporeal Membrane Oxygenation), providing this service to patients requiring this life-saving modality. UMMC is the only ECMO center in the state. Prior to the cases presented, ECMO use at UMMC has been limited to neonates and the pediatric patient population as well as by the cardiothoracic service for patients with cardiac failure or inability to wean from bypass. The use of ECMO for non-cardiac support in the adult population has been limited in the past, but recent reports in the literature and experience elsewhere has proven the viability of the technology. This is a retrospective report of the first three adult non-cardiac cases employing ECMO for ARDS (Adult Respiratory Distress Syndrome) in Mississippi. We achieved 100% survival in a disease process which reportedly carries a mortality ranging from 20-50%. A brief review of ECMO and its use in this population is also presented. PMID- 24073542 TI - The power of saying thank you. PMID- 24073541 TI - The educational struggles of African-American physicians in Mississippi: finding a path toward reconciliation. PMID- 24073543 TI - "Bottomline-itis": Race for the cure ... please! PMID- 24073544 TI - Maples' musings (or musings of a madman) We need more doctors. Really? PMID- 24073545 TI - Opening the doors of the great republic: sex, race, and organized medicine in Mississippi. PMID- 24073546 TI - Disease state? PMID- 24073547 TI - Epilepsy in children with subacute sclerosing panencephalitis. AB - INTRODUCTION: Subacute sclerosing panencephalitis (SSPE) is a rare, progressive, fatal neurodegenerative disease of childhood and early adolescence caused by defective measles virus. The initial symptoms of SSPE usually involve regression in cognitive functioning and behavior or recurrent myoclonic jerks. Seizures revealing SSPE and epilepsy during the clinical course can occur. OBJECTIVE: The aim of the study was to analyze clinical and EEG characteristics of both initially occurred seizures and epilepsy which developed in the course of the disease. METHODS: Retrospective study was carried out on 19 children (14 boys, 5 girls) with SSPE diagnosed and treated at our Clinic from 1995 to 2010. Seizures revealed SSPE in our patients aged from 6.5 to 11.5 years (mean 8.6 years). RESULTS: SSPE onset ranged from 4.5 to 16.5 years (mean 10.05). Complete vaccination was performed in nine patients. Cognitive and behavioral decline was preceeded by 6-18 months in two children with intractable focal motor seizures with secondary generalization, one child with complex partial seizures and one with atypical absences. During the clinical course of the disease epilepsy developed in 10 (52.6%) cases, including four patients with seizures as the initial SSPE sign. It occurred mainly in the first year, while in three cases seizures appeared between 1 and 5 years of the disease evolution. Myoclonus was present independently from seizures. No significant inter-group differences were found relating to the type of SSPE progression and history of epilepsy. The only child with fulminant SSPE presented with initial seizures. Favorable seizure control was achieved in 60.0% patients. Intractable epilepsy developed in four patients. CONCLUSION: Atypical SSPE presentation can include mainly focal intractable seizures. Epilepsy developed during clinical course in 52.6% cases. No significant influence was found of the history of epilepsy on the type of SSPE progression. PMID- 24073548 TI - Comparison of the efficacy and safety of fixed combination travoprost/timolol and dorzolamide/ timolol in patients with primary open-angle glaucoma and ocular hypertension. AB - INTRODUCTION: Combining two medications in one bottle may improve compliance by reducing the time required to administer drops and the frequency of the total number of medication bottles. OBJECTIVE: To compare the efficacy of reduced intraocular pressure (IOP) and safety of fixed combination travoprost 0.004%/timolol 0.5% vs. fixed combination dorzolamide 2%/timolol 0.5% in patients with primary open-angle glaucoma or ocular hypertension. METHODS: Prospective randomized clinical study included 60 patients divided into 2 groups. Follow-up was done at day 14 and 45 and month 3. IOP measurements were taken at each follow up examination at 8 am, 10 am and 4 pm. RESULTS: Both fixed combinations reduced IOP significantly compared to initial values at all follow-ups (p < 0.001). Mean pooled IOP at all visits and time points was slightly lower in the travoprost/timolol group compared with the dorzolamide/timolol group (16.13 mmHg vs. 16.15 mmHg). Mean IOP reduction from baseline ranged from -7.46 mmHg to -9.92 mmHg in the travoprost/timolol group and from -6.93 mmHg to -8.93 mmHg for the dorzolamide/timolol group. Mean (+/- standard error of the mean) reduction in diurnal LOP from baseline to 3rd month was 8.96 +/- 2.79 in the travoprost/timolol group versus 8.07 +/- 2.91 in patients receiving dorzolamide/timolol fixed combination (p = 0.196). The most frequent treatment related adverse events were conjunctival hyperemia in the travoprost/timolol group, and dry eye and foreign body sensation in the dorzolamide/timolol group. CONCLUSION: Travoprost/timolol fixed combination was slightly more effective than dorzolamide/timolol fixed combination in reducing mean diurnal IOP. Travoprost/timolol group resulted in an IOP reduction for up to 1.07 mmHg higher than dorzolamide/timolol group. Both fixed combinations were well tolerated and safe. PMID- 24073549 TI - Postoperative sensitivity associated with low shrinkage versus conventional composites. AB - INTRODUCTION: Postoperative sensitivity in restorative dentistry can be related to preparation trauma, dentin adhesives' ability to seal open dentinal tubules, deformation of restorations under occlusal stresses and microleakage. OBJECTIVE: The study assessed possible reduction in postoperative sensitivity with low shrinkage compared to conventional composites using different bonding agents and the influence of the operator skill on the incidence of postoperative sensitivity. METHODS: Nine hundred and sixty permanent premolars and molars with primary carious lesions from patients 21 to 40 years old were used. Cavities 2 to 3 mm deep and with margins in enamel were prepared by four operators. Two operators had five years (A and B) and two had over 20 years (C and D) of clinical experience. Teeth were divided into eight groups each contained 120 restorations: (1) Els+James-2 (original formula), (2) Els+James-2 (new formula), (3) Els+Excite, (4) InTenSe+James-2 (original formula), (5) InTenSe+James-2 (new formula), (6) InTenSe+Excite, (7) Tetric Ceram+Excite, and (8) Point 4+OptiBond Solo Plus. At 14 days postoperatively, two independent operators, who did not take part in the clinical procedure, assessed postoperative teeth sensitivity using special questionnaires. Data were analyzed using non-parametric chi-square, Mann-Whitney and ANOVA tests. RESULTS: Group 8 showed significantly higher score than the other groups. Less postoperative sensitivity was reported with two low shrinkage composites (groups 2, 3, and 5) but with no significant difference. There was no statistical difference between groups 1, 2, 3, 4, 5, 6 and 7. Operator A had the highest postoperative sensitivity score compared to the other three. CONCLUSION: Conventional composite material Point 4 with its bonding agent caused significantly more postoperative sensitivity than low shrinkage composites combined with different adhesives. Operator skill influenced the incidence of postoperative sensitivity. PMID- 24073550 TI - [Applicability of visual-analogue scale in patients with orofacial ain]. AB - INTRODUCTION: Orofacial pain occurs in various disorders of the orofacial region. OBJECTIVE: The aim of this study was to examine applicability of the visual analogue scale (VAS) in patients with orofacial pain (model of acute and chronic pain). METHODS: The study involved 60 patients, aged 18-70 years. The first group consisted of patients with dentin hypersensitivity, and the second group of patients with chronic rhinosinusitis. All patients were asked to fill-in a pain questionnaire and to rate pain intensity on the modified visual analogue scale (VAS; 0-10). Air indexing method was performed in the patients with dentin hypersensitivity in order to provoke pain, while the patients with chronic rhinosinusitis underwent CT imaging of paranasal sinuses. Wilcoxon's test and Pearson's correlation coefficient were used for statistical analysis. RESULTS: In patients with dentin hypersensitivity provocation increased subjective feeling of pain, but without statistical significance (t = 164.5; p > 0.05). In patients with chronic rhinosinusitis a significant statistical correlation (r = 0.53; p < 0.05) was found between subjective pain assessment of VAS and CT findings. CONCLUSION: Applying VAS in the evaluation of acute and chronic pain can indicate progression or regression of pathological state under clinical conditions. This study showed that VAS, as a method for follow-up of pathological state, is more applicable and efficient when applied in chronic pain evaluation. PMID- 24073551 TI - Relationship between abdominal obesity and other cardiovascular risk factors: cross sectional study of patients with symptomatic carotid disease. AB - INTRODUCTION: Obesity, particularly visceral obesity, is considered one of major risk factors for cardiovascular events. OBJECTIVES: The aim of the present study was to investigate relationship between abdominal obesity and other cardiovascular risk factors. METHODS: The cross-sectional study involved 657 consecutive patients with verified carotid atherosclerosis. Carotid atherosclerosis was estimated by high resolution B-mode ultrasonography. Abdominal obesity was defined as waist circumference > 102 cm in men and > 88 cm in women. RESULTS: Abdominal obesity was present in 324 (49.3%) participants. Multivariate analyses showed that abdominal obesity was significantly positively associated with female sex, increased Baecke's Work Index of physical activity at work, years of school completed < 12, metabolic syndrome, increased triglycerides, hyperglycemia and high serum uric acid. Smoking, alcohol consumption, physical inactivity, hypertension, increased total cholesterol, increased HDL and LDL cholesterols, increased high sensitive C-reactive protein, increased fibrinogen, anti-lipid therapy and anti-diabetic therapy were not significantly related to abdominal obesity. CONCLUSION: Abdominal obesity among patients with symptomatic carotid disease is significantly related to other cardiovascular risk factors, especially metabolic syndrome, metabolic syndrome components and high level of serum uric acid. PMID- 24073552 TI - Diagnostic relevance of ADAMTS13 activity: evaluation of 28 patients with thrombotic thrombocytopenic purpura - hemolytic uremic syndrome clinical diagnosis. AB - INTRODUCTION: The significance of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif-13) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) is still a controversial issue. OBJECTIVE: The aim of this report was to analyze the value of ADAMTS13 measurements in the diagnosis of TTP and HUS. METHODS: At presentation, we analyzed patients with idiopathic TTP (n = 18), secondary TTP (n = 4), diarrhea positive HUS (n = 3) and diarrhea negative HUS (n = 3) treated in Belgrade, Serbia from 2004 to 2010. ADAMTS13 activity from acute phase samples was measured using the residual collagen binding activity assay at the Haemophilia and Thrombosis Centre, Milan, Italy. RESULTS: There was a significant correlation between reduced ADAMTS13 activity and idiopathic TTP diagnosis (p = 0.000) as well as between lower ADAMTS13 activities and higher reticulocytes (p = 0.017) and lactate dehydrogenase levels (p = 0.027). Significant correlation was also found between higher protease activity and diagnosis of HUS (p = 0.000). There was a statistically significant correlation between higher ADAMTS13 activities and higher platelets count (p = 0.002), blood urea nitrogen (p = 0.000), and creatinine level (p = 0.000). CONCLUSION: Severe ADAMTS13 deficiency points at the diagnosis of idiopathic TTP and it is present in the secondary TTP but not in HUS. PMID- 24073553 TI - [Laparoscopic myotomy in achalasia cardia treatment: experience after 36 operations]. AB - INTRODUCTION: Laparoscopic Heller-Dor operation, a standard method in the treatment of achalasia, has been performed at the Center for Esophageal Surgery of the First Surgical Clinic since April 2006. OBJECTIVE: The aim of this study was to present this surgical procedure and initial experiences after 36 consecutive laparoscopic Heller-Dor operations. METHODS: This partly retrospective, partly prospective study presented our results after laparoscopic Heller-Dor operation (presentation of the treatment method). We performed a standard anterior esophagocardioymiotomy, without releasing the posterior aspect of the cardia, and anterior partial fundoplication. The type and severity of symptoms and their duration were evaluated based on questionnaires fulfilled by patients. The diagnosis was made based on radiological, endoscopic and manometric findings. Laparoscopic surgery as the method of treatment was evaluated based on the duration of surgery, intra- and postoperative complications, time interval until the initiation of oral feeding, length of hospital stay, need for additional therapeutic measures after the operation and effect of surgery on the severity of symptoms. RESULTS: Preopereratively, dysphagia was the predominant symptom in all patients, while regurgitation was much lower (44%). The average duration of operation was 127 minutes. Postoperative hospitalization lasted on the average 5.7 days. From 36 treated patients, 34 (94.4%) considered that the effect of treatment was good or excellent. Postoperative dysphagia was present in two patients (5.6%) and was successfully solved by balloon dilatation. CONCLUSION: Laparoscopic Heller-Dor operation is an effective and safe surgical procedure in resolving symptoms of achalasia and today presents the method of the first choice in the treatment of this disease. PMID- 24073554 TI - [Epidemiological characteristics of nosocomial diarrhea caused by Clostridium difficile in a tertiary level hospital in Serbia]. AB - INTRODUCTION: Among the most important causes of diarrhea in modern hospitals is Clostridium difficile (C. difficile). A wide spectrum of diseases caused by this bacterium is now known as C. difficile associated disease (CDAD). The development of CDAD is usually preceded by the administration of antimicrobial therapy and fecal-oral infections with C. difficile. Over the last years epidemiology of CDAD has significantly changed. Recently, a hypervirulent BI/NAP1/027 strain, the cause of severe epidemics in North America and Western Europe, has been identified. OBJECTIVE: The aim of this study was to identify risk factors for CDAD in patients operated on at the Military Medical Academy (MMA). METHODS: The study included all patients who underwent surgery at the MMA during 2010. Nested case-control study design was used. The subjects were divided into groups of operated patients with and without CDAD. The patients were under prospective follow-up, while their data were collected using a questionnaire during a routine epidemiological control. RESULTS: During 2010 the incidence rate of CDAD was 3.3 per 10,000 hospital days. Univariate regression analysis showed that the length of administration of one or two antibiotics, as well as concurrent administration of two antibiotics, were far more frequently observed in the patients with than in the patients without CDAD. Independent risk factor for the development of CDAD was the length of the administration of one antibiotic. CONCLUSION: Reduction in the incidence rate of CDAD can be achieved by using reliable measures of prevention and control; the rational use of antibiotics, early diagnosis and therapy of infected patients, contact isolation of infected persons, proper disinfection, and continued education of medical and nonmedical personnel. PMID- 24073555 TI - First IKBKG gene mutation study in Serbian incontinentia pigmenti patients. AB - INTRODUCTION: Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis. Mutations of the IKBKG gene are the only known cause of IP. The presence or other than skin changes is important in the diagnosis of atypical IP cases when skin changes are discrete. OBJECTIVE: The study was designed to analyze clinical manifestation, family histories and the frequency of IKBKG gene mutation in IP patients in Serbia for the first time and to compare them with other reported findings. METHODS: Two Serbian unrelated families with eight female subjects were investigated. Blood samples were used for IKBKG exon 4-10 deletion testing using modified PCR protocol. For probands pathohistological and ultrastructural analyses of skin biopsies were done. RESULTS: Positive clinical diagnosis according to IP criteria was present in seven cases. In six of them, including probands, positive molecular gene testing for IKBKG exon 4-10 deletion was present. CONCLUSION: This is the first report of genetically confirmed IP in two Serbian families. The IP patients presented a common IKBKG exon 4-10 deletion. The frequency and type of IKBKG mutation found in investigated IP patients in Serbia were similar to results of other studies. Various clinical features of investigated patients have allowed us to demonstrate that molecular genetic testing which specifically detects the common IKBKG mutations, the only known cause of IP, is useful in diagnosing IP especially in mild or atypical cases. The molecular genetic testing of the IKBKG mutations may be helpful for rapid confirmation of IP diagnosis, prenatal diagnosis and carrier detection. PMID- 24073556 TI - [Etanercept therapy in rheumatoid arthritis: efficacy and safety]. AB - INTRODUCTION: Etanercept, tumor necrosis factor (TNF-alpha) antagonist, lowers the disease activity level in patients with rheumatoid arthritis (RA), reduces joint destruction saving physical functions and improving life quality. OBJECTIVE: The aim of this study was to establish efficacy and safety of etanercept in combination with disease modifying antirheumatic drugs (DMARDs) in the treatment of RA. METHODS: To patients with active RA, who were on therapy with DMARD, etanercept was introduced in weekly doses of 50 mg, with continuation of DMARD. Efficacy of this form of treatment was evaluated in the 12th week. Maintenance of the effect of treatment was also evaluated during 24, 48 and 96 weeks. Long-term evaluation of etanercept safety was assessed by registering all unwanted events during a two-year period. RESULTS: After 12 weeks of treatment with etanercept, 80% of patients had ACR20 response, while 85% showed clinically significant decrease of DAS28 index. We achieved remission in five patients (12.5%) and low activity of RA in 17 patients (42.5%). During a 96-week of follow up period, achieved therapy effects were maintained. In four patients (10%) etanercept therapy was interrupted after 24 weeks because of inadequate response. In one of them (2.5%) we recorded a cardiovascular incident. Acute infections were registered in 47 cases. Four of those were severe infections. Neither cases of malignancy development were noted, nor were there any lethal disease outcomes. CONCLUSION: Etanercept in combination with DMARD shows a high level of efficacy in the treatment of RA. The safety profile of the drug is satisfactory. PMID- 24073557 TI - [Minimal invasive surgical correction of pectus excavatum deformities in adolescents: our institutional experience]. AB - INTRODUCTION: Nuss procedure is a minimal invasive surgical technique based on retrosternal placement of a metal plate to correct pectus excavatum chest deformity. We are presenting our five-year (2006-2011) institutional experience of 21 patients. OBJECTIVE: The aim of this study was to determine characteristics and advantages of minimal invasive surgical approach in correcting deformities of the chest. METHODS: Surgical procedure, named after its author Nuss, involves the surgical placement of a molded metal plate, the so-called pectus bar, behind the sternum under thoracoscopic view whereby immediate controlled intraoperative corrections and stabilizations of the depression can be made.The great advantage of this method is reflected in a significant shortening of operative time, usually without indications for compensation in blood volume, and with a significantly shortened postoperative recovery that allows patients to quickly return to their normal activities. RESULTS: In the period 2006-2011, 21 patients were operated by the Nuss procedure. The pectus bar was set in front or behind the muscles of the chest. Among the complications listed were inflammation of wounds in three patients, dislocation (shifting) of the bar requiring a reoperation in two patients, an occurrence of a pericardial effusion in one patient, and allergic response to foreign body in one patient. Five patients required extraction of the bar two years later, and three patients after three years, all with excellent results. CONCLUSION: Minimally invasive Nuss procedure is safe and effective. It currently represents the primary method of choice for solving the chest deformity pectus excavatum for patients of all ages. Modification of thoracoscopic control allows a safe field of operation. Postoperative results are excellent with very few complications that can be attributed to the learning curve. PMID- 24073558 TI - [Importance of adherence for efficacy of hepatitis C combined therapy]. AB - INTRODUCTION: Dual antiviral therapy with pegylated interferon alfa-2a and ribavirin leads do sustained elimination of hepatitis C virus infection in over 50% patients with genotypes 1 and 4 and in over 80% with genotypes 2 and 3. In addition to genotype, for predicting success of therapy, important factors are baseline HCV RNA level, age, sex, stage of fibrosis, insulin resistance, degree of fat in liver, and patient's weight and genetics. Also, adherence to therapy could be a very important factor associated with success of therapy. OBJECTIVE: The aim of this study was to assess importance of therapy adherence and reduced doses of pegylated interferon alfa-2a and ribavirin on sustained virological response. METHODS: One hundred and sixteen patients with chronic hepatitis C were analyzed. Sustained virological response was analyzed in relation to whether the patients received a full cumulative dose of pegylated interferon alfa-2a, a full cumulative dose of pegylated interferon alfa-2a and ribavirin, and a full cumulative dose of pegylated interferon alfa-2a and at least 60% the expected cumulative dose of ribavirin. RESULTS: At the end of the follow-up period, sustained virological response was achieved in 26 (96.3%) patients who received full cumulative dose of pegylated interferon alfa-2a and in 66 (74.2%) who did not (p < 0.05). Sustained virological response was achieved in 18 (94.7%) patients who received full cumulative dose of pegylated inteferon alfa-2a and ribavirin, and in 73 (76%) who did not (p < 0.05). Sustained virological response was achieved in 25 (96.2%) patients who received full cumulative dose of pegylated inteferon alfa-2a and at least 60% of cumulative dose of ribavirin and in 66 (74.2%) who did not (p < 0.05). CONCLUSION: These findings indicate that adherence to therapy for chronic hepatitis C is a very important factor for achieving sustained virological response. PMID- 24073559 TI - Metabolic syndrome and C-reactive protein in patients with depressive disorder on antidepressive medication. AB - INTRODUCTION: Recurrent depression is a psychiatric disorder of which etiology and pathogenesis might be related to immune response. Metabolic Syndrome (MetS) and its components are also strongly associated with elevated inflammatory indicators, as so as the body mass index (BMI) and total cholesterol levels. OBJECTIVE: Objective of this study was to investigate if there was any difference in C-reactive protein (CRP) levels in patients with recurrent depressive disorder, treated with antidepressants, compared to a healthy control group of subjects and if there was an association between increased CRP levels and the presence of MetS in these two groups. METHODS: Sixty subjects entered the study; of these 35 patients with the diagnosis of recurrent depressive disorder, while the healthy control group included 25 subjects. MetS was defined according to the NCEP ATP III criteria. The cut-off point for CRP was set at > 5 mg/L. RESULTS: There was no statistically significant difference in the prevalence of MetS and CRP values between the studied groups. Waist circumference and total cholesterol levels were significantly higher in the experimental group. Patients that fulfilled the criteria for MetS showed significantly higher values of central obesity and arterial hypertension in the experimental group as well. The elevated CRP levels were associated with increased frequency of MetS in depressed patients. CONCLUSION: Both CRP levels and metabolic risk profile screening, according to the international criteria, may be beneficial in order to obtain better assessment for depressive long-term medicated patients. PMID- 24073560 TI - [Big intraocular foreign body: case report]. AB - INTRODUCTION: Penetrated injuries are most difficult injuries of the eye. Intraocular foreign body (IOFB) may lodge in any of the structures it encounters, from anterior chamber to the retina and choroid. Notable effects caused by foreign body injury include traumatic cataract, vitreous liquefaction, retinal and subretinal hemorrhages, retinal detachment and development of endophtalmitis. CASE OUTLINE: A 49-year-old man sustained injury of the right eye with a piece of metal wire. On admission visual acuity was VOD: 1.0 and lower intraocular tension TOD = 6 mmHg (10-22 mmHg). Corneal entry wound was noticed near limb on 11 h with a prominating foreign body of 18 mm in length that passed through the iris, lens and vitreous. X-ray findings confirmed existence of a large foreign body extending along the entire length of the globe. IOFB removal was done with anatomic forceps. On postoperative detailed clinical examination we observed retinal rupture in the upper temporal quadrant fitting in the area of the IOFB damaged retina. Laser photocoagulation of retinal tear (laser retinal barrage) was done. Visual acuity on discharge was the same (1.0) and intraocular tension was within normal limits (10 mmHg). CONCLUSION: Penetrated injury of eye requires detailed examination of all eye structures, beginning from the anterior to posterior segment. Timely diagnosed ruptures of the posterior segment of eye before the development of traumatic cataract, and adequate therapeutic procedures prevent serious complications of IOFB penetrated eye injury such as retinal detachment and permanent reduction of visual acuity. PMID- 24073561 TI - [Pulmonary embolism as a cause of cardiac arrest: hypothermia in post resuscitation period (cooling therapy)]. AB - INTRODUCTION: Pulmonary embolism as a possible cause of acute heart failure is a potentially fatal condition that can cause death in all age groups. Patients successfully resuscitated after cardiac arrest have a high risk of increased mortality and their poor long-term outcome is often associated with severe neurological complications. CASE OUTLINE: This is a case report of a 67-year-old man after a successful cardiopulmonary resuscitation (CPR) which was followed by therapeutic hypothermia (TH). The patient visited the dermatological outpatients' department with clinical presentation of pain and swelling of the right leg, shortness of breath and chest pain. During examination the patient lost consciousness, stopped breathing and had cardiac arrest. ECG was done which registered asystole. We began CPR. After 59 minutes of resuscitation return of heartbeat was achieved. The patient was transported to the Emergency Department. On admission, after computerized tomography (CT) of the chest confirmed massive pulmonary embolism (PE), the patient was administered thrombolytic therapy with Metalyse (tenecteplase) and anticoagulation therapy (heparin). After stabilization, therapeutic hypothermia was applied. Combination of EMCOOLSpad on the chest and abdomen and cold Ringer lactate 500 ml at 4 degrees C was flushed. Temperature was decreased to 33 degrees C and kept stabile for 24 hours. After eight days the patient was conscious with a minimal neurological deficit. CONCLUSION: As shown in this case report, and according to the rich experience elsewhere, cooling therapy after out-of-hospital cardiac arrest and successful CRP may be useful in preventing neurological complications. PMID- 24073562 TI - [Term pregnancy after minimally invasive surgical treatment of Herlyn-Werner Wunderlich syndrome]. AB - INTRODUCTION: Uterus didelphys with obstructed hemivagina and ipsilateral renal agenesis represents a complex congenital anomaly, also known in the literature as Herlyn-Werner-Wunderlich (HWW) syndrome. CASE OUTLINE: A 16-year-old patient presented with secondary amenorrhoea and abdominal pain. Her history revealed anorexia nervosa; she had menarche at the age of 14; her menstrual cycles were regular, with progressive dysmenorrhoea. Nine months after the explorative laparotomy performed at the regional healthcare center there was no a definitive diagnosis. Pelvic examination showed a paravaginal pelvic mass located on the right side. Magnetic resonance imaging of the abdomen and pelvis confirmed the diagnosis of HWW syndrome. Transvaginal excision and marsupialisation of the vaginal septum were performed. Regular menstrual cycles were resumed after four years following the treatment of anorexia nervosa. Twelve years after the operation, the patient conceived spontaneously; pregnancy developed in the left non-obstructed uterus. She underwent Cesarean section at the 37th gestational week and gave birth to a healthy female infant. CONCLUSION: HWW syndrome is an uncommon cause of abdominal pain and progressive menstrual discomfort shortly after menarche. It is therefore essential to maintain a high index of suspicion of the existence of this syndrome in such cases, since prompt and adequate treatment prevents the development of complications and allows for preservation of the reproductive potential of both hemi-uteri. PMID- 24073563 TI - [Diagnosis and treatment of rib fracture during spontaneous vaginal delivery]. AB - INTRODUCTION: Progress of labor in multiparous women usually is not accompanied with risk of any kind of birth trauma. CASE OUTLINE: We report a very rare case of rib fracture in a neonate during vaginal delivery in the 39/40 week of gestation. The expulsion started spontaneously without any manipulation from the obstetrician. Live male newborn was delivered 4650 g. in weight, 55 cm long, with head circumference of 39 cm, Apgar score 9. The child was immediately examined by the neonatologist. Crepitations were palpable over the left hemithorax, and auscultatory on the left side inspiratory cracks. Finding was suspicious for rib fracture on the left side posteriorly and brachial plexus palsy, while other findings were normal. X-ray finding was inconclusive, but suspicious for fracture of the 4th, 5th, and 6th left rib posteriorly, without dislocation of bone fragments. There were no signs of pneumothorax. Dorsal position of the newborn was considered sufficient, accompanied with analgetics. X-ray was scheduled in a week because formation of the calus would be the only objective sign of previous rib fracture. On the control X-ray fracture lines were clearly visible on the 3rd, 4th, 5th 6th and 7th rib posteriorly, without dislocation of bone fragments with initial calus formation. The child was discharged from hospital in good condition after two weeks, for further outpatient care. CONCLUSION: With timely diagnostics of this very rare intrapartal fracture, adequate treatment, dorsal position and close control of clinical condition of the newborn, serious and potentially life threatening complications can be avoided. PMID- 24073564 TI - Ultrasonographic diagnostics and evaluation of calcaneal fracture: case report. AB - INTRODUCTION: Radiography is the standard tool in the diagnostics of bone fractures. This paper presents a case of calcaneal fracture diagnosed by ultrasonography that was also used in the follow-up of recovery progress. CASE OUTLINE: A 68-year-old male patient was diagnosed avulsion fracture of the calcaneus by ultrasonography (US) examination using a multi-frequency linear probe (7-15 MHz) and confirmed by X-ray findings; US also provided insight into the dynamics of the reparatory processes. Control examinations were performed on day 14, 21, 30, 60 and 300 (10 months) after the occurrence of the fracture. During this time rehabilitation process was carried out. The diameters of the wedge defect of the calcaneus were measured by US for the follow-up of the healing process of the injured bone. Postero-anterior (PA) or longitudinal diameter and latero-medial or medio-lateral or transverse diameter were measured. CONCLUSION: Study results indicate a possible use of US in the diagnostics of fractures and monitoring of calcaneal healing. PMID- 24073565 TI - [Humeral lengthening: case report]. AB - INTRODUCTION: Difference in length of upper extremities has mainly esthetic significance and is therefore not so often a subject of operative treatment, compared to lower extremities. CASE OUTLINE: We are presenting a case of a 16 year-old patient in whom a shortening of 9 cm of the right humerus was determined at the end of growth. This shortening was the result of surgical treatment of solitary bone cyst at the proximal end of the humerus done at the age of 10 years. In order to correct the length of the humerus we applied distraction osteogenesis with a compressive-distracting device according to Mitkovic (Traffix), and we achieved the lengthening of 7.5 cm. During the period of distraction we encountered the following complications: minimal suppuration at the site of the wedges that was successfully resolved with intensive local treatment, while pain and paresthesias along the N. radialis were resolved with a temporarily slowing of the distraction process. Fixation with a plate, i.e. bone grafting was not necessary, and final functional and esthetic result was excellent. CONCLUSION: Successful lengthening of the shortened humerus can be achieved with a unilateral compressive-distracting device according to Mitkovic as its application up to a complete bone reconstruction does not require additional plate fixation or bone grafting. The patient was capable of performing usual daily activities during application of the device. PMID- 24073566 TI - [Pontomedullary lacerations and concomitant injuries: a review of possible underlying mechanisms]. AB - Anatomically, brainstem is constituted of medulla oblongata, pons and mesencephalon. Traumatic lesions of brainstem most commonly occur on pontomedullary junction. There are several possible mechanisms of pontomedullary lacerations. The first mechanism includes impact to the chin, with or without a skull base fracture, and most often leads to this fatal injury, due to impact force transmission through the jawbone and temporomandibular joint. The second mechanism includes lateral and posterior head impacts with subsequent hinge fractures, where occurrence of pontomedullary lacerations in these cases may depend on the energy of impact, as well as on the exact position of the fracture line, but less so on the head's movement. The third mechanism includes frontoposterior hyperextension of the head, due to frontal impact, concomitant with fractures or dislocations of upper spine. In the fourth mechanism, there is an absence of direct impact to the head, due to the indirect force of action after feet or buttocks-first impact. Most of these cases are accompanied by ring fractures as well. In situations such as these, the impact force is transmitted up the spinal column and upper vertebrae, and telescopically intruded into the skull, causing brainstem laceration. The jawbone and other facial bones can act as shock absorbers, and their fracture could diminish the energy transfer towards the skull and protect the brain and brainstem from injury. In all the cases with pontomedullary laceration posterior neck dissection should be performed during the autopsy, since upper spine injuries are often associated with this type of injury. PMID- 24073567 TI - Basis of bone strength vs. bone fragility: a review of determinants of age related hip fracture risk. AB - The burden of hip fractures in elderly population has been growing worldwide. A particular focus has been directed towards identifying persons at high risk of fracture. However, bone mineral density (BMD), which is currently used in clinical settings as an indicator of risk of age-related fracture, cannot explain all fracture cases in the elderly. In fact, the risk of hip fractures in the elderly is associated with numerous bone features that degrade bone strength. This review focuses on complexity of bone features that could account for increased bone fragility in advanced age. Besides a decrease in BMD, various macroscopic and microscopic structural parameters, as well as the material of which the bone is composed, are subject to age-related changes. Therefore, in order to have a more thorough assessment of the fracture risk, it is essential to provide integrative approaches that combine BMD measure with other relevant bone features. PMID- 24073568 TI - [The role of psychiatry in family violence treatment]. AB - The aim of the paper is reassessment of the role of psychiatry in the treatment of family violence within the context of contemporary approaches and researches. There are prejudices in the general and professional public that perpetrators of family violence are usually persons with mental disorders and that psychiatry is primarily in charge of their treatment; it has been shown that severe mental disorders do not increase the risk of violence. Application of classical psychiatrics approach to family violence treatment is discussed, as well as the roles of psychiatry in current theoretical and therapeutic approaches to this issue, including systemic family therapy, social psychiatry primarily concerned with their treatment. Studies have shown that severe mental disorders do not increase ecology, unwillingness therapy and model of protection of family violence victims that is developed in Serbia. PMID- 24073569 TI - [Diagnosis of bacterial vaginosis]. AB - Bacterial vaginosis is a common, complex clinical syndrome characterized by alterations in the normal vaginal flora. When symptomatic, it is associated with a malodorous vaginal discharge and on occasion vaginal burning or itching. Under normal conditions, lactobacilli constitute 95% of the bacteria in the vagina. Bacterial vaginosis is associated with severe reduction or absence of the normal H2O2-producing lactobacilli and overgrowth of anaerobic bacteria and Gardnerella vaginalis, Atopobium vaginae, Mycoplasma hominis and Mobiluncus species. Most types of infectious disease are diagnosed by culture, by isolating an antigen or RNA/DNA from the microbe, or by serodiagnosis to determine the presence of antibodies to the microbe. Therefore, demonstration of the presence of an infectious agent is often a necessary criterion for the diagnosis of the disease. This is not the case for bacterial vaginosis, since the ultimate cause of the disease is not yet known. There are a variety of methods for the diagnosis of bacterial vaginosis but no method can at present be regarded as the best. Diagnosing bacterial vaginosis has long been based on the clinical criteria of Amsel, whereby three of four defined criteria must be satisfied. Nugent's scoring system has been further developed and includes validation of the categories of observable bacteria structures. Up-to-date molecular tests are introduced, and better understanding of vaginal microbiome, a clear definition for bacterial vaginosis, and short-term and long-term fluctuations in vaginal microflora will help to better define molecular tests within the broader clinical context. PMID- 24073570 TI - [What language is your doctor speaking? Facing the problems of translating medical documents into English]. AB - What is translation--a craft, an art, a profession or a job? Although one of the oldest human activities, translation has not still been fully defined, and it is still young in terms of an academic discipline. The paper defines the difference between translation and interpreting and then attempts to find the answer to the question what characteristics, knowledge and skills a translator must have, particularly the one involved in court translation, and where his/her place in the communication process (both written and oral communication) is. When translating medical documentation, a translator is set within a medical language environment as an intermediary between two doctors (in other words, two professionals) in the process of communication which would be impossible without him, since it is conducted in two different languages. The paper also gives an insight into types of medical documentation and who they are intended for. It gives practical examples of the problems faced in the course of translation of certain types of medical documentation (hospital discharge papers, diagnoses, case reports,...). Is it possible to make this kind of communication between professionals (doctors) standardized, which would subsequently make their translation easier? Although great efforts are made in Serbia regarding medical language and medical terminology, the conclusion is that specific problems encountered by translators can hardly be overcome using only dictionaries and translation manuals. PMID- 24073571 TI - [Congenital malformations of the external and middle ear]. AB - Congenital malformations of the external and middle ear is the common reason of pediatric hearing impairment and cosmic problem. The treatment composes of auricular plastic surgery and auditory reconstruction surgery. The use of BAHA, vibrant sound-bridge and tissue engineering materials can significantly improve the treatment outcomes. PMID- 24073572 TI - [Prevention and treatment of common complications of ear reconstruction]. AB - OBJECTIVE: To explore the prevention and treatment of common complications of ear reconstruction. METHOD: To summarize complications of 46 patients of microtia whom underwent auricular reconstructions using soft tissue skin expander and autogenous rib cartilage framework by two stages from November 2011 to October 2012. RESULT: One patient had flap necrosis resulting to exposures of the expanders in the first surgical stage. Three cases of flap necrosis occurred in the second surgical stage. After repair the defect with pedicled flap, the reconstructed auricles of patients with complications were aesthetically satisfied. CONCLUSION: Treating every step of the reconstruction seriously and correctly could prevent the happening of complications, and when confronting the complications, apply the right treatment such as using pedicled flaps repair the defect to reconstruct the lifelike auricles. PMID- 24073573 TI - [Clinical application of osseointegrated prosthetic in reconstruction of auricular defects]. AB - Auricular deformity, a common disease of the external ear in China, can be divided into congenital deformity and acquired deformity caused by trauma or ablative origin. Ear reconstruction with autogenous rib cartilage grafts provides consistent emotional relief and psychological benefits due to the repair. However, autogenous reconstruction is complex and challenging, and can be fraught with complications, in addition sometimes it may not be an option for the patients with poor skin cover, severe craniofacial anomalies, those with microtia who have had a failed previous reconstruction and microtia patients with a very low hairline and residual lobe. As an alternative to the significant surgical morbidity of autogenous reconstruction, osseointegrated implant reconstruction has several distinct advantages. This current essay was to illustrate the superiority, indications, feasibility and complications of osseointegrated implant reconstruction, and provide alternative way to help patient who was deprived of ear(s). PMID- 24073574 TI - [Management and classification of first branchial cleft anomalies]. AB - OBJECTIVE: We aimed to identify the different courses of first branchial cleft anomalies and to discuss the management and classification of these anomalies. METHOD: Twenty-four patients with first branchial cleft anomalies were reviewed. The courses of first branchial cleft anomalies and their corresponding managements were analyzed. Each case was classified according to Olsen's criteria and Works criteria. RESULT: According to Olsen's criteria, 3 types of first branchial cleft anomalies are identified: cysts (n = 4), sinuses (n = 13), and fistulas (n = 7). The internal opening was in the external auditory meatus in 16 cases. Two fistulas were parallel to the external auditory canal and the Eustachian tube, with the internal openings on the Eustachian tube. Fourteen cases had close relations to the parotid gland and dissection of the facial nerve had to be done in the operation. Temporary weakness of the mandibular branch of facial nerve occurred in 2 cases. Salivary fistula of the parotid gland occurred in one patient, which was managed by pressure dressing for two weeks. Canal stenosis occurred in one patient, who underwent canalplasty after three months. The presence of squamous epithelium was reported in all cases, adnexal skin structures in 6 cases, and cartilage in 14 cases. The specimens of the fistula which extended to the nasopharynx were reported as tracts lined with squamous epithelium (the external part) and ciliated columnar epithelium (the internal part). According to Work's criteria, 9 cases were classified as Type I lesions, 13 cases were classified as Type II lesions, and two special cases could not be classified. The average follow-up was 83 months (ranging from 12 to 152 months). No recurrence was found. CONCLUSION: First branchial cleft anomalies have high variability in the courses. If a patient is suspected to have first branchial anomalies, the external auditory canal must be examined for the internal opening. CT should be done to understand the extension of the lesion. For cases without internal openings in the external auditory canal, CT fistulography should be done to demonstrate the courses, followed by corresponding treatment. Two special cases might be classified as a new type of lesions. PMID- 24073575 TI - [Evaluation of intra-operative EABR characteristics and rehabilitation effects of cochlear implantation in patients with internal auditory canal stenosis]. AB - OBJECTIVE: To investigate the intra-operative electrical evoked auditory brain stem response (EABR) characteristics and the hearing and speech rehabilitation effects of cochlear implantation (CI) in patients with internal auditory canal stenosis (IACS). METHOD: A retrospective study was performed on 16 patients with IACS (IACS group) matched with 16 implanted without IACS (control group), who received multi- channel CI because of pre-lingual sensorineural hearing loss. The integrity and functional status of the auditory pathway were assessed by EABR, recording waveforms, thresholds and dynamic ranges intra-operation before CI. Interviewed the implanted parents or teachers, asking them to rate the implanted hearing and speech ability according to Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR). Paired T test was performed to compare scores of CAP and SIR between before and 1 year after CI, while Spearman test was performed to compare correlation between EABR grades and post-operative CAP scores. RESULT: Among the IACS group, 2 cases weren't recorded typical EABR waveforms and without auditory response 1 year after a successful CI. The EABR waveforms in the IACS group were poorer than that in the control group, their EABR thresholds higher than the control group, and their EABR dynamic ranges less than the control group. The hearing and speech rehabilitation after CI showed that the results of CAP and SIR values (3.47 +/- 1.09 and 1.62 +/- 0.50) scored significantly lower than the control group (5.06 +/- 0.79 and 2.59 +/- 0.58) (P < 0.05), but significantly increased compared with pre-operation. Intra-operative EABR grades and post-operative CAP scores showed significant correlation (r = 0.78 , P < 0.05). CONCLUSION: Intra-operative EABR can accurately monitor the integrity and functional status of the auditory pathway, be of important clinical value in predicting whether patients can acquire auditory responses with the aid of CI. CI can help patients with IACS to improve the ability of hearing and speech with EABR to screen out compatible implanted. PMID- 24073576 TI - [Study on relationship between operation timing and clinical prognosis of cases with Bell palsy]. AB - OBJECTIVE: To study on relationship between diverse handling time following onset and clinical prognosis of cases with Bell palsy. METHOD: Two hundred and sixteen cases with Bell palsy, who were admitted in our department between Jun. 2006 and Dec. 2009, were collected and divided into 6 groups according to disease time: 1 2 months, > 2 - 3 months, > 3 - 4 months, > 4 - 5 months, > 5 - 6 months, and > 6 months. Cases in all groups received subtotal course decompression of facial nerve and other compound treatment, and the relationship between handling timing and clinical prognosis were compared. RESULT: It was found that the difference of prognosis and handling timing was statistically significant, after comparison between all groups with Facial Grading Standards (H-B) as the standard to assess prognosis. CONCLUSION: Clinical prognosis of cases with Bell palsy was related to alternative handling time, and subtotal course decompression of facial nerve was recommended to be performed as early as possible for those cases who were irresponsive after conservative treatment for one month. PMID- 24073577 TI - [The relationship between ossicular status and conductive hearing loss in cholesteatoma]. AB - OBJECTIVE: To investigate and analyze the characteristic of destructive ossicular chain and it's impact on air-bone gap (ABG) among patients with cholesteatoma. METHOD: Data from 204 cases (213 ears) undergoing an initial surgery for cholesteatoma were retrospectively reviewed to evaluate the relationships between preoperative pure tone audiometry data and intraoperative assessment of individual ossicular destruction. RESULT: Incus was the most significantly affected ossicle. Furthermore, the destruction of malleus and stapes was often accompanied by the destruction of incus. A partially eroded incus caused significantly increase in ABG from that of an intact incus with cholesteatoma abutting (P < 0.05). A partially eroded incus and a partially eroded stapes caused significantly increase in ABG compared to a partially eroded incus (P < 0.05). A completely eroded incus caused significantly increase in ABG compared to a partially eroded incus (P < 0.05). False fibre-connected would significantly influence on ABG in some ossicular chain erosion patterns (P < 0.05). Cholesteatoma abutting an intact ossicle significantly altered average ABG compared to a normal ossicle (P < 0 01). CONCLUSION: Different ossicular chain erosion pattern caused different degrees of ABG. PMID- 24073578 TI - [Clinical analysis of Langerhans cell histiocytosis of head and face]. AB - OBJECTIVE: To study the diagnosis and treatment for Langerhans cell histiocytosis (LCH) of head and face. METHOD: Clinical data of 19 cases suffering from LCH of head and face verified by pathology was retrospectively analyzed. The clinical presentation, diagnosis and treatment were discussed. RESULT: Of all the 19 cases, 5 patients had an involvement of the scalp or skull, 5 had the maxilla involvement and 9 temporal bone. Among the 19 patients, type I stage I was 8 cases(all adults), type II stage I 7 cases (all children), type ILL stage II 2 (1 adult, 1 child), stage III 1 and stage IV 1 (both child). Their main clinical manifestations included scalp mass, defect of skull, swelling or mass of facial maxilla and of ear or temporal bone, otorrhea, granuloma of auricular canal, and so on. Fifteen cases were cured by surgical curettage combined with radiotherapy and 4 by surgical curettage combined with chemotherapy. One patient had the sequelae of diabetes insipidus. CONCLUSION: Diagnosis of LCH should be based on synthetical analyses of clinical manifestations, features of imaging and histopathology. Surgical curettage, radiotherapy and chemotherapy are effective treatment regimens. The prognosis is generally good if the patient gets correct diagnosis and timely rational treatment. PMID- 24073579 TI - [Anatomical measurements and clinical applications through facial recess approach]. AB - OBJECTIVE: To provide the anatomic data for the correlated otologic microsurgery by the microdissection of temporal bone through facial recess approach. METHOD: Sixteen human temporal bones of eight adult cadaveric heads were dissected under surgical microscope through facial recess approach, and the relative anatomic structures were observed and measured, such as the bony entrance of facial recess approach, facial nerve, stapes, round window, round window niche, pyramidal eminence, cochleariform process, etc. The data were analyzed statistically. RESULT: The width of the bony entrance of facial recess approach was (2.94 +/- 0.32) mm, the height was (8.83 +/- 0.84) mm, the depth was (3.51 +/- 0.17) mm. The distances from stapes to tympanic segment of facial nerve, mastoid segment of facial nerve, round window, cochleariform process and anterior ligament of malleus were (1.38 +/- 0.21) mm, (6.94 +/- 0.47) mm, (3.60 +/- 0.55)mm, (2.23 +/- 0.33)mm, (4.93 +/- 0.61) mm, respectively. The distances from pyramidal eminence to tympanic segment of facial nerve, mastoid segment of facial nerve, round window, round window niche and cochleariform process were (1.05 +/- 0.09) mm, (5.63 +/- 0.41) mm, (3.01 +/- 0.34) mm, (3.29 +/- 0.44) mm, (4.13 +/- 0.51) mm, respectively. The distances from round window to cochleariform process and tympanic segment of facial nerve were (5.11 +/- 0.61) mm and (3.97 +/- 0.61) mm. The distances from round window niche to tympanic segment of facial nerve and mastoid segment of facial nerve were (4.13 +/- 0.38) mm and (7.28 +/- 0.29) mm. CONCLUSION: The facial recess approach played an important role in modern otologic microsurgery. The position of anatomical structure was constant relatively, including short crus of incus, stapes, pyramidal eminence and cochleariform process, etc. These could be used as reference marks for otologic microsurgery. PMID- 24073580 TI - [A study on the normal values of musical sounds in cochlear implants test battery]. AB - OBJECTIVE: To establish music reference values for normal-hearing (NH) person in China, in order to give convenience in clinical application. METHOD: The NH participant group included 39 subjects, of which 21 females and 18 males. Musical Sounds in Cochlear Implants test battery was used to assess the music perception ability for normal-hearing participants. RESULT: The median pitch difference NH participants could discriminate for string was 2.5 semitones and 0.5 for flute. The average scores of rhythm discrimination, melody discrimination, chord discrimination, instrument identification and instrument number detection test were 86.1% (SD = 11.2), 76.5% (SD = 11.1), 75.6% (SD = 11.4), 89.9% (SD = 13.0) and 74.1% (SD = 20.7), respectively. CONCLUSION: The MuSIC test could be a test for music perception ability for China users and in further study the material that more suited for our culture should be added into it. PMID- 24073581 TI - [Apoptosis of nasopharyngeal carcinoma cells line CNE-2 induced by dihydroartemisinin and its possible mechanism]. AB - OBJECTIVE: Dihydroartemisinin is a traditional anti-malarial drug, a derivative of the artemisinin, it has anti-tumor activity of a variety of tumor cells. This study investigated the effect of growth inhibition of nasopharyngeal carcinoma cells line CNE-2 induced by dihydroartemisinin and its possible mechanism. METHOD: The effect of DHA on the cell proliferation of CNE-2 was detected by CCK 8 assay with different concentrations and time. The effects of DHA on the cell apoptosis of CNE-2 were detected by Annexin V-FITC assay through flow cytometry and caspase-3 activity assay. RESULT: CCK-8 experimental results show that CNE-2 cell proliferation was suppressed with DHA treatment, as compared with the control group. DHA could induce marked apoptosis in CNE-2 by apoptosis assay, as compared with the control group, The percentages of apoptotic cells increased along with the increase of DHA concentrations in CNE-2; The activity of caspase-3 was increased following DHA treatment in a dose-dependent manner. CONCLUSION: DHA could effectively inhibit proliferation and induce apoptosis of human nasopharyngeal carcinoma cells line CNE-2, the possible mechanism DHA induce apoptosis of CNE-2 cells by upregulating the expression of caspase-3. PMID- 24073582 TI - [Efficacy observation of auditory reconstruction using three different materials in ossiculoplasty and mastoidectomy to treat chronic otitis media]. AB - OBJECTIVE: To study the effects of different types of prosthesis used in ossiculoplasty on mastoidectomy of treating chronic otitis media. METHOD: One hundred and forty three patients with chronic otitis media were treated by canal wall-down tympanoplasty with ossiculoplasty in a single stage. According to material of prosthesis, they were classified as titanium group (group A, 52 cases), hydroxypatite group (group B, 47 cases) and autogenous bone group(group C, 44 cases). The postoperative complication and hearing thresholds were analyzed in the 24 months follow-up. Average postoperative air-conduction gain and air bone gap were measured at four frequencies: 0.5, 1.0.2, and 4.0 kHz. RESULT: 12 month after operation, the average air threshold and air-bone gaps of the three groups were reduced (P < 0.05). The reconstruction successful rate (78.7%) of group A was slightly better than that of B, C (68.1%, 70.4%), there was no statistically significant difference. The difference of the average air threshold and air-bone gaps of group B, C after 24-month of operation and 12-month after operation was statistically significant (P < 0.05). The reconstruction successful rate (48.9%, 45.5%) of group B, C was lower than that of A (76.9%), the difference was also statistically significant (P < 0.05). CONCLUSION: Prostheses using titanium type could give good functional results and strong stability with low complication. PMID- 24073583 TI - [The correlation studies between recurrent otitis media and adenoid hypertrophy in children]. AB - OBJECTIVE: To investigate the relationship between the immune status of adenoids and secretory otitis media (SOM). METHOD: The adenoids tissue samples of 30 cases of recurrent secretory otitis media (SOM), 17 cases of non-recurrent secretory otitis media and 20 cases of the adenoids hypertrophy without SOM were studied by immunohistochemical method. RESULT: The expression of PCNA, BCL-2, CD4+, CD8+ cells and CD4+/CD8+ in recurrent SOM tissue were 30.85 +/- 1.73, 21.27 +/- 1.25, 41.90 +/- 9.07; 20.45 +/- 7.08 and 2.10 +/- 0.17, respectively, which was remarkably higher than those of non-recurrent SOM, (25.50 +/- 1.66, 14.23 +/- 1.06, 17.40 +/- 6.85, 13.02 +/- 5.88, 1.33 +/- 0.11, respectively) and those of simple adenoid hypertrophy (25.25 +/- 1.75, 14.05 +/- 1.02, 16.30 +/- 8.21, 11.15 +/- 5.71 and 1.39 +/- 0.15, respectively) (P < 0.01); the difference of the expression of PCNA, BCL-2, CD4+, CD8+ and CD4+/CD8+ between the latter two groups was not significant. Differences of the gender or the size were not significant (P > 0.05). In group of simple adenoid hypertrophy, PCNA in the subgroup of the age 3 to 6 was significantly higher than those in the other groups (P < 0.05). CONCLUSION: In adenoid tissues of recurrent SOM patients, the activities of T lymphocyte subsets cells in hypertrophic status increase, the adenoids enlarge and local immunity enhances. The age and gender have nothing to do with the SOM, but low age is one of the influencing factors of adenoid hypertrophy. Therefore, adenoidectomy for recurrent SOM patients with adenoid hypertrophy should be carried out as early as possible. PMID- 24073584 TI - [Through a postauricular approach canal wall flap fenestration inlay myringoplasty]. PMID- 24073585 TI - [The surgery efficacy and the observation and treatment of the complications of the elderly secretory otitis media]. PMID- 24073586 TI - [The operation effect of 156 cases with cholesteatoma otitis media]. PMID- 24073587 TI - [Comparison of the curative effect of two kinds of methods for T tube grommet insertion in the treatment of secretory otitis media]. PMID- 24073588 TI - [Ethmoid sinus foreign body long-term residence in one case]. AB - Ethmoid sinus foreign body can be divided into endogenous and exogenous, the clinically referred mostly belonging to the exogenous foreign body. The exogenous ethmoid sinus foreign body generally has a history of facial trauma, its clinical manifestations are associated with the foreign body size, nature, residence time and location. Using X-ray, CT scan can further confirm the diagnosis. Removing the ethmoid sinus foreign body may have a better therapeutic effect by endoscopic sinus surgery. Here we report a rare case of foreign body in the ethmoid sinus. PMID- 24073589 TI - [One case report: removal of foreign body in ethmoidal sinus-medial orbital wall through nose assisted by endoscope]. AB - The patient was male, 20 years old, and complained of pain, bleeding and decreased vision after the right eye was injured by nail for an hour. PHYSICAL EXAMINATION: right exophthalmos, conjunctival edema, skin laceration at the lower eyelid of right eye, limitation of eye movement, asymmetric eyes and weak light reflecting. X-ray showed: metallic foreign body shadow in the right orbit, 0.5 cm x 0.4 cm approximately. Orbit and paranasal sinus CT showed: 1 hematoma of the right eye and inside. 2 high density foreign body embedded in the bone wall of the inside of right orbit and ethmoid. 3 medial wall fracture of right eye orbit. 4 bilateral maxillary sinus and right ethmoidal sinus effusion. 5 slightly left side of nasal septum. The patient was initially diagnosed as foreign body in right ethmoidal sinus, skin laceration of right lower eyelid, retrobulbar hematoma. PMID- 24073590 TI - [A case of neuroglia choristoma in middle ear]. AB - A 14-year-old young man presented with a white oval mass on the right side of external auditory canal. PHYSICAL EXAMINATION: Under ear endoscope, a size of 0.6 cm x 0.8 cm x 0.6 cm, smooth and unmovable mass was on the right side of external auditory canal. In surgery, a cystic neoplasm which is connected to neoplasm of the external auditory canal by bone defect was found in aditus of drum sinus, and local bone defect in the back wall of drum sinus. Tympanic membrane and auditory ossicle chain is complete. Postoperative pathologic findings were consistent with neuroglia choristoma. The diagnosis mainly relied on the postoperative pathological findings. PMID- 24073591 TI - [Hearing and speech assessment of the hearing-impaired children with cochlear implantation]. PMID- 24073592 TI - Assessment of peeling of Astragalus roots using 1H NMR- and UPLC-MS-based metabolite profiling. AB - A metabolomic analysis was performed to examine the postharvest processing of Astragalus membranaceus roots with a focus on the peeling procedure using (1)H NMR and UPLC-MS analyses. Principal component analysis (PCA) score plots from the (1)H NMR and UPLC-MS data showed clear separation between peeled and unpeeled Astragalus roots. Peeled roots exhibited significant losses of several primary metabolites, including acetate, alanine, arginine, caprate, fumarate, glutamate, histidine, N-acetylaspartate, malate, proline, sucrose, trigonelline, and valine. In contrast, the peeled roots contained higher levels of asparagine, aspartate, and xylose, which are xylem-related compounds, and formate, which is produced in response to wound stress incurred during postharvest processing. In addition, the levels of isoflavonoids and astragalosides were significantly reduced in peeled Astragalus root. These results demonstrate that metabolite profiling based on a combination of (1)H NMR and UPLC-MS analyses can be used to evaluate peeling procedures used in the postharvest processing of herbal medicines. PMID- 24073593 TI - Fab-PEG-Fab as a potential antibody mimetic. AB - IgG antibodies have evolved to be flexible so that they can bind to epitopes located over a wide spatial range. The two Fabs in an IgG antibody are linked together as if each Fab is at the end of a linear, flexible molecule. PEG was used as a scaffold molecule to link two Fabs together to give Fab-PEG-Fab molecules, or FpFs. Preparation of FpFs was achieved with reagents that undergo site-specific conjugation at each PEG terminus by bis-alkylation with the two cysteine thiols from a disulfide bond. This allowed each Fab to be conjugated to the PEG scaffold in essentially the same region that each Fab is linked in an IgG. Fabs were sourced directly (e.g., ranibizumab) or monoclonal IgG antibodies were proteolytically digested to obtain the Fabs. This allowed the resulting FpFs to be directly compared to parent IgGs. PEG scaffolds of 6, 10, and 20 kDa were used to make the corresponding FpFs. Dynamic light scatting data suggested the resulting FpFs were similar in size to an IgG antibody and about half the size of a 20 kDa PEGylated-Fab. The solution size of PEG-conjugated proteins is known to be dominated by the extended solution structure of PEG, so it is thought that the smaller size of the FpFs is due to interactions between the two Fabs. Anti-VEGF and anti-Her2 FpFs were prepared and evaluated. The FpFs displayed similar apparent affinities to their parent IgGs. Slower dissociation rates were observed for the anti-VEGF FpFs compared to bevacizumab. The anti-VEGF FpFs also displayed in vitro anti-angiogenic properties comparable to or better than bevacizumab. These first studies indicate that FpFs warrant further examination in a therapeutic indication where the presence of the Fc may not be required. PMID- 24073594 TI - Capture of an elusive nitrile ylide as an intermediate in isoxazole-oxazole photoisomerization. AB - The unimolecular photochemistry of 3,5-dimethylisoxazole (1) induced by a narrow band tunable UV laser was studied using low-temperature matrix isolation coupled with infrared spectroscopy. Monomers of 1 were isolated in argon matrices at 15 K and characterized spectroscopically. Irradiation of matrix-isolated 1 at lambda = 222 nm (near its absorption maximum) led to the corresponding 2H-azirine 3 and ketenimine 6 as primary photoproducts and also to nitrile ylide 4 and 2,5 dimethyloxazole (5). The photoproducts were identified (i) by comparison with infrared spectra of authentic matrix-isolated samples of 3 and 5 and (ii) using additional irradiations at longer wavelengths (where 1 does not react) which induce selective photoisomerizations of 4 and 6. In particular, irradiation with lambda = 340 nm led to the unequivocal identification of the nitrile ylide anti 4, which was transformed into oxazole 5. The details of the 1,5 electrocyclization of the carbonyl nitrile ylide 4 and its structural nature (propargyl-like versus allene-like geometry) were also characterized using theoretical calculations. Thus, the elusive carbonyl nitrile ylide 4 was captured and characterized for the first time as an intermediate in the isoxazole-oxazole photoisomerization. PMID- 24073595 TI - Easing the transition of HIV-infected adolescents to adult care. AB - The past two decades have witnessed dramatic reductions in HIV-related morbidity and mortality following the introduction of combination antiretroviral therapy (cART) for infants and children. Improved therapeutic outcomes have changed the face of the HIV epidemic and with it the needs of patients and families. Consequently, many perinatally- and behaviorally-infected adolescents are now transitioning to adult care. What follows is a brief review and commentary concerning original research, reviews, and clinical guidelines describing challenges and best practices in facilitating care transitions for HIV-infected youth to adult care. Over 25,000 HIV-infected US youth aged 13-24 years will require transition to adult care within the next decade. Transition planning must address issues of cognitive development and mental health, medication adherence, sexuality, reproductive, and gender identity, socioeconomic and health insurance status, stigma and disclosure, disrupted relationships with pediatric care providers, and communication. Clinical experience with HIV and other chronic illnesses supports a multidisciplinary, developmentally-sensitive approach to meeting the challenges inherent in care transition that begins early and is monitored with regular evaluation and revision. Specific clinical recommendations have been made by the U.S. Department of Health and Human Services and the New York State Department of Health AIDS Institute. PMID- 24073596 TI - Photocatalytic reduction of artificial and natural nucleotide co-factors with a chlorophyll-like tin-dihydroporphyrin sensitizer. AB - An efficient photocatalytic two-electron reduction and protonation of nicotine amide adenine dinucleotide (NAD(+)), as well as the synthetic nucleotide co factor analogue N-benzyl-3-carbamoyl-pyridinium (BNAD(+)), powered by photons in the long-wavelength region of visible light (lambdairr > 610 nm), is demonstrated for the first time. This functional artificial photosynthetic counterpart of the complete energy-trapping and solar-to-fuel conversion primary processes occurring in natural photosystem I (PS I) is achieved with a robust water-soluble tin(IV) complex of meso-tetrakis(N-methylpyridinium)-chlorin acting as the light harvesting sensitizer (threshold wavelength of lambdathr = 660 nm). In buffered aqueous solution, this chlorophyll-like compound photocatalytically recycles a rhodium hydride complex of the type [Cp*Rh(bpy)H](+), which is able to mediate regioselective hydride transfer processes. Different one- and two-electron donors are tested for the reductive quenching of the irradiated tin complex to initiate the secondary dark reactions leading to nucleotide co-factor reduction. Very promising conversion efficiencies, quantum yields, and excellent photosensitizer stabilities are observed. As an example of a catalytic dark reaction utilizing the reduction equivalents of accumulated NADH, an enzymatic process for the selective transformation of aldehydes with alcohol dehydrogenase (ADH) coupled to the primary photoreactions of the system is also demonstrated. A tentative reaction mechanism for the transfer of two electrons and one proton from the reductively quenched tin chlorin sensitizer to the rhodium co-catalyst, acting as a reversible hydride carrier, is proposed. PMID- 24073597 TI - X-linked Megalocornea Associated with the Novel CHRDL1 Gene Mutation p.(Pro56Leu*8). AB - BACKGROUND: The genetic basis of X-linked megalocornea (MGC1) was reported in 2012 to be caused by mutations in the CHRDL1 gene. We sought to confirm that mutations in CHRDL1 are associated with MGC1 in a previously unreported pedigree. MATERIALS AND METHODS: Slit lamp examination, corneal pachymetry, corneal topography and DNA collection for screening of the CHRDL1 gene were performed for members of an affected family. RESULTS: Examination of a woman and her four sons, ranging in age between 3 and 15 years, demonstrated horizontal corneal diameters of 14 mm in three of the four sons and a normal corneal diameter of 12 mm in the mother and other son. Central corneal thickness in the individuals with enlarged corneal diameters averaged 474 microns, compared to 604 microns in their unaffected brother. Corneal topographic imaging demonstrated an average K value of 44.4 D in the affected individuals compared with 41.6 D in their unaffected sibling. Screening of the CHRDL1 gene demonstrated the novel hemizygous frameshift mutation c.167delC (p.(Pro56Leu*8)) in exon 3 in the affected individuals and in the heterozygous state in their mother. This mutation was not present in the unaffected brother or in unrelated controls. CONCLUSION: We provide the initial confirmation that X-linked megalocornea is associated with mutations in the CHRDL1 gene. PMID- 24073598 TI - Neurodegenerative Genes Polymorphisms of the -491A/T APOE, the -877T/C APP and the Risk of Primary Open-angle Glaucoma in the Polish Population. AB - BACKGROUND: Glaucoma is characterized by optic neuropathy of the retinal ganglion cell. It may be possible that beta-amyloid (Abeta) and apolipoprotein E (APOE), the main proteins of the pathogenesis of AD, play a role in glaucoma development. The aim of this study was to evaluate a relationship between the APP and APOE gene polymorphisms and the risk of primary open-angle glaucoma (POAG) occurrence. MATERIALS AND METHODS: The study consisted of 183 patients with POAG and 209 healthy subjects. Genomic DNA was extracted from peripheral blood. Analysis of the gene polymorphisms was performed using PCR-RFLP. RESULTS: We found a statistically significant increase of the -491 T allele frequency (p=0.02; OR=1.48; 95% CI=1.06-2.08) of APOE in POAG compared to healthy controls. There were no differences in the genotype and allele distributions and odds ratios of the APP polymorphism between patients and controls group. We also found an association between APOE polymorphic variant and retinal nerve fiber layer (RNFL). There was a statistically significant difference in the APOE gene A/T genotype frequency in the early POAG stage and middle-advanced POAG stage in comparison to the advanced POAG stage (p=0.04; OR=3.38; 95% CI=1.04-10.97). CONCLUSIONS: The -491 T allele of APOE polymorphism may be associated with a risk of POAG occurrence in the Polish population. PMID- 24073599 TI - Photoelectrochemical detection of glutathione by IrO2-hemin-TiO2 nanowire arrays. AB - We have developed sensitive detection of glutathione using the IrO2-hemin-TiO2 nanowire arrays. Single-crystalline TiO2 nanowires are synthesized by a hydrothermal reaction, followed by surface functionalization of ~3 nm thick hemin and ~1-2 nm diameter IrO2 nanoparticles. The IrO2-hemin-TiO2 nanowire arrays offer much enhanced photocurrent with ~100% increase compared to the pristine TiO2 nanowires and allow for label-free, real-time, sensitive photoelectrochemical detection of glutathione. The sensitivity achieved is ~10 nM in buffer, comparable to or better than most of the existing glutathione detection methods. Furthermore, cell extracts containing glutathione are robustly detected, with ~8000 cells/mL for HeLa cells and ~5000 cells/mL for human embryonic kidney 293T cells. This nanowire PEC sensor assay exhibits excellent selectivity and stability, suggesting a potential detection platform for analyzing the glutathione level in biosamples. PMID- 24073600 TI - Therapeutic potential of gossypol: an overview. AB - CONTEXT: Polyphenols are naturally occurring compounds found in fruits, vegetables, cereals, and beverages. Polyphenols occupy a unique place in biological science for their pharmacological properties. Gossypol is a polyphenolic compound that has attracted attention because of its biological effects. OBJECTIVE: Gossypol is reported to exhibit antifertility, antioxidant, anticancer, antivirus, antiparasitic, and antimicrobial properties and lower plasma cholesterol. These are summarized with attention to the mechanisms of activity. METHODS: This review summarizes the results of studies obtained in a comprehensive search of ScienceDirect, PubMed, Scirus, and Web of Science. RESULTS AND CONCLUSION: The results of these studies provide a comprehensive understanding of the biological action of gossypol and its potential for the prevention of and therapy for resistant tumors and chronic human diseases such as HIV, malaria, and psoriasis. PMID- 24073601 TI - Increased expression of c-Fos, c-Jun and c-Jun N-terminal kinase associated with neuronal cell death in retinas of diabetic patients. AB - PURPOSE: To examine whether c-Fos, phosphorylated c-Jun (p-c-Jun), members of transcriptional factor activator protein 1 (AP-1) family and phosphorylated c-Jun N-terminal kinase (p-JNK) are associated with neuronal degeneration in retinas of diabetic patients. MATERIALS AND METHODS: Retinal cryosections from five pairs of normal and five pairs of diabetic human eyes were immunostained for c-Fos, p-c Jun and p-JNK followed by costaining with Fluoro-Jade B (FJB), a marker for identifying degenerative neurons. Additionally, cells were stained with 4, 6 diamidino-2-phenyl indole (DAPI) to facilitate counting the total number of cells. The number of c-Fos, p-c-Jun and p-JNK positive cells costained with FJB was assessed in the ganglion cell layer (GCL) together with the total number of DAPI-positive cells. RESULTS: The number of FJB-positive cells in the GCL of diabetic retinas was significantly increased compared to those of non-diabetic retinas. The GCL of diabetic retinas, compared to those of the non-diabetic retinas, showed increased number of c-Fos, p-c-Jun and p-JNK-positive cells that coexisted with FJB-positive signals. CONCLUSIONS: This study indicates that increased expression of c-Fos, p-c-Jun, members of AP-1 transcriptional factor and p-JNK is associated with neuronal degeneration in the GCL of retinas in diabetic patients. PMID- 24073602 TI - Novel therapeutic approaches to chronic kidney disease. PMID- 24073603 TI - Global research integrity in relation to the United States' research-integrity infrastructure. AB - Recent global attention to research integrity has led to international meetings and the development of international policies and guidelines. The United States's infrastructure for fostering research integrity (policy, instruction, oversight) has usefully supported these international initiatives. The United States cannot and should not, however, expect other national and global systems to match exactly its approach to research integrity. PMID- 24073604 TI - Evaluating U.S. medical schools' efforts to educate faculty researchers on research integrity and research misconduct policies and procedures. AB - This paper examines how well U.S. medical school institutions are doing to promote research integrity. It is an important question to ask in order to determine whether there are sufficient and adequate protections in place to protect the U.S. Public Health Service's (PHS) resources devoted to medical research. This paper focuses on 5,100 medical school researchers' knowledge of what constitutes research misconduct as well as their willingness to report it to the research integrity officer (RIO) and educate their Ph.D. trainees. We learned that 5.6% of researchers could correctly distinguish seven or more of the nine scenarios that depicted likely research misconduct, as defined by the PHS regulations, from scenarios describing other ethical issues. Instead, researchers had expansive definitions and often inappropriately identified infractions such as conflicts of interest, Institutional Review Board (IRB) violations, and other breaches in ethical standards to be research misconduct. In addition, researchers who correctly identified four instances of likely research misconduct in the test items were highly unlikely to report their observations to a RIO. Researchers also provided insight on the factors they believe influence their decision making process of whether to report research misconduct. In addition, this paper also reports on the guidance that faculty said they provided their trainees on research misconduct issues. We conclude with a discussion and recommendations on what institutional leaders might consider doing in order to enhance their research integrity efforts and protect their institution's reputation. PMID- 24073605 TI - Articulating a role for program evaluation in responsible conduct of research programs. AB - Since Integrity in Scientific Research: Creating an Environment That Promotes Responsible Conduct was released in 2001, there has been increased interest in evaluating programs designed to foster the responsible conduct of research (RCR). The field of program evaluation is designed to determine the worth or value of programs and can serve as a resource for institutions interested in evaluating their RCR programs. This article provides a very brief overview of program evaluation, demonstrates how it can be applied to RCR, and provides key reference information. Evaluating RCR programs can promote institutional accountability for the resources that are used in supporting those programs. PMID- 24073606 TI - Team-based learning instruction for responsible conduct of research positively impacts ethical decision-making. AB - Common practices for responsible conduct of research (RCR) instruction have recently been shown to have no positive impact on and possibly to undermine ethical decision-making (EDM). We show that a team-based learning (TBL) RCR curriculum results in some gains in decision ethicality, the use of more helpful metacognitive reasoning strategies in decision-making, and elimination of most negative effects of other forms of RCR instruction on social-behavioral responses. TBL supports the reasoning strategies and social mechanisms that underlie EDM and ethics instruction, and may provide a more effective method for RCR instruction than lectures and small group discussion. PMID- 24073607 TI - A systematic approach to instruction in research ethics. AB - This article describes a systematic approach for developing instructional programs that emphasizes defining learning needs, planning the learning environment, and evaluating learning to ensure continuous course improvement. This review outlines the nature of these interrelated components of instructional development and draws attention to issues specific to instruction in research ethics. Guiding questions summarize key, practical considerations, and the discussion suggests future steps in the pursuit of effective instruction in research ethics. Overall, the variety of approaches to instruction and mixed findings regarding its effectiveness underscore the need to apply a systematic framework to instruction in research ethics. PMID- 24073608 TI - Rescuing responsible conduct of research (RCR) education. AB - Responsible conduct of research (RCR) education requirements, resources, and research have proliferated over the past twenty years, but evidence and experience highlight shortcomings in many domains: goals, audience, content, teaching tools, use of the Internet for instruction, instructors, allocation of responsibility for education, education requirements, and sources of funding. Revised approaches and suggested roles and responsibilities are proposed to meet these challenges. The unifying theme for these recommendations is to shift the focus from RCR education to RCR culture building. PMID- 24073609 TI - Differences in proliferative capacity of primary human acute myelogenous leukaemia cells are associated with altered gene expression profiles and can be used for subclassification of patients. AB - OBJECTIVES: Proliferative capacity of acute myelogenous leukaemia (AML) blasts is important for leukaemogenesis, and we have investigated whether proliferative capacity of primary human AML cells could be used for subclassification of patients. MATERIALS AND METHODS: In vitro proliferative capacity of AML cells derived from two independent groups was investigated. Cells were cultured under highly standardized conditions and proliferation assayed by (3) H-thymidine incorporation after seven days culture. Patients were subclassified by clustering models, and gene expression profile was examined by microarray analyses. RESULTS: Based on proliferative capacity of the AML cells, three different patient clusters were identified: (i) autocrine proliferation that was increased by exogenous cytokines; (ii) detectable proliferation only in presence of exogenous cytokines; and (iii) low or undetectable proliferation even in presence of exogenous cytokines. Patients with highest proliferative capacity cells had no favourable prognostic impact by NPM-1 mutation. Analysis of gene expression profiles showed that the most proliferative cells generally had altered expression of genes involved in regulation of transcription/RNA functions, whereas patients with high proliferative capacity and internal tandem duplications (ITDs) in the FLT3 cytokine receptor gene had altered expression of several molecules involved in cytoplasmic signal transduction. CONCLUSIONS: In vitro proliferative capacity of primary human AML cells was considerably variable between patients and could be used to identify biologically distinct patient subsets. PMID- 24073610 TI - Patient-centered outcomes and trials of hydroxyethyl starch. PMID- 24073611 TI - Branched polyethylenimine-based PKCalpha-responsive gene carriers. AB - We examined in vitro performance of the branched polyethylenimine (bPEI)-based gene carriers which respond to cancer-specific activation of protein kinase Calpha (PKCalpha) to express plasmid DNA. The carriers were synthesized straightforward by using amide bond formation between a peptide terminal carboxyl and a primary amine group of bPEI. To examine the effect of the peptide contents in the carrier, we prepared several carriers with various peptide contents. The obtained polymers form polyplexes with tighter condensation of plasmid DNA than our previous gene carriers. After internalization of the polyplexes via endocytosis, the polyplexes effectively escaped from the endosome into cytosol. Then, the polyplexes showed a clear-cut response to PKCalpha to release plasmid DNA for gene expression. We determined the optimum contents of the peptides in carriers as 5 mol% to achieve the clear-cut response to PKCalpha. PMID- 24073612 TI - Supramolecular elastomer based on polydimethylsiloxanes (SESi) film: synthesis, characterization, biocompatibility, and its application in the context of wound dressing. AB - Supramolecular elastomer based on polydimethylsiloxanes (SESi) is a kind of novel elastomer cross-linked by the multihydrogen bonds supplied by the functional groups linked to the end of the PDMS chains, such as amide, imidazolidone, pending urea (1,1-dialkyl urea), and bridging urea (1,3-dialkyl urea). SESi showed lower glass transition temperature (T g) at about -113 degrees C because of the softer chain of PDMS, and could show real rubber-like elastic behaviors and acceptable water vapor transmission rate under room temperature. The high biocompatibility of SESi in the form of films was demonstrated by the cytotoxicity evaluation (MTT cytotoxicity assay and direct contact assay), hemolysis assay, and skin irritation evaluation. Based on detailed comparisons between commercial Tegaderm(TM) film and SESi film using a full-thickness rat skin model experiment, it was found that SESi film showed similar wound contraction rate as that of Tegaderm(TM) film on day seven, 10, and 14; only on day five, SESi film showed a significant (p < 0.05) lower wound contraction rate. And, the wounds covered with SESi film were filled with new epithelium without any significant adverse reactions, similar with that of Tegaderm(TM) film. PMID- 24073613 TI - Risk factors for Clostridium difficile infection in the community: a case-control study in patients in general practice, Denmark, 2009-2011. AB - To identify risk factors for Clostridium difficile infection (CDI) in Danish patients consulting general practice with gastrointestinal symptoms, a prospective matched case-control study was performed; cases (N = 259) had positive cultures for toxigenic C. difficile and controls (N = 455) negative cultures. Data were analysed by conditional logistic regression. In patients aged ?2 years (138 cases), hospitalization [odds ratio (OR) 8.4, 95% confidence interval (CI) 3.1-23], consumption of beef (OR 5.5, 95% CI 2.0-15), phenoxymethylpenicillin (OR 15, 95% CI 2.7-82), dicloxacillin (OR 27, 95% CI 3.6 211), and extended spectrum penicillins (OR 9.2, 95% CI 1.9-45) were associated with CDI. In patients aged <2 years none of these were associated with CDI, but in a subgroup analysis contact with animals was associated with CDI (OR 8.1, 95% CI 1.0-64). This study emphasizes narrow-spectrum penicillins, and suggests beef consumption, as risk factors for CDI in adults, and indicates a different epidemiology of CDI in infants. PMID- 24073614 TI - Supine or prone percutaneous nephrolithotomy: do anatomical changes make it worse? AB - PURPOSE: To evaluate the different anatomical properties and determine the risk of visceral organ injury in supine, prone, and prone-flex positions. MATERIALS AND METHODS: A total of 30 patients with renal stones >2 cm were included. A dose reduced abdominopelvic tomography in a supine, prone, and 30 degrees prone-flex position was performed. The access tract length, subcutaneous tissue length, nearest organ distance, maximum access angle, access field, and the degree of renal displacement were measured in axial and coronal images. The parameters were analyzed by the paired t-test and Wilcoxon signed test according to normalcy analysis. RESULTS: The mean tract lengths and the subcutaneous fat tissue lengths in the lower, middle, and upper poles of kidney were significantly longer in the supine position. The significance of access tract lengths had disappeared when we subtracted the subcutaneous fat tissue length from the whole tract length, exhibiting that the main determinant of tract length was subcutaneous tissue thickness. The maximum access angles were 96.7+/-22.0 degrees , 94.2+/-23.6 degrees , and 89.1+/-23.9 degrees in the supine, prone, and prone-flex position, respectively (p>0.05). The access field was shorter in the supine (80.8+/-13.3 mm) than prone (86.3+/-15.0 mm) and prone-flex (86.7+/-18.4 mm) position (p<0.001). The nearest organ distance to access tract was similar between the supine and prone position in every pole of kidney. CONCLUSIONS: The anatomical changes related to supine positioning does not increase the risk of percutaneous nephrolithotomy (PCNL) complications. Although supine PCNL may have some benefits over prone PCNL, there will also be some technical difficulties related to the surgeon's manipulations, which are related with the longer access tract and more limited access field. PMID- 24073615 TI - Towards a methodology for cluster searching to provide conceptual and contextual "richness" for systematic reviews of complex interventions: case study (CLUSTER). AB - BACKGROUND: Systematic review methodologies can be harnessed to help researchers to understand and explain how complex interventions may work. Typically, when reviewing complex interventions, a review team will seek to understand the theories that underpin an intervention and the specific context for that intervention. A single published report from a research project does not typically contain this required level of detail. A review team may find it more useful to examine a "study cluster"; a group of related papers that explore and explain various features of a single project and thus supply necessary detail relating to theory and/or context.We sought to conduct a preliminary investigation, from a single case study review, of techniques required to identify a cluster of related research reports, to document the yield from such methods, and to outline a systematic methodology for cluster searching. METHODS: In a systematic review of community engagement we identified a relevant project - the Gay Men's Task Force. From a single "key pearl citation" we conducted a series of related searches to find contextually or theoretically proximate documents. We followed up Citations, traced Lead authors, identified Unpublished materials, searched Google Scholar, tracked Theories, undertook ancestry searching for Early examples and followed up Related projects (embodied in the CLUSTER mnemonic). RESULTS: Our structured, formalised procedure for cluster searching identified useful reports that are not typically identified from topic based searches on bibliographic databases. Items previously rejected by an initial sift were subsequently found to inform our understanding of underpinning theory (for example Diffusion of Innovations Theory), context or both. Relevant material included book chapters, a Web-based process evaluation, and peer reviewed reports of projects sharing a common ancestry. We used these reports to understand the context for the intervention and to explore explanations for its relative lack of success. Additional data helped us to challenge simplistic assumptions on the homogeneity of the target population. CONCLUSIONS: A single case study suggests the potential utility of cluster searching, particularly for reviews that depend on an understanding of context, e.g. realist synthesis. The methodology is transparent, explicit and reproducible. There is no reason to believe that cluster searching is not generalizable to other review topics. Further research should examine the contribution of the methodology beyond improved yield, to the final synthesis and interpretation, possibly by utilizing qualitative sensitivity analysis. PMID- 24073617 TI - Four issues in undernutrition-related health impact modeling. AB - Undernutrition modeling makes it possible to evaluate the potential impact of such events as a food-price shock or harvest failure on the prevalence and severity of undernutrition. There are, however, uncertainties in such modeling. In this paper we discuss four methodological issues pertinent to impact estimation: (1) the conventional emphasis on energy intake rather than dietary quality; (2) the importance of the distribution of nutrient intakes; (3) the timing of both the 'food shock' and when the response is assessed; and (4) catch up growth and risk accumulation. PMID- 24073618 TI - Latency can be conferred to a variety of cytokines by fusion with latency associated peptide from TGF-beta. AB - OBJECTIVES: Targeting cytokines to sites of disease has clear advantages because it increases their therapeutic index. We designed fusion proteins of the latent associated peptide (LAP) derived from TGF-beta with various cytokines via a matrix metalloproteinase (MMP) cleavage site. This design confers latency, increased half-life and targeting to sites of inflammation. The aim of this study is to determine whether this approach can be applied to cytokines of different molecular structures and sizes. METHODS: Mature cytokines cloned downstream of LAP and a MMP cleavage site were expressed in 293T cells and assessed for latency and biological activity by Western blotting and bioassay. RESULTS: We demonstrate here that fusion proteins of TGF-beta, erythropoietin, IL-1ra, IL-10, IL-4, BMP 7, IGF1 and IL-17 were rendered latent by fusion to LAP, requiring cleavage to become active in respective bioassays. As further proof of principle, we also show that delivery of engineered TGF-beta can inhibit experimental autoimmune encephalomyelitis and that this approach can be used to efficiently deliver cytokines to the brain and spinal cord in mice with this disease. CONCLUSIONS: The latent cytokine approach can be successfully applied to a range of molecules, including cytokines of different molecular structure and mass, growth factors and a cytokine antagonist. PMID- 24073621 TI - Eyes on new product development. PMID- 24073620 TI - House calls by community health workers and public health nurses to improve adherence to isoniazid monotherapy for latent tuberculosis infection: a retrospective study. AB - BACKGROUND: Patient adherence to isoniazid (INH) monotherapy for latent tuberculosis infection (LTBI) has been suboptimal despite its proven efficacy. Various strategies have been studied to improve adherence, but all have been based at a clinic or treatment program. At the Santa Clara Valley Tuberculosis Clinic, it was our practice to refer a subset of high-risk LTBI patients to the Public Health Department for monthly follow-up at home instead of at the clinic. Our goal was to assess whether house calls by community health workers and public health nurses affected INH adherence or frequency of adverse effects. METHODS: We retrospectively studied 3918 LTBI patients who received INH. At the discretion of the treating physician, 986 (25.2%) received house calls instead of clinic follow up. Home-based follow-up included language translation, medication delivery, assessment of compliance with pill counts, monitoring for adverse effects, and active tracking of noncompliant patients. We assessed differences in patient characteristics, treatment completion, and reasons for treatment discontinuation between patients followed at home versus in the clinic. Multivariate analyses to address possible referral bias or confounding were performed using logistic regression. RESULTS: More patients followed with house calls completed INH treatment (90% home versus 73.2% clinic). This was the case across all subgroups of patients, including those with historically the lowest adherence: patients from correctional and rehabilitation facilities (77.8% home versus 46.9% clinic), postpartum women (86.4% home versus 55.6% clinic), and patients aged between 18 and 35 years (87% home versus 63.1% clinic). After adjusting for age, place of birth, referral category (TB contacts/skin test converters, correctional/rehabilitation patients, postpartum women, tuberculin positive patients from other screening), and prescribed INH regimen duration (9 versus 6 months), home-based follow-up of LTBI patients was a significant predictor of treatment completion (AOR 2.94, 95% CI: 2.33, 3.71). Patients followed at home were 21% more likely to complete therapy (ARR 1.21, p<0.001). Risk of adverse effects was similar between the two types of follow-up. CONCLUSION: Home-based follow-up of LTBI patients taking isoniazid was associated with improved treatment completion and no increase in adverse effects regardless of patient characteristics or prescribed duration of INH therapy. PMID- 24073624 TI - Validation of reference genes for normalization of qPCR gene expression data from Coffea spp. hypocotyls inoculated with Colletotrichum kahawae. AB - BACKGROUND: Coffee production in Africa represents a significant share of the total export revenues and influences the lives of millions of people, yet severe socio-economic repercussions are annually felt in result of the overall losses caused by the coffee berry disease (CBD). This quarantine disease is caused by the fungus Colletotrichum kahawae Waller and Bridge, which remains one of the most devastating threats to Coffea arabica production in Africa at high altitude, and its dispersal to Latin America and Asia represents a serious concern. Understanding the molecular genetic basis of coffee resistance to this disease is of high priority to support breeding strategies. Selection and validation of suitable reference genes presenting stable expression in the system studied is the first step to engage studies of gene expression profiling. RESULTS: In this study, a set of ten genes (S24, 14-3-3, RPL7, GAPDH, UBQ9, VATP16, SAND, UQCC, IDE and beta-Tub9) was evaluated to identify reference genes during the first hours of interaction (12, 48 and 72 hpi) between resistant and susceptible coffee genotypes and C. kahawae. Three analyses were done for the selection of these genes considering the entire dataset and the two genotypes (resistant and susceptible), separately. The three statistical methods applied GeNorm, NormFinder, and BestKeeper, allowed identifying IDE as one of the most stable genes for all datasets analysed, and in contrast GADPH and UBQ9 as the least stable ones. In addition, the expression of two defense-related transcripts, encoding for a receptor like kinase and a pathogenesis related protein 10, were used to validate the reference genes selected. CONCLUSION: Taken together, our results provide guidelines for reference gene(s) selection towards a more accurate and widespread use of qPCR to study the interaction between Coffea spp. and C. kahawae. PMID- 24073625 TI - Performance-based financing as a health system reform: mapping the key dimensions for monitoring and evaluation. AB - BACKGROUND: Performance-based financing is increasingly being applied in a variety of contexts, with the expectation that it can improve the performance of health systems. However, while there is a growing literature on implementation issues and effects on outputs, there has been relatively little focus on interactions between PBF and health systems and how these should be studied. This paper aims to contribute to filling that gap by developing a framework for assessing the interactions between PBF and health systems, focusing on low and middle income countries. In doing so, it elaborates a general framework for monitoring and evaluating health system reforms in general. METHODS: This paper is based on an exploratory literature review and on the work of a group of academics and PBF practitioners. The group developed ideas for the monitoring and evaluation framework through exchange of emails and working documents. Ideas were further refined through discussion at the Health Systems Research symposium in Beijing in October 2012, through comments from members of the online PBF Community of Practice and Beijing participants, and through discussion with PBF experts in Bergen in June 2013. RESULTS: The paper starts with a discussion of definitions, to clarify the core concept of PBF and how the different terms are used. It then develops a framework for monitoring its interactions with the health system, structured around five domains of context, the development process, design, implementation and effects. Some of the key questions for monitoring and evaluation are highlighted, and a systematic approach to monitoring effects proposed, structured according to the health system pillars, but also according to inputs, processes and outputs. CONCLUSIONS: The paper lays out a broad framework within which indicators can be prioritised for monitoring and evaluation of PBF or other health system reforms. It highlights the dynamic linkages between the domains and the different pillars. All of these are also framed within inter-sectoral and wider societal contexts. It highlights the importance of differentiating short term and long term effects, and also effects (intended and unintended) at different levels of the health system, and for different sectors and areas of the country. Outstanding work will include using and refining the framework and agreeing on the most important hypotheses to test using it, in relation to PBF but also other purchasing and provider payment reforms, as well as appropriate research methods to use for this task. PMID- 24073626 TI - Phenolic ester mediated oligopeptide synthesis promoted by HOBt. AB - Although substituted phenolic ester mediated peptide synthesis is an efficient and well established method, the same via totally unsubstituted phenyl ester is not preferred due to the extremely slow rate of aminolysis. We have investigated the scope of the unsubstituted phenyl ester as an intermediate in peptide bond formation and found that it may be useful for the design of chemoselective peptide ligation when HOBt is used as an acyl transfer catalyst. The scope of HOBt catalyzed, oxo ester mediated ligation is explored for the synthesis of oligopeptides containing a cysteine, serine and threonine at the N-terminus of the ligating peptide. PMID- 24073627 TI - Kinetics of furan formation from ascorbic acid during heating under reducing and oxidizing conditions. AB - This study aimed to investigate the effect of oxidizing and reducing agents on the formation of furan through ascorbic acid (AA) degradation during heating at elevated temperatures (>=100 degrees C) under low moisture conditions. To obtain these conditions, oxidizing agent, ferric chloride (Fe), or reducing agent, cysteine (Cys), was added to reaction medium. Kinetic constants, estimated by multiresponse modeling, stated that adding Fe significantly increased furan formation rate constant, namely 369-fold higher than that of control model at 100 degrees C. Rate-limiting step of furan formation was found as the reversible reaction step between intermediate (Int) and diketogluconic acid (DKG). Additionally, Fe decreased activation energy of AA dehydration and furan formation steps by 28.6% and 60.9%, respectively. Results of this study are important for heated foods, fortified by ferric ions and vitamins, which targets specific consumers, e.g. infant formulations. PMID- 24073628 TI - Super-resolution mbPAINT for optical localization of single-stranded DNA. AB - We demonstrate the application of superlocalization microscopy to identify sequence-specific portions of single-stranded DNA (ssDNA) with sequence resolution of 50 nucleotides, corresponding to a spatial resolution of 30 nm. Super-resolution imaging was achieved using a variation of a single-molecule localization method, termed as "motion blur" point accumulation for imaging in nanoscale topography (mbPAINT). The target ssDNA molecules were immobilized on the substrate. Short, dye-labeled, and complementary ssDNA molecules stochastically bound to the target ssDNA, with repeated binding events allowing super-resolution. Sequence specificity was demonstrated via the use of a control, noncomplementary probe. The results support the possibility of employing relatively inexpensive short ssDNAs to identify gene sequence specificity with improved resolution in comparison to the existing methods. PMID- 24073629 TI - Genetic incorporation of a 2-naphthol group into proteins for site-specific azo coupling. AB - The 2-naphthol analogue of tyrosine, 2-amino-3-(6-hydroxy-2-naphthyl)propanoic acid (NpOH), has been genetically introduced into proteins in Escherichia coli . This is achieved through the directed evolution of orthogonal aminoacyl-tRNA synthetase/tRNA pairs that selectively charge the target amino acid in response to the amber stop codon, UAG. Moreover, chemoselective azo coupling reactions have been revealed between the 2-naphthol group and diazotized aniline derivatives that are substituted with an electron donating moiety. The coupling reactions required a very mild condition (pH 7) with great reaction rate (less than 2 h at 0 degrees C), high efficiency, and excellent selectivity. PMID- 24073630 TI - Cytotoxic properties of sunitinib and sorafenib on human corneal epithelial cells. AB - PURPOSE: To generate toxicology profiles of individual drugs on human corneal epithelial cells (HCEC) and compare their in vitro cytotoxicity. METHODS: Monolayer cultures of HCEC were harvested from two human donor eyes. Sunitinib (0.3-10 ug/mL) and Sorafenib (0.3-100 ug/mL), diluted in culture medium (CnT BM.1, CELLnTEC Advanced Cell Systems AG, Bern, Switzerland), 1% Penicillin and 1% Streptomycin were added to cells that were being grown in cell culture dishes. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was performed 24 hours, three days and five days after incubation. Live/dead viability/cytotoxicity assay (Live/dead assay) was performed and analyzed using fluorescence microscopy after 24 hours of incubation. The expression of p63, ABCG2 and PDGFRbeta was evaluated by immunocytochemistry prior to exposure. Cell morphology was assessed with a phase contrast microscope after 24 hours of exposure. RESULTS: Significant toxicity of Sunitinib was seen at concentrations of >3.3 ug/mL and of Sorafenib at concentrations of >1.0 ug/mL after 24 hours of incubation. Both drugs exhibited increasing toxicities over time. HCEC stained positively for p63, ABCG2 and PDGFRbeta. In comparison, the IC50 (inhibitory concentration 50) of Sorafenib was 2.26 times the IC50 of Sunitinib using Live/dead assay after 24 hours and 2.39, 1.29 and 0.78 times the IC50 of Sunitinib using the MTT test after 24 hours, three days and five days, respectively. CONCLUSIONS: These in vitro experimental findings support the safety of Sunitinib and Sorafenib on HCEC when used at a concentration of <3.3 ug/mL and <1.0 ug/mL, respectively, after 24 hours of exposure. The in vitro cytotoxicity of Sorafenib on HCEC was higher than Sunitinib. PMID- 24073631 TI - Long-term mortality after critical care: what is the starting point? AB - Mortality is still the most assessed outcome in the critically ill patient and is routinely used as the primary end-point in intervention trials, cohort studies, and benchmarking analysis. Despite this, interest in patient-centered prognosis after ICU discharge is increasing, and several studies report quality of life and long-term outcomes after critical illness. In a recent issue of Critical Care, Cuthbertson and colleagues reported interesting results from a cohort of 439 patients with sepsis, who showed high ongoing long-term mortality rates after severe sepsis, reaching 61% at 5 years (from a starting point of ICU admission). Follow-up may start at ICU admission, after ICU discharge, or after hospital discharge. Using ICU admission as a starting point will include patients with a wide range of illness severities and reasons for ICU admission. As a result, important consequences of the ICU, such as rehabilitation and reduced quality of life, may be diluted in an unselected population. ICU discharge is another frequently used starting point. ICU discharge is a marker of better outcome and reduced risk for acute deterioration, making this an interesting starting point for studying long-term mortality, need for ICU readmission, and critical illness rehabilitation. Finally, using hospital discharge as the starting point will include patients with the minimal requirements to sustain an adequate condition in a non-monitored environment but will add a ?survivors bias?; that is, patients who survive critical illness are a special group among the critically ill. In this commentary, we discuss the heterogeneity in long-term mortality from recent studies in critical care medicine ? heterogeneity that may be a consequence simply of changing the follow-up starting point ? and propose a standardized follow-up starting point for future studies according to the outcome of interest. PMID- 24073632 TI - Electrochemical and quantum chemical investigation of tetranitrocalix[4]arenes: molecules with multiple redox centers. AB - The calix[4]arene skeleton is electrochemically inactive, but it is a useful stable frame for building "smart" molecules and supramolecular assemblies. Suitable substitution on the upper (and/or lower) rim leads to unusual and surprising properties in this system. Polynitrocalix[4]arenes with reducible nitro groups located at the upper rim represent molecules with multiple redox centers where the potential for interactions between them is the focus of interest. The title compounds are promising precursors, e.g., for design and synthesis of sensors. In this work, the stepwise reduction of two tetranitrocalixarenes was investigated electrochemically, and the results were correlated with quantum chemical calculations. The order of individual electron transfers was described as a consequence of molecular geometry. Two independent pairs of equivalent nitro groups were identified whose reduction potential depends upon their respective locations in the molecule. All nitro groups are electronically isolated and thus are reduced independently yielding poly radical ions. The increasing charge has negligible impact on the geometry of the calixarene, which maintains its pinched shape even when carrying an overall molecular charge of -4. PMID- 24073633 TI - Characterization of multi-drug resistant Mycobacterium tuberculosis from immigrants residing in the USA using Ion Torrent full-gene sequencing. AB - SUMMARY: Drug-resistant Mycobacterium tuberculosis bacterium (MTB) is spreading worldwide. Three drug-resistant isolates were detected in Burmese, Hmong, and Indian immigrants currently residing in Milwaukee, Wisconsin, USA. Ion Torrent full-gene sequencing and complete genetic analysis was performed within 5 days and compared to results from traditional drug sensitivity testing (DST). Genetic characterization of seven, full-length resistance-associated genes revealed two MDR and one highly resistant strain with important drug-resistant mutations that were confirmed by traditional DST. The rapid turnaround from sample-to-sequence underscores the public health value of Ion Torrent full-gene sequencing of MDR/XDR genes from epidemiologically significant clinical isolates. PMID- 24073634 TI - Assessing regression to the mean effects in health care initiatives. AB - BACKGROUND: Interventions targeting individuals classified as "high-risk" have become common-place in health care. High-risk may represent outlier values on utilization, cost, or clinical measures. Typically, such individuals are invited to participate in an intervention intended to reduce their level of risk, and after a period of time, a follow-up measurement is taken. However, individuals initially identified by their outlier values will likely have lower values on re measurement in the absence of an intervention. This statistical phenomenon is known as "regression to the mean" (RTM) and often leads to an inaccurate conclusion that the intervention caused the effect. Concerns about RTM are rarely raised in connection with most health care interventions, and it is uncommon to find evaluators who estimate its effect. This may be due to lack of awareness, cognitive biases that may cause people to systematically misinterpret RTM effects by creating (erroneous) explanations to account for it, or by design. METHODS: In this paper, the author fully describes the RTM phenomenon, and tests the accuracy of the traditional approach in calculating RTM assuming normality, using normally distributed data from a Monte Carlo simulation and skewed data from a control group in a pre-post evaluation of a health intervention. Confidence intervals are generated around the traditional RTM calculation to provide more insight into the potential magnitude of the bias introduced by RTM. Finally, suggestions are offered for designing interventions and evaluations to mitigate the effects of RTM. RESULTS: On multivariate normal data, the calculated RTM estimates are identical to true estimates. As expected, when using skewed data the calculated method underestimated the true RTM effect. Confidence intervals provide helpful guidance on the magnitude of the RTM effect. CONCLUSION: Decision-makers should always consider RTM to be a viable explanation of the observed change in an outcome in a pre-post study, and evaluators of health care initiatives should always take the appropriate steps to estimate the magnitude of the effect and control for it when possible. Regardless of the cause, failure to address RTM may result in wasteful pursuit of ineffective interventions, both at the organizational level and at the policy level. PMID- 24073635 TI - Geographic setting influences Great Lakes beach microbiological water quality. AB - Understanding of factors that influence Escherichia coli (EC) and enterococci (ENT) concentrations, pathogen occurrence, and microbial sources at Great Lakes beaches comes largely from individual beach studies. Using 12 representative beaches, we tested enrichment cultures from 273 beach water and 22 tributary samples for EC, ENT, and genes indicating the bacterial pathogens Shiga-toxin producing E. coli (STEC), Shigella spp. , Salmonella spp , Campylobacter jejuni/coli , and methicillin-resistant Staphylococcus aureus , and 108-145 samples for Bacteroides human, ruminant, and gull source-marker genes. EC/ENT temporal patterns, general Bacteroides concentration, and pathogen types and occurrence were regionally consistent (up to 40 km), but beach catchment variables (drains/creeks, impervious surface, urban land cover) influenced exceedances of EC/ENT standards and detections of Salmonella and STEC. Pathogen detections were more numerous when the EC/ENT Beach Action Value (but not when the Geometric Mean and Statistical Threshold Value) was exceeded. EC, ENT, and pathogens were not necessarily influenced by the same variables. Multiple Bacteroides sources, varying by date, occurred at every beach. Study of multiple beaches in different geographic settings provided new insights on the contrasting influences of regional and local variables, and a broader-scale perspective, on significance of EC/ENT exceedances, bacterial sources, and pathogen occurrence. PMID- 24073636 TI - Self-replicating twins in nanowires. AB - Based on molecular-dynamics simulations validated with quantum-mechanical calculations, we predict that (111) twin planes in a [111]-oriented GaAs nanowire attain attractive interactions mediated by surface strain. This gives rise to a self-replication mechanism that continuously generates a twin superlattice in a nanowire during growth. We demonstrate significant implications of the twin-twin interaction for the electronic, mechanical, and chemical properties of nanowires. These unique properties suggest potential applications such as catalysts for solar fuel production and nanoscale mechanical dampers. PMID- 24073637 TI - Two new constituents from Erigeron breviscapus. AB - Two novel constituents, named erigeronones A (1) and B (2), together with apigenin-7-O-beta-galacturonide (3), quercetin-7-O-beta-glucuronide (4), quercetin-3-O-beta-galacturonide (5), and eriodictyol-7-O-beta-glucuronide (6), were isolated from the whole grass of Erigeron breviscapus (Vant) Hand.-Mazz (Compositae). Their structures were established on the basis of spectral analyses and comparison with the literature data. Both new compounds 1 and 2 possess a gamma-pyrone moiety that is rare in nature. Compound 1 showed significant protective effect on H2O2-injured human umbilical vein endothelial cells. PMID- 24073638 TI - Objectively determined physical activity levels of primary school children in south-west Germany. AB - BACKGROUND: Only a small proportion of children and adolescents meet current recommendations of at least 60 min of moderate to vigorous physical activity (MVPA) daily. Most of the available data, however, relies on subjective reports; there is limited objective data on physical activity (PA) levels in German primary school children. The purpose of this study, therefore, was to accurately determine how much time children spend undertaking different intensities of PA and being sedentary during weekdays and weekend using objective assessment tools. Gender-specific and age-related differences were examined along with differences between normal weight and overweight/obese children. METHODS: Children's height and weight were measured according to standard procedures and objective PA measurements were determined in a sub-cohort of 384 primary school children (20% of the whole cohort), participating in a large school-based intervention study in south-west Germany (n = 1947). Baseline data collection occurred on six consecutive days, including weekend days, using multi-sensor accelerometry (Actiheart, CamNtech Ltd., Cambridge UK). 318 children (7.1 +/- 0.6 years, male: 50%, first grade: 51%) provided data for at least 3 days including one weekend day. According to the amount of energy expended, defined as metabolic equivalents (METs), different activity intensities were categorised as follows: sedentary < 1.5 METs; light = 1.5-3.0 METs; moderate = 3.0-6.0 METs, and vigorous > 6.0 METs. RESULTS: Average wear time was 1403 +/- 94 min/day. Children spent 808 +/- 97 min/day being sedentary; 497 +/- 72 min/day in light; 128 +/- 54 min/day in moderate, and 8 +/- 10 min/day in vigorous intensity. 48% of children met the current MVPA guidelines. MVPA was significantly higher on weekdays compared to weekend days (144 +/- 66 vs. 113 +/- 66 min/day; p < 0.001). Furthermore, boys displayed higher MVPA levels compared to girls (164 +/- 57 vs. 106 +/- 50 min/day; p < 0.001). CONCLUSION: Measured objectively, less than half of primary school children in the study met current PA recommendations, emphasising the necessity for early intervention to promote PA. Consistent with previous research, PA levels were higher in boys and during weekdays. These results indicate that PA levels of girls should especially be promoted in primary schools and that parents should be more involved in interventions to improve PA, particularly during weekends. PMID- 24073639 TI - Exogenous trehalose induces defenses in wheat before and during a biotic stress caused by powdery mildew. AB - Powdery mildew would be one of the most damaging wheat diseases without the extensive use of conventional fungicides. Some of the alternative control strategies currently emerging are based on the use of resistance inducers. The disacharride trehalose (TR) is classically described as an inducer of defenses in plants to abiotic stress. In this work, the elicitor or priming effect of TR was investigated in wheat both before and during a compatible wheat-powdery mildew interaction through molecular, biochemical, and cytological approaches. In noninoculated conditions, TR elicited the expression of genes encoding chitinase (chi, chi1, and chi4 precursor), pathogenesis-related protein 1, as well as oxalate oxidase (oxo). Moreover, lipid metabolism was shown to be altered by TR spraying via the upregulation of lipoxygenase (lox) and lipid-transfer protein (ltp)-encoding gene expression. On the other hand, the protection conferred by TR to wheat against powdery mildew is associated with the induction of two specific defense markers. Indeed, in infectious conditions following TR spraying, upregulations of chi4 precursor and lox gene expression as well as an induction of the LOX activity were observed. These results are also discussed with regard to the impact of TR on the fungal infectious process, which was shown to be stopped at the appressorial germ tube stage. Our findings strongly suggest that TR is a true inducer of wheat defense and resistance, at least toward powdery mildew. PMID- 24073640 TI - Characterization and quantification of fungal colonization of Phakopsora pachyrhizi in soybean genotypes. AB - Soybean rust, caused by the fungus Phakopsora pachyrhizi, is an economically important disease of soybean with potential to cause severe epidemics resulting in significant yield losses. Host resistance is one of the management tools to control this disease. This study compared soybean genotypes exhibiting immunity, complete and incomplete resistance, and susceptibility to an isolate of P. pachyrhizi based on visual assessment of reaction type, other visual traits such as sporulation, quantitative measurements of the amount of fungal DNA (FDNA) present in leaf tissues, and data on infection and colonization levels. Soybean genotype UG5 (immune), and plant introduction (PI) 567102B and PI 567104B (complete resistance) had lower quantities of uredinia and FDNA than four other genotypes with incomplete resistance. Based on microscopic observations, early events of spore germination, appressorium formation, and fungal penetration of the epidermis occurred within 24 h postinoculation and were similar among the tested soybean genotypes. Differences in infection among the genotypes were evident once the hyphae penetrated into the intercellular spaces between the mesophyll cells. At 2 days after inoculation (dai), soybean genotype Williams 82 had a significantly (P < 0.05) higher percentage of hyphae in the mesophyll tissue than other soybean genotypes, with UG5 having significantly (P < 0.05) lower percentages than all of the other soybean genotypes at 3, 4, and 5 dai. The percentage of interaction sites with mesophyll cell death was significantly (P < 0.05) higher in UG5 than other genotypes at 3, 4, and 5 dai. There was a significant positive correlation (r = 0.30, P < 0.001) between quantities of hyphae in the mesophyll cells and FDNA. These results demonstrated that incompatible soybean-P. pachyrhizi interaction results in restricted hyphal development in mesophyll cell tissue, likely due to hypersensitive apoptosis. PMID- 24073641 TI - How to describe a cryptic species? Practical challenges of molecular taxonomy. AB - BACKGROUND: Molecular methods of species delineation are rapidly developing and widely considered as fast and efficient means to discover species and face the 'taxonomic impediment' in times of biodiversity crisis. So far, however, this form of DNA taxonomy frequently remains incomplete, lacking the final step of formal species description, thus enhancing rather than reducing impediments in taxonomy. DNA sequence information contributes valuable diagnostic characters and -at least for cryptic species - could even serve as the backbone of a taxonomic description. To this end solutions for a number of practical problems must be found, including a way in which molecular data can be presented to fulfill the formal requirements every description must meet. Multi-gene barcoding and a combined molecular species delineation approach recently revealed a radiation of at least 12 more or less cryptic species in the marine meiofaunal slug genus Pontohedyle (Acochlidia, Heterobranchia). All identified candidate species are well delimited by a consensus across different methods based on mitochondrial and nuclear markers. RESULTS: The detailed microanatomical redescription of Pontohedyle verrucosa provided in the present paper does not reveal reliable characters for diagnosing even the two major clades identified within the genus on molecular data. We thus characterize three previously valid Pontohedyle species based on four genetic markers (mitochondrial cytochrome c oxidase subunit I, 16S rRNA, nuclear 28S and 18S rRNA) and formally describe nine cryptic new species (P. kepii sp. nov., P. joni sp. nov., P. neridae sp. nov., P. liliae sp. nov., P. wiggi sp. nov., P. wenzli sp. nov., P. peteryalli sp. nov., P. martynovi sp. nov., P. yurihookeri sp. nov.) applying molecular taxonomy, based on diagnostic nucleotides in DNA sequences of the four markers. Due to the minute size of the animals, entire specimens were used for extraction, consequently the holotype is a voucher of extracted DNA ('DNA-type'). We used the Character Attribute Organization System (CAOS) to determine diagnostic nucleotides, explore the dependence on input data and data processing, and aim for maximum traceability in our diagnoses for future research. Challenges, pitfalls and necessary considerations for applied DNA taxonomy are critically evaluated. CONCLUSIONS: To describe cryptic species traditional lines of evidence in taxonomy need to be modified. DNA sequence information, for example, could even serve as the backbone of a taxonomic description. The present contribution demonstrates that few adaptations are needed to integrate into traditional taxonomy novel diagnoses based on molecular data. The taxonomic community is encouraged to join the discussion and develop a quality standard for molecular taxonomy, ideally in the form of an automated final step in molecular species delineation procedures. PMID- 24073642 TI - Web-based office ergonomics intervention on work-related complaints: a field study. AB - The aim of this study was a proof of concept to examine the effects of a Web based office ergonomics intervention on subjects' individual workplace adjustments. An intervention study was conducted with 24 office workers lasting 6 weeks with three consecutive phases (before, 1 and 5 weeks after the intervention). Employees used a purpose-made website for adjusting their computer workplaces without any personal support of ergonomics experts. Workplace measurements were taken directly on site and by analysing photos taken of the employee. Self-reported complaints were assessed by filling in a questionnaire. It was found that 96% of the employees changed their workplaces on their own and retained them mostly unchanged after the intervention. Furthermore, self-reported musculoskeletal complaints and headache symptoms decreased significantly after the intervention. These findings suggest an improvement of workplace conditions so that cost-effective ergonomic Web-based interventions appear promising in further research and application. PMID- 24073644 TI - Editorial comment for Zeng et al. PMID- 24073643 TI - Urinary adiponectin concentration is positively associated with micro- and macro vascular complications. AB - BACKGROUND: A relationship between plasma adiponectin level and a number of metabolic conditions, including insulin resistance, obesity, and type 2 diabetes, has been reported. This study aimed to assess whether urinary adiponectin concentration is correlated with vascular complications. METHODS: The study comprised 708 subjects who enrolled in the Seoul Metro City Diabetes Prevention Program and were carefully monitored from September 2008 to December 2008. Levels of urinary adiponectin were measured using an enzyme linked immunosorbent assay (ELISA) kit (AdipoGen, Korea). Urinary albumin excretion was assessed by the ratio of urinary albumin to creatinine (A/C ratio). Participants were divided into three groups based on tertiles of urinary adiponectin concentration, and we investigated whether urinary adiponectin levels are associated with microalbuminuria and pulse wave velocity. RESULTS: Urinary adiponectin concentrations were significantly higher in subjects with microalbuminuria than subjects with normoalbuminuria (P < 0.001). Urinary adiponectin concentration was positively correlated with age, fasting plasma glucose level, HbA1C level, triglyceride level, HOMA-IR, systolic/diastolic blood pressure, and urinary A/C ratio (all P < 0.05). Subjects in the highest tertile of urinary adiponectin concentration had an increased likelihood of microalbuminuria than those in the lowest tertile (Odds ratio (OR), 6.437; 95% confidence interval (CI), 4.202 to 9.862; P < 0.001). After adjusting for age, sex, and estimated creatinine clearance rate (eCcr), the OR remained significant (OR, 5.607; 95% CI, 3.562 to 8.828; P < 0.001). Backward multiple linear regression analysis revealed urinary adiponectin concentration to be a significant determinant of mean brachial-ankle pulse wave velocity (baPWV). CONCLUSIONS: An increased urinary adiponectin concentration is significantly associated with microalbuminuria and increased mean baPWV. These results suggest that urinary adiponectin may play an important role as a biomarker for vascular dysfunction. PMID- 24073645 TI - Comparison of intuitiveness, ease of use and preference among three prefilled, disposable growth hormone injection pens. AB - BACKGROUND: Growth hormone (GH) therapy is an effective treatment for growth failure in children. Adherence rates are often low, resulting in poor linear growth. Intuitive and easy-to-use injection devices may improve adherence. OBJECTIVES: To determine injection time, ease of use, intuitiveness and subjects' preference for Norditropin FlexPro (FP) pen (Novo Nordisk A/S, Denmark) versus Genotropin GoQuick (GQ; Pfizer Inc., USA) and Norditropin NordiFlex (NF; Novo Nordisk) pens. METHODS: Subjects aged >= 10 to < 18 years, with GH deficiency, Turner syndrome or short stature following small-for-gestational-age birth were randomized to intuitiveness (no instruction) or instruction groups. Time taken to perform an injection, dose accuracy and errors were recorded. Intuitiveness, ease of-learning and overall preference were assessed using questionnaires. RESULTS: Sixty-four subjects, randomized to intuitiveness (n = 32; mean [SD] age, 13.1 [2.1] years) and instruction (n = 32; 13.4 [2.0] years) groups, required less time to perform the injection with FP than with GQ (mean [SD], intuitiveness 39.8 s [17.0] vs. 65.6 s [42.9], p < 0.01; instruction 40.7 s [19.7] vs. 48.1 s [25.8], p < 0.05), and a similar amount of time with NF. NF and FP were more accurate than GQ (intuitiveness group only). Fewer errors were recorded with NF followed by FP and GQ. FP and NF were considered easier to learn than GQ in both groups. In the intuitiveness group, the majority of subjects (31/32) felt confident using FP without instruction. FP was the device of overall preference in both groups. CONCLUSION: FP was the device that was most intuitive, easiest to use and the device of overall preference. PMID- 24073646 TI - Kennedy disease misdiagnosed as polymyositis: a case report. AB - BACKGROUND: Polymyositis is an immune-mediated myopathy with clinical features of proximal muscle weakness. Dysphagia and neck flexor weakness can develop along with respiratory muscle weakness as the disease progresses. Kennedy disease or X linked spinobulbar muscular atrophy is a rare X-linked recessive disorder with clinical features of slowly progressive atrophy and weakness of limb and bulbar muscles. These two disorders may have overlapping clinical manifestations. CASE PRESENTATION: We present the case of a 52-year-old Filipino man with chronic weakness involving his proximal muscle groups who carried the diagnosis of polymyositis and was refractory to multiple immunomodulatory therapies. Further neurologic examination and history taking along with selective serologic and electrodiagnostic studies instead confirmed the diagnosis of Kennedy disease. CONCLUSIONS: Distinction between polymyositis and Kennedy disease may be difficult given the potential overlapping clinical manifestations. However, with careful neurological history taking, examination, and selective serologic plus electrodiagnostic investigations the correct diagnosis may be made, thus sparing the patient ineffective therapy. One must always be sure of the diagnosis of polymyositis before it's classified as refractory. PMID- 24073648 TI - The needle in the haystack: searching for biomarkers in acute respiratory distress syndrome. AB - The acute respiratory distress syndrome commonly accompanies critical illness and is associated with significant morbidity and mortality. The implementation of life saving therapies is dependent on accurately identifying patients with this syndrome; however, beyond clinical definitions, we lack ancillary tests aimed at this specific diagnosis. This commentary discusses recent advances in the use of biomarkers to fill this diagnostic void. PMID- 24073649 TI - Computational prediction and in vitro analysis of potential physiological ligands of the bile acid binding site in cytochrome c oxidase. AB - A conserved bile acid site has been crystallographically defined in the membrane domain of mammalian and Rhodobacter sphaeroides cytochrome c oxidase (RsCcO). Diverse amphipathic ligands were shown previously to bind to this site and affect the electron transfer equilibrium between heme a and a3 cofactors by blocking the K proton uptake path. Current studies identify physiologically relevant ligands for the bile acid site using a novel three-pronged computational approach: ROCS comparison of ligand shape and electrostatics, SimSite3D comparison of ligand binding site features, and SLIDE screening of potential ligands by docking. Identified candidate ligands include steroids, nicotinamides, flavins, nucleotides, retinoic acid, and thyroid hormones, which are predicted to make key protein contacts with the residues involved in bile acid binding. In vitro oxygen consumption and ligand competition assays on RsCcO wildtype and its Glu101Ala mutant support regulatory activity and specificity of some of these ligands. An ATP analog and GDP inhibit RsCcO under low substrate conditions, while fusidic acid, cholesteryl hemisuccinate, retinoic acid, and T3 thyroid hormone are more potent inhibitors under both high and low substrate conditions. The sigmoidal kinetics of RsCcO inhibition in the presence of certain nucleotides is reminiscent of previously reported ATP inhibition of mammalian CcO, suggesting regulation involving the conserved core subunits of both mammalian and bacterial oxidases. Ligand binding to the bile acid site is noncompetitive with respect to cytochrome c and appears to arrest CcO in a semioxidized state with some resemblance to the "resting" state of the enzyme. PMID- 24073651 TI - Plant architecture and growth response of kudzu (fabaceae: Fabaceae) to simulated insect herbivory. AB - Kudzu [Pueraria montana variety lobata (Willd.) Maesen & S. M. Almeida] plant architecture and growth were compared for plants subjected to 4 wk of simulated herbivory (75% leaf cutting) and no damage. Simulated herbivory reduced above ground and root biomass by 40 and 47%, respectively, whereas total vine length and average length of the 10 longest vines were reduced by 48 and 43%, respectively, compared with control plants. Plant architecture was also affected, with damaged plants showing a significantly reduced proportion of primary vines, shorter secondary vines, and reduced average internode distances compared with the control plants. In natural situations, these changes would reduce the ability of kudzu to compete for light and other resources by affecting the plant's climbing habit. PMID- 24073652 TI - Large plaque-like glomangioma in a patient with multiple glomus tumours: review of imaging and histology. AB - Glomus tumours are benign tumours of the temperature-sensitive neuromyoarterial glomus body, present within the dermis, which are most commonly seen as solitary subungual lesions on the arms. Multiple glomus tumours or glomangiomas are a less common subtype of extradigital glomus tumours, which very rarely present as large plaque-like dermal lesions. Glomangiomas do not often show the classic triad of symptoms associated with glomus tumours, namely: pain, point tenderness on compression, and temperature sensitivity. As a result of this and of their atypical morphology, they can often be misdiagnosed as vascular malformations (VMs), resulting in delayed diagnosis and inappropriate treatment. We report a 29 year-old man with multiple extradigital glomus tumours that had been present since childhood, with the lesion on the patient's leg being the largest plaque like glomangioma yet reported, to our knowledge. Spectral greyscale and Doppler shift ultrasonography showed multiple, tubulonodular, ectatic, noncompressible, vascular structures with aberrant flow within the thickened dermis. Using magnetic resonance imaging, low to intermediate signal was seen on T1-weighted images and high signal on T2-weighted images, and there was florid enhancement with gadolinium, with no evidence of extension into muscle or bone. Histology showed abnormal, dilated, thin-walled, vascular channels lined with multiple layers of glomus cells, confirming the diagnosis of a glomangioma. We discuss imaging techniques for plaque-like glomangiomas, and review the clinical, radiological and histological characteristics that help differentiate them from other superficial VMs. PMID- 24073650 TI - An empirical comparison of character-based and coalescent-based approaches to species delimitation in a young avian complex. AB - The process of discovering species is a fundamental responsibility of systematics. Recently, there has been a growing interest in coalescent-based methods of species delimitation aimed at objectively identifying species early in the divergence process. However, few empirical studies have compared these new methods with character-based approaches for discovering species. In this study, we applied both a character-based and a coalescent-based approaches to delimit species in a closely related avian complex, the light-vented/Taiwan bulbul (Pycnonotus sinensis/Pycnonotus taivanus). Population aggregation analyses of plumage, mitochondrial and 13 nuclear intron character data sets produced conflicting species hypotheses with plumage data suggesting three species, mitochondrial data suggesting two species, and nuclear intron data suggesting one species. Such conflict is expected among recently diverged species, and by integrating all sources of data, we delimited three species verified with independently congruent character evidence as well as a more weakly supported fourth species identified by a single character. Attempts to validate species hypothesis using Bayesian Phylogenetics and Phylogeography (BPP), a coalescent based method of species delimitation, revealed several issues that can seemingly affect statistical support for species recognition. We found that theta priors had a dramatic impact on speciation probabilities, with lower values consistently favouring splitting and higher values consistently favouring lumping. More resolved guide trees also resulted in overall higher speciation probabilities. Finally, we found suggestive evidence that BPP is sensitive to the divergent effects of nonrandom mating caused by intraspecific processes such as isolation with-distance, and therefore, BPP may not be a conservative method for delimiting independently evolving population lineages. Based on these concerns, we questioned the reliability of BPP results and based our conclusions about species limits exclusively on character data. PMID- 24073653 TI - The incidence of skin cancer in dermatology. AB - BACKGROUND: It is known that the incidence of skin cancer is rising rapidly worldwide, but no reliable figures on multiple nonmelanoma skin cancer (NMSC) are available. AIM: To determine the actual incidence of skin cancer in dermatology practice and to estimate how this relates to the first primary tumours (registered at the Eindhoven Cancer Registry). METHODS: We examined 1001 randomly selected patient records at Catharina Hospital Eindhoven for mention of skin cancer. For each patient, skin cancers were recorded in a database, starting from 1 January 2004 until 1 March 2010. The time interval between tumours and any history of skin cancer were also recorded. RESULTS: Of this group, 876 patients were treated for skin cancer during the study period. We recorded a total of 2106 tumours with a mean of 2.4 skin cancers per patient. Nearly half (46%) of patients developed multiple tumours, and the second tumour developed within a median period of 5 months. Over a quarter (28%) of patients were known to have had skin cancer before 2004, the start of the study period. CONCLUSIONS: The number of NMSCs in practice differs substantially from the number of first primary histologically confirmed NMSCs, as usually reported by the Eindhoven Cancer Registry. To obtain the optimum benefit from registration of NMSC, it is recommended to register all NMSCs, because only this complete number will give an insight into the incidence of the rising skin-cancer numbers. Because subsequent tumours occur frequently, NMSC should be regarded as a chronic disease, and innovations in disease management are required for cost-effective control. PMID- 24073654 TI - Raised serum levels of interleukins 6 and 8 and antiphospholipid antibodies in an adult patient with Henoch-Schonlein purpura. AB - BACKGROUND: The long-term prognosis of Henoch-Schonlein purpura (HSP) is determined by the severity of renal involvement, known as HSP nephritis, which varies considerably from patient to patient. There is now increasing evidence that dysregulated cytokine production plays a crucial role in human autoimmune and inflammatory processes. AIM: To explore the possible contributions of serum antistreptolysin O, C-reactive protein, IgA, interleukin (IL)-6, IL-8, tumour necrosis factor (TNF)-alpha, anticardiolipin antibody (aCL) and antiphosphatidylserine-prothrombin complex antibody (anti-PSPT) in the pathogenesis of HSP, and to evaluate correlations between those biological parameters and the clinical features. METHODS: Records were reviewed of 58 patients with HSP who presented initially with palpable purpura between 2003 and 2009. Serum IL-6 levels were determined by chemiluminescent enzyme immunoassay, IL-8 levels by ELISA and TNF-alpha levels by quantitative sandwich enzyme immunoassay. Serum aCL and anti-PSPT levels were measured according to our previously published procedures. RESULTS: There was a significant correlation between the serum IL-6 and IgA anti-PSPT levels, and also between the serum IL-8 and IgA anti-PSPT levels. Serum IL-8 and IgA aCL levels were both significantly higher in patients with renal involvement than in those without. Serum IL-6 and IgM anti-PSPT levels were also significantly higher in patients with gastrointestinal symptoms than in those without. CONCLUSIONS: We suggest that serum IL-6 and IL-8 associated with antiphospholipid antibodies play a pivotal role in the induction of HSP. Based on our results, IL-8 and IgA aCL levels could be useful as markers to monitor the development of HSP nephritis, and IL-6 and IgM anti-PSPT levels could be used as markers to monitor the development of gastrointestinal involvement. PMID- 24073655 TI - Homozygous variegate porphyria presenting with developmental and language delay in childhood. AB - Variegate porphyria is an autosomal dominant disorder that usually presents with photosensitivity and acute neurological crises in adulthood. It is caused by heterozygous mutations in the protoporphyrinogen oxidase gene (PPOX). A rarer variant, homozygous variegate porphyria (HVP), presents in childhood with recurrent skin blisters and scarring. More variable features of HVP are short stature, brachydactyly, nystagmus, epilepsy, developmental delay and mental retardation. We describe a child who presented with nystagmus, developmental delay and ataxia, combined with a photosensitive eruption. Analysis of porphyrins in plasma, urine and stool supported a clinical diagnosis of HVP. DNA from the patient showed that he is compound heterozygous for two novel missense mutations in the PPOX coding region: c.169G>C (p.Gly57Arg) and c.1259C>G (Pro420Arg). Interestingly, cranial magnetic resonance imaging showed an absence of myelin, a feature not previously reported in HVP, which expands the differential diagnosis of childhood hypomyelinating leucoencephalopathies. PMID- 24073656 TI - Relapsing lymphomatoid papulosis after allogenic bone-marrow transplant. AB - Lymphomatoid papulosis (LyP) is a rare cutaneous lymphoproliferative disorder in children, which can rarely be associated with a cutaneous or systemic lymphoma. We report a 13-year-old girl who presented with typical LyP and pathological features of subtype A. Six months later, the patient presented with rapidly progressive peripheral and systemic lymphadenopathy. On examination of a lymph node biopsy, a lymphoid infiltrate negative for anaplastic lymphoma kinase (ALK) and positive for CD30 was found, suggestive of systemic anaplastic large T-cell lymphoma (S-ALCL). The patient was treated with chemotherapy, followed by allogeneic bone-marrow transplant (BMT). Over the following 6 years, she presented with biopsy-confirmed LyP relapses with complete cutaneous, peripheral blood and bone-marrow chimerism. This is only the third reported paediatric association of S-ALCL with LyP to our knowledge, and seems to be the first paediatric case of recurrent relapses of LyP after bone-marrow allograft for S ALCL with total (100%) cutaneous and bone-marrow chimerism. LyP occurring after allogenic BMT does not appear to be donor-derived. PMID- 24073657 TI - Ectodermal dysplasia-skin fragility syndrome: a novel mutation in the PKP1 gene. AB - Ectodermal dysplasia-skin fragility syndrome (EDSFS) is an autosomal recessive genodermatosis characterized by skin fragility, palmoplantar hyperkeratosis, onichodystrophy, perioral fissuring and noncicatricial alopecia. It is caused by plakophilin-1 (PKP1) deficiency, which results in desmosomal abnormality and poor intercellular cohesion between the epidermal cells. We report a case with a novel PKP1 mutation in intron 6. PMID- 24073658 TI - The Mercedes flap: a modified closure for circular skin defects around the eyebrow. PMID- 24073659 TI - Physicochemical and pharmacological investigation of water/oil microemulsion of non-selective beta blocker for treatment of glaucoma. AB - PURPOSE: Ocular drug delivery system always remained associated with lots of difficulties and faced issues of poor drug absorption and poor bioavailability. Timolol maleate is a nonspecific beta blocker used for reduction of elevated intraocular pressure in glaucoma. Timolol maleate is absorbed systemically and is contraindicated in asthmatic patients. This study is focused to deliver Timolol maleate by a water/oil microemulsion to extend the time of reduced intraocular pressure of glaucomatous rabbit's eye measured by using a Schoetz tonometer. METHODS: The microemulsion is prepared by mixing the oily components with two nonionic surfactants, drug and water, and evaluated for the physicochemical, in vitro and in vivo parameters. RESULTS: The colloidal system demonstrates monodisperse distribution behavior and exhibits a uniform size distribution of finite width. In vitro drug release from microemulsion was found to follow Higuchi's pattern followed by a zero-order drug release by the emulsion. Ex vivo permeation through goat cornea revealed delayed release of Timolol maleate from microemulsion as compared with its aqueous solution. A reduction in intraocular pressure is seen lasting for 12 h compared to aqueous eye drop that lasted for only 5 h. CONCLUSION. In vivo reduction of intraocular pressure revealed a similar efficacy for once daily dosed 0.3% Timolol maleate in microemulsion formulation compared to 0.5% concentration in both microemulsion as well as aqueous formulation. The possible outcome of dose reduction will reduce the cardiovascular side effects generally reported with Timolol maleate eye drops. PMID- 24073660 TI - Comparative evaluation of antimutagenicity of commonly consumed fruits and activity-guided identification of bioactive principles from the most potent fruit, Java plum (Syzygium cumini). AB - Commonly consumed fruits showed remarkable variation in antimutagenicity when assayed by E. coli rifampicin resistance assay, and Java plum (Syzygium cumini) was found to be one of the most potent fruits. Its anthocyanins contributed maximally to the observed antimutagenicity and resolved into three distinct bands in HPTLC. Although these bands displayed similar antioxidant capacity, the band at R(f) 0.22 was the most antimutagenic and resolved into two peaks in HPLC. The second peak (t(R) 3.8 min) displayed a strong and broad spectrum antimutagenicity and was identified as petunidin-3,5-diglucoside by analysis of its molecular ion and fragmentation pattern by ESI-MS/MS. The presence of glucose moiety was confirmed by TLC analysis of acid-hydrolyzed products. This purified anthocyanin was found to suppress mutagenic SOS DNA repair process in E. coli and thus indicated suppression of the error-prone DNA repair pathway as one of the major mechanisms of antimutagenicity of this fruit. PMID- 24073661 TI - An investigation of a novel transdiagnostic model of delusions in a group with positive schizotypal symptoms. AB - INTRODUCTION: Although several theories of delusions have been put forward, most do not offer a comprehensive diagnosis-independent explanation of delusion aetiology. This study used a non-clinical sample to provide empirical support for a novel transdiagnostic model of delusions that implicates aberrant semantic memory and emotion perception processes as key factors in delusion formation and maintenance. It was hypothesised that among a non-clinical sample, people high in schizotypy would demonstrate differences in semantic memory and emotion perception, relative to people low in schizotypy. METHODS: Using the Cognitive Disorganisation subscale of the Oxford-Liverpool Inventory of Feelings and Experiences, 41 healthy participants were separated into high and low schizotypy groups and completed facial emotion perception and semantic priming tasks. RESULTS: As expected, participants in the high schizotypy group demonstrated different performance on the semantic priming task and reduced facial affect accuracy for the emotion anger, and reaction time differences to fearful faces. CONCLUSION: These findings suggest that such processes may be involved in the development of the sorts of unusual beliefs which underlie delusions. Investigation of how emotion perception and semantic memory may interrelate in the aetiology of delusions would be of value in furthering our understanding of their role in delusion formation. PMID- 24073662 TI - Pre-linguistic children with cleft palate: growth of gesture, vocalization, and word use. AB - Children with cleft lip and/or palate show early delays in speech and vocabulary development that may have an impact on later communication and social development. While delays in the complexity of babbling may put children at risk for later delays in speech and language development, there is considerable variability in development. This study focused on the rate of children's communication acts, canonical vocalizations, and word use as they made the transition from the pre-linguistic to linguistic development. The study included 15 children with non-syndromic cleft lip and/or palate who were seen at three time points between 17-34 months age. Communication rates were calculated from parent-child language samples collected during play activities. Assignment to linguistic stages was based on the children's expressive vocabulary, as reported on the MacArthur Communicative Development Inventory: Words and Sentences. From the pre-linguistic to linguistic level, the children's average rate per minute of: communicative acts overall increased significantly from 1.49 to 3.07 per minute; canonical vocalizations from 0.21 to 0.90 per minute; and word use from 0.16 to 3.61 per minute. Rates of communicative acts were associated with later word use. It appears that children with clefts rely on non-verbal communicative acts when verbal development is delayed. PMID- 24073663 TI - Clinical symptoms and sonographic follow-up after surgical treatment of nonparasitic liver cysts. AB - BACKGROUND: The optimal treatment of nonparasitic liver cysts is still a topic of debate. Only symptomatic cysts are being considered as requiring treatment. Aim of this study is to evaluate our experience with this disease over the past ten years with a structured follow-up program. METHODS: From January 2000 to August 2010, 56 consecutive patients with nonparasitic liver cysts were treated at our institution. We assessed morbidity, recurrence and complication rates, quality of life as well as pre- and post-operative sonographic status of the cysts and course of clinical symptoms. RESULTS: In 84% of the patients surgery was started as a laparoscopic procedure. Conversion rate was 6.4%. Average diameter of deroofed cysts was 12 cm. Overall complication rate was 16% and overall recurrence rate 28.3% (8.7% recurrences at the surgical site, 19.6% new or enlarged cysts). One half of the patients were symptom-free after surgery and the other half had at least one persisting symptom post-operatively. In one half of these patients with persisting symptoms, symptoms were ameliorated by surgery. In the other half of patients the number of symptoms increased after surgery. Two thirds of the overall patients reported their post-operative health as being good or very good. CONCLUSIONS: Surgical deroofing is the most effective treatment option for symptomatic liver cysts. Half of our patient population retained at least one symptom from a group of more than ten abdominal symptoms.Only the minority of these cases may be attributed to true recurrence, de-novo cysts or growing pre-existing cysts. The analysis of our cases suggests that the persistent symptoms in our patients may in part be due to the fact that the association between clinical complaints and the liver cysts was not sufficiently established. A more rigid patient selection should be implemented in order to achieve better results from the treatment of cysts. Because even large cysts are frequently asymptomatic, patient selection should not primarily be based on the cyst size only. The decision should be based strictly on the correlation between cyst / cyst location and symptoms / clinical complaints. In our opinion, further diagnostic procedures may be necessary in individual cases to clarify such a correlation. PMID- 24073664 TI - Ranachensinin: a novel aliphatic tachykinin from the skin secretion of the Chinese brown frog, Rana chensinensis. AB - Amphibian skin secretions contain a plethora of pharmacologically-active substances and represent established sources of bioactive peptides, including tachykinins. Tachykinins are one of the most widely-studied peptide families in animals and are found in neuroendocrine tissues from the lowest vertebrates to mammals. They are characterized by the presence of a highly-conserved C-terminal pentapeptide amide sequence motif (-FXGLM-amide) that also constitutes the bioactive core of the peptide. Amidation of the C-terminal methioninyl residue appears to be mandatory in the expression of biological activity. Here, we describe the isolation, characterization and molecular cloning of a novel tachykinin named ranachensinin, from the skin secretion of the Chinese brown frog, Rana chensinensis. This peptide, DDTSDRSN QFIGLM-amide, contains the classical C-terminal pentapeptide amide motif in its primary structure and an Ile (I) residue in the variable X position. A synthetic replicate of ranachensinin, synthesized by solid-phase Fmoc chemistry, was found to contract the smooth muscle of rat urinary bladder with an EC50 of 20.46 nM. However, in contrast, it was found to be of low potency in contraction of rat ileum smooth muscle with an EC50 of 2.98 uM. These data illustrate that amphibian skin secretions continue to provide novel bioactive peptides with selective effects on functional targets in mammalian tissues. PMID- 24073665 TI - Mechanistic and chiroptical studies on the desulfurization of epidithiodioxopiperazines reveal universal retention of configuration at the bridgehead carbon atoms. AB - The stereochemistry of the desulfurization products of chiral natural and synthetic 3,6-epidithiodiketopiperazines (ETPs) is specified inconsistently in the literature. Qualitative mechanisms have been put forward to explain apparently divergent stereochemical pathways, but the quantitative feasibility of such mechanistic pathways has not been assessed. We report a computational study revealing that desulfurization of ETPs should occur universally with retention of configuration. While the majority of stereochemically assigned and reassigned cases fit this model, until now desulfurization of the synthetic gliotoxin analogue shown has remained assigned as proceeding via inversion of configuration. Through detailed chiroptical studies comparing experimentally obtained optical rotation values, electronic circular dichroism spectra, and vibrational circular dichroism spectra to their computationally simulated counterparts as well as chemical derivatization studies, we have unambiguously demonstrated that contrary to its current assignment in the literature, the desulfurization of this synthetic ETP also proceeds with retention of configuration. PMID- 24073666 TI - Social capital and health among older adults in South Africa. AB - BACKGROUND: Little is known about social capital and health among older adults in South Africa. This study investigates the association between social capital and several health variables, namely: self-rated health, depressive symptoms, cognitive functioning and physical inactivity, among older South Africans. METHODS: We conducted a national population-based cross-sectional study with a national probability sample of 3840 individuals aged 50 years or older who participated in the Study of Global Ageing and Adults Health (SAGE wave 1) in 2008 in South Africa. Measures included socio-demographic characteristics, health variables, cognitive functioning and physical activity. Social capital was assessed with six components, namely: marital status, social action, sociability, trust and solidarity, safety, and civic engagement. RESULTS: The social capital assessment revealed that 56% of the respondents were married or cohabiting, 45% reported low (0) social action, 42% reported medium (2-3) sociability, 43% reported high (2) trust and solidarity, 50% reported high (2-4) civic engagement and 42% reported medium (6) psychological resources. In multivariate analysis, self-reported good health was associated with younger age, having secondary education and higher social capital (being married or cohabiting, high trust and solidarity and greater psychological resources). Depressive symptoms were associated with lower social capital (not being married or cohabiting, lack of high trust and solidarity and low psychological resources). Better cognitive functioning was associated with younger age, higher educational level, greater wealth and higher social capital (being married or cohabiting, high trust and solidarity, lack of safety, higher civic engagement and greater psychological resources). Physical inactivity was associated with older age and lower social capital (lower social action, lack of safety, lower civic engagement and poorer psychological resources). CONCLUSIONS: Given the basis of these findings on cross sectional data and subsequent limitation, it was found that these study findings mimic the findings of many European and American studies. Social capital among the elderly generation in South Africa is imperative for better health. PMID- 24073667 TI - A miniature ultrasound probe is useful in reducing rebleeding after endoscopic cyanoacrylate injection for hemorrhagic gastric varices. AB - OBJECTIVE: To better assess the usefulness of miniature ultrasound probe (MUP) sonography in the evaluation of the adequacy of gastric variceal injection with cyanoacrylate to decrease the risk of post injection rebleeding. MATERIAL AND METHODS: Sixty-nine patients with bleeding gastric varices were included in this study. Endoscopic cyanoacrylate injection was performed in the acute phase for variceal hemostasis. After injection, patients (n = 34) included in the MUP group prospectively received endoscopic ultrasonography (EUS) with MUP during each scheduled endoscopic follow-up session. Patients (n = 35) in the control group who were included historically were followed up with the same interval with endoscopy only. RESULTS: Four (11.4%) patients in the control group received reinjection, and there were 10 episodes of rebleeding in 7 (20.0%) patients. Nine (26.5%) patients received reinjection due to inadequate obturation as judged by EUS. There were six episodes of rebleeding in three (8.8%) patients in the MUP group. The free-of-rebleeding rate for the MUP group was significantly higher than that for the control group (p < 0.05). The cumulative survival for the MUP group was slightly better than that for the control group but was not statistically significant. The patients' compliance in both groups was similar. The endosonographers considered the performance of MUP sonography to be convenient. CONCLUSIONS: MUP sonography is useful for the evaluation of the adequacy of tissue adhesive obturation of gastric varices that may reduce the probability of rebleeding. PMID- 24073668 TI - Plasmodium ovale curtisi and Plasmodium ovale wallikeri in North-West Ethiopia. AB - BACKGROUND: In Ethiopia Plasmodium falciparum and Plasmodium vivax are the dominant species accounting for roughly 60 and 40% of malaria cases, respectively. Recently a major shift from P. falciparum to P. vivax has been observed in various parts of the country but the epidemiology of the other human malaria species, Plasmodium ovale spp. and Plasmodium malariae remains poorly understood. The aim of this study was to assess P. ovale curtisi and wallikeri infection in north-west Ethiopia by using microscopy and nested PCR. METHODS: A health institution-based survey using non-probability sampling techniques was conducted at Maksegnet, Enfranze and Kola Diba health centres and Metema hospital in North Gondar. Three-hundred patients with signs and symptoms consistent with malaria were included in this study and capillary blood was collected for microscopic examination and molecular analysis of Plasmodium species. Samples were collected on Whatman 903 filter papers, stored in small plastic bags with desiccant and transported to Vienna (Austria) for molecular analysis. Data from study participants were entered and analysed by SPSS 20 software. RESULTS: Out of 300 study participants (167 males and 133 females), 184 samples were classified positive for malaria (133 P. falciparum and 51 P. vivax) by microscopy. By species-specific PCR 233 Plasmodium spp (95% CI: 72.6-82) were detected and the majority 155 (66.5%, 95% CI: 60.2-72.3) were P. falciparum followed by P. vivax 69 (29.6%, 95% CI; 24.1-35.8) and 9 (3.9%, 95% CI: 2-7.2) samples were positive for P. ovale. Seven of P. ovale parasites were confirmed as P. ovale wallikeri and two were confirmed as P. ovale curtisi. None of the samples tested positive for P. malariae. During microscopic examination there were high (16.3%) false negative reports and all mixed infections and P. ovale cases were missed or misclassified. CONCLUSION: This study indicates that P. ovale malaria is under reported in Ethiopia and provides the first known evidence of the sympatric distribution of indigenous P. ovale wallikeri and P. ovale curtisi in Ethiopia. Therefore, further studies assessing the prevalence of the rare species P. ovale and P. malariae are urgently needed to better understand the species distribution and to adapt malaria control strategies. PMID- 24073669 TI - Sixty years of the Interamerican Society of Psychology (SIP): origins and development. AB - This paper presents a historical overview of the Interamerican Society of Psychology, which was founded on December 17, 1951, in Mexico City. Firstly, the historical circumstances of the foundation period are presented, as well as the people who made this organization possible, and the state of psychology on the American continent at that time. Secondly, the most important activities that the Interamerican Society of Psychology has developed during its 60 years are mentioned, such as the publication of books and scientific journals, the creation of several task forces and the Interamerican Congresses of Psychology. Basically, the purpose of this paper is to review the history of the Interamerican Society of Psychology through the recovery and use of various documentary sources. PMID- 24073670 TI - Adaptive training algorithm for robot-assisted upper-arm rehabilitation, applicable to individualised and therapeutic human-robot interaction. AB - BACKGROUND: Rehabilitation robotics is progressing towards developing robots that can be used as advanced tools to augment the role of a therapist. These robots are capable of not only offering more frequent and more accessible therapies but also providing new insights into treatment effectiveness based on their ability to measure interaction parameters. A requirement for having more advanced therapies is to identify how robots can 'adapt' to each individual's needs at different stages of recovery. Hence, our research focused on developing an adaptive interface for the GENTLE/A rehabilitation system. The interface was based on a lead-lag performance model utilising the interaction between the human and the robot. The goal of the present study was to test the adaptability of the GENTLE/A system to the performance of the user. METHODS: Point-to-point movements were executed using the HapticMaster (HM) robotic arm, the main component of the GENTLE/A rehabilitation system. The points were displayed as balls on the screen and some of the points also had a real object, providing a test-bed for the human robot interaction (HRI) experiment. The HM was operated in various modes to test the adaptability of the GENTLE/A system based on the leading/lagging performance of the user. Thirty-two healthy participants took part in the experiment comprising of a training phase followed by the actual-performance phase. RESULTS: The leading or lagging role of the participant could be used successfully to adjust the duration required by that participant to execute point-to-point movements, in various modes of robot operation and under various conditions. The adaptability of the GENTLE/A system was clearly evident from the durations recorded. The regression results showed that the participants required lower execution times with the help from a real object when compared to just a virtual object. The 'reaching away' movements were longer to execute when compared to the 'returning towards' movements irrespective of the influence of the gravity on the direction of the movement. CONCLUSIONS: The GENTLE/A system was able to adapt so that the duration required to execute point-to-point movement was according to the leading or lagging performance of the user with respect to the robot. This adaptability could be useful in the clinical settings when stroke subjects interact with the system and could also serve as an assessment parameter across various interaction sessions. As the system adapts to user input, and as the task becomes easier through practice, the robot would auto-tune for more demanding and challenging interactions. The improvement in performance of the participants in an embedded environment when compared to a virtual environment also shows promise for clinical applicability, to be tested in due time. Studying the physiology of upper arm to understand the muscle groups involved, and their influence on various movements executed during this study forms a key part of our future work. PMID- 24073671 TI - Analysis of the microRNA transcriptome and expression of different isomiRs in human peripheral blood mononuclear cells. AB - BACKGROUND: MicroRNAs (miRNAs) have been recognized as one of the key regulatory non-coding RNAs that are involved in a number of basic cellular processes. miRNA expression profiling helps to identify miRNAs that could serve as biomarkers. Next generation sequencing (NGS) platforms provide the most effective way of miRNA profiling, particularly as expression of different isoforms of miRNA (IsomiRs) can be estimated by NGS. Therefore, it is now possible to discern the overall complexity of miRNA populations that participate in gene regulatory networks. It is thus important to consider different isoforms of miRNA as part of total profiling in order to understand all aspects of the biology of miRNAs. RESULTS: Here next generation sequencing data of small RNAs derived from normal peripheral blood mononuclear cells (PBMC) and Chronic myeloid leukemia (CML) patients has been used to generate miRNA profiles using a computation pipeline which can identify isomiRs that are natural variants of mature miRNAs. IsomiR profiles have been generated for all the 5p and 3p miRNAs (previously known as major mature miRNA and minor or miRNA*) and the data has been presented as a composite total miRNA transcriptome. The results indicated that the most abundant isomiR sequence of about 68% miRNAs, did not match the reference miRNA sequence as entered in the miRBase and that there is a definite pattern in relative concentration of different isomiRs derived from same precursors. Finally, a total of 17 potential novel miRNA sequences were identified suggesting that there are still some new miRNAs yet to be discovered. CONCLUSIONS: Inclusion of different isoforms provides a detailed miRnome of a cell type or tissues. Availability of miRnome will be useful for finding biomarkers of different cell types and disease states. Our results also indicate that the relative expression levels of different isoforms of a miRNA are likely to be dynamic and may change with respect to changes in the cell or differentiation status. PMID- 24073672 TI - Predictors of influenza in the adult population during seasonal and A(H1N1)pdm09 pandemic influenza periods. AB - We aimed to assess whether the characteristics of influenza-like illness (ILI) cases in the general population were similar during the seasonal and pandemic A(H1N1)pdm09 influenza periods. We conducted a study using a general population database, which included demographic (sex, age) and clinical (underlying medical conditions, influenza vaccination status) information on more than 80 000 subjects. We assessed the most important predictors of ILI during each season by using multiple logistic regression. We descriptively compared whether they were similar during different seasons. The model, including all demographic and clinical characteristics, showed that age ?60 years decreased the odds for ILI by 52% and 81% during the seasonal and A(H1N1)pdm09 pandemic periods, respectively. Being vaccinated decreased the odds of ILI for seasonal influenza by 32%, while suffering from the comorbidities other than lung or cardiovascular diseases doubled the odds of ILI during the A(H1N1)pdm09 pandemic. PMID- 24073673 TI - Progress or lack of progress in hospitalized heart failure. PMID- 24073674 TI - Acute ischemic stroke therapy: current status and future directions. PMID- 24073676 TI - Effectiveness of the fixed-dose combination of olmesartan/amlodipine/hydrochlorothiazide for the treatment of hypertension in patients stratified by age, race and diabetes, CKD and chronic CVD. AB - The prevalence of hypertension is high in patients with diabetes mellitus (DM), chronic kidney disease (CKD) and chronic cardiovascular disease (CVD), as well as in black and elderly subjects. In addition, these subjects have the lowest control of blood pressure (BP) among the hypertensive population, and also the risk of having a morbid or fatal cardiovascular event >20% in 10 years. For these reasons, aggressive control of BP to <130/80 mm Hg for these subjects is strongly recommended by National and International guidelines. To accomplish this goal, combination therapy with two or more antihypertensive drugs with a complementary mechanism of action is necessary. Drugs that block the renin-angiotensin system (RAS) in combination with a calcium channel blocker (CCB) and a diuretic have been shown to be the most effective combinations to accomplish this goal. However, this will require the administration of multiple drugs given separately, which will decrease the patient compliance and adherence to treatment. Poor patient compliance and adherence to treatment is a major factor for poor BP control. Several studies have shown that patient compliance is inversely related to the number of drugs being administered. To overcome this problem, several dual and triple-drug, fixed-dose combinations with a RAS blocker, a CCB and a diuretic have been developed and marketed, which are easier to administer, and have been shown to increase patient compliance and adherence to treatment. In this concise review, the effectiveness and safety of the fixed-dose, triple-combination of the RAS blocker olmesartan medoxomil, the CCB amlodipine besylate and the diuretic hydrochlorothiazide, as well as other similar combinations for the treatment of hypertension, will be discussed. These drug combinations have been shown to be effective, safe and well tolerated by most patients. PMID- 24073677 TI - Aggressive salt and water restriction in acutely decompensated heart failure: is it worth its weight in salt? AB - Acute decompensated heart failure (ADHF) is the leading cause of hospitalization worldwide, especially in the elderly, and is associated with a high readmission rate and increased first year mortality. Fluid overload manifested by pulmonary congestion is seen in the majority of patients with ADHF and is believed to be the reason behind most admissions. ADHF is commonly treated with intravenous diuretics aimed to alleviate congestion and restore euvolemia. In fact, current European and American guidelines for heart failure (HF) consider relief of congestion as the first-line therapy in ADHF. Following the same theme of reducing fluid retention, historical approaches have recommended water and salt restriction as an essential non-pharmacological therapy in the management of symptomatic HF. This 'common sense' dietary practice was mainly based on experts' opinions and has been challenged by recent data suggesting that salt or fluid restriction has neutral outcomes in achieving clinical stability and improving signs and symptoms of HF. PMID- 24073678 TI - Treatment of acute heart failure in the emergency department. AB - Millions of patients are hospitalized for acute heart failure (AHF) every year throughout the world. Despite tremendous advances in cardiovascular care, morbidity and mortality for AHF remain high, consuming billions of health care dollars. With the aging of the population, the incidence and prevalence of HF is projected to increase. Yet, initial treatment of AHF today is similar to 40 years ago. Multiple studies have yielded new insights regarding initial management, with regards to both treatment and strategies of care. These advances will be reviewed in the context of initial or early AHF management. There remains, however, an unmet need to improve outcomes for AHF patients. PMID- 24073679 TI - Emerging role of multimodality imaging in management of inflammatory pericardial diseases. AB - The non-specific and highly variable symptomatology of inflammatory pericardial diseases create clinical challenges in making accurate diagnosis, which often requires the integration of clinical findings, imaging and invasive hemodynamic assessment. Echocardiography is considered to be a first-line imaging test in pericardial diseases. Emerging imaging modalities, especially cardiac MRI allowed better understanding of pericardial anatomy, physiology and, for the first time, enable demonstration of the pericardial inflammation. On the other hand, cardiac computed tomography is excellent tool to define pericardial thickness, pericardial calcification and is useful for preoperative planning once pericardiectomy is indicated especially in the patients with prior cardiac surgery. PMID- 24073680 TI - Enterococcus faecalis infective endocarditis: focus on clinical aspects. AB - Enterococcus faecalis infective endocarditis (IE) is a disease of increasing importance, with more patients infected, increasing frequency of health-care associated infections and increasing incidence of antimicrobial resistances. The typical clinical presentation is a subacute course with fever, malaise and generalized aches, difficult to distinguish from other more common diseases. Of paramount importance is transthoracic- and transesophageal-echocardiography to establish the diagnosis. At the moment, the predominant strategies recommend ampicillin in combination with either gentamicin or ceftriaxone. E. faecalis infective endocarditis continues to be a very serious disease with considerable percentages of high-level gentamicin resistant strains and in-hospital mortality around 20%. Strategies to prevent E. faecalis IE, improve diagnostics, optimize treatment and reduce morbidity will be necessary to improve the overall prognosis. PMID- 24073683 TI - Ultraviolet electroluminescence of light-emitting diodes based on single n-ZnO/p AlGaN heterojunction nanowires. AB - We present successful fabrication of single n-ZnO/p-AlGaN heterojunction nanowires with excellent optoelectronic properties. Because of the formation of high-quality interfacial structure, heterojunction nanowire showed a diodelike rectification behavior and an electroluminescence (EL) ultraviolet (UV) emission centered at 394 nm from a single nanowire was observed when the injection current is 4 MUA due to high exciton efficiency in the interfacial layer between ZnO and AlGaN. With the increase of the applied current, the EL peak at 5 MUA becomes weaker revealing an optimal injection current of less than 5 MUA. These results are expected to open up new application possibilities in nanoscale UV light emitting devices based on single ZnO heterostructure. PMID- 24073684 TI - Improving the hospital 'soundscape': a framework to measure individual perceptual response to hospital sounds. AB - Work on the perception of urban soundscapes has generated a number of perceptual models which are proposed as tools to test and evaluate soundscape interventions. However, despite the excessive sound levels and noise within hospital environments, perceptual models have not been developed for these spaces. To address this, a two-stage approach was developed by the authors to create such a model. First, semantics were obtained from listening evaluations which captured the feelings of individuals from hearing hospital sounds. Then, 30 participants rated a range of sound clips representative of a ward soundscape based on these semantics. Principal component analysis extracted a two-dimensional space representing an emotional-cognitive response. The framework enables soundscape interventions to be tested which may improve the perception of these hospital environments. PMID- 24073682 TI - Clinical consequences of polypharmacy in elderly. AB - INTRODUCTION: Polypharmacy, defined as the use of multiple drugs or more than are medically necessary, is a growing concern for older adults. MEDLINE and EMBASE databases were searched from January 1, 1986 to June 30, 2013) to identify relevant articles in people aged > 65 years. AREAS COVERED: We present information about: i) prevalence of polypharmacy and unnecessary medication use; ii) negative consequences of polypharmacy; and iii) interventions to improve polypharmacy. EXPERT OPINION: International research shows that polypharmacy is common in older adults with the highest number of drugs taken by those residing in nursing homes. Nearly 50% of older adults take one or more medications that are not medically necessary. Research has clearly established a strong relationship between polypharmacy and negative clinical consequences. Moreover, well-designed interprofessional (often including clinical pharmacist) intervention studies that focus on enrolling high-risk older patients with polypharmacy have shown that they can be effective in reducing aspects of unnecessary prescribing with mixed results on distal health outcomes. PMID- 24073686 TI - Treating depression after heart transplantation #273. PMID- 24073685 TI - Racial and ethnic disparities in palliative care. AB - Racial and ethnic disparities in health care access and quality are well documented for some minority groups. However, compared to other areas of health care, such as disease prevention, early detection, and curative care, research in disparities in palliative care is limited. Given the rapidly growing population of minority older adults, many of whom will face advanced serious illness, the availability of high-quality palliative care that meets the varied needs of older adults of all races and ethnicities is a priority. This paper reviews existing data on racial and ethnic disparities in use of and quality of palliative care and outlines priorities for future research. PMID- 24073687 TI - Emerging hepatotoxicity biomarkers and their potential to improve understanding and management of drug-induced liver injury. AB - Biomarkers of drug-induced liver injury (DILI) are essential for the diagnosis of severe cases of DILI in clinical trials and clinical practice, but the currently used biomarker paradigm detects damage after it has occurred and has limited prognostic value. The development of new biomarker strategies that improve the diagnosis of DILI by providing increased specificity and/or by identifying individual patients who are at risk for DILI is therefore crucial. See related Research, http://genomemedicine.com/content/5/9/86. PMID- 24073689 TI - Lactobacillus plantarum IFPL935 favors the initial metabolism of red wine polyphenols when added to a colonic microbiota. AB - This work aimed to unravel the role of Lactobacillus plantarum IFPL935 strain in the colonic metabolism of a polyphenolic red wine extract, when added to a complex human colonic microbiota from the dynamic simulator of the human intestinal microbial ecosystem (SHIME). The concentration of microbial-derived phenolic metabolites and microbial community changes along with fermentative and proteolytic activities were monitored. The results showed that L. plantarum IFPL935 significantly increased the concentration of the initial microbial ring fission catabolite of catechins and procyanidins, diphenylpropanol, and, similarly, 4-hydroxy-5-(3'-hydroxyphenyl)valeric acid production. Overall, the addition of L. plantarum IFPL935 did not have an impact on the total concentration of phenolic metabolites, except for batches inoculated with colonic microbiota from the effluent compartment (EC), where the figures were significantly higher when L. plantarum IFPL935 was added (24 h). In summary, the data highlighted that L. plantarum IFPL935 may have an impact on the bioavailability of these dietary polyphenols. Some of the microbial-derived metabolites may play a key role in the protective effects that have been linked to a polyphenol-rich diet. PMID- 24073690 TI - Regulation of human corneal epithelial mucins by rebamipide. AB - PURPOSE: Membrane-associated mucins (MAMs) play important roles in barrier function and tear stability, and their expression on the ocular surface is altered in dry eye disease. Rebamipide is a mucin secretagogue that promotes the production of mucin-like glycoproteins in human corneal epithelial (HCE) cells. However, the expression of MAMs on the corneal epithelia (MUC1, MUC4, MUC16), which is induced by rebamipide, is poorly understood. In this study, we investigated the effect of rebamipide on the regulation of MAM expression in HCE cells. MATERIALS AND METHODS: MUC16, Ki67 and PCNA expression levels in HCE cells isolated at confluence and at 24 hours after confluence were examined by Western blotting to assess cell proliferation. HCE cells isolated at 24 hours after confluence were cultured in medium supplemented with 1-10 uM rebamipide or 0.3-30 nM of epidermal growth factor (EGF). Real-time PCR (RT-PCR) and Western blot analysis of MAMs were performed to evaluate the effect of rebamipide. Western blot analysis of cells treated with an EGF receptor inhibitor (AG1478) or MEK1/2 inhibitor (U0126) was performed to reveal the relationship between EGF receptor activation and rebamipide-induced MAM expression. RESULTS: HCE cells isolated at 24 hours after confluence had lower cell proliferation activity and increased MUC16 expression compared with cells isolated at confluence. RT-PCR and Western blot analysis revealed that rebamipide increased MAM gene expression for 2 hours and protein expression for 24 hours in HCE cells. EGF inhibitor treatment led to reduced levels of all three MAMs that are normally induced by rebamipide, whereas EGF induced the expression of all three MAMs. CONCLUSIONS: We suggested that rebamipide increased MUC1, MUC4 and MUC16 expression levels through signals involved in EGF receptor activation in the human corneal epithelia. These data suggest that rebamipide may improve subjective symptoms of dry eye disease by upregulating MAM expression. PMID- 24073691 TI - Interfacial properties of oxidized polystyrene and its interaction with water. AB - All-atom molecular dynamics simulations have been carried out to study the wetting of atactic polystyrene (aPS) thin films by water droplets. The effect of oxidation of the aPS surface on the contact angle has been studied as a function of oxygen concentration. Oxidation of aPS has been achieved by randomly replacing with oxygen the ortho and/or meta hydrogens on the aromatic rings within 1 nm of the aPS surface until the desired concentration of oxygen is reached. The simulated contact angle is found to decrease monotonically with increasing degree of oxidation, consistent with recent experimental results. The number of hydrogen bonds between water molecules and polystyrene at the interface is found to monotonically increase with oxygen concentration. By use of a modified Good Girafalco-Fowkes-Young equation, the contribution of nondispersion interactions, gammasl(P), to the interfacial energy at the aPS/water interface has been determined as a function of the degree of oxidation. The values of gammasl(P) extracted appear to follow a quadratic dependence on oxygen concentration of the aPS surface. The roughness of the polystyrene surface appears to be independent of oxygen concentration when the polystyrene is exposed to vacuum, and it appears to increase slightly when it is in contact with water. The orientational ordering of the phenyl rings at the polystyrene surface exhibits no dependence on oxygen concentration for polystyrene in vacuum. However, the ordering appears to decrease slightly with increasing oxygen concentration when the polystyrene is in contact with water. PMID- 24073692 TI - Spatial dynamics of two oriental fruit fly (Diptera: Tephritidae) parasitoids, Fopius arisanus and Diachasmimorpha longicaudata (Hymenoptera: Braconidae), in a Guava orchard in Hawaii. AB - We examined spatial patterns of both sexes of oriental fruit fly, Bactrocera dorsalis (Hendel), and its two most abundant parasitoids, Fopius arisanus (Sonan) and Diachasmimorpha longicaudata (Ashmead) in a commercial guava (Psidium guajava L.) orchard. Oriental fruit fly spatial patterns were initially random, but became highly aggregated with host fruit ripening and the subsequent colonization of, first, F. arisanus (egg-pupal parasitoid) and, second, D. longicaudata (larval-pupal parasitoid). There was a significant positive relationship between populations of oriental fruit fly and F. arisanus during each of the F. arisanus increases, a pattern not exhibited between oriental fruit fly and D. longicaudata. Generally, highest total numbers of males and females (oriental fruit fly, F. arisanus, and D. longicaudata) occurred on or about the same date. There was a significant positive correlation between male and female populations of all three species; we measured a lag of 2-4 wk between increases of female F. arisanus and conspecific males. There was a similar trend in one of the two years for the second most abundant species, D. longicaudata, but no sign of a time lag between the sexes for oriental fruit fly. Spatially, we found a significant positive relationship between numbers of F. arisanus in blocks and the average number in adjoining blocks. We did not find the same effect for oriental fruit fly and D. longicaudata, possibly a result of lower overall numbers of the latter two species or less movement of F. arisanus within the field. PMID- 24073693 TI - A TFG-TEC nuclear localization mutant forms complexes with the wild-type TFG-TEC oncoprotein and suppresses its activity. AB - Human EMCs (extraskeletal myxoid chondrosarcomas) are soft tissue tumours characterized by specific chromosomal abnormalities. Recently, a proportion of EMCs were found to harbour a characteristic translocation, t(3;9)(q11-12;q22), involving the TFG (TRK-fused gene) at 3q11-12 and the TEC (translocated in extraskeletal chondrosarcoma) gene at 9q22. The present study used both in vitro and in vivo systems to show that the TFG-TEC protein self-associates, and that this is dependent upon the CC (coiled-coil) domain (amino acids 97-124), the AF1 (activation function 1) domain (amino acids 275-562) and the DBD (DNA-binding domain) (amino acids 563-655). The TFG-TEC protein also associated with a mutant NLS-TFG-TEC (AAAA) protein, which harbours mutations in the NLS (nuclear localization signal). Subcellular localization assays showed that the NLS mutant TFG-TEC (AAAA) protein interfered with the nuclear localization of wild-type TFG TEC. Most importantly, the mutant protein inhibited TFG-TEC-mediated transcriptional activation in vivo. Thus mutations in the TFG-TEC NLS yield a dominant-negative protein. These results show that the biological functions of the TFG-TEC oncogene can be modulated by a dominant-negative mutant. PMID- 24073694 TI - Effects of three levels of arousal on 3-back working memory task performance. AB - This study investigated how three levels of arousal affected performance of a 3 back working memory task. Ten female and ten male university students participated in this experiment. With pictures selected from a group test, three levels of arousal were induced--i.e., tense, neutral, and relaxed emotions. Each subject was run through the procedure three times, once for each arousal level. The procedure consisted of six phases for each arousal condition: (1) Rest 1 (2 min), (2) Picture 1 (presenting emotion arousing photos for 2 min), (3) 3-back working memory task 1 (2 min), (4) Picture 2 (presenting emotion-arousing photos for 2 min), (5) 3-back working memory task 2 (2 min), and (6) Rest 2 (2 min). The skin conductance level of electrodermal activity was also measured during all phases of the experiment. The accuracy rate of 3-back working memory task performance was the highest at a neutral emotional state, followed by relaxed and then tense emotional states. There were no significant differences in reaction time. PMID- 24073695 TI - Bi-frontal direct current stimulation affects delay discounting choices. AB - In delay discounting tasks, participants decide between receiving a certain amount of money now or a larger sum sometime in the future. This study investigated the effects of transcranial direct current stimulation on delay discounting. Participants made delay discounting choices while receiving a bi frontal stimulation of right-hemisphere anodal/left-hemisphere cathodal, left hemisphere anodal/right-hemisphere cathodal, and sham stimulation, in three separate sessions. When the difference between the alternatives was 10% or more, participants generally preferred to wait for the larger sum. Nevertheless, there were more choices of smaller "immediate" gains, instead of the larger delayed options, when the left dorsolateral prefrontal cortex (DLPFC) was facilitated and the right DLPFC inhibited, compared to the sham stimulation. These observations indicate the significant role of the prefrontal cortex in delay discounting choices, and demonstrate that increased left frontal activation combined with decreased right frontal activation can alter decision-making by intensifying a tendency to choose immediate gains. PMID- 24073696 TI - Effects of emotional music on visual processes in inferior temporal area. AB - To investigate the effects of emotional music on visual processes, we analyzed visual evoked magnetic fields (VEF) on listening to emotional music in 14 healthy subjects. Positive and negative pieces of music were delivered during VEF recording following stimulation by emotionally neutral pictures of faces and landscapes. VEF components at 100 (M100) and 150 (M170)ms after stimulus onset were analyzed, and the estimated current strength for M170 following face stimulation was enhanced with negative compared to positive music in the right hemisphere. The equivalent current dipole for M100 and M170 was estimated in the primary visual cortex (V1) and inferior temporal area (IT), respectively. The present results indicate that background music showed a top-down control of the visual processes in IT, which is a core site responsible for the interpretation of facial expression. The emotional contents of music could alter visual processes, especially those involving the face. PMID- 24073697 TI - The "side" matters: how configurality is reflected in completion. AB - The perception of figure-ground organization is a highly context-sensitive phenomenon. Accumulating evidence suggests that the so-called completion phenomenon is tightly linked to this figure-ground organization. While many computational models have applied borderline completion algorithms based on the detection of boundary alignments, we point out the problems of this approach. We hypothesize that completion is a result of computing the figure-ground organization. Specifically, the global interactions in the neural network activate the "border-ownership" sensitive neurons at the location where no luminance contrast is given and this activation corresponds to the perception of illusory contours. The implications of this result to the general property of emerging Gestalt percepts are discussed. PMID- 24073698 TI - Long range grouping mechanisms for object perception. AB - The case made by Kogo and Wagemans for border ownership of surface boundaries to explain modal completion of illusory contours is well argued, and is compatible with psychophysical and physiological research on configural interactions with stereoscopic depth processing. However, it is important to contextualize such a mechanism of surface interpolation with related object grouping mechanisms in visual cortex, such as those not necessarily related to depth. Additionally, it's worth considering how the BOWN model can be generalized beyond Kanizsa shapes to more complex volumetric surface interpolations. PMID- 24073699 TI - "Connectability" matters too: completion theories need to be complete. AB - Kogo and Wagemans provide an intriguing way of assigning a polarity value to closed edges in fragmented images (solving the border ownership problem), but their model lacks generality and disregards connectability as a relevant aspect of visual completion. The lack of generality depends on considering concave disk sectors (pacmen) as the main inducers of illusory contours. Connectability is crucial for defining the occurrence, the salience and the shape of completed contours. A complete theory of completion should integrate border ownership and connectability, rather than emphasizing one aspect over the other. PMID- 24073700 TI - Filling-in the gaps in models of completion. AB - Kogo and Wagemans' appropriately link completion phenomena to figure-ground computations. I argue that this link can be strengthened by considering the ecological conditions that give rise to completion phenomena. However, despite their polemics, the model that they offer can be viewed as an elaboration of the "borderline completion plus filling-in" model they eschew. Finally, I argue that it is unclear whether their model can: (1) Explain how surface structure and/or border ownership modulate the shape of interpolated contours; or (2) give meaningful outputs for images of natural scenes that contain a variety of different edge types. PMID- 24073701 TI - Neurophysiological constraints on models of illusory contours. AB - Illusory contours can appear as interpolation between edges of the stimulus, as in the Kanizsa triangle, or run orthogonal to the inducing elements, as in the Ehrenstein illusion. Single-cell recordings from monkey visual cortex suggest that both are produced by the same mechanism. Neural border ownership coding, on the other hand, which shows a much larger range of context integration, might involve a different mechanism. PMID- 24073702 TI - Surface reconstruction, figure-ground modulation, and border-ownership. AB - The Differentiation-Integration for Surface Completion (DISC) model aims to explain the reconstruction of visual surfaces. We find the model a valuable contribution to our understanding of figure-ground organization. We point out that, next to border-ownership, neurons in visual cortex code whether surface elements belong to a figure or the background and that this is influenced by attention. We furthermore suggest that there must be strong links between object recognition and figure-ground assignment in order to resolve the status of interior contours. Incorporation of these factors in neurocomputational models will further improve our understanding of surface reconstruction, figure-ground organization, and border-ownership. PMID- 24073703 TI - Borders, contours, and mechanism. AB - Kogo and Wagemans claim that subjective contours are assigned from the earliest processing stages. I argue that in making this claim, Kogo and Wagemans are mistaking subjective experience with the perceptual mechanism. There is ample evidence that before figure assignment occurs object properties on opposite sides of unassigned borders compete for perception as figures. In order for these properties to compete, these must be a point in processing at which a border exists before it is assigned to one side. PMID- 24073704 TI - The emergent property of border-ownership and the perception of illusory surfaces in a dynamic hierarchical system. AB - We argued that borderline completion does not explain the completion, that the computation of border-ownership (BOWN) causes illusory signals, and that neurons activated at illusory contours represent BOWN. Although most commentaries show support to our view, they further emphasized the importance of feedback and also pointed out some examples challenging our view. The signal processing in the hierarchy and the classification of neurons are also discussed. In this reply, we explain our position on a dynamic feedback system reflecting the global configuration, and clarify our view on completion, by examining the example figures and neurophysiological data indicated in the commentaries. PMID- 24073705 TI - Intensified neoadjuvant radiochemotherapy for rectal cancer enhances surgical complications. AB - BACKGROUND: Neoadjuvant radiochemotherapy has proven superior to adjuvant treatment in reducing the rate of local recurrence without impairing cancer related survival or the incidence of distant metastases. The present study aimed at addressing the effects of an intensified protocol of neoadjuvant treatment on the development of postoperative complications. METHODS: A total of 387 patients underwent oncological resection for rectal cancer in our institution between January 2000 and December 2009. 106 patients received an intensified radiochemotherapy. Perioperative morbidity and mortality were analyzed retrospectively with special attention on complication rates after intensified radio-chemotherapy. Therefore, for each patient subjected to neoadjuvant treatment a patient without neoadjuvant treatment was matched in the following order for tumor height, discontinuous resection/exstirpation, T-category of the TNM-system, dividing stoma and UICC stage. RESULTS: Of all patients operated for rectal cancer, 27.4% received an intensified neoadjuvant treatment. Tumor location in the matched patients were in the lower third (55.2%), middle third (41.0%) and upper third (3.8%) of the rectum. Postoperatively, surgical morbidity was higher after intensified neoadjuvant treatment. In the subgroup with low anterior resection (LAR) the anastomosis leakage rate was higher (26.6% vs. 9.7%) and in the subgroup of patients with rectal exstirpations the perineal wound infection rate was increased (42.2% vs. 18.8%) after intensified radiochemotherapy. CONCLUSIONS: In rectal cancer the decision for an intensified neoadjuvant treatment comes along with an increase of anastomotic leakage and perineal wound infection. Quality of life is often reduced considerably and has to be balanced against the potential benefit of intensifying neoadjuvant radiochemotherapy. PMID- 24073706 TI - Microwave-assisted protection of primary amines as 2,5-dimethylpyrroles and their orthogonal deprotection. AB - Primary amines can be readily doubly protected as N-substituted 2,5 dimethylpyrroles. Although this protecting group is stable toward strong bases and nucleophiles, long reaction times are required for both the protection and deprotection steps, generally resulting in low deprotection yields. By employing microwave irradiation, protection and deprotection reaction times are dramatically reduced. Furthermore, deprotection with dilute hydrochloric acid in ethanol increases reaction yields. Diverse deprotection conditions have been developed in conjunction with microwave irradiation, so that protection as an N substituted 2,5-dimethylpyrrole can be orthogonal to other standard amine protecting groups, such as tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), and 9-fluorenylmethyloxycarbonyl (Fmoc). PMID- 24073707 TI - Exploring bacterial flora in oral squamous cell carcinoma: a microbiological study. AB - The oral cavity contains a unique and diverse microflora. While most of these organisms exhibit commensalism, shifts in bacterial community dynamics cause pathological changes within the oral cavity and at distant sites. We assessed the microbial flora using cultured saliva and oral swabs from subjects with oral squamous cell carcinoma (OSCC) and healthy controls. Microbial samples were collected from the carcinoma site, contralateral healthy mucosa, and saliva of the study group and samples were collected from healthy mucosa and saliva of controls. Samples were stored on ice and transported to the laboratory for culture. The median number of colony forming units (CFU)/ml at carcinoma sites was significantly greater than at the contralateral healthy mucosa. Similarly, in saliva of carcinoma subjects, the median number of CFU/ml was significantly greater than in saliva of control subjects. PMID- 24073708 TI - A survey of the Queensland healthcare workforce: attitudes towards dementia care and training. AB - BACKGROUND: Positive attitudes of healthcare staff towards people with dementia promote higher quality care, although little is known about important factors that underlie positive attitudes. Key aims of this project were to explore the relationships between staff attitudes towards dementia, self-confidence in caring for people with dementia, experience and dementia education and training. METHODS: A brief online survey was developed and widely distributed to registered nurses and allied health professionals working in Queensland in 2012. Regression analyses were performed to identify important predictors of self-confidence in caring for people with dementia and positive attitudes towards people with dementia. RESULTS: Five hundred and twenty-four surveys were completed by respondents working in a range of care settings across Queensland. Respondents were predominantly female (94.1%), and most were registered nurses (60%), aged between 41 and 60 years (65.6%). Around 40% regularly worked with people with dementia and high levels of self-confidence in caring for this population and positive attitudes towards people with dementia were reported. The majority of respondents (67%) had participated in a dementia education/training activity in the past 12 months. More experience working with people with dementia predicted greater self-confidence while recent participation in a dementia education/training and higher self-confidence in caring for a person with dementia significantly predicted more positive attitudes towards people with dementia. CONCLUSIONS: These results confirm the importance of self-confidence and dementia education in fostering positive attitudes and care practices towards people with dementia. Our results also indicate that the demand for ongoing dementia education is high amongst health care workers and it is recommended that regular dementia education/ training be provided and promoted for all healthcare personnel who work with people with dementia. PMID- 24073709 TI - High burden of iron deficiency and different types of anemia in inflammatory bowel disease outpatients in Scandinavia: a longitudinal 2-year follow-up study. AB - OBJECTIVE: The prevalence of anemia in inflammatory bowel disease (IBD) has been broadly described. The recurrence, type and burden of anemia remain unenlightened. The primary objective was to describe this. The secondary objective was to evaluate the implementation of European guidelines. MATERIALS AND METHODS: This longitudinal follow-up study included 300 IBD outpatients from six centers in Scandinavia. Patients were enrolled in a research cohort, in which each center included 5% of their IBD cohort. The study was prospectively planned, while data were retrospectively collected. The burden of anemia was calculated as number of months with anemia. A Markov model was used to calculate the probabilities of transitioning between stages. The European guidelines were used as the standard for anemia management. RESULTS: Anemia affected > 50% of IBD outpatients during the 2-year observation period. Totally, 20% of the total observation time was spent in anemia. Over the 7200 months of observation, anemia was found in 1410 months. The most frequent type was combined anemia (63%). Combined anemia covers both anemia of chronic disease (ACD) and iron-deficiency anemia (IDA). Pure ACD was present in 21% of burden time, while pure IDA was present in 16% of burden time. The European guidelines have mainly been implemented. CONCLUSION: Anemia affected a majority of the IBD outpatients. One in five months, the patients were anemic. Anemia related to inflammation dominated the different types of anemia. Pure IDA was found in for 16%. These findings, despite a fair implementation of guidelines. PMID- 24073710 TI - Reducing the airflow waveform distortions from breathing style and body position with improved calibration of respiratory effort belts. AB - BACKGROUND: Respiratory effort belt measurement is a widely used method to monitor respiration. Signal waveforms of respiratory volume and flow may indicate pathological signs of several diseases and, thus, it would be highly desirable to predict them accurately. Calibrated effort belts are sufficiently accurate for estimating respiratory rate, but the respiratory volume and flow prediction accuracies degrade considerably with changes in the subject's body position and breathing style. METHODS: An improved calibration method of respiratory effort belts is presented in this paper. It is based on an optimally trained FIR (Finite Impulse Response) filter bank constructed as a MISO system (Multiple-Input Single Output) between respiratory effort belt signals and the spirometer in order to reduce waveform errors. Ten healthy adult volunteers were recruited. Breathing was varied between the following styles: metronome-guided controlled breathing rate of 0.1 Hz, 0.15 Hz, 0.25 Hz and 0.33 Hz, and a free rate that was felt normal by each subject. Body position was varied between supine, sitting and standing. The proposed calibration method was tested against these variations and compared with the state-of-the-art methods from the literature. RESULTS: Relative waveform error decreased 60-70% when predicting airflow under changing breathing styles. The coefficient of determination R2 varied between 0.88-0.95 and 0.65 0.79 with the proposed and the standard method, respectively. Standard deviation of respiratory volume error decreased even 80%. The proposed method outperformed other methods. CONCLUSIONS: Results show that not only the respiratory volume can be computed more precisely from the predicted airflow, but also the flow waveforms are very accurate with the proposed method. The method is robust to breathing style changes and body position changes improving greatly the accuracy of the calibration of respiratory effort belts over the standard method. The enhanced accuracy of the belt calibration offers interesting opportunities, e.g. in pulmonary and critical care medicine when objective measurements are required. PMID- 24073711 TI - Antiplatelet therapy for patients with stable ischemic heart disease and baseline thrombocytopenia: ask the hematologist. AB - Baseline thrombocytopenia (TP) is relatively common in patients referred for percutaneous coronary intervention (PCI). Its detection may have implications for long-term antiplatelet medication prescription and adherence. The aim of this article is to review several practical aspects in managing patients with baseline TP and stable coronary artery disease (CAD). Moving from two clinical cases, we tried to picture cardiological scenarios associated with baseline TP and to provide flow charts for patient's management which take into consideration both the cardiological and the hematological conditions. TP in patients with stable CAD on antiplatelet treatment may follow diverse clinical courses depending upon TP inferred etiology, baseline degree of thrombocytopenia and its time course as outlined by previous complete blood counts, when available. Evaluation of these three parameters may guide the planning of further patient work-up and the choice of the most appropriate cardiological treatment (medical, invasive with stent implantation or coronary artery bypass). A multidisciplinary evaluation comprehensive of hematological counseling is also recommended in these patients before planning prolonged dual anti-platelet therapy. PMID- 24073712 TI - Bordetella pertussis seroprevalence in Belgian adults aged 20-39 years, 2012. AB - SUMMARY The last report on pertussis seroprevalence in Belgium concerned samples collected during 1993-1994. In the context of the Eupert-Labnet WP6 seroprevalence study (comparing sera from 16 European member states), 1500 anonymized leftover diagnostic samples were collected randomly during the second semester of 2012 by the clinical chemistry laboratories of six participating Belgian centres, distributed equally between Flanders, Wallonia and Brussels Capital Region. As suggested by the WP6 organizers, a total of 750 samples (125/centre) were selected from subjects in the 20-29 years age group and 750 samples (125/centre) from subjects in the 30-39 years age group. Anti-PT IgG levels were measured using Virion-Serion ELISA and analysed using predefined cut off levels. Sixty-one (4%) sera were indicative of an infection in the past 2 years (between 50 and 100 IU/ml) and another 61 (4%) sera had anti-PT IgG antibodies reflecting acute infection (>100 IU/ml). These results highlight the presence of a Bordetella pertussis reservoir in the adult 'healthy' Belgian population. PMID- 24073713 TI - Lack of variant specific CD8+ T-cell response against mutant and pre-existing variants leads to outgrowth of particular clones in acute hepatitis C. AB - BACKGROUND: CTL escape mutations have been described during acute hepatitis C in patients who developed chronic disease later on. Our aim was to investigate the mutual relationship between HCV specific CD8+ T cells and evolution of the viral sequence during early acute HCV infection. RESULTS: We sequenced multiple clones of NS3 1406 epitope in 4 HLA-A*02 patients with acute hepatitis C genotype 1b infection. Pentamers specific for the variants were used to monitor the corresponding CD8+ T cell response. We observed outgrowth of mutations, which induced only a weak and thus potentially insufficient CD8+ T cell response. In one patient we observed outgrowth of variant epitopes with similarities to a different genotype rather than de novo mutations most probably due to a lack of responsiveness to these likely pre-existing variants. We could show that in acute hepatitis C CTL escape mutations occur much earlier than demonstrated in previous studies. CONCLUSIONS: The adaption of the virus to a new host is characterized by a high and rapid variability in epitopes under CD8+ T cell immune pressure. This adaption takes place during the very early phase of acute infection and strikingly some sequences were reduced below the limit of detection at some time points but were detected at high frequency again at later time points. Independent of the observed variability, HCV-specific CD8+ T cell responses decline and no adaption to different or new antigens during the course of infection could be detected. PMID- 24073714 TI - Idiosyncratic drug-induced liver injury: an update on the 2007 overview. AB - INTRODUCTION: Idiosyncratic drug induced liver injury (DILI) is rare, with an incidence of approximately 19 per 100,000 treated individuals. AREAS COVERED: An update on the epidemiology, pathogenic mechanisms, diagnosis, outcome, risk factors for idiosyncratic drug-induced hepatotoxicity, specific classes of drug hepatotoxicity and biomarkers to predict DILI are covered. Cumulative drug exposure and HLA phenotypes play an important role in the pathogenesis of DILI. Patients who present with suspected DILI and jaundice should have biliary obstruction and acute viral hepatitis, including hepatitis E excluded. Immune mediated DILI will respond to steroid therapy. Patients with an elevated bilirubin and a hepatocellular pattern of liver function tests have severe liver injury with a mortality of greater than 10% and a risk of acute liver failure. Women have an increased risk of hepatocellular DILI. Antibiotics, anticonvulsants, and antidepressant therapy remain the commonest causes of DILI in the Western Hemisphere. Statin therapy rarely causes severe liver injury. EXPERT OPINION: The establishment of prospective registries for DILI has provided valuable data on the pathogenesis and outcome of DILI. Drug-specific computerised causality assessment tools should improve the diagnosis of DILI. The clinical utility of genetic polymorphisms associated with drug-specific DILI is limited. PMID- 24073716 TI - Origin of size dependency in coherent-twin-propagation-mediated tensile deformation of noble metal nanowires. AB - Researchers have recently discovered ultrastrong and ductile behavior of Au nanowires (NWs) through long-ranged coherent-twin-propagation. An elusive but fundamentally important question arises whether the size and surface effects impact the twin propagation behavior with a decreasing diameter. In this work, we demonstrate size-dependent strength behavior of ultrastrong and ductile metallic NWs. For Au, Pd, and AuPd NWs, high ductility of about 50% is observed through coherent twin propagation, which occurs by a concurrent reorientation of the bounding surfaces from {111} to {100}. Importantly, the ductility is not reduced with an increase in strength, while the twin propagation stress dramatically increases with decreasing NW diameter from 250 to 40 nm. Furthermore, we find that the power-law exponent describing the twin propagation stress is fundamentally different from the exponent describing the size-dependence of the yield strength. Specifically, the inverse diameter-dependence of the twin propagation stress is directly attributed to surface reorientation, which can be captured by a surface energy differential model. Our work further highlights the fundamental role that surface reorientations play in enhancing the size-dependent mechanical behavior and properties of metal NWs that imply the feasibility of high efficiency mechanical energy storage devices suggested before. PMID- 24073715 TI - Changes in the symptom pattern and the densities of large-intestinal endocrine cells following Campylobacter infection in irritable bowel syndrome: a case report. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder. Post-infectious IBS (PI-IBS) is a subset of IBS that accounts for a large proportion of IBS patients. The PI-IBS symptoms meet the Rome criteria for IBS with diarrhoea (IBS-D) or IBS with mixed bowel habits (IBS M). A low-grade inflammation has been reported to occur in PI-IBS. Abnormalities in intestinal endocrine cells have been reported in both sporadic IBS and PI-IBS. CASE PRESENTATION: A 20-year-old female with a diagnosis of IBS with constipation (IBS-C), according to Rome III criteria, contracted Campylobacter-induced gastroenteritis, after which her symptom pattern changed to IBS-M. She showed an intestinal low-grade inflammation that was manifested by an increase in the number of intraepithelial and lamina propria leucocytes and lymphocytes and an increase in the density of mast cells in lamina propria. There was also an increase in the density of intestinal serotonin and peptide YY (PYY) cells and a decrease in the density of rectal somatostatin cells. Follow-up of the patient at 4-months post-infection revealed reduction of IBS symptoms and an improvement in her quality of life. However, 6 months following the Campylobacter infection, the patient switched back from IBS-M to IBS-C, probably due to recovery from PI-IBS. The patient was treated with prucalopride, which is serotonin 5HT4 receptor agonist. Six months later following this treatment, the symptoms were reduced and the quality of life improved in the reported patient. CONCLUSIONS: Gastroenteritis in patients with IBS-C causes a post-infectious, low-grade inflammation. Interaction between immune-cells and intestinal endocrine cells increases the density of certain endocrine cells, which in turn might be responsible for the change in the symptom pattern, the milder symptoms and the improvement in the quality of life seen in the reported patient. The findings in this case raise the question as to whether intestinal infections are responsible for the previously reported switching of IBS from one subtype to another over time. PMID- 24073717 TI - Severe vitamin D-deficiency and increased bone turnover in patients with hepatitis B from northeastern China. AB - INTRODUCTION: Vitamin D plays a key role in maintaining calcium homeostasis and skeletal health. The liver is critically involved in vitamin D metabolism, as 25 hydroxyvitamin D3 (25(OH)D3) is synthesized in the liver. Therefore liver dysfunction may lead to vitamin D deficiency and bone problems. The aim of this study was to examine vitamin D status and bone turnover markers in hepatitis B patients from northeastern China. METHODS: We recruited 39 patients with hepatitis B (23 noncirrhotic and 16 cirrhotic) and 48 healthy controls in Shenyang, a metropolitan city in northeastern China, and measured serum 25(OH)D3 levels and serum and urinary bone turnover markers in these subjects. RESULTS: Serum 25(OH)D3 levels in the patients with or without cirrhosis were markedly lower compared to the nonhepatitis controls (19.2 +/- 1.2 and 18.5 +/- 1.3 vs. 31.6 +/- 1.3 nmol/L control), whereas serum and urinary bone turnover markers (alkaline phosphatase, C-terminal telopeptide of type I collagen, and pyridinoline) were significantly higher in these patients than in the controls. Moreover, serum levels of osteoprotegerin, a bone mass-regulating protein, were substantially reduced in the patients, with the lowest seen in patients with cirrhosis (2.7 +/- 1.1 and 1.4 +/- 0.4 vs. 3.4 +/- 0.7 pg/mL control). Serum 25(OH)D3 levels below 30 nmol/L were positively correlated with serum osteoprotegerin levels in this cohort. CONCLUSIONS: Severe vitamin D deficiency is very common in hepatitis B patients in northeastern China, which negatively impacts their bone health. These data strongly suggest a need to treat these patients with vitamin D supplementation to protect their bone health. PMID- 24073718 TI - Carrying and spine loading. AB - The advantages and disadvantages of different methods of carrying objects on spine loading are still not fully understood. Previous studies have either examined the effects of carrying using physiological measures or examined isolated spine segments using biomechanical models. Additionally, most studies have been restricted to only a small number of carrying conditions. Very few studies have attempted to examine the various factors influencing spine loading together. To improve understanding of interacting factors on carrying, this study assessed the lumbar spine loads of 16 subjects as they assumed six styles of carrying at two weight levels and two activity levels (walking vs. standing). Concurrent with each trial, a subject-specific biomechanical model was used to assess spine forces over the full lumbar spine. Most carrying methods in the trials resulted in relatively low levels of spine loading. Anterior/posterior (A/P) shear loading was the only spine-loading dimension that reached biomechanically meaningful levels. Two carrying conditions, with bins carried in front of the body, significantly increased A/P shear compared with other carrying styles. This increase appeared to be due to the greater moment arms occurring in these conditions. Many of the other carrying styles produced A/P shears that were similar to those observed when carrying nothing at all. Of all the tasks, the backpack carry characteristically produced especially low spine loads. The findings of the study suggest that to achieve optimal carrying in terms of spine loading, loads should be positioned close to the body, even when carrying relatively light loads. PMID- 24073719 TI - The palliative care knowledge questionnaire for PEACE: reliability and validity of an instrument to measure palliative care knowledge among physicians. AB - BACKGROUND: In Japan, a nationwide palliative care education program for primary palliative care (the Palliative care Emphasis program on symptom management and Assessment for Continuous medical Education: PEACE) was established in 2008. Effective delivery of such programs relies on adequate evaluations of program efficacy; however, such an instrument does not exist. OBJECTIVE: This study aimed to develop and validate a measurement tool to quantify knowledge level of physicians about broader areas of palliative care, by which the effect of an education program could be measured. METHODS: We conducted a cross-sectional, anonymous, self-administered questionnaire survey with a group of 801 conveniently sampled physicians in October 2010. To examine the test-retest reliability of items and domains, the questionnaire was reissued two weeks after the first survey was completed. This study used psychometric methods, including item response theory, intraclass correlation coefficients, and known-group validity. RESULTS: The response rate was 54% (n=434). We included 33 items across the following 9 domains: (1) philosophy of palliative care, (2) cancer pain, (3) side effects of opioids, (4) dyspnea, (5) nausea and vomiting, (6) psychological distress, (7) delirium, (8) communication regarding palliative care, and (9) community-based palliative care. For these items, the intraclass correlation was 0.84 and the Kuder-Richardson Formula 20 (KR-20) test of internal consistency was 0.87. There was a significant difference in the scores between palliative care specialists and other physicians. CONCLUSIONS: We successfully validated a newly developed palliative care knowledge questionnaire to evaluate PEACE effectiveness (PEACE-Q). The PEACE-Q could be useful for evaluating both palliative care knowledge among physicians and education programs in primary palliative care. PMID- 24073720 TI - Time and life perception in the terminally ill: its utility in screening for depression. AB - OBJECTIVE: The objective was to explore the utility of a new three-item depression screening tool concerning time and life perception (TLP-3), compared with the DSM-IV criteria. METHODS: This was a cross-sectional study of 63 Portuguese terminally ill patients, from May 2010 to November 2012. Patients were eligible if they fulfilled the following inclusion criteria: age >=18 years old; having a life-threatening disease with prognosis of 6 months or less; no evidence of dementia or delirium, based on documentation within the medical chart or by clinical consensus; Mini Mental State score >=20; being able to read and speak Portuguese; and provision of written informed consent. Participants were assessed for depression using DSM-IV criteria and the newly developed TLP-3. Screening performance for depression using the TLP-3 compared with DSM-IV was calculated using measures of sensitivity, specificity, positive and negative predictive values. Logistic regression was calculated with the aim of identifying variables with the best predictive ability for diagnosing depression. RESULTS: After logistic regression analysis was made to all three items composing TLP-3, only two items were maintained (OR=2.9, 95% CI [0.9-8.7]; OR=7.6, 95% CI [0.9-65.3], respectively). This final regression model composed of two questions (TLP-2) was able to diagnose correctly 70% of the depressed patients with a sensitivity of 63% and a specificity of 74%. The area under the ROC curve was 72% (95% CI [59 85]). CONCLUSION: TLP-3 is a novel and clinically applicable approach to assessing depression among palliative care patients. Further investigation is needed on the psychological significance of time and life perception distortions, and its possible application to screen for depression among patients nearing end of life. PMID- 24073721 TI - "Isn't there anything more you can do?": When empathic statements work, and when they don't. AB - The query, "Isn't there anything more you can do?" represents a classic informational question with an emotional subtext. In our previous work we have emphasized the value of noticing the emotional cue implicit in this question, and responding with an empathic statement. Yet responding explicitly to patients' emotions is not the best initial communication strategy for all patients. In this paper we discuss four different opening communication strategies--verbalize empathy, exchange information, contain chaos, respect searching--for patients who ask, "Isn't there anything more you can do?" PMID- 24073722 TI - What is the effect of pseudoexfoliation syndrome on renal function in patients without glaucoma? AB - PURPOSE: To evaluate renal function in patients with pseudoexfoliation syndrome. MATERIALS AND METHODS: This prospective, cross-sectional, case-control study involved 49 patients with pseudoexfoliation syndrome (PEX) and 42 control subjects. Renal function was examined by biochemical parameters and Doppler ultrasonography. Serum creatinine, blood urea nitrogen, urea levels, urine microalbumin level and creatinine clearance were measured. Renal volume, resistive index and pulsatility index were calculated using Doppler ultrasonography. RESULTS: The mean laboratory values for both groups were as follows: Creatinine, PEX: 0.81 +/- 0.28 mg/dL - Control: 0.79 +/- 0.22 mg/dL; urea, PEX: 31.6 +/- 9.7 mg/dL - Control: 32.2 +/- 8.4 mg/dL; blood urea nitrogen, PEX: 14.8 +/- 4.6 mg/dL - Control: 15.1 +/- 4.0 mg/dL; creatinine clearance, PEX: 89.1 +/- 35.6 mL/min - Control: 99.0 +/- 47.2 mL/min; microalbumin, PEX: 5.8 +/- 22.7 mg/dL - Control: 2.7 +/- 6.0 mg/dL. The differences between groups were not significant (p > 0.300). Renal volume, resistive index and pulsatility index values were similar in both groups (p > 0.200). CONCLUSIONS: This study showed that pseudoexfoliation syndrome does not affect biochemical and ultrasonographic parameters associated with renal function. PMID- 24073723 TI - Cancer mutation signatures, DNA damage mechanisms, and potential clinical implications. AB - Knowledge of cancer genomic DNA sequences has created unprecedented opportunities for mutation studies. Computational analyses have begun to decipher mutational signatures that identify underlying causes. A recent analysis encompassing 30 cancer types reported 20 distinct mutation signatures, resulting from ultraviolet light, deficiencies in DNA replication and repair, and unexpectedly large contributions from both spontaneous and APOBEC-catalyzed DNA cytosine deamination. Mutational signatures have the potential to become diagnostic, prognostic, and therapeutic biomarkers as well as factors in therapy development. PMID- 24073724 TI - GLP-1-based diabetes therapies; trial by media. PMID- 24073725 TI - The potential risks of pancreatitis and pancreatic cancer with GLP-1-based therapies are far outweighed by the proven and potential (cardiovascular) benefits. AB - Recent suggestions that glucagon-like peptide-1 (GLP-1)-based therapies could cause pancreatitis, and even pancreatic cancer, are based on: ANIMAL STUDIES: The worrying histological changes are not reproduced in all studies and are unexpectedly variable with different GLP-1-based therapies. AN OBSERVATIONAL STUDY: Singh's findings that pancreatitis is doubled with GLP-1-based therapies could relate to their use in obese patients who are prone to pancreatitis risk factors--gallstones and hypertriglyceridaemia. The other observational studies do not find an association between GLP-1-based therapies and pancreatitis. US FOOD AND DRUG ADMINISTRATION ADVERSE EVENT REPORTING SYSTEM: The increased reports of pancreatitis and pancreatic cancer are likely to be attributable to 'notoriety bias'. A STUDY OF ORGAN DONOR PANCREASES: Butler's findings for those on GLP-1 based therapies vs. those not, could have other explanations. Meanwhile: META ANALYSIS: Randomized control trials with GLP-1-based therapies do not find increased pancreatitis risk. Meta-analysis of 53 randomized controlled trials including 20 212 dipeptidyl peptidase-4 inhibitor-treated patients found a significantly reduced risk of major adverse cardiovascular events [odds ratio 0.689 (0.528-0.899), P = 0.006] for dipeptidyl peptidase-4 inhibitors compared with control subjects. CARDIOVASCULAR RISK: The evidence suggests that there is more than a possibility that some of the GLP-1 receptor agonists, and possibly also some dipeptidyl peptidase-4 inhibitors, may be associated with reduced cardiovascular events. Eight ongoing long-term cardiovascular randomized controlled trials will report from September 2013 onwards. These trials should resolve the issue of pancreatitis risk and substantiate the extent of benefit. CONCLUSION: Whilst we should remain vigilant, currently the balance of evidence is strongly in support of GLP-1-based therapy, with benefits far outweighing potential risks. PMID- 24073726 TI - Incretins and pancreatitis--what happens next? A personal viewpoint. PMID- 24073728 TI - Using DNA-driven assembled phospholipid nanodiscs as a scaffold for gold nanoparticle patterning. AB - Recently, a new class of materials emerged with the assembly of DNA-coated phospholipid nanodiscs into columnar BioNanoStacks. Within these stacks, lipid discs are periodically incorporated, resulting into quasi-one-dimensional superstructures. With each disc surrounded by two recombinant scaffolding proteins, we decided to examine whether the polyhistidine tags of these proteins could be utilized to bind additional molecules or particles to these BioNanoStacks. Here we demonstrate that patterning of gold nanoparticles onto these BioNanoStacks is indeed possible. Binding occurs via a nickel-mediated interaction between the nanogolds nitrilotriacetic acid and the histidine tags of the scaffold proteins surrounding the nanodiscs. Using Monte Carlo simulations, we determine that the binding of the nanogold particles to the stacks is not a random event. By comparing the simulation and experimental results, we find that there are preferred binding sites, which affects the binding statistics. PMID- 24073729 TI - Trends in breast reconstruction: patients, providers, and health care. PMID- 24073730 TI - Percutaneous radiofrequency ablation for liver metastases in breast cancer patients. PMID- 24073731 TI - Recent download statistics for Cognitive Neuroscience. AB - Download statistics of citations offer a complementary insight into a journal's health and progress, and are a more immediate indicator of influential articles than citations. This Editorial reports some download statistics for the journal and also draws attention to the most downloaded articles that have appeared in the last two years. PMID- 24073732 TI - Lateral asymmetry in saccadic eye movements during face processing: the role of individual differences in schizotypy. AB - Healthy individuals with high as compared to low levels of schizotypal personality traits make more first saccades to the left side of faces, suggesting increased right hemisphere (RH) dominance for face processing. Patients with schizophrenia, however, show attenuated or reversed RH dominance for face processing. It is unclear whether the increased RH dominance found in high schizotypes is specific to face processing or whether it is also observable for other stimuli matched in terms of low-level visual properties. We measured gaze to faces and symmetrical fractal patterns and found higher Magical Ideation (MI) is associated with an increased left-side bias for initial saccade landing points and dwell times when free-viewing faces. These laterality biases were unaffected by facial emotion. Schizotypy scores were not related to laterality biases when viewing fractals. Our results provide further evidence that high schizotypy is associated with an increase in RH dominance for face processing. PMID- 24073733 TI - The role of spatial attention during spatial encoding. AB - In the present fMRI study, we aimed to assess whether spatial encoding is mediated by spatial attention. During encoding, participants were presented with abstract shapes to the left or right of fixation. During retrieval, old and new shapes were presented at fixation and participants classified each shape as "old left", "old-right", or "new". Subsequently remembered items were assumed to have been attended during encoding, while subsequently forgotten items were assumed to have been unattended during encoding. Mirroring classic spatial attention contralateral extrastriate effects, contralateral subsequent memory effects were observed in extrastriate cortical regions BA18 and BA19 (e.g., encoding-left hits>encoding-left-misses activated the right extrastriate cortex). An additional individual-trial modeling procedure revealed that 79.35% and 100% of accurately encoded items in the left hemisphere and the right hemisphere, respectively, reflected spatial processing. These results suggest that spatial encoding is largely, but not completely, mediated by spatial attention. PMID- 24073734 TI - In the here and now: enhanced motor corticospinal excitability in novices when watching live compared to video recorded dance. AB - Enhanced motor corticospinal excitability (MCE) in passive action observation is thought to signify covert motor resonance with the actions seen. Actions performed by others are an important social stimulus and thus, motor resonance is prevalent during social interaction. However, most studies employ simple/short snippets of recorded movements devoid of any real-life social context, which has recently been criticized for lacking ecological validity. Here, we investigated whether the co-presence of the actor and the spectator has an impact on motor resonance by comparing novices' MCE for the finger (FDI) and the arm (ECR) with single-pulse transcranial magnetic stimulation when watching five-minute solos of ballet dance, Bharatanatyam (Indian dance) and an acting control condition either live or on video. We found that (1) MCE measured in the arm muscle was significantly enhanced in the live compared to the video condition, (2) differences across performances were only evident in the live condition, and (3) our novices reported enjoying the live presentations significantly more. We suggest that novice spectators' MCE is susceptible to the performers' live presence. PMID- 24073735 TI - Linguistic multi-feature paradigm as an eligible measure of central auditory processing and novelty detection in 2-year-old children. AB - This study evaluated whether the linguistic multi-feature paradigm with five types of speech-sound changes and novel sounds is an eligible neurophysiologic measure of central auditory processing in toddlers. Participants were 18 typically developing 2-year-old children. Syllable stimuli elicited significant obligatory responses and syllable changes significant MMN (mismatch negativity) which suggests that toddlers can discriminate auditory features from alternating speech-sound stream. The MMNs were lateralized similarly as found earlier in adults. Furthermore, novel sounds elicited a significant novelty P3 response. Thus, the linguistic multi-feature paradigm with novel sounds is feasible for the concurrent investigation of the different stages of central auditory processing in 2-year-old children, ranging from pre-attentive encoding and discrimination of stimuli to attentional mechanisms in speech-like research compositions. As a conclusion, this time-efficient paradigm can be applied to investigating central auditory development and impairments in toddlers in whom developmental changes of speech-related cortical functions and language are rapid. PMID- 24073736 TI - Neural correlates of cognitive decline in ALS: an fNIRS study of the prefrontal cortex. AB - Functional near infrared spectroscopy (fNIRS) is a clinically feasible functional neuroimaging modality for detecting early cortical changes due to neurodegenerative diseases that affect cognition. The objective of this preliminary investigation was to test for reduced prefrontal activity in persons with cognitive impairments due to amyotrophic lateral sclerosis (ALS). Participants were required to complete two N-back working memory tasks of increasing complexity during fNIRS recordings. Five participants with ALS and age and gender-matched healthy participants comprised the experimental and control groups, respectively. Significant reductions in prefrontal oxygenation levels were observed for the left and right hemispheres in the ALS group compared to the control group. Reduced prefrontal activation despite intact behavioral performance for a working memory task may suggest early neuroanatomical, neurophysiological and/or compensatory mechanisms in affected individuals. The fNIRS-derived oxygenation measure shows promise as a sensitive neural marker to identify early neuropsychological impairments due to ALS. PMID- 24073738 TI - Mitochondrial fission mediates ceramide-induced metabolic disruption in skeletal muscle. AB - Ceramide is a sphingolipid that serves as an important second messenger in an increasing number of stress-induced pathways. Ceramide has long been known to affect the mitochondria, altering both morphology and physiology. We sought to assess the impact of ceramide on skeletal muscle mitochondrial structure and function. A primary observation was the rapid and dramatic division of mitochondria in ceramide-treated cells. This effect is likely to be a result of increased Drp1 (dynamin-related protein 1) action, as ceramide increased Drp1 expression and Drp1 inhibition prevented ceramide-induced mitochondrial fission. Further, we found that ceramide treatment reduced mitochondrial O2 consumption (i.e. respiration) in cultured myotubes and permeabilized red gastrocnemius muscle fibre bundles. Ceramide treatment also increased H2O2 levels and reduced Akt/PKB (protein kinase B) phosphorylation in myotubes. However, inhibition of mitochondrial fission via Drp1 knockdown completely protected the myotubes and fibre bundles from ceramide-induced metabolic disruption, including maintained mitochondrial respiration, reduced H2O2 levels and unaffected insulin signalling. These data suggest that the forced and sustained mitochondrial fission that results from ceramide accrual may alter metabolic function in skeletal muscle, which is a prominent site not only of energy demand (via the mitochondria), but also of ceramide accrual with weight gain. PMID- 24073737 TI - Mimotope vaccination for epitope-specific induction of anti-VEGF antibodies. AB - BACKGROUND: Tumor angiogenesis is critical for tumor growth, infiltration and metastasis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor and targeting it is important in reducing angiogenesis. Bevacizumab (Avastin), a monoclonal antibody that reacts directly against VEGF, has been demonstrated to be an effective treatment for various cancers such as rectal cancer, colon carcinoma, and non-small cell lung cancer, etc. RESULTS: In the current study, we used the phage display technique to generate mimotopes that complemented the screening Avastin antibody (Ab). The candidate mimotopes of VEGF were isolated from a 12-mer peptide library. The phage displaying peptide DHTLYTPYHTHP (designated as 12P) exhibited high affinity to Avastin. The chemically synthesized 12P was conjugated to keyhole limpet hemocyanin (KLH) by glutaraldehyde (GA) to form vaccine KLH-12 peptide (KLH-12P). This epitope vaccine significantly induced humoral immunity in mice. The blood serum from KLH 12P-immunized mice associated with VEGF and blocked its binding to VEGFR, thus inhibiting vascular endothelial cell proliferation and migration. CONCLUSIONS: Our data indicate that the isolated mimotope 12P reported here could potentially elicit specific antibodies against VEGF and result in the induction of anti angiogenesis responses. PMID- 24073739 TI - Biodegradable theranostic plasmonic vesicles of amphiphilic gold nanorods. AB - We have developed surface-initiated organocatalytic ring-opening polymerization on functional nanocrystals and synthesized amphiphilic gold nanorods carrying well-defined mixed polymer brushes of poly(ethylene glycol) and polylactide. Self assembly of the amphiphilic gold nanorods affords biodegradable plasmonic vesicles that can be destructed by both enzymatic degradation and near-infrared photothermal heating. When tagged with Raman probes, strongly coupled gold nanorods in the self-assembled vesicles give rise to highly active SERS signals. The biodegradable plasmonic vesicles exhibit a unique combination of optical and structural properties that are of particular interest for theranostic applications. We have demonstrated that bioconjugated SERS-active plasmonic vesicles can specifically target EpCAM-positive cancer cells, leading to ultrasensitive spectroscopic detection of cancer cells. Furthermore, integration of photothermal effect of gold nanorods and large loading capacity of the vesicles provides opportunities for localized synergistic photothermal ablation and photoactivated chemotherapy, which have shown higher efficiency in killing targeted cancer cells than either single therapeutic modality. The versatile chemistry of organocatalytic ring-opening polymerization, in conjugation with recent development in synthesizing functional nanocrystals with tailored optical, electronic, and magnetic properties opens the possibilities for constructing multifunctional biodegradable platforms for clinical translation. PMID- 24073740 TI - Comparison of rectal swabs and faeces for real-time PCR detection of enteric agents in Rwandan children with gastroenteritis. AB - BACKGROUND: Molecular diagnostics have emerged as an efficient and feasible alternative for broad detection of pathogens in faeces. However, collection of stool samples is often impractical in both clinical work and in epidemiology studies. The aim of this study was to investigate the diagnostic performance of rectal swabs as compared with traditional faeces samples for detection of enteric agents by PCR. METHOD: Three hundred twenty-six pairs of rectal swab and stool samples, obtained from Rwandan children aged 0.5-4.99 years, with or without diarrhoea, were analysed by multiple real-time PCR amplifying 3 viral, 6 bacterial and one protozoan target. RESULTS: For all agents there was a significant correlation (R2 0.31-0.85) between Ct values in faeces and rectal swabs. For most agents the Ct values, a marker for target concentration, were significantly lower (by 1-3 cycles) in faeces, indicating pathogen content up to ten times higher than in rectal swabs. Despite this, there was no significant difference in detection rate between faeces and rectal swabs for any agent, reflecting that pathogen concentration was far above the limit of detection in the majority of cases. CONCLUSION: The similar detection rates and the Ct value correlations as compared with traditional faeces samples indicate that rectal swabs are accurate for real-time PCR-based identification of enteric agents and may be used also for quantitative estimation of pathogen load. PMID- 24073741 TI - Chlorophyll content and chlorophyll fluorescence in tomato leaves infested with an invasive mealybug, Phenacoccus solenopsis (Hemiptera: Pseudococcidae). AB - Herbivore injury has indirect effects on the growth and performance of host plants through photosynthetic suppression. It causes uncertain reduction in photosynthesis, which likely depends on the degree of infestation. Rapid light curves provide detailed information on the saturation characteristics of electron transport as well as the overall photosynthetic performance of a plant. We examined the effects of different intensities of infestation of the invasive mealybug, Phenacoccus solenopsis Tinsley (Hemiptera: Pseudococcidae), on the relative chlorophyll content and rapid light curves of tomato Solanum lycopersicum L. leaves using a chlorophyll meter and chlorophyll fluorescence measurement system, respectively, under greenhouse conditions. After 38 d of P. solenopsis feeding, relative chlorophyll content of tomato plants with initial high of P. solenopsis was reduced by 57.3%. Light utilization efficiency (alpha) for the initial high-density treatment was reduced by 42.4%. However, no significant difference between initial low-density treatment and uninfested control was found. The values of the maximum electron transport rate and minimum saturating irradiance for initial high-density treatment were reduced by 82.0 and 69.7%, respectively, whereas the corresponding values for low-density treatment were reduced by 55.9 and 58.1%, respectively. These data indicated that changes were induced by P. solenopsis feeding in the relative chlorophyll content and chlorophyll fluorescence of infested tomato plants. The results indicating that low initial infestation by P. solenopsis caused no change in relative leaf chlorophyll content or light utilization efficiency could have been because the plants rapidly adapted to P. solenopsis feeding or because of compensatory photosynthesis. PMID- 24073742 TI - The cognitive and neural correlates of psychopathy and especially callous unemotional traits in youths: a systematic review of the evidence. AB - It is unclear whether the concepts and findings of the underlying neurobiology of adult psychopathy apply to youths as well. If so, a life span approach to treatment should be taken. Because youths' brains are still developing, interventions at an early age may be far more effective in the long run. The aim of this systematic review is to examine whether the neurocognitive and neurobiological factors that underlie juvenile psychopathy, and specifically callous-unemotional (CU) traits, are similar to those underlying adult psychopathy. The results show that youths with CU traits show lower levels of prosocial reasoning, lower emotional responsivity, and decreased harm avoidance. Brain imaging studies in youths with CU traits are still rare. Available studies suggest specific neural correlates, such as a reduced response of the amygdala and a weaker functional connectivity between the amygdala and the ventromedial prefrontal cortex. These findings are largely in line with existing theories of adult psychopathy, such as the dual-hormone serotonergic hypothesis and the integrated emotions systems theory. We recommend that future studies investigate the role of oxytocin, invest in the study of neural mechanisms, and study the precursors, risk factors, and correlates of CU traits in early infancy and in longitudinal designs. PMID- 24073743 TI - Phase transition behavior of a series of even n-alkane C(n)/C(n+2) mixtures confined in microcapsules: from total miscibility to phase separation determined by confinement geometry and repulsion energy. AB - The phase behaviors of binary consecutive even normal alkane (n-alkane) mixtures (n-C(n)H(2n+2)/n-C(n+2)H(2n+6), with mass ratios of 90/10 and 10/90) with different average carbon numbers n- both in the bulk state (abbreviated as C(n)/C(n+2)) and in nearly monodisperse microcapsules (abbreviated as m C(n)/C(n+2)), have been investigated by the combination of differential scanning calorimetry and temperature-dependent X-ray diffraction. The phase behavior of n alkane mixtures gradually shifts from complete phase separation, partial miscibility to total miscibility in both bulk and microcapsules with the increase of average carbon numbers n-. There are critical points for average carbon numbers of C(n)/C(n+2), where the corresponding mixtures exhibit coexistence of a triclinic phase (formed by alkane with a longer chain) and an orthorhombic ordered phase (formed by the two components of mixtures). Due to the confinement from hard shells of microcapsules, the critical points of m-C(n)/C(n+2) are smaller than those of C(n)/C(n+2). Such a phase behavior originates from the delicate combined action of confinement and repulsion energy for the encapsulated n-alkane mixtures with different average carbon numbers n-. When n- is less than the critical point, the repulsion energy between the two kinds of molecules exceeds the suppression effect of confinement, and phase separation occurs in microcapsules. It is believed that the average carbon number is another important factor that exerts strong negative influence on the phase separation of m C(n)/C(n+2) systems. PMID- 24073744 TI - Health related social exclusion in Europe: a multilevel study of the role of welfare generosity. AB - INTRODUCTION: The aim of this paper was to investigate the association between health, social position, social participation and the welfare state. Extending recent research on the social consequences of poor health, we asked whether and how welfare generosity is related to the risk of social exclusion associated with combinations of poor health, low education and economic inactivity. METHODS: Our analyses are based on data from the European Social Survey, round 3 (2006/7), comprising between 21,205 and 21,397 individuals, aged 25-59 years, within 21 European welfare states. The analyses were conducted by means of multilevel logistic regression analysis in STATA 12. RESULTS: The results demonstrated that the risk of non-participation in social networks decreased as welfare generosity increased. The risk of social exclusion, i.e. non-participation in social networks among disadvantaged groups, seldom differed from the overall association, and in absolute terms it was invariably smaller in more generous welfare state contexts. CONCLUSIONS: The results showed that there were no indications of higher levels of non-participation among disadvantaged groups in more generous welfare states. On the contrary, resources made available by the welfare state seemed to matter to all individuals in terms of overall lower levels of non-participation. As such, these results demonstrate the importance of linking health related social exclusion to the social policy context. PMID- 24073745 TI - Incidence trend of malignant polyps through the data of a specialized colorectal cancer registry: clinical features and effect of screening. AB - OBJECTIVES: The purposes of the study are to describe the incidence trend of malignant polyp of large bowel over a 25-year period in the District of Modena and to assess the effect of an organized colorectal cancer screening program. MATERIAL AND METHODS: Through the data of a specialized colorectal cancer Registry, we evaluate the clinical and pathological features of the polyps. Trend analysis was assessed with the Joinpoint Regression Program. RESULTS: A total of 172 patients with malignant polyps were diagnosed throughout the study (3.5% of 4.835 registered patients); their overall frequency during the registration period increased from zero cases in the initial years (1984-85) to 57 cases in the past 3 years (2006-2008). Crude incidence rate passed from 0.37 in 1986-89 to 10.2 in 2006. Joinpoint trend analysis of crude rates showed a significant increase of incidence during the study period, with percent of annual variation ranging between 38.6% (95% CI 12.5-70.7) and 7.3% (95% CI 2.6-12.1). During the screening period (2005-2008, the past 4 years of registration) there was a significant increase of sessile polyps (p < 0.001), while other clinical and morphological features, including the number of low- and high-risk malignant polyps, remained unchanged. The surgery (after polypectomy) tended to raise both in low- and high-risk subgroups. CONCLUSION: The incidence of malignant polyps increased significantly from the initial to the most recent periods of colorectal cancer registration. Screening was associated with changes in gross morphology of polyps and with an increased use of the surgery after endoscopic polypectomy. PMID- 24073746 TI - Pathogenesis of Staphylococcus aureus necrotizing pneumonia: the role of PVL and an influenza coinfection. AB - Only recently necrotizing pneumonia was defined as a specific disease entity that is caused by a Panton-Valentine leukocidin (PVL)-producing Staphylococcus aureus strain and is frequently preceded by an influenza infection. Necrotizing pneumonia is characterized by a sudden onset and rapid worsening of symptoms, leukopenia, airway hemorrhages, severe respiratory failure and a high mortality rate. Despite clear epidemiological data, the function of PVL in necrotizing pneumonia has been controversially discussed due to conflicting results from different disease models. Furthermore, there are many proposed mechanisms how a viral infection could facilitate and interact with a bacterial superinfection. In this review, we summarize current data from 43 clinical cases and results from various infection models on necrotizing pneumonia. We discuss the contribution of S. aureus PVL and a preceding influenza infection and present a concept of the pathogenesis of necrotizing pneumonia. PMID- 24073747 TI - Metal-catalyzed benzylic fluorination as a synthetic equivalent to 1,4-conjugate addition of fluoride. AB - We explore in detail the iron-catalyzed benzylic fluorination of substrates containing aromatic rings and electron-withdrawing groups positioned beta to one another, thus providing direct access to beta-fluorinated adducts. This operationally convenient process can be thought of not only as a contribution to the timely problem of benzylic fluorination but also as a functional equivalent to a conjugate addition of fluoride, furnishing products in moderate to good yields and in excellent selectivity. PMID- 24073748 TI - Polytypic InP nanolaser monolithically integrated on (001) silicon. AB - On-chip optical interconnects still miss a high-performance laser monolithically integrated on silicon. Here, we demonstrate a silicon-integrated InP nanolaser that operates at room temperature with a low threshold of 1.69 pJ and a large spontaneous emission factor of 0.04. An epitaxial scheme to grow relatively thick InP nanowires on (001) silicon is developed. The zincblende/wurtzite crystal phase polytypism and the formed type II heterostructures are found to promote lasing over a wide wavelength range. PMID- 24073749 TI - Occipitocondylar hyperplasia and syringomyelia presenting with facial pain. AB - The authors describe a unique presentation and long-term management of a rare craniovertebral abnormality in a patient presenting to their institution. This 10 year-old girl presented with right-sided facial pain and subjective dysesthesia of the chest wall without evidence of cervical myelopathy. She was found to have extensive cervicothoracic syringomyelia secondary to compression at the foramen magnum by hypertrophic occipital condyles. Posterior decompression and medial condylectomy was performed, with significant radiological and clinical improvement over the next 5 years of follow-up. The authors discuss the clinical pathophysiology and operative techniques used. PMID- 24073750 TI - The lost art of localization: Franc Ingraham's legacy in pediatric neurosurgery. AB - The authors describe an 8-year-old girl who underwent emergency posterior fossa surgery for resection of a large cerebellar astrocytoma in November 1939. The surgery was carried out by Franc D. Ingraham at Boston Children's Hospital a decade after he established the first pediatric neurosurgical service in the world at the same institution. Four years later the tumor recurred and the patient underwent repeat resection followed by external-beam radiation therapy. The pathological diagnosis by Sidney Farber was fibrillary astrocytoma. The young girl is currently a healthy, functional 82-year-old woman. The authors believe that this 74-year follow-up represents one of the longest in history, if not the longest, of a patient undergoing resection of a brain tumor. A recent MRI study shows postoperative changes with no evidence of residual or recurrent tumor. The original block tissue specimen had been preserved. It was restained and examined, revealing the pathological diagnosis to be juvenile pilocytic astrocytoma. The case is analyzed in the context of Ingraham's powerful and lasting impact on the field of pediatric neurosurgery. PMID- 24073751 TI - Cerebellar mutism. AB - Mutism of cerebellar origin is a well-described clinical entity that complicates operations for posterior fossa tumors, especially in children. This review focuses on the current understanding of principal pathophysiological aspects and risk factors, epidemiology, clinical characteristics, treatment strategies, and outcome considerations. The PubMed database was searched using the term cerebellar mutism and relevant definitions to identify publications in the English-language literature. Pertinent publications were selected from the reference lists of the previously identified articles. Over the last few years an increasing number of prospective studies and reviews have provided valuable information regarding the cerebellar mutism syndrome. Importantly, the clarification of principal terminology that surrounds the wide clinical spectrum of the syndrome results in more focused research and more effective identification of this entity. In children who undergo surgery for medulloblastoma the incidence of cerebellar mutism syndrome was reported to be 24%, and significant risk factors so far are brainstem involvement and midline location of the tumor. The dentate-thalamo-cortical tracts and lesions that affect their integrity are considered significant pathophysiological issues, especially the tract that originates in the right cerebellar hemisphere. Moderate and severe forms of the cerebellar mutism syndrome are the most frequent types during the initial presentation, and the overall neurocognitive outcome is not as favorable as thought in the earlier publications. Advanced neuroimaging techniques could contribute to identification of high-risk patients preoperatively and allow for more effective surgical planning that should focus on maximal tumor resection with minimal risk to important neural structures. Properly designed multicenter trials are needed to provide stronger evidence regarding effective prevention of cerebellar mutism and the best therapeutic approaches for such patients with a combination of pharmacological agents and multidisciplinary speech and behavior augmentation. PMID- 24073752 TI - A simple consensus approach improves somatic mutation prediction accuracy. AB - Differentiating true somatic mutations from artifacts in massively parallel sequencing data is an immense challenge. To develop methods for optimal somatic mutation detection and to identify factors influencing somatic mutation prediction accuracy, we validated predictions from three somatic mutation detection algorithms, MuTect, JointSNVMix2 and SomaticSniper, by Sanger sequencing. Full consensus predictions had a validation rate of >98%, but some partial consensus predictions validated too. In cases of partial consensus, read depth and mapping quality data, along with additional prediction methods, aided in removing inaccurate predictions. Our consensus approach is fast, flexible and provides a high-confidence list of putative somatic mutations. PMID- 24073753 TI - Solventless fabrication of porous-on-porous materials. AB - Here we fabricate patterned porous polymer membranes on porous substrates by a combination of physical masking and chemical vapor deposition. This all-dry technique eliminates solvent-related issues and allows for the fabrication of hierarchical porous-on-porous structures with a wide range of chemical compositions and shapes. The porous polymer membranes are made by operating at unconventional processing conditions to simultaneously deposit and polymerize monomer. The solid monomer serves as a porogen and creates microstructures around which polymer forms. Membranes with thicknesses ranging from a few hundred micrometers to a millimeter are fabricated on porous paper substrates. The resolution of the patterning process and the structure of the resulting membranes are analyzed as a function of the deposition time. It was found that the patterned membranes exhibit a tapered structure and the dimensions are in good agreement with the dimensions of the mask. One potential application of these patterned polymer membranes is demonstrated for the selective separation of analytes for diagnostic applications on paper-based microfluidic devices. The ability to pattern porous-on-porous structures can be useful for the development of hierarchical membranes for water purification and gas separation, and for sensing, patterned tissue scaffolding, and other lab-on-a-chip applications. PMID- 24073754 TI - GABAergic agents modify the response of chick scleral fibroblasts to myopic and hyperopic eye cup tissues. AB - PURPOSE: GABA antagonists inhibit experimental myopia in chick and GABA receptors have been localized to chick sclera and the retinal pigment epithelium (RPE). The RPE and the choroid alter scleral DNA and glycosaminoglycan (GAG) content in vitro; opposite effects have been observed for tissues from myopic and hyperopic eyes. The aim was to determine the effect of GABAergic agents on the DNA and GAG content of chick scleral fibroblasts directly and in co-culture with ocular tissues from myopic and hyperopic chick eyes. MATERIALS AND METHODS: Primary cultures of fibroblastic cells expressing vimentin and alpha-smooth muscle actin were established. GABAergic agents were added separately (i) to the culture medium of the scleral cells and (ii) to the culture medium of the scleral cells with the addition of posterior eye cup tissue (retina, RPE, retina + RPE, choroid + RPE) to cell culture inserts. Ocular tissues were obtained from chick eyes wearing + 15D (lens-induced hyperopia, LIH) or -15D lenses (lens-induced myopia, LIM) for three days (post-hatch day 5-8) (n = 12). GAG and DNA content of scleral fibroblasts were measured. RESULTS: GABA agents had a small direct effect on scleral cell GAG and DNA content but a larger effect was measured when GABA agents were added to the culture medium with myopic and hyperopic RPE and choroid + RPE tissues. GABA agonists increased (p = 0.002) whereas antagonists decreased (p = 0.0004) DNA content of scleral cells; effects were opposite for scleral GAG content. GABA agents significantly altered the effect of both LIM and LIH tissues (p = 0.0005) compared to control; the effects were greater for LIM tissue versus LIH tissue co-culture (p = 0.0004). CONCLUSION: GABAergic agents affect the DNA and GAG content of scleral fibroblasts both directly and when co-cultured with ocular tissues. GABA antagonists that prevent myopia development in chick model could act via a scleral mechanism utilizing the RPE/choroid. PMID- 24073755 TI - Continuous perioperative apomorphine in deep brain stimulation surgery for Parkinson's disease. AB - BACKGROUND: Patients with Parkinson's disease (PD) deprived of dopaminergic medication to facilitate awake testing during the deep brain stimulation (DBS) procedure are at increased risk of neurologic deterioration.. The aim of this survey was to demonstrate the safety of subcutaneous apomorphine treatment for reducing surgery-related neurologic deterioration in patients undergoing DBS surgery for PD. METHODS: Ninety-two patients who underwent DBS surgery for PD between 11/2007 and 10/2011 in our department were retrospectively analyzed for this survey. Demographic data, apomorphine dosage, side-effects and need of ICU/IMC stay were collected and analyzed. RESULTS: Seventy-two out of 92 patients (78.3%) received apomorphine treatment; main reason for omission of treatment was intolerable nausea (16/92, 17.3%). Apomorphine treatment was well tolerated and the most common side effect was nodular panniculitis. No severe complications were observed. No patient required ICU/IMC stay related to dopaminergic deprivation. CONCLUSIONS: Perioperative withdrawal of dopaminergic medication in PD patients leads to an increased risk of neurologic and respiratory deterioration during DBS procedures. These complications can likely be tempered using perioperative subcutaneous apomorphine as a substitute. Our 5-year experience indicates a reduction in postoperative neurologic deterioration and ICU/IMC stay need. We consider perioperative apomorphine safe during DBS surgery for PD. PMID- 24073756 TI - Apnea as an uncommon preoperative manifestation of medulla cavernous malformation: surgical treatment and literature review. AB - OBJECTIVE: Apnea is not a common preoperative manifestation of medulla cavernous malformations (CMs). The role of surgical resection in patients suffering from apnea secondary to hemorrhage from medulla CMs requires further definition. METHODS: Medical records and radiographs were reviewed retrospectively for four patients treated surgically for medulla CMs in our institution between 2008 and 2011. Recent outcomes for these patients were also evaluated. The modified Rankin Scale (mRS) was used to evaluate neurological function. RESULTS: All four patients (3 male, 1 female; mean age: 41.3 years) suffered two or three hemorrhages with a preoperative mRS of five and, due to the loss of autonomous respiration and consciousness, underwent a preoperative tracheotomy for mechanical ventilation, which lasted an average of 4.5 days. Prior to surgery, all patients had recovered to the point of maintaining spontaneous breath and normal blood gas values with oxygen supplementation. Lesions were totally resected in all patients via the posterior suboccipital approach. Postoperative ventilation was continued in one patient for 1 day. The mean postoperative mRS score at discharge was 3.5, and all patients had improved from their previous scores. The tracheostomy was closed in three patients at 15, 16, and 35 days after surgery. After a mean follow-up of 34.7 months, the most recent mRS scores were 3, 2, 2, and 2; no recurrent hemorrhage was noted, and three patients lived independently. CONCLUSION: In carefully selected patients with hemorrhage due to medulla CMs, favorable outcomes can be achieved even if apnea was a part of the preoperative clinical presentation. Surgery should be considered in these patients, particularly in those with repeated hemorrhages, and apnea should not be considered an absolute contraindication to surgery. PMID- 24073757 TI - Successful treatment of bilateral symmetrical skeletal haemangiomata: a case report. AB - We describe a case of giant bilateral skull vault haemangiomas in a patient with diffuse skeletal haemangiomatosis. The clinical details, histological and radiographic findings and surgical management are reviewed. This is the first described case of radical surgical management of bilateral giant haemangiomas with relief of intractable headache. PMID- 24073758 TI - Extradural spinal cavernous malformation: a rare but important mimic. AB - Purely extradural spinal cavernous malformations (ESCMs) are rare, but the number of cases reported seems to be increasing. A 44-year-old woman presented with progressive cervicothoracic back pain, lower limb paraesthesia and hypertonia. MRI showed a well-circumscribed, convex lesion in the T1-4 extradural space causing cord compression and encroaching into the left T2/3 neural foramen. Selective spinal angiography demonstrated a vascular blush at the T2/T3 level corresponding with the mass. A feeding vessel arising from the base of the T1 spinous process was identified and successfully catheterised, but embolisation was precluded by unfavourable anatomy of the posterior spinal artery. At hemilaminectomy, the lesion was found to be an ESCM. The patient went on to make a full recovery. We reviewed 71 cases of ESCM reported in the last decade. Incidence of ESCM is unclear; the largest case series reported on nine patients, but most published accounts were single case studies. Patients presented with back pain (33%), myelopathy (56%) and/or radiculopathy (39%). Onset of symptoms was usually insidious over months to years, but 30% presented with sudden-onset neurological symptoms, often due to spontaneous haemorrhage. Mean age at diagnosis was 44 (range, 2-74; SD, 19.6) years with a 1:1 sex ratio. Lesions were found at all levels except C1-C2, but a strong predilection for the dorsal thoracic spine (68%) was shown. The lesion extended into an intravertebral foramen in at least 24 cases (34%). MRI is the investigation of choice, and angiography of ESCM has rarely been described. Most (87%) were hypo- to isointense on T1 MRI while hyperintensity on T2 (91%) and avid (89%), usually homogenous gadolinium update was almost universal. Perilesional haemosiderin, characteristic of intracranial and intramedullary cavernous malformation was rarely seen. In many cases, meningioma or nerve sheath tumour was misdiagnosed prior to surgery. All patients underwent total (95%) or subtotal (5%) microsurgical resection with excellent results; all improved (23%) or recovered fully (77%) after surgery. Those who presented acutely did worse; 38% had residual deficits. PMID- 24073759 TI - Outcome of elderly patients undergoing intracranial meningioma resection--a systematic review and meta-analysis. AB - BACKGROUND: Intracranial meningioma is a common condition in the elderly population. Surgical resection in this group of patients may be rendered more hazardous due to the patients' ageing physiology and to multiple comorbidities. This systematic review and meta-analysis aimed to summarise outcome data of elderly patients undergoing intracranial meningioma resection. METHODS: Using Ovid Medline, longitudinal studies published from 2002 to October 2012 with patients aged >= 65 years that described outcomes after intracranial meningioma resection were reviewed. Outcome data included mortality, recurrence, complication rate and length of hospital stay (LoS). Grading score systems and covariates for predicting outcome were collected. Pooled estimates of mortality data were calculated in StatsDirect using a random effects method. I(2) statistic was used to assess heterogeneity. RESULTS: Thirteen eligible studies with a total of 7010 patients (mean age, 73.6 years) were included, in which 82% patients came from one study. The pooled estimates of 90-day and 1-year mortality from available data were 6.6% (95% confidence interval [CI], 4.6-9.1%; n = 735; I(2) = 32.1) and 9.6% (95% CI, 7.0-12.6%; n = 564; I(2) = 24.3), respectively. The overall complication rates ranged from 2.7% to 29.8%, and the overall incidence of complications was 20% per patient (range, 3-61%). Other outcome data were heterogeneous mainly due to incomparable study designs. CONCLUSIONS: Current evidence indicates satisfactory surgical outcomes in the elderly with intracranial meningiomas, though the risks of complications necessitate careful consideration when deciding to operate. Risk factor analysis emphasised the importance of considering pre-operative status and comorbidities during patient selection. Future research should address the causes and prevention of complications, and compare outcomes between younger and older patients using detailed stratifications of tumour characteristics. PMID- 24073760 TI - The safety of prescribing opioids in pediatrics. AB - INTRODUCTION: Pain management has become a widely discussed topic throughout all medical subspecialties. Although pediatric pain management has evolved significantly in its recent history, there is continued interest in the adequacy of pain treatment, both in the acute inpatient setting as well as the postoperative and chronic pain management setting. Although health care providers are becoming more aggressive concerning prompt and effective treatment of acute and chronic pain, safety data and adverse effects of narcotic analgesics may be overlooked. AREAS COVERED: The authors review the current paradigm of acute pain management with an emphasis on oral narcotic medications, and the safety data available concerning prescribing these medications. EXPERT OPINION: Further, the authors present their opinions concerning current and future practices regarding the prescribing practice of opiate analgesics, as well as a step-wise approach for acute oral pain management. PMID- 24073761 TI - Efficacy of Praziquantel against Schistosoma haematobium in Dulshatalo village, western Ethiopia. AB - BACKGROUND: Praziquantel (PZQ) is the drug of choice for treatment of all human schistosomes. It is used in population based targeted or mass deworming strategies in several countries. The effect of PZQ on S. hematobium has not been studied in Ethiopia. The objective of this study was to determine the efficacy of PZQ against S. haematobium in Dulshatalo village, western Ethiopia. METHODS: A prospective study was conducted from October to December, 2007. Urine samples from 341 residents were collected and screened for haematuria and proteinuria using urinalysis dipstick. S. haematobium eggs were detected and quantified using filtration techniques. The participants who were positive for haematuria were treated with a standard dose of PZQ (40 mg/kg). Data on pre and 24 hours post treatment symptoms were collected via questionnaire. Urine samples were also collected 7 weeks after treatment and examined to assess the cure and the egg reduction rates. RESULTS: The prevalence of S. haematobium among the study participants was 57.8% (197/341). Haematuria was detected in 234 (68.6%) of the study participants. For PZQ efficacy asessment, 152 of the treated participants were considered. The presence of S. haemetaobium eggs showed statistically significant association (p < 0.05) with haematuria and proteinuria. Seven weeks post treatment, the extent of haematuria and proteinuria decreased from 100% to 40.8% and 94.07% to 48.7%, respectively. The cure and the parasitological egg reduction rates seven weeks post treatment were 86% and 85%, respectively. Post treatment symptoms revealed a wide range of side effects including straining, abdominal pain, nausea and headache. CONCLUSIONS: There were marked cure and egg reduction rates, together with mild and short lived side effects of PZQ for treatment of S. haematobium, in this study. PMID- 24073763 TI - N-chlorinated poly(N-isopropylacrylamide) microgels. AB - The treatment of poly(N-isopropylacrylamide) (PNIPAM) microgels with aqueous bleach (NaClO) at pH 10.5 resulted in the partial conversion of the amide hydrogen to the corresponding chloramide. N-Chlorinated microgels poly(NIPAM-co NIPAMCl) are more hydrophobic than the parent PNIPAM microgels. Thus, the volume phase transition temperature decreases with increasing chlorination. During chlorination, the microgels coagulate once they undergo a volume phase transition. The chlorination reaction stops once the microgels dehydrate and coagulate, presumably as a result of the decreased diffusion rate of the ClO(-) anion into the microgels. The microgels are reversibly dechlorinated by glutathione (GSH), first giving PNIPAM shell + poly(NIPAM-co-NIPAMCl) core microgels. Because GSH is an important redox actor in biological cells, this work suggests that chlorinated microgels may be employed to deliver active chlorine to targeted cells. PMID- 24073762 TI - H9N2 avian influenza infection altered expression pattern of sphiogosine-1 phosphate receptor 1 in BALB/c mice. AB - BACKGROUND: The pathological damage inflicted by virulent AIV strains is often caused by inducing a positive feedback loop of cytokines in immune cells that cause excessive inflammation. Previous research has shown that a G protein coupled receptor, sphingosine-1-phosphate receptor 1 (S1PR1), plays a crucial role in the development of excessive inflammation in influenza virus infection (Cell 146:861-862, 2011; Cell 146:980-991, 2011). BALB/c mice are common laboratory animals used in research of influenza virus; however the effects of influenza infections on expression patterns of S1PR1 in mice are unknown. METHODS: We investigated the expression patterns of S1PR1 in normal BALB/c mice and those infected by two distinct H9N2 AIV strains, one (A/chicken/Guangdong/V/2008,V) highly pathogenic, and the other (A/chicken/Guangdong/Ts/2004,Ts), non-pathogenic in mice, using quantitative PCR and immunohistochemistry (IHC) to detect S1PR1 mRNA and protein, respectively. RESULTS: S1PR1 mRNA was ubiquitously expressed in all the tissues examined, and significant differences were seen in mRNA expression between infected Ts, V and control mice in detected tissues, heart, liver, spleen, kidney and brain. S1PR1 protein was expressed in the cytoplasm and also demonstrated quantitative changes in expression in the various tissues between mice infected with the two strains of AIV. CONCLUSIONS: Our results provided the first look at differences in S1PR1 expression patterns in BALB/c mice infected by non-pathogenic and highly pathogenic H9N2 influenza viruses. This information will not only be helpful in designing experiments to better understand the role of S1PR1 in virus-host interactions but also in developing novel anti-influenza agents to minimize the mortality and morbidity associated with highly virulent strains in avian and human populations. PMID- 24073764 TI - Road traffic crashes and fatalities in Japan 2000-2010 with special reference to the elderly road user. AB - OBJECTIVE: To investigate comparative road user crash and fatality rates in Japan between 2000 and 2010 in the elderly and young. METHODS: Data from the Japan Ministry of Health, Labor and Welfare Vital Statistics Database and the Institute for Traffic Accident Research and Data Analysis were used to calculate crash rates by age group, vehicle, and license category. RESULTS: Fatal crash rates per 100,000 licensed drivers for 4-wheeled motor vehicle drivers decreased by 53, 56, and 42 percent among the 65-69, 70-74, and >=75 age groups between 2000 and 2010, respectively, compared to 66 and 60 percent among the 16-19 and 20-24 age groups, respectively. Fatal crash rates per 100,000 licensed riders for 2-wheeled motor vehicles decreased by 64, 23, and 33 percent in the 65-69, 70-74, and >=75 age groups, respectively. Similarly, fatal crash rates per million population among bicyclists and pedestrians decreased in all age groups but were highest in the elderly age group in all years; the annual fatal crash rate for elderly pedestrians was 3 to 10 times higher than that for younger pedestrians. CONCLUSIONS: Despite the overall decrease in the elderly crash and fatal crash rates in all road use categories, elderly pedestrians are more susceptible to road traffic crashes and are more likely to be killed than younger persons. Further research may reduce this risk. PMID- 24073765 TI - The driving competence of 90-year-old drivers: from a hospital-based driving clinic. AB - OBJECTIVES: To compare the performance on a standardized driving evaluation of a group of oldest old adults (age 90-97) against younger old adults (age 80-87) and examine whether the same cognitive variables and brake reaction time performance were associated with pass-fail status on a road test in both groups. Secondary objectives focused on an examination of the specific driving errors of both groups. METHODS: This retrospective cohort study was conducted in the setting of a clinical driving evaluation program at an academic medical center in the United States. In this study we examined the performance of 88 participants (27 age 90 97 and 61 age 80-87) who completed comprehensive driving evaluations between 1997 and 2011. The outcome variable was performance on a standardized road test. Measures included the Trail Making Test (TMT), the Mini Mental State Examination (MMSE), and brake reaction time (BRT). An exploratory analysis of the possible predictive value of specific MMSE subtests was also performed. RESULTS: Results indicate that the oldest old adults (90-97 years old) were at no greater driving risk than were a younger old (80-87 years old) cohort and made similar types and frequency of driving errors. TMT-B time was associated with pass-fail status in both groups. MMSE attention items discriminated between safe and unsafe younger old drivers, and MMSE orientation items were associated with pass-fail status in the oldest old cohort. CONCLUSION: Drivers age 90 and above were at no greater driving risk than those one decade younger. MMSE orientation questions may be useful to assist in identifying which oldest old drivers could benefit from a comprehensive driving evaluation including an on-road test. PMID- 24073766 TI - Psychomotor performance of truck drivers before and after day shifts. AB - OBJECTIVE: The aim of the present study is to evaluate the psychomotor performance of professional drivers in a field setting and in relation to certain variables, including age, behavioral factors, urinary levels of 6 sulfatoxymelatonin (aMT6s) normalized to urinary creatinine excretion, and the characteristics of the work shifts. METHODS: The study was carried out on 16 professional male truck drivers aged 34-53 years. The drivers were submitted to the Vienna Reaction Test (RT) and Vienna Determination Test (DT) and provided urine specimens before and after 39 work shifts. They were also asked to record the road and traffic conditions (motorways, suburban and urban roads, traffic jams, visibility), duration, and mileage for each driving shift. RESULTS: Using the 50th percentile as a cut point to arbitrarily categorize the performance measurements (Vienna RT reaction time and motor time, Vienna DT reaction time and number of correct reactions) into low and high performance levels, a direct relation emerged between the risk of low performance levels, as assessed by RT reaction time and motor time, and morning urinary levels of aMT6s categorized by tertiles. Before the driving shifts, the odds ratios of low performance levels (adjusted for start time and age) were 8.39 (95% confidence interval [CI]: 1.23 57.10) in the highest tertile compared to the lower tertile of aMT6s for RT reaction time and 4.15 (95% CI: 1.26-13.65) for RT motor time, respectively. After driving shifts, negative age-related effects on motor performance were detected. Multiple linear regression analyses, performed using early morning urinary aMT6s levels, age, and driving shift characteristics (start time, duration of driving shift) as predictors of performance measurements, showed aMT6s levels to be the primary independent predictor of RT reaction time before driving shifts and age as the primary predictor of RT motor time after driving shifts. No correlation was found between the risk of low performance levels as assessed by Vienna DT (reaction time and number of correct reactions) and aMT6s levels. CONCLUSIONS: The wide interindividual variability of urinary aMT6s excretion observed before driving shifts and the direct association between aMT6s levels in the early morning and performance measurements suggest that the circadian typology of drivers should be taken into account when scheduling the work shifts of professional drivers. PMID- 24073767 TI - Kinematics and shoulder belt position of child anthropomorphic test devices during steering maneuvers. AB - OBJECTIVES: The objective of this study was to quantify and compare the kinematics and shoulder belt position of child anthropomorphic test devices (ATDs) during emergency steering maneuvers. Furthermore, the ATDs were compared to the results from child volunteers aged 4 to 12 in the same test setup (Bohman, Stockman, et al. 2011). METHODS: A driving study was conducted on a test track comprising 4 ATDs: the Q6, Q10, and Hybrid III (HIII) 6- and 10-year-old ATDs restrained in the rear seat of a passenger vehicle. The ATDs were exposed to 2 repeated steering maneuvers in each restraint system. The Q6 and HIII 6-year-old were restrained on booster cushions as well as high-back booster seats. The Q10 and HIII 10-year-old were restrained on booster cushions or restrained by 3-point seat belts directly on the seat. Lateral motion of the forehead and upper sternum was determined, as well as shoulder belt movement on shoulder and torso tilting angle. RESULTS: All ATDs began to move approximately at the same point in time corresponding to a vehicle lateral acceleration of just below 0.2 g. In the later phase of the maneuver, Q10 had moved 26 percent less than the children when restrained by seat belt only and 35 percent less when on a booster cushion. Corresponding numbers for the HIII 10-year-old were 43 and 44 percent higher than for children. Compared to children, the Q6 had moved 34 percent less when restrained on a high-back booster seat and 31 percent less when on a booster cushion. Corresponding numbers for HIII 6-year-old were 7 and 28 percent higher than for children. Due to extensive variety of lateral displacements observed in the children, child performance range covers both ATD families for the evaluated sizes of 6- and 10-year-old ATDs. CONCLUSIONS: Compared to children, the HIII ATDs were closer with regards to mean values in the initial phase of the maneuver and the Q ATDs were closer in the end of the ramping phase of the lateral acceleration. The question regarding which ATD replicates better the behavior of children exposed to steering maneuvers still remains open. As shown in this study, it depends on the focus of the comparison and on what phase of the maneuver is of interest. This study provides valuable knowledge on how representative the current ATDs are for replicating potential precrash postures of children as a result of vehicle emergency steering maneuvers for a variety of restraint systems and ATD sizes. PMID- 24073768 TI - Real-world injury patterns associated with Hybrid III sternal deflections in frontal crash tests. AB - OBJECTIVE: This study investigated the relationship between the peak sternal deflection measurements recorded by the Hybrid III 50th percentile male anthropometric test device (ATD) in frontal crash tests and injury and fatality outcomes for drivers in field crashes. METHODS: ATD sternal deflection data were obtained from the Insurance Institute for Highway Safety's 64 km/h, 40 percent overlap crashworthiness evaluation tests for vehicles with seat belt crash tensioners, load limiters, and good-rated structure. The National Automotive Sampling System Crashworthiness Data System (NASS-CDS) was queried for frontal crashes of these vehicles in which the driver was restrained by a seat belt and air bag. Injury probability curves were calculated by frontal crash type using the injuries coded in NASS-CDS and peak ATD sternal deflection data. Fatality Analysis Reporting System (FARS) front-to-front crashes with exactly one driver death were also studied to determine whether the difference in measured sternal deflections for the 2 vehicles was related to the odds of fatality. RESULTS: For center impacts, moderate overlaps, and large overlaps in NASS-CDS, the probability of the driver sustaining an Abbreviated Injury Scale (AIS) score >= 3 thoracic injury, or any nonextremity AIS >= 3 injury, increased with increasing ATD sternal deflection measured in crash tests. For small overlaps, however, these probabilities decreased with increasing deflection. For FARS crashes, the fatally injured driver more often was in the vehicle with the lower measured deflection in crash tests (55 vs. 45%). After controlling for other factors, a 5 mm difference in measured sternal deflections between the 2 vehicles was associated with a fatality odds ratio of 0.762 for the driver in the vehicle with the greater deflection (95% confidence interval = 0.373, 1.449). CONCLUSIONS: Restraint systems that reduce peak Hybrid III sternal deflection in a moderate overlap crash test are beneficial in real-world crashes with similar or greater overlap but likely have a disbenefit in crashes with small overlap. This may occur because belt-force limiters employed to control deflections allow excursion that could produce contact with interior vehicle components in small overlaps, given the more oblique occupant motion and potential inboard movement of the air bag. Although based on a limited number of cases, this interpretation is supported by differences in skeletal fracture locations among drivers in crashes with different overlaps. Current restraint systems could be improved by designs that reduce sternal deflection in moderate and large overlap crashes without increasing occupant excursion in small overlap crashes. PMID- 24073769 TI - Influencing factors and sensitivity analysis of occupant impact injury in passenger compartment. AB - OBJECTIVE: The study reported in this article addressed the influence of each factor (impact acceleration, table height h, table to seat distance l1, interseat distance l2, table contact stiffness k1, seat contact stiffness k2, etc.) on the extent of occupant impact injury in a railway vehicle secondary collision. METHODS: The vehicle's passenger compartment-occupant coupling model was established using proprietary software (MADYMO). The simulated occupant was MADYMO's validated Hybrid III 50th percentile dummy model, and the vehicle's passenger compartment model included the floor surface, side wall, seat (with cushion), backrest, and table. The floor surface and side wall were modeled as flat surfaces; the seat (with its cushion), backrest, and table were modeled as ellipsoids. Some 25 samples were selected for numerical simulation based on a 2 factor, 5-level, full-factorial experimental design: the response surface method (RSM) was applied to fit the mapping relationship between the occupant's injury parameters (head injury criterion [HIC] and thoracic cumulative 3-ms injury criterion [TC(3ms)]) and other multi-influence factors. RESULTS: Taking the seat table structure model and seat-seat structure model as examples, the influence of each factor on the extent of the passenger compartment occupant's impact injury was assessed from the basis of traditional passenger compartment configurations found on Chinese trains. The sensitivity analysis of occupant injury parameters on these influence factors was carried out to determine the extent of the influence of each factor on each impact injury parameter. CONCLUSIONS: The response surfaces of the occupant's injury parameters (HIC and TC(3ms)), and changes therein as the system's variables were altered showed that impact injury parameters and change thereto could be described intuitively and qualitatively. Some meaningful conclusions were obtained through the sensitivity analysis of occupant injury parameters to changes in these influence factors. The research offered a guideline for the design and manufacture of a train's passenger compartment structure. PMID- 24073770 TI - Car crash fatalities associated with fire in Sweden. AB - OBJECTIVE: To study the epidemiology and causes of death in fatal car crashes on Swedish roads in which the victim's vehicle caught fire. METHODS: The data set is from the Swedish Transport Administrations in-depth studies of fatal crashes 1998 2008. Autopsies from all cases provided data on injuries, toxicological analyses, and cause of death. RESULTS: In total, 181 people died in 133 burning cars, accounting for 5 percent of all deaths in passenger cars, sport utility vehicles, vans, and minibuses during 1998 to 2008. The cause of death for a third of the victims was fire related, as burns and/or smoke inhalation injuries, with no fatal trauma injuries. Twenty-five of these 55 deaths were persons 19 years or younger and included 15 of 18 rear seat deaths. Over half of the 181 deaths were in vehicles that had collided with another vehicle and, of these cases, half were killed in collisions with heavy vehicles. The percentage of drivers with illegal blood alcohol concentrations (27%) and suicides (5.5%) were not higher than in other fatal crashes on Swedish roads. The ignition point of the fire was indicated in only half of the cases and, of those, half started in the engine compartment and one fourth started around the fuel tank or lines. CONCLUSIONS: Car fires are a deadly postcrash problem. Reducing this risk would be primarily a responsibility for the automotive industry. A multifactor approach could be considered as follows: risk-reducing design, insulation, reduced flammability in motor compartment fluids and plastics, and automatic fire extinguishing equipment. Inspiration could be found in how, for example, the auto racing and aviation industries handle this problem. PMID- 24073771 TI - Muscle pathologies after cervical spine distortion-like exposure--a porcine model. AB - OBJECTIVE: Histological evaluation of porcine posterior cervical muscles after a forceful translational and extensional head retraction simulating high-speed rear end impact. METHODS: Four anesthetized pigs were exposed to a cervical spine distortion (CSD)-like motion in a lying position. After 2 different survival times of 4 and 6 h (posttrauma), the pigs were euthanized and tissue sampling of posterior cervical muscles was performed. A standard histological staining method involving paraffin-embedded sections was used to analyze the muscles, focusing on injury signs like hemorrhage and inflammatory cell reaction. A pig that was not subjected to impact was used as a control pig and was subjected to the same procedure to exclude any potential artifacts from the autopsy. RESULTS: The differentiation of 8 different posterior neck muscles in the dissection process was successful in more than 50 percent for each muscle of interest. Staining and valid analysis was possible from all extracted samples. Muscle injuries to the deepest posterior neck muscles could be found, especially in the musculus obliquus samples, which showed laminar bleedings in 4 out of 4 samples. In addition, in 4 out of 4 samples we were able to see increased cellular reactions. The splenius muscle also showed bleeding in all 4 samples. All animals showed muscle injury signs in more than three quarters of analyzed neck muscles. Differences between survival times of 4 and 6 h in terms of muscular injury were not of primary interest and could not be found. CONCLUSIONS: By simulating a CSD like motion we were able to confirm injuries in the posterior cervical muscles under severe loading conditions. Further studies need to be conducted to determine whether these muscle injuries also occur under lower exposure forces. PMID- 24073772 TI - Motorcycle helmets: head and neck dynamics in helmeted and unhelmeted oblique impacts. AB - OBJECTIVE: To assess the factors that contribute to head and neck dynamics in motorcycle crash simulation tests. METHOD: A series of laboratory tests was undertaken using an oblique impact rig. The impact rig included a drop assembly with a Hybrid III head and neck. The head struck the top surface of a horizontally moving striker plate. Head linear and angular acceleration, striker plate force, and upper neck loads were measured. The following test parameters were varied: drop height to a maximum of 1.5 m, horizontal speed to a maximum of 35 km/h, impact orientation/location, and restraint adjustment. Two helmet models were used for the majority of tests. Visor impacts were conducted as were comparisons across 4 helmet models. Descriptive statistics were derived and multiple regression was applied to examine the role of each parameter. The data were compared to unhelmeted tests. RESULTS: The tests confirmed that motorcycle helmets compared to no helmet provide a high level of protection to the head and neck through management of both linear and angular head acceleration and neck loads. In the most severe lateral impacts (drop height 1.5 m and horizontal speed 35 km/h): the mean head injury criterion (HIC15) and mean maximum headform acceleration were respectively 648, 150 g for 4 helmet models; the mean +alphay was +9.5 krad/s2 and +alphax was +5.1 krad/s2; the upper neck resultant force, Mx and -My, respectively, were 4947 N, -80 Nm, and 55 Nm. Drop height was a significant predictor of peak linear headform acceleration, HIC15, and striker force. Horizontal speed and impact orientation were significant predictors of peak angular acceleration, in addition to drop height. Peak head and neck loads observed in visor impacts were similar to those observed in impacts directly to the shell. Peak head and neck loads observed in frontal impacts with tightly and loosely adjusted restraints were similar, but the helmet with the loosely adjusted restraint was ejected during the impact. CONCLUSIONS: Further research and development is required on the oblique test rig to establish its reliability and validity, the latter through comparisons to real-world impacts. Motorcycle helmets certified to a national standard manage linear acceleration well, but further developments are required to reduce angular acceleration. Within the range of impact conditions, there was no indication that helmets posed a neck injury risk. PMID- 24073773 TI - Toward a more robust lower neck compressive injury tolerance-an approach combining multiple test methodologies. AB - OBJECTIVE: The compressive tolerance of the cervical spine has traditionally been reported in terms of axial force at failure. Previous studies suggest that axial compressive force at failure is particularly sensitive to the alignment of the cervical vertebra and the end conditions of the test methodology used. The present study was designed to develop a methodology to combine the data of previous experiments into a diverse data set utilizing multiple test methods to allow for the evaluation of the robustness of current and proposed eccentricity based injury criteria. METHODS: Data were combined from 2 studies composed of dynamic experiments including whole cervical spine and head kinematics that utilized different test methodologies with known end conditions, spinal posture, injury outcomes, and measured kinetics at the base of the neck. Loads were transformed to the center of the C7-T1 intervertebral disc and the eccentricity of the sagittal plane resultant force relative to the center of the disc was calculated. The correlation between sagittal plane resultant force and eccentricity at failure was evaluated and compared to the correlation between axial force and sagittal plane moment and axial force alone. RESULTS: Accounting for the eccentricity of the failure loads decreased the scatter in the failure data when compared to the linear combination of axial force and sagittal plane moment and axial force alone. A correlation between axial load and sagittal plane flexion moment at failure (R2 = 0.44) was identified. The sagittal plane extension moment at failure did not have an identified correlation with the compressive failure load for the tests evaluated in this data set (R2 = 0.001). The coefficients of determination for the linear combinations of sagittal plane resultant force with anterior and posterior eccentricity are 0.56 and 0.29, respectively. These correlations are an improvement compared to the combination of axial force and sagittal plane moment. CONCLUSIONS: Results using the outlined approach indicate that the combination of lower neck sagittal plane resultant force and the anterior-posterior eccentricity at which the load is applied generally correlate with the type of cervical damage identified. These results show promise at better defining the tolerance for compressive cervical fractures in male postmortem human subjects (PMHS) than axial force alone. The current analysis requires expansion to include more tolerance data so the robustness of the approach across various applied loading vectors and cervical postures can be evaluated. PMID- 24073774 TI - Chinese carless young drivers' self-reported driving behavior and simulated driving performance. AB - OBJECTIVE: Carless young drivers refers to those drivers aged between 18 and 25 years who have a driver's license but seldom have opportunities to practice their driving skills because they do not have their own cars. Due to China's lower private car ownership, many young drivers become carless young drivers after licensure, and the safety issue associated with them has raised great concern in China. This study aims to provide initial insight into the self-reported driving behaviors and simulated driving performance of Chinese carless young drivers. METHODS: Thirty-three carless young drivers and 32 young drivers with their own cars (as a comparison group) participated in this study. A modified Driver Behavior Questionnaire (DBQ) with a 4-factor structure (errors, violations, attention lapses, and memory lapses) was used to study carless young drivers' self-reported driving behaviors. A simulated driving experiment using a low-cost, fixed-base driving simulator was conducted to measure their simulated driving performance (errors, violations, attention lapses, driving maintenance, reaction time, and accidents). RESULTS: Self-reported DBQ outcomes showed that carless young drivers reported similar errors, more attention lapses, fewer memory lapses, and significantly fewer violation behaviors relative to young drivers with their own cars, whereas simulated driving results revealed that they committed significantly more errors, attention lapses, and violation behaviors than the comparison group. Carless young drivers had a lower ability to maintain the stability of speed and lane position, drove more cautiously approaching and passing through red traffic lights, and committed more accidents during simulated driving. A tendency to speed was not found among carless young drivers; their average speed and speeding frequency were all much lower than that of the comparison group. Lifetime mileage was the only significant predictor of carless young drivers' self-reported violations, simulated violations, speed, and reaction time, whereas no significant predictor was found for young drivers with their own cars. CONCLUSIONS: Carless young drivers had poorer driving performance and were more overconfident of their self-reported driving skills compared to those young drivers with greater access to vehicles. Given that the lifetime mileage positively predicted the simulated violations measure of carless young drivers, immediate interventions are needed to help them increase driving exposure and gain driving experience gradually before moving to more challenging on-road driving tasks. Supplemental materials are available for this article. PMID- 24073775 TI - Evaluation of the impacts of speed variation on freeway traffic collisions in various traffic states. AB - OBJECTIVE: To evaluate the impacts of speed variation on the likelihood of traffic collision in various types of traffic states in a freeway section. METHODS: The overall traffic state is divided into free flow (FF), congested traffic (CT), back of queue (BQ), and front of queue (FQ) according to the speed at up- and downstream detector locations. Based on 448 crash recordings from a freeway stretch in California, the logistic regression model is used to estimate the impacts of average speed (AS) and standard deviation of speed (SD) as well as coefficient of speed variation (CSV) for each traffic state separately. RESULTS: For the overall state, both the SD and CSV are significantly related to the traffic collisions. For the separate states, the model estimates vary in different states: in FF, the CSV is positively related to collisions, whereas the SD is not a good indicator for collisions; in CT and BQ, the SD and CSV have positive impacts on the collision likelihood (especially for rear-end collisions); in FQ, the speed variation indexes were not found to have significant impacts. The coefficients of SD and CSV were found to be different in distinct traffic states. The impact of AS was significant only in FF and BQ. CONCLUSIONS: Considering the overall traffic as one state could hide important relationships between speed variation and collisions. The impacts of speed variation on collision likelihood are different in various traffic states. The SD and CSV are effective surrogate safety measures for traffic collisions in CT and BQ but may not be good measures in FF and FQ. The AS is an accident determinant in FF and BQ but not a contributing factor in other states. PMID- 24073776 TI - An application of the driver behavior questionnaire to Chinese carless young drivers. AB - OBJECTIVE: Carless young drivers refers to those drivers aged between 18 and 25 years who have a driver's license but seldom have opportunities to practice their driving skills because they do not have their own cars. Due to China's lower private car ownership, many young drivers turn into carless young drivers after licensure, and the safety issue associated with them has become a matter of great concern in China. Because few studies have examined the driving behaviors of these drivers, this study aims to utilize the Driver Behavior Questionnaire (DBQ) to investigate the self-reported driving behaviors of Chinese carless young drivers. METHODS: A total of 523 Chinese carless young drivers (214 females, 309 males) with an average age of 21.91 years completed a questionnaire including the 27-item DBQ and demographics. The data were first randomized into 2 subsamples for factor analysis and then combined together for the following analyses. Both an exploratory factor analysis (EFA, n = 174) and a confirmatory factor analysis (CFA, n = 349) were performed to investigate the factor structure of the DBQ. Correlation analysis was conducted to examine the relationships between the demographics and the DBQ scales' variables. Multivariate linear regression and logistic regression were performed to investigate the prediction of the DBQ scales and crash involvement in the previous year. RESULTS: The EFA produced a 4 factor structure identified as errors, violations, attention lapses, and memory lapses, and the CFA revealed a good model fit after the removal of one item with a low factor loading and the permission of the error covariance between some items. The Chinese carless young drivers reported a comparatively low level of aberrant driving behaviors. The 3 most frequently reported behaviors were all lapses and the 3 least were all violations. Gender was the only significant predictor of the 2 lapses scales and lifetime mileage was the only significant predictor of the violations scale. Only the violations factor was found to be significantly predictive of crash involvement in the previous year. CONCLUSIONS: The current study provides evidence that the DBQ can successfully be utilized to examine the self-reported driving behaviors of Chinese carless young drivers. However, the factor structure as well as the level of reported aberrant driving behaviors suggests that Chinese carless young drivers are a special population and thus should be treated differently when interventions are performed. Supplemental materials are available for this article. PMID- 24073777 TI - Crash barriers and driver behavior: a simulator study. AB - OBJECTIVE: The study examines how drivers experience a conventional W-beam guardrail (metal crash barrier) along both sides of narrow versus wider roads (single carriageway with 2 lanes) in terms of stress, feelings, and driving patterns and whether subjective experience concurs with the actual driving patterns captured by the quantitative data. METHODS: The study used different methods to capture data, including the VTI Driving Simulator III (speed and lateral vehicle position) in conjunction with electrocardiogram (ECG) data on heart rate variability (HRV) and questionnaires (oral during driving and written after driving). Eighteen participants--8 men and 10 women--were recruited for the simulator study and the simulator road section was 10 km long. RESULTS: Driving speeds increased slightly on the wider road and on the road with a crash barrier, and the lateral driving position was nearer to the road center on the narrower road and on the road with a crash barrier. The HRV data did not indicate that participants experienced greater stress due to road width or due to the presence of a crash barrier. Participant experience captured in the oral questionnaires suggested that road width did not affect driver stress or driving patterns; however, the written questionnaire results supported the simulator data, indicating that a wider road led to increased speed. None of the participants felt that crash barriers made them feel calmer. CONCLUSIONS: We believe that there is a possibility that the increased speed on roads with crash barriers may be explained by drivers' sense of increased security. This study demonstrates that an experimental design including experience-based data captured using both a simulator and questionnaires is productive. It also demonstrates that driving simulators can be used to study road features such as crash barriers. It seems more than likely that features such as street lamps, signs, and landscape objects could be tested in this way. PMID- 24073783 TI - Developments in therapy and diagnosis of yaws and future prospects. AB - Yaws, a chronic and debilitating infectious disease caused by Treponema pallidum subsp. pertenue, and closely related to syphilis, although transmitted by skin-to skin contact, remains an important public health challenge, causing a significant burden of morbidity in children in certain areas of the Pacific and Africa. Recent advances in its diagnosis and treatment have led to an enthusiastic upsurge of activities related to its control, and exciting perspectives of global eradication. Although possibly considered among the most neglected of all neglected diseases during decades, there seems to be now agreement that massive drug administration of the antibiotic azithromycin, coupled with adequate surveillance of foci of transmission could result in its eradication. In this review, we summarize current knowledge regarding the therapeutics of yaws and its diagnosis. PMID- 24073782 TI - Do differences in risk factors explain the lower rates of coronary heart disease in Japanese versus U.S. women? AB - BACKGROUND: Mortality from coronary heart disease (CHD) in women in Japan is one of the lowest in developed countries. In an attempt to shed some light on possible reasons of lower CHD in women in Japan compared with the United States, we extensively reviewed and analyzed existing national data and recent literature. METHODS: We searched recent epidemiological studies that reported incidence of acute myocardial infarction (AMI) and examined risk factors for CHD in women in Japan. Then, we compared trends in risk factors between women currently aged 50-69 years in Japan and the United States, using national statistics and other available resources. RESULTS: Recent epidemiological studies have clearly shown that AMI incidence in women in Japan is lower than that reported from other countries, and that lipids, blood pressure (BP), diabetes, smoking, and early menopause are independent risk factors. Comparing trends in risk factors between women in Japan and the United States, current levels of serum total cholesterol are higher in women in Japan and levels have been similar at least since 1990. Levels of BP have been higher in in Japan for the past 3 decades. Prevalence of type 2 diabetes has been similar in Japanese and white women currently aged 60-69 for the past 2 decades. In contrast, rates of cigarette smoking, although low in women in both countries, have been lower in women in Japan. CONCLUSIONS: Differences in risk factors and their trends are unlikely to explain the difference in CHD rates in women in Japan and the United States. Determining the currently unknown factors responsible for low CHD mortality in women in Japan may lead to new strategy for CHD prevention. PMID- 24073784 TI - Molecular dynamic simulations of ocular tablet dissolution. AB - Small tablets for implantation into the subconjunctival space in the eye are being developed to inhibit scarring after glaucoma filtration surgery (GFS). There is a need to evaluate drug dissolution at the molecular level to determine how the chemical structure of the active may correlate with dissolution in the nonsink conditions of the conjunctival space. We conducted molecular dynamics simulations to study the dissolution process of tablets derived from two drugs that can inhibit fibrosis after GFS, 5-fluorouracil (5-FU) and the matrix metalloprotease inhibitor (MMPi), ilomastat. The dissolution was simulated in the presence of simple point charge (SPC) water molecules, and the liquid turnover of the aqueous humor in the subconjunctival space was simulated by removal of the dissolved drug molecules at regular intervals and replacement by new water molecules. At the end of the simulation, the total molecular solvent accessible surface area of 5-FU tablets increased by 60 times more than that of ilomastat as a result of tablet swelling and release of molecules into solution. The tablet dissolution pattern shown in our molecular dynamic simulations tends to correlate with experimental release profiles. This work indicates that a series of molecular dynamic simulations can be used to predict the influence of the molecular properties of a drug on its dissolution profile and could be useful during preformulation where sufficient amounts of the drug are not always available to perform dissolution studies. PMID- 24073786 TI - Hunger strikers: ethical and legal dimensions of medical complicity in torture at Guantanamo Bay. AB - Physicians and other licensed health professionals are involved in force-feeding prisoners on hunger strike at the US Naval Base at Guantanamo Bay (GTMO), Cuba, the detention center established to hold individuals captured and suspected of being terrorists in the wake of September 11, 2001. The force-feeding of competent hunger strikers violates medical ethics and constitutes medical complicity in torture. Given the failure of civilian and military law to end the practice, the medical profession must exert policy and regulatory pressure to bring the policy and operations of the US Department of Defense into compliance with established ethical standards. Physicians, other health professionals, and organized medicine must appeal to civilian state oversight bodies and federal regulators of medical science to revoke the licenses of health professionals who have committed prisoner abuses at GTMO. PMID- 24073785 TI - Ranavirus infections associated with skin lesions in lizards. AB - Ranaviral disease in amphibians has been studied intensely during the last decade, as associated mass-mortality events are considered to be a global threat to wild animal populations. Several studies have also included other susceptible ectothermic vertebrates (fish and reptiles), but only very few cases of ranavirus infections in lizards have been previously detected. In this study, we focused on clinically suspicious lizards and tested these animals for the presence of ranaviruses. Virological screening of samples from lizards with increased mortality and skin lesions over a course of four years led to the detection of ranaviral infections in seven different groups. Affected species were: brown anoles (Anolis sagrei), Asian glass lizards (Dopasia gracilis), green anoles (Anolis carolinensis), green iguanas (Iguana iguana), and a central bearded dragon (Pogona vitticeps). Purulent to ulcerative-necrotizing dermatitis and hyperkeratosis were diagnosed in pathological examinations. All animals tested positive for the presence of ranavirus by PCR and a part of the major capsid protein (MCP) gene of each virus was sequenced. Three different ranaviruses were isolated in cell culture. The analyzed portions of the MCP gene from each of the five different viruses detected were distinct from one another and were 98.4-100% identical to the corresponding portion of the frog virus 3 (FV3) genome. This is the first description of ranavirus infections in these five lizard species. The similarity in the pathological lesions observed in these different cases indicates that ranaviral infection may be an important differential diagnosis for skin lesions in lizards. PMID- 24073787 TI - Bulky DNA adducts in human sperm associated with semen parameters and sperm DNA fragmentation in infertile men: a cross-sectional study. AB - BACKGROUND: DNA adducts are widely used marker of DNA damage induced by environmental pollutants. The present study was designed to explore whether sperm polycyclic aromatic hydrocarbon-DNA adducts were associated with sperm DNA integrity and semen quality. METHODS: A total of 433 Han Chinese men were recruited from an infertility clinic. Immunofluorescence was applied to analyze sperm PAH-DNA adducts. Sperm DNA fragmentation was detected by terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP nick end labelling (TUNEL) assay. RESULTS: After adjustment for potential confounders using linear regression, sperm PAH-DNA adducts were negatively associated with sperm concentration, total sperm count, sperm motility, and curvilinear velocity (VCL). In addition, a positive relationship between sperm PAH-DNA adducts and sperm DNA fragmentation was found. CONCLUSIONS: Our findings suggested an inverse association between sperm PAH-DNA adducts and semen quality, and provided the first epidemiologic evidence of an adverse effect of PAH-DNA adducts on sperm DNA integrity. PMID- 24073788 TI - Intradiploic dermoid cyst: a rare cause of intracranial hypertension. AB - In this study, we report a rare case of intradiploic dermoid cyst in a patient who developed rapid symptoms of intracranial hypertension (ICH) that mimicked Pseudotumor cerebri syndrome clinically. A 25-year-old female presented with a history of headache, nausea, vertigo and blurred vision in the past 4 months. Images revealed a small supratentorial extradural intradiploic tumor. A midline occipital craniotomy was performed and total removal of the dermoid cyst was accomplished. Present case demonstrated that dermoid cysts can be considered an exceptionally rare basic cause of ICH. PMID- 24073790 TI - Palladium-catalyzed C-2 selective arylation of quinolines. AB - An efficient method for the Pd-catalyzed regioselective C-2 arylation of quinolines is presented. Reactions of various substituted quinolines and unactivated arenes have been conducted under mild conditions. The result shows good product yields of 2-arylquinolines, which are highly useful building blocks for the synthesis of bioactive alkaloid natural products and drug molecules. PMID- 24073791 TI - Computational and experimental characterizations of silver nanoparticle apolipoprotein biocorona. AB - With the advancement of nanotoxicology and nanomedicine, it has been realized that nanoparticles (NPs) interact readily with biomolecular species and other chemical and organic matter to result in biocorona formation. The field of the environmental health and safety of nanotechnology, or NanoEHS, is currently lacking significant molecular-resolution data, and we set out to characterize biocorona formation through electron microscopy imaging and circular dichroism spectroscopy that inspired a novel approach for molecular dynamics (MD) simulations of protein-NP interactions. In our present study, we developed a novel GPU-optimized coarse-grained MD simulation methodology for the study of biocorona formation, a first in the field. Specifically, we performed MD simulations of a spherical, negatively charged citrate-covered silver nanoparticle (AgNP) interacting with 15 apolipoproteins. At low ion concentrations, we observed the formation of an AgNP-apolipoprotein biocorona. Consistent with the circular dichroism (CD) spectra, we observed a decrease in alpha-helices coupled with an increase in beta-sheets in apolipoprotein upon biocorona formation. PMID- 24073792 TI - Characteristic profiles of benzonphenone-3 and its derivatives in urine of children and adults from the United States and China. AB - Widespread exposure of humans to benzophenone-3 (BP-3) is a concern due to this compound's potential to disrupt endocrine function. BP-3 can be metabolized by phase I and phase II reactions of the human cytochrome P450 system. Urinary measurements of BP-3 have been used as a biomarker of exposure. Nevertheless, metabolic transformation pathway and the transformation products of BP-3 in humans are still less known. In this study, 166 urine samples collected from children and adults in the U.S. and China were analyzed for free and total forms (free plus conjugated) of BP-3 as well as four of its metabolic derivatives, 4-OH BP, 2,4-diOH-BP, 2,2',4,4'-tetraOH-BP, and 2,2'-diOH-4-MeO-BP, using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). BP-3 was found in almost all urine samples from the U.S. and China. Concentrations of BP-3 in urine from children (GM: 9.97 ng/mL) and adults (15.7 ng/mL) in the U.S. were significantly higher than those in children (0.622 ng/mL) and adults (0.977) from China. A significant positive relationship was found between the concentrations of urinary BP-3 and its derivatives. The profiles of BP derivatives in urine suggested that demethylation was a major route of BP-3 metabolism. The percentage of the free form of BP-3 in urine was used in the determination of efficacy of phase II metabolism among the different population groups studied. A significantly lower percentage of the free form of BP-3 was found in urine from the U.S. population than in the Chinese population. PMID- 24073793 TI - Population-based prevalence survey of tuberculosis in the Tigray region of Ethiopia. AB - BACKGROUND: Population based prevalence survey is an important epidemiological index to measure the burden of tuberculosis (TB) disease and monitor progress towards TB control in high burden countries like Ethiopia. This study was aimed to estimate the prevalence of bacteriologically confirmed pulmonary tuberculosis (PTB) in the Tigray region of Ethiopia. METHODS: Sixteen rural and urban villages were randomly selected in a stratified multistage cluster sampling. Individuals aged 15 years and older were screened by symptom inquiry for PTB. Those individuals who were symptomatic of PTB provided two sputum samples for smear microscopy, culture and molecular typing. RESULTS: The study covering 4,765 households screened a total of 12,175 individuals aged 15 years and above. The overall weighted prevalence of bacteriologically confirmed PTB in the Tigray region of Ethiopia was found to be 216/100,000 (95% CI: 202.08, 230.76) while the weighted prevalence of smear-positive PTB was 169/100,000 (95% CI: 155.53, 181.60). The prevalence of bacteriologically confirmed TB was higher amongst males (352/100 000; 95% CI: 339.05, 364.52) than females (162/100 000; 95% CI: 153.60, 171.17) and among rural (222/100,000; 95% CI: 212.77-231.53) as compared to urban residents (193/100,000; 95% CI: 183.39-203.59). CONCLUSIONS: This study found a relatively higher prevalence smear-positive PTB in the region than in a same period nationwide survey and identified a significant number of undetected PTB cases. The urgency for improved TB case detection and intensified community awareness is emphasized. PMID- 24073794 TI - Evaluating seasonal variation in bottom-up and top-down forces and their impact on an exotic wood borer, Tetropium fuscum (Coleoptera: Cerambycidae). AB - It is well understood that forces from multiple trophic levels simultaneously influence herbivore performance, but how the relative strength of these forces vary over space and time is less clear. We evaluated seasonal variation in the impact of bottom-up forces (host condition), top-down forces (natural enemies), and competition on the performance of an exotic wood borer. Tetropium fuscum (F.) (Coleoptera: Cerambycidae) eggs that were either protected or exposed were placed on healthy and stressed red spruce, Picea rubens Sargent, trees at three different times during the natural T. fuscum flight period. We also measured the length of necrotic lesions (i.e., an induced hypersensitive response) that developed in response to attacking T. fuscum. As predicted, T. fuscum performance was usually greater, and induced host defenses lower, on stressed than on healthy trees, but the impact of host condition on T. fuscum performance varied seasonally. Timing of attack was critical, influencing the strength of bottom-up forces and consequently all measures of T. fuscum performance. Survival was reduced when T. fuscum attacked too early (late-May) or too late (late-June), which may result in stabilizing selection for attack time in this species. Parasitism and competition were generally negligible during this study. Our results suggest that timing of attack is critical for this wood borer and that temporal variation in the impact of top-down and bottom-up forces should be considered in other systems. PMID- 24073795 TI - Evaluation of antihyperlipidemic and antitumor activities of isolated coumarins from Salvadora indica. AB - CONTEXT: Salvadora indica Wight (Salvadoraceae) contains a number of medically beneficial properties including abrasives, astringents and antiseptics. Traditionally, it was used by ancient Arabs to whiten and polish teeth. OBJECTIVE: This study explores the antihyperlipidemic and antitumor effects of an ethanol extract of S. indica and its isolated phytoconstituents in rodents. MATERIAL AND METHODS: Flash chromatography was used for the isolation of phytoconstituents from the stems of S. indica. An antihyperlipidemic study was carried out in Triton loaded rats. Animal groups were given intraperitoneal (i.p.) injection of Triton WR 1339 at dose of 400 mg/kg body weight (b.w.). Furthermore, antitumor activity was investigated in hybrid mice (of C57BL strain + Swiss albino strain). The animals were observed for tumor growth after injection of B16F10 melanoma cells into the dorsal skin of mice. RESULTS: The stems of S. indica yielded xanthotoxin and umbelliferone through chromatographic separation techniques. The structures of the compounds were elucidated by spectroscopic data interpretation and showed antihyperlipidemic activity. The study showed significant reduction in total cholesterol (TC) (p < 0.01), triglycerides (TGs) (p < 0.001), low-density lipoproteins (p < 0.01) level whereas increased in high-density lipoprotein (p < 0.01) at a significant level, after the treatment. Pretreatment with the extract and phytoconstituents also showed delayed tumor growth by increasing the volume doubling time (VDT) (p < 0.01), growth delay (GD) (p < 0.01) and mean survival time (p < 0.001). DISCUSSION AND CONCLUSION: Acute treatment caused a stimulatory effect on high density lipoprotein level and inhibition in TC and TG elevation induced by Triton. Tumor regression studies showed a regression response for tumor growth in vivo of murine mouse melanoma as demonstrated by increasing the VDT and GD. PMID- 24073796 TI - Association of tumor necrosis factor alpha promoter polymorphism (TNF-alpha 238 G/A and TNF-alpha 308 G/A) with diabetic mellitus, diabetic retinopathy and diabetic nephropathy: a meta-analysis. AB - AIM: To examine the association between tumor necrosis factor alpha (TNF-alpha) polymorphism and risk for diabetic mellitus (DM), diabetic retinopathy (DR) and diabetic nephropathy (DN). METHODS: Systematic searches of electronic databases such as PubMed, Medline, Web of knowledge and CNKI, as well as hand searching of the references of identified articles were performed. A total of 8979 subjects in 14 studies from 12 eligible publications were included in this meta-analysis (6 of 12 eligible studies were analyzed for TNF 238 G/A polymorphism and Type 1 DM (T1DM), 5 of 12 were analyzed for TNF 308 G/A polymorphism and DR in Type 2 DM (T2DM), and 3 of 12 were analyzed for TNF 308 G/A polymorphism and DN in T2DM). Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed or random effects model. The I(2) statistics were used to evaluate between study heterogeneity. Sensitivity analysis was also performed. RESULTS: The results showed no evidence for significant association between TNF 238 G/A polymorphism and T1DM (for AA + GA versus GG: OR = 0.95, 95% CI = 0.48-1.88, p = 0.89), and also no association between TNF 308 G/A polymorphism and DR and DN risk in T2DM (for AA + GA versus GG: OR = 1.04, 95% CI = 0.87-1.25, p = 0.68; OR = 0.88, 95% CI = 0.71-1.08, p = 0.21; respectively). In addition, the similar results were obtained in the subgroup analysis based on the ethnicity. CONCLUSIONS: In summary, results from this meta-analysis suggest that the TNF 238 G/A polymorphism was not associated with T1DM. No association between TNF 308 G/A polymorphism and DR and DN in T2DM was detected. PMID- 24073797 TI - Plasma and dialysate potassium concentrations and haemodialysis associated mortality. PMID- 24073799 TI - Purification and characterization of a novel neutral and heat-tolerant phytase from a newly isolated strain Bacillus nealsonii ZJ0702. AB - BACKGROUND: Phytic acid and phytates can interact with biomolecules, such as proteins and carbohydrates, and are anti-nutritional factors found in food and feed. Therefore, it is necessary to remove these compounds in food and feed processing. Phytase can hydrolyze phytic acid and phytates to release a series of lower phosphate esters of myoinositol and orthophosphate. Thus, the purification and characterization of novel phytases that can be used in food and feed processing is of particular interest to the food and feed industries. RESULTS: A novel neutral and heat-tolerant phytase from a newly isolated strain Bacillus nealsonii ZJ0702 was purified to homogeneity with a yield of 5.7% and a purification fold of 44. The molecular weight of the purified phytase obtained by SDS-PAGE was 43 kDa. The homology analysis based on N-terminal amino acid and DNA sequencing indicated that the purified phytase was different from other known phytases. The optimal thermal and pH activity of the phytase was observed at 55 degrees C and 7.5, respectively. Seventy-three percent of the original activity of the phytase was maintained following incubation at 90 degrees C for 10 min. The phytase was stable within a pH range of 6.0-8.0 and showed high substrate specificity for sodium phytate. Cu2+, Co2+, Zn2+, Mn2+, Ba2+ and Ni2+ ions were found to inhibit the activity of the phytase. CONCLUSIONS: A novel phytase purified from B. nealsonii ZJ0702 was identified. The phytase was found to be thermally stable over a wide temperature range at neutral pH. These properties suggest that this phytase is a suitable alternative to fungal phytases for the hydrolysis of phytic acid and phytates in food and feed processing industries. PMID- 24073801 TI - Factors affecting patient's perception of anticancer treatments side-effects: an observational study. AB - BACKGROUND: Analysis of relative importance of side effects of anticancer therapy is extremely useful in the process of clinical decision making. There is evidence that patients' perception of the side effects of anticancer treatments changes over time. OBJECTIVES: Aim of this study was to evaluate the cancer patients' perceptions of physical and non-physical side effects of contemporary anticancer therapy. Four hundred and sixty-four patients entered the study (153 men and 311 women). Participants were asked to rank their side effects in order of distress by using two sets of cards naming physical and non-physical effects, respectively. Influencing factors, including treatment and patient characteristics, were also analysed. RESULTS: Patients ranked the non-physical side effect 'Affects my family or partner' first. 'Constantly tired' and 'Loss of hair' were ranked second and third, respectively. Significant differences from previous studies on this topic emerged. In particular, 'Vomiting', a predominant concern in previous studies, almost disappeared, whereas 'Nausea' and 'Loss of hair' remained important side effects in the patients' perception. Interestingly, marital status was predominant in driving patients' perception, being associated with several side effects ('Constantly tired', 'Loss of appetite', 'Affects my work/Home duties', 'Affects my social activities', 'Infertility'). Other significant factors influencing patient's perception of side effects included age, disease characteristics and ongoing anticancer therapy. CONCLUSIONS: This study provided information on current status of patients' perceptions of side effects of anticancer treatment. These results could be used in pre-treatment patient education and counselling. PMID- 24073800 TI - The degradation of airway tight junction protein under acidic conditions is probably mediated by transient receptor potential vanilloid 1 receptor. AB - Acidic airway microenvironment is one of the representative pathophysiological features of chronic inflammatory respiratory diseases. Epithelial barrier function is maintained by TJs (tight junctions), which act as the first physical barrier against the inhaled substances and pathogens of airway. As previous studies described, acid stress caused impaired epithelial barriers and led the hyperpermeability of epithelium. However, the specific mechanism is still unclear. We have showed previously the existence of TRPV (transient receptor potential vanilloid) 1 channel in airway epithelium, as well as its activation by acidic stress in 16HBE cells. In this study, we explored the acidic stress on airway barrier function and TJ proteins in vitro with 16HBE cell lines. Airway epithelial barrier function was determined by measuring by TER (trans-epithelial electrical resistance). TJ-related protein [claudin-1, claudin-3, claudin-4, claudin-5, claudin-7 and ZO-1 (zonula occluden 1)] expression was examined by western blotting of insoluble fractions of cell extraction. The localization of TJ proteins were visualized by immunofluorescent staining. Interestingly, stimulation by pH 6.0 for 8 h slightly increased the epithelial resistance in 16HBE cells insignificantly. However, higher concentration of hydrochloric acid (lower than pH 5.0) did reduce the airway epithelial TER of 16HBE cells. The decline of epithelial barrier function induced by acidic stress exhibited a TRPV1 [Ca2+]i-dependent pathway. Of the TJ proteins, claudin-3 and claudin-4 seemed to be sensitive to acidic stress. The degradation of claudin-3 and claudin-4 induced by acidic stress could be attenuated by the specific TRPV1 blocker or intracellular Ca2+ chelator BAPTA/AM [1,2-bis-(o-aminophenoxy)ethane-N,N,N',N' tetra-acetic acid tetrakis(acetoxymethyl ester)]. PMID- 24073798 TI - Thyrotropin isoforms: implications for thyrotropin analysis and clinical practice. AB - Serum thyrotropin (TSH) is considered the single most sensitive and specific measure of thyroid function in the general population owing to its negative logarithmic association with free triiodothyronine and free thyroxine concentrations. It is therefore often the test of choice for screening, diagnosis, and monitoring of primary hypothyroidism. Serum TSH concentrations can be analyzed quantitatively using third-generation immunoassays, whereas its bioactivity can be measured by TSH activity assays in cell culture. Theoretically, if serum TSH concentrations are directly related to TSH activity, the two tests should yield comparable results. However, on occasion, the results are discordant, with serum concentrations being higher than TSH biological activity. This review focuses on the dissociation between the clinical state and serum TSH concentrations and addresses clinically important aspects of TSH analysis. PMID- 24073802 TI - PMMA/polysaccharides nanofilm loaded with adenosine deaminase inhibitor for targeted anti-inflammatory drug delivery. AB - A novel drug delivery vector, a free-standing polymeric ultrathin film (nanofilm) composed of PMMA and a polysaccharides multilayer, is presented. Chitosan and sodium alginate are alternatively deposited by spin-assisted LbL assembly onto a plasma-treated PMMA thin film. Hydrophobic anti-inflammatory drugs, an adenosine deaminase inhibitor (APP) and its fluorescent dansyl derivate (APP-Dns), are encapsulated inside the LbL multilayer using a simple casting deposition procedure. The resulting drug loaded nanofilm can be suspended in water upon dissolution of a PVA sacrificial layer. Morphological characterization of the nanofilm shows that PMMA/LbL nanofilms possess nanometric thickness (<200 nm) and very low surface roughness (1-2 nm for drug loaded nanofilms and <1 nm for blank nanofilm). Drug loaded films exhibit a diffusion controlled release mechanism following the Korsmayer-Peppas release model, confirmed by the fit of release data with a characteristic power law. Drug release is impaired through the PMMA layer, which acts effectively as a barrier for drug transport. This ultrathin polymer film can find application as a nanopatch for targeted inflammatory drug delivery to treat localized pathologies as inflammatory bowel disease. PMID- 24073806 TI - Predictors of mortality in multidrug-resistant Klebsiella pneumoniae bloodstream infections. AB - The dramatic increase of antibiotic resistance in Klebsiella pneumoniae has been associated with fatal outcomes. First, bloodstream infections (BSIs) caused by extended-spectrum beta-lactamases (ESBL) Enterobacteriaceae have been associated with treatment failure, more recently BSIs caused by carbapenem-resistant K. pneumoniae (CR-KP) have been reported to be fatal in approximately 50% of cases. Severity of underlying disease, intensive care unit stay at infection onset, infection with ESBL or CR-KP strain and delay in administration of appropriate therapy are among the most common risk factors for mortality in patients with K. pneumoniae BSI, while infection source control and early appropriate antimicrobial treatment have been associated with survival. Thus, risk assessment for ESBL and/or CR-KP is mandatory in patients with suspicion of K. pneumoniae BSI. Here, we examine current evidence regarding risk factors for mortality in patients with K. pneumoniae BSI and address the issue of a risk prediction model for CR-KP BSI. PMID- 24073807 TI - Synchronous metastatic pulmonary adenocarcinoma with small cell lymphoma. PMID- 24073803 TI - The effects of HIV Tat DNA on regulating the immune response of HIV DNA vaccine in mice. AB - BACKGROUND: HIV trans-activator protein (Tat) is the crucial factor to control HIV transcription, and is usually considered as an important immunogen for the design of HIV vaccine. Recent studies reported some special bio-activities of Tat protein on immunoregulation. However, to date, few studies have focused on exploring the effects of Tat expression plasmid (pTat) on regulating the immune responses induced by HIV DNA vaccines. In this study, our main objective is to investigate the immunoregulation mediated by pTat in mice. METHODS: Four gene coding plasmids (pTat, pGag, pEnv and pPol) were constructed, and the gene expression was detected by western blot method. The effects of pTat on regulating the immune responses to antigens Gag, Env, Pol were assessed by enzyme-linked immunospot and enzyme-linked immunosorbent assay. The data was analysed by one way analysis of variance. RESULTS: After two immunizations, mice vaccinated with antigen expressing plasmid (pGag, pEnv or pPol) plus pTat exhibited significantly stronger IFN-gamma response than that vaccinated with the corresponding antigen alone. Moreover, mice receiving two injections of antigen plus pTat exhibited the same strong IFN-gamma response as those receiving three injections of antigen alone did. Furthermore, addition of pTat not only induced a more balanced Th1 and Th2 response, but also broadened IgG subclass responses to antigens Gag and Pol. CONCLUSION: pTat exhibited the appreciable effects on modulating immune responses to HIV antigens Gag, Env and Pol, providing us interesting clues on how to optimize HIV DNA vaccine. PMID- 24073808 TI - The "new conservation". PMID- 24073809 TI - The anthropocebo effect. PMID- 24073810 TI - Implications of ash dieback for associated epiphytes. PMID- 24073811 TI - Reassessment of the use of fire as a management tool in deciduous forests of eastern North America. AB - Prescribed burning is increasingly being used in the deciduous forests of eastern North America. Recent work suggests that historical fire frequency has been overestimated east of the prairie-woodland transition zone, and its introduction could potentially reduce forest herb and shrub diversity. Fire-history recreations derived from sedimentary charcoal, tree fire scars, and estimates of Native American burning suggest point-return times ranging from 5-10 years to centuries and millennia. Actual return times were probably longer because such records suffer from selective sampling, small sample sizes, and a probable publication bias toward frequent fire. Archeological evidence shows the environmental effect of fire could be severe in the immediate neighborhood of a Native American village. Population density appears to have been low through most of the Holocene, however, and villages were strongly clustered at a regional scale. Thus, it appears that the majority of forests of the eastern United States were little affected by burning before European settlement. Use of prescribed burning assumes that most forest species are tolerant of fire and that burning will have only a minimal effect on diversity. However, common adaptations such as serotiny, epicormic sprouting, resprouting from rhizomes, and smoke-cued germination are unknown across most of the deciduous region. Experimental studies of burning show vegetation responses similar to other forms of disturbance that remove stems and litter and do not necessarily imply adaptation to fire. The general lack of adaptation could potentially cause a reduction in diversity if burning were introduced. These observations suggest a need for a fine-grained examination of fire history with systematic sampling in which all subregions, landscape positions, and community types are represented. Responses to burning need to be examined in noncommercial and nonwoody species in rigorous manipulative experiments. Until such information is available, it seems prudent to limit the use of prescribed burning east of the prairie-woodland transition zone. PMID- 24073812 TI - Accounting for complementarity to maximize monitoring power for species management. AB - To choose among conservation actions that may benefit many species, managers need to monitor the consequences of those actions. Decisions about which species to monitor from a suite of different species being managed are hindered by natural variability in populations and uncertainty in several factors: the ability of the monitoring to detect a change, the likelihood of the management action being successful for a species, and how representative species are of one another. However, the literature provides little guidance about how to account for these uncertainties when deciding which species to monitor to determine whether the management actions are delivering outcomes. We devised an approach that applies decision science and selects the best complementary suite of species to monitor to meet specific conservation objectives. We created an index for indicator selection that accounts for the likelihood of successfully detecting a real trend due to a management action and whether that signal provides information about other species. We illustrated the benefit of our approach by analyzing a monitoring program for invasive predator management aimed at recovering 14 native Australian mammals of conservation concern. Our method selected the species that provided more monitoring power at lower cost relative to the current strategy and traditional approaches that consider only a subset of the important considerations. Our benefit function accounted for natural variability in species growth rates, uncertainty in the responses of species to the prescribed action, and how well species represent others. Monitoring programs that ignore uncertainty, likelihood of detecting change, and complementarity between species will be more costly and less efficient and may waste funding that could otherwise be used for management. PMID- 24073815 TI - Randomised controlled trial of a cognitive narrative intervention for complicated grief in widowhood. AB - OBJECTIVE: The implementation of bereavement interventions is frequently requested, and its effectiveness has been controversial. The aim of this study is to evaluate the effectiveness of a cognitive narrative intervention for complicated grief (CG) for controlling post-traumatic and depressive issues. METHOD: The study is a randomised controlled trial and uses the Socio Demographic Questionnaire (SDQ), the Inventory of Complicated Grief (ICG), the Beck Depression Inventory (BDI) and the Impact of Events Scale-Revised (IES-R). There were three phases in the study: (1) The SDQ and CG evaluations were applied to bereaved elders (n = 82). The bereaved elders with the 40 highest ICG values (>=25) were randomly allocated into two groups: the intervention group (n = 20) and control group (n = 20); (2) participants were evaluated using the BDI and IES R and the IG gave informed consent to participate in an intervention with four weekly 60-min sessions addressing recall, emotional and cognitive subjectivation, metaphorisation and projecting. (3) Two months later, the ICG, BDI and IES-R assessments were repeated. RESULTS: Outcome measures showed a statistically significant reduction of CG, depressive and traumatic symptoms compared to the controls. Very high effect sizes for the ICG, BDI and IES-R reflect the effectiveness of the intervention along the longitudinal profile. CONCLUSIONS: These results reinforce the importance of brief interventions that combine a reduced number of sessions with lower costs, which is reflected in an increased adherence to the programme along with high effectiveness. PMID- 24073814 TI - Cyprinid herpesvirus 3: an interesting virus for applied and fundamental research. AB - Cyprinid herpesvirus 3 (CyHV-3), a member of the family Alloherpesviridae is the causative agent of a lethal, highly contagious and notifiable disease in common and koi carp. The economic importance of common and koi carp industries together with the rapid spread of CyHV-3 worldwide, explain why this virus became soon after its isolation in the 1990s a subject of applied research. In addition to its economic importance, an increasing number of fundamental studies demonstrated that CyHV-3 is an original and interesting subject for fundamental research. In this review, we summarized recent advances in CyHV-3 research with a special interest for studies related to host-virus interactions. PMID- 24073817 TI - Optimised heart rate formulae to monitor endurance training in sedentary individuals. AB - The aim of this study was to assess the validity of the heart rate formula 170 - 0.5 age +/- 10 used to prescribe endurance training for healthy sedentary or moderately trained individuals. A total of 795 incremental tests of women and men during running and cycling were analysed. The maximum heart rate, heart rate at deflection and age-dependent declines of these heart rates were determined. The maximum heart rate and the heart rate at deflection were greater during running (women: 192 +/- 10 and 181 +/- 9 bpm; men: 191 +/- 10 and 179 +/- 10 bpm) than cycling (women: 185 +/- 11 and 170 +/- 11 bpm; men: 187 +/- 10 and 169 +/- 11 bpm, P < 0.001) without any sex-based difference. With the upper limit of the existing heart rate formula, 4% during running and 35% during cycling exceeded the heart rate at deflection. We suggest two heart rate formulae for healthy sedentary or moderately endurance trained individuals separated for mode of exercise but not for sex: 165 - 0.5 age +/- 5 for running and 160 - 0.5 age +/- 5 for cycling. PMID- 24073818 TI - Optoelectronic properties of a fullerene derivative containing adamantane group. AB - A fullerene derivative linked with an adamantane cage, [6,6]-phenyl-C61-butyric acid 1-adamantane methyl ester (PC61BAd), has been designed and synthesized. Systematic investigations on its organic field effect performance, photovoltaic properties, and corresponding thermal stability have been made. In OFET device, the electron mobility (MUe) of PC61BAd was found to reach a value as high as 0.01 cm(2)/V.s with a high on-off (Ion/Ioff) ratio of 4.9 * 10(6) that is useful for logic device applications. In the organic photovoltaic devices of P3HT:PC61BAd, the power conversion efficiency (PCE) was found to reach 3.31 % in the optimized device. More importantly, the active layer of P3HT:PC61BAd was found to exhibit superior thermal stability over that of P3HT:PC61BM. After heating at 150 degrees C for 20 h, the P3HT:PC61BAd device still showed a PCE of 2.44 %, demonstrating the applicability of PC61BAd as an acceptor material for the preparation of thermally stable organic solar cells. X-ray diffraction and atomic force microscopy were employed to probe the structure and morphology of PC61BAd and to rationalize its performance as an organic electronic material. PMID- 24073816 TI - Bone-stromal cells up-regulate tumourigenic markers in a tumour-stromal 3D model of prostate cancer. AB - BACKGROUND: The cellular and molecular mechanisms that mediate interactions between tumour cells and the surrounding bone stroma are to date largely undetermined in prostate cancer (PCa) progression. The purpose of this study was to evaluate the role of alpha 6 and beta 1 integrin subunits in mediating tumour stromal interactions. METHODS: Utilising 3D in vitro assays we evaluated and compared 1. Monocultures of prostate metastatic PC3, bone stromal derived HS5 and prostate epithelial RWPE-1 cells and 2. Tumour-stromal co-cultures (PC3 + HS5) to ascertain changes in cellular phenotype, function and expression of metastatic markers. RESULTS: In comparison to 3D monocultures of PC3 or HS5 cells, when cultured together, these cells displayed up-regulated invasive and proliferative qualities, along with altered expression of epithelial-to-mesenchymal and chemokine protein constituents implicated in metastatic dissemination. When co cultured, HS5 cells were found to re-express N-Cadherin and chemokine receptor CXCR7. Alterations in N-Cadherin expression were found to be mediated by soluble factors secreted by PC3 tumour cells, while chemokine receptor re-expression was dependent on direct cell-cell interactions. We have also shown that integrins beta 1 and alpha 6 play an integral role in maintaining cell homeostasis and mediating expression of E-Cadherin, N-Cadherin and vimentin, in addition to chemokine receptor CXCR7. CONCLUSIONS: Collectively our results suggest that both PC3 and HS5 cells provide a "protective" and reciprocal milieu that promotes tumour growth. As such 3D co-cultures may serve as a more complex and valid biological model in the drug discovery pipeline. PMID- 24073819 TI - Metal-free oxidative spirocyclization of hydroxymethylacrylamide with 1,3 dicarbonyl compounds: a new route to spirooxindoles. AB - A metal-free oxidative spirocyclization of hydroxymethylacrylamide with 1,3 dicarbonyl compounds is described. The reaction proceeds through tandem dual C-H functionalization and intramolecular dehydration, in which two new C-C bonds and one C-O bond were formed. This method affords a novel and straightforward access to various spirooxindoles under mild conditions. PMID- 24073820 TI - Deposition history of polychlorinated biphenyls to the Lomonosovfonna Glacier, Svalbard: a 209 congener analysis. AB - A 37 m deep ice core representing 1957-2009 and snow from 2009 to 2010 were collected on the Lomonosovfonna glacier, Svalbard (78.82 degrees N; 17.43 degrees E) and analyzed for 209 polychlorinated biphenyl (PCB) congeners using high-resolution mass spectrometry. Congener profiles in all samples showed the prevalence of tetra- and pentachlorobiphenyls, dominated in all samples by PCB 44, PCB-52, PCB-70 + PCB-74, PCB-87 + PCB-97, PCB-95, PCB-99, PCB-101, and PCB 110. The ?PCB flux varied over time, but the peak flux, ~19 pg cm(-2) year(-1) from 1957 to 1966, recurred in 1974-1983, 1998-2009, and 2009-2010. The minimum was 5.75 pg cm(-2) year(-1) in 1989-1998, following a 15 year decline. Peak ?PCB fluxes here are lower than measured in the Canadian Arctic. The analysis of all 209 congeners revealed that PCB-11 (3,3'-dichlorobiphenyl) was present in all samples, representing 0.9-4.5% of ?PCB. PCB-11 was not produced in a commercial PCB product, and its source to the Arctic has not been well-characterized; however, our results confirm that the sources to Lomonosovfonna have been active since 1957. The higher fluxes of ?PCB correspond to periods when average 5 day air mass back trajectories have a frequency of 8-10% and reach 60 degrees N or beyond over northern Europe and western Russia or the North Sea into the U.K. PMID- 24073821 TI - A hierarchical spatial modelling approach to investigate MRSA transmission in a tertiary hospital. AB - BACKGROUND: Most hospitals have a hierarchical design with beds positioned within cubicles and cubicles positioned within wards. Transmission of MRSA may be facilitated by patient proximity and thus the spatial arrangements of beds, cubicles and wards could be important in understanding MRSA transmission risk. Identifying high-risk areas of transmission may be useful in the design of more effective, targeted MRSA interventions. METHODS: Retrospective data on numbers of multi-resistant and non-multiresistant MRSA acquisitions were collected for 52 weeks in 2007 in a tertiary hospital in Brisbane, Australia. A hierarchical Bayesian spatio-temporal modelling approach was used to investigate spatial correlation in the hierarchically arranged datasets. The spatial component of the model decomposes cubicle-level variation into a spatially structured component and a spatially unstructured component, thereby encapsulating the influence of unmeasured predictor variables that themselves are spatially clustered and/or random. A fixed effect for the presence of another patient with the same type of MRSA in the cubicles two weeks prior was included. RESULTS: The best-fitting model for non-multiresistant MRSA had an unstructured random effect but no spatially structured random effect. The best-fitting model for multiresistant MRSA incorporated both spatially structured and unstructured random effects. While between-cubicle variability in risk of MRSA acquisition within the hospital was significant, there was only weak evidence to suggest that MRSA is spatially clustered. Presence of another patient with the same type of MRSA in the cubicles two weeks prior was a significant predictor of both types of MRSA in all models. CONCLUSIONS: We found weak evidence of clustering of MRSA acquisition within the hospital. The presence of an infected patient in the same cubicle two weeks prior may support the importance of environmental contamination as a source of MRSA transmission. PMID- 24073822 TI - Tuning the dielectric properties of organic semiconductors via salt doping. AB - Enhancing the dielectric permittivity of organic semiconductors may open new opportunities to control charge generation and recombination dynamics in organic solar cells. The potential to tune the dielectric permittivity of organic semiconductors by doping them with redox inactive salts was explored using a combination of organic synthesis, electrical characterization, and time-resolved infrared spectroscopy. The addition of the salt, LiTFSI (lithium bis(trifluoro methyl-sulfonyl)imide), to a conjugated polymer specifically designed to incorporate ions into its bulk phase increased the density of holes and enhanced the static dielectric permittivity of the polymer blend by more than an order of magnitude. The frequency and phase dependence of the real dielectric function demonstrates that the increase in dielectric permittivity resulted from dipolar motion of bound ion pairs or clusters of ions. Interestingly, the increases in the hole density and dielectric permittivity were associated with enhancement of the hole mobility by 2 orders of magnitude relative to the undoped polymer. The charge recombination lifetime also increased by an order of magnitude in the blend with a fullerene electron acceptor when ions were added to the polymer. The findings indicate that ion doping enables organic semiconductors with large increases in low frequency dielectric permittivity and that these changes result in improved charge transport and suppressed charge recombination on the microsecond time scale. PMID- 24073823 TI - Synergistic antimicrobial profiling of violacein with commercial antibiotics against pathogenic micro-organisms. AB - CONTEXT: Chromobacterium violaceum Bergonzini (Neisseriaceae), a Gram-negative bacterium, secretes a spectacular pigment called violacein. Violacein is a quorum sensing metabolite and is also an active antimicrobial, anticancer agent. However, its efficiency as a potential drug, alone or in synergy with other active principles, has not being completely exploited. With the advent of different multi-drug resistant strains, it becomes essential to find a new natural product(s) that could be effectively used as a therapeutic agent. OBJECTIVE: This work focused on the extraction of violacein from an isolated strain of C. violaceum and determined the combinatory effect of violacein with commercial antibiotics against various pathogens. MATERIALS AND METHODS: Violacein production was optimized and was later extracted using ethanol and characterized by liquid chromatography-mass spectrometry and infrared spectroscopy. Then, individual minimum inhibitory concentration (MIC) values for each of the antibiotics were determined followed by violacein-commercial antibiotics (1:1) combinations, tested at different concentrations starting from 500 to 1 ug/ml against major pathogens. RESULTS AND DISCUSSION: The individual MIC data for violacein was found to be 5.7 ug/ml (Staphylococcus aureus), 15.6 ug/ml (Klebsiella pneumoniae), 18.5 ug/ml (Pseudomonas aeruginosa), 20.0 ug/ml (Vibrio cholerae) and 5.7 ug/ml (Salmonella typhi). Violacein-gentamicin and violacein-cefadroxil combinations had MIC of 1.0 ug/ml against S. aureus. Most violacein-macrolide and violacein--aminoglycoside class combinations revealed fractional inhibitory concentration indices (FICI) of <0.5, thus exhibiting synergism. Furthermore, violacein-azithromycin and violacein-kanamycin combination, exhibited significant synergy (FICI-0.3) against S. typhi. CONCLUSION: Violacein works synergistically with most commercial antibiotics and could be used as drug in combination with other antimicrobial agents. PMID- 24073824 TI - Differential regulation of the production of reactive oxygen species in Th1 cytokine-treated thyroid cells. AB - BACKGROUND: Th1 cytokines exert pleiotropic effects in Hashimoto's thyroiditis. Previous studies reported a downregulation of thyroperoxidase and dual oxidase (DUOX) protein and mRNA expression in thyroid cells treated with Th1 cytokines. Although this effect is partially mediated by intracellular reactive oxygen species (ROS) and reactive nitrogen species, the nature and the source of the ROS involved are currently unknown. The aim of this study was to examine further the nature and source of the ROS produced in response to Th1 cytokines. METHODS: Two rat thyroid cell lines (PCCL3 and FRTL-5) and human thyrocytes were incubated with Th1 cytokines (interleukin [IL]-1alpha and interferon-gamma) in the presence or absence of the Th2 cytokine IL-4, the nitric oxide synthase inhibitor N nitroso-L-arginine methyl ester (L-NAME), or the synthetic antioxidant N acetylcysteine. The nature and source of the intracellular and extracellular ROS produced were determined. RESULTS: A rapid increase in intracellular ROS was observed in cells incubated with Th1 cytokines. This increase was not caused by extracellular hydrogen peroxide (H2O2) produced by DUOX because both DUOX expression and extracellular H2O2 synthesis were decreased by Th1 cytokines. Confocal colocalization experiments showed that the Th1 cytokine-triggered ROS were not produced from mitochondria. Electron paramagnetic resonance investigations of PCCL3 cells indicated that the highly reactive hydroxyl radical was not involved in the response to Th1 cytokines. NOX2 mRNA expression was significantly increased in PCCL3 cells incubated with Th1 cytokines, as was the expression of the protein in the thyroid of Hashimoto's thyroiditis patients. NOX4 expression was by contrast unaffected. These results suggest that at least superoxide could be produced after exposure of thyroid cells to Th1 cytokines. The effects of L-NAME and IL-4, both of which partially or totally reverse Th1 cytokine-induced effects, on ROS release were also analyzed. L-NAME and IL-4 significantly reduced the Th1 cytokine-induced surge of intracellular ROS in PCCL3 and human thyroid cells. CONCLUSION: The data presented here reinforce the idea that ROS, other than extracellular H2O2 produced by DUOX, are released from NOX2 after exposure of thyroid cells to Th1 cytokines. ROS/reactive nitrogen species act as important, but as further explained, not exclusive intracellular mediators of Th1 cytokine-induced effects in thyroid cells. PMID- 24073825 TI - Neurogastroenterology and motility's impact factor. PMID- 24073826 TI - High-resolution manometry changes our views of gastrointestinal motility. AB - High-resolution manometry using catheters with 36 solid-state sensors spaced 1 cm apart has already become an established technique for esophageal manometry where it has replaced water-perfused and station pull-through manometry. Spatiotemporal plots with color coding of pressure have greatly facilitated the analysis of esophageal peristalsis. Although suitable for the length of the esophagus, the solid-state catheter is insufficient for the study of longer segments of the gastrointestinal tract. A new technique with fiber-optic sensors has made it possible to construct catheters with 72-144 sensors. Studies of colonic motility have revealed that the most common motor pattern of the colon is a peristaltic contraction that travels 7-10 cm in the retrograde direction. Earlier studies using low-resolution manometry with 7-45 cm between sensors led us to erroneous conclusions regarding direction and frequency of contractions and they largely missed both antegrade and retrograde contractions traveling short distances. Fiber-optic high-resolution manometry holds promise for greatly improving our understanding of gut motor physiology and hopefully also our understanding of patients with symptoms of disordered gut motility. PMID- 24073827 TI - Hyperthyroidism and antithyroid medications: a friend and an enemy of psychosis. PMID- 24073828 TI - Characterization of the biochemical properties of Campylobacter jejuni RNase III. AB - Campylobacter jejuni is a foodborne bacterial pathogen, which is now considered as a leading cause of human bacterial gastroenteritis. The information regarding ribonucleases in C. jejuni is very scarce but there are hints that they can be instrumental in virulence mechanisms. Namely, PNPase (polynucleotide phosphorylase) was shown to allow survival of C. jejuni in refrigerated conditions, to facilitate bacterial swimming, cell adhesion, colonization and invasion. In several microorganisms PNPase synthesis is auto-controlled in an RNase III (ribonuclease III)-dependent mechanism. Thereby, we have cloned, overexpressed, purified and characterized Cj-RNase III (C. jejuni RNase III). We have demonstrated that Cj-RNase III is able to complement an Escherichia coli rnc deficient strain in 30S rRNA processing and PNPase regulation. Cj-RNase III was shown to be active in an unexpectedly large range of conditions, and Mn2+ seems to be its preferred co-factor, contrarily to what was described for other RNase III orthologues. The results lead us to speculate that Cj-RNase III may have an important role under a Mn2+-rich environment. Mutational analysis strengthened the function of some residues in the catalytic mechanism of action of RNase III, which was shown to be conserved. PMID- 24073829 TI - Simultaneous display of two large proteins on the head and tail of bacteriophage lambda. AB - BACKGROUND: Consistent progress in the development of bacteriophage lambda display platform as an alternative to filamentous phage display system was achieved in the recent years. The lambda phage has been engineered to display efficiently multiple copies of peptides or even large protein domains providing a powerful tool for screening libraries of peptides, proteins and cDNA. RESULTS: In the present work we describe an original method for dual display of large proteins on the surface of lambda particles. An anti-CEA single-chain antibody fragment and green fluorescent protein or alkaline phosphatase were simultaneously displayed by engineering both gpD and gpV lambda proteins. CONCLUSIONS: Here we show that such modified phage particles can be used for the detection of target molecules in vitro and in vivo. Dual expression of functional moieties on the surface of the lambda phage might open the way to generation of a new class of diagnostic and therapeutic targeted nanoparticles. PMID- 24073830 TI - Natural gelatin capped mesoporous silica nanoparticles for intracellular acid triggered drug delivery. AB - This paper proposed a natural gelatin capped mesoporous silica nanoparticles (MSN@Gelatin) based pH-responsive delivery system for intracellular anticancer drug controlled release. In this system, the gelatin, a proteinaceous biopolymer derived from the processing of animal collagen, was grafted onto the MSN to form a capping layer via temperature-induced gelation and subsequent glutaraldehyde mediated cross-linking, resulting in gelatin coated MSN. At neutral pH, the gelatin capping layer could effectively prohibit the release of loaded drug molecules. However, the slightly acidic environment would lead to enhanced electrostatic repulsion between the gelatin and MSN, giving rise to uncapping and the subsequent controlled release of the entrapped drug. As a proof-of-concept, doxorubicin (DOX) was selected as the model anticancer drug. The loading and pH responsive release experiments demonstrated that the system had excellent loading efficiency (47.3 mmol g(-1) SiO2), and almost no DOX was leaked at neutral. After being in the slightly acidic condition, the DOX release from the DOX-loaded MSN@Gelatin (DOX/MSN@Gelatin) occurred immediately. The cellular uptake and release studies using Hep-G2 hepatoma cells indicated that the DOX/MSN@Gelatin could be endocytosed and accumulated within lysosomes. Triggered by acidic endosomal pH, the intracellular release of the loaded DOX was obviously eventuated. Further cell viability results demonstrated that DOX/MSN@Gelatin exhibited dose-dependent toxicity and high killing efficacy (IC50 = 17.27 +/- 0.63 MUg mL(-1)), whereas the MSN@Gelatin showed negligible cytotoxicity (IC50 > 100 MUg mL(-1)). This biocompatible and effective delivery system will provide great potential for developing delivery of cancer therapeutic agents. PMID- 24073831 TI - Effects of dexamethasone, ascorbic acid and beta-glycerophosphate on the osteogenic differentiation of stem cells in vitro. AB - The standard procedure for the osteogenic differentiation of multipotent stem cells is treatment of a confluent monolayer with a cocktail of dexamethasone (Dex), ascorbic acid (Asc) and beta-glycerophosphate (beta-Gly). This review describes the effects of these substances on intracellular signaling cascades that lead to osteogenic differentiation of bone marrow stroma-derived stem cells. We conclude that Dex induces Runx2 expression by FHL2/beta-catenin-mediated transcriptional activation and that Dex enhances Runx2 activity by upregulation of TAZ and MKP1. Asc leads to the increased secretion of collagen type I (Col1), which in turn leads to increased Col1/alpha2beta1 integrin-mediated intracellular signaling. The phosphate from beta-Gly serves as a source for the phosphate in hydroxylapatite and in addition influences intracellular signaling molecules. In this context we give special attention to the differences between dystrophic and bone-specific mineralization. PMID- 24073835 TI - Diagnosis and treatment of adenovirus infection in immunocompromised patients. AB - In immunocompromised patients, human adenovirus (HAdV) infections can cause life threatening multiorgan disease. This review summarizes the incidence and risk factors of invasive human adenovirus infections in immunocompromised patients as well as the recently developed standards for diagnostic methods and strategies according to the predominant risk factors in adults and children. Recommendations for preemptive and therapeutic treatment strategies and the outcome in different risk groups are presented. Novel therapeutic approaches including CMX001, a new orally bioavailable lipid conjugate of cidofovir and the transfer of adenovirus specific donor T cells in the context of allogeneic stem cell transplantation are discussed. PMID- 24073832 TI - Brain-derived neurotrophic factor enhances the excitability of small-diameter trigeminal ganglion neurons projecting to the trigeminal nucleus interpolaris/caudalis transition zone following masseter muscle inflammation. AB - BACKGROUND: The trigeminal subnuclei interpolaris/caudalis transition zones (Vi/Vc) play an important role in orofacial deep pain, however, the role of primary afferent projections to the Vi/Vc remains to be determined. This study investigated the functional significance of hyperalgesia to the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (trkB) signaling system in trigeminal ganglion (TRG) neurons projecting to the Vi/Vc transition zone following masseter muscle (MM) inflammation. RESULTS: The escape threshold from mechanical stimulation applied to skin above the inflamed MM was significantly lower than in naive rats. Fluorogold (FG) labeling was used to identify the TRG neurons innervating the MM, while microbeads (MB) were used to label neurons projecting to the Vi/Vc region. FG/MB-labeled TRG neurons were immunoreactive (IR) for BDNF and trkB. The mean number of BDNF/trkB-IR small/medium-diameter TRG neurons was significantly higher in inflamed rats than in naive rats. In whole cell current-clamp experiments, the majority of dissociated small-diameter TRG neurons showed a depolarization response to BDNF that was associated with spike discharge, and the concentration of BDNF that evoked a depolarizing response was significantly lower in the inflamed rats. In addition, the relative number of BDNF-induced spikes during current injection was significantly higher in inflamed rats. The BDNF-induced changes in TRG neuron excitability was abolished by tyrosine kinase inhibitor, K252a. CONCLUSION: The present study provided evidence that BDNF enhances the excitability of the small-diameter TRG neurons projecting onto the Vi/Vc following MM inflammation. These findings suggest that ganglionic BDNF-trkB signaling is a therapeutic target for the treatment of trigeminal inflammatory hyperalgesia. PMID- 24073836 TI - Laparoscopic versus open liver resection for benign and malignant solid liver tumors: a case-matched study. AB - BACKGROUND: Laparoscopic liver resection (LLR) is proposed as an alternative to open liver resection (OLR) for treatment of liver tumors. The aim of this study was to compare the surgical and oncological outcomes of LLR versus OLR in benign and malignant solid liver tumors. STUDY DESIGN: In this case-matched study, charts of 497 patients with liver lesions who had LLR or OLR in our center were retrospectively reviewed. Among them, 54 consecutive patients with benign or malignant solid liver tumors who had LLR were matched with a similar number of patients with OLR based on the pathology and extent of liver resection. Additionally, the surgical and oncological outcomes such as operating room time, amount of blood transfusion requirement, free resection margin rate, length of hospital stay, complication rate, perioperative mortality, and survival were compared between the two groups. RESULTS: Demographics, pathological characteristics of the tumor, and extent of liver resection were similar between the two groups. Twenty-nine (54%) patients in each group had malignant lesions. There were no statistically significant differences between the two groups in terms of operating room time, amount of blood transfusion requirement, free resection margin, or postoperative complication rate or survival. However, hospital stay was significantly shorter in the laparoscopic group (5.9 versus 9 days, P=.006). Although no perioperative mortality was observed in patients with benign tumors, among the patients with malignant tumors, 2 died perioperatively in each group. CONCLUSIONS: Our results in accordance with previous studies demonstrated that although the oncological outcomes of LLR and OLR were comparable, LLR patients had a shorter hospital stay. PMID- 24073837 TI - Thoracoscopic segmentectomy for congenital and acquired pulmonary disease: a case for lung-sparing surgery. AB - PURPOSE: Over the last 15 years thoracoscopic lobectomy for congenital and acquired lesions has become an accepted modality in pediatric thoracic surgery. There is still debate about the need to perform a complete lobectomy for some of these lesions, and some advocate observation rather than resection, despite possible long-term complications of untreated lesions. High-resolution computed tomography (CT) scans and physical findings at the time of surgery, along with new advanced techniques, now allow for discrete partial anatomic resections, which may preserve normal lung. This study evaluates the feasibility and early results using these techniques in selected cases. PATIENTS AND METHODS: With institutional review board approval, the records of all patients undergoing thoracoscopic lung resection were reviewed. From January 2006 to December 2012, 23 patients, ranging from 1 month to 16 years of age and weighing 3.8-42 kg, underwent thoracoscopy for planned resection. Pathology was congenital cystic lung disease in 19 patients, bronchiectasis in 3 patients, and arteriovenous malformation in 1 patient. In each case findings on CT scan and at the time of surgery warranted consideration of lung-preserving surgery. Procedures were performed through three ports using single lung ventilation and CO2 insufflation to achieve lung collapse. The LigaSureTM device (Covidien, Norwalk, CT) was the primary instrument used to seal and divide the lung parenchyma and seal vessels. RESULTS: All procedures were completed successfully thoracoscopically. An anatomic segmental resection was achieved in 22 of 23 cases. Operative time ranged from 30 to 300 minutes (mean, 120 minutes). Segmental resections included the left upper lobe apical/posterior (n=4), lingula (n=3), left lower lobe superior (n=5), medial or posterior basal (n=3), right middle lobe medial (n=1), right upper lobe apical (n=1), right lower lobe superior (n=4), and posterior basal (n=2). Two patients had more than one segment excised. Chest tubes were left in for 24 hours in 16 cases, 48 hours in 4 cases, and 5 days in 1 case. Hospital stay ranged from 1 to 6 days (mean, 2 days). Follow-up CT scans obtained at 1-6 years (mean, 28 months) show no residual disease in 20 of 21 patients. One patient underwent a nonanatomic resection and had evidence of recurrent congenital pulmonary airway malformation at the 4-year follow-up. This patient underwent a secondary thoracoscopic resection. CONCLUSIONS: Thoracoscopic lung conserving therapy is technically feasible and safe in infants and children. The magnification provided by a thoracoscopic approach makes identification of segmental anatomic planes easier, aiding in safe dissection and resection. Anatomic resection appears to be associated with a low morbidity. It may be appropriate in the case of bilateral or extensive disease or in cases where the diseased tissue is clearly limited to an anatomic segment. Continued long-term follow-up is needed. PMID- 24073838 TI - Outcome of laparoscopic sleeve gastrectomy with and without staple line oversewing in morbidly obese patients: a randomized study. AB - INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) is a popular bariatric procedure with a low complication rate. Serious complications after LSG include gastric leak and staple line bleeding. In order to reduce these complications, staple line reinforcement has been practiced variably by many surgeons. There is no conclusive evidence to suggest that routine oversewing of the staple line or reinforcement with buttressing material after LSG decreases these complications. We therefore undertook a prospective randomized controlled trial to evaluate the impact of oversewing of the staple line in preventing complications after LSG. PATIENTS AND METHODS: Sixty patients undergoing LSG were randomly allocated to two groups. In Group A, the entire staple line was reinforced with continuous suturing, and in Group B, no reinforcement was used. Thirty patients were enrolled in each group. Indications for this procedure were morbidly obese (body mass index >=40 kg/m(2)) or severely obese (body mass index >=35 kg/m(2)) patients with comorbidities including type 2 diabetes mellitus, hypertension, sleep apnea, and osteoarthritis. Complications including gastric leak, bleeding, and stricture were recorded. RESULTS: The demographic parameters were comparable in the two groups. Two cases of early gastric leak occurred in Group B and none in Group A. There was no case of staple line bleeding or stricture in either group, although 1 patient in Group B had bleeding from the omentum that required re-operation. The overall surgical complication rate was 5%. The mean operative time in Group A (139+/-10 minutes) was significantly greater than in Group B (117+/-19 minutes) (P=.02). CONCLUSIONS: Oversewing of the staple line may lead to reduction in leak rate, although a larger study is required to reach a definitive conclusion. The incidence of staple line bleeding can be minimized by following meticulous technique and adequate compression time after closure of the stapler rather than placing undue emphasis on oversewing and expensive buttressing materials. PMID- 24073839 TI - Long-term results of laparoscopic treatment of esophageal achalasia in children: a multicentric survey. AB - BACKGROUND: This report describes three Italian centers' experience in the treatment of children with esophageal achalasia. PATIENTS AND METHODS: Between June 2000 and June 2012, 31 children (13 girls and 18 boys, with a median age of 8.4 years) affected by esophageal achalasia were treated in three different institutions with an esophagomyotomy according to Heller's procedure via laparoscopy associated with a Dor antireflux procedure. Between 2000 and 2005 (for 14 patients) we used mono- or bipolar coagulation to perform myotomy; after 2005 (for 17 patients) we used the new hemostatic devices to perform it. RESULTS: Median length of surgery was 120 minutes. Median hospital stay was 4 days. We recorded eight complications in our series: 3 patients (9.6%) had a mucosal perforation, and 5 children (16.1%) presented dysphagia after surgery. When comparing the data before and after 2005, it seems that the new hemostatic devices statistically shortened the length of surgery (P<.01, Student's t test). CONCLUSIONS: On the basis of our experience, laparoscopic Heller's myotomy associated with an antireflux procedure is a safe and effective method for the treatment of achalasia in the pediatric population. Intraoperative complications were <10%, and they occurred mostly at the beginning of our experience. Residual dysphagia occurred in about 16% of cases. The use of the new hemostatic devices seems to reduce the length of surgery and intraoperative bleeding. Considering the rarity of this pathology, we believe that patients with achalasia have to be treated only at centers with a strong experience in the treatment of this pathology. PMID- 24073840 TI - Laparoscopic excision of urachal remnants is a safe and effective alternative to open surgery in children. AB - BACKGROUND: An infected urachal remnant is an uncommon benign condition that usually recurs and has the potential to become malignant. This study aimed to review our experience in laparoscopic excision of urachal remnants and report the efficacy and outcomes of the procedure in children. PATIENTS AND METHODS: Between January 2010 and January 2012, five children with a median age of 35 months presented with urachal remnants at our institute. The data and treatment outcomes of all the patients were retrospectively reviewed. Laparoscopic surgery was performed using three ports, including the umbilical port. In all five children, the urachal remnant was excised from the umbilicus to the bladder dome by electrocauterization, and the stump on the bladder was ligated with endoloop sutures and some absorbable sutures. RESULTS: All the five procedures were completed successfully. The median pneumoperitoneum time was 75 minutes. The boundary between the normal bladder wall and the urachal remnant was clearly identified using a laparoscope, allowing excision of the remnant and muscle layer of the bladder wall. No intraoperative or postoperative complications were reported at a median follow-up of 16 months. Complete resection of the urachal remnant was confirmed by pathological evaluation. No symptom recurrences were encountered. Laparoscopic resection had good cosmetic outcomes. CONCLUSIONS: Laparoscopic resection of urachal remnants in children allows for better anatomical visualization and may be considered as a safer, more effective, and more cosmetically beneficial alternative to open surgery. PMID- 24073841 TI - D2 receptor occupancy following lurasidone treatment in patients with schizophrenia or schizoaffective disorder. AB - OBJECTIVE/INTRODUCTION: Lurasidone is an atypical antipsychotic medication approved for the treatment of schizophrenia over a dose range of 40-160 mg/day. This study examined D2 receptor occupancy and its association with clinical improvement and side effects in patients with schizophrenia or schizoaffective disorder following repeated doses of 80, 120, or 160 mg/day of lurasidone. METHODS: Twenty-five patients with The Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnoses of schizophrenia or schizoaffective disorder were washed out of their antipsychotic medications (5 half-lives) and randomly assigned to 80, 120, or 160 mg/day of lurasidone. Subjects were imaged with 18F-fallypride at baseline and at steady-state lurasidone treatment to determine D2 receptor occupancy. RESULTS: Blood lurasidone concentration (plus major metabolite), but not dose, significantly correlated with D2 receptor occupancy. D2 receptor occupancy in several subcortical structures is associated with positive but not negative symptom improvement or the presence of movement symptoms. DISCUSSION: Blood concentrations greater than 70 ng/mL may be required to achieve a 65% occupancy level in subcortical areas. Intersubject blood concentrations at fixed dose were highly variable and may account for the lack of dose correlations. CONCLUSIONS: Positron emission tomography (PET) occupancy data suggest that greater than 65% occupancy can be achieved across the dose range of 80-160 mg/day and that some patients require higher doses to achieve antipsychotic efficacy; this finding supports prior randomized clinical trial results. PMID- 24073842 TI - Potential identification of pediatric asthma patients within pediatric research database using low rank matrix decomposition. AB - Asthma is a prevalent disease in pediatric patients and most of the cases begin at very early years of life in children. Early identification of patients at high risk of developing the disease can alert us to provide them the best treatment to manage asthma symptoms. Often evaluating patients with high risk of developing asthma from huge data sets (e.g., electronic medical record) is challenging and very time consuming, and lack of complex analysis of data or proper clinical logic determination might produce invalid results and irrelevant treatments. In this article, we used data from the Pediatric Research Database (PRD) to develop an asthma prediction model from past All Patient Refined Diagnosis Related Groupings (APR-DRGs) coding assignments. The knowledge gleamed in this asthma prediction model, from both routinely use by physicians and experimental findings, will become fused into a knowledge-based database for dissemination to those involved with asthma patients. Success with this model may lead to expansion with other diseases. PMID- 24073843 TI - Potassium balance in dialysis patients. AB - The advent of dialytic therapy has enabled nephrologists to provide life-saving therapy, but potassium balance continues to be an ever present challenge in the ESRD population. Although a small percent of patients are chronically hypokalemic, hyperkalemia is by far the most common abnormality in dialysis patients. It is associated with increased all-cause mortality, cardiovascular mortality, and arrhythmogenic death. Although alterations of the dialysis bath may decrease predialysis potassium, potassium baths <2 mEq/l are associated with a higher risk of sudden cardiac death. Studies show that patients are aware of the risks of hyperkalemia, but adherence to a low potassium diet is suboptimal. ACEI, ARBs, and spironolactone may cause slight increases in potassium even in anuric patients, requiring increased surveillance. Fludrocortisone and potassium binders have not been proven to be beneficial in lowering interdialytic potassium levels. Frequent hemodialysis may be a viable option, and studies of prophylactic placement of implantable cardioverter/defibrillators are underway. PMID- 24073847 TI - Cognitive bibliotherapy and memory training for older adults with depressive symptoms. AB - OBJECTIVES: Substantial evidence indicates that depressed participants perform more poorly than nondepressed participants on a number of memory tasks. Cognitive deficits associated with depression (i.e., poor allocation of attention, poor encoding strategies), may help explain why depressed older adults are particularly prone to evidence poorer memory performance. METHOD: The present study compared the impact of two self-administered treatment protocols, cognitive bibliotherapy for depression plus memory training (CBT + MT) and cognitive bibliotherapy alone (CBT), to a wait-list control condition on measures of memory functioning and depression in a group of older adults experiencing depressive symptoms and memory complaints. RESULTS: Results provide partial support for CBT as a treatment for depressive symptoms; however, memory training augmentation did not produce improvements. CONCLUSION: Suggestions for improving retention of older adults in self-administered treatments are discussed. PMID- 24073846 TI - Physiological beta-catenin signaling controls self-renewal networks and generation of stem-like cells from nasopharyngeal carcinoma. AB - BACKGROUND: A few reports suggested that low levels of Wnt signaling might drive cell reprogramming, but these studies could not establish a clear relationship between Wnt signaling and self-renewal networks. There are ongoing debates as to whether and how the Wnt/beta-catenin signaling is involved in the control of pluripotency gene networks. Additionally, whether physiological beta-catenin signaling generates stem-like cells through interactions with other pathways is as yet unclear. The nasopharyngeal carcinoma HONE1 cells have low expression of beta-catenin and wild-type expression of p53, which provided a possibility to study regulatory mechanism of stemness networks induced by physiological levels of Wnt signaling in these cells. RESULTS: Introduction of increased beta-catenin signaling, haploid expression of beta-catenin under control by its natural regulators in transferred chromosome 3, resulted in activation of Wnt/beta catenin networks and dedifferentiation in HONE1 hybrid cell lines, but not in esophageal carcinoma SLMT1 hybrid cells that had high levels of endogenous beta catenin expression. HONE1 hybrid cells displayed stem cell-like properties, including enhancement of CD24(+) and CD44(+) populations and generation of spheres that were not observed in parental HONE1 cells. Signaling cascades were detected in HONE1 hybrid cells, including activation of p53- and RB1-mediated tumor suppressor pathways, up-regulation of Nanog-, Oct4-, Sox2-, and Klf4 mediated pluripotency networks, and altered E-cadherin expression in both in vitro and in vivo assays. qPCR array analyses further revealed interactions of physiological Wnt/beta-catenin signaling with other pathways such as epithelial mesenchymal transition, TGF-beta, Activin, BMPR, FGFR2, and LIFR- and IL6ST mediated cell self-renewal networks. Using beta-catenin shRNA inhibitory assays, a dominant role for beta-catenin in these cellular network activities was observed. The expression of cell surface markers such as CD9, CD24, CD44, CD90, and CD133 in generated spheres was progressively up-regulated compared to HONE1 hybrid cells. Thirty-four up-regulated components of the Wnt pathway were identified in these spheres. CONCLUSIONS: Wnt/beta-catenin signaling regulates self-renewal networks and plays a central role in the control of pluripotency genes, tumor suppressive pathways and expression of cancer stem cell markers. This current study provides a novel platform to investigate the interaction of physiological Wnt/beta-catenin signaling with stemness transition networks. PMID- 24073848 TI - Plant-mediated changes in the feeding behavior of an invasive whitefly. AB - The invasive whitefly Bemisia tabaci (Gennadius) is a worldwide pest of agricultural crops that feeds on a wide variety of host plants. Although host plant preference is known to vary among B. tabaci biotypes, far less is known about the potential for intraspecific divergence caused by long-term isolation on a single species of host plant. We tested the hypothesis that multigenerational isolation of B. tabaci B, a biotype that has been well-established in China for nearly two decades, on three different host plants would lead to population-level divergence in feeding behaviors. We used individuals from a cabbage-feeding (Brassica oleracea L.) population of B. tabaci B to create three populations reared exclusively on B. oleracea, cucumber (Cucumis sativus L.), or tomato (Lycopersicon esculentum Mill.) for >80 generations. We then used electrical penetration graph techniques to investigate the feeding behavior of the three B. tabaci populations on each of the three host plants (nine total treatments). Across all three host plants, the cabbage-specific population equaled or exceeded the performance of the cucumber-specific (CuSP) and tomato-specific (ToSP) populations. Strikingly, neither CuSP nor ToSP ever had the best feeding performance on their natal hosts. Our results support the hypothesis that feeding differentiation has occurred, but we found no evidence that these changes increased the feeding performance of either CuSP or ToSP. Although confirming that rapid interpopulation divergence is possible, our findings nonetheless suggest that this differentiation did not yield highly adapted populations that might pose problems for future efforts at pest management. PMID- 24073850 TI - Late maturers at a performance disadvantage to their more mature peers in junior Australian football. AB - Children and adolescents mature at different rates such that individuals competing in the same competition may differ in physical and biological maturity despite being of similar chronological age. Whether or not differences translate into on-field performance in competition is relatively unknown. This study investigated the influence of biological maturity on fitness and match running performance in junior Australian football. Eighty-seven under-15 years players were categorised into early (n = 20), average (n = 45) and late (n = 22) maturity groups based on self-reported and anthropometric assessment of biological maturity. Running movements during competition were collected using GPS (5 Hz) technology. Early maturers were heavier and taller than all other boys (P < 0.05), while biological maturity was significantly correlated to 20 m sprint (r = 0.53, P < 0.01). Total distance, high-intensity (>14.4 km . h(-1)) running distance and number of high-intensity efforts were significantly greater (20.8%, 53.6%, 31.7%, respectively; P < 0.01) in early compared to late maturers. Number of sprints and peak speed in competition were not different. Pubertal development and maturity status partially explained the differences between players in physical size, functional running fitness and match running performance. Late maturing players in this Australian football under-15 age group were at a physical and performance disadvantage to their earlier maturing peers. PMID- 24073849 TI - A novel polymorphism (901G > a) of C5L2 gene is associated with coronary artery disease in Chinese Han and Uyghur population. AB - BACKGROUND: C5L2, a G protein-coupled receptor (GPCR), has been demonstrated to be a ligand for acylation-stimulating protein (ASP). The aim of the present study is to evaluate the association of a novel variation (901A > G) of C5L2 gene with coronary artery disease (CAD). METHODS: We identified a novel single nucleotide polymorphism (SNP), (901G > A), in exon 2 using a polymerase chain reaction direct-sequencing method. This nucleotide change causes the amino-acid order from Arginine to glutaminate at codon 300. We analyzed the relationship between this SNP and CAD in two independent case-control studies: one was in a Han population (492 CAD patients and 577 control subjects) and the other was in a Uygur population (319 CAD patients and 554 control subjects). RESULTS: The frequency of AG genotype in CAD subjects was less than that in the control subjects not only in Han (1.8% vs 8.6%, P < 0.001, OR = 0.143, 95% CI: 0.068 ~ 0.302) but also in Uygur population (0.9% vs 5.2%, P = 0.001, OR = 0.246, 95% CI: 0.072 ~ 0.837). After adjustment for known CAD risk factors such as hypertension, diabetes, smoking, age and gender, the difference remained significant. CONCLUSION: The 901G > A polymorphism of C5L2 may be a genetic maker of CAD in the Han and Uygur population in western China. PMID- 24073851 TI - Structural basis for the BRCA1 BRCT interaction with the proteins ATRIP and BAAT1. AB - The breast and ovarian cancer susceptibility protein 1 (BRCA1) plays a central role in DNA damage response (DDR). Two tandem BRCA1 C-terminal (BRCT) domains interact with several proteins that function in DDR and contain the generally accepted motif pS-X-X-F (pS denoting phosphoserine and X any amino acid), including the ATR-interacting protein (ATRIP) and the BRCA1-associated protein required for ATM activation-1 (BAAT1). The crystal structures of the BRCA1 BRCTs bound to the phosphopeptides ATRIP (235-PEACpSPQFG-243) and BAAT1 (266-VARpSPVFSS 274) were determined at 1.75 A and 2.2 A resolution, respectively. The pSer and Phe(+3) anchor the phosphopeptides into the BRCT binding groove, with adjacent peptide residues contributing to the interaction. In the BRCA1-ATRIP structure, Gln(+2) is accommodated through a conformational change of the BRCA1 E1698 side chain. Importantly, isothermal titration calorimetry experiments showed that the size and charge of the side chains at peptide positions +1 and +2 contribute significantly to the BRCA1 BRCT-peptide binding affinity. In particular, the Asp(+1) and Glu(+2) in the human CDC27 peptide 816-HAAEpSDEF-823 abrogate the interaction with the BRCA1 BRCTs due in large part to electrostatic repulsion between Glu(+2) and E1698, indicating a preference of these domains for specific side chains at positions +1 and +2. These results emphasize the need for a systematic assessment of the contribution of the peptide residues surrounding pSer and Phe(+3) to the binding affinity and specificity of the BRCA1 BRCTs in order to elucidate the molecular mechanisms underlying the hierarchy of target selection by these versatile domains during DDR and tumorigenesis. PMID- 24073852 TI - Synthesis of peptide thioacids at neutral pH using bis(2-sulfanylethyl)amido peptide precursors. AB - Reaction of bis(2-sulfanylethyl)amido (SEA) peptides with triisopropylsilylthiol in water at neutral pH yields peptide thiocarboxylates. An alkylthioester derived from beta-alanine was used to trap the released bis(2-sulfanylethyl)amine and displace the equilibrium toward the peptide thiocarboxylate. PMID- 24073853 TI - Modeling PCB-bioaccumulation in the Bottlenose Dolphin ( Tursiops truncatus ): estimating a dietary threshold concentration. AB - An individually based (IB) model to predict PCB concentrations in the bottlenose dolphin population of Charleston, SC, USA, was developed with the aim to gain a better understanding of the bioaccumulation behavior and health risk of dietary PCBs across the population and their prey. PCB concentrations predicted in male and female bottlenose dolphin were in good agreement with observed tissue concentrations corroborating the reliability of the model performance and its utility in gaining a more complete view of risk. The modeled cumulative distribution of SigmaPCB concentrations for the population with a breakdown into juvenile, adult male, and female subclasses ranged from 3600 to 144,400 ng/g lipid with 66% to >80% of the population exceeding the established threshold for adverse health effects of 17,000 ng/g lipid. The model estimated that a dietary PCB concentration not exceeding 5.1 ng/g wet wt would be required to reach a condition where 95% of the population would have tissue levels below the health effect threshold. The IB model for PCBs in bottlenose dolphins provides a novel approach to estimating the maximum acceptable dietary concentration for PCBs, a central and important factor to protect these apex predators. The model also enables effective prediction of concentrations in dolphins from fish contaminant surveys which are logistically easier and less costly to collect. PMID- 24073855 TI - Quantum chemical challenges for the binding of simple alkanes to supramolecular hosts. AB - Binding of hydrocarbon guests to supramolecular hosts can lead to unusual geometric changes such as bending or coiling of guests upon encapsulation. Cucurbiturils (CBs) are classic cation binders that were recently used for the selective binding of small-membered hydrocarbons with a very high association constant (Ka ~ 10(6) M(-1)). In this study, we have systematically investigated the binding of some alkanes to CB-[6] using a series of quantum chemical methods. The calculated binding free energies are very strong and are largely influenced by guest orientations inside the host and reorganization of host and guests. The computed (1)H NMR chemical shifts of the encapsulated alkanes agree with the experimental estimates thus confirming guest encapsulation. Further, we have shown that although binding of both cyclopentane and neopentane have very strong binding affinities (>20 kcal mol(-1)), the selectivity of cyclopentane to neopentane at CB-[6] is a kinetically driven process through the computation of approximate transition state structures of both alkanes to CB-[6]. The calculated binding affinities with dispersion corrected density functionals (DFs) are very close to the experimental estimates, whereas DFs that lack dispersion correction predict that alkane binding to CB-[6] is largely unfavorable. Finally, we have investigated the binding of some long chain alkanes to several supramolecular hosts using dispersion corrected semiempirical methods which cannot be routinely studied through density functional theory methods due to the larger size of the system. PMID- 24073854 TI - Relationship between polymorphisms in vitamin D metabolism-related genes and the risk of rickets in Han Chinese children. AB - BACKGROUND: Vitamin D deficiency rickets is common in China. Genetic factors may play an important role in the susceptibility to rickets. Our study aimed to identify the relationship between three vitamin D-related genes (group specific component [GC], cytochrome P450, family 2, subfamily R, polypeptide 1 (CYP2R1), and 7-dehydrocholesterol reductase/nicotinamide-adenine dinucleotide synthetase 1 (DHCR7/NADSYN1) and rickets in Han Chinese children from northeastern China. METHODS: A total of 506 Han children from northeastern China were enrolled in the current study. Twelve SNPs in three candidate genes were genotyped using the SNaPshot assay. Linear regression was used to examine the effect of 12 single nucleotide polymorphisms (SNPs) on the risk of rickets. RESULTS: In our case control cohort, six alleles of the 12 SNPs conferred a significantly increased risk of rickets in GC (rs4588 C, P = 0.003, OR: 0.583, 95% CI: 0.412-0.836; rs222020 C, P = 0.009, OR: 1.526, 95% CI: 1.117-2.0985; rs2282679 A, P = 0.010, OR: 0.636, 95% CI: 0.449-0.900; and rs2298849 C, P = 0.001, OR: 1.709, 95% CI: 1.250-2.338) and in CYP2R1 (rs10741657 G, P = 0.019, OR: 1.467, 95% CI: 1.070 2.011; and rs2060793 G, P = 0.023, OR: 0.689, 95% CI: 0.502-0.944). The results remained significant after adjustment for sex and body mass index. We further analyzed the effect of genotypes under three different genetic models. After using Bonferroni's method for multiple corrections, rs4588, rs2282679, and rs2298849 of the GC gene were significantly associated with rickets under the dominant (P =0.003 for rs4588, P =0.024 for rs2282679, and P =0.005 for rs2298849) and additive models (P = 0.006 for rs4588, P = 0.024 for rs2282679, and P = 0.005 for rs2298849). Haplotype analysis showed that the CAT haplotype of the GC gene (P = 0.005) and the GAA haplotype of the CYP2R1 gene (P = 0.026) were associated with susceptibility to rickets. CONCLUSIONS: This case-control study confirmed the strong effect of GC and CYP2R1 loci on rickets in Han children from northeastern China. PMID- 24073857 TI - Protective effect of Basella alba and Carpolobia alba extracts against maneb induced male infertility. AB - CONTEXT: Male infertility is one of the leading causes of social frustration and marginalization, mainly in the developing world. It is attributed to many factors including exposure to agropesticides such as manganese ethylenebis (dithiocarbamate) (maneb), which is one of the most frequently used fungicides in Cameroon. Previous reports support efficiency of some medicinal plants commonly used in Cameroonian folk medicine for the treatment of this disorder. OBJECTIVE: The present study was aimed at assessing the protective effect of extracts from selected plant species, namely Basella alba L. (Basellaceae) (MEBa) and Carpolobia alba G. Don (Polygalaceae) (AECa), in alleviating the maneb-induced impairment of male reproductive function in Wistar albino rats. MATERIALS AND METHODS: The rats were treated with vehicle, plant extract (MEBa or AECa), maneb and maneb plus plant extract, respectively, and their fertility was assessed. Animals were thereafter sacrificed and organs (liver, kidneys and reproductive organs) were dissected out and weighed. Serum androgens together with alanine aminotransferase, liver glutathione and thiobarbituric acid reactive species (TBARS) were also measured. RESULTS AND DISCUSSION: From this study, both plant extracts stimulated testosterone and improved fertility. Administration of MEBa plus maneb prevented fertility reduction by maneb and minimized the inhibitory effect of maneb on testosterone levels. AECa also improved fertility of the maneb exposed rats, though without restoring testosterone levels, and other investigated parameters remained unaffected by different treatments. CONCLUSION: These findings emphasized the beneficial effects of B. alba and C. alba extracts on male fertility, and suggest their protective effect against maneb-induced toxicity in male reproductive function. PMID- 24073856 TI - In vivo 5FU-exposed human medullary thyroid carcinoma cells contain a chemoresistant CD133+ tumor-initiating cell subset. AB - BACKGROUND: The hierarchical model of solid tumor proposes the existence of rare tumor cell subpopulations with stem-cell properties. The glycoprotein prominin-1 (CD133) represents one of the cancer stem-cell markers in several tumor types. The CD133+ cell subpopulation was shown to be enriched for tumor-initiating and highly chemoresistant cells in human cancer(s). METHODS: We investigated whether CD133+ cells derived from human medullary thyroid carcinoma (MTC) possess tumor initiating properties in vivo and exhibit differential responses to chemotherapeutic agents. We demonstrated that separated CD133+ cells from the human MTC cell line TT are enriched for tumor-initiating cells as demonstrated by tumor formation in vivo. Nevertheless, TT CD133+ cells do not exhibit increased chemoresistance in comparison to parental cells. However, when MTC xenotransplants were treated with the chemotherapeutic drug 5-fluorouracil (5FU) in vivo, CD133 expression increased in MTC cells. RESULTS: This cell line, designated FTTiv isolated from the drug-exposed xenotransplants, exhibits a significantly different response to 5FU associated with the substantial change in the expression profile of genes involved in 5FU metabolism and drug resistance. Moreover, the CD133+ tumor-initiating subpopulation derived from these drug exposed FTTiv cells is significantly more resistant to 5FU and retains the chemoresistant properties upon FTTiv culture propagation. CONCLUSIONS: These data suggest that the chemoresistant phenotype and the CD133+ MTC subpopulation emerged in response to chemotherapy in vivo. PMID- 24073858 TI - The interactional organization of aphasia naming testing. AB - In this article, Conversation Analysis (CA) is used to investigate the nature of aphasia naming tests in terms of their properties as a specialized form of social interaction. The basic test-item sequence which occurs in these tests is shown to be made up of a three-part sequential structure consisting of (1) a testing prompt, (2) a proffered answer by the testee, and (3) an acceptance or declining of that proffered answer by the tester. A declining prompts a further answer to be proffered, and this cycle continues until either an answer is accepted by the tester or until the participants treat the testee as being unable to produce the relevant picture name. It is suggested that the results of the analysis have implications for understanding naming tests as instruments which generate theoretical and clinical findings through particular talk-in-interaction practices. PMID- 24073859 TI - New G-CSF agonists for neutropenia therapy. AB - INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF; filgrastim) and its pegylated form (pegfilgrastim) are widely used to treat neutropenia associated with myelosuppressive chemotherapy and bone marrow transplantation, AIDS associated or drug-induced neutropenia, and neutropenic diseases. G-CSF facilitates restoration of neutrophil counts, decreases incidence of infection/febrile neutropenia and reduces resource utilization. G-CSF is also widely used to mobilize peripheral blood stem cells for hematopoietic transplant. AREAS COVERED: We review the therapeutic use, cost effectiveness and disease impact of G-CSF for neutropenia, development of G-CSF biosimilars and current next-generation discovery efforts. EXPERT OPINION: G-CSF has impacted the treatment and survival of patients with congenital neutropenias. For chemotherapy associated neutropenia, cost effectiveness and impact on survival are still unclear. G-CSFs are expensive and require systemic administration. Market entry of new biosimilars, some with enhanced half-life profiles, will probably reduce cost and increase cost effectiveness. There is no evidence that marketed or late development biosimilars display effectiveness superior to current G-CSFs. Second generation compounds that mimic the activity of G-CSF at its receptor, induce endogenous ligand(s) or offer adjunct activity have been reported and represent attractive G-CSF alternatives, but are in preclinical stages. A significant therapeutic advance will require reduced depth and duration of neutropenia compared to current G-CSFs. PMID- 24073860 TI - Polymorphisms in GC and NADSYN1 Genes are associated with vitamin D status and metabolic profile in Non-diabetic adults. AB - BACKGROUND: Our aim was to assess the associations between vitamin D (vitD) status, metabolic profile and polymorphisms in genes involved in the transport (Group-Component: GC) and the hydroxylation (NAD synthetase 1: NADSYN1) of 25 hydroxyvitamin D (25(OH)D) in non-diabetic individuals. METHODS: We conducted a cross-sectional study with 323 individuals recruited from the Health Center of Guadeloupe, France. The rs2282679 T > G and rs2298849 T > C in GC and rs12785878 G > T in NADSYN1 were genotyped. RESULTS: Mean age was 46(range 18-86) years. 57% of participants had vitD insufficiency, 8% had vitD deficiency, 61% were overweight and 58% had dyslipidemia. A higher frequency of overweight was noted in women carrying rs2298849T allele v CC carriers (71% v 50%; P = 0.035). The rs2282679G allele was associated with increased risks of vitD deficiency and vitD insufficiency (OR =3.53, P = 0.008, OR = 2.34, P = 0.02 respectively). The rs2298849 TT genotype was associated with vitD deficiency and overweight (OR =3.4, P = 0.004 and OR = 1.76, P = 0.04 respectively) and the rs12785878 GG genotype with vitD insufficiency and dyslipidemia (OR = 1.80, P = 0.01 and OR = 1.72, P = 0.03 respectively). Based on the number of risk alleles for rs2282679 and rs12785878 combined, a genotype score of 3 (vs. 0-1) was associated with a 5.5 ng/mL average reduction in serum 25(OH)D levels (P = 0.001). CONCLUSIONS: The GC and NADSYN1 genes are associated with the vitamin D status and might contribute to dyslipidemia and overweight independently of 25(OH)D levels. PMID- 24073861 TI - Surrogate measures and consistent surrogates. AB - Surrogates which allow one to predict the effect of the treatment on the outcome of interest from the effect of the treatment on the surrogate are of importance when it is difficult or expensive to measure the primary outcome. Unfortunately, the use of such surrogates can give rise to paradoxical situations in which the effect of the treatment on the surrogate is positive, the surrogate and outcome are strongly positively correlated, but the effect of the treatment on the outcome is negative, a phenomenon sometimes referred to as the "surrogate paradox." New results are given for consistent surrogates that extend the existing literature on sufficient conditions that ensure the surrogate paradox is not manifest. Specifically, it is shown that for the surrogate paradox to be manifest it must be the case that either there is (i) a direct effect of treatment on the outcome not through the surrogate and in the opposite direction as that through the surrogate or (ii) confounding for the effect of the surrogate on the outcome, or (iii) a lack of transitivity so that treatment does not positively affect the surrogate for all the same individuals for whom the surrogate positively affects the outcome. The conditions for consistent surrogates and the results of the article are important because they allow investigators to predict the direction of the effect of the treatment on the outcome simply from the direction of the effect of the treatment on the surrogate. These results on consistent surrogates are then related to the four approaches to surrogate outcomes described by Joffe and Greene (2009, Biometrics 65, 530-538) to assess whether the standard criteria used by these approaches to assess whether a surrogate is "good" suffice to avoid the surrogate paradox. PMID- 24073862 TI - Discussion on "surrogate measures and consistent surrogates". PMID- 24073863 TI - Discussion on "surrogate measures and consistent surrogates". PMID- 24073864 TI - Discussion on "surrogate measures and consistent surrogates". PMID- 24073865 TI - Rejoinder. PMID- 24073866 TI - Comment on Cai and Betensky (2003), on the poisson approximation for hazard regression. PMID- 24073867 TI - Reply to Sabanes Bove and Held's "comment on Cai and Betensky (2003), on the poisson approximation for hazard regression". PMID- 24073872 TI - Self-assembly of nonionic surfactant Tween 20@2beta-CD inclusion complexes in dilute solution. AB - It has long been considered that the addition of cyclodextrins (CDs) disfavors the self-assembly of surfactants in dilute solutions since the hydrophobic effect is destroyed upon the formation of the hydrophiphilic CD/surfactant inclusion complex. However, in this work, we found that beta-CD/nonionic surfactant inclusion complexes are able to self-assemble into vesicles in dilute solutions, namely in solutions with concentration lower than the CMC of surfactants. When using Tween 20 as a model surfactant, HNMR and MS measurements indicate that the building block for the vesicles is the channel type Tween 20@2beta-CD inclusion complex. Structure and IR analysis suggests that the self-assembly of hydrophilic Tween 20@2beta-CD is driven by H-bonds between both the headgroup of Tween 20 and the hydroxyl groups of beta-CD. The self-assembly of the inclusion complex between the beta-CD and the nonionic surfactant in dilute solution is found to be a general phenomenon. Undoubtedly, surfactant@2beta-CD inclusion complex can be a novel building block for nonamphiphilic self-assembly, which provides a new physical insight for the influence of cyclodextrins on the self-assembly of surfactants. PMID- 24073873 TI - Prebiotic consumption in pregnant and lactating women increases IL-27 expression in human milk. AB - The consumption of probiotics by pregnant and lactating women may prevent the onset of allergic disorders in their children by increasing the concentrations of immunoactive agents such as cytokines in breast milk. Prebiotics such as fructo oligosaccharides (FOS) increase the number of beneficial organisms such as bifidobacteria. Thus, prebiotics may have an effect similar to that of probiotics. The objective of the present study was to carry out a comprehensive analysis of mRNA expression in human milk cells to identify changes in the concentrations of cytokines in breast milk after the consumption of FOS (4 g * 2 times/d) by pregnant and lactating women. The microarray analysis of human milk cells demonstrated that the expression levels of five genes in colostrum samples and fourteen genes in 1-month breast milk samples differed more than 3-fold between the FOS and control groups (sucrose group). The mRNA expression level of IL-27, a cytokine associated with immunoregulatory function, was significantly higher in 1-month breast milk samples obtained from the FOS group than in those obtained from the control group. In addition, the protein concentrations of IL-27 in colostrum and 1-month breast milk samples were significantly higher in the FOS group than in the control group. In conclusion, the consumption of FOS by pregnant and lactating women increases the production of IL-27 in breast milk. Future studies will address the association of this phenomenon with the onset of allergic disorders in children. PMID- 24073874 TI - Down deep in the holler: chasing seeds and stories in southern Appalachia. AB - This essay, which is the third in the series "Recollections, Reflections, and Revelations: Ethnobiologists and their First Time in the Field", is a personal reflection by the researcher on his experience and involvement in kinship and friendship networks while conducting agrobiodiversity research in southern Appalachia, USA. Vignettes are given from moving moments spent with Native spiritual leaders, backcountry mountain people, and local co-collaborators in the research process. The author demonstrates how lasting field friendships have helped lead to groundbreaking ethnoecological research. PMID- 24073877 TI - Introducing the special section on openness to experience: review of openness taxonomies, measurement, and nomological net. AB - In this introduction to the Special Section on Openness to Experience, we review the historical background of the construct and its measurement. We also provide a meta-analytically based review of its broader nomological net. Specifically, we review relationships with other individual differences constructs, including personality traits, interests, and cognitive ability. We highlight the various roles that openness and intellect play in educational performance, occupational attitudes and behaviors, job performance, career success, and psychological health and well-being. In doing so, we emphasize the unique contributions of the articles published in this special section (Albrecht, Dilchert, Deller, & Paulus; Connelly, Ones, Davies, & Birkland; DeYoung, Quilty, Peterson, & Gray; Roets, Cornelis, & Van Hiel; Woo, Chernyshenko, Longley, Zhang, Chiu, & Stark; Woo, Chernyshenko, Stark, & Conz). Finally, we note fruitful venues for future research involving Openness constructs. PMID- 24073878 TI - Chronic rhinosinusitis and age: is the pathogenesis different? AB - Chronic rhinosinusitis (CRS) is a common disease with a significant impact on quality of life, which is seen across all age groups. There are differences in symptomatology, histopathology and associated diseases when comparing pediatric versus adult patients with CRS. Nasal polyposis tends to be less commonly seen in pediatric CRS compared with adults except in children with cystic fibrosis or allergic fungal rhinosinusitis. The differences in histopathology of CRS in different age groups include higher cellularity and more prominent lymphocytic infiltration in children compared with adults who tend to have a stronger eosinophilic infiltration and more prominent glandular hyperplasia. There are data supporting a stronger association of gastroesophageal reflux disease and otitis media with CRS in children compared with adults. Adenoids may play a role in pediatric, but not adult CRS. Immunodeficiencies and asthma are strongly associated with CRS in all age groups. There is a paucity of data on pathophysiology of disease on elderly CRS. PMID- 24073879 TI - Priming moral self-ambivalence heightens deliberative behaviour in self ambivalent individuals. AB - BACKGROUND: Recent work on cognitive-behavioural models of obsessive-compulsive disorder has focused on the roles played by various aspects of self-perception. In particular, moral self-ambivalence has been found to be associated with obsessive-compulsive phenomena. AIMS: In this study we used an experimental task to investigate whether artificially priming moral self-ambivalence would increase participants' deliberation on ethical problems, an index that might be analogous to obsessive-compulsive behaviour. METHOD: Non-clinical participants completed two online tasks designed to prime either moral self-ambivalence, general uncertainty, or neither. All participants then completed a task requiring them to consider solutions to moral dilemmas. We recorded the time participants took to respond to the dilemmas and the length of their responses; we then combined these variables to create a measure of deliberation. RESULTS: Priming moral self ambivalence led to increases in deliberation, but this was only significant among those participants who scored highly on a baseline measure of moral self ambivalence. Priming general uncertainty had no significant effect upon deliberation. CONCLUSIONS: The results suggest that moral self-ambivalence may play a role in the maintenance of obsessive-compulsive behaviour. We propose that individuals who are morally self-ambivalent might respond to situations in which this ambivalence is made salient by exhibiting behaviour with obsessive compulsive characteristics. These findings have implications for the incorporation of ideas about self-concept into theories of obsessive-compulsive disorder. PMID- 24073880 TI - Mycosphaerella graminicola LysM effector-mediated stealth pathogenesis subverts recognition through both CERK1 and CEBiP homologues in wheat. AB - Fungal cell-wall chitin is a well-recognized pathogen-associated molecular pattern. Recognition of chitin in plants by pattern recognition receptors activates pathogen-triggered immunity (PTI). In Arabidopsis, this process is mediated by a plasma membrane receptor kinase, CERK1, whereas in rice, a receptor like protein, CEBiP, in addition to CERK1 is required. Secreted chitin-binding lysin motif (LysM) containing fungal effector proteins, such as Ecp6 from the biotrophic fungus Cladosporium fulvum, have been reported to interfere with PTI. Here, we identified wheat homologues of CERK1 and CEBiP and investigated their role in the interaction with the nonbiotrophic pathogen of wheat Mycosphaerella graminicola (synonym Zymoseptoria tritici). We show that silencing of either CERK1 or CEBiP in wheat, using Barley stripe mosaic virus-mediated virus-induced gene silencing, is sufficient in allowing leaf colonization by the normally nonpathogenic M. graminicola Mg3LysM (homologue of Ecp6) deletion mutant, while the Mg1LysM deletion mutant was fully pathogenic toward both silenced and wild type wheat leaves. These data indicate that Mg3LysM is important for fungal evasion of PTI in wheat leaf tissue and that both CERK1 and CEBiP are required for activation of chitin-induced defenses, a feature conserved between rice and wheat, and perhaps, also in other cereal species. PMID- 24073881 TI - Nodulin 22, a novel small heat-shock protein of the endoplasmic reticulum, is linked to the unfolded protein response in common bean. AB - The importance of plant small heat shock proteins (sHsp) in multiple cellular processes has been evidenced by their unusual abundance and diversity; however, little is known about their biological role. Here, we characterized the in vitro chaperone activity and subcellular localization of nodulin 22 of Phaseolus vulgaris (PvNod22; common bean) and explored its cellular function through a virus-induced gene silencing-based reverse genetics approach. We established that PvNod22 facilitated the refolding of a model substrate in vitro, suggesting that it acts as a molecular chaperone in the cell. Through microscopy analyses of PvNod22, we determined its localization in the endoplasmic reticulum (ER). Furthermore, we found that silencing of PvNod22 resulted in necrotic lesions in the aerial organs of P. vulgaris plants cultivated under optimal conditions and that downregulation of PvNod22 activated the ER-unfolded protein response (UPR) and cell death. We also established that PvNod22 expression in wild-type bean plants was modulated by abiotic stress but not by chemicals that trigger the UPR, indicating PvNod22 is not under UPR control. Our results suggest that the ability of PvNod22 to suppress protein aggregation contributes to the maintenance of ER homeostasis, thus preventing the induction of cell death via UPR in response to oxidative stress during plant-microbe interactions. PMID- 24073882 TI - The multiple roles of microRNA-155 in oncogenesis. AB - The microRNA miR-155 is prominent in cancer biology. Among microRNAs that have been linked to cancer, it is the most commonly overexpressed in malignancies (PNAS 109:20047-20052, 2012). Since its discovery, miR-155 has been implicated in promoting cancers of the breast, lung, liver, and lymphatic system. As such, targeted therapies may prove beneficial to cancer treatment. This review discusses the important role of miR-155 in oncogenesis. It synthesizes information from ten recent papers on miR-155, and includes an analysis and discussion of its association with cancer, interactions with other miRNAs, mechanisms of action, and the most promising available treatment options.Current debates in the field include the importance of miRNAs in general and their utility as targets in preventing tumorigenesis (Blood 119:513-520, 2012). Most of the papers being reviewed here confirm the role of miR-155 in oncogenesis (EMBO Mol Med 1:288-295, 2009). While there is some controversy surrounding recent research that claims that miR-155 may display anti-oncogenic or pro-immunological benefits (Cell Rep 2:1697-1709, 2012), most research seems to point to the importance of anti-miRs, with anti-miR-155 in particular, for cancer therapy. PMID- 24073883 TI - Evolution of mate-harm, longevity and behaviour in male fruit flies subjected to different levels of interlocus conflict. AB - BACKGROUND: Interlocus conflict predicts (a) evolution of traits, beneficial to males but detrimental to females and (b) evolution of aging and life-span under the influence of the cost of bearing these traits. However, there are very few empirical investigations shedding light on these predictions. Those that do address these issues, mostly reported response of male reproductive traits or the lack of it and do not address the life-history consequence of such evolution. Here, we test both the above mentioned predictions using experimental evolution on replicate populations of Drosophila melanogaster. We present responses observed after >45 generations of altered levels of interlocus conflict (generated by varying the operational sex ratio). RESULTS: Males from the male biased (high conflict, M-regime) regime evolved higher spontaneous locomotor activity and courtship frequency. Females exposed to these males were found to have higher mortality rate. Males from the female biased regime (low conflict, F regime) did not evolve altered courtship frequency and activity. However, progeny production of females continuously exposed to F-males was significantly higher than the progeny production of females exposed to M-males indicating that the F males are relatively benign towards their mates. We found that males from male biased regime lived shorter compared to males from the female biased regime. CONCLUSION: F-males (evolving under lower levels of sexual conflict) evolved decreased mate harming ability indicating the cost of maintenance of the suit of traits that cause mate-harm. The M-males (evolving under higher levels sexual conflict) caused higher female mortality indicating that they had evolved increased mate harming ability, possibly as a by product of increased reproduction related activity. There was a correlated evolution of life-history of the M and F-males. M-regime males lived shorter compared to the males from F regime, possibly due to the cost of investing more in reproductive traits. In combination, these results suggest that male reproductive traits and life-history traits can evolve in response to the altered levels of interlocus sexual conflict. PMID- 24073884 TI - Outcomes of kidney allograft in recipients with kidney disease of unknown etiology. AB - The etiology of renal disease is important because the primary renal pathology may affect the outcomes of kidney allograft with respect to recurrence, rejection, and survival. However, for a significant number of patients who undergo kidney transplantation, the disease etiology is unknown. Here, allograft outcomes for patients with kidney disease of unknown etiology (UEK) at three affiliated Korean hospitals were identified. The incidence of biopsy-proven acute rejection (BPAR) for UEK was 22.9%, which was similar to the rates for diabetic nephropathy (DN, 24.4%) and IgA nephropathy (IgAN, 20.0%; p = 0.345). The cumulative incidence of post-transplant glomerulonephritis (PTGN) among patients with UEK was significantly lower than that among patients with IgAN (p < 0.001). Overall graft survival of the UEK group was superior to that of the DN group (hazards ratio 0.39, 95% confidence interval 0.17-0.92, p = 0.030). Preemptive transplantation for UEK significantly reduced the incidence of BPAR (preemptive vs. non-preemptive 9.6% vs. 30.3%, p = 0.001), but graft survival and recurrence were not affected by preemptive transplantation. The outcomes of kidney transplantation for patients with UEK were not inferior to those for patients with IgAN or DN. Preemptive kidney transplantation may be encouraged for UEK patients. PMID- 24073885 TI - Are larks future-oriented and owls present-oriented? Age- and sex-related shifts in chronotype-time perspective associations. AB - The chronotype (morningness/eveningness) relates to individual differences in circadian preferences. Time perspective (past, present, future) refers to the preference to rely on a particular temporal frame for decision-making processes and behavior. First evidence suggests that future time perspective is associated with greater morningness and present time perspective with greater eveningness. However, little is known about how chronotype-time perspective relationships may alter over the life span. This present study investigated links between chronotype and time perspective more thoroughly by taking age and sex into account as well. Seven hundred six participants aged between 17 and 74 completed German adaptations of the Morningness--Eveningness Questionnaire (MEQ) and Zimbardo Time Perspective Inventory (ZTPI). Controlling for age and sex, relationships between morningness and future time perspective as well as between eveningness and present time perspective were replicated. These findings were supported by significant associations between time perspective and midpoint of sleep. Future time perspective was linked to earlier midpoints of sleep, indicating an early chronotype. Present time perspective was associated with later midpoints of sleep, indicating a late chronotype. However, age and sex had an impact on the chronotype-time perspective relationships. In all age groups, male larks were more future-oriented and less present-oriented, male owls more present-oriented and less future-oriented. The same conclusion could be drawn for female adolescents and young adults. For female adults above 30, there was no interrelationship between morningness and future time perspective but between eveningness and past time perspective. Female adult owls were more present oriented as well as more past-oriented. Female adult larks were less present oriented and less past-oriented. Findings are discussed in the light of neuroendocrine and serotonergic functioning. PMID- 24073886 TI - The Aeromonas salmonicida subsp. salmonicida exoproteome: determination of the complete repertoire of Type-Three Secretion System effectors and identification of other virulence factors. AB - BACKGROUND: Aeromonas salmonicida subsp. salmonicida, the etiologic agent of furunculosis, is a major pathogen of fisheries worldwide. Several virulence factors have been described, but the type-three secretion system (T3SS) is recognized as having a major effect on virulence by injecting effectors directly into fish cells. In this study we used high-throughput proteomics to display the differences between in vitro secretome of A. salmonicida wild-type (wt, hypervirulent, JF2267) and T3SS-deficient (isogenic DeltaascV, extremely low virulent, JF2747) strains in exponential and stationary phases of growth. RESULTS: Results confirmed the secretion of effectors AopH, AexT, AopP and AopO via T3SS, and for the first time demonstrated the impact of T3SS in secretion of Ati2, AopN and ExsE that are known as effectors in other pathogens. Translocators, needle subunits, Ati1, and AscX were also secreted in supernatants (SNs) dependent on T3SS. AopH, Ati2, AexT, AopB and AopD were in the top seven most abundant excreted proteins. EF-G, EF-Tu, DnaK, HtpG, PNPase, PepN and MdeA were moderately secreted in wt SNs and predicted to be putative T3 effectors by bioinformatics. Pta and ASA_P5G088 were increased in wt SNs and T3-associated in other bacteria. Ten conserved cytoplasmic proteins were more abundant in wt SNs than in the DeltaascV mutant, but without any clear association to a secretion system. T1-secreted proteins were predominantly found in wt SNs: OmpAI, OmpK40, DegQ, insulinase ASA_0716, hypothetical ASA_0852 and ASA_3619. Presence of T3SS components in pellets was clearly decreased by ascV deletion, while no impact was observed on T1- and T2SS. Our results demonstrated that the DeltaascV mutant strain excreted well-described (VapA, AerA, AerB, GCAT, Pla1, PlaC, TagA, Ahe2, GbpA and enolase) and yet uncharacterized potential toxins, adhesins and enzymes as much as or even more than the wt strain. Other putative important virulence factors were not detected. CONCLUSIONS: We demonstrated the whole in vitro secretome and T3SS repertoire of hypervirulent A. salmonicida. Several toxins, adhesins and enzymes that are not part of the T3SS secretome were secreted to a higher extent in the extremely low-virulent DeltaascV mutant. All together, our results show the high importance of an intact T3SS to initiate the furunculosis and offer new information about the pathogenesis. PMID- 24073887 TI - Optical regulation of protein adsorption and cell adhesion by photoresponsive GaN nanowires. AB - Interfacing nanowires with living cells is attracting more and more interest due to the potential applications, such as cell culture engineering and drug delivery. We report on the feasibility of using photoresponsive semiconductor gallium nitride (GaN) nanowires (NWs) for regulating the behaviors of biomolecules and cells at the nano/biointerface. The GaN NWs have been fabricated by a facile chemical vapor deposition method. The superhydrophobicity to superhydrophilicity transition of the NWs is achieved by UV illumination. Bovine serum albumin adsorption could be modulated by photoresponsive GaN NWs. Tunable cell detachment and adhesion are also observed. The mechanism of the NW surface responsible for modulating both of protein adsorption and cell adhesion is discussed. These observations of the modulation effects on protein adsorption and cell adhesion by GaN NWs could provide a novel approach toward the regulation of the behaviors of biomolecules and cells at the nano/biointerface, which may be of considerable importance in the development of high-performance semiconductor nanowire-based biomedical devices for cell culture engineering, bioseparation, and diagnostics. PMID- 24073888 TI - An improvement index to quantify the evolution of performance in running. AB - Improvements in track and field sports have been attributed to factors such as population increase, drugs and new technologies, but previous research has found it difficult to distinguish the contributions from specific influences. Here it is shown how this is possible by means of a performance improvement index based on useful work done combined with modelling of the annual top 25 performances. The index was set to 100 in 1948 and showed that, by 2012, it had increased in running events to between 110.5 and 146.7 (men's 100 m and marathon). Underlying global effects accounted for the majority of all improvements (16.2 to 46.7) with smaller influences attributable to an influx of African runners (3.6 to 9.3), and a 4-year oscillation that arose from staging of the Olympic Games (+/-0.2 to +/ 0.6). Performance decreased with the introduction of compulsory random drug testing (-0.9 to -3.9) the World Anti-Doping Agency (WADA; -0.5 to -2.5) and fully automated timing (-0.6 to -2.5). Changes in elite sporting performance since the 1890s are attributable to societal changes caused by the industrial revolution and globalisation superimposed on millennia of human evolution. PMID- 24073889 TI - What controls regiochemistry in 1,3-dipolar cycloadditions of munchnones with nitrostyrenes? AB - The distinct experimentally observed regiochemistries of the reactions between mesoionic munchnones and beta-nitrostyrenes or phenylacetylene are shown by DFT/BDA/ETS-NOCV analyses of the transition states to be dominated by steric and reactant reorganization factors, rather than the orbital overlap considerations predicted by Frontier Molecular Orbital (FMO) Theory. PMID- 24073890 TI - Phthalate levels in nursery schools and related factors. AB - Phthalate esters, which are known endocrine disruptors, are ubiquitously present throughout indoor environments. Leaching from building materials may be a major source of phthalate esters. In this study, we evaluated phthalate ester concentrations in dust samples from 64 classrooms located in 50 nursery schools and explored the critical factors affecting phthalate concentrations, especially with regard to building materials. Dust was sampled by a modified vacuuming method, and building materials were assessed using a portable X-ray fluorescence (XRF) analyzer to determine whether they contained polyvinyl chloride. Di-n-butyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP), and di-isononyl phthalate (DINP) were the most frequently detected phthalates. Of these, DEHP was the most abundant phthalate, with a geometric mean of 3170 MUg/g dust, and concentrations were significantly correlated with the area of polyvinyl chloride (PVC)-verified flooring. DINP, which has not been well-reported in other studies, was the second most abundant phthalate, with a geometric mean of 688 MUg/g dust, and showed a critical relationship with the number of children in the institution and the agency operating the nursery school. This is the first study to verify the sources of phthalates with an XRF analyzer and to evaluate the relationship between phthalate concentrations and PVC-verified materials. PMID- 24073891 TI - Conformational analysis of the frog skin peptide, plasticin-L1, and its effects on production of proinflammatory cytokines by macrophages. AB - Plasticin-L1 (GLVNGLLSSVLGGGQGGGGLLGGIL) is a conformationally flexible glycine/leucine-rich peptide originally isolated from norepinephrine-stimulated skin secretions of the South-American Santa Fe frog Leptodactylus laticeps (Leptodactylidae). A nuclear magnetic resonance/molecular dynamics characterization of plasticin-L1 in the presence of dodecylphosphocholine (DPC) and DPC/sodium dodecylsulphate micelles as membrane-mimetic models showed that the peptide has affinity for both neutral and anionic membranes. The peptide adopts a stable helical conformation at the N-terminal region and a more disordered helix at the C-terminal region, separated by an unstructured loop wherein the highest number of glycines is localized. In both micelle environments, plasticin-L1 slowly inserts between the detergent head groups but always remains localized at the micelle/water interface. Plasticin-L1 lacks direct antimicrobial activity but stimulates cytokine production by macrophages. Incubation with plasticin-L1 (20 MUg/mL) significantly (P < 0.05) increased the production of the proinflammatory cytokines IL-1beta, IL-12, IL-23, and TNF-alpha from unstimulated peritoneal macrophages from both C57BL/6 and BALB/C mice. The peptide also increased IL-6 production by unstimulated (P < 0.01) and lipopolysaccharide-stimulated (P < 0.01) macrophages, whereas the effects on production of the anti-inflammatory cytokine IL-10 were not significant. These findings suggest that plasticin-L1 may play an immunomodulatory role in vivo by stimulating cytokine production from frog skin macrophages in response to microbial pathogens. This peptide may represent a template for the design of peptides with therapeutic applications as immunostimulatory agents. PMID- 24073892 TI - Context-dependent interpretation of the prognostic value of BRAF and KRAS mutations in colorectal cancer. AB - BACKGROUND: The mutation status of the BRAF and KRAS genes has been proposed as prognostic biomarker in colorectal cancer. Of them, only the BRAF V600E mutation has been validated independently as prognostic for overall survival and survival after relapse, while the prognostic value of KRAS mutation is still unclear. We investigated the prognostic value of BRAF and KRAS mutations in various contexts defined by stratifications of the patient population. METHODS: We retrospectively analyzed a cohort of patients with stage II and III colorectal cancer from the PETACC-3 clinical trial (N = 1,423), by assessing the prognostic value of the BRAF and KRAS mutations in subpopulations defined by all possible combinations of the following clinico-pathological variables: T stage, N stage, tumor site, tumor grade and microsatellite instability status. In each such subpopulation, the prognostic value was assessed by log rank test for three endpoints: overall survival, relapse-free survival, and survival after relapse. The significance level was set to 0.01 for Bonferroni-adjusted p-values, and a second threshold for a trend towards statistical significance was set at 0.05 for unadjusted p values. The significance of the interactions was tested by Wald test, with significance level of 0.05. RESULTS: In stage II-III colorectal cancer, BRAF mutation was confirmed a marker of poor survival only in subpopulations involving microsatellite stable and left-sided tumors, with higher effects than in the whole population. There was no evidence for prognostic value in microsatellite instable or right-sided tumor groups. We found that BRAF was also prognostic for relapse-free survival in some subpopulations. We found no evidence that KRAS mutations had prognostic value, although a trend was observed in some stratifications. We also show evidence of heterogeneity in survival of patients with BRAF V600E mutation. CONCLUSIONS: The BRAF mutation represents an additional risk factor only in some subpopulations of colorectal cancers, in others having limited prognostic value. However, in the subpopulations where it is prognostic, it represents a marker of much higher risk than previously considered. KRAS mutation status does not seem to represent a strong prognostic variable. PMID- 24073893 TI - Mitochondria-targeted reaction-based two-photon fluorescent probe for imaging of superoxide anion in live cells and in vivo. AB - A newly synthesized reaction-based two-photon (TP) fluorescence imaging probe, 9 butyltriphenylphosphoniumacylamino-2,7-dibenzothiazolineflurene (MF-DBZH), composed of a superoxide anion (O2(*-)) responsive group and a mitochondria targeted site, has been shown to have high selectivity toward mitochondrial O2(* ) fluxes. The fluorescence intensity of MF-DBZH responds proportionally to changes in O2(*-) concentrations. Moreover, MF-DBZH was proved to be insensitive toward pH changes and has high photostability. Favorable features of this probe also include convenient cell loading, easy staining of both cells and small animals, and excellent biocompibility. Most importantly, MF-DBZH gives reliable TP fluorescent signal to changes of O2(*-) levels in vivo. PMID- 24073894 TI - Real-time probing of hydrogen-bond exchange dynamics in aqueous NaPF6 solutions by two-dimensional infrared spectroscopy. AB - Ultrafast two-dimensional infrared (2DIR) spectroscopy was used to study H-bond exchange dynamics in aqueous NaPF6 solutions. Interestingly, there are two spectrally distinct hydrogen-bond (H-bond) configurations in aqueous NaPF6 solutions: water molecules that are H-bonded to PF6(-) (ODA) or other water molecules (ODW). These two spectrally distinct subsets of water in aqueous NaPF6 solutions provide an opportunity to study the individual dynamics of water in two H-bond configurations as well as interconversion dynamics between them. Most significantly, we have successfully measured H-bond exchange dynamics between two spectrally distinct H-bond configurations in real time by ultrafast 2DIR spectroscopy. In aqueous 5.0 M NaPF6 solution, water molecules switch their H bond partners from PF6(-) to water molecule (ODA -> ODW) with a time constant of 12.0 ps and from water molecule to PF6(-) (ODW -> ODA) with a time constant of 21.6 ps at room temperature. H-bond exchange dynamics in aqueous NaPF6 solution were found to be relatively slower than those in aqueous NaBF4 and NaClO4 solutions which were studied previously, which was attributed to the asymmetric potential energy curve for the H-bond exchange process based on the orientational jump mechanism. PMID- 24073895 TI - DrML: probabilistic modeling of gene duplications. AB - DrML is a software program for inferring evolutionary scenarios from a gene tree and a species tree with speciation time estimates that is based on a general maximum likelihood model. The program implements novel algorithms that efficiently infer most likely scenarios of gene duplication and loss events. Our comparative studies suggest that the general maximum likelihood model provides more credible estimates than standard parsimony reconciliation, especially when speciation times differ significantly. DrML is an open source project written in Python, and along with an on-line manual and sample data sets publicly available. PMID- 24073896 TI - Update on the status of DP2 receptor antagonists; from proof of concept through clinical failures to promising new drugs. AB - INTRODUCTION: The identification of PGD2 as the cognate ligand for the DP2 (formerly CRTH2) receptor and the apparent role of that receptor in allergic disease has led to considerable interest in the development of DP2 receptor antagonists for the treatment of asthma. Around 20 DP2 receptor antagonists have progressed into development. AREAS COVERED: The DP2 antagonists in clinical development and those whose development has been discontinued are discussed in detail. This article highlights the former and examines the available clinical data in respect of both groups of antagonists. It draws upon data that are available from clinical trial registries as well as data that have been presented. EXPERT OPINION: The unpromising clinical outcomes obtained with setipiprant, vidupiprant and AZD-1981, and the reason why development of OC-459 appears stalled, are all considered. An assessment of the nine DP2 antagonists currently in clinical development highlights the apparent advantages of ADC-3680 and MK-1029. The scope for licensing opportunities in this field is also highlighted. PMID- 24073897 TI - Abundance, diversity, and seasonal population dynamics of aquatic Coleoptera and Heteroptera in rice fields: effects of direct seeding management. AB - Recent introduction of modern drainage systems has produced intensely dry conditions in rice farmlands and has degraded habitats for aquatic animals. In this study, we compared water beetle (Coleoptera) and water bug (Heteroptera) communities within rice fields cultivated under different management regimes: V furrow no-till direct-seeding (DS) and conventional regimes. In DS fields, rice is sown in well-drained fields, and flooding is performed a month later than in conventional rice fields. DS fields are then continuously flooded until harvesting; unlike in conventional fields, where midseason drainage is performed in summer. We observed that DS fields supported higher densities of water beetles and water bugs than conventional fields, probably because of the high compatibility between the flooding period and the reproductive season of the insects. The species richness of water beetles was higher in DS fields than in conventional fields. Overall, DS fields showed higher water beetle and water bug abundance, but the effect was variable for individual species: seven species were more abundant in DS than in conventional fields, whereas two species showed opposite tendencies. Considering the differential responses among species to the management regimes, a mosaic of DS and conventional fields is preferable to either field alone for the conservation of aquatic insects in rice agroecosystems. PMID- 24073898 TI - Ten steps to establishing an e-consultation service to improve access to specialist care. AB - There is dissatisfaction among primary care physicians, specialists, and patients with respect to the consultation process. Excessive wait times for receiving specialist services and inefficient communication between practitioners result in decreased access to care and jeopardize patient safety. We created and implemented an electronic consultation (e-consultation) system in Eastern Ontario to address these problems and improve the consultation process. The e consultation system has passed through the proof-of-concept and pilot study stages and has effectively reduced unnecessary referrals while receiving resoundingly positive feedback from physician-users. Using our experience, we have outlined the 10 steps to developing an e-consultation service. We detail the technical, administrative, and strategic considerations with respect to (1) identifying your partners, (2) choosing your platform, (3) starting as a pilot project, (4) designing your product, (5) ensuring patient privacy, (6) thinking through the process, (7) fostering relationships with your participants, (8) being prepared to provide physician payment, (9) providing feedback, and (10) planning the transition from pilot to permanency. In following these 10 steps, we believe that the e-consultation system and its associated improvements on the consultation process can be effectively implemented in other healthcare settings. PMID- 24073899 TI - Adapting the content of cancer web sites to the information needs of patients: reliability and readability. AB - BACKGROUND: People who use the Internet to research health topics do not usually find all the information they need and do not trust what they read. This study was designed to assess the reliability, accessibility, readability, and popularity of cancer Web sites in Spanish and to analyze the suitability of Web site content in accordance with the specific information needs of cancer patients. MATERIALS AND METHODS: This was a two-phase, cross-sectional, descriptive study. The first phase involved data gathering through online searches and direct observation. The second phase involved individual structured interviews with 169 patients with breast, prostate, bladder, and kidney cancer. Spearman rank correlations were calculated between variables. RESULTS: Most sites belonged to nonprofit organizations, followed by universities or medical centers (14%). Thirty-one percent of the Web sites had quality seals, 59% provided details of authorship, 62% provided references to bibliographic sources, 38% identified their funding sources, and 54% showed the date of their last update. Twenty-one percent of the Web sites did not meet the minimum accessibility criteria. With regard to readability, 24% of the texts were considered to be "quite difficult." Patients' information needs vary depending on the type of cancer they have, although all patients want to know about the likelihood of a cure, survival rates, the side effects, and risks of treatment. CONCLUSIONS: The health information on cancer available on the Internet in Spanish is not very reliable, accessible, or readable and is not necessarily the information that breast, kidney, prostate, and bladder cancer patients require. The content of cancer Web sites needs to be assessed according to the information needs of patients. PMID- 24073900 TI - Videoconference-based mini mental state examination: a validation study. AB - BACKGROUND: Neuropsychological testing is a prime criterion of good practice to document cognitive deficits in a rapidly aging population. Telecommunication technologies may overcome limitations related to test administration. We compared performance of the Italian videoconference-based version of the Mini Mental State Examination (VMMSE) with performance of the standard MMSE administered face-to face (F2F), to validate the Italian version of the 28-item VMMSE. MATERIALS AND METHODS: To validate the Italian version of the VMMSE, we compared its performance with standard F2F. The sample (n=342) was administered three VMMSEs within 6 weeks after F2F testing. We identified the optimal cutoff through the receiver operating characteristic curve, as well as the VMMSE consistency through inter- and intrarater reliability (Inter/RR and Intra/RR) analysis. RESULTS: We found high levels of sensitivity and specificity for the optimal VMMSE cutoff identification and an accuracy of 0.96 (95% confidence interval 0.94-0.98). Intra/RR and inter/RR were highly significant. CONCLUSIONS: This study demonstrates that VMMSE is a valid instrument in clinical and research screening and monitoring of subjects affected by cognitive disorders. This study shows a significant correlation between videoconference assessment and the F2F one, providing an important impetus to expand studies and the knowledge about the usefulness of tele-assistance services. Our findings have important implications for both longitudinal assistance and clinical care of demented patients. PMID- 24073901 TI - Quality control tests for the crude drug of Conyza filaginoides. AB - CONTEXT: Conyza filaginoides (D.C.) Hieron (Asteraceae) is a medicinal Mexican plant highly prized in contemporary Mexico for the treatment of upset stomach and diabetes. OBJECTIVE: This work was undertaken to develop a suitable high performance liquid chromatography (HPLC)-diode array detection (DAD) method for quantifying rutin (1), the main active principle from the aerial parts of C. filaginoides. MATERIALS AND METHODS: The method was performed using a LiChrospher 100 RP-18 column. The mobile phase was water (containing 0.1% phosphoric acid) methanol-acetonitrile (80:5:15, v/v) at a flow rate of 1.2 mL min-1. RESULTS: Limits of detection and quantification were 7.5 and 22.8 MUg mL-1, respectively. The main recoveries measured at three concentrations were higher than 98%, with RSD <2%. Quantitative analysis of a few samples showed the presence of high concentrations of 1 (3.6 +/- 0.2 g/100 g of dry plant material). The volatile components were extracted by hydrodistillation or head space solid-phase microextraction (HS-SPME), and thereafter analyzed by gas chromatography coupled to mass spectrometry (GC-MS). Forty-three chemical constituents representing 90% of the total content of the oil were identified. The major light volatile compounds obtained by HS-SPME revealed a high content of monoterpene hydrocarbons. CONCLUSIONS: A precise, reliable, and accurate analytical HPLC method to detect and quantify 1 in the crude drug and some preparations were developed and fully validated. The volatile components of the plant are described for the first time. The proposed method would be useful for quality control assurance of this important Mexican plant. PMID- 24073902 TI - Flood-related skin diseases: a literature review. AB - Flood is one of the most common natural disasters, which commonly occurs in all parts of the world. The effects of the disasters considerably become enormous problems to overall public health systems. Flood-related skin diseases are a portion of these consequences presenting with cutaneous manifestations and/or signs of systemic illnesses. We conducted a systematic literature review of research publications relating to flooding and skin diseases. The purpose of this review was to provide dermatologists as well as general practitioners with comprehensive conditions of flood-related skin diseases and suggested treatments. Moreover, we categorized these flood-related diseases into four groups comprising inflammatory skin diseases, skin infections, traumatic skin diseases, and other miscellaneous skin diseases in a bid to implement early interventions and educate, prevent, and efficaciously handle those skin diseases under such a catastrophic situation so that better treatment outcomes and prevention of further complications could be ultimately achieved and accomplished. PMID- 24073903 TI - Epstein-Barr virus and skin manifestations in childhood. AB - Epstein-Barr virus (EBV) is a human B-lymphotropic herpes virus and one of the most common viruses in humans. Specific skin signs related to EBV infection are the exanthem of mononucleosis, which is observed more frequently after ingestion of amoxicillin, and oral hairy leukoplakia, a disease occurring mostly in immunocompromised subjects with HIV infection. Other more uncommon cutaneous disorders that have been associated with EBV infection include virus-related exanthems or diseases such as Gianotti-Crosti syndrome, erythema multiforme, and acute genital ulcers. Other skin manifestations, not correlated to virus infection, such as hydroa vacciniforme and drug-induced hypersensitivity syndrome have also been linked to EBV. The putative involvement of EBV in skin diseases is growing similarly to other areas of medicine, where the role of EBV infection is being investigated in potentially debilitating inflammatory diseases. The prognosis of EBV infection in healthy, immunocompetent individuals is excellent. However, lifelong infection, which is kept in check by the host immune system, determines an unpredictable risk of pathologic unpredictable scenarios. In this review, we describe the spectrum of non-tumoral dermatological manifestations that can follow EBV primary infection or reactivation of EBV in childhood. PMID- 24073904 TI - Associated pyoderma gangrenosum, erythema elevatum diutinum, and Sweet's syndrome: the concept of neutrophilic disease. AB - BACKGROUND: The association of three neutrophilic dermatoses supports the concept of "neutrophilic disease" as a syndrome representing a continuous spectrum of clinical entities. RESULTS: This report describes three neutrophilic pathologies arising in the same patient, in association with seronegative rheumatoid arthritis. The successive occurrence of erythema elevatum diutinum, pyoderma gangrenosum, and Sweet's syndrome illustrates the concept of "neutrophilic disease" developed by Wallach et al. in the 1990s. Most authors agree that neutrophilic dermatosis is defined as a cutaneous disease mainly characterized by polymorphonuclear neutrophil infiltration without infectious cause.The assessment of neutrophilic dermatosis includes identification of the type of cutaneous lesion, the existence of possible extracutaneous sites, and a search for associated disease. CONCLUSIONS: The occurrence of three separate neutrophilic dermatoses in a single patient lends further support to the concept that these entities form a spectrum of diseases called neutrophilic disease. PMID- 24073905 TI - A dermatology surgical safety checklist: an objective resident performance tool. PMID- 24073906 TI - Molecular diagnosis and therapeutic experience of subcutaneous Pyrenochaeta romeroi infection: a case report and review of the literature. PMID- 24073907 TI - Leprosy of Lucio and Latapi with extremity livedoid vascular changes. PMID- 24073908 TI - Intractable erythematous plaques on the hands: palmoplantar eosinophilic pustular folliculitis. PMID- 24073909 TI - Radiotherapy supports a better outcome than chemotherapy in cutaneous natural killer (NK)/T cell lymphoma nasal type. PMID- 24073910 TI - Three novel mutations of TSC1 gene in Chinese patients with tuberous sclerosis complex. PMID- 24073911 TI - Combination of narrow-band ultraviolet B and topical tacrolimus is effective for segmental vitiligo. PMID- 24073912 TI - Diagnostic applicability of confocal laser scanning microscopy in tinea corporis. PMID- 24073913 TI - Sarcoidosis presenting as psoriasiform Koebnerized papules in an Indian male. PMID- 24073915 TI - Controlled self-assembly and luminescence characteristics of Eu(III) complexes in binary aqueous/organic media. AB - Luminescence of sodium tetrakis(naphthoyl trifluoroacetonato) europium(III) (Na[Eu(nta)4]) in binary aqueous-ethanol media is quenched continuously with an increase in the water content, which is ascribed to commonly observed relaxation of photoexcited lanthanide complexes through vibrational coupling with coordinating water. Meanwhile, replacement of sodium ion with an ammonium amphiphile 1 gives a lipid complex 1[Eu(nta)4] which shows distinct changes: its luminescence quantum yield Phi is remarkably increased to ~0.6 above the water content of ~60 vol. %. This unusual enhancement in luminescence intensity occurs in response to self-assembly of 1[Eu(nta)4] into nanoparticles. The lipid counterions provide a hydrophobic atmosphere inside nanoparticles, and they simultaneously form monolayers on the nanoparticle surface that enhance dispersion stability. The size of nanoparticles is tunable depending on the volume fraction of water in the binary media. The lipid-assisted self-assembly of lanthanide complexes provides a unique means to fabricate luminescent nanomaterials, and this approach will be widely applied to fabricate functional coordination nanomaterials. PMID- 24073916 TI - TRANS producer's response to media review by Dr. Anne Lawrence. PMID- 24073918 TI - Trends in infant and young child feeding practices in Bangladesh, 1993-2011. AB - BACKGROUND: Optimal infant and young child feeding practices are crucial to improving the health and nutritional status of children. Bangladesh Breastfeeding Foundation, UNICEF and several other organizations are working in the country for the promotion of healthy feeding practices. This article presents trends in breastfeeding and complementary feeding practices in Bangladesh from 1993-2011, based on data in Bangladesh Demographic and Health Surveys. The following Bangladesh Demographic and Health Surveys were studied: BDHS 93-94, BDHS 96-97, BDHS 99-00, BDHS 04, BDHS 07 and BDHS 11. Values of indicators for infant and young child feeding proposed by WHO, along with their 95% confidence intervals, were calculated, and trends were assessed. FINDINGS: Among the core indicators, early initiation of breastfeeding, exclusive breastfeeding under six months, introduction of solid, semi-solid and soft foods, and consumption of iron-rich foods have improved, while continued breastfeeding at one year does not display a statistically significant development. Of the optional indicators, the prevalence of age-appropriate breastfeeding and children ever breastfed improved, while the prevalence of predominant breastfeeding under six months witnessed a decline. Median duration of breastfeeding declined, and there was no change in the other optional indicators (continued breastfeeding at two years and bottle feeding). Developments in the other optional indicators were not statistically significant. The ratings of early initiation of breastfeeding and complementary feeding have gone up from poor to fair, those of exclusive breastfeeding under six months from fair to good, while those of bottle-feeding are fair. CONCLUSION: The developments in breastfeeding and complementary feeding practices in the country have been considerable, but there is still substantial scope for improvement. PMID- 24073917 TI - Study on the antiviral activity of San Huang Yi Gan Capsule against hepatitis B virus with seropharmacological method. AB - BACKGROUND: Seropharmacology arising recently is a novel method of in vitro pharmacological study on Chinese herb using drug-containing animal serum. As seropharmacology possesses the advantages of experiments in vitro and in vivo, it is increasingly applied in pharmacological research on Chinese medicine. However, some issues of seropharmacology remain controversial and need to be clearly defined. San Huang Yi Gan Capsule (SHYGC) is a Chinese herbal formula with antiviral property against hepatitis B virus (HBV), but little is known about the mechanism underlying its anti-HBV activity. The aim of the present study was to elucidate the action mechanism of SHYGC using seropharmacological method and systematically address the methodology of preparing drug-containing serum. METHODS: New Zealand rabbits were orally administrated SHYGC with various regimens, followed by preparation of SHYGC-containing rabbit sera with a variety of methods. After HBV-producing HepG2 2.2.15 cells were treated with SHYGC containing sera or entecavir for 9 days, the levels of hepatitis B surface antigen (HBsAg) and HBV DNA and the activity of DNA Polymerase were determined in HepG2 2.2.15 cells-conditioned media. RESULTS: An optimally standardized method of preparing drug-containing serum was raised for seropharmacology, with which SHYGC was demonstrated to suppress HBsAg expression, HBV DNA replication and DNA Polymerase activity in a dose-dependent fashion. CONCLUSIONS: This seropharmacological study shows SHYGC is a potentially powerful anti-HBV agent. Additionally, seropharmacology is a promising pharmacological method with a broad range of advantages, and it can be widely used in biomedical research, if combined with pharmacokinetics. PMID- 24073919 TI - Robust, superamphiphobic fabric with multiple self-healing ability against both physical and chemical damages. AB - Superamphiphobic coatings with excellent repellency to low surface tension liquids and multiple self-healing abilities are very useful for practical applications, but remain challenging to realize. Previous papers on self-healing superamphiphobic coatings have demonstrated limited liquid repellency with single self-healing ability against either physical or chemical damage. Herein, we describe a superamphiphobic fabric that has remarkable multi-self-healing ability against both physical and chemical damages. The superamphiphobicity was prepared by a two-step surface coating technique. Fabric after coating treatment showed exceptional liquid-repellency to low surface tension liquids including ethanol. The fabric coating was also durable to withstand 200 cycles of laundries and 5000 cycles of Martindale abrasion without apparently changing the superamphiphobicity. This highly robust, superamphiphobic fabric may find applications for the development of "smart" functional textiles for various applications. PMID- 24073920 TI - Long-term resveratrol treatment prevents ovariectomy-induced osteopenia in rats without hyperplastic effects on the uterus. AB - Resveratrol (Res), a polyphenol that is abundant in many medicinal plants and is a selective oestrogen receptor modulator, exhibits multiple biological activities. In the present study, we determined whether Res prevents oestrogen deficiency-induced osteopenia and whether Res administration decreases pathological changes in the endometrium and lumen of the uterus compared with oestradiol replacement therapy (ERT). A total of sixty 3-4-month-old female Wistar rats were randomly divided into a sham-operated group (Sham) and five ovariectomy (OVX) subgroups, i.e. OVX rats as a control group (OVX); OVX rats receiving oestradiol valerate (ERT, 0.8 mg/kg); and OVX rats receiving Res 20, 40 and 80 mg/kg. Daily oral administration was initiated at week 2 after OVX for 12 weeks. A dose-response difference was observed in the effects of Res on bone mineral density (BMD) and trabecular microarchitecture. Only at the highest dose, bone loss was almost equivalent to that observed in the ERT group. The dose response effects of Res on the biochemical parameters (alkaline phosphatase, IL 6, TNF-alpha and transforming growth factor-beta1 concentrations in the serum as well as urinary Ca and P excretion) and the expressions of receptor activator of nuclear factor kappaB ligand (RANKL) and the RANKL:osteoprotegerin protein ratio in the femur were also observed. Furthermore, the thickening of the endometrium and the infiltration of lymphocytes were prevented in all the three Res-treated groups compared with the ERT group. In conclusion, Res treatment not only improves BMD and trabecular microarchitecture but also does not affect the uterus and Res might be a potential remedy for the treatment of postmenopausal osteoporosis. PMID- 24073921 TI - Bacterial meningitis: new therapeutic approaches. AB - Bacterial meningitis remains a disease with high mortality and long-term morbidity. Outcome critically depends on the rapid initiation of effective antibiotic therapy. Since a further increase of the incidence of pathogens resistant to antibacterials can be expected both in community-acquired and nosocomial bacterial meningitis, the choice of an optimum initial empirical antibiotic regimen will gain significance. In this context, the use of antibiotics which are bactericidal but do not lyse bacteria, may emerge as a therapeutic option. Conversely, the role of corticosteroids, which decrease the entry of hydrophilic antibacterials into the cerebrospinal fluid, as adjunctive therapy will probably decline as a consequence of the increasing antibiotic resistance of bacteria causing meningitis. Consequent vaccination of all children at present is the most efficient manner to reduce disease burden. PMID- 24073923 TI - An improved satisfiability algorithm for nested canalyzing functions and its application to determining a singleton attractor of a Boolean network. AB - We study the problem of finding a 0-1 assignment to Boolean variables satisfying a given set of nested canalyzing functions, a class of Boolean functions that is known to be of interest in biology. For this problem, an extension of the satisfiability problem for a conjunctive normal form formula, an O(min(2(k), 2((k+m)/2))poly(m)) time algorithm has been known, where m and k are the number of nested canalyzing functions and variables, respectively. Here we present an improved O(min(2(k), 1.325(k+m), 2(m))poly(m)) time algorithm for this problem. We also study the problem of finding a singleton attractor of a Boolean network consisting of n nested canalyzing functions. Although an O(1.799(n)) time algorithm was proposed in a previous study, it was implicitly assumed that the network does not contain any positive self-loops. By utilizing the improved satisfiability algorithm for nested canalyzing functions, while allowing for the presence of positive self-loops, we show that the general case can be solved in O(1.871(n)) time. PMID- 24073922 TI - Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR. AB - BACKGROUND: The t(6;9)(p23;q34) chromosomal translocation is found in 1% of acute myeloid leukemia and encodes the fusion protein DEK-NUP214 (formerly DEK-CAN) with largely uncharacterized functions. METHODS: We expressed DEK-NUP214 in the myeloid cell lines U937 and PL-21 and studied the effects on cellular functions. RESULTS: In this study, we demonstrate that expression of DEK-NUP214 increases cellular proliferation. Western blot analysis revealed elevated levels of one of the key proteins regulating proliferation, the mechanistic target of rapamycin, mTOR. This conferred increased mTORC1 but not mTORC2 activity, as determined by the phosphorylation of their substrates, p70 S6 kinase and Akt. The functional importance of the mTOR upregulation was determined by assaying the downstream cellular processes; protein synthesis and glucose metabolism. A global translation assay revealed a substantial increase in the translation rate and a metabolic assay detected a shift from glycolysis to oxidative phosphorylation, as determined by a reduction in lactate production without a concomitant decrease in glucose consumption. Both these effects are in concordance with increased mTORC1 activity. Treatment with the mTORC1 inhibitor everolimus (RAD001) selectively reversed the DEK-NUP214-induced proliferation, demonstrating that the effect is mTOR-dependent. CONCLUSIONS: Our study shows that the DEK-NUP214 fusion gene increases proliferation by upregulation of mTOR, suggesting that patients with leukemias carrying DEK-NUP214 may benefit from treatment with mTOR inhibitors. PMID- 24073924 TI - The approximability of shortest path-based graph orientations of protein-protein interaction networks. AB - The graph orientation problem calls for orienting the edges of an undirected graph so as to maximize the number of prespecified source-target vertex pairs that admit a directed path from the source to the target. Most algorithmic approaches to this problem share a common preprocessing step, in which the input graph is reduced to a tree by repeatedly contracting its cycles. Although this reduction is valid from an algorithmic perspective, the assignment of directions to the edges of the contracted cycles becomes arbitrary and, consequently, the connecting source-target paths may be arbitrarily long. In the context of biological networks, the connection of vertex pairs via shortest paths is highly motivated, leading to the following variant: Given an undirected graph and a collection of source-target vertex pairs, assign directions to the edges so as to maximize the number of pairs that are connected by a shortest (in the original graph) directed path. Here we study this variant, provide strong inapproximability results for it, and propose approximation algorithms for the problem, as well as for relaxations where the connecting paths need only be approximately shortest. PMID- 24073925 TI - Motion and interaction of aspirin crystals at aqueous-air interfaces. AB - Small-molecule amphiphiles such as aspirin have unique properties arising from a combination of an aromatic hydrophobic part and a hydrophilic part. We show that crystals of aspirin are capable of generating convective flows at the air-aqueous interface from both Marangoni effects (through weak surface activity) and capillarity (surface deformations). The flow-driven motion of millimeter-sized crystals was found to depend on the presence of other ions in solution as well as the distance and orientation of the crystals. The interactions lead to the formation of groups of two or more crystals that also underwent motion. The convective flows created by small amphiphile crystals might be exploited in the dynamic self-organization of particles at interfaces. PMID- 24073926 TI - Effects of ginsenosides on rat jejunal contractility. AB - CONTEXT: Ginsenosides are primary active ingredients of ginseng, which are believed to have various health benefits. It is found that the biotransformation of ginsenosides mainly takes place in the gastrointestinal tract and the information about ginsenosides-exerted effects on intestinal contractility is not sufficient. AIMS: The present study proposed that ginsenosides could exert stimulatory or inhibitory effects on intestinal motility depending on the assay condition-related intestinal contractile states and was to characterize the effects of ginsenosides on intestinal motility. METHODS: Jejunal contractility determination, Western blotting analysis, and real-time polymerase chain reaction were performed to test the effects of total ginsenosides isolated from Panax ginseng C. A. Mey (Araliaceae) root. RESULTS: The results showed that ginsenosides at the fixed concentration of 20 mg/L exerted bidirectional regulation (BR) on the contractility of isolated jejunal segment (IJS), depending on the contractile states. The contractility of IJS was increased by ginsenosides in low contractile states, which were correlated to the cholinergic activation, and the contractility of IJS was decreased by ginsenosides in high contractile states, which were correlated to the adrenergic activation and nitric oxide related mechanisms. Ginsenosides-induced BR was abolished in the absence of Ca(2+) or by using tetrodotoxin, implicating the requirement of Ca(2+) and the enteric nervous system. Effects of ginsenosides on myosin light chain phosphorylation and the mRNA expression of myosin light chain kinase were also bidirectional. DISCUSSION AND CONCLUSION: Results suggest that ginsenosides may have the potential clinical implication for reliving the symptoms of alternative hypo- and hyper-intestinal motility. PMID- 24073927 TI - NMR detection and study of hydrolysis of HNO-derived sulfinamides. AB - Nitroxyl (HNO), a potential heart failure therapeutic, is known to post translationally modify cysteine residues. Among reactive nitrogen oxide species, the modification of cysteine residues to sulfinamides [RS(O)NH2] is unique to HNO. We have applied (15)N-edited (1)H NMR techniques to detect the HNO-induced thiol to sulfinamide modification in several small organic molecules, peptides, and the cysteine protease, papain. Relevant reactions of sulfinamides involve reduction to free thiols in the presence of excess thiol and hydrolysis to form sulfinic acids [RS(O)OH]. We have investigated sulfinamide hydrolysis at physiological pH and temperature. Studies with papain and a related model peptide containing the active site thiol suggest that sulfinamide hydrolysis can be enhanced in a protein environment. These findings are also supported by modeling studies. In addition, analysis of peptide sulfinamides at various pH values suggests that hydrolysis becomes more facile under acidic conditions. PMID- 24073930 TI - An empirical study of defensive avoidance in paranoia. AB - BACKGROUND: There is controversy as to whether psychological defensive avoidance is associated with paranoia. AIMS: To elucidate whether "Poor-me" paranoid patients, who believe that the persecution they perceive is undeserved, show more prominent avoidance of negative thoughts about themselves than healthy and clinical controls. METHOD: The act of avoidance of aversive mental contents was assessed in 27 healthy controls and 48 patients with poor-me, bad-me (perceived to be deserved) or no paranoia. Defensive avoidance was assessed via established questionnaires, a novel task based on self-discrepancy theory and research clinician ratings. RESULTS: Participants in all groups showed substantial levels of verbal defensive avoidance. Paranoia was associated with reduced self-reported tolerance of negative mental contents (high Experiential Avoidance, EA). Contrary to our hypotheses, poor-me and bad-me patients showed similar EA. All participant groups showed similar levels of verbal defensive avoidance. CONCLUSION: The findings do not support an association of psychological avoidance with paranoia. PMID- 24073932 TI - Major response with sorafenib in advanced renal cell carcinoma after 14 years of follow-up. AB - Tyrosine kinase inhibitors have dramatically improved the prognosis of metastatic renal cell carcinoma (RCC). However, it remains unknown whether treatment should be continued until progression or discontinued in patients with good response. We present the history of a woman diagnosed with RCC in 1997, who started sorafenib in 2004, two years after the occurrence of lung and mediastinal metastases. Over the following 8 years, the sorafenib dose was reduced at least 3 times due to toxicity and the treatment was discontinued twice upon the patient's decision, from May 2005 to March 2009, then from January 2011 to August 2011. The last evaluation in January 2013 showed stable disease. This case illustrates the feasibility of treatment discontinuation without negative impact on survival, as previously shown by some authors. PMID- 24073931 TI - Is the covering of the resection margin after distal pancreatectomy advantageous? AB - BACKGROUND: In recent years, many advances in pancreatic surgery have been achieved. Nevertheless, the rate of pancreatic fistula following pancreatic tail resection does not differ between various techniques, still reaching up to 30% in prospective multicentric studies. Taking into account contradictory results concerning the usefulness of covering resection margins after distal pancreatectomy, we sought to perform a systematic, retrospective analysis of patients that underwent distal pancreatectomy at our center. METHODS: We retrospectively analysed the data of 74 patients that underwent distal pancreatectomy between 2001 and 2011 at the community hospital in Neuss. Demographic factors, indications, postoperative complications, surgical or interventional revisions, and length of hospital stay were registered to compare the outcome of patients undergoing distal pancreatectomy with coverage of the resection margins vs. patients undergoing distal pancreatectomy without coverage of the resection margins. Differences between groups were calculated using Fisher's exact and Mann-Whitney U test. RESULTS: Main indications for pancreatic surgery were insulinoma (n=18, 24%), ductal adenocarcinoma (n=9, 12%), non-single insulinoma-pancreatogenic-hypoglycemia-syndrome (NSIPHS) (n=8, 11%), and pancreatic cysts with pancreatitis (n=8, 11%). In 39 of 74 (53%) patients no postoperative complications were noted. In detail we found that 23/42 (55%) patients with coverage vs. 16/32 (50%) without coverage of the resection margins had no postoperative complications. The most common complications were pancreatic fistulas in eleven patients (15%), and postoperative bleeding in nine patients (12%). Pancreatic fistulas occurred in patients without coverage of the resection margins in 7/32 (22%) vs. 4/42 (1011%) with coverage are of the resection margins, yet without reaching statistical significance. Postoperative bleeding ensued with equal frequency in both groups (12% with coverage versus 13% without coverage of the resection margins). The reoperation rate was 8%. The hospital stay for patients without coverage was 13 days (5-60) vs. 17 days (8-60) for patients with coverage. CONCLUSIONS: The results show no significant difference in the fistula rate after covering of the resection margin after distal pancreatectomy, which contributes to the picture of an unsolved problem. PMID- 24073934 TI - Medical student perceptions of hospital discharge transitions in care. PMID- 24073933 TI - Do psychobiosocial states mediate the relationship between perceived motivational climate and individual motivation in youngsters? AB - Grounded in achievement goal theory and self-determination theory, this cross sectional study examined the relationship between perceived motivational climate and individuals' motivation as well as the mediation effect of psychobiosocial states as conceptualised within the individual zones of optimal functioning (IZOF) model. Young students (N = 167, age range 14-15 years) taking part in physical education classes completed measures of teacher-initiated motivational climate, task and ego orientation, motivation and psychobiosocial states. Simple and serial mediation analyses indicated that a perceived mastery climate and individuals' task orientation were related to intrinsic motivation and identified regulation through the mediation of pleasant/functional psychobiosocial states. In contrast, a perceived performance climate was related to external regulation and amotivation through the mediation of unpleasant/dysfunctional psychobiosocial states. Regression analysis results also showed that discrete psychobiosocial states accounted for a significant proportion of variance in motivational variables. Taken together, findings highlight the role of psychobiosocial states as mediators of the relationship between motivational climate and an individual's motivation, and suggest that educators should consider a wide range of individual's functional and dysfunctional reactions deriving from their instructional activity. PMID- 24073935 TI - Patient participation in, and attitudes towards, community-based medical education. PMID- 24073936 TI - Students as teachers: the impact of a near-peer-led didactic teaching model on tutee confidence. PMID- 24073937 TI - Gender awareness in a medical curriculum: surveying final year students undertaking a Women's Health rotation. PMID- 24073938 TI - Superoleophobic textured copper surfaces fabricated by chemical etching/oxidation and surface fluorination. AB - We report a convenient route to fabricate superoleophobic surfaces (abridged as SOS) on copper substrate by combining a two-step surface texturing process (first, the substrate is immersed in an aqueous solution of HNO3 and cetyltrimethyl ammonium bromide, and then in an aqueous solution of NaOH and (NH4)2S2O8) and succeeding surface fluorination with 1H,1H,2H,2H perfluorodecanethiol (PFDT) or 1-decanethiol. The surface morphologies and compositions were characterized by field emission scanning electron microscopy and X-ray diffraction, respectively. The results showed that spherical micro-pits (SMP) with diameter of 50-100 MUm were formed in the first step of surface texturing; in the second step, Cu(OH)2 or/and CuO with structures of nanorods/microflowers/microballs were formed thereon. The surface wettability was further assessed by optical contact angle meter by using water (surface tension of 72.1 mN m(-1) at 20 degrees C), rapeseed oil (35.7 mN m(-1) at 20 degrees C), and hexadecane (25.7 mN m(-1) at 20 degrees C) as probe liquids. The results showed that, as the surface tension decreasing, stricter choosing of surface structures and surface chemistry are required to obtain SOS. Specifically, for hexadecane, which records the lowest surface tension, the ideal surface structures are a combination of densely distributed SMP and nanorods, and the surface chemistry should be tuned by grafted with low-surface-energy molecules of PFDT. Moreover, the stability of the so-fabricated sample was tested and the results showed that, under the testing conditions, superhydrophobicity and superoleophobicity may be deteriorated after wear/humidity resistance test. Such deterioration may be due to the loss of outermost PFDT layer or/and the destruction of the above-mentioned ideal surface structures. For UV and oxidation resistance, the sample remained stable for a period of 10 days. PMID- 24073939 TI - Self-assembly of mono- and bidentate oligoarylene thiols onto polycrystalline Au. AB - Four thiolated oligoarylene molecules (i) 4-methoxy-terphenyl-4"-methanethiol (MTM), (ii) 4-methoxy-terphenyl-3",5"-dimethanethiol (MTD), (iii) 4-nitro terphenyl-4"-methanethiol (NTM), and (iv) 4-nitro-terphenyl-3",5"-dimethanethiol (NTD) were synthesized and self-assembled as monolayers (SAMs) on polycrystalline Au electrodes of organic field-effect transistors (OFETs). SAMs were characterized by contact angle and AC/DC electrochemical measurements, whereas atomic force microscopy was used for imaging the pentacene films grown on the coated electrodes. The electrical properties of functionalized OFETs, the electrochemical SAMs features and the morphology of pentacene films were correlated to the molecular organization of the thiolated oligoarylenes on Au, as calculated by means of the density functional theory. This multi-methodological approach allows us to associate the systematic replacement of the SAM anchoring head group (viz. methanethiol and dimethanethiol) and/or terminal tail group (viz. nitro-, -NO2, and methoxy, -OCH3) with the change of the electrical features. The dimethanethiol head group endows SAMs with higher resistive features along with higher surface tensions compared with methanethiol. Furthermore, the different number of thiolated heads affects the kinetics of Au passivation as well as the pentacene morphology. On the other hand, the nitro group confers further distinctive properties, such as the positive shift of both threshold and critical voltages of OFETs with respect to the methoxy one. The latter experimental evidence arise from its electron-withdrawing capability, which has been verified by both DFT calculations and DC electrochemical measurements. PMID- 24073940 TI - Insulin sensitizers in 2013: new insights for the development of novel therapeutic agents to treat metabolic diseases. AB - Insulin-sensitizing thiazolidinediones (TZDs) correct a root cause of type 2 diabetes and potentially other diseases of metabolic dysfunction, including conditions ranging from oncologic, inflammatory, and neurodegenerative diseases. Importantly, compounds with this mode of action can modify disease progression, as opposed to simply mitigating symptoms. However, side effects have limited the use of marketed agents. Moreover, the same and additional issues have prevented development of newer agents, and no new compounds with this mode of action have been approved since 1999. Here we briefly review the drug discovery track record of compounds in the TZD class as well as several classes of compounds that have been designed with substitutes for the TZD ring, while maintaining and/or expanding the ability to directly activate peroxisome proliferator-activated receptor (PPAR) transcription factors. A key discovery that could change the course of drug discovery in this area is a newly identified mitochondrial target for the insulin sensitizers. This has allowed new drug discovery into molecules designed to maintain this mitochondrial interaction while specifically avoiding significant interactions with PPAR receptors. This commentary suggests that a fresh approach could pave the way for a new directed group of therapeutic agents with potential for disease modification of common metabolic disorders. PMID- 24073941 TI - Antimicrobial therapies for Q fever. AB - Q fever is caused by the bacterium Coxiella burnetii and has both acute and chronic forms. The acute disease is a febrile illness often with headache and myalgia that can be self-limiting, whereas the chronic disease typically presents as endocarditis and can be life threatening. The normal therapy for the acute disease is a 2 week course of doxycycline, whereas chronic disease requires 18-24 months of doxycycline in combination with hydroxychloroquine. Alternative treatments are used for pregnant women, young children and those who cannot tolerate doxycycline. Doxycycline resistance is rare, but has been reported. Co trimoxazole is a currently recommended alternative treatment, but quinolones, rifampin and newer macrolides may also provide some benefit. PMID- 24073943 TI - Connecting the cell cycle with cellular identity. AB - The remarkable ability of oocytes to reinstate the totipotent state from a unipotent somatic cell, allowing the cloning of animals and the generation of human stem cells, has fascinated scientists for decades. Due to the complexity of oocytes, it has remained challenging to understand the rapid reprogramming following nuclear transfer at a molecular level. Conversely, the detailed characterization of molecular mechanisms is also often insufficient to comprehend the functional relevance of a complex molecular process, such as the dissociation of transcription factors from chromatin during cell division, the role of chromatin modifications in cellular memory, or of cell type-specific DNA replication. This review attempts to bridge the gap between nuclear transfer and molecular biology by focusing on the role of the cell cycle in reprogramming. PMID- 24073942 TI - Instrument-assisted cross fiber massage increases tissue perfusion and alters microvascular morphology in the vicinity of healing knee ligaments. AB - BACKGROUND: Ligament injuries are common clinical problems for which there are few established interventions. Instrument-assisted cross fiber massage (IACFM) was recently shown to accelerate the restoration of biomechanical properties in injured rodent knee medial collateral ligaments (MCL). The current study aimed to investigate the influence of IACFM on regional perfusion and vascularity in the vicinity of healing rodent knee MCL injuries. METHODS: Bilateral knee MCL injuries were induced in female Sprague-Dawley rats. Commencing 1 week post injury, 1 minute of IACFM was introduced unilaterally 3 times/week for 3 weeks. The contralateral injured MCL served as an internal control. Regional tissue perfusion was assessed in vivo throughout healing using laser Doppler imaging, whereas regional microvascular morphology was assessed ex vivo via micro-computed tomography of vessels filled with contrast. RESULTS: IACFM had no effect on tissue perfusion when assessed immediately, or at 5, 10, 15 or 20 min following intervention (all p > 0.05). However, IACFM-treated hindlimbs had enhanced tissue perfusion when assessed 1 day following the 4th and 9th (last) treatment sessions (all p < 0.05). IACFM-treated hindlimbs also had greater perfusion when assessed 1 wk following the final treatment session (32 days post-injury) (p < 0.05). Subsequent investigation of microvascular morphology found IACFM to increase the proportion of arteriole-sized blood vessels (5.9 to <41.2 MUm) in the tibial third of the ligament (p < 0.05). CONCLUSIONS: These findings suggest IACFM alters regional perfusion and vascularity in the vicinity of healing rodent knee MCL injuries. This effect may contribute to the beneficial effect of IACFM observed on the recovery of knee ligament biomechanical properties following injury. PMID- 24073944 TI - Effect of exogenous Oct4 overexpression on cardiomyocyte differentiation of human amniotic mesenchymal cells. AB - Regenerative therapy is a new strategy for the end-stage heart failure; however, the ideal cell source has not yet been established for this therapy. We expected that the amnion might be an ideal cell source for cardiac regenerative therapy and that the differentiation potency of the human amnion mesenchymal cells (hAMCs) could be improved by overexpression of Oct4, a key factor that maintains the undifferentiated state. A plasmid vector was made by insertion of the Oct4 open reading frame (ORF) under control of a cytomegalovirus (CMV) promoter (pCMV hOct4) and transfected into hAMCs by electroporation. The optimum induction time was investigated by comparing the quantity of stem cell-specific mRNAs, cardiac specific mRNAs, and cardiac-specific proteins with time. hAMCs already expressed cardiac-specific proteins such as Nkx2.5 and Connexin43. After pCMV-hOct4 transfection, endogenous Oct4 mRNA and other stem cell markers showed a transient increase. With 5-azacytidine treatment, quantities of the cardiac-specific mRNAs, such as GATA4 and myosin light-chain-2v (Mlc-2v), were increased significantly. After Oct4 overexpression, the highest expression of cardiac-specific mRNAs and stem cell makers was seen at almost the same time. Furthermore, more mature myocardial contraction proteins were observed when hAMCs were induced at specific optimal times after gene transfection. In conclusion, hAMCs were activated to an undifferentiated state by overexpression of Oct4, and their cardiac differentiation potency was improved. Thus, the single-time transfection of the Oct4 expression vector may be a useful strategy for effective cell therapy. The use of cryopreserved hAMCs in cell therapy still requires more investigation. PMID- 24073945 TI - Dengue virus type 1 clade replacement in recurring homotypic outbreaks. AB - BACKGROUND: Recurring dengue outbreaks occur in cyclical pattern in most endemic countries. The recurrences of dengue virus (DENV) infection predispose the population to increased risk of contracting the severe forms of dengue. Understanding the DENV evolutionary mechanism underlying the recurring dengue outbreaks has important implications for epidemic prediction and disease control. RESULTS: We used a set of viral envelope (E) gene to reconstruct the phylogeny of DENV-1 isolated between the periods of 1987-2011 in Malaysia. Phylogenetic analysis of DENV-1 E gene revealed that genotype I virus clade replacements were associated with the cyclical pattern of major DENV-1 outbreaks in Malaysia. A total of 9 non-conservative amino acid substitutions in the DENV-1 E gene consensus were identified; 4 in domain I, 3 in domain II and 2 in domain III. Selection pressure analyses did not reveal any positively selected codon site within the full length E gene sequences (1485 nt, 495 codons). A total of 183 (mean dN/dS = 0.0413) negatively selected sites were found within the Malaysian isolates; neither positive nor negative selection was noted for the remaining 312 codons. All the viruses were cross-neutralized by the respective patient sera suggesting no strong support for immunological advantage of any of the amino acid substitutions. CONCLUSION: DENV-1 clade replacement is associated with recurrences of major DENV-1 outbreaks in Malaysia. Our findings are consistent with those of other studies that the DENV-1 clade replacement is a stochastic event independent of positive selection. PMID- 24073947 TI - [Does physical activity produce clinically significant changes during discontinuation of insulin pump in type 1 diabetic patients?]. AB - INTRODUCTION: Discontinuation of insulin pump treatment (CSII) before, during and after physical activity is a common practice among a number of patients. The aim of the study was to evaluate the course of insulinemia during a 3- hour insulin pump suspension and after consecutive insulin bolus administration, and additionally, to assess the effect of physical activity (mid intensity aerobic exercise). PATIENT AND METHODS: We enrolled 12 patients with diabetes mellitus type 1 in the study (men, mean age 33.4 +/- 8.66 years, diabetes duration 16.3 +/ 8.76 years, CSII treatment duration 6.9 +/- 4.60 years, BMI 25.7 +/- 3.75 mg/ m2, HbA1c 8.4 +/- 0.95%, total insulin dose 50.3 +/- 12.50 IU/ day). The tests were performed after night fasting at usual insulin doses, without serving breakfast and morning bolus dose. In the course of the test, insulin administration by a pump was suspended for 3 hours. Blood for assessment of blood glucose and insulinemia was taken in 30- minute intervals during the test. A test with or without physical exercise on bicycle ergometer was performed in each patient 2 weeks later. RESULTS: We did not prove any influence of physical exercise on insulinemia during suspended insulin deli-very by an insulin pump. Insulinemia of approximately 50% of the original value persisted for another 90 minutes following insulin pump suspension. A rapid increase in insulinemia occurred after bolus administration in the 180th minute of the test. However, the decrease in blood glucose level did not occur until after another 90 minutes. CONCLUSION: When modifying CSII treatment by reduction or suspension of insulin delivery it is essential to bear in mind the gradual decrease in insulinemia as well as the delay in insulin action following bolus administration. PMID- 24073948 TI - [Use of natriuretic peptides in diagnosis of left ventricular hypertrophy in obese hypertensive patients with metabolic syndrome]. AB - INTRODUCTION: Presence of left ventricular (LV) hypertrophy significantly increases cardiovascular risk in patients suffering from hypertension. Diagnostics of LV hypertrophy in hypertensive patients is not easy and there is still no method of enabling a simple and sufficiently sensitive dia-gnosis across a large patient population. The golden standard in LV hypertrophy diagnostics is echocardiography, and there are adverse opinions regarding the use of natriuretic peptides BNP and NT proBNP (NP) to diagnose LV hypertrophy. PATIENTS AND METHODS: We examined through echocardiography 173 hypertensive patients with signs of metabolic syndrome and a moderate increase in blood pressure (130- 159/ 85- 99 mm Hg) with an average age of 54.8 +/- 13.54 years, i.e. 119 men and 54 women, who were divided into 2 groups; 1 with BMI > 30 (group A with a severe obesity) and the other without obesity, BMI < 30 (group B). Both groups were examined for BNP and NT proBNP levels. RESULTS: We found a positive correlation between NP and LVMi, both for BNP (r = 0.169; p = 0.033) and for NT proBNP (r = 0.240; p = 0.002). NT proBNP statistically significantly predicts the given LV hypertrophy LK in people with BMI < 30 but not in obese people (BMI > 30). CONCLUSION: Obese patients suffer from a higher occurrence of left ventricular hypertrophy and paradoxically a lower NP value than patients with a metabolic syndrome (MS) who are not obese. Natriuretic peptides have a limited diagnostic value when assessing left ventricular hypertrophy. They are only of value in patients who are not obese and whose kidney function and systolic myocardial function have not been impaired. PMID- 24073949 TI - [The importance of cardiac bio-marker assay for the stratification and monitoring of AL amyloidosis patients - single center experience]. AB - INTRODUCTION: Cardiac involvement is a dominant prognostic factor in AL amyloidosis patients. A detailed assessment of the presence and degree of cardiac involvement utilizes an array of noninvasive investigation methods, particularly echocardiography and MRI; laboratory parameters include troponins and natriuretic peptides. Cardiac involvement detection aside, cardiac bio-markers are used as a relatively strong stratification and prognostic factor. OBJECTIVE: The presentation of cardiac bio-markers assay applications in AL amyloidosis patients at an individual treatment center. PATIENTS AND METHODS: The monitored patient set consisted of 22 patients with histologically confirmed AL amyloidosis, of whom 18 met the criteria for cardiac involvement. Levels of cardiac bio-markers troponin T (TnT) and Nterminal probrain natriuretic peptide (NT ProBNP) were determined in all patients. Risk stratification of the patients utilized the Mayo staging system which is based on both bio-markers assays; Log Rank Test was applied to survival evaluation. RESULTS: Median survival of patients with cardiac involvement stigmata was 10 months vs 60 months survival of patients without signs of cardiac involvement (p = 0.133). Of the 4 patients without cardiac involvement, 1 has shown positive levels of TnT and 2 positive levels of NT ProBNP. All cardiac involvement patients exhibited abnormal levels of NT ProBNP (median 4,752 ng/ l; 415.7- 35,000) as well as positive levels of TnT (median 0.0815 MUg/ l; 0.02- 0.986). The application of the Mayo stratification system to the set had determined 2 patients at stage I, 5 patients at stage II and 15 patients at stage III. The median survival of the Mayo I + II group vs the Mayo III group was 60 vs 6 months (p = 0.015), revealing extremely limited survival of stage III patients. Assessment of TnT and NT ProBNP levels relative to treatment response shows that the degree of decrease in both markers depends on maximum treatment response - respectively the attainment of a complete hematological remission. CONCLUSION: The results, although obtained from a limited set of patients, confirm a definitive benefit of the application of cardiac bio-markers assay in the diagnostic and therapeutic algorithm of AL amyloidosis patients. The Mayo stratification system utilizing the cardiac indicator values represents a robust tool for risk stratification of AL amyloidosis patients. PMID- 24073950 TI - [Assessment of selected markers of apoptosis and angiogenesis in chronic lymphocytic leukemia]. AB - INTRODUCTION: Search for new prognostic markers in order to improve prognostic accuracy and predict clinical outcome at the time of dia-gnosis has recently become one of the major trends in chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS, AIM OF STUDY: The aim of our study was assessment of selected markers of apoptosis and angiogenesis and their potential as new prognostic factors. We evaluated serum levels of tumor necrosis factor alpha (TNFalpha) and transforming growth factor beta 1 (TGFbeta1) using commercially available enzyme linked immunosorbent assay; furthermore, we quantified expression of type II receptor for transforming growth factor beta (TGFbetaRII) and type 2 receptor for fibroblast growth factor 2 (FGFR2) on CLL cells using flow cytometry analysis in 75 previously untreated patients with CLL (47 males and 28 females, median age, 65 years, range 38- 82) and healthy donors. RESULTS: We found significantly elevated TNFalpha in patients with CLL compared to the control group (p < 0.0001); high expression of TNFalpha was associated with unfavourable prognosis: significantly higher concentrations were found in patients with Rai highrisk group compared to low and intermediate-risk group (p = 0.0008 and p = 0.0097), with high serum beta2- microglobulin (p = 0.045), massive lymphadenopathy (p = 0.0083), unmutated genes for variable region of immunoglobulin heavy chain (IgVH) (p = 0.041) and unfavourable cytogenetic aberrations (p = 0.0014). In addition, patients with progressive CLL had significantly higher TNFalpha than those with stable clinical course (p = 0.0009); time to treatment was significantly shorter in patients with higher TNFalpha (p = 0.0049). Higher TGFbeta1 concentrations were associated with favourable subgroups: with Rai low risk group compared to high risk group (p = 0.011), patients without massive lymphadenopathy (p = 0.041), patients with mutated IgVH (p = 0.012) and ZAP 70 negativity (zeta associated protein of 70 kilodaltons) (p = 0.044). Patients with progressive CLL had significantly lower TGFbeta1 levels than those with stable course (p = 0.0014) and time to treatment was significantly longer in patients with higher TGFbeta1 (p = 0.016). Patients with Rai high risk group had significantly lower TGFbetaRII expression than those with low risk group (p = 0.022). The prognostic significance of FGFR2 was not found. Significant and independent prognostic factors for overall survival were high serum concentrations of TNFalpha and massive lymphadenopathy (p = 0.036, resp. p = 0.047). CONCLUSION: Based on our results, TNFalpha and TGFbeta1 possess prognostic significance in CLL; further research in this direction may also be important therapeutically, because these signal pathways could serve as possible treatment targets. PMID- 24073951 TI - [Compliance of senior / elderly patients with cognitive impairment]. AB - The contribution presents the results of investigation conducted at a department of the Longterm Care and Rehabilitation Centre of The Merciful Brothers Hospital in Brno. Altogether, 100 seniors were examined, 20 men and 80 women, with an average age of 81.6 +/- 6.88 years and an age range of 70 to 98 years. The wellknown and repeatedly demonstrated errors in the therapeutic regime of the patients, especially older seniors, compel us to focus our attention on consistent prevention of these situations. The present work summarises the knowledge about the diminished compliance of geriatric patients. It compares the mutual relationship of cognitive functions and the subjective and objective rates of the patients compliance regarding the taking of medicaments and observation of therapeutic recommendations. Key words: geriatric patient - compliance - testing of cognitive functions - dementia - pharmacotherapy in elderly. PMID- 24073952 TI - [RESOLUTE Study in the Czech Republic: insulin glargine improves the compensation of type 2 diabetes in patients with unsatisfactory results of therapy with a combination of insulin detemir and oral antidiabetics. Results of the nonintervention RESOLUTE Project in the Czech Republic]. AB - INTRODUCTION: The RESOLUTE was a multinational, non interventional, 6 month prospective observational project evaluating in clinical practice, whether patients with type 2 diabetes mellitus (T2DM) inadequately controlled with detemir in combination with oral antidiabetic drugs (OADs) may benefit from switching to glargine. In Czech Republic 200 patients, for whom the participating physician according to their own consideration, had decided to prescribe insulin glargine in replacement of insulin detemir, were included in this project. OBJECTIVES: The primary endpoint was to assess the change in HbA1c over the 6- month period in T2DM patients treated with insulin glargin after switch from insulin detemir. Secondary endpoints included the evaluation of the change in fasting plasma glucose, insulin dose, body weight over the 6-month period after starting insulin glargine , the evaluation of the number of hypoglycemia during the last month of therapy which each basal insulin and the frequency of adverse events (AE) during treatment with insulin glargine. RESULTS: Insulin glargine therapy resulted in a statistically significant improvement in compensation of diabetes characterized by a mean HbA1c decrease of about 0.82 (+/- 0.93) % (p < 0.001) and a mean decrease of recorded fasting glycemia about 1.91 (+/- 2.81) mmol/ l (p < 0.001). No significant change in the mean body weight was recorded du-ring study [+0.12 (+/- 2.98) kg; p = NS]. The mean daily insulin glargine dose used at the end of the observation increased in comparison with last mean daily dose of insulin detemir [+2.99 (+/- 7.54) U; p < 0.001]. The improvement in glycemic control was accompanied by low risk of hypoglycemia. The percentage of patients with documented symptomatic (5.0%), nocturnal (2.5%) and severe (0%) hypoglycemia in the last month of glargine therapy was consistently lower compared with the last month of previous treatment with detemir (14.6%, 9.5% and 2.5%, respectively). Other adverse events were reported in 3.0% of patients on glargine therapy. No adverse events were considered as adverse event related to insulin glargin treatment. No serious adverse or no serious adverse events leading to treatment discontinuation or death were documented during the course of the study. CONCLUSION: Under reallife conditions, switching from insulin detemir to once daily insulin glargine in poorly controlled T2DM patients resulted in clinically relevant improvements in glycemic control without an increase in weight and hypoglycemia risk. PMID- 24073953 TI - [Food intake regulation - 1st part]. AB - The review article summarizes a very complex process of appetite regulation: the part focused on homeostatic regulation of food intake. The aim of homeostatic regulation is to achieve energy balance, stabile weight and optimal nutrient intake, in contrast to hedonic regulation of food intake, in which emotional and motivational factors are involved. Homeostatic regulation could be divided into shortterm and longterm regulation and comprises mainly gastrointestinal peptides, fat tissue hormones and central mechanisms localized in hypothalamus. It is a resultant of the action of orexigenic factors (increasing appetite and food intake) and anorexigenic factors (decreasing appetite and thus food intake), respectively. The anorexigenic factors include gastrointestinal peptides (e.g. cholecystokinin, glucagonlike peptide 1, bombesin, peptide YY and others), hormone of fat tissue leptin and centrally acting melanocortin system. On the contrary, orexigenic factors comprise of gastric ghrelin and centrally acting system of neuropeptide Y/ Agoutirelated peptide. Understanding the principles of the regulation of food intake is essential for comprehension of pathogenesis of eating disorders and obesity, whose prevalence has been recently increasing, and it provides potential targets for pharmacological interventions. PMID- 24073954 TI - [Recommendation of the Czech Society of Endocrinology for the treatment of Cushing's syndrome in adults]. AB - Cushing's syndrome is a rare disorder with variable aetiology which is connected with significantly increased morbidity and mortality. Therefore, early determination of correct aetiology and early treatment are essential for a decrease of morbidity and mortality of patients. Present article introduces review and current recommendation of Czech Society of Endocrinology for the treatment of Cushings syndrome. PMID- 24073955 TI - [Cold agglutinin disease - no response to glucocorticoids and rituximab, what treatment is best for the 3rd line of therapy? Case report and review of the literature]. AB - Acquired autoimmune haemolytic anaemia is divided according to the characteristics of immunoglobulin causing haemolysis. The most frequent are haemolytic anaemia with thermal antibodies. They bind to erythrocytes and initiate their destruction in the reticuloendothelial system cells, leading to extravascular haemolysis. Cold agglutinin disease differs significantly from haemolytic anaemia with thermal antibodies. Agglutination is caused by monoclonal antibodies, in most cases class IgM and very rarely class IgG. Under cold conditions they bind to erythrocytes and cause their agglutination and subsequent disorder of blood circulation in body parts with a lower temperature. Agglutinins binding initiate the binding of the complement to the erythrocytes. Under warm conditions the binding becomes loose but the parts of the complement, which are already bound, cause haemolysis, which is mainly of an intravascular nature. The loose haemoglobin causes haemoglobinuria. Description of a patient with the disease. The 1st symptoms of the disease, i.e. anaemia + circulatory disorders in the acral parts of the body, disappearing under warm conditions followed with haemoglobinuria, led to the dia-gnosis of cold agglutinin disease. The 1st line treatment, prednison, did not show any response. The 2nd line treatment used was rituximab and dexametazon. Rituximab was administered in doses of 500 mg/ m2 to 4 times in a row in weekly intervals. Dexametazon was administered in doses of 40 mg from 1st to 4th day and from 15th to 18th day of the cycle. This treatment, however, did not show any response either. Therefore this article brings an overview of all publications regarding the disease treatment with the aim of choosing the most effective treatment options in the case of failure of the monotherapy using rituximab. The 1st line treatment for cold agglutinin disease is rituximab in monotherapy, usually administered once per week at least for 4 weeks. This treatment shows a response in about one half of treated patients and the remission duration median after rituximab administration is 11 months. A combination of rituximab with fludarabin was more effective, though more toxic; this combination, in a clinical study, led to 75% of patients responding to treatment, including 20% experiencing complete remission. The treatment response median reached over 66 months. In a small study (10 patients) an increase in the amount of rituximab administrations from 4 to 8 led to a treatment response in 6 patients in whom administration of 4 doses of rituximab had no response. When treating Waldenstrom macroglobulinemia, effectiveness of the following drugs and their combinations was proven: rituximab, chlorambucil, cyclophosphamide, fludarabin, bortezomib, lenalidomid, bendamustin and alemtuzumab. The same drugs and treatment procedures are used for the treatment of the cold agglutinin disease as for Waldenstrom macroglobulinemia. Successful treatment with vortezomibem, combinations of rituximab + bendamustin, rituximab + cyclophosphamide or rituximab + fludarabin + cyclophosphamide, were recorded in the form of a description as regards the cold agglutinin disease treatment. An important benefit is also shown through treatment with the monoclonal antibody antiC5, eculizumab, which is otherwise used for the treatment of paroxysmal nocturnal haemoglobinuria. Eculizumab blocks the C5 element of the component and thus stops haemolysis in a patient with cold agglutinin disease. As cold agglutinin disease is very rare, there are only a few clinical studies and when treating this rare disease we have no other option than to take into account the information contained in the descriptions of the particular cases of cold agglutinin disease and the experience of Waldenstrom macroglobulinemia disease treatment. The discussion seeks to solve the issue regarding what 3rd line treatment option to use in the described patient. PMID- 24073956 TI - [Regional migrating osteoporosis - a case report]. AB - Regional migrating osteoporosis (RMO) was observed in young man with episodes of bone pain in bearing joints, which migrated from hip to leg and subsequently to knee on the unilateral side. Dynamic scintigraphy (SPECT) carried out during relapse of pain demonstrated increased accumulation of radioizotope in Lisfrank joint, distal epiphysis of femur and proximal epiphysis of tibia on the unilateral side due to hyperperfusion and high metabolic turnover in these regions of the skeleton. Dia-gnosis of RMO was confirmed by magnetic resonance (MRI), which showed bone marrow edema of corresponding regions. Although RMO is relatively benign disease with spontaneous remissions, infection etiology or the more serious avascular necrosis should be taken into account. PMID- 24073959 TI - Change in mRNA expression of sirtuin 1 and sirtuin 3 in cats fed on high fat diet. AB - BACKGROUND: Mammalian sirtuins are homologs to the yeast silent information regulator 2 (Sir2), which is an NAD-dependent deacetylase. Sirtuins are comprised of 7 proteins, and each has different target proteins. Sirtuin 1 (SIRT1) plays important roles in maintaining metabolic functions and immune responses, and SIRT3 protects cells from oxidative stress-induced cell death. Both SIRT1 and SIRT3 are regulated by metabolic status and aging. Hence, SIRT1 and SIRT3 have been researched in metabolic diseases, such as type 2 diabetes mellitus (DM), fatty liver, and heart diseases. Although these diseases have been increasing, there is little information about relation between the diseases and SIRT1 and SIRT3 in cats. Therefore we cloned SIRT1 and SIRT3 cDNA, examined mRNA expression in cat tissues, and investigated the changes in SIRT1 and SIRT3 mRNA expression in peripheral blood leukocyte of cats fed on HFD for 6 weeks. RESULTS: Cat SIRT1 and SIRT3 contained a catalytic core region and showed high sequence homology with other vertebrate SIRT1 (>61.3%) and SIRT3 (>65.9%) amino acids. Real-time polymerase chain reaction analyses revealed that high expression levels were observed in the liver and skeletal muscle for SIRT1 and in the heart for SIRT3 in cats. In addition, both cat SIRT1 and SIRT3 expression levels in the pancreas were different between individuals. Cat SIRT1 mRNA expression in peripheral blood leukocytes was significantly elevated in obese cats fed on HFD (P < 0.05). CONCLUSIONS: Cat SIRT1 and SIRT3 genes are highly conserved among vertebrates, and HFD feeding may be related to SIRT1 mRNA expression mechanisms in cat peripheral blood leukocytes. PMID- 24073960 TI - Quantification of maternal offloading of organic contaminants in elasmobranchs using the histotrophic round stingray (Urobatis halleri) as a model. AB - Maternal offloading is one route by which young animals may accumulate persistent organic pollutants, such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs), but has not been well documented in elasmobranchs despite their propensity to accumulate high concentrations of contaminants. Using the round stingray (Urobatis halleri) as a coastal elasmobranch model, we examined maternal offloading processes at two stages in the stingray's entire reproductive cycle. Post-ovulated and near-term pregnant female stingrays were sampled from southern California, and organic contaminants were measured in the ova and embryonic tissues and compared to concentrations measured in corresponding female livers to determine route and extent of transfer. Total organic contaminant loads measured in ovulated eggs were about two times lower than loads measured in embryos (p < 0.001) indicating mothers have the ability to transfer contaminants throughout pregnancy. Contaminant loads measured in pups showed a positive relationship with mother's contaminant concentrations (p < 0.001); however, mothers offloaded relatively low percentages (1.5 +/- 1.7%) of their total contaminant load using contaminants measured in the liver as a proxy. However, histotrophy is only one form of supplemental provisioning utilized by elasmobranchs and variation in reproductive modes likely influences the extent to which female elasmobranchs may maternally offload contaminants. PMID- 24073961 TI - Coupled large amplitude motions: a case study of the dimethylbenzaldehyde isomers. AB - The microwave spectra of the 3,4- (syn and anti), 2,5- (syn), and 3,5 dimethylbenzaldehyde (DMBA) molecules have been recorded for the first time in the 2-26.5 GHz frequency range, using the high resolution COBRA-FTMW spectrometer in Hannover. The experimental assignments and fits are supplemented by ab initio quantum chemical calculations of the conformational energy landscape and dipole moment components. The analysis of the spectra of the four observed isomers, including spectroscopic constants and large amplitude motion parameters, are presented in this paper. The DMBA isomers belong to a series of similar molecules obtained formally by adding one or more methyl group(s) at the aromatic ring. These molecules serve as prototype systems for the development of the theoretical model of asymmetric top molecules having C(s) symmetry while containing in addition two nonequivalent methyl tops (C(3v)), exhibiting different barrier heights and coupling terms. Thus, the DMBA isomers represent good species for testing the recently written two-top internal rotors BELGI program. PMID- 24073963 TI - Comparison of macular and retinal nerve fiber layer thickness in untreated and treated binocular amblyopia. AB - PURPOSES: To identify morphological retinal relationships to visual acuity (VA), refraction and axial length in binocular hyperopic amblyopia. MATERIALS AND METHODS: Children (n = 118), ages 5-12 years, were divided into three groups: those with current amblyopia (n = 53), those with fully corrected previous amblyopia (n = 26) and those with emmetropia and normal VA (n = 39). Macular thickness and peripapillary retinal nerve fiber layer (RNFL) thickness were measured by optical coherence tomography (OCT) and compared among the three groups. RESULTS: The outer macular ring and RNFL of the current amblyopia group were significantly (independent t-test) thicker than those of the emmetropia group. However, significance of this difference disappeared after adjustment for axial length and refractive error. There was no significant difference in foveal or inner macular ring thickness among the three groups, either before or after adjustment for age, gender, axial length, and refractive error. When controlled for age, gender and VA, outer macular ring and RNFL thicknesses correlated with axial length (r = -0.350 and -0.334, respectively; p < 0.001) and refraction (r = 0.298 and -0.237, respectively; p <= 0.011). CONCLUSIONS: Macular and RNFL thicknesses appear to be more extensively associated with differences in axial length and refraction than with amblyopic development, based on the fact that these thicknesses remained unchanged after amblyopic treatment. PMID- 24073962 TI - Expression of activator protein-1 (AP-1) family members in breast cancer. AB - BACKGROUND: The activator protein-1 (AP-1) transcription factor is believed to be important in tumorigenesis and altered AP-1 activity was associated with cell transformation. We aimed to assess the potential role of AP-1 family members as novel biomarkers in breast cancer. METHODS: We studied the expression of AP-1 members at the mRNA level in 72 primary breast tumors and 37 adjacent non-tumor tissues and evaluated its correlation with clinicopathological parameters including estrogen receptor (ER), progesterone receptor (PR) and HER2/neu status. Expression levels of Ubiquitin C (UBC) were used for normalization. Protein expression of AP-1 members was assessed using Western blot analysis in a subset of tumors. We used student's t-test, one-way ANOVA, logistic regression and Pearson's correlation coefficient for statistical analyses. RESULTS: We found significant differences in the expression of AP-1 family members between tumor and adjacent non-tumor tissues for all AP-1 family members except Fos B. Fra-1, Fra-2, Jun-B and Jun-D mRNA levels were significantly higher in tumors compared to adjacent non-tumor tissues (p < 0.001), whilst c-Fos and c-Jun mRNA levels were significantly lower in tumors compared with adjacent non-tumor tissues (p < 0.001). In addition, Jun-B overexpression had outstanding discrimination ability to differentiate tumor tissues from adjacent non-tumor tissues as determined by ROC curve analysis. Moreover, Fra-1 was significantly overexpressed in the tumors biochemically classified as ERalpha negative (p = 0.012) and PR negative (p = 0.037). Interestingly, Fra-1 expression was significantly higher in triple negative tumors compared with luminal carcinomas (p = 0.01). CONCLUSIONS: Expression levels of Fra-1 and Jun-B might be possible biomarkers for prognosis of breast cancer. PMID- 24073964 TI - Carotenoid-rich dietary patterns during midlife and subsequent cognitive function. AB - Carotenoids may help to prevent the ageing of the brain. Previous findings regarding beta-carotene alone are not consistent. In the present study, we evaluated the cross-time association between a carotenoid-rich dietary pattern (CDP) and subsequent cognitive performance using a sample of 2983 middle-aged adults participating in the SU.VI.MAX (Supplementation en Vitamines et Mineraux Antioxydants) study. Cognitive performance was assessed in 2007-9 using six neuropsychological tests, and a composite cognitive score was computed. The cognitive data were related to dietary data obtained by repeated 24 h dietary records (1994-6) and to measurements of baseline plasma concentrations of carotenoids (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, trans-beta-carotene and cis-beta-carotene). DP were extracted using the reduced rank regression method for 381 participants and then extrapolated to the whole sample using plasma carotenoid concentrations as response variables. Associations between a CDP and cognitive function measured 13 years later were estimated with ANCOVA providing mean difference values and 95 % CI across the tertiles of CDP. A correlation between CDP and consumption of orange- and green-coloured fruits and vegetables, vegetable oils and soup was observed. CDP was found to be associated with a higher composite cognitive score (mean difference 1.04, 95 % CI 0.20, 1.87, P for trend 0.02), after adjustment for sociodemographic, lifestyle and health factors. Similar findings were obtained for scores obtained in the cued recall task, backward digit span task, trail making test and semantic fluency task (all P for trend < 0.05). Further studies ought to confirm whether a diet providing sufficient quantity and variety of coloured fruits and vegetables may contribute to the preservation of cognitive function during ageing. PMID- 24073965 TI - Chemical composition and bioactivity of essential oils of Hypericum helianthemoides, Hypericum perforatum and Hypericum scabrum. AB - CONTEXT: A number Hypericum species are well known for their therapeutic efficacy and use in traditional medicine. The various species of Hypericum have been traditionally used for the treatment of wounds, eczema, burns, trauma, rheumatism, neuralgia, gastroenteritis, ulcers, hysteria, bedwetting and depression. OBJECTIVE: This study evaluated the in vitro antioxidant, antibacterial and phytochemical properties of essential oils of Hypericum helianthemoides (Spach) Boiss., Hypericum perforatum L. and Hypericum scabrum L. (Hypericaceae) collected from alpine region of Southwest Iran. MATERIALS AND METHODS: The essential oils obtained from dried flowering aerial parts of three Hypericum species were analyzed by gas chromatography and gas chromatography/mass spectrometry to determine chemical compositions. The antibacterial activity of essential oils within concentration ranges from 16 to 500 ug/mL was individually evaluated against Bacillus cereus, Listeria monocytogenes. Proteus vulgaris and Salmonella typhimurium. The 1,1-diphenyl-2-picrilhydrazyl (DPPH) radical scavenging activity of essential oils was determined using DPPH assay. RESULTS: Essential oil yield of H. helianthemoides. H. scabrum and H. perforatum were 0.12, 0.20 and 0.21 mL/100 g dried material, respectively. The major constituents of the essential oils were alpha-pinene (12.52-49.96%), beta-pinene (6.34-9.70%), (E)-beta-ocimene (4.44-12.54%), beta-caryophyllene (1.19-5.67%), and germacrene-D (2.34-6.92%). The essential oils of three Hypericum species indicated moderate-to good inhibitory activities against four bacteria, especially against L. monocytogenes. DISCUSSION AND CONCLUSION: The essential oils of the three studied Hypericum species sourced in alpine region of West Iran were rich in monoterpene and sesquiterpenes hydrocarbons. Among the three tested species, the essential oil of H. scabrum showed the highest antibacterial and antioxidant activities. PMID- 24073966 TI - Preserving books by destroying them: a foray into digitization of a professional library. PMID- 24073967 TI - Can the Internet help people with cardiovascular disease? PMID- 24073968 TI - Current issues in managing men with lower urinary tract symptoms in primary care. PMID- 24073969 TI - Ramadan: type 2 diabetes and risk of hypoglycaemia. PMID- 24073970 TI - Vitamin D and cardiovascular disease - dilemma, delight or 'dont know?'. AB - The current lack of sufficient evidence of vitamin D's role in CVD calls for perspective and caution to avoid that health claims, vitamin D testing and supplementations' sales will continue to run well ahead of the scientific evidence. PMID- 24073971 TI - How to promote and support a culture of patient-centred openness and transparency in the NHS. AB - Low standards in the NHS have been put down to a failure to make patients the focus of care that is also transparent. This paper defines clinical transparency as explaining each decision by pointing to the diagnosis for that decision and justifying each diagnosis with the findings that support it. Such transparency can be put in writing in a summary that not only keeps patients and carers informed and reminded about what should be happening but also all the doctors, nurses and other health professionals looking after the patient in hospitals and in the community. Such transparency not only improves the quality of care but also its efficiency by avoiding costly delays and errors due to poor communication. PMID- 24073972 TI - Metabolic syndrome in normoglycaemic elderly men. AB - OBJECTIVE: Type-2 diabetes is mainly the metabolic defect involving multiple organs. To conclude their intricate relationships, the term 'ominous octet' had been proposed to denote this phenomenon. In this study, we enrolled older men without any medications for MetS components to further elucidate the relationships between normoglycaemic state and MetS. METHODS: We enrolled male subjects with FPG less than 100 mg/dl and aged 65 and older undergoing routine health check-ups in Taiwan. After excluding subjects taking medications that might affect the components of MetS, a total of 6679 men were eligible for the analysis. Study subjects were further grouped into FPG tertiles (< 91 mg/dl, 92 95 mg/dl and > 95 mg/dl for tertil 1, tertil 2 and tertil 3, respectively). RESULTS: There was a significant trend between the FPG and percentages of subjects having MetS (p = 0.009). The relationships between the MetS components were higher in FPG 2 and FPG 3 than FPG 1. In simple correlation, all of the MetS and LDL-C were positively correlated with FPG level and multiple regression further confirmed the same result except for HDL-C that became non-significant. Subjects in FPG3 had significantly higher ORs (ORs = 1.19) for having MetS than those in FPG1. CONCLUSIONS: In conclusion, higher FPG still had higher risk of having MetS in normoglycaemic range in elderly male. More strict FPG level control may be valuable in CVD prevention and warrants further investigations. PMID- 24073973 TI - Internet use in patients with cardiovascular diseases: Bad Berka Cross-Sectional Study (BABSY). AB - BACKGROUND: Internet has become a significant resource for dissemination of medical information. We sought to investigate prevalence and usage patterns of Internet access among consecutive patients with cardiovascular diseases. METHODS: A cross-sectional study was performed using a questionnaire as study tool. Among patients with Internet access, the type of health information sought and the impact of these on daily life were assessed. RESULTS: Of 1063 patients invited to the study, 1000 patients [68% male gender, mean age 66 +/- 11 years (range 27-83 years)] agreed to complete the questionnaire. 216/1000 (21.6%) used Internet to obtain information related to their disease. The patient education was graded as: low (15%), medium (66%) and high (19%). Reasons for Internet use were as follows: 24-h availability 142/216 (65.7%); free of charge 58/216 (26.9%); and anonymity 50/216 (23.2%). Younger (<= 66 years) age (35.2% vs. 15.3%; p = 0.0001), male gender (24.6% vs. 15.4%; p = 0.001) and higher education level (49.4% vs. 16.1%; p = 0.001) were significantly associated with Internet use. 30.6% (66/216) of Internet users changed their individual health behaviour attributable to information found on the Internet. However, this was not related to age, gender or level of education (p = 0.5, p = 0.6 and p = 0.4, respectively). Patients without Internet use obtain health information mainly from the pharmacist (62%) or from their treating physician (58%). CONCLUSIONS: A relevant number of patients with cardiovascular disease access the Internet for health information. The impact of such information on health-related behaviour in daily life was low. PMID- 24073974 TI - Comorbidities and personal burden of urgency urinary incontinence: a systematic review. AB - AIMS: Studies on the burden and comorbidities associated with urgency urinary incontinence (UUI) are difficult to compare, partly because of the evolution of definitions for lower urinary tract symptoms and the various instruments used to assess health-related quality of life (HRQL). This article summarises published evidence on comorbidities and the personal burden associated specifically with UUI to provide clinicians with a clear perspective on the impact of UUI on patients. METHODS: A PubMed search was conducted using the terms: (urgency urinary incontinence OR urge incontinence OR mixed incontinence OR overactive bladder) AND (burden OR quality of life OR well-being OR depression OR mental health OR sexual health OR comorbid), with limits for English-language articles published between 1991 and 2011. RESULTS: Of 1364 identified articles, data from 70 retained articles indicate that UUI is a bothersome condition that has a marked negative impact on HRQL, with the severity of UUI a predictor of HRQL. UUI is significantly associated with falls in elderly individuals, depression, urinary tract infections, increased body mass index, diabetes and deaths. The burden of UUI appears to be greater than that of stress urinary incontinence or overactive bladder symptoms without UUI. UUI adversely impacts physical and mental health, sexual function and work productivity. CONCLUSIONS: UUI is associated with numerous comorbid conditions and inflicts a substantial personal burden on many aspects of patients' lives. Healthcare providers should discuss UUI with patients and be aware of the impact of UUI and its associated comorbidities on patients' lives. PMID- 24073975 TI - Erectile function, erection hardness and tolerability in men treated with sildenafil 100 mg vs. 50 mg for erectile dysfunction. AB - AIM: To compare efficacy and tolerability between 100-mg and 50-mg sildenafil doses in five double-blind, placebo-controlled (DBPC) fixed-dose studies. METHODS: Doses were compared for the change (baseline to end of 8-12 weeks of DBPC treatment) in score on the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF; from five fixed-dose studies, > 1500 men); the per-patient estimated percentage of occasions that a specified Erection Hardness Score (EHS; from two of the five fixed-dose studies, > 500 men) was achieved, computed from logistic regression; the odds ratio (OR) of achieving EHS3 (hard enough for penetration, but not completely hard) and EHS4 (fully hard and completely rigid); and the adverse event incidence by treatment (from all five fixed-dose studies). RESULTS: For the 100-mg vs. 50-mg dose, IIEF-EF score improvement was consistently greater across the five studies and was statistically significant when data from two studies with similar design were pooled (10.7 +/- 0.64 vs. 8.9 +/- 0.83, p = 0.0287); and during the first 2 weeks of treatment, the odds of achieving EHS4 erections were almost doubled in one study (OR = 1.77, p = 0.0398). Sildenafil was generally well tolerated at either dose. CONCLUSION: Men with erectile dysfunction treated with 100-mg compared with 50-mg sildenafil may be more likely to achieve a greater improvement in erectile function and, within the first 2 weeks, completely hard and fully rigid erections, with little or no greater risk to tolerability. PMID- 24073976 TI - Evaluation of the pressure leak test in increasing the lifespan of flexible ureteroscopes. AB - INTRODUCTION: Flexible ureteroscopes are expensive and delicate instruments that are integral in the offering of a minimally invasive technique of diagnosis and treatment of urolithiasis. Published literature has identified the importance of early damage recognition in preventing frequent use of the scope that would lead to further damage and high repair and replacement costs. Our study was designed to examine the outcome of the pressure leak test on the condition of flexible ureteroscopes after every use and analysing the damage and costs of maintenance. PATIENTS AND METHODS: A prospective study was designed with two treatment groups. Group 1, 95 consecutive procedures (n = 95) of flexible ureterorenoscopy and laser fragmentation of renal calculi were performed with ACMI DUR 8, (a scope with no in-built leak test facility). This was compared against group 2, where 98 procedures of laser fragmentation of renal calculi (n = 98) were performed using Storz Flex X(2) Ureteroscopes (with a in-built leak test facility). All scopes in Group 2 were tested for pressure leak after every procedure and the outcome of the tests recorded. RESULTS: Both groups were comparable for grade of surgeon; stone location, size & number; access sheath usage and duration of lasering. In Group 1, there were seven scope damages resulting in repairs/replacement amounting to costs $46264.40 (7.1% damage). In Group 2, three scopes revealed a positive pressure leak test, implying damage with repair costs of $9952.80 (3.1% damage) (p < 0.05). Significant cost savings and reduction in downtime were made in Group 2. CONCLUSIONS: Pressure leak testing following flexible ureterorenoscopy helped to significantly control costs of maintenance and repair. Newer scopes should have a leak testing mechanism as it prevents further detrimental damage to the scope, build-up of repair costs are avoided and there is an increase in the longevity of these delicate instruments. PMID- 24073977 TI - Therapeutic outcome and quality of life between urethral and detrusor botulinum toxin treatment for patients with spinal cord lesions and detrusor sphincter dyssynergia. AB - AIMS: Patients with spinal cord lesions and detrusor sphincter dyssynergia (DSD) may be treated with urethral sphincter botulinum toxin A (BoNT-A) injection for difficult urination or detrusor BoNT-A injection for incontinence. Although objective data showed improvement, patients might not be satisfied with the result especially in quality of life (QOL) issue. This study investigated the therapeutic results and QOL and patients' satisfaction to these two treatments. PATIENTS AND METHODS: Patients with spinal cord lesion and DSD were treated with urethral sphincter injection of 100 U of BoNT-A for main symptoms of difficult urination and detrusor injection of 200 U of BoNT-A for main symptom of incontinence. The urodynamic parameters, QOL scores using UDI-6 and IIIQ-7 and general satisfaction were compared between two groups. RESULTS: The overall satisfactory result was perceived in 60.6% and 77.3% in patients who received urethral and detrusor BoNT-A injection, respectively. Urodynamic parameters showed significant improvement in both groups. Urethral injection group had improvement in IIQ-7, but not in UDI-6 scores whereas detrusor injection group had improvement in all scores. The improvement of UDI-6 and IIQ-7 was significantly greater in detrusor than urethral injection group. Increase in incontinence grade was the major cause of dissatisfaction in urethral injection group, whereas increase in difficult urination and needing catheterisation were the main dissatisfaction causes in detrusor injection group. CONCLUSION: There was discrepancy between the objective urodynamic results and patient satisfaction in treatment of DSD by BoNT-A injection. Patients with DSD and treated with detrusor BoNT-A had greater QOL improvement than those treated with urethral injection. PMID- 24073978 TI - Evaluation of an 8-item Severe Impairment Battery (SIB-8) vs. the full SIB in moderate to severe Alzheimer's disease patients participating in a donepezil study. AB - AIM: The Severe Impairment Battery (SIB), a reliable cognitive measure for evaluating treatment response in advanced Alzheimer's disease (AD), takes approximately 20 min to administer. A recently derived 8-item version of the SIB the SIB-8 - which takes about 3 min to administer, may represent a more convenient tool for use in clinical practice. The current analyses further explored the SIB-8 scale with respect to its validity and sensitivity. METHODS: A post hoc analysis was performed using data from a 24-week trial of donepezil 23 mg/day and 10 mg/day in > 1400 patients with moderate to severe AD [baseline Mini Mental State Examination (MMSE) score 0-20]. Treatment effects on cognition (patterns of score change) were assessed using the full SIB and SIB-8 in the total study population and subgroups based on concomitant memantine use and baseline MMSE. Internal consistency/agreement and correlations between the SIB and SIB-8 and other clinical end points were evaluated. RESULTS: Assessment of score changes from baseline to week 24 with donepezil (23 or 10 mg/day) demonstrated comparable patterns of change when using the SIB-8 and the full SIB, despite inherent differences in the total score ranges for the two scales. Internal consistency/agreement between the full SIB and SIB-8 was good (Cronbach's alphas: 0.77-0.95). SIB-8 scores reliably correlated with SIB total scores (r = 0.859, baseline; r = 0.900, week 24; p < 0.0001), as well as MMSE scores (r = 0.7163, baseline; r = 0.7963, week 24; p < 0.0001). Scores on both SIB scales were moderately associated with functional measures at baseline and week 24. CONCLUSIONS: In this post hoc analysis, similar treatment effects were measured by the full SIB and the SIB-8. Very good internal consistency/agreement and strong correlations between the SIB and the more rapid and convenient SIB-8 indicate that the SIB-8 may be a useful and efficient clinical proxy for the full SIB in evaluating treatment response in patients with advanced AD. PMID- 24073979 TI - Temporal trends in imaging and associated radiation exposure in inflammatory bowel disease. AB - OBJECTIVES: Increasing use of diagnostic imaging in inflammatory bowel disease (IBD) has led to concerns about the malignant potential of ionising radiation in a cohort that have an increased lifetime risk of gastrointestinal malignancy. The aim was to quantify radiation exposure in IBD patients referred from primary care, determine predictors of high exposure and evaluate temporal trends in diagnostic imaging over a 20-year period. METHODS: This was a retrospective cohort study whereby IBD patients were recruited from the outpatient clinic and evaluated retrospectively. The total cumulative effective dose (CED) received from tests was calculated for each subject. Cox regression was performed to assess factors associated with potentially harmful levels of ionising radiation defined as total CED > 50 milli-sieverts (mSv; equivalent to five CT abdomen scans). RESULTS: The cohort included 415 patients. Median total CED was 7.2 mSv (IQR: 3.0-22.7) in Crohn's disease and 2.8 mSv (IQR: 0.8-8.9) in ulcerative colitis patients, respectively. A total of 32 patients (8%) received a CED > 50 mSv. A history of IBD-related surgery was associated with high exposure (HR 7.7). During the study period, usage of abdominal CT increased by 310%. CONCLUSION: Approximately 1 in 13 patients in the study cohort were exposed to potentially harmful levels of ionising radiation. Strategies to minimise exposure to diagnostic medical radiation in IBD patients are required. PMID- 24073980 TI - The role of angiotensin II type 1 receptor-activating antibodies in patients with lupus nephritis. PMID- 24073981 TI - Acute confusional migraine and transient global amnesia: variants of cognitive migraine? PMID- 24073983 TI - Understanding the market dynamics associated with new payment models emerging from health reform-lessons from postacute care payment changes. PMID- 24073982 TI - Undifferentiated embryonal sarcoma of the liver in a middle-aged adult with systemic lupus erythematosus. AB - Adult primary undifferentiated embryonal sarcoma of the liver (UESL) is a rare disease. While the etiology of UESL remains largely unknown, association with systemic inflammatory disorders has been observed. Here, we report a case of UESL in a 46-year-old woman with systemic lupus erythematosus (SLE) and without chronic hepatitis or liver cirrhosis. Systematic review of the publicly available English language medical literature identified only 27 cases of UESL in patients aged >45 years and none with SLE. Our patient presented with abdominal pain and had a 2-year history of SLE. Abdominal ultrasonography and enhanced computed tomography revealed a solid mass in the right lobe of the liver. Presumptive diagnosis of atypical hepatocellular carcinoma was made and the patient was treated with segmentectomy of S5 and S4a and cholecystectomy. The final diagnosis of UESL was made according to the pathology results. Since SLE patients may be at increased risk of malignancy, it is possible that the SLE pathogenesis may have contributed to the development of UESL in our patient. According to this case, UESL should be considered when SLE patients present with hepatic space-occupying lesions. PMID- 24073984 TI - Potential value of targeting von Willebrand factor in atherosclerotic cardiovascular disease. AB - INTRODUCTION: Animal studies show that von Willebrand factor (vWF) deficiency is associated with lower risks for atherosclerosis and atherothrombosis, including events such as acute myocardial infarction and ischemic stroke. vWF enables the binding of platelets along the damaged vessels leading to thrombogenesis. Interruption of this early stage of thrombus formation may prevent downstream amplification of the inflammatory and thrombotic processes that contribute to the plaque instability. AREAS COVERED: Increased levels of vWF have been related to the atherothrombotic complications and endothelial damage. Therefore, vWF has been suggested as a useful biomarker of endothelial damage/dysfunction. Preliminary data from Phase II trials in patients with acute myocardial infarction and thrombotic disorders have been promising, but many unanswered questions remain regarding the optimal therapeutic use of vWF blockade. This article describes the molecular structure of vWF, its functions and its interactions with the platelet membrane glycoprotein (GP) receptors GPIb and GPIIb-IIIa, as well as collagen. In addition, the article provides an overview of most promising investigational compounds tested as antithrombotic agents targeting vWF. METHODS: Preclinical and clinical data for vWF blockage are discussed. EXPERT OPINION: The therapeutic approaches aiming to block the collagen-vWF-platelet axis have potentially beneficial effects for prevention and treatment of cardiovascular disease. However, the evidence directly associating vWF blockage with beneficial clinical outcomes is limited and needs further research. Optimal treatment regimes need to be established in relation of specific clinical circumstances and conditions. PMID- 24073985 TI - CAM use among overweight and obese persons with radiographic knee osteoarthritis. AB - BACKGROUND: Obesity is associated with knee pain and is an independent predictor of incident knee osteoarthritis (OA); increased pain with movement often leads patients to adopt sedentary lifestyles to avoid pain. Detailed descriptions of pain management strategies by body mass index (BMI) level among OA patients are lacking. The objectives were to describe complementary and alternative medicine (CAM) and conventional medication use by BMI level and identify correlates of CAM use by BMI level. METHODS: Using Osteoarthritis Initiative baseline data, 2,675 patients with radiographic tibiofemoral OA in at least one knee were identified. Use of CAM therapies and conventional medications was determined by interviewers. Potential correlates included SF-12, CES-D, Western Ontario and McMaster Universities Osteoarthritis Index, and Knee injury and Osteoarthritis Outcome Score quality of life. Multinomial logistic regression models adjusting for sociodemographic and clinical factors provided estimates of the association between BMI levels and treatment use; binary logistic regression identified correlates of CAM use. RESULTS: BMI was inversely associated with CAM use (45% users had BMI >=35 kg/m2; 54% had BMI <25 kg/m2), but positively associated with conventional medication use (54% users had BMI >=35 kg/m2; 35.1% had BMI <25 kg/m2). Those with BMI >=30 kg/m2 were less likely to use CAM alone or in combination with conventional medications when compared to patients with BMI <25 kg/m2. CONCLUSIONS: CAM use is common among people with knee OA but is inversely associated with BMI. Understanding ways to further symptom management in OA among overweight and obese patients is warranted. PMID- 24073986 TI - Novel selective and potent inhibitors of malaria parasite dihydroorotate dehydrogenase: discovery and optimization of dihydrothiophenone derivatives. AB - Taking the emergence of drug resistance and lack of effective antimalarial vaccines into consideration, it is of significant importance to develop novel antimalarial agents for the treatment of malaria. Herein, we elucidated the discovery and structure-activity relationships of a series of dihydrothiophenone derivatives as novel specific inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). The most promising compound, 50, selectively inhibited PfDHODH (IC50 = 6 nM, with >14,000-fold species-selectivity over hDHODH) and parasite growth in vitro (IC50 = 15 and 18 nM against 3D7 and Dd2 cells, respectively). Moreover, an oral bioavailability of 40% for compound 50 was determined from in vivo pharmacokinetic studies. These results further indicate that PfDHODH is an effective target for antimalarial chemotherapy, and the novel scaffolds reported in this work might lead to the discovery of new antimalarial agents. PMID- 24073987 TI - Electronic waste disassembly with industrial waste heat. AB - Waste printed circuit boards (WPCBs) are resource-rich but hazardous, demanding innovative strategies for post-consumer collection, recycling, and mining for economically precious constituents. A novel technology for disassembling electronic components from WPCBs is proposed, using hot air to melt solders and to separate the components and base boards. An automatic heated-air disassembling equipment was designed to operate at a heating source temperature at a maximum of 260 degrees C and an inlet pressure of 0.5 MPa. A total of 13 individual WPCBs were subjected to disassembling tests at different preheat temperatures in increments of 20 degrees C between 80 and 160 degrees C, heating source temperatures ranging from 220 to 300 degrees C in increments of 20 degrees C, and incubation periods of 1, 2, 4, 6, or 8 min. For each experimental treatment, the disassembly efficiency was calculated as the ratio of electronic components released from the board to the total number of its original components. The optimal preheat temperature, heating source temperature, and incubation period to disassemble intact components were 120 degrees C, 260 degrees C, and 2 min, respectively. The disassembly rate of small surface mount components (side length <= 3 mm) was 40-50% lower than that of other surface mount components and pin through hole components. On the basis of these results, a reproducible and sustainable industrial ecological protocol using steam produced by industrial exhaust heat coupled to electronic-waste recycling is proposed, providing an efficient, promising, and green method for both electronic component recovery and industrial exhaust heat reutilization. PMID- 24073988 TI - Redox-controlled polymerization of lactide catalyzed by bis(imino)pyridine iron bis(alkoxide) complexes. AB - Bis(imino)pyridine iron bis(alkoxide) complexes have been synthesized and utilized in the polymerization of (rac)-lactide. The activities of the catalysts were particularly sensitive to the identity of the initiating alkoxide with more electron-donating alkoxides resulting in faster polymerization rates. The reaction displayed characteristics of a living polymerization with production of polymers that exhibited low molecular weight distributions, linear relationships between molecular weight and conversion, and polymer growth observed for up to fifteen sequential additions of lactide monomer to the polymerization reaction. Mechanistic experiments revealed that iron bis(aryloxide) catalysts initiate polymerization with one alkoxide ligand, while iron bis(alkylalkoxide) catalysts initiate polymerization with both alkoxide ligands. Oxidation of an iron(II) catalyst precursor lead to a cationic iron(III) bis-alkoxide complex that was completely inactive toward lactide polymerization. When redox reactions were carried out during lactide polymerization, catalysis could be switched off and turned back on upon oxidation and reduction of the iron catalyst, respectively. PMID- 24073991 TI - Determinants of child malnutrition in rural and urban Ecuadorian highlands. AB - OBJECTIVE: To identify and compare the sociodemographic determinants of stunting, wasting and overweight among infants of urban and rural areas in the Ecuadorian highlands. DESIGN: Cross-sectional study. SETTING: Nabon (rural) and Cuenca (urban) cantons, Azuay Province, Ecuador. SUBJECTS: A total of 703 children aged 0-24 months and their caregivers (227 rural and 476 urban) recruited during the period from June to September 2008. RESULTS: Stunting prevalence was significantly higher in the rural area (37.4 % v. 17.7 %; P < 0.001) while wasting (7.1 %) and overweight (17.1 %) prevalence were more similar between areas. Determinants of stunting for the pooled sample were male gender (OR = 1.43; 95 % CI 1.06, 1.92; P = 0.02), preterm delivery (OR = 1.65; 95 % CI 1.14, 2.38; P = 0.008), child's age (OR = 1.04; 95 % CI 1.01, 1.07; P = 0.011), maternal education (OR = 0.95; 95 % CI 0.92, 0.99; P = 0.025) and facility-based delivery (OR = 0.57; 95 % CI 0.45, 0.74; P < 0.001). The latter was also a determinant of overweight (OR = 0.39; 95 % CI 0.25, 0.62; P < 0.001). Rural determinants of stunting were maternal height (OR = 0.004; 95 % CI 0.00004, 0.39; P = 0.018), diarrhoea prevalence (OR = 2.18; 95 % CI 1.13, 4.21; P = 0.02), socio economic status (OR = 0.79; 95 % CI 0.64, 0.98; P = 0.030) and child's age (OR = 1.07; 95 % CI 1.02, 1.11; P = 0.005). Urban determinants were: maternal BMI for stunting (OR = 0.91; 95 % CI 0.84, 0.99; P = 0.027), cough prevalence (OR = 0.57; 95 % CI 0.34, 0.96; P = 0.036) and facility-based delivery (OR = 0.25; 95 % CI 0.09, 0.73; P = 0.011) for overweight, and hygiene for wasting (OR = 0.57; 95 % CI 0.36, 0.89; P = 0.013). CONCLUSIONS: Infant malnutrition was associated with different sociodemographic determinants between urban and rural areas in the Ecuadorian highlands, a finding which contributes to prioritize the determinants to be assessed in nutritional interventions. PMID- 24073992 TI - New functional aspects of the atypical protein tyrosine phosphatase VHZ. AB - LDP3 (VHZ) is the smallest classical protein tyrosine phosphatase (PTP) known to date and was originally misclassified as an atypical dual-specificity phosphatase. Kinetic isotope effects with steady-state and pre-steady-state kinetics of VHZ and mutants with p-nitrophenol phosphate have revealed several unusual properties. VHZ is significantly more active than previously reported but remains one of the least active PTPs. Highly unusual for a PTP, VHZ possesses two acidic residues (E134 and D65) in the active site. D65 occupies the position corresponding to the typical general acid in the PTP family. However, VHZ primarily utilizes E134 as the general acid, with D65 taking over this role when E134 is mutated. This unusual behavior is facilitated by two coexisting, but unequally populated, substrate binding modes. Unlike most classical PTPs, VHZ exhibits phosphotransferase activity. Despite the presence of the Q-loop that normally prevents alcoholysis of the phosphoenzyme intermediate in other classical PTPs, VHZ readily phosphorylates ethylene glycol. Although mutations of Q-loop residues affect this phosphotransferase activity, mutations on the IPD loop that contains the general acid exert more control over this process. A single P68V substitution on this loop completely abolishes phosphotransferase activity. The ability of native VHZ to catalyze transphosphorylation may lead to an imbalance of intracellular phosphorylation, which could explain the correlation of its overexpression with several types of cancer. PMID- 24073993 TI - The relationship between C-reactive protein and prognostic factors in chronic obstructive pulmonary disease. AB - BACKGROUND: The purpose of the study was to determine the relationship between high sensitivity C-reactive protein (hs-CRP) levels and prognostic factors in chronic obstructive pulmonary disease. METHODS: We studied 50 stable COPD patients with: spirometry, 6 minute walk distance, body mass index, GOLD stage (spirometric classification) and smoking status. In these patients hs-CRP values were measured and compared with those of 50 healthy controls. Then the serum hs CRP was subjected to evaluation for any correlation with the predictors of outcomes in COPD subjects. RESULTS: Hs-CRP levels were higher in COPD patients than in controls (4.82 vs. 0.88 mg/L p < 0.01). Correlation was found between hs CRP and the following variables: FEV1 (r= -0.813; p < 0.01), 6MWD (r= -0.876; p < 0.01), body mass index (r= -0.710; p < 0.01), GOLD stage (r= 0.797, p < 0.01) and smoking status (r= 0.796; p < 0.01). Using multivariate analysis, FEV1 and 6MWD showed the strongest negative association with hs-CRP levels. CONCLUSIONS: The circulating levels of the inflammatory marker hs-CRP are significantly elevated in patients with COPD, supporting the view that COPD is in part an inflammatory disorder. Hs-CRP levels in stable COPD patients are best correlated with FEV1 and 6-minute walk distance (6MWD). This information should be considered when hs-CRP levels are measured in stable COPD patients. PMID- 24073994 TI - Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype. AB - BACKGROUND: Klippel-Feil syndrome (KFS) is characterized by the developmental failure of the cervical spine and has two dominantly inherited subtypes. Affected individuals who are the children of a consanguineous marriage are extremely rare in the medical literature, but the gene responsible for this recessive trait subtype of KFS has recently been reported. RESULTS: We identified a family with the KFS phenotype in which their parents have a consanguineous marriage. Radiological examinations revealed that they carry fusion defects and numerical abnormalities in the cervical spine, scoliosis, malformations of the cranial base, and Sprengel's deformity. We applied whole genome linkage and whole-exome sequencing analysis to identify the chromosomal locus and gene mutated in this family. Whole genome linkage analysis revealed a significant linkage to chromosome 17q12-q33 with a LOD score of 4.2. Exome sequencing identified the G > A p.Q84X mutation in the MEOX1 gene, which is segregated based on pedigree status. Homozygous MEOX1 mutations have reportedly caused a similar phenotype in knockout mice. CONCLUSIONS: Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait. Together with another recently reported study and the knockout mouse model, our results suggest that mutations in MEOX1 cause a recessive KFS phenotype in humans. PMID- 24073995 TI - Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52 week CANTATA-M study. AB - OBJECTIVE: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for treatment of type 2 diabetes mellitus (T2DM). The long-term efficacy and safety of canagliflozin monotherapy were evaluated over 52 weeks in patients with T2DM inadequately controlled with diet and exercise. RESEARCH DESIGN AND METHODS: This randomized, double-blind, Phase 3 study included a placebo-controlled, 26 week core period (canagliflozin 100 or 300 mg vs placebo) and an active controlled, 26-week extension (blinded switch of placebo-treated patients to sitagliptin 100 mg [placebo/sitagliptin]). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834. MAIN OUTCOME MEASURES: Efficacy endpoints assessed at 52 weeks included changes in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and systolic blood pressure (BP); and percentage changes in body weight and fasting plasma lipids. Adverse events (AEs) were recorded throughout the study. Efficacy data are reported for canagliflozin 100 and 300 mg (placebo/sitagliptin group was used to maintain the double-blind and to serve as a control group for safety purposes; not as an efficacy comparator); safety data are reported for canagliflozin 100 and 300 mg and placebo/sitagliptin. RESULTS: Efficacy analyses included 451 patients who were randomized and dosed, entered the extension, and did not receive rescue therapy during the core period. Safety analyses included 584 patients who were randomized and dosed. At Week 52, canagliflozin 100 and 300 mg provided dose-related decreases from baseline in HbA1c of -0.81% and -1.11%. Canagliflozin 100 and 300 mg decreased FPG (-1.5 and 2.2 mmol/L [-27.4 and -39.1 mg/dL]), body weight (-3.3% and -4.4%), and systolic BP (-1.4 and -3.9 mmHg); decreased triglycerides and increased HDL-C and LDL-C were also seen. Over 52 weeks, overall AE rates were 67.2%, 66.0%, and 64.1% with canagliflozin 100 and 300 mg and placebo/sitagliptin; rates of serious AEs and AE related discontinuations were low across groups. Compared with placebo/sitagliptin, canagliflozin was associated with higher rates of genital mycotic infections and AEs related to osmotic diuresis; these led to few discontinuations. Rates of volume depletion AEs and documented hypoglycemia were low across groups. CONCLUSIONS: Canagliflozin monotherapy provided sustained improvement in glycemic control and body weight reduction, and was generally well tolerated in patients with T2DM over 52 weeks. PMID- 24073999 TI - Emerging BRAF inhibitors for melanoma. AB - INTRODUCTION: The clinical activity of BRAF inhibitor (BRAF-I) therapy is a major breakthrough in the treatment of metastatic melanoma carrying BRAF mutations. However, the therapeutic efficacy of BRAF-I therapy is limited due to the onset of intrinsic and acquired drug resistance. AREAS COVERED: The role of wild-type BRAF in melanocytes and of the mutated BRAF in the pathogenesis of melanoma is described in this article. The results obtained with BRAF-I in patients with mutated BRAF are reviewed. The mechanisms driving the intrinsic and acquired BRAF I resistance, the development of combinatorial strategies designed to overcome them and their potential limitations are discussed. Lastly, the many questions that have to be addressed to optimize therapy with BRAF-I are listed. EXPERT OPINION: Melanoma is an aggressive form of skin cancer characterized by poor prognosis and high mortality. The discovery of BRAF mutations which drive melanoma tumorigenesis and the development of agents which selectively inhibit mutant-activated BRAF represent a major breakthrough in the treatment of metastatic melanoma. However, the development of drug resistance underlies the need of more effective and individualized combinatorial treatments to counteract the multiple escape mechanisms utilized by BRAF-mutant melanoma. Although combinatorial strategies using agents which target different protumorigenic signaling pathway components have been shown to increase the clinical efficacy of BRAF-I, novel strategies which utilize different antitumor mechanisms are needed. PMID- 24074000 TI - Are schools able to improve the physical fitness of children and adolescents? PMID- 24074001 TI - A R54L mutation of CRYAA associated with autosomal dominant nuclear cataracts in a Chinese family. AB - PURPOSE: To identify the genetic defect in a three-generation Chinese family with congenital cataracts. METHODS: The phenotype of a three-generation Chinese family with congenital cataract was recruited. Detailed family history and clinical data of the family were recorded. Candidate genes sequencing was performed to screen out the disease-causing mutation. Bioinformatics analysis was performed to predict the function of mutant gene. RESULTS: The phenotype of the family was identified as nuclear cataract. Direct sequencing revealed a c.161 G > T transversion in exon 1 of crystallin alpha-A (CRYAA). This mutation co-segregated with all affected individuals in the family and was not found in unaffected family members nor in the 100 unrelated controls. Bioinformatics analysis indicated that the 54th amino acid position was highly conserved and the mutation R54L caused an increase of local hydrophobicity around the substitution site. CONCLUSIONS: This study identified a novel disease-causing mutation c.161 G > T (p.R54L) in CRYAA in a Chinese family with autosomal dominant nuclear cataracts, this is the first report relating a G > T mutation in CRYAA leading to congenital nuclear cataract. PMID- 24074002 TI - Luteolin supplementation modulates mammary tumor growth in C3H mice fed diet with high- and low-fat content. AB - In this study we investigated the effects of luteolin supplementation (0.05% w/w) on mammary tumor growth in C3H mice, a strain of mouse mammary tumor virus negative, fed either high-fat (45% fat of energy) or low-fat diet (15% fat of energy). Animals (n = 12/group) were allocated into 4 experimental groups (low fat diet, low-fat diet + luteolin supplementation, high-fat diet, high-fat diet + luteolin supplementation). Experimental diet were fed for 13 wk and 7,12 dimethylbenz[a]anthracene was administered once a week for 6 wk starting at Week 1 to induce mammary tumors. Study results showed that animals on low-fat diet supplemented with luteolin exhibited longer tumor latency and lower tumor weights and sizes compared to the other groups. Animals fed high-fat diet showed increased serum IGF-1 levels and the elevated mammary tissue expression of Ki-67, IRS-1, pp38, Cdk4, and Cdk6. Luteolin inhibited IRS-1, Cdk4, and Cdk6 expression in high-fat fed animals. The expression of pp38, cyclinD1, and Bcl-xL was suppressed by luteolin supplementation both in the low-fat and high-fat diet groups. These results suggest that excess energy supply increases the risk of mammary tumor formation and luteolin suppresses tumor formation regardless of dietary fat content through its cell cycle regulatory and proapoptotic activity. PMID- 24074003 TI - An online survey of horse-owners in Great Britain. AB - BACKGROUND: Contingency planning for potential equine infectious disease outbreaks relies on accurate information on horse location and movements to estimate the risk of dissemination of disease(s). An online questionnaire was used to obtain unique information linking owner and horse location to characteristics of horse movements within and outwith Great Britain (GB). RESULTS: This online survey yielded a strong response, providing more than four times the target number of respondents (1000 target respondents) living in all parts of GB. Key demographic findings of this study indicated that horses which were kept on livery yards and riding schools were likely to be found in urban environments, some distance away from the owner's home and vaccinated against influenza and herpes virus. Survey respondents were likely to travel greater than 10 miles to attend activities such as eventing or endurance but were also likely to travel and return home within a single day (58.6%, 2063/3522). This may affect the geographical extent and speed of disease spread, if large numbers of people from disparate parts of the country are attending the same event and the disease agent is highly infectious or virulent. The greatest risk for disease introduction and spread may be represented by a small proportion of people who import or travel internationally with their horses. These respondents were likely to have foreign horse passports, which were not necessarily recorded in the National Equine Database (NED), making the location of these horses untraceable. CONCLUSIONS: These results illustrate the difficulties which exist with national GB horse traceability despite the existence of the NED and the horse passport system. This study also demonstrates that an online approach could be adopted to obtain important demographic data on GB horse owners on a more routine and frequent basis to inform decisions or policy pertaining to equine disease control. This represents a reasonable alternative to collection of GB horse location and movement data given that the NED no longer exists and there is no immediate plan to replace it. PMID- 24074004 TI - Low-cost label-free electrical detection of artificial DNA nanostructures using solution-processed oxide thin-film transistors. AB - A high-sensitivity, label-free method for detecting deoxyribonucleic acid (DNA) using solution-processed oxide thin-film transistors (TFTs) was developed. Double crossover (DX) DNA nanostructures with different concentrations of divalent Cu ion (Cu(2+)) were immobilized on an In-Ga-Zn-O (IGZO) back-channel surface, which changed the electrical performance of the IGZO TFTs. The detection mechanism of the IGZO TFT-based DNA biosensor is attributed to electron trapping and electrostatic interactions caused by negatively charged phosphate groups on the DNA backbone. Furthermore, Cu(2+) in DX DNA nanostructures generates a current path when a gate bias is applied. The direct effect on the electrical response implies that solution-processed IGZO TFTs could be used to realize low-cost and high-sensitivity DNA biosensors. PMID- 24074005 TI - Atypical X-linked agammaglobulinaemia caused by a novel BTK mutation in a selective immunoglobulin M deficiency patient. AB - BACKGROUND: X-linked agammaglobulinaemia (XLA) is the most common inherited humoural immunodeficiency disorder. Mutations in the gene coding for Bruton's tyrosine kinase (BTK) have been identified as the cause of XLA. Most affected patients exhibit a marked reduction of serum immunoglobulins, mature B cells, and an increased susceptibility to recurrent bacterial infections. However, the diagnosis of XLA can be a challenge in certain patients who have near-normal levels of serum immunoglobulin. Furthermore, reports on XLA with renal involvement are scant. CASE PRESENTATION: We report an atypical XLA patient who presented with selective immunoglobulin M (IgM) immunodeficiency and nephropathy. He was diagnosed with selective IgM immunodeficiency, based on his normal serum immunoglobulin G (IgG) and immunoglobulin A (IgA) levels but undetectable serum IgM level. Intravenous immunoglobulin was initiated due to increased infections and persistent proteinuria but no improvement in proteinuria was found. A lupus like nephritis was detected in his kidney biopsy and the proteinuria subsided after receiving a mycophenolate mofetil regimen. Although he had a history of recurrent bacterial infections since childhood, XLA was not diagnosed until B lymphocyte surface antigen studies and a genetic analysis were conducted. CONCLUSIONS: We suggest that B-lymphocyte surface antigen studies and a BTK mutation analysis should be performed in familial patients with selective IgM deficiency to rule out atypical XLA. PMID- 24074006 TI - Web-based survey to assess the perceptions of managed care organization representatives on use of copay subsidy coupons for prescription drugs. AB - BACKGROUND: Promotion of prescription drug coupons and vouchers by pharmaceutical manufacturers has increased in recent years. These coupons and vouchers usually subsidize patients' cost-sharing obligations. In other words, drug companies pay for a patient's portion of the drug cost, and the remaining cost is paid by the patient and the patient's health plan. This practice is normally used for brand name drugs but can and has been used for generic drugs. Copayments (also known as copays), and especially high copays for higher cost drugs, are used by managed care organizations (MCOs) to place a higher financial burden on patients and also provide an appreciation of the medication cost. At the same time, tiered copay plans offer incentives, in the form of lower copays, to use available equivalent generic alternatives or lower cost brand name drugs, instead of high cost brand name drugs. With higher tiered copays for brand name drugs being offset by coupons, little is known about MCO representatives' perceptions about the use of copay subsidy coupons for brand name prescription drugs. OBJECTIVE: To assess health plan managers' and pharmacy benefit managers' (PBMs) perceptions about the use of prescription drug copay subsidy coupons. METHODS: A 28-item online survey instrument was used to collect data from health plan and PBM representatives. A sample of 834 MCO representatives was selected from the Academy of Managed Care Pharmacy membership directory. Pharmacists, managers, directors, and executive officers working in pharmacy, formulary, and clinical pharmacy operations were selected for the survey. Respondents from non-MCO settings and government sponsored health plans were excluded from the survey. RESULTS: A total of 122 surveys were returned after 3 emails (i.e., an invitation and 2 reminder emails) of which 105 were usable surveys, giving a response rate of 13.7%. A 5-point, 11 item Likert scale (1 = Strongly Disagree and 5 = Strongly Agree) was used to measure respondents' perceptions toward prescription drug coupons. Some items referred to coupons used repeatedly over a year to get copay discounts (i.e., long-term use coupons) whereas some items referred to coupons distributed for trial purposes (i.e., short-term use coupons). Of the 105 respondents, 100 (95.2%) agreed that copay subsidy coupons encouraged nonpreferred brand name drugs over preferred brand name drugs. A total of 102 (97.2%) respondents agreed that brand name drug coupons undermined tiered formulary structure. Ninety-two (87.6%) respondents agreed that short-term use coupons increased plan sponsor's costs while 96 (91.5%) respondents agreed that sponsor cost increased with long term use coupons. A total of 68 (64.8%) agreed that short-term use coupons should be eliminated whereas 78 (74.3%) respondents agreed that long-term use coupons should be eliminated. CONCLUSION: Among MCOs' many business activities are efforts to contain rising pharmacy costs. The results of this survey indicate that MCO representatives believe that incentive programs such as prescription drug coupons and vouchers lead to an increase in brand name drug utilization, which undermines their formulary controls and, in turn, can be expected to increase overall health care costs. PMID- 24074007 TI - Medical claim cost impact of improved diabetes control for medicare and commercially insured patients with type 2 diabetes. AB - BACKGROUND: Diabetes prevalence is increasing in the United States, yet the control of critical clinical metrics (e.g., hemoglobin A1c [A1c], blood pressure, and lipids) remains suboptimal. Lower A1c levels have been shown to be associated with lower diabetes complication rates, and reduced medical costs have been reported in individuals with diabetes who have improved glycemic control. While many studies have quantified the impact of A1c control on medical claim costs, this article provides new information on the cost and event impact of better control for all 3 metrics for the commercial population and Medicare population separately. OBJECTIVES: To (a) quantify current type 2 diabetes control rates for A1c, blood pressure, and lipids and (b) model the impact of scenarios for better control of these metrics on diabetes complication rates and complication costs in people with diabetes in commercially insured and Medicare populations. METHODS: 858 adults with commercial (n = 392) or Medicare (n = 466) coverage and type 2 diabetes were identified from approximately 10,000 individuals in the National Health and Nutrition Examination Survey (NHANES; combined series 2005-2006 and 2007-2008). Based on each individual's risk factors, the United Kingdom Prospective Diabetes Study modeling tool was used to project rates of 7 diabetes complications under status quo A1c, blood pressure, and lipid levels and complication rates under better management. Three improved management scenarios were created to model the impact of better control in all commercially insured and Medicare individuals with type 2 diabetes who had A1c, blood pressure, or lipids not at goal and in a subset of individuals whose A1c levels were >= 7%, with or without blood pressure or lipids not at goal. Thomson Reuters MarketScan Commercial Claims and Encounters Database (2006-2009) and Medicare 5% sample data (2006-2009), including the eligibility data for each, were used to develop both the average annual costs and per-patient-per-month (PPPM) costs, adjusted to 2012 dollars, in commercially insured and Medicare fee-for-service patients with diabetes and the cost of diabetes-related complications to monetize the impact of reducing complications. RESULTS: Analysis of NHANES data showed that type 2 diabetes prevalence is 6.1% in commercially insured individuals aged 20 to 64 years and 19.4% in Medicare beneficiaries aged 65 years and older. Of patients with type 2 diabetes, 47% of commercially insured patients and 38% of Medicare patients were found to have A1c >= 7%. With improved control of A1c, blood pressure, and lipid levels that were not at goal, as modeled in 3 management scenarios, reductions in the probability of complications across all patients with diabetes ranged from 43% to 67% in the commercial population and 28% to 49% in the Medicare population. The cost savings effect from reduced complications across all patients with diabetes ranged from $67 to $105 PPPM in the commercial population and $99 to $158 in the Medicare population. The high end of this savings range yielded a reduction of about 10% in total costs when compared with an average of $1,090 PPPM in commercially insured patients with diabetes and an average of $1,565 PPPM in Medicare patients with diabetes derived from large claims databases, both in projected 2012 dollars. CONCLUSION: Results of this analysis suggest that better control of A1c, blood pressure, and lipids is associated with savings opportunities in commercially insured and Medicare patients with type 2 diabetes. A focus on only patients with uncontrolled A1c offers a somewhat higher per-patient cost reduction than for all uncontrolled diabetes patients but greatly diminishes the number of targeted patients. PMID- 24074008 TI - Costs of tumor necrosis factor blockers per treated patient using real-world drug data in a managed care population. AB - BACKGROUND: Several anti-inflammatory biologic medications are available in the United States for the treatment of moderate-to-severe rheumatoid arthritis, moderate-to-severe psoriasis, psoriatic arthritis, or ankylosing spondylitis. The tumor necrosis factor (TNF) blockers etanercept, adalimumab, and infliximab are approved for use in adults with any of these conditions, but predicting the annual costs of TNF-blocker treatment is complex due to differences in dosing schedules, treatment gaps, switching between TNF blockers, and dose escalation over time. OBJECTIVES: To estimate the annual cost per treated patient from the payer perspective for etanercept, adalimumab, or infliximab in adults with rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis. METHODS: Adults in the IMS LifeLink Health Plan Claims Database were analyzed if they had at least 1 claim for etanercept, adalimumab, or infliximab between February 1, 2008, and July 5, 2010, and were continuously enrolled for at least 180 days before (pre-index period) through 360 days after the index claim (the first TNF-blocker claim after 6 months of continuous enrollment in the study period). Patients had a diagnosis of rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis, or a combination of these conditions, in the pre-index period. Cost was based on dose and price using April 2012 wholesale acquisition cost. Costs of administration were included for the first subcutaneous dose (etanercept or adalimumab) for new patients and for every intravenous dose (infliximab). Total TNF-blocker drug and administration costs, including nonindex TNF-blocker costs among patients who switched treatments, were divided by number of patients to yield cost per treated patient for each index TNF blocker. Subgroup analyses included cost by condition and cost for patients who were new to TNF-blocker treatment (no index TNF-blocker claim in the pre index period) or continuing TNF-blocker treatment. RESULTS: Of the 30,107 patients in the analysis, the majority received etanercept (15,488 patients; 51.4%), followed by adalimumab (8,959 patients; 29.8%) and infliximab (5,660 patients; 18.8%). Approximately 2 in 3 patients (18,897 patients) were continuing TNF-blocker treatment, including 66.0%, 52.6%, and 70.0% of patients in the etanercept, adalimumab, and infliximab groups, respectively. Across all indications, the annual TNF-blocker cost per treated patient was lowest for etanercept, followed by adalimumab and then infliximab, respectively: overall ($17,767, $19,272, and $24,273); new patients ($17,270, $17,959, and $21,482); and continuing patients ($18,203, $20,453, and $25,468). Cost by condition among all patients ranged from $14,838 to $20,251 for etanercept, from $18,051 to $20,233 for adalimumab, and from $22,939 to $28,519 for infliximab. Cost by condition was 3% to 31% greater for adalimumab than for etanercept (relative cost, 103% to 131%), except among patients with psoriasis (relative cost, 94%), and was 26% to 72% greater for infliximab than for etanercept (relative cost, 126% to 172%). Approximately 9% to 11% of patients in each group switched TNF blockers in the first year, and the costs of nonindex TNF blockers comprised 16.8% of the total cost for etanercept, 13.4% for adalimumab, and 6.9% for infliximab. CONCLUSIONS: In adult patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis, or some combination of these conditions, etanercept had a lower cost per treated patient than adalimumab or infliximab, except in patients with psoriasis alone. In these patients, adalimumab had a lower cost per treated patient than etanercept or infliximab. PMID- 24074009 TI - Effectiveness of homeopathic medicine associated with allopathic medicine in the outpatient management of influenza-like illnesses or ear, nose, and throat disorders by pharmacists. AB - BACKGROUND: Pharmacists play an increasing role in advising on treatment for minor illnesses such as influenza-like illness (ILI) or ear, nose, and throat (ENT) disorders. However, the profile of patients consulting pharmacists with these illnesses, the types of over-the-counter (OTC) medicines recommended by pharmacists, and the effectiveness of these treatments have not been studied. OBJECTIVES: To describe the sociodemographic and clinical characteristics of patients recommended allopathic and/or homeopathic medicines for ILI or ENT disorders by pharmacists in France and to investigate the effectiveness of these treatments. METHODS: A prospective, observational, multicenter study was carried out in randomly selected pharmacies across the 8 IDREM medical regions of France. Pharmacies that agreed to participate recruited male or female patients who responded to the following inclusion criteria: age >= 12 years presenting with the first symptoms of an ILI or ENT disorder that were ?present for less than 36 hours prior to the pharmacy visit. All medicines recorded in the study were recommended by the pharmacists. The following data were recorded at inclusion and after 3 days of treatment: the intensity of 13 symptoms, global symptom score, and disease impact on daily activities and sleep. Two groups of patients were compared: those recommended allopathic medicine only (AT group) and those recommended homeopathic medicine with or without allopathic medicine (HAT group). The number and severity of symptoms, change in global symptom score, and disease impact on daily activities and sleep were compared in the 2 treatment groups after 3 days of treatment. Independent predictors of recommendations for homeopathic medicine were identified by multi-?factorial logistic regression analysis. RESULTS: A total of 242 pharmacies out of 4,809 (5.0%) contacted agreed to participate in the study, and 133 (2.8%) included at least 1 patient; 573 patients were analyzed (mean age: 42.5 +/- 16.2 years; 61.9% female). Of these, 428 received allopathic medicines only (74.7%; AT group), and 145 (25.3%) received homeopathic medicines (HAT group) alone (9/145, 1.6%) or associated with allopathy (136/145, 23.7%). At inclusion, HAT patients were significantly younger (39.6 +/- 14.8 vs. 43.4 +/- 16.1 years; P less than 0.05), had a higher mean number of symptoms (5.2 +/- 2.5 vs. 4.4 +/- 2.5; P less than 0.01), and more severe symptoms (mean global symptom score: 24.3 +/- 5.5 vs. 22.3 +/- 5.8; P = 0.0019) than AT patients. After 3 days, the improvement in symptoms and disease impact on daily activities and sleep was comparable in both groups of patients. CONCLUSIONS: Patients recommended homeopathic medicine by pharmacists were younger and had more severe symptoms than those recommended allopathic medicine. After 3 days of treatment, clinical improvement was comparable in both treatment groups. Pharmacists have an important role to play in the effective management of ILI and ENT disorders. PMID- 24074010 TI - Formulary management of 2 new agents: lorcaserin and phentermine/topiramate for weight loss. AB - BACKGROUND: Obesity may lead to the development of multiple chronic disease states, including hypertension, dyslipidemia, and type 2 diabetes mellitus. Over a half billion adults worldwide are affected by obesity, and more than two-thirds of adults are either obese or overweight in the United States. Diet and exercise have been the mainstays of treatment in this population; however, once failed, noninvasive, long-term effective treatment modality is lacking, and medications may potentially fill the void. Lorcaserin and phentermine/topiramate were approved by the FDA in June 2012 and July 2012, respectively, as adjuncts to diet and exercise for chronic weight management of obese (body mass index [BMI] >= 30 kg/m2) or overweight (BMI >= 27 kg/m2) individuals with comorbidities. OBJECTIVE: To review the phase 3 trials of lorcaserin and phentermine/topiramate and provide managed care considerations that may be taken into account as a result. METHODS: A MEDLINE review was performed for articles published and available through September 17, 2012, using keywords "lorcaserin" or "phentermine/topiramate" with an emphasis on phase 3 trials. The literature search was limited to randomized controlled trials in humans published in the English language. Additional information on lorcaserin from its FDA review was obtained from the FDA website. RESULTS: 5 pivotal phase 3 trials were identified: 3 for lorcaserin and 2 for phentermine/topiramate. Both agents demonstrated a statistically significant higher proportion of individuals who lost >= 5% of body weight, as well as higher mean weight loss when compared with placebo. Safety concerns for lorcaserin include cardiac valvulopathy and increased risk of psychiatric, cognitive, and serotonergic adverse effects. Teratogenicity and increased heart rate are major safety concerns regarding phentermine/topiramate. CONCLUSIONS: Health care decision makers have many factors to consider when developing strategies to fight obesity. Despite a great need for new therapies to treat obesity, medications used for weight loss have significant side-effect profiles and contraindications that may limit therapy. An appropriate utilization management strategy is needed. PMID- 24074011 TI - Cutting cancer waiting times: streamlining cervical lymph node biopsy. AB - BACKGROUND: Patients with enlarged lymph nodes present to a number of different specialties and diagnosis is often made following a biopsy. OBJECTIVE: This study aimed to establish department waiting times for cervical lymph node biopsy, and compare these to the cancer services guidelines. METHODS: A retrospective audit was carried out to record patient waiting times (defined as the number of days from referral to biopsy) between May and December 2010. A proforma for referral was introduced. In addition, appointments for biopsies were arranged by a co ordinator. A prospective re-audit was carried out from March to September 2011. RESULTS: The first audit showed that national guidelines were not met; there was a median waiting time of 74 days (interquartile range, 47-113). Re-audit demonstrated a significant reduction in waiting times using the proforma; the median waiting time had decreased to 18 days (interquartile range, 9-22). CONCLUSION: A proforma for lymph node biopsy and a designated co-ordinator streamlined the service, significantly reducing waiting times. Together, these can aid referral for meeting guidelines and improve patient care. PMID- 24074014 TI - The favorable kinetics and balance of nebivolol-stimulated nitric oxide and peroxynitrite release in human endothelial cells. AB - BACKGROUND: Nebivolol is a third-generation beta-blocker used to treat hypertension. The vasodilation properties of nebivolol have been attributed to nitric oxide (NO) release. However, the kinetics and mechanism of nebivolol stimulated bioavailable NO are not fully understood. METHODS: Using amperometric NO and peroxynitrite (ONOO-) nanosensors, beta3-receptor (agonist: L-755,507; antagonists: SR59230A and L-748,337), ATP efflux (the mechanosensitive ATP channel blocker, gadolinium) and P2Y-receptor (agonists: ATP and 2-MeSATP; antagonist: suramin) modulators, superoxide dismutase and a NADPH oxidase inhibitor (VAS2870), we evaluated the kinetics and balance of NO and ONOO- stimulated by nebivolol in human umbilical vein endothelial cells (HUVECs). NO and ONOO- were measured with nanosensors (diameter ~ 300 nm) placed 5 +/- 2 MUm from the cell membrane and ATP levels were determined with a bioluminescent method. The kinetics and balance of nebivolol-stimulated NO and ONOO- were compared with those of ATP, 2-MeSATP, and L-755,507. RESULTS: Nebivolol stimulates endothelial NO release through beta3-receptor and ATP-dependent, P2Y receptor activation with relatively slow kinetics (75 +/- 5 nM/s) as compared to the kinetics of ATP (194 +/- 10 nM/s), L-755,507 (108 +/- 6 nM/s), and 2-MeSATP (105 +/- 5 nM/s). The balance between cytoprotective NO and cytotoxic ONOO- was expressed as the ratio of [NO]/[ONOO-] concentrations. This ratio for nebivolol was 1.80 +/- 0.10 and significantly higher than that for ATP (0.80 +/- 0.08), L 755,507 (1.08 +/- 0.08), and 2-MeSATP (1.09 +/- 0.09). Nebivolol induced ATP release in a concentration-dependent manner. CONCLUSION: The two major pathways (ATP efflux/P2Y receptors and beta3 receptors) and several steps of nebivolol induced NO and ONOO- stimulation are mainly responsible for the slow kinetics of NO release and low ONOO-. The net effect of this slow kinetics of NO is reflected by a favorable high ratio of [NO]/[ONOO-] which may explain the beneficial effects of nebivolol in the treatment of endothelial dysfunction, hypertension, heart failure, and angiogenesis. PMID- 24074015 TI - Addressing oral health disparities, inequity in access and workforce issues in a developing country. AB - The health sector challenges in India like those in other low and middle income countries are formidable. India has almost one-third of the world's dental schools. However, provisions of oral health-care services are few in rural parts of India where the majority of the Indian population resides. Disparities exist between the oral health status in urban and rural areas. The present unequal system of mainly private practice directed towards a minority of the population and based on reparative services needs to be modified. National oral health policy needs to be implemented as a priority, with an emphasis on strengthening dental care services under public health facilities. A fast-changing demographic profile and its implications needs to be considered while planning for the future oral health-care workforce. Current oral health status in developing countries, including India, is a result of government public health policies, not lack of dentists. The aim of the article is to discuss pertinent issues relating to oral health disparities, equity in health-care access, dental workforce planning and quality concerns pertaining to the present-day dental education and practices in India, which have implications for other developing countries. PMID- 24074016 TI - Carpal tunnel syndrome - an occupational hazard facing dentistry. AB - BACKGROUND: The authors wished to evaluate the comprehensive literature on carpal tunnel syndrome to discover work specific to carpal tunnel syndrome among dentists in order to determine whether there is any correlation with dentists having a higher prevalence of its occurrence. METHODS: A review of dental literature involving carpal tunnel syndrome was undertaken. Details appearing in the literature before 1995 was reviewed in a comprehensive manner and the literature after 1995 were reviewed electronically. RESULTS: The prevalence of carpal tunnel syndrome is higher in dental professionals involved in various aspects of dental specialties. CONCLUSIONS: Abnormal postures, including muscle imbalances, muscle necrosis, trigger points, hypomobile joints, nerve compression and spinal disk herniation or degeneration may result in serious detrimental physiological changes in the body. These changes often result in pain, injury or possible neuroskeletal disorders. CLINICAL IMPLICATIONS: Dentists have an increased risk of carpal tunnel syndrome and precautions and care should be exercised to prevent detrimental irreversible changes occurring. PMID- 24074017 TI - Oral health in the context of primary care in Brazil. AB - This article presents an integrative literature review that analyses the advances and challenges in oral health care of the Brazilian primary health care system, based on a political agenda that envisages re-organising the unified health system (SistemaUnico de Saude - SUS). It is presumed that the actions suggested by the Alma-Ata Conference of 1978 are still up-to-date and relevant when adapted to the situation in Brazil. Several studies and policies are reviewed, including works demonstrating the importance of primary care as an organising platform in an integrated health-care network, Brazil's strategy for reorganising the primary care network known as the Family Health Strategy, and the National Oral Health Policy. This review discusses results obtained over the last twenty years, with special attention paid to changes in oral health-care practices, as well as the funding of action programmes and assistance cover. The conclusion is that oral healthcare in the Brazilian primary health care system has advanced over the past decades; however, serious obstacles have been experienced, especially with regard to the guarantee of universal access to services and funding. The continuous efforts of public managers and society should focus on the goal of achieving universal coverage for all Brazilians. PMID- 24074018 TI - Knowledge and attitude towards smoking among Indian students of dentistry. AB - Active cigarette smoking is the major cause of lung cancer and an important established cause of cardiovascular disease mortality. Risks have been shown to increase with even light or intermittent active smoking. OBJECTIVES: To assess the prevalence of smoking, age of initiation and the knowledge and attitude towards smoking among dental college students of Rajasthan, India. METHODS: A cross-sectional study was conducted among 1,383 undergraduate and postgraduate dental college students of Rajasthan using self-administered closed-ended questionnaires consisting of 14 questions divided into four sections. A chi square test was used to determine the association between dependent and independent variables. RESULTS: Of all the participants, 777 (56.2%) were male and 606 (43.8%) were female. Among these 258 (33.2%) males and 51 (8.4%) females had tried or experimented smoking. Majority of males (24.7%) initiated this habit at a very young age, before 16 years. About 79.5% males and 72.3% females felt that it was difficult to quit smoking. According to 88.1% females and 48.7% males, people feel less comfortable at public places or social gatherings. CONCLUSION: The study has shown that the smoking prevalence among dental college students is high and has managed to contribute additional information regarding their attitude towards smoking. Comprehensive tobacco education and smoking cessation programmes should be aggressively promoted in dental settings. PMID- 24074019 TI - Correlation between health-care costs and salivary tests. AB - The burden of health-care costs relative to gross domestic product in Japan is increasing. A large percentage (7.6% in 2009) of the Japanese gross domestic product has been spent on health care, and this percentage has been increasing annually. Soaring health-care costs have been recognised as a serious social problem. In this study, we attempted to estimate the relationship between periodontal disease and health-care costs. Subjects consisted of teachers and staff members (35 men, 26 women; mean age, 45 +/- 9 years) from two high schools. The salivary levels of lactate dehydrogenase and haemoglobin were adopted as biomarkers to assess periodontal disease. After salivary tests, data for the health-care costs over the subsequent 6 months were provided by the mutual association of the public schools on an individual basis. Curve-fit estimations were then performed where health-care costs were used as a dependent variable and age or salivary levels of haemoglobin or lactate dehydrogenase were used as independent variables. However, no good fitness was obtained. Subsequently, multilayer perceptron neural networks were applied. With the neural networks, good fitness was obtained by using lactate dehydrogenase as an independent variable. The results of this study show that oral health, particularly periodontal disease, is correlated with total health-care costs. The data presented in this study suggests that, from the perspective of both oral and systemic health, oral health can be a signpost in well-being and health promotion. PMID- 24074020 TI - Oral rehydration therapy products - a plaque pH study under normal and dry mouth conditions. AB - AIM: The aim of this study was to investigate oral rehydration therapy (ORT) products and their effect on plaque pH under normal and dry mouth conditions. DESIGN: Three commercial oral rehydration therapy products, prepared according to the manufacturers' instruction, plus a 10% glucose solution, which served as control, were tested in 10 healthy subjects (mean age 25 years): (1) Electral (Arrow Pharmaceuticals), (2) Resorb Junior (Nestle) and (3) Vatskeersattning (Semper). pH was measured in the maxillary premolar region in situ with the so called microtouch method. The area under the pH curve was calculated. Their carbohydrate content was also analysed. RESULTS: The oral rehydration therapy products gave the same low pH values in plaque as the glucose solution. Dry mouth condition, obtained by injection of methylscopolamine nitrate in the labial sulcus, resulted in an overall more pronounced fall in pH and in a delay in the pH recovery compared with normal salivary conditions. The chemical analyses showed that all three test-products contained glucose and starch as the main carbohydrates. CONCLUSIONS: Rinsing with oral rehydration therapy products leads to a greater pH decrease in dental plaque during low compared with normal salivary conditions. As diarrhoea may result in dehydration and thereby in dry mouth, we believe that ORT products have a high cariogenic potential. PMID- 24074021 TI - Motivation for a career in dentistry: the views of dental students in the United Arab Emirates. AB - OBJECTIVES: To investigate final-year dental students' perceived motivation for choosing dentistry as a professional career at one dental school in the United Arab Emirates (UAE). METHOD: Final-year dental students of Ajman University (n = 87) completed a questionnaire. Univariate and multivariate analysis of the data were undertaken using statistical software. RESULTS: A response rate of 82% (n = 71) was achieved, 65% of whom were female. Students ranged from 21 to 29 years of age. Motivation to study dentistry was led by a 'desire to work in health care' (93%), 'wish to provide a public service' (88.7%) and because 'degree leads to a recognised job' (84.5%). Males were significantly more likely to report 'high income' (84% vs. 67%; P = 0.01) and females 'influence of family' (80% vs. 60%; P = 0.02) as motivating influences. The reliability and internal consistency of the instrument as calculated by Cronbach's alpha was 0.82. Eight factors explaining the 71% of the variation were: 'professional job factors' (11.7%), 'experience and advice' (9.8%), 'business and financial with independence' (9.7%), 'careers, advice and possibilities' (8.9%), 'knowledge and job security' (8.8%), 'health care, people and public service' (8%), 'family and friends' (7.2%) and 'career in dentistry' (6.9%). Gender was a significant predictor of 'business and financial' factor (b = -0.76; P = 0.003) and age for 'careers in dentistry' (b = -0.18; P = 0.03). CONCLUSION: Students are motivated by a wide range of factors similar to those found in other studies; however, business features and family influences were significantly associated with gender. PMID- 24074022 TI - Analysis of the extent and efficiency of the partnership and collaboration between the dental faculties and National Dental Associations within the FDI-ERO zone: a dental faculties' perspective. AB - BACKGROUND AND AIM: As National Dental Associations and dental faculties can be considered as the two major institutions representing national organised dentistry, their further extended collaboration is crucial in responding to the many global oral health matters and issues. The main aim of the present study is to analyse the nature and extent of the partnership between the dental faculties and NDAs. METHODS: A questionnaire was developed focusing on the relationship between National Dental Associations and the dental faculties within the World Dental Federation-European Regional Organisation zone regarding their major professional activities such as dental education, workforce issues, improvement of national oral health, science and knowledge transfer. The questionnaire was sent to 173 dental faculties within the countries in the European Regional Organisation zone. RESULTS: Response rate was 62/173 (35.8%). Major activities of dental faculties were listed as implementation of new technologies into practice (72%), followed by improvement of national oral health (65%), while the least involved activity was dental workforce issues (42%). The dental faculties perceived their relationship with the National Dental Associations as quite satisfactory in the field of continuing education and science and knowledge transfer. However, their relationship was suggested to need significant improvement when dealing with undergraduate dental education curriculum, dental workforce issues and negotiations with the authorities regarding professional matters/issues. DISCUSSION AND CONCLUSIONS: Despite the fact that there are differences between the perceived competences and responsibilities of the two bodies, the presence of so many potential areas of collaboration, the increasing expectations from the individual dentists/dental profession and the new challenges of the dental profession give this relationship significant importance. Communication, regular contacts, more joint activities and improved collaboration is needed between dental faculties and National Dental Associations to overcome such professional matters and issues. PMID- 24074023 TI - The care of the primary dentition by general dental practitioners and paediatric dentists. AB - OBJECTIVES: This study aimed to explore the preferred treatment for pre-school children with caries of different severities in primary teeth among general dental practitioners (GDPs) and specialists in paediatric dentistry (PDs) in Hong Kong, and to determine the difference in practice patterns between the groups. METHODS: A random sample of 476 GDPs (approximately 25% of all registered dentists) and all registered PDs (n = 28) were invited to participate in the study. Both groups were asked to select their single most preferred treatment option on eight hypothetical clinical case scenarios in which the severity of dental caries in a single primary molar/incisor of a 4-year-old healthy and cooperative boy differed. The distribution frequency of responses was tabled. Difference in the care approach patterns of GDPs and PDs were examined in bivariate and regression analyses. RESULTS: The overall response rate of the study was 61.5% (310/504). There were significant differences between the GDPs and PDs on their preferred treatment in six out of eight case scenarios (P < 0.05). PDs favoured comprehensive restorative treatment more than GDPs. Non interventionist approach, atraumatic restorative technique or extraction were more popular among GDPs. Variation in treatment choices was apparent within both GDPs and PDs, in which spread of treatment options was wider among GDPs. CONCLUSIONS: GDPs and PDs have different dental care approach patterns for pre school children with dental caries. Wide variation in the views about the best way to treat the child exists within both groups. PMID- 24074024 TI - Alternative technologies for the reduction of greenhouse gas emissions from palm oil mills in Thailand. AB - Alternative methodologies for the reduction of greenhouse gas (GHG) emissions from crude palm oil (CPO) production by a wet extraction mill in Thailand were developed. The production of 1 t of CPO from mills with biogas capture (four mills) and without biogas capture (two mills) in 2010 produced GHG emissions of 935 kg carbon dioxide equivalent (CO2eq), on average. Wastewater treatment plants with and without biogas capture produced GHG emissions of 64 and 47% of total GHG emission, respectively. The rest of the emissions mostly originated from the acquisition of fresh fruit bunches. The establishment of a biogas recovery system must be the first step in the reduction of GHG emissions. It could reduce GHG emissions by 373 kgCO2eq/t of CPO. The main source of GHG emission of 163 kgCO2eq/t of CPO from the mills with biogas capture was the open pond used for cooling of wastewater before it enters the biogas recovery system. The reduction of GHG emissions could be accomplished by (i) using a wastewater-dispersed unit for cooling, (ii) using a covered pond, (iii) enhancing the performance of the biogas recovery system, and (iv) changing the stabilization pond to an aerated lagoon. By using options i-iv, reductions of GHG emissions of 216, 208, 92.2, and 87.6 kgCO2eq/t of CPO, respectively, can be achieved. PMID- 24074025 TI - Investigating the selectivity of metalloenzyme inhibitors. AB - The inhibitory activity of a broad group of known metalloenzyme inhibitors against a panel of metalloenzymes was evaluated. Clinically approved inhibitors were selected as well as several other reported metalloprotein inhibitors in order to represent a broad range of metal binding groups (MBGs), including hydroxamic acid, carboxylate, hydroxypyridinonate, thiol, and N-hydroxyurea functional groups. A panel of metalloenzymes, including carbonic anhydrase (hCAII), several matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), histone deacetylase (HDAC-2), and tyrosinase (TY), was selected based on their clinical importance for a range of pathologies. In addition, each inhibitor was evaluated for its ability to remove Fe(3+) from holo-transferrin to gauge the ability of the inhibitors to access Fe(3+) from a primary transport protein. The results show that the metalloenzyme inhibitors are quite selective for their intended targets, suggesting that despite their ability to bind metal ions, metalloprotein inhibitors are not prone to widespread off-target enzyme inhibition activity. PMID- 24074026 TI - Antioxidant and pro-oxidant effects of oil palm (Elaeis guineensis) leaves extract in experimental diabetic nephropathy: a duration-dependent outcome. AB - BACKGROUND: Catechins-rich oil palm (Elaeis guineensis) leaves extract (OPLE) is known to have antioxidant activity. Several polyphenolic compounds reported as antioxidants such as quercetin, catechins and gallic acid have been highlighted to have pro-oxidant activity at high doses. Therefore, the present study was conducted to investigate the antioxidant and pro-oxidant effects of chronically administering high dose of OPLE (1000 mg kg-1) in an animal model of diabetic nephropathy (DN). METHODS: Animal body weight, indexes of glycaemia, renal function and morphology were assessed in diabetic animals with and without OPLE (1000 mg kg-1) for 4 and 12 weeks respectively. Oxidative stress was quantified by measuring levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), lipid peroxides (LPO) and reduced glutathione (GSH). Transforming growth factor-beta1 (TGF beta1), a key mediator of extracellular matrix accumulation, was analysed in plasma. The mechanisms of OPLE action were evaluated by assessing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits (p22phox and p67phox) expression. RESULTS: Oral administration with high dose of catechins-rich OPLE (1000 mg kg-1) to STZ-induced diabetic rats for 4 weeks attenuated renal dysfunction (hyperfiltration, proteinuria) and development of glomerulosclerosis and tubulointerstitial fibrosis, features that are associated with DN. Suppression of increases in oxidative stress markers (8-OHdG, LPO) and the fibrotic cytokine, TGF-beta1 was observed. OPLE also reduced renal expression of NADPH oxidase subunits p22phox and p67phox. In contrast and surprisingly, identical dose of OPLE when administered to diabetic animals for 12 weeks caused worsening of renal dysfunction, histopathology in addition to further elevation of oxidative stress marker (LPO) and TGF-beta1. These unfavourable effects of prolonged treatment with 1000 mg kg-1 OPLE were accompanied by increase expression of one of the NADPH oxidase subunits, p22phox. CONCLUSION: Our study indicates that chronic administration of 1000 mg kg-1 OPLE exerts both antioxidant and pro-oxidant effects in DN depending on the duration of treatment. The present study also reveals that the antioxidant/pro-oxidant effects of OPLE are in part, due to modulation of NADPH activity. PMID- 24074027 TI - Cycle scheduling for in vitro fertilization with oral contraceptive pills versus oral estradiol valerate: a randomized, controlled trial. AB - BACKGROUND: Both oral contraceptive pills (OCPs) and estradiol (E2) valerate have been used to schedule gonadotropin-releasing hormone (GnRH) antagonist in vitro fertilization (IVF) cycles and, consequently, laboratory activities. However, there are no studies comparing treatment outcomes directly between these two pretreatment methods. This randomized controlled trial was aimed at finding differences in ongoing pregnancy rates between GnRH antagonist IVF cycles scheduled with OCPs or E2 valerate. METHODS: Between January and May 2012, one hundred consecutive patients (nonobese, regularly cycling women 18-38 years with normal day 3 hormone levels and <3 previous IVF/ICSI attempts) undergoing IVF with the GnRH antagonist protocol were randomized to either the OCP or E2 pretreatment arms, with no restrictions such as blocking or stratification. Authors involved in data collection and analysis were blinded to group assignment. Fifty patients received OCP (30 MUg ethinyl E2/150 MUg levonorgestrel) for 12-16 days from day 1 or 2, and stimulation was started 5 days after stopping OCP. Similarly, 50 patients received 4 mg/day oral E2 valerate from day 20 for 5-12 days, until the day before starting stimulation. RESULTS: Pretreatment with OCP (mean+/-SD, 14.5+/-1.7 days) was significantly longer than with E2 (7.8+/-1.9 days). Stimulation and embryological characteristics were similar. Ongoing pregnancy rates (46.0% vs. 44.0%; risk difference, -2.0% [95% CI -21.2% to 17.3%]), as well as implantation (43.5% vs. 47.4%), clinical pregnancy (50.0% vs. 48.0%), clinical miscarriage (7.1% vs. 7.7%), and live birth (42.0% vs. 40.0%) rates were comparable between groups. CONCLUSIONS: This is the first study to directly compare these two methods of cycle scheduling in GnRH antagonist cycles. Our results fail to show statistically significant differences in ongoing pregnancy rates between pretreatment with OCP and E2 for IVF with the GnRH antagonist protocol. Although the study is limited by its sample size, our results may contribute to a future meta-analysis. An interesting future direction would be to extend our study to women with decreased ovarian reserve, as these are the patients in whom an increase in oocyte yield-due to the hypothetical beneficial effect of steroid pretreatment on follicular synchronization-could more easily be demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov http://NCT01501448. PMID- 24074029 TI - Abstracts of the ACHMN's 39th International Mental Health Nursing Conference Collaboration and Partnership in Mental Health Nursing. October 22-24, 2013. Perth, Western Australia. PMID- 24074028 TI - Male-specific Fruitless isoforms have different regulatory roles conferred by distinct zinc finger DNA binding domains. AB - BACKGROUND: Drosophila melanogaster adult males perform an elaborate courtship ritual to entice females to mate. fruitless (fru), a gene that is one of the key regulators of male courtship behavior, encodes multiple male-specific isoforms (Fru(M)). These isoforms vary in their carboxy-terminal zinc finger domains, which are predicted to facilitate DNA binding. RESULTS: By over-expressing individual Fru(M) isoforms in fru-expressing neurons in either males or females and assaying the global transcriptional response by RNA-sequencing, we show that three Fru(M) isoforms have different regulatory activities that depend on the sex of the fly. We identified several sets of genes regulated downstream of Fru(M) isoforms, including many annotated with neuronal functions. By determining the binding sites of individual Fru(M) isoforms using SELEX we demonstrate that the distinct zinc finger domain of each Fru(M) isoforms confers different DNA binding specificities. A genome-wide search for these binding site sequences finds that the gene sets identified as induced by over-expression of Fru(M) isoforms in males are enriched for genes that contain the binding sites. An analysis of the chromosomal distribution of genes downstream of Fru(M) shows that those that are induced and repressed in males are highly enriched and depleted on the X chromosome, respectively. CONCLUSIONS: This study elucidates the different regulatory and DNA binding activities of three Fru(M) isoforms on a genome-wide scale and identifies genes regulated by these isoforms. These results add to our understanding of sex chromosome biology and further support the hypothesis that in some cell-types genes with male-biased expression are enriched on the X chromosome. PMID- 24074030 TI - Bioactivities of six sterols isolated from marine invertebrates. AB - CONTEXT: Epidioxy sterols and sterols with special side chains, such as hydroperoxyl sterols, usually obtained from marine natural products, are attractive for bioactivities. OBJECTIVE: To isolate and screen bioactive and special sterols from China Sea invertebrates. MATERIALS AND METHODS: Two hydroperoxyl sterols (1 and 2) from the sponge Xestospongia testudinaria Lamarck (Petrosiidae), three epidioxy sterols (3-5) from the sea urchin Glyptocidaris crenularis A. Agassiz (Glyptocidaridae), sponge Mycale sp. (Mycalidae) and gorgonian Dichotella gemmacea Milne Edwards and Haime (Ellisellidae) and an unusual sterol with 25-acetoxy-19-oate (6) also from D. gemmacea were obtained and identified. Using high-throughput screening, their bioactivities were tested toward Forkhead box O 3a (Foxo3a), 3-hydroxy-3-methylglutaryl CoA reductase gene fluorescent protein (HMGCR-GFP), nuclear factor kappa B (NF-kappaB) luciferase, peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC 1alpha), protein-tyrosine phosphatase 1B (PTP1B), mitochondrial membrane permeabilization (MMP) and adenosine monophosphate-activated protein kinase. RESULTS: Their structures were determined by comparing their nuclear magnetic resonance data with those reported in the literature. Three epidioxy sterols (3 5) showed inhibitory activities toward Foxo3a, HMGCR-GFP and NF-kappaB-luciferase with the IC50 values 4.9-6.8 MUg/mL. The hydroperoxyl sterol 29 hydroperoxystigmasta-5,24(28)-dien-3-ol (2) had diverse inhibitory activities against Foxo3a, HMGCR-GFP, NF-kappaB-luciferase, PGC-1alpha, PTP1B and MMP, with IC50 values of 3.8-19.1 MUg/mL. DISCUSSION AND CONCLUSION: The bioactivities of 3 5 showed that 5alpha,8alpha-epidioxy is the active group. Otherwise, the most plausible biosynthesis pathway for 1 and 2 in sponge involves the abstraction of an allylic proton by an activated oxygen, such as O2, along with migration of carbon-carbon double bond. Therefore, the bioactive and unstable steroid should be biosynthesized in sponge under a special ecological environment to act as a defensive strategy against invaders. PMID- 24074031 TI - Vehicle selection for nonclinical oral safety studies. AB - INTRODUCTION: The development of poorly soluble or permeable new chemical entities within the pharmaceutical industry often requires the use of nonstandard enabling nonclinical oral formulations. Despite this, the toxicity profile of many commonly used nonclinical vehicles is poorly understood. This lack of data can lead to unexpected formulation-related effects being observed in critical oral safety studies. AREAS COVERED: This article summarizes the key considerations for formulation selection for oral nonclinical safety studies, and provides a strategy for appropriate development-phase formulation selection. The industry's use of oral nonclinical vehicles is reviewed, based on data from the FDA's Orange Book. Finally, a summary of the repeat dose oral toxicity of commonly used vehicles is presented. EXPERT OPINION: The rapid identification of a suitable nonclinical oral formulation is a critical step in small-molecule drug development. In order to maintain flexibility and address the needs of a diverse set of new chemical entities (NCEs) with widely varying physiochemical properties, a "tool belt" of multiple oral formulations is recommended. The appropriate formulation is identified based on the goals of the study, as well as exposure required, species, duration and therapeutic indication of the NCE. PMID- 24074033 TI - Targeting selectins for the treatment of inflammatory diseases. AB - INTRODUCTION: Selectins mediate tethering and rolling of leukocytes to the vascular endothelium, the first adhesive step in the recruitment of immune cells to inflamed tissues. Selectins are involved in constitutive lymphocyte homing, and in chronic and acute inflammation processes, including post-ischemic, brain, lung, heart and skin inflammation, atherosclerosis and cancer progression. Because blockade of the steps of leukocyte recruitment has been predicted to interrupt leukocyte extravasation, pharmacological interference with the function of key molecules in the multistep recruitment cascade represents a promising strategy for therapeutic intervention in inflammatory disorders. Selectin neutralizing monoclonal antibodies, recombinant soluble P-selectin glycoprotein ligand 1 and small-molecule inhibitors of selectins have been tested in preclinical and clinical studies associated with inflammation. AREAS COVERED: This article explores the experimental studies describing the beneficial effects of selectin modulators in the treatment of inflammatory diseases. EXPERT OPINION: Many of the selectin-directed compounds have not held up to the high expectations, in some cases due to overlapping and mutually compensating functions of selectins or suboptimal pharmacokinetic properties of the compounds, while other agents appear to be more promising candidates and have already entered clinical trials. PMID- 24074032 TI - Splicing kinase SRPK1 conforms to the landscape of its SR protein substrate. AB - The splicing function of SR proteins is regulated by multisite phosphorylation of their C-terminal RS (arginine-serine rich) domains. SRPK1 has been shown to phosphorylate the prototype SR protein SRSF1 using a directional mechanism in which 11 serines flanked by arginines are sequentially fed from a docking groove in the large lobe of the kinase domain to the active site. Although this process is expected to operate on lengthy arginine-serine repeats (>=8), many SR proteins contain smaller repeats of only 1-4 dipeptides, raising the question of how alternate RS domain configurations are phosphorylated. To address this, we studied a splice variant of Tra2beta that contains a C-terminal RS domain with short arginine-serine repeats [Tra2beta(DeltaN)]. We showed that SRPK1 selectively phosphorylates several serines near the C-terminus of the RS domain. SRPK1 uses a distributive mechanism for Tra2beta(DeltaN) where the rate-limiting step is the dissociation of the protein substrate rather than nucleotide exchange as in the case of SRSF1. Although a functioning docking groove is required for efficient SRSF1 phosphorylation, this conserved structural element is dispensable for Tra2beta(DeltaN) phosphorylation. These large shifts in mechanism are likely to account for the slower net turnover rate of Tra2beta(DeltaN) compared to SRSF1 and may signal fundamental differences in phosphorylation among SR proteins with distinctive arginine-serine profiles. Overall, these data indicate that SRPK1 conforms to changes in RS domain architecture using a flexible kinetic mechanism and selective usage of a conserved docking groove. PMID- 24074034 TI - Characterization of polymer adsorption onto drug nanoparticles using depletion measurements and small-angle neutron scattering. AB - Production of polymer and/or surfactant-coated crystalline nanoparticles of water insoluble drugs (nanosuspensions) using wet bead milling is an important formulation approach to improve the bioavailability of said compounds. Despite the fact that there are a number of nanosuspensions on the market, there is still a deficiency in the characterization of these nanoparticles where further understanding may lead to the rational selection of polymer/surfactant. To this end small-angle neutron scattering (SANS) measurements were performed on drug nanoparticles milled in the presence of a range of polymers of varying molecular weight. Isotopic substitution of the aqueous solvent to match the scattering length density of the drug nanoparticles (i.e., the technique of contrast matching) meant that neutron scattering resulted only from the adsorbed polymer layer. The layer thickness and amount of hydroxypropylcellulose adsorbed on nabumetone nanoparticles derived from fitting the SANS data to both model independent and model dependent volume fraction profiles were insensitive to polymer molecular weight over the range Mv = 47-112 kg/mol, indicating that the adsorbed layer is relatively flat but with tails extending up to approximately 23 nm. The constancy of the absorbed amount is in agreement with the adsorption isotherm determined by measuring polymer depletion from solution in the presence of the nanoparticles. Insensitivity to polymer molecular weight was similarly determined using SANS measurements of nabumetone or halofantrine nanoparticles stabilized with hydroxypropylmethylcellulose or poly(vinylpyrrolidone). Additionally SANS studies revealed the amount adsorbed, and the thickness of the polymer layer was dependent on both the nature of the polymer and drug particle surface. The insensitivity of the adsorbed polymer layer to polymer molecular weight has important implications for the production of nanoparticles, suggesting that lower molecular weight polymers should be used when preparing nanoparticles by wet bead milling since nanoparticle formation is more rapid but with no likely consequence on the resultant physical stability of the nanoparticles. PMID- 24074035 TI - High-throughput oenomics: shotgun polyphenomics of wines. AB - Red wine is a complex mixture of organic compounds including polyphenols and the use of ultra high performance liquid chromatography-electrospray ionization quadrupole-time-of-flight-mass spectrometry (UHPLC-ESI-Q-TOF-MS) is a promising technique to better understand its quality and authenticity. To optimize the characterization of red wine, we developed an original and fast method that represents the first shotgun polyphenomics analysis of wine. We show that our new method yields significantly more information than previous fast methods such as direct injection-ESI-MS of wine, with the identification of 103 compounds in 2 min. As a first application, we show that the use of a specific selected ion ratio demonstrates significant differences between Pinot Noir, Merlot, and Syrah wine spectra in a preliminary study. PMID- 24074036 TI - Dietary and supplemental antioxidant and anti-inflammatory nutrient intakes and pulmonary function. AB - OBJECTIVE: A limited but growing body of evidence supports a significant role of antioxidant and anti-inflammatory micronutrients in pulmonary health. We investigated the associations of dietary and supplemental intakes of vitamins A, C, E and D, Se and n-3 PUFA with pulmonary function in a population-based study. DESIGN: Population-based, cross-sectional study and data analysis of fruits and vegetables, dairy products and fish, vitamins A, C, E and D, Se and n-3 PUFA supplemental intakes, pulmonary risk factors and spirometry. SUBJECTS: Chinese older adults (n 2478) aged 55 years and above in the Singapore Longitudinal Ageing Studies. RESULTS: In multiple regression models that controlled simultaneously for gender, age, height, smoking, occupational exposure and history of asthma/chronic obstructive pulmonary disease, BMI, physical activity, and in the presence of other nutrient variables, daily supplementary vitamins A/C/E (b = 0.044, SE = 0.022, P = 0.04), dietary fish intake at least thrice weekly (b = 0.058, SE = 0.016, P < 0.0001) and daily supplementary n-3 PUFA (b = 0.068, SE = 0.032, P = 0.034) were individually associated with forced expiratory volume in the first second. Supplemental n-3 PUFA was also positively associated with forced vital capacity (b = 0.091, SE = 0.045, P = 0.045). No significant association with daily dairy product intake, vitamin D or Se supplements was observed. CONCLUSIONS: The findings support the roles of antioxidant vitamins and n-3 PUFA in the pulmonary health of older persons. PMID- 24074037 TI - Discovery and partial characterization of a non-LTR retrotransposon that may be associated with abdominal segment deformity disease (ASDD) in the whiteleg shrimp Penaeus (Litopenaeus) vannamei. AB - BACKGROUND: Abdominal segment deformity disease (ASDD) of cultivated whiteleg shrimp Penaeus (Litopenaeus) vannamei causes economic loss of approximately 10% in affected specimens because of the unsightliness of distorted abdominal muscles. It is associated with the presence of viral-like particles seen by electron microscopy in the ventral nerve cords of affected shrimp. Thus, shotgun cloning was carried out to seek viral-like sequences in affected shrimp. RESULTS: A new retrovirus-like element of 5052 bp (named abdominal segment deformity element or ASDE) was compiled by shotgun cloning and 3' and 5' RACE using RNA and DNA extracted from ventral nerve cords of ASDD shrimp. ASDE contained 7 putative open reading frames (ORF). One ORF (called the PENS sub-domain), had a deduced amino acid (aa) sequence homologous to the GIY-YIG endonuclease domain of penelope-like retrotransposons while two others were homologous to the reverse transcriptase (RT) and RNaseH domains of the pol gene of non-long terminal repeat (non-LTR) retrotransposons (called the NLRS sub-domain). No single amplicon of 5 kb containing both these elements was obtained by PCR or RT-PCR from ASDD shrimp. Subsequent analysis indicated that PENS and NLRS were not contiguous and that NLRS was a host genetic element. In situ hybridization using a dioxygenin-labeled NLRS probe revealed that NLRS gave positive reactions in abdominal-ganglion neurons of ASDD shrimp but not normal shrimp. Preliminary analysis indicated that long-term use of female broodstock after eyestalk ablation in the hatchery increased the intensity of RT-PCR amplicons for NLRS and also the prevalence of ASDD in mysis 3 offspring of the broodstock. The deformities persist upon further cultivation until shrimp harvest but do not increase in prevalence and do not affect growth or survival. CONCLUSIONS: Our results suggested that NLRS is a shrimp genetic element associated with ASDD and that immediate preventative measures could include shorter-term use of broodstock after eyestalk ablation and/or discard of broodstock that give strong RT-PCR reactions for NLRS. In the longer term, it is recommended, if possible, that currently used, domesticated shrimp lines be selected for freedom from NLRS. The molecular tools developed in this work will facilitate the management and further study of ASDD. PMID- 24074039 TI - MicroCT image-generated tumour geometry and SAR distribution for tumour temperature elevation simulations in magnetic nanoparticle hyperthermia. AB - OBJECTIVES: The objective of this study was to develop and test computer algorithms to export micro computed tomography (microCT) images and to generate tumour geometry and specific absorption rate (SAR) distribution for heat transfer simulation in magnetic nanoparticle hyperthermia. METHODS: Computer algorithms were written to analyse and export microCT images of 3D tumours containing magnetic nanoparticles. MATLAB((r)) and ProE((r)) programs were used to generate a prototype of the tumour geometry. The enhancements in the microCT pixel index number due to presence of nanoparticles in the tumours were first converted into corresponding SAR values. The SAR data were then averaged over three-dimensional clusters of pixels using the SAS((r)) program. This greatly decreased the size of the SAR file, while in the meantime it ensured that the amount of total energy deposited in the tumour was conserved. Both the tumour geometry and the SAR file were then imported into the COMSOL((r)) software package to simulate temperature elevations in the tumour and their surrounding tissue region during magnetic nanoparticle hyperthermia. RESULTS: A linear relationship was obtained to relate individual pixel index numbers in the microCT images to the SAR values under a specific magnetic field. The generated prototype of the tumour geometry based on only 30 slices of microCT images resembled the original tumour shape and size. The tumour geometry and the simplified SAR data set were successfully accepted by the COMSOL software for heat transfer simulation. Up to 20 degrees C temperature elevations from its baseline temperature were found inside the tumours, implying possible thermal damage to the tumour during magnetic nanoparticle hyperthermia. PMID- 24074038 TI - 6(th) Annual Symposium on Self-Monitoring of Blood Glucose (SMBG) applications and beyond, April 25-27, 2013, Riga, Latvia. AB - International experts in the fields of diabetes, diabetes technology, endocrinology, and pediatrics gathered for the 6(th) Annual Symposium on Self Monitoring of Blood Glucose (SMBG) Applications and beyond. The aim of this meeting was to continue setting up a global network of experts in this field and provide an international platform for exchange of ideas to improve life for people with diabetes. The 2013 meeting comprised a comprehensive scientific program, parallel interactive workshops, and two keynote lectures. All these discussions were intended to help identify gaps and areas where further scientific work and clinical studies are warranted. PMID- 24074040 TI - Polymorphic variants of MnSOD Val16Ala, CAT-262 C < T and GPx1 Pro198Leu genotypes and the risk of laryngeal cancer in a smoking population. AB - OBJECTIVE: To investigate the relationship between development of laryngeal cancer and the presence of polymorphisms of the MnSOD Val16Ala, CAT-262 C < T and GPx1 Pro198Leu genes in a smoking population. PATIENTS AND METHODS: Single nucleotide polymorphisms were determined in DNA from the peripheral blood erythrocytes of 48 heavy smokers (25 patients with laryngeal cancer and 23 cancer free controls), using polymerase chain reaction. RESULTS: There were no significant differences in age, smoking duration or smoking intensity, comparing the two groups. The homozygous AA genotype of MnSOD Val16Ala was significantly more prevalent in the cancer group than the control group (92 vs 13 per cent, respectively), while the heterozygous AV genotype of MnSOD Val16Ala was more prevalent in the control group than the cancer group (87 vs 8 per cent, respectively) (p < 0.001). There were no significant differences between the cancer and control groups regarding GPx1 Pro198Leu or CAT-262 C < T polymorphisms. CONCLUSION: Polymorphism of the MnSOD Val16Ala gene may contribute to susceptibility to laryngeal cancer among smokers. PMID- 24074041 TI - Edaravone, a free radical scavenger, attenuates cerebral infarction and hemorrhagic infarction in rats with hyperglycemia. AB - BACKGROUND: Thrombolysis due to acute ischemic stroke is associated with the risk of hemorrhagic infarction, especially after reperfusion. Recent experimental studies suggest that the main mechanism contributing to hemorrhagic infarction is oxidative stress caused by disruption of the blood-brain barrier. Edaravone, a free radical scavenger, decreases oxidative stress, thereby preventing hemorrhagic infarction during ischemia and reperfusion. In this study, we investigated the effects of edaravone on hemorrhagic infarction in a rat model of hemorrhagic transformation. METHODS: We used a previously established hemorrhagic transformation model of rats with hyperglycemia. Hyperglycemia was induced by intraperitoneal injection of glucose to all rats (n = 20). The rats with hyperglycemia showed a high incidence of hemorrhagic infarction. Middle cerebral artery occlusion (MCAO) for 1.5 hours followed by reperfusion for 24 hours was performed in edaravone-treated rats (n = 10) and control rats (n = 10). Upon completion of reperfusion, both groups were evaluated for infarct size and hemorrhage volume and the results obtained were compared. RESULTS: Edaravone significantly decreased infarct volume, with the average infarct volume in the edaravone-treated rats (227.6 mm(3)) being significantly lower than that in the control rats (264.0 mm(3)). Edaravone treatment also decreased the postischemic hemorrhage volumes (53.4 mm(3) in edaravone-treated rats vs 176.4 mm(3) in controls). In addition, the ratio of hemorrhage volume to infarct volume was lower in the edaravone-treated rats (23.5%) than in the untreated rats (63.2%). CONCLUSION: Edaravone attenuates cerebral infarction and hemorrhagic infarction in rats with hyperglycemia. PMID- 24074044 TI - Selective formation of hydrogen and hydroxyl radicals by electron beam irradiation and their reactivity with perfluorosulfonated acid ionomer. AB - Selective formation and reactivity of hydrogen (H(*)) and hydroxyl (HO(*)) radicals with perfluorinated sulfonated ionomer membrane, Nafion 211, is described. Selective formation of radicals was achieved by electron beam irradiation of aqueous solutions of H2O2 or H2SO4 to form HO(*) and H(*), respectively, and confirmed by ESR spectroscopy using a spin trap. The structure of Nafion 211 after reaction with H(*) or HO(*) was determined using calibrated (19)F magic angle spinning NMR spectroscopy. Soluble residues of degradation were analyzed by liquid and solid-state NMR. NMR and ATR-FTIR spectroscopy, together with determination of ion exchange capacity, water uptake, proton conductivity, and fluoride ion release, strongly indicate that attack by H(*) occurs at the tertiary carbon C-F bond on both the main and side chain; whereas attack by HO(*) occurs solely on the side chain, specifically, the alpha-O-C bond. PMID- 24074043 TI - Validation of a transcutaneous bilirubin meter in Mongolian neonates: comparison with total serum bilirubin. AB - BACKGROUND: Neonatal hyperbilirubinemia, especially kernicterus, can be prevented by screening for neonatal jaundice. The transcutaneous bilirubin (TcB) meter is a non-invasive medical device for screening neonates. The study aimed to investigate the validity of a TcB meter in a resource-limited setting such as Mongolia. METHODS: Term and late preterm neonates from the National Center for Maternal and Child Health of Ulaanbaatar in Mongolia who met the inclusion criteria (gestational age >=35 weeks, birth weight >=2000 g, postnatal age <= 1 month) were enrolled in the study. We used a TcB meter, JM-103 to screen for neonatal jaundice. TcB measurements at the infant's forehead and midsternum were performed within 3 h of obtaining samples for total serum bilirubin (TSB) measurement. We analyzed the correlation between TcB measurements and TSB measurements to validate the meter. RESULTS: A total of 47 term and six late preterm neonates were included in the study. TcB measured by the meter at both the forehead and the midsternum showed a strong correlation with TSB measured in the laboratory. The correlation equations were TSB = 1.409+0.8655 * TcB (R2=0.78871) at the forehead, and TSB = 0.7555+0.8974 * TcB (R2=0.78488) at the midsternum. Bland-Altman plots and the Bradley-Blackwood test showed no significant differences between the two methods at all measured ranges of bilirubin. The mean areas under the curves of TcB at the forehead and midsternum at three TSB levels (>10 mg/dL, >13 mg/dL, >15 mg/dL) of TcB were greater than 0.9, and all had high sensitivity and specificity. CONCLUSIONS: This study established the validity of the JM-103 meter as a screening tool for neonatal jaundice in term and late preterm infants in Mongolia. Future studies are needed, including the establishment of a TcB hour-specific nomogram, for more effective clinical practice to prevent severe hyperbilirubinemia. PMID- 24074042 TI - Genetic variation in the serotonin transporter and HTR1B receptor predicts reduced bone formation during serotonin reuptake inhibitor treatment in older adults. AB - OBJECTIVES: Studies have reported an association between serotonin reuptake inhibitors (SRIs) and accelerated bone loss. Genetic variation in the serotonin system might modulate bone metabolism changes during SRI treatment. In a clinical trial we examined functional genetic polymorphisms of serotonin transporter and receptors involved in bone metabolism to determine whether they predict changes in bone metabolism during SRI treatment. METHODS: In 69 adults (age >= 60) participating in a 12-week, open-label trial of the SRI venlafaxine for major depression, serum markers of bone formation (P1NP) and resorption (beta-CTX) were assayed before and after treatment. Participants were genotyped for putative high versus low-expressing polymorphisms in the serotonin transporter (5HTTLPR) and 1B receptor (HTR1B) genes. RESULTS: Bone formation was significantly reduced with administration of venlafaxine in participants with the high-expressing 5HTTLPR genotype and those with the low-expressing HTR1B genotype. This primarily occurred in individuals with the combination of the high-expressing 5HTTLPR genotype and the low-expressing HTR1B genotype. CONCLUSIONS: These preliminary findings indicate that genetic variation in the serotonin receptors predicts changes in bone metabolism during SRI use. If these results are replicated and clinically confirmed, we will have identified a genetic subgroup at high risk for deleterious bone outcomes with the use of SRIs. PMID- 24074045 TI - Highly sensitive two-photon sensing of thrombin in serum using aptamers and silver nanoparticles. AB - Thrombin plays an important role in pathological conditions. It is important, however challenging, to detect thrombin in complex biological media for clinical practice and diagnostic applications. Here we demonstrate a label-free, fast, highly sensitive and selective two-photon sensing scheme for detection of thrombin on the picomolar level. The assay is based on interactions between thrombin and a DNA aptamer, which induce aggregation of silver nanoparticles to display significantly enhanced two-photon photoluminescence. The limit of detection (LOD) of this two-photon sensing assay is as low as 3.1 pM in the buffer solution, more than 400 times lower than that of the extinction method (1.3 nM). The dynamic range of this method covers more than 4 orders of magnitude. Furthermore, this two-photon sensing assay can be applied to detection of thrombin in 100% fetal bovine serum with LOD of 1.8 nM. In addition to the unique advantages of two-photon sensing such as deep penetration and localized detection, this method could be potentially integrated with two-photon microscopy to offer additional advantages of 3D detection and mapping for potential in vivo applications. PMID- 24074049 TI - The application of autologous serum eye drops in severe dry eye patients; subjective and objective parameters before and after treatment. AB - AIM: To assess the impact of autologous serum (AS) eye drops on the ocular surface of patients with bilateral severe dry eye and to draw a comparison between the clinical and laboratory examinations and the degree of subjective symptoms before and after serum treatment. MATERIALS AND METHODS: A three-month prospective study was conducted on 17 patients with severe dry eye. AS eye drops were applied a maximum of 12 times a day together with regular therapy. Dry eye status was evaluated by clinical examination (visual acuity, Schirmer test, tear film breakup time, vital staining, tear film debris and meniscus), conjunctival impression cytology (epithelial and goblet cell density, snake-like chromatin, HLA-DR-positive and apoptotic cells) and subjectively by the patients. RESULTS: The application of AS eye drops led to a significant improvement in the Schirmer test (p < 0.01) and tear film debris (p < 0.05). The densities of goblet (p < 0.0001) and epithelial cells (p < 0.05) were significantly increased, indicating a decrease of squamous metaplasia after AS treatment. A significant decrease (p < 0.05) was found in the number of apoptotic, HLA-DR-positive and snake-like chromatin cells on the ocular surface. A significant improvement was found in all evaluated subjective symptoms. Altogether, the clinical results were improved in 77%, the laboratory results in 75% and the subjective feelings in 63% of the eyes. CONCLUSIONS: We found that three-month AS treatment led especially to the improvement of ocular surface dryness and damage of the epithelium. The improvement of dry eye after AS treatment correlated well with the clinical, laboratory and subjective findings. From the patients' subjective point of view, the positive effect of AS decreased with time, but still persisted up to three months after the end of therapy. PMID- 24074050 TI - Dynamics of organohalogenated contaminants in human serum from obese individuals during one year of weight loss treatment. AB - We investigated the dynamics of several organohalogenated contaminants (OHCs) and their metabolites in an obese population during weight loss. Serum samples from obese individuals were taken before patients lost weight and after three, six, and twelve months. Samples were also collected from a matched lean control population. Analyzed OHCs were polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (HO-PCBs), pentachlorophenol (PCP), polybrominated diphenyl ethers, and organochlorine pesticides (OCPs). Significantly lower concentrations of major PCBs, their metabolites, and PCP were measured in obese individuals at the initial moment of their enrolling in the project. While dilution differences might be responsible for the lower concentrations in the neutral OHCs, we suggest that a lower CYP-mediated metabolic activity can partially explain the data for the HO-PCBs. Additionally, lower chlorinated substituted PCBs had a higher percentage contribution to the sum PCBs in obese individuals, while higher chlorinated PCBs had a higher contribution for the controls. Increasing serum levels for all OHCs were observed during weight loss. The release from adipose tissue seemed dependent on the octanol-water partition coefficient, since OHCs with higher log Kow values displayed a higher release in serum. This also influenced the HO-PCBs profile after weight loss with lower chlorinated HO-PCBs increasingly gaining importance. Although weight loss is beneficial, it also influences the release of OHCs from adipose tissue and their metabolism. Therefore, the increase in the levels of compounds with endocrine effects might be of concern. PMID- 24074051 TI - The experience of disagreement between students and supervisors in PhD education: a qualitative study. AB - BACKGROUND: PhD supervision is mostly individual and disagreement between supervisors and PhD students is a seldom-discussed topic at universities. The present study aimed to describe the experience of disagreement between PhD students and supervisors. METHODS: Nine supervisors and seven PhD students from Sweden and England were interviewed using a video recorder. The recorded material was analysed using inductive content analysis. RESULTS: Disagreements in PhD education can be described with the overarching theme: the nature of the disagreements changes over time. Five categories emerged to describe the variations of the experiences: involvement in important decisions, supervisors not being up-to-date, dubious advice from supervisors, mediating between supervisors, and interpersonal relationships. CONCLUSIONS: There is a gradual shift in competence where PhD students may excel supervisors in subject knowledge. Early disagreements may indicate immaturity of the student while disagreements later may indicate that the student is maturing making their own decisions. Consequently, disagreements may need to be addressed differently depending on when they occur. Addressing them inappropriately might slow the progressions and result in higher attrition rate among PhD students. The five categories may be elements in future PhD supervisor training programs and should be further evaluated for their importance and impact on PhD education. PMID- 24074052 TI - Probing structural requirements of positive allosteric modulators of the M4 muscarinic receptor. AB - The M4 mAChR is implicated in several CNS disorders and possesses an allosteric binding site for which ligands modulating the affinity and/or efficacy of ACh may be exploited for selective receptor targeting. We report the synthesis of a focused library of putative M4 PAMs derived from VU0152100 and VU10005. These compounds investigate the pharmacological effects of previously identified methoxy and fluoro substituents, providing useful estimates of affinity (KB), cooperativity (alphabeta), and direct agonist properties (tauB). PMID- 24074055 TI - Is exercise-in-a-bottle likely to proffer new insights into Alzheimer's disease? PMID- 24074053 TI - Correlates of physician burnout across regions and specialties: a meta-analysis. AB - BACKGROUND: Health care organizations globally realize the need to address physician burnout due to its close linkages with quality of care, retention and migration. The many functions of health human resources include identifying and managing burnout risk factors for health professionals, while also promoting effective coping. Our study of physician burnout aims to show: (1) which correlates are most strongly associated with emotional exhaustion (EE) and depersonalization (DP), and (2) whether the associations vary across regions and specialties. METHODS: Meta-analysis allowed us to examine a diverse range of correlates. Our search yielded 65 samples of physicians from various regions and specialties. RESULTS: EE was negatively associated with autonomy, positive work attitudes, and quality and safety culture. It was positively associated with workload, constraining organizational structure, incivility/conflicts/violence, low quality and safety standards, negative work attitudes, work-life conflict, and contributors to poor mental health. We found a similar but weaker pattern of associations for DP.Physicians in the Americas experienced lower EE levels than physicians in Europe when quality and safety culture and career development opportunities were both strong, and when they used problem-focused coping. The former experienced higher EE levels when work-life conflict was strong and they used ineffective coping. Physicians in Europe experienced lower EE levels than physicians in the Americas with positive work attitudes. We found a similar but weaker pattern of associations for DP.Outpatient specialties experienced higher EE levels than inpatient specialties when organization structures were constraining and contributors to poor mental health were present. The former experienced lower EE levels when autonomy was present. Inpatient specialties experienced lower EE levels than outpatient specialties with positive work attitudes. As above, we found a similar but weaker pattern of associations for DP. CONCLUSIONS: Although we could not infer causality, our findings suggest: (1) that EE represents the core burnout dimension; (2) that certain individual and organizational-level correlates are associated with reduced physician burnout; (3) the benefits of directing resources where they are most needed to physicians of different regions and specialties; and (4) a call for research to link physician burnout with performance. PMID- 24074056 TI - The current status and trend of clinical pharmacology in developing countries. AB - BACKGROUND: Several international forums for promoting clinical pharmacology in developing countries have been held since 1980, and several clinical pharmacology programmes targeting developing countries were instituted such that the status of clinical pharmacology in developing countries is not where it was 50 years ago. Therefore, a survey and an appraisal of the literature on the current status of clinical pharmacology in developing countries were undertaken with a hope that it would enable development of appropriate strategies for further promotion of clinical pharmacology in these countries. METHODS: First, nine determinants (or enabling factors) for running a successful clinical pharmacology programme were identified, i.e., disease burden, drug situation, economic growth, clinical pharmacology activities, recognition, human capital, government support, international collaboration, and support for traditional/alternative medicines. These factors were then evaluated with regard to their current status in the developing countries that responded to an electronic questionnaire, and their historical perspective, using the literature appraisal. From these, a projected trend was constructed with recommendations on the way forward. RESULTS: Clinical pharmacology services, research and teaching in developing countries have improved over the past 50 years with over 90% of countries having the appropriate policies for regulation and rational use of medicines in place. Unfortunately, policy implementation remains a challenge, owing to a worsening disease burden and drug situation, versus fewer clinical pharmacologists and other competing priorities for the national budgets. This has led to a preference for training 'a physician clinical pharmacologist' in programmes emphasizing local relevancy and for a shorter time, and the training of other professionals in therapeutics for endemic diseases (task shifting), as the most promising strategies of ensuring rational use of medicines. CONCLUSION: Clinical pharmacology in developing countries is advancing in a different way to that in the developed world and continuing support for these efforts will go a long way in promoting improved health for all. PMID- 24074057 TI - The effects of acute renal failure on drug metabolism. AB - INTRODUCTION: Acute kidney injury (AKI) is common in all hospital admissions and affects 10% of acute admissions in hospital. It increases the risk of adverse events and mortality, although the precise reasons for this are still unclear. The impact of chronic kidney disease (CKD) on nonrenal drug clearance is increasingly apparent and is now considered an important factor by the Food and Drug Administration for drug dose recommendations in CKD. AREAS COVERED: This review explores the evidence of the impact of AKI on nonrenal drug metabolism. The review uses evidence from investigations of both CKD and AKI describing the manner of the inhibition and the most likely mediators of renohepatic crosstalk. The review also considers other forms of nonrenal clearance, including gut metabolism. Changes are related to critical illness in general, where appropriate. EXPERT OPINION: Renal and hepatic interactions are highly complex with increasing evidence for an important relationship between AKI and hepatic metabolism. Current recommended dosing regimens are inadequate for AKI patients and much greater understanding of the interaction between the kidney and liver is required. More extensive therapeutic drug monitoring may be required to optimize drug regimens. PMID- 24074058 TI - Zizyphus jujuba protects against ibuprofen-induced nephrotoxicity in rats. AB - CONTEXT: Zizyphus jujuba Mill. (Rhamnaceae) has long been used for the treatment of anxiety and insomnia in Chinese traditional medicine. The edible part is the fruit. Different parts of Z. jujuba possess medicinal properties such as anti inflammatory, anticancer and antifertility. OBJECTIVES: This study evaluated the therapeutic effect of Z. jujuba fruit aqueous extract (ZE) on nephrotoxicity induced by ibuprofen (IBP) in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were grouped as normal saline (control), ZE (500 mg/kg), IBP (400 mg/kg) and ZE + IBP-treated groups. After five days of oral administration, rats were sacrificed. The protective effect of ZE was evaluated by measuring kidney biomarkers, and histopathological changes of kidney were observed. Kidney antioxidant enzymes such as superoxide dismutase, catalase (CAT), glutathione S transferase (GST) and lipid peroxidase were investigated. RESULTS: Administration of IBP resulted in a significant increase in urea and creatinine (p < 0.05) and a significant decrease in albumin and total protein (p < 0.05). Damage in glomeruli and proximal convoluted tubules was observed. IBP also increased CAT (p < 0.05) and GST (p < 0.001) activities compared to the control group. Administration of ZE with IBP significantly decreased serum urea and creatinine (p < 0.05) and reduced the severity of kidney damage. There was also a significant increase in the activities of CAT (p < 0.05) and GST (p < 0.001). DISCUSSION AND CONCLUSION: These results indicated that Z. jujuba aqueous extract could have a therapeutic role in reducing nephrotoxicity induced by ibuprofen. PMID- 24074059 TI - Knockout of a putative ergothioneine transporter in Caenorhabditis elegans decreases lifespan and increases susceptibility to oxidative damage. AB - In addition to excretion of metabolic waste products, organic ionic transporters facilitate uptake of specific compounds of physiological importance. In animals, the organic cation transporter, OCTN1 was found to enable the specific uptake of the unique amino acid, ergothioneine (EGT). EGT can accumulate in the body at up to millimolar concentrations and is believed to function as a physiological antioxidant. However the main function of EGT and the reasons for its active accumulation in the body remain obscure. Through bioinformatic approaches, we identified an analogous EGT transporter in the nematode, Caenorhabditis elegans. The present study investigated and characterized deletion mutants of this gene, OCT-1, in the nematodes. Gene deletion mutations of the OCT-1 transporter were shown to decrease overall lifespan of the worms and increase oxidative damage. However the absence of impaired EGT uptake and the inability of excess EGT to rescue the debilitating phenotype indicate that EGT transport does not explain the deleterious effects of the gene deletion. PMID- 24074060 TI - Emerging insights into the function and regulation of the cytosolic sulfotransferases. Preface. PMID- 24074061 TI - Quantum information processing with hybrid spin-photon qubit encoding. AB - We introduce a scheme to perform quantum information processing that is based on a hybrid spin-photon qubit encoding. The proposed qubits consist of spin ensembles coherently coupled to microwave photons in coplanar waveguide resonators. The quantum gates are performed solely by shifting the resonance frequencies of the resonators on a nanosecond time scale. An additional cavity containing a Cooper-pair box is exploited as an auxiliary degree of freedom to implement two-qubit gates. The generality of the scheme allows its potential implementation with a wide class of spin systems. PMID- 24074062 TI - Maximally entangled set of multipartite quantum states. AB - Entanglement is a resource in quantum information theory when state manipulation is restricted to local operations assisted by classical communication (LOCC). It is therefore of paramount importance to decide which LOCC transformations are possible and, particularly, which states are maximally useful under this restriction. While the bipartite maximally entangled state is well known (it is the only state that cannot be obtained from any other and, at the same time, it can be transformed to any other by LOCC), no such state exists in the multipartite case. In order to cope with this fact, we introduce here the notion of the maximally entangled set (MES) of n-partite states. This is the set of states which are maximally useful under LOCC manipulation; i.e., any state outside of this set can be obtained via LOCC from one of the states within the set and no state in the set can be obtained from any other state via LOCC. We determine the MES for states of three and four qubits and provide a simple characterization for them. In both cases, infinitely many states are required. However, while the MES is of measure zero for 3-qubit states, almost all 4-qubit states are in the MES. This is because, in contrast to the 3-qubit case, deterministic LOCC transformations are almost never possible among fully entangled four-partite states. We determine the measure-zero subset of the MES of LOCC convertible states. This is the only relevant class of states for entanglement manipulation. PMID- 24074063 TI - Multipartite entanglement witnesses. AB - We derive a set of algebraic equations, the so-called multipartite separability eigenvalue equations. Based on their solutions, we introduce a universal method for the construction of multipartite entanglement witnesses. We witness multipartite entanglement of 10(3) coupled quantum oscillators, by solving our basic equations analytically. This clearly demonstrates the feasibility of our method for studying ultrahigh orders of multipartite entanglement in complex quantum systems. PMID- 24074064 TI - Superconducting circuits for quantum simulation of dynamical gauge fields. AB - We describe a superconducting-circuit lattice design for the implementation and simulation of dynamical lattice gauge theories. We illustrate our proposal by analyzing a one-dimensional U(1) quantum-link model, where superconducting qubits play the role of matter fields on the lattice sites and the gauge fields are represented by two coupled microwave resonators on each link between neighboring sites. A detailed analysis of a minimal experimental protocol for probing the physics related to string breaking effects shows that, despite the presence of decoherence in these systems, distinctive phenomena from condensed-matter and high-energy physics can be visualized with state-of-the-art technology in small superconducting-circuit arrays. PMID- 24074065 TI - Diffusion of interacting particles in discrete geometries. AB - We evaluate the self-diffusion and transport diffusion of interacting particles in a discrete geometry consisting of a linear chain of cavities, with interactions within a cavity described by a free-energy function. Exact analytical expressions are obtained in the absence of correlations, showing that the self-diffusion can exceed the transport diffusion if the free-energy function is concave. The effect of correlations is elucidated by comparison with numerical results. Quantitative agreement is obtained with recent experimental data for diffusion in a nanoporous zeolitic imidazolate framework material, ZIF-8. PMID- 24074066 TI - Thermodynamic efficiency of pumped heat electricity storage. AB - Pumped heat electricity storage (PHES) has been recently suggested as a potential solution to the large-scale energy storage problem. PHES requires neither underground caverns as compressed air energy storage (CAES) nor kilometer-sized water reservoirs like pumped hydrostorage and can therefore be constructed anywhere in the world. However, since no large PHES system exists yet, and theoretical predictions are scarce, the efficiency of such systems is unknown. Here we formulate a simple thermodynamic model that predicts the efficiency of PHES as a function of the temperature of the thermal energy storage at maximum output power. The resulting equation is free of adjustable parameters and nearly as simple as the well-known Carnot formula. Our theory predicts that for storage temperatures above 400 degrees C PHES has a higher efficiency than existing CAES and that PHES can even compete with the efficiencies predicted for advanced adiabatic CAES. PMID- 24074067 TI - Optical-frequency transfer over a single-span 1840 km fiber link. AB - To compare the increasing number of optical frequency standards, highly stable optical signals have to be transferred over continental distances. We demonstrate optical-frequency transfer over a 1840-km underground optical fiber link using a single-span stabilization. The low inherent noise introduced by the fiber allows us to reach short term instabilities expressed as the modified Allan deviation of 2*10(-15) for a gate time tau of 1 s reaching 4*10(-19) in just 100 s. We find no systematic offset between the sent and transferred frequencies within the statistical uncertainty of about 3*10(-19). The spectral noise distribution of our fiber link at low Fourier frequencies leads to a tau(-2) slope in the modified Allan deviation, which is also derived theoretically. PMID- 24074068 TI - Black holes with surrounding matter in scalar-tensor theories. AB - We uncover two mechanisms that can render Kerr black holes unstable in scalar tensor gravity, both associated with the presence of matter in the vicinity of the black hole and the fact that this introduces an effective mass for the scalar. Our results highlight the importance of understanding the structure of spacetime in realistic, astrophysical black holes in scalar-tensor theories. PMID- 24074069 TI - Zwei-dreibein gravity: a two-frame-field model of 3D massive gravity. AB - We present a generally covariant and parity-invariant two-frame field ("zwei dreibein") action for gravity in three space-time dimensions that propagates two massive spin-2 modes, unitarily, and we use Hamiltonian methods to confirm the absence of unphysical degrees of freedom. We show how zwei-dreibein gravity unifies previous "3D massive gravity" models and extends them, in the context of the AdS/CFT correspondence, to allow for a positive central charge consistent with bulk unitarity. PMID- 24074070 TI - No-scale supergravity realization of the Starobinsky model of inflation. AB - We present a model for cosmological inflation based on a no-scale supergravity sector with an SU(2,1)/SU(2)*U(1) Kahler potential, a single modulus T, and an inflaton superfield Phi described by a Wess-Zumino model with superpotential parameters (MU, lambda). When T is fixed, this model yields a scalar spectral index n(s) and a tensor-to-scalar ratio r that are compatible with the Planck measurements for values of lambda?MU/3M(P). For the specific choice lambda=MU/3M(P), the model is a no-scale supergravity realization of the R+R2 Starobinsky model. PMID- 24074071 TI - Cosmic microwave background anomalies in an open universe. AB - We argue that the observed large-scale cosmic microwave anomalies, discovered by WMAP and confirmed by the Planck satellite, are most naturally explained in the context of a marginally open universe. Particular focus is placed on the dipole power asymmetry, via an open universe implementation of the large-scale gradient mechanism of Erickcek et al. Open inflation models, which are motivated by the string landscape and which can excite "supercurvature" perturbation modes, can explain the presence of a very-large-scale perturbation that leads to a dipole modulation of the power spectrum measured by a typical observer. We provide a specific implementation of the scenario which appears compatible with all existing constraints. PMID- 24074073 TI - Bounding the Higgs boson width through interferometry. AB - We study the change in the diphoton-invariant-mass distribution for Higgs boson decays to two photons, due to interference between the Higgs resonance in gluon fusion and the continuum background amplitude for gg->gammagamma. Previously, the apparent Higgs mass was found to shift by around 100 MeV in the standard model in the leading-order approximation, which may potentially be experimentally observable. We compute the next-to-leading-order QCD corrections to the apparent mass shift, which reduce it by about 40%. The apparent mass shift may provide a way to measure, or at least bound, the Higgs boson width at the Large Hadron Collider through "interferometry." We investigate how the shift depends on the Higgs width, in a model that maintains constant Higgs boson signal yields. At Higgs widths above 30 MeV, the mass shift is over 200 MeV and increases with the square root of the width. The apparent mass shift could be measured by comparing with the ZZ* channel, where the shift is much smaller. It might be possible to measure the shift more accurately by exploiting its strong dependence on the Higgs transverse momentum. PMID- 24074075 TI - Physics of the gluon-helicity contribution to proton spin. AB - The total gluon helicity in a polarized proton, measurable in high-energy scattering, is shown to be the large momentum limit of a gauge-invariant but nonlocal, frame-dependent gluon spin E * A? in QCD. This opens a door for a nonperturbative calculation of this quantity in lattice QCD and also justifies using free-field expressions in the light-cone gauge as physical observables. PMID- 24074074 TI - Search for bottomonium states in exclusive radiative Upsilon(2S) decays. AB - We search for bottomonium states in Upsilon(2S) -> (bb)gamma decays with an integrated luminosity of 24.7 fb(-1) recorded at the Upsilon(2S) resonance with the Belle detector at KEK, containing (157.8+/-3.6)*10(6) Upsilon(2S) events. The (bb) system is reconstructed in 26 exclusive hadronic final states composed of charged pions, kaons, protons, and K(S)(0) mesons. We find no evidence for the state recently observed around 9975 MeV (X(bb)) in an analysis based on a data sample of 9.3*10(6) Upsilon(2S) events collected with the CLEO III detector. We set a 90% confidence level upper limit on the branching fraction B[Upsilon(2S) -> X(bb)gamma] * ?(i)B[X(bb) -> h(i)] < 4.9*10(-6), summed over the exclusive hadronic final states employed in our analysis. This result is an order of magnitude smaller than the measurement reported with CLEO data. We also set an upper limit for the etab(1S) state of B[Upsilon(2S) -> etab(1S)gamma] * ?(i)B[etab(1S) -> h(i)] < 3.7*10(-6). PMID- 24074077 TI - Model-independent extraction of the pole and Breit-Wigner resonance parameters. AB - We show that a slightly modified Breit-Wigner formula can successfully describe the total cross section even for the broad resonances, from the light rho(770) to the heavy Z boson. In addition to the mass, width, and branching fraction, we include another resonance parameter that turns out to be directly related to the pole residue phase. The new formula has two mathematically equivalent forms: one with the pole and the other with the Breit-Wigner parameters. PMID- 24074078 TI - Cross-section measurements of the 86Kr(gamma,n) reaction to probe the s-process branching at 85Kr. AB - We have carried out photodisintegration cross-section measurements on 86Kr using monoenergetic photon beams ranging from the neutron separation energy, S(n) = 9.86 MeV, to 13 MeV. We combine our experimental 86Kr(gamma,n)85Kr cross section with results from our recent 86Kr(gamma,gamma') measurement below the neutron separation energy to obtain the complete nuclear dipole response of 86Kr. The new experimental information is used to predict the neutron capture cross section of 85Kr, an important branching point nucleus on the abundance flow path during s process nucleosynthesis. Our new and more precise 85Kr(n,gamma)86Kr cross section allows us to produce more precise predictions of the 86Kr abundance from s process models. In particular, we find that the models of the s process in asymptotic giant branch stars of mass <1.5M?, where the 13C neutron source burns convectively rather than radiatively, represent a possible solution for the highest 86Kr:82Kr ratios observed in meteoritic stardust SiC grains. PMID- 24074080 TI - Equation of state for nucleonic matter and its quark mass dependence from the nuclear force in lattice QCD. AB - Quark mass dependence of the equation of state (EOS) for nucleonic matter is investigated, on the basis of the Brueckner-Hartree-Fock method with the nucleon nucleon interaction extracted from lattice QCD simulations. We observe saturation of nuclear matter at the lightest available quark mass corresponding to the pseudoscalar meson mass ?469 MeV. Mass-radius relation of the neutron stars is also studied with the EOS for neutron-star matter from the same nuclear force in lattice QCD. We observe that the EOS becomes stiffer and thus the maximum mass of neutron star increases as the quark mass decreases toward the physical point. PMID- 24074079 TI - Spectroscopy of element 115 decay chains. AB - A high-resolution alpha, x-ray, and gamma-ray coincidence spectroscopy experiment was conducted at the GSI Helmholtzzentrum fur Schwerionenforschung. Thirty correlated alpha-decay chains were detected following the fusion-evaporation reaction 48Ca + 243Am. The observations are consistent with previous assignments of similar decay chains to originate from element Z=115. For the first time, precise spectroscopy allows the derivation of excitation schemes of isotopes along the decay chains starting with elements Z>112. Comprehensive Monte Carlo simulations accompany the data analysis. Nuclear structure models provide a first level interpretation. PMID- 24074081 TI - Wigner crystallization of single photons in cold Rydberg ensembles. AB - The coupling of weak light fields to Rydberg states of atoms under conditions of electromagnetically induced transparency leads to the formation of Rydberg polaritons which are quasiparticles with tunable effective mass and nonlocal interactions. Confined to one spatial dimension their low energy physics is that of a moving-frame Luttinger liquid which, due to the nonlocal character of the repulsive interaction, can form a Wigner crystal of individual photons. We calculate the Luttinger K parameter using density-matrix renormalization group simulations and find that under typical slow-light conditions kinetic energy contributions are too strong for crystal formation. However, adiabatically increasing the polariton mass by turning a light pulse into stationary spin excitations allows us to generate true crystalline order over a finite length. The dynamics of this process and asymptotic correlations are analyzed in terms of a time-dependent Luttinger theory. PMID- 24074072 TI - Measurement of the D*(2010)+ meson width and the D*(2010)+ - D0 mass difference. AB - We measure the mass difference Deltam0 between the D*(2010)+ and the D0 and the natural linewidth Gamma of the transition D*(2010)+ -> D0pi+. The data were recorded with the BABAR detector at center-of-mass energies at and near the Upsilon(4S) resonance, and correspond to an integrated luminosity of approximately 477 fb(-1). The D0 is reconstructed in the decay modes D0 -> K- pi+ and D0 -> K- pi+ pi- pi+. For the decay mode D0 -> K- pi+ we obtain Gamma = (83.4+/-1.7+/-1.5) keV and Deltam0 = (145425.6+/-0.6+/-1.7) keV, [corrected] where the quoted errors are statistical and systematic, respectively. For the D0 > K- pi+ pi- pi+ mode we obtain Gamma = (83.2+/-1.5+/-2.6) keV and Deltam0 = (145426.6+/-0.5+/-1.9) keV. [corrected] The combined measurements yield Gamma = (83.3+/-1.2+/-1.4) keV and Deltam0 = (145425.9+/-0.4+/-1.7) keV; the width is a factor of approximately 12 times more precise than the previous value, while the mass difference is a factor of approximately 6 times more precise. PMID- 24074082 TI - Enhanced atom interferometer readout through the application of phase shear. AB - We present a method for determining the phase and contrast of a single shot of an atom interferometer. The application of a phase shear across the atom ensemble yields a spatially varying fringe pattern at each output port, which can be imaged directly. This method is broadly relevant to atom-interferometric precision measurement, as we demonstrate in a 10 m 87Rb atomic fountain by implementing an atom-interferometric gyrocompass with 10 mdeg precision. PMID- 24074083 TI - Observation of electron energy discretization in strong field double ionization. AB - We report on the observation of discrete structures in the electron energy distribution for strong field double ionization of argon at 394 nm. The experimental conditions were chosen in order to ensure a nonsequential ejection of both electrons with an intermediate rescattering step. We have found discrete above-threshold ionization like peaks in the sum energy of both electrons, as predicted by all quantum mechanical calculations. More surprisingly, however, is the observation of two above-threshold ionization combs in the energy distribution of the individual electrons. PMID- 24074084 TI - Three-body bound states in atomic mixtures with resonant p-wave interaction. AB - We employ the Born-Oppenheimer approximation to find the effective potential in a three-body system consisting of a light particle and two heavy ones when the heavy-light short-range interaction potential has a resonance corresponding to a nonzero orbital angular momentum. In the case of an exact resonance in the p-wave scattering amplitude, the effective potential is attractive and long range; namely, it decreases as the third power of the interatomic distance. Moreover, we show that the range and power of the potential, as well as the number of bound states, are determined by the mass ratio of the particles and the parameters of the heavy-light short-range potential. PMID- 24074085 TI - Stochastic Heisenberg limit: optimal estimation of a fluctuating phase. AB - The ultimate limits to estimating a fluctuating phase imposed on an optical beam can be found using the recently derived continuous quantum Cramer-Rao bound. For Gaussian stationary statistics, and a phase spectrum scaling asymptotically as omega(-p) with p>1, the minimum mean-square error in any (single-time) phase estimate scales as N(-2(p-1)/(p+1)), where N is the photon flux. This gives the usual Heisenberg limit for a constant phase (as the limit p->infinity) and provides a stochastic Heisenberg limit for fluctuating phases. For p=2 (Brownian motion), this limit can be attained by phase tracking. PMID- 24074086 TI - Coherent control of quantum fluctuations using cavity electromagnetically induced transparency. AB - We study the all-optical control of the quantum fluctuations of a light beam via a combination of single-atom cavity quantum electrodynamics (CQED) and electromagnetically induced transparency (EIT). Specifically, the EIT control field is used to tune the CQED transition frequencies in and out of resonance with the probe light. In this way, photon blockade and antiblockade effects are employed to produce sub-Poissonian and super-Poissonian light fields, respectively. The achievable quantum control paves the way towards the realization of a prototype of a novel quantum transistor which amplifies or attenuates the relative intensity noise of a light beam. Its feasibility is demonstrated by calculations using realistic parameters from recent experiments. PMID- 24074087 TI - Nonequilibrium phase transition in a dilute Rydberg ensemble. AB - We demonstrate a nonequilibrium phase transition in a dilute thermal atomic gas. The phase transition, between states of low and high Rydberg occupancy, is induced by resonant dipole-dipole interactions between Rydberg atoms. The gas can be considered as dilute as the atoms are separated by distances much greater than the wavelength of the optical transitions used to excite them. In the frequency domain, we observe a mean-field shift of the Rydberg state which results in intrinsic optical bistability above a critical Rydberg number density. In the time domain, we observe critical slowing down where the recovery time to system perturbations diverges with critical exponent alpha=-0.53+/-0.10. The atomic emission spectrum of the phase with high Rydberg occupancy provides evidence for a superradiant cascade. PMID- 24074088 TI - Incoherent dispersive shocks in the spectral evolution of random waves. AB - We predict theoretically and numerically the existence of incoherent dispersive shock waves. They manifest themselves as an unstable singular behavior of the spectrum of incoherent waves that evolve in a noninstantaneous nonlinear environment. This phenomenon of "spectral wave breaking" develops in the weakly nonlinear regime of the random wave. We elaborate a general theoretical formulation of these incoherent objects on the basis of a weakly nonlinear statistical approach: a family of singular integro-differential kinetic equations is derived, which provides a detailed deterministic description of the incoherent dispersive shock wave phenomenon. PMID- 24074089 TI - Rogue waves emerging from the resonant interaction of three waves. AB - We introduce a novel family of analytic solutions of the three-wave resonant interaction equations for the purpose of modeling unique events, i.e., "amplitude peaks" which are isolated in space and time. The description of these solutions is likely to be a crucial step in the understanding and forecasting of rogue waves in a variety of multicomponent wave dynamics, from oceanography to optics and from plasma physics to acoustics. PMID- 24074090 TI - Hierarchical fractal Weyl laws for chaotic resonance states in open mixed systems. AB - In open chaotic systems the number of long-lived resonance states obeys a fractal Weyl law, which depends on the fractal dimension of the chaotic saddle. We study the generic case of a mixed phase space with regular and chaotic dynamics. We find a hierarchy of fractal Weyl laws, one for each region of the hierarchical decomposition of the chaotic phase-space component. This is based on our observation of hierarchical resonance states localizing on these regions. Numerically this is verified for the standard map and a hierarchical model system. PMID- 24074091 TI - Solid drops: large capillary deformations of immersed elastic rods. AB - Under the effect of surface tension, a blob of liquid adopts a spherical shape when immersed in another fluid. We demonstrate experimentally that soft, centimeter-size elastic solids can exhibit a similar behavior: when immersed into a liquid, a gel having a low elastic modulus undergoes large, reversible deformations. We analyze three fundamental types of deformations of a slender elastic solid driven by surface stress, depending on the shape of its cross section: a circular elastic cylinder shortens in the longitudinal direction and stretches transversally; the sharp edges of a square based prism get rounded off as its cross sections tend to become circular; and a slender, triangular based prism bends. These experimental results are compared to analysis and nonlinear simulations of neo-Hookean solids deformed by surface tension and are found to be in good agreement with each other. PMID- 24074092 TI - Polymer-induced drag enhancement in turbulent Taylor-Couette flows: direct numerical simulations and mechanistic insight. AB - We report for the first time the polymer-induced breakdown of large-scale Taylor vortex structures leading to drag enhancement in viscoelastic turbulent Taylor Couette flows. Specifically, we demonstrate that upon the addition of trace amounts of soluble high molecular weight macromolecules the Newtonian large-scale Taylor vortices are replaced by small-scale vortices in the inner and outer cylinder wall regions. This flow transition and a commensurate drag increase of up to 62% are facilitated by the presence of large polymeric normal stresses in a narrow region immediately close to the outer wall. A simple mechanism for this striking flow transition is proposed with the aim of paving the way for a mechanistic understanding of polymer-induced structure and drag modifications in high-Re turbulent curvilinear flows. PMID- 24074094 TI - Observation of time-domain modulation of free-electron-laser pulses by multipeaked electron-energy spectrum. AB - We present the experimental demonstration of a new scheme for the generation of ultrashort pulse trains based on free-electron-laser (FEL) emission from a multipeaked electron energy distribution. Two electron beamlets with energy difference larger than the FEL parameter rho have been generated by illuminating the cathode with two ps-spaced laser pulses, followed by a rotation of the longitudinal phase space by velocity bunching in the linac. The resulting self amplified spontaneous emission FEL radiation, measured through frequency-resolved optical gating diagnostics, reveals a double-peaked spectrum and a temporally modulated pulse structure. PMID- 24074093 TI - Generation of coherent 19- and 38-nm radiation at a free-electron laser directly seeded at 38 nm. AB - Initiating the gain process in a free-electron laser (FEL) from an external highly coherent source of radiation is a promising way to improve the pulse properties such as temporal coherence and synchronization performance in time resolved pump-probe experiments at FEL facilities, but this so-called "seeding" suffers from the lack of adequate sources at short wavelengths. We report on the first successful seeding at a wavelength as short as 38.2 nm, resulting in GW level, coherent FEL radiation pulses at this wavelength as well as significant second harmonic emission at 19.1 nm. The external seed pulses are about 1 order of magnitude shorter compared to previous experiments allowing an ultimate time resolution for the investigation of dynamic processes enabling breakthroughs in ultrafast science with FELs. The seeding pulse is the 21st harmonic of an 800-nm, 15-fs (rms) laser pulse generated in an argon medium. Methods for finding the overlap of seed pulses with electron bunches in spatial, longitudinal, and spectral dimensions are discussed and results are presented. The experiment was conducted at FLASH, the FEL user facility at DESY in Hamburg, Germany. PMID- 24074095 TI - High resolution energy-angle correlation measurement of hard x rays from laser Thomson backscattering. AB - Thomson backscattering of intense laser pulses from relativistic electrons not only allows for the generation of bright x-ray pulses but also for the investigation of the complex particle dynamics at the interaction point. For this purpose a complete spectral characterization of a Thomson source powered by a compact linear electron accelerator is performed with unprecedented angular and energy resolution. A rigorous statistical analysis comparing experimental data to 3D simulations enables, e.g., the extraction of the angular distribution of electrons with 1.5% accuracy and, in total, provides predictive capability for the future high brightness hard x-ray source PHOENIX (photon electron collider for narrow bandwidth intense x rays) and potential gamma-ray sources. PMID- 24074096 TI - Dynamics of nonlinear coupling between electron-temperature-gradient mode and drift-wave mode in linear magnetized plasmas. AB - A high-frequency (~0.4 MHz) fluctuation is excited by an electron temperature gradient (ETG) perpendicular to magnetic field lines, which is consistent with an ETG mode. When the fluctuation amplitude of the ETG mode exceeds a certain threshold, the mode gradually becomes saturated and a low-frequency (~7 kHz) fluctuation which is originally caused by a drift wave is enhanced, corresponding to the saturation of the ETG mode. In addition, a nonlinear coupling, specifically, the bicoherence between the ETG mode and the drift wave mode, begins to increase when the ETG strength exceeds the threshold, which simultaneously occurs with the saturation of the ETG mode. Thus, it was determined that the ETG mode stimulates the drift wave mode excitement via multiscale nonlinear interaction between the high-frequency (~MHz) and low frequency (~kHz) fluctuations, which ultimately causes ETG mode energy to be transferred to the drift wave mode. PMID- 24074097 TI - Sheath-induced instabilities in plasmas with E0*B0 drift. AB - It is shown that ion acoustic waves in plasmas with E0*B0 electron drift become unstable due to the closure of plasma current in the chamber wall. Such unstable modes may enhance both near-wall conductivity and turbulent electron transport in plasma devices with E0*B0 electron drift and unmagnetized ions. It is shown that the instability is sensitive to the wall material: a high value of the dielectric permittivity (such as in metal walls) reduces the mode growth rate by an order of magnitude but does not eliminate the instability completely. PMID- 24074098 TI - Observation of neutron bursts produced by laboratory high-voltage atmospheric discharge. AB - For the first time the emission of neutron bursts in the process of high-voltage discharge in air was observed. Experiments were carried out at an average electric field strength of ~1 MV.m(-1) and discharge current of ~10 kA. Two independent methods (CR-39 track detectors and plastic scintillation detectors) registered neutrons within the range from thermal energies up to energies above 10 MeV and with an average flux density of ?10(6) cm(-2) per shot inside the discharge zone. Neutron generation occurs at the initial phase of the discharge and correlates with x-ray generation. The data obtained allow us to assume that during the discharge fast neutrons are mainly produced. PMID- 24074099 TI - Selective excitation of low frequency drift waves by density modulation and parametric excitation of higher frequency mode. AB - Excitation of low frequency drift waves in a radial region of a weak density gradient is demonstrated experimentally by strong temporal modulation of the plasma density. Though a parallel electron current can destabilize drift waves throughout the region, we observe mode selection at the resonant location matching the frequency of modulation. Parametric mode-mode interaction among two excited drift modes to destabilize a higher frequency one is reported under the specific condition of the growth rate. Theoretically estimated growth rates fit well with the experiment. PMID- 24074100 TI - Transport of a Bose gas in 1D disordered lattices at the fluid-insulator transition. AB - We investigate the momentum-dependent transport of 1D quasicondensates in quasiperiodic optical lattices. We observe a sharp crossover from a weakly dissipative regime to a strongly unstable one at a disorder-dependent critical momentum. In the limit of nondisordered lattices the observations suggest a contribution of quantum phase slips to the dissipation. We identify a set of critical disorder and interaction strengths for which such critical momentum vanishes, separating a fluid regime from an insulating one. We relate our observation to the predicted zero-temperature superfluid-Bose glass transition. PMID- 24074101 TI - Phase transitions for a collective coordinate coupled to Luttinger liquids. AB - We study various realizations of collective coordinates, e.g., the position of a particle, the charge of a Coulomb box, or the phase of a Bose or a superconducting condensate, coupled to Luttinger liquids with N flavors. We find that for a Luttinger parameter (1/2) K+ MU+ MU- decays at low recoil. AB - A broad peaking structure is observed in the dimuon spectrum of B+ -> K+ MU+ MU- decays in the kinematic region where the kaon has a low recoil against the dimuon system. The structure is consistent with interference between the B+ -> K+ MU+ MU decay and a resonance and has a statistical significance exceeding six standard deviations. The mean and width of the resonance are measured to be 4191(-8)(+9) MeV/c2 and 65(-16)(+22) MeV/c2, respectively, where the uncertainties include statistical and systematic contributions. These measurements are compatible with the properties of the psi(4160) meson. First observations of both the decay B+ -> psi(4160)K+ and the subsequent decay psi(4160) -> MU+ MU- are reported. The resonant decay and the interference contribution make up 20% of the yield for dimuon masses above 3770 MeV/c2. This contribution is larger than theoretical estimates. PMID- 24074102 TI - Atomic quantum simulation of the lattice gauge-Higgs model: Higgs couplings and emergence of exact local gauge symmetry. AB - Recently, the possibility of quantum simulation of dynamical gauge fields was pointed out by using a system of cold atoms trapped on each link in an optical lattice. However, to implement exact local gauge invariance, fine-tuning the interaction parameters among atoms is necessary. In the present Letter, we study the effect of violation of the U(1) local gauge invariance by relaxing the fine tuning of the parameters and showing that a wide variety of cold atoms is still a faithful quantum simulator for a U(1) gauge-Higgs model containing a Higgs field sitting on sites. The clarification of the dynamics of this gauge-Higgs model sheds some light upon various unsolved problems, including the inflation process of the early Universe. We study the phase structure of this model by Monte Carlo simulation and also discuss the atomic characteristics of the Higgs phase in each simulator. PMID- 24074103 TI - Tkachenko polarons in vortex lattices. AB - We analyze the properties of impurities immersed in a vortex lattice formed by ultracold bosons in the mean field quantum Hall regime. In addition to the effects of a periodic lattice potential, the impurity is dressed by collective modes with parabolic dispersion (Tkachenko modes). We derive the effective polaron model, which contains a marginal impurity-phonon interaction. The polaron spectral function exhibits a Lorentzian broadening for arbitrarily small wave vectors even at zero temperature, in contrast with the result for optical or acoustic phonons. The anomalous damping of Tkachenko polarons could be detected experimentally using momentum-resolved spectroscopy. PMID- 24074104 TI - Stacking principle and magic sizes of transition metal nanoclusters based on generalized Wulff construction. AB - Nanoclusters with extra stability at certain cluster sizes are known as magic clusters with exotic properties. The classic Wulff construction principle, which stipulates that the preferred structure of a cluster should minimize its total surface energy, is often invoked in determining the cluster magicity, resulting in close-shelled Mackay icosahedronal clusters with odd-numbered magic sizes of 13, 55, 147, etc. Here we use transition metal clusters around size 55 as prototypical examples to demonstrate that, in the nanometer regime, the classic Wulff construction principle needs to be generalized to primarily emphasize the edge atom effect instead of the surface energy. Specifically, our detailed calculations show that nanoclusters with much shorter total edge lengths but substantially enlarged total surface areas are energetically much more stable. As a consequence, a large majority of the nanoclusters within the 3d-, 4d-, and 5d transition metal series are found to be fcc or hcp crystal fragments with much lower edge energies, and the widely perceived magic size of 55 is shifted to its nearby even numbers. PMID- 24074105 TI - Tunable adsorbate-adsorbate interactions on graphene. AB - We propose a mechanism to control the interaction between adsorbates on graphene. The interaction between a pair of adsorbates--the change in adsorption energy of one adsorbate in the presence of another--is dominated by the interaction mediated by graphene's pi electrons and has two distinct regimes. Ab initio density functional, numerical tight-binding, and analytical calculations are used to develop the theory. We demonstrate that the interaction can be tuned in a wide range by adjusting the adsorbate-graphene bonding or the chemical potential. PMID- 24074106 TI - Topological defects in flat geometry: the role of density inhomogeneity. AB - Topological defects are found in particles confined to planar disks interacting via the 1/r Coulomb potential. The total interior topological charge is found to monotonically converge to a negative value as the energy decreases during the relaxation process regardless of initial configurations; it is more negative in a larger cluster. The comparison with a uniform hyperbolic tessellation reveals an underlying hyperbolic structure in a low-energy configuration where the particle density increases from the center of the disk to its boundary. An elliptic structure is identified in an opposite particle distribution where the particle density decreases from the center to the edge of the disk. The novel mechanism of density inhomogeneity driven topological defects as well as the underlying geometric structure may shed light in understanding a wide variety of relevant systems. PMID- 24074107 TI - Role of surface-segregation-driven intermixing on the thermal transport through planar Si/Ge superlattices. AB - It has been highly debated whether the thermal conductivity kappa of a disordered SiGe alloy can be lowered by redistributing its constituent species so as to form an ordered superlattice. By ab initio calculations backed by systematic experiments, we show that Ge segregation occurring during epitaxial growth can lead to kappa values not only lower than the alloy's, but also lower than the perfect superlattice values. Thus we theoretically demonstrate that kappa does not monotonically decrease as the Si- and Ge-rich regions become more sharply defined. Instead, an intermediate concentration profile is able to lower kappa below both the alloy limit (total intermixing) and also the abrupt interface limit (zero intermixing). This unexpected result is attributed to the peculiar behavior of the phonon mean free path in realistic Si/Ge superlattices, which shows a crossover from abrupt-interface- to alloylike values at intermediate phonon frequencies of ~3 THz. Our calculated kappa's quantitatively agree with the measurements when the realistic, partially intermixed profiles produced by segregation are considered. PMID- 24074108 TI - Quantum bicriticality in the heavy-fermion metamagnet YbAgGe. AB - Bicritical points, at which two distinct symmetry-broken phases become simultaneously unstable, are typical for spin-flop metamagnetism. Interestingly, the heavy-fermion compound YbAgGe also possesses such a bicritical point (BCP) with a low temperature T(BCP)~0.3 K at a magnetic field of MUH(BCP)~4.5 T. In its vicinity, YbAgGe exhibits anomalous behavior that we attribute to the influence of a quantum bicritical point that is close in parameter space yet can be reached by tuning T(BCP) further to zero. Using high-resolution measurements of the magnetocaloric effect, we demonstrate that the magnetic Gruneisen parameter GammaH indeed both changes sign and diverges as required for quantum criticality. Moreover, GammaH displays a characteristic scaling behavior but only on the low-field side H?H(BCP), indicating a pronounced asymmetry with respect to the critical field. We speculate that the small value of T(BCP) is related to the geometric frustration of the Kondo lattice of YbAgGe. PMID- 24074109 TI - Inducing time-reversal-invariant topological superconductivity and fermion parity pumping in quantum wires. AB - We propose a setup to realize time-reversal-invariant topological superconductors in quantum wires, proximity coupled to conventional superconductors. We consider a model of quantum wire with strong spin-orbit coupling and proximity coupling to two s-wave superconductors. When the relative phase between the two superconductors is phi=pi a Kramers pair of Majorana zero modes appears at each edge of the wire. We study the robustness of the phase in the presence of both time-reversal-invariant and time-reversal-breaking perturbations. In addition, we show that the system forms a natural realization of a fermion parity pump, switching the local fermion parity of both edges when the relative phase between the superconductors is changed adiabatically by 2pi. PMID- 24074110 TI - Engineering correlation effects via artificially designed oxide superlattices. AB - Ab initio calculations are used to predict that a superlattice composed of layers of LaTiO3 and LaNiO3 alternating along the [001] direction is a S=1 Mott insulator with large magnetic moments on the Ni sites, negligible moments on the Ti sites and a charge transfer gap set by the energy difference between Ni d and Ti d states, distinct from conventional Mott insulators. Correlation effects are enhanced on the Ni sites via filling the oxygen p states and reducing the Ni-O-Ni bond angle. Small hole (electron) doping of the superlattice leads to a two dimensional single-band situation with holes (electrons) residing on the Ni d(x2 y2) (Ti d(xy)) orbital and coupled to antiferromagnetically correlated spins in the NiO2 layer. PMID- 24074111 TI - Condensed astatine: monatomic and metallic. AB - The condensed matter properties of the nominal terminating element of the halogen group with atomic number 85, astatine, are as yet unknown. In the intervening more than 70 years since its discovery significant advances have been made in substrate cooling and the other techniques necessary for the production of the element to the point where we might now enquire about the key properties astatine might have if it attained a condensed phase. This subject is addressed here using density functional theory and structural selection methods, with an accounting for relativistic physics that is essential. Condensed astatine is predicted to be quite different in fascinating ways from iodine, being already at 1 atm a metal, and monatomic at that, and possibly a superconductor (as is dense iodine). PMID- 24074112 TI - Field-effect birefringent spin lens in ultrathin film of magnetically doped topological insulators. AB - We investigate the low-energy electron dynamics in two-dimensional ultrathin film of magnetically doped topological insulators in the context of gate-tuned coherent spin manipulation. Our first-principles calculations for such film unambiguously identify its spin-resolved topological band structure arising from spin-orbit coupling and time-reversal symmetry breaking. Exploiting this characteristic, we predict a negative birefraction for chiral electron tunneling through a gate-controlled p-n interface in the film, analogous to optical birefringence. By fine-tuning the gate voltage, a series of unusual phenomena, including electron double focusing, spatial modulation of spin polarizations, and quantum-interference-induced beating patterns, could be efficiently implemented, offering a powerful platform to establish spin-resolved electron optics by all electrical means. PMID- 24074113 TI - Topological Raman band in the carbon nanohorn. AB - Raman spectroscopy has been used in chemistry and physics to investigate the fundamental process involving light and phonons. The carbon nanohorn introduces a new subject to Raman spectroscopy, namely topology. We show theoretically that a photoexcited carrier with a nonzero winding number activates a topological D Raman band through the Aharonov-Bohm effect. The topology-induced D Raman band can be distinguished from the ordinary D Raman band for a graphene edge by its peak position. PMID- 24074114 TI - Hidden T-linear scattering rate in Ba0.6K0.4Fe2As2 revealed by optical spectroscopy. AB - The optical properties of Ba0.6K0.4Fe2As2 have been determined in the normal state for a number of temperatures over a wide frequency range. Two Drude terms, representing two groups of carriers with different scattering rates (1/tau), well describe the real part of the optical conductivity sigma1(omega). A "broad" Drude component results in an incoherent background with a T-independent 1/taub, while a "narrow" Drude component reveals a T-linear 1/taun resulting in a resistivity rhon=1/sigma1n(omega->0) also linear in temperature. An arctan(T) low-frequency spectral weight is also strong evidence for a T-linear 1/tau. A comparison to other materials with similar behavior suggests that the T-linear 1/taun and rhon in Ba0.6K0.4Fe2As2 originate from scattering from spin fluctuations and hence that an antiferromagnetic quantum critical point is likely to exist in the superconducting dome. PMID- 24074115 TI - Evidence for nonlocal electrodynamics in planar Josephson junctions. AB - We study the temperature dependence of the critical current modulation I(c)(H) for two types of planar Josephson junctions: a low-Tc Nb/CuNi/Nb and a high-Tc YBa2Cu3O(7-delta) bicrystal grain-boundary junction. At low T both junctions exhibit a conventional behavior, described by the local sine-Gordon equation. However, at elevated T the behavior becomes qualitatively different: the I(c)(H) modulation field DeltaH becomes almost T independent and neither DeltaH nor the critical field for the penetration of Josephson vortices vanish at Tc. Such an unusual behavior is in good agreement with theoretical predictions for junctions with nonlocal electrodynamics. We extract absolute values of the London penetration depth lambda from our data and show that a crossover from local to nonlocal electrodynamics occurs with increasing T when lambda(T) becomes larger than the electrode thickness. PMID- 24074116 TI - Experimental demonstration of scanned spin-precession microscopy. AB - We present a new tool for imaging spin properties. We show that a spatially averaged spin signal, measured as a function of a scanned magnetic probe's position, contains information about the local spin properties. In this first demonstration we map the injected spin density in GaAs by measuring spin photoluminescence with a resolution of 1.2 MUm. The ultimate limit of the technique is set by the gradient of the probe's field, allowing for a resolution beyond the optical diffraction limit. Such probes can also be integrated with other detection methods. This generality allows the technique to be extended to buried interfaces and optically inactive materials. PMID- 24074117 TI - Dynamics of localized modes in a composite multiferroic chain. AB - In a coupled ferroelectric-ferromagnetic system, i.e., a composite multiferroic, the propagation of magnetic or ferroelectric excitations across the whole structure is a key issue for applications. Of special interest is the dynamics of localized magnetic or ferroelectric modes (LM) across the ferroelectric ferromagnetic interface, particularly when the LM's carrier frequency is in the band of the ferroelectric and in the band gap of the ferromagnet. For a proper choice of the system's parameters, we find that there is a threshold amplitude above which the interface becomes transparent and an in-band ferroelectric LM penetrates the ferromagnetic array. Below that threshold, the LM is fully reflected. Slightly below this transmission threshold, the addition of noise may lead to energy transmission, provided that the noise level is neither too low nor too high, an effect that resembles stochastic resonance. These findings represent an important step towards the application of ferroelectric and/or ferromagnetic LM-based logic. PMID- 24074118 TI - Gradient dynamics description for films of mixtures and suspensions: dewetting triggered by coupled film height and concentration fluctuations. AB - A thermodynamically consistent gradient dynamics model for the evolution of thin layers of liquid mixtures, solutions, and suspensions on solid substrates is presented which is based on a film-height- and mean-concentration-dependent free energy functional. It is able to describe a large variety of structuring processes, including coupled dewetting and decomposition processes. As an example, the model is employed to investigate the dewetting of thin films of liquid mixtures and suspensions under the influence of effective long-range van der Waals forces that depend on solute concentration. The occurring fluxes are discussed, and it is shown that spinodal dewetting may be triggered through the coupling of film height and concentration fluctuations. Fully nonlinear calculations provide the time evolution and resulting steady film height and concentration profiles. PMID- 24074119 TI - Velocity correlations in an active nematic. AB - The flow properties of a continuum model for an active nematic are studied and compared with recent experiments on suspensions of microtubule bundles and molecular motors. The velocity correlation length is found to be independent of the strength of the activity while the characteristic velocity scale increases monotonically as the activity is increased, both in agreement with the experimental observations. We interpret our results in terms of the creation and annihilation dynamics of a gas of topological defects. PMID- 24074120 TI - Revealing long-range interconnected hubs in human chromatin interaction data using graph theory. AB - We use graph theory to analyze chromatin interaction (Hi-C) data in the human genome. We show that a key functional feature of the genome--"master" replication origins--corresponds to DNA loci of maximal network centrality. These loci form a set of interconnected hubs both within chromosomes and between different chromosomes. Our results open the way to a fruitful use of graph theory concepts to decipher DNA structural organization in relation to genome functions such as replication and transcription. This quantitative information should prove useful to discriminate between possible polymer models of nuclear organization. PMID- 24074121 TI - Anomalous anisotropic diffusion dynamics of hydration water at lipid membranes. AB - The diffusional water dynamics in the hydration layer of a dipalmitoylphosphatidylcholine bilayer is studied using molecular dynamics simulations. By mapping the perpendicular water motion on the ordinary diffusion equation, we disentangle free energetic and friction effects and show that perpendicular diffusion is strongly reduced. The lateral water motion exhibits anomalous diffusion up to several nanoseconds and is characterized by even further decreased diffusion coefficients, which by comparison with coarse-grained simulations are explained by the transient corrugated effective free energy landscape imposed by the lipids. This is in contrast to homogenous surfaces, where boundary hydrodynamic theory quantitatively predicts the anisotropy of water diffusion. PMID- 24074122 TI - Hydrodynamic fluctuations in confined particle-laden fluids. AB - We address the collective dynamics of non-Brownian particles cruising in a confined microfluidic geometry and provide a comprehensive characterization of their spatiotemporal density fluctuations. We show that density excitations freely propagate at all scales, and in all directions even though the particles are neither affected by potential forces nor by inertia. We introduce a kinetic theory which quantitatively accounts for our experimental findings, demonstrating that the fluctuation spectrum of this nonequilibrium system is shaped by the combination of truly long-range hydrodynamic interactions and local collisions. We also demonstrate that the free propagation of density waves is a generic phenomenon which should be observed in a much broader range of hydrodynamic systems. PMID- 24074123 TI - Triboelectric charging of volcanic ash from the 2011 Grimsvotn eruption. AB - The plume from the 2011 eruption of Grimsvotn was highly electrically charged, as shown by the considerable lightning activity measured by the United Kingdom Met Office's low-frequency lightning detection network. Previous measurements of volcanic plumes have shown that ash particles are electrically charged up to hundreds of kilometers away from the vent, which indicates that the ash continues to charge in the plume [R. G. Harrison, K. A. Nicoll, Z. Ulanowski, and T. A. Mather, Environ. Res. Lett. 5, 024004 (2010); H. Hatakeyama J. Meteorol. Soc. Jpn. 27, 372 (1949)]. In this Letter, we study triboelectric charging of different size fractions of a sample of volcanic ash experimentally. Consistently with previous work, we find that the particle size distribution is a determining factor in the charging. Specifically, our laboratory experiments demonstrate that the normalized span of the particle size distribution plays an important role in the magnitude of charging generated. The influence of the normalized span on plume charging suggests that all ash plumes are likely to be charged, with implications for remote sensing and plume lifetime through scavenging effects. PMID- 24074124 TI - Comment on "Giant plasticity of a quantum crystal". PMID- 24074125 TI - Haziot et al. reply. PMID- 24074127 TI - Recessed ring-disk nanoelectrode arrays integrated in nanofluidic structures for selective electrochemical detection. AB - Arrays of recessed ring-disk (RRD) electrodes with nanoscale spacing fabricated by multilayer deposition, nanosphere lithography, and multistep reactive ion etching were incorporated into nanofluidic channels. These arrays, which characteristically exhibit redox cycling leading to current amplification during cyclic voltammetry, can selectively analyze electroactive species based on differences in redox reversibility, redox potential, or both. Using Ru(NH3)6(3+) and ascorbic acid (AA) as model reversible and irreversible redox species, the selectivity for electrochemical measurement of Ru(NH3)6(3+) against a background of AA improves from ~10, for an array operated in a fluidically unconstrained geometry, to ~70 for an array integrated within nanofluidic channels. RRD arrays were also used for the detection of dopamine in the presence of AA by cyclic voltammetry. A linear response ranging from 100 nM to 1 mM with a detection limit of 20 nM was obtained for dopamine alone without nanofluidic confinement. In nanochannel-confined arrays, AA was depleted by holding the ring electrodes at +0.5 V versus Ag/AgCl, allowing interference-free determination of dopamine at the disk electrodes in the presence of a 100-fold excess of AA. For selective detection of electrochemically reversible interfering species on an RRD array without nanochannel confinement, a ring potential can be chosen such that one species exhibits exclusively cathodic (anodic) current, allowing the other species to be determined from its anodic (cathodic) current. This approach for selective detection is demonstrated in a mixture of Ru(NH3)6(3+) and Fe(CN)6(3-), which have resolved redox potentials. The same principle was successfully applied to differentiate species with overlapping redox potentials, such as dopamine/Fe(CN)6(3-) and ferrocenemethanol/Fe(CN)6(4-). PMID- 24074126 TI - Custom microarray construction and analysis for determining potential biomarkers of subchronic androgen exposure in the Eastern Mosquitofish (Gambusia holbrooki). AB - BACKGROUND: The eastern mosquitofish (Gambusia holbrooki) has the potential to become a bioindicator organism of endocrine disrupting chemicals (EDCs) due to its androgen-driven secondary sexual characteristics. However, the lack of molecular information on G. holbrooki hinders its use as a bioindicator coupled with biomarker data. While traditional gene-by-gene approaches provide insight for biomarker development, a holistic analysis would provide more rapid and expansive determination of potential biomarkers. The objective of this study was to develop and utilize a mosquitofish microarray to determine potential biomarkers of subchronic androgen exposure. To achieve this objective, two specific aims were developed: 1) Sequence a G. holbrooki cDNA library, and 2) Use microarray analysis to determine genes that are differentially regulated by subchronic androgen exposure in hepatic tissues of 17beta-trenbolone (TB) exposed adult female G. holbrooki. RESULTS: A normalized library of multiple organs of male and female G. holbrooki was prepared and sequenced by the Illumina GA IIx and Roche 454 XLR70. Over 30,000 genes with e-value <= 10-4 were annotated and 14,758 of these genes were selected for inclusion on the microarray. Hepatic microarray analysis of adult female G. holbrooki exposed to the vehicle control or 1 MUg/L of TB (a potent anabolic androgen) revealed 229 genes upregulated and 279 downregulated by TB (one-way ANOVA, p < 0.05, FDR alpha = 0.05, fold change > 1.5 and < -1.5). Fifteen gene ontology biological processes were enriched by TB exposure (Fisher's Exact Test, p < 0.05). The expression levels of 17beta hydroxysteroid dehydrogenase 3 and zona pellucida glycoprotein 2 were validated by quantitative polymerase chain reaction (qPCR) (Student's t-test, p < 0.05). CONCLUSIONS: Coupling microarray data with phenotypic changes driven by androgen exposure in mosquitofish is key for developing this organism into a bioindicator for EDCs. Future studies using this array will enhance knowledge of the biology and toxicological response of this species. This work provides a foundation of molecular knowledge and tools that can be used to delve further into understanding the biology of G. holbrooki and how this organism can be used as a bioindicator organism for endocrine disrupting pollutants in the environment. PMID- 24074128 TI - Adverse events for hospitalized medicare patients: is there a difference between HMO and FFS enrollees? AB - The study examines the likelihood of adverse outcomes associated with selected hospital safety events for two groups of Medicare patients: those enrolled in health maintenance organizations (HMOs) versus those enrolled in fee-for-service (FFS) insurance plans. The authors hypothesize that HMO patients may receive different qualities of hospital services and/or physician services relative to FFS patients. Based on the Healthcare Cost and Utilization Project State Inpatient Database, the authors include discharge data on all hospitalized elderly Medicare patients in Florida in 2002 and use multivariate logistic regression models with adjustments for hospital-level clusters. The findings demonstrate that, after adjusting for hospital quality, Medicare HMO patients were at higher risk of adverse outcomes than Medicare FFS patients for iatrogenic pneumothorax, accidental puncture or laceration, and postoperative respiratory failure. PMID- 24074129 TI - Social epidemiology: a tool for examining prostate cancer early-detection decision making among older African American men. AB - The article explores the disparate burden of prostate cancer among older African American men, and this population's minimal use of cancer early-detection strategies. Social epidemiology is introduced as an emerging field that studies the social context of disease with an emphasis on how macrostructural forces and human interactions affect population health. A conceptual model is presented as a social epidemiological tool for investigating complex health and social issues and developing culturally relevant programs and interventions based on empirical findings. The model is then applied to the problem of prostate cancer early detection decision making among older African American men. PMID- 24074130 TI - African American women living with mental disorders: factors associated with help seeking from professional services and informal supports. AB - This study utilized data from the National Survey of American Life to investigate the use of professional services and informal support among Black women with a lifetime mood, anxiety, or substance use disorder. Forty-seven percent combined professional services and informal support, 14% relied on professional services only, 2% used informal support only, and 16% did not seek help. Co-occurring disorders, recent episodes, social networks, marital status, age, and level of education were significantly related to help seeking from professional and informal helpers, demonstrating the importance of both. Targeting interventions in these areas will likely increase treatment effectiveness. PMID- 24074131 TI - "Young women": the meaning of a collaborative program supporting young women's rehabilitation and reintegration into the labor market. AB - Women are at a higher risk for long-term sick leaves and mental ill health. The aim of this study was to explore a supportive program's meaning for women with anxiety/stress/depression problems that are unemployed and/or on a sick leave, and for the personnel involved. Seven women and the personnel (n = 5) were interviewed individually pre- and post-intervention. Data was analyzed using content analysis. The program appeared to provide participants with tools to handle their physical and mental health, and occupational support, improving their social situation. Collaboration between organizations appears to be beneficial for all parties involved. PMID- 24074132 TI - Generation Y, shifting funding structures, and health care reform: reconceiving the public health paradigm through social work. AB - Public health agencies are facing a convergence of forces that require a reexamination of the existing paradigm. The need to replace an aging workforce with a new generation that possesses a different worldview, in the context of budget austerity, will be challenging. In addition, the uncertainty of health care reform poses a challenge for public health leadership. This "perfect storm" provides the opportunity for the social work paradigm to come in and fill the void. PMID- 24074133 TI - The rise and fall of medicaid managed care in Mississippi: lessons for public health policy makers. AB - This article describes the development, implementation, and termination of a primary care case management program in the State of Mississippi. The study provides policy makers with critical information as to factors associated with successful implementation of current health care initiatives. PMID- 24074134 TI - Is there new public health management (NPM) in Nepal? Arguments for and against NPM in Nepal. AB - This article is a reflection about whether new public management (NPM) styles of reforms seen in other developing countries are also seen in Nepal, and to substantiate these facts with the available evidence and findings. The author saw the emergence of NPM ideas in Western industrialized countries like the United Kingdom and New Zealand. Now it exists in several developing countries of Africa and Asia; but it is very hard to generalize the degree and scope of NPM elements' existence. In Southeast Asia, there is still a mix of the old bureaucratic system with new NPM-oriented reform initiatives. Series of administrative reforms, donor conditionality, and the reestablishment of democracy in the country after 1991 have influenced an orientation toward an efficient, people-oriented, mixed economy model with increasing partnership of private agencies and nongovernmental organizations in Nepal. The political movement of the last 15 years in the country has strongly called for a new, efficient, and performance-oriented administration and management culture in the country. There are several initiatives already introduced (public-private partnership, decentralization, good governance, accountability/public auditing, performance-based outcome/results-oriented financing and reporting systems). However, to take this momentum up, it still requires strong willingness of political leaders and senior administrators. At the moment, peace and stability of turmoil, political stability, state-of-the-art management skills, and supportive organizational culture are the fundamental requirements for increasing the realization of, and sustaining the NPM-oriented reforms in Nepal. PMID- 24074135 TI - Unmet need of contraception: a critical juncture toward family planning goals. AB - India is the first country in the world to implement a family planning program, and this program has succeeded in generating universal knowledge about family planning methods. In spite of this, there exists a wide gap between knowledge and acceptance of family planning methods reflecting an unmet need for contraception. Different communication channels used to disseminate knowledge like television, radio, and newspapers aim to change the family planning methods. Being a didactic method, these have the least potential to change the attitudes of the people. This article represents the tip of the iceberg of the fate arising out of incomplete information provided through mass media not supported by a formal family planning program. One primipara woman after getting pregnant took an emergency contraceptive pill and attended a clinic with vaginal bleeding, abdominal pain, and pallor. Ultimately she underwent suction evacuation and survived. This indicates that mass media should not be a substitute, but rather a supplement to the routine program of the health worker to promote contraception. PMID- 24074137 TI - Predictors of performance-based measures of instrumental activities of daily living in nondemented patients with Parkinson's disease. AB - Few studies have examined instrumental activities of daily living (iADLs) in nondemented Parkinson's disease (PD), and the majority of these studies have used report-based measures, which can have limited validity. The present study had two main goals: (a) to examine the performance of nondemented PD patients on two performance-based measures of iADLs, which are considered more objective functional measures, and (b) to examine the cognitive, motor, and psychiatric correlates of iADL impairment in PD. Ninety-eight nondemented PD patients and 47 healthy older adults were administered performance-based measures that assess the ability to manage medications (Medication Management Ability Assessment) and finances (University of California, San Diego, UCSD, Performance-based Skills Assessment), the Mattis Dementia Rating Scale to assess global cognitive functioning, the Unified Parkinson's Disease Rating Scale Part III to assess motor symptom severity, and the Geriatric Depression Scale to assess depressive symptoms. Nondemented PD patients demonstrated significantly impaired scores relative to the healthy comparison group on the performance-based measure of financial management, but there were no significant group differences in medication management. Global cognitive functioning, motor severity, and depressive symptoms did not correlate with scores on either of the functional measures, except for a small correlation between depressive symptoms and financial management. The two performance-based measures of iADL functioning did not correlate with one another. These findings suggest that medication and financial management may not be predicted based on global cognitive functioning and that iADLs may not be represented by a single construct. Furthermore, these findings suggest the potential need for a multidimensional approach to assessing iADLs. PMID- 24074138 TI - Impact of heart failure on the behavior of human neonatal stem cells in vitro. AB - BACKGROUND: Clinical cardiac cell therapy using autologous somatic stem cells is restricted by age and disease-associated impairment of stem cell function. Juvenile cells possibly represent a more potent alternative, but the impact of patient-related variables on such cell products is unknown. We therefore evaluated the behavior of neonatal cord blood mesenchymal stem cells (CB-MSC) in the presence of serum from patients with advanced heart failure (HF). METHODS: Human serum was obtained from patients with severe HF (n = 21) and from healthy volunteers (n = 12). To confirm the systemic quality of HF in the sera, TNF-alpha and IL-6 were quantified. CB-MSC from healthy neonates were cultivated for up to 14 days in medium supplemented with 10% protein-normalized human HF or control serum or fetal calf serum (FCS). RESULTS: All HF sera contained increased cytokine concentrations (IL-6, TNF-alpha). When exposed to HF serum, CB-MSC maintained basic MSC properties as confirmed by immunophenotyping and differentiation assays, but clonogenic cells were reduced in number and gave rise to substantially smaller colonies in the CFU-F assay. Cell cycle analysis pointed towards G1 arrest. CB-MSC metabolic activity and proliferation were significantly impaired for up to 3 days as measured by MTS turnover, BrdU incorporation and DAPI + nuclei counting. On day 5, however, CB-MSC growth kinetics approached control serum levels, though protein expression of cell cycle inhibitors (p21, p27), and apoptosis marker Caspase 3 remained elevated. Signal transduction included the stress and cytokine-induced JNK and ERK1/2 MAP kinase pathways. CONCLUSIONS: Heart failure temporarily inhibits clonality and proliferation of "healthy" juvenile MSC in vitro. Further studies should address the in vivo and clinical relevance of this finding. PMID- 24074139 TI - Alterations in brain structure in adults with anorexia nervosa and the impact of illness duration. AB - BACKGROUND: Brain structure alterations have been reported in anorexia nervosa, but findings have been inconsistent. This may be due to inadequate sample size, sample heterogeneity or differences in methodology. METHOD: High resolution magnetic resonance images were acquired of 33 adult participants with anorexia nervosa and 33 healthy participants, the largest study sample to date, in order to assess whole-brain volume, ventricular cerebrospinal fluid, white matter and grey matter volume. Voxel-based morphometry was conducted to assess regional grey matter volume. Levels of depression, anxiety, obsessionality and eating disorder related symptoms were measured and used to explore correlations with brain structure. RESULTS: Participants with anorexia nervosa had smaller brain volumes as well as a global decrease in grey matter volume with ventricular enlargement. Voxel-based morphometry revealed a decrease in grey matter volume spanning across the cerebellum, temporal, frontal and occipital lobes. A correlation was found between grey matter volume loss and duration of illness in the cerebellum and mesencephalon. No correlations were found with clinical measures. CONCLUSIONS: Findings are in accordance with several previous studies on brain structure and match functional studies that have assessed the symptomatology of anorexia nervosa, such as body image distortion and cognitive bias to food. The correlation with duration of illness supports the implication of cerebellar atrophy in the maintenance of low weight and disrupted eating behaviour and illustrates its role in the chronic phase of anorexia nervosa. The lack of other correlations suggests that these findings are not related to the presence of co morbid disorders. PMID- 24074140 TI - A molecular dynamics approach for predicting the glass transition temperature and plasticization effect in amorphous pharmaceuticals. AB - The objectives of this study were as follows: (i) To develop an in silico technique, based on molecular dynamics (MD) simulations, to predict glass transition temperatures (Tg) of amorphous pharmaceuticals. (ii) To computationally study the effect of plasticizer on Tg. (iii) To investigate the intermolecular interactions using radial distribution function (RDF). Amorphous sucrose and water were selected as the model compound and plasticizer, respectively. MD simulations were performed using COMPASS force field and isothermal-isobaric ensembles. The specific volumes of amorphous cells were computed in the temperature range of 440-265 K. The characteristic "kink" observed in volume-temperature curves, in conjunction with regression analysis, defined the Tg. The MD computed Tg values were 367 K, 352 K and 343 K for amorphous sucrose containing 0%, 3% and 5% w/w water, respectively. The MD technique thus effectively simulated the plasticization effect of water; and the corresponding Tg values were in reasonable agreement with theoretical models and literature reports. The RDF measurements revealed strong hydrogen bond interactions between sucrose hydroxyl oxygens and water oxygen. Steric effects led to weak interactions between sucrose acetal oxygens and water oxygen. MD is thus a powerful predictive tool for probing temperature and water effects on the stability of amorphous systems during drug development. PMID- 24074141 TI - Typical and atypical antipsychotics do not differ markedly in their reversibility of antagonism of the dopamine D2 receptor. AB - It has been suggested that the favorable side-effect profiles of atypical antipsychotics (e.g. clozapine and amisulpride) are related to their ~100-fold faster dissociation from dopamine D2 receptors (D2R) compared with typical antipsychotics (e.g. haloperidol and chlorpromazine). Fast dissociation would entail rapidly reversible antagonism; however, this has not been thoroughly studied using functional assays. We compared the reversibilities of D2R antagonism by 17 compounds using an electrophysiological method to measure dopamine-evoked potassium channel activation via D2R. Varying rates and amplitudes of D2R response recovery were observed following antagonist removal. Whereas recovery rates differed 15-fold between atypical drugs, recovery from clozapine and amisulpride antagonism was, unexpectedly, less than twofold faster than from chlorpromazine. The recovery amplitude correlated with calculated water solubility and lipid/water distribution coefficients, suggesting variable drug partitioning into cell membranes. Our data do not support the notion that the rate of reversibility of D2R antagonism is what distinguishes atypical from typical antipsychotics. PMID- 24074142 TI - Design of aerosol face masks for children using computerized 3D face analysis. AB - BACKGROUND: Aerosol masks were originally developed for adults and downsized for children. Overall fit to minimize dead space and a tight seal are problematic, because children's faces undergo rapid and marked topographic and internal anthropometric changes in their first few months/years of life. Facial three dimensional (3D) anthropometric data were used to design an optimized pediatric mask. METHODS: Children's faces (n=271, aged 1 month to 4 years) were scanned with 3D technology. Data for the distance from the bridge of the nose to the tip of the chin (H) and the width of the mouth opening (W) were used to categorize the scans into "small," "medium," and "large" "clusters." RESULTS: "Average" masks were developed from each cluster to provide an optimal seal with minimal dead space. The resulting computerized contour, W and H, were used to develop the SootherMask(r) that enables children, "suckling" on their own pacifier, to keep the mask on their face, mainly by means of subatmospheric pressure. The relatively wide and flexible rim of the mask accommodates variations in facial size within and between clusters. CONCLUSIONS: Unique pediatric face masks were developed based on anthropometric data obtained through computerized 3D face analysis. These masks follow facial contours and gently seal to the child's face, and thus may minimize aerosol leakage and dead space. PMID- 24074144 TI - Detection of interfraction displacement and volume variance during radiotherapy of primary thoracic esophageal cancer based on repeated four-dimensional CT scans. AB - BACKGROUND: To investigate the interfraction displacement and volume variation of primary thoracic esophagus carcinoma with enhanced four-dimensional computed tomography (4DCT) scanning during fractionated radiotherapy. METHODS: 4DCT data sets were acquired at the time of treatment simulation and every ten fraction for each of 32 patients throughout treatment. Scans were registered to baseline (simulation) 4DCT scans by using bony landmarks. The gross tumor volumes (GTVs) were delineated on each data set. Coordinates of the GTV centroids were acquired on each respiration phase. Distance between center of the GTV contour on the simulation scan and the centers on subsequent scans were used to assess interfraction displacement between fractions. Volumes were constructed using three approaches: The GTV delineated from the maximum intensity projection (MIP) was defined IGTVMIP, all 10 GTVs were combined to form IGTV10, GTVmean was the average of all 10 phases of each GTV. RESULTS: Interfraction displacement in left right (LR), anterior-posterior (AP), superior-inferior (SI) directions and 3D vector were 0.13 +/- 0.09 cm, 0.16 +/- 0.12 cm, 0.34 +/- 0.26 cm and 0.43 +/- 0.24 cm, respectively between the tenth fraction and simulation 4DCT scan. 0.14 +/- 0.09 cm, 0.19 +/- 0.16 cm, 0.45 +/- 0.43 cm and 0.56 +/- 0.40 cm in LR, AP, SI and 3D vector respectively between the twentieth fraction and simulation 4DCT scan. Displacement in SI direction was larger than LR and AP directions during treatment. For distal esophageal cancer, increased interfraction displacements were observed in SI direction and 3D vector (P = 0.002 and P = 0.001, respectively) during radiotherapy. The volume of GTVmean, IGTVMIP, and IGTV10 decreased significantly at the twentieth fraction for middle (median: 34.01%, 33.09% and 28.71%, respectively) and distal (median: 22.76%, 25.27% and 23.96%, respectively) esophageal cancer, but for the upper third, no significant variation were observed during radiotherapy. CONCLUSIONS: Interfractional displacements in SI direction were larger than LR and AP directions. For distal location, significant changes were observed in SI direction and 3D vector during radiotherapy. For middle and distal locations, the best time to reset position should be selected at the twentieth fraction when the primary tumor target volume changed significantly, and it was preferable to guide target correction and planning modification. PMID- 24074143 TI - Pharmacokinetics and pharmacodynamics of fluticasone propionate and salmeterol delivered as a combination dry powder from a capsule-based inhaler and a multidose inhaler in asthma and COPD patients. AB - BACKGROUND: The object of this study was to assess whether a capsule-based and multidose dry powder inhaler containing salmeterol (as xinafoate salt) 50 MUg plus fluticasone propionate (FP) 250 MUg [combination (SFC 50/250)] could be equivalent in terms of in vivo drug delivery and systemic exposure. METHODS: This was a randomized, double-blind, double-dummy, replicate treatment design comparative bioavailability study of SFC 50/250 delivered in a capsule-based inhaler (Rotahaler(r)) and a multidose dry powder inhaler (Diskus(r)). Subjects with asthma or chronic obstructive pulmonary (COPD) disease (n=60) were randomized to receive twice-daily SFC 50/250 via a Rotahaler and via Diskus each for two 10-day treatment periods (GlaxoSmithKline Protocol ASR114334). RESULTS: For FP and salmeterol, the in vitro aerodynamic particle size profiles were within+/-15% of Diskus for the fine particle mass (FPM) and emitted dose (ED) using the Andersen Cascade Impactor, and ED, mass median aerodynamic diameter, and geometric standard deviation using the New Generation Impactor (NGI). This was also the case for FP but not salmeterol for FPM and fine particle dose using the NGI. For the combined asthma and COPD subjects, the plasma AUC and Cmax for FP and salmeterol were higher for Rotahaler:Rotahaler/Diskus geometric mean ratios (90% confidence intervals) for FP AUC0-tau of 1.52 (1.37-1.67) and Cmax of 1.94 (1.75-2.10) and salmeterol AUC0-tau of 1.15 (1.09-1.21) and Cmax of 1.56 (1.42-1.67). Corresponding values for the primary pharmacodynamic endpoint, weighted mean (0-12 hr) serum cortisol, were 0.928 (0.886-0.971). Inhaled FP/salmeterol via both inhalers was well-tolerated. One serious adverse event, considered possibly related to study medication, resulted in subject withdrawal from the study. CONCLUSIONS: The in vitro tests and systemic pharmacodynamic endpoints revealed no major differences between the two inhalers, but lacked predictive power and sensitivity to guide in vivo drug delivery performance and systemic exposure. Based on pharmacokinetic endpoints, the inhalers were not considered bioequivalent in terms of systemic exposure. Further studies to refine the Rotahaler performance are ongoing. PMID- 24074145 TI - Mesoscale climatic simulation of surface air temperature cooling by highly reflective greenhouses in SE Spain. AB - A long-term local cooling trend in surface air temperature has been monitored at the largest concentration of reflective greenhouses in the world, at the Province of Almeria, SE Spain, associated with a dramatic increase in surface albedo in the area. The availability of reliable long-term climatic field data at this site offers a unique opportunity to test the skill of mesoscale meteorological models describing and predicting the impacts of land use change on local climate. Using the Weather Research and Forecast (WRF) mesoscale model, we have run a sensitivity experiment to simulate the impact of the observed surface albedo change on monthly and annual surface air temperatures. The model output showed a mean annual cooling of 0.25 degrees C associated with a 0.09 albedo increase, and a reduction of 22.8 W m(-2) of net incoming solar radiation at surface. Mean reduction of summer daily maximum temperatures was 0.49 degrees C, with the largest single-day decrease equal to 1.3 degrees C. WRF output was evaluated and compared with observations. A mean annual warm bias (MBE) of 0.42 degrees C was estimated. High correlation coefficients (R(2) > 0.9) were found between modeled and observed values. This study has particular interest in the assessment of the potential for urban temperature cooling by cool roofs deployment projects, as well as in the evaluation of mesoscale climatic models performance. PMID- 24074146 TI - Monophosphoryl lipid A is an lipopolysaccharide-derived Toll-like receptor 4 agonist which may improve Alzheimer's disease pathology. AB - INTRODUCTION: Alzheimer's disease (AD) is partly characterized by the formation of plaques composed of beta-amyloid (Abeta) as a result of excessive accumulation of Abeta. Monophosphoryl lipid A (MPL) is a Toll-like receptor 4 agonist commonly used as a nontoxic, FDA-approved adjuvant in viral vaccines. AREAS COVERED: Previous reports had shown MPL as an effective adjuvant for Abeta vaccinations to decrease Abeta deposition. Recently, it was discovered that MPL monotherapy in APP/PS1 transgenic AD mice had beneficial effects, such as decreasing the number and size of deposits, decreasing soluble Abeta monomers and improving cognition through phagocytic activation of microglia. Unlike the parental endotoxin lipopolysaccharide (LPS), MPL stimulated microglial phagocytosis of Abeta, while only minimally increasing a proinflammatory response. EXPERT OPINION: MPL is a promising therapeutic option for AD treatment due to its ability to promote Abeta clearance without eliciting a strong adverse inflammatory response. Since MPL is already FDA-approved in humans, clinical application can be accelerated. Further analysis of how MPL affects other hallmarks of AD pathology such as dystrophic neurites and hyperphosphorylated tau aggregates, as well as its mechanism of action, will facilitate the understanding of the therapeutic benefits that MPL can produce. PMID- 24074147 TI - Cadmium stress responses in Brassica juncea: hints from proteomics and metabolomics. AB - Among heavy metal stressors, cadmium (Cd) pollution is one leading threat to the environment. In this view, research efforts have been increasingly put forward to promote the individuation of phytoextractor plants that are capable of accumulating and withstanding the toxic metals, including Cd, in the aerial parts. We hereby adopted the hyperaccumulator B. juncea (Indian mustard) as a model to investigate plant responses to Cd stress at low (25 MUM) and high (100 MUM) doses. Analytical strategies included mass-spectrometry-based determination of Cd and the assessment of its effect on the leaf proteome and metabolome. Results were thus integrated with routine physiological data. Taken together, physiology results highlighted the deregulation of photosynthesis efficiency, ATP synthesis, reduced transpiration, and the impairment of light-independent carbon fixation reactions. These results were supported at the proteomics level by the observed Cd-dependent alteration of photosystem components and the alteration of metabolic enzymes, including ATP synthase subunits, carbonic anhydrase, and enzymes involved in antioxidant responses (especially glutathione and phytochelatin homeostasis) and the Calvin cycle. Metabolomics results confirmed the alterations of energy-generating metabolic pathways, sulfur-compound metabolism (GSH and PCs), and Calvin cycle. Besides, metabolomics results highlighted the up-regulation of phosphoglycolate, a byproduct of the photorespiration metabolism. This was suggestive of the likely increased photorespiration rate as a means to cope with Cd-induced unbalance in stomatal conductance and deregulation of CO2 homeostasis, which would, in turn, promote CO2 depletion and O2 (and thus oxidative stress) accumulation under prolonged photosynthesis in the leaves from plants exposed to high doses of CdCl2. Overall, it emerges that Cd-stressed B. juncea might rely on photorespiration, an adaptation that would prevent the over-reduction of the photosynthetic electron transport chain and photoinhibition. PMID- 24074151 TI - The Swiss Neonatal Quality Cycle, a monitor for clinical performance and tool for quality improvement. AB - BACKGROUND: We describe the setup of a neonatal quality improvement tool and list which peer-reviewed requirements it fulfils and which it does not. We report on the so-far observed effects, how the units can identify quality improvement potential, and how they can measure the effect of changes made to improve quality. METHODS: Application of a prospective longitudinal national cohort data collection that uses algorithms to ensure high data quality (i.e. checks for completeness, plausibility and reliability), and to perform data imaging (Plsek's p-charts and standardized mortality or morbidity ratio SMR charts). The collected data allows monitoring a study collective of very low birth-weight infants born from 2009 to 2011 by applying a quality cycle following the steps 'guideline - perform - falsify - reform'. RESULTS: 2025 VLBW live-births from 2009 to 2011 representing 96.1% of all VLBW live-births in Switzerland display a similar mortality rate but better morbidity rates when compared to other networks. Data quality in general is high but subject to improvement in some units. Seven measurements display quality improvement potential in individual units. The methods used fulfil several international recommendations. CONCLUSIONS: The Quality Cycle of the Swiss Neonatal Network is a helpful instrument to monitor and gradually help improve the quality of care in a region with high quality standards and low statistical discrimination capacity. PMID- 24074152 TI - Direct construction of quaternary carbons from tertiary alcohols via photoredox catalyzed fragmentation of tert-alkyl N-phthalimidoyl oxalates. AB - A convenient method for the direct construction of quaternary carbons from tertiary alcohols by visible-light photoredox coupling of tert-alkyl N phthalimidoyl oxalate intermediates with electron-deficient alkenes is reported. PMID- 24074153 TI - The prophylaxis of hereditary angioedema attacks with recombinant human C1 inhibitor: who will take advantage of the individualized treatment approach? PMID- 24074154 TI - Increased mortality in AR patients? PMID- 24074155 TI - Genome wide profiling of dopaminergic neurons derived from human embryonic and induced pluripotent stem cells. AB - Recent advances in human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) biology enable generation of dopaminergic neurons for potential therapy and drug screening. However, our current understanding of molecular and cellular signaling that controls human dopaminergic development and function is limited. Here, we report on a whole genome analysis of gene expression during dopaminergic differentiation of human ESC/iPSC using Illumina bead microarrays. We generated a transcriptome data set containing the expression levels of 28,688 unique transcripts by profiling five lines (three ESC and two iPSC lines) at four stages of differentiation: (1) undifferentiated ESC/iPSC, (2) neural stem cells, (3) dopaminergic precursors, and (4) dopaminergic neurons. This data set provides comprehensive information about genes expressed at each stage of differentiation. Our data indicate that distinct pathways are activated during neural and dopaminergic neuronal differentiation. For example, WNT, sonic hedgehog (SHH), and cAMP signaling pathways were found over-represented in dopaminergic populations by gene enrichment and pathway analysis, and their role was confirmed by perturbation analyses using RNAi (small interfering RNA of SHH and WNT) or small molecule [dibutyryl cyclic AMP (dcAMP)]. In summary, whole genome profiling of dopaminergic differentiation enables systematic analysis of genes/pathways, networks, and cellular/molecular processes that control cell fate decisions. Such analyses will serve as the foundation for better understanding of dopaminergic development, function, and development of future stem cell-based therapies. PMID- 24074156 TI - Renal cell recurrence for T1 tumors after laparoscopic partial nephrectomy. AB - OBJECTIVES: There is lack of consensus in the Urology community regarding surveillance after laparoscopic partial nephrectomy (LPN), particularly for patients with stage I tumors. The purpose of this article is to characterize the rate of recurrence after partial nephrectomy in a low risk cohort. METHODS: Data were collected on all laparoscopic partial nephrectomies performed at a single institution from January 2006 through May 2011. Patients without at least 1 year of follow-up information were excluded from examination. Patients were stratified based on the pathologic tumor stage at the time of partial nephrectomy. Patients with stage I (a and b) tumors were then examined for recurrence. RESULTS: A total of 639 patients underwent LPN during the time period. Of this, 360 patients had stage T1 renal cell carcinoma (RCC) (302 with pT1a and 58 with pT1b) and met research criteria. There were 8 recurrences (2.2%) within this cohort ( Table 1 ). All of the tumors were of clear cell histology and none had Furhman grade 1 histology. Only one of these patients had a positive margin at the time of partial nephrectomy and all patients had negative biopsy of the tumor resection bed. A majority of the recurrences occurred locally in the ipsilateral kidney or retroperitoneum. Most of the recurrences occurred within 1-2 years postoperatively. CONCLUSIONS: Approximately 2% of patients who underwent LPN for RCC with resultant low risk, stage I tumor pathology developed metastasis. There were no recurrences in nonclear cell pathologies and no recurrences with Furhman grade 1 or tumors smaller than 3 cm. PMID- 24074157 TI - Resident and family perceptions of the nurse practitioner role in long term care settings: a qualitative descriptive study. AB - BACKGROUND: Research evidence supports the positive impact on resident outcomes of nurse practitioners (NPs) working in long term care (LTC) homes. There are few studies that report the perceptions of residents and family members about the role of the NP in these settings. The purpose of this study was to explore the perceptions of residents and family members regarding the role of the NP in LTC homes. METHODS: The study applied a qualitative descriptive approach. In-depth individual and focus group interviews were conducted with 35 residents and family members from four LTC settings that employed a NP. Conventional content analysis was used to identify themes and sub-themes. RESULTS: Two major themes were identified: NPs were seen as providing resident and family-centred care and as providing enhanced quality of care. NPs established caring relationships with residents and families, providing both informational and emotional support, as well as facilitating their participation in decision making. Residents and families perceived the NP as improving availability and timeliness of care and helping to prevent unnecessary hospitalization. CONCLUSIONS: The perceptions of residents and family members of the NP role in LTC are consistent with the concepts of person-centred and relationship-centred care. The relationships NPs develop with residents and families are a central means through which enhanced quality of care occurs. Given the limited use of NPs in LTC settings, there is an opportunity for health care policy and decision makers to address service inadequacies through strategic deployment of NPs in LTC settings. NPs can use their expert knowledge and skill to assist residents and families to make informed choices regarding their health care and maintain a positive care experience. PMID- 24074159 TI - President's report. PMID- 24074163 TI - Diets involved in PPAR and PI3K/AKT/PTEN pathway may contribute to neuroprotection in a traumatic brain injury. AB - Traumatic encephalopathy has emerged as a significant public health problem. It is believed that traumatic encephalopathy is caused by exposure to repetitive brain trauma prior to the initial symptoms of neurodegenerative disease. Therefore, prevention is important for the disease. The PI3K/AKT/PTEN (phosphoinositide-3 kinase/AKT/phosphatase and tensin homologue deleted on chromosome 10) pathway has been shown to play a pivotal role in neuroprotection, enhancing cell survival by stimulating cell proliferation and inhibiting apoptosis. PTEN negatively regulates the PI3K/AKT pathways through its lipid phosphatase activity. Although PTEN has been discovered as a tumor suppressor, PTEN is also involved in several other diseases, including diabetes and Alzheimer's disease. Dietary fish oil rich in polyunsaturated fatty acids may induce the PTEN expression by activation of peroxisome proliferator-activated receptor. Supplementation of these natural compounds may provide a new therapeutic approach to the brain disorder. We review recent studies on the features of several diets and the signaling pathways involved in traumatic encephalopathy. PMID- 24074164 TI - Stromal cell-derived factor 1alpha-stimulated mesenchymal stem cells confer enhanced protection against light-induced retinal degeneration in rats. AB - PURPOSE: Mesenchymal stem cells (MSCs) are currently considered to be modulators of repair in various tissues. After MSC transplant, photoreceptor rescue has been demonstrated in models of retinal degeneration. Herein, we evaluate the roles of MSCs in modulating the host reaction and photoreceptor preservation in rats suffering from light-induced retinal degeneration. METHODS: Unstimulated and stromal cell-derived factor 1alpha (SDF-1alpha)-stimulated MSCs were intravenously transplanted into light-injured rats. Their photoreceptor rescue effect was compared with untreated light-injured rats and light-injured rats received only medium injection. Ciliary neurotrophic factor (CNTF) and glial fibrillary acidic protein (GFAP) expression was identified to assess host reaction post-transplantation. Retinal localization and integration of MSCs were determined by green fluorescence protein labeling. RESULTS: MSCs were able to migrate and integrate into the host retina, and significantly inhibited retinal cell death. CNTF and GFAP were induced upregluation after MSC injection. SDF 1alpha stimulation elicited superior effects in both MSC migration and the inhibition of apoptosis. CNTF and GFAP expression in host retinas that received stimulated MSCs were stronger than in retinas that received unstimulated MSCs. CONCLUSIONS: Systemic administration of MSCs exerts a protective effect against light-induced retinal degeneration, and upregulates neurotrophin expression in the host retina. MSCs can be stimulated to enhance the therapeutic effect. PMID- 24074166 TI - Diuretic activity and toxicity of some Verbascum nigrum extracts and fractions. AB - CONTEXT: Verbascum nigrum L. (Scrophulariaceae) is a perennial plant used in folk medicine for the treatment of kidney diseases due to its presumable diuretic properties. OBJECTIVE: We investigated the diuretic activity and toxicity of extracts from different parts of V. nigrum and identified a group of compounds responsible for the biological effect. MATERIALS AND METHODS: Five ethanol extracts from herb, roots, flowers, leaves and stems as well as five fractions of polar compounds isolated from herb of V. nigrum were orally administrated as a single dose of 50 mg/kg to rats. Urinary excretion and electrolyte content were measured at 3 and 6 h after the treatment. The acute toxicity of the V. nigrum extracts and fractions was evaluated in mice. RESULTS: All extracts, except the one prepared from the roots, showed a significant increase of the urine output within first 3 h after their administration. The extract from stems was the most active, inducing urine output of 14.6 +/- 0.8 ml/kg BW versus 5.2 +/- 1.4 ml/kg BW of the control. It also demonstrated saluretic activity with a natriuretic index 4.1 and a kaliuretic index 3.8. The diuretic activity was correlated with the flavonoid content in the plant organs. Flavonoid fractions demonstrated significant activity; the higher content of flavonoids (expressed as hesperidin) translated into more pronounced diuretic (35.9 +/- 2.1 ml/kg BW) and saluretic effects (natriuretic index 4.5 and kaliuretic index 5.4). CONCLUSION: The diuretic activity of traditionally used V. nigrum was validated experimentally. The pharmacological effect was attributed to flavonoids, which accumulated in aerial parts of the plant, mainly in stems. PMID- 24074167 TI - Solvothermal-induced conversion of one-dimensional multilayer nanotubes to two dimensional hydrophilic VOx nanosheets: synthesis and water treatment application. AB - Ultrathin 2D nanostructures have shown many unique properties and are attractive for various potential applications. Here, we demonstrated a strategy to synthesize ultrathin VOx nanosheets. The as-obtained ultrathin VOx nanosheets showed a large Brunauer-Emmett-Teller (BET) surface area of 136.3 m2 g(-1), which is much larger than that of 1D multilayer VOx nanotubes. As a proof of concept, these hydrophilic ultrathin nanosheets were applied in water treatment and exhibited excellent absorption capability to remove Rhodamine B (RhB) in wastewater owing to their large specific surface area, good hydrophilic property, and more negative zeta potential. In addition, this method could be generalized to prepare other 2D nanostructures with great potential for various attractive applications. PMID- 24074168 TI - Facile strategy for protein conjugation with chitosan-poly(ethylene glycol) hybrid microparticle platforms via strain-promoted alkyne-azide cycloaddition (SPAAC) reaction. AB - We demonstrate a facile fabrication-conjugation scheme for protein-conjugated biosensing platforms. Specifically, we utilize a chitosan-poly(ethylene glycol) hybrid system to fabricate highly uniform and chemically reactive microparticle platforms via simple replica molding. Strain-promoted alkyne-azide cycloaddition (SPAAC) reaction between azide-modified proteins and microparticles activated with strain-promoted cyclooctynes allows tunable protein conjugation under mild reaction conditions. Upon conjugation of a model red fluorescent protein, fluorescence and confocal micrographs show selective protein conjugation near the particle surfaces as well as long-term stability of the conjugation scheme. Fluorescence and AFM results upon conjugation with varying protein concentrations indicate controllable protein conjugation. Examination of protein-particle conjugation kinetics shows multiple reaction regimes; rapid initial, intermediate, and steady final stage. Lastly, we demonstrate antibody conjugation with the particles and selective and rapid target protein capture with antibody conjugated particles. Combined, these results illustrate a facile fabrication conjugation scheme for robust protein-conjugated platforms that can be readily enlisted in various protein sensing applications. PMID- 24074169 TI - Sequencing millions of animals for genomic selection 2.0. PMID- 24074170 TI - Accuracy of genomic prediction using different models and response variables in the Nordic Red cattle population. AB - Breeding animals can be accurately evaluated using appropriate genomic prediction models, based on marker data and phenotype information. In this study, direct genomic values (DGV) were estimated for 16 traits of Nordic Total Merit (NTM) Index in Nordic Red cattle population using three models and two different response variables. The three models were as follows: a linear mixed model (GBLUP), a Bayesian variable selection model similar to BayesA (BayesA*) and a Bayesian least absolute shrinkage and selection operator model (Bayesian Lasso). The response variables were deregressed proofs (DRP) and conventional estimated breeding values (EBV). The reliability of genomic predictions was measured on bulls in the validation data set as the squared correlation between DGV and DRP divided by the reliability of DRP. Using DRP as response variable, the reliabilities of DGV among the 16 traits ranged from 0.151 to 0.569 (average 0.317) for GBLUP, from 0.152 to 0.576 (average 0.318) for BayesA* and from 0.150 to 0.570 (average 0.320) for Bayesian Lasso. Using EBV as response variable, the reliabilities ranged from 0.159 to 0.580 (average 0.322) for GBLUP, from 0.157 to 0.578 (average 0.319) for BayesA* and from 0.159 to 0.582 (average 0.325) for Bayesian Lasso. In summary, Bayesian Lasso performed slightly better than the other two models, and EBV performed slightly better than DRP as response variable, with regard to prediction reliability of DGV. However, these differences were not statistically significant. Moreover, using EBV as response variable would result in problems with the scale of the resulting DGV and potential problem due to double counting. PMID- 24074171 TI - Estimation of accuracies and expected genetic change from selection for selection indexes that use multiple-trait predictions of breeding values. AB - Procedures are described for estimating selection index accuracies for individual animals and expected genetic change from selection for the general case where indexes of EBVs predict an aggregate breeding objective of traits that may or may not have been measured. Index accuracies for the breeding objective are shown to take an important general form, being able to be expressed as the product of the accuracy of the index function of true breeding values and the accuracy with which that function predicts the breeding objective. When the accuracies of the individual EBVs of the index are known, prediction error variances (PEVs) and covariances (PECs) for the EBVs within animal are able to be well approximated, and index accuracies and expected genetic change from selection estimated with high accuracy. The procedures are suited to routine use in estimating index accuracies in genetic evaluation, and for providing important information, without additional modelling, on the directions in which a population will move under selection. PMID- 24074172 TI - Measuring inbreeding and inbreeding depression on pig growth from pedigree or SNP derived metrics. AB - Multilocus homozygosity, measured as the proportion of the autosomal genome in homozygous genotypes or in runs of homozygosity, was compared with the respective pedigree inbreeding coefficients in 64 Iberian pigs genotyped using the Porcine SNP60 Beadchip. Pigs were sampled from a set of experimental animals with a large inbreeding variation born in a closed strain with a completely recorded multi generation genealogy. Individual inbreeding coefficients calculated from pedigree were strongly correlated with the different SNP-derived metrics of homozygosity (r = 0.814-0.919). However, unequal correlations between molecular and pedigree inbreeding were observed at chromosomal level being mainly dependent on the number of SNPs and on the correlation between heterozygosities measured across different loci. A panel of 192 SNPs of intermediate frequencies was selected for genotyping 322 piglets to test inbreeding depression on postweaning growth performance (daily gain and weight at 90 days). The negative effects on these traits of homozygosities calculated from the genotypes of 168 quality-checked SNPs were similar to those of inbreeding coefficients. The results support that few hundreds of SNPs may be useful for measuring inbreeding and inbreeding depression, when the population structure or the mating system causes a large variance of inbreeding. PMID- 24074173 TI - Relationships between longevity, lifetime productivity, carcass traits and conformation in Polish maternal pig breeds. AB - The objective of this study was to obtain heritability estimates for longevity (length of life, length of productive life, number of litters) and lifetime productivity traits (lifetime pig production, lifetime pig efficiency, lifetime litter efficiency) and genetic correlation between them and litter size at first farrowing, growth (ADG), backfat thickness (BF), loin depth, lean meat percentage (LMP), phenotypic selection index (PSI), and exterior in 19423 Polish Landrace (L) and 16049 Polish Large White (LW) sows. Heritabilities for longevity and lifetime productivity traits were 0.10-0.13 for L sows and 0.09-0.11 for LW sows depending on the trait definition. The genetic correlations among these traits were all high and positive, ranging from 0.76 to 0.99. Antagonistic genetic correlations (-0.21 to -0.26) were found between longevity traits and PSI and LMP in LW sows, while in L sows the respective parameters were lower and not significant for length of productive life. The number of live-born piglets in the first litter was positively correlated with lifetime pig production and lifetime pig efficiency in both breeds. The genetic correlations of longevity and lifetime pig production with ADG, BF, loin depth and exterior were small, and in most cases, not significant. PMID- 24074174 TI - Identification and validation of differentially expressed genes from pig skeletal muscle. AB - Pig is an important animal for meat production; this is generally associated with characteristics determined prenatally during myogenesis. Expressed sequence tags (EST) can provide direct information on the transcriptome and indirect information on the relation between the genome and phenotype, giving information about differentially expressed genes (DEG). In this work, the identification and annotation of DEG from EST libraries of three pig breeds (Duroc, Large White and Local Breed Piau) were performed followed by real-time PCR analyses during pre- and postnatal stages (21, 40, 70 and 90 days of pregnancy and 107, 121 and 171 days postnatal) from commercial breed animals for analysis of genes expression levels. Therefore, 34 genes differentially expressed were identified, of which 21 grouped in a network related with muscle development. From this, the expression profile of 13 genes was measured, to confirm their relationship with myogenesis like ANKRD2, MYBPC1, NEB and MYL2. These genes showed a prenatal high expression in this study. Besides, novels candidates for muscle development (TP53 and DCTN1) were listed. These findings can contribute to better explaining gene function mechanism and are helpful in uncovering the pathways that mediate pre- and postnatal skeletal muscle development in vertebrates. PMID- 24074175 TI - Allelic frequencies of PRKAG3 in several pig breeds and its technological consequences on a Duroc * Landrace-Large White cross. AB - The allelic frequencies of PRKAG3 gene (the RN gene) have been investigated in several pig breeds. R200Q mutation appear only in Hampshire pigs, whereas V199I mutation is most abundant in Iberian, Porco Celta or Bizaro, and less in breeds selected for muscularity as Duroc, Landrace and Pietrain. A thorough study of phenotypic effects of V1991 has been performed in a Duroc * Landrace-Large White cross. 199I homozygous pigs show increased pH24 values in ham homogenates and loin (0.14 and 0.16 pH units, respectively) compared to 199V homozygous ones. Meat of 199I homozygous pigs exudates 42.6% less fluid and is darker (2.46 'L' value units). 199I homozygous pigs are fatter (4.2 mm more backfat thickness) and contain less muscle mass in ham (1.0 percentage points) and shoulder (2.7 percentage points), than 199V homozygous ones. 199I homozygous pigs contain 7.3% less protein in the belly and 8.5% more fat in shoulder muscle mass than 199V homozygous pigs. 199I homozygous pigs have also superior functional properties: better gelling (22.8% larger G' value) and emulsion capacities (14 percentage points less of total exuded fluid), and higher curing yield in the belly (6 percentage points more). These data support the adipogenic character of the V199I mutation. The advantages and disadvantages of selecting any of the two PRKAG3 alleles for position 199 are discussed. PMID- 24074176 TI - Genotype by environment interaction and model comparison for growth traits of Santa Ines sheep. AB - The objectives of the present study were to compare alternative models for the genetic evaluation and assess the importance of genotype by environment interaction (G*E) in the estimation of genetic parameters and genetic evaluation of birth weight (BW), weight at 60 days of age (W60) and weight at 180 days of age (W180) of Santa Ines sheep. Data comprise 7622 BW, 4673 W60 and 2830 W180 records from animals born in 44 Brazilian herds. Four models were used for the analyses: animal model (AM) with homogeneous residual variance (1), or heterogeneous residual variance (2), hierarchical reaction norms model (HRNM) with homogeneous (1) or heterogeneous residual variance (2). The models that best fit the BW, W60 and W180 data were AM2, HRNM1 and HRNM2 respectively. Thus, models for genetic evaluation that consider heterogeneity of variances are recommended to evaluate growth traits of sheep. The correlation between intercept and slope of the HRNM was higher than 0.70 for all traits studied, indicating that animals with higher average breeding values responded better to improvement in environmental conditions, a fact characterizing the scale effect of G*E. Therefore, G*E is an important factor to be considered in the estimation of genetic parameters and genetic evaluation of growth traits of sheep. PMID- 24074177 TI - Genetic parameters for birthweight environmental variability in mice. AB - Data from a divergent experiment for birthweight (BrW) environmental variability were used to estimate genetic parameters for BrW trait and its environmental variability by fitting both homoscedastic (HO) and heteroscedastic (HE) models. A total of 5 475 records of BrW from animals born from inbred dams, and 7 140 pedigree records were used. The heritability of BrW using the model HO was 0.27, with the litter effect much more important, 0.43. The model HE provided a genetic correlation between the trait and its environmental variability that was very high and negative, -0.97, and a high value for the additive genetic variance for environmental variability, suggesting an artefact in the model. The residual skewness was found to be essentially null. A model considering the genetic correlation null was also fitted, and used to obtain the breeding values for the selection process. Moreover, the trait was considered as maternal resulting in similar estimates under the model HO, but more reasonable for the genetic correlation between the trait and its environmental variability of 0.48 with a value of 0.25 for the additive genetic variance regarding environmental variability under the model HE. This led to the conclusion that environmental variability of BrW in mice must be selected via dams. Estimated parameters in a reduced dataset without inbred animals did not substantially change this conclusion. PMID- 24074178 TI - Role of colchicine-induced microtubule depolymerization in hyperalgesia via TRPV4 in rats with chronic compression of the dorsal root ganglion. AB - The aim of this study is to investigate the effect of microtubule depolymerization by colchicine on hyperalgesia mediated by transient receptor potential vanilloid 4 (TRPV4) in a neuropathic pain model of chronic compression of the dorsal root ganglion (DRG) (hereafter termed CCD) in rat. Intrathecal administration of microtubule-depolymerizing agent, colchicine, attenuated the activated effect of 4alpha-phorbol 12, 13-didecanoate (4alpha-PDD, TRPV4 specific agonist) on mechanical and thermal hyperalgesia in CCD rats. This observation is in agreement with our in vitro experiments with DRG cells that showed a significant attenuation of 4alpha-PDD-activated Ca(2+)-influx and substance P (SP) release with the colchicine treatment. We conclude that microtubule depolymerization by colchicine can regulate pain sensitivity by depressing the hyperalgesia mediated by TRPV4. PMID- 24074179 TI - Neuropsychological functions among adolescents with persistent, subsyndromal and remitted attention deficit hyperactivity disorder. AB - BACKGROUND: Previous studies have reported mixed results on neuropsychological deficits in attention deficit hyperactivity disorder (ADHD) and only a few studies have focused on adolescents. There is also a debate about whether the executive function (EF) impairments in ADHD are primary deficits or have some contribution from the underlying non-EF processes. The aim of this study was to investigate the impairments in EF and neuropsychological function with relatively low executive demand (low-EF) in adolescents with childhood diagnosis of ADHD as a function of current ADHD status. METHOD: Psychiatric diagnostic interviews and computerized neuropsychological tests classified into EF and low-EF tasks were completed by 435 adolescents with a childhood diagnosis of ADHD (300 adolescents classified as persistent ADHD, 109 as subsyndromal ADHD and 26 as remitted ADHD based on the current diagnosis) and 263 typically developing (TD) adolescents. RESULTS: There were significant EF (spatial working memory, spatial planning and verbal working memory) and low-EF (signal detectability, spatial span and visual recognition memory) impairments in persistent and subsyndromal ADHD. The impairments in EF were independent of low-EF despite significant moderate correlations between any two of these tasks. Adolescents with remitted ADHD showed no deficit in either EF or low-EF. CONCLUSIONS: This study suggests that adolescents with persistent and subsyndromal ADHD have EF and low-EF impairments that might contribute to ADHD independently. PMID- 24074180 TI - The impact of severe osteogenesis imperfecta on the lives of young patients and their parents - a qualitative analysis. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic disorder that causes increased bone fragility. Living with, caring for, and parenting a child with OI are all highly demanding and challenging. This study is a temporal analysis of the impact of severe OI on the lives of young patients and their parents. METHODS: This study was carried out at the Shriners Hospital for Children, a pediatric orthopedic hospital located in Montreal, Canada. Using qualitative interpretative description, we conducted semi-structured interviews with 24 subjects - 12 young patients diagnosed with severe OI and 12 of their parents. The interview data were subject to a predominantly inductive open thematic analysis and a temporal comparative analysis. We did a retrospective chart review to complement our data collection. RESULTS: We found that the impact of severe OI on the young patients and their parents was characterized by four themes: 1) Starting at the time of diagnosis, a series of stages shaped life and the return to every day "normal", 2) Living with OI was full of "ups and downs" throughout life, 3) Every day "normal" life with OI consisted of significant changes for parents and challenges for the whole family, and 4) Living with OI generated some positive experiences. CONCLUSION: This study contributes to a better theoretical understanding of the impact of severe OI on families. It also has some practical implications for the development of effective support systems for patients with severe OI and their families. PMID- 24074184 TI - One-step solvothermal synthesis of targetable optomagnetic upconversion nanoparticles for in vivo bimodal imaging. AB - Bionanoparticles and nanostructures with high biocompatibility and stability, low toxicity, diversification of imaging modality, and specificity of targeting to desired organs or cells are of great interest in nanobiology and medicine. However, integrating all of these desired features into a single bionanoparticle, which can be applied to biomedical applications and eventually in clinical prediagnosis and therapy, is still a challenge. We herein report a facile one step solvothermal approach to fabricate targetable and biocompatible beta NaYF4:Yb,Gd,Tm upconversion nanoparticles (UCNPs) with bimodal-signals (near infrared (NIR) fluorescence and magnetic resonance (MR) signals) using hyaluronic acid (HA) as a multifunctional molecule. The prepared UCNPs with low toxicity are successfully applied for in vitro and in vivo targeted tumor imaging. The developed biomimetic surface modification approach for the synthesis of biomolecule-guided multifunctional UCNPs holds great potential applications in medical diagnostics and therapy. PMID- 24074185 TI - A systematic approach to statistical analysis in dosimetry and patient-specific IMRT plan verification measurements. AB - PURPOSE: In the presence of random uncertainties, delivered radiation treatment doses in patient likely exhibit a statistical distribution. The expected dose and variance of this distribution are unknown and are most likely not equal to the planned value since the current treatment planning systems cannot exactly model and simulate treatment machine. Relevant clinical questions are 1) how to quantitatively estimate the expected delivered dose and extrapolate the expected dose to the treatment dose over a treatment course and 2) how to evaluate the treatment dose relative to the corresponding planned dose. This study is to present a systematic approach to address these questions and to apply this approach to patient-specific IMRT (PSIMRT) plan verifications. METHODS: The expected delivered dose in patient and variance are quantitatively estimated using Student T distribution and Chi Distribution, respectively, based on pre treatment QA measurements. Relationships between the expected dose and the delivered dose over a treatment course and between the expected dose and the planned dose are quantified with mathematical formalisms. The requirement and evaluation of the pre-treatment QA measurement results are also quantitatively related to the desired treatment accuracy and to the to-be-delivered treatment course itself. The developed methodology was applied to PSIMRT plan verification procedures for both QA result evaluation and treatment quality estimation. RESULTS: Statistically, the pre-treatment QA measurement process was dictated not only by the corresponding plan but also by the delivered dose deviation, number of measurements, treatment fractionation, potential uncertainties during patient treatment, and desired treatment accuracy tolerance. For the PSIMRT QA procedures, in theory, more than one measurement had to be performed to evaluate whether the to-be-delivered treatment course would meet the desired dose coverage and treatment tolerance. CONCLUSION: By acknowledging and considering the statistical nature of multi-fractional delivery of radiation treatment, we have established a quantitative methodology to evaluate the PSIMRT QA results. Both the statistical parameters associated with the QA measurement procedure and treatment course need to be taken into account to evaluate the QA outcome and to determine whether the plan is acceptable and whether additional measures should be taken to reduce treatment uncertainties. The result from a single QA measurement without the appropriate statistical analysis can be misleading. When the required number of measurements is comparable to the planned number of fractions and the variance is unacceptably high, action must be taken to either modify the plan or adjust the beam delivery system. PMID- 24074186 TI - Effects of oxidation on copper-binding properties of Abeta1-16 peptide: a pulse radiolysis study. AB - The reaction of hydroxyl radicals ((*)OH) with Abeta1-16 peptide was carried out using pulse radiolysis to understand the effect of oxidation of peptide on its copper-binding properties. This reaction produced oxidized, dimeric and trimeric Abeta1-16 peptide species. The formation of these products was established with the help of fluorescence spectroscopy and mass spectrometry. The mass spectral data indicate that the major site of oxidation is at His6, while the site for dimerization is at Tyr10. Diethyl pyrocarbonate-treated Abeta1-16 peptide did not produce any trimeric species upon oxidation with (*)OH. The quantitative chemical modification studies indicated that one of the three histidine residues is covalently modified during pulse radiolysis. The copper-binding studies of the oxidized peptide revealed that it has similar copper-binding properties as the unoxidized peptide. Further, the cytotoxicity studies point out that both oxidized and unoxidized Abeta1-16 peptide are equally efficient in producing free radicals in presence of copper and ascorbate that resulted in comparable cell death. PMID- 24074187 TI - Developing translational research infrastructure and capabilities associated with cancer clinical trials. AB - The integration of molecular information in clinical decision making is becoming a reality. These changes are shaping the way clinical research is conducted, and as reality sets in, the challenges in conducting, managing and organising multi disciplinary research become apparent. Clinical trials provide a platform to conduct translational research (TR) within the context of high quality clinical data accrual. Integrating TR objectives in trials allows the execution of pivotal studies that provide clinical evidence for biomarker-driven treatment strategies, targeting early drug development trials to a homogeneous and well defined patient population, supports the development of companion diagnostics and provides an opportunity for deepening our understanding of cancer biology and mechanisms of drug action. To achieve these goals within a clinical trial, developing translational research infrastructure and capabilities (TRIC) plays a critical catalytic role for translating preclinical data into successful clinical research and development. TRIC represents a technical platform, dedicated resources and access to expertise promoting high quality standards, logistical and operational support and unified streamlined procedures under an appropriate governance framework. TRIC promotes integration of multiple disciplines including biobanking, laboratory analysis, molecular data, informatics, statistical analysis and dissemination of results which are all required for successful TR projects and scientific progress. Such a supporting infrastructure is absolutely essential in order to promote high quality robust research, avoid duplication and coordinate resources. Lack of such infrastructure, we would argue, is one reason for the limited effect of TR in clinical practice beyond clinical trials. PMID- 24074188 TI - Electronic transitions of C6H4+ isomers: neon matrix and theoretical studies. AB - Three open-chain isomers of C6H4(+) and two cyclic ones were detected following mass-selective trapping in 6 K neon matrixes. The open-chain cations 5-hexene-1,3 diyne (CH2?CH-CC-CC-H)(+) and cis- (cis-HCC-CH?CH-CCH)(+) and trans-3-hexene-1,5 diyne (trans-HCC-CH?CH-CCH)(+), possess two absorption systems commencing at 609 and 373, 622 and 385, and 585 and 373 nm, respectively. They are assigned to the 1 (2)A" and 2 (2)A" <- X (2)A", 1(2)A2 and 2 (2)A2 <- X (2)B1, and 1 (2)Bg and 2 (2)B(g) <- X (2)A(u) electronic transitions of these cations. Two overlapping systems are detected at around 420 nm and tentatively assigned to the 1 (2)A" <- X (2)A" electronic transitions of propargyl cyclopropene and 2 (2)B1 <- X (2)A2 of o-benzyne cation structures. The assignment of the electronic transitions is based on theoretical vertical excitation energies calculated with CASPT2 and EOMEE-CCSDT methods for 12 isomers of C6H4(+). These have been carried out at the geometries optimized using several ab initio methods. Adiabatic excitation energies were calculated for the five identified isomers of C6H4(+). PMID- 24074189 TI - Uniform standards and case definitions for classifying opioid-related deaths: recommendations by a SAMHSA consensus panel. AB - Deaths involving prescription and illicit opioids are on the rise, which is an issue of increasing concern to health care professionals, policymakers, and the public. However, because medical examiners, coroners, and other practitioners do not use uniform standards and case definitions in classifying such drug-related deaths, the incidence and prevalence data are challenging to analyze and difficult to interpret, and thus form a poor basis for crafting effective responses. To address this situation, the Substance Abuse and Mental Health Services Administration convened a Consensus Panel and charged it with devising uniform standards and case definitions that can assist medical examiners, coroners, public health officials, and others in consistently distinguishing between deaths that were caused by a certain opioids and deaths in which such a drug was detected but was not a major cause of or contributor to the death. The consensus statement presented here incorporates the panel's recommendations in four key areas. PMID- 24074190 TI - Comparison of QTc interval prolongation for patients in methadone versus buprenorphine maintenance treatment: a 5-year follow-up. AB - The authors investigated whether patients receiving buprenorphine maintenance treatment (BMT) will have corrected QT (QTc) prolongation after taking buprenorphine for an extended period of time. They also compared QTc prolongation for patients in methadone maintenance treatment (MMT) versus BMT to determine which medication is the better option for patients with heart disease. A retrospective chart review study of 73 patients in BMT and 55 patients in MMT was performed. A linear regression model with a one-sided P value was used for data analysis. The MMT group had statistically significant prolongation of QTc compared with the BMT group (F = 3.94, P = .0001). Being diagnosed with congestive heart failure and taking methadone were the only individual variables that showed a statistically significant association with a QTc prolongation > 500 ms. The model as a whole showed statistical significance (F = 5.203, P = .007). Being diagnosed with congestive heart failure was the only individual variable that showed a statistically significant association with mortality. The model as a whole also showed statistical significance (F = 17.15, P = .000). This study supports previous findings that methadone may be associated with QTc prolongation, whereas buprenorphine may not. This study has the advantage of confirming that QTc prolongation persists in patients in MMT but not in those in BMT over an extended period of time (i.e., 5 years). Buprenorphine might a better first-line opioid maintenance treatment for patients with heart disease because buprenorphine was not associated with QTc prolongation. Patients in BMT may not need to be screened routinely for QTc prolongation. PMID- 24074191 TI - The effects of ADHD in adult substance abusers. AB - The aim of this study was to evaluate the psychiatric comorbidities and different areas of life functioning in substance abusers with attention deficit hyperactivity disorder symptoms. A cross-sectional, multi-center study involving 285 adult substance abusers from outpatient and inpatient clinics was performed. The Adult ADHD Self-Report Scale, the sixth version of the Addiction Severity Index, and the Mini International Neuropsychiatry Interview were used for data collection. Individuals with comorbid attention deficit hyperactivity disorder and substance use disorders showed increased addiction severity when compared with individuals without attention deficit hyperactivity disorder (53.3 +/- 7.3 vs. 48.4 +/- 8.4, respectively). Our results suggest that comorbid attention deficit hyperactivity disorder and substance use disorders is associated with a more severe course of substance use and with social and psychiatric impairment. PMID- 24074192 TI - Cocaine-induced psychosis and impulsivity in cocaine-dependent patients. AB - Cocaine-dependent patients have high impulsiveness. Cocaine-induced psychosis is common among cocaine-dependent patients. Different risk factors associated with cocaine-induced psychosis have been reported. The aim of this study is to analyze the relationship between psychotic symptoms in cocaine-dependent patients and impulsivity and mental disorders characterized by impulsivity. This descriptive study included 287 outpatients with cocaine dependence according to the DSM-IV-TR criteria. The Structured Clinical Interview for DSM-IV Axis I and II, the Barratt Impulsiveness Scale, and a specific questionnaire on the presence of cocaine induced psychosis were used to assess patients. Symptoms were observed in 59.9% of the study population. Total and cognitive impulsiveness scores obtained from the Barratt Impulsiveness Scale were significantly higher in patients with cocaine-induced psychosis. Individuals from this group reported more overdose incidents, initiated more treatments during their lifetime, and had a significantly greater prevalence of attention deficit hyperactivity disorder. Patients with cocaine-induced psychosis have a greater degree of impulsivity and a higher prevalence of attention deficit hyperactivity disorder. Thus, if these disorders are observed in cocaine-dependent participants, the presence of psychotic symptoms should be evaluated to prevent further occurrence and their consequences. PMID- 24074193 TI - A systematic review comparing cognitive-behavioral therapy and contingency management for cocaine dependence. AB - The main objective of this review was to compare the effectiveness of cognitive behavioral therapy and contingency management for cocaine dependence. Contingency management alone reliably reduced cocaine use during active treatment in all cited trials, whereas the positive effect of cognitive-behavioral therapy emerged after treatment in 3 of 5 trials. Synergistic effects of the combination of contingency management plus cognitive-behavioral therapy are shown in 2 trials, but another 3 trials found no additive effects. Positive, rapid, and enduring effects on cocaine use are reliably seen with contingency management interventions, whereas measurable effects of cognitive-behavioral therapy emerge after treatment and are not as reliable as effects with contingency management. PMID- 24074194 TI - A comparison of two alcohol biomarkers in clinical practice: ethyl glucuronide versus ethyl sulfate. AB - This study compared the characteristics of two direct alcohol biomarkers, ethyl glucuronide and ethyl sulfate. Both biomarkers were analyzed from urine specimens submitted by 58 active duty service members at Walter Reed National Military Medical Center's Addiction Treatment Service. These 58 individuals, as a result of serial testing, submitted a total of 374 urine specimens for laboratory analysis. Of 374 specimens, the paired tests were most often negative (n = 295, 78.9%).The paired tests were both positive less frequently (n = 38, 10.2%). In an interesting development ethyl sulfate produced more positive results than ethyl glucuronide (n = 32, 8.6%). PMID- 24074195 TI - Molecular and genetic determinants of alcohol dependence. AB - Alcohol dependence is a complex disorder affecting all social and ethnic groups. Although the scientific understanding of the mechanism governing this multifactorial disease is still in its infancy, understanding its biological bases, including the potential contribution of genetic factors, is key to characterizing individual's risk and developing efficacious therapeutic target to combat the disease. This review provides an overview of different approaches that are being increasingly integrated to extend our knowledge of the genetic underpinnings of alcohol dependence. PMID- 24074196 TI - Exploring the focus and experiences of smartphone applications for addiction recovery. AB - Addiction recovery Smartphone applications (apps) (n = 87) identified on the Google Play store in 2012 were coded, along with app user reviews, to explore functions, foci, and user experiences. Content analysis revealed that apps typically provided information on recovery, as well as content to enhance motivation, promote social support and tools to monitor progress. App users commented that the apps helped to inform them, keep them focussed, inspire them, and connect them with other people and groups. Because few addiction recovery apps appear to have been formally evaluated, further research is needed to ascertain their effectiveness as stand-alone or adjunctive interventions. PMID- 24074197 TI - Reefer sadness. PMID- 24074199 TI - Characterization of perioperative leukocytosis in patients undergoing robot assisted radical prostatectomy: effects of Gleason score and race. AB - INTRODUCTION: Our objective was to determine the impact of race and tumor grade on perioperative leukocytosis on patients undergoing robot-assisted radical prostatectomy (RARP). METHODS: A retrospective review of our urologic oncology database for patients undergoing RARP from August 2002 to July 2011 was conducted. A total of 768 patients were identified with complete data. Demographic data, preoperative prostate specific antigen (PSA), biopsy Gleason score, pathology Gleason score, pathology stage, margin status, and node status were collected. White blood cell (WBC) counts were captured preoperatively, 1 hour postoperatively, and on postoperative day 1. We assessed the differences in leukocyte responses according to the race and Gleason score using ANOVA testing. RESULTS: Preoperative WBC was lowest in black men and comparable between white and Hispanic men. At 1 hour, postoperative WBC remained lowest in Black men (p<0.001). Post-RARP leukocytosis varied significantly depending on the race (p<0.001). At 1 hour, patients with Gleason 8-10 tumors had decreased WBC compared to Gleason 6 patients (p<0.05) despite similar preoperative WBC and Charlson comorbidity index values. CONCLUSIONS: We report novel clinical observations that suggest differences in the immune response associated with the race and Gleason grade following RARP. The clinical utility of these findings are yet to be determined. PMID- 24074200 TI - Total synthesis of vineomycin B2. AB - The first total synthesis of vineomycin B2 (1) has been accomplished. The aglycon segment, a vineomycinone B2 derivative, and the glycon segment, an alpha-L acurosyl-L-rhodinose derivative, were prepared via C-glycosylation using an unprotected sugar and powerful chemoselective O-glycosylation using a 2,3 unsaturated sugar, respectively, as the key steps. Furthermore, effective and simultaneous introduction of the two glycon moieties to the aglycon part by concentration-controlled glycosylation led to the total synthesis of 1. PMID- 24074201 TI - Do concentrations of ethinylestradiol, estradiol, and diclofenac in European rivers exceed proposed EU environmental quality standards? AB - This study used a geographic based water model to predict the environmental concentrations of three pharmaceuticals, 17alpha-ethinylestradiol (EE2), 17beta estradiol (E2), and diclofenac throughout European rivers. The work was prompted by the proposal of the European Community (COM(2011)876) to consider these chemicals as candidates for future control via environmental quality standards (EQS). National drug consumption information, excretion, national water use, and sewage removal rates, were used to derive per capita sewage effluent values for the European countries . For E2, excretion rates of the natural hormone and national demographics were also included. Incorporating this information into the GWAVA model allowed water concentrations throughout Europe's rivers to be predicted. The mean concentration from the expected sewage discharge scenario indicated that 12% by length of Europe's rivers would reach concentrations greater than the proposed 0.035 ng/L EQS for EE2. For several countries, between a quarter and a third of their total river length would fail such an EE2 EQS. For E2, just over 1% by length of rivers would reach concentrations greater than the 0.4 ng/L proposed EQS, while just over 2% by length of rivers would reach concentrations greater than the proposed EQS of 100 ng/L for diclofenac. PMID- 24074202 TI - Congenital bilateral upper eyelid eversion: report of a case. AB - Congenital bilateral upper eyelid eversion is a rare condition and the definite cause is not known. It is often seen in Black babies or babies with Down's syndrome. With early diagnosis and appropriate treatment, the condition can be managed without surgery. We report a case of congenital upper eyelid eversion in an otherwise healthy Caucasian neonate, born by normal vaginal delivery. The case responded well to conservative treatment, including eyelid repositioning, lubricants, antibiotic ointment, and eyelid patching. PMID- 24074204 TI - Structured myeloid cells and anti-angiogenic therapy in alveolar soft part sarcoma. AB - Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma and the clinical management of patients with unresectable, metastatic disease is still challenging. ASPS expresses an array of potentially therapeutically targetable, angiogenesis-related molecules and, importantly, it has a distinctive angiogenic phenotype marked by a peculiar tumor-associated vasculature. Several studies, conducted in transgenic mouse models and in a large variety of human tumors of different histotype, clearly proved the substantial contribution of tumor infiltrating myeloid cells, such as myeloid derived suppressor cells, monocytes and macrophages, in the formation and maintenance of abnormal blood vessels in tumors. By immunohistochemistry we thus explored the presence and the distribution of cells expressing myeloid markers in the inflammatory infiltrate of surgical treated metastatic ASPS. Indeed, we found that myeloid cells expressing CD14 and CD163 markers constitute the prominent cells in the inflammatory infiltrate of ASPS. These macrophage-like cells form a network surrounding the endothelial cells, or, interspersed in the tumor nest, they keep deep contact with tumor cells. In this commentary, we discussed our findings in relation to the recently published paper by Kummar and colleagues reporting the clinical and molecular results of a phase II clinical trial in patients with unresectable, metastatic ASPS treated with the anti-angiogenic drug cediranib, targeting the VEGFR-1,-2,-3 tyrosine kinases. PMID- 24074203 TI - RIP-seq of BmAgo2-associated small RNAs reveal various types of small non-coding RNAs in the silkworm, Bombyx mori. AB - BACKGROUND: Small non-coding RNAs (ncRNAs) are important regulators of gene expression in eukaryotes. Previously, only microRNAs (miRNAs) and piRNAs have been identified in the silkworm, Bombyx mori. Furthermore, only ncRNAs (50-500nt) of intermediate size have been systematically identified in the silkworm. RESULTS: Here, we performed a systematic identification and analysis of small RNAs (18-50nt) associated with the Bombyx mori argonaute2 (BmAgo2) protein. Using RIP-seq, we identified various types of small ncRNAs associated with BmAGO2. These ncRNAs showed a multimodal length distribution, with three peaks at ~20nt, ~27nt and ~33nt, which included tRNA-, transposable element (TE)-, rRNA-, snoRNA- and snRNA-derived small RNAs as well as miRNAs and piRNAs. The tRNA-derived fragments (tRFs) were found at an extremely high abundance and accounted for 69.90% of the BmAgo2-associated small RNAs. Northern blotting confirmed that many tRFs were expressed or up-regulated only in the BmNPV-infected cells, implying that the tRFs play a prominent role by binding to BmAgo2 during BmNPV infection. Additional evidence suggested that there are potential cleavage sites on the D, anti-codon and TpsiC loops of the tRNAs. TE-derived small RNAs and piRNAs also accounted for a significant proportion of the BmAgo2-associated small RNAs, suggesting that BmAgo2 could be involved in the maintenance of genome stability by suppressing the activities of transposons guided by these small RNAs. Finally, Northern blotting was also used to confirm the Bombyx 5.8 s rRNA-derived small RNAs, demonstrating that various novel small RNAs exist in the silkworm. CONCLUSIONS: Using an RIP-seq method in combination with Northern blotting, we identified various types of small RNAs associated with the BmAgo2 protein, including tRNA-, TE-, rRNA-, snoRNA- and snRNA-derived small RNAs as well as miRNAs and piRNAs. Our findings provide new clues for future functional studies of the role of small RNAs in insect development and evolution. PMID- 24074206 TI - INFORMAS (International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support): overview and key principles. AB - Non-communicable diseases (NCDs) dominate disease burdens globally and poor nutrition increasingly contributes to this global burden. Comprehensive monitoring of food environments, and evaluation of the impact of public and private sector policies on food environments is needed to strengthen accountability systems to reduce NCDs. The International Network for Food and Obesity/NCDs Research, Monitoring and Action Support (INFORMAS) is a global network of public-interest organizations and researchers that aims to monitor, benchmark and support public and private sector actions to create healthy food environments and reduce obesity, NCDs and their related inequalities. The INFORMAS framework includes two 'process' modules, that monitor the policies and actions of the public and private sectors, seven 'impact' modules that monitor the key characteristics of food environments and three 'outcome' modules that monitor dietary quality, risk factors and NCD morbidity and mortality. Monitoring frameworks and indicators have been developed for 10 modules to provide consistency, but allowing for stepwise approaches ('minimal', 'expanded', 'optimal') to data collection and analysis. INFORMAS data will enable benchmarking of food environments between countries, and monitoring of progress over time within countries. Through monitoring and benchmarking, INFORMAS will strengthen the accountability systems needed to help reduce the burden of obesity, NCDs and their related inequalities. PMID- 24074205 TI - Repeated retrieval during working memory is sensitive to amnestic mild cognitive impairment. AB - Study of repeated learning mechanisms has been limited in amnestic mild cognitive impairment, a preclinical stage of Alzheimer disease modifiable by cognitive rehabilitation. We assessed repeated contextual working memory decline as an indicator of amnestic mild cognitive impairment in a sample of 45 older adults recruited from the tertiary care setting. Results indicated that contextual working memory impairment distinguished adults with preclinical disease from those without impairment despite similar overall cognitive performance, and comparison of the indicator with standard-of-care neuropsychological measures indicated discriminant validity. Contextual working memory impairment may represent a novel predictor of Alzheimer disease conversion risk. PMID- 24074207 TI - Monitoring policy and actions on food environments: rationale and outline of the INFORMAS policy engagement and communication strategies. AB - The International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support (INFORMAS) proposes to collect performance indicators on food policies, actions and environments related to obesity and non-communicable diseases. This paper reviews existing communications strategies used for performance indicators and proposes the approach to be taken for INFORMAS. Twenty-seven scoring and rating tools were identified in various fields of public health including alcohol, tobacco, physical activity, infant feeding and food environments. These were compared based on the types of indicators used and how they were quantified, scoring methods, presentation and the communication and reporting strategies used. There are several implications of these analyses for INFORMAS: the ratings/benchmarking approach is very commonly used, presumably because it is an effective way to communicate progress and stimulate action, although this has not been formally evaluated; the tools used must be trustworthy, pragmatic and policy-relevant; multiple channels of communication will be needed; communications need to be tailored and targeted to decision-makers; data and methods should be freely accessible. The proposed communications strategy for INFORMAS has been built around these lessons to ensure that INFORMAS's outputs have the greatest chance of being used to improve food environments. PMID- 24074208 TI - Monitoring and benchmarking government policies and actions to improve the healthiness of food environments: a proposed Government Healthy Food Environment Policy Index. AB - Government action is essential to increase the healthiness of food environments and reduce obesity, diet-related non-communicable diseases (NCDs), and their related inequalities. This paper proposes a monitoring framework to assess government policies and actions for creating healthy food environments. Recommendations from relevant authoritative organizations and expert advisory groups for reducing obesity and NCDs were examined, and pertinent components were incorporated into a comprehensive framework for monitoring government policies and actions. A Government Healthy Food Environment Policy Index (Food-EPI) was developed, which comprises a 'policy' component with seven domains on specific aspects of food environments, and an 'infrastructure support' component with seven domains to strengthen systems to prevent obesity and NCDs. These were revised through a week-long consultation process with international experts. Examples of good practice statements are proposed within each domain, and these will evolve into benchmarks established by governments at the forefront of creating and implementing food policies for good health. A rating process is proposed to assess a government's level of policy implementation towards good practice. The Food-EPI will be pre-tested and piloted in countries of varying size and income levels. The benchmarking of government policy implementation has the potential to catalyse greater action to reduce obesity and NCDs. PMID- 24074209 TI - A proposed approach to monitor private-sector policies and practices related to food environments, obesity and non-communicable disease prevention. AB - Private-sector organizations play a critical role in shaping the food environments of individuals and populations. However, there is currently very limited independent monitoring of private-sector actions related to food environments. This paper reviews previous efforts to monitor the private sector in this area, and outlines a proposed approach to monitor private-sector policies and practices related to food environments, and their influence on obesity and non-communicable disease (NCD) prevention. A step-wise approach to data collection is recommended, in which the first ('minimal') step is the collation of publicly available food and nutrition-related policies of selected private sector organizations. The second ('expanded') step assesses the nutritional composition of each organization's products, their promotions to children, their labelling practices, and the accessibility, availability and affordability of their products. The third ('optimal') step includes data on other commercial activities that may influence food environments, such as political lobbying and corporate philanthropy. The proposed approach will be further developed and piloted in countries of varying size and income levels. There is potential for this approach to enable national and international benchmarking of private-sector policies and practices, and to inform efforts to hold the private sector to account for their role in obesity and NCD prevention. PMID- 24074210 TI - Monitoring the levels of important nutrients in the food supply. AB - A food supply that delivers energy-dense products with high levels of salt, saturated fats and trans fats, in large portion sizes, is a major cause of non communicable diseases (NCDs). The highly processed foods produced by large food corporations are primary drivers of increases in consumption of these adverse nutrients. The objective of this paper is to present an approach to monitoring food composition that can both document the extent of the problem and underpin novel actions to address it. The monitoring approach seeks to systematically collect information on high-level contextual factors influencing food composition and assess the energy density, salt, saturated fat, trans fats and portion sizes of highly processed foods for sale in retail outlets (with a focus on supermarkets and quick-service restaurants). Regular surveys of food composition are proposed across geographies and over time using a pragmatic, standardized methodology. Surveys have already been undertaken in several high- and middle income countries, and the trends have been valuable in informing policy approaches. The purpose of collecting data is not to exhaustively document the composition of all foods in the food supply in each country, but rather to provide information to support governments, industry and communities to develop and enact strategies to curb food-related NCDs. PMID- 24074211 TI - Monitoring food and non-alcoholic beverage promotions to children. AB - Food and non-alcoholic beverage marketing is recognized as an important factor influencing food choices related to non-communicable diseases. The monitoring of populations' exposure to food and non-alcoholic beverage promotions, and the content of these promotions, is necessary to generate evidence to understand the extent of the problem, and to determine appropriate and effective policy responses. A review of studies measuring the nature and extent of exposure to food promotions was conducted to identify approaches to monitoring food promotions via dominant media platforms. A step-wise approach, comprising 'minimal', 'expanded' and 'optimal' monitoring activities, was designed. This approach can be used to assess the frequency and level of exposure of population groups (especially children) to food promotions, the persuasive power of techniques used in promotional communications (power of promotions) and the nutritional composition of promoted food products. Detailed procedures for data sampling, data collection and data analysis for a range of media types are presented, as well as quantifiable measurement indicators for assessing exposure to and power of food and non-alcoholic beverage promotions. The proposed framework supports the development of a consistent system for monitoring food and non-alcoholic beverage promotions for comparison between countries and over time. PMID- 24074212 TI - Monitoring the health-related labelling of foods and non-alcoholic beverages in retail settings. AB - Food labelling on food packaging has the potential to have both positive and negative effects on diets. Monitoring different aspects of food labelling would help to identify priority policy options to help people make healthier food choices. A taxonomy of the elements of health-related food labelling is proposed. A systematic review of studies that assessed the nature and extent of health related food labelling has been conducted to identify approaches to monitoring food labelling. A step-wise approach has been developed for independently assessing the nature and extent of health-related food labelling in different countries and over time. Procedures for sampling the food supply, and collecting and analysing data are proposed, as well as quantifiable measurement indicators and benchmarks for health-related food labelling. PMID- 24074213 TI - Monitoring the price and affordability of foods and diets globally. AB - Food prices and food affordability are important determinants of food choices, obesity and non-communicable diseases. As governments around the world consider policies to promote the consumption of healthier foods, data on the relative price and affordability of foods, with a particular focus on the difference between 'less healthy' and 'healthy' foods and diets, are urgently needed. This paper briefly reviews past and current approaches to monitoring food prices, and identifies key issues affecting the development of practical tools and methods for food price data collection, analysis and reporting. A step-wise monitoring framework, including measurement indicators, is proposed. 'Minimal' data collection will assess the differential price of 'healthy' and 'less healthy' foods; 'expanded' monitoring will assess the differential price of 'healthy' and 'less healthy' diets; and the 'optimal' approach will also monitor food affordability, by taking into account household income. The monitoring of the price and affordability of 'healthy' and 'less healthy' foods and diets globally will provide robust data and benchmarks to inform economic and fiscal policy responses. Given the range of methodological, cultural and logistical challenges in this area, it is imperative that all aspects of the proposed monitoring framework are tested rigorously before implementation. PMID- 24074214 TI - Monitoring foods and beverages provided and sold in public sector settings. AB - This paper outlines a step-wise framework for monitoring foods and beverages provided or sold in publicly funded institutions. The focus is on foods in schools, but the framework can also be applied to foods provided or sold in other publicly funded institutions. Data collection and evaluation within this monitoring framework will consist of two components. In component I, information on existing food or nutrition policies and/or programmes within settings would be compiled. Currently, nutrition standards and voluntary guidelines associated with such policies/programmes vary widely globally. This paper, which provides a comprehensive review of such standards and guidelines, will facilitate institutional learnings for those jurisdictions that have not yet established them or are undergoing review of existing ones. In component II, the quality of foods provided or sold in public sector settings is evaluated relative to existing national or sub-national nutrition standards or voluntary guidelines. Where there are no (or only poor) standards or guidelines available, the nutritional quality of foods can be evaluated relative to standards of a similar jurisdiction or other appropriate standards. Measurement indicators are proposed (within 'minimal', 'expanded' and 'optimal' approaches) that can be used to monitor progress over time in meeting policy objectives, and facilitate comparisons between countries. PMID- 24074215 TI - Monitoring the availability of healthy and unhealthy foods and non-alcoholic beverages in community and consumer retail food environments globally. AB - Retail food environments are increasingly considered influential in determining dietary behaviours and health outcomes. We reviewed the available evidence on associations between community (type, availability and accessibility of food outlets) and consumer (product availability, prices, promotions and nutritional quality within stores) food environments and dietary outcomes in order to develop an evidence-based framework for monitoring the availability of healthy and unhealthy foods and non-alcoholic beverages in retail food environments. Current evidence is suggestive of an association between community and consumer food environments and dietary outcomes; however, substantial heterogeneity in study designs, methods and measurement tools makes it difficult to draw firm conclusions. The use of standardized tools to monitor local food environments within and across countries may help to validate this relationship. We propose a step-wise framework to monitor and benchmark community and consumer retail food environments that can be used to assess density of healthy and unhealthy food outlets; measure proximity of healthy and unhealthy food outlets to homes/schools; evaluate availability of healthy and unhealthy foods in-store; compare food environments over time and between regions and countries; evaluate compliance with local policies, guidelines or voluntary codes of practice; and determine the impact of changes to retail food environments on health outcomes, such as obesity. PMID- 24074216 TI - Monitoring the impacts of trade agreements on food environments. AB - The liberalization of international trade and foreign direct investment through multilateral, regional and bilateral agreements has had profound implications for the structure and nature of food systems, and therefore, for the availability, nutritional quality, accessibility, price and promotion of foods in different locations. Public health attention has only relatively recently turned to the links between trade and investment agreements, diets and health, and there is currently no systematic monitoring of this area. This paper reviews the available evidence on the links between trade agreements, food environments and diets from an obesity and non-communicable disease (NCD) perspective. Based on the key issues identified through the review, the paper outlines an approach for monitoring the potential impact of trade agreements on food environments and obesity/NCD risks. The proposed monitoring approach encompasses a set of guiding principles, recommended procedures for data collection and analysis, and quantifiable 'minimal', 'expanded' and 'optimal' measurement indicators to be tailored to national priorities, capacity and resources. Formal risk assessment processes of existing and evolving trade and investment agreements, which focus on their impacts on food environments will help inform the development of healthy trade policy, strengthen domestic nutrition and health policy space and ultimately protect population nutrition. PMID- 24074217 TI - Monitoring and benchmarking population diet quality globally: a step-wise approach. AB - INFORMAS (International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support) aims to monitor and benchmark the healthiness of food environments globally. In order to assess the impact of food environments on population diets, it is necessary to monitor population diet quality between countries and over time. This paper reviews existing data sources suitable for monitoring population diet quality, and assesses their strengths and limitations. A step-wise framework is then proposed for monitoring population diet quality. Food balance sheets (FBaS), household budget and expenditure surveys (HBES) and food intake surveys are all suitable methods for assessing population diet quality. In the proposed 'minimal' approach, national trends of food and energy availability can be explored using FBaS. In the 'expanded' and 'optimal' approaches, the dietary share of ultra-processed products is measured as an indicator of energy-dense, nutrient-poor diets using HBES and food intake surveys, respectively. In addition, it is proposed that pre-defined diet quality indices are used to score diets, and some of those have been designed for application within all three monitoring approaches. However, in order to enhance the value of global efforts to monitor diet quality, data collection methods and diet quality indicators need further development work. PMID- 24074218 TI - INFORMAS and advocacy for public health nutrition and obesity prevention. PMID- 24074219 TI - INFORMAS (International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support): summary and future directions. AB - This supplement presents the foundational elements for INFORMAS (International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support). As explained in the overview article by Swinburn and colleagues, INFORMAS has a compelling rationale and has set forth clear objectives, outcomes, principles and frameworks for monitoring and benchmarking key aspects of food environments and the policies and actions that influence the healthiness of food environments. This summary highlights the proposed monitoring approaches for the 10 interrelated INFORMAS modules: public and private sector policies and actions; key aspects of food environments (food composition, labelling, promotion, provision, retail, prices, and trade and investment) and population outcomes (diet quality). This ambitious effort should be feasible when approached in a step-wise manner, taking into account existing monitoring efforts, data sources, country contexts and capacity, and when adequately resourced. After protocol development and pilot testing of the modules, INFORMAS aims to be a sustainable, low-cost monitoring framework. Future directions relate to institutionalization, implementation and, ultimately, to leveraging INFORMAS data in ways that will bring key drivers of food environments into alignment with public health goals. PMID- 24074220 TI - Cirrus high-definition optical coherence tomography versus spectral optical coherence tomography/scanning laser ophthalmoscopy in the diagnosis of glaucoma. AB - PURPOSE: This study was performed to compare the positive predictive value of peripapillary retinal nerve fiber layer (RNFL) thickness measurements obtained using Cirrus high-definition optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA) and spectral OCT/scanning laser ophthalmoscopy (SLO) (OPKO/OTI, Miami, FL) in the diagnosis of glaucoma. METHODS: A total of 50 eyes of 50 healthy subjects and 60 eyes of 60 subjects with glaucoma were included. All participants underwent RNFL thickness measurement using Cirrus HD-OCT and spectral OCT/SLO on the same day. Average, quadrant, clock-hour RNFL thicknesses, area under the receiver operating characteristic curve (AUC), and sensitivities at fixed specificities (80% and 95%) were calculated for comparison. RESULTS: RNFL thickness as measured by spectral OCT/SLO was greater than that measured using Cirrus HD-OCT (p < 0.001). For both the Cirrus HD-OCT and spectral OCT/SLO, the parameter with the largest AUC was average RNFL thickness (0.954 and 0.944, respectively). The AUCs of RNFL thickness for the discrimination of glaucoma did not differ significantly between the devices (p > 0.05), with the exception of RNFL thickness in the nasal area (nasal quadrant, clock-hour sectors 3 and 4); in these areas, spectral OCL/SLO yielded greater AUCs than Cirrus HD-OCT (p < 0.05). Sensitivities varied similarly to AUCs. CONCLUSIONS: RNFL thicknesses measures using Cirrus HD-OCT and spectral OCT/SLO were not interchangeable. The utility of RNFL thickness measurements in the diagnosis of glaucoma was similar for both the devices. PMID- 24074222 TI - Nanobiology of RNA polymerase: biological consequence of inhomogeneity in reactant. PMID- 24074221 TI - Mass fingerprinting of complex mixtures: protein inference from high-resolution peptide masses and predicted retention times. AB - In typical shotgun experiments, the mass spectrometer records the masses of a large set of ionized analytes but fragments only a fraction of them. In the subsequent analyses, normally only the fragmented ions are used to compile a set of peptide identifications, while the unfragmented ones are disregarded. In this work, we show how the unfragmented ions, here denoted MS1-features, can be used to increase the confidence of the proteins identified in shotgun experiments. Specifically, we propose the usage of in silico mass tags, where the observed MS1 features are matched against de novo predicted masses and retention times for all peptides derived from a sequence database. We present a statistical model to assign protein-level probabilities based on the MS1-features and combine this data with the fragmentation spectra. Our approach was evaluated for two triplicate data sets from yeast and human, respectively, leading to up to 7% more protein identifications at a fixed protein-level false discovery rate of 1%. The additional protein identifications were validated both in the context of the mass spectrometry data and by examining their estimated transcript levels generated using RNA-Seq. The proposed method is reproducible, straightforward to apply, and can even be used to reanalyze and increase the yield of existing data sets. PMID- 24074223 TI - NK4 therapy: a new approach to target angiogenesis and inflammation in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a progressive autoimmune disease characterized by synovial membrane hyperplasia, inflammation, and angiogenesis. Hepatocyte growth factor (HGF) and its receptor, c-Met, are both overexpressed in the RA synovium. NK4 is an antagonist of HGF which has been shown to inhibit tumor growth, metastasis, and angiogenesis. In an experimental model of RA, NK4 gene therapy inhibited joint damage and inflammation in both preventative and therapeutic models. NK4 treatment therefore represents a possible therapeutic option in combating RA. PMID- 24074224 TI - Adalimumab for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis - a five-year update. AB - INTRODUCTION: Following its marketing authorization for the treatment of ankylosing spondylitis (AS) in 2006 in the United States und in the European Union, adalimumab became one of the most frequently prescribed tumor necrosis factor (TNF) alpha blockers available for this indication. Recently, the label for adalimumab was extended to nonradiographic axial spondyloarthritis (nr axSpA), which might be considered as an early stage of AS. The increasing number of patients with AS being treated with adalimumab raises issues concerning long term safety, efficacy in the prevention of structural damage in the spine and high treatment costs. AREAS COVERED: Herein, we summarize data on efficacy and safety of adalimumab treatment in AS and nr-axSpA obtained over the past 5 years. EXPERT OPINION: Adalimumab is clinically effective and reasonably safe in the short-term and long-term treatment of patients with AS who do not respond to standard therapy. Recent data indicate good efficacy of adalimumab also in patients with nr-axSpA but only in the presence of objective signs of active inflammation. Yet unresolved questions relate to the ability of adalimumab to stop or retard structural damage development in the spine in patients with AS and nr-axSpA. The introduction of biosimilar drugs in the near future may potentially reduce the currently very high treatment costs associated with adalimumab treatment. PMID- 24074225 TI - Jaccard index based similarity measure to compare transcription factor binding site models. AB - BACKGROUND: Positional weight matrix (PWM) remains the most popular for quantification of transcription factor (TF) binding. PWM supplied with a score threshold defines a set of putative transcription factor binding sites (TFBS), thus providing a TFBS model.TF binding DNA fragments obtained by different experimental methods usually give similar but not identical PWMs. This is also common for different TFs from the same structural family. Thus it is often necessary to measure the similarity between PWMs. The popular tools compare PWMs directly using matrix elements. Yet, for log-odds PWMs, negative elements do not contribute to the scores of highly scoring TFBS and thus may be different without affecting the sets of the best recognized binding sites. Moreover, the two TFBS sets recognized by a given pair of PWMs can be more or less different depending on the score thresholds. RESULTS: We propose a practical approach for comparing two TFBS models, each consisting of a PWM and the respective scoring threshold. The proposed measure is a variant of the Jaccard index between two TFBS sets. The measure defines a metric space for TFBS models of all finite lengths. The algorithm can compare TFBS models constructed using substantially different approaches, like PWMs with raw positional counts and log-odds. We present the efficient software implementation: MACRO-APE (MAtrix CompaRisOn by Approximate P value Estimation). CONCLUSIONS: MACRO-APE can be effectively used to compute the Jaccard index based similarity for two TFBS models. A two-pass scanning algorithm is presented to scan a given collection of PWMs for PWMs similar to a given query. AVAILABILITY AND IMPLEMENTATION: MACRO-APE is implemented in ruby 1.9; software including source code and a manual is freely available at http://autosome.ru/macroape/ and in supplementary materials. PMID- 24074226 TI - Characterizing the financial burden of pulmonary arterial hypertension within an integrated healthcare delivery system. AB - PURPOSE: Financial burden associated with providing healthcare to patients with pulmonary arterial hypertension (PAH) is poorly characterized. This study sought to quantify 3-year healthcare expenditures and determine whether expenditures differed between incident and prevalent PAH cases. METHODS: This was a retrospective cohort study of Kaiser Permanente Colorado (KPCO) patients with confirmed diagnosis of PAH. Included patients were followed from study entry until 3 years, death, or termination of KPCO membership, whichever came first. All expenditures were reported in 2011 US dollars from the KPCO perspective. RESULTS: In total, 157 patients were included: 44 (28%) prevalent and 113 (72%) incident cases. Mean age (prevalent vs incident cases) was 61 years vs 67 years and 13.6% vs 27.4% were males. The majority of patients (55%) were classified as WHO Group 1 PAH. Prevalent cases had less follow-up (843 vs 975 days; p = 0.033). Overall, median total per patient per day (PPPD) and 3-year total expenditures were $56 (interquartile range (IQR = $29-$166) and $50,599 (IQR = $25,958 $135,535), respectively. After adjustment for patient characteristics and chronic disease burden, median PPPD ($54 vs $56; p = 0.950) and 3-year ($37,340 vs $55,073; p = 0.111) total expenditures were equivalent between prevalent and incident cases; however, the risk of death during the 3-year follow-up was lower among incident cases (hazard ratio = 0.41, 95% CI = 0.18-0.91). No significant differences were detected in pharmacy, inpatient, medical office, emergency department, or other expenditures. Median PAH specialty medication PPPD expenditures were also equivalent, also ($226 vs $223 among specialty medication users; p = 0.861). CONCLUSION: Healthcare expenditures related to PAH represent substantial financial burden. Significant differences according to prevalent or incident case status appeared to be driven by median ED and inpatient expenditures; however, PAH specialty medication expenditures represented a substantial cost-driver overall. Future efforts should focus on optimizing care for patients with PAH to avoid unnecessary harm or waste. PMID- 24074228 TI - Minimally invasive percutaneous management of large bladder stones with a laparoscopic entrapment bag. AB - INTRODUCTION: The treatment of large volume bladder stones is a management conundrum. Transurethral methods are plagued by long operative times, trauma to the bladder mucosa, and the need for a postoperative urethral catheter. Open cystolithotomy has higher morbidity. We present the percutaneous management of bladder stones with the novel use of a laparoscopic entrapment bag. MATERIALS AND METHODS: Twenty-five patients (mean age 65.7), including 22 men and 3 women, 4 with a neurogenic bladder and 21 with a prior diagnosis of benign prostatic hyperplasia, underwent our novel technique. The mean number of stones was 6.8+/ 8.0 (range, 1 to 30) and total stone burden 10.4+/-10.5 cm (range, 3.0 to 50.0 cm). Using regional or general anesthesia and flexible cystoscopic guidance, percutaneous bladder access was achieved. The tract was balloon dilated to 30F and stones captured in a laparoscopic entrapment bag. The bag's opening was exteriorized and stone fragmentation and comminution were achieved using a nephroscope and pneumatic or ultrasonic lithotripters. The bag was extracted and a 22F suprapubic catheter was inserted into the bladder; the patient was discharged the next day after a voiding trial. The procedure was done without fluoroscopy. No foley catheter was necessary. RESULTS: All patients were rendered stone free. The mean estimated blood loss was 11.1+/-3.93 mL (range, 10 to 25 mL). The mean operative time was 102.3 minutes. There was minimal trauma to the bladder mucosa and no complications of fluid extravasation, hematuria, or urethral trauma were noted. All patients were discharged within 24 hours of the operation. CONCLUSION: Percutaneous cystolithotomy with the use of an entrapment bag is an efficient, safe technique for treating large volume bladder calculi. We recommend this technique as an alternative to open surgery for patients with too large a stone burden to remove transurethrally. PMID- 24074229 TI - A young pancreas or no pancreas? PMID- 24074230 TI - How is affective instability defined and measured? A systematic review. AB - BACKGROUND: Affective instability (AI) is poorly defined but considered clinically important. The aim of this study was to examine definitions and measures of AI employed in clinical populations. METHOD: This study was a systematic review using the PRISMA guidelines. MEDLINE, Embase, PsycINFO, PsycArticles and Web of Science databases were searched. Also five journals were hand searched. Primary empirical studies involving randomized controlled trials (RCTs), non-RCTs, controlled before and after, and observational investigations were included. Studies were selected, data extracted and quality appraised. A narrative synthesis was completed. RESULTS: A total of 11 443 abstracts were screened and 37 studies selected for final analysis on the basis that they provided a definition and measure of AI. Numbers of definitions for each of the terms employed in included studies were: AI (n = 7), affective lability (n = 6), affective dysregulation (n = 1), emotional dysregulation (n = 4), emotion regulation (n = 2), emotional lability (n = 1), mood instability (n = 2), mood lability (n = 1) and mood swings (n = 1); however, these concepts showed considerable overlap in features. A total of 24 distinct measures were identified that could be categorized as primarily measuring one of four facets of AI (oscillation, intensity, ability to regulate and affect change triggered by environment) or as measuring general emotional regulation. CONCLUSIONS: A clearer definition of AI is required. We propose AI be defined as 'rapid oscillations of intense affect, with a difficulty in regulating these oscillations or their behavioural consequences'. No single measure comprehensively assesses AI and a combination of current measures is required for assessment. A new short measure of AI that is reliable and validated against external criteria is needed. PMID- 24074231 TI - A molecular connection of Pterocarpus marsupium, Eugenia jambolana and Gymnema sylvestre with dipeptidyl peptidase-4 in the treatment of diabetes. AB - CONTEXT: Pterocarpus marsupium (PM) (Leguminosae), Eugenia jambolana (EJ) (Myrtaceae) and Gymnema sylvestre (GS) (Asclepiadaceae) are the most important medicinal plants in the Indian system of traditional medicine for the treatment of hyperglycemia. OBJECTIVES: Dipeptidyl peptidase-4 (DPP-4) inhibitors are the emerging class of anti-diabetic agents. However, only few compounds are commercially available. Therefore, in the present study we tried to explore the naturally occurring PM, EJ and GS semi-standardized extracts for their potential DPP-4 inhibition in vitro and in vivo. MATERIALS AND METHODS: DPP-4 inhibition was evaluated by in vitro inhibitory assay, and enzyme kinetics were calculated using one-phase exponential decay equation. Glucose load (2 g/kg) was administered to control and diabetic rats 30 min following extract administration (100, 200 and 400 mg/kg) orally once, and blood samples were withdrawn at 0, 0.5, 1, 1.5, 2 and 3 h to measure plasma active glucagon-like peptide-1 (GLP-1) levels. RESULTS: PM and EJ inhibit DPP-4 potently with IC50 values of 273.73 +/- 2.96 and 278.94 +/- 6.73 ug/mL, respectively, compared to GS (773.22 +/- 9.21 ug/mL). PM, EJ and GS exhibit long duration of action with enzyme inhibitory half lives of 462.3, 317.2 and 153.8 min, respectively. Extracts significantly increase GLP-1 levels compared to negative control groups and peak GLP-1 level was observed at 2 h for PM and EJ, whereas for GS it was at 1.5 h DISCUSSION AND CONCLUSION: Taken together, results suggest the extracts may have potent DPP-4 inhibitory action, and their hypoglycemic action attributed through an increase in plasma active GLP-1 levels. PMID- 24074232 TI - An organic coprecipitation route to synthesize high voltage LiNi0.5Mn1.5O4. AB - High-voltage cathode material LiNi0.5Mn1.5O4 has been prepared with a novel organic coprecipitation route. The as-prepared sample was compared with samples produced through traditional solid state method and hydroxide coprecipitation method. The morphology was observed by scanning electron microscopy, and the spinel structures were characterized by X-ray diffraction and Fourier transform infrared spectroscopy. Besides the ordered/disordered distribution of Ni/Mn on octahedral sites, the confusion between Li and transition metal is pointed out to be another important factor responsible for the corresponding performance, which is worthy further investigation. Galvanostatic cycles, cyclic voltammetry, and electrochemical impedance spectroscopy are employed to characterize the electrochemical properties. The organic coprecipitation route produced sample shows superior rate capability and stable structure during cycling. PMID- 24074236 TI - Risk assessment of drug-drug interactions using hepatocytes suspended in serum during the drug discovery process. AB - 1. This study optimized the reported approach for the prediction of drug-drug interactions (DDIs) using hepatocytes suspended in serum (HHSS) and provided a practical usage of HHSS in the early and late phases of drug discovery. 2. First, the IC50 was determined using HHSS and evaluated as a qualitative index for DDI risks in the early phase. A retrospective study on clinical DDI cases revealed that inhibitors with IC50 < 100 MUmol/L caused clinical DDIs while those with IC50 > 100 MUmol/L showed weak or no potential for DDIs. Meanwhile, a pragmatic cutoff value could not be determined using previously reported Ki values of recombinant human cytochrome P450s. 3. Second, for a more substantial DDI risk assessment in the later phase, quantitative predictions of clinical DDI based on a static model were attempted by optimizing the most appropriate inhibitor concentration ([I]). The use of hepatic input plasma concentrations as a surrogate for [I] achieved the most successful predictions of the magnitude of increase in the AUC (within a 2-fold range of the observed values for 93.8% of inhibitors). 4. Through this study, we proposed the practical application of HHSS for an effective workflow to explore and profile candidates with less DDI liability. PMID- 24074237 TI - Metabolism and mass balance of SGLT2 inhibitor tofogliflozin following oral administration to humans. AB - 1. Tofogliflozin is a novel and selective SGLT2 inhibitor increasing glucosuria by inhibition of glucose re-absorption in the kidney for the treatment of type 2 diabetes mellitus. 2. In this study, the metabolism and the mass balance of tofogliflozin was evaluated following administration of a single oral dose of 20 mg [(14)C]-tofogliflozin to six healthy subjects. 3. Tofogliflozin underwent mainly oxidative metabolism in the ethylphenyl moiety, but also minor glucuronide conjugates of metabolites and the parent drug were formed. 4. In plasma, the parent drug and its major phenyl acetic acid metabolite M1 accounted for 42% and 52% of the total drug-related material, respectively. The hydroxyl metabolites and their successor ketone metabolite showed an exposure well below 5%, along with an acyl glucuronide of M1. 5. Tofogliflozin was completely absorbed with subsequent predominate metabolic clearance and a small contribution of direct urinary elimination. Approximately, 76% of the dose was excreted in urine and 20% in faeces within 72 h. The high absorption of tofogliflozin was exemplified by the small trace of parent drug in faeces. The phenyl acetic acid metabolite M1 was the major component excreted in urine and faeces accounting for more than half of the dose. Tofogliflozin demonstrated a high metabolic turnover. PMID- 24074238 TI - Unravelling mechanisms of cisplatin sensitivity and resistance in testicular cancer. AB - Testicular cancer is the most frequent solid malignant tumour type in men 20-40 years of age. At the time of diagnosis up to 50% of the patients suffer from metastatic disease. In contrast to most other metastatic solid tumours, the majority of metastatic testicular cancer patients can be cured with highly effective cisplatin-based chemotherapy. This review aims to summarise the current knowledge on response to chemotherapy and the biological basis of cisplatin induced apoptosis in testicular cancer. The frequent presence of wild-type TP53 and the low levels of p53 in complex with the p53 negative feed-back regulator MDM2 contribute to cisplatin sensitivity. Moreover, the high levels of the pluripotency regulator Oct4 and as a consequence of Oct4 expression high levels of miR-17/106b seed family and pro-apoptotic Noxa and the low levels of cytoplasmic p21 (WAF1/Cip1) appear to be causative for the exquisite sensitivity to cisplatin-based therapy of testicular cancer. However, resistance of testicular cancer to cisplatin-based therapy does occur and can be mediated through aberrant levels of the above mentioned key players. Drugs targeting these key players showed, at least pre-clinically, a sensitising effect to cisplatin treatment. Further clinical development of such treatment strategies will lead to new treatment options for platinum-resistant testicular cancers. PMID- 24074239 TI - Scaling up the delivery of refractive error services within a district health system: the KwaZulu-Natal, South Africa experience. AB - BACKGROUND: In South Africa, the health service is based on a Primary Health Care (PHC) philosophy with the District Health System (DHS) as the locus of delivery. However eye care services, particularly primary eye care, refractive error and low vision, have not been prioritised accordingly. Hence the aim of the Giving Sight to KwaZulu-Natal (GSKZN) project was to integrate the delivery of eye care services into the district health system, with emphasis on addressing the need for uncorrected refractive error and low vision services.The project was implemented in the KwaZulu-Natal province, South Africa, to scale up the delivery of refractive error services utilising a four pronged approach; including advocacy, human resource development, equipment provision and research. METHODS: This paper is a description of the project and a retrospective analysis of data received through the course of the project from July 2007 to June 2011. Data were collected from training registers, equipment schedules and service delivery reports from institutions. Reports from the data base were then analysed and achievements in training and trends in service delivery were determined. RESULTS: Over a four year period (July 2007 and July 2011) 1004 persons received training in rendering eye health services appropriate to their level of deployment within the DHS. During the course of the project, these 1004 persons examined 1,064,087 patients. Furthermore, the total number of clinics offering primary eye care, refractive error and low vision services increased from 96 (10%) to 748 (76%). With increased numbers of PHC Nurses trained in primary eye care, a subsequent decrease of 51.08 percent was also observed in the number of patients seeking services at higher levels of care, thus streamlining eye health service delivery. CONCLUSION: This project has shown that scaling up can occur in delivering eye health services within a health district, through a multi-faceted approach that encompasses focused training, advocacy, development of appropriate infrastructure and the development of referral criteria with clear guidelines for the management of patients. PMID- 24074241 TI - Birth oxidative stress and the development of an antioxidant system in newborn piglets. AB - Birth oxidative stress is an oxidative response to a sudden transition process from maternal mediated respiration in uterus to autonomous pulmonary respiration outside the uterus. Meanwhile, oxidative stress has been demonstrated to be associated with various pathologies recorded in newborns. So, this research aimed to study the oxidative stress and the development of antioxidant system in newborn piglets. The measured variables include plasma lipid, protein and DNA oxidant injury, the activities of plasma antioxidant enzymes and the jejunal and ileal antioxidant gene expressions at 1, 7, 14, and 21 days after birth. Meanwhile, the nuclear factor erythroid 2-related factor 2 (Nrf2), transcription factor p65, and tumor protein 53 (p53) were determined by western blot. The results showed that newborn piglets suffered seriously from birth oxidative stress because of the naive antioxidant system. In addition, oxidant injury activated Nrf2 signaling pathway, resulting in the expression of antioxidant genes and release of antioxidant enzymes. With the development of antioxidant system, the oxidative balance gradually recovered on Day 7 after birth. In conclusion, birth caused oxidative stress and the oxidative balance gradually recovered with the development of antioxidant system. PMID- 24074240 TI - Long-acting methylphenidate formulations in the treatment of attention deficit/hyperactivity disorder: a systematic review of head-to-head studies. AB - BACKGROUND: The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed.The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection. METHODS: A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included. RESULTS: Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study. CONCLUSIONS: Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response. PMID- 24074242 TI - Solvent-mediated reduction of carbon dioxide in anionic complexes with silver atoms. AB - The development of efficient routes toward sustainable fuel sources by electrochemical reduction of CO2 is an important goal for catalysis research. While these processes usually occur in the presence of solvent, solvation effects in catalysis are largely not understood or even characterized. In this work, mass selected clusters of silver anions with CO2 serve as a model system for reductive activation of CO2 by a catalyst in the presence of a well-controlled number of solvent molecules. Vibrational spectroscopy and electronic structure calculations are used to obtain molecular-level information on the interaction of solvent with the catalyst-CO2 complex and the effects of solvation on one-electron reductive activation of CO2. Charge transfer from the silver catalyst to CO2 increases with increasing cluster size. We observe the coexistence of catalyst-ligand complexes with CO2 monomer and dimer anions, indicating that CO2-based charge carriers can exist in the presence of a silver atom. PMID- 24074244 TI - Congress summary: the 20th congress of the international society for rotary blood pumps. PMID- 24074245 TI - Exercise hemodynamics during extended continuous flow left ventricular assist device support: the response of systemic cardiovascular parameters and pump performance. AB - Patients on continuous flow left ventricular assist devices (cf-LVADs) are able to return to an active lifestyle and perform all sorts of physical activities. This study aims to evaluate exercise hemodynamics in patients with a HeartMate II cf-LVAD (HM II). Thirty (30) patients underwent a bicycle exercise test. Along with exercise capacity, systemic cardiovascular responses and pump performance were evaluated at 6 and 12 months after HM II implantation. From rest to maximum exercise, heart rate increased from 87 +/- 14 to 140 +/- 32 beats/minute (bpm) (P<0.01), while systolic arterial blood pressure increased from 93 +/- 12 to 116 +/- 21 mm Hg (P<0.01). Total cardiac output (TCO) increased from 4.1 +/- 1.1 to 8.5 +/- 2.8 L/min (P<0.01) while pump flow increased less, from 5.1 +/- 0.7 to 6.4 +/- 0.6 L/min (P<0.01). Systemic vascular resistance (SVR) decreased from 1776 +/- 750 to 1013 +/- 83 dynes.s/cm(5) (P<0.001) and showed the strongest correlation with TCO (r= -0.72; P<0.01). Exercise capacity was affected by older age, while blood pressure increased significantly in men compared with women. Exercise capacity remained consistent at 6 and 12 months after HM II implantation, 51% +/- 13% and 52% +/- 13% of predicted VO2 max for normal subjects corrected for age and gender. In conclusion, pump flow of the HM II may contribute partially to TCO during exercise, while SVR was the strongest determinant of TCO. PMID- 24074247 TI - Point-of-care assay platform for quantifying active enzymes to femtomolar levels using measurements of time as the readout. AB - This Article describes a strategy for quantifying active enzyme analytes in a paper-based device by measuring the time for a reference region in the paper to turn green relative to an assay region. The assay requires a single step by the user, yet accounts for variations in sample volume, assay temperature, humidity, and contaminants in a sample that would otherwise prevent a quantitative measurement. The assay is capable of measuring enzymes in the low to mid femtomolar range with measurement times that range from ~30 s to ~15 min (lower measurement times correspond to lower quantities of the analyte). Different targets can be selected in the assay by changing a small molecule reagent within the paper-based device, and the sensitivity and dynamic range of the assays can be tuned easily by changing the composition and quantity of a signal amplification reagent or by modifying the configuration of the paper-based microfluidic device. By tuning these parameters, limits-of-detection for assays can be adjusted over an analyte concentration range of low femtomolar to low nanomolar, with dynamic ranges for the assays of at least 1 order of magnitude. Furthermore, the assay strategy is compatible with complex fluids such as serum. PMID- 24074248 TI - Base metal catalysts for photochemical C-H borylation that utilize metal-metal cooperativity. AB - Heterobimetallic Cu-Fe and Zn-Fe complexes catalyze C-H borylation, a transformation that previously required noble metal catalysts. The optimal catalyst, (IPr)Cu-FeCp(CO)2, exhibits efficient activity at 5 mol% loading under photochemical conditions, shows only minimal decrease in activity upon reuse, and is able to catalyze borylation of a variety of arene substrates. Stoichiometric reactivity studies are consistent with a proposed mechanism that exploits metal metal cooperativity and showcases bimetallic versions of the classical organometallic processes, oxidative addition and reductive elimination. PMID- 24074249 TI - Cubane-type Cu(II)4 and Mn(II)2Mn(III)2 complexes based on pyridoxine: a versatile ligand for metal assembling. AB - By using Vitamin B6 in its monodeprotonated pyridoxine form (PN-H) [PN = 3 hydroxy-4,5-bis(hydroxymethyl)-2-methylpyridine], two tetranuclear compounds of formula [Mn4(PN-H)4(CH3CO2)3Cl2]Cl.2CH3OH.2H2O (1) and [Cu4(PN-H)4Cl2(H2O)2]Cl2 (2) have been synthesized and magneto-structurally characterized. 1 crystallizes in the triclinic system with space group P1 whereas 2 crystallizes in the orthorhombic system with Fdd2 as space group. They exhibit Mn(II)2Mn(III)2 (1) and Cu(II)4 (2) cubane cores containing four monodeprotonated pyridoxine groups simultaneously acting as chelating and bridging ligands (1 and 2), three bridging acetate ligands in the syn-syn conformation (1), and two terminally bound chloride anions (1 and 2) plus two coordinated water molecules (2). The electroneutrality is achieved by the presence of chloride counterions in both compounds. Tri- [Mn(1) and Mn(3)] and divalent [Mn(2) and Mn(4)] manganese centers coexist in 1, all being six-coordinate with distorted Mn(1/3)O6 and Mn(2/4)O5Cl octahedral surroundings, respectively, the equatorial Mn-O bonds being about 0.2 A shorter at the former ones. The two crystallographically independent copper(II) ions in 2 are five-coordinate in somewhat distorted CuO5 [Cu(1)] and CuO4Cl [Cu(2)] square pyramidal geometries. The values of the intracore metal-metal separation cover the ranges 3.144(1)-3.535(1) (1) and 2.922(6)-3.376(1) A (2). The magnetic properties of 1 and 2 were investigated in the temperature range 1.9-300 K, and they correspond to an overall antiferromagnetic behavior with susceptibility maxima at 5.0 (1) and 65.0 K (2). The analysis of the magnetic susceptibility data showed the coexistence of intracore antiferro- and ferromagnetic interactions in the two compounds. Their values compare well with those existing in the literature for the parent systems. PMID- 24074250 TI - Prazosin has low potency at alpha1A-adrenoceptors and high potency at alpha1D adrenoceptors in rat vas deferens. AB - (1) We have investigated alpha1 -adrenoceptor subtypes mediating contractions to noradrenaline in epididymal portions of rat vas deferens. (2) Contractions to noradrenaline were investigated in the absence or presence of the noradrenaline transporter blocker cocaine. (3) In the absence of cocaine, contractions to noradrenaline were potently antagonized by RS100329, but not by BMY7378, and so are mediated mainly by alpha1A -adrenoceptors. (4) In the presence of cocaine, noradrenaline potency was increased, particularly in terms of low concentrations and phasic contractions. Contractions to low concentrations of noradrenaline in the presence of cocaine were resistant to RS100329 but potently antagonized by BMY7378, demonstrating that alpha1D-adrenoceptors are additionally involved in contractions amplified by cocaine. (5) In the absence of cocaine, prazosin exhibited relatively low potency as an antagonist against the alpha1A adrenoceptor-mediated component to the response. In the presence of cocaine, prazosin exhibited higher potency against the alpha1D-adrenoceptor-mediated component. (6) In conclusion, prazosin has previously unreported selectivity for alpha1D-over alpha1A -adrenoceptors in functional studies of rat vas deferens. Contractions of rat vas deferens are mediated by alpha1A-and alpha1D adrenoceptors. The range of prazosin potencies and of receptor subtypes previously reported in rat vas deferens may be explained by the presence of these two subtypes. PMID- 24074251 TI - CXCR7 expression in esophageal cancer. AB - BACKGROUND: The chemokine CXCL12 and its receptor CXCR4 play a major role in tumor invasion, proliferation and metastasis in different malignant diseases, including esophageal carcinoma, amongst others. CXCR7 was recently identified as a novel alternate receptor for CXCL12. The aim of this study was to evaluate the prognostic impact of expression of chemokine receptor CXCR7 in patients with esophageal carcinoma (EC). METHODS: Expression of CXCR7 in primary tumors, lymph nodes and distant metastases of 299 patients with EC was evaluated by immunohistochemistry on a tissue microarray and compared with clinical and histopathological data. RESULTS: In esophageal cancer sections, CXCR7-specific reactivity was apparent in 45% of the squamous cell carcinomas (ESCC), but only occasionally in adenocarcinomas. No correlation between CXCR4 and CXCR7 expression was evident. We correlated expression with clinical and histopathological characteristics, but could not find any association. CONCLUSIONS: Contrary to the other known CXCL12 receptor, CXCR4, CXCR7 is expressed in ESCC only, underlining the divergent mechanisms and backgrounds of EAC and ESCC. The results of the study do not indicate a significant functional role for CXCR7 in EAC or ESCC of the esophagus. However, its variable expression in the main two main types of EC needs to be further investigated. PMID- 24074252 TI - Fixed mydriatic pupil associated with an intraocular pressure rise as a complication of the implant of a Phakic Refractive Lens (PRL). AB - We describe a case report of a patient that was implanted with a posterior chamber phakic intraocular lens (Phakic Refractive Lens, PRL) for the correction of moderate myopia and who developed postoperatively a fixed mydriasis compatible with an Urrets-Zavalia Syndrome (UZS). Specifically, a sudden acute increase of IOP in the left eye was observed in the immediate postoperative period. After IOP stabilization, the refractive result was good, but a fixed and mydriatic pupil appeared. This condition led the patient to experience visual discomfort, halos, and glare associated with high levels of higher-order aberrations in spite of the good visual result. A tinted-contact lens was fitted in order to minimize those symptoms. The UZS should be considered as a possible complication after implantation of posterior chamber phakic intraocular lenses. PMID- 24074253 TI - Denosumab as a promising novel bone-targeted agent in castration resistant prostate cancer. AB - Fortunately, more therapeutic progress has been achieved during the last 3 years for patients with castration resistant prostate cancer (CRPC) than during the previous 30 years. During this limited time frame, six compounds (sipuleucel-T, cabazitaxel, denosumab, abiraterone, radium-223 and enzalutamide, listed in chronologic order) yielded positive results in Phase III trials (Fizazi K. Nonhormone therapy for metastatic castration-resistant prostate cancer. Soc Clin Oncol Educ Book 2013;2013:161-5; Papatsoris AG, Karamouzis MV, Papavassiliou AG. Novel biological agents for the treatment of hormone-refractory prostate cancer (HRPC). Curr Med Chem 2005;12(3):277-96). Regarding skeletal related event (SREs) in patients with CRPC the last 20 years bisphosphonates (i.e., zolendronic acid) were the standard of care until the development of denosumab, which is a novel receptor-activated nuclear factor kappa-beta ligand inhibitor. Recent studies demonstrated that denosumab (subcutaneous use) was better than zolendronic acid (intravenous use) for the prevention of SREs and the increase of the bone metastasis-free survival, while the rate and grade of adverse effects was similar, except for osteonecrosis of the jaw and hypocalcemia. Cost-effectiveness of denosumab is under review in ongoing comparative studies. PMID- 24074254 TI - Lifestyle and semen quality: role of modifiable risk factors. AB - The relationship between exposure to lifestyle factors and adverse effects on human reproductive health is debated in the scientific literature and these controversies have increased public and regulatory attention. The aim of the study was to examine the association between modifiable lifestyle factors and main semen parameters, sperm morphology, and sperm chromatin structure. The study population consisted of 344 men who were attending an infertility clinic for diagnostic purposes with normal semen concentration of 20-300 M/ml or with slight oligozoospermia (semen total concentration of 15-20 M/ml) [WHO 1999]. Participants were interviewed and provided semen samples. The interview included questions about demographics, socio-economic status, medical history, lifestyle factors (consumption of alcohol, tobacco, coffee intake, cell phone and sauna usage), and physical activity. The results of the study suggest that lifestyle factors may affect semen quality. A negative association was found between increased body mass index (BMI) and semen volume (p = 0.03). Leisure time activity was positively associated with sperm concentration (p = 0.04) and coffee drinking with the percentage of motile sperm cells, and the percentage of sperm head and neck abnormalities (p = 0.01, p = 0.05, and p = 0.03, respectively). Drinking red wine 1-3 times per week was negatively related to sperm neck abnormalities (p = 0.01). Additionally, using a cell phone more than 10 years decreased the percentage of motile sperm cells (p = 0.02). Men who wore boxer shorts had a lower percentage of sperm neck abnormalities (p = 0.002) and percentage of sperm with DNA damage (p = 0.02). These findings may have important implications for semen quality and lifestyle. PMID- 24074256 TI - Association of TLR2 and TLR4 gene single nucleotide polymorphisms with Fungal Keratitis in Chinese Han population. AB - PURPOSE: Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) play a crucial role in the primary defense against fungal pathogens, and since genetic variation in genes may regulate the response. This study aimed to test whether variants in the TLR4 gene are associated with fungal keratitis (FK) of Chinese Han population. MATERIALS AND METHODS: Two-hundred sixty-nine subjects (109 cases and 160 matched controls) in a Han Chinese population were genotyped. Seven single nucleotide polymorphisms (SNPs) which located, respectively, in the TLR2 and TLR4 genes were selected and their associations with FK risk factors were assessed. RESULTS: Allele A of TLR4 rs10983755 was found significantly higher in the group of FK patients, being detected in 32.11% of the FK patients alleles and in 22.19% of the healthy control alleles (p = 0.01).Those AA/AG genotypes carrying the allele A of rs10983755 had a risk effect on the etiology of FK, and the odds ratio for the FK patients versus controls was 2.075 (OR = 2.075, 95%CI = 1.264-3.407). The Ht3 haplotype, which carried the A allele of TLR4 rs10983755, was associated with the significantly increased risk of FK (OR = 1.786, 95%CI = 1.207-2.642). While, the Ht2 haplotype, which carried the wild G allele of TLR4 rs10983755, was a protective haplotype (OR = 0.488, 95%CI = 0.333-0.715). The genotype and allele frequency of TLR2 showed no differences between the two groups (p > 0.05). CONCLUSIONS: The rs10983755, located in the 5'-untranslated region (UTR) of TLR4, was most strongly associated with FK of Chinese Han population (p < 0.05). The analysis of TLR2 gene polymorphisms showed no significant association upon FK susceptibilities of Chinese Han population. PMID- 24074255 TI - Transcriptome sequencing and whole genome expression profiling of chrysanthemum under dehydration stress. AB - BACKGROUND: Chrysanthemum is one of the most important ornamental crops in the world and drought stress seriously limits its production and distribution. In order to generate a functional genomics resource and obtain a deeper understanding of the molecular mechanisms regarding chrysanthemum responses to dehydration stress, we performed large-scale transcriptome sequencing of chrysanthemum plants under dehydration stress using the Illumina sequencing technology. RESULTS: Two cDNA libraries constructed from mRNAs of control and dehydration-treated seedlings were sequenced by Illumina technology. A total of more than 100 million reads were generated and de novo assembled into 98,180 unique transcripts which were further extensively annotated by comparing their sequencing to different protein databases. Biochemical pathways were predicted from these transcript sequences. Furthermore, we performed gene expression profiling analysis upon dehydration treatment in chrysanthemum and identified 8,558 dehydration-responsive unique transcripts, including 307 transcription factors and 229 protein kinases and many well-known stress responsive genes. Gene ontology (GO) term enrichment and biochemical pathway analyses showed that dehydration stress caused changes in hormone response, secondary and amino acid metabolism, and light and photoperiod response. These findings suggest that drought tolerance of chrysanthemum plants may be related to the regulation of hormone biosynthesis and signaling, reduction of oxidative damage, stabilization of cell proteins and structures, and maintenance of energy and carbon supply. CONCLUSIONS: Our transcriptome sequences can provide a valuable resource for chrysanthemum breeding and research and novel insights into chrysanthemum responses to dehydration stress and offer candidate genes or markers that can be used to guide future studies attempting to breed drought tolerant chrysanthemum cultivars. PMID- 24074257 TI - Synthesis and bioconversions of formestane. AB - In an effort to generate new steroidal aromatase inhibitors, formestane (4 hydroxyandrost-4-ene-3,17-dione) (1) was biotransformed by Rhizopus oryzae to yield the known 4beta,5alpha-dihydroxyandrostane-3,17-dione as the major product (5) and bioconverted by Beauveria bassiana to afford the known reduced 4,17beta dihydroxyandrost-4-en-3-one (6) and 3alpha,17beta-dihydroxy-5beta-androstan-4-one (7) and the new 4,11alpha,17beta-trihydroxyandrost-4-en-3-one (8). All the metabolites showed more potent activities than their parent congener in the aromatase and MCF-7 breast cancer assays. The bioactivities and structural elucidation of these metabolites as well as the semisynthesis of formestane (1) from testosterone (2) are reported herein. PMID- 24074258 TI - Healthcare costs, treatment patterns, and resource utilization among pancreatic cancer patients in a managed care population. AB - BACKGROUND: Pancreatic adenocarcinoma has few effective treatment options and poor survival. The objective of this study was to characterize treatment patterns and estimate the costs and resource use associated with its treatment in a commercially-insured US population. METHODS: In this retrospective claims-based analysis, individuals >=18 years old with evidence of pancreatic adenocarcinoma between January 1, 2001 and December 31, 2010 were selected from a managed care database. Treatment phase (either initial non-metastatic or metastatic) was determined using a claims-based algorithm. Patients in the pancreatic cancer population were matched 1:3 to a control population. Resource use (events/person years), treatment patterns, and healthcare costs (per-patient per-month, PPPM) were determined during a variable length follow-up period (from first pancreatic cancer diagnosis to earliest of death, disenrollment, or study end). RESULTS: In this study, 5262 pancreatic cancer patients were matched to 15,786 controls. Rates of office visits, inpatient visits, ER visits, and inpatient stays, and mean total all-cause healthcare costs PPPM ($15,480 vs $1001) were significantly higher among cancer patients than controls (all p < 0.001). Mean inpatient costs were the single largest cost driver ($9917 PPPM). Also, mean total all-cause healthcare costs were significantly higher during the metastatic treatment phase vs the initial treatment phase of non-metastatic disease ($21,637 vs $10,358, p < 0.001). CONCLUSIONS: These results indicate that pancreatic cancer imposes a substantial burden on the US healthcare system, and that treatment of more advanced disease is significantly more costly than initial treatment of non metastatic disease. LIMITATIONS: Additional research is needed to validate the accuracy of the claims-based algorithms used to identify the treatment phase. PMID- 24074259 TI - Robotic-assisted urethrolysis for urethral obstruction after retropubic bladder neck suspension-a case series report. AB - INTRODUCTION: Urethral/bladder outlet obstruction (BOO) is a recognized complication after most surgical procedures for stress urinary incontinence. The mechanisms involved are thought to be related to an overcorrection of the urethra (by kinking and/or compressing the urethra) or excessive scar formation between the pubis and urethra. The recommended treatment is usually surgical that aims to free up the obstructed urethra (urethrolysis). For retropubic bladder neck suspension (BNS), robotic-assisted surgery offers a less invasive alternative to classical abdominal approach. We report methods and results of performing robotic assisted urethrolysis in patients with urethral obstruction after Burch colposuspension. PATIENTS AND METHODS: Six patients presented with voiding difficulties and urinary irritative symptoms after an abdominal hysterectomy and Burch colposuspension. BOO was diagnosed based on history, presenting symptoms, and urodynamic findings, including the maximum flow rate (Qmax) of <=12 mL/second and detrusor pressure at maximum flow (PdetQmax) of >=20 cmH2O. Patients underwent robotic-assisted urethrolysis, which consisted of the usual robotic exposure of the abdominal cavity, access to the space of Retzius, removal of Burch sutures, and hypermobilization of the urethra. The intraoperative and postoperative complications, recovery time, and outcome of the procedure to successfully address the patients' symptoms were reviewed and herein reported. RESULTS: Postoperatively, five of the six patients had complete resolution of the obstructive and irritative symptoms. All had improvement of the postvoid residual volume with a median of 46.5 mL (range 0-176 mL). Postoperatively, urodynamic studies were repeated in two patients and PdetQmax decreased from 39 cmH2O before surgery to 21 cmH2O after urethrolysis and from 31 to 21 cmH2O, respectively. Qmax increased from 0 to 17 mL/second and from 6 to 10 mL/second, respectively. CONCLUSIONS: Robotic-assisted urethrolysis is a feasible and attractive minimally invasive procedure to treat BOO after retropubic BNS. PMID- 24074260 TI - Proteomic analysis of leaves and roots of common wheat (Triticum aestivum L.) under copper-stress conditions. AB - Proteomic studies were performed to identify the protein species involved in copper (Cu) stress responses in common wheat. Two-week-old wheat seedlings were exposed to 100 MUM CuSO4 treatment for 3 days. Growth of shoots and roots was markedly inhibited and lipid peroxidation was greatly increased. Cu was readily absorbed by wheat seedlings, with greater Cu contents in roots than in leaves. Using 2-DE method, 98 protein spots showed significantly enhanced or reduced abundance, of which 93 were successfully identified. Of these identified protein species, 49 and 44 were found in roots and leaves, respectively. Abundance of most of identified protein species, which function in signal transduction, stress defense, and energy production, was significantly enhanced, while that of many protein species involved in carbohydrate metabolism, protein metabolism, and photosynthesis was severely reduced. The Cu-responsive protein interaction network revealed 36 key proteins, most of which may be regulated by abscisic acid (ABA), ethylene, jasmonic acid (JA), and so on. Exogenous JA application showed a protective effect against Cu stress and significantly increased transcripts of the glutathione S-transferase (GST) gene. This study provides insight into the molecular mechanisms of Cu responses in higher plants. PMID- 24074261 TI - Cdc42 overexpression induces hyperbranching in the developing mammary gland by enhancing cell migration. AB - INTRODUCTION: The Rho GTPase Cdc42 is overexpressed and hyperactivated in breast tumors compared to normal breast tissue. Cdc42 regulates key processes that are critical for mammary gland morphogenesis and become disrupted during the development, progression, and metastasis of breast cancer. However, the contribution of Cdc42 to normal and neoplastic mammary gland development in vivo remains poorly understood. We were therefore interested in investigating the effects of Cdc42 overexpression on mammary gland morphogenesis as a first step toward understanding how its overexpression may contribute to mammary tumorigenesis. METHODS: We developed a tetracycline-regulatable Cdc42 overexpression mouse model in which Cdc42 can be inducibly overexpressed in the developing mammary gland. The effects of Cdc42 overexpression during postnatal mammary gland development were investigated using in vivo and in vitro approaches, including morphometric analysis of wholemounted mammary glands, quantification of histological markers, and primary mammary epithelial cell (MEC) functional and biochemical assays. RESULTS: Analysis of Cdc42-overexpressing mammary glands revealed abnormal terminal end bud (TEB) morphologies, characterized by hyperbudding and trifurcation, and increased side branching within the ductal tree. Quantification of markers of proliferation and apoptosis suggested that these phenotypes were not due to increased cell proliferation or survival. Rather, Cdc42 overexpressing MECs were more migratory and contractile and formed dysmorphic, invasive acini in three-dimensional cultures. Cdc42 and RhoA activities, phosphorylated myosin light chain, and MAPK signaling, which contribute to migration and invasion, were markedly elevated in Cdc42 overexpressing MECs. Interestingly, Cdc42 overexpressing mammary glands displayed several features associated with altered epithelial-stromal interactions, which are known to regulate branching morphogenesis. These included increased stromal thickness and collagen deposition, and stromal cells isolated from Cdc42 overexpressing mammary glands exhibited elevated mRNA expression of extracellular matrix proteins and remodeling enzymes. CONCLUSIONS: These data suggest that Cdc42 overexpression disrupts mammary gland branching morphogenesis by altering Rho GTPase and MAPK signaling, leading to increased MEC contractility and migration in association with stromal alterations. Our studies provide insight into how aberrant Cdc42 expression may contribute to mammary tumorigenesis. PMID- 24074262 TI - Subjective cognitive complaints across the adult life span: a 14-year analysis of trends and associations using the 1993, 2000 and 2007 English Psychiatric Morbidity Surveys. AB - BACKGROUND: Cognitive complaints are common in all age groups but most often researched in old age. We aimed to investigate prevalences and time trends over 14 years of subjective memory complaints (SMC) and subjective concentration complaints (SCC) in adults and investigate associations with mood disorders and cognitive function. METHOD: Data from three English national mental health surveys carried out in 1993, 2000 and 2007 were analysed. SMC and SCC were measured using the Clinical Interview Schedule-Revised and cognitive function using the modified Telephone Interview for Cognitive Status. RESULTS: Both SMC and SCC increased up to middle age and then declined, followed by a second rise in the very oldest age groups. Age-specific prevalence of both increased across survey years but relationships with mental health and cognitive outcomes were relatively stable. CONCLUSIONS: Cognitive complaints are most common in middle age and have become more prevalent over time. PMID- 24074263 TI - Expression changes of ionic channels in early phase of cultured rat atrial myocytes induced by rapid pacing. AB - BACKGROUND: Recent studies have demonstrated that atrial electrical remodeling was an important contributing factor for the occurrence, persistence and maintenance of atrial fibrillation. The expression changes of ionic channels, especially L-type calcium channel and potassium channel Kv4.3, were the important molecular mechanism of atrial electrical remodeling. This study aimed to observe the expression changes of ionic channels in a rapid paced cell model with primary cultured atrial myocytes. METHODS: The primary rat atrial myocytes were cultured, characteristics of the cultured myocytes were observed with light microscope and the cell phenotype was harvested by immunocytochemical stain to detect alpha actin. The cellular model of rapid pacing was established with primary cultured atrial myocytes. The expressions of L-type calcium channel alpha1c and potassium channel Kv4.3 in cultured atrial myocytes were detected by immunocytochemistry, reverse transcription polymerase chain reaction and Western blot after rapid pacing. RESULTS: The primary rat atrial myocytes were isolated and cultured successfully, and used for following experiment by identification of activity and purity. Cellular model of rapid electrical field pacing was established successfully. There is no significant difference in cell activity after pacing compared to that before pacing by 3-[4, 5-dimethylthiazol-2-y1]-2, 5 diphenytetrazolium bromide assay, and cell degeneration can be observed by transmission electron microscope. The mRNA expression of L-type calcium channel alpha1c started to reduce after 6 h of rapid pacing and continued to decline as pacing continued. Protein expression changes were paralleled with decreased mRNA expression of the L-type calcium channel alpha1c. The mRNA expressions of potassium channel Kv4.3 were not altered within the first 6 h, but after 12 h, mRNA expressions were reduced. Longer pacing periods did not further decrease mRNA expression of potassium channel Kv4.3. Protein expression changes were paralleled with decreased mRNA expression of potassium channel Kv4.3. CONCLUSIONS: Rapid paced cultured atrial myocyte model was established utilized primary cultured atrial myocytes and this model can be used for studying the early electrical remodeling in atrial fibrillation. Expressions of L-type calcium channel alpha1c and potassium channel Kv4.3 were both reduced at different levels in early phase of rapid pacing atrial myocytes. It implicates the occurrence of ionic channel remodeling of atrial myocytes. PMID- 24074264 TI - Tuning InAs nanowire density for HEK293 cell viability, adhesion, and morphology: perspectives for nanowire-based biosensors. AB - Arrays of nanowires (NWs) are currently being established as vehicles for molecule delivery and electrical- and fluorescence-based platforms in the development of biosensors. It is conceivable that NW-based biosensors can be optimized through increased understanding of how the nanotopography influences the interfaced biological material. Using state-of-the-art homogenous NW arrays allow for a systematic investigation of how the broad range of NW densities used by the community influences cells. Here it is demonstrated that indium arsenide NW arrays provide a cell-promoting surface, which affects both cell division and focal adhesion up-regulation. Furthermore, a systematic variation in NW spacing affects both the detailed cell morphology and adhesion properties, where the latter can be predicted based on changes in free-energy states using the proposed theoretical model. As the NW density influences cellular parameters, such as cell size and adhesion tightness, it will be important to take NW density into consideration in the continued development of NW-based platforms for cellular applications, such as molecule delivery and electrical measurements. PMID- 24074268 TI - Absorption, distribution, metabolism and excretion of the novel SARM GTx-024 [(S) N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2 methylpropanamide] in rats. AB - 1. GTx-024, a novel selective androgen receptor modulator, is currently being investigated as an oral treatment for muscle wasting disorders associated with cancer and other chronic conditions. 2. Absorption of GTx-024 was rapid and complete, with high oral bioavailability. A wide tissue distribution of [(14)C]GTx-024 derived radioactivity was observed. [(14)C]GTx-024-derived radioactivity had a moderate plasma clearance (117.7 and 74.5 mL/h/kg) and mean elimination half-life of 0.6 h and 16.4 h in male and female rats, respectively. 3. Fecal excretion was the predominant route of elimination, with ~70% of total radioactivity recovered in feces and 21-25% in urine within 48 h. Feces of intact rats contained primarily unchanged [(14)C]GTx-024 (49.3-64.6%). Metabolites were identified in urine and feces resulting from oxidation of the cyanophenol ring (M8, 17.6%), hydrolysis and/or further conjugation of the amide moiety (M3, 8 12%) and the cyanophenol ring (M4, 1.3-1.5%), and glucuronidation of [(14)C]GTx 024 at the tertiary alcohol (M6, 3.5-3.7%). There was no quantifiable metabolite in plasma. 4. In summary, in the rat GTx-024 is completely absorbed, widely distributed, biotransformed through several metabolic pathways, and eliminated in feces primarily as an unchanged drug. PMID- 24074270 TI - Survey of patients' view on functional split of consultant psychiatrists. AB - BACKGROUND: The functional split model of consultant psychiatrist care for inpatients has been one of the major service redesign that has occurred in the NHS in the last decade. It is unclear if this new split model offers any advantages over the previous sectorised model of working. More recent evidence has suggested that patients, carers and professionals have varied views regarding the benefits of this model. This survey of patient's views on models of consultant working is the first in Scotland and we have attempted to include a large sample size. The results suggest that after providing sufficient information on both models, the majority of patients from various Scottish health boards have opted for the traditional sectorised model of working. METHOD: During a four week period consecutive patients across 4 health boards attending the General Adult consultant outpatient clinics and those who were admitted to their inpatient ward were offered a structured questionnaire regarding their views on the functional split versus traditional sectorised model. Space was provided for additional comments. The study used descriptive statistical measures for analysis of its results. Ethical approval was confirmed as not being required for this survey of local services. RESULTS: We had a response rate of 67%. A significant majority (76%) of service users across the four different health boards indicated a preference for the same consultant to manage their care irrespective of whether they were an inpatient or in the community (Chi-squared = 65, df = 1, p < 0.0001). In their unstructured comments patients often mentioned the value of the therapeutic relationship and trust in a single consultant psychiatrist. CONCLUSIONS: Our survey suggests that most patients prefer the traditional model where they see a single consultant throughout their journey of care. The views of patients should be sought as much as possible and should be taken into account when considering the best way to organize psychiatric services. PMID- 24074269 TI - STRIDE: a randomized trial of a lifestyle intervention to promote weight loss among individuals taking antipsychotic medications. AB - BACKGROUND: Individuals diagnosed with serious mental illnesses are at increased risk of obesity- and cardiovascular-related morbidity and early mortality. Lifestyle interventions aimed at weight loss, even those adapted to suit the needs of this particular subgroup, have rarely produced clinically meaningful reductions in weight. METHODS/DESIGN: The STRIDE study is a multi-site, parallel, two-arm randomized controlled translational trial. Participants were recruited from community mental health clinics and an integrated not-for-profit health system. Participants were randomized either to usual care or to a 12-month intervention that consisted of: 1) weekly group participation for six months covering topics on nutrition, physical activity and lifestyle changes; 2) monthly group participation for an additional six month maintenance period; and 3) individual monthly contacts from intervention group facilitators during the second six month phase. All participants are assessed at baseline, 6, 12, and 24 months post-enrollment. Process and implementation evaluations are included and the study design includes a cost-utility analysis. Participants include 200 individuals with serious mental illness with an average age of 47.1 years, a mean body-mass index of 38.3 kg/m(2) and taking an average of 3.2 psychiatric medications at baseline. Baseline physiological measures included mean blood pressure (SBP/DBP) measurements of 119.2 (SD = 14.7)/79.4 (SD = 10.1); 35% reported a hypertension diagnosis and 11% took antihypertensive medications. Average lipid levels (mg/dL) were: a) triglycerides 188.0 (SD = 138.6), ranged from 43 to 1145; b) LDL 101.4 (SD = 32.9) and ranged from 17 to 185; c) HDL 45.8 (SD = 12.7) and ranged from 22 to 89; and d) total cholesterol 181.6 (SD = 39.7) and ranged from 50 to 324. Average fasting glucose levels were 108.9 (SD = 32.5) and ranged from 24 to 289. Average fasting insulin levels were 13.0 (SD=11.9) and ranged from 2 to 99. DISCUSSION: The STRIDE study is based on a modified version of the PREMIER comprehensive lifestyle intervention, DASH diet arm. STRIDE has successfully enrolled 200 individuals with serious mental illness in community based settings. Baseline characteristics present a population at high risk for obesity-related negative health outcomes and demonstrate the need for evidence based interventions to reduce these risks. TRIAL REGISTRATION: Clinical Trials.gov NCT00790517. PMID- 24074271 TI - Temperature dependence of the piezotronic effect in ZnO nanowires. AB - A comprehensive investigation was carried out on n-type ZnO nanowires for studying the temperature dependence of the piezotronic effect from 77 to 300 K. In general, lowering the temperature results in a largely enhanced piezotronic effect. The experimental results show that the behaviors can be divided into three groups depending on the carrier doping level or conductivity of the ZnO nanowires. For nanowires with a low carrier density (<10(17)/cm(3) at 77 K), the pieozotronic effect is dominant at low temperature for dictating the transport properties of the nanowires; an opposite change of Schottky barrier heights at the two contacts as a function of temperature at a fixed strain was observed for the first time. At a moderate doping (between 10(17)/cm(3) and 10(18)/cm(3) at 77 K), the piezotronic effect is only dominant at one contact, because the screening effect of the carriers to the positive piezoelectric polarization charges at the other end (for n-type semiconductors). For nanowires with a high density of carriers (>10(18)/cm(3) at 77 K), the piezotronic effect almost vanishes. This study not only proves the proposed fundamental mechanism of piezotronic effect, but also provides guidance for fabricating piezotronic devices. PMID- 24074272 TI - Evaluation of in silico, in vitro alpha-amylase inhibition potential and antidiabetic activity of Pterospermum acerifolium bark. AB - CONTEXT: Pterospermum acerifolium (L.) Willd (Sterculiaceae) has been traditionally used in the treatment of diabetes mellitus but no scientific data has been published supporting the claimed ethnomedical use. OBJECTIVE: The present study was designed to estimate the in silico, in vitro alpha-amylase inhibition potential and anti-diabetic activity of Pterospermum acerifolium bark. MATERIALS AND METHODS: In silico studies were performed between human pancreatic alpha-amylase (HPA) and beta-sitosterol by using autodock 4.2 software. In vitro alpha-amylase inhibition study was carried out with 50% ethanol extract of the bark (PABEE) and its various fractions. The active ethyl acetate fraction (PABEF) was sub-fractionated into three fractions (PABE1, PABE2 and PABE3). Two doses (15 and 30 mg/kg) based on acute toxicity studies, of the above fractions were subjected to antidiabetic screening in vivo by STZ-nicotinamide induced type II diabetic rats. RESULTS: In silico studies showed the potent inhibition of beta sitosterol on human pancreatic amylase (HPA) with an estimated inhibition constant (Ki) of 269.35 nmol and two hydrogen bond interactions. PABEF showed marked alpha-amylase inhibition (69.94%) compared to other fractions. Diabetic rats treated with PABE3 (30 mg/kg) reduced the levels of fasting blood glucose, HbA1c, ALT, AST, ALP, triglycerides, total cholesterol, TBARS significantly (p < 0.01) and increased the levels of HDL-C, catalase, GSH, SOD significantly (p < 0.01) as compared to that of diabetic control animals. Histological studies on PABE3 treated group showed remarkable positive changes in beta-cells. CONCLUSION: The present study confirmed the antihyperglycemic activity along with its status on hepatic biomarkers, antihyperlipidemic and antioxidant properties of Pterospermum acerifolium bark. PMID- 24074273 TI - Transcriptomic insights into the molecular response of Saccharomyces cerevisiae to linoleic acid hydroperoxide. AB - Eukaryotic microorganisms are constantly challenged by reactive oxygen species derived endogenously or encountered in their environment. Such adversity is particularly applied to Saccharomyces cerevisiae under harsh industrial conditions. One of the major oxidants to challenge S. cerevisiae is linoleic acid hydroperoxide (LoaOOH). This study, which used genome-wide microarray analysis in conjunction with deletion mutant screening, uncovered the molecular pathways of S. cerevisiae that were altered by an arresting concentration of LoaOOH (75 MUM). The oxidative stress response, iron homeostasis, detoxification through PDR transport and direct lipid beta-oxidation were evident through the induction of the genes encoding for peroxiredoxins (GPX2, TSA2), the NADPH:oxidoreductase (OYE3), iron uptake (FIT2, ARN2, FET3), PDR transporters (PDR5, PDR15, SNQ2) and beta-oxidation machinery (FAA2, POX1). Further, we discovered that Gpx3p, the dual redox sensor and peroxidase, is required for protection against LoaOOH, indicated by the sensitivity of gpx3Delta to a mild dose of LoaOOH (37.5 MUM). Deletion of GPX3 conferred a greater sensitivity to LoaOOH than the loss of its signalling partner YAP1. Deletion of either of the iron homeostasis regulators AFT1 or AFT2 also resulted in sensitivity to LoaOOH. These novel findings for Gpx3p, Aft1p and Aft2p point to their distinct roles in response to the lipid peroxide. Finally, the expression of 89 previously uncharacterised genes was significantly altered against LoaOOH, which will contribute to their eventual annotation. PMID- 24074274 TI - Quantification of transferrin in human serum using both QconCAT and synthetic internal standards. AB - Transferrin, an iron transport protein, is a clinically important biomarker in diseases such as iron-deficiency anemia. Current diagnostic methods for transferrin levels lack quantitative accuracy, suggesting the need for alternative approaches like LC-MS with isotope-labeled peptides as internal standards. Besides solid-phase synthesis, isotope-labeled peptides are also generated by a method called QconCAT where peptides are expressed from DNA in the presence of heavy isotope media. After evaluation of the expressed QconCAT, this study compares transferrin levels obtained by synthetic peptides versus QconCAT peptides as internal standards. Transferrin levels obtained by both internal standards give overlapping, or nearly overlapping, uncertainty values and are near ~200 mg/dL of transferrin in human serum. Close agreement between the two methods suggests that the quantitative values are reasonable. Using QconCAT and synthetic peptides in parallel gives a refined focus on method development, and the resulting methods should be applicable to other clinically relevant proteins. PMID- 24074275 TI - Survival of the scheming: a genetically informed link between the dark triad and mental toughness. AB - The present study is the first behavioral genetic investigation of the Dark Triad traits of personality, consisting of Machiavellianism, narcissism, and psychopathy, and the variable of mental toughness, reflecting individual differences in the ability to cope when under pressure. The purpose of this investigation was to explore a potential explanation for the success of individuals exhibiting the Dark Triad traits in workplace and social settings. Participants were adult twins who completed the MACH-IV, the Narcissistic Personality Inventory, and the Self-Report Psychopathy Scale assessing Machiavellianism, narcissism, and psychopathy, respectively, as well as the MT48, measuring mental toughness. Correlational analyses of the data revealed significant positive phenotypic associations between mental toughness and narcissism. Psychopathy and Machiavellianism, however, both showed some significant negative phenotypic correlations with mental toughness. Bivariate behavioral genetic analyses of the data were conducted to assess the extent to which these significant phenotypic correlations were attributable to common genetic and/or common environmental factors. Results indicate that correlations between narcissism and mental toughness were attributable primarily to common non shared environmental factors, correlations between Machiavellianism and mental toughness were influenced by both common genetic and common non-shared environmental factors, and the correlations between psychopathy and mental toughness were attributable entirely to correlated genetic factors. Implications of these findings in the context of etiology and organizational adaptation are discussed. PMID- 24074276 TI - Self-assembled HCV core virus-like particles targeted and inhibited tumor cell migration and invasion. AB - We used a baculovirus expression system to express fusion proteins of HCV core, RGD (Arg-Gly-Asp) peptide, and IFN-alpha2a fragments in Sf9 cells. Western blotting and electron microscopy demonstrate that HCV core, peptides RGD, and IFN alpha2a fusion proteins assemble into 30 to 40 nm nano-particles (virus-like particles, VLPs). Xenograft assays show that VLPs greatly reduced tumor volume and weight with regard to a nontreated xenograft. Migration and invasion results show that VLPs can inhibit the migration and invasion of the breast cancer cells MDA-MB231. This study will provide theoretical and experimental basis for the establishment of safe and effective tumor-targeted drug delivery systems and clinical application of VLPs carrying cell interacting cargo. PMID- 24074277 TI - Iron and manganese pyridoxal-based complexes as fluorescent probes for nitrite and nitrate anions in aqueous solution. AB - Water-soluble iron and manganese pyridoxal-based complexes pyr2enFeCl (1) and pyr2enMnCl (2) (pyr2en = N,N'-ethylenebis(pyridoxylideneiminato) have been synthesized and characterized. Proof-of-principle results that the title complexes can be efficiently used as fluorescent probes for nitrite and nitrate detection are provided. The fluorescent complex pyr2enFeCl (1) selectively recognizes nitrate anions by fluorescent enhancement in an aqueous solution displaying high binding affinities. ESI-MS experiments clearly show the binding of these anions via the substitution of the chloride anion at the metal center. The pyridoxal-based manganese complexes of NO2(-) and NO3(-) have been isolated, and their structures have been established by single-crystal XRD. Density functional theory (DFT) calculations show that the substitution of the chloride anion at the metal center by the nitrite or nitrate anion is favored by the gain in the energies of hydration. PMID- 24074278 TI - Homology of the enigmatic nuchal bone reveals novel reorganization of the shoulder girdle in the evolution of the turtle shell. AB - The turtle shell represents a unique modification of the ancestral tetrapod body plan. The homologies of its approximately 50 bones have been the subject of debate for more than 200 years. Although most of those homologies are now firmly established, the evolutionary origin of the dorsal median nuchal bone of the carapace remains unresolved. We propose a novel hypothesis in which the nuchal is derived from the paired, laterally positioned cleithra-dorsal elements of the ancestral tetrapod pectoral girdle that are otherwise retained among extant tetrapods only in frogs. This hypothesis is supported by origin of the nuchal as paired, mesenchymal condensations likely derived from the neural crest followed by a unique two-stage pattern of ossification. Further support is drawn from the establishment of the nuchal as part of a highly conserved "muscle scaffold" wherein the cleithrum (and its evolutionary derivatives) serves as the origin of the Musculus trapezius. Identification of the nuchal as fused cleithra is congruent with its general spatial relationships to other elements of the shoulder girdle in the adult morphology of extant turtles, and it is further supported by patterns of connectivity and transformations documented by critical fossils from the turtle stem group. The cleithral derivation of the nuchal implies an anatomical reorganization of the pectoral girdle in which the dermal portion of the girdle was transformed from a continuous lateral-ventral arc into separate dorsal and ventral components. This transformation involved the reduction and eventual loss of the scapular rami of the clavicles along with the dorsal and superficial migration of the cleithra, which then fused with one another and became incorporated into the carapace. PMID- 24074279 TI - Developmental sequences of squamate reptiles are taxon specific. AB - Recent studies in comparative vertebrate embryology have focused on two related questions. One concerns the existence of a phylotypic period, or indeed any period, during development in which sequence variation among taxa is constrained. The second question concerns the degree to which developmental characters exhibit a phylogenetic signal. These questions are important because they underpin attempts to understand the evolution of developmental characters and their links to adult morphology. To address these questions, we compared the sequence of developmental events spanning the so-called phylotypic period of vertebrate development in squamate reptiles (lizards and snakes), from the formation of the primary optic placode to the first appearance of scale anlagen. We used Bayesian phylogenetic ancestral state reconstruction analyses and estimates of Bayesian posterior probabilities of the rank order of developmental events to determine the level of support for phylogenetically associated variation in development. We assessed the amount of variation in event sequences by plotting the proportions of reconstructed ranks (excluding unlikely events, PP < 0.05) associated with each event. Sequence variability was the lowest towards the middle of the phylotypic period and involved three events (allantois contacts chorion, maximum number of pharyngeal slits, and appearance of the apical epidermal ridge [AER]); these events each had only two reconstructed ranks. Squamate clades also differed in the rank order of developmental events. Of the 20 events in our analyses, 12 had strongly supported (PP >= 0.95) sequence ranks that differed at two or more internal nodes of the tree. For example, gekkotans are distinguished by the late appearance of the allantois bud compared to all other squamates (ranks 7 and 8 vs. rank 3, respectively) and Serpentes are distinguished by the earlier completion of torsion (rank 3) compared to acrodonts and pleurodonts (ranks 7 and 5, respectively). Clade specific sequences of developmental events mean that investigators should not extend observations on the development on particular squamate species to distantly related taxa for use in comparative studies. PMID- 24074280 TI - Ossification sequence heterochrony among amphibians. AB - Heterochrony is an important mechanism in the evolution of amphibians. Although studies have centered on the relationship between size and shape and the rates of development, ossification sequence heterochrony also may have been important. Rigorous, phylogenetic methods for assessing sequence heterochrony are relatively new, and a comprehensive study of the relative timing of ossification of skeletal elements has not been used to identify instances of sequence heterochrony across Amphibia. In this study, a new version of the program Parsimov-based genetic inference (PGi) was used to identify shifts in ossification sequences across all extant orders of amphibians, for all major structural units of the skeleton. PGi identified a number of heterochronic sequence shifts in all analyses, the most interesting of which seem to be tied to differences in metamorphic patterns among major clades. Early ossification of the vomer, premaxilla, and dentary is retained by Apateon caducus and members of Gymnophiona and Urodela, which lack the strongly biphasic development seen in anurans. In contrast, bones associated with the jaws and face were identified as shifting late in the ancestor of Anura. The bones that do not shift late, and thereby occupy the earliest positions in the anuran cranial sequence, are those in regions of the skull that undergo the least restructuring throughout anuran metamorphosis. Additionally, within Anura, bones of the hind limb and pelvic girdle were also identified as shifting early in the sequence of ossification, which may be a result of functional constraints imposed by the drastic metamorphosis of most anurans. PMID- 24074281 TI - Expression patterns of Wnt genes in the venom claws of centipedes. AB - The venom claws of centipedes, also known as forcipules, represent an evolutionary novelty that must have arisen in the centipede stem species, as they are not found in any other myriapods. The developmental-genetic changes that are involved in the origin of novelties are of considerable interest. It has previously been shown that centipede forcipules have a unique Hox code. However, this is a combinatorial code: no single Hox gene has a forcipule-specific expression. Here, we focus on Wnt genes. Two genes of this family show forcipule specific expression in the "model centipede" Strigamia maritima: Wnt7 and Wnt11. For Wnt7, this forcipular expression zone seems to be a new one, which has arisen in evolution subsequently to other expression zones of the same gene. However, for Wnt11, the forcipule-specific expression probably arose by reduction of a more general pattern that originally included most or all of the limbs of an ancestral myriapod. Thus the developmental-genetic basis of the evolutionary change that turned the first pair of walking legs into venom claws is complex, involving different types of change in expression pattern. This sort of complexity is likely to be the case regarding evolutionary changes in morphology in general. Whether the origins of those features that can be considered as novelties are different in terms of their developmental-genetic basis from more routine evolutionary changes remains an open question. PMID- 24074282 TI - Expression of Wnt pathway genes in polyps and medusa-like structures of Ectopleura larynx (Cnidaria: Hydrozoa). AB - The canonical Wnt signaling pathway is conserved in its role in axial patterning throughout Metazoa. In some hydrozoans (Phylum Cnidaria), Wnt signaling is implicated in oral-aboral patterning of the different life cycle stages-the planula, polyp and medusa. Unlike most hydrozoans, members of Aplanulata lack a planula larva and the polyp instead develops directly from a brooded or encysted embryo. The Aplanulata species Ectopleura larynx broods such embryos within gonophores. These gonophores are truncated medusae that remain attached to the polyps from which they bud, and retain evolutionary remnants of medusa structures. In E. larynx, gonophores differ between males and females in their degree of medusa truncation, making them an ideal system for examining truncated medusa development. Using next-generation sequencing, we isolated genes from Wnt signaling pathways and examined their expression in E. larynx. Our data are consistent with the Wnt pathway being involved in axial patterning of the polyp and truncated medusa. Changes in the spatial expression of Wnt pathway genes are correlated with the development of different oral structures in male and female gonophores. The absence of expression of components of the Wnt pathway and presence of a Wnt pathway antagonist SFRP in the developing anterior end of the gonophore suggest that downregulation of the Wnt pathway could play a role in medusa reduction in E. larynx. PMID- 24074283 TI - Evolution of full-thickness macular hole formation in a case of myopic foveoschisis. AB - PURPOSE: To describe the evolution of a full-thickness macular hole in myopic foveoschisis. METHODS: A 62-year-old woman with myopic foveoschisis developed a full-thickness maculare hole after 36 months. The evolution of the macular hole was observed by optical coherence tomography (Stratus OCT3). RESULTS: During the first stages of macular hole formation, a small triangular foveolar retinal detachment, with corresponding elevation of inner segment/outer segment junction line, was observed. The retinal detachment later enlarged. A concrete intraretinal columnar structure, extending between the inner fovea's layer and the roof of foveal detachment, was observed. CONCLUSION: The so-called columnar structure, detected in our case, possibly transmitted the vitreomacular traction contributing to the opening of the RD roof, the outer lamellar macular hole formation, and finally in the creation of a full-thickness macular hole. PMID- 24074284 TI - Carbohydrate utilization and metabolism is highly differentiated in Agaricus bisporus. AB - BACKGROUND: Agaricus bisporus is commercially grown on compost, in which the available carbon sources consist mainly of plant-derived polysaccharides that are built out of various different constituent monosaccharides. The major constituent monosaccharides of these polysaccharides are glucose, xylose, and arabinose, while smaller amounts of galactose, glucuronic acid, rhamnose and mannose are also present. RESULTS: In this study, genes encoding putative enzymes from carbon metabolism were identified and their expression was studied in different growth stages of A. bisporus. We correlated the expression of genes encoding plant and fungal polysaccharide modifying enzymes identified in the A. bisporus genome to the soluble carbohydrates and the composition of mycelium grown compost, casing layer and fruiting bodies. CONCLUSIONS: The compost grown vegetative mycelium of A. bisporus consumes a wide variety of monosaccharides. However, in fruiting bodies only hexose catabolism occurs, and no accumulation of other sugars was observed. This suggests that only hexoses or their conversion products are transported from the vegetative mycelium to the fruiting body, while the other sugars likely provide energy for growth and maintenance of the vegetative mycelium. Clear correlations were found between expression of the genes and composition of carbohydrates. Genes encoding plant cell wall polysaccharide degrading enzymes were mainly expressed in compost-grown mycelium, and largely absent in fruiting bodies. In contrast, genes encoding fungal cell wall polysaccharide modifying enzymes were expressed in both fruiting bodies and vegetative mycelium, but different gene sets were expressed in these samples. PMID- 24074285 TI - The molecular mechanisms on glomangiopericytoma invasion. AB - PURPOSE: To observed the imaging and pathological features of the glomangiopericytoma. EXPERIMENTAL DESIGN: In this paper we report a typical case of glomangiopericytoma arising in the skull base area and summarize the clinical manifestations, imaging and pathological features of such diseases. RESULTS: Immunohistochemical staining confirmed the tumor cells were strongly positive to Vim, SMA, MSA and negative to CD31, CD34. Partial cells were positive to FVIII. The imaging can't confirm the diagnosis but indicate the the tumor has intact envelope.The cells in the tumor envelope is positive to Vim and negative SMA and FVIII. These findings were compatible with glomangiopericytoma and the cells in the tumor envelope is not glomangiopericytoma cells. CONCLUSION: In view of the clinical and pathological features of the glomangiopericytoma, we believe that the surgery is the best treatment so far and the tumor can be resected completely. The above results can be preliminary reason to explain the low recurrence of such diseases. PMID- 24074286 TI - Meta-analysis of all-trans retinoic acid-linked arsenic trioxide treatment for acute promyelocytic leukemia. AB - OBJECTIVES: To explore the combination therapy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO, As2O3) on acute promyelocytic leukemia (APL). METHODS: A meta-analysis of six studies was performed. Among 415 included cases, 165 cases were in the ATRA + ATO group, 129 cases in the ATRA-alone group, and 121 cases in the ATO-alone group. The complete remission (CR) rate and incidences of three groups were compared, respectively, between the therapies of ATRA + ATO with ATRA alone, ATRA + ATO with ATO-alone, and ATRA with ATO. RESULTS: The assessment results showed that ATRA + ATO therapy significantly improved the CR rate and decreased the incidences of cutaneous reaction compared with ATRA-alone (P < 0.05). However, incidence of liver injury was higher in the ATRA + ATO and ATO alone groups than that in ATRA-alone group (P < 0.05). Difference in the complications between ATRA + ATO therapy and ATO-alone was not significant (P > 0.05). CONCLUSIONS: In conclusion, we suggest low-dose ATRA and ATO combination therapy may be more effective for the treatment of APL. PMID- 24074287 TI - Therapeutic evaluation of a microbioartificial liver with recombinant HepG2 cells for rats with hepatic failure. AB - BACKGROUND: HepG2/(ArgI+OTC)4 (previously constructed) is a recombinant human liver cell line with a strong ability to reduce ammonia in vitro. However, its application value ex vivo has not been investigated. OBJECTIVES: To examine the efficacy of HepG2/(ArgI+OTC)4 cells in a micro-bioartificial liver (micro-BAL) device for application ex vivo. METHODS: A simple micro-BAL device containing a microbioreactor and a small-type peristaltic pump was installed. The rats with hepatic failure were randomly divided into three groups (n = 10) and were treated with different micro-BAL loaded HepG2/(ArgI+OTC)4 cells, HepG2 cells and control (without cells), respectively. Changes in the liver and kidney function of the rats were determined before and after the treatment. The lifespan of the rats were observed and recorded. RESULTS: Despite the difference in survival time between experimental groups of rat model was not statistically significant, the capacity of HepG2/(ArgI+OTC)4 cells treatment group for tolerance and detoxifying ammonia was increased much more than that of HepG2 cells (p < 0.05), and other biochemical indicators of HepG2/(ArgI+OTC)4 cells treatment group were also better than that of HepG2 cells treatment group (p < 0.05). CONCLUSIONS: HepG2/(ArgI+OTC)4 cells can provide a better biological support for rats with hepatic failure in a short period of time, and they may be used as a convenient and useful choice for further cell material research of BAL. PMID- 24074288 TI - Robot-assisted radical cystectomy in octogenarians. AB - BACKGROUND AND PURPOSE: Radical cystectomy is the standard of care for muscle invasive bladder cancer; however, few patients over age 75 undergo cystectomy. Morbidity and mortality rates in this age group approach 60% and 10%, respectively. We sought to determine if minimally invasive surgery, in the form of robot-assisted radical cystectomy (RARC), may reduce morbidity and mortality associated with this operation in elderly patients. PATIENTS AND METHODS: After Institutional Review Board approval, all RARC performed between 2009 and 2012 from one institution were reviewed, and 23 cases in patients over the age of 80 were identified. Data analyzed included age, indication for cystectomy, American Society of Anesthesiologists score (ASA), Charlson Comorbidity Index, pathologic stage, estimated blood loss, transfusion rate, and 90-day morbidity and mortality rate. RESULTS: Twenty-three patients over the age of 80 years underwent RARC by a single surgeon (IT) between April 2009 and October 2012. Average age was 83.7 years (range 80-88 years) with average Charlson Comorbidity Index score of 4.3 (age-weighted 8.3). Indication for cystectomy was oncologic in all cases (21 bladder malignancy, 2 hemorrhagic cystitis in the setting of prostate cancer). The average blood loss and operative times were 208 mL (range 50-650 mL) and 253 minutes (range 175-365 min). Seven (30.4%) patients needed blood transfusions. The average length of hospital stay was 8.2 days (range 6-24 days). The overall complication rate within 90 days was 34.8% (8 patients) with no mortality. Longest follow-up is 34 months. CONCLUSIONS: RARC should be strongly considered for patients over the age of 80 with clinical indications for cystectomy. The complication rate is acceptable even in complicated patients with multiple comorbidities and those with previous abdominal surgery or pelvic radiation. Hospital stay remains shorter than with open surgery, and complication rates appear to be lower than previously reported for this age group. PMID- 24074289 TI - Unrevealing culture-negative severe sepsis. AB - Sepsis involves a wide array of sources and microorganisms, only a fraction of which are microbiologically documented. Culture-negative sepsis poses special diagnostic challenges to both clinicians and microbiologists and further questions the validity of sepsis definitions. PMID- 24074290 TI - Characterization of a novel international clonal complex (CC32) of Acinetobacter baumannii with epidemic potential. AB - Twelve non-replicate Acinetobacter baumannii isolates from five European hospitals, Kuwait, and the US military healthcare system collected between 1980 and 2005 revealed a new clone, CC32. These included representative isolates of outbreaks/cross-infections. Antimicrobial susceptibility and carbapenem-resistant genetic traits varied. The widespread occurrence, the association with an outbreak and the carbapenem resistance indicate that CC32 has epidemic potential. PMID- 24074291 TI - Comparative evaluation of olopatadine 0.01% combined fluorometholone 0.1% treatment versus olopatadine 0.01% combined ketorolac 0.4% treatment in patients with acute seasonal allergic conjunctivitis. AB - PURPOSE: To evaluate the therapeutic effects of low-effective steroid fluorometholone 0.1% and non-steroidal anti-inflammatory ketorolac 0.4% when concomitantly used with olopatadine 0.01% in relieving clinical signs and symptoms of acute seasonal allergic conjunctivitis (SAC). METHODS: In this randomized, placebo-controlled, multi-center study, 104 eyes of 52 patients with the diagnosis of SAC were conducted. The patients were assigned into two groups to receive either olopatadine and fluorometholone one eye and placebo in the contralateral eye or olopatadine and ketorolac one eye and placebo in the contralateral. The clinical signs (chemosis, mucus secretion, eyelid edema) and symptoms (itching, redness, tearing, burning) of the patients were evaluated by summing up the scores using a 3-point scale. Results were analyzed by Mann Whitney U test, p values less than 0.05 were defined as significant. RESULTS: All parameters were improved less amount on the first day of the treatment in both groups, however, significant reduction in clinical signs and symptoms were seen on the 10th day compared with those receiving placebo. Fluorometholone was found superior to ketorolac in reducing redness, mucus secretion, chemosis and eyelid edema (p = 0.032 for redness, p = 0.028 for mucus secretion, p = 0.030 for chemosis, p = 0.042 for eyelid edema) and both drugs were similar in alleviating the symptoms itching, burning and tearing (p = 0.074 for itching, p = 0.064 for burning, p = 0.072 for tearing). CONCLUSIONS: Fluorometholone was better than ketorolac in relieving redness, chemosis, mucus secretion and eyelid edema when concomitantly used with olopatadine, however, these two drugs were found equal in attenuating the symptoms itching, burning and tearing. PMID- 24074292 TI - Synthesis of a TREN in which the aryl substituents are part of a 45 atom macrocycle. AB - A substituted TREN has been prepared in which the aryl groups in (ArylNHCH2CH2)3N are substituted at the 3- and 5-positions with a total of six OCH2(CH2)nCH?CH2 groups (n = 1, 2, 3). Molybdenum nitride complexes, [(ArylNCH2CH2)3N]Mo(N), have been isolated as adducts that contain B(C6F5)3 bound to the nitride. Two of these [(ArylNCH2CH2)3N]Mo(NB(C6F5)3) complexes (n = 1 and 3) were crystallographically characterized. After removal of the borane from [(ArylNCH2CH2)3N]Mo(NB(C6F5)3) with PMe3, ring-closing olefin metathesis (RCM) was employed to join the aryl rings with OCH2(CH2)nCH?CH(CH2)nCH2O links (n = 1-3) between them. RCM worked best with a W(O)(CHCMe3)(Me2Pyr)(OHMT)(PMe2Ph) catalyst (OHMT = hexamethylterphenoxide, Me2Pyr = 2,5-dimethylpyrrolide) and n = 3. The macrocyclic ligand was removed from the metal through hydrolysis and isolated in 70-75% yields relative to the borane adducts. Crystallographic characterization showed that the macrocyclic TREN ligand in which n = 3 contains three cis double bonds. Hydrogenation produced a TREN in which the three links are saturated, i.e., O(CH2)10O. PMID- 24074293 TI - Antinociceptive effect of the essential oil of tarragon (Artemisia dracunculus). AB - CONTEXT: Tarragon [Artemisia dracunculus L. (Asteraceae)] is used as a commercial flavoring and in perfumery. In traditional folk medicine, tarragon has been used for treatment of pain and gastrointestinal disturbances. OBJECTIVE: This study investigated the antinociceptive effect of the essential oil of A. dracunculus (EOAD) in various experimental models. MATERIALS AND METHODS: The median lethal dose (LD50) of EOAD was estimated using the method of Lorke. The antinociceptive effect was assessed using chemical (formalin and acetic acid) and thermal (hot plate) nociceptive tests in rats and mice. In all experiments, EOAD was administered intraperitoneally at the doses of 10, 30, 100 and 300 mg/kg. RESULTS: In the acute toxicity test, the value of estimated LD50 for EOAD was 1250 mg/kg. EOAD (100 and 300 mg/kg) significantly reduced (p < 0.001) the pain response in the first (59.5 and 91.4%) and second (52.5 and 86.3%) phases of the formalin test, respectively. Central involvement in analgesic profile was confirmed by the hot-plate test, in which the EOAD showed a significant analgesic activity by increasing latency time. EOAD (10, 30, 100 and 300 mg/kg) significantly (p < 0.001) inhibited (89, 95, 97 and 97%) the nociception produced by acetic acid. Naloxone failed to antagonize the antinociceptive effect of the essential oil in the acetic acid-induced writhing test. It seems that mechanism(s) other than opioid receptors is (are) involved in the analgesic effect of EOAD. CONCLUSIONS: This study reported the peripheral and central antinociceptive activity of the EOAD and rationalized the traditional use of the plant in the treatment of different painful conditions. PMID- 24074294 TI - Evaluation of health care providers' role transition and satisfaction in hospital at-home for chronic obstructive pulmonary disease exacerbations: a survey study. AB - BACKGROUND: Hospital-at-home is an accepted alternative for usual hospital treatment for patients with a Chronic Obstructive Pulmonary Disease (COPD) exacerbation. The introduction of hospital-at-home may lead to changes in health care providers' roles and responsibilities. To date, the impact on providers' roles is unknown and in addition, little is known about the satisfaction and acceptance of care providers involved in hospital-at-home. METHODS: Objective of this survey study was to investigate the role differentiation, role transitions and satisfaction of professional care providers (i.e. pulmonologists, residents, hospital respiratory nurses, generic and specialised community nurses and general practitioners) from 3 hospitals and 2 home care organisations, involved in a community-based hospital-at-home scheme. A combined multiple-choice and open-end questionnaire was administered in study participants. RESULTS: Response rate was 10/17 in pulmonologists, 10/23 in residents, 9/12 in hospital respiratory nurses, 15/60 in generic community nurses, 6/10 in specialised community nurses and 25/47 in general practitioners. For between 66% and 100% of respondents the role in early discharge was clear and between 57% and 78% of respondents was satisfied with their role in early discharge. For nurses the role in early discharge was different compared to their role in usual care. 67% of generic community nurses felt they had sufficient knowledge and skills to monitor patients at home, compared to 100% of specialised community nurses. Specialised community nurses felt they should monitor patients. 60% of generic community nurses responded they should monitor patients at home. 78% of pulmonologists, 12% of general practitioners, 55% of hospital respiratory nurses and 48 of community nurses was satisfied with early discharge in general. For coordination of care 29% of community nurses had an unsatisfied response. For continuity of care this was 12% and 10% for hospital respiratory nurses and community nurses, respectively. CONCLUSION: A community-based early assisted discharge for COPD exacerbations is possible and well accepted from the perspective of health care providers' involved. Satisfaction with the different aspects is good and the transfer of patients in the community while supervised by generic community nurses is possible. Attention should be paid to coordination and continuity of care, especially information transfer between providers. PMID- 24074295 TI - Gromwell (Lithospermum erythrorhizon) supplementation enhances epidermal levels of ceramides, glucosylceramides, beta-glucocerebrosidase, and acidic sphingomyelinase in NC/Nga mice. AB - We have previously reported that dietary gromwell (Lithospermum erythrorhizon; LE) prevents the development of atopic dermatitis (AD) with increased epidermal levels of total ceramide (Cer), the major lipid maintaining epidermal barrier. In this study, we investigated whether the increased level of total Cer induced by dietary LE would be related to the altered metabolism of glucosylceramide (GlcCer) and sphingomyelin (SM), two major precursor lipids in Cer generation. NC/Nga mice, an animal model of AD, were fed a control diet (group CA: atopic control) or a diet with 70% ethanol LE extracts (1% in diet; group LE) for 10 weeks. Individual species of Cer, GlcCer, and SM were analyzed by high performance thin layer chromatography. In the epidermis of group CA, total Cer (including Cer2 and Cer5-7) and total GlcCer (including GlcCer-B/C/D) were significantly reduced; these levels in group LE were increased to levels similar to the normal control group of BALB/c mice (group C). In addition, protein expressions and activities of beta-glucocerebrosidase (beta-GlcCer'ase) and acidic sphingomyelinase (aSMase), enzymes for GlcCer or SM hydrolysis, respectively, were increased in group LE. However, alterations of Cer1, Cer3/4, GlcCer-A, and all SM species (including SM1-3) were not significant among groups C, CA, and LE. Dietary gromwell increases GlcCer-B/C/D, and further enhances the generation of Cer2 and Cer5-7 with high protein expressions and activities of beta-GlcCer'ase and aSMase. PMID- 24074296 TI - Moscatilin induces apoptosis and mitotic catastrophe in human esophageal cancer cells. AB - Moscatilin, a bibenzyl derivative from the orchid Dendrobium loddigesii, has been shown to possess anticancer activity. We examined the effect of moscatilin on human esophageal cancer cells, including squamous cell carcinoma (SCC) and adenocarcinoma (ADC) cells and its possible mechanisms. Moscatilin suppressed the growth of both the histological cell lines in a dose- and time-dependent manner. Morphological changes indicative of apoptosis and mitotic catastrophe were observed following moscatilin treatment. The population of cells in the sub-G1 phase and polyploidy phase significantly increased after treatment. Immunofluorescence revealed multipolar mitosis and subsequent multinucleation in moscatilin-treated cells, indicating the development of mitotic catastrophe. Western blot showed a marked increase in expressions of polo-like kinase 1 and cyclin B1 after exposure to moscatilin. In conclusion, moscatilin inhibits growth and induces apoptosis and mitotic catastrophe in human esophageal SCC- and ADC derived cell lines, indicating that moscatilin has broad potential against esophageal cancer. PMID- 24074297 TI - Top-down mass spectrometry on tissue extracts and biofluids with isoelectric focusing and superficially porous silica liquid chromatography. AB - Top-down mass spectrometry (MS) has emerged as a powerful complement to peptide based proteomics. Despite advancements, the field has had limited application to clinical proteomics investigations due to the complexity and poor dynamic range of chromatography used to separate intact proteins from tissue and biofluids. To address these limitations, we developed a two-dimensional (2D) chromatography platform that includes isoelectric focusing (IEF) through immobilized pH gradient and superficially porous liquid chromatography (SPLC). Analysis of standard proteins demonstrates compatibility of IEF-SPLC processing and high resolving power MS analysis with results showing ~7.0 femtomole detection limits and linear spectral response for proteins fractionated over ~4 log sample loads. For proteins from heart myofibrils and cerebrospinal fluid (CSF), compared to one dimensional SPLC-MS, the 2D IEF-SPLC-MS platform resulted in a 5-6* increase in the number of unique monoisotopic masses observed <30 kDa and an ~4* improved mass range enabling the observation of proteins >200 kDa. In the heart myofibrils, common protein proteoforms observed were associated with phosphorylation of contractile proteins with results showing that quantitative evaluation of their PTM stoichiometry was possible despite differentially modified forms being fractionated into separate pI compartments. In CSF, diverse protein mutations and PTM classes were also observed, including differentially glycosylated protein forms separated to different pI. Results also demonstrate that by the generation of IEF-SPLC protein libraries by fraction collection, the platform enables prospective protein identification and proteoform analysis investigations by complementary top-down and bottom-up strategies. Overall, the 2D platform presented may provide the speed, dynamic range, and detection limits necessary for routine characterization of proteoform-based biomarkers from biofluids and tissues. PMID- 24074298 TI - Tempol-nebivolol therapy potentiates hypotensive effect increasing NO bioavailability and signaling pathway. AB - Nebivolol is a third generation beta blocker with endothelial nitric oxide synthase (eNOS) agonist properties. Considering the role of reactive oxygen species (ROS) in the uncoupling of eNOS, we hypothesized that the preadministration of an antioxidant as tempol, could improve the hypotensive response of nebivolol in normotensive animals increasing the nitric oxide (NO) bioavailability by a reduction of superoxide (O2(*-)) basal level production in the vascular tissue. Male Sprague Dawley rats were given tap water to drink (control group) or tempol (an antioxidant scavenger of superoxide) for 1 week. After 1 week, Nebivolol, at a dose of 3 mg/kg, was injected intravenously to the control group or to the tempol-treated group. Mean arterial pressure, heart rate, and blood pressure variability were evaluated in the control, tempol, nebivolol, and tempol nebivolol groups, as well as, the effect of different inhibitor as Nbeta-nitro-l-arginine methyl ester (L-NAME, a Nitric oxide synthase blocker) or glybenclamide, a KATP channel inhibitor. Also, the expression of alpha,beta soluble guanylate cyclase (sGC), phospho-eNOS, and phospho-vasodilator-stimulated phosphoprotein (P-VASP) were evaluated by Western Blot and cyclic guanosine monophosphate (cGMP) levels by an enzyme-linked immunosorbent assay (ELISA) commercial kit assay. We showed that pretreatment with tempol in normotensive rats produces a hypotensive response after nebivolol administration through an increase in the NO bioavailability and sGC, improving the NO/cGMP/protein kinase G (PKG) pathway compared to that of the nebivolol group. We demonstrated that tempol preadministration beneficiates the response of a third-generation beta blocker with eNOS stimulation properties, decreasing the basal uncoupling of eNOS, and improving NO bioavailability. Our results clearly open a possible new strategy therapeutic for treating hypertension. PMID- 24074300 TI - Participation in social internet-based activities: five seniors' intervention processes. AB - OBJECTIVE: To explore how client-centred occupational therapy intervention processes for participation in meaningful Social Internet-Based Activities (SIBAs) can be designed, and to explore the influences of participation in SIBAs on seniors' social activities and social contacts. METHOD: A qualitative, descriptive, multiple-case study was conducted, and an intervention was provided to the five participants, who were aged 65-85. Data were collected through assessment tools, field notes, and interviews. RESULTS: The participants' needs and challenges related to SIBAs varied during the intervention processes. Individual-adapted support was provided for the seniors (by the occupational therapist) to managing the introduction to different SIBAs, their appearance on the internet, and the lack of privacy. The association between the seniors' participation in SIBAs and their satisfaction with these activities, as well as their social contacts, requires further exploration. CONCLUSIONS: Client-centred occupational therapy interventions can support seniors' participation in SIBAs and their self-reliance when performing these activities. PMID- 24074299 TI - The EVIDENT-trial: protocol and rationale of a multicenter randomized controlled trial testing the effectiveness of an online-based psychological intervention. AB - BACKGROUND: Depressive disorders are among the leading causes of worldwide disability with mild to moderate forms of depression being particularly common. Low-intensity treatments such as online psychological treatments may be an effective way to treat mild to moderate depressive symptoms and prevent the emergence or relapse of major depression. METHODS/DESIGN: This study is a currently recruiting multicentre parallel-groups pragmatic randomized-controlled single-blind trial. A total of 1000 participants with mild to moderate symptoms of depression from various settings including in- and outpatient services will be randomized to an online psychological treatment or care as usual (CAU). We hypothesize that the intervention will be superior to CAU in reducing depressive symptoms assessed with the Personal Health Questionnaire (PHQ-9, primary outcome measure) following the intervention (12 wks) and at follow-up (24 and 48 wks). Further outcome parameters include quality of life, use of health care resources and attitude towards online psychological treatments. DISCUSSION: The study will yield meaningful answers to the question of whether online psychological treatment can contribute to the effective and efficient prevention and treatment of mild to moderate depression on a population level with a low barrier to entry. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: NCT01636752. PMID- 24074302 TI - Synthesis of titanate nanotube-CdS nanocomposites with enhanced visible light photocatalytic activity. AB - CdS-1D titanate nanotubes (CdS/TNTs) nanocomposites have been synthesized via a facile one-step in situ hydrothermal method. The structure and properties of CdS/TNTs nanocomposites have been characterized by X-ray diffraction, UV-vis diffuse reflectance spectra, transmission electron microscopy, photoluminescence spectra, nitrogen adsorption-desorption, and electron spin resonance spectra. The results show that (i) as compared to blank-CdS, it is found that the morphology of CdS in the CdS/TNTs nanocomposites can be finely tuned by TNTs formed during the one-step in situ hydrothermal process; and (ii) the CdS/TNTs nanocomposites exhibit remarkably much higher visible light photocatalytic activity than both blank-CdS and blank-TNT toward aerobic selective oxidation of alcohols under mild conditions. Three integrative factors lead to such a drastic photoactivity enhancement for CdS/TNTs nanocomposites. The first one is the different morphology of CdS in the CdS/TNTs nanocomposites from blank-CdS. The second one is the prolonged lifetime of photogenerated electron-hole pairs from CdS in CdS/TNTs nanocomposites under visible light irradiation. The third one is the higher surface area and adsorption capacity of CdS/TNTs nanocomposites than blank CdS. In addition, the possible reaction mechanism for photocatalytic selective oxidation of alcohols over CdS/TNTs nanocomposites has also been investigated using the radical scavengers technique. It is hoped that this work could promote further interest in fabrication of various 1D TNT-based composite materials and their application to visible-light-driven photocatalytic selective organic transformations. PMID- 24074301 TI - Analysis of HIV quasispecies suggests compartmentalization in the liver. AB - Liver disease is now a major cause of morbidity and mortality among persons infected with the human immunodeficiency virus (HIV). An increasing body of evidence suggests that HIV infection is associated with exacerbated liver fibrosis and that HIV has the ability to infect several hepatic cell types. Despite the recognized existence of genetically distinct subpopulations of HIV in the central nervous system and genital tract, viral diversity and compartmentalization in the liver have not been explored extensively. Therefore, phylogenetic analysis was performed on full-length env and nef sequences for four patients. Distinct clustering of viral variants was observed for all patients in both areas of the genome. Statistical evidence of HIV compartmentalization in the liver was demonstrated in 85.4% of comparisons. Signature sequence analysis identified several liver-specific amino acids in all patients. Thus, the current study demonstrates statistically significant evidence for HIV compartmentalization in the liver. Additionally, these data suggest that the hepatic microenvironment harbors unique selective pressures that drive viral adaptation. PMID- 24074303 TI - Improvement of gastrointestinal health status in subjects consuming Lactobacillus reuteri NCIMB 30242 capsules: a post-hoc analysis of a randomized controlled trial. AB - OBJECTIVE: Gastrointestinal (GI) symptoms are conditions that are frequently observed in clinical practice. A post-hoc analysis has been undertaken to evaluate the effect of bile salt hydrolase-active L. reuteri NCIMB 30242 on GI health status based on Rome III questionnaire response in otherwise healthy hypercholesterolemic subjects. RESEARCH DESIGN/METHODS: A total of 127 subjects received either L. reuteri NCIMB 30242 or placebo capsules over a 9-week intervention in a randomized, double-blind, placebo-controlled, parallel-arm, multicenter study. Subjects were asked to complete the Rome III diagnostic GI questionnaire prior to the baseline and end point visits of the clinical study. MAIN OUTCOME MEASURE: GI health status was evaluated, per questionnaire, by assessing all questions with 5- or 7-point response scales for symptoms of the stomach and intestines. RESULTS: Subjects receiving L. reuteri NCIMB 30242 reported significant improvements in general GI health status (p = 0.029) and in symptoms related to diarrhea (p = 0.018) as compared to placebo over the intervention period. Further, a greater proportion of L. reuteri-treated subjects showed improved general GI health status (p = 0.042) and improved diarrhea symptoms (p = 0.03). CONCLUSIONS: L. reuteri NCIMB 30242 capsules appear to be well tolerated and potentially beneficial for GI health status. Further clinical investigation is warranted for the treatment of functional GI disorders. PMID- 24074304 TI - The effect of microdosimetric 12C6+ heavy ion irradiation and Mg2+ on canthaxanthin production in a novel strain of Dietzia natronolimnaea. AB - BACKGROUND: Dietzia natronolimnaea is one of the most important bacterial bioresources for high efficiency canthaxanthin production. It produces the robust and stable pigment canthaxanthin, which is of special interest for the development of integrated biorefineries. Mutagenesis employing 12C6+ irradiation is a novel technique commonly used to improve microorganism productivity. This study presents a promising route to obtaining the highest feasible levels of biomass dry weight (BDW), and total canthaxanthin by using a microdosimetric model of 12C6+ irradiation mutation in combination with the optimization of nutrient medium components. RESULTS: This work characterized the rate of both lethal and non-lethal dose mutations for 12C6+ irradiation and the microdosimetric kinetic model using the model organism, D. natronolimnaea svgcc1.2736. Irradiation with 12C6+ ions resulted in enhanced production of canthaxanthin, and is therefore an effective method for strain improvement of D. natronolimnaea svgcc1.2736. Based on these results an optimal dose of 0.5-4.5 Gy, Linear energy transfer (LET) of 80 keV MUm-1and energy of 60 MeV u-1 for 12C6+ irradiation are ideal for optimum and specific production of canthaxanthin in the bacterium. Second-order empirical calculations displaying high R-squared (0.996) values between the responses and independent variables were derived from validation experiments using response surface methodology. The highest canthaxanthin yield (8.14 mg) was obtained with an optimized growth medium containing 21.5 g L-1 D-glucose, 23.5 g L-1 mannose and 25 ppm Mg2+ in 1 L with an irradiation dose of 4.5 Gy. CONCLUSIONS: The microdosimetric 12C6+ irradiation model was an effective mutagenic technique for the strain improvement of D. natronolimnaea svgcc1.2736 specifically for enhanced canthaxanthin production. At the very least, random mutagenesis methods using 12C6+ions can be used as a first step in a combined approach with long-term continuous fermentation processes. Central composite design-response surface methodologies (CCD-RSM) were carried out to optimize the conditions for canthaxanthin yield. It was discovered D glucose, Mg2+ and mannose have significant influence on canthaxanthin biosynthesis and growth of the mutant strain. PMID- 24074305 TI - Effects of N-acetyl-L-cysteine and hyaluronic acid on HBOC-201-induced systemic and cerebral vasoconstriction in the rat. AB - Hemoglobin-based oxygen carrier-201 (HBOC) was developed as a resuscitative fluid but concerns exist over potentially adverse vasoconstriction. This study evaluated whether concurrent IV (intra venous) N-acetyl-L-cysteine (NAC) or hyaluronic acid (HA) would attenuate HBOC-associated vasoconstriction, assessed by systemic blood pressures and cerebral pial microvasculature, when administered to healthy, anesthetized rats. Rats (8-9/group) received a 30 min infusion of 3 ml/kg HBOC, HBOC plus 600 mg/kg NAC (HBOC/NAC), HBOC plus 1.5 mg/kg HA (HBOC/HA) or 3 ml/kg Albumin. Mean (MAP) and systolic (SBP) blood pressures, blood chemistries and cerebral pial vessel diameters were measured at baseline, end of infusion, and intermittently for an additional 90 min. HBOC caused immediate and sustained increases in SBP and MAP (35.3 +/- 3.6 and 29.1 +/- 2.5 mm Hg peak increases above baseline, respectively; mean +/- SEM) and immediate but progressive vasoconstriction (11 um maximum reduction) in medium-sized (50-100 um) pial arterioles. When NAC was co-administered, blood pressure changes were attenuated and vessel changes were abolished. Similar trends were noted with co administration of HA but were not statistically different from HBOC-alone. Small sized (< 50 um) pial vessels and blood parameters showed no differences from baseline or among groups. No adverse clinical signs were observed. We demonstrated that it is possible for adjuvant drugs to reduce the vasoconstriction associated with HBOC-201. Coinfusion of the anti-oxidant NAC mitigated HBOC-201-associated increases in blood pressures and vasoconstriction in medium-sized cerebral pial vessels. The drag-reducing polymer HA may be more effective at a higher dose as a similar but non-significant trend was observed. PMID- 24074306 TI - Design and characterization of microcrystals for enhanced dissolution rate of celecoxib. AB - Poor aqueous solubility and bioavailability of drugs are one of the important factors affecting the absorption of drugs and consequently their therapeutic effectiveness. Celecoxib is a widely used anti-inflammatory agent, with special use in rheumatoid arthritis. It belongs to biopharmaceutical classification system (BCS) class II drug with low solubility and high permeability. The present study was aimed to prepare and characterize the microcrystals of celecoxib, employing in situ micronization technique by rapid solvent change approach to enhance the solubility and dissolution rate and to optimize the solvent and anti solvent ratio (v/v) using hydrophilic stabilizers such as guar gum, maltodextrin and PVP K30. The prepared formulations were evaluated for percentage crystal yield, mean particle size, drug content and in vitro dissolution studies. Amongst the formulations prepared (F1-F9), F6 formulation containing maltodextrin as stabilizing agent at 0.1% w/v concentration with 1:6 ratio of solvent to anti solvent (v/v) respectively was considered as optimized formulation in which percentage drug release was found to be 89.33% within 60 minutes in comparison with that of the pure drug dissolution of 30.26% only within 60 minutes. Characterization studies like SEM, DSC and XRD indicate the solubility enhancement of celecoxib microcrystals due to decrease in particle size when compared to that of pure drug. FT-IR spectroscopy studies revealed that there is no chemical interaction between the drug and stabilizer and crystalline habit modification occurs in the microcrystals without any polymorphic changes. PMID- 24074307 TI - Commentary: salvage medical therapy for acute severe colitis - ciclosporin or infliximab? PMID- 24074308 TI - Commentary: salvage medical therapy for acute severe colitis - ciclosporin or infliximab? Author's reply. PMID- 24074309 TI - Commentary: H. pylori eradication therapy after subtotal gastrectomy for gastric cancer - can the qualitative be quantified? PMID- 24074310 TI - Commentary: H. pylori eradication therapy after subtotal gastrectomy for gastric cancer - can the qualitative be quantified? Authors' reply. PMID- 24074311 TI - Letter: ciclosporin or infliximab in acute ulcerative colitis - still undecided. PMID- 24074312 TI - Letter: ciclosporin or infliximab in acute ulcerative colitis - still undecided; authors' reply. PMID- 24074313 TI - Influence of the nanofibrous morphology on the catalytic activity of NiO nanostructures: an effective impact toward methanol electrooxidation. AB - In this study, the influence of the morphology on the electrocatalytic activity of nickel oxide nanostructures toward methanol oxidation is investigated. Two nanostructures were utilized: nanoparticles and nanofibers. NiO nanofibers have been synthesized by using the electrospinning technique. Briefly, electrospun nanofiber mats composed of polyvinylpyrolidine and nickel acetate were calcined at 700 degrees C for 1 h. Interestingly, compared to nanoparticles, the nanofibrous morphology strongly enhanced the electrocatalytic performance. The corresponding current densities for the NiO nanofibers and nanoparticles were 25 and 6 mA/cm2, respectively. Moreover, the optimum methanol concentration increased to 1 M in case of the nanofibrous morphology while it was 0.1 M for the NiO nanoparticles. Actually, the one-dimensional feature of the nanofibrous morphology facilitates electrons' motion which enhances the electrocatalytic activity. Overall, this study emphasizes the distinct positive impact of the nanofibrous morphology on the electrocatalytic activity which will open a new avenue for modification of the electrocatalysts. PMID- 24074314 TI - Promoting healthy growth and preventing childhood stunting: a global challenge. PMID- 24074315 TI - The World Health Organization's global target for reducing childhood stunting by 2025: rationale and proposed actions. AB - In 2012, the World Health Organization adopted a resolution on maternal, infant and young child nutrition that included a global target to reduce by 40% the number of stunted under-five children by 2025. The target was based on analyses of time series data from 148 countries and national success stories in tackling undernutrition. The global target translates to a 3.9% reduction per year and implies decreasing the number of stunted children from 171 million in 2010 to about 100 million in 2025. However, at current rates of progress, there will be 127 million stunted children by 2025, that is, 27 million more than the target or a reduction of only 26%. The translation of the global target into national targets needs to consider nutrition profiles, risk factor trends, demographic changes, experience with developing and implementing nutrition policies, and health system development. This paper presents a methodology to set individual country targets, without precluding the use of others. Any method applied will be influenced by country-specific population growth rates. A key question is what countries should do to meet the target. Nutrition interventions alone are almost certainly insufficient, hence the importance of ongoing efforts to foster nutrition-sensitive development and encourage development of evidence-based, multisectoral plans to address stunting at national scale, combining direct nutrition interventions with strategies concerning health, family planning, water and sanitation, and other factors that affect the risk of stunting. In addition, an accountability framework needs to be developed and surveillance systems strengthened to monitor the achievement of commitments and targets. PMID- 24074316 TI - Contextualising complementary feeding in a broader framework for stunting prevention. AB - An estimated 165 million children are stunted due to the combined effects of poor nutrition, repeated infection and inadequate psychosocial stimulation. The complementary feeding period, generally corresponding to age 6-24 months, represents an important period of sensitivity to stunting with lifelong, possibly irrevocable consequences. Interventions to improve complementary feeding practices or the nutritional quality of complementary foods must take into consideration the contextual as well as proximal determinants of stunting. This review presents a conceptual framework that highlights the role of complementary feeding within the layers of contextual and causal factors that lead to stunted growth and development and the resulting short- and long-term consequences. Contextual factors are organized into the following groups: political economy; health and health care systems; education; society and culture; agriculture and food systems; and water, sanitation and environment. We argue that these community and societal conditions underlie infant and young child feeding practices, which are a central pillar to healthy growth and development, and can serve to either impede or enable progress. Effectiveness studies with a strong process evaluation component are needed to identify transdisciplinary solutions. Programme and policy interventions aimed at preventing stunting should be informed by careful assessment of these factors at all levels. PMID- 24074317 TI - Multi-sectoral interventions for healthy growth. AB - The risk of stunted growth and development is affected by the context in which a child is born and grows. This includes such interdependent influences as the political economy, health and health care, education, society and culture, agriculture and food systems, water and sanitation, and the environment. Here, we briefly review how factors linked with the key sectors can contribute to healthy growth and reduced childhood stunting. Emphasis is placed on the role of agriculture/food security, especially family farming; education, particularly of girls and women; water, sanitation, and hygiene and their integration in stunting reduction strategies; social protection including cash transfers, bearing in mind that success in this regard is linked to reducing the gap between rich and poor; economic investment in stunting reduction including the work with the for-profit commercial sector balancing risks linked to marketing foods that can displace affordable and more sustainable alternatives; health with emphasis on implementing comprehensive and effective health care interventions and building the capacity of health care providers. We complete the review with examples of national and subnational multi-sectoral interventions that illustrate how critical it is for sectors to work together to reduce stunting. PMID- 24074318 TI - Parental height and child growth from birth to 2 years in the WHO Multicentre Growth Reference Study. AB - Linear growth from birth to 2 years of children enrolled in the World Health Organization Multicentre Growth Reference Study was similar despite substantial parental height differences among the six study sites. Within-site variability in child length attributable to parental height was estimated by repeated measures analysis of variance using generalized linear models. This approach was also used to examine relationships among selected traits (e.g. breastfeeding duration and child morbidity) and linear growth between 6 and 24 months of age. Differences in intergenerational adult heights were evaluated within sites by comparing mid parental heights (average of the mother's and father's heights) to the children's predicted adult height. Mid-parental height consistently accounted for greater proportions of observed variability in attained child length than did either paternal or maternal height alone. The proportion of variability explained by mid parental height ranged from 11% in Ghana to 21% in India. The average proportion of between-child variability accounted for by mid-parental height was 16% and the analogous within-child estimate was 6%. In the Norwegian and US samples, no significant differences were observed between mid-parental and children's predicted adult heights. For the other sites, predicted adult heights exceeded mid-parental heights by 6.2-7.8 cm. To the extent that adult height is predicted by height at age 2 years, these results support the expectation that significant community-wide advances in stature are attainable within one generation when care and nutrition approximate international recommendations, notwithstanding adverse conditions likely experienced by the previous generation. PMID- 24074319 TI - The economic rationale for investing in stunting reduction. AB - This paper outlines the economic rationale for investments that reduce stunting. We present a framework that illustrates the functional consequences of stunting in the 1000 days after conception throughout the life cycle: from childhood through to old age. We summarize the key empirical literature around each of the links in the life cycle, highlighting gaps in knowledge where they exist. We construct credible estimates of benefit-cost ratios for a plausible set of nutritional interventions to reduce stunting. There are considerable challenges in doing so that we document. We assume an uplift in income of 11% due to the prevention of one fifth of stunting and a 5% discount rate of future benefit streams. Our estimates of the country-specific benefit-cost ratios for investments that reduce stunting in 17 high-burden countries range from 3.6 (DRC) to 48 (Indonesia) with a median value of 18 (Bangladesh). Mindful that these results hinge on a number of assumptions, they compare favourably with other investments for which public funds compete. PMID- 24074320 TI - The principles and practices of nutrition advocacy: evidence, experience and the way forward for stunting reduction. AB - Advocacy represents an intervention into complex, dynamic and highly contextual socio-political systems, in which strategies and tactics must be adjusted on a continual basis in light of rapidly changing conditions, reactions from actors and feedback. For this reason, the practice of advocacy is often considered more art than science. However, capacities and practices for advocacy can be strengthened by sharing and analysing experiences in varying contexts, deriving general principles and learning to adapt these principles to new contexts. Nutrition is a particular context for advocacy, but to date, there has been little systematic analysis of experiences. The purpose of this paper is to illustrate and draw lessons from the practice of nutrition advocacy, especially in relation to stunting and complementary feeding, and suggest ways to strengthen capacities and practices in the future. The strategies and tactics, achievements and lessons learnt are described for three case studies: Uganda, Vietnam and Bangladesh. These cases, and experience from elsewhere, demonstrate that concerted, well-planned and well-implemented advocacy can bring significant achievements, even in short period of time. In light of the global and national attention being given to stunting reduction through the SUN (Scaling Up Nutrition) movement and other initiatives, there is now a need for much stronger investments in strategic and operational capacities for advocacy, including the human, organisational and financial resources for the advocacy and strategic communication themselves, as well as for monitoring and evaluation, supportive research and institutional capacity-building. PMID- 24074321 TI - Key principles to improve programmes and interventions in complementary feeding. AB - Although there are some examples of successful complementary feeding programmes to promote healthy growth and prevent stunting at the community level, to date there are few, if any, examples of successful programmes at scale. A lack of systematic process and impact evaluations on pilot projects to generate lessons learned has precluded scaling up of effective programmes. Programmes to effect positive change in nutrition rarely follow systematic planning, implementation, and evaluation (PIE) processes to enhance effectiveness over the long term. As a result a set of programme-oriented key principles to promote healthy growth remains elusive. The purpose of this paper is to fill this gap by proposing a set of principles to improve programmes and interventions to promote healthy growth and development. Identifying such principles for programme success has three requirements: rethinking traditional paradigms used to promote improved infant and young child feeding; ensuring better linkages to delivery platforms; and, improving programming. Following the PIE model for programmes and learning from experiences from four relatively large-scale programmes described in this paper, 10 key principles are identified in the areas of programme planning, programme implementation, programme evaluation, and dissemination, replication, and scaling up. Nonetheless, numerous operational research questions remain, some of which are highlighted in this paper. PMID- 24074322 TI - Designing appropriate complementary feeding recommendations: tools for programmatic action. AB - Suboptimal complementary feeding practices contribute to a rapid increase in the prevalence of stunting in young children from age 6 months. The design of effective programmes to improve infant and young child feeding requires a sound understanding of the local situation and a systematic process for prioritizing interventions, integrating them into existing delivery platforms and monitoring their implementation and impact. The identification of adequate food-based feeding recommendations that respect locally available foods and address gaps in nutrient availability is particularly challenging. We describe two tools that are now available to strengthen infant and young child-feeding programming at national and subnational levels. ProPAN is a set of research tools that guide users through a step-by-step process for identifying problems related to young child nutrition; defining the context in which these problems occur; formulating, testing, and selecting behaviour-change recommendations and nutritional recipes; developing the interventions to promote them; and designing a monitoring and evaluation system to measure progress towards intervention goals. Optifood is a computer-based platform based on linear programming analysis to develop nutrient adequate feeding recommendations at lowest cost, based on locally available foods with the addition of fortified products or supplements when needed, or best recommendations when the latter are not available. The tools complement each other and a case study from Peru illustrates how they have been used. The readiness of both instruments will enable partners to invest in capacity development for their use in countries and strengthen programmes to address infant and young child feeding and prevent malnutrition. PMID- 24074323 TI - Introducing infant and young child feeding indicators into national nutrition surveillance systems: lessons from Vietnam. AB - A comprehensive set of infant and young child feeding (IYCF) indicators for international use was published in 2008. We describe the process followed to incorporate these indicators into Vietnam's National Nutrition Surveillance System (NNSS). Following its establishment in 1980, the National Institute of Nutrition introduced the Vietnam NNSS to provide an evidence base for nutrition interventions. While anthropometric indicators based on international standards were regularly used for programme purposes, data on IYCF could not be collected with similar rigor until 2010. In 2009, with support from Alive & Thrive and UNICEF, the NNSS questionnaire was reviewed and additional content incorporated to measure IYCF practices. The tool was pilot-tested in 10 provinces and revised before nationwide roll-out in 2010.The tool comprises four pages, the first three of which focus on collecting data relating to maternal nutrition and IYCF. The last page is flexibly designed to incorporate planners' data requests for other relevant activities (e.g. mass media interventions, food security). Once analysed, the data are presented in a report comprising provincial profiles and maps illustrating IYCF practices. Importantly, the IYCF data have been used for policy advocacy (e.g. maternity leave legislation, advertisement law), programme planning, trend monitoring and capacity building. Adoption of the IYCF indicators was successful due to strategic timing, a phased approach, buy-in from stakeholders and capacity building at all levels to ensure the quality and use of data. Further revisions to the NNSS (e.g. sampling methodology, quality assurance systems) will be important to ensure the reliability of indicators. PMID- 24074324 TI - Adverse events resulting from lasers used in urology. AB - OBJECTIVE: To collate world reports of adverse events (AEs) resulting from lasers used in urology. METHODS: The Manufacturer and User Facility Device Experience (MAUDE) database of the United States Food and Drug Administration (FDA) was searched using the term "Laser for gastro-urology use." In addition, the Rockwell Laser Industries (RLI) Laser Accident Database was searched for the following types of lasers: neodymium-doped yttrium aluminum garnet (Nd:YAG), holmium:yttrium aluminum garnet (Ho:YAG), potassium titanyl phosphate (KTP), diode and thulium:YAG (Tm:YAG). RESULTS: Both databases were last accessed on October 1, 2012. Overall, there were 433 AEs; 166 in MAUDE database (1992-2012) and 267 in RLI database (1964-2005). Most of the AEs (198/433 or 46%) resulted from generator failure or fiber tip breaking. Whereas there were 20 (4.6%) AEs harming medical operators, there were 159 (37%) AEs harming nonmedical operators using Nd:YAG, KTP, and diode lasers. Eye injuries ranging from mild corneal abrasions to total vision loss were reported in 164 AEs with the use of Nd:YAG, KTP, and diode lasers. Overall, there were 36 (8.3%) AEs resulting in patient harm, including 7 (1.6%) mortalities, 3 deaths from ureteral perforation using the Ho:YAG laser, and 4 deaths from air emboli using the Nd:YAG laser. Other reported patient injuries included bladder perforation resulting in urinary diversion in a patient, in addition to minor skin burns, internal burns, and bleeding in others. There were no AEs reported with the use of Tm:YAG laser. CONCLUSIONS: Most of the AEs reported relate to equipment failure. There were no eye injuries reported with the use of Ho:YAG lasers. Caution must be exercised when using lasers in urology, including wearing appropriate eye protection when using Nd:YAG, KTP, and diode lasers. PMID- 24074326 TI - Dusting the cause for the time trends in asthma. PMID- 24074327 TI - Turning up the heat on skin testing for baked egg allergy. PMID- 24074328 TI - Advanced phenotyping in hypersensitivity drug reactions to NSAIDs. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are the medications most frequently involved in hypersensitivity drug reactions. Because NSAIDs are prescribed for many conditions, this is a world-wide problem affecting patients of all ages. Various hypersensitivity reactions have been reported, mainly affecting the skin and/or the respiratory airways. The most frequent of these is acute urticaria, which can be induced by several different NSAIDs. Both specific and non-specific immunological pathways have been proposed as underlying mechanisms. This review presents the clinical phenotypes and the drugs involved in NSAID hypersensitivity. Five major clinical syndromes can be distinguished: aspirin-exacerbated respiratory disease (AERD), aspirin-exacerbated cutaneous disease (AECD), multiple NSAID-induced urticaria/angioedema (MNSAID-UA), single NSAID-IgE reactions and single NSAID T cell responses. However, further classification is possible within these five major entities, by detailed descriptions of the clinical characteristics enabling more phenotypes to be defined. This detailed differentiation now seems required in order to undertake appropriate pharmacogenetic studies. PMID- 24074329 TI - Epidemiological associations of allergy, IgE and cancer. AB - Several epidemiological studies have evaluated potential associations between allergy and risk of malignancy. It remains clear that the relationship between allergy and cancer is complex. Three hypotheses have been proposed to account for observed relationships: these are chronic inflammation, immunosurveillance, prophylaxis, and we propose adding a fourth: inappropriate T-helper 2 (Th2) immune skewing. Each of these attempts to explain either the increased or decreased risk of different cancer types in 'allergic' patients reported in the literature. All four hypotheses are based on known mechanisms of allergic inflammation and/or IgE antibody functions, and uphold the view of an immunological basis for the relationship between allergy and malignancies. This review summarizes and draws conclusions from the epidemiological literature examining the relationships between specific types of cancer and allergic diseases. Particular emphasis is placed on the most recent contributions to the field, and on consideration of the allergic immune mechanisms that may influence positive or negative associations. PMID- 24074330 TI - Effect of topical corticosteroids on allergic airway inflammation and disease severity in obstructive sleep apnoea. AB - BACKGROUND: The incidence of sleep-related breathing disorders is correlated with lower and upper airway inflammatory diseases, such as asthma and allergic rhinitis. We hypothesized that corticosteroids treatment would lead to a greater reduction in disease severity in obstructive sleep apnoea syndrome (OSAS) patients with concomitant allergic rhinitis vs. non-allergic OSAS patients by reducing the level of inflammation in upper airway tissues. OBJECTIVE: This study was performed to determine whether treatment with intranasal corticosteroids could reduce upper airway inflammation and improve sleep parameters in obstructive sleep apnoea syndrome patients with or without concomitant allergic rhinitis. METHODS: Obstructive sleep apnoea syndrome patients with (n = 34) or without (n = 21) documented allergic rhinitis voluntarily enrolled in the study and were assessed at baseline and after corticosteroids treatment for 10-12 weeks. Sleep studies were performed and biopsies were obtained from the inferior turbinate, nasopharynx, and uvula. The apnoea-hypopnoea index, sleep quality, and level of daytime alertness were determined, and immunocytochemistry was used to phenotype tissue inflammation. RESULTS: Standard sleep indices improved following treatment in the entire cohort of obstructive sleep apnoea syndrome patients, with greater improvement seen in the allergic rhinitis group. Allergic rhinitis patients demonstrated significantly improved O2 saturation and a lower supine apnoea-hypopnoea index score after corticosteroid treatment; similar improvements were not seen in the non-allergic rhinitis group. Eosinophilia was detected at all three sites in the allergic rhinitis group, but not in the non-allergic rhinitis group. Following treatment, fewer eosinophils and CD4 lymphocytes were documented at all three biopsy sites in the allergic group; the reduction in inflammation was less apparent in the non-allergic rhinitis group. CONCLUSION: This study has provided important molecular and clinical evidence regarding the ability of corticosteroids to reduce upper airway inflammation and improve obstructive sleep apnoea syndrome morbidity patients with concomitant allergic rhinitis. PMID- 24074331 TI - Nasal levels of soluble IL-33R ST2 and IL-16 in allergic rhinitis: inverse correlation trends with disease severity. AB - BACKGROUND: Serum levels of IL-16, IL-33 and the decoy receptor of IL-33, soluble ST2, are elevated in allergic rhinitis. Recent studies show that IL-16, soluble ST2 or anti-IL-33 reduce type 2 cytokines (such as IL-5) and eosinophilia in murine models of allergic asthma or allergic rhinitis respectively. OBJECTIVE: In this study, we studied the release of IL-5, IL-16, IL-33 and soluble ST2 in allergic rhinitis patients after nasal allergen challenge and natural pollen exposure. METHODS: The nasal lavages of 15 allergic and 14 non-allergic volunteers were collected during the pollen allergy season. In addition, six allergic volunteers underwent unilateral nasal allergen and control challenge out of season and nasal secretions and sera were collected. IL-5, IL-16, IL-33 and soluble ST2 in nasal secretions and sera were measured by electrochemiluminescent assay or ELISA, respectively. RESULTS: Nasal IL-5, IL-16 and soluble ST2 levels were significantly increased in seasonally pollen exposed allergic volunteers compared to control subjects (P < 0.001, P = 0.018 and P = 0.002 respectively), whereas IL-33 remained undetectable. Nasal IL-16 showed a weak inverse correlation trend with nasal symptoms (r = -0.48, P = 0.07). Nasal soluble ST2 concentrations were inversely correlated with nasal symptoms (r = -0.61, P = 0.02) and positively correlated with IL-16 (r = 0.56, P = 0.03). Significant increases of nasal IL-5, IL-16 and ST2 but not IL-33 were observed after nasal allergen challenge. At 24 h after allergen challenge, local ST2 and IL-5 concentrations showed an inverse correlation trend (r = -0.83, P = 0.04). Serum levels of IL-5, IL-16 and soluble ST2 rose in at least five of six volunteers tested at 5 or 24 h post-challenge. CONCLUSIONS AND CLINICAL RELEVANCE: The observed upregulation of soluble ST2 and IL-16 after nasal allergen challenge and during peak pollination season suggests potential regulatory roles of these cytokines in the inflammatory reaction in allergic rhinitis. PMID- 24074332 TI - Metrics of salbutamol use as predictors of future adverse outcomes in asthma. AB - BACKGROUND: Beta-agonist overuse is associated with adverse outcomes in asthma, however, the relationships between different metrics of salbutamol use and future risk are uncertain. OBJECTIVE: To investigate the relationship between metrics of salbutamol use and adverse outcome. METHODS: In a 24-week randomized controlled trial of 303 asthma patients at risk of severe exacerbations which compared the efficacy and safety of combination budesonide/formoterol inhaler according to a single inhaler regimen (SMART) with a fixed-dose regimen with salbutamol as reliever ('Standard'), actual medication use was measured by electronic monitoring (Australian New Zealand Clinical Trials Registry Number ACTRN12610000515099). A nested cohort study explored the relationship between metrics of baseline salbutamol use over 2 weeks and future severe asthma exacerbations, poor asthma control (ACQ-5 >= 1.5) or 'extreme' salbutamol overuse (> 32 salbutamol actuations/24-h period). RESULTS: Higher mean daily salbutamol use (per two actuations/day) [Odds ratio (OR) (95% CI) 1.24 (1.06-1.46)], higher days of salbutamol use (per 2 days in 2 weeks) [OR 1.15 (1.00-1.31)] and higher maximal 24-h use (per two actuations/day) [OR 1.09 (1.02-1.16)] were associated with future severe exacerbations. Higher mean daily salbutamol use was associated with future poor asthma control [OR 1.13 (1.02-1.26)]. Higher mean daily salbutamol use [OR 2.73 (1.84-4.07)], number of days of use [OR 1.46 (1.24 1.71)], and maximal daily use [OR 1.57 (1.31-1.89)] were associated with an increased risk of future extreme salbutamol overuse. CONCLUSION AND CLINICAL RELEVANCE: Electronically recorded frequency of current salbutamol use is a strong predictor of risk of future adverse outcomes in asthma, with average daily use performing the best. These findings provide new information for clinicians considering metrics of salbutamol as predictors of future adverse outcomes in asthma. PMID- 24074333 TI - Polymorphisms in the IRF-4 gene, asthma and recurrent bronchitis in children. AB - BACKGROUND: Interferon-regulatory factors (IRFs) play a crucial role in immunity, not only influencing interferon expression but also T cell differentiation. IRF-4 was only recently recognized as a further major player in T cell differentiation. OBJECTIVE: As IRF-1 polymorphisms were shown to be associated with atopy and allergy, we comprehensively investigated effects of IRF-4 variants on allergy, asthma and related phenotypes in German children. METHODS: Fifteen tagging single nucleotide polymorphisms (SNPs) in the IRF-4 gene were genotyped by MALDI-TOF MS in the cross-sectional ISAAC phase II study population from Munich and Dresden (age 9-11; N = 3099). Replication was performed in our previously established genome-wide association study (GWAS) data set (N = 1303) consisting of asthma cases from the Multicenter Asthma Genetic in Childhood (MAGIC) study and reference children from the ISAAC II study. RESULTS: SNPs were not significantly associated with asthma but with bronchial hyperresponsiveness, atopy and, most interestingly, with recurrent bronchitis in the first data set. The IRF-4 variant rs9378805 was associated with recurrent bronchitis in the ISAAC population and replicated in the GWAS data set where further SNPs showed associations with recurrent bronchitis and asthma. CONCLUSIONS: We found genetic associations in IRF-4 to be associated with recurrent bronchitis in our two study populations. Associated polymorphisms are localized in a putative regulatory element in the 3'UTR region of IRF-4. These findings suggest a putative role of IRF-4 in the development of bronchitis. PMID- 24074334 TI - Sensitization to food and inhalant allergens in relation to age and wheeze among children with atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is common in children; however, persistence of AD with or without asthma is less common. Longitudinal studies remain limited in their ability to characterize how IgE antibody responses evolve in AD, and their relationship with asthma. OBJECTIVE: To use a cross-sectional study design of children with active AD to analyse age-related differences in IgE antibodies and relation to wheeze. METHODS: IgE antibodies to food and inhalant allergens were measured in children with active AD (5 months to 15 years of age, n = 66), with and without history of wheeze. RESULTS: Whereas IgE antibodies to foods persisted at a similar prevalence and titre throughout childhood, IgE antibodies to all aeroallergens rose sharply into adolescence. From birth, the chance of sensitization for any aeroallergen increased for each 12-month increment in age (OR >= 1.21, P < 0.01), with the largest effect observed for dust mite (OR = 1.56, P < 0.001). A steeper age-related rise in IgE antibody titre to dust mite, but no other allergen was associated with more severe disease. Despite this, sensitization to cat was more strongly associated with wheeze (OR = 4.5, P < 0.01), and linked to Fel d 1 and Fel d 4, but not Fel d 2. Comparison of cat allergic children with AD to those without, revealed higher IgE levels to Fel d 2 and Fel d 4 (P < 0.05), but not Fel d 1. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in sensitization to cat and dust mite among young children with AD may aid in identifying those at increased risk for disease progression and development of asthma. Early sensitization to cat and risk for wheeze among children with AD may be linked to an increased risk for sensitization to a broader spectrum of allergen components from early life. Collectively, our findings argue for early intervention strategies designed to mitigate skin inflammation in children with AD. PMID- 24074335 TI - House dust mite sensitization is the main risk factor for the increase in prevalence of wheeze in 13- to 14-year-old schoolchildren in Guangzhou city, China. AB - BACKGROUND: Little is known about time trend of prevalence of asthma and the association between the changing prevalence and allergen sensitization in Chinese children. OBJECTIVE: To determine the changes in prevalence of asthma and allergen sensitization in schoolchildren over a period of 15 years. METHODS: A total of 6928 schoolchildren aged 13-14 years in 2009 were recruited for the study using the Phase III Protocol of the International Study of Asthma and Allergic disease in Childhood (ISAAC) and 2531 of them underwent skin prick test for seven common aeroallergens. The results were compared with those obtained in the Phase I (1994/95) and III (2001/02) ISAAC studies. RESULTS: The prevalence of asthma ever and current wheeze increased from 3.9% and 3.4% in 1994, to 4.6% and 4.8% in 2001 (P<0.001), and to 6.9% and 6.1% in 2009 (P <= 0.008). The prevalence of higher degree of skin response to house dust mites (HDMs) and cat, and atopic index increased significantly in all children in 2010 when compared with those in 2002 (P<0.001). Prevalence of wheeze remained unchanged in subjects without sensitization to any tested allergen including HDMs (P > 0.05). Sensitization to HDMs, especially Dermatophagoides Pteronyssinus was associated with increase in prevalence of wheeze. CONCLUSION: The prevalence of wheeze and sensitization to common aeroallergens in secondary schoolchildren in Guangzhou China has increased significantly since 1994. Sensitization to HDMs is an important risk factor associated with the increase in prevalence of wheeze in this group of population in Guangzhou city. PMID- 24074336 TI - Maternal 25-hydroxyvitamin D and its association with childhood atopic outcomes and lung function. AB - BACKGROUND: It has been suggested that maternal vitamin D status in pregnancy influences the risk of asthma and atopy in the offspring. The epidemiological evidence to support these claims is conflicting and may reflect chance findings and differences in how vitamin D was assessed. OBJECTIVE: To examine the association between blood total maternal 25-hydroxy vitamin D (25(OH)D) concentrations in pregnancy and offspring asthma, atopy and lung function in the largest birth cohort study to date. METHODS: Participants were largely of white European origin and resident in the South West of England. We examined the associations of maternal 25(OH)D concentrations in pregnancy with the following outcomes in the offspring: wheeze, asthma, atopy, eczema, hayfever, at mean age 7.5 years (n = 3652-4696 depending on outcome), IgE at 7 years (n = 2915) and lung function and bronchial responsiveness at mean age 8.7 years (n = 3728-3784). RESULTS: Sixty-eight per cent of mothers had sufficient (> 50 nmol/L) concentrations of 25(OH)D, 27% were insufficient (27.5-49.99 nmol/L) and 5% were deficient (< 27.5 nmol/L). There was no evidence to suggest that maternal 25(OH)D concentration in pregnancy was associated with any respiratory or atopic outcome in the offspring. These findings remained after adjustment for season of measurement and for potential confounders. There was also no evidence that these relationships followed a non-linear form and no evidence that either deficient or high concentrations of maternal 25(OH)D were associated with atopic or respiratory outcomes. CONCLUSIONS: We found no evidence that maternal blood 25(OH)D concentration in pregnancy is associated with childhood atopic or respiratory outcomes. PMID- 24074337 TI - Baked egg food challenges - clinical utility of skin test to baked egg and ovomucoid in children with egg allergy. AB - BACKGROUND: Many children with IgE-mediated egg allergy can tolerate products containing extensively heated (baked) egg. Aside from food challenge, there are no tests which reliably predict tolerance to baked egg in egg-allergic individuals. OBJECTIVES: To determine if skin prick test (SPT) to baked egg (muffin) and ovomucoid can predict the outcome of baked egg challenges in egg allergic patients. METHODS: In this prospective study, children with a recent history of immediate allergic reactions to egg [and corroborative positive SPT or serum-specific IgE (ssIgE) to egg] or those with SPT/ssIgE > 95% PPV for egg allergy were invited to undergo an open standardized baked egg (muffin) challenge. SPT to egg white, ovomucoid, and fresh muffin were performed immediately prior to challenge. RESULTS: One hundred and forty-three egg allergic children underwent baked egg challenge and of these, 90 (63%) tolerated 1 g of egg protein in a baked muffin. Of the 53 positive challenges, eight (15%) had respiratory and/or cardiovascular symptoms. The median SPT diameters in positive challenges compared with negative challenges were baked muffin - 6.0 mm/4.0 mm and ovomucoid 7.5 mm/5.0 mm respectively. Receiver operating characteristic (ROC) curves were generated for SPT to baked egg and ovomucoid. The area under the curve was 0.68 for baked egg, and 0.67 for ovomucoid. A muffin SPT of < 2 mm had a negative predictive value of 88% and an ovomucoid SPT >= 11 mm had a positive predictive value of 100%. CONCLUSIONS AND CLINICAL RELEVANCE: A SPT of < 2 mm to muffin had a high negative predictive value to baked egg challenge. Ovomucoid SPT >= 11 mm was very likely to predict a reaction to baked egg. In these children, deferring the challenge would be appropriate. PMID- 24074339 TI - Novel directions for psychiatric diagnosis: from psychopathology to motor function to monitoring technology. AB - In the light of the recent publication of the DSM-5, there is renewed debate about the relative merit of categorical diagnosis, as laid down in Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD) diagnostic manuals. Issues such as validity, usefulness and acceptability of the diagnoses in this manual are increasingly debated. Several alternative possibilities have been suggested including: (i) the introduction of truly cross-cutting dimensional measures, that would facilitate dynamic multidimensional formulations of psychopathology, (ii) the Research Domain Criteria, that may facilitate biological research but move away from clinical symptoms, (iii) a system of personalized diagnosis based on psychopathology as a network of symptoms and contexts, and (iv) enhanced focus on motor alterations, other than catatonia, as a possible additional informative dimension of diagnosis in psychiatry, particularly as a possible marker of underlying neurodevelopmental alterations. We suggest that novel systems of diagnosis are likely to rely more on continuous monitoring of diagnostically relevant information in daily life, complementing retrospective symptom criteria in DSM and ICD. Patients and their families are likely to benefit from these projects, as novel models of diagnosis based on daily life information may be linked more strongly to treatment needs and prognosis. PMID- 24074340 TI - The development of a fully-integrated immune response model (FIRM) simulator of the immune response through integration of multiple subset models. AB - BACKGROUND: The complexity and multiscale nature of the mammalian immune response provides an excellent test bed for the potential of mathematical modeling and simulation to facilitate mechanistic understanding. Historically, mathematical models of the immune response focused on subsets of the immune system and/or specific aspects of the response. Mathematical models have been developed for the humoral side of the immune response, or for the cellular side, or for cytokine kinetics, but rarely have they been proposed to encompass the overall system complexity. We propose here a framework for integration of subset models, based on a system biology approach. RESULTS: A dynamic simulator, the Fully-integrated Immune Response Model (FIRM), was built in a stepwise fashion by integrating published subset models and adding novel features. The approach used to build the model includes the formulation of the network of interacting species and the subsequent introduction of rate laws to describe each biological process. The resulting model represents a multi-organ structure, comprised of the target organ where the immune response takes place, circulating blood, lymphoid T, and lymphoid B tissue. The cell types accounted for include macrophages, a few T-cell lineages (cytotoxic, regulatory, helper 1, and helper 2), and B-cell activation to plasma cells. Four different cytokines were accounted for: IFN-gamma, IL-4, IL 10 and IL-12. In addition, generic inflammatory signals are used to represent the kinetics of IL-1, IL-2, and TGF-beta. Cell recruitment, differentiation, replication, apoptosis and migration are described as appropriate for the different cell types. The model is a hybrid structure containing information from several mammalian species. The structure of the network was built to be physiologically and biochemically consistent. Rate laws for all the cellular fate processes, growth factor production rates and half-lives, together with antibody production rates and half-lives, are provided. The results demonstrate how this framework can be used to integrate mathematical models of the immune response from several published sources and describe qualitative predictions of global immune system response arising from the integrated, hybrid model. In addition, we show how the model can be expanded to include novel biological findings. Case studies were carried out to simulate TB infection, tumor rejection, response to a blood borne pathogen and the consequences of accounting for regulatory T-cells. CONCLUSIONS: The final result of this work is a postulated and increasingly comprehensive representation of the mammalian immune system, based on physiological knowledge and susceptible to further experimental testing and validation. We believe that the integrated nature of FIRM has the potential to simulate a range of responses under a variety of conditions, from modeling of immune responses after tuberculosis (TB) infection to tumor formation in tissues. FIRM also has the flexibility to be expanded to include both complex and novel immunological response features as our knowledge of the immune system advances. PMID- 24074342 TI - Bond elasticity controls molecular recognition specificity in antibody-antigen binding. AB - Force-spectroscopy experiments make it possible to characterize single ligand receptor pairs. Here we measure the spectrum of bond strengths and flexibilities in antibody-antigen interactions using optical tweezers. We characterize the mechanical evolution of polyclonal antibodies generated under infection and the ability of a monoclonal antibody to cross-react against different antigens. Our results suggest that bond flexibility plays a major role in remodeling antibody antigen bonds in order to improve recognition during the maturation of the humoral immune system. PMID- 24074341 TI - Comparative haematological parameters of HbAA and HbAS genotype children infected with Plasmodium falciparum malaria in Yemen. AB - BACKGROUND: Sickle haemoglobin (HbS) is known to offer considerable protection against falciparum malaria. However, the mechanism of protection is not yet completely understood. In this study, we investigate how the presence of the sickle cell trait affects the haematological profile of AS persons with malaria, in comparison with similarly infected persons with HbAA. This study is based on the hypothesis that the sickle cell trait plays a protective role against malaria. METHODS: Children from an endemic malaria transmission area in Yemen were enrolled in this study. Hematological parameters were estimated using manual methods, the percentage of parasite density on stained thin smear was calculated, haemoglobin genotypes were determined on paper electrophoresis, ferritin was measured using enzyme-linked immunosorbent assay, serum iron and TIBC were assayed using spectrophotometer, transferrin saturation index was calculated by dividing serum iron by TIBC and expressing the result as a percentage. Haematological parameters were compared in HbAA- and HbAS-infected children. RESULTS: Falciparum malaria parasitaemia was confirmed in the blood smears of 62 children, 44 (55.7%) of AA and 18 (37.5%) AS, so there was higher prevalence in HbAA children (P = 0.047). Parasite density was lower in HbAS- than HbAA-infected children (P = 0.003). Anaemia was prominent in malaria-infected children, with high proportions of moderate and severe forms in HbAA (P = 0.001). The mean levels of haemoglobin, packed cell volume, reticulocyte count, platelets count, lymphocytes, eosinophils, and serum iron were significantly lower while total leukocytes, immature granulocytes, monocytes, erythrocyte sedimentation rate, transferrin saturation, and serum ferritin were significantly higher in HbAA infected children than HbAS-infected children. CONCLUSION: Infection with Plasmodium falciparum malaria caused more significant haematological alterations of HbAA children than HbAS. This study supports the observation that sickle cell trait seems to be a beneficial genetic factor that resists malaria, since inheriting it protects against significant haematological consequences of malaria. PMID- 24074343 TI - Choroidal changes and duration of diabetes. AB - PURPOSE: We investigate changes in macular choroidal thickness in eyes without diabetic retinopathy of patients with various durations of diabetes, using enhanced depth imaging optical coherence tomography (EDI OCT). METHODS: The 134 Type-2 diabetic patients who presented without diabetic retinopathy were prospectively imaged using EDI OCT on Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany) sd-OCT. The patients with diabetes were classified into three groups, according to the duration of diabetes: Group I (5-9 years, n = 63); Group II (10-14 years, n = 37); Group III (15-40 years, n = 34). The retinal and choroidal thickness was evaluated between these groups at central fovea and at the regions at 500-mm intervals up to 1500 mm temporal and nasal to the fovea. RESULTS: The central foveal retinal thickness was significantly different between groups (group I: 273.05 +/- 19.51 u, group II: 267.12 +/- 20.78 u, group III: 261.34 +/- 22.27 u; p = 0.04). The choroidal thickness measurements at central fovea, at 500, 1000, and 1500 micron intervals temporal and nasal to the center of the fovea were not significantly different between groups. The duration of diabetes was weakly correlated with choroidal thickness in all measured distances and they were not statistically significant. The central foveal choroidal thickness was weakly correlated with serum creatinine (r = 0.18, p = 0.03). CONCLUSION: Foveal retinal thickness was significantly decreased in patients with longer duration of diabetes. Duration of diabetes does not seem to be related to foveal chorodial thickness. On the other hand, the weak relation between creatinine and choroidal thickness may be evaluated further. The choroidal thickness changes that may be an early sign of nephropathy can be submitted to an easy, noninvasive scanning test at the same time. PMID- 24074344 TI - Compliance and satisfaction with deferasirox (Exjade(r)) compared with deferoxamine in patients with transfusion-dependent beta-thalassemia. AB - OBJECTIVE: The current standard option for iron chelation therapy (ICT) in transfusion-dependent patients with beta-thalassemia is deferoxamine (DFO). We aimed to compare the compliance with DFO vs. deferasirox (Exjade(r)), a novel oral iron chelator, in patients with transfusion-dependent beta-thalassemia. METHODS: In this cross-sectional study, 220 patients from Southern Iran who were receiving DFO or Exjade(r) for the last 2 years were investigated in 2012. Satisfaction, compliance, convenience, and life disturbances of the patients with ICT were evaluated. Assessments were performed at four different occasions during 1 year. RESULTS: According to the results, 114 patients received treatment with DFO and 106 patients were treated with Exjade(r). In comparison with the patients who were treated with DFO, those receiving Exjade(r) reported a significantly higher rate of compliance and convenience (P < 0.05). However, no significant difference was observed between the two groups regarding their satisfaction (P > 0.05). In the DFO group, 44.9% of the patients reported irritation and pain at the injection site. CONCLUSIONS: Considering higher rate of compliance and convenience with Exjade(r) and the comparable efficacy of these two modalities of ICT documented in previous studies, Exjade(r) can be used as a preferable choice of ICT in iron-overload patients with beta-thalassemia. PMID- 24074345 TI - Repeated blast exposures cause brain DNA fragmentation in mice. AB - The pathophysiology of blast-induced traumatic brain injury (TBI) and subsequent behavioral deficits are not well understood. Unraveling the mechanisms of injury is critical to derive effective countermeasures against this form of neurotrauma. Preservation of the integrity of cellular DNA is crucial for the function and survival of cells. We evaluated the effect of repeated blast exposures on the integrity of brain DNA and tested the utility of cell-free DNA (CFD) in plasma as a biomarker for the diagnosis and prognosis of blast-induced polytrauma. The results revealed time-dependent breakdown in cellular DNA in different brain regions, with the maximum damage at 24 h post-blast exposures. CFD levels in plasma showed a significant transient increase, which was largely independent of the timing and severity of brain DNA damage; maximum levels were recorded at 2 h after repeated blast exposure and returned to baseline at 24 h. A positive correlation was observed between the righting reflex time and CFD level in plasma at 2 h after blast exposure. Brain DNA damage subsequent to repeated blast was associated with decreased mitochondrial membrane potential, increased release of cytochrome C, and up-regulation of caspase-3, all of which are indicative of cellular apoptosis. Shock-wave-induced DNA damage and initiation of mitochondrial driven cellular apoptosis in the brain after repeated blast exposures indicate that therapeutic strategies directed toward inhibition of DNA damage or instigation of DNA repair may be effective countermeasures. PMID- 24074347 TI - Surface pretreatment boosts the performance of supramolecular affinity materials on quartz crystal microbalances for sensor applications. AB - A Teflon-like coating is the key for the boost in sensitivity of quartz microbalances for the tracing of airborne analytes. Since the undesired signals for the interfering compounds are suppressed and the ones for the targeted compounds (e.g., peroxide explosives) are enhanced, the PCA output is improved. PMID- 24074346 TI - Occurrence and preventability of adverse drug events in surgical patients: a systematic review of literature. AB - BACKGROUND: Adverse drug events (ADEs) are a considerable cause of inhospital morbidity and mortality. Patient flow differs substantially for surgical and nonsurgical patients: surgical patients are subjected to multiple medication changes related to surgical intervention or postoperative care. The objective of this study is to systematically review the occurrence and nature of ADEs in surgical patients. Also, a comparison with nonsurgical patients was made. METHODS: A search was conducted in Embase and Medline identifying studies that reported observational data on the occurrence and nature of ADEs in surgical hospitalised adult patients. If sufficient data were available, the occurrence of (preventable) ADEs was compared between surgical and nonsurgical patients. RESULTS: Six studies fulfilled the inclusion criteria. The occurrence of ADEs in surgical patients ranged from 2.0 to 27.7 per 100 admissions, from 4.7 to 8.9 per 1,000 patient days, or involved 8.9% of the patients. Proportions of preventable ADEs in surgical patients were 18% and 54%, described in two studies. A head-to head comparison of surgical patients and nonsurgical patients was possible for five of six studies. The occurrence of ADEs in nonsurgical patients was significantly higher than in surgical patients in three studies. CONCLUSIONS: ADEs are a relevant problem in surgical patients and nonsurgical patients, with a high proportion of preventable ADEs. The occurrence of ADEs appears to be higher in nonsurgical patients than in surgical patients. However, studies lack details on the differences in nature of ADEs between hospital populations. To improve medication safety this knowledge is essential. PMID- 24074348 TI - The measurement properties of the Occupational Circumstances Interview and Rating Scale - Sweden (OCAIRS-S V2). AB - AIM: This paper reports the measurement properties of the Occupational Circumstances Assessment Interview and Rating Scale - Sweden (OCAIRS-S V2). The OCAIRS is a semi-structured interview and rating scale designed to capture, in detail, a person's occupational participation. The English version 4.0 has been translated into Swedish. The psychometric properties of the Swedish version are unknown. METHODS: Eleven Swedish occupational therapists working in mental health completed 38 OCAIRS-S (V2) assessments in addition to linking videotapes. A total of 60 clients were, therefore, entered into the analysis. Many-faceted Rasch analysis was used to analyse the data. RESULTS AND CONCLUSIONS: Results supported internal, construct, and person response validity of the OCAIRS-S (V2). Inter rater reliability was established. The scale was shown to discriminate between people who were living in the community. In addition, the results indicate a need to explore the skill items. PMID- 24074350 TI - Development of a chiral bis(guanidino)iminophosphorane as an uncharged organosuperbase for the enantioselective amination of ketones. AB - Chiral bis(guanidino)iminophosphoranes were designed and synthesized as chiral uncharged organosuperbase catalysts that facilitate activation of less-acidic pro nucleophiles. The newly developed bis(guanidino)iminophosphoranes, which possess the highest basicity among chiral organocatalysts reported to date, were proven to be a superb class of chiral organosuperbases by reaction of azodicarboxylates with 2-alkyltetralones and their analogues as the less acidic pro-nucleophiles. PMID- 24074349 TI - The mosaic accessory gene structures of the SXT/R391-like integrative and conjugative elements derived from Vibrio spp. isolated from aquatic products and environment in the Yangtze River Estuary, China. AB - BACKGROUND: The emergence, resurgence and spread of human food-borne pathogenic Vibrios are one of the major contributors to disease burden and mortality particularly in developing countries with disputable sanitary conditions. Previous research on pathogenic Vibrio cholerae and Vibrio parahaemolitycus derived from clinical samples has proposed links between acquisition of virulence and multiple drug resistance traits and intercellular transmissibility of mobile genetic elements in the environment. To date, very few information is available on environmental Vibrio isolates. In this study, we characterized eleven Vibrio strains bearing the SXT/R391-like integrative and conjugative elements (ICEs) derived from aquatic products and environment in the Yangtze River Estuary, China. RESULTS: The eleven Vibrio strains were isolated in 2010 to 2011, and taxonomically identified, which included six Vibrio cholerae, three Vibrio parahaemolyticus, one Vibrio alginolyticus and one Vibrio natriegens. Most of the strains displayed strong resistance phenotypes to ampicillin, mercury and chromium. The majority of their ICEs, which belong to S and R exclusion system groups, contain ICEs-chromosome junction sequences and highly conserved core genes required for ICE transfer. However, comparative sequence analysis uncovered interesting diversity in their mosaic accessory gene structures, which carry many novel genes that have not been described in any known ICEs to date. In addition, antibiotic resistance was transmitted by ICEVchChn6 and ICEVpaChn1 from V. cholerae, V. parahaemolyticus to E. coli MG1655 via conjugation, respectively. Our data also revealed that the ICEs characterized in this study are phylogenetically distant from most of the SXT/R391 ICEs reported previously, which may represent a novel cluster likely shaped by the ecological environment in the Yangtze River Estuary, China. CONCLUSIONS: This study constitutes the first investigation of ICEs-positive Vibrio spp. in the Yangze River Estuary, China. The newly identified ICEs were characterized with mosaic accessory gene structures and many novel genes. The results demonstrated self-transmissibility of antibiotic resistance mediated by two of the ICEs from V. cholerae, V. parahaemolyticus to E. coli via conjugation, respectively. Our results also revealed that the ICEs examined in this study may represent a novel cluster in the SXT/R391 family. PMID- 24074351 TI - Synthesis, crystal structure, and proton conductivity of one-dimensional, two dimensional, and three-dimensional zirconium phosphonates based on glyphosate and glyphosine. AB - The reaction of two small phosphono-amino acids based on glycine (glyphosine and glyphosate) with zirconium under mild conditions led to the attainment of three related zirconium derivatives with 1D, 2D, and 3D structures of formulas ZrF[H3(O3PCH2NHCH2COO)2] (1), Zr3H8[(O3PCH2)2NCH2COO]4.2H2O (2), and Zr[(O3PCH2)(HO3PCH2)NHCH2COOH]2.2H2O (3), respectively, whose structures were solved by X-ray powder and single-crystal diffraction data. The glyphosate derivative has 1D ribbon-type structure whereas the dimensionality of the glyphosine-derived materials (2D and 3D) can be tuned by changing the synthesis conditions. The low-dimensional compounds (1 and 2) can be directly produced in the form of nanoparticles with different size and morphology whereas the 3D compound (3) has a higher crystallinity and can be obtained as single crystals with a prismatic shape. The different structural dimensionality reflects the shape and size of the crystals and also differently affects the proton conductivity properties, measured over a wide range of temperature at 95% relative humidity. Their high thermal and chemical stability together with the small size may promote their use as fillers for polymeric electrolyte membranes for fuel cells applications. PMID- 24074352 TI - Retinal ganglion cell complex thickness after internal limiting membrane peeling for idiopathic macular hole. PMID- 24074353 TI - Mad, bad and dangerous to know: the biochemistry, ecology and evolution of slow loris venom. AB - Only seven types of mammals are known to be venomous, including slow lorises (Nycticebus spp.). Despite the evolutionary significance of this unique adaptation amongst Nycticebus, the structure and function of slow loris venom is only just beginning to be understood. Here we review what is known about the chemical structure of slow loris venom. Research on a handful of captive samples from three of eight slow loris species reveals that the protein within slow loris venom resembles the disulphide-bridged heterodimeric structure of Fel-d1, more commonly known as cat allergen. In a comparison of N. pygmaeus and N. coucang, 212 and 68 compounds were found, respectively. Venom is activated by combining the oil from the brachial arm gland with saliva, and can cause death in small mammals and anaphylactic shock and death in humans. We examine four hypotheses for the function of slow loris venom. The least evidence is found for the hypothesis that loris venom evolved to kill prey. Although the venom's primary function in nature seems to be as a defense against parasites and conspecifics, it may also serve to thwart olfactory-orientated predators. Combined with numerous other serpentine features of slow lorises, including extra vertebra in the spine leading to snake-like movement, serpentine aggressive vocalisations, a long dark dorsal stripe and the venom itself, we propose that venom may have evolved to mimic cobras (Naja sp.). During the Miocene when both slow lorises and cobras migrated throughout Southeast Asia, the evolution of venom may have been an adaptive strategy against predators used by slow lorises as a form of Mullerian mimicry with spectacled cobras. PMID- 24074354 TI - Evolution of laparoscopic live donor nephrectomy: a single-center experience with 1510 cases over 14 years. AB - OBJECTIVE: This study evaluated the outcomes of laparoscopic donor nephrectomy (LDN) and proposed modifications for kidney donation surgery. From February 1997 to February 2011, 1510 LDNs were performed. PATIENTS AND METHODS: Surgical modifications included a modified open access technique for entry into the abdominal cavity, using vascular clips for safe and cost-effective control of the renal pedicle, control of the lumbar veins, and adrenal vein using bipolar cautery instead of clips, and leaving the gonadal vein intact with the ureter. Kidneys were extracted by hand through a Pfannenstiel incision. Heparin was not used after the first 300 cases to prevent potential hemorrhagic complications. RESULTS: Although three major vascular injuries occurred using the closed access method that were managed successfully, no access-related complications occurred using the modified open access technique. Clip failure did not happen in any cases. Patient and graft survival at 1 year post-transplantation were 96.5% and 95.5%, respectively, and at 5 years post-transplantation were 95.3% and 89.5%, respectively. CONCLUSION: The proposed surgical modifications are based on 14 years of experience and 1510 cases, and make LDN simple, safe, and cost effective. The excellent recipient and graft outcomes with minimal morbidity obtained further confirm that LDN can be considered as the gold standard for kidney donation surgery. PMID- 24074356 TI - Retraction of "Genome sequences of a novel HIV 1 circulating recombinant form (CRF59_01B) identified among MSM in China". PMID- 24074355 TI - Manipulating the sleeping beauty mutase operon for the production of 1-propanol in engineered Escherichia coli. AB - BACKGROUND: While most resources in biofuels were directed towards implementing bioethanol programs, 1-propanol has recently received attention as a promising alternative biofuel. Nevertheless, no microorganism has been identified as a natural 1-propanol producer. In this study, we manipulated a novel metabolic pathway for the synthesis of 1-propanol in the genetically tractable bacterium Escherichia coli. RESULTS: E. coli strains capable of producing heterologous 1 propanol were engineered by extending the dissimilation of succinate via propionyl-CoA. This was accomplished by expressing a selection of key genes, i.e. (1) three native genes in the sleeping beauty mutase (Sbm) operon, i.e. sbm-ygfD ygfG from E. coli, (2) the genes encoding bifunctional aldehyde/alcohol dehydrogenases (ADHs) from several microbial sources, and (3) the sucCD gene encoding succinyl-CoA synthetase from E. coli. Using the developed whole-cell biocatalyst under anaerobic conditions, production titers up to 150 mg/L of 1 propanol were obtained. In addition, several genetic and chemical effects on the production of 1-propanol were investigated, indicating that certain host-gene deletions could abolish 1-propanol production as well as that the expression of a putative protein kinase (encoded by ygfD/argK) was crucial for 1-propanol biosynthesis. CONCLUSIONS: The study has provided a novel route for 1-propanol production in E. coli, which is subjected to further improvement by identifying limiting conversion steps, shifting major carbon flux to the productive pathway, and optimizing gene expression and culture conditions. PMID- 24074357 TI - Efficacy and safety of haloperidol versus atypical antipsychotic medications in the treatment of delirium. AB - BACKGROUND: Most previous studies on the efficacy of antipsychotic medication for the treatment of delirium have reported that there is no significant difference between typical and atypical antipsychotic medications. It is known, however, that older age might be a predictor of poor response to antipsychotics in the treatment of delirium. The objective of this study was to compare the efficacy and safety of haloperidol versus three atypical antipsychotic medications (risperidone, olanzapine, and quetiapine) for the treatment of delirium with consideration of patient age. METHODS: This study was a 6-day, prospective, comparative clinical observational study of haloperidol versus atypical antipsychotic medications (risperidone, olanzapine, and quetiapine) in patients with delirium at a tertiary level hospital. The subjects were referred to the consultation-liaison psychiatric service for management of delirium and were screened before enrollment in this study. A total of 80 subjects were assigned to receive either haloperidol (N = 23), risperidone (N = 21), olanzapine (N = 18), or quetiapine (N = 18). The efficacy was evaluated using the Korean version of the Delirium Rating Scale-Revised-98 (DRS-K) and the Korean version of the Mini Mental Status Examination (K-MMSE). The safety was evaluated by the Udvalg Kliniske Undersogelser side effect rating scale. RESULTS: There were no significant differences in mean DRS-K severity or K-MMSE scores among the four groups at baseline. In all groups, the DRS-K severity score decreased and the K MMSE score increased significantly over the study period. However, there were no significant differences in the improvement of DRS-K or K-MMSE scores among the four groups. Similarly, cognitive and non-cognitive subscale DRS-K scores decreased regardless of the treatment group. The treatment response rate was lower in patients over 75 years old than in patients under 75 years old. Particularly, the response rate to olanzapine was poorer in the older age group. Fifteen subjects experienced a few adverse events, but there were no significant differences in adverse event profiles among the four groups. CONCLUSIONS: Haloperidol, risperidone, olanzapine, and quetiapine were equally efficacious and safe in the treatment of delirium. However, age is a factor that needs to be considered when making a choice of antipsychotic medication for the treatment of delirium. TRIAL REGISTRATION: Clinical Research Information Service, Republic of Korea, (http://cris.nih.go.kr/cris/en/search/basic_search.jsp, Registered Trial No. KCT0000632). PMID- 24074358 TI - Antioxidant and pro-apoptotic effects of marine-derived, multi-mineral aquamin supplemented with a pine bark extract, Enzogenol, and a green tea extract, Sunphenon. AB - A high dietary intake of polyphenols has been associated with a decreased risk of cardiovascular disease and cancer, attributed in part to their antioxidant activity and pro-apoptotic effects. Aquamin is a multi-mineral algal extract that enhances bone mineralization, relieves osteoarthritis, and aids digestion; however, Aquamin has not demonstrated antioxidant activity. In the present study, Aquamin was supplemented with 8% Enzogenol, a pine bark extract with a high phenolic content, and 2% Sunphenon, a green tea extract that also has a high phenolic content to produce a mixed product (A:E:S). The antioxidant activity of A:E:S was compared with that of its constituent compounds and also with catechin and epigallocatechin by measuring total phenol content, ferric-reducing antioxidant potential, and 2,2-diphenyl-2-picrylhydrazyl hydrate. The cytotoxic and apoptotic effects of the compounds were also measured in the U937, human monocytic blood cell line. A:E:S demonstrated an antioxidant activity that was equal to that of the compounds used in its preparation. Aquamin was not cytotoxic in the U937 cell line; however, A:E:S was cytotoxic and the primary mechanism of cell death was apoptosis. The biological effects of Aquamin were enhanced by supplementation with Enzogenol and Sunphenon to include antioxidant effects and the ability to induce apoptosis in U937 cells. PMID- 24074360 TI - The I148M variant of PNPLA3 reduces the response to docosahexaenoic acid in children with non-alcoholic fatty liver disease. AB - The aim of this secondary analysis of a randomized controlled trial was to test whether the I148M variant of Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with the response to docosahexaenoic acid (DHA) in children with non-alcoholic fatty liver disease (NAFLD). Sixty children with NAFLD were randomized in equal numbers to DHA 250 mg/day, DHA 500 mg/day or placebo. Coherently with the primary analysis, the probability of more severe steatosis after 24 months of DHA supplementation was 50% lower [95% confidence interval (CI) -59% to -42%)] in the combined DHA 250 and 500 mg/day groups versus placebo. The present secondary analysis revealed an independent effect of PNPLA3 status on the response to DHA. In fact, the probability of more severe steatosis was higher (37%, 95% CI 26-48%) for the PNPLA3 M/M versus I/M genotype and lower (-12%, 95% CI -21% to -3%) for the I/I versus I/M genotype (Somers' D for repeated measures). We conclude that the 148M allele of PNPLA3 is associated with lower response, and the 148I allele with greater response, to DHA supplementation in children with NAFLD. PMID- 24074359 TI - 2,4-Di-tert-butylphenol from sweet potato protects against oxidative stress in PC12 cells and in mice. AB - In this study, the protective effect of sweet potato extract against hydrogen peroxide-induced oxidative stress and cytotoxicity on the pheochromocytoma cell line (PC12) was investigated. The active component of the sweet potato extract was purified and determined to be 2,4-di-tert-butylphenol. The antioxidant capacity of 2,4-di-tert-butylphenol was measured by using 2,2'-azino-bis(3 ethylbenzthiazoline-6-sulfonic acid (ABTS) radical. To examine the effects of 2,4 di-tert-butylphenol on amyloid-beta peptide (Abeta11-42)-induced learning and memory impairment in mice, in vivo behavioral tests were performed. Administration of 2,4-di-tert-butylphenol increased alternation behavior in mice injected with Abeta1-42. These results suggest that sweet potato extract could be protective against Abeta-induced neurotoxicity, possibly due to the antioxidative capacity of its constituent, 2,4-di-tert-butylphenol. PMID- 24074361 TI - Evidence for NQO1 and NQO2 catalyzed reduction of ortho- and para-quinone methides. AB - NAD(P)H: quinone oxidoreductase (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinones and thereby prevent generation of toxic radicals. Quinone methides (QMs) covalently react with cellular macromolecules to form DNA adducts and/or protein conjugates resulting in toxicity and carcinogenesis. Based on similar structural features of quinones and QMs, it is logical to assume that NQO1 and/or NQO2 could also catalyze the two electron reduction of QMs. However, hitherto the reduction of QMs, as both endogenous and/or exogenous biological substrates, by either NQO1/NQO2 has never been demonstrated. Here we show for the first time that both NQO1 and NQO2 can catalyze the reduction of electrophilic ortho-/para-QMs. The involvement of the enzyme in the reduction of p-cresol quinone methide (PCQM) and o-cresol quinone methide (OCQM) was demonstrated by reappearance of NQO1/NQO2-FAD peak at 450 nm after addition of the QMs to the assay mixture. Further reduction of methides by NQO1/NQO2 was confirmed by analyzing the assay mixture by tandem mass spectrometry. Preliminary kinetic studies show that NQO2 is faster in reducing QMs than its homolog NQO1, and moreover, ortho-QMs are reduced faster than para QMs. Enzyme-substrate docking studies showed results consistent with enzyme catalysis. Thus, NQO1/NQO2 can play a significant role in deactivation of QMs. PMID- 24074362 TI - Optimization of the extraction conditions and quantification by RP-LC analysis of three alkaloids in Zanthoxylum nitidum roots. AB - CONTEXT: A classic traditional Chinese medicine, Zanthoxylum nitidum (Roxb.) DC. widely used in China, exhibits anticancer, anti-inflammatory and antianalgesic activities. Alkaloids are one of the main bioactive components. It is urgent to develop a simple and reliable method to determine the main alkaloids in Z. nitidum roots. OBJECTIVE: To determine the three alkaloids in Z. nitidum roots, a reversed-phase liquid chromatographic (RP-LC) method combined with an optimum extraction condition was established. MATERIALS AND METHODS: A method involving four-factor-three-level orthogonal array design including the extracting solvent and the RP-LC condition was assayed. Twenty batches were collected from different areas of the Guangxi Province at different harvesting times. The determined alkaloids were nitidine chloride (NC, 1), ethoxychelerythrine (2) and liriodenine (3). The stable mobile phase was a C18 packing, and the mobile phase was acetonitril-aqueous phosphoric acid-triethylamine-buffer solution. RESULTS: The optimum extraction and detection conditions have been determined in the process of quantification of Z. nitidum root alkaloids. The three alkaloids were detected simultaneously in the 20 batches of samples. The results clearly showed that alkaloid concentrations differed significantly among Z. nitidum collected from various collection areas. DISCUSSION AND CONCLUSION: We have established an optimum extraction and detection conditions in the process of quantification the three alkaloids in Z. nitidum roots. From this research, the most influenced factor on Z. nitidum roots was the collecting location, and the next factor was the harvesting time. The collecting location and the harvesting time should be considered as the high-quality medicinal herbs factors. PMID- 24074364 TI - Follicular psoriasis. PMID- 24074365 TI - The company you keep. PMID- 24074366 TI - Cochlear implant outcomes in patients with superior canal dehiscence. AB - OBJECTIVE: To determine whether adult cochlear implant (CI) users with superior canal dehiscence syndrome (SCDS) or asymptomatic superior semicircular canal dehiscence (SCD) have different surgical, vestibular, and audiologic outcomes when compared to CI users with normal temporal bone anatomy. METHODS: A retrospective single institution review of CI users with either superior semicircular canal dehiscence syndrome or asymptomatic superior semicircular canal dehiscence identified eight post-lingually deafened adults with unilateral or bilateral cochlear implantation between 2006 and 2010. Preoperative and postoperative speech perception scores as well as medical and epidemiological data were recorded and analyzed. RESULTS: One patient with superior canal dehiscence syndrome and seven patients with asymptomatic superior semicircular canal dehiscence were identified, representing 7% or 8/113 of CI patients that fulfilled selection criteria. Average dehiscence length was 3.3 mm +/- 0.79 SEM. Three patients received bilateral implants and five patients received a unilateral implant. Among asymptomatic superior semicircular canal dehiscence patients, subjective rates of post-operative dizziness were similar to those seen in patients with normal temporal bone anatomy (12.5 % vs. 15.9%, respectively). Speech perception abilities after surgery were poorer in SCD patients compared to the non-SCD cohort (Consonant Nucleus Consonant 33.7 +/- 7.78 SEM vs. 56.7 +/- 2.15 SEM P = 0.011), although both groups improved substantially relative to pre operative performance. We also completed detailed analyses of auditory and vestibular outcomes in one patient with SCDS who underwent CI surgery in the symptomatic ear, which demonstrated preservation of vestibular function post operatively, improved quality-of-life measures, and reduced dizziness symptomatology. CONCLUSIONS: Our data suggest that patients with asymptomatic superior canal dehiscence at the time of CI surgery have similar albeit decreased speech perception scores compared to non-SCD adult CI users. Subjective rate of dizziness or vertigo following CI surgery was similar in both asymptomatic SCD and non-SCD cohorts, with detailed analyses of a single symptomatic SCD patient revealing improved vestibular function and reduced SCD symptoms following CI. PMID- 24074368 TI - Missense mutation in the MEN1 gene discovered through whole exome sequencing co segregates with familial hyperparathyroidism. AB - Familial isolated hyperparathyroidism (FIHP) can be encountered in the context of multiple endocrine neoplasia type 1 (MEN1), hyperparathyroidism and jaw tumour syndrome (HPT-JT) and in familial hypocalciuric hypercalcaemia (FHH). In these syndromes, germline mutations in the relevant genes (MEN1, HPRT2 and CaSR, respectively) are detected. In some FIHP cases, the causative gene is still elusive. The objective of this study is to define the genetic basis of FIHP in a Georgian Jewish family with FIHP using whole exome capture and sequencing. DNA extracted from two sibs and one offspring from a single family all affected with multiglandular hyperparathyroidism was subjected to whole exome capturing and sequencing using the Roche NimbleGen V2 chip and the Illumina HiSeq2000 sequencing platform. Genetic variants were detected and annotated using a combination of the Genome Analysis Tool Kit and in-house scripts. Subsequent confirmation of the mutations and co-segregation analyses were carried out by Sanger sequencing in additional affected and unaffected family members. Whole exome capture and sequencing revealed the collection of variations common to the three-sequenced patients, including a very rare previously described missense mutation (c.T1021C: p.W341R) in the MEN1 gene. The p.W341R mutation in the MEN1 gene showed complete co-segregation in the family. Whole exome capture and sequencing led to the discovery of a missense mutation in the MEN1 gene and ruling out of the additional candidates in a single experiment. The limited expressivity of this mutation may imply a specific genotype-phenotype correlation for this mutation. PMID- 24074367 TI - Discovery of a cAMP deaminase that quenches cyclic AMP-dependent regulation. AB - An enzyme of unknown function within the amidohydrolase superfamily was discovered to catalyze the hydrolysis of the universal second messenger, cyclic 3',5'-adenosine monophosphate (cAMP). The enzyme, which we have named CadD, is encoded by the human pathogenic bacterium Leptospira interrogans. Although CadD is annotated as an adenosine deaminase, the protein specifically deaminates cAMP to cyclic-3',5'-inosine monophosphate (cIMP) with a kcat/Km of 2.7 +/- 0.4 * 10(5) M(-1) s(-1) and has no activity on adenosine, adenine, or 5'-adenosine monophosphate (AMP). This is the first identification of a deaminase specific for cAMP. Expression of CadD in Escherichia coli mimics the loss of adenylate cyclase in that it blocks growth on carbon sources that require the cAMP-CRP transcriptional activator complex for expression of the cognate genes. The cIMP reaction product cannot replace cAMP as the ligand for CRP binding to DNA in vitro and cIMP is a very poor competitor of cAMP activation of CRP for DNA binding. Transcriptional analyses indicate that CadD expression represses expression of several cAMP-CRP dependent genes. CadD adds a new activity to the cAMP metabolic network and may be a useful tool in intracellular study of cAMP dependent processes. PMID- 24074369 TI - High-throughput sequencing of autism spectrum disorders comes of age. AB - Autism spectrum disorders (ASDs) are lifelong neurodevelopmental disabilities that affect 1 in 88 children in the USA. Despite the high heritability, the genetic basis for a majority of the ASDs remains elusive. The considerable clinical and genetic heterogeneity pose a significant challenge technically. State-of-the-art high-throughput sequencing (HTS), which makes the analyses of any specific single/multiple genes or whole exomes feasible, has shown a promising perspective in disease gene discovery. To date, numerous genetic studies using HTS have been reported and many rare inherited or de novo mutations have been identified. This review will focus on the progress and prospective of genome studies of ASDs using HTS. PMID- 24074370 TI - A very rare entity of diabetes insipidus associated with Edwards syndrome. AB - Edwards syndrome is the second most commonly seen trisomy. It was first described by John Hamilton Edwards in 1960. Although most cases result in termination or foetal loss, live births have been documented in 5%. Edwards syndrome is characterized by multisystem anomalies, of which holoprosencephaly (HPE) is observed in 4-8% of cases. The clinical findings correspond to the degree of HPE malformation. Convulsions and endocrinopathies are among the severe clinical findings. The most common endocrinopathies are central diabetes insipidus (DI), hypothyroidism, hypocortisolism and growth hormone deficiency. The coexistence of holoproencephaly and DI in Edwards syndrome was discussed under the light of literature. PMID- 24074371 TI - Wound communities become a reality. PMID- 24074372 TI - Canadian Association Of Wound Care(CAWC). Innovations at reducing the diabetic foot burden in Canada. PMID- 24074373 TI - Surgical knife that detects cancerous cells. PMID- 24074374 TI - Reply to Cytotoxicity of silver dressings--time to think and react by Nagoba et al. PMID- 24074376 TI - Sensitivity and specificity of HPV testing: what are the facts? PMID- 24074377 TI - Meteorological factors and El Nino Southern Oscillation are associated with paediatric varicella infections in Hong Kong, 2004-2010. AB - Varicella accounts for substantial morbidities and remains a public health issue worldwide, especially in children. Little is known about the effect of meteorological variables on varicella infection risk for children. This study described the epidemiology of paediatric varicella notifications in Hong Kong from 2004 to 2010, and explored the association between paediatric varicella notifications in children aged <18 years and various meteorological factors using a time-stratified case-crossover model, with adjustment of potential confounding factors. The analysis found that daily mean temperature, atmospheric pressure and Southern Oscillation Index (SOI) were positively associated with paediatric varicella notifications. We found that an interquartile range (IQR) increase in temperature (8.38 degrees C) at lag 1 day, a 9.50 hPa increase in atmospheric pressure for the current day, and a 21.91 unit increase in SOI for the current day may lead to an increase in daily cases of 5.19% [95% confidence interval (CI) 1.90-8.58], 5.77% (95% CI 3.01-8.61), and 4.32% (95% CI 2.98-5.68), respectively. An IQR increase in daily relative humidity (by 11.96%) was associated with a decrease in daily paediatric varicella (-2.79%, 95% CI -3.84 to -1.73). These findings suggest that meteorological factors might be important predictors of paediatric varicella infection in Hong Kong. PMID- 24074378 TI - Novel PPV/mesoporous organosilica composites: influence of the host chirality on a conjugated polymer guest. AB - The conjugated polymer poly(p-phenylenevinylene) (PPV) was polymerized in the pores of chiral nematic mesoporous organosilica to give a composite film showing the strong characteristic fluorescence of PPV as well as the iridescence due to the photonic band gap of the host material. Detailed circular dichroism (CD) studies reveal a chiral structure of the polymer within the pores. These new fluorescent materials undergo fluorescence quenching upon exposure to electron deficient aromatics such as 2,4,6-trinitrotoluene (TNT), indicating that they may be useful for developing chemical sensors. PMID- 24074379 TI - The proliferation arrest of primary tumor cells out-of-niche is associated with widespread downregulation of mitotic and transcriptional genes. AB - In recording the changes acquired in gene expression profile during culture of fresh bone marrow samples from patients with multiple myeloma or acute myeloid leukemia, the most remarkable finding in both instances was widespread downregulation of mitotic and transcriptional genes (e.g. MKI67, CCNB1, ASPM, SGOL1, DLGAP5, CENPF, BUB1, KIF23, KIF18a, KIF11, KIF14, KIF4, NUF2, KIF1, AE2FB, TOP2A, NCAPG, TTK, CDC20, and AURKB), which could account for the ensuing proliferation arrest. Many of these genes were also underexpressed in leukemic cells from the blood or myeloma cells from an extramedullary site compared with their expression in the aspirates. Taken together, our results exhibited mitotic and transcriptional gene subsets where their expression appears to be coordinated and niche dependent. In addition, the genes induced during culture specified a variety of angiogenic factors (e.g. interleukin-8 and CXCL-5) and extracellular matrix proteins (e.g. osteopontin and fibronectin) probably released by the tumor cells while generating their favored microenvironment. PMID- 24074380 TI - Ordered Ag/Si nanowires array: wide-range surface-enhanced Raman spectroscopy for reproducible biomolecule detection. AB - Surface-enhanced Raman scattering (SERS) systems utilizing the interparticle nanogaps as hot spots have demonstrated ultrasensitive single-molecule detection with excellent selectivity yet the electric fields are too confined in the small nanogaps to enable reproducible biomolecule detections. Here, guided by finite difference-time-domain simulation, we report hexagonal-packed silver-coated silicon nanowire (Ag/SiNW) arrays as a nanogap-free SERS system with wide-range electric fields and controlled interwire separation. Significantly, the system achieves a SERS detection of long double-strand DNA of 25-50 nm in length with a relative standard deviation (RSD) of 14% for measurements of above 4000 spots over an area of 200 * 200 MUm(2). The high reproducibility in the SERS detection is attributed to (1) the large interwire spacing of 150 nm that allows access and excitation of large biomolecules; and (2) 600 nm wide-range electric field generated by propagating surface plasmons along the surface of continuous Ag coating on a SiNW. Moreover, a reproducible multiplex SERS measurement is also demonstrated with RSDs of 7-16% with an enhancement factor of ~10(6). The above results show that the ordered Ag/SiNW array system may serve as an excellent SERS platform for practical chemical and biological detection. PMID- 24074381 TI - DNA origami nanopores: an emerging tool in biomedicine. PMID- 24074382 TI - Ferritin nanocages: great potential as clinically translatable drug delivery vehicles? PMID- 24074383 TI - Prodrug micelle-based nanomedicine for cancer treatment. PMID- 24074387 TI - Nanosilicon for nanomedicine: a step towards biodegradable electronic implants? AB - Leigh Canham received his BSc degree in physics from University College London (London, UK) in 1979 and his PhD in solid state physics from King's College London (London, UK). He now has over 30 years of experience conducting research on widely differing aspects of silicon technology. Two key personal discoveries- that nanostructured silicon can emit visible light efficiently (1990) and can be rendered medically biodegradable (1995)--have had significant academic (>15,000 citations) and commercial (multiple companies created) impact. Professor Canham is a scientist who is devoted to finding novel properties and uses for semiconductors that already pervade our everyday lives. He has 13 years of experience of start up company management, right through from cofounding with seed venture capital finance to NASDAQ listing. He has served on the board of two companies based in England, UK, one in Singapore and one in Australia. Since 1999, he has held an Honorary Professorship at the School of Physics, University of Birmingham (Birmingham, UK) for his work on luminescent silicon. In 2011, Leigh was a shortlisted finalist for the European Inventor of the Year Award from the European Patent Office for his work on biodegradable silicon. In 2012, he became a Thomson Reuters Citation Laureate for his work on luminescent silicon. Professor Canham has authored over 150 peer-reviewed papers and has more than 100 granted patents worldwide. PMID- 24074388 TI - Gateway to understanding microparticles: standardized isolation and identification of plasma membrane-derived vesicles. AB - Microparticles (MPs) are small plasma membrane-derived vesicles that can expose molecules originating from their parental cells. As vectors of biological information they are likely to play an active role in both homeostasis and pathogenesis, making them promising biomarkers and nanomedicine tools. Therefore, there is an urgent need for standardization of MP isolation and analysis protocols to propel our understanding of MP biology to the next level. Based on current methodology and recent insights, this review proposes an optimized protocol for the isolation and biochemical characterization of MPs. PMID- 24074389 TI - Graphene-based nanomaterials for nanobiotechnology and biomedical applications. AB - Graphene family nanomaterials are currently being extensively explored for applications in the field of nanotechnology. The unique intrinsic properties treasured in their simple molecular design and their ability to work in coherence with other existing nanomaterials make graphene family nanomaterials the most promising candidates for different types of applications. This review highlights the scope and utility of these multifaceted nanomaterials in nanobiotechnology and biomedicine. In a tandem approach, this review presents the smooth inclusion of these nanomaterials into existing designs for creating efficient working models at the nanoscale level as well as discussing their broad future possibilities. PMID- 24074391 TI - A platelet-inspired paradigm for nanomedicine targeted to multiple diseases. AB - Platelets are megakaryocyte-derived anucleated cells found in the blood. They are mainly responsible for rendering hemostasis or clotting to prevent bleeding complications. Decreased platelet numbers or deficiencies in platelet functions can lead to various acute or chronic bleeding conditions and hemorrhage. On the other hand, dysregulated hyperactivity of the clotting process can lead to thrombosis and vascular occlusion. There is significant evidence that beyond hemostasis and thrombosis, platelets play crucial mechanistic roles in other disease scenarios such as inflammation, immune response and cancer metastasis by mediating several cell-cell and cell-matrix interactions, as well as aiding the disease microenvironment via secretion of multiple soluble factors. Therefore, elucidating these mechanistic functions of platelets can provide unique avenues for developing platelet-inspired nanomedicine strategies targeted to these diseases. To this end, the current review provides detailed mechanistic insight into platelets' disease-relevant functions and discusses how these mechanisms can be utilized to engineer targeted nanomedicine systems. PMID- 24074393 TI - Quality assurance in digital dental imaging: a systematic review. AB - OBJECTIVES: Doses induced by individual dental examinations are low. However, dental radiography accounts for nearly one third of the total number of radiological examinations in the European Union. Therefore, special attention is needed with regard to radiation protection. In order to lower patient doses, the staff performing dental examinations must have competence in imaging as well as in radiation protection issues. This paper presents a systematic review about the core competencies needed by the healthcare staff in performing digital dental radiological imaging quality assurance. MATERIALS AND METHODS: The following databases were searched: Pubmed, Cinahl, Pro Quest and IEEXplore digital library. Also volumes of some dental imaging journals and doctoral theses of the Finnish universities educating dentists were searched. The search was performed using both MeSH terms and keywords using the option 'search all text'. The original keywords were: dental imaging, digital, x-ray, panoramic, quality, assurance, competence, competency, skills, knowledge, radiographer, radiologist technician, dentist, oral hygienist, radiation protection and their Finnish synonyms. RESULTS: Core competencies needed by the healthcare staff performing digital dental radiological imaging quality assurance described in the selected studies were: management of dental imaging equipment, competence in image quality and factors associated with it, dose optimization and quality assurance. CONCLUSIONS: In the future there will be higher doses in dental imaging due to increasing use of CBCT and digital imaging. The staff performing dental imaging must have competence in dental imaging quality assurance issues found in this review. They also have to practice ethical radiation safety culture in clinical practice. PMID- 24074390 TI - Thermal potentiation of chemotherapy by magnetic nanoparticles. AB - Clinical studies have demonstrated the effectiveness of hyperthermia as an adjuvant for chemotherapy and radiotherapy. However, significant clinical challenges have been encountered, such as a broader spectrum of toxicity, lack of patient tolerance, temperature control and significant invasiveness. Hyperthermia induced by magnetic nanoparticles in high-frequency oscillating magnetic fields, commonly termed magnetic fluid hyperthermia, is a promising form of heat delivery in which thermal energy is supplied at the nanoscale to the tumor. This review discusses the mechanisms of heat dissipation of iron oxide-based magnetic nanoparticles, current methods and challenges to deliver heat in the clinic, and the current work related to the use of magnetic nanoparticles for the thermal chemopotentiation of therapeutic drugs. PMID- 24074394 TI - The bacterial adhesion on and the cytotoxicity of various dental cements used for implant-supported fixed restorations. AB - OBJECTIVE: Bacterial adhesion on and cytotoxicity of eight luting agents used for implant-supported restorations were investigated. MATERIALS AND METHOD: Surface roughness (Ra), surface free energy (SFE) values and three-dimensional images by atomic-force microscopy of circular specimens were determined. Bacterial suspensions of Streptococcus sanguinis and Streptococcus epidermidis were incubated at 37 degrees C for 2 h. Adhering bacteria were examined with fluorescence dye CytoX-Violet, stained with 4',6-diamidino-2-phenylindole (DAPI) and visualized by fluorescence-microscopy. Cytotoxicity-testing was done with WST 1-tests (water soluble tetrazolium). No significant differences, neither with regard to Ra nor regarding SFE were determined. RESULTS: Adherence of S. sanguinis was less on titanium, TempBondNE and TempBond. TempBond, TempBondNE, RelyX Unicem and Implantlink Semi Classic presented low amounts of S. epidermidis. WST-testing showed high cytotoxic potential of Harvard, Aqualox, TempBondNE and TempBond. No combination of low adherent bacteria with low cytotoxicity was found. CONCLUSION: From a biological in-vitro perspective, none of the cements may be recommended for implant-supported restorations. PMID- 24074395 TI - Managment of superficial infantile capillary hemangiomas with topical timolol maleate solution. AB - Capillary hemangioma is the most common benign tumor of eyelids and orbit in children. Recently, a topical beta blocker has been reported as an effective treatment for superficial capillary hemangiomas. We present a case report of two children having large capillary hemangiomas who responded well to topical treatment by 0.5% timolol maleate solution. After 12 months of treatment, the lesion has significantly reduced in size, thickness, and color in both cases. Thus, we conclude that long-term use of topical 0.5% timolol maleate solution is safe and effective in treating superficial capillary hemangiomas. PMID- 24074397 TI - Cloud point extraction of plutonium in environmental matrixes coupled to ICPMS and alpha spectrometry in highly acidic conditions. AB - A new cloud point extraction procedure has been developed for the quantification of plutonium(IV) in environmental samples. The separation procedure can be either coupled to inductively coupled plasma mass spectrometry (ICPMS) or alpha spectrometry for plutonium quantification. The method uses a combination of selective ligand (P,P'-di(2-ethylhexyl) methanediphosphonic acid (H2DEH[MDP])) and micelle shielding by bromine formation to enable quantitative extraction of Pu in highly acidic solutions. Cross-optimization of all parameters (nonionic and ionic surfactant, chelating agent, bromate, bromide, and pH) led to optimal of the extraction conditions. Figures of merit of the method for the detection using alpha spectrometry and ICPMS are reported (limit of detection, limit of quantification, minimal detectable activity, and recovery). Quantitative extractions (>95%) were obtained for a wide variety of aqueous and digested samples (synthetic urine, wastewater, drinking water, seawater, and soil samples). The method features the first successful coupling between alpha spectrometry and cloud point extraction and is the first demonstration of CPE suitability with metaborate fusion as a sample preparation approach, techniques used extensively in nuclear industries. PMID- 24074396 TI - Use of health services in people with multiple sclerosis with and without depressive symptoms: a two-year prospective study. AB - BACKGROUND: To organize tailored healthcare for people with multiple sclerosis (MS), knowledge about patterns in the use of healthcare among subgroups, such as those with depressive symptoms, is essential. Thus, the purpose of this study was to explore and compare the use of health services in people with MS and depressive symptoms, and without depressive symptoms over a period of 30 months. METHODS: Data on the use of health services by 71 people with MS and depressive symptoms, and 102 with no depressive symptoms were collected from a computerised register and by interview, then categorized with regard to disease severity (Expanded Disability Status Scale). RESULTS: People with EDSS mild and depressive symptoms used more outpatient and inpatient care compared to those with no depressive symptoms. Furthermore, they received more unsalaried informal care as well as intense rehabilitation periods. CONCLUSIONS: The issues underlying the differences in the use of healthcare need to be explored further, as well as the plausible implications for the organization of healthcare services for people with MS and depressive symptoms. Furthermore, the life situations of caregivers of people with MS and depressive symptoms should be considered, and appropriate interventions supplied in order to diminish caregiver burden. PMID- 24074398 TI - Hb Koln [beta98(FG5) [GTG -> ATG, Val -> Met]: the first report from India. AB - BACKGROUND: The group of unstable hemoglobins are associated with congenital non spherocytic hemolytic anemia due to instability of the hemoglobin molecule. They often lead to formation of the characteristic inclusion bodies or Heinz bodies. AIM: To identity the cause of mild anemia, reticulocytosis, and hepatosplenomegly in a case of non-spherocytic hemolytic anemia. MATERIALS AND METHODS: A 34-year old female patient originating from Maharashtra, western India presented with mild anemia and jaundice which had persisted since childhood. Investigations included a complete blood count, screening for red cell membrane protein defects, Hb analysis by high-performance liquid chromatography (HPLC) and cellulose acetate electrophoresis (pH 8.9), heat instability test and DNA sequencing. RESULTS: Hemoglobin analysis by HPLC showed an abnormal peak in the Hb C window (9.8%) with a retention time of 4.90 minutes. Cellulose acetate electrophoresis (pH 8.9) showed a slow moving band (6.15%) between Hb A2 and Hb S. The heat instability test was positive. DNA analysis of alpha globin genes showed absence of both deletional and non- deletional alpha thalassemia. DNA sequencing of the beta globin gene revealed heterozygosity for a mutation at codon 98 [GTG -> ATG, Val -> Met], which gives rise to Hb-Koln. CONCLUSION: Hb Koln is the commonest unstable Hb variant reported from many populations in the world. However, this is the first report of this unstable Hb variant from India. PMID- 24074399 TI - Total synthesis of herbicidin C and aureonuclemycin: impasses and new avenues. AB - The undecose nucleoside antibiotics herbicidin C and aureonuclemycin are biologically highly active and represent challenging targets for total synthesis. Herein, the gradual evolution of our synthetic strategy toward these natural products is described in detail. The initial route encompasses metalate addition chemistry but suffers from poor stereochemical control. In contrast, the ultimately successful strategy benefits from a variety of reagent-controlled stereoselective transformations, including a surprisingly facile and highly diastereoselective N-glycosylation process. The presented work also describes new building blocks that might find further application in carbohydrate chemistry. PMID- 24074401 TI - Pt@CeO2 multicore@shell self-assembled nanospheres: clean synthesis, structure optimization, and catalytic applications. AB - A clean nonorganic synthetic method has been developed to fabricate the uniform pomegranate-like Pt@CeO2 multicore@shell nanospheres in a large scale. Under the effective protection of Ar atmosphere the redox reaction just simply happened between Ce(NO3)3 and K2PtCl4 in an alkaline aqueous solution, in which no other reducing agents or surfactants were added. The as-obtained nanospheres exhibited excellent structure stability even being calcined at 600 degrees C for 5 h. Moreover, the as-obtained Pt@CeO2 multicore@shell nanospheres can be further supported on reduced graphene oxide (RGO) to form heterogeneous nanocatalyst, which has been successfully applied in the chemical reduction reaction of nitrophenol (NP) by ammonia borane (NH3BH3, dubbed as AB) instead of hazardous H2 or NaBH4. PMID- 24074400 TI - Promotion of chloroplast proliferation upon enhanced post-mitotic cell expansion in leaves. AB - BACKGROUND: Leaves are determinate organs; hence, precise control of cell proliferation and post-mitotic cell expansion is essential for their growth. A defect in cell proliferation often triggers enhanced post-mitotic cell expansion in leaves. This phenomenon is referred to as 'compensation'. Several lines of evidence from studies on compensation have shown that cell proliferation and post mitotic cell expansion are coordinately regulated during leaf development. Therefore, compensation has attracted much attention to the mechanisms for leaf growth. However, our understanding of compensation at the subcellular level remains limited because studies of compensation have focused mainly on cellular level phenotypes. Proper leaf growth requires quantitative control of subcellular components in association with cellular-level changes. To gain insight into the subcellular aspect of compensation, we investigated the well-known relationship between cell area and chloroplast number per cell in compensation-exhibiting lines, and asked whether chloroplast proliferation is modulated in response to the induction of compensation. RESULTS: We first established a convenient and reliable method for observation of chloroplasts in situ. Using this method, we analyzed Arabidopsis thaliana mutants fugu5 and angustifolia3 (an3), and a transgenic line KIP-RELATED PROTEIN2 overexpressor (KRP2 OE), which are known to exhibit typical features of compensation. We here showed that chloroplast number per cell increased in the subepidermal palisade tissue of these lines. We analyzed tetraploidized wild type, fugu5, an3 and KRP2 OE, and found that cell area itself, but not nuclear ploidy, is a key parameter that determines the activity of chloroplast proliferation. In particular, in the case of an3, we uncovered that promotion of chloroplast proliferation depends on the enhanced post-mitotic cell expansion. The expression levels of chloroplast proliferation related genes are similar to or lower than that in the wild type during this process. CONCLUSIONS: This study demonstrates that chloroplast proliferation is promoted in compensation-exhibiting lines. This promotion of chloroplast proliferation takes place in response to cell-area increase in post-mitotic phase in an3. The expression of chloroplast proliferation-related genes were not promoted in compensation-exhibiting lines including an3, arguing that an as-yet unknown mechanism is responsible for modulation of chloroplast proliferation in these lines. PMID- 24074403 TI - Presidential address for the Central Surgical Association: March 15, 2013: Practice of surgery in the next decade: The future is still bright. PMID- 24074402 TI - Lung phenotype of juvenile and adult cystic fibrosis transmembrane conductance regulator-knockout ferrets. AB - Chronic bacterial lung infections in cystic fibrosis (CF) are caused by defects in the CF transmembrane conductance regulator chloride channel. Previously, we described that newborn CF transmembrane conductance regulator-knockout ferrets rapidly develop lung infections within the first week of life. Here, we report a more slowly progressing lung bacterial colonization phenotype observed in juvenile to adult CF ferrets reared on a layered antibiotic regimen. Even on antibiotics, CF ferrets were still very susceptible to bacterial lung infection. The severity of lung histopathology ranged from mild to severe, and variably included mucus obstruction of the airways and submucosal glands, air trapping, atelectasis, bronchopneumonia, and interstitial pneumonia. In all CF lungs, significant numbers of bacteria were detected and impaired tracheal mucociliary clearance was observed. Although Streptococcus, Staphylococcus, and Enterococcus were observed most frequently in the lungs of CF animals, each animal displayed a predominant bacterial species that accounted for over 50% of the culturable bacteria, with no one bacterial taxon predominating in all animals. Matrix assisted laser desorption-ionization time-of-flight mass spectrometry fingerprinting was used to quantify lung bacteria in 10 CF animals and demonstrated Streptococcus, Staphylococcus, Enterococcus, or Escherichia as the most abundant genera. Interestingly, there was significant overlap in the types of bacteria observed in the lung and intestine of a given CF animal, including bacterial taxa unique to the lung and gut of each CF animal analyzed. These findings demonstrate that CF ferrets develop lung disease during the juvenile and adult stages that is similar to patients with CF, and suggest that enteric bacterial flora may seed the lung of CF ferrets. PMID- 24074404 TI - Percutaneous pigtail catheter versus tube thoracostomy for pediatric empyema: A comparison of outcomes. AB - PURPOSE: Randomized trials have shown no benefit to thoracoscopic decortication over pleural drainage with fibrinolytic installation for pediatric empyema. However, the optimal method of pleural drainage has not been defined. The present study compares outcomes of 8.5-Fr soft pigtail catheters (PC) placed via Seldinger technique with larger caliber, stiff chest tubes (12- to 24-Fr) placed via tube thoracostomy (TT). METHODS: A retrospective review of all pediatric patients treated for empyema during a 5-year period (2006-2011) was conducted. Clinical, therapeutic, and outcomes data from patients treated by PC were compared with those treated by TT. Treatment failure, the primary outcome, was defined as need for an additional invasive thoracic procedure (second tube or catheter or thoracoscopic decortication). RESULTS: We treated 43 patients, 21 by PC and 22 by TT. Fibrinolytics were used in 71% of the PC and 64% of the TT groups. Baseline clinical parameters were not different between the 2 groups. Treatment failure was significantly higher in the PC group (43% vs 14%; P = .045). When the analysis was limited to patients who received fibrinolytics, the failure rate was greater in the PC group (40% vs 14%; P = .129), and duration of illness was shorter (18.3 +/- 1.0 vs 25.6 +/- 3.5 days; P = .048). CONCLUSION: Soft PCs are associated with higher failure rates but shorter total duration of illness in the treatment of pediatric empyema. The ideal method for draining pediatric empyema may be a small-caliber, stiff chest tube placed percutaneously. PMID- 24074405 TI - Single-incision results in similar pain and quality of life scores compared with multi-incision laparoscopic cholecystectomy: A blinded prospective randomized trial of 100 patients. AB - BACKGROUND: Our objective was to compare hospital charges and both perioperative and mid-term quality of life between single- (SILC) and multi-incision (MILC) laparoscopic cholecystectomy in a randomized controlled trial. METHODS: Patients with acute or chronic biliary disease were invited to participate. Pain scores, quality of life, and perioperative outcomes were measured. Patients were followed for 1 year postoperatively in the clinic with examination to document hernia formation. RESULTS: One hundred subjects were randomized to SILC (n = 49) or MILC (n = 51). Demographics were similar for both groups except more women underwent SILC (86% vs 67%, P = .026). Operative time was greater for SILC (63.5 +/- 21.0 vs 43.8 +/- 24.2 minute, P < .0001). Five SILC patients required added ports. One substantial complication occurred in SILC. Pain, the use of analgesics, and duration of hospital stay were equal between groups; however, charges were greater in the SILC group ($17,602 +/- $6,089 vs $13,342 +/- $8,197, P < .0001). Both groups reported similar quality of life and cosmesis. At an average follow up of SILC (16.4 +/- 12.1 months) and MILC (16.2 +/- 10.5 months), no novel umbilical hernias were identified. CONCLUSION: SILC results in longer operative time and greater hospital charges with similar pain and quality of life scores compared with a standard laparoscopic approach. PMID- 24074406 TI - Anastomotic leak or organ space surgical site infection: What are we missing in our quality improvement programs? AB - BACKGROUND: Expert panels of colorectal surgeons consistently rank anastomotic leak as among the most important quality metrics for colectomies. Nonetheless, most administrative and clinical databases do not collect data on anastomotic leaks and rely on reported organ space surgical site infections (OSI) as a proxy for identifying anastomotic leaks. This study questions the validity of using OSI as a surrogate for anastomotic leak. METHODS: The Upstate New York Surgical Quality Initiative (UNYSQI) is a collaboration of 12 hospitals that prospectively collects colectomy-specific metrics, including anastomotic leak, in addition to standard National Surgical Quality Improvement Program (NSQIP) data, including OSIs. Cases with an organ space infection and/or anastomotic leak were selected from the 2010-2011 UNYSQI database. Patient characteristics and outcomes were compared for cases with organ space infections and anastomotic leaks. RESULTS: Overall, 3% of colectomies had a reported organ space infection and 4% had an anastomotic leak. Among cases having anastomotic leaks, only 25% were also coded as having an organ space infection, leaving 75% of anastomotic leaks not captured by the NSQIP database (kappa = 0.272; P <= .001). CONCLUSION: Organ space infection is a poor surrogate for anastomotic leak, resulting in grossly underestimated leak rates and seemingly represents different postoperative courses. Procedure-specific quality measures for colorectal surgery should include data collection on anastomotic leaks to provide accurate data for use in improving patient care. PMID- 24074407 TI - Construct validation and comparison of a novel postoperative quality-of-life metric and the Short Form-36 in colorectal surgery patients. AB - PURPOSE: Several methods have been used to measure quality of life (QOL) in colorectal patients, but existing QOL assessment tools are often complex, require complicated analysis, lack specificity for colorectal surgery, and are not focused on assessment of perioperative care. The postoperative QOL (PQL) assessment is designed to capture subtle yet important QOL factors in an easy tool validated for the postoperative period. Although internally validated, PQL lacks external validation with a universally accepted QOL metric, such as the Rand Short Form-36 (SF-36). The purpose of this study was to externally validate the PQL metric to the SF-36 for colorectal surgery. METHODS: The PQL was designed using 14 questions ranked on a Likert scale (1-10) with surgeon and patient input. After obtaining institutional review board approval, 100 consecutive colorectal surgery patients at University Hospitals, Case Medical Center were administered baseline and postoperative (2, 4, 8, 12, 30, 60, and 90 days) PQL and SF-36 questionnaires prospectively. Patients undergoing colorectal surgery via an abdominal approach (laparoscopic or open) for benign or malignant disease were included. Factor analysis and Spearman's rank test were performed between each of the 8 SF-36 scales and the 14 PQL questions and summary score. Convergent validity was demonstrated using Spearman's correlation coefficient at the domain and scale levels. The degree of agreement between PQL and SF-36 was assessed through Bland-Altman plots. Pairwise comparisons were made to determine any significant differences between the 2 scales. RESULTS: Eighty-eight patients met all inclusion criteria and had a complete dataset, and were included in the analysis. SF-36 factor analysis confirmed comparability between the study group and the general population. All PQL items correlated with all 8 mental and physical health domains in the SF-36 (P < .0001). Bland-Altman plots demonstrated consistently similar measure for level of agreement between PQL and SF-36 as indicated by the 95% limits of agreement. CONCLUSION: The PQL and SF-36 demonstrated a strong and consistent level of agreement across all 8 domains for pre- and postoperative scores in colorectal surgery patients. PQL is constructually valid in the perioperative period. Based on our analysis, the novel PQL metric represents a simple, point-of-care alternative to SF-36 for rapid QOL assessment, and validates use of the PQL metric in abdominal surgery. PMID- 24074408 TI - Trends and disparities in education between specialties in thyroid and parathyroid surgery: An analysis of 55,402 NSQIP patients. AB - PURPOSE: To determine practice patterns/outcomes and educational opportunities in endocrine surgery by resident involvement in general surgery (GS) and otolaryngology (ENT). METHODS: We queried the American College of Surgeon National Surgical Quality Improvement Program for thyroid/parathyroid operations. Resident involvement was categorized by postgraduate year (PGY) and specialty. RESULTS: Of 38,257 thyroid patients, attendings alone performed 28% in GS versus 65% in ENT, and of 17,145 parathyroid patients, 22.1% vs 66.5%. Of GS cases done with housestaff, the percentages with junior residents (PGY1-3), senior residents (PGY4,5), and fellows were 42%, 50%, and 7%, respectively, whereas for ENT operations, the percentages were 35%, 46%, and 16%. For parathyroidectomies, the percentages were 41.1%/46.8%/12.1% vs 38.7%/45.9%/15.5%. Operative time was less for GS (115 minutes) versus ENT (123 minutes). Time in the operating room increased with increasing PGY in ENT, but not in GS. Case complexity and outcomes were similar. Duration of hospital stay was greater in ENT. CONCLUSION: No differences exist in case complexity between specialties. More thyroid/parathyroid operations are performed with residents in GS; junior residents in GS perform a large percentage of these cases (~40%), indicating early exposure to endocrine surgery and balanced experience between resident levels with minimal effect of fellows. Although junior residents receive exposure in ENT, a greater proportion is performed by fellows. Outcomes were similar by resident level, except operative time, which was greater for ENT at all levels. Ultimately, equal outcomes but lesser operating times and durations of hospital stay are seen with GS residents than their ENT counterparts. PMID- 24074409 TI - Nodule size is an independent predictor of malignancy in mutation-negative nodules with follicular lesion of undetermined significance cytology. AB - BACKGROUND: In thyroid nodule fine-needle aspiration (FNA) cytology, the atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) category has a 5-15% malignancy risk that increases to 85-99% when mutation testing for BRAF, RAS, RET/PTC, or PAX8/PPARgamma is positive. However, negative testing does not exclude malignancy. The study objective was to identify clinical and imaging features that predict cancer in mutation-negative AUS/FLUS thyroid nodules. METHODS: All patients were reviewed (April 2007 to April 2009) who had AUS/FLUS cytology, negative prospective molecular testing of FNA, and histopathology. RESULTS: Of the 230 nodules, 12 (5.2%) were malignant in 11 of 190 patients, and known clinical risk factors for thyroid cancer did not predict malignancy. On preoperative imaging, >=1 suspicious ultrasound feature was identified in 33% of nodules and occurred regardless of histology (P = .23). Malignant mutation-negative AUS/FLUS nodules were larger than benign nodules (mean maximum diameter, 33.6 vs 24.0 mm; P = .007). On multivariate analysis, nodule size remained an independent predictor of malignancy (odds ratio, 1.043; P = .018). We observed no malignancies in 88 mutation-negative AUS/FLUS nodules <18.5 mm. CONCLUSION: Size is an independent predictor of malignancy in mutation negative AUS/FLUS nodules and the risk increased 4.3% with every millimeter increase in nodule size. Selected patients with small, mutation-negative AUS/FLUS thyroid nodules may be managed with ultrasound surveillance in lieu of thyroidectomy. PMID- 24074410 TI - EZH2-shRNA-mediated upregulation of p21waf1/cip1 and its transcriptional enhancers with concomitant downmodulation of mutant p53 in pancreatic ductal adenocarcinoma. AB - PURPOSE: Enhancer of zeste homologue 2 (EZH2), a component of the chromatin modification protein complex, is upregulated in pancreatic ductal adenocarcinoma (PDAC), whereas loss of p53 and its downstream target, p21(waf1/cip1), is also observed frequently. We sought to investigate the role of the p53-p21(waf1/cip1) pathway in relation to EZH2-mediated inhibition of PDAC. METHODS: The PANC-1 cell line was utilized in chromatin immunoprecipitation, gene profiling, Western blot, cell invasion, cell proliferation, and tumor xenograft assays. RESULTS: Western blot analysis with antibodies that recognize both wild-type and mutant p53 did not show any alterations in band intensity; however, antibody that detects only mutant p53 showed a band of significantly lesser intensity with EZH2 knockdown. Western blot analysis further revealed a significant upregulation of p21(waf1/cip1). Gene expression profile analysis indicated significantly enhanced transcripts of transcriptional inducers of p21(waf1/cip1), with downregulation of mutant p53 transcript, corroborating the Western blot analysis. PANC-1 cells expressing EZH2-short hairpin RNA displayed markedly attenuated growth in SCID mice. CONCLUSION: Downregulation of mutant p53 with concomitant enhanced expression of p21(waf1/cip1) and its transcriptional trans-activators may contribute toward EZH2-mediated suppression of PDAC. PMID- 24074411 TI - Clinical scenarios associated with local recurrence after laparoscopic radiofrequency thermal ablation of colorectal liver metastases. AB - BACKGROUND: Over the last decade, radiofrequency thermal ablation (RFA) has been incorporated into the treatment algorithm of patients with unresectable colorectal liver metastases (CLM). For this population, the local recurrence (LR) rate is a key parameter used to assess the success of RFA. LR is defined as development of new tumor abutting and/or in 1 cm of an ablation zone. The aim of this study is to correlate LR with other hepatic or extrahepatic recurrence and patient survival. METHODS: Between 2000 and 2011, 252 patients with CLM underwent laparoscopic RFA of 883 lesions. These patients were followed under a prospective protocol with quarterly liver computed tomography and blood work, including carcinoembryonic antigen levels quarterly for the first 2 years and then biannually. Clinical scenarios associated with LR were identified and categorized as being "isolated LR," "LR associated with new liver disease," or "LR associated with systemic disease." Demographic, clinical, and survival data were assessed using analysis of variance, Chi-square test, and univariate and multivariate Kaplan-Meier analysis. RESULTS: One hundred eighteen patients (47%) developed LR after their initial laparoscopic RFA. These were 85 men (72%) and 33 women (28%), with a mean age of 70 +/- 8 years. For this cohort, the mean of number of lesions was 3.1 +/- 0.2 cm (range, 1-11) and dominant tumor size 2.9 +/- 0.1 cm (range, 0.7-6.5) at the time of initial RFA. The LR rate per lesion was 29%. Of the patients who developed treatment failure at the RFA site, this was an isolated LR in 31 (26%) patients, associated with new liver disease in 51 (43%) and systemic metastases in 36 patients (31%). When patients with different clinical scenarios associated with LR were compared, no clinical predictors were identified to differentiate these subgroups. At a median follow up of 30 months (range, 3-113), the Kaplan-Meier median overall survival (OS) for patients with and without LR were 28 vs 31 months, respectively (P = .103). The OS for patients whose LR was isolated, associated with new liver and systemic recurrences was 39, 26, and 22 months, respectively (P = .009). CONCLUSION: This study shows that, although the presence of LR does not negatively impact on survival, the pattern of recurrent disease does. LR after RFA for CLM is most often associated with new liver and systemic recurrences, reflecting the aggressive biology of cancer in patients channeled to this treatment modality. PMID- 24074412 TI - Clinical evaluation of somatostatin use in pancreatic resections: Clinical efficacy or limited benefit? AB - BACKGROUND: The benefit of somatostatin for the prevention of pancreatic fistula has been debated widely in the literature. The aim of this study was to evaluate the efficacy of somatostatin in preventing pancreatic fistulas and improving postoperative outcomes after pancreatic resection. HYPOTHESIS: Somatostatin improves postoperative outcomes after pancreatectomy. METHODS: A review was performed of a prospectively collected 2002 patient hepatopancreaticobiliary database. Patients were included if they underwent pancreatectomy between October 1, 2000, and May 16, 2012. Patients received somatostatin prophylactically at the discretion of their surgeon. Data were analyzed using univariate and multivariate analysis to determine if somatostatin had any effect on pancreatic fistula formation, fistula severity, duration of stay, and readmission rates. RESULTS: We identified 510 patients who underwent pancreatectomy. Overall, patients 30 (6%) developed postoperative pancreatic fistulas and 27 (5%) fistulas were of clinical significance (grade B or C). Somatostatin was administered prophylactically to 215 (42%) patients, 57 patients (11%) were readmitted; the median duration of stay was 9 days (range, 2-81). Pancreatic fistula developed in 7 patients (3%) who received somatostatin versus 23 (8%) who did not receive somatostatin (P = .031). Among patients receiving somatostatin, 6 fistulas (3%) were of clinical significance versus 21 fistulas (7%) for patients who did not receive somatostatin (P = .031). Readmission occurred in 27 patients (13%) who received somatostatin versus 30 patients (10%) who did not receive somatostatin (P = .398). The median duration of stay was 9 days (range, 2-48) for patients who received somatostatin versus 9 days (range, 2-81) for patients who did not receive somatostatin (P = .462). CONCLUSION: Somatostatin use was associated with a significant decrease in both the rate of fistula formation and the number of clinically important fistulas in our pancreatectomy patients. Continued evaluation of somatostatin use in relation to both intraoperative predictors and costa are needed to better define the population that will gain clinical benefit and cost savings. PMID- 24074413 TI - Laparoscopic cholecystectomy for biliary dyskinesia: Which patients have long term benefit? AB - PURPOSE: Biliary dyskinesia (BD) is described as biliary colic in the absence of gallstones. The diagnosis relies on imaging studies and decreased excretion of bile in response to cholecystokinin during quantitative cholescintigraphy. The purpose of this study was to evaluate the success of laparoscopic cholecystectomy (LC) for relieving symptoms in patients diagnosed with BD and correlate gallbladder ejection fraction (EF) with symptom relief. METHODS: A retrospective review was performed at a single institution of all patients who underwent LC for BD from January 2005 through January 2012. The diagnosis of BD was determined by a normal gallbladder as viewed with ultrasonography and cholescintigraphy with a gallbladder EF less than or equal to 45%. Data collection included demographics, results of imaging studies, pathologic diagnosis, and early postoperative pain relief. Patients were contacted by phone after being discharged from the surgeon's care for evaluation of symptom relief. Data were analyzed with nonparametric statistical methods, including Mann-Whitney U test, receiver operator characteristic, Fisher exact test, and chi(2) test. All data are expressed as median and 25th and 75th percentile range. RESULTS: There were 126 patients who had a LC for BD during the study period. The median biliary EF was 20% (10-29%). The most common pathologic finding was chronic cholecystitis (n = 95; 75%). Median length of follow-up in the perioperative period was 11 days (8 17), during which time 98 patients (78%) had relief of symptoms. Phone interviews (n = 53; 42%) confirmed 66% (n = 35) of patients remained free of pain. There was no difference in the mean EF among those with resolution of pain 20% (10-29%) compared with patients with persistent pain 23% (11-29%), P = .62. Obese patients were more likely to have persistent symptoms in the perioperative period with a shift to lower body mass index at the time of the phone survey. Receiver operator characteristic characteristic for the association between scintigraphic EF and resolution of postoperative pain demonstrated no association, with the area under the curve equal to 0.47. CONCLUSION: The majority of patients in this series with BD had resolution of symptoms with LC. However, cholescintigraphy EF did not correlate with outcome. Further studies are needed to better identify patients diagnosed with BD who will benefit from LC. PMID- 24074414 TI - Use of the Gastrografin challenge in patients with a history of abdominal or pelvic malignancy. AB - BACKGROUND: The Gastrografin (GG) challenge was developed to predict the need for operative management in patients with small bowel obstruction (SBO). Although clinical trials have demonstrated that it is an effective diagnostic and therapeutic modality, these studies excluded patients with a history of abdominal/pelvic malignancy. This study aims to examine the outcomes of the GG challenge for patients with a history of abdominal/pelvic malignancies. METHODS: Institutional review board approval was obtained to review retrospectively patients admitted with SBO in 3 separate categories: Group 1, patients presenting between 2010 and 2012 with SBO who received the GG challenge and had a concurrent history of abdominal or pelvic malignancy; group 2, patients presenting between 2010 and 2012 with SBO who underwent the GG challenge but did not have a concurrent history of abdominal or pelvic malignancy; and group 3, patients presenting between 2007 and 2010 (before our incorporation of the GG challenge protocol) with SBO and a concurrent history of abdominal or pelvic malignancy who did not receive GG . Two distinct comparisons were made. The first analysis was made between groups 1 and 2. The second comparison was performed comparing patients from groups 1 and 3. RESULTS: A total of 237 patients (74 group 1, 83 group 2, 80 group 3) were identified with a mean age of 69.1 years (range, 20 101); 115 were male (48%).There were no adverse events related to GG administration in our study. Analysis of groups 1 and 2 showed similar rates of exploration (25% vs 18%) and complications (32% vs 24%); however, mortality was greater among patients with history of malignancy at 12 months (26% vs 7%). Both groups had similar readmission rates for SBO, as well as exploration upon readmission. Analysis between groups 1 and 3 showed that the need for operative exploration at index admission was less in patients who underwent the GG challenge (26% vs 41%); however, hospital duration of stay was similar (8 vs 9 days). There was no difference in SBO recurrence at 12 months (28% vs 26%); however, mortality was significantly greater among patients not receiving GG (26% vs 41%). CONCLUSION: The GG challenge was safe and effective in patients presenting with SBO and a history of abdominal or pelvic malignancy. As a result, GG has the potential to improve these terminal patients' quality of life. PMID- 24074415 TI - Surgical outcomes after total pancreatectomy and islet cell autotransplantation in pediatric patients. AB - BACKGROUND: This study aims to review surgical outcomes of pediatric patients undergoing total pancreatectomy with islet cell autotransplantation (TP/IAT) for the treatment of chronic pancreatitis (CP). METHODS: All pediatric patients (<=18 years old) undergoing TP/IAT over a 10-year period (December 2002-June 2012) were identified for inclusion in a single-center, observational cohort study. Retrospective chart review was performed to identify pertinent preoperative, perioperative, and postoperative data, including narcotic usage, insulin requirements, etiology of pancreatitis, previous operative interventions, operative times, islet cell yields, duration of hospital stay, and overall quality of life. Quality of life was assessed using the Short Form-36 health questionnaire. RESULTS: Fourteen pediatric patients underwent TP/IAT for the treatment of CP at the University of Cincinnati with a mean age of 15.9 years (range, 14-18) and a mean body mass index of 21.8 kg/m(2) (range, 14-37). Of the patients, 50% (n = 7) were male and 29% had undergone previous pancreatic operations (1 each of Whipple, Puestow, Frey, and Berne procedures). Etiology of pancreatitis was idiopathic for 57% (n = 8); the remainder had identified genetic mutations predisposing to pancreatitis (CFTR, n = 4; SPINK1, n = 1; PRSS1, n = 1). Mean operative time was 532 minutes (range, 360-674) with an average hospital duration of stay of 16 days (range, 7-37). Islet cell isolation resulted in mean islet cell equivalents (IEQ) of 500,443 in patients without previous pancreatic surgery versus 413,671 IEQ in patients with prior pancreatic surgery (P = .12). Median patient follow-up was 9 months from surgery (range, 1-78). Preoperatively, patients required on average 32.7 morphine equivalent mg per day (MEQ), which improved to 13.9 MEQ at most recent follow-up. Eleven patients (79%) were narcotic independent. None of the patients were diabetic preoperatively. All of the patients were discharged after the operation with scheduled insulin requirements (mean, 17 U/d). This requirement decreased to a mean of 10.1 U/d at most recent follow-up visit. Four patients (29%) progressed to insulin independence. All patients in this series achieved stable glycemic control postoperatively and there was no incidence of "brittle" diabetes. Quality-of-life surveys showed improvement in all tested modules. CONCLUSION: This study represents one of the largest series examining TP/IAT in the pediatric population. Pediatric patients benefitted from TP/IAT with a decrease in postoperative narcotic requirements, stable glycemic control, and improved quality of life. PMID- 24074416 TI - Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors. AB - PURPOSE: The biologic potential of nonfunctioning pancreatic neuroendocrine tumors (PNETs) is highly variable and difficult to predict before resection. This study was conducted to identify clinical and pathologic factors associated with malignant behavior and death in patients diagnosed with PNETs. METHODS: We used International Classification of Diseases 9th edition codes to identify patients who underwent pancreatectomy for PNETs from 1998 to 2011 in the databases of 4 institutions. Functioning PNETs were excluded. Multivariate regression Cox proportional models were constructed to identify clinical and pathologic factors associated with distant metastasis and survival. RESULTS: The study included 128 patients-57 females and 71 males. The age (mean +/- standard deviation) was 55 +/ 14 years. The body mass index was 28 +/- 5 kg/m(2). Eighty-nine (70%) patients presented with symptoms, and 39 (30%) had tumors discovered incidentally. The tumor size was 3.3 +/- 2 cm with 56 (44%) of the tumors measuring <=2 cm. Seventy three (57%) patients had grade 1 histology tumors, 37 (29%) had grade 2, and 18 (14%) had grade 3. Peripancreatic lymph node involvement was present in 31 patients (24%), absent in 75 (59%), and unknown in 22 (17%). Distant metastasis occurred in 18 patients (14%). There were 12 deaths, including 1 perioperative, 8 disease related, and 3 of unknown cause. With a median follow-up of 33 months, the overall 5-year survival was 75%. Multivariate Cox regression analysis identified age >55 (hazard ratio [HR], 5.89; 95% confidence interval [CI], 1.64 20.58), grade 3 histology (HR, 6.08; 95% CI, 1.32-30.2), and distant metastasis (HR, 8.79; 95% CI, 2.67-28.9) as risk factors associated with death (P < .05). Gender, race, body mass index, clinical symptoms, lymphovascular and perineural invasion, and tumor size were not related to metastasis or survival (P > .05). Three patients with tumors <=2 cm developed distant metastasis resulting in 2 disease-related deaths. CONCLUSION: Age >55 years, grade 3 histology, and distant metastasis predict a greater risk of death from nonfunctioning PNETs. Resection or short-term surveillance should be considered regardless of tumor size. PMID- 24074417 TI - Rate of growth of pancreatic serous cystadenoma as an indication for resection. AB - BACKGROUND: The purpose of this study was to examine the natural history and growth rate of pancreatic serous cystadenomas (SCAs) to determine which factors lead to resection for these benign neoplasms. METHODS: We reviewed retrospectively a prospectively maintained database, identifying patients diagnosed with SCAs of the pancreas. The diagnosis was made via a combination of classic imaging features with or without cyst aspiration results consistent with SCA. To determine growth rates, gamma regression models were used and the average was modeled using the log function. RESULTS: A prospectively maintained database of 1,241 pancreatic cystic neoplasms was queried from 1998 to 2010. A total of 219 patients (18%) were diagnosed with SCA, 194 in the surveillance group and 25 in the resection group. Twenty patients underwent resection after initial imaging principally for presence of symptoms and indeterminate diagnosis, and 5 underwent resection after surveillance for development of symptoms and/or rapid rate of growth. Rate of growth increased at a steady state over time, with an estimated doubling time of 12 years (95% confidence interval, 7.8-21.5). CONCLUSION: This study shows that growth patterns are similar for SCAs of the pancreas regardless of initial size. When doubling time is faster than 12 years, resection should be considered. PMID- 24074419 TI - Risk of pulmonary embolism in trauma patients: Not all created equal. AB - INTRODUCTION: Patients with traumatic brain injury (TBI) are assumed to be at an increased risk for pulmonary embolism (PE). Delay in the initiation of chemoprophylaxis and prophylactic placement of inferior vena cava filters have been advocated by some because of concerns for increased intracranial hemorrhage in the presence of prophylactic anticoagulation. We hypothesized that patients with isolated TBI would not be at increased risk for the development of PE compared with the general trauma population. METHODS: Patients from the National Trauma Data Bank from the year 2008 were analyzed. Patient demographics, Injury Severity Score, and the prevalence of deep-vein thrombosis and PE were extracted. Studied injuries were assigned to six categories: thorax, abdominal solid organs, pelvic fracture, lower extremity fracture, spine fracture, and TBI. RESULTS: Of a total of 627,775 injured patients, 2,182 (0.35%) had a documented PE. The prevalence of PE in patients with isolated TBI, lower extremity, pelvic fracture, liver and/or spleen, thorax, spine, multiple injuries, and none of the studied injuries were 0.25%, 0.36%, 0.35%, 0.37%, 0.52%, 0.37%, 1.1%, and 0.12%, respectively. Using an age-, sex- and race-adjusted multivariable logistic regression model and controlling for interaction between inferior vena cava filters and injury types, we found that isolated TBI was not associated with PE. CONCLUSION: Isolated TBI does not appear to be associated with an increased incidence of PE compared with other injuries. Patients with isolated TBI may not require early aggressive prophylaxis as is the standard for other high-risk groups. PMID- 24074418 TI - Obesity increases malignant risk in patients with branch-duct intraductal papillary mucinous neoplasm. AB - BACKGROUND: Obesity is an established risk factor for pancreatic adenocarcinoma. No study has examined specifically the influence of obesity on malignant risk in patients with intraductal papillary mucinous neoplasm (IPMN), a group at substantial risk of pancreatic adenocarcinoma. We hypothesize that obesity is associated with a greater frequency of malignancy in IPMN. METHODS: Data on patients undergoing resection for IPMN between 1992 and 2012 at a high-volume university institution were collected prospectively. Clinicopathologic and demographic parameters were reviewed. Patients were classified according to World Health Organization categories of body mass index (BMI). Malignancy was defined as high-grade dysplastic or invasive IPMN. RESULTS: We collected data on 357 patients who underwent resection for IPMN. Of these, 274 had complete data for calculation of preoperative BMI and 31% had malignant IPMN. Of 254 patients with a BMI of <35 kg/m(2), 30% had malignant IPMN versus 50% in patients with BMI of >=35 (P = .08). In branch-duct IPMN, patients with a BMI of <35 had 12% of malignant IPMN compared with 46% in severely obese patients (P = .01). Alternatively, in main-duct IPMN, no difference was found in the malignancy rate (48% vs 56%; P = .74). CONCLUSION: These findings suggest that obesity is associated with an increased frequency of malignancy in branch-duct IPMN. Obesity is a potentially modifiable risk factor that may influence oncologic risk stratification, patient counseling, and surveillance strategy. PMID- 24074420 TI - Radiographic assessment of ground-level falls in elderly patients: Is the "PAN SCAN" overdoing it? AB - INTRODUCTION: Routine, whole-body computed tomography imaging (PAN-SCAN) has been shown to identify unexpected injuries and alter the management of patients presenting with blunt trauma. We sought to characterize the changes in practice over time and the utility of PAN-SCAN imaging in elderly patients who fall and require admission to a trauma center. METHODS: We performed a retrospective analysis by using data derived from a Pennsylvania state-wide trauma registry (2007-2010). All hemodynamically stable patients (>65 years) who had a ground level fall and were admitted for >24 hours were selected. Patients who underwent a combination of all three scans within 2 hours of arrival were considered to have underwent PAN-SCAN imaging. Clinical outcomes were compared across PAN-SCAN patients relative to less diagnostic imaging. Regression analysis was used to determine whether PAN-SCAN imaging was an independent determinate of mortality and resource use. RESULTS: Over the period of study, 13,043 patients met inclusion criteria. The annual rate of PAN-SCAN imaging after ground-level falls increased over time. After we controlled for important confounders, PAN-SCAN imaging was not associated with mortality (odds ratio 0.97, P = .74, 95% confidence interval 0.80-1.18). Despite greater injury severity, PAN-SCAN imaging was independently associated with significantly lesser intensive care unit requirements, step-down days, and a lesser overall duration of stay. CONCLUSION: PAN-SCAN imaging has become more common over time in elderly patients having a ground-level fall. Although PAN-SCAN imaging during the initial trauma evaluation was not associated with an independent decrease in the risk of mortality, it was independently associated with lesser hospital resource use. These data suggest that whole-body computed tomography imaging may benefit trauma center resource use for patients with ground-level falls. PMID- 24074421 TI - Retention of suturing and knot-tying skills in senior medical students after proficiency-based training: Results of a prospective, randomized trial. AB - PURPOSE: We evaluated suturing skills performance and retention in senior medical students (MS4) at the beginning of their fourth year and 7 months later. METHODS: MS4 students entering a surgery specialty were randomized to a proficiency-based suturing/knot-tying curriculum at the beginning of fourth year (Intervention, n = 11) versus no training (Control, n = 10). Time and technical proficiency (TP, proficiency >=3) were assessed at baseline and 7 months. Performance was compared with past "Boot-Camp" MS4, categorical PGY-1 interns and PGY-2 residents. Data are mean +/- SD. RESULTS: At baseline, Intervention and Control MS4 had similar total task times (848 +/- 199 vs 845 +/- 209 seconds) and TP scores (1.8 +/- 0.15 vs 1.8 +/- 0.3). At 7 months, Intervention MS4 total task times were faster (549 +/- 80 vs 719 +/- 151 seconds, P < .01) and mean TP scores greater (3.3 +/- 0.6 vs 2.1 vs 0.4, P < .001) than Control MS4. Intervention MS4 also performed better at 7 months than Boot-Camp MS4 (662 +/- 171 seconds and 2.6 +/- 0.5, P < .04) and were similar to PGY-1 interns (601 +/- 74 seconds, TP 2.7 +/- 0.7 seconds) and end of PGY-2 residents (475 +/- 81 seconds and 3.6 +/- 0.3 seconds). CONCLUSION: A proficiency-based suturing and knot-tying curriculum taught early in the fourth year results in improved MS4 performance compared with no training or a traditional "boot camp" program. PMID- 24074422 TI - Preoperative axillary imaging with percutaneous lymph node biopsy is valuable in the contemporary management of patients with breast cancer. AB - BACKGROUND: ACOSOG Z11 and other studies showing little benefit to axillary dissection (ALND) for early-stage breast cancers with limited nodal disease have led to questioning the value of preoperative axillary imaging +/- ultrasound guided needle biopsy (USNB). Data are lacking on the value of this approach in identifying cases that fall outside Z11 guidelines. METHODS: We studied 988 consecutive patients with invasive breast cancers who underwent operation including axillary surgery in 2010-2011. RESULTS: Preoperative axillary ultrasonography (AUS) was performed in 92% and breast/axillary magnetic resonance imaging (MRI) in 51%; 82 (33.5%) of 245 patients with suspicious lymph nodes (LN) were USNB-positive. Regarding nodal status, AUS, MRI, and USNB had negative and positive predictive values of 78%, 76%, 70% and 54%, 58%, 100%, respectively. AUS/MRI visualization of one versus multiple abnormal LNs visualized predicted >2LN+ on final pathology (13.5%/15.1% % vs 30.8%/32.6%, P < .009). Among USNB-LN+ T1/T2 patients, 51.6% had 1-2 LN+ while 60% with multiple and 31% with one AUS abnormal LN(s) had > 2LN+, P = .001. CONCLUSION: In our contemporary series, preoperative AUS+/-USNB streamlined surgical care for 29% of node-positive patients. Two-thirds of T1/T2 USNB-LN+ patients with multiple AUS-suspicious LNs had >2LN+, suggesting they should undergo ALND without SLNB. AUS+/-USNB helps identify node-positive breast cancer patients who fall outside Z11 guidelines. PMID- 24074423 TI - Pharmacologic stimulation of the nicotinic anti-inflammatory pathway modulates gut and lung injury after hypoxia-reoxygenation injury. AB - PURPOSE: Pre-injury vagal nerve stimulation protects against gut and lung injury after experimental hemorrhagic shock (HS). This likely occurs via the cholinergic anti-inflammatory pathway and the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). We hypothesized that, in an in vitro model, either nicotine or a selective alpha7nAChR agonist (AR-R17779) would modulate intestinal and pulmonary effects of gut ischemia-reperfusion after hypoxic insult. METHODS: Confluent HT29 intestinal epithelial cells were co-cultured with Escherichia coli. Cell cultures were subjected to 21% (control) or 5% O2 (hypoxia) for 90 minutes followed by reoxygenation (H/R). HT29 cells were treated with nicotine or AR-R17779 before or immediately after hypoxic insult. From the HT29 cell culture supernatants, tumor necrosis factor-alpha and interleukin-6 levels were quantitated. Confluent pulmonary microvascular epithelial cells (HMVEC) were co-cultured with HT29 supernatants and permeability and intercellular adhesion molecule-1 expression were determined. RESULTS: In post H/R insult treatments with the receptor agonist, cytokine levels in HT29 cells were reduced to control levels. In HMVEC experiments, a protective effect was seen with treatment post H/R injury. Disruption of HT29 actin microfilaments was demonstrated after H/R insult and was abrogated by both agonists. CONCLUSION: Post-insult pharmacologic stimulation seems to mimic the protective effects of pre-HS vagal nerve stimulation seen in animal studies. PMID- 24074424 TI - Partial versus total splenectomy in children with hereditary spherocytosis. AB - BACKGROUND: Partial splenectomy is utilized selectively in children with hereditary spherocytosis (HS) to decrease hemolysis while maintaining immunity. Our aim was to compare outcomes between laparoscopic total splenectomy (LTS) and laparoscopic partial splenectomy (LPS). METHODS: After obtaining institutional review board approval, we reviewed the records for all children <=18 years with HS undergoing LTS and LPS between 2002 and 2012. Wilcoxon rank-sum tests were used. RESULTS: Eighty-seven HS children underwent LTS (n = 71) and LPS (n = 16). Mean age was 7.1 +/- 3.6 years (LTS) and 5.5 +/- 2.8 years (LPS; P = .14). Concomitant cholecystectomy was performed in 32% of LTS and 38% of LPS cases. Operative time was 87 +/- 33 minutes (LTS) and 140 +/- 36 minutes (LPS; P = .0005). Duration of stay was 1.2 +/- 0.5 days (LTS) and 2.4 +/- 1.4 days (LPS; P = .003). Reticulocyte and hemoglobin levels improved after both operations. LPS children had lower preoperative (8.8 +/- 1.9 vs 10.2 +/- 1.7 g/dL; P = .0148) and postoperative (10.5 +/- 1.7 vs 13.8 +/- 1.1 g/dL; P < .0001) hemoglobin levels than did LTS patients. Three LPS children required transfusion (at 2, 4 and 5 postoperative years) for parvovirus-associated aplastic crises. No LTS child developed splenic function or anemia. CONCLUSION: These data demonstrate that LPS decreases hemolysis, although LTS is more effective. LPS children had lower preoperative hemoglobin levels, indicating more severe hemolysis. LPS also has greater operative time and duration of stay, disadvantages balanced by retained immunity. PMID- 24074425 TI - Gastroesophageal reflux disease, proton-pump inhibitor use and Barrett's esophagus in esophageal adenocarcinoma: Trends revisited. AB - PURPOSE: Screening for esophageal adenocarcinoma (EAC) has not become policy in part over concerns in identifying the high-risk group. It is often claimed that a significant proportion of patients developing EAC do not report preexisting reflux symptoms or prior treatment for gastroesophageal reflux disease (GERD). As such, our aim was to assess the prevalence of GERD symptoms, proton pump inhibitor (PPI) use and Barrett's esophagus (BE) and their impact on survival in patients undergoing esophagectomy for EAC. METHODS: The study population consisted of 345 consecutive patients who underwent esophagectomy for EAC between 2000 and 2011 at a university-based medical center. Patients with a diagnosis of esophageal squamous cell carcinoma and those who underwent esophagectomy for benign disease were excluded. The prevalence of preoperative GERD symptoms, defined as presence of heartburn, regurgitation or epigastric pain, PPI use (>6 months) and BE, defined by the phrases "Barrett's esophagus," "intestinal epithelium," "specialized epithelium," or "goblet cell metaplasia" in the patients' preoperative clinical notes were retrospectively collected. Overall long-term and stage-specific survival was compared in patients with and without the presence of preoperative GERD symptoms, PPI use, or BE. RESULTS: The majority of patients (64%; 221/345) had preoperative GERD symptoms and a history of PPI use (52%; 179/345). A preoperative diagnosis of BE was present in 34% (118/345) of patients. Kaplan-Meier survival analysis revealed a marked survival advantage in patients undergoing esophagectomy who had preoperative GERD symptoms, PPI use or BE diagnosis (P <= .001). The survival advantage remained when stratified for American Joint Committee on Cancer stage in patients with preoperative PPI use (P = .015) but was less pronounced in patients with GERD symptoms or BE (P = .136 and P = .225, respectively). CONCLUSION: These data show that the oft-quoted statistic that the majority of patients with EAC do not report preexisting GERD or PPI use is false. Furthermore, a diagnosis of BE is present in a surprisingly high proportion of patients (34%). There is a distinct survival advantage in patients with preoperative GERD symptoms, PPI use, and BE diagnosis, which may not be simply owing to earlier stage at diagnosis. Screening may affect survival outcomes in more patients with EAC than previously anticipated. PMID- 24074426 TI - Acute care surgery practice model: Targeted growth for fiscal success. AB - PURPOSE: Acute care surgery (ACS) remains in its infancy as a defined surgical specialty within hospital systems. Little has been published regarding the financial impact of this method of care delivery to hospital systems and departments when combining trauma, surgical critical care, emergent, and elective general surgery into a single practice model. We sought to compare hospital net income and divisional clinical productivity measures of a newly formed, university division of ACS based on patient type-trauma, emergency general surgery, and elective surgery-to determine the best avenues by which to focus on programmatic growth. METHODS: Single calendar year, retrospective review of hospital system income and divisional fiscal productivity of specific patient visits by patient type (trauma, emergent, or elective) admitted to or discharged by the acute care surgeons. Demographic data, payor mix, patient volumes, and operative rates were determined for each patient type. Fiscal contribution by patient type to both hospital and clinical productivity were measured by hospital net income and divisional work relative value units (wRVU) production respectively. The Chi-square test for independence compared payor mix and analysis of variance was used for comparison of fiscal performance between patient types. RESULTS: We included 1,492 patients in the analysis of calendar year 2010; 1,056 trauma (67% male; mean age, 41.9; range, 0-102), 346 emergent (53% male; mean age, 44.6; range, 15-91), and 90 elective (51% male; mean age, 46; range, 16-87) patient encounters met criteria for analysis. There were no differences in payor mix between patient types. Significant differences were seen in average per patient encounter hospital net income, divisional wRVU production and duration of stay. The ACS team (n = 3) operated on 12% of trauma patients compared with 52% of emergent and 100% of elective surgery encounters. Hospital net income per patient was greatest for trauma encounters, whereas divisional clinical productivity per patient encounter was greatest for emergent patients. Elective encounters contributed negatively to hospital margins. CONCLUSION: Per patient hospital system income and a majority of clinical wRVU productivity remains greatest for the care of injured patients in our ACS practice model; emergent general surgical encounters demonstrate the greatest per-patient rates of divisional clinical productivity. PMID- 24074427 TI - Regional collaboration across hospital systems to develop and implement trauma protocols saves lives within 2 years. AB - BACKGROUND: The Northern Ohio Trauma System (NOTS) was created with the expressed goal of improving trauma care through collaboration, system-wide protocol implementation, and evidence-based process improvement. The primary goal of this study was to evaluate the mortality of trauma patients seen across the region after 2 years of beginning NOTS. METHODS: Regional data was compared with the 2 years pre-NOTS (2008 and 2009) to the 2 years post-NOTS (2010 and 2011). The regional system consisted of two large hospital systems, initially including one level 1 center, four level 2 centers, seven nontrauma hospitals, and local emergency medical services groups. Two level 2 trauma centers closed during the study period. Mortality was the primary outcome for this study. Multivariate logistic regression also was performed to evaluate for independent predictors of mortality. An odds ratio (OR) and 95% confidence interval (CI) of survival were determined after we adjusted for other factors associated with mortality. RESULT: During the 4-year period 29,890 trauma patients were seen throughout NOTS. The mean age was 44 with a mean Injury Severity Score (ISS) of 8; 65% of the patients were male. Racial breakdown demonstrated that 64.0% were white, 31.9% were black, and 4.1% were other races. The hospital stay (mean +/- SD) was 3.0 +/- 5.2 days, and overall mortality was 3.4%. A separate analysis in which we used multivariate logistic regression demonstrated that patients treated in the post-NOTS period was an independent predictor for survival when we controlled for age, sex, ethnicity, mechanism, and ISS. The OR of survival of post NOTS was 0.81 (95% CI 0.70-0.94) when we evaluated all patients. The OR for admitted patients was 0.79 (95% CI 0.67-0.94) and 0.76 (0.62-0.95) in patients with ISS > 24. There was an increase in the percentage of patients seen at the level 1 center in the post NOTS period, which was especially demonstrated in patients with greater ISS. CONCLUSION: NOTS appears to have contributed to the saving of lives within 2 years of its formation. Regionalized protocols, collaboration, and consolidation resulted in an improvement in mortality. PMID- 24074428 TI - Peroral esophageal myotomy (POEM) and laparoscopic Heller myotomy produce a similar short-term anatomic and functional effect. AB - BACKGROUND: Peroral esophageal myotomy (POEM) differs from laparoscopic Heller myotomy (LHM) in that only the circular muscle layer of the esophagus is divided, the hiatus is not mobilized, and an antireflux procedure is not performed. The effect of these differences on anatomic and functional outcomes is unknown. METHODS: Patients who underwent LHM or POEM and had both a pre- and postoperative timed barium esophagogram were selected for analysis. Timed barium esophagograms were performed with 200 mL of contrast, with radiographs taken at 1, 2, and 5 minutes. RESULTS: A total o f 17 LHM and 12 POEM patients had undergone pre- and postoperative timed barium esophagograms. Both groups had decreased column heights postoperatively at 1, 2, and 5 minutes (LHM: pre, 15.6, 12.7, 11.3 cm vs post, 3.6, 2.5, 1.8 cm; P < .001 and POEM: pre, 14.7, 11, 9.4 cm vs post, 4.4, 2.5, 1.2 cm; P < .001). There was no difference between procedures in changes from baseline column height. Both operations resulted in decreased esophageal width and less angulation between the esophageal body and esophagogastric junction. CONCLUSION: POEM and LHM produce a similar short-term anatomic and functional result at the esophagogastric junction. POEM results in a similar narrowing and straightening of the esophagus despite the fact that POEM does not involve hiatal mobilization. PMID- 24074429 TI - Peroral endoscopic myotomy: A short-term comparison with the standard laparoscopic approach. AB - BACKGROUND: We report our short-term experience with peroral endoscopic myotomy (POEM) and compare perioperative outcomes with laparoscopic Heller myotomy (LHM) for achalasia. METHODS: Patients from an institutional review board-approved protocol underwent POEM and were followed prospectively. Comparisons were made, in a prospective esophageal database, with patients who underwent LHM over the same period. RESULTS: We studied 18 patients who underwent POEM and compared them to 21 who underwent LHM. Demographics, preoperative Eckardt scores, motility data, and prior intervention history were comparable. Operative time, myotomy length, and complication rates (1 perforation in each group) were equal. Postoperative pain was significantly different by visual analogue score (POEM 3.9 +/- 0.6 versus LHM 5.7 +/- 0.4, P = .02) and analgesic use (POEM 26.0 +/- 13.7 versus LHM 90.0 +/- 48.5 mg morphine, P = .02). Return to activities of daily living was significantly faster in the POEM group (2.2 +/- 0.6 vs 6.4 +/- 1.0 days, P = .03). Postoperative dysphagia and Eckardt scores were equally successful in both groups. CONCLUSION: POEM results in similar relief of dysphagia with less postoperative pain and quicker return to normal activities. PMID- 24074430 TI - The use of laparoscopic ultrasound in difficult cholecystectomy cases significantly decreases morbidity. AB - BACKGROUND: Laparoscopic ultrasound (LUS) is a method of intraoperative bile duct imaging that can be used prior to any potentially hazardous dissection. The purpose of this study was to determine whether LUS could permit safe laparoscopic completion of difficult cholecystectomy (LC) cases and to assess whether its use had any impact on clinical outcome. METHODS: We identified prospectively 44 patients with severe cholecystitis in whom LUS was considered critical for intraoperative identification of the bile ducts. LC patients were compared, on an intention to treat basis, with 41 contemporaneous patients with severe cholecystitis who had planned open cholecystectomy (OC). RESULTS: LUS identified the extrahepatic bile ducts in all cases. Of the cases, 40 (91%) were completed laparoscopically. OC patients had a higher rate of acute cholecystitis and preoperative percutaneous cholecystostomy tubes and a higher mean ASA classification. Intraoperatively, LC patients had significantly less estimated blood loss and fewer drains were placed. Postoperatively, LC patients had significantly fewer total complications, Clavien-Dindo grade 3 complications, biliary complications, biliary reinterventions, intra-abdominal abscesses, and bleeding complications. LC patients had significantly fewer ICU admissions and shorter LOS. CONCLUSION: By allowing identification of the extrahepatic bile ducts during difficult cholecystectomy, LUS results in a high rate of successful laparoscopic completions. Laparoscopic cholecystectomy is associated with better clinical outcomes than OC for patients with severe cholecystitis. PMID- 24074431 TI - Automated analysis of electronic medical record data reflects the pathophysiology of operative complications. AB - PURPOSE: We hypothesized that a novel algorithm that uses data from the electronic medical record (EMR) from multiple clinical and biometric sources could provide early warning of organ dysfunction in patients with high risk for postoperative complications and sepsis. Operative patients undergoing colorectal procedures were evaluated. METHODS: The Rothman Index (RI) is a predictive model based on heuristic equations derived from 26 variables related to inpatient care. The RI integrates clinical nursing observations, bedside biometrics, and laboratory data into a continuously updated, numeric physiologic assessment, ranging from 100 (unimpaired) to -91. The RI can be displayed within the EMR as a graphic trend, with a decreasing trend reflecting physiologic dysfunction. Patients undergoing colorectal procedures between June and October 2011 were evaluated to determine correlation of initial RI, average inpatient RI, and lowest RI to incidence of complications and/or postoperative sepsis. Patients were stratified by color-coded RI risk group (100-65, blue; 64-40, yellow; <40 red). One-way or repeated-measures analysis of variance was used to compare groups by age, number of complications, and presence of sepsis defined by discharge International Classification of Diseases, 9(th) Revision, codes. Mean direct cost of care and duration of stay also was calculated for each group. RESULTS: The overall incidence of perioperative complications in the 124 patient cohort was 51% (n = 64 patients). The 261 complications sustained by this group represented 82 distinct diagnoses. The 10 patients with sepsis (8%) experienced a 40% mortality. Analysis of initial RI for the population stratified by number of complications and/or sepsis demonstrated a risk-related difference. With progressive onset of complications, the RI decreased, suggesting worsening physiologic dysfunction and linear increase in direct cost of care. CONCLUSION: These findings demonstrate that EMR data can be automatically compiled into an objective metric that reflects patient risk and changing physiologic state. The automated process of continuous update reflects a physiologic trajectory associated with evolving organ system dysfunction indicative of postoperative complications. Early intervention based on these trends may guide preoperative counseling, enhance pre-emptive management of adverse occurrences, and improve cost-efficiency of care. PMID- 24074432 TI - Etiology and incidence of pediatric gallbladder disease. AB - PURPOSE: The spectrum of pediatric biliary tract disease is changing. The goal of this study was to examine the causes and comorbidities of pediatric gallbladder disease at our institution. METHODS: We performed a retrospective chart review on consecutive patient at Kosair Children's Hospital who underwent cholecystectomy over a 9-year time period ending in 2012. RESULTS: Among the 453 patients in the study group, the average age was 13.3 years and 67.2% were female. Indications for cholecystectomy were gallstones in 285 (63%) and biliary dyskinesia in 140 (33%). Of the patients with gallstones, 68 children (15%) had hemolytic disease. Although the number of cholecystectomies for hemolytic disease was relatively stable throughout our study, the number for biliary dyskinesia and non-hemolytic (cholesterol) cholelithiasis rose by 63% and 216%, respectively. Average body mass index (BMI) for patients with non-hemolytic (cholesterol) stones and biliary dyskinesia were significantly greater than the average BMI for patients with hemolytic stones (P < .0001). In addition, the average BMI for children with non hemolytic (cholesterol) stones was greater than the average BMI with biliary dyskinesia (P < .0001). CONCLUSION: Symptomatic gallbladder disease increased over the study period. Biliary dyskinesia and children with non-hemolytic disease are responsible for this increase. PMID- 24074433 TI - Longitudinal age-and cohort trends in body mass index in Sweden--a 24-year follow up study. AB - BACKGROUND: The aim of this longitudinal study was to analyze whether mean Body Mass Index (BMI), assessed at four occasions, changed within different age groups and birth cohorts over time, i.e., between 1980/81 and 2004/05, after adjustment for possible confounders. METHODS: A sample of 2728 men and 2770 women aged 16-71 years at study start were randomly drawn from the Swedish Total Population Register and followed from 1980/81 to 2004/05. The same sample was assessed on four occasions during the 24-year study period (i.e., every eighth year). The outcome variable, BMI, was based on self-reported height and weight. A mixed model, with random intercept and random slope, was used to estimate annual changes in BMI within the different age groups and birth cohorts. RESULTS: Mean BMI increased from 24.1 to 25.5 for men and from 23.1 to 24.3 for women during the 24-year study period. The annual change by age group was highest in the ages of 32-39, 40-47 and 48-55 years among men, and in the ages of 24-31, 32-39, and 40-47 years among women. The highest annual changes were found in the youngest birth cohorts for both men and women, i.e., those born 1958-65, 1966-73, and 1974 81. For each birth cohort, the annual change in BMI increased compared to the previous, i.e., older, birth cohort. In addition, age-by-cohort interaction tests revealed that the increase in BMI by increasing age was higher in the younger birth cohorts (1966-1989) than in the older ones. CONCLUSIONS: Public health policies should target those age groups and birth cohorts with the highest increases in BMI. For example, younger birth cohorts had higher annual increases in BMI than older birth cohorts, which means that younger cohorts increased their BMI more than older ones during the study period. PMID- 24074434 TI - Functional characteristics of connective tissue growth factor on human tenon's capsule fibroblast. AB - PURPOSE OF THE STUDY: To explore the characteristic of connective tissue growth factor (CTGF) on the phenotype transition, extracellular matrix (ECM) synthesis and proliferation of human Tenon's capsule fibroblasts (HTFs). MATERIALS AND METHODS: HTFs were obtained from patients during cataract surgery and induced by CTGF (1 to 100 ug/L). Western blot and immunofluorescence were performed to observe the expression of alpha smooth muscle actin (alpha-SM-actin) protein. The levels of mRNAs were quantified by real-time PCR. Col I and FN expression at both protein and RNA levels were tested after induction by CTGF and transforming growth factor beta (TGF-beta), respectively. Statistical significance was assumed if p < 0.05. RESULTS: CTGF upregulated the expression of alpha-SM-actin in cultured HTFs. Its maximum effect at protein level attained under the optimal concentration of 50 MUg/L at the peak time of 48 hours, though still weaker than the effect of TGF-beta1 (10 MUg/L, p < 0.05). The expression of Col I and FN at both protein and mRNA levels was elevated by the induction of CTGF (50 MUg/L) (p < 0.01) and TGF-beta1 (10 MUg/L) (p < 0.05), while CTGF (50 MUg/L) showed a greater effect than the latter (p < 0.05). CTGF (1 to100 MUg/L) increased the proliferation of HTFs significantly (p < 0.05). CONCLUSIONS: CTGF induced the phenotype transition of HTFs individually and significantly promoted their proliferation. Moreover, it promoted ECM synthesis, thus demonstrating its role as a crucial factor in fibrosis. Thus, CTGF could potentially be a safer and more efficient target than TGF-beta at suppressing scar formation after filtering surgery. PMID- 24074435 TI - Polymorphisms of the cytokine genes TGFB1 and IL10 in a mixed-race population with Crohn's disease. AB - BACKGROUND: Most Crohn's disease (CD) genes discovered in recent years are associated with biological systems critical to the development of this disease. TGFB1 and IL10 are cytokines with important roles in CD. The aim of this study was to evaluate the association between CD, its clinical features and TGFB1 and IL10 gene polymorphisms. METHODS: This case-control study enrolled 91 patients and 91 controls from the state of Bahia, Brazil. Five single nucleotide polymorphisms (SNPs) were studied in the TGFB1 gene (codon 10 T > C--rs1800470; codon 25 G > C--rs1800471) and IL10 gene (-1082 A > G--rs1800896; -819 T > C- rs1800871; -592 A > C--rs1800872). An analysis of the genetic polymorphisms was performed using a commercial kit. A comparison of allele frequencies and genotypes was estimated by calculating the odds ratio (OR) with a confidence interval adjusted via the Bonferroni test for a local alpha of 1%. A stratified analysis was applied for gender, race and smoking history. Patients with CD were characterized according to the Montreal classification. RESULTS: The C allele and CC genotype of the TGFB1 gene rs1800470 were both significantly associated with CD. The stratified analysis showed no confounding factors for the co-variables of gender, race and smoking history. The IL10 gene rs1800896 G allele was significantly associated with age at diagnosis of CD, while the T allele of the IL10 gene rs1800871 was significantly associated with perianal disease. The SNPs rs1800871 and rs1800872 were in 100% linkage disequilibrium. CONCLUSIONS: TGFB1 gene polymorphisms may be associated with susceptibility to the development of CD, and IL10 gene polymorphisms appear to influence the CD phenotype in this admixed population. PMID- 24074436 TI - Analysis of tuberculosis prevalence surveys: new guidance on best-practice methods. AB - BACKGROUND: An unprecedented number of nationwide tuberculosis (TB) prevalence surveys will be implemented between 2010 and 2015, to better estimate the burden of disease caused by TB and assess whether global targets for TB control set for 2015 are achieved. It is crucial that results are analysed using best-practice methods. OBJECTIVE: To provide new theoretical and practical guidance on best practice methods for the analysis of TB prevalence surveys, including analyses at the individual as well as cluster level and correction for biases arising from missing data. ANALYTIC METHODS: TB prevalence surveys have a cluster sample survey design; typically 50-100 clusters are selected, with 400-1000 eligible individuals in each cluster. The strategy recommended by the World Health Organization (WHO) for diagnosing pulmonary TB in a nationwide survey is symptom and chest X-ray screening, followed by smear microscopy and culture examinations for those with an abnormal X-ray and/or TB symptoms. Three possible methods of analysis are described and explained. Method 1 is restricted to participants, and individuals with missing data on smear and/or culture results are excluded. Method 2 includes all eligible individuals irrespective of participation, through multiple missing value imputation. Method 3 is restricted to participants, with multiple missing value imputation for individuals with missing smear and/or culture results, and inverse probability weighting to represent all eligible individuals. The results for each method are then compared and illustrated using data from the 2007 national TB prevalence survey in the Philippines. Simulation studies are used to investigate the performance of each method. KEY FINDINGS: A cluster-level analysis, and Methods 1 and 2, gave similar prevalence estimates (660 per 100,000 aged >= 10 years old), with a higher estimate using Method 3 (680 per 100,000). Simulation studies for each of 4 plausible scenarios show that Method 3 performs best, with Method 1 systematically underestimating TB prevalence by around 10%. CONCLUSION: Both cluster-level and individual-level analyses should be conducted, and individual-level analyses should be conducted both with and without multiple missing value imputation. Method 3 is the safest approach to correct the bias introduced by missing data and provides the single best estimate of TB prevalence at the population level. PMID- 24074437 TI - Online open access: we all want it, but can we afford it? PMID- 24074438 TI - Effect of enoxaparin and onion extract on human skin fibroblast cell line - therapeutic implications for the treatment of keloids. AB - CONTEXT: Keloids and hypertrophic scars are hyperproliferative skin disorders resulting in abnormal wound healing. In the prevention and treatment of keloids and hypertrophic scars, ointments containing heparin and onion extract are very popular. Their therapeutic effects, however, are still controversial and the mechanism of action is not fully understood. OBJECTIVE: The aim of this study was to assess the effect of enoxaparin and dry onion extract on proliferation, apoptosis and beta1 integrin expression in human fibroblasts. MATERIALS AND METHODS: Fibroblast human cell lines (46 BR.1 N) were treated for 48 h with various concentrations of enoxaparin sodium (20, 100, 500 ug/mL) and/or onion [Allium cepa L. (Alliaceae)] extract (50, 250, 1000 ug/mL). The cell proliferation was evaluated by [(3)H]-thymidine incorporation assay. Furthermore, the expression of beta1 integrin and apoptosis was determined by flow cytometry. RESULTS AND DISCUSSION: The results demonstrate that enoxaparin and onion extract inhibited the proliferation of human fibroblasts. Almost complete inhibition of cell proliferation was achieved by enoxaparin in 500 ug/mL concentration (91.5% reduction). The onion extract at a concentration of 250 ug/mL also strongly inhibited the proliferation of cells (50.8% reduction). Depending on concentration, enoxaparin and onion extract induced apoptosis (500 and 1000 ug/mL, respectively) and, depending on concentration, downregulated the expression of beta1 integrin on human fibroblasts. CONCLUSION: This work points at possible mechanism of action of enoxaparin and onion extract, when administered in the treatment of patients with keloids and hypertrophic scars. PMID- 24074440 TI - Breaking the carrier injection bottleneck of phosphor-free nanowire white light emitting diodes. AB - We have examined the carrier injection process of axial nanowire light-emitting diode (LED) structures and identified that poor carrier injection efficiency, due to the large surface recombination, is the primary cause for the extremely low output power of phosphor-free nanowire white LEDs. We have further developed InGaN/GaN/AlGaN dot-in-a-wire core-shell white LEDs on Si substrate, which can break the carrier injection efficiency bottleneck, leading to a massive enhancement in the output power. At room temperature, the devices can exhibit an output power of ~1.5 mW, which is more than 2 orders of magnitude stronger than nanowire LEDs without shell coverage. Additionally, such phosphor-free nanowire white LEDs can deliver an unprecedentedly high color rendering index of ~92-98 in both the warm and cool white regions, with the color rendering capability approaching that of an ideal light source, i.e. a blackbody. PMID- 24074439 TI - Emergence of speech sounds between 7 and 24 months of cochlear implant use. AB - OBJECTIVES: To investigate the process of speech development in five 42-month-old children with profound deafness who received cochlear implants (CIs) between 19 and 36 months of age and five normal hearing (NH) age mates. METHODS: Conversational samples were collected and transcribed. Sounds produced correctly within meaningful words (target sounds) and recognizable sounds produced in spontaneous productions (target-less sounds) were analyzed for all 10 children. RESULTS: Revealed that there was overlap in the total number of vowels and consonants produced by the two groups. The differences between the two groups were more evident in the target condition, whereas the two groups were more similar in the target-less condition. DISCUSSION: The similarities documented in the target-less repertoire of CI and NH children underscore the importance of examining the emerging sound system to predict the end-point sound system in children with CIs. Using target and target-less speech sound comparisons offers a supplementary view of the emergent process of speech sound development and is a valid method of analysis. Results suggest that early implantation may help some children with profound deafness develop speech sounds in a manner similar to NH age mates. PMID- 24074441 TI - Subsequent obstetrics outcomes after intrauterine death during the first pregnancy. AB - OBJECTIVE: We aimed to determine whether the risks of adverse outcomes were greater in women who had pregnancies ending in stillbirth than in those with no previous history of stillbirth. METHODS: This retrospective cohort study included all women who had undergone their first and second deliveries at Bakirkoy Women's and Children's Education and Research Hospital between 2002 and 2011. Women who delivered following a previous stillbirth after 20 complete weeks of gestation were compared with those who had delivered but had no history of stillbirth after 20 weeks of gestation. RESULTS: We compared 201 subsequent births to women with previous histories of stillbirth with 402 live births to women with no such history. The rates of pre-eclampsia [odds ratio (OR), 3.4; 95% confidence interval (CI), 1.5-7.4], HELLP syndrome (OR, 3.1; 95% CI, 1.2-9.6), low birth weight (OR, 1.6; 95% CI, 0.7-3.5) and malpresentation (OR, 2.9; 95% CI, 1.6-4.8) were significantly higher in the case group. Howewer, the rates of stillbirth were similar between the groups. CONCLUSION: We found increased rates of obstetric and perinatal complications in subsequent pregnancies in women with histories of stillbirth. Thus, the results of this study suggest that pregnant women with histories of stillbirth should be followed closely, beginning in the early gestational period. PMID- 24074442 TI - Onion extract structural changes during in vitro digestion and its potential antioxidant effect on brain lipids obtained from low- and high-fat-fed mice. AB - This study investigated the effects of onion (Allium cepa, L.) extract on the antioxidant activity of lipids in low-and high-fat-fed mouse brain lipids and its structural change during in vitro human digestion. The onion extracts were passed through an in vitro human digestion model that simulated the composition of the mouth, stomach, and small intestine juice. The brain lipids were collected from low- and high-fat-fed mouse brain and then incubated with the in vitro-digested onion extracts to determine the lipid oxidation. The results confirmed that the main phenolics of onion extract were kaempferol, myricetin, quercetin, and quercitrin. The quercetin content increased with digestion of the onion extract. Antioxidant activity was strongly influenced by in vitro human digestion of both onion extract and quercetin standard. After digestion by the small intestine, the antioxidant activity values were dramatically increased, whereas the antioxidant activity was less influenced by digestion in the stomach for both onion extract and quercetin standard. The inhibitory effect of lipid oxidation of onion extract in mouse brain lipids increased after digestion in the stomach. The inhibitory effect of lipid oxidation of onion extract was higher in the high-fat-fed mouse brain lipids than that in the low-fat-fed mouse brain lipids. The major study finding is that the antioxidative effect of onion extract may be higher in high fat-fed mouse brain lipids than that in low-fat-fed mouse brain lipids. Thus, dietary onion may have important applications as a natural antioxidant agent in a high-fat diet. PMID- 24074443 TI - Low-temperature nitridation of manganese and iron oxides using NaNH2 molten salt. AB - Manganese and iron nitrides are important functional materials, but their synthesis processes from oxides often require high temperatures. Herein, we show a novel meta-synthesis method for manganese and iron nitrides by low-temperature nitridation of their oxides using NaNH2 molten salt as the nitrogen source in an autoclave at 240 degrees C. With this method, nitridation of micrometer-sized oxide particles kept their initial morphologies, but the size of the primary particles decreased. The thermodynamic driving force is considered to be the conversion of oxides to sodium hydroxide, and the kinetic of nitridation is improved by the decrease of particle size and the low melting point of NaNH2. This technique as developed here has the advantages of low reaction temperature, reduced consumption of ammonia, employing nonspecialized equipment, and providing facile control of the reactions for producing nitrides from oxides. PMID- 24074446 TI - Epigenomic approach in understanding Alzheimer's disease and type 2 diabetes mellitus. AB - Cognitive decline is a debilitating feature of Alzheimer's disease (AD). The causes leading to such impairment are still poorly understood and effective treatments for AD are still unavailable. Type 2 diabetes mellitus (T2DM) has been identified as a risk factor for AD due to desensitisation of insulin receptors in the brain. Recent studies have suggested that epigenetic mechanisms may also play a pivotal role in the pathogenesis of both AD and T2DM. This article describes the correlation between AD and T2DM and provides the insights to the epigenetics of AD. Currently, more research is needed to clarify the exact role of epigenetic regulation in the course and development of AD and also in relation to insulin. Research conducted especially in the earlier stages of the disease could provide more insight into its underlying pathophysiology to help in early diagnosis and the development of more effective treatment strategies. PMID- 24074447 TI - Editorial: current update on association between Alzheimer's disease and type 2 diabetes: volume I. PMID- 24074449 TI - Comparative study of non-high density lipoproteins cholesterol level and lipid profile in pre-diabetic and diabetic patients. AB - OBJECTIVES: The present study compares the role and significance of non-high density lipoproteins (non-HDL) cholesterol level in pre-diabetic and diabetic patients. This study also compares non-HDL cholesterol level between males and females and with different age groups as well. METHODS: An observational study was conducted among 3830 randomly selected individuals to envisage the association of non-HDL cholesterol and other lipid parameters with age, gender, and diabetic status. On the basis of health status, the subjects were classified as diabetic, pre-diabetic and normal. Fasting blood samples were collected and analyzed on Roche p-800 modular system. Total cholesterol, high density lipoproteins (HDL), low density lipoproteins (LDL) and fasting triglycerides were also measured. From the above mentioned parameters, the level of non-HDL cholesterol level was also calculated. RESULTS: Significant association was observed with non-HDL cholesterol level and all other studied lipid parameters (total cholesterol, HDL, LDL and triglycerides) compared with age and gender of the subjects studied. Moreover, the calculated non-HDL level, total cholesterol and triglycerides were found to be significantly co-related with diabetic status of the patients involved in the study. However, HDL and LDL values did not show any significant association with diabetic status of the patients. CONCLUSION: In this study, we found that age and gender of the studied subjects are associated with non-HDL cholesterol. Moreover, our data clearly indicates the positive association of non-HDL cholesterol level with pre-diabetic and diabetic status of the patients. Based on our study, we recommend estimation of non-HDL level in routine clinical practice to differentiate pre-diabetic and diabetic patients. PMID- 24074450 TI - Ribosomal protein S14 silencing inhibits growth of acute myeloid leukemia transformed from myelodysplastic syndromes via activating p53. AB - OBJECTIVES: Ribosomal protein S14 (RPS14) plays a key role in erythropoiesis and causes p53 activation in 5q- syndrome. However, the oncogenic potential of RPS14 is not understood in leukemia and high-risk myelodysplastic syndrome (MDS). Here, we investigated the changes of proliferation and apoptosis of SKM-1, an acute myeloid leukemia (MDS/AML) cell line transformed from MDS, and explored the role of RPS14 in them. METHODS: SKM-1 cells were transfected with recombined lentiviral vector shRPS14. Reverse-transcribed polymerase chain reaction and western blot assay were carried to detect the expression of RPS14 and p53. Cell proliferation was determined by MTT assay. Cell cycle and apoptosis were detected through flow cytometry. RESULTS: When compared with negative control, the proliferation rate of SKM-1 cells transfected with RPS14 hairpin siRNA dropped by 30%. Transfected SKM-1 cells presented with activation of p53. Transfection also arrested cells in G0/G1 phase and induced apoptosis, indicating that RPS14 is involved in the pathophysiology of MDS/AML. DISCUSSION: These findings indicate that partial silencing of RPS14 inhibits the proliferation of MDS/AML cells, and RPS14 may negatively regulate p53 activation in MDS/AML cells. PMID- 24074448 TI - Linking Alzheimer's disease and type 2 diabetes mellitus via aberrant insulin signaling and inflammation. AB - Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two progressive and devastating health disorders afflicting millions of people worldwide. The probability and incidence of both have increased considerably in recent years consequent to increased longevity and population growth. Progressively more links are being continuously found between inflammation and central nervous system disorders like AD, Parkinson's disease, Huntington's disease, motor neuron disease, multiple sclerosis, stroke, traumatic brain injury and even cancers of the nervous tissue. The depth of the relationship depends on the timing and extent of anti- or pro-inflammatory gene expression. Inflammation has also been implicated in T2DM. Misfolding and fibrillization (of tissue specific and/or non specific proteins) are features common to both AD and T2DM and are induced by as well as contribute to inflammation and stress (oxidative/ glycation). This review appraises the roles of inflammation and abnormalities in the insulin signaling system as important shared features of T2DM and AD. The capacity of anti cholinesterases in reducing the level of certain common inflammatory markers in particular if they may provide therapeutic potential to mitigate awry mechanisms leading to AD. PMID- 24074451 TI - Assessment of corneal alterations by confocal microscopy in vernal keratoconjunctivitis. AB - BACKGROUND: Vernal keratoconjunctivitis (VKC) is a bilateral chronic, seasonally exacerbated inflammation of the ocular surface that especially affects male children and young boys. AIM: To evaluate the corneal microscopic features of patients affected by VKC and to assess whether some corneal changes were associated with specific ocular symptoms and/or signs. METHODS: 20 children aged between 4 and 14 years were enrolled. All patients underwent corneal confocal microscopy by Confoscan CS3 (Nidek). 350 images of the central cornea of each eye were obtained with a *40 noncontact lens 3,5 micron gap in automode. RESULTS: Some alterations of the sub-basal and stromal corneal nerves were detected. These alterations were more evident in patients with higher severity of photophobia. On the other hand, there were scarce other signs of the anterior segment of the eye. CONCLUSIONS: Our preliminary findings show that there is another group of patients affected by VKC, characterized by an intense photophobia caused by corneal damage and without other significant ocular alterations. Therefore confocal microscopy may be useful for an early identification of corneal alterations before the onset of severe ocular symptoms and to set an appropriate therapeutic management. PMID- 24074452 TI - Optical coherence tomography in retinal arterial occlusions: case series and review of the literature. AB - Retinal arterial occlusions (RAOs) are an uncommon source of monocular vision loss, typically occurring in patients over the age of 60. Diagnosis is typically made by history and clinical examination, while ancillary testing may include fluorescein angiography. Optical coherence tomography (OCT) is not routinely utilized in the diagnostic assessment of RAO, and its role in the diagnosis and management of patients with RAO is still evolving. In this series, we review the literature on OCT findings in RAOs, particularly noting the role of OCT in delineating anatomic findings, chronicity and natural course, and functional outcomes. A case series of five patients with RAOs is provided to illustrate these findings. PMID- 24074453 TI - Brain natriuretic peptide protects against hyperresponsiveness of human asthmatic airway smooth muscle via an epithelial cell-dependent mechanism. AB - Brain natriuretic peptide (BNP) relaxes airways by activating natriuretic peptide receptor-A and elevating cyclic guanosine monophosphate. BNP is more effective in passively sensitized human bronchi compared with control airways. The molecular and cellular patterns involved in this signaling are unknown. The aim of this study was to investigate the influence of BNP on airway smooth muscle (ASM) cells obtained from donors with asthma and healthy donors and to identify the mechanisms involved in BNP-mediated relaxation. The contractile response of ASM cells was microscopically assessed in vitro in the presence of 1 MUM BNP or with supernatant from human bronchial epithelial (BEAS-2B) cells pretreated with 1 MUM BNP. We investigated the role of muscarinic M2 receptors and inducible nitric oxide synthase (iNOS), quantified the release of acetylcholine and nitric oxide (NO), and assessed the gene/protein expression of iNOS and myosin phosphatase target subunit 1 (MYPT1). Supernatant from BEAS-2B cells treated with BNP reduced the hyperreactivity of asthmatic ASM cells by shifting the potency of histamine by 1.19-fold but had no effect in healthy ASM cells. BNP was not effective directly on ASM cells. Blocking muscarinic M2-receptors and iNOS abolished the protective role of supernatant from BEAS-2B treated with BNP. BNP stimulated the release of acetylcholine (210.7 +/- 11.1%) from BEAS-2B cells that in turn increased MYPT1 and iNOS gene/protein expression and enhanced NO levels in asthmatic ASM supernatant (35.0 +/- 13.0%). This study provides evidence that BNP protects against bronchial hyperresponsiveness via an interaction between respiratory epithelium and ASM in subjects with asthma. PMID- 24074454 TI - Applicability of a previously validated readmission predictive index in medical patients in Singapore: a retrospective study. AB - BACKGROUND: Hospital readmissions are serious and costly events, and readmission rates are considered to be an indicator of quality in health care management. Several models to identify patients at risk of unplanned readmissions have been developed in Western countries, but little is known about their performance in other countries. This paper reports the possible utility of one such model developed in Canada, the LACE index, in patients in a tertiary hospital in Singapore. METHODS: We used administrative data from Singapore General Hospital for patients admitted between 1st January 2006 and 31st December 2010. Data such as demographic and clinical data including disease codes were extracted. The patient cohort was divided into two groups with a LACE index of 10 as the cutoff. Multivariate logistic regression analysis models were used to compare the outcomes between the two groups of patients with adjustment for age, sex, ethnicity, year of discharge, intensive care unit admission, and admission ward class. RESULTS: Overall, 127 550 patients were eligible for analysis. Patients with a LACE index >= 10 had a higher risk of 30-day unplanned readmission after index discharge (odds ratio [OR]: 4.37; 95% confidence interval [CI]: 4.18-4.57). After adjustment, the risk remained significant (OR: 4.88; 95% CI: CI 4.57-5.22). The C-statistic for the adjusted model was 0.70 (P < 0.001). Similar results were shown for 90-day unplanned readmission and emergency visits after the same adjustment. CONCLUSION: The use of the LACE index may have significant application in identifying medical patients at high risk of readmission and visits to the Emergency Department in Singapore. PMID- 24074455 TI - Concurrent stepwise and concerted substitution reactions of 4-methoxybenzyl derivatives and the lifetime of the 4-methoxybenzyl carbocation. PMID- 24074456 TI - Quantifying the information in the long-range order of words: semantic structures and universal linguistic constraints. AB - We review some recent progress on the characterisation of long-range patterns of word use in language using methods from information theory. In particular, two levels of structure in language are considered. The first level corresponds to the patterns of words usage over different contextual domains. A direct application of information theory to quantify the specificity of words across different sections of a linguistic sequence leads to a measure of semantic information. Moreover, a natural scale emerges that characterises the typical size of semantic structures. Since the information measure is made up of additive contributions from individual words, it is possible to rank the words according to their overall weight in the total information. This allows the extraction of keywords most relevant to the semantic content of the sequence without any prior knowledge of the language. The second level considered is the complex structure of correlations among words in linguistic sequences. The degree of order in language can be quantified by means of the entropy. Reliable estimates of the entropy were obtained from corpora of texts from several linguistic families by means of lossless compression algorithms. The value of the entropy fluctuates across different languages since it depends on linguistic organisation at various levels. However, when a measure of relative entropy that specifically quantifies the degree of word ordering in language is estimated, it presents an almost constant value over all the linguistic families studied. This suggests that the entropy of word ordering is a novel quantitative linguistic universal. PMID- 24074457 TI - Intranasal inhalation of oxytocin improves face processing in developmental prosopagnosia. AB - Developmental prosopagnosia (DP) is characterised by a severe lifelong impairment in face recognition. In recent years it has become clear that DP affects a substantial number of people, yet little work has attempted to improve face processing in these individuals. Intriguingly, recent evidence suggests that intranasal inhalation of the hormone oxytocin can improve face processing in unimpaired participants, and we investigated whether similar findings might be noted in DP. Ten adults with DP and 10 matched controls were tested using a randomized placebo-controlled double-blind within-subject experimental design (AB BA). Each participant took part in two testing sessions separated by a 14-25 day interval. In each session, participants inhaled 24 IU of oxytocin or placebo spray, followed by a 45 min resting period to allow central oxytocin levels to plateau. Participants then completed two face processing tests: one assessing memory for a set of newly encoded faces, and one measuring the ability to match simultaneously presented faces according to identity. Participants completed the Multidimensional Mood Questionnaire (MMQ) at three points in each testing session to assess the possible mood-altering effects of oxytocin and to control for attention and wakefulness. Statistical comparisons revealed an improvement for DP but not control participants on both tests in the oxytocin condition, and analysis of scores on the MMQ indicated that the effect cannot be attributed to changes in mood, attention or wakefulness. This investigation provides the first evidence that oxytocin can improve face processing in DP, and the potential neural underpinnings of the findings are discussed alongside their implications for the treatment of face processing disorders. PMID- 24074458 TI - The healthy migrant effect may confound the link between bilingualism and delayed onset of Alzheimer's disease. PMID- 24074459 TI - Conflict adaptation in prefrontal cortex: now you see it, now you don't. AB - Daily life requires people to monitor and resolve conflict arising from distracting information irrelevant to current goals. The highly influential conflict monitoring theory (CMT) holds that the anterior cingulate cortex (ACC) detects conflict and subsequently triggers the dorsolateral prefrontal cortex (DLPFC) to regulate that conflict. Multiple lines of evidence have provided support for CMT. For example, performance is faster on incongruent trials that follow other incongruent trials (iI), and is accompanied by reduced ACC and increased DLPFC activation (the conflict adaptation effect). In this fMRI study, we explored whether ACC-DLPFC conflict signaling can result in behavioral adjustments beyond on-line contexts. Participants completed a modified version of the Stroop conflict adaptation paradigm which tested for conflict adaptation effects on the current (N) trial associated with not only the immediately preceding (N - 1) trial, but also 2-back (N - 2) trials. Results demonstrated evidence for direct relationships between ACC activity on N - 2 trials and both N trial DLPFC activity and behavioral adjustment when intervening trials were congruent (i.e., icI). In contrast, when N - 1 trials were incongruent (i.e., iiI), ACC-DLPFC signaling failed and conflict adaptation was absent. These results provide new evidence demonstrating that the conflict monitor-controller maintains previously experienced conflict in the service of subsequent behavioral adjustment. However, the processing of multiple, temporally proximal conflict signals takes a toll on the working memory (WM) system, which appears to require resetting in order to adapt our behavior to frequently changing environmental demands. PMID- 24074460 TI - Calmodulin-dependent and calmodulin-independent glutamate decarboxylases in apple fruit. AB - BACKGROUND: The ubiquitous, non-proteinaceous amino acid GABA (gamma aminobutyrate) accumulates in plants subjected to abiotic stresses such as chilling, O2 deficiency and elevated CO2. Recent evidence indicates that controlled atmosphere storage causes the accumulation of GABA in apple (Malus x domestica Borkh.) fruit, and now there is increasing interest in the biochemical mechanisms responsible for this phenomenon. Here, we investigated whether this phenomenon could be mediated via Ca(2+)/calmodulin (CaM) activation of glutamate decarboxylase (GAD) activity. RESULTS: GAD activity in cell-free extracts of apple fruit was stimulated by Ca(2+)/CaM at physiological pH, but not at the acidic pH optimum. Based on bioinformatics analysis of the apple genome, three apple GAD genes were identified and their expression determined in various apple organs, including fruit. Like recombinant Arabidopsis GAD1, the activity and spectral properties of recombinant MdGAD1 and MdGAD2 were regulated by Ca(2+)/CaM at physiological pH and both enzymes possessed a highly conserved CaM-binding domain that was autoinhibitory. In contrast, the activity and spectral properties of recombinant MdGAD3 were not affected by Ca(2+)/CaM and they were much less sensitive to pH than MdGAD1, MdGAD2 and Arabidopsis GAD1; furthermore, the C terminal region neither bound CaM nor functioned as an autoinhibitory domain. CONCLUSIONS: Plant GADs typically differ from microbial and animal GAD enzymes in possessing a C-terminal 30-50 amino acid residue CaM-binding domain. To date, rice GAD2 is the only exception to this generalization; notably, the C-terminal region of this enzyme still functions as an autoinhibitory domain. In the present study, apple fruit were found to contain two CaM-dependent GADs, as well as a novel CaM-independent GAD that does not possess a C-terminal autoinhibitory domain. PMID- 24074461 TI - Ultrasensitive surface-enhanced Raman scattering flow detector using hydrodynamic focusing. AB - Label-free, chemical specific detection in flow is important for high throughput characterization of analytes in applications such as flow injection analysis, electrophoresis, and chromatography. We have developed a surface-enhanced Raman scattering (SERS) flow detector capable of ultrasensitive optical detection on the millisecond time scale. The device employs hydrodynamic focusing to improve SERS detection in a flow channel where a sheath flow confines analyte molecules eluted from a fused silica capillary over a planar SERS-active substrate. Increased analyte interactions with the SERS substrate significantly improve detection sensitivity. The performance of this flow detector was investigated using a combination of finite element simulations, fluorescence imaging, and Raman experiments. Computational fluid dynamics based on finite element analysis was used to optimize the flow conditions. The modeling indicates that a number of factors, such as the capillary dimensions and the ratio of the sheath flow to analyte flow rates, are critical for obtaining optimal results. Sample confinement resulting from the flow dynamics was confirmed using wide-field fluorescence imaging of rhodamine 6G (R6G). Raman experiments at different sheath flow rates showed increased sensitivity compared with the modeling predictions, suggesting increased adsorption. Using a 50 ms acquisition, a sheath flow rate of 180 MUL/min, and a sample flow rate of 5 MUL/min, a linear dynamic range from nanomolar to micromolar concentrations of R6G with a limit of detection (LOD) of 1 nM is observed. At low analyte concentrations, rapid analyte desorption is observed, enabling repeated and high-throughput SERS detection. The flow detector offers substantial advantages over conventional SERS-based assays such as minimal sample volumes and high detection efficiency. PMID- 24074462 TI - Here/in this issue and there/abstract thinking: human brain development in a dish. PMID- 24074463 TI - A new generation of gender: learning patience from our gender nonconforming patients. PMID- 24074464 TI - Therapeutic interventions with oxytocin: current status and concerns. PMID- 24074465 TI - The Journal at the Academy's Sixtieth Anniversary. PMID- 24074466 TI - Bipolar disorder and the onset of substance use disorders in adolescents: the emerging story. PMID- 24074467 TI - Real progress in molecular psychiatric genetics. PMID- 24074468 TI - Dissemination and implementation of evidence-based practices for child and adolescent mental health: a systematic review. AB - OBJECTIVE: Although there has been a dramatic increase in the number of evidence based practices (EBPs) to improve child and adolescent mental health, the poor uptake of these EBPs has led to investigations of factors related to their successful dissemination and implementation. The purpose of this systematic review was to identify key findings from empirical studies examining the dissemination and implementation of EBPs for child and adolescent mental health. METHOD: Of 14,247 citations initially identified, 73 articles drawn from 44 studies met inclusion criteria. The articles were classified by implementation phase (exploration, preparation, implementation, and sustainment) and specific implementation factors examined. These factors were divided into outer (i.e., system level) and inner (i.e., organizational level) contexts. RESULTS: Few studies used true experimental designs; most were observational. Of the many inner context factors that were examined in these studies (e.g., provider characteristics, organizational resources, leadership), fidelity monitoring and supervision had the strongest empirical evidence. Albeit the focus of fewer studies, implementation interventions focused on improving organizational climate and culture were associated with better intervention sustainment as well as child and adolescent outcomes. Outer contextual factors such as training and use of specific technologies to support intervention use were also important in facilitating the implementation process. CONCLUSIONS: The further development and testing of dissemination and implementation strategies is needed to more efficiently move EBPs into usual care. PMID- 24074469 TI - Predictors of first-onset substance use disorders during the prospective course of bipolar spectrum disorders in adolescents. AB - OBJECTIVE: Substance use disorders (SUD) are common and problematic in bipolar disorder (BP). We prospectively examined predictors of first-onset SUD among adolescents with BP. METHOD: Adolescents (12-17 years old; N = 167) in the Course and Outcome of Bipolar Youth (COBY) study fulfilling criteria for BP-I, BP-II, or operationalized BP not otherwise specified, without SUD at intake, were included. Baseline demographic, clinical, and family history variables, and clinical variables assessed during follow-up, were examined in relation to first-onset SUD. Participants were prospectively interviewed every 38.5 +/- 22.2 weeks for an average of 4.25 +/- 2.11 years. RESULTS: First-onset SUD developed among 32% of subjects, after a mean of 2.7 +/- 2.0 years from intake. Lifetime alcohol experimentation at intake most robustly predicted first-onset SUD. Lifetime oppositional defiant disorder and panic disorder, family history of SUD, low family cohesiveness, and absence of antidepressant treatment at intake were also associated with increased risk of SUD, whereas BP subtype was not. Risk of SUD increased with increasing number of these 6 predictors: 54.7% of subjects with 3 or more predictors developed SUD vs. 14.1% of those with fewer than 3 predictors (hazard ratio = 5.41 95% confidence interval = 2.7-11.0 p < .0001). Greater hypo/manic symptom severity in the preceding 12 weeks predicted greater likelihood of SUD onset. Lithium exposure in the preceding 12 weeks predicted lower likelihood of SUD. CONCLUSIONS: This study identifies several predictors of first-onset SUD in the COBY sample that, if replicated, may suggest targets for preventive interventions for SUD among youth with BP. Treatment-related findings are inconclusive and must be interpreted tentatively, given the limitations of observational naturalistic treatment data. There is a substantial window of opportunity between BP and SUD onset during which preventive strategies may be used. PMID- 24074470 TI - Maternal and early postnatal nutrition and mental health of offspring by age 5 years: a prospective cohort study. AB - OBJECTIVE: Diet quality is related to the risk for depression and anxiety in adults and adolescents; however, the possible impact of maternal and early postnatal nutritional exposures on children's subsequent mental health is unexplored. METHOD: The large prospective Norwegian Mother and Child Cohort Study recruited pregnant women between 1999 and 2008. Data were collected from mothers during pregnancy and when children were 6 months and 1.5, 3, and 5 years of age. Latent growth curve models were used to model linear development in children's internalizing and externalizing problems from 1.5 to 5 years of age as a function of diet quality during pregnancy and at 1.5 and 3 years. Diet quality was evaluated by dietary pattern extraction and characterized as "healthy" or "unhealthy." The sample comprised 23,020 eligible women and their children. Adjustments were made for variables including sex of the child, maternal depression, maternal and paternal age, maternal educational attainment, household income, maternal smoking before and during pregnancy, mothers' parental locus of control, and marital status. RESULTS: Higher intakes of unhealthy foods during pregnancy predicted externalizing problems among children, independently of other potential confounding factors and childhood diet. Children with a high level of unhealthy diet postnatally had higher levels of both internalizing and externalizing problems. Moreover, children with a low level of postnatal healthy diet also had higher levels of both internalizing and externalizing problems. CONCLUSION: Among this large cohort of mothers and children, early nutritional exposures were independently related to the risk for behavioral and emotional problems in children. PMID- 24074471 TI - No genetic influence for childhood behavior problems from DNA analysis. AB - OBJECTIVE: Twin studies of behavior problems in childhood point to substantial genetic influence. It is now possible to estimate genetic influence using DNA alone in samples of unrelated individuals, not relying on family-based designs such as twins. A linear mixed model, which incorporates DNA microarray data, has confirmed twin results by showing substantial genetic influence for diverse traits in adults. Here we present direct comparisons between twin and DNA heritability estimates for childhood behavior problems as rated by parents, teachers, and children themselves. METHOD: Behavior problem data from 2,500 UK representative 12-year-old twin pairs were used in twin analyses; DNA analyses were based on 1 member of the twin pair with genotype data for 1.7 million DNA markers. Diverse behavior problems were assessed, including autistic, depressive, and hyperactive symptoms. Genetic influence from DNA was estimated using genome wide complex trait analysis (GCTA), and the twin estimates of heritability were based on standard twin model fitting. RESULTS: Behavior problems in childhood whether rated by parents, teachers, or children themselves-show no significant genetic influence using GCTA, even though twin study estimates of heritability are substantial in the same sample, and even though both GCTA and twin study estimates of genetic influence are substantial for cognitive and anthropometric traits. CONCLUSIONS: We suggest that this new type of "missing heritability," that is, the gap between GCTA and twin study estimates for behavior problems in childhood, is due to nonadditive genetic influence, which will make it more difficult to identify genes responsible for heritability. PMID- 24074472 TI - Psychopathology trajectories of children with autism spectrum disorder: the role of family poverty and parenting. AB - OBJECTIVE: Children with autism spectrum disorder (ASD) are reported to have high rates of co-occurring psychopathology. Little is known about risk factors that might contribute to this psychopathology. This study modeled the effect of family poverty on psychopathology trajectories in young children with ASD, and examined whether home organization and maternal warmth and involvement could buffer the effect of poverty on children's psychopathology. METHOD: The sample comprised 209 children with ASD who participated in the UK's Millennium Cohort Study, a population birth cohort study. Individual trajectories of psychopathology at ages 3, 5, and 7 years were analyzed using growth curve models. Psychopathology was assessed with the Strengths and Difficulties Questionnaire. RESULTS: Children with ASD exhibited increasingly high rates of psychopathology over time. Family poverty was associated with broad and specific (emotional and conduct problems) psychopathology, but not with changes in psychopathology over time. Warmth, involvement, and home organization did not buffer the association of family poverty with psychopathology. However, low warmth explained the relationship between poverty and broad psychopathology, and predicted annual changes in broad psychopathology. Warmth was associated with fewer conduct problems and less hyperactivity, and with an annual decrease in peer and conduct problems. Household chaos was a risk factor for conduct problems, as was maternal involvement for peer problems. CONCLUSIONS: Family poverty, low maternal warmth, and household chaos are risk factors for externalizing problems in children with ASD. Maternal warmth may be a key target for intervention, particularly in poorer families of children with ASD. PMID- 24074473 TI - Localized brain volume and white matter integrity alterations in adolescent anorexia nervosa. AB - OBJECTIVE: The neurobiological underpinnings of anorexia nervosa (AN) are poorly understood. In this study, we tested whether brain gray matter (GM) and white matter (WM) in adolescents with AN would show alterations comparable to those in adults. METHOD: We used magnetic resonance imaging to study GM and WM volume, and diffusion tensor imaging to assess fractional anisotropy for WM integrity in 19 adolescents with AN and 22 controls. RESULTS: Individuals with AN showed greater left orbitofrontal, right insular, and bilateral temporal cortex GM, as well as temporal lobe WM volumes compared to controls. WM integrity in adolescents with AN was lower (lower fractional anisotropy) in fornix, posterior frontal, and parietal areas, but higher in anterior frontal, orbitofrontal, and temporal lobes. In individuals with AN, orbitofrontal GM volume correlated negatively with sweet taste pleasantness. An additional comparison of this study cohort with adult individuals with AN and healthy controls supported greater orbitofrontal cortex and insula volumes in AN across age groups. CONCLUSIONS: This study indicates larger orbitofrontal and insular GM volumes, as well as lower fornix WM integrity in adolescents with AN, similar to adults. The pattern of larger anteroventral GM and WM volume as well as WM integrity, but lower WM integrity in posterior frontal and parietal regions may indicate that developmental factors such as GM pruning and WM growth could contribute to brain alterations in AN. The negative correlation between taste pleasantness and orbitofrontal cortex volume in individuals with AN could contribute to food avoidance in this disorder. PMID- 24074475 TI - Ending the silence on gun violence ... or silencing the debate? PMID- 24074476 TI - Dr. Brent et al. reply. PMID- 24074477 TI - Heterogeneity in autism spectrum disorder(s). PMID- 24074474 TI - Altered cerebral perfusion in executive, affective, and motor networks during adolescent depression. AB - OBJECTIVE: Although substantial literature has reported regional cerebral blood flow (rCBF) abnormalities in adults with depression, these studies commonly necessitated the injection of radioisotopes into subjects. The recent development of arterial spin labeling (ASL), however, allows noninvasive measurements of rCBF. Currently, no published ASL studies have examined cerebral perfusion in adolescents with depression. Thus, the aim of the present study was to examine baseline cerebral perfusion in adolescent depression using a newly developed ASL technique: pseudocontinuous arterial spin labeling (PCASL). METHOD: A total of 25 medication-naive adolescents (13-17 years of age) diagnosed with major depressive disorder (MDD) and 26 well-matched control subjects underwent functional magnetic resonance imaging. Baseline rCBF was measured via a novel PCASL method that optimizes tagging efficiency. RESULTS: Voxel-based whole brain analyses revealed significant frontal, limbic, paralimbic, and cingulate hypoperfusion in the group with depression (p < .05, corrected). Hyperperfusion was also observed within the subcallosal cingulate, putamen, and fusiform gyrus (p < .05, corrected). Similarly, region-of-interest analyses revealed amygdalar and insular hypoperfusion in the group with depression, as well as hyperperfusion in the putamen and superior insula (p < .05, corrected). CONCLUSIONS: Adolescents with depression and healthy adolescents appear to differ on rCBF in executive, affective, and motor networks. Dysfunction in these regions may contribute to the cognitive, emotional, and psychomotor symptoms commonly present in adolescent depression. These findings point to possible biomarkers for adolescent depression that could inform early interventions and treatments, and establishes a methodology for using PCASL to noninvasively measure rCBF in clinical and healthy adolescent populations. PMID- 24074479 TI - Practice parameter for cultural competence in child and adolescent psychiatric practice. AB - The United States faces a rapidly changing demographic and cultural landscape, with its population becoming increasingly multiracial and multicultural. In consequence, cultural and racial factors relating to mental illness and emotional disturbances deserve closer attention and consideration. This Practice Parameter outlines clinical applications of the principle of cultural competence that will enable child and adolescent mental health clinicians to better serve diverse children, adolescents, and their families. PMID- 24074480 TI - Self-referent information processing in individuals with bipolar spectrum disorders. AB - BACKGROUND: Bipolar spectrum disorders (BSDs) are common and impairing, which has led to an examination of risk factors for their development and maintenance. Historically, research has examined cognitive vulnerabilities to BSDs derived largely from the unipolar depression literature. Specifically, theorists propose that dysfunctional information processing guided by negative self-schemata may be a risk factor for depression. However, few studies have examined whether BSD individuals also show self-referent processing biases. METHODS: This study examined self-referent information processing differences between 66 individuals with and 58 individuals without a BSD in a young adult sample (age M=19.65, SD=1.74; 62% female; 47% Caucasian). Repeated measures multivariate analysis of variance (MANOVA) was conducted to examine multivariate effects of BSD diagnosis on 4 self-referent processing variables (self-referent judgments, response latency, behavioral predictions, and recall) in response to depression-related and nondepression-related stimuli. RESULTS: Bipolar individuals endorsed and recalled more negative and fewer positive self-referent adjectives, as well as made more negative and fewer positive behavioral predictions. Many of these information-processing biases were partially, but not fully, mediated by depressive symptoms. LIMITATIONS: Our sample was not a clinical or treatment seeking sample, so we cannot generalize our results to clinical BSD samples. No participants had a bipolar I disorder at baseline. CONCLUSIONS: This study provides further evidence that individuals with BSDs exhibit a negative self referent information processing bias. This may mean that those with BSDs have selective attention and recall of negative information about themselves, highlighting the need for attention to cognitive biases in therapy. PMID- 24074481 TI - Bereavement-related depression in the older adult population: a distinct disorder? AB - BACKGROUND: Bereavement is a phenomenon that shares many symptoms with depression, and that a great number of older adults experience following the loss of a close relative. The objectives of the present study were to (1) determine whether the symptoms of depression reported by bereaved individuals differ from those with non-bereavement minor/major depression (NBRD), (2) assess whether BRD is as persistent during a one year follow-up as compared to NBRD, and (3) identify factors and consequences associated with BRD. METHODS: The data used for this study came from the Longitudinal Study ESA (Study Health of Elders), conducted between 2005 and 2008, using a representative sample (n=2811) of community-dwelling older adults, aged 65 and over. To test our hypothesis, an exploratory latent class analysis and multivariate logistic regression were used. RESULTS: BRD prevalence among older adults suffering from depression was 39%. BRD individuals report all symptoms of depression, but in lower probabilities, and BRD is as persistent as MDD over 12 months, suggesting that it does not differ from NBRD. The principal factors associated with BRD were widowhood and lower level of education. Individuals with BRD are less likely to consult medical services and be dispensed an antidepressant, compared to NBRD. LIMITATIONS: We have to be cautious when generalizing our findings to individuals with major depression alone, since our results included both minor and major depressions in the same group. CONCLUSION: No evidence was found that BRD differed from non BRD in terms of depressive symptoms and persistence. The bereavement exclusion criterion in the DSM-IV should be reconsidered. PMID- 24074482 TI - Clinical subtypes of severe bipolar mixed states. AB - OBJECTIVE: The aim of the present study was to identify different clinical subtypes in severe, treatment resistant bipolar mixed state (MS). METHOD: The sample comprised 202 Bipolar I patients currently in MS referred for an Electro convulsive Therapy (ECT) trial and evaluated in the first week of hospitalization and one week after the ECT course. Principal component factor analysis (PCA) followed by Varimax rotation was performed on 21 non-overlapping items selected from Hamilton rating-scale for depression (HAMD) and from Young mania rating scale (YMRS) at baseline evaluation. Cluster subtypes derived from the factor scores were compared in clinical variables and final HAMD, YMRS, Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI) scores. RESULTS: The principal-component analysis extracted 6 interpretable factors explaining 55.9% of the total variance. Cluster analysis identified four groups, including respectively 63 (31.2%) subjects with Agitated-Irritable Mixed Depression, 59 (29.2%) with Psychotic Mixed-Mania, 17 (8.5%) with Anxious Irritable-Psychotic Mixed-Mania, and 63 (31.2%) with Retarded-Psychotic Mixed Depression. The four clusters were statistically distinct and did not show significant overlap in the main symptomatological presentation. Cluster subtypes reported differences in number of past mood episodes, duration of the current episode, suicide attempts, lifetime comorbidity with panic and eating disorders, baseline and final rating-scale scores and rate of remission after ECT trial. CONCLUSIONS: Our study indicates that, at least in severe treatment resistant MS, multiple depressive and manic subtypes can be observed with substantial differences in terms of clinical presentation, course, associated comorbidities and treatment response. PMID- 24074483 TI - Auditory-prosodic processing in bipolar disorder; from sensory perception to emotion. AB - OBJECTIVES: Accurate emotion processing is critical to understanding the social world. Despite growing evidence of facial emotion processing impairments in patients with bipolar disorder (BD), comprehensive investigations of emotional prosodic processing is limited. The existing (albeit sparse) literature is inconsistent at best, and confounded by failures to control for the effects of gender or low level sensory-perceptual impairments. The present study sought to address this paucity of research by utilizing a novel behavioural battery to comprehensively investigate the auditory-prosodic profile of BD. METHODS: Fifty BD patients and 52 healthy controls completed tasks assessing emotional and linguistic prosody, and sensitivity for discriminating tones that deviate in amplitude, duration and pitch. RESULTS: BD patients were less sensitive than their control counterparts in discriminating amplitude and durational cues but not pitch cues or linguistic prosody. They also demonstrated impaired ability to recognize happy intonations; although this was specific to male's with the disorder. The recognition of happy in the patient group was correlated with pitch and amplitude sensitivity in female patients only. LIMITATIONS: The small sample size of patients after stratification by current mood state prevented us from conducting subgroup comparisons between symptomatic, euthymic and control participants to explicitly examine the effects of mood. CONCLUSIONS: Our findings indicate the existence of a female advantage for the processing of emotional prosody in BD, specifically for the processing of happy. Although male BD patients were impaired in their ability to recognize happy prosody, this was unrelated to reduced tone discrimination sensitivity. This study indicates the importance of examining both gender and low order sensory perceptual capacity when examining emotional prosody. PMID- 24074484 TI - Aripiprazole augmentation to antidepressant therapy in Japanese patients with major depressive disorder: a randomized, double-blind, placebo-controlled study (ADMIRE study). AB - OBJECTIVE: This randomized, placebo-controlled study evaluated the efficacy and safety of a fixed dose (3mg/day) and flexible dose (3-15 mg/day) schedule of aripiprazole as augmentation therapy in Japanese patients with inadequate response to antidepressant therapy (ADT). METHOD: During an 8-week prospective treatment phase, patients experiencing a major depressive episode received clinicians' choice of ADT. Subjects with inadequate response to ADT were randomized to receive adjunctive treatment with placebo (n=195), fixed dose aripiprazole (n=197) or flexible dose aripiprazole (n=194) for 6 weeks. The primary efficacy endpoint was mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from the end of prospective treatment (baseline) to the end of randomized treatment. RESULTS: More than 90% of patients in all treatment groups completed the 6-week double-blind treatment phase. Mean MADRS total score was improved to a significantly greater extent with fixed dose aripiprazole and flexible dose aripiprazole (-10.5 and -9.6, respectively) than with placebo (-7.4). Aripiprazole was well tolerated. The incidence of akathisia observed in the flexible dose group may relate to a higher prevalence of the CYP2D6(*)10 allele in Asian populations. LIMITATIONS: Six weeks of adjunctive treatment is insufficient to draw conclusions about the long-term benefits of aripiprazole. Exclusion of patients with established medical comorbidities does not reflect real-world practice. CONCLUSIONS: Aripiprazole augmentation at a fixed or flexible dose was superior to ADT alone and was reasonably well tolerated in Japanese patients with inadequate response to ADT. PMID- 24074485 TI - A killer revealed: 10-year experience with beta-thalassemia intermedia. AB - OBJECTIVES: Patients with beta-thalassemia intermedia tend to present later in life with milder anemia than beta-thalassemia major patients. The incidence of mortality and its causes in this patient population remains unknown. We aim to reveal the incidence and most common causes of death in this population. METHODS AND RESULTS: We reviewed the charts of all of the beta-thalassemia intermedia patients who had been followed at the Chronic Care Center in Hazmieh, Lebanon during a 10-year period. A total of 18 patients out of 127 had died during the follow-up period giving a cumulative 10-year mortality incidence of 14%. The most common causes of cardiac deaths were due to renal and cardiac causes. DISCUSSION: Most causes of death have been linked to the high levels of iron coupled with anemia present in this patient population. Many of deaths could be prevented by adequate treatment. CONCLUSION: Larger studies with more comprehensive data capture on risk factors of mortality in this patient population are called for. PMID- 24074486 TI - Assessment of the risk of haemorrhage and its control following minor oral surgical procedures in patients on anti-platelet therapy: a prospective study. AB - Controversy exists concerning the suspension or maintenance of anti-platelet drugs before elective surgical procedures. We assessed the association of the risk of prolonged postoperative bleeding with anti-platelet therapy by type of minor surgical procedure and the association between anti-platelet therapy and the level of hemostatic measures required. Five hundred and forty-six patients were included in the study group: those on aspirin (n = 310), clopidogrel (n = 97), and aspirin + clopidogrel dual therapy (n = 139); the control group comprised 575 healthy individuals. Cramer's V test was significant (P < 0.05) but showed a weak association between anti-platelet therapy and prolonged immediate postoperative bleeding. Compared to controls, the odds ratio revealed that the risk of prolonged bleeding in the immediate postoperative period was significantly higher with dual therapy, followed by clopidogrel and aspirin. Prolonged bleeding occurred in 22 patients in the study group and 20 in the control group, and was successfully controlled with local hemostatic measures. Fisher's exact test showed a significant association between dual therapy and higher levels of hemostatic measures (P = 0.004; P = 0.035). Prolonged bleeding in patients on anti-platelet therapy was independent of the type of minor surgical procedure. The greatest risk of prolonged bleeding was found in patients on dual therapy; this required higher levels of hemostatic measures. PMID- 24074487 TI - The feasibility of using Patients Concerns Inventory (PCI) in managing Malaysian oral cancer patients. AB - The feasibility of using the Patients Concerns Inventory (PCI) to identify oral cancer patient concerns during consultation in oral and maxillofacial specialist clinics in Malaysia was assessed. A cross-sectional study was conducted using a consecutive clinical sampling technique of all new and follow-up oral cancer patients. Surgeons and counter staff were also recruited. Two-thirds of patients were elderly, 63.9% female, 55.6% Indian, 63.9% of lower-level education, and half had the lowest level household income. Patient status was mostly post treatment (87.5%) and most were at cancer stage III/IV (63.9%); 59.7% had surgery. Patients took an average 5.9 min (95% CI 5.1-6.7 min) to complete the PCI. Physical domain appeared highest (94.4%); social/family relationship issues (4.2%) were lowest. Significant associations included patient age-personal function (P=0.02); patient education level-emotional status (P=0.05) and social/family relationship issues (P=0.04), and patient TNM staging-personal function (P=0.03). The patients' mean feasibility score for the PCI was 5.3 (95% CI 5.1-5.5) out of 6. Patients (93.1%) and surgeons (90%) found the PCI to be feasible. Only 57.1% of counter staff agreed on the use of the PCI during patient registration. Overall, the PCI was considered feasible, thus favouring its future use in routine oral cancer patient management. PMID- 24074488 TI - Evaluation of biopsy methods in the diagnosis of submandibular space pathology. AB - The aim of this study was to evaluate the performance of fine needle aspiration cytology (FNAC), ultrasound-guided core needle biopsy (USCNB), punch biopsy, and surgical excision biopsy in neoplasms presenting within the submandibular space. A retrospective analysis of all patients with a pathological diagnosis of a submandibular space neoplasm within a 12-year period (February 1999 to June 2011) was performed. Biopsy results were compared to histopathological diagnosis obtained from surgical excision biopsy. Eighty-one specimens from 44 patients met the search criteria (15 FNAC, 24 USCNB, 7 punch biopsy, and 35 surgical excision biopsy). The final diagnosis was established by USCNB, punch biopsy, or surgical excision biopsy and not by FNAC alone. Surgical excision biopsy was performed as a primary diagnostic (n = 8), secondary diagnostic (n = 15), or as a post diagnostic therapeutic procedure (n = 12). Non-diagnostic results were: FNAC 11/15, USCNB 2/24, and punch biopsy 1/7. Diagnostic results were: FNAC 2/15, USCNB 20/24, and punch biopsy 5/7. No complications were reported. Although punch biopsy demonstrated good yield and accuracy, its use is restricted to a small cohort of patients. USCNB is a safe and accurate technique in the submandibular space, with a low non-diagnostic rate. PMID- 24074489 TI - Outcome of a Single Intravitreal Bevacizumab Injection on the Visual Acuity and Course of Pars Plana Vitrectomy in Proliferative Diabetic Retinopathy. AB - Abstract Purpose: To evaluate the effect of a single intravitreal 1.25 mg/0.05 ml bevacizumab (IVB) (Avastin, Genentech) injection on the visual outcome and both intraoperative and postoperative course of pars plana vitrectomy (PPV) in proliferative diabetic retinopathy. Study Design: Prospective case-control interventional comparative study. Methods: One hundred patients (100 eyes) were divided into two groups: Group I had undergone PPV with preoperactive IVB (50 patients), and Group II had undergone PPV without IVB (50 patients). Best corrected visual acuity (BCVA), intraoperative and postoperative complications were compared between both groups. Patients were followed-up for one year. Results: After one year, there was a highly statistically significant difference in the mean BCVA, as it was (0.146 +/- 0.103) in Group I and 0.069 +/- 0.049 in Group II with (p < 0.001), while mean bleeding frequency in Group I was 0.7 +/- 0.78 times/case with range between 0 and 2 bleeding attacks/case and mean bleeding frequency in Group II was 3.12 +/- 1.31times/case with range between 3 and 6 bleeding attacks/case and the difference was statistically significant as (p < 0.001). Diathermy was used in Group I in 15 patients only with mean frequency of 0.3 +/- 0.46 times/case with range between 0 and 1 attack/case; while diathermy was used in all cases in Group II with mean frequency of 2.4 +/- 1.06 times/case with range between 1 to 4 times/case and this difference was also statistically significant as p < 0.001. Postoperative vitreous hemorrhage developed in 3 eyes (6%) in Group I and 15 eyes (30%) in Group II and this difference was statistically significant (p < 0.003). All the other intraoperative and postoperative complications were reduced in Group I, but with no statistically significant difference between both groups. Conclusions: The use of intravitreal bevacizumab before pars plana vitrectomy is beneficial in improving visual outcome, minimizing the incidence of intraoperative bleeding and reducing the need for intraoperative diathermy. PMID- 24074490 TI - Role of gamma knife surgery for intracranial atypical (WHO grade II) meningiomas. AB - OBJECT: Atypical meningioma often recurs even after resection. As a salvage modality, radiotherapy or stereotactic radiosurgery (SRS) is attempted for this aggressive tumor. This retrospective study was performed to evaluate the efficacy of SRS that involved Gamma Knife surgery (GKS) for atypical meningioma. METHODS: The authors reviewed records from 22 patients with histologically proven atypical meningioma who underwent GKS for 28 lesions at the authors' institute. The median patient age was 70 years (range 24-91 years), and the median tumor volume for each procedure was 6.0 cm3 (range 1.6-38.7 cm3). The margin dose ranged from 14 to 20 Gy (median 18 Gy). Follow-up periods ranged from 3 months to 98 months (median 23.5 months). RESULTS: In total, 39 GKS procedures were performed for 28 lesions. The local control rates at 1, 2, and 5 years were 74%, 39%, and 16%, respectively. Volume less than 6 cm3 (p = 0.01), a margin dose higher than 18 Gy (p = 0.02), and a Karnofsky Performance Scale (KPS) score of 90 or more (p = 0.02) were factors associated with a longer duration of tumor control in the univariate analysis. CONCLUSIONS: Atypical meningioma could be more successfully controlled when a higher margin dose was used to treat patients with a good performance (KPS score of >= 90) status and smaller tumor volumes. It would be desired if patients are treated with a relatively higher margin dose, ideally as high as the dose applied for malignant tumor. A boost SRS after fractionated radiotherapy may be effective to achieve better local control. PMID- 24074491 TI - The callosal angle measured on MRI as a predictor of outcome in idiopathic normal pressure hydrocephalus. AB - OBJECT: Different neuroimaging biomarkers have been studied to find a tool for prediction of response to CSF shunting in idiopathic normal-pressure hydrocephalus (iNPH). The callosal angle (CA) has been described as useful in discriminating iNPH from ventricular dilation secondary to atrophy. However, the usefulness of the CA as a prognostic tool for the selection of shunt candidates among patients with iNPH is unclear. The aim of this study was to compare the CA in shunt responders with that in nonresponders and clarify whether the CA can serve as a predictor of the outcome. METHODS: Preoperative MRI brain scans were evaluated in 109 patients who had undergone shunt surgery for iNPH during 2006 2010. Multiplanar reconstruction was performed interactively to obtain a coronal image through the posterior commissure, perpendicular to the anterior-posterior commissure plane. The CA was measured as the angle between the lateral ventricles on the coronal image. The patients were examined clinically before surgery and at 12 months postoperatively. RESULTS: Shunt responders had a significantly smaller mean preoperative CA compared with nonresponders: 59 degrees (95% CI 56 degrees 63 degrees ) versus 68 degrees (95% CI 61 degrees -75 degrees ) (p < 0.05). A CA cutoff value of 63 degrees showed the best prognostic accuracy. CONCLUSIONS: The preoperative CA is smaller in patients whose condition improves after shunt surgery and may be a useful tool in the selection of shunt candidates among patients with iNPH. PMID- 24074492 TI - Comparison of plaintiff and defendant expert witness qualification in malpractice litigation in neurological surgery. AB - OBJECT: Expert witnesses provide a valuable societal service, interpreting complex pieces of evidence that may be misunderstood by nonmedical laypersons. The role of medical expert witness testimony and the potential professional repercussions, however, have been controversial in the medical community. The objective of the present analysis was to characterize the expertise of neurological surgeons testifying as expert witnesses in malpractice litigation. METHODS: Malpractice litigation involving expert testimony from neurological surgeons was obtained using the WestlawNext legal database. Data pertaining to duration of a surgeon's practice, scholarly impact (as measured by the h index), practice setting, and the frequency with which a surgeon testifies were obtained for these expert witnesses from various online resources including the Scopus database, online medical facility and practice sites, and state medical licensing boards. RESULTS: Neurological surgeons testifying in 326 cases since 2008 averaged over 30 years of experience per person (34.5 years for plaintiff witnesses vs 33.2 for defense witnesses, p = 0.35). Defense witnesses had statistically higher scholarly impact than plaintiff witnesses (h index = 8.76 vs 5.46, p < 0.001). A greater proportion of defense witnesses were involved in academic practice (46.1% vs 24.4%, p < 0.001). Those testifying on behalf of plaintiffs were more likely to testify multiple times than those testifying on behalf of defendants (20.4% vs 12.6%). CONCLUSIONS: Practitioners testifying for either side tend to be very experienced, while those testifying on behalf of defendants have significantly higher scholarly impact and are more likely to practice in an academic setting, potentially indicating a greater level of expertise. Experts for plaintiffs were more likely to testify multiple times. Surgical societies may need to clarify the necessary qualifications and ethical responsibilities of those who choose to testify. PMID- 24074493 TI - The relationship between clinical phenotype and early staged bilateral deep brain stimulation in Parkinson disease. AB - OBJECT: While many centers place bilateral deep brain stimulation (DBS) systems simultaneously, unilateral subthalamic nucleus (STN) DBS followed by a staged contralateral procedure has emerged as a treatment option for many patients. However, little is known about whether the preoperative phenotype predicts when staged placement of a DBS electrode in the opposite STN will be required. The authors aimed to determine whether preoperative clinical phenotype predicts early staged placement of a second STN DBS electrode in patients who undergo unilateral STN DBS for Parkinson disease (PD). METHODS: Eighty-two consecutive patients with advanced PD underwent unilateral STN DBS contralateral to the most affected hemibody and had at least 2 years of follow-up. Multivariate logistic regression analysis determined preoperative characteristics that predicted staged placement of a second electrode in the opposite STN. Preoperative measurements included aspects of the Unified Parkinson's Disease Rating Scale (UPDRS), motor asymmetry index, and body weight. RESULTS: At 2-year follow-up, 28 (34%) of the 82 patients had undergone staged placement of a contralateral electrode while the remainder chose to continue with unilateral stimulation. Statistically significant improvements in UPDRS total and Part 3 scores were retained at the end of the 2 year follow-up period in both subsets of patients. Multivariate logistic regression analysis showed that the most important predictors for early staged placement of a second subthalamic stimulator were low asymmetry index (OR 13.4, 95% CI 2.8-64.9), high tremor subscore (OR 7.2, CI 1.5-35.0), and low body weight (OR 5.5, 95% CI 1.4-22.3). CONCLUSIONS: This single-center study provides evidence that elements of the preoperative PD phenotype predict whether patients will require early staged bilateral STN DBS. These data may aid in the management of patients with advanced PD who undergo STN DBS. PMID- 24074494 TI - Cavitation-based third ventriculostomy using MRI-guided focused ultrasound. AB - OBJECT: Transcranial focused ultrasound is increasingly being investigated as a minimally invasive treatment for a range of intracranial pathologies. At higher peak rarefaction pressures than those used for thermal ablation, focused ultrasound can initiate inertial cavitation and create holes in the brain by fractionation of the tissue elements. The authors investigated the technical feasibility of using MRI-guided focused ultrasound to perform a third ventriculostomy as a possible noninvasive alternative to endoscopic third ventriculostomy for hydrocephalus. METHODS: A craniectomy was performed in male pigs weighing 13-19 kg to expose the supratentorial brain, leaving the dura mater intact. Seven pigs were treated through the craniectomy, while 2 pigs were treated through ex vivo human skulls placed in the beam path. Registration and targeting was done using T2-weighted MRI sequences. For transcranial treatments a CT scan was used to correct the beam from aberrations due to the skull and maintain a small, high-intensity focus. Sonications were performed at both 650 kHz and 230 kHz at a range of intensities, and the in situ pressures were estimated both from simulations and experimental data to establish a threshold for tissue fractionation in the brain. RESULTS: In craniectomized animals at 650 kHz, a peak pressure >= 22.7 MPa for 1 second was needed to reliably create a ventriculostomy. Transcranially at this frequency the ExAblate 4000 was unable to generate the required intensity to fractionate tissue, although cavitation was initiated. At 230 kHz, ventriculostomy was successful through the skull with a peak pressure of 8.8 MPa. CONCLUSIONS: This is the first study to suggest that it is possible to perform a completely noninvasive third ventriculostomy using ultrasound. This may pave the way for future studies and eventually provide an alternative means for the creation of CSF communications in the brain, including perforation of the septum pellucidum or intraventricular membranes. PMID- 24074495 TI - Tumor shrinkage after transsphenoidal surgery for nonfunctioning pituitary adenoma. AB - OBJECT: Volume reduction of nonfunctioning pituitary adenomas has been described, for example, after radiotherapy and pituitary tumor apoplexy. Even when considerable remnants remain after surgery, spontaneous shrinkage and relief of mass lesion symptoms can sometimes occur. The aim of this study was to assess shrinkage of tumor residues after transsphenoidal surgery and to identify predictors of tumor shrinkage. METHODS: A total of 140 patients with postoperative remnants of nonfunctioning pituitary adenomas treated at the Department of Neurosurgery, University Hospital Erlangen, Erlangen, Germany, were included in this study. All patients underwent transsphenoidal procedures with guidance by 1.5-T intraoperative MRI. The intraoperative images of remnants were compared with images taken at 3 months and at 1 year after surgery. The possible predictors analyzed were age; sex; preoperative and intraoperative tumor dimensions; tumor growth pattern; endocrinological, ophthalmological, and histological characteristics; and history of previous pituitary surgery. For statistical analyses, the Fisher's exact test, Mann-Whitney U-test, and multivariate regression table analysis were used. RESULTS: Follow-up imaging 3 months after surgery showed tumor remnant shrinkage of 0.5 +/- 0.6 cm3 for 70 (50%) patients. This reduction was 89% +/- 20% of the residual volume depicted by intraoperative MRI. In 45 (64%) patients, the remnants disappeared completely. Age, sex, and preoperative tumor volume did not significantly differ between the shrinkage and no-shrinkage groups. Positive predictors for postoperative shrinkage were cystic tumor growth (p = 0.02), additional resection of tumor remnants guided by intraoperative MRI (p = 0.04), smaller tumor volume (p = 0.04), and smaller craniocaudal tumor diameter of remnants (p = 0.0014). Negative predictors were growth into the cavernous sinus (p = 0.009), history of previous pituitary surgery (p = 0.0006) and tumor recurrence (p = 0.04), and preoperative panhypopituitarism (p = 0.04). Multivariate regression analysis indicated a positive correlation between tumor shrinkage and smaller tumor remnants (p < 0.0001) and no history of previous pituitary surgery (p = 0.003). No spontaneous change in tumor remnant volume was detected between 3 months and 1 year postoperatively. During a mean follow-up time of 2.7 years, 1 (2%) patient with postoperative tumor shrinkage had to undergo another operation because of tumor progression. CONCLUSIONS: Spontaneous volume reduction of nonfunctioning pituitary adenoma remnants can occur within 3 months after surgery. Predictors of shrinkage are smaller tumor remnant volume and no history of previous pituitary surgery. PMID- 24074497 TI - Acinetobacter baumannii. PMID- 24074496 TI - Treatment of acromegaly by endoscopic transsphenoidal surgery: surgical experience in 214 cases and cure rates according to current consensus criteria. AB - OBJECT: Acromegaly is a disease that has significant morbidity and mortality related to high levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I), and is usually caused by pituitary adenomas. The goal in this study was to investigate the role of endoscopic transsphenoidal surgery and surgical experience in the treatment of GH adenoma cases in relation to surgical results and hormonal cure rates, and to perform a review of the literature. METHODS: The authors present a retrospective analysis of 214 GH adenoma cases. Restoration of IGF-I levels to normal for age and sex, suppression of GH levels below 0.4 MUg/L on the oral glucose tolerance test, and demonstration of the total removal of the tumor on MRI studies obtained after administration of contrast material at the 3 month postoperative follow-up visit were the criteria for cure. RESULTS: In total 214 patients with a mean age of 41.9 +/- 12 years (range 17-75 years) and a male/female ratio of 106/108 were enrolled in the study. Cure was achieved in 134 (62.6%) of 214 patients. One hundred sixty-nine patients were primary cases, and of these 109 (64.5%) were cured, whereas 61 patients were previously operated cases and of these 25 (41%) were cured. With a 51.1% decrease in the 1st month postoperatively, IGF-I levels were found to be predictive of cure (74.4% sensitivity and 73.7% specificity). Cut-off values for GH levels in predicting cure for the 1st day, 1st week, and 1st month postoperatively were 2.33, 2.05, and 2.25 MUg/L, respectively. The cut-off value for surgical experience was 57 for primary surgeries (58.5% cure rate before this cut-off value compared with 72.6% after it; p = 0.025) and 108 for all operations (45.8% vs. 79.4%, p = 0.037). Although 28 patients were found to be in remission according to the criteria in 2000, they were not in remission according to the new consensus criteria. Nine of these cases (32.1%) had random GH levels < 1 MUg/L at the 1 year follow-up. The 1-year IGF-I and GH levels in these 28 patients showed no significant difference when compared with the cases defined as cured according to the current criteria. CONCLUSIONS: In acromegaly treatment, transsphenoidal endoscopic surgery performed by an expert senior surgeon and increased surgical experience are important for higher cure rates. Random GH levels < 2.33 MUg/L after the 1st day postoperatively and a > 50% decrease in IGF-I levels after the 1st month postoperatively are predictive of cure. Moreover, there is no urgency for additional therapy in patients with GH levels of 0.4-1 MUg/L and MRI sequences showing no tumor at the 3-month follow-up, because for these cases remission can be achieved at the 1-year follow-up. PMID- 24074498 TI - Unchanged safety outcomes in deep brain stimulation surgery for Parkinson disease despite a decentralization of care. AB - OBJECT: Early work on deep brain stimulation (DBS) surgery, when procedures were mostly carried out in a small number of high-volume centers, demonstrated a relationship between surgical volume and procedural safety. However, over the past decade, DBS has become more widely available in the community rather than solely at academic medical centers. The authors examined the Nationwide Inpatient Sample (NIS) to study the safety of DBS surgery for Parkinson disease (PD) in association with this change in practice patterns. METHODS: The NIS is a stratified sample of 20% of all patient discharges from nonfederal hospitals in the United States. The authors identified patients with a primary diagnosis of PD (332.0) and a primary procedure code for implantation/replacement of intracranial neurostimulator leads (02.93) who underwent surgery between 2002 and 2009. They analyzed outcomes using univariate and hierarchical, logistic regression analyses. RESULTS: The total number of DBS cases remained stable from 2002 through 2009. Despite older and sicker patients undergoing DBS, procedural safety (rates of non-home discharges, complications) remained stable. Patients at low volume hospitals were virtually indistinguishable from those at high-volume hospitals, except that patients at low-volume hospitals had slightly higher comorbidity scores (0.90 vs 0.75, p < 0.01). Complications, non-home discharges, length of hospital stay, and mortality rates did not significantly differ between low- and high-volume hospitals when accounting for hospital-related variables (caseload, teaching status, location). CONCLUSIONS: Prior investigations have demonstrated a robust volume-outcome relationship for a variety of surgical procedures. However, the present study supports safety of DBS at smaller-volume centers. Prospective studies are required to determine whether low-volume centers and higher-volume centers have similar DBS efficacy, a critical factor in determining whether DBS is comparable between centers. PMID- 24074500 TI - PNPLA2 mutation: a paediatric case with early onset but indolent course. AB - Neutral lipid storage disease (NLSD) due to PNPLA2 mutation is a rare disorder with a severe muscular and cardiac outcome. All but one reported cases have been diagnosed during adulthood. It is thus ordinarily distinguished from Chanarin Dorfman syndrome, a paediatric NLSD with a more widespread symptomatology. We report the case of a young child incidentally diagnosed with significant and persistent hyperCKemia. At 3 years, muscle biopsy showed marked lipid storage. A homozygous mutation in PNPLA2 was found. Fourteen years later, the noticeable outcome is the absence of muscle weakness at rest, a normal muscular MRI, and no cardiac involvement. Yet the patient exhibits some systemic features, notably hearing loss. This paediatric case of NLSD with myopathy indicates that important lipid accumulation may occur very early in the absence of patent clinical and imaging muscle involvement. Furthermore, PNPLA2 mutations may be associated with multisystem features more frequently encountered in Chanarin-Dorfman syndrome. PMID- 24074501 TI - Prepubertal anti-Musk positive myasthenia gravis with long remission. AB - Anti-MuSK positive myasthenia gravis (MuSK-MG) is rare prepuberty. We report a female patient with MuSK-MG starting at 3.5years with ptosis as the sole symptom for 2years. A brief period of generalization was followed by complete stable remission for 6years. Prolonged ocular symptoms and long remissions are not features of MuSK-MG, but are often seen in prepubertal onset MG. The patient then presented at age 12 with moderately severe symptoms which were almost confined to oculobulbar muscles and were unresponsive to pyridostigmine. She was dependent on corticosteroids and thymectomy did not seem to be effective. She was later noted to have tongue atrophy after a period without treatment. Our patient thus presented with features seen in many prepubertal patients, but the later course was quite typical of MuSK-MG. PMID- 24074502 TI - Impairment of wound healing after operative treatment of mandibular fractures, and the influence of dexamethasone. AB - Our aim was to clarify the incidence of impaired wound healing after open reduction and ostheosynthesis of mandibular fractures, and to find out whether the use of dexamethasone during the operation increased the risk. Patients were drawn from a larger group of healthy adult dentate patients who had participated in a single-blind, randomised study, the aim of which was to clarify the benefits of operative dexamethasone after treatment of facial fractures. The present analysis comprised 41 patients who had had open reduction and fixation of mandibular fractures with titanium miniplates and monocortical screws through one or 2 intraoral approaches. The outcome variable was impaired healing of the wound. The primary predictive variable was the perioperative use of dexamethasone; other potential predictive variables were age, sex, smoking habit, type of fracture, delay in treatment, and duration of operation. Wound healing was impaired in 13/41 patients (32%) (13/53 of all fractures). The incidence among patients who were given dexamethasone and those who were not did not differ significantly. Only age over 25 was significantly associated with delayed healing (p=0.02). The use of dexamethasone 30 mg perioperatively did not significantly increase the risk of impaired wound healing in healthy patients with clinically uninfected mandibular fractures fixed with titanium miniplates through an intraoral approach. Older age is a significant predictor of impaired healing, which emphasises the importance of thorough anti-infective care in these patients during and after the operation. PMID- 24074503 TI - Reverse sliding onlay graft from the chin for lateral reconstruction of the alveolar ridge. PMID- 24074504 TI - Multicentre evaluation of music perception in adult users of Advanced Bionics cochlear implants. AB - OBJECTIVES: To document musical listening and enjoyment in recipients of Advanced Bionics cochlear implants (CIs) and to compare musical perception in those using early coding strategies with subjects using the newer HiRes and HiRes 120 strategies. METHODS: A questionnaire was completed by 136 adult subjects, including questions on the ability to identify specific musical features. The subjects were in three groups: those using early coding strategies (n = 29), HiRes (n = 59), and HiRes 120 (n = 48), and results were compared with a group of 84 normally hearing (NH) subjects. RESULTS: Of the CI users, 79% reported listening to music. The NH group rated listening frequency and enjoyment higher than the CI users. Thirty-five users reported that they sang and this group had significantly higher overall performance. There were no significant differences in overall perception of specific musical features among the strategy groups, though some individual questions showed significantly higher performance in the HiRes 120 users. DISCUSSION: Users of current CI technology show a high level of musical appreciation, though still significantly less than NH subjects. Frequency of listening and enjoyment were significantly correlated and active participation in musical activities, specifically singing, resulted in significantly higher overall performance scores. PMID- 24074505 TI - A nanoscale characterization of the interaction of a novel alginate oligomer with the cell surface and motility of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa (PA) biofilm-associated infections are a common cause of morbidity in chronic respiratory disease and represent a therapeutic challenge. Recently, the ability of a novel alginate oligomer (OligoG) to potentiate the effect of antibiotics against gram-negative, multi-drug-resistant bacteria and inhibit biofilm formation in vitro has been described. Interaction of OligoG with the cell surface of PA was characterized at the nanoscale using atomic force microscopy (AFM), zeta potential measurement (surface charge), and sizing measurements (dynamic light scattering). The ability of OligoG to modify motility was studied in motility assays. AFM demonstrated binding of OligoG to the bacterial cell surface, which was irreversible after exposure to hydrodynamic shear (5,500 * g). Zeta potential analysis (pH 5-9; 0.1-0.001 M NaCl) demonstrated that binding was associated with marked changes in the bacterial surface charge (-30.9 +/- 0.8 to -47.0 +/- 2.3 mV; 0.01 M NaCl [pH 5]; P < 0.001). Sizing analysis demonstrated that alteration of surface charge was associated with cell aggregation with a 2- to 3-fold increase in mean particle size at OligoG concentrations greater than 2% (914 +/- 284 to 2599 +/- 472 nm; 0.01 M NaCl [pH 5]; P < 0.001). These changes were associated with marked dose dependent inhibition in bacterial swarming motility in PA and Burkholderia spp. The ability of OligoG to bind to a bacterial surface, modulate surface charge, induce microbial aggregation, and inhibit motility represents important direct mechanisms by which antibiotic potentiation and biofilm disruption is affected. These results highlight the value of combining multiple nanoscale technologies to further our understanding of the mechanisms of action of novel antibacterial therapies. PMID- 24074506 TI - The posterior pedicle screw construct: 5-year results for thoracolumbar and lumbar curves. AB - OBJECT: Several studies of the outcomes of patients with adolescent idiopathic scoliosis (AIS) with thoracolumbar and lumbar curves after treatment with posterior pedicle screws have been reported, but most of these studies reported only 2-year follow-up. The authors analyzed the radiographic and clinical outcomes of patients with thoracolumbar and lumbar curves treated with posterior pedicle screws after 5 years of follow-up. METHODS: A multicenter database was retrospectively queried to identify patients with AIS who underwent spinal fusion for Lenke 3C, 5C, and 6C curves. Radiographs from the following times were compared: preoperative, first follow-up visit, 1-year follow-up visit, 2-year follow-up visit, and 5-year follow-up visit. Chart review included scoliometer measurements, Scoliosis Research Society (SRS)-22 questionnaires, and complications requiring return to the operating room. RESULTS: Among 26 patients with Lenke 3C, 5C, and 6C curves, the mean (+/- SD) age was 14.6 +/- 2.1 years. From the time of the preoperative radiographs to the 5-year follow-up radiographs, there was a statistically significant improvement in the mean coronal lumbar Cobb angles (p < 0.0001), and from the time of the first postoperative radiographs to the 5-year follow-up radiographs, the lumbar curve remained stable (p = 0.14). From the time of the preoperative radiographs to the 5-year follow-up radiographs, there was a statistically significant improvement in the mean coronal thoracic Cobb angles (p < 0.0001), and from the time of the first postoperative radiographs to the 5-year follow-up radiographs, the thoracic curve remained stable (p = 0.10). From the first postoperative visit to the 5 year follow-up visit, the thoracic kyphosis (T5-12) remained stable (p = 0.10), and from the time of the preoperative radiographs to the 5-year follow-up radiographs, the lumbar lordosis (T-12 to top of sacrum) remained stable (p = 0.44). From the preoperative visit to the 5-year follow-up visit, the coronal balance improved significantly (p < 0.05) and remained stable from the first postoperative visit to the 5-year follow-up visit (p = 0.20). The SRS-22 total scores improved significantly from before surgery to 5 years after surgery (p < 0.0001). No patients required reoperation because of complications. CONCLUSIONS: Correction of the coronal, sagittal, and axial planes in this cohort of patients was maintained from the first follow-up measurements to 5 years after surgery. In addition, at 5 years after surgery total SRS-22 scores and inclinometer readings were improved from preoperative scores and measurements. PMID- 24074507 TI - Cervical myelopathy caused by invagination of anomalous lamina of the axis. AB - The authors report a case of cervical myelopathy caused by invagination of the bilaterally separated lamina of the axis. They also present a literature review. The patient was a previously healthy 68-year-old man with a 1-year history of slowly progressive gait disturbance, right-hand clumsiness, and right dominant sensory disturbance in his trunk and extremities. Both MRI and CT showed that the spinal cord was markedly compressed at the C2-3 level, on the right side, by a deeply invaginated anomalous lamina of the axis. A bilaterally separated lamina was also visible. The patient underwent removal of the anomalous invaginated fragment of the separated lamina and the spinous process of the axis. One year after surgery, his myelopathic symptoms had almost completely resolved. Here, the authors present the case of a patient with an extremely rare anomaly of the lamina of the axis. The underlying pathogenesis of this anomaly could be the failure of the 2 chondrification centers on either side to fuse into a single ossification center. Surgical removal of the anomalous invaginated lamina produced a satisfactory outcome. PMID- 24074508 TI - Comparative study of fibrin and chemical synthetic sealant on dural regeneration and brain damage. AB - OBJECT: Several materials, such as polyethylene glycol (PEG) hydrogel and fibrin glue, have been used to seal dural incisions after brain and spinal surgeries. Although the use of PEG sealant is gaining popularity, it can be associated with postoperative cerebrospinal fluid leakage and infection. However, the reasons for this association are currently unknown. The present study aimed to investigate the effects of PEG sealant and fibrin glue on wound healing and brain damage in vivo. METHODS: Oval-shaped bone defects and dural defects were created bilaterally over the parietal lobes of 22 Japanese white rabbits. The dural defects were covered with 0.5 ml of fibrin glue on one side and 0.5 ml of PEG sealant on the other side. Dural regeneration and brain damage were investigated in each harvested brain and dura mater using light microscopy. RESULTS: Dural regeneration was more effective in the presence of fibrin glue than it was with PEG sealant (p = 0.014). Of the 22 rabbits, 11 showed thick (Grades ++ and +++) dural regeneration by 28 days postsurgery in the hemisphere where fibrin glue was used, whereas Grade +++ dural regeneration was not observed in the PEG hydrogel hemisphere, and only 4 rabbits showed Grade ++ regeneration. Abscess and granulation formation also tended to be more severe when PEG hydrogel sealant was used. No Grade ++ granulation/abscess formation was observed with fibrin glue, and Grade + was only observed in 13 of 22 rabbits. Conversely, with PEG hydrogel sealant, only 2 rabbits did not show granulation/abscess formation, and Grade +, ++, and +++ granulation/abscess formation was observed in 8, 7, and 5 rabbits, respectively. The extent of cortical damage was significantly greater in rabbits with abscesses and granulations, compared with rabbits without these lesions (p = 0.007). CONCLUSIONS: Dural regeneration tended to occur more rapidly with fibrin glue, whereas granulation was more likely with PEG hydrogel sealant, which led to postoperative complications. Histological analysis indicated that PEG hydrogel sealant inhibited the normal tissue healing process and that outcomes were improved by the use of fibrin glue. PMID- 24074509 TI - Little-known Swiss contributions to the description, diagnosis, and surgery of lumbar disc disease before the Mixter and Barr era. AB - The understanding of lumbar spine pathologies made substantial progress at the turn of the twentieth century. The authors review the original publication of Otto Veraguth in 1929 reporting on the successful resection of a herniated lumbar disc, published exclusively in the German language. His early report is put into the historical context, and its impact on the understanding of pathologies of the intervertebral disc (IVD) is estimated. The Swiss surgeon and Nobel Prize laureate Emil Theodor Kocher was among the first physicians to describe the traumatic rupture of the IVD in 1896. As early as 1909 Oppenheim and Krause published 2 case reports on surgery for a herniated lumbar disc. Goldthwait was the first physician to delineate the etiopathogenes is between annulus rupture, symptoms of sciatica, and neurological signs in his publication of 1911. Further publications by Middleton and Teacher in 1911 and Schmorl in 1929 added to the understanding of lumbar spinal pathologies. In 1929, the Swiss neurologist Veraguth (surgery performed by Hans Brun) and the American neurosurgeon Walter Edward Dandy both published their early experiences with the surgical therapy of a herniated lumbar disc. Veraguth's contribution, however, has not been appreciated internationally to date. The causal relationship between lumbar disc pathology and sciatica remained uncertain for some years to come. The causal relationship was not confirmed until Mixter and Barr's landmark paper in 1934 describing the association of sciatica and lumbar disc herniation, after which the surgical treatment became increasingly popular. Veraguth was among the first physicians to report on the clinical course of a patient with successful resection of a herniated lumbar disc. His observations should be acknowledged in view of the limited experience and literature on this ailment at that time. PMID- 24074510 TI - Surgical seroma. PMID- 24074511 TI - Intramuscular pressure of the multifidus muscle and low-back pain after posterior lumbar interbody fusion: comparison of mini-open and conventional approaches. AB - OBJECT: This randomized study was designed to elucidate the time course of the perioperative development of intramuscular multifidus muscle pressure after posterior lumbar interbody fusion (PLIF) and to investigate whether the route of pedicle screw insertion affects this pressure and resultant low-back pain. Although several studies have focused on intramuscular pressure associated with posterior lumbar surgery, those studies examined intramuscular pressure generated by the muscle retractors during surgery. No study has investigated the intramuscular pressure after PLIF. METHODS: Forty patients with L4-5 degenerative spondylolisthesis were randomly assigned to undergo either the mini-open PLIF procedure with pedicle screw insertion between the multifidus and longissimus muscles (n = 20) or the conventional PLIF procedure via a midline approach only (n = 20). Intramuscular pressure was measured 5 times (at 30 minutes and at 6, 12, 24, and 48 hours after surgery) with an intraoperatively installed sensor. Concurrently, the FACES Pain Rating Scale score for low-back pain and the total dose of postoperative analgesics were recorded. RESULTS: With the patients in the supine position, for both groups the mean pressure values were consistently 40-50 mm Hg, which exceeded the critical capillary pressure of the muscle. With the patients in the lateral decubitus position, the pressure decreased over time (from 14 to 9 mm Hg in the mini-open group and from 20 to 10 mm Hg in the conventional group). Among patients in the mini-open group, the pressure was lower, but the difference was not statistically significant. Postoperative pain and postoperative analgesic dosages were also lower. CONCLUSIONS: To the authors' knowledge, this is the first study to evaluate postoperative intramuscular pressure after PLIF. Although the results did not demonstrate a significant difference in the intramuscular pressure between the 2 types of PLIF, mini-open PLIF was associated with less pain after surgery. PMID- 24074512 TI - Persistent negative tuberculin reactors. PMID- 24074513 TI - C950T and C1181G osteoprotegerin gene polymorphisms in myeloma bone disease. AB - OBJECTIVES: Bone disease is one of the hallmarks of multiple myeloma (MM). The role of osteoprotegerin (OPG) in the RANK/RANKL/OPG signaling system is well defined in the myeloma bone disease. Polymorphisms of the TNFRSF11B gene encoding OPG have been studied in various bone diseases. However, relationship between the levels of OPG and development of bone lesions regardless of RANKL is yet unknown. In this study, the effects of OPG gene polymorphism on the development of bone lesions in MM were investigated. METHODS: C950T and C1181G polymorphisms of the OPG gene were studied in 52 MM patients (36 with bone lesions and 16 without bone lesions) and in another 20 control subjects using DNA sequencing. RESULTS: 1181 G and 950 T alleles were overrepresented in MM patients having bone lesions. 950 TT/1181 GG haplotype frequency and TT/GG combined haplotype were also higher in MM patients having bone lesions compared to MM patients without bone lesions or to control. DISCUSSION: This is the first study searching for the relationship between OPG gene variants C950T (promoter), C1181G (exon 1), and myeloma bone disease. It was concluded that the presence of polymorphic 1181 G/950 T alleles and 950 TT/1181 GG genotypes may play a role in the development of bone disease. PMID- 24074514 TI - A new early cognitive screening measure to detect cognitive side-effects of electroconvulsive therapy? AB - Cognitive side-effects from electroconvulsive therapy (ECT) can be distressing for patients and early detection may have an important role in guiding treatment decisions over the ECT course. This prospective study examined the utility of an early cognitive screening battery for predicting cognitive side-effects which develop later in the ECT course. The screening battery, together with the Mini Mental Status Examination (MMSE), was administered to 123 patients at baseline and after 3 ECT treatments. A more detailed cognitive battery was administered at baseline, after six treatments (post ECT 6) and after the last ECT treatment (post treatment) to assess cognitive side-effects across several domains: global cognition, anterograde memory, executive function, speed and concentration, and retrograde memory. Multivariate analyses examined the predictive utility of change on items from the screening battery for later cognitive changes at post ECT 6 and post treatment. Results showed that changes on a combination of items from the screening battery were predictive of later cognitive changes at post treatment, particularly for anterograde memory (p < 0.01), after controlling for patient and treatment factors. Change on the MMSE predicted cognitive changes at post ECT 6 but not at post treatment. A scoring method for the new screening battery was tested for discriminative ability in a sub-sample of patients. This study provides preliminary evidence that a simple and easy-to-administer measure may potentially be used to help guide clinical treatment decisions to optimise efficacy and cognitive outcomes. Further development of this measure and validation in a more representative ECT clinical population is required. PMID- 24074515 TI - Predicting post-traumatic stress disorder in veterans: interaction of traumatic load with COMT gene variation. AB - BACKGROUND: Because post-traumatic stress disorder (PTSD) by definition can occur only after exposure to a traumatic event, military veterans who are at high risk for trauma exposure are a particularly relevant population for studying the interaction of trauma with genetic factors that may predispose for the disorder. A number of studies have implicated specific genes as possible risk factors in developing PTSD, including the catechol-O-methyltransferase gene (COMT). METHODS: Data from Iraq War veterans (n = 236) were used to examine the interaction between COMT and traumatic experiences in predicting later development of PTSD symptoms. Subjects were assessed for exposure to traumatic events both before and during deployment. RESULTS: The interaction between trauma load and COMT was a significant predictor of PTSD symptoms. Those with the heterozygous genotype (Val/Met) showed fewer symptoms associated with trauma exposure compared to those with either homozygous genotype. This interaction remained significant after controlling for other risk factors for PTSD, including personality dimensions of Internalizing and Externalizing. CONCLUSIONS: COMT genotype affects risk for development of PTSD symptoms following exposure to trauma. PMID- 24074516 TI - Interleukin-1beta is associated with depressive episode in major depression but not in bipolar disorder. AB - Our work was sought to investigate possible changes in peripheral levels of interleukin-1beta (IL-1beta) according to the diagnosis of major depression (MD) and bipolar disorder (BD) and in different mood episodes. This is a cross sectional nested in a population-based study comparing 240 young adults (80 controls, 80 MD and 80 BD), balanced for age and gender. Serum levels of IL-1beta were significantly higher in MD when compared to control or BD subjects. In addition, when divided by current mood episode, MD subjects in current depression presented higher IL-1beta levels than controls. No differences in IL-1beta levels were found between different episodes of BD (euthymic, depressed, mania or mixed). Moreover, the use of psychiatric medication was very low in our sample and not associated with changes in IL-1beta levels. In conclusion, increased peripheral IL-1beta might be a useful marker associated with a depressive episode in the context of MD. PMID- 24074517 TI - Predictors of outcome in outpatients with anxiety disorders: the Leiden routine outcome monitoring study. AB - Little is known about the predictors of outcome in anxiety disorders in naturalistic outpatient settings. We analyzed 2-year follow-up data collected through Routine Outcome Monitoring (ROM) in a naturalistic sample of 917 outpatients in psychiatric specialty care in order to identify factors predicting outcome. We included patients with panic disorder with or without agoraphobia, agoraphobia without panic, social phobia, or generalized anxiety disorder. Main findings from Cox regression analyses demonstrated that several socio-demographic variables (having a non-Dutch ethnicity [HR = 0.71)], not having a daily occupation [HR = 0.76]) and clinical factors (having a diagnosis of agoraphobia [HR = 0.67], high affective lability [HR = 0.80] and behavior problems [HR = 0.84]) decreased chances of response (defined as 50% reduction of anxiety severity) over the period of two years. Living with family had a protective predictive value [HR = 1.41]. These results may imply that factors that could be thought to limit societal participation, are associated with elevated risk of poor outcome. A comprehensive ROM screening process at intake may aid clinicians in the identification of patients at risk of chronicity. PMID- 24074518 TI - No differences between drug naive and drug experienced unipolar depressed patients in terms of neurobiological testing: a cross sectional study. AB - Successful antidepressant treatment has been associated with concomitant changes in brain function, consolidated as long as treatment is continued and remission is preserved. The present study aimed at assessing the impact of prior antidepressant treatment on brain function in currently depressed but unmedicated individuals by investigating for any differences between antidepressant-naive vs. antidepressant-experienced subjects. Fifty right-handed patients (22 medication naive vs. 28 medication-experienced), suffering from major depression participated in the study. They all underwent a standardised clinical interview and psychometric assessment combined with neurobiological tests (brain SPECT, Dexamethasone Suppression Test, Dexfenfluramine Challenge Test, electro oculogram, flash-electroretinogram and flash-visual evoked potentials and pattern reversal visual evoked potentials). No significant differences between medication naive and medication-experienced depressed subjects were found in terms of the neurobiological markers assessed, after controlling for age, sex, age at onset, number of depressive episodes, depression subtype (melancholic, atypical or undifferentiated) and severity of current episode. Unmedicated currently depressed patients, no matter their previous exposure to antidepressants, show similar changes in brain function. This does not necessarily mean that antidepressants do not have a long term effect on brain physiology, since not all patients relapse. However, it seems that those patients who relapse after stopping medication, seem to 'regress' to an 'as if never medicated' state, with regard to brain function. These findings might suggest that continuous maintenance treatment with antidepressants is essential for patients at high risk to relapse. Alternatively, they might suggest that our methodology assesses only a shallow and mainly state part of the pathophysiology of depression. PMID- 24074519 TI - Replication study of genetic variants associated with chronic rhinosinusitis and nasal polyposis. PMID- 24074520 TI - Hemodynamic profiles of intubated and mechanically ventilated carbon monoxide poisoned patients during systemic hyperbaric oxygen therapy. AB - BACKGROUND: Carbon monoxide (CO) poisoning can be a life threatening condition. Systemic hyperbaric oxygen (HBO) therapy is used to induce CO detoxification. However, little is known about the hemodynamic response to HBO in severely intoxicated patients. METHODS: We retrospectively analyzed the medical records of 6 CO-poisoned patients treated with propofol, rocuronium bromide, and HBO. The HBO protocol comprised 3 HBO treatments (HBOT1 to HBOT3) within 24 hours. During all HBO sessions heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse blood pressure (DeltaBP) were measured every five minutes. Non-parametric tests were used to compare data between HBO sessions. RESULTS: HR increased significantly as the number of HBOT increased, from 68 beats per minute (bpm) during HBOT1 to 77 and 86 bpm during HBOT2 and HBOT3, respectively (p < 0.05). In addition, while no significant change was found for DBP, both SBP and DeltaBP showed a transient and significant increase during HBOT2, compared to HBOT1, that did not return to basal values during HBOT3. CONCLUSION: Based on previous studies that have established the respective effects of rocuronium bromide, propofol, HBO, and CO alone on HR, SBP, and DeltaBP, it is concluded that the hemodynamic responses observed in the present study are likely to be due to CO. If such, given that neither HR nor SBP and DeltaBP returned to basal values by the end of HBOT3, it is suggested that more than 3 HBOT sessions could be necessary to provide full hemodynamic recovery in CO-poisoned patients. PMID- 24074521 TI - Prognostic impact of Wilms tumor gene mutations in Egyptian patients with acute myeloid leukemia with normal karyotype. AB - The Wilms' tumor (WT1) gene mutations were detected in patients with most forms of acute leukemia. However, the biological significance and the prognostic impact of WT1 mutation in Egyptian patients with acute myeloid leukemia with normal karyotype (AML-NK) are still uncertain. We aimed to evaluate the incidence and clinical relevance of WT1 gene mutations in acute myeloid leukemia with normal karyotype (AML-NK). Exons 7 and 9 of WT1 were screened in samples from 216 adult NK-AML using polymerase chain reaction single-strand conformation polymorphism techniques. Twenty-three patients (10.6%) harbored WT1 mutations. Younger ages and higher marrow blasts were significantly associated with WT1 mutations (P = 0.006 and 0.003 respectively). Complete remission rates were significantly lower in patients with WT1 mutations than those with WT1 wild-type (P = 0.015). Resistance, relapse, and mortality rates were significantly higher in patients with WT1 mutations than those without (P = 0.041, 0.016, and 0.008 respectively). WT1 mutations were inversely associated with NPM1 mutations (P = 0.007). Patients with WT1 mutations had worse disease-free survival (P < 0.001) and overall survival (P < 0.001) than patients with WT1 wild-type. In multivariable analyses, WT1 mutations independently predicted worse DFS (P < 0.001; hazard ratio [HR] 0.036) and overall survival (P = 0.001; HR = 0.376) when controlling for age, total leukocytic count (TLC), and NPM1 mutational status. In conclusion, WT1 mutations are a negative prognostic indicator in intensively treated patients with AML-NK, may be a part of molecularly based risk assessment and risk-adapted treatment stratification of patients with AML-NK. PMID- 24074523 TI - Stimuli responsive elastin-like polypeptides and applications in medicine and biotechnology. AB - Elastin-like polypeptides (ELPs) are artificial biopolymers composed of the pentapeptide repeat Val-Pro-Gly-Xaa-Gly. They are a class of stimuli responsive biopolymers exhibiting an inverse temperature transition, which are particularly attractive in biological applications. In this paper, the methods of synthesizing ELPs and the applications in medicine and biotechnology such as purification of fusion proteins, drug delivery, and tissue engineering are reviewed. In addition, further perspective will be presented. PMID- 24074524 TI - Effect of low frequency electrical stimulation on spike and wave discharges of perioral somatosensory cortex in WAG/Rij rats. AB - Low frequency electrical stimulation has been revealed that as a potential cure in patient with drug resistant to epilepsy. This study tries to evaluate the effect of low frequency electrical stimulation (LFS) on absence seizure of perioral region primary somatosensory cortex (S1po). Eighteen male WAG/Rij rats were received LFS (3Hz, square wave, monophasic, 200MUs, and 400MUA) for 25min into S1po for a period of five days. There is 6 animals per group .The stimulating electrodes were implanted according to stereotaxic landmarks and EEG recording was obtained 30min before and after LFS to analyse frequency, number and duration of spike-wave discharges (SWD). The results showed that in animals with unilateral stimulating electrodes (Exp1) in first and second days and also in animals with bilateral stimulating electrodes (Exp2) in days 3rd and 4th. LFS had significant decrease effects (p<0.05) on mean number of SWD between pre-LFS. In comparison pre-LFS to post-LFS, mean of duration in Exp2 decreased significantly. In continuous application of LFS (5 days) only the data of first day was differently significant (p<0.05) but data of other days had no difference. Comparison of data between Exp1, Exp2 and control groups showed that the mean number of Exp1 was significantly different (p<0.05) and mean pick frequency in Exp2 was significantly decreased in comparison with Exp1 group (p<0.05). The LFS of S1po produces significant antiepileptic effect on absence seizure but it was not persistent till the next day and shows a short time effect. PMID- 24074525 TI - An interesting cause of wide complex tachycardia: Ashman's phenomenon in atrial fibrillation. AB - BACKGROUND: Ashman's phenomenon is an aberrant intraventricular conduction abnormality that occurs in response to a change in QRS cycle length. In atrial fibrillation, Ashman's phenomenon will present as a long RR cycle followed by a short RR cycle, with the subsequent QRS complex manifesting a right bundle branch block morphology. This morphologic variation can create difficulty with electrocardiographic interpretation, and can alter management in patients with this dysrhythmia. OBJECTIVES: This report presents a case, describes the Ashman's phenomenon in atrial fibrillation, and discusses interpretation of this electrocardiographic finding. CASE REPORT: This is a 27-year-old woman who presented with palpitations and chest pain. The patient was symptomatic with a heart rate >200 beats/min and a wide complex tachycardia on electrocardiogram. CONCLUSIONS: Ashman's phenomenon should be suspected in atrial fibrillation when there is a long cycle followed by a short cycle, with the subsequent QRS complex manifesting a right bundle branch block pattern. Emergency physician awareness of this phenomenon may improve diagnostic certainty and have an impact on dysrhythmia management. PMID- 24074526 TI - Chest pain a manifestation of migraine. AB - BACKGROUND: Chest pain is an alarming symptom; it justifies many visits to the emergency department (ED). The etiology is often unknown. Chest wall pain in the presence of migraine headache, although not a common occurrence, is intriguing when it resolves with antimigraine treatment. OBJECTIVES: To characterize the manifestations and outcomes and investigate the relationship between chest wall pain and headache as a manifestation of migraine exacerbation. METHODS: Among patients visiting our ED, we identified those individuals whose pain originated in the chest wall in the setting of migraine exacerbation. Patients with clinical indications for specific treatments were dispositioned accordingly. Control of symptoms including chest pain and headache with antimigraine agents was considered the primary outcome. A prospective follow-up via telephone interview and medical records review was performed. RESULTS: We collected a convenience sample of 33 patients. All manifested migraine headache with an earlier onset than the chest pain, and all had taken medications prior to visiting the ED. Twelve patients reported a higher visual analog scale score for the headache than for the chest pain. Still, chest pain was the main complaint. The chest pain originated at the chest wall. Ten patients received sublingual nitroglycerin or opiates, or both; no pain relief was reported. However, all symptoms resolved with metoclopramide. On follow-up, 6 patients reported recurrence of chest pain with subsequent migraines. CONCLUSIONS: Chest pain can be a complication of migraine. The treatment should be focused on migraine control. Migraine should be included in the differential diagnosis of chest pain. PMID- 24074527 TI - Survival in pulmonary arterial hypertension patients awaiting lung transplantation. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease with lung transplantation as the only option for those patients refractory to medical therapy. Although several equations have been developed to predict PAH patient survival, it is unclear whether they can predict survival for patients awaiting transplantation. METHODS: Data were analyzed on 827 patients listed since 1991 on the Scientific Registry of Transplant Recipients. Overall survival and survival for patients listed prior to and after January 1, 2006 was estimated using the Kaplan-Meier (K-M) method and compared with predicted survival from the pulmonary hypertension connection (PHC) and lung allocation system (LAS) equations. A new equation using a novel model selection algorithm for correlated covariates and missing data was developed using clinical factors and variables in the LAS score. Model validation statistics were calculated and averaged across 500 bootstrap resamples within each of 5 imputation data sets. K-M with 95% confidence intervals and receiver-operator characteristic (ROC) curves assessed model performance. RESULTS: PHC predicted overall survival but underestimated and overestimated survival for those listed pre- and post-2006, respectively. The best model included baseline 6-minute walk distance (6MWD), invasive cardiac output and resting oxygen requirement (O2). Factors associated with 1-year waitlist survival included: resting O2 amount; invasive hemodynamics; 6MWD; and functional class. The new equation by ROC analysis outperformed the LAS and PHC equations. CONCLUSIONS: Current prediction models overestimate survival for PAH patients listed for transplant in the LAS era. This new survival equation can help guide clinicians caring for PAH patients with progression of disease requiring transplant. PMID- 24074528 TI - Tailored central nervous system-directed treatment strategy for isolated CNS recurrence of adult acute myeloid leukemia. AB - OBJECTIVES: The aim of this report was to investigate the tailored treatment strategies for isolated central nervous system (CNS) recurrence in adult patients with acute myeloid leukemia (AML). METHODS: Isolated CNS recurrence was documented in 34 patients: there were 18, 6, and 10 patients with meningeal involvement type (type A), cranial nerve palsy type (type B), and myeloid sarcoma type (type C), respectively. For patients with type A, intrathecal chemotherapy was the predominant strategy. For type B, systemic HD-Ara-C with four cycles was the main treatment. For type C, cranial irradiation or craniospinal irradiation was adopted and two cycles of HD-Ara-C were given after the irradiation. RESULTS: The 5-year cumulative incidence of CNS recurrence was 12.8%. There was a significantly higher WBC count (32.6~60.8 * 10(9)/l) in patients at first diagnosis who developed CNS recurrence (all of the three types) compared with patients with no CNS recurrence (10.1 * 10(9)/l) (P = 0.005). We found that a significantly more patients with AML-M5 and 11q23 abnormalities developed CNS recurrence in type A (P < 0.001, 0.005). Twenty-four out of 34 patients (70.6%) with CNS recurrence achieved CNS complete remission at a median of 58 days (range, 30-120). The 3-year disease-free survival and overall survival estimates for all CNS recurrence patients were 21.6 and 25.3%, respectively. DISCUSSION: This report indicates that the tailored CNS-directed strategy is an effective modality to treat CNS recurrence in adult AML, but further studies are needed to improve the long-term survival. PMID- 24074529 TI - Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. AB - Hyponatremia is a serious, but often overlooked, electrolyte imbalance that has been independently associated with a wide range of deleterious changes involving many different body systems. Untreated acute hyponatremia can cause substantial morbidity and mortality as a result of osmotically induced cerebral edema, and excessively rapid correction of chronic hyponatremia can cause severe neurologic impairment and death as a result of osmotic demyelination. The diverse etiologies and comorbidities associated with hyponatremia pose substantial challenges in managing this disorder. In 2007, a panel of experts in hyponatremia convened to develop the Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations that defined strategies for clinicians caring for patients with hyponatremia. In the 6 years since the publication of that document, the field has seen several notable developments, including new evidence on morbidities and complications associated with hyponatremia, the importance of treating mild to moderate hyponatremia, and the efficacy and safety of vasopressin receptor antagonist therapy for hyponatremic patients. Therefore, additional guidance was deemed necessary and a panel of hyponatremia experts (which included all of the original panel members) was convened to update the previous recommendations for optimal current management of this disorder. The updated expert panel recommendations in this document represent recommended approaches for multiple etiologies of hyponatremia that are based on both consensus opinions of experts in hyponatremia and the most recent published data in this field. PMID- 24074530 TI - Alpha thalassemia gene mutations in neonates from Mazandaran, Iran, 2012. AB - AIM: Alpha thalassemia is one of the most prevalent disorders worldwide and carrier frequency of the disease is varied in different parts of the world. Although different studies in Iran and Mazandaran province have been carried out to identify different mutations of alpha globin gene among people with low hematological indices, frequencies of these mutations were unknown in general population, and thus the aim of this study was to evaluate the carrier frequencies of alpha globin gene mutations among neonates in Mazandaran. MATERIAL AND METHODS: Four hundred and twelve neonates were collected from a delivery ward of a hospital in Sari. DNA was extracted from their cord blood samples using phenol-chloroform-based method. For the detection of five common alpha thalassemia gene mutations, multiplex-GAP-PCR and PCR-RFLP methods were applied. RESULTS: Sixty three (15.29%, confidence interval, CI 95%: 11.81-18.77) of investigated neonates had at least one of the five evaluated mutations. The alpha(3.7) deletion had the highest frequency (9.7%, CI 95%: 6.84-12.56) and none of the neonates had -(Med) double gene deletion. The -alpha(4.2) deletion, alphaalphaalpha(anti3.7) triplication, and alpha(-5nt) mutations had frequencies of 4.1% (CI 95%: 2.19-36.01), 2.2% (CI 95%: 0.78-3.62), and 0.49% (CI 95%: -0.18 1.16), respectively. DISCUSSION: Our study showed that in most of the alpha thalassemia carriers just one copy of alpha globin gene was absent and they are not at risk of having children with Hb H disease or hydrops fetalis; however, up to 2.2% of neonates were carriers for alphaalphaalpha(anti3.7) triplication and they will be at risk for having a child with thalassemia intermediate if they marry a person which is a carrier of beta thalassemia. PMID- 24074531 TI - Dysregulation of mammalian target of rapamycin pathway in upper tract urothelial carcinoma. AB - Upper tract urothelial carcinoma (UTUC) accounts for 5% to 10% of all urothelial carcinomas. Despite many shared features, key clinical and molecular genetic differences between upper tract and bladder urothelial carcinomas are becoming apparent. We have previously demonstrated alterations of mammalian target of rapamycin (mTOR) pathway in bladder carcinoma with a potential impact on biological behavior. In the current study, we evaluated the expression status and prognostic significance of mTOR pathway members in UTUC. Archival formalin-fixed and paraffin-embedded tissues from 99 primary UTUCs were retrieved from one of the authors' institution. Tissue microarrays were constructed with triplicate tumor samples and paired nonneoplastic urothelium. Tissue microarrays were analyzed using immunohistochemistry for mTOR pathway members: PTEN, phos-AKT, phos-mTOR, phos-S6, phos-4EBP1, and related markers p27 and c-MYC; correlation with clinicopathologic parameters and outcome was performed. We found significantly lower expression of PTEN, phos-AKT, phos-mTOR, phos-S6, phos-4EBP1, p27, and c-MYC in UTUC compared with paired benign urothelium (P < .0005). We found a strong positive correlation between PTEN and phos-AKT. Moderate correlation was observed between phos-mTOR and phos-S6, PTEN and p27, phos-AKT and p27, phos-S6 and p27, phos-mTOR and c-MYC, phos-S6 and c-MYC, and p27 and c MYC. None of the evaluated biomarkers were associated with increased hazard ratios for tumor recurrence or for cancer-specific mortality, when adjusting for relevant clinicopathologic variables. Dysregulation of the mTOR pathway was observed in UTUC compared with normal urothelium, implicating a potential pathogenic role in tumor development. In our cohort, expression of the evaluated biomarkers had no prognostic value. PMID- 24074533 TI - Heterogeneity of ERG expression in core needle biopsies of patients with early prostate cancer. AB - Prostate cancer is a heterogeneous, frequently multifocal disease with a broad spectrum of clinical, pathologic, and molecular characteristics. The TMPRSS2-ERG gene rearrangement is highly specific for prostate cancer. We used immunohistochemistry as a surrogate marker of the TMPRSS2-ERG fusion to study the heterogeneity of ERG expression in 280 prostate core needle biopsy series from 256 patients with early prostate cancer defined as 3 or less positive cores with no more than 50% of cancer per biopsy and a Gleason score of 7 or lower (3 + 4). Among the 163 patients with 2 or 3 cancer-positive biopsies, we found a subset of 19 patients (11.7%) with heterogeneous ERG expression. Thirteen (68.4%) of these patients showed biopsies with distinct positive and negative ERG staining in separate cores. The remaining 6 patients showed a mixture of both positive and negative staining within 1 biopsy core. This was either caused by different cancer foci (n = 3) or by one single, ERG-heterogeneous cancer focus (n = 3) in 1 core. Furthermore, we observed a heterogeneous ERG staining pattern over time in 6 (2.3%) of the 256 patients, in biopsies taken at various time points. An interobserver study of 21 cases with 2 separate cancer foci revealed that heterogeneity of ERG status in different cancer foci can be suspected based on morphologic differences (kappa = 0.44). We conclude that heterogeneity of ERG expression is detectable in 10% to 15% of core biopsies of early prostate cancer. Further studies are needed to explore the clinical impact of heterogeneous ERG status in this patient group. PMID- 24074532 TI - Fibroblast activation protein expression by stromal cells and tumor-associated macrophages in human breast cancer. AB - Fibroblast activation protein (FAP) has long been known to be expressed in the stroma of breast cancer. However, very little is known if the magnitude of FAP expression within the stroma may have a prognostic value and reflect the heterogeneous biology of the tumor cell. An earlier study had suggested that stromal FAP expression in breast cancer was inversely proportional to prognosis. We, therefore, hypothesized that stromal FAP expression may correlate with clinicopathologic variables and may serve as an adjunct prognostic factor in breast cancer. We evaluated the expression of FAP in a panel of breast cancer tissues (n = 52) using a combination of immunostain analyses at the tissue and single-cell level using freshly frozen or freshly digested human breast tumor samples, respectively. Our results showed that FAP expression was abundantly expressed in the stroma across all breast cancer subtypes without significant correlation with clinicopathologic factors. We further identified a subset of FAP positive (or FAP(+)) stromal cells that also expressed CD45, a pan-leukocyte marker. Using freshly dissociated human breast tumor specimens (n = 5), we demonstrated that some of these FAP(+)CD45(+) cells were CD11b(+)CD14(+)MHC II(+), indicating that they were likely tumor-associated macrophages (TAMs). Although FAP(+)CD45(+) cells have been demonstrated in the mouse tumor stroma, our results demonstrating that human breast TAMs expressed FAP were novel and suggested that existing and future FAP-directed therapy may have dual-therapeutic benefits targeting both stromal mesenchymal cells and immune cells such as TAMs. More work is needed to explore the role of FAP as a potential targetable molecule in breast cancer treatment. PMID- 24074534 TI - Peritoneal elastic lamina invasion: limitations in its use as a prognostic marker in stage II colorectal cancer. AB - Peritoneal involvement in colorectal cancer (CRC) is an adverse prognostic feature, which may prompt consideration of adjuvant chemotherapy in stage II disease. Controversies and challenges surrounding its assessment have led to consideration of peritoneal elastic lamina invasion (ELI) as an alternative marker of advanced local spread. The objectives of this study were (1) to evaluate the prognostic significance of peritoneal ELI in stage II CRC and (2) to determine the feasibility of ELI assessment in routine practice with the use of an elastic stain. Two hundred seventeen patients with stage II CRC (186, pT3; 31, pT4) were assessed for ELI and other established adverse histologic features. Of the pT3 tumors, 31 (16.7%) were ELI positive, 121 (65%) were ELI negative, and 34 (18.3%) lacked an identifiable elastic lamina. There were no significant differences in disease-free survival between pT3 ELI-negative and ELI-positive tumors (P = .517). The disease-free survival of pT4 tumors was significantly lower than that of pT3 ELI-negative tumors (P = .024) and pT3 ELI-positive tumors (P = .026), respectively. The elastic lamina was detected less frequently in right-sided pT3 tumors compared with left-sided tumors (65/91 [71.4%] versus 87/95 [91.6%], P < .001). Right-sided tumors were also associated with a reduction in the staining intensity of the elastic lamina (P < .001). In conclusion, peritoneal ELI was not an adverse prognostic factor in this study. The frequent absence of an identifiable elastic lamina, particularly in right sided tumors, may limit the use of ELI as a prognostic marker in CRC. PMID- 24074535 TI - Pulmonary pathology in pediatric cerebral malaria. AB - Respiratory signs are common in African children where malaria is highly endemic, and thus, parsing the role of pulmonary pathology in illness is challenging. We examined the lungs of 100 children from an autopsy series in Blantyre, Malawi, many of whom death was attributed to Plasmodium falciparum malaria. Our aim was to describe the pathologic manifestations of fatal malaria; to understand the role of parasites, pigment, and macrophages; and to catalog comorbidities. From available patients, which included 55 patients with cerebral malaria and 45 controls, we obtained 4 cores of lung tissue for immunohistochemistry and morphological evaluation. We found that, in patients with cerebral malaria, large numbers of malaria parasites were present in pulmonary alveolar capillaries, together with extensive deposits of malaria pigment (hemozoin). The number of pulmonary macrophages in this vascular bed did not differ between patients with cerebral malaria, noncerebral malaria, and nonmalarial diagnoses. Comorbidities found in some cerebral malaria patients included pneumonia, pulmonary edema, hemorrhage, and systemic activation of coagulation. We conclude that the respiratory distress seen in patients with cerebral malaria does not appear to be anatomic in origin but that increasing malaria pigment is strongly associated with cerebral malaria at autopsy. PMID- 24074536 TI - Associations of immature defense mechanisms with personal importance of junk food, television and alcohol are independent of age. PMID- 24074537 TI - Managing female sexual dysfunction. AB - Female sexual dysfunctions (FSDs) range from short-term aggravations to major emotional disturbances adversely affecting family and workplace. This review highlights diagnosis and management of the four most widely diagnosed FSDs. It initially focuses on hypoactive sexual desire disorder (HSDD) as a driving force at the heart of all other FSDs; nothing happens without sexual desire. Successful resolution of HSDD frequently facilitates resolution of other disorders. Central to understanding HSDD is the impact of aging female sexual endocrinology and its effect on both prevalence and expression patterns of FSD. Advances in this field have enabled introduction of some the most effective treatments yet described for HSDD. Sexual arousal disorder, though commonly affected by the same factors as HSDD, is heavily associated with psychotropic drugs and mood elevators. Orgasmic disorder is frequently the downstream result of other sexual dysfunctions, particularly HSDD, or the result of a major psychosexual trauma. Successful management of the underlying disorder often resolves orgasmic disorder. Sexual pain disorder is frequently the result of a gynecologic disorder, such as endometriosis, that can be substantially managed through successful treatment of that disorder. This article ends with the article's most important note: how to initiate the conversation. PMID- 24074539 TI - It's flu season again! PMID- 24074538 TI - Donating embryos for human embryonic stem cell (hESC) research: a committee opinion. AB - hESC research is an ethically acceptable use of human embryos that are in excess of those needed to meet the fertility goals of patients. The ethical basis for this view and issues to be considered during the informed consent process for the donation of embryos are developed in this document. This report replaces the Committee's 2009 report, "Donating spare embryos for stem cell research" (Fertil Steril 2009;91:667-70). PMID- 24074540 TI - Interactions between anesthesiologists and the environment while providing anesthesia care in the operating room. AB - We describe 1,132 contacts between anesthesiologists and the operating room. Objects most commonly touched included anesthesia machines and keyboards. Only 13 hand hygiene events were witnessed during 8 hours of observations. Line insertions, bronchoscopies, or blood exposures were not followed by hand hygiene. Stopcocks were accessed 66 times and only disinfected on 10 (15%) of these occasions. PMID- 24074541 TI - Vagus nerve stimulation for drug-resistant Epilepsia Partialis Continua: report of four cases. AB - BACKGROUND: Vagus nerve stimulation (VNS) represents an adjunctive surgical option for adult and pediatric patients with drug-resistant epilepsy, who are not eligible for surgical resection or disconnection. However, little is known on its efficacy in the treatment of Epilepsia Partialis Continua (EPC), a rare but serious form of motor status epilepticus associated either with progressive or with non-evolving neurological diseases. PURPOSE AND METHODS: To evaluate the effect of VNS in a series of four children affected by medically unresponsive EPC secondary to chronic inflammatory encephalopathy (two cases), Rasmussen encephalitis (one case) and poliodystrophy (one case). RESULTS: After VNS implantation, the stimulation amplitude was progressively increased and, after a mean interval of 47 days, a partial reduction of EPC and associated focal seizures was observed in all patients. After a mean follow-up of three years, one child stopped EPC, two presented short and rare episodes and in one patient 2-3 residual seizures per day was reported. In all cases, reduction of epileptic activity was associated with mild improvement of motor and cognitive abilities. No serious side effects were reported. CONCLUSION: VNS may be considered as an option for EPC when medical treatment fails and other more invasive neurosurgical options are not feasible. PMID- 24074542 TI - Verapamil effect on phenytoin pharmacokinetics in rats. AB - Efflux transporter and enzyme overexpression can be induced by certain antiepileptic drugs. Phenytoin (PHT) is at the same time substrate and inducer of CYP2C isoenzymes and efflux carriers. Its inductive effect has been postulated to be concentration and time-dependent. Since verapamil (VPM) is a well known substrate and inhibitor of P-glycoprotein, its administration could modify PHT systemic exposure. The objective of this work was to determine if single doses (40mg/kg) of VPM might change PHT body fate in the same way when given at the beginning or several days after 100mg/kg of PHT daily doses were started. Both drugs were administered intraperitoneally to female Sprague Dawley rats. VPM increased plasma PHT concentrations after one day of treatment, while a decrease in PHT plasma exposure was observed when VPM was added at the fifth day of the antiepileptic treatment. These results suggested that VPM would have different impact on PHT pharmacokinetics, depending on the level of expression of both efflux transporters and enzymes. Before the hepatic cells could acquire a high content of enzymes due to the inductive effect of PHT dosing, VPM decreased the predominant intestinal clearance of PHT. But, once the enzymatic machinery at the hepatocyte became more important than that at the intestine, although ineffective because of the high hepatobiliary efflux transporter overexpression, VPM blockade from the liver resulted in an increased total PHT clearance. PMID- 24074543 TI - Impact of sensor and measurement timing errors on model-based insulin sensitivity. AB - A model-based insulin sensitivity parameter (SI) is often used in glucose-insulin system models to define the glycaemic response to insulin. As a parameter identified from clinical data, insulin sensitivity can be affected by blood glucose (BG) sensor error and measurement timing error, which can subsequently impact analyses or glycaemic variability during control. This study assessed the impact of both measurement timing and BG sensor errors on identified values of SI and its hour-to-hour variability within a common type of glucose-insulin system model. Retrospective clinical data were used from 270 patients admitted to the Christchurch Hospital ICU between 2005 and 2007 to identify insulin sensitivity profiles. We developed error models for the Abbott Optium Xceed glucometer and measurement timing from clinical data. The effect of these errors on the re identified insulin sensitivity was investigated by Monte-Carlo analysis. The results of the study show that timing errors in isolation have little clinically significant impact on identified SI level or variability. The clinical impact of changes to SI level induced by combined sensor and timing errors is likely to be significant during glycaemic control. Identified values of SI were mostly (90th percentile) within 29% of the true value when influenced by both sources of error. However, these effects may be overshadowed by physiological factors arising from the critical condition of the patients or other under-modelled or un modelled dynamics. Thus, glycaemic control protocols that are designed to work with data from glucometers need to be robust to these errors and not be too aggressive in dosing insulin. PMID- 24074544 TI - Biological reactions of forests to climate change and air pollution. PMID- 24074545 TI - From reaching the end of the road to a new lighter life - people's experiences of undergoing gastric bypass surgery. AB - OBJECTIVES: It is limited research that focuses on people's experiences from prior to surgery to the postoperative period after a gastric bypass. The aim of this retrospective study was to describe people's experiences of undergoing gastric bypass surgery. METHOD: A qualitative approach was used. Interviews with ten participants were subjected to qualitative content analysis. RESULTS: The analysis of the interviews resulted in one theme: from reaching the end of the road to a new lighter life. Prior to surgery participants described a sense of inferiority and that they were not able to 'take any more'. Shortly after surgery participants felt both vulnerable and safe in the unknown environment and expressed needs of orientation and to have the staff close. Despite information prior to surgery it was difficult to imagine ones' situation after homecoming, thus it was worth it so far. CONCLUSION: The care given in the acute postoperative phase for people who undergo gastric bypass surgery, should aim to provide predictability and management based on individual needs. Being treated with respect, receiving closeness, and that the information received prior to surgery complies with what then happens may facilitate postoperative recovery after a gastric bypass surgery. PMID- 24074546 TI - Novel phenotype in a family with infantile convulsions and paroxysmal choreoathetosis syndrome and PRRT2 gene mutation. PMID- 24074547 TI - Reproducibility of gastric emptying in overweight and obese males. AB - BACKGROUND & AIM: To understand whether any change in gastric emptying (GE) is physiologically relevant, it is important to identify its variability. Information regarding the variability of GE in overweight and obese individuals is lacking. The aim of this study was to determine the reproducibility of GE in overweight and obese males. METHODS: Fifteen overweight and obese males [body mass index 30.3 (4.9) kg/m(2)] completed two identical GE tests 7 days apart. GE of a standard pancake breakfast was assessed by (13)C-octanoic acid breath test. Data are presented as mean (+/-SD). RESULTS: There were no significant differences in GE between test days (half time (t1/2): 179 (15) and 176 (19 min), p = 0.56; lag time (tlag): 108 (14) and 104 (8) min, p = 0.26). Mean intra individual coefficient of variation for t1/2 was 7.9% and tlag 7.5%. Based on these findings, to detect a treatment effect in a paired design with a power of 80% and alpha = 0.05, minimum mean effect sizes for t1/2 would need to be >=14.4 min and tlag >= 8.1 min. CONCLUSIONS: These data show that GE is reproducible in overweight and obese males and provide minimum mean effect sizes required to detect a hypothetical treatment effect in this population. PMID- 24074548 TI - Cost-effectiveness analysis of immune-modulating nutritional support for gastrointestinal cancer patients. AB - BACKGROUND & AIM: Immune-modulating nutritional formula containing arginine, omega-3 fatty acids and nucleotides has been demonstrated to decrease complications and length of stay in surgical patients. This study aims at assessing the impact of immune-modulating formula on hospital costs in gastrointestinal cancer surgical patients in Switzerland. METHOD: Based on a previously published meta-analysis, the relative risks of overall and infectious complications with immune-modulating versus standard nutrition formula were computed. Swiss hospital costs of patients undergoing gastrointestinal cancer surgery were retrieved. A method was developed to compute the patients' severity level, not taking into account the complications from the surgery. Incremental costs of complications were computed for both treatment groups, and sensitivity analyses were carried out. RESULTS: Relative risk of complications with pre-, peri- and post-operative use of immune-modulating formula was 0.69 (95%CI 0.58 0.83), 0.62 (95%CI 0.53-0.73) and 0.73 (95%CI 0.35-0.96) respectively. The estimated average contribution of complications to the cost of stay was CHF 14,949 (?10,901) per patient (95%CI 10,712-19,186), independently of case's severity. Based on this cost, immune-modulating nutritional support decreased costs of hospital stay by CHF 1638 to CHF 2488 per patient (?1195-?1814). Net hospital savings were present for baseline complications rates as low as 5%. CONCLUSION: Immune-modulating nutritional solution is a cost-saving intervention in gastrointestinal cancer patients. The additional cost of immune-modulating formula are more than offset by savings associated with decreased treatment of complications. PMID- 24074549 TI - Additional role of sarcopenia to waist circumference in predicting the odds of metabolic syndrome. AB - BACKGROUND & AIMS: It is unclear whether sarcopenia contributes to the prediction of metabolic dysregulations in addition to that predicted by waist circumference. METHODS: Subjects consisted of 6832 adult participants in the 2009 Korea National Health and Nutrition Examination Survey, grouped into categories of waist circumference (normal vs. high). Sarcopenia was assessed by appendicular skeletal muscle mass divided by weight. RESULTS: In the normal waist circumference category, the risk of metabolic syndrome was nearly 3.5-fold higher in sarcopenic men (OR, 3.39; 95% CI, 1.67-6.90) than in those without sarcopenia. For the high waist circumference category, the risk of metabolic syndrome was 2.5-fold higher in sarcopenic women (OR, 2.37; 95% CI, 1.66-3.40) than in those without sarcopenia. The corresponding risk was also higher in sarcopenic men (OR, 1.81; 95% CI, 1.11-2.94) than in those without sarcopenia. With the exception in men with high waist circumference category, adjustments for other potential confounders did not substantially affect the results. Appendicular skeletal muscle mass divided by weight as a continuous variable was also associated with metabolic syndrome in men (OR, 0.39; 95% CI, 0.35-0.44) and women (OR, 0.53; 95% CI, 0.48-0.60). CONCLUSIONS: Sarcopenia is associated with metabolic syndrome in men with normal waist circumference and women with high waist circumference. Our results emphasize that sarcopenia may contribute additionally to the risk of metabolic abnormalities beyond what is predicted by the abdominal obesity category. PMID- 24074550 TI - Characteristics of inconsistent responders to prophylaxis therapy with lomerizine in patients with migraine: a retrospective study in Japan. AB - Although lomerizine is used as a first-line prophylactic drug for migraines in Japan, approximately 30% of patients fail to respond to this treatment. On the basis of medical records, we investigated the involvement of clinical factors in response to lomerizine used in patients with migraine as primary headache and established a scoring system for predicting clinical responses to prophylactic therapy. Ninety-four consistent responders and 33 inconsistent responders to lomerizine were enrolled in this study. Multivariate stepwise logistic regression analysis revealed that migraine plus tension-type headache as primary headache and frequency of headache attacks were significant factors that contributed independently to negative response [odds ratio, 3.817 (no vs. yes; 95% confidence interval (CI), 1.264-11.628) and 5.814 (>15 episode days/month vs. 0-14 episode days/month; 95% CI, 2.381-14.286), respectively]. The predictive index (PI) of clinical responses to lomerizine in patients with migraine was calculated using the regression coefficients of two factors as an integer, where the score for inconsistent responders (1.00+/-0.71) was significantly higher than that for consistent responders (0.37+/-0.53, p<0.001). Sensibility of the low-scoring group (PI=0) was 75.8%, and specificity of the high-scoring group (PI=2) was 97.9%. Groups scoring low, intermediated and high included 11.6%, 35.4% and 80.0% of inconsistent responders, respectively. The PI value obtained might represent an appropriate scoring system to predict responses in these patients. PMID- 24074551 TI - A Neurodegenerative Disease Sleep Questionnaire: principal component analysis in Parkinson's disease. AB - Sleep disturbances are common in many neurodegenerative diseases and may include altered sleep duration, fragmented sleep, nocturia, excessive daytime sleepiness, and vivid dreaming experiences, with occasional parasomnias. Although representing the "gold standard," polysomnography is not always cost-effective or available for measuring sleep disturbance, particularly for screening. Although numerous sleep-related questionnaires exist, many focus on a specific sleep disturbance (e.g., restless legs, REM Behavior Disorder) and do not capture efficiently the variety of sleep issues experienced by such patients. We administered the 12-item Neurodegenerative Disease Sleep Questionnaire (NDSQ) and the Epworth Sleepiness Scale to 145 idiopathic Parkinson's disease patients. Principal component analysis using eigenvalues greater than 1 suggested five separate components: sleep quality (e.g., sleep fragmentation), nocturia, vivid dreams/nightmares, restless legs symptoms, and sleep-disordered breathing. These results demonstrate construct validity of our sleep questionnaire and suggest that the NDSQ may be a useful screening tool for sleep disturbances in at least some types of neurodegenerative disorders. PMID- 24074552 TI - Steroids with anti-inflammatory activity from Vernonia nigritiana Oliv. & Hiern. AB - The leaves of Vernonia nigritiana Oliv. & Hiern. (Asteraceae) were investigated for their in vivo topical anti-inflammatory properties, following a bioassay oriented fractionation approach. Petroleum ether, chloroform and chloroform methanol extracts inhibited the Croton oil-induced ear dermatitis in mice. The chloroform extract was only about half as active as the non steroidal anti inflammatory drug indomethacin (ID50=237 and 93 MUg/cm(2), respectively). Phytochemical investigation of this extract led to the isolation of nine polyhydroxylated stigmasterol glycosides and six polyhydroxylated stigmasterols. Their structures were elucidated by NMR, MS and chemical methods. Each compound exerted a significant anti-oedema activity, the most active being 1 (3beta-O-beta D-glucopyranosyloxy-5alpha-stigmasta-7,9(11),24(28)Z-triene-6beta,16beta,26,29 tetrol) and 3 (3beta-O-beta-D-glucopyranosyloxy-5alpha-stigmasta-7,9(11),24(28)Z triene-6beta,16beta,29-triol), only two and five fold less potent than the steroidal drug hydrocortisone (ID50=0.10, 0.21 and 0.04 MUmol/cm(2), respectively). Compound 1 (50 MUM) also completely inhibited the transcription factor NF-kappaB in vitro. PMID- 24074553 TI - Biosynthesis of the biphenyl phytoalexin aucuparin in Sorbus aucuparia cell cultures treated with Venturia inaequalis. AB - Aucuparin is the most widely distributed biphenyl phytoalexin in the rosaceous subtribe Pyrinae, which includes the economically important fruit trees apple and pear. The biphenyl scaffold is formed by biphenyl synthase, which catalyzes biosynthesis of 3,5-dihydroxybiphenyl. Conversion of this precursor to aucuparin (3,5-dimethoxy-4-hydroxybiphenyl) was studied in cell cultures of Sorbus aucuparia after treatment with an elicitor preparation from the scab-causing fungus Venturia inaequalis. The sequence of the biosynthetic steps detected was O methylation - 4-hydroxylation - O-methylation. The two alkylation reactions were catalyzed by distinct methyltransferases, which differed in pH and temperature optima as well as stability. Biphenyl 4-hydroxylase was a microsomal cytochrome P450 monooxygenase, whose activity was appreciably decreased by the addition of established P450 inhibitors. When fed to V. inaequalis-treated S. aucuparia cell cultures, radioactively labeled 3,5-dihydroxybiphenyl was not only incorporated into aucuparin but also into the dibenzofuran eriobofuran, the accumulation of which paralleled that of aucuparin. However, biphenyl 2'-hydroxylase activity proposed to be involved in dibenzofuran formation was detected in neither microsomes nor cell-free extracts in the presence of NADPH and 2-oxoglutarate, respectively. Nevertheless, a basis for studying biphenyl biosynthesis at the gene level is provided. PMID- 24074554 TI - Prenylflavonoids isolated from Artocarpus champeden with TRAIL-resistance overcoming activity. AB - In a screening program for bioactive natural products which can overcome Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-resistance, three prenylflavonoids, named pannokin A-C, were isolated from a MeOH extract of Artocarpus champeden (Moraceae) roots, together with three known prenylflavonoids. The structures of pannokin A-C were elucidated by spectroscopic analysis. These of the prenylflavonoids in combination with TRAIL, showed cytotoxic activity in sensitizing TRAIL-resistant human gastric adenocarcinoma (AGS) cells. Of these compounds, heterophyllin increased caspase 3/7 activity when combined with TRAIL in AGS cells, and enhanced the expression of DR4 and DR5 mRNA. Moreover, heterophyllin up-regulated mRNA expression of CCAAT/enhancer binding protein-homologous protein (CHOP) which was reported to be an important regulator of DR5 expression. Thus, heterophyllin was presumed to cause a CHOP dependent up-regulation of DR5 expression resulting in apoptosis in AGS cells. PMID- 24074555 TI - Isolation and characterization of terpene synthases in cotton (Gossypium hirsutum). AB - Cotton plants accumulate gossypol and related sesquiterpene aldehydes, which function as phytoalexins against pathogens and feeding deterrents to herbivorous insects. However, to date little is known about the biosynthesis of volatile terpenes in this crop. Herein is reported that 5 monoterpenes and 11 sesquiterpenes from extracts of a glanded cotton cultivar, Gossypium hirsutum cv. CCRI12, were detected by gas chromatography-mass spectrometry (GC-MS). By EST data mining combined with Rapid Amplification of cDNA Ends (RACE), full-length cDNAs of three terpene synthases (TPSs), GhTPS1, GhTPS2 and GhTPS3 were isolated. By in vitro assays of the recombinant proteins, it was found that GhTPS1 and GhTPS2 are sesquiterpene synthases: the former converted farnesyl pyrophosphate (FPP) into beta-caryophyllene and alpha-humulene in a ratio of 2:1, whereas the latter produced several sesquiterpenes with guaia-1(10),11-diene as the major product. By contrast, GhTPS3 is a monoterpene synthase, which produced alpha pinene, beta-pinene, beta-phellandrene and trace amounts of other monoterpenes from geranyl pyrophosphate (GPP). The TPS activities were also supported by Virus Induced Gene Silencing (VIGS) in the cotton plant. GhTPS1 and GhTPS3 were highly expressed in the cotton plant overall, whereas GhTPS2 was expressed only in leaves. When stimulated by mechanical wounding, Verticillium dahliae (Vde) elicitor or methyl jasmonate (MeJA), production of terpenes and expression of the corresponding synthase genes were induced. These data demonstrate that the three genes account for the biosynthesis of volatile terpenes of cotton, at least of this Upland cotton. PMID- 24074556 TI - Iron in eukaryotic microbes: regulation, trafficking and theft. PMID- 24074557 TI - Continuous treatment in multiple myeloma: the future? AB - Major therapeutic advances in the treatment of multiple myeloma (MM) have dramatically improved response rate, remission duration and overall survival. These advances include the introduction of high-dose therapy plus autologous stem cell transplantation in younger patients and, in more recent years, the use of "novel" agents such as Thalidomide, Bortezomib, and Lenalidomide. However, despite this progress, most patient will ultimately relapse and die from resistant disease. The role of maintenance therapy in MM has been investigated for more than 30 years, but evidence of clear benefit has only recently emerged. The widely use of novel agents renewed the concept of maintenance or "continuous" treatment, after high dose therapy, as well as after conventional therapy in elderly patients. Recently, a number of randomized studies showed a benefit from maintenance therapy with these agents, including increased response rate, PFS and even OS. PMID- 24074558 TI - Single stage tuberous breast reconstruction: the medical wedge technique. PMID- 24074559 TI - CT-guided cervical transforaminal epidural steroid injections: technical insights. AB - Recent studies have described the safety and efficacy of computed tomography (CT) guided cervical transforaminal epidural steroid injections with both the anterolateral and posterior approach. Although fluoroscopy is the most common form of image guidance for these procedures, CT guidance offers many advantages. However, some key features of CT guidance in these procedures need to be considered to ensure safe and technically successful outcomes. PMID- 24074560 TI - Onyx embolization using dual-lumen balloon catheter: initial experience and technical note. AB - INTRODUCTION: Onyx as an embolization agent for the management of vascular malformation is well established. We report our initial experience with dimethyl sulphoxide (DMSO) compatible double lumen balloon catheters used for Onyx embolization. METHODS AND TECHNIQUE: Between December 2011 and March 2013, we treated 22 patients aged between 1.5 to 70years with two types of DMSO compatible dual-lumen balloon catheters (Scepter C and Ascent) to treat dural arteriovenous fistulas, brain arteriovenous malformation (AVM) with dural feeders, mandibular, facial, lingual, vertebral and paravertebral AVMs. The catheter has good navigability, compliant balloon on inflation formed a "plug" that has more resistance than Onyx plug enhancing better penetration. During injection, the balloon remained stable without spontaneous deflation or rupture and withstood the pressure build-up well. The retrieval of the catheter in most cases took less than a minute (19/28) while in five, it was less than five minutes and in the remaining four, it was longer that includes a trapped catheter on prolonged attempted retrieval resulted in an epidural hematoma, requiring emergent surgical evacuation. The fluoroscopy time is reduced, as we do not form a proximal onyx plug, the injection time is shorter along with easy and instantaneous removal of the catheter after balloon deflation in most cases. CONCLUSION: Dual-lumen balloon catheter Onyx embolization is a safe and effective technique. Currently, an important tool to circumvent some of the shortcomings associated with Onyx embolization. The catheter has good navigability, the balloon has stability, tolerance, enhances penetrability. It is easy to retrieve the microcatheter. With the experience gained, and with more compliant balloon catheters available, this technique can be applied to cerebral vessels in near future. PMID- 24074561 TI - Growth and characterization of different human rhinovirus C types in three dimensional human airway epithelia reconstituted in vitro. AB - New molecular diagnostic tools have recently allowed the discovery of human rhinovirus species C (HRV-C) that may be overrepresented in children with lower respiratory tract complications. Unlike HRV-A and HRV-B, HRV-C cannot be propagated in conventional immortalized cell lines and their biological properties have been difficult to study. Recent studies have described the successful amplification of HRV-C15, HRV-C11, and HRV-C41 in sinus mucosal organ cultures and in fully differentiated human airway epithelial cells. Consistent with these studies, we report that a panel of clinical HRV-C specimens including HRV-C2, HRV-C7, HRV-C12, HRV-C15, and HRV-C29 types were all capable of mediating productive infection in reconstituted 3D human primary upper airway epithelial tissues and that the virions enter and exit preferentially through the apical surface. Similar to HRV-A and HRV-B, our data support the acid sensitivity of HRV C. We observed also that the optimum temperature requirement during HRV-C growth may be type-dependent. PMID- 24074562 TI - The LKB1 tumor suppressor differentially affects anchorage independent growth of HPV positive cervical cancer cell lines. AB - Infection with high-risk human papillomaviruses is causally linked to cervical carcinogenesis. However, most lesions caused by high-risk HPV infections do not progress to cancer. Host cell mutations contribute to malignant progression but the molecular nature of such mutations is unknown. Based on a previous study that reported an association between liver kinase B1 (LKB1) tumor suppressor loss and poor outcome in cervical cancer, we sought to determine the molecular basis for this observation. LKB1-negative cervical and lung cancer cells were reconstituted with wild type or kinase defective LKB1 mutants and we examined the importance of LKB1 catalytic activity in known LKB1-regulated processes including inhibition of cell proliferation and elevated resistance to energy stress. Our studies revealed marked differences in the biological activities of two kinase defective LKB1 mutants in the various cell lines. Thus, our results suggest that LKB1 may be a cell-type specific tumor suppressor. PMID- 24074563 TI - An unbiased in vivo screen reveals multiple transcription factors that control HPV E6-regulated hTERT in keratinocytes. AB - Activation of telomerase by human papillomavirus 16 (HPV16) E6 is a critical step for cell immortalization and transformation in human foreskin keratinocytes (HFKs). Multiple transcription factors have been identified as being involved in E6-induced hTERT expression. Here, we adapted an unbiased in vivo screen using a LacO-LacI system in human cells to discover hTERT promoter-interacting regulators. This approach allowed us to identify a novel hTERT repressor, Maz, which bound the hTERT promoter. E6 expression reduced Maz binding and correspondingly increased Sp1 binding at the hTERT promoter. Knockdown of Maz further increased histone acetylation, as well as hTERT expression in the presence of E6. Overall, these data indicate the utility of a novel screen for promoter-interacting and transcription-regulating proteins. These data also highlight multiple factors that normally regulate hTERT repression in HFKs, and therefore are targeted by E6 for hTERT expression. PMID- 24074564 TI - Membrane-bound SIV envelope trimers are immunogenic in ferrets after intranasal vaccination with a replication-competent canine distemper virus vector. AB - We are investigating canine distemper virus (CDV) as a vaccine vector for the delivery of HIV envelope (Env) that closely resembles the native trimeric spike. We selected CDV because it will promote vaccine delivery to lymphoid tissues, and because human exposure is infrequent, reducing potential effects of pre-existing immunity. Using SIV Env as a model, we tested a number of vector and gene insert designs. Vectors containing a gene inserted between the CDV H and L genes, which encoded Env lacking most of its cytoplasmic tail, propagated efficiently in Vero cells, expressed the immunogen on the cell surface, and incorporated the SIV glycoprotein into progeny virus particles. When ferrets were vaccinated intranasally, there were no signs of distress, vector replication was observed in the gut-associated lymphoid tissues, and the animals produced anti-SIV Env antibodies. These data show that live CDV-SIV Env vectors can safely induce anti Env immune responses following intranasal vaccination. PMID- 24074566 TI - Virological and serological study of human infection with swine influenza A H1N1 virus in China. AB - BACKGROUND: Pigs are considered to be "mixing vessels" for the emergence of influenza viruses with pandemic potential. 2009 Pandemic Influenza H1N1 further proved this hypothesis, and raised the needs for risk assessment of human cases caused by swine influenza virus. METHODS: A field investigation was conducted after a case identified with infection of European avian-like swine influenza H1N1 virus. The diagnosis was confirmed by real-time PCR, virus isolation, whole genome sequencing and serological assays. Samples from local pigs and close contacts were tested to identify the source of infection and route of transmission. RESULTS: The virus from the index case was similar to viruses circulating in the local pigs. The case's grandfather was asymptomatic with sero conversion. A total of 42.8% of swine sera were positive for European avian-like swine H1N1. CONCLUSIONS: This study highlighted the importance of performing surveillance on swine influenza to monitor new virus emergence in humans. PMID- 24074565 TI - Distinct host cell fates for human malignant melanoma targeted by oncolytic rodent parvoviruses. AB - The rodent parvoviruses are known to be oncoselective, and lytically infect many transformed human cells. Because current therapeutic regimens for metastatic melanoma have low response rates and have little effect on improving survival, this disease is a prime candidate for novel approaches to therapy, including oncolytic parvoviruses. Screening of low-passage, patient-derived melanoma cell lines for multiplicity-dependent killing by a panel of five rodent parvoviruses identified LuIII as the most melanoma-lytic. This property was mapped to the LuIII capsid gene, and an efficiently melanoma tropic chimeric virus shown to undergo three types of interaction with primary human melanoma cells: (1) complete lysis of cultures infected at very low multiplicities; (2) acute killing resulting from viral protein synthesis and DNA replication, without concomitant expansion of the infection, due to failure to export progeny virions efficiently; or (3) complete resistance that operates at an intracellular step following virion uptake, but preceding viral transcription. PMID- 24074567 TI - Chemical cross-linking of HIV-1 Env for direct TLR7/8 ligand conjugation compromises recognition of conserved antigenic determinants. AB - Covalent conjugation of immune-stimulatory compounds to protein antigens is a potential means to self-adjuvant non-replicating subunit vaccines. Previously, it was demonstrated that covalent coupling of a Toll-like receptor (TLR) ligand to the exterior HIV-1 envelope glycoprotein, gp120, enhanced its immunogenicity. However, the consequences of chemical conjugation to gp120 on broadly neutralizing antibody (bNAb) epitopes were so far not examined. Here, we conjugated a TLR7/8 ligand to lysine residues on gp120 using NHS-PEO8-maleimide linkers and investigated if this affected Ab recognition of the CD4 binding site (CD4bs), a highly conserved target for bNAbs. We demonstrate that the recognition of the CD4bs was reduced following coupling, especially at a higher coupling ratio. These results have implications for the coupling of ligands to vaccine antigens where elicitation of humoral immune responses to specific neutralizing determinants is desired. PMID- 24074568 TI - Mechanisms of HIV-1 subtype C resistance to GRFT, CV-N and SVN. AB - We examined the ability of HIV-1 subtype C to develop resistance to the inhibitory lectins, griffithsin (GRFT), cyanovirin-N (CV-N) and scytovirin (SVN), which bind multiple mannose-rich glycans on gp120. Four primary HIV-1 strains cultured under escalating concentrations of these lectins became increasingly resistant tolerating 2 to 12 times their 50% inhibitory concentrations. Sequence analysis of gp120 showed that most had deletions of 1 to 5 mannose-rich glycans. Glycosylation sites at positions 230, 234, 241, 289 located in the C2 region and 339, 392 and 448 in the C3-C4 region were affected. Furthermore, deletions and insertions of up to 5 amino acids in the V4 region were observed in 3 of the 4 isolates. These data suggest that loss of glycosylation sites on gp120 as well as rearrangement of glycans in V4 are mechanisms involved in HIV-1 subtype C escape from GRFT, CV-N and SVN. PMID- 24074569 TI - Kinetics of liver macrophages (Kupffer cells) in SIV-infected macaques. AB - Since the liver drains antigens from the intestinal tract, and since the intestinal tract is a major site of viral replication, we examined the dynamics of liver macrophages (Kupffer cells) throughout SIV infection. Absolute numbers of Kupffer cells increased in the livers in acute infection, and in animals with AIDS. Significantly higher percentages of proliferating (BrdU+) Kupffer cells were detected in acute infection and in AIDS with similar trends in blood monocytes. Significantly higher percentages of apoptotic (AC3+) Kupffer cells were also found in acute and AIDS stages. However, productively infected cells were not detected in liver of 41/42 animals examined, despite abundant infected cells in gut and lymph nodes of all animals. Increased rates of Kupffer cell proliferation resulting in an increase in Kupffer cells without productive infection indicate SIV infection affects Kupffer cells, but the liver does not appear to be a major site of productive viral replication. PMID- 24074570 TI - The crystal structure of HIV CRF07 B'/C gp41 reveals a hyper-mutant site in the middle of HR2 heptad repeat. AB - HIV CRF07 B'/C is a strain circulating mainly in northwest region of China. The gp41 region of CRF07 is derived from a clade C virus. In order to compare the difference of CRF07 gp41 with that of typical clade B virus, we solved the crystal structure of the core region of CRF07 gp41. Compared with clade B gp41, CRF07 gp41 evolved more basic and hydrophilic residues on its helix bundle surface. Based on sequence alignment, a hyper-mutant cluster located in the middle of HR2 heptads repeat was identified. The mutational study of these residues revealed that this site is important in HIV mediated cell-cell fusion and plays critical roles in conformational changes during viral invasion. PMID- 24074571 TI - The charged residues in the surface-exposed C-terminus of the Soybean mosaic virus coat protein are critical for cell-to-cell movement. AB - The Soybean mosaic virus (SMV) coat protein (CP) is necessary for virion assembly and viral cell-to-cell and long-distance movements in plants. We previously showed that the C-terminal region of the SMV CP is required for CP self interaction. In the present study, we generated SMV mutants containing CPs with single amino acid substitutions of the charged amino acids in the C-proximal region. Infectivity and cell-to-cell movement of the SMV mutants were examined in soybean plants. Through this genetic approach, we identified three charged amino acid residues (R245, H246, and D250) in the surface-exposed C-terminus of the SMV CP that are critical for virus cell-to-cell and long-distance movement. Our findings suggest that the identified charged amino acids in the surface-exposed C terminus of SMV CP are critical for CP intersubunit interactions and thereby for cell-to-cell and long-distance movement and virion assembly. PMID- 24074572 TI - In vitro and in vivo evidence for differences in the protease activity of two arabis mosaic nepovirus isolates and their impact on the infectivity of chimeric cDNA clones. AB - Regulated processing of nepovirus polyproteins allows the release of mature proteins and intermediate polyproteins. Infectious cDNA clones of the mild NW isolate of arabis mosaic virus (ArMV) and chimeric clones incorporating RNA1 segments of Lv, a severe isolate, were generated. Clones containing the Lv X2-NTB cleavage site were not infectious unless the Lv protease was present. The Lv and NW X2-NTB cleavage sites differ at positions P6, P4 and P2. In vitro, processing at the X2-NTB site was undetectable or reduced in chimeric polyproteins containing the Lv X2-NTB site and the NW protease but was restored when both the Lv protease and X2-NTB site were present. In contrast, cleavage at this site was increased in polyproteins that contained the NW X2-NTB site and the Lv protease. These results show that the ArMV-Lv protease has greater activity and is active on a greater range of cleavage sites than that of ArMV-NW. PMID- 24074573 TI - Structural basis for the divergent evolution of influenza B virus hemagglutinin. AB - Influenza A and B viruses are responsible for the severe morbidity and mortality worldwide in annual influenza epidemics. Currently circulating influenza B virus belongs to the B/Victoria or B/Yamagata lineage that was diverged from each other about 30-40 years ago. However, a mechanistic understanding of their divergent evolution is still lacking. Here we report the crystal structures of influenza B/Yamanashi/166/1998 hemagglutinin (HA) belonging to B/Yamagata lineage and its complex with the avian-like receptor analogue. Comparison of these structures with those of undiverged and diverged influenza B virus HAs, in conjunction with sequence analysis, reveals the molecular basis for the divergent evolution of influenza B virus HAs. Furthermore, HAs of diverged influenza B virus strains display much stronger molecular interactions with terminal sialic acid of bound receptors, which may allow for a different tissue tropism for current influenza B viruses, for which further investigation is required. PMID- 24074574 TI - Non-encapsidation activities of the capsid proteins of positive-strand RNA viruses. AB - Viral capsid proteins (CPs) are characterized by their role in forming protective shells around viral genomes. However, CPs have additional and important roles in the virus infection cycles and in the cellular responses to infection. These activities involve CP binding to RNAs in both sequence-specific and nonspecific manners as well as association with other proteins. This review focuses on CPs of both plant and animal-infecting viruses with positive-strand RNA genomes. We summarize the structural features of CPs and describe their modulatory roles in viral translation, RNA-dependent RNA synthesis, and host defense responses. PMID- 24074577 TI - Differential potential for envelope glycoprotein-mediated steric shielding of host cell surface proteins among filoviruses. AB - The viral envelope glycoprotein (GP) is thought to play important roles in the pathogenesis of filovirus infection. It is known that GP expressed on the cell surface forms a steric shield over host proteins such as major histocompatibility complex class I and integrin beta1, which may result in the disorder of cell-to cell contacts and/or inhibition of the immune response. However, it is not clarified whether this phenomenon contributes to the pathogenicity of filoviruses. In this study, we found that the steric shielding efficiency differed among filovirus strains and was correlated with the difference in their relative pathogenicities. While the highly glycosylated mucin-like region of GP was indispensable, the differential shielding efficiency did not necessarily depend on the primary structure of the mucin-like region, suggesting the importance of the overall properties (e.g., flexibility and stability) of the GP molecule for efficient shielding of host proteins. PMID- 24074576 TI - Identification and molecular characterization of SIV Vpr R50G mutation associated with long term survival in SIV-infected morphine dependent and control macaques. AB - Viral protein R (Vpr) is an accessory protein of HIV and SIV involved in the pathogenesis of viral infection. In this study, we monitored SIV evolution in the central nervous system and other organs from morphine-dependent and control animals by sequencing vpr in an attempt to understand the relationship between drug abuse, disease progression, and compartmentalization of viral evolution. Animals in the morphine group developed accelerated disease and died within twenty weeks post-infection. A unique mutation, R50G, was identified in the macaques that survived regardless of morphine exposure. Functional studies revealed that the R50G mutation exhibited altered cellular localization and decreased the expression levels of both IL-6 and IL-8. Our results, therefore, suggest that sequence changes within the SIV/17E-Fr vpr occur regardless of drug abuse but correlate with survival, and that they alter disease progression rates by affecting Vpr functions. PMID- 24074575 TI - Discovery of a new motion mechanism of biomotors similar to the earth revolving around the sun without rotation. AB - Biomotors have been classified into linear and rotational motors. For 35 years, it has been popularly believed that viral dsDNA-packaging apparatuses are pentameric rotation motors. Recently, a third class of hexameric motor has been found in bacteriophage phi29 that utilizes a mechanism of revolution without rotation, friction, coiling, or torque. This review addresses how packaging motors control dsDNA one-way traffic; how four electropositive layers in the channel interact with the electronegative phosphate backbone to generate four steps in translocating one dsDNA helix; how motors resolve the mismatch between 10.5 bases and 12 connector subunits per cycle of revolution; and how ATP regulates sequential action of motor ATPase. Since motors with all number of subunits can utilize the revolution mechanism, this finding helps resolve puzzles and debates concerning the oligomeric nature of packaging motors in many phage systems. This revolution mechanism helps to solve the undesirable dsDNA supercoiling issue involved in rotation. PMID- 24074578 TI - Biochemical and structural studies of the oligomerization domain of the Nipah virus phosphoprotein: evidence for an elongated coiled-coil homotrimer. AB - Nipah virus (NiV) is a recently emerged severe human pathogen that belongs to the Henipavirus genus within the Paramyxoviridae family. The NiV genome is encapsidated by the nucleoprotein (N) within a helical nucleocapsid that is the substrate used by the polymerase for transcription and replication. The polymerase is recruited onto the nucleocapsid via its cofactor, the phosphoprotein (P). The NiV P protein has a modular organization, with alternating disordered and ordered domains. Among these latter, is the P multimerization domain (PMD) that was predicted to adopt a coiled-coil conformation. Using both biochemical and biophysical approaches, we show that NiV PMD forms a highly stable and elongated coiled-coil trimer, a finding in striking contrast with respect to the PMDs of Paramyxoviridae members investigated so far that were all found to tetramerize. The present results therefore represent the first report of a paramyxoviral P protein forming trimers. PMID- 24074579 TI - Human parvovirus B19 infection leads to downregulation of thyroid, estrogen, and retinoid hormone receptor expression. AB - Erythrovirus B19 (B19V) is a member of the family Parvoviridae. Infection with B19V has been linked to a variety of diseases including erythroid, thyroid, neurological and autoimmune diseases. Here we show that infection of primary CD36+ cells with B19V coincides with downregulation of thyroid, retinoid, and estrogen hormone receptors. In addition we show changes in expression of a variety of related downstream signaling genes participating in cancer and cardiac related diseases in B19V-infected erythroid primary cells. PMID- 24074580 TI - Cellular bioenergetics, caspase activity and glutathione in murine lungs infected with influenza A virus. AB - Inhibition of cellular respiration, oxidation of glutathione and induction of apoptosis have been reported in epithelial cells infected in vitro with influenza A virus (IAV). Here, the same biomarkers were investigated in vivo by assessing the lungs of BALB/c mice infected with IAV. Cellular respiration declined on day 3 and recovered on day 7 post-infection. For days 3-5, the rate (mean+/-SD) of respiration (uMO2min(-1)mg(-1)) in uninfected lungs was 0.103+/-0.021 (n=4) and in infected lungs was 0.076+/-0.025 (n=4, p=0.026). Relative cellular ATP (infected/uninfected) was 4.7 on day 2 and 1.07 on day 7. Intracellular caspase activity peaked on day 7. Cellular glutathione decreased by >=10% on days 3-7. Lung pathology was prominent on day 3 and caspase-3 labeling was prominent on day 5. IAV infection was associated with suppression of cellular respiration, diminished glutathione, and induction of apoptosis. These functional biomarkers were associated with structural changes noted in infected mice. PMID- 24074581 TI - Identification, phylogenetic analysis and classification of porcine group C rotavirus VP7 sequences from the United States and Canada. AB - Rotavirus C (RVC) is a major cause of gastroenteritis in swine. Between December 2009 and October 2011, 7520 porcine samples were analyzed from herds in the US and Canada. RVC RNA was detected in 46% of the tested samples. In very young pigs (<=3 days old) and young piglets (4-20 days old), 78% and 65%, respectively, RVC positive samples were negative for RVA and RVB. RVC RNA was also detected in 10% of tested lung tissues. Additionally, we investigated the porcine RVC molecular diversity by sequencing the VP7 gene segment of 65 specimens, yielding 70 VP7 gene sequences. Based on pairwise identity frequency profiles and phylogenetic analyses, an 85% nucleotide classification cut-off value was calculated using the novel sequence data generated in this study (n=70) and previously published RVC VP7 sequences (n=82), which resulted in the identification of 9 VP7 RVC genotypes, G1 to G9. PMID- 24074583 TI - Viruses of the family Bunyaviridae: are all available isolates reassortants? AB - Viruses of the family Bunyaviridae (the bunyaviruses) possess three distinct linear, single-stranded, negative sense or ambisense RNA segments (large, medium, and small). Dual infections of arthropod and perhaps vertebrate and plant hosts provide substantial opportunity for segment reassortment and an increasingly recognized number of the nearly 300 viruses in this family have been shown to be reassortants. Reassortment of RNA segments (genetic shift) complements genetic drift (accumulation of point mutations) as a powerful mechanism underlying bunyavirus evolution. Here we consider the possibility, if not likelihood, that most if not all bunyaviruses currently recognized may represent reassortants, some of which may be reassortants of existing viruses, and some of which may be reassortants of extinct viruses. If this hypothesis is correct, then the roots of the family and genus trees of bunyaviruses as currently described (or ignored) are incomplete or incorrect. PMID- 24074582 TI - Interleukin-1 receptor-associated kinase M (IRAK-M) promotes human rhinovirus infection in lung epithelial cells via the autophagic pathway. AB - Human rhinovirus (HRV) is the most common viral etiology in acute exacerbations of asthma. However, the exact mechanisms underlying HRV infection in allergic airways are poorly understood. IL-13 increases interleukin-1 receptor associated kinase M (IRAK-M) and subsequently inhibits airway innate immunity against bacteria. However, the role of IRAK-M in lung HRV infection remains unclear. Here, we provide the first evidence that IRAK-M over-expression promotes lung epithelial HRV-16 replication and autophagy, but inhibits HRV-16-induced IFN-beta and IFN-lambda1 expression. Inhibiting autophagy reduces HRV-16 replication. Exogenous IFN-beta and IFN-lambda1 inhibit autophagy and HRV-16 replication. Our data indicate the enhancing effect of IRAK-M on epithelial HRV-16 infection, which is partly through the autophagic pathway. Impaired anti-viral interferon production may serve as a direct or an indirect (e.g., autophagy) mechanism of enhanced HRV-16 infection by IRAK-M over-expression. Targeting autophagic pathway or administrating anti-viral interferons may prevent or attenuate viral (e.g., HRV-16) infections in allergic airways. PMID- 24074584 TI - Hantaviruses induce cell type- and viral species-specific host microRNA expression signatures. AB - The mechanisms of hantavirus-induced modulation of host cellular immunity remain poorly understood. Recently, microRNAs (miRNAs) have emerged as a class of essential regulators of host immune response genes. To ascertain if differential host miRNA expression toward representative hantavirus species correlated with immune response genes, miRNA expression profiles were analyzed in human endothelial cells, macrophages and epithelial cells infected with pathogenic and nonpathogenic rodent- and shrew-borne hantaviruses. Distinct miRNA expression profiles were observed in a cell type- and viral species-specific pattern. A subset of miRNAs, including miR-151-5p and miR-1973, were differentially expressed between Hantaan virus and Prospect Hill virus. Pathway analyses confirmed that the targets of selected miRNAs were associated with inflammatory responses and innate immune receptor-mediated signaling pathways. Our data suggest that differential immune responses following hantavirus infection may be regulated in part by cellular miRNA through dysregulation of genes critical to the inflammatory process. PMID- 24074585 TI - Mutation from arginine to lysine at the position 189 of hemagglutinin contributes to the antigenic drift in H3N2 swine influenza viruses. AB - Two distinct antigenic clusters were previously identified among the H3N2 swine influenza A viruses (IAVs) and were designated H3N2SIV-alpha and H3N2SIV-beta (Feng et al., 2013. Journal of Virology 87 (13), 7655-7667). A consistent mutation was observed at the position 189 of hemagglutinin (R189K) between H3N2SIV-alpha and H3N2SIV-beta fair isolates. To evaluate the contribution of R189K mutation to the antigenic drift from H3N2SIV-alpha to H3N2SIV-beta, four reassortant viruses with 189R or 189K were generated. The antigenic cartography demonstrated that the R189K mutation in the hemagglutinin of H3N2 IAV contributed to the antigenic drift, separating these viruses into H3N2SIV-alpha to H3N2SIV beta. This R189K mutation was also found to contribute to the cross-reaction with several ferret sera raised against historical human IAVs with hemagglutinin carrying 189K. This study suggests that the R189K mutation plays a vital role in the antigenicity of swine and human H3N2 IAVs and identification of this antigenic determinant will help us rapidly identify antigenic variants in influenza surveillance. PMID- 24074586 TI - Development of a reverse genetics system to generate recombinant Marburg virus derived from a bat isolate. AB - Recent investigations have shown the Egyptian fruit bat (Rousettus aegyptiacus) to be a natural reservoir for marburgviruses. To better understand the life cycle of these viruses in the natural host, a new reverse genetics system was developed for the reliable rescue of a Marburg virus (MARV) originally isolated directly from a R. aegyptiacus bat (371Bat). To develop this system, the exact terminal sequences were first determined by 5' and 3' RACE, followed by the cloning of viral proteins NP, VP35, VP30 and L into expression plasmids. Novel conditions were then developed to efficiently replicate virus mini-genomes followed by the construction of full-length genomic clones from which recombinant wild type and GFP-containing MARVs were rescued. Surprisingly, when these recombinant MARVs were propagated in primary human macrophages, a dramatic difference was found in their ability to grow and to elicit anti-viral cytokine responses. PMID- 24074587 TI - Chinese and Vietnamese strains of HP-PRRSV cause different pathogenic outcomes in United States high health swine. AB - An infectious clone of a highly pathogenic PRRSV strain from Vietnam (rSRV07) was prepared and was demonstrated to contain multiple amino acid differences throughout the genome when compared to Chinese highly pathogenic PRRSV strain rJXwn06. Virus rescued from the rSRV07 infectious clone was compared to rJXwn06 and US Type 2 prototype strain VR-2332 to examine the effects of virus genotype and phenotype on in vitro growth, and virus challenge dose on in vivo pathogenicity and host response. After swine inoculation at high- and low-doses of virus, rSRV07 was shown to replicate to an approximately 10-fold lower level in serum than rJXwn06, produced lower body temperatures than rJXwn06 and resulted in decreased mortality. Furthermore, a 9-plex cytokine panel revealed that the cytokine responses varied between different strains of PRRSV, as well as between tissues examined and by inoculum dose. PMID- 24074588 TI - Human papillomavirus type 16 E7 oncoprotein inhibits the anaphase promoting complex/cyclosome activity by dysregulating EMI1 expression in mitosis. AB - The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase complex that orchestrates mitotic progression by targeting key mitotic regulators for proteasomal degradation. APC/C dysfunction is a frequent event during cancer development and can give rise to genomic instability. Here we report that the HPV16 E7 oncoprotein interferes with the degradation of APC/C substrates and that the APC/C inhibitor, EMI1, is expressed at higher levels in HPV16 E7-expressing mitotic cells. HPV16 E7 expression causes increased EMI1 mRNA expression and also inhibits EMI1 degradation. The resulting abnormally high EMI1 levels in HPV16 E7 expressing mitotic cells may inhibit degradation of APC/C substrates and cause the prometaphase delay that we have previously observed in such cells. PMID- 24074589 TI - A partial deletion in non-structural protein 3A can attenuate foot-and-mouth disease virus in cattle. AB - The role of non-structural protein 3A of foot-and-mouth disease virus (FMDV) on the virulence in cattle has received significant attention. Particularly, a characteristic 10-20 amino acid deletion has been implicated as responsible for virus attenuation in cattle: a 10 amino acid deletion in the naturally occurring, porcinophilic FMDV O1 Taiwanese strain, and an approximately 20 amino acid deletion found in egg-adapted derivatives of FMDV serotypes O1 and C3. Previous reports using chimeric viruses linked the presence of these deletions to an attenuated phenotype in cattle although results were not conclusive. We report here the construction of a FMDV O1Campos variant differing exclusively from the highly virulent parental virus in a 20 amino acid deletion between 3A residues 87 106, and its characterization in vitro and in vivo. We describe a direct link between a deletion in the FMDV 3A protein and disease attenuation in cattle. PMID- 24074591 TI - Selectively maintained paleoviruses in Holarctic water fleas reveal an ancient origin for phleboviruses. AB - The ecological model, Daphnia pulex (Cladocera: Daphniidae), is broadly distributed in Holarctic freshwater habitats and has been the subject of multidisciplinary study for over half a century, but never has a natural RNA virus infection been reported in daphnids. Here we report on a group of paleoviruses related to RNA dependent RNA polymerase in the genome of D. pulex. Phylogenetic analysis suggests that these paleoviruses are derived from a viral lineage within the genus Phlebovirus. Comparison of the genomic sequences flanking individual paleoviruses reveal that some are orthologous viral insertions having been present in the common ancestor of the D. pulex species complex, which is millions of years old. Still, we detected some sites that have the signature of purifying selection. In contrast, other paleoviruses in this group seem to be unique to specific host lineages and even contain undisrupted open reading frames, suggesting either more recent acquisition, or selective maintenance. PMID- 24074590 TI - Anti-HIV designer T cells progressively eradicate a latently infected cell line by sequentially inducing HIV reactivation then killing the newly gp120-positive cells. AB - The current antiretroviral therapy (ART) can effectively reduce plasma HIV loads to undetectable levels, but cannot eliminate latently infected resting memory CD4 T cells that persist for the lifetime of infected patients. Therefore, designing new therapeutic approaches to eliminate these latently infected cells or the cells that produce HIV upon reactivation from latency is a priority in the ART era in order to progress to a cure of HIV. Here, we show that "designer" T cells expressing chimeric antigen receptor (CAR), CD4-CD28-CD3zeta, can target and kill HIV Env-expressing cells. Further, they secrete effector cytokines upon contact with HIV Env+ target cells that can reactivate latent HIV in a cell line model, thereby exposing those cells to recognition and killing by anti-HIV CAR+ T cells. Taken to the limit, this process could form the basis for an eventual functional or sterilizing cure for HIV in patients. PMID- 24074592 TI - Dual-color HIV reporters trace a population of latently infected cells and enable their purification. AB - HIV latency constitutes the main barrier for clearing HIV infection from patients. Our inability to recognize and isolate latently infected cells hinders the study of latent HIV. We engineered two HIV-based viral reporters expressing different fluorescent markers: one HIV promoter-dependent marker for productive HIV infection, and a second marker under a constitutive promoter independent of HIV promoter activity. Infection of cells with these viruses allows the identification and separation of latently infected cells from uninfected and productively infected cells. These reporters are sufficiently sensitive and robust for high-throughput screening to identify drugs that reactivate latent HIV. These reporters can be used in primary CD4 T lymphocytes and reveal a rare population of latently infected cells responsive to physiological stimuli. In summary, our HIV-1 reporters enable visualization and purification of latent-cell populations and open up new perspectives for studies of latent HIV infection. PMID- 24074594 TI - The interaction between claudin-1 and dengue viral prM/M protein for its entry. AB - Dengue disease is becoming a huge public health concern around the world as more than one-third of the world's population living in areas at risk of infection. In an effort to assess host factors interacting with dengue virus, we identified claudin-1, a major tight junction component, as an essential cell surface protein for dengue virus entry. When claudin-1 was knocked down in Huh 7.5 cells via shRNA, the amount of dengue virus entering host cells was reduced. Consequently, the progeny virus productions were decreased and dengue virus-induced CPE was prevented. Furthermore, restoring the expression of claudin-1 in the knockdown cells facilitated dengue virus entry. The interaction between claudin-1 and dengue viral prM protein was further demonstrated using the pull-down assay. Deletion of the extracellular loop 1 (ECL1) of claudin-1 abolished such interaction, so did point mutations C54A, C64A and I32M on ECL1. These results suggest that the interaction between viral protein prM and host protein claudin-1 was essential for dengue entry. Since host and viral factors involved in virus entry are promising therapeutic targets, determining the essential role of claudin-1 could lead to the discovery of entry inhibitors with attractive therapeutic potential against dengue disease. PMID- 24074593 TI - The C-terminal domain of the bacteriophage T4 terminase docks on the prohead portal clip region during DNA packaging. AB - Bacteriophage ATP-based packaging motors translocate DNA into a pre-formed prohead through a dodecameric portal ring channel to high density. We investigated portal-terminase docking interactions at specifically localized residues within a terminase-interaction region (aa279-316) in the phage T4 portal protein gp20 equated to the clip domain of the SPP1 portal crystal structure by 3D modeling. Within this region, three residues allowed A to C mutations whereas three others did not, consistent with informatics analyses showing the tolerated residues are not strongly conserved evolutionarily. About 7.5nm was calculated by FCS-FRET studies employing maleimide Alexa488 dye labeled A316C proheads and gp17 CT-ReAsH supporting previous work docking the C-terminal end of the T4 terminase (gp17) closer to the N-terminal GFP-labeled portal (gp20) than the N-terminal end of the terminase. Such a terminase-portal orientation fits better to a proposed "DNA crunching" compression packaging motor and to portal determined DNA headful cutting. PMID- 24074595 TI - Preventive and curative effects of Apple latent spherical virus vectors harboring part of the target virus genome against potyvirus and cucumovirus infections. AB - Apple latent spherical virus (ALSV)-based vectors experimentally infect a broad range of plant species without causing symptoms and can effectively induce stable virus-induced gene silencing in plants. Here, we show that pre-infection of ALSV vectors harboring part of a target viral genome (we called ALSV vector vaccines here) inhibits the multiplication and spread of the corresponding challenge viruses [Bean yellow mosaic virus, Zucchini yellow mosaic virus (ZYMV), and Cucumber mosaic virus (CMV)] by a homology-dependent resistance. Further, the plants pre-infected with an ALSV vector having genome sequences of both ZYMV and CMV were protected against double inoculation of ZYMV and CMV. More interestingly, a curative effect of an ALSV vector vaccine could also be expected in ZYMV-infected cucumber plants, because the symptoms subsided on subsequent inoculation with an ALSV vector vaccine. This may be due to the invasion of ALSV, but not ZYMV, in the shoot apical meristem of cucumber. PMID- 24074596 TI - Identification of RNA aptamers that internalize into HPV-16 E6/E7 transformed tonsillar epithelial cells. AB - Human papillomavirus type 16 (HPV-16) associated oropharyngeal cancers are on a significant increase and better therapeutic strategies are needed. The HPV-16 oncogenes E6 and E7 are expressed in HPV-associated cancers and are able to transform human tonsillar epithelial cells (HTECs). We used cell-Systematic Evolution of Ligands by Exponential Enrichment (SELEX) to select for RNA aptamers that entered into HPV-16 E6/E7-HTECs. After 12 rounds of cell-SELEX, a pool of aptamers was obtained that had significantly greater internalization capacity (~5 fold) into E6/E7-HTECs as compared to primary HTECs or fibroblasts. Analysis of individual aptamers from the pool indicated variable internalization into E6/E7 HTECs (1-8-fold as compared to a negative control). Most of the individual aptamers internalized into E6/E7 and primary HTECs with similar efficiency, while one aptamer exhibited ~3-fold better internalization into E6/E7-HTECs. Aptamers that internalize into cells may be useful for delivering therapeutic agents to HPV-16 associated malignancies. PMID- 24074597 TI - Nuclear import of high risk HPV16 E7 oncoprotein is mediated by its zinc-binding domain via hydrophobic interactions with Nup62. AB - We previously discovered that nuclear import of high risk HPV16 E7 is mediated by a cNLS located within the zinc-binding domain via a pathway that is independent of karyopherins/importins (Angeline et al., 2003; Knapp et al., 2009). In this study we continued our characterization of the cNLS and nuclear import pathway of HPV16 E7. We find that an intact zinc-binding domain is essential for the cNLS function in mediating nuclear import of HPV16 E7. Mutagenesis of cysteine residues to alanine in each of the two CysXXCys motifs involved in zinc-binding changes the nuclear localization of the EGFP-16E7 and 2xEGFP-16E7 mutants. We further discover that a patch of hydrophobic residues, 65LRLCV69, within the zinc binding domain of HPV16 E7 mediates its nuclear import via hydrophobic interactions with the FG domain of the central channel nucleoporin Nup62. PMID- 24074598 TI - Divergent gyroviruses in the feces of Tunisian children. AB - The Gyrovirus genus consists of the immunosuppressive Chicken Anemia Virus (CAV) prototype and since 2011 three other viral species found in sera/tissues of chickens, human feces, and on human skin. Here the genomes of two other gyrovirus species were characterized in diarrhea samples from Tunisian children whose main ORFs shared amino acid identity of 46-59% with those of the previously characterized gyroviruses and were provisionally named GyV5 and GyV6. All currently known gyroviruses grouped into two clades with distinct genomic features including replacement of the VP2 overlapping Apoptin gene with a distinct ORF of unknown function. Previous reports of gyrovirus DNA in human blood and on human skins warrant studies of possible human tropisms for these newly characterized gyroviruses. PMID- 24074599 TI - Receptor specificity does not affect replication or virulence of the 2009 pandemic H1N1 influenza virus in mice and ferrets. AB - Human influenza viruses predominantly bind alpha2,6 linked sialic acid (SA) while avian viruses bind alpha2,3 SA-containing complex glycans. Virulence and tissue tropism of influenza viruses have been ascribed to this binding preference. We generated 2009 pandemic H1N1 (pH1N1) viruses with either predominant alpha2,3 or alpha2,6 SA binding and evaluated these viruses in mice and ferrets. The alpha2,3 pH1N1 virus had similar virulence in mice and replicated to similar titers in the respiratory tract of mice and ferrets as the alpha2,6 and WT pH1N1 viruses. Immunohistochemical analysis determined that all viruses infected similar cell types in ferret lungs. There is increasing evidence that receptor specificity of influenza viruses is more complex than the binary model of alpha2,6 and alpha2,3 SA binding and our data suggest that influenza viruses use a wide range of SA moieties to infect host cells. PMID- 24074600 TI - Duck hepatitis B virus covalently closed circular DNA appears to survive hepatocyte mitosis in the growing liver. AB - Nucleos(t)ide analogues that inhibit hepatitis B virus (HBV) DNA replication are typically used as monotherapy for chronically infected patients. Treatment with a nucleos(t)ide analogue eliminates most HBV DNA replication intermediates and produces a gradual decline in levels of covalently closed circular DNA (cccDNA), the template for viral RNA synthesis. It remains uncertain if levels of cccDNA decline primarily through hepatocyte death, or if loss also occurs during hepatocyte mitosis. To determine if cccDNA survives mitosis, growing ducklings infected with duck hepatitis B virus (DHBV) were treated with the nucleoside analogue, Entecavir. Viremia was suppressed at least 10(5)-fold, during a period when average liver mass increased 23-fold. Analysis of the data suggested that if cccDNA synthesis was completely inhibited, at least 49% of cccDNA survived hepatocyte mitosis. However, there was a large duck-to-duck variation in cccDNA levels, suggesting that low level cccDNA synthesis may contribute to this apparent survival through mitosis. PMID- 24074601 TI - Protein-protein interactions among West Nile non-structural proteins and transmembrane complex formation in mammalian cells. AB - To study the membrane orientation of flavivirus non-structural proteins (NSPs) in the replication complex, the seven major West Nile (WN) NSPs were separately expressed in monkey cells, and their subcellular localization was investigated by imaging-based techniques. First, we observed by confocal microscopy that four small transmembrane proteins (TP) (NS2A, NS2B, NS4A, and NS4B) were located to the endoplasmic reticulum (ER), whereas the largest NSPs, NS1, NS3, and NS5 were not. We then analyzed the colocalization and the association of WN NSPs using the methods of confocal microscopy, fluorescence resonance energy transfer (FRET), and biologic fluorescence complementation (BiFC). Through these combined imaging techniques, protein-protein interactions (PPI) among WNNSPs were detected. Our data demonstrate that there are interactions between NS2A and NS4A, and interactions of NS2B with three other TPs (NS2A, NS4A, and NS4B) as well as the expected interaction with NS3. PPI between NS2A and NS4B or between NS4A and NS4B were not detected. By the criteria of these techniques, NS5 interacted only with NS3, and NS1 was not shown to be in close proximity with other NSPs. In addition, homo-oligomerization of some NSPs was observed and three-way interactions between NS2A, NS4A, and NA4B with NS2B-NS3 were also observed, respectively. Our results suggest that the four TPs are required for formation of transmembrane complex. NS2B protein seems to play a key role in bringing the TPs together on the ER membrane and in bridging the TPs with non-membrane-associated proteins (NS3 and NS5). PMID- 24074603 TI - Interaction of HPV E6 oncoproteins with specific proteasomal subunits. AB - The Human Papillomavirus E6 oncoproteins have the capacity to target several of their cellular interacting partners for proteasome mediated degradation, and recent proteomic analyses suggest a close involvement of E6 with the cellular proteasome machinery. In this study we have performed an extensive analysis of the capacity of different E6 oncoproteins to interact with specific proteasome components. We demonstrate that multiple subunits of the proteasome can be bound by different HPV E6 oncoproteins. Furthermore, whilst most of these interactions appear independent of the E6AP ubiquitin ligase, the association of E6 with the major ubiquitin-accepting proteasome subunit, S5a, does require the presence of E6AP. One consequence of the interaction between E6/E6AP and S5a is enhanced ubiquitination of this proteasome subunit. These results suggest a complex interplay between E6 and the proteasome, only some aspects of which are dependent upon the E6AP ubiquitin ligase. PMID- 24074602 TI - HIV-associated disruption of mucosal epithelium facilitates paracellular penetration by human papillomavirus. AB - The incidence of human papillomavirus (HPV)-associated epithelial lesions is substantially higher in human immunodeficiency virus (HIV)-infected individuals than in HIV-uninfected individuals. The molecular mechanisms underlying the increased risk of HPV infection in HIV-infected individuals are poorly understood. We found that HIV proteins tat and gp120 were expressed within the oral and anal mucosal epithelial microenvironment of HIV-infected individuals. Expression of HIV proteins in the mucosal epithelium was correlated with the disruption of epithelial tight junctions (TJ). Treatment of polarized oral, cervical and anal epithelial cells, and oral tissue explants with tat and gp120 led to disruption of epithelial TJ and increased HPV pseudovirion (PsV) paracellular penetration in to the epithelium. PsV entry was observed in the basal/parabasal cells, the cells in which the HPV life cycle is initiated. Our data suggest that HIV-associated TJ disruption of mucosal epithelia may potentiate HPV infection and subsequent development of HPV-associated neoplasia. PMID- 24074604 TI - Patterns of current use of tobacco products among U.S. high school students for 2000-2012--findings from the National Youth Tobacco Survey. AB - PURPOSE: The purpose of this study was to assess patterns and trends of tobacco use among high school students to better understand which products are used individually or concurrently. METHODS: Data from the National Youth Tobacco Survey from 2000 through 2012 were used to assess patterns and trends of current tobacco use (cigarettes, cigars, smokeless tobacco, and other tobacco products) among U.S. high school students. We assessed use of products individually and concurrently. RESULTS: During 2000-2012, overall linear declines were observed in current use of any tobacco product from 33.6% to 20.4% (p < .05), current use of only 1 tobacco product, from 18.8% to 10.5% (p < .05), and current poly tobacco use, from 14.7% to 9.9% (p < .05), among high school students. Overall current use of only cigarettes had both a linear decline, from 14.0% to 4.7%, as well as a quadratic trend. CONCLUSIONS: During 2000-2012, the most significant overall decline observed was for students who reported smoking only cigarettes. The results suggest that more data on the use of multiple tobacco products, not just cigarettes, is needed to guide tobacco prevention and control policies and programs. PMID- 24074605 TI - Minor consent and delivery of adolescent vaccines. AB - PURPOSE: To explore whether, and to what extent, minor consent influences adolescent vaccine delivery in the United States. METHODS: A telephone survey was completed by 263 professionals with responsibilities for adolescent health care and/or vaccination in 43 states. Measures included perceived frequency of unaccompanied minor visits and perceived likelihood of vaccine delivery to unaccompanied minors in hypothetical scenarios that varied by adolescent age, vaccine type, visit type, and clinical setting. RESULTS: Among the 76 respondents most familiar with private primary care clinics, 47.1% reported perceptions that 17-year-old patients often present without a parent/legal guardian. Among the 104 respondents most familiar with public primary care clinics, 56.7% reported that 17-year-old patients often present alone. In response to hypothetical scenarios, approximately 30% of respondents familiar with private clinics and 50% of respondents familiar with public clinics reported perceptions that unaccompanied 17-year-old adolescents would not receive influenza, Tdap, or human papillomavirus vaccines during routine check-ups because they could not provide consent. Perceived likelihood of unaccompanied minors receiving vaccines when seen for confidential services in primary care, sexually transmitted disease, and Title X/family planning clinics varied significantly by vaccine type and clinical setting. On average, respondents reported that they would support minors having the ability to self-consent for vaccines at age 14. CONCLUSIONS: The inability of minors to consent for vaccines is likely one barrier to vaccination. Interventions to increase adolescent vaccination should consider strategies that increase the ability of unaccompanied minors, particularly older minors, to receive vaccines within the context of legal, ethical, and professional guidelines. PMID- 24074607 TI - In vitro and in vivo efficacy of garlic compounds against Gyrodactylus turnbulli infecting the guppy (Poecilia reticulata). AB - Traditional compounds used to treat fish diseases in aquaculture and the ornamental fish industry (such as formalin and malachite green) can be more toxic to the hosts than their parasites. With the reviviscence in the use of herbal products, various botanicals have been heralded as cures for particular pathogens, but the efficacy of these compounds for parasitic worms is questionable. Here, we tested a range of garlic (Allium sativum) products against a major aquarium pathogen, Gyrodactylus turnbulli, infecting the guppy (Poecilia reticulata). All garlic products significantly reduced parasite mean survival time in vitro, from 13 h to <1 h. In fully randomised trials, the number of parasites was also significantly reduced on infected fish exposed to garlic from different sources. Two garlic treatments (minced and granule forms) reduced worm burdens by 66% and 75% after three doses, whereas Chinese freeze-dried garlic and allyl disulphide were 95% effective after a single application. In fact, Chinese freeze dried garlic was equally effective as Levamisole, a licensed livestock dewormer that is highly effective against G. turnbulli but not routinely prescribed for use in fish; hence, garlic may be a potential alternative treatment for gyrodactylosis. PMID- 24074606 TI - Dual use of condoms with other contraceptive methods among adolescents and young women in the United States. AB - PURPOSE: To estimate the prevalence of and factors associated with dual method use (i.e., condom with hormonal contraception or an intrauterine device) among adolescents and young women in the United States. METHODS: We used 2006-2010 National Survey of Family Growth data from 2,093 unmarried females aged 15-24 years and at risk for unintended pregnancy. Using multivariable logistic regression, we estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) to assess the associations between dual method use at last sex and sociodemographic, behavioral, reproductive history, and sexual behavior factors. RESULTS: At last sex, 20.7% of adolescents and young women used dual methods, 34.4% used condoms alone, 29.1% used hormonal contraception or an intrauterine device alone, and 15.8% used another method or no method. Factors associated with decreased odds of dual method use versus dual method nonuse included having a previous pregnancy (aOR = .44, 95% CI .27-.69), not having health insurance coverage over the past 12 months (aOR = .41, 95% CI .19-.91), and having sex prior to age 16 (aOR = .49, 95% CI .30-.78). CONCLUSIONS: The prevalence of dual method use is low among adolescents and young women. Adolescents and young women who may have a higher risk of pregnancy and sexually transmitted infections (e.g., those with a previous pregnancy) were less likely to use dual methods at last sex. Interventions are needed to increase the correct and consistent use of dual methods among adolescents and young women who may be at greater risk for unintended pregnancy and sexually transmitted infections. PMID- 24074608 TI - Managing anthelmintic resistance--parasite fitness, drug use strategy and the potential for reversion towards susceptibility. AB - The rotation of different anthelmintic classes, on an approximately annual basis, has been widely promoted and adopted as a strategy to delay the development of anthelmintic resistance in nematode parasites. Part of the rationale for recommending this practice was the expectation that resistant genotype worms have a lower ecological fitness than susceptible worms, at least in the early stages of selection, and so reversion towards susceptibility could be expected in those years when an alternative class of anthelmintic was used. The routine use of combination anthelmintics might be expected to negate this opportunity for reversion because multiple classes of anthelmintic would be used simultaneously. A simulation model was used to investigate whether the optimal strategy for use of multiple drug classes (i.e. an annual rotation of two classes of anthelmintic or continuous use of two classes in combination) changed with the size of the fitness cost associated with resistance. Model simulations were run in which the fitness cost associated with each resistance gene was varied from 0% to 15% and the rate at which resistance developed was compared for each of the drug-use strategies. Other factors evaluated were the initial frequency of the resistance genes and the proportion of the population not exposed to treatment (i.e. in refugia). Increasing the proportion of the population in refugia always slowed the development of resistance, as did using combinations in preference to an annual rotation. As the fitness cost associated with resistance increased, resistance developed more slowly and this was more pronounced when a combination was used compared to a rotation. If the fitness cost was sufficiently high then resistance did not develop (i.e. the resistance gene frequency declined over time) and this occurred at lower fitness costs when a combination was used. The results, therefore, indicate that the optimal drug-use strategy to maximise the benefit of any fitness cost associated with resistance is the use of combinations of different anthelmintic classes. Manual calculations confirmed that, within the model, the only resistant genotypes capable of surviving treatment with a combination are those carrying multiple resistance genes. These individuals are less fit, resulting in the worm population surviving treatment having a lower overall ecological fitness. This is a previously unreported perspective on the use of combination anthelmintics and strengthens the argument that any new class of anthelmintic, for which resistance genes can be expected to be rare, should be brought to market in combination. PMID- 24074609 TI - A comparison of individualized treatment guided by VeriStrat with standard of care treatment strategies in patients receiving second-line treatment for advanced non-small cell lung cancer: A cost-utility analysis. AB - OBJECTIVES: Two therapies are appropriate as 2nd-line treatment of non-small cell lung cancer (NSCLC) patients: chemotherapy and epidermal growth factor receptor (EGFR) inhibitor therapy. VeriStrat, a serum proteomic test, can be used to guide treatment decisions for NSCLC patients. The test classifies patients as likely to benefit from either of these two treatment options. The objective of this research was to model the anticipated survival and cost-effectiveness of four different treatment strategies: chemotherapy for all patients (C-all), EGFR inhibitor for all (E-all), a performance status guided selection strategy (PS guided), and a strategy guided by VeriStrat test results (V-guided). MATERIALS AND METHODS: We developed a Markov model with the perspective of the U.S. health care system. Model inputs were taken from published literature for the base-case analysis. One-way and probabilistic sensitivity analyses were performed. RESULTS AND CONCLUSION: The C-all treatment strategy showed the best overall survival outcome (10.1 months), followed by V-guided (9.6 months), PS-guided (9.2 months), and E-all (8.2 months) strategies. The incremental cost-effectiveness ratio (ICER) of a V-guided treatment strategy was $91,111 (vs. E-all) and $8462 (vs. PS guided) per quality-adjusted life year (QALY). The ICER for C-all compared to V guided was $105,616. This cost-utility analysis indicates that a treatment strategy guided by the VeriStrat test in patients receiving second-line therapy for NSCLC may experience an overall survival benefit at an incremental cost effectiveness ratio that is reasonable when compared with other practices, including cancer treatments, generally covered in the U.S. health care system. However, treating all patients with chemotherapy yielded the greatest expected survival. PMID- 24074610 TI - Combination therapy: a new strategy to manage diabetes and its complications. AB - Diabetes mellitus is the most common metabolic disorder. The major cause of mortality and morbidity here is due to the complications caused by increased glucose concentrations. All the available commercial antidiabetic drugs are associated with side effects. The combination therapy could be a new and highly effective therapeutic strategy to manage hyperglycemia. Combination of commercial drugs with phytochemicals may reduce the side effects caused by these synthetic drugs. Herbal products have been thought to be inherently safe, because of their natural origin and traditional use rather than based on systemic studies. New formulation and cocrystallisation strategies need to be adopted to match the bioavailability of the drug and the phytochemical. This review describes in detail, the observed synergy and mechanism of action between phytochemicals and synthetic drugs in effectively combating. The mode of action of combination differs significantly than that of the drugs alone; hence isolating a single component may lose its importance thereby simplifying the task of pharma industries. PMID- 24074611 TI - The fragmented character of Middle Palaeolithic stone tool technology. AB - The importance of the transport of stone artefacts in structuring Neandertal lithic assemblages has often been addressed, but the degree to which this led to fragmentation of lithic reduction over Middle Palaeolithic landscapes has not been explicitly studied thus far. Large-scale excavations of Middle Palaeolithic open-air sites and refitting studies of the retrieved assemblages have yielded new, high-resolution data on the mobile aspects of Neandertal stone tool technology. In this paper, we integrate lithic technology and raw material data from recent studies of Middle Palaeolithic open-air and rock shelter sites in Western Europe. We demonstrate that the results of a variety of typological, technological (especially refitting), and lithological studies have important consequences for our knowledge of the acquisition of raw materials and subsequent production, usage and discard of stone artefacts in the Middle Palaeolithic. Neandertal production and use of stone tools was fragmented in three domains: the spatial, the temporal and the social domain. We show that this versatile segmentation of stone artefact handling strategies is a main determinant of the character of the Neandertal archaeological record. Our data testify to ubiquitous and continuous transport of stone artefacts of a wide variety of forms, picked by Neandertals using selection criteria that were sometimes far removed from what archaeologists have traditionally considered, and to some degree still consider, to be desired end products of knapping activities. The data presented here testify to the variability and versatility of Middle Palaeolithic stone tool technology, whose fragmented character created very heterogeneous archaeological assemblages, usually the product of a wide variety of independent import, use, discard and/or subsequent transport events. PMID- 24074612 TI - Stent fracture: an ongoing story. PMID- 24074613 TI - Low trichorhinophalangeal syndrome 1 gene transcript levels in basal-like breast cancer associate with mesenchymal-to-epithelial transition. AB - OBJECTIVE: To investigate trichorhinophalangeal syndrome 1 gene (TRPS-1) expression patterns in different subtypes of breast cancer and its correlations with other genes and survival using microarray data sets. METHODS: The transcripts of TRPS-1 and its role in survival in breast cancer were analyzed using published microarray data sets#x02014;Netherlands Cancer Institute (NKI) cohort and Wang cohort. RESULTS: TRPS-1 expression was lower in basal-like breast cancer. The mRNA levels of TRPS-1 negatively correlated with Slug (Pearson correlation coefficient=-0.1366, P=0.0189 in NKI data set and Pearson correlation coefficient=-0.1571, P=0.0078 in Wang data set), FOXC1 (Pearson correlation coefficient=-0.1211, P=0.0376 in NKI data set and Pearson correlation coefficient=-0.1709, P=0.0037 in Wang data set), and CXCL1 (Pearson correlation coefficient=-0.1197, P=0.0399 in NKI data set and Pearson correlation coefficient=-0.3436, P<0.0001 in Wang data set), but positively correlated with BRCA1 (Pearson correlation coefficient=0.1728, P=0.0029 in NKI data set and Pearson correlation coefficient=0.1805, P=0.0022 in Wang data set). Low TRPS-1 expression associated with poor overall survival (hazard ratio 1.79, 95% CI of ratio 0.9894 to 3.238, P=0.054) and relapse-free survival (hazard ratio 1.913, 95% CI of ratio 1.159 to 3.156, P<0.05). The low TRPS-1 mRNA levels predicted poor outcome in breast cancer patients by the 70-gene signature. CONCLUSION: The strong expression of TRPS-1 may serve as a good prognostic marker in breast cancer. PMID- 24074614 TI - Role of sclerostin in the bone loss of postmenopausal chinese women with type 2 diabetes. AB - OBJECTIVE: To evaluate the role of sclerostin in bone loss of postmenopausal Chinese women with type 2 diabetes mellitus. METHODS: The postmenopausal patients suffering from type 2 diabetes mellitus and age, body mass index, and duration of menopause matched healthy controls were enrolled into this cross-sectional study according to criteria of inclusion and exclusion. The serum sclerostin level and bone mineral density of the anterior-posterior lumbar spine (L1-L4), femoral neck, and total hip were determined by using a quantitative sandwich ELISA kit and dual X-ray absorptiometry, respectively. Meanwhile, the clinical and laboratory indexes of bone mineral metabolism were analyzed. Associations between serum sclerostin level and bone mineral density as well as bone turnover markers were evaluated by linear regression analysis. RESULTS: Finally, 265 postmenopausal women with type 2 diabetes and 225 non-diabetic women were recruited in the diabetic group and control group, respectively. Serum sclerostin level of the diabetic group was significantly higher than that of the control group (48.2+/-19.4 vs. 37.2+/-18.6 pmol/L, P<0.001) and was increased with age in both groups (diabetic group, r=0.374, P<0.001; control group, r=0.312, P<0.001). In type 2 diabetes patients, serum sclerostin concentration was positively correlated with hemoglobin A1c level (r=0.237; P=0.021). Biochemical bone turnover markers, intact parathyroid hormone and bone-specific alkaline phosphatase, were negatively associated with serum sclerostin level (r=-0.138, P=0.078 and r=-0.265, P<0.001). Conversely, the positive correlation between sclerostin and C-terminal cross-linking telopeptide of type I collagen was found in diabetic patients (r=0.354, P<0.001). Serum sclerostin levels of the diabetic group were positively correlated with bone mineral density of the lumbar spine, femoral neck, and total hip (r=0.324, 0.367, and 0.416, respectively; all P<0.001). CONCLUSIONS: Sclerostin might participate in the pathogenesis of bone loss of type 2 diabetes. The high sclerostin level might serve as a marker of increased osteocyte activity in postmenopausal patients with type 2 diabetes mellitus. PMID- 24074615 TI - Expression of microRNA-29b2-c cluster is positively regulated by MyoD in L6 cells. AB - OBJECTIVES: To evaluate the expression profile of myoD microRNA-29 (miR-29) family in L6 myoblast differentiated to myotube of L6 myotube treated by glucose and insulin, and to further probe the molecular mechanism of myoD regulating the expression of miR-29 clusters. METHODS: The expression of myoD and miR-29 family was detected by using real-time PCR and Western blot analysis. The potential promoter and transcription factors binding sites of miR-29 clusters were predicted by Promoter scan and transcriptional factor search. The promoter sequence of miR-29b1-a and miR-29b2-c cluster was cloned into a luciferase reporter plasmid and the regulatory effect of myoD was analyzed by using dual luciferase reporter assay. Electrophoretic mobility shift assay was further conducted to indicate the binding of myoD on specific sequence. Moreover, overexpression of myoD was achieved by a recombinant adenovirus system (Ad-myoD). L6 cells were infected with Ad-myoD and real-time PCR was conducted to analyze the expression of miR-29b and miR-29c. RESULTS: The expression levels of myoD, miR-29a, miR-29b, and miR-29c were increased in L6 myoblast differentiated to myotube. The expression of myoD, miR-29b, and miR-29c was up-regulated in L6 myotube treated with glucose and insulin, but miR-29a depicted no significant change. Dual luciferase reporter gene assay showed that myoD functioned as a positive regulator of miR-29b2-c expression and myoD could bind to the specific sequence located at the promoter region of miR-29b2-c cluster. Enforced expression of myoD led to a marked increase of miR-29b and miR-29c levels in L6 cells. CONCLUSION: MyoD might act as a crucial regulator of myogenesis and glucose metabolism in muscle through regulating the expression of miR-29b2-c. PMID- 24074616 TI - Relationship between programmed death-ligand 1 and clinicopathological characteristics in non-small cell lung cancer patients. AB - OBJECTIVE: To evaluate the correlation between programmed death-ligand 1 (PD-L1) expression in primary lung cancer cells, tumor associated macrophages (TAM) and patients' clinicopathological characteristics. METHODS: From 2008 to 2010, 208 non-small cell lung cancer patients who underwent surgery or CT-guided biopsy were recruited from Huadong Hospital, Fudan University. Immunohistochemistry staining was performed to evaluate the PD-L1 expression in both primary lung cancer cells and CD68 positive TAM. The relationship between PD-L1 expression and the clinical pathology was evaluated using chi(2) test. Spearman's rank correlations were used to determine the correlation between PD-L1 expression in tumor cells and macrophages. RESULTS: Positive PD-L1 expression in primary cancer cells was found in 136 (65.3%) patients, which were negatively correlated with lymph node metastasis (P=0.009) and smoking history (P=0.036). Besides, TAM with PD-L1 expression (found in 116 patients) was positively associated with smoking history (P=0.034), well-differentiation (P=0.029) and negative lymph node metastasis (P=0.0096). A correlation between PD-L1 expression in primary tumor cells and non-small cell lung cancer associated macrophages was found (r=0.228, P=0.021). CONCLUSION: PD-L1, secreted from TAM, might induce cancer cells apoptosis, and decrease lymph node metastasis. PMID- 24074617 TI - Assessment of left atrial function by full volume real-time three-dimensional echocardiography and left atrial tracking in essential hypertension patients with different patterns of left ventricular geometric models. AB - OBJECTIVE: To evaluate left atrial function in essential hypertension patients with different patterns of left ventricular geometric models by real time three dimensional echocardiography (RT-3DE) and left atrial tracking (LAT). METHODS: One hundred and thirty-three patients with essential hypertension were divided into four groups according to criteria proposed by Ganau et al: 36 patients in normal pattern group (I), 34 patients in concentric remodelling pattern group (II), 33 patients in concentric hypertrophy pattern group (III), and 30 patients in eccentric hypertrophy pattern group (IV). Thirty-two healthy volunteers were enrolled in this study. RT-3DE and LAT were used to obtain the volume-time and emptying fraction curves, and then the maximal volume, minimal volume, stroke volume, presystolic volume, ejection fraction, systolic filling rate, early diastolic emptying rate and late diastolic emptying rate of the left atrium were measured. Conduit volume and passive emptying volume of the left atrium were calculated. RESULTS: Left atrial indexes, conduit volume, passive emptying volume, and early diastolic emptying rate decreased, while the other indices increased in the group I compared with the control group (all P<0.05). Compared with the control group, I and II groups, the left atrial volume parameters manifested change in the group III and group IV (all P<0.01). Left atrial ejection fraction measured by RT-3DE or LAT, and late diastolic emptying rate were lower in the group IV compared with the group III (all P<0.05). There was no difference in left atrial conduit volume, passive emptying volume, and early diastolic left atrial emptying rate between the group II and group I (all P>0.05). There was a positive correlation between RT-3DE and LAT in evaluating left atrial function. CONCLUSIONS: Left atrial booster pump function decreases in the eccentric hypertrophy pattern. Left atrial conduit function is unchanged in the normal pattern and the concentric remodelling pattern groups. RT-3DE and LAT technology can be used for quantitative evaluation of left atrial volume and function. PMID- 24074618 TI - Effect of timing of tracheotomy on clinical outcomes: an update meta-analysis including 11 trials. AB - OBJECTIVE: To estimate the relative effect of early vs. late tracheotomy on clinical end-points in unselected intensive care unit (ICU) patients undergoing mechanical ventilation. METHODS: We searched electronic databases (up to February 27, 2013) for both randomized control trials and observational studies satisfying the predefined inclusion criteria. RESULTS: We retrieved 11 reports of studies including a total of 13 705 patients. Early tracheotomy was associated with significant reductions in mortality [33.3% vs. 36.3%; relative risk (RR); 0.92; 95% confidence interval (CI): 0.88, 0.97; I(2): 29%], length of ICU stay (mean difference: -6.55 days; 95% CI: -8.19, -4.90; I(2): 98%) and duration of mechanical ventilation (mean difference: -6.53 days; 95% CI: -11.43, -1.63; I(2): 100%). However, as compared with late tracheotomy, early tracheotomy did not reduce the incidence of hospital pneumonia (21.9% vs. 21.0%, RR: 0.85; 95% CI: 0.68, 1.06; I(2): 67%). CONCLUSIONS: Early tracheotomy can reduce length of ICU stay, duration of mechanical ventilation and mortality but has no influence on hospital pneumonia when compared with late tracheotomy. Once the decision has been made about tracheotomy, clinical physicians should not hesitate to perform the procedure. PMID- 24074619 TI - Clinical application of Loewenstein Occupational Therapy Cognitive Assessment Battery-Second Edition in evaluating of cognitive function of Chinese patients with post-stroke aphasia. AB - OBJECTIVE: To investigate the clinical application value of Loewenstein Occupational Therapy Cognitive Assessment battery in Chinese patients with post stroke aphasia. METHODS: Cognitive functions of 59 Chinese patients with aphasia following a stroke were assessed with the Chinese version of the second edition of LOTCA battery and their linguistic functions were tested with the Western Aphasia Battery (WAB) Scale, respectively. The Results of LOTCA were analyzed and compared across different groups, in the light of gender, age, educational background, the length of illness, and the degree of aphasia. RESULTS: Neither the score of subtests of the LOTCA nor the overall scores of LOTCA of aphasia patients with different gender and educational background differed (all P>0.05). In different age groups, apart from thinking operation (F=3.373, P=0.016), visuomotor organization (F=3.124, P=0.022), attention (F=3.729, P=0.009) and the total score (F=2.683, P=0.041), there was no difference in terms of the other subtest scores of LOTCA (all P>0.05). In the groups of different length of time with illness, apart from orientation (F=2.982, P=0.039) and attention (F=3.485, P=0.022), the score of other subtests and the total score of LOTCA were not different (all P>0.05). In the groups of different degree of aphasia, apart from attention (F=2.061, P=0.074), both the score of other subtests and the total score of LOTCA differed (all P<0.05). CONCLUSION: LOTCA might be suitable to assessing the cognitive ability of post-stroke Chinese patients with aphasia. PMID- 24074620 TI - Mirizzi syndrome: our experience with 27 cases in PUMC Hospital. AB - OBJECTIVE: To retrospectively evaluate the diagnosis and treatment of Mirizzi syndrome (MS). METHODS: Patients who received elective or emergency cholecystectomies in our center during 23 years were retrospectively evaluated. The data reviewed included demography, clinical presentations, diagnostic methods, surgical procedures, postoperative complications, and follow-up. RESULTS: There were 27 patients diagnosed with MS among 8697 cholecystectomies performed during that period. The preoperative diagnostic modalities included ultrasonography, computed tomography, magnetic resonance cholangiopancreatography, and endoscopic retrograde cholangiopancreatography. The incidence of MS Type I (12/27, 44.4%) had the dominance in the four types, the incidence of MS Type II and III were 33.3% (9/27) and 22.2% (6/27), and there were no MS Type IV patients. Laparoscopic cholecystectomy was performed in 15 (55.6%) patients, but only 3 (11.1%) patients with MS Type I had a successful surgery, and the other 12 were converted to open cholecystectomy. The remaining 12 patients directly underwent open cholecystectomy. The surgical procedures except laparoscopic cholecystectomy included simply open cholecystectomy (including laparoscopic cholecystectomy converted to open cholecystectomy) (6/27, 22.2%), open cholecystectomy, T-tube placement with choledochotomy (9/27, 33.3%), open cholecystectomy, closure of the fistula with gallbladder cuff, T-tube placement (3/27, 11.1%), and open cholecystectomy with excision of the external bile ducts, and Roux-en-Y hepatico-jejunostomy (6/27, 22.2%). Of them, 88.9% (24/27) patients recovered uneventfully and were discharged in good condition without any operation related mortality. CONCLUSIONS: Endoscopic retrograde cholangiopancreatography is a good method with diagnostic and therapeutic purposes. Total or partial cholecystectomy is generally adequate for MS Type I. For MS Type II-IV, paritial cholecystectomy, choledochoplasty, or if impossible, Roux-en-Y hepatico-jejunostomy may be performed. Laparoscopic cholecystectomy may be successful in selected preoperatively diagnosed MS Type I patients, and open cholecystectomy is the standard therapeutic method. PMID- 24074622 TI - Haploidentical allogeneic hematopoietic stem cell transplantation for thymoma associated severe aplastic anemia: a case report. PMID- 24074621 TI - Neurotoxicity and biomarkers of lead exposure: a review. AB - Appropriate selection and measurement of lead biomarkers of exposure are critically important for health care management purposes, public health decision making, and primary prevention synthesis. Lead is one of the neurotoxicants that seems to be involved in the etiology of psychologies. Biomarkers are generally classified into three groups: biomarkers of exposure, effect, and susceptibility.The main body compartments that store lead are the blood, soft tissues, and bone; the half-life of lead in these tissues is measured in weeks for blood, months for soft tissues, and years for bone. Within the brain, lead induced damage in the prefrontal cerebral cortex, hippocampus, and cerebellum can lead to a variety of neurological disorders, such as brain damage, mental retardation, behavioral problems, nerve damage, and possibly Alzheimer's disease, Parkinsons disease, and schizophrenia. This paper presents an overview of biomarkers of lead exposure and discusses the neurotoxic effects of lead with regard to children and adults. PMID- 24074623 TI - Medical foreign bodies in urinary bladder: a case report. PMID- 24074624 TI - Is intensive monitoring during the first transfusion in pediatric patients necessary? AB - BACKGROUND: Some pediatric patients, typically those that are very young or felt to be especially sick are temporarily admitted to the intensive care unit (ICU) for observation during their first transfusion. If a significant reaction that requires ICU management does not occur, these patients are then transferred to a regular ward where future blood products are administered. The aim of this project was to determine if heightened observation such as temporary ICU admissions for the first transfusion are warranted. METHODS: From the blood bank records of a tertiary care pediatric hospital, a list of patients on whom a transfusion reaction was reported between 2007 and 2012, the type of reaction and the patient's transfusion history, were extracted. The hospital location where the transfusion occurred, and whether the patient was evaluated by the ICU team or transferred to the ICU for management of the reaction was determined from the patient's electronic medical record. RESULTS: There were 174 acute reactions in 150 patients. Of these 150 patients, 13 (8.7%) different patients experienced a reaction during their first transfusion; all 13 patients experienced clinically mild reactions (8 febrile non-hemolytic, 4 mild allergic, and 1 patient who simultaneously had a mild allergic and a febrile non-hemolytic), and none required ICU management. Six severe reactions (6 of 174, 3.4%) involving significant hypotension and/or hypoxia that required acute and intensive management occurred during subsequent (i.e. not the first) transfusion in six patients. CONCLUSIONS: The practice of intensive observation for the first transfusion in pediatric patients is probably unnecessary. PMID- 24074625 TI - Effect of Lactobacillus brevis ATCC 8287 as a feeding supplement on the performance and immune function of piglets. AB - Lactobacillus brevis ATCC 8287, a surface (S-layer) strain, possesses a variety of functional properties that make it both a potential probiotic and a good vaccine vector candidate. With this in mind, our aim was to study the survival of L. brevis in the porcine gut and investigate the effect of this strain on the growth and immune function of recently weaned piglets during a feeding trial. For this, 20 piglets were divided evenly into a treatment and a control group. Piglets in the treatment group were fed L. brevis cells (1*10(10)) daily for three weeks, whereas those in the control group were provided an equivalent amount of probiotic-free placebo. For assessing the impact of L. brevis supplementation during the feeding trial, health status and weight gain of the piglets were monitored, pre- and post-trial samples of serum and feces were obtained, and specimens of the small and large intestinal mucosa and digesta were collected at slaughter. The results we obtained indicated that L. brevis supplemented feeding induced a non-significant increase in piglet body weight and caused no change in the morphology of the intestinal mucosa. L. brevis cells were found to localize mainly in the large intestine, but they could not be isolated from feces. To a lesser extent, L. brevis was detected in the small intestine, although there was no specific attachment to the Peyer's patches. Changes in total serum IgG and IgA concentrations were not caused by supplemented L. brevis and no measurable rise in L. brevis-specific IgG was observed. However, analysis of cytokine gene expression in intestinal mucosa revealed downregulation of TGF beta1 in the ileum and upregulation of IL-6 in the cecum in the L. brevis supplemented group. Based on the results from this study, we conclude that whereas L. brevis appears to have some intestinal immunomodulatory effects, the ability of this strain to survive and colonize within the porcine gut appears to be limited. PMID- 24074626 TI - Anodal transcranial pulsed current stimulation: A novel technique to enhance corticospinal excitability. AB - OBJECTIVE: We aimed to compare the effects of anodal-transcranial pulsed current stimulation (a-tPCS) with conventional anodal transcranial direct current stimulation (a-tDCS) on corticospinal excitability (CSE) in healthy individuals. METHODS: CSE of the dominant primary motor cortex of the resting right extensor carpi radialis muscle was assessed before, immediately, 10, 20 and 30min after application of four experimental conditions: (1) a-tDCS, (2) a-tPCS with short inter-pulse interval (a-tPCSSIPI, 50ms), (3) a-tPCS with long inter-pulse interval (a-tPCSLIPI., 650ms) and (4) sham a-tPCS. The total charges were kept constant in all experimental conditions except sham condition. The outcome measure in this study was motor evoked potentials. RESULTS: Only a-tDCS and a tPCSSIPI (P<0.05) induced significant increases in CSE, lasted for at least 30min. Post-hoc tests indicated that this increase was larger in a-tPCSSIPI (P<0.05). There were no significant changes following application of a-tPCSLIPI and sham a-tPCS. All participants tolerated the applied currents in all experimental conditions very well. CONCLUSIONS: Compared to a-tDCS, a-tPCSSIPI is a better technique for enhancement of CSE. There were no sham effects for application of a-tPCS. However, unlike a-tDCS which modifies neuronal excitability by tonic depolarization of the resting membrane potential, a-tPCS modifies neuronal excitability by a combination of tonic and phasic effects. SIGNIFICANCE: a-tPCS could be considered as a promising neuromodulatory tool in basic neuroscience and as a therapeutic technique in neurorehabilitation. PMID- 24074627 TI - Motoneurone afterhyperpolarisation time-course following stroke. AB - OBJECTIVE: Our aim was to investigate any changes in the estimated time-course of the afterhyperpolarisation (AHP) in motoneurones innervating the tibialis anterior following stroke, with a secondary objective to compare the results from two different AHP estimation techniques. METHODS: Motor units from tibialis anterior on the paretic and non-paretic sides of 15 subjects with chronic stroke were recorded using intramuscular electrodes during voluntary isometric contraction. Participants varied the motor unit firing rate from its lowest rate to approximately 10 Hz. The AHP duration was estimated using the interval death rate (IDR) and transition point methods. RESULTS: The AHP decay time-constant was significantly different between sides (paretic: 41.7 +/- 8.5 ms, non-paretic: 36.2 +/- 6.4 ms). Additionally, the paretic AHP time-constant was significantly longer in participants with low motor recovery (45.9 +/- 9.1 ms) than with high motor recovery (39.3 +/- 10.0 ms) as measured by CMSA score. The AHP estimates from the two techniques were correlated (r=0.78). CONCLUSIONS: The AHP time course prolongation on the paretic side of people with chronic stroke is more pronounced in people with low motor recovery. SIGNIFICANCE: Changes in the motoneurone AHP time course post-stroke were related to muscle function and may play a role in the commonly-observed reduction of motor unit discharge rate during voluntary contractions following stroke. PMID- 24074628 TI - Analysis of age-period-cohort effects on overall mortality in Andalusia (Southern Spain). AB - OBJECTIVES: To evaluate the age-period-cohort effects on overall mortality in Andalusia (Spain). STUDY DESIGN: An ecological study was implemented with a Lexis diagram triangle comprising each annual age group, year of death and year of birth as the unit of analysis. METHODS: In all 1,384,899 deaths from all causes were analysed for individuals between the ages of 1 and 84 years who died in Andalusia in the period 1981-2008. A non-linear regression model was estimated for each gender group and geographical area. The effects of age, year of death and birth cohort were parameterized using B-spline smoothing functions. RESULTS: There is a downward trend in mortality by age to around the age of 15 years, from which point the trend turned upwards. For cohorts born between 1945 and 1965, the rate climbed steadily. From 1965, the rate turned downwards. Death rates increased between 1995 and 2000, only to turn down again until the end of the period. Broadly, these results were similar for both men and women, in all the provinces of Andalusia and for Andalusia as a whole. CONCLUSIONS: This study points to an age-period-cohort effect on deaths from all causes in all the geographic areas studied. PMID- 24074629 TI - Nou tout an dlo-la: a swimming-based physical activity promotion program. PMID- 24074630 TI - A pilot study examining depressive symptoms, Internet use, and sexual risk behaviour among Asian men who have sex with men. PMID- 24074631 TI - Trajectory of intimate partner violence and healthcare seeking over the life course: study of Japanese women in the Tokyo metropolitan area, Japan. AB - OBJECTIVES: To describe the trajectory of, and examine factors affecting, intimate partner violence (IPV) and IPV-specific healthcare seeking among Japanese women over the life course. STUDY DESIGN: Life course study. METHOD: One hundred and one women, aged 24-80 years, who had a lifetime history of IPV were interviewed in the Tokyo metropolitan area, Japan in 2005 and 2006. Life course data were collected according to the life history calendar method. Hierarchical linear modelling was used to examine IPV-specific healthcare seeking over the life course. RESULTS: Injury, formal or informal help seeking, public assistance, worse self-rated health status and smoking significantly increased the likelihood of IPV-specific healthcare seeking over the life course. There are significant cohort effects on healthcare seeking. The results suggest that women who experience IPV may seek healthcare services not only immediately after the first occurrence of IPV, but also later in life. CONCLUSIONS: IPV is not always associated with immediate healthcare seeking. In particular, sexual IPV is not significantly associated with healthcare seeking. Pursuing formal and informal help is associated with healthcare seeking. PMID- 24074632 TI - Attitudes towards antidepressants among people living with inflammatory bowel disease: an online Australia-wide survey. AB - BACKGROUND AND AIMS: Little research has been conducted on antidepressants (ADs) in inflammatory bowel disease (IBD) despite their widespread use and evidence that they may improve immunoregulatory activity. The present study aimed 1) To explore the use and type(s) of ADs currently prescribed to people living with IBD and to collect evidence with respect to any observed effect of ADs on the course of IBD, and 2) To explore experiences and opinions regarding the effect of ADs on IBD course and attitudes towards future trials with ADs. METHODS: A cross sectional exploratory Australia-wide online survey was conducted. Numerical results of the survey were summarised using descriptive statistics and open-ended questions using a simple content analysis. RESULTS: Overall, 98 IBD respondents participated in the survey, 50% with Crohn's disease, and 79% females. Sixty five (66%) participants reported current and 46 (47%) reported past AD use. Of the current AD users, 51 (79%) reported that the symptoms ADs were prescribed for improved. Psychological well-being improved in 87% of participants. The majority of respondents observed no change in IBD activity while on ADs, however, 16 (25%) believed that ADs improved their IBD. Most (84%) respondents would recommend ADs to other people living with IBD, and 81% reported willingness to participate in clinical trials with ADs. CONCLUSIONS: Future clinical trials on ADs are warranted and likely to be accepted by people living with IBD in need of mental health care; however, it is yet unknown whether ADs will have a specific impact on long-term IBD activity. PMID- 24074633 TI - Perforasomes of the upper abdomen: an anatomical study. AB - INTRODUCTION: Pedicled perforator flaps in the trunk such as the DIEAP or the IMAP-flap have increasingly been used for reconstructive purposes. However, perforator flaps of the upper abdominal wall derived from the SEA and DIEA have not been widely reported in literature. The aim of this study was to investigate the vascular basis of perforator flaps of the upper abdominal wall based on the epigastric vascular axis and to describe the location and size of the individual flaps. METHODS: The superior and deep inferior epigastric artery perforators (SEAPs and DIEAPs) of the supraumbilical abdominal wall of ten fresh anatomical specimens were selectively injected with Methylene blue solution or India ink. The location and size of the labeled skin area was observed. Finally, the arterial perforators were dissected and the length, diameter and the distance of the perforation point to the midline, xiphoid process and umbilicus were recorded. RESULTS: The SEAPs and DIEAPs supplied the ventromedial skin of the lower thoracic and supraumbilical abdominal wall in a sequential order. The mean size of all injected skin areas was 65 +/- 31.4 cm(2) (10.2 * 8.8 cm). A mean number of 9.7 +/- 4.2 perforators per specimen was identified. The mean external diameter of the dissected perforators was 0.82 +/- 0.32 mm. The perforator length until arborization averaged 3.44 +/- 1.07 cm. Most perforators were located in an area 2-6 cm from the midline and 0-10 cm below the xiphoid process. DISCUSSION: Through selective injection of perforators, a reliable anatomy of SEAP- and DIEAP flaps of the upper abdominal wall could be demonstrated. From a clinical point of view, subcostal SEAP-flaps are of special interest. These flaps may be rotated cranially for lower chest wall or breast reconstruction or deflected caudally for abdominal wall reconstructive purposes. The harvest site can be closed directly or via a reverse abdominoplasty procedure. PMID- 24074634 TI - The longest intraneural ganglion cyst: it's not about size but principle(s). PMID- 24074635 TI - Fear and anxiety from principle to practice: implications for when to treat youth with anxiety disorders. PMID- 24074636 TI - The National Institutes of Health Neurobiobank: a federated national network of human brain and tissue repositories. PMID- 24074637 TI - Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD. METHODS: We conducted a randomized, double blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250 750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint. RESULTS: Sodium benzoate produced a better improvement than placebo in Alzheimer's Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects. CONCLUSIONS: Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes. PMID- 24074638 TI - Recent mercury contamination from artisanal gold mining on Buru Island, Indonesia -potential future risks to environmental health and food safety. AB - In November 2011 gold was found at Mount Botak, Buru Island, Mollucas Province, Indonesia. Since 2012 mercury has been used to extract the gold requiring large volumes of water and resulting in deposition of mercury into Wamsait River and Kayeli Bay. Total mercury in waste ponds was over 680 mg/kg. In sediments at the mouth of the local river and a small feeder creek >3.00 mg/kg and >7.66 mg/kg respectively. River and bay sediments were proportionately higher in available mercury than elemental mercury and more strongly bound mercuric sulfide compared to that in trommel waste. This preliminary investigation raises concerns about the long term distribution and speciation of mercury. The floodplain is an important agricultural resource, and Mollucas Province is recognised nationally as the centre for Indonesian fish stocks. Challenges for management include communicating the potential future risks to the community and leaders and identifying mechanisms to reduce mercury waste. PMID- 24074639 TI - Mercury in muscle and liver of ten ray species from Northwest Mexico. AB - We determined total mercury (Hg) distribution in muscle and liver of ten ray species and assessed health risk considering Hg levels in muscle and average consumption of rays in Mexico. Rays were collected from five sites in NW Mexico between March and November 2012. Hg concentrations ranged from 4.465 MUg g(-1) in muscle of the longtail stingray Dasyatis longa to 0.036 MUg g(-1) in liver of the diamond stingray Dasyatis dipterura. Considering all the individuals, Hg in muscle (1.612+/-1.322 MUg g(-1)) was significantly (p<0.05) higher than in liver (0.745+/-0.616 MUg g(-1)). Regarding local health risk assessment, none of the ray species may cause adverse effects on consumers. PMID- 24074640 TI - Cleaning, disinfection and sterilization of surface prion contamination. AB - BACKGROUND: Prion contamination is a risk during device reprocessing, being difficult to remove and inactivate. Little is known of the combined effects of cleaning, disinfection and sterilization during a typical reprocessing cycle in clinical practice. AIM: To investigate the combination of cleaning, disinfection and/or sterilization on reducing the risk of surface prion contamination. METHODS: In vivo test methods were used to study the impact of cleaning alone and cleaning combined with thermal disinfection and high- or low-temperature sterilization processes. A standardized test method, based on contamination of stainless steel wires with high titres of scrapie-infected brain homogenates, was used to determine infectivity reduction. FINDINGS: Traditional chemical methods of surface decontamination against prions were confirmed to be effective, but extended steam sterilization was more variable. Steam sterilization alone reduced the risk of prion contamination under normal or extended exposure conditions, but did show significant variation. Thermal disinfection had no impact in these studies. Cleaning with certain defined formulations in combination with steam sterilization can be an effective prion decontamination process, in particular with alkaline formulations. Low-temperature, gaseous hydrogen peroxide sterilization was also confirmed to reduce infectivity in the presence and absence of cleaning. CONCLUSION: Prion decontamination is affected by the full reprocessing cycle used on contaminated surfaces. The correct use of defined cleaning, disinfection and sterilization methods as tested in this report in the scrapie infectivity assay can provide a standard precaution against prion contamination. PMID- 24074641 TI - Successful control of an outbreak of colonization by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae sequence type 258 in a neonatal intensive care unit, Italy. AB - This article reports an outbreak of colonization by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) sequence type (ST) 258 in a neonatal intensive care unit (NICU) in Palermo, Italy. KPC-Kp ST258 was detected by an active surveillance culture programme. Between 18th September and 14th November 2012, KPC-Kp was isolated from 10 out of 54 neonates admitted in the outbreak period. No cases of infection were recorded. Male sex was associated with colonization, whereas administration of ampicillin- sulbactam plus gentamicin was protective. Infection control interventions interrupted the spread of KPC-Kp without the need to close the NICU to new admissions. PMID- 24074642 TI - Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. AB - BACKGROUND: In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment. We present the 96 week results. METHODS: SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir-emtricitabine or abacavir lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96. FINDINGS: Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4?5%, 95% CI -1?1% to 10?0%) confirming non inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA <50 copies per mL: 83% for dolutegravir and 80% for raltegravir) and treatment related discontinuation equals failure (93% without failure for dolutegravir; 91% for raltegravir) supported non-inferiority. Virological non-response occurred less frequently in the dolutegravir group (22 [5%] patients for dolutegravir vs 43 [10%] patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per MUL for dolutegravir and 264 cells per MUL for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir. INTERPRETATION: At week 96, once-daily dolutegravir was non inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once daily dosing without requirement for a pharmacokinetic booster makes dolutegravir based therapy an attractive treatment option for HIV-1-infected treatment-naive patients. PMID- 24074643 TI - SPRING-2 the future of antiretroviral therapy. PMID- 24074644 TI - The risks and benefits of glucocorticoid treatment for tendinopathy: a systematic review of the effects of local glucocorticoid on tendon. AB - OBJECTIVE: Our primary objective was to summarise the known effects of locally administered glucocorticoid on tendon tissue and tendon cells. METHODS: We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline database using specific search criteria. The search yielded 50 articles, which consisted of 13 human studies, 36 animal studies and one combined human/animal study. RESULTS: Histologically, there was a loss of collagen organisation (6 studies) and an increase in collagen necrosis (3 studies). The proliferation (8 studies) and viability (9 studies) of fibroblasts was reduced. Collagen synthesis was decreased in 17 studies. An increased inflammatory cell infiltrate was shown in 4 studies. Increased cellular toxicity was demonstrated by 3 studies. The mechanical properties of tendon were investigated by 18 studies. Descriptively, 6 of these studies showed a decrease in mechanical properties, 3 showed an increase, while the remaining 9 showed no significant change. A meta-analysis of the mechanical data revealed a significant deterioration in mechanical properties, with an overall effect size of -0.67 (95% CI = 0.01 to -1.33) (data from 9 studies). CONCLUSIONS: Overall it is clear that the local administration of glucocorticoid has significant negative effects on tendon cells in vitro, including reduced cell viability, cell proliferation and collagen synthesis. There is increased collagen disorganisation and necrosis as shown by in vivo studies. The mechanical properties of tendon are also significantly reduced. This review supports the emerging clinical evidence that shows significant long-term harms to tendon tissue and cells associated with glucocorticoid injections. PMID- 24074645 TI - Radiological and clinicopathological features of pPNET. AB - PURPOSE: To analyze the radiological and clinicopathological features of peripheral primitive neuroectodermal tumor (pPNET). MATERIALS AND METHODS: We retrospectively reviewed the computed tomography (CT) and magnetic resonance (MR) imaging of 14 cases of pPNET confirmed immunohistochemically. Relevant clinical data was also obtained. RESULTS: Of 14 cases, there were 10 male and 4 female with a mean age of 28 years. The main symptoms were the aggravated pain of the lesion site and enlarged palpable masses. Fourteen lesions were located in the chest wall (n = 4), retroperitoneum (n = 3), pelvic cavity (n = 2), intraspinal area (n = 2), nasal cavity (n = 1), leg ( n= 1) and iliac bone (n = 1). Eleven lesions originating from the soft tissue mainly demonstrated large and infiltrative mass with (n = 4) or without (n = 7) bony invasion. Ten cases of them showed heterogeneous density with patchy, necrotic foci and moderate heterogeneous enhancement. Four of them with large cystic area contained irregular septations within them. Two intraspinal cases had extradural lesions, extending through the intervertebral foramen and formed paraspinal soft tissue masses with vertebral destruction. The case within iliac bone demonstrated extensive mixed (lytic/osteoblastic) lesion with large adjacent soft tissue mass. After surgery or therapy, 10 patients died of local recurrences or metastases. CONCLUSION: The diagnosis of pPNET should be suggested in young patient when imaging depicts a large, ill-defined, soft-tissue mass containing area of cystic degeneration with internal septations and extending along the neural route and nearby the middle of the trunk. The key for correct diagnosis is to inosculate imaging to clinical data. PMID- 24074646 TI - Fat-suppressed volume isotropic turbo spin echo acquisition (VISTA) MR imaging in evaluating radial and root tears of the meniscus: focusing on reader-defined axial reconstruction. AB - OBJECTIVE: To assess the diagnostic value of fat-suppressed (FS) three dimensional (3D) volume isotropic turbo spin echo acquisition (VISTA) imaging in detecting radial and root tears of the meniscus, including the reader-defined reformatted axial (RDA) plane. MATERIALS AND METHODS: Twenty-three patients with arthroscopically confirmed radial or root tears of the meniscus underwent magnetic resonance imaging (MRI) with 2D and FS 3D VISTA sequences. MRIs were reviewed independently by two musculoskeletal radiologists blinded to the arthroscopic findings. Sensitivity, specificity, accuracy, and interobserver agreement were calculated for radial and root tears. Both radiologists reported confidence scale for the presence of meniscal tears in 2D axial imaging, 3D axial imaging, and RDA imaging, based on a five-point scale. Wilcoxon's signed rank test was used to compare confidence scale. RESULTS: The sensitivity, specificity, and accuracy of FS 3D VISTA MR imaging versus 2D MR imaging were as follows: 96%, 96%, and 96% versus 91%, 91%, and 91%, respectively in reader 1, and 96%, 96%, and 96% versus 83%, 91%, and 87%, respectively, in reader 2. Interobserver agreement for detecting meniscal tears was excellent (kappa=1) with FS 3D VISTA. The confidence scale was significantly higher for 3D axial images than 2D imaging (p=0.03) and significantly higher in RDA images than 3D axial image in detecting radial and root tears. CONCLUSIONS: FS 3D VISTA had a better diagnostic performance in evaluating radial and root tears of the meniscus. The reader defined reformatted axial plane obtained from FS 3D VISTA MR imaging is useful in detecting radial and root tears of the meniscus. PMID- 24074647 TI - Diagnostic value of whole-body low-dose computed tomography (WBLDCT) in bone lesions detection in patients with multiple myeloma (MM). AB - PURPOSE: To assess the role of whole-body low-dose computed tomography (WBLDCT) in the diagnosis and staging of patients with suspicion of multiple myeloma (MM). MATERIALS AND METHODS: A total of 138 patients (76 male and 62 female; mean age 63.5 years, range 50-81 years), with early MM, underwent WBLDCT protocol study, performed on 16-slice scanner (Brilliance, Philips Medical System, Eindhoven, The Netherlands): tube voltage 120 kV; tube current time product 40 mAs. Diagnosis of osteolytic lesions was performed on the basis of axial and multiplanar reformatted images, whereas the assessment of spinal misalignment and fracture was done by using multiplanar reformatted images. The overall dose delivered to each patient was 4.2 mSv. Every patient gave personal informed consent, as required by our institution guidelines. RESULTS: The diagnosis was established either by histopathology or imaging follow-up (size increase of over a period time). In all 138 patients, image resolution was diagnostic, enabling correct classification of multiple myeloma patients. WBLDCT showed a total of 328 pathologic bone findings in 81/138 patients. CT scanning resulted in complete evaluation of the bone lesions in these areas of the skeleton: skull (42), humerus (15), femur (20), ribs (7), scapulae (13), pelvis (35), clavicle (13), sternum (10), cervical (39), dorsal (65), lombar (48) and sacral rachis (21). In 40/81 bone involvement detected by CT was the only CRAB criterion present. Furthermore, WBLDCT demonstrated pleuro-pulmonary lesions in 20 patients (11 infective, 9 as MM localizations) and 1 renal neoplasia. CONCLUSION: WBLDCT, detecting bone marrow localizations and demonstrating extra-osseous findings, with a fast scanning time and high resolution images, is a reliable imaging-based tool for a proper management of MM patients. PMID- 24074648 TI - Lung cancer screening with CT: evaluation of radiologists and different computer assisted detection software (CAD) as first and second readers for lung nodule detection at different dose levels. AB - OBJECTIVES: To find the best pairing of first and second reader at highest sensitivity for detecting lung nodules with CT at various dose levels. MATERIALS AND METHODS: An anthropomorphic lung phantom and artificial lung nodules were used to simulate screening CT-examination at standard dose (100 mAs, 120 kVp) and 8 different low dose levels, using 120, 100 and 80 kVp combined with 100, 50 and 25 mAs. At each dose level 40 phantoms were randomly filled with 75 solid and 25 ground glass nodules (5-12 mm). Two radiologists and 3 different computer aided detection softwares (CAD) were paired to find the highest sensitivity. RESULTS: Sensitivities at standard dose were 92%, 90%, 84%, 79% and 73% for reader 1, 2, CAD1, CAD2, CAD3, respectively. Combined sensitivity for human readers 1 and 2 improved to 97%, (p1=0.063, p2=0.016). Highest sensitivities--between 97% and 99.0%--were achieved by combining any radiologist with any CAD at any dose level. Combining any two CADs, sensitivities between 85% and 88% were significantly lower than for radiologists combined with CAD (p<0.03). CONCLUSIONS: Combination of a human observer with any of the tested CAD systems provide optimal sensitivity for lung nodule detection even at reduced dose at 25 mAs/80 kVp. PMID- 24074650 TI - The concentration of manganese, iron, and strontium in hip joint bone obtained from patients undergoing hip replacement surgery. AB - The aim of this study was to determine the concentrations of manganese (Mn), iron (Fe) and strontium (Sr) in the cartilage with adjacent compact bone and spongy bone collected from patients after total hip replacement surgery. In addition, we examined relations between the concentrations of the metals in the bone and selected environmental factors. The concentration of Fe was the highest while Mn concentration was the lowest. The concentrations of Fe in the spongy bone in patients from larger cities were higher than in those living in smaller towns and villages. Significant correlations were found between Fe and Mn concentrations in the cartilage with adjacent compact bone and in the spongy bone, and between Mn and Sr in the spongy bone. In general, Mn, Fe and Sr concentrations in the bones of patients from NW Poland were lower than in other Polish regions and Europe, especially in industrialized countries. In conclusion, it seems that in addition to routine monitoring of the abiotic environment, it is essential to monitor concentrations of heavy metals having a long-term impact in humans. PMID- 24074649 TI - Intensive motivational interviewing for women with concurrent alcohol problems and methamphetamine dependence. AB - Motivational interviewing (MI) for the treatment of alcohol and drug problems is typically conducted over 1 to 3 sessions. The current work evaluates an intensive 9-session version of MI (Intensive MI) compared to a standard single MI session (Standard MI) using 163 methamphetamine (MA) dependent individuals. The primary purpose of this paper is to report the unexpected finding that women with co occurring alcohol problems in the Intensive MI condition reduced the severity of their alcohol problems significantly more than women in the Standard MI condition at the 6-month follow-up. Stronger perceived alliance with the therapist was inversely associated with alcohol problem severity scores. Findings indicate that Intensive MI is a beneficial treatment for alcohol problems among women with MA dependence. PMID- 24074651 TI - Antioxidant and cytotoxic effect of biologically synthesized selenium nanoparticles in comparison to selenium dioxide. AB - The present study was designed to evaluate antioxidant and cytotoxic effect of selenium nanoparticles (Se NPs) biosynthesized by a newly isolated marine bacterial strain Bacillus sp. MSh-1. An organic-aqueous partitioning system was applied for purification of the biogenic Se NPs and the purified Se NPs were then investigated for antioxidant activity using DPPH scavenging activity and reducing power assay. Cytotoxic effect of the biogenic Se NPs and selenium dioxide (SeO2) on MCF-7 cell line was assesed by MTT assay. Tranmission electron micrograph (TEM) of the purified Se NPs showed individual and spherical nanostructure in size range of about 80-220nm. The obtained results showed that, at the same concentration of 200MUg/mL, Se NPs and SeO2 represented scavenging activity of 23.1+/-3.4% and 13.2+/-3.1%, respectively. However, the data obtained from reducing power assay revealed higher electron-donating activity of SeO2 compared to Se NPs. Higher IC50 of the Se NPs (41.5+/-0.9MUg/mL) compared to SeO2 (6.7+/ 0.8MUg/mL) confirmed lower cytotoxicity of the biogenic Se NPs on MCF-7 cell line. PMID- 24074652 TI - Developmental alterations of physical properties and components of neonatal infantile stratum corneum of upper thighs and diaper-covered buttocks during the 1st year of life. AB - BACKGROUND: Although physical properties of neonatal-infantile stratum corneum (SC) change drastically after birth, precise developmental alterations of specific sites have not been fully elucidated. OBJECTIVE: To determine the longitudinal alterations of neonatal-infantile SC functions and components of upper thighs and diaper-covered buttocks during the first year of life. The data were compared with those of adults. METHODS: Nineteen full-term neonates and their mothers were subjected to the measurements. Skin hydration, water sorption/retention capacity, TEWL were measured. Superficial SC analyses for NMF, ester binding sebum, and free fatty acids were performed by ATR-FTIR spectrometer. Total amount of ceramides (CERs) and CER subclasses were analyzed by NPLC-ESI-MS. RESULTS: SC hydration of neonatal thighs was lower than that of their mothers, which rapidly increased during the 1st month. Skin hydration of neonatal buttocks was similar to that of their mothers. This also rapidly increased during the 1st month. The neonatal TEWL was less than those of their mothers indicating more efficient barrier function at both sites, which significantly increased during the 1st year development. This was mostly correlated decreased in the omega-hydroxy fatty acid-esterified CERs. Superficial ester-binding sebum content of neonates was similar to that of their mothers, which significantly decreased during the measurement; the decrease was more marked on buttocks. Neither NMF nor FFA of the superficial SC showed significant alteration during the 1-year development. CONCLUSION: Our results indicate that physical functions and components of neonatal-infantile SC show considerable alterations between diaper-covered buttocks and upper thighs during the 1st year development. PMID- 24074653 TI - Outcome of CDH infants following fetoscopic tracheal occlusion - influence of premature delivery. AB - PURPOSE: To evaluate the mortality and morbidity of infants with congenital diaphragmatic hernia who had undergone fetal endoscopic tracheal occlusion (FETO) and whether this was influenced by premature birth. METHODS: The gestational age at delivery, lung-head ratio (LHR) pre and post FETO, neonatal outcomes, and respiratory, gastro-intestinal, neurological, surgical, and musculoskeletal problems at follow up of consecutive infants who had undergone FETO were determined. Elective reversal of FETO was planned at 34 weeks of gestation. RESULTS: The survival rate of the 61 FETO infants was 48%, with 84% delivered prematurely. Thirty-one delivered <35 weeks of gestation. Their survival rate was 18%. Twenty-three of 24 infants who had emergency balloon removal were born <35 weeks of gestation. Survival was related to gestational age at delivery (OR 0.55, 95% CI 0.420, 0.77, p<0.001) and the duration of FETO (OR 0.73, 95% CI 0.59, 0.91, p<0.005). Infants born prior to 35 weeks of gestation compared to those born at >= 35 weeks required a longer duration of ventilation (median 45 days versus 12 days, p<0.001), and a greater proportion had surgery for gastro oesophageal reflux (50% versus 9%, p=0.011). CONCLUSION: These results emphasize the need to reduce premature delivery following FETO. PMID- 24074654 TI - Antithrombin III administration in neonates with congenital diaphragmatic hernia during the first three days of extracorporeal membrane oxygenation. AB - PURPOSE: To evaluate the effect of Antithrombin III (ATIII) on blood product requirement in neonates receiving extracorporeal membrane oxygenation (ECMO). METHODS: A retrospective case control study of neonates presenting with or without congenital diaphragmatic hernia (CDH) requiring ECMO between 2006 and 2010 was performed. Patient demographics, laboratory data, and information on blood products administered were compared in patients treated before (n=37) and after (n=38) a protocol for antithrombin-III (ATIII) administration was implemented. RESULTS: During the first three days on ECMO patients with CDH received less fresh frozen plasma (FFP) and platelets after ATIII administration was introduced (78.1 +/- 19.2 ml/kg vs. 27.8 +/- 6.2 ml/kg, p<0.007 and 67.8 +/- 8.6 ml/kg vs. 47.8 +/- 8.4 ml/kg, p=0.05 respectively), while FFP and platelet administration in patients without CDH was not different between the two periods. Patients both with and without CDH received less packed red blood cell (PRBC) transfusions after the ATIII protocol was introduced (230 +/- 51.5 ml/kg vs. 73.8 +/- 9.7 ml/kg, p<0.002 and 173.2 +/- 22.2 ml/kg vs. 66.0 +/- 6.6 ml/kg, p<0.001, respectively). Finally, cryoprecipitate administered was not different in patients with and without CDH between the two periods (13 +/- 2.9 ml/kg vs. 15.9 +/- 7.2 ml/kg, p=NS and 6.1 +/- 1.8 ml/kg vs. 3.4 +/- 0.6 ml/kg, p=NS, respectively). CONCLUSIONS: Introduction of routine ATIII administration was associated with decreases in FFP, platelet, and PRBC exposure in neonates with CDH and decreases in PRBC transfusions in neonates without CDH during the first three days of ECMO support. PMID- 24074655 TI - Standardization of operative equipment reduces cost. AB - BACKGROUND: We hypothesize that standardizing operative equipment, and reducing variability can safely achieve cost reduction. METHODS: We retrospectively measured supply costs, operative time, intra-operative complications, and length of stay in a cohort of 145 patients at a children's hospital who underwent a laparoscopic appendectomy. A standardized preference card for laparoscopic appendectomy was developed and implemented. Data were prospectively collected on 101 consecutive patients and compared to the retrospective cohort using multiple linear regression. A survey assessing the perception of surgeons, nurses and scrub technologists of the impact of standardization on patient safety, patient care, OR efficiency, and cost was conducted. Wilcoxon rank sum test was used to evaluate associations between clinical role and years of experience with the total level of agreement on the survey. RESULTS: A 20% average reduction was achieved in supply cost per case, with no significant change in operative time (p=0.14), total time in OR (p=0.15), or length of stay (p=0.60). No intra operative complications were identified in either group. Survey participants agreed that standardization improves cost and safety. Nurses tended to have greater agreement that standardization improved efficiency and patient care compared to other roles (p=0.06). CONCLUSIONS: Standardization of operative equipment can result in a significant cost reduction without impacting quality or delivery of care. Based on average case number per year, a total annual cost savings of >$41,000 could be realized. Survey participants agree that standardization improves cost and patient safety, yet perceptions regarding the impact on efficiency and patient care varied by occupation. PMID- 24074656 TI - Using the Pediatric Health Information System to study rare congenital pediatric surgical diseases: development of a cohort of esophageal atresia patients. AB - BACKGROUND/PURPOSE: Administrative databases include large multi-institutional cohorts of patients with rare congenital anomalies that can potentially be used to characterize these diseases and study variations in practice and outcomes. The purpose of this study was to develop a methodology to accurately identify a cohort of patients with a rare disease (esophageal atresia and tracheoesophageal fistula, EA/TEF) in the Pediatric Health Information System (PHIS) database. METHODS: Patients with EA/TEF treated from 2001 to 2010 were identified by chart review at two institutions and then located within the PHIS database to find ICD 9-CM coding patterns unique to EA/TEF. Subsequently, a step-wise search strategy for PHIS was developed to identify patients with EA/TEF: this included searching the ICD-9-CM diagnosis code for congenital EA/TEF; adding the ICD-9-CM code for acquired TEF; limiting age to <= 30 days; and adding at least one of a number of specified ICD-9-CM procedure codes. The PHIS search results were subsequently validated by chart review at each institution. RESULTS: The institutional chart reviews identified 207 patients with EA/TEF. The most refined PHIS search strategy identified 221 patients. The positive predictive value of the search increased incrementally from 65% with using only the correct ICD-9 code to 96% with the full methodology. A cohort of 2977 patients with EA/TEF is identified when this search strategy is applied to the entire PHIS database. CONCLUSION: Administrative databases such as PHIS can be utilized to identify cohorts of patients with rare congenital anomalies; however, cohort development requires a systematic search strategy and validation process to ensure correct identification of patients. PMID- 24074657 TI - Gastric emptying in children with gastroesophageal reflux and in healthy children. AB - PURPOSE: The aim of this report is to examine whether children with gastroesophageal reflux (GER) have delayed gastric emptying compared to healthy children. METHODS: All patients had GER verified by 24-hour pH monitoring. Gastric emptying of cow's milk was examined by radionuclide scintigraphy in 51 patients with GER and in 24 controls. Gastric emptying rate was expressed as exponential half time (T1/2). RESULTS: Median age was 4.4 years [range 0.1-15.4] in patients and 6.1 years [range 2.5-10.0] in controls (p=.10). A wide range of gastric emptying rates was observed both in GER patients [range 16-121] and controls [range 29-94]. One GER patient (2%) had slower gastric emptying (T1/2=121 min) than the healthy child with the longest T1/2 (94 min). Mean T1/2 was 49 minutes (SD 20.1) and 46 minutes (SD 14.2) in GER patients and controls, respectively (p=.51). CONCLUSIONS: Gastric emptying rate of milk was not significantly different between children with GER and healthy children. A wide range of gastric emptying rates was observed in both groups. PMID- 24074658 TI - Autologous blood patch for persistent air leak in children. AB - PURPOSE: Persistent air leak (PAL) is associated with increased morbidity. Standard treatment of PAL includes chemical or mechanical pleurodesis. Long-term impact of these interventions is not known in the pediatric population. Autologous blood patch (ABP) offers a novel treatment option. We report our experience with autologous blood patch to successfully treat PAL in eight children. METHODS: Children with PAL were treated with ABP. A fresh whole blood sample was obtained from each patient and injected via their pre-existing chest tube. Volume of blood injected, time to cessation of air leak, time to chest tube removal, outcomes and complications were reviewed. RESULTS: Eight children aged 2 months to 18 years underwent ABP. Three children had immediate seal of air leak, while two patients sealed after 1 and 2 days. Three patients required a second ABP, after which they had immediate seal of air leak. Chest tubes were removed within 2-3 days in 7 cases. One child developed an asymptomatic pneumothorax and required 8 days for radiographic resolution. CONCLUSION: ABP appears to be a safe and effective treatment option for PAL in children. ABP offers an inexpensive, easy to perform technique and avoids use of toxic chemicals for pleurodesis in pediatric patients. PMID- 24074659 TI - Predictors of radiolucent foreign body aspiration. AB - BACKGROUND: Children frequently present for suspected foreign body aspiration, many have mild symptoms and/or negative radiographs raising the question of a radiolucent foreign body aspiration. METHOD: Retrospective review of patients having bronchoscopy for suspected radiolucent foreign body aspiration from 2000 to 2010 collecting demographics, history, hospital presentation, radiographic, and operative details. Pearson's correlation was used between event history, presentation, radiographic details and bronchoscopically identified foreign body with P value <0.01. RESULTS: 138 patients, mean age 2.6 years, mean weight 15.6 kg, 68% male. Event symptoms: 81% witnessed events, 64% wheezing, 43% coughing, 39% choking, 6% stridor, and 0.7% lethargy. Hospital presentation: 70% persistent symptoms, wheezing 56%, coughing 15%, desaturations 11%, stridor 7%, choking 4%, and lethargy 1%. 92% of patients had a chest x-ray; air trapping found in 38%, and lung collapse in 21%. 2 patients received CT scans; 1 had lung collapse. Bronchoscopy identified foreign bodies in 93% of patients: food 68%, plastic 18%, non-descript 11%, rocks 3%. No correlations between event symptoms, hospital presentation, radiographs and foreign body presence. CONCLUSION: Event history, hospital presentation, and radiographs are insufficient in proving the absence of a radiolucent foreign body. Patients with suspected radiolucent foreign body aspiration should undergo diagnostic bronchoscopy prior to discharge. PMID- 24074660 TI - The use of spinal angiography in the management of posterior mediastinal tumors: case series and review of the literature. AB - INTRODUCTION: Resection of inferiorly located posterior mediastinal tumors can be complicated by their proximity to the artery of Adamkiewicz (AKA). Although uncommon, intraoperative injury to the AKA may result in paraparesis or paralysis secondary to spinal cord ischemia. The use of preoperative spinal angiography may serve as a useful adjunct to the surgeon in guiding extent of resection of the tumor to avoid injury to this critical artery. METHODS: After IRB approval (H 31712), three patients, from 2008 to 2011, with lower posterior mediastinal tumors were identified. Their charts were reviewed for information concerning preoperative imaging, operative details, and postoperative neurologic complications. The literature regarding imaging of the AKA, cases of injury in pediatric patients, and recommendations for treatment after its injury were reviewed. RESULTS: One patient, who did not have preoperative spinal angiography, developed transient paresis lasting 6 weeks after posterior mediastinal tumor resection. Two patients underwent preoperative spinal angiography with successful localization of the AKA. In both cases, the patients subsequently underwent posterior mediastinal tumor resection without injury to the artery and without postoperative neurologic sequelae. CONCLUSIONS: Preoperative spinal angiography may serve as a useful adjunct in the evaluation of children with inferior posterior mediastinal tumors in order to delineate the relationship of the artery of Adamkiewicz to the tumor for the purpose of guiding surgical resection. PMID- 24074661 TI - Variations of the soft tissue thicknesses external to the ribs in pectus excavatum patients. AB - BACKGROUND: Surgical repair of pectus excavatum (PE) has become more popular due to improvements in the minimally invasive Nuss procedure. The pre-surgical assessment of PE patients requires Computerized Tomography (CT), as the malformation characteristics vary from patient to patient. OBJECTIVE: This work aims to characterize soft tissue thickness (STT) external to the ribs among PE patients. It also presents a comparative analysis between the anterior chest wall surface before and after surgical correction. METHODS: Through surrounding tissue segmentation in CT data, STT values were calculated at different lines along the thoracic wall, with a reference point in the intersection of coronal and median planes. The comparative analysis between the two 3D anterior chest surfaces sets a surgical correction influence area (SCIA) and a volume of interest (VOI) based on image processing algorithms, 3D surface algorithms, and registration methods. RESULTS: There are always variations between left and right side STTs (2.54 +/- 2.05 mm and 2.95 +/- 2.97 mm for female and male patients, respectively). STTs are dependent on age, sex, and body mass index of each patient. On female patients, breast tissue induces additional errors in bar manual conception. The distances starting at the deformity's largest depression point at the SCIA are similar in all directions. Some diverging measures and outliers were found, being difficult to find similar characteristics between them, especially in asymmetric patients. CONCLUSION: The Nuss procedure metal bar must be modeled according to each patient's special characteristics. The studied relationships between STT and chest surface could represent a step forward to eliminate the CT scan from PE pre surgical evaluation. PMID- 24074662 TI - Retained central venous lines (CVLs) after attempted removal: an 11-year series and literature review. AB - BACKGROUND: Central venous lines (CVLs) are frequently used in the management of many neonatal and pediatric conditions. Failure to remove the luminal part of the line (retained CVL) is rare. Consequently, there is lack of experience and consensus in its optimal management. AIM: To document the incidence and management of retained CVLs in a tertiary pediatric surgical centre with access to interventional cardiology services. To review the literature and report efficacy/morbidity of attempted extraction of retained CVLs. METHODS: Children with retained CVLs were identified from departmental morbidity and mortality records over an 11-year period. A literature search was performed in PubMed and Scopus to identify studies reporting retained CVLs (earliest date to 1 January 2012). This was supplemented by scanning bibliographies of retrieved articles. RESULTS: The 11-year incidence of retained CVL was 0.3% (n=10; median duration in situ 66.5 {range 47-146} months). The underlying pathology in 8 was cystic fibrosis. Antegrade transfemoral snare retrieval was successful in 6 of 7 attempts. In the remaining 3, a conservative approach was adopted following consultation with the family. None of the 4 with retained CVL developed complications (median follow-up 7.5 {range 1-53} months). The literature describes 38 pediatric index cases (including 10 from the current series). Seventeen (49%) were managed conservatively either intentionally or by default after failed endovascular removal attempt (n=4). No complications directly attributed to retained CVLs have been reported (median follow-up 40 {range 1-120} months). Reported morbidity associated with endovascular retrieval includes: procedural failure 30%, line embolization 8%, and intra-operative thrombo embolism 8%. CONCLUSION: Literature regarding management of retained CVLs is anecdotal. Although uncommon, the complication should feature in consent for removal of CVLs. Conservative management carries long-term risks of infection, thrombosis, and even migration, albeit unquantified over a child's lifetime. Endovascular retrieval is feasible with appropriate expertise. PMID- 24074663 TI - Ultrasonographic dimensions of the common bile duct in Chinese children: results of 343 cases. AB - BACKGROUND: At present, the diagnostic criteria of congenital cholangiectasis are still vague. PURPOSE: The aim of this study was to assess the diameter references of the common bile duct (CBD) in pediatric population in different age groups with ultrasound. METHODS: The diameter of the common bile duct was measured with ultrasound in 343 Chinese Han children aged 1 day to 14 years (mean: 3.2 years, median: 2.8 years) who were all free of hepatic and biliary tract disease. The ultrasound records, gender, and age were collected for reviewed analysis. RESULTS: A total of 343 children were included, and the CBD was clearly detected in 322 cases (93.9%). The mean diameter of this population was 1.58 +/- 0.70 mm. (ranging from 0.4 to 4.4mm). Spearman correlation analysis showed that the diameter of CBD was positively associated with age (r=0.573, P<0.001). The percentile method demonstrated that the diameter references of CBD was as follows: <= 1 years: <= 2.26 mm; <= 4 years: <= 2.99 mm; <= 7 years: <= 3.03 mm; and <= 14 years: <= 4.10mm. CONCLUSIONS: There was a close correlation between CBD width and the age. The range of CBD widths in each age group will be helpful in the diagnosis of biliary dilatation in childhood. PMID- 24074664 TI - Pancreatic complications in pediatric choledochal cysts. AB - BACKGROUND/PURPOSE: The aim of this study is to clarify the clinical features and risk factors of pre- and postoperative pancreatic complications in pediatric choledochal cysts. METHODS: A retrospective chart review was carried out on pediatric patients with choledochal cysts who underwent radical operation at our department. RESULTS: Twenty-one, 24, and 24 patients were classified into the Todani Ia, Ic, and IV-A choledochal cyst, respectively. Preoperative acute pancreatitis and protein plugs were observed in 31 (43.7%) and 11 (15.5%) patients, respectively. Patients with preoperative pancreatitis were more likely to have fusiform dilatation of choledochal cysts (79.3% vs. 35.0%) and a dilated common channel (53.9% vs. 23.1%) compared to those without preoperative pancreatitis. Compared to patients without preoperative protein plugs, those with protein plugs were more likely to have fusiform dilatation (90.9% vs. 46.5%) and pancreatic divisum with communicating ducts and a dilated ductal system (60.0% vs. 2.5%). Postoperatively, three patients (4.2%) experienced acute pancreatitis. One of these and all 3 had protein plugs and preoperative pancreatitis, respectively. CONCLUSIONS: Fusiform-type choledochal cyst is a significant risk factor for preoperative pancreatic complications in choledochal cysts. While postoperative pancreatic complications were relatively rare, preoperative pancreatic complications might be risk factors for postoperative pancreatitis. PMID- 24074665 TI - Sentinel lymph node biopsy in pediatric soft tissue sarcoma patients: utility and concordance with imaging. AB - BACKGROUND: The purpose of this study was to report our experience with sentinel lymph node biopsy (SLNB) for pediatric soft tissue sarcomas to add to the limited literature about its feasibility, utility, and concordance with pre-operative imaging, including CT and (18)F-FDG PET (PET) scanning. METHODS: Medical records of patients with a sarcoma who underwent SLNB as part of their treatment for a soft tissue sarcoma at our institution from 2000 to 2011 were identified and reviewed. RESULTS: Eight patients underwent SLNB for soft tissue sarcoma during the study period. Two patients had positive SLNBs; both of these patients had rhabdomyosarcoma. Three patients with pathologically enlarged lymph nodes on CT scan underwent PET functional imaging prior to SLNB. The PET suggested the presence of nodal disease in all three patients; however, only one of these patients had a positive SLNB. CONCLUSIONS: Our series confirms that SLNB is feasible in pediatric sarcoma patients. Small numbers preclude definitive conclusions regarding the utility of SLNB compared with PET, however our data suggest functional imaging alone may not be sufficient to definitively determine lymph node status in these patients. Surgical lymph node sampling may still need to be performed to accurately identify nodal status in pediatric patients with soft tissue sarcoma. PMID- 24074666 TI - Spiral intestinal lengthening and tailoring - first in vivo study. AB - INTRODUCTION: Spiral Intestinal Lengthening and Tailoring (SILT) offers a new opportunity for the surgical treatment of short bowel syndrome. SILT requires less manipulation on the mesentery than the Bianchi procedure and does not alter the orientation of the muscle fibers like serial transverse enteroplasty (STEP). This study reports the first SILT results in a surviving animal model. MATERIAL AND METHODS: Vietnamese minipigs (n=6) underwent interposition of a reversed intestinal segment to produce proximal small bowel dilation. Five weeks later the reversed segment was resected, and the wall of the dilated intestine was cut spirally at 45 degrees -60 degrees to its longitudinal axis. The bowel was lengthened longitudinally, and the spiral shaped intestinal wound was sutured. Five weeks later, the animals were explored, and the lengthened segments were measured. Haematoxylin and eosin, picrosirius, neuron specific enolase, S-100, C kit, and immunohistochemistry were performed. RESULTS: Mean lengthening was 74.8% +/- 29.5% and mean tailoring (lumen reduction) was 56.25% +/- 18.8%. No instances of necrosis, perforation, suture break down, or peritonitis were observed in 6/6 animals. Four of six animals recovered uneventfully with viable lengthened segments. Statistical analysis showed no significant difference in length (p=0,078) and width (p=0,182) after 5 weeks. Two animals developed bowel obstruction due to narrowed lumen, adhesion, and strangulation after 14 and 24 days of surgery. In both animals the lumen was tailored by more than 70% to less than 1.5 cm diameter. The mucosa and the muscle layers in the operated segment had become hypertrophic, but the orientation of the circular and longitudinal muscle fibres remained normal after the SILT procedure. There were no signs of chronic ischemia or collagen accumulation after the SILT. The myenteric and submucosal plexuses and the Cajal cell network appeared normal. CONCLUSION: The bowel remained viable macroscopically and microscopically after SILT, such that SILT may be an alternative or an addition to the present technical repertoire of intestinal lengthening. However the limitations of tailoring should be kept in mind. PMID- 24074667 TI - Transanal endorectal pull-through for classic segment Hirschsprung's disease: with or without laparoscopic mobilization of the rectosigmoid? AB - BACKGROUND: It has been suggested that the outcome of transanal endorectal pull through for classic Hirschprung's disease can be improved by laparoscopically mobilizing the colon before the pullthrough. METHODS: Charts of 43 patients (2005 2009) with proven recto-sigmoid aganglionosis were retrospectively analyzed with respect to postoperative outcomes. Twenty-one had been treated with the transanal endorectal pull through (TERPT) and 22 with the laparoscopically assisted TERPT (LTERPT). RESULTS: Gender ratio, congenital anomalies, preoperative enterostomy, and follow up did not differ between the groups. More colon was resected in the TERPT group: median 25 cm vs. 15 cm in the L-TERPT group (p<0.001). The TERPT procedure took less time: median 153 min. vs. L-TERPT 263 min (p<0.001). Postoperatively, three patients showed colonic torsions after TERPT (p=0.07). The long-term clinical outcomes did not differ significantly between both groups. There was a significant association between length of resection and obstructive symptoms (OR=0.92, p=0.01). CONCLUSION: Postoperative and clinical outcomes are similar using the TERPT or L-TERPT to correct classic segment Hirschsprung's disease. Prevention of colonic torsion should be the prime concern during the TERPT procedure. L-TERPT requires laparoscopic equipment and takes more operation time, whereas TERPT leaves no visible scars. The positive relation between the larger length of resection and obstructive symptoms requires additional research. PMID- 24074668 TI - Single-incision laparoscopic versus conventional laparoscopic endorectal pull through for Hirschsprung's disease: a comparison of short-term surgical results. AB - BACKGROUND: Single-incision laparoscopy has recently become a popular procedure in pediatric surgery. The current series is the largest study to evaluate the operative complications and results of single-incision laparoscopic endorectal pull-through (SILEP) for the treatment of HD through a retrospective comparison with conventional laparoscopic endorectal pull-through (CLEP). METHODS: Twenty eight patients who underwent single-incision laparoscopic endorectal pull-through for HD between July 2010 and August 2011 were compared to thirty patients who underwent CLEP. Patient age, gender, transitional zone, operative time, blood loss, intraoperative and postoperative complications, as well as short-term results, were assessed. RESULTS: A total of 28 patients were included for SILEP, and historical reported 30 patients were completed by CLEP. The SILEP and CLEP groups were similar in regard to age, gender, transition zone, operative time, blood loss, hospital stay, and intraoperative complications. Postoperative results were not different, including equal daily defecation frequency and early postoperative complications. No patients with recurrent constipation were seen. Two patients with the transitional zone in the descending colon in the SILEP group had a 3mm trocar added in the left abdomen, and there were no conversions in the conventional laparoscopic group. CONCLUSION: We have shown that in selected HD patients, the SILEP technique was safe and technically feasible in experienced hands. It results in similar operative results compared with conventional laparoscopic endorectal pull-through. However, the operation is more difficult if the transition zone was higher than the rectosigmoid. PMID- 24074669 TI - Potential benefits of fast-track concepts in paediatric colorectal surgery. AB - BACKGROUND: Structured care pathways optimising peri-operative care have been shown to significantly enhance post-operative recovery. We aim to determine if enhanced recovery after surgery (ERAS) principles could provide benefit for paediatric patients undergoing major colorectal resection for inflammatory bowel disease (IBD). METHODS: Children undergoing elective bowel resection for IBD at a regional paediatric unit using standard methods of peri-operative care were matched to adult cases from an associated tertiary referral university hospital already using an ERAS program. Cases were matched for disease type, gender, operative procedure, and ASA grade. RESULTS: Forty-four children undergoing fifty procedures were identified. Thirty-four were matched to adult cases. Total length of stay in the paediatric group was significantly longer than in the adult group (6 vs. 9 days; P=0.001). Paediatric patients were slower to start solid diet (1 vs. 4 days; P<0.0001) and were slower to mobilize post-operatively (1 vs. 4 days; P<0.0001). No difference was seen in time to restoration of bowel function (2 vs. 3 days; P=0.49). Thirty day readmissions and total in-hospital morbidity were not significantly different between the groups. CONCLUSION: Potentially, application of ERAS in paediatric surgery could accelerate recovery and reduce length of post operative stay thereby improving quality and efficiency of care. PMID- 24074670 TI - Management of pediatric patients with refractory constipation who fail cecostomy. AB - BACKGROUND: Antegrade continence enema (ACE) is a recognized therapeutic option in the management of pediatric refractory constipation. Data on the long-term outcome of patients who fail to improve after an ACE-procedure are lacking. PURPOSE: To describe the rate of ACE bowel management failure in pediatric refractory constipation, and the management and long term outcome of these patients. METHODS: Retrospective analysis of a cohort of patients that underwent ACE-procedure and had at least 3-year-follow-up. Detailed analysis of subsequent treatment and outcome of those patients with a poor functional outcome was performed. RESULTS: 76 patients were included. 12 (16%) failed successful bowel management after ACE requiring additional intervention. Mean follow-up was 66.3 (range 35-95 months) after ACE-procedure. Colonic motility studies demonstrated colonic neuropathy in 7 patients (58%); abnormal motility in 4 patients (33%), and abnormal left-sided colonic motility in 1 patient (9%). All 12 patients were ultimately treated surgically. Nine patients (75%) had marked clinical improvement, whereas 3 patients (25%) continued to have poor function issues at long term follow-up. CONCLUSIONS: Colonic resection, either segmental or total, led to improvement or resolution of symptoms in the majority of patients who failed cecostomy. However, this is a complex and heterogeneous group and some patients will have continued issues. PMID- 24074671 TI - Profound systemic inflammatory response syndrome following non-emergent intestinal surgery in children. AB - PURPOSE: Systemic inflammatory response syndrome (SIRS) is an uncommon but severe complication in surgical patients. While SIRS is well known, it is poorly described in the pediatric population. The goal of this study was to describe the incidence of profound SIRS following non-emergent intestinal surgery in children and to identify potential risk factors. METHODS: A retrospective review was conducted for patients 0-19 years of age following intestinal surgery and/or lysis of adhesions from 01/01/1999-02/28/2012. Children were excluded for preoperative instability or frank bowel perforation. Patients were then placed in a post-operative SIRS or non-SIRS group as defined by the 2005 International Pediatric Sepsis Consensus Conference Guidelines (6. B. Goldstein, B. Giroir, A. Randolph, and Sepsis International Consensus Conference on Pediatric, 'International Pediatric Sepsis Consensus Conference: Definitions for Sepsis and Organ Dysfunction in Pediatrics', Pediatr Crit Care Med, 6 (2005), 2-8.). RESULTS: SIRS was identified in 17 of the 381 patients. Logistic regression analysis was performed and showed heart disease, kidney disease, PN dependence, and intestinal obstruction to be predictive of post-operative SIRS. CONCLUSION: This study represents one of the first reports to identify a previously poorly described process of significant SIRS after intestinal surgery in children. Both systemic organ failure and intestinal dysfunction are strong risk factors for post-operative SIRS in children. Potentially, these pre-existing conditions may lead to disruption of normal intestinal flora or barrier function, which in turn may predispose these children to dramatic SIRS episodes after intestinal surgery. Understanding how these factors lead to SIRS will be critical to developing prevention strategies. PMID- 24074672 TI - Laparoscopy utilization and outcomes for appendicitis in small children. AB - PURPOSE: To examine the trends in laparoscopic appendectomy (LA) utilization and outcomes for children 5 years or younger. METHODS: We studied 16,028 inpatient admissions for children 5 years of age or less undergoing an appendectomy for acute appendicitis in 2000, 2003, and 2006 using the Kids' Inpatient Database (KID). Laparoscopy frequency, hospital length of stay, and complications were reviewed. RESULTS: In 2000, 2003 and 2006 appendectomies were done laparoscopically 11.4%, 18.7% and 31.3% of the time, respectively. Children were more likely to undergo LA at a children's hospital (P<0.001). LA complications were less likely overall (OR: 0.80, CI: 0.70-0.92, P=0.002) and in perforated cases (OR: 0.78, CI: 0.67-0.91, P=0.001). LA decreased hospital length of stay by 0.54 days for all patients and 0.70 days for perforated cases (P<0.001). CONCLUSIONS: Open appendectomy has historically been the standard in children 5 years of age and younger. Laparoscopic appendectomy has slowly gained acceptance for the treatment of appendicitis in smaller children. The use of laparoscopy has increased significantly at all facilities. Furthermore, laparoscopic appendectomy in this age group has a comparatively low complication rate and short hospital length of stay, and is safe in complicated perforated appendicitis cases. PMID- 24074673 TI - Ovarian torsion in children: management and outcomes. AB - BACKGROUND: The purpose of this study is to evaluate the clinical symptoms, diagnosis, management, and outcomes in children with ovarian torsion. METHODS: The charts of 50 patients with 53 cases of ovarian torsion treated between January 1989 and March 2012 were reviewed retrospectively. Long term follow up was available for 20 girls who had their ovaries left in the abdominal cavity after detorsion. RESULTS: In 22 cases ovaries were removed, and in 31 cases the torsion was relieved and the ovaries left in the abdominal cavity. Twenty-five of the salvaged ovaries were black-bluish and 10 bluish in color. Since 2005, after a change in preferred treatment, all ovaries treated by detorsion were left in the abdominal cavity. The long term results were observed clinically and by ultrasound in 20 girls. Multifollicular ovaries were found in 17 girls. One girl had a normal size paucifollicular ovary, a one-year-old girl had a normal size ovary with microfollicles, and one girl had no ovarian material detectable by ultrasound. CONCLUSIONS: Long term analysis of the treatment of ovarian torsion revealed that ovaries treated by detorsion and left in the abdominal cavity preserved their normal anatomy and function. Conservative surgical treatment proved to be safe. None of the girls had thromboembolism or peritonitis, and no malignant tumors were found in the operated ovaries. PMID- 24074674 TI - Ureterovesical junction obstruction causes increment in smooth muscle contractility, and cholinergic and adrenergic activity in distal ureter of rabbits. AB - BACKGROUND/PURPOSE: The controversy in management of primary obstructed megaureter necessitates further elucidation of the underlying pathophysiology. We evaluated smooth muscle contractility, and cholinergic, adrenergic and serotonergic activity of rabbit distal ureters after ureterovesical junction (UVJ) obstruction. METHODS: Sham (SH) operation, partial obstruction (PO) and complete obstruction (CO) of the right UVJ were performed in rabbits. Three weeks later, distal ureters were isolated; spontaneous contractions (SC), contractile responses to electrical field stimulation (EFS), high KCl, carbachol, phenylephrine and serotonin were recorded. RESULTS: SC amplitudes increased in CO compared to PO and SH (p<0.001). SC frequency was higher in CO (p<0.05). EFS induced contraction amplitudes were greater in CO than other groups (p<0.05). High KCl-induced contractions were greater in CO (p<0.001) and PO (p<0.01). Carbachol-induced contractility was enhanced in CO and PO (p<0.05). Contractile response to phenylephrine was greater in CO than other groups (p<0.05). Serotonin induced contractile responses in CO and PO, greater in CO (p<0.05). UVJ obstruction also increased spontaneous contractility in contralateral PO and CO ureters. CONCLUSIONS: UVJ obstruction increased spontaneous and neurotransmitter induced contractions in an obstruction grade-dependent manner. Obstruction also altered contractility of the contralateral ureters. Our findings may serve to provide further understanding of the pathophysiology of megaureter. PMID- 24074676 TI - The role of preoperative CT scan in patients with tracheoesophageal fistula: a review. AB - PURPOSE: The morbidity and mortality associated with esophageal atresia with or without a fistula make it a challenging congenital abnormality for the pediatric surgeon. Anatomic factors like inter-pouch gap and origin of fistula are not taken into consideration in various prognostic classifications. The preoperative evaluation of these cases with computerized tomography (CT) has been used by various investigators to delineate these factors. We reviewed these studies to evaluate the usefulness of this investigation in the intra operative and post operative period. MATERIALS AND METHODS: A literature search was done on all peer reviewed articles published on preoperative computed tomography (CT) in cases of tracheoesophageal fistula using the PUBMED and MEDLINE search engines. Key words included tracheoesophageal fistula, computerized tomography, virtual bronchoscopy, and 3D computerized tomography reconstruction. Further, additional articles were selected from the list of references obtained from the retrieved publications. A total of 8 articles were selected for analysis. RESULTS: In most of the studies, comprising 96 patients, observations noted in preoperative CT were confirmed during surgery. In a study by Mahalik et al [Mahalik SK, Sodhi KS, Narasimhan KL, Rao KL. Role of preoperative 3D CT reconstruction for evaluation of patients with esophageal atresia and tracheoesophageal fistula. Pediatr Surg Int. 2012 Jun 22. [Epub ahead of print]], in 6 patients the fistula could not be identified pre-operatively by CT. One study found a difference of 0.43 cm in the intraoperative gap length compared to that given by CT when compared to +/- 2 mm shown by another [1. Mahalik SK, Sodhi KS, Narasimhan KL, Rao KL. Role of preoperative 3D CT reconstruction for evaluation of patients with esophageal atresia and tracheoesophageal fistula. Pediatr Surg Int. 2012 Jun 22. [Epub ahead of print], 3. Ratan SK, Varshney A, Mullick S, Saxena NC, Kakkar S, Sodhi PK. Evaluation of neonates with esophageal atresia using chest CT scan. Pediatr Surg Int. 2004 Oct; 20(10):757-61.]. Only three studies showed surgical utility of pre operative CT, and the surgical plan changed based on the CT findings. CONCLUSION: The usefulness of pre-operative computerized tomography in cases of tracheoesophageal fistula is controversial. The safety of this technique is questionable due to limited facilities and associated radiation hazards. Further, limited information obtained which may help in changing the surgical plan can easily be managed intra-operatively by careful and meticulous surgery. Overall, the safety concerns outweigh its efficacy. Thus, the use of pre-operative CT scan cannot be generalized and protocolized as a standard of care in the management of tracheoesophageal atresia. PMID- 24074675 TI - Incision and drainage of subcutaneous abscesses without the use of packing. AB - PURPOSE: The classic intervention for subcutaneous abscesses is incision and drainage followed by wound packing. This is thought to aid hemostasis, and prevent reorganization of the abscess. Removal of packing material may be painful and anxiety provoking. We sought to determine whether packing could be omitted with equal efficacy. METHODS: One hundred pediatric patients with subcutaneous abscesses were enrolled between May, 2008 and December, 2010. All underwent incision and drainage, then seven days of oral antibiotics and warm soaks. Patients were randomized to the packing group (PG) or non-packing group (NPG). Packing was removed 24h after the procedure. Patients were excluded if: 1) diabetic/immunosuppressed, 2) the abscess was perianal or pilonidal, or 3) the abscess was secondary to a previous operation. Patients were evaluated in clinic if recurrence was suspected during follow-up calls on postoperative days seven and 30. RESULTS: Eighty-five patients completed the study (43 PG/42 NPG). The two groups were not statistically different with respect to initial parameters, recurrent abscesses (one in each group), or MRSA incidence (81.4% PG/85.7% NPG). CONCLUSION: Incision and drainage of subcutaneous abscesses without the use of packing is a safe and effective technique. This approach omits a traditional, but painful and anxiety provoking, component of therapy. PMID- 24074677 TI - Cardiorespiratory complications after laparoscopic hernia repair in term and preterm babies. AB - PURPOSE: The aim of this study was to clarify the incidence of postoperative complications in infants undergoing laparoscopic hernia repair within the first six months of life. METHODS: Retrospective, single-institution study comparing term and preterm babies undergoing surgery between March 2005 and September 2012. The charts were reviewed for postoperative complications and pre-existing diseases. RESULTS: In the term group 188 of 199 babies (94.5%) had an uneventful postoperative course. Eleven patients (5.5%) presented postoperative complications, three of them (1.5%) developed severe respiratory complications. A relation between pre-existing diseases and postoperative complications could be identified in two patients. Laparoscopy possibly induced cardiorespiratory instability in one infant. In the preterm group 109 of 137 babies (79.6%) had an uneventful postoperative course. 28 preterm infants (20.4%) developed postoperative complications, seven of them (5.1%) presented severe respiratory complications. Pre-existing diseases were identified as an influencing factor in 22 preterm infants. In one patient laparoscopy possibly caused minor instability of a pre-existing cardiac anomaly. CONCLUSIONS: Postoperative complications are low in both groups, although the incidence is increased in preterm infants. Pre existing diseases are a major influencing factor for preterm infants. In very few infants laparoscopy may have induced instability of cardiac anomalies. PMID- 24074678 TI - A unique presentation and rare pathological finding for urachal sinus. AB - We report an otherwise well developing 2-year-old girl who presented with a urachal sinus with its opening located at the midline between umbilicus and the pubic symphysis. Diagnosis was made by ultrasound preoperatively, and confirmed during surgery. Additionally, columnar epithelium was found in the portion of sinus tract traversing the abdominal wall. Metaplasia of the sinus tract is worrisome, as urachal carcinomas have been traditionally characterized to result from this process. PMID- 24074679 TI - Supraumbilical incision with U-u umbilicoplasty for congenital duodenal atresia: the Stockholm experience. AB - BACKGROUND: Minimizing scars has become a major concern in pediatric surgery. Since Tan and Bianchi introduced the minimally invasive umbilical incision for Ramstedt's pyloromyotomy, their technique has been adopted for a variety of neonatal abdominal conditions. The aim of this study was to evaluate a modification of the skin incision. MATERIAL AND METHODS: We have modified Bianchi's original technique to access the abdomen through the linea alba by introducing a novel U-to-u umbilicoplasty and compare the results with the traditional transverse incision. This new approach improves the abdominal access and is easy to perform. RESULTS: The operating time with the U-to-u umbilicoplasty is not longer than in standard transverse laparotomy, the access to the abdomen is more than adequate, the incidence of postoperative complications is similar and the cosmetic results are excellent. CONCLUSIONS: We conclude that the umbilical approach with this novel U-to-u umbilicoplasty to treat congenital duodenal obstruction in the newborn is a safe and effective method and a good alternative to the standard transverse laparotomy approach. PMID- 24074680 TI - Undescended testis: the underlying mechanism and the effects on germ cells that cause infertility and cancer. PMID- 24074681 TI - Reply to letter to the editor. PMID- 24074682 TI - Earthquake correspondence. PMID- 24074683 TI - Longer term effects of closed repair of pectus excavatum on cardiopulmonary status. PMID- 24074684 TI - Reply to letter to the editor. PMID- 24074685 TI - Letter to the editor: gonadal function after childhood ovarian surgery. PMID- 24074686 TI - Reply to letter to the editor: gonadal function after childhood ovarian surgery. PMID- 24074687 TI - Postoperative sleep disruptions: a potential catalyst of acute pain? AB - Despite the substantial advances in the understanding of pain mechanisms and management, postoperative pain relief remains an important health care issue. Surgical patients also frequently report postoperative sleep complaints. Major sleep alterations in the postoperative period include sleep fragmentation, reduced total sleep time, and loss of time spent in slow wave and rapid eye movement sleep. Clinical and experimental studies show that sleep disturbances may exacerbate pain, whereas pain and opioid treatments disturb sleep. Surgical stress appears to be a major contributor to both sleep disruptions and altered pain perception. However, pain and the use of opioid analgesics could worsen sleep alterations, whereas sleep disruptions may contribute to intensify pain. Nevertheless, little is known about the relationship between postoperative sleep and pain. Although the sleep-pain interaction has been addressed from both ends, this review focuses on the impact of sleep disruptions on pain perception. A better understanding of the effect of postoperative sleep disruptions on pain perception would help in selecting patients at risk for more severe pain and may facilitate the development of more effective and safer pain management programs. PMID- 24074688 TI - Magnetic resonance imaging predicts survival and occult metastasis in oral cancer: a dual-centre, retrospective study. AB - The purpose of this study was to investigate the effectiveness of tumour variables measured on magnetic resonance imaging (MRI) to predict 2-year disease related survival and occult cervical lymph node metastasis in oral carcinoma. In this retrospective, dual-centre study the volume and thickness of tumours were measured using archived MRI staging scans of 199 patients who had curative primary resection for histologically confirmed oral carcinoma. Tumour volume predicted survival when grouped using the median (3.0 cm(3), HR 3.41, p 0.005) and first and third quartiles (0.5 cm(3), HR 8.22, p 0.04; 8.0 cm(3), HR 18.6, p 0.005). Tumour thickness predicted survival using a median of 11.0 mm (HR 2.65, p 0.02). Volume predicted occult cervical lymph node metastasis using a median of 3.0 cm(3) (HR 5.02, p<0.001) and quartiles of 0.5 cm(3) (HR 6.92, p=0.01) and 8.0 cm(3) (HR 11.3, p 0.005); thickness predicted it using a median of 11.0 mm (HR 4.39, p 0.002) and quartiles of 4.0 mm (HR 4.33, p 0.06) and 16 mm (HR 11.9, p 0.003). The thickness and volume of tumour measured on MRI may predict 2-year disease-related survival and occult cervical lymph node metastasis in oral cancer. PMID- 24074689 TI - In response to: Umar G, Obisesan O, Bryant C, Rood JP. Elimination of permanent injuries to the inferior alveolar nerve following surgical intervention of the "high risk" third molar. Br J Oral Maxillofac Surg 2013;51(4):353-7. PMID- 24074690 TI - Chicken 7SK promoter drives efficient shRNA transcription with species specificity. AB - To extend the use of RNAi in chicken, we have developed a RNA interference (RNAi) system using a shortened chicken 7SK (ch7SK) promoter. The results stated that the cloned ch7SK promoter includes multiple Oct-1 motifs, SPH domain, PSE and TATA box, without CACCC box. All RNAi groups driven by ch7SK promoter showed significant mean fluorescence intensity (MFI) reduction. In the pch7SK-shEGFP transfected DF-EGFP cell culture, the MFI reduction ratio was smaller than the pmU6-shEGFP did. In the pmU6-shEGFP transfected Vero-EGFP cell culture, the MFI was reduced significantly than the pch7SK-shEGFP did. In summary, the essential part of ch7SK promoter was capable of efficiently expressing shRNAs with relatively different interfering degrees in avian and mammalian cells, respectively. Our results suggest that ch7SK promoter is an efficient alternative to commercially mouse U6 promoter in shRNA expression with chicken cells, and provide references for furthering functional genome analysis and disease resistant breeding in chicken. PMID- 24074691 TI - Elevation of neutrophil gelatinase-associated lipocalin (NGAL) in non-azotemic dogs with urinary tract infection. AB - Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker in humans and dogs with kidney disease. This protein is expressed by many cells including renal tubular cells and neutrophils. The aim of this study was to evaluate the effect of urinary tract infection (UTI) on urinary NGAL (uNGAL) concentration in dogs. Urine culture and measurement of uNGAL level were performed in 80 non-azotemic dogs suspected of UTI and 19 healthy dogs. Dogs were divided in three groups: 19 healthy dogs, 25 dogs with positive culture and 55 dogs suspected of UTI but with negative culture. uNGAL and uNGAL/Creatinine was significantly higher (P < 0.0001) in dogs with UTI (14.22 ng/mL;19.74 MUg/g) compared to Healthy (0.24 ng/mL;0.11 MUg/g) and Negative (1.13 ng/mL;1.28 MUg/g) dogs. A uNGAL value <3.38 ng/mL had a negative predictive value for UTI of 87%. Presence of UTI has to be considered when uNGAL is used to detect kidney disease. PMID- 24074692 TI - Gender, socioeconomic, and ethnic differences in sleep patterns in school-aged children. AB - OBJECTIVES: Age-related changes in sleep behavior are well described in children, yet the effect of gender, socioeconomic status (SES), and ethnicity is less clear. These factors are important when developing culturally and socially appropriate guidelines for healthy sleep. The objective of our study was to examine the effects of age, gender, SES, and ethnicity on sleep patterns in school-aged children. METHODS: A cross-sectional survey was conducted through primary schools in Adelaide, South Australia. Parents reported demographic information and sleep patterns for school and non-school days for 1845 children aged 5 to 10years. RESULTS: 48% of the cohort were boys (mean age, 7.7+/-1.7y), 85% were Caucasian, and there was an equal distribution across defined SES bands. Sleep duration reduced with age and was shorter on non-school than school nights as a result of later bedtimes. Boys, children from low SES areas, and non Caucasian children reported shorter sleep times than girls, children from high SES areas, and Caucasian children, respectively. Non-Caucasian children from low SES areas reported the shortest sleep opportunity. CONCLUSIONS: The results from our study suggest that in addition to biological mechanisms, sleep behaviors are culturally and socially driven and should be considered when developing recommendations for healthy sleep in children. PMID- 24074693 TI - Mild cognitive impairment in rapid eye movement sleep behavior disorder: a predictor of dementia? PMID- 24074695 TI - Propranolol treatment in life-threatening airway hemangiomas: a case series and review of literature. AB - OBJECTIVES: Infantile hemangiomas (IHs) in the airway may be potentially life threatening during the proliferative phase. Available treatments like oral corticosteroids (OCS) and chemotherapeutic agents usually showed variable responses and serious side effects. Propranolol is a new and promising treatment option. METHODS: A case series of five IH patients with airway involvement is presented, supplemented with a review of literature. Propranolol treatment (2.0 3.0mg/kg/day) was initiated between 3 weeks and 6 months of age. Three cases were treated with propranolol monotherapy, 2 cases with OCS primarily and propranolol secondarily, in which treatment with OCS could be reduced rapidly. RESULTS: In our case series a dramatic, fast response was observed in all cases, with a permanent effect after discontinuation in four cases. In one patient a relapse of airway problems occurred two months after discontinuation of propranolol at 16 months of age; this resolved after re-start of propranolol. Review of literature together with these five cases showed 81 patients with airway IHs treated with propranolol. Propranolol was effective in 90% of the cases and seven patients were classified as non-responders. Eight IHs relapsed while weaning of propranolol or after discontinuation; dose adjustment or restart was effective in most cases but one patient appeared resistant to therapy. CONCLUSIONS: Propranolol seems to be a rapidly effective and safe treatment strategy for most IHs obstructing the airway. Because of the fast and important effects of propranolol, randomized controlled trials are hardly justifiable for this specific, relatively rare but, acute treatment indication. Despite the efficacy of propranolol, close monitoring of the patients with an airway IH is required, considering the risk of relapse of symptoms during or after treatment and the reported resistance to propranolol in at least 9% of the published cases. The dose and duration of treatment should be high and long enough to prevent relapse. Further research should focus on the optimal treatment protocol; the actual percentage of non-responders and also the mechanism of resistance to propranolol is unknown and needs to be illuminated. PMID- 24074694 TI - Psychosocial correlates of sleep quality and architecture in women with metastatic breast cancer. AB - BACKGROUND: Sleep disturbance is prevalent among women with metastatic breast cancer (MBC). Our study examined the relationship of depression and marital status to sleep assessed over three nights of polysomnography (PSG). METHODS: Women with MBC (N=103) were recruited; they were predominately white (88.2%) and 57.8+/-7.7 years of age. Linear regression analyses assessed relationships among depression, marital status, and sleep parameters. RESULTS: Women with MBC who reported more depressive symptoms had lighter sleep (e.g., stage 1 sleep; P<.05), less slow-wave sleep (SWS) (P<.05), and less rapid eye movement (REM) sleep (P<.05). Single women had less total sleep time (TST) (P<.01), more wake after sleep onset (WASO) (P<.05), worse sleep efficiency (SE) (P<.05), lighter sleep (e.g., stage 1; P<.05), and less REM sleep (P<.05) than married women. Significant interactions indicated that depressed and single women had worse sleep quality than partnered women or those who were not depressed. CONCLUSION: Women with MBC and greater symptoms of depression had increased light sleep and reduced SWS and REM sleep, and single women had worse sleep quality and greater light sleep than married counterparts. Marriage was related to improved sleep for women with more depressive symptoms. PMID- 24074696 TI - Paediatric adenotonsillectomy as a daycase for obstructive sleep apnoea: how we do it in a tertiary unit. AB - BACKGROUND: Paediatric adenotonsillectomy is a common ENT operation. Daycase surgery for uncomplicated, elective procedures is encouraged in order to improve efficiency in healthcare. For patients with obstructive sleep apnoea (OSA), most units advocate an overnight stay for adenotonsillectomy, a procedure usually performed as a daycase in other contexts. METHODS: A retrospective casenote review was carried out from 1st December 2011 to 1st December 2012 for all children undergoing daycase adenotonsillectomy for treatment of OSA at Bart's Children's and the Royal London Hospital. RESULTS: 250 children underwent adenotonsillectomies for OSA as daycase procedures over twelve months. 6% had immediate, unplanned overnight admissions. 3% were readmitted within 30 days. No patients readmitted required surgical intervention. CONCLUSION: For an appropriately selected child, adenotonsillectomy can be safely performed as a daycase procedure in a tertiary centre. PMID- 24074697 TI - [Esthetic reconstructive surgery of the face. Introduction]. PMID- 24074698 TI - [Percutaneous fasciotomies to improve fat grafting into the breast]. AB - INTRODUCTION: Breast reconstruction or for breast deformities is a difficult challenge to get excellent results. Lipomodeling technique can improve thoracic malformations and breast deformities. Percutaneous fasciotomies can be an excellent tool for recipient site improvement. The aim of this study is to discuss interest of percutaneous needle fasciotomies with fat grafting into breast surgery. MATERIAL AND METHODS: We have realized a retrospective study with fat transfer into the breast surgery. Recipient site prepared fasciotomies during fat grafting surgical procedure. Fat was harvested and centrifugated. Fat was injected into breast reconstructions or thoracic malformations. We did notice: population (age, BMI, uni/bilateral breasts), surgical procedure (mean sessions number, mean fat transfer). Aesthetic aspects of breasts were rated by both surgeon and patient: skin improvement, volume and shape of breast. Each complication was noticed: tissue wounds, scar evolution, hematoma, infection. RESULTS: We started a retrospective study between 2006 and 2011. One thousand patients were treated with fasciotomies and fat grafting during the same procedure. Main indications were breast reconstruction with latissimus dorsi flap, breast implant reconstruction, breast cancer conservative surgeries, tuberous breast and Poland syndrom. Sessions number expected was between 1 and 3. No complication has been noticed, except 1 tissular wound that needed a medical treatment to solve the problem. CONCLUSION: Fasciotomie is an indispensable complement tool for fat grafting. It is a safe and reliable technique. It improves aesthetic outcomes of breast surgery. Main indications of fasciotomies with fat grafting are breast reconstruction with radiation, breast cancer conservative surgery, and tuberous breast. Percutaneous fasciotomies provide excellent aesthetic result with no scar. They improve the shape of the breast with long-standing result. PMID- 24074699 TI - Targeting high-density lipoproteins: update on a promising therapy. AB - Numerous epidemiological studies have demonstrated the atheroprotective roles of high density lipoproteins (HDL), so that HDL is established as an independent negative risk factor. The protective effect of HDL against atherosclerosis is mainly attributed to their capacity to bring peripheral excess cholesterol back to the liver for further elimination into the bile. In addition, HDL can exert other protective functions on the vascular wall, through their anti-inflammatory, antioxidant, antithrombotic and cytoprotective properties. HDL-targeted therapy is thus an innovative approach against cardiovascular risk and atherosclerosis. These pleiotropic atheroprotective properties of HDL have led experts to believe that "HDL-related therapies" represent the most promising next step in fighting against atherosclerosis. However, because of the heterogeneity of HDL functions, targeting HDL is not a simple task and HDL therapies that lower cardiovascular risk are NOT yet available. In this paper, an overview is presented about the therapeutic strategies currently under consideration to raise HDL levels and/or functions. Recently, clinical trials of drugs targeting HDL-C levels have disappointingly failed, suggesting that HDL functions through specific mechanisms should be targeted rather than increasing per se HDL levels. PMID- 24074700 TI - Can fish consumption advisories do better? Providing benefit and risk information to increase knowledge. AB - Humans exposed to methylmercury (MeHg) can suffer from adverse health impacts, e.g., serious neurological damage; however, fish is also a good source of omega-3 fish oils which promotes infants' neurological development. Because eating fish is the primary mechanism of MeHg exposure, federal and state agencies issue fish consumption advisories to inform the public about the risks of eating contaminated fish. An advisory's purpose is to provide information to consumers to increase their knowledge of specific product attributes; however, the difficulty in communicating both the risks and benefits of eating fish leads readers of fish advisories to over-restrict their fish consumption. Because the effectiveness of fish consumption advisories are not often evaluated by states, we help fill this gap by evaluating the effectiveness of Maine's fish consumption advisory in terms of improving knowledge. The results suggest the advisory successfully increased women's knowledge of both the benefits and risks of consuming fish while pregnant. The advisory also increased their ability to differentiate fish by their MeHg content, knowledge of both low and high-MeHg fish and knowledge of detailed attributes of seemingly substitutable goods, such as white tuna, light tuna and pre-packaged salmon. People who did not read the advisory lack the knowledge of how to identify fish that provide: health benefits like Omega-3 fatty acids, or health risks like MeHg; reading the advisory reduces this lack of knowledge. Readers increased ability to make specific substitutions to minimize risk while maintaining the benefits of fish eating suggests the advisory has the potential of reducing MeHg-related health risks while avoiding the drop in fish consumption show in other studies. PMID- 24074701 TI - Effects of stocking rates on gastrointestinal nematode infection levels in a goat/cattle rotational stocking system. AB - Gastrointestinal nematodes (GIN) are increasingly resistant to anthelmintic drugs worldwide, so integrated control methods are more and more needed for the sustainability of small ruminant farming. Such methods rely on knowledge in epidemiology, physiology, and genetics. Ecological studies have highlighted the effect of host density on parasite populations, and in the humid tropics, rotational grazing systems were designed according to the survival of GIN free living stages. This study aimed to assess the effects of mixed stocking and host stocking rate on host GIN infection level. Four groups of 15-17 Creole male kids were raised on irrigated pasture from weaning (about 3 months) until the age of 7 months, at four partial stocking rates (pSR): 100% (control), 75% (G75), 50% (G50), and 25% (G25) of the total stocking rate of the pasture. The last three groups were associated with weaned Creole heifers to obtain the same overall stocking rate as the control. Animals grazed in a 'leader' goat and 'follower' cattle design: the G25, G50, and G75 paddocks were split into six plots; each plot was grazed by goats for 1 week and by heifers the following week. The pasture then rested for 4 weeks before the animals were returned for a new grazing sequence. Five control plots were grazed rotationally for 1 week, and rested for 4 weeks. This design was repeated three times a year for a total of 10 repetitions. Average faecal egg counts (FEC) decreased according to a power function of the pSR: FEC=1829pSR(3.7). The observed death rate decreased significantly with the pSR (27.6%, 16.4%, 11.9%, and 12.2%). The kids grew faster in G25 (51 g d(-1)) than in G50 (43 g d(-1)) and G75 or control (32 g d(-1), p<0.05). Heifers were not significantly infected with GIN and grew normally (about 0.48 kg d(-1)). Reducing the pSR by associating a non-host species in a rotational stocking system may be a very promising component of integrated GIN control, at least for the humid tropics. PMID- 24074702 TI - Who are at risk for thromboembolism after arthroplasty? A systematic review and meta-analysis. AB - BACKGROUND: Thromboembolism, including deep venous thrombosis and pulmonary embolism, is a grave threat to patients undergoing total joint replacement. Using a systematic review and meta-analysis we asked whether gene mutations or polymorphisms could be risk factors for thrombosis after arthroplasty. METHODS: We performed a comprehensive search of Medline, PubMed, Embase, Cochrane databases, China National Knowledge Infrastructure (CNKI), and Google Scholar, and identified 19 studies detailing genetic investigations of patients with thromboembolism following joint replacement. RESULTS: Our meta-analyses included 5149 patients who underwent arthroplasty surgery. Significant associations with venous thromboembolism were identified for factor G1691A (odds ratio (OR) 1.41, 95% confidence interval (CI) 1.03 - 1.94, p=0.03), prothrombin G20210A (OR 2.16, 95% CI, 1.27- 3.69, p=0.005), and MTHFR/C677T/TT (OR 2.36, 95% CI 1.03 - 5.42, p=0.04) in Caucasian populations. No significant gene mutation was identified in Asian populations. CONCLUSION: This study suggests a way to identify patients scheduled for arthroplasty who are at higher risk of thrombosis, enabling individualized treatment. PMID- 24074703 TI - Chemotherapy induces enhanced procoagulant activity through phosphatidylserine exposure in acute lymphoblastic leukemia. AB - INTRODUCTION: Thromboembolism is a serious complication in patients with acute lymphoblastic leukemia (ALL). Coagulation disorders can be induced and worsened by cytotoxic drugs; however, the mechanisms are largely unknown. Our study aims to investigate the effects of daunorubicin (DNR) and L-asparaginase (L-ASP) on phosphatidylserine (PS) exposure and the procoagulant activity (PCA) of Jurkat/ALL cells. The anticoagulant properties of lactadherin were also explored. MATERIALS AND METHODS: Jurkat cells and cells from 10 newly diagnosed patients with ALL were treated with DNR or L-ASP. Flow cytometry and confocal microscopy were used to quantify and locate PS exposure, respectively. PCA was evaluated using coagulation assays and purified coagulation complex assays. Lactadherin, a glycoprotein of the milk fat globule membrane with stereospecific binding to phosphatidyl-L-serine, was used as a probe for the detection of exposed PS. RESULTS: Untreated Jurkat/ALL cells exhibited higher PS exposure and greater PCA than mononuclear cells (MNCs). The PCA of cells treated with DNR or L-ASP was markedly increased. Flow cytometry and confocal microscopy indicated that the increased PCA occurred in parallel with PS exposure. The blocking of PS with lactadherin prolonged the coagulation time and inhibited approximately 85-90% of the activities of procoagulant enzyme complexes in Jurkat/ALL cells. CONCLUSIONS: Our results indicate that DNR and L-ASP increased the PCA of Jurkat/ALL cells through PS exposure and played a critical role in inducing thrombosis in ALL patients. Lactadherin is an ideal probe for PS detection at an early stage and a potential anticoagulant to improve the hypercoagulability of ALL patients. PMID- 24074704 TI - Usefulness of the Kyoto criteria as expanded selection criteria for liver transplantation for hepatocellular carcinoma. AB - BACKGROUND: Previously, we proposed expanded selection criteria for liver transplantation (LT) for hepatocellular carcinoma (HCC), the Kyoto criteria, involving a combination of tumor number <=10, maximal diameter of each tumor <=5 cm, and serum des-gamma-carboxy prothrombin levels <=400 mAU/mL, and we have used these criteria since January 2007. In the present study, the usefulness of the criteria was validated prospectively as well as retrospectively. METHODS: One hundred ninety-eight patients with HCC who underwent living donor LT (LDLT) from February 1999 through December 2011 were enrolled in this study. Overall survival and recurrence rates were investigated in patients classified according to the Kyoto criteria, the Milan criteria, or previous treatments for HCC. Tumor biological aggressiveness, including microvascular invasion and histologic differentiation, according to selection criteria was also examined. RESULTS: The 5-year overall survival for patients within the Kyoto criteria (n = 147; 82%) was greater than that for the 49 patients exceeding them (n = 49; 42%; P < .001). The 5-year recurrence rate for patients within the Kyoto criteria (4.4%) was less than that for patients exceeding them (51%; P < .001). Intention-to-treat analysis of the 62 patients who underwent LDLT after implementation of the Kyoto criteria showed that the 5-year overall survival rate and the recurrence rate were 82% and 7%, respectively. Tumor biology was significantly less aggressive in patients within the Kyoto criteria. CONCLUSION: The Kyoto criteria are useful expanded criteria for LDLT for HCC and could help to achieve favorable outcomes. PMID- 24074706 TI - [Efficacy and safety of peginterferon alfa-2a (40 kd) plus adefovir for 96 weeks in HBeAg-negative chronic hepatitis B patients]. AB - OBJECTIVE: To investigate the efficacy and safety of an extended course (96-week) of combination treatment with peginterferon alfa-2a (Peg-IFNa-2a; 40 kd] plus adefovir (ADV) for treating chronic hepatitis B (CHB) in Chinese patients with negativity for hepatitis B e antigen (HBeAg). METHODS: A total of 25 consecutive patients with HBeAg-negative CHB were administered Peg-IFNa-2a (135-180 mug/week) plus ADV (10 mg/day) for 96 weeks. All patients were followed-up for 24 weeks after treatment completion. Levels of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HbsAg) were measured by fluorescence quantitative polymerase chain reaction (FQ-PCR) and chemiluminescent microparticle immunoassay, respectively, at 12-week intervals throughout the treatment course and at the end of-follow-up (week 120). Patients underwent serological analysis at 3-6 month intervals during treatment and follow-up to evaluate occurrence of adverse events; serological parameters included blood count, markers of liver, kidney and thyroid function, and levels of autoantibodies and creatine kinase. RESULTS: For all patients, the 96-week course of Peg-IFNa-2a plus ADV reduced the level of HBV DNA below the detection threshold (less than 500 copies/ml by FQ-PCR). The overall rate of HBsAg seroconversion was 12% (3/25) at week 48, 28% (7/25) at week 96, and 32% (8/25) at week 120. The occurrences of adverse events were similar at week 48 and week 96. CONCLUSION: The extended-course Peg-IFNa-2a plus ADV combination therapy achieved a 100% virological response and better rates of HBsAg seroconversion than 48 weeks of therapy, without a decrease in safety. PMID- 24074707 TI - [HBeAg seroconversion achieved by sequential peginterferon alfa-2a therapy in chronic hepatitis B patients with unsatisfactory end point following entecavir treatment]. AB - OBJECTIVE: To investigate the efficacy and safety of peginterferon alfa-2a (Peg IFNa-2a) therapy for treating chronic hepatitis B (CHB) in patients who failed to achieve a satisfactory end point with entecavir (ETV) treatment. METHODS: Fifty seven CHB patients with positivity for hepatitis B e antigen (HBeAg) who had completed a standard ETV monotherapy course, of at least 96 weeks, and who had achieved a virological response (defined as HBV DNA less than 500 copies/ml) but without HBeAg seroconversion (defined as 0.227 PEI U/ml less than HBeAg less than or equal to 50 PEI U/ml) were enrolled in the study. The patients were randomly assigned to receive a 48-week treatment with Peg -IFNa-2a (experimental group, n = 27) or continued ETV therapy (control group, n = 30). Serum samples were collected from all patients for assessment of biochemical, virological and serological responses to treatment. Inter-group differences were statistically evaluated by t-test or Chi-squared test. RESULTS: The baseline levels of alanine aminotransferase, hepatitis B surface antigen (HBsAg), and HBeAg were similar between the patients comprising the experimental and controls groups. At treatment week 48, the experimental group showed significantly higher rates of HBeAg clearance (Peg-IFNa-2a: 40.7% vs. ETV: 16.7%, x2 = 4.079, P less than 0.05) and seroconversion (37.0% vs. 13.3%, x2 = 5.110, P less than 0.05). The experimental group also showed higher rates of HBsAg clearance (7.4% vs. 0%) and HBV DNA relapse (11.1% vs. 0%), but the differences did not reach statistical significance (x2 = 2.307 and 3.519, both P more than 0.05). However, the level of HBsAg was significantly lower in the experimental group (2866.0+2580.4 vs. 4335.8+2650.0 IU/ml, t = 5.11, P less than 0.05). CONCLUSION: HBeAg-positive CHB patients with unsatisfactory response to initial ETV monotherapy achieved HBeAg seroconversion and clearance following sequential Peg-IFN a-2a treatment. PMID- 24074708 TI - [Meta-analysis of the efficacy and safety of telaprevir combined with peginterferon alfa plus ribavirin in patients with chronic hepatitis C]. AB - OBJECTIVE: To evaluate the efficacy and safety of telaprevir combined with peginterferon alfa (Peg-IFNa) plus ribavirin (RBV) (collectively, TPR therapy) in patients with chronic hepatitis C (CHC) using a meta-analysis approach. METHODS: The Pubmed literature database was searched for randomized controlled trials of TRP therapy in CHC patients published between 2009 and 2011. The following outcome data was extracted for meta-analysis of efficacy: sustained virological response (SVR), defined as serum HCV RNA of less than 1000 copies/ml at end-of treatment (week 24); rapid virological response (RVR), defined as serum HCV RNA of less than 1000 copies/ml at treatment week 4; recurrence, defined as serum HCV RNA of less than 1000 copies/mL at end-of-treatment and more than 1000 copies/ml at follow-up (week 24 after treatment completion). The pooled odds ratio (OR) or relative risk (RR) were calculated, with 95% confidence interval (CI). Heterogeneity was assessed by the Chi-squared test based on the Q statistic. RESULTS: Six studies of TPR triple therapy, representing a total of 2677 CHC patients, were included in the meta-analysis. Among the 1850 patients who received TPR, 56.3% (n = 1041) achieved RVR, 66.8% (n = 1235) achieved SVR, and 12.1% (n = 176/1460) experienced recurrence. Among the 827 patients who received PR double-therapy, 7.0% (n = 58) achieved RVR, 35.8% (n = 296) achieved SVR, and 32.3% (n = 145/449) experienced recurrence. The TRP group had significantly higher rates of RVR (OR = 29.83, 95% CI: 16.16 to 55.05) and SVR (OR = 3.97, 95% CI: 2.58 to 6.11) than the PR group (both P less than 0.01), and significantly lower rate of recurrence (RR = 0.36, 95% CI: 0.24 to 0.56, P less than 0.01). CONCLUSION: The therapeutic effect of research group is better than that of control group, suggesting that ornithine aspartate combined with naloxone treatment in hepatic encephalopathy is worthy of promoting. PMID- 24074709 TI - [Functional analysis of hepatitis B virus immune escape mutants with insertion mutations in the surface antigen]. AB - OBJECTIVE: To evaluate the influence of insertion mutations occurring in the hydrophobic region, between amino acids 114 and 115, of the hepatitis B surface antigen (HBsAg) on viral antigenicity and replication. METHODS: Hepatitis B virus (HBV) DNA was obtained from patients with HBsAg-positive chronic hepatitis B (CHB) infection and subjected to sequence analysis and comparison to GenBank reference sequences for HBV genotype B (AB073826) and genotype C (AF286594). Insertion mutations detected in the HBsAg region were used to make recombinant expression plasmids via site-directed mutagenesis. After transfecting the recombinant HBsAg into Huh7 cells, the mutants' effects on viral antigenicity and replication were evaluated by chemiluminescence microparticle immunoassay (CMIA) and Southern blot hybridization, respectively. The viral antigenicity of each mutant was predicted by bioinformatic analysis, using the Jameson-Wolf method to predict the antigenic index, the Hopp-Woods method to predict hydrophilicity, the Emini method to predict the probability of a region lying of the protein's surface, and the Karplus-Schulz method to predict the flexibility of the protein backbone. RESULTS: Two CHB patients harbored HBV with insertion mutations in HBsAg: one with two (NT) and one with three (NTT) inserted amino acids between 114 and 115. The NTT recombinant HBsAg mutant showed no impact on viral replication and reacted weakly with anti-HBs in CMIA (P = 0.02). The antigen indices for the insertion of NTT were 1.00, -0.16, and 0.18, and insertion of the three amino acids affected the index values of five proximal amino acid sites (with an average increase of 0.13). The hydrophilic indices for the insertion of NTT were 0.2, -0.4, and -0.4, with no significant effect on the proximal amino acids. The insertion of the three amino acids changed both the surface probability (range: -0.55 to 2.97; affecting eight proximal amino acids) and the flexibility (range: -0.01 to 1.1; affecting five proximal amino acids). CONCLUSION: The NTT three amino acids insertion in the HBsAg open reading frame, between 114 and 115 of the wild-type sequence, detected in a CHB patient may play a role in HBV immune escape without influencing the viral replicative capacity. PMID- 24074710 TI - [Supplemental Fuzhenghuayu capsule therapy for improving liver fibrosis markers in patients with chronic hepatitis B following unsatisfactory outcome of nucleos(t)ide analogue monotherapy]. AB - OBJECTIVE: To investigate the ability of Fuzhenghuayu capsule to improve markers of liver fibrosis when provided as supplemental therapy in patients with chronic hepatitis B (CHB) who achieved complete virological response but unsatisfactory resolution of fibrosis markers with nucleos(t)ide analog (NAs) monotherapy. METHODS: One-hundred-and-ten patients with CHB-related liver fibrosis who had received NA for more than or equal to 2 years and achieved sustained virological response (SVR) but no improvement in liver fibrosis index were randomly divided into two equal groups: experimental group, continued oral NAs (one tablet, 1 time/day) with simultaneous Fuzhenghuayu capsule (1.5 g, 3 times/day) for 48 weeks; control group, continued oral NAs only for 48 weeks. Serum fibrosis markers (hyaluronic acid (HA), laminin (LN), amino terminal propeptide of type III procollagen (PIIIP) and IV collagen (IV-C)), liver fibrosis stages, B ultrasonic wave, and liver function were observed before (baseline) and after treatment and compared by statistical analysis. RESULTS: The baseline levels of fibrosis markers were not significantly different between the experimental and control groups. After treatment, the levels of all of the fibrosis markers were lower in the experimental group (P less than 0.05 vs. control group; HA t = 19.548, LN t = 2.264, PIIIP t = 2.230, and IV-C t = 6.649) and lower than the baseline levels (P less than 0.01; HA t = 12.458, LN t = 7.402, PIIIP t = 4.620, IV-C t = 8.937). The control group also showed a significant reduction in HA and LN levels after treatment (P less than 0.01 vs. baseline; t = 5.202 and 3.444), but PIIIP and IV-C were unaffected. The baseline liver fibrosis stages were not significantly different between the experimental and control groups. After treatment, only the experimental group showed significant improvement in liver fibrosis stages (P less than 0.01). The rates of excellent therapeutic outcome, effectiveness, and non-effectiveness were significantly different between the experimental group (11.3%, 43.4%, and 45.3%) and the control group (1.0%, 22.2%, and 75.6%) (x2 = 9.408, P less than 0.01). Similar trends were observed for improvements in B ultrasonic wave for liver and spleen and in markers of liver function. Finally, neither treatment group experienced adverse effects. CONCLUSION: For CHB patients who achieve SVR by antiviral treatment with NAs, but unsatifactory improvement in liver fibrosis indices, administration of supplemental Fuzhenghuayu capsule with continued NAs therapy may represent a safe and effective treatment. PMID- 24074711 TI - [Aldosterone antagonist inhibits fibrosis-induced NOX4 protein expression in hepatic cells and tissues of rats]. AB - OBJECTIVE: To investigate the inhibitory potential of aldosterone antagonist on NOX4 protein expression in hepatic fibrosis by using a rat model of carbon tetrachloride (CCl4)-induced hepatotoxicity. METHODS: Twenty-four male Wistar rats were randomly divided into three equal groups: fibrosis model group (receiving three subcutaneous injections per week of 2.5 ml/kg 40% CCl4); spironolactone (Sp)-treated fibrosis model group (receiving CCl4 regimen plus three injections per day of 20 mg/kg Sp in olive oil); negative-treatment fibrosis model group (receiving CCl4 regimen plus three injections per day of olive oil alone). Unmanipulated rats (receiving no CCl4 and no supplemental treatments) served as normal controls. After 4 weeks, liver histology was carried out to assess cytotoxicity (by hematoxylin-eosin staining), fibrosis (by Masson staining and METAVIR scoring), and NOX4 protein expression (by immunohistochemistry). In addition, in vitro analyses of immortalized rat hepatic stellate cells, HSC-T6, were performed to evaluate dose-response (10-9, 10-7 and 10-5 mol/L) and time-response (6, 12 and 24 h) of aldosterone agonist (Ald) and an aldosterone antagonist, eplerenone (EPLE). Effects on NOX4 protein expression were evaluated by western blotting. RESULTS: The fibrosis model group showed significantly more fibrosis than the normal control group (16.060 +/- 0.300 vs. 2.471 +/- 0.160, P = 0.000]; however, the Sp-treated fibrosis model group showed significantly less CCl4-induced fibrosis (5.761 +/- 0.152 vs. model: 16.060 +/- 0.300, P = 0.000). The fibrosis model group also showed significantly higher NOX4 protein expression in liver tissues than the normal control group (7.231 +/- 0.211 vs. 1.350 +/- 0.252, P = 0.000), and the Sp-treated fibrosis model tissues showed significantly less CCl4-induced up-regulated NOX4 protein expression (4.270 +/- 0.242 vs. model: 7.231 +/- 0.211, P = 0.000]. Ald induced up-regulated NOX4 protein expression in HSC-T6 cells in dose- and concentration-dependent manners, with the peak expression being induced by the 10-5 mol/L concentration and 24 h exposure. The Ald-treated cells expressed significantly more NOX4 protein than the untreated control cells (0.710 +/- 0.011 vs. 0.316 +/- 0.015, P = 0.000]. and the EPLE-treated cells showed significantly less Ald-induced up regulated NOX4 expression (0.615 +/- 0.014 vs. 0.710 +/- 0.011, P = 0.000]. CONCLUSION: Aldosterone antagonists inhibit the fibrosis-induced NOX4 protein expression in rat hepatic cells. PMID- 24074712 TI - [Role of chemokine CCL28 in hypoxia-induced migration of hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the role of CCL28 in hypoxia-induced cell migration of hepatocellular carcinoma (HCC). METHODS: Resected liver tissues from 50 HCC patients were subjected to real-time (rt)-PCR analysis to evaluate the mRNA expression levels of the hypoxia-induced factor HIF-1a and the chemokine CCL28. Patient data on treatment and outcome were analyzed. The human HCC cell lines HepG2 and HCCLM3 were used to investigate effects of hypoxic conditions on HIF-1a and CCL28 expressions by rt-PCR, western blotting, and enzyme-linked immunoassay. The CCL28-mediated effects of hypoxic conditions on cell mobility and invasion were assessed by trans-well and matrigel assays, respectively, in HCCLM3 with CCL28 expression silenced by small-interfering (si)RNA transfection. Spearman's rank test was used to assess the correlation between CCL28 and effects on disease and treatment-related factors. RESULTS: The mRNA levels of CCL28 (0.025 +/- 0.075) were found to be strongly correlated with HIF-1a(0.065 +/- 0.098) in human clinical samples of HCC (r = 0.595, P less than 0.01), with higher expressions of both related to recurrence after surgery (P = 0.011 and 0.019, respectively). In vitro hypoxic conditions stimulated HIF-1a and CCL28 expression in a time dependent manner in both HepG2 (HIF-1a: F = 873.5; CCL28: F = 151.6) and HCCLM3 (HIF-1a: F = 964.5; CCL28: F = 285.8) (all P less than 0.01). siRNA inhibition of CCL28 in HCCLM3 cells led to a significant reduction in hypoxia-induced invasion and migration (all P = 0.011). CONCLUSION: Chemokine CCL28 expression is up regulated in human HCC and under in vitro hypoxic conditions, and may play an important role in hypoxia-induced HCC migration and invasion. PMID- 24074713 TI - [Aspartate-ornithine granules in the treatment of nonalcoholic steatohepatitis: a multiple-dose parallel controlled clinical trial]. AB - OBJECTIVE: To investigate the therapeutic efficacy and safety of aspartate ornithine granules in patients with nonalcoholic steatohepatitis (NASH). METHODS: Seventy-two patients with NASH were included in this multiple-dose parallel controlled clinical trial and received a 12-week course of aspartate-ornithine granule treatment at either high-dose (6 g bid po; n = 38) or low-dose (3 g bid po; n = 34). Clinical efficacy was assessed by monitoring data from urinalysis, serologic tests (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and triglyceride (TG)), and abdominal computed tomography (CT) scan. Safety was assessed by occurrence of adverse events (fatigue, anorexia, abdominal distension, nausea, and vomiting). Statistical analyses were conducted to determine the significance of differences between parameters before (baseline) and after treatment. RESULTS: After 12 weeks of treatment, the liver and spleen CT ratios in both the high-dose group (0.89 +/ 0.19) and the low-dose group (0.80 +/- 0.15) were significantly higher than at baseline (S = 329, P less than 0.0001 and S = 246, P less than 0.0001); the overall improvement was more robust in the high-dose group (52.63%) than in the low-dose group (38.23%) (Z = -2.1042, P less than 0.05). After 6 and 12 weeks of treatment, the serum ALT levels in both the high-dose group and the low-dose group were significantly lower than at baseline (6 weeks: S = 324.5, P less than 0.0001 and S = 223, P less than 0.0001; 12 weeks: S = 370.5, P less than 0.0001 and S = 297.5, P less than 0.0001); the overall improvement was more robust in the high-dose group (79.0%) than in the low-dose group (53.0%) (Z = -2.0533, P less than 0.05). Similar trends were seen for the serum levels of AST and GGT after 6 and 12 weeks of treatment (all P less than 0.01) and serum levels of TG after 12 weeks of treatment. The rate of adverse reactions was low and similar between the two groups (high-dose: 4.8% and low-dose: 4.4%; all gastrointestinal). CONCLUSION: Aspartate-ornithine granule therapy was an effective and safe treatment of nonalcoholic steatohepatitis, with the higher dose of 6 g bid po providing more robust clinical benefit without affecting the safety profile. PMID- 24074714 TI - [Abnormal expression of miR-let-7b in primary biliary cirrhosis and its clinical significance]. AB - OBJECTIVE: To evaluate the expression of microRNA (miR)-let-7b in peripheral blood cells of patients with primary biliary cirrhosis (PBC) and investigate its relationship to clinical disease parameters. METHODS: Peripheral blood and serum samples were obtained for study from 60 PBC patients and 60 healthy controls. Peripheral blood cells were extracted and subjected to real-time PCR to measure miR-let-7b expression. Serum levels of interleukin (IL)-18, total bilirubin (TBIL), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) were measured by standard biochemical assays. The relationship between miR-let-7b expression and disease parameters was assessed by Spearman's rank correlation test. RESULTS: PBC patients showed significantly lower expression of miR-let-7b in peripheral blood cells than healthy controls (P less than 0.001); moreover, the miR-let-7b expression level decreased in parallel to increases in disease severity (stage I > II / III > IV). In PBC patients, the miR-let-7b expression was significantly correlated with Mayo risk scores (r = -0.4930, P less than 0.001), IL-18 (r = -0.4643, P less than 0.001) and ALP (r = -4119, P less than 0.001), but not with TBIL or GGT. CONCLUSION: Decreased expression of miR-let-7b may be associated with development and progression of PBC, and this miRNA may represent a novel target of improved diagnostic and preventive strategies for PBC. PMID- 24074716 TI - Reconsidering the effects of blue-light installation for prevention of railway suicides. AB - BACKGROUND: A recent preliminary communication suggested that the calming effect of blue lights installed at the ends of railway platforms in Japan reduced suicides by 84%. This estimate is potentially misleading from an epidemiological point of view and is reconsidered in the present study. METHODS: Governmental data listing all railway suicide attempts in Japan from April 2002 to March 2012 were used to investigate the proportion of suicide attempts within station premises, where blue lights are potentially installed, and at night, when they would be lit. For those suicide attempts within station premises, we also estimated the proportion that occurred at the ends of the platforms at night. RESULTS: Of 5841 total reported suicide attempts, 43% occurred within the station premises, 43% occurred at night (from 18:00 to 05:59), and 14% occurred both within the station premises and at night. Of the 2535 attempts within station premises, 32% occurred at night and 28% at most were at the end of a platform at night. LIMITATIONS: The exact proportion of nighttime suicide attempts at the ends of railway platforms was not calculable. Nonetheless, the proportion of suicide attempts that is potentially preventable by blue lights should be less than our conservative estimate. CONCLUSIONS: The installation of blue lights on platforms, even were they to have some effect in preventing railway suicides at night, would have a much smaller impact than previously estimated. PMID- 24074715 TI - [Non-canonical Wnt signaling contributes to development of non-alcoholic steatohepatitis in a rat model of type 2 diabetes mellitus]. AB - OBJECTIVE: To investigate the role of the non-canonical Wnt signaling pathway in development of non-alcoholic steatohepatitis (NASH) related to type 2 diabetes mellitus (T2DM) using a rat model. METHODS: Twenty-four male Sprague-Dawley rats were randomly divided into two equal groups: control group, fed a stand diet; T2DM-NASH model group, fed a high sucrose and fat diet for 4 weeks and intraperitoneally injected with streptozotocin (30 mg/kg). Twelve weeks after model establishment, all rats were sacrificed. Serum levels of glucose, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by biochemical analysis. Liver pathological changes were assessed microscopically by hematoxylin-eosin and oil red O staining. The liver expression of Wnt5a and NF-kB p65 were detected by immunohistochemistry and western blotting (protein), and quantitative real-time PCR (mRNA). RESULTS: The T2DM-NASH model group showed significantly higher levels of glucose (control group: 6.25 +/- 1.28 vs. 31.21 +/ 0.86 mmol/L, t = -36.204, P less than 0.01), ALT (31.00 +/- 3.69 vs. 301.50 +/- 8.62 U/L, t = -99.94, P less than 0.01), and AST (77.58 +/- 1.83 vs. 344.75 +/- 1.82 U/L, t = -358.85, P less than 0.01). The T2DM-NASH group also showed remarkable signs of steatosis and inflammation in hepatic tissues. The T2DM-NASH group had significantly higher integral optical density (IOD) detection of Wnt5a (control group: 1.15E4 +/- 577.45 vs. 4.04E5 +/- 2.42E4, t = -56.24, P less than 0.01) and NF-kB p65 (1.28E4 +/- 1.59E3 vs. 4.21E5 +/- 1.68E4, t = -83.895, P less than 0.01), as well as protein levels detected by western blot (Wnt5a: 4.21 +/- 0.34 vs. 1.00 +/- 0.25, t = 17.030, P less than 0.01; NF-kB p65: 4.93 +/- 0.76 vs. 1 +/- 0.13, t = 11.438, P less than 0.01). The hepatic mRNA levels followed the same trend (Wnt5a: 9.53 +/- 0.64 vs. 1.04 +/- 0.35, t = 20.165, P less than 0.01; NF-kB p65: 0.60 +/- 0.13 vs. 0.74 +/- 0.10, t = -1.802, P = 0.125). In the T2DM-NASH group, hepatic Wnt5a protein expression was positively correlated with ALT (r = 0.64, P less than 0.05), AST (r = 0.59, P less than 0.05), and NF-kB p65 protein expression (r = 0.58, P less than 0.05). CONCLUSION: Wnt5a may activate NF-kB to stimulate an inflammatory response leading to development of NASH related to T2DM. PMID- 24074717 TI - Dissociation of regional activity in the default mode network in first-episode, drug-naive major depressive disorder at rest. AB - BACKGROUND: Major depressive disorder (MDD) is associated with altered neural activity in the default mode network (DMN). In the present study, we used a fractional amplitude of low-frequency fluctuations (fALFF) approach to directly investigate the features of spontaneous brain activity of the DMN in patients with the first-episode, drug-naive MDD at rest. METHODS: Twenty-four first episode, drug-naive patients with MDD and 24 age-, gender-, and education-matched healthy subjects participated in the study. The fALFF and independent component analysis (ICA) approaches were utilized to analyze the data. RESULTS: Patients with MDD exhibited a dissociation pattern of resting-state fALFF in the DMN, with increased fALFF in the left dorsal medial prefrontal cortex (MPFC) and decreased fALFF in the left parahippocampal gyrus (PHG). The increased fALFF values of the left dorsal MPFC were positively correlated to the Hamilton Rating Scale for Depression (HRSD) scores. CONCLUSIONS: Our results first suggested that there was a dissociation pattern of resting-state fALFF in the DMN in patient with MDD, which highlighted the importance of the DMN in the pathogenesis of MDD. PMID- 24074718 TI - Evaluation of soluble CD14 subtype (presepsin) in burn sepsis. AB - BACKGROUND: Diagnosing sepsis is difficult in burn patients because of the inflammatory mediators that alter postburn metabolic profile. Here, we compare a new marker presepsin with procalcitonin (PCT), c-reactive protein (CRP) and white blood cell (WBC) in diagnosis and follow up of sepsis in burn patients. METHODS: Patients admitted to burn center of our institute were prospectively investigated. Presepsin, PCT, CRP and WBC levels were measured at admission and every 6h for first day and daily thereafter. At all timing samples, patients were classified as sepsis or non-sepsis according to the current American Burn Association Consensus Criteria (ABA) 2007. RESULT: 37 adult patients were evaluated. A total data of 611 time points were supplied. Sepsis time points differ significantly from non-sepsis in presepsin (p < 0.0001), PCT (p = 0.0012) and CRP (p < 0.0001) levels. Non-surviving patient results differ significantly from survivors in presepsin (p < 0.0001), PCT (p = 0.0210) and CRP (p = 0.0008). AUC-ROC % values for diagnosing sepsis were 83.4% for presepsin, 84.7% for PCT, 81.9% for CRP and 50.8% for WBC. Sepsis patients had significantly different presepsin, CRP and WBC but not PCT levels on their first day of sepsis compared to previous days. CONCLUSION: Plasma presepsin levels have comparable performance in burn sepsis. PMID- 24074719 TI - A novel rapid and selective enzymatic debridement agent for burn wound management: a multi-center RCT. AB - OBJECTIVES: Excisional debridement followed by autografting is the standard of care (SOC) for deep burns, but is associated with serious potential complications. Conservative, non-surgical and current enzymatic debridement methods are inefficiently slow. We determined whether a non-surgical option of rapid enzymatic debridement with the debriding enzyme NexoBridTM (NXB) would reduce need for surgery while achieving similar esthetic and functional outcomes as SOC. METHODS: We conducted a multi-center, open-label, randomized, controlled clinical trial including patients aged 4-55 years with deep partial and full thickness burns covering 5-30% of their total body surface area (TBSA). Patients were randomly assigned to burn debridement with NXB (applied for 4h) or SOC, which included surgical excisional or non-surgical debridement. RESULTS: NXB significantly reduced the time from injury to complete debridement (2.2 vs. 8.7 days, P<0.0001), need for surgery (24.5% vs. 70.0%, P<0.0001), the area of burns excised (13.1% vs. 56.7%, P<0.0001) and the need for autografting (17.9% vs. 34.1%, P=0.01). Scar quality and quality of life scores were similar in both study groups as were the rates of adverse events. CONCLUSIONS: Enzymatic debridement with NXB resulted in reduced need for and extent of surgery compared with SOC while achieving comparable long-term results in patients with deep burns. TRIAL REGISTRATION: Clinical Trials.gov NCT00324311. PMID- 24074720 TI - Effect of isokinetic training on muscle strength, size and gait after healed pediatric burn: a randomized controlled study. AB - OBJECTIVE: The aim of this study was to investigate the effects of isokinetic training program on muscle strength, muscle size and gait parameters after healed pediatric burn. DESIGN: Randomized controlled trial. SUBJECTS: Thirty three pediatric burned patients with circumferential lower extremity burn with total body surface area (TBSA) ranging from 36 to 45%, and ages from 10 to 15 years participated in the study and were randomized into isokinetic group and a control group. Non-burned healthy pediatric subjects were assessed similarly to burned subjects and served as matched healthy controls. METHODS: Patients in the isokinetic group (n=16) participated in the isokinetic training program for 12 weeks for quadriceps dominant limb, 3 times per week, at angular velocity 150 degrees /s, concentric mode of contraction, time rest between each set for 3 min, 3 sets/day and control group (n=17) participated in home based physical therapy exercise program without isokinetic. MAIN MEASURES: Assessment of quadriceps strength by isokinetic dynamometer, quadriceps size and gait parameters were performed at baseline and at the end of the training period for both groups. RESULTS: Patients in isokinetic group showed a significant improvement in quadriceps strength, quadriceps size and gait parameters as compared with those in the control group. Quadriceps strength and percentage of improvement was 79.25 +/- 0.93 Nm (68.40%) for isokinetic group and 51.88 +/- 1.31 Nm (9.84%) for the control group. Quadriceps size and percentage of improvement was 31.50 +/- 0.89 cm (7.47%) for isokinetic group and 29.26 +/- 1.02 cm (1.02%) for the control group. Stride length, step length, velocity and cadence and percentage of improvement for isokinetic group was 135.50 +/- 2.82 (53.97%), 63.25 +/- 2.97 (63.77%), 135.94 +/- 1.65 (81.42%), 137.63 +/- 1.36 (66.96%) and for the control group was 94.00 +/- 2.69 (6.68%), 43.76 +/- 1.34 (15.15%), 81.11 +/- 1.91 (8.6%), 90.35 +/- 1.32 (9.01%) respectively. CONCLUSIONS: Participation in the isokinetic training program resulted in a greater improvement in quadriceps muscle strength, size and gait parameters in pediatric burn. PMID- 24074721 TI - 1H NMR metabolomics analysis of the effect of dichloroacetate and allopurinol on breast cancers. AB - Metabolomics analysis was used to determine the effect of two well known, non proprietary metabolic modulators, dichloroacetate and allopurinol on breast cancer cell lines. Dichloroacetate, a pyruvate dehydrogenase kinase inhibitor and allopurinol, a xanthine oxidase/dehydrogenase inhibitor, have been previously explored as chemotherapeutics showing potential in some cancer subtypes while at the same time leading to unexpected increase in proliferation in others. In this work, metabolic effects of these drugs, applied singly and in combination, were explored in three different breast cell lines including cancer cells, MDA-MB-231 and MCF-7 and normal control cell line, MCF-10A. The metabolic changes induced by these drugs were monitored by (1)H NMR metabolic profiling. Analyses were performed on complete spectral data as well as quantified metabolic data in intracellular fractions and extracellular media leading to the determination of the most significantly affected metabolites. The effect of dichloroacetate and allopurinol is the most apparent in the metabolic profile of extracellular media. In MCF-7 cells, dichloroacetate treatment is dominant with only a minor observed influence of allopurinol in combined treatment. In MDA-MB-231 cells, both allopurinol and DCA lead to a metabolic shift with the allopurinol change dominating the effect of combined treatment. Results show the power of metabolomics as a tool for fast molecular profiling of drug effects in cells. In summary, treatments of breast cancer cells with DCA and allopurinol result in larger changes in metabolites found in extracellular medium than intracellular pools. PMID- 24074722 TI - Does hormonal control obviate positive airway pressure therapy in acromegaly with sleep-disordered breathing? AB - INTRODUCTION: Acromegaly is a disease in which uncontrolled release of growth hormone occurs after closure of epiphyseal plates, causing changes in the body that can lead to sleep disordered breathing (SDB). No definite guidelines regarding the treatment of SDB in acromegaly are available. In this study, we aimed to investigate the prevalence of SDB in acromegaly and whether hormonal control alters the necessity of positive airway pressure (PAP) therapy in acromegaly patients with SDB. METHODS: Forty-two acromegaly patients were included in the study and divided into two groups according to disease status, i.e., active or well controlled. All patients underwent polysomnography. Fourteen patients with active acromegaly were diagnosed with SDB and were evaluated for PAP therapy with polysomnography both before and 6 months after disease control was achieved. RESULTS: Sleep-disorder breathing was diagnosed in 22 of 42 patients, 7 of 20 patients with controlled-disease and 15 of 20 patients with active diseases. There were significant reductions in respiratory disturbance index (RDI), apnea index, desaturation index, central apnea number, and rapid eye movement-phase RDI at the control polysomnography. Initially, PAP therapy was indicated in 12 of 14 patients and PAP therapy indication held in 11 patients after acromegaly control was achieved. CONCLUSION: Our study revealed that over half of patients with acromegaly had SDB. Furthermore, SDB severity decreases with acromegaly treatment; however, this decrease does not change the indication for PAP therapy; therefore, PAP therapy should not be delayed in acromegalic SDB patients. PMID- 24074723 TI - Combination pharmacotherapy for management of chronic pain: from bench to bedside. AB - Chronic pain, a frequently neglected problem, is treated with different classes of drugs. Current agents are limited by incomplete efficacy and dose-limiting side-effects. Knowledge of pain processing implicates multiple concurrent mechanisms of nociceptive transmission and modulation. Thus, synergistic interactions of drug combinations might provide superior analgesia and fewer side effects than monotherapy by targeting of multiple mechanisms. Several trials in neuropathic pain, fibromyalgia, arthritis, and other disorders have assessed various two-drug combinations containing antidepressants, anticonvulsants, non steroidal anti-inflammatories, opioids, and other agents. In some trials, combined treatment showed superiority over monotherapy, but in others improved benefit or tolerability was not seen. Escalating efforts to develop novel analgesics that surpass the efficacy of current treatments have not yet been successful; therefore, combination therapy remains an important beneficial strategy. Methodological improvements in future translational research efforts are needed to maximise the potential of combination pharmacotherapy for pain. PMID- 24074724 TI - Brain banking for neurological disorders. AB - Brain banks are used to gather, store, and provide human brain tissue for research and have been fundamental to improving our knowledge of the brain in health and disease. To maintain this role, the legal and ethical issues relevant to the operations of brain banks need to be more widely understood. In recent years, researchers have reported that shortages of high-quality brain tissue samples from both healthy and diseased people have impaired their efforts. Closer collaborations between brain banks and improved strategies for brain donation programmes will be essential to overcome these problems as the demand for brain tissue increases and new research techniques become more widespread, with the potential for substantial scientific advances in increasingly common neurological disorders. PMID- 24074725 TI - An uncommon complication following transcatheter aortic valve implantation: contained aortic annulus rupture. PMID- 24074726 TI - Percutaneous pulmonary valve implantation and surgical valve replacement in patients with right ventricular outflow tract dysfunction--a complementary treatment concept. PMID- 24074727 TI - Rapid systemic and local treatments with the antibacterial peptide dimer A3-APO and its monomeric metabolite eliminate bacteria and reduce inflammation in intradermal lesions infected with Propionibacterium acnes and meticillin resistant Staphylococcus aureus. AB - When administered intramuscularly, the designer antibacterial peptide dimer A3 APO is highly efficacious in mouse models of Acinetobacter baumannii and Staphylococcus aureus burn infections. Here we compared the efficacy of A3-APO and its monomeric metabolite in mouse models of S. aureus and Propionibacterium acnes intradermal infections following administration as intramuscular (i.m.) or topical treatments. In the animal models, either (i) the ears of CD-1 mice were infected with P. acnes or (ii) S. aureus was injected into burn wounds inflicted to the back. A3-APO or the monomer were injected intramuscularly at 5 mg/kg one to three times or were applied three times as 1% local treatment in phosphate buffered saline or Vaseline((r)). Despite being inactive against the strains in vitro, in vivo the skin conditions of the mice were dramatically improved upon peptide treatment regardless of dosing frequency, administration mode or drug valency. In the P. acnes study, A3-APO statistically significantly reduced ear thickness and ear bacterial counts. The amount of ear connective tissue and epithelial macrophages correlated with therapeutic success. Bacterial load in the lesions was more representative of physical improvement than ear dimensions. In the S. aureus model, both peptides eliminated wound bacteria from >10(7) CFU/mg to almost background levels, with monomer treatment being somewhat more successful. In conclusion, A3-APO and its monomeric metabolite very efficiently ameliorate resistant aerobic and anaerobic intradermal infections, but the protection is apparently not due to direct bacterial killing. Immunostimulatory and anti-inflammatory actions are likely involved. Nevertheless, topical and i.m. administrations are equally effective. PMID- 24074728 TI - Role of radiation therapy in the conservative management of sarcoma within an irradiated field. AB - PURPOSE: To report on clinical outcome and toxicity profile after combined treatment that included radiation therapy (RT) in patients with localized sarcoma within an irradiated field. PATIENTS AND METHODS: Individual clinical data from all consecutive patients diagnosed and treated for a localized SIF between January 2000 and October 2011 at the Institut Claudius Regaud, Toulouse, France, were retrospectively reviewed. Outcomes of patients with SIF who underwent adjuvant or definitive radiotherapy were compared with patients who did not receive further RT. RESULTS: Of the 27 patients eligible for this study: surgery alone (S), surgery followed by RT (S + RT) or definitive RT (RT) was performed in 16, 8 and 2 cases respectively. The rate of unresectable, gross or microscopically positive margin disease among the 10 re-irradiated patients was significantly higher than the non re-irradiated group (90% vs. 12% p < 0.001). After a median follow-up of 3.8 years, there was a trend toward longer survival and better local control in the subgroup of patients who received adjuvant or definitive RT compared to the rest of the cohort with an acceptable toxicity profile. The 4-year relapse free survival rates of patients treated with and without RT were 53% and 27% respectively (p = 0.09). CONCLUSION: SIF complete surgical resection is often difficult to achieve, enhancing the risk of relapse. RT should be discussed in case of unresectable tumor or after suboptimal surgery as part of intensified local management that has a curative intent. PMID- 24074729 TI - Gait initiation: the first four steps in adults aged 20-25 years, 65-79 years, and 80-91 years. AB - Transitioning from standing to walking requires equilibrium to be maintained while a forward propulsive force is generated. The ability to manage these competing demands is compromised by the progressive sensory, neural and motor declines associated with aging. The purpose of this study was to establish the age-related changes in the first four steps of gait in three age groups: 20-25 years old (yo) (N=19), 65-79 yo (N=11), and 80-91 yo (N=18). Participants stood comfortably and then walked at a self-selected pace for 3.2m. Gait speed and step length (SL) both significantly decreased with each age category at each of the first four steps. However, the gait speed changes suggest that older groups control speed in a principled manner across the four steps, which was similar to the speed control of 20-25 yo. With successive steps, 20-25 yo demonstrated a progressive decrease in SL variability, but SL variability of the two older groups did not change. Step width (SW) did not change as a function of age, but SW variability was higher for the two older groups. Higher SL and SW variability may reflect more errors in foot placement and/or decreased center of mass control in the older groups. Further, it appears that AP COM control improves with successive steps in young adults while ML COM control decreases with successive steps in all age groups. When comparing the two older groups, healthy 80-91 yo walked slower with a shorter SL, but did not demonstrate changes associated with falls (SL and/or SW variability). PMID- 24074730 TI - Functional reach test: movement strategies in diabetic subjects. AB - Functional reach (FR) is a clinical measure, defined as the maximum distance one can reach, forward beyond arm's length, able to identify elderly subjects at risk of recurrent falls. Subjects, exhibiting the same FR can perform the motor task in different ways: a kinematic analysis of the FR, task can help to identify the motor strategy adopted. The FR test was applied to 17 diabetic non-neuropathic, (CTRL) and 37 neuropathic (DN) subjects. Motor strategies adopted were defined as: "hip" or "other" strategy; the latter included: "mixed" and "trunk rotation" strategies. Principal Component Analysis and non-parametric statistical tests were used to study the different execution modalities of the FR test. Results show that, in CTRL, the most important parameters are those related to trunk flexion in the sagittal plane. Instead, for DN, the main features are related not only to trunk flexion but also to trunk rotation in the transverse plane. Percentages of subjects who used "hip" or "other" strategies are similar for CTRL and DN subjects. However, within the "other" strategy group, the percentage of DN that used a "trunk rotation" strategy was much higher than for CTRL. Results show that individuals, although exhibiting the same reaching distance, adopt different movement strategies. Consequently it is important to evaluate the kinematic behaviour and not only the clinical measure, because the evaluation of the motor strategy might be useful in the early detection of subjects at risk of postural instability. PMID- 24074732 TI - Cassandra's prophecy and the trend of delaying childbearing: the paradigm of Greece. PMID- 24074731 TI - Meningitis and legal liability: an otolaryngology perspective. AB - PURPOSE: Meningitis is a potential complication in otolaryngologic procedures and conditions. Severe sequelae make understanding factors involved in relevant malpractice litigation critical. We analyze pertinent litigation for awards, outcomes, patient demographic factors, and other alleged causes of malpractice. METHODS: Pertinent jury verdict and settlement reports were examined using the Westlaw legal database (Thomson Reuters, New York, NY). RESULTS: Twenty-three cases (60.5%) involved non-iatrogenic injuries, including inadequate treatment or failure to diagnose sinusitis or otitis media, while 15 (39.5%) involved iatrogenic cases, mostly rhinologic procedures. 36.8% of cases were resolved for the defendant, 28.9% with juries awarding damages, and 34.2% with settlements. Although not statistically significant, mean damages awarded were higher than settlements ($2.1 vs. 1.5M, p=0.056), and cases involving pediatric patients were more likely to be resolved with payment than those with adult litigants (80.0% vs. 52.2%, p=0.08 respectively). Other frequent alleged factors included permanent deficits (63.2%), requiring additional surgery (41.1%), death (34.2%), cognitive deficits (21.2%), deafness (15.8%), and inadequate informed consent (33.0% of iatrogenic cases). CONCLUSIONS: Practitioners facing litigation related to meningitis may wish to consider these findings, notably for cases involving death or permanent functional deficits, as cases with out of court settlements tended to be resolved with lower payments. Cases involving misdiagnosis may be more likely to be resolved with payment compared with iatrogenic cases. By understanding the issues detailed in this analysis and including them in the informed consent process for patients undergoing rhinologic and otologic procedures, otolaryngologists may potentially improve patient safety and decrease liability. PMID- 24074733 TI - Work and workload of Dutch primary care midwives in 2010. AB - OBJECTIVE: to re-assess the work and workload of primary care midwives in the Netherlands. BACKGROUND: in the Netherlands most midwives work in primary care as independent practitioners in a midwifery practice with two or more colleagues. Each practice provides 24/7 care coverage through office hours and on-call hours of the midwives. In 2006 the results of a time registration project of primary care midwives were published as part of a 4-year monitor study. This time the registration project was repeated, albeit on a smaller scale, in 2010. METHOD: as part of a larger study (the Deliver study) all midwives working in 20 midwifery practices kept a time register 24 hours a day, for one week. They also filled out questionnaires about their background, work schedules and experiences of workload. A second component of this study collected data from all midwifery practices in the Netherlands and included questions about practice size (number of midwives and number of clients in the previous year). FINDINGS: in 2010, primary care midwives actually worked on an average 32.6 hours per week and approximately 67% of their working time (almost 22 hours per week) was spent on client-related activities. On an average a midwife was on-call for 39 hours a week and almost 13 of the 32.6 hours of work took place during on-call-hours. This means that the total hours that an average midwife was involved in her work (either actually working or on-call) was almost 59 hours a week. Compared to 2004 the number of hours an average midwife was actually working increased by 4 hours (from 29 to 32.6 hours) whereas the total number of hours an average midwife was involved with her work decreased by 6 hours (from 65 to 59 hours). In 2010, compared to 2001-2004, the midwives spent proportionally less time on direct client care (67% versus 73%), although in actual number of hours this did not change much (22 versus 21). In 2009 the average workload of a midwife was 99 clients at booking, 56 at the start of labour, 33 at childbirth, and 90 clients in post partum care. CONCLUSION: the midwives worked on an average more hours in 2010 than they did in 2004 or 2001, but spent these extra hours increasingly on non-client-related activities. PMID- 24074734 TI - Autism. AB - Autism is a set of heterogeneous neurodevelopmental conditions, characterised by early-onset difficulties in social communication and unusually restricted, repetitive behaviour and interests. The worldwide population prevalence is about 1%. Autism affects more male than female individuals, and comorbidity is common (>70% have concurrent conditions). Individuals with autism have atypical cognitive profiles, such as impaired social cognition and social perception, executive dysfunction, and atypical perceptual and information processing. These profiles are underpinned by atypical neural development at the systems level. Genetics has a key role in the aetiology of autism, in conjunction with developmentally early environmental factors. Large-effect rare mutations and small-effect common variants contribute to risk. Assessment needs to be multidisciplinary and developmental, and early detection is essential for early intervention. Early comprehensive and targeted behavioural interventions can improve social communication and reduce anxiety and aggression. Drugs can reduce comorbid symptoms, but do not directly improve social communication. Creation of a supportive environment that accepts and respects that the individual is different is crucial. PMID- 24074735 TI - Liver enzymes but not free fatty acid levels predict markers of insulin sensitivity in overweight and obese, nondiabetic adults. AB - Although obesity is a key predisposing risk factor in the development of insulin resistance (IR) and type 2 diabetes mellitus, not all obese individuals develop IR. This study aimed to identify key anthropometric and biochemical parameters that predict insulin sensitivity in overweight and obese adults. Based on previous literature, we hypothesized that markers of insulin sensitivity would be negatively correlated with plasma concentrations of free fatty acids and liver enzymes. Forty nondiabetic adult participants (body mass index >= 25.0 kg/m2) were recruited. Data collection included anthropometric measurements and fasting plasma samples for the quantification of liver enzymes (alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase), blood lipid profile, and markers of insulin sensitivity. Questionnaires relating to dietary intake, physical activity, and fatigue were also completed. Insulin and Homeostasis Model of Assessment (HOMA) scores were significantly correlated with indirect measures of central obesity (P < .05). Glycosylated hemoglobin, insulin, and HOMA scores for IR were all positively correlated with selected liver function markers (P < .05). Scores of HOMA-IR were significantly positively correlated with plasma phospholipid levels of n-3 fatty acids (P = .04) and ratio of n-3/n-6 fatty acids (P < .05) and negatively correlated with n-6 fatty acids (P = .03). No significant correlations were found between markers of insulin sensitivity and cholesterol levels, physical activity, or self-reported fatigue. These results have reinforced the integral role of liver function in the development of IR. Despite previous data linking elevations in free fatty acid to the development of IR, we found no relationship between these variables in this study. PMID- 24074736 TI - Association of adherence to the seventh report of the Joint National Committee guidelines with hypertension in Korean men and women. AB - Whether the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) guidelines can be applied to the Asian population remains unclear. We aim to test the hypothesis that adherence to the JNC-7 guidelines is associated with hypertension in a representative sample of the Korean population in the fourth Korea National Health and Nutrition Examination Survey. Participants completed a non quantitative food frequency questionnaire and 24-hour diet recall through interviews. Blood pressure, height, and weight were directly measured, and questions about physical activity and other lifestyle factors were administered. A total of 500 hypertensive and 4567 normotensive participants were identified. We estimated the odds ratio and 95% confidence intervals using a multivariate logistic regression. The following components of the JNC-7 guidelines were considered: dietary approaches to stop a hypertension style diet, moderate consumption of alcohol, adequate physical activity, and a normal body mass index. Those individuals who fell in the low-risk category for all 4 lifestyle components had an odds ratio of 0.48 (95% confidence interval, 0.30-0.78) compared with the remainder of the participants. In conclusion, we found an inverse association between adherence to the JNC-7 guidelines and hypertension prevalence among Korean adults, suggesting the importance of lifestyle modification for the prevention and management of hypertension. PMID- 24074737 TI - Eating behaviors are risk factors for the development of overweight. AB - This research aimed to characterize eating behavior in a sample of Chilean adults according to their gender and body mass index and to analyze the possible links between these variables and abnormal eating behaviors. We hypothesized that there would be significant differences in the eating behavior of normal-weight and overweight people, and also between men and women. Further, we hypothesized that overweight participants would show more abnormal eating behaviors than their normal-weight counterparts. Two hundred ninety-two participants (205 women and 87 men, age range 18-64 years) were evaluated with a battery of self-administered questionnaires. Mean body mass index was 26.58 kg/m2 (women 26.22 kg/m2, men 27.41 kg/m2), that is, within the overweight range. Participants with overweight (BMI >= 25 kg/m2) tended to eat faster and in greater quantities, selected more hyper-calorie foods, and engaged in a greater number of abnormal eating behaviors of various kinds. The results suggest that, in addition to what people eat, the question of how people eat may also contribute to the rapid increase in the levels of overweight and obesity in the Chilean population. PMID- 24074738 TI - D-aspartic acid supplementation combined with 28 days of heavy resistance training has no effect on body composition, muscle strength, and serum hormones associated with the hypothalamo-pituitary-gonadal axis in resistance-trained men. AB - It was hypothesized that D-aspartic acid (D-ASP) supplementation would not increase endogenous testosterone levels or improve muscular performance associated with resistance training. Therefore, body composition, muscle strength, and serum hormone levels associated with the hypothalamo-pituitary gonadal axis were studied after 28 days of resistance training and D-ASP supplementation. Resistance-trained men resistance trained 4 times/wk for 28 days while orally ingesting either 3 g of placebo or 3 g of D-ASP. Data were analyzed with 2 * 2 analysis of variance (P < .05). Before and after resistance training and supplementation, body composition and muscle strength, serum gonadal hormones, and serum D-ASP and d-aspartate oxidase (DDO) were determined. Body composition and muscle strength were significantly increased in both groups in response to resistance training (P < .05) but not different from one another (P > .05). Total and free testosterone, luteinizing hormone, gonadotropin-releasing hormone, and estradiol were unchanged with resistance training and D-ASP supplementation (P > .05). For serum D-ASP and DDO, D-ASP resulted in a slight increase compared with baseline levels (P > .05). For the D-ASP group, the levels of serum DDO were significantly increased compared with placebo (P < .05). The gonadal hormones were unaffected by 28 days of D-ASP supplementation and not associated with the observed increases in muscle strength and mass. Therefore, at the dose provided, D-ASP supplementation is ineffective in up-regulating the activity of the hypothalamo-pituitary-gonadal axis and has no anabolic or ergogenic effects in skeletal muscle. PMID- 24074739 TI - Fiber from a regular diet is directly associated with fecal short-chain fatty acid concentrations in the elderly. AB - It has recently been suggested that fiber exerts a considerable effect on microbiota composition and on fecal short-chain fatty acid (SCFA) production, the concentration of which in the colon is important for immune regulation and for maintaining gut and overall health. To test the hypothesis that the fiber consumed in a regular diet affects fecal SCFA concentrations in the elderly, the authors investigated the association between different types of fiber intake and fecal SCFA concentrations in 32 institutionalized elderly subjects aged between 76 and 95 years. Food intake was recorded by means of a validated food frequency questionnaire. Total, soluble (pectin and hemicellulose) and insoluble (pectin, hemicellulose, Klason lignin, and cellulose) fiber was determined using Marlett Food Composition Tables. Analysis of acetic, propionic, and butyric acid concentrations was performed using gas chromatography-mass spectrometry. Potato intake was directly associated with SCFA concentrations and apple intake with propionate concentration. Of the fibers, cellulose showed an independent association with acetate and butyrate concentrations, and insoluble pectin explained a part of the variation in propionate. In conclusion, our results provide further evidence regarding the relation between diet and SCFA concentration in the elderly. The identification of an association between the regular intake of foods such as potatoes and the production of SCFAs provides an opportunity to improve public health. PMID- 24074740 TI - Plant extracts of spices and coffee synergistically dampen nuclear factor-kappaB in U937 cells. AB - A large array of bioactive plant compounds (phytochemicals) has been identified and synergy among these compounds might contribute to the beneficial effects of plant foods. The transcription factor nuclear factor-kappaB (NF-kappaB) has been suggested as a target for many phytochemicals. Due to the complexity of mechanisms involved in NF-kappaB regulation, including numerous feedback loops, and the large number of phytochemicals which regulate NF-kappaB activity, we hypothesize that synergistic or antagonistic effects are involved. The objectives of our study were to develop a statistical methodology to evaluate the concept of synergy and antagonism and to use this methodology in a monocytic cell line (U937 expressing an NF-kappaB-luciferase reporter) treated with lipopolysaccharide and phytochemical-rich plant extracts. Both synergistic and antagonistic effects were clearly observed. Observed synergy was most pronounced for the combinations of oregano and coffee, and thyme and oregano. For oregano and coffee the synergistic effect was highest at 5 mg/mL with 13.9% (P < .001), and for thyme and oregano the highest synergistic effects was at 3 mg/mL with 13.7% (P < .001). Dose dependent synergistic and antagonistic effects were observed for all combinations tested. In conclusion, this work presents a methodological tool to define synergy in experimental studies. Our results support the hypothesis that phytochemical rich plants may exert synergistic and antagonistic effects on NF-kappaB regulation. Such complex mechanistic interactions between phytochemicals are likely to underlie the protective effects of a plant-based diet on life-style related diseases. PMID- 24074741 TI - Bioengineered 2'-fucosyllactose and 3-fucosyllactose inhibit the adhesion of Pseudomonas aeruginosa and enteric pathogens to human intestinal and respiratory cell lines. AB - Human milk oligosaccharides help to prevent infectious diseases in breastfed infants. Larger scale testing, particularly in animal models and human clinical studies, is still limited due to shortened availability of more complex oligosaccharides. The purpose of this study was to evaluate 2'-fucosyllactose (2' FL) and 3-fucosyllactose (3-FL) synthesized by whole-cell biocatalysis for their biological activity in vitro. Therefore, we have tested these oligosaccharides for their inhibitory potential of pathogen adhesion in two different human epithelial cell lines. 2'-FL could inhibit adhesion of Campylobacter jejuni, enteropathogenic Escherichia coli, Salmonella enterica serovar fyris, and Pseudomonas aeruginosa to the intestinal human cell line Caco-2 (reduction of 26%, 18%, 12%, and 17%, respectively), as could be shown for 3-FL (enteropathogenic E coli 29%, P aeruginosa 26%). Furthermore, adherence of P aeruginosa to the human respiratory epithelial cell line A549 was significantly inhibited by 2'-FL and 3-FL (reduction of 24% and 23%, respectively). These results confirm the biological and functional activity of biotechnologically synthesized human milk oligosaccharides. Mass-tailored human milk oligosaccharides could be used in the future to supplement infant formula ingredients or as preventatives to reduce the impact of infectious diseases. PMID- 24074742 TI - Modified apple polysaccharides suppress the migration and invasion of colorectal cancer cells induced by lipopolysaccharide. AB - Metastasis is the major cause of death in colorectal cancer (CRC). In colitis associated carcinogenesis, the activation of nuclear factor-kappaB (NF-kappaB) occurs via lipopolysaccharide (LPS) binding to the toll-like receptor 4 (TLR4). The LPS/TLR4/NF-kappaB pathway contributes to the development and metastasis of colitis-associated colon cancer. In the present study, we hypothesized that an extracted modified Fuji apple polysaccharide (MAP) would alter the LPS/TLR4/NF kappaB pathway. Thus, we evaluated the effect of MAP in vitro on the LPS/TLR4/NF kappaB pathway in CRC cells (HT-29 and SW620 cells). The results suggest that (i) MAP competed with LPS for binding to TLR4 to reduce LPS-induced NF-kappaB expression and (ii) MAP suppressed the nuclear translocation of NF-kappaB p65. MAP significantly decreased LPS-induced expression of TLR4, cyclooxygenase-2, matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 2, inducible nitric oxide synthase, and prostaglandin E2, and it increased the protein expression of the inhibitor of kappaBalpha and NF-kappaB p65 in cytoplasm when it was given in combination with LPS. These results indicate that MAP suppressed LPS-induced migration and invasiveness of CRC cells by targeting the LPS/TLR4/NF-kappaB pathway. Therefore, we propose that MAP has potential for the clinical prevention of CRC cell metastasis. PMID- 24074743 TI - A high ratio of dietary n-3/n-6 polyunsaturated fatty acids improves obesity linked inflammation and insulin resistance through suppressing activation of TLR4 in SD rats. AB - Dietary ratios of n-3/n-6 polyunsaturated fatty acids (PUFAs) have been implicated in controlling markers of metabolic disorders, including obesity, insulin resistance (IR), inflammation, and lipid profiles, which are also presumed to be partly related to type 2 diabetes mellitus (T2DM). However, molecular mechanisms of the different PUFAs related to metabolic disorders have not been systematically addressed. The present study aimed to investigate the impact of dietary n-3/n-6 PUFA ratios on obesity and IR and, further, to determine the underlying mechanisms. For 16 weeks, 32 SD male rats, randomly divided into four groups (n = 8 per group), received one of the following diets: normal chow, high saturated fatty acid (SFA), high n-3/n-6 PUFA ratio (1?1, PUFA1:1), or low n-3/n-6 PUFA ratio (1?4, PUFA1:4). Following the experimental diet period, metabolic parameters related to obesity and IR were measured. Compared to SFA diet-fed rats, PUFA1:1 diet-fed rats exhibited decreased body and visceral fat weight, lowered blood lipids, and improved glucose tolerance and insulin sensitivity. Interestingly, these changes were accompanied with decreased expression levels of circulating pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, and C-reactive protein. Moreover, the TLR4 protein and mRNA levels were markedly down-regulated by PUFA1:1 compared with SFA; however, PUFA1:4 diet-fed rats failed to exhibit these changes. Cumulatively, our data highlight a role for a PUFA1:1 diet in the prevention of obesity and related metabolic disorders by suppressing the activation of TLR4, a critical modulator of pro-inflammatory cytokines. PMID- 24074744 TI - Guinea pig ascorbate status predicts tetrahydrobiopterin plasma concentration and oxidation ratio in vivo. AB - Tetrahydrobiopterin (BH4) is an essential co-factor of nitric oxide synthases and is easily oxidized to dihydrobiopterin (BH2) which promotes endothelial nitric oxide synthase uncoupling and deleterious superoxide production. Vitamin C has been shown to improve endothelial function by different mechanisms, some involving BH4. The hypothesis of the present study was that vitamin C status, in particular low levels, influences biopterin redox status in vivo. Like humans, the guinea pig lacks the ability to synthesize vitamin C and was therefore used as model. Seven day old animals (n = 10/group) were given a diet containing 100, 250, 500, 750, 1000, or 1500 ppm vitamin C until euthanasia at age 60-64 days. Blood samples were drawn from the heart and analyzed for ascorbate, dehydroascorbic acid (DHA), BH4 and BH2 by high-performance liquid chromatography. Plasma BH4 levels were found to be significantly lower in animals fed 100 ppm vitamin C compared to all other groups (P < .05 or less). BH2 levels were not significantly different between groups but the BH2-to-BH4 ratio was higher in the group fed 100 ppm vitamin C (P < .001 all cases). Significant positive correlations between BH4 and ascorbate and between BH2-to-BH4 ratio and DHA were observed (P < .0001 both cases). Likewise, BH2-to-BH4 ratio was negatively correlated with ascorbate (P < .0001) as was BH4 and DHA (P < .005). In conclusion, the redox status of plasma biopterins, essentially involved in vasodilation, depends on the vitamin C status in vivo. Thus, ingestion of insufficient quantities of vitamin C not only leads to vitamin C deficiency but also to increased BH4 oxidation which may promote endothelial dysfunction. PMID- 24074745 TI - alpha-Tocopherol, ascorbic acid, and beta-carotene protect against oxidative stress but reveal no direct influence on p53 expression in rats subjected to stress. AB - We hypothesized that alpha-tocopherol, ascorbic acid, and beta-carotene, either applied individually or in combination, would modulate redox homeostasis and affect the regulation of genes involved in DNA repair under stress conditions. To test this hypothesis, we analyzed the influence of these vitamins, either supplied individually or in combination, on the plasma lipid peroxide level and the hepatic level of 8-hydroxy-2'-deoxyguanosine in rats. We also evaluated the expression of p53 and Mdm2 protein in the intestinal epithelium, as these proteins are involved in the cellular regulation of DNA damage repair. Male Wistar rats (n = 112) were supplemented with alpha-tocopherol (2 mg), ascorbic acid (12 mg), and beta-carotene (1 mg), both individually and in combination, for 14 days; 32 control rats were treated with placebo. Half of the animals in each group (n = 8) were subjected to 15-minute treadmill running at 20 m/min to cause exercise-induced oxidative stress. A statistically significant reduction in lipid peroxide levels was observed in the plasma of rats subjected to exercise and given 2 or 3 of the antioxidants (P < .0001). Exercise, as well as coadministration of the antioxidants, had no significant effect on the amount of DNA damage. Downward trends in the level of p53 protein expression were observed both in exercised and nonexercised animals, especially when the studied vitamins were administered in combination. Our findings suggest that alpha-tocopherol, ascorbic acid, and beta-carotene, when given concurrently, have primarily antioxidant effects on lipids under stress but do not significantly affect the regulation of p53 gene expression. PMID- 24074746 TI - Heterogeneity in clinical course of EBV-associated lymphoproliferative disorder after allogeneic stem cell transplantation. AB - OBJECTIVE AND IMPORTANCE: Post-transplant lymphoproliferative disorder (PTLD) is a severe complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) associated with Epstein-Barr virus (EBV). CLINICAL PRESENTATIONS: Among 263 individuals treated with allo-HSCT for severe aplastic anemia, pure white cell aplasia, T-prolymphocytic leukemia, and relapsed Hodgkin lymphoma, we diagnosed EBV-PTLD in 5 patients. Median age was 29 years (range 19-70 years) and four of five patients were EBV-seropositive prior to HSCT. All five had unrelated EBV-positive donors. In all cases, PTLD occurred within the first year post transplant (median 4 months). INTERVENTION: There were two rapidly fatal courses with extensive organ involvement. Both patients showed lymphopenia and thrombocytopenia. In contrast, the three surviving patients had higher lymphocytes and normal platelet counts, while PTLD was restricted to one site and resolved after 2-4 cycles of rituximab. CONCLUSION: In this case series courses of PTLD showed substantial diversity. PMID- 24074747 TI - Taxane-induced pneumonitis: our clinical experience. PMID- 24074748 TI - Repeated Baclofen treatment ameliorates motor dysfunction, suppresses reflex activity and decreases the expression of signaling proteins in reticular nuclei and lumbar motoneurons after spinal trauma in rats. AB - The interruption of supraspinal input to the spinal cord leads to motor dysfunction and the development of spasticity. Clinical studies have shown that Baclofen (a GABAB agonist), while effective in modulating spasticity is associated with side-effects and the development of tolerance. The aim of the present study was to assess if discontinued Baclofen treatment and its repeated application leads antispasticity effects, and whether such changes affect neuronal nitric oxide synthase (nNOS) in the brainstem, nNOS and parvalbumin (PV) in lumbar alpha-motoneurons and glial fibrillary acidic protein in the ventral horn of the spinal cord. Adult male Wistar rats were exposed to Th9 spinal cord transection. Baclofen (30mg/b.w.) diluted in drinking water, was administered for 6 days, starting at week 1 after injury and then repeated till week 4 after injury. The behavior of the animals was tested (tail-flick test, BBB locomotor score) from 1 to 8 weeks. Our results clearly indicate the role of nitric oxide, produced by nNOS in the initiation and the maintenance of spasticity states 1, 6 and 8 weeks after spinal trauma. A considerable decrease of nNOS staining after Baclofen treatment correlates with improvement of motor dysfunction. The findings also show that parvalbumin and astrocytes participate in the regulation of ion concentrations in the sub-acute phase after the injury. PMID- 24074749 TI - Concomitance in single bubble sonoluminescence of period doubling in emission and shape distortion. AB - We report the first direct observation for a single stable sonoluminescing bubble of a shape instability. Furthermore we show that stable saturation of the shape distortion caused by the instability for a certain range of parameters is experimentally possible and furthermore is directly linked to the curious phenomenon of flash by flash period doubling of the sonoluminescent emission as the afterbounce instability causing the shape distortion is always period doubled whenever the emission is & vice versa. PMID- 24074750 TI - Analysis of multiple wavelengths of Lamb waves generated by meander-line coil EMATs. AB - The electromagnetic acoustic transducers (EMATs) with a meander-line coil possess the capability of generating Lamb waves carrying multiple wavelengths, and the characteristics of multiple wavelengths is analyzed by developing a spatial transversal filter model for the EMAT. It is shown that the characteristics is due to the wavelength spectrum of the EMATs, which is a wavelength-domain representation of information about the wavelength components, and the magnitude of each components is modulated by an envelope which depends on the geometric pattern of the meander-line coil. The characteristics of multiple wavelengths might cause the multi-modes phenomenon, therefore a method for removing the effect of multiple wavelengths is proposed. It is shown that the effect can be removed by designing an EMAT which can produce a special envelop to suppress the harmonic wavelengths. Experiments are set up to study the characteristics of multiple wavelengths and verify the validity of the proposed method. PMID- 24074751 TI - Excitation of ultrasonic Lamb waves using a phased array system with two array probes: phantom and in vitro bone studies. AB - Long bones are good waveguides to support the propagation of ultrasonic guided waves. The low-order guided waves have been consistently observed in quantitative ultrasound bone studies. Selective excitation of these low-order guided modes requires oblique incidence of the ultrasound beam using a transducer-wedge system. It is generally assumed that an angle of incidence, thetai, generates a specific phase velocity of interest, co, via Snell's law, thetai=sin(-1)(vw/co) where vw is the velocity of the coupling medium. In this study, we investigated the excitation of guided waves within a 6.3-mm thick brass plate and a 6.5-mm thick bovine bone plate using an ultrasound phased array system with two 0.75-mm pitch array probes. Arranging five elements as a group, the first group of a 16 element probe was used as a transmitter and a 64-element probe was a receiver array. The beam was steered for six angles (0 degrees , 20 degrees , 30 degrees , 40 degrees , 50 degrees , and 60 degrees ) with a 1.6-MHz source signal. An adjoint Radon transform algorithm mapped the time-offset matrix into the frequency-phase velocity dispersion panels. The imaged Lamb plate modes were identified by the theoretical dispersion curves. The results show that the 0 degrees excitation generated many modes with no modal discrimination and the oblique beam excited a spectrum of phase velocities spread asymmetrically about co. The width of the excitation region decreased as the steering angle increased, rendering modal selectivity at large angles. The phenomena were well predicted by the excitation function of the source influence theory. The low-order modes were better imaged at steering angle ?30 degrees for both plates. The study has also demonstrated the feasibility of using the two-probe phased array system for future in vivo study. PMID- 24074752 TI - Aspirin for prophylactic use in the primary prevention of cardiovascular disease and cancer: a systematic review and overview of reviews. AB - BACKGROUND: Prophylactic aspirin has been considered to be beneficial in reducing the risks of heart disease and cancer. However, potential benefits must be balanced against the possible harm from side effects, such as bleeding and gastrointestinal (GI) symptoms. It is particularly important to know the risk of side effects when aspirin is used as primary prevention--that is when used by people as yet free of, but at risk of developing, cardiovascular disease (CVD) or cancer. In this report we aim to identify and re-analyse randomised controlled trials (RCTs), systematic reviews and meta-analyses to summarise the current scientific evidence with a focus on possible harms of prophylactic aspirin in primary prevention of CVD and cancer. OBJECTIVES: To identify RCTs, systematic reviews and meta-analyses of RCTs of the prophylactic use of aspirin in primary prevention of CVD or cancer. To undertake a quality assessment of identified systematic reviews and meta-analyses using meta-analysis to investigate study level effects on estimates of benefits and risks of adverse events; cumulative meta-analysis; exploratory multivariable meta-regression; and to quantify relative and absolute risks and benefits. METHODS: We identified RCTs, meta analyses and systematic reviews, and searched electronic bibliographic databases (from 2008 September 2012) including MEDLINE, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, NHS Centre for Reviews and Dissemination, and Science Citation Index. We limited searches to publications since 2008, based on timing of the most recent comprehensive systematic reviews. RESULTS: In total, 2572 potentially relevant papers were identified and 27 met the inclusion criteria. Benefits of aspirin ranged from 6% reduction in relative risk (RR) for all-cause mortality [RR 0.94, 95% confidence interval (CI) 0.88 to 1.00] and 10% reduction in major cardiovascular events (MCEs) (RR 0.90, 95% CI 0.85 to 0.96) to a reduction in total coronary heart disease (CHD) of 15% (RR 0.85, 95% CI 0.69 to 1.06). Reported pooled odds ratios (ORs) for total cancer mortality ranged between 0.76 (95% CI 0.66 to 0.88) and 0.93 (95% CI 0.84 to 1.03). Inclusion of the Women's Health Study changed the estimated OR to 0.82 (95% CI 0.69 to 0.97). Aspirin reduced reported colorectal cancer (CRC) incidence (OR 0.66, 95% CI 0.90 to 1.02). However, including studies in which aspirin was given every other day raised the OR to 0.91 (95% CI 0.74 to 1.11). Reported cancer benefits appeared approximately 5 years from start of treatment. Calculation of absolute effects per 100,000 patient-years of follow-up showed reductions ranging from 33 to 46 deaths (all-cause mortality), 60-84 MCEs and 47-64 incidents of CHD and a possible avoidance of 34 deaths from CRC. Reported increased RRs of adverse events from aspirin use were 37% for GI bleeding (RR 1.37, 95% CI 1.15 to 1.62), between 54% (RR 1.54, 95% CI 1.30 to 1.82) and 62% (RR 1.62, 95% CI 1.31 to 2.00) for major bleeds, and between 32% (RR 1.32, 95% CI 1.00 to 1.74) and 38% (RR 1.38, 95% CI 1.01 to 1.82) for haemorrhagic stroke. Pooled estimates of increased RR for bleeding remained stable across trials conducted over several decades. Estimates of absolute rates of harm from aspirin use, per 100,000 patient-years of follow-up, were 99-178 for non-trivial bleeds, 46-49 for major bleeds, 68-117 for GI bleeds and 8-10 for haemorrhagic stroke. Meta-analyses aimed at judging risk of bleed according to sex and in individuals with diabetes were insufficiently powered for firm conclusions to be drawn. LIMITATIONS: Searches were date limited to 2008 because of the intense interest that this subject has generated and the cataloguing of all primary research in so many previous systematic reviews. A further limitation was our potential over-reliance on study-level systematic reviews in which the person-years of follow-up were not accurately ascertainable. However, estimates of number of events averted or incurred through aspirin use calculated from data in study-level meta-analyses did not differ substantially from estimates based on individual patient data-level meta-analyses, for which person-years of follow-up were more accurate (although based on less-than-complete assemblies of currently available primary studies). CONCLUSIONS: We have found that there is a fine balance between benefits and risks from regular aspirin use in primary prevention of CVD. Effects on cancer prevention have a long lead time and are at present reliant on post hoc analyses. All absolute effects are relatively small compared with the burden of these diseases. Several potentially relevant ongoing trials will be completed between 2013 and 2019, which may clarify the extent of benefit of aspirin in reducing cancer incidence and mortality. Future research considerations include expanding the use of IPD meta-analysis of RCTs by pooling data from available studies and investigating the impact of different dose regimens on cardiovascular and cancer outcomes. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 24074753 TI - Introduction: Cancer treatment and male fertility: effects of therapy and current and future management options. AB - Cancer treatments are detrimental to spermatogenesis. This series reviews effects of anticancer therapies on male fertility, current and future approaches to determine sperm health, and gives recommendations for patient management. PMID- 24074754 TI - Uterus transplantation. PMID- 24074755 TI - Thin endometrial stripe does not affect likelihood of achieving pregnancy in clomiphene citrate/intrauterine insemination cycles. AB - OBJECTIVE: To determine whether there is a correlation between preovulatory endometrial stripe thickness (EST) and pregnancy rates in clomiphene citrate (CC)/IUI cycles. DESIGN: Retrospective cohort. SETTING: Infertility clinic of an academic medical center. PATIENT(S): A total of 262 patients completed 562 transvaginal ultrasound-monitored CC/IUI cycles from January 2005 through December 2012. INTERVENTION(S): All patients received oral CC. In 362 of the cycles, a single dose of gonadotropin was administered on cycle day 9 (MinStim). A transvaginal ultrasound was performed on cycle day 10, 11, or 12. MAIN OUTCOME MEASURE(S): Pregnancy rate per initiated cycle. RESULT(S): A total of 91 pregnancies ensued, yielding a pregnancy rate of 16.2% per initiated cycle. Pregnancy rates did not vary with EST <6 mm, 6-9 mm, and >9 mm (14.8%, 16.3%, and 19.0%, respectively). There was no significant difference in mean EST between stimulation types (6.8 mm for CC vs. 6.7 mm for MinStim). When conception and nonconception cycles were compared, no difference in mean EST (6.9 mm vs. 6.8 mm, respectively) was observed. Area under the receiver operating characteristic curve for the probability of pregnancy based on EST was 0.51. CONCLUSION(S): Preovulatory EST had no significant correlation with pregnancy rates in CC/IUI cycles. The decision to switch from CC to another treatment strategy should be influenced by factors other than thin endometrial stripe. PMID- 24074756 TI - Delta-like ligand 4 regulates vascular endothelial growth factor receptor 2 driven luteal angiogenesis through induction of a tip/stalk phenotype in proliferating endothelial cells. AB - OBJECTIVE: To explore whether the Dll4/Notch-1 signaling pathway modulates vascular endothelial growth factor (VEGF)-dependent luteal angiogenesis and related function, by inducing a tip/stalk phenotype in endothelial cells (ECs). DESIGN: Experimental laboratory animal study. SETTING: University-affiliated infertility center. ANIMAL(S): Immature female mice. INTERVENTION(S): The presence of leading tip ECs in growing luteal vessel was identified by immunofluorescent analysis of Dll4 in the ovaries of hormonally stimulated female mice. The effects of Dll4 inhibition on luteal vessels functionality and related corpus luteum function were assessed by administering a Dll4 blocking antibody or placebo to hormonally stimulated female mice. MAIN OUTCOME MEASURE(S): Alteration of the tip/stalk phenotype was identified by immunofluorescence analysis of luteal vascular density, Dll4, Notch-1, and VEGF receptor 2 expression. Lectin perfusion was used to assay blood vessel functionality, whereas apoptosis and P levels were quantified to determine the effects on luteal function. RESULT(S): Expression of Dll4 was restricted to the tip of growing vessels. Inhibition of Dll4 signaling promotes promiscuous Dll4 expression, leading to increased, but paradoxically, nonfunctional vascularization, which was associated with decreased P levels. CONCLUSION(S): The Dll4/Notch-1 signaling pathway has a modulatory role in VEGF-dependent luteal angiogenesis and related function through induction of a tip/stalk phenotype. PMID- 24074757 TI - Reply of the authors. PMID- 24074758 TI - Microsurgical subinguinal varicocelectomy with testicular delivery. AB - OBJECTIVE: To demonstrate our approach to the microsurgical subinguinal varicocelectomy with testicular delivery. DESIGN: An instructional video demonstrating the surgical procedure in a step-by-step manner, highlighting useful surgical techniques. SETTING: Not applicable. PATIENT(S): Patients with male factor infertility. INTERVENTION(S): After appropriate patient selection and counseling, varicocelectomy is performed with a subinguinal approach utilizing the surgical microscope. The patient is under general anesthesia and we employ an operating microscope. The patient is positioned supine. MAIN OUTCOME MEASURE(S): Not applicable. RESULTS: A 2.5-cm subinguinal incision was made and the testicle was then delivered. Through the operating microscope at 10-20X magnification, internal spermatic veins were identified and ligated. Smaller veins were taken with electrocautery. The testicular artery was identified using the microdoppler probe. We employ hydrodissection in identifying and isolating the testicular artery. The spermatic cord is then repeatedly examined until no veins other than deferential veins remain. The gubernaculum is also thinned sufficiently so that veins on both sides can be identified and ligated. Testicular delivery was performed and external spermatic veins as well as gubernacular veins ligated. CONCLUSION(S): Varicoceles are found in up to 15% of all men, and in up to 40% of infertile men. Varicoceles have negative effects on testicular function. Varicocelectomy improves testicular function and may halt the accelerated rate of decline in testicular function associated with varicoceles. Sperm parameters, serum testosterone levels, and pregnancy rates have all been shown to improve following varicocelectomy. Use of the operating microscope, the microdoppler probe, and black and white sutures aid in efficiency. Testicular delivery is useful to ligate external spermatic veins as well as gubernacular veins. PMID- 24074759 TI - Accuracy of a home-based device for giving an early estimate of pregnancy duration compared with reference methods. AB - OBJECTIVE: To assess a home pregnancy test's accuracy to concurrently detect pregnancy and determine pregnancy duration. DESIGN: Multicenter, prospective study. SETTING: Study sites in the United States. PATIENT(S): Women actively attempting to conceive who have menstrual bleeds (18-45 years). INTERVENTION(S): Volunteers collected early morning urine samples (three or fewer menstrual cycles). Pregnant volunteers underwent ultrasound dating scans. Ovulation day (LH surge +1 day) during pregnancy-resulting cycles was determined by quantitative measurement of LH. Random urine samples were tested with the hCG-measuring pregnancy test from 4 days before the expected period until 4 weeks later. MAIN OUTCOME MEASURE(S): A home pregnancy test's accuracy in determining pregnancy duration compared with ultrasound and ovulation day. RESULT(S): Agreement between pregnancy test results and time since ovulation was 93% (confidence interval [CI], 91.5-94.4). Agreement with ultrasound was dependent on the formula: there was 99% agreement when calculated with adjustment for Hadlock formula bias (Pexsters; CI, 98.2-99.4) or using a nonbias formula (Wu; CI, 98.6-99.6), when ultrasound error was accommodated. Agreement was lower when bias/measurement errors were not accounted for (Wu, 86%, CI, 83.9-88; Hadlock, 80.8, CI, 78.2 83.3). CONCLUSION(S): This home pregnancy test provides an accurate estimation of pregnancy duration in weeks categories, 1-2, 2-3, 3+ weeks since ovulation, thereby showing utility in dating pregnancy. PMID- 24074760 TI - Mobile technologies and communication strategies in an urban Midwifery Group Practice setting. An exploratory study. AB - BACKGROUND: Around-the-clock access to a known midwife is a distinct feature of Midwifery Group Practice (MGP) and caseload midwifery settings; although the literature suggests this aspect of working life may hinder recruitment and retention to this model of care. Mobile technologies, known as mHealth where they are used in health care, facilitate access and hence communication, however little is known about this area of midwifery practice. RESEARCH QUESTION: Which communication modalities are used, and most frequently, by MGP midwives and clients? METHODS: A prospective, cross sectional design included a purposive sample of MGP midwives from an Australian tertiary maternity hospital. Data on modes of midwife-client contact were collected 24h/day, for two consecutive weeks, and included: visits, phone-calls, texts and emails. Demographic data were also collected. FINDINGS: Details about 1442 midwife-client contacts were obtained. The majority of contact was via text, between the hours of 07:00 and 14:59, with primiparous women, when the primary midwife was on-call. An average of 96 contacts per fortnight occurred. CONCLUSION: The majority of contact was between the midwife and their primary clients, reiterating a key tenet of caseload models and confirming mobile technologies as a significant and evolving aspect of practice. The pattern of contact within social (or daytime) hours is reassuring for midwives considering caseload midwifery, who are concerned about the on-call burden. The use of text as the preferred communication modality raises issues regarding data security and retrieval, accountability, confidentiality and text management during off-duty periods. The development of Australian-wide guidelines to inform local policies and best practice is recommended. PMID- 24074761 TI - Lumbosacral arthrodesis for neuromuscular scoliosis using a simplified Jackson technique. AB - Treating patients with severe neuromuscular scoliosis by long spinal fusion improves their quality of life and provides significant comfort for the patient and caregivers. But lumbosacral (L5-S1) fusion is challenging in these patients because of the significant deformities that result in poor bone anchoring quality and a risk of impingement between the skin and implants. In 1993, Jackson described a L5-S1 fusion technique using S1 pedicle screws and intrasacral rods (implanted under X-ray guidance) that are linked to the construct above with connectors. The goal of this study was to evaluate the clinical and radiological results and the postoperative complications of a simplified version of this technique, which does not require connectors or X-ray guidance. MATERIALS AND METHODS: Thirty-three patients were evaluated with a minimum follow-up of 4years (average 82months). Frontal balance, sagittal balance, Cobb angle, sacral slope, lumbar lordosis and lateral pelvic tilt in the frontal plane were assessed on preoperative, postoperative and follow-up X-rays. Intraoperative and postoperative complications were recorded. RESULTS: Complete fusion was obtained in 32 patients. The average Cobb angle was 62 degrees initially and was reduced to 20 degrees after surgery and 24 degrees at the final follow-up. The average lateral pelvic tilt was 10.3 degrees (0 to 26 degrees ) initially; it was surgically corrected to an average of 7.5 degrees (0 to 24 degrees ); the average secondary loss of correction was 1.2 degrees (0 to 9 degrees ). The sacral slope was corrected to an average of 11.2 degrees ; an average of 0.2 degrees had been lost at the last follow-up (0 to 18 degrees ). Although the average for lumbar lordosis was unchanged, the standard deviation went from 29 degrees to 16 degrees after the corrective surgery and 17 degrees at the last follow-up, with large cluster of measurements around the average value of 40 degrees . The deformity correction was comparable to the results with other techniques (Galveston, sacroiliac screws); the complication rate was similar but the non-union rate was lower. This simplified Jackson technique appears to be an effective, simple method for L5-S1 fusion to correct neuromuscular scoliosis as it provides stable results over time. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 24074762 TI - Pelvic sacral and hemi lumbar spine resection of low grade pelvic chondrosarcoma: a multistage procedure involving vascular bypass, spine fixation and vascular exclusion. AB - Peripheral chondrosarcoma is a rare tumor particularly insidious when arising from the pelvis, becoming symptomatic later in time when surgery may be too difficult and dangerous due to this complex area. In the present case, the tumor arose from an exostosis located on the medial surface of the left iliac wing. Its diameter was 25 cm * 20 cm * 15 cm, adhering to the last three vertebrae, involving the left iliac vein and artery, displacing the left ureter. In a similar case, a hindquarter amputation is indicated but, if the patient refuses, a resection remains possible. In this paper, we describe a multistage technique consisting of an extra-anatomic vascular bypass, a lumbar stabilization, a neurovascular bundles anterior isolation and a postero-lateral resection of this mass. After a five-year follow-up, the patient is alive and able to stand and walk with support, after undergoing twice lung metastasis removal. PMID- 24074763 TI - Adjuvant 5-flurouracil, alpha-interferon and interleukin-2 versus observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma: results of a phase III randomised European Organisation for Research and Treatment of Cancer (Genito-Urinary Cancers Group)/National Cancer Research Institute trial. AB - BACKGROUND: The purpose of this trial was to compare adjuvant 5-flurouracil, alpha-interferon and interleukin-2 to observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma (RCC) in terms of disease free survival, overall survival and quality of life (QoL). PATIENTS AND METHODS: Patients 8weeks post nephrectomy for RCC, without macroscopic residual disease, with stage T3b-c,T4 or any pT and pN1 or pN2 or positive microscopic margins or microscopic vascular invasion, and no metastases were randomised to receive adjuvant treatment or observation. QoL was assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-30 (QLQC 30). Treatment delivery and toxicity were monitored. The trial was designed to detect an increase in 3year disease free survival (DFS) from 50% on observation to 65% on treatment (hazard ratio (HR)=0.63) with 90% power and two-sided alpha=0.05. RESULTS: From 1998 to 2007, 309 patients were randomised (155 to observation; 154 to treatment). 35% did not complete the treatment, primarily due to toxicity (92% of patients experienced ?grade 2, 41% ?grade 3). Statistically significant differences between the arms in QoL parameters at 2months disappeared by 6months although there was suggestion of a persistent deficit in fatigue and physical function. Median follow-up was 7years (maximum 12.1years). 182 patients relapsed or died. DFS at 3years was 50% with observation and 61% with treatment (HR 0.84, 95% confidence interval (CI) 0.63-1.12, p=0.233). 124 patients died. Overall survival (OS) at 5years was 63% with observation and 70% with treatment (HR 0.87, 95% CI 0.61-1.23, p=0.428). CONCLUSIONS: The treatment is associated with significant toxicity. There is no statistically significant benefit for the regimen in terms of disease free or overall survival. PMID- 24074765 TI - The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients. AB - INTRODUCTION: Sentinel node (SN) biopsy (SNB) and completion lymph node dissection (CLND) when SN-positive have become standard of care in most cancer centres for melanoma. Various SN tumour burden parameters are assessed to determine the heterogeneity of SN-positivity. The aim of the present study was to validate the prognostic significance of various SN tumour burden micromorphometric features and classification schemes in a large cohort of SN positive melanoma patients. METHODS: In 1539 SN-positive patients treated between 1993 and 2008 at 11 melanoma treatment centres in Europe and Australia, indices of SN tumour burden (intranodal location, tumour penetrative depth (TPD) and maximum size of SN tumour deposits) were evaluated. RESULTS: Non-subcapsular location, increasing TPD and increasing maximum size were all predictive factors for non-SN (NSN) status and were independently associated with poorer melanoma specific survival (MSS). Patients with subcapsular micrometastases <0.1mm in maximum dimension had the lowest frequency of NSN metastasis (5.5%). Despite differences in SN biopsy protocols and clinicopathologic features of the patient cohorts (between centres), most SN parameters remained predictive in individual centre populations. Maximum SN tumour size>1mm was the most reliable and consistent parameter independently associated with higher non-SN-positivity, poorer disease-free survival (DFS) and poorer MSS. CONCLUSIONS: In this large retrospective, multicenter cohort study, several parameters of SN tumour burden including intranodal location, TPD and maximum size provided prognostic information, but their prognostic significance varied considerably between the different centres. This could be due to sample size limitations or to differences in SN detection, removal and examination techniques. PMID- 24074764 TI - Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. AB - BACKGROUND: The new generation anti-androgen enzalutamide and the potent CYP17 inhibitor abiraterone have both demonstrated survival benefits in patients with metastatic castration-resistant prostate cancer (CRPC) progressing after docetaxel. Preliminary data on the antitumour activity of abiraterone after enzalutamide have suggested limited activity. The antitumour activity and safety of enzalutamide after abiraterone in metastatic CRPC patients is still unknown. PATIENTS AND METHODS: We retrospectively identified patients treated with docetaxel and abiraterone prior to enzalutamide to investigate the activity and safety of enzalutamide in a more advanced setting. Prostate specific antigen (PSA), radiological and clinical assessments were analysed. RESULTS: 39 patients with metastatic CRPC were identified for this analysis (median age 70years, range: 54-85years). Overall 16 patients (41%) had a confirmed PSA decline of at least 30%. Confirmed PSA declines of ?50% and ?90% were achieved in 5/39 (12.8%) and 1/39 (2.5%) respectively. Of the 15 patients who responded to abiraterone, two (13.3%) also had a confirmed ?50% PSA decline on subsequent enzalutamide. Among the 22 abiraterone-refractory patients, two (9%) achieved a confirmed ?50% PSA decline on enzalutamide. CONCLUSION: Our preliminary case series data suggest limited activity of enzalutamide in the post-docetaxel and post-abiraterone patient population. PMID- 24074766 TI - Molecular epidemiology characterization of OXA-23 carbapenemase-producing Acinetobacter baumannii isolated from 8 Brazilian hospitals using repetitive sequence-based PCR. AB - The typing of multidrug-resistant Acinetobacter baumannii isolates is important for the control and prevention of hospital outbreaks. This study aimed to analyze the molecular epidemiology of 46 OXA-23 carbapenemase-producing A. baumannii strains and compare them to previously described local and international clones (ICs). Isolates were recovered during May 2009-August 2011, from 8 different hospitals in the state of Parana (Brazil). The molecular profiles were determined by repetitive extragenic palindromic PCR. Seven different clusters were identified (A to G). Thirty-two isolates were clustered in the same pattern (clone A), which belong to IC 4. PMID- 24074767 TI - Better agreement between independent assessors of three-dimensional global longitudinal strain of whole right ventricle using transthoracic echocardiography than for other three-dimensional right ventricular parameters. PMID- 24074768 TI - Oncoplastic and reconstructive surgery of the breast. AB - INTRODUCTION: Oncoplastic surgery has been widely developed during the last decade. The combination of a large tumor resection performed by the breast surgeon and the immediate breast reconstruction by the plastic surgeon has numerous advantages. This technique provides safer resection with larger margins and immediate aesthetic results. MATERIALS & METHODS: During the last decade, we have used an algorithm in oncoplastic surgery: Small and moderate size breast tumors (T1-2) are considered the best indications for conserving breast surgery. Depending on the breast size and tumor/breast size relation, determinesthe reconstructive technique is used. A glandular flap, as a part of breast reduction techniques, was raised from the breast itself to fill defects after tumorectomy in large-size breast. However, contralateral breast reduction is necessary to achieve breast symmetry. In the case of smaller breast size, partial breast reconstruction is performed using pedicled flaps (LD or muscle sparing LD, TDAP, LICAP, SAAP) harvested from the back and/or the axillary region. Adequate symmetry is obtained without operating on the contralateral breast. Adjuvant radiotherapy can be started after 4-6 weeks postoperatively. RESULTS: In total 119 patients, in whom bilateral breast remodeling techniques and pedicled flaps were used in 26 and 93 patients respectively. In three cases, margins were involved with the tumor. Wider excision was done in two patients. Total mastectomy was performed in the third patient. With an average follow-up of 4 years, further surgery was indicated in only three patients because of fat necrosis. Converting to total mastectomy with immediate breast reconstruction with a DIEAP flap was necessary in one patient at 2 years after the initial partial breast reconstruction with a TDAP because of major fat necrosis. Aesthetic results and patient satisfaction are promising, however, longer follow up is still required to confirm our 4-year-follow-up outcome. CONCLUSION: Oncoplastic surgery offers a better cosmetic outcome as partial breast reconstruction, using various techniques, when performed during the same procedure. In partial breast reconstruction, therapeutic mammaplasty techniques offer creative options for large and pendulous breast. On the other hand, perforator flaps, which spare latissimus dorsi muscle function, provide valuable method for small size breasts. PMID- 24074769 TI - Personalizing extent of breast cancer surgery according to molecular subtypes. AB - The molecular subtype of breast cancer is the major determinant of the type of systemic therapy, but less attention has been paid to the impact of subtype on local therapy outcomes. Presenting features of breast cancer vary with hormone receptor status, with triple negative cancers being significantly less likely than hormone receptor positive cancers to have nodal metastases, and HER2 overexpressing cancers being more likely to be multifocal or multicentric and to have an extensive intraductal component. The risk of local recurrence varies with subtype as well, with triple negative cancers having the highest risk of local recurrence after both breast-conserving therapy and mastectomy, indicating that bigger surgery does not overcome bad biology. PMID- 24074770 TI - Who should not undergo breast conservation? AB - Optimal local control is one of the three main aims of breast cancer treatment (next to optimal regional control and reducing the risk of distant relapses by adequate systemic treatments). To this end, many women desire breast conservation provided local control is comparable to that of ablative procedures, the cosmetic outcome is good and side effects of treatment are limited. To achieve this delicate balance the following should be part of the information to the patient with an operable breast cancer: Patients should have an open discussion with there care providers to enable a shared decision: this will lead to less anxiety and stress with the best satisfaction and recovery. The possibility of breast conservation should always be explored. Even with equal local control and survival outlook, quite a minority (about 20%) of patients opt for ablative procedures (with or without breast reconstruction). Higher risk of local relapse (i.e. persistent cancer growth in the breast) is associated with higher risk of distant disease and subsequent risk of dying of breast cancer. Rough estimates indicate that for every four local relapses one patient may die from breast cancer due to persistent disease. This estimate may vary substantially with the type of cancers (see dr. Morrow), age at diagnosis, application and duration of systemic treatments. To limit the negative effect on overall survival through local relapses, it is generally accepted that for early breast cancer local relapse rates should be within the limit of 1% per year, or within 10% at 10 years. Current population based overviews and hospital based studies show that the risk of local relapse after breast conservations are very well below this limit, being around 2-3% at 5 years. There is no absolute risk threshold of local relapse incidence above which breast conservation is absolutely contra indicated: this will remain an individual decision. Oncoplastic procedures should widely be available to adjust to the width of the local excision and to improve cosmetic outcome. In larger cancers, the option of neo-adjuvant chemotherapy must be considered: about one-third of "mastectomy candidates" can be conversed to an oncologically safe breast conservation. The most important independent risk factors for a breast relapse are: more than focally incomplete margins (roughly 2 times increased risk), young age (<35 years, 2 times increased risk) no radiotherapy (2-4 times increased risk). These risk factors again may also be influenced by the biological type of breast cancer. Combination of risk factors should be added: e.g. young women (<35 years) who had breast conservation for DCIS without radiotherapy may face 15 years breast relapse rate of over 40%. In aggregate, in the following clinical situations the increased risk of breast relapse should be extensively discussed with the patient and breast conservation should be executed with caution: Very young women (<35 years) Extensive DCIS (heralded by extensive microcalcifications) mounting up to one quarter of the breast, particularly in women under 40 years of age. More than focally incomplete resection of an invasive or in situ cancer. Radiotherapy cannot be given. The following factors should, as it stands, not be considered as a contra indication for breast conservation:multi-focal breast cancer, multi-centric breast cancer, the location of the cancer in the breast (including retro areola location), vascular invasion and lobular histology. All with the provision that by the breast conserving surgery complete margins a good cosmetic outcome should be achieved. PMID- 24074771 TI - Close/positive margins after breast-conserving therapy: additional resection or no resection? AB - The primary goal of breast conserving surgery or mastectomy is the prevention of recurrent breast cancer. The distinguishing goal of breast conserving surgery is preservation of a breast as normal in appearance as possible. If the margins of the excised breast cancer extend to the border of the excised specimen one cannot determine the amount of gross tumor that was not excised. Retrospective analyses of surgical series show a 2-3 fold increase in local recurrence of the breast tumor if the margin is positive under the microscope, even when the surgeon believed it to be clear on gross examination. This fact has led to a variety of techniques attempting to ensure that the margins of the excised specimen are free of obvious tumor including pre-operative and specimen imaging and mapping, neo adjuvant therapy to shrink the primary tumor, touch-prep and frozen section of the specimen margins during the procedure, shaving additional margins about the specimen at the closest aspects grossly or on all six surfaces, and examinations of the in situ walls of the remaining breast with new instrumentation. An obvious approach to diminishing the likelihood of positive specimen margins is taking a wider margin of normal tissue. As the volume of resected breast increases by the cube of the radius of excised tissue, this tracks all too well with diminishing cosmetic results and patient approval of the conserved breast. The question posed regards the finding of a positive or close margin after the surgical procedure. The finding of a positive margin can be parsed to a microscopic focus of tumor at the margin vs. the margin inking on a tumor surface. The latter demands re excision despite the morbidity involved barring an extraordinary contra indication or patient refusal. It represents the very real possibility of sufficient residual gross tumor in the breast that even with systemic therapy and breast irradiation the tumor will be un-controlled. A microscopic focus separated from the bulk of the primary tumor and adjacent to a margin has not been shown to carry such risk. The margin of normal tissue beyond the primary tumor that significantly reduces the risk of local recurrence remains undefined. Sufficient data are available to say that in the era of systemic therapy, excellent radiation therapy techniques, and boost doses when indicated, no margin of normal breast tissue beyond the tumor has been shown to be clearly superior to a layer of cells between the ink and the tumor. The larger the tumor and the more aggressive its biology is judged to be the lower the confidence that a single layer of cells at the point of histologic study accurately represents a clear margin. As in all medical decisions wise judgment must integrate all of the known factors to reach the best recommendation. There are few circumstances that would warrant a second surgical procedure for a close but clear margin today. PMID- 24074772 TI - Is regional nodes radiotherapy an alternative to surgery? AB - Sentinel node biopsy (SN) in breast cancer treatment was introduced in the mid 1990s in order to be able to stage patients before decision of definitive surgery. Since then, both the pathological examinations of the SN and the systemic adjuvant treatment have improved and cause new challenges in the correct decision making regarding whether or not to radically treat the axilla in case of a positive SN. In SN positive patients, current St. Gallen guidelines support no completion ALND (axillary lymph node dissection) in clinically node-negative patients with 1-2 macrometastatic sentinel nodes operated with breast conservation and receiving tangential field adjuvant radiotherapy (RT). ALND is being questioned due to increased morbidity compared with SN biopsy alone, and to limited long term benefit on disease free survival in selected patients. An alternative to ALND is treating the axilla with nodal RT although this treatment is mostly used as adjuvant treatment after ALND in high risk patients. Few studies have investigated the benefit of nodal RT compared to ALND, and no consensus has yet been reached. Clinical decision making regarding treating the axilla should be based on relevant data, and in this review studies aiming at deciding whether or not and how the axilla should be treated in SN positive patients will be discussed. Furthermore treatment choice will be discussed, since besides ALND, both breast irradiation and nodal irradiation might cure residual disease after SN. Also the issue of improved systemic adjuvant treatment will be discussed in relation to eventually no regional axillary treatment. PMID- 24074773 TI - Hypofractionation in the era of modulated radiotherapy (RT). AB - The use of radiation therapy (RT) as a component of breast-conserving therapy (BCT) has been shown to reduce the risk of local-regional recurrence and improve overall survival. As has been the common practice in the United States and Continental Europe, the majority of studies that demonstrated these benefits utilized daily radiation doses ranging from 1.8 to 2.0 Gray (Gy) per day given for approximately 5 weeks. However, due to geographic limitations, patient preferences, and financial considerations, there have been continued attempts to evaluate the efficacy and safety of abbreviated or hypofractionated courses of whole-breast radiation. Two key factors in these attempts have been: 1) advances in radiobiology allowing for a more precise estimation of equivalent dosing, and 2) advances in the delivery of RT ('modulation') that have resulted in substantially improved dose homogeneity in the target volume. Hypofractionated schedules have been compared to conventional radiation courses in several randomized controlled trials, as well as many prospective and retrospective experiences. These studies, now with about 10 years of follow-up, have demonstrated equivalent rates of local-regional recurrence, disease-free survival, and overall survival. The rates of toxicity have generally not been increased with hypofractionated regimens; however, certain toxicities may take decades to manifest. The generalizability of these results is unclear, as the majority of patients in the trials were elderly with early-stage hormone-receptor positive disease. Nevertheless, there is now sufficient evidence to recommend hypofractionated whole breast RT for a substantial percentage of patients. PMID- 24074774 TI - Partial breast irradiation: targeting volume or breast molecular subtypes? AB - The eligibility criteria for partial breast irradiation (APBI) are mainly based on histopathological factors, which not always explain the clinical behaviour of breast cancers. International guidelines represent useful platform to collect data for continued refinement of patient selection, but the clinical applicability to APBI series showed some limitations, particularly among the intermediate and high-risk groups. The heterogeneity of APBI techniques, along with the heterogeneity of breast cancer, generates clinical results, where the predictive value of the histopathological factors can assume different weight. There is a need of further refinement and implementation of risk factors. Currently, the impact of breast cancer subtype on local control is matter of investigation, and treatment decision about radiotherapy is generally made without regard to the breast cancer subtype. However, receptor status information is easily available and some histopathological factors have not a definite role, there is no uniform interpretation. As molecular classification becomes more feasible in the clinical practice, it will provide added value to conventional clinical tumour characteristics in predicting local recurrence in breast cancer and may play an important role as predictor of eventual patient outcomes. PMID- 24074775 TI - Partial breast re-irradiation for local recurrence of breast carcinoma: Benefit and long term side effects. AB - INTRODUCTION AND AIMS: To evaluate the outcome after partial breast re irradiation for in-breast tumor recurrence (IBTR) following second breast conserving surgery (BCS) as alternative to salvage mastectomy. METHODS AND RESULTS: A survey of the literature was performed including publications between 2002 and 2012 (PubMed). Strategies comprised partial breast radiotherapy by external beam radiotherapy (EBRT), interstitial brachytherapy (BT) in low-, high- and pulse-dose rate technique, combined EBRT/BT, and intraoperative radiotherapy (IORT). Published evidence is scarce, with altogether ten articles identified, in sum reporting about 310 patients. The vast majority (82%) was treated by brachytherapy. Selection criteria for a second breast conservation attempt were comparable within all reports: all women presented with T0-2 recurrent lesions, late onset after primary treatment (70 months, mean of means) and no evidence of metastatic disease before undergoing gross tumor resection with free surgical margins. Treatment doses were in a similar range for brachytherapy (LDR 30-55 Gy, HDR 30-34 Gy; PDR 40-50 Gy), biologically comparable to the only series exclusively using EBRT (50 Gy). Follow-up times amounted 49 months (mean of the means, range 21-89). Oncologic results were similar among the different methods with local control rates ranging between 76% and 100%, and disease free and overall survival rates comparable to mastectomy series. Acute toxicity was low in all cohorts. All authors reported cosmetic outcome, scoring results from excellent to good in 60-80% of patients, mostly without using standardized evaluation schemes. Major late effects were fibrosis in re-irradiated parenchyma as a function of dose and volume, asymmetry (primarily due to double surgery), and breast pain. There were hardly any G3 and no G4 late reactions noted. DISCUSSION AND CONCLUSION: In a highly selected group of patients with IBTR, partial breast irradiation after second BCS is a viable alternative to mastectomy, yielding high breast preservation rates without compromising oncologic safety. Whereas the evidence for brachytherapy is more solid, there is still little information about the effectiveness of PBI via EBRT or novel strategies like IORT, which therefore should preferably be investigated within trials. PMID- 24074776 TI - Patients with triple negative breast cancer: is there an optimal adjuvant treatment? PMID- 24074777 TI - Selecting the neoadjuvant treatment by molecular subtype: how to maximize the benefit? AB - The relationship between achievement of a pathologic complete response (pCR) and favorable long-term outcome varies among breast cancer subtypes. We aimed to highlight which neoadjuvant treatment strategy could be most successful in each breast cancer subtype. A recent FDA meta-analysis on randomized neoadjuvant breast cancer trials suggests that the survival differences of patients with or without a pCR were less pronounced in luminal A-like tumors, despite the overall favorable prognosis of these patients. Moreover, even though the strong prognostic effect of pCR in HER2 positive and TNBC, the NOAH study was the only trial which showed a trend in surrogacy of pCR for long-term outcome in HER2 positive subtype. Results from GeparTrio study suggest that patients with hormone positive tumors might need a response-guided approach, with either an intensification of treatment in case of an early response or a change to other chemotherapy in case of no early response. Furthermore, data from German neoadjuvant trials confirm that an increasing number of chemotherapy cycles is associated with a higher pCR rate, especially in patients with HER2 positive/hormone-positive tumors. In line with these suggestions, Tryphaena study showed a pCR rate that exceeding the 60% threshold, the highest pCR results presented in a large multicenter study. In TNBC, the highest pCR rate in the German neoadjuvant studies was obtained with the simultaneous application of docetaxel, doxorubicin and cyclophosphamide for 6 cycles. However, as shown in GaparQuinto and NSABP 40 trials, treatment effect in TNBC might be further maximized by adding bevacizumab, and two randomized neoadjuvant trials are expected this year to report data on the efficacy of carboplatin. PMID- 24074778 TI - Trastuzumab for patients with HER2 positive breast cancer: delivery, duration and combination therapies. AB - With the exception of endocrine therapy, no other systemic treatment of patients with breast cancer has reached such a magnitude of beneficial effect as trastuzumab. This targeted agent (monoclonal antibody) is associated with a significant improvement in both disease-free (DFS) and overall survival (OS) in women with HER-2 positive breast cancer when given in combination with or in sequence to adjuvant chemotherapy. This has been confirmed in a recent Cochrane meta-analysis of randomized controlled trials (RCTs), including 6 adjuvant and 2 neoadjuvant studies (NSABP B-31, NCCTG N9831, BCIRG 006, HERA, FinHer, PACS-04, Buzdar and NOAH), with data collection until February 2010. Overall, mortality is reduced by one-third and the risk of relapse by 40%. Concerns regarding cardiac dysfunction are declining, with reports indicating its reversibility in most instances, however truly long term cardiac evaluation is still lacking. Hence, the benefit of trastuzumab could be challenged by cardiac toxicity, in lower-risk patients [T1a,b node-negative (N0) tumors] or those with increased cardiovascular risk (older women and patients with previous significant heart disease/suboptimal left ventricular ejection fraction [LVEF (<55%)], all of whom were largely excluded from the aforementioned adjuvant RCTs. These patient subgroups might warrant a specific approach, such as anti-HER2 treatment combined with just a taxane (avoiding anthracyclines) or with endocrine therapy. Reasonably large phase II trials aimed at exploring these more individualized regimens are underway in the US. The optimal duration of trastuzumab therapy remains unknown since the selection of the one year duration in the pivotal trials was arbitrary. The HERA trial showed that prolonging trastuzumab administration to two years does not confer additional advantage over one year. The PHARE trial compared 6 versus 12 months of trastuzumab and failed to show non-inferiority of the shorter treatment administration. At the present time, one year of adjuvant trastuzumab remains the standard-of-care until results from SOLD, Short-HER and PERSEPHONE consolidate or negate this finding. The route of trastuzumab administration has also been recently challenged. A subcutaneous formulation is being evaluated in several studies. The HannaH phase III trial compared the subcutaneous (SC) to the intravenous (IV) formulation of trastuzumab. The former was proven non-inferior to the latter, although the incidence of serious adverse events was slightly higher in the SC arm. The authors concluded that SC trastuzumab, administered at a fixed dose of 600mg over 5min, is a valid alternative option, with the potential for human and economic savings in clinical practice. PMID- 24074779 TI - Follow-up tests to detect recurrent disease: patient's reassurance or medical need? AB - It is widely believed by both doctors and patients that regular follow-up with imaging is important for patients who have been treated for early breast cancer. In reality, current evidence does not support this. Randomised trials have shown no benefit for intensive versus routine follow-up and studies have also shown that follow-up by a general practitioner or nurse specialist is likely to be as effective as by a breast cancer specialist. Specifically there is no evidence that specialised imaging including PET/CT is of any benefit. Newer approaches including the assessment of circulating tumour cells and/or circulating tumour DNA may eventually prove advantageous, but currently must be considered experimental. In summary, current evidence suggests that there is no basis for intensive follow-up beyond standard regular clinical assessment and annual mammography following treatment of early breast cancer. There may be better models for follow-up than the traditional resource-intensive hospital outpatient visit, including nurse-led open access follow-up. Monitoring for long-term sequelae of treatment is becoming as important as the detection of recurrence in an era where long-term survival is increasingly common. PMID- 24074780 TI - Extended adjuvant chemotherapy in endocrine non-responsive disease. AB - INTRODUCTION AND AIMS: There is a biological rationale for expecting benefit from longer duration therapy in the subpopulation of patients with endocrine non responsive disease. Such tumors have a rapid cell proliferation and are associated with a high risk of relapse despite adjuvant chemotherapy. Moreover, prolonged duration of chemotherapy may be particularly relevant for patients with triple negative disease to inhibit the growth of tumors that are not susceptible to the effects of endocrine therapies due to lack of steroid hormone receptors, or to the effects of anti-HER2 target treatment. METHODS AND RESULTS: The question of duration of adjuvant chemotherapy for breast cancer has been directly addressed in several trials herein presented. Most of these were small and, therefore, unsuitable for detecting differences of modest magnitude in intrinsic biological subtypes. In addition, a number of trials examine regimens which differ in duration of therapy, but also in the drugs given. In these trials the effects of duration and choice of drug are inextricably confounded. However incremental chemotherapy strategies, compared with less extensive therapies, were more effective in past studies particularly in patients with endocrine non responsive disease. CONCLUSIONS: The evidence resulting from past trials indicates that conventional-dose chemotherapy for 4-6 months is an adequate option in patients whose tumors present a low or no expression of steroid hormone receptors. These tumor subtypes are part of a highly heterogeneous subgroup (e.g., basal-like, molecular apocrine, claudin-low, HER-enriched). Tailored research through international cooperation is key to solidify consensus on how to treat individual patients with endocrine non-responsive breast cancer. PMID- 24074781 TI - Optimal systemic therapy for premenopausal women with hormone receptor-positive breast cancer. AB - Although systemic therapy is one of the cornerstones of therapy for premenopausal women with early stage breast cancer, there remain many unknowns regarding its optimal use. By accident of clinical trial design, much clinical investigation in premenopausal women has focused on chemotherapy. More recently the value of endocrine therapy (tamoxifen and ovarian suppression/ablation via surgery, LHRH agonists, or chemotherapy-induced menopause) has become apparent, and some form of endocrine therapy is viewed as standard for virtually all premenopausal women with early stage invasive breast cancer that expresses estrogen and/or progesterone receptor. Critical open questions include type and duration of endocrine therapy and the development of prognostic/predictive markers to help identify patients who are likely to benefit from chemotherapy in addition to endocrine therapy. For some years, five years of tamoxifen has been viewed as the standard endocrine therapy for premenopausal hormone-responsive breast cancer, although the ATLAS trial suggests that an additional five years of tamoxifen can be considered. The MA17 trial also suggests that an additional five years of an aromatase inhibitor can be considered for women who become postmenopausal during tamoxifen therapy. Information about the value of ovarian suppression continues to emerge, most recently with the demonstration of excellent outcome with goserelin plus tamoxifen in the ABCSG12 trial. The SOFT and TEXT trials, whose accrual is now complete, should help to define optimal endocrine therapy. In addition, use of the 21-gene recurrence score assay may help to delineate the additional value of chemotherapy for patients with node-negative breast cancer, and its utility in the setting of women with 1-3 positive lymph nodes is under study in the RxPONDER trial. Nonetheless, the need for other predictive biomarkers to select appropriate therapy remains real. Finally, attention to long term benefits and side effects of therapy will continue to be vital for these young women. PMID- 24074782 TI - Extended adjuvant endocrine therapy in hormone-receptor positive breast cancer. AB - A high ongoing recurrence rate in patients with endocrine responsive breast cancer provides the rationale for offering endocrine treatment for more than five years. The MA.17 study, comparing the aromatase inhibitor (AI) letrozole for five years after an initial five years of tamoxifen to no further treatment, provided the proof-of-principle for extended endocrine treatment. These results have meanwhile been confirmed by several other studies and an EBCTCG meta-analysis. More recently, data from the ATLAS trial, comparing 10 to five years of tamoxifen, have been published, similarly showing a benefit for longer endocrine treatment with tamoxifen. In postmenopausal women -including those who had been premenopausal at initial diagnosis - a cross-trial comparison of ATLAS and the AI studies indicates superiority of switching to letrozole versus ongoing tamoxifen, similar to superiority of the AIs over tamoxifen in the metastatic and early breast cancer settings. PMID- 24074783 TI - Management of breast cancer in very young women. AB - Breast cancer is the leading cause of cancer-related deaths in women age 40 and younger in developed countries, and although generally improving, survival rates for young women with breast cancer remain lower than for older women. Young women are more likely to develop more aggressive subtypes of breast cancer and previous research has suggested that young age is an independent risk factor for disease recurrence and death, and there may be unique biologic features of breast cancer that occurs in young women. Certainly, there are host differences biologically as well as psychosocially that affect the management of breast cancer and survivorship concerns for young women compared to older women. Multi-agent chemotherapy and biologic therapy targeting the tumor similar to the treatment in older women is standard, with careful attention to unique survivorship concerns including genetics, infertility, and psychosocial issues. Select young women will do well with hormone therapy only, although at present, the optimal hormonal therapy for very young women remains unclear. Recent data demonstrating that 10 years of tamoxifen improves outcomes compared to 5 may be particularly beneficial for young women with hormone receptor-positive tumors given the risk benefit profile. Future and ongoing studies focused on breast cancer in young women, addressing both biology as well as psychosocial issues, including supportive care interventions should improve outcomes for young women with breast cancer. PMID- 24074784 TI - Postmenopausal women with hormone receptor-positive breast cancer: balancing benefit and toxicity from aromatase inhibitors. AB - Extensive clinical trial experience is available for aromatase inhibitors (AIs) in postmenopausal women upon which to evaluate the balance of potential benefit and toxicities. A meta-analysis revealed an advantage for AIs over tamoxifen in the monotherapy setting for recurrence but not breast cancer mortality, and an advantage in both of these parameters for switching to an AI after several years of tamoxifen. Importantly, no indication of a deleterious effect of AIs was identified in terms of death without recurrence in these meta-analyses. Regarding serious adverse events (AEs), there are data indicating an increase in cardiovascular AEs and bone fractures but a lower incidence of thromboembolic phenomena and endometrial cancer with AIs vis-a-vis tamoxifen. There does not appear to be a difference in cerebrovascular AEs. Musculoskeletal AEs are the most common clinically important AEs as they are the most common cause of discontinuation of therapy, which can have an adverse effect on outcomes. The balance of benefit and toxicity favors the use of AIs in the adjuvant setting but the absolute benefit from AIs can be decreased in patients with advancing age or increasing comorbidities. PMID- 24074785 TI - Mutational analysis of breast cancer: guiding personalized treatments. AB - The application of high throughput techniques to profile DNA, RNA and protein in breast cancer samples from hundreds of patients has profoundly increased our knowledge of the disease. However there remain many knowledge gaps that will require a long process of extended clinical correlation studies, deeper integrated 'omic analysis and functional annotation to address. This article reviews conclusions from recent breast cancer 'omics profiling' papers and considers pathways forward for extracting medically valuable information from large dimension data sets. PMID- 24074786 TI - From genome to bedside: are we lost in translation? AB - The preceding decade has seen a remarkable technical explosion resulting in an entirely new field designated as "omics". A committee convened by the United States Institute of Medicine (IOM) has defined omics as "characterization of global sets of biological molecules such as DNAs, RNAs, proteins, and metabolites". The IOM report has established a roadmap for translating a newly discovered signature that emerges from an omics-based exploratory study to a true, analytically valid test that has both clinical validity and clinical utility for a specific intended use. This roadmap requires a multi-disciplinary team with expertise in the technical aspects of high-throughput assay development, bioinformatics, clinical test development, and clinical research and statistics. The investigative team should follow one of the pathways laid out by the IOM committee to establish clinical utility of an analytically validated omics-based test, and therefore acceptance by regulatory and guideline bodies: Prospective retrospective studies, or prospective studies in which the omics based test is the primary objective of the trial itself. Although developed for omics-based tests, these concepts are applicable to any diagnostic test used to direct care of patients with cancer. These pathways are rigorous, and therefore not easily accomplished. However, if we are to apply these tests to direct management of our patients, we must approach the science of biomarker development with the same rigor that is used for therapeutic agent assessment. A "Bad Tumor Marker Is as Bad as a Bad Drug". PMID- 24074787 TI - p53 in breast cancer subtypes and new insights into response to chemotherapy. AB - Despite an obvious central role of p53 in the hallmarks of cancer, TP53 status is not yet used for the management of breast cancer. Recent findings may lead to reconsider the role of p53 in breast cancer. TP53 mutations are the most frequent genetic alterations in breast cancer, observed in 30% of breast carcinomas. Their distribution is highly linked to molecular tumor subtypes found in 26% of luminal tumors (17% of luminal A, 41% of luminal B), in 50% of HER2 amplified tumors, in 69% of molecular apocrine breast carcinomas and in 88% of basal-like carcinomas. The type of mutation is linked to the tumor subtype with higher frequency of base pair substitutions in luminal tumors, whereas molecular apocrine and basal-like tumors present much higher frequency of complex mutations (deletions/insertions). The timing of TP53 mutation also depends on the tumor subtype, being the first important event in luminal tumors but occurring after PTEN loss in basal-like tumors. Regarding response to cytotoxic chemotherapy, the situation is far from the p53-dependent apoptosis paradigm with subsequent clinical response. We reported that TP53 mutated non inflammatory locally advanced breast carcinomas had a high rate of complete pathological response to dose-dense doxorubicin cyclophosphamide chemotherapy, while TP53 wild-type (WT) tumors never achieved complete response. Using human breast cancer xenograft models, we suggested that this could be due to the induction of senescence in TP53 WT tumor cells. A recent work confirmed these findings in MMTV-Wnt1 mammary tumors, showing that growth arrest and senescent phenotype, not apoptosis, were induced in TP53 WT tumors following doxorubicin treatment, while lack of arrest in mutant tumors resulted in aberrant mitoses, cell death and a superior clinical response. Furthermore, in ER positive (ER(+)) breast tumors, it has been recently reported that ER represses the p53-mediated apoptotic response induced by DNA damage. Taken together, these data can help to better understand p53-mediated response to doxorubicin-based chemotherapy in breast cancer: in ER(+) TP53 WT breast cancers, ER-induced inhibition of p53 apoptotic response would lead preferentially to tumor cell senescence and subsequent resistance to treatment. Conversely, in ER negative (ER(-)) TP53 mutated breast cancers, accumulation of genetic abnormalities would lead to mitotic catastrophe and subsequent better response. In view of these recent results, p53 impact in breast cancer should be reconsidered. PMID- 24074788 TI - Personalized adjuvant therapies: lessons from the past: the opening address by the St. Gallen 2013 award recipient. AB - For several decades, personalized adjuvant therapies have been prescribed based on features that predict response to specific types of treatment. In this summary four specific issues regarding adjuvant therapies are described. Each one developed using information from past experience and is ready to be challenged by future findings from clinical trials and maturation of follow-up data. 1) Accuracy of determination of steroid hormone receptors and of HER2-status was the key feature in International Breast Cancer Study Group (IBCSG) and Breast International Group (BIG) trials. 2) Investigations on ovarian function suppression in IBCSG clinical trials led to the design of two trials (SOFT and TEXT), which are likely to lead to improved adjuvant therapy for premenopausal women with breast cancer. 3) Data from the BIG 1-98 trial of letrozole vs tamoxifen for postmenopausal patients with endocrine-responsive breast cancer provided information on which patients might obtain increased benefit from aromatase inhibitors and which might achieve similar treatment outcome with tamoxifen alone. 4) Finally, low-dose, frequently administered cytotoxics (metronomic chemotherapy) were tested in advanced disease with surprisingly favorable disease control and very low incidence of side effects. Personalized treatments are likely to improve substantially with increasingly accurate determination of their targets and by using risk- and toxicity-modulated therapies. PMID- 24074789 TI - Nutrition and physical activity influence on breast cancer incidence and outcome. AB - INTRODUCTION AND AIMS: To provide a current perspective on nutrition and physical activity influence on breast cancer. METHODS AND RESULTS: A comprehensive literature review was conducted and selective presentation of findings follows. While some observational studies have associated higher dietary fat intake with higher breast cancer incidence, two full-scale randomized, clinical trials of dietary fat intake reduction programs were negative. However, a lifestyle intervention targeting fat intake reduction in the Women's Intervention Nutrition Study (WINS), resulted in weight loss and also reduced breast cancer recurrences in women with early stage disease. Observational studies evaluating specific nutrient intakes and dietary supplements have provided mixed results. Several observational studies find women with early stage breast cancer with lower 25 hydroxyvitamin D levels at higher recurrence risk, a finding requiring cautious interpretation. The lifestyle factor most strongly and consistently associated with both breast cancer incidence and breast cancer recurrence risk is physical activity. A meta-analyses of observational studies supports the concept that moderate recreational physical activity (about 3-4 h walking per week) may reduce breast cancer incidence and that women with early stage breast cancer who increased or maintain their physical activity may have lower recurrence risk as well. Feasibility of achieving increased physical activity and weight loss in women with early-stage breast cancer has been established. Two full-scale randomized clinical trials are evaluating weight loss/maintenance and increased physical activity in relation to recurrence risk in women with early-stage, resected breast cancer. DISCUSSION/CONCLUSIONS: Dietary intake may influence breast cancer but influence is difficult to separate from influence of body weight. A consistent body of observational study evidence suggests higher physical activity has favorable influence on breast cancer incidence and outcome. While awaiting definitive evidence from ongoing randomized trials, breast cancer patients can reasonably be counseled to avoid weight gain and reduce body weight if overweight or obese and increase or maintain a moderate level of physical activity. PMID- 24074790 TI - Sex hormones and breast cancer risk and prognosis. AB - The study of large prospective collections of plasma samples from women prior to the development of breast cancer has firmly established certain sex steroids as being significantly associated with risk. The strongest associations have been found in postmenopausal women in whom the within person variability of most hormones is markedly reduced but some positive associations have also been seen in premenopausal women. Plasma estrogens show the strongest correlations with risk and these are strengthened by measurement or calculation of the proportion of estradiol that circulates free of sex hormone binding globulin (SHBG), consistent with this being the most active fraction. The relationships have been reported to potentially explain virtually all of the association of breast cancer with body mass index in postmenopausal women; this is likely to be due to non ovarian estrogen synthesis being prominent in subcutaneous fat. These strong relationships have led to plasma and urine estrogen levels being used as intermediate end-points in the search for genes that affect breast cancer risk via their role in steroid disposition. Plasma androgen levels also show a relationship with breast cancer risk that is weakened but not eliminated by 'correction' for estrogen levels. This has been argued to be evidence of the local production of estrogens being important in the etiology of breast cancer. Given that plasma steroid levels do not correlate closely with mammographic density, which is strongly associated with risk, the opportunity exists to combine the two factors in assessing breast cancer risk but the low availability of suitable estrogen assays is a major impediment to this. In established breast cancer, plasma estrogens have been found to correlate with gene expression of estrogen dependent genes and the expression of these varies across the menstrual cycle of premenopausal women. There is infrequently a need for routine measurement of plasma estrogen levels but it has been important in the comparative pharmacology and dose-related effectiveness of aromatase inhibitors. Measurement may be needed to identify residual ovarian function in women who have amenorrhea subsequent to cytotoxic chemotherapy indicating their unsuitability for aromatase inhibitor treatment. Use of highly sensitive assays has also revealed that the association between BMI and plasma estrogen levels persists in patients on 3rd generation aromatase inhibitors and that measurable increments in plasma estrogen levels occur with some vaginal estrogen preparations that are of concern in relation to treatment efficacy. PMID- 24074791 TI - Obesity and endocrine therapy: host factors and breast cancer outcome. AB - Obesity is becoming increasingly prevalent and it has been linked to poor breast cancer outcomes. Because obesity is associated with increased adipose tissue mass and aromatase activity [the target of aromatase inhibitors (AIs)], there is concern that these agents may be less effective in women who are overweight or obese. Four of the randomized trials of AIs vs. tamoxifen conducted in the adjuvant breast cancer setting (ATAC, BIG 1-98 and TEAM in the postmenopausal setting and ABCSG-12 in the premenopausal setting) have reported effects of body mass index (BMI) on the relative effectiveness of an AI vs. tamoxifen. Obesity was confirmed as an adverse prognostic factor in ATAC and BIG 1-98 but not the TEAM study; in ABSCG-12, obesity was associated with poor outcomes in the anastrozole arm only. In the three postmenopausal trials, the use of an AI vs. tamoxifen was associated with better outcomes at all levels of BMI [all hazard ratios for recurrence <1, although 95% confidence intervals often included 1 due to lower power and smaller reductions in risk]. Of note, there was no significant interaction of BMI with letrozole (vs. tamoxifen) in the BIG 1-98 trial; while ATAC investigators concluded that the relative benefit of anastrozole (vs. tamoxifen) might be better in thinner (vs. heavier) women. In ABCSG-12, the use of anastrozole (vs. tamoxifen) was associated with significantly worse outcomes in women with BMI >=25 kg/m(2) (similar to the detrimental effect of anastrozole on overall survival seen in the parent trial). These findings do not support the use of BMI as a predictor of AI (vs. tamoxifen) benefit in the adjuvant setting in postmenopausal breast cancer. PMID- 24074792 TI - Adipose tissue and breast cancer progression: a link between metabolism and cancer. AB - INTRODUCTION/AIMS: Obesity, an excess accumulation of adipose tissue occurring in mammalians when caloric intake exceeds energy expenditure, is associated with an increased incidence, morbidity and mortality from several types of neoplastic diseases including postmenopausal breast cancer. METHODS AND RESULTS: Several investigators have recently studied the role of human white adipose tissue (WAT) progenitors in preclinical models of breast cancer. WAT progenitors were found to promote breast cancer local growth, angiogenesis, EMT, migration and metastatic spreading. Breast cancer patients with intraepithelial neoplasia who received autologous WAT cells for breast reconstruction after surgical removal of breast cancer showed an increased risk of recurrence of local events when compared to controls. DISCUSSION/CONCLUSION: There is an urgent need for a better understanding of the role of WAT progenitors in breast cancer local and metastatic growth. A rigorous cancer screening and follow-up of patients enrolled for WAT progenitor-based therapies should be implemented. PMID- 24074793 TI - The metastatic microenvironment of breast cancer: clinical implications. AB - Metastasis to bone, and indeed potentially to other sites, results from the numerous interactions between cancer cells, haematopoietic stem cells and normal bone cells within the bone marrow microenvironment. These interactions are in turn influenced by multiple endocrine, paracrine and physical factors. Bone targeted treatments may modify the course of the disease via both direct and indirect inhibitory effects on this "vicious cycle" of growth factor and cytokine signalling between tumour and bone cells. Improvements in both disease free (DFS) and overall survival in women with early breast cancer have been demonstrated in several large randomised adjuvant trials of oral clodronate and intravenous zoledronic acid. The evidence for a beneficial impact on disease outcome is particularly strong in patients with low levels of reproductive hormones, including pre-menopausal women receiving ovarian suppression therapy and those who have passed through menopause at the time of diagnosis. A recent meta analysis of postmenopausal women treated with adjuvant bisphosphonates showed an 18% improvement in DFS (hazard ratio [HR] = 0.82; 95%CI 0.74-0.92, 2P = <0.001), with reductions in relapse rates not only in bone but also at extra-skeletal and loco-regional sites. These exciting findings are beginning to change clinical practice. PMID- 24074794 TI - Preclinical recapitulation of antiangiogenic drug clinical efficacies using models of early or late stage breast cancer metastatis. AB - Historically, preclinical tumor therapy models in mice have frequently been deficient in predicting subsequent clinical activity; over-prediction of clinical anti-tumor efficacy is common. Several approaches are being made in an attempt to improve the clinical relevance of preclinical models, and include the use of genetically engineered mouse models (GEMMs) of cancer or patient derived xenografts (PDXs). Here we summarize, in the context of breast cancer, another approach, namely, the development of postsurgical models of either macroscopic or microscopic metastatic disease to mimic metastatic or adjuvant therapy. To do so we used in vivo selected metastatic variants of established human breast cancer cell lines such as MDA-MB-231. Testing antiangiogenic drugs such as the oral tyrosine kinase inhibitor (TKI) sunitinib alone or combined with chemotherapy in models involving treatment of established primary tumors invariably resulted in demonstrable anti-tumor activity. In contrast, identical treatments of postsurgical mice with advanced metastatic disease did not: survival times were not prolonged. This reflects multiple failed phase III trials of sunitinib based therapies in metastatic breast cancer patients. However, using a VEGF pathway targeting antibody drug instead of a TKI, with (paclitaxel) chemotherapy, resulted in anti-tumor activity in the metastatic setting, partially reflecting prior clinical results of the E2100 phase III trial of weekly paclitaxel plus bevacizumab. Other experiments involving postsurgical adjuvant treatment of early stage disease foreshadowed the phase III clinical trial failures of adjuvant bevacizumab in colorectal or breast cancer. In contrast, some investigational metronomic oral chemotherapy protocols alone or in combination with an antiangiogenic drug demonstrated potent activity in the advanced metastatic setting; these encouraging results have yet to be validated in randomized phase III clinical trials, which are underway based on some encouraging phase II clinical trial results. We have also observed circumstances where mice with advanced systemic disease, when successfully treated so as to prolong survival, sometimes relapse with brain metastases, reflecting a similar clinical phenomenon. Given our overall findings, we suggest that using preclinical mouse tumor models which mimic postsurgical adjuvant or metastatic therapy may be a promising strategy to help improve the ability to predict subsequent clinical outcomes. PMID- 24074795 TI - Extracellular matrix components in breast cancer progression and metastasis. AB - The extracellular matrix (ECM) is composed of highly variable and dynamic components that regulate cell behavior. The protein composition and physical properties of the ECM govern cell fate through biochemical and biomechanical mechanisms. This requires a carefully orchestrated and thorough regulation considering that a disturbed ECM can have serious consequences and lead to pathological conditions like cancer. In breast cancer, many ECM proteins are significantly deregulated and specific matrix components promote tumor progression and metastatic spread. Intriguingly, several ECM proteins that are associated with breast cancer development, overlap substantially with a group of ECM proteins induced during the state of tissue remodeling such as mammary gland involution. Fibrillar collagens, fibronectin, hyaluronan and matricellular proteins are matrix components that are common to both involution and cancer. Moreover, some of these proteins have in recent years been identified as important constituents of metastatic niches in breast cancer. In addition, specific ECM molecules, their receptors or enzymatic modifiers are significantly involved in resistance to therapeutic intervention. Further analysis of these ECM proteins and the downstream ECM mediated signaling pathways may provide a range of possibilities to identify druggable targets against advanced breast cancer. PMID- 24074796 TI - Breast cancer screening: controversy of impact. AB - Few medical issues have been as controversial--or as political, at least in the United States-as the role of mammographic screening for breast cancer. The advantages of finding a cancer early seem obvious. Indeed, randomized trials evaluating screening mammography demonstrate a reduction in breast cancer mortality, but the benefits are less than one would hope. Moreover, the randomized trials are themselves subject to criticism, including that they are irrelevant in the modern era because most were conducted before chemotherapy and hormonal therapy became widely used. In this article I chronicle the evidence and controversies regarding mammographic screening, including attempts to assess the relative contributions of screening and therapy in the substantial decreases in breast cancer mortality that have been observed in many countries over the last 20-25 years. I emphasize the trade-off between harms and benefits depending on the woman's age and other risk factors. I also discuss ways for communicating the associated risks to women who have to decide whether screening (and what screening strategy) is right for them. PMID- 24074797 TI - Magnetic resonance imaging: the evolution of breast imaging. AB - INTRODUCTION AND AIMS: To provide an overview of the principle of current breast MRI, the available evidence concerning its indications and optimum use and future potentials. METHODS AND RESULTS: To date sensitivities of 90-91% have been achieved with a specificity of 72-75%. MRI is the most sensitive method for detecting invasive carcinoma and comparable to mammography concerning detection of DCIS. The achievable specificity, false positive and biopsy rates, however, are much lower than for screening mammography thus do not allow its use for screening of the general population. Indications with proven advantages concern screening of women at high risk and special diagnostic problems that cannot be solved by conventional imaging and percutaneous biopsy: search for primary tumour in CUP syndrome, differentiation of nipple retraction, differentiation of scarring versus recurrence and selected difficult cases. There is no proven benefit for its general use for preoperative staging. One major problem may concern the imperfect interface between imaging and surgery. Further research is also needed for the use of MRI in women at intermediate risk. In women at low risk MRI screening is not recommended. Novel possibilities of MRI concern diffusion weighted imaging as well as MR spectroscopy. Their value for improved lesion differentiation is not yet fully established. Their main potential appears to concern an improved and earlier prediction of response to neoadjuvant therapy. Future developments might address development of more specific contrast agents, replacement of vascular enhancing agents by special MR techniques, testing of sodium MRI or image fusion with other imaging modalities. DISCUSSION/CONCLUSION: MRI allows new patho-physiological information and thus can complement the information available by conventional methods. Present research should concentrate on improving specificity, improving the interface of imaging and surgery and has to include outcome analyses. Due to issues of specificity the responsible use of MRI should be limited to appropriate indications. PMID- 24074798 TI - The continued evidence from overviews: what is the clinical utility? AB - The Oxford Overview process has provided us with extremely high-powered meta analyses assessing the role of adjuvant chemotherapy in early breast cancer. From the most recent publication, the proportional benefits from chemotherapy are relatively equivalent across all patient subgroups, a finding contradictory to our growing understanding of the role of tumour biology in dictating chemosensitivity. Several factors, including heterogeneity of patient groups and chemotherapy regimens, lack of data on underlying tumour biological subtypes, and confounding effect of chemotherapy-induced ovarian suppression in premenopausal women with hormone receptor positive breast cancer, impact on the applicability and clinical utility of the Overview in current and future oncological practice. With these considerations, the Overview has become less clinically relevant as a tool for guiding adjuvant chemotherapy treatment decisions, and a new direction is required. PMID- 24074799 TI - Influence of genomics on adjuvant treatments for pre-invasive and invasive breast cancer. AB - INTRODUCTION AND AIM: Tribute to the improved quality of tumor marker studies all major national and international practice guidelines now recognized the potential clinical value of multivariate genomic prognostic tests. There are several diagnostic companies that offer these products for clinical use. This paper reviews recent trends in genomic prognostic testing in the clinic and briefly discusses future trends. METHODS AND RESULTS: Published manuscripts on breast cancer biomarkers, genomic prognostic and predictive tests were reviewed along with abstracts and proceedings of major conferences to extract information on the clinical utility, cost-effectiveness and usage of molecular tests in the management of early stage breast cancers. Genomic test use has steadily increased over the past 5 years, approximately 30%, 13% and 1% of stage I, II and III ER positive breast cancer breast cancers are tested. Among those who are tested, approximately, 25-30% of the time treatment recommendations change due to test results. Testing is associated with decreased use of chemotherapy overall, however in clinically low risk patients who are tested tend to receive chemotherapy more frequently than low risk patients who are untested. Almost all cost-effectiveness studies concluded that genomic testing is cost effective under a broad range of assumptions when used within current guidelines. Simple immunohistochemistry based assays when performed following a standard operating procedure and combined into a multivariate prognostic model, have the potential to substitute for genomic tests in the future. DISCUSSION AND CONCLUSIONS: Genomic testing, when available, is widely used to assist in adjuvant chemotherapy treatment recommendations for clinically intermediate risk (e.g. grade 2, stage I-II) ER-positive breast cancers. PMID- 24074800 TI - Characterization and clinical impact of residual disease after neoadjuvant chemotherapy. AB - One of the most important lessons learned from trials of neoadjuvant chemotherapy (NACT) is that achievement of pathological complete response (pCR) is a powerful prognostic predictor of long-term outcome, with significantly better disease-free and overall survival for patients achieving pCR, as compared with patients having residual tumour after NACT. The pathologists' role in the neoadjuvant setting is: (i) to ensure an accurate assessment of pCR, and (ii) to evaluate burden and biological characteristics of residual tumour if pCR has not been achieved. A conversion of receptor status from the core biopsy to the post-NACT surgical specimen may cause uncertainty in the choice of the post-surgical systemic treatment for the patients. It is therefore imperative to ensure accuracy in the assessment of ER, PgR and HER2, and to double check any apparent conversion by re staining the previous core biopsy and the residual tumour in the same run, thus minimizing the technical artifacts, and to use both immunohistochemical and in situ hybridization assays to evaluate HER2 status. It is essential that protocols for evaluation of tumour response and for assessment of prognostic/predictive parameters of residual disease after NACT be eventually harmonized. PMID- 24074801 TI - Quantification of residual risk of relapse in breast cancer patients optimally treated. AB - Despite remarkable improvements in breast cancer survival in the last decades, a proportion of patients still relapse after treatment for early disease. Different prognostic parameters may permit to roughly quantify the residual risk of relapse after (neo)adjuvant therapy. They include: tumor stage and classical molecular features at baseline, newly proposed prognosticators (such as tumor-infiltrating lymphocytes and integrated genomic tools) and the evaluation of tumor response after primary systemic therapy. However, the performance of these factors is still suboptimal and should be improved. Further research aimed to discover new possible prognostic factors in patients who received optimal systemic therapy is needed. Moreover, to exploit at the best the potential of each of these parameters, they should be integrated into algorithms to guide treatment decisions and to select those patients who may deserve the inclusion in clinical trials. PMID- 24074802 TI - Developing an effective breast cancer vaccine: challenges to achieving sterile immunity versus resetting equilibrium. AB - INTRODUCTION: Evading immune destruction is an emerging hallmark of cancer. Immunotherapy of cancer is categorized as either specific stimulation of the immune system by active immunization, with cancer vaccines, or passive transfer of humor or cellular materials, such as, tumor specific antibodies (including immunomodulators) or adoptive cell therapy that inhibit the function of- or directly kill tumor cells. Modulation of immune response in cancer patients is the result of a balanced activity of T regulators and T effector cells. METHODS AND RESULTS: We will present the current information and the prospects for the future of immunotherapy in patients with breast cancer including tumor antigens for vaccines and targets for monoclonal antibodies and adoptive T-cell therapy. DISCUSSION: Active immunotherapy in breast cancer and its implementation into clinical trials has largely been a frustrating experience in the last decades. After many years of controversy, the concept that the immune system regulates cancer development is experiencing a new resurgence. It is clear that the cancer immunosurveillance process indeed exists and potentially acts as an extrinsic tumor suppressor. It has been also clear that the immune system can facilitate tumor progression by sculpting the immunogenic phenotype of tumors as they develop. Cancer immunoediting represents a refinement of the cancer immunosurveillance hypothesis and resumes the complex interaction between tumor and immune system into three phases: elimination, equilibrium, and escape. CONCLUSION: What do we know about tumor immunogenicity and how might we therapeutically improve tumor immunogenicity? The first vaccine and the first immunomodulating agent were recently approved by the US Food and Drug Administration (FDA) for the treatment of prostate cancer (sipuleucel-T) and melanoma (ipilimumab), respectively. The success of future immunotherapy strategies will depend on the identification of additional immunogenic antigens that can serve as the best tumor-rejection targets. Therapeutic success will depend on developing the best antigen delivery systems and on the elucidation of the entire network of immune signalingsignaling pathways that regulate immune responses in the tumor microenvironment. PMID- 24074803 TI - Time dependent effects of stress prior to encoding on event-related potentials and 24 h delayed retrieval. AB - Stress can exert profound effects on memory encoding. Here, we investigated whether (sub)cortical information processing during encoding and memory retrieval at a 24 h delayed test are affected by the temporal proximity between stress and memory encoding. Sixty-four participants engaged in the Maastricht Acute Stress Test (MAST) or a no-stress control condition either immediately before (i.e., proximate condition) or 30 min before (i.e., distant condition) a picture encoding task. In general, stress decreased the number of freely recalled and recognized pictures and increased the number of false alarms. However, timing of stress exposure did not differentially affect picture recall, recognition or selective attention processes (i.e., LPP). Nevertheless, stress-induced cortisol responses and correctly recognized neutral pictures were positively associated within the proximate stress condition but negatively associated within the distant stress condition. These findings suggest that the time at which a stressor is applied might differentially impact the association between stress induced cortisol elevations and memory formation and indicate the need for a finer delineation of the time window during which glucocorticoids affect memory formation processes. PMID- 24074804 TI - Cortisol and depression in pre-diagnosed and early stage Huntington's disease. AB - Hypothalamic-pituitary-adrenal (HPA) axis dysfunction and depression have both been shown to occur in Huntington's disease (HD) gene carriers prior to diagnosis (pre-HD) and in diagnosed HD patients. However, the relationship between HPA axis dysfunction and the severity of depressive symptomatology in pre-HD and early-HD has not been systematically examined, despite morning hypercortisolism being a characteristic feature of some subtypes of idiopathic depression. The aim of this study was to investigate whether HPA axis function is related to levels of depression in pre-HD and early-HD. To assess HPA axis function we obtained salivary cortisol concentrations from 20 controls, 20 pre-HD, and 17 early-HD participants at four time points over a 24h period. Depression symptoms were assessed using the Inventory of Depressive Symptomatology - Self-Report. Of the participants who were found not to be depressed, the early-HD group had significantly lower morning cortisol levels relative to pre-HD and controls. In contrast, the early-HD group with at least mild or greater levels of depression symptoms had a comparable cortisol concentration to pre-HD and controls. The results suggest that early-HD may be associated with hypocortisolism. However when depressed, a hyperactive HPA axis response may still be induced in early-HD and lead to cortisol levels that are similar to pre-HD and controls. Our study reveals that cortisol levels in HD may be modified by the presence or absence of depressive symptomatology. Depression may be an important factor for understanding how the HPA axis is affected in HD, particularly in the morning. PMID- 24074805 TI - Cushing's disease: a single centre's experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy. AB - Cushing's disease is hypercortisolaemia secondary to an adrenocorticotrophic hormone secreting pituitary adenoma. Primary management is almost always surgical, with limited effective medical interventions available. Adjuvant therapy in the form of radiation is gaining popularity, with the bulk of the literature related to the Gamma Knife. We present the results from our own institution using the linear accelerator (LINAC) since 1990. Thirty-six patients who underwent stereotactic radiosurgery (SRS), one patient who underwent fractionated stereotactic radiotherapy (FSRT) and for the purposes of comparison, 13 patients who had undergone conventional radiotherapy prior to 1990, were included in the analysis. Serum cortisol levels improved in nine of 36 (25%) SRS patients and 24 hour urinary free cortisol levels improved in 13 of 36 patients (36.1%). Tumour volume control was excellent in the SRS group with deterioration in only one patient (3%). The patient who underwent FSRT had a highly aggressive tumour refractory to radiation. PMID- 24074806 TI - Trehalose diesters, lipoteichoic acids and alpha-GalCer: using chemistry to understand immunology. AB - It is now widely recognised that glycolipids can play an important role in the activation and modulation of the immune system. Seminal findings in this field included the discovery of 'endotoxin' from Gram-negative bacteria, lipoteichoic acids from Gram-positive bacteria and 'cord factor' or trehalose dimycolates from mycobacteria. In this mini-review, we present our latest developments on deciphering how glycolipids modulate the immune response through the synthesis and biological evaluation of trehalose glycolipids, lipoteichoic acids and derivatives of alpha-GalCer. By doing so, we illustrate how chemistry can interface with immunology to aid in the understanding of disease, and show that synthesis can provide a powerful molecular tool for studying the role of glycolipids in biological systems. PMID- 24074807 TI - Specific scapular kinematic patterns to differentiate two forms of dynamic scapular winging. AB - BACKGROUND: Dynamic scapular winging (DSW) is a rare and misdiagnosed disorder causing considerable disability due to reduced scapular stability and abnormal motion. Two common causes are long thoracic nerve lesions resulting in serratus anterior muscle palsy and spinal accessory nerve lesions resulting in trapezius muscle palsy. The aim of this study was to analyse 3D scapular kinematic patterns in patients with DSW due to long thoracic (LTNL) or spinal accessory nerve lesions (SANL). METHODS: 3D scapular kinematics were assessed using a non invasive method involving an electromagnetic device during arm elevation in the frontal and sagittal planes in 9 patients (4 with SANL and 5 with LTNL) with unilateral DSW confirmed by electrical evidence. Within subject affected unaffected differences were measured and compared between pathological groups (Mann-Whitney). FINDINGS: Differences between affected and unaffected shoulders were significantly greater for scapular posterior tilt (at rest and 30 degrees for sagittal arm elevation, at rest, 30 degrees and 60 degrees for frontal arm elevation) in the LTNL compared to the SANL group. Differences between affected and unaffected shoulders were significantly greater for scapular protraction (at rest and 60 degrees of sagittal arm elevation, at rest, 30 degrees and 60 degrees of frontal arm elevation) and scapular lateral rotation at 60 degrees for frontal arm elevation in the SANL compared to the LTNL group. INTERPRETATIONS: These kinematic findings show two different scapular patterns that are specific to the neurological lesion. Moreover our kinematic data relate to specific clinical signs and the functional roles of the muscles involved. PMID- 24074808 TI - Reduced functional connectivity in early-stage drug-naive Parkinson's disease: a resting-state fMRI study. AB - Although cardinal motor symptoms in Parkinson's disease (PD) are attributed to dysfunction of corticostriatal loops, early clinical nonmotor features are more likely to be associated with other pathologic mechanisms. We enrolled 52 early stage drug-naive PD patients and 52 age- and sex-matched healthy controls and used resting-state functional connectivity magnetic resonance imaging to evaluate alteration of the functional brain network in PD, focusing in particular on the functional connectivity of the striatum subregions. Relative to healthy controls, the PD patient group showed reduced functional connectivity in mesolimbic striatal and corticostriatal loops. Although the deceased functional connectivity within cortical sensorimotor areas was only evident in the most affected putamen subregion, reduced functional connectivity with mesolimbic regions was prevalent throughout the striatum. No increased functional connectivity was found in this cohort. By studying a cohort of early-stage drug-naive PD patients, we ruled out the potential confounding effect of prolonged antiparkinson medication use on the functional integration of neural networks. We demonstrate decreased functional integration across neural networks involving striatum, mesolimbic cortex, and sensorimotor regions in these patients and postulate that the prevalent disconnection in mesolimbic-striatal loops is associated with some early clinical nonmotor features in PD. This study offers additional insight into the early functional integration of neural networks in PD. PMID- 24074809 TI - Oral topotecan: Bioavailability, pharmacokinetics and impact of ABCG2 genotyping in Chinese patients with advanced cancers. AB - Oral topotecan (Hycamtin((r))) has been recently approved for the treatment of relapsed small cell lung cancer (SCLC) in 2007, however, the bioavailability and pharmacokinetic data of topotecan for Chinese patients is still limited. Xinze((r)) is a new and the only capsule formulation of topotecan used in China that is similar to Hycamtin((r)). The current study aimed to investigate the absolute bioavailability and pharmacokinetics of Xinze((r)) in Chinese patients with advanced cancers. On day 1, an IV dose of 1.5 mg/m(2)/d as a 30 min continuous infusion was administered. Patients took the oral topotecan at one of two dose levels: 1.5 mg/m(2)/d (six patients) or 1.9 mg/m(2)/d (seven patients) on day 2. Plasma pharmacokinetics of total topotecan and topotecan in the lactone form were performed on both days using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Single-nucleotide polymorphisms (SNPs) identified in exon 5 (421C>A) and in exon 2 (34G>A) in ATP binding cassette sub-family G member 2 (ABCG2) were analyzed by direct sequencing. Safety assessments were performed throughout the study. The maximum plasma concentration (Cmax) reached at 1-2 h and the elimination half-life time (T1/2) was approximately 4.2 h after oral administration. The absolute bioavailability of total topotecan in the 1.5 mg/m(2)/d and 1.9 mg/m(2)/d groups averaged 41.23 +/- 11.8% and 36.00 +/- 14.8%, respectively. The patients with heterozygous SNPs had essentially the same bioavailability and pharmacokinetics. The bioavailability of topotecan after oral administration illustrates good systemic exposure at dosages of 1.5 mg/m(2)/d and 1.9 mg/m(2)/d over a five-day schedule in Chinese patients. On a dose-normalized basis, the values of Cmax and AUC0-t for total topotecan in Chinese patients were higher than in Caucasians following oral and intravenous administration, while the T1/2 was consistent. PMID- 24074811 TI - Risk analysis and stratification of surgical morbidity after immediate breast reconstruction. AB - BACKGROUND: Surgical complications after breast reconstruction can be associated with significant morbidity, dissatisfaction, and cost. We used the ACS-NSQIP datasets from 2005 to 2011 to derive predictors of morbidity and to stratify risk after immediate breast reconstruction (IBR). STUDY DESIGN: Surgical complications after implant and autologous reconstruction were assessed using the ACS-NSQIP 2005 to 2011 datasets. Patient demographics, clinical characteristics, and operative factors were associated with the likelihood of experiencing a surgical complication. A "model cohort" of 12,129 patients was randomly selected from the study cohort to derive predictors. Weighted odds ratios derived from logistic regression analysis were used to create a composite risk score and to stratify patients. The remaining one-third of the cohort (n = 6,065) were used as the "validation cohort" to assess the accuracy value of the risk model. RESULTS: On adjusted analysis, autologous reconstruction (odds ratio [OR] 1.41, p < 0.001), American Society of Anesthesiologists physical status >= 3 (OR 1.25, p = 0.004), class I obesity (OR 1.38, p < 0.001), class II obesity (OR 1.91, p < 0.001), class III obesity (OR 1.70, p < 0.001), and active smoking (OR 1.46, p < 0.001) were associated with complications. Risk factors were weighted and patients were stratified into low (0 to 2, n = 9,133, risk = 7.14%), intermediate (3 to 4, n = 1,935, risk = 10.90%), high (5 to 7, n = 1,024, risk = 16.70%), and very high (8 to 9, n = 37, risk = 27.02%) risk categories based on their total risk score (p < 0.001). Internal validation of the "model cohort" using the "validation cohort" was performed demonstrating accurate prediction of risk across groups: low (7.1% vs 7.1%, respectively, p = 0.9), intermediate (10.9% vs 12.0%, respectively, p = 0.38), high (16.7% vs 16.8%, respectively, p = 0.95), and very high (27.0% vs 30.0%, respectively, p = 1.0). CONCLUSIONS: Surgical complications after IBR are related to preoperatively identifiable factors that can be used to accurately risk stratify patients, which may assist with counseling, selection, and perioperative decision-making. PMID- 24074810 TI - Gender determines ACTH recovery from hypercortisolemia in healthy older humans. AB - OBJECTIVE: Available clinical data raise the possibility that stress-adaptive mechanisms differ by gender. However, this notion has not been rigorously tested in relation to cortisol-mediated negative feedback. MATERIALS/METHODS: Degree of ACTH inhibition during and recovery from an experimental cortisol clamp was tested in 20 healthy older subjects (age 60+/-2.2 y). Volunteers received oral placebo or ketoconazole (KTCZ) to inhibit adrenal steroidogenesis along with i.v. infusions of saline or a low vs high physiological dose of cortisol in a prospectively randomized double-blind, placebo-controlled design. ACTH and cortisol concentrations were measured every 10 min during the feedback-clamp phase and thereafter (recovery or escape phase). Corticosteroid-binding globulin (CBG) was measured, and free cortisol concentrations were calculated. RESULTS: Gender did not determine mean ACTH concentrations during the saline or cortisol feedback-clamp phases per se. However, women had markedly impaired ACTH recovery after stopping both low- and high-dose cortisol infusions compared with men (P=0.005, KTCZ/low-dose cortisol arm; and P=0.006, KTCZ/high-dose cortisol arm). Decreased ACTH recovery in women was accompanied by lower total and free cortisol concentrations, pointing to heightened feedback inhibition of hypothalamo pituitary drive of ACTH secretion as the main mechanism. CONCLUSIONS: In summary, gender or a factor related to gender, such as sex steroids or body composition, determines recovery of ACTH secretion from cortisol-enforced negative feedback. Attenuated ACTH recovery in post-menopausal women may have relevance to sex differences in stress-related adaptations. PMID- 24074813 TI - Contact tracing using provider referral: how difficult is it? AB - Contact tracing using provider referral is often perceived as time-consuming. To assess the workload involved in provider referral at a sexual health clinic, we studied the number of attempts required, the contact method used, the time taken and the success of provider referral for 230 contacts referred over a 3-year period. For 87% of these contacts, a mobile number was available; 78.7% of these were successfully contacted. A median of two calls was required and the median time to complete the contact tracing process was within the same day. In 91% of cases, contact tracing was successful. In our setting, provider notification was not time-consuming. PMID- 24074812 TI - The General Surgeon's quandary: atypical lipomatous tumor vs lipoma, who needs a surgical oncologist? AB - BACKGROUND: Differentiating large lipomas from atypical lipomatous tumors (ALT) is challenging, and preoperative management guidelines are not well defined. The diagnostic ambiguity leads many surgeons to refer all patients with large lipomatous masses to an oncologic specialist, perhaps unnecessarily. STUDY DESIGN: In this retrospective cohort study of patients with nonretroperitoneal lipomatous tumors, preoperative characteristics discernible without invasive diagnostic procedures were evaluated for diagnostic predictive value. RESULTS: We identified 319 patients (256 with lipomas, 63 with ALTs) treated between 1994 and 2012. Patients with ALTs were older (60.5 vs 53.5 years, p < 0.0001), had larger tumors (16.0 vs 8.3 cm, p < 0.0001), had tumors more often located on an extremity (88.9% vs 60.5% torso, p < 0.0001), and more frequently had a history of previous operations at the same site, exclusive of excision leading to diagnosis and referral (20.6% vs 5.9%, p = 0.001). Local recurrence was observed in 2 patients with lipomas (0.8%) vs 14 with ALTs (22.6%, p < 0.0001). No patients with ALTs developed distant metastases or disease-specific mortality, with a median follow-up of 27.4 months (range 0 to 164.6 months). On multivariate analysis, age >= 55 years, tumor size >= 10 cm, extremity location, and history of previous resections were predictors for diagnosis of ALT (p < 0.05). CONCLUSIONS: Characteristics of lipomatous masses associated with a diagnosis of ALT include patient age >= 55 years, tumor size >= 10 cm, previous resection, and extremity location (vs torso). These easily identifiable traits may guide surgical management or referral to a specialist. PMID- 24074814 TI - Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy. AB - BACKGROUND AND PURPOSE: We reported the incidence of severe late esophagus toxicity (LET) in locally advanced NSCLC patients treated with intensity modulated radiation therapy (IMRT) and concurrent chemotherapy. Acute esophagus toxicity (AET) and the dose to the esophagus were analyzed for their associations with severe LET. MATERIAL AND METHODS: Two hundred and thirty-one patients treated from 2008 to 2011 with hypofractionated IMRT (66Gy/24fx) and concurrent daily low dose cisplatin were included. The association between AET and severe LET (grade >= 3 RTOG/EORTC) was tested through Cox-proportional-hazards model. Equivalent uniform dose (EUD) to the esophagus and the volume percentage receiving more than x Gy (Vx) were applied by Lyman-Kutcher-Burman (LKB) model. RESULTS: A total of 171 patients were eligible for this study. Severe LET was observed in 6% patients. Both the maximum grade and the recovery rate of AET were significantly associated with severe LET. In the EUDn-LKB model, the fitted values and 95% confidence intervals (CIs) were TD50=76.1 Gy (73.2-78.6), m=0.03 (0.02-0.06) and n=0.03 (0-0.08). In the Vx-LKB model, the fitted values and 95% CIs were Tx50=23.5% (16.4-46.6), m=0.44 (0.32-0.60) and x=76.7 Gy (74.7-77.5). CONCLUSIONS: Severe AET, EUD (n=0.03) and V76.7 to the esophagus were significantly associated with severe LET. An independent validation study is required. PMID- 24074815 TI - Operation of a horizontal subsurface flow constructed wetland--microbial fuel cell treating wastewater under different organic loading rates. AB - The aim of the present work is to determine whether a horizontal subsurface flow constructed wetland treating wastewater could act simultaneously as a microbial fuel cell (MFC). Specifically, and as the main variable under study, different organic loading rates were used, and the response of the system was monitored. The installation consisted of a synthetic domestic wastewater-feeding system and a pilot-scale constructed wetland for wastewater treatment, which also included coupled devices necessary to function as an MFC. The wetland worked under continuous operation for 180 d, treating three types of synthetic wastewater with increasing organic loading rates: 13.9 g COD m(-2) d(-1), 31.1 g COD m(-2) d(-1), and 61.1 g COD m(-2) d(-1). The COD removal efficiencies and the cell voltage generation were continuously monitored. The wetland worked simultaneously as an MFC generating electric power. Under low organic loading rates, the wastewater organic matter was completely oxidised in the lower anaerobic compartment, and there were slight aerobic conditions in the upper cathodic compartment, thus causing an electrical current. Under high organic loading rates, the organic matter could not be completely oxidised in the anodic compartment and flowed to the cathodic one, which entered into anaerobic conditions and caused the MFC to stop working. The system developed in this work offered similar cell voltage, power density, and current density values compared with the ones obtained in previous studies using photosynthetic MFCs, sediment-type MFCs, and plant-type MFCs. The light/darkness changes caused voltage fluctuations due to the photosynthetic activity of the macrophytes used (Phragmites australis), which affected the conditions in the cathodic compartment. PMID- 24074816 TI - pH impact on reductive dechlorination of cis-dichloroethylene by Fe precipitates: an X-ray absorption spectroscopy study. AB - The pH impact on reductive dechlorination of cis-dichloroethylene (cis-DCE) was investigated using in situ Fe precipitates formed under iron-rich sulfate reducing conditions. The dechlorination rate of cis-DCE increased with pH, which was attributed to changes in the solid-phase Fe concentration, the composition of Fe minerals, and the surface speciation of Fe minerals. With increasing pH, larger quantities of Fe minerals, having much greater reactivity than dissolved Fe(II), were produced. Fe-K edge X-ray absorption spectroscopy (XAS) analysis of Fe precipitates revealed the presence of multiple Fe phases with their composition varying with pH. Correlation analyses were performed to examine how the solid-phase Fe concentration, the composition of Fe minerals, and their surface speciation were linked with the cis-DCE dechlorination rate. Such analyses revealed that neither mackinawite (FeS) nor magnetite (Fe3O4) was reactive with cis-DCE dechlorination, but that Fe (oxyhydr)oxides including green rusts and Fe(OH)2 were reactive. Based on a proposed model of the surface acidity of Fe minerals, the increasing deprotonated surface Fe(II) groups with pH correlated well with the enhanced cis-DCE dechlorination. PMID- 24074817 TI - Power induced by bubbles of different sizes and frequencies on to hollow fibers in submerged membrane systems. AB - To shed light onto the relationship between sparging conditions and fouling control in submerged hollow fiber membranes, the effects of bubble size and frequency on the hydrodynamic conditions induced in membrane system were studied. Two general classes of bubbles were considered: coarse (0.75-2.5 mL) and pulse (100-500 mL). The power transferred (P(trans)) onto membranes could be used to characterise the multiple effects induced under different sparging conditions. P(trans) is proportional to root mean square of shear stress (tau(rms)), the area of zone of influence (i.e. the fraction in the system where high velocity and high vorticity (turbulence) are induced by the bubble) and their rise velocity. At a given sparging rate, the power transferred onto membranes was less with coarse bubble sparging than pulse bubble sparging and increased with the size of pulse bubbles. For all cases, the power transfer efficiency was consistently higher for pulse bubble sparging than for coarse bubble sparging. The power transfer efficiency to the system was greatest for the small pulse bubbles considered when a small amount of power is required for fouling control. However, when fouling is extensive, large pulse bubbles may be required to generate the required amount of power for fouling control. PMID- 24074818 TI - [Dementia: new concepts, new goals]. PMID- 24074819 TI - Bacterial respiratory tract infections are promoted by systemic hyperglycemia after severe burn injury in pediatric patients. AB - BACKGROUND: Burns are associated with hyperglycemia leading to increased incidence of infections with pneumonia being one of the most prominent and adverse complications. Recently, various studies in critically ill patients indicated that increased pulmonary glucose levels with airway/blood glucose threshold over 150 mg/dl lead to an overwhelming growth of bacteria in the broncho-pulmonary system, subsequently resulting in an increased risk of pulmonary infections. The aim of the present study was to determine whether a similar cutoff value exists for severely burned pediatric patients. METHODS: One hundred six severely burned pediatric patients were enrolled in the study. Patients were divided in two groups: high (H) defined as daily average glucose levels >75% of LOS >150 mg/dl), and low (L) with daily average glucose levels >75% of the LOS <150 mg/dl). Incidences of pneumonia, atelectasis, and acute respiratory distress syndrome (ARDS) were assessed. Incidence of infections, sepsis, and respiratory parameters were recorded. Blood was analyzed for glucose and insulin levels. Statistical analysis was performed using Student's t-test and chi-square test. Significance was set at p<0.05. RESULTS: Patient groups were similar in demographics and injury characteristics. Pneumonia in patients on the mechanical ventilation (L: 21%, H: 32%) and off mechanical ventilation (L: 5%, H: 15%), as well as ARDS were significantly higher in the high group (L: 3%, H: 19%), p<0.05, while atelectasis was not different. Patients in the high group required significantly longer ventilation compared to low patients (p<0.05). Furthermore, incidence of infection and sepsis were significantly higher in the high group, p<0.05. CONCLUSION: Our results indicate that systemic glucose levels over 150 mg/dl are associated with a higher incidence of pneumonia confirming the previous studies in critically ill patients. PMID- 24074820 TI - Effectiveness of an alarm intervention with overlearning for primary nocturnal enuresis. AB - OBJECTIVE: To explore the effectiveness of the enuresis alarm with overlearning for treatment of primary nocturnal enuresis (PNE). A key objective was to explore the effect of overlearning on treatment gains, and its impact on relapse. PATIENTS AND METHODS: The RMIT University Psychology Clinic has been treating PNE in the community for more than 20 years following a standardized treatment protocol. The study analysed archival data of 126 participants, aged >= 5 years, presenting with PNE. A mean wetting frequency of 5.13 wet nights per week was observed at baseline. RESULTS: Treatment significantly reduced mean wetting from baseline levels during both treatment and overlearning phases, F(1.41, 176.10) = 588.54, p < 0.001, r(2) = 0.77, 95% CI (0.74-0.81). Wet nights per week reduced from a mean of 5.13 (SD = 1.77) during baseline to 1.88 (SD = 0.85) during treatment, and 0.64 (SD = 0.60) during overlearning. Alarm treatment with overlearning produced a treatment response of 87%, compared with 59% for alarm treatment only. CONCLUSIONS: Evidence of improved treatment response with the addition of overlearning suggests overlearning should be considered as a potentially useful adjunct to alarm treatment for PNE. Overlearning was not unreasonably onerous for participants. Further research is required to explore the impact overlearning has on reducing relapse rates. PMID- 24074821 TI - Fluorescence of neutrophil granulocytes as a biomarker for clozapine use. AB - Non-adherence to medication is a major issue in the treatment of schizophrenia in general and in particular for those treated with clozapine. A reliable tool to quantify patients long-term adherence to clozapine is currently unavailable. Enhanced FL3 neutrophil granulocyte fluorescence was serendipitously observed in a small population of schizophrenic patients treated with clozapine. The present study was aimed at assessing the association between clozapine use and FL3 fluorescence. A cross-sectional study was performed using data from the Utrecht Patient Oriented Database (UPOD). A total of 38,390 inpatients were included, of which 124 (0.33%) used clozapine. FL3-fluorescence was significantly higher (U=240,179, P<0.001) in clozapine users (mean (SD)=90.5 (11.8)) than in non-users (mean (SD)=69.8 (3.3)). Observed FL3-fluorescence was found to increase with increasing clozapine dose. The area under the receiver operating characteristic curve was 0.95. Our results confirm the association between use of clozapine and elevated FL3-fluorescence. Further research is needed to unravel the underlying mechanism and to investigate the true potential of FL3-fluorescence as a clozapine-adherence biomarker in clinical practice. PMID- 24074822 TI - Estimation of GFR in South Asians: a study from the general population in Pakistan. AB - BACKGROUND: South Asians are at high risk for chronic kidney disease. However, unlike those in the United States and United Kingdom, laboratories in South Asian countries do not routinely report estimated glomerular filtration rate (eGFR) when serum creatinine is measured. The objectives of the study were to: (1) evaluate the performance of existing GFR estimating equations in South Asians, and (2) modify the existing equations or develop a new equation for use in this population. STUDY DESIGN: Cross-sectional population-based study. SETTING & PARTICIPANTS: 581 participants 40 years or older were enrolled from 10 randomly selected communities and renal clinics in Karachi. PREDICTORS: eGFR, age, sex, serum creatinine level. OUTCOMES: Bias (the median difference between measured GFR [mGFR] and eGFR), precision (the IQR of the difference), accuracy (P30; percentage of participants with eGFR within 30% of mGFR), and the root mean squared error reported as cross-validated estimates along with bootstrapped 95% CIs based on 1,000 replications. RESULTS: The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation performed better than the MDRD (Modification of Diet in Renal Disease) Study equation in terms of greater accuracy at P30 (76.1% [95% CI, 72.7%-79.5%] vs 68.0% [95% CI, 64.3%-71.7%]; P < 0.001) and improved precision (IQR, 22.6 [95% CI, 19.9-25.3] vs 28.6 [95% CI, 25.8-31.5] mL/min/1.73 m(2); P < 0.001). However, both equations overestimated mGFR. Applying modification factors for slope and intercept to the CKD-EPI equation to create a CKD-EPI Pakistan equation (such that eGFRCKD-EPI(PK) = 0.686 * eGFRCKD-EPI(1.059)) in order to eliminate bias improved accuracy (P30, 81.6% [95% CI, 78.4%-84.8%]; P < 0.001) comparably to new estimating equations developed using creatinine level and additional variables. LIMITATIONS: Lack of external validation data set and few participants with low GFR. CONCLUSIONS: The CKD-EPI creatinine equation is more accurate and precise than the MDRD Study equation in estimating GFR in a South Asian population in Karachi. The CKD-EPI Pakistan equation further improves the performance of the CKD-EPI equation in South Asians and could be used for eGFR reporting. PMID- 24074823 TI - Community mobility among older adults with reduced kidney function: a study of life-space. AB - BACKGROUND: Life-Space Assessment captures community mobility and social participation and quantifies the distance, frequency, and independence obtained as an older adult moves through his or her environment. Reduced estimated glomerular filtration rate (eGFR) is associated with decline in activities of daily living among older adults, but less is known about the association of eGFR with restrictions in mobility. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: Community-dwelling Medicare beneficiaries from the University of Alabama at Birmingham Study of Aging who had serum creatinine measured during a baseline in-home study visit and completed at least one telephone follow-up (N = 390). PREDICTOR: eGFR >= 60, 45-59, and <45 mL/min/1.73 m(2). OUTCOME: Life-space mobility trajectory. MEASUREMENTS: Life-space mobility was evaluated by telephone every 6 months for up to 4.5 years using the previously validated Life-Space Assessment. Scores using this tool range from 0 120 (higher scores indicate greater mobility). RESULTS: Mean age of the 390 participants was 77.6 +/- 5.8 (SD) years, 41% were African American, 50.5% were women; 30.0% had eGFR of 45-59 mL/min/1.73 m(2), and 20.2% had eGFR < 45 mL/min/1.73 m(2). Age-, race-, and sex-adjusted mean baseline life-space mobility scores were 64.8(95% CI, 62.0-67.6), 63.8 (95% CI, 60.3-67.4), and 58.3 (95% CI, 53.8-62.7) among those with eGFR categories >= 60, 45-59, and <45 mL/min/1.73 m(2), respectively. Compared with those with eGFRs >= 60 mL/min/1.73 m(2), a more rapid decline in life-space mobility was found among those with eGFRs < 45 mL/min/1.73 m(2), though this did not reach statistical significance (P=0.06); a similar effect was not seen among those with eGFRs of 45-59 mL/min/1.73 m(2) (P=0.3). LIMITATIONS: Urinary albumin or longitudinal measures of eGFR were not available. CONCLUSIONS: eGFR < 45 mL/min/1.73 m(2) was associated with a trend toward a more rapid decline in life-space mobility among community-dwelling older adults. Findings should be confirmed in a larger population. PMID- 24074824 TI - High-risk clinical presentations in atherosclerotic renovascular disease: prognosis and response to renal artery revascularization. AB - BACKGROUND: Current trial data may not be directly applicable to patients with the highest risk presentations of atherosclerotic renovascular disease, including flash pulmonary edema, rapidly declining kidney function, and refractory hypertension. We consider the prognostic implications of these presentations and response to percutaneous revascularization. STUDY DESIGN: Single-center prospective cohort study; retrospectively analyzed. SETTING & PARTICIPANTS: 467 patients with renal artery stenosis >=50%, managed according to clinical presentation and physician/patient preference. PREDICTORS: Presentation with flash pulmonary edema (n = 37 [7.8%]), refractory hypertension (n = 116 [24.3%]), or rapidly declining kidney function (n = 46 [9.7%]) compared to low-risk presentation with none of these phenotypes (n = 230 [49%]). Percutaneous revascularization (performed in 32% of flash pulmonary edema, 28% of rapidly declining kidney function, and 28% of refractory hypertension patients) compared to medical management. OUTCOMES: Death, cardiovascular (CV) event, end-stage kidney disease. RESULTS: During a median follow-up of 3.8 (IQR, 1.8-5.8) years, 55% died, 33% had a CV event, and 18% reached end-stage kidney disease. In medically treated patients, flash pulmonary edema was associated with increased risk of death (HR, 2.2; 95% CI, 1.4-3.5; P < 0.001) and CV event (HR, 3.1; 95% CI, 1.7-5.5; P < 0.001), but not end-stage kidney disease, compared to the low risk phenotype. No increased risk for any end point was observed in patients presenting with rapidly declining kidney function or refractory hypertension. Compared to medical treatment, revascularization was associated with reduced risk for death (HR, 0.4; 95% CI, 0.2-0.9; P = 0.01), but not CV event or end-stage kidney disease, in patients presenting with flash pulmonary edema. Revascularization was not associated significantly with reduced risk for any end point in rapidly declining kidney function or refractory hypertension. When these presentations were present in combination (n = 31), revascularization was associated with reduced risk for death (HR, 0.15; 95% CI, 0.02-0.9; P = 0.04) and CV event (HR, 0.23; 95% CI, 0.1-0.6; P = 0.02). LIMITATIONS: Observational study; retrospective analysis; potential treatment bias. CONCLUSIONS: This analysis supports guidelines citing flash pulmonary edema as an indication for renal artery revascularization in atherosclerotic renovascular disease. Patients presenting with a combination of rapidly declining kidney function and refractory hypertension also may benefit from revascularization and may represent a subgroup worthy of further investigation in more robust trials. PMID- 24074826 TI - The multitalented Mediator complex. AB - The Mediator complex is needed for regulated transcription of RNA polymerase II (Pol II)-dependent genes. Initially, Mediator was only seen as a protein bridge that conveyed regulatory information from enhancers to the promoter. Later studies have added many other functions to the Mediator repertoire. Indeed, recent findings show that Mediator influences nearly all stages of transcription and coordinates these events with concomitant changes in chromatin organization. We review the multitude of activities associated with Mediator and discuss how this complex coordinates transcription with other cellular events. We also discuss the inherent difficulties associated with in vivo characterization of a coactivator complex that can indirectly affect diverse cellular processes via changes in gene transcription. PMID- 24074825 TI - Prehypertension and Incidence of ESRD: a systematic review and meta-analysis. AB - BACKGROUND: Studies of the association of prehypertension with the incidence of end-stage renal disease (ESRD) after adjusting for other cardiovascular risk factors have shown controversial results. STUDY DESIGN: Systematic review and meta-analysis of prospective cohort studies. SETTING & POPULATION: Adults with prehypertension. SELECTION CRITERIA FOR STUDIES: Studies evaluating the association of prehypertension with the incidence of ESRD identified by searches in PubMed, EMBASE, and Cochrane Library databases and conference proceedings, without language restriction. PREDICTOR: Prehypertension. OUTCOMES: The relative risks (RRs) of ESRD were calculated and reported with 95% CIs. Subgroup analyses were conducted according to blood pressure (BP), age, sex, ethnicity, and study characteristics. RESULTS: Data from 1,003,793 participants were derived from 6 prospective cohort studies. Compared with optimal BP, prehypertension significantly increased the risk of ESRD (RR, 1.59; 95% CI, 1.39-1.91). In subgroup analyses, prehypertension significantly predicted higher ESRD risk across age, sex, ethnicity, and study characteristics. Even low-range (BP, 120 129/80-84 mm Hg) prehypertension increased the risk of ESRD compared with optimal BP (RR, 1.44; 95% CI, 1.19-1.74), and the risk increased further with high-range (BP, 130-139/85-89 mm Hg) prehypertension (RR, 2.02; 95% CI, 1.70-2.40). The RR was significantly higher in the high-range compared with the low-range prehypertensive population (P = 0.01). LIMITATIONS: No access to individual patient-level data. CONCLUSIONS: Prehypertension is associated with incident ESRD. The increased risk is driven largely by high-range prehypertension. PMID- 24074827 TI - Yellow fever vaccination: is one dose always enough? AB - In March 2013, the World Health Organization (WHO) Strategic Advisory Group of Experts on Immunisation (SAGE) considered a number of issues in order to update the WHO Position Paper on Yellow Fever (2003). A key conclusion of this review was that a single dose of yellow fever (YF) vaccine appears to confer life-long protection against YF disease, and that a booster dose of YF vaccine is not needed to maintain immunity. While the efficacy of YF vaccine in the majority of vaccine recipients is not in doubt, the WHO announcement is somewhat surprising as there are some limitations in the evidence base, but more importantly, this announcement is not accompanied by any imminent change in the International Health Regulations 2005. The tension between what is considered best clinical practice and the law will be difficult to reconcile for many health professionals, travellers, and the travel industry, in an area of travel medicine that is already subject to debate and confusion. This commentary reviews the recent WHO announcement, and considers the practical implications for health professionals providing YF vaccine to international travellers. PMID- 24074828 TI - Tranexamic acid in the prehospital setting: Israel Defense Forces' initial experience. AB - BACKGROUND: The leading cause of preventable death in the military setting is haemorrhage. Accumulating evidence has established the benefit of tranexamic acid (TXA), an antifibrinolytic, for treating traumatic haemorrhage in the hospital setting. The use of TXA in the prehospital setting, however, has not been previously described. The present study details our initial experience with a field protocol that advances TXA administration to (or as close as possible to) the point of injury. METHODS: We present a series of all casualties treated with TXA by Israel Defense Forces' (IDF) prehospital advanced life support providers between December 2011 and February 2013. Data were abstracted from the IDF Trauma Registry at the Research Section of the Trauma and Combat Medicine Branch, Surgeon General's Headquarters. RESULTS: Forty casualties who received TXA in the prehospital setting were identified. Most casualties were male (n=35; 88%) and young adults (median 28 years). The mechanism of injury was penetrating in 22 cases (55%). TXA was administered earlier than it could have been in the hospital setting without delaying evacuation. There were no reports of adverse outcomes that could be reasonably attributed to TXA. Casualties who received TXA per protocol were sicker than those who received it not per protocol. CONCLUSIONS: We have shown that TXA may be successfully given in the prehospital setting without any apparent delays in evacuation. In light of recent evidence, the ability to give TXA closer to the time of wounding represents an important step towards improving the survival of trauma victims with haemorrhage, even before definitive care is available. While this may be especially relevant in austere combat environments, there is likely benefit in the civilian sector as well. The safety profile of TXA is an important consideration as prehospital personnel tended to overtreat casualties without indications for TXA per protocol. We suggest that TXA be considered a viable option for use by advanced life support providers at or near the point of injury. PMID- 24074829 TI - Cost effectiveness of tibial nonunion treatment: A comparison between rhBMP-7 and autologous bone graft in two Italian centres. AB - Current evidences show that recombinant human bone morphogenetic protein 7 (rhBMP 7, eptotermin alfa) can be considered an effective alternative to autologous bone graft (ABG) in the treatment of tibial nonunions. Few studies, so far, have analysed the costs of treating tibial nonunions with either rhBMP-7 or ABG and none of them has specifically considered the Italian situation. The aim of the present study was to capture, through observational retrospective methods, the direct medical costs associated with the treatment of tibial nonunions with rhBMP 7 or ABG in Italy and to compare the cost effectiveness of the two interventions. The secondary objective was to perform a cost-reimbursement analysis for hospitalisations associated with the two treatments. Data of 54 patients with indication for tibial nonunion were collected from existing data sources. Of these patients, 26 were treated with ABG and 28 with rhBMP-7. The study captured the direct medical costs for treating each tibial nonunion, considering both inpatient and outpatient care. The hospital reimbursement was calculated from discharge registries, based on diagnosis-related group (DRG) values. A subgroup of patients (n=30) was also interviewed to capture perceived health during the follow-up, and the quality-adjusted life years (QALYs) were subsequently computed. The two groups were similar for what concerns baseline characteristics. While the medical costs incurred during the hospitalisation associated with treatment were on average ?3091.21 higher (P<0.001) in patients treated with rhBMP-7 (reflecting the product procurement costs), the costs incurred during the follow-up were on average ?2344.45 higher (P=0.02) in patients treated with ABG. Considering all costs incurred from the treatment, there was a borderline statistical evidence (P=0.04) for a mean increase of ?795.42, in the rhBMP-7 group. Furthermore, the study demonstrated that, without appropriate reimbursement, the hospital undergoes significant losses (P=0.003) when using rhBMP-7 instead of ABG. In contrast to these losses, in Italy, the average cost to achieve a successful outcome was ?488.96 lower in patients treated with rhBMP 7 and, additionally, the cost per QALY gained was below the cost-utility threshold of $50,000. PMID- 24074830 TI - Assessment of the role of fibular fixation in distal-third tibia-fibula fractures and its significance in decreasing malrotation and malalignment. AB - BACKGROUND: In the treatment of distal-third tibia/fibula fractures treated by interlocking nailing, the role of fibular fixation is not clearly defined. This study aimed to assess the benefits of fibular fixation in such fractures. METHODS: Sixty patients with fractures of the lower third of the leg were enrolled into the study and divided into two groups based on whether the fibula was fixed (group A) or not (group B). Fracture tibia was treated with interlocked intramedullary nailing and fibular fixation was done using a 3.5-mm Limited Contact Dynamic Compression Plate (LC-DCP). The two groups were compared for differences in rotation at ankle, angulation at the fracture site, time of union and complications. Clinical and functional outcomes were assessed regularly. Merchant-Dietz criteria were used to assess ankle function. RESULTS: The demographics of the two groups were similar. Average valgus angulation was significantly less in group A (average 5 degrees ) versus group B (average 9 degrees ). The degree of rotational malalignment at the ankle in group A was average 7 degrees versus average 15 degrees in group B. The outcome of two groups for clinical ankle score, time of union and complications showed no significant differences. CONCLUSION: Fixation of the fibula along with interlocking nailing of the tibia decreases the malalignment of the tibia and malrotation of the ankle in distal-third fractures of the tibia and fibula as compared with only interlocking nailing. PMID- 24074831 TI - Sonography on injury of the medial patellofemoral ligament after acute traumatic lateral patellar dislocation: Injury patterns and correlation analysis with injury of articular cartilage of the inferomedial patella. AB - OBJECTIVE: The purpose of this study was to investigate the accuracy of high frequency ultrasonography in the diagnosis of injuries of medial patellofemoral ligaments (MPFLs), analyse the characteristics of MPFL injury and correlations between injury of the MPFL and articular cartilage of the inferomedial patella in patients with acute traumatic lateral patellar dislocation. METHODS: High frequency sonographic images of 49 patients with acute traumatic lateral patellar dislocations treated surgically were reviewed. The chi(2) tests were performed for statistical analysis. RESULTS: Twenty-eight cases of complete MPFL tear and 21 cases of partial MPFL tear were identified in operation, with 27 cases of MPFL tear located at their femoral attachment, 21 cases of tear at the patellar attachment and one case of midsubstance tear. The diagnostic accuracy of sonography regarding partial MPFL tear and complete MPFL tear was 89.8% and 89.8%. Among the patients with MPFL tear at the patellar attachment, eight and six cases were concomitant with chondral and osteochondral lesions in the inferomedial patella, respectively, in contrast to nine and six cases in patients with MPFL tear at the femoral attachment, respectively. There was no significant difference between the two locations described above regarding the prevalence rates of chondral or osteochondral lesions of the inferomedial patella (P=0.732, P=0.614). Among the patients with complete MPFL tear, 12 and 10 cases were concomitant with chondral and osteochondral lesions in the inferomedial patella, respectively, while six and two cases were concomitant with partial MPFL tear. There was no significant difference between the two types of injuries discussed above on the prevalence rates of chondral lesions of the inferomedial patella (P=0.305), but the prevalence rate of osteochondral lesions between the two types of injuries discussed above was statistically different (P=0.035). CONCLUSIONS: The MPFL is most easily injured at the femoral attachment, secondly at the patellar attachment. High-frequency ultrasonography is an accurate method in the diagnosis of an MPFL tear. There are neither significant differences on the prevalence rates of chondral or osteochondral lesions of the inferomedial patella between locations of MPFL injuries, nor significant difference on the prevalence rates of chondral lesions between MPFL injury types; but the complete MPFL tear is more often concomitant with inferomedial patellar osteochondral lesions than the partial MPFL tear. PMID- 24074832 TI - Vascular damage: a persisting pathology common to Alzheimer's disease and traumatic brain injury. AB - Alzheimer's disease (AD) and traumatic brain injury (TBI) are both significant clinical problems characterized by debilitating symptoms with limited available treatments. Interestingly, both neurological diseases are characterized by neurovascular damage. This impaired brain vasculature correlates with the onset of dementia, a symptom associated with hippocampal degeneration seen in both diseases. We posit that vascular damage is a major pathological link between TBI and AD, in that TBI victims are predisposed to AD symptoms due to altered brain vasculature; vice versa, the progression of AD pathology may be accelerated by TBI especially when the brain insult worsens hippocampal degeneration. Our hypothesis is supported by recent data reporting expedited AD pathology in presymptomatic transgenic AD mice subjected to TBI. If our hypothesis is correct, treatments targeted at repairing the vasculature may prove effective at treating both diseases and preventing the evolution of AD symptoms in TBI victims. PMID- 24074834 TI - Is peptic ulcer disease a risk factor of postherpetic neuralgia in patients with herpes zoster? AB - Postherpetic neuralgia is the most common complication of herpes zoster which is caused by a reactivation of latent varicella zoster virus. The pathogenesis of postherpetic neuralgia may involve peripheral and central mechanisms. Reported risk factors for postherpetic neuralgia include female gender, old age, diminished cell-mediated immunity and nutritional deficiencies. Based on our clinical observation which revealed that peptic ulcer disease (PUD) is one of the common comorbidities in patients with postherpetic neuralgia, we hypothesize that herpes zoster patients with PUD may be at a greater risk for the development of postherpetic neuralgia due to their impaired cellular immunity and depressed nutritional status. Major causes of PUD include Helicobacter pylori infection and usage of ulcerogenic medications. Patients with H. pylori infection may develop T cell dysfunctions and nutritional deficiencies including vitamin C, iron, cobalamin, carotenes and alpha-tocopherol. Ulcerogenic medications such as nonsteroidal anti-inflammatory drugs and steroids have been found not only to be ulcerogenic but also immunosuppressive to T cells. In addition, usage of steroids and nonsteroidal anti-inflammatory drugs may cause deficiencies of alpha tocopherol, carotenes, cobalamin, iron, zinc and vitamin C. Vitamin C, carotenes and alpha-tocopherol are anti-inflammatory and the major oxidant scavengers in the aqua phase and biomembranes. Deficiencies of these nutrients may induce dysregulated inflammation and oxidative damage leading to neuropathic pain in patients with herpes zoster. Furthermore, nutrient deficiencies including zinc, iron, cobalamin and vitamin C are associated with dysregulation of Ca(v)3.2 T channels and N-methyl-D-aspartate receptors, upregulation of nitric oxide synthase, the increase of nitric oxide formation and dysfunction of central norepinephrine inhibitory pain pathway. Prospective cohort studies are suggested to test the hypothesis. We further propose that a follow-up study that contains two groups of herpes zoster patients, i.e., with or without gastroendoscopy proven PUD, be conducted to determine their incidence of postherpetic neuralgia. In addition, despite of the high proportion of zoster patients having been treated with antiviral therapies, prevention and treatment of postherpetic neuralgia remain challenging in clinical practice. The potential risk of postherpetic neuralgia in zoster patients with PUD could mean that physicians need to pay more attention to the comorbidity--PUD in patients with herpes zoster and treat PUD earlier in order to prevent the development of postherpetic neuralgia. PMID- 24074833 TI - The long term oral regulation of blood glucose in diabetic patients by using of Escherichia coli Nissle 1917 expressing CTB-IGF-1 hybrid protein. AB - Regarding to the high prevalence and comorbidities of chronic high blood glucose in diabetic patients and the limited efficacy and current painful treatments. It is necessary to improve new treatments that are non-invasive and long-term for controlling blood glucose. Recent studies have shown that the healthy microflora in different body organs can perform as the gene vectors for expressing different types of gene therapies in situ. We have proposed that by constructing a recombinant Escherichia coli Nissle 1917 that expresses CTB-IGF-1 hybrid gene under control of ompC glucose sensitive promoter, the intestinal glucose level can be regulated. This method in comparison with other methods is a non-invasive way to control the blood glucose orally and it can be used for all types of diabetes. PMID- 24074835 TI - Interleukin-2 priming chemotherapy: a strategy to improve the remission of refractory/relapsed T cell acute lymphoblastic leukemia. AB - Regardless of the salvage therapy used, primary induction failure in acute lymphoblastic leukemia (refractory ALL) and relapse after a complete remission (CR) are associated with dismal outcomes. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be the best treatment option for relapsed/refractory ALL. However, the outcome of allo-HSCT is very poor when a patient is not in CR. Quiescent leukemia cells protect them from the commonly used cell cycle-specific chemotherapeutic agents. Interleukin-2 (IL-2), a very well characterized T cell growth factor, is responsible for the progression of T lymphocytes from the G0 to the S phase of the cell cycle. IL-2 receptors are present on malignant T cells. Interaction of IL-2 with the IL-2 receptor triggers T cell proliferation, but T cells must change from a resting to an activated state, which leads to the de novo synthesis of IL-2 and expression of the IL-2 receptor. Thus, exogenous IL-2 administration is pivotal for the activation of T cells. Based on the findings above mentioned, we hypothesized that IL-2 priming chemotherapy improves the remission of refractory/relapsed T cell acute lymphoblastic leukemia. PMID- 24074836 TI - CD31 expression in plasmacytic/plasmablastic lesions. AB - Although CD31 has been considered one of the better, if not the best, immunohistochemical marker of endothelial cells and thereby vascular neoplasia, it is not unequivocally specific to this group of tumors. We examined CD31 staining in 34 plasmacytic lesions including 15 plasma cell myelomas, 1 extraosseous plasmacytoma, 10 plasmablastic variants of myeloma, 5 plasmablastic non-Hodgkin lymphomas, and 3 reactive plasmacytic infiltrates. All reactive plasma cellular infiltrates, 93% of plasma cell myelomas, 80% of plasmablastic variants of myelomas, and 20% of plasmablastic non-Hodgkin lymphoma cases were CD31 positive with usually diffuse and strong membranous staining. When ERG staining was performed, none were ERG positive. Plasmablastic variant of myeloma is another large cell malignancy that has the potential to be mistaken for a poorly differentiated epithelioid vascular neoplasm if CD31 is presumed to be an explicit marker of endothelial cells. PMID- 24074837 TI - Macrophage polarization following chitosan implantation. AB - Macrophages are a key cell in the host response to implants and can be polarized into different phenotypes capable of inducing both detrimental and beneficial outcomes in tissue repair and remodeling, being important in tissue engineering and regenerative medicine. The objective of this study was to evaluate the macrophage response to 3D porous chitosan (Ch) scaffolds with different degrees of acetylation (DA, 5% and 15%). The M1/M2 phenotypic polarization profile of macrophages was investigated in vivo using a rodent air-pouch model. Our results show that the DA affects the macrophage response. Ch scaffolds with DA 5% induced the adhesion of lower numbers of inflammatory cells, being the M2 the predominant phenotypic profile among the adherent macrophages. In the inflammatory exudates F4/80(+)/CD206(+) cells (M2 macrophages) appeared in higher numbers then F4/80(+)/CCR7(+) cells (M1 macrophages), in addition, lower levels of pro inflammatory cytokines together with higher levels of anti-inflammatory cytokines were found. Ch scaffolds with DA 15% showed opposite results, since M1 were the predominant macrophages both adherent to the scaffold and in the exudates, together with high levels of pro-inflammatory cytokines. In conclusion, Ch scaffolds with DA 5% induced a benign M2 anti-inflammatory macrophage response, whereas Ch scaffolds with DA 15% caused a macrophage M1 pro-inflammatory response. PMID- 24074838 TI - A photo-triggered layered surface coating producing reactive oxygen species. AB - We report a photoactive surface coating which produces cytotoxic reactive oxygen species (ROS) upon irradiation with near infrared (NIR) light. The coating is assembled layer-by-layer, and consists of cross-linked hyaluronic acid (HA) and poly-l-lysine (PLL) modified with the photoactive molecule pheophorbide a. Pheophorbide a loading can be fine-tuned by varying the number of bilayers, yielding stable materials with the capacity to generate repeated and/or prolonged light-triggered ROS release. Light irradiation of the photoactive surface coatings provides a versatile platform for the spatiotemporal control of events at the material-tissue interface, such as bacterial colonization, platelet adhesion, and mammalian cell attachment. PMID- 24074839 TI - Comparative efficacy of blood cell immunocamouflage by membrane grafting of methoxypoly(ethylene glycol) and polyethyloxazoline. AB - The grafting of low-immunogenic polymers to cells dramatically reduces antigenic recognition and immunogenicity of allogeneic donor cells consequent to steric and charge camouflage (i.e., immunocamouflage). While methoxypoly(ethylene glycol) [mPEG] has historically been utilized for the immunocamouflage of cells, other low-immunogenic polymers such as polyethyloxazoline propionic acid (PEOZ) may also be capable of conferring immunoprotection. Moreover, PEOZ may have attributes that could have enhanced pharmacological and biological utility relative to mPEG. To evaluate the immunocamouflage efficacy of PEOZ relative to mPEG, human red blood cells (RBC) and leukocytes were modified with mPEG or PEOZ. The differential effects of mPEG and PEOZ was assessed via grafting efficacy, cell morphology and viability, immunocamouflage of surface antigens, and the prevention of in vitro immune recognition (RhD and HLA). Although membrane grafting of mPEG and PEOZ were similar, mPEG demonstrated superior immunocamouflage efficacy as measured by antibody binding and phagocytosis of opsonized RBC while PEOZ showed improved RBC morphology. While mPEG appears to be superior to PEOZ in the immunocamouflage of cells, PEOZ may still be a valuable addition to our repertoire of immunomodulatory polymers. Moreover, our results demonstrate the importance of indirect immunocamouflage of antigens found in membrane protein complexes. PMID- 24074840 TI - The regulation of growth and metabolism of kidney stem cells with regional specificity using extracellular matrix derived from kidney. AB - Native extracellular matrix (ECM) that is secreted and maintained by resident cells is of great interest for cell culture and cell delivery. We hypothesized that specialized bioengineered niches for stem cells can be established using ECM derived scaffolding materials. Kidney was selected as a model system because of the high regional diversification of renal tissue matrix. By preparing the ECM from three specialized regions of the kidney (cortex, medulla, and papilla; whole kidney, heart, and bladder as controls) in three forms: (i) intact sheets of decellularized ECM, (ii) ECM hydrogels, and (iii) solubilized ECM, we investigated how the structure and composition of ECM affect the function of kidney stem cells (with mesenchymal stem cells, MSCs, as controls). All three forms of the ECM regulated KSC function, with differential structural and compositional effects. KSCs cultured on papilla ECM consistently displayed lower proliferation, higher metabolic activity, and differences in cell morphology, alignment, and structure formation as compared to KSCs on cortex and medulla ECM, effects not observed in corresponding MSC cultures. These data suggest that tissue- and region-specific ECM can provide an effective substrate for in vitro studies of therapeutic stem cells. PMID- 24074841 TI - A double-blind block randomized clinical trial on the effect of zinc as a treatment for diarrhea in neonatal Holstein calves under natural challenge conditions. AB - Diarrhea is the leading cause of death in neonatal calves and contributes to major economic losses. The objective of this double-blind randomized clinical trial was to evaluate the effect of oral inorganic or organic zinc supplementation as a treatment for neonatal diarrhea in calves. Seventy nine 1 to 8 day old male Holstein calves on a California calf ranch were block randomized to one of 3 treatments within 24h from their first onset of diarrhea. Calves received a daily dose of either a placebo composed of 80 mg of zinc-free powder, 381.54 mg of zinc methionine (Met) (equivalent to 80 mg of zinc), or 99.69 mg of zinc oxide (ZO) (equivalent to 80 mg of zinc) in 2L of a zinc-free oral rehydration solution (ORS). Calves were treated once daily until normal fecal consistency or for a maximum of 14 days. Upon enrollment and exit, calves were weighed, and blood, feces, and liver biopsies were collected for trace mineral analysis. Fecal samples at enrollment and exit were tested for E. coli K99, Cryptosporidium spp., rotavirus and coronavirus. Pre-treatment liver zinc concentrations for the 71 calves in the placebo, zinc Met, and ZO treatment groups were 710.6 (SEM=147.7), 852.3 (SEM=129.6), and 750.7 (SEM=202.9)mg/kg dry weight (DW), respectively. Exit liver zinc concentrations for the calves in the placebo, zinc Met, and ZO treatment groups were 728.9 (SEM=182.9), 1141.0 (SEM=423.8), and 636.8 (SEM=81.5)mg/kg dry weight, respectively. Although statistically non-significant, there were clinically important findings identified for each of zinc Met and ZO treatments. Calves treated with zinc Met gained on average 40 g/day during a diarrhea episode compared to a weight loss of 67 g/day on average in the placebo-treated calves (Power 19.9%). Calves treated with ZO had 1.4 times higher hazard of clinical cure compared to calves in the placebo group (Power 5.3%). Calves that were fecal positive to cryptosporidium spp. at enrollment and treated with zinc Met had higher odds of testing negative at exit compared to placebo calves (Odds Ratio (OR)=16.0). In contrast, calves treated with ZO tended to recover (fecal score=1) one day earlier compared to calves treated with a placebo (8.5 d vs. 9.7 d). The current trial identified clinically important findings that warrant further research to investigate zinc's therapeutic effect for calf diarrhea. PMID- 24074842 TI - Studies on substituted benzo[h]quinazolines, benzo[g]indazoles, pyrazoles, 2,6 diarylpyridines as anti-tubercular agents. AB - Various substituted 5,6-dihydro-8-methoxybenzo[h]quinazolin-2-amine, 1-(3-(4 alkoxyphenyl)-7-methoxy-3,3a,4,5-tetrahydro-2H benzo[g]indazol-2-yl)ethanone, pyrazole and 2,6-diarylpyridine derivatives have been synthesized in good yields by an efficient methodology. The synthesized compounds (4-23) were evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. Compounds 6a, 6c, 8a, 19a and 19e exhibited significant anti-tubercular activity at MIC values 50, 100, 50, 25 and 100MUM concentration. In vitro cytotoxicity data using THP-1 cells indicated that most active compound 19a is safe as its MIC value is much lower than the cytotoxic value. PMID- 24074844 TI - Identification of novel PARP-1 inhibitors by structure-based virtual screening. AB - Poly(ADP-ribose)polymerase-1 (PARP-1) is an abundant and ubiquitous chromatin bound nuclear protein. PARP-1, a DNA repair enzyme, has been in the limelight as a chemotherapeutic target. In this study, we demonstrated the successful use of structure-based virtual screening to identify inhibitors of PARP-1 from Otava databases comprised of nearly 260,000 compounds. Five novel inhibitors belonging to thienopyrimidinone, isoquinolinoquinazolinone, pyrroloquinazolinone, and cyclopentenothienopyrimidinone scaffolds revealed inhibitory potencies with IC50 values ranged from 9.57MUM to 0.72MUM. Structural features relevant to the activity of these novel compounds within the active site of PARP-1 are discussed in detail and will guide future SAR investigation on these scaffolds. PMID- 24074843 TI - Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety. AB - Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of tool compound VU0409106 is described in this Letter. VU0409106 is a potent and selective negative allosteric modulator of mGlu5 that binds at the known allosteric binding site and demonstrates good CNS exposure following intraperitoneal dosing in mice. VU0409106 also proved efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists as well as clinically efficacious anxiolytics. PMID- 24074845 TI - Molecular mechanisms of cognitive impairment in iron deficiency: alterations in brain-derived neurotrophic factor and insulin-like growth factor expression and function in the central nervous system. AB - OBJECTIVE: The present review examines the relationship between iron deficiency and central nervous system (CNS) development and cognitive impairment, focusing on the cellular and molecular mechanisms related to the expression and function of growth factors, particularly the insulin-like growth factors I and II (IGF I/II) and brain-derived neurotrophic factor (BDNF), in the CNS. METHODS: Nutritional deficiencies are important determinants in human cognitive impairment. Among these, iron deficiency has the highest prevalence worldwide. Although this ailment is known to induce psychomotor deficits during development, the precise molecular and cellular mechanisms underlying these alterations have not been properly elucidated. This review summarizes the available information on the effect of iron deficiency on the expression and function of growth factors in the CNS, with an emphasis on IGF-I/II and BDNF. RESULTS AND DISCUSSION: Recent studies have shown that specific growth factors, such as IGF-I/II and BDNF, have an essential role in cognition, particularly in processes involving learning and memory, by the activation of intracellular-signaling pathways involved in cell proliferation, differentiation, and survival. It is known that nutritional deficiencies promote reductions in systemic and CNS concentrations of growth factors, and that altered expression of these molecules and their receptors in the CNS leads to psychomotor and developmental deficits. Iron deficiency may induce these deficits by decreasing the expression and function of IGF-I/II and BDNF in specific areas of the brain. PMID- 24074847 TI - Pathological and problem gambling in substance use treatment: a systematic review and meta-analysis. AB - Pathological and problem gambling refer to a class of disorders, including those meeting criteria for a psychiatric diagnosis (i.e., pathological gambling), and others comprising a spectrum of severity defined by significant personal and social harm (i.e., problem gambling), that may be common in substance use treatment but are frequently unrecognized. This paper presents a systematic review and meta-analysis of available evidence indicating the prevalence of such gambling disorders in substance use treatment. It provides weighted mean estimates from across studies of clinical samples of substance users, and suggests around 14% of patients that demonstrate comorbid pathological gambling. Around 23% suffer conditions along the broader spectrum of problem gambling. The review also highlights important limitations of existing evidence, including scant data on current versus lifetime comorbidity, as well as reliance on convenience samples and self-administered measures of gambling problems. Notwithstanding a concomitant need for caution when applying these results, the findings suggest a strong need to identify and manage gambling comorbidity in substance use treatment. Strategies for identification of gambling disorders, and therapies that may provide useful adjunctive interventions in substance use treatment are discussed. PMID- 24074846 TI - Tuberculosis screening in a novel substance abuse treatment center in Malaysia: implications for a comprehensive approach for integrated care. AB - People who use drugs (PWUD) represent a key high risk group for tuberculosis (TB). The prevalence of both latent TB infection (LTBI) and active disease in drug treatment centers in Malaysia is unknown. A cross-sectional convenience survey was conducted to assess the prevalence and correlates of LTBI among attendees at a recently created voluntary drug treatment center using a standardized questionnaire and tuberculin skin testing (TST). Participants (N=196) were mostly men (95%), under 40 (median age=36 years) and reported heroin use immediately before treatment entry (75%). Positive TST prevalence was 86.7%. Nine (4.6%) participants were HIV-infected. Previous arrest/incarcerations (AOR=1.1 for every entry, p<0.05) and not being HIV-infected (AOR=6.04, p=0.03) were significantly associated with TST positivity. There is an urgent need to establish TB screening and treatment programs in substance abuse treatment centers and to tailor service delivery to the complex treatment needs of patients with multiple medical and psychiatric co-morbidities. PMID- 24074848 TI - Attentional avoidance of smoking cues in former smokers. AB - It has been speculated that attentional bias (AB) to smoking cues is a permanent feature of addiction. The objective of the present study was to investigate if abstinence duration has an influence on AB. Performance on a visual probe task of three groups (recent, intermediate and prolonged) of ex-smokers (n=62, mean age 50+/-11 years) with different abstinence durations was compared. Target/Control images were presented at three stimulus onset asynchronies (SOAs: 200, 500, and 2000 ms) on a 17-inch monitor. Former smokers avoided target images (TIs). Mean reaction time to control images was shorter than to TIs, confirming the attentional avoidance of TIs. Attentional avoidance of TIs and the lower emotional valence of these stimuli may have been a strategy to avoid relapse. Sustained avoidance to smoking-related cues may be a predictor of long-term abstinence. Direct training of AB away from drug cues may improve the results of smoking cessation therapy. PMID- 24074849 TI - Association of deferring a quit attempt with smoking cessation success: a secondary analysis. AB - Several smoking cessation treatments ask smokers to wait to quit to obtain treatment. We report a secondary analysis of whether a later quit attempt is associated with less success. In a placebo-controlled trial of varenicline that allowed smokers to set their quit date within 5 weeks after starting medication, 24% had their first quit attempt during week 1, and 27%, 19%, 18% and 12% in subsequent weeks. Continuous abstinence between 9 and 24 weeks declined over time; that is, from 36% to 37%, 35%, 29%, and 18% across the 5 weeks (p<0.001). The only statistically significant difference was between the last week and prior weeks. Whether a later quit attempt actually causes less success or is a marker for other variables (e.g., low motivation) is unclear. PMID- 24074850 TI - Meeting health and psychological needs of women in drug treatment court. AB - We explored healthcare-related experiences of women drug court participants through combining context from the socio-ecological model with motivation needs for health behavior as indicated by self-determination theory. Five focus groups with 8 women drug court participants, 8 court staff, and 9 community service providers were examined using qualitative framework analysis. Themes emerged across the socio-ecological model and were cross-mapped with self-determination theory-defined motivation needs for autonomy, relatedness, and competence. Socio ecological levels contained experiences either supporting or eroding women's motivation needs: (1) intrapersonal challenges participants termed an "evil cycle" of relapse, recidivism, trauma, and life challenges; (2) interpersonal context of parenting and stigma involving features of this "evil cycle"; (3) institutions with logistical barriers to legal and medical assistance; (4) community resources inadequate to support living and employment needs. Self determination theory helps explain motivation required to address the women's healthcare needs and multiple demands at all levels of the socio-ecological model. PMID- 24074851 TI - Addiction treatment centers' progress in preparing for health care reform. AB - The Patient Protection and Affordable Care Act (PPACA) is expected to significantly alter addiction treatment service delivery. Researchers designed the Health Reform Readiness Index (HRRI) for addiction treatment organizations to assess their readiness for the PPACA. Four-hundred twenty-seven organizations completed the HRRI throughout a 3-year period, using a four-point scale to rank their readiness on 13 conditions. HRRI results completed during two different time periods (between 10/1/2010-6/30/2011 and 9/1/2011-9/30/2012) were analyzed and compared. Most respondents self-assessed as being in the early stages of preparation for 9 of the 13 conditions. Survey results showed that organizations with annual budgets < $5 million (n=295) were less likely to be prepared for the PPACA than organizations with annual budgets > $5 million (n=132). The HRRI results suggest that the addiction field, and in particular smaller organizations, is not preparing adequately for health care reform; organizations that are making preparations are making only modest gains. PMID- 24074853 TI - FOXO in the hole: leveraging GWAS for outcome and function. AB - GWAS studies of autoimmune disorders have yielded hundreds of replicated associations, but moving from genetic association to functional studies with potential clinical relevance is a challenge. Leveraging GWAS data, Lee et al. now identify FOXO3 activity as predictive of disease severity in Crohn's disease and rheumatoid arthritis as well as malaria, likely by acting through regulation of cytokine production in monocytes. PMID- 24074852 TI - Psychometric properties of the adjective rating scale for withdrawal across treatment groups, gender, and over time. AB - The adjective rating scale for withdrawal (ARSW) is commonly used to assess opiate withdrawal in clinical practice and research. The aims of this study were to examine the factor structure of the ARSW, test measurement invariance across gender and treatment groups, and assess longitudinal measurement invariance across the clinical trial. Secondary data analysis of the National Drug Abuse Treatment Clinical Trials Network 000-3, a randomized clinical trial comparing two tapering strategies, was performed. The ARSW was analyzed at baseline, end of taper and 1-month follow-up (N=515 opioid-dependent individuals). A 1-factor model of the ARSW fit the data and demonstrated acceptable reliability. Measurement invariance was supported across gender and taper groups. Longitudinal measurement invariance was not found across the course of the trial, with baseline assessment contributing to the lack of invariance. If change over time is of interest, change from post-treatment through follow-up may offer the most valid comparison. PMID- 24074854 TI - G1 compartmentalization and cell fate coordination. AB - Pauklin and Vallier show that, whereas early G1 is permissive for TGF-beta dependent endoderm differentiation, cyclin D restricts the activity of Smad2/3 in late G1, resulting in a switch from endoderm to neuroectoderm potential in pluripotent stem cells. These findings provide insight into how signaling, the cell cycle, and lineage specification are coordinated. PMID- 24074855 TI - For genomes to stay in shape, insulators must be up to PAR. AB - Insulators drive nuclear organization by blocking or facilitating interactions between DNA regulatory elements. Ong et al. show that poly(ADP-ribosyl)ation of insulator binding proteins modulates their ability to physically interact with distant regulatory elements, implicating posttranslational modifications of nonhistone proteins in genome architecture. PMID- 24074856 TI - Mitofusins: mighty regulators of metabolism. AB - Mitochondria are central regulators of cellular metabolism but how their function in a subset of cells affects whole-body energy balance is less understood. Two studies in this issue of Cell identify how diet-dependent modulation of mitochondrial fusion in specific neuronal circuits impact the metabolic status of an animal. PMID- 24074857 TI - Cerebral organoids in a dish: progress and prospects. AB - A three-dimensional culture of cortical tissues derived from pluripotent stem cells offers an opportunity to model human brain development and disorders. In a recent issue of Nature, Lancaster et al. describe a new method for generating cerebral organoids in a dish and use it to model microcephaly. PMID- 24074858 TI - Distilling pathophysiology from complex disease genetics. AB - Technologies for genome-wide sequence interrogation have dramatically improved our ability to identify loci associated with complex human disease. However, a chasm remains between correlations and causality that stems, in part, from a limiting theoretical framework derived from Mendelian genetics and an incomplete understanding of disease physiology. Here we propose a set of criteria, akin to Koch's postulates for infectious disease, for assigning causality between genetic variants and human disease phenotypes. PMID- 24074859 TI - The next-generation sequencing revolution and its impact on genomics. AB - Genomics is a relatively new scientific discipline, having DNA sequencing as its core technology. As technology has improved the cost and scale of genome characterization over sequencing's 40-year history, the scope of inquiry has commensurately broadened. Massively parallel sequencing has proven revolutionary, shifting the paradigm of genomics to address biological questions at a genome wide scale. Sequencing now empowers clinical diagnostics and other aspects of medical care, including disease risk, therapeutic identification, and prenatal testing. This Review explores the current state of genomics in the massively parallel sequencing era. PMID- 24074860 TI - Mapping human epigenomes. AB - As the second dimension to the genome, the epigenome contains key information specific to every type of cells. Thousands of human epigenome maps have been produced in recent years thanks to rapid development of high throughput epigenome mapping technologies. In this review, we discuss the current epigenome mapping toolkit and utilities of epigenome maps. We focus particularly on mapping of DNA methylation, chromatin modification state, and chromatin structures, and emphasize the use of epigenome maps to delineate human gene regulatory sequences and developmental programs. We also provide a perspective on the progress of the epigenomics field and challenges ahead. PMID- 24074861 TI - A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk. AB - Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases. PMID- 24074862 TI - Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. AB - The importance of maternal folate consumption for normal development is well established, yet the molecular mechanism linking folate metabolism to development remains poorly understood. The enzyme methionine synthase reductase (Mtrr) is necessary for utilization of methyl groups from the folate cycle. We found that a hypomorphic mutation of the mouse Mtrr gene results in intrauterine growth restriction, developmental delay, and congenital malformations, including neural tube, heart, and placental defects. Importantly, these defects were dependent upon the Mtrr genotypes of the maternal grandparents. Furthermore, we observed widespread epigenetic instability associated with altered gene expression in the placentas of wild-type grandprogeny of Mtrr-deficient maternal grandparents. Embryo transfer experiments revealed that Mtrr deficiency in mice lead to two distinct, separable phenotypes: adverse effects on their wild-type daughters' uterine environment, leading to growth defects in wild-type grandprogeny, and the appearance of congenital malformations independent of maternal environment that persist for five generations, likely through transgenerational epigenetic inheritance. PMID- 24074863 TI - Transcription recovery after DNA damage requires chromatin priming by the H3.3 histone chaperone HIRA. AB - Understanding how to recover fully functional and transcriptionally active chromatin when its integrity has been challenged by genotoxic stress is a critical issue. Here, by investigating how chromatin dynamics regulate transcriptional activity in response to DNA damage in human cells, we identify a pathway involving the histone chaperone histone regulator A (HIRA) to promote transcription restart after UVC damage. Our mechanistic studies reveal that HIRA accumulates at sites of UVC irradiation upon detection of DNA damage prior to repair and deposits newly synthesized H3.3 histones. This local action of HIRA depends on ubiquitylation events associated with damage recognition. Furthermore, we demonstrate that the early and transient function of HIRA in response to DNA damage primes chromatin for later reactivation of transcription. We propose that HIRA-dependent histone deposition serves as a chromatin bookmarking system to facilitate transcription recovery after genotoxic stress. PMID- 24074864 TI - Hira-dependent histone H3.3 deposition facilitates PRC2 recruitment at developmental loci in ES cells. AB - Polycomb repressive complex 2 (PRC2) regulates gene expression during lineage specification through trimethylation of lysine 27 on histone H3 (H3K27me3). In Drosophila, polycomb binding sites are dynamic chromatin regions enriched with the histone variant H3.3. Here, we show that, in mouse embryonic stem cells (ESCs), H3.3 is required for proper establishment of H3K27me3 at the promoters of developmentally regulated genes. Upon H3.3 depletion, these promoters show reduced nucleosome turnover measured by deposition of de novo synthesized histones and reduced PRC2 occupancy. Further, we show H3.3-dependent interaction of PRC2 with the histone chaperone, Hira, and that Hira localization to chromatin requires H3.3. Our data demonstrate the importance of H3.3 in maintaining a chromatin landscape in ESCs that is important for proper gene regulation during differentiation. Moreover, our findings support the emerging notion that H3.3 has multiple functions in distinct genomic locations that are not always correlated with an "active" chromatin state. PMID- 24074865 TI - Dnmt3L antagonizes DNA methylation at bivalent promoters and favors DNA methylation at gene bodies in ESCs. AB - The de novo DNA methyltransferase 3-like (Dnmt3L) is a catalytically inactive DNA methyltransferase that cooperates with Dnmt3a and Dnmt3b to methylate DNA. Dnmt3L is highly expressed in mouse embryonic stem cells (ESCs), but its function in these cells is unknown. Through genome-wide analysis of Dnmt3L knockdown in ESCs, we found that Dnmt3L is a positive regulator of methylation at the gene bodies of housekeeping genes and, more surprisingly, is also a negative regulator of methylation at promoters of bivalent genes. Dnmt3L is required for the differentiation of ESCs into primordial germ cells (PGCs) through the activation of the homeotic gene Rhox5. We demonstrate that Dnmt3L interacts with the Polycomb PRC2 complex in competition with the DNA methyltransferases Dnmt3a and Dnmt3b to maintain low methylation levels at the H3K27me3 regions. Thus, in ESCs, Dnmt3L counteracts the activity of de novo DNA methylases to maintain hypomethylation at promoters of bivalent developmental genes. PMID- 24074866 TI - The cell-cycle state of stem cells determines cell fate propensity. AB - Self-renewal and differentiation of stem cells are fundamentally associated with cell-cycle progression to enable tissue specification, organ homeostasis, and potentially tumorigenesis. However, technical challenges have impaired the study of the molecular interactions coordinating cell fate choice and cell-cycle progression. Here, we bypass these limitations by using the FUCCI reporter system in human pluripotent stem cells and show that their capacity of differentiation varies during the progression of their cell cycle. These mechanisms are governed by the cell-cycle regulators cyclin D1-3 that control differentiation signals such as the TGF-beta-Smad2/3 pathway. Conversely, cell-cycle manipulation using a small molecule directs differentiation of hPSCs and provides an approach to generate cell types with a clinical interest. Our results demonstrate that cell fate decisions are tightly associated with the cell-cycle machinery and reveal insights in the mechanisms synchronizing differentiation and proliferation in developing tissues. PMID- 24074867 TI - Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. AB - Mitofusin 2 (MFN2) plays critical roles in both mitochondrial fusion and the establishment of mitochondria-endoplasmic reticulum (ER) interactions. Hypothalamic ER stress has emerged as a causative factor for the development of leptin resistance, but the underlying mechanisms are largely unknown. Here, we show that mitochondria-ER contacts in anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus are decreased in diet-induced obesity. POMC-specific ablation of Mfn2 resulted in loss of mitochondria-ER contacts, defective POMC processing, ER stress-induced leptin resistance, hyperphagia, reduced energy expenditure, and obesity. Pharmacological relieve of hypothalamic ER stress reversed these metabolic alterations. Our data establish MFN2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. This previously unrecognized role for MFN2 argues for a crucial involvement in mediating ER stress-induced leptin resistance. PMID- 24074868 TI - Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. AB - Mitochondria are key organelles in the maintenance of cellular energy metabolism and integrity. Here, we show that mitochondria number decrease but their size increase in orexigenic agouti-related protein (Agrp) neurons during the transition from fasted to fed to overfed state. These fusion-like dynamic changes were cell-type specific, as they occurred in the opposite direction in anorexigenic pro-opiomelanocortin (POMC) neurons. Interfering with mitochondrial fusion mechanisms in Agrp neurons by cell-selectively knocking down mitofusin 1 (Mfn1) or mitofusin 2 (Mfn2) resulted in altered mitochondria size and density in these cells. Deficiency in mitofusins impaired the electric activity of Agrp neurons during high-fat diet (HFD), an event reversed by cell-selective administration of ATP. Agrp-specific Mfn1 or Mfn2 knockout mice gained less weight when fed a HFD due to decreased fat mass. Overall, our data unmask an important role for mitochondrial dynamics governed by Mfn1 and Mfn2 in Agrp neurons in central regulation of whole-body energy metabolism. PMID- 24074869 TI - NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids. AB - Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and omega3 fatty acids. Remarkably, the increased omega3 fatty acid levels primarily inhibit NF-kappaB-dependent inflammatory responses by uncoupling NF-kappaB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies. PMID- 24074870 TI - Retinoic acid signaling is essential for embryonic hematopoietic stem cell development. AB - Hematopoietic stem cells (HSCs) develop from a specialized subpopulation of endothelial cells known as hemogenic endothelium (HE). Although the HE origin of HSCs is now well established in different species, the signaling pathways that control this transition remain poorly understood. Here, we show that activation of retinoic acid (RA) signaling in aorta-gonad-mesonephros-derived HE ex vivo dramatically enhanced its HSC potential, whereas conditional inactivation of the RA metabolizing enzyme retinal dehydrogenase 2 in VE-cadherin expressing endothelial cells in vivo abrogated HSC development. Wnt signaling completely blocked the HSC inductive effects of RA modulators, whereas inhibition of the pathway promoted the development of HSCs in the absence of RA signaling. Collectively, these findings position RA and Wnt signaling as key regulators of HSC development and in doing so provide molecular insights that will aid in developing strategies for their generation from pluripotent stem cells. PMID- 24074871 TI - Maternal and offspring pools of osteocalcin influence brain development and functions. AB - The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain, and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression, and favors learning and memory independently of its metabolic functions. In addition to these postnatal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result, the severity of the neuroanatomical defects and learning and memory deficits of Osteocalcin(-/-) mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin(-/-) mothers rescues these abnormalities in their Osteocalcin(-/-) progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development. PMID- 24074873 TI - Safety analysis of discrete event systems using a simplified Petri net controller. AB - This paper deals with the problem of forbidden states in discrete event systems based on Petri net models. So, a method is presented to prevent the system from entering these states by constructing a small number of generalized mutual exclusion constraints. This goal is achieved by solving three types of Integer Linear Programming problems. The problems are designed to verify the constraints that some of them are related to verifying authorized states and the others are related to avoiding forbidden states. The obtained constraints can be enforced on the system using a small number of control places. Moreover, the number of arcs related to these places is small, and the controller after connecting them is maximally permissive. PMID- 24074872 TI - Genetic variants regulating immune cell levels in health and disease. AB - The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing ~8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease. PMID- 24074874 TI - Selection for lean meat yield in lambs reduces indicators of oxidative metabolism in the longissimus muscle. AB - Selection for increased lean meat yield using Australian Sheep Breeding Values for reduced post-weaning c-site fat depth (PFAT) and increased post-weaning eye muscle depth (PEMD) reduces the oxidative capacity of muscle. Isocitrate dehydrogenase (ICDH) activity and myoglobin concentration were measured in 3178 and 5580 lambs, respectively, to indicate oxidative capacity. In the progeny of sires with a reduced PFAT, ICDH activity and myoglobin concentration were reduced by 0.46 MUmol/min/g tissue and 0.67 mg/g tissue across the 5 and 6mm PFAT ranges respectively. In the progeny of sires with an increased PEMD, ICDH activity and myoglobin concentration were reduced by 0.50 MUmol/min/g tissue and 0.49 mg/g tissue across the 7 and 6 mm PEMD ranges respectively. However, the sites at which the lambs were raised had a larger impact on oxidative capacity than genetic or other production factors. PMID- 24074875 TI - National estimates of the burden of inflammatory bowel disease among racial and ethnic groups in the United States. AB - BACKGROUND: The epidemiology of inflammatory bowel disease (IBD) is poorly characterized in minorities in the U.S. We sought to enumerate the burden of IBD among racial and ethnic groups using national-level data. METHODS: Data from the National Health Interview Survey was used to calculate prevalence and incidence of IBD among adults (>= 18 years) in 1999. The Nationwide Inpatient Sample was queried to ascertain rates of IBD-related hospitalizations and the Underlying Cause of Death Database was accessed to quantify IBD-related mortality. RESULTS: An estimated 1,810,773 adult Americans were affected by IBD yielding a prevalence of 908/100,000, which was higher in Non-Hispanic Whites (1099/100,000) compared with Non-Hispanic Blacks (324/100,000), Hispanics (383/100,000), and non-Hispanic Other (314/100,000). Relative to Non-Hispanic Whites, the odds ratios for having a diagnosis of IBD associated with being Non-Hispanic Black, Hispanic, and Other Non-Hispanic race after adjusting for age, sex, and geographic region were 0.33 (95% CI: 0.19 - 0.57), 0.45 (95% CI: 0.26 - 0.77), and 0.34 (95% CI: 0.12 - 0.93), respectively. IBD incidence was similarly lower in Non-Hispanic Blacks (24.9/100,000) and Hispanics (9.9/100,000) compared to Non-Hispanic Whites (70.2/100,000). The ratio of IBD hospitalizations to prevalence was disproportionately higher among Non-Hispanic Blacks (7.3%) compared with Non Hispanic Whites (3.0%) and Hispanics (2.7%). Similarly, the ratio of IBD-related mortality was greater in Non-Hispanic Blacks (0.061%) compared to Non-Hispanic Whites (0.036%) and Hispanics (0.026%). CONCLUSIONS: IBD disease burden is lower in ethnic minorities compared to Non-Hispanic Whites. However, IBD-related hospitalizations and deaths seem disproportionately high in Non-Hispanic Blacks. PMID- 24074876 TI - Synthesis of sterically encumbered 11beta-aminoprogesterone derivatives and evaluation as 11beta-hydroxysteroid dehydrogenase inhibitors and mineralocorticoid receptor antagonists. AB - 11beta-Hydroxyprogesterone is a well-known nonselective inhibitor of 11beta hydroxysteroid dehydrogenase (11betaHSD) types 1 and 2. It also activates the mineralocorticoid receptor (MR). Modulation of corticosteroid action by inhibition of 11betaHSDs or blocking MR is currently under consideration for treatment of electrolyte disturbances, metabolic diseases and chronic inflammatory disorders. We established conditions to synthesize sterically demanding 11beta-aminoprogesterone, which following subsequent nucleophilic or reductive amination, allowed extension of the amino group to prepare amino acid derivatives. Biological testing revealed that some of the 11beta aminoprogesterone derivatives selectively inhibit 11betaHSD2. Moreover, two compounds that did not significantly inhibit 11betaHSDs had antagonist properties on MR. The 11beta-aminoprogesterone derivatives form a basis for the further development of improved modulators of corticosteroid action. PMID- 24074877 TI - Dimeric argininamide-type neuropeptide Y receptor antagonists: chiral discrimination between Y1 and Y4 receptors. AB - The structurally related peptides neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) are endogenous agonists of the NPY receptor (YR) family, which in humans comprises four functionally expressed subtypes, designated Y1R, Y2R, Y4R and Y5R. Nonpeptide antagonists with high affinity and selectivity have been described for the Y1R, Y2R and Y5R, but such compounds are still lacking for the Y4R. In this work, the structures of the high affinity selective (R)-argininamide-type Y1R antagonists BIBP3226 and BIBO3304 were linked via the guanidine or urea moieties to give homo-dimeric argininamides with linker lengths ranging from 31 to 41 atoms. Interestingly, the twin compounds proved to be by far less selective for the Y1R than the R-configured monovalent parent compounds. The decrease in selectivity ratio was most pronounced for Y1R versus Y4R subtype, resulting in comparable affinities of bivalent ligands for Y1R and Y4R (e.g. UR-MK177 ((R,R)-49): Ki=230nM (Y1R) and 290nM (Y4R)). With a Ki value of 130nM and a Kb value of 20nM, UR-MK188 ((R,R)-51) was superior to all Y4R antagonists known to date. The S,S-configured optical antipodes of UR-MK177 and UR-MK188 (UR-MEK381 ((S,S)-49) and UR-MEK388 ((S,S)-51)) were synthesized to investigate the stereochemical discrimination by the different receptor subtypes. Whereas preference for R,R-configured argininamides was characteristic of the Y1R, stereochemical discrimination by the Y4R was not observed. This may pave the way to selective Y4R antagonists. PMID- 24074878 TI - Synthesis and anti-Trypanosoma cruzi activity of naphthoquinone-containing triazoles: electrochemical studies on the effects of the quinoidal moiety. AB - In our continued search for novel trypanocidal compounds, twenty-six derivatives of para- and ortho-naphthoquinones coupled to 1,2,3-triazoles were synthesized. These compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Compounds 17-24, 28 30 and 36-38 are described herein for the first time. Three of these novel compounds (28-30) were found to be more potent than the standard drug benznidazole, with IC50/24h values between 6.8 and 80.8MUM. Analysis of the toxicity to heart muscle cells led to LC50/24h of <125, 63.1 and 281.6MUM for 28, 29 and 30, respectively. Displaying a selectivity index of 34.3, compound 30 will be further evaluated in vivo. The electrochemical properties of selected compounds were evaluated in an attempt to find correlations with trypanocidal activity, and it was observed that more electrophilic quinones were generally more potent. PMID- 24074879 TI - Phase II study of liposome-encapsulated doxorubicin plus cyclophosphamide, followed by sequential trastuzumab plus docetaxel as primary systemic therapy for breast cancer patients with HER2 overexpression or amplification. AB - PURPOSE OF THE STUDY: Trastuzumab combined with sequential chemotherapy with taxanes and anthracyclines as primary systemic therapy achieved high rates of pathologic complete response (pCR). Non-pegylated liposome-encapsulated doxorubicin (NPLD) has shown equal efficacy but minor cardiotoxicity compared to doxorubicin. This phase II study aimed to evaluate the activity and safety of trastuzumab with sequential chemotherapy for early or locally advanced HER2 positive BC. METHODS: Preoperative treatment included NPLD (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by docetaxel (35 mg/mq iv) plus trastuzumab (4 mg/mq loading dose iv, then 2 mg/mq iv) weekly for 16 weeks. Primary endpoint was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes. Clinical staging was exploratory evaluated by CT-PET. RESULTS: 43 pts were treated from december 2005 to September 2011, 39 of them were evaluable for the purpose of study. Median age was 53 years (range: 31-78), the majority of pts had tumour stage cT2 (63%), tumour grade 3 (86%), clinical nodes involvement N+ (77%), ER positive (56%) and Ki-67 >=20% (77%). pCR was reported in 19 (49%) of 39 pts. There was an association between Ki-67 >=20% at baseline and pCR (p = 0.018). No cardiac toxicity or discontinuation of trastuzumab was reported. CT-PET modified the clinical stage for 10 patients showing new loco-regional lymph nodes. CONCLUSIONS: This study confirms that integrating anti-HER2 therapy in primary treatment for HER2 positive breast cancer is active. NPLD is a safe option to minimize cardiotoxicity. PMID- 24074880 TI - Occurrence and removal of selected micropollutants in a water treatment plant. AB - The levels of 14 micropollutants including nine pharmaceuticals, two pesticides, and three endocrine disruptors were measured in a water treatment plant (WTP) in Seoul, Korea. Among the measured micropollutants, 12 (excluding atrazine and triclocarban) were found in the influent and effluent from the WTP, at levels ranging from 2 to 482 ng L(-1). The removal efficiencies of the detected micropollutants in the WTP ranged from 6% to 100%. Among them diclofenac, acetaminophen, caffeine, carbamazepine, and 2,4-D were effectively removed (>80%). Metoprolol was unlikely to be removed (6%) in the WTP process. Concentrations of acetaminophen, metoprolol, ibuprofen, and naproxen were higher in winter, while levels of herbicides of 2,4-dichloro-phenoxyacetic acid (2,4-D) were higher in summer. Metoprolol was hardly removed in the water treatment process. Laboratory experiments showed that compounds with logKow>2.5 (especially bisphenol-A, 2,4-D, carbamazepine, triclocarban and 4-nonylphenol) were effectively removed by coagulation process, and adsorption effect increased in proportion with hydrophobicity of micropollutants and the turbidity of water. Sunlight photodegradation also effectively removed sulfamethoxazole, sulfamethazine, caffeine, diclofenac, ibuprofen, and acetaminophen, which are photosensitizes. Chlorination was relatively not effective for the removal of micropollutants due to the lower chlorine dosage (2 mg L(-1)), lower contact time (1h), and already lower levels of micropollutants at the chlorination stage at WTP. Our results imply that micropollutants during coagulation stage at WTP can be removed not only by coagulation itself, but also by adsorption to clay particle especially for high turbidity water, and by sunlight photodegradation in the areas open to the atmosphere. PMID- 24074881 TI - Synthesized magnetic nanoparticles coated zeolite for the adsorption of pharmaceutical compounds from aqueous solution using batch and column studies. AB - The contamination of fresh water with pharmaceutical and personal care products (PPCPs) has risen during the last few years. The adsorption of some PPCPs namely, Diclofenac-Na, Naproxen, Gemfibrozil and Ibuprofen from aqueous solution has been studied, magnetic nanoparticles coated zeolite (MNCZ) has been used as the adsorbent. Batch adsorption experiment was conducted to study the influences of different adsorption parameters such as contact time, solution pH and PPCPs concentrations in order to optimize the reaction conditions. The removal was favored at low pH values. Thus, as pH turns from acidic to basic conditions these compounds were less efficiently removed. The initial concentration does not appear to exert a noticeable effect on the removal efficiency of the studied PPCPs at low concentrations, but it showed less removal efficiency during high concentration of PPCPs especially for Ibuprofen. The removal of Diclofenac-Na was independent on time, while the contact time was of significant effect on the adsorption of Naproxen, Gemfibrozil and Ibuprofen even though these compounds were removed up to 95% during 10 min using MNCZ. From the isotherm adsorption study, the adsorption of PPCPs studied on MNCZ was best fitted with Freundlich isotherm equation. Pseudo-second order model providing the best fit model with the experimental data. Column adsorption study was conducted to compare the removal efficiency of MNCZ with other processes used at drinking water treatment plants (DWTPs), MNCZ showed high removal efficiency (>99%) than other used processes at DWTPs. PMID- 24074882 TI - Factors affecting bilateral temporal lobe hypometabolism on 18F-FDG PET brain scan in unilateral medial temporal lobe epilepsy. AB - Bilateral temporal lobe hypometabolism (BTH) on (18)F-FDG PET brain scan is frequently seen in unilateral medial temporal lobe epilepsy (mTLE). This study aimed to identify the factors that influence BTH in patients with mTLE in order to minimize the significant factor(s) prior to performing a FDG-PET brain scan. Forty patients with unilateral mTLE who underwent (18)F-FDG PET scan for presurgical epilepsy workup were included. Bilateral temporal lobe hypometabolism of the anterior and medial parts of the temporal lobe was identified by a semiquantitative visual scale. Lateralization of TLE was identified by either intracranial EEG (22/40 cases) and/or improvement of seizure 2 years after temporal lobectomy (37/40 cases). The factors analyzed included basic demographic characteristics (age, sex, occupation, years of education, and handedness), history related to seizure (age at epilepsy onset and epilepsy duration, history of febrile seizure and head injury, frequency of seizure with impaired cognition in the last 3 months, presence of secondarily generalized tonic-clonic seizure, automatism side, presence of postictal confusion, and side of MRI temporal abnormality), information during video-EEG monitoring (clinical lateralization, interictal scalp EEG lateralization (interictal epileptiform discharge), and ictal scalp EEG lateralization), and information during the FDG-PET study (duration from the last seizure (<=2 days or >2 days), last seizure type, and the presence of slow waves or sharp waves during the FDG uptake period). Significant factors related to BTH were analyzed using multivariate analysis. Only the <=2 day duration from the last seizure to the PET scan shows a significant effect (p=0.021) on BTH finding with 15 times greater incidence compared to a duration >2 days. Bilateral temporal lobe hypometabolism, which causes conflict in lateralizing the epileptogenic zone in temporal lobe epilepsy, can be avoided by performing PET scan more than 2 days after the last seizure. PMID- 24074883 TI - Psychiatric comorbidity and social aspects in pregnant women with epilepsy - the Norwegian Mother and Child Cohort Study. AB - OBJECTIVE: The objective of this study was to investigate psychiatric disease and social aspects in young women with epilepsy before and during pregnancy. METHOD: The study included self-reported data from 106,935 pregnancies. RESULTS: Seven hundred eleven women reported having epilepsy, and 45.9% of them were using antiepileptic drugs (AEDs). Compared to the reference group, self-reported eating disorders and depression were increased in the untreated epilepsy group before pregnancy. Both AED-treated and untreated women with epilepsy reported higher depression scores as assessed by the Hopkins Symptom Checklist, and the Lifetime Major Depression scale was increased in AED-treated women. Antiepileptic drug treatment was linked to low income (27.4% vs. 18.4%, p<0.001) and no income (5.5% vs. 2.6%, p=0.001). Low educational level was associated with epilepsy in AED treated and untreated women (50.5%, p<0.001 and 46.9%, p<0.001 vs. 32.2%), as was unemployment due to disability (7.9%, p<0.001 and 6.5%, p<0.001 vs. 1.5%) and single parenting (4.4%, p=0.016 and 4.5%, p=0.007 vs. 2.4%). No difference was found for smoking, alcohol use, or narcotic use. CONCLUSION: Symptoms of depression were associated with epilepsy both during and before pregnancy. Epilepsy was linked to eating disorders before pregnancy. Unemployment, single parenting, and low educational level were linked to epilepsy in young pregnant females. Efforts aiming at treatment and screening for psychiatric comorbidity in pregnant women with epilepsy are important in the follow-up of these patients. PMID- 24074884 TI - The change in cerebral glucose metabolism generated by electroacupuncture may predict the outcome of stimulation of the anterior nucleus thalamus in refractory epilepsy. PMID- 24074885 TI - Physical exercise as a coping strategy for people with epilepsy and depression. PMID- 24074886 TI - Linguistic biomarkers of Hubris syndrome. AB - Owen and Davidson coined the term 'Hubris Syndrome' (HS) for a characteristic pattern of exuberant self-confidence, recklessness, and contempt for others, shown by some individuals holding substantial power. Meaning, emotion and attitude are communicated intentionally through language, but psychological and cognitive changes can be reflected in more subtle ways, of which a speaker remains unaware. Of the fourteen symptoms of HS, four imply lexical choices: use of the third person/'royal we'; excessive confidence; exaggerated self-belief; and supposed accountability to God or History. One other feature (recklessness) could influence language complexity if impulsivity leads to unpredictability. These hypotheses were tested by examining transcribed spoken discourse samples produced by two British Prime Ministers (Margaret Thatcher and Tony Blair) who were said to meet criteria for HS, and one (John Major) who did not. We used Shannon entropy to reflect informational complexity, and temporal correlations (words or phrases whose relative frequency correlated negatively with time in office) and keyness values to identify lexical choices corresponding to periods during which HS was evident. Entropy fluctuated in all three subjects, but consistent (upward) trends in HS-positive subjects corresponded to periods of hubristic behaviour. The first person pronouns 'I' and 'me' and the word 'sure' were among the strongest positive temporal correlates in Blair's speeches. Words and phrases that correlated in the speeches of Thatcher and Blair but not in those of Major included the phrase 'we shall' and 'duties' (both negative). The keyness ratio of 'we' to 'I' was clearly higher throughout the terms of office of Thatcher and Blair that at any point in the premiership of Major, and this difference was particularly marked in the case of Blair. The findings are discussed in the context of historical evidence and ideas for enhancing the signal to noise ratio put forward. PMID- 24074887 TI - Induction of a sense of bliss by electrical stimulation of the anterior insula. PMID- 24074888 TI - The relationship between facility delivery and infant immunization in Ethiopia. AB - OBJECTIVE: To determine whether facility delivery is related to compliance with recommended infant immunizations, particularly those that occur weeks or months after delivery. METHODS: In a retrospective analysis, multivariate logistic regression was used to assess data from the 2011 Ethiopia Demographic and Health Survey (EDHS) to determine the strongest correlates of facility delivery. These correlates were then used, along with facility delivery itself, to determine the relationship between facility delivery and infant immunization. RESULTS: In total, 3334 women delivered a newborn 12-24months before the 2011 EDHS: 90.2% (3007) delivered at home, and 9.8% (327) delivered in a facility. Education, wealth status, urban residence, and number of children under 5years living in the household were the factors most strongly associated with facility delivery. When facility delivery and its strongest correlates were entered into multivariate logistic regression models with infant immunizations as the outcome, facility delivery was significantly associated with increased likelihood of DPT-HepB-Hib, polio, and measles vaccination, and increased likelihood of being fully immunized (all P<0.01). Facility delivery was the strongest single factor associated with infants being immunized, doubling the odds of full immunization. CONCLUSION: The impact of facility delivery on health outcomes transcends the immediate delivery and postpartum period. PMID- 24074889 TI - Use of intraoperative X-rays to optimize component position and leg length during total hip arthroplasty. AB - Proper femoral and acetabular component position and leg length equality are important intraoperative considerations during total hip arthroplasty. Unfortunately, traditional surgical techniques often lead to suboptimal component position, and such deviations have been associated with increased rates of prosthetic wear, dislocation, component loosening, and patient dissatisfaction. Although surgical navigation has been shown to improve reproducibility of component alignment, such technology is not universally available and is associated with significant costs and additional surgical/anesthetic time. In the current study, we found that a routine intraoperative pelvic radiograph could successfully identify malpositioned components and leg length inequalities and could allow for successful correction of identified problems. Unexpected component malposition and leg length inequality occurred in only 1.5% of cases where an intraoperative pelvic radiograph was utilized. PMID- 24074890 TI - Cemented liner exchange with bone grafting halts the progression of periacetabular osteolysis. AB - The aims of this were to examine the effect of acetabular liner exchange and intra-operative bone grafting surgery on peri-prosthetic osteolysis. Seven patients with well-fixed Harris-Galante-1 acetabular components received cemented exchange liners for worn liners associated with pre-operatively CT-quantified osteolysis. During surgery, accessible osteolytic lesions were debrided and bone grafted. Except for one patient with recurrent dislocation and acetabular component revision, the other patients had CT scans at a median of 4 months and at approximately 4 years after surgery. None of the pre-operative lesions increased in volume during the post-operative reporting period and no new lesions were detected. These results show that cemented liner exchange surgery can halt the progression of osteolysis and that bone grafting has the potential to restore bone. PMID- 24074891 TI - Amygdala enlargement occurs in patients with mesial temporal lobe epilepsy and hippocampal sclerosis with early epilepsy onset. AB - Mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) is considered an electroclinical syndrome, and there is a debate whether it is a unique disease or an entity with distinct subtypes. Together with other mesial temporal structures, the amygdala is important in the epileptogenic network of patients with MTLE with HS. During automatic volumetric analysis of mesial structures in a group of 102 patients with MTLE with MRI signs of HS, we observed significant amygdala enlargement in 14 (14%) individuals compared to a group of 79 healthy subjects. The increased amygdala volume was contralateral to the epileptogenic zone and MRI signs of HS in 93% of these patients. Patients with MTLE with HS and enlarged amygdala had significantly earlier epilepsy onset than those without an increase of amygdala volumes. Mesial temporal lobe epilepsy with HS and enlarged amygdala may be a part of the spectrum of this condition. PMID- 24074892 TI - Reversible antisocial behavior in ventromedial prefrontal lobe epilepsy. AB - Frontal lobe dysfunction is known to be associated with impairment in social behavior. We investigated the link between severe pharmacoresistant frontal lobe epilepsy and antisocial trait. We studied four patients with pharmacoresistant epilepsy involving the prefrontal cortex, presenting abnormal interictal social behavior. Noninvasive investigations (video-EEG, PET, MRI) and intracerebral recording (stereoelectroencephalography (SEEG)) were performed as part of a presurgical assessment. Comprehensive psychiatric and cognitive evaluation was performed pre- and postoperatively for frontal lobe epilepsy, with at least 7years of follow-up. All patients shared a characteristic epilepsy pattern: (1) chronic severe prefrontal epilepsy with daily seizures and (2) an epileptogenic zone as defined by intracerebral recording involving the anterior cingulate cortex, ventromedial PFC, and the posterior part of the orbitofrontal cortex, with early propagation to contralateral prefrontal and ipsilateral medial temporal structures. All patients fulfilled the diagnostic criteria (DSM-IV) of antisocial personality disorder, which proved to be reversible following seizure control. Pharmacoresistant epilepsy involving a prefrontal network is associated with antisocial personality. We hypothesize that the occurrence of frequent seizures in this region over a prolonged period produces functional damage leading to impaired prefrontal control of social behavior. This functional damage is reversible since successful epilepsy surgery markedly improved antisocial behavior in these patients. The results are in line with previous reports of impairment of social and moral behavior following ventromedial frontal lobe injury. PMID- 24074893 TI - Cardiac arrest and epilepsy: what is the role of educational programs for health professionals and caregivers? PMID- 24074894 TI - Procedural risk following carotid endarterectomy in the hyperacute period after onset of symptoms. AB - OBJECTIVES: There have been concerns that performing carotid endarterectomy (CEA) in the hyperacute period after onset of a transient ischaemic attack (TIA) or stroke may be associated with a significant increase in the procedural risk that could offset any long-term benefit to the patient. The aim of this audit was to determine the 30-day risk of stroke/death after CEA in symptomatic patients, stratified for delay from the most recent neurological event, mode of presentation, and age. METHODS: Retrospective audit in 475 recently symptomatic patients between October 1, 2008, and April 24, 2013. RESULTS: Forty-one patients (9%) underwent surgery <48 hours of their most recent event, with a 30-day death/stroke rate of 2.4% (1/41). The procedural risk was 1.8% in 167 patients who underwent surgery within 3-7 days (3/167), falling to 0.8% in 133 patients who underwent surgery between 8 and 14 days (1/133) and 0.8% in 134 patients whose surgery took place after >14 days had elapsed (1/134). Overall, 208 (44%) underwent surgery within 7 days of their most recent neurological event (30-day risk = 1.9%), while 341 (72%) underwent CEA within 14 days (30 day risk = 1.5%). There was no evidence of any systematic differences in procedural risk by operating in the hyperacute period relating to mode of presentation (TIA, stroke, amaurosis) or age (<80 years; >80 years). CONCLUSIONS: This audit found no evidence that the procedural risk was increased when CEA was performed in the hyperacute period whether this time period was defined as <48 hours, <7 days, or <14 days. PMID- 24074895 TI - Phenotypic differences between IgG4+ and IgG1+ B cells point to distinct regulation of the IgG4 response. PMID- 24074896 TI - Inhibitory effect of metformin on bone metastasis of cancer via OPG/RANKL/RANK system. AB - Diabetes and cancer are both serious health problems worldwide and can lead to a significant burden on society with high incidence. Studies show that diabetes, which may be the reason of cancer metastasis, can increase cancer incidence and mortality. Bone is one of the most preferential metastatic target sites for cancers. Studies also indicate that OPG and RANKL which regulate bone reabsorption play significant roles in the process of bone tumor metastasis. In addition, metformin as a commonly used medicine for type 2 diabetes is a negative regulator of RANKL and inhibits the differentiation of osteoclasts. We present a hypothesis that metformin serves an inhibitory effect on bone metastasis of cancer via OPG/RANKL/RANK system. PMID- 24074897 TI - Pathological niche environment transforms dermal stem cells to keloid stem cells: a hypothesis of keloid formation and development. AB - Keloid is a disease that is difficult to cure because of its high recurrence rate after chemotherapy or radiotherapy, therefore it is considered as a benign skin tumor. Tumor stem cells are proposed as the source for tumor development and post therapy recurrence. Interestingly, keloid stem cells have also been discovered, which share some characters with those of skin progenitor cells. Keloid patients possess specific diathesis including genetic predisposition and gene mutation, abnormal levels of hormones, growth factors and cytokines, and strong inflammatory response. This article reviews related literatures and hypothesizes that keloid stem cells might be transformed from normal dermal progenitor cells in the pathological niche of keloid tissues. These keloid stem cells are highly self-renewal and drug resistant, and can sustain themselves by asymmetric division, and continually generate new keloid cells to replenish the cells killed by drugs or radiation, thus leading to over growth of keloid and high post therapy recurrence rate. PMID- 24074898 TI - Contralateral suppression of distortion-product otoacoustic emissions: a potential diagnostic tool to evaluate the vestibular nerve. AB - The amplitude of distortion-product otoacoustic emission (DPOAE) is suppressed in one ear when the contralateral ear is subjected to sound stimulation. Contralateral suppression of DPOAE is the phenomenon resulted by the efferent cochlear innervation on the outer hair cells via medial olivocochlear bundle (MOCB) and inferior vestibular nerve. We assumed that DPOAE would not be suppressed by contralateral sound stimulation in patients with vestibular nerve lesion as long as the specific pathway conveying that efferent innervation is affected. To test this hypothesis, we compared the amount of DPOAE contralateral suppression in patients with vestibular neuritis and healthy controls. Twenty healthy volunteers without hearing loss and vestibulopathy, and 13 patients with vestibular neuritis were recruited. DP audiogram was measured without contralateral sound stimulation and then with contralateral sound stimulation (70 dB HL of 2 kHz narrow band noise, NBN). The suppression value of DPOAE was evaluated according to the f2 frequency and was defined as the amount of DPOAE suppression: An-Ao, where An represents the DPOAE amplitude in the presence of contralateral NBN, and Ao represents the DPOAE amplitude in the absence of NBN. Cervical vestibular evoked myogenic potential (cVEMP) was performed in some patients with vestibular neuritis. The suppression values of DPOAE were compared between groups and were analyzed according to the results of cVEMP. The amount of suppression of DPOAE during contralateral sound stimulation was significantly reduced in the patient group compared to control at the f2 frequencies of 1257, 1587, and 2002 Hz (P=0.045, P<0.001, P=0.009, respectively). However, the results of contralateral suppression of DPOAE were not consistent with the results of cVEMP in this study. Efferent cochlear innervation was affected in vestibular neuritis. Evaluation of contralateral suppression of DPOAE can be a potential diagnostic tool to evaluate the functional integrity of the vestibular nerve. Further studies are necessary to clarify this mechanism. PMID- 24074899 TI - Spinal cord compression revealing a lambda light chain multiple myeloma. PMID- 24074901 TI - The role of leukemia inhibitory factor in tubal ectopic pregnancy. AB - INTRODUCTION: Ectopic pregnancy is unique to humans and a leading cause of maternal morbidity and mortality. The etiology remains unknown however factors regulating embryo implantation likely contribute. Leukemia inhibitory factor (LIF) has roles in extravillous trophoblast adhesion and invasion and is present in ectopic implantation sites. We hypothesised that LIF facilitates blastocyst adhesion/invasion in the Fallopian tube, contributing to ectopic pregnancy. METHODS: We immunolocalised LIF receptor (R) in tubal ectopic pregnancy (N = 5). We used an oviduct cell line (OE-E6/E7) to model Fallopian tube epithelial cells and a trophoblast spheroid co-culture model (HTR-8/SVneo cell line formed spheroids) to model blastocyst attachment to the Fallopian tube. We examined LIF signaling pathways in OE-E6/E7 cells by Western blot. The effect of LIF and LIF inhibition (using a novel LIF inhibitor, PEGLA) on first-trimester placental outgrowth was determined. RESULTS: LIFR localised to villous and extravillous trophoblast and Fallopian tube epithelium in ectopic pregnancy. LIF activated STAT3 but not the ERK pathway in OE-E6/E7 cells. LIF stimulated HTR-8/SVneo spheroid adhesion to OE-E6/E7 cells which was significantly reduced after PEGLA treatment. LIF promoted placental explants outgrowth, while co-treatment with PEGLA blocked outgrowth. DISCUSSION: Our data suggests LIF facilitates the development of ectopic pregnancy by stimulating blastocyst adhesion and trophoblast outgrowth from placental explants. Ectopic pregnancy is usually diagnosed after 6 weeks of pregnancy, therefore PEGLA may be useful in targeting trophoblast growth/invasion. CONCLUSION: LIF may contribute to the development of ectopic pregnancies and that pharmacologically targeting LIF-mediated trophoblast outgrowth may be useful as a treatment for ectopic pregnancy. PMID- 24074900 TI - Differential apoptosis in BeWo cells after infection with highly (RH) or moderately (ME49) virulent strains of Toxoplasma gondii is related to the cytokine profile secreted, the death receptor Fas expression and phosphorylated ERK1/2 expression. AB - INTRODUCTION: Alterations of apoptosis are commonly associated with pregnancy complications and abortion. Modulation of apoptosis is a relevant feature of Toxoplasma gondii infection and it is related to parasite strain types. The aim of the present study was to evaluate the possible factors that are involved in the differential apoptosis of BeWo cells infected with distinct T. gondii strain types. METHODS: Human trophoblastic cells (BeWo cell line) were infected with RH or ME49 strains, the cytokine production was measured and the phosphorylation of anti-apoptotic ERK1/2 protein was analyzed. Also, cells were treated with different cytokines, infected with RH or ME49 strain, and analyzed for apoptosis index and Fas/CD95 death receptor expression. RESULTS: ME49-infected BeWo cells exhibited a predominantly pro-inflammatory cytokine profile, whereas cells infected with RH strain had a higher production of anti-inflammatory cytokines. Also, the incidence of apoptosis was higher in ME49-infected cells, which have been treated with pro-inflammatory cytokines compared to cells infected with RH and treated with anti-inflammatory cytokines. Moreover, Fas/CD95 expression was higher in cells infected with either ME49 or RH strain and treated with pro inflammatory cytokines compared to anti-inflammatory cytokine treatment. The phosphorylation of ERK1/2 protein increased after 24 h of infection only with the RH strain. CONCLUSION: These results suggest that opposing mechanisms of interference in apoptosis of BeWo cells after infection with RH or ME49 strains of T. gondii can be associated with the differential cytokine profile secreted, the Fas/CD95 expression and the phosphorylated ERK1/2 expression. PMID- 24074902 TI - Analysis of females with Chlamydia trachomatis infections attending a sexually transmissible infection clinic in Singapore in 2010. AB - BACKGROUND: Chlamydia (Chlamydia trachomatis) is the most commonly diagnosed sexually transmissible infection (STI) in Singapore, with rising incidence. METHOD: Random sampling was performed on all chlamydia-positive samples collected from female patients who attended a women's clinic from January 2010 to December 2010. Some 250 electronic medical records were analysed. Population demographics, sexual histories, symptoms, diagnostic methods and management were recorded. RESULTS: One hundred and forty-two (56.8%) patients were under 25 years of age. The predominant race diagnosed with Chlamydia cervicitis were Chinese (116 cases, 46.4%) followed by 86 (34.4%) Malays and 20 (8%) Filipinos. Sixty-three (25.2%) were skilled workers and (47) 18.8% were students. Professionals and office workers together formed 68 (27.2%) of the patients. Some 248 (99.2%) patients were heterosexual and 2 (0.8%) patients were bisexual; 229 (91.6%) patients had regular partners, 18 (7.2%) had casual partners and 3 (1.2%) had both. Concurrency prevalence accounted for 49 cases (19.6%) and condom use was less common. Patients were generally asymptomatic, with 114 (45.5%) presenting with symptoms. One hundred and eight (43.2%) patients had 2-5 sexual partners in their lifetime. Patients with a termination made up 12% of our cohort. This episode of infection was the first diagnosis of an STI for 198 (79.2%) patients; 24 (9.6%) of patients had been previously diagnosed with chlamydia. CONCLUSION: Chlamydia infection was most prevalent in skilled workers and their regular partners with heterosexual practices under 25 years old. Most patients had 2-5 sexual partners and did not use condoms consistently or at all. PMID- 24074903 TI - First case of autochthonous Clostridium difficile PCR ribotype 027 detected in Spain. AB - INTRODUCTION: Clostridium difficile ribotype 027 (Cd027) has caused outbreaks in the United States, Canada, and Europe since 2001. In Spain, the importance of Cd027 is still unknown. In 2007, we began active surveillance of Cd027 to determine its incidence in our hospital. METHODS: From January 2007 to April 2012, isolates of C. difficile by multiplex PCR were studied to detect toxin genes. Binary toxin-positive isolates were characterized using PCR-ribotyping. Cd027 were further characterized by toxino-typing, sequencing of tcdC gene, and MLVA (multilocus-variable-number-tandem-repeat-analysis). RESULTS: Only 8 strains were Cd027 from 3666 isolates of C. difficile analyzed during the study period. These strains were isolated from 4 patients: a Spanish patient previously hospitalized in the UK, a pregnant laboratory technician, a British tourist, and a Spanish patient without epidemiological antecedents for acquiring Cd027. MLVA typing of Cd027 isolates revealed 4 different patterns. The first patient had 2 episodes of diarrhea caused by different Cd027. The strains from the first episode of patient 1 and the strain from patient 2 were grouped in the same clonal cluster (these cases were previously published as laboratory transmission), while strains from patients 3 and 4 were genetically unrelated to each other, and to the strains from patients 1 and 2. CONCLUSION: We report the first finding of an autochthonous case of non-severe Cd027 infection. Our results indicate that Cd027 diarrhea is uncommon in our area, and it appears mainly as imported cases. MLVA typing enables us to distinguish different genotypes among our Cd027 isolates. PMID- 24074904 TI - [Multiresistant Neisseria gonorrhoeae: back to the past?]. PMID- 24074905 TI - Assessment of dietary adequacy for important brain micronutrients in patients presenting to a traumatic brain injury clinic for evaluation. AB - OBJECTIVE: To evaluate dietary adequacy of patients presenting for evaluation at an outpatient traumatic brain injury (TBI) clinic. METHODS: We identified 14 key micronutrients with defined dietary intake reference ranges that are considered important for brain health. Adult patients completed the Brief NutritionQuest Food Frequency Questionnaire (FFQ) to calculate estimated nutrient intake. Medical records were abstracted for diagnoses, body mass index, and neurobehavioral subscale scores. Nutrients were assessed individually and were also summarized into a summary score. Associations between individual nutrients, summary nutrient intake, and neurobehavioral scores were assessed. RESULTS: A total of 39 FFQs were completed by subjects, and 25 (64%) had recorded neurobehavioral scores. No subjects met the recommended dietary allowances (RDAs) for all 14 micronutrients. Ten (26%) met the RDAs for 6 or fewer nutrients, and 10 met the RDAs for 11-12 nutrients. Of 12 nutrients with sufficient sample size for analysis, 11 (92%) were associated with worse mean somatic scores, 9 (75%) were associated with worse cognitive scores, and 8 (67%) were linked with worse affective scores for those with the lowest nutrient intake compared with those who had the highest intake. However, only four nutrients were statistically associated with the somatic mean score: folate (P = 0.010), magnesium (P = 0.082), vitamin C (P = 0.021), and vitamin K (P = 0.024). None were linked with cognitive or affective scores. DISCUSSION: Diets failing to meet RDAs for important brain nutrients were common in an outpatient TBI clinic, with the worst mean neurobehavioral scores for those patients not meeting the estimated average requirements. PMID- 24074906 TI - The effect of lateral banking on the kinematics and kinetics of the lower extremity during lateral cutting movements. AB - There are many aspects of cutting movements that can limit performance, however, the implementation of lateral banking may reduce some of these limitations. Banking could provide a protective mechanism, placing the foot and ankle in orientations that keep them out of dangerous positions. This study sought to determine the effect of two banking angles on the kinematics and kinetics of the lower extremity during two athletic maneuvers. Kinematic and kinetic data were collected on 10 recreational athletes performing v-cuts and side shuffle movements on different banked surfaces (0 degrees , 10 degrees , 20 degrees ). Each sample surface was rigidly attached to the force platform. Joint moments were calculated and compared between conditions using a repeated measures ANOVA. Banking had a pronounced effect on the ankle joint. As banking increased, the amount of joint loading in the transverse and frontal planes decreased likely leading to a reduction in injury risk. Also an increase in knee joint loading in the frontal plane was seen during the 20 degrees bank during the v-cut. Conversely loading in the sagittal plane at the ankle joint increased with banking and coupled with a reorientation of the ground reaction vector may facilitate a performance increase. The current study indicates that the 10 degrees bank may be the optimal bank, in that it decreases ankle joint loading, as well as increases specific performance variables while not increasing frontal plane knee joint loading. If banking could be incorporated in footwear it may be able to provide a protective mechanism for athletes. PMID- 24074907 TI - Intra-limb coordination in karate kicking: Effect of impacting or not impacting a target. AB - This study aimed to investigate the kicking limb coordinative patterns adopted by karate practitioners (karateka) when impacting (IRK), or not impacting (NIRK) a target during a roundhouse kick. Six karateka performed three repetitions of both kicks while kicking limb kinematics were recorded using a stereophotogrammetric system. Intra-limb coordination was quantified for hip and knee flexion-extension from toe-off to kick completion, using the Continuous relative phase (CRP). Across the same time interval, thigh and shank angular momentum about the vertical axis of the body was calculated. For all trials, across all participants, CRP curve peaks and maximum and minimum angular momentum were determined. A RM-ANOVA was performed to test for differences between kicking conditions. The CRP analysis highlighted, during the central portion of both kicks, a delayed flexion of the hip with respect to the knee. Conversely, during the terminal portion of the CRP curves, the NIRK is performed with a more in phase action, caused by a higher hip angular displacement. The NIRK is characterized by a lower angular momentum which may enhance control of the striking limb. It would seem that the issue of no impact appears to be solved through the control of all segments of the kicking limb, in contrast to the primary control of the lower leg only observed during the IRK. PMID- 24074908 TI - Grip selection for sequential movements in children and adults with and without Developmental Coordination Disorder. AB - When generating a movement adults favor grasps which start the body in an uncomfortable position if they end in a comfortable position (the end-state comfort effect). In contrast, children with Developmental Coordination Disorder (DCD) select grasps which require little initial hand rotation even though they result in an uncomfortable end position. The current study considered grip selection of individuals with DCD when asked to make simple one step movements and when making more complex multi-staged movements. Adults with DCD (N=17, mean age 24:09, SD age=52months) and children with DCD (N=20, mean age 9:00, SD age=20months) and age and gender matched controls rotated a disc so an arrow pointed toward a specific target(s). Task complexity was increased by increasing the number of targets from 1 to 3. Planning for end-state-comfort was seen in all groups albeit to a lesser extent in children versus adults. The children with DCD showed fewer grips for end-state-comfort compared to their peers and this was explained by a propensity to select minimal initial rotation grasps. This result was mirrored in adults with DCD but only for the longest movement sequence. These results suggest some changes in ability from childhood to adulthood in individuals with DCD. PMID- 24074909 TI - Capillary measurement of lactate and glucose for free flap monitoring. AB - BACKGROUND: It is reported that the salvage rate of free flaps is inversely related to the time interval between the onset of pedicle impairments and their clinical recognition. Monitoring of free flaps is therefore of major importance and clinical monitoring remains the most used technique because of lack of low cost and non-invasive techniques. The authors suggested an efficient, simple and cheap technique to detect early thrombotic events in monitoring free flaps with skin paddle. METHODS: In this multicentre prospective study, measurements of capillary glucose and lactate in the flaps were done. These parameters were compared to standardized clinical monitoring during the first five days. Two sets of data (eventful versus uneventful postoperative period) were analyzed to define the thresholds of lactate and glucose values for diagnosis of pedicle complications, and to establish parameters for this screening test. RESULTS: Over a period of 19 months, 37 patients were included. With 5 pedicle impairments, complication thresholds were defined as lactate >= 6.4 mmol L(-1) and glucose <= 3.85 mmol L(-1), in order to obtain a sensitivity of 98.5% and a specificity of 99.5% for the test. Modifications of capillary glucose and lactate measurements appeared in average 5.7 hours earlier than clinical symptoms in pedicle impairments. The mean cost of a five-day monitoring was about 90 USD. CONCLUSION: This simple and cheap technique could be used as a routine technique in monitoring free flaps to improve safety of this reconstructive technique. PMID- 24074910 TI - In reply to Froehner et al. PMID- 24074911 TI - Comorbidity and mortality after brachytherapy: in regard to Nanda et al. PMID- 24074912 TI - Quality indicators in radiation oncology: in regard to Albert and Das. PMID- 24074913 TI - In reply to Gueda and Malicki. PMID- 24074914 TI - Obituary--Kie Kian Ang, MD, PhD, FACR, FASTRO. PMID- 24074915 TI - Radiation oncologists, mortality, and treatment choices. PMID- 24074916 TI - High-risk prostate cancer in the modern era: does a single standard of care exist? PMID- 24074917 TI - The radiation oncology in-training examination: an appeal for better testing. PMID- 24074918 TI - Correlation of Smad4 status with outcomes in patients receiving erlotinib combined with adjuvant chemoradiation and chemotherapy after resection for pancreatic adenocarcinoma. PMID- 24074919 TI - Is cetuximab-induced rash conclusion really a remnant of the skin erythema dose? PMID- 24074920 TI - How radiation oncologists evaluate and incorporate life expectancy estimates into the treatment of palliative cancer patients: a survey-based study. AB - PURPOSE: We surveyed how radiation oncologists think about and incorporate a palliative cancer patient's life expectancy (LE) into their treatment recommendations. METHODS AND MATERIALS: A 41-item survey was e-mailed to 113 radiation oncology attending physicians and residents at radiation oncology centers within the Boston area. Physicians estimated how frequently they assessed the LE of their palliative cancer patients and rated the importance of 18 factors in formulating LE estimates. For 3 common palliative case scenarios, physicians estimated LE and reported whether they had an LE threshold below which they would modify their treatment recommendation. LE estimates were considered accurate when within the 95% confidence interval of median survival estimates from an established prognostic model. RESULTS: Among 92 respondents (81%), the majority were male (62%), from an academic practice (75%), and an attending physician (70%). Physicians reported assessing LE in 91% of their evaluations and most frequently rated performance status (92%), overall metastatic burden (90%), presence of central nervous system metastases (75%), and primary cancer site (73%) as "very important" in assessing LE. Across the 3 cases, most (88%-97%) had LE thresholds that would alter treatment recommendations. Overall, physicians' LE estimates were 22% accurate with 67% over the range predicted by the prognostic model. CONCLUSIONS: Physicians often incorporate LE estimates into palliative cancer care and identify important prognostic factors. Most have LE thresholds that guide their treatment recommendations. However, physicians overestimated patient survival times in most cases. Future studies focused on improving LE assessment are needed. PMID- 24074921 TI - A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer. AB - PURPOSE: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. METHODS AND MATERIALS: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m(2) weekly * 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and neck cancer. The study had a standard 3 + 3 dose-escalation design. RESULTS: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer free margins. The most common grade >=3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. CONCLUSIONS: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins. PMID- 24074922 TI - Prospective multicenter trial evaluating balloon-catheter partial-breast irradiation for ductal carcinoma in situ. AB - PURPOSE: To determine outcomes of accelerated partial-breast irradiation (APBI) with MammoSite in the treatment of ductal carcinoma in situ (DCIS) after breast conserving surgery. METHODS AND MATERIALS: We conducted a prospective, multicenter trial between 2003 and 2009. Inclusion criteria included age >18 years, core needle biopsy diagnosis of DCIS, and no prior breast cancer history. Patients underwent breast-conserving surgery plus MammoSite placement. Radiation was given twice daily for 5 days for a total of 34 Gy. Patients were evaluated for development of toxicities, cosmetic outcome, and ipsilateral breast tumor recurrence (IBTR). RESULTS: A total of 41 patients (42 breasts) completed treatment in the study, with a median follow up of 5.3 years. Overall, 28 patients (68.3%) experienced an adverse event. Skin changes and pain were the most common adverse events. Cosmetic outcome at 6 months was judged excellent/good by 100% of physicians and by 96.8% of patients. At 12 months, 86.7% of physicians and 92.3% of patients rated the cosmetic outcome as excellent/good. Overall, 4 patients (9.8%) developed an IBTR (all DCIS), with a 5 year actuarial rate of 11.3%. All IBTRs were outside the treatment field. Among patients with IBTRs, the mean time to recurrence was 3.2 years. CONCLUSIONS: Accelerated partial-breast irradiation using MammoSite seems to provide a safe and cosmetically acceptable outcome; however, the 9.8% IBTR rate with median follow-up of 5.3 years is concerning. Prospective randomized trials are necessary before routine use of APBI for DCIS can be recommended. PMID- 24074923 TI - Nomogram prediction of survival and recurrence in patients with extrahepatic bile duct cancer undergoing curative resection followed by adjuvant chemoradiation therapy. AB - PURPOSE: To develop nomograms for predicting the overall survival (OS) and relapse-free survival (RFS) in patients with extrahepatic bile duct cancer undergoing adjuvant chemoradiation therapy after curative resection. METHODS AND MATERIALS: From January 1995 through August 2006, a total of 166 consecutive patients underwent curative resection followed by adjuvant chemoradiation therapy. Multivariate analysis using Cox proportional hazards regression was performed, and this Cox model was used as the basis for the nomograms of OS and RFS. We calculated concordance indices of the constructed nomograms and American Joint Committee on Cancer (AJCC) staging system. RESULTS: The OS rate at 2 years and 5 years was 60.8% and 42.5%, respectively, and the RFS rate at 2 years and 5 years was 52.5% and 38.2%, respectively. The model containing age, sex, tumor location, histologic differentiation, perineural invasion, and lymph node involvement was selected for nomograms. The bootstrap-corrected concordance index of the nomogram for OS and RFS was 0.63 and 0.62, respectively, and that of AJCC staging for OS and RFS was 0.50 and 0.52, respectively. CONCLUSIONS: We developed nomograms that predicted survival and recurrence better than AJCC staging. With caution, clinicians may use these nomograms as an adjunct to or substitute for AJCC staging for predicting an individual's prognosis and offering tailored adjuvant therapy. PMID- 24074924 TI - MRI predictive factors for tumor response in rectal cancer following neoadjuvant chemoradiation therapy--implications for induction chemotherapy? AB - PURPOSE: Clinical and magnetic resonance imaging (MRI) characteristics at baseline and following chemoradiation therapy (CRT) most strongly associated with histopathologic response were investigated and survival outcomes evaluated in accordance with imaging and pathological response. METHODS AND MATERIALS: Responders were defined as mrT3c/d-4 downstaged to ypT0-2 on pathology or low at risk mrT2 downstaged to ypT1 or T0. Multivariate logistic regression of baseline and posttreatment MRI: T, N, extramural venous invasion (EMVI), circumferential resection margin, craniocaudal length <5 cm, and MRI tumor height <=5 cm were used to identify independent predictor(s) for response. An association between induction chemotherapy and EMVI status was analyzed. Survival outcomes for pathologic and MRI responders and nonresponders were analyzed. RESULTS: Two hundred eighty-one patients were eligible; 114 (41%) patients were pathology responders. Baseline MRI negative EMVI (odds ratio 2.94, P=.007), tumor height <=5 cm (OR 1.96, P=.02), and mrEMVI status change (positive to negative) following CRT (OR 3.09, P<.001) were the only predictors for response. There was a strong association detected between induction chemotherapy and ymrEMVI status change after CRT (OR 9.0, P<.003). ymrT0-2 gave a positive predictive value of 80% and OR of 9.1 for ypT0-2. ymrN stage accuracy of ypN stage was 75%. Three year disease-free survival for pathology and MRI responders were similar at 80% and 79% and significantly better than poor responders. CONCLUSIONS: Tumor height and mrEMVI status are more important than baseline size and stage of the tumor as predictors of response to CRT. Both MRI- and pathologic-defined responders have significantly improved survival. "Good response" to CRT in locally advanced rectal cancer with ypT0-2 carries significantly better 3-year overall survival and disease-free survival. Use of induction chemotherapy for improving mrEMVI status and knowledge of MRI predictive factors could be taken into account in the pursuit of individualized neoadjuvant treatments for patients with rectal cancer. PMID- 24074925 TI - The effect of radiation timing on patients with high-risk features of parameningeal rhabdomyosarcoma: an analysis of IRS-IV and D9803. AB - PURPOSE: Radiation therapy remains an essential treatment for patients with parameningeal rhabdomyosarcoma (PMRMS), and early radiation therapy may improve local control for patients with intracranial extension (ICE). METHODS AND MATERIALS: To address the role of radiation therapy timing in PMRMS in the current era, we reviewed the outcome from 2 recent clinical trials for intermediate-risk RMS: Intergroup Rhabdomyosarcoma Study (IRS)-IV and Children's Oncology Group (COG) D9803. The PMRMS patients on IRS-IV with any high-risk features (cranial nerve palsy [CNP], cranial base bony erosion [CBBE], or ICE) were treated immediately at day 0, and PMRMS patients without any of these 3 features received week 6-9 radiation therapy. The D9803 PMRMS patients with ICE received day 0 X-Ray Therapy (XRT) as well; however, those with either CNP or CBBE had XRT at week 12. RESULTS: Compared with the 198 PMRMS patients from IRS IV, the 192 PMRMS patients from D9803 had no difference (P<.05) in 5-year local failure (19% vs 19%), failure-free-survival (70% vs 67%), or overall survival (75% vs 73%) in aggregate. The 5-year local failure rates by subset did not differ when patients were classified as having no risk features (None, 15% vs 19%, P=.25), cranial nerve palsy/cranial base of skull erosion (CNP/CBBE, 15% vs 28%, P=.22), or intracranial extension (ICE, 21% vs 15%, P=.27). The D9083 patients were more likely to have received initial staging by magnetic resonance imaging (71% vs 53%). CONCLUSIONS: These data support that a delay in radiation therapy for high-risk PMRMS features of CNP/CBBE does not compromise clinical outcomes. PMID- 24074926 TI - Long-term evaluation of radiation-induced optic neuropathy after single-fraction stereotactic radiosurgery. AB - PURPOSE: To determine the long-term risk of radiation-induced optic neuropathy (RION) in patients having single-fraction stereotactic radiosurgery (SRS) for benign skull base tumors. METHODS AND MATERIALS: Retrospective review of 222 patients having Gamma Knife radiosurgery for benign tumors adjacent to the anterior visual pathway (AVP) between 1991 and 1999. Excluded were patients with prior or concurrent external beam radiation therapy or SRS. One hundred twenty nine patients (58%) had undergone previous surgery. Tumor types included confirmed World Health Organization grade 1 or presumed cavernous sinus meningioma (n=143), pituitary adenoma (n=72), and craniopharyngioma (n=7). The maximum dose to the AVP was <=8.0 Gy (n=126), 8.1-10.0 Gy (n=39), 10.1-12.0 Gy (n=47), and >12 Gy (n=10). RESULTS: The mean clinical and imaging follow-up periods were 83 and 123 months, respectively. One patient (0.5%) who received a maximum radiation dose of 12.8 Gy to the AVP developed unilateral blindness 18 months after SRS. The chance of RION according to the maximum radiation dose received by the AVP was 0 (95% confidence interval [CI] 0-3.6%), 0 (95% CI 0 10.7%), 0 (95% CI 0-9.0%), and 10% (95% CI 0-43.0%) for patients receiving <=8 Gy, 8.1-10.0 Gy, 10.1-12.0 Gy, and >12 Gy, respectively. The overall risk of RION in patients receiving >8 Gy to the AVP was 1.0% (95% CI 0-6.2%). CONCLUSIONS: The risk of RION after single-fraction SRS in patients with benign skull base tumors who have no prior radiation exposure is very low if the maximum dose to the AVP is <=12 Gy. Physicians performing single-fraction SRS should remain cautious when treating lesions adjacent to the AVP, especially when the maximum dose exceeds 10 Gy. PMID- 24074927 TI - Early clinical outcomes and toxicity of intensity modulated versus conventional pelvic radiation therapy for locally advanced cervix carcinoma: a prospective randomized study. AB - PURPOSE: To evaluate the toxicity and clinical outcome in patients with locally advanced cervical cancer (LACC) treated with whole pelvic conventional radiation therapy (WP-CRT) versus intensity modulated radiation therapy (WP-IMRT). METHODS AND MATERIALS: Between January 2010 and January 2012, 44 patients with International Federation of Gynecology and Obstetrics (FIGO 2009) stage IIB-IIIB squamous cell carcinoma of the cervix were randomized to receive 50.4 Gy in 28 fractions delivered via either WP-CRT or WP-IMRT with concurrent weekly cisplatin 40 mg/m(2). Acute toxicity was graded according to the Common Terminology Criteria for Adverse Events, version 3.0, and late toxicity was graded according to the Radiation Therapy Oncology Group system. The primary and secondary endpoints were acute gastrointestinal toxicity and disease-free survival, respectively. RESULTS: Of 44 patients, 22 patients received WP-CRT and 22 received WP-IMRT. In the WP-CRT arm, 13 patients had stage IIB disease and 9 had stage IIIB disease; in the IMRT arm, 12 patients had stage IIB disease and 10 had stage IIIB disease. The median follow-up time in the WP-CRT arm was 21.7 months (range, 10.7-37.4 months), and in the WP-IMRT arm it was 21.6 months (range, 7.7 34.4 months). At 27 months, disease-free survival was 79.4% in the WP-CRT group versus 60% in the WP-IMRT group (P=.651), and overall survival was 76% in the WP CRT group versus 85.7% in the WP-IMRT group (P=.645). Patients in the WP-IMRT arm experienced significantly fewer grade >=2 acute gastrointestinal toxicities (31.8% vs 63.6%, P=.034) and grade >=3 gastrointestinal toxicities (4.5% vs 27.3%, P=.047) than did patients receiving WP-CRT and had less chronic gastrointestinal toxicity (13.6% vs 50%, P=.011). CONCLUSION: WP-IMRT is associated with significantly less toxicity compared with WP-CRT and has a comparable clinical outcome. Further studies with larger sample sizes and longer follow-up times are warranted to justify its use in routine clinical practice. PMID- 24074928 TI - Prognostic significance of tumor response as assessed by sequential 18F fluorodeoxyglucose-positron emission tomography/computed tomography during concurrent chemoradiation therapy for cervical cancer. AB - PURPOSE: To investigate the prognostic role of metabolic response by the use of serial sets of positron emission tomography/computed tomography (PET/CT) in patients with cervical cancer who were treated with concurrent chemoradiation therapy (CCRT). METHODS AND MATERIALS: A total of 60 patients who were treated with CCRT between February 2009 and December 2010 were analyzed. Three sequential PET/CT images were acquired for each patient: pre-CCRT, during-CCRT at 4 weeks of CCRT, and 1 month post-CCRT PET/CT. Metabolic responses were assessed qualitatively. The percentage changes in the maximum values of standardized uptake value (DeltaSUV(max)%) from the PET/CT images acquired pre-CCRT and during CCRT were calculated. Receiver operating characteristic (ROC) curve analysis was performed to evaluate whether DeltaSUV(max)% could predict complete response (CR) on the post-CCRT PET/CT and to identify the best cutoff value. Prognostic factors of progression-free survival (PFS) were analyzed. RESULTS: During-CCRT PET/CT showed that 8 patients (13%) had CR, and the other 52 patients (87%) had partial response (PR). On the post-CCRT PET/CT, 43 patients (73%) had CR, 12 patients (20%) had PR, and 4 patients (7%) had progressive disease. The average SUV(max) in primary tumors was 16.3 (range, 6.4-53.0) on the pre-CCRT PET/CT images and 5.3 (range, 0-19.4) on the during-CCRT PET/CT images. According to ROC curve analysis, DeltaSUV(max)% could predict CR response on post-CCRT PET/CT (P<.001, cutoff value of 59.7%). In all patients, the PFS rate was 71.9% at 2 years. Multivariate analysis showed that DeltaSUV(max)% >=60% (P=.045) and CR response on the post-CCRT PET/CT (P=.012) were statistically significant predictors of PFS. CONCLUSION: Metabolic responses on the during-CCRT images at 4 weeks of treatment and 1-month post-CCRT PET/CT images may predict treatment outcomes in patients with cervical cancer. DeltaSUV(max)% >=60% at 4 weeks of CCRT may predict CR response on 1-month post-CCRT PET/CT and also PFS. PMID- 24074929 TI - Proton: the particle. AB - The purpose of this article is to review briefly the nature of protons: creation at the Big Bang, abundance, physical characteristics, internal components, and life span. Several particle discoveries by proton as the experimental tool are considered. Protons play important roles in science, medicine, and industry. This article was prompted by my experience in the curative treatment of cancer patients by protons and my interest in the nature of protons as particles. The latter has been stimulated by many discussions with particle physicists and reading related books and journals. Protons in our universe number ~10(80). Protons were created at 10(-6) -1 second after the Big Bang at ~1.37 * 10(10) years beforethe present. Proton life span has been experimentally determined to be >=10(34) years; that is, the age of the universe is 10(-24)th of the minimum life span of a proton. The abundance of the elements is hydrogen, ~74%; helium, ~24%; and heavier atoms, ~2%. Accordingly, protons are the dominant baryonic subatomic particle in the universe because ~87% are protons. They are in each atom in our universe and thus involved in virtually every activity of matter in the visible universe, including life on our planet. Protons were discovered in 1919. In 1968, they were determined to be composed of even smaller particles, principally quarks and gluons. Protons have been the experimental tool in the discoveries of quarks (charm, bottom, and top), bosons (W(+), W(-), Z(0), and Higgs), antiprotons, and antineutrons. Industrial applications of protons are numerous and important. Additionally, protons are well appreciated in medicine for their role in radiation oncology and in magnetic resonance imaging. Protons are the dominant baryonic subatomic particle in the visible universe, comprising ~87% of the particle mass. They are present in each atom of our universe and thus a participant in every activity involving matter. PMID- 24074930 TI - A comparison of amplitude-based and phase-based positron emission tomography gating algorithms for segmentation of internal target volumes of tumors subject to respiratory motion. AB - PURPOSE: To quantitatively compare the accuracy of tumor volume segmentation in amplitude-based and phase-based respiratory gating algorithms in respiratory correlated positron emission tomography (PET). METHODS AND MATERIALS: List-mode fluorodeoxyglucose-PET data was acquired for 10 patients with a total of 12 fluorodeoxyglucose-avid tumors and 9 lymph nodes. Additionally, a phantom experiment was performed in which 4 plastic butyrate spheres with inner diameters ranging from 1 to 4 cm were imaged as they underwent 1-dimensional motion based on 2 measured patient breathing trajectories. PET list-mode data were gated into 8 bins using 2 amplitude-based (equal amplitude bins [A1] and equal counts per bin [A2]) and 2 temporal phase-based gating algorithms. Gated images were segmented using a commercially available gradient-based technique and a fixed 40% threshold of maximum uptake. Internal target volumes (ITVs) were generated by taking the union of all 8 contours per gated image. Segmented phantom ITVs were compared with their respective ground-truth ITVs, defined as the volume subtended by the tumor model positions covering 99% of breathing amplitude. Superior inferior distances between sphere centroids in the end-inhale and end-exhale phases were also calculated. RESULTS: Tumor ITVs from amplitude-based methods were significantly larger than those from temporal-based techniques (P=.002). For lymph nodes, A2 resulted in ITVs that were significantly larger than either of the temporal-based techniques (P<.0323). A1 produced the largest and most accurate ITVs for spheres with diameters of >=2 cm (P=.002). No significant difference was shown between algorithms in the 1-cm sphere data set. For phantom spheres, amplitude-based methods recovered an average of 9.5% more motion displacement than temporal-based methods under regular breathing conditions and an average of 45.7% more in the presence of baseline drift (P<.001). CONCLUSIONS: Target volumes in images generated from amplitude-based gating are larger and more accurate, at levels that are potentially clinically significant, compared with those from temporal phase-based gating. PMID- 24074931 TI - Malfunctions of implantable cardiac devices in patients receiving proton beam therapy: incidence and predictors. AB - PURPOSE: Photon therapy has been reported to induce resets of implanted cardiac devices, but the clinical sequelae of treating patients with such devices with proton beam therapy (PBT) are not well known. We reviewed the incidence of device malfunctions among patients undergoing PBT. METHODS AND MATERIALS: From March 2009 through July 2012, 42 patients with implanted cardiac implantable electronic devices (CIED; 28 pacemakers and 14 cardioverter-defibrillators) underwent 42 courses of PBT for thoracic (23, 55%), prostate (15, 36%), liver (3, 7%), or base of skull (1, 2%) tumors at a single institution. The median prescribed dose was 74 Gy (relative biological effectiveness; range 46.8-87.5 Gy), and the median distance from the treatment field to the CIED was 10 cm (range 0.8-40 cm). Maximum proton and neutron doses were estimated for each treatment course. All CIEDs were checked before radiation delivery and monitored throughout treatment. RESULTS: Median estimated peak proton and neutron doses to the CIED in all patients were 0.8 Gy (range 0.13-21 Gy) and 346 Sv (range 11-1100 mSv). Six CIED malfunctions occurred in 5 patients (2 pacemakers and 3 defibrillators). Five of these malfunctions were CIED resets, and 1 patient with a defibrillator (in a patient with a liver tumor) had an elective replacement indicator after therapy that was not influenced by radiation. The mean distance from the proton beam to the CIED among devices that reset was 7.0 cm (range 0.9-8 cm), and the mean maximum neutron dose was 655 mSv (range 330-1100 mSv). All resets occurred in patients receiving thoracic PBT and were corrected without clinical incident. The generator for the defibrillator with the elective replacement indicator message was replaced uneventfully after treatment. CONCLUSIONS: The incidence of CIED resets was about 20% among patients receiving PBT to the thorax. We recommend that PBT be avoided in pacing-dependent patients and that patients with any type of CIED receiving thoracic PBT be followed closely. PMID- 24074932 TI - Effects of respiratory motion on passively scattered proton therapy versus intensity modulated photon therapy for stage III lung cancer: are proton plans more sensitive to breathing motion? AB - PURPOSE: To quantify and compare the effects of respiratory motion on paired passively scattered proton therapy (PSPT) and intensity modulated photon therapy (IMRT) plans; and to establish the relationship between the magnitude of tumor motion and the respiratory-induced dose difference for both modalities. METHODS AND MATERIALS: In a randomized clinical trial comparing PSPT and IMRT, radiation therapy plans have been designed according to common planning protocols. Four dimensional (4D) dose was computed for PSPT and IMRT plans for a patient cohort with respiratory motion ranging from 3 to 17 mm. Image registration and dose accumulation were performed using grayscale-based deformable image registration algorithms. The dose-volume histogram (DVH) differences (4D-3D [3D = 3 dimensional]) were compared for PSPT and IMRT. Changes in 4D-3D dose were correlated to the magnitude of tumor respiratory motion. RESULTS: The average 4D 3D dose to 95% of the internal target volume was close to zero, with 19 of 20 patients within 1% of prescribed dose for both modalities. The mean 4D-3D between the 2 modalities was not statistically significant (P<.05) for all dose-volume histogram indices (mean +/- SD) except the lung V5 (PSPT: +1.1% +/- 0.9%; IMRT: +0.4% +/- 1.2%) and maximum cord dose (PSPT: +1.5 +/- 2.9 Gy; IMRT: 0.0 +/- 0.2 Gy). Changes in 4D-3D dose were correlated to tumor motion for only 2 indices: dose to 95% planning target volume, and heterogeneity index. CONCLUSIONS: With our current margin formalisms, target coverage was maintained in the presence of respiratory motion up to 17 mm for both PSPT and IMRT. Only 2 of 11 4D-3D indices (lung V5 and spinal cord maximum) were statistically distinguishable between PSPT and IMRT, contrary to the notion that proton therapy will be more susceptible to respiratory motion. Because of the lack of strong correlations with 4D-3D dose differences in PSPT and IMRT, the extent of tumor motion was not an adequate predictor of potential dosimetric error caused by breathing motion. PMID- 24074933 TI - Retrospective cohort study of bronchial doses and radiation-induced atelectasis after stereotactic body radiation therapy of lung tumors located close to the bronchial tree. AB - PURPOSE: To evaluate the dose-response relationship between radiation-induced atelectasis after stereotactic body radiation therapy (SBRT) and bronchial dose. METHODS AND MATERIALS: Seventy-four patients treated with SBRT for tumors close to main, lobar, or segmental bronchi were selected. The association between incidence of atelectasis and bronchial dose parameters (maximum point-dose and minimum dose to the high-dose bronchial volume [ranging from 0.1 cm(3) up to 2.0 cm(3)]) was statistically evaluated with survival analysis models. RESULTS: Prescribed doses varied between 4 and 20 Gy per fraction in 2-5 fractions. Eighteen patients (24.3%) developed atelectasis considered to be radiation induced. Statistical analysis showed a significant correlation between the incidence of radiation-induced atelectasis and minimum dose to the high-dose bronchial volumes, of which 0.1 cm(3) (D(0.1cm3)) was used for further analysis. The median value of D(0.1cm3) (alpha/beta = 3 Gy) was EQD(2,LQ) = 147 Gy3 (range, 20-293 Gy3). For patients who developed atelectasis the median value was EQD(2,LQ) = 210 Gy3, and for patients who did not develop atelectasis, EQD(2,LQ) = 105 Gy3. Median time from treatment to development of atelectasis was 8.0 months (range, 1.1-30.1 months). CONCLUSION: In this retrospective study a significant dose-response relationship between the incidence of atelectasis and the dose to the high-dose volume of the bronchi is shown. PMID- 24074934 TI - Estimation of rectal dose using daily megavoltage cone-beam computed tomography and deformable image registration. AB - PURPOSE: The actual dose delivered to critical organs will differ from the simulated dose because of interfractional organ motion and deformation. Here, we developed a method to estimate the rectal dose in prostate intensity modulated radiation therapy with consideration to interfractional organ motion using daily megavoltage cone-beam computed tomography (MVCBCT). METHODS AND MATERIALS: Under exemption status from our institutional review board, we retrospectively reviewed 231 series of MVCBCT of 8 patients with prostate cancer. On both planning CT (pCT) and MVCBCT images, the rectal contours were delineated and the CT value within the contours was replaced by the mean CT value within the pelvis, with the addition of 100 Hounsfield units. MVCBCT images were rigidly registered to pCT and then nonrigidly registered using B-Spline deformable image registration (DIR) with Velocity AI software. The concordance between the rectal contours on MVCBCT and pCT was evaluated using the Dice similarity coefficient (DSC). The dose distributions normalized for 1 fraction were also deformed and summed to estimate the actual total dose. RESULTS: The DSC of all treatment fractions of 8 patients was improved from 0.75+/-0.04 (mean +/-SD) to 0.90 +/-0.02 by DIR. Six patients showed a decrease of the generalized equivalent uniform dose (gEUD) from total dose compared with treatment plans. Although the rectal volume of each treatment fraction did not show any correlation with the change in gEUD (R(2)=0.18+/-0.13), the displacement of the center of gravity of rectal contours in the anterior posterior (AP) direction showed an intermediate relationship (R(2)=0.61+/-0.16). CONCLUSION: We developed a method for evaluation of rectal dose using DIR and MVCBCT images and showed the necessity of DIR for the evaluation of total dose. Displacement of the rectum in the AP direction showed a greater effect on the change in rectal dose compared with the rectal volume. PMID- 24074935 TI - Selenoprotein P inhibits radiation-induced late reactive oxygen species accumulation and normal cell injury. AB - PURPOSE: Radiation is a common mode of cancer therapy whose outcome is often limited because of normal tissue toxicity. We have shown previously that the accumulation of radiation-induced late reactive oxygen species (ROS) precedes cell death, suggesting that metabolic oxidative stress could regulate cellular radiation response. The purpose of this study was to investigate whether selenoprotein P (SEPP1), a major supplier of selenium to tissues and an antioxidant, regulates late ROS accumulation and toxicity in irradiated normal human fibroblasts (NHFs). METHODS AND MATERIALS: Flow cytometry analysis of cell viability, cell cycle phase distribution, and dihydroethidium oxidation, along with clonogenic assays, were used to measure oxidative stress and toxicity. Human antioxidant mechanisms array and quantitative real-time polymerase chain reaction assays were used to measure gene expression during late ROS accumulation in irradiated NHFs. Sodium selenite addition and SEPP1 overexpression were used to determine the causality of SEPP1 regulating late ROS accumulation and toxicity in irradiated NHFs. RESULTS: Irradiated NHFs showed late ROS accumulation (4.5-fold increase from control; P<.05) that occurs after activation of the cell cycle checkpoint pathways and precedes cell death. The mRNA levels of CuZn- and Mn superoxide dismutase, catalase, peroxiredoxin 3, and thioredoxin reductase 1 increased approximately 2- to 3-fold, whereas mRNA levels of cold shock domain containing E1 and SEPP1 increased more than 6-fold (P<.05). The addition of sodium selenite before the radiation treatment suppressed toxicity (45%; P<.05). SEPP1 overexpression suppressed radiation-induced late ROS accumulation (35%; P<.05) and protected NHFs from radiation-induced toxicity (58%; P<.05). CONCLUSION: SEPP1 mitigates radiation-induced late ROS accumulation and normal cell injury. PMID- 24074938 TI - Results of carotid artery stenting with transcervical access. AB - OBJECTIVE: Carotid artery stenting (CAS) is usually performed with femoral access; however, this access may be impeded by anatomic limitations. Moreover, many embolic events happen during aortic arch catheterization. To overcome these problems, transcervical access to the carotid artery can be used as an alternative approach for CAS. METHODS: An electronic search of the literature using PubMed was performed. All studies reporting the results of CAS using the transcervical approach were retrieved and analyzed. RESULTS: The analysis included 12 studies reporting the results of 739 CAS procedures performed in 722 patients (mean age, 75.5 years). Of 533 lesions reported, 235 (44%) were symptomatic, with no data regarding symptomatic status available for 206 lesions. Two techniques were used: direct CAS with transcervical access (filter protected or unprotected) in 250 patients and CAS with transcervical access under reversed flow (with arteriovenous shunt in most cases) in 489 patients. Local anesthesia was used in 464 of 739 procedures (63%), and the remaining were performed under general anesthesia or cervical block. Technical success was 96.3% for 579 procedures with available data (558 successful procedures and 21 failures: inability to cross the lesion, 10; dissection, 5; failure of predilatation, 1; stent thrombosis, 1; patient agitation, 1; and no data, 3). The incidence of conversion to open repair was 3.0% (20 of 579 procedures: 18 carotid endarterectomies and two common carotid-internal carotid bypass grafts). Stroke occurred in eight patients (two fatal) and a fatal myocardial infarction in one patient. The incidence of stroke, myocardial infarction, and death was 1.1%, 0.14%, and 0.41%, respectively. The incidence of stroke was 1.2% (3 of 250) in direct CAS with transcervical access and 1.02% (5 of 489) in CAS under reversed flow (P > .05). Transient ischemic attack occurred in 20 patients (2.7%). Local complications were encountered in 17 of 579 CAS (2.9%), comprising 15 hematomas and two patients with transient laryngeal palsy. CONCLUSIONS: CAS with the transcervical approach is a safe procedure with low incidence of stroke and complications. It can be used as an alternative to femoral access in patients with unfavorable aortoiliac or aortic arch anatomy. PMID- 24074939 TI - Characteristics and effectiveness of complex nursing interventions aimed at reducing symptom burden in adult patients treated with chemotherapy: a systematic review of randomized controlled trials. AB - OBJECTIVES: The multiplicity and complexity of symptoms in patients treated with chemotherapy requires multifaceted symptom management interventions. The aim of this systematic review was to describe the characteristics and evaluate the effectiveness of complex nursing interventions that target multiple symptoms in patients receiving chemotherapy. DESIGN: We searched Medline, Embase, Cinahl and the Cochrane Central Register of Controlled Trials for randomized controlled trials that compared complex nursing interventions to usual care and that provided data on symptom prevalence, severity, distress or limitations. Characteristics of the interventions were described in a narrative way. Regarding the effectiveness of the interventions, ratios of means were calculated in order to present data in a comparable and clinically interpretable way. RESULTS: We included 11 studies, some with considerable risk of bias. Despite being heterogeneous, the interventions have patient education, symptom assessment and coaching in common. Although some interventions fail to show significant effects, others significantly reduce aspects of symptom burden by 10-88%. CONCLUSION: Although some complex nursing interventions in this systematic review produce clinically meaningful and statistically relevant reductions in symptom burden, based on the available data it is not possible to make definitive conclusions about the vital parts, circumstances or preferred target population of the interventions. Quality of the studies and modeling and piloting of the interventions are important challenges for future research. PMID- 24074940 TI - AOT versus OAT. PMID- 24074942 TI - Kinetics of cross-slope running. AB - The purpose of the present study was to identify kinetic responses to running on mediolaterally elevated (cross-sloped) running surfaces. Ground reaction forces (GRFs), GRF lever arms and joint moment characteristics of 19 male runners were analyzed when running at 3.5m/s on a custom-made, tiltable runway. Tilt angles of 3 degrees and 6 degrees for medial and lateral elevation were analyzed using a 10 camera Vicon Nexus system and a force platform. The point of force application of the GRF showed a systematic shift in the order of 1-1.5cm to either the lateral or medial aspect of the foot for lateral or medial inclinations, respectively. Consequently, the strongest significant effects of tilt orientation and level on joint kinetics and ground reaction force lever arms were identified at the ankle, knee and hip joint in the frontal plane of movement. External eversion moments at the ankle were significantly increased by 35% for 6 degrees of lateral elevation and decreased by 16% for 6 degrees of medial elevation. Altering the cross-slope of the running surface changed the pattern of ankle joint moments in the transversal plane. Effect sizes were on average larger for laterally elevated conditions, indicating a higher sensitivity of kinetic parameters to this kind of surface tilt. These alterations in joint kinetics should be considered in the choice of the running environment, especially for specific risk groups, like runners in rehabilitation processes. PMID- 24074941 TI - Subject-specific knee joint geometry improves predictions of medial tibiofemoral contact forces. AB - Estimating tibiofemoral joint contact forces is important for understanding the initiation and progression of knee osteoarthritis. However, tibiofemoral contact force predictions are influenced by many factors including muscle forces and anatomical representations of the knee joint. This study aimed to investigate the influence of subject-specific geometry and knee joint kinematics on the prediction of tibiofemoral contact forces using a calibrated EMG-driven neuromusculoskeletal model of the knee. One participant fitted with an instrumented total knee replacement walked at a self-selected speed while medial and lateral tibiofemoral contact forces, ground reaction forces, whole-body kinematics, and lower-limb muscle activity were simultaneously measured. The combination of generic and subject-specific knee joint geometry and kinematics resulted in four different OpenSim models used to estimate muscle-tendon lengths and moment arms. The subject-specific geometric model was created from CT scans and the subject-specific knee joint kinematics representing the translation of the tibia relative to the femur was obtained from fluoroscopy. The EMG-driven model was calibrated using one walking trial, but with three different cost functions that tracked the knee flexion/extension moments with and without constraint over the estimated joint contact forces. The calibrated models then predicted the medial and lateral tibiofemoral contact forces for five other different walking trials. The use of subject-specific models with minimization of the peak tibiofemoral contact forces improved the accuracy of medial contact forces by 47% and lateral contact forces by 7%, respectively compared with the use of generic musculoskeletal model. PMID- 24074943 TI - Fluorine-for-hydrogen: a strategy for radiolabeling, not a replacement. PMID- 24074945 TI - Spontaneous methicillin-sensitive Staphylococcus aureus spondylodiscitis-Short course antibiotic therapy may be adequate: Evidence from a single centre cohort. AB - Spontaneous methicillin-sensitive Staphylococcus aureus spondylodiscitis is increasing in prevalence and there appears to be little consensus on the optimum management of this condition. This paper analyses antimicrobial therapy and associated outcomes over a seven-year period at a large UK hospital trust. A retrospective search strategy identified 55 patients; notes were available for 39. Patients were treated with a median 12 weeks of antibiotics (IQR 7), with 6 weeks intravenous (IQR 3) and 9 weeks oral therapy (IQR 6). 23 different treatment regimens were utilised. 33/36 (92%) patients for whom outcomes were available were cured or improved at latest follow-up. This study reports a wide variation in antibiotic prescribing at a single centre. Outcomes were generally positive regardless of total duration of therapy and proportion of intravenous therapy. These findings highlight the need for multi-centre prospective randomised controlled trials to determine the most clinically effective and low risk treatment strategy. PMID- 24074944 TI - Determining efficacy of breast cancer therapy by PET imaging of HER2 mRNA. AB - INTRODUCTION: Monitoring the effectiveness of therapy early and accurately continues to be challenging. We hypothesize that determination of Human Epidermal Growth Factor Receptor 2 (HER2) mRNA in malignant breast cancer (BC) cells by positron emission tomography (PET) imaging, before and after treatment, would reflect therapeutic efficacy. METHOD: WT4340, a peptide nucleic acid (PNA) 12-mer complementary to HER2 mRNA was synthesized together with -CSKC, a cyclic peptide, which facilitated internalization of the PNA via IGFR expressed on BC cells, and DOTA that chelated Cu-64. Mice (n = 8) with BT474 ER+/HER2+ human BC received doxorubicin (DOX, 1.5mg/kg) i.p. once a week for six weeks. Mice (n = 8) without DOX served as controls. All mice were PET imaged with F-18-FDG and 48 h later with Cu-64-WT4340. PET imaging were performed before and 72 h after each treatment. Standardized uptake values (SUVs) were determined and percent change calculated. Animal body weight (BW) and tumor volume (TV) were measured. RESULTS: SUVs for Cu-64-WT4340 after DOX treatment declined by 54% +/- 17% after the second dose, 41% +/- 15% after the fourth dose, and 29% +/- 7% after the sixth dose, compared with 42% +/- 22%, 31% +/- 18%, and 13% +/- 9% (p<0.05) for F-18 FDG. In untreated mice, the corresponding percent SUVs for Cu-64-WT4340 were 145% +/- 82%, 165% +/- 39%, and 212% +/- 105% of pretreatment SUV, compared with 108% +/- 28%, 151% +/- 8%, and 152% +/- 35.5%, (p<0.08) for F-18-FDG. TV in mice after second dose was 114.15% +/- 61.83%, compared with 144.7% +/- 64.4% for control mice. BW of DOX-treated mice was 103.4% +/- 7.6% of pretreatment, vs. 100.1% +/- 4.3% for control mice. CONCLUSION: Therapeutic efficacy was apparent sooner by molecular PET imaging than by determination of reduction in TV. PMID- 24074946 TI - Recombinant growth hormone therapy for cystic fibrosis in children and young adults. PMID- 24074948 TI - An acquired, calcium-dependent, factor X inhibitor. AB - Acquired factor X (FX) deficiency unrelated to amyloidosis is a rare disorder in which an anti-FX antibody is infrequently detected. A patient with severe bleeding due to a calcium ion-dependent anti-FX IgG antibody is described. The FX affinity purified IgG bound the light chain of FX, but not FX lacking its gamma carboxyglutamic acid domain, and binding was enhanced >1000-fold in the presence of calcium ions. The antibody also recognized prothrombin and factor VII with about 100-fold and 1000-fold lower affinity. Like a lupus anticoagulant, increasing concentrations of phospholipids in functional assays reduced the inhibitory activity of the antibody. The effect of these properties of the inhibitor on laboratory diagnostic studies is considered. PMID- 24074947 TI - Mesenchymal stroma: primary determinant and therapeutic target for epithelial cancer. AB - Multifocal and recurrent epithelial tumors, originating from either dormant or de novo cancer cells, are major causes of morbidity and mortality. The age-dependent increase of cancer incidence has long been assumed to result from the sequential accumulation of cancer-driving or -facilitating mutations with induction of cellular senescence as a protective mechanism. However, recent evidence suggests that the initiation and development of epithelial cancer results from a close interplay with its altered tissue microenvironment, with chronic inflammation, stromal senescence, autophagy, and the activation of cancer-associated fibroblasts (CAFs) playing possible primary roles. We will discuss recent progress in these areas, and highlight how this understanding may be used for devising novel preventive and therapeutic approaches to the epithelial cancer problem. PMID- 24074949 TI - The canonical transient receptor potential 6 (TRPC6) channel is sensitive to extracellular pH in mouse platelets. AB - The canonical transient receptor potential-6 (TRPC6) is a receptor-activated non selective Ca(2+) channel regulated by a variety of modulators such as diacylglycerol, Ca(2+)/calmodulin or phosphorylation. The present study is aimed to investigate whether different situations, such as acidic pH, exposure to reactive oxygen species (ROS) or hypoxic-like conditions modulate TRPC6 channel function. Here we show normal aggregation and Ca(2+) mobilization stimulated by thrombin in TRPC6 KO platelets; however, OAG (1-oleoyl-2-acetyl-sn-glycerol) evoked Ca(2+) entry was attenuated in the absence of TRPC6. Exposure of mouse platelets to acidic pH resulted in abolishment of thrombin-evoked aggregation and attenuated platelet aggregation induced by thapsigargin (TG) or OAG. Both OAG induced Ca(2+) entry and platelet aggregation were greatly attenuated in cells expressing TRPC6 channels. Exposure of platelets to H2O2 or deferoxamine did not clearly alter thrombin, TG or OAG-induced platelet aggregation. Our results indicate that TRPC6 is sensitive to acidic pH but not to exposure to ROS or hypoxic-like conditions, which might be involved in the pathogenesis of the altered platelet responsiveness to DAG-generating agonists in disorders associated to acidic pH. PMID- 24074950 TI - TERRA -a calling card for telomerase. AB - Transcription of telomeric DNA has long been thought to inhibit telomerase. Using live cell imaging, in this issue, Cusanelli et al. (2013) now reveal a different scenario: telomeric RNA is preferentially generated at short telomeres and delivers telomerase to the chromosome end from which the transcript originated. PMID- 24074951 TI - Circuitous route to transcription regulation. AB - In this issue of Molecular Cell, Zhang and colleagues (2013) identify a new class of intron-derived circular RNAs (ciRNAs) and show that they have the potential to enhance transcription of their host gene. PMID- 24074952 TI - Phosphorylation-dependent assembly and coordination of the DNA damage checkpoint apparatus by Rad4(TopBP1). AB - The BRCT-domain protein Rad4(TopBP1) facilitates activation of the DNA damage checkpoint in Schizosaccharomyces pombe by physically coupling the Rad9-Rad1-Hus1 clamp, the Rad3(ATR) -Rad26(ATRIP) kinase complex, and the Crb2(53BP1) mediator. We have now determined crystal structures of the BRCT repeats of Rad4(TopBP1), revealing a distinctive domain architecture, and characterized their phosphorylation-dependent interactions with Rad9 and Crb2(53BP1). We identify a cluster of phosphorylation sites in the N-terminal region of Crb2(53BP1) that mediate interaction with Rad4(TopBP1) and reveal a hierarchical phosphorylation mechanism in which phosphorylation of Crb2(53BP1) residues Thr215 and Thr235 promotes phosphorylation of the noncanonical Thr187 site by scaffolding cyclin dependent kinase (CDK) recruitment. Finally, we show that the simultaneous interaction of a single Rad4(TopBP1) molecule with both Thr187 phosphorylation sites in a Crb2(53BP1) dimer is essential for establishing the DNA damage checkpoint. PMID- 24074953 TI - Human inositol polyphosphate multikinase regulates transcript-selective nuclear mRNA export to preserve genome integrity. AB - Messenger RNA (mRNA) export from the nucleus is essential for eukaryotic gene expression. Here we identify a transcript-selective nuclear export mechanism affecting certain human transcripts, enriched for functions in genome duplication and repair, controlled by inositol polyphosphate multikinase (IPMK), an enzyme catalyzing inositol polyphosphate and phosphoinositide turnover. We studied transcripts encoding RAD51, a protein essential for DNA repair by homologous recombination (HR), to characterize the mechanism underlying IPMK-regulated mRNA export. IPMK depletion or catalytic inactivation selectively decreases RAD51 protein abundance and the nuclear export of RAD51 mRNA, thereby impairing HR. Recognition of a sequence motif in the untranslated region of RAD51 transcripts by the mRNA export factor ALY requires IPMK. Phosphatidylinositol (3,4,5) trisphosphate (PIP3), an IPMK product, restores ALY recognition in IPMK-depleted cell extracts, suggesting a mechanism underlying transcript selection. Our findings implicate IPMK in a transcript-selective mRNA export pathway controlled by phosphoinositide turnover that preserves genome integrity in humans. PMID- 24074954 TI - BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response. AB - Apoptosis is a highly regulated form of cell death that controls normal homeostasis as well as the antitumor activity of many chemotherapeutic agents. Commitment to death via the mitochondrial apoptotic pathway requires activation of the mitochondrial pore-forming proteins BAK or BAX. Activation can be effected by the activator BH3-only proteins BID or BIM, which have been considered to be functionally redundant in this role. Herein, we show that significant activation preferences exist between these proteins: BID preferentially activates BAK while BIM preferentially activates BAX. Furthermore, we find that cells lacking BAK are relatively resistant to agents that require BID activation for maximal induction of apoptosis, including topoisomerase inhibitors and TRAIL. Consequently, patients with tumors that harbor a loss of BAK1 exhibit an inferior response to topoisomerase inhibitor treatment in the clinic. Therefore, BID and BIM have nonoverlapping roles in the induction of apoptosis via BAK and BAX, affecting chemotherapy response. PMID- 24074956 TI - Telomeric noncoding RNA TERRA is induced by telomere shortening to nucleate telomerase molecules at short telomeres. AB - Elongation of a short telomere depends on the action of multiple telomerase molecules, which are visible as telomerase RNA foci or clusters associated with telomeres in yeast and mammalian cells. How several telomerase molecules act on a single short telomere is unknown. Herein, we report that the telomeric noncoding RNA TERRA is involved in the nucleation of telomerase molecules into clusters prior to their recruitment at a short telomere. We find that telomere shortening induces TERRA expression, leading to the accumulation of TERRA molecules into a nuclear focus. Simultaneous time-lapse imaging of telomerase RNA and TERRA reveals spontaneous events of telomerase nucleation on TERRA foci in early S phase, generating TERRA-telomerase clusters. This cluster is subsequently recruited to the short telomere from which TERRA transcripts originate during S phase. We propose that telomere shortening induces noncoding RNA expression to coordinate the recruitment and activity of telomerase molecules at short telomeres. PMID- 24074955 TI - Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly. AB - The CARMA1/Bcl10/MALT1 (CBM) signalosome mediates antigen receptor-induced NF kappaB signaling to regulate multiple lymphocyte functions. While CARMA1 and Bcl10 contain caspase recruitment domains (CARDs), MALT1 is a paracaspase with structural similarity to caspases. Here we show that the reconstituted CBM signalosome is a helical filamentous assembly in which substoichiometric CARMA1 nucleates Bcl10 filaments. Bcl10 filament formation is a highly cooperative process whose threshold is sensitized by oligomerized CARMA1 upon receptor activation. In cells, both cotransfected CARMA1/Bcl10 complex and the endogenous CBM signalosome are filamentous morphologically. Combining crystallography, nuclear magnetic resonance, and electron microscopy, we reveal the structure of the Bcl10 CARD filament and the mode of interaction between CARMA1 and Bcl10. Structure-guided mutagenesis confirmed the observed interfaces in Bcl10 filament assembly and MALT1 activation in vitro and NF-kappaB activation in cells. These data support a paradigm of nucleation-induced signal transduction with threshold response due to cooperativity and signal amplification by polymerization. PMID- 24074957 TI - The nuclear pore regulates GAL1 gene transcription by controlling the localization of the SUMO protease Ulp1. AB - Transcription activation of some yeast genes correlates with their repositioning to the nuclear pore complex (NPC). The NPC-bound Mlp1 and Mlp2 proteins have been shown to associate with the GAL1 gene promoter and to maintain Ulp1, a key SUMO protease, at the NPC. Here, we show that the release of Ulp1 from the NPC increases the kinetics of GAL1 derepression, whereas artificial NPC anchoring of Ulp1 in the Deltamlp1/2 strain restores normal GAL1 regulation. Moreover, artificial tethering of the Ulp1 catalytic domain to the GAL1 locus enhances the derepression kinetics. Our results also indicate that Ulp1 modulates the sumoylation state of Tup1 and Ssn6, two regulators of glucose-repressed genes, and that a loss of Ssn6 sumoylation correlates with an increase in GAL1 derepression kinetics. Altogether, our data highlight a role for the NPC associated SUMO protease Ulp1 in regulating the sumoylation of gene-bound transcription regulators, positively affecting transcription kinetics in the context of the NPC. PMID- 24074958 TI - Risk prediction of hospital mortality for adult patients admitted to Australian and New Zealand intensive care units: development and validation of the Australian and New Zealand Risk of Death model. AB - PURPOSE: The purpose of this study is to develop and validate a new mortality prediction model (Australian and New Zealand Risk of Death [ANZROD]) for Australian and New Zealand intensive care units (ICUs) and compare its performance with the existing Acute Physiology and Chronic Health Evaluation (APACHE) III-j. MATERIALS AND METHODS: All ICU admissions from 2004 to 2009 were extracted from the Australian and New Zealand Intensive Care Society Adult Patient Database. Hospital mortality was modeled using logistic regression with training (two third) and validation (one third) data sets. Predictor variables included APACHE III score components, source of admission to ICU and hospital, lead time, elective surgery, treatment limitation, ventilation status, and APACHE III diagnoses. Model performance was assessed by standardized mortality ratio, Hosmer-Lemeshow C and H statistics, Brier score, Cox calibration regression, area under the receiver operating characteristic curve, and calibration curves. RESULTS: There were 456605 patients available for model development and validation. Observed mortality was 11.3%. Performance measures (standardized mortality ratio, Hosmer-Lemeshow C and H statistics, and receiver operating characteristic curve) for the ANZROD and APACHE III-j model in the validation data set were 1.01, 104.9 and 111.4, and 0.902; 0.84, 1596.6 and 2087.3, and 0.885, respectively. CONCLUSIONS: The ANZROD has better calibration; discrimination compared with the APACHE III-j. Further research is required to validate performance over time and in specific subgroups of ICU population. PMID- 24074959 TI - Ultrasound-assisted synthesis of PbS quantum dots stabilized by 1,2 benzenedimethanethiol and attachment to single-walled carbon nanotubes. AB - Lead sulfide (PbS) quantum dots stabilized by 1,2-benzenedimethanethiol can be synthesized by mixing Pb(NO3)2 and Na2S solutions in ethanol under ultrasound irradiation. The PbS quantum dots (2.7 and 3.6 nm in diameter) are characterized by their absorption and fluorescence spectra in the near infrared region and by other surface analytical techniques. With addition of single-walled carbon nanotubes (SWNT) to the system, this ultrasound-assisted procedure allows attachment of PbS nanoparticles to SWNT surface via pi-pi stacking, thus providing a simple one-pot method for preparation of SWNT-PbS nanoparticle composite materials. Using the ultrasound-assisted method for synthesizing silica composites containing PbS nanoparticles by a sol-gel process is also described. PMID- 24074960 TI - A novel sodium iodide and ammonium molybdate co-catalytic system for the efficient synthesis of 2-benzimidazoles using hydrogen peroxide under ultrasound irradiation. AB - The reaction of aldehydes and o-phenylenediamine for the preparation of 2 benzimidazoles has been studied using hydrogen peroxide as an oxidant under ultrasound irradiation at room temperature in this paper. The combination of substoichiometric sodium iodide and ammonium molybdate as co-catalysts, together with using small amounts of hydrogen peroxide, makes this transformation very efficient and attractive under ultrasound. Thus, a mild, green and efficient method is established to carry out this reaction in high yield. PMID- 24074961 TI - Evidence-informed guidelines for treating frail older adults with type 2 diabetes: from the Diabetes Care Program of Nova Scotia (DCPNS) and the Palliative and Therapeutic Harmonization (PATH) program. AB - Clinical practice guidelines specific to the medical care of frail older adults have yet to be widely disseminated. Because of the complex conditions associated with frailty, guidelines for frail older patients should be based on careful consideration of the characteristics of this population, balanced against the benefits and harms associated with treatment. In response to this need, the Diabetes Care Program of Nova Scotia (DCPNS) collaborated with the Palliative and Therapeutic Harmonization (PATH) program to develop and disseminate guidelines for the treatment of frail older adults with type 2 diabetes. The DCPNS/PATH guidelines are unique in that they recommend the following: 1. Maintain HbA1c at or above 8% rather than below a specific level, in keeping with the conclusion that lower HbA1c levels are associated with increased hypoglycemic events without accruing meaningful benefit for frail older adults with type 2 diabetes. The guideline supports a wide range of acceptable HbA1c targets so that treatment decisions can focus on whether to aim for HbA1c levels between 8% and 9% or within a higher range (ie, >9% and <12%) based on individual circumstances and symptoms. 2. Simplify treatment by administering basal insulin alone and avoiding administration of regular and rapid-acting insulin when feasible. This recommendation takes into account the variations in oral intake that are commonly associated with frailty. 3. Use neutral protamine Hagedorn (NPH) insulin instead of long-acting insulin analogues, such as insulin glargine (Lantus) or insulin detemir (Levemir), as insulin analogues do not appear to provide clinically meaningful benefit but are significantly more costly. 4. With acceptance of more liberalized blood glucose targets, there is no need for routine blood glucose testing when oral hypoglycemic medications or well-established doses of basal insulin (used alone) are not routinely changed as a result of blood glucose testing.Although these recommendations may appear radical, they are based on careful review of research findings. PMID- 24074962 TI - Knowledge of and perceived need for evidence-based education about antipsychotic medications among nursing home leadership and staff. AB - BACKGROUND/OBJECTIVES: Antipsychotic use is common in US nursing homes, despite evidence of increased risk of morbidity and mortality, and limited efficacy in older adults with dementia. Knowledge, attitudes, and beliefs regarding antipsychotic use among nursing home staff are unclear. The study aim was to describe nursing home leadership and direct care staff members' knowledge of antipsychotic risks, beliefs and attitudes about the effectiveness of antipsychotics and nonpharmacologic management of dementia-related behaviors, and perceived need for evidence-based training about antipsychotic medication safety. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Survey of leadership and direct care staff of nursing homes in Connecticut was conducted in June 2011. Questionnaire domains included knowledge of antipsychotic risks, attitudes about caring for residents with dementia, satisfaction with current behavior management training, beliefs about antipsychotic effectiveness, and need for staff training about antipsychotics and behavior management. RESULTS: A total of 138 nursing home leaders and 779 direct care staff provided useable questionnaires. Only 24% of nursing home leaders identified at least 1 severe adverse effect of antipsychotics; 13% of LPNs and 12% of RNs listed at least 1 severe adverse effect. Fifty-six percent of direct care staff believed that medications worked well to manage resident behavior. Leaders were satisfied with the training that staff received to manage residents with challenging behaviors (62%). Fifty-five percent of direct care staff felt that they had enough training on how to handle difficult residents; only 37% felt they could do so without using medications. CONCLUSIONS: Findings suggest that a comprehensive multifaceted intervention designed for nursing homes should aim to improve knowledge of antipsychotic medication risks, change beliefs about appropriateness and effectiveness of antipsychotics for behavior management, and impart strategies and approaches for nonpharmacologic behavior management. PMID- 24074963 TI - Reduced white matter integrity in the cingulum and anterior corona radiata in posttraumatic stress disorder in male combat veterans: a diffusion tensor imaging study. AB - Posttraumatic stress (PTSD) and alcohol use (AUD) disorders are associated with abnormal anterior cingulate cortex/ventromedial prefrontal cortex, thalamus, and amygdala function, yet microstructural white matter (WM) differences in executive limbic tracts are likely also involved. Investigating WM in limbic-thalamo cortical tracts, this study hypothesized (1) fractional anisotropy (FA) in dorsal cingulum, parahippocampal cingulum, and anterior corona radiata (ACR) would be lower in individuals with comorbid PTSD/AUD compared to in individuals with AUD only and (2) that FA would be related to both AUD and PTSD severity. 22 combat veterans with comorbid PTSD/AUD or AUD-only completed DTI scans. ANCOVAs indicated lower FA in right (F(df=1,19)=9.091, P=0.0071) and left (F(df=1,19)=10.375, P=0.0045) dorsal cingulum and right ACR (F(df=1,19)=18.914, P=0.0003) for individuals with comorbid PTSD/AUD vs. individuals with AUD-only, even controlling for alcohol use. Multiple linear regressions revealed that FA in the right ACR was inversely related to PTSD severity (r=-0.683, P=0.004). FA was not significantly related to alcohol severity. Reduced WM integrity in limbic thalamo-cortical tracts is implicated in PTSD, even in the presence of comorbid AUD. These findings suggest that diminished WM integrity in tracts important for top-down control may be an important anomaly in PTSD and/or comorbid PTSD/AUD. PMID- 24074965 TI - Etiological pattern of community-acquired pneumonia: importance of the geographical factor. PMID- 24074964 TI - Calcium homeostasis in Pseudomonas aeruginosa requires multiple transporters and modulates swarming motility. AB - Pseudomonas aeruginosa is an opportunistic human pathogen causing severe acute and chronic infections. Earlier we have shown that calcium (Ca(2+)) induces P. aeruginosa biofilm formation and production of virulence factors. To enable further studies of the regulatory role of Ca(2+), we characterized Ca(2+) homeostasis in P. aeruginosa PAO1 cells. By using Ca(2+)-binding photoprotein aequorin, we determined that the concentration of free intracellular Ca(2+) ([Ca(2+)]in) is 0.14+/-0.05MUM. In response to external Ca(2+), the [Ca(2+)]in quickly increased at least 13-fold followed by a multi-phase decline by up to 73%. Growth at elevated Ca(2+) modulated this response. Treatment with inhibitors known to affect Ca(2+) channels, monovalent cations gradient, or P-type and F type ATPases impaired [Ca(2+)]in response, suggesting the importance of the corresponding mechanisms in Ca(2+) homeostasis. To identify Ca(2+) transporters maintaining this homeostasis, bioinformatic and LC-MS/MS-based membrane proteomic analyses were used. [Ca(2+)]in homeostasis was monitored for seven Ca(2+) affected and eleven bioinformatically predicted transporters by using transposon insertion mutants. Disruption of P-type ATPases PA2435, PA3920, and ion exchanger PA2092 significantly impaired Ca(2+) homeostasis. The lack of PA3920 and vanadate treatment abolished Ca(2+)-induced swarming, suggesting the role of the P-type ATPase in regulating P. aeruginosa response to Ca(2+). PMID- 24074966 TI - [Hyperthyroidism in molar pregnancy]. AB - INTRODUCTION: Hyperthyroidism is a rare complication of molar pregnancy. CASE REPORT: We report a 39-year-old woman who presented a thyrotoxic syndrome accompanying a molar pregnancy. Serum thyroid hormones were elevated and returned to normal level after uterine evacuation of a molar pregnancy. The authors detail the role of thyroid stimulating property of human gonadotropin chorionic hormone and its structural changes during the gestational trophoblastic diseases. These changes give the latter the thyroid stimulating properties and signs of hyperthyroidism. CONCLUSION: Molar pregnancy may be a cause of hyperthyroidism. The diagnosis of molar pregnancy should be a mention to thyrotoxicosique syndrome in a woman of childbearing age. PMID- 24074967 TI - [Multiple costal lesions in a hemodialysis patient]. PMID- 24074968 TI - [Heparin-induced thrombocytopenia: recent data]. AB - Despite less frequent, heparin-induced thrombocytopenia (HIT) remains a severe complication of treatment with heparin, and is important to diagnose and manage appropriately. HIT results from an atypical immune response to heparin, with the synthesis of IgG antibodies specific to heparin-modified platelet factor 4 (PF4) which activate platelets, leukocytes and the endothelium. This activation explains that low platelet count is associated with thrombotic events in 50% of patients. The diagnosis of HIT is sometimes evoked because of atypical manifestations (i.e. cutaneous necrosis, amnesia, hypotension or dyspnea following intravenous injection of heparin). Biological assays are always necessary to confirm HIT in case of clinical suspicion, and specific rapid tests are now available for detecting anti-PF4 antibodies. However, their specificity is poor and functional assays such as serotonin release assay or platelet aggregation test are often necessary. Argatroban that is a direct antithrombin drug can be used in patients with severe renal failure and will be preferred to danaparoid sodium in this situation. Fondaparinux is not licensed for treating confirmed HIT and can only be used in case of suspicion. The early detection of HIT is based on the monitoring of platelet count recommended in surgical patients receiving a low molecular weight heparin and in all patients treated with unfractionated heparin. PMID- 24074969 TI - [Sustained response with tocilizumab in a case of refractory relapsing polychondritis]. AB - INTRODUCTION: Relapsing polychondritis (RP) is a rare inflammatory disease characterized by diffuse cartilage involvement, especially those of the respiratory tract, leading to potentially life threatening complications. Corticosteroids remain the first-line empirical therapy. Immunosuppressive drugs such as azathioprine, cyclophosphamide and tumor necrosis factor blockers (anti TNFalpha) are commonly used as second-line therapy with varying degrees of success. CASE REPORT: We report a 40-year-old man with severe RP for whom conventional therapy and immunosuppressive treatments were ineffective. Prolonged clinical remission was obtained after introduction of the anti-interleukin-6 receptor antibody (tocilizumab), which was perfectly tolerated and allowed to taper steroids and methotrexate to a very low dosage. CONCLUSION: Our patient is the fifth published one documenting the efficacy of tocilizumab in severe refractory RP, which strengthens the use of anti-IL-6 in that indication. PMID- 24074970 TI - [Bullosis of the lower limb]. PMID- 24074971 TI - Value of magnetic resonance imaging in guiding atrial fibrillation management. AB - Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice today. Until recently, the therapeutic approaches for AF have been limited by imperfect risk prediction models and suboptimal approaches for AF ablation. Magnetic resonance imaging (MRI) for the detection of left atrial (LA) fibrosis and correlation of these structural remodelling changes to outcomes of stroke, AF recurrence, and congestive heart failure have provided us with information to optimize the care of our patients with AF based on screening for fibrotic atrial cardiomyopathy, for which AF is the arrhythmic manifestation. These data allow us to bring these new imaging modalities to the forefront of AF management and the delivery of personalized medicine. Future developments promise to improve the outcomes and safety for AF and fibrotic atrial cardiomyopathy. PMID- 24074972 TI - Lone atrial fibrillation in the pediatric population. AB - BACKGROUND: There are few reports of pediatric studies of atrial fibrillation (AF). We sought to describe the clinical characteristics, management strategies, and recurrence rates and to identify predictors of AF recurrence in a contemporary pediatric population. METHODS: A retrospective review was performed of patients <= 18 years with lone AF who were seen at 4 pediatric institutions from 1996-2011. Patients with AF in the setting of thyroid disease, ventricular pre-excitation, coexisting congenital heart disease, or a history of cardiac surgery were excluded. Demographics, clinical presentation, investigations, treatment, and follow-up were analyzed. RESULTS: Forty-two patients were diagnosed with a first episode of lone AF, and 4 of these cases were later classified as persistent AF. Thirty-one (74%) were male patients, median age was 15.3 years, and median (interquartile range [IQR]) duration of AF episode was 12 (IQR, 7-24) hours. AF recurred in 39% (15 of 38) of patients. The Kaplan-Meier median time to estimated recurrence was 19 months. By univariate analysis, initial AF episode duration was associated with a higher risk of recurrence (hazard ratio [HR], 1.01; 95% confidence interval [CI], 1-1.02; P = 0.034). Sex, age, family history, size of the left atrium, and history of cardioversion were not associated with recurrence. Recurrence with another supraventricular tachyarrhythmia (SVT) was observed in 6 of 38 (16%) patients, and 12 patients underwent electrophysiology (EP) study, with 6 patients receiving ablation. CONCLUSIONS: Our reported rate of recurrence of 39% is important when counseling pediatric patients and their parents on the expected course and treatment goals. PMID- 24074973 TI - Genetic modifier of the QTc interval associated with early-onset atrial fibrillation. AB - BACKGROUND: Both shortening and prolongation of the QTc interval have been associated with atrial fibrillation (AF). We investigated whether 8 single nucleotide polymorphisms (SNPs) at loci previously shown to affect QTc interval duration were associated with lone AF. METHODS: We included 358 patients diagnosed with lone AF (defined as onset of AF at < 50 years of age in the absence of traditional cardiovascular risk factors) and a control group consisting of 751 individuals free of AF. The 8 loci were genotyped using TaqMan assays. Genotype frequencies in lone AF cases and controls were compared using an additive logistic regression model. RESULTS: Risk of the development of early onset lone AF in individuals homozygous for the variant rs2968863 (7q36.1) was higher than in individuals with no copies of the risk allele (odds ratio [OR], 2.40; P = 0.001). The association was also significant after Bonferroni correction (P = 0.016). This polymorphism has been shown to decrease the QTc interval by 1.4 ms in genome-wide association studies (GWAS). The genetic variant is situated close to the long QT syndrome (LQTS) type 2 gene KCNH2 that encodes the potassium channel Kv11.1 (hERG). Sanger sequencing of KCNH2 confirmed the known high linkage disequilibrium between rs2968863 and the nonsynonymous variant K897T in KCNH2. No novel mutations were found in the gene. CONCLUSIONS: The variant rs2968863 (7q36.1), reported in GWAS to shorten the QTc interval, was found to be associated with early-onset lone AF. This may have implications for the pathophysiological understanding of AF. PMID- 24074974 TI - The relative value of some new drugs used to treat prostate cancer. PMID- 24074976 TI - Is low testosterone concentration a risk factor for metabolic syndrome in healthy middle-aged men? AB - OBJECTIVE: To clarify the probability of low serum testosterone level as a risk factor for metabolic syndrome (MS) in middle-aged men, we measured serum total testosterone (TT) and assessed several metabolic factors because the direct risk for MS has not been investigated fully in men. METHODS: This study comprised 1150 men aged >=30 years. Physical and laboratory variables were assessed. Analyses were conducted to determine the association between serum TT level and incidence risk of MS and MS factors by a separate logistic regression model. RESULTS: Mean (+/- standard deviation [SD]) serum TT level was 5.4 +/- 1.7 ng/mL in the 1150 men, and only 92 men (8.0%) were classified as having MS by the Japanese criteria. In age-adjusted analyses, higher levels of serum TT were independently associated with a lower risk of MS (odds ratio, per SD decrement of TT, 2.3; 95% confidence interval [CI], 1.7-2.9). MS risk increased by lower quintile of TT: ORs were 15.1 (95% CI, 4.6-50.0) for first quintile, 8.8 (95% CI, 2.6-29.9) for second quintile, 5.8 (95% CI, 1.7-20.5) for third quintile, and 5.0 (95% CI, 1.4 17.9) for fourth quintile compared with highest quintile of TT. Age-adjusted ORs for the incidence of dichotomous components of MS per SD decrement of TT were 1.8 (95% CI, 1.5-2.3) for waist circumference, 1.6 (95% CI, 1.1-2.2) for dyslipidemia, and 1.5 (95% CI, 1.2-1.8) for hypertension. CONCLUSION: We found that higher probability of MS was associated with lower levels of serum TT level in relatively healthy middle-aged Japanese men. PMID- 24074977 TI - Cystectomy for ulcerative interstitial cystitis: sequelae and patients' perceptions of improvement. AB - OBJECTIVE: To evaluate the outcomes after cystectomy for ulcerative interstitial cystitis (IC). METHODS: Medical records were reviewed for history, operative data, and postoperative events. A mailed survey assessed preoperative symptom severity/duration, providers seen, and symptom changes on 7-point scaled global response assessments. Descriptive statistics were performed. RESULTS: Of 10 women (mean age 64 +/- 12.5 years), 9 had cystectomy with ileal conduit and 1 had a neobladder. All had previous cautery of Hunner's ulcer (median 3.0 cautery procedures). Maximum bladder capacity at first and last cautery was median 325 and 188 mL, respectively. Median operative time was 321 minutes, blood loss was 200 mL (range, 100-900), 4 of 10 were transfused, and length of stay was 8 days. During a mean follow-up of 3.9 years, 6 patients required 1 or more reoperations, including hernia repair (2), urostomy revision (2), revision of ureteroileal anastomosis (1), small bowel resection (1), and neobladder cutaneous fistula repair (1). Survey respondents (n = 9) reported having seen (mean) 5.4 +/- 3.8 providers before cystectomy. Median duration of symptoms was 5 years, and day and nighttime urinary frequencies were 30 and 15 times, respectively. Postoperatively, IC pain had resolved in all patients except for one. On the global response assessments, patients had moderate/marked improvement in overall symptoms (8 of 8), pain (9 of 9), sexual function (4 of 6), and quality of life (8 of 9), 7 of 9 were very satisfied with the treatment, and 8 of 9 would make the same decision again. CONCLUSION: Despite subsequent reoperations, symptom improvements lead to high levels of satisfaction with cystectomy for IC. PMID- 24074979 TI - Editorial comment. PMID- 24074980 TI - Evolving epidemiologic trends in nonclear cell renal cell cancer: an analysis of the California Cancer Registry. AB - OBJECTIVE: To evaluate the California Cancer Registry in order to define nonclear cell renal cell cancer (RCC) clinical features and outcomes, identify prognostic variables, and generate hypotheses for further study. METHODS: Patients with invasive RCC tumors in the California Cancer Registry from 1998 to 2009 (n = 38,251) were analyzed, of which 4483 (11.7%) were of the nonclear cell type. Baseline clinical demographics and tumor characteristics were collected. Primary outcome measures were 3-year cause-specific survival (CSS) and overall survival (OS). RESULTS: Of 4483 nonclear cell RCC cases, 3304 (73.7%) were diagnosed between 2004 and 2009. Histologic distribution was as follows: papillary 63.9%, chromophobe 33.6%, and "other" 2.5% (including medullary and collecting duct tumors). Univariate analysis showed that chromophobe histology, female sex, and higher socioeconomic status were associated with significantly better OS and CSS. Patients in the later era (2004-2009) appeared to have better OS. Multivariate analysis showed the following to be independently associated with outcomes (hazard ratios shown for CSS and OS, respectively): chromophobe (0.48, 0.56; P <.001), medullary/collecting duct (2.99, 2.42; P <.001), no nephrectomy (2.84, 3.18; P <.001), regional stage (5.84, 1.98; P <.001), distant stage (25.7, 7.67; P <.001), and non-Hispanic blacks (1.5, P = .006; 1.25, P = .03). CONCLUSION: This large registry analysis demonstrated emerging epidemiologic trends in this uncommon RCC subset. Clinical variables associated with CSS and OS were identified that can potentially inform the design of future clinical trials in nonclear cell RCC. PMID- 24074981 TI - Prognostic factors of patients with metastatic renal cell carcinoma with removed metastases: a multicenter study of 556 patients. AB - OBJECTIVE: To investigate the prognosis and prognostic factors of patients with metastatic renal cell carcinoma who underwent metastasectomy. METHODS: We sent questionnaires to Japanese hospitals. The questionnaires included data of patients with metastatic renal cell carcinoma who had their metastatic lesions removed between January 1988 and December 2009. We collected them and retrospectively analyzed these data and calculated the overall survival from the first metastasectomy until death or last follow-up. We also analyzed the relationship between survival and clinico-pathologic features and determined adverse prognostic factors. Furthermore, we identified a poor prognostic group by counting the number of prognostic factors. RESULTS: A sample size of 556 patients from 48 institutions was studied. The median overall survival was 80 months. Four adverse prognostic factors were detected: incomplete resection by metastasectomy (hazard ratio [HR], 2.15), brain metastasis (HR, 3.73), >1.0 mg/dL C-reactive protein (HR, 2.45), and the highest histologic grade in Japanese classification (nuclei of tumor cells are larger than nuclei of normal tubular cells; HR, 1.88). The median overall survivals of patients with 3 or 4 prognostic factors, 2 factors, and 0 and 1 factors were 10 months, 42 months, and 105 months, respectively. CONCLUSION: Four adverse prognostic factors for predicting the survival of patients with removed metastases were identified. Patients with 3 or 4 of these adverse prognostic factors had a worse prognosis. PMID- 24074982 TI - Outcome analysis of tumors in undescended testes--a single center experience of 15 years. AB - OBJECTIVE: To present our experience in managing tumors in undescended testes (UDT) in the last 15 years at our institute, in an attempt to understand the tumor behavior and the optimum approach to management in these patients. METHODS: This is a retrospective review of all patients with tumors in UDT who had registered and undergone treatment at our institute in the last 15 years. The available records of 50 of these patients were reviewed with respect to the presentation, pathologic type, treatment schedule followed, and the survival and recurrence statistics. RESULTS: There were 23 patients with seminomatous and 27 with nonseminomatous germ cell tumors. The median follow-up was 21 months (range, 4-180). The 5-year recurrence-free survival was 77.5% in patients receiving chemotherapy first and 59.5% in patients being operated first. There were 4 disease-related deaths in our patients. The 5-year overall survival estimates were 100% for stage I disease, 93.75% for stage II disease, and 76.10% for stage III disease. CONCLUSION: Most patients with UDT still presented at a higher stage, that is, stage II or stage III disease. Patients receiving chemotherapy first had lesser recurrences than those being operated first. Overall survival was dependent on the stage at presentation and comparable with the rates commonly seen for germ cell tumors in the normally descended testes. PMID- 24074983 TI - Editorial comment. PMID- 24074985 TI - Long-term clinical outcome of inverted urothelial papilloma including cases with focal papillary pattern: is continuous surveillance necessary? AB - OBJECTIVE: To investigate the necessity for continuous cystoscopic surveillance of inverted papilloma (IP), including tumors exhibiting mixed morphology (IP with focal papillary architecture). METHODS: We retrieved all cases of de novo ("primary") IP, diagnosed in our institution during 10 years (from January 2000 to December 2009), from the information database. Patients with a history of urothelial carcinoma or concurrent urothelial carcinoma were excluded. Surveillance was performed by routine cystoscopy, and follow-up was obtained from our institutional and regional clinical and pathology databases. RESULTS: We identified 35 patients with IP, including 3 with focal papillary architecture. Mean patient age was 60 years (range, 26-88) with male-to-female ratio of 1.9:1. Most common tumor location was urinary bladder (86%), followed by urethra (14%). Focal papillary architecture was identified in 3 patients (aged 51, 52, and 78 years). Mean follow-up was 66 months (median 68; range, 11-132). Only 1 male patient (age 81) had a subsequent diagnosis of IP on follow-up cystoscopy at 9 months; no recurrence or progression was documented in the other patients diagnosed with IP. CONCLUSION: The absence of progression of IP on long-term follow-up in this study strongly argues against the need of continuous surveillance for patients in whom (1) strict diagnostic criteria are followed, (2) a complete resection can be ascertained, and (3) no previous or concurrent urothelial malignancies are documented. In this study, the 3 patients with IP showing focal papillary architecture had a benign course, similar to the previously documented cases. PMID- 24074986 TI - Two sequential diagnoses of atypical foci suspicious for carcinoma on prostate biopsy: a follow-up study of 179 cases. AB - OBJECTIVE: To follow-up the outcomes with patients who have had 2 consecutive "atypical foci suspicious for carcinoma (ATYP)" diagnoses from prostate biopsies. MATERIALS AND METHODS: A total of 516 men who had prostate core biopsy specimens with 2 sequential diagnoses of ATYP from 2003 to 2012 from 1 institution were studied. RESULTS: Of the 516 men, 179 underwent additional repeat biopsy (34.8%) after 2 ATYP diagnoses. No difference was found between the patients with and without a repeat biopsy after 2 ATYPs in terms of patient age, serum prostate specific antigen levels, and digital rectal examination and transrectal ultrasound findings. On repeat biopsy after 2 ATYP findings, 95 of the 179 men (53.1%) had benign prostatic tissue or high-grade prostatic intraepithelial neoplasia, 65 (36.3%) had cancer, and 19 (10.6%) had a third finding of ATYP. The Gleason score in the cancer group was 3+3=6 (50 patients, 77%), 3+4=7 (12 patients, 18.5%), 4+3=7 (1 patient, 1.5%), and 4+4=8 (2 patients, 3%). No difference was seen between those without (benign, high-grade prostatic intraepithelial neoplasia, or ATYP) and with cancer in terms of patient age, serum prostate-specific antigen level, digital rectal examination and transrectal ultrasound findings, and interval between the 2 ATYP biopsies and the interval between the first ATYP and last biopsy. CONCLUSION: The results of our study have shown that 36.3% men will be diagnosed with cancer on biopsy after 2 ATYP diagnoses, with 23% having a Gleason score of >=7. Because no clinical features were predictive of which patients would have cancer on the follow-up biopsy, close follow-up and repeat biopsy are warranted. PMID- 24074987 TI - Is prolonged catheterization a risk factor for artificial urinary sphincter cuff erosion? AB - OBJECTIVE: To evaluate the relative risk of prolonged urethral catheterization (PC), >48 hours, on artificial urinary sphincter (AUS) cuff erosion in a tertiary referral population. METHODS: All men who had undergone AUS implantation or revision by multiple surgeons at our institution from 2000 to 2010 with >=6 months of follow-up were reviewed for urethral erosion, catheterization after AUS placement, and comorbid conditions. RESULTS: Of the 258 AUS patients reviewed, 200 met the inclusion criteria, with an average follow-up of 24 months. AUS cuff erosions were noted in 24 men (12%) and were diagnosed at a mean of 16.9 months (range 0.8-87.1). PC was identified in 44 of the 200 men (22%)-of these men, erosions occurred in 17 (39%, P <.001). The indication for PC was most often major nongenitourinary surgery (36%) or urinary retention (32%). Univariate analysis identified an increased risk of erosion associated with hypertension, diabetes, coronary artery disease, PC, previous radiotherapy, and secondary AUS placement (P <.05). On multivariate analysis, only PC, radiotherapy, and revision surgery were significant (P <.05), but cuff size and concomitant inflatable penile prosthesis were not associated with AUS cuff erosion. CONCLUSION: PC is an independent risk factor for AUS cuff erosion. PMID- 24074988 TI - Editorial comment. PMID- 24074990 TI - Laparoscopic removal of spermatic cord to reduce incision size of open retroperitoneal lymph node dissection. AB - OBJECTIVE: To describe a laparoscopic-assisted modification to the traditional open retroperitoneal lymph node dissection (RPLND) to significantly shorten incision length and decrease morbidity of the laparotomy. METHODS: We describe 3 patients who underwent primary RPLND using the laparoscopic-assisted cord excision for stage I nonseminomatous germ cell testicular tumors. Spermatic cord excision is performed laparoscopically, and a standard nerve-sparing bilateral template RPLND is then performed through a supraumbilical incision. Operative time, intraoperative estimated blood loss, number of lymph nodes resected, complications, length of hospital stay, and follow-up were determined. RESULTS: All patients were clinical stage 1 (T1-2, Nx, M0 S0). The primary testicular tumor size was 2.2-5.5 cm with embryonal components, and all had negative results on abdominal and chest computed tomography imaging. Mean estimated blood loss was 267 mL (range, 100-500), operating room time was 293 minutes (range, 254-306), and all patients were discharged on postoperative day 5. There were no complications noted. Node counts were 22-33. The median length of follow-up was 20 months with no recurrence. CONCLUSION: Laparoscopic removal of the spermatic cord during open RPLND is a simple modification to the standard technique that reduces incision size without compromising the quality of open RPLND. PMID- 24074991 TI - Learning curve in the application of a hydrogel spacer to protect the rectal wall during radiotherapy of localized prostate cancer. AB - OBJECTIVE: To evaluate the effect of increasing experience on hydrogel dimensions, rectal dose, and acute toxicity, and to discuss important technical issues gained from this experience. METHODS: Sixty-four consecutive patients with prostate cancer were included in this analysis (G1/G2 corresponding to first/second 32 patients) after injection of 10 mL spacer gel. All patients were treated with a 5-field intensity-modulated radiotherapy technique to 76-78 Gy. Treatment toxicity was evaluated with a validated quality of life questionnaire (expanded prostate cancer index composite) before and after radiotherapy. RESULTS: Rectum volume could be entirely excluded from the planning target volume in 31% in G1 vs 56% in G2 (P = .04). Increasing symmetry was detected comparing the first 15 patients to the subsequent rest, with mean differences between right and left of 0.6 cm vs 0.3 cm at the midgland (P = .03). Mean distance between prostate and anterior rectal wall increased from 0.8 cm/1.1 cm/0.8 cm (G1) at the base/middle/apex to 1.3 cm/1.5 cm/1.2 cm (G2), respectively, so that the dose to the rectum decreased significantly (6% vs 2% of the volume inside the 70 Gy isodose; P <.01). Bowel function and bother score changes were smaller comparing baseline with last day of radiotherapy levels (mean 16/18 in G1 vs 9/12 in G2). CONCLUSION: A learning curve could be demonstrated in our patient population, respecting improved and more symmetrical spacer placement, improved treatment planning, and less treatment-related acute toxicity. Several important technical aspects need to be considered. PMID- 24074992 TI - Re: Wenske et al.: Outcomes of distal ureteral reconstruction through reimplantation with psoas hitch, Boari flap, or ureteroneocystostomy for benign or malignant ureteral obstruction or injury (Urology 2013;82:231-236). PMID- 24074993 TI - Reply by the authors. PMID- 24074994 TI - Re: Tiryaki et al.: Ureteroscopy for treatment of ureteral stones in children: factors influencing the outcome (Urology 2013;81:1047-1051). PMID- 24074995 TI - Re: Ebadi et al.: Endoureterotomy as the initial management of concurrent ureteropelvic and ureterovesical junction obstruction after failed conservative therapy (Urology 2013;82:214-219). PMID- 24074996 TI - Reply by the authors. PMID- 24074997 TI - Reply by the authors. PMID- 24074998 TI - Re: Okhunov et al.: S.T.O.N.E. nephrolithometry: novel surgical classification system for kidney calculi (Urology 2013;81:1154-1160). PMID- 24074999 TI - Re: Schroeck et al.: Differential adoption of laser prostatectomy for treatment of benign prostatic hyperplasia (Urology 2013;81:1177-1183). PMID- 24075000 TI - Re: Phe et al : involvement of connexins 43 and 45 in functional mechanism of human detrusor overactivity in neurogenic bladder (Urology 2013;81:1108.e1-e6). PMID- 24075001 TI - Reply by the authors. PMID- 24075002 TI - Reply by the authors. PMID- 24075004 TI - TRK-380, a novel selective human beta3-adrenoceptor agonist, ameliorates formalin induced pollakiuria in rats and carbachol-induced bladder contraction in dogs. AB - OBJECTIVE: To investigate the effects of TRK-380, a selective beta3-adrenoceptor (beta3-AR) agonist, on voiding behavior in rats with pollakiuria and on carbachol (CCh)-induced bladder contraction in dogs. METHODS: The voiding behavior of female Sprague Dawley rats was recorded continuously with a balance. Rats were intravesically pretreated with 2.5% formalin under isoflurane anesthesia. The next day, the effect of TRK-380 (7.5-30 mg/kg, orally) or tolterodine, an antimuscarinic drug (3.75-15 mg/kg, orally), on the voiding frequency was evaluated. In another experiment, male beagle dogs were anesthetized with pentobarbital, CCh (3 MUg/kg, intravenously) was administered to them, and the effect of TRK-380 (0.1 or 0.3 MUg/kg/minute, intravenously infusion) on CCh induced bladder contraction was evaluated. RESULTS: Rats treated with formalin showed a significant increase in the voiding frequency compared with the sham group, and the increase in it was significantly and dose-dependently suppressed by TRK-380 at doses of >=15 mg/kg. In contrast, tolterodine did not lead to a significant change in the voiding frequency even at the highest dose. In dogs, CCh-induced bladder contraction was dose-dependently suppressed by TRK-380; the plasma concentration required for 30% suppression of the CCh-induced bladder contraction (30% relaxation) was 4.90 ng/mL. CONCLUSION: This study indicated that TRK-380 ameliorated pollakiuria, which was resistant to an antimuscarinic drug, and that it also suppressed the bladder contraction induced by cholinergic stimulation in dogs, whose bladder relaxation is known to be predominantly mediated by beta3-ARs, as in humans. These data strengthen the therapeutic potential of beta3-AR for the treatment of overactive bladder. PMID- 24075003 TI - Fibrotic protein expression profiles in penile tissue of patients with erectile dysfunction. AB - OBJECTIVE: To characterize transforming growth factor beta 1 (TGFbeta1) and related signaling pathway proteins in a large cohort of human penile tissue (HPT) samples. METHODS: HPT was collected from patients undergoing penile prosthesis implantation for erectile dysfunction (ED) and divided into the following 2 groups: postradical prostatectomy ED (RP-ED; n = 57) and organic ED (O-ED; n = 30). HPT from patients undergoing partial penectomy without ED was used as controls (CON; n = 6). Western blot analysis was performed to investigate the protein expressions of TGFbeta1, thrombospondin 1 (TSP1; an activator of TGFbeta1), fibronectin (an extracellular matrix glycoprotein induced by TGFbeta1), and a family of transcriptional factors activated by TGFbeta1 (Smad2, phospho-Smad2-serine-465/467 [pSmad2], Smad3, phospho-Smad3-serine-423/425 [pSmad3]). RESULTS: Expressions of TGFbeta1 and TSP1 were significantly higher in RP-ED (P <.05) and O-ED (P <.05) groups compared with that of the CON group and were not different between either ED groups. Expressions of Smad2, pSmad2, Smad3, pSmad3, and fibronectin were similar among all groups. Within the RP-ED group, a subgroup analysis showed that time from RP to penile prosthesis implantation was related to increased expression of pSmad2 (P <.05), and previous history of intracavernosal injection was related to increased expression of TGFbeta1 (P <.05). CONCLUSION: Our results demonstrate that TSP1- and TGFbeta1-dependent fibrotic changes occur in penile tissue in patients with ED regardless of etiology. The unchanged expression of the Smad transcriptional factors may be reconciled by a Smad-independent downstream signaling pathway transmitting TGFbeta1 signals. PMID- 24075005 TI - Penile Fournier's gangrene. AB - Fournier's gangrene is a fulminant, necrotizing soft-tissue infection of the genital, perineal, and perianal regions. Fournier's isolated to the penis is a rare occurrence due the highly vascular nature of the penis. Reported occurrences of penile Fournier's gangrene have occurred in the setting of a clear vascular or traumatic insult. Here we present a case of Fournier's gangrene isolated to the penis in an adult with calciphylaxis secondary to end-stage renal disease. PMID- 24075007 TI - Registries of implantable medical devices in Europe. AB - BACKGROUND: In early 2012, a number of serious events in the implant area raised public awareness and started a discussion on safety issues and monitoring medical devices in academics and politics. Apparently, there is a lack in the surveillance of medical devices. Therefore, the objective of this work is to detect and classify implant registries in Europe. METHODS AND FINDINGS: A systematic search of literature was carried out to identify the different types of registries. Furthermore, to characterize the implant registries by different criteria a medical device classification system was established. One hundred and one European registries were found. Most registries exist in the field of cardiac implants and arthroplasty (38 and 29) and their distribution showed variation within Europe. For a lot of implant categories, none or very few registries could be identified. Some countries run more registries than others. There are a lot of differences in aim and structure among the registries. CONCLUSION: There is only a limited number of reviews on registries and a centralized monitoring system in Europe is missing. Our results reveal a lack of transparency concerning number, aim, structure and quality of registries. This is crucial, as registries work as early warning systems for identifying and notifying patients at risk. PMID- 24075006 TI - Neoplastic wounds and degenerescence. AB - Between 5% and 10% of cancer patients develop malignant wounds. Cancer wounds can occur as a clinical entity, especially over the breast, with the development of painful, spreading cancer invasions of the skin. Marjolin's ulcers develop in open wounds after a long period, and form rare malignancies arising from previously traumatised, chronically inflamed, or scarred skin. Marjolin's ulcer is associated with malignant transformation of chronic ulcers, sinus tracts, and burn scars. Squamous cell carcinoma may be linked to a wide variety of medical and surgical clinical situations, such as chronic ulcers, sinuses, chronic osteomyelitis, radiotherapy, burn scars, chronic pressure ulcers, as well as cystostomy sites, and Fournier's gangrene scars. Melanomas, lymphomas, and other cancers can also be observed. Basal cell carcinoma is more frequently observed in ulcers associated with venous insufficiency. According to some reports, the ulcer should have existed for at least 3 years to evoke a diagnosis of degenerescence as opposed ulcerated tumour. Epidermoid carcinomas represent between 0.21% and 0.34% of cancers that develop over leg ulcers, but large series are still lacking. The current lack of epidemiological data could be rectified by more frequent evocation of the diagnosis and a policy of systematic biopsy of chronically open wounds. PMID- 24075008 TI - Price cuts and drug spending in South Korea: the case of antihyperlipidemic agents. AB - OBJECTIVE: To identify the effect of price control policies on drug expenditure in South Korea. METHODS: We retrospectively examined the effects of price reduction policies on drug expenditures, in particular regarding anti hyperlipidemic drugs. The National Health Insurance claims data for a 60-month period between 2006 and 2010 were analysed. A segmented regression analysis was conducted with three intervention variables: July 2008, April 2009, and January 2010. RESULTS: Despite three rounds of price cuts, monthly drug expenditures increased by KRW 599.67 million (USD 523,726) after the third intervention (p=0.0781). The trend in volume increased consistently, but not significantly. The unit prices showed a steady downward trend over time, but rebounded after the third price cut. The number of patients with hyperlipidemia more than doubled to 3729 (p=0.0801) per month after the entry of generics for atorvastatin in July 2008. CONCLUSION: Extensive price controls did not effectively suppress the growth of pharmaceutical expenditures. The increased number of patients, attributable to the newly launched generic drug atorvastatin, and the increased use of expensive drugs were major factors affecting the increase in drug spending. Policies that regulate both drug prices and utilisation, and that reduce financial burdens via enhanced use of generics need to be introduced. PMID- 24075009 TI - The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. AB - Tissue homeostasis in metazoans is regulated by transitions of cells between quiescence and proliferation. The hallmark of proliferating populations is progression through the cell cycle, which is driven by cyclin-dependent kinase (CDK) activity. Here, we introduce a live-cell sensor for CDK2 activity and unexpectedly found that proliferating cells bifurcate into two populations as they exit mitosis. Many cells immediately commit to the next cell cycle by building up CDK2 activity from an intermediate level, while other cells lack CDK2 activity and enter a transient state of quiescence. This bifurcation is directly controlled by the CDK inhibitor p21 and is regulated by mitogens during a restriction window at the end of the previous cell cycle. Thus, cells decide at the end of mitosis to either start the next cell cycle by immediately building up CDK2 activity or to enter a transient G0-like state by suppressing CDK2 activity. PMID- 24075011 TI - Endoscopic repair of partial-thickness undersurface tears of the gluteus medius tendon. AB - Partial-thickness tear of the gluteus medius and minimus muscles has recently been recognized as a cause of chronic trochanteric pain resistant to medical treatment. The present article reports an original endoscopic technique of identification and repair. It uses a standard arthroscope at 30 degrees , with the patient in lateral decubitus, without fluoroscopy. In case of partial thickness undersurface tear, careful hook palpation followed by bursa exploration enables the pathological tendon to be diagnosed. A trans-tendinous approach then allows debridement, with systematic resection of the bone structures implicated in the impingement, followed by side-to-side tendon suture. LEVEL OF EVIDENCE: Level IV (case series). PMID- 24075012 TI - Depletion of high-abundance flavonoids by metal complexation and identification of low-abundance flavonoids in Scutellaria baicalensis Georgi. AB - The complexation of metal cations and flavonoids with 5-hydroxyl or ortho hydroxyl groups was successfully used for high-abundance flavone depletion from a botanical extract in this study. Due to their structural differences, five of the most highly abundant constituents, baicalin, wogonoside, baicalein, wogonin and oroxylin A, were successfully depleted from the ethanol extract of Radix Scutellariae. The depletion rates were approximately 99%, 85%, 99%, 70% and 76%, respectively. The recoveries of low-abundance constituents were very strong (approximately 70-100%). The efficiency of the low-abundance compounds' identification by high performance liquid chromatography electrospray tandem mass spectrometry (HPLC ESI MS/MS) was remarkable after the high-abundance constituents were removed. The number of compounds identified from the HPLC MS/MS data was 250% greater than the number of compounds identified in the untreated total extract. One hundred seventeen flavonoids were identified in the ethanol extract of Radix Scutellariae using this method, which was much greater than the number identified in previous studies without high-abundance constituent depletion. Among them, 13 sulphated flavonoids were identified. These low abundance sulphated flavonoids can barely be detected in untreated total extracts. To the best of our knowledge, this is the first reported evidence that sulphated flavonoids have been identified from Radix Scutellariae. This method will facilitate the removal of high-abundance flavonoids and the identification of low-abundance compounds in botanical extracts. PMID- 24075010 TI - MEF2 is an in vivo immune-metabolic switch. AB - Infections disturb metabolic homeostasis in many contexts, but the underlying connections are not completely understood. To address this, we use paired genetic and computational screens in Drosophila to identify transcriptional regulators of immunity and pathology and their associated target genes and physiologies. We show that Mef2 is required in the fat body for anabolic function and the immune response. Using genetic and biochemical approaches, we find that MEF2 is phosphorylated at a conserved site in healthy flies and promotes expression of lipogenic and glycogenic enzymes. Upon infection, this phosphorylation is lost, and the activity of MEF2 changes--MEF2 now associates with the TATA binding protein to bind a distinct TATA box sequence and promote antimicrobial peptide expression. The loss of phosphorylated MEF2 contributes to loss of anabolic enzyme expression in Gram-negative bacterial infection. MEF2 is thus a critical transcriptional switch in the adult fat body between metabolism and immunity. PMID- 24075013 TI - Kinetic efficiency of polar monolithic capillary columns in high-pressure gas chromatography. AB - Poppe plots were used for analysis of kinetic efficiency of monolithic sorbents synthesized in quartz capillaries for utilization in high-pressure gas chromatography. Values of theoretical plate time and maximum number of theoretical plates occurred to depend significantly on synthetic parameters such as relative amount of monomer in the initial polymerization mixture, temperature and polymerization time. Poppe plots let one to find synthesis conditions suitable either for high-speed separations or for maximal efficiency. It is shown that construction of kinetic Poppe curves using potential Van Deemter data demands compressibility of mobile phase to be taken into consideration in the case of gas chromatography. Model mixture of light hydrocarbons C1 to C4 was then used for investigation of influence of carrier gas nature on kinetic efficiency of polymeric monolithic columns. Minimal values of theoretical plate times were found for CO2 and N2O carrier gases. PMID- 24075014 TI - Stir bar sorptive extraction with gas chromatography-mass spectrometry for the determination of resveratrol, piceatannol and oxyresveratrol isomers in wines. AB - A simple and highly sensitive procedure based on stir bar sorptive extraction coupled to gas chromatography-mass spectrometry by means of a thermal desorption unit (SBSE-TD-GC-MS) has been optimized for the determination of cis/trans isomers of resveratrol, piceatannol and oxyresveratrol in wine samples. Quantification of the cis-isomers was carried out by generating the standards from the corresponding trans-species once they had been preconcentrated on the SBSE extracting phase. The optimization of the acetylation derivatization, SBSE extraction and thermal desorption steps was investigated using Plackett-Burman designs, taking into account the high number of variables to be considered. The use of bisphenol F as internal standard allowed quantification of the samples against aqueous standards. Repeatability, expressed as relative standard deviation of 10 successive analyses was between 5% and 9%, confirming the high precision attained under the optimized conditions. Satisfactory recovery values of between 79% and 109% were obtained for spiked samples in the 0.2-1.0 MUgL(-1) concentration range, depending on the compound. The main compound determined in the analyzed samples was trans-resveratrol, with concentrations in the range of 3 230 MUgL(-1), depending on the type of wine. PMID- 24075015 TI - Detection of C-reactive protein based on magnetic nanoparticles and capillary zone electrophoresis with laser-induced fluorescence detection. AB - A simple and fast method based on magnetic nanoparticles (MNPs) and capillary zone electrophoresis (CZE) with laser-induced fluorescence (LIF) detection was developed for the detection of C-reactive protein (CRP). To optimize the CZE conditions, several factors including buffer compositions, buffer ionic strength, buffer pH, applied voltage and capillary temperature have been examined. The optimal separation buffer selected was a 30 mM sodium phosphate (PB) buffer, pH 8.0. The optimal CE applied voltage and temperature selected were 20 kV and 35 degrees C, respectively. The CZE profile of the MNP-1 degrees Ab-CRP-2 degrees Ab/FITC bioconjugates showed good reproducibility. One major peak was observed for the MNP bioconjugates. The quantitative analysis also showed good results. The coefficient of variation (CV%) for the major peak area was 8.7%, and the CV% for the major peak migration time was 2.5%. The linear range for CRP analysis was 10-150 MUg/mL, and the concentration limit of detection (LOD) was 9.2 MUg/mL. Non specific interactions between bovine serum albumin (BSA) and the system can be prevented by including 10% (v/v) of human plasma in the binding buffers. The CE/LIF method might be helpful for analyzing high concentrations of CRP in a patient's plasma after an acute-phase inflammation. This new method demonstrated the possibility of using MNPs and CE/LIF for the detection of proteins, and provided information for the establishment of appropriate CE conditions. PMID- 24075016 TI - Preparation and kinetic performance assessment of thick film 10-20 MUm open tubular silica capillaries in normal phase high pressure liquid chromatography. AB - It is well-known that the open tubular column design basically can offer very high plate numbers. Experimental realization has however not kept pace with theoretical considerations, lacking efficient methods for the deposition of a thick film porous layer within a microbore capillary. A previously published sol gel synthesis method was extended from 20 MUm to 10 MUm inner diameter fused silica capillaries and the resulting columns were compared to a monolithic reference capillary in terms of kinetic performance at pressure maximum. Column permeability was investigated and pressure/flow-diagrams were obtained with a 400 fold permeability gain for the open tubes. Structural characterizations regarding layer thickness and surface porosity were carried out and displayed via scanning electron microscopy and nitrogen sorption analysis. Chromatographic results in normal phase mode at elevated mobile phase flow rate reveal the intrinsic performance potential of this column format when it comes to kinetic performance limitation plots, which were constructed for all columns prepared and compared to the monolithic silica reference capillary. PMID- 24075017 TI - Molecularly imprinted polymers for the isolation of bioactive naphthoquinones from plant extracts. AB - Molecularly Imprinted Polymers (MIPs) targeting shikonin, a potent antioxidant and wound healing agent, have been prepared using methacrylic acid (MAA) and 2 diethylaminoethyl methacrylate (DEAEMA) as functional monomers. An investigation of solution association between shikonin and both acidic and basic functional monomers by UV-vis titrations, suggested stronger affinity towards the basic functionality. Strong inhibition of the co-polymerisation reaction of such basic monomers was observed, but was overcome by reduction of the amount of template used during polymer synthesis. Polymer morphology was severely impacted by the template's radical scavenging behaviour as demonstrated by solid state NMR spectroscopy measurements. HPLC evaluation of the final materials in polar conditions revealed limited imprinting effects and selectivity, with the MAA polymers exhibiting marginally better performance. During application of the polymers as MI-SPE sorbents in non-polar solvents it was found that the DEAEMA based polymer was more selective towards shikonin compared to the MAA counterpart, while shikonin recoveries of up to 72% were achieved from hexane solutions of a commercial sample of shikonin, hexane extract of Alkanna tinctoria roots and a commercial pharmaceutical ointment. PMID- 24075019 TI - Statistical evaluation of the influence of soil properties on recoveries and matrix effects during the analysis of pharmaceutical compounds and steroids by quick, easy, cheap, effective, rugged and safe extraction followed by liquid chromatography-tandem mass spectrometry. AB - Numerous chemical products are dispersed in our environment. Many of them are recognized as harmful to humans and the ecosystem. Among these harmful substances are antibiotics and steroid hormones. Currently, very few data are available on the presence and fate of these substances in the environment, in particular for solid matrices, mainly due to a lack of analytical methodologies. Indeed, soil is a very complex matrix, and the nature and composition of the soil has a significant impact on the extraction efficiency and the sensitivity of the method. For this reason a statistical approach was performed to study the influence of soil parameters (clay, silt, sand and organic carbon percentages and cation exchange capacity (CEC)) on recoveries and matrix effects of various pharmaceuticals and steroids. Thus, an analysis of covariance (ANCOVA) was performed when several substances were analyzed simultaneously, whereas a Pearson correlation was used to study the compounds individually. To the best of our knowledge, this study is the first time such an experiment was performed. The results showed that clay and organic carbon percentages as well as the CEC have an impact on the recoveries of most of the target substances, the variables being anti-correlated. This result suggests that the compounds are trapped in soils with high levels of clay and organic carbon and a high CEC. For the matrix effects, it was shown that the organic carbon content has a significant effect on steroid hormones and penicillin G matrix effects (positive correlation). Finally, interaction effects (first order) were evaluated. This latter point corresponds to the crossed effects that occur between explanatory variables (soil parameters). Indeed, the value taken by an explanatory variable can have an influence on the effect that another explanatory variable has on a dependent variable. For instance, it was shown that some parameters (silt, sand) have an impact on the effect that clay content has on recoveries. Besides, CEC and silt affect the influence that organic carbon percentage has on matrix effect. This original approach provides a better understanding of the complex interactions that occur in soil and could be useful to understand and predict the performance of an analytical method. PMID- 24075020 TI - Clinical management of calcific uremic arteriolopathy before and after therapeutic inclusion of bisphosphonates. AB - BACKGROUND AND OBJECTIVES: Calcific uremic arteriolopathy (CUA) is a life threatening condition almost exclusively affecting patients with end-stage renal failure. Several therapies have been employed to treat this disease with irregular results. METHODS: Comparison of a prospective case series with a historical cohort. Group I: 12 patients with CUA diagnosed before 2002 (5 men, 6 on dialysis and 6 with functioning allografts) treated with standard treatment. Group II: 11 patients with CUA diagnosed between 2002 and 2010 (4 men, 6 on dialysis and 5 with functioning allografts) treated with standard treatment and bisphosphonates for 6 months. The diagnosis was made by clinical suspicion and a confirmatory biopsy in both groups. Ten patients had a previous history of high calcium-phosphorus product, 9 had a history of high parathyroid hormone (> 800 pg/ml) levels, 13 had a history of high cumulative steroids and 9 patients were under dicoumarin treatment. Two patients were obese and 5 had diabetes mellitus. RESULTS: In Group I, 58.7% required amputation of the affected limb, 3 patients recovered and 2 died. In all patients of Group II the progression of the skin lesions decreased between 2 and 4 weeks after the start of bisphosphonate therapy with no changes in blood levels of calcium and phosphate. The improvement in pain and lesions was faster in the patients receiving endovenous bisphosphonates. Renal function remained stable in transplant recipients. No adverse effects were observed. CONCLUSIONS: Bisphosphonates could constitute an alternative to treat CUA in addition to standard therapy. PMID- 24075018 TI - Determination of haloacetic acids in swimming pool waters by membrane-protected micro-solid phase extraction. AB - In this study, a simple and efficient extraction method for determining haloacetic acids (HAAs) in swimming pool waters has been developed. HAAs are toxic organic pollutants of disinfection origin most commonly detected in swimming pool and drinking waters at trace level concentrations. For the first time, a highly efficient sorbent was developed using rice husk and used for micro solid phase extraction (MU-SPE) technique. To increase the extraction capability of rice husk silica, iron oxide was incorporated via sol-gel process. In MU-SPE device, the novel sorbent was packed and used for extraction of HAAs prior to analysis using ultra performance liquid chromatography-ultraviolet detection (UPLC-UV). Various extraction parameters were optimized to improve the extraction efficiency of MU-SPE. Under optimum conditions, linearity (coefficient of determination, r(2)>=0.991 over the concentration range of 1-150 MUg/L), detection limits in the range of 0.001-0.092 MUg/L, mean recoveries up to 110% with corresponding relative standard deviations of 2-7% (n=3) had been obtained. Finally, the method was applied to swimming pool water to evaluate its feasibility. The mean concentrations for HAAs from the pool waters were in the range of 6.8 and 48.6 MUg/L which are far below the standard values set by United States Environmental Protection Agency. PMID- 24075021 TI - Role of ultrasound in revealing complications following percutaneous renal biopsy in children. AB - BACKGROUND: This retrospective case series aimed to investigate the role of ultrasound immediately post-percutaneous renal biopsy (PRB) for detecting post biopsy complications in pediatric patients. METHODS: Data from 380 (male/female = 209/171) consecutive biopsies of native kidney tissue of 344 children from January 2001 to October 2009 were analyzed to investigate the role of an ultrasound immediately post-PRB and the predictive value of demographic, clinical, and baseline chemistry factors in predicting the risk of post-PRB complications. RESULTS: Post-PRB ultrasound identified hematoma formation in 33 (8.7%) patients. Of the 19 (5.0%) patients whose hematomas were large (>= 1 cm), post-biopsy courses of 16 patients were clinically complicated. On the other hand, of the 14 patients whose hematomas were small (< 1 cm), all patients but one showed an uncomplicated clinical course. Of the 17 complications, 79.1% were detected within the first 24 hours and 21.9% (cases of resorption fever) between 24 and 144 hours post-PRB. Age >= 10 is an independent risk factor for post-PRB complication. CONCLUSIONS: Age >= 10 is an independent risk factor for post-PRB complication. After the procedure, the formation of a large hematoma predicted a complicated clinical course. PMID- 24075022 TI - Readmission after hospitalization for heart failure among patients with chronic kidney disease: a prediction model. AB - AIMS: 30-day readmission rates after hospitalization for heart failure (HF) approach 25%, and patients with chronic kidney disease (CKD) are disproportionately represented. A retrospective cohort study was conducted to develop a prediction tool for 30-day readmission after hospitalization for HF among those with non-dialysis dependent CKD. METHODS: Geisinger primary care patients with Stage 3 - 5 CKD hospitalized with a primary discharge diagnosis of HF during the period July 1, 2004 through February 28, 2010 were eligible. Multivariate logistic regression was employed to build models from predictors of 30-day readmission, drawn from demographic, clinical, laboratory, and pharmaceutical variables in the electronic health record. Variables were manually removed to achieve a model with satisfactory goodness-of-fit and parsimony while maximizing area under the receiver operating characteristic curve (AUC). Internal validation was performed using the bootstrap resampling method (1,000 samples) to provide a bias-corrected AUC. RESULTS: 607 patients with CKD were admitted for HF during the study period; 116 (19.1%) were readmitted within 30 days. A model incorporating 23 variables across domains of medical history, active outpatient pharmaceuticals, vital signs, laboratory tests, and recent inpatient and outpatient resource utilization yielded an AUC (95% CI) of 0.792 (0.746 - 0.838). The bias-corrected AUC was 0.743. At an estimated readmission probability of 20%, the model correctly classified readmission status for 73% of the population, with a sensitivity of 69% and a specificity of 73%. CONCLUSION: A robust electronic health record may facilitate the identification of CKD patients at risk for readmission after hospitalization for HF. PMID- 24075023 TI - Mycophenolate mofetil as a steroid-sparing agent in sarcoid-associated renal disease. AB - Steroids are the mainstay of treatment for renal sarcoidosis. Many patients with sarcoidosis are chronically dependent on steroids and there is limited data on the use of steroid-sparing agents. This is a case of a patient that has remained in remission using mycophenolate mofetil (MMF) as a steroid-sparing agent. The patient is a 56-year-old female with a history of sarcoidosis diagnosed by lymph node biopsy who developed 3 episodes of acute kidney injury (AKI) in the setting of exacerbations of her sarcoidosis, each responding to prednisone treatment. Due to possible lifelong need for prednisone, MMF was started as a steroid-sparing treatment. She tolerated the MMF well and has now been steroidfree for 22 months. There have been only a few case reports about the use of MMF as a steroid-sparing agent in sarcoid-associated renal disease, in which patients could be successfully weaned off steroids. This is the longest reported follow-up of a patient being off steroids while on MMF. It is also notable for the patient having a relapse on the MMF which responded to an increased dose. MMF should be studied further as a potential steroid-sparing agent in the treatment of sarcoid associated renal disease. PMID- 24075024 TI - The impact of documentation of severe acute kidney injury on mortality. AB - AIMS: Modification of the mortality risk associated with acute kidney injury (AKI) necessitates recognition of AKI when it occurs. We sought to determine whether formal documentation of AKI in the medical record, assessed by billing codes for AKI, would be associated with improved clinical outcomes. METHODS: Retrospective cohort study conducted at three hospitals within a single university health system. Adults without severe underlying kidney disease who suffered in-hospital AKI as defined by a doubling of baseline creatinine (n = 5,438) were included. Those whose AKI was formally documented according to discharge billing codes were compared to those without such documentation in terms of 30-day mortality. RESULTS: Formal documentation of AKI occurred in 2,325 patients (43%). Higher baseline creatinine, higher peak creatinine, medical admission status, and higher Sequential Organ Failure Assessment (SOFA) score were strongly associated with documentation of AKI. After adjustment for severity of disease, formal AKI documentation was associated with reduced 30-day mortality - OR 0.81 (0.68 - 0.96, p = 0.02). Patients with formal documentation were more likely to receive a nephrology consultation (31% vs. 6%, p < 0.001) and fluid boluses (64% vs. 45%, p < 0.001), and had a more rapid discontinuation of angiotensin-converting enzyme inhibitor and angiotensin-receptor blocker medications (HR 2.04, CI 1.69 - 2.46, p < 0.001). CONCLUSIONS: Formal documentation of AKI is associated with improved survival after adjustment for illness severity among patients with creatinine-defined AKI. PMID- 24075025 TI - A boy with IgA nephropathy complicated by tubulointerstitial nephritis and uveitis (TINU) syndrome. AB - BACKGROUND: Abnormal cellular and humoral immunity underlie both immunoglobulin A (IgA) nephropathy and tubulointerstitial nephritis and uveitis (TINU) syndrome. We encountered a teenage boy who developed TINU syndrome during the course of IgA nephropathy. CASE REPORT: 1 year after onset of IgA nephropathy following acute enteritis, a 14-year-old boy again experienced acute enteritis caused by Campylobacter jejuni, which was followed by TINU syndrome with prominent low molecular-weight proteinuria. Renal histologic examination showed T-cell-dominant tubulointerstitial infiltration of marked immune cells including CD54-positive cells. Steroid therapy improved renal function, reversing aggravation of IgA nephropathy by TINU syndrome. CONCLUSIONS: The boy's human leukocyte antigen profile suggested predisposition to these two diseases, triggered by which were intestinal infections. The enteritis probably induced abnormalities in cellular and humoral immunity. Low-molecular-weight proteinuria, which reflected our patient's tubulointerstitial lesions, should call for consideration of TINU syndrome, including ophthalmologic assessment for possible uveitis. PMID- 24075026 TI - A comparison of dynamic views using plain radiographs and thin-section three dimensional computed tomography in the evaluation of fusion after posterior lumbar interbody fusion surgery. AB - BACKGROUND CONTEXT: Accurate evaluation of the postsurgery status of interbody fusion is important in deciding the patient's treatment. Dynamic plain radiographs are used as a convenient method, but the accuracy is not so good. PURPOSE: This study aimed to evaluate the usefulness of dynamic flexion-extension radiographs as a method for evaluating fusion, by comparing it with three dimensional thin-section computed tomography (CT). STUDY DESIGN: Prospective controlled study. METHODS: We conducted a prospective study with 108 patients (158 levels) who, diagnosed with severe spinal stenosis and Grade I and Grade II spondylolisthesis, underwent posterior lumbar interbody fusion (PLIF) surgery, with follow-up by dynamic plain radiographs, functional rating scale, and three dimensional (3D) thin-section CT for 1 year after surgery. In the plain radiographs, we looked for less than 3 degrees of lordotic angle change, less than 3 mm of translation between vertebral bodies, and no presence of halo signs; satisfying all the criteria was regarded as fusion (Group A), whereas failure to satisfy any condition was referred to as probable nonfusion (Group B) and if none were satisfied as nonfusion (Group C). The patients were classified into fusion or nonfusion groups based on CT. Correlation between plain radiographs and CT groups was analyzed. Moreover, clinical assessment and cross-comparison between observers were done. RESULTS: In 158 levels, 95 (60.8%) levels were classified into the fusion group by plain radiographs and 131 (83%) levels by CT. When we analyzed the results of each groups, in Group A, 78 (81.3%) levels belonged to the CT fusion group and 18 (18.7%) levels to the CT nonfusion group, in Group B, 51 (89.5%) and 6 (10.5%) levels, and in Group C, 2 (40%) and 3 (60%) levels, respectively. For each of the CT fusion group, a cross-comparison using dynamic radiographs reconfirmed 78 (59.5%) levels for Group A, 51 (38.9%) levels for Group B, and 2 (1.6%) levels for Group C; for the CT nonfusion groups, 18 (66.7%) levels, 6 (22.2%) levels, and 3 (11.1%) levels were for Groups A, B, and C, respectively. In clinical evaluation, all groups showed clear postsurgery improvement, but there was no statistically significant difference. In terms of observer-to-observer error and agreement between diagnoses, CT showed a statistically higher level of correlation than plain radiographs. CONCLUSIONS: Dynamic flexion-extension radiographs cannot be seen as an objective standard in the evaluation of fusion after PLIF surgery. It would be desirable to confirm the fusion status by thin-section 3D-CT for an objective analysis. PMID- 24075027 TI - Comparison of adjacent segment degeneration after successful posterolateral fusion with unilateral or bilateral pedicle screw instrumentation: a minimum 10 year follow-up. AB - BACKGROUND CONTEXT: In the instrumented fusion, adjacent segment facet joint violation or impingement by pedicle screws is unavoidable especially in cephalad segment, despite taking specific intraoperative precautions in terms of surgical approach. In such circumstances, unlike its original purpose, unilateral pedicle screw instrumentation can contribute to reduce the degeneration of cephalad adjacent segment by preventing contralateral cephalad adjacent facet joint from the unavoidable injury by pedicle screw insertion. However, to our knowledge, no long-term follow-up study has compared adjacent segment degeneration (ASD) between unilateral and bilateral pedicle screw instrumented fusion. PURPOSE: To compare ASD after successful posterolateral fusion using either unilateral or bilateral pedicle screw instrumentation for patients with lumbar spinal stenosis and/or Grade 1 spondylolisthesis. STUDY DESIGN: Retrospective case-control study. PATIENT SAMPLE: One hundred forty-seven patients who had undergone one- or two level posterolateral fusion with unilateral or bilateral pedicle screw instrumentation for lumbar spinal stenosis with or without low-grade spondylolisthesis and achieved successful fusion, with a minimum 10-year follow up. OUTCOME MEASURE: The occurrence of radiologic ASD, Oswestry disability index (ODI) scores, and revision rates. METHODS: A total of 194 consecutive patients were contacted and encouraged to visit our hospital and to participate in our study. Radiologic ASD was evaluated at three motion segments: cephalad adjacent segment (first cephalad adjacent segment), one cephalad to cephalad adjacent segment (second cephalad adjacent segment), and caudal adjacent segment. Clinical outcomes were compared by ODI scores and revision rates. RESULTS: In total, 147 of 194 (75.8%) patients were available for at least 10 years of radiologic and clinical follow-up. Adjacent segment degeneration (in first cephalad or caudal adjacent segment) was noted in 55.9% (33 of 59 patients) of the unilateral group and 72.7% (64 of 88 patients) of the bilateral group (p=.035). The occurrence of ASD in each first cephalad and caudal adjacent segment was not significantly different between groups but that in second cephalad adjacent segment was significantly different between groups (p=.004). Clinical outcomes according to ODI showed significant difference between groups (p=.016), especially when ODI scores were compared in patients with ASD (p=.004). CONCLUSIONS: In a minimum 10 year follow-up retrospective study of posterolateral fusion for lumbar spinal stenosis and/or Grade 1 spondylolisthesis, unilateral pedicle screw instrumentation showed a lower rate of radiologic ASD, especially in second cephalad adjacent segment, and a better clinical outcome by ODI. PMID- 24075028 TI - Optimal aspiration volume of vertebral bone marrow for use in spinal fusion. AB - BACKGROUND CONTEXT: Bone marrow aspirate (BMA) has shown promise as a bone graft option in spinal fusion. The vertebral body is a convenient source for marrow aspirate as it is accessed in routine course of pedicle screw instrumentation. Studies have relied on data from the iliac crest to determine optimal aspiration volume from the vertebral body. PURPOSE: This study is designed to determine the optimal aspiration volume for BMA taken from the vertebral body. STUDY DESIGN: Prospective clinical study. PATIENT SAMPLE: Data are drawn from 18 pedicles and 180 aspirations. The average age of the subjects was 50.3 years, and the subject pool comprised five men and seven women. OUTCOME MEASURES: Nucleated cell count and alkaline phosphatase staining colony forming units. METHODS: Ten 1 mL aliquots of BMA were incrementally aspirated through a cannulated pedicle tap for each instrumented vertebral body. The numbers of nucleated cells per mL of BMA were analyzed with a hemocytometer, and the percentage of osteoprogenitor cells per mL aspirate were estimated by an alk phos production assay. The study was funded through departmental funds, and none of the authors have any conflicts of interest to report related to the study. RESULTS: Nucleated cell count decreased with increasing aspirate number (p<.001). The average cell count for the first mL was 45.8 million cells. Cell counts did not differ by age or sex (p=.943 and p=.685, respectively). Likewise, osteoprogenitor cell percentage decreased with increasing aspirate number (p<.001). CONCLUSIONS: The 2 mL aspirate volume has been defined as ideal for the iliac crest, but there has been no analogous assessment of the effect of aspiration volume for other sources such as the vertebral body. This information is important for the clinical implementation of vertebral body aspirations if volume, cells, and presumably performance, of this potential bone graft option are to be optimized for spine cases. Our data show a direct relationship between increasing aspiration number and decreasing osteoprogenitor cellular concentration, with a drop to 50% of the original aspirate cell count by the 4th mL aspirate. The vertebral body is a potentially exciting source of osteoprogenitor cells that can be implemented for a variety of spinal uses. PMID- 24075029 TI - Accuracy of the non-sentinel node risk score (N-SNORE) in patients with cutaneous melanoma and positive sentinel lymph nodes: a retrospective study. AB - BACKGROUND: Sentinel node (SLN) biopsy in patients with melanoma permits identification of those at risk for further metastases in non-sentinel lymph nodes (NSLN). However, a mere 20% of SLN-positive patients have metastases in NSLN. Therefore we need criteria to predict NSLN-positivity. A new score system known as the non-sentinel risk score, (N-SNORE) based on five clinical and pathological characteristics (gender, regression in primary melanoma, proportion of SNs containing melanoma, perinodal lymphatic invasion, and SN tumor burden), was first published in 2010. In this study, the accuracy of N-SNORE was validated in melanoma patients with positive SLN. METHODS: A total of 106 melanoma patients with positive SLN, who had undergone complete lymph node dissection (CLND) subsequently, were included in the study. The N-SNORE was calculated in all patients, and the risk was compared to the frequency of NSLN metastases. Statistical analysis of the data was performed. RESULTS: Thirteen patients were at very low risk for NSN metastasis (score 0), 63 patients at low risk (score 1 3), 19 at intermediate risk (score 4-5), 6 at high risk (score 6-7), and 5 at very high risk (score >8). NSLN positivity rates for these 5 risk groups were 7.7%, 18.2%, 21.1%, 33.3%, and 80%, respectively. According to Fisher's exact test, the contingency coefficient was .322; the p-value was .025. CONCLUSION: An increasing N-SNORE was clearly correlated with a higher risk of NSLN positivity. Based on the p-value and the contingency coefficient, the overall accuracy of the N-SNORE was proven on statistical calculation. PMID- 24075031 TI - Variation in surgery and surgical research. PMID- 24075030 TI - The role of VEGFR-2 expression in outcomes and survival of patients with peritoneal carcinomatosis from appendiceal cancer. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a prognostic factor and target treatment for metastatic colorectal and ovarian cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival on peritoneal carcinomatosis (PC) from appendiceal cancer. We hypothesize that tumoral high expression of VEGF receptor 2 (VEGFR-2) is a negative prognostic factor for survival in patients with PC from appendiceal cancer. METHODS: A retrospective study of a prospective database revealed 89 patients with PC from appendiceal cancer who underwent 127 CRS/HIPECs. Surgical specimens from 59 patients were tested to identify high vs. low VEGFR-2 expression. Patient outcomes and survival were analyzed. RESULTS: There were 26 males and 33 females. Mean age was 51 years. Forty-seven VEGFR-2 high expressers and 15 low expressers were identified. Mean follow-up of high and low expressers was 25.1 and 26.6 months, respectively (p = 0.806). At follow-up, 33 (70%) high expressers were alive and 14 (30%) deceased, while 11 (92%) low expressers were alive and 1 (8%) deceased. Recurrence, use of bevacizumab, CC score, PCI, and LN status showed no differences between high and low expressers. OS for high expressers was 90.5%, 59.8%, and 47.1% at 1-, 3-, and 5-years, respectively, while OS for low expressers remained stable at 91.7% at 1-, 3-, and 5-years (p = 0.133). CONCLUSION: There is a trend towards better outcomes and survival in patients with PC from appendiceal cancer who have low expression of VEGFR-2 compared to high expression. More studies are encouraged to confirm this trend. PMID- 24075032 TI - Antibiotic resistance: a final warning. PMID- 24075033 TI - Child maltreatment in Europe: taking a public health approach. PMID- 24075034 TI - Secure use of individual patient data from clinical trials. PMID- 24075035 TI - Total hip replacement: mortality and risks. PMID- 24075036 TI - Sutures or staples for abdominal wound closure: case closed? PMID- 24075037 TI - Adipose stem cell therapy for soft tissue reconstruction. PMID- 24075039 TI - Bill Schwab: at the cutting edge of trauma care. PMID- 24075040 TI - Surgical research collaboratives in the UK. PMID- 24075041 TI - Alcohol-related road traffic injury and Global Burden of Disease 2010. PMID- 24075042 TI - Alcohol-related road traffic injury and Global Burden of Disease 2010 - Authors' reply. PMID- 24075043 TI - Treatment for patients with indolent and mantle cell lymphoma. PMID- 24075044 TI - Treatment for patients with indolent and mantle cell lymphoma. PMID- 24075045 TI - Treatment for patients with indolent and mantle cell lymphoma. PMID- 24075046 TI - HIV infections and injecting drug users in Greece. PMID- 24075047 TI - HIV, HCV, and drug use in men who have sex with men. PMID- 24075048 TI - Poliomyelitis: threats to eradication. PMID- 24075049 TI - 90-day mortality after 409,096 total hip replacements for osteoarthritis, from the National Joint Registry for England and Wales: a retrospective analysis. AB - BACKGROUND: Death within 90 days after total hip replacement is rare but might be avoidable dependent on patient and treatment factors. We assessed whether a secular decrease in death caused by hip replacement has occurred in England and Wales and whether modifiable perioperative factors exist that could reduce deaths. METHODS: We took data about hip replacements done in England and Wales between April, 2003, and December, 2011, from the National Joint Registry for England and Wales. Patient identifiers were used to link these data to the national mortality database and the Hospital Episode Statistics database to obtain details of death, sociodemographics, and comorbidity. We assessed mortality within 90 days of operation by Kaplan-Meier analysis and assessed the role of patient and treatment factors by Cox proportional hazards model. FINDINGS: 409,096 primary hip replacements were done to treat osteoarthritis. 1743 patients died within 90 days of surgery during 8 years, with a substantial secular decrease in mortality, from 0.56% in 2003 to 0.29% in 2011, even after adjustment for age, sex, and comorbidity. Several modifiable clinical factors were associated with decreased mortality according to an adjusted model: posterior surgical approach (hazard ratio [HR] 0.82, 95% CI 0.73-0.92; p=0.001), mechanical thromboprophylaxis (0.85, 0.74-0.99; p=0.036), chemical thromboprophylaxis with heparin with or without aspirin (0.79, 0.66-0.93; p=0.005), and spinal versus general anaesthetic (0.85, 0.74-0.97; p=0.019). Type of prosthesis was unrelated to mortality. Being overweight was associated with lower mortality (0.76, 0.62-0.92; p=0.006). INTERPRETATION: Postoperative mortality after hip joint replacement has fallen substantially. Widespread adoption of four simple clinical management strategies (posterior surgical approach, mechanical and chemical prophylaxis, and spinal anaesthesia) could, if causally related, reduce mortality further. FUNDING: National Joint Registry for England and Wales. PMID- 24075050 TI - Subcuticular sutures versus staples for skin closure after open gastrointestinal surgery: a phase 3, multicentre, open-label, randomised controlled trial. AB - BACKGROUND: Staples have been widely used for skin closure after open gastrointestinal surgery. The potential advantages of subcuticular sutures compared with staples have not been assessed. We assessed the differences in the frequency of wound complications, including superficial incisional surgical site infection and hypertrophic scar formation, depending on whether subcuticular sutures or staples are used. METHODS: We did a multicentre, open-label, randomised controlled trial at 24 institutions between June 1, 2009, and Feb 28, 2012. Eligible patients aged 20 years or older, with adequate organ function and undergoing elective open upper or lower gastrointestinal surgery, were randomly assigned preoperatively to either staples or subcuticular sutures for skin closure. Randomisation was done via a computer-generated permuted-block sequence, and was stratified by institution, sex, and type of surgery (ie, upper or lower gastrointestinal surgery). Our primary endpoint was the incidence of wound complications within 30 days of surgery. Analysis was done by intention to treat. This study is registered with UMINCTR, UMIN000002480. FINDINGS: 1080 patients were enrolled and randomly assigned in a one to one ratio: 562 to subcuticular sutures and 518 to staples. 1072 were eligible for the primary endpoint and 1058 for the secondary endpoint. Of the 558 patients who received subcuticular sutures, 382 underwent upper gastrointestinal surgery and 176 underwent lower gastrointestinal surgery. Wound complications occurred in 47 of 558 patients (8.4%, 95% CI 6.3-11.0). Of the 514 who received staples, 413 underwent upper gastrointestinal surgery and 101 underwent lower gastrointestinal surgery. Wound complications occurred in 59 of 514 (11.5%, 95% CI 8.9-14.6). Overall, the rate of wound complications did not differ significantly between the subcuticular sutures and staples groups (odds ratio 0.709, 95% CI 0.474-1.062; p=0.12). INTERPRETATION: The efficacy of subcuticular sutures was not validated as an improvement over a standard procedure for skin closure to reduce the incidence of wound complications after open gastrointestinal surgery. FUNDING: Johnson & Johnson. PMID- 24075051 TI - Enrichment of autologous fat grafts with ex-vivo expanded adipose tissue-derived stem cells for graft survival: a randomised placebo-controlled trial. AB - BACKGROUND: Autologous fat grafting is increasingly used in reconstructive surgery. However, resorption rates ranging from 25% to 80% have been reported. Therefore, methods to increase graft viability are needed. Here, we report the results of a triple-blind, placebo-controlled trial to compare the survival of fat grafts enriched with autologous adipose-derived stem cells (ASCs) versus non enriched fat grafts. METHODS: Healthy participants underwent two liposuctions taken 14 days apart: one for ASC isolation and ex-vivo expansion, and another for the preparation of fat grafts. Two purified fat grafts (30 mL each) taken from the second liposuction were prepared for each participant. One graft was enriched with ASCs (20 * 10(6) cells per mL fat), and another graft without ASC enrichment served as a control. The fat grafts were injected subcutaneously as a bolus to the posterior part of the right and left upper arm according to the randomisation sequence. The volumes of injected fat grafts were measured by MRI immediately after injection and after 121 days before surgical removal. The primary goal was to compare the residual graft volumes of ASC-enriched grafts with those of control grafts. This study is registered at www.clinicaltrialsregister.eu, number 2010-023006-12. FINDINGS: 13 participants were enrolled, three of whom were excluded. Compared with the control grafts, the ASC-enriched fat grafts had significantly higher residual volumes: 23.00 (95% CI 20.57-25.43) cm(3) versus 4.66 (3.16-6.16) cm(3) for the controls, corresponding to 80.9% (76.6-85.2) versus 16.3% (11.1-21.4) of the initial volumes, respectively (p<0.0001). The difference between the groups was 18.34 (95% CI 15.70-20.98) cm(3), equivalent to 64.6% (57.1-72.1; p<0.0001). No serious adverse events were noted. INTERPRETATION: The procedure of ASC-enriched fat grafting had excellent feasibility and safety. These promising results add significantly to the prospect of stem cell use in clinical settings, and indicate that ASC graft enrichment could render lipofilling a reliable alternative to major tissue augmentation, such as breast surgery, with allogeneic material or major flap surgery. FUNDING: Danish Cancer Society, Centre of Head and Orthopaedics Rigshospitalet, and Moalem Weitemeyer Bendtsen. PMID- 24075052 TI - Understanding of regional variation in the use of surgery. AB - The use of common surgical procedures varies widely across regions. Differences in illness burden, diagnostic practices, and patient attitudes about medical intervention explain only a small degree of regional variation in surgery rates. Evidence suggests that surgical variation results mainly from differences in physician beliefs about the indications for surgery, and the extent to which patient preferences are incorporated into treatment decisions. These two components of clinical decision making help to explain the so-called surgical signatures of specific procedures, and why some consistently vary more than others. Variation in clinical decision making is, in turn, affected by broad environmental factors, including technology diffusion, supply of specialists, local training frameworks, financial incentives, and regulatory factors, which vary across countries. Better scientific evidence about the comparative effectiveness of surgical and non-surgical interventions could help to mitigate regional variation, but broader dissemination of shared decision aids will be essential to reduce variation in preference-sensitive disorders. PMID- 24075053 TI - Strategies to reduce variation in the use of surgery. AB - Provision rates for surgery vary widely in relation to identifiable need, suggesting that reduction of this variation might be appropriate. The definition of unwarranted variation is difficult because the boundaries of acceptable practice are wide, and information about patient preference is lacking. Very little direct research evidence exists on the modification of variations in surgery rates, so inferences must be drawn from research on the alteration of overall rates. The available evidence has large gaps, which suggests that some proposed strategies produce only marginal change. Micro-level interventions target decision making that affects individuals, whereas macro-level interventions target health-care systems with the use of financial, regulatory, or incentivisation strategies. Financial and regulatory changes can have major effects on provision rates, but these effects are often complex and can include unintended adverse effects. The net effects of micro-level strategies (such as improvement of evidence and dissemination of evidence, and support for shared decision making) can be smaller, but better directed. Further research is needed to identify what level of variation in surgery rates is appropriate in a specific context, and how variation can be reduced where desirable. PMID- 24075054 TI - Strategies to improve clinical research in surgery through international collaboration. AB - More than 235 million patients undergo surgery every year worldwide, but less than 1% are enrolled in surgical clinical trials--few of which are international collaborations. Several levels of action are needed to improve this situation. International research collaborations in surgery between developed and developing countries could encourage capacity building and quality improvement, and mutually enhance care for patients with surgical disorders. Low-income and middle-income countries increasingly report much the same range of surgical diseases as do high income countries (eg, cancer, cardiovascular disease, and the surgical sequelae of metabolic syndrome); collaboration is therefore of mutual interest. Large multinational trials that cross cultures and levels of socioeconomic development might have faster results and wider applicability than do single-country trials. Surgeons educated in research methods, and aided by research networks and trial centres, are needed to foster these international collaborations. Barriers to collaboration could be overcome by adoption of global strategies for regulation, health insurance, ethical approval, and indemnity coverage for doctors. PMID- 24075055 TI - Delayed haemoptysis from explosive device fragments. PMID- 24075056 TI - Effect of advanced trauma life support (ATLS) on the time needed for treatment in simulated mountain medicine emergencies. AB - OBJECTIVE: The number of tourists exploring mountainous areas continues to increase. As a consequence, rescue operations are increasing, especially for trauma and polytrauma victims. The outcome of such patients depends greatly on the duration of the prehospital stabilization. Limited medical training of mountain rescuers may adversely affect the outcome of patients. There is no study investigating high altitude trauma treatment. The aim of this study is to analyze the impact of advanced trauma life support (ATLS) principles in mountain trauma, and to discuss a possible role of ATLS in mountain medicine education programs. METHODS: We designed 5 tasks representing life-threatening trauma problems encountered in mountain rescue. They were used to evaluate the physician's ability to adequately diagnose and react to trauma situations. We created 2 groups: 1) the ATLS group, consisting of physicians who passed the ATLS course and the mountain medicine course, and 2) the non-ATLS group, consisting of physicians who did not obtain the ATLS training but who did pass the mountain medicine course. We compared the time spent to complete the tasks in both groups. RESULTS: In 4 of the 5 tasks (airway, breathing, circulation, and combination), the ATLS group completed the task significantly faster. In the environment task, however, the ATLS group was slower. This was the only not significant result. CONCLUSIONS: ATLS principles adapted and implemented for high altitude medicine education may have a positive impact on high altitude trauma treatment and outcomes. PMID- 24075058 TI - Patterns of outdoor recreational injury in northern British Columbia. AB - OBJECTIVE: The objective of this study was to examine the patterns of severe injury documented at a northern British Columbia regional trauma center based on age, sex, month of year, activity type, injury type, and injury severity as they relate to participation in outdoor recreational activities. METHODS: A retrospective analysis of data abstracted from the British Columbia Trauma Registry for patients sustaining injuries between April 1, 2004, and March 31, 2007, while engaged in outdoor recreational activities in the Northern Health Authority. The British Columbia Trauma Registry inclusion criteria are as follows: 1) admitted for treatment of injuries sustained from the transfer of external energy or force; 2) admitted to the facility within 7 days of injury; and 3) length of stay more than 2 days or in-hospital mortality. RESULTS: In all, 159 patients met study criteria. August and September were peak injury months (mean 7.3 and 7.0 per month, respectively). The highest injury patterns involved cycling (n = 31), all-terrain vehicle operation (n = 30), horseback riding (n = 22), and snowmobiling (n = 22). Of the 159 patients, 76.1% were male, with a peak age distribution between 10 years and 19 years (22%). Males were more commonly injured than females among cycling (83.9%), all-terrain vehicle (86.7%), and snowmobile (100%) traumas. Females were more commonly injured from horseback riding events (42.1%). CONCLUSIONS: This study emphasizes the need for rapid translation of research findings into injury prevention awareness and programming in northern British Columbia, particularly relating to cycling, horseback riding, snowmobiling, and all-terrain vehicle operation. Further investigation is required to analyze long-term outcomes for this common injury population. PMID- 24075057 TI - An observational study of personal ultraviolet dosimetry and acute diffuse reflectance skin changes at extreme altitude. AB - OBJECTIVE: To determine the level of UV radiation at extreme altitude and to assess the effect it has on the skin. METHODS: Fifteen expeditioners and 10 Sherpas were assessed during a climbing expedition on the north side of Mt Everest (8848 m). UV exposure measurement and diffuse skin reflectance spectrophotometry were performed at the beginning and end of the expedition. RESULTS: Over the course of the expedition, the expeditioners and Sherpas received a median dose of 93.6 (interquartile range [IQR], 61.0-102.8) and 102.5 (IQR, 72.2-117.8) minimal erythemal doses (MEDs) of UV radiation. The maximum dosage exceeded 106 +/- 1.4 MEDs. Using reflectance spectrophotometry, expeditioner and Sherpa melanin-hemoglobin increased by 83.6% (IQR, -1.5 to 89.8%) and 24.7% (IQR, -22.4 to 61.5%) for exposed skin, respectively. The amount of subcutaneous lipid-water decreased by a factor of 196.6 (IQR, 52.1-308.4) and 46.7 (IQR, 1.8-1156.5), for expeditioners and Sherpas, respectively. CONCLUSIONS: This expedition's participants received massive doses of UV radiation during their time at high altitude. In many individuals this was similar to the annual exposure of northern European office-workers (100 MEDs). Diffuse skin reflectance spectroscopy revealed considerable subcutaneous lipid loss, skin dehydration, and increased melanin in keeping with these levels of exposure. PMID- 24075059 TI - Methods of overcoming treatment resistance in colorectal cancer. AB - Metastatic colorectal cancer remains a lethal disease with a poor prognosis in the majority of patients. Multiple drug combinations have been developed in recent years that have significantly improved response rates and overall survival however resistance to these drugs is inevitable. Novel agents are currently being developed and participation in clinical trials should be encouraged. In the absence of other treatment options in a patient with good performance status, there is compelling evidence for re-challenging with previously administered agents in different combinations. The aim of this review is to discuss mechanisms of resistance and methods to overcome treatment resistance in patients with metastatic colorectal cancer who are refractory to 5-FU, irinotecan, oxaliplatin, cetuximab and bevacizumab therapy. PMID- 24075060 TI - Peripheral T-cell lymphoma: the role of hematopoietic stem cell transplantation. AB - Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of non Hodgkin lymphomas (NHLs). Whereas the incidence of the disease appears to increase during last decades and the prognosis remains dramatically poor, so far no standard treatment has been established. High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) has been proven effective in relapsed PTCL, while retrospective studies have shown a survival benefit as first-line treatment in some subsets of PTCL patients. However, given disease rarity, there is a paucity of randomized trials in both upfront and relapse setting. Here, we critically evaluated eligible prospective and retrospective studies that address the role of ASCT in treatment of PTCL, with respect to quality of design and performance. Additionally, the role of allogeneic transplantation has been reviewed. The comparison of ASCT with novel agents that emerge or the combination of both, are to be ascertained via prospective randomized trials in this field. PMID- 24075061 TI - Histopathological, immunohistochemical criteria and confocal laser-scanning data of arthrofibrosis. AB - Arthrofibrosis (af) is defined as a fibrosing disease of the synovial membrane, after joint operations, with painful restricted range of motion. The aim of this paper was to describe the histopathological substrate of af, hitherto only defined by clinical criteria. Based on a group of 222 tissue samples, the characteristic changes to af were analyzed. The control group comprised 29 cases with neosynovialis of the indifferent type. Due to cytoplasmic SM-actin positivity and the absence of specific cytoplasmic reactivity in CD 68 representation, af fibroblasts were characterized as myofibroblasts. In confocal laser-scanning microscopy, beta-catenin-positive aggregates were detected in the cytoplasm. Over and above this, unequivocal colocalization of beta-catenin and the tight junction protein ZO-1 became manifest, particularly on the cell membrane and, partly, in the cytoplasm. A threshold value of 20 beta-catenin positive cells/HPF was determined. This enables the histopathological diagnosis of an af to be made (sensitivity: 0.733, specificity: 0.867). Af is a fibrosing disease of the synovial membrane with variable grade of fibrotization (fibroblast cellularity). A threshold value of 20 beta-catenin-positive fibroblasts per HPF was defined, which enables the histopathological diagnosis of af. PMID- 24075062 TI - Immunohistochemical validation of INI1/SMARCB1 in a spectrum of musculoskeletal tumors: an experience at a Tertiary Cancer Referral Centre. AB - The purpose of this study was to evaluate and validate immunohistochemical (IHC) expression of INI1/SMARCB1 in various musculoskeletal tumors in the light of the established literature. Twenty-seven cases of epithelioid sarcoma (ES); 4 of extrarenal rhabdoid tumor (ERRT) of soft tissue and 97 other tumors, including 16 cases of synovial sarcoma (SS), were evaluated for IHC expression of INI1 on formalin-fixed, paraffin-embedded tissue sections of various biopsies. Out of 128 tumors, INI1/SMARCB1 staining was completely lacking in cases of ES (23/27) (85.1%), ERRTs (4/4) (100%), myoepithelial tumors (4/14) (28.5%) and in (1/16) (6.2%) cases of SS. Fourteen out of 15 SSs displayed a reduced staining pattern. Other 67 studied tumors were INI1-positive. Sensitivity for complete INI1 negativity in ES was 85.1%, and specificity with respect to its differentials, excluding ERRTs, was 94.8%. Complete lack of INI1 immunostaining in most ESs indicates its value as a diagnostic marker for ESs, including those occurring at rare sites; in ERRTs and in some myoepithelial tumors, within an appropriate clinicopathological context, in all kinds of biopsies. ES, at least in some cases, is immunohistochemically the most closely related tumor to an ERRT. A unique pattern of reduced INI1 expression in a SS is useful during triage of some cases for molecular testing. Its expression should be interpreted in the tumor cells, rather than intermixed stromal cells and or inflammatory cells that retain INI1 expression. PMID- 24075063 TI - Reactions to children's transgressions in at-risk caregivers: does mitigating information, type of transgression, or caregiver directive matter? AB - This study examined whether caregivers who exhibit high risk for child physical abuse differ from low-risk caregivers in reactions to transgressing children. Caregivers read vignettes describing child transgressions. These vignettes varied in: (a) the type of transgression described (moral, conventional, personal), (b) presentation of transgression-mitigating information (present, absent), and (c) whether a directive to avoid the transgression was in the vignette (yes, no). After reading each vignette, caregivers provided ratings reflecting their: (a) perceptions of transgression wrongness, (b) internal attributions about the transgressing child, (c) perceptions of the transgressing child's hostile intent, (d) own expected negative post-transgression affect, and (e) perceived likelihood of responding to the transgression with discipline that displayed power assertion and/or induction. For moral transgressions (cruelty, dishonesty, hostility, or greed), mitigating information reduced caregiver expectations that they would feel negative affect and, subsequent to the transgression, use disciplinary strategies that display power assertion. These mitigating effects were smaller among at-risk caregivers than among low-risk caregivers. Moreover, when transgressions disobeyed a directive, among low-risk caregivers, mitigating information reduced the expectation that responses to transgressions would include inductive disciplinary strategies, but it did not do so among at-risk caregivers. In certain circumstances, compared to low-risk caregivers, at-risk caregivers expect to be relatively unaffected by transgression-mitigating information. These results suggest that interventions that increase an at-risk caregiver's ability to properly assess and integrate mitigating information may play a role in reducing the caregiver's risk of child physical abuse. PMID- 24075064 TI - Enhanced mycobacterial diagnostics in liquid medium by microaerobic bubble flow in Portable Microbe Enrichment Unit. AB - Portable Microbe Enrichment Unit (PMEU) method with microaerobic bubbling speeded up the growth of otherwise slowly starting and propagating Mycobacterium sp. Mycobacterium fortuitum growth was detected after 10-11h and Mycobacterium marinum produced clear growth in 4 days. A mycobacterial environmental isolate was verified in 2 days in the PMEU Spectrion((r)) equipped with infrared sensors. In parallel static (without gas bubbling) cultures hardly any growth occurred. In conclusion, PMEU technology provided thus a rapid detection of environmental and clinical mycobacterial isolates. It would also help in the field diagnosis of antibiotic resistant Mycobacterium tuberculosis. PMID- 24075065 TI - Dextrose infusion and glucose disorders in people without diabetes hospitalized in general wards. AB - We measured fasting plasma glucose (FPG) on a single day in all persons without diabetes history admitted in general wards (N=1922). After age and length of stay adjustment, dextrose infusion was associated with a 3-fold increase (p<0.001) of hospital-related hyperglycemia (FPG >= 7 mmol/l), highlighting the need to interpret glucose disorders cautiously. PMID- 24075066 TI - Medication events on a tertiary neurology inpatient service. AB - This study aimed to determine the prevalence and attributes of medication events in a tertiary inpatient neurology setting. These findings were compared with the results of a physician survey designed to assess general knowledge of medication events. We reviewed all medication events reported through an established voluntary event recording system for adult neurology inpatients at a tertiary referral center over a 2 year period. An electronic survey was sent to all neurology residents and hospital staff regarding medication events. One hundred and forty-three medication events were reported, for a rate of 8.6 events per 1000 patient-days. The medication event rate was comparable to published rates on medicine services. There was no evidence of events being more prevalent at the beginning of the academic year or on nights. One hundred and seventeen events (81.8%) reached the patient, but most (92.7%, 108/117) did not result in harm. The most common medication types involved were anticoagulants (24 events, 16.8%), anticonvulsants (17 events, 11.9%), and antibiotics (16 events, 11.2%). Nurses were involved in reporting 133 events (93%), while physicians were involved in reporting 20 events (14%). Physicians completed the survey at a rate of 60.8% (48/79). There were notable differences between physician presumptions as to medication event attributes and actual results. No trend referable to time of year or day was identified, which contrasted with physician beliefs in our survey. Nursing staff reported the majority of events. PMID- 24075067 TI - Morsellised sawbones is an acceptable experimental substitute for the in vitro elastic and viscoelastic mechanical characterisation of morsellised cancellous bone undergoing impaction grafting. AB - Impaction grafting using morsellised bone chips is widely used during surgery to mitigate the effects of bone loss. The technique typically involves the packing of morsellised allograft cancellous bone into bone defects, and has found extensive application in revision hip and knee surgery. In the ideal situation, the presence of the bone graft prevents subsidence of the revised prosthesis in the short term, and integrates with the host bone in the longer term. However, the configuration of particles within the graft remains to be optimised, and is highly likely to vary across potential sites and loading conditions. Human bone, for use in experimental investigation, is often difficult to obtain with properties that are relevant from a clinical point of view. This study, therefore, has explored the mechanical response of a Sawbones based experimental substitute. An established confined compression technique was used to characterise the morsellised Sawbones material. Comparison of the results with published values for bovine and human bone indicate that the mechanical response of the morsellised Sawbones material map well onto the elastic and viscoelastic response of bone of a biological origin. PMID- 24075068 TI - Marker-based validation of a biplane fluoroscopy system for quantifying foot kinematics. AB - INTRODUCTION: Radiostereometric analysis has demonstrated its capacity to track precise motion of the bones within a subject during motion. Existing devices for imaging the body in two planes are often custom built systems; we present here the design and marker-based validation of a system that has been optimized to image the foot during gait. METHODS: Mechanical modifications were made to paired BV Pulsera C-arms (Philips Medical Systems) to allow unfettered gait through the imaging area. Image quality improvements were obtained with high speed cameras and the correction of image distorting artifacts. To assess the system's accuracy, we placed beads at known locations throughout the imaging field, and used post processing software to calculate their apparent locations. RESULTS: Distortion correction reduced overall RMS error from 6.56 mm to 0.17 mm. When tracking beads in static images a translational accuracy of 0.094 +/- 0.081 mm and rotational accuracy of 0.083 +/- 0.068 degrees was determined. In dynamic trials simulating speeds seen during walking, accuracy was 0.126 +/- 0.122 mm. DISCUSSION: The accuracies and precisions found are within the reported ranges from other such systems. With the completion of marker-based validation, we look to model-based validation of the foot during gait. PMID- 24075069 TI - Design of a flexible fetoscopy manipulation system for congenital diaphragmatic hernia. AB - Recent advancements in fetal surgery have proven that tracheal occlusion in fetuses with congenital diaphragmatic hernia is an effective way to prevent the occurrence of pulmonary hypoplasia. A novel flexible fetoscope with a parallel mechanism structure of a thumbstick to carry on the fetal tracheal balloon occlusion by the targeting and manipulation of the fetal endoscope at a high standard of quick response and dexterity is proposed in this paper. This design is compared with a commercial rigid fetoscope in terms of operation timing and reduced stress to the fetus at neck level. Experiments using a phantom have demonstrated that the flexible fetoscope has a better dexterity and is able to perform stable tracheoscopy and balloon inflation at different levels of the trachea, with the help of a fiberoptic camera. PMID- 24075070 TI - Positive smoker identity as a barrier to quitting smoking: findings from a national survey of smokers in England. AB - BACKGROUND: It has been proposed that positive smoker identity may be an important factor undermining smoking cessation but very little research exists on this. This study tested the hypothesis that a simple measure of positive smoker identity would predict quit attempts over and above other known predictors in a population sample. More tentatively it explored whether this measure would also predict quit success. METHODS: A representative sample of adult smokers in England (n=9456) was included at baseline and 2099 were followed-up at six months. Demographic and smoking characteristics, a single item measure of positive smoker identity (endorsing the statement: 'I like being a smoker'), measures of smoking-related attitudes, quit attempts and quit success were included. RESULTS: A total of 18.3% (95% CI=17.5-19.2) of smokers reported a positive smoker identity. Adjusting for all other predictors, those with a positive smoker identity were more likely to be older (p<0.001), male (p=0.013), more nicotine dependent (p<0.001), have lower motivation to stop (p<0.001), have not made a quit attempt in the past year (p=0.025), enjoy smoking (p<0.001), and consider themselves to be addicted (p<0.001). Having a positive smoker identity independently predicted failure to make a quit attempt at six months (p=0.007). The independent association with quit success was similar in magnitude but did not reach statistical significance (p=0.053). CONCLUSIONS: Only a minority of smokers in England have a positive smoker identity. However, where it is present it may be an important barrier to quitting smoking and merits further study. PMID- 24075071 TI - Prevention of bovine herpesvirus-1 transmission by the transfer of embryos disinfected with recombinant bovine trypsin. AB - This study deals with the potential for the introduction of infectious agents through the use of animal-derived products. The efficacy of a recombinant bovine trypsin (RBTr) as a replacement for porcine pancreatic trypsin and a disinfectant for bovine herpesvirus-1 (BHV-1)-infected embryos was investigated according to the sanitary guidelines of the International Embryo Transfer Society. Treatment of in vivo and in vitro fertilized embryos contaminated with BHV-1 (10(5) TCID50/mL) in the presence of RBTr (525 U/mL) for 120 s, effectively removed the infectious virus compared with untreated and washed embryos (P < 0.05). Transfer of in vivo fertilized and disinfected embryos to BHV-1 seronegative recipients (n = 24) resulted in 14 pregnancies and 11 calves born free of BHV-1. In contrast, transfer of unwashed or undisinfected embryos to four recipients resulted in seroconversion and no pregnancies at term. It was concluded that the use of RBTr could be considered as an alternative method of rendering embryos free of BHV-1 and thus reduce the potential risk of disease transmission to embryo recipients and offspring. PMID- 24075072 TI - Volatile organic compounds characterized from grapevine (Vitis vinifera L. cv. Malbec) berries increase at pre-harvest and in response to UV-B radiation. AB - Ultraviolet-B solar radiation (UV-B) is an environmental signal with biological effects in plant tissues. Recent investigations have assigned a protective role of volatile organic compounds (VOCs) in plant tissues submitted to biotic and abiotic stresses. This study investigated VOCs in berries at three developmental stages (veraison, pre-harvest and harvest) of Vitis vinifera L. cv. Malbec exposed (or not) to UV-B both, in in vitro and field experiments. By Head Space Solid Phase Micro Extraction-Gas Chromatography-Electron Impact Mass Spectrometry (HS-SPME-GC-EIMS) analysis, 10 VOCs were identified at all developmental stages: four monoterpenes, three aldehydes, two alcohols and one ketone. Monoterpenes increased at pre-harvest and in response to UV-B in both, in vitro and field conditions. UV-B also augmented levels of some aldehydes, alcohols and ketones. These results along with others from the literature suggest that UV-B induce grape berries to produce VOCs (mainly monoterpenes) that protect the tissues from UV-B itself and other abiotic and biotic stresses, and could affect the wine flavor. Higher emission of monoterpenes was observed in the field experiments as compared in vitro, suggesting the UV-B/PAR ratio is not a signal in itself. PMID- 24075073 TI - Pain relief is associated with improvement in motor function in complex regional pain syndrome type 1: secondary analysis of a placebo-controlled study on the effects of ketamine. AB - There are indications of motor circuit changes in patients with complex regional pain syndrome (CRPS). Nevertheless, although several studies have analyzed motor behavior in CRPS, a relation with pain could not be detected. This might be explained by the use of cross-sectional designs in these studies, in which pain is considered as a trait- rather than a state-dependent variable. We therefore studied the time-dependent relation between pain and motor function in affected arms of 29 CRPS patients during their participation in a placebo-controlled ketamine study. Movement parameters (velocity, frequency, amplitude, and number of arrests) were assessed during a finger tapping task. Linear mixed model analysis of the effects of pain (numerical rating scale score), treatment (ketamine/placebo), and week (1, 3, 6, and 12 weeks after treatment) on the movement parameters revealed that pain intensity was significantly (inversely) related to motor function, irrespective of whether patients had received ketamine or placebo. Movement parameters changed 3-12% per point numerical rating scale change. Because patients were unaware of possible effects of ketamine on motor function, these findings suggest that motor function changes were mediated by, or occurred simultaneously with, changes in pain intensity. By improving motor function, pain relief may offer a window of opportunity for rehabilitation programs in CRPS. PERSPECTIVE: This article provides evidence for a direct relation between pain and motor function in CRPS, which indicates that pain relief may be an important factor in the treatment of motor disturbances in this condition. These findings may help to advance our understanding of the pathways underlying motor disturbances in CRPS. PMID- 24075074 TI - Simulation of porosity decrease with protein adsorption using the distributed pore model. AB - Chromatographic stationary phases such as Fractogel EMD SO3 (M) have a pore size distribution that is close to the size of proteins. The accessible porosity and the mass transfer inside the particles are therefore strongly affected by the pore to solute size ratio. This effect was simulated using the distributed pore model for three media: Base Fractogel SO3, Fractogel EMD SO3 (M) and (S). This model was extended so as to be able to account for the effect of pore shrinkage due to protein loading on the chromatographic behavior of other proteins. Pulse chromatographic experiments using dextrans of various sizes on column pre-loaded with antibodies have been conducted to test the model reliability. PMID- 24075075 TI - Rapid analysis of aminoglycoside antibiotics in bovine tissues using disposable pipette extraction and ultrahigh performance liquid chromatography-tandem mass spectrometry. AB - A high-throughput qualitative screening and identification method for 9 aminoglycosides of regulatory interest has been developed, validated, and implemented for bovine kidney, liver, and muscle tissues. The method involves extraction at previously validated conditions, cleanup using disposable pipette extraction, and analysis by a 3 min ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method. The drug analytes include neomycin, streptomycin, dihydrosptreptomycin, and spectinomycin, which have residue tolerances in bovine in the US, and kanamicin, gentamicin, apramycin, amikacin, and hygromycin, which do not have US tolerances established in bovine tissues. Tobramycin was used as an internal standard. An additional drug, paromomycin also was validated in the method, but it was dropped during implementation due to conversion of neomycin into paromomycin. Proposed fragmentation patterns for the monitored ions of each analyte were elucidated with the aid of high resolution MS using a quadrupole-time-of-flight instrument. Recoveries from spiking experiments at regulatory levels of concern showed that all analytes averaged 70-120% recoveries in all tissues, except hygromycin averaged 61% recovery. Lowest calibrated levels were as low as 0.005 MUg/g in matrix extracts, which approximately corresponded to the limit of detection for screening purposes. Drug identifications at levels <0.05 MUg/g were made in spiked and/or real samples for all analytes and tissues tested. Analyses of 60 samples from 20 slaughtered cattle previously screened positive for aminoglycosides showed that this method worked well in practice. The UHPLC-MS/MS method has several advantages compared to the previous microbial inhibition screening assay, especially for distinguishing individual drugs from a mixture and improving identification of gentamicin in tissue samples. PMID- 24075076 TI - Simultaneous spreading and evaporation: recent developments. AB - The recent progress in theoretical and experimental studies of simultaneous spreading and evaporation of liquid droplets on solid substrates is discussed for pure liquids including nanodroplets, nanosuspensions of inorganic particles (nanofluids) and surfactant solutions. Evaporation of both complete wetting and partial wetting liquids into a nonsaturated vapour atmosphere are considered. However, the main attention is paid to the case of partial wetting when the hysteresis of static contact angle takes place. In the case of complete wetting the spreading/evaporation process proceeds in two stages. A theory was suggested for this case and a good agreement with available experimental data was achieved. In the case of partial wetting the spreading/evaporation of a sessile droplet of pure liquid goes through four subsequent stages: (i) the initial stage, spreading, is relatively short (1-2 min) and therefore evaporation can be neglected during this stage; during the initial stage the contact angle reaches the value of advancing contact angle and the radius of the droplet base reaches its maximum value, (ii) the first stage of evaporation is characterised by the constant value of the radius of the droplet base; the value of the contact angle during the first stage decreases from static advancing to static receding contact angle; (iii) during the second stage of evaporation the contact angle remains constant and equal to its receding value, while the radius of the droplet base decreases; and (iv) at the third stage of evaporation both the contact angle and the radius of the droplet base decrease until the drop completely disappears. It has been shown theoretically and confirmed experimentally that during the first and second stages of evaporation the volume of droplet to power 2/3 decreases linearly with time. The universal dependence of the contact angle during the first stage and of the radius of the droplet base during the second stage on the reduced time has been derived theoretically and confirmed experimentally. The theory developed for pure liquids is applicable also to nanofluids, where a good agreement with the available experimental data has been found. However, in the case of evaporation of surfactant solutions the process deviates from the theoretical predictions for pure liquids at concentration below critical wetting concentration and is in agreement with the theoretical predictions at concentrations above it. PMID- 24075077 TI - Antihypertensive medications and survival in patients with cancer: a population based retrospective cohort study. AB - BACKGROUND: The association between antihypertensive medications and survival in cancer patients remains unclear. OBJECTIVES: To explore the association between classes of antihypertensive drugs and survival in cancer patients. METHODS: Provincial Cancer Registry data was linked with a Provincial Drug Program Information Network (DPIN) for patients with lung (n=4241), colorectal (n=3967), breast (n=4019) or prostate (n=3355) cancer between the years of 2004 and 2008. Cox regression analyses were used to compare survival of patients using beta blockers (BBs), angiotensin-converting enzyme inhibitors/receptor blockers (ACEi/ARB), calcium channel blockers (CCBs) or thiazide diuretics (TDs) to survival of patients who did not use any of these antihypertensive drugs. Survival of patients using only one class of antihypertensive drugs were compared to each other, with BBs as the reference class. RESULTS: Compared to the antihypertensive drug non-user cohort, BBs had no effect on survival for any of the cancers. ACEi/ARBs use was weakly associated with increased deaths for breast cancer (HR: 1.22, 95% CI: 1.04-1.44) and lung cancer (HR: 1.11, 95% CI: 1.03 1.21) patients. Deaths were also increased with CCB use in patients with breast cancer (HR: 1.22, 95% CI: 1.02-1.47) and with TD use in lung cancer patients (HR: 1.1, 95% CI: 1.01-1.19). There was strong evidence (p-value <0.0001) of an increase in deaths with TD use for colorectal (HR: 1.28, 95% CI: 1.15-1.42), and prostate (HR 1.41, 1.2-1.65) cancer patients. When including only antihypertensive drug users prescribed one drug class, lung cancer patients receiving CCBs had improved survival compared to BBs (HR 0.79, 95% CI: 0.64 0.98). CONCLUSIONS: Some classes of antihypertensive agents are associated with a decreased survival in certain cancers. The decrease could be due to more comorbidities in antihypertensive drug users. However, CCB use was associated with improved survival in lung cancer patients. PMID- 24075078 TI - Modulation of oxidative stress, apoptosis, and calcium entry in leukocytes of patients with multiple sclerosis by Hypericum perforatum. AB - OBJECTIVES: Hypericum perfortarum (HP, St John's wort) is a modulator of Ca(2+) entry in neutrophils and it may modulate intracellular free Ca(2+) ([Ca(2+)]i) entry in leukocytes of patients with multiple sclerosis (MS). We investigated effects of HP on oxidative stress, apoptosis, and [Ca(2+)]i concentrations in serum and leukocytes of patients with MS. METHODS: Neutrophils of nine newly diagnosed MS patients and nine healthy subjects within four subgroups were used in the study. The first group was a control; the second group was patients with MS. The neutrophils from patient group were incubated non-specific TRPM2 channel blocker (2-APB), voltage-gated calcium channel blockers, verapamil and diltiazem (V + D) with HP before N-formyl-L-methionyl-L-leucyl-L-phenylalanine stimulation, respectively. RESULTS: Neutrophil and serum lipid peroxidation, neutrophil apoptosis and [Ca(2+)]i levels in patients with MS were higher than in control although their levels were decreased by HP, 2-APB, and V + D incubations. The modulator role of V + D in MS and MS + HP groups was higher than in the 2-APB group. Neutrophilic glutathione peroxidase (GSH-Px) and serum vitamin A and E concentrations were lower in the MS group than in control. However, the neutrophil GSH-Px activity was increased by HP incubation. The neutrophil reduced glutathione, serum vitamin C and beta-carotene concentrations did not change in control and patients. DISCUSSION: We observed that HP-induced protective effects on oxidative stress and [Ca(2+)]i concentrations by modulating transient receptor potential and voltage gated calcium channel in the patients with MS. Thus, it may provide useful treatment of neutrophil activity in the patients. PMID- 24075079 TI - A coarse-to-fine approach for segmenting melanocytic skin lesions in standard camera images. AB - Melanoma is a type of malignant melanocytic skin lesion, and it is among the most life threatening existing cancers if not treated at an early stage. Computer aided prescreening systems for melanocytic skin lesions is a recent trend to detect malignant melanocytic skin lesions in their early stages, and lesion segmentation is an important initial processing step. A good definition of the lesion area and its border is very important for discriminating between benign and malignant cases. In this paper, we propose to segment melanocytic skin lesions using a sequence of steps. We start by pre-segmenting the skin lesion, creating a new image representation (channel) where the lesion features are more evident. This new channel is thresholded, and the lesion border pre-detection is refined using an active-contours algorithm followed by morphological operations. Our experimental results based on a publicly available dataset suggest that our method potentially can be more accurate than comparable state-of-the-art methods proposed in literature. PMID- 24075080 TI - Entropy analysis of muscular near-infrared spectroscopy (NIRS) signals during exercise programme of type 2 diabetic patients: quantitative assessment of muscle metabolic pattern. AB - Diabetes mellitus (DM) is a metabolic disorder that is widely rampant throughout the world population these days. The uncontrolled DM may lead to complications of eye, heart, kidney and nerves. The most common type of diabetes is the type 2 diabetes or insulin-resistant DM. Near-infrared spectroscopy (NIRS) technology is widely used in non-invasive monitoring of physiological signals. Three types of NIRS signals are used in this work: (i) variation in the oxygenated haemoglobin (O2Hb) concentration, (ii) deoxygenated haemoglobin (HHb), and (iii) ratio of oxygenated over the sum of the oxygenated and deoxygenated haemoglobin which is defined as: tissue oxygenation index (TOI) to analyze the effect of exercise on diabetes subjects. The NIRS signal has the characteristics of non-linearity and non-stationarity. Hence, the very small changes in this time series can be efficiently extracted using higher order statistics (HOS) method. Hence, in this work, we have used sample and HOS entropies to analyze these NIRS signals. These computer aided techniques will assist the clinicians to diagnose and monitor the health accurately and easily without any inter or intra observer variability. Results showed that after a one-year of physical exercise programme, all diabetic subjects increased the sample entropy of the NIRS signals, thus revealing a better muscle performance and an improved recruitment by the central nervous system. Moreover, after one year of physical therapy, diabetic subjects showed a NIRS muscular metabolic pattern that was not distinguished from that of controls. We believe that sample and bispectral entropy analysis is need when the aim is to compare the inner structure of the NIRS signals during muscle contraction, particularly when dealing with neuromuscular impairments. PMID- 24075081 TI - Identification and experimental validation of an HIV model for HAART treated patients. AB - The objective of this paper is to identify the parameters of a human immunodeficiency virus (HIV) evolution model from a clinical data set of patients treated with two different highly active antiretroviral therapy (HAART) protocols. After introducing a model with six state variables, a preliminary step considers the reduction of the number of parameters to be identified by means of sensitivity analysis, and then identifiability items are discussed. A nonlinear optimization-based procedure for identification is developed, which divides the unknown parameters into two families: the group dependent and the patient dependent parameters. Numerical results show that the identified model can be individually adapted to each patient and this result is promising for predicting the effects (e.g., failures or successes) of therapeutic actions. PMID- 24075082 TI - MCF: a tool to find multi-scale community profiles in biological networks. AB - Recent developments of complex graph clustering methods have implicated the practical applications with biological networks in different settings. Multi scale Community Finder (MCF) is a tool to profile network communities (i.e., clusters of nodes) with the control of community sizes. The controlling parameter is referred to as the scale of the network community profile. MCF is able to find communities in all major types of networks including directed, signed, bipartite, and multi-slice networks. The fast computation promotes the practicability of the tool for large-scaled analysis (e.g., protein-protein interaction and gene co expression networks). MCF is distributed as an open-source C++ package for academic use with both command line and user interface options, and can be downloaded at http://bsdxd.cpsc.ucalgary.ca/MCF. Detailed user manual and sample data sets are also available at the project website. PMID- 24075083 TI - Pediatricians' beliefs and prescribing patterns of adolescent contraception: a provider survey. AB - STUDY OBJECTIVE: Teen pregnancy and sexually transmitted infection (STI) rates continue to be significant public health problems in the United States. While general pediatricians are in a unique position to improve these issues by addressing contraception with their adolescent patients, there are no data describing their current prescribing patterns. This study sought to elucidate the beliefs and prescribing patterns of general pediatricians and pediatrics residents and to distinguish whether these were affected by practice setting, level of training, or gender. DESIGN, SETTING, PARTICIPANTS: General pediatricians and pediatrics residents affiliated with Lurie Children's Hospital in Chicago, IL, were asked to complete a survey regarding adolescent contraception. MAIN OUTCOME MEASURES: Questions were related to obtaining information about contraception, contraceptive counseling, knowledge of contraceptive methods, prescribing patterns of contraceptives, and concerns about individual contraceptive methods. RESULTS: 120 physicians of an eligible 411 physicians participated in this study (29%). 79% of participants had prescribed at least 1 contraceptive method. The most commonly prescribed method was oral contraceptive pills at 72%. We noted few differences in prescribing patterns based on above criteria. Numerous misconceptions existed among participants, including a high rate of concern about infertility with IUD use (29% among physicians who prescribed at least 1 method of contraception). CONCLUSIONS: General pediatricians can improve their rates of prescribing contraception to adolescents, and could utilize more of the approved methods. One way to do so may be to implement educational interventions among general pediatricians. PMID- 24075084 TI - Factors related to contraceptive methods among female higher education students in Greece. AB - STUDY OBJECTIVE: We aimed to determine the prevalence of contraceptive methods and identify factors associated with the use of contraception by Greek female higher education students. DESIGN: Cross-sectional epidemiologic survey on the factors determining the use of contraception among higher educational students. SUBJECT: 3,624 female students between 18 and 26 years of age. MAIN OUTCOME MEASURES: We used primary individualized data drawn from a survey carried among female college students in Greece. The dependent dichotomous variables were the responses "YES" or "NO" to the question: "During the last 12 months, what contraceptive method have you generally used in your sexual intercourses?" The methods were male condoms, oral contraceptive use (OCs) and emergency contraception (EC). The independent variables which were analysed in this survey were socio-demographic characteristics, variables related to lifestyle and variables associated with sexual habits. RESULTS: Condom was the most widely used (53.87%). The variables associated independently and significantly with a greater likelihood of the use of condoms were condom use at first sexual intercourse, occupational status and higher educational level of parents. As for OCs, those who had relationship, had more than 2 sexual lifetime partners and had ever visited gynecologist (OR 6.40; 95%CI 2.80-9.40) was more likely to use. For the use of EC, those who were older, had relationship, were smokers and had more than 2 sexual lifetime partners (OR 2.15; 95%CI 1.75-2.64), was more likely to use this method. CONCLUSIONS: Condom is the most used contraceptive method among female higher educational students in Greece, followed by EC. The variable most strongly associated with use of the OCs was a gynecologist visit. The factors associated with use of EC were having more than 2 sexual partners, smoking, and having a stable sexual partner. PMID- 24075085 TI - Asynchronous bilateral ovarian torsion. A case report and mini review. AB - BACKGROUND: Adnexal torsion is a serious condition and delay in surgical intervention may result in loss of ovary. Children and adolescents who have suffered from uterine adnexal torsion may be at risk for asynchronous torsion of the contralateral adnexa. CASE: We report the case of asynchronous bilateral ovarian torsion in a 9-year-old girl, resulting in right and subsequently left salpingo-oophorectomy. CONCLUSION: The diagnosis of ovarian torsion often is delayed. When ovarian torsion is suspected, laparoscopy should be performed without delay, and conservative management should be strongly considered to prevent surgical castration. Oophoropexy of the ipsilateral and contralateral ovary should be considered to prevent a recurrent torsion. PMID- 24075086 TI - OHVIRA with a twist: obstructed hemivagina ipsilateral renal anomaly with urogenital sinus in 2 patients. AB - BACKGROUND: OHVIRA syndrome is a rare diagnosis involving the triad of obstructed hemivagina, uterine anomaly, and ipsilateral renal anomaly. OHVIRA syndrome can be associated with other anomalies due to abnormal embryologic development of the urogenital system. CASES: A 14-year-old female with known left renal agenesis, long-standing urinary incontinence, and history of recurrent urinary tract infections presented with abdominal distention. A 4-year-old female with known right renal agenesis and urinary incontinence was found to have a single common channel at the introitus that communicated with the bladder and a hemivagina on the left. SUMMARY AND CONCLUSION: It is important to identify the presence of a urogenital sinus in the OHVIRA setting, as surgical management for these patients may be affected. In both cases, the urogenital sinus was preserved as the vaginal opening. PMID- 24075087 TI - Congenital perineal mass with cervovaginal duplication: a case report and literature review. AB - BACKGROUND: Congenital perineal mass is rare. Although there have been several reports describing male neonates with a perineal mass with urogenital anomalies, no similar cases have been reported in female infants. CASE: We present a case of a 17-month-old girl with a congenital, slowly enlarging perineal mass with cervovaginal duplication. Excision of the mass was performed and histopathogic examination revealed it to be a hamartoma. CONCLUSION: Congenital perineal mass may be the result of urorectal septum outgrowth and it is likely to be associated with urogenital and/or anorectal anomalies. PMID- 24075088 TI - Relationship between dysmenorrhea and posttraumatic stress disorder in Japanese high school students 9 months after the Great East Japan Earthquake. AB - STUDY OBJECTIVE: To determine the relationship between dysmenorrhea and posttraumatic stress disorder (PTSD) among Japanese adolescent girls 9 months after the Great East Japan Earthquake. DESIGN: Cross-sectional study. SETTING: Two high schools in Sendai, the largest city in northeastern Japan. PARTICIPANTS: 1489 female adolescents aged between 15 and 18 years. MAIN OUTCOME MEASURES: Impact of Event Scale-Revised (IES-R), intensity of menstrual pain. RESULTS: The intensity of menstrual pain increased according to the comorbidity of PTSD (P < .001). The IES-R subscale and total scores significantly increased according to the severity of menstrual pain. CONCLUSIONS: This study showed a significant association between natural disaster-induced PTSD and the severity of dysmenorrhea. PMID- 24075089 TI - Assessment of anxiety and depression in adolescents with primary dysmenorrhea: a case-control study. AB - STUDY OBJECTIVE: To examine the relationship between primary dysmenorrhea and symptoms of depression and anxiety among adolescent female students in Tbilisi, Georgia. DESIGN: A case-control study. SETTING: Tbilisi, Georgia. PARTICIPANTS: Four hundred twenty-four postmenarcheal girls aged 14-20 years (a subset of a larger study involving 2561 girls). METHODS: The data was gathered in 2011 by the use of a questionnaire prepared for the purpose of this study, completed anonymously. Menstrual pattern, depression and anxiety level were evaluated in both groups; continuous and categorical variables were compared by Pearson chi square test. Depressive symptoms were determined by a self-reporting scale (Beck Depression Inventory); anxiety was determined using Taylor Manifest Anxiety Scale (TMAS) and Spielberger State-Trait Anxiety Inventory (STAI). MAIN OUTCOME MEASURES: Differences in mental health between two groups. RESULTS: Patients with primary dysmenorrhea (PD) had significantly higher scores of depression than the control subjects: moderate depression, 15.9% in PD patients vs 6.2% in control subjects and severe depression, 1.8% vs 0% (P < .003, LR 0.001). High anxiety (TMAS) was also more prevalent in adolescents with primary dysmenorrhea (44% vs 9.9%; P < .001, LR < 0.001). STAI scores were also significantly higher in these patients than in healthy women (68.9% vs 25.0%; P < .001, LR < 0.001). CONCLUSION: Primary dysmenorrhea is strongly linked with positive scores for depression and anxiety. Because of this association, attention should be given to effective mental health screening in these patients; psychological support may be necessary during their treatment and follow-up. PMID- 24075090 TI - Non-surgical management of the auto-amputated adnexa in the neonate: a report on two cases. AB - BACKGROUND: Prenatal ovarian torsion is a rare but significant gynecologic abnormality. Current literature has yet to establish standard management in the case of auto-amputated adnexa secondary to ovarian torsion in the neonate. CASES: We report 2 cases of abdominal masses that were diagnosed in the antenatal period and were clinically consistent with auto-amputated adnexa followed with serial ultrasonography until resolution. SUMMARY AND CONCLUSION: To our knowledge this is the first report in the literature to document resolution of 2 pelvic masses due to auto-amputated adnexa with expectant management. This suggests expectant management is an appropriate alternative to surgical management in carefully selected cases. PMID- 24075091 TI - The growth of maternal-fetal emotional attachment in pregnant adolescents: a prospective cohort study. AB - STUDY OBJECTIVE: To describe self-reported maternal-fetal emotional attachment in adolescent women over the course of pregnancy, compare it with adult pregnant women, and identify risk factors for poor attachment. DESIGN: A prospective cohort study. SETTING: Young mothers' clinics in 2 public hospitals in metropolitan Melbourne, Australia. PARTICIPANTS: English-speaking young women aged 20 years and under attending their first antenatal visit. METHODS: Self report questionnaires were completed in each trimester. Validated measures were used to assess anxiety and depression symptoms and maternal-fetal emotional attachment. Data were analyzed with existing data from pregnant adults. Regression analyses were conducted to establish factors independently associated with higher mean first-trimester attachment score and lowest-quartile third trimester score adjusting for confounding variables. MAIN OUTCOME MEASURE: Maternal-fetal emotional attachment, assessed by the Quality and Intensity subscales and Global score on Maternal Antenatal Attachment Scale (MAAS). RESULTS: 165/194 (85%) completed the first questionnaire; 130/165 (79%) provided complete data. Mean anxiety but not depression scores were significantly higher in adolescents than adults across pregnancy. Mean (95%CI) first-trimester adolescent Global MAAS was significantly lower than adults (70.3 (68.4, 72.2) vs 76.8 (75.4, 78.2) P < .01), but there were no significant second- or third trimester between-group differences. Adjusted odds of a lowest-quartile third trimester MAAS score was significantly associated with lower first-trimester score (P < .001), previous abortion (P = .02) and being born overseas (P = .002). CONCLUSION: Adolescents report slower development of antenatal emotional attachment than adults. Women with risk factors for poor attachment in late pregnancy are identifiable in early pregnancy and may benefit from additional multidisciplinary care. PMID- 24075092 TI - Neonate presenting with a midline supraumbilical raphe. PMID- 24075093 TI - Correlation of skin toxicity and hypertension with clinical benefit in advanced hepatocellular carcinoma patients treated with sorafenib. AB - OBJECTIVE: The purpose of this study was to identify the correlation of skin toxicity and hypertension with clinical benefit in advanced hepatocellular carcinoma (HCC) patients treated with sorafenib by analyzing medical records retrospectively. METHODS: Data from medical records was statistically analyzed to identify a correlation of skin toxicity and hypertension with treatment response and prognosis in advanced HCC patients who had received sorafenib at the Asan Medical Center from July 2010 to June 2012. This study investigated prognostic factors for overall survival and the correlation between the development of skin toxicities and hypertension. RESULTS: A total of 99 patients receiving sorafenib were included in this study. 29 patients who developed skin toxicities Grade 2 or higher showed significantly longer survival than the 70 patients who developed skin toxicities less than Grade 2 or those without skin toxicity (p = 0.024). However, development of hypertension was not related to survival (p = 0.262). In a multivariate analysis, skin toxicities were found to be good prognostic factors for overall survival (hazard ratio, 0.320; 95% CI, 0.119 - 0.861; p = 0.024) as well as low alpha-fetoprotein level (hazard ratio, 0.195; 95% CI, 0.076 - 0.500; p = 0.001). On the other hand, no correlation was found between the development of skin toxicities and hypertension (p = 0.109). CONCLUSIONS: Skin toxicities that are common adverse reactions in advanced HCC patients treated with sorafenib may be used as surrogate markers for clinical benefit. Therefore, early detection and proper management of these toxicities is crucial for continuing treatment with sorafenib. PMID- 24075094 TI - Single-dose and steady-state pharmacokinetics of ospemifene, a selective estrogen receptor modulator, in postmenopausal women. AB - OBJECTIVE: To characterize the pharmacokinetics of the oral, non-estrogen agent ospemifene, an estrogen agonist/antagonist with tissue-selective effects (also called a selective estrogen receptor modulator) that was recently approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women. METHODS: Two open-label, Phase 1 studies were conducted to determine the pharmacokinetics of ospemifene in healthy postmenopausal women. In the single-dose study, 60 mg of [3H]-ospemifene was orally administered to 6 subjects. Blood, urine, and fecal samples were collected predose and serially up to 240 hours postdose. In the multiple-dose study, 12 subjects received 60 mg of ospemifene once daily for 9 days. Blood samples were collected predose and serially postdose on Day 1, predose on Days 7 and 8, and predose and serially postdose on Day 9. RESULTS: Ospemifene exhibited high plasma protein binding and was extensively metabolized, predominantly to 4-hydroxyospemifene and 4' hydroxyospemifene. In the single-dose study, ospemifene was rapidly absorbed, with a median tmax of 1.50 hours and geometric mean Cmax of 612 ng/ml. The geometric mean (CV%) t1/2 was 24.5 (21.3) hours and 29.0 (18.0) hours for ospemifene and 4-hydroxyospemifene, respectively. Fecal elimination accounted for 75% of the administered [3H]-ospemifene dose in 240 hours. In the multiple dosing study, steady state was reached by Day 7. The mean t1/2 at steady state for ospemifene was 29.1 hours. High values for volume of distribution and total clearance suggested extensive tissue distribution and efficient elimination of ospemifene. CONCLUSIONS: In healthy postmenopausal women, ospemifene 60 mg/day reached steady state concentrations by Day 7 and showed minimal accumulation of parent drug or its two main metabolites, indicating that once daily dosing is appropriate. PMID- 24075095 TI - The role of sevelamer carbonate in increasing serum bicarbonate in hyperphosphatemic predialysis patients who have metabolic acidosis. PMID- 24075096 TI - Interventions to reduce wrong blood in tube errors in transfusion: a systematic review. AB - This systematic review addresses the issue of wrong blood in tube (WBIT). The objective was to identify interventions that have been implemented and the effectiveness of these interventions to reduce WBIT incidence in red blood cell transfusion. Eligible articles were identified through a comprehensive search of The Cochrane Library, MEDLINE, EMBASE, Cinahl, BNID, and the Transfusion Evidence Library to April 2013. Initial search criteria were wide including primary intervention or observational studies, case reports, expert opinion, and guidelines. There was no restriction by study type, language, or status. Publications before 1995, reviews or reports of a secondary nature, studies of sampling errors outwith transfusion, and articles involving animals were excluded. The primary outcome was a reduction in errors. Study characteristics, outcomes measured, and methodological quality were extracted by 2 authors independently. The principal method of analysis was descriptive. A total of 12,703 references were initially identified. Preliminary secondary screening by 2 reviewers reduced articles for detailed screening to 128 articles. Eleven articles were eventually identified as eligible, resulting in 9 independent studies being included in the review. The overall finding was that all the identified interventions reduced WBIT incidence. Five studies measured the effect of a single intervention, for example, changes to blood sample labeling, weekly feedback, handwritten transfusion requests, and an electronic transfusion system. Four studies reported multiple interventions including education, second check of ID at sampling, and confirmatory sampling. It was not clear which intervention was the most effective. Sustainability of the effectiveness of interventions was also unclear. Targeted interventions, either single or multiple, can lead to a reduction in WBIT; but the sustainability of effectiveness is uncertain. Data on the pre- and postimplementation of interventions need to be collected in future trials to demonstrate effectiveness, and comparative studies are needed of different interventions. PMID- 24075097 TI - A retrospective review of patient factors, transfusion practices, and outcomes in patients with transfusion-associated circulatory overload. AB - Transfusion-associated circulatory overload (TACO) is a common yet underrecognized and underreported complication of transfusion associated with significant morbidity and mortality. The objective of this study was to examine patient and transfusion characteristics in a cohort of TACO cases. A retrospective medical record review of 100 consecutive TACO episodes reported at 2 academic centers was performed. Information related to demographics, medical history, radiologic and echocardiographic investigations, infusion practices, reaction features, management, and outcome were collected. Ninety-eight cases were accessible for review. A history of congestive heart failure (41%), renal dysfunction (44%), and age more than 70 years (56%) were common in TACO patients. Suboptimal fluid status management and inappropriate infusion practices were often seen (eg, verbal orders, double red cell transfusions, rapid infusion rates, lack or improper timing of preemptive diuretics). The median volume of blood ordered was 500 mL, and the median volume of crystalloid or colloid (preceding 24 hours) was 2200 mL. A physician order specifying the infusion rate was documented in 50% of transfusion orders. Preemptive diuretics were ordered in only 29% of cases, most commonly introduced midway or after the transfusion at a dose of furosemide 20 mg intravenously. After TACO, 18% of patients required transfer to the intensive care unit, 8% suffered a major complication, and 2% died. Suboptimal ordering and infusion practices may be contributing to the high incidence and severity of TACO. Research in TACO prevention strategies, such as slow rates of infusion and preemptive diuretics, is warranted. PMID- 24075098 TI - Characterizing dose-responses of catalase to nitrofurazone exposure in model ciliated protozoan Euplotes vannus for ecotoxicity assessment: enzyme activity and mRNA expression. AB - In environmental studies, some biological responses, known as biomarkers, have been used as a powerful bioassay tool for more than four decades. Disparity between enzyme activity and mRNA abundance leads to correlation equivocality, which makes the application of biomarkers for environmental risk assessment more complicated. This study investigates this disparity in the case of catalase when used as a biomarker for detecting ecotoxicity induced by antibiotics in aquatic ecosystems. In particular, dose-responses for catalase activity and mRNA expression abundance were investigated in Euplotes vannus which were exposed to graded doses of nitrofurazone for several discrete durations, and dose-response models were developed to characterize the dose-response dynamics. Significant differences were found in both catalase activity and mRNA expression abundance among the E. vannus treated with nitrofurazone. Catalase activity showed a hormetic-like effect in terms of dose-response, characterized by a biphasic relationship which was more clearly evident after a longer exposure period, while mRNA expression abundance increased linearly with the exposure duration. Additionally, the correlation between catalase activity and mRNA expression abundance reversed along with the duration of exposure to nitrofurazone. Taken together, our results demonstrate that catalase mRNA expression offers a more straightforward dose-response model than enzyme activity. Our findings suggest that both catalase enzyme activity and mRNA expression abundance can be used jointly as bioassay tools for detecting ecotoxicity induced by nitrofurazone in aquatic ecosystems. PMID- 24075099 TI - Carbon dioxide regulation of autotrophy and diazotrophy in the nitrogen-fixing cyanobacterium Nostoc muscorum. AB - To understand how carbon and nitrogen metabolism are regulated in diazotrophically and non-diazotrophically grown cultures of the cyanobacterium Nostoc muscorum, we investigated the role of bicarbonate (HCO3-) in regulating diazotrophy and autotrophy. Results showed that HCO3- concentration up to 12 mol m-3 enhanced growth, specific growth rate, photosynthetic pigments, photosynthetic O2 evolution and nitrogenase activity under diazotrophic growth conditions. The co-existence of different nitrogen sources in the growth medium further accelerate the examined parameters in the order of NO3-0.05). Although there was no significant difference in flexor or extensor deficits, one-leg-hop test, or shuttle run test, "return-to-sports" group obtained significantly better scores in the co-contraction and carioca tests (P<0.05). CONCLUSIONS: Tests that assess rotational stability showed statistically significant differences between the two groups. Further prospective studies with larger cohort are needed to determine the factors associated with returning to sports after ACL reconstruction. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 24075100 TI - The TGFbeta1 pathway is required for NFkappaB dependent gene expression in mouse keratinocytes. AB - The transforming growth factor-beta 1 (TGFbeta1) and NFkappaB pathways are important regulators of epidermal homeostasis, inflammatory responses and carcinogenesis. Previous studies have shown extensive crosstalk between these pathways that is cell type and context dependent, but this has not been well characterized in epidermal keratinocytes. Here we show that in primary mouse keratinocytes, TGFbeta1 induces NFkappaB-luciferase reporter activity that is dependent on both NFkappaB and Smad3. TGFbeta1-induced NFkappaB-luciferase activity was blocked by the IkappaB inhibitor parthenolide, the IkappaB super repressor, a dominant negative TGFbeta1-activated kinase 1 (TAK1) and genetic deletion of NFkappaB1. Coexpression of NFkappaB p50 or p65 subunits enhanced NFkappaB-luciferase activity. Similarly, inhibition of the TGFbeta1 type I receptor with SB431542 or genetic deletion of Smad3 blocked TGFbeta1 induction of NFkappaB-luciferase. TGFbeta1 rapidly induced IKK phosphorylation but did not cause a detectable decrease in cytoplasmic IkappaB levels or nuclear translocation of NFkappaB subunits, although EMSA showed rapid NFkappaB nuclear binding activity that could be blocked by SB431542 treatment. TNFalpha, a well characterized NFkappaB target gene was also induced by TGFbeta1 and this was blocked in NFkappaB+/- and -/- keratinocytes and by the IkappaB super-repressor. To test the effects of the TGFbeta1 pathway on a biologically relevant activator of NFkappaB, we exposed mice and primary keratinocytes in culture to UVB irradiation. In primary keratinocytes UVB caused a detectable increase in levels of Smad2 phosphorylation that was dependent on ALK5, but no significant increase in SBE-dependent gene expression. Inhibition of TGFbeta1 signaling in primary keratinocytes with SB431542 or genetic deletion of Tgfb1 or Smad3 suppressed UVB induction of TNFalpha message. Similarly, UVB induction of TNFalpha mRNA was blocked in skin of Tgfb1+/- mice. These studies demonstrate that intact TGFbeta1 signaling is required for NFkappaB-dependent gene expression in mouse keratinocytes and skin and suggest that a convergence of these pathways in the nucleus rather than the cytoplasm may be critical for regulation of inflammatory pathways in skin by TGFbeta1. PMID- 24075102 TI - Invited commentary. PMID- 24075103 TI - Contralateral carotid artery occlusion is not a contraindication to carotid endarterectomy even if shunts are not routinely used. AB - OBJECTIVE: Although controversial, carotid artery stenting (CAS) has been proposed as being safer than carotid endarterectomy (CEA) for patients with a contralateral internal carotid occlusion (CCO). Arguably, with a CCO, CAS should be even safer than CEA if a shunt is not used. Accordingly, we reviewed our experience with 2183 CEAs performed routinely without a shunt to evaluate the risk of CEA performed in a subset of 147 patients with a CCO. METHODS: Between 1988 and 2011, 147 CEAs (111 men [75%], 36 women [25%]) were routinely performed without a shunt despite CCO. Of these patients, 76% were asymptomatic. CEAs were performed by seven surgeons using standard techniques (not eversion), with patients under general anesthesia and blood pressure maintained at >130 mm Hg. All patients received heparin (7500 U), and protamine reversal was routine. Median cross-clamp time was 20 minutes (range, 14-40 minutes). RESULTS: Three neurologic events occurred <= 30 days (2.0%). One transient ischemic attack (TIA) occurred immediately, and one occurred on the first postoperative day due to occlusion of the endarterectomy site. One patient sustained an immediate stroke and died of a large computed tomography-documented atheroembolic shower. CONCLUSIONS: Our data demonstrate the safety of CEA in the presence of a CCO, even when performed without a shunt. It is unlikely that the stroke or delayed TIA could be attributed to nonshunting or CCO. Even if so, the stroke and death rates would be lower than those previously reported for patients undergoing CEA in the presence of a CCO. This may be due to short cross-clamp times, careful technique, general anesthesia, and blood pressure support. Given these low adverse event rates, our experience refutes the assumption that patients with a CCO are at such a high risk for CEA that the only alternative is CAS. PMID- 24075104 TI - Invited commentary. PMID- 24075105 TI - Changes in functional status after treatment of critical limb ischemia. AB - OBJECTIVE: This study evaluated changes in functional status with the Academic Medical Center Linear Disability Score (ALDS) and in quality of life with the Vascular Quality of Life Questionnaire (VascuQol) in patients treated for critical limb ischemia (CLI). METHODS: We conducted a prospective observational cohort study in a single academic center that included consecutive patients with CLI who presented between May 2007 and May 2010. The ALDS and VascuQol questionnaires were administered before treatment (baseline) and after treatment at 6 and 12 months of follow-up. Changes in functional status (ALDS) and quality of life (VascuQol) scores after 6 and 12 months, compared with baseline, were tested with the appropriate statistical tests, with significance set at P < .05. RESULTS: The study included 150 patients, 96 (64%) were men, and mean (+/- standard deviation) age was 68.1 (+/- 12.4) years. The primary treatment was endovascular in 98 (65.3%), surgical in 36 (24%), conservative in 11 (7.3%), or a major amputation in five (3.3%). The ALDS was completed by 112 patients after 12 months. At that time, the median ALDS score had increased by 10 points (median, 83; range, 12-89; P = .001) in patients who achieved limb salvage, which corresponds with more difficult outdoor and indoor activities. In patients with a major amputation, the median ALDS score decreased by 14 points (median, 55; range, 16-89; P = .117) after 12 months, which corresponds with domestic activities only. VascuQol scores improved significantly in all separate domains for the limb salvage group (P < .001). All VascuQol scores, except for the activity and social domains, increased significantly after amputation. CONCLUSIONS: Our study confirms the clinical validity of the ALDS in patients treated for CLI and shows that it is a valuable and sophisticated instrument to measure changes in functional status in these patients. PMID- 24075106 TI - Hybrid treatment of anastomotic pseudoaneurysm of the isthmus portion of the thoracic aorta. PMID- 24075107 TI - Increased fluorodeoxyglucose activity of a vascular graft representing a potential pitfall of fluorodeoxyglucose positron emission tomography/computed tomography imaging. PMID- 24075108 TI - Asymptomatic ruptured giant popliteal aneurysm. PMID- 24075109 TI - Endovascular repair for ruptured abdominal aortic aneurysm confers an early survival benefit over open repair. AB - BACKGROUND: Despite the intuitive advantages of endovascular repair (EVAR) of ruptured abdominal aortic aneurysms (AAAs), uncertainty remains about the optimal management in the absence of convincing high-quality evidence. Our objective was to undertake a comprehensive literature review and perform a meta-analysis of outcome data of treatment modalities for ruptured AAAs. METHODS: Systematic searches were conducted of electronic information sources to identify studies comparing perioperative outcomes of EVAR and open repair for AAA rupture. Summary estimates of odds ratios (ORs) or standardized mean difference and 95% confidence intervals (CIs) were obtained with a random-effects model. Meta-regression models were formed to explore potential heterogeneity as a result of changes in practice over time. RESULTS: We selected 41 studies for analysis. The entire meta-analysis population comprised 59,941 patients (8201 EVAR patients and 51,740 open repair patients). EVAR was associated with a significantly lower incidence of in hospital mortality (OR, 0.56; 95% CI, 0.50-0.64; P < .01; meta-analysis of risk adjusted observational studies and randomized controlled trials: OR, 0.58; 95% CI, 0.46-0.73; P < .01). EVAR patients had a significantly decreased risk of developing respiratory complications (OR, 0.59; 95% CI, 0.49-0.69; P < .01) and acute renal failure (OR, 0.65; 95% CI, 0.55-0.78; P < .01) and a trend toward a reduced incidence of cardiac complications (OR, -0.02; 95% CI, -0.03 to 0.00; P = .05) and mesenteric ischemia (OR, 0.66; 95% CI, 0.44-1.00; P = .05). Patients treated with EVAR had significantly less requirements of intraoperative blood transfusion (standardized mean difference, -0.88; 95% CI, -1.06 to -0.70; P < .01). Random-effects meta-regression revealed no statistical evidence for an association between death and year of publication (P = .19). CONCLUSIONS: Our analysis provides evidence to motivate the adoption of an EVAR-first policy in a nonelective setting and the establishment of standardized protocols for the management ruptured AAAs. PMID- 24075110 TI - When money and principles clash: the ethics of a surgical teaching service. AB - During your preoperative visit, a very wealthy patient, Gill Bates, who donated a wing to the large teaching hospital in which you practice, has an unusual request: He does not want any residents involved with his care. He is scheduled for an open infrarenal aneurysmectomy. He explains that his decision is based on the experience of a relative many years ago who was harmed by a resident's error. You clarify that you will do the procedure but that this is a teaching hospital and residents provide excellent assistance and postoperative care. He is resolute in demanding that only grown-up surgeons provide his care. PMID- 24075111 TI - The influence of a Vascular Surgery Hospitalist program on physician and patient satisfaction, resident education, and resource utilization. AB - A number of surgery practice models have been developed to address general and trauma surgeon workforce shortages and on-call issues and to improve surgeon satisfaction. These include the creation of acute or urgent care surgery services and "surgical hospitalist" programs. To date, no practice models corresponding to those developed for general and trauma surgeons have been proposed to address these same issues among vascular surgeons or other surgical subspecialists. In 2003, our practice established a Vascular Surgery Hospitalist program. Since its inception nearly a decade ago, it has undergone several modifications. We reviewed hospital administrative databases and surveys of faculty, residents, and patients to evaluate the program's impact. Benefits of the Vascular Surgery Hospitalist program include improved surgeon satisfaction, resource utilization, timeliness of patient care, communication among referring physicians and ancillary staff, and resident teaching/supervision. Elements of this program may be applicable to a variety of surgical subspecialty settings. PMID- 24075112 TI - Best evidence for medical therapy for carotid artery stenosis. AB - Carotid atheromatous disease is an important cause of stroke and represents a key target in stroke prevention. Randomized trials have shown the efficacy of carotid endarterectomy in secondary stroke prevention. Carotid stenting presents a less invasive alternative to surgical intervention. Advances in medical management, if compliance can be ensured, are leading to improvement in outcomes when implemented as sole therapy in the treatment of atherosclerotic carotid stenosis. This includes lifestyle modification, blood pressure control, and antiplatelet and statin therapy. Over the last 20 years, the annual rate of ipsilateral stroke associated with asymptomatic carotid stenosis has decreased from 2% to 4% to less than 1%. This is largely due to improvements in medical therapy. However, despite numerous trials and years of clinical research, the optimal management of symptomatic and asymptomatic carotid disease remains controversial. This article presents and summarizes the evidence supporting best medical treatment for carotid artery stenosis. PMID- 24075113 TI - Regarding "Derivation and validation of a practical risk score for prediction of mortality after open repair of ruptured abdominal aortic aneurysms in a U.S. regional cohort and comparison to existing scoring systems". PMID- 24075114 TI - Reply: To PMID 23182157. PMID- 24075115 TI - Regarding "Intraoperative use of dextran is associated with cardiac complications after carotid endarterectomy". PMID- 24075116 TI - Reply: To PMID 23337295. PMID- 24075117 TI - Radioiodine concentrated in a wetland. AB - Most subsurface environmental radioactivity contamination is expected to eventually resurface in riparian zones, or wetlands. There are a number of extremely sharp biogeochemical interfaces in wetlands that could alter radionuclide speciation and promote accumulation. The objective of this study was to determine if a wetland concentrated (129)I emanating from a former waste disposal basin located on the Savannah River Site (SRS) in South Carolina, USA. Additionally, studies were conducted to evaluate the role of sediment organic matter in immobilizing the radioiodine. Groundwater samples were collected along a 0.7-km transect away from the seepage basin and in the downstream wetlands. The samples were analyzed for (129)I speciation (iodide (I(-)), iodate (IO3(-)), and organo-I). Groundwater (129)I concentrations in many locations in the wetlands (as high as 59.9 Bq L(-1)(129)I) were greatly elevated with respect to the source term (5.9 Bq L(-1)(129)I). (129)I concentration profiles in sediment cores were closely correlated to organic matter concentrations (r(2) = 0.992; n = 5). While the sediment organic matter promoted the uptake of (129)I to the wetland sediment, it also promoted the formation of a soluble organic fraction: 74% of the wetland groundwater (129)I could pass through a 1 kDa (<1 nm) membrane and only 26% of the (129)I was colloidal. Of that fraction that could pass through a 1 kDa membrane, 39% of the (129)I was organo-I. Therefore, while wetlands may be highly effective at immobilizing aqueous (129)I, they may also promote the formation of a low-molecular-weight organic species that does not partition to sediments. This study provides a rare example of radioactivity concentrations increasing rather than decreasing as it migrates from a point source and brings into question assumptions in risk models regarding continuous dilution of released contaminants. PMID- 24075118 TI - Retrovirus replication strategies. PMID- 24075119 TI - Plant pararetroviruses: interactions of cauliflower mosaic virus with plants and insects. AB - Virion associated protein (VAP) binds to the icosahedral capsid of cauliflower mosaic virus (CaMV) - a plant pararetrovirus. The interactive coiled-coil domains of this protein can interact with the coiled-coils of either the movement protein or the aphid transmission factor, thereby mediating both cell-to-cell movement and aphid transmission. The host counters CaMV infection with two lines of defense: innate immunity and silencing. The viral protein 'transactivator/viroplasmin' (TAV) is recognized as an effector and either initiates the innate immunity reaction in a non-permissive host or interferes with it in a permissive host. As a silencing suppressor, TAV interferes with dicing of dsRNAs. PMID- 24075120 TI - Giardiasis is not uncommon in Taiwan. PMID- 24075121 TI - A closer look at FBXO41 as a Parkinson's disease risk factor. PMID- 24075122 TI - CSF levels of DJ-1 and tau distinguish MSA patients from PD patients and controls. AB - Differential diagnosis between Parkinson's disease (PD) and multiple system atrophy (MSA) is difficult, particularly at early disease stages, but is important for therapeutic management. The protein DJ-1 is implicated in the pathology of PD but little is known about its involvement in MSA. We aimed to determine the diagnostic value of CSF DJ-1 and tau proteins for discriminating PD and MSA. DJ-1 and total tau levels were quantified in the CSF of 43 PD patients, 23 MSA patients and 30 non-neurological controls matched for age and gender. Patients were part of a study with a 3-year prospective design with extended case review follow-up of up to 9 years, ensuring maximum accuracy of the clinical diagnosis. Our results showed that CSF DJ-1 levels could distinguish MSA from PD with a 78% sensitivity and 78% specificity (AUC = 0.84). The combination of DJ-1 and tau proteins significantly improved this discrimination to 82% sensitivity and 81% specificity to identify MSA from PD (AUC = 0.92). Our results highlight the potential benefits of a combination of DJ-1 and total tau as biomarkers for differential diagnosis of MSA and PD. PMID- 24075123 TI - The early career consultation psychiatrist: manager, director, boss--leadership and psychiatric practice. PMID- 24075124 TI - Primary non-small cell lung cancer response upon treatment with denosumab. AB - Here we report the case of a patient with metastatic adenocarcinoma of the lung harboring an ALK gene translocation. In this patient a response of the primary tumor and metastases has been detected upon treatment with denosumab. A possible link between ALK and RANK is postulated. PMID- 24075125 TI - A randomized, phase II study of vandetanib maintenance for advanced or metastatic non-small-cell lung cancer following first-line platinum-doublet chemotherapy. AB - BACKGROUND: This randomized, phase II study investigated whether benefit could be obtained by giving vandetanib, an oral inhibitor of vascular endothelial and epithelial growth factor receptor, as a maintenance treatment in non-small cell lung cancer (NSCLC). METHODS: Patients were randomly assigned to either vandetanib or placebo after completion of 4 cycles of first-line chemotherapy. A progression-free survival (PFS) rate at 3 months was selected as the primary endpoint. We set a maximum PFS rate at 3 months to 30% (null hypothesis), and a minimum PFS rate at 3 months to 50% (alternative hypothesis). RESULTS: At the interim analysis, 9 of 24 patients in the vandetanib arm were progression-free at 3 months, whereas 7 of 24 in the placebo arm were progression-free. The placebo arm was closed at the first stage. The vandetanib arm proceeded to the second stage, and recruited a total of 75 patients. At the second stage, 28 out of 63 evaluable patients receiving vandetanib achieved PFS at 3 months. The alternative hypothesis that the PFS rate at 3 months is at least 50% was accepted. The median PFS was 2.7 months (95% CI, 1.9-4.4 months) in the vandetanib arm and 1.7 months (95% CI, 0.9-2.6 months) in the placebo arm. The most common adverse events in patients receiving vandetanib were rash (77.3%) and diarrhea (60.0%). CONCLUSIONS: Maintenance therapy with vandetanib for patients with NSCLC after standard platinum doublet chemotherapy is well tolerated and may prolong PFS compared with placebo, and needs additional investigation. PMID- 24075126 TI - QRS complex and ST segment manifestations of ventricular ischemia: the effect of regional slowing of ventricular activation. AB - OBJECTIVE: Reduction or interruption of the blood supply to myocardium due to occlusion of coronary artery and consequent ischemia leads to changes of electrogenesis: changes in morphology and duration of action potentials and slowing of conduction velocity in the affected area. In this study we simulated the effects of localized changes in depolarization sequence on the QRS and ST segment patterns, using computer modeling. METHODS: The model defines the geometry of cardiac ventricles analytically as parts of ellipsoids and allows changing the velocity of impulse propagation in the myocardium. An intramural electrically inactive area encircled by a transmural area with slowed impulse propagation velocity was introduced in anteroseptal and inferior locations. The effects on the QRS complex and the ST segment of the 12-lead electrocardiogram are presented. RESULTS: The intramural electrically inactive area caused QRS changes typical for corresponding locations of a myocardial infarction observed in patients, which were further considerably modified by slowed impulse propagation velocity in the surrounding area. Additionally, areas of slowed impulse propagation velocity led to ST segment deviations in the "reciprocal" leads, shifting the ST segment towards the affected areas. CONCLUSION: Using computer modeling we showed that the localized alteration of impulse propagation not only modified the QRS complex, but produced also changes in the ST segment consistent with changes which are usually interpreted as the effect of "injury current". PMID- 24075127 TI - J wave patterns--morphology, prevalence and nomenclature. AB - The recent resurgence of interest in early repolarization has demonstrated a variation in the definition of the term and a consequent variation in the prevalence of the pattern in different studies. This can vary from 35% in males and 21.5% in females if ST elevation is not considered part of the definition, to 3.3% and 0.5% in females with the inclusion of ST elevation. In contrast, the prevalence of the Brugada Syndrome is in the order of 0.1%-0.2% in Japan for example and has been found to be significantly lower in Denmark. Standardisation of measurement definitions, particularly for early repolarisation, is required. PMID- 24075128 TI - Posttraumatic elbow joint contractures: defining pathologic capsular mechanisms and potential future treatment paradigms. AB - The Andrew J. Weiland Medal is presented by the American Society for Surgery of the Hand to a midcareer researcher who is dedicated to advancing patient care in the field of hand surgery. This essay, awarded the Weiland Medal in 2012, focuses on posttraumatic elbow joint contractures. Joint contractures are well known to hand surgeons because they limit function of our patients. There is a thorough understanding of the pathoanatomy underlying joint contractures. However, the mechanisms leading to the pathoanatomy are either unknown or partially understood, depending on the etiology of the particular clinical condition. This review describes our research over the past 14 years on posttraumatic elbow joint contractures. It defines pathologic cellular, matrix, and growth factor changes in the joint capsule, elaborates on the development of an animal model of posttraumatic joint contractures, presents an evaluation of a potential prevention strategy based on our research, and outlines future plans to bring this work to the clinical realm for the benefit of patients. PMID- 24075129 TI - The link between vitamin D metabolism and sleep medicine. AB - Vitamin D is a hormone that interacts with intranuclear receptors to effect transcriptional changes in many cell types including those in gut, bone, breast, prostate, brain, skeletal muscle, and the immune system. Inadequacy of vitamin D is widely prevalent, and leads to the classic diseases of bone demineralization as well as to more recently recognized problems such as nonspecific pain and noninflammatory skeletal myopathy, which may disrupt sleep and directly cause daytime impairment. Emerging lines of evidence suggest that low vitamin D levels increase the risk for autoimmune disease, chronic rhinitis, tonsillar hypertrophy, cardiovascular disease, and diabetes. These conditions are mediated by altered immunomodulation, increased propensity to infection, and increased levels of inflammatory substances, including those that regulate sleep, such as tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1, and prostaglandin D2 (PD2). Together, the recent reports suggest a role for inadequate vitamin D in the development of symptoms of wake impairment commonly associated with sleep disorders. Persistent inadequacy of vitamin D may also increase the risk for obstructive sleep apnea via promotion of adenotonsillar hypertrophy, airway muscle myopathy, and/or chronic rhinitis. Much remains to be learned concerning the complex relationship between chronically low levels of vitamin D, normal sleep, sleep disruption, and daytime neurocognitive impairment. PMID- 24075130 TI - Lower extremity pediatric history and physical examination. AB - Although the pediatric foot and ankle examination is essentially similar to that of the adult patient, there are subtle differences unique to a child's examination. The unique findings are discussed in this article based on the following: weight-bearing examination, gait evaluation, non-weight-bearing examination, vascular examination, neurologic examination, and dermatologic examination for pediatric patients. A comprehensive overview is provided; however, other challenges presented in evaluating children include management of a child's parents and a child's temperament. The setting for an examination and a child's mood must be taken into consideration to ensure a successful outcome. PMID- 24075131 TI - Pediatric forefoot pathology. AB - Surgical management of the pediatric forefoot often brings challenges to the foot and ankle surgeon. It requires a thorough understanding of the pathologic abnormality and underlying causes involved, which include the contributing genetic conditions. Albeit most of the deformities carry a rare level of incidence, they do however have a significant level of psychological component and stress on the pediatric patient. The goals of managing those pathologic abnormalities are ultimately to improve function while achieving a cosmetically acceptable outcome. The common forefoot pathologic abnormalities in the pediatric population are reviewed with an added focus toward management of forefoot trauma. PMID- 24075132 TI - Pediatric first ray deformities. AB - Pediatric first ray deformities may present in many ways similar to those effecting adults. However, these patients are not adults. Management of the patient and the deformity necessitates special consideration of timing, the patient's general health, techniques, and perhaps goals. Any simple broad brush approach to the care of these patients will certainly result in both undertreatment and overtreatment. The proper care of these patients is an ongoing process of appropriate management tailored to the patient's needs, deformities, and developmental age. Proper adherence to these recommendations can improve the patient's quality of life. PMID- 24075133 TI - Pediatric heel pain. AB - Heel pain is a common complaint among young children and adolescents. It has many causes, including trauma, overuse injuries, and tumors, and therefore a thorough clinical examination is warranted. This article outlines some common causes of pediatric heel pain. PMID- 24075134 TI - Treatment of the neglected and relapsed clubfoot. AB - Treatment of the neglected and the relapsed clubfoot is one of the most controversial topics in pediatric foot care. This article reviews the breadth of treatment options for practicing podiatrists or orthopedists with a specialty in complex clubfoot treatment. Discussion includes the appropriate circumstances for the use of the different procedures presented and the author's preferred treatment algorithm, based on 15 years of treating neglected, relapsed, and nonidiopathic clubfeet. PMID- 24075135 TI - The intoeing child: etiology, prognosis, and current treatment options. AB - Intoeing, a common entrance complaint in infants, toddlers, and young children, is best defined as internal rotation of the long axis of the foot to the line of progression. Intoeing may be caused by primary deformities within the foot, issues with tibial torsion, and femoral antetorsion (anteversion). Problems within the foot include hallux varus, metatarsus adductus, talipes equinovarus, and pes cavus, each of which has specific treatments available. Treatment must be individualized, and the risks and complications weighed against the predictable morbidity of intoeing. PMID- 24075136 TI - Congenital talotarsal joint displacement and pes planovalgus: evaluation, conservative management, and surgical management. AB - The diagnosis of and preferred treatment regimens for pediatric flatfoot, a complex and ambiguous deformity, continues to be debated. Incongruence of the talotarsal joint, whether flexible or rigid, is always present in pes planovalgus. However, it is important to note that talotarsal dislocation can occur without a flatfoot. The displacement of the talus on the hindfoot bones serves as the apex of the deformity. External measures, such as conservative care, are limited in providing correction to this internal deformity. Extraosseous talotarsal stabilization provides a minimally invasive internal option that should be considered before more radical surgical intervention is decided upon. PMID- 24075137 TI - Principles of management of growth plate fractures in the foot and ankle. AB - Providers treating pediatric injuries must understand the properties of the pediatric skeleton and be sensitive to the psychological and social expectations of patients and their families. Immediate needs must be addressed, and the long term prognosis must be explained. Detailed understanding of fracture mechanism and fracture patterns is essential for diagnosis and treatment. The provider must remain vigilant for changes in the osseous and soft tissue structures during treatment. Failure to recognize signs of growth interruption and changes in position may lead to functional abnormalities. This article presents an overview of pediatric growth plate injury management. PMID- 24075138 TI - Simultaneous surgical repair of a tibialis anterior tendon rupture and diabetic charcot neuroarthropathy of the midfoot: a case report. AB - The combination of simultaneous rupture of a tibialis anterior tendon and Charcot neuroarthropathy of the midfoot in a diabetic patient is a rare and challenging condition that can lead to major complications if not addressed appropriately. This article discusses a tibialis anterior tendon rupture that may have developed before or after the incidence of the diabetic Charcot neuroarthropathy midfoot deformity and raises awareness to potential spontaneous tendon ruptures that may be associated with the diabetic Charcot foot. PMID- 24075139 TI - Pediatric foot deformities. PMID- 24075140 TI - Pediatric foot deformities. PMID- 24075141 TI - Data mining the ScanBrit study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders: behavioural and psychometric measures of dietary response. AB - We previously reported results based on the examination of a gluten- and casein free diet as an intervention for children diagnosed with an autism spectrum disorder as part of the ScanBrit collaboration. Analysis based on grouped results indicated several significant differences between dietary and non-dietary participants across various core and peripheral areas of functioning. Results also indicated some disparity in individual responses to dietary modification potentially indicative of responder and non-responder differences. Further examination of the behavioural and psychometric data garnered from participants was undertaken, with a view to determining potential factors pertinent to response to dietary intervention. Participants with clinically significant scores indicative of inattention and hyperactivity behaviours and who had a significant positive changes to said scores were defined as responders to the dietary intervention. Analyses indicated several factors to be potentially pertinent to a positive response to dietary intervention in terms of symptom presentation. Chronological age was found to be the strongest predictor of response, where those participants aged between 7 and 9 years seemed to derive most benefit from dietary intervention. Further analysis based on the criteria for original study inclusion on the presence of the urine compound, trans-indolyl-3-acryloylglycine may also merit further investigation. These preliminary observations on potential best responder characteristics to a gluten- and casein-free diet for children with autism require independent replication. PMID- 24075142 TI - A novel pH sensitive water soluble fluorescent nanomicellar sensor for potential biomedical applications. AB - Herein we report on the synthesis and sensor activity of a novel pH sensitive probe designed as highly water-soluble fluorescent micelles by grafting of 1,8 naphthalimide-rhodamine bichromophoric FRET system (RNI) to the PMMA block of a well-defined amphiphilic diblock copolymer-poly(methyl methacrylate)-b poly(methacrylic acid) (PMMA48-b-PMAA27). The RNI-PMMA48-b-PMAA27 adduct is capable of self-assembling into micelles with a hydrophobic PMMA core, containing the anchored fluorescent probe, and a hydrophilic shell composed of PMAA block. Novel fluorescent micelles are able to serve as a highly sensitive pH probe in water and to internalize successfully HeLa and HEK cells. Furthermore, they showed cell specificity and significantly higher photostability than that of a pure organic dye label such as BODIPY. The valuable properties of the newly prepared fluorescent micelles indicate the high potential of the probe for future biological and biomedical applications. PMID- 24075143 TI - Antimycobacterial and herbicidal activity of ring-substituted 1 hydroxynaphthalene-2-carboxanilides. AB - In this study, a series of 22 ring-substituted 1-hydroxynaphthalene-2 carboxanilides were prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Mycobacterium marinum, Mycobacterium kansasii and Mycobacterium smegmatis. The compounds were also tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Most of tested compounds showed the antimycobacterial activity against the three strains comparable or higher than the standard isoniazid. N-(3-Fluorophenyl)-1-hydroxynaphthalene-2-carboxamide showed the highest biological activity (MIC=28.4MUmol/L) against M. marinum, N-(4 fluorophenyl)-1-hydroxynaphthalene-2-carboxamide showed the highest biological activity (MIC=14.2MUmol/L) against M. kansasii, and N-(4-bromophenyl)-1 hydroxynaphthalene-2-carboxamide expressed the highest biological activity (MIC=46.7MUmol/L) against M. smegmatis. This compound and 1-hydroxy-N-(3 methylphenyl)naphthalene-2-carboxamide were the most active compounds against all three tested strains. The PET inhibition expressed by IC50 value of the most active compound 1-hydroxy-N-(3-trifluoromethylphenyl)naphthalene-2-carboxamide was 5.3MUmol/L. The most effective compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. For all compounds, structure-activity relationships are discussed. PMID- 24075144 TI - Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis. AB - A series of 2-aminothiazoles was synthesized based on a HTS scaffold from a whole cell screen against Mycobacterium tuberculosis (Mtb). The SAR shows the central thiazole moiety and the 2-pyridyl moiety at C-4 of the thiazole are intolerant to modification. However, the N-2 position of the aminothiazole exhibits high flexibility and we successfully improved the antitubercular activity of the initial hit by more than 128-fold through introduction of substituted benzoyl groups at this position. N-(3-Chlorobenzoyl)-4-(2-pyridinyl)-1,3-thiazol-2-amine (55) emerged as one of the most promising analogues with a MIC of 0.024MUM or 0.008MUg/mL in 7H9 media and therapeutic index of nearly ~300. However, 55 is rapidly metabolized by human liver microsomes (t1/2=28min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous low level resistance with a frequency of ~10(-5). PMID- 24075145 TI - Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate. AB - The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties. PMID- 24075147 TI - Casualty evacuation: an innovative role for emergency nurses. PMID- 24075146 TI - Right to know: reducing risks of fecal pathogen exposure for ED patients and staff. AB - INTRODUCTION: The purpose of this article is to review the literature regarding the multiple challenges that contribute to ED bedside toileting and examine best practices that will reduce fecal exposure, cross-contamination among patients, and employee splash injuries. METHODS: We searched the Cumulative Index to Nursing and Allied Health Literature, MEDLINE, and Cochrane database for information about the multiple challenges involved in bedside toileting, using the following search terms: bedside toileting, gastroenteritis, macerator, sluice machine, fecal pathogen exposure, and splash injury. In addition, costs and benefits of reusable versus disposable bedside toileting equipment were compared and contrasted. DISCUSSION: Emergency departments have a higher exposure rate to fecal pathogens with current methods of bedside toileting. Short incubation periods may not allow the proper lead time needed for patients to access primary care providers. As a result, emergency departments and urgent care centers become a likely point of entry into the health care system. Although most inpatient rooms have built-in bathrooms, most emergency departments and outpatient examination rooms do not. Although many patients are ambulatory, restrictive monitoring equipment is required. For safety reasons, staff must bring toileting equipment to the bedsides of both ambulatory and non-ambulatory patients. Hopper dependence creates longer walking distances and delays. These delays may lead to incontinence events, skin breakdown, more frequent bed changes, and higher linen and labor costs. Reusable bedside toileting equipment is associated with at-risk behaviors. Examples are procrastination and sanitization shortcuts. These behaviors risk cross-contamination of patients especially when urgent situations require equipment to be reused in the interim. ED patients and staff are 5 times more likely to undergo fecal exposure. The 5 phases of ED bedside toileting at which risks occur are as follows: equipment setup, transport of human waste to drainage areas, transfer of waste, pre-cleaning, and equipment disinfection. Therefore it is imperative that ED staff have a full understanding of hazardous materials involved, know safer bedside toileting practices, and have safer equipment available to protect all involved. Upgrading our knowledge, equipment, and practices must become a higher priority for ED leadership. BIASES/DISCLOSURES: The East Bank Emergency Department of the University of Minnesota Medical Center, Fairview, will be moving toward 100% disposable bedside commode pails in addition to disposable bedpans, currently in use. On the basis of a literature review to understand best-practice ED bedside toileting, the following article was created. As a result of our learning, the University of Minnesota Medical Center emergency staff has designed, patented, and developed a landfill-compliant disposable commode pail that absorbs waste while reducing splashes and spills. Disposable commode pails (bags) are conveniently wall mounted for quick availability, and "at-risk behavior" is reduced. Advantages are all point-of-care. Both setup and waste treatment and disposal start and end at the bedside. The advantages are faster response times, reduction of soiled linens and bed changes, prevention of incontinence and skin breakdown events, and reduced splash injuries or pathogen transmission. Patient satisfaction improves with shorter bedside toileting delays. Employee satisfaction increases with reduced human waste handling. The cost of each unit is comparable to an adult overnight diaper. Bariatric commode pails or bags are in the planning phase, and a "green" disposable commode pail, made from biodegradable corn byproducts, will be made available at a higher cost. PMID- 24075148 TI - Influence of time and length size feature selections for human activity sequences recognition. AB - In this paper, Viterbi algorithm based on a hidden Markov model is applied to recognize activity sequences from observed sensors events. Alternative features selections of time feature values of sensors events and activity length size feature values are tested, respectively, and then the results of activity sequences recognition performances of Viterbi algorithm are evaluated. The results show that the selection of larger time feature values of sensor events and/or smaller activity length size feature values will generate relatively better results on the activity sequences recognition performances. PMID- 24075149 TI - Static feedback stabilization of nonlinear systems with single sensor and single actuator. AB - This paper considers a single sensor and single actuator approach to the static feedback stabilization of nonlinear systems. This is essentially a remote control problem that is present in many engineering applications. The proposed method solves this problem that is less expensive to implement and more reliable in practice. Significant results are obtained on the design of controllers for stabilizing the nonlinear systems. Important issues on control implementation are also discussed. The proposed design method is validated through its application to nonlinear control of aircraft engines. PMID- 24075150 TI - Prophylactic midazolam and clonidine for emergence from agitation in children after emergence from sevoflurane anesthesia: a meta-analysis. AB - BACKGROUND: Emergence agitation (EA) after emergence from sevoflurane anesthesia is a common phenomenon in children. The efficacy of prophylactic midazolam or clonidine in preventing EA is controversial. OBJECTIVE: We performed a meta analysis of clinical trials of the 2 drugs to evaluate their ability to prevent EA in pediatric patients after emergence from sevoflurane anesthesia. METHODS: A comprehensive literature search was conducted to identify clinical trials that observed the effect of midazolam and clonidine on preventing EA in children after their emergence from sevoflurane anesthesia. All data were examined using the Mantel-Haenszel model to calculate the pooled odds ratio (OR) and 95% CI. I(2) was used to assess heterogeneity. Subgroup analysis was used to assess the effects of preoperative analgesics, routes of administration, and dose, and funnel plots were used to check publication bias. RESULTS: After a comprehensive literature search, we found 12 papers that met the criteria for inclusion in this analysis, with a total of 447 children in the midazolam group and 767 children in the clonidine group. We found that both midazolam and clonidine decreased the incidence of EA (OR = 0.45 [95% CI, 0.29-0.70], P = 0.0004, I(2) = 46%; and OR = 0.24 [95% CI, 0.13-0.43], P < 0.00001, I(2) = 48%, respectively). Subgroup analysis indicated that preoperative analgesia may decrease the effect of midazolam against EA, whereas for clonidine, neither the route of administration (intravenous or caudal) nor the dose affected the results. Funnel plots did not detect publication bias in the midazolam group, but a bias was detected in the clonidine group. CONCLUSIONS: This meta-analysis suggests that prophylactic administration of midazolam or clonidine could significantly decrease the incidence of sevoflurane-induced EA in pediatric patients. PMID- 24075151 TI - Bleeding as an outcome among patients with nonvalvular atrial fibrillation in a large managed care population. AB - BACKGROUND: Patients with nonvalvular atrial fibrillation (NVAF) are at increased risk for stroke and bleeding events, but bleeding as an outcome has not been extensively studied in this patient population. OBJECTIVES: The goal of this study was to estimate the incidence of bleeding events among patients with NVAF enrolled in managed care, investigate the relationships between bleeding incidence and bleeding and stroke risks, and estimate health care costs for patients who had a major bleeding event. METHODS: Adults with commercial insurance or Medicare Advantage coverage and health care claims related to AF between January 2005 and June 2009 but with no evidence of valvular disease were included in this retrospective claims data analysis. Baseline stroke risk (CHADS2 [Congestive Heart Failure, Hypertension, Age >75 Years, Diabetes Mellitus, and Prior Stroke or Transient Ischemic Attack]) and bleeding risk (HAS-BLED [Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratios, Elderly, Drugs/Alcohol]) were estimated. Bleeding events were identified during the variable follow-up period, which lasted from the date of the first qualifying AF visit until the earlier of death, disenrollment from the health plan, or June 30, 2010. Bleeding events were classified as major, serious nonmajor, or minor. Health care costs for patients with major bleeding events were calculated. RESULTS: Among 48,260 patients with NVAF (mean age, 67 years), 34% had an incident bleeding event during a mean (SD) follow-up period of 802 (540) days. Incidence rates for bleeding events of any severity and major events were 29.6 and 10.4 per 100 patient-years, respectively. Bleeding incidence rates increased with greater CHADS2 and HAS-BLED risk scores. All-cause health care costs for patients during a major bleeding event averaged $16,830. Average costs per patient with a major event increased from approximately $52 per day in the prebleeding period to approximately $63 per day in the postbleeding period. Costs for patients who did not experience a major bleeding event averaged approximately $38 per day. CONCLUSIONS: Bleeding incidence among patients with NVAF in a real-world setting was high and increased with greater stroke and bleeding risk scores. Health care costs for patients with major bleeding events were elevated. All rights reserved. PMID- 24075152 TI - Use of preoperative magnetic resonance angiography and the Artis zeego fusion program to minimize contrast during endovascular repair of an iliac artery aneurysm. AB - BACKGROUND: A 61-year-old man with a previous endovascular repair and stage 5 chronic kidney disease presented with a symptomatic 4.5-cm left internal iliac artery aneurysm. The decision was made to proceed with endovascular repair. METHODS: The preoperative magnetic resonance angiography (MRA) scan was linked to on-table rotational imaging using the Artis zeego Fusion program (Siemens AG, Forchheim, Germany). Using the fused image as a road map, we undertook coil embolization of the left internal iliac artery, and a tapered stent graft was extended from the previous graft into the external iliac artery. RESULTS: Completion angiography revealed exclusion of the aneurysm sac. Three milliliters of contrast were used throughout the procedure. A follow-up magnetic resonance angiography scan at 1 month and duplex ultrasonography at 1 year revealed continued exclusion of the aneurysm sac. The patient's renal function remained unchanged. CONCLUSIONS: This case shows that in a patient with severe chronic kidney disease, fusion of preoperative imaging with intraoperative rotational imaging is feasible and can limit significantly the amount of contrast used during a complex endovascular procedure. PMID- 24075153 TI - Venous cystic adventitial disease presenting as an enlarging groin mass. AB - Venous cystic adventitial disease is an exceedingly rare vascular disorder, with 12 cases reported in the past decade. A 60-year-old woman presented with a painful, palpable groin mass without leg swelling. She was initially thought to have a nonreducible inguinal hernia. A computed tomography scan was obtained that revealed a cystic mass involving the right common femoral vein. Previous imaging revealed that the mass had enlarged over time. In the operating room, the cyst wall was excised without compromising vein integrity. The patient had an uneventful recovery and her pain resolved. We review the presentation, diagnosis, and treatment of this condition. We believe that the rapid evolution of this lesion suggests that an unknown inciting factor triggers its onset and growth. PMID- 24075154 TI - A Gauss-Newton approach to joint image registration and intensity correction. AB - We develop a new efficient numerical methodology for automated simultaneous registration and intensity correction of images. The approach separates the intensity correction term from the images being registered in a regularized expression. Our formulation is consistent with the existing non-parametric image registration techniques, however, an extra additive intensity correction term is carried throughout. An objective functional is formed for which the corresponding Hessian and Jacobian is computed and employed in a multi-level Gauss-Newton minimization approach. In this paper, our experiments are based on elastic regularization on the transformation and total variation on the intensity correction. Validations on dynamic contrast enhanced MR abdominal images for both real and simulated data verified the efficacy of the model. The pursued approach is flexible in which we can exploit various forms of regularization on the transformation and the intensity correction. PMID- 24075155 TI - Binocular vision. PMID- 24075156 TI - Surgical iridotomy in aphakic eyes and eyes with anterior chamber intraocular lenses. AB - We describe a simple technique to create a peripheral surgical iridotomy using a microvitreoretinal blade. The blade passes perpendicular to the iris dilator fibers to create a permanent opening. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24075157 TI - Comparative analysis of the visual and refractive outcomes of an aspheric diffractive intraocular lens with and without toricity. AB - PURPOSE: To analyze and compare the postoperative visual and refractive outcomes and patients' visual satisfaction after implantation of an aspheric or an aspheric toric multifocal diffractive intraocular lens (IOL) in eyes with equivalent biometric characteristics. SETTING: Private clinic, Munich, Germany. DESIGN: Comparative case series. METHODS: Patients having cataract surgery were assigned to 1 of 2 groups: aspheric, which had AT Lisa 809M IOL implantation, and aspheric toric, which had AT Lisa 909M IOL implantation (corneal toricity >=0.75 diopter [D]). Visual and refractive postoperative outcomes were evaluated, as was the patient's ability to perform daily tasks related to vision and the incidence of photic phenomena. RESULTS: The aspheric group comprised 77 eyes (42 patients) and the aspheric toric group, 26 eyes (17 patients). A significant improvement in corrected distance and near visual acuity was observed postoperatively in both groups, as was a significant reduction in the astigmatic component J0 (P<.01). The aspheric toric group had significantly better uncorrected intermediate visual acuity (P=.01). In both groups, the postoperative astigmatic power vectors and spherical equivalent were within +/-0.50 D in 100% of eyes and in more than 88% of eyes, respectively. No statistically significant differences were found in any subjective patient questionnaire item. There was no difference in the incidence of photic phenomena between the groups (P>=0.16). CONCLUSION: The addition of a toric surface to the aspheric diffractive multifocal platform resulted in a comparable visual performance and ability to perform visual tasks. FINANCIAL DISCLOSURE: The author has no financial or proprietary interest in any material or method mentioned. PMID- 24075158 TI - Visual acuity and refraction with a diffractive multifocal toric intraocular lens. AB - PURPOSE: To evaluate clinical outcomes and optical performance of the AT Lisa 909M diffractive multifocal toric intraocular lens (IOL). SETTING: Multicenter study. DESIGN: Cohort study. METHODS: The measured outcomes included refractive error; distance, near (40 cm), and intermediate (60 cm and 80 cm) visual acuities; defocus curve; rotational stability; and monocular and binocular photopic and mesopic contrast sensitivity. Astigmatism was evaluated by Alpins vector analysis. RESULTS: The multifocal toric IOL was implanted in 284 eyes of 142 patients. At 6 months, 89.4% of eyes were within +/-1.00 diopter (D) of emmetropia. The mean refractive cylinder decreased from -2.39 D +/- 1.48 (SD) to 0.49 +/- 0.53 D; it was lower than 1.00 D in 80.9% of eyes. The mean visual acuities (logMAR) were monocular uncorrected distance 0.16 +/- 0.22, monocular corrected distance 0.04 +/- 0.15, binocular corrected distance -0.00 +/- 0.09; monocular uncorrected near 0.21 +/- 0.22, monocular corrected near 0.08 +/- 0.16, binocular distance-corrected near 0.07 +/- 0.14; intermediate at 60 cm (80 cm): monocular uncorrected 0.16 +/- 0.21 (0.09 +/- 0.21), monocular distance corrected 0.13 +/- 0.19 (0.07 +/- 0.20), and binocular distance corrected 0.07 +/- 0.17 (0.00 +/- 0.18). At 3 months and 6 months, 95.8% of IOLs showed no rotation over 5 degrees. CONCLUSIONS: This is the largest study yet on the first commercially available diffractive multifocal toric IOL. Results confirm its efficacy, predictability, and safety in restoring distance, near, and intermediate vision and allowing patients with significant levels of corneal astigmatism to achieve spectacle independence. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24075159 TI - Scanning electron microscopy evaluation of capsulorhexis in femtosecond laser assisted cataract surgery. AB - PURPOSE: To use scanning electron microscopy (SEM) to evaluate capsulorhexis-cut quality obtained during femtosecond laser-assisted cataract surgery at different energy settings and evaluate whether there are differences between this technique and a standard manual technique. SETTING: Ophthalmology Clinic, Department of Medicine and Science of Ageing, University G. D'Annunzio Chieti-Pescara, Chieti, Italy. DESIGN: Prospective nonrandomized single blinded study. METHODS: Sixty capsulorhexes obtained using the conventional manual technique and the femtosecond laser with different laser energy settings were divided into 5 groups as follows: Group 1 (12 capsulorhexes) obtained with the manual technique and Groups 2 to 5 (each with 12 capsulorhexes) obtained with the femtosecond laser at 7.0 MUJ, 13.5 MUJ, 14.0 MUJ, and 15.0 MUJ, respectively. All samples were evaluated using SEM to compare the thickness along the capsulorhexis edge and the overall irregularity of the cut surface. RESULTS: Capsulorhexes obtained with the femtosecond laser at all energy settings were perfectly circular with negligible deformation. Group 1 and Group 2 had a significantly higher thickness and lower thickness, respectively, of the capsulorhexis edge than the other 3 groups (P<.001). There was also a statistically significant correlation between the degree of irregularity and increasing energy (P<.001). CONCLUSIONS: The use of the femtosecond laser in cataract surgery resulted in better capsulorhexis geometry and circularity than the manual capsulorhexis. The cut surface was smoother in the manual group. In the femtosecond laser groups, the degree of irregularity was higher at increasing energy settings. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24075160 TI - Light microscopy and scanning electron microscopy analysis of rigid curved interface femtosecond laser-assisted and manual anterior capsulotomy. AB - PURPOSE: To study the microanatomic edge structures of anterior lens capsule specimens derived from manual and femtosecond laser-assisted capsulotomies. SETTING: Department of Ophthalmology, Goethe-University, Frankfurt, Germany. DESIGN: Experimental study. METHODS: Of 60 eyes with lens removal and intraocular lens implantation, 30 received a manual capsulotomy and 30 received a femtosecond laser-assisted capsulotomy (Lensx, rigid curved interface, pulse energy 15 MUJ, spot separation 4 MUm, layer separation 3 MUm). After anterior capsule removal, tissues were immediately fixed in 4.5% formalin. Approximately 30 minutes after fixation, the tissues were removed from the fixation containers and air dried for at least 2 hours. Fifteen capsules in each group had further staining for light microscopy (LM). The surface of the capsulotomy edge was the primary focus of LM and scanning electron microscopy (SEM). Cell configuration, capsule shape, and abnormalities were evaluated. RESULTS: Subjective LM and SEM analysis showed smooth edges at all magnifications, no cell destruction, and cells up to the cutting edge in the manual capsulotomy group. Light microscopy demonstrated almost continuous anterior capsule incisions of the femtosecond laser-assisted capsulotomy, a prominent demarcation line along the cutting edge, and several tags and bridges. Scanning electron microscopy showed microgrooves and valley- and mountain-like structures as signs of the photodisruption process. CONCLUSION: Compared with manual procedures, curved, rigid interface femtosecond laser assisted capsulotomy specimens using 15 MUJ pulse energy showed tags, bridges, rougher edges, and demarcation lines on the capsulotomy edges on SEM but subjectively estimated a more round shape on LM. FINANCIAL DISCLOSURES: Mr. Klaproth received travel reimbursements and/or lecture fees from Alcon Laboratories, Inc., Rayner Intraocular Lenses Ltd., and Oculus GmbH. Dr. Kohnen received travel reimbursements, grant support, and/or lecture fees from Alcon Laboratories, Inc., Abbott Medical Optics, Inc., Bausch & Lomb, Carl Zeiss Meditec AG, Neoptics AG, Rayner Intraocular Lenses Ltd., and Schwind eye-tech solutions GmbH and Co. KG; he is a consultant to Alcon Laboratories, Inc., Carl Zeiss Meditec AG, Rayner Intraocular Lenses Ltd., and Schwind eye-tech-solutions GmbH and Co. KG. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 24075161 TI - Evaluating the benefits of second-eye cataract surgery among the elderly. AB - The aim of this systematic review was to synthesize and appraise the evidence of benefits of second-eye cataract extraction for visual function, patient-reported quality of life, falls, and driving ability among the elderly. We conducted a comprehensive search in MEDLINE using "surgery," "cataract extraction," "second eye," and "bilateral." Ten studies met the inclusion and quality criteria. We found "moderate" evidence supporting improvement in stereopsis, stereoacuity, and anisometropia over and above the benefits of first-eye surgery. We also found "moderate" evidence supporting improvement in visual acuity, contrast sensitivity, and self-reported visual functioning. Studies included in the review do not provide definitive evidence of second-eye surgery benefits on health related quality of life, visual fields, falls prevention, and driving performance. However, the heterogeneity of outcome measures and the limited number of studies likely contributed to our findings. The findings have implications for clinicians and policymakers in the health-care industry and emphasize the need for additional trials examining this important and widely performed clinical procedure. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24075162 TI - Implantation of phakic intraocular lens in 3 patients with oculocutaneous albinism. AB - We present 3 cases with oculocutaneous albinism in which a high refractive error was optically corrected by implantation of an Artisan iris-fixated phakic intraocular lens, with a follow-up of 8 to 14 years. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24075163 TI - Two-stage operation for the treatment of cataract associated with persistent pupillary membrane. PMID- 24075164 TI - Cost analysis of virtual-reality phacoemulsification simulation in ophthalmology training programs. PMID- 24075165 TI - Corneal surgical problem: October consultation #1. PMID- 24075166 TI - October consultation #2. PMID- 24075167 TI - October consuoltation #3. PMID- 24075168 TI - October consultation #4. PMID- 24075169 TI - October consultation #5. PMID- 24075170 TI - October consultation #7. PMID- 24075171 TI - October consultation #6. PMID- 24075172 TI - Reply: To PMID 23571288. PMID- 24075173 TI - Intraocular lens power selection and optic capture. PMID- 24075174 TI - Simultaneous correction of aniridia and aphakia. PMID- 24075175 TI - Reply: To PMID 23688869. PMID- 24075176 TI - Vector analysis terminology. PMID- 24075177 TI - Reply: To PMID 23608569. PMID- 24075178 TI - Interpretation of doubled-angle plots. PMID- 24075179 TI - Intraocular lens optic capture and zonular impairment. PMID- 24075180 TI - Reply: To PMID 23608569. PMID- 24075181 TI - Intraocular lens optic capture in eyes with zonular weakness. PMID- 24075182 TI - Reply: To PMID 23608566. PMID- 24075183 TI - Reply: To PMID 23608566. PMID- 24075184 TI - Cole Disease Results from Mutations in ENPP1. AB - The coexistence of abnormal keratinization and aberrant pigmentation in a number of cornification disorders has long suggested a mechanistic link between these two processes. Here, we deciphered the genetic basis of Cole disease, a rare autosomal-dominant genodermatosis featuring punctate keratoderma, patchy hypopigmentation, and uncommonly, cutaneous calcifications. Using a combination of exome and direct sequencing, we showed complete cosegregation of the disease phenotype with three heterozygous ENPP1 mutations in three unrelated families. All mutations were found to affect cysteine residues in the somatomedin-B-like 2 (SMB2) domain in the encoded protein, which has been implicated in insulin signaling. ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which is responsible for the generation of inorganic pyrophosphate, a natural inhibitor of mineralization. Previously, biallelic mutations in ENPP1 were shown to underlie a number of recessive conditions characterized by ectopic calcification, thus providing evidence of profound phenotypic heterogeneity in ENPP1-associated genetic diseases. PMID- 24075185 TI - Reliable identification of genomic variants from RNA-seq data. AB - Identifying genomic variation is a crucial step for unraveling the relationship between genotype and phenotype and can yield important insights into human diseases. Prevailing methods rely on cost-intensive whole-genome sequencing (WGS) or whole-exome sequencing (WES) approaches while the identification of genomic variants from often existing RNA sequencing (RNA-seq) data remains a challenge because of the intrinsic complexity in the transcriptome. Here, we present a highly accurate approach termed SNPiR to identify SNPs in RNA-seq data. We applied SNPiR to RNA-seq data of samples for which WGS and WES data are also available and achieved high specificity and sensitivity. Of the SNPs called from the RNA-seq data, >98% were also identified by WGS or WES. Over 70% of all expressed coding variants were identified from RNA-seq, and comparable numbers of exonic variants were identified in RNA-seq and WES. Despite our method's limitation in detecting variants in expressed regions only, our results demonstrate that SNPiR outperforms current state-of-the-art approaches for variant detection from RNA-seq data and offers a cost-effective and reliable alternative for SNP discovery. PMID- 24075186 TI - Mutations in NALCN cause an autosomal-recessive syndrome with severe hypotonia, speech impairment, and cognitive delay. AB - Sodium leak channel, nonselective (NALCN) is a voltage-independent and cation nonselective channel that is mainly responsible for the leaky sodium transport across neuronal membranes and controls neuronal excitability. Although NALCN variants have been conflictingly reported to be in linkage disequilibrium with schizophrenia and bipolar disorder, to our knowledge, no mutations have been reported to date for any inherited disorders. Using linkage, SNP-based homozygosity mapping, targeted sequencing, and confirmatory exome sequencing, we identified two mutations, one missense and one nonsense, in NALCN in two unrelated families. The mutations cause an autosomal-recessive syndrome characterized by subtle facial dysmorphism, variable degrees of hypotonia, speech impairment, chronic constipation, and intellectual disability. Furthermore, one of the families pursued preimplantation genetic diagnosis on the basis of the results from this study, and the mother recently delivered healthy twins, a boy and a girl, with no symptoms of hypotonia, which was present in all the affected children at birth. Hence, the two families we describe here represent instances of loss of function in human NALCN. PMID- 24075187 TI - The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. AB - Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. The residual number of D4Z4 units inversely correlates with clinical severity, but significant clinical variability exists. Each unit contains a copy of the DUX4 retrogene. Repeat contractions are associated with changes in D4Z4 chromatin structure that increase the likelihood of DUX4 expression in skeletal muscle, but only when the repeat resides in a genetic background that contains a DUX4 polyadenylation signal. Mutations in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) gene, encoding a chromatin modifier of D4Z4, also result in the increased likelihood of DUX4 expression in individuals with a rare form of FSHD (FSHD2). Because SMCHD1 directly binds to D4Z4 and suppresses somatic expression of DUX4, we hypothesized that SMCHD1 may act as a genetic modifier in FSHD1. We describe three unrelated individuals with FSHD1 presenting an unusual high clinical severity based on their upper-sized FSHD1 repeat array of nine units. Each of these individuals also carries a mutation in the SMCHD1 gene. Familial carriers of the FSHD1 allele without the SMCHD1 mutation were only mildly affected, suggesting a modifier effect of the SMCHD1 mutation. Knocking down SMCHD1 in FSHD1 myotubes increased DUX4 expression, lending molecular support to a modifier role for SMCHD1 in FSHD1. We conclude that FSHD1 and FSHD2 share a common pathophysiological pathway in which the FSHD2 gene can act as modifier for disease severity in families affected by FSHD1. PMID- 24075188 TI - The IL-33-ST2L pathway is associated with coronary artery disease in a Chinese Han population. AB - The effects of interleukin-33 (IL-33) on the immune system have been clearly demonstrated; however, in cardiovascular diseases, especially in coronary artery disease (CAD), these effects have not yet been clarified. In this study, we investigate the genetic role of the IL-33-ST2L pathway in CAD. We performed three stage case-control association analyses on a total of 4,521 individuals with CAD and 4,809 controls via tag SNPs in the genes encoding IL-33 and ST2L-IL-1RL1. One tag SNP in each gene was significantly associated with CAD (rs7025417(T) in IL33, padj = 1.19 * 10(-28), OR = 1.39, 95% CI: 1.31-1.47; rs11685424(G) in IL1RL1, padj = 6.93 * 10(-30), OR = 1.40, 95% CI: 1.32-1.48). Combining significant variants in two genes, the risk for CAD increased nearly 5-fold (padj = 8.90 * 10(-21), OR = 4.98, 95% CI: 3.56-6.97). Traditional risk factors for CAD were adjusted for the association studies by SPSS with logistic regression analysis. With the two variants above, both located within the gene promoter regions, reporter gene analysis indicated that the rs7025417 C>T and rs11685424 A>G changes resulted in altered regulation of IL33 and IL1RL1 gene expression, respectively (p < 0.005). Further studies revealed that the rs7025417 genotype was significantly associated with plasma IL-33 levels in the detectable subjects (n = 227, R(2) = 0.276, p = 1.77 * 10(-17)): the level of IL-33 protein increased with the number of rs7025417 risk (T) alleles. Based on genetic evidence in humans, the IL-33-ST2L pathway appears to have a causal role in the development of CAD, highlighting this pathway as a valuable target for the prevention and treatment of CAD. PMID- 24075189 TI - Recessive and dominant mutations in retinoic acid receptor beta in cases with microphthalmia and diaphragmatic hernia. AB - Anophthalmia and/or microphthalmia, pulmonary hypoplasia, diaphragmatic hernia, and cardiac defects are the main features of PDAC syndrome. Recessive mutations in STRA6, encoding a membrane receptor for the retinol-binding protein, have been identified in some cases with PDAC syndrome, although many cases have remained unexplained. Using whole-exome sequencing, we found that two PDAC-syndrome affected siblings, but not their unaffected sibling, were compound heterozygous for nonsense (c.355C>T [p.Arg119(*)]) and frameshift (c.1201_1202insCT [p.Ile403Serfs(*)15]) mutations in retinoic acid receptor beta (RARB). Transfection studies showed that p.Arg119(*) and p.Ile403Serfs(*)15 altered RARB had no transcriptional activity in response to ligands, confirming that the mutations induced a loss of function. We then sequenced RARB in 15 subjects with anophthalmia and/or microphthalmia and at least one other feature of PDAC syndrome. Surprisingly, three unrelated subjects with microphthalmia and diaphragmatic hernia showed de novo missense mutations affecting the same codon; two of the subjects had the c.1159C>T (Arg387Cys) mutation, whereas the other one carried the c.1159C>A (p.Arg387Ser) mutation. We found that compared to the wild type receptor, p.Arg387Ser and p.Arg387Cys altered RARB induced a 2- to 3-fold increase in transcriptional activity in response to retinoic acid ligands, suggesting a gain-of-function mechanism. Our study thus suggests that both recessive and dominant mutations in RARB cause anophthalmia and/or microphthalmia and diaphragmatic hernia, providing further evidence of the crucial role of the retinoic acid pathway during eye development and organogenesis. PMID- 24075192 TI - Stress, beta-blockers, and putting. PMID- 24075193 TI - Simple steatosis is a more relevant source of serum inflammatory markers than omental adipose tissue. AB - BACKGROUND AND AIMS: Serum inflammatory biomarkers are closely associated with the risk of cardiovascular disease. However, the major source of these biomarkers is not yet determined. Therefore, we aimed to assess whether simple steatosis or visceral adiposity was a more relevant predictor for serum inflammatory biomarkers. METHODS: A double approach was used: i) clinical: 50 patients with biopsy-proven simple steatosis, 50 non-simple steatosis overweight patients, and 50 controls were explored for their serum biomarkers (high-sensitivity C-reactive protein, plasminogen activator inhibitor-1 activity, tumor necrosis factor alpha, and fibrinogen levels) and for visceral adiposity (measured by computed tomography); ii) experimental: using a rat simple steatosis model the effect of omentectomy on inflammatory biomarkers was investigated. RESULTS: Serum inflammatory biomarkers were significantly higher in the simple steatosis group than in the overweight group. Using multivariate analysis, simple steatosis, visceral adiposity index and visceral adiposity were independently associated with inflammatory biomarkers. In particular, serum inflammatory biomarkers increased with the severity of liver histology (p<0.05), but no with visceral adipose tissue increase. In rats with simple steatosis, the omentectomy treatment was not associated with a decrease of serum inflammatory biomarkers in rats with simple steatosis. CONCLUSIONS: Clinical and experimental data both indicate that simple steatosis may be more associated with inflammatory biomarkers than omental adipose tissue. PMID- 24075194 TI - Fat accretion in a subpopulation of hepatocytes as a strategy to protect the whole liver against oxidative stress and lipotoxicity. AB - Fatty liver can be induced by obesity, some drugs and alcohol intoxication. In this liver lesion, lipid accumulation can involve only some hepatocytes but the significance of this cell-to-cell heterogeneity is unknown. In a recent work, Dr Pol et al. propose that high-fat hepatocytes could protect the cell population against oxidative stress and lipotoxicity. PMID- 24075190 TI - Basophils and allergic inflammation. AB - Basophils were discovered by Paul Ehrlich in 1879 and represent the least abundant granulocyte population in mammals. The relative rarity of basophils and their phenotypic similarities with mast cells resulted in this cell lineage being historically overlooked, both clinically and experimentally. However, recent studies in human subjects and murine systems have shown that basophils perform nonredundant effector functions and significantly contribute to the development and progression of TH2 cytokine-mediated inflammation. Although the potential functions of murine and human basophils have provoked some controversy, recent genetic approaches indicate that basophils can migrate into lymphoid tissues and, in some circumstances, cooperate with other immune cells to promote optimal TH2 cytokine responses in vivo. This article provides a brief historical perspective on basophil-related research and discusses recent studies that have identified previously unappreciated molecules and pathways that regulate basophil development, activation, and function in the context of allergic inflammation. Furthermore, we highlight the unique effector functions of basophils and discuss their contributions to the development and pathogenesis of allergic inflammation in human disease. Finally, we discuss the therapeutic potential of targeting basophils in preventing or alleviating the development and progression of allergic inflammation. PMID- 24075195 TI - Endoscopic retrograde cholangioscopic removal of migrated vascular coils from the common bile duct. PMID- 24075196 TI - Effectiveness and equity impacts of town-wide cycling initiatives in England: a longitudinal, controlled natural experimental study. AB - Cycling confers health and environmental benefits, but few robust studies have evaluated large-scale programmes to promote cycling. In England, recent years have seen substantial, town-wide cycling initiatives in six Cycling Demonstration Towns (funded 2005-2011) and 12 Cycling Cities and Towns (funded 2008-2011). The initiatives involved mixtures of capital investment (e.g. cycle lanes) and revenue investment (e.g. cycle training), tailored to each town. This controlled before-after natural experimental study used English census data to examine impacts on the prevalence of travelling to work by bicycle and other modes, comparing changes in the intervention towns with changes in three comparison groups (matched towns, unfunded towns and a national comparison group). We also compared effects between more and less deprived areas, and used random-effects meta-analysis to compare intervention effects between towns. Among 1.3 million commuters in 18 intervention towns, we found that the prevalence of cycling to work rose from 5.8% in 2001 to 6.8% in 2011. This represented a significant increase relative to all three comparison groups (e.g. +0.69 (95% CI 0.60,0.77) percentage points for intervention vs. matched towns). Walking to work also increased significantly compared with comparison towns, while driving to work decreased and public transport use was unchanged. These effects were observed across all fifths of area deprivation, with larger relative changes in deprived areas. There was substantial variation in effect sizes between towns, however, and the average town-level effect on cycling was non-significant (+0.29 ( 0.26,0.84) percentage points for intervention vs. matched towns). We conclude that to date, cycling to work has increased (and driving to work decreased) in the intervention towns, in a relatively equitable manner. The variation in effects between towns indicates uncertainty regarding the likely impact of comparable investment in future towns. Nevertheless these results support the case for implementing and evaluating further town-wide cycling initiatives. PMID- 24075197 TI - [Ischemic stroke: A rare complication of liver hydatid cyst]. AB - Hydatid cyst of the liver (HCL) is a widespread disease in North African countries. We report the case of a 39-year-old patient who was admitted in our intensive care unit because of anaphylactic shock due to a cracked HCL fortuitously discovered. This accident was also complicated by an ischemic stroke witch underline mechanisms are discussed. PMID- 24075198 TI - [Hemorrhagic shock on posttraumatic retroperitoneal hematoma revealing a horseshoe kidney]. PMID- 24075199 TI - Evolution of socio-economic inequalities in mortality in small geographical areas of the two largest cities in Spain (Barcelona and Madrid), 1996-2007. AB - OBJECTIVES: To describe the evolution of socio-economic inequalities in mortality in small areas of two Spanish cities (Barcelona and Madrid) from 1996 to 2001 and from 2002 to 2007. STUDY DESIGN: A small-area ecological study of trends was performed, in which the units of analysis were census tracts. METHODS: The association between mortality and socio-economic deprivation was assessed through Poisson regression analysis. Models were stratified by sex, age group and period of study. The trend in inequalities in mortality was assessed by introducing an interaction term between deprivation and the period of study. RESULTS: Mortality in the most-deprived areas was significantly higher than mortality in the less deprived areas in both periods and most age groups. However, inequalities seemed to diminish in young people and elderly women, especially in Barcelona. CONCLUSIONS: There is a need to monitor inequalities in mortality in the near future because the current financial crisis could change this situation. PMID- 24075200 TI - In response to: Fabio Franciscatto Stieven, master candidate; Ferreira E Giovanni, undergraduate; Silva F Marcelo, doctor; Rosa T Luis, doctor. Thrust manipulation versus non-thrust manipulation: a question that still needs to be answered. PMID- 24075202 TI - Using mice to treat (wo)men: mining genetic changes in patient xenografts to attack breast cancer. AB - In this issue of Cell Reports, Li et al. show that the analysis of genetic changes in patient-derived xenografts can reveal crucial details of tumor evolution, such as the emergence of functional estrogen receptor mutations in endocrine-resistant breast cancer. PMID- 24075201 TI - Population genomics of rapid adaptation by soft selective sweeps. AB - Organisms can often adapt surprisingly quickly to evolutionary challenges, such as the application of pesticides or antibiotics, suggesting an abundant supply of adaptive genetic variation. In these situations, adaptation should commonly produce 'soft' selective sweeps, where multiple adaptive alleles sweep through the population at the same time, either because the alleles were already present as standing genetic variation or arose independently by recurrent de novo mutations. Most well-known examples of rapid molecular adaptation indeed show signatures of such soft selective sweeps. Here, we review the current understanding of the mechanisms that produce soft sweeps and the approaches used for their identification in population genomic data. We argue that soft sweeps might be the dominant mode of adaptation in many species. PMID- 24075203 TI - High prevalence of paratuberculosis in rabbits is associated with difficulties in controlling the disease in cattle. AB - There is increasing evidence that the European wild rabbit (Oryctolagus cuniculus) is a wildlife reservoir for paratuberculosis and infected populations may contribute to the persistence of infection in livestock. The aim of this study was to test the hypothesis that farms with difficulties controlling paratuberculosis in their cattle herds have a higher prevalence of Mycobacterium avium subsp. paratuberculosis (MAP) infection in their rabbit populations. A total of 281 rabbits from 13 beef farms in the East of Scotland were randomly sampled in early spring 2007. Participating farms were in paratuberculosis control programmes under the Premium Cattle Health Scheme (PCHS), and were classified as 'responder' (paratuberculosis under control) or 'low responder' (a persistent number of paratuberculosis-positive cattle despite control measures in place) farms. Of the rabbits sampled, 23.8% tested positive for MAP, with those on 'low responder' farms having a greater probability of being infected (0.4) relative to rabbits on 'responder' farms (0.1). The association suggests that MAP infected rabbits may contribute to the persistence of paratuberculosis in domestic livestock and undermine control strategies that focus on livestock alone. This study provides the first evidence of an association between the persistence of paratuberculosis in livestock despite the implementation of disease control strategies, and MAP-infected sympatric wild rabbit populations. PMID- 24075204 TI - Effect of TRIF on permeability and apoptosis in bovine microvascular endothelial cells exposed to lipopolysaccharide. AB - Bovine respiratory disease complex (BRDC) can be caused by several Gram negative bacteria. Lung endothelial cells may be damaged by the release of lipopolysaccharide (LPS) from these organisms. Toll-like receptor (TLR-4) signaling pathways include the myeloid differentiation primary response gene 88 (MyD88) and the Toll/interleukin (IL)-1 receptor (TIR) domain-containing adapter inducing interferon-beta (TRIF) pathways. The aim of this study was to determine which of these pathways is responsible for permeability changes, apoptosis and cytokine production in bovine lung microvascular cells exposed to LPS. Bovine lung endothelial cells were treated with a peptide to inhibit MyD88 signaling or small interfering RNA (siRNA) to inhibit TRIF signaling. Effects were measured using trans-well endothelial electrical resistance to determine cell monolayer permeability, annexin staining to estimate apoptosis and real-time PCR to measure levels of expression of IL-1beta and tumor necrosis factor (TNF)-alpha mRNA. Inhibition of TRIF signaling reduced permeability changes and apoptosis in endothelial cells exposed to LPS. In contrast, MyD88 inhibition reduced expression of IL-1beta and TNF-alpha mRNA in LPS treated cells, but had no effect on permeability. It was concluded that TRIF signaling in LPS-stimulated lung endothelial cells results in permeability changes and apoptosis. PMID- 24075205 TI - Optimal timing of umbilical cord clamping for term and preterm babies. AB - Deferring cord clamping allows blood flow between baby and placenta to continue for a few moments. This often leads to increased neonatal blood volume at birth. It also allows for longer transition to the neonatal circulation. Optimal timing for clamping the cord remains uncertain. This paper discusses the physiology of placental transfusion and presents the evidence from systematic reviews of randomised trials comparing alternative strategies for cord clamping for both term and preterm births. For healthy term infants, deferring cord clamping increases iron stores in infancy. Therefore, a more liberal approach to deferring cord clamping appears to be warranted, provided screening and treatment for jaundice requiring phototherapy is available. For preterm births, although there are few data on the main clinical outcomes, the evidence is promising that deferred cord clamping may be beneficial. For both term and preterm infants there is little information about long term development. PMID- 24075206 TI - Less invasive surfactant administration (LISA) - ways to deliver surfactant in spontaneously breathing infants. AB - The idea to deliver surfactant to spontaneously breathing premature infants is not new. The spectrum of methods reported reaches from aerosol administration over pharyngeal deposition, the use of laryngeal masks, short term intubation, surfactant administration and rapid extubation (INSURE) to an approach of keeping premature neonates on spontaneous breathing with continuous positive airway pressure support and administering surfactant by laryngoscopy via a small diameter tube. This way of Less Invasive Surfactant Administration (LISA) is in increasing use in the last decade in Germany. More than 1000 babies have been included in clinical studies on LISA by now. A first prospective randomized controlled trial (AMV-trial) demonstrated a significant reduction in the use of mechanical ventilation in LISA patients compared to standard treatment with intratracheal bolus administration of surfactant. Another recent study (Take Care study) indicates, that LISA may even be superior to INSURE. The search for even more "gentle" methods (e.g. nebulization) to deliver surfactant continues. PMID- 24075207 TI - P300 in obsessive-compulsive disorder: source localization and the effects of treatment. AB - Converging evidence suggests that frontostriatal abnormalities underlie OCD symptoms. The event-related potential P300 is generated along a widely distributed network involving several of the areas implicated in OCD. P300 abnormalities reported in patients with OCD suggest increased activity in these areas. The aim of the present study was to investigate this assumption in unmedicated patients with OCD, and to assess the effects of OCD treatment on P300 brain activity patterns. Seventy-one unmedicated patients with a DSM-IV diagnosis of OCD and 71 age- and gender-matched healthy control subjects participated in the study. The P300 was obtained through 32-channel EEG during an auditory oddball paradigm. Forty-three patients underwent a second EEG assessment after treatment with sertraline and behavioural therapy. Low-resolution electromagnetic tomography (LORETA) was used to localize the sources of brain electrical activity. RESULTS: Increased P300-related activity was observed predominantly in the left orbitofrontal cortex, but also in left prefrontal, parietal and temporal areas, in patients compared to controls at baseline. After treatment, reduction of left middle frontal cortex hyperactivity was observed in patients. CONCLUSIONS: Findings of increased activity in frontoparietal areas in patients are consistent with several previous studies. Importantly, OCD treatment led to reduction of hyperactivity in the left middle frontal cortex, an area associated with context processing and uncertainty that might be important for the emergence of OCD symptoms. Thus, the present study is the first to show an association between P300 abnormalities and activity in brain regions postulated to be involved in the pathophysiology of OCD. PMID- 24075208 TI - [Reperfusion delays in acute coronary syndromes with ST segment elevation (STEMI) depending on prehospital care]. AB - INTRODUCTION: Acute coronary syndrome with ST segment elevation (STEMI) remains a major cause of morbidity and mortality in France, directly correlated with the time management of the patient to achieve reperfusion of the artery as early as possible. But the delay of reperfusion is related to the course that will take the patient to the revascularization. METHODS: To make an observation of departmental practices, we conducted a retrospective monocentric study on the STEMI supported on 4years in the Departmental Hospital of La Roche-sur-Yon by comparing the time of reperfusion in two groups: patients who used the recommended chain=diRect chain (Call the emergency number-specialist mobile emergency unit-Cardiac intensive care unit or cardiac catheterization laboratory), and patients who used another chain=Long chain. RESULTS: On 838 patients with STEMI, 356 (42.5%) used the Direct chain. The average time of reperfusion in the Direct chain group is 4.26hours (+/-3.12), 6.17hours (+/-4.82) in the Long chain group. There is a significant difference between the two groups of 1.9hours (P<0.001). Of 186 patients who consulted a general practitioner, 40.3% of patients were not supported by the mobile emergency unit. CONCLUSION: These results should lead to improved practices, to carry on continuing medical education with all actors in the chain and patient information to shorten up the time of reperfusion. PMID- 24075209 TI - Promoting osteoblast differentiation by the flavanes from Huangshan Maofeng tea is linked to a reduction of oxidative stress. AB - Epidemiological evidence has shown an association between tea consumption and the prevention of bone loss in the elderly. Previous studies indicated that green tea exerted osteoprotective effect in vivo. This study aims to investigate the constituents in Huangshan Maofeng tea and systemically evaluate their antioxidative and osteogenic effects in vitro. Five flavanes, isolated from Huangshan Maofeng tea, showed effects on proliferation of osteoblastic cells and ameliorated H2O2-induced C2C12 mouse myoblast cell apoptosis at 3.125-50 MUg/ml. (-)-Epicatechin observably increased alkaline phosphatase (ALP) activity and hydroxyproline content. (-)-Epiafzelechin at 25 MUg/ml significantly increased the area of mineralized bone nodules. The activities of flavanes in promoting osteblastic proliferation and differentiation are positively correlated with activities in protecting against apoptosis in C2C12 cells. It indicates that anti osteoporosis effect of these flavanes may be linked to their antioxidative activity. The observed effects of these flavanes suggest that these flavanes may have beneficial effects on bone health. PMID- 24075210 TI - Cytotoxicity and modes of action of three naturally occurring xanthones (8 hydroxycudraxanthone G, morusignin I and cudraxanthone I) against sensitive and multidrug-resistant cancer cell lines. AB - BACKGROUND: Resistance of cancer to chemotherapy remains a challenging issue for scientists as well as physicians. Naturally occurring xanthones possess a variety of biological activities such as anti-inflammatory, anti-bacterial, and anti cancer effects. The present study was aimed at investigating the cytotoxicity and the modes of action of three naturally occurring xanthones namely, morusignin I (1), 8-hydroxycudraxanthone G (2) and cudraxanthone I (3) against a panel of nine cancer cell lines, including various sensitive and drug-resistant phenotypes. METHODS: The cytotoxicity of the compounds was determined using a resazurin reduction assay, whereas the caspase-Glo assay was used to detect the activation of caspases 3/7, caspase 8 and caspase 9 in cells treated with compounds 3. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells, analysis of mitochondrial membrane potential (MMP) as well as measurement of reactive oxygen species (ROS). RESULTS: Compounds 1 and 3 inhibited the proliferation of all tested cancer cell lines including sensitive and drug resistant phenotypes. Compound 2 was active on 8/9 cell lines with the IC50 values ranging from 16.65 MUM (against leukemia CCRF-CEM cells) to 70.38 MUM (against hepatocarcinoma HepG2 cells). The IC50 value ranged from 7.15 MUM (against CCRF-CEM cells) to 53.85 MUM [against human glioblastoma U87MG.DeltaEGFR cells] for compound 1, and from 2.78 MUM (against breast cancer MDA-MB231 BCRP cells) to 22.49 MUM (against U87MG cells) for compound 3. P-glycoprotein expressing CEM/ADR5000 cells were cross-resistant to compounds 1 and 2 (4.21- to 610-fold) while no cross-resistance or even collateral cross-sensitivity were observed in other drug-resistant cell lines to the three compounds. Normal AML12 liver cells were more resistant to the three compounds than HepG2 liver cancer cells. Compounds 3 arrested the cell cycle between G0/G1 and S phases, strongly induced apoptosis via caspases 3/7, caspase 8, caspase 9 activation and disrupted the MMP in CCRF-CEM cells. CONCLUSIONS: The cytotoxicity of the studied xanthones and especially compound 3 deserve more detailed exploration in the future to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes. PMID- 24075211 TI - Antidiabetic and antihyperlipidemic activity of asiatic acid in diabetic rats, role of HMG CoA: in vivo and in silico approaches. AB - Hyperlipidemia is an associated complication of diabetes and also a major risk factor for cardiovascular diseases. The present study was designed to examine the antihyperlipidemic effect of asiatic acid (AA) in streptozotocin (STZ) induced diabetic rats. Diabetes was induced in male Wistar rats by a single intraperitoneal injection of STZ (40 mg/kg b.w.). Diabetic rats show increased plasma glucose, total cholesterol, triglycerides, free fatty acids, phospholipids, low density lipoprotein, very low density liprotein, atherogenic index and decreased insulin and high density lipoprotein in diabetic rats. The activity of 3-hydroxy 3-methylglutaryl coenzyme A (HMG CoA) reductase increased significantly in contrast to the activities of lipoprotein lipase and lecithin cholesterol acyltransferase. In addition, the molecular docking of AA against HMG CoA reductase involved in cholesterol biosynthesis using Argus software. Diabetic rats were treated with AA shifted all these parameters towards normalcy. AA has shown best ligand binding energy 11.8122 kcal/mol. The antihyperlipidemic effect of AA was compared with glibenclamide; a well-known antihyperglycemic drug. In conclusion, this study indicates that AA showed an antihyperlipidemic effect in addition to its antidiabetic effect in experimental diabetes. PMID- 24075212 TI - Ginsenoside Rg1 of Panax ginseng stimulates the proliferation, odontogenic/osteogenic differentiation and gene expression profiles of human dental pulp stem cells. AB - Ginsenoside Rg1 is one of the major active components of Panax ginseng C. A. Mey. Human dental pulp stem cells (hDPSCs) play an important role in the dentin formation, reparation and tooth tissue engineering. This study investigated the effects of ginsenoside Rg1 on the proliferation, odontogenic differentiation of hDPSCs and revealed the underlying molecular mechanisms. [3H]-thymidine incorporation assay and cell cycle analysis were applied to investigate the proliferation of hDPSCs after the treatment of ginsenoside Rg1. Immunocytochemistry analysis and fluorescent quantitative reverse transcriptase polymerase chain reaction (FQ-PCR) were performed to evaluate the odontogenic differentiation of hDPSCs. Gene and protein expressions of bone morphogenetic protein-2 (BMP-2) and fibroblast growth factor 2 (FGF2) were detected by FQ-PCR and enzyme-linked immunosorbent assay. The Roche Nimblegen Whole Human Genome Expression profile microarray was used to detected representative gene expression profiles of hDPSCs by ginsenoside Rg1. The results indicated that ginsenoside Rg1 significantly increased hDPSCs proliferation (p<0.05). Gene expressions of DSPP, ALP, OCN, BMP-2, FGF2 and protein expressions of BMP-2 and FGF2 were increased compared with the untreated group (p<0.05). Gene expression profile analysis revealed that 2059 differentially expressed genes were detected by ginsenoside Rg1. Ginsenoside Rg1 promoted the proliferation and differentiation of hDPSCs through alteration of gene expression profiles. PMID- 24075213 TI - Effects of praeruptorin C on blood pressure and expression of phospholamban in spontaneously hypertensive rats. AB - BACKGROUND: The traditional Chinese medicine Praeruptorin c (Pra-c) has many physiological and pharmacological effects, including antagonistic effects on blood pressure and calcium levels, maintenance of cellular calcium homeostasis, and improved cardiac systolic and diastolic function. It is potentially a novel and versatile drug for the treatment and prevention of cardiovascular diseases. OBJECTIVE: To explore the possible impact of Pra-c on blood pressure in SHR and its mechanism of action. MATERIALS AND METHODS: Twenty SHR were randomly divided into a Pra-c group [Pra-c was administered intragastrically, 20 mg kg(-1) d(-1), n=10] or an untreated control group (n=10), containing 10 age-matched SD rats. Each group of rats was followed for 8 weeks. Before and during the treatment, tail artery systolic blood pressure was measured using a tail-cuff every 2 weeks. After 8 weeks, the rats were sacrificed and RNA was extracted from homogenates of cardiac tissue. Tissue from the left ventricle was fixed, sectioned and H&E stained to assess possible changes in myocardial cell structure and morphology. Semi-quantitative RT-PCR was used to assess changes in phospholamban gene expression in treated and untreated rats. RESULTS: SHR treated with Pra-c for 8 weeks had a lower systolic pressure than untreated SHR (p<0.05), two measures of cardiac damage, the heart mass index and left ventricle mass index (HMI and LVMI, respectively) were improved, and the level of PLB mRNA expression was lower in the untreated SHR group (p<0.05). DISCUSSION AND CONCLUSION: With continuous hypertension, SHR gradually formed or developed cardiac hypertrophy and fibrosis. Pra-c had a clear effect on blood pressure in SHR, and reversed SHR ventricular remodeling by upregulating the gene expression of sarcoplasmic reticulum PLB. PMID- 24075214 TI - Synthesis of novel anticancer iridoid derivatives and their cell cycle arrest and caspase dependent apoptosis. AB - Nyctanthes arbortristis Linn (Oleaceae) is widely distributed in sub-Himalayan regions and southwards to Godavari, India commonly known as Harsingar and Night Jasmine. In continuation of our drug discovery programme on Indian medicinal plants, we isolated arbortristoside-A (1) and 7-O-trans-cinnamoyl 6beta hydroxyloganin (2) from the seeds of N. Arbortristis, which exhibited moderate in vitro anticancer activity. Chemical transformation of 2 led to significant improvement in the activity in derivative 8 and 15 against HepG2 (human hepatocellular carcinoma), MCF-7 (breast adenocarcinoma) cell lines. The compounds 8 and 15 were also capable of cell cycle arrest and caspase dependent apoptosis in HepG2 cell lines. These iridoid derivatives hold promise for developing safer alternatives to the marketed drugs. PMID- 24075216 TI - Regional variation in medicare imaging utilization and expenditures: 2007-2011 trends and comparison with other health services. AB - PURPOSE: A 2008 federal report expressed concern regarding substantial regional variation in imaging expenditures. The aims of this study were to evaluate trends in regional variation in Medicare imaging utilization and expenditures from 2007 to 2011 and to compare these trends with regional variation in other health service categories. METHODS: Data were based on CMS's Chronic Condition Data Warehouse and organized on the basis of 306 US health referral regions (HRRs). Imaging costs per beneficiary, standardized for regional differences in reimbursement rates, and imaging utilization per beneficiary were recorded per HRR from 2007 through 2011. Costs and utilization were also recorded for other service categories in 2011. Regional variation was assessed via relative risk (RR; the ratio between the highest and lowest HRRs) and coefficient of variation (CV; the standard deviation divided by the mean among all HRRs). Correlations between imaging and other service categories were assessed using Pearson's correlation coefficient. RESULTS: There was minimal change in regional variation in imaging costs or utilization between 2007 and 2011. Regional variation in imaging costs (RR, 5.70-5.88; CV, 33.0%-33.3%) was considerably greater than variation in imaging utilization (RR, 2.11%-2.25%; CV, 14.2%-14.6%). Imaging costs and utilization showed moderate to strong correlations with those of other service categories (r = 0.572-0.869). In 2011, regional variation in imaging utilization (RR, 2.25; CV, 14.2%) was considerably lower than variation in utilization of other service categories (RR, 2.80-10.78; CV, 20.9%-33.3%). CONCLUSIONS: Regional variation in imaging utilization is considerably lower than both variation in imaging costs and variation in utilization of other major service categories. It is unclear whether variation in imaging utilization provides an optimal individual target for major policy decisions. PMID- 24075215 TI - Hautriwaic acid as one of the hepatoprotective constituent of Dodonaea viscosa. AB - It is widely known that hepatitis and its complications such as cirrhosis or hepatocellular carcinoma are one of the major health problems of the world especially since no specific treatment is available. In the present study we investigated the hepatoprotective potential of the methanolic extract of the whole plant of Dodonaea viscosa and its ethyl acetate, aqueous, butanol and n hexane fractions against carbon tetrachloride (CCl4) induced hepatoxicity in rats. Hepatoprotection was assessed in terms of reduction in serum enzymes (ALT, AST, and ALP) that occur after CCl4 injury, and by histopathology and immunohistochemistry. The methanolic extract reduced the serum enzyme level (ALT, AST, and ALP) down to control levels despite CCl4 treatment. It also reduced the CCl4-induced damaged area to 0% as assessed by histopathology. The CD68+ macrophages were also reduced in number around the central vein area by the methanolic extract. These hepatoprotective effects were better than the positive control silymarin. Similar hepatoprotective activities were found with the ethyl acetate, and aqueous fractions of the methanolic extract. The butanol and n hexane fractions showed elevated levels of ALT, AST and ALP as compared to the positive control silymarin. Histopathology showed ~30% damage to the liver cells with the butanol and n-hexane fractions which still showed some protective activity compared to the CCl4 treated control. HPLC fingerprinting suggested that hautriwaic acid present in the methanolic extract and its ethyl acetate, and aqueous fractions may be responsible for this hepatoprotective activity of Dodonaea viscosa which was confirmed by in vivo experiments. PMID- 24075217 TI - Residents teaching medical students: how do they compare with attending educators? AB - PURPOSE: Educating medical students is a core mission of academic radiology departments. In some programs, residents participate in student teaching. The aim of this study was to retrospectively compare medical student evaluations of radiology resident lectures with lecture evaluations of radiology faculty members. METHODS: Numeric evaluations for lectures given by faculty members, fellows, and residents were collected over a 1-year period as part of routine course evaluations for a fourth-year medical student radiology elective. Faculty member, fellow, and resident lecture scores were compared, overall using analysis of variance and pairwise using Student's t test. A predefined low P-value threshold was used for the t tests to account for the multiple comparisons. To account for the inherent clustering of the data due to repeat lecturers, the data were reanalyzed on a "per lecturer" basis. RESULTS: Three hundred seven individual lecture scores were collected. There was no statistical difference between the lecture scores received by attending faculty members (mean, 9.10 on a scale of 10) and residents (mean, 8.99) (P = .08). Fellows, however, scored statistically significantly lower (mean, 8.45) than attending faculty members and residents (P <.001 for both comparisons). The per lecturer analysis yielded similar results. CONCLUSIONS: Lectures delivered by residents received similar evaluations as lectures delivered by faculty members. Given that teaching can be an educational experience for residents, involving radiology residents in medical student teaching may benefit students and residents alike. PMID- 24075218 TI - Insertion of PICCs with minimum number of lumens reduces complications and costs. AB - BACKGROUND: Inappropriate catheter requests at the McGill University Health Centre (MUHC) led to significantly increased costs and early catheter malfunction or infection. Dual-lumen catheters were often requested and inserted when only a single lumen was required, and inappropriate catheter care on the wards led to early infection or thrombosis. METHODS: A full-time registered nurse was hired to analyze and transform the vascular access program of the MUHC. Catheter selection was streamlined on the basis of clinical unit need. Clinical and cost data were collected between May 2011 and January 2012. RESULTS: Requests for vascular access at the MUHC have been standardized and centralized. Single-lumen catheters are inserted unless a specific indication for a dual-lumen catheter is provided. To date, data have been collected on >4,000 catheter insertions, both before and after the switch to the single-lumen program. Dual-lumen catheters have been required in only 50% of cases. Reinsertion rates have decreased, leading to the first year-over-year reduction in peripherally inserted central venous catheter insertion since data collection began in 2002. The program has also resulted in significant reductions in central line-associated bloodstream infection and catheter-related thrombosis. Decreased maintenance and reinsertion costs have led to overall savings for the MUHC of approximately $1.1 million. PMID- 24075219 TI - Fracture non-union: Can biomarkers predict outcome? AB - Delayed bone healing and non-union occurs in approximately 10-15% of long bone fractures. Both pathologies may result in prolonged period of pain, disability and repetitive operative interventions. Despite intense investigations and progress done in understanding the pathophysiologic processes governing bone healing, the diagnostic tools have not been altered. The clinical findings and radiographic features remain the two important landmarks of diagnosing non-union and even when the diagnosis is established there is debate on the ideal timing and mode of intervention. Emerging evidence suggest that there are certain molecules and genes that can serve as predictors of potentially unsuccessful fracture union. This article summarises the current evidence on the available 'bio-markers'to predict fracture non-union. PMID- 24075220 TI - Distally based perforator flaps for reconstruction of post-traumatic defects of the lower leg and foot. A review of the anatomy and clinical outcomes. AB - STUDY AIMS: To report the surgical anatomy of the perforator arteries at the lower leg, analyse clinical outcomes in previous studies, and forward methodological recommendations for future studies of post-traumatic perforator flap reconstructions. METHODS: A study sample of 640 human patients drawn from 24 clinical reports was included for review. The sample comprised of four subsets: sural flap reconstructions (n=257), saphenous flaps (n=122), supramalleolar flaps (n=92), and propeller flaps (n=169). RESULTS: Statistical analysis of samples from anatomical studies documents significant differences in the perforator distribution from the tibial and peroneal artery; peroneal perforator arteries are randomly organised whereas tibial artery perforators are clustered at three definite levels. The failure rates in clinical studies ranged from 0% to 6%, being lowest for supramalleolar flap reconstructions and highest for saphenous flaps; however, differences between the four subsets were not statistically significant at the 95% confidence level. Due to methodological flaws, outcome comparisons in the actual study sample should be interpreted cautiously; in most clinical studies both risk variables and outcome indicators are poorly defined. The outcome of Dynamic Infrared Thermography imaging of post-transposition changes of flap perfusion is reported. SUMMARY: Fasciocutaneous perforator flaps seem to have high survival rates and represent a feasible approach to post traumatic reconstructions, especially in low-resource settings. A template for data gathering is recommended for higher accuracy in future comparative studies, and for scientific analysis of success and risk factors. New imaging techniques indicate a promising potential of micro-circular angiogenesis during the first two weeks after flap transpose. PMID- 24075223 TI - From the Medical Board of the National Psoriasis Foundation: Vaccination in adult patients on systemic therapy for psoriasis. AB - Patients with moderate to severe psoriasis often require systemic immunomodulatory medications that place them at risk for infection. Vaccination is a proven strategy to reduce infections. However, vaccination rates among patients with inflammatory autoimmune conditions, including psoriasis, remain low. We review the literature regarding vaccine-preventable illness and vaccinations commonly used in the United States in patients older than 18 years on immunosuppressive therapies that are used in the treatment of psoriasis. The medical board of the National Psoriasis Foundation recommends that dermatologists counsel patients on updating vaccinations in accordance with recommendations of the Advisory Committee for Immunization Practices as any measures taken to prevent infection can increase the safety of immunomodulatory therapies. PMID- 24075224 TI - In vitro rapid clearance of infectious bursal disease virus in peripheral blood mononuclear cells of chicken lines divergent for antibody response might be related to the enhanced expression of proinflammatory cytokines. AB - Infectious bursal disease (IBD) is an acute and highly contagious viral disease of young chickens caused by infectious bursal disease virus (IBDV). An effective way to control IBDV would be to breed chickens with a reduced susceptibility to IBDV infection. In the present work, we used chickens selected for high and low specific responses to sheep red blood cells (SRBC) (H and L, respectively) to assess the susceptibility of differential immune competent animals to IBDV infection. The peripheral blood mononuclear cells (PBMCs) of high SRBC line (HL) and low SRBC line (LL) were infected with IBDV and viral RNA loads were determined at different time post-IBDV infection. Chicken orthologues of the T helper 1 (Th1) cytokines, interferon-gamma (IFN-gamma) and interleukin-2 (IL-2); a Th2 cytokine, IL-10; a pro inflammatory cytokine, IL-6; the CCL chemokines, chCCLi2, chCCLi4 and chCCLi7; colony stimulating factor, GM-CSF; and a anti inflammatory cytokine, transforming growth factor beta-2 (TGFbeta-2) were quantified. The expression of chCCLi2, chCCLi4 and chCCLi7 was significantly higher in L line as compared to H line. However, in H line the viral RNA loads were significantly lower than in L line. Therefore, the upregulated chemokines might be associated with the susceptibility to IBDV. The expression of IFN-gamma, IL-2 and IL-6 was significantly higher in H line as compared to L line. We assume that the higher proinflammatory cytokines expression in H line might be related to the rapid clearance of virus from PBMCs. Significantly higher levels of IL-10 and TGFbeta-2 mRNAs in L line might be related to the pathogenesis of IBDV. In conclusion, selection for antibody responses appears to influence the expression profiles of chemokines and cytokines against IBDV. Further, the selection for high SRBC response might improve the immuno-competence of chickens against IBDV. PMID- 24075225 TI - Analysis of thermal distributions in veneered zirconia and metal restorations during firing. AB - OBJECTIVE: The present work evaluated the thermal behavior of porcelain-metal and porcelain-zirconia restorations during fast and slow firing and cooling. METHODS: All-ceramic (porcelain on zirconia) and porcelain-fused-to-metal (PFM) molar crowns were fabricated with 1 or 2mm porcelain thickness. Thermocouples were attached to the cementation (T1) and occlusal (T4) surfaces of the restoration and embedded at the framework-porcelain interface (T2) and inside the porcelain (T3) to acquire temperature readings by time. Slow heating was set as 45 degrees C/min and fast heating as 140 degrees C/min. For fast cooling, the furnace was opened immediately after the holding time. Slow cooling was effected by opening the furnace when it reached 50 degrees C below the Tg. Porcelains Tg were calculated for each cooling rate. RESULTS: Slow heating rate was measured at T4 as being 30 degrees C/min while fast heating at T4 was 100 degrees C/min. The measured cooling rates within the porcelain (T2) around the Tg range were 20 degrees C/min and 900 degrees C/min for slow and fast cooling, respectively. During slow cooling, similar temperatures were found for both zirconia and metal crowns. Remarkable temperature gradients were observed for the fast cooled all ceramic crown (T1-T4=100 degrees C) and, of lower magnitude for PFM (T1-T4=30 degrees C). Tg of porcelains increase with faster cooling rates. SIGNIFICANCE: Slow cooling appears to be especially important for all-ceramic crowns to prevent high magnitude thermal gradients, which could influence cracking and fracture of the porcelain. PMID- 24075227 TI - Levamisole toxicity mimicking autoimmune disease. AB - BACKGROUND: Levamisole is present as a contaminant or additive in most cocaine sold in the United States. Cases of agranulocytosis attributed to levamisole tainted cocaine have been widely described. A vasculopathic reaction to levamisole has also been reported; however, diagnostic features such as antineutrophil cytoplasmic antibody (ANCA) and additional autoimmune marker positivity are not well recognized. As such, many patients are given a misdiagnosis, prompting aggressive and often unnecessary treatment. OBJECTIVE: We hope to educate practitioners about the clinical and laboratory features of levamisole-induced vasculopathy to ensure accurate diagnosis and management. METHODS: This was a case series. RESULTS: Six patients were admitted with purpuric lesions and vasculitic changes on biopsy specimen; 5 of them were given the diagnosis of and treated for autoimmune conditions before their true diagnosis was revealed. All patients had ANCA positivity, and 4 had additional abnormalities in autoimmune markers. All patients reported recent cocaine abuse, and were ultimately given the diagnosis of levamisole-induced vasculopathy. LIMITATIONS: This observational study is limited by sample size. CONCLUSIONS: Patients presenting with purpuric lesions with ANCA positivity should be assessed for cocaine exposure. It is important to recognize that levamisole may not only induce ANCA positivity but also other autoimmune marker abnormalities. Patients can often be treated with less aggressive therapeutic strategies than what is used for primary ANCA-associated vasculitides. PMID- 24075226 TI - A tale of two stimulants: mentholated cigarettes may play a role in cocaine, but not methamphetamine, dependence. AB - BACKGROUND: Research suggests that mentholated cigarettes may play a role in cocaine dependence. The purpose of the present study was to expand upon the research on mentholated cigarettes and cocaine dependence and to evaluate the role of mentholated cigarettes in methamphetamine dependence. METHODS: Secondary analysis of a multisite, randomized trial evaluating the impact of smoking cessation treatment in stimulant-dependent outpatients (N=538). Participants' reasons for concurrent use of cigarettes and illicit stimulants were assessed via self-report. Stimulant-abstinence was measured by self-report and urine drug screens. Smoking cessation was assessed via self-report and carbon monoxide levels. RESULTS: Of the 301 cocaine-dependent participants, 201 (67%) were menthol and 100 (33%) were non-menthol cigarette smokers. Cocaine-dependent participants who smoked menthol, compared to non-menthol, cigarettes were significantly more likely to report that cigarettes prolong their cocaine high (X(2)(1)=16.3, p<.0001, OR=3.58 [95% CI: 1.88-6.79]) and were less likely to be stimulant abstinent during active treatment (W=3.6, p<0.001, d=.39 [95% CI: 0.16 0.62]), at 3-month follow-up (X(2)(1)=14.4, p<0.001, OR=.32 [95% CI: 0.17-0.58]), and at 6-month follow-up (X(2)(1)=4.6, p=0.03, OR=.53 [95% CI: 0.29-0.95]). No parallel differences were found between menthol and non-menthol methamphetamine dependent smokers. The prevalence of Caucasian menthol smokers was significantly greater in the cocaine-dependent participants (37.2%) than in the methamphetamine dependent participants (17.61%), (X(2)(1)=14.4, p<.001, OR=2.77 [95% CI:1.62 4.73]). Smoking cessation was not significantly associated with cigarette type for either cocaine- or methamphetamine-dependent participants. CONCLUSIONS: The present results suggest that mentholated cigarettes play a role in cocaine, but not methamphetamine, dependence. PMID- 24075228 TI - A phase II randomized vehicle-controlled trial of intradermal allogeneic fibroblasts for recessive dystrophic epidermolysis bullosa. AB - BACKGROUND: Chronic wounds are a major source of morbidity and mortality in generalized severe recessive dystrophic epidermolysis bullosa (RDEB-GS). OBJECTIVE: This was a phase II double-blinded randomized controlled trial of intralesional allogeneic cultured fibroblasts in suspension solution versus suspension solution alone for wound healing in RDEB-GS. METHODS: Adult patients with RDEB-GS were screened for chronic ulcers and reduced collagen VII expression. Up to 6 pairs of symmetric wounds were measured and biopsied at baseline, then randomized to cultured allogeneic fibroblasts in a crystalloid suspension solution with 2% albumin or suspension solution alone. Ulcer size, collagen VII protein and messenger RNA expression, anchoring fibril numbers, morphology, and inflammatory markers were measured at 2 weeks and at 3, 6, and 12 months. RESULTS: All wounds healed significantly more rapidly with fibroblasts and vehicle injections, with an area decrease of 50% by 12 weeks, compared with noninjected wounds. Collagen VII expression increased to a similar degree in both study arms in wounds from 3 of 5 patients. LIMITATIONS: The number of patients with RDEB-GS who met inclusion criteria was a limitation, as was 1 trial center rather than multicenter. CONCLUSIONS: The injection of both allogeneic fibroblasts and suspension solution alone improved wound healing in chronic nonhealing RDEB-GS wounds independently of collagen VII regeneration. This may provide feasible therapy for wound healing in patients with RDEB-GS. PMID- 24075230 TI - Comparison of phenotypes of childhood wheeze and cough in 2 independent cohorts. AB - BACKGROUND: Among children with wheeze and recurrent cough there is great variation in clinical presentation and time course of the disease. We previously distinguished 5 phenotypes of wheeze and cough in early childhood by applying latent class analysis to longitudinal data from a population-based cohort (original cohort). OBJECTIVE: To validate previously identified phenotypes of childhood cough and wheeze in an independent cohort. METHODS: We included 903 children reporting wheeze or recurrent cough from an independent population-based cohort (validation cohort). As in the original cohort, we used latent class analysis to identify phenotypes on the basis of symptoms of wheeze and cough at 2 time points (preschool and school age) and objective measurements of atopy, lung function, and airway responsiveness (school age). Prognostic outcomes (wheeze, bronchodilator use, cough apart from colds) 5 years later were compared across phenotypes. RESULTS: When using a 5-phenotype model, the analysis distinguished 3 phenotypes of wheeze and 2 of cough as in the original cohort. Two phenotypes were closely similar in both cohorts: Atopic persistent wheeze (persistent multiple trigger wheeze and chronic cough, atopy and reduced lung function, poor prognosis) and transient viral wheeze (early-onset transient wheeze with viral triggers, favorable prognosis). The other phenotypes differed more between cohorts. These differences might be explained by differences in age at measurements. CONCLUSIONS: Applying the same method to 2 different cohorts, we consistently identified 2 phenotypes of wheeze (atopic persistent wheeze, transient viral wheeze), suggesting that these represent distinct disease processes. Differences found in other phenotypes suggest that the age when features are assessed is critical and should be considered carefully when defining phenotypes. PMID- 24075229 TI - Validation study of the accuracy of echocardiographic measurements of systemic blood flow volume in newborn infants. AB - BACKGROUND: The echocardiographic assessment of circulatory function in sick newborn infants has the potential to improve patient care. However, measurements are prone to error and have not been sufficiently validated. Phase-contrast magnetic resonance imaging (MRI) provides highly validated measures of blood flow and has recently been applied to the newborn population. The aim of this study was to validate measures of left ventricular output and superior vena caval flow volume in newborn infants. METHODS: Echocardiographic and MRI assessments were performed within 1 working day of each other in a cohort of newborn infants. RESULTS: Examinations were performed in 49 infants with a median corrected gestational age at scan of 34.43 weeks (range, 27.43-40 weeks) and a median weight at scan of 1,880 g (range, 660-3,760 g). Echocardiographic assessment of left ventricular output showed a strong correlation with MRI assessment (R(2) = 0.83; mean bias, -9.6 mL/kg/min; limits of agreement, -79.6 to +60.0 mL/kg/min; repeatability index, 28.2%). Echocardiographic assessment of superior vena caval flow showed a poor correlation with MRI assessment (R(2) = 0.22; mean bias, -13.7 mL/kg/min; limits of agreement, -89.1 to +61.7 mL/kg/min; repeatability index, 68.0%). Calculating superior vena caval flow volume from an axial area measurement and applying a 50% reduction to stroke distance to compensate for overestimation gave a slightly improved correlation with MRI (R(2) = 0.29; mean bias, 2.6 mL/kg/min; limits of agreement, -53.4 to +58.6 mL/kg/min; repeatability index, 54.5%). CONCLUSIONS: Echocardiographic assessment of left ventricular output appears relatively robust in newborn infant. Echocardiographic assessment of superior vena caval flow is of limited accuracy in this population, casting doubt on the utility of the measurement for diagnostic decision making. PMID- 24075231 TI - Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. AB - BACKGROUND: The 3-gene signature of periostin, chloride channel accessory 1 (CLCA1), and Serpin beta2 (SERPINB2) in airway epithelial brushings is used to classify asthma into TH2-high and TH2-low endotypes. Little is known about the utility of gene profiling in sputum as a molecular phenotyping method. OBJECTIVE: We sought to determine whether gene profiling in sputum cells can identify T(H)2 high and T(H)2-low subtypes of asthma. METHODS: In induced sputum cell pellets from 37 asthmatic patients and 15 healthy control subjects, PCR was used to profile gene expression of the epithelial cell signature of IL-13 activation (periostin, CLCA1, and SERPINB2), TH2 genes (IL4, IL5, and IL13), and other genes associated with airway TH2 inflammation. RESULTS: Gene expression levels of CLCA1 and periostin, but not SerpinB2, were significantly higher than normal in sputum cells from asthmatic subjects. Expression levels of IL-4, IL-5, and IL-13 were also significantly increased in asthmatic patients and highly correlated within individual subjects. By combining the expression levels of IL-4, IL-5, and IL-13 in a single quantitative metric ("T(H)2 gene mean"), 26 (70%) of the 37 asthmatic patients had T(H)2-high asthma, which was characterized by more severe measures of asthma and increased blood and sputum eosinophilia. TH2 gene mean values tended to be stable when initial values were very high or very low but fluctuated above or below the T(H)2-high cutoff when initial values were intermediate. CONCLUSION: IL-4, IL-5, and IL-13 transcripts are easily detected in sputum cells from asthmatic patients, and their expression levels can be used to classify asthma into T(H)2-high and T(H)2-low endotypes. PMID- 24075233 TI - Which craniofacial fractures are associated with external auditory canal bleeding? AB - PURPOSE: External auditory canal bleeding (EACB) after facial trauma has been strongly associated with skull base fractures; however, EACB also can occur with other craniofacial fractures. The aim of this study was to analyze the frequency and causes of EACB in different craniofacial fracture types. PATIENTS AND METHODS: The investigators used a retrospective cohort study design and enrolled a sample composed of patients with craniofacial fractures evaluated and treated from April 2006 through December 2011. The predictor variable was fracture type, which was categorized into 4 types: skull base fracture, midface fracture, and mandibular fracture with and without involvement of the condyle. The frequency of EACB among fracture types was compared with SPSS 13.0 (SPSS, Inc, Chicago, IL) and chi(2) test. Computed tomographic (CT) scans were analyzed to determine the cause of EACB. RESULTS: EACB was found in 43 of 573 craniofacial fracture cases, with a frequency of 7.5%. There were 19 EACB sides in 123 skull base fracture cases (15.4%), 26 EACB sides in 150 mandibular fracture cases involving the 196 condyles (13.3%; of these 196 condyles, 92.3% were intracapsular condylar fractures [ICFs]), 2 EACB sides in 150 mandibular fracture cases not involving the condyle (1.3%), and 1 EACB case in 150 midface fracture cases (0.7%). Statistical analysis of EACB frequency for each fracture type showed a significant difference between skull base or mandibular fractures with condylar involvement and midface or mandibular fractures without condylar involvement (P < .05). However, there was no significant difference between skull base and mandibular fractures involving the condyle and midface fracture and mandibular fractures not involving the condyle (P > .05). CONCLUSIONS: EACB is uncommon in craniofacial fractures. The frequency varies significantly based on fracture type. Skull base fracture and mandibular ICF are the 2 main causes of EACB. PMID- 24075234 TI - Osteotomy of the nasal wall using a newly designed piezo scalpel--a cadaver study. AB - PURPOSE: Achieving the desired outcome in rhinoplasty depends on many factors. Osteotomy and adjustment of the lateral nasal wall are important steps that necessitate careful planning and execution. A cadaver study was performed to evaluate the osteotomy result obtained with a newly designed piezoelectric-based scalpel. MATERIALS AND METHODS: Twenty lateral osteotomies of the nasal wall were performed in 10 human cadaver noses. The osteotomies were conducted in 6 female and 4 male cadavers (age range, 65 to 83 yr; mean age, 74.8 yr). A specially designed Piezosurgery-based scalpel was used endonasally to perform the lateral osteotomy. Cutting of the bony nasal wall was performed subperiostally along the planned osteotomy route under tactile control. Digital infracturing was accomplished by applying gentle pressure. After completing the osteotomy, the osteotomy line and nasal mucosa were examined endoscopically. The skin cover was removed to examine the lateral bony nasal wall for the shape and amount of bone fragments, the osteotomy path, and mucosa involvement. RESULTS: Using the Piezosurgery-based scalpel required a learning curve, but the handling was easy. It allowed an exact performance of the osteotomy and caused no mucosal tearing. If excessive force was used, the piezo tip stopped working. There was no comminuted fracture pattern and the lateral nasal wall remained in 1 piece. The duration of the osteotomy was 5 to 10 minutes on each side. CONCLUSION: The piezoelectric-based scalpel is a useful tool, which can be used to perform osteotomy of the nasal wall. In addition, this specifically designed tool tip allows an endonasal approach, is easy to handle, and allows effective irrigation of the osteotomy region. PMID- 24075232 TI - Prostaglandin E2 suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells. AB - BACKGROUND: Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin (PG) E2 or of specific E prostanoid (EP) receptors is not known. OBJECTIVE: Here we tested the role of EP2 signaling in allergic asthma. METHODS: Wild-type (WT) and EP2(-/-) mice were subjected to ovalbumin sensitization and acute airway challenge. The PGE2 analog misoprostol was administered during sensitization in both genotypes. In vitro culture of splenocytes and flow-sorted dendritic cells and T cells defined the mechanism by which EP2 exerted its protective effect. Adoptive transfer of WT and EP2(-/-) CD4 T cells was used to validate the importance of EP2 expression on T cells. RESULTS: Compared with WT mice, EP2(-/-) mice had exaggerated airway inflammation in this model. Splenocytes and lung lymph node cells from sensitized EP2(-/-) mice produced more IL-13 than did WT cells, suggesting increased sensitization. In WT but not EP2(-/-) mice, subcutaneous administration of misoprostol during sensitization inhibited allergic inflammation. PGE2 decreased cytokine production and inhibited signal transducer and activator of transcription 6 phosphorylation by CD3/CD28 stimulated CD4(+) T cells. Coculture of flow cytometry-sorted splenic CD4(+) T cells and CD11c(+) dendritic cells from WT or EP2(-/-) mice suggested that the increased IL-13 production in EP2(-/-) mice was due to the lack of EP2 specifically on T cells. Adoptive transfer of CD4(+) EP2(-/-) T cells caused greater cytokine production in the lungs of WT mice than did transfer of WT CD4(+) T cells. CONCLUSION: We conclude that the PGE2-EP2 axis is an important endogenous brake on allergic airway inflammation and primarily targets T cells and that its agonism represents a potential novel therapeutic approach to asthma. PMID- 24075235 TI - Management of bisphosphonate-related osteonecrosis of the jaw with a platelet rich fibrin membrane: technical report. AB - Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a challenging complication resulting from the long-term application of bisphosphonates. In most cases, BRONJ occurs after a surgical procedure involving the jawbone. Currently, the management of BRONJ remains controversial, and there is no definitive treatment other than palliative methods. Platelet-rich fibrin (PRF) represents a relatively new biotechnology for the stimulation and acceleration of tissue healing and bone regeneration. This technical note describes the total closure of moderate bone exposure in persistent BRONJ in 2 weeks with a double-layer PRF membrane. PRF may stimulate gingival healing and act as a barrier membrane between the alveolar bone and the oral cavity. PRF may offer a fast, easy, and effective alternative method for the closure of bone exposure in BRONJ. PMID- 24075236 TI - Treatment outcomes with the use of maxillomandibular fixation screws in the management of mandible fractures. AB - PURPOSE: The purpose of this prospective randomized study was to assess whether uncomplicated mandible fractures could be treated successfully in an open or closed fashion using maxillomandibular fixation (MMF) screws. MATERIALS AND METHODS: This was a prospective institutional review board-approved study involving 20 adult patients who presented to the university emergency department or oral and maxillofacial surgical clinic with uncomplicated mandible fractures. Patients who met the exclusion criteria consented to enter the study in the open reduction internal fixation (ORIF) or the closed (MMF) study group. Six to 8 MMF screws were used to obtain intermaxillary fixation (IMF) in the 2 groups. Screw failure was documented. All screws were removed at 5 to 6 weeks postoperatively. Insertional torque (IT) was measured at time of screw placement to assess primary stability. Clinical and photographic documentation was performed to assess fracture healing, occlusion, and gingival health. Ten-centimeter visual analog scales were used to assess patient-centered outcomes. Cone-beam computed tomography was performed to assess the long-term effects on the periodontium and roots. A cost comparison was performed to determine whether the use of screws was cost effective compared with arch bars. RESULTS: Fifteen men and 5 women (mean age, 25.2 yr) entered the study. All patients displayed adequate fracture healing based on clinical examination. All patients had acceptable occlusion at 5 to 6 weeks postoperatively. Total screw failure was 27 of 106 screws (25.5%). Forty percent of screws placed in the MMF group failed compared with only 6% in the ORIF group. Gingival health scores were favorable. Factors that had a significant effect on screw failure included a lower IT (P = .002), use in closed (MMF) treatment (P < .001), and use in the posterior jaw (P = .012). Minimal pain was associated with the MMF screws and pre-existing occlusion was re-established based on patients' subjective responses. The MMF group reported a statistically significant lower quality of life (P < .001) compared with the ORIF group. There was only 1 screw site that had a facial cortical bone defect noted at 6-month follow-up CBCT examination. There were no discernible long-term root defects. Cost analysis showed that the use of MMF screws saved around $600 per patient in operating room usage cost alone compared with the estimated use of arch bars. CONCLUSIONS: Uncomplicated mandible fractures were successfully treated using MMF screws in open and closed treatments. However, the utility in closed treatment was decreased because of significant screw failure and patient noncompliance. The screws were well tolerated by the patients. There was minimal long-term damage to the periodontium and dental roots. The cost of screws was more than offset by time savings. PMID- 24075237 TI - What is the role of positron emission tomography in osteonecrosis of the jaws? AB - PURPOSE: Bisphosphonate-related osteonecrosis of the jaw (BP-ONJ) has become an associated side effect of BP therapy and several imaging modalities have been studied to show an ability to detect clinical disease. Because most patients at the authors' university hospital who develop BP-ONJ also undergo concurrent positron emission tomographic (PET) scanning, the authors investigated the utility of PET scans for diagnosis of BP-ONJ. PATIENTS AND METHODS: A retrospective chart review was performed of patients whose PET scans were acquired within 1 year of their BP-ONJ diagnosis (1998 through 2006). BP-ONJ was defined as intraoral exposure of the maxilla or mandible in patients on BPs and not given radiation to that area. This was performed at a university hospital with oncologic patients treated with BPs. All PET scans in this study were secondarily reviewed by a single expert reader for internal consistency (T.B.B.). A detailed timeline of the course of BP-ONJ was constructed by the review of medical records for each patient and the relation of each patient's PET scan results to that patient's BP-ONJ disease was evaluated. Data analysis was a descriptive analysis of PET scan findings in this patient population. RESULTS: Of the 25 patients studied, 5 were excluded for insufficient clinical or radiologic data. Of the 20 remaining patients (16 male, 4 female), 46 PET scans were performed and showed 53 areas of enhancement. Many patients had multiple PET scans performed while experiencing exposed bone, and 5 of these patients had alternating positive and negative scans with exposed bone, resulting in 13 patients with positive enhancement on a scan with exposed bone and 9 patients with no enhancement on a scan with exposed bone. Of the 13 patients with PET enhancement, 4 had signs of clinical infection documented at the time of examination. Sensitivity, specificity, and accuracy of PET scanning for BP-ONJ were 43%, 19%, and 62%, respectively. There were 7 patients with PET scans performed after clinical resolution of their exposed bone and 6 of those had no enhancement. CONCLUSION: The purpose of this study was to report findings on PET scanning for patients with BP-ONJ. Although PET scans are useful in oncology, the present findings do not support their routine use for exclusively diagnosing or following cases of BP-ONJ. PMID- 24075238 TI - Postoperative complications associated with the retromandibular approach: a retrospective analysis of 118 subcondylar fractures. AB - PURPOSE: The purpose of this study was to evaluate the rate of complications associated with the retromandibular approach. MATERIALS AND METHODS: The design of this research was a retrospective case-series study. Included were patients who 1) underwent open reduction and internal fixation of the condylar or subcondylar area through a retromandibular approach and 2) had a complete and available medical chart. Excluded were 1) patients treated endoscopically or by other approaches and 2) patients with preoperative facial paralysis. The data collected were age, gender, medical comorbidities, tobacco use, mechanism of injury, anatomic location, concomitant facial fractures, follow-up time, antibiotic protocol, and complications. RESULTS: One hundred eight patients (81 male; 118 condyles; age, 13 to 82 yr; mean, 35.6 +/- 15.8 yr) met the inclusion criteria. Six patients never returned for postoperative visits and the mean follow-up time for all other patients was 6.5 months (8 days to 5.5 years). Twenty-six cases (22%) of temporary paralysis and 1 case of permanent facial paralysis were noted. Eight patients (6.8%) had persistent partial facial paralysis at their last visit, but all had short postoperative follow-ups. Fourteen cases (11.9%) of infection, 4 salivary fistulas, 2 sialoceles, 1 case of Frey syndrome, and 2 seromas were observed. CONCLUSION: The retromandibular approach is a safe method for the treatment of condylar process fractures and major complications are rare. PMID- 24075239 TI - Nutrition counseling for patients with osteoporosis: a personal approach. AB - Patients are often bombarded with information from the internet, family, friends, and television about what is good and bad for their bones-particularly in the area of diet and nutrition. Although some information is valid and evidence based, much is not. Patients often believe that adequate nutrition alone is enough to improve bone density and decrease fragility fracture risk. Although calcium and vitamin D remain the mainstays of medical nutrition therapy, many patients are not receiving adequate counseling on how to get the right amounts of these 2 nutrients and may not understand that calcium and vitamin D are but 2 of many factors in this multifactorial disease. Clinicians must listen carefully to their patients' concerns, beliefs, and questions and help them develop a personalized plan to achieve their daily calcium and vitamin D intakes. Clinicians must stay apprised of the recent research in nutrition and bone health and evaluate the evidence to adequately educate their patients. PMID- 24075240 TI - A preliminary investigation into the effects of ocular lubricants on higher order aberrations in normal and dry eye subjects. AB - PURPOSE: To study the effects of ocular lubricants on higher order aberrations in normal and self-diagnosed dry eyes. METHODS: Unpreserved hypromellose drops, Tears AgainTM liposome spray and a combination of both were administered to the right eye of 24 normal and 24 dry eye subjects following classification according to a 5 point questionnaire. Total ocular higher order aberrations, coma, spherical aberration and Strehl ratios for higher order aberrations were measured using the Nidek OPD-Scan III (Nidek Technologies, Gamagori, Japan) at baseline, immediately after application and after 60 min. The aberration data were analyzed over a 5mm natural pupil using Zernike polynomials. Each intervention was assessed on a separate day and comfort levels were recorded before and after application. Corneal staining was assessed and product preference recorded after the final measurement for each intervention. RESULTS: Hypromellose drops caused an increase in total higher order aberrations (p=<0.01 in normal and dry eyes) and a reduction in Strehl ratio (normal eyes: p=<0.01, dry eyes p=0.01) immediately after instillation. There were no significant differences between normal and self-diagnosed dry eyes for response to intervention and no improvement in visual quality or reduction in higher order aberrations after 60 min. Differences in comfort levels failed to reach statistical significance. CONCLUSION: Combining treatments does not offer any benefit over individual treatments in self-diagnosed dry eyes and no individual intervention reached statistical significance. Symptomatic subjects with dry eye and no corneal staining reported an improvement in comfort after using lubricants. PMID- 24075241 TI - Percutaneous column fixation and total hip arthroplasty for the treatment of acute acetabular fracture in the elderly. AB - We used our database of primary total hip arthroplasties to identify those patients who had acetabular fractures fixed with percutaneous screws under the same anesthesia as for the arthroplasty procedure. There were 19 patients with the average follow-up of 22 months. Fourteen patients sustained the fracture secondary to a low-energy trauma, while the remaining patients were involved in a high-energy trauma accident. The mean survival time was calculated to be 2.5 +/- 0.6 years for the low-energy group and 4 +/- 1.4 years for the high-energy group. We believe that this unique treatment of acetabular fractures has a role in carefully selected patients and provides the necessary reduction and immediate stability of the fracture needed to ensure adequate fit for the acetabular cup in the subsequent THA. PMID- 24075242 TI - Endocrine monitoring of the ovarian cycle in captive female Amazonian manatees (Trichechus inunguis). AB - The Amazonian manatee (Trichechus inunguis; Mammalia: Sirenia), a threatened aquatic mammal endemic to the Amazon basin, is the only sirenian that lives exclusively in fresh water. Information about the reproductive endocrinology of the Amazonian manatee is scarce; therefore, the aim of this study was to monitor salivary progesterone and estradiol patterns during the ovarian cycle in T. inunguis. Salivary samples were collected daily during a 12-week period of two consecutive years from two captive adult females. The salivary estradiol and progesterone were measured by enzyme immunoassay. The results were analyzed in an iterative process of excluding values that were higher than the mean plus 2 standard deviations until the basal values were determined. The interval between two peaks of salivary estradiol followed by a rise of progesterone was considered as one complete cycle for the calculation of the cycle length. We observed only three complete cycles in all samples analyzed. The cycle length ranged from 42 to 48 days (mean of 44.67 days). We also observed two distinct salivary estradiol peaks during all cycles analyzed, with the first peak occurring before the rise in salivary progesterone and the second occurred followed by a return to basal progesterone levels. This is the first in-depth study of the ovarian cycle in Amazonian manatees. Our results demonstrate that salivary samples can be a useful tool in the endocrine monitoring of this species and suggest that T. inunguis shows a peculiar hormonal pattern during the ovarian cycle, a finding that may have physiological and ecological significance in the reproductive strategy of these animals. PMID- 24075243 TI - Yes, we can define an infant's need from the composition of human milk as long as the breastmilk derives from mothers with healthy lifestyles. PMID- 24075245 TI - Appetite loss may be induced by lower serum ghrelin and higher serum leptin concentrations in subarachnoid hemorrhage patients. AB - BACKGROUND: Patients with aneurysmal subarachnoid hemorrhage (SAH) typically develop appetite loss. However, the mechanisms regulating appetite are not understood. Ghrelin and leptin, both of which signal nutritional status and energy storage levels to the hypothalamus, are essential elements of the appetite system. Thus, the goal of this study was to investigate the relationship between appetite and ghrelin and leptin concentrations in patients with SAH. METHODS: Blood plasma or serum profiles and appetite status were measured in 19 patients with SAH who underwent aneurysmal clipping within 48 hours of SAH onset. Appetite status was measured using dietary oral calorie intake. All outcome variables were measured at an early (day 3) and late (day 8) time point after SAH onset (day 0). RESULTS: Of the 19 patients studied, 6 (31.6%) showed lower dietary oral calorie intake at the late time point than at the early time point. In these patients with appetite loss, plasma hemoglobin (P < 0.02), albumin (P < 0.01), glucose (P < 0.01), plasma insulin (P < 0.04), and serum ghrelin (P < 0.03) concentrations were lower at the late time point than at the early time point. Serum leptin was higher at the late time point than at the early time point (P < 0.02). CONCLUSION: In SAH patients, appetite loss may be induced by lower serum ghrelin and higher serum leptin concentrations resulting from high plasma glucose and insulin levels due to a catecholamine surge following SAH. PMID- 24075246 TI - Railway suicide attempts are associated with amount of sunlight in recent days. AB - BACKGROUND: To assess the relationship between hours of sunlight and railway suicide attempts, 3-7 days before these attempts. METHODS: All railway suicide attempts causing railway suspensions or delays of 30 min or more between 2002 and 2006. We used a linear probability model to assess this relationship. This study was conducted at Tokyo, Kanagawa, and Osaka prefectures in Japan. Data were collected from the railway delay incident database of the Japanese Railway Technical Research Institute and public weather database of the Japan Meteorological Agency. RESULTS: About 971 railway suicides attempts occurred between 2002 and 2006 in Tokyo, Kanagawa, and Osaka. Less sunlight in the 7 days leading up to the railway suicide attempts was associated with a higher proportion of attempts (p=0.0243). Sunlight over the 3 days before an attempt had a similar trend (p=0.0888). No difference was found in sunlight hours between the days with (median: 5.6 [IQR: 1.1-8.8]) and without (median: 5.7 [IQR: 1.0-8.9]) railway suicide attempts in the evening. Finally, there was no apparent correlation between the railway suicide attempts and the monthly average sunlight hours of the attempted month or those of a month before. LIMITATIONS: Railway suicides were not the main suicidal methods in Japan, CONCLUSIONS: We observed an increased proportion of railway suicide attempts after several days without sunlight. Light exposure (blue light or bright white light) in trains may be useful in reducing railway suicides, especially when consecutive days without sunshine are forecasted. PMID- 24075244 TI - Dietary arachidonic acid and docosahexaenoic acid regulate liver fatty acid desaturase (FADS) alternative transcript expression in suckling piglets. AB - Molecular regulation of fatty acid desaturase (Fads) gene expression by dietary arachidonic acid (ARA) and docosahexaenoic acid (DHA) during early post-natal period, when the demand for long chain polyunsaturated fatty acids (LC-PUFA) is very high, has not been well defined. The objective of the current study was to determine regulation of liver Fads1, Fads2 and Fads3 classical (CS) and alternative transcripts (AT) expression by dietary ARA and DHA, within the physiological range present in human breast milk, in suckling piglets. Piglets were fed one of six milk replacer formula diets (formula-reared groups, FR) with varying ARA and DHA content from days 3-28 of age. The ARA/DHA levels of the six formula diets were as follows (% total fatty acid, FA/FA): (A1) 0.1/1.0; (A2) 0.53/1.0; (A3-D3) 0.69/1.0; (A4) 1.1/1.0; (D2) 0.67/0.62; and (D1) 0.66/0.33. The control maternal-reared (MR) group remained with the dam. Fads1 expression was not significantly different between FR and MR groups. Fads2 expression was down regulated significantly in diets with 1:1 ratio of ARA:DHA, compared to MR. Fads2 AT1 expression was highly correlated to Fads2 expression. Fads3 AT7 was the only Fads3 transcript sensitive to dietary LC-PUFA intake and was up-regulated in the formula diets with lowest ARA and DHA contents compared to MR. Thus, the present study provides evidence that the proportion of dietary ARA:DHA is a significant determinant of Fads2 expression and LC-PUFA metabolism during the early postnatal period. Further, the data suggest that Fads3 AT7 may have functional significance when dietary supply of ARA and DHA are low during early development. PMID- 24075247 TI - Two longterm studies of seasonal variation in depressive symptoms among community participants. AB - BACKGROUND: There is evidence that seasonal variation in depressive symptoms is common in the population. However, research is limited by a reliance on longterm retrospective methods. METHODS: Seasonal patterns were tested in two samples of community participants recruited in separate prospective studies in the Midwestern (n=556 males/females) and Pacific Northwestern (n=206 males) United States. Participants completed self-report measures of depressive symptoms 10-19 times from ages 14 to 36 years (n=8316 person observations). These data were compared with local meteorological conditions (e.g., solar radiation) recorded across the 2 weeks prior to each self-report. RESULTS: In within-subjects analyses, participants' depressive symptoms and the probability of clinically significant symptoms varied with the time of year, as hypothesized (highest in the weeks of early Winter; lowest in early Fall). However, effect sizes were modest and were not explained by recent sunlight or other meteorological conditions. LIMITATIONS: Samples were not nationally representative. Participants did not complete retrospective reports of seasonal depression or measures of current vegetative symptoms. CONCLUSIONS: Neither time of the year nor recent seasonally linked meteorological conditions were powerful influences on depressive symptoms experienced by community populations in relevant geographic regions. Prior studies may have overestimated the prevalence and significance of seasonal variation in depressive symptoms for the general population. PMID- 24075252 TI - Towards better end-of-life care: a major opportunity for nurses to contribute to the debate. PMID- 24075253 TI - Biodistribution and radiation dosimetry in humans of [11C]FLB 457, a positron emission tomography ligand for the extrastriatal dopamine D2 receptor. AB - PURPOSE: [(11)C]FLB 457, a radioligand with very high affinity and selectivity for dopamine D2/3 receptors, is used to measure receptor binding in extrastriatal regions showing low density of the receptors. The purpose of this study was to estimate the whole-body biodistribution of radioactivity and the radiation absorbed doses to organs after intravenous injection of [(11)C]FLB 457 in healthy human subjects. METHODS: Whole-body images were acquired for 2 h after an injection of [(11)C]FLB 457 in six healthy humans. Radiation absorbed doses were estimated by the MIRD scheme implemented in OLINDA/EXM 1.1 software. RESULTS: Organs with the longest residence time were the liver, lungs, and brain. The organs with the highest radiation doses were the kidneys, liver, and pancreas. The effective dose delivered by [(11)C]FLB 457 is 5.9 MUSv/MBq, similar to those of other (11)C-labeled tracers. CONCLUSIONS: This effective dose would allow multiple scans in the same individual based on prevailing maximum recommended dose guidelines in the USA and Europe. PMID- 24075254 TI - Postshock mesenteric lymph drainage ameliorates vascular reactivity and calcium sensitivity through RhoA. AB - BACKGROUND: Vascular hyporeactivity plays an important role in the pathogenesis of severe shock. Previous studies have shown that postshock mesenteric lymph (PSML) blockage ameliorates the vascular reactivity and calcium sensitivity, and RhoA is involved in the regulation of vascular reactivity after hemorrhagic shock. Therefore, the present study tested whether small GTPase RhoA mediates the improvement of the vascular reactivity and calcium sensitivity in superior mesenteric artery (SMA) of rats with PSML drainage. MATERIALS AND METHODS: The hemorrhagic shock model (blood pressure to 40 +/- 2 mm Hg) was established, and PSML was drained from immediate hypotension for 3 h, after which SMA was isolated, and the vascular reactivity and calcium sensitivity were tested in the presence of RhoA agonist (U-46619) or inhibitor (C3 transferase). The protein expressions of small GTPase RhoA and phospho-RhoA were also examined in SMA. RESULTS: The hemorrhagic shock resulted in a significant decrease in the SMA reactivity and calcium sensitivity, which was enhanced by the application of U 46619 to the SMA. In contrast, the PSML drainage ameliorated the deleterious effect of the hemorrhagic shock on the SMA. This beneficial effect of the PSML drainage was abolished by C3 transferase. Western blotting revealed that the expressions of the RhoA and phospho-RhoA in SMA tissue obtained from the shock group were significantly decreased, and the PSML drainage markedly enhanced these protein expressions. CONCLUSIONS: RhoA is an important contributor to the PSML drainage-induced amelioration of the vascular reactivity and calcium sensitivity in rats with hemorrhagic shock. PMID- 24075255 TI - A boy with unexplained recurrent abdominal pain. PMID- 24075256 TI - Nurse educators: can we model life/work balance? PMID- 24075257 TI - Developing DNP students as adaptive leaders: a key strategy in transforming health care. AB - The success of graduates with a doctor of nursing practice (DNP) degree in transforming health care will depend significantly on their leadership ability to think strategically, innovate, and engage stakeholders in meaningful system improvement. Known as adaptive work, these graduates will need a portfolio of adaptive leadership skills that prepare them to move health care from a volume driven to value-based system. This article describes development of a core DNP leadership course in a postmaster's point of entry DNP program at an academic health science center school of nursing. The course, designed as DNP students' initial step on their professional development journey to becoming adaptive leaders capable of driving transformative change, created an alternative lens for students to undertake strategic adaptive change initiatives within themselves and their organizations. PMID- 24075258 TI - The academic story: introducing the clinical nurse leader role in a multifacility health care system. AB - Introducing the clinical nurse leader (CNL) role in a multifacility health care system is an exciting but obstacle-filled journey. This story includes facilitating factors, opportunities, and successes plus suggestions for other academic-practice partners considering implementing the CNL role. A sample course sequence with course descriptions is provided. PMID- 24075259 TI - The potential for nurse practitioners in health care reform. AB - In Canada, health care reform is underway to address escalating costs, access and quality of care issues, and existing personnel shortages in various health disciplines. One response of the nursing profession to these stimuli has been the development of the advanced practice nurse, namely, the nurse practitioner (NP). NPs are in an excellent position to address current shortcomings through increasing points of access to the health care system, providing an emphasis on education and disease prevention, and delivering high-quality, cost-effective care in a multitude of practice settings. With an emphasis on the social determinants of health, NPs are in a prime position to provide care to underserved and vulnerable populations across Canada. Despite the potential for NPs to be instrumental in health care reform, there is a lack of support and regulation necessary for their optimal use. Barriers to mobilizing NPs in Canada exist and impede the integration of NPs into the Canadian health care system, which has both quality of care and social justice implications. PMID- 24075260 TI - Graduate nursing faculty workload in the United States. AB - Faculty workload is an ever-present issue in nursing education, but little is known about how workload is managed across institutions. Even less is known about faculty workload in the supervision of research and practice for graduate nursing students. The purpose of this study was to describe workload assignments for graduate nursing faculty supervising both research and advanced clinical nursing students. Using the American Association of Colleges of Nursing's list of schools, we sent 617 e-mails with links to an electronic survey to administrators of colleges of nursing. One hundred sixty (26%) administrators responded. Forty schools reported having a doctor of philosophy program, and 31 administrators answered the question about workload for dissertations, with 20 (65%) giving workload credit. Of the 36 respondents with a doctor of nursing practice (DNP) program, 22 (61%) gave credit for DNP project supervision. Great variability exists among schools of nursing in the United States for the amount of workload given for supervision of graduate student research and practice. PMID- 24075261 TI - Voices of culturally diverse faculty on strategies for facilitating their success in academia. AB - Despite the benefits of culturally diverse faculty (CDF) in nursing education, studies on strategies to help them succeed in academia are lacking. The purposes of this article were to identify factors important for CDF's academic success by first surveying faculty teaching strategies that may be useful for CDF as they work with students, and to explore some factors that may be useful for administrators/leaders to help CDF be successful in academia. Data from 20 participants who met the inclusion criteria were used for data analysis. CDF seem to incorporate cultural issues in their teaching. A summary of teaching strategies and factors that CDF want from administrators/leaders are listed in this study. PMID- 24075262 TI - Faculty perception of bullying in schools of nursing. AB - This article is a report of a study conducted to determine the prevalence of bullying among faculty members in schools or colleges of nursing. The issue of bullying of nursing faculty in the academic setting is of interest in terms of recruitment, retention, job satisfaction, and the overall quality of the work environment. This cross-sectional, descriptive study of faculty in three northeastern states of the United States was carried out in 2010. The Negative Acts Questionnaire-Revised (NAQ-R) was used to survey faculty members in schools of nursing who award a baccalaureate degree (or higher) in nursing. A total of 473 faculty members met the inclusion criteria and responded to the NAQ-R. An iterative exploratory principal components analysis with orthogonal rotation was performed. Of the original 22 items, 13 were retained to measure the experiences of negative acts in the nursing faculty workplaces. The mean total score for the 13-item instrument was 17.90 (SD = 6.07) and ranged from 13 to 56. The resulting components structure produced three clear subscales identifying the experiences of verbal abuse, physical abuse, and devaluing. The revised 13-item instrument had a Cronbach's alpha value of .88. Experiences of bullying were reported in 169 of the 473 (36%) respondents. A significant correlation was found between meeting frequency and the report of bullying (r = .18, P <= .001). Administrators and senior faculty were more likely than expected to be the perpetrators of bullying. If the leaders are identified as bullies, the environment cannot be perceived as supportive and healthy. These unhealthy environments may have serious consequences related to retaining nursing faculty. PMID- 24075263 TI - The perceived needs of nurse clinicians as they move into an adjunct clinical faculty role. AB - The ability to respond to the increasing need for nurses is directly related to the availability of adequate numbers of faculty. One solution that is currently being utilized by many educational institutions is the employment of adjunct clinical faculty. As more and more adjunct clinical faculty are being used to educate nursing students, the manner in which these clinicians are being prepared for an educator role must be examined. Subsequently, the purpose of this study was to determine how adjunct clinical faculty describe their role and the needs they have related to actualizing that role. Naturalistic inquiry methodology was chosen for this study. Twenty-one adjunct clinical faculty were interviewed. Based on the participants' narratives, adjunct clinical faculty is defined as a registered nurse who is a clinical expert and employed part time by an educational institution to coach students in the clinical setting, helping them apply theory to clinical situations. Four themes emerged from an analysis of the data: orientation, role, support, and connection. Participant perspectives revealed that their transition from a nurse clinician into the role of adjunct clinical faculty is one that should be intentionally guided and supported by a mentor, with a focus on the acquisition of educational skills needed for that role. PMID- 24075264 TI - Methods of evaluating an accelerated associate degree registered nurse to baccalaureate degree continuation program. AB - Program evaluation guides curricular decision making and change. This article describes a comprehensive program evaluation of an accelerated associate degree to baccalaureate continuation program and includes some findings and lessons learned. Educators need to be responsible and accountable for the curricular changes that they make and assure that rigor is maintained and essentials are met. The use of comprehensive program evaluation adds significant value and richness of data because use of multiple study methods leads to data from multiple vantage points. Although a comprehensive program evaluation can be time consuming, not all of the methods described in this article may be required. Using the matrix provided, the reader may choose to carry out 1 or 2 of the methods described here. PMID- 24075265 TI - Second-degree bachelor of science in nursing students' preconceived attitudes toward the homeless and poor: a pilot study. AB - The current economic climate of the United States has contributed to the crisis in health care delivery services. As a result, an increasing number of individuals present as poor and vulnerable. Currently, poverty rates in the United States are climbing, with literature clearly reflecting an association between poverty and ill health. With a number of economic barriers to health care, it has been suggested that health care providers' attitudes and subtle prejudices have also contributed to access. These preconceived negative attitudes can shame and embarrass vulnerable, homeless, immigrant, and poor individuals from attempting to access care. This research attempted to identify preconceived attitudes that second-degree baccalaureate nursing students possess prior to clinical exposure to poor and homeless populations through qualitative and quantitative investigative methods. Senior-level community health students preparing to deliver health care at a suburban homeless day shelter were asked to describe their experiences and opinions relative to homeless and poor persons before and after their actual contact with this population. Collected data suggest that there are subtle stereotyping and negative attitudes regarding the plight of overtly impoverished individuals before rendering care. After an 8-hour clinical experience with the aforementioned population, attitudes toward the vulnerable slightly improved, suggesting that clinical and didactic exposure to the plight of poor populations may assist to sensitize student nurses to exude compassion through a holistic therapeutic nurse-client relationship. PMID- 24075266 TI - Status limbo: analysis of nurse faculty member reports of administrator response to workplace bullying complaints. AB - Increasing concern about bullying among adults in workplaces is notable internationally. Unlike blatant physical bullying, workplace bullying often involves bullies' dismissive, demeaning, and typically surreptitious, one-on-one communications with their intended victims. These communications challenge recognition when they are examined beyond the interpersonal margins of the bully victim dyad. Thus, they tend to elude formal, administrative reproach, despite the negative, long-term outcomes they herald for workplace employees--those immediately involved as victims and those who are bystanders--and for employing organizations and the consumers they serve. This article offers a hermeneutic analysis of workplace bullying victims' narrative reports of administrator responses to their complaints of having been bullied at work. Analysis demonstrated respondent perceptions of the variability and unevenness of administrative responses to their reports and, more broadly, respondents' collective sense of administrative abandonment. That sense is characterized in this report as status limbo, a term employed by Facebook users to represent a state of perceived neglect and oblivion. PMID- 24075267 TI - An integrative review of student evaluations of teaching: implications for evaluation of nursing faculty. AB - Student evaluations of teaching often play an important role in the promotion and tenure of faculty. Many of the instruments in use within the university setting are self-developed and have not undergone psychometric testing. More specifically, nursing education has many unique challenges, yet the effectiveness of student evaluations of teaching in nursing is understudied. The purposes of this integrative review were to review the current research literature on the design and psychometric testing of teaching evaluation scales, to synthesize the results, and to propose implications specific to nursing programs that are evidence based and will provide guidance on faculty teaching evaluations. A systematic literature review was conducted using Cooper, H. (1998). Synthesizing research: A guide for literature review (3rd ed.). Thousand Oaks, CA: Sage Publications methodology. Data analysis led to the identification of 6 themes: faculty characteristics and perceptions, student characteristics and perceptions, course characteristics, on-line versus paper student evaluations, reliability and validity, and development of new instruments. This literature review provides the context in which to interpret student evaluations of teaching and discusses implications for practice. PMID- 24075268 TI - Mentoring relationships and the levels of role conflict and role ambiguity experienced by novice nursing faculty. AB - This study explored the effect of mentoring on the levels of role conflict and role ambiguity experienced by novice nursing faculty related to their transitions into academe using a descriptive, comparative design. It also measured the relationship between the quality of mentoring experiences of novice nursing faculty and their levels of role conflict and role ambiguity using a correlational design. P. Benner's (1984) novice to expert model was utilized as a framework for successful role transition. J. R. Rizzo, R. J. House, and S. I. Lirtzman's (1970) role conflict and role ambiguity scale was used to measure the levels of role conflict and role ambiguity experienced by novice nursing faculty. Results indicate that participants (n = 224) who were mentored have significantly lower levels of role conflict (M = 3.57) and role ambiguity (M = 3.02) than those who were not mentored (M = 4.62 and M = 3.90, respectively). Also significant, the higher the participants' reported levels of quality of mentoring experiences were, the lower their levels of role conflict and role ambiguity were. The results of this study indicate that mentoring eases the transition of novice nursing faculty from practice into academe by decreasing the degree of role ambiguity and role conflict that they experience. PMID- 24075269 TI - Empowering nursing preceptors to mentoring undergraduate senior students in acute care settings. AB - Nurse preceptors play an important role in the transition of nursing students from classroom to clinical practice not only in the United States but also internationally. However, many preceptors feel a lack of confidence in their role as mentors to nursing students rather than experienced nurses because of inadequate preparation or formal training. A study looking at the educational needs of nurse preceptors would be invaluable to academic educators because they choose strategies and develop content for a handbook to serve as a quick reference. Thus, the mentorship experience for preceptors would be enhanced by incorporating the needs and preferences of the preceptors into their training and resource materials. The purposes of this study were to identify the needs of the nurses who precept students rather than nurses who mentor other nurses and to evaluate if the current handbook was a useful reference for preceptors during a practicum in acute care settings. METHOD: A multiprocedural mixed method study was used. Data were collected through a questionnaire that was adapted with the permission of the author. Descriptive statistics and a chi-square test were used to compare differences in the means. The preceptorship handbook helped preceptors mentor undergraduate senior nursing students. In addition, the currently developed preceptorship handbook was recognized as a useful reference in mentoring nursing students by 100% of the participants. PMID- 24075270 TI - Oncology scan--intermittent androgen deprivation and the randomized evidence. PMID- 24075271 TI - Total thyroidectomy for Graves' disease: compliance with American Thyroid Association guidelines may not always be necessary. AB - BACKGROUND: Total thyroidectomy (TT) is the preferred operative approach to Graves' disease. Current guidelines of the American Thyroid Association call for the administration of potassium iodide (KI) and achievement of euthyroid state before operation. Small numbers and a mixture of operative approaches spanning several decades hinder previous operative series. We present the outcomes for TT at a single high-volume center. METHODS: A retrospective cohort study was conducted on 165 patients undergoing TT for Graves' disease from July 2007 to May 2012. RESULTS: Mean age was 43 years (range, 17-78), and 128 patients (78%) were female. A total of 95% of patients were on methimazole or propylthiouracil, and 42% remained hyperthyroid at time of TT. Only 3 (2%) patients received KI. Mean operative time was 132 minutes (range, 59-271). Mean gland size and blood loss were 41 g (range, 8-180) and 55 mL (range, 10-1050), respectively. No patient developed thyroid storm. Median follow-up was 7.5 months. Temporary and permanent hypocalcemia developed in 51 (31%) and 2 patients (1.2%), respectively. Temporary and permanent recurrent laryngeal nerve paresis occurred in 12 (7%) and one (0.6%) patient, respectively. Sixty-one (37%) patients experienced at least one complication. On multivariate analysis, patient age younger than 45 years (odds ratio 2.93, 95% confidence interval 1.39-6.19) and obesity (odds ratio 2.11, 95% confidence interval 1.00-4.43) were associated with the occurrence of complications. CONCLUSION: This high-volume surgeon experience demonstrates no appreciable detriment to patient outcomes when recommendations of the American Thyroid Association for routine use of KI and euthyroid state before thyroidectomy are not met. Transient hypocalcemia and hoarseness are frequent complications of TT for Graves' disease, resolving within 6 months in most patients. Age younger than 45 years and obesity are risk factors for postoperative complications. PMID- 24075272 TI - Predicting the need for urgent intubation in a surgical/trauma intensive care unit. AB - BACKGROUND: Analysis and modeling of data monitoring vital signs and waveforms in patients in a surgical/trauma intensive care unit (STICU) may allow for early identification and treatment of patients with evolving respiratory failure. METHODS: Between February 2011 and March 2012, data of vital signs and waveforms for STICU patients were collected. Every-15-minute calculations (n = 172,326) of means and standard deviations of heart rate (HR), respiratory rate (RR), pulse oxygen saturation (SpO2), cross-correlation coefficients, and cross-sample entropy for HR-RR, RR-SpO2, and HR-SpO2, and cardiorespiratory coupling were calculated. Urgent intubations were recorded. Univariate analyses were performed for the periods <24 and >=24 hours before intubation. Multivariate predictive models for the risk of unplanned intubation were developed and validated internally by subsequent sample and bootstrapping techniques. RESULTS: Fifty unplanned intubations (41 patients) were identified from 798 STICU patients. The optimal multivariate predictive model (HR, RR, and SpO2 means, and RR-SpO2 correlation coefficient) had a receiving operating characteristic (ROC) area of 0.770 (95% confidence interval [CI], 0.712-0.841). For this model, relative risks of intubation in the next 24 hours for the lowest and highest quintiles were 0.20 and 2.95, respectively (15-fold increase, baseline risk 1.46%). Adding age and days since previous extubation to this model increased ROC area to 0.865 (95 % CI, 0.821-0.910). CONCLUSION: Among STICU patients, a multivariate model predicted increases in risk of intubation in the following 24 hours based on vital sign data available currently on bedside monitors. Further refinement could allow for earlier detection of respiratory decompensation and intervention to decrease preventable morbidity and mortality in surgical/trauma patients. PMID- 24075274 TI - A prospective randomized controlled trial of hemostasis with a bipolar sealer during hepatic transection for liver resection. AB - BACKGROUND: Excessive intraoperative blood loss and the possible requirement for blood transfusion are major problems in hepatic resection for liver tumors. The decrease of blood loss is a goal in liver surgery, and several technical developments have been introduced for this purpose. The aim of this prospective randomized study was to compare the use of the Cavitron Ultrasonic Surgical Aspirator (CUSA) with a radiofrequency-based bipolar hemostatic sealer versus CUSA with standard bipolar cautery (BC) in patients undergoing hepatic resection. METHODS: One hundred nine patients with liver tumors were randomized to undergo hepatic transection via CUSA with a bipolar sealer (Aquamantys 2.3 Bipolar Sealer; n = 55) or BC (n = 54). Blood loss during parenchymal transection and speed of transection were the primary end points, whereas the degree of postoperative liver injury and morbidity were secondary end points. RESULTS: Compared with the BC group, the bipolar sealer showed lesser blood loss during transection and blood loss divided by resection area (P = .0079 and .0008, respectively), shorter transection time (P = .0025), faster speed of transection (P < .0001), and fewer ties and ties divided by resection area required during transection (P < .0001). CONCLUSION: CUSA with a bipolar sealer is superior to CUSA with standard BC for various hepatectomy in terms of less blood loss and faster speed of transection, with no increase in morbidity. PMID- 24075273 TI - Is the negative prognostic impact of signet ring cell histology maintained in early gastric adenocarcinoma? AB - BACKGROUND: Although the signet ring cell histologic subtype (SRC) is an independent predictor of poor prognosis in advanced gastric adenocarcinomas (GA), its prognostic value in early GA remains highly controversial. The aim of the study was to evaluate the prognostic impact of SRC in mucosal and submucosal GAs. METHODS: Based on a multicenter cohort of 3,010 patients operated on for GA between January 1997 and January 2010, patients with pTis or pT1 tumors were extracted and analyzed comparatively between the SRC and non-SRC groups. The primary objective was to compare the 5-year survival rate between groups. RESULTS: Among 421 patients with a pTis or pT1 tumor, 104 (25%) were SRC and 317 (75%) were non-SRC. Demographic variables were comparable between groups, except median age, which was less in the SRC group (59.6 vs 68.8 years; P < .001). Submucosal involvement was more frequent in the SRC group (94% vs 85%; P = .043), whereas lymph node involvement and number of invaded nodes were comparable between the 2 groups. When comparing SRC and non-SRC, recurrence rates (6% vs 9%; P = .223) and sites of recurrence were similar. The 5-year overall survival benefit in SRC patients (85% vs 76%, respectively; P = .035), was not evident when considering exclusively disease-specific survival or in multivariable analysis. CONCLUSION: Contrary to more advanced GA, SRC morphologic subtype is not a negative prognostic factor in early GA. Better survival identified in some reports may be related to the younger age in SRC patients. PMID- 24075275 TI - What provider volumes and characteristics are appropriate for gastric cancer resection? Results of an international RAND/UCLA expert panel. AB - BACKGROUND: A relationship between higher volume providers and improved outcomes has been suggested by some studies and has been used to construct guidelines for many diseases. For gastric cancer (GC), however, optimal volume cutoffs are not clear. METHODS: A multidisciplinary expert panel of 16 physicians from 6 countries scored 120 scenarios regarding provider characteristics for gastric resections for GC. Appropriateness of scenarios was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores from 1 to 3 were considered inappropriate, 4 to 6 uncertain, and 7 to 9 appropriate. Agreement was reached when 12 of 16 panelists scored the statement similarly. Appropriate scenarios agreed on were scored subsequently for necessity. RESULTS: Surgeon and hospital practice volume scenarios were evaluated. The panel felt it was inappropriate for surgeons doing <=2 GC cases per year to perform a multivisceral resection (MVR), D2 lymphadenectomy (D2-LND), or laparoscopic total gastrectomy, and <=6 GC cases per year for an MVR involving a pancreatoduodenectomy (MVR-PD), or endoscopic mucosal resections (EMR). It was considered appropriate for surgeons doing >=11 GC cases per year to perform open gastrectomy or D2-LND, and >=20 GC cases per year for any MVR, laparoscopic gastrectomy, or EMR. For hospitals, it was considered inappropriate for hospitals managing <=4 GC cases per year to perform D2-LND or laparoscopic total gastrectomy, and <=10 GC cases per year, for MVR-PD or EMR. Hospital volumes >=21 cases per year was considered appropriate for any GC procedure. It was inappropriate for an MVR to be performed in a hospital without interventional radiology services and for a MVR-PD in a hospital with no level I intensive care unit. CONCLUSION: Appropriate and inappropriate provider volumes for a variety of gastric procedures have been defined by an international expert panel. PMID- 24075276 TI - Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer. AB - BACKGROUND: Pancreatic cancer has a dismal prognosis that is attributed to common local invasiveness and metastasis. Epithelial-to-mesenchymal transition (EMT) plays an important role in cancer invasion and metastasis and is associated with early dissemination. The aim of this study was to evaluate the association between EMT and the prognoses for patients with pancreatic cancer. METHODS: Immunohistochemistry of E-cadherin and vimentin was performed on surgical specimens from 174 patients who underwent resection of their pancreatic cancers. Tumoral stainings of E-cadherin and vimentin were graded, and EMT statuses were determined by calculating the ratio of vimentin to E-cadherin, whereby patients were categorized into 3 groups: epithelial, intermediate, and mesenchymal. The correlations between EMT statuses and clinicopathologic factors and prognoses were analyzed. RESULTS: There was a significant correlation between EMT status and CA19-9 levels (P = .020); peritoneal washing cytology (P = .025); portal vein invasion (P = .038); and lymph node metastasis (P = .030). The median survival for patients with epithelial tumors was 40.2 months as compared to 13.7 months for patients with mesenchymal tumors. Multivariate analysis demonstrated that perineural invasion (P = .024); lymph node metastasis (P = .033); and EMT status (P < .0001) were significant prognostic factors. It is interesting that adjuvant chemotherapy (gemcitabine and/or S-1) improved the median survival time from 10.8 to 16.1 months in patients with mesenchymal tumors (P = .002); however, no significant difference was seen in patients with epithelial tumors. CONCLUSION: EMT status is an important prognostic factor for pancreatic cancer and is associated with portal vein invasion and lymph node metastasis. PMID- 24075277 TI - Detecting postoperative hemorrhage or hematoma from administrative data: the performance of the AHRQ Patient Safety Indicator. AB - BACKGROUND: Patient Safety Indicator (PSI) 9, "postoperative hemorrhage or hematoma" (PHH), of the US Agency for Healthcare Research and Quality has been considered for public quality of care reporting. We sought to evaluate its performance in detecting true complications. METHODS: We conducted a retrospective, cross-sectional study of hospitalizations that met PSI 9 eligibility criteria. We sampled records flagged positive and negative by PSI 9 from a diverse set of 31 hospitals between February 2006, and June 2009. Trained abstractors reviewed medical records using standard instruments. We determined the sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values of the indicator. RESULTS: Of 181 analyzable records flagged by PSI 9, 168 (93%; weighted PPV, 95% [95% confidence interval (CI), 90-98%]) involved an accurately coded event, but only 126 (70%; weighted PPV, 78% [95% CI, 58-90%]) represented true PHH. Thirty-two false positives involved only intraoperative hemorrhage. Among true positives, hypotension occurred in 28% and death attributed to the PHH in 4%. Thirty-two of 281 records flagged negative by PSI 9 (but enriched with questionably negative records) represented true PHH. The indicator's sensitivity was 42% (95% CI, 23-64%), specificity 99.9% (95% CI, 99.8 100%), and NPV 99.7% (95% CI, 99.0-99.9%). Modifying the indicator to include additional procedure codes improved both sensitivity (85% [95% CI, 67-94%]) and PPV (76% [95% CI, 60-88%]). CONCLUSION: PSI 9 holds promise in detecting serious, possibly preventable complications. The indicator might be improved by specification of the 998.11 hemorrhage code to exclude purely intraoperative events and addition of procedure codes to the indicator's numerator criteria. PMID- 24075278 TI - Adhesion barriers for abdominal surgery: a sticky problem. PMID- 24075279 TI - Benefits and harms of adhesion barriers for abdominal surgery: a systematic review and meta-analysis. AB - BACKGROUND: Formation of adhesions after peritoneal surgery results in high morbidity. Barriers to prevent adhesion are seldom applied, despite their ability to reduce the severity of adhesion formation. We evaluated the benefits and harms of four adhesion barriers that have been approved for clinical use. METHODS: In this systematic review and meta-analysis, we searched PubMed, CENTRAL, and Embase for randomised clinical trials assessing use of oxidised regenerated cellulose, hyaluronate carboxymethylcellulose, icodextrin, or polyethylene glycol in abdominal surgery. Two researchers independently identified reports and extracted data. We compared use of a barrier with no barrier for nine predefined outcomes, graded for clinical relevance. The primary outcome was reoperation for adhesive small bowel obstruction. We assessed systematic error, random error, and design error with the error matrix approach. This study is registered with PROSPERO, number CRD42012003321. FINDINGS: Our search returned 1840 results, from which 28 trials (5191 patients) were included in our meta-analysis. The risks of systematic and random errors were low. No trials reported data for the effect of oxidised regenerated cellulose or polyethylene glycol on reoperations for adhesive small bowel obstruction. Oxidised regenerated cellulose reduced the incidence of adhesions (relative risk [RR] 0.51, 95% CI 0.31-0.86). Some evidence suggests that hyaluronate carboxymethylcellulose reduces the incidence of reoperations for adhesive small bowel obstruction (RR 0.49, 95% CI 0.28-0.88). For icodextrin, reoperation for adhesive small bowel obstruction did not differ significantly between groups (RR 0.33, 95% CI 0.03-3.11). No barriers were associated with an increase in serious adverse events. INTERPRETATION: Oxidised regenerated cellulose and hyaluronate carboxymethylcellulose can safely reduce clinically relevant consequences of adhesions. FUNDING: None. PMID- 24075280 TI - Identification of concomitant ruptured plaque and intracoronary thrombus by optical coherence tomography. PMID- 24075281 TI - Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. AB - The management of individual patients requiring anthracyclines remains challenging because uncertainty persists on predictors of cardiotoxicity. We aimed to perform a systematic review and meta-analysis on incidence and predictors of anthracycline chemotherapy in patients with cancer. Databases were searched for pertinent studies. Meta-analytic pooling with random-effects methods was performed for incidence estimates, while relying on descriptive statistics for prevalence and strength of association of predictors. From 16,054 retrieved citations, 18 studies reporting on 49,017 patients with cancer were included, with 22,815 treated with anthracyclines. After a median follow-up of 9 years, clinically overt cardiotoxicity occurred in 6% (95% confidence interval 3% to 9%), whereas subclinical cardiotoxicity developed in 18% (95% confidence interval 12% to 24%). Appraisal of independent risk factors of cardiotoxicity showed that cumulative anthracycline dose was most consistently reported as an accurate and robust predictor of cardiotoxicity, with an acceptable prognostic role also for chest radiotherapy, African-American ethnicity, very young or very old age, diabetes, hypertension, very high or very low body weight, or severe co morbidities. In conclusion, despite ongoing refinements in chemotherapy regimens, anthracyclines still pose a significant risk of cardiotoxicity, especially in those requiring a high cumulative dose or chest radiotherapy. PMID- 24075282 TI - Risk factors and outcomes associated with the development of myocardial ischemic events in patients who receive cardiac resynchronization therapy. AB - There are limited data regarding risk factors for the development of ischemic events (IEs) among patients with ischemic cardiomyopathy (IC) who receive cardiac resynchronization therapy with a defibrillator (CRT-D) and their effect on the efficacy of the device. The present study population comprised 1,045 patients with IC enrolled in the Multicenter Automatic Defibrillator Implantation Trial Cardiac Resynchronization Therapy. We used multivariate Cox proportional hazards regression modeling to identify risk factors for the development of IE (comprising hospitalization for acute coronary syndromes and/or coronary interventions during the trial) among study patients. Time-dependent analysis was performed to identify the effect of IE on the risk for subsequent heart failure (HF) or death in CRT-D recipients. Independent predictors for the development of IE among study patients included previous revascularization (coronary artery bypass surgery: hazard ratio [HR] 1.88, p = 0.003; percutaneous coronary intervention: HR 3.21, p <0.001) and increased systolic blood pressure (HR 1.67, p = 0.02), whereas a left bundle branch block pattern on the baseline electrocardiogram was associated with reduced risk for IE (HR 0.62, p = 0.02). Treatment with CRT-D did not have a significant effect on IE risk compared with defibrillator-only therapy (HR 0.87, p = 0.51). Time-dependent analysis showed that the development of IEs among CRT-D recipients was associated with more than twofold (p = 0.01) increased risk for subsequent heart failure or death. In conclusion, our data suggest that treatment with CRT-D does not reduce the risk of IE in patients with IC and that the benefit of CRT-D is attenuated after the development of IEs in this population. PMID- 24075283 TI - Hemodynamic phenotype of the failing Fontan in an adult population. AB - Fontan failure can occur even with normal systolic ventricular function and often in the context of significant liver disease. We hypothesized that Fontan failure is hemodynamically distinct from traditional heart failure and characterized by low systemic vascular resistance (SVR) index and preserved cardiac index. Twenty seven symptomatic adult Fontan (SAF) patients who underwent catheterization from 2001 to 2011 constituted our study group. Fifty-four predominantly asymptomatic pediatric Fontan (PF) patients who underwent catheterization during the same period were randomly selected to perform a control:case cohort analysis. Clinical comparisons were made between the 2 groups. The adults were more symptomatic than the PF cohort (New York Heart Association classes I and II or III and IV: 48% or 52% [SAF] vs 94% or 6% [PF], respectively, p <0.01). SAF versus PF mean catheterization findings were central venous pressure 18 +/- 6 versus 14 +/- 3 mm Hg (p <0.01), SVR index 1,680 +/- 368 versus 1,960 +/- 550 dyn s/cm(5)/m(2) (p = 0.02), and cardiac index 2.7 +/- 0.8 versus 2.8 +/- 0.7 L/min/m(2) (p = 0.25). By imaging, the SAF cohort demonstrated a greater incidence of abnormal liver texture changes (96% vs 75%, p = 0.04) and nodularity (77% vs 42%, p = 0.02). In conclusion, adult patients with failing Fontan circulation had a lower SVR index and similar cardiac index compared with the pediatric cohort. Liver disease in the adults was more advanced. Our data suggest that Fontan failure is a distinct circulatory derangement with hemodynamic features similar to portal hypertension, albeit with limited ability to augment cardiac output. PMID- 24075284 TI - Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors. AB - Dabigatran has been associated with greater risk of myocardial infarction (MI) than warfarin. It is unknown whether the increased risk is unique to dabigatran, an adverse effect shared by other oral direct thrombin inhibitors (DTIs), or the result of a protective effect of warfarin against MI. To address these questions, we systematically searched MEDLINE and performed a meta-analysis on randomized trials that compared oral DTIs with warfarin for any indication with end point of MIs after randomization. We furthermore performed a secondary meta-analysis on atrial fibrillation stroke prevention trials with alternative anticoagulants compared with warfarin with end point of MIs after randomization. A total of 11 trials (39,357 patients) that compared warfarin to DTIs (dabigatran, ximelagatran, and AZD0837) were identified. In these trials, patients treated with oral DTIs were more likely to experience an MI than their counterparts treated with warfarin (285 of 23,333 vs 133 of 16,024, odds ratio 1.35, 95% confidence interval 1.10 to 1.66, p = 0.005). For secondary analysis, 8 studies (69,615 patients) were identified that compared warfarin with alternative anticoagulant including factor Xa inhibitors, DTIs, aspirin, and clopidogrel. There was no significant advantage in the rate of MIs with the use of warfarin versus comparators (odds ratio 1.06, 95% confidence interval 0.85 to 1.34, p = 0.59). In conclusion, our data suggest that oral DTIs were associated with increased risk of MI. This increased risk appears to be a class effect of these agents, not a specific phenomenon unique to dabigatran or protective effect of warfarin. These findings support the need for enhanced postmarket surveillance of oral DTIs and other novel agents. PMID- 24075285 TI - Relation of electrocardiographic changes in pulmonary embolism to right ventricular enlargement. AB - The electrocardiographic (ECG) findings in patients with pulmonary embolism (PE) and no previous cardiopulmonary disease are well documented; however, investigation of the relation of ECG abnormalities to right ventricular (RV) enlargement has been limited. The purpose of the present investigation was to assess further the relation of ECG changes in acute PE to RV cavity enlargement (dilation). The records of patients hospitalized from January 2009 to December 2012 with acute PE and no previous cardiopulmonary disease were reviewed. A total of 289 patients were included. RV cavity enlargement was present in 141 patients (49%). Normal ECG findings were less prevalent in patients with PE and RV enlargement than those with PE and no RV enlargement (35 of 141 [25%] vs 56 of 148 [38%]; p = 0.02). One or more of the traditional ECG manifestations of acute cor pulmonale (S1Q3T3, complete right bundle branch block, P pulmonale, or right axis deviation) was found in 18 of 141 patients (13%) with RV enlargement and 13 of 148 (8.8%) with a normal size RV (p = NS). None of the ECG abnormalities was sensitive for RV enlargement. The specificity of P and QRS abnormalities was high. The positive predictive values were <=83% or had wide 95% confidence intervals. The negative predictive values ranged from 50% to 61%. In conclusion, ECG findings were not useful for the detection or exclusion of RV cavity enlargement in patients with acute PE. PMID- 24075286 TI - Right ventricular dilatation on bedside echocardiography performed by emergency physicians aids in the diagnosis of pulmonary embolism. AB - STUDY OBJECTIVE: The objective of this study was to determine the diagnostic performance of right ventricular dilatation identified by emergency physicians on bedside echocardiography in patients with a suspected or confirmed pulmonary embolism. The secondary objective included an exploratory analysis of the predictive value of a subgroup of findings associated with advanced right ventricular dysfunction (right ventricular hypokinesis, paradoxical septal motion, McConnell's sign). METHODS: This was a prospective observational study using a convenience sample of patients with suspected (moderate to high pretest probability) or confirmed pulmonary embolism. Participants had bedside echocardiography evaluating for right ventricular dilatation (defined as right ventricular to left ventricular ratio greater than 1:1) and right ventricular dysfunction (right ventricular hypokinesis, paradoxical septal motion, or McConnell's sign). The patient's medical records were reviewed for the final reading on all imaging, disposition, hospital length of stay, 30-day inhospital mortality, and discharge diagnosis. RESULTS: Thirty of 146 patients had a pulmonary embolism. Right ventricular dilatation on echocardiography had a sensitivity of 50% (95% confidence interval [CI] 32% to 68%), a specificity of 98% (95% CI 95% to 100%), a positive predictive value of 88% (95% CI 66% to 100%), and a negative predictive value of 88% (95% CI 83% to 94%). Positive and negative likelihood ratios were determined to be 29 (95% CI 6.1% to 64%) and 0.51 (95% CI 0.4% to 0.7%), respectively. Ten of 11 patients with right ventricular hypokinesis had a pulmonary embolism. All 6 patients with McConnell's sign and all 8 patients with paradoxical septal motion had a diagnosis of pulmonary embolism. There was a 96% observed agreement between coinvestigators and principal investigator interpretation of images obtained and recorded. CONCLUSION: Right ventricular dilatation and right ventricular dysfunction identified on emergency physician performed echocardiography were found to be highly specific for pulmonary embolism but had poor sensitivity. Bedside echocardiography is a useful tool that can be incorporated into the algorithm of patients with a moderate to high pretest probability of pulmonary embolism. PMID- 24075287 TI - Design and evaluation of small, linear QWERTY keyboards. AB - Miniature keyboard design is motivated by the need for smaller mobile devices with maximum user display area. Thus, this study developed four miniature keyboard designs which varied from conventional keyboard design in terms of their configuration and layout. The purpose of this study was to evaluate the input speed, accuracy, comfort, likability and learnability of four miniature keyboards. Sixteen fast typists and 16 slow typists were recruited to use these four miniature keyboards. The results showed that the rectangular-shaped keycaps of 3 letters with separated keycaps of numerals obtained the best proficiency speed, highest comfort and greatest user acceptance among the four keyboards. Moreover, the keyboards with square-shaped keycaps had better input accuracy compared to rectangular-shaped keycaps. Finally, the proposed keyboards were smaller than current keyboards, and the performance for all of the small keyboards was worse than that of the conventional keyboard. PMID- 24075288 TI - Whole-body vibration transmissibility in supine humans: effects of board litter and neck collar. AB - Whole-body vibration has been identified as a stressor to supine patients during medical transportation. The transmissibility between the input platform acceleration and the output acceleration of the head, sternum, pelvis, head sternum, and pelvis-sternum of eight supine subjects were investigated. Vibration files were utilized in the fore-aft, lateral, and vertical directions. The power spectral density across the bandwidth of 0.5-20 Hz was approximately flat for each file. A comparison between a baseline rigid-support and a support with a long spinal board strapped to a litter has shown that the latter has considerable effects on the transmitted motion in all directions with a double magnification in the vertical direction around 5 Hz. The results also showed that the neck collar has increased the relative head-sternum flexion-extension because of the input fore-aft vibration, but reduced the head-sternum extension-compression due to the input vertical vibration. PMID- 24075289 TI - Upper extremity hemodynamics and sensation with backpack loads. AB - Heavy backpacks are often used in extreme environments, for example by military during combat, therefore completion of tasks quickly and efficiently is of operational relevance. The purpose of this study was to quantify hemodynamic parameters (brachial artery Doppler and microvascular flow by photoplethysmography; tissue oxygenation by near-infrared spectroscopy; arterial oxygen saturation by pulse oximeter) and sensation in upper extremities and hands (Semmes-Weinstein monofilament test and 2-point discrimination test) while wearing a loaded backpack (12 kg) in healthy adults for 10 min. All values were compared to baseline before wearing a backpack. Moderate weight loaded backpack loads significantly decreased upper extremity sensation as well as all macrovascular and microvascular hemodynamic values. Decreased macrovascular and microvascular hemodynamics may produce neurological dysfunction and consequently, probably affect fine motor control of the hands. PMID- 24075290 TI - Recurrent hiatal hernia repair after sleeve gastrectomy. PMID- 24075291 TI - The Quick Mild Cognitive Impairment screen correlated with the Standardized Alzheimer's Disease Assessment Scale-cognitive section in clinical trials. AB - OBJECTIVES: The Alzheimer's Disease Assessment Scale-cognitive section and its standardized version (SADAS-cog) are the current standard for assessing cognitive outcomes in clinical trials of dementia. This study compares a shorter cognitive instrument, the Quick Mild Cognitive Impairment (Qmci) screen, with the SADAS-cog as outcome measures in clinical trials. STUDY DESIGN AND SETTING: The SADAS-cog, Qmci, Clinical Dementia Rating (CDR) scale, and the Lawton-Brady activities of daily living (ADL) scale were assessed at multiple time points, over 1 year in a multicenter randomized clinical trial of 406 patients with mild to moderate Alzheimer's dementia. Correlations were estimated using regression at each time point, all time points, and mean values across time. Responsiveness was assessed using the standardized response mean (SRM). RESULTS: Regression for pooled time points showed strong and significant correlation between the SADAS-cog and Qmci (r = -0.75, P < 0.001). Correlations remained strong for mean values across time and at each time point. The SADAS-cog and Qmci also correlated with CDR and ADL scores. There was no difference in SRMs between the SADAS-cog and Qmci [t(357) = 0.32, P = 0.75]. CONCLUSION: The Qmci correlated strongly with the SADAS-cog and both were equally responsive to deterioration. We suggest that clinicians and investigators can substitute the shorter Qmci for the SADAS-cog. PMID- 24075293 TI - Teaching and practicing cost-awareness in the intensive care unit: a TARGET to aim for. AB - Intensive care is one of the main contributors to rising inpatient hospital costs due to frequent use of expensive diagnostics and therapies. With successful track records of team- and protocol-based care, intensive care units are ideal sites to take the lead in reducing overuse and misuse of diagnostic tests and prescribing. We offer a framework for practicing and teaching cost-awareness in the intensive care unit based on the acronym TARGET. The components of the care are as follows: Talk to patients about their preferences for care, Ask for outside tests, avoid Routine and/or Repeated tests, prescribe Generic medications, Educate about costs, and Transfuse appropriately. PMID- 24075292 TI - Dispersal of antibiotic-resistant high-risk clones by hospital networks: changing the patient direction can make all the difference. AB - BACKGROUND: Patients who seek treatment in hospitals can introduce high-risk clones of hospital-acquired, antibiotic-resistant pathogens from previous admissions. In this manner, different healthcare institutions become linked epidemiologically. All links combined form the national patient referral network, through which high-risk clones can propagate. AIM: To assess the influence of changes in referral patterns and network structure on the dispersal of these pathogens. METHODS: Hospital admission data were mapped to reconstruct the English patient referral network, and 12 geographically distinct healthcare collectives were identified. The number of patients admitted and referred to hospitals outside their collective was measured. Simulation models were used to assess the influence of changing network structure on the spread of hospital acquired pathogens. FINDINGS: Simulation models showed that decreasing the number of between-collective referrals by redirecting, on average, just 1.5 patients/hospital/day had a strong effect on dispersal. By decreasing the number of between-collective referrals, the spread of high-risk clones through the network can be reduced by 36%. Conversely, by creating supra-regional specialist centres that provide specialist care at national level, the rate of dispersal can increase by 48%. CONCLUSION: The structure of the patient referral network has a profound effect on the epidemic behaviour of high-risk clones. Any changes that affect the number of referrals between healthcare collectives, inevitably affect the national dispersal of these pathogens. These effects should be taken into account when creating national specialist centres, which may jeopardize control efforts. PMID- 24075294 TI - Association between weight change and clinical outcomes in critically ill patients. AB - PURPOSE: Body weight fluctuates daily throughout a patient's stay in the intensive care unit (ICU) due to a variety of factors, including fluid balance, nutritional status, type of acute illness, and presence of comorbidities. This study investigated the association between change in body weight and clinical outcomes in critically ill patients during short-term hospitalization in the ICU. METHODS: All patients admitted to the Gyeongsang National University hospital between January 2010 and December 2011 who met the inclusion criteria of age 18 or above and ICU hospitalization for at least 2 days were prospectively enrolled in this study. Body weight was measured at admission and daily thereafter using a bed scale. Univariate and multivariate linear and logistic regression analyses were performed to evaluate factors associated with mortality and the association between changes in body weight and clinical outcomes, including duration of mechanical ventilation (MV) use, length of ICU stay, and ICU mortality. RESULTS: Of the 140 patients examined, 33 died during ICU hospitalization, yielding an ICU mortality rate of 23.6%. Non-survivors experienced higher rates of severe sepsis and septic shock and greater weight gain than survivors on days 2, 3, 4, 5, and 6 of ICU hospitalization (P < .05). Increase of body weight on days 2 through 7 on ICU admission was correlated with the longer stay of ICU, and increase on days 3 through 7 on ICU admission was correlated with the prolonged use of mechanical ventilation. Increase of body weight on days 3 through 5 on ICU admission was associated with ICU mortality. CONCLUSIONS: Increase in body weight of critically ill patients may be correlated with duration of mechanical ventilation use and longer stay of ICU hospitalization and be associated with ICU mortality. PMID- 24075295 TI - A pilot investigation of the association of genetic polymorphisms regulating corticotrophin-releasing hormone with posttraumatic stress and depressive symptoms in medical-surgical intensive care unit survivors. AB - PURPOSE: To determine if single nucleotide polymorphisms of the corticotrophin releasing hormone binding protein (CRHBP, rs10055255) and CRH receptor type 1 (CRHR1, rs1876831) were associated with posttraumatic stress disorder (PTSD) and depressive symptoms following medical-surgical intensive care unit (ICU) hospitalization. MATERIALS AND METHODS: We extracted DNA for genotyping from saliva samples of 93 ICU patients enrolled in a prospective cohort investigation. Follow-up interviews conducted 3 and 12-months post-ICU included assessment of PTSD symptoms with the PTSD Checklist-Civilian Version and depressive symptoms with the Patient Health Questionnaire-9. RESULTS: Homozygosity for the CRHBP rs10055255 T allele was associated with significantly fewer post-ICU PTSD (beta = -10.8, 95% confidence interval [95% CI], -17.7 to -3.9; P = .002) and depressive symptoms (beta = -3.7, 95% CI, -6.7 to -0.7; P = .02). Carrying a CRHR1 rs1876831 C allele was associated with significantly more post-ICU depressive symptoms compared to T/T homozygotes (C/T heterozygtes: beta = 6.9, 95% CI, 1.2-12.6; P = .02; C/C homozygotes: beta = 5.8; 95% CI: 0.2-11.3; P = .04). These associations remained significant after adjustment for age, race, illness severity, and in-ICU steroid exposure. CONCLUSIONS: Despite a small sample size, our findings suggest a potential role for genetic variants of CRHBP and CRHR1 in the development of post-ICU psychiatric morbidity. PMID- 24075296 TI - Impairment of thrombin generation in the early phases of the host response of sepsis. AB - PURPOSE: The purpose was to investigate the presence of hypercoagulability in the very early phase of the host response to an infection in the clinical course of sepsis and septic shock. MATERIAL AND METHODS: Twenty-four patients with chemotherapy-associated febrile neutropenia were evaluated at baseline, at the time of fever onset, and 48 hours thereafter using the thrombin generation test, a more physiological and global assay of hemostasis. RESULTS: The rate of thrombin generation was decreased and no signals of systemic hypercoagulability could be observed during the first 48 hours of sepsis. Moreover, patients that evolved to septic shock presented a more significant impairment in thrombin generation than those with noncomplicated sepsis. CONCLUSIONS: Patients with sepsis and febrile neutropenia present an impairment in thrombin generation from very early stages of their disease course. These results suggest that the procoagulant in vitro alterations described during sepsis do not necessarily translate into a clinically relevant systemic hypercoagulable state. These findings could help explain why treatment with systemic anticoagulants did not translate to clinical benefits in human sepsis and highlight the need for a better understanding of the hemostatic alterations in sepsis before new treatments targeting coagulation activation are developed. PMID- 24075298 TI - Bedside assessment of right atrial pressure in critically ill septic patients using tissue Doppler ultrasonography. AB - PURPOSE: Right atrial pressure (RAP) is considered a surrogate for right ventricular filling pressure or cardiac preload. It is an important parameter for fluid management in patients with septic shock. It is commonly approximated by the central venous pressure (CVP) either invasively using a catheter placed in the superior vena cava or by bedside ultrasound, in which the size and respiratory variations of the inferior vena cava (IVC) are measured from the subcostal view. Doppler imaging of the tricuspid valve from the apical 4-chamber view has been proposed as an alternative approach for the estimation of RAP. The tricuspid E/Ea ratio is measured, where E is the peak velocity of the early diastolic tricuspid inflow and Ea is the peak velocity of the early diastolic relaxation of the lateral tricuspid annulus. We hypothesized that the tricuspid E/Ea ratio may represent an alternative to IVC metrics, using invasive CVP as the criterion standard, for the assessment of RAP in critically ill septic patients. MATERIALS AND METHODS: A convenience sample of 30 septic patients, both mechanically ventilated and non-mechanically ventilated, was enrolled. Using a portable ultrasound system, maximum velocity of tricuspid E and Ea was measured from the apical 4-chamber view; and IVC diameter and degree of collapse were measured from the subcostal view. Decision tree induction was used to determine the performance of each model compared with invasive CVP. RESULTS: Our results suggest that a tricuspid E/Ea ratio of greater than 4.7 can predict a CVP greater than 10 mm Hg in septic patients with sensitivity greater than 85% and specificity greater than 90%. CONCLUSIONS: In this pilot study, Doppler imaging of the tricuspid valve provided a valuable alternative for noninvasive bedside estimation of RAP in septic patients. PMID- 24075297 TI - Prehospital use of inhaled steroids and incidence of acute lung injury among patients at risk. AB - PURPOSE: Inhaled corticosteroids (ICSs) attenuated lung injury in animal studies. We investigated the association between prehospital ICS and incidence of acute lung injury (ALI) among patients at risk. METHODS: In this ancillary analysis of the large multicenter Lung Injury Prediction Study cohort, we developed a propensity score for prehospital ICS use followed by matching, for all patients and for a subgroup of patients with at least 1 risk factor for direct pulmonary injury. The primary outcome was ALI; secondary outcomes included acute respiratory distress syndrome, need for invasive mechanical ventilation, and hospital mortality. RESULTS: Of the 5126 patients, 401 (8%) were using ICS. Acute lung injury developed in 343 (7%). The unadjusted incidence of ALI was 4.7% vs 6.9% (P = .12) among those in ICS compared with non-ICS group. In the "direct" lung injury subgroup, the unadjusted incidence of ALI was 4.1% vs 10.6% (P = 0.006). After propensity matching, the estimated effect for ALI in the whole cohort was 0.69 (95% confidence interval, 0.39-1.2; P = .18), and that in the direct subgroup was 0.56 (95% confidence interval, 0.22-1.46; P = .24). CONCLUSIONS: Preadmission use of ICS in a hospitalized population of patients at risk for ALI was not significantly associated with a lower incidence of ALI once controlled by comprehensive propensity-matched analysis. PMID- 24075299 TI - Corrected QT interval. But corrected how? PMID- 24075300 TI - Surgical rib fixation for flail chest deformity improves liberation from mechanical ventilation. AB - PURPOSE: The goal of this study was to determine the impact of surgical rib fixation (SRF) in a treatment protocol for severe blunt chest trauma. MATERIALS AND METHODS: Patients with flail chest admitted between September 2009 and June 2010 to our level I trauma center who failed traditional management and underwent SRF were matched with an historical group. Outcome variables evaluated include age, injury severity score, intensive care unit length of stay (LOS), hospital LOS, ventilator days, total number of rib fractures, and total number of segmental rib fractures. RESULTS: The 2 groups were similar in age, injury severity score, intensive care unit LOS, hospital LOS, total number of rib fractures, and total segmental rib fractures. The operative group demonstrated a significant reduction in total ventilator days as compared with the nonsurgical group (4.5 [0-30] vs 16.0 [4-40]; P = .040). Patients with SRF were permanently liberated from the ventilator within a median of 1.5 days (0-8 days). CONCLUSIONS: Surgical rib fixation resulted in a significant decrease in ventilator days and may represent a novel approach to decreasing morbidity in flail chest patients when used as a rescue therapy in patients with declining pulmonary status. Larger studies are required to further identify these benefits. PMID- 24075301 TI - Community-acquired pneumonia in patients with chronic obstructive pulmonary disease requiring admission to the intensive care unit: risk factors for mortality. AB - PURPOSE: The aims of this study are to identify factors predicting mortality in patients with chronic obstructive pulmonary disease (COPD) and community-acquired pneumonia (CAP) requiring intensive care unit (ICU) admission and to examine whether noninvasive ventilation treatment reduces mortality. MATERIALS AND METHODS: An analysis was performed on data from patients with CAP hospitalized in the ICUs of 19 different hospitals in Turkey between October 2008 and January 2011. Predictors of mortality were assessed by both univariate and multivariate statistical analyses. RESULTS: Two hundred eleven patients with COPD and CAP were included. The overall ICU mortality was 23.9%. Noninvasive ventilation treatment (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.03-0.49; P = .003), hypertension (OR, 0.13; 95% CI, 0.02-0.93; P = .042), bilateral infiltration (OR, 13.92; 95% CI, 2.94-65.84; P = .001), systemic corticosteroid treatment (OR, 0.19; 95% CI, 0.35-0.96; P = .045), length of ICU stay (OR, 0.65; 95% CI, 0.47 0.89; P = .007), and duration of invasive mechanical ventilation (OR, 1.11; 95% CI, 1.01-1.22; P = .032) were independent factors related to mortality. CONCLUSION: Noninvasive ventilation, hypertension, systemic corticosteroid treatment, and shorter ICU stay are associated with reduced mortality, whereas bilateral infiltration and longer duration of invasive mechanical ventilation are associated with increased risk of mortality in patients with COPD and CAP requiring ICU admission. PMID- 24075302 TI - Association between renal replacement therapy in critically ill patients with severe acute kidney injury and mortality. AB - PURPOSE: To evaluate the characteristics and outcomes of critically ill patients with severe acute kidney injury (AKI) treated and not treated with renal replacement therapy (RRT). METHODS: Secondary analysis of a multi-centre cohort study. Primary exposure was RRT. Primary outcome was propensity and multi variable adjusted-hospital mortality. RESULTS: We studied 1250 patients (71.3%) who received and 502 (28.7%) who did not receive RRT. Reasons for not starting RRT (not mutually exclusive) were limitations of support (33.6%, n = 169), adequate urine output (46.2%; n = 232), plan to observe (56.4%; n = 283), and advanced age (12.6%; n = 63). Mortality was higher in those not receiving RRT due to limitations and advanced age but lower for adequate urine output and plan to observe. Propensity and multi-variable adjusted analysis showed no statistical difference in hospital mortality (adj-OR 1.47; 95% CI, 0.93-2.24) in patients receiving RRT. Results were similar in a sensitivity analysis restricted to patients fulfilling risk, injury, failure, loss, end-stage kidney disease-FAILURE criteria (37.0%; n = 446) (adj-OR 1.36; 95% CI, 0.70-2.66). CONCLUSION: In this cohort, reasons for not starting RRT included limitations of support and perception of impending renal recovery. Despite similar risk of mortality after adjusting for selection bias and confounders, RRT-treated patients were fundamentally different from non-treated patients across a spectrum of variables that precludes valid comparison in observational data. PMID- 24075303 TI - Phenotypic variation among seven members of one family with deficiency of hypoxanthine-guanine phosphoribosyltransferase. AB - We describe a family of seven boys affected by Lesch-Nyhan disease with various phenotypes. Further investigations revealed a mutation c.203T>C in the gene encoding HGprt of all members, with substitution of leucine to proline at residue 68 (p.Leu68Pro). Thus patients from this family display a wide variety of symptoms although sharing the same mutation. Mutant HGprt enzyme was prepared by site-directed mutagenesis and the kinetics of the enzyme revealed that the catalytic activity of the mutant was reduced, in association with marked reductions in the affinity towards phosphoribosylpyrophosphate (PRPP). Its Km for PRPP was increased 215-fold with hypoxanthine as substrate and 40-fold with guanine as substrate with associated reduced catalytic potential. Molecular modeling confirmed that the most prominent defect was the dramatically reduced affinity towards PRPP. Our studies suggest that the p.Leu68Pro mutation has a strong impact on PRPP binding and on stability of the active conformation. This suggests that factors other than HGprt activity per se may influence the phenotype of Lesch-Nyhan patients. PMID- 24075304 TI - Biotinidase knockout mice show cellular energy deficit and altered carbon metabolism gene expression similar to that of nutritional biotin deprivation: clues for the pathogenesis in the human inherited disorder. AB - Biotin is the prosthetic group of carboxylases that have important roles in the metabolism of glucose, fatty acids and amino acids. Biotinidase has a key role in the reutilization of the biotin, catalyzing the hydrolysis of biocytin (epsilon-N biotinyl-l-lysine) and biocytin-containing peptides derived from carboxylase turnover, thus contributing substantially to the bioavailability of this vitamin. Deficient activity of biotinidase causes late-onset multiple carboxylase in humans, whose pathogenic mechanisms are poorly understood. Here we show that a knock-out biotinidase-deficient mouse from a C57BL/6 background that was fed a low biotin diet develops severe ATP deficit with activation of the energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK), inhibition of the signaling protein mTOR, driver of protein synthesis and growth, and affecting the expression of central-carbon metabolism genes. In addition, sensitivity to insulin is augmented. These changes are similar to those observed in nutritionally biotin-starved rats. These findings further our understanding of the pathogenesis of human biotinidase deficiency. PMID- 24075305 TI - Physical activity and longitudinal change in 6-min walk distance in COPD patients. AB - BACKGROUND: The 6-min walk distance (6MWD) is widely used to evaluate functional capacity in patients with chronic obstructive pulmonary disease (COPD). AIM: To examine predictors for longitudinal change in 6MWD including self-reported physical activity, smoking habits, body composition, exacerbations, comorbidity and lung function. METHODS: The cohort included 389 patients aged 44-75 years, with clinically stable COPD in GOLD stages II-IV. The follow-up time was 3 years. Measurements included 6MWD, spirometry, fat and fat free mass index (FMI and FFMI), and assessment of physical activity, smoking habits, comorbidities and exacerbations by questionnaires. Generalized estimating equations (GEE) regression analyses were used to analyze predictors for the change in 6MWD. RESULTS: There was a reduction in 6MWD from baseline to 3 years for patients in GOLD stages III and IV (B = -36 m, 95% CI = -51 to -7, p = 0.009 and B = -79 m, CI = -125 to -20, p = 0.007). The unadjusted GEE analysis demonstrated that baseline self-reported physical activity level, forced expiratory volume in one second (FEV1), forced vital capacity, FFMI, GOLD stages and age predicted change in 6MWD, but in the adjusted GEE analysis only self-reported physical activity level (p = 0.001) and FEV1 (p = 0.019) predicted change over time. CONCLUSION: Patients in GOLD stage II maintained their functional capacity assessed by 6MWD over 3 years, while it was significantly reduced for patients in GOLD stages III and IV. Level of physical activity and FEV1 were predictors for longitudinal change in functional capacity. PMID- 24075306 TI - Social cognition throughout the three phases of bipolar disorder: a state-of-the art overview. AB - Although it is now well documented that bipolar disorder (BD) often presents with cognitive deficits and suboptimal social adjustment, the social cognitive profile of the illness throughout its three phases remains unclear. An extensive search was conducted through the online databases EBSCO, PsychInfo, PubMed, ScienceDirect, and Wiley-Blackwell, covering the period between 1990 and 2012. Fifty-one studies comparing the social cognitive performance of bipolar patients with that of healthy controls were identified. Deficits in emotion recognition and theory of mind were found in manic, depressed, and euthymic bipolar subjects. Furthermore, altered face emotion recognition and brain-related abnormalities were noted both in euthymic patients and subjects at risk for BD. The influence of clinical and neurocognitive variables on the social cognitive performance of bipolar patients remains to be ascertained. Future directions for research are discussed. PMID- 24075307 TI - Insecure attachment style as a vulnerability factor for depression: recent findings in a community-based study of Malay single and married mothers. AB - The role of marital breakdown in women's mental health is of key concern in Malaysia and internationally. A cross-sectional questionnaire study of married and separated/divorced and widowed women examined insecure attachment style as an associated risk factor for depression among 1002 mothers in an urban community in Malaysia. A previous report replicated a UK-based vulnerability-provoking agent model of depression involving negative evaluation of self (NES) and negative elements in close relationships (NECRs) interacting with severe life events to model depression. This article reports on the additional contribution of insecure attachment style to the model using the Vulnerable Attachment Style Questionnaire (VASQ). The results showed that VASQ scores were highly correlated with NES, NECR and depression. A multiple regression analysis of depression with backward elimination found that VASQ scores had a significant additional effect. Group comparisons showed different risk patterns for single and married mothers. NES was the strongest risk factor for both groups, with the 'anxious style' subset of the VASQ being the best additional predictor for married mothers and the total VASQ score (general attachment insecurity) for single mothers. The findings indicate that attachment insecurity adds to a psychosocial vulnerability model of depression among mothers cross-culturally and is important in understanding and identifying risk. PMID- 24075308 TI - A ring for all: gamma-tubulin-containing nucleation complexes in acentrosomal plant microtubule arrays. AB - The construction of dynamic polar microtubules from 13 protofilaments consisting of alpha-tubulin and beta-tubulin heterodimers requires a preformed nucleation seed that specifies subcellular localization and timing of microtubule polymerization in vivo. An evolutionarily conserved gamma-tubulin-containing ring complex is recruited to the lateral wall of preexisting microtubules or outer nuclear membranes in plant cells, and is then activated as a template for new microtubules of defined geometry. Specific regulators are thought to target/activate the ring complex to nucleate nascent microtubules in distinct polymerization patterns, as seen in interphase and mitotic arrays. The augmin complex, which was initially identified in metazoan cells, recruits the ring complex to plant mitotic microtubules, where new polymers are abundantly generated at shallow angles. PMID- 24075309 TI - The role of lymphatic and blood vessel invasion in predicting survival and methods of detection in patients with primary operable breast cancer. AB - Lymphovascular invasion (LBVI) has long been recognized as an essential step of metastases in patients with cancer. However, the process of invasion into lymphatic and blood vessels is still not well defined in breast cancer. To examine the evidence for LBVI, lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) in predicting survival in patients with primary operable breast cancer, and to evaluate the detection methods of vessel invasion. A systematic review of data published from 1964 to 2012 was undertaken according to a pre defined protocol. There is robust evidence that general LBVI and LVI are independent prognostic factors of poorer survival. The prognostic role of BVI remains unclear. Most studies detected LBVI using H&E stained sections. The overall weighted average of the LBVI rate using immunostaining was higher (35%) than H&E (24%). The LBVI rate using H&E was variable (9-50%) and less variable using immunostaining (32-41%). The overall weighted average of the LVI rate was similar using H&E and immunostaining (33% vs. 25%). The LVI rate using H&E was variable (10-49%) and less variable using immunostaining (21-42%). The overall weighted average of the BVI rate was similar using H&E and/or classical staining and immunostaining (16% vs. 10%). The BVI rates using H&E and/or classical staining approach (4-46%) and immunostaining (1-29%) were both variable. The LBVI and LVI are powerful prognostic factors in primary operable breast cancer. However, BVI was rarely specifically examined and its role in predicting survival is not clear. Further work is required using reliable specific staining to establish the routine use of LVI and BVI in the prediction of outcome in patients with primary operable breast cancer. PMID- 24075310 TI - Are day-to-day variations of airborne particles associated with emergency ambulance dispatches? AB - BACKGROUND: Much of the evidence on the health effects of airborne particles is based on mortality and hospital admissions, while the evidence from other morbidity indicators is still limited. OBJECTIVE: To measure the relationship between particles with diameter below 10 microm (PM10) and emergency ambulance dispatches (EAD). METHODS: Daily EAD for six towns of the Emilia-Romagna region (Italy) were obtained from a database collecting real-time data. Time series analyses were performed, and city-specific estimates were combined using meta analytic techniques. RESULTS: We found a significant percentage change of EAD associated with a 10 microg/m3 increase of PM10 for non-traumatic diseases (0.86%, 95% CI: 0.61,1.1%). A positive relationship was also found for cardiovascular and respiratory diseases without reaching statistical significance. The risks were much higher in the warm (April-September) than in the cold season (January-March and October-December). CONCLUSIONS: Emergency ambulance dispatches provide useful insight into the health effects of air pollution and may be useful to establish surveillance systems. PMID- 24075311 TI - A pharmacoepidemiological cohort study of subjects starting strong opioids for nonmalignant pain: a study from the Norwegian Prescription Database. AB - Clinical studies of short duration have demonstrated that strong opioids improve pain control in selected patients with chronic nonmalignant pain. However, high discontinuation rates and dose escalation during long-term treatment have been indicated. The aim of the present study was to determine discontinuation rates, dose escalation, and patterns of co-medication with benzodiazepines. The Norwegian Prescription Database provides complete national data at an individual level on dispensed drugs. A complete national cohort of new users of strong opioids was followed up for 5 years after initiation of therapy with strong opioids. Of the 17,248 persons who were new users of strong opioids in 2005, 7229 were dispensed a second prescription within 70 days and were assumed to be intended long-term users. A total of 1233 persons in the study cohort were still on opioid therapy 5 years later. This equals 24% of the study cohort who were still alive. Of the participants, 21% decreased their annual opioid dose by 25% or more, whereas 21% kept a stable dose (+/- 24%) and 34% more than doubled their opioid dose from the first to the fifth year. High annual doses of opioids were associated with high annual doses of benzodiazepines at the end of follow-up. It is an issue of major concern that large dose escalation is common during long term treatment, and that that high doses of opioids are associated with high doses of benzodiazepines. These findings make it necessary to question whether the appropriate patient population receives long-term opioid treatment. PMID- 24075312 TI - Anti Mycobacterium avium subsp. paratuberculosis heat shock protein 70 antibodies in the sera of Sardinian patients with multiple sclerosis. AB - Heat shock protein (HSP) family members are highly conserved in both prokaryotic and eukaryotic organisms and are known to be immunodominant antigens in many bacteria. In particular, HSP70 has been linked to multiple sclerosis (MS), even if the available data are contradictory. Since different studies conducted on Sardinian subjects, have linked Mycobacterium avium subspecies paratuberculosis (MAP) presence to MS disease, and in view of the fact that human HSP70 is highly homologue to the majority of mycobacterial HSP70 proteins, we searched for anti MAP HSP70 antibodies in the sera of 268 MS patients and 231 age and sex-matched healthy controls (HCs). All the subjects enrolled in the study were from Sardinia, which is an excellent setting for investigation since it has one of the highest prevalence of MS worldwide. HSP70 detection was carried out using ELISA methodology. A statistically significant difference was found between MS patients and HCs when analyzing the humoral response mounted against MAP HSP70 protein. Our study confirms that mycobacterial HSP70 might be involved in MS, and provides another piece of evidence sustaining the role played by MAP in MS in the context of Sardinian population. PMID- 24075313 TI - Recurrent de novo c.316G>A mutation in NIPA1 hotspot. AB - Mutations in the NIPA1 cause autosomal dominant form of hereditary spastic paraplegia. Allelic heterogeneity of known NIPA1 mutations is quite limited and the most common mutation is c.316G>A resulting in p.G106R protein change. Here we report the first direct evidence of de novo c.316G>A mutation in the same hotspot of the gene in two unrelated patients who had otherwise a prototypical NIPA1 associated phenotype with a severe form of uncomplicated spastic paraplegia. De novo nature of these mutations was confirmed by sequencing both sets of clinically unaffected parents and confirmation of paternity. We also discuss likely molecular mechanisms accounting for recurrent mutations in this segment of the gene. Apparently sporadic patients without a positive family history of hereditary spastic paraplegia need to be also evaluated for possible disease causing mutations in genes that are inherited in an autosomal dominant fashion. PMID- 24075314 TI - Impact of thrombus aspiration during primary percutaneous coronary intervention in cardiogenic shock complicating ST-segment elevation myocardial infarction. AB - AIM: To assess the impact on in-hospital and long-term survival of thrombus aspiration (TA) during primary percutaneous coronary intervention (PPCI) for ST segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS). METHODS AND RESULTS: From September 2001 to May 2010 we collected data from 155 patients affected with STEMI complicated by CS undergoing PPCI (12.4% of all PPCI) including 70 patients (45.2%) in TA group and 85 patients (54.8%) in conventional PCI group. Patients in TA group were more likely to have right ventricular infarction (24.3% vs 5.9%, p=0.002), higher mean left ventricular ejection fraction (40% +/- 9% vs 35% +/- 7%, p<0.0001) and lower left main coronary artery occlusion (2.8% vs 21.2%, p=0.002). TA was associated with a lower rate of in-hospital and long-term mortality (31.4% vs 48.2%, p=0.05 and 42.8% vs 64.7%, p=0.01 respectively) at a mean follow-up time of 6.1 +/- 2.1 years. At multivariate analysis the only independent predictor of in-hospital and long-term survival was the procedural success (HR 0.18 95% CI 0.025-0.31, p=0.03 and HR 0.46 95% CI 0.09-0.74, p=0.034 respectively). CONCLUSIONS: In this retrospective study TA, performed during PPCI for STEMI complicated by CS, was not an independent predictor of in-hospital and long-term survival. PMID- 24075326 TI - The latent structure of oppositional defiant disorder in children and adults. AB - An understanding of the latent structure of oppositional defiant disorder (ODD) is essential for better developing causal models, improving diagnostic and assessment procedures, and enhancing treatments for the disorder. Although much research has focused on ODD-including recent studies informing the diagnostic criteria for DSM-5-research examining the latent structure of ODD is sparse, and no known study has specifically undertaken a taxometric analysis to address the issue of whether ODD is a categorical or dimensional construct. To address this gap, the authors conducted two separate studies using a set of taxometric analyses with data from the NICHD Study of Early Child Care and Youth Development (child study; n = 969) and with data from a large mixed sample of adults, which included participants reporting psychiatric difficulties as well as healthy controls (adult study; n = 600). The results of a variety of non-redundant analyses across both studies revealed a dimensional latent structure for ODD symptoms among both children and adults. These findings are consistent with previous studies that have examined latent structure of related constructs (e.g., aggression, antisocial behavior) as well as studies that have examined the dimensional versus categorical structure of ODD using methods other than taxometric analysis. PMID- 24075327 TI - Altered intracellular signaling cascades in peripheral blood mononuclear cells from BD patients. AB - Bipolar disorder (BD) is a severe psychiatric disorder of complex physiopathology that has been associated with a pro-inflammatory state. The aim of the present study was to investigate intracellular pathways associated with inflammatory signaling, assessing the phosphorylation levels of transcription factor nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPKs) in peripheral blood mononuclear cells of euthymic BD patients and healthy controls. Fifteen BD euthymic type I patients, and 12 healthy controls matched by age and gender were enrolled in this study. All subjects were assessed by the Mini International Neuropsychiatry Interview and the patients also by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. Phosphorylation levels of p65 NF-kappaB subunit, and MAPK ERK1/2, and p38 were assessed by Western blot and flow cytometry. Plasma cytokines (IL-2, IL-4, IL6, IL-10, IFN-gamma, TNF-alpha, and IL-17A) were measured using cytometric bead arrays. Western blot and flow cytometry analyses showed increased phosphorylation levels of p65 NF-kappaB subunit, and MAPKs ERK1/2, and p38 in BD patients in euthymia in comparison with controls. BD patients presented increased pro-inflammatory cytokines levels in comparison with controls, and TNF-alpha correlated with the levels of phosphorylated p65 NF-kappaB. The present study found increased activation of MAPK and NF-kappaB pathways in BD patients, which is in line with a pro inflammatory status. PMID- 24075328 TI - Increased influence through innovation in processes. PMID- 24075329 TI - Publishing letters to the editor. PMID- 24075330 TI - Additional information about advanced practice RN first assistant education requirements. PMID- 24075331 TI - Modifiable factors to decrease the cost of robotic-assisted procedures. AB - In 2000, the US Food and Drug Administration approved the da Vinci Surgical System(r) for use in the United States. Since that time, the number of surgical robotic systems throughout the United States has continued to grow. The costs for using the system include the initial purchase ($1 million to $2.3 million) plus annual maintenance fees ($100,000 to $150,000) and the cost of limited-use or disposable instruments. Increasing the number of procedures that are performed using the robotic system can decrease the per-procedure costs. Two modifiable factors that contribute to increasing the annual caseload are increasing the number of surgeons capable of using the system and having a properly educated perioperative nursing team. An educated surgical team decreases turnover time, facilitates proper flow of each surgical procedure, and is able to actively and passively solve intraoperative problems. PMID- 24075332 TI - Forced-air warming devices and the risk of surgical site infections. AB - The potential that forced-air warming systems may increase the risk of surgical site infections (SSIs) by acting as a vector or causing unwanted airflow disturbances is a concern to health care providers. To investigate this potential, we examined the literature to determine whether forced-air warming devices increase the risk of SSIs in patients undergoing general, vascular, or orthopedic surgical procedures. We examined 192 evidence sources, 15 of which met our inclusion criteria. Most sources we found indirectly addressed the issue of forced-air warming and only three studies followed patients who were warmed intraoperatively with forced-air warming devices to determine whether there was an increased incidence of SSIs. All of the sources we examined contained methodological concerns, and the evidence did not conclusively suggest that the use of forced-air warming systems increases the risk of SSIs. Given the efficacy of these devices in preventing inadvertent perioperative hypothermia, practitioners should continue to use and clean forced-air warming systems according to the manufacturer's instructions until well-conducted, large-scale trials can further examine the issue. PMID- 24075333 TI - Standardizing documentation for postoperative nausea and vomiting in the electronic health record. AB - Postoperative nausea and vomiting (PONV) remains a common postoperative complication that causes patient discomfort and increases health care costs. Clinicians use the American Society of PeriAnesthesia Nurses (ASPAN) guideline to help prevent and treat PONV. However, the lack of standardized terminology in the electronic health record (EHR) and the lack of clinical decision support tools make it difficult for clinicians to document guideline implementation and to determine the effects of nursing care on PONV. To address this, we created a concept map of the Perioperative Nursing Data Set (PNDS) that illustrates the relationship between elements of this standardized nursing terminology and the ASPAN guideline, using the Systematized Nomenclature of Medicine-Clinical Terms multidisciplinary terminology to fill any gaps. This mapping results in a standardized dataset specific to PONV for use in an EHR, which links nursing care to nursing diagnoses, interventions, and outcomes. The mapping and documentation in the EHR also allows standardized data collection for research, evaluation, and benchmarking, which makes perioperative nursing care of patients who are at risk for or experiencing PONV measureable and visible. Distributing this information to perioperative and perianesthesia nursing personnel, in addition to implementing risk assessment tools for PONV and clinical support alerts in electronic documentation systems, will help support implementation of the PONV clinical practice guideline in the EHR. PMID- 24075334 TI - Implementing AORN recommended practices for care of patients undergoing pneumatic tourniquet-assisted procedures. AB - Perioperative nurses are likely to encounter the use of pneumatic tourniquets in a variety of operative and invasive extremity procedures. Use of a pneumatic tourniquet offers an opportunity to obtain a near-bloodless surgical field; however, the use of tourniquets is not without risk. Unfavorable outcomes include pain, thrombotic events, nerve compression injuries, and disruption of skin integrity. Perioperative nurses should be familiar with the indications, contraindications, and changes in physiology associated with pneumatic tourniquet use. The revised AORN "Recommended practices for care of patients undergoing pneumatic tourniquet-assisted procedures" is focused on the perioperative nurse's role in patient care and provides guidance for developing, implementing, and evaluating practices that promote patient safety and improve the likelihood of positive outcomes. PMID- 24075335 TI - A retrospective review of leg wound complications after coronary artery bypass surgery. AB - Little research or attention has been paid to finding out whether wound closure with sutures or staples attains the best outcomes after saphenous vein harvest for coronary artery bypass grafting. We undertook a quality improvement project to compare the prevalence of leg wound complications (eg, infection, seroma, hematoma, dehiscence) between two types of skin closure (ie, staples, subcuticular sutures) after conventional open surgery with bridging between incisions and vein harvesting during coronary revascularization to determine the need for practice changes. We found no significant differences between patients with wound complications and those without. However, in this project, the risk for infections was greater for patients with diabetes whose wounds were closed by using subcuticular sutures. These findings have led to practice changes for reducing leg wound complications within our institution: clinicians now assess patients for increased risk of leg wound complications preoperatively and opt to close wounds with staples for patients who have diabetes. PMID- 24075336 TI - Putting the patient into patient safety checklists. PMID- 24075338 TI - Duty to disclose someone else's error? PMID- 24075340 TI - Bioefficacy of crude extract of Cyperus aromaticus (Family: Cyperaceae) cultured cells, against Aedes aegypti and Aedes albopictus mosquitoes. AB - OBJECTIVE: To evaluate the growth inhibition activity of the crude extract of Cyperus aromaticus (C. aromaticus) cultured cells against the 3rd instar larvae of Aedes aegypti (Linn.) and Aedes albopictus Skuse (Ae. albopictus) under laboratory conditions, and determine the sublethal effects (EI50) of the crude extract of C. aromaticus cultured cells on some biological and morphological parameters of both Aedes mosquito species during two generations as well. METHODS: The cell suspension cultures of C. aromaticus were activated from five callus lines (P4, Pa, Z1, Z6 and Ml) derived from the root explants of in vitro plantlets. The cultured cells were extracted in chloroform and used as plant material for the present study. For detection of juvenile hormone III, the crude extracts were analyzed by HPLC. Then the crude extracts of the three C. aromaticus cultured cell lines which contained varied amounts of juvenile hormone III [high level (P4 cell line), medium level (Z1 cell line) and low level (Ml cell line)] were tested against Aedes mosquito species. Laboratory evaluation was performed against late third instar larvae of the Vector Control Research Unit strains of Ae. aegypti and Ae. albopictus using the standard WHO method. The effects of EI50 of the C. aromaticus cultured P4 cells on fecundity, fertility, growth period, sex ratio, adult size and longevity of Aedes mosquitoes were assessed. RESULTS: Bioassay tests presented the remarkable growth inhibition activity of the crude extracts of C. aromaticus cultured cells against the two Aedes mosquitoes. Between the two mosquito species, Ae. albopictus was more susceptible to the crude extracts with lower EI50 values. EI50 of the crude extract of C. aromaticus cultured cells (P4) increased the sterility indices in the parental generation females in both Aedes mosquito species. A significant delay in the pupal formation and adult emergence were observed in the parental generation of the both mosquito species. The sex ratio of the adult population either parental or F1 generation of the Aedes mosquito species was not significantly affected by the EI50 dosage of the crude extract of C. aromaticus cultured P4 cells. A significant decrease in the wing length of the treated adult (female and male) of Aedes aegypti as well as the treated female of Ae. albopictus were observed. Longevity of the adult female of the parental generation of both Aedes mosquitoes as well as females of F1 generation of Ae. albopictus were significantly decreased. CONCLUSIONS: The present study revealed the potential of the crude extract of C. aromaticus cultured cells in controlling vector mosquito populations in the effort to reduce the transmission of vector borne diseases. PMID- 24075339 TI - African eggplant (Solanum anguivi Lam.) fruit with bioactive polyphenolic compounds exerts in vitro antioxidant properties and inhibits Ca(2+)-induced mitochondrial swelling. AB - OBJECTIVE: To evaluate the antioxidant and radical scavenging activities of Solanum anguivi fruit (SAG) and its possible effect on mitochondrial permeability transition pore as well as mitochondrial membrane potential (DeltaPsim) isolated from rat liver. METHODS: Antioxidant activity of SAG was assayed by using 2,2 diphenyl-1-picrylhydrazyl (DPPH), reducing power, iron chelation and ability to inhibit lipid peroxidation in both liver and brain homogenate of rats. Also, the effect of SAG on mitochondrial membrane potential and mitochondrial swelling were determined. Identification and quantification of bioactive polyphenolics was done by HPLC-DAD. RESULTS: SAG exhibited potent and concentration dependent free radical-scavenging activity (IC50/DPPH=275.03+/-7.8 MUg/mL). Reductive and iron chelation abilities also increase with increase in SAG concentration. SAG also inhibited peroxidation of cerebral and hepatic lipids subjected to iron oxidative assault. SAG protected against Ca(2+) (110 MUmol/L)-induced mitochondrial swelling and maintained the DeltaPsim. HPLC analysis revealed the presence of gallic acid [(17.54+/-0.04) mg/g], chlorogenic acid (21.90+/-0.02 mg/g), caffeic acid (16.64+/-0.01 mg/g), rutin [(14.71+/-0.03) mg/g] and quercetin [(7.39+/ 0.05) mg/g]. CONCLUSIONS: These effects could be attributed to the bioactive polyphenolic compounds present in the extract. Our results suggest that SAG extract is a potential source of natural antioxidants that may be used not only in pharmaceutical and food industry but also in the treatment of diseases associated with oxidative stress. PMID- 24075341 TI - Vasorelaxant activity of extracts obtained from Apium graveolens: possible source for vasorelaxant molecules isolation with potential antihypertensive effect. AB - OBJECTIVE: To investigate vasorelaxant effect of organic extracts from Apium graveolens (A. graveolens) which is a part of a group of plants subjected to pharmacological and phytochemical study with the purpose of offering it as an ideal source for obtaining lead compounds for designing new therapeutic agents with potential vasorelaxant and antihypertensive effects. METHODS: An ex vivo method was employed to assess the vasorelaxant activity. This consisted of using rat aortic rings with and without endothelium precontracted with norepinephrine. RESULTS: All extracts caused concentration-dependent relaxation in precontracted aortic rings with and without endothelium; the most active extracts were Dichloromethane and Ethyl Acetate extracts from A. graveolens. These results suggested that secondary metabolites responsible for the vasorelaxant activity belong to a group of compounds of medium polarity. Also, our evidence showed that effect induced by dichloromethane and ethyl acetate extracts from A. graveolens is mediated probably by calcium antagonism. CONCLUSIONS: A. graveolens represents an ideal source for obtaining lead compounds for designing new therapeutic agents with potential vasorelaxant and antihypertensive effects. PMID- 24075342 TI - Antiplasmodial, cytotoxic activities and characterization of a new naturally occurring quinone methide pentacyclic triterpenoid derivative isolated from Salacia leptoclada Tul. (Celastraceae) originated from Madagascar. AB - OBJECTIVE: To validate scientifically the traditional use of Salacia leptoclada Tul. (Celastraceae) (S. leptoclada) and to isolate and elucidate the structure of the biologically active compound. METHODS: Bioassay-guided fractionation of the acetonic extract of the stem barks of S. leptoclada was carried out by a combination of chromatography technique and biological experiments in viro using Plasmodium falciparum and P388 leukemia cell lines as models. The structure of the biologically active pure compound was elucidated by 1D and 2D NMR spectroscopy and mass spectrometry. RESULTS: Biological screening of S. leptoclada extracts resulted in the isolation of a pentacyclic triterpenic quinone methide. The pure compound exhibited both in vitro a cytotoxic effect on murine P388 leukemia cells with IC50 value of (0.041+/-0.020) MUg/mL and an antiplasmodial activity against the chloroquine-resistant strain FC29 of Plasmodium falciparum with an IC50 value of (0.052+/-0.030) MUg/mL. Despite this interesting anti-malarial property of the lead compound, the therapeutic index was weak (0.788). In the best of our knowledge, the quinone methide pentacyclic triterpenoid derivative compound is reported for the first time in S. leptoclada. CONCLUSIONS: The results suggest that furthers studies involving antineoplastic activity is needed for the development of this lead compound as anticancer drug. PMID- 24075343 TI - Identification of an anticancer compound against HT-29 cells from Phellinus linteus grown on germinated brown rice. AB - OBJECTIVE: To isolate and identify the anticancer compound against proliferation of human colon cancer cells from ethyl acetate (EtOAc) extract of Phellinus linteus grown on germinated brown rice (PB). METHODS: EtOAc extract of PB was partitioned with n-hexane, EtOAc, and water-saturated n-butanol. Anticancer compound of n-hexane layer was isolated and identified by HPLC and NMR, respectively. Cytotoxicity against HT-29 cells was tested by SRB assay. RESULTS: The n-hexane layer obtained after solvent fractionation of PB EtOAc extracts showed a potent anticancer activity against the HT-29 cell line. Atractylenolide I, a eudesmane-type sesquiterpene lactone, a major anticancer substance of PB, was isolated from the n-hexane layer by silica gel column chromatography and preparative-HPLC. This structure was elucidated by one- and two-dimensional NMR spectroscopic data. Atractylenolide I has not been reported in mushrooms or rice as of yet. The isolated compound dose-dependently inhibited the growth of HT-29 human colon cancer cells. CONCLUSIONS: Atractylenolide I might contribute to the anticancer effect of PB. PMID- 24075344 TI - Production of microbial medium from defatted brebra (Milletia ferruginea) seed flour to substitute commercial peptone agar. AB - OBJECTIVE: To investigate and optimize microbial media that substitute peptone agar using brebra seed defatted flour. METHODS: Defatted process, inoculums preparation, evaluation of bacterial growth, preparation of cooked and hydrolyzed media and growth turbidity of tested bacteria were determined. RESULTS: Two percent defatted flour was found to be suitable concentration for the growth of pathogenic bacteria: Escherichia coli (ATCC 25922) (E. coli), Pseudomonas aeruginosa (ATCC 27853), Salmonella (NCTC 8385) and Shigella flexneri (ATCC 12022) (S. flexneri), while 3% defatted flour was suitable for Staphylococcus aureus (ATCC 25923) (S. aureus). E. coli (93+/-1) and S. flexneri (524+/-1) colony count were significantly (P<=0.05) greater in defatted flour without supplement than in supplemented medium. E. coli [(3.72*10(9)+/-2) CFU/mL], S. aureus [(7.4*10(9)+/-2) CFU/mL], S. flexneri [(4.03*10(9)+/-2) CFU/mL] and Salmonella [(2.37*10(9)+/-1) CFU/mL] in non-hydrolyzed sample were statistically (P<=0.05) greater than hydrolyzed one and commercial peptone agar. Colony count of Salmonella [(4.55*10(9)+/-3) CFU/mL], S. flexneri [(5.40*10(9)+/-3) CFU/mL] and Lyesria moncytogenes (ATCC 19116) [(5.4*10(9)+/-3) CFU/mL] on raw defatted flour agar was significantly (P<=0.05) greater than cooked defatted flour and commercial peptone agar. Biomass of E. coli, S. aureus, Salmonella and Enterococcus faecalis in non-hydrolyzed defatted flour is highly increased over hydrolyzed defatted flour and commercial peptone broth. CONCLUSIONS: The defatted flour agar was found to be better microbial media or comparable with peptone agar. The substances in it can serve as sources of carbon, nitrogen, vitamins and minerals that are essential to support the growth of microorganisms without any supplements. Currently, all supplements of peptone agar are very expensive in the market. PMID- 24075345 TI - Anti-inflammatory and antioxidant activities of ethanolic extract of aerial parts of Vernonia patula (Dryand.) Merr. AB - OBJECTIVE: To investigate the inflammatory and antioxidant activities of ethanolic extract of aerial part of Vernonia patula (Dryand.) Merr (EAV). METHODS: The anti-inflammatory activity of EAV was studied using carrageenan and histamine-induced rat paw edema test at different doses (100, 200 and 400 mg/kg body weight). DPPH free radical scavenging, nitric oxide scavenging, reducing power and Fe(2+) ion chelating ability were used for determining antioxidant activities. RESULTS: The EAV, at the dose of 400 mg/kg, showed a significant anti inflammatory activity (P<0.01) both in the carrageenan and histamine-induced oedema test models in rats, showing 62.86% and 64.42% reduction in the paw volume comparable to that produced by the standard drug indomethacin (67.26% and 66.01%) at 5 h respectively. In DPPH free radical scavenging test, IC50 value for EAV was found fairly significant 36.59 MUg/mL when compared to the IC50 value of the reference standards ascorbic acid 8.97 MUg/mL. The IC50 values of the extract and ascorbic acid were 47.72 and 12.39 MUg/mL, respectively in nitric oxide scavenging assay. The IC50 value of the EAV (33.59 MUg/mL) as percentage of Fe(2+) ion chelating ability was also found significant compared to that of EDTA (9.16 MUg/mL). The maximum absorbance for reducing power assay was found to be 1.928 at 100 MUg/mL when compared to 2.449 for standard ascorbic acid. The total phenolic content was 198.81 mg/g of gallic acid equivalent. Acute toxicity test showed that the plant might be safe for pharmacological uses up to a dose level of 3 200 mg/kg of body weight in rats. CONCLUSIONS: Therefore, the obtained results suggest the acute anti-inflammatory and antioxidant activities of the EAV and thus provide the scientific basis for the traditional uses of this plant part as a remedy for inflammations. PMID- 24075346 TI - Production of asiaticoside from centella (Centella asiatica L. Urban) cells in bioreactor. AB - OBJECTIVE: To investigate the effects of some culture conditions on production of asiaticoside from centella (Centella asiatica L. Urban) cells cultured in 5-L bioreactor. METHODS: The centell cell suspension culture was conducted in 5-L bioreactor to investigate the growth and asiaticoside accumulation under various conditions. Asiaticoside content was determined by HPLC analysis. RESULTS: The results showed that the cell growth and asiaticoside accumulation peaked after 24 d of culture at an agitation speed of 150 r/min and aeration rate of 2.5 L/min. The cell biomass reached a maximum value of 302.45 g fresh weight (31.45 g dry weight) and growth index of 3.03 with inoculum size of 100 g. However, asiaticoside content was the highest (60.08 mg/g dry weight) when culture was initiated with an inoculum size of 50 g. CONCLUSIONS: The present study found the suitable conditions for growth of centella cells and their asiaticoside production in bioreactor. PMID- 24075347 TI - In vitro treatments of Echinococcus granulosus with fungal chitosan, as a novel biomolecule. AB - OBJECTIVE: To determined the antiparasitic activity of the isolated chitosan from Penicillium viridicatum, Penicillium aurantiogriseum and commercial chitosan against protoscolicidal of hydatid cysts were determined. METHODS: After isolating chitosan from fungal cell walls, four concentrations (50, 100, 200, 400 MUg/mL) of each type of prepared chitosan and commercial chitosan were used for 10, 30, 60, and 180 min, respectively. RESULTS: Among different type of chitosan, commercial chitosan with the highest degree of deacetylation showed high scolicidal activity in vitro. Fungal chitosan could be recommended, as good as commercial chitosan, for hydatic cysts control. CONCLUSIONS: It seems to be a good alternative to synthetic and chemical scolicidal. PMID- 24075348 TI - In vitro activity of natural honey alone and in combination with curcuma starch against Rhodotorula mucilaginosa in correlation with bioactive compounds and diastase activity. AB - OBJECTIVE: To evaluate the in vitro activity and synergism of the combinations of natural honey and curcuma starch against Rhodotorula mucilaginosa in correlation with total phenolic, flavonoid contents, and diastase activity. METHODS: The Folin-Ciocalteu test was used to determine the total polyphenols content and the flavonoid content was analyzed using by the aluminum chloride method. The antifungal activity of the natural honey, determined by an agar well diffusion assay and agar incorporation method. RESULTS: Total phenolic content varied from (63.930.11) to (95.366.08) mg GAE/100 g honey as gallic acid equivalent. Total flavonoids content varied from (5.41+/-0.04) to (9.94+/-0.54) mg CE/100 g. Diastase activity values were between (7.3+/-2.8) and (26+/-2.8). The zone inhibition diameter for the six honey samples without starch ranged between 6 and 20 mm. When starch was mixed with honey and then added to well, a zone inhibition increase diameter 7 and 21 mm. The percentage increase was noticed with each variety and it ranged between 5% and 62.5%. The minimal inhibitory concentrations for the six varieties of honey without starch against Rhodotorula mucilaginosa ranged between 28% and 36% (v/v). When starch was incubated with honey and then added to media, a minimal inhibitory concentration drop has been noticed with each variety. It ranged between 6.66 % and 20% (w/v). No significant correlation was established between diastase activity and bioactive compounds. CONCLUSIONS: The mixture of curcuma starch and honey could lead to the development of new combination antibiotics against Rhodotorula infections. PMID- 24075349 TI - Seroprevalence of avian influenza (H9N2) in broiler chickens in Northwest of Iran. AB - OBJECTIVE: To demonstrate seroprevalence of avian invluenza (H9N2) subtybe in broiler chickens in Northwest of Iran. MATERIALS: A total of 310 blood samples were collected from 25 broiler flocks in slaughterhouses of West Azarbayjan, Iran. Serum samples were subjected to haemagglutination inhibition test. RESULTS: The test showed 40.6% of positive serums. Mean antibody titer of avian influenza virus differed between geographical locations in this survey. CONCLUSIONS: High prevalence of avian influenza virus antibodies in serum of birds emphasize that avian influenza has an important role in respiratory complexes in broiler chickens in this region, and probably throughout Iran. Biosecurity measures, monitoring and surveillance programs, and to some degree vaccination are effective tools to prevent introduction of H9N2 infection and its economic losses. PMID- 24075350 TI - First detection of Leishmania infantum DNA in wild caught Phlebotomus papatasi in endemic focus of cutaneous leishmaniasis, South of Iran. AB - OBJECTIVE: To identify the vectors and reservoirs of cutaneous leishmaniasis in the endemic focus of Farashband, Fars Province, South of Iran. METHODS: Sticky papers and Sherman trap were used for collection of sand flies and rodents, respectively. Polymerase chain reaction (PCR) of kDNA, ITS1-rDNA were used for identification of Leishmania parasite in sand flies as well as rodents. RESULTS: Totally 2 010 sand flies were collected and the species of Phlebotomus papatasi Scopoli was the common specimen in outdoors and indoors places. PCR technique was employed on 130 females of Phlebotomus papatasi. One of them (0.76%) was positive to parasite Leishmania major (L. major) and one specimen (0.76%) was positive to Leishmania infantum. Microscopic investigation on blood smear of the animal reservoirs for amastigote parasites revealed 16 (44%) infected Tatera indica. Infection of them to L. major was confirmed by PCR against kDNA loci of the parasite. CONCLUSIONS: The results indicated that Phlebotomus papatasi was the dominant species circulating two species of parasites including L. major and Leishmania infantum among human and reservoirs. Furthermore, Tatera indica is the only main host reservoir for maintenance of the parasite source in the area. PMID- 24075351 TI - Mucormycosis in a diabetic ketoacidosis patient. AB - Oral cavity is considered to be a kaleidoscope for body's general health. Many systemic conditions do present with diverse oral manifestations. Mucormycosis involving the oral cavity is one such entity that presents as necrosis of bone in immunocompromised patients. Mucormycosis is an opportunistic fungal infection that mainly affects the patients with uncontrolled diabetes mellitus. Hereby, we report a case of mucormycosis involving the palate in a patient with diabetic ketoacidosis. PMID- 24075352 TI - Review on pharmacological and toxicologyical effects of oleum azadirachti oil. AB - Oleum azadirachti consists of the oil obtained from dried seeds of Azadirachta indica A. Juss. (family: Meliaceae). Local names of Azadirachta indica A. Juss. are Abodua, aforo-oyinbo, anwe egyane, arista, azad dirakht, azadarakht, azedarach and bead tree. Indigenous to India, and widely distributed in South and South-East Asia and cultivated in Africa, the South Pacific Islands, South and Central America and Australia, and in southern Florida and California, United States of America, it is a straight-boled deciduous tree, which is 6-25 m high. Bark is dark-brown, externally fissured with a buff inner surface and fibrous fracture. Leaves alternately arranged, pinnately compound and up to 40 cm long, and composed of 8-18 short-petiolate narrow-ovate, pointed and curved toothed leaflets, 3-10 cm long and 1-4 cm wide arranged in alternate pairs. The major constituents are oxidized tetranortriterpenes including azadirachtin (azadirachtin A), azadiriadione, epoxyazadiradione, azadirone, nimbidin, nimbin, deacetylnimbin, salannin, gedunin, mahmoodin, 17-hydroxydiradione and related derivatives. It is of various medicinal uses, such as a contraceptive for intravaginal use, a mosquito repellent, and treatment of vaginal infections, treatment of gastric ulcers, cardiovascular disease, malaria, rheumatism and skin disorders, external applications for treatment of septic wounds, ulcers and boils, treatment of allergic skin reactions, asthma, bruises, colic, conjunctivitis, dysmenorrhoea, fever, gout, headache, itching due to varicella, kidney stones, leukorrhoea, psoriasis, scabies, sprains and muscular pain, and wounds. It is also used as an emmenagogue, tonic, stomatic and vermicide. In conclusion, the plant oil had antifertility, antihyperglycaemic, anti inflammatory, antimicrobial, antiviral, antiulcer, estrogenic, immune, contraceptive, antibacterial, insect repellent, and skin treatment effects. PMID- 24075353 TI - Gene polymorphisms of Interleukin-4 in allergic rhinitis and its association with clinical phenotypes. AB - BACKGROUND: Allergic rhinitis (AR) is an inflammatory disorder of the upper airway. T-helper (Th)2 cytokines seems to have major roles behind the scene of unpleasant symptoms resulted from AR. Expression of interleukin (IL)-4 and its receptor could be affected by single nucleotide polymorphisms (SNPs). This study assessed the effect of 4 genetic variants within genes of IL-4 and IL-4R in AR. METHODS: Allele frequencies of one IL-4R variant (rs1801275) and three SNPs of IL 4 (rs2243248, rs2243250, and rs2070874) were investigated in 98 patients with AR, compared to a group of controls, using PCR sequence-specific-primers (PCR-SSP) method. RESULTS: Homozygosity for the C allele of rs2243250 in IL-4 was significantly overrepresented in the patient group. CC genotype in rs2070874 significantly was correlated with AR. GG/CC/CC and TT/TT/TT (rs2243248, rs2243250, and rs2070874) haplotypes in the IL-4 gene had a significant negative correlation with AR. CONCLUSION: SNPs in IL-4 are associated with AR and could change the clinical picture of the disease in patients. PMID- 24075354 TI - A classically enlarged cardiac silhouette. PMID- 24075355 TI - Improving diabetes control using shared medical appointments. PMID- 24075356 TI - The role of TonB-dependent receptor TbdR1 in Riemerella anatipestifer in iron acquisition and virulence. AB - Riemerella anatipestifer is an important duck pathogen and causes serious economic losses to the duck industry worldwide. To date, four full R. anatipestifer genomic sequences have been submitted to the GenBank database and 31 TonB-dependent outer membrane receptors, which may play critical roles in host bacteria interactions, were predicted for R. anatipestifer strain GSM15868. In our previous study, we reported that the TonB-dependent receptor TbdR1 was a cross immunogenic antigen among R. anatipestifer serotypes 1, 2, and 10. However, the biological functions of TbdR1 in R. anatipestifer remain unclear. In the present study, a tbdR1 (Riean_1607) deletion mutant CH3DeltatbdR1 of R. anatipestifer strain CH3 was constructed and characterized for iron-limited growth, biofilm formation, and pathogenicity to ducklings. Our results showed that TbdR1 was involved in hemin iron acquisition and the tbdR1 deletion significantly reduced biofilm formation and adhesion to and invasion of Vero cells. Animal experiments indicated that the median lethal dose of the CH3DeltatbdR1 mutant in ducklings was about 45-fold higher than that of the wild type CH3 strain. Additional analysis indicated that bacterial loads in blood, liver, and brain tissues in CH3DeltatbdR1-infected ducklings were decreased significantly compared to those in wild-type CH3-infected ducklings. Thus, our results demonstrated that TbdR1 was involved in hemin iron acquisition and necessary for optimal bacterial virulence. PMID- 24075357 TI - Brucella ovis lacking a species-specific putative ATP-binding cassette transporter is attenuated but immunogenic in rams. AB - Ovine brucellosis caused by Brucella ovis is considered one of the most important reproductive diseases of rams worldwide. This study aimed to characterize the kinetics of infection of a DeltaabcAB B. ovis mutant strain in rams. Twelve 1 year-old crossbred rams were used. Six rams were challenged with 2 mL of a suspension containing 1.2*10(9) CFU/mL of B. ovis strain ATCC25840 (wild type) by intraprepucial inoculation and additional 50 MUL in each conjunctival sac of a suspension containing 1.2*10(10) CFU/mL of the same strain. The other six rams were challenged with an equivalent number of CFU of the mutant strain DeltaabcAB B. ovis through the same routes. Serum samples for serology and semen and urine samples for bacteriologic culture and PCR were collected weekly during 24 weeks. At 24 weeks post infection, tissue samples were collected for bacteriologic culture and PCR. All rams inoculated with wild type or the DeltaabcAB strain seroconverted at the fourth week post infection, remaining positive up to the 16th week post infection. PCR and bacteriology demonstrated that only rams inoculated with the wild type strain shed the organism in semen and urine. Lymphocytes from rams inoculated with wild type or DeltaabcAB B. ovis had significantly higher proliferation in response to B. ovis antigens when compared with unstimulated controls. Tissue bacteriology and PCR detected B. ovis in all rams challenged with the wild type strain, whereas only one DeltaabcAB-infected ram had a positive iliac lymph node sample by PCR. PMID- 24075358 TI - GSTA1, GSTM1, GSTP1, and GSTT1 polymorphisms and susceptibility to smoking related bladder cancer: a case-control study. AB - OBJECTIVES: Glutathione S-transferases (GSTs) are a family of enzymes involved in detoxification. Genes encoding for GSTA1, GSTM1, GSTP1, and GSTT1 proteins are polymorphic, which can result in complete or partial loss of enzyme activity. Previous studies have associated polymorphisms of GSTA1, GSTM1, and GSTP1 genes with a higher risk of bladder cancer, but this is still controversial. Potential role of GSTA1 polymorphism in susceptibility to bladder cancer in Whites is lacking. We examined association between GSTA1, GSTM1, GSTP1, and GSTT1 gene variants and bladder cancer risk and evaluated whether they were modified by smoking. MATERIALS AND METHODS: A hospital-based case-control study recruited 201 incidence cases and 122 age-matched controls. Deletion polymorphism of GSTM1 and GSTT1 was identified by polymerase chain reaction method. Single nucleotide polymorphism of GSTA1 and GSTP1 was identified by restriction fragment length polymorphism method. Uniconditional multivariate logistic regression was applied to model association between genetic polymorphisms and bladder cancer risk, as well as effect modification by smoking. RESULTS: No significant difference was observed in the distributions of GSTM1, GSTT1, GSTA1, and GSTP1 gene variants between patients and controls. None of the examined polymorphisms was significantly associated with bladder cancer risk independently. The results of gene-smoking interaction analyses indicated a significant combined effect of smoking and all common GST polymorphisms tested (P for trend = 0.001). However, the most significant effect on bladder cancer risk was observed in smokers carrying lower activity GSTA1-AB/BB and GSTM-null genotype (OR = 3.5, P < 0.05) compared with GSTA1-AA and GSTM1-active non-smokers. Overall, the risk observed did not significantly differ with respect to quantity of cigarettes smoked. However, heavy smokers with GSTM1-null genotype had 2 times higher risk of bladder cancer than GSTM1-null light smokers (OR = 4.8 vs. OR = 2.0) when GSTM1 active non-smokers served as reference group. Smokers carrying both GSTM1-null and GSTA1-AB + BB genotypes exhibited the highest risk of bladder cancer (OR = 2.00, P = 0.123). CONCLUSIONS: Null or low-activity genotypes of the GSTA1, GSTM1, GSTT1, and GSTP1 did not contribute independently towards the risk of bladder cancer in our patients. However, in association with smoking, both low activity GSTA1 and GSTM1-null genotype increase individual susceptibility to bladder cancer. PMID- 24075359 TI - Early coverage of Bioabsorbable Scaffold after STEMI analysed by 2D and 3D optical coherence tomography. PMID- 24075360 TI - A fusion-based approach for uterine cervical cancer histology image classification. AB - Expert pathologists commonly perform visual interpretation of histology slides for cervix tissue abnormality diagnosis. We investigated an automated, localized, fusion-based approach for cervix histology image analysis for squamous epithelium classification into Normal, CIN1, CIN2, and CIN3 grades of cervical intraepithelial neoplasia (CIN). The epithelium image analysis approach includes medial axis determination, vertical segment partitioning as medial axis orthogonal cuts, individual vertical segment feature extraction and classification, and image-based classification using a voting scheme fusing the vertical segment CIN grades. Results using 61 images showed at least 15.5% CIN exact grade classification improvement using the localized vertical segment fusion versus global image features. PMID- 24075361 TI - Dextrose gel for neonatal hypoglycaemia (the Sugar Babies Study): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Neonatal hypoglycaemia is common, and a preventable cause of brain damage. Dextrose gel is used to reverse hypoglycaemia in individuals with diabetes; however, little evidence exists for its use in babies. We aimed to assess whether treatment with dextrose gel was more effective than feeding alone for reversal of neonatal hypoglycaemia in at-risk babies. METHODS: We undertook a randomised, double-blind, placebo-controlled trial at a tertiary centre in New Zealand between Dec 1, 2008, and Nov 31, 2010. Babies aged 35-42 weeks' gestation, younger than 48-h-old, and at risk of hypoglycaemia were randomly assigned (1:1), via computer-generated blocked randomisation, to 40% dextrose gel 200 mg/kg or placebo gel. Randomisation was stratified by maternal diabetes and birthweight. Group allocation was concealed from clinicians, families, and all study investigators. The primary outcome was treatment failure, defined as a blood glucose concentration of less than 2.6 mmol/L after two treatment attempts. Analysis was by intention to treat. The trial is registered with Australian New Zealand Clinical Trials Registry, number ACTRN12608000623392. FINDINGS: Of 514 enrolled babies, 242 (47%) became hypoglycaemic and were randomised. Five babies were randomised in error, leaving 237 for analysis: 118 (50%) in the dextrose group and 119 (50%) in the placebo group. Dextrose gel reduced the frequency of treatment failure compared with placebo (16 [14%] vs 29 [24%]; relative risk 0.57, 95% CI 0.33-0.98; p=0.04). We noted no serious adverse events. Three (3%) babies in the placebo group each had one blood glucose concentration of 0.9 mmol/L. No other adverse events took place. INTERPRETATION: Treatment with dextrose gel is inexpensive and simple to administer. Dextrose gel should be considered for first-line treatment to manage hypoglycaemia in late preterm and term babies in the first 48 h after birth. FUNDING: Waikato Medical Research Foundation, the Auckland Medical Research Foundation, the Maurice and Phyllis Paykel Trust, the Health Research Council of New Zealand, and the Rebecca Roberts Scholarship. PMID- 24075362 TI - Jonas Gahr Store: health as a collective responsibility. PMID- 24075363 TI - Treatment of blood glucose concentrations in newborn babies. PMID- 24075364 TI - Complication from hearing aid mold material: a case report and review of legal matters. AB - Ear mold impression middle ear foreign bodies are a rare complication of hearing aid fitting. Only a small number of cases have been reported; however, the actual incidence is unknown and likely much higher than expected. We present the case of a 77-year-old man with a history of preexisting tympanic membrane perforations who presented with an ear mold impression middle ear foreign body that required surgical removal. We explore the state and federal laws that guide the interaction between patients, hearing aid sellers and otolaryngologists. We highlight steps that can be taken to reduce the incidence of this complication. PMID- 24075365 TI - Modern role of sacrospinous ligament fixation for pelvic organ prolapse surgery- a systemic review. AB - Pelvic organ prolapse (POP) is a common condition in women. Women with POP often experience pelvic discomfort, urinary and fecal problems, sexual dysfunction, and an overall decrease in their quality of life. Surgical treatment is a feasible option if conservative management fails. Various surgical techniques have been proposed to correct POP with or without the use of graft material. Owing to recent U.S. Food and Drug Administration warnings about mesh-related complications, sacrospinous ligament fixation (SSF), as a traditional vaginal procedure, may play an important role again. To answer this question and evaluate quantitatively the efficacy of SSF in POP, we conducted a systemic review of the available data about SSF and POP. Interventions had to include SSF as a point of attachment. To eliminate confounding bias and effect modification, at least one arm must include SSF without mesh or graft. All follow-up periods were allowed. Information on the following parameters was extracted and entered into a database: study design, type of intervention, number of patients, follow-up in months, cure rate, recurrence rate, intra/postoperative complications, and/or uni/bilateral, preventive/therapeutic, or concomitant procedures. Published papers from the years 1995 to 2011 were selected for analysis. PMID- 24075366 TI - Postpartum aortic dissection. AB - Postpartum aortic dissection is a rare but lethal event. Until now, only a limited number of cases have been reported, and a comprehensive literature review from 1988 to 2012 yielded 27 cases. Postpartum aortic dissection occurred between Day 1 and Day 42 after delivery, either vaginally or by cesarean section. Pregnancy alone without underlying contributing risk factors and Marfan syndrome were the two main risk factors for postpartum aortic dissection, accounting for 44.4% and 40.7% of cases, respectively. Late presentation and delayed diagnosis may lead to sudden death. Improving prenatal and peripartum care is, therefore, crucial in preventing the development of aortic dissection. Prompt diagnosis and timely treatment of postpartum aortic dissection may prevent patient death. PMID- 24075367 TI - Two-year neurological outcome of very-low-birth-weight children with prenatal absent or reversed end-diastolic flow velocity in the umbilical artery. AB - OBJECTIVE: The aim of this study was to investigate the 2-year neurological outcome of very-low-birth-weight (VLBW) children who had abnormal umbilical blood flow velocity prenatally. MATERIALS AND METHODS: We performed a prospective collection of infants prenatally diagnosed with abnormal umbilical blood flow velocity at a tertiary referral center from January 1, 2001 to September 30, 2005. VLBW children with prenatal absent or reversed end-diastolic flow velocity (AREDV) in the umbilical artery were investigated and compared with two similar demographic control groups of VLBW children without AREDV: one group with fetal growth restriction and the other without it. A follow-up study at 2 years of age for Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) of the Bayley Scales among the three groups was analyzed. RESULTS: Twenty-four VLBW children were identified to have AREDV prenatally, of whom four died during the neonatal period. After 2 years, five children were lost to follow-up and 15 were rescued, of whom 11 had absent end-diastolic velocity and four reversed end diastolic velocity. We compared the remaining 15 children with the two control groups [28 children in the matched control group with intrauterine fetal growth restriction (IUGR), and 38 children in the matched control group without IUGR], and no significant differences were found in MDI (p = 0.938) and PDI (p = 0.496) scores at 2 years of age. However, we also surveyed the children with a gestational age of <= 29 weeks and found a significant difference in MDI scores (p = 0.048), but not in PDI scores (p = 0.219), among the three groups. CONCLUSION: VLBW children delivered earlier than 29 gestational weeks with abnormal umbilical blood flow velocity prenatally have greater mental developmental delay at 2 years of age. PMID- 24075368 TI - Pregnancy outcome and neonatal data of children born after intracytoplasmic sperm injection with a different duration of cryopreservation of spermatozoa obtained through testicular sperm extraction. AB - OBJECTIVE: To evaluate the impact of the duration of cryopreservation of testicular sperm on clinical and neonatal outcomes after intracytoplasmic sperm injection (ICSI) for patients experiencing azoospermia. MATERIALS AND METHODS: This study included 132 azoospermic men who participated in 212 ICSI cycles. The participating men underwent testicular biopsy for the cryopreservation of tissue to be used for subsequent ICSI cycles. The duration of the storage of testicular sperm was determined by the time of oocyte retrieval. Fertilization, embryo development in vitro, pregnancy rates, and neonatal outcomes were assessed. RESULTS: Although the mean percentage of viability decreased from 73.2% prior to freezing to 50.2% after thawing, viable spermatozoa were visualized subsequent to thawing of the tissue samples for all patients. The potential for fertilization and subsequent embryonic development was not influenced by the duration of sperm cryopreservation up to 2 years longer. The pregnancy outcomes also varied independently of the duration of sperm cryopreservation. The duration of storage did not appear to affect the neonatal outcomes adversely, including the Apgar score and intensive care unit admission rates, although neonatal outcomes were influenced by advanced maternal age. It also has no obvious impact on the major and minor congenital malformation rate of the newborns. CONCLUSION: ICSI outcomes, pregnancy outcome, neonatal outcome, and congenital malformation rate appear not to be affected by the duration of the period of cryostorage. An earlier start of the ICSI cycle following the testicular sperm cryopreservation is preferable because longer preservation is associated with more advanced maternal age. PMID- 24075369 TI - Effects of sex hormones on cell proliferation and apoptosis in the urinary bladder muscle of ovariectomized rat. AB - OBJECTIVE: To reveal the exogenous effects of sex hormones on cell proliferation and apoptosis in the detrusor muscle of ovariectomized rat urinary bladder. MATERIALS AND METHODS: Proliferating cell nuclear antigen (PCNA) and in-situ apoptosis detection kit were used to evaluate cell proliferation and death in the detrusor muscle of castrated female rats after 1 day, 3 days, and 7 days of supplementary sex steroid hormone administration, including estrogen, progesterone, and testosterone. The percentage of cells positive for PCNA (proliferative index) and for apoptosis (apoptotic index) in various groups was calculated. RESULTS: When compared to the group of bilateral ovariectomy without hormonal supplementation, the groups given 3 days and 7 days of estrogen supplementation (p = 0.031 and p = 0.005, respectively) and the group given 7 days of combined supplementation with estrogen and progesterone (p = 0.044) had a significant increase in the proliferative indices. A significant decrease of apoptotic index was found in the group given 7 days of estrogen supplementation when compared to bilateral ovariectomy without hormonal supplementation (p = 0.035). CONCLUSIONS: Exogenous estrogen supplementation stimulates proliferation and slows down apoptosis in the detrusor muscle of ovariectomized rat urinary bladder, an effect not counteracted by concomitant use of progesterone. Our results may have clinical implications for estrogen supplementation in offering benefits to menopausal women with lower urinary tract syndromes, based on evaluating the relationship between cell apoptosis and cell proliferation. PMID- 24075370 TI - Following the 2009 American Institute of Medicine recommendations for normal body mass index and overweight women led to an increased risk of fetal macrosomia among Taiwanese women. AB - OBJECTIVE: This study aimed to investigate the risk of birth weights over 4000 g (macrosomia) in association with following the 2009 American Institute of Medicine (AIOM) recommendations. MATERIALS AND METHODS: Seventy-six nondiabetic women who delivered a singleton, term macrosomic fetus and 82 women who delivered a singleton, term fetus weighing <4000 g were analyzed retrospectively. The relationship between the risk of macrosomia and gestational weight gain in different periods of pregnancy was investigated using logistic regression. RESULTS: The incidence of macrosomia from January 2008 to December 2009 was 1.8% among the Taiwanese women. The incidences of cesarean delivery (54.5% vs. 18.2%, p < 0.001) and blood loss >1000 mL at delivery (35.5% vs. 6.1%, p < 0.0001) were associated with macrosomia. The risk of macrosomia among normal weight women with gestational weight gain greater than 13 kg increased four-fold [odds ratio (OR) = 4.88; 95% confidence interval (CI) 1.84-12.90]. For overweight women with total gestational weight gain >11.5 kg, the risk of macrosomia increased nine-fold (OR = 9.63; 95% CI 1.76-52.74). CONCLUSION: Macrosomia resulted in more cesarean deliveries and greater maternal blood loss at birth. In Taiwan, to prevent macrosomia, we suggest that the total gestational weight gain should be <11.5 kg among normal weight women and within 10 kg for overweight women. PMID- 24075371 TI - Perinatal outcome in normal pregnant women with incidental thrombocytopenia at delivery. AB - OBJECTIVE: To investigate the perinatal outcomes of women who suffered from thrombocytopenia at delivery but did not have other diseases during pregnancy. MATERIALS AND METHODS: We considered all singleton deliveries after 24 weeks of gestation at Chang Gung Memorial Hospital, Taipei, Taiwan between 2001 and 2010. Women were excluded from this study if they suffered from any of the following conditions: chronic hypertension, hepatitis, acute fatty liver, liver cirrhosis, nephropathy, overt diabetes mellitus, connective tissue disease, systemic lupus erythematosus, or immune thrombocytopenia. Pregnancies complicated by gestational hypertension, preeclampsia, or fetal anomalies during gestation were also excluded. A total of 18,384 deliveries were included for analysis. Women were divided into three groups according to platelet count at admission. RESULTS: A total of 787 pregnancies (4.3%) were complicated by thrombocytopenia. Thrombocytopenic women had a significantly higher rate of cesarean delivery compared to women who did not have this condition. No other differences were observed among these three groups regarding the rates of adverse pregnancy outcomes. CONCLUSIONS: The results indicate that women who suffered from incidental thrombocytopenia at delivery but did not have other diseases during pregnancy were not at increased risk for adverse pregnancy outcomes. PMID- 24075372 TI - The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa. AB - OBJECTIVE: To determine whether advanced male age influences the outcome of intracytoplasmic sperm injection (ICSI) following the cryopreservation of spermatozoa obtained through testicular sperm extraction (TESE). MATERIALS AND METHODS: Data were collected from infertile couples suffering from azoospermia who underwent TESE and ICSI from January 1998 to August 2010. There were 212 ICSI cycles using extracted testicular sperm after cryopreservation in this retrospective clinical analysis. The participating men all underwent testicular biopsy and subsequent tissue cryopreservation in a single academic tertiary care medical center. Those cryopreserved sperm were used during consecutive intracytoplasmic sperm injection treatment cycles. Female partners underwent individualized controlled ovarian hyperstimulation programs. RESULTS: A total of 184 ICSI cycles were divided into the following two evaluation designs: (1) total cycles irrespective maternal age; (2) ICSI cycles with maternal age <34 years. Male partners were stratified into age categories at 5-year intervals (31-35 years, 36-40 years, and 41-51 years) in these two designs. In the first design, most outcomes of assisted reproductive techniques were similar during the three groups, but the maternal age is much lower in the first group, and the mean number of retried oocytes and estradiol level on the day of human chorionic gonadotropin injection was significantly higher in the first group. In the second design, the outcome of intracytoplasmic sperm injection and clinical factors including the estradiol level on the day of human chorionic gonadotropin injection, the number of retrieved oocytes, the rate of cleaved oocytes, the number of transferred embryos, the numbers of transferred good embryos, the clinical pregnancy rate per transfer cycle and the implantation rate were similar among the three groups of women aged <34 years after adjusting for female age. CONCLUSIONS: There is insufficient evidence to demonstrate an unfavorable effect of advanced paternal age on the fertility outcome for TESE-ICSI. The thawed testicular spermatozoa from males aged <= 40 years did not have an adverse impact on ICSI outcomes. PMID- 24075373 TI - Seroprevalence of influenza A H1N1 and seroconversion of mothers and infants induced by a single dose of monovalent vaccine. AB - OBJECTIVE: To determine the prevalence of preexisting antibodies against the pandemic 2009 Influenza A (H1N1) virus in pregnant women and to evaluate the seroprotection of the mothers and infants by a single injection of monovalent vaccine during the pandemic. MATERIALS AND METHODS: Seropositivity rate of H1N1 among the nonvaccinated were compared with the vaccinated women. A single dose of vaccine, either nonadjuvanted AdimFlu-S or MF59-adjuvanted vaccine, was injected to the voluntarily vaccinated group. Maternal and cord blood sera were collected to evaluate the antibody response of the H1N1 virus. Seropositivity was defined as a hemagglutination inhibition titer to H1N1 (A/Taiwan/126/09) >= 1:40. RESULTS: A total of 210 healthy, singleton, pregnant women were enrolled between January 2010 and May 2010. Seropositivity (>= 1:40) of maternal hemagglutination inhibition was significantly higher in the vaccinated group (78%) than the nonvaccinated group (9.5%); 41.6% (20/48) of seropositive titers were >1:80. In nine vaccinated cases resulting in negative serum titers (<1:40), the prevalence of negative titer in the women received AdimFlu-S (14.8%, 4/31) was lower (p = 0.025) than those received MF59-adjuvanted vaccine (50%, 5/10). CONCLUSIONS: Subclinical infection against H1N1 was low in Taiwanese pregnant women in the pandemic 2009. Seropositivity >75% could be achieved in the paired maternal and cord serum samples by a single injection of monovalent H1N1 vaccine. PMID- 24075374 TI - Treatment of infertile women with unilateral tubal occlusion by intrauterine insemination and ovarian stimulation. AB - OBJECTIVE: The aim of this study was to evaluate the value of intrauterine insemination (IUI) combined with ovarian stimulation in women with unilateral tubal occlusion detected on hysterosalpingography (HSG). MATERIALS AND METHODS: A total of 703 patients undergoing IUI and controlled ovarian hyperstimulation were enrolled in this study. The study group consisted of 133 patients treated for unilateral tubal occlusion diagnosed by HSG during 2005-2011. The control group consisted of 570 patients with unexplained infertility treated during the same period. In all cases of the retrospective study, menstrual cycles were regular, basal serum follicle-stimulating hormone levels and sperm parameters were normal. RESULTS: There were no significant differences in pregnancy rate per cycle between the study (17.3%) and control groups (18.9%). The pregnancy rate was higher in patients with proximal tubal occlusion (21.7%) compared with mid-distal tubal occlusion (12.5%) or unexplained infertility (18.9%), but the difference was not statistically significant. CONCLUSIONS: Infertile patients with only unilateral proximal tubal occlusion detected on HSG can be treated initially by IUI combined with ovarian stimulation. The cycle outcomes in patients with proximal tubal occlusion are similar to patients with unexplained infertility. However, the stimulated IUI might not be a good choice for patients with unilateral mid-distal tubal occlusion because of a lower success rate, although further evidence is needed. PMID- 24075375 TI - Effects of estradiol and progestogens on human breast cells: regulation of sex steroid receptors. AB - OBJECTIVES: To examine the effects of 17beta-estradiol (E2) and progestogens, used in hormone therapy, on estrogen receptors (ER), progesterone receptors (PR), and human breast tumor cell growth. MATERIALS AND METHODS: MCF-7 cells were incubated in pure E2 (1 nM and 10 nM) as well as in E2 in conjunction with 10 nM progestogens, including progesterone (P4), medroxyprogesterone acetate (MPA), norethisterone acetate (NET), and cyproterone acetate (CPA). Cell proliferation, apoptosis, expression of caspase-3, and both ER and PR isoforms were evaluated. RESULTS: Caspase-3 was significantly diminished in cultures with only E2, whereas ERalpha significantly increased. A significant increase of caspase-3 in addition to the entire abolishment of E2-induced augmentation of ERalpha was observed in 1 nM E2 plus MPA and 10 nM E2 plus NET, whereas PR isoform B (PRB) was significantly increased. The ratios of apoptosis: proliferation significantly increased in 1 nM E2 plus progestogens (except P4) and 10 nM E2 plus NET. The changes of the PRA/PRB ratio were inversely related to the changes of the apoptosis to proliferation ratio. Significant increase of ERbeta and PRB was noted in the E2 plus MPA or NET, in addition to a significant increase of ERalpha and decrease of PRA in the E2 plus CPA, as well as an increase of ERalpha and decrease of PRA and PRB in the E2 plus P4. CONCLUSIONS: The combination of E2 and various progestogens resulted in diverging effects on ERs and PRs expressions, which induced different effects on MCF-7 cell growth. Compared with P4, aberrant hormone and biological activity of synthetic progestin, by way of altered receptor expression, may be an important factor in affecting breast cell growth. PMID- 24075376 TI - Blastocyst morphology score as an indicator of embryo competence for women aged younger than 38 years in in vitro fertilization cycles. AB - OBJECTIVE: This study aimed to clarify the usefulness of blastocyst scores and female age as embryo competence markers for embryo transfer in in vitro fertilization (IVF) cycles. MATERIALS AND METHODS: A total of 352 IVF cycles were investigated. The relevance of blastocyst scores and female age to pregnancy outcome was assessed by logistic regression analysis. RESULTS: We revealed that, for patients aged < 35 years, the score of the best embryo was the sole factor related to multiple pregnancy, whereas the score of the best two embryos was the only factor relevant to pregnancy. For patients aged 35-37 years, the score of the best three embryos was the sole factor correlated to both pregnancy and multiple pregnancy. As for older patients, the correlation between blastocyst morphology and pregnancy outcome was mainly affected by female age. CONCLUSION: The blastocyst score could be used to determine the number of blastocysts transferred to younger patients, but it is less useful for patients aged > 38 years. For older patients, female age is a better indicator to determine the number of transferred blastocysts. PMID- 24075377 TI - Clinical and urodynamic effects of tolterodine in women with an overactive bladder. AB - OBJECTIVE: The aim of this study was to compare the changes in urinary symptoms and urodynamic parameters after administration of tolterodine in women with an overactive bladder (OAB). MATERIALS AND METHODS: Thirty-eight women diagnosed with OAB and treated with tolterodine were reviewed. Urinalysis, pelvic examination, 3-day bladder diary, urodynamic study, and a personal interview to identify urinary symptoms prior to and 3 months after treatment were recorded and interpreted. RESULTS: Most of our patients were menopausal (76.3%; mean age 55.7 years) and multiparous (mean parity 3.3) women. Urinary symptoms such as urinary frequency, urgency, urge incontinence, and nocturia were decreased significantly (p < 0.05). All urodynamic parameters did not change significantly except for the maximum cystometric capacity (p < 0.05), showing a significant increase after 3 months of medication. CONCLUSIONS: Tolterodine, at a recommended dose, improves the symptoms of OAB syndrome without causing urine retention, as proved by the changes of urodynamic parameters. PMID- 24075378 TI - Is conization once following by simple hysterectomy sufficient for all clinical stage IA1 cervical squamous cell carcinoma? AB - OBJECTIVE: The goal of this study is to assess the feasibility of simple extrafascial hysterectomy for patients with clinical stage IA1 cervical squamous cell carcinoma (SCC) after once conization regardless of any pathologic risk factor. MATERIALS AND METHODS: All cases with T1a1, SCC lesion in their cervical cone specimen were retrospectively collected after chart and pathology review for the period between January 2002 and December 2009. All cases underwent subsequent hysterectomies within a month of diagnosis. Pathologic risk factors of conization, surgical scale of hysterectomy, residual lesion of the uterus, necessity of adjuvant radiation therapy, complications, and survival were analyzed in this study. RESULTS: Eighty-one cases were identified from the registry. Most were managed by simple hysterectomy (SH; 60/81, 74%), and the remaining 21 cases underwent modified radical hysterectomy (MRH). All cases without any risk factors in their cone specimens demonstrated residual lesion <=T1a1 in both SH and MRH groups, whereas those with existing risk factor were confirmed positive for residual lesions <=T1a1 [SH, 95.8% (46/48) vs. MRH, 75% (15/20)]. Only two cases in the SH group received adjuvant radiation for residual lesions >T1a1. On the contrary, 15 cases in the MRH group can receive smaller scale surgery than MRH. All cases were recurrence-free without any permanent treatment-related complication by the end of the study. CONCLUSION: Extrafascial simple hysterectomy may be recommended for clinical T1a1 cervical SCC regardless of the pathologic risk factor. PMID- 24075379 TI - High success rate and considerable adverse events of pelvic prolapse surgery with Prolift: a single center experience. AB - OBJECTIVES: The aim of this study was to analyze short-term outcomes of pelvic prolapse surgery using Prolift transvaginal mesh in a teaching hospital. MATERIALS AND METHODS: Thirty-four patients who received prolapse surgery with Prolift were followed up for 7-26 months. Assessment included pre- and postoperative Pelvic Organ Prolapse Quantification (POP-Q) stage, and Urogenital Distress Inventory (UDI)-6, and Incontinence Impact Questionnaire (IIQ)-7 scores. Surgical characteristics and adverse events during follow-up were also recorded. RESULTS: Objective and subjective data were available for 29 patients. The overall anatomical success rate was 96.5 % (28/29) after a mean of 18 +/- 6.3 months follow-up. The POP-Q, UDI, and IIQ all improved significantly after surgery. Uterine sparing prolapsed surgery with Prolift unexpectedly yielded a cure rate of 100%. Ten adverse events occurred during and after prolapse surgery with dyspareunia (3/34) as the most common, followed by bladder injury (2/34). CONCLUSIONS: Prolapse surgery with Prolift yielded a good anatomical outcome and satisfactory symptom improvement at different periods of follow-up, especially in uterus-sparing prolapse surgery. However, adverse events were not uncommon, and patients should be fully informed of all possible adverse events prior to surgery. PMID- 24075380 TI - Prenatal diagnosis of mosaic trisomy 2 associated with abnormal maternal serum screening, oligohydramnios, intrauterine growth restriction, ventricular septal defect, preaxial polydactyly, and facial dysmorphism. AB - OBJECTIVE: To present prenatal diagnosis of mosaic trisomy 2. MATERIALS AND METHODS: A 29-year-old woman underwent amniocentesis at 17 weeks of gestation because of abnormal maternal serum screening, and the cytogenetic result was 47,XY,+2[8]/46,XY[22]. She underwent repeated amniocentesis at 19 weeks of gestation. Interphase fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and quantitative fluorescent polymerase chain reaction (QF-PCR) were performed on uncultured amniocytes. Ultrasound at 22 weeks of gestation revealed severe oligohydramnios, intrauterine growth restriction, and ventricular septal defect. The pregnancy was terminated at 22 weeks of gestation. Cytogenetic analysis was performed on parental blood, cultured amniocytes, cord blood, skin, liver, lung, umbilical cord, amnion, and placenta. aCGH analysis was performed on cord blood, skin, and liver. RESULTS: In the samples of uncultured amniocytes, interphase FISH detected 11.1% (13/117) mosaicism for trisomy 2, aCGH analysis showed the result of arr [hg19] 2p25.3q37.3 (0-242,936,883)*2.46, and QF-PCR excluded uniparental disomy 2. QF PCR on placenta revealed trisomy 2 derived from maternal meiosis I non disjunction. Cytogenetic analysis revealed the following results: cultured amniocytes: 46,XY[21 colonies]; cord blood: 46,XY[40 cells]; skin: 46,XY[40 cells]; lung: 46,XY[40 cells]; liver: 47,XY,+2[4 cells]/46,XY[36 cells]; umbilical cord: 47,XY,+2[4 cells]/46,XY[36 cells]; amniotic membrane: 47,XY,+2[20 cells]/46,XY[20 cells]; and placenta: 47,XY,+2[40 cells]. The fetus postnatally manifested facial dysmorphism and preaxial polydactyly of the hand. CONCLUSION: Interphase FISH and aCGH analyses on uncultured amniocytes are useful for rapid confirmation of low-level mosaic trisomy 2 at amniocentesis. PMID- 24075381 TI - De novo unbalanced translocation resulting in monosomy for distal 5p (5p14.1 -> pter) and 14q (14q32.31 -> qter) associated with fetal nuchal edema, microcephaly, intrauterine growth restriction, and single umbilical artery: prenatal diagnosis and molecular cytogenetic characterization. AB - OBJECTIVE: To present prenatal diagnosis of partial monosomy 5p (5p14.1 -> pter) and partial monosomy 14q (14q32.31 -> qter). MATERIALS AND METHODS: A 33-year-old woman underwent amniocentesis at 20 weeks of gestation because of abnormal fetal ultrasound. Amniocentesis revealed a dicentric chromosome of dic(5;14). Level II ultrasound at 23 weeks of gestation revealed a fetus with intrauterine growth restriction, microcephaly, nuchal edema, a single umbilical artery, and fetal biometry equivalent to 19 weeks. At 23 weeks of gestation, she requested repeated amniocentesis. Whole-genome array comparative genomic hybridization on uncultured amniocytes was performed. Quantitative fluorescent polymerase chain reaction analysis was performed on uncultured cord blood and parental blood. A fetus was delivered with microcephaly, low-set ears, hypertelorism, depressed nasal bridge, increased nuchal fold, and a single umbilical artery. RESULTS: The fetal karyotype was 45,XX,dic(5;14)(p14.1;q32.31)dn. Whole-genome array comparative genomic hybridization analysis on uncultured amniocytes detected arr 5p15.33p14.1 (36,238-28,798,509)*1 and arr 14q32.31q32.33 (101,508,967-107,349,540)*1. Quantitative fluorescent polymerase chain reaction assays showed that the aberrant dic(5;14) was from paternal origin. CONCLUSION: Concomitant occurrence of monosomy for distal 5p and distal 14q my present nuchal edema, microcephaly, IUGR, and single umbilical artery on prenatal ultrasound. PMID- 24075382 TI - Coexistent squamous cell carcinoma and adenoid basal carcinoma in the uterine cervix and infection with human papillomavirus (HPV 31). AB - OBJECTIVE: Adenoid basal carcinoma (ABC) is an uncommon neoplasm of the uterine cervix. ABC can be accompanied by carcinoma in situ or invasive carcinoma. Most cases are discovered accidentally during radical hysterectomy. ABC is associated with a high risk of human papillomavirus infection (HPV), most often HPV 16 infection. CASE REPORT: We present a rare case of an 86-year-old Taiwanese married woman who suffered from bloody vaginal discharge and occasional lower abdominal pain and received cervical biopsy. The pathological report revealed squamous cell carcinoma (SCC) of the uterine cervix. After radical hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymph node dissection, the final pathological report revealed SCC coexisting with ABC, and both of the components were infected by HPV 31. After receiving radiotherapy, she maintained outpatient department follow-up. CONCLUSION: A literature review revealed that this was a rare case of combined ABC-SCC associated with HPV 31 infection. In this case, the ABC component did not affect the tumor stage because it was confined to the cervix. However, we must avoid overestimating the clinical stage because the ABC component is thought to be a benign lesion. PMID- 24075383 TI - Delayed uterine rupture occurred 4 weeks after cesarean section following sexual intercourse: a case report and literature review. AB - OBJECTIVE: Spontaneous delayed uterine rupture is life-threatening and extremely rare following sexual intercourse in postpartum. Here, we present a case of delayed uterine rupture that occurred 4 weeks after cesarean section following intercourse. CASE REPORT: A 31-year-old postpartum woman, gravida 4, para 1, abortion 3, underwent a cesarean section for prolonged labor. She was transferred to our hospital in shock status with brisk vaginal bleeding following intercourse 4 weeks after delivery. An emergency subtotal hysterectomy was performed to stop the bleeding. The pathology confirmed tissue necrosis and suture granuloma at the previous surgical wound. CONCLUSION: The presented case demonstrated that delayed uterine rupture may occur even 4 weeks after delivery following intercourse, without any obvious abdominal pain or infection signs, which deserved the attention of obstetricians. PMID- 24075384 TI - Detection of maternal transmission of a splicing mutation in the TSC2 gene following prenatal diagnosis of fetal cardiac rhabdomyomas mimicking congenital cystic adenomatoid malformation of the lung and cerebral tubers and awareness of a family history of maternal epilepsy. AB - OBJECTIVE: To present a prenatal diagnosis of familial tuberous sclerosis complex (TSC). CASE REPORT: A 29-year-old woman was referred to our institution for amniocentesis at 24 weeks of gestation because of congenital anomaly. The fetus had been found to have an intrathoracic echogenic mass, suspicious of type III congenital cystic adenomatoid malformation of the lung (CCAML). The woman presented with a medical history of epilepsy and had received anticonvulsants but did not disclose the disease entity associated with the epilepsy. Amniocentesis revealed a karyotype of 46,XX. A fetal ultrasound examination at 26 weeks of gestation reported the diagnosis of type III CCAML. At 30 weeks of gestation, magnetic resonance imaging showed multiple cortical tubers in the brain along with an intracardiac mass suspicious of cardiac rhabdomyoma, and a diagnosis of fetal TSC was made. A prenatal ultrasound examination at 30 weeks of gestation revealed multiple cardiac tumors and multiple cortical tubers in the brain. The mother admitted that she had been diagnosed to have TSC. Molecular analysis of the cultured amniocytes and the parental blood showed a splicing mutation of c.2639+1G>C in the splice donor site of intron 22 of TSC2 gene in the mother and the fetus. CONCLUSION: Prenatal diagnosis of an intrathoracic lesion with a family history of parental epilepsy should raise a suspicion of fetal cardiac rhabdomyoma and TSC, and prompt magnetic resonance imaging investigation and molecular genetic analysis if necessary. PMID- 24075385 TI - Rapid detection of K650E mutation in FGFR3 using uncultured amniocytes in a pregnancy affected with fetal cloverleaf skull, occipital pseudoencephalocele, ventriculomegaly, straight short femurs, and thanatophoric dysplasia type II. AB - OBJECTIVE: To present the ultrasound and molecular genetic diagnosis of thanatophoric dysplasia type II (TD2). CASE REPORT: A 35-year-old, primigravid woman was referred to our institution for genetic counseling and amniocentesis at 19 weeks of gestation because of advanced maternal age and sonographic abnormalities in the fetus. The prenatal ultrasound showed short straight femurs, prominent forehead, narrow chest, skin edema, short limbs, and cloverleaf skull consistent with the diagnosis of TD2. Amniocentesis revealed a karyotype of 46,XX. DNA testing for the FGFR3 gene using uncultured amniocytes revealed a heterozygous c.1948A>G, AAG>GAG transversion leading to a p.Lys650Glu(K650E) mutation in the FGFR3 gene. A prenatal ultrasound at 21 weeks of gestation showed ventriculomegaly, cloverleaf skull, straight femurs, micromelia, narrow chest, and pseudoencephalocele with a bulging occipital bone mimicking encephalocele. The pregnancy was subsequently terminated, and a 480-g malformed fetus was delivered with macrocephaly, depressed nasal bridge, short upturned nasal tip, hypoplastic midface, frontal bossing, short digits, trident-shaped hands, short limbs, cloverleaf skull, narrow chest, brachydactyly, nuchal edema, and bulging occipital bone. CONCLUSION: A prenatal diagnosis of cloverleaf skull, short limbs, straight femurs, and occipital pseudoencephalocele should include a differential diagnosis of TD2. A molecular analysis of FGFR3 using uncultured amniocytes is useful for the rapid confirmation of TD2 at prenatal diagnosis. PMID- 24075386 TI - Huge asymptomatic pyometra with an intrauterine device. PMID- 24075387 TI - Xanthogranulomatous inflammation of myometrium with uterine perforation. PMID- 24075388 TI - Postpartum eclampsia with cerebral air embolism. PMID- 24075389 TI - Lower urinary tract dysfunction resulting from a 10-year retained intravesical absorbable suture from a uterine myomectomy. PMID- 24075390 TI - Robot-assisted excision of a symptomatic deep infiltrating cervical endometrioma. PMID- 24075391 TI - An atypical and fatal case of pyometra accompanied by the superficial spread of squamous cell carcinoma of the endometrium and the fallopian tubes. PMID- 24075392 TI - A dicentric Y chromosome resulting from pericentric inversion between the centromere and Yq heterochromatin. PMID- 24075393 TI - Mosaic trisomy 14 at amniocentesis: prenatal diagnosis and literature review. PMID- 24075394 TI - Application of interphase fluorescence in situ hybridization to uncultured amniocytes for differential diagnosis of pseudomosaicism from true mosaicism in mosaic isochromosome 20q detected at amniocentesis. PMID- 24075395 TI - Prenatal diagnosis of mosaic trisomy 12 associated with congenital overgrowth. PMID- 24075396 TI - Absent fetal movement and brain sparing effect associated with multiple tight nuchal cords. PMID- 24075397 TI - Multiple factors causing acute renal failure. PMID- 24075398 TI - Quantitative and qualitative problems of infectious diseases fellowship in Japan. AB - Postgraduate clinical training in infectious diseases in Japan is still under developed and needs further improvement. There are both quantitative and qualitative problems that need to be overcome. The system is unusual and two layered, precluding young applicants from participating in many fellowship programs. To-date, less than half the programs actually have acting fellows involved in training. The system needs fundamental reform, with a better evaluation system for each program. PMID- 24075399 TI - Opioid pharmacotherapy: Treatment, regimes, constructions and control. PMID- 24075400 TI - The complexity of nurses' attitudes and practice of sedation at the end of life: a systematic literature review. AB - CONTEXT: Sedation is administered to some palliative care patients at the end of their life. Nurses play an important role in this practice. OBJECTIVES: To systematically review the evidence on nurses' attitudes and practice of end-of life sedation. METHODS: We searched eight electronic databases, four key palliative care journals, and reference lists for empirical studies published in English, between 1990 and 2012, on nurses and their attitudes toward and practice of sedation until a patient's death. A total of 10 studies met the inclusion criteria. RESULTS: Data were generated from 7515 nurses in four main settings (specialized palliative care unit, home, nursing home, and acute hospital) from seven countries (Belgium, Canada, Japan, The Netherlands, Norway, U.K., and U.S.). On average, the quality of the evidence was good; hence, we analyzed all selected studies. Based on the findings from a previous review, we categorized the emerging themes into: 1) important factors leading to the patient receiving palliative sedation (PS), 2) nurses' attitudes toward PS, and 3) nurses' experience of PS at the end of a patient's life. In general, nurses had a positive but cautious attitude toward the practice of PS. Most saw it as a last resort treatment for relieving suffering and refractory symptoms, and its practice was often influenced by their level of education, expertise, and the roles they played per setting. CONCLUSION: Most nurses administered sedation until death only within the given circumstances because of the anticipatory benefits in controlling refractory symptoms and suffering. Some of them experienced burdens during PS delivery; these could be supported by operational guidelines and task-related training. PMID- 24075401 TI - Evaluation of risk factors predicting chemotherapy-related nausea and vomiting: results from a European prospective observational study. AB - CONTEXT: Demographic, personal, clinical, and behavioral factors predicting chemotherapy-induced nausea and vomiting (CINV) have been assessed in the past, but inconsistencies exist in the literature, studies have methodological shortcomings, and many risk factors have been examined in cross-sectional studies and univariate analyses. OBJECTIVES: To evaluate the predictive power of personal and treatment-related characteristics in the development of CINV, using a large and prospectively evaluated sample of a heterogeneous group of cancer patients receiving routine chemotherapy. METHODS: This was a multicountry, multisite prospective study over three cycles of chemotherapy. Adult patients from eight European countries about to receive highly and moderately emetogenic chemotherapy were recruited. Clinicians completed a case report form at or before the initial chemotherapy treatment, recording patient demographic and baseline clinical characteristics. Participants completed a daily patient diary for six days per chemotherapy cycle describing their CINV experience. Baseline patient data also included a history of nausea/vomiting (yes/no), patient expectation of nausea (0 100 mm visual analogue scale [VAS]), prechemotherapy anxiety (0-100 mm VAS), and prechemotherapy nausea (0-100 mm VAS) measured during the 24-hour period before chemotherapy initiation. RESULTS: There were 991 evaluable patients with complete Cycle 1 data, 888 for Cycle 2 data, and 769 for Cycle 3 data. A complex picture of predictor variables was shown, with different contribution of variables to the acute, delayed, and overall phases of CINV. Key predictor variables included the use of antiemetics inconsistent with international guidelines, younger age, prechemotherapy nausea, and no CINV complete response in an earlier cycle (all at P < 0.05). Anxiety, history of nausea/vomiting, and expectations of nausea were important predictors for some phases and cycles but not consistently across the CINV pathway. CONCLUSION: The results of this study provide clarity for the relative contribution of a set of characteristics in the development of CINV. Following evidence-based clinical antiemetic guidelines is of paramount importance, alongside treating patients with increased risk for CINV more aggressively, which both could lead to more optimal CINV management. These data can assist clinicians in making decisions about the antiemetic management of their patients. PMID- 24075402 TI - Impact of type 2 diabetes on cardiac autonomic responses to sympathetic stimuli in patients with coronary artery disease. AB - Type 2 diabetes (T2D) has shown limited impact on cardiac autonomic function in patients with cardiac disease at rest. The effect of T2D on autonomic responses to sympathetic stimuli, such as passive tilt and static exercise, is not well known in patients with coronary artery disease (CAD). Heart rate, arterial pressure, and their variability along with baroreflex sensitivity (BRS) were analyzed at supine rest and during passive head-up tilt (TILT) and static handgrip exercise (HG) in CAD patients with (T2D+, n=68, 61+/-6 years, 14 women) and without T2D (T2D-, n=68, 62+/-6 years, 17 women). The effect of T2D at rest and in responses to TILT and HG was examined. In T2D+, the normalized low frequency (0.04-0.15 Hz) power of R-R intervals was higher at rest (44+/-17 vs. 38+/-17 nu, p=0.015) and its response to TILT and HG was lower than that in T2D- (8+/-21 vs. 2+/-17 nu, p=0.041 and 3+/-18 vs. -4+/-15 nu, p=0.019, respectively). Vagally mediated heart rate variability indices and BRS were not different between T2D+ and T2D-. We concluded that T2D has a specific impact on low frequency oscillation of R-R interval among patients with angiographically documented CAD. This may indicate increased basal sympathetic modulation of sinoatrial node and lower sympathetic responsiveness to sympathetic activation by baroreceptor unloading and exercise pressor response. Limited effects of T2D on vagally mediated heart rate variability and baroreflex were observed in the patients with CAD. PMID- 24075403 TI - Fiber micro-architecture in the longitudinal-radial and circumferential-radial planes of ascending thoracic aortic aneurysm media. AB - It was recently demonstrated by our group that the delamination strength of ascending thoracic aortic aneurysms (ATAA) was lower than that of control (CTRL, non-aneurysmal) ascending thoracic aorta (ATA), and the reduced strength was more pronounced among bicuspid (BAV) vs. tricuspid aortic valve (TAV) patients, suggesting a different risk of aortic dissection for BAV patients. We hypothesized that aortic valve morphologic phenotype predicts fiber micro architectural anomalies in ATA. To test the hypothesis, we characterized the micro-architecture in the longitudinal-radial (Z-RAD) and circumferential-radial (Theta-RAD) planes of human ATA tissue that was artificially dissected medially. The outer and inner-media of CTRL-ATA, BAV-ATAA and TAV-ATAA were imaged using multi-photon microscopy in the Z-RAD and Theta-RAD planes to observe collagen and elastin. Micrographs were processed using an image-based tool to quantify several micro-architectural characteristics. In the outer-media of BAV-ATAA, elastin was more undulated and less aligned about the Theta-axis when compared with CTRL-ATA, which is consistent with increased tensile stretch at inflection point of Theta strips of adventitial-medial half of BAV-ATAA (1.28) when compared with CTRL-ATA (1.13). With increasing age, collagen became more undulated about the Z-axis within the outer-media of TAV-ATAA, and elastin became more oriented in the Z axis and collagen less radially-oriented within the inner-media of TAV-ATAA. This discrepancy in the micro-architecture with fibers in the inner layers being more stretched and with disrupted radially-oriented components than fibers in the outer layers may be associated with the development, progression and vascular remodeling in aneurysms arising in TAV patients. PMID- 24075404 TI - The use of tranexamic acid to reduce blood loss and transfusion in major orthopedic surgery: a meta-analysis. AB - BACKGROUND: Conflicting reports have been published regarding the effect of tranexamic acid (TXA) on reducing blood loss and transfusion in patients undergoing orthopedic surgery. We performed a meta-analysis to evaluate the effectiveness and safety of TXA treatment in reducing blood loss and transfusion in major orthopedic surgery. MATERIALS AND METHODS: MEDLINE, PubMed, EMBASE, and Cochrane databases were searched for relevant studies. Only randomized controlled trials were eligible for this study. The weighted mean difference in blood loss, number of transfusions per patient, and the summary risk ratio of transfusion and deep vein thrombosis (DVT) were calculated in the TXA-treated group and the control group. RESULTS: A total of 46 randomized controlled trials involving 2925 patients were included. The use of TXA reduced total blood loss by a mean of 408.33 mL (95% confidence interval [CI], -505.69 to -310.77), intraoperative blood loss by a mean of 125.65 mL (95% CI, -182.58 to -68.72), postoperative blood loss by a mean of 214.58 mL (95% CI, -274.63 to -154.52), the number of blood transfusions per patient by 0.78 U (95% CI, -0.19 to -0.37), and the volumes of blood transfusions per patient by 205.33 mL (95% CI, -301.37 to 109.28). TXA led to a significant reduction in transfusion requirements (relative risk, 0.51; 95% CI, 0.46-0.56), and no increase in the risk of DVT (relative risk, 1.11; 95% CI, 0.69-1.79). CONCLUSIONS: TXA significantly reduced blood loss and blood transfusion requirements in patients undergoing orthopedic surgery, and did not appear to increase the risk of DVT. PMID- 24075405 TI - Microdistribution of MC1R-targeted polyplexes in murine melanoma tumor tissue. AB - Targeted sodium-iodide symporter (NIS) gene transfer can be considered as a promising approach for diagnostics of specific types of cancer. For this purpose we used targeted polyplexes based on PEI-PEG-MC1SP block-copolymer containing MC1SP-peptide, a ligand specific for melanocortin receptor-1 (MC1R) overexpressed on melanoma cells. Targeted polyplexes demonstrated enhanced NIS gene transfer compared to non-targeted (lacking MC1SP) ones in vitro. Using dorsal skinfold chamber and intravital microscopy we evaluated accumulation and microdistribution of quantum dot-labeled polyplexes in tumor and normal subcutaneous tissues up to 4 h after intravenous injection. Polyplexes demonstrated significantly higher total accumulation in tumor tissue in comparison with subcutaneous ones (control). Targeted and non-targeted polyplexes extravasated and penetrated into the tumor tissue up to 20 MUm from the vessel walls. In contrast, in normal subcutaneous tissue polyplexes penetrated not more than 3 MUm from the vessel walls with the level of extravasated polyplexes 400-fold less than in tumor. Accumulated polyplexes in tumor tissue caused NIS gene expression. Subsequent (123)I(-) intravenous injection resulted in 6.8 +/- 1.1 and 4.5 +/- 0.8% ID/g (p < 0.001) iodide accumulation in tumors in the case of targeted and non-targeted polyplexes, respectively, as was shown using SPECT/CT. PMID- 24075406 TI - The use of nanolipoprotein particles to enhance the immunostimulatory properties of innate immune agonists against lethal influenza challenge. AB - Recent studies have demonstrated that therapies targeting the innate immune system have the potential to provide transient, non-specific protection from a variety of infectious organisms; however, the potential of enhancing the efficacy of such treatments using nano-scale delivery platforms requires more in depth evaluation. As such, we employed a nanolipoprotein (NLP) platform to enhance the efficacy of innate immune agonists. Here, we demonstrate that the synthetic Toll like receptor (TLR) agonists monophosphoryl lipid A (MPLA) and CpG oligodeoxynucleotides (CpG) can be readily incorporated into NLPs. Conjugation of MPLA and CpG to NLPs (MPLA:NLP and CpG:NLP, respectively) significantly enhanced their immunostimulatory profiles both in vitro and in vivo compared to administration of agonists alone, as evidenced by significant increases in cytokine production, cell surface expression of activation markers, and upregulation of immunoregulatory genes. Importantly, enhancement of cytokine production by agonist conjugation to NLPs was also observed in primary human dendritic cells. Furthermore, BALB/c mice pretreated with CpG:NLP constructs survived a lethal influenza challenge whereas pretreatment with CpG alone had no effect on survival. PMID- 24075407 TI - Functionalized liposomes loaded with siRNAs targeting ion channels in effector memory T cells as a potential therapy for autoimmunity. AB - Effector memory T cells (TM) play a key role in the pathology of certain autoimmune disorders. The activity of effector TM cells is under the control of Kv1.3 ion channels, which facilitate the Ca(2+) influx necessary for T cell activation and function, i.e. cytokine release and proliferation. Consequently, the knock-down of Kv1.3 expression in effector TM's may be utilized as a therapy for the treatment of autoimmune diseases. In this study we synthesized lipid unilamellar nanoparticles (NPs) that can selectively deliver Kv1.3 siRNAs into TM cells in vitro. NPs made from a mixture of phosphatidylcholine, pegylated/biotinylated phosphoethanolamine and cholesterol were functionalized with biotinylated-CD45RO (cell surface marker of TM's) antibodies via fluorophore conjugated streptavidin (CD45RO-NPs). Incubation of T cells with CD45RO-NPs resulted into the selective attachment and endocytosis of the NPs into TM's. Furthermore, the siRNA against Kv1.3, encapsulated into the CD45RO-NPs, was released into the cytosol. Consequently, the expression of Kv1.3 channels decreased significantly in TM's, which led to a remarkable decrease in Ca(2+) influx. Our results can form the basis of an innovative therapeutic approach in autoimmunity. PMID- 24075408 TI - Mutant MCP-1 protein delivery from layer-by-layer coatings on orthopedic implants to modulate inflammatory response. AB - Total joint replacement (TJR) is a common and effective surgical procedure for hip or knee joint reconstruction. However, the production of wear particles is inevitable for all TJRs, which activates macrophages and initiates an inflammatory cascade often resulting in bone loss, prosthetic loosening and eventual TJR failure. Macrophage Chemoattractant Protein-1 (MCP-1) is one of the most potent cytokines responsible for macrophage cell recruitment, and previous studies suggest that mutant MCP-1 proteins such as 7ND may be used as a decoy drug to block the receptor and reduce inflammatory cell recruitment. Here we report the development of a biodegradable, layer-by-layer (LBL) coating platform that allows efficient loading and controlled release of 7ND proteins from the surface of orthopedic implants using as few as 14 layers. Scanning electron microscopy and fluorescence imaging confirmed effective coating using the LBL procedure on titanium rods. 7ND protein loading concentration and release kinetics can be modulated by varying the polyelectrolytes of choice, the polymer chemistry, the pH of the polyelectrolyte solution, and the degradation rate of the LBL assembly. The released 7ND from LBL coating retained its bioactivity and effectively reduced macrophage migration towards MCP-1. Finally, the LBL coating remained intact following a femoral rod implantation procedure as determined by immunostaining of the 7ND coating. The LBL platform reported herein may be applied for in situ controlled release of 7ND protein from orthopedic implants, to reduce wear particle-induced inflammatory responses in an effort to prolong the lifetime of implants. PMID- 24075409 TI - Use of the antimicrobial peptide Epinecidin-1 to protect against MRSA infection in mice with skin injuries. AB - Methicillin-resistant Staphylococcus aureus (MRSA) causes infections through open skin injuries, and its resistance makes treatment difficult. The antimicrobial peptide Epinecidin-1 (Epi-1) has been reported to possess antibacterial, antifungal, antiviral, and antitumor functions. This study investigated the antimicrobial activity of Epi-1 against skin trauma-mediated MRSA infection in mice. One square centimeter of outer skin was excised from the ventral region of mice, and a lethal dose of MRSA was applied in the presence or absence of methicillin, vancomycin, or Epi-1. While untreated mice and mice treated with methicillin died within four days, mice treated with Epi-1 survived infection. Epi-1 decreased MRSA bacterial counts in the wounded region, enhanced wound closure, and increased angiogenesis at the injury site. Treatment with Epi-1 decreased serum levels of the proinflammatory cytokines TNF-alpha, IL-6, and MCP 1, and regulated the recruitment of monocytes and clearance of lymphocytes around the wounded region during healing. In conclusion, Epi-1 may be effective at treating clinical MRSA, and may enhance wound recovery when combined with collagen. PMID- 24075411 TI - Relationships among cell morphology, intrinsic cell stiffness and cell-substrate interactions. AB - Cell modulus (stiffness) is a critical cell property that is important in normal cell functions and increasingly associated with disease states, yet most methods to characterize modulus may skew results. Here we show strong evidence indicating that the fundamental nature of free energies associated with cell/substrate interactions regulates adherent cell morphology and can be used to deduce cell modulus. These results are based on a mathematical model of biophysics and confirmed by the measured morphology of normal and cancerous liver cells adhered on a substrate. Cells select their final morphology by minimizing the total free energy in the cell/substrate system. The key mechanism by which substrate stiffness influences cell morphology is the energy tradeoff between the stabilizing influence of the cell-substrate interfacial adhesive energy and the destabilizing influence of the total elastic energies in the system. Using these findings, we establish a noninvasive methodology to determine the intrinsic modulus of cells by observing global changes in cell morphology in response to substrate stiffness. We also highlight the importance of selecting a relevant morphological index, cell roundness, that reflects the interchange between forms of energy governing cell morphology. Thus, cell-substrate interactions can be rationalized by the underlying biophysics, and cell modulus is easily measured. PMID- 24075410 TI - Porous chitosan-hyaluronic acid scaffolds as a mimic of glioblastoma microenvironment ECM. AB - Cancer therapeutics are developed through extensive screening; however, many therapeutics evaluated with 2D in vitro cultures during pre-clinical trials suffer from lower efficacy in patients. Replicating the in vivo tumor microenvironment in vitro with three-dimensional (3D) porous scaffolds offers the possibility of generating more predictive pre-clinical models to enhance cancer treatment efficacy. We developed a chitosan and hyaluronic acid (HA) polyelectrolyte complex 3D porous scaffold and evaluated its physical properties. Chitosan-HA (C-HA) scaffolds had a highly porous network. C-HA scaffolds were compared to 2D surfaces for in vitro culture of U-118 MG human glioblastoma (GBM) cells. C-HA scaffold cultures promoted tumor spheroid formation and increased stem-like properties of GBM cells as evidenced by the upregulation of CD44, Nestin, Musashi-1, GFAP, and HIF-1alpha as compared with 2D cultures. Additionally, the invasiveness of GBM cells cultured in C-HA scaffolds was significantly enhanced compared to those grown in 2D cultures. C-HA scaffold cultures were also more resistant to chemotherapy drugs, which corresponded to the increased expression of ABCG2 drug efflux transporter. These findings suggest that C-HA scaffolds offer promise as an in vitro GBM platform for study and screening of novel cancer therapeutics. PMID- 24075412 TI - Body weight-supported high-intensity locomotor training and adapted physical activity program in patients with Parkinson's disease: a complementary approach? PMID- 24075413 TI - The authors respond. PMID- 24075414 TI - How to make health information technology effective: the challenge of patient engagement. PMID- 24075415 TI - Information/Education page. Alcohol use after traumatic brain injury. PMID- 24075416 TI - A technique for evaluating the oil/heavy-oil viscosity changes under ultrasound in a simulated porous medium. AB - Theoretically, Ultrasound method is an economical and environmentally friendly or "green" technology, which has been of interest for more than six decades for the purpose of enhancement of oil/heavy-oil production. However, in spite of many studies, questions about the effective mechanisms causing increase in oil recovery still existed. In addition, the majority of the mechanisms mentioned in the previous studies are theoretical or speculative. One of the changes that could be recognized in the fluid properties is viscosity reduction due to radiation of ultrasound waves. In this study, a technique was developed to investigate directly the effect of ultrasonic waves (different frequencies of 25, 40, 68 kHz and powers of 100, 250, 500 W) on viscosity changes of three types of oil (Paraffin oil, Synthetic oil, and Kerosene) and a Brine sample. The viscosity calculations in the smooth capillary tube were based on the mathematical models developed from the Poiseuille's equation. The experiments were carried out for uncontrolled and controlled temperature conditions. It was observed that the viscosity of all the liquids was decreased under ultrasound in all the experiments. This reduction was more significant for uncontrolled temperature condition cases. However, the reduction in viscosity under ultrasound was higher for lighter liquids compare to heavier ones. Pressure difference was diminished by decreasing in the fluid viscosity in all the cases which increases fluid flow ability, which in turn aids to higher oil recovery in enhanced oil recovery (EOR) operations. Higher ultrasound power showed higher liquid viscosity reduction in all the cases. Higher ultrasound frequency revealed higher and lower viscosity reduction for uncontrolled and controlled temperature condition experiments, respectively. In other words, the reduction in viscosity was inversely proportional to increasing the frequency in temperature controlled experiments. It was concluded that cavitation, heat generation, and viscosity reduction are three of the promising mechanisms causing increase in oil recovery under ultrasound. PMID- 24075417 TI - Molecular and serological prevalence of Babesia bigemina and Babesia bovis in cattle and water buffalos under small-scale dairy farming in Beheira and Faiyum Provinces, Egypt. AB - In order to determine the molecular and serological prevalence of Babesia bigemina and Babesia bovis, a total of 247 blood samples were collected from cattle and water buffalos in Beheira and Faiyum Provinces in Egypt and examined by nested polymerase chain reaction (nPCR) and enzyme-linked immunosorbent assay (ELISA). In cattle, the prevalence of B. bigemina and B. bovis was 5.30% and 3.97% by nPCR and 10.60% and 9.27% by ELISA, respectively, whereas those of water buffalos were 10.42% and 4.17% by nPCR and 15.63% and 11.46% by ELISA, respectively. Statistically significant differences in the prevalence of the two infections were observed on the basis of age and health status. Sequencing analysis revealed two genotypes for B. bovis spherical body protein-4. In conclusion, the current data provide valuable information regarding the epidemiology of B. bigemina and B. bovis infections in cattle and water buffalos from Egypt, which can be employed in developing future strategies for disease management and control. PMID- 24075418 TI - The in vitro interactions and in vivo efficacy of atovaquone and proguanil against Babesia gibsoni infection in dogs. AB - In vitro interactions between atovaquone (ATV) and proguanil (PG) against Babesia gibsoni and the clinical efficacy of this combination therapy using Malarone((r)) which is the antimalarial drug containing ATV and PG were evaluated. This combination showed synergism against uncloned wild-type and ATV-resistant B. gibsoni in vitro examinations using a modified fixed ratio method. Administration of Malarone((r)) to experimentally B. gibsoni infected two dogs in chronic stage and three dogs in acute stage resulted in decrease in parasitemia, and clinical improvements were observed. However, all dogs showed relapse of parasitic infection with a single-nucleotide polymorphism in the cytchrome b gene (M121I). Some side effects were confirmed: self-limiting vomiting in two dogs and hyperphosphatasia in another dog. Mild increases in the levels of alanine aminotransferase were confirmed in two dogs. This is the first study to evaluate the interactions in vitro and the clinical efficacy of ATV and PG against canine B. gibsoni infection in dogs. PMID- 24075419 TI - Sequence and organization of the rhoptry-associated-protein-1 (rap-1) locus for the sheep hemoprotozoan Babesia sp. BQ1 Lintan (B. motasi phylogenetic group). AB - Babesiosis is a frequent infection of animals worldwide by tick borne pathogen Babesia, and several species are responsible for ovine babesiosis. Recently, several Babesia motasi-like isolates were described in sheep in China. In this study, we sequenced the multigenic rap-1 gene locus of one of these isolates, Babesia sp. BQ1 Lintan. The RAP-1 proteins are involved in the process of red blood cells invasion and thus represent a potential target for vaccine development. A complex composition and organization of the rap-1 locus was discovered with: (1) the presence of 3 different types of rap-1 sequences (rap 1a, rap-1b and rap-1c); (2) the presence of multiple copies of rap-1a and rap-1b; (3) polymorphism among the rap-1a copies, with two classes (named rap-1a61 and rap-1a67) having a similarity of 95.7%, each class represented by two close variants; (4) polymorphism between rap-1a61-1 and rap-1a61-2 limited to three nucleotide positions; (5) a difference of eight nucleotides between rap-1a67-1 and rap-1a67-2 from position 1270 to the putative stop site of rap-1a67-1 which might produce two putative proteins of slightly different sizes; (6) the ratio of rap-1a copies corresponding to one rap-1a67, one rap-1a61-1 and one rap-1a61-2; (7) the presence of three different intergenic regions separating rap-1a, rap-1b and rap-1c; (8) interspacing of the rap-1a copies with rap-1b copies; and (9) the terminal position of rap-1c in the locus. A 31kb locus composed of 6 rap-1a sequences interspaced with 5 rap-1b sequences and with a terminal rap-1c copy was hypothesized. A strikingly similar sequence composition (rap-1a, rap-1b and rap 1c), as well as strong gene identities and similar locus organization with B. bigemina were found and highlight the conservation of synteny at this locus in this phylogenetic clade. PMID- 24075420 TI - The 8-oxoguanine DNA glycosylase 1 (ogg1) decreases the vulnerability of the developing brain to DNA damage. AB - The developing brain is particularly vulnerable to oxidative DNA damage, which may be the cause of most major congenital mental anomalies. The repair enzyme ogg1 initiates the highly conserved base-excision repair pathway. However, its function in the embryonic brain is largely unknown. This study is the first to validate the function of ogg1 during brain development using zebrafish embryos. Ogg1 was found to be highly expressed in the brain throughout early embryonic development, with particularly enrichment observed in the midbrain. The lack of ogg1 causes severe brain defects including changes in brain volume and integrity, destruction of the midbrain-hindbrain boundary, and balance and motor impairment, while overexpression of ogg1 can partially rescue these defects. Multiple cellular and molecular events were involved in the manifestation of brain defects due primarily to the lack of ogg1. These included (1) increased apoptosis; (2) decreased proliferation; and (3) aberrant axon distribution and extension from the inner surface towards the outer layers. The results of a microarray analysis showed that the expression of genes involved in cell cycle checkpoint, apoptosis, and neurogenesis were significantly changed in response to ogg1 knockdown. Cmyb was the key downstream gene that responses to DNA damage caused by ogg1 deficiency. Notably, the recruitment of ogg1 mRNA can alleviate the effects on the brain due to neural DNA damage. In summary, we introduce here that ogg1 is fundamentally required for protecting the developing brain, which may be helpful in understanding the aetiology of congenital brain deficits. PMID- 24075421 TI - Reticular pattern dystrophy of the retina: a spectral-domain optical coherence tomography analysis. AB - PURPOSE: To analyze the outer retinal and retinal pigment epithelium (RPE) features of reticular pattern dystrophy of the retina using spectral-domain optical coherence tomography (SDOCT). DESIGN: Retrospective observational case series. METHODS: Consecutive patients with reticular pattern dystrophy of the retina underwent a complete ophthalmologic examination, including assessment of best-corrected visual acuity (BCVA), fundus biomicroscopy, fluorescein angiography (FA), and SDOCT. RESULTS: Twenty-two eyes of 13 patients (6 men, 7 women, mean age 68.6 +/- 14.5 years) were included. In the foveal area, the RPE layer appeared normal in 45.5% of eyes, while small RPE elevations and RPE bumps were detected in 31.8% and 22.7% of eyes, respectively. The SDOCT scans showed disruption of inner segment/outer segment (IS/OS) junction in 54.6% of eyes, a slight elevation in 59.1% of eyes, and an absence in 45.5% of eyes. The outer limiting membrane (OLM) appeared disrupted in 50.0% of eyes, absent in 22.7% of eyes, and elevated in 63.6% of eyes. Hyper-reflective subretinal material accumulation or hyporeflective subretinal lesions in the retrofoveolar region were detected in 70% and in 20% of eyes, respectively. SDOCT showed hyporeflective retinal pseudocysts in 13.6% of eyes. CONCLUSION: In this study on reticular pattern dystrophy of the retina, SDOCT provided a description of the material deposits and the alterations of the RPE and the different retinal layers. We observe that the lesions present specific features distinct from other macular dystrophies, but closer to those reported in fundus flavimaculatus than those reported in adult-onset foveomacular vitelliform dystrophy. Further analyses are needed, particularly to analyze the progression of the lesions. PMID- 24075422 TI - Macular ganglion cell/inner plexiform layer measurements by spectral domain optical coherence tomography for detection of early glaucoma and comparison to retinal nerve fiber layer measurements. AB - PURPOSE: To evaluate the performance of ganglion cell layer/inner plexiform layer (GCL/IPL) measurements with spectral-domain optical coherence tomography (Cirrus HD-OCT) for detection of early glaucoma and to compare results to retinal nerve fiber layer (RNFL) measurements. DESIGN: Cross-sectional prospective diagnostic study. METHODS: We enrolled 99 subjects, including 59 eyes with glaucoma (47 subjects) (mean deviation >-6.0 dB) and 91 normal eyes (52 subjects). Patients underwent biometry and peripapillary and macular OCT imaging. Performance of the GCL/IPL and RNFL algorithms was evaluated with area under receiver operating characteristic curves (AUC), likelihood ratios, and sensitivities/specificities adjusting for covariates. Combination of best parameters was explored. RESULTS: Average (SD) mean deviation in the glaucoma group was -2.5 (1.9) dB. On multivariate analyses, age (P < 0.001) and axial length (P = 0.03) predicted GC/IPL measurements in normal subjects. No significant correlation was found between average or regional GC/IPL thickness and respective outer retina (OR) thickness measurements (P > 0.05). Average RNFL thickness performed better than average GCL/IPL measurements for detection of glaucoma (AUC = 0.964 vs 0.937; P = 0.04). The best regional measures from each algorithm (inferior quadrant RNFL vs minimum GCL/IPL) had comparable performances (P = 0.78). Entering the GC/IPL to OR ratio into prediction models did not enhance the performance of the GCL/IPL measures. Combining the best parameters from each algorithm improved detection of glaucoma (P = 0.04). CONCLUSIONS: Regional GCL/IPL measures derived from Cirrus HD-OCT performed as well as regional RNFL outcomes for detection of early glaucoma. Using the GC/IPL to OR ratio did not enhance the performance of GCL/IPL parameters. Combining the best measures from the 2 algorithms improved detection of glaucoma. PMID- 24075423 TI - Detection and influencing factors of capsular bag distention syndrome after cataract surgery using the Pentacam Scheimpflug system. AB - PURPOSE: To investigate the prevalence and morphologic changes of capsular bag distention syndrome after cataract surgery using the Pentacam and to analyze its clinical characteristics and influencing factors. DESIGN: Retrospective, cross sectional study. METHODS: Clinical records of 239 consecutive patients who underwent cataract surgery were reviewed. Demographic data, use of intraoperative ophthalmic viscosurgical devices, type of intraocular lens implanted, axial length, and white-to-white corneal diameter were recorded. One month after surgery, dilated Scheimpflug imaging was performed. Prevalence, morphologic changes, and characteristic clinical findings of this syndrome were evaluated. RESULTS: Using Scheimpflug imaging, the prevalence of capsular bag distention syndrome was high at 26.8% (64/239), and it was possible to classify its morphologic changes into 3 types. Patients with the syndrome had poorer best corrected visual acuity and lower satisfaction scores than those without the syndrome (P = .041 and P = .008, respectively). Although there was no significant difference observed in rate of this syndrome between the 2 ophthalmic viscosurgical devices used in our study (P > .05), implantation of 4-haptic intraocular lenses was associated with a high prevalence of the syndrome (odds ratio, 2.07; 95% confidence interval, 1.05 to 4.07; P = .0346). Patients with this syndrome had significantly longer AL (26.26 +/- 2.84 mm) and white-to-white diameter (12.02 +/- 0.34 mm) than those without (AL, 24.63 +/- 2.89 mm; white-to white diameter, 11.81 +/- 0.32 mm; P = .0002 and P < .0001, respectively). CONCLUSIONS: Scheimpflug imaging revealed the prevalence of capsular bag distention syndrome to be high, and these patients generally had poorer visual outcomes. Intraocular lens design and dimensions of the eyes significantly influenced the prevalence of this syndrome. PMID- 24075424 TI - Retinal asymmetry in children measured with optical coherence tomography. AB - PURPOSE: To determinate the physiological asymmetry of retinal measurements in the pediatric population with Fourier-domain optical coherence tomography (Cirrus HD-OCT). DESIGN: Prospective cross-sectional study. METHODS: Three hundred and fifty-seven healthy children were recruited. All subjects underwent a comprehensive ophthalmologic examination and an evaluation of the retinal nerve fiber layer (RNFL), optic nerve head, and macula with Cirrus OCT. Differences between right and left eyes were calculated and values were compared by means of a paired t test. Normal ranges of interocular differences were established as the 2.5th and the 97.5th percentiles. The correlations between right and left eyes were assessed by the intraclass correlation coefficients. RESULTS: Mean best corrected visual acuity (logMAR) was -0.01. Differences in the average RNFL between right and left eyes were not statistically significant. The RNFL in the right eyes was thicker in the temporal and nasal quadrants, whereas the left eyes showed thicker RNFL in the superior quadrant. The interocular difference tolerance limits for average RNFL and macular thicknesses were 13.00 MUm and 23.20 MUm, respectively. There was a strong correlation for all the parameters between the right and the left eyes. CONCLUSIONS: The asymmetry of retinal parameters might be more valuable than the absolute values in assessing certain early diseases. The interocular differences in average RNFL and macular thickness of normal individuals should not exceed 13 MUm and 23 MUm, respectively, if measured with Cirrus HD-OCT. PMID- 24075425 TI - Evaluating the accuracy of the visual field index for the Humphrey Visual Field Analyzer in patients with mild to moderate glaucoma. AB - PURPOSE: To evaluate the accuracy of the visual field index (VFI) for the Humphrey Visual Field Analyzer in a population of patients with mild to moderate glaucoma. DESIGN: Retrospective cohort study. METHODS: The study included 42 patients (61 eyes) with at least 11 years of follow-up, and annual automated visual fields (VFs). Patients with mean deviations <=-20 dB were excluded. All unreliable fields were omitted (fixation losses >=20%, false-positive >=15%, false-negative >=33%). The VFs were divided into two 5-year series and the data were analyzed by the new Humphrey Visual Field Analyzer software. Projected VFIs from the first 5 years were compared with observed values obtained from the last 5 years. Unreliable fields initially excluded were reintroduced into the series (22 eyes) to create a comparison. RESULTS: Predicted VFIs were accurate with a mean overestimation of VF deterioration of 1.37% (95% CI: -0.22%, 2.96%). Of the predicted values, 95% were between -4.5% and 5.2% of the observed values when the predicted VFI was >=90%; and between -13.8% and 20.5% when the predicted VFI was <90%. No statistical difference was found between the reliable and unreliable series (mean difference of 0.09% [95% CI: -0.41%, 0.59%]). CONCLUSION: The new software for the Humphrey Visual Field Analyzer projects an accurate value for patients when the predicted VFI is >=90%. Clinicians should consider the limitations of the software, especially for those patients with greater initial VF loss. PMID- 24075426 TI - Expanding the cone location and magnitude index to include corneal thickness and posterior surface information for the detection of keratoconus. AB - PURPOSE: To extend the capabilities of the Cone Location and Magnitude Index algorithm to include a combination of topographic information from the anterior and posterior corneal surfaces and corneal thickness measurements to further improve our ability to correctly identify keratoconus using this new index: ConeLocationMagnitudeIndex_X. DESIGN: Retrospective case-control study. METHODS: Three independent data sets were analyzed: 1 development and 2 validation. The AnteriorCornealPower index was calculated to stratify the keratoconus data from mild to severe. The ConeLocationMagnitudeIndex algorithm was applied to all tomography data collected using a dual Scheimpflug-Placido-based tomographer. The ConeLocationMagnitudeIndex_X formula, resulting from analysis of the Development set, was used to determine the logistic regression model that best separates keratoconus from normal and was applied to all data sets to calculate PercentProbabilityKeratoconus_X. The sensitivity/specificity of PercentProbabilityKeratoconus_X was compared with the original PercentProbabilityKeratoconus, which only uses anterior axial data. RESULTS: The AnteriorCornealPower severity distribution for the combined data sets are 136 mild, 12 moderate, and 7 severe. The logistic regression model generated for ConeLocationMagnitudeIndex_X produces complete separation for the Development set. Validation Set 1 has 1 false-negative and Validation Set 2 has 1 false positive. The overall sensitivity/specificity results for the logistic model produced using the ConeLocationMagnitudeIndex_X algorithm are 99.4% and 99.6%, respectively. The overall sensitivity/specificity results for using the original ConeLocationMagnitudeIndex algorithm are 89.2% and 98.8%, respectively. CONCLUSIONS: ConeLocationMagnitudeIndex_X provides a robust index that can detect the presence or absence of a keratoconic pattern in corneal tomography maps with improved sensitivity/specificity from the original anterior surface-only ConeLocationMagnitudeIndex algorithm. PMID- 24075427 TI - The effect of enoxaparin-containing irrigation fluid used during cataract surgery on postoperative inflammation in patients with diabetes. AB - PURPOSE: To investigate effects of enoxaparin on postoperative inflammation in patients with moderate nonproliferative diabetic retinopathy (NPDR) and nuclear cataract. DESIGN: Prospective masked controlled trial. METHODS: setting: Institutional practice. study population: The study included 51 eyes of 51 diabetes mellitus (DM) patients with moderate NPDR and grade 2-3 nuclear cataracts. Group 1 included randomly selected patients who received enoxaparin in balanced salt solution (BSS) during cataract surgery, while standard BSS was used in Group 2. observation procedure: Patients were followed up 1 day, 1 week, and 1 and 2 months after the surgery. main outcome measures: Anterior chamber cell and flare. RESULTS: Postoperatively, 20 patients from Group 1 and 4 patients in Group 2 had less than a mean of 10 cells at day 1 (P = .012). At the first week, 20 patients from Group 1 and 10 patients from Group 2 had less than a mean of 10 cells (P = .004). When compared for flare, 20 patients from Group 1 and 8 patients from Group 2 had a flare between 0 and +1 at postoperative day 1 (P < .001). By the end of postoperative first week, 24 patients from Group 1and 18 patients from Group 2 had a flare between 0 and +1 (P = .012). There was no difference between groups in terms of postoperative inflammation at the first and second months after the surgery. CONCLUSION: The results of the study suggest that enoxaparin added into the infusion fluid may reduce postoperative inflammation in patients with DM, and this result supports the anti-inflammatory effect of enoxaparin. PMID- 24075428 TI - Six-year incidence of angle-closure disease in a South Indian population: the Chennai Eye Disease Incidence Study. AB - PURPOSE: To estimate the 6-year incidence of primary angle-closure (PAC) disease among adult population aged 40 years and older from rural and urban south India. DESIGN: Population-based longitudinal study. METHODS: A complete ophthalmologic examination, including applanation tonometry, gonioscopy, biometry, stereoscopic fundus examination, and automated perimetry was performed at both baseline and at the 6-year follow up at base hospital. Incident PAC disease was defined as the development of PAC disease during the 6-year follow-up in phakic subjects without PAC disease at baseline. Diagnosis was made using the International Society Geographical and Epidemiological Ophthalmology classification. RESULTS: The data were analyzed for 3350 subjects (mean age, 56.4 +/- 8.9 years; 1547 males, 1803 females) for a diagnosis of PAC disease at baseline and at follow-up examinations. The incidence of PAC disease was identified in 134 subjects (6-year incidence rate, 4.0%; 95% confidence interval (CI), 3.3-4.7). Among the 134 subjects, 88 subjects (2.6%, 95% CI, 2.1-3.2) were primary angle-closure suspects; 37 subjects (1.1%, 95% CI, 0.7-1.5) had primary angle closure, and 9 subjects (0.3%, 95% CI, 0.1-0.4) had primary angle-closure glaucoma. There was an inverse relationship between the incidence of PAC disease and the cataract surgery rates. Significant risk factors for PAC disease on logistic regressions were higher intraocular pressure, increased lens thickness, shorter axial length, shallow anterior chamber depth, anteriorly positioned lens, and hyperopia. CONCLUSIONS: The average incidence of PAC disease per year was 0.7%. All biometric parameters were found to be strong predictors for the incidence of PAC disease. PMID- 24075429 TI - Prognostic factors of eyes with naive subfoveal myopic choroidal neovascularization after intravitreal bevacizumab. AB - PURPOSE: To determine the efficacy of 1 intravitreal bevacizumab injection followed by pro re nata (1 + PRN) injection in cases of subfoveal myopic choroidal neovascularization (CNV) and to identify CNV-recurrence-related prognostic factors. DESIGN: Retrospective observational case series. METHODS: In total, 103 eyes of 89 consecutive naive patients who had subfoveal myopic CNV and had been followed-up for at least 2 years were included. Of those eyes, 24 had recurrences. The remaining eyes were stable after the initial treatment. RESULTS: The average patient age was 51.1 +/- 15.2 years. The average follow-up duration was 44.1 +/- 12.7 months. At baseline and at the 1-year, 2-year, and final visits, the average best corrected visual acuities (BCVAs) were 0.57 +/- 0.45, 0.38 +/- 0.51, 0.40 +/- 0.52, and 0.41 +/- 0.41 logMAR, respectively. The recurrence rate during follow-up was 23.3%. The BCVA improved by 0.2 logMAR after 2.7 injections in the eyes without recurrence but by only 0.08 logMAR after 6.9 injections in the eyes with recurrence. In univariate analysis, recurrence was associated with older age, more myopic refraction, thinner choroid, larger CNV lesions, and subfoveal hemorrhage at baseline. In multivariate analysis, only baseline CNV lesion size associated significantly with CNV recurrence (P = 0.002). Recurrence, baseline BCVA, choroidal thickness, and CNV size associated significantly with final BCVA (P = 0.026, <0.0001, 0.007, and 0.002, respectively). Baseline choroidal thickness, CNV size, age, and presence of lacquer cracks associated significantly with injection number (P < 0.0001, <0.0001, 0.026, and 0.035, respectively). CONCLUSIONS: 1 + PRN intravitreal bevacizumab monotherapy effectively stabilized subfoveal myopic CNV. The CNV size, the baseline BCVA, and the choroidal thickness were the main prognostic factors of subfoveal myopic CNV after 1 + PRN injection of bevacizumab. PMID- 24075430 TI - The association between cataract surgery and atypical antipsychotic use: a nested case-control study. AB - PURPOSE: To investigate cataract risk associated with the use of atypical antipsychotics. DESIGN: Retrospective, nested case-control study. METHODS: A large health claims database (The British Columbia Ministry of Health Databases) from British Columbia, Canada, was used from January 2000 through December 2007. Cases were defined as clinically significant cataracts requiring surgery and were identified using cataract surgery procedure codes. For each case, 4 to 10 controls were selected randomly using a density-based sampling approach and were matched to cases by age and calendar time. Rate ratios were calculated for users of atypical and typical antipsychotics adjusting for known cataractogenic factors. RESULTS: One hundred sixty-two thousand five hundred one cases of cataract surgery and 650 004 controls were included. The adjusted rate ratio for current users of atypical antipsychotics was 0.84 (95% confidence interval, 0.80 to 0.89) compared with nonusers. A greater number of prescriptions filled in the year before cataract surgery compared with the median number of filled prescriptions was associated with a lower cataract surgery rate (adjusted rate ratio, 0.70; 95% confidence interval, 0.65 to 0.75) than those with fewer prescriptions filled (adjusted rate ratio, 0.85; 95% confidence interval, 0.79 to 0.91). CONCLUSIONS: A protective association between the use of atypical antipsychotics and risk of clinically significant cataracts requiring surgery was established. Potential biochemical and neurochemical mechanisms for this protective effect are discussed. PMID- 24075431 TI - Demographic patterns and treatment outcomes of patients with recurrent corneal erosions related to trauma and epithelial and bowman layer disorders. AB - PURPOSE: To evaluate demographics and outcomes of patients with recurrent corneal erosions related to trauma and epithelial and Bowman layer disorders. DESIGN: Retrospective case series. METHODS: setting: Wills Eye Institute, Philadelphia, Pennsylvania. study population: Two hundred seventy-two eyes (230 patients) presenting between 2008 and 2011 with recurrent corneal erosions related to trauma and epithelial and Bowman layer disorders. procedure: Conservative management, diamond burr polishing, excimer laser phototherapeutic keratectomy (PTK), and epithelial debridement alone. main outcome measure: Recurrence of erosions, more than 6 weeks after commencing treatment. RESULTS: Mean age was 46.5 +/- 14.6 (2-85) years. Female subjects accounted for 53% of patients and 18.3% had bilateral involvement. Etiology included epithelial basement membrane dystrophy in 52.9% (144/272) and trauma in 25.7% (70/272). One hundred sixty-six eyes with more than a single visit were initially managed conservatively, 68 of 166 (40.9%) had diamond burr polishing, 7 of 166 (4.2%) had PTK, and 4 of 166 (2.4%) had epithelial debridement alone. Many eyes had >6 weeks follow-up: 120 of 166 (72.3%) after conservative management, 54 of 68 (79.4%) after diamond burr polishing, 7 of 7 (100%) after PTK, and 4 of 4 (100%) after epithelial debridement. Percentage of eyes with recurrence was 56.7% (68/120) after conservative management, 14.8% (8/54) after diamond burr polishing, and 28.6% (2/7) after PTK. Rate of recurrence (eye-years) was 0.74, 0.19, and 0.23 with conservative management, diamond burr polishing, and PTK, respectively. Mild haze was seen in 22.2% of eyes (12 eyes) after diamond burr polishing and 28.6% (2 eyes) after PTK. CONCLUSION: Recurrent corneal erosions are most commonly associated with epithelial basement membrane dystrophy. Patients are generally initially managed conservatively, with recurrence in more than half of eyes. Diamond burr polishing is the most common surgical intervention and is effective in a majority of eyes. PMID- 24075432 TI - Treatment of persistent corneal epithelial defect with overnight wear of a prosthetic device for the ocular surface. AB - PURPOSE: To report experience in the treatment of persistent corneal epithelial defect using overnight wear of a prosthetic device for the ocular surface. DESIGN: Retrospective interventional case series. METHODS: A clinical database of patients who underwent prosthetic replacement of the ocular surface ecosystem (PROSE) treatment from March 2003 to August 2008 was searched to identify patients treated for persistent corneal epithelial defect. In early 2003, overnight wear of a PROSE device and addition of commercially available, nonpreserved, topical ophthalmic moxifloxacin to the saline in the device reservoir became standard practice at this center when treating persistent corneal epithelial defect. Medical records were abstracted to obtain underlying diagnoses, previous treatments, days to re-epithelialization, and complications for subsequent analysis. RESULTS: PROSE treatment incorporating overnight wear, with adjunctive use of moxifloxacin, was employed in 20 eyes of 19 patients for a total of 372 days. Re-epithelialization occurred in 17 of 20 eyes. Median duration of treatment incorporating overnight wear was 8.5 days (range = 2-76 days). Healing occurred in <=7 days in 12 eyes, 8-14 days in 3 eyes, and >14 days in 2 eyes (range = 1-35 days). There were no cases of microbial keratitis. CONCLUSIONS: Overnight wear of a PROSE device is effective in promoting healing of persistent corneal epithelial defect. In comparison to an earlier series from this center, the rate of microbial keratitis as a complication of treatment has been reduced with the use of a nonpreserved topical fourth-generation fluoroquinolone in the device reservoir. PMID- 24075433 TI - Optical coherence tomography-guided transepithelial phototherapeutic keratectomy for the treatment of anterior corneal scarring. AB - PURPOSE: To report the visual and anatomic outcomes of a novel technique for the management of anterior corneal scarring using optical coherence tomography (OCT) guided transepithelial phototherapeutic keratectomy (transepithelial PTK). DESIGN: Retrospective, consecutive case series. METHODS: The charts of 22 patients with anterior corneal scarring associated with irregularities in the Bowman layer who had undergone transepithelial PTK according to a novel protocol were reviewed. The protocol consisted of a preoperative OCT-measured depth-of treatment calculation, followed by a dual excimer laser treatment profile set to achieve the desired refractive outcome while eliminating or reducing corneal scarring. The primary outcomes were change in best spectacle-corrected visual acuity (BSCVA) and change in corneal topography indices at 4 months after ablation. RESULTS: BSCVA (in logMAR) improved from a mean of 0.82 (0.61-1.02; 95% confidence interval) preoperatively to a mean of 0.40 postoperatively (0.19-0.61) (P = 0.0070). All patients gained a minimum of 1 line of BSCVA postoperatively. Preoperative and postoperative corneal topographic indices showed significant improvement in corneal cylinder (P = 0.0173) and projected visual acuity (P = 0.0261) but not in the surface asymmetry index (P = 0.0849) or the surface regularity index (P = 0.0543). Postoperative spherical equivalent averaged 0.78 diopters (0.49-1.07) of error from the intended target refractive outcome. No complications were associated with the treatment, and no patients required or desired subsequent treatment with either repeat PTK or with more invasive surgery such as lamellar or penetrating keratoplasty. CONCLUSIONS: OCT-guided transepithelial PTK using a dual ablation excimer laser profile can provide favorable results as well as predictable refractive outcomes in the treatment of corneal scarring associated with Bowman layer irregularities. Future investigations are warranted to further validate the technique reported in this study. PMID- 24075447 TI - Mussel mimetic tissue adhesive for fetal membrane repair: initial in vivo investigation in rabbits. AB - OBJECTIVE: Iatrogenic preterm prelabour rupture of fetal membranes (iPPROM) remains the main complication after invasive interventions into the intrauterine cavity. The aim of this study was to evaluate the sealing capability and tissue interaction of mussel-mimetic tissue adhesive (mussel glue) in comparison to fibrin glue on punctured fetal membranes in vivo. STUDY DESIGN: A mid-gestational rabbit model was used for testing the materials. The fetal sacs of pregnant rabbits at day 23 were randomly assigned into experimental groups: unoperated (negative control), unclosed puncture (positive control), commercially available fibrin glue (FG) with decellularized amnion scaffold (DAM), mussel glue (MG) with DAM, or mussel glue alone. Evaluation was done at term (30 days' gestation) assessing fetal survival, fetal membrane integrity and histology of the membranes. RESULTS: Fetal survival was not significantly lower in any of the treatment groups compared to the negative control. All plugging materials could be found at the end of the pregnancy and no adverse effects on the fetus or the pregnant does could be observed. Sac integrity was higher in all treatment groups compared to the positive control group but significant only in the FG+DAM group. Cellular infiltration could be seen in fibrin glue and DAM in contrast to mussel glue which was only tightly adhering to the surrounding tissue. These cells were mostly of mesenchymal phenotype staining positive for vimentin. CD68 positive macrophages were found clustered around all the plugging materials, but their numbers were only significantly increased for the mussel glue alone group compared to negative controls. CONCLUSIONS: Mussel glues performance in sealing fetal membranes in the rabbit model was comparable to that of fibrin glue. Taking into account its other favorable properties, it is a noteworthy candidate for a clinically applicable fetal membrane sealant. PMID- 24075449 TI - Meeting at the crossroads: common mechanisms in Fragile X and Down syndrome. AB - Intellectual disability is characterized by significantly impaired cognitive abilities and is due to various etiological factors, including both genetic and non-genetic causes. Two of the most common genetic forms of intellectual disability are Fragile X syndrome (FXS) and Down syndrome (DS). Recent studies have shown that proteins altered in FXS and DS can physically interact and participate in common signaling pathways regulating dendritic spine development and local protein synthesis, thus supporting the notion that spine dysmorphogenesis and abnormal local protein synthesis may be molecular underpinnings of intellectual disability. Here we review the molecular constituents regulating local protein synthesis and spine morphology and their alterations in FXS and DS. We argue that these changes might ultimately affect synaptic homeostasis and alter cognitive performance. PMID- 24075450 TI - Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals. AB - A major concept in autoimmunity is that disruption of Foxp3(+) regulatory T cells (Tregs) predisposes to breach of tolerance. This is exemplified by the Foxp3 linked disorder termed IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) which affects newborn children. There has been considerable clinical interest in the role of non-depleting anti-CD4 antibodies as a means of upregulating the function of Foxp3(+) Tregs in order to control detrimental inflammatory responses such as transplant rejection. However, according to the paradigm of a Treg-dependent mechanism of action, the effectiveness of anti-CD4 antibodies as a therapy for human autoimmune diseases is unclear considering that Treg function might be intrinsically impaired. Specifically, anti-CD4 therapy is expected to fail in patients suffering from the IPEX syndrome due to the lack of functional Foxp3(+) Tregs. Taking advantage of natural Foxp3 mutant scurfy (sf) mice closely resembling the IPEX syndrome, and genetically engineered mice depleted of Foxp3(+) Tregs, we report here that anti CD4 treatment induces tolerance independent of Foxp3(+) Tregs. This so far undefined mechanism is dependent on the recessive non-infectious tolerization of autoreactive T cells. Treg-independent tolerance alone is powerful enough to suppress both the onset and severity of autoimmunity and reduces clinically relevant autoantibody levels and liver fibrosis. Mechanistically, tolerance induction requires the concomitant activation of autoreactive T cells and is associated with the down-regulation of the co-stimulatory TNF-receptor superfamily members OX40 and CD30 sustaining CD4(+) T cell survival. In the light of ongoing clinical trials, our results highlight an unexpected potency of anti CD4 antibodies for the treatment of autoimmune diseases. Particularly, CD4 blockade might represent a novel therapeutic option for the human IPEX syndrome. PMID- 24075452 TI - Effects of lipid concentration on anaerobic co-digestion of municipal biomass wastes. AB - The influence of the lipid concentration on the anaerobic co-digestion of municipal biomass waste and waste-activated sludge was assessed by biochemical methane potential (BMP) tests and by bench-scale tests in a mesophilic semi continuous stirred tank reactor. The effect of increasing the volatile solid (VS) concentration of lipid from 0% to 75% was investigated. BMP tests showed that lipids in municipal biomass waste could enhance the methane production. The results of bench-scale tests showed that a lipids concentration of 65% of total VS was the inhibition concentration. Methane yields increased with increasing lipid concentration when lipid concentrations were below 60%, but when lipid concentration was set as 65% or higher, methane yields decreased sharply. When lipid concentrations were below 60%, the pH values were in the optimum range for the growth of methanogenic bacteria and the ratios of volatile fatty acid (VFA)/alkalinity were in the range of 0.2-0.6. When lipid concentrations exceeded 65%, the pH values were below 5.2, the reactor was acidized and the values of VFA/alkalinity rose to 2.0. The amount of Brevibacterium decreased with increasing lipid content. Long chain fatty acids stacked on the methanogenic bacteria and blocked the mass transfer process, thereby inhibiting anaerobic digestion. PMID- 24075451 TI - Limitations and plausibility of the Pliocene lignite hypothesis in explaining the etiology of Balkan endemic nephropathy. AB - BACKGROUND: Balkan endemic nephropathy (BEN) is a chronic, tubulointerstitial renal disease often accompanied by urothelial cancer that has a lethality of nearly 100%. INTRODUCTION: One of the many factors that have been proposed to play an etiological role in BEN is exposure to organic compounds from Pliocene lignite coal deposits via the drinking water in endemic areas. OBJECTIVES: The objective of this study was to systematically evaluate the role of the tenets of the Pliocene lignite hypothesis in the etiology of BEN in order to provide an improved understanding of the hypothesis for colleagues and patients alike. METHODS: A comprehensive compilation of the possible limitations of the hypothesis, with each limitation addressed in turn is presented. RESULTS: The Pliocene lignite hypothesis can best account for, is consistent with, or has the potential to explain the evidence associated with the myriad of factors related to BEN. CONCLUSIONS: Residents of endemic areas are exposed to complex mixtures containing hundreds of organic compounds at varying doses and their potentially more toxic (including nephrotoxic) and/or carcinogenic metabolites; however, a multifactorial etiology of BEN appears most likely. PMID- 24075453 TI - Impact of interleukin-1beta antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial. AB - AIMS/HYPOTHESIS: This study was conducted to determine the optimal monthly subcutaneous dose of canakinumab (a human monoclonal anti-human IL-1beta antibody) needed to improve glucose control in metformin-treated patients with type 2 diabetes mellitus (T2DM). METHODS: This was a parallel-group, randomized, double-blind, multicentre, placebo-controlled study designed to assess the effect on HbA(1c) and the safety/tolerability of four monthly doses of canakinumab (5, 15, 50, or 150 mg) as an add-on to metformin over 4 months. RESULTS: Patients (n=551; mean age 54.1 years; mean baseline HbA(1c) 7.4%) were randomized and treated in a double-blind fashion to canakinumab 5 mg (n=93), 15 mg (n=95), 50 mg (n=92), 150 mg (n=92) or placebo (n=179) monthly. There was no dose response detected between active canakinumab doses, but all doses numerically lowered HbA(1c) (primary endpoint) from baseline between 0.19% and 0.31% (placebo unadjusted), with maximal effect noted in the 50mg dose of canakinumab (-0.18% difference vs placebo; multiplicity-adjusted, P=0.13902) as reported earlier (Ridker et al., 2012). No other glycaemic control parameters (FPG, fasting insulin, plasma glucose AUC(0-4h), 2-h PPG, peak glucose, C-peptide AUC(0-4h), peak C-peptide, insulin AUC(0-4h), peak insulin, ISR(0-2h), HOMA-beta and HOMA IR) showed any meaningful changes by canakinumab therapy. Canakinumab treatment was safe and well tolerated. There were no relevant differences in adverse events between the canakinumab and placebo groups. CONCLUSIONS/INTERPRETATION: A 4-month course of monthly canakinumab (50 mg) produced a numerical reduction of HbA(1c) in T2DM patients on metformin, potentially by improving beta-cell function. The safety and tolerability profile of canakinumab was consistent with prior trials. TRIAL REGISTRATION: Registry: http://www.ClinicalTrials.gov, Registration No.: NCT00900146. PMID- 24075454 TI - NR4A orphan nuclear receptors in glucose homeostasis: a minireview. AB - Type 2 diabetes mellitus is a disorder characterized by insulin resistance and a relative deficit in insulin secretion, both of which result in elevated blood glucose. Understanding the molecular mechanisms underlying the pathophysiology of diabetes could lead to the development of new therapeutic approaches. An ever growing body of evidence suggests that members of the NR4A family of nuclear receptors could play a pivotal role in glucose homeostasis. This review aims to present and discuss advances so far in the evaluation of the potential role of NR4A in the regulation of glucose homeostasis and the development of type 2 diabetes. PMID- 24075455 TI - Dyssynchrony: a different kind of mitral regurgitation. PMID- 24075456 TI - Gas velocity at the point of re-injection: an additional parameter in comprehensive two-dimensional gas chromatography optimization. AB - The present research is focused on the introduction of a new optimization parameter in the field of comprehensive 2D GC (GC*GC), herein defined as "gas velocity at the point of re-injection". GC*GC experiments were performed using a loop-type cryogenic modulator and a rapid-scanning quadrupole mass spectrometer, as detection system. All experiments were performed using a 30m*0.25mm ID apolar primary column, and a 1m*0.10mm ID medium-polarity secondary one. With regards to the modulator loops, three types of uncoated columns were used, namely with a 0.25, 0.18, and 0.10mm ID. It was found that under the same second-dimension analytical conditions (modulation, oven temperature, gas velocity) the quality of the GC*GC separation was dependent on the gas velocity at the moment of re injection. For a loop-type modulator, the re-injection point is located at the downstream cooling/heating point of the delay loop. It was found that the GC*GC performance gradually improved when the ID of the modulator loop decreased (and the re-injection gas velocity increased), and reached its best when the 0.10mm ID uncoated column was used. GC*GC experiments were performed on a C14 n-alkane (to evaluate the efficiency of band re-injection, in terms of peak widths) and on an essential oil sample (to evaluate peak widths, resolution and the overall separation performance). The results herein reported are valid for practically any type of cryogenic modulator. PMID- 24075457 TI - Chemically modified cellulose paper as a thin film microextraction phase. AB - In this paper, chemically modified cellulose paper was introduced as a novel extracting phase for thin film microextraction (TFME). Different reagents (Octadecyltrichlorosilane, diphenyldichlorosilane, cyclohexyl isocyanate and phenyl isocyanate) were used to modify the cellulose papers. The modified papers were evaluated as a sorbent for the extraction of some synthetic and natural estrogenic hormones (17alpha-ethynylestradiol, estriol and estradiol) from aqueous samples. Liquid chromatography-fluorescence detection was used for the quantification of the extracted compounds. The cellulose paper modified with phenyl isocyanate showed the best affinity to the target compounds. TEME parameters such as desorption condition, shaking rate, sample ionic strength and extraction time were investigated and optimized. Limit of detections were between 0.05 and 0.23MUgL(-1) and relative standard deviations were less than 11.1% under the optimized condition. The calibration curves were obtained in the range of 0.2 100MUgL(-1) with a good linearity (r(2)>0.9935). Wastewater, human urine, pool and river water samples were studied as real samples for the evaluation of the method. Relative recoveries were found to be between 75% and 101%. PMID- 24075458 TI - Preparation a new sorbent based on polymeric ionic liquid for stir cake sorptive extraction of organic compounds and inorganic anions. AB - A new multi-interaction sorbent (MIS) based on polymeric ionic liquid was prepared and used as extractive medium of stir cake sorptive extraction (SCSE). In the presence of dimethyl sulfoxide, an ionic liquid, 1-vinylbenzyl-3 methylimidazolium chloride was used as monomer to copolymerize in situ with divinylbenzene to form the MIS. The influences of the content of monomer and the porogen solvent in the polymerization mixture on the extraction performance were investigated thoroughly. The MIS was characterized by infrared spectroscopy, elemental analysis, scanning electron microscopy and mercury intrusion porosimetry. Parabens and aromatic amines were used to investigate the extraction performance of MIS-SCSE for apolar and strongly polar analytes, respectively. The extraction parameters for parabens and aromatic amines were optimized. At the same time, simple and sensitive analytical methods for parabens and aromatic amines in real samples were developed by the combination of MIS-SCSE and HPLC/DAD. Some inorganic anions, such as F(-), Br(-), NO3(-), PO4(3-) and SO4(2 ), were used to test the extraction performance of MIS-SCSE for anions. Results indicated that mechanism involved in the extraction of MIS is the multi interaction modes including pi-pi, hydrophobic, hydrogen-bonding, dipole-dipole and anion-exchange interactions. PMID- 24075459 TI - Chromatography and the hundred year mystery of inorganic ions at aqueous interfaces: adsorption of inorganic ions at the Porous Graphitic Carbon Aqueous Interface follows the Hofmeister series. AB - Many physical phenomena are affected by the structure of water interfaces, yet it remains an active and controversial subject. A great deal of recent theoretical endeavour and computer simulations question the validity of the Onsager Samaras theory of the ion-free interface between an electrolyte solution and an hydrophobic surface. Experimental results play a crucial role in assessing the legitimacy of the theories. Experimental data are scarce, while simulation results suggest an increasing surface affinity of ions with increasing chaotropic character, in dramatic contradiction to the classical view. Chromatography is a powerful separative technique, but we originally used it as a tool to detect the adsorption of chloride electrolytes and sodium electrolytes, strongly expected to shun any dielectric boundary, onto an hydrophobic surface, and to rank ions according to their adsorbophilicities. Frontal analysis gave unequivocal experimental evidence to this unexpected phenomenon and it was used to quantify it. The infinite dilution equilibrium constants for adsorption of kosmotropes and chaotropes onto the interface were obtained and contrasted to the Jones-Dole B viscosity coefficients, that is a common quantifier of the Hofmeister effect. It is clear that (i) the more chaotropic the ion is, the more it contributes to the global adsorbophilicity of the electrolyte; (ii) the influence of the variable anion is more than twofold that of the variable cation, thereby confirming a robust observation in many other physical systems. Standard free energy of adsorption for each electrolyte was calculated and its reliability was commented upon. The central issue in this paper is the effective and ascertained adsorption of electrolytes onto an hydrophobic surface and the fact that the adsorbophilicity of an electrolyte may be inferred from its position in the Hofmeister series. PMID- 24075460 TI - Glutathione-based zwitterionic stationary phase for hydrophilic interaction/cation-exchange mixed-mode chromatography. AB - As a naturally hydrophilic peptide, glutathione was facilely immobilized onto silica surface to obtain a novel hydrophilic interaction/cation-exchange mixed mode chromatographic stationary phase (Click TE-GSH) via copper-free "thiol-ene" click chemistry. The resulting material was characterized by solid state (13)C/CP MAS NMR and elemental analysis. The measurement of zeta-potential indicated the cation-exchange characteristics and adjustable surface charge density of Click TE GSH material. The influence of acetonitrile content and pH value on the retention of ionic compounds was investigated for understanding the chromatographic behaviors. The results demonstrated that Click TE-GSH column could provide both hydrophilic and cation-exchange interaction. Taking advantage of the good hydrophilicity and inherent cation-exchange characteristics of Click TE-GSH material, the resolution of neutral fructosan with high degree of polymerization (DP), basic chitooligosaccharides and strongly acidic carrageenan oligosaccharides was successfully realized in hydrophilic interaction chromatography (HILIC), hydrophilic interaction/cation-exchange mixed-mode chromatography (HILIC/CEX), cation-exchange chromatography (CEX) and electrostatic repulsion/hydrophilic interaction chromatography (ERLIC). On the other hand, the separation of standard peptides varying in hydrophobicity/hydrophilicity and charge was achieved in both CEX and HILIC/CEX mode with high efficiency and distinct selectivity. To further demonstrate the versatility and applicability of Click TE-GSH stationary phase, the separation of a human serum albumin (HSA) tryptic digest was performed in HILIC/CEX mode. Peptides were adequately resolved and up to 86 HSA peptides were identified with sequence coverage of 85%. The results indicated the good potential of Click TE GSH material in glycomics and proteomics. PMID- 24075461 TI - Human protein kinase inhibitor screening by capillary electrophoresis using transverse diffusion of laminar flow profiles for reactant mixing. AB - A capillary electrophoresis (CE)-based enzyme assay method has been developed to screen protein kinase inhibitors. Four human kinases GSK3beta, DYRK1A, CDK5/p25 and CDK1/cyclin B were chosen to test this novel method. These enzymes have been identified as very promising targets to develop treatments against cancer and neurodegenerative diseases. The efficiency of drugs against these relevant biological targets has never been carried out by CE. For this proposal, the capillary was used as a nanoreactor in which four reactants (the enzyme, its two substrates and its potential inhibitor) were successively injected, mixed by using transverse diffusion of laminar flow profiles and incubated. The adenosine 5'-diphosphate (ADP) formed during the enzymatic reaction was detected by UV and quantified. The efficiency of the developed CE method was validated by determining the IC50 values of a wide variety of inhibitors covering a large domain of affinity toward kinases and containing representative and chemically divergent skeletons. Excellent agreement was found between the results obtained by CE and those reported in the literature when using conventional radiometric enzyme assays. Moreover, CE was successfully used to determine the inhibitory effect of several potential inhibitors that was not yet assessed by conventional methods and is crucial for structure activity relation studies. This novel CE method is simple, rapid, very economic (few tens of nanoliters per IC50) and eco friendly since no radioactivity was required. It could be extended to high throughput screening of kinase inhibitors, which is of great interest for biomedical and pharmaceutical research fields. PMID- 24075462 TI - The effect of the Cox-maze procedure for atrial fibrillation concomitant to mitral and tricuspid valve surgery. AB - OBJECTIVES: Atrial fibrillation (AF) is associated with less favorable outcomes in patients undergoing mitral valve and tricuspid valve surgery. Despite growing evidence on the potential benefits of surgical ablation for AF there is significant variability among surgeons in treatment of AF. The purpose of our study was to assess the effect of the Cox-maze procedure on operative and follow up outcomes. METHODS: In our prospective study, patients who underwent isolated mitral valve or mitral valve+tricuspid valve surgery without history of AF (n = 506), with untreated AF (n = 75), or with Cox-maze procedure (n = 236) were included (N = 817). Sinus rhythm was captured according to Heart Rhythm Society guidelines. Patients who underwent the Cox-maze procedure were propensity score matched to patients without history of AF resulting in 208 pairs of patients. RESULTS: Operative outcomes were comparable after propensity score matching (Cox maze procedure vs no AF) stroke/transient ischemic attack (0.5% vs 0.5%; P = 1.00), renal failure (2.9% vs 1.4%; P = .34), and operative mortality (1.4% vs 1.4%; P = 1.00). High return to sinus rhythm was documented at 6, 12, and 24 months (92%, 91%, and 86%, respectively) as well as sinus rhythm off antiarrhythmic drugs (79%, 84%, and 82%, respectively). Incidence of embolic stroke in patients who underwent Cox-maze procedure was 1.7% (4 out of 232 patients) and 5.1 cases per 1000 person-years. No difference in 4-year cumulative survival between propensity score-matched groups (91.9% vs 86.9%; log rank, 1.67; P = .20), but higher for patients who underwent Cox-maze procedure versus patients with untreated AF (hazard ratio, 2.47; P = .048). Higher additive European System for Cardiac Operative Risk Evaluation (odds ratio, 1.40; P < .001) and limited surgeon experience with Cox-maze procedure (odds ratio, 3.60; P < .001) were significant predictors for failure to perform Cox-maze procedure. CONCLUSIONS: In our center, 76% of patients undergoing mitral valve or mitral valve+tricuspid valve surgery experiencing AF underwent concomitant Cox-maze procedure, which is considerably higher than the national average. No increased morbidity was associated with the Cox-maze procedure with the benefit of very low thromboembolic rate. These results suggest the need for performance-based education for AF surgical ablation to achieve optimal outcomes. PMID- 24075463 TI - Epicardial infarct repair with basic fibroblast growth factor-enhanced CorMatrix ECM biomaterial attenuates postischemic cardiac remodeling. AB - OBJECTIVES: Dysregulation of extracellular matrix (ECM) following myocardial infarction is a key contributor to myocardial fibrosis, chamber dilation, and progression to heart failure. Basic fibroblast growth factor is a potent inhibitor of fibrosis. We propose a novel surgical procedure leveraging a commercially available ECM biomaterial for the treatment of ischemic heart failure. METHODS: Epicardial infarct repair using CorMatrix-ECM biomaterial patch (CorMatrix Cardiovascular Inc, Roswell, Ga) was compared with sham in a rat myocardial infarction model. Key indices of ischemic remodeling, including inflammation, fibrosis, and myocardial performance were evaluated 16 weeks post treatment. RESULTS: Histology and immunohistochemistry demonstrated comprehensive integration of CorMatrix-ECM biomaterial patch without evidence of immune reaction and an increase in basic fibroblast growth factor expression in treated animals. Functional analysis by serial echocardiography of normal (n = 13), sham (n = 15), nonenhanced CorMatrix-ECM patch (n = 18), and basic fibroblast growth factor-enhanced CorMatrix-ECM patch (n = 10) animals revealed an improvement in ejection fraction in basic fibroblast growth factor-enhanced CorMatrix-ECM patch animals compared with shams (55.3% +/- 8.0% vs 35.1% +/- 7.6%; P < .001). Prevention of left ventricle remodeling was also confirmed by pressure volume loop analysis, which demonstrated reduced left ventricular end diastolic volumes in basic fibroblast growth factor-enhanced CorMatrix-ECM patch animals (n = 5) compared with shams (n = 6) (208.0 +/- 59.3 MUL vs 363. 1 +/- 108.7 MUL; P < .01) and improved left ventricle contractility in nonenhanced CorMatrix-ECM patch (n = 7) and basic fibroblast growth factor-enhanced CorMatrix-ECM patch animals compared with shams (0.709 +/- 0.306 and 0.609 +/- 0.160 vs 0.437 +/- 0.218; P < .05). CONCLUSIONS: Epicardial infarct repair with basic growth factor-enhanced CorMatrix-ECM biomaterial patch attenuates myocardial remodeling and improves cardiac performance after subacute myocardial infarction in a rat coronary ligation model. These observations establish proof-of-concept for this novel surgical approach. PMID- 24075464 TI - Incidence of cerebrovascular accidents in patients undergoing minimally invasive valve surgery. AB - OBJECTIVES: Minimally invasive valve surgery has been associated with increased cerebrovascular complications. Our objective was to evaluate the incidence of cerebrovascular accidents in patients undergoing minimally invasive valve surgery. METHODS: We retrospectively reviewed all the minimally invasive valve surgery performed at our institution from January 2009 to June 2012. The operative times, lengths of stay, postoperative complications, and mortality were analyzed. RESULTS: A total of 1501 consecutive patients were identified. The mean age was 73 +/- 13 years, and 808 patients (54%) were male. Of the 1501 patients, 206 (13.7%) had a history of a cerebrovascular accident, and 225 (15%) had undergone previous heart surgery. The procedures performed were 617 isolated aortic valve replacements (41.1%), 658 isolated mitral valve operations (43.8%), 6 tricuspid valve repairs (0.4%), 216 double valve surgery (14.4%), and 4 triple valve surgery (0.3%). Femoral cannulation was used in 1359 patients (90.5%) and central cannulation in 142 (9.5%). In 1392 patients (92.7%), the aorta was clamped, and in 109 (7.3%), the surgery was performed with the heart fibrillating. The median aortic crossclamp and cardiopulmonary bypass times were 86 minutes (interquartile range [IQR], 70-107) minutes and 116 minutes (IQR, 96 143), respectively. The median intensive care unit length of stay was 47 hours (IQR, 29-74), and the median postoperative hospital length of stay was 7 days (IQR, 5-10). A total of 23 cerebrovascular accidents (1.53%) and 38 deaths (2.53%) had occurred at 30 days postoperatively. CONCLUSIONS: Minimally invasive valve surgery was associated with an acceptable stroke rate, regardless of the cannulation technique. PMID- 24075465 TI - Short-term reduction in intrinsic heart rate during biventricular pacing after cardiac surgery: a substudy of a randomized clinical trial. AB - BACKGROUND: The Biventricular Pacing After Cardiac Surgery trial investigates hemodynamics of temporary pacing in selected patients at risk of left ventricular dysfunction. This trial demonstrates improved hemodynamics during optimized biventricular pacing compared with atrial pacing at the same heart rate 1 and 2 hours after bypass and reduced vasoactive-inotropic score over the first 4 hours after bypass. However, this advantage of biventricular versus atrial pacing disappears 12 to 24 hours later. We hypothesized that changes in intrinsic heart rate can explain variable effects of atrial pacing in this setting. METHODS: Heart rate, mean arterial pressure, cardiac output, and medications depressing heart rate were analyzed in patients randomized to continuous biventricular pacing (n = 16) or standard of care (n = 18). RESULTS: During 30-second testing periods without pacing, intrinsic heart rate was lower in the paced group 12 to 24 hours after bypass (76.5 +/- 17.5 vs 91.7 +/- 13.0 beats per minute; P = .040) but not 1 or 2 hours after bypass. Cardiac output (4.4 +/- 1.2 vs 3.6 +/- 1.9 L/min; P = .054) and stroke volume (53 +/- 2 vs 42 +/- 2 mL; P = .051) increased overnight in the paced group. Vasoactive medication doses were not different between groups, whereas dexmedetomidine administration was prolonged over postoperative hours 12 to 24 in the paced group (793 +/- 528 vs 478 +/- 295 minutes; P = .013). CONCLUSIONS: These observations suggest that hemodynamic benefits of biventricular pacing 12 to 24 hours after cardiopulmonary bypass lead to withdrawal of sympathetic drive and decreased intrinsic heart rate. Depression of intrinsic rate increases the apparent benefit of atrial pacing in the chronically paced group but not in the control group. Additional study is needed to define clinical benefits of these effects. PMID- 24075466 TI - Primary pulmonary artery Rosai-Dorfman disease mimicking sarcoma. PMID- 24075467 TI - Duration and magnitude of blood pressure below cerebral autoregulation threshold during cardiopulmonary bypass is associated with major morbidity and operative mortality. AB - OBJECTIVES: Optimizing blood pressure using near-infrared spectroscopy monitoring has been suggested to ensure organ perfusion during cardiac surgery. Near infrared spectroscopy is a reliable surrogate for cerebral blood flow in clinical cerebral autoregulation monitoring and might provide an earlier warning of malperfusion than indicators of cerebral ischemia. We hypothesized that blood pressure below the limits of cerebral autoregulation during cardiopulmonary bypass would be associated with major morbidity and operative mortality after cardiac surgery. METHODS: Autoregulation was monitored during cardiopulmonary bypass in 450 patients undergoing coronary artery bypass grafting and/or valve surgery. A continuous, moving Pearson's correlation coefficient was calculated between the arterial pressure and low-frequency near-infrared spectroscopy signals and displayed continuously during surgery using a laptop computer. The area under the curve of the product of the duration and magnitude of blood pressure below the limits of autoregulation was compared between patients with and without major morbidity (eg, stroke, renal failure, mechanical lung ventilation >48 hours, inotrope use >24 hours, or intra-aortic balloon pump insertion) or operative mortality. RESULTS: Of the 450 patients, 83 experienced major morbidity or operative mortality. The area under the curve of the product of the duration and magnitude of blood pressure below the limits of autoregulation was independently associated with major morbidity or operative mortality after cardiac surgery (odds ratio, 1.36; 95% confidence interval, 1.08 1.71; P = .008). CONCLUSIONS: Blood pressure management during cardiopulmonary bypass using physiologic endpoints such as cerebral autoregulation monitoring might provide a method of optimizing organ perfusion and improving patient outcomes from cardiac surgery. PMID- 24075470 TI - Clinical evaluation of functional mitral stenosis after mitral valve repair for degenerative disease: potential affect on surgical strategy. AB - BACKGROUND: Mitral annuloplasty with either a partial band or complete ring is an integral part of mitral valve repair for degenerative disease. The affect of annuloplasty type on outcomes has not been well described. The objective of our study was to compare echocardiographic and functional characteristics of patients who underwent mitral repair with either a complete ring or a partial band. METHODS: We evaluated 107 patients who underwent mitral repair of myxomatous degeneration at our institution by stress echocardiography, 6-minute walk testing, and short form-36 questionnaire. These assessments were performed 4.3 +/ 2.2 years following mitral repair by a single surgeon. A band was used in 65 patients (61%) and a ring in 42 patients (39%). Parametric and nonparametric tests were used in the analyses. RESULTS: The labeled band and ring size used for repair were 30.7 +/- 2.8 mm and 30.4 +/- 2.1 mm, respectively (P = .6). The resting mean mitral gradient and valve area were 3.7 +/- 1.9 mm Hg and 2.3 +/- 0.6 cm(2) for patients who received a band and 5.8 +/- 2.6 mm Hg and 1.8 +/- 0.5 cm(2) for patients who received a ring (both P < .001). Distance traversed on 6 minute walk testing was 471 +/- 77 m in the band group and 443 +/- 107 m in the ring group (P = .1). At peak exercise, the mean mitral gradient (15.3 +/- 8.2 mm Hg vs 10.6 +/- 4.8 mm Hg; P < .001) and right ventricular systolic pressure (52.6 +/- 14.2 mm Hg vs 45.8 +/- 9.5 mm Hg; P = .004) were higher for patients who received a ring versus a band. Ring patients reported lower levels of energy (P = .02) and general health (P = .007) on short form-36 assessment. CONCLUSIONS: Annuloplasty using a complete ring may be associated with a higher mitral valve gradient at rest and at peak exercise in certain patients. These patients may also have worse quality of life. In view of these findings, we recommend careful consideration of annuloplasty type and size at the time of mitral repair of organic disease. PMID- 24075472 TI - Thalamic hypoperfusion in early stage of progressive supranuclear palsy (Richardson's syndrome): report of an autopsy-confirmed case. AB - Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) is a neurodegenerative disease characterized by postural instability and vertical gaze palsy, but the clinical diagnosis of PSP-RS is often difficult in the early stage of the disease. A 64-year-old male experienced frequent falls, followed by dysarthria and dysphagia. Neurological examination at age 64 demonstrated vertical gaze palsy, dysarthria, dysphagia, and retropulsion. At that time, while brain MRI demonstrated no apparent abnormalities, SPECT showed the reduction of the cerebral blood flow in the thalamus as well as the medial frontal lobe cortices. The patient was diagnosed with probable PSP-RS, and died at age 70. On postmortem examination, there were abundant tuft-shaped astrocytes, neurofibrillary tangles, coiled bodies, and argyrophilic threads in the brain, establishing the diagnosis of PSP-RS. Our definite PSP-RS case suggests that thalamic hypoperfusion may provide helpful evidence to support a diagnosis of PSP RS in the early stage of the disease. PMID- 24075471 TI - Surgical treatment of primary pulmonary artery sarcoma. AB - OBJECTIVE: Primary pulmonary artery sarcoma is a severe and underdiagnosed disease, with the clinical and surgical approach not clearly established. Only a few individual case reports or small series on this topic have been published. The aim of the present study was to report our surgical experience in this field. METHODS: From March 2004 to December 2012, 13 patients underwent surgery for pulmonary artery sarcoma at our institution. In 7 patients, the sarcoma was unilateral (53.8%), and in 6 (46.2%), the tumor had already extended to both lungs. The surgical strategy evolved over the years, but the 2 techniques used were always the same: pneumonectomy in 5 patients and pulmonary endarterectomy in 8. RESULTS: Two patients died in-hospital, both in the pneumonectomy group. The median length of the intensive care unit and hospital stay was 1 day (range, 1 10) and 14 days (range, 11-17) for the pneumonectomy group and 6 days (range, 3 23) and 19 days (range, 10-32) fort the pulmonary endarterectomy group, respectively. The median survival was 26.8 months after pneumonectomy and 6.6 months after pulmonary endarterectomy. CONCLUSIONS: Primary pulmonary artery sarcoma has a poor prognosis. The surgical strategy at our institution included pneumonectomy, for possible radical resection, and palliative endarterectomy, to reduce symptoms and increase the life expectancy. The correct surgical approach must be evaluated individually, according to the tumor presentation, the presence of pulmonary hypertension, and the patient's clinical condition. PMID- 24075473 TI - Influence of quaternary ammonium compounds on the microbial reductive dechlorination of pentachloroaniline. AB - The inhibitory effect of two widely used quaternary ammonium compounds (QACs)- alkyl benzyl dimethyl (AB) and hexadecyl trimethyl (HD) ammonium chloride--on fermentation, methanogenesis and pentachloroaniline (PCA) dechlorination was assessed using a mixed, methanogenic, PCA-dechlorinating culture amended with AB or HD at a concentration range from 5 to 70 MUM. PCA dechlorination was inhibited at 5 MUM AB and was completely inhibited at 25 or 5 MUM by AB or HD, respectively. However, the PCA dechlorination pathway was the same in both the QACs-free and QACs-amended culture series. Fermentation (acidogenesis) and methanogenesis were inhibited by both AB and HD at and above 25 MUM but to a lesser degree than PCA dechlorination. Overall, HD resulted in a more severe inhibition of the mixed culture than AB. Adsorption of both QACs to the mixed culture biomass followed the Freundlich isotherm model. The adsorption affinity of HD for the mixed culture biomass was significantly higher than that of AB, which may be related to the observed higher inhibitory effects of HD compared to AB. Both AB and HD were not degraded in the mixed, dechlorinating culture used in this study. PMID- 24075474 TI - Evaluation of statistical models for predicting Escherichia coli particle attachment in fluvial systems. AB - Modeling surface water Escherichia coli fate and transport requires partitioning E. coli into particle-attached and unattached fractions. Attachment is often assumed to be a constant fraction or is estimated using simple linear models. The objectives of this study were to: (i) develop statistical models for predicting E. coli attachment and virulence marker presence in fluvial systems, and (ii) relate E. coli attachment to a variety of environmental parameters. Stream water samples (n = 60) were collected at four locations in a rural, mixed-use watershed between June and October 2012, with four storm events (>20 mm rainfall) being captured. The percentage of E. coli attached to particles (>5 MUm) and the occurrences of virulence markers were modeled using water quality, particle concentration, particle size distribution, hydrology and land use factors as explanatory variables. Three types of statistical models appropriate for highly collinear, multidimensional data were compared: least angle shrinkage and selection operator (LASSO), classification and regression trees using the general, unbiased, interaction detection and estimation (GUIDE) algorithm, and multivariate adaptive regression splines (MARS). All models showed that E. coli particle attachment and the presence of E. coli virulence markers in the attached and unattached states were influenced by a combination of water quality, hydrology, land-use and particle properties. Model performance statistics indicate that MARS models outperform LASSO and GUIDE models for predicting E. coli particle attachment and virulence marker occurrence. Validating the MARS modeling approach in multiple watersheds may allow for the development of a parameterizing model to be included in watershed simulation models. PMID- 24075475 TI - Bench-scale evaluation of drinking water treatment parameters on iron particles and water quality. AB - Discoloration of water resulting from suspended iron particles is one of the main customer complaints received by water suppliers. However, understanding of the mechanisms of discoloration as well as role of materials involved in the process is limited. In this study, an array of bench scale experiments were conducted to evaluate the impact of the most common variables (pH, PO4, Cl2 and DOM) on the properties of iron particles and suspensions derived from the oxygenation of Fe(II) ions in NaHCO3 buffered synthetic water systems. The most important factors as well as their rank influencing iron suspension color and turbidity formation were identified for a range of water quality parameters. This was accomplished using a 2(4) full factorial design approach at a 95% confidence level. The statistical analysis revealed that phosphate was found to be the most significant factor to alter color (contribution: 37.9%) and turbidity (contribution: 45.5%) in an iron-water system. A comprehensive study revealed that phosphate and chlorine produced iron suspension with reduced color and turbidity, made zeta-potential more negative, reduced the average particle size, and increased iron suspension stability. In the presence of DOM, color was observed to increase but a reverse trend was observed to decrease the turbidity and to alter particle size distribution. HPSEC results suggest that higher molecular weight fractions of DOM tend to adsorb onto the surfaces of iron particles at early stages, resulting in alteration of the surface charge of iron particles. This in turn limits particles aggregation and makes iron colloids highly stable. In the presence of a phosphate based corrosion inhibitor, this study demonstrated that color and turbidity resulting from suspended iron were lower at a pH value of 6.5 (compared to pH of 8.5). The same trend was observed in presence of DOM. This study also suggested that iron colloid suspension color and turbidity in chlorinated drinking water systems could be lower than non chlorinated systems. PMID- 24075476 TI - Plasma treated with methylene blue and light: clinical efficacy and safety profile. AB - Methylene blue (MB) was the first method developed for pathogen inactivation of a labile blood component that was introduced in 1991. MB and light (MBL) inactivates most lipid-enveloped viruses and those non-enveloped are, in general, resistant. MBL treatment affects several coagulation factors, most noticeably fibrinogen and factor VIII with a loss of approximately 30%. Using endogenous thrombin potential, a global hemostasis evaluation, MBL treatment of plasma resulted in a 7% to 10% of reduction in thrombin potential. Although, originally, the scientific evidence of its efficacy and safety were scarce, the 4.4 million of units transfused have provided a wide body of evidence of its efficacy and safety in most of clinical situations. Nevertheless, some doubts have arisen about the efficacy of MBL plasma when used as a replacement solution for plasma exchange in the treatment of patients suffering from TTP. Probably only randomized controlled trials would provide definite evidence to clarify this point. Reports of severe allergic reactions in a few patients receiving MBL plasma have provoked the recent decision to remove the product from the market in France. Interestingly hemovigilance data in countries such as the same France, Spain, and United Kingdom have not corroborated an increase in severe allergic reaction. Close monitoring of the patients receiving plasma and suffering from allergic reactions and reporting to hemovigilance schemes hopefully will provide the needed data to definitely establish the exact risk of this complication for MBL vs other types of plasma. PMID- 24075477 TI - Tendon-to-bone healing using an injectable calcium phosphate cement combined with bone xenograft/BMP composite. AB - Injectable calcium phosphate cement (ICPC) has been applied to enhance the tendon to-bone healing. However, its slow degradation delays the osteointegration of grafted tendon in bone tunnels. We therefore constructed a synthetic biomaterial of ICPC combined with recombined bone xenograft granules (RBX). In this study, the first stage study demonstrated that the ICPCB contained 3 mg BMPs (ICPCB-3) obtained a porous structure. More importantly, the values of ICPCB-3 were highest in cell proliferation, alkaline phosphatase (ALP) activity, expression of osteogenic genes, and newly ectopic bone-forming area (P < 0.05). Then, ICPCB-3 was used in an anterior cruciate ligament (ACL) reconstruction model. Ninety skeletal mature rabbits underwent bilateral ACL reconstructions and were assigned to 3 groups: control group, ICPC alone group, and ICPCB-3 group. Animals were sacrificed at 6, 12 and 24 weeks. The results showed compared with ICPC, ICPCB-3 composite markedly accelerated tendon-to-bone healing. In addition, little remnants were observed in ICPCB-3 group. Moreover, the maximum loads to failure of ICPCB-3 group was significantly higher than ICPC group at 24 weeks (P < 0.01). We conclude that the ICPCB composite, with a porous structure and better osteointegration effect, has direct clinical instruction to arthroscopic techniques of the ACL reconstruction. PMID- 24075478 TI - Polycaprolactone scaffold and reduced rhBMP-7 dose for the regeneration of critical-sized defects in sheep tibiae. AB - The transplantation of autologous bone graft as a treatment for large bone defects has the limitation of harvesting co-morbidity and limited availability. This drives the orthopaedic research community to develop bone graft substitutes. Routinely, supra-physiological doses of bone morphogenetic proteins (BMPs) are applied perpetuating concerns over undesired side effects and cost of BMPs. We therefore aimed to design a composite scaffold that allows maintenance of protein bioactivity and enhances growth factor retention at the implantation site. Critical-sized defects in sheep tibiae were treated with the autograft and with two dosages of rhBMP-7, 3.5 mg and 1.75 mg, embedded in a slowly degradable medical grade poly(epsilon-caprolactone) (PCL) scaffold with beta-tricalcium phosphate microparticles (mPCL-TCP). Specimens were characterised by biomechanical testing, microcomputed tomography and histology. Bridging was observed within 3 months for the autograft and both rhBMP-7 treatments. No significant difference was observed between the low and high rhBMP-7 dosages or between any of the rhBMP-7 groups and autograft implantation. Scaffolds alone did not induce comparable levels of bone formation compared to the autograft and rhBMP-7 groups. In summary, the mPCL-TCP scaffold with the lower rhBMP-7 dose led to equivalent results to autograft transplantation or the high BMP dosage. Our data suggest a promising clinical future for BMP application in scaffold-based bone tissue engineering, lowering and optimising the amount of required BMP. PMID- 24075480 TI - Encapsulation of liver microsomes into a thermosensitive hydrogel for characterization of drug metabolism and toxicity. AB - This study reported the encapsulation of liver microsomes into a thermosensitive hydrogel to characterize drug metabolism and predict drug effects. Pluronic((r))F 127 (F127) and acrylamide-bisacrylamide (Acr-Bis) were utilized as the two precursors. After chemical crosslinking catalyzed by ammonium persulfate (APS) and N,N,N',N'-tetramethylethylenediamine (TEMED), the resulting Pluronic F127 acrylamide-bisacrylamide (FAB) hydrogel could encapsulate microsomes at 4 degrees C and facilitate metabolic reactions at 37 degrees C. The gel morphology at different Acr-Bis concentrations was characterized using field emission scanning electron microscopy (FE-SEM). Higher concentrations of Acr-Bis could lead to higher degrees of cross-linking of the gel. A fluorescent staining assay was subsequently used to demonstrate successful encapsulation of microsomes into the gel as well as the free diffusion process of micromolecular substrates. The thermosensitivity of the FAB gel was studied using swelling ratio and protein release assay to verify its ability to encapsulate microsomes. The metabolic activity of microsomes encapsulated in gels was investigated by detecting the metabolites of FDA-approved substrates, including dextromethorphan, chlorzoxazone and testosterone. Compared with the traditional method of microsomal incubation, the FAB gel maintained 60%-70% of microsome activity. Lastly, the classic anticancer prodrug cyclophosphamide (CTX) was chosen as a model drug for the study of drug metabolism and the prediction of drug effects. When the microsomes encapsulated in the FAB gel were used in the cell culture system, CTX induced a higher level of apoptosis in MCF-7 cells compared with traditional microsomes. PMID- 24075479 TI - Engineering functional anisotropy in fibrocartilage neotissues. AB - The knee meniscus, intervertebral disc, and temporomandibular joint (TMJ) disc all possess complex geometric shapes and anisotropic matrix organization. While these characteristics are imperative for proper tissue function, they are seldom recapitulated following injury or disease. Thus, this study's objective was to engineer fibrocartilages that capture both gross and molecular structural features of native tissues. Self-assembled TMJ discs were selected as the model system, as the disc exhibits a unique biconcave shape and functional anisotropy. To drive anisotropy, 50:50 co-cultures of meniscus cells and articular chondrocytes were grown in biconcave, TMJ-shaped molds and treated with two exogenous stimuli: biomechanical (BM) stimulation via passive axial compression and bioactive agent (BA) stimulation via chondroitinase-ABC and transforming growth factor-beta1. BM + BA synergistically increased Col/WW, Young's modulus, and ultimate tensile strength 5.8-fold, 14.7-fold, and 13.8-fold that of controls, respectively; it also promoted collagen fibril alignment akin to native tissue. Finite element analysis found BM stimulation to create direction dependent strains within the neotissue, suggesting shape plays an essential role toward driving in vitro anisotropic neotissue development. Methods used in this study offer insight on the ability to achieve physiologic anisotropy in biomaterials through the strategic application of spatial, biomechanical, and biochemical cues. PMID- 24075481 TI - Phenotypic modulation of human cardiospheres between stemness and paracrine activity, and implications for combined transplantation in cardiovascular regeneration. AB - As the search for new cell types for cardiovascular regeneration continues, it has become increasingly important to optimize ex vivo cell processing. We aimed to develop an optimal processing strategy for human cardiac progenitor cells. We hypothesized that enhancing the stemness potential and promoting the secretory activity for paracrine effects are mutually exclusive routes. Therefore, we investigated the two divergent cell processing methods to enhance cellular potency and humoral activity, respectively. We obtained human right ventricular tissues and sequentially generated primary cardiosphere (CS), primary CS-derived cells (PCDC) and secondary CSs. During secondary CS formation, inhibiting the ERK pathway, using selective RTK1 and TGF-beta inhibitors, Oct4 increased 20 fold and VEGF was decreased. When the ERK pathway was stimulated by addition of EGF and TGF-beta, VEGF expression was upregulated and Oct4 was downregulated, indicating that the ERK pathway serves a directional role for cellular potency versus paracrine capacity. Transplantation of PCDCs or secondary CSs into the infarcted heart of immunocompromised mouse showed significant angiogenic effects compared with PBS injection. Interestingly, combined transplantation of the two differently-processed, dual-purpose secondary CSs resulted in an additional increase in neovascularization. Human VEGF was primarily produced from secondary CSs under ERK stimulating conditions. Cardiomyocyte-like cells were produced from secondary CSs under ERK inhibitory conditions. These findings indicate that combined transplantation of specifically-processed human secondary CSs enhances infarct repair through the complementary enhancement of cardiopoietic regenerative and paracrine protective effect. Furthermore, these results underscore the fact that optimal cell processing methods have the potential to maximize the therapeutic benefits. PMID- 24075482 TI - A cancer vaccine based on the marine antimicrobial peptide pardaxin (GE33) for control of bladder-associated tumors. AB - The marine antimicrobial peptide (AMP) GE33, also known as pardaxin, possesses antimicrobial and anticancer properties, and modulates host signaling. GE33 has cytotoxic effects on murine bladder carcinoma (MBT-2) cells. Here, we investigated the potential of GE33 combined with inactivated MBT-2 as a cancer vaccine. The presence of up to 12.5 MUg of GE33 did not inhibit the proliferation or endogenous nitrous oxide (NO) levels of RAW264.7 cells. However, the secretion of MCP-1, IL-6, and IL-12 by RAW264.7 cells was affected by GE33. We proceeded to test the effectiveness of the vaccine by immunizing mice at 7, 14, and 21 days of age, and injecting live MBT-2 cells on the 28th day. Tumor growth by the 58th day was attenuated in mice treated with the vaccine, as compared to the control group. Induction of MBT-2 specific-tumor antigens was increased in mice immunized with our vaccine. Furthermore, activation of T-cell receptors, cytotoxic T-cells, and NK cells was enhanced, and these showed high specificity for targeting tumor cells. Finally, immunization controlled excess recruitment of monocytes, lymphocytes, T-helper cells, and NK cells, and decreased the expression of VEGF. This report provides empirical evidence that our GE33-based vaccine enhances antitumor immunity in mice. PMID- 24075483 TI - Phenylboronic acid-functionalized polymeric micelles with a HepG2 cell targetability. AB - Phenylboronic acid-functionalized amphiphilic block copolymer Pluronic-PMCC-BA was synthesized via ring-opening polymerization of 5-methyl-5-benzyloxycarbonyl 1,3-dioxan-2-one (MBC) with fumaric acid as a catalyst followed by the deprotection of carboxyl groups by catalyzed hydrogenation and the condensation of 3-aminophenylboronic acid with the copolymer side groups. Pluronic-PMCC-BA can form stable micelle solution by self-assembly in water. The phenylboronic acid groups are located at the shell of micelle as proved by (1)H NMR. The diameter of drug-free micelles is approximate 60 nm. Nano-spheres with narrow size distribution could be observed in the TEM image. MTT assay results show that Pluronic-PMCC-BA exhibits slight cytotoxicity when the polymer concentration is higher than 25 MUg mL(-1). The toxicities of DOX@Pluronic-PMCC and DOX@Pluronic PMCC-BA to COS7, HeLa, and HepG2 cell lines are similar with those of free DOX. Interestingly, phenylboronic acid groups located at the surface of Pluronic-PMCC BA micelles can recognize HepG2 cells and promote the drug uptake of the cells, which are observed by confocal laser scanning microscopy (CLSM). The results imply that Pluronic-PMCC-BA would be a promising material for targeted drug delivery to the cancer cells. PMID- 24075484 TI - Blood pressure control in continuous flow left ventricular assist devices: efficacy and impact on adverse events. AB - BACKGROUND: Continuous flow (CF) left ventricular assist devices (LVAD) are afterload sensitive and therefore pump performance is affected by hypertension. In addition, poorly controlled hypertension may increase the risk of aortic insufficiency (AI) and stroke. Blood pressure regimens after CF LVAD have not been studied and their impact on rates of AI and stroke are unknown. METHODS: Patients who had CF LVAD at a single center and were supported greater than 30 days were included. Blood pressure was monitored at home by Doppler. Outpatient management of blood pressure was conducted according to a predefined institutional protocol (target mean arterial pressure <= 80 mm Hg). RESULTS: A total of 96 patients were included. At the end of follow-up, 25 patients were not on an antihypertensive drug, of these 9 died. Of the 74% receiving antihypertensives, 54% required 1 medication, 34% were on 2, 10% were on 3, and 3% were on 4 or more. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (85% of patients on an antihypertensive) and beta blockers (30%) were the most commonly prescribed medications. There was a significantly higher neurologic event rate in those on no antihypertensives compared with those on antihypertensives (p = 0.009). Only 3% of patients with no or mild AI at baseline progressed to develop moderate or greater AI after a mean of 201 days of follow-up. CONCLUSIONS: Blood pressure control can be achieved in patients with CF LVADs, with the majority of patients requiring only 1 or 2 antihypertensives. PMID- 24075485 TI - Sivelestat attenuates lung injury in surgery for congenital heart disease with pulmonary hypertension. AB - BACKGROUND: Pulmonary hypertension associated with congenital heart disease increases the risk of surgery using cardiopulmonary bypass. Sivelestat is a neutrophil elastase inhibitor thought to have a prophylactic effect against lung injury after surgery using bypass. We elucidated that Sivelestat had the protective effect on lung in patients with congenital heart disease and pulmonary hypertension who underwent surgery using bypass. METHODS: This study was a controlled prospective randomized trial and enrolled 13 neonates or infants with ventricular septal defect and pulmonary hypertension. The patients were assigned to either sivelestat with the dose of 0.2 mg/kg per hour (sivelestat group, n = 7) or saline (placebo group, n = 6) from the start of bypass until 6 hours after bypass. Proinflammatory cytokines and adhesion molecules on leukocytes were measured at 10 time points during the above period. Pulmonary function was assessed perioperatively. RESULTS: Compared with the placebo group, the sivelestat group had significantly lower values of alveolar-arterial oxygen tension gradient at 24 hours (p = 0.038) and at 48 hours (p = 0.028) after bypass, and significantly better balance of hydration at 48 hours after bypass (p = 0.012). The sivelestat group also showed significantly lower plasma levels of interleukin-8 immediately after bypass (p = 0.041) and interleukin-10 at 15 minutes after removal of the aortic cross-clamp (p = 0.048), and immediately after bypass (p = 0.037). CONCLUSIONS: Administration of sivelestat during bypass prevented pulmonary damage and activities of proinflammatory cytokines at the cardiac operation in neonates or infants. Our results show that sivelestat may be considered to protect pulmonary function against the injury by bypass. PMID- 24075486 TI - Improved left ventricular function and remodeling after the david v for significant aortic insufficiency. AB - BACKGROUND: Valve-sparing root replacement is controversial in patients with significant aortic insufficiency (AI) because the aortic valve cusps often require repair, which may potentially jeopardize long-term valve function. The purpose of this study was to evaluate valve function and left ventricular reverse remodeling in patients undergoing valve-sparing root replacement in the setting of significant AI. METHODS: A review of the Emory Aortic Surgery database between 2004 and 2012 identified 616 aortic root replacements. Of these procedures, 169 were performed for patients with 3+ or greater AI. Fifty-one patients (30%) underwent a David V procedure. Echocardiography was used to evaluate the degree of AI, left ventricular end-diastolic diameter, and left ventricular end-systolic diameter. RESULTS: The mean echocardiographic follow-up was 18 +/- 21 months (range, 1 to 89). Patients undergoing valve-sparing root replacement had an increase in ejection fraction (preoperative 51% +/- 7% versus postoperative 57% +/- 6%, p < 0.01) and a reduction in left ventricular end-diastolic diameter (preoperative 58 +/- 8 mm versus postoperative 48 +/- 6 mm, p < 0.01) and left ventricular end-systolic diameter (preoperative 40 +/- 8 mm versus postoperative 32 +/- 6 mm, p < 0.01). During the follow-up period, freedom from greater than 1+ AI was 96%, and freedom from aortic valve replacement was 98%. The addition of cusp repair did not represent a significant risk factor for recurrent postoperative AI (p = 0.21). CONCLUSIONS: The David V technique produces significant left ventricular reverse remodeling and improved ventricular function in patients with chronic severe AI. Long-term data and close follow-up will be paramount in evaluating the durability of valve repair in this patient population. PMID- 24075487 TI - Impact of failed mitral clipping on subsequent mitral valve operations. AB - BACKGROUND: This study analyzed the effect of failed percutaneous mitral intervention with the MitraClip device (Abbott Laboratories, Abbott Park, IL) on subsequent mitral valve (MV) operations. METHODS: Nineteen patients (74 +/- 9 years) with treatment failure after implantation of 37 MitraClips (mean, 1.9 +/- 0.8; range, 1 to 4) for functional or degenerative MV disease underwent operations a median of 12 days later (range, 0 to 546 days). All patients were studied before and after the operation by clinical investigation and echocardiographic analysis. Intraoperative findings and the effect on the operation were analyzed and are described in detail. Data before clipping and at the time of operation were compared, and the surgical outcome was recorded. RESULTS: There was a significant increase in risk between that at the time of clipping and that at subsequent operations, noted as a rise of the European System for Cardiac Operative Risk Evaluation II from a median 12.74% to 26.87%, respectively (p < 0.0001, Wilcoxon signed rank test). Severe clip implantation induced tissue damage was found in most patients. Surgical MV repair could be performed in 5 of 6 patients (83%) with a 1-clip implant and in only 3 of 13 patients (23%) when 2 or more clips had been inserted (p = 0.0188, Wilcoxon-Mann Whitney test). All patients required other associated procedures: closure of an artificial atrial septal defect that was caused by the clipping procedure (100%), tricuspid valve repair (37%), atrial fibrillation ablation operations (37%), coronary artery bypass grafting (16%), and aortic valve replacement (11%). Two early cardiac deaths (< 30 days) occurred. Survival at 1 year was 68%. CONCLUSIONS: There is a remarkable impact of failed clipping procedures on MV operations. We observed a severely aggravated cardiac pathology in parallel with a reduced preoperative clinical state compared with the original condition. Moreover, the likelihood of an optimal surgical solution with valve reconstruction was reduced thereafter. However, operations in the critical situation of an unsuccessful mitral clipping procedure should be discussed immediately, because it still seems to be an option compared with conservative therapy. PMID- 24075488 TI - [Topics and considerations on reducing hospital admission: from evidence to practice]. AB - Demographic changes and the economic situation of the recent years have conditioned a turning point in health policies, which have decided to progressively prioritize chronicity care programs. Given that hospital costs were concentrated in attention to patients with chronic diseases, reduction on admissions is now a priority target. Meanwhile, we state that among the obviously community handling paradigmatic aim for those patients and the current care situation, there is a long way to do that should be done gradually. According to the current scientific evidence: Is it sensible to assume that there is a proper level of admissions or is it better for the patients to reduce the number of admissions? Is it possible to operationally and reliably define which hospital admissions are avoidable? Is it harmful to a patient and to the health care system to admit a patient with multiple chronic disease? Maybe are hospital admissions are avoidable and readmissions are indicators of a fragmented health care system? Given that situation, a reasonable approach requires firstly a critical analysis of the various realities of care (microsystems) and a systematic review of the scientific evidence-breaking, and rejecting some topics if necessary. Secondly, we should bring all this knowledge to clinical practice, conciliating "what" and the know-how, individual and population view, sole disease and multimorbidity, and finally clinical approach and health planning. PMID- 24075490 TI - Suprarenal retroperitoneal liposarcoma with intracaval tumor thrombus: an imaging mimic of adrenocortical carcinoma. AB - We report a 57-year-old previously healthy man who presented with dull right upper quadrant pain, weight loss, fatigue, and night sweats. Computed tomography demonstrated a large, heterogeneously enhancing, soft tissue mass with no macroscopic fat above the right kidney with tumor thrombus extending into the inferior vena cava and right atrium. Positron Emission Tomography scanning demonstrated intense Fluorodeoxyglucose avidity in the primary tumor and tumor thrombus. The presumptive radiological diagnosis was adrenocortical carcinoma, but surgical pathology revealed a dedifferentiated liposarcoma. We conclude that suprarenal retroperitoneal liposarcoma should be included in the differential diagnosis for an apparent adrenal mass with venous invasion. PMID- 24075491 TI - Neural correlates of attention-deficit/hyperactivity disorder in adulthood. PMID- 24075492 TI - Toward systems neuroscience of shared and distinct neural effects of medications used to treat attention-deficit/hyperactivity disorder. PMID- 24075493 TI - A model for the hysteresis observed in gating of lysenin channels. AB - The pore-forming toxin lysenin self-inserts to form conductance channels in natural and artificial lipid membranes containing sphingomyelin. The inserted channels exhibit voltage regulation and hysteresis of the macroscopic current during the application of positive periodic voltage stimuli. We explored the bi stable behavior of lysenin channels and present a theoretical approach for the mechanism of the hysteresis to explain its static and dynamic components. This investigation develops a model to incorporate the role of charge accumulation on the bilayer lipid membrane in influencing the channel conduction state. Our model is supported by experimental results and also provides insight into the temperature dependence of lysenin channel hysteresis. Through this work we gain perspective into the mechanism of how the response of a channel protein is determined by previous stimuli. PMID- 24075494 TI - The relationship between metabolic conditions and prevalence of periodontal disease in rural Korean elderly. AB - The aim of this study was to investigate the relationship between the duration and number of components of metabolic syndrome and periodontal disease among rural elderly in Korea over 60 years old. This longitudinal study consisted of 399 participants who underwent regular health examinations at Seongju-gun Public Health Center from 2000 to 2007. The components of metabolic syndrome (diabetes mellitus, hypertension, obesity, and hypercholesterolemia) were evaluated from clinical records of Seongju-gun Public Health Center, which were recorded from 2000 to 2007, and periodontal examination by Community Periodontal Index, recorded from 2006 to 2007. Participants suffering from longer durations of diabetes mellitus, hypertension, and obesity were more likely to have periodontal disease. Individuals with a greater number of metabolic syndrome components were more likely to have periodontal disease. Older rural Koreans with components of metabolic syndrome have unmet periodontal treatment needs. Medical and dental professionals need to coordinated systemic and oral care for these people. PMID- 24075495 TI - Effects on cognition of conventional and robotically assisted cardiac valve operation. AB - BACKGROUND: The effect of valve surgical procedures on cognition was investigated in patients undergoing conventional or robotically assisted techniques. The confounding factors of surgical procedure, mood state, preexisting cognitive impairment, and repeated experience with cognitive tests were controlled for. METHODS: Patients undergoing conventional valve procedures (n = 15), robotically assisted valve procedures (n = 15), and thoracic surgical procedures (n = 15), along with a nonsurgical control group (n = 15) were tested preoperatively, 1 week after operation, and 8 weeks after operation by use of a battery of cognitive tests and a mood state assessment. Surgical group data were normalized against data from the nonsurgical control group before statistical analysis. RESULTS: Patients undergoing conventional valve procedures performed worse than those undergoing robotically assisted valve procedures on every subtest before operation, and this disadvantage persisted after operation. Age and premorbid intelligence quotient were significantly associated with performance on several cognitive subtests. Anxiety, depression, and stress were not associated with impaired cognitive performance in the surgical groups after operation. A week after operation, patients undergoing conventional valve procedures performed worse on the cognitive tests that had a motor component, which may reflect discomfort caused by the sternotomy. Patients undergoing robotically assisted valve procedures were significantly less impaired on information processing tasks 1 week after operation when compared with those undergoing conventional valve procedures. The majority of patients who were impaired 1 week after operation recovered to preoperation levels within 8 weeks. CONCLUSIONS: The robotically assisted valve surgical procedure results in more rapid recovery of performance on cognitive tests. However, regardless of the type of surgical intervention, the prospect of a recovery of cognitive performance to preoperative levels is high. PMID- 24075496 TI - Outcome of repair of myocardial bridging at the time of septal myectomy. AB - BACKGROUND: Myocardial bridging describes systolic compression of the muscular investment of a portion of an epicardial coronary artery. We evaluated the outcome of muscular bridge unroofing of the left anterior descending artery at the time of septal myectomy in patients with hypertrophic cardiomyopathy. METHODS: We conducted a case-controlled study of 36 patients (23 men; median age, 42 years) with hypertrophic cardiomyopathy and myocardial bridging. Group 1 patients had septal myectomy and concomitant unroofing (n = 13), group 2 patients underwent myectomy alone (n = 10), and group 3 patients were treated medically (n = 13). RESULTS: Angina was more prevalent preoperatively in group 1, 46% compared with 20% in group 2. Preoperative left ventricular outflow tract gradients of 67.8 +/- 58.2 mm Hg and 74.1 +/- 19.7 mm Hg were reduced to 1.9 +/- 2.9 mm Hg in group 1 (p < 0.0001) and to 5.6 +/- 8.8 mm Hg in group 2 (p < 0.0001). In the surgical groups, there were no early deaths or complications related to unroofing. Survival at 10 years was 83.3% in group 1 (p = 0.297), 100.0% in group 2, and 67.9% in group 3; there were no late sudden deaths. At follow-up, 77% in group 1 were asymptomatic compared with 70% of patients in group 2 (p = 0.19). There was no recurrent angina in group 1. CONCLUSIONS: Myocardial unroofing can be performed safely at the time of septal myectomy for left ventricular outflow tract obstruction. Angina was improved, but we found no difference in late survival compared with patients who had myocardial bridging and myectomy alone. Unroofing should be considered in patients with angina who have significant left anterior descending artery bridging and require myectomy. PMID- 24075497 TI - Transapical aortic valve implantation in patients with previous cardiac surgery. AB - BACKGROUND: This study compared surgical outcomes of patients with previous cardiac surgery undergoing transapical transcatheter aortic valve implantation (PCS-TA-TAVI) with those of patients undergoing transapical transcatheter aortic valve implantation as an initial procedure (initial TA-TAVI) by using propensity analysis. METHODS: From January 2005 through January 2013, 267 consecutive high risk patients underwent transapical transcatheter aortic valve implantation using a pericardial xenograft fixed within a stainless steel, balloon-expandable stent (Edwards SAPIEN). Of these, 59 patients underwent PCS-TA-TAVI (coronary artery bypass grafting: n = 31; valve surgery: n = 28), and the remaining 208 had an initial TA-TAVI procedure. Logistic regression analysis was used to identify covariates among 10 baseline patient variables. Using the significant regression coefficients, each patient's propensity score was calculated, allowing selectively matched subgroups of 45 patients in the two groups. Operative outcomes were analyzed for differences. Follow-up was 4 +/- 2 years and 100% complete. RESULTS: There was no significant difference between PCS-TA-TAVI and initial TA-TAVI patients in operative time, postoperative bleeding, 30-day survival (91% versus 93%), and survival at late follow-up (63% versus 68%; p >= 0.28). Overall incidence of early stroke was low with 0% for the PCS-TA-TAVI and 4% for initial TA-TAVI group (p = 0.56). Transapical transcatheter aortic valve implantation was successfully performed in all but 1 patient from the initial TA TAVI group who required conversion to sternotomy. CONCLUSIONS: Transapical transcatheter aortic valve implantation has simplified surgical treatment of high risk patients with previous cardiac surgery and severe aortic valve stenosis and is associated with minimal risk of stroke. Furthermore, current data suggest that the presence of previous cardiac surgery does not impair outcomes after transapical transcatheter aortic valve implantation, making this subset of patients particularly applicable for this evolving approach. PMID- 24075498 TI - Long-term survival after off-pump coronary artery bypass surgery: a Swedish nationwide cohort study. AB - BACKGROUND: The aim of this study was to analyze long-term survival after primary isolated off-pump coronary artery bypass grafting (CABG) compared with on-pump CABG in a nationwide patient cohort. METHODS: Patients who underwent primary isolated nonemergent CABG in Sweden between 1998 and 2008 were identified. Swedish registers were used to gather patient data and outcomes. Multivariable regression models were used to estimate the association between off-pump CABG and early mortality, long-term survival, and a composite of death from any cause or rehospitalization for myocardial infarction, heart failure, or stroke. Similar analyses were repeated in a propensity score-matched cohort. RESULTS: The study included 50,676 patients, and 3,337 (6.6%) underwent off-pump CABG. In the adjusted analyses, off-pump CABG was not associated with better survival compared with on-pump CABG in the overall cohort (hazard ratio [HR] for death: 0.99, 95% confidence interval [CI]): 0.92 to 1.06) or in the matched cohort (HR: 1.02, 95% CI: 0.91 to 1.16). The results were similar for early mortality (odds ratio: 1.25, 95% CI: 0.95 to 1.65), and the composite endpoint (HR: 0.99, 95% CI: 0.94 to 1.05). CONCLUSIONS: Long-term survival was similar between off-pump and on pump CABG in patients undergoing non-emergent primary isolated CABG in Sweden from 1998 to 2008. Off-pump CABG was performed infrequently and there was a continuous decline in the number of procedures during the study period. PMID- 24075499 TI - Predictors of anastomotic leak after esophagectomy: an analysis of the society of thoracic surgeons general thoracic database. AB - BACKGROUND: Anastomotic leak is an important cause of morbidity and mortality after esophagectomy. Few studies have targeted risk factors for the development of leak after esophagectomy. The purpose of this study is to use The Society of Thoracic Surgeons Database to identify variables associated with leak after esophagectomy. METHODS: The Society of Thoracic Surgeons Database was queried for patients treated with esophagectomy for esophageal cancer between 2001 and 2011. Univariate and multivariate analysis of variables associated with an increased risk anastomotic leak was performed. RESULTS: There were 7,595 esophagectomies, with 804 (10.6%) leaks. Thirty-day mortality and length of stay were higher for patients with anastomotic leak. Mortality in patients requiring surgical management was 11.6% (38 of 327) compared with 4.4% (20 of 458) in medically managed leaks (p < 0.001). The leak rate was higher in patients with cervical anastomosis compared with those with intrathoracic anastomoses, 12.3% versus 9.3%, respectively (p = 0.006). There was no difference in leak-associated mortality between the two approaches. Factors associated with leak on univariate analysis include obesity, heart failure, coronary disease, vascular disease, hypertension, steroids, diabetes, renal insufficiency, tobacco use, procedure duration greater than 5 hours, and type of procedure (p < 0.05). Multivariable regression analysis associated heart failure, hypertension, renal insufficiency, and type of procedure as risk factors for the development of leak (p < 0.05). CONCLUSIONS: Anastomotic leak after esophagectomy is an important cause of postoperative mortality and increased length of stay. We have identified important risk factors for the development of esophageal anastomotic leak after esophagectomy. Further studies aimed at risk reduction are warranted. PMID- 24075500 TI - Left atrial appendage resection versus preservation during the surgical ablation of atrial fibrillation. AB - BACKGROUND: Left atrial appendage (LAA) resection during the Maze procedure may decrease thromboembolic risks, but its preservation may improve left atrial contractile function. This study compared the clinical effects of LAA resection and preservation after the Maze procedure. METHODS: A retrospective review was made of 379 patients (mean age 53.3 +/- 12.6 years, 244 females) who underwent the cryo-Maze procedure in conjunction with mitral surgery from 1999 to 2011. The LAA was resected in 187 patients (resection group) but preserved in 192 patients (preservation group). Outcomes were compared using a propensity score study design based on 20 baseline characteristics to obtain well-matched patient pairs. RESULTS: Propensity score matching yielded 119 pairs of patients in whom there were no significant differences in baseline profiles between the two groups. During a mean follow-up of 3.1 +/- 2.8 years, there were 16 deaths, 6 cases of stroke, and 39 cases of atrial fibrillation recurrence. There were no significant differences in stroke-free survival (p = 0.88) and freedom from AF while off antiarrhythmic drugs (p = 0.46) between the two groups. On serial echocardiographic assessments, patients in the preservation group showed a higher transmitral A-wave velocity (peak atrial contraction wave velocity; p = 0.47, 0.020, and 0.001 at 3, 6, and 12 months, respectively) and lower E/A ratio (peak early filling wave [E-wave] velocity / A-wave velocity; p = 0.34, 0.065, and 0.001 at 3, 6, and 12 months, respectively) at each timepoint compared with the resection group. CONCLUSIONS: Preservation of the LAA during the Maze procedure resulted in similar clinical and rhythm outcomes, but LA contractile function superior to that of LAA resection. PMID- 24075501 TI - [Reconstruction of the thumb for an epithelioid sarcoma using a kite flap. A case report]. AB - Epithelioid sarcoma is a rare lesion usually involving extremities. We report the case of a patient presenting with an epithelioid sarcoma of the dorsal aspect of the thumb. Surgical treatment consisted in a wide resection, arthrodesis of the metacarpophalangeal joint of the thumb and skin coverage with a kite flap. This case report illustrates a rare diagnosis potentially encountered by hand surgeons and the possible use of a kite flap in a non-traumatic context. PMID- 24075502 TI - [Incidence of painful neuroma after end-to-end nerve suture wrapped into a collagen conduit. A prospective study of 185 cases]. AB - Three to 5% of the nerves directly and correctly sutured evolve towards significant neuropathy pain. The psychological, social and economic impact of such a consequence is very important. The purpose of this retrospective study was to evaluate the incidence of the occurrence of a trigger zone or a neuroma, at 6months of maximum follow-up after direct nervous suture bushed in a type 1 collagen tube. Every patient taken care for a traumatic nervous injury from November 2008 to March 2012 was included in the study. The exclusion criteria were any replantation, nervous tissue defect and any distal nervous stump which could not technically be wrapped around. The only conduct used was made of collagen type 1 (Revolnerv((r)), OrthomedTM). All patients were examined after one, three and sixmonths for a clinical evaluation made by the same surgeon. The apparition of a trigger zone or a real neuroma was clinically assessed. One hundred and seventy-four patients for a total of 197 sutured nerves were included in the study. At the 6 months follow-up, 163 patients were evaluated for a total of 185 nerves. No patient suffered from a neuroma at this time. As the treatment of neuroma is very difficult, considering the cost and the results, wrapping direct end-to-end sutures by a collagen type 1 tube seems helping to prevent the appearance of a neuroma. PMID- 24075503 TI - HLA and MICA allosensitization patterns among patients supported by ventricular assist devices. AB - BACKGROUND: Ventricular assist devices (VADs) are increasingly being used as a bridge to transplantation and have been implicated as a risk factor for allosensitization to human leukocyte antigens (HLA). We investigate the association between VAD and allosensitization to human leukocyte antigens (HLA) and major-histocompatibility-complex (MHC) class I-related Chain A (MICA) antigens. METHODS: We considered all patients who received a VAD at our institution between 2000 and 2009; 89 of them had pre-VAD and post-VAD (<=6 months after implant) HLA antibody screening. A control group of non-VAD heart transplant candidates was constructed with at least 2 pre-transplant panel reactive antibody (PRA) tests within 8 months. Two controls were randomly selected/VAD patient matched for year (n = 178). Patients and controls with available sera from these time-points were tested by Luminex/flow PRA single antigen beads and by MICA antibody Luminex single-antigen beads. Medical records were reviewed for comparison of pre-transplant immunologic risk factors and post transplant outcomes between the 2 groups. RESULTS: Compared with controls, VAD patients had greater Class I differences between peak and initial PRA (18% vs. 0%, p < 0.0001) and higher peak PRA (24% vs. 6%, p < 0.0001). The differences between the 2 groups in Class II were less pronounced than in Class I. Of patients who had single-antigen testing, VAD implantation was significantly associated with development of new HLA antibody specificities (Class I and/or Class II) post-VAD with an increase in calculated PRA (cPRA) post-VAD compared with controls (16% vs. 0%, p < 0.0001). This risk was still present after adjusting for age, gender, pre-VAD PRA, transfusion and duration of follow-up in a multivariate analysis (p < 0.0001 and 0.02, respectively). There were no differences in development of MICA antibodies between the 2 groups (14% in both). There was no significant difference in the incidence of pre-transplant positive T cell crossmatch, pre-transplant donor-specific HLA antibodies, rejection episodes or graft survival between the 2 groups. CONCLUSION: Our results suggest that VAD is associated with significant HLA allosensitization independent of common risk factors. PMID- 24075504 TI - Isolated plantar dislocation of the 1st metatarsophalangeal joint. AB - Plantar dislocation of the 1st metatarsophalangeal joint is an extremely rare injury. To the best of our knowledge, there are no previous reports in the literature of an isolated dislocation of this type requiring open reduction and surgical repair. In this case report, we describe the clinical and operative findings and discuss in detail our surgical technique for the successful management of this unusual injury. PMID- 24075506 TI - Serum and cerebrospinal fluid levels of visinin-like protein-1 in acute encephalopathy with biphasic seizures and late reduced diffusion. AB - BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) has recently been recognized as an encephalopathy subtype. Typical clinical symptoms of AESD are biphasic seizures, and MRI findings show reduced subcortical diffusion during clustering seizures with unconsciousness after the acute phase. Visinin-like protein-1 (VILIP-1) is a recently discovered protein that is abundant in the central nervous system, and some reports have shown that VILIP-1 may be a prognostic biomarker of conditions such as Alzheimer's disease, stroke, and brain injury. METHODS: However, there have been no reports regarding serum and cerebrospinal fluid (CSF) levels of VILIP-1 in patients with AESD. We measured the serum and CSF levels of VILIP-1 in patients with AESD, and compared the levels to those in patients with prolonged febrile seizures (FS). RESULTS: Both serum and CSF levels of VILIP-1 were significantly higher in patients with AESD than in patients with prolonged FS. Serum and CSF VILIP-1 levels were normal on day 1 of AESD. CONCLUSIONS: Our results suggest that both serum and CSF levels of VILIP-1 may be one of predictive markers of AESD. PMID- 24075507 TI - Dibutyl phthalate-induced neurotoxicity in the brain of immature and mature rat offspring. AB - PURPOSE: We aim to investigate the neurotoxicity induced by perinatal exposure of dibutyl phthalate (DBP) on the immature and mature offspring animals using a rodent model. METHODS: Pregnant rats were given intragastric administration of 500mg/kg body weight DBP daily from gestational day 6 to postnatal day 21 while control animals received the same volume of edible corn oil. Serum estradiol and testosterone levels of the offspring were evaluated. Protein levels of AROM, ER beta, BDNF and p-CREB in the hippocampus were also measured. RESULTS: Perinatal exposure of DBP significantly up-regulated the serum estradiol levels in both immature and mature offspring rats. DBP exposure also significantly down regulated the testosterone levels in immature male and female rats and mature male rats but had no influence on the testosterone levels in mature female rats. DBP exposure up-regulated AROM, but down-regulated ER-beta, BDNF and p-CREB expression in the hippocampus of immature rat offspring, while it had no influence on the levels of these proteins in the mature animals. CONCLUSIONS: Perinatal exposure of DBP could induce neurotoxicity in immature offspring rats through regulation of AROM, ER-beta, BDNF and p-CREB expression, while it has no influence on mature offspring animals. PMID- 24075505 TI - Consuming a hypocaloric high fat low carbohydrate diet for 12 weeks lowers C reactive protein, and raises serum adiponectin and high density lipoprotein cholesterol in obese subjects. AB - OBJECTIVE: High fat, low carbohydrate (HFLC) diets have become popular tools for weight management. We sought to determine the effects of a HFLC diet compared to a low fat high carbohydrate (LFHC) diet on the change in weight loss, cardiovascular risk factors and inflammation in subjects with obesity. METHODS: Obese subjects (29.0-44.6 kg/m2) recruited from Boston Medical Center were randomized to a hypocaloric LFHC (n=26) or HFLC (n=29) diet for 12 weeks. RESULTS: The age range of subjects was 21-62 years. As a percentage of daily calories, the HFLC group consumed 33.5% protein, 56.0% fat and 9.6% carbohydrate and the LFHC group consumed 22.0% protein, 25.0% fat and 55.7% carbohydrate. The change in percent body weight, lean and fat mass, blood pressure, flow mediated dilation, hip:waist ratio, hemoglobin A1C, fasting insulin and glucose, and glucose and insulin response to a 2h oral glucose tolerance test did not differ (P>0.05) between diets after 12 weeks. The HFLC group had greater mean decreases in serum triglyceride (P=0.07), and hs-CRP (P=0.03), and greater mean increases in HDL cholesterol (P=0.004), and total adiponectin (P=0.045) relative to the LFHC. Secreted adipose tissue adiponectin or TNF-alpha did not differ after weight loss for either diet. CONCLUSIONS: Relative to the LFHC group, the HFLC group had greater improvements in blood lipids and systemic inflammation with similar changes in body weight and composition. This small-scale study suggests that HFLC diets may be more beneficial to cardiovascular health and inflammation in free-living obese adults compared to LFHC diets. PMID- 24075508 TI - Terminology, characterization, and measurement of ICD defibrillation impedance. PMID- 24075509 TI - Acute pancreatitis associated with molecular targeted therapies: a retrospective review of the clinico-radiological features, management and outcome. AB - PURPOSE: To study the presentation, radiological features, management and outcome of acute pancreatitis detected on imaging in patients receiving molecular targeted therapy (MTT). MATERIALS AND METHODS: In this IRB-approved, HIPAA compliant retrospective study, search of the radiology database from January 2005 through September 2012 revealed 91 cancer patients with radiologic evidence of acute pancreatitis. Of these, 15 patients receiving MTT (7 women, 8 men; mean age 59 years, range 25-84 years) and fulfilling the criteria of acute pancreatitis without any confounding factors were included. Imaging at initial diagnosis of pancreatitis and subsequently were reviewed by three radiologists in consensus; clinical presentation, management, and outcome were documented from the medical record. RESULTS: Eleven patients had focal and four had diffuse pancreatitis. The tail of the pancreas (n = 6) was the most common site of focal pancreatitis. Of the 14/15 patients who underwent CT, modified CT severity index was 2 in 12 patients and 4 in 2 patients. One patient (1/15) who underwent only FDG-PET/CT showed focal pancreatitis. None of the patients had pancreatic necrosis or peripancreatic collections. Findings resolved in all the patients after discontinuation of MTT, except in one patient who died of progressive disease. No radiological or surgical interventions were required in any of the patients. Findings recurred in 4/9 patients (44%) in whom MTT was restarted. CONCLUSION: MTT-associated pancreatitis is usually mild, focal, and managed conservatively with discontinuation of MTT. The imaging findings are subtle and in our study, pancreatitis recurred in 44% of patients after restarting MTT. PMID- 24075510 TI - Glutamine supplementation in acute pancreatitis: a meta-analysis of randomized controlled trials. AB - BACKGROUND: There is emerging evidence that glutamine supplementation should be considered in patients with acute and critical illness associated with a catabolic response. There are reports of glutamine supplementation in acute pancreatitis but the results of these studies are conflicting. The aim of this study was to systematically review the randomised controlled trials (RCT) of glutamine in patients with acute pancreatitis. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, SCOPUS and 3 major Chinese databases were searched. The outcomes studied were mortality, total infectious complications, and length of hospital stay. A random effects model was used for meta-analysis of the outcomes in the included trials. A number of pre-specified subgroup analyses were also conducted. The summary estimates were reported as risk ratio (RR) for categorical variables and mean difference (MD) for continuous variables together with the corresponding 95% confidence interval. RESULTS: Twelve RCT that enrolled 505 patients with acute pancreatitis were included in the final analysis. Overall, glutamine supplementation resulted in a significantly reduced risk of mortality (RR 0.30; 95% CI, 0.15 to 0.60; P < 0.001) and total infectious complications (RR 0.58; 95% CI, 0.39 to 0.87; P = 0.009) but not length of hospital stay (MD -1.35; 95% CI, -3.25 to 0.56, P = 0.17). In the subgroup analyses, only patients who received parenteral nutrition and those who received glutamine in combination with other immunonutrients demonstrated a statistically significant benefit in terms of all the studied outcomes. CONCLUSIONS: This meta-analysis demonstrates a clear advantage for glutamine supplementation in patients with acute pancreatitis who receive total parenteral nutrition. Patients with acute pancreatitis who receive enteral nutrition do not require glutamine supplementation. Further studies are warranted to determine whether patients who receive combined enteral and parenteral nutrition need glutamine supplementation. PMID- 24075511 TI - Amino acid transporters expression in acinar cells is changed during acute pancreatitis. AB - Pancreatic acinar cells accumulate amino acids against a marked concentration gradient to synthesize digestive enzymes. Thus, the function of acinar cells depends on amino acid uptake mediated by active transport. Despite the importance of this process, pancreatic amino acid transporter expression and cellular localization is still unclear. We screened mouse pancreas for the expression of genes encoding amino acid transporters. We showed that the most highly expressed transporters, namely sodium dependent SNAT3 (Slc38a3) and SNAT5 (Slc38a5) and sodium independent neutral amino acids transporters LAT1 (Slc7a5) and LAT2 (Slc7a8), are expressed in the basolateral membrane of acinar cells. SNAT3 and SNAT5, LAT1 and LAT2 are expressed in acinar cells. Additional evidence that these transporters are expressed in mature acinar cells was gained using acinar cell culture and acute pancreatitis models. In the acute phase of pancreatic injury, when acinar cell loss occurs, and in an acinar cell culture model, which mimics changes occurring during pancreatitis, SNAT3 and SNAT5 are strongly down regulated. LAT1 and LAT2 were down-regulated only in the in vitro model. At protein level, SNAT3 and SNAT5 expression was also reduced during pancreatitis. Expression of other amino acid transporters was also modified in both models of pancreatitis. The subset of transporters with differential expression patterns during acute pancreatitis might be involved in the injury/regeneration phases. Further expression, localization and functional studies will follow to better understand changes occurring during acute pancreatitis. These findings provide insight into pancreatic amino acid transport in healthy pancreas and during acute pancreatitis injury. PMID- 24075512 TI - Consequences of long term indwelling transmural stents in patients with walled off pancreatic necrosis & disconnected pancreatic duct syndrome. AB - INTRODUCTION: There is limited data on the long term consequences and safety profile of long term indwelling transmural stents after successful treatment of walled off pancreatic necrosis (WOPN). AIM: To retrospectively evaluate consequences of long term indwelling transmural stents in patients with WOPN. METHODS: The records of patients who underwent endoscopic transmural drainage of WOPN and had disconnected pancreatic duct syndrome (DPDS) were analyzed. RESULTS: Thirty patients (26 M; mean age 37.1 +/- 7.8 years) with long term indwelling transmural stents and DPDS were followed up for a mean of 20.4 +/- 12.2 months (range: 3-38 months). The etiology of acute necrotizing pancreatitis was alcohol in 21, gall stones in 7 and idiopathic in 2 patients. In all patients two or three, 7 (17 patients) or 10 Fr (13 patients) 5 cm double pigtail stents were placed. ERCP revealed disconnected PD at the pancreatic head, body and tail region in 22, 7, and 1 patient respectively. Five patients (16.6%) had spontaneous migration of stents (both the stents in four patients and one stent in one patient; 7 Fr in four and 10 Fr in one patient respectively). Stent migration led to recurrence of pancreatic fluid collection (PFC) in one patient whereas in the remaining 4 patients it did not cause any symptoms. There was no recurrence of symptomatic PFC in remaining 25 patients. CONCLUSION: Long term indwelling transmural stents in patients with WOPN and DPDS seem to be safe and also appear to decrease the risk of PFC recurrence. PMID- 24075513 TI - Correlation between secretin-enhanced MRCP findings and histopathologic severity of chronic pancreatitis in a cat model. AB - BACKGROUND/OBJECTIVES: To evaluate the usefulness of secretin-enhanced magnetic resonance cholangiopancreatography (S-MRCP) in chronic pancreatitis (CP), we compared the severity of disease determined histopathologically with that indicated by S-MRCP imaging parameters in an induced CP cat model. MATERIALS AND METHODS: An experimental group of randomly chosen cats (n = 24) underwent ligation of the pancreatic duct to induce CP, and cats in a similarly chosen control group (n = 8) were sham-operated. MRCP was performed prior to secretin stimulation, and 5 and 15 min afterward, noting in particular the pancreatic duct caliber change (PDC) and the increasing degree of fluid volume (IDFV). Histopathological changes were observed in pancreatic samples processed for hematoxylin-eosin and Sirius red staining, and CP was classified as normal, minimal, moderate, or advanced. Correlations were investigated between these groups and the PDC at 5 min and the IDFV at 15 min. RESULTS: Between cats with minimal CP and the controls, the differences in mean IDFV and PDC were not significant although diseased cats showed a downward trend in both parameters. However, compared with the control group both the mean IDFV and PDC were significantly lower in cats with moderate (IDFV, P = 0.001; PDC, P = 0.013) or advanced (IDFV, P = 0.013; PDC, P = 0.001) CP. CONCLUSION: The S-MRCP parameters IDFV and PDC correlated with the histopathological severity of induced CP. S-MRCP could be used to evaluate the severity of CP, although it is somewhat insensitive for depicting very early disease. PMID- 24075514 TI - GLP-1R agonist may activate pancreatic stellate cells to induce rat pancreatic tissue lesion. AB - OBJECTIVE: To explore the mechanism of GLP-1R agonist-induced rat pancreatic tissue lesion. METHODS: Thirty SD male rats were divided into three groups, namely GLP-1R agonist experimental group, diabetes-model experimental group and control group. Diabetes-model rats were induced by streptozotocin and high-sugar high-fat diet. GLP-1R agonist group and diabetes-model group were administered with GLP-1R agonist in dose 5 MUg/kg each time, twice a day. After 10 weeks of treatment, the amount of matrix metalloproteinase (MMP)-2 and MMP-9, and expression of alpha-smooth muscle actin (alpha-SMA) and type III collagen protein in pancreatic tissue were measured. RESULTS: The amount of MMP-2 and MMP-9 in GLP 1R agonist group and diabetes-model group were significantly higher than the control group. Compared with the GLP-1R agonist group, the diabetic model group had more severe pathological changes of pancreatic tissue interstitial edema, inflammatory cell infiltration, glandular atrophy and fibrosis, and significantly increased pancreatic tissue MMP-2 and MMP-9 levels, significantly increased alpha SMA and collagen III-positive cell counts, all the differences were statistically significant. alpha-SMA and type III collagen were expressed in all parts of the lesions of GLP-1R agonist group and diabetes-model group. alpha-SMA can only be observed in the vessel wall in control group, however, in the other two groups, alpha-SMA can also be observed in pancreatic acinar cell interstitia, in addition to vessel wall. CONCLUSIONS: Long-term subcutaneous GLP-1R agonist injection may activate pancreatic stellate cells, causing the expression of alpha-SMA and collagen III and the amount of MMP-2 and MMP-9 in pancreatic acinar cell interstitial significantly increasing, and thus inducing chronic inflammatory change. PMID- 24075515 TI - Simvastatin delay progression of pancreatic intraepithelial neoplasia and cancer formation in a genetically engineered mouse model of pancreatic cancer. AB - BACKGROUND AND AIMS: Pancreatic cancer is among the most dismal of human malignancies. There are no chemopreventive strategies for pancreatic cancer or its precursor lesions, pancreatic intraepithelial neoplasia (PanINs). Recent evidence suggests that statins have potential chemopreventive abilities. In this study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the chemopreventive potential of this drug. METHODS: Simvastatin was injected i.p. in LsL-Kras(G12D); Pdx1-Cre or LsL-Kras(G12D);LsL-Trp53(R172H);Pdx1 Cre mice. After five months, animals were sacrificed. The effect of simvastatin was evaluated by histopathological analyses, immunostaining, and real-time PCR. RESULTS: After five months of treatment, simvastatin was able to significantly delay progression of mPanINs in LsL-Kras(G12D); Pdx1-Cre mice. Furthermore, formation of invasive pancreatic cancer in LsL-Kras(G12D); LsL-Trp53(R172H); Pdx1 Cre transgenic mice was partially inhibited by simvastatin. Invasive murine pancreatic cancer was identified in 9 of 12 (75%) LsL-Kras(G12D); LsL Trp53(R172H);Pdx1-Cre untreated control mice. In contrast, transgenic mice treated with Simvastatin, only 4 out of 10 (40%, p = 0.004) developed murine pancreatic cancer during the study. Using real-time PCR we found a significant up regulation of Hmgcr as sign of blocking HMG-CoA reductase, a key enzyme in the cholesterol biosynthesis. This shows our ability to achieve effective pharmacologic levels of simvastatin during pancreatic cancer formation in vivo. CONCLUSION: Using a transgenic mouse model that recapitulates human pancreatic cancer, this study provides first evidence that simvastatin is an effective chemopreventive agent by delaying the progression of PanINs and partially inhibit the formation of murine pancreatic cancer. PMID- 24075516 TI - Induction of M2-macrophages by tumour cells and tumour growth promotion by M2 macrophages: a quid pro quo in pancreatic cancer. AB - INTRODUCTION: More effective therapies are required to improve survival of pancreatic cancer. Possible immunologic targets include tumour associated macrophages (TAMs), generally consisting of M1- and M2-macrophages. We have analysed the impact of TAMS on pancreatic cancer in a syngeneic orthotopic murine model. METHODS: 6606PDA murine pancreatic cancer cells were orthotopically injected into C57BL6 mice. Tumour growth was monitored using MRI. Macrophages were depleted by clodronate liposomes. Tumours including microvessel density were evaluated using immunohistochemistry, immunofluorescence and/or cytometric beads assays. Naive macrophages were generated employing peritoneal macrophages. In vitro experiments included culturing of macrophages in tumour supernatants as well as tumour cells cultured in macrophage supernatants using arginase as well as Griess assays. RESULTS: Clodronate treatment depleted macrophages by 80% in livers (p = 0.0051) and by 60% in pancreatic tumours (p = 0.0169). MRI revealed tumour growth inhibition from 221.8 mm(3) to 92.3 mm(3) (p = 0.0216). Micro vessel densities were decreased by 44% (p = 0.0315). Yet, MCP-1-, IL-4- and IL-10 levels within pancreatic tumours were unchanged. 6606PDA culture supernatants led to a shift from naive macrophages towards an M2-phenotype after a 36 h treatment (p < 0.0001), reducing M1-macrophages at the same time (p < 0.037). In vivo, M2 macrophages represented 85% of all TAMs (p < 0.0001). Finally, culture supernatants of M2-macrophages induced tumour growth in vitro by 63.2% (p = 0.0034). CONCLUSIONS: This quid pro quo of tumour cells and M2-macrophages could serve as a new target for future immunotherapies that interrupt tumour promoting activities of TAMs and change the iNOS-arginase balance towards their tumoricidal capacities. PMID- 24075517 TI - Involvement of microRNA-181b in the gemcitabine resistance of pancreatic cancer cells. AB - BACKGROUND/OBJECTIVES: MicroRNAs (miRs) have been shown to regulate the sensitivity to several chemotherapeutic agents in various types of cancers. MiR 181b is one of such regulators, yet its importance in pancreatic cancer is not determined so far. The aim of this study was to investigate the relationship between microRNA (miR)-181b expression and gemcitabine resistance in pancreatic cancer cells. METHODS: The effects of overexpression or knockdown of miR-181b on four pancreatic cancer cell lines exposed to gemcitabine were examined. The induction of apoptosis and the changes of the cylindromatosis (CYLD) protein were examined. Furthermore, the effect of small interference RNA for CYLD (siCYLD) on cell viability and the relationship between CYLD and nuclear factor kappa B (NF kappaB) were investigated. RESULTS: The expression of miR-181b was higher in BxPC3, Panc1 and PSN1 cells compared with MiaPaCa2 cells. Pre-miR-181b transfection into MiaPaCa2 cells increased their gemcitabine resistance, whereas anti-miR-181b transfection into the other pancreatic cancer cell lines reduced their resistance to gemcitabine and led to the induction of apoptosis. The protein levels of CYLD were increased by anti-miR-181b in Panc1 and PSN1 cells. Inhibition of CYLD increased the NF-kappaB activity and gemcitabine resistance in Panc1 and PSN1 cells. CONCLUSIONS: The present study demonstrated that miR-181b was associated with the resistance of pancreatic cancer cells to gemcitabine, and verified that miR-181b enhances the activity of NF-kappaB by inhibiting CYLD, leading to the resistance to gemcitabine. Our results suggest that miR-181b is a potential target for decreasing gemcitabine resistance. PMID- 24075518 TI - Factors affecting the yield of endoscopic transpapillary bile duct biopsy for the diagnosis of pancreatic head cancer. AB - BACKGROUND: Transpapillary biliary biopsy (TBB) is a simple endoscopic technique that can be performed during an initial biliary drainage session. This procedure has the potential to reduce the load of another tissue sampling in cases of pancreatic head cancer (PHC) with biliary stricture. The aim of this study is to identify factors associated with a positive outcome using TBB for PHC. METHODS: In total, 130 cases that underwent TBB for investigation of distal biliary stricture were included [62 cases of PHC, 36 cases of distal biliary cancer (DBC), and 32 cases of benign biliary stricture (BBS)]. Factors affecting the diagnostic efficiency of TBB were determined using univariate and multivariate logistic analyses. RESULTS: Cancer tissue was obtained in 31 cases (50%) of PHC and 33 cases (91.7%) of DBC. Multivariable analysis showed that ?10 mg/dl of serum bilirubin level (odds ratio [OR]: 5.58; 95% confidence interval [CI]: 1.29 28.20; P = 0.021) and ?3 tissue samplings (OR: 3.59; 95% CI: 1.02-14.27, P = 0.046) were independent factors affecting cancer-positive rate in cases of PHC. In >90% of resected cases of PHC, cancer involved the left side of the biliary mucosa and the range of cancer invasion (?2/3 of circumference of biliary mucosa) was also a significant factor (P = 0.001). CONCLUSIONS: PHC showing high level of serum bilirubin (>10 mg/dl) and high circumferential proportion of bile duct invasion (>2/3 judging from MDCT) is a good indication for biliary biopsy. Targeting the left-side wall and ?3 tissue samplings will lead to the higher sensitivity. PMID- 24075519 TI - Cyst fluid SPINK1 may help to differentiate benign and potentially malignant cystic pancreatic lesions. AB - OBJECTIVE: Differential diagnosis between benign and potentially malignant cystic pancreatic lesions may be difficult. Previously we have compared cyst fluid serine protease inhibitor Kazal type I (SPINK1) with some traditionally used tumour markers (amylase, CEA, Ca19-9) and found that it may be a new promising maker in the differential diagnosis of cystic pancreatic lesions. In the present study, we focused on cyst fluid SPINK1 levels in benign and potentially malignant cystic pancreatic lesions. DESIGN: Sixty-one patients operated on for cystic pancreatic lesion in Tampere University Hospital, Finland and in Verona University Hospital, Italy, were included. Cyst fluid was aspirated during surgery, stored at -70 degrees C, and analysed with immunofluorometric assay for SPINK1. The final diagnosis was acute pancreatitis with fluid collection (Acute FC) in 4 patients, chronic pseudocyst (PS) in 17 patients, serous cystadenoma (SCA) in 7 patients, mucinous cystadenoma (MCA) in 21 patients and intraductal papillary-mucinous neoplasm (IPMN) in 12 patients (9 main/mixed duct type and 3 branch duct type). RESULTS: The acute FC patients had high SPINK1 levels. Among chronic cysts, SPINK1 levels were significantly higher in patients with potentially malignant cysts (main/mixed duct IPMN and MCA) than with benign cysts (side branch IPMN and SCA), (median and range, [480 (13-3602) vs. 18 (0.1-278) MUg/L]; p < 0.0001). In the subcohort of 24 patients with <3 cm chronic cyst, cyst fluid SPINK 1 levels were significantly lower in SCA or side branch IPMN (3 [2-116] MUg/L) than in main duct IPMN or MCA (638 [66-3602] MUg/L; p = 0.018). The best sensitivity and specificity to differentiate any size MCA or main/mixed type IPMN from SCA or side branch IPMN were 85% and 84% (AUC 0.94; cut-off value 118 MUg/L). The best sensitivity and specificity to differentiate <3 cm MCA or main duct IPMN from SCA or side branch IPMN were 93% and 89% (AUC 0.98; cut-off value 146 MUg/L). CONCLUSIONS: Cyst fluid SPINK1 may be a possible marker in the differential diagnosis of benign and potentially malignant cystic pancreatic lesions. PMID- 24075520 TI - Elevated pre-operative neutrophil to lymphocyte ratio predicts disease free survival following pancreatic resection for periampullary carcinomas. AB - BACKGROUND: The pre-operative neutrophil-to-lymphocyte ratio (NLR), when >=5 has been associated with reduced survival for patients with various gastrointestinal tract cancers, however, it's prognostic value in patients with periampullary tumour has not been reported to date. OBJECTIVES: To determine the prognostic value of pre-operative NLR in terms of survival and recurrence of resected periampullary carcinomas. METHODS: This was a retrospective cohort study of consecutive patients undergoing pancreatoduodenectomy (PD) for periampullary carcinoma (pancreatic, ampullary, cholangiocarcinoma) identified from a departmental database. The effect of NLR upon survival and recurrence was explored. RESULTS: Overall median survival amongst 228 patients was 24 months (inter-quartile range [IQR]: 12-43). The median survival for those whose NLR was <5 was not significantly greater than those patients whose NLR was >=5 (24 months [IQR: 14-42] versus 13 months [IQR: 8-48], respectively; p = 0.234). However, for those that developed recurrence, survival was greater in those with an NLR <5 at (20 months [IQR: 12-27] versus 11 months [IQR: 7-22], respectively; p = 0.038). This effect was most marked in those patients with cholangiocarcinoma (p = 0.019) whilst a trend to worse survival was seen in those with pancreatic adenocarcinoma. No effect was seen in patients with ampullary carcinoma (p = 0.516). CONCLUSIONS: This study provides further evidence that pre-operative NLR offers important prognostic information regarding disease-free survival. This effect, however, is dependent upon the tumour type amongst patients undergoing PD. PMID- 24075521 TI - Gemcitabine based neoadjuvant chemoradiotherapy therapy in patients with borderline resectable pancreatic cancer. AB - BACKGROUND: Surgical resection is the only curative treatment for pancreatic cancer, but surgical outcomes for borderline resectable pancreatic cancer (BRPC) are generally poor because of the complexity of the surgery and the advanced nature of the tumor. The aim of this study was to evaluate whether neoadjuvant concurrent chemoradiation therapy (CCRT) in BRPC patients could improve surgical outcome. METHODS: Baseline characteristics and treatment outcomes for patients who underwent surgery for BRPC with (CCRT (+) group) and without neoadjuvant treatment (CCRT (-) group) were retrospectively compared. Treatment outcomes measured included overall survival, recurrence-free survival, and perioperative complications. RESULTS: A total of 30 patients were included in the CCRT (+) group and 21 patients in the CCRT (-) group. Baseline characteristics were not different before CCRT, but pathological examination after resection revealed reduced tumor size and a lower neurovascular invasion rate in the CCRT (+) group. Overall median survival time was 45.0 months in the CCRT (+) group and 23.5 months in the CCRT (-) group (p = 0.045). The CCRT (+) group had a lower recurrence rate (50.0% vs. 81.0%; p = 0.024) and a longer median disease-free survival period (21.0 months vs. 10.6 months; p = 0.004) than the CCRT (-) group. Perioperative complication rates were not different between the two groups. CONCLUSIONS: Neoadjuvant chemoradiation therapy combined with surgical resection yielded better treatment outcomes in patients with BRPC compared with surgery alone. Further larger prospective clinical trials with well defined enrollment criteria and treatment plan are needed. PMID- 24075522 TI - Nesidioblastosis. A case of hyperplasia of the islets of Langerhans in the adult. AB - INTRODUCTION: Nesidioblastosis is a rare disease caused by hyperplasia of pancreatic islets, developing a state of hypoglycemia due to an increase in the insulin production. It is the leading cause of hyperinsulinic hypoglycemia in childhood, whereas in adults it only represents the 0.5-5% of cases. The pathogenesis is still unknown. We have studied several genetic mutations associated with dependent potassium channel of ATP present in the beta cells of the pancreas, as well as in patients underwent bariatric surgery because of the metabolic changes involved. REPORT: Woman (38 years old) attends consultation of General Surgery derived from Endocrinology before symptoms of persistent hypoglycemia. Factitious hypoglycemia and syndromes of neuroendocrine origin were ruled out. Imaging tests failed to identify space-occupying lesions. The medical treatment failed, persisting hypoglycemia symptoms. Before the given analytical and radiological findings obtained, and the persistence of symptoms affecting the quality of life of the patient, we opted for surgical treatment performing a pancreatectomy of the 80% of the gland. The final pathologic diagnosis was nesidioblastosis. DISCUSSION: Nesidioblastosis is a rare pathology, but it must be present in the differential diagnosis of hypoglycemia symptoms with endogenous hyperinsulinism in adults, once the intake of sulfonylureas and possible pancreatic neoformations have been ruled out. PMID- 24075523 TI - "Chronic" metastatic pancreatic acinar cell carcinoma. AB - Acinar cell carcinoma (ACC) of the pancreas is a rare exocrine tumour for which there is very limited information about chemotherapy regimens and prognosis. Even though there are clinical guidelines for management of ductal cell carcinoma, a definitive and specific regime has not yet been agreed for this type of pancreatic cancer. We report a case of metastatic ACC of pancreas who has been treated with a multimodal approach, including novel combinations of different targeted drugs with conventional chemotherapy, surgery and radiofrequency ablation since the last 11 years. This degree of long term survival has not been reported so far in such a case of metastatic ACC of the pancreas. This case highlights the importance of a personalised multidisciplinary therapeutic strategy, employing locoregional therapies along with combinations of established and novel systemic therapies to control the disease, and the importance of flexibility when instigating new treatment paradigms for progressive cancer. Also, this case demonstrates that complete tumour eradication may not be the sole purpose of surgical oncology. PMID- 24075524 TI - Rapid progression of a splenic aneurysm due to segmental arterial mediolysis: a rare cause of acute pancreatitis. AB - BACKGROUND: The etiology of acute pancreatitis can be manifold, beside the usual causes. We are reporting an unusual cause that triggered acute pancreatitis. PATIENT & RESULTS: A 50 year-old male experienced attacks of acute pancreatitis (abdominal pain and elevated amylase and lipase) during sexual arousal. Serial imaging showed a rapidly-progressing, partly-thrombosed splenic artery aneurysm, with local compression of the pancreas. After angiographic coiling, the attacks subsided. Further angiography revealed additional aneurysms consistent with segmental arterial mediolysis at other sites of the body. Molecular analysis regarding Ehlers-Danlos-syndrome and genetic factors for pancreatitis, autoantibodies and Syphilis serology was negative. CONCLUSIONS: Acute pancreatitis was triggered by a transient rise in blood pressure during sexual stimulation, which caused rapid progression of a splenic artery aneurysm as part of systemic segmental arterial mediolysis. PMID- 24075525 TI - Knee joint angle affects EMG-force relationship in the vastus intermedius muscle. AB - It is not understood how the knee joint angle affects the relationship between electromyography (EMG) and force of four individual quadriceps femoris (QF) muscles. The purpose of this study was to examine the effect of the knee joint angle on the EMG-force relationship of the four individual QF muscles, particularly the vastus intermedius (VI), during isometric knee extensions. Eleven healthy men performed 20-100% of maximal voluntary contraction (MVC) at knee joint angles of 90 degrees , 120 degrees and 150 degrees . Surface EMG of the four QF synergists was recorded and normalized by the root mean square during MVC. The normalized EMG of the four QF synergists at a knee joint angle of 150 degrees was significantly lower than that at 90 degrees and 120 degrees (P < 0.05). Comparing the normalized EMG among the four QF synergists, a significantly lower normalized EMG was observed in the VI at 150 degrees as compared with the other three QF muscles (P < 0.05). These results suggest that the EMG-force relationship of the four QF synergists shifted downward at an extended knee joint angle of 150 degrees . Furthermore, the neuromuscular activation of the VI was the most sensitive to change in muscle length among the four QF synergistic muscles. PMID- 24075526 TI - Effective treatment of a highly active antiretroviral regimen through jejunostomy. AB - A 49-year-old woman voluntarily not receiving HIV treatment was admitted to the emergency department showing sepsis and peritonism. She required several surgical procedures for intestinal perforations. Finally, a proximal-terminal jejunostomy and a distal mucous jejunostomy were performed. At this time, her HIV viral load was 531 388 copies/ml and CD4 count was 193 cells/MUl. Then, HAART was restarted with lopinavir/ritonavir 400/100 mg plus lamivudine 150 mg/12 hours, and etravirine 400 mg/24 hours. Each drug was dissolved in 20 ml of water and administered through the distal jejunostomy. In 2 months, her HIV viral load decreased in 3.9 log and CD4 count increased in 70 cells/MUl. On day 250, an intestinal tract reconstruction was performed and short after highly active antiretroviral therapy (HAART) was restarted orally. Lopinavir/ritonavir, etravirine, and lamivudine administered through a jejunostomy resulted effective in decreasing HIV viral load and increasing CD4 lymphocyte count in a HIV patient who could not receive treatment orally. PMID- 24075527 TI - The effects of self-controlled feedback on learning of a "relaxed phonation task". AB - BACKGROUND: This study examined the effects of self-controlled feedback paradigm on motor learning of a relaxed phonation task. It investigated whether providing the learner with more control over practice condition has positive influences on the performance and learning of "relaxed phonation" skill. METHODS: Vocally healthy individuals were randomly assigned into either self-controlled feedback group (SELF) or clinician-controlled feedback group (YOKED). All participants were engaged in a reading aloud task. Throughout the task, their perilaryngeal muscle activities were measured at thyrohyoid (TH) and orofacial (OF) sites using surface electromyography (EMG). The EMG values measured at the TH site were provided to participants as terminal biofeedback. Participants were required to minimize the EMG values. The SELF group received EMG biofeedback whenever they requested it, whereas the YOKED group received the same feedback schedule as chosen by their self-controlled counterparts. RESULTS AND DISCUSSION: The pooled data for all participants revealed that there was a significant reduction of muscle tension across baseline, training, and retention phases. Generalization was shown to reading of untrained passage. Interestingly, significant reduction of muscle tension across training and retention tests was found in the control OF site but not in the target TH site. The results failed to demonstrate significant differences between SELF and YOKED groups. It provided no clear evidence to conclude that self-controlled feedback paradigm was beneficial to learning of relaxed phonation. PMID- 24075528 TI - Time-integrated monitoring of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in urban and industrial wastewaters using a ceramic toximeter and the CALUX bioassay. AB - The ceramic toximeter as a passive sampler in combination with the CALUX bioassay was utilized as a time-integrated pollution-assessment technique for dioxin-like PCDD/Fs in wastewaters. Toximeters filled with XCARB and enclosed in stainless steel cages were submerged in wastewater of Belbeis drainage-canal and EMAK paper mill, located in Egypt, for 28 days. Two samplers were removed every week from each site. Extracts from toximeters, from bottom-sediments, and from paper-mill sludge were analyzed by the CALUX. Results showed a regular increase in the amounts of PCDD/Fs trapped by the toximeters as sampling time increased. Time weighted average concentrations (TWA) of PCDD/Fs in the wastewaters of the drainage-canal and paper-mill were 231 (214-281) and 26 (24.1-32.6) pg-BEQL(-1), respectively. Compared to literature data, this means a high pollution level for the drainage-canal water, while the pollution level in the paper-mill wastewater is similar to that reported for other paper mills. The PCDD/Fs levels in the drainage-canal bottom-sediments and in the paper-mill sludge were 8.3 and 14.6 pg BEQg(-1) dry-weight, at the lower end of internationally reported values in similar compartments. The sampling rate of the tested toximeters for dissolved PCDD/Fs was about 3.6 mL d(-1). Sediment/water partitioning coefficient logKd of PCDD/Fs in the drainage-canal and the paper-mill was 1.42 and 2.70 respectively. The organic-carbon normalized partition coefficient logKoc was 4.17 and 3.19 respectively, and is lower than the reported values for other sites. PMID- 24075529 TI - A marine phytoplankton (Prymnesium parvum) up-regulates ABC transporters and several other proteins to acclimatize with Fe-limitation. AB - Iron (Fe) is one of the vital limiting factors for phytoplankton in vast regions of the contemporary oceans, notably the high nutrient low chlorophyll regions. Therefore, it is apparent to be acquainted with the Fe uptake strategy of marine phytoplankton under Fe-limited condition. In the present study, marine phytoplankton Prymnesium parvum was grown under Fe-deplete (0.0025 MUM) and Fe rich (0.05 MUM) conditions, and proteomic responses of the organism to Fe conditions were compared. In sodium dodecyl sulfate (SDS) gel electrophoresis, 7 proteins (16, 18, 32, 34, 75, 82, and 116 kDa) were highly expressed under Fe deplete condition, while one protein (23 kDa) was highly expressed under Fe-rich condition. These proteins were subjected to 2-dimensional gel electrophoresis (2 D DIGE) to differentiate individual proteins, and were identified by matrix assisted laser desorption-ionization-time of flight-mass spectrometer (MALDI-TOF MS) analysis. The results showed that under Fe-deplete condition P. parvum increases the biosynthesis of ATP binding cassette (ABC) transporters, flagellar associated protein (FAP), and Phosphoribosylaminoimidazole-succinocarboxamide synthase. These proteins are assumed to be involved in a number of cellular biochemical processes that facilitate Fe acquisition in phytoplankton. Under Fe deplete condition, P. parvum increases the synthesis of ribulose biphosphate carboxylase (RuBisCo), malate dehydrogenase, and two Fe-independent oxidative stress response proteins, manganese superoxide dismutase (MnSOD) and Serine threonine kinase (STK). Thus, marine phytoplankton may change their Fe acquisition strategy by altering the biosynthesis of several proteins in order to cope with Fe-limitation. PMID- 24075530 TI - Toxicity assessment of the maize herbicides S-metolachlor, benoxacor, mesotrione and nicosulfuron, and their corresponding commercial formulations, alone and in mixtures, using the Microtox((r)) test. AB - The Microtox((r)) test, using the prokaryote Vibrio fischeri, was employed to assess the toxicity of the maize herbicides S-metolachlor, benoxacor, mesotrione and nicosulfuron, and their formulated compounds: Dual Gold Safeneur((r)), Callisto((r)) and Milagro((r)); alone and in mixtures. For each compound we obtained original IC50 values, with consistent higher toxicities for formulated compounds compared to active ingredients alone. Mixtures of the four herbicides, prepared according to application doses encountered in agriculture, were found to be toxic at a lower concentration than single molecules. Mesotrione and nicosulfuron mixture appeared to be highly toxic to V. fischeri, however, this recommended post-emergence combination for maize crops got its toxicity decreased in formulated compound mixtures, suggesting that chemical interactions could potentially reduce the toxicity. Data comparisons to theoretical models showed a good prediction of mixture toxicity by Concentration Addition concept. Results seemed to exclude any synergistic effects on V. fischeri for the tested herbicide mixtures. Additional work coupling these bioassay data to ecosystemic level studies (aquatic and soil compartments) and data on additives and degradation products toxicity, will help to fill the gap in our knowledge of the environmental impact of these xenobiotics and in the choice of a more sustainable use of pesticides. PMID- 24075531 TI - Human health risk from heavy metal via food crops consumption with wastewater irrigation practices in Pakistan. AB - The current study was designed to investigate the potential human health risks associated with consumption of food crops contaminated with toxic heavy metals. Cadmium (Cd) concentration in surface soils; Cd, lead (Pb) and chromium (Cr) in the irrigation water and food crops were above permissible limits. The accumulation factor (AF) was >1 for manganese (Mn) and Pb in different food crops. The Health Risk Index (HRI) was >1 for Pb in all food crops irrigated with wastewater and tube well water. HRI >1 was also recorded for Cd in all selected vegetables; and for Mn in Spinacia oleracea irrigated with wastewater. All wastewater irrigated samples (soil and food crops) exhibited high relative contamination level as compared to samples irrigated with tube well water. Our results emphasized the need for pretreatment of wastewater and routine monitoring in order to avoid contamination of food crops from the wastewater irrigation system. PMID- 24075532 TI - Degradation of 2,4-dinitroanisole (DNAN) by metabolic cooperative activity of Pseudomonas sp. strain FK357and Rhodococcus imtechensis strain RKJ300. AB - 2,4-Dinitroanisole (DNAN) is an insensitive explosive ingredient used by many defense agencies as a replacement for 2,4,6-trinitrotoluene. Although the biotransformation of DNAN under anaerobic condition has been reported, aerobic microbial degradation pathway has not been elucidated. An n-methyl-4-nitroaniline degrading bacterium Pseudomonas sp. strain FK357 transformed DNAN into 2,4 dinitrophenol (2,4-DNP) as an end product. Interestingly, when strain FK357 was co-cultured with a 2,4-DNP degrading Rhodococcus imtechensis strain RKJ300, complete and high rate of DNAN degradation was observed with no accumulation of intermediates. Enzyme assay using cell extracts of strain FK357 demonstrated that O-demethylation reaction is the first step of DNAN degradation with formation of 2,4-DNP and formaldehyde as intermediates. Subsequently, 2,4-DNP was degraded by strain RKJ300 via the formation of hydride-Meisenheimer complex. The present study clearly demonstrates that complete degradation of DNAN occurs as a result of the metabolic cooperative activity of two members within a bacterial consortium. PMID- 24075533 TI - Unravelling survival pathways: the road to next-generation chronic myeloid leukaemia drugs? PMID- 24075534 TI - A phase I study using bortezomib with weekly idarubicin for treatment of elderly patients with acute myeloid leukemia. AB - We report the results of a phase I study with four dose levels of bortezomib in combination with idarubicin. Eligible patients were newly diagnosed with acute myeloid leukemia (AML) age >=60 years, or any adult with relapsed AML. Bortezomib was given twice weekly at 0.8, 1.0, or 1.2 mg/m(2) with once weekly idarubicin 10 mg/m(2) for four weeks. Twenty patients were treated: 13 newly diagnosed (median age 68, range 61-83) and 7 relapsed (median age 58, range 40-77). Prior myelodysplastic syndrome (MDS) was documented in 10/13 (77%) newly diagnosed and 1/7 (14%) relapsed patients; the three newly diagnosed patients without prior MDS had dyspoietic morphology. Two dose-limiting toxicities occurred at the initial dose level (bortezomib 0.8 mg/m(2) and idarubicin 10 mg/m(2)); idarubicin was reduced to 8 mg/m(2) without observing subsequent dose-limiting toxicities. The maximum tolerated dose in this study was bortezomib 1.2 mg/m(2) and idarubicin 8 mg/m(2). Common adverse events included: neutropenic fever, infections, constitutional symptoms, and gastrointestinal symptoms. No subjects experienced neurotoxicity. Most patients demonstrated hematologic response as evidenced by decreased circulating blasts. Four patients (20%) achieved complete remission. There was one treatment-related death. The combination of bortezomib and idarubicin in this mostly poor-risk, older AML group was well tolerated and did not result in high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00382954. PMID- 24075535 TI - Formation and characterization of silver nanoparticles in aqueous solution via ultrasonic irradiation. AB - In this study, a simple and green method to synthesize silver nanoparticles (Ag NPs) in aqueous solution via ultrasonic irradiation has been developed. Ultrafine Ag NPs with average diameter of 8 nm were obtained through sonicating aqueous solution of sodium hydroxide (NaOH, 0.1 mM) with adding silver nitrate solution (AgNO3, 5.88 mM) drop by drop. In pure aqueous solution, the reactive route related to hydroxyl radicals (OH) is presented. Furthermore, in alkaline aqueous solution, the effects of hydroxyl ions (OH(-)) on formation of Ag NPs are discussed detailedly. The formation of Ag NPs was tracked by surface plasmon resonance (SPR) band of ultraviolet-visible (UV-Vis) spectrum; the morphology of the obtained Ag NPs was characterized through transmission electron microscopy (TEM); energy dispersive X-ray spectroscopy (EDX) and X-ray powder diffraction (XRD) confirmed the formation of metallic Ag NPs. PMID- 24075536 TI - Bronchial inflammation in seasonal allergic rhinitis with or without asthma in relation to natural exposure to pollen allergens. AB - BACKGROUND: Nasal inflammation in allergic rhinitis enhances bronchial Th2 driven inflammation and development of asthma. We assessed bronchial inflammation induced by natural allergen exposure during pollen season in patients with pollinosis with or without asthma to show the intensity of inflammation in asthma and rhinitis and possible persistence of inflammation in periods without allergen exposure. METHODS: Sputum was induced in 52 patients with seasonal allergic rhinitis without asthma, 38 patients with seasonal allergic rhinitis and seasonal asthma and 23 healthy volunteers. Sampling was performed 6-8 weeks before the expected beginning of symptoms, during symptomatic period and 6-8 weeks after the end of symptoms. Sputum ECP was measured by means of chemi-luminiscent immunometric assay and sputum cell counts were assessed by classical staining and immunocytochemistry. RESULTS: Sputum eosinophils were on the whole higher in both asthma and rhinitis compared to controls (p<0.001, p=0.003). The rise of eosinophils during pollen season compared with values out of pollen season was significant in asthma (classical staining) (p=0.014) and slightly apparent in rhinitis (immunocytochemistry) (p=0.073). The seasonal rise of sputum ECP was observed only in rhinitis (p=0.006). CONCLUSIONS: Inflammation of the lower airway in patients with allergic rhinitis with and without asthma has been confirmed by means of both sputum eosinophil count and sputum ECP level. Persistent inflammation of lower airway in periods without allergen exposure was proven in seasonal asthma. This may have implications for the therapy of seasonal allergic rhinitis with and without asthma in terms of promoting long-term anti inflammatory treatment. PMID- 24075537 TI - [Initial evaluation of a programme to prevent mother-to-child transmission of human immunodeficiency virus infection in Equatorial Guinea]. AB - BACKGROUND: The prevalence of human immunodeficiency virus (HIV)-infected pregnant women in Equatorial Guinea (EG) has been reported as 7.3%. In 2008 an updated version of the PMTCT protocol was accepted according to the current WHO guidelines. The aim of this study was to describe the characteristics and outcome of children exposed to HIV after the introduction of the protocol. METHODS: A retrospective review was conducted on the clinical characteristics of the infants born to HIV-infected mothers in the Hospital Regional de Bata and Primary Health Care Centre Maria Rafols in Bata (EG) between June 2008 and November 2011. The diagnosis of HIV infection in children was based on rapid serology tests. RESULTS: A total of 103 children were included, of which 47 were males. Fifty three patients (51%) completed the follow-up (51%). Fourteen children (26%) were diagnosed with HIV infection (11 presumptive diagnosis, 3 due to persistence of antibodies at 18 months). Six children (12%) died before a definitive diagnosis. Just over than half (52%) of mothers received antiretroviral therapy (ART) during pregnancy. The transmission rate in children whose mothers received ART was 16% (3/19), compared with 43% (10/23) in children whose mothers did not receive it. Only one child was infected (8%) when the mother received ART, and child received postnatal prophylaxis. CONCLUSIONS: The PMTCT protocol compliance was still very low. Antiretroviral therapy in pregnant women decreased the rate of vertical transmission, but the rate still remains very high. Many children were lost to follow-up. Strategies to prevent loss to follow-up and methods for earlier virological diagnostic are needed. PMID- 24075538 TI - [Group C Streptococcus meningitis: a case report]. PMID- 24075539 TI - Imprecision in TBSA calculation. PMID- 24075540 TI - A new method for measurement of placental elasticity: acoustic radiation force impulse imaging. AB - INTRODUCTION: The velocities of the lateral shear waves (Vs; m s-1) generated by an acoustic radiation force impulse (ARFI) correlate with Young's modulus. Therefore, ARFI can be used as a new method to evaluate tissue elasticity. The aim of this study was to investigate the safety of ARFI imaging and the differences in placental elasticity in complicated cases. METHODS: The study population included 115 patients between 26 and 41 weeks gestation, who were divided into three groups, namely normal, fetal growth restriction (FGR) and pregnancy-induced hypertension (PIH). After delivery, the Vs values of the placenta were measured ex vivo. After ARFI imaging, microscopic examination was performed, the Vs values were compared among the three groups and the relationship between the Vs values and neonatal birthweight Z-score was investigated. RESULTS: No histological changes were noted even after ARFI imaging. The Vs values in the FGR group were significantly higher than those in the normal group (1.94 +/- 0.74 and 1.31 +/- 0.35 m s-1, respectively; p < 0.05). The Vs values demonstrated a significant negative correlation with the Z-score. Moreover, as the Z-score became lower, the Vs values became higher in the range of Z-scores under -0.5 standard deviation (SD). DISCUSSION: We speculate that the increased Vs values in the FGR group may have been caused by histological changes, and that a more severe FGR might result in increased Vs values. CONCLUSION: ARFI imaging was observed to have no apparent histological damage to the placental tissue. Ex vivo placentas from the FGR group were significantly more firm. Moreover, Vs values and Z-scores of birthweight had a significant negative correlation. Additional investigations are needed about the utility of this method for the evaluation of placental function in vivo. PMID- 24075541 TI - Evidence-based dermoscopy. AB - Dermoscopy has been shown in meta-analyses to improve the diagnostic accuracy of melanoma unequivocally compared with naked eye examination and to reduce excision rates of benign melanocytic lesions in clinical trials. Sequential digital dermoscopy imaging (SDDI) allows the detection of dermoscopic featureless melanoma. When used in high-risk individuals or on individual suspicious melanocytic lesions, it has a gross impact for detecting melanoma in clinical practice, with a range of 34% to 61% of melanomas detected exclusively using SDDI in these patients. Furthermore, SDDI has been shown to reduce the excision of benign lesions when used in combination with dermoscopy. PMID- 24075542 TI - A clinico-dermoscopic approach for skin cancer screening: recommendations involving a survey of the International Dermoscopy Society. AB - Dermoscopy is useful for skin cancer screening, but a detailed approach is required that integrates this tool into a rational clinical work flow. To investigate clinician perceptions and behavior in approaching patients with skin tumors, a survey was launched by electronic mail through the International Dermoscopy Society. After 4 months, the responses were analyzed and significant findings calculated. Considering the current approach of study participants in examining patients for skin cancer, an up-to-date system of triage is presented in this review, which aims to promote an improved diagnostic accuracy and more timely management of skin malignancy. PMID- 24075543 TI - Problematic lesions in children. AB - Melanoma in childhood is rare, and appears more commonly either in association with a preexisting (congenital) nevus, or with spitzoid features than de novo. Thus, problematic melanocytic lesions in children are essentially represented by congenital nevi and Spitz nevi that can be regarded as melanoma precursors and melanoma simulators, respectively. As a consequence, clinical and dermoscopic features of melanoma in children differ from those in an adult population. Herein we describe common clinical and dermoscopic features of problematic lesions in children, focusing on congenital and Spitz/Reed nevi, and including other problematic lesions, such as atypical, blue, acral, and scalp nevi. PMID- 24075544 TI - Problematic lesions in the elderly. AB - As the population continues to age, clinicians and dermatologists are increasingly faced with geriatric patients presenting with a range of dermatologic manifestations, including benign and malignant skin tumors. Knowledge of epidemiologic and morphologic features, including dermoscopy of common and benign melanocytic and nonmelanocytic skin tumors, provides the basis for a better understanding and management of problematic skin tumors in this age group. This article provides an overview of common and problematic skin lesions in elderly patients and addresses epidemiologic, clinical, and dermoscopic clues that aid the differential diagnosis and management of challenging skin lesions. PMID- 24075545 TI - Monitoring patients with multiple nevi. AB - Early recognition is the most effective intervention to improve melanoma mortality. Early diagnosis of melanoma in atypical mole syndrome patients, however, may be challenging. Skin self-examination and periodic physician-based total-body skin examinations are recommended in atypical mole patients but dermoscopy, total-body photography, and digital dermatoscopy have been proved to improve accuracy in early detection of melanoma in these high-risk patients. Digital follow-up in atypical mole syndrome patients allows detection of new lesions and changes in preexisting lesions. PMID- 24075546 TI - Dysplastic nevus: why this term should be abandoned in dermatoscopy. AB - The term "dysplastic nevus" is a misnomer and should be abandoned. Dysplastic nevus is not just a name, it is the root of the concept that histomorphology (or any morphologic examination including dermatoscopy) is able to predict the fate of a benign melanocytic proliferation. There is no evidence that this hypothesis is true but there are observations that falsify it. Preferably a specific diagnosis should be made based on dermatoscopic pattern and, if this is not possible, on clinical or dermatoscopic grounds alone the term "nevus, not otherwise specified" should be used. PMID- 24075547 TI - Spitz nevus, Spitz tumor, and spitzoid melanoma: a comprehensive clinicopathologic overview. AB - Spitz nevus can clinically present either in the classical (reddish pink) or the pigmented (brownish black) variant. Dermoscopy demonstrates that the pigmented variant is much more common than the classical variant; however, none of these show dermoscopic patterns clearly distinguishable from melanoma. Even histopathologically, a clear-cut differentiation between benign and malignant spitzoid neoplasms is often difficult, so that intermediate diagnostic categories (atypical Spitz nevus and Spitz tumor) are admitted. Because of these difficulties in clinical and histopathologic evaluation, surgical excision is recommended for clinically atypical spitzoid lesions of childhood and for all spitzoid lesions of adulthood. PMID- 24075548 TI - The morphologic universe of melanoma. AB - Differentiating dysplastic nevi from melanoma remains one of the main objectives of dermoscopy. Melanomas tend not to manifest any of the benign patterns described for nevi and instead usually display chaotic dermoscopic morphologies. Melanomas located on the face, chronically sun-damaged skin, volar surfaces, nails, and mucosal surfaces have additional features that can assist in their identification. However, some melanomas lack any defined dermoscopic structures. These so-called featureless melanomas can be identified via digital surveillance. This article reviews the melanoma-specific structures as a function of anatomic location (ie, melanomas on nonglabrous skin, face, volar surfaces, mucosae, and nails). PMID- 24075549 TI - Special locations dermoscopy: facial, acral, and nail. AB - Although dermoscopy reflects the anatomy, skin anatomy is different on facial and acral skin as well as in the nail unit. Malignant patterns on acral sites include the parallel ridge pattern and irregular diffuse pigmentation, whose presence should lead to a biopsy. Malignant patterns on the face include features of follicular invasion (signet-ring images, annular granular images, and rhomboidal structures) and atypical vessels. Malignant patterns on the nail unit include the micro-Hutchinson sign and irregular longitudinal lines. PMID- 24075550 TI - Special criteria for special locations 2: scalp, mucosal, and milk line. AB - The anatomic region influences the dermoscopic features of different lesions. In this article, the particular characteristics of the scalp, mucosal membranes, and lesions located on the milk line are explained. In histopathology, the benign melanocytic lesions in these locations are also named nevi of special sites, considering the difficulty of the histopathologic diagnosis. PMID- 24075551 TI - Blue lesions. AB - Blue color is found in a wide range of malignant and benign melanocytic and nonmelanocytic lesions and in lesions that result from penetration of exogenous materials, such as radiation or amalgam tattoo or traumatic penetration of particles. Discriminating between different diagnostic entities that display blue color relies on careful patient examination and lesion assessment. Dermoscopically, the extent, distribution, and patterns created by blue color can help diagnose lesions with specificity and differentiate between benign and malignant entities. This article provides an overview of the main diagnoses whereby blue color can be found, providing simple management rules for these lesions. PMID- 24075552 TI - Pink lesions. AB - Dermoscopy (dermatoscopy or surface microscopy) is an ancillary dermatologic tool that in experienced hands can improve the accuracy of diagnosis of a variety of benign and malignant pigmented skin tumors. The early and more accurate diagnosis of nonpigmented, or pink, tumors can also be assisted by dermoscopy. This review focuses on the dermoscopic diagnosis of pink lesions, with emphasis on blood vessel morphology and pattern. A 3-step algorithm is presented, which facilitates the timely and more accurate diagnosis of pink tumors and subsequently guides the management for such lesions. PMID- 24075553 TI - Dermoscopy in general dermatology. AB - In addition to its traditional use for the evaluation of skin tumors, dermoscopy continuously gains appreciation in other fields of dermatology. The patterns of several inflammatory and infectious skin diseases have already been described, and dermoscopy has been shown to improve the clinical diagnostic performance in the daily practice. The increasing use of dermoscopy was significantly enhanced by the development of the new generation hand-held dermatoscopes that can be easily placed in every dermatologist's pocket and do not require the use of immersion fluid. In this article, we provide an up-to-date summary of data on dermoscopy in general dermatology. PMID- 24075554 TI - Hair shafts in trichoscopy: clues for diagnosis of hair and scalp diseases. AB - Trichoscopy (hair and scalp dermoscopy) analyzes the structure and size of growing hair shafts, providing diagnostic clues for inherited and acquired causes of hair loss. Types of hair shaft abnormalities observed include exclamation mark hairs (alopecia areata, trichotillomania, chemotherapy-induced alopecia), Pohl Pinkus constrictions (alopecia areata, chemotherapy-induced alopecia, blood loss, malnutrition), comma hairs (tinea capitis), corkscrew hairs (tinea capitis), coiled hairs (trichotillomania), flame hairs (trichotillomania), and tulip hairs (in trichotillomania, alopecia areata). Trichoscopy allows differential diagnosis of most genetic hair shaft disorders. This article proposes a classification of hair shaft abnormalities observed by trichoscopy. PMID- 24075555 TI - Preface. Dermoscopy. PMID- 24075556 TI - Dilated cardiomyopathy in a 32-year-old woman with Russell-Silver syndrome. AB - INTRODUCTION: Russell-Silver Syndrome (RSS) is a genetically determined condition characterized by severe intrauterine and postnatal growth retardation; relative macrocephaly; a small, triangular face; and fifth-finger clinodactyly. The etiology of RSS involves epigenetic regulation through either uniparental disomy or genomic imprinting via DNA methylation. There has been no documented association between RSS and cardiomyopathy. METHODS: We present an original case of a 32-year-old woman with RSS with dilated a cardiomyopathy who on cardiac biopsy showed occasional hypertrophic and atrophic myocytes with no evidence of inflammation, abnormal sarcomeres and disintegration of the Z bands on ultrastructural analysis, abnormal desmin, and normal C9 immunoreactivity. CONCLUSION: This case represents the first reported association between RSS and cardiomyopathy. Given the complex mechanisms of disease etiology in RSS, this novel case provides insights into the mechanism of progressive dilated cardiomyopathy in an older individual with RSS. PMID- 24075557 TI - Thermoregulatory modeling use and application in the military workforce. AB - Thermoregulatory models have been used in the military to quantify probabilities of individuals' thermal-related illness/injury. The uses of the models have diversified over the past decade. This paper revisits an overall view of selected thermoregulatory models used in the U.S. military and provides examples of actual practical military applications: 1) the latest military vehicle designed with armor and blast/bulletproof windows was assessed to predict crews' thermal strains levels inside vehicles under hot environment (air temperature [Ta]: 29-43 degrees C, dew point: 13 degrees C); 2) a military working dog (MWD) model was developed by modifying existing human thermoregulatory models with canine physical appearance and physiological mechanisms; 3) thermal tolerance range of individuals from a large military group (n = 100) exposed to 35 degrees C/40% relative humidity were examined using thermoregulatory modeling and multivariate statistical analyses. Model simulation results assist in the decisions for the strategic planning and preventions of heat stress. PMID- 24075558 TI - The independent role of the aortic root ganglionated plexi in the initiation of atrial fibrillation: An experimental study. AB - OBJECTIVE: The major atrial ganglionated plexi (GP) can initiate atrial fibrillation alone without any contribution from the extrinsic cardiac nervous system. However, if stimulation of the ventricular GP, especially the aortic root GP, can provoke atrial fibrillation (AF) alone is unknown. Our study was designed to investigate the independent role of aortic root GP activity in the initiation of AF. METHODS: In 10 Langendorff-perfused canine hearts, the atrial effective refractory period, pulmonary vein effective refractory period, and percentage of AF induced were measured at baseline and during aortic root GP stimulation. RESULTS: Stimulation of the aortic root GP shortened the atrial effective refractory period from 128 +/- 10 ms at baseline to 103 +/- 15 ms (P < .05) and shortened the pulmonary vein effective refractory period from 139 +/- 14 ms to 114 +/- 15 ms (P < .05). Furthermore, the percentage of AF induced in the 10 isolated hearts increased from 10% at baseline to 90% during aortic root GP stimulation (P < .05). CONCLUSIONS: In Langendorff-perfused canine hearts, stimulation of the aortic root GP provokes AF in the absence of any extrinsic cardiac nerve activity. The aortic root GP is an important element in the intrinsic neuronal loop that can increase the risk of AF in isolated heart models. PMID- 24075560 TI - Sternal force distribution during median sternotomy retraction. AB - BACKGROUND: Median sternotomy is the access of choice in cardiac surgery. Sternal retractors exert significant forces on the thoracic cage and might cause considerable damage. The aim of this study was to determine the effects of retractor shape on local force distribution to obtain criteria for retractor design. METHODS: Two types of sternal retractors (straight [SSR] and curved [CSR]) were equipped with force sensors. Force distribution, total force, and displacement were recorded to a spread width of 10 cm in 18 corpses (11 males and 7 females; age, 62 +/- 12 years). Both retractors were used in alternating sequence in 4 iterations in every corpse. Data were compared with respect to the different retractor blade shapes. RESULTS: Maximum total forces for full retraction of both retractors resulted in 349.4 +/- 77.9 N. Force distribution during the first retraction for the cranial/median/caudal part of the sternum was 101.5 +/- 43.9/29.1 +/- 33.9/63.0 +/- 31.4 N for the SSR and 38.7 +/- 41.3/80.9 +/- 64.5/34.0 +/- 25.8 N for the CSR, respectively. During the 4 spreading cycles, the average force decreased from 224.6 +/- 61.3 N in the first to 110.8 +/- 39.8 N in the fourth iteration. The mean total force for the first retraction revealed 226.4 +/- 71.9 N for the CSR and 222.8 +/- 52.9 N for the SSR. CONCLUSIONS: The shape of sternal retractors considerably influences the force distribution on the sternal incision. In the SSR, forces on the cranial and caudal sternum are significantly higher than in the median section, whereas in the CSR, forces in the median section are highest. PMID- 24075562 TI - Perventricular device closure of ventricular defects in 235 young children: a single-center experience. PMID- 24075563 TI - Endovascular versus open elephant trunk completion for extensive aortic disease. AB - OBJECTIVES: To compare the outcomes between patients undergoing endovascular (EEC) or open (OEC) approaches to second-stage elephant trunk completion (EC). METHODS: From 1993 to 2010, 225 patients underwent second-stage EC (EEC, n = 92; OEC, n = 133). Propensity matching was performed for a fair comparison. RESULTS: The EEC patients were older, more likely to have atrial fibrillation, and had a smaller proximal aorta. The 30-day mortality was 6.2% (6.5% EEC vs 6% OEC, P = .88). No difference was found in bleeding (8.8%), stroke (3%), renal failure (4%), or spinal cord injury (4%); however, the OEC patients required tracheostomy more often (10 vs 1, P = .014). Survival after second-stage EC at 6 months and 1 and 5 years was 91%, 90%, and 77%, respectively. Survival and major morbidity did not differ after matching (44 pairs). However, the EEC group had shorter stays (9.9 +/- 13 vs 13 +/- 9 days, P < .0001) and received less blood (3 +/- 8 vs 6 +/ 8 U, P = .0001) than did the OEC group. This was maintained after matching. During follow-up, 32 endoleaks (3 type I, 27 type II, 2 type III) occurred; 26 (28%) EEC and 13 of 76 (17%) OEC patients underwent reoperation. The approach was not related to the risk of death in either hazard phase, but a larger descending diameter predicted a greater risk in the early phase. CONCLUSIONS: Death and complications occur similarly after OEC or EEC. The early toll might be greater after OEC, at the cost of reintervention for EEC. EEC expands the options to older patients and allows for earlier completion. Second-stage repair should not be delayed, and all patients require lifelong imaging surveillance. PMID- 24075565 TI - Attaining proficiency with endobronchial ultrasound-guided transbronchial needle aspiration. AB - OBJECTIVES: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is becoming the preferred method of mediastinal staging for lung cancer. We investigated the learning curve for EBUS-TBNA using risk-adjusted cumulative sum (Cusum). METHODS: A retrospective study of EBUS-TBNA was performed at a single academic institution for patients with mediastinal or hilar lymphadenopathy in the setting of proven or suspected lung cancer. A sampling pass was defined as a full retraction and repositioning of the aspiration needle. Rapid on-site evaluation was not available. To track proficiency, risk-adjusted Cusum analysis was performed using acceptable and unacceptable failure rates of 10% and 20%, respectively. Failure was defined as false negative or nondiagnostic results. RESULTS: During the study period, 231 patients underwent EBUS-TBNA. Prevalence of mediastinal or hilar malignancy was 66.7% (154 out of 231). Sensitivity was 92.2% (142 out of 154), and negative predictive value was 87.9% (58 out of 66). Node size was identified as a significant predictor of EBUS-TBNA success by multiple regression. Risk-adjusted Cusum analysis demonstrated that the first and only unacceptable decision interval was crossed at 22 cases. Individual practitioner learning curves were highly variable, and the operator with the highest volume was the most consistently proficient. CONCLUSIONS: In our experience, attainment of an acceptable failure rate for EBUS-TBNA required 22 cases. Node size is a predictor of EBUS-TBNA success. Risk-adjusted Cusum proved a powerful evaluative tool to monitor the training process of this new procedure. PMID- 24075564 TI - Risk factors for prolonged length of stay after the stage 2 procedure in the single-ventricle reconstruction trial. AB - BACKGROUND: The single-ventricle reconstruction trial randomized patients with single right ventricle lesions to a modified Blalock-Taussig or right ventricle to-pulmonary artery shunt at the Norwood. This analysis describes outcomes at the stage 2 procedure and factors associated with a longer hospital length of stay (LOS). METHODS: We examined the association of shunt type with stage 2 hospital outcomes. Cox regression and bootstrapping were used to evaluate risk factors for longer LOS. We also examined characteristics associated with in-hospital death. RESULTS: There were 393 subjects in the analytic cohort. Median stage 2 procedure hospital LOS (8 days; interquartile range [IQR], 6-14 days), hospital mortality (4.3%), transplantation (0.8%), median ventilator time (2 days; IQR, 1-3 days), median intensive care unit LOS (4 days; IQR, 3-7 days), number of additional cardiac procedures or complications, and serious adverse events did not differ by shunt type. Longer LOS was associated (R(2) = 0.26) with center, longer post Norwood LOS (hazard ratio [HR], 1.93 per log day; P < .001), nonelective timing of the stage 2 procedure (HR, 1.78; P < .001), and pulmonary artery (PA) stenosis (HR, 1.56; P < .001). By univariate analysis, nonelective stage 2 (65% vs 32%; P = .009), moderate or greater atrioventricular valve (AVV) regurgitation (75% vs 24%; P < .001), and AVV repair (53% vs 9%; P < .001) were among the risk factors associated with in-hospital death. CONCLUSIONS: Norwood LOS, PA stenoses, and nonelective stage 2 procedure, but not shunt type, are independently associated with longer LOS. Nonelective stage 2 procedure, moderate or greater AVV regurgitation, and need for AVV repair are among the risk factors for death. PMID- 24075566 TI - Impact of varying degrees of renal dysfunction on transcatheter and surgical aortic valve replacement. AB - BACKGROUND: Renal impairment portends adverse outcomes in patients undergoing valvular heart surgery. The relationship between renal dysfunction in patients undergoing transcatheter aortic valve replacement (TAVR) is incompletely understood. METHODS: A retrospective review of 1336 patients undergoing surgical aortic valve replacement (SAVR; 2002-2012) and 321 patients undergoing TAVR (2007 2012) was performed. Patients were divided into 3 glomerular filtration rate (GFR) groups: GFR greater than 60 mL/min, GFR 31 to 60 mL/min, and GFR 30 mL/min or less. Logistic and linear regression analysis was performed to estimate the TAVR effect on outcomes. Risk adjustments were made using the Society for Thoracic Surgeons (STS) predicted risk of mortality (PROM). RESULTS: TAVR patients were older (82 vs 65 years; P < .001), had a poorer ejection fraction (48% vs 53%; P < .001), were more likely female (45% vs 41%; P = .23), and had a higher STS PROM (11.9% vs 4.6%; P < .001). In-hospital mortality rates for TAVR and SAVR were 3.5% and 4.1%, respectively (P = .60), a result that marginally favors TAVR after risk adjustment (adjusted odds ratio = .52, P = .06). In SAVR patients, worsening preoperative renal failure was associated with increased in hospital mortality (P = .004) and hospital (P < .001) and intensive care unit (ICU) (P < .001) lengths of stay. In contrast, worsening renal function did not influence in-hospital mortality (P = .78) and hospital (P < .23) and ICU (P = .88) lengths of stay in TAVR patients. CONCLUSIONS: Worsening renal function was associated with increased in-hospital mortality, hospital length of stay, and ICU length of stay in SAVR patients, but not in TAVR patients. This unexpected finding may have important clinical implications in patients with aortic stenosis and preoperative renal dysfunction. PMID- 24075567 TI - Outcomes of patients born with single-ventricle physiology and aortic arch obstruction: the 26-year Melbourne experience. AB - BACKGROUND: To review the long-term outcomes of patients born with single ventricle physiology and aortic arch obstruction. METHODS: Follow-up of 70 consecutive neonates undergoing single-ventricle palliation and arch repair, excluding hypoplastic left heart syndrome, between 1983 and 2008, was reviewed. Dominant arch anomalies were coarctation (n = 48), interrupted arch (n = 10), and hypoplastic arch alone (n = 12). Neonatal Damus procedure with arch repair and shunt became the dominant approach, being performed in 1 (10%) of 10 in 1983 to 1989, 9 (32%) of 28 in 1990 to 1999, and 23 (72%) of 32 in 2000 to 2008. RESULTS: All patients underwent an initial procedure at a median of 6 days (range, 4-12 days): pulmonary artery banding and arch repair (n = 35); Damus, arch repair, and shunt (n = 33); and other (n = 2). Twenty-six patients died before Fontan completion. Of the 34 survivors of initial banding, 17 (50%) later required a Damus and 4 (12%) required subaortic stenosis relief. Forty patients underwent Fontan completion at a median age of 5 years (range, 4-7 years). After a mean of 5 +/- 6 years after Fontan, there was 1 hospital death and 1 Fontan takedown. Overall survival was similar if patients initially underwent a Damus or pulmonary artery banding (P = .3). Overall survival at 10 years was 53% (95% confidence interval, 42%-67%). CONCLUSIONS: Patients born with single-ventricle physiology and arch obstruction have a high risk of mortality in the first years of life. Their outcomes seem excellent once they reach Fontan status. It is likely that, in patients with single-ventricle and arch obstruction, strategies to avoid systemic outflow tract obstruction should be implemented in early life, and regular monitoring of blood pressure is warranted. PMID- 24075568 TI - Use of femoral vein homograft for unifocalizing major aortopulmonary collateral arteries in a patient with pulmonary atresia with ventricular septal defect. PMID- 24075570 TI - BACH2: a marker of DNA damage and ageing. AB - DNA damage and ageing share expression changes involving alterations in many aspects of metabolism, suppression of growth and upregulation of defence and genome maintenance systems. "Omics" technologies have permitted large-scale parallel measurements covering global cellular constituents and aided the identification of specific response pathways that change during ageing and after DNA damage. We have set out to identify genes with highly conserved response patterns through meta-analysis of mRNA expression datasets collected during natural ageing and accelerated ageing caused by a Transcription-Coupled Nucleotide Excision Repair (TC-NER) defect in a diverse set of organs and tissues in mice, and from in vitro UV-induced DNA damage in a variety of murine cells. The identified set of genes that show similar expression patterns in response to organ ageing (accelerated and normal), and endogenously and exogenously induced DNA damage, consists of genes involved in anti-oxidant systems and includes the transcription factor Bach2 as one of the most consistent markers. BACH2 was originally identified as a partner of the small Maf proteins and antagonist of the NRF2 anti-oxidant defence pathway and has been implicated in B-cell differentiation and immune system homeostasis. Although BACH2 has never before been associated with UV-induced damage or ageing, it shows a strong downregulation in both conditions. We have characterized the dynamics of Bach2 expression in response to DNA damage and show that it is a highly sensitive responder to transcription-blocking DNA lesions. Gene expression profiling using Affymetrix microarray analysis after siRNA-mediated silencing of Bach2 identified cell cycle and transcription regulation as the most significantly altered processes consistent with a function as transcription factor affecting proliferation. PMID- 24075569 TI - Adolescent risk factors for child maltreatment. AB - We investigate adolescent risk factors, measured at both early and late adolescence, for involvement in child maltreatment during adulthood. Comprehensive assessments of risk factors for maltreatment that use representative samples with longitudinal data are scarce and can inform multilevel prevention. We use data from the Rochester Youth Development Study, a longitudinal study begun in 1988 with a sample of 1,000 seventh and eighth graders. Participants have been interviewed 14 times and, at the last assessment (age 31), 80% were retained. Risk factors represent 10 developmental domains: area characteristics, family background/structure, parent stressors, exposure to family violence, parent-child relationships, education, peer relationships, adolescent stressors, antisocial behaviors, and precocious transitions to adulthood. Maltreatment is measured by substantiated reports from Child Protective Services records. Many individual risk factors (20 at early adolescence and 14 at later adolescence) are significantly, albeit moderately, predictive of maltreatment. Several developmental domains stand out, including family background/structure, education, antisocial behaviors, and precocious transitions. In addition, there is a pronounced impact of cumulative risk on the likelihood of maltreatment. For example, only 3% of the youth with no risk domains in their background at early adolescence were involved in later maltreatment, but for those with risk in 9 developmental domains the rate was 45%. Prevention programs targeting youth at high risk for engaging in maltreatment should begin during early adolescence when risk factors are already at play. These programs need to be comprehensive, capable of addressing the multiple and interwoven nature of risk that is associated with maltreatment. PMID- 24075571 TI - Thymineless death is inhibited by CsrA in Escherichia coli lacking the SOS response. AB - Thymineless death (TLD) is the rapid loss of colony-forming ability in bacterial, yeast and human cells starved for thymine, and is the mechanism of action of common chemotherapeutic drugs. In Escherichia coli, significant loss of viability during TLD requires the SOS replication-stress/DNA-damage response, specifically its role in inducing the inhibitor of cell division, SulA. An independent RecQ- and RecJ-dependent TLD pathway accounts for a similarly large additional component of TLD, and a third SOS- and RecQ/J-independent TLD pathway has also been observed. Although two groups have implicated the SOS-response in TLD, an SOS-deficient mutant strain from an earlier study was found to be sensitive to thymine deprivation. We performed whole-genome resequencing on that SOS-deficient strain and find that, compared with the SOS-proficient control strain, it contains five mutations in addition to the SOS-blocking lexA(Ind(-)) mutation. One of the additional mutations, csrA, confers TLD sensitivity specifically in SOS-defective strains. We find that CsrA, a carbon storage regulator, reduces TLD in SOS- or SulA-defective cells, and that the increased TLD that occurs in csrA( ) SOS-defective cells is dependent on RecQ. We consider a hypothesis in which the modulation of nucleotide pools by CsrA might inhibit TLD specifically in SOS deficient (SulA-deficient) cells. PMID- 24075572 TI - Solanidane and iminosolanidane alkaloids from Solanum campaniforme. AB - From the leaves of Solanum campaniforme (Solanaceae), eight solanidane alkaloids were isolated, four of which contain a p-hydroxyphenylethylamine unit. Their structures were established as: 22beta,23beta-epoxy-solanida-1,4-dien-3-one; 22alpha,23alpha-epoxy-10-epi-solanida-1,4,9-trien-3-one; 22alpha,23alpha-epoxy solanida-4-en-3-one; 22beta,23beta-epoxy-solanida-4-en-3-one; (E)-N-[8'(4 hydroxyphenyl)ethyl]-22alpha,23alpha-epoxy-solanida-1,4,9-trien-3-imine; (E)-N [8'(4-hydroxyphenyl)ethyl]-22alpha,23alpha-epoxy-solanida-1,4-dien-3-imine; (Z)-N [8'(4-hydroxyphenyl)ethyl]-22alpha,23alpha-epoxy-solanida-1,4,9-trien-3-imine and (Z)-N-[8'(4-hydroxyphenyl)ethyl]-22alpha,23alpha-epoxy-solanida-1,4-dien-3-imine. All structures were determined using spectroscopic techniques, such as 1D and 2D NMR, and HRESIMS. The cytotoxicity and the antiophidic activities of the alkaloids were evaluated. The alkaloids did not show any cytotoxicity, but inhibited the main toxic actions of Bothrops pauloensis venom. PMID- 24075573 TI - Determination of optimum periods between onset of suspected acute myocarditis and 18F-fluorodeoxyglucose positron emission tomography in the diagnosis of inflammatory left ventricular myocardium. AB - PURPOSE: To determine optimum periods for (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) examination in subjects with suspected acute myocarditis, we compared (18)F-FDG PET with endomyocardial biopsy (EMB) using the latest definition of (18)F-FDG PET for inflammatory left ventricular (LV) myocardium. MATERIALS AND METHODS: Retrospective analysis of 29 subjects (18 male, 48 +/- 18 years) who have symptoms or LV dysfunction underwent both (18)F FDG PET (Advance NXi, GE-Healthcare) under fasting conditions and EMB from LV posterior wall within 3 months. RESULTS: When we defined (18)F-FDG PET positive inflammatory LV posterior wall as 'focal on diffuse' pattern, sensitivity, specificity, and positive predictive values (PPV), and negative predictive values (NPV) of (18)F-FDG PET for detecting active inflammatory LV posterior wall compared with EMB were 46.2, 81.3, 66.7, and 65.0%, respectively. Receiver operating characteristic curve of periods (days) between onset of clinically suspected acute myocarditis and performance of (18)F-FDG PET for detecting inflammatory LV posterior wall demonstrated 17 days as a best cut off values with area under the curve (0.497, P=0.982) with sensitivity=21.1% and specificity=100%. Sensitivity, specificity, PPV and NPV of (18)F-FDG PET for detecting inflammatory LV posterior wall on EMB were all 100% when (18)F-FDG PET was performed at 1-14 days after onset of suspected acute myocarditis. CONCLUSIONS: In our definition, (18)F-FDG PET showed excellent agreement with EMB for detecting active inflammatory LV posterior wall in subjects with clinically suspected active acute myocarditis. If possible, (18)F-FDG PET should be performed within 14 days after the onset to maintain high diagnostic accuracy compared with EMB. PMID- 24075574 TI - Childhood lifestyle and clinical determinants of adult ideal cardiovascular health: the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Princeton Follow-Up Study. AB - BACKGROUND: The American Heart Association recently defined ideal cardiovascular health by simultaneous presence of seven health behaviors and factors. The concept is associated with cardiovascular disease incidence, and cardiovascular disease and all-cause mortality. To effectively promote ideal cardiovascular health already early in life, childhood factors predicting future ideal cardiovascular health should be investigated. Our aim was thus to comprehensively explore childhood determinants of adult ideal cardiovascular health in population based cohorts from three continents. METHODS: The sample comprised a total of 4409 participants aged 3-19 years at baseline from the Cardiovascular Risk in Young Finns Study (YFS; N = 1883) from Finland, Childhood Determinants of Adult Health Study (CDAH; N = 1803) from Australia and Princeton Follow-up Study (PFS; N = 723) from the United States. Participants were re-examined 19-31 years later when aged 30-48 years. RESULTS: In multivariable analyses, independent childhood predictors of adult ideal cardiovascular health were family socioeconomic status (P < 0.01; direct association) and BMI (P < 0.001; inverse association) in all cohorts. In addition, blood pressure (P = 0.007), LDL-cholesterol (P < 0.001) and parental smoking (P = 0.006) in the YFS, and own smoking (P = 0.001) in CDAH were inversely associated with future ideal cardiovascular health. CONCLUSIONS: Among several lifestyle and clinical indicators studied, higher family socioeconomic status and non-smoking (parental/own) in childhood independently predict ideal cardiovascular health in adulthood. As atherosclerotic cardiovascular diseases are rooted in childhood, our findings suggest that special attention could be paid to children who are from low socioeconomic status families, and who smoke or whose parents smoke, to prevent cardiovascular disease morbidity and mortality. PMID- 24075575 TI - Autosomal monoallelic expression: genetics of epigenetic diversity? AB - In mammals, relative expression of the two parental alleles of many genes is controlled by one of three major epigenetic phenomena: X chromosome inactivation, imprinting, and mitotically stable autosomal monoallelic expression (MAE). MAE affects a large fraction of human autosomal genes and introduces enormous epigenetic heterogeneity in otherwise similar cell populations. Despite its prevalence, many functional and mechanistic aspects of MAE biology remain unknown. Several lines of evidence imply that MAE establishment and maintenance are controlled by a variety of genetic elements. Based on known genomic features regulating X-inactivation and imprinting, we outline likely features of MAE controlling elements. We also assess implications of MAE for genotype-phenotype relationship, with a focus on haploinsufficiency. PMID- 24075576 TI - The quest for an optimal definition of prostate-specific antigen failure following radical prostatectomy: the risk of not seeing the forest for the trees. PMID- 24075577 TI - Towards random sequencing or precision medicine in castration-resistant prostate cancer? PMID- 24075578 TI - Long-term follow-up after regenerative therapy of the urethral sphincter for female stress urinary incontinence. PMID- 24075579 TI - Can we eat our way to a lower prostate cancer risk, and if so, how? PMID- 24075581 TI - Impact of different breathing protocols on multiple-breath washout outcomes in children. AB - BACKGROUND: To standardize multiple-breath washout (MBW) measurements, 1L tidal volume (VT) protocols were suggested. The effect on MBW derived ventilation inhomogeneity (VI) indices is unclear. METHODS: We compared VI indices from free breathing MBW at baseline to 1L VT MBW performed in triplicates in 35 children (20 with CF). Mean (range) age was 12.8 (7.0-16.7) years, weight 42 (20-64) kg and height 151 (117-170) cm. RESULTS: Baseline lung clearance index (LCI) increased from mean (SD) 11.0 (2.2) to 13.0 (2.6), p = 0.011, in CF and from 6.8 (0.5) to 7.7 (1.4), p = 0.004, in controls. Moment ratio and Scond similarly increased. While change in VI indices was heterogeneous in individuals, decrease in functional residual capacity was most strongly associated with LCI increase. CONCLUSION: MBW protocols strongly influence measures of VI. The 1L VT MBW protocol leads to overestimation of VI and is not recommended in children. PMID- 24075582 TI - Experience with immunotherapy in 3 patients with cerebellar ataxia associated with anti-glutamic acid decarboxylase antibodies. PMID- 24075583 TI - Internal ophthalmoplegia as the initial symptom of Miller-Fisher syndrome. PMID- 24075584 TI - Large artery occlusion diagnosed by computed tomography angiography in acute ischaemic stroke: frequency, predictive factors, and safety. AB - INTRODUCTION: Demonstrating artery occlusion in ischaemic stroke has gained importance due to the increasing availability of endovascular therapies. This study evaluates the frequency of artery occlusion, its associated factors, and complications following the use of CT-angiography in acute stroke. METHODS: We retrospectively analysed a cohort of patients who suffered acute ischaemic stroke between July and-December 2011. RESULTS: We included 157 patients (mean age, 74+/ 11; mean NIHSS score, 5 [2-13]). Of that total, 56.7% of the patients were admitted to hospital during the first 8hours. CT-angiography was performed in 71 cases (45.2%); arterial large-vessel occlusion was detected in 37 (52.1%) of these cases, and the most frequent site was M1 (40%). Univariate analysis showed that the NIHSS score (17 vs 7, P<.001) and atrial fibrillation (64% vs 32%, P=.006) were associated with artery occlusion. A logistic regression analysis was performed subsequently, confirming these associations. There were no cases of contrast-induced nephropathy. Door-to-needle time for intravenous thrombolysis was 61.2+/-24.5minutes in patients who underwent CT-angiography, and 53.5+/ 34.3minutes in those who did not (P=.495). CONCLUSIONS: Arterial occlusions are seen in 23.6% of patients, especially in those who are admitted during the first few hours. NIHSS score serves as a useful predictive factor. PMID- 24075585 TI - Prior cancer in patients with ischemic stroke: the Bergen NORSTROKE study. AB - BACKGROUND: To compare the prevalence of prior or on-going cancer in patients with ischemic stroke and in the general population. We hypothesized that cardioembolic stroke is the most common stroke etiology in patients with prior cancer and that the outcome for ischemic stroke patients (ISP) with prior cancer is poor. METHODS: All ISP registered in the Norwegian Stroke Research Registry (NORSTROKE) as part of the ongoing Bergen NORSTROKE Study were included. Stroke etiology was determined by the Trial of Org 10172 in Acute Stroke Treatment criteria, and the severity of the stroke was defined from the National Institutes of Health Stroke Scale score. Information about prior or ongoing cancer disease and type was retrospectively obtained from the medical patient record and The Cancer Registry of Norway. The prevalence of cancer among stroke patients was compared with the prevalence of cancer in the general population. RESULTS: Among 1456 ISP, 229 (15.7%) patients had 1 or more cancer diagnoses before the stroke. The prevalence of cancer was higher among stroke patients compared with the general population (P = .001). The most common cancer types were colorectal cancer (20.2%), prostate cancer (15.6%), breast cancer (12.7 %), cancer of the urinary tract system (10.3%), gynecological cancer (6.2%), and lung cancer (4.5%). Logistic regression analysis showed that patients with prior cancer had cardioembolic strokes at a higher rate (P = .03). CONCLUSIONS: The prevalence of prior cancer is higher in ISP than in the general population. ISPs with prior cancer are more prone to cardioembolism. PMID- 24075586 TI - Interobserver reproducibility of signal intensity ratio on magnetic resonance angiography for hemodynamic impact of intracranial atherosclerosis. AB - BACKGROUND: Changes of signal intensities (SIs) across intracranial atherosclerosis (ICAS) on magnetic resonance angiography (MRA) may reflect hemodynamic impact of the lesion. We evaluated the interobserver reproducibility of an index termed signal intensity ratio (SIR), developed in a previous study to represent the changes of SIs across ICAS on MRA. METHODS: Symptomatic ICAS on MRA were retrospectively recruited. Two observers respectively evaluated the images and calculated the SIR as follows, blinded to each other's readings: SIR=(mean poststenotic SI-mean background SI)/(mean prestenotic SI-mean background SI). Statistical analyses were performed to evaluate the interobserver reproducibility of this index. RESULTS: A total of 102 symptomatic ICASs were enrolled, with 36 (35.3%) lesions of 50%-69% MRA stenoses and others being 70%-99% stenoses or flow void on MRA. Overall, mean SIRs were not significantly different between the 2 observers (.92+/-.17 versus .93+/-.17; mean difference -.006+/-.09; P=.496 for paired t test). Pearson correlation coefficients were >.80 for all analyses, indicating strong linear correlations between SIRs by the 2 observers. Bland Altman analysis for SIRs of all cases showed no systematic bias between the 2 observers. For different cut-points ranging from .75 to 1.00, the kappa statistics were mostly greater than .6 and interobserver agreements were all greater than 80%, implying substantial agreement between observers. CONCLUSIONS: SIR was demonstrated to be highly reproducible between observers in the present study. Future studies are warranted to further explore the role of this index in comprehensive evaluation and risk stratification of symptomatic ICAS. PMID- 24075587 TI - Diagnosis of stroke by emergency medical dispatchers and its impact on the prehospital care of patients. AB - BACKGROUND: Emergency medical dispatchers represent the first line of communication with a patient, and their decision plays an important role in the prehospital care of stroke. We evaluated the rate and accuracy of stroke diagnosis by dispatchers and its influence in the prehospital care of potential stroke patients. METHODS: We analyzed the 2009 National Emergency Medical Services Information System. Study population was based on the diagnosis of stroke made by emergency medical technicians (EMT). This was then divided in those coded as stroke/cerebrovascular accident versus others reported by dispatchers and compared with each other. RESULTS: In all, 67,844 cases were identified as stroke by EMT, but transportation time was available for 52,282 cases that represented the final cohort. Cases identified as stroke by dispatchers were 27,566 (52.7%). When this group compared with stroke cases not identified by dispatchers, we found that the mean age was significantly higher (71.2 versus 68.6 years, P<.0001); advanced life support was dispatched more frequently (84% versus 72.8%, P<.0001), dispatchers offered help and instructions to the caller more frequently, and they arrived at a facility at a shorter time (41.8 versus 49.8 minutes, P<0001). Sensitivity and specificity for the diagnosis of stroke by dispatchers were 34.61 and 99.46, respectively. CONCLUSIONS: Recognition of symptoms and diagnosis of a potential stroke by dispatchers positively affect the care of patients by decreasing the arrival time to a hospital and providing the highest level of prehospital care possible. Education is needed to increase dispatcher's detection of stroke cases. PMID- 24075588 TI - Upregulation of ANGPTL4 messenger RNA and protein in severely calcified carotid plaques. AB - BACKGROUND: In carotid atherosclerotic lesions, calcified plaques are thought to be stable and to evoke very few symptoms. However, the molecular activity in calcified plaques and their clinical significance have not been fully clarified yet. METHODS: Carotid plaques from 18 endarterectomy patients were classified into high- and low-calcified plaques on the basis of Agatston calcium score. Twelve plaques were investigated for the alteration of gene expression by microarray analysis and real-time polymerase chain reaction (PCR) and 6 other plaques underwent protein assessment to elucidate the difference in molecular biological activity between the groups. RESULTS: Microarray analysis demonstrated 93 angiogenesis or growth factor-related transcripts that are reliably expressed (175 probe sets). Among them, angiopoietin-like protein 4 (ANGPTL4) expression was significantly elevated, whereas fibroblast growth factor receptor 2 (FGFR2) expression was significantly suppressed. Quantitative messenger RNA analysis was performed with real-time PCR. Augmented or decreased protein expression of each gene was confirmed by Western blotting analysis and immunohistochemistry. CONCLUSIONS: In high-calcified plaques, ANGPTL4 might be upregulated for antiangiogenic modulating function together with the downregulation of FGFR2, contributing to the stability of the plaques. PMID- 24075589 TI - A wearable inertial system to assess the cervical spine mobility: comparison with an optoelectronic-based motion capture evaluation. AB - In clinical settings, the cervical range of motion (ROM) is commonly used to assess cervical spine function. This study aimed at assessing cervical spine mobility based on head and thorax kinematics measured with a wearable inertial system (WS). Sequences of imposed active head movements (lateral bending, axial rotation and flexion-extension) were recorded in ten controls and 13 patients who had undergone an arthrodesis. Orientation of the head relative to the thorax was computed in terms of 3D helical angles and compared with the values obtained using an optoelectronic reference system (RS). Movement patterns from WS and RS showed excellent concurrent validity (CMC up to 1.00), but presented slight differences of bias (mean bias<2.5 degrees ) and dispersion (mean dispersion<4.2 degrees ). ROM obtained using WS also showed some differences compared to RS (mean difference<5.7 degrees ), within the range of those reported in literature. WS enabled the observation of the same significant differences between controls and patients as RS. Moreover, ROM from WS presented good test-retest repeatability (ICC between 0.63 and 0.99 and SEM<6.2 degrees ). In conclusion, WS can provide angles and ROM comparable to those obtained with RS and relevant for the cervical assessment after treatment. PMID- 24075590 TI - [Lower limb edema and monoclonal gammopathy in a 74-year-old man]. PMID- 24075591 TI - Relationship between maternal antibody type and antenatal course following intrauterine transfusion for red cell alloimmunisation. AB - OBJECTIVE: To determine the antenatal course of severe red cell alloimmunisation in pregnancies requiring intrauterine fetal transfusion. STUDY DESIGN: A retrospective cohort study over 16 years in a single national quaternary fetal medicine centre. From 1996 to 2011, 242 red cell intrauterine transfusions (IUT) were performed in 102 alloimmunised pregnancies. Antibody type was categorized into Rh(D) and non-Rh(D) (including Rh(c), Kell and Rh(E)). Women with Rh(D) antibodies were further stratified into those with and without additional red cell antibodies. Data were compared using the Mann-Whitney U and Fisher's exact tests. Two-tailed P values at the 5% level were considered significant. RESULTS: Comparing Rh(D) and non-Rh(D) pregnancies, there were no differences in either gestational age or fetal haemoglobin at first IUT, number of transfusions required, gestation at delivery, caesarean delivery rates or perinatal losses. In women sensitized to Rh(D), the presence of additional antibodies did not influence the degree of fetal anaemia or the first transfusion-delivery interval, although rates of fetal hydrops were higher in the presence of multiple antibodies. The "procedure-related" loss rate was 1.7% per procedure in our institution. CONCLUSION: Antibody status does not appear to influence clinical outcomes following fetal transfusion for alloimmunisation. PMID- 24075592 TI - Developmental trajectories of abuse--an hypothesis for the effects of early childhood maltreatment on dorsolateral prefrontal cortical development. AB - The United States has a high rate of child maltreatment, with nearly 12 in 1000 children being victims of abuse or neglect. Child abuse strongly predicts negative life outcomes, especially in areas of emotional and mental health. Abused children are also more likely than their peers to engage in violence and enter the juvenile justice system, as well as to become abusive parents themselves. Research has shown that child abuse and trauma can lead to decreased hippocampal volume, which could be indicative of abnormal hippocampal development. Hippocampal development appears to directly affect the development of the dorsolateral prefrontal cortex, a brain area responsible for emotion regulation, cognitive reappraisal, and general executive function. Therefore, I hypothesize that if child abuse results in abnormal hippocampal development, which leads to abnormal dorsolateral prefrontal cortex development, many of the correlated risk factors of child abuse, such as emotionally-laden parenting and unfavorable cognitive distortions regarding children's behaviors, may be in part caused by underdevelopment or abnormal functioning of the dorsolateral prefrontal cortex, as a function of the individual's own experiences with abuse during childhood. If this hypothesis is supported with future research, more targeted, successful, and cost-effective prevention and treatment protocols could ensue. For instance, programs that have been empirically shown to increase the activity of the dorsolateral prefrontal cortex, such as cognitive behavioral therapy, could be effective in decreasing the incidence of intergenerational transfer of abuse. PMID- 24075593 TI - Inhibitory role for GABA in atherosclerosis. AB - gamma-Aminobutyric acid (GABA), the classical inhibitory neurotransmitter in the nervous system, has a parallel inhibitory role in the immune system. It affects a variety of functional properties of the immune cells like monocyte migration, macrophage cholesterol efflux, regulatory T cell proliferation and inflammatory cytokine secretion. All of these are the main pathologic processes of atherosclerosis, a chronic inflammatory disease involving both innate and adaptive immune responses in the artery wall. Moreover, GABA has neuroprotective effects in brain ischemic injury, which is one of the serious complications of atherosclerosis. Therefore, we hypothesize GABA may be a prospect immune cell targeting therapy in atherosclerosis. PMID- 24075594 TI - Are the different patterns of stress-induced (Takotsubo) cardiomyopathy explained by regional mechanical overload and demand: supply mismatch in selected ventricular regions? AB - Takotsubo cardiomyopathy (TCM) or stress-induced cardiomyopathy is an increasingly recognized syndrome characterized by severe regional left ventricular dysfunction in the absence of an explanatory coronary lesion. TCM may lead to lethal complications but is completely reversible if the patient survives the acute phase. The pathogenesis of TCM and the mechanism behind this remarkable recovery are unknown. Plasma levels of catecholamine are elevated in many TCM patients and exogenously administered catecholamine induces TCM-like cardiac dysfunction in both humans and rats. A catecholamine excess increases myocardial metabolic demand by increasing the force of contraction as well as the heart rate, and also alters cardiac depolarization patterns. We propose that an altered spatiotemporal pattern of cardiac contraction and excessive force of contraction may lead to a redistribution of wall stresses in the left ventricle. This redistribution of wall stress causes regional mechanical overload of regions where wall tension becomes disproportionately great and renders these cardiomyocytes "metabolically insufficient". In other words, these cardiomyocytes experience a demand: supply mismatch on the basis of excessive metabolic demand. In order to prevent the death of these cardiomyocytes and to prevent excessive wall tension from developing in neighboring regions, a protective metabolic shutdown occurs in the affected cardiomyocytes. This metabolic shutdown, i.e., acute down regulation of non-vital cellular functions, serves to protect the affected regions from necrosis and explains the apparently complete recovery observed in TCM. We propose that this phenomenon may share important characteristics with phenomena such as ischemic conditioning, stunning and hibernation. In this manuscript, we discuss our hypothesis in the context of available knowledge and discuss important experiments that would help to corroborate or refute the hypothesis. PMID- 24075595 TI - A neurobiological model for cry-fuss problems in the first three to four months of life. AB - Although problem crying in the first three to four months of life is usually self limiting, it is not a trivial condition. Early intervention is important, yet families receive conflicting advice from health professionals. The past decade has seen significant advances in neuroscience, lactation science, and developmental psychology, including new insights into the significance of developmentally sensitive windows. We propose a neurobiological model to explain the mechanisms of cry-fuss problems in the first months of life, and the mechanisms which underlie effective intervention, with a view to facilitating research collaboration and consistency of advice across health disciplines. We hypothesise that crying in the first three to four neurodevelopmentally sensitive months signals activation of the hypothalamic-pituitary-adrenal axis and adrenergic neuronal circuitry in response to perceptions of discomfort or threat. Susceptible infants may be conditioned by early stress, for example, by unidentified feeding difficulties, into a sensitised stress response, which usually settles at three to four months of age with neurodevelopmental maturity. Bouts of prolonged and unsoothable crying result from positive feedback loops in the hypothalamic-pituitary-adrenal and adrenergic systems. Importantly, epigenetic modulation of the infant's limbic neuronal circuitry may explain correlations between regulatory problems in the first months of life, and behavioural problems including feeding problems in later childhood. PMID- 24075596 TI - Physicians' prescribing preferences were a potential instrument for patients' actual prescriptions of antidepressants. AB - OBJECTIVES: To investigate whether physicians' prescribing preferences were valid instrumental variables for the antidepressant prescriptions they issued to their patients. STUDY DESIGN AND SETTING: We investigated whether physicians' previous prescriptions of (1) tricyclic antidepressants (TCAs) vs. selective serotonin reuptake inhibitors (SSRIs) and (2) paroxetine vs. other SSRIs were valid instruments. We investigated whether the instrumental variable assumptions are likely to hold and whether TCAs (vs. SSRIs) were associated with hospital admission for self-harm or death by suicide using both conventional and instrumental variable regressions. The setting for the study was general practices in the United Kingdom. RESULTS: Prior prescriptions were strongly associated with actual prescriptions: physicians who previously prescribed TCAs were 14.9 percentage points (95% confidence interval [CI], 14.4, 15.4) more likely to prescribe TCAs, and those who previously prescribed paroxetine were 27.7 percentage points (95% CI, 26.7, 28.8) more likely to prescribe paroxetine, to their next patient. Physicians' previous prescriptions were less strongly associated with patients' baseline characteristics than actual prescriptions. We found no evidence that the estimated association of TCAs with self-harm/suicide using instrumental variable regression differed from conventional regression estimates (P-value = 0.45). CONCLUSION: The main instrumental variable assumptions held, suggesting that physicians' prescribing preferences are valid instruments for evaluating the short-term effects of antidepressants. PMID- 24075597 TI - Health problems are more common, but less severe when measured using newer EQ-5D versions. AB - OBJECTIVES: The EuroQol Group recently released youth (Y) and 5-level (5L) versions of its 3-level EQ-5D instrument (3L) that measures health-related quality of life. In this study, we (1) compare 3L, Y, and 5L responses among US adults and (2) assess construct validity. STUDY DESIGN AND SETTING: Using a nationally representative sample of US adults (N = 2,619), we collected 3L, Y, and 5L responses in random order and estimated their associations and their relationship with a 0 to 100 numerical visual analog scale. RESULTS: The prevalence of US adults in the best possible EQ-5D state (i.e., 11111) was lower for the Y (38%) and 5L (35%) than for the 3L (44%), capturing more health problems. However, the prevalence of extreme responses in pain/discomfort and anxiety/depression decreased substantially between the 3L and 5L (from 44% to 17% and from 29% to 13%, respectively). CONCLUSION: Compared with the 3L, the Y and 5L versions describe population health as having more, yet milder, health problems. Although the 5L may have advantages in patient populations in which extreme problems are more prevalent, population studies or studies that follow patients from childhood may consider using the Y. PMID- 24075598 TI - Cohort study of trials submitted to ethics committee identified discrepant reporting of outcomes in publications. AB - OBJECTIVES: To identify factors associated with discrepant outcome reporting in randomized drug trials. STUDY DESIGN AND SETTING: Cohort study of protocols submitted to a Swiss ethics committee 1988-1998: 227 protocols and amendments were compared with 333 matching articles published during 1990-2008. Discrepant reporting was defined as addition, omission, or reclassification of outcomes. RESULTS: Overall, 870 of 2,966 unique outcomes were reported discrepantly (29.3%). Among protocol-defined primary outcomes, 6.9% were not reported (19 of 274), whereas 10.4% of reported outcomes (30 of 288) were not defined in the protocol. Corresponding percentages for secondary outcomes were 19.0% (284 of 1,495) and 14.1% (334 of 2,375). Discrepant reporting was more likely if P values were <0.05 compared with P >= 0.05 [adjusted odds ratio (aOR): 1.38; 95% confidence interval (CI): 1.07, 1.78], more likely for efficacy compared with harm outcomes (aOR: 2.99; 95% CI: 2.08, 4.30) and more likely for composite than for single outcomes (aOR: 1.48; 95% CI: 1.00, 2.20). Cardiology (aOR: 2.34; 95% CI: 1.44, 3.79) and infectious diseases (aOR: 1.77; 95% CI: 1.01, 3.13) had more discrepancies compared with all specialties combined. CONCLUSION: Discrepant reporting was associated with statistical significance of results, type of outcome, and specialty area. Trial protocols should be made freely available, and the publications should describe and justify any changes made to protocol-defined outcomes. PMID- 24075599 TI - A comparison of cervical histopathology variability using whole slide digitized images versus glass slides: experience with a statewide registry. AB - Whole slide imaging is increasingly used for primary and consultative diagnoses, teaching, telepathology, slide sharing, and archiving. We compared pathologist evaluations of glass slides and corresponding digitized images within the context of a statewide surveillance effort. Cervical specimens collected by the New Mexico HPV Pap Registry research program targeted cases diagnosed between 2006 and 2010. Two samples of 250 slides each were digitized with the ScanScope XT (Aperio, Vista, CA) microscope and reviewed with Aperio ImageScope reader. (1) A "random set" had a distribution of community diagnoses: 70% from cases of cervical intraepithelial neoplasia grade 2 or higher, 20% from cases of cervical intraepithelial neoplasia grade 1 and 10% from negative cases. (2) A "discrepant set" was represented by difficult cases where 2 study pathologists initially disagreed. Within the regular workflow of the New Mexico HPV Pap Registry, 3 pathologists read the slides 2 to 3 times each without knowledge of clinical history, previous readings or sampling scheme. Pathologists also read each corresponding image twice. For within- and between-reader comparisons we calculated unweighted kappa statistics and asymmetry chi(2) tests. Across all comparisons, slides and images yielded similar results. For the random set, almost all within-reader and between-reader Kappa values ranged between 0.7 and 0.8 and 0.6 and 0.7, respectively. For the discrepant set, most within- and between-reader kappa values were 0.4 to 0.6. As cervical intraepithelial neoplasia diagnostic terminology changes, pathologists may need to re-read histopathology slides to compare disease trends over time, eg, before/after introduction of human papillomavirus vaccination. Diagnosis of cervical intraepithelial neoplasia differed little between slides and corresponding digitized images. PMID- 24075600 TI - Validation and workflow optimization of human epidermal growth factor receptor 2 testing using INFORM HER2 dual-color in situ hybridization. AB - Human epidermal growth factor receptor 2 (HER2) status is useful for predicting response to trastuzumab. Fluorescence in situ hybridization (FISH) for HER2 gene amplification is accurate but limited because of cost, the need for fluorescence microscopy, the limited assessment of histology, and the fading of its signal over time. Dual-color in situ hybridization (Dual ISH) is fully automated, is viewable by bright-field microscopy, has a stable signal, and has separate colors for HER2 and chromosome 17 signals. HER2 immunohistochemistry (IHC), FISH, and Dual ISH were performed on 101 breast cancer cases. Sixteen of 17 cases with 3+ HER2 by IHC showed gene amplification by FISH, and 15 showed amplification by Dual ISH. Three of the 2+ IHC cases were either amplified or equivocal by Dual ISH. None of the IHC-negative cases were amplified by either FISH or Dual ISH. Dual ISH agreed with FISH in 93% of cases. Among the 6 discrepancies, 4 were for an equivocal result for 1 test compared with either a positive or a negative result for the other test. The average differences in readings between Dual ISH and FISH in the discrepant cases were only 0.02, with a range of -1.37 to 1.85. Turnaround time for FISH as a send-out test from test ordering to reporting averaged 8.27 workdays, whereas the turnaround time for Dual ISH performed in house averaged 4.94 workdays (P < .0000001). Our results indicated that automated Dual ISH is a useful method for evaluating HER2 status in a clinical setting. PMID- 24075601 TI - The epidermal growth factor receptor is frequently overexpressed in penile squamous cell carcinomas: a tissue microarray and digital image analysis study of 112 cases. AB - Disseminated penile cancer is usually treated with chemotherapy. However, response rates are far from acceptable. Recently, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies have shown to be clinically useful in penile carcinomas. Nevertheless, only a few cases of penile carcinomas have been evaluated for EGFR expression. In this study, we assessed the immunohistochemical expression of EGFR in 112 patients with penile squamous cell carcinoma. We built 4 tissue microarrays and evaluated EGFR expression using a monoclonal mouse anti EGFR antibody. For digital image analysis, we used the open-source software ImageJ version 1.47 (NIH, Bethesda, MD) along with the immunomembrane plug-in. Membranous EGFR expression was evaluated, taking into account staining completeness (0-10 points) and staining intensity (0-10 points) for a combined score (0-20 points). We classified the cases as follows: negative EGFR expression, 0 to 3 points; low EGFR expression, 4 to 8 points; and high EGFR expression, 9 to 20 points. The distribution of EGFR immunohistochemical expression was as follows: 13 cases (12%) were EGFR negative, 49 cases (44%) had low EGFR expression, and 50 cases (44%) had high EGFR expression. EGFR expression was not associated with histologic subtype (P = .47), histologic grade (P = .77), or human papillomavirus status (P = .14). In conclusion, immunohistochemical EGFR expression appears to be a common feature of penile carcinomas, independently of histologic subtype, histologic grade, and human papillomavirus presence. Whether or not EGFR expression is associated with EGFR gene mutation or if it can be used to predict response to therapy in patients with disseminated penile cancer should be evaluated in future studies. PMID- 24075602 TI - Auditory event-related potentials at preschool age in children born very preterm. AB - OBJECTIVE: To assess auditory event-related potentials at preschool age in children born very preterm (VP, 27.4 +/- 1.9 gestational weeks, n=70) with a high risk of cognitive dysfunction. METHODS: We used an oddball paradigm consisting of a standard tone randomly replaced by one of three infrequent deviants (differing in frequency, sound direction or duration). RESULTS: The P1 and N2 latencies were inversely correlated to age (50-63 months) both in VP (r=-0.451, p<0.001, and r= 0.305, p=0.01, respectively) and term born controls (TC; n=15). VP children had smaller P1 than near-term (n=12) or TC (1.70 +/- 0.17 MUV vs 2.68 +/- 0.41 and 2.92 +/- 0.43, respectively; p<0.05). Mismatch negativity response did not differ between groups. CONCLUSIONS: Our data suggest a fast maturation of P1 and N2 responses with fast decrease in P1 and N2 latencies around the age of 5 years. Mismatch negativity response does not seem to be a robust measure for defining abnormalities in VP children. SIGNIFICANCE: In ERP studies in preschool children, even small, non-significant group differences in age at recording should be corrected for. Very preterm born children at preschool age have aERP patterns as earlier described in full-term born children with cognitive deficits. PMID- 24075603 TI - Long-term effects of asenapine or olanzapine in patients with persistent negative symptoms of schizophrenia: a pooled analysis. AB - BACKGROUND: A Phase 2 efficacy study suggested that asenapine (ASE) was superior to risperidone in decreasing negative symptoms in schizophrenia at 6 weeks, prompting design of two negative symptom studies. Two 26-week core studies with 26-week extensions compared asenapine (ASE: 5-10mg twice-daily] and olanzapine (OLA: 5-20mg once-daily) as monotherapies in reducing persistent negative symptoms (PNS). While neither study met the primary endpoint of superiority of ASE over OLA, ASE was statistically superior to OLA in one extension study. This prompted a pooled analysis of the treatment effects of both drugs. METHODS: Data were pooled from two 26-week core studies and extensions. Efficacy endpoints: change in Negative Symptom Assessment scale-16 (NSA-16) total score at Week 26 (prespecified primary endpoint) and Week 52. Additional measures: change in Positive and Negative Syndrome Scale (PANSS)-total, Marder factors, negative subscale scores, Clinical Global Impression Severity of Illness score (CGI-S) assessments, NSA-16 factor domains, NSA global score, and individual items. RESULTS: Pooled data from the extension studies (n=502) showed no differences between ASE and OLA at Week 26. At Week 52, ASE showed superiority over OLA in NSA-16 total score, NSA global, PANSS Marder negative and PANSS negative subscales, some NSA-16 items, and four of five factor domains. In addition, pooled data for patients who entered the core trials (n=949) were analyzed over 52weeks (whether or not patients entered the extension). No significant differences between groups were observed in change in NSA-16 total score at 26 weeks. At Week 52, ASE was significantly superior over OLA in this measure, NSA global score and PANSS Marder negative factor. There were more early dropouts due to AEs, including worsening of the disease, in the ASE group. CONCLUSION: In this pooled analysis, ASE and OLA did not differ significantly over 26 weeks, but indicated a signal of superiority for ASE with continued treatment up to 52 weeks. PMID- 24075604 TI - Neuropsychological functioning and jumping to conclusions in delusions. AB - BACKGROUND: It has been consistently demonstrated that delusions are related to jumping to conclusions (JTC), a data-gathering bias and potential candidate endophenotype of psychosis. Recent research suggests that JTC may be a marker of treatment response. However, we know little about the factors contributing to the occurrence of this reasoning bias. This study investigated the relationship between JTC and hypothesised deficits in working memory, employing standard well validated neuropsychological tests, in people with current delusions. METHOD: One hundred and twenty six people with schizophrenia spectrum psychosis and current delusions were assessed for current symptoms, and tested for JTC. We compared performance on tests of working memory in those with the reasoning bias and those without. RESULTS: As expected, 30-40% of this sample of people with current delusions showed the JTC bias. There were no differences in premorbid IQ between those with and without the JTC reasoning bias. However, the performance of the JTC group was significantly worse on tests of working memory. CONCLUSIONS: The JTC data-gathering bias is associated with impairments in working memory. New non pharmacological interventions for people with delusions, designed to improve data gathering, may benefit from incorporating strategies to overcome deficits in working memory. PMID- 24075605 TI - Cartilage treatment and biologics current research. PMID- 24075606 TI - Authors' reply. PMID- 24075607 TI - Comments on "Repeated platelet concentrate injections enhance reparative response of microfractures in the treatment of chondral defects of the knee: an experimental study in an animal model" by Milano et al. PMID- 24075608 TI - "Biomechanical performance of traditional arthroscopic knots versus slippage proof knots": a word from the developer of the slippage-proof (SP) knot. PMID- 24075609 TI - Authors' reply. PMID- 24075610 TI - Authors' reply. PMID- 24075611 TI - How should we define failure after surgical shoulder stabilization? PMID- 24075612 TI - Computed tomographic analysis of curved and straight guides for placement of suture anchors for acetabular labral refixation. AB - PURPOSE: The purpose of this study was to compare suture anchor placement in the acetabular rim between straight and curved drill guides regarding angle and distance of the suture anchor tip from the articular cartilage during labral refixation. METHODS: A total of 14 fresh-frozen cadaveric hips underwent arthroscopic labral incision from the 12 to 3 o'clock positions and subsequent repair with either a curved drill guide or a straight drill guide. These hips were then compared by computed tomographic imaging analysis by measuring the angle of suture anchor insertion and the distance of the tip of the suture anchor to the articular cartilage at the 1 o'clock, 2 o'clock, and 3 o'clock positions. RESULTS: The curved suture anchor (CSA) guide significantly increased the insertion angle (P = .009) and distance from the articular cartilage to anchor (P = .003) at the 1 o'clock position on the acetabulum. The angle of insertion at the 2 and 3 o'clock positions was greater for the CSA guide compared with the straight suture anchor (SSA) guide but did not reach statistical significance. CONCLUSIONS: A CSA guide was shown to be significantly more effective in increasing the angle of insertion of suture anchors and increased the distance of the suture anchor tip to the articular cartilage surface at the 1 o'clock position but not at the 2 or 3 o'clock position. CLINICAL RELEVANCE: The use of SSA guides can be difficult because of the osseous morphologic characteristics of the acetabular rim, leading to placement of the suture anchor away from the acetabular rim and therefore resulting in a nonanatomical refixation of the acetabular labrum. The use of a curved guide, flexible drill, and flexible suture anchor inserter may provide more precise placement of suture anchors in the acetabular rim. PMID- 24075613 TI - Comparison of intra-articular injections of plasma rich in growth factors (PRGF Endoret) versus Durolane hyaluronic acid in the treatment of patients with symptomatic osteoarthritis: a randomized controlled trial. AB - PURPOSE: The purpose of this study was to compare the efficacy and safety in a randomized, clinical trial of 3 injections of PRGF-Endoret (BTI Biotechnology Institute, Vitoria, Spain) versus one single intra-articular injection of Durolane hyaluronic acid (HA) (Q-MED AB, Uppsala, Sweden) as a treatment for reducing symptoms in patients with knee osteoarthritis (OA). METHODS: Ninety-six patients with symptomatic knee OA were randomly assigned to receive PRGF-Endoret (3 injections on a weekly basis) or one infiltration with Durolane HA. The primary outcome measures were a 30% decrease and a 50% decrease in the summed score for the pain, physical function, and stiffness subscales of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Lequesne scores from baseline to weeks 24 and 48. The percentage of OMERACT-OARSI (Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative) responders was also documented. As secondary outcomes, pain, stiffness, and physical function by use of the WOMAC and the Lequesne score were considered and overall safety of the injection themselves. RESULTS: The mean age of the patients was 63.6 years. Treatment with PRGF-Endoret was significantly more efficient than treatment with Durolane HA in reducing knee pain and stiffness and improving physical function in patients with knee OA. The rate of response to PRGF-Endoret was significantly higher than the rate of response to HA for all the scores including pain, stiffness, and physical function on the WOMAC, Lequesne index, and OMERACT-OARSI responders at 24 and 48 weeks. Adverse events were mild and evenly distributed between the groups. CONCLUSIONS: Our findings show that PRGF-Endoret is safe and significantly superior to Durolane HA in primary and secondary efficacy analysis both at 24 and 48 weeks; provides a significant clinical improvement, reducing patients' pain and improving joint stiffness and physical function with respect to basal levels in patients with knee OA; and should be considered in the treatment of patients with knee OA. PMID- 24075614 TI - Supplementation with platelet-rich plasma improves the in vitro formation of tissue-engineered cartilage with enhanced mechanical properties. AB - PURPOSE: This study aimed to determine the effects of platelet-rich plasma (PRP) on the histologic, biochemical, and biomechanical properties of tissue-engineered cartilage. METHODS: Chondrocytes isolated from bovine metacarpal-phalangeal articular cartilage were seeded on top of a porous ceramic substrate (calcium polyphosphate [CPP]). Cultures were supplemented with fetal bovine serum (FBS), PRP, or platelet-poor plasma (PPP) at 5%. On day 5, the concentration was increased to 20%. PRP and PPP were obtained through centrifugation of whole blood withdrawn from a mature cow. After 2 weeks, samples (n = 8) were analyzed histologically, biochemically, and biomechanically. Data were analyzed using the Wilcoxon test (significance, P < .05). RESULTS: Chondrocytes cultured in 20% PRP formed thicker cartilage tissue (1.6 +/- 0.2 mm) than did cells grown in 20% FBS (0.7 +/- 0.008 mm; P = .002) and 20% PPP (0.8 +/- 0.2 mm; P = .03). Cartilage tissue generated in the presence of 20% PRP had a greater equilibrium modulus of 38.1 +/- 3.6 kPa versus 15.6 +/- 1.5 kPa (P = .0002) for 20% PPP and 20.4 +/- 3.5 kPa (P = .007) for 20% FBS. Glycosaminoglycan (GAG) content was increased in tissues formed in 20% PRP (176 +/- 18.8 MUg GAG/mg) compared with those grown in 20% FBS (112 +/- 10.6 MUg GAG/mg; P = .01) or 20% PPP (131.5 +/- 14.8 MUg GAG/mg; P = .11). Hydroxyproline content was similar whether the media was supplemented with 20% PRP (8.7 +/- 0.9 MUg/mg), 20% FBS (7.6 +/- 0.9 MUg/mg; P = .37), or 20% PPP (6.4 +/- 1 MUg/mg; P = .28). DNA content was similar in all tissues whether formed in 20% PRP (11.9 +/- 3.5 MUg/mg), 20% FBS (9.3 +/- 2.5 MUg/mg; P = .99), or 20% PPP (7.2 +/- 1.3 MUg/mg; P = .78). Immunostained samples showed prevalence of type II collagen in tissues formed in the presence of 20% PRP. CONCLUSIONS: The presence of PRP in the culture media enhances the in vitro formation of cartilage, with increased GAG content and greater compressive mechanical properties, while maintaining characteristics of hyaline phenotype. CLINICAL RELEVANCE: Understanding the in vitro effects of PRP on tissue-engineered cartilage may lead to the creation of engineered cartilage tissue with enhanced properties suitable for cartilage repair. PMID- 24075615 TI - Child homicide and neglect in France: 1991-2008. AB - The aim of this study is to investigate epidemiological characteristics of the victims and the offenders in children homicide cases and to propose preventive measures. We retrospectively investigated homicides and deaths by neglect involving children aged 15 or less, which have been autopsied in the Department of Pathology and Legal Medicine of the Raymond Poincare Hospital, Garches, France, during the 18-year period from 1991 to 2008. Cases included were analyzed for victims' age and gender, victim-assailant's relation, death cause and scenery, and offender's motivation. For the purposes of the study, victims were divided into four age groups: new born; infants (1-23 months); young children (2 5 years); and children (6-15 years). During the study period, 70 victims of homicide or fatal neglect were identified, which equates to a child homicide prevalence of 0.56 per 100,000 children per year. Slightly more than half of the victims (51.4%) were less than 1 year old. Neonaticide prevalence was 0.12 per 100,000 births with an equal distribution between genders. Neonates were most likely to be killed by their mothers while fathers were the most frequent assailants in both infants and children groups. Stepparents were involved in only one case. Familicide cases where children and spouses are killed were perpetrated only by fathers. The leading cause of death was blunt trauma (especially head trauma). In the neonaticide group, half of the victims died from passive neglect whereas gunshots were predominant in the children groups. PMID- 24075616 TI - Prevention of invasive fungal infections in patients with acute myeloid leukaemia: results of a single centre retrospective observational study with the use of posaconazole versus conventional mould-active azoles. PMID- 24075617 TI - Polychlorinated biphenyls in sediments of the Yellow Sea: distribution, source identification and flux estimation. AB - Although there is no direct major riverine input, a large quantity of waste produced in mainland China and Korea is transported continuously to the Yellow Sea (YS) through atmospheric deposition, currents and tides; therefore, the environment is distinctly influenced by man-made pollution. This study focuses on the associated pollutant transport mechanisms and fluxes by sampling polychlorinated biphenyls (PCBs). PCBs (Sigma24PCB) in YS sediments ranged between 99 pg/g and 3.13 ng/g of dry sediment (with a mean value of 715 pg/g). PCBs produced unintentionally by industrial and other processes appeared to be the major source of PCBs in the sediments, accounting for 60.5%. Industrially synthesized PCBs with 3Cl and 5Cl accounted for 15.5% and 24.0%, respectively. PCBs were mainly from atmospheric deposition (84.5%), followed by continental runoff (15.5%). The average atmospheric deposition flux of technical PCBs was 789 ng/(m(2)a) and flux of surface runoff was 2.27 ng/L. PMID- 24075618 TI - Drawing lines at the sand: evidence for functional vs. visual reef boundaries in temperate Marine Protected Areas. AB - Marine Protected Areas (MPAs) can either protect all seabed habitats within them or discrete features. If discrete features within the MPA are to be protected humans have to know where the boundaries are. In Lyme Bay, SW England a MPA excluded towed demersal fishing gear from 206 km(2) to protect rocky reef habitats and the associated species. The site comprised a mosaic of sedimentary and reef habitats and so 'non reef' habitat also benefited from the MPA. Following 3 years protection, video data showed that sessile Reef Associated Species (RAS) had colonised sedimentary habitat indicating that 'reef' was present. This suggested that the functional extent of the reef was potentially greater than its visual boundary. Feature based MPA management may not adequately protect targeted features, whereas site based management allows for shifting baselines and will be more effective at delivering ecosystem goods and services. PMID- 24075619 TI - Implementing shared medical appointments for heart failure patients in a community cardiology practice: a pilot study. AB - OBJECTIVE: To examine patient and staff satisfaction, billing charges, and programmatic feasibility of shared medical appointments (SMA) in a nurse practitioner-managed heart failure (HF) clinic in a community cardiology practice. METHODS: Twenty patients were scheduled among four SMAs for this pilot study. All aspects of a usual clinic appointment were utilized during the SMA, but an additional 20-minute teaching session was presented. All patients completed a satisfaction questionnaire. The office staff completed satisfaction questionnaires about the SMA. Billing charges, cancellations and missed appointments without cancellation for SMAs were compared to usual clinic appointment days. RESULTS: Satisfaction was high among patients and office staff. Rates for no-shows were similar for SMAs versus usual appointments (15% versus 5.5%), but there were fewer cancellations among SMAs (0% versus 28%). This may be a reflection of the personalized appointment reminder calls that were made to the patients scheduled for SMAs. Billing charges were not significantly different for SMAs versus usual appointments. CONCLUSION: SMAs are a feasible option in a community cardiology practice. PMID- 24075620 TI - Serological evidence of Ostertagia ostertagi infection in dairy cows does not impact the efficacy of rabies vaccination during the housing period. AB - Nematode infections modulate the immune reaction of humans and livestock and may impair immune responses to non-parasitic antigens such as those present in vaccines. In this study, the relationship between antibodies directed against Ostertagia ostertagi, the economically most important nematode infection of cattle in temperate regions, and the magnitude and the kinetics of the antibody response to rabies vaccination was investigated in a commercial dairy herd of 46 cows. During the stabling period, all animals received a single intramuscular administration with a commercial inactivated rabies vaccine (Rabisin(r), Merial). The serum antibody levels against O. ostertagi on day 0 were compared with anti rabies IgM, IgA, IgG1, IgG2 and virus-neutralizing antibodies on days 0, 7, 14 and 21 after vaccination. In addition, to explore the potential effect of newly acquired O. ostertagi infections, the kinetics of the O. ostertagi antibody levels during the first 2 months after turnout on pasture were compared with concurrent changes in the rabies antibodies. During the stabling period the O. ostertagi antibody level tended to be positively associated with the magnitude, rate of increase and rate of decrease of the rabies antibodies. However, none of these associations were significant (P>0.05). Over the first 2 months at pasture, an increase in O. ostertagi antibody level tended to be associated with a decrease in rabies IgG2 and IgM, but again these associations lacked statistical significance (P>0.20). We conclude that the O. ostertagi antibody level in adult cattle over the housing period has no significant association with the antibody response to rabies vaccination. We recommend that future studies aiming to assess the relationship of nematode infections with humoral immune responses to vaccines are conducted on a larger scale and focus on the summer period when cattle are exposed continuously to nematode challenge from the pasture and hence are actively responding immunologically to nematode antigen exposure. PMID- 24075621 TI - Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial. AB - BACKGROUND: Abiraterone acetate plus prednisone significantly improves radiographic progression-free survival in asymptomatic or mildly symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer compared with prednisone alone. We describe analyses of data for patient-reported pain and functional status in a preplanned interim analysis of a phase 3 trial. METHODS: Between April 28, 2009, and June 23, 2010, patients with progressive, metastatic castration-resistant prostate cancer were enrolled into a multinational, double-blind, placebo-controlled trial. Patients were eligible if they were asymptomatic (score of 0 or 1 on item three of the Brief Pain Inventory Short Form [BPI-SF] questionnaire) or mildly symptomatic (score of 2 or 3) and had not previously received chemotherapy. Patients were randomly assigned (1:1) to receive oral abiraterone (1 g daily) plus prednisone (5 mg twice daily) or placebo plus prednisone in continuous 4-week cycles. Pain was assessed with the BPI-SF questionnaire, and health-related quality of life (HRQoL) with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. We analysed data with prespecified criteria for clinically meaningful pain progression and deterioration in HRQoL. All patients who underwent randomisation were included in analyses. FINDINGS: 1088 patients underwent randomisation: 546 were assigned to abiraterone plus prednisone and 542 to placebo plus prednisone. At the time of the second prespecified interim analysis, median follow-up was 22.2 months (IQR 20.2-24.8). Median time to progression of mean pain intensity was longer in patients assigned to abiraterone plus prednisone (26.7 months [95% CI 19.3-not estimable]) than in those assigned to placebo plus prednisone (18.4 months [14.9-not estimable]; hazard ratio [HR] 0.82, 95% CI 0.67-1.00; p=0.0490), as was median time to progression of pain interference with daily activities (10.3 months [95% CI 9.3-13.0] vs 7.4 months [6.4-8.6]; HR 0.79, 95% CI 0.67 0.93; p=0.005). Median time to progression of worst pain was also longer with abiraterone plus prednisone (26.7 months [95% CI 19.4-not estimable]) than with placebo plus prednisone (19.4 months [16.6-not estimable]), but the difference was not significant (HR 0.85, 95% CI 0.69-1.04; p=0.109). Median time to HRQoL deterioration was longer in patients assigned to abiraterone plus prednisone than in those assigned to placebo plus prednisone as assessed by the FACT-P total score (12.7 months [95% CI 11.1-14.0] vs 8.3 months [7.4-10.6]; HR 0.78, 95% CI 0.66-0.92; p=0.003) and by the score on its prostate-cancer-specific subscale (11.1 months [8.6-13.8] vs 5.8 months [5.5-8.3]; HR 0.70, 95% CI 0.60-0.83; p<0.0001). INTERPRETATION: Abiraterone plus prednisone delays patient-reported pain progression and HRQoL deterioration in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. These results provide further support for the efficacy of abiraterone in this population. PMID- 24075622 TI - Sex assessment using clavicle measurements: inter- and intra-population comparisons. AB - We studied sexual dimorphism of the human clavicle in order to describe size variation and create population-specific discriminant tools for morphometric sex assessment. The studied sample consisted of 200 skeletons of adult individuals obtained from the University of Athens Human Skeletal Reference Collection, Athens, Greece. The specimens were well-documented and represented a modern population from cemeteries in the Athens area. Six dimensions typically used for clavicle measurements were recorded. For sexing clavicles, we used both traditional univariate (limiting, demarking and sectioning points) and multivariate discriminant function analysis. The accuracy of the best five classification equations/functions ranged from 91.62% to 92.55% of correctly assigned specimens. By testing new and previously published sexing functions (Greeks, Polynesians, Guatemalans) on four available population samples (English, Indians from Amritsar, Indians from Varanasi, and data from the present study) we found that, for some combinations of tested and reference samples, the accuracy of the sex assessment may decrease even below the probability given by random sex assignment. Therefore, measurements of the clavicle should not be used for sex assessment of individual cases (both forensic and archeological) whose population origin is unknown. However, significant metric differences were also recorded among three different Greek samples (i.e. within a population). As a consequence, application of a sexing method generated from one Greek sample and applied to another Greek sample led to negligible reduction in the success of sex assessment, despite general similarities in ethnic origin (Greeks), generation structure and presumed social background of the samples. Therefore, we believe that future studies should focus on understanding the nature of the differences among within-population reference samples. PMID- 24075623 TI - What factors influence uptake into family-based obesity treatment after weight screening? AB - OBJECTIVES: To determine what factors drive participation in a family-based weight management program for 4- to 8-year-old children following screening for overweight or obesity. STUDY DESIGN: Children (n = 1093) attended a comprehensive screening appointment where parents completed questionnaires on demographics, motivation for healthy lifestyles, feeding practices, and beliefs about child size, prior to feedback about the child's weight. Parents of overweight or obese children (body mass index >=85th percentile) attended a follow-up interview to assess reactions to feedback and willingness to participate in a 2-year intervention. RESULTS: A total of 271 (24.8%) children were overweight or obese with 197 (72.7%) agreeing to the intervention. Socioeconomic status differed in intervention participants (n = 197) compared with non-participants (n = 74), whereas no differences were observed in parental feeding practices, ineffective parenting practices, or self-determined forms of motivation. However, fewer non participating parents believed their child to be overweight (23% vs 49%, P < .001) or were concerned about it (16% vs 43%, P < .001), despite children having an average body mass index approximating the 95th percentile. Non-participating parents did not expect their child to be overweight (P = .002) and rated receiving this information as less useful (P = .008) than participating parents. CONCLUSION: Preconceptions about child weight and reactions to feedback determined intervention uptake more than parenting or motivation for health. Many parents agreed to participate in the intervention despite not viewing their child as overweight. PMID- 24075624 TI - [From spondyloarthropathies to spondyloarthritis: towards a new terminology for an early diagnosis and new therapeutic interventions?]. PMID- 24075625 TI - [Hemiplegia in 34-year-old woman]. PMID- 24075627 TI - [Clinical and biological efficacy of tocilizumab in giant cell arteritis: report of three patients and literature review]. AB - INTRODUCTION: Treatment of giant cell arteritis is based on prolonged corticosteroid therapy but adverse side effects are common especially in the elderly. CASE REPORTS: We report three patients with giant cell vasculitis treated by tocilizumab, an interleukin-6 receptor antibody, owing to resistance or intolerance to corticosteroid therapy. A favorable outcome was rapidly observed both on clinical and biological data allowing a corticoid therapy sparing. CONCLUSION: Tocilizumab is a promising treatment of giant cell arteritis but controlled trials are needed to confirm its efficacy. PMID- 24075626 TI - [Weight loss, dementia and ataxia susceptible to doxycycline: a likely new case report caused by T. whipplei]. AB - INTRODUCTION: Whipple's disease is a rare infectious disease due to Tropheryma whipplei, a bacterium rarely causing severe localized neurological infection (only 25 cases reported in the literature), which are more often diagnosed by a positive T. whipplei PCR performed on cerebrospinal fluid. CASE REPORT: We report the third case of progressive dementia associated with obesity and ataxia in a 52 year-old man. Classic laboratory results performed to identify the etiology of the clinical features were non-contributive: only a saliva T. whipplei PCR was strongly positive and the Western blot serology has detected an asymptomatic carriage profile. The (18)FDG-PET highlighted a frontal area hypometabolism. An antibiotic treatment by doxycycline allowed a partial regression of the neurological manifestations, a weight loss and a significant improvement of the (18)FDG frontal hypometabolism. CONCLUSION: Progressive dementia associated with ataxia and obesity is a new clinical syndrome caused by T. whipplei. Antibiotic test by doxycycline can help to the diagnosis and (18)-FDG could facilitate the follow-up. PMID- 24075628 TI - [How to manage a patient with chronic arterial hypertension during pregnancy and the postpartum period]. AB - The management of chronic arterial hypertension during pregnancy and postpartum requires first to estimate the risk of the pregnancy, linked with the severity of hypertension, with cardiac and renal involvement, with its cause as well as with the background (obesity, diabetes, possible history of placental vascular pathology). On a very practical approach, antihypertensive drug has to be started or increased if systolic pressure reaches or exceeds 160 mmHg or if diastolic pressure reaches or exceeds 105 mmHg. Below this level, there are no evidence based medicine data, but it seems reasonable to treat if pressure increases over 150/100 mmHg (140/90 mmHg in case of ambulatory monitoring). Excessive pressure figures control must be avoided as much as insufficient ones: in practice, it is necessary to decrease the treatment dose if figures are below 130/80 mmHg. Three antihypertensive drugs are consensually recommended today: alphametyldopa, calcium-channel blockers and labetalol. Monotherapy is most often sufficient; if needed, two of these drugs can easily be associated, and even three if necessary. Converting enzyme inhibitors and angiotensin receptor II antagonists should not be prescribed to pregnant women. Betablockers and diuretics are not recommended. Whatever is the antihypertensive drug used, it is necessary to detect the signs of bad placenta blood circulation with uterine Doppler ultrasound and regular controls of fetal growth, and to check for appearance of proteinuria, defining then over-imposed pre-eclampsia needing immediate admission to the maternity. After delivery, lacatation suppresion with bromocriptin should not be prescribed. PMID- 24075629 TI - Characterization of oral Helicobacter pylori strain by 4 methods. AB - The aim of the study was to describe oral Helicobacter pylori strain from a child by 4 methods. The strain was positive by immunofluorescence, ureA- and cagA positive, vacA s1 m2 genotype and resistant to metronidazole and clarithromycin. In conclusion, virulent and antibiotic resistant H. pylori strains can be present in oral cavity from patients with chronic dental and gastroduodenal diseases. PMID- 24075630 TI - Pyrazinamide resistance among drug-resistant Mycobacterium tuberculosis isolates at a referral hospital. PMID- 24075631 TI - Microbial etiology and antimicrobial resistance in healthcare-associated versus community-acquired and hospital-acquired bloodstream infection in a tertiary care hospital. AB - Infections that occur in patients with significant exposure to the nosocomial environment while they reside in the community are currently classified separately as healthcare-associated infections. In this retrospective study, conducted at Ghent University Hospital between January 1, 2009, and May 31, 2011, we compared microbial characteristics of healthcare-associated bloodstream infection (HCAB) with that of community-acquired bloodstream infection (CAB) and hospital-acquired bloodstream infection (HAB). Three hundred eighty-six pathogens isolated from patients with HCAB were compared with 141 and 605 pathogens identified in patients with CAB and HAB, respectively. HCAB was associated with a distinct pathogen profile and with an antimicrobial susceptibility pattern different from that of other categories of bloodstream infection. We conclude that the concept of HCAB provides guidance in the choice of empirical antibiotic therapy but should be translated according to local epidemiology. PMID- 24075632 TI - Pneumorachis associated with multiorgan infection due to Citrobacter koseri. AB - Pneumorachis rarely occurs after spreading from a contiguous site of infection or after a traumatic event. We describe an adult patient who developed sepsis and a renal abscess due to Citrobacter koseri, and computed tomographic imaging identified gas within the entire spinal canal as well as an iliopsoas abscess. This patient recovered from pneumorachis caused by disseminated infection. PMID- 24075633 TI - Alcohol misuse in bipolar disorder. A systematic review and meta-analysis of comorbidity rates. AB - AIMS: To assess the comorbidity rates of alcohol use disorders (AUDs) in bipolar disorder (BD) and to explore possible sources of heterogeneity. METHODS: Studies were identified through database searches. Meta-analytic techniques were employed to aggregate data on lifetime comorbidity and to explore possible sources of heterogeneity. Funnel plots were used to detect publication bias. RESULTS: In clinical studies, AUDs affected more than one in three subjects with BD. Significant heterogeneity was found, which was largely explained by the geographical location of study populations and gender ratio of participants. AUDs affected more than one in five women and two in five men. CONCLUSION: AUDs are highly prevalent in BD. Our study revealed a substantial heterogeneity across studies. Further research including control groups is needed. Patients with BD should be assessed for current and previous AUDs. PMID- 24075634 TI - Dementia with Lewy bodies: a common condition in nursing homes? PMID- 24075635 TI - Past as prologue: applying enduring evidence to improve rehabilitative care. PMID- 24075636 TI - Delayed spinal epidural hematoma after epidural catheter removal with reinitiation of warfarin. PMID- 24075637 TI - Disturbance in venous outflow from the cerebral circulation intensifies the release of blood-brain barrier injury biomarkers in patients undergoing cardiac surgery. AB - OBJECTIVE: Disturbances in venous outflow from the cerebral circulation may result in brain injury. Severe increases in brain venous pressure lead to brain ischemia and, subsequently, brain edema and intracranial hemorrhages. The purpose of this study was to determine the effect of changes in jugular venous bulb pressure (JVBP) on plasma blood brain-barrier biomarkers concentration and disturbances in arteriovenous total and ionized magnesium (a-vtMg and a-viMg) in brain circulation in patients undergoing coronary artery bypass grafting surgery (CABG) with cardiopulmonary bypass (CPB). DESIGN: Prospective observational study. SETTING: Department of Cardiac Surgery at a Medical University Hospital. PARTICIPANTS: Ninety-two adult patients undergoing elective CABG with CPB under general anaesthesia were studied. METHODS: Central venous pressure (CVP) was measured using a pulmonary artery catheter. The right jugular vein was cannulized retrogradely for jugular venous bulb pressure (JVBP) measurement. Concentrations of plasma S100beta protein, matrix metalloproteinase 9 (MMP-9), creatine kinase isoenzyme BB (CK-BB) a-vtMg and a-viMg were measured as the markers of blood brain barrier dysfunction. All of them were analyzed in comparison with JVBP during surgery and the early postoperative period. RESULTS: Elevated JVBP was noted after CPB and after surgery. Its increase above 12 mmHg intensified release of S100beta, MMP-9 and CK-BB as well as disorders in a-vtMg and a-viMg. CVP correlated with JVBP, S100beta, and MMP-9. Moreover, JVBP correlated with S100beta and MMP-9. CONCLUSIONS: Cardiac surgery increased JVBP, and JVBP elevated above 12 mmHg intensified an increase in biomarkers of plasma blood brain barrier disruption. PMID- 24075638 TI - Real-time Doppler-based arterial vascular impedance and peripheral pressure-flow loops: a pilot study. AB - OBJECTIVE: Arterial pressure-flow loops and vascular impedance provide additional data that could be used to assess the hemodynamic effects of therapeutic interventions in anesthetized patients. To evaluate the utility of such an approach, the authors sought to design a device that combines flow waveforms from an esophageal Doppler probe and pressure waveforms from a peripheral artery to produce real-time pressure-flow loops and estimates of arterial vascular impedance. DESIGN: Prospective, cohort study. SETTING: Single center, university based teaching hospital. PARTICIPANTS: Patients undergoing surgery in whom the attending anesthesiologist had opted to place an esophageal Doppler probe and a peripheral arterial catheter for hemodynamic monitoring. INTERVENTIONS: This was a non-interventional study designed to record pressure-flow loops and arterial vascular impedance intraoperatively using a novel, noninvasive device. MEASUREMENTS AND MAIN RESULTS: Pressure-flow loops and arterial vascular impedance were measured noninvasively using radial artery pressure and descending thoracic aorta flow waveforms in real time. CONCLUSIONS: Real-time arterial vascular impedance and peripheral pressure-volume loops can be determined using available monitoring devices. Technical feasibility of this technology in patients is a crucial first step to permit meaningful evaluation of the clinical value of this approach for accurate determination of complex hemodynamic indices and, eventually, improvement of outcomes. PMID- 24075639 TI - Physiologic goal-directed therapy in the perioperative period: the volume prescription for high-risk patients. PMID- 24075640 TI - Mitral regurgitation: focusing on the cause rather than the effect. PMID- 24075641 TI - Three-dimensional echocardiographic assessment of the repaired mitral valve. AB - OBJECTIVE: This study examined the geometric changes of the mitral valve (MV) after repair using conventional and three-dimensional echocardiography. DESIGN: Prospective evaluation of consecutive patients undergoing mitral valve repair. TYPE OF HOSPITAL: Tertiary care university hospital. PARTICIPANTS: Fifty consecutive patients scheduled for elective repair of the mitral valve for regurgitant disease. INTERVENTIONS: Intraoperative transesophageal echocardiography. MEASUREMENTS: Assessments of valve area (MVA) were performed using two-dimensional planimetry (2D-Plan), pressure half-time (PHT), and three dimensional planimetry (3D-Plan). In addition, the direction of ventricular inflow was assessed from the three-dimensional imaging. MAIN RESULTS: Good correlations (r = 0.83) and agreement (-0.08 +/- 0.43 cm(2)) were seen between the MVA measured with 3D-Plan and PHT, and were better than either compared to 2D Plan. MVAs were smaller after repair of functional disease repaired with an annuloplasty ring. After repair, ventricular inflow was directed toward the lateral ventricular wall. Subgroup analysis showed that the change in inflow angle was not different after repair of functional disease (168 to 171 degrees) as compared to those presenting with degenerative disease (168 to 148 degrees; p<0.0001). CONCLUSIONS: Three-dimensional imaging provides caregivers with a unique ability to assess changes in valve function after mitral valve repair. PMID- 24075643 TI - Toxicity assessments with Daphnia magna of Guadipyr, a new neonicotinoid insecticide and studies of its effect on acetylcholinesterase (AChE), glutathione S-transferase (GST), catalase (CAT) and chitobiase activities. AB - Guadipyr is a novel neonicotinoid insecticide, developed by the China Agricultural University. This work investigated its aquatic toxicity on Daphnia magna. The acute immobilization test showed that guadipyr was slightly toxic to daphnids, with a 48 h EC50 of 13.01 mg/L. In addition, guadipyr significantly enhanced the acetylcholinesterase (AChE) and glutathione S-transferase (GST) activity (per gram of protein), but had no obvious impact on catalase (CAT) activity within 48 h. The 21 d chronic exposure of D. magna to guadipyr induced a significant decrease in body growth and reproduction; both share the same lowest observed effect concentration (LOEC) at 0.10 mg/L. In the 14 d chronic test, a significant increase in chitobiase activity in test media was observed at day 8 (days to the first breeding), while a significant decrease was observed from days 10 to 14, which might be due to the endocrine imbalance resulting from guadipyr stress. These results demonstrated that guadipyr can induce notable negative ecotoxicological impacts on the aquatic system in long-term exposure at a sub lethal dose. Further research in environmental behaviors is needed to regulate guadipyr use in the future. PMID- 24075644 TI - Effect of a glyphosate-based herbicide in Cyprinus carpio: assessment of acetylcholinesterase activity, hematological responses and serum biochemical parameters. AB - The objective of this study was to investigate the toxicity effects of acute and sublethal of Roundup(r) as a glyphosate-based herbicide on acetylcholinesterase (AChE) activity and several hematological and biochemical parameters of Cyprinus carpio. The LC50-96 h of Roundup(r) to C. carpio was found to be 22.19 ppm. Common carp was subjected to Roundup(r) at 0 (control), 3.5, 7 and 14 ppm for 16 days, and the AChE activity is verified in tissues of gill, muscle, brain and liver. After 5 days, a significant decrease was observed in the AChE activity of muscle, brain and liver tissues. Besides, a time- and dose-dependent increase in mean cell hemoglobin (MCH) and mean cell volume (MCV) was observed. In contrast, a significant decrease was found in the quantities of hemoglobin (Hb), hematocrit (HCT) and, red (RBC) and white (WBC) blood cell count. Also, the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) in Roundup(r) treated groups were significantly higher than the controlled group at experimental periods. However, the level of alkaline phosphatase (ALP) had a significant reduction behavior during the sampling days. It seems that the changes in hematological and biochemical parameters as well as AChE activity could be used as efficient biomarkers in order to determine Roundup(r) toxicity in aquatic environment. PMID- 24075642 TI - Detailed insight into the impact of postoperative neuropsychiatric complications on mortality in a cohort of cardiac surgery subjects: a 23,000-patient-year analysis. AB - OBJECTIVES: This study sought to evaluate the impact of postoperative delirium with/without cerebral ischemia on short- and long-term mortality in a large cohort of cardiac surgery patients. DESIGN: The study constituted a prospective cohort observation of patients following various cardiac surgery procedures. SETTING: The investigation was conducted in a single high-volume tertiary cardiac surgery center. PARTICIPANTS: Consecutive candidates for cardiac surgery (n = 8,792) from 2003 to 2008 were subjected to the following exclusion criteria: History of any psychiatric disorders, alcohol abuse and intake of psychoactive drugs and incomplete data. INTERVENTIONS: No additional interventions were performed, except for standard perioperative management. MEASUREMENTS AND MAIN RESULTS: 5,781 patients finally were assigned to cohorts depending on the presence of postoperative delirium with/without cerebral ischemia and then prospectively followed up over the median time of 46 months. Overall 30-day mortality in patients with delirium was 15.25%, including 6.43% of patients without and 38.46% of subjects with cerebral ischemia. After adjustment for more than 100 perioperative variables, short-term mortality was associated independently with delirium (OR = 3.735), stroke (OR = 5.698), hypertension (OR = 0.333), urgency of surgery (OR = 13.018), baseline plasma glucose and protein concentrations and blood transfusions (AUROC for the model 0.94). Long-term mortality in patients who developed delirium was 23.31%, including 15.2% of patients without and 44.62% of those with postoperative stroke. Long-term mortality independently corresponded with stroke (HR = 3.968), urgent surgery (HR = 27.643), baseline plasma glucose and protein concentrations, chronic obstructive pulmonary disease and blood transfusions. Impact of postoperative delirium was insignificant (p = 0.2). Compared to subjects with cerebral ischemia, death in patients only with delirium was less frequently of cardiovascular cause (p < 0.01). CONCLUSIONS: Delirium with/without cerebral ischemia significantly worsened the short-term prognosis. Stroke, yet not delirium, considerably increased the long-term mortality, especially of cardiovascular origin. PMID- 24075645 TI - Heterogeneity in metal binding by individual fluorescent components in a eutrophic algae-rich lake. AB - Dissolved organic matter (DOM) affects the toxicity, mobility and bioavailability of metals in aquatic environment. In this study, the interactions between two metals of environmental concern [Cu(II) and Fe(III)] with DOM in a euthrophic algae-rich lake (Lake Taihu, China), including dissolved natural organic matter (NOM) and algal extracellular polymeric substance (EPS), were studied using fluorescence excitation-emission matrix (EEM) quenching titration combined with parallel factor (PARAFAC) analysis. Obvious protein-like peaks were detected in algal EPS matrix, while both protein- and humic-like peaks can be found in NOM. PARAFAC analysis identified four fluorescent components, including one humic-, one tryptophan- and two tyrosine-like components, from 114 EEM samples. It was shown that fluorescent tyrosine- (log K(M) > 5.21) and humic-like substances (log K(M) > 4.84) in NOM fraction exhibited higher metal binding capacities than those in EPS matrix, while algal EPS was characterized with a high metal-tryptophan like substances affinity (log K(M) > 5.08). Moreover, for the eutrophic algae rich lakes, fluorescent tryptophan- and humic-like substances were responsible for Cu transportation, whereas the mobility of Fe would be related with the tyrosine-like substances. The results facilitate a further insight into the biogeochemical behaviors of metals in eutrophic algae-rich ecosystems as well as other related aquatic environments. PMID- 24075646 TI - Transition from an autoimmune-prone state to fatal autoimmune disease in CCR7 and RORgammat double-deficient mice is dependent on gut microbiota. AB - Autoimmunity is associated with a strong genetic component, but onset and persistence of clinically apparent autoimmune diseases often require an additional environmental trigger. The balance between immunity and tolerance is regulated by numerous molecular factors including nuclear hormone and homeostatic chemokine receptors. The nuclear hormone receptor RORgammat and the chemokine receptor CCR7 are both essentially involved in functional lymphoid organogenesis and maintenance of lymphocyte homeostasis. Lack of one or the other impairs thymic T cell development and alters T cell homeostasis. Mice deficient for both, Ccr7(-/-)Rorgammat(-/-), succumbed early to acute destructive inflammation, characterized by massive recruitment of inflammatory leukocytes, pro-inflammatory cytokine and autoantibody production, and wasting disease. Antibiotic-treatment of mice before disease onset reduced the overall gut microflora and abrogated the development of fatal mucosal inflammation. Hence, commensal bacteria and a confined tissue-specific inflammatory milieu serve as complementary trigger to initiate the lethal pathophysiologic process in Ccr7(-/-)Rorgammat(-/-) mice. PMID- 24075647 TI - Role of the intestinal microbiome in liver disease. AB - The liver integrates metabolic outcomes with nutrient intake while preventing harmful signals derived from the gut to spread throughout the body. Direct blood influx from the gastrointestinal tract through the portal vein makes the liver a critical firewall equipped with a broad array of immune cells and innate immune receptors that recognize microbial-derived products, microorganisms, toxins and food antigens that have breached the intestinal barrier. An overwhelming amount of evidence obtained in the last decade indicates that the intestinal microbiota is a key component of a wide variety of physiological processes, and alterations in the delicate balance that represents the intestinal bacterial communities are now considered important determinants of metabolic syndrome and immunopathologies. Moreover, it is now evident that the interaction between the innate immune system and the intestinal microbiota during obesity or autoimmunity promotes chronic liver disease progression and therefore it might lead to novel and individualized therapeutic approaches. In this review, we discuss a growing body of evidence that highlights the central relationship between the immune system, the microbiome, and chronic liver disease initiation and progression. PMID- 24075648 TI - Components of the metabolic syndrome are negative predictors of weight loss in obese children with lifestyle intervention. AB - BACKGROUND AND AIMS: Insulin resistance has been proposed to be associated with weight gain in obesity. Therefore, we analyzed the impact of insulin resistance and its associated cardiovascular risk factors (CRFs) summarized in the Metabolic Syndrome (MetS) on change of weight status in obese children. METHODS: We analyzed 484 obese children who had participated in a lifestyle intervention and 533 obese children without lifestyle intervention. The changes of BMI-SDS in the time period of 1-year were related to baseline fasting insulin resistance index HOMA, blood pressure, waist circumference, waist-to-height ratio, lipids, uric acid, and HbA1c. RESULTS: In contrast to obese children without lifestyle intervention, BMI-SDS decreased and the majority of CRFs improved significantly in obese children with lifestyle intervention. Age, BMI, waist circumference, waist-to-height ratio, blood pressure, uric acid, triglycerides, and HOMA were negatively significantly related to reduction of BMI-SDS in children with lifestyle intervention. In multiple linear regression analysis adjusted for gender, pubertal stage, and treatment center (R2 = 0.26), waist circumference (r = -0.016 [confidence interval -0.019 up to -0.013], p < 0.001) was the strongest negative predictor of weight loss in children with lifestyle intervention. In children without lifestyle intervention, we did not find significant relationships between change of BMI-SDS and CRFs including insulin resistance in multiple regression analysis. CONCLUSIONS: Insulin resistance and components of the MetS were associated negatively with weight loss in lifestyle intervention. Waist circumference at baseline was the strongest negative predictor of weight loss suggesting that obese children with abdominal fat distribution need more intensive interventions. This study is registered at clinicaltrials.gov (NCT00435734). PMID- 24075649 TI - CT-perfusion time-maps likely disclose the earliest imaging signs of posterior reversible encephalopathy syndrome (PRES). PMID- 24075650 TI - In memory of Vincent G. Kokich, Editor-in-Chief, 2011-2013. PMID- 24075651 TI - Authors' response. PMID- 24075652 TI - Meta-analysis 101. PMID- 24075653 TI - The null hypothesis. PMID- 24075654 TI - Authors' response. PMID- 24075655 TI - Ethics in leadership personified. PMID- 24075657 TI - Assessment of the effect of combined multimedia and verbal information vs verbal information alone on anxiety levels before bond-up in adolescent orthodontic patients: a single-center randomized controlled trial. AB - INTRODUCTION: Despite the high prevalence of dental anxiety in children, there is little research examining anxiety before orthodontic procedures. This parallel group randomized controlled trial assessed whether provision of additional multimedia information regarding the bond-up procedure affected anxiety in adolescent orthodontic patients. The effects of sex, ethnicity, and age were also investigated. METHODS: Participants were recruited from the orthodontic department of the Eastman Dental Hospital, University College London Hospitals Foundation Trust, in the United Kingdom; all were 10 to 16 years of age, with no history of orthodontic treatment, and patient assent and parental consent were obtained. The participants were randomized into control (n = 45) and intervention (n = 45) groups using a random number table. Both groups were given verbal information regarding the bond-up procedure, and the intervention group was additionally given a DVD showing a bond-up. Anxiety was assessed in the department immediately before the bond-up using the State-Trait Anxiety Inventory for Children, with state anxiety as the primary outcome measure. The researchers were unaware of group allocations while enrolling patients, scoring questionnaires, and analyzing data. RESULTS: A statistically significant difference was found between groups, with a difference in scores of 2 (95% confidence interval for the difference = 0.15 to 3.85). The median state anxiety was 32 in the control group (n = 42) and 30 in the intervention group (n = 43; P = 0.012). Sex, ethnicity, and age did not significantly affect anxiety. No harmful effects were noted. CONCLUSIONS: Additional information reduces anxiety levels, but other methods could be more cost-effective than the DVD. Sex, ethnicity, and age did not statistically affect the anxiety levels. PMID- 24075658 TI - Condylar position assessed by magnetic resonance imaging after various bite position registrations. AB - INTRODUCTION: In this study, we evaluated the reliability and validity of 3 bite registrations in relation to condylar position in the glenoid fossae using magnetic resonance imaging in a symptom-free population. METHODS: Nineteen subjects, 14 men and 5 women (ages, 20-39 years) without temporomandibular disorders were examined. Three bite registrations were taken and evaluated on each subject: centric occlusion, centric relation, and Roth power centric relation. The differences in condyle position among the 3 bite registrations were determined for the left and right condyles: centric occlusion-centric relation, centric occlusion-Roth power centric relation, and centric relation-Roth power centric relation for each plane of space. RESULTS: The results indicated that (1) all measurements collected had large standard deviations and ranges with no statistical significance, and (2) of the 19 subjects and 38 condyles assessed, 33 condyles (87%) were concentric in an anteroposterior plane. In the transverse anatomic plane, all condyles were concentric. CONCLUSIONS: The clinical concept of positioning the condyles in specific positions in the fossae with various bite registrations as a preventive measure for temporomandibular disorders and as a diagnosis and treatment planning tool is not supported by this study. PMID- 24075659 TI - Pulp vitality and histologic changes in human dental pulp after the application of moderate and severe intrusive orthodontic forces. AB - INTRODUCTION: Orthodontic forces produce a series of changes in dental pulp. However, no one has attempted to investigate the incidence of pulp necrosis after orthodontic therapy in the clinic. In this study, we aimed to investigate pulp vitality and histologic changes after the application of moderate and severe intrusive forces. METHODS: Twenty-seven adolescent patients were assigned to 1 of 3 groups: the control group of 3 subjects; the moderate-force group, with 12 subjects who received a 50-g force to the first premolars bilaterally; and the severe-force group, with 12 subjects who received a 300-g force. The forces were applied for 1, 4, 8, or 12 weeks. An electric pulp tester was used to test for vitality, and teeth that did not respond to the electric pulp tester were subsequently tested thermally with a stick of heated gutta-percha. RESULTS: The teeth with a negative response to the electric pulp tester still responded to the thermal test. We found odontoblast disruption, vacuolization, and moderate vascular congestion in both force groups, but no necrosis was observed. Pulp stones were formed only in the severe-force group. CONCLUSIONS: Dental pulp still has vitality after intrusive treatment with different forces. These data provide new insights into the effects of intrusive orthodontic forces. PMID- 24075660 TI - Effect of parathyroid hormone on experimental tooth movement in rats. AB - INTRODUCTION: The aim of this study was to investigate the effect of parathyroid hormone injection on experimental tooth movement in rats. METHODS: Sixty male Wistar rats were randomly divided into 2 groups. Their maxillary right first molars were moved mesially with nickel-titanium closed-coil springs. The experimental group received daily subcutaneous injections of parathyroid hormone at a dose of 4 MUg per 100 g of body weight for 12 days, and the control group received vehicle injections. The results were evaluated by intraoral measurements and by hematoxylin and eosin, tartrate-resistant acid phosphatase, and immunohistochemistry staining. RESULTS: The tooth movement and osteoclast numbers were significantly increased in the parathyroid hormone group compared with the control group. The expressions of receptor activator of nuclear factor kappa B ligand and insulin-like growth factor-I were significantly stimulated in the parathyroid hormone group. CONCLUSIONS: The data suggest that short-term parathyroid hormone injection might be a potential method for accelerating orthodontic tooth movement by increasing the alveolar bone turnover rate. PMID- 24075661 TI - Quantification of patient compliance with Hawley retainers and removable functional appliances during the retention phase. AB - INTRODUCTION: The success of retention with removable retainers is highly dependent on efficient patient compliance. The aim of this study was to quantify patient compliance with removable retainers using microelectronic wear-time documentation during the retention phase. METHODS: One hundred patients, between 13 and 20 years of age, were retained with removable Hawley retainers and functional appliance retainers after successful multibracket treatment at the University Hospital of Tubingen, Germany, and in 4 private practices in Germany. Microsensors were incorporated into the orthodontic retainers by polymerization, and daily wear time was documented in 15-minute intervals during the retention phase for up to 15 months. Patient compliance was quantified with wear-time documentation. Additionally, the influences of age, sex, place of treatment, device type, and health insurance status on compliance were determined and statistically evaluated. RESULTS: Most study participants complied with the prescribed wear time of 8 hours or more per day. Combined patient data indicated a median wear time of 7.0 hours per day over the evaluation period. Wear-time documentation showed either regular or irregular patterns of compliance. Initial compliance did not usually alter over the retention phase. Compliance was not influenced by device type, but age, sex, place of treatment, and insurance status produced changes in the median wear time of up to 50%. CONCLUSIONS: Electronic wear-time documentation of patients' compliance is an easily comprehensible measurement that allows orthodontists to examine the patient's contribution to the success of retention and personalize treatment accordingly. Place of treatment and health insurance status are more closely associated with compliance than are basic patient demographics. PMID- 24075662 TI - Influence on smile attractiveness of the smile arc in conjunction with gingival display. AB - INTRODUCTION: Many variables affecting smile esthetics and attractiveness have been evaluated. However, the influence of the interaction of several variables is not as well known. Furthermore, patients and dental professionals might view smile esthetics differently. Therefore, the purpose of this research was to evaluate the influence of the smile arc in conjunction with the amount of maxillary gingival display on the perception of smile attractiveness by orthodontists, dentists, and laypersons. METHODS: A frontal intraoral photograph of ideally aligned teeth was modified using image-processing software. Photos showing 7 smile arcs, from flat to vaulted, were obtained, and these were combined with photos showing 4 different amounts of maxillary gingival display. The attractiveness of the 28 images of different smiles was evaluated by 3 groups of raters (orthodontists, dentists, and laypersons), each consisting of 70 persons. RESULTS: Both smile arc (P <0.05) and gingival display amount (P <0.001) had statistically significant influences on the perception of smile attractiveness. Smile attractiveness scores with reference to gingival display amount showed a statistically significant (P <0.001) difference between the rater groups. A significant (P <0.05) interaction between smile arc and gingival display amount was observed. CONCLUSIONS: Examining other components influencing the perception of smile attractiveness might help clinicians develop more satisfying treatment plans for their patients. PMID- 24075663 TI - Load system of segmental T-loops for canine retraction. AB - INTRODUCTION: The orthodontic load system, especially ideal moment-to-force ratios, is the commonly used design parameter of segmental T-loops for canine retraction. However, the load system, including moment-to-force ratios, can be affected by the changes in canine angulations and interbracket distances. We hypothesized that clinical changes in canine position and angulation during canine retraction will significantly affect the load system delivered to the tooth. METHODS: The load systems of 2 T-loop groups, one for translation and the other for controlled tipping, from 9 bilateral canine retraction patients were made to the targeted values obtained from finite element analyses and validated. Each loop was tested on the corresponding maxillary dental cast obtained in the clinic. The casts were made before and after each treatment interval so that both initial and residual load systems could be obtained. The pretreatment and posttreatment interbracket distances were recorded for calculating interbracket distance changes. RESULTS: As the interbracket distances decreased, the average retraction-force drop per interbracket distance reduction was 36 cN/mm, a 30% drop per 1 mm of interbracket distance decrease. The average antitipping-moment drops per interbracket distance reductions were 0.02 N-mm per millimeter for controlled tipping and 1.4 N-mm per millimeter for translation, about 0.6% and 17% drops per 1 mm of interbracket decrease, respectively. Consequently, the average moment-to-force ratio increases per 1 mm of interbracket distance reduction were 1.24 mm per millimeter for controlled tipping and 6.34 mm per millimeter for translation. There was a significant residual load, which could continue to move the tooth if the patient missed the next-scheduled appointment. CONCLUSIONS: Clinical changes in canine position and angulation during canine retraction significantly affect the load system. The initial planned moment-to force ratio needs to be lower to reach the expected average ideal value. Patients should be required to follow the office visit schedule closely to prevent negative effects because of significant moment-to-force ratios increases with time. PMID- 24075664 TI - Impact of bisphosphonate drug burden in alveolar bone during orthodontic tooth movement in a rat model: a pilot study. AB - INTRODUCTION: The aim of this pilot study was to investigate the effect of long term bisphosphonate drug use (bone burden) on orthodontic tooth movement in a rat model. METHODS: Sprague Dawley rats were used for orthodontic protraction of the maxillary first molars with nickel-titanium coil springs and temporary anchorage devices as anchorage. Four groups of 5 rats each were included in the study; the first 2 groups were dosed with alendronate or a vehicle during concurrent orthodontic tooth movement. The third and fourth groups were pretreated for 3 months with alendronate or vehicle injections, and bisphosphonate drug treatment was discontinued before orthodontic tooth movement. Tooth movement measurements were obtained at 0, 4, and 8 weeks using high-resolution in-vivo microcomputed tomography, and the tissues were analyzed with histology and dynamic labeling of bone turnover. RESULTS: Appreciable tooth movement was achieved during the 8-week duration of this study with nickel-titanium coil springs and temporary anchorage devices. Both bisphosphonate treatment groups exhibited reduced tooth movement compared with the vehicle-dosed controls with a tendency toward more severe reduction in the bisphosphonate predosed group. Concurrent dosing of the bisphosphonate drug resulted in 56% and 65% reductions in tooth protraction at the 4-week and 8-week times, respectively. The impact of bisphosphonate bone burden in retarding tooth movement was even greater, with 77% and 86% reductions in tooth movement at 4 and 8 weeks, respectively. CONCLUSIONS: In this study, we used a robust rat model of orthodontic tooth movement with temporary anchorage devices. It has provided evidence that the bone burden of previous bisphosphonate use will significantly inhibit orthodontic tooth movement. PMID- 24075666 TI - Etiquette in scientific publishing. AB - Publishing a scientific article in a journal with a high impact factor and a good reputation is considered prestigious among one's peer group and an essential achievement for career progression. In the drive to get their work published, researchers can forget, either intentionally or unintentionally, the ethics that should be followed in scientific publishing. In an environment where "publish or perish" rules the day, some authors might be tempted to bend or break rules. This special article is intended to raise awareness among orthodontic journal editors, authors, and readers about the types of scientific misconduct in the current publishing scenario and to provide insight into the ways these misconducts are managed by the Committee of Publishing Ethics. Case studies are presented, and various plagiarism detection software programs used by publishing companies are briefly described. PMID- 24075665 TI - Epigenetic influence of KAT6B and HDAC4 in the development of skeletal malocclusion. AB - INTRODUCTION: Genetic influences on the development of malocclusion include heritable effects on both masticatory muscles and jaw skeletal morphology. Beyond genetic variations, however, the characteristics of muscle and bone are also influenced by epigenetic mechanisms that produce differences in gene expression. We studied 2 enzymes known to change gene expressions through histone modifications, chromatin-modifying histone acetyltransferase KAT6B and deacetylase HDAC4, to determine their associations with musculoskeletal variations in jaw deformation malocclusions. METHODS: Samples of masseter muscle were obtained from subjects undergoing orthognathic surgery from 6 malocclusion classes based on skeletal sagittal and vertical dysplasia. The muscles were characterized for fiber type properties by immunohistochemistry, and their total RNA was isolated for gene expression studies by microarray analysis and quantitative real-time polymerase chain reaction. RESULTS: Gene expressions for fast isoforms of myosins and contractile regulatory proteins and for KAT6B and HDAC4 were severalfold greater in masseter muscles from a patient with a deepbite compared with one with an open bite, and genes related to exercise and activity did not differ substantially. In the total population, expressions of HDAC4 (P = 0.03) and KAT6B (P = 0.004) were significantly greater in subjects with sagittal Class III than in Class II malocclusion, whereas HDAC4 tended to correlate negatively with slow myosin type I and positively with fast myosin gene, especially type IIX. CONCLUSIONS: These data support other published reports of epigenetic regulation in the determination of skeletal muscle fiber phenotypes and bone growth. Further investigations are needed to elucidate how this regulatory model might apply to musculoskeletal development and malocclusion. PMID- 24075667 TI - Asymmetrical distalization of maxillary molars with zygomatic anchorage, improved superelastic nickel-titanium alloy wires, and open-coil springs. AB - INTRODUCTION: In nongrowing patients with skeletal Class II malocclusion, premolar extraction or maxillary distalization can be used as camouflage treatment. Zygomatic anchorage enables distalization in uncooperative or noncompliant patients. We describe 1 such procedure in a 24-year-old woman. METHODS: We used novel improved superelastic nickel-titanium archwires combined with nickel-titanium open-coil springs to provide a constant and continuous low force to the dentition. RESULTS: We were able to successfully eliminate the protrusive profile and correct the Class II molar relationship using this system of zygomatic anchorage. The posterior occlusal relationships were improved to achieve Class I canine and molar relationships on both sides, and ideal overbite and overjet relationships were established. Facial esthetics was improved with decreased protrusion of the upper and lower lips. CONCLUSIONS: The method used here is a promising alternative to traditional distalization techniques and might offer an effective and simple means of distalizing maxillary molars in uncooperative patients. PMID- 24075668 TI - Treatment and retreatment of a patient with a severe anterior open bite. AB - An 8-mm anterior and posterior open bite caused by a tongue rest posture habit was closed in a 25-year-old man by means of mandibular soldered tongue spurs and without orthognathic surgery. All maxillary and mandibular first molars were extracted, and the spaces were closed. Inappropriate retention protocol allowed for relapse in a 6-month period. A new 1-year orthodontic retreatment was conducted; after an appropriate retention protocol, the outcomes of treatment were significantly improved. PMID- 24075669 TI - Six-year follow-up of maxillary anterior rehabilitation with forced orthodontic extrusion: achieving esthetic excellence with a multidisciplinary approach. AB - Orthodontic extrusion with multidisciplinary treatment can provide predictable outcomes in selected situations, reducing the costs and the adaptation times of gingival tissues after implant integration. Forced orthodontic extrusion is strongly related to interactions of teeth with their supportive periodontal tissues. This article reports a case of orthodontic extrusion of the maxillary incisors for later implant rehabilitation in a patient with periodontal disease. Slow forces were applied for 14 months. After this time, the teeth were extracted, and the implants were placed on the same day. Also in the same session, the provisional crown was fabricated for restoration of the anterior maxillary interdental papillae loss and for gingival contouring. Clinical and radiographic examinations at the 6-year follow-up showed successful tooth replacement and an improved esthetic appearance achieved by this multidisciplinary treatment. The decision to perform orthodontic extrusion for implant placement in adult patients should be multidisciplinary. PMID- 24075670 TI - Mandibular condylar pseudocyst: an introduction to the orthodontist. AB - The aims of this article are to introduce mandibular condylar pseudocysts to orthodontists, present 2 relevant case reports, and discuss possible differential diagnoses. Condylar pseudocyst is a radiologic variant of pterygoid fovea, which is the site of insertion of the lateral pterygoid muscle to the head of the mandibular condyle. A pathognomonic picture of a solitary well-defined radiolucency with radiopaque borders, located on the anterior aspect of the condyle in an asymptomatic orthodontic patient, is characteristic. PMID- 24075672 TI - Litigation and legislation: getting clear on clearance. PMID- 24075671 TI - Assessment of the accuracy and reliability of new 3-dimensional scanning devices. AB - INTRODUCTION: The primary objective of this study was to assess the accuracy and the reliability of the SureSmile OraScanner (Orametrix, Richardson, Tex) by comparing it with other desktop 3-dimensional scanners: VIVID910 (Konica Minolta, Tokyo, Japan) and R700 (3Shape, Copenhagen, Denmark). A laser-based scanner, the SLP250 Laser Probe (Laser Design, Detroit, Mich), served as the gold standard. METHODS: Five sets of dental casts were used. First, the accuracy of each scanner was studied by comparing the 3-dimensional models created by OraScanner, VIVID910, and R700 with the gold standard 3-dimensional models of the SLP250. To assess the reliability of the 3-dimensional models, the shell/shell deviation of each model was calculated based on the same surface-based registrations for all 5 sets of dental casts. RESULTS: OraScanner, VIVID910, and R700 were sufficiently accurate when compared with the gold standard. In the assessment of reliability, there were no significant differences between all comparisons. CONCLUSIONS: The results showed that the OraScanner system has a sophisticated algorithm for 3 dimensional surface registration and can be used to generate accurate and reliable 3-dimensional digital models for use by clinicians. PMID- 24075673 TI - Analyzing longitudinal orthodontic data. Part 2: nonlinear growth models. PMID- 24075674 TI - A study of recurrence and death from papillary thyroid cancer with 27 years of median follow-up. AB - BACKGROUND: Although recurrence and death can occur in patients with papillary thyroid cancer (PTC) several years after being diagnosed, the necessary duration of follow-up for these patients remains unclear. METHODS: This was a single institution, retrospective review of 269 patients with PTC. Cox proportional hazards model and Kaplan-Meier curves were used to identify risk factors for recurrence and death. Risk predictors included age, sex, radiation exposure history, extent of operation, radioactive iodine treatment, follicular variant of PTC (FVPTC), extrathyroidal invasion, multifocality, TNM status, and stage. RESULTS: Median follow-up was 27 years. Of 269 patients, 180 (66%) were female, and 196 (73%) were <=45 years of age. Recurrence and cancer-specific death rates were 28% and 9%, respectively. Time to recurrence (+/-SD) was 8.1 (+/- 8.3) years and to cancer-specific death was 9.0 (+/- 11.0) years; however, 11% of recurrences and 17% of deaths occurred after 20 years. Risk factors for recurrence were older age, FVPTC, T4 tumors, cervical lymph node involvement, metastases, and stage >= 4a. Predictors of death from PTC were older age, metastases, and stage >= 3. CONCLUSION: Both recurrences and death from PTC can occur more than 30 years after being treated, thus lifelong follow-up of patients with PTC is necessary. PMID- 24075675 TI - Degradation of acetochlor by consortium of two bacterial strains and cloning of a novel amidase gene involved in acetochlor-degrading pathway. AB - Two bacterial strains Sphingobium quisquiliarum DC-2 and Sphingobium baderi DE-13 were isolated from activated sludge. Acetochlor was transformed by S. quisquiliarum DC-2 to a transitory intermediate 2-chloro-N-(2-methyl-6 ethylphenyl)acetamide (CMEPA), which was further transformed to 2-methyl-6 ethylaniline (MEA), and MEA could not be degraded by strain DC-2. S. baderi DE 13, incapable of degrading acetochlor, showed capability of degrading MEA to an intermediate 2-methyl-6-ethylaminophenol (MEAOH). MEAOH was further transformed to 2-methyl-6-ethylbenzoquinoneimine (MEBQI), which was mineralized by strain DE 13. A gene, cmeH, encoding an amidase that catalyzed the amide bond cleavage of CMEPA was cloned from strain DC-2. CmeH was expressed in Escherichia coli BL21 and homogenously purified using Ni-nitrilotriacetic acid affinity. CmeH efficiently hydrolyzed CMEPA and other important herbicide, such as propanil, fenoxaprop-p-ethyl and clodinafop-propargyl. PMID- 24075676 TI - [Family practice centered care in Baden-Wurttemberg: is it successful in overcoming the organized irresponsibility?]. PMID- 24075677 TI - [Family doctor-centred care in Baden-Wuerttemberg: concept and results of a controlled evaluation study]. AB - BACKGROUND AND RESEARCH QUESTION: Pursuant to Section 73b, volume V of the German Social Security Code (SGB V), the agreement on family doctor-centred care (HzV), which went into effect in Baden-Wuerttemberg on July 1, 2008, provides for spatially inclusive and comprehensive medical coverage. The most important elements of the agreement are: the voluntary registration of family practices and patients, the strengthening of the coordinative function of family practices, the fulfilment of certain training, quality and qualification requirements, the standardised remuneration system and the use of specified practice software for billing and the prescription of drugs. The aim of this complex intervention is to strengthen family medicine, improve health care, in particular for patients with chronic disease, and to limit primary health care costs while improving its quality wherever possible. This first controlled nationwide evaluation examines the question whether these objectives were met in the early phase (2008 to 2011) and, if so, to what extent. METHOD: Four work packages were defined: 1. differences in health care processes (utilisation, contact to specialists, hospitalisations, drug prescriptions); 2. developments in practice teams and of patient satisfaction; 3. deployment of specially trained health care assistants in family practices (VERAH); 4. implementation of the DEGAM (German Society of General Practice and Family Medicine) heart failure guideline. To the extent that it was possible to use the statutory health insurance company AOK Baden Wuerttemberg's routine data, an adjusted comparison of the target variables was made for HzV- and non-HzV-insured patients between the first and second or between the third and fourth quarters of 2008, and between the first and second or third and fourth quarters of 2010. RESULTS: HzV participants were older, had a higher disease burden (Charlson Index 1.45 vs. 1.19), and were attended to more intensively than patients receiving routine care (1.7 more contacts with the family doctor per half-year). The number of non-referred contacts to specialists fell by 12.5 %. An increase in the number of referrals and hospitalisations was not observed. Participation in structured treatment programmes was substantially higher, e.g. 15 % vs. 7.5 % (non-HzV) in DMP diabetes mellitus Type 2. In the HzV, the rise in medication costs due to family physician prescriptions (ignoring the effect of discount agreements) was lower by 2.5 %, and the me-too rate was significantly lower. Higher remuneration contributed to greater satisfaction among HzV physicians despite the perceived increase in the workload. In a survey of 2,535 patients HzV participants showed a high rate of patient satisfaction overall, and physical examinations and services aimed at preventing illness were regarded particularly favourably. A survey of 294 VERAH showed that they more often accepted patient-related tasks such as home visits, geriatric assessments, patient training, and vaccination and preventive management. Family physicians were prepared to delegate responsibilities and, as a result, felt disburdened. In accordance with the latest DEGAM guideline patients with heart failure enjoyed an improvement to an overall high level in their drug therapies with ACE inhibitors, AT1 antagonists and beta blockers. Further improvement resulting from medical quality circles and training was not observed. DISCUSSION AND CONCLUSIONS: The results confirm the findings of international studies: in particular, HzV benefits patients with chronic disease, and patients receive improved health care when they participate in the Baden-Wuerttemberg HzV. All four evaluation modules reveal that changes towards the intended direction are taking place. Family doctors assumed more responsibility for coordination. These findings reflect the early start-up phase and the development phase of HzV in Baden-Wuerttemberg. These effects, together with those of other prioritised topics, will be continuously monitored as part of an accompanying evaluation process. PMID- 24075678 TI - [Evaluation of family doctor centred medical care based on AOK routine data in Baden-Wurttemberg]. AB - The agreement on family-doctor centred care (Hausarztzentrierte Versorgung, "HzV") pursuant to Sect. 73b, Volume V of the German Social Security Code became effective in Baden-Wuerttemberg, Germany, on July 1(st), 2008. This complex intervention, which is voluntary for both family doctors and patients, aims to strengthen the coordinative function of family practices. As a result, this intervention is believed to increase the quality of medical health care for persons insured - in the medium to long-term - and thereby, ideally, to additionally save expenses. Working package 1 was one out of a total of four working packages and focused on the evaluation of potential intervention effects of the HzV intervention based on the analyses of AOK routine data in Baden Wuerttemberg. A total of 1.44 million insured persons were eligible for the present analyses. Insured adults voluntarily participating in the family doctor centred health care intervention (HzV insured persons: n=580,924 in the intervention group) of the AOK were compared to those not participating in this intervention (non-HzV insured persons: n=862,237 in the control group). For both HzV and non-HzV insured persons, a comparison of each outcome of interest (encounters with family doctors, encounters with specialists, rate of hospitalisations, duration of hospitalisations, rate of re-hospitalisations, costs of pharmacotherapy, rate of polypharmacy, rate of Me-Too pharmaceuticals) was conducted for quarters 3 and 4 of 2008 as well as for quarters 3 and 4 in 2010. Both groups of insured persons differed in that they either participated in the HzV intervention between January 1, 2009 and June 30, 2011 or not. Before January 1, 2009 individuals in both groups did not participate in the HzV intervention. This design allowed for both longitudinal and cross-sectional comparisons. Moreover, the design implicitly controlled for potential seasonal bias. In order to adjust for relevant covariates (insured persons' age, gender, nationality, insurance state, morbidity), multivariate multilevel regression models were developed and applied. On average, HzV insured persons were about 3 years older (56.2 +/- 27.3 vs. 53.1 +/- 18.4 years) and had higher levels of comorbidity (Charlson Comorbidity Index: 1.45 +/- 1.86 vs. 1.19 +/- 1.71). No significant differences in terms of rate and duration of hospitalisations were observed. The same applied to the number of rehospitalisations within 30 days. After adjustment for covariates, however, an increase in visits to the respective family doctor of 38% was found in the intervention group. Moreover, a decrease of encounters to specialists with and without referrals from family doctors could be observed (-29.8 % and -12.5%, respectively). Interestingly, even costs of pharmacotherapy, polypharmacy and prescriptions of Me-Too drugs were statistically significantly lower or less frequent, respectively, in the group of HzV insured persons. In conclusion, besides the observed associations in terms of pharmacotherapy, the HzV intervention appears to have advantageous effects in terms of family doctor centred health care. PMID- 24075679 TI - [How chronically ill patients evaluate their care: results of an evaluation study of the family doctor-centred health care model]. AB - Considering the demographic development models for primary care have to be focused on chronic illness care especially. The so called "Hausarztzentrierte Versorgung" (HzV) in Baden-Wuerttemberg constitutes such a model of an implementation of family doctor-centred health care. For evaluation purposes the perspective of patients is of particular interest. Therefore the aim of this study was to analyse how chronically ill patients assess their medical care. Altogether 53 primary care practices in Baden-Wuerttemberg took part in a patient survey. The quality of chronic illness care from the patients' perspective was assessed by means of the PACIC short form. Furthermore the general satisfaction with care as well as sociodemographic characteristics were determined. For analysis two different groups were regarded: HzV-doctor and HzV-patient with a chronic condition (group 1) and non-HzV-doctor and non-HzV-patient with a chronic condition (group 2). Altogether 2,535 patients were recruited for the survey (response rate 47.8%). Out of these, 836 patients could be assigned to group 1 and 319 patients could be assigned to group 2. Patients in both groups were very satisfied with their care. The patients in group 1 stated more frequently that they received a written treatment plan from their general practitioner and that they were asked about their state of health when leaving the practice. Overall satisfaction was positively associated with organisation of care (beta= 0.484), support in difficult situations (beta= 0.171) and information on the usefulness of consulting other doctors (beta= 0.163) with an explained variation of R(2)=0.459. Irrespective of their group affiliation patients rate the medical care of their chronic condition very positively. Especially the assessment of the quality of care from the perspective of different patient groups (HzV participants and non-HzV participants) could contribute essentially as a feedback for physicians concerning the implementation of the main contents of the HzV for participating physicians. PMID- 24075680 TI - [Evaluating the deployment of VERAHs in family doctor-centred health care in Baden-Wuerttemberg]. AB - BACKGROUND: The contract covering family doctor-centred health care (HzV) in Baden-Wuerttemberg supports and remunerates the deployment of specially trained health care assistants (VERAHs). It is as yet unknown to what extent VERAHs are actually deployed in HzV, what the focus of their work is, what changes and shifts in responsibility have resulted in the practice team, and whether they have relieved the burden on family doctors. METHOD: A full survey of all VERAHs in HzV practices in Baden-Wuerttemberg was conducted using a questionnaire (response rate over 32 %, N = 294). The questions aimed to gather information on how often and where VERAHs were deployed and on observed changes in their fields of responsibility. The family doctors employing VERAHs also received a questionnaire containing questions related to the changes observed, and additional questions on the delegation of responsibilities to VERAHs. RESULTS: To an increasing extent, VERAHs take on responsibilities that directly involve the patient, such as home visits agreed on with the doctor, vaccination and drug management, wound management and case management. Thus they take on tasks traditionally reserved for doctors. Both family doctors and VERAHs said that patient health care has improved and that the use of VERAHs helps doctors save time. CONCLUSIONS: The deployment of VERAHs in family doctor-centred health care leads to the redistribution of responsibilities in the practice and thus relieves physician burden. Chronically ill patients benefit from continuous care and an additional contact person. Health care assistants benefit from new career options. PMID- 24075681 TI - [Guideline compliance in the treatment of patients with chronic heart failure through family doctor-centred health care: results of an evaluation study]. AB - PROBLEM: Family doctor centred health care (German abbreviation: HzV) agreements in Baden-Wuerttemberg provides that every year the strategies and results of at least two high-quality guidelines shall be discussed and worked on in quality circles. In this regard, the 'heart failure' guideline by the German Society of General Practice and Family Medicine (DEGAM) is especially important due to the high treatment costs and the continuously increasing prevalence of this medical condition. Another specified objective of the HzV agreements is to increase the DMP participation rate. The study addressed two questions: Is the medical care provided to patients with chronic heart failure who are being treated under HzV more compliant with guidelines than routine care? Does further improvement result from working on the guidelines in quality circles? METHODS: Routine data were provided by the AOK Baden-Wuerttemberg statutory health insurance company. Patients with heart failure receiving treatment under an HzV agreement (HzV group) were compared with patients receiving routine care (control group) with regard to quality of care eight months before and eight months after working on the guideline on heart failure in quality circles. Primary endpoints were the prescription of ACE inhibitors, AT1 antagonists and beta blockers in accordance with guidelines. Adjustment for various covariates was done by means of multivariate multilevel regression. RESULTS: Data were available for 3,667 practices [1,295 HzV practices; 2,158 non-HzV practices]. After applying validated diagnosis criteria, 16,584 patients were included in the intervention group and 28,992 in the control group. The HzV group received significantly better care in terms of the primary endpoint "prescription of ACE inhibitors or AT1 antagonists" (73.1 % vs. 69.3 % of the patients received ACE inhibitors or AT1 antagonists at T0 (OR 1.40; 95% CI [1,25; 1,57]; p < .001). 54.2 % vs. 52.3 % of the patients received beta blockers at T0 (not significant after adjustment, p = .260). No further improvement could be demonstrated to result from working on guidelines in quality circles. DISCUSSION AND CONCLUSION: The treatment of HzV patients with chronic heart failure is more compliant with guidelines than that of patients receiving routine care. Quality of care was already high at the beginning, and working on guidelines in quality circles had no noticeable effect. The increased DMP participation rate, which is one of the specified objectives of the HzV agreements, appears to have a mediation effect. PMID- 24075682 TI - [Screening for diabetic retinopathy in type 2 diabetes: a critical review of an annual routine]. AB - BACKGROUND: The German diabetes guideline published in 2010 recommends an annual retinopathy screening for all type 2 diabetics. Patients' and physicians' questions about the need for this routine procedure prompted our critical review. METHODS: Based on guidelines from six industrial nations, recent scientific studies, and from the type 2 disease management programme of North Rhine Westphalia we reviewed alternative retinopathy screening strategies and their implications for over- and underuse. RESULTS: A comparison of the English, Australian, US, Swedish, Canadian and German guidelines shows that a fixed screening interval is recommended in four countries, while an individualised, risk profile-adjusted screening interval of up to two to three years is favoured in two countries (Sweden, Canada). Current studies indicate that diabetes patients without retinopathy may safely be screened every two to three years without adverse health outcomes if performed consequently. CONCLUSIONS: An individualised retinopathy screening based on the patient's risk factor profile may be a reasonable alternative to achieve the best possible health outcome and to avoid overuse. PMID- 24075684 TI - [IQWiG in dialog 2013: "Significance of instituting benefit assessment"]. PMID- 24075683 TI - ["All of us actually practice EBM!" - Attitudes of German GPs towards evidence based medicine and clinical guidelines in daily practice: a focus group study]. AB - BACKGROUND: Implementation of guidelines in general practice is difficult. Do general practitioners (GPs) reject evidence-based medicine (EBM) in general? Which attitudes do GPs have towards EBM and guidelines, and which value do they attach to EBM in daily routine? METHODS: We conducted a qualitative study using five focus groups with 53 GPs. The study was set in the German federal states of Bavaria, Saxony, North Rhine-Westphalia, Hesse and Hamburg. Participants were selected according to area (rural/urban), region (North/South, East/West) and grade of professionalisation. Focus groups were digitally recorded and fully transcribed. Data were analysed in a multidisciplinary team using qualitative content analysis. RESULTS: Most participants felt positive towards EBM. Lack of feasibility was explicitly mentioned: the participants distinguished between "practised" and "true" EBM. Guidelines are often considered unsuitable for general practice. The GPs felt confident that their treatment of patients was evidence-based. CONCLUSIONS: Compared to older studies, German GPs have an increasingly favourable opinion about EBM. In order to enhance the practical application of EBM and guidelines the attitudes of GPs need to be considered. PMID- 24075685 TI - Combination of low-dose gemcitabine in 6-hour infusion and carboplatin is a favorable option for patients in poor performance status with advanced non-small cell lung cancer. AB - This study sought to investigate the efficacy and tolerability of the regimen of low-dose gemcitabine combined with carboplatin in chemo-naive patients with non small cell lung cancer (NSCLC). The study involved 37 chemo-naive patients with unresectable stage IIIB or stage IV NSCLC. The predominant histological type was squamous carcinoma (22/37), and the performance status (PS) was 2 in 23 patients (62%). All received gemcitabine, 250 mg/m(2) in 6-hour infusion on days 1 and 8 plus carboplatin area under the curve (AUC) = 5 on day 1, every 28 days. The overall response rate (ORR) was 62.2% and disease stabilization was achieved in 21.6% of the patients. After a median follow-up duration of 13 months, the median overall survival (OS) time was 14.0 months (95% CI 13.3-16.6 months), and the median progression-free survival (PFS) time was 7.0 months (95% CI 6.1-8.9 months). Hematological toxicities were well-tolerated with the development of grade 3/4 neutropenia and thrombocytopenia in 10.3 and 10.3% of patients respectively, and the gastrointestinal toxicities were mild. PMID- 24075686 TI - Pseudo-subarachnoid hemorrhage: a potential imaging pitfall associated with spontaneous intracranial hypotension. AB - OBJECTIVE: (1) To determine the frequency of CT mimics of subarachnoid hemorrhage (SAH) in a large cohort of subjects with spontaneous intracranial hypotension (SIH). (2) To emphasize the distinctive radiologic features of SIH. PATIENTS AND METHODS: CT scans of 95 subjects with SIH were retrieved and reviewed to search for findings of pseudo-SAH (CT mimics of SAH in the absence of blood). RESULTS: Pseudo-SAH radiologic findings (increased attenuation in the basilar cisterns, sylvian fissures, or along the tentorium) were detected on CT scans of 10 of the 95 SIH subjects. However, on MRI scans, these subjects exhibited the typical SIH abnormalities (diffuse pachymeningeal enhancement and brain sagging with obliteration of basilar cisterns). CONCLUSIONS: In the emergency room, SIH should be considered in the differential diagnosis between SAH and pseudo-SAH. Although SIH and SAH can share some radiologic features, SIH has distinctive MRI and CT findings. Their recognition should obviate the need for more invasive procedures (e.g., cerebral angiography) to definitely rule out SAH and an aneurismal source of bleeding. PMID- 24075688 TI - Pathophysiology of pain. PMID- 24075689 TI - Neural dynamics of inflectional and derivational morphology processing in the human brain. AB - We investigated neural distinctions between inflectional and derivational morphology and their interaction with lexical frequency using the mismatch negativity (MMN), an established neurophysiological index of experience-dependent linguistic memory traces and automatic syntactic processing. We presented our electroencephalography (EEG) study participants with derived and inflected words of variable lexical frequencies against their monomorphemic base forms in a passive oddball paradigm, along with acoustically matched pseudowords. Sensor space and distributed source modelling results showed that at 100-150 msec after the suffix onset, derived words elicited larger responses than inflected words. Furthermore, real derived words showed advantage over pseudo-derivations and frequent derivations elicited larger activation than less frequent ones. This pattern of results is fully in line with previous research that explained lexical MMN enhancement by an activation of strongly connected word-specific long-term memory circuits, and thus suggests stronger lexicalisation for frequently used complex words. At the same time, a strikingly different pattern was found for inflectional forms: higher response amplitude for pseudo-inflections than for real inflected words, with no clear frequency effects. This is fully in line with previous MMN results on combinatorial processing of (morpho)syntactic stimuli: higher response to ungrammatical morpheme strings than grammatical ones, which does not depend on the string's surface frequency. This pattern suggests that, for inflectional forms, combinatorial processing route dominates over whole-form storage and access. In sum, our results suggest that derivations are more likely to form unitary representations than inflections which are likely to be processed combinatorially, and imply at least partially distinct brain mechanisms for the processing and representation of these two types of morphology. These dynamic mechanisms, underpinned by perisylvian networks, are activated rapidly, at 100 150 msec after the information arrives at the input, and in a largely automatic fashion, possibly providing neural basis for the first-pass morphological processing of spoken words. PMID- 24075690 TI - A dynamical system perspective to understanding badminton singles game play. AB - By altering the task constraints of cooperative and competitive game contexts in badminton, insights can be obtained from a dynamical systems perspective to investigate the underlying processes that results in either a gradual shift or transition of playing patterns. Positional data of three pairs of skilled female badminton players (average age 20.5+/-1.38years) were captured and analyzed. Local correlation coefficient, which provides information on the relationship of players' displacement data, between each pair of players was computed for angle and distance from base position. Speed scalar product was in turn established from speed vectors of the players. The results revealed two patterns of playing behaviors (i.e., in-phase and anti-phase patterns) for movement displacement. Anti-phase relation was the dominant coupling pattern for speed scalar relationships among the pairs of players. Speed scalar product, as a collective variable, was different between cooperative and competitive plays with a greater variability in amplitude seen in competitive plays leading to a winning point. The findings from this study provide evidence for increasing stroke variability to perturb existing stable patterns of play and highlights the potential for speed scalar product to be a collective variable to distinguish different patterns of play (e.g., cooperative and competitive). PMID- 24075691 TI - Response-repetition effects depend on motor set: evidence for anatomical coding in response selection. AB - Successful motor performance requires a process of response selection that chooses the correct response out of a set of possible ones. Most theories of response selection assume that this selection process operates on spatial codes, which define the location of stimuli and responses in environmental coordinates, with little or no role for the anatomical codes of the effectors involved. In this study, we tested this assumption by investigating response-repetition effects in a response-cuing paradigm using two motor sets (fingers on one hand vs. fingers on two hands). Reaction time results demonstrated a robust response repetition benefit that was greater for the one-hand set than for the two-hands set. Furthermore, with the one-hand set the repetition benefit was independent of cue type and cue-stimulus interval on the previous trial, whereas with the two hands set it was strongly modulated by these two factors. These differential response-repetition effects for one- and two-hands motor sets demonstrate the important role of the neuro-anatomical hand distinction in response selection, thereby supporting multiple coding notions. PMID- 24075692 TI - A new process-centered description tool to initiate meta-reporting methodology in healthcare - 7CARECATTM. Feasibility study in a post-anesthesia care unit. AB - BACKGROUND: In the healthcare domain, different analytic tools focused on accidents appeared to be poorly adapted to sub-accidental issues. Improving local management and intra-institutional communication with simpler methods, allowing rapid and uncomplicated meta-reporting, could be an attractive alternative. METHODS: A process-centered structure derived from the industrial domain - DEPOSE(E) - was selected and modified for its use in the healthcare domain. The seven exclusive meta-categories defined - Patient, Equipment, Process, Actor, Supplies, work Room and Organization- constitute 7CARECATTM. A collection of 536 "improvement" reports from a tertiary hospital Post anesthesia care unit (PACU) was used and four meta-categorization rules edited prior to the analysis. Both the relevance of the metacategories and of the rules were tested to build a meta reporting methodology. The distribution of these categories was analyzed with a chi 2 test. RESULTS: Five hundred and ninety independent facts were collected out of the 536 reports. The frequencies of the categories are: Organization 44%, Actor 37%, Patient 11%, Process 3%, work Room 3%, Equipment 1% and Supplies 1%, with a p-value <0.005 (chi 2). During the analysis, three more rules were edited. The reproducibility, tested randomly on 200 reports, showed a <2% error rate. CONCLUSION: This meta-reporting methodology, developed with the 7CARECATTM structure and using a reduced number of operational rules, has successfully produced a stable and consistent classification of sub-accidental events voluntarily reported. This model represents a relevant tool to exchange meta informations important for local and transversal communication in healthcare institutions. It could be used as a promising tool to improve quality and risk management. PMID- 24075693 TI - Urinary podocalyxin positive-element occurs in the early stage of diabetic nephropathy and is correlated with a clinical diagnosis of diabetic nephropathy. AB - AIMS: We tested whether urinary podocalyxin-positive element (PCX+EL) can be a marker of early stage of diabetic nephropathy (DN). METHODS: DN patients (n=68) and health controls (n=28) were enrolled in this study. Patients were classified into three groups: normoalbuminuria, microalbuminuria and macroalbuminuria. Urinary PCX+EL, serum cystatin C (Scys C) and serum creatinine (SCr) were quantified, and correlations between urinary PCX+EL and urinary albumin, Scys C and SCr were examined. The comparison of diagnosis efficiency among urinary PCX+EL, Scys C and SCr was made by receiver operating characteristic (ROC) analysis. RESULTS: Urinary PCX+EL, Scys C and SCr significantly increased in DN patients compared with controls. Urinary PCX+EL increased significantly in all three patients groups compared with controls. However, the concentration of Scys C and SCr did not increase in normoalbuminuria group. Urinary albumin, Scys C and SCr correlated with urinary PCX+EL. ROC curve analysis indicated that area under the curve (AUC) of urinary PCX+EL (0.966) is higher than that of Scys C (0.857) and SCr (0.726) for discriminating nephropathy between DN patients and controls. CONCLUSION: Urinary PCX+EL may be a noninvasive marker for the early stage of DN. PMID- 24075695 TI - The co-emergence of language and rules: indirection, not recursion, is the key: comment on "The bilingual brain: flexibility and control in the human cortex" by Buchweitz and Prat. PMID- 24075694 TI - Common polymorphism in the cannabinoid type 1 receptor gene (CNR1) is associated with microvascular complications in type 2 diabetes. AB - Endocannabinoids exert their biological effects via interaction with G-protein coupled cannabinoid receptors CB1 and CB2. Polymorphisms in the CNR1 gene (encoding CB1 receptor) were previously found to be associated with dyslipidemia and cardiovascular diseases. We investigated a role of the polymorphism in CNR1 gene in type 2 diabetes and its complications. The study involved 667 T2DM patients and 450 healthy individuals. All subjects were genotyped for G1359A polymorphism by PCR-RFLP procedure. Genotype frequencies did not differ significantly between patients and controls. The statistically significant differences were seen between T2DM patients with diabetic nephropathy (DN) and those without it (OR for risk allele 2.84, 95% CI 2.04-3.94, p<0.0001). There were also differences between patients with diabetic retinopathy (DR) and those without DR (OR for risk allele 1.81, 95% CI 1.30-2.53, p=0.0005). No differences were observed in diabetic neuropathy. The A allele was more frequent in patients with coexisting cardiovascular disease (CVD) compared to patients without CVD (p=0.0044). The novel finding of our study is the association of the G1359A polymorphism with diabetic nephropathy and diabetic retinopathy in patients with T2DM. This polymorphism was also associated with cardiovascular disease in the patient group. PMID- 24075696 TI - [Health economics: a major challenge for the pharmacist]. PMID- 24075697 TI - [8th Descartes-Berkeley interuniversity symposium on health economics, May 2013, Paris, France: an overview]. PMID- 24075698 TI - [Trust-based economics with medicine outcome-based pricing]. AB - In recent decades, the pharmaceutical industry as built a high level of confidence thanks to innovative medicines that improve both duration and quality of life. Some recent scandals have however discredited this industry, now suspected of cheating or bribery. Even the scientific progresses are challenged on the ground of possible conflicts of interests and value uncertainty. This situation is deleterious. Simultaneously the economic crisis exacerbates the payers' expectations in terms of clinical value and value/price ratio. It also stimulates the demand for outcomes in real life. This induces a new economic approach for the market access of highly expensive reimbursable drugs. It consists in paying only for drugs actually proven effective in terms of actual outcomes, with a full or partial refund of the payer in case of failure, according to accurate and simple criteria in so called "performance agreement". Confidence is restored accordingly. PMID- 24075699 TI - Value and payment for oncology in the United States. AB - Rather than focus on reducing prices for innovative biopharmaceuticals, insurers in the United States are changing methods of payment for oncologists in order to moderate the growth in cancer drug expenditures. The desire is for a better pattern of utilization and expenditures without adversely affecting incentives for research and development. After an overview of the contemporary discussions of price and value, this paper describes three initiatives to influence the selection and management of oncology drugs. This includes initiatives to reduce the profit margins earned by oncologists as part of the purchasing of office infused biopharmaceuticals; "episode-of-care" payments that bundle into a single fee the reimbursement for care management and specialty drugs; and payment methods that case rates for physician care management activities with cost-based reimbursement for the oncology drugs. PMID- 24075700 TI - [Conditional pricing for innovative medicines in France: stop telling about risk sharing!]. AB - Across global borders and throughout the various sectors of health care, the search for viable methods to pay for value has intensified. Driven by soaring costs and constrained budgets, public and private payers are seeking innovative ways to incentivize providers and product manufacturers to focus on effective outcomes for patients according to key performance indexes. Conditional pricing and performance-based payment for innovative medicines could facilitate access to quasi-monopsonic french market, in a context of financial crisis, loss of reciprocal confidence, and growing aversion for therapeutic and economical uncertainty. However, we consider these new methods of payment should not be termed "risk-sharing agreements", a misleading term despite its common use today. They also should not impact the national list prices of medicines, that is a decisive tool for stabilizing international trade. PMID- 24075701 TI - [Innovative medicines and market access agreements]. AB - Market Access Agreements (MAA) for drugs have emerged in response to the need to control health expenditures, as well as to the uncertainty about the true benefit of a drug. It is possible to group MAA in two types of agreements: financial agreements and outcome-based agreements. MAA is a growing trend and is shifting towards conditional access. However, the willingness to use these contracts and their implementation differ across countries, and some are still resistant to put them in place. The MAA challenges to overcome encompass the complexity of the schemes, the administrative burden and the difficulty of evaluating MAA. It is likely that these agreements might experience further evolution in the future to become a faster pathway for therapeutic innovations, at a fair price. PMID- 24075702 TI - [Conditional reimbursement: a tool to reduce uncertainty relating the value of medicines and reinforce their continuous evaluation in real-life]. AB - In order to alleviate the inherent uncertainty that comes with the market access and public funding of new health products, a conditional reimbursement mechanism is proposed. The latter is circumscribed by recommendations regarding its implementation in limited cases in order to allow for a fair access of patients to therapeutic innovations, within economic conditions both optimum and reviewable. PMID- 24075703 TI - [Toward a conditional price for medicine?]. AB - For the first time, and as an exceptional option, the 2012 LEEM-CEPS framework agreement introduces the notion of conditional prices in conventional practice. The contractualization of drug price according to changes in its value that could occur in "real world" enables the Payer and the Company to settle, in a predictable manner, the "bet" represented by first registration price setting. Its systematization is based on the ability to standardize the implementation and assessment of observational studies, whereas the analysis and sharing of the risk of value changes (depreciation, appreciation) are structuring elements of the contractualization. Ethical from both the payer's and patient's point of view, drug price conditionality on its value is impeded by compliance with legal and economic constraints for the company, that should be taken into account by legalising this latter's ability to influence it through observance or therapeutic education and by guaranteeing a sufficiently long period of revenues for the company. PMID- 24075704 TI - [Contracts including performance and management of uncertainty]. AB - Since many decades in France, the most important part of ambulatory health care expenditure is represented by drug consumption. By the fact, French patient is indeed the greatest world consumer of pharmaceuticals treatments. Therefore, the regulation authorities by successive strategies, attempt to limit or even restrict market access for new drugs in the health care sector secured by public social insurance coverage. Common objectives are to assess the reimbursement to scientific studies and to fix the price of therapeutics at an acceptable level for both industries and government. New trends try then to determine recently the drug price in a dual approach, as a component of global and effective contract, including performance and outcome. The first diffusion authorization is diffusion concerned, but this concept takes into account the eventual success of new produces in long-term survey. Signed for a fixed period as reciprocal partnership between regulation authorities and pharmaceutics industries, the contract integrates two dimensions of incertitude. The first one is represented by the strategy of new treatments development according to efficacy and adapted price, and the second one is linked to the result of diffusion and determines adapted rules if eventual non-respects of the previous engagement are registered. This paper discusses problems related to this new dimension of incertitude affected by conditional drug prices in market access strategy and the adapted follow-up of new treatment diffusion fixed by "outcome" contract between French regulation administration and pharmaceutics industries in our recent economic context. PMID- 24075705 TI - [Risk-sharing agreements: choice of study design and assessment criteria]. AB - A new taxonomy of market entry agreements (MEA), also known as risk-sharing agreements, was built. It is no longer based on the conventional distinction between outcome performance and financial contracts, proposed by Carlson. Instead, it formulates a clear distinction between monitoring studies and evaluation or impact studies. The nature of the studies implemented within these two categories is fundamentally different: monitoring studies contribute to continuous program performance tracking against expected results and evaluation studies seek to identify the specific effect associated with the treatment while controlling for potential sources of selection bias. In accordance with this framework, differential study designs, indicators and financial clauses were proposed to reduce clinical, economic and budgetary uncertainty. PMID- 24075706 TI - Physicochemical stability study of a new Trimix formulation for treatment of erectile dysfunction. AB - Currently, severe erectile dysfunction can be treated by intracavernous injections of solutions containing three active ingredients: prostaglandin E1 (PGE1), papaverine and urapidil. Very few data exist on this mixture where phentolamine has been replaced by Urapidil because Phentolamine is not used for this indication in France. The aim of our study was to assess the stability of this formulation and to extend its expiration to permit preparation of batches. Three batches of the preparation containing 15MUg/mL PGE1, 15mg/mL of papaverine and 2mg/mL urapidil were made aseptically and then packed in polypropylene syringes stored at 4 degrees C. The physico-chemical stability has been tested as follows: HPLC stability-indicating method, visual observation, measurement of pH and osmolarity. We found that the limiting factor was PGE1 and we exceeded the threshold of 10% loss after 55 days. Replacement of Urapidil by Phentolamine seems to have a slight detrimental effect on stability. Nevertheless, these results allow us to consider the advance preparation of this formulation and provide quality treatment to these patients by avoiding too frequent visits to the hospital. PMID- 24075707 TI - [Share experiment: hospital mobile pharmaceutical teams, a proven concept!]. AB - A few months ago, the pharmacy department of the University Hospital of Poitiers was located in the basement of the hospital; communicating with care units by fax, phone or messenger. Today, drugs and medical devices, are stored in a 3400m(2) logistic platform and most of the delivery activity is robotized. Control and validation of prescriptions and dispensing activities are done by the pharmaceutical teams directly in the care units. Quality indicators allow us to improve our services regularly. A great success and interesting prospects for clinical pharmacy. PMID- 24075708 TI - Psychometric properties of Japanese version of the Swanson, Nolan, and Pelham, version-IV Scale-Teacher Form: a study of school children in community samples. AB - BACKGROUND: Psychometric properties of The Japanese version of Swanson, Nolan, and Pelham IV scale (SNAP-IV)-Teacher Form were examined in this study. METHOD: Community samples of 1296 children (Grade 1-9, boys 52.9%) were collected from public elementary/middle schools in suburban areas. Teachers rated their children's behavior using Japanese version of SNAP-IV-Teacher Form and Strength and Difficulties Questionnaire (SDQ). RESULTS: A three-factor structure model, which was equivalent with AD/HD symptoms subscales (inattention, hyperactivity/impulsivity) and oppositional-defiant disorder symptoms subscale was obtained and confirmed in an explorative/confirmative factorial analysis (Goodness-of-Fit Index=0.913, Comparative Fit Index=0.959, root mean square error of approximation=0.056). The current version of the SNAP-IV-Teacher Form demonstrated good test-retest reliability (intra-class correlation=0.752-0.822), high internal consistency (Cronbach's alpha=0.933-0.952), significant correlations with relevant subscales of Japanese version of SDQ, and typical effects of age and gender on those subscales. CONCLUSION: The current study indicates that the Japanese version of SNAP-IV-Teacher Form is a reliable and valid instrument for rating symptoms related to AD/HD and ODD. PMID- 24075709 TI - Thickness of the lower trapezius and serratus anterior using ultrasound imaging during a repeated arm lifting task. AB - The purposes of this study were to establish the reliability for measuring scapular muscle thickness, and to examine how scapular muscle thickness changes with respect to external loads. Participants were asymptomatic subjects recruited from a sample of convenience. Thickness Measures were taken using rehabilitative ultrasound imaging (RUSI) under 11 conditions, rest and 10 progressive loads, for the Lower Trapezius (LT) and Serratus Anterior (SA). The procedures were repeated 1 week later to determine reliability. Bland and Altman limits of agreement and Interclass correlation coefficients (ICC) were used to determine reliability. Separate repeated measure ANOVAs were performed to determine differences in muscle thickness for both muscles across 3 conditions; rest and the 2 loaded conditions that represented the lowest and highest torque values. Results demonstrate good within and between day reliability for the LT (ICC = .86 to .99) and SA (ICC = .88 to .99). For the LT and SA, there were significant differences between the resting thickness and 2 lifting conditions (p <= .01) but not between the two lifting conditions. It was concluded that RUSI is reliable in measuring scapular muscle thickness. RUSI is sensitive enough to detect absolute changes in thickness from resting to a contracted state but unable to detect differences between loads imposed on the shoulder. PMID- 24075710 TI - The opinion and experiences of Dutch orthopedic surgeons and radiologists about diagnostic musculoskeletal ultrasound imaging in primary care: a survey. AB - INTRODUCTION AND AIM: The use of diagnostic musculoskeletal ultrasound (DMUS) in primary health care has increased in the recent years. Nevertheless, there are hardly any data concerning the reliability, accuracy and treatment consequences of DMUS used by physical therapists or general practitioners. Moreover, there are no papers published about how orthopedic surgeons or radiologists deal with the results of DMUS performed in primary care. Therefore, our aim is to evaluate the opinion, possible advantages or disadvantages and experiences of Dutch orthopedic surgeons and radiologists about DMUS in primary care. METHODS: A cross-sectional survey in which respondents completed a self-developed questionnaire to determine their opinion, experiences, advantages, disadvantages of performing DMUS in primary care. RESULTS: Questionnaires were sent to 838 Dutch orthopedic surgeons and radiologists of which 213 were returned (response rate 25.4%). Our respondents saw no additional value for health care for diagnostic DMUS in primary care. DMUSs were generally repeated in secondary care. They perceived more disadvantages than advantages of performing DMUS in primary care. Mentioned disadvantages were: 'false positive results' (71.4%), 'lack of experience' (70%), 'insufficient education' (69.5%), not able to relate the outcomes of DMUS with other forms of diagnostic imaging' (65.7%), and 'false negative results' (65.3%). CONCLUSION: Radiologists and orthopedic surgeons sampled in the Netherlands show low trust in DMUS knowledge of physical therapists and general practitioners. The results should be interpreted with caution because of the small response rate and the lack of representativeness to other countries. PMID- 24075711 TI - Thrust manipulation versus non-thrust manipulation: a question that still needs to be answered. PMID- 24075712 TI - Knowledge transfer from an e-learning course to clinical practice. AB - BACKGROUND: Continuing education is essential in improving practical psychiatric nursing skills. However, little is known about how knowledge gained in continuing education is transferred to nurses' daily work. OBJECTIVES: To describe the transfer of knowledge gained from an e-learning course to daily practice. DESIGN: Qualitative study design. SETTINGS: One hospital district in Southern Finland with three specialized psychiatric wards (acute, rehabilitation, geriatric wards). PARTICIPANTS: Nursing staff (N=53) were recruited and 35 participated voluntarily in the e-learning continuing education course in spring 2009. METHODS: The data comprised nurses' reflective writing during the e-learning course and course evaluation forms completed after the course. We used qualitative design with inductive content analysis to analyze nurses' writings. RESULTS: The nurses were willing and able to transfer what they learned to their daily practice including the course themes, communication and co-operation among staff members, understanding of preventive and alternative treatment methods and critical thinking regarding one's own work. After the e-learning course the nurses were able to identify development areas such as issues related to staff members' daily work, the patient's role on the ward, alternative methods to avoid coercion, issues pertaining to the care environment on the ward, psychiatric nurses' education, and making an action plan for aggressive situations. All nurses would recommend the course to other nurses. CONCLUSIONS: New knowledge is easily adopted and transferred to daily practice. PMID- 24075713 TI - Long-term seizure outcomes following resection of supratentorial cavernous malformations. AB - OBJECTIVE: Symptomatic supratentorial cavernous malformations may present with seizure, headache, neurological deficit, or a combination thereof. Factors that contribute to treatment algorithms commonly include patient age, lesion size and location, lesion multiplicity, hemorrhage history, and the ability to control seizure activity with medication. A better appreciation of the impact of patient and lesion characteristics on post-operative seizure control may provide insight into management strategies. To determine long-term seizure outcomes following surgical resection of supratentorial cavernous malformations, the predictive value of characteristics including seizure duration and number, presence of generalized seizures, and lesion multiplicity and size on seizure control rate was evaluated. METHODS: We performed a single institution retrospective review of consecutive patients with supratentorial cavernous malformations presenting with at least one seizure between 1995 and 2008. Univariate and multivariate analyses were used to determine the influence of patient and lesion characteristics on postoperative seizure control. RESULTS: Fifty-six patients met inclusion criteria. Mean follow-up duration was 87.9 months. At last follow-up there were 46 patients (82.1%) that were free from impairing seizures (Engel Class 1). Ten patients (17.9%) were classified as Engel Class 2-4. Univariate analysis demonstrated that only the presence of multiple cavernomas was associated with worse post-operative seizure outcome (p=0.006). Multivariate analysis demonstrated that multiple cavernomas remained a significant predictor for development of worse seizure outcome controlling for number and duration of seizures prior to operation, presence of generalized tonic-clonic seizures, and size (odds ratio, 0.17; 95% confidence interval, 0.03, 0.99). CONCLUSION: Resection of supratentorial cavernomas is associated with a high rate of postoperative seizure freedom. The presence of multiple cavernomas is predictive of seizure persistence following surgery. PMID- 24075714 TI - Pain in Parkinson's disease: analysis and literature review. AB - Pain is a common problem faced by Parkinson's disease (PD) patients. Despite its impact and disabling effects pain is still frequently overlooked. In this study we analyze a representative sample of peer reviewed literature for the prevalence and types of pain in PD, the impact and significance of pain in the quality of life of the PD patient and the challenges inherent in the diagnosis and management of pain in PD patients. We compared and analyzed the findings of articles indexed in the PubMed database which looked at symptoms reported by large cohorts of PD patients. These articles all reported the incidence, nature and quality of pain in these patients and described the effects of pain on quality of life and generally were cross-sectional, retrospective or case-control studies, though a major pharmacoepidemiological design study was also analyzed. Results of our analysis showed that the pain was prevalent in 59.77% of PD patients. Five different types of pain were reported by PD patients--dystonia, musculoskeletal pain, nerve/nerve root pain, primary/central pain and according to some, akathisia. Patients who reported pain symptoms were also significantly more likely to report associated depression and a decreased quality of life. Many PD patients also reported poor management of pain and lower analgesic use than would be expected. We further discuss some of the possible approaches toward the development of a treatment algorithm regarding the management of pain in PD. We conclude that pain in is an under-recognized and under treated symptom in PD patients. Effective management of pain in PD patients would significantly improve their quality of life. Our analysis is in line with current thinking that identifies PD is much more of a multisystem disease with non-motor symptoms than previously thought. PMID- 24075715 TI - [Natural history of isolated increased thyrotropin (TSH) levels in childhood]. PMID- 24075716 TI - Challenging sequential approach to treatment resistant depression: cost-utility analysis based on the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) trial. AB - In major depression, when a first antidepressant does not cause remission of symptoms (60%-75%), there are several options for continuing treatment in the next step. This study is a cost-utility analysis (CUA) of different second-line approaches. In a simulated trial outpatients with MDD were treated with citalopram for 13 weeks (level 1), then based on two alternative algorithms implemented from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study. Algorithm A: citalopram was continued until study endpoint (week 26). Algorithm B: patients who remitted during level 1 continued citalopram. Those who did not remit could opt for switching to another antidepressant (venlafaxine; sertraline) (b1) or adding bupropion to citalopram treatment (augmentation; b2). Algorithm B increased remission rate by 10.6% over Algorithm A (number needed to treat: 9.9; sensitivity range: 9.1-12.5). As a comparison, differences between active antidepressants and placebo are associated with NNT values of 6 to 8. In CUA Algorithm B was dominant with an ICER of $11,813 (sensitivity range=$1783 - $21,784), which is <1GDP per capita cost effectiveness threshold (USA=$47,193). Among Algorithm B options, switching (b1) dominated Algorithm A with a smaller number of responders than augmentation approach (b2) (NNT 11 vs. 7.7), whereas ICER values were similar (b1: $14,738; b2: $15,458). However we cannot exclude a bias in selecting second treatment. This cost-utility analysis shows (in line with current guidelines) a benefit in modifying antidepressant treatment if response to first-line agent does not occur within 3 months, but not a clear-cut evidence in terms of NNT. PMID- 24075718 TI - Gut microbiota, enteroendocrine functions and metabolism. AB - The gut microbiota affects host metabolism through a number of physiological processes. Emerging evidence suggests that gut microbes interact with the host through several pathways involving enteroendocrine cells (e.g. L cells). The activation of specific G protein coupled receptors expressed on L cells (e.g. GPR41, GPR43, GPR119 and TGR5) triggers the secretion of glucagon-like peptides (GLP-1 and GLP-2) and PYY. These gut peptides are known to control energy homeostasis, glucose metabolism, gut barrier function and metabolic inflammation. Here, we explore how crosstalk between the ligands produced by the gut microbiota (short chain fatty acids, or SCFAs), or produced by the host but influenced by gut microbes (endocannabinoids and bile acids), impact host physiology. PMID- 24075717 TI - The gut hormone glucagon-like peptide-1 produced in brain: is this physiologically relevant? AB - Glucagon-like peptide-1 (GLP-1) is both a peripherally expressed incretin and a centrally active neuropeptide. Brain derived GLP-1, produced in preproglucagon (PPG) neurons located in the nucleus of the solitary tract (NTS) and projecting to numerous brain regions, is ideally placed to activate central GLP-1 receptors in a range of autonomic control areas. In vivo analysis of central GLP-1 using GLP-1 receptor antagonists has demonstrated the control of a range of feeding responses mediated by GLP-1 receptor activation. Recent advances enabling identification and targeting of the neurons in the NTS has specifically implicated PPG neurons at the core of GLP-1 dependent central and peripheral control for short-term and long-term energy balance. PMID- 24075719 TI - The hypothalamus and metabolism: integrating signals to control energy and glucose homeostasis. AB - Molecules acting in the central nervous system play a critical role in the control of both energy and glucose homeostasis. The hypothalamus consists of a highly diverse collection of interconnected neurons and supporting glial cells that allow this region of the brain to sense and respond to a diverse range of hormonal and metabolic signals. We review recent advances in our understanding of the anatomical architecture and molecular mechanisms within the hypothalamus and how these facilitate the orchestration of systemic metabolic processes. PMID- 24075720 TI - Determination of iodide, iodate and organo-iodine in waters with a new total organic iodine measurement approach. AB - The dissolved iodine species that dominate aquatic systems are iodide, iodate and organo-iodine. These species may undergo transformation to one another and thus affect the formation of iodinated disinfection byproducts during disinfection of drinking waters or wastewater effluents. In this study, a fast, sensitive and accurate method for determining these iodine species in waters was developed by derivatizing iodide and iodate to organic iodine and measuring organic iodine with a total organic iodine (TOI) measurement approach. Within this method, organo-iodine was determined directly by TOI measurement; iodide was oxidized by monochloramine to hypoiodous acid and then hypoiodous acid reacted with phenol to form organic iodine, which was determined by TOI measurement; iodate was reduced by ascorbic acid to iodide and then determined as iodide. The quantitation limit of organo-iodine or sum of organo-iodine and iodide or sum of organo-iodine, iodide and iodate was 5 MUg/L as I for a 40 mL water sample (or 2.5 MUg/L as I for an 80 mL water sample, or 1.25 MUg/L as I for a 160 mL water sample). This method was successfully applied to the determination of iodide, iodate and organo iodine in a variety of water samples, including tap water, seawater, urine and wastewater. The recoveries of iodide, iodate and organo-iodine were 91-109%, 90 108% and 91-108%, respectively. The concentrations and distributions of iodine species in different water samples were obtained and compared. PMID- 24075721 TI - Bacteria, viruses, and parasites in an intermittent stream protected from and exposed to pasturing cattle: prevalence, densities, and quantitative microbial risk assessment. AB - Over 3500 individual water samples, for 131 sampling times, targeting waterborne pathogens/fecal indicator bacteria were collected during a 7-year period from 4 sites along an intermittent stream running through a small livestock pasture system with and without cattle access-to-stream restriction measures. The study assessed the impact of cattle pasturing/riparian zone protection on: pathogen (bacterial, viral, parasite) occurrence, concentrations of fecal indicators, and quantitative microbial risk assessments (QMRA) of the risk of Cryptosporidium, Giardia and Escherichia coli O157:H7 infection in humans. Methodologies were developed to compute QMRA mean risks on the basis of water samples exhibiting potentially human infectious Cryptosporidium and E. coli based on genotyping Crytosporidium, and E. coli O157:H7 presence/absence information paired with enumerated E. coli. All Giardia spp. were considered infectious. No significant pasturing treatment effects were observed among pathogens, with the exception of Campylobacter spp. and E. coli O157:H7. Campylobacter spp. prevalence significantly decreased downstream through pasture treatments and E. coli O157:H7 was observed in a few instances in the middle of the unrestricted pasture. Densities of total coliform, fecal coliform, and E. coli reduced significantly downstream in the restricted pasture system, but not in the unrestricted system. Seasonal and flow conditions were associated with greater indicator bacteria densities, especially in the summer. Norovirus GII was detected at rates of 7-22% of samples for all monitoring sites, and rotavirus in 0-7% of samples for all monitoring sites; pasture treatment trends were not evident, however. Seasonal and stream flow variables (and their interactions) were relatively more important than pasture treatments for initially stratifying pathogen occurrence and higher fecal indicator bacteria densities. Significant positive associations among fecal indicator bacteria and Campylobacter spp. detection were observed. For QMRA, adjusting for the proportion of Cryptosporidium spp. detected that are infectious for humans reduces downstream risk estimates by roughly one order of magnitude. Using QMRA in this manner provides a more refined estimate of beneficial management practice effects on pathogen exposure risks to humans. PMID- 24075722 TI - Carbon isotopic characterisation of dissolved organic matter during water treatment. AB - Water treatment is a series of physio-chemical processes to aid organic matter (OM) removal, which helps to minimise the formation of potentially carcinogenic disinfection by-products and microbial regrowth. Changes in OM character through the treatment processes can provide insight into the treatment efficiency, but radiogenic isotopic characterisation techniques have yet to be applied. Here, we show for the first time that analysis of (13)C and (14)C of dissolved organic carbon (DOC) effectively characterises dissolved OM through a water treatment works. At the sites investigated: post-clarification, DOC becomes isotopically lighter, due to an increased proportion of relatively hydrophilic DOC. Filtration adds 'old' (14)C-DOC from abrasion of the filter media, whilst the use of activated carbon adds 'young' (14)C-DOC, most likely from the presence of biofilms. Overall, carbon isotopes provide clear evidence for the first time that new sources of organic carbon are added within the treatment processes, and that treated water is isotopically lighter and typically younger in (14)C-DOC age than untreated water. We anticipate our findings will precipitate real-time monitoring of treatment performance using stable carbon isotopes, with associated improvements in energy and carbon footprint (e.g. isotopic analysis used as triggers for filter washing and activated carbon regeneration) and public health benefits resulting from improved carbon removal. PMID- 24075723 TI - Enhanced chitosan beads-supported Fe(0)-nanoparticles for removal of heavy metals from electroplating wastewater in permeable reactive barriers. AB - The removal of heavy metals from electroplating wastewater is a matter of paramount importance due to their high toxicity causing major environmental pollution problems. Nanoscale zero-valent iron (NZVI) became more effective to remove heavy metals from electroplating wastewater when enhanced chitosan (CS) beads were introduced as a support material in permeable reactive barriers (PRBs). The removal rate of Cr (VI) decreased with an increase of pH and initial Cr (VI) concentration. However, the removal rates of Cu (II), Cd (II) and Pb (II) increased with an increase of pH while decreased with an increase of their initial concentrations. The initial concentrations of heavy metals showed an effect on their removal sequence. Scanning electron microscope images showed that CS-NZVI beads enhanced by ethylene glycol diglycidyl ether (EGDE) had a loose and porous surface with a nucleus-shell structure. The pore size of the nucleus ranged from 19.2 to 138.6 MUm with an average aperture size of around 58.6 MUm. The shell showed a tube structure and electroplating wastewaters may reach NZVI through these tubes. X-ray photoelectron spectroscope (XPS) demonstrated that the reduction of Cr (VI) to Cr (III) was complete in less than 2 h. Cu (II) and Pb (II) were removed via predominant reduction and auxiliary adsorption. However, main adsorption and auxiliary reduction worked for the removal of Cd (II). The removal rate of total Cr, Cu (II), Cd (II) and Pb (II) from actual electroplating wastewater was 89.4%, 98.9%, 94.9% and 99.4%, respectively. The findings revealed that EGDE-CS-NZVI-beads PRBs had the capacity to remediate actual electroplating wastewater and may become an effective and promising technology for in situ remediation of heavy metals. PMID- 24075724 TI - Electrochemical degradation of chlortetracycline using N-doped Ti/TiO2 photoanode under sunlight irradiations. AB - The appearance and the persistence of pharmaceutical products in the aquatic environment urgently call for the development of an innovative and practical water treatment technology. This study deals with the development of nanostructured nitrogen-doped TiO2 photoanodes and their subsequent use for chlortetracycline (CTC) photoelectrocatalytic oxidation under visible light. The N-doped TiO2 photoanodes with different nitrogen contents were prepared by means of a radiofrequency magnetron sputtering (RF-MS) process, with the objective to tune shift their optical absorption from the UV towards the visible. The N-doped TiO2 consist of nanostructured anatase phase with average TiO2 nanocrystallite size of 29 nm. The nitrogen doping is clearly shown to produce the desired red shift of the absorption onset of the TiO2 coatings (from ~380 nm to ~550 nm). Likewise, the N-doped TiO2 are found to be highly photo-electroactive not only under the UV light but most interestingly under the visible light as well. Using the optimal N-doped photoanodes, 99.6% of CTC (100 MUg/L) was successfully degraded after 180 min of treatment time with a current intensity of 0.6 A. Under these conditions, a relatively high mineralization of CTC (92.5% +/- 0.26% of TOC removal and 90.3% +/- 1.1% of TN removal) was achieved. PMID- 24075725 TI - Point-of-care derived INR does not reliably detect significant coagulopathy following Australian snakebite. AB - INTRODUCTION: Point-of-care international normalised ratio (INR) has been suggested as a way to screen for venom-induced consumption coagulopathy following snakebite, but has not been validated for this. This study aimed to assess the diagnostic reliability of point-of-care INR for venom-induced consumption coagulopathy. METHODS: This was a prospective study of snakebite patients recruited between January 2011 and May 2012 where a point-of-care INR was done and compared to an INR done on a laboratory coagulation analyser, as part of a quality assurance exercise. Data was obtained for each patient, including demographics, information on the snake bite, the point-of-care INR results and any laboratory derived coagulation studies. Snake identification was confirmed by expert identification or venom specific enzyme immunoassay. RESULTS: There were 15 patients with a median age of 29 years (2 to 68 y) and 13 were male. Four of the 7 patients with venom-induced consumption coagulopathy had an abnormal point of-care INR (3 false negatives) and 1 of the 7 non-envenomed patients had an abnormal point-of-care INR (1 false positive). The patient with a falsely elevated point-of-care INR was given antivenom prior to formal coagulation studies. The point-of-care INR was also negative in the patient with an anticoagulant coagulopathy. CONCLUSIONS: The study shows that point-of-care INR testing devices should not be used in suspected snakebite cases in Australia to diagnose venom-induced consumption coagulopathy. PMID- 24075726 TI - Bortezomib subcutaneous injection in combination regimens for myeloma or systemic light-chain amyloidosis: a retrospective chart review of response rates and toxicity in newly diagnosed patients. AB - BACKGROUND: Bortezomib is a first-in-class proteasome inhibitor approved by the US Food and Drug Administration for the treatment of all phases of multiple myeloma (MM) and it is also used for the treatment of [corrected] light-chain amyloidosis (AL). The subcutaneous formulation of bortezomib was approved in 2012 based on data from Phase III studies in patients with relapsed MM. OBJECTIVE: This article reports experience with subcutaneous bortezomib in patients with newly diagnosed MM or AL in a tertiary care center. METHODS: This retrospective study analyzed data from all patients newly diagnosed with MM or AL and treated at our center between April 1, 2011, when the hospital pharmacy approved and implemented the option of subcutaneous bortezomib, and April 1, 2013. Patients who received subcutaneous bortezomib as a part of the first line of therapy were identified through the pharmacy's database. Data were abstracted from electronic medical records, and data on demographic characteristics, disease profiles, toxicities, responses, and survival were collected. RESULTS: Data from 29 patients (MM, 16; AL, 13; 62% male; median age, 66 years [range, 46-84]) were analyzed. Ninety percent of patients received cyclophosphamide, bortezomib, and dexamethasone (CyBorD) as the first line of treatment. None of the patients developed grade 3/4 peripheral neuropathy, whereas 1 patient experienced grade 3 diarrhea, and 2 patients developed grade 3 thrombocytopenia requiring dose reductions. The overall response rate was 93%, with 59% of patients achieving very good partial response or complete response. CONCLUSIONS: With the use of subcutaneous bortezomib in combination regimens in patients with newly diagnosed MM or AL, there was a high overall response rate and minimal toxicity. These results are consistent with the findings from prior studies and provide a basis for further studies comparing new proteasome inhibitors to subcutaneous bortezomib in combination regimens for patients with newly diagnosed MM or AL. PMID- 24075728 TI - Development and pilot testing of a novel education method for training medical interpreters. AB - OBJECTIVE: The goal of this study was to determine core competencies by means of a systematic literature review and to design and test an interpreter training program. METHODS: Core competencies in medical interpreting were searched using a systematic literature review. An intervention program was developed to improve core competencies. Pretests and posttests were conducted to pilot-test knowledge and interpreting skills in participants aged 22-62 years (n=43). Results of the tests were compared. RESULTS: Results of the systematic review indicated five core competencies: (a) maintaining accuracy and completeness; (b) medical terminology and understanding the human body; (c) behaving ethically and making ethical decisions; (d) nonverbal communication skills; and (e) cross-cultural communication skills. Statistical analysis showed a significant improvement in knowledge and interpreting skills in the intervention program compared with the control program. CONCLUSION: Posttest assessment showed that the developed training system can be useful in improving knowledge and quality in medical interpreting. PRACTICE IMPLICATIONS: A 3-day training program for medical interpreters could bridge the gap between medical professionals and patients with limited English proficiency while being amenable to integration into clinical flow. PMID- 24075727 TI - Implementation and outcomes of telephone disclosure of clinical BRCA1/2 test results. AB - OBJECTIVES: With an increasing demand for genetic services, effective and efficient delivery models for genetic testing are needed. METHODS: In this prospective single-arm communication study, participants received clinical BRCA1/2 results by telephone with a genetic counselor and completed surveys at baseline, after telephone disclosure (TD) and after in-person clinical follow-up. RESULTS: Sixty percent of women agreed to participate; 73% of decliners preferred in-person communication. Anxiety decreased from baseline to post-TD (p=0.03) and satisfaction increased (p<0.01). Knowledge did not change significantly from baseline to post-TD, but was higher post-clinical follow-up (p=0.04). Cancer patients had greater declines in state anxiety and African-American participants reported less increase in satisfaction. 28% of participants did not return for in person clinical follow-up, particularly those with less formal education, and higher post-disclosure anxiety and depression (p<0.01). CONCLUSIONS: Telephone disclosure of BRCA1/2 test results may not be associated with negative cognitive and affective responses among willing patients, although some subgroups may experience less favorable responses. Some patients do not return for in-person clinical follow-up and longitudinal outcomes are unknown. PRACTICE IMPLICATIONS: Further evaluation of longitudinal outcomes of telephone disclosure and differences among subgroups can inform how to best incorporate telephone communication into delivery of genetic services. PMID- 24075729 TI - Structure-based identification of novel PPAR gamma ligands. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor with an important role in the glucose metabolism and a target for type 2 diabetes mellitus therapy. The recent findings relating the use of the receptor full agonist rosiglitazone and the incidence of myocardial infarction raised concerns regarding whether receptor activation can actually be useful for diabetes management. The discovery of MRL-24 and GQ-16, ligands that can partially activate PPARgamma and prevent weight gain and fluid retention, showed that a submaximal receptor activation can be a goal in the development of new ligands for PPARgamma. Additionally, two previously described receptor antagonists, SR-202 and BADGE, were also shown to improve insulin sensitivity and decrease TNF-alpha level, revealing that receptor antagonism may also be an approach to pursue. Here, we used a structure-based approach to screen the subset 'Drugs-Now' of ZINC database. Fifteen ligands were selected after visual inspection and tested for their ability to bind to PPARgamma. A benzoimidazol acetate, a bromobenzyl-thio-tetrazol benzoate and a [[2-[(1,3-dioxoinden-2 ylidene)methyl]phenoxy]methyl]benzoate were identified as PPARgamma ligands, with IC50 values smaller than 10MUM. Molecular dynamic simulations showed that the residues H323, H449, Y327, Y473, K367 and S289 are key structural elements for the molecular recognition of these ligands and the polar arm of PPARgamma binding pocket. PMID- 24075730 TI - Tyrosine specific sequential labeling of proteins. AB - We report (a) on the synthesis of a long-wavelength fluorescent coumarin containing an allyloxy acetate moiety, (b) the synthesis of two linkers containing an allyloxy acetate and an alkyne or azide function, respectively, and (c) the selective modification human serum albumin by a sequential method involving Pd(II) catalyzed modification of the phenolic side chain of tyrosine residues with an alkyne bearing linker and a subsequent azide-alkyne click reaction with an azide functionalized long-wavelength emitting coumarin dye. The method is likely to be applicable to various kinds of azido-modified fluorophores, and the Pd(II)-catalyzed modification of the tyrosines may also be used to introduce other kinds of tags. With these reagents, tyrosine specific modulation of proteins and peptides becomes possible either directly or in a sequential manner. PMID- 24075731 TI - Discovery and structure-activity relationships of 6-(benzoylamino)benzoxaboroles as orally active anti-inflammatory agents. AB - Structure-activity relationships of 6-(benzoylamino)benzoxaborole analogs were investigated for the inhibition of TNF-alpha, IL-1beta, and IL-6 from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compound 1q showed potent activity against all three cytokines with IC50 values between 0.19 and 0.50MUM, inhibited LPS-induced TNF-alpha and IL-6 elevation in mice and improved collagen-induced arthritis in mice. Compound 1q (AN4161) is considered to be a promising lead for novel anti-inflammatory agent with an excellent pharmacokinetic profile. PMID- 24075732 TI - Discovery of a novel sub-class of ROMK channel inhibitors typified by 5-(2-(4-(2 (4-(1H-Tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one. AB - A sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents. PMID- 24075733 TI - Health care providers' knowledge assessment of measles, mumps, and rubella vaccine. AB - The aim of this study was to assess educational needs of health care personnel in vaccine storage and handling. The Immunization Knowledge Assessment Tool (IKAT) was used to evaluate knowledge related to delivery and storage of measles, mumps and rubella (MMR) vaccine among health care personnel in Idaho. Using descriptive analysis, only 61% of respondents achieved a passing score of 80%. Knowledge deficits were revealed among health care personnel, physicians, and other providers in immunization administration and handling of the MMR vaccine. Scores were highest among registered nurses, licensed practical nurses, and medical assistants. PMID- 24075734 TI - Pain intensity, interference and patient pain management strategies the first 12 weeks after coronary artery bypass graft surgery. AB - BACKGROUND: Pain is a distressing and often undertreated symptom of cardiac surgery. Little is known about pain levels, interference and treatment strategies beyond the 9 week period. AIM: The purpose of this study was to describe pain intensity, interference and strategies used to manage pain in post-operative CABG patients. METHODS: Baseline data were collected by interview in the hospital after CABG surgery using the Modified Brief Pain Inventory. One to 12 weeks after discharge, weekly telephone interviews were conducted to collect data. RESULTS: Pain levels and interference with activities of daily living were greatest during hospitalization and decreased over 12 weeks. Pain interfered the most with coughing and sleep. Once opioid medications ran out, activity modification was primarily used to manage pain. CONCLUSIONS: Activity modification below recommended levels was reported as a pain management strategy. Patients reported pain lasting longer than they expected and the need for more education about activity and pain management strategies. PMID- 24075735 TI - Brain biopsy findings link major depressive disorder to neuroinflammation, oxidative stress, and neurovascular dysfunction: a case report. PMID- 24075736 TI - Surgical efficiency in bilateral cochlear implantation: a cost analysis. AB - OBJECTIVE: (1) Compare the non-device-related costs of bilateral simultaneous cochlear implantation (BSiCI) vs. unilateral, and (2) establish a dollar amount for potential cost savings in direct costs for BSiCI vs. sequential cochlear implantation (CI). METHODS: Data from all CI cases performed during the fiscal year 2010-2011 were retrospectively reviewed without exception. Fifty-four patients received unilateral CI and 36 received BSiCI. Demographics and data regarding direct costs associated with the operation and immediate in hospital post-operative period were collected. RESULTS: The total operating room (OR) time for unilateral and BSiCI was 3 hours 00 minutes and 4 hours 37 minutes, respectively, with a mean difference of 1 hour and 36 minutes (SD = 0 hours:06 minutes). The cost of OR and post-anesthetic care unit supporting staff was $3102 and $4240 for unilateral and BSiCI, respectively, with a mean difference of $1138 (SD = 216). Unilateral CI supplies totaled $1348 compared to $1822 for BSiCI supplies with an average difference of $438 (SD = 123). CONCLUSION: The total direct costs for a unilateral CI (excluding implantable device and surgeon fees) were $4362 compared to $5823 dollars for BSiCI. Simultaneous implantation can lead to a potential saving of $2901 compared to sequential implantation. PMID- 24075737 TI - Association between serotonin transporter (SERT) gene polymorphism and idiopathic pulmonary arterial hypertension: a meta-analysis and review of the literature. AB - OBJECTIVE: Idiopathic pulmonary arterial hypertension (IPAH) is a rare and often fatal disease of unknown etiology. Serotonin transporter (SERT) protein, whose genes can have two allelic forms, namely long (L) and short (S), is suspected to be related to IPAH risk. Several studies have investigated the association between SERT's different allelic forms and IPAH but showed conflicting results. A meta-analysis of published studies was performed to allow a more reliable estimate of this association. METHODS: Relevant databases were searched to identify eligible studies published from 2000 to 2013. Odds ratios (OR) and 95% confidence intervals (CI) were determined for the gene-disease association using fixed or random effects models. RESULTS: A total of 6 studies with 451 IPAH subjects and 664 controls were included in this meta-analysis. A significant difference was found in the comparison between IPAH subjects and controls with LL vs. SS genotypes, and the pooled odds ratio (OR) with the fixed effects model was 1.446 (95% CI=1.036-2.018, p=0.030, I(2)=38.8%). However, no statistically significant differences were observed for LL vs. LS or LL vs. LS+SS. The pooled OR indicated no significant differences in IPAH risk between carriers of SERT L and S alleles (ORL VS. S=1.327, 95% CI=0.933-1.886, p=0.115). CONCLUSION: This meta-analysis provides evidence suggesting an association between the SERT L/S polymorphism and IPAH. Individuals with the LL genotype have an obviously higher risk of developing IPAH than those with the SS genotype. PMID- 24075739 TI - Acute changes in lipoprotein subclasses during exercise. AB - OBJECTIVE: Lipids are important substrates for oxidation in the basal fasting state and during exercise. Studies have demonstrated beneficial changes in lipoprotein subclass composition the day after an exercise bout. However, the acute effect of exercise on TG concentration and lipoprotein subclass composition remains unclear. MATERIALS/METHODS: Sixteen lean, healthy individuals (8 men and 8 women) were recruited (age 20-30 years, BMI<25 kg/m(2)). The subjects were studied during basal fasting conditions as well as during and after 90 min of cycling at 50% of VO2peak. Lipoprotein subclass composition was measured with (1)H NMR spectroscopy. RESULTS: During exercise, LDL and HDL particle concentration increased significantly (p<0.05) despite lower total TG concentration. In addition, exercise resulted in a shift towards smaller VLDL particles in men (p<0.05), but VLDL-TG concentration was unaltered. CONCLUSIONS: Acute exercise induces beneficial changes in lipoprotein subclass composition. These changes are similar to the effects of exercise training. PMID- 24075738 TI - Salt loading exacerbates diastolic dysfunction and cardiac remodeling in young female Ren2 rats. AB - OBJECTIVE: Recent data would suggest pre-menopausal insulin resistant women are more prone to diastolic dysfunction than men, yet it is unclear why. We and others have reported that transgenic (mRen2)27 (Ren2) rats overexpressing the murine renin transgene are insulin resistant due to oxidative stress in insulin sensitive tissues. As increased salt intake promotes inflammation and oxidative stress, we hypothesized that excess dietary salt would promote diastolic dysfunction in transgenic females under conditions of excess tissue Ang II and circulating aldosterone levels. MATERIALS/METHODS: For this purpose we evaluated cardiac function in young female Ren2 rats or age-matched Sprague-Dawley (SD) littermates exposed to a high (4%) salt or normal rat chow intake for three weeks. RESULTS: Compared to SD littermates, at 10weeks of age, female Ren2 rats fed normal chow showed elevations in left ventricular (LV) systolic pressures, LV and cardiomyocyte hypertrophy, and displayed reductions in LV initial filling rate accompanied by increases in 3-nitrotyrosine content as a marker of oxidant stress. Following 3weeks of a salt diet, female Ren2 rats exhibited no further changes in LV systolic pressure, insulin resistance, or markers of hypertrophy but exaggerated increases in type 1 collagen, 3-nitrotryosine content, and diastolic dysfunction. These findings occurred in parallel with ultrastructural findings of pericapillary fibrosis, increased LV remodeling, and mitochondrial biogenesis. CONCLUSION: These data suggest that a diet high in salt in hypertensive female Ren2 rats promotes greater oxidative stress, maladaptive LV remodeling, fibrosis, and associated diastolic dysfunction without further changes in LV systolic pressure or hypertrophy. PMID- 24075740 TI - Long-term use of statins reduces the risk of hospitalization for dementia. AB - BACKGROUND: Dementia is a major public health problem because of its high prevalence in elderly individuals, particularly in the growing category of subjects aged 80 years or more. There is accumulating evidence that cholesterol may be implicated in the pathogenesis of dementia, and this has led us to assess the relationship between time spent with statins available and the risk of hospitalization for dementia. METHODS: A population-based, nested case-control study was carried out by including the cohort of 152,729 patients from Lombardy (Italy) aged 40 years or older who were newly treated with statins between 2003 and 2004. Cases were the 1380 patients who experienced hospitalization for dementia disease from initial prescription until 2010. Up to twenty controls were randomly selected for each case. Logistic regression was used to model the risk of dementia associated with the cumulative time during which statins were available. Monte-Carlo and rule-out sensitivity analyses were performed to account for unmeasured confounders. RESULTS: Compared with patients who had very short statins coverage (less than 6 months), those on 7-24, 25-48, and >48 months of coverage respectively had risk reductions of 15% (OR: 0.85; 95% CI: 0.74 to 0.98), 28% (OR: 0.72; 95% CI: 0.61 to 0.85), and 25% (OR: 0.75; 95% CI: 0.61 to 0.94). Simvastatin and atorvastatin were both associated with a reduced risk of dementia, while no similar evidence was observed for fluvastatin and pravastatin. CONCLUSIONS: Long-term use of statins seems effective for the prevention of dementia. PMID- 24075741 TI - Perivascular adipose tissue in the pathogenesis of cardiovascular disease. AB - Adipose tissue, which has been considered mainly as a site of energy storage and mobilization, is found in many depots throughout the body. Adipose depots may have structural properties such as, for instance, the fat pads located in the hands and feet and the periorbital fat supporting the eyes. Adipose tissue also shows remarkable regional heterogeneity. For instance, substantial differences have been reported in the metabolic properties of visceral (intra-abdominal) vs. subcutaneous adipose depots. Visceral adipose tissue (VAT) has active endocrine and paracrine functions with the secretion of various pro-inflammatory chemokines potentially contributing to the progression of atherosclerosis related with obesity. In addition, adipose depots surrounding the heart, such as epicardial (EAT) and perivascular adipose tissues (PAT) may also exert important roles in the pathogenesis of cardiovascular disease beyond the contribution of VAT due to their close anatomic relationships with vascular structures and myocardium. The purpose of the present review is to outline the current understanding of the pathophysiological links between EAT, PAT and atherosclerotic cardiovascular disease. Also, we discuss the current investigative methods for PAT quantification and discuss the potential impact of PAT on cardiovascular risk prediction. Finally, potential clinical implications of these notions are discussed. PMID- 24075742 TI - Increased monocyte adhesion by endothelial expression of VCAM-1 missense variation in vitro. AB - OBJECTIVE: In whole genome and single gene analyses, genetic variation at the vascular cell adhesion molecule-1 (VCAM-1) locus has been associated with inflammatory disease and stroke in sickle cell anaemia. In the current work, we investigated the functional impact of VCAM-1 missense variants and their effect on cell-cell adhesion. METHODS AND RESULTS: To determine the functional in vitro relevance of five missense VCAM-1 variants (S318F; T384A; G413A; L555V; I716L), we generated wild type and single variant VCAM-1 forms [318F, 384A, 413A, 555V, 716L] in EA.hy926 endothelial cells. Real-time PCR, western blot and ELISA analyses revealed significant differences in mRNA and protein levels for VCAM-1 variants. Monocytic cell lines THP-1 and U937 showed significantly increased adhesion to endothelial cells overexpressing VCAM-1 forms 318F, 555V and 716L compared to those overexpressing wild type VCAM-1 (p < 0.05). CONCLUSIONS: VCAM-1 dependent cell adhesion to endothelial cells in vitro is significantly increased when expressing VCAM-1 missense mutations 318F, 555V and 716L. The underlying mechanism involves altered VCAM-1 protein levels and function. This observation may be of particular relevance for chronic inflammatory pathophysiologic conditions involving cell-cell adhesion such as atherosclerosis and other proinflammatory conditions. PMID- 24075743 TI - Epigenetic signatures and vascular risk in type 2 diabetes: a clinical perspective. AB - Risk of diabetic complications continues to escalate overtime despite a multifactorial intervention with glucose-lowering drugs, anti-hypertensive agents and statins. In this perspective, a mechanisms-based therapeutic approach to vascular disease in diabetes represents a major challenge. Epigenetic signatures are emerging as important determinants of vascular disease in this setting. Methylation and acetylation of DNA and histones is a reversible process leading to dysregulation of oxidant and inflammatory genes such as mitochondrial adaptor p66(Shc) and transcription factor NF-kB p65. Epigenetic modifications associated with diabetes may contribute to the early identification of high risk individuals. Ongoing epigenomic analyses will be instrumental in identifying the epigenetic variations that are specifically associated with cardiovascular disease in patients with diabetes. Here, we describe a complex scenario of epigenetic changes and their putative link with diabetic vascular disease. Pharmacological reprogramming of diabetes-induced epigenetic signatures may be a promising option to dampen oxidative stress and inflammation, and thus prevent cardiovascular complications in this setting. PMID- 24075744 TI - A difference in systolic blood pressure between arms is a novel predictor of the development and progression of diabetic nephropathy in patients with type 2 diabetes. AB - OBJECTIVE: Recent studies have suggested that a difference in systolic blood pressure (SBP) between arms is associated with both vascular disease and mortality. The aim of this study was to investigate the relationship between a difference in SBP between arms and change in urinary albumin excretion or development of albuminuria in patients with type 2 diabetes. METHODS: We measured SBP in 408 consecutive patients with type 2 diabetes, and calculated a difference in SBP between arms. We performed follow-up study to assess change in urinary albumin excretion or development of albuminuria, mean interval of which was 4.6 +/- 1.7 years. We then evaluated the relationship of a difference in SBP between arms to diabetic nephropathy using multiple regression analysis and multiple Cox regression model. RESULTS: Multiple regression analyses demonstrated that a difference in SBP between arms was independently associated with change in urinary albumin excretion (beta = 0.1869, P = 0.0010). Adjusted Cox regression analyses demonstrated that a difference in SBP between arms was associated with an increased hazard of development of albuminuria; hazard ratio was 1.215 (95% confidence interval 1.077-1.376). Moreover, the risk of development of albuminuria was increased in patients with a difference in SBP of equal to or more than 10 mmHg between arms; hazard ratio was 4.168 (95% confidence interval 1.478-11.70). CONCLUSION: A difference in SBP between arms could be a novel predictor of the development and progression of diabetic nephropathy in patients with type 2 diabetes. PMID- 24075745 TI - DNA modifications in atherosclerosis: from the past to the future. AB - The role of DNA damage in the pathogenesis of atherosclerosis has been extensively investigated in recent decades. There is now clear that oxidative stress is an important inducer of both DNA damage and telomere attrition which, in turn, can gives rise to genome instability and vascular senescence. This review discusses the role of the DNA damage response, including the key DNA repair pathways (base excision repair, nucleotide excision repair, homologous recombination and non-homologous end joining), deregulated cell cycle and apoptosis in atherosclerosis. We also highlight emerging evidence suggesting that epigenetic changes (DNA methylation and microRNA-mediated mechanisms), not associated with alterations in DNA sequences, may play a critical role in the regulation of the DNA damage response. Nevertheless, further investigation is still required to better understand the complexity of DNA repair and DNA damage response in atherosclerosis, making this topic an exciting and promising field for future investigation. Unraveling these molecular mechanisms provide the rationale for the development of novel efficient therapies to combat the vascular aging process. PMID- 24075746 TI - Relationship of Von Willebrand Factor with carotid artery and aortic arch calcification in ischemic stroke patients. AB - BACKGROUND: Large population studies have revealed that increased von Willebrand Factor (VWF) levels are associated with an increased risk of ischemic stroke. In previous studies VWF was associated with atherosclerosis in healthy individuals. However, it is yet unknown what the association is between atherosclerosis and VWF levels in patients with ischemic stroke. OBJECTIVES: The aim of our study was to determine the association of atherosclerosis, measured with recent developed techniques, and VWF levels in a large, well characterized, cohort of ischemic stroke patients and to determine the prognostic value. METHODS: We included 925 consecutive patients with transient ischemic attack (TIA) or ischemic stroke. Calcification volumes (mm(3)) were scored in the aortic arch and both carotid arteries using multidetector computed tomography (CT) angiography. VWF antigen (VWF:Ag) levels were measured using ELISA. RESULTS: Mean VWF:Ag levels were significantly higher in the presence of calcification in either the aortic arch (1.47 vs. 1.37 IU/ml [P = 0.039]) or the carotid arteries (1.49 vs. 1.34 IU/ml [P = 0.001]). Patients with a large artery atherosclerosis ischemic stroke had significantly higher VWF:Ag levels then the other TOAST subtypes (P < 0.0001). High VWF:Ag levels were associated with an unfavorable outcome (modified Rankin Scale >2 vs. <=2; 1.64 vs. 1.41 IU/ml, [P < 0.0001]). CONCLUSION: Our study showed a strong association between the extent of atherosclerosis in both the aortic arch and the carotid arteries and VWF levels in patients with TIA or ischemic stroke. Higher VWF levels are found in large artery atherosclerosis and are associated with a poor outcome. PMID- 24075747 TI - Akt and ERK/Nrf2 activation by PUFA oxidation-derived aldehydes upregulates FABP4 expression in human macrophages. AB - OBJECTIVE: In macrophages, adipocyte fatty acid-binding protein (FABP4) coordinates key events in oxidized LDL-induced foam cell formation, such as cholesterol trafficking and inflammatory responses. Nrf2 is a redox-sensitive transcription factor with antioxidant and anti-inflammatory properties. We investigated the involvement of the Nrf2 signaling pathway in FABP4-upregulation in response to aldehydes that are derived from polyunsaturated fatty acid (PUFA) oxidation. METHODS AND RESULTS: Using RT-PCR and western blotting, we found that the aldehyde 2,4-decadienal (2,4-DDE) produced a marked increase in FABP4 mRNA and protein levels. 2,4-DDE acts at the transcriptional level of FABP4 by promoting mRNA synthesis and prolonging the half-life of the de novo synthesized mRNA. 2,4-DDE consistently enhanced nuclear translocation of phosphorylated Nrf2, which was mediated by the activation of the Akt and ERK signaling pathways. A chromatin immunoprecipitation assay showed the in vivo binding of activated Nrf2 to a newly identified ARE site in the human FABP4 promoter. CONCLUSIONS: We propose an Akt and ERK/Nrf2-dependent FABP4 upregulation pathway in response to PUFA oxidation end-products in human macrophages. These results open a new avenue for putative therapeutic targets addressed to control atherogenesis. PMID- 24075748 TI - Serum lipopolysaccharide-binding protein as a marker of atherosclerosis. AB - BACKGROUND: Recently, serum lipopolysaccharide-binding protein (LBP) has been closely associated with coronary artery disease. Here, we aimed to investigate the possible relationship between serum LBP and markers of atherosclerosis. METHODS: Serum LBP and carotid intima media thickness (C-IMT) were measured in 332 subjects (101 men and 231 women) who were recruited from an ongoing multicenter project. RESULTS: Serum LBP was significantly associated with obesity [BMI, fat mass and waist circumference (r > 0.38, p < 0.0001)], HOMA (r = 0.36, p < 0.0001) and high sensitivity CRP (hsCRP) (r = 0.50, p < 0.0001). Circulating LBP was also positively associated with C-IMT (r = 0.27, p < 0.0001). Circulating LBP (beta = 0.16; p = 0.001) contributed independently to C-IMT variance, after controlling for the effects of age, gender, BMI and hsCRP. Of note, circulating LBP was found to be increased in the population with carotid plaque (n = 50; 32.7 +/- 12.5 vs 28.7 +/- 10.7; p = 0.021). CONCLUSION: The consistent association between serum LBP and the carotid intima media thickness, a widely used atherosclerosis marker, reveals serum LBP as a putative factor related to atherosclerosis. PMID- 24075749 TI - Haptoglobin 2 allele associates with unstable carotid plaque and major cardiovascular events. AB - OBJECTIVE: Intraplaque hemorrhages (IPH) may predispose to unstable atherosclerotic disease and its atherothrombotic complications, ischemic stroke and coronary syndromes. However, the discriminative value of IPH has been limited in histological and imaging studies suggesting that confounding factors modulate the response to IPH. We studied whether common variants of haptoglobin (Hp), which facilitates the removal of free hemoglobin and protects tissues from heme iron induced oxidative damage, would modify the inflammatory response to IPH and the risk of unstable carotid stenosis (CS) and major cardiovascular diseases. METHODS: We genotyped Hp polymorphism in 91 patients with a high-grade CS from Helsinki Carotid Endarterectomy Study (HeCES) and in 1417 individuals from Health 2000, a Finnish epidemiological cross-sectional health survey, and determined heme oxygenase-1 (HO1) expression in relation to Hp genotypes in carotid plaques. RESULTS: In the Health 2000 cohort, Hp genotype frequencies were 0.143 (hp1-1), 0.486 (hp1-2) and 0.371 (hp2-2) consistent with Hardy-Weinberg equilibrium and those reported from other Caucasian populations. Among patients with unstable CS, the frequency of hp2-2 genotype was higher than in the control population (0.516 vs. 0.371, P = 0.025). Hp genotypes correlated with HO1 expression in the plaque (r = 0.47, P = 0.027). In the Health 2000 cohort, hp2 allele was associated with an increased risk of major cardiovascular diseases (ischemic stroke, TIA, myocardial infarction, coronary heart disease) with an adjusted OR of 1.46 (95% CI 1.03-2.06). CONCLUSION: Common haptoglobin variants modulate the inflammatory response to IPH and associate with the risk of unstable carotid stenosis and major ischemic cardiovascular events. PMID- 24075750 TI - Plasma MR-proANP levels are associated with carotid intima-media thickness in the general community: the KORA F4 study. AB - OBJECTIVE: Subjects with metabolic syndrome (MetS) and individuals with type 2 diabetes are at high risk for vascular complications. Hormones acting on vascular endothelium may be involved in the atherogenic process associated with metabolic disorders. The objective of this study was to determine the correlation of pro atrial natriuretic hormone (proANP) with the presence of subclinical atherosclerosis. METHODS: In 1272 subjects participating in the KORA F4 study, we determined plasma levels of mid-regional proANP (MR-proANP) and the intima-media thickness (IMT) of the carotid artery. We used logistic regression models to investigate the relation of MR-proANP with components of MetS and IMT. RESULTS: In multiple adjusted regression models, MR-proANP levels were inversely associated with MetS (OR = 0.66, 95% CI 0.47-0.93), central obesity (OR = 0.67, 95% CI 0.46-0.96), raised triglyceride levels (OR = 0.53, 95% CI 0.37-0.77), prediabetes (OR = 0.62, 95%, CI 0.44-0.87) and type 2 diabetes (OR = 0.55, 95% CI 0.35-0.88) when comparing the top quartile vs. the lower three quartiles. Furthermore, there was an inverse relationship between MR-proANP and IMT. After adjustment for traditional cardiovascular risk markers, individuals with high MR proANP plasma levels in the top quartile (Q4) had significantly lower IMT values (Q4 vs. Q1-Q3: beta -0.0178, 95% CI -0.0344; -0.0013). CONCLUSIONS: In this population-based study, high plasma concentrations of MR-proANP were significantly associated with a lower incidence of MetS components and lower measures of early atherosclerosis. The data suggest a link between MR-proANP levels and the development of vascular complications. PMID- 24075751 TI - Elevated serum bilirubin levels are inversely associated with coronary artery atherosclerosis. AB - BACKGROUND: Inverse correlations of high serum bilirubin with metabolic and cardiovascular disease have been suggested. However, anti-atherogenic effects of bilirubin have not been well-established in terms of the presence of plaques and stenosis identified in coronary computed tomography (CT). METHODS: A cross sectional study was conducted on 2862 men who were free of cardiovascular disease and underwent coronary CT as part of a routine medical screening examination. Coronary stenotic lesions were considered to be incidences of coronary atherosclerosis, and stenosis was classified as stenosis <50% or >=50%, according to degree of stenosis. RESULTS: The prevalences of coronary atherosclerosis and stenosis >=50% in subjects with elevated bilirubin levels (>1.2 mg/dL) were lower than those in subjects with normal bilirubin levels (<=1.2 mg/dL) (19.9% vs. 27.9%, p < 0.001, 8.5% vs. 10.3%, p = 0.044). Bilirubin was inversely associated with total plaques (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.48-0.73 in the 4th quartile vs. 1st quartile) and calcified plaques (OR 0.60, 95% CI 0.49 0.75) in univariate analysis. After adjusting for traditional risk factors, it was found that coronary atherosclerosis (OR 0.73, 95% CI 0.56-0.94 in the 4th quartile vs. 1st quartile) and calcified plaque (OR 0.66, 95% CI 0.53-0.84) were inversely associated with the bilirubin grade in a dose-dependent manner. CONCLUSIONS: The serum bilirubin level was inversely associated with coronary atherosclerosis and calcified plaques in a dose-dependent manner. These results suggested that serum bilirubin could be used as a protective biomarker of coronary artery disease. PMID- 24075752 TI - Detection of variations and identifying genomic breakpoints for large deletions in the LDLR by Ion Torrent semiconductor sequencing. AB - OBJECTIVES: The aims of this study were to 1) compare LDLR variant detection between Ion Torrent Personal Genome Machine (PGM) sequencing and conventional methods used for familial hypercholesterolaemia (FH) diagnosis i.e. exon-by-exon sequence analysis and multiplex ligation-dependent probe amplification (MLPA) and 2) identify genomic breakpoints for 12 cases of large deletions in LDLR previously identified by MLPA. METHODS: Thirty FH patient samples were selected, 22 with mutations previously determined. Primers were designed and optimised to generate six amplicons covering the entire LDLR and sequenced on a PGM. An additional twelve samples carrying MLPA variants were sequenced on the PGM followed by Sanger sequencing to establish the breakpoints. RESULTS: A total of 2179 LDLR variants were identified in the 30 samples, with 383 variants in the region sequenced that was common to both PGM and Sanger methods. Three discrepancies were identified; two of these were identified by visual inspection of the BAM files, whilst the remaining discrepancy was likely an artefact of the PCR approach. Approximate genomic breakpoints for the 12 MLPA variants were identified using PGM sequencing, and Sanger sequencing of these regions established causative breakpoints. Eleven different rearrangements/mutational events were found, with eight out of eleven occurring in Alus. Two of the three samples with exons 2-6del had identical breakpoints. Two samples with exons 11 12del had unique breakpoints, indicating separate ancestral origin or mutational events. CONCLUSIONS: This study showed that Ion Torrent PGM sequencing is an accurate and efficient method to detect LDLR variants while providing additional information such as genomic breakpoints. PMID- 24075753 TI - STOMPing forward: statins, muscle complaints and CK. PMID- 24075754 TI - A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an emerging disease and a leading cause of chronic liver disease. The prevalence in the general population is approximately 15-30% and it increases to 70-90% in obese or diabetic populations. NAFLD has been linked to increased cardiovascular disease (CVD) risk. It is therefore critical to evaluate the relationship between markers of subclinical CVD and NAFLD. METHOD: An extensive search of databases; including the National Library of Medicine and other relevant databases for research articles meeting inclusion criteria: observational or cohort, studies in adult populations and clearly defined NAFLD and markers of subclinical CVD. RESULTS: Twenty-seven studies were included in the review; 16 (59%) presented the association of NAFLD and carotid intima-media thickness (CIMT), 7 (26%) the association with coronary calcification and 7 (26%) the effect on endothelial dysfunction and 6 (22%) influence on arterial stiffness. CIMT studies showed significant increases among NAFLD patients compared to controls. These were independent of traditional risk factors and metabolic syndrome. The association was similar in coronary calcification studies. The presence of NAFLD is associated with the severity of the calcification. Endothelial dysfunction and arterial stiffness showed significant independent associations with NAFLD. Two studies argued the associations were not significant; however, these studies were limited to diabetic populations. CONCLUSION: There is evidence to support the association of NAFLD with subclinical atherosclerosis independent of traditional risk factors and metabolic syndrome. However, there is need for future longitudinal studies to review this association to ascertain causality and include other ethnic populations. PMID- 24075756 TI - Journal bibliometrics indicators and citation ethics: a discussion of current issues. AB - Science has recently been accelerating at a fast rate, resulting in what has been called "information overload" and more recently "filter failure". In this perspective, journal performance indicators can play an important role in journal evaluation. Opinions on the appropriate use of journal-level bibliometrics indicators can be divided but they have now long been used as measures in research evaluation, and many editors see it as part of their editorial duty to try and improve bibliometrics indicators and rankings for their journal. There are various techniques through which this can be attempted, some more ethical than others. Some editors may try to boost the bibliometrics performance of their journals through gratuitous citations. This is problematic because citations are meant to provide useful references, scientifically justifiable, to previously published literature. As such citations can be used as widely accepted measures of scientific impact. Therefore, superfluous citations can distort the validity of bibliometrics indicators. It might be tempting to try to improve a journal's bibliometrics rankings at all costs, but these are only as meaningful as the data that feed into them. Exceedingly inflated indicators due to unethical behaviours can damage the reputation of a journal and its editors, and can lead to a loss of quality manuscript submissions, which in turn is likely to affect the journal's future citation impact. PMID- 24075755 TI - The prospective association of Chlamydia pneumoniae and four other pathogens with development of coronary artery calcium: the multi-ethnic study of atherosclerosis (MESA). AB - OBJECTIVE: Previous basic and cross-sectional studies obtained conflicting results regarding the association of pathogens with coronary artery calcium (CAC). The aim of this study is to prospectively evaluate this association in a population-based cohort. METHODS: We examined 5744 individuals aged 45-84 years at baseline (2000-02) who underwent repeated CAC assessment on average 2.4 years later (a half at visit 2 [2002-04] and the other half at visit 3 [2004-05]). CAC incidence was defined as newly detectable CAC at follow-up (475 cases of 2942 participants). CAC progression was defined as annualized change in CAC Agatston score >=10 units/year if baseline CAC score >0 to <100 or >=10%/year if baseline score >= 100 (1537 cases of 2802 participants). Seropositivity was assessed in the entire cohort for Chlamydia pneumoniae and in a random sample (n = 873) for Helicobacter pylori, cytomegalovirus, herpes simplex virus, and hepatitis A virus. RESULTS: Seropositivity to C. pneumoniae was not significantly associated with CAC incidence (odds ratio [OR] 1.11 [95% CI, 0.88-1.39], P = 0.371) or progression (1.14 [0.96-1.36], P = 0.135) even in unadjusted models. When CAC incidence and progression were combined, we observed significant association with C. pneumoniae seropositivity before adjustment (OR 1.17 [1.03-1.33], P = 0.016) but not in a model adjusting for traditional risk factors (1.04 [0.90-1.19], P = 0.611). The results were consistent across subgroups according to age, sex, and race/ethnicity. None of five pathogens or their accrual was associated with CAC incidence and progression in the subsample. CONCLUSION: Our prospective study does not support the pathophysiological involvement of these pathogens in CAC development. PMID- 24075757 TI - The association between physical activity and both incident coronary artery calcification and ankle brachial index progression: the multi-ethnic study of atherosclerosis. AB - OBJECTIVE: Both coronary artery calcification (CAC) and the ankle brachial index (ABI) are measures of subclinical atherosclerotic disease. The influence of physical activity on the longitudinal change in these measures remains unclear. To assess this relation we examined the association between these measures and self-reported physical activity in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: At baseline, the MESA participants were free of clinically evident cardiovascular disease. We included all participants with an ABI between 0.90 and 1.40 (n = 5656). Predictor variables were based on self-reported measures with physical activity being assessed using the Typical Week Physical Activity Survey from which metabolic equivalent-minutes/week of activity were calculated. We focused on physical activity intensity, intentional exercise, sedentary behavior, and conditioning. Incident peripheral artery disease (PAD) was defined as the progression of ABI to values below 0.90 (given the baseline range of 0.90-1.40). Incident CAC was defined as a CAC score >0 Agatston units upon follow up with a baseline score of 0 Agatston units. RESULTS: Mean age of participants was 61 years, 53% were female, and mean body mass index was 28 kg/m(2). After adjusting for traditional cardiovascular risk factors and socioeconomic factors, intentional exercise was protective for incident peripheral artery disease (Relative Risk (RR) = 0.85, 95% Confidence Interval (CI): 0.74-0.98). After adjusting for traditional cardiovascular risk factors and socioeconomic factors, there was a significant association between vigorous PA and incident CAC (RR = 0.97, 95% CI: 0.94-1.00). There was also a significant association between sedentary behavior and increased amount of CAC among participants with CAC at baseline (Deltalog (Agatston Units + 25) = 0.027, 95% CI 0.002, 0.052). CONCLUSIONS: These data suggest that there is an association between physical activity/sedentary behavior and the progression of two different measures of subclinical atherosclerotic disease. PMID- 24075758 TI - Wild rice (Zizania palustris L.) prevents atherogenesis in LDL receptor knockout mice. AB - OBJECTIVES: Dietary modifications including healthy eating constitute one of the first line strategies for prevention and treatment of cardiovascular disease (CVD) risk factors including high cholesterol and atherosclerosis. The purpose of the present study was to investigate the potential cardiovascular benefits of wild rice in male and female LDL-receptor-deficient (LDLr-KO) mice. METHODS: Wild rice was used to create a semi-synthetic diet containing approximately 60% of total energy from carbohydrate. Two other experimental diets were similar in macronutrient composition, but containing either white rice or commercial carbohydrate sources. All diets were supplemented with 0.06% (w/w) dietary cholesterol. The mice were divided into six experimental groups and fed with these diets over 24 weeks. RESULTS: Consumption of wild rice significantly reduced the size and severity of atherosclerotic lesions in the aortic roots of male and female mice by 71 and 61% respectively, compared to the control group of the same gender. This effect was associated with significant reductions of plasma cholesterol levels by 15 and 40%, low density lipoprotein (LDL) levels by 12 and 42%, and very low density lipoprotein (VLDL) levels by 35 and 75% respectively, in male and female mice compared to the control group of the same gender. Increased fecal cholesterol excretion of up to 34% was also noted, compared to the control group of the same gender. However, the antiatherogenic effect of wild rice was not associated with increased superoxide dismutase (SOD) and catalase (CAT) activities. CONCLUSION: Current data suggest that cholesterol-lowering effects of wild rice may be the main factor for the prevention of atherogenesis in LDLr-KO mice. Additional studies are needed to understand the mechanism of action. PMID- 24075759 TI - Effect of short-term vitamin D supplementation on markers of vascular health in South Asian women living in the UK--a randomised controlled trial. AB - OBJECTIVE: Low vitamin D levels and risk factors for vascular disease are both common in South Asian women. This trial evaluated whether vitamin D supplementation could improve markers of vascular health in South Asian women with low 25-hydroxyvitamin D levels. METHODS: Parallel-group, double-blind, randomised placebo-controlled trial. Healthy South Asian women with baseline serum 25-hydroxyvitamin D levels of <75 nmol/L were randomised to receive a single dose of 100,000 units oral vitamin D3 or matching placebo. Outcomes were measured at baseline, 4 and 8 weeks. The primary outcome was change in endothelial function measured using brachial artery flow-mediated dilatation. Secondary outcomes included blood pressure, arterial stiffness, microvascular function measured using laser Doppler iontophoresis, insulin resistance, serum lipids, circulating markers of inflammation, thrombosis and adipokines. RESULTS: 50 women were randomised, 25 to each group. Mean age was 41 years; mean baseline 25-hydroxyvitamin D level was 27 nmol/L. 25-Hydroxyvitamin D levels rose in the vitamin D group relative to the placebo group by 4 weeks (16 nmol/L, 95% CI 11 to 21, p < 0.001). There was no improvement in flow-mediated dilatation in the vitamin D group relative to placebo at 4 weeks (0.1%, 95% CI -0.9 to 1.1, p = 0.84) or 8 weeks (0.0%, 95% CI -1.4 to 1.4, p = 0.98). There was no improvement in cholesterol, insulin resistance or markers of inflammation. Both platelet activation inhibitor-1 and tissue plasminogen activator levels fell significantly in the vitamin D group relative to placebo at 8 weeks. CONCLUSION: A single large dose of vitamin D3 did not improve blood pressure or endothelial function in South Asian women with low baseline 25-hydroxyvitamin D levels. TRIAL REGISTRATION: ISRCTN75081811. PMID- 24075760 TI - No association of 9p21 with arterial elasticity and retinal microvascular findings. AB - OBJECTIVE: How 9p21 variation affects risk of cardiovascular disease is unclear, so we assessed whether 9p21 variants are associated with arterial elasticity or retinal microvascular findings. METHODS: In the prospective Multi-Ethnic Study of Atherosclerosis (MESA) we assessed 378 SNPs in the 9p21 locus. Within four ethnic groups, we used an additive genetic model to relate the 9p21 SNPs to five vascular phenotypes: small and large elasticity derived from radial diastolic pulse contour analysis; Young's elastic modulus from carotid artery ultrasound measurements; and the diameter of the central retinal arteries and veins. RESULTS: In neither ethnic-specific nor pooled data was there any statistically significant association between any of the 9p21 SNPs and any of the five vascular phenotypes. CONCLUSION: Our study does not support an association of 9p21 variation with arterial elasticity or retinal microvascular abnormalities. PMID- 24075761 TI - Atherogenesis in youth--early consequence of adolescent smoking. AB - BACKGROUND: Cigarette smoking is a prevalent risk behavior among adolescents and tracks into adulthood. Little is known on the early impact of smoking on the vasculature in adolescence, although smoking is considered highly atherogenic in adults. We investigated the association between active smoking and Carotid artery Intima Media Thickness (CIMT), an early indicator of atherosclerosis. METHODS AND RESULTS: The SAPALDIA Youth Study is a nested study involving 356 offspring (8-20 yrs) of the Swiss SAPALDIA cohort who reported on early life, health and lifestyle, smoking habits and disease history. 288 youth underwent clinical examination. Mean average and maximum CIMT were calculated across all images of right and left common carotid. Multi-level linear regression was performed with weekly smoking, daily number of cigarettes and serum cotinine, adjusting for participant's and parental confounders. Valid CIMT data was available in 275 offspring (mean age 15 yrs, 53% girls). Weekly smoking was reported by 10% and current parental smoking by 24%. Individual mean and maximal CIMT averaged to 0.52 mm (sd 0.05) and 0.60 mm (sd. 0.05), respectively. Regression analyses yielded significant increase in average CIMT (mm) in weekly smokers (0.025, 95% CI 0.006; 0.045), per cigarette/day (0.003, 95% CI 0.001; 0.005) and serum cotinine level (0.008/100 MUg/l, 95% CI 0.002; 0.015), which remained consistent after adjusting for parental confounders. CONCLUSION: Our study yields evidence of an early adverse impact of active tobacco exposure on atherogenesis in adolescents, independent of parental smoking, underlining the public health importance of prevention of adolescent smoking. PMID- 24075762 TI - Daily non-soy legume consumption reverses vascular impairment due to peripheral artery disease. AB - OBJECTIVE: Peripheral artery disease (PAD) results from a decrease in blood flow to the limbs due to the presence of atherosclerotic plaque. It has been reported that isoflavones isolated from soybeans reduce arterial stiffness, a component of atherosclerotic disease. This study examined the effect of consuming whole legumes (non-soy) on arterial function in humans with PAD. METHODS: Twenty-six individuals with PAD consumed 1/2 cup/day cooked legumes (beans, peas, lentils, chickpeas) daily for 8 weeks. Measurements of circulating factors and vascular function at baseline and study conclusion were compared. RESULTS: No changes in were detected relative to baseline values for most parameters. Total and LDL cholesterol were reduced by 5.0% and 8.7%, respectively. The ankle-brachial index (ABI) showed a 5.5% increase. Changes in ABI and LDL-cholesterol did not correlate. Serum markers of endothelial dysfunction and inflammation were unchanged, but short-chain acylcarnitine concentrations were significantly decreased. CONCLUSIONS: A legume-rich diet can elicit major improvements in arterial function and serum cholesterol in the absence of changes in either body mass or blood pressure, although the improvements in vascular function and serum lipids were unrelated. Although the positive results obtained with this dietary intervention were not explained by biomarkers of endothelial function and inflammation, altered acylcarnitine levels indicate an improvement in skeletal muscle metabolism due to enhanced tissue perfusion. PMID- 24075763 TI - Central hemodynamic modifications in diabetes mellitus. AB - Arterial stiffness in hypertension is markedly influenced by age, mean arterial pressure (MAP) and heart rate, whereas factors influencing this parameter in diabetes mellitus are not yet fully understood. The aim of our study was to compare central hemodynamics in diabetics (n = 126) versus non-diabetic controls (n = 203), most of whom were hypertensive, and with similar MAP. Anthropometric, laboratory and clinical measurements were collected. Hemodynamic parameters (central blood pressure, aortic pulse wave velocity [PWV], augmentation index [AIx] and pulse pressure amplification [PPA]) were measured using applanation tonometry. PWV and AIx were significantly higher in diabetics, after adjustment for age, gender, MAP, and heart rate. After further adjustment for metabolic syndrome, only the difference in PWV persisted (P < 0.0001). PPA was marginally altered though not significantly. In diabetics, PWV did not correlate with MAP, suggesting that other structural alterations, resulting from insulin resistance, may account for diabetic arterial stiffening to a greater extent than, and independently of, blood pressure. Chronic treatment with insulin was associated with increased PWV, independently of blood pressure, diabetes control and duration, or other common confounding variables. In conclusion, hypertensive diabetics had greater arterial stiffness than hypertensive controls. In diabetes, multiple factors affect arterial stiffening independently of hemodynamic status. Notably, insulin therapy (IT) is associated with more severe arterial stiffness, suggesting a consistent relationship between these parameters. It remains to be determined whether IT should be considered as a marker of diabetes severity that leads to increased arterial stiffness, or whether it has a direct/indirect effect on arterial wall modifications. PMID- 24075764 TI - Inhibition of intestinal cholesterol absorption with ezetimibe increases components of reverse cholesterol transport in humans. AB - OBJECTIVE: Reverse cholesterol transport (RCT) can be defined as a pathway of flux of cholesterol from peripheral tissues to the liver for potential excretion into feces. This prospective, placebo-controlled, double-blind crossover study assessed the effect of ezetimibe on several RCT parameters in hyperlipidemic patients. METHODS: Following 7 weeks of treatment (ezetimibe 10 mg/day or placebo), 26 patients received 24-h continuous IV infusions of [3,4-(13)C2] cholesterol, then took heavy water ((2)H2O) by mouth. Cholesterol excretion was measured by quantification of neutral/acid sterols in stool and blood samples during 7 days post-infusion with continued treatment. Plasma de novo cholesterol synthesis was assessed by (2)H-labeling from (2)H2O. RESULTS: Ezetimibe significantly reduced levels of low-density lipoprotein cholesterol (22%, P < 0.001) without significant changes in triglycerides and high-density lipoprotein cholesterol and significantly increased the flux of plasma-derived cholesterol into fecal neutral sterols by 52% (P = 0.04) without change in flux into fecal bile acids. Total fecal neutral sterol output increased by 23% (P = 0.02). Plasma de novo cholesterol synthesis increased by 57% (P < 0.001). The fractional clearance rate (FCR) of plasma cholesteryl-ester trended higher (7%; P = 0.055) with a reduction in absolute cholesteryl-ester production rate (9%, P < 0.01). Whole-body free cholesterol efflux rate from extra-hepatic tissues into plasma was not measurably changed by ezetimibe. CONCLUSION: Ezetimibe treatment approximately doubled the flux of plasma-derived cholesterol into fecal neutral sterols, in association with increases in total fecal neutral sterol excretion, FCR of plasma cholesterol ester, and plasma de novo cholesterol synthesis. These effects are consistent with increased cholesterol transport through the plasma compartment and excretion from the body, in response to ezetimibe treatment in hyperlipidemic humans. Clintrials.gov: NCT00701727. PMID- 24075765 TI - Asymptomatic cervicocerebral atherosclerosis, intracranial vascular resistance and cognition: the AsIA-neuropsychology study. AB - BACKGROUND AND PURPOSE: Carotid atherosclerosis has emerged as a relevant contributor to cognitive impairment and dementia whereas the role of intracranial stenosis and vascular resistance in cognition remains unknown. This study aims to assess the association of asymptomatic cervicocerebral atherosclerosis and intracranial vascular resistance with cognitive performance in a large dementia free population. METHODS: The Barcelona-AsIA (Asymptomatic Intracranial Atherosclerosis) Neuropsychology Study included 747 Caucasian subjects older than 50 with a moderate-high vascular risk (assessed by REGICOR score) and without history of neither symptomatic vascular disease nor dementia. Extracranial and transcranial color-coded duplex ultrasound examination was performed to assess carotid intima-media thickness (IMT), presence of carotid plaques (ECAD group), intracranial stenosis (ICAD group), and middle cerebral artery pulsatility index (MCA-PI) as a measure of intracranial vascular resistance. Neuropsychological assessment included tests in three cognitive domains: visuospatial skills and speed, verbal memory and verbal fluency. RESULTS: In univariate analyses, carotid IMT, ECAD and MCA-PI were associated with lower performance in almost all cognitive domains, and ICAD was associated with poor performance in some visuospatial and verbal cognitive tests. After adjustment for age, sex, vascular risk score, years of education and depressive symptoms, ECAD remained associated with poor performance in the three cognitive domains and elevated MCA-PI with worse performance in visuospatial skills and speed. CONCLUSIONS: Carotid plaques and increased intracranial vascular resistance are independently associated with low cognitive functioning in Caucasian stroke and dementia-free subjects. We failed to find an independent association of intracranial large vessel stenosis with cognitive performance. PMID- 24075766 TI - Consumption of plant sterol-enriched foods and effects on plasma plant sterol concentrations--a meta-analysis of randomized controlled studies. AB - OBJECTIVE: Intake of plant sterol (PS)-enriched foods effectively lowers plasma total- and LDL-cholesterol concentrations while increasing plasma PS concentrations. The magnitude of this increase has not been systematically assessed. This study aimed to investigate the effect of PS-enriched foods on plasma PS concentrations by performing a meta-analysis of randomized controlled studies. METHODS: Published PS intervention studies reporting plasma PS concentrations were searched through June 2012. Studies were selected that fulfilled pre-defined in- and exclusion criteria. Data were extracted, particularly on campesterol, sitosterol, total- and LDL-cholesterol. Random effects models were used to calculate net effects while weighing each study by the inverse of its variance. Potential sources of heterogeneity were investigated. RESULTS: The meta-analysis included data from 41 studies (55 strata) with in total 2084 subjects. The average dose of PS from enriched foods was 1.6 g/d (range: 0.3-3.2 g/d). Plasma sitosterol and campesterol concentrations were increased by on average 2.24 MUmol/L (31%) and 5.00 MUmol/L (37%), respectively, compared to control. Total- and LDL-cholesterol were reduced by on average 0.36 mmol/L (5.9%) and 0.33 mmol/L (8.5%), respectively. The increase in sitosterol and campesterol was impacted by the dose of PS, the baseline PS concentration and the PS composition of the test products. In the highest PS dose category (2.0-3.2 g/d), increases in sitosterol and campesterol were on average 3.56 and 7.64 MUmol/L, respectively. CONCLUSION: Intake of PS enriched foods increases plasma sitosterol and campesterol concentrations. However, total PS remain below 1% of total sterols circulating in the blood. PMID- 24075767 TI - Mediterranean diet supplemented with nuts reduces waist circumference and shifts lipoprotein subfractions to a less atherogenic pattern in subjects at high cardiovascular risk. AB - OBJECTIVE: The PREDIMED trial showed that Mediterranean diets supplemented with either extra-virgin olive oil or nuts reduced incident cardiovascular events compared to a control diet. Consumption of both supplemental foods has been associated with reduced LDL-cholesterol, but it is unknown whether they can shift lipoprotein subfractions to a less atherogenic pattern. We investigated changes in adiposity and lipoprotein subfractions after consumption of the PREDIMED diets. METHODS: In a PREDIMED sub-cohort (n = 169), lipoprotein subclasses (particle concentrations and size) were determined by nuclear magnetic resonance spectroscopy at baseline and after intervention for 1 year. RESULTS: Participants allocated to the Mediterranean diet supplemented with nuts showed significant reductions from baseline of waist circumference (mean [95% CI]; -5 cm [-7; -3]) and concentrations of medium-small (-27 nmol/l [-46; -8]) and very small LDL ( 111 nmol/l [-180; -42]); decreased LDL particle number (a nuclear magnetic resonance-specific measurement) (-98 nmol/l [-184; -11]); and an increase of large LDL concentrations (54 nmol/l [18; 90]), with a net increase (0.2 nmol/l [0.1; 0.4]) of LDL size. The Mediterranean diets with olive oil and nuts increased large HDL concentrations (0.6 MUM [0.0; 1.1] and 1.0 MUM [0.4; 1.5], respectively). Compared to the other two intervention groups, participants in the nut-enriched diet showed significantly reduced waist circumference (p <= 0.006, both) and increased LDL size (p < 0.05, both). CONCLUSION: Lipoprotein subfractions are shifted to a less atherogenic pattern by consumption of Mediterranean diets enriched with nuts. The results contribute mechanistic evidence for the reduction of cardiovascular events observed in the PREDIMED trial. PMID- 24075768 TI - New insights into lipid raft function regulating myocardial vascularization competency in human idiopathic dilated cardiomyopathy. AB - OBJECTIVE: Idiopathic dilated cardiomyopathy (IDCM) affects myocardial vascularization. Whether a lack of demand for increased myocardial vascularization and/or an impaired response of circulating angiogenic-supportive cells are responsible for the vascular derangements found in IDCM is unknown. METHODS AND RESULTS: Left ventricle (LV) samples obtained at transplant from IDCM hearts were compared to control hearts from non-cardiac decedents. Peripheral colony-forming myeloid cells were extracted from age- and sex-matched IDCM patients and healthy volunteers. At the tissue level, no differences were detected in stromal cell-derived factor (SDF)-1alpha expression, but integrin linked kinase (ILK) levels and activity were increased in IDCM. A marked co localization of SDF-1alpha and the specific marker of cholesterol-enriched lipid rafts Flotillin (Flot)-1 was found in IDCM. SDF-1alpha was also highly distributed into IDCM lipid rafts. Non-adherent pro-angiogenic cells from both groups, which were found increased in patients but showed similar surface levels of CXCR-4, equally supported Matrigel-mediated cell network formation. However, SDF-1-mediated migration was reduced in IDCM-derived cells, which also exhibited decreased ILK activity and downstream ERK activation. CONCLUSIONS: Taken together, our results point out that myocardial competency to increase vascularization is not altered in IDCM, but dysfunctional SDF-1-mediated migration by peripheral pro-angiogenic cells through ILK and downstream ERK signaling may compromise endothelial recovery in patients. We provide new insights into lipid raft function in human IDCM and envision more effective treatments. PMID- 24075769 TI - Regulation of monocyte/macrophage function by factor VII activating protease (FSAP). AB - OBJECTIVE: Factor VII activating protease (FSAP) is a novel regulator of vascular inflammation and hemostasis. However, the molecular mechanism by which circulating FSAP influences inflammatory events and progression of atherosclerosis is not yet entirely understood. Here we have investigated the influence of FSAP on monocyte/macrophage functions. METHODS: We stimulated human monocyte-derived macrophages with FSAP and analyzed their cellular responses. RESULTS: FSAP induced IkappaB-dependent NF-kappaB activation in a time- and concentration-dependent fashion. FSAP also activated the phosphorylation and proteolytic degradation of the inhibitor protein IkappaBalpha. The phosphorylation of the p65 subunit of NF-kappaB was induced by FSAP, which is known to contribute to the enhancement of DNA-binding activity of NF-kappaB. Concomitantly, FSAP up-regulated the expression of pro-inflammatory cytokines, matrix metalloproteinases, cell adhesion molecules and tissue factor. In the presence of FSAP there was increased monocytes adhesion and transendothelial migration in a beta2 integrin dependent manner. CONCLUSIONS: Our findings suggest that FSAP activates the NF-kappaB pathway and the associated downstream pro inflammatory factors in monocytic cells. This adds to a spectrum of FSAP effects on the vascular system that may explain its association with cardiovascular diseases. PMID- 24075770 TI - Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-beta agonist. AB - MGL-3196 is an oral, liver-targeted selective agonist for the thyroid hormone receptor-beta (THR-beta) that is being developed for the treatment of dyslipidemia. The safety profile and tolerability of THR-beta agonist MGL-3196 was assessed in first-in humans studies, including a single ascending dose study (NCT01367873) in which MGL-3196 appeared safe at all doses tested. A two-week multiple dose study was conducted at doses of 5, 20, 50, 80, 100, and 200 mg per day in healthy subjects with mildly elevated low density lipoprotein (LDL) cholesterol (>110 mg/dL) (NCT01519531). MGL-3196 was well-tolerated at all doses with no dose-related adverse events or liver enzyme, ECG or vital-sign changes. At the highest dose, there was a reversible reduction of ~20% in the level of pro hormone, free thyroxine (free T4) that was significantly different from placebo (p < 0.0001) that may be explained by increased hepatic metabolism of T4. There was no change in thyrotropin (TSH) or triiodothyronine (free T3) or other evidence of central thyroid axis dysfunction at any dose. Doses ranging from 50 to 200 mg demonstrated highly statistically significant reductions relative to placebo of up to: 30% for LDL cholesterol (range, p = 0.05-<0.0001); 28% for non- high density lipoprotein (HDL) cholesterol (range, p = 0.027-0.0001); 24% for Apolipoprotein B (range, p = 0.008-0.0004), and statistical trends of up to 60% reduction in triglycerides (TG) (range, p = 0.13-0.016). The near maximal lipid effects were observed at a dose of 80 mg daily. In summary, in a two-week study in healthy volunteers with mild LDL cholesterol elevation, MGL-3196 appeared safe, was well-tolerated and showed a beneficial effect on lipid parameters. PMID- 24075771 TI - Update on marine omega-3 fatty acids: management of dyslipidemia and current omega-3 treatment options. AB - Low-density lipoprotein cholesterol (LDL-C) is currently the primary target in the management of dyslipidemia, and statins are first-line pharmacologic interventions. Adjunct therapy such as niacins, fibrates, bile acid sequestrants, or cholesterol absorption inhibitors may be considered to help reduce cardiovascular risk. This review discusses the need for alternative adjunct treatment options and the potential place for omega-3 fatty acids as such. The cardiovascular benefits of fish consumption are attributed to the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and a variety of omega-3 fatty acid products are available with varied amounts of EPA and DHA. The product types include prescription drugs, food supplements, and medical foods sourced from fish, krill, algal and plant oils or purified from these oils. Two prescription omega-3 fatty acids are currently available, omega-3 fatty acid ethyl esters (contains both EPA and DHA ethyl esters), and icosapent ethyl (IPE; contains high-purity EPA ethyl ester). A pharmaceutical containing free fatty acid forms of omega-3 is currently in development. Omega-3 fatty acid formulations containing EPA and DHA have been shown to increase LDL-C levels while IPE has been shown to lower triglyceride levels without raising LDL-C levels, alone or in combination with statin therapy. In addition, recent studies have not been able to demonstrate reduced cardiovascular risk following treatment with fibrates, niacins, cholesterol absorption inhibitors, or omega-3 fatty acid formulations containing both EPA and DHA in statin-treated patients; thus, there remains a need for further cardiovascular outcomes studies for adjunct therapy. PMID- 24075773 TI - Statins and dementia: does length of statins use matter? PMID- 24075772 TI - Tumor necrosis factor-alpha inhibition improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women. AB - OBJECTIVE: Tumor necrosis factor (TNF)-alpha, a pleiotropic pro-inflammatory cytokine involved in a variety of biological processes including oxidative stress, has been associated with vascular dysfunction in aged and ovariectomized animals. We determined whether acute inhibition of TNF-alpha improves vascular endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women. METHODS: Arterial stiffness (carotid artery compliance) and endothelial function (brachial artery flow-mediated dilation [FMD]) were measured in postmenopausal women (n = 23; 57 +/- 1 years, mean +/- SE) before and following randomization to two days of either transdermal estradiol (0.05 mg/d, N = 12) or placebo (N = 11) alone and following a single subcutaneous injection of the TNF-alpha inhibitor, etanercept (25 mg), and in premenopausal (n = 9; 33 +/- 2 years) before and following etanercept. RESULTS AND CONCLUSIONS: Baseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than premenopausal women (P < 0.0001). In postmenopausal women, carotid artery compliance (n = 12; 0.59 +/- 0.05-0.78 +/- 0.06 mm(2)/mmHg * 10(-1), P < 0.001) and FMD (4.1 +/- 0.6-6.0 +/- 0.7%, P = 0.02) increased in response to estradiol but not placebo (n = 11). Carotid artery compliance (0.71 +/- 0.06-0.81 +/- 0.06 mm(2)/mmHg * 10(-1), P = 0.02) and FMD (5.2 +/- 0.7-7.5 +/- 0.9%, P = 0.003) increased with etanercept in the placebo group but had no effect in postmenopausal randomized to estradiol or premenopausal women. These results suggest that TNF-alpha contributes to impaired endothelial-dependent vasodilation and arterial stiffening in estrogen-deficient postmenopausal women. PMID- 24075774 TI - The utility of ultrasonic tissue characterization of carotid plaque in the prediction of cardiovascular events in diabetic patients. AB - OBJECTIVE: The aim of this study was to evaluate whether non-invasive ultrasonic tissue characterization of carotid plaque using gray-scale median (GSM) can be a predictor of future cardiovascular disease (CVD) events in type 2 diabetic patients. METHODS: A total of 287 type 2 diabetic patients with carotid plaque but without CVD were enrolled (male 72%, mean age 65 +/- 7 years). We prospectively evaluated the association between GSM, a quantitative parameter of the plaque echogenicity, and CVD. RESULTS: The median follow-up period was 55 months, and there were 34 new CVD events. The risk of CVD event was significantly higher in the patients with echolucent (GSM <= 37) plaque (n = 67) as compared to those without (n = 220) (HR = 6.99, 95% CI 3.46-14.14, p < 0.001). Cox proportional hazards regression analysis showed that the presence of echolucent plaque (HR = 4.55, 95% CI 2.10-19.84, p < 0.001) as well as plaque thickness (HR = 1.44, 95% CI 1.01-2.06, p = 0.005) were independent predictors of CVD, even after adjustment for other risk factors. Time-dependent receiver-operating characteristic curve analysis revealed that the addition of plaque thickness to Framingham risk score (FRS) resulted in significant increase in area under the curve (AUC) [from 0.60 (95% CI; 0.49-0.70) to 0.73 (95% CI; 0.63-0.82), p < 0.05]. Notably, the addition of plaque echogenicity (presence/absence of echolucent plaque) to the FRS and plaque thickness resulted in further and significant increase in AUC [from 0.73 (95% CI; 0.63-0.82) to 0.82 (95% CI; 0.75 0.88), p < 0.05]. CONCLUSION: Ultrasonic tissue characterization of carotid plaque using the GSM can improve the risk prediction of cardiovascular event in asymptomatic type 2 diabetic patients with carotid plaque. PMID- 24075776 TI - CD4+ CD28(null) cells are an independent predictor of mortality in patients with heart failure. AB - AIMS: Immune activation and subsequent release of proinflammatory cytokines plays a central role in the pathophysiology of chronic heart failure (CHF). Cytotoxic CD4(+)CD28(null) cells are generated under inflammatory conditions and implicated in a variety of pathological processes like atherosclerosis and autoimmune diseases. The study aim was to assess the impact of CD4(+)CD28(null) cells on survival in CHF patients. METHODS AND RESULTS: Circulating lymphocytes from 107 CHF patients were analyzed for the distribution of CD4 subsets by flow cytometry. During a median follow-up of 23 months, 22 (20%) persons died. CD4(+)CD28(null) cells independently predicted all-cause mortality with an adjusted hazard ratio (HR) of 1.88 per 1-standard deviation increase (95% confidence interval (CI): 1.26-2.79, P = 0.002) and with a HR of 1.83 for cardiovascular mortality (95% CI: 1.18-2.86, P = 0.008), respectively. Further, we found a significant association with NT-proBNP (r = 0.23). CONCLUSION: Circulating CD4(+)CD28(null) cells are associated with CHF severity and are a strong and independent predictor of mortality in CHF fostering the implication of the immune system in CHF pathophysiology. PMID- 24075775 TI - Docosahexaenoic acid (DHA)-induced heme oxygenase-1 attenuates cytotoxic effects of DHA in vascular smooth muscle cells. AB - OBJECTIVE: Docosahexaenoic acid (DHA), a member of n-3 polyunsaturated fatty acids (n-3 PUFA) is a potent regulator of molecular events implicated in cardiovascular health. In a previous study we found that Ca(2+)-dependent oxidative stress is the central and initial event responsible for induction of unfolded protein response (UPR), cell cycle arrest and apoptosis in DHA treated primary human smooth muscle cells isolated from small pulmonary artery (hPASMC). In the present study we examined the impact of heme oxygenase (HO)-1, induced by DHA, on DHA-induced oxidative stress, UPR, cell proliferation and apoptosis in hPASMC. METHODS & RESULTS: DHA led to a time- and concentration-dependent increase in HO-1 mRNA and protein levels in hPASMC. The DHA-induced HO-1 upregulation could be attenuated by preincubation of cells with a strong antioxidant Tempol or by siRNA-mediated depletion of nuclear factor erythroid 2 related factor-2 (Nrf2). In DHA-treated hPASMC, depletion of HO-1 by siRNA mediated silencing resulted in increased levels of reactive oxygen species (ROS) and increased duration of UPR, the latter revealed by monitoring of spliced X-box binding protein 1 (XBP-1) variant. Moreover, HO-1 silencing augmented apoptosis in DHA-treated hPASMC as found by increased numbers of cleaved caspase-3-positive cells. HO-1 silencing did not affect proliferation of hPASMC exposed to DHA. CONCLUSION: Our results indicate that DHA-induced, ROS-dependent upregulation of HO-1 attenuates oxidative stress, UPR and apoptosis in DHA-treated hPASMC. PMID- 24075777 TI - A phase 1B study of dulanermin in combination with modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer. AB - OBJECTIVES: The study objectives were to evaluate the safety, tolerability, and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced, recurrent, or metastatic colorectal cancer. PATIENTS AND METHODS: A total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed. RESULTS: In the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0 12.7). CONCLUSIONS: Overall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population. PMID- 24075778 TI - Validity of administrative data for identifying patients who have had a stroke or transient ischemic attack using EMRALD as a reference standard. AB - BACKGROUND: Surveillance for stroke/transient ischemic attack (TIA) using administrative data has traditionally been limited to reporting patients who had an acute event and were hospitalized. This underestimates the true prevalence because many events do not result in hospitalization. We examined whether the accuracy of administrative data for identifying prevalent stroke/TIA could be improved by using data from both inpatient and outpatient visits. METHODS: An administrative data validation reference standard was developed through chart abstraction of 5000 adult patients randomly sampled from 73,014 patients of 83 family physicians who participate in the Electronic Medical Record Administrative Data Linked Database (EMRALD), in Ontario, Canada. RESULTS: The prevalence of stroke/TIA in our adult population was 3.0%. An algorithm of 1 hospital record had a sensitivity of 35.3% (27.7%-43.0%) and specificity of 99.8% (99.7%-99.9%), whereas an algorithm of 2 physician billings within 1 year or 1 hospitalization had a sensitivity of 68.0% (95% confidence interval [CI], 60.5%-75.5%) and specificity of 98.9% (95% CI, 98.6%-99.2%) for the identification of patients who had ever had a stroke/TIA. We found that hospitalization data underestimated the prevalence of stroke by > 50% and TIA by > 66% compared with using both hospitalization and physician claims data. CONCLUSIONS: The use of outpatient physician claims data in addition to hospitalization data improves the sensitivity of administrative data for the identification of prevalent stroke/TIA and may be used to estimate the prevalence of cerebrovascular events in large populations and over time. PMID- 24075779 TI - Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic breast cancer. AB - In 2009 a prospective, randomized Phase II trial (NCT00842998) was initiated to evaluate the activity of HER2-targeting agents without chemotherapy (CT) in HER2 positive metastatic breast cancer (MBC) patients. The primary tumors of the patients enrolled in this study offered a unique opportunity to identify biomarkers that could predict durable clinical benefit from CT-free anti-HER2 therapy. Patients with HER2-positive MBC were randomized to trastuzumab or lapatinib as first-line therapy. CT was added to anti-HER2 therapy in patients failing to achieve tumor regression at the 8-week evaluation and in those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded primary tumor samples. The research-based PAM50 intrinsic subtypes were also identified. Additionally, quantitative HER2 (H2T) and p95HER2 (p95) protein expression were evaluated by HERmark(r) and VeraTag(r) assay, respectively. Predictors of persistence on protocol (PP) were studied by Cox univariate and multivariate analysis. Nineteen patients were enrolled. Median overall survival was 43 months and median PP was 3.8 months (0.8 38.8+), with 4 patients (21.1%) persisting on single agent trastuzumab or lapatinib for longer than 12 mo (14.9-38.8 + mo). Seventeen patients were evaluable for PP. Gene expression analysis revealed that high expression of the 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were significantly associated with longer PP. Conversely, high expression of luminal-related genes such as PGR, MDM2 or PIK3CA, or the PAM50 luminal intrinsic profile correlated with reduced PP. Moreover, increasing H2T/p95 ratio was found to be significantly associated with longer PP (HR 0.56 per 2-fold increase in H2T/p95, P = 0.0015). Our data suggest that patients belonging to the "HER2-enriched" subtype and/or having high H2T/p95 protein expression ratio are exquisitely sensitive to anti-HER2 agents. MBC patients with these tumors could be candidates for studies aimed at establishing chemotherapy free regimens. PMID- 24075780 TI - Epidemiology of distal humerus fractures in the elderly. AB - INTRODUCTION: Despite recent treatment advances, management of distal humerus fractures in the elderly remains one of the most challenging aspects of trauma surgery. Although these fractures are relatively rare, they fall under the umbrella of osteoporotic fractures, which themselves are increasing in frequency. MATERIAL AND METHODS: Two studies were performed: one retrospective study of 410 patients over a 10-year period and one prospective study of 87 patients over a 1.5-year period. This allowed us to analyse the epidemiology of distal humerus fractures in subjects above 64years of age in 19 different French hospitals. All of the included patients were reviewed, except for one subject in the retrospective study who had died, but whose data was still used. RESULTS: Most of the fractures were AO type C, occurred in women in more than 80%, and occurred in nearly one of two persons above 80 years of age. Most of the patients had a high level of autonomy and lived at home. Unlike other upper limb fracture sites, nearly 90% of patients required surgical treatment. The presence of osteoporosis was found to have a tremendous impact on fracture care, complications and results. CONCLUSION: Functional status is more important than chronological age in this patient population; the former must be taken into account when determining treatment indications. LEVEL OF EVIDENCE: Level IV. PMID- 24075781 TI - Ikappa B kinase alpha involvement in the development of nasopharyngeal carcinoma through a NF-kappaB-independent and ERK-dependent pathway. AB - OBJECTIVES: Ikappa B kinase alpha (IKKalpha) plays an inhibitory role in the development of epithelial-derived tumors. However, its specific function in the development of nasopharyngeal carcinoma (NPC) remains unknown. In this study we identify the role and mechanism of IKKalpha in IKKalpha-mediated NPC development. MATERIAL AND METHODS: The effect of IKKalpha on migration, invasion and tumorigenesis of NPC cell lines was determined using in vitro and in vivo studies. SUNE-1-5-8F cells transfected to overexpress IKKalpha, SUNE-1-6-10B cells with shRNA-mediated knockdown of IKKalpha, and three NPC cell lines were studied using Western blotting techniques to compare the major molecules in NF kappaB pathways. Additionally, the extracellular signal-regulated kinase (ERK) pathway and matrix metalloproteinases (MMPs) in IKKalpha-regulated NPC and the effect of Epstein-Barr Nuclear Antigen 1 (EBNA1) on IKKalpha were examined. RESULTS: IKKalpha was underexpressed in highly invasive SUNE-1-5-8F cells compared with non-invasive cells (SUNE-1 and SUNE-6-10B). Overexpression of IKKalpha in SUNE-1-5-8F cells was achieved through transfection and resulted in inhibited migration and invasion in vitro. Furthermore, IKKalpha inhibited tumorigenesis in mice inoculated with IKKalpha-transfected NPC cells in vivo. These processes were independent of the conventional effect of IKKalpha on Nuclear factor kappaB (NF-kappaB) pathways. The ERK pathway was involved in IKKalpha-related NPC inhibition. Phosphorylation of ERK1/2 and subsequent secretion of MMP-9 were inhibited by the ERK inhibitor U0126 and not regulated by overexpressed IKKalpha. EBNA1 knockdown using small interfering RNA (siRNA) did not alter the expression of IKKalpha. CONCLUSION: Increase in IKKalpha expression suppresses the progression of NPC through a NF-kappaB-independent and ERK dependent pathway. PMID- 24075782 TI - Scapulothoracic and glenohumeral contributions to motion in children with brachial plexus birth palsy. AB - BACKGROUND: Brachial plexus birth palsy occurs in 0.4 to 4.6 of every 1000 live births, with residual shoulder dysfunction in approximately one third of cases. Clinical measures, such as the Mallet classification, provide no insight into the scapulothoracic and glenohumeral contributions to tested global shoulder movements. This study describes the scapulothoracic and glenohumeral components of shoulder motion during the modified Mallet test. METHODS: Twelve children with Erb's palsy (C5-6) and 8 children with extended Erb's palsy (C5-7) were recruited. The unaffected limbs of 6 subjects were also tested. Locations of markers placed on the thorax, humerus, and scapula were recorded in a neutral position and each of the modified Mallet positions. Scapulothoracic, glenohumeral, and humerothoracic helical displacements and acromion process linear displacements were compared between groups. RESULTS: The brachial plexus birth palsy groups exhibited significantly smaller glenohumeral displacements in all modified Mallet positions and significantly larger scapulothoracic displacements in the global external rotation and hand to mouth positions. Discriminant function analysis using only humerothoracic variables correctly classified 76.9% of subjects. Discriminant function analysis incorporating scapulothoracic, glenohumeral, and acromion process displacement variables produced accuracy of 92.6%. CONCLUSIONS: Children with brachial plexus birth palsy demonstrated decreased glenohumeral contributions to achieve every modified Mallet position and increased scapulothoracic contribution in two positions compared with the unaffected group. Different scapulothoracic and glenohumeral strategies were identified between groups. Finally, scapulothoracic and glenohumeral components of shoulder motion are more specific than humerothoracic measures to diagnostic classification. PMID- 24075783 TI - High-pitch coronary CT angiography in dual-source CT during free breathing vs. breath holding in patients with low heart rates. AB - BACKGROUND: Coronary CT angiography (CCTA) is usually performed during breath holding to reduce motion artifacts caused by respiration. However, some patients are not able to follow the breathing commands adequately due to deafness, hearing impairment, agitation or pulmonary diseases. The aim of this study was to evaluate the potential of high-pitch CCTA in free breathing patients when compared to breath holding patients. METHODS: In this study we evaluated 40 patients (20 free breathing and 20 breath holding patients) with a heart rate of 60 bpm or below referred for CCTA who were examined on a 2nd generation dual source CT system. Image quality of each coronary artery segment was rated using a 4-point grading scale (1: non diagnostic-4: excellent). RESULTS: Mean heart rate during image acquisition was 52 +/- 5 bpm in both groups. There was no significant difference in mean image quality, slightly favoring image acquisition during breath holding (mean image quality score 3.76 +/- 0.32 in breath holding patients vs. 3.61 +/- 0.45 in free breathing patients; p = 0.411). Due to a smaller amount of injected contrast medium, there was a trend for signal intensity to be slightly lower in free breathing patients, but this was not statistically significant (435 +/- 123 HU vs. 473 +/- 117 HU; p=0.648). CONCLUSION: In patients with a low heart rate who are not able to hold their breath adequately, CCTA can also be acquired during free breathing without substantial loss of image quality when using a high pitch scan mode in 2nd generation dual-source CT. PMID- 24075784 TI - Proton MRI in the evaluation of pulmonary sarcoidosis: comparison to chest CT. AB - PURPOSE: The purpose of this study was to determine the feasibility of proton MRI of the lung in sarcoidosis patients and the agreement between the imaging appearance of pulmonary sarcoidosis on MRI and CT. MATERIALS AND METHODS: Chest CT scans and dedicated pulmonary MRI scans (including HASTE, VIBE, and TrueFISP sequences) were performed within 90 days of each other in 29 patients. The scans were scored for gross parenchymal opacification, reticulation, nodules, and masses using a 3-point lobar scale. Total and subset scores for corresponding MRI and CT scans were compared using the Spearman correlation test, Bland-Altman plots, and Cohen's quadratic-weighted kappa analysis. MRI scores were compared to CT by lobe and disease category, using percentage agreement, Spearman rank correlation, and Cohen's quadratic-weighted kappa. RESULTS: The mean (+/- s.d.) time between MRI and CT scans was 33 +/- 32 days. There was substantial correlation and agreement between total disease scoring on MRI and CT with a Spearman correlation coefficient of 0.774 (p<0.0001) and a Cohen's weighted kappa score of 0.646. Correlation and agreement were highest for gross parenchymal opacification (0.695, 0.528) and reticulation (0.609, 0.445), and lowest in the setting of nodules (0.501, 0.305). Agreement testing was not performed for mass scores due to low prevalence. Upper lobe scoring on MRI and CT demonstrated greater agreement compared to the lower lobes (average difference in Cohen's weighted kappa score of 0.112). CONCLUSION: There is substantial correlation and agreement between MRI and CT in the scoring of pulmonary sarcoidosis, though MRI evaluation in the upper lobes may be more accurate than in the lower lobes. PMID- 24075785 TI - Outcome of uterine artery embolization versus MR-guided high-intensity focused ultrasound treatment for uterine fibroids: long-term results. AB - OBJECTIVES: To compare the long-term outcome after uterine artery embolization (UAE) versus magnetic resonance-guided high-intensity focused ultrasound (MR-g HIFU) for symptomatic uterine fibroids. METHODS: Seventy-seven women (median age, 39.3 years; range, 29.2-52.2 years) with symptomatic uterine fibroids, equally eligible for UAE and MR-g HIFU based on our exclusion criteria underwent treatment (UAE, N = 41; MR-g HIFU, N = 36) from 2002 to 2009 at our institution. Symptom severity (SS) and total health-related quality of life (Total HRQoL) scores were assessed by the uterine fibroid symptom and quality of life (UFS-QoL) questionnaire before treatment and at long-term follow-up after UAE (median 61.9 months) and after MR-g HIFU (median: 60.7 months). Re-intervention rates were assessed for each therapy and compared. RESULTS: Re-intervention was significantly lower after UAE (12.2%) than after MR-g HIFU (66.7%) at long-term follow-up (p<0.001). After UAE changes in SS (50 pre-treatment vs. 6.3 post treatment) and Total HRQoL (57.8 pre-treatment vs. 100 post-treatment) were significantly better than changes in SS (42.2 pre-treatment vs. 26.6 post treatment) and Total HRQoL score (66.4 pre-treatment vs. 87.9 post-treatment) after MR-g HIFU (p = 0.019 and 0.049 respectively). CONCLUSIONS: Improvement of SS and Total HRQoL scores was significantly better after UAE resulting in a significant lower re-intervention rate compared to MR-g HIFU. PMID- 24075786 TI - Preparation of uniform-sized exenatide-loaded PLGA microspheres as long-effective release system with high encapsulation efficiency and bio-stability. AB - Exenatide-loaded poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres hold great potential as a drug delivery system to treat type 2 diabetes mellitus (T2DM) because they can overcome the shortcoming of exenatide's short half-life and realize sustained efficacy. However, conventional preparation methods often lead to microspheres with a broad size distribution, which in turn would cause poor preparation repeatability, drug efficacy and so forth. In this study, we used Shirasu Porous Glass (SPG) premix membrane emulsification technique characterized with high trans-membrane flux and size controllability to prepare uniform-sized PLGA microspheres. By optimizing trans-membrane pressure and PVA concentration in external aqueous phase, uniform-sized PLGA microspheres with large size (around 20MUm) were successfully obtained. To achieve high encapsulation efficiency (EE) and improve in vitro release behavior, we have carefully examined the process parameters. Our results show that using ultrasonication to form primary emulsion, microspheres with high EE were easily obtained, but the rate of in vitro release was very slow. Instead, high EE and appropriate in vitro release were achieved when homogenization with optimized time and speed were employed. Besides, we also systematically investigated the effect of formulations on loading efficiency (LE) as well as the relationship between the resultant size of the microspheres and pore size of the membrane. Finally, through RP-HPLC and CD spectra analysis, we have demonstrated that the bio-stability of exenatide in microspheres was preserved during the preparation process. PMID- 24075787 TI - New function of molybdenum trioxide nanoplates: toxicity towards pathogenic bacteria through membrane stress. AB - Inorganic nanostructures are highly recognized for their potential use in the development of new functional materials for biomedical applications. In this study, we investigated the antibacterial efficiency of molybdenum trioxide (MoO3) nanoplates against four types of pathogenic bacteria. MoO3 nanoplates are synthesized by a simple wet chemical approach. X-ray diffraction and FT-IR analysis showed the presence of an orthorhombic phase of MoO3 nanoplates. Field emission scanning electron microscope studies confirmed the formation of plate like structures of MoO3. The minimum inhibitory concentration (MIC) of MoO3 nanoplates against pathogenic bacteria was evaluated using a microdilution method. MICs such as 8MUg/mL (against Escherichia coli and Salmonella typhimurium), 16MUg/mL (against Enterococcus faecalis), and 8MUg/mL (against Bacillus subtilis) show that MoO3 nanoplates have predominant antibacterial activity compared to the standard antibiotic, kanamycin. Evaluation of bacterial enzymatic (beta-d-galactosidase) activity in the hydrolysis of o-nitrophenol and beta-d-galactopyranoside suggested the disruption of the bacterial cell wall mechanism responsible for bacterial toxicity. PMID- 24075788 TI - Pancreatitis, polyarthritis and panniculitis syndrome. PMID- 24075789 TI - Iodine status similarly suboptimal in Australian women who have desirable salt intakes compared to those with excessive intakes. PMID- 24075790 TI - Iron levels in the human brain: a post-mortem study of anatomical region differences and age-related changes. AB - The link between brain iron homeostasis and neurodegenerative disease has been the subject of extensive research. There is increasing evidence of iron accumulation during ageing, and altered iron levels in some specific brain regions in neurodegenerative disease patients have been reported. Using graphite furnace atomic absorption spectrometry after microwave-assisted acid digestion of the samples, iron levels were determined in 14 different areas of the human brain [frontal cortex, superior and middle temporal, caudate nucleus, putamen, globus pallidus, cingulated gyrus, hippocampus, inferior parietal lobule, visual cortex of the occipital lobe, midbrain, pons (locus coeruleus), medulla and cerebellum (dentate nucleus)] of n=42 adult individuals (71+/-12 years old, range: 53-101 years old) with no known history or evidence of neurodegenerative, neurological or psychiatric disorders. It was found that the iron distribution in the adult human brain is quite heterogeneous. The highest levels were found in the putamen (mean+/-SD, range: 855+/-295MUg/g, 304-1628MUg/g) and globus pallidus (739+/ 390MUg/g, 225-1870MUg/g), and the lowest levels were observed in the pons (98+/ 43MUg/g, 11-253MUg/g) and medulla (56+/-25MUg/g, 13-115MUg/g). Globally, iron levels proved to be age-related. The positive correlation between iron levels and age was most significant in the basal ganglia (caudate nucleus, putamen and globus pallidus). Compared with the age-matched control group, altered iron levels were observed in specific brain areas of one Parkinson's disease patient (the basal ganglia) and two Alzheimer's disease patients (the hippocampus). PMID- 24075791 TI - Readmission, mortality, and first-year medical costs after stroke. AB - BACKGROUND: Stroke is the leading cause of adult disability and mortality in Taiwan, resulting in a tremendous burden on the healthcare system. The purpose of this study was to characterize disease burden by evaluating readmissions, mortality, and medical cost during the first year after acute stroke under the National Health Insurance (NHI) program. METHODS: This retrospective cohort study extracted information about patients hospitalized with acute stroke from claims data of 200,000 randomly sampled NHI enrollees in Taiwan, with a 1-year follow-up duration. The incidence of the first-year adverse events (AEs) indicated by readmissions or mortality, and the amount of the first-year medical cost (FYMC) were assessed with predictive factors explored. Additionally, we also estimated the cost per life and life-year saved. RESULTS: There were 2368 first-ever stroke patients in our study, including those with subarachnoid hemorrhage (SAH) 3.3%, intracerebral hemorrhage (ICH) 17.9%, ischemic stroke (IS) 49.8%, and transient ischemic attack/other ill-defined cerebrovascular diseases (TIA/unspecified) 29.0%; each stroke type was identified with an all-cause AE of 59.0%, 63.0%, 48.6%, and 46.8%, respectively. Readmissions were mainly because of acute recurrent stroke or the late effects of previous stroke, respiratory disease/infections, heart/circulatory disease, and diseases of the digestive system. Advanced age, hemorrhagic stroke type, respiratory distress/infections, and greater comorbidities were predictive of increased AE risk. Admission to neurology/rehabilitation wards, undertaking neurosurgery, or use of inpatient/outpatient rehabilitation was less likely to incur AEs. Initial hospitalization, readmission, and ambulatory care constituted 44%, 29%, and 27%, respectively, of FYMC with the initial length of stay being the most reliable predictor. The FYMCs were NT $217,959, $246,358, $168,003, and $122,084 for SAH, ICH, IS, and TIA/unspecified, respectively. The cost per life saved were estimated to be NT $435,919, $384,028, $196,281, and $138,888, whereas cost per life-year saved were estimated to be NT$43,926, $48,019, $97,830, and $188,770 for SAH, ICH, IS, and TIA/unspecified, respectively. CONCLUSION: Half of the patients encountered readmission or death during the first year after stroke. Patients with advanced age, more complications, or comorbidities during initial stay tended to be highly vulnerable to AE occurrence, whereas TIA/unspecified stroke carried no less risk for AEs. FYMC or estimated cost per life saved for IS or TIA/unspecified was lower relative to SAH or ICH; however, their estimated cost per life-year saved became higher because of reduced life expectancy. PMID- 24075792 TI - Corrected QT interval for possible drug-drug interactions in the intensive care unit. PMID- 24075793 TI - A prospective cohort study examining the preferred learning styles of acute care registered nurses. AB - OBJECTIVES: This paper reports on the preferred learning styles of Registered Nurses practicing in acute care environments and relationships between gender, age, post-graduate experience and the identified preferred learning styles. METHODS: A prospective cohort study design was used. Participants completed a demographic questionnaire and the Felder-Silverman Index of Learning Styles (ILS) questionnaire to determine preferred learning styles. RESULTS: Most of the Registered Nurse participants were balanced across the Active-Reflective (n = 77, 54%), and Sequential-Global (n = 96, 68%) scales. Across the other scales, sensing (n = 97, 68%) and visual (n = 76, 53%) were the most common preferred learning style. There were only a small proportion who had a preferred learning style of reflective (n = 21, 15%), intuitive (n = 5, 4%), verbal (n = 11, 8%) or global learning (n = 15, 11%). Results indicated that gender, age and years since undergraduate education were not related to the identified preferred learning styles. CONCLUSIONS: The identification of Registered Nurses' learning style provides information that nurse educators and others can use to make informed choices about modification, development and strengthening of professional hospital-based educational programs. The use of the Index of Learning Styles questionnaire and its ability to identify 'balanced' learning style preferences may potentially yield additional preferred learning style information for other health-related disciplines. PMID- 24075794 TI - Giant hepatocellular adenoma in a child. PMID- 24075795 TI - Disseminated Mycobacterium avium intracellulare complex presenting as abdominal pain. PMID- 24075796 TI - How effective is continuing care for substance use disorders? A meta-analytic review. AB - Given the often chronic nature of substance use disorders, patients sometimes receive less intensive continuing care following an initial period of more intensive treatment. This meta-analysis estimated the effect of continuing care and formally tested several proposed moderators (intervention duration, intensity, modality, and setting) of that effect. A systematic search identified 33 controlled trials of continuing care; 19 included a no/minimal treatment condition and were analyzed to assess the overall effect of continuing care versus control. Continuing care had a small, but significant, positive effect size, both at the end of the continuing care interventions (g=0.187, p<0.001) and at follow-up (g=0.271, p<0.01). Limited by a small number of studies, analyses did not identify any significant moderators of overall effects. These results show that continuing care can provide at least modest benefit after initial treatment. We discuss study characteristics that may have reduced the magnitude of the overall continuing care effect estimate. PMID- 24075797 TI - Skin self-examinations and visual identification of atypical nevi: comparing individual and crowdsourcing approaches. AB - PURPOSE: Skin self-examination (SSE) is one method for identifying atypical nevi among members of the general public. Unfortunately, past research has shown that SSE has low sensitivity in detecting atypical nevi. The current study investigates whether crowdsourcing (collective effort) can improve SSE identification accuracy. Collective effort is potentially useful for improving people's visual identification of atypical nevi during SSE because, even when a single person has low reliability at a task, the pattern of the group can overcome the limitations of each individual. METHODS: Adults (N=500) were recruited from a shopping mall in the Midwest. Participants viewed educational pamphlets about SSE and then completed a mole identification task. For the task, participants were asked to circle mole images that appeared atypical. Forty nevi images were provided; nine of the images were of nevi that were later diagnosed as melanoma. RESULTS: Consistent with past research, individual effort exhibited modest sensitivity (.58) for identifying atypical nevi in the mole identification task. As predicted, collective effort overcame the limitations of individual effort. Specifically, a 19% collective effort identification threshold exhibited superior sensitivity (.90). CONCLUSIONS: The results of the current study suggest that limitations of SSE can be countered by collective effort, a finding that supports the pursuit of interventions promoting early melanoma detection that contain crowdsourced visual identification components. PMID- 24075798 TI - Association between ultraviolet radiation, skin sun sensitivity and risk of pancreatic cancer. AB - BACKGROUND: Ecological studies showing an inverse association between pancreatic cancer incidence and mortality and levels of ultraviolet radiation (UVR), suggest that higher levels of sun exposure may reduce risks of pancreatic cancer but there has been only one individual-level study that examined this issue. We aimed to examine the association between pancreatic cancer and markers of exposure to solar UVR, namely skin type, treatment of skin lesions, ambient UVR and time outdoors on work days. METHODS: We used data from an Australian case-control study. Location at birth, residential location during adulthood, outdoors work, history of skin lesion treatment and sensitivity of the skin to the sun were obtained by questionnaire. We limited the analyses to Caucasians who answered the questionnaire about UVR (controls=589/711 recruited; cases=496/705 recruited). We used NASA's Total Ozone Mapping Spectrometer to estimate ambient UVR. RESULTS: Being born in or living in areas of higher ambient UVR (compared to lower ambient UVR) was associated with about 30-40% lower risk of pancreatic cancer. People with fair skin colour had 47% lower risk of pancreatic cancer than those with dark skin colour (95% CI 0.37-0.75). There was some suggestion of increased risk with increased average number of hours spent outside at work. CONCLUSIONS: This study suggests that people with light skin colour or those born or living in areas of high ambient UVR have lower risk of pancreatic cancer. Our analysis supports an association between UVR and pancreatic cancer, possibly mediated through production of vitamin D. PMID- 24075799 TI - Vitamin D receptor polymorphism and colorectal cancer-specific and all-cause mortality. AB - BACKGROUND: The vitamin D receptor (VDR) gene is present in colorectal cancer (CRC) cells and its genetic variants have been associated with an increased risk of CRC. The association with colorectal cancer prognosis remains widely unexplored. METHODS: 1397 colorectal cancer patients participating in two cancer cohorts (ESTHER II and VERDI) and in a population-based case-control study (DACHS) were followed for 5 years. Unadjusted and adjusted hazard ratios for all cause mortality (469 events) and CRC-specific mortality (336 events) were estimated for VDR variants rs731236 (TaqI), rs2228570 (FokI), rs11568820 (Cdx2), and rs1989969 (VDR-5132). RESULTS: No association was found between VDR polymorphism and CRC specific and all-cause mortality. Adjusted hazard ratios ranged from 0.79 (95% CI 0.57-1.12) to 1.14 (95% CI 0.89-1.46) for CRC-specific mortality and from 0.89 (95% CI 0.67-1.18) to 1.22 (95% CI 0.99-1.50) for all cause mortality. All 95% confidence intervals included the null value. CONCLUSIONS: Our findings do not support the hypothesis that the common VDR gene variants investigated in this study are of clinical relevance with respect to CRC prognosis. PMID- 24075800 TI - Attending the breast screening programme after breast cancer treatment: a population-based study. AB - INTRODUCTION: In the Netherlands, breast cancer patients are treated and followed at least 5 years after diagnosis. Furthermore, all women aged 50-74 are invited biennially for mammography by the nationwide screening programme. The relation between the outpatient follow-up (follow-up visits in the outpatient clinic for 5 years after treatment) and the screening programme is not well established and attending the screening programme as well as outpatient follow-up is considered undesirable. This study evaluates potential factors influencing women to attend the screening programme during their outpatient follow-up (overlap) and the (re )attendance to the screening programme after 5 years of outpatient follow-up. METHODS: Data of breast cancer patients aged 50-74 years, treated for primary breast cancer between 1996 and 2007 were selected from the Netherlands Cancer Registry and linked to the National Breast Cancer Screening Programme in the Northern region. Cox regression analyses were used to study women (re-)attending the screening programme over time, possible overlap with the outpatient follow-up and factors influencing this. RESULTS: In total 11227 breast cancer patients were included, of whom 19% attended the screening programme after breast cancer treatment, 4.4% within 5 years and 15.4% after more than 5 years. Factors that independently influenced attendance within 5 years as well as more than 5 years after treatment were: interval tumours (HR 0.77; 95%CI 0.61-0.97 and HR 0.69; 95%CI 0.53-0.88, ref: screen-detected tumours), receiving adjuvant radiotherapy (HR 0.65; 95%CI 0.47-0.90 and HR 0.66; 95%CI 0.47-0.93; ref: none) and diagnosis of in situ tumours (HR 1.67; 95%CI 1.25-2.23 and HR 1.39; 95%CI 1.05-1.85; ref: stage I tumours). Non-screen related tumours (HR 0.41; 95%CI 0.29-0.58) and recent diagnosis (HR 0.89 per year; 95%CI 0.86-0.92) were only associated with attendance within 5 years after treatment. CONCLUSION: The interrelation between outpatient follow-up and screening should be improved to avoid overlap and low attendance to the screening programme after outpatient follow-up. Breast cancer patients should be informed that attending the screening programme during the outpatient follow-up is not necessary. PMID- 24075801 TI - Surgical timing of craniosynostosis: what to do and when. AB - Craniosynostosis, both isolated and syndromic, are challenging malformations for the craniofacial team. They present the team with an articulated cascade of choices, which need to be addressed early in life and in the growing age to intercept, remove, or correct the direct and indirect consequences of the malformation. Timing of treatment is thus critical and it stands on the experience of a multi-specialty trained craniofacial team. In this paper the authors discuss the timing of treatment of the major craniosynostosis, isolated and syndromic, reviewing the options for treatment and their experience in this complex field. PMID- 24075802 TI - Roles of thrombelastography and thromboelastometry for patient blood management in cardiac surgery. AB - The value of thrombelastography (TEG) and thromboelastometry (ROTEM) to improve perioperative hemostasis is under debate. We aimed to assess the effects of TEG- or ROTEM-guided therapy in patients undergoing cardiac surgery on the use of allogeneic blood products. We analyzed 12 trials including 6835 patients, 749 of them included in 7 randomized controlled trials (RCTs). We collected data on the amount of transfused allogeneic blood products and on the proportion of patients who received allogeneic blood products or coagulation factor concentrates. Including all trials, the odds ratios (ORs) for transfusion of red blood cell (RBC) concentrates, fresh-frozen plasma (FFP), and platelets were 0.62 (95% confidence interval [CI], 0.56-0.69; P<.001), 0.28 (95% CI, 0.24-0.33; P<.001), and 0.55 (95% CI, 0.49-0.62; P<.001), respectively. However, more than 50% of the patients in this analysis were derived from one retrospective study. Including RCTs only, the ORs for transfusion of RBC, FFP, and platelets were 0.54 (95% CI, 0.38-0.77; P<.001), 0.36 (95% CI, 0.25-0.53; P<.001), and 0.57 (95% CI, 0.39 0.81; P=.002), respectively. The use of coagulation factor concentrates was reported in 6 studies, 2 of them were RCTs. The ORs for the infusion of fibrinogen and prothrombin complex concentrate were 1.56 (95% CI, 1.29-1.87; P<.001) and 1.74 (95% CI, 1.40-2.18; P<.001), respectively. However, frequencies and amounts were similar in the intervention and control group in the 2 RCTs. It is presumed that TEG- or ROTEM-guided hemostatic management reduces the proportion of patients undergoing cardiac surgery transfused with RBC, FFP, and platelets. This presumption is strongly supported by similar ORs found in the analysis including RCTs only. Patient blood management based on the transfusion triggers by TEG or ROTEM appears to be more restrictive than the one based on conventional laboratory testing. However, evidence for improved clinical outcome is limited at this time. PMID- 24075803 TI - Cellular technology improves transmission success of pre-hospital electrocardiograms. AB - STUDY OBJECTIVE: In rural settings, long distances and transport times pose a challenge for achieving early reperfusion goals in patients with ST-elevation myocardial infarction (STEMI). This study investigated the association between the method of pre-hospital 12-lead ECG transmission (radio transmission vs. cellular phone transmission) and the success of transmission and legibility of 12 lead ECGs in a rural setting. METHODS: Observational study of pre-hospital 12 lead ECG transmission to the emergency department (ED) in a predominantly rural area. Success of transmission and the legibility of the 12-lead ECG were analyzed to identify barriers to 12-lead ECG transmission and reasons for failed transmission. RESULTS: Emergency medical services performed ECGs on 1140 patients, 917 of which they attempted to transmit, including 43 cases requiring emergent catheterization. Twelve-lead ECG transmission was successful in 236 (70%) of 337 radio attempts and 441 (76%) of 580 cellular attempts (difference 6.0%, 95% CI 1.1-12.1). Legibility increased from 164 (49%) of 337 radio attempts to 389 (67%) of 580 cellular attempts (difference 18.4%, 95% CI 11.8-24.9). CONCLUSION: The success of transmission and legibility of 12-lead ECGs was significantly higher with cellular technology by emergency medical service agencies in comparison to radio transmission. In rural settings with lengthy transport times, utilization of cellular technology for transmission of pre hospital 12-lead ECGs may improve door-to-balloon times for STEMI patients. PMID- 24075804 TI - A prepatellar Morel-Lavallee lesion in a pedestrian vs automobile collision. AB - A small truck collided with a 67-year-old female pedestrian. She sustained blunt, closed trauma to her right knee, and developed a prepatellar Morel-Lavallee lesion (MLL). A MLL is a closed soft tissue degloving injury, resulting from high energy shearing forces, which separate the skin and subcutaneous tissue from the underlying fascia. The resultant space collects fluid and is prone to infection, tissue necrosis, and symptoms of ongoing mass effects. The diagnosis is elusive because of its rarity and often subtle initial symptoms. Prompt diagnosis is critical, given the potentially severe complications when missed, and less invasive and more successful treatment when found early. Most reported cases are proximal to the pelvis, whereas the few reported peri-knee MLLs involve young athletes or postsurgical complications. To our knowledge, this is the third reported case of a non-sport-related MLL of the knee, all of which involved high inertia force to the knee. Therefore, MLL of the knee should be considered in patients with knee trauma, particularly in the setting of pedestrians struck by motor vehicles. PMID- 24075805 TI - Propofol for benzodiazepine-refractory alcohol withdrawal in a non-mechanically ventilated patient. AB - Long-term alcohol use confers neurochemical changes in response to alcohol's exogenous inhibitory effects. Downregulation and decreased sensitivity of gamma aminobutyric acid receptors render benzodiazepines less effective at controlling psychomotor agitation. Propofol has been reported to have successfully relieved alcohol withdrawal syndrome (AWS) symptoms in part because of activation of gamma aminobutyric acid channels in combination with antagonism of excitatory amino acids such as N-methyl-D-aspartate. Successful use of propofol in refractory AWS in patients with endotracheal intubation and mechanical ventilation has been reported. We present a case of resolution of AWS symptoms in a benzodiazepine refractory, nonintubated, non-mechanically ventilated alcohol withdrawal patient with low-dose, continuous-infusion propofol. PMID- 24075806 TI - A multijurisdictional experience with the EZ-IO intraosseous device in the prehospital setting. PMID- 24075807 TI - Chromatin-bound Xenopus Dppa2 shapes the nucleus by locally inhibiting microtubule assembly. AB - Nuclear shape and size vary between species, during development, and in many tissue pathologies, but the causes and effects of these differences remain poorly understood. During fertilization, sperm nuclei undergo a dramatic conversion from a heavily compacted form into decondensed, spherical pronuclei, accompanied by rapid nucleation of microtubules from centrosomes. Here we report that the assembly of the spherical nucleus depends on a critical balance of microtubule dynamics, which is regulated by the chromatin-binding protein Developmental pluripotency-associated 2 (Dppa2). Whereas microtubules normally promote sperm pronuclear expansion, in Dppa2-depleted Xenopus egg extracts excess microtubules cause pronuclear assembly defects, leading to abnormal morphology and disorganized DNA replication. Dppa2 inhibits microtubule polymerization in vitro, and Dppa2 activity is needed at a precise time and location during nascent pronuclear formation. This demonstrates a strict spatiotemporal requirement for local suppression of microtubules during nuclear formation, fulfilled by chromatin-bound microtubule regulators. PMID- 24075809 TI - Herpes simplex meningo-encephalitis following cochlear implantation: a case study. AB - OBJECTIVE AND IMPORTANCE: Herpes simplex virus (HSV) is reported to be the most common cause of viral encephalitis. Although extremely rare, reactivation of the virus has been reported following central nervous system surgery. To the best of our knowledge, there is no report in the literature that describes HSV encephalitis following cochlear implantation. CLINICAL PRESENTATION: We report a case of meningo-encephalitis occurring 17 days after cochlear implantation using an electro-acoustic stimulation device, with oerioperative steroid medication. Intensive anti-viral therapy was given and the patient recovered from the acute illness over 2 weeks. Agitation and anxiety followed the encephalitis and subsequent progress with the cochlear implant was slow. Twelve months after cochlear implantation this patient shows a gradual and steady progress with her hearing rehabilitation. CONCLUSION: Cochlear implantation surgery was either coincidental or was the trigger factor for reactivation of the HSV. Surgeons must be vigilant to post-surgical meningism symptoms particularly if patients have a history of herpes infections. PMID- 24075808 TI - Deuterosome-mediated centriole biogenesis. AB - The ability of cells to faithfully duplicate their two centrioles once per cell cycle is critical for proper mitotic progression and chromosome segregation. Multiciliated cells represent an interesting variation of centriole duplication in that these cells generate greater than 100 centrioles, which form the basal bodies of their motile cilia. This centriole amplification is proposed to require a structure termed the deuterosome, thought to be capable of promoting de novo centriole biogenesis. Here, we begin to molecularly characterize the deuterosome and identify it as a site for the localization of Cep152, Plk4, and SAS6. Additionally we identify CCDC78 as a centriole-associated and deuterosome protein that is essential for centriole amplification. Overexpression of Cep152, but not Plk4, SAS6, or CCDC78, drives overamplification of centrioles. However, in CCDC78 morphants, Cep152 fails to localize to the deuterosome and centriole biogenesis is impaired, indicating that CCDC78-mediated recruitment of Cep152 is required for deuterosome-mediated centriole biogenesis. PMID- 24075810 TI - Nationwide spread of Klebsiella pneumoniae carbapenemase-2-producing K. pneumoniae sequence type 11 in Taiwan. PMID- 24075811 TI - Scavenging of hydroxyl radical by resveratrol and related natural stilbenes after hydrogen peroxide attack on DNA. AB - Resveratrol (3,5,4'-trihydroxystilbene) is of interest due to its role in prevention and therapy of degenerative diseases as cancer and aging. However, depending on its concentration and cell type studied, resveratrol activity appears conflicting. It exerts antioxidant action, as a scavenger of free radicals and as promoter of antioxidant enzyme activity, but resveratrol acts also as a pro-oxidant. Here we present experimental and theoretical studies for resveratrol and two methoxy-derivatives found in plants, pterostilbene and 3,5,4' trimethoxystilbene. We show that both methoxy-derivatives induce less DNA damage than resveratrol. The protective effects of the three molecules against oxidative DNA damage induced by hydrogen peroxide treatment were analyzed on mammalian cells in vitro. Our data show for the first time that methoxylated derivatives of resveratrol are very efficient in reducing DNA damage: using the same concentration of the three molecules we obtain a relative reduction of 85.5% (pterostilbene), 43.7% (trimethoxystilbene) and 21.1% (resveratrol). Analysis of the crystal structures of pterostilbene and 3,5,4'-trimethoxystilbene, compared to resveratrol, show fewer intermolecular interactions and a lack of planarity, due to packing forces, which is confirmed by density functional theory (DFT) calculations. We also describe the results of DFT calculations (including water solvent effects) in which the three stilbene species scavenge the hydroxyl radical (associated with the H2O2 insult). PMID- 24075812 TI - Immunogenetics and transplantation. PMID- 24075813 TI - [Salmonella enteritidis arthritis complicating systemic lupus erythematosus]. AB - Septic arthritis due to Salmonella in systemic lupus erythematosus is rare. We report a case of septic arthritis by Salmonella enteritidis which occurred during the evolution of systemic lupus erythematosus. A 23-year-old man was diagnosed as suffering from systemic lupus erythematosus. This diagnosis was taken on the basis of general symptoms, skin lesions, hemolytic anemia, thrombocytopenia and glomerulonephritis (class III). He was treated with three methylprednisolone boli related by high-dose regimen of prednisolone. A month and a half later, he presented fever with monoarthritis of the left elbow without any other new sign of underlying systemic disease. Bacteriological examinations isolated S. enteritidis. The patient improved with antibiotics and joint lavage. Feverish monoarthritis in systemic lupus erythematosus should be suspect to be septic arthritis. Appropriate treatment should be promptly instituted to improve the prognosis. PMID- 24075814 TI - Finger replantation: surgical technique and indications. AB - In this article, we discuss the surgical technique of finger replantation in detail, distinguishing particularities of technique in cases of thumb amputation, children fingertip replantation, ring finger avulsion, and very distal replantations. We emphasize the principles of bone shortening, the spare part concept, the special importance of nerve sutures and the use of vein graft in case of avulsion or crushing. However, even if finger replantation is now a routine procedure, a clear distinction should be made between revascularization and functional success. The indications for finger replantation are then detailed in the second part of this paper. The absolute indications for replantation are thumb, multiple fingers, transmetacarpal or hand, and any upper extremity amputation in a child whatever the level. Fingertip amputations distal to the insertion of the Flexor digitorum superficialis (FDS) are also a good indication. Other cases are more controversial because of the poor functional outcome, especially for the index finger, which is often functionally excluded. PMID- 24075815 TI - Health equity: utopian and scientific. PMID- 24075816 TI - Alcohol use and death from respiratory disease in a prospective Chinese elderly cohort study in Hong Kong. AB - OBJECTIVE: In Western settings, moderate drinking is negatively associated with respiratory disease. However, moderate drinking is socially patterned, making this association vulnerable to contextual biases. Evidence from other contexts where the typical drinking pattern is different may clarify such observations. METHODS: Multivariable Cox regression analysis was used to assess the adjusted associations of alcohol use with death from respiratory disease using a population-based prospective cohort of 66,820 Chinese aged >=65 years enrolled from July 1998 to December 2001 at all the 18 Elderly Health Centers of the Hong Kong Government Department of Health and followed till May 30, 2012. RESULTS: During ten-year follow-up, 4065 deaths from respiratory disease occurred. Most current drinkers were occasional drinkers (<1 day/week). Both moderate and occasional drinking (<1 day/week) were associated with a lower risk of death from respiratory disease, but the point estimates and pattern of associations were similar between these two types of drinkers. CONCLUSION: The typical drinking pattern, i.e. occasional drinking (<1 day/week), which is unlikely to have any biological effect, was similarly associated with a lower risk of respiratory disease as moderate alcohol use, suggesting the attributes of being a typical drinker may be protective. PMID- 24075817 TI - Authors' response to 'The association of religiosity with overweight/obese body mass index among Asian Indian immigrants in California'. PMID- 24075818 TI - Workplace social capital and smoking among Chinese male employees: a multi-level, cross-sectional study. AB - OBJECTIVES: The present study sought to investigate the associations between workplace social capital and smoking status among Chinese male employees. METHODS: A cross sectional study with a two-stage stratified sampling procedure was conducted in Shanghai in 2012. In total, 1603 male workers from 35 workplaces were involved. Workplace social capital was assessed using a validated and psychometrically tested eight-item measure. Multilevel logistic regression analysis was conducted to explore whether individual-level social capital and aggregated workplace-level social capital were associated with smoking. RESULTS: Overall, 54.2% of the subjects smoked currently. After controlling for individual covariates (age, education level, marital status, occupational status and job stress), compared to workers in the highest quartile of individual-level social capital, the prevalence ratios of smoking for workers in the third quartile, second quartile and lowest quartile were 1.26 (95% CI: 1.11-1.38), 1.35 (95% CI: 1.19-1.50) and 1.39 (95% CI: 1.24-1.51) respectively. However, there was no relationship between workplace-level social capital and smoking status. CONCLUSIONS: Higher individual-level social capital was associated with a lower likelihood of smoking among Chinese male employees. By contrast, no clear association was found between workplace-level social capital and smoking. Further longitudinal studies are warranted to examine the possible link between workplace social capital and smoking cessation in Chinese workplaces. PMID- 24075819 TI - Overweight trajectories and psychosocial adjustment among adolescents. AB - OBJECTIVES: Few studies have investigated overweight trajectories and psychosocial adjustment among adolescents. We conducted analyses with data from the multisite Study of Early Child Care and Youth Development (SECCYD). METHODS: The sample included 1350 youths born in 1991. Data consisted of repeated measures of weight, height, and multiple subscales of internalizing and externalizing behavioral problems measured by the Child Behavior Checklist (CBCL) from age 9 to age 15. RESULTS: Three trajectory patterns were identified: never/rarely overweight/obese (59.5%), late start/light overweight/obese (12.1%), and chronically/heavy overweight/obese (28.4%). Youths with chronically/heavy overweight/obese trajectory pattern had significantly higher scores of internalizing problems over time, as well as syndrome subscales of somatic complaints, social problems and social withdrawal over time than youths with the never/rare overweight/obese trajectory pattern. There was no significant difference in either broad-band behavioral problems or narrow-band syndrome subscales between youths with the never/rare overweight/obese trajectory pattern and those with the late start/light overweight/obesity trajectory pattern. CONCLUSIONS: Study findings may advance knowledge on the distinct developmental trajectory patterns of overweight youth and their linkages to the psychosocial adjustment during the period of pubertal transition. The results highlight the need for future prevention research to improve the physical development and mental well-being of adolescents. PMID- 24075820 TI - Dendrimer-enabled transformation of Chlamydia trachomatis. AB - Lack of a system for genetic manipulation of Chlamydia trachomatis has been a key challenge to advancing understanding the molecular genetic basis of virulence for this bacterial pathogen. We developed a non-viral, dendrimer-enabled system for transformation of this organism and used it to characterize the effects of inserting the common 7.5 kbp chlamydial plasmid into strain L2(25667R), a C. trachomatis isolate lacking it. The plasmid was cloned in pUC19 and the clone complexed to polyamidoamine dendrimers, producing ~83 nm spherical particles. Nearly confluent McCoy cell cultures were infected with L2(25667R) and reference strain L2(434). At 16 h post-infection, medium was replaced with dendrimer plasmid complexes in medium lacking additives (L2(25667R)) or with additive-free medium alone (L2(434)). Three h later complexes/buffer were removed, and medium was replaced; cultures were harvested at various times post-transformation for analyses. Real time PCR and RT-PCR of nucleic acids from transformed cultures demonstrated plasmid replication and gene expression. A previous report indicated that one or more plasmid-encoded product govern(s) transcription of the glycogen synthase gene (glgA) in standard strains. In L2(25667R) the gene is not expressed, but transformants of that strain given the cloned chlamydial plasmid increase glgA expression, as does L2(434). The cloned plasmid is retained, replicated, and expressed in transformants over at least 5 passages, and GFP is expressed when transformed into growing L2(25667R). This transformation system will allow study of chlamydial gene function in pathogenesis. PMID- 24075822 TI - A preliminary longitudinal volumetric MRI study of amygdala and hippocampal volumes in autism. AB - BACKGROUND: Previous studies suggest that amygdala volume, when compared with healthy controls, is increased in young children with autism, is unchanged in cohorts of older youth, and is smaller in adults. Hippocampal volume, however, does not appear to have age-related changes, and it is unclear whether individuals with autism have volumetric differences in this structure. The goal of this pilot investigation is to characterize the developmental trajectories of the amygdala and hippocampus in children with autism between the ages of 8 and 14years and to examine clinical correlates of volume change. METHODS: Twenty three children with autism and 23 controls between the ages of 8 and 12 underwent a magnetic resonance imaging procedure of the brain (T1-weighted) at two time points. Nine children with autism and 14 controls had good quality scans from both time points; however, all usable scans from all subjects (15 children with autism and 22 controls) were included in a mixed effect analysis. Regression models were used to estimate group differences in amygdala and hippocampal volumes. Changes in amygdala and hippocampal volumes (Time 2-Time 1) were correlated with clinical severity measures. RESULTS: Amygdala volume changes with time were similar between the two groups. Within the autism group, right amygdala volume change was correlated with the ability to establish appropriate eye contact. Right hippocampal volume was significantly increased in the autism group when compared with controls. Differences in right hippocampal volume change with time between the two groups approached significance. CONCLUSION: This study provides preliminary evidence of normalization of amygdala volumes in late childhood and adolescence. It also suggests that hippocampal volumetric differences may exist in autism in late childhood and adolescence. PMID- 24075821 TI - No sex differences in neuropsychological performance in first episode psychosis patients. AB - OBJECTIVE: The purpose of this study was to verify whether male patients with psychosis have greater neurocognitive impairment than female patients at illness onset. METHOD: Participants with a first episode of psychosis (74 women/86 men) and healthy controls (62 women/97 men) were assessed with an extensive neuropsychological test battery. RESULTS: Women in the clinical group were older at illness onset and had achieved higher formal education than men. This trend was the same for the control group. The patient group presented with lower premorbid IQ compared to healthy controls, and performed below for most neuropsychological tests. Women scored higher than men on a test of verbal memory, whereas men scored higher than women on a test of reaction time, visual memory, and a planning task. There were no group-by-sex interactions for any of the neuropsychological tests. CONCLUSION: The present study shows that at the onset of psychosis there are no differences between males and females in neuropsychological performance. The differential pattern of cognitive performance observed is similar to that in healthy males and females. Furthermore, females with a late onset of psychosis may represent a subgroup with specific visuospatial and problem solving impairments. SIGNIFICANT OUTCOMES: LIMITATIONS: PMID- 24075823 TI - Outflow modulation to target liver regeneration: something old, something new. AB - BACKGROUND: Stimulation of hepatic hypertrophy is a useful aid to accomplish hepatic resections when the future liver remnant (FLR) is small. Although inflow occlusion, especially through portal flow, has been extensively studied, the role of outflow modulation has not yet been described. METHODS: Description of outflow modulation to tailor hypertrophy of future liver remnant in the context of bilobar metastatic disease. A patient with small FLR (segments I and IV) was managed with a two-stage procedure. The first stage consisted of a right hepatectomy and modulation of the left hepatic vein outflow through reduction of its diameter, with macroscopic congestion of segments II-III. The second stage consisted of a left lateral sectionectomy six weeks later. Postoperative courses were uneventful without any sign of liver failure. RESULTS: Following the first stage procedure computed tomography revealed distinct hypertrophy rates between sections. The non-congested area had an increase of 156% in the volume of segment IV (from 137 to 351 cm(3)) and 100% in the volume of segment I (from 20 to 40 cm(3)). The congested area, segments II-III, increased only 24% (from 205 to 253 cm(3)). CONCLUSION: Modulation of liver outflow allows maintenance of function in the segments to be resected while avoiding their hypertrophy. This process prevents liver failure and optimizes regeneration of hepatic territories to be preserved. PMID- 24075824 TI - Prognosis for gastric carcinomas with an insufficient number of examined negative lymph nodes. AB - BACKGROUND: The optimal system for lymph node (LN) staging in gastric cancer is still a subject of debate. The aim of our study was to analyse the probability of error in negative LN (pN0) gastric carcinomas when a low number of LNs were harvested using a probabilistic model. METHODS: Patients with gastric carcinoma who underwent R0 resection at three university hospitals between 2004 and 2009 were retrospectively included. A Bayesian model was used to analyse the probability of error for negative LNs (pN0) gastric carcinomas. Kaplan-Meier survival curves and the log-rank test were used to compare the overall and specific mortality of prognosis groups. RESULTS: Of the 291 patients included, 123 were classified as pN0 (42%). A significant correlation was found between the extent of the LN dissection performed and the number of the LNs retrieved. According to the Bayesian model the carcinomas with 9 or fewer negative lymph nodes were considered to have a high risk (HR) of misclassification, whereas patients with 10-25 LNs analysed and those with more than 26 negative lymph nodes were considered to have a moderate risk (MR) and low risk (LR), respectively. The log-rank test showed a significant improvement in the disease-specific survival for the MR pN0 (p < 0.001) and LR pN0 (p < 0.04) but not for the HR pN0 patients compared to pN1 patients. CONCLUSIONS: The proposed probabilistic model is clinically useful for differentiating the prognosis in pN0 gastric carcinomas when an insufficient number of negative lymph nodes are retrieved. PMID- 24075825 TI - Favorable outcome after complete resection in elderly soft tissue sarcoma patients: Japanese Musculoskeletal Oncology Group study. AB - BACKGROUND: The surgical management of soft tissue sarcoma (STS) in elderly patients has only been addressed in a few studies. The objective of the current study was to assess surgical outcomes in patients with STS aged 70 years and older and the association of older age with the survival after complete resection. METHODS: A retrospective analysis was conducted in 158 elderly patients with localized STS who visited 11 institutions participating in Japanese Musculoskeletal Oncology Group between 1995 and 2006 and were treated by surgical resection. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Median follow-up period was 38 months. Histologically high-grade tumors were detected in 71% of the patients. Wide resection with adequate margins was performed in 66% of the cases. Systemic chemotherapy was performed in only 5 patients. Univariate analysis identified histological grade and gender as statistically significant prognostic factors for sarcoma-specific survival. Multivariate analysis did not identify significant prognostic factors for sarcoma-specific survival, although high grade sarcoma emerged as a potentially significant prognostic factor (P = 0.050). Local recurrence was detected in 19% of the patients. Multivariate analysis of local recurrence-free survival showed that tumor site and surgical margins were statistically significant prognostic factors. CONCLUSIONS: Older age was not identified as a prognostic factor for sarcoma-specific survival, which is not consistent with the findings of previous studies showing that older age was associated with decreased sarcoma-specific survival. Complete resection should be indicated and can lead to optimal treatment outcome for properly selected elderly patients. PMID- 24075826 TI - Electrochemotherapy as "new standard of care" treatment for cutaneous Kaposi's sarcoma. AB - BACKGROUND: Electrochemotherapy (ECT) is a novel modality for the treatment of skin nodules and cutaneous or subcutaneous tumors that allows delivery of low and non-permeant drug into cells. The aim of this prospective single-center study was to evaluate ECT efficacy in the local treatment of Classic Kaposi's sarcoma (CKS) skin localization stage I-II sec. Brambilla et al. METHODS: Nineteen consecutive patients affected by classic KS were included in this study. All patients underwent blood sampling and concurrent incisional biopsy for histological diagnosis and Kaposi's sarcoma related herpes virus 8 (HHV-8) molecular analysis. ECT treatment of KS cutaneous lesions were performed according to the European Standard Operating Procedures of Electrochemotherapy (ESOPE). The primary endpoint of the study was the evaluation of ECT efficacy in the treatment of KS skin nodules and the assessment of HHV-8 viral load in the peripheral blood following the ECT therapy. RESULTS: Complete response (CR) was observed in 14 (73.6%) patients after first ECT session, while 3 (15.7%) and 2 (10.5%) out of 19 patients received a second and a third ECT treatment, respectively. Clinical response dragged out the whole follow-up period that ranged between 6 and 31 months with a median of 16 months. CONCLUSIONS: Clinical management of CKS skin localizations still represents a challenging task for surgeons and oncologists. Therefore, according to this and other author's recent experiences, ECT is claimed to become the "new standard of care" as first line treatment strategy for stage I-II CKS patients. PMID- 24075827 TI - Y-box-binding protein 1 (YB1) in breast carcinomas: relation to aggressive tumor phenotype and identification of patients at high risk for relapse. AB - AIMS: To investigate the expression pattern of Y-box-binding protein 1 (YB1) in breast carcinomas, its clinicopathological and prognostic value, and its association with the breast cancer stem cell phenotype [CD44(+)/CD24(-/low)]. METHODS AND RESULTS: Immunohistochemistry was performed on 225 paraffin embedded specimens of invasive breast carcinomas to detect the expression of the proteins YB1, ER, PR, HER2, p53, Ki67, bcl-2, CD44 and CD24. YB1 protein was detected in the nuclei, the cytoplasm and the stroma of the tumor cells. Cytoplasmic YB1 was detected more often in carcinomas of ductal type (p = 0.002), of higher nuclear grade (p < 0.001), with lack of ER expression (p = 0.002), positive expression of p53 and Ki67 (p = 0.002 and p = 022, respectively), and with present CD44(+)/CD24(-/low) breast cancer stem cells (p = 0.001), while its association with bcl-2 was found to be inverse (p = 0.042). Nuclear YB1 was found to exert unfavorable impact on the disease-free survival of the unselected patients (p = 0.05) and the patients having been subjected to adjuvant chemotherapy and radiotherapy (p = 0.036 and p = 0.05, respectively). CONCLUSIONS: Cytoplasmic YB1 is associated with an aggressive and "stem cell-like" tumor phenotype, while nuclear localization discriminates patients at high risk for recurrence, especially those who are subjected to chemo- and radiotherapy. PMID- 24075828 TI - Comparison of the accuracy for three dental impression techniques and index: an in vitro study. AB - OBJECTIVES: This in vitro study compared the dimensional accuracy of stone index (I) and three impression techniques: tapered impression copings (T), squared impression copings (S) and modified squared impression copings (MS) for implant supported prostheses. METHODS: A master cast, with four parallel implant abutment analogs and a passive framework, were fabricated. Vinyl polysiloxane impression material was used for all impressions with two metal stock trays (open and closed tray). Four groups (I, T, S and MS) were tested (n=5). A metallic framework was seated on each of the casts, one abutment screw was tightened, and the gap between the analog of implant and the framework was measured with a stereomicroscope. The groups' measurements (80 gap values) were analyzed using software (LeicaQWin - Leica Imaging Systems Ltd.) that received the images of a video camera coupled to a Leica stereomicroscope at 100* magnification. The results were statistically analyzed with Kruskal-Wallis One Way ANOVA on Ranks test followed by Dunn's Method, 0.05. RESULTS: The mean values of abutment/framework interface gaps were: Master Cast=32 MUm (SD 2); Group I=45 MUm (SD 3); Group T=78 MUm (SD 25); Group S=134 MUm (SD 30); Group MS=143 MUm (SD 27). No significant difference was detected among Index and Master Cast (P=.05). CONCLUSION: Under the limitations of this study, it could be suggested that a more accurate working cast is possible using tapered impression copings techniques and stone index. PMID- 24075829 TI - Bayesian two-step Lasso strategy for biomarker selection in personalized medicine development for time-to-event endpoints. AB - Clinical trial designs for targeted therapy development are progressing toward the goal of personalized medicine. Motivated by the need of ongoing efforts to develop targeted agents for lung cancer patients, we propose a Bayesian two-step Lasso procedure for biomarker selection under the proportional hazards model. We seek to identify the key markers that are either prognostic or predictive with respect to treatment from a large number of biomarkers. In the first step of our two-step strategy, we use the Bayesian group Lasso to identify the important marker groups, wherein each group contains the main effect of a single marker and its interactions with treatments. Applying a loose selection criterion in the first step, the goal of first step is to screen out unimportant biomarkers. In the second step, we zoom in to select the individual markers and interactions between markers and treatments in order to identify prognostic or predictive markers using the Bayesian adaptive Lasso. Our strategy takes a full Bayesian approach and is built upon rapid advancement of Lasso methodologies with variable selection. The proposed method is generally applicable to the development of targeted therapies in clinical trials. Our simulation study demonstrates the good performance of the two-step Lasso: Important biomarkers can typically be selected with high probabilities, and unimportant markers can be effectively eliminated from the model. PMID- 24075830 TI - Control of vessel sprouting by genetic and metabolic determinants. AB - Vessel sprouting by endothelial cells (ECs) during angiogenesis relies on a navigating tip cell and on proliferating stalk cells that elongate the shaft. To date, only genetic signals have been shown to regulate vessel sprouting. However, emerging evidence indicates that the angiogenic switch also requires a metabolic switch. Indeed, angiogenic signals not only induce a change in EC metabolism but this metabolic adaptation also co-determines vessel sprouting. The glycolytic activator PFKFB3 regulates stalk cell proliferation and renders ECs more competitive to reach the tip. We discuss the emerging link between angiogenesis and EC metabolism during the various stages of vessel sprouting, focusing only on genetic signals for which an effect on EC metabolism has been documented. PMID- 24075832 TI - Body appreciation, sexual relationship status, and protective sexual behaviors in women. AB - The relationship between body appreciation and sexual risk reduction behavior in women is under-explored. This cross-sectional study examined the relationships between body appreciation, male condom use, and sexually transmitted infection (STI) testing among a community-based sample of women (n=285). Logistic regression results revealed that after controlling for age, BMI, and sexual orientation, having more than one sexual partner moderated body appreciation and current male condom use (OR=4.21, p<.01, CI=1.510-11.726). Body appreciation was not a significant predictor of STI testing in the previous 12 months. This suggests that women with higher body appreciation may be more likely to engage in some protective sexual health behaviors. Interventions that seek to improve body appreciation instead of body size change such as weight loss or gain may encourage certain protective sexual behaviors in women. PMID- 24075831 TI - Responses to capture stress and exogenous corticosterone vary with body condition in female red-sided garter snakes (Thamnophis sirtalis parietalis). AB - This study examined whether hormonal and behavioral responses to capture stress and exogenous corticosterone (CORT) vary with body condition in female red-sided garter snakes (Thamnophis sirtalis parietalis). Female snakes were collected during the spring mating season and treated with 4 h of capture stress. We measured plasma CORT and estradiol before, during and after capture stress treatment followed by latency to copulate, a measure of female receptivity. Body condition was determined as the residual from a regression of body mass on snout vent-length. Baseline CORT did not differ between females in positive and negative body condition, but females in negative body condition showed a significantly larger increase in plasma CORT in response to capture stress. Estradiol, which is generally low during the mating season in this population, did not change in response to capture stress. Body condition, but not capture stress, influenced latency to copulate, suggesting that females are resistant to the behavioral effects of capture stress during the spring mating season. In a second experiment, only females in negative body condition increased latency to copulate in response to injection of a physiological (15 MUg) dose of exogenous CORT, while all females responded to a pharmacological (60 MUg) dose. These results indicate that behavioral responses to exogenous CORT vary with female body condition during the short mating season. Taken together, our data suggest that variation in body condition may be associated with differences in HPA axis sensitivity and/or glucocorticoid receptor density in the brain. PMID- 24075833 TI - WITHDRAWN: Special issue on Pregnancy and Steroids. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jsbmb.2013.08.007. The duplicate article has therefore been withdrawn. PMID- 24075834 TI - A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. AB - Aberrant expression of embryonic epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs) in epithelial cells triggers EMT, neoplastic transformation, stemness, and metastatic dissemination. We found that regulation and functions of EMT-TFs are different in malignant melanoma. SNAIL2 and ZEB2 transcription factors are expressed in normal melanocytes and behave as tumor suppressor proteins by activating an MITF-dependent melanocyte differentiation program. In response to NRAS/BRAF activation, EMT-TF network undergoes a profound reorganization in favor of TWIST1 and ZEB1. This reversible switch cooperates with BRAF in promoting dedifferentiation and neoplastic transformation of melanocytes. We detected EMT-TF reprogramming in late-stage melanoma in association with enhanced phospho-ERK levels. This switch results in E-cadherin loss, enhanced invasion, and constitutes an independent factor of poor prognosis in melanoma patients. PMID- 24075835 TI - Scaffold biomaterials for nano-pathophysiology. AB - This review is intended to provide an overview of tissue engineering strategies using scaffold biomaterials to develop a vascularized tissue engineered construct for nano-pathophysiology. Two primary topics are discussed. The first is the biological or synthetic microenvironments that regulate cell behaviors in pathological conditions and tissue regeneration. Second is the use of scaffold biomaterials with angiogenic factors and/or cells to realize vascularized tissue engineered constructs for nano-pathophysiology. These topics are significantly overlapped in terms of three-dimensional (3-D) geometry of cells and blood vessels. Therefore, this review focuses on neovascularization of 3-D scaffold biomaterials induced by angiogenic factors and/or cells. The novel strategy of this approach in nano-pathophysiology is to utilize the vascularized tissue engineered construct as a tissue model to predict the distribution and subsequent therapeutic efficacy of a drug delivery system with different physicochemical and biological properties. PMID- 24075836 TI - Rectal mesh exposure after laparoscopic sacrocolpopexy. AB - Herein we report the case of a 68-year-old woman who had rectal bleeding 13 days after laparoscopic sacrocolpopexy. Clinical examination and rectoscopy revealed rectal exposure of the posterior polyester mesh placed during the surgery. Endorectal surgery was performed to remove the exposed mesh and repair the rectal erosion. No further complications occurred during follow-up. Although vaginal erosions are a well-known complication of synthetic implants after surgery to repair pelvic organ prolapse, one must keep in mind the possibility of more uncommon types of mesh exposure. PMID- 24075837 TI - Ultrasound-guided high-intensity focused ultrasound vs laparoscopic myomectomy for symptomatic uterine myomas. AB - STUDY OBJECTIVE: To assess the quality of life (QoL) of women at 1 and 12 months after ultrasound-guided high-intensity focused ultrasound (USgHIFU) treatment as compared with laparoscopic myomectomy for treatment of symptomatic uterine myomas. DESIGN: Nonrandomized prospective clinical trial (Canadian Task Force classification II-2). SETTING: Urban university-based hospital in China. INTERVENTIONS: One hundred thirty premenopausal women underwent USgHIFU (n = 89) or laparoscopic myomectomy (n = 41) for treatment of symptomatic uterine myomas. MEASUREMENTS AND MAIN RESULTS: Eighty-three patients in the HIFU group and 39 in the surgical group were followed up at 1 and 12 months. QoL was assessed using the Medical Outcomes Study 36-Item Short-Form General Health Survey, which showed no significant differences between groups in any of the 8 subscales at the 12 month follow-up visit. Symptom score, willingness to recommend the treatment to a friend, hospital stay, and recovery period were compared between the 2 groups. In the HIFU group, hospital stay was shorter (mean [SD] 2.9 [1.5] days vs 6.2 [2.7] days; p <.001) and patients resumed normal activities sooner (4.5 [1.5] days vs 10.9 [3.8] days; p <.001). Significant clinical complications and adverse events after each treatment were documented and compared, and HIFU yielded significantly better results. CONCLUSIONS: Compared with laparoscopic myomectomy, HIFU treatment of symptomatic uterine myomas leads to comparable QoL and symptom improvement, fewer significant clinical complications and adverse events, shorter hospital stay, and faster recovery. Randomized studies with long-term follow-up are needed to reach definitive conclusions insofar as HIFU treatment of uterine myomas. PMID- 24075838 TI - Fast-track surgery in intestinal deep infiltrating endometriosis. AB - STUDY OBJECTIVE: To evaluate the length of hospital stay (LOS) and the readmission rate in patients undergoing laparoscopic surgery to treat intestinal deep infiltrating endometriosis (DIE) with application of the concepts of fast track surgery. DESIGN: Retrospective study of women undergoing laparoscopic treatment of intestinal DIE (Canadian Task Force classification II-3). SETTING: Tertiary referral private hospital. INTERVENTIONS: We evaluated 161 women who underwent laparoscopic surgery between January 2010 and April 2013 for complete treatment of intestinal DIE, via either conservative surgery (rectal shaving, mucosal skinning, or anterior disk resection) or radical surgery (segmental bowel resection). After surgery, all specimens were sent for pathologic examination to confirm the presence of endometriosis. MEASUREMENTS AND MAIN RESULTS: Patients were divided into 2 groups according to type of surgery (conservative [n = 102] or radical [n = 59]), and LOS and readmission rate were measured in both groups. Median LOS was shorter in the conservative group compared with the segmental bowel resection group (19 vs 28 hours; p < .001). Ninety-two patients (90.2%) in the conservative surgery group were discharged to home on the first postoperative day, compared with only 38 patients (64.4%) in the segmental bowel resection group. Overall, the readmission rate was low (3.1%): 6.8% in the segmental bowel resection group and 1% in the conservative group (p = .04; odds ratio, 7.34; 95% confidence interval, 0.8-67.3); however, the need for repeat operation was similar in both groups (3.4% vs 1%; p = .28; odds ratio, 3.54; 95% confidence interval, 0.31-39.95). CONCLUSION: Implementation of fast-track concepts in the laparoscopic treatment of intestinal DIE resulted in a short LOS and low readmission rate in both the segmental bowel resection and conservative surgery groups. PMID- 24075839 TI - Intracorporeal knot tying in a box trainer: how proficient is in vitro evaluation in laparoscopic experts? AB - OBJECTIVE: To determine the applicability of motion analysis parameters of intracorporeal knot tying in box trainers in experts as predictors of surgical outcome. DESIGN: Consecutive series of 1534 advanced laparoscopic hysterectomies (Canadian Task Force classification II-2). INTERVENTION: Time, path length, and motion in depth of a standardized intracorporeal knot-tying task were compared with mean risk-adjusted primary clinical outcomes for each participant. RESULTS: Although a large variety in proficient knot tying and surgical skills factors was observed; after correction for patient mix in 50 expert surgeons, motion analysis of intracorporeal knot tying could not significantly determine surgical outcome skills in advanced laparoscopic surgery. CONCLUSION: Levels of proficiency in advanced laparoscopic surgery cannot be appropriately determined using motion analysis in box trainers. Therefore, box trainer assessments do not adequately differentiate proficient from suboptimal clinical performance. PMID- 24075840 TI - Solid-state NMR investigations of peptide-lipid interactions of the transmembrane domain of a plant-derived protein, Hcf106. AB - The chloroplast twin arginine translocation system transports highly folded precursor proteins across the thylakoid using the protonmotive force as its only energy source. Hcf106 and another thylakoid protein, cpTatC compose the precursor receptor complex. Hcf106 is predicted to contain a single amino terminal transmembrane domain (TMD) followed by a Pro-Gly hinge, an amphipathic alpha helix, and a loosely structured carboxyl terminus. Hcf106 has been shown biochemically to insert spontaneously into thylakoid membranes; however, how this occurs is not understood. To investigate how Hcf106 inserts itself into the membrane unassisted, solid-state NMR spectroscopy was used to investigate the membrane activity of the TMD. A synthetic peptide of the Hcf106 TMD was incorporated into multilamellar vesicles made of 100% 1-palmitoyl-2-oleoyl-sn glycero-phosphocholine (POPC) or 85%:15% ratio with monogalactosyl diacylglycerol (POPC/MGDG) to probe peptide-lipid interaction. Solid-state (31)P NMR and (2)H NMR spectroscopic techniques were used to reveal peptide perturbations of the phospholipid membranes. Changes in spectral lineshape, chemical shift anisotropy width, (31)P T1 relaxation time and SCD order parameters demonstrated that the Hcf106 TMD peptide interacted with the phospholipids. Furthermore, the comparison between POPC and POPC/MGDG multilamellar vesicles indicated that lipid bilayer composition affected the peptide-lipid interaction with the peptide interacting preferentially with vesicles that more closely mimic the thylakoid. PMID- 24075841 TI - Priming and statistical learning in right brain damaged patients. AB - We investigated how right hemisphere lesions affected location priming and statistical learning in four groups of participants: young controls, older controls, and right brain damaged patients with or without spatial neglect. Using a version of the Maljkovic and Nakayama's (1994) priming task, but with all the targets presented at the mid-line, we biased the transition probability for targets to repeat their spatial location. The decrease in response time with spatial repetition allowed us to quantify priming, and the modulation of priming strength as a function of repeat probability allowed us to assess for statistical learning. Contrary to the healthy controls, right brain damage decreased (but did not abolish) spatial priming. Right brain damaged patients did not modulate the magnitude of the spatial priming effect with variation in repeat frequency, as did the control groups. We conclude that damage to the right hemisphere impairs spatial priming and that priming impairment co-exists with, and may contribute to an inability to learn environmental statistical regularities. Such deficits could contribute to functional deficits and a poorer response to rehabilitation. PMID- 24075842 TI - Discharge intervention pilot improves satisfaction for patients and professionals. AB - BACKGROUND: The risk of adverse events and information loss following hospital discharge is particularly high for vulnerable multimorbid patients. Poor coordination of care at discharge increases the burden upon patients, caregivers and professionals, and can lead to increased morbidity and costs. Targeted programs can improve efficiency and health outcomes, but the ideal organization of hospital discharge remains to be specified. METHODS: This single-blind, randomized, controlled interprofessional pilot on two internal medicine wards in a teaching hospital in Baden, Switzerland tested a discharge management intervention using nurse care managers. Patients (n=60) were at high risk for adverse events, fulfilling criteria such as polypharmacy, therapy with anticoagulants or insulin, plus secondary criteria indicating vulnerability. Primary composite endpoint was fulfilled by any of the following: death, rehospitalization, urgent physician visit within five days of discharge or adverse medicine reaction. Secondary endpoints evaluated patient quality-of-life, caregiver burden, adequacy of information provided to primary care physicians and home care nurses, and satisfaction with discharge for all groups. Endpoint evaluation was via telephone interviews on days 5 and 30 post-discharge. Design was critically evaluated in anticipation of a larger trial. RESULTS: Intervention acceptance was high. In the intervention group, satisfaction was higher among patients (p=0.027) and caregivers (p=0.008), and primary care physicians rated discharge information higher (p=0.031). Primary endpoint showed no significant difference between groups. Necessary design modifications were identified. CONCLUSION: Discharge coordination and follow-up care by nurse care managers significantly improved subjective endpoints. A modified design is planned to test effectiveness in a well-powered study. PMID- 24075843 TI - An infant with seizures and macrocephaly. PMID- 24075844 TI - "No-no" type bobble-head doll syndrome in an infant with an arachnoid cyst of the posterior fossa: a case report. AB - BACKGROUND: Bobble-head doll syndrome is a rare and surgically treatable movement disorder characterized by up-and-down (yes-yes) head bobbing occurring at a rate of 2-3 Hz. Side-to-side (no-no) head bobbing is less frequently described. Bobble head doll syndrome is usually associated with dilation of the third ventricle, but is rarely associated with posterior fossa disease. PATIENT: We describe an infant with fetal hydrocephalus and an arachnoid cyst of the posterior fossa. Endoscopic fenestration of the arachnoid cyst was performed on postnatal day 12. A routine examination at 4 months indicated the infant showed "no-no" type head bobbing, but no other neurological disorder was observed. The third ventricle was dilated during the perioperative period, but not at 2-4 months. In contrast, cerebellar compression decreased gradually and persisted at 4 months. CONCLUSION: Although few patients with bobble-head doll syndrome do not have third ventricle dilation, these patients typically show cerebellar dysfunction. Our findings support the hypothesis that cerebellar dysfunction is present in bobble-head doll syndrome when third ventricle dilation is absent. PMID- 24075845 TI - A needle in a haystack: Sturge-Weber syndrome gene discovery. PMID- 24075846 TI - Differential roles of KLF4 in the development and differentiation of CD8+ T cells. AB - The transcription factor Kruppel-like factor 4 (KLF4) can activate or repress gene expression in a cell-context dependent manner. We have previously shown that KLF4 inhibits the proliferation of naive CD8(+) T cells in vitro downstream of the transcription factor ELF4. In this work, we describe a novel role of KLF4 in the differentiation of CD8(+) T cells upon infection. Loss of KLF4 had minimal effect on thymic T cell development and distribution of mature T cells in the spleen, blood, and lymph nodes. KLF4-deficient naive CD8(+) T cells also displayed normal homeostatic proliferation upon adoptive transfer into lymphopenic hosts. However, activation of KLF4-deficient naive CD8(+) T cells by in vitro TCR crosslink and co-stimulation resulted in increased proliferation. Furthermore, naive KLF4-deficient OT-I CD8(+) T cells generated increased numbers of functional memory CD8(+) T cells compared to wild type OT-I CD8(+) T cells co injected in the same recipient in both primary and recall responses to Listeria monocytogenes-OVA. Collectively, our data demonstrate that KLF4 regulates differentiation of functional memory CD8(+) T cells while sparing development and homeostasis of naive CD8(+) T cells. PMID- 24075847 TI - The effects of dietary saturated fat on basal hypothalamic neuroinflammation in rats. AB - Recent evidence has demonstrated that consumption of high fat diets can trigger brain inflammation and subsequent injury in the absence of any peripheral inflammatory signaling. Here we sought to investigate whether a link exists between the concentration of highly saturated fats in the diet and the development of inflammation in the brain of rats and, whether the source of the saturated fat was an important factor in this process. Adult male rats had access to diets with a moderate level of total fat (32% of calories as fat) varying in level of saturated fat [low (20%) vs high (>60%)] and its source (butter or coconut oil). After 8 weeks of diet exposure peripheral and central tissues were collected for analysis of inflammatory signals. Neither blood nor white adipose tissue exhibited any changes in inflammatory mediators regardless of the saturated fat content or the source. In the brain however, we observed significant hypothalamic upregulation of the expression of markers of glial activation as well as of interleukin (IL)-1,6 and nuclear factor (NF)-IL-6, which were highest in the group fed the butter-based diets. The increase in these inflammatory mediators had no effect on basal body temperature or the temperature response to systemic lipopolysaccharide (LPS). The present results indicate that hypothalamic inflammation associated with consumption of diets high in fat is directly linked to the saturated fat content as well as the source of that fat. These effects are likely linked to other pathophysiological changes in the regulation of metabolism. PMID- 24075848 TI - The gene-immune-behavioral pathway: Gamma-interferon (IFN-gamma) simultaneously coordinates susceptibility to infectious disease and harm avoidance behaviors. AB - Cytokine gene variants are known to influence both infectious disease susceptibility and harm-avoidant behaviors, suggesting that these risk variants may be pleiotropically linked to instinctual disease-avoidant traits. The gamma interferon (IFNG) +874 T>A polymorphism (rs2430561) is an ideal candidate gene variant for immune-behavioral studies. It is a functional SNP, regulating IFNG mRNA expression; it is known to modulate serotonergic activity and is therefore capable of modifying behavior; and it has previously been associated with increased susceptibility to malaria, tuberculosis, leprosy and Chagas disease. We hypothesized that the infectious disease-high-risk IFNG +874 A-allele would be associated with four personality traits previously reported as behavioral defenses against infection: Harm Avoidance (HA), Extraversion (E), Exploratory Excitability (Exp E), and Openness to Experience (O). We tested this hypothesis in a sample of 168 healthy university students from Southern California genotyped for IFNG +874 T>A and evaluated by the Temperament and Character Inventory Revised (TCI-R) and the NEO Five-Factor Inventory (NEO-FFI). We found that the infectious disease-high-risk IFNG +874 A-allele was associated with increased HA (P=0.001) and decreased E (P=0.030) and Exp E (P=0.030). These findings suggest that the IFNG +874 A gene variant is linked both to infectious disease susceptibility and to proactive behavioral defenses that reduce infection risk in healthy subjects. PMID- 24075849 TI - Sonochemical fabrication of mesoporous TiO2 inside diatom frustules for photocatalyst. AB - Mesoporous titanium dioxide (TiO2) has been assembled inside the macropores of diatom frustules by sonochemical condensation of titania precursor, and then thermal treated at an elevated temperature. The resulting hierarchical macro/mesoporous-structures of the TiO2 inside diatom were confirmed by characterizations of X-ray diffraction (XRD) and transmission electron microscopy (TEM). The amount of TiO2 inside the periodic macropores of diatom was controlled by varying the sonication time. It was found that the resultant composite with only 30 wt% TiO2 loading delivered a high photocatalytic performance, even better than that of pure P25. This is attributed to its hierarchical macro/mesoporous structure as it provides a large number of accessible active sites for efficient transportations of guest species to framework binding sites. Other macro/mesoporous structures with a nearly endless variety of functional chemistries and shapes are expected to be produced, leading to a range of novel applications in remediation, molecular transportation and environmental field by using this facile strategy. PMID- 24075850 TI - In vivo spectrophotometric evaluation of pure enamel and enamel-dentine complex in relationship with different age groups. AB - OBJECTIVE: The aim of this in vivo study was to investigate the influence of age on optical properties of pure enamel and enamel-dentine complex. METHODS: A spectrophotometric study was performed on two different age groups: young (10-35 years old) and adult (36-60 years old). In both groups, the tooth's total area of the upper right central incisor was recorded. Areas of 2mm thick pure enamel and 3mm enamel-dentine complex were detected and their L a b and CR evaluated. RESULTS: For 2mm pure enamel medians in the young group were L 74.8, a 3.1, b 15.1, against white background; and L 65.5, a 0.9, b 10.3 against black background. The correspondent opacity was 75%. In the adult group medians were L 70.0, a 4.1, b 15.4 against white background; and L 61.2, a 1.6, b 9.6, against black background. The correspondent opacity was 75%. For 3mm enamel-dentine complex medians in the young group were L 77.8, a 3.0, b 19.8 against white background; and L 74.2, a 1.1, b 15.9, against black background. The correspondent opacity was 89%. In the adult group medians were L 73.4, a 4.0, b 18.5 against white background; and L 71.0, a 2.0, and b 15.3 against black background. The correspondent opacity was 90%. DISCUSSION: The application of this method on a larger group of subjects of different ages may serve as a database for a more exact characterization of optical properties of natural enamel and dentine. CONCLUSIONS: L values in enamel, as well as a* value of 3mm thick enamel-dentine complex and 2mm pure enamel were significantly higher in the young age group. CLINICAL SIGNIFICANCE: L and a values of enamel over white and black backgrounds were statistically different within the 2 age groups considered. L values over white background and a values over black background of the enamel dentine complex seem to change with age. The opacity (CR) for enamel nor for enamel dentine complex does not change within the two age groups considered in this study. PMID- 24075851 TI - Evidence-based status of second- and third-generation autologous chondrocyte implantation over first generation: a systematic review of level I and II studies. AB - PURPOSE: The purpose of this study was to examine the Level I and II evidence for newer generations of autologous chondrocyte implantation (ACI) versus first generation ACI and to establish whether the newer generations have overcome the limitations associated with first-generation ACI. METHODS: A literature search was carried out for Level I and II evidence studies on cartilage repair using the PubMed database. All the studies that dealt with ACI were identified. Only Level I and II studies that compared newer generations against earlier generations were selected, whereas studies that compared ACI against other methods of cartilage repair were excluded. RESULTS: A total of 7 studies matched the selection criteria. Two studies compared periosteum-based autologous chondrocyte implantation (P-ACI) against collagen membrane-based autologous chondrocyte implantation (C-ACI), whereas one study each compared membrane-associated autologous chondrocyte implantation (MACI) against P-ACI and C-ACI. One study on C-ACI compared results related to age, whereas 2 studies evaluated postoperative rehabilitation after MACI. There was weak evidence showing that C-ACI is better than P-ACI and that MACI is comparable with both P-ACI and C-ACI. The weak evidence is because of studies with short durations of follow-up, small numbers of patients, medium-sized defects, and younger age groups. There is good evidence favoring an accelerated weight-bearing regimen after MACI. There is currently no evidence that supports scaffold-based ACI or arthroscopic implantation over first generation ACI. CONCLUSIONS: The hypothesis is thus partly proved in favor of C ACI/MACI against P-ACI with weak evidence, in favor of accelerated weight bearing after MACI with strong evidence, and not in favor of arthroscopic and scaffold based implantations because of unavailable evidence. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies. PMID- 24075853 TI - Mast cells protect from post-traumatic spinal cord damage in mice by degrading inflammation-associated cytokines via mouse mast cell protease 4. AB - Mast cells (MCs) are found abundantly in the central nervous system and play a complex role in neuroinflammatory diseases such as multiple sclerosis and stroke. In the present study, we show that MC-deficient Kit(W-sh/W-sh) mice display significantly increased astrogliosis and T cell infiltration as well as significantly reduced functional recovery after spinal cord injury compared to wildtype mice. In addition, MC-deficient mice show significantly increased levels of MCP-1, TNF-alpha, IL-10 and IL-13 protein levels in the spinal cord. Mice deficient in mouse mast cell protease 4 (mMCP4), an MC-specific chymase, also showed increased MCP-1, IL-6 and IL-13 protein levels in spinal cord samples and a decreased functional outcome after spinal cord injury. A degradation assay using supernatant from MCs derived from either mMCP4(-/-) mice or controls revealed that mMCP4 cleaves MCP-1, IL-6, and IL-13 suggesting a protective role for MC proteases in neuroinflammation. These data show for the first time that MCs may be protective after spinal cord injury and that they may reduce CNS damage by degrading inflammation-associated cytokines via the MC-specific chymase mMCP4. PMID- 24075852 TI - Surprising behavioral and neurochemical enhancements in mice with combined mutations linked to Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder behind Alzheimer's disease. There are currently no therapies proven to halt or slow the progressive neuronal cell loss in PD. A better understanding of the molecular and cellular causes of PD is needed to develop disease-modifying therapies. PD is an age-dependent disease that causes the progressive death of dopamine-producing neurons in the brain. Loss of substantia nigra dopaminergic neurons results in locomotor symptoms such as slowness of movement, tremor, rigidity and postural instability. Abnormalities in other neurotransmitters, such as serotonin, may also be involved in both the motor and non-motor symptoms of PD. Most cases of PD are sporadic but many families show a Mendelian pattern of inherited Parkinsonism and causative mutations have been identified in genes such as Parkin, DJ-1, PINK1, alpha-synuclein and leucine rich repeat kinase 2 (LRRK2). Although the definitive causes of idiopathic PD remain uncertain, the activity of the antioxidant enzyme glutathione peroxidase 1 (Gpx1) is reduced in PD brains and has been shown to be a key determinant of vulnerability to dopaminergic neuron loss in PD animal models. Furthermore, Gpx1 activity decreases with age in human substantia nigra but not rodent substantia nigra. Therefore, we crossed mice deficient for both Parkin and DJ-1 with mice deficient for Gpx1 to test the hypothesis that loss-of-function mutations in Parkin and DJ-1 cause PD by increasing vulnerability to Gpx1 deficiency. Surprisingly, mice lacking Parkin, DJ-1 and Gpx1 have increased striatal dopamine levels in the absence of nigral cell loss compared to wild type, Gpx1(-/-), and Parkin(-/-)DJ-1(-/-) mutant mice. Additionally, Parkin(-/-)DJ-1(-/-) mice exhibit improved rotarod performance and have increased serotonin in the striatum and hippocampus. Stereological analysis indicated that the increased serotonin levels were not due to increased serotonergic projections. The results of our behavioral, neurochemical and immunohistochemical analyses reveal that PD-linked mutations in Parkin and DJ-1 cause dysregulation of neurotransmitter systems beyond the nigrostriatal dopaminergic circuit and that loss-of-function mutations in Parkin and DJ-1 lead to adaptive changes in dopamine and serotonin especially in the context of Gpx1 deficiency. PMID- 24075854 TI - Insulin growth factor binding protein 7 is a novel target to treat dementia. AB - Alzheimer's disease (AD) is the most common form of dementia in the elderly but effective therapeutic strategies to treat AD are not yet available. This is also due to the fact that the pathological mechanisms that drive the pathogenesis of sporadic AD are still not sufficiently understood and may differ on the individual level. Several risk factors such as altered insulin-like peptide (ILP) signaling have been linked to AD and modulating the ILP system has been discussed as a potential therapeutic avenue. Here we show that insulin-like growth factor binding protein 7 (IGFBP7), a protein that attenuates the function of ILPs, is up regulated in the brains of AD patients and in a mouse model for AD via a process that involves altered DNA-methylation and coincides with decreased ILP signaling. Mimicking the AD-situation in wild type mice, by increasing hippocampal IGFBP7 levels leads to impaired memory consolidation. Consistently, inhibiting IGFBP7 function in mice that develop AD-like memory impairment reinstates associative learning behavior. These data suggest that IGFBP7 is a critical regulator of memory consolidation and might be used as a biomarker for AD. Targeting IGFBP7 could be a novel therapeutic avenue for the treatment of AD patients. PMID- 24075855 TI - Circadian aspects of energy metabolism and aging. AB - Life span extension has been a goal of research for several decades. Resetting circadian rhythms leads to well being and increased life span, while clock disruption is associated with increased morbidity accelerated aging. Increased longevity and improved health can be achieved by different feeding regimens that reset circadian rhythms and may lead to better synchrony in metabolism and physiology. This review focuses on the circadian aspects of energy metabolism and their relationship with aging in mammals. PMID- 24075856 TI - An intra-abdominal mass in a 56-year-old woman. PMID- 24075857 TI - Crohn's disease with worsening symptoms. PMID- 24075858 TI - The increasing role of nonradiologists in performing ultrasound-guided invasive procedures. AB - PURPOSE: Recent proliferation of mobile diagnostic ultrasound (US) units and improved resolution have allowed for widespread use of US by more providers, both for diagnosis and US-guided procedures (USGP). This study aims to document recent trends in utilization for USGP in the Medicare population. METHODS: Source data were obtained from the CMS Physician Supplier Procedure Summary Master Files from 2004 to 2010. Allowed billing claims submitted for USGP were extracted and volume was analyzed by provider type and setting. Compound annual growth rates were calculated. RESULTS: The total utilization rate for all USGP was 2,425 per 100,000 in 2004 and 4,870 in 2010, an increase of 100.8% (+2,445 per 100,000) with a compound annual growth rate of 12.3%. The year 2010 represents the first year that nonradiologists as a group performed more USGP than radiologists, at 922,672 versus 794,497 examinations, respectively. Nonradiologists accounted for 72.2% (599,751 of 830,925) of the USGP volume growth from 2004 to 2010. Most 2010 claims were submitted by radiologists (n = 794,497; 46.3%) and surgeons (n = 332,294; 19.4%). The largest overall volume increases from 2004 to 2010 were observed among radiologists, surgeons, anesthesiologists, rheumatologists, midlevel providers, primary care physicians, nonrheumatologist internal medicine subspecialists, and the aggregate of all other provider types. CONCLUSION: The year 2010 represents the first year that nonradiologists performed more USGP than radiologists. From 2004 to 2010, radiologists and surgeons experienced only modest growth in USGP volume, whereas several other provider types experienced more rapid growth. It is likely that many procedures that were previously performed without US guidance are now being performed with US guidance. PMID- 24075859 TI - Nuclear medicine therapy clinics: a golden opportunity for direct longitudinal patient care. PMID- 24075861 TI - Design of antibiotic containing hydrogel wound dressings: biomedical properties and histological study of wound healing. AB - Keeping in view the antioxidant nature of the acacia gum and mucoadhesive nature of carbopol hydrogels, in the present studies, an attempt has been made to explore the potential of these materials in designing new hydrogel wound dressings meant for slow release of gentamicin, an antibiotic drug, and to enhance the wound healing potential. The hydrogel films were characterized by SEM, FTIR, XRD and swelling studies. Biomedical properties of hydrogel films like blood compatibility, antioxidant activity, mucoadhesion, antimicrobial activity, oxygen/water vapour permeability, microbial penetration and mechanical properties (tensile strength, burst strength, resilience, relaxation, and folding endurance) have been evaluated. The histological studies of wound healing were also carried out on swiss albino mice of strain Balb C and it has been observed that in case of wounds covered with hydrogel dressings shown faster wound healing, formation of well developed fibroblasts and blood capillaries as compared to open wounds. The results of biomedical properties indicated that hydrogel films are non thrombogenic, non-haemolytic, antioxidant and mucoadhesive in nature, and are permeable to oxygen and moisture while impermeable to micro-organisms. The hydrogel wound dressings have absorbed (8.772 +/- 0.184 g/g film) simulated wound fluid. Release of gentamicin drug from wound dressings occurred through Fickian diffusion mechanism in simulated wound fluid. PMID- 24075860 TI - Reciprocal inhibition between intracellular antiviral signaling and the RNAi machinery in mammalian cells. AB - RNA interference (RNAi) is an established antiviral defense mechanism in plants and invertebrates. Whether RNAi serves a similar function in mammalian cells remains unresolved. We find that in some cell types, mammalian RNAi activity is reduced shortly after viral infection via poly-ADP-ribosylation of the RNA induced silencing complex (RISC), a core component of RNAi. Well-established antiviral signaling pathways, including RIG-I/MAVS and RNaseL, contribute to inhibition of RISC. In the absence of virus infection, microRNAs repress interferon-stimulated genes (ISGs) associated with cell death and proliferation, thus maintaining homeostasis. Upon detection of intracellular pathogen-associated molecular patterns, RISC activity decreases, contributing to increased expression of ISGs. Our results suggest that, unlike in lower eukaryotes, mammalian RISC is not antiviral in some contexts, but rather RISC has been co-opted to negatively regulate toxic host antiviral effectors via microRNAs. PMID- 24075862 TI - Psychological benefits of weight loss following behavioural and/or dietary weight loss interventions. A systematic research review. AB - It is generally accepted that weight loss has significant physiological benefits, such as reduced risk of diabetes, lowered blood pressure and blood lipid levels. However, few behavioural and dietary interventions have investigated psychological benefit as the primary outcome. Hence, systematic review methodology was adopted to evaluate the psychological outcomes of weight loss following participation in a behavioural and/or dietary weight loss intervention in overweight/obese populations. 36 Studies were selected for inclusion and were reviewed. Changes in self-esteem, depressive symptoms, body image and health related quality of life (HRQoL) were evaluated and discussed. Where possible, effect sizes to indicate the magnitude of change pre- to post- intervention were calculated using Hedges' g standardised mean difference. The results demonstrated consistent improvements in psychological outcomes concurrent with and sometimes without weight loss. Improvements in body image and HRQoL (especially vitality) were closely related to changes in weight. Calculated effect sizes varied considerably and reflected the heterogeneous nature of the studies included in the review. Although the quality of the studies reviewed was generally acceptable, only 9 out of 36 studies included a suitable control/comparison group and the content, duration of intervention and measures used to assess psychological outcomes varied considerably. Further research is required to improve the quality of studies assessing the benefits of weight loss to fully elucidate the relationship between weight loss and psychological outcomes. PMID- 24075863 TI - Surveillance of herpes simplex virus resistance to antivirals: a 4-year survey. AB - Herpes simplex virus (HSV) resistance to antivirals constitutes a therapeutic challenge, especially among immunocompromised patients. This observational survey on HSV resistance to antivirals was conducted retrospectively over a 4-year period (2008-2012). A total of 211 HSV-positive clinical samples (94 HSV-1 and 117 HSV-2) recovered from 139 patients (11 immunocompetent patients, 85 immunocompromised patients, and 43 patients with unknown immune status) with suspected HSV drug-resistance were analyzed for acyclovir and foscarnet susceptibility. Antiviral resistance testing consisted in a two-step procedure including a first-step genotypic assay, based on UL23 (thymidine kinase, TK) and UL30 (Pol) gene sequencing, and a second-step phenotypic assay (i.e., plaque reduction assay) performed when unpreviously described mutations were detected. As a whole, susceptibility and resistance to antivirals were evidenced for 58 (30.7%) and 86 (45.5%) HSV, respectively, whereas antiviral profile remained undetermined for 45 (23.8%) HSV. The prevalence of drug resistance was significantly higher among HSV-2 isolates than among HSV-1 isolates (53.8% vs. 34.9%; p=0.012). The majority (i.e., 79.7%) of cases of ACV resistance conferred by TK mutations resulted from UL23 gene frameshift reading. Apart from the changes surely related to natural polymorphism or drug-resistance, 91 unpreviously reported mutations were identified in TK and Pol, including 51 potential natural polymorphisms, 22 mutations likely conferring resistance to antivirals, and 18 mutations of unclear significance. PMID- 24075864 TI - Ulinastatin is a novel candidate drug for sepsis and secondary acute lung injury, evidence from an optimized CLP rat model. AB - Ulinastatin is a potent multivalent serine protease inhibitor, which was recently found with therapeutic potentials in treating sepsis, and the most life threatening complication of critically ill population. However, the pharmacological features and possible mechanisms need to be further elucidated in reliable and clinical relevant sepsis models. As known, sepsis induced by surgery of cecal ligation and puncture (CLP) is widely accepted as the gold standard animal model, but the inconsistency of outcomes is the most obvious problem. In the present experiments, we reported an improved rat CLP model with much more consistent outcomes using self-made three edged puncture needles in our lab. Results from this optimized model revealed that ulinastatin improved survivals of CLP rats, attenuated proinflammatory response and prevented systemic disorder and organ dysfunction. Ulinastatin was also found to be effective in ameliorating sepsis-related ALI, a syndrome most frequent and fatal in sepsis. The molecular mechanism investigation showed that ulinastatin's protection against ALI was probably related to the down-regulation of NF-kappaB activity and inhibition of TNF-alpha, IL-6 and elastase expressions in the lung tissue. In conclusion, based on a successful establishment of optimized rat CLP model ulinastatin is proved to be an effective candidate for sepsis treatment, due to its anti-inflammation and anti-protease activities that ameliorate systemic disorders, prevent organ injuries and thus improve the survival outcomes of sepsis in animals. PMID- 24075865 TI - Effect of vasopressin injection technique in laparoscopic excision of bilateral ovarian endometriomas on ovarian reserve: prospective randomized study. AB - STUDY OBJECTIVE: To evaluate the effects of vasopressin injection technique in laparoscopic cystectomy on ovarian reserve in patients with bilateral endometriomas. DESIGN: Randomized prospective study (Canadian Task Force classification I). SETTING: University hospital. PATIENTS: Eighty-six women with bilateral endometriomas. INTERVENTIONS: Laparoscopic cystectomy of bilateral endometriomas was performed using different techniques including laparoscopic cystectomy by stripping without injection (control group), laparoscopic cystectomy by stripping with injection of saline solution (saline group), and laparoscopic cystectomy by stripping with vasopressin injection technique (VIT group). MEASUREMENTS AND MAIN RESULTS: The number of coagulation events on the ovarian cortex for hemostasis was counted in different groups, and the thickness of ovarian tissues removed was measured. The basal follicle-stimulating hormone (FSH) level was determined before surgery and at 3-, 6-, and 12-month follow-up after laparoscopic cystectomy in the different groups. In the saline group, fewer coagulation events were required to achieve hemostasis, less ovarian tissues were removed, and lower preoperative FSH levels were detected than in the control group (p < .01). In the VIT group, even fewer coagulation events (p < .01) and lower preoperative FSH levels (p < .01) were detected than in the saline group. There was no significant difference in the thickness of ovarian tissues removed in the 2 groups (p > .05). Basal FSH levels were significantly different before and after surgery in the control and saline groups (p < .01) but not in the VIT group (p > .05). CONCLUSION: Vasopressin injection is an ideal procedure to reduce damage from usual laparoscopic cystectomy of bilateral ovarian endometriomas to protect ovarian reserve. PMID- 24075866 TI - Mutation scanning-based identification of larval and nymphal ticks (Acari: Ixodidae) from Richardson's ground squirrels (Spermophilus richardsonii). AB - The objective of this study was to identify the tick species parasitizing Richardson's ground squirrels (Spermophilus richardsonii) in southern Saskatchewan (Canada). Morphological examination of the adult ticks revealed the presence of three tick species, Ixodes sculptus, Ixodes kingi and Dermacentor andersoni. However, given the difficulties in identifying some of the larval and nymphal (immature) ticks using this approach, PCR-based single-strand conformation polymorphism (SSCP) and DNA sequence analyses of a portion of the mitochondrial (mt) 16S rRNA gene were used to determine their species identity. The results showed that each tick species had a unique set of SSCP profiles and DNA sequences using this mt marker. The species identity of larval and nymphal ticks was determined based on a comparison of these profiles and sequences with those of morphologically-identified adults. The detection of three tick species, which are known vectors of disease-causing agents, on the same host has important implications for understanding the ecology of vector-borne diseases, and provides an opportunity to examine fundamental questions regarding the structure and composition of the bacterial communities (i.e., both endosymbiotic and pathogenic species) in these ticks. This study shows the utility and benefits of using the present molecular method for the accurate identification of ticks at any stage of development. PMID- 24075867 TI - The antiviral innate immune response in fish: evolution and conservation of the IFN system. AB - Innate immunity constitutes the first line of the host defense after pathogen invasion. Viruses trigger the expression of interferons (IFNs). These master antiviral cytokines induce in turn a large number of interferon-stimulated genes, which possess diverse effector and regulatory functions. The IFN system is conserved in all tetrapods as well as in fishes, but not in tunicates or in the lancelet, suggesting that it originated in early vertebrates. Viral diseases are an important concern of fish aquaculture, which is why fish viruses and antiviral responses have been studied mostly in species of commercial value, such as salmonids. More recently, there has been an interest in the use of more tractable model fish species, notably the zebrafish. Progress in genomics now makes it possible to get a relatively complete image of the genes involved in innate antiviral responses in fish. In this review, by comparing the IFN system between teleosts and mammals, we will focus on its evolution in vertebrates. PMID- 24075868 TI - Why are there so many diverse replication machineries? AB - The replicon model has initiated a major research line in molecular biology: the study of DNA replication mechanisms. Until now, the majority of studies have focused on a limited set of model organisms, mainly from Bacteria or Opisthokont eukaryotes (human, yeasts) and a few viral systems. However, molecular evolutionists have shown that the living world is more complex and diverse than believed when the operon model was proposed. Comparison of DNA replication proteins in the three domains, Archaea, Bacteria, and Eukarya, have surprisingly revealed the existence of two distinct sets of non-homologous cellular DNA replication proteins, one in Bacteria and the other in Archaea and Eukarya, suggesting that the last universal common ancestor possibly still had an RNA genome. A major puzzle is the presence in eukaryotes of the unfaithful DNA polymerase alpha (Pol alpha) to prime Okazaki fragments. Interestingly, Pol alpha is specifically involved in telomere biosynthesis, and its absence in Archaea correlates with the absence of telomeres. The recent discovery of telomere-like GC quartets in eukaryotic replication origins suggests a link between Pol alpha and the overall organization of the eukaryotic chromosome. As previously proposed by Takemura, Pol alpha might have originated from a mobile element of viral origin that played a critical role in the emergence of the complex eukaryotic genomes. Notably, most large DNA viruses encode DNA replication proteins very divergent from their cellular counterparts. The diversity of viral replication machineries compared to cellular ones suggests that DNA and DNA replication mechanisms first originated and diversified in the ancient virosphere, possibly explaining why they are so many different types of replication machinerie. PMID- 24075869 TI - Disruption of helix-capping residues 671 and 674 reveals a role in HIV-1 entry for a specialized hinge segment of the membrane proximal external region of gp41. AB - HIV-1 (human immunodeficiency virus type 1) uses its trimeric gp160 envelope (Env) protein consisting of non-covalently associated gp120 and gp41 subunits to mediate entry into human T lymphocytes. A facile virus fusion mechanism compensates for the sparse Env copy number observed on viral particles and includes a 22-amino-acid, lentivirus-specific adaptation at the gp41 base (amino acid residues 662-683), termed the membrane proximal external region (MPER). We show by NMR and EPR that the MPER consists of a structurally conserved pair of viral lipid-immersed helices separated by a hinge with tandem joints that can be locked by capping residues between helices. This design fosters efficient HIV-1 fusion via interconverting structures while, at the same time, affording immune escape. Disruption of both joints by double alanine mutations at Env positions 671 and 674 (AA) results in attenuation of Env-mediated cell-cell fusion and hemifusion, as well as viral infectivity mediated by both CD4-dependent and CD4 independent viruses. The potential mechanism of disruption was revealed by structural analysis of MPER conformational changes induced by AA mutation. A deeper acyl chain-buried MPER middle section and the elimination of cross-hinge rigid-body motion almost certainly impede requisite structural rearrangements during the fusion process, explaining the absence of MPER AA variants among all known naturally occurring HIV-1 viral sequences. Furthermore, those broadly neutralization antibodies directed against the HIV-1 MPER exploit the tandem joint architecture involving helix capping, thereby disrupting hinge function. PMID- 24075871 TI - Subunit positioning and stator filament stiffness in regulation and power transmission in the V1 motor of the Manduca sexta V-ATPase. AB - The vacuolar H(+)-ATPase (V-ATPase) is an ATP-driven proton pump essential to the function of eukaryotic cells. Its cytoplasmic V1 domain is an ATPase, normally coupled to membrane-bound proton pump Vo via a rotary mechanism. How these asymmetric motors are coupled remains poorly understood. Low energy status can trigger release of V1 from the membrane and curtail ATP hydrolysis. To investigate the molecular basis for these processes, we have carried out cryo electron microscopy three-dimensional reconstruction of deactivated V1 from Manduca sexta. In the resulting model, three peripheral stalks that are parts of the mechanical stator of the V-ATPase are clearly resolved as unsupported filaments in the same conformations as in the holoenzyme. They are likely therefore to have inherent stiffness consistent with a role as flexible rods in buffering elastic power transmission between the domains of the V-ATPase. Inactivated V1 adopted a homogeneous resting state with one open active site adjacent to the stator filament normally linked to the H subunit. Although present at 1:1 stoichiometry with V1, both recombinant subunit C reconstituted with V1 and its endogenous subunit H were poorly resolved in three-dimensional reconstructions, suggesting structural heterogeneity in the region at the base of V1 that could indicate positional variability. If the position of H can vary, existing mechanistic models of deactivation in which it binds to and locks the axle of the V-ATPase rotary motor would need to be re-evaluated. PMID- 24075870 TI - Innate immune response to arenaviral infection: a focus on the highly pathogenic New World hemorrhagic arenaviruses. AB - Arenaviruses are enveloped, negative-stranded RNA viruses that belong to the family Arenaviridae. This diverse family can be further classified into OW (Old World) and NW (New World) arenaviruses based on their antigenicity, phylogeny, and geographical distribution. Many of the NW arenaviruses are highly pathogenic viruses that cause systemic human infections characterized by hemorrhagic fever and/or neurological manifestations, constituting public health problems in their endemic regions. NW arenavirus infection induces a variety of host innate immune responses, which could contribute to the viral pathogenesis and/or influence the final outcome of virus infection in vitro and in vivo. On the other hand, NW arenaviruses have also developed several strategies to counteract the host innate immune response. We will review current knowledge regarding the interplay between the host innate immune response and NW arenavirus infection in vitro and in vivo, with emphasis on viral-encoded proteins and their effect on the type I interferon response. PMID- 24075872 TI - Emerging role of the host restriction factor tetherin in viral immune sensing. AB - Tetherin (BST-2, CD317) is an interferon-inducible cellular factor that inhibits the release of diverse enveloped viruses by tethering them to the cell surface. Its importance in antiviral immunity is underscored by the observation that various viruses have evolved antagonists against this restriction factor. Accumulating evidence suggests that this is not only due to its ability to inhibit virus release but that tetherin also acts as an innate immune sensor of viral infections that activates NF-kappaB to induce an inflammatory response. Furthermore, tetherin modulates immune activation through interactions with the immunoglobulin-like transcript 7 (ILT7, LILRA4). This surface receptor is specifically expressed on plasmacytoid dendritic cells, which are the main producers of type I interferons in response to viral infections. Here, we summarize some of our current knowledge about the role of tetherin as a viral immune sensor and discuss how the accessory HIV-1 (human immunodeficiency virus type 1) Vpu protein counteracts this effect. PMID- 24075873 TI - Mapping the UDP-N-acetylglucosamine regulatory site of human glucosamine-6P synthase by saturation-transfer difference NMR and site-directed mutagenesis. AB - The enzyme glucosamine-6P Synthase (Gfat, L-glutamine:D-fructose-6P amidotransferase) is involved in the hexosamine biosynthetic pathway and catalyzes the formation of glucosamine-6P from the substrates d-fructose-6 phosphate and l-glutamine. In eukaryotic cells, Gfat is inhibited by UDPGlcNAc, the end product of the biochemical pathway. In this work we present the dissection of the binding and inhibition properties of this feedback inhibitor and of its fragments by a combination of STD-NMR experiments and inhibition measurements on the wild type human enzyme (hGfat) as well as on site-directed mutants. We demonstrate that the UDPGlcNAc binding site is located in the isomerase domain of hGfat. Two amino acid residues (G445 and G461) located at the bottom of the binding site are identified to play a key role in the specificity of UDPGlcNAc inhibition of hGfat activity vs its bacterial Escherichia coli counterpart. We also show that UDPGlcNAc subcomponents have distinct features: the nucleotidic moiety is entirely responsible for binding whereas the N-acetyl group is mandatory for inhibition but not for binding, and the sugar moiety acts as a linker between the nucleotidic and N-acetyl groups. Combining these structural recognition determinants therefore appears as a promising strategy to selectively inhibit hGfat, which may for example help reduce complications in diabetes. PMID- 24075874 TI - The plant mitochondrial genome: dynamics and maintenance. AB - Plant mitochondria have a complex and peculiar genetic system. They have the largest genomes, as compared to organelles from other eukaryotic organisms. These can expand tremendously in some species, reaching the megabase range. Nevertheless, whichever the size, the gene content remains modest and restricted to a few polypeptides required for the biogenesis of the oxidative phosphorylation chain complexes, ribosomal proteins, transfer RNAs and ribosomal RNAs. The presence of autonomous plasmids of essentially unknown function further enhances the level of complexity. The physical organization of the plant mitochondrial DNA includes a set of sub-genomic forms resulting from homologous recombination between repeats, with a mixture of linear, circular and branched structures. This material is compacted into membrane-bound nucleoids, which are the inheritance units but also the centers of genome maintenance and expression. Recombination appears to be an essential characteristic of plant mitochondrial genetic processes, both in shaping and maintaining the genome. Under nuclear surveillance, recombination is also the basis for the generation of new mitotypes and is involved in the evolution of the mitochondrial DNA. In line with, or as a consequence of its complex physical organization, replication of the plant mitochondrial DNA is likely to occur through multiple mechanisms, potentially involving recombination processes. We give here a synthetic view of these aspects. PMID- 24075875 TI - The human peroxisome in health and disease: the story of an oddity becoming a vital organelle. AB - Since the first report by Rhodin in 1954, our knowledge on mammalian microbodies/peroxisomes has known several periods. An initial two decades period (1954-1973) has contributed to the biochemical individualisation of peroxisomes as a new class of subcellular organelles (de Duve, 1965). The corresponding research period failed to define a clear role of mammalian peroxisomes in vital functions and intermediary metabolism, explaining why feeling that peroxisomes might be in the human cell oddities has prevailed during several decades. The period standing from 1973 to nowadays has progressively removed this cell oddity view of peroxisomes by highlighting vital function and metabolic role of peroxisomes in health and disease along with genetic and metabolic regulation of peroxisomal protein content, organelle envelope formation and protein signal targeting mechanisms. Research on peroxisomes and their response to various drugs and metabolites, dietary and physiological conditions has also played a key role in the discovery of peroxisome proliferator activated receptors (PPARs) belonging to the nuclear hormone receptor superfamily and for which impact in science and medicine goes now by far beyond that of the peroxisomes. PMID- 24075877 TI - Genotyping of 38 insertion/deletion polymorphisms for human identification using universal fluorescent PCR. AB - Short insertion/deletion (Indel) polymorphisms of approximately 2-6 bp are useful as biallelic markers for forensic analysis, and the application of Indel genotyping as a supplementary tool would improve human identification accuracy. We examined the allele frequencies of 37 autosomal Indels in the Japanese population and developed a novel dual-color genotyping method for human identification on the basis of universal fluorescent PCR, including the sex typing amelogenin locus. Target genomic fragment sizes for 38 Indels were 49-143 bp. We analyzed these Indels in 100 Japanese individuals using the M13(-47) sequence as a universal primer. For dual-color genotyping, we designed a novel universal primer with high amplification efficiency and specificity. Using FAM labeled M13(-47) and HEX-labeled modified M13(-47) primers, fluorescent signals at all loci were clearly distinguished in two independent multiplex PCRs. Average minor allele frequency was 0.39, and accumulated matching probability was 2.12 * 10(-15). Complete profiles were successfully amplified with as little as 0.25 ng of DNA. This method provides robust, sensitive, and cost-effective genotyping for human identification. PMID- 24075876 TI - A conserved loop in polynucleotide phosphorylase (PNPase) essential for both RNA and ADP/phosphate binding. AB - Polynucleotide phosphorylase (PNPase) reversibly catalyzes RNA phosphorolysis and polymerization of nucleoside diphosphates. Its homotrimeric structure forms a central channel where RNA is accommodated. Each protomer core is formed by two paralogous RNase PH domains: PNPase1, whose function is largely unknown, hosts a conserved FFRR loop interacting with RNA, whereas PNPase2 bears the putative catalytic site, ~20 A away from the FFRR loop. To date, little is known regarding PNPase catalytic mechanism. We analyzed the kinetic properties of two Escherichia coli PNPase mutants in the FFRR loop (R79A and R80A), which exhibited a dramatic increase in Km for ADP/Pi binding, but not for poly(A), suggesting that the two residues may be essential for binding ADP and Pi. However, both mutants were severely impaired in shifting RNA electrophoretic mobility, implying that the two arginines contribute also to RNA binding. Additional interactions between RNA and other PNPase domains (such as KH and S1) may preserve the enzymatic activity in R79A and R80A mutants. Inspection of enzyme structure showed that PNPase has evolved a long-range acting hydrogen bonding network that connects the FFRR loop with the catalytic site via the F380 residue. This hypothesis was supported by mutation analysis. Phylogenetic analysis of PNPase domains and RNase PH suggests that such network is a unique feature of PNPase1 domain, which coevolved with the paralogous PNPase2 domain. PMID- 24075878 TI - High resolution melting analysis of deletion/insertion polymorphisms: A new method for the detection and quantification of mixed chimerism in allogeneic stem cell transplantation. AB - Increasing mixed chimerism after allogeneic stem cell transplantation has been associated with a high risk of relapse and probable graft failure in patient with hematological malignancies as well as non-malignant conditions. We evaluated a new method for chimerism detection, based on the quantitative High Resolution Melting Analysis (HRMA) of deletion/insertion polymorphisms (DIPs). The study consisted in the selection of a panel of DIPs, all generating genotype-specific melting curves, and in the use of samples containing opposite molecular species (homozygous INS/INS and DEL/DEL) mixed in different percentages to create a standard curve for each polymorphism. The detection of mixed chimerism with the HRMA attained a sensitivity of <1%, as well as good accuracy and precision with Percent Errors and Coefficients of Variation not exceeding 30% in reconstruction experiments with DNA mixtures. The present approach provides accurate and precise estimates of mixed chimerism and makes the method open to evaluation for its use in clinical practice. PMID- 24075879 TI - Selection of Pseudomonas aeruginosa reference genes for RT-qPCR analysis from sputum of cystic fibrosis patients. AB - The prerequisite to monitor gene expression is the selection of reference genes for normalization of RT-qPCR results. Using 13 sputum samples collected from 9 CF patients, we demonstrated that PA2875 and PA3340 are better reference genes than the previously used clpX and oprL genes. PMID- 24075880 TI - The effect of low doses of zearalenone and its metabolites on progesterone and 17beta-estradiol concentrations in peripheral blood and body weights of pre pubertal female Beagle dogs. AB - The experiment involved 30 clinically healthy female Beagle dogs aged approximately 70 days with estimated initial body weight (BW) of 8 kg. The animals were randomly divided into two experimental groups (EI and EII) and a control group of 10 animals each. Group EI was intoxicated with 50 MUg zearalenone/kg BW per os for 42 days, group EII received 75 MUg zearalenone/kg BW per os for 42 days, and the control group was administered placebo per os for 42 days. The animals were weighed, and blood samples for analyses of the concentrations of zearalenone, its metabolites, progesterone and 17beta-estradiol were collected seven times at seven-day intervals, one hour after mycotoxin administration. Biotransformation of zearalenone was observed in all groups throughout the experiment, and the highest percentage share of alpha-zearalenol was reported in group EII on the last five sampling dates (0.637-0.788 ng/ml, i.e. percentage share of 57.96-73.64%). The above had a significant influence on the non-physiological concentrations of progesterone and 17beta-estradiol in both experimental (E) groups throughout the experiment. The lowest progesterone levels (0.131 ng/ml) were observed in group EII during the last test, and high concentrations of 17beta-estradiol were found in group EII on the last two sampling dates (17.434 and 21.581 ng/ml, respectively) in comparison with control. Inhibited proliferation, manifested by a slower rate of body weight gain, was observed on the last but one day of zearalenone administration in both experimental groups. Our results indicate that NOAEL doses have stimulating/adaptive effects, whereas doses above NOAEL values suggest that even very low zearalenone doses can act as endocrine disruptors with regard to progesterone and 17beta-estradiol. PMID- 24075881 TI - Gender's equality in evaluation of urine particles: Results of a multicenter study of the Italian Urinalysis Group. AB - OBJECTIVE: We performed a multicenter study to calculate the upper reference limits (URL) for urine particle quantification in mid-stream samples by using automated urine analyzers. DESIGN & METHODS: Two laboratories tested 283 subjects using a Sysmex UF-100, two other laboratories tested 313 subjects using Sysmex UF 1000i, whereas two other laboratories tested 267 subjects using Iris IQ(r)200. RESULTS: The URLs of UF-100 in females and males were 7.8/MUL and 6.7/MUL for epithelial cells (EC), 11.1/MUL and 9.9/MUL for red blood cells (RBC), 10.2/MUL and 9.7/MUL for white blood cells (WBC), and 0.85/MUL and 0.87/MUL for cylinders (CAST). The URLs of UF-1000i in females and males were 7.6/MUL and 7.1/MUL for EC, 12.2/MUL and 11.1/MUL for RBC, 11.9/MUL and 11.7/MUL for WBC, and 0.88/MUL and 0.86/MUL for CAST. The URLs of Iris IQ(r)200 in females and males were 7.8/MUL and 6.6/MUL for EC, 12.4/MUL and 10.1/MUL for RBC, 10.9/MUL and 9.9/MUL for WBC, and 1.1/MUL and 1.0/MUL for CAST. CONCLUSION: The URLs obtained in this study were comparable to the lowest values previously reported in the literature. Moreover, no gender-related difference was observed, and analyzer-specific upper reference limits were very similar. PMID- 24075882 TI - Autoantibody profiling of patients with antiphospholipid syndrome using an automated multiplexed immunoassay system. AB - The antiphospholipid syndrome (APS) is an autoimmune disease defined by the co occurrence of clinical and serological symptoms [presence of at least one of the antiphospholipid autoantibodies (aPL), such as anti-cardiolipin (aCL) IgG/IgM and anti-beta2glycoprotein I (abeta2GPI) IgG/IgM]. The measurement of these autoantibodies constitutes the first-line approach for the diagnosis of APS. Recently the advent of multiplex proteomic technologies seems to be an optimal solution for the parallel detection of autoantibodies (IgG, IgA, IgM) related to APS. The BioPlex 2200 is an automated commercial platform based on the multi analyte profiling technology that allows the detection of different types of autoantibodies, particularly ANA, ENA, dsDNA, PR3, MPO, GBM. We performed firstly a study to evaluate the diagnostic accuracy of this analytical system in a group of APS patients. The BioPlex system showed a good diagnostic accuracy for all test evaluated, very similar to that of the other established commercial singleplex immunoassays. In our study, the simultaneous detection of aCL and abeta2GPI of IgA isotype in addition to IgG and IgM isotypes did not increase the diagnostic sensitivity for APS. The good diagnostic accuracy, the high level of automation, and the high throughput make this multiplex platform a very useful and practical tool for the laboratory diagnosis of aPL in daily practice. PMID- 24075883 TI - Meso-cavo-jugular shunt for complicated portal hypertension: a case report with 8 years of follow-up. AB - BACKGROUND: The treatment of portal hypertension caused by an occlusive lesion in the retrohepatic inferior vena cava and terminal portal venules is complicated because both portal and system venous flow are compromised. METHODS: A 47-year old woman presented with this issue, and we reasoned that the only way to achieve successful management was to create a meso-cavo-jugular shunt. This patient was referred to us after undergoing a splenectomy for hypersplenism, which made her ascites intractable. She had a retrohepatic vena caval stenosis and noncirrhotic portal hypertension. Percutaneous transluminal angioplasty of the inferior vena cava stenosis failed. She underwent substernal placement of a 14-mm ringed GoreTex graft (WL Gore and Associates, Flagstaff, AZ) with end-to-side connections to the superior mesenteric vein, internal jugular vein, and vena cava. RESULT: Her ascites resolved, and at follow-up 8 years later her graft was patent. CONCLUSION: The meso-cavo-jugular shunt can simultaneously decompress both portal and systemic venous systems and is worth considering in the rare circumstance of suprahepatic vena caval obstruction coupled with occlusion of the portal venules. PMID- 24075884 TI - TRPV4 channel activation leads to endothelium-dependent relaxation mediated by nitric oxide and endothelium-derived hyperpolarizing factor in rat pulmonary artery. AB - The purpose of the present study was to characterize TRPV4 channels in the rat pulmonary artery and examine their role in endothelium-dependent relaxation. Tension, Real-Time polymerase chain reaction (Real-Time PCR) and Western blot experiments were conducted on left and right branches of the main pulmonary artery from male Wistar rats. TRPV4 channel agonist GSK1016790A (GSK) caused concentration-related robust relaxation (Emax 88.6+/-5.5%; pD2 8.7+/-0.2) of the endothelium-intact pulmonary artery. Endothelium-denudation nearly abolished the relaxation (Emax 5.6+/-1.3%) to GSK. TRPV4 channel selective antagonist HC067047 significantly attenuated GSK-induced relaxation (Emax 56.2+/-6.6% vs. control Emax 87.9+/-3.3%) in endothelium-intact vessels, but had no effect on either ACh induced endothelium-dependent or SNP-induced endothelium-independent relaxations. GSK-induced relaxations were markedly inhibited either in the presence of NO synthase inhibitor L-NAME (Emax 8.5+/-2.7%) or sGC inhibitor ODQ (Emax 28.1+/ 5.9%). A significant portion (Emax 30.2+/-4.4%) of endothelium-dependent relaxation still persisted in the combined presence of L-NAME and cyclooxygenase inhibitor indomethacin. This EDHF-mediated relaxation was sensitive to inhibition by 60mM K(+) depolarizing solution or K(+) channel blockers apamin (SKCa; KCa2.3) and TRAM-34 (IKCa; KCa3.1). GSK (10(-10)-10(-7)M) caused either modest decrease or increase in the basal tone of endothelium-intact or denuded rings, respectively. We found a greater abundance (>1.5 fold) of TRPV4 mRNA and protein expressions in endothelium-intact vs. denuded vessels, suggesting the presence of this channel in pulmonary endothelial and smooth muscle cells as well. The present study demonstrated that NO and EDHF significantly contributed to TRPV4 channel-mediated endothelium-dependent relaxation of the rat pulmonary artery. PMID- 24075885 TI - Serum low density lipoprotein subclasses in asthma. AB - BACKGROUND: The levels of serum low-density lipoproteins (LDL) have been implicated in the inflammatory cascade in a murine model of asthma. Recent findings suggest that LDL may modulate the inflammatory state of the asthmatic airways in humans. OBJECTIVE: We explored whether LDL subclasses are associated with the occurrence and severity of asthma. METHODS: 24 asthmatics (M/F: 11/13) and 24 healthy individuals, with normal BMI and absence of metabolic syndrome, matched for age and gender. Serum concentrations of LDL subclasses were distributed as seven bands (LDL-1 and -2 defined as large, least pro-inflammatory LDL, and LDL-3 to -7 defined as small, most pro-inflammatory LDL), using the LipoPrint((c)) System (Quantimetrix Corporation, Redondo Beach, CA, USA). RESULTS: LDL-1 was similar in the two groups (56 +/- 16% vs. 53 +/- 11, p = NS), while LDL-2 was significantly lower in asthmatics as compared to controls (35 +/- 8% vs. 43 +/- 10%, p = 0.0074). LDL-3 levels were two-fold higher in the asthmatics, but the difference did not reach the statistical significance (8 +/- 7.3% vs. 4 +/- 3%, p = NS). Smaller subclasses LDL-4 to LDL-7 were undetectable in controls. In asthmatics, LDL-1 was positively associated with VC% predicted (r = +0.572, p = 0.0035) and FEV1% predicted (r = +0.492, p = 0.0146). LDL-3 was inversely correlated with both VC% predicted (r = -0.535, p = 0.0071) and FEV1% predicted (r = -0.465, p = 0.0222). CONCLUSIONS: The findings of this pilot study suggest a role of LDL in asthma, and advocate for larger studies to confirm the association between asthma and dyslipidemia. PMID- 24075886 TI - pH-sensitive Laponite((r))/doxorubicin/alginate nanohybrids with improved anticancer efficacy. AB - The efficacy of the anticancer drug doxorubicin (Dox) is limited by an insufficient cellular uptake and drug resistance, which is partially due to ion trapping in acidic environments such as the extracellular environment of solid tumors and the interior of endolysosome vesicles. Herein, we describe the preparation and in vitro evaluation of a new type of nanohybrid for anticancer drug delivery which is capable of carrying a high load of the cationic Dox through the cell membrane. In addition, the nanohybrids use the acidic environment of the endolysosomes to release the drug, simultaneously helping to disrupt the endolysosomes and diminishing endolysosome Dox trapping. Furthermore, as the nanohybrid carriers are capable of sustained drug delivery, those that remain in the cytoplasm and still contain Dox are expected to exert a prolonged anticancer activity. Briefly, Dox is loaded onto biocompatible anionic Laponite((r)) (LP) nanodisks with a high aspect ratio (25 nm in diameter and 0.92 nm in thickness) through strong electrostatic interactions to get Dox-loaded LP disks. Alginate (AG), a biocompatible natural polymer, is then coated onto the Dox-loaded LP disks (LP/Dox/AG nanohybrids) to prevent the burst release of the drug. The results demonstrate that the nanohybrids have a high encapsulation efficiency (80.8 +/- 10.6%), are sensitive to pH and display a sustained drug release behavior. Cell culture experiments indicate that the LP/Dox/AG nanohybrids can be effectively internalized by CAL-72 cells (an osteosarcoma cell line), and exhibit a remarkable higher cytotoxicity to cancer cells than the free Dox. The merits of Laponite((r))/alginate nanohybrids, such as biocompatibility, high loading capacity and stimulus responsive release of cationic chemotherapeutic drugs, render them as excellent platforms for drug delivery. PMID- 24075887 TI - Lysine-based polycation:heparin coacervate for controlled protein delivery. AB - Polycations have good potential as carriers of proteins and genetic material. However, poor control over the release rate and safety issues currently limit their use as delivery vehicles. Here we introduce a new lysine-based polycation, poly(ethylene lysinylaspartate diglyceride) (PELD), which exhibits high cytocompatibility. PELD self-assembles with the biological polyanion heparin into a coacervate that incorporates proteins with high loading efficiency. Coacervates of varying surface charge were obtained by simple alteration of the PELD:heparin ratio and resulted in diverse release profiles of the model protein bovine serum albumin. Therefore, coacervate charge represents a direct means of control over release rate and duration. The PELD coacervate also rapidly adsorbed onto a porous polymeric scaffold, demonstrating potential use in tissue engineering applications. This coacervate represents a safe and tunable protein delivery system for biomedical applications. PMID- 24075888 TI - Artificial neural network for modeling the elastic modulus of electrospun polycaprolactone/gelatin scaffolds. AB - Scaffolds for tissue engineering (TE) require the consideration of multiple aspects, including polymeric composition and the structure and mechanical properties of the scaffolds, in order to mimic the native extracellular matrix of the tissue. Electrospun fibers are frequently utilized in TE due to their tunable physical, chemical, and mechanical properties and porosity. The mechanical properties of electrospun scaffolds made from specific polymers are highly dependent on the processing parameters, which can therefore be tuned for particular applications. Fiber diameter and orientation along with polymeric composition are the major factors that determine the elastic modulus of electrospun nano- and microfibers. Here we have developed a neural network model to investigate the simultaneous effects of composition, fiber diameter and fiber orientation of electrospun polycaprolactone/gelatin mats on the elastic modulus of the scaffolds under ambient and simulated physiological conditions. The model generated might assist bioengineers to fabricate electrospun scaffolds with defined fiber diameters, orientations and constituents, thereby replicating the mechanical properties of the native target tissue. PMID- 24075889 TI - Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation. AB - BACKGROUND & AIMS: Patients with irritable bowel syndrome with constipation (IBS C) have abdominal symptoms that vary in severity. Linaclotide, a guanylate cyclase-C agonist, improves abdominal and bowel symptoms in these patients. We examined the prevalence of severe abdominal symptoms in patients with IBS-C and assessed the effects of linaclotide on abdominal symptoms, global measures, and quality of life (QOL). METHODS: In two phase 3 trials, patients who met modified Rome II criteria for IBS-C were randomly assigned to groups given oral, once daily linaclotide (290 MUg) or placebo for 12 weeks. During the baseline (2 weeks prior to treatment) and treatment periods, patients rated abdominal pain, discomfort, bloating, fullness, and cramping daily (from 0 = none to 10 = very severe). Linaclotide's effects on abdominal symptoms, global measures, and IBS related QOL were assessed in subpopulations of patients who rated specific individual abdominal symptoms as severe (>= 7.0) at baseline. RESULTS: In the intent-to-treat population (1602 patients; 797 receiving placebo and 805 receiving linaclotide), baseline prevalence values for severe abdominal symptoms were 44% for bloating, 44% for fullness, 32% for discomfort, 23% for pain, and 22% for cramping, with considerable overlap among symptoms. In patients with severe symptoms, linaclotide reduced all abdominal symptoms; mean changes from baseline severity scores ranged from -2.7 to -3.4 for linaclotide vs -1.4 to -1.9 for placebo (P < .0001). Linaclotide improved global measures (P < .0001) and IBS QOL scores (P < .01) compared with placebo. Diarrhea was the most common adverse event of linaclotide in patients with severe abdominal symptoms (18.8%-21.0%). CONCLUSIONS: Of 5 severe abdominal symptoms assessed, bloating and fullness were most prevalent in patients with IBS-C. Linaclotide significantly improved all abdominal symptoms, global measures, and IBS-QOL in subpopulations of IBS-C patients with severe abdominal symptoms. Clinicaltrials.gov NUMBERS: NCT00938717, NCT00948818. PMID- 24075890 TI - Ileal pouch symptoms do not correlate with inflammation of the pouch. AB - BACKGROUND & AIMS: Pouchitis is the most common complication after ileal pouch anal anastomosis (IPAA). However, symptoms are not specific. The Pouchitis Disease Activity Index (PDAI) and the Pouchitis Activity Score (PAS) have been used to diagnose pouchitis. We evaluated the correlation between the clinical components of these scores and endoscopic and histologic findings. METHODS: We performed a cross-sectional study, analyzing data from 278 patients from Mount Sinai Hospital (Toronto, Canada) who had an IPAA. Patients underwent pouchoscopy with a biopsy, and data were collected on patients' clinical status. The PDAI and PAS were calculated for each subject. The Spearman rank correlation (rho) statistical test was used to evaluate correlations between the PDAI scores and PAS, and between total scores and subscores. RESULTS: The total PDAI scores and PAS scores were correlated; the clinical components of each correlated with the total score (rho = 0.59 and rho = 0.71, respectively). However, we observed a low level of correlation between clinical and endoscopic or histologic subscores, with rho of 0.20 and 0.10, respectively, by PDAI, and rho of 0.19 and 0.04, respectively, by PAS. CONCLUSIONS: There is a low level of correlation between clinical and endoscopic and histologic subscores of patients with IPAA; clinical symptoms therefore might not reflect objective evidence of inflammation. These findings, along with evidence of correlation between total scores and clinical symptoms, indicate that these indices do not accurately identify patients with pouch inflammation. Further research is required to understand additional factors that contribute to clinical symptoms in the absence of objective signs of pouch inflammation. PMID- 24075891 TI - Capsule endoscopy is superior to small-bowel follow-through and equivalent to ileocolonoscopy in suspected Crohn's disease. AB - BACKGROUND & AIMS: Evaluation of the small intestine for inflammation has traditionally relied on small-bowel follow-through (SBFT), but multiple studies have demonstrated its low diagnostic accuracy. Capsule endoscopy (CE) transmits high-quality images of the small intestinal mucosa; it can be used to visualize the entire length of the small bowel and much of the mucosa. We compared the diagnostic yields of CE vs SBFT in a prospective study of patients with suspected small-bowel Crohn's disease. METHODS: Eighty patients with signs and/or symptoms of small-bowel Crohn's disease (age, 10-65 years) underwent CE, followed by SBFT and ileocolonoscopy. Readers were blinded to other test results. The primary outcome was the diagnostic yield for inflammatory lesions found with CE before ileocolonoscopy compared with SBFT and ileocolonoscopy. A secondary outcome was the incremental diagnostic yield of CE compared with ileocolonoscopy and CE compared with SBFT. RESULTS: The combination of CE and ileocolonoscopy detected 107 of 110 inflammatory lesions (97.3%), whereas the combination of SBFT and ileocolonoscopy detected only 63 lesions (57.3%) (P < .001). The diagnostic yield of CE compared with ileocolonoscopy was not different (P = .09). The diagnostic yield was higher for CE than for SBFT (P < .001). Of the 80 patients with suspected Crohn's disease, 25 (31.3%) had the diagnosis confirmed. Eleven were diagnosed by CE findings alone and 5 by ileocolonoscopy findings alone. In the remaining 9 patients, diagnostic findings were identified by at least 2 of the 3 modalities. No diagnoses were made on the basis of SBFT findings alone. CONCLUSIONS: CE was better than SBFT and equivalent to ileocolonoscopy in detecting small-bowel inflammation. Although ileocolonoscopy remains the initial diagnostic test of choice, CE is safe and can establish the diagnosis of Crohn's disease in patients when ileocolonoscopy results are negative or the terminal ileum cannot be evaluated. ClinicalTrials.gov Number: NCT00487396. PMID- 24075892 TI - WITHDRAWN: Antioxidants-GRABbing new headlines. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, 10.1016/j.freeradbiomed.2013.09.018. The duplicate article has therefore been withdrawn. PMID- 24075893 TI - gamma-Tocopherol-rich supplementation additively improves vascular endothelial function during smoking cessation. AB - Oxidative stress and inflammation persist years after smoking cessation thereby limiting the restoration of vascular endothelial function (VEF). Although short term smoking cessation improves VEF, no studies have examined co-therapy of antioxidants in combination with smoking cessation to improve VEF. We hypothesized that improvements in gamma-tocopherol (gamma-T) status during smoking cessation would improve VEF beyond that from smoking cessation alone by decreasing oxidative stress and proinflammatory responses. A randomized, double blind, placebo-controlled study was conducted in otherwise healthy smokers (22 +/ 1 years; mean +/- SEM) who quit smoking for 7 days with placebo (n=14) or gamma T-rich supplementation (n=16; 500 mg gamma-T/day). Brachial artery flow-mediated dilation (FMD), cotinine, and biomarkers of antioxidant status, oxidative stress, and inflammation were measured before and after 7 days of smoking cessation. Smoking cessation regardless of supplementation similarly decreased plasma cotinine, whereas gamma-T-rich supplementation increased plasma gamma-T by seven times and its urinary metabolite gamma-carboxyethyl hydroxychroman by nine times (P<0.05). Smoking cessation with gamma-T-rich supplementation increased FMD responses by 1.3% (P<0.05) beyond smoking cessation alone (4.1 +/- 0.6% vs 2.8 +/ 0.3%; mean +/- SEM). Although plasma malondialdehyde decreased similarly in both groups (P<0.05), plasma oxidized LDL and urinary F2-isoprostanes were unaffected by smoking cessation or gamma-T-rich supplementation. Plasma TNF-alpha and myeloperoxidase decreased (P<0.05) only in those receiving gamma-T-rich supplements and these were inversely related to FMD (P<0.05; R=-0.46 and -0.37, respectively). These findings demonstrate that short-term gamma-T-rich supplementation in combination with smoking cessation improved VEF beyond that from smoking cessation alone in young smokers, probably by decreasing the proinflammatory mediators TNF-alpha and myeloperoxidase. PMID- 24075894 TI - Role of oxidative stress in impaired insulin signaling associated with exercise induced muscle damage. AB - Skeletal muscle is a major tissue that utilizes blood glucose. A single bout of exercise improves glucose uptake in skeletal muscle through insulin-dependent and insulin-independent signal transduction mechanisms. However, glucose utilization is decreased in muscle damage induced by acute, unaccustomed, or eccentric exercise. The decrease in glucose utilization is caused by decreased insulin stimulated glucose uptake in damaged muscles with inhibition of the membrane translocation of glucose transporter 4 through phosphatidyl 3-kinase/Akt signaling. In addition to inflammatory cytokines, reactive oxygen species including 4-hydroxy-2-nonenal and peroxynitrate can induce degradation or inactivation of signaling proteins through posttranslational modification, thereby resulting in a disturbance in insulin signal transduction. In contrast, treatment with factors that attenuate oxidative stress in damaged muscle suppresses the impairment of insulin sensitivity. Muscle-damaging exercise may thus lead to decreased endurance capacity and muscle fatigue in exercise, and it may decrease the efficiency of exercise therapy for metabolic improvement. PMID- 24075895 TI - Evolutionary dynamics of the Warburg effect: glycolysis as a collective action problem among cancer cells. AB - The upregulation of glycolysis in cancer cells (the "Warburg effect") is common and has implications for prognosis and treatment. As it is energetically inefficient under adequate oxygen supply, its adaptive value for a tumor remains unclear. It has been suggested that the acidity produced by glycolysis is beneficial for cancer cells because it promotes proliferation against normal cells. Current models of this acid-mediated tumor invasion hypothesis, however, do not account for increased glycolysis under non-limiting oxygen concentrations and therefore do not fully explain the Warburg effect. Here I show that the Warburg effect can be explained as a form of cooperation among cancer cells, in which the products of glycolysis act as a public good, even when oxygen supply is high enough to make glycolysis energetically inefficient. A multiplayer game with non-linear, non-monotonic payoff functions that models the benefits of the acidity induced by glycolysis reveals that clonal selection can stabilize glycolysis even when energetically costly, that is, under non-limiting oxygen concentration. Characterizing the evolutionary dynamics of glycolysis reveals cases in which anti-cancer therapies that rely on the modification of acidity can be effective. PMID- 24075896 TI - Prenatal cannabis exposure and infant outcomes: overview of studies. AB - Accumulating evidence from both human and preclinical studies indicates maternal substance use during pregnancy can affect fetal development, birth weight and infant outcomes. Thus, the prenatal period can be regarded as an important and potentially sensitive period of development. In this manuscript, an updated overview of studies on prenatal cannabis exposure in humans is presented, including recent studies conducted within the Generation R study. Findings on fetal growth, birth outcomes, early neonatal behavior and infant behavior and cognitive development are discussed in detail. Preclinical evidence and potential mechanisms are described as well, and recommendations for future studies are provided. It is concluded that evidence seems to suggest that fetal development is affected by prenatal maternal cannabis use, while findings on effects on infant behavior or cognition are inconsistent. Beyond infancy, subtle differences may be found in specific cognitive or behavioral outcomes, although replication studies in which pregnant women and their fetuses are exposed to current and probably higher levels of Delta9-tetrahydrocannabinol and novel designs are needed to come to firm conclusions. PMID- 24075897 TI - Decreased resting-state interhemispheric coordination in first-episode, drug naive paranoid schizophrenia. AB - BACKGROUND: Dysconnectivity hypothesis posits that schizophrenia relates to abnormalities in neuronal connectivity. However, little is known about the alterations of the interhemispheric resting-state functional connectivity (FC) in patients with paranoid schizophrenia. In the present study, we used a newly developed voxel-mirrored homotopic connectivity (VMHC) method to investigate the interhemispheric FC of the whole brain in patients with paranoid schizophrenia at rest. METHODS: Forty-nine first-episode, drug-naive patients with paranoid schizophrenia and 50 age-, gender-, and education-matched healthy subjects underwent a resting-state functional magnetic resonance imaging (fMRI) scans. An automated VMHC approach was used to analyze the data. RESULTS: Patients exhibited lower VMHC than healthy subjects in the precuneus (PCu), the precentral gyrus, the superior temporal gyrus (STG), the middle occipital gyrus (MOG), and the fusiform gyrus/cerebellum lobule VI. No region showed greater VMHC in the patient group than in the control group. Significantly negative correlation was observed between VMHC in the precentral gyrus and the PANSS positive/total scores, and between VMHC in the STG and the PANSS positive/negative/total scores. CONCLUSIONS: Our results suggest that interhemispheric resting-state FC of VMHC is reduced in paranoid schizophrenia with clinical implications for psychiatric symptomatology thus further contribute to the dysconnectivity hypothesis of schizophrenia. PMID- 24075899 TI - The time course of estimating time-to-contact: switching between sources of information. AB - The different sources of information that can be used to estimate time-to-contact may have different degrees of reliability across time. For example, after a given presentation or display time, an absolute change of angular size can be more reliable than the corresponding estimation of the rate of angular expansion (e.g. motion information). One could then expect systematic biases in the observer's responses for different times of stimulus exposure. In one experiment, observers judged whether approaching objects arrived at the point of observation before or after a reference beep (1.2s) under monocular, and binocular plus monocular vision. Five display times from 0.1 to 0.9s were used. Unlike monocular viewing, where accuracy increased monotonically with display time, an interesting non linearity occurred for objects with small size when binocular information was available. Accuracy reached maximum values for small objects with only 0.3s of vision with stereopsis. This accuracy, however, dropped significantly after 0.4s of exposure and increased again linearly with time. This is consistent with subjects switching from using binocular information to using monocular motion information when it started to become more reliable. We also explored whether monocular cues were combined differently across time by fitting a model that relates visual angle to its rate of expansion. Results show that subjects relied more on angular motion information (i.e. rate of expansion) with presentation time but interrupting this motion integration process led to a loss of accuracy in time-to-contact judgments. PMID- 24075898 TI - High molecular weight complex analysis of Epstein-Barr virus Latent Membrane Protein 1 (LMP-1): structural insights into LMP-1's homo-oligomerization and lipid raft association. AB - LMP-1 is a constitutively active Tumor Necrosis Factor Receptor analog encoded by Epstein-Barr virus. LMP-1 activation correlates with oligomerization and raft localization, but direct evidence of LMP-1 oligomers is limited. We report that LMP-1 forms multiple high molecular weight native LMP-1 complexes when analyzed by BN-PAGE, the largest of which are enriched in detergent resistant membranes. The largest of these high molecular weight complexes are not formed by purified LMP-1 or by loss of function LMP-1 mutants. Consistent with these results we find a dimeric form of LMP-1 that can be stabilized by disulfide crosslinking. We identify cysteine 238 in the C-terminus of LMP-1 as the crosslinked cysteine. Disulfide crosslinking occurs post-lysis but the dimer can be crosslinked in intact cells with membrane permeable crosslinkers. LMP-1/C238A retains wild type LMP-1 NF-kappaB activity. LMP-1's TRAF binding, raft association and oligomerization are associated with the dimeric form of LMP-1. Our results suggest the possibility that the observed dimeric species results from inter oligomeric crosslinking of LMP-1 molecules in adjacent core LMP-1 oligomers. PMID- 24075900 TI - Memory and incidental learning for visual frozen noise sequences. AB - Five experiments explored short-term memory and incidental learning for random visual spatio-temporal sequences. In each experiment, human observers saw samples of 8 Hz temporally-modulated 1D or 2D contrast noise sequences whose members were either uncorrelated across an entire 1-s long stimulus sequence, or comprised two frozen noise sequences that repeated identically between a stimulus' first and second 500 ms halves ("Repeated" noise). Presented with randomly intermixed stimuli of both types, observers judged whether each sequence repeated or not. Additionally, a particular exemplar of Repeated noise (a frozen or "Fixed Repeated" noise) was interspersed multiple times within a block of trials. As previously shown with auditory frozen noise stimuli (Agus, Thorpe, & Pressnitzer, 2010) recognition performance (d') increased with successive presentations of a Fixed Repeated stimulus, and exceeded performance with regular Repeated noise. However, unlike the case with auditory stimuli, learning of random visual stimuli was slow and gradual, rather than fast and abrupt. Reverse correlation revealed that contrasts occupying particular temporal positions within a sequence had disproportionately heavy weight in observers' judgments. A subsequent experiment suggested that this result arose from observers' uncertainty about the temporal mid-point of the noise sequences. Additionally, discrimination performance fell dramatically when a sequence of contrast values was repeated, but in reverse ("mirror image") order. This poor performance with temporal mirror images is strikingly different from vision's exquisite sensitivity to spatial mirror images. PMID- 24075901 TI - Three promoters regulate the transcriptional activity of the human holocarboxylase synthetase gene. AB - Holocarboxylase synthetase (HLCS) is the only protein biotin ligase in the human proteome. HLCS-dependent biotinylation of carboxylases plays crucial roles in macronutrient metabolism. HLCS appears to be an essential part of multiprotein complexes in the chromatin that cause gene repression and contribute toward genome stability. Consistent with these essential functions, HLCS knockdown causes strong phenotypes including shortened life span and low stress resistance in Drosophila melanogaster, and de-repression of long-terminal repeats in humans, other mammalian cell lines and Drosophila. Despite previous observations that the expression of HLCS depends on biotin status in rats and in human cell lines, little is known about the regulation of HLCS expression. The goal of this study was to identify promoters that regulate the expression of the human HLCS gene. Initially, the human HLCS locus was interrogated in silico using predictors of promoters including sequences of HLCS mRNA and expressed sequence tags, CpG islands, histone marks denoting transcriptionally poised chromatin, transcription factor binding sites and DNaseI hypersensitive regions. Our predictions revealed three putative HLCS promoters, denoted P1, P2 and P3. Promoters lacked a TATA box, which is typical for housekeeping genes. When the three promoters were cloned into a luciferase reporter plasmid, reporter gene activity was at least three times background noise in human breast, colon and kidney cell lines; activities consistently followed the pattern P1>>P3>P2. Promoter activity depended on the concentration of biotin in culture media, but the effect was moderate. We conclude that we have identified promoters in the human HLCS gene. PMID- 24075902 TI - Influence of gestational overfeeding on myocardial proinflammatory mediators in fetal sheep heart. AB - Maternal overnutrition is associated with predisposition of offspring to cardiovascular disease in later life. Since maternal overnutrition may promote fetal and placental inflammatory responses, we hypothesized that maternal overnutrition/obesity increases expression of fetal cardiac proinflammatory mediators and alter cardiac morphometry. Multiparous ewes were fed either 150% of National Research Council (NRC) nutrient recommendations (overfed) or 100% of NRC requirement (control) from 60 days prior to mating to gestation Day 75 (D75), when ewes were euthanized. An additional cohort of overfed and control ewes were necropsied on D135. Cardiac morphometry, histology, mRNA and protein expression of toll-like receptor 4, iNOS, IL-1a, IL-1b, IL-6, IL-18, CD-14, CD-68, M-CSF and protein levels of phosphorylated I-kappaB and nuclear factor kappaB (NF-kappaB) were examined. Immunohistochemistry was performed to assess neutrophil and monocyte infiltration. Crown rump length, left and right ventricular free wall weights as well as left and right ventricular wall thickness were significantly increased in D75 fetuses of overfed mothers. Hematoxylin and eosin staining revealed irregular myofiber orientation and increased interstitial space in fetal ventricular tissues born to overfed mothers. Oil red O staining exhibited marked lipid droplet accumulation in the overfed fetuses. Overfeeding significantly enhanced TLR4, IL-1a, IL-1b IL-6 expression, promoted phosphorylation of IkappaB, decreased cytoplasmic NF-kappaB levels and increased neutrophil and monocyte infiltration. Collectively, these data suggest that maternal overfeeding prior to and throughout gestation leads to inflammation in the fetal heart and alters fetal cardiac morphometry. PMID- 24075903 TI - Hypolipidemic effect of Goami-3 rice (Oryza sativa L. cv. Goami-3) on C57BL/6J mice is mediated by the regulation of peroxisome proliferator-activated receptor alpha and -gamma. AB - We investigated the hypolipidemic effects of Goami-3 rice (GR; Oryza sativa L. cv. Goami-3), a newly developed strain with high levels of amylose and fibers. Diet-induced obese mice were fed three types of isocaloric diets for 8 weeks: a high-fat diet, a high-fat diet with GR or control rice (CR; O. sativa L. cv. Ilpumbyeo). Mice fed GR exhibited a significant reduction in body fat (-23%), total cholesterol (-20%) and triglyceride concentrations (-30%) compared to mice fed CR. The mice fed GR showed induction of peroxisome proliferator-activated receptor (PPAR)-alpha and inhibition of gamma expressions in the liver and adipose tissue. The reduced adiposity of mice fed GC was supported by changes in the expression of genes related to lipid accumulation and hydrolysis in adipose tissues and the plasma concentrations of insulin, adiponectin and leptin. Principal components analysis with gas chromatography-time-of-flight mass spectrometry-based metabolomic data revealed that the average level of specific plasma metabolites in the GR group was statistically different from that in the other groups after 4weeks. These metabolites included propionic acid, valine, leucine and proline. Based on partial least-squares analysis, the plasma concentrations of valine were inversely correlated with the high-density lipoprotein (HDL) to non-HDL and HDL to total cholesterol ratios. In conclusion, GR feeding for 8 weeks significantly improved dyslipidemia and adiposity in diet induced obese mice by regulating gene expression of PPARs and its target genes. Key plasma metabolites (including valine) were significantly altered by the hypolipidemic effects of GR. PMID- 24075904 TI - Regulation of ubiquitin and 26S proteasome mediated by phenolic compounds during oxidative stress. AB - Little attention has been devoted to studying the roles of natural antioxidants in the ubiquitin-proteasome pathway during oxidative stress. We demonstrated that a time course revealed that the reassociation of the 19S regulators with the 20S proteasomes occurred automatically and rapidly to reconstitute the 26S proteasomes, with up to 80% completion, within 5 min after H2O2 treatment. Ubiquitin, methyl gallate and tannic acid are able to prevent H2O2 from inhibiting the 26S activity. We further show that the level of the ubiquitin, S5a and 20S core subunits decreased within 30 min and increased after 24 h of H2O2 treatment in Hep-2 cells. Phenolic compounds not only inhibited the 26S activity but also decreased the USP47 levels, which reduce the DNA damage repair rate during oxidative stress; in addition, the presence of DNA fragments, procaspase-3 and a decreased poly (ADP-ribose) polymerase also appeared as a result of the above conditions. Ubiquitin could serve as a protective substrate in H2O2 and phenolic compound-treated Hep-2 cells. Methyl gallate and tannic acid, as prooxidants, can attenuate the apoptotic response resulting from long-term oxidative stress. Collectively, these data demonstrate an important role for phenolic compounds in regulating the 26S proteasome and ubiquitin during oxidative stress. PMID- 24075905 TI - Functional dissection of the splice variants of the Drosophila gene homothorax (hth). AB - Homothorax belongs to the TALE-homeodomain family of transcription factors, together with its vertebrate counterparts, the Meis family of proto-oncogenes. It fulfills many important different functions during embryonic and larval developments in Drosophila, which encompass from subdivision and specification of body parts to assembly of heterochromatin structures. Hth interacts with Extradenticle, another member of the TALE-homeodomain family of conserved transcription factors, to facilitate its entrance to the nucleus. The many different functions described for Hth rely on the complexity of the locus, from which six different isoforms arise. The isoforms can be grouped into full-length and short versions, which contain either one or the two conserved domains of the protein (homeodomain and Exd-interacting domain). We have used molecular and genetic tools to analyze the levels of expression, the distribution and the function of the isoforms during embryonic development. Our results clearly show that the isoforms display distinct levels of expression and are differentially distributed in the embryo. This detailed study also shows that during normal embryonic development not all the Hth isoforms translocate Exd into the nucleus, suggesting that both the proteins can also function separately. We have demonstrated that the full-length Hth protein activates transcription of exd, augmenting the levels of exd mRNA in the cell. The higher levels of Exd protein in those cells facilitate its entrance to the nucleus. Our work demonstrates that hth is a complex gene that should not be considered as a functional unit. The roles of the different isoforms probably rely on their distinct protein domains and conformations and, at the end, on interactions with particular partners. PMID- 24075906 TI - Forward genetics identifies Kdf1/1810019J16Rik as an essential regulator of the proliferation-differentiation decision in epidermal progenitor cells. AB - Cell fate decisions during embryogenesis and adult life govern tissue formation, homeostasis and repair. Two key decisions that must be tightly coordinated are proliferation and differentiation. Overproliferation can lead to hyperplasia or tumor formation while premature differentiation can result in a depletion of proliferating cells and organ failure. Maintaining this balance is especially important in tissues that undergo rapid turnover like skin however, despite recent advances, the genetic mechanisms that balance cell differentiation and proliferation are still unclear. In an unbiased genetic screen to identify genes affecting early development, we identified an essential regulator of the proliferation-differentiation balance in epidermal progenitor cells, the Keratinocyte differentiation factor 1 (Kdf1; 1810019J16Rik) gene. Kdf1 is expressed in epidermal cells from early stages of epidermis formation through adulthood. Specifically, Kdf1 is expressed both in epidermal progenitor cells where it acts to curb the rate of proliferation as well as in their progeny where it is required to block proliferation and promote differentiation. Consequently, Kdf1 mutants display both uncontrolled cell proliferation in the epidermis and failure to develop terminal fates. Our findings reveal a dual role for the novel gene Kdf1 both as a repressive signal for progenitor cell proliferation through its inhibition of p63 and a strong inductive signal for terminal differentiation through its interaction with the cell cycle regulator Stratifin. PMID- 24075907 TI - tal1 Regulates the formation of intercellular junctions and the maintenance of identity in the endocardium. AB - The endocardium forms the inner lining of the heart tube, where it enables blood flow and also interacts with the myocardium during the formation of valves and trabeculae. Although a number of studies have identified regulators in the morphogenesis of the myocardium, relatively little is known about the molecules that control endocardial morphogenesis. Prior work has implicated the bHLH transcription factor Tal1 in endocardial tube formation: in zebrafish embryos lacking Tal1, endocardial cells form a disorganized mass within the ventricle and do not populate the atrium. Through blastomere transplantation, we find that tal1 plays a cell-autonomous role in regulating endocardial extension, suggesting that Tal1 activity influences the behavior of individual endocardial cells. The defects in endocardial behavior in tal1-deficient embryos originate during the earliest steps of endocardial morphogenesis: tal1-deficient endocardial cells fail to generate a cohesive monolayer at the midline and instead pack tightly together into a multi-layered aggregate. Moreover, the tight junction protein ZO 1 is mislocalized in the tal1-deficient endocardium, indicating a defect in intercellular junction formation. In addition, we find that the tal1-deficient endocardium fails to maintain its identity; over time, a progressively increasing number of tal1-deficient endocardial cells initiate myocardial gene expression. However, the onset of defects in intercellular junction formation precedes the onset of ectopic myocardial gene expression in the tal1-deficient endocardium. We therefore propose a model in which Tal1 has distinct roles in regulating the formation of endocardial intercellular junctions and maintaining endocardial identity. PMID- 24075908 TI - Insulin-activated Elk-1 recruits the TIP60/NuA4 complex to increase prolactin gene transcription. AB - Insulin increases prolactin gene expression in GH4 cells through phosphorylation of Elk-1 (Jacob and Stanley, 2001). We preformed a reverse two-hybrid screen using Elk-1-B42 as bait to identify proteins from GH4 cells that might serve as co-activators or co-repressors for insulin-increased prolactin gene expression. A number of the components of the TIP60/NuA4 complex interacted with Elk-1 suggesting that Elk-1 might activate transcription by recruiting the TIP60 chromatin-remodeling complex to the prolactin promoter. Inhibition of insulin increased prolactin-luciferase expression by wild type and mutant adenovirus E1A protein provided physiological context for these yeast studies. Inhibition of histone deacetylases dramatically increased both basal and insulin-increased prolactin gene transcription. Co-immune precipitation experiments demonstrated Elk-1 and TIP60 associate in vitro. Transient or stable expression of TIP60 activated insulin-increased prolactin gene expression while a mutated TIP60 blocked insulin-increased prolactin gene expression. Analysis of the prolactin mRNA by quantitative RT-PCR showed that insulin-increased prolactin mRNA accumulation and that this was inhibited in GH4 cells that stably expressed mutant TIP60. Finally, ChIP experiments demonstrate the insulin-dependent occupancy of the prolactin promoter by Elk-1 and TIP60. Our studies suggest that insulin activates prolactin gene transcription by activating Elk-1 that recruits the NuA4 complex to the promoter. PMID- 24075909 TI - Immunolocalization of murine type VI 3beta-hydroxysteroid dehydrogenase in the adrenal gland, testis, skin, and placenta. AB - The enzyme 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) is essential for the biosynthesis of all active steroid hormones, such as those secreted from the adrenal gland, testis, ovary, skin and placenta. The 3beta-HSD enzymes exist in multiple isoforms in humans and rodents. To date, six different isoforms have been identified in the mouse, and these isoforms are speculated to play different roles in different tissues. We previously showed that the murine type VI 3beta HSD isoform (Hsd3b6) is expressed specifically in the aldosterone-producing zona glomerulosa cells within the adrenal gland and that its overexpression causes abnormally increased aldosterone synthesis, revealing a crucial (or rate limiting) role of this enzyme in steroidogenesis. However, potential contributions of this enzyme to the steroid hormone synthesis outside the adrenal glands are poorly understood. This paucity of knowledge is partly because of the lack of isoform-specific antibody that can be used for immunohistochemistry. Here, we report the development and characterization of specific antibody to Hsd3b6 and show the results of immunohistochemistry for the adrenal gland, testis, ovary, skin and placenta. As expected, Hsd3b6 immunoreactivities within the adrenal gland were essentially confined to the zona glomerulosa cells, where aldosterone is produced. By contrast, no immunopositive cells were observed in the zona fasciculata, which is where corticosterone is produced. In the gonads, while the ovaries did not show any detectable immunoreactivity to Hsd3b6, the testes displayed intense immunoreactivities within the interstitial Leydig cells, where testosterone is produced. In the skin, positive immunoreactivities to Hsd3b6 were only seen in the sebaceous glands, suggesting a specific role of this enzyme in sebaceous function. Moreover, in the placenta, Hsd3b6 was specifically found in the giant trophoblast cells surrounding the embryonic cavity, which suggests a role for this enzyme in local progesterone production that is required for proper embryonic implantation and/or maintenance of pregnancy. Taken together, our data revealed that Hsd3b6 is localized in multiple specific tissues and cell types, perhaps thereby involved in biosynthesis of a number of tissue specific steroid hormones with different physiological roles. PMID- 24075910 TI - The effect of change in spectral slope and formant frequencies on the perception of loudness. AB - OBJECTIVE/HYPOTHESIS: This study attempts to understand how changes in spectral slope and formant frequency influence changes in perceived loudness. It was hypothesized that voices synthesized with steeper spectral slopes will be perceived as less loud than voices synthesized with less steep spectral slopes, in spite of the fact that they are of equal root mean square (RMS) amplitude. It was also hypothesized that stimuli with higher formant patterns will be perceived as louder than those with lower formant patterns, in spite of the fact that they are of equal RMS amplitude. STUDY DESIGN: Repeated measures factorial design. METHODS: For the pitches A3, C4, B4, and F5, three different source signals were synthesized with varying slopes of -9, -12, and -15 dB/octave using a frequency vibrato rate of 5.6 Hz and a frequency vibrato extent of 50 cents. Each of the three source signals were filtered using two formant patterns, a lower formant pattern typical of a mezzo-soprano (pattern A) and a higher formant pattern typical of a soprano (pattern B) for the vowel /a/. For each pitch, the six stimuli were combined into all possible pairs and normalized to equal RMS amplitude. Listeners were presented with 120 paired stimuli (60 pairs repeated twice). The listener's task was to indicate whether the first or second stimulus in the pair was louder. RESULTS: Generally, as the spectral slope decreased, perceived loudness increased, with the magnitude of the perceived difference in loudness being related to the degree of difference in spectral slope. Likewise, at all pitches except A3, perceived loudness increased as formant frequency increased. CONCLUSION: RMS amplitude is an important predictor of loudness perception, but many other factors also affect the perception of this important vocal parameter. Spectral composition is one such factor and must be considered when using loudness perception in the process of clinical diagnostics. PMID- 24075911 TI - Office-based pulsed-dye laser surgery for laryngeal lesions: a retrospective review. AB - OBJECTIVES: The 585-nm pulsed-dye laser (PDL) is used for in-office treatment of recurrent respiratory papillomatosis (RRP), premalignant/early malignant lesions, vascular lesions, and proliferative lesions of the larynx. Reported advantages of this technique include avoidance of general anesthesia, improved efficiency, lower overall cost, and treatment of the anterior commissure with minimal web formation. Our objective was to review our experience with office-based PDL procedures for laryngeal lesions. STUDY DESIGN: Retrospective review. METHODS: A chart review of patients undergoing office-based PDL procedures of laryngeal lesions from the years 2005 to 2012. RESULTS: Of 33 patients, 32 (97%) tolerated the procedure without complication. One patient experienced an anxiety attack and the procedure was aborted. There were no complications. The following pathologies were treated: vascular lesions (n = 10), RRP (n = 8), granuloma (n = 5), premalignant lesions (n = 5), benign mass (n = 2), amyloidosis (n = 1), and anterior web (n = 1). Six (19%) patients, all with vascular lesions, were treated successfully with the in-office PDL and no operating room (OR) procedures. All six patients reported complete resolution of symptoms at 6 months posttreatment. Twenty-six (81%) patients were treated with a combination of in-office PDL and OR procedures, most commonly for RRP (n = 8). Seventeen patients had complete resolution of their symptoms with in-office PDL and OR procedures. CONCLUSIONS: PDL treatment is a safe, well-tolerated, effective, adjunctive therapy and may function as monotherapy in the treatment of selected laryngeal lesions. PMID- 24075912 TI - Laryngeal and pharyngeal activity during semioccluded vocal tract postures in subjects diagnosed with hyperfunctional dysphonia. AB - High vertical laryngeal position (VLP), pharyngeal constriction, and laryngeal compression are common features associated with hyperfunctional voice disorders. The present study aimed to observe the effect on these variables of different semioccluded vocal tract postures in 20 subjects diagnosed with hyperfunctional dysphonia. During observation with flexible endoscope, each participant was asked to produce eight different semioccluded exercises: lip trills, hand-over-mouth technique, phonation into four different tubes, and tube phonation into water using two different depth levels. Participants were required to produce each exercise at three loudness levels: habitual, soft, and loud. To determine the VLP, anterior-to-posterior (A-P) compression, and pharyngeal width, a human evaluation test with three blinded laryngologists was conducted. Judges rated the three endoscopic variables using a five-point Likert scale. An intraclass correlation coefficient to assess intrarater and interrater agreement was performed. A multivariate linear regression model considering VLP, pharyngeal width, and A-P laryngeal compression as outcomes and phonatory tasks and intensity levels as predictive variables were carried out. Correlation analysis between variables was also conducted. Results indicate that all variables differ significantly. Therefore, VLP, A-P constriction, and pharyngeal width changed differently throughout the eight semioccluded postures. All semioccluded techniques produced a lower VLP, narrower aryepiglottic opening, and a wider pharynx than resting position. More prominent changes were obtained with a tube into the water and narrow tube into the air. VLP significantly correlated with pharyngeal width and A-P laryngeal compression. Moreover, pharyngeal width significantly correlated with A-P laryngeal compression. PMID- 24075913 TI - Knowledge, experience, and anxieties of young classical singers in training. AB - OBJECTIVE/HYPOTHESIS: Young classical singers in training have a wide variety of knowledge about the anatomy and physiology of the voice and vocal pathology and harbor anxiety about treatment of vocal fold disorders. This study aimed to examine differences in knowledge, experience, and anxiety across levels of training at elite conservatories and young artist programs in the United States. STUDY DESIGN: Prospective cohort questionnaire. METHODS: Undergraduate (50), master's (35), and doctoral/young artist (25) singers (n = 110) were given an 80 point questionnaire assessing experience with vocal pathology, otolaryngologists, speech pathologists, and participation in choir or teaching. Participants were asked questions to test their medical knowledge in vocal anatomy, physiology, and care. They were also asked questions about their anxiety about medical visits and vocal pathology and about their habits in the care of their own voices. RESULTS: There was no statistically significant difference in test scores for vocal knowledge across the three levels of training (P = 0.47). Mean scores were just above 50% with standard deviations around 12-13 points. The lowest score was 26% and the highest score was 84%. Doctoral/young artist-level participants were more anxious regarding general office visits to an otolaryngologist compared with undergraduate and master's level participants. There were no other significant differences by level of training regarding anxiety about vocal pathology, scope examinations, or visits to a speech pathologist. There were no significant differences in self-reported levels of knowledge. All groups of young singers expressed marked interest in expanding their knowledge of anatomy and physiology, speech pathology, care of the vocal mechanism, and vocal disorders. CONCLUSIONS: More advanced singers do not have significantly greater knowledge of vocal form and function and are more anxious about visits to otolaryngologists and vocal pathology; a clear majority of singers indicate interest in knowing more. There is thus ample opportunity for innovation in the development of medical curricula in the instruction of young singers and clear interest in more knowledge on their part. PMID- 24075914 TI - Voice disorders in actors. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to investigate the prevalence of vocal pathology among first-year acting students. STUDY DESIGN: A retrospective review of 30 first-year graduate-level drama students between 2009 and 2011 was performed. METHODS: Stroboscopy, Voice Handicap Index-10 questionnaires, and acoustic measures were analyzed. RESULTS: The prevalence of incomplete glottal closure, laryngeal hyperfunction, and decreased mucosal wave was 62%, 59%, and 55%, respectively. Laryngoscopic findings consistent with laryngopharyngeal reflux (LPR) were demonstrated in 48% of subjects. Subgroup analysis of laryngeal hyperfunctioning (HF) and nonhyperfunctioning drama students revealed an increased prevalence of all videostroboscopic abnormalities in the HF group. The increased prevalence of LPR stigmata in HF actors reached statistical significance (P = 0.04). CONCLUSIONS: The vocal demands of actors are unique, requiring the effective use of volume, pitch control, and endurance. This is the first study that systematically analyzes the prevalence of vocal pathology in actors. This study will continue throughout their education, anticipating that our feedback along with their vocal training will improve outcomes. PMID- 24075915 TI - Influence of waveform and current direction on short-interval intracortical facilitation: a paired-pulse TMS study. AB - BACKGROUND: Transcranial magnetic stimulation (TMS) of the human primary motor hand area (M1-HAND) can produce multiple descending volleys in fast-conducting corticospinal neurons, especially so-called indirect waves (I-waves) resulting from trans-synaptic excitation. Facilitatory interaction between these I-waves can be studied non-invasively using a paired-pulse paradigm referred to as short interval intracortical facilitation (SICF). OBJECTIVE/HYPOTHESIS: We examined whether SICF depends on waveform and current direction of the TMS pulses. METHODS: In young healthy volunteers, we applied single- and paired-pulse TMS to M1-HAND. We probed SICF by pairs of monophasic or half-sine pulses at suprathreshold stimulation intensity and inter-stimulus intervals (ISIs) between 1.0 and 5.0 ms. For monophasic paired-pulse stimulation, both pulses had either a posterior-anterior (PA) or anterior-posterior (AP) current direction (AP-AP or PA PA), whereas current direction was reversed between first and second pulse for half-sine paired-pulse stimulation (PA-AP and AP-PA). RESULTS: Monophasic AP-AP stimulation resulted in stronger early SICF at 1.4 ms relative to late SICF at 2.8 and 4.4 ms, whereas monophasic PA-PA stimulation produced SICF of comparable size at all three peaks. With half-sine stimulation the third SICF peak was reduced for PA-AP current orientation compared with AP-PA. CONCLUSION: SICF elicited using monophasic as well as half-sine pulses is affected by current direction at clearly suprathreshold intensities. The impact of current orientation is stronger for monophasic compared with half-sine pulses. The direction-specific effect of paired-pulse TMS on the strength of early versus late SICF shows that different cortical circuits mediate early and late SICF. PMID- 24075916 TI - Toxicology of some important medicinal plants in southern Africa. AB - Africa is home to two major floral kingdoms: the Paleotropical kingdom of central Africa and the Capensis kingdom of the Western Cape province of South Africa, the latter of which consists of approximately 10,000 species, representing about 20% of Africa's floral 'gold mine', better known as the Cape herbal medicine. Needless to say, such rich flora comes with numerous plants with a potential to cause poisoning to humans. This review document reports important toxic medicinal plants and their toxic ingredients for plant species resident in the southern African region. These include important medicinal uses and pharmacological properties ranging from antimicrobial, antiviral, anticancer, anti-inflammatory as well as those that are used as aphrodisiacs and for maternal health care. PMID- 24075917 TI - Relationship between arsenic content of food and water applied for food processing. AB - As part of a survey conducted by the Central Agricultural Office of Hungary, 67 food samples including beverages were taken from 57 food industrial and catering companies, 75% of them being small and medium-sized enterprises (SMEs). Moreover, 40% of the SMEs were micro entities. Water used for food processing was simultaneously sampled. The arsenic (As) content of solid food stuff was determined by hydride generation atomic absorption spectrometry after dry ashing. Food stuff with high water content and water samples were analyzed by inductively coupled plasma mass spectrometry. The As concentration exceeded 10 MUg/L in 74% of the water samples taken from SMEs. The As concentrations of samples with high water content and water used were linearly correlated. Estimated As intake from combined exposure to drinking water and food of the population was on average 40% of the daily lower limit of WHO on the benchmark dose for a 0.5% increased incidence of lung cancer (BMDL0.5) for As. Five settlements had higher As intake than the BMDL0.5. Three of these settlements are situated in Csongrad county and the distance between them is less than 55 km. The maximum As intake might be 3.8 MUg/kg body weight. PMID- 24075918 TI - Cost-effectiveness of targeted vaccination to protect new-borns against pertussis: comparing neonatal, maternal, and cocooning vaccination strategies. AB - Pertussis (whooping cough) is a severe infectious disease in infants less than 6 months old. Mass vaccination programmes have been unable to halt transmission effectively. Strategies to protect new-borns against infection include vaccination of the neonate or the mother directly after birth (cocooning), or the mother during pregnancy (maternal). Here we investigate the cost-effectiveness of these three strategies in the Netherlands. Costs for health care utilization and productivity losses, as well as impact on quality of life were calculated for a 10-year vaccination programme, assuming that vaccine-induced immunity lasts 5 years. Cocooning was the most attractive option from a cost-effectiveness viewpoint (?89,000/QALY). However, both cocooning and maternal vaccination would reduce the disease burden in infants and mothers vaccinated (about 17-20 QALY/year). Specifically, with a persistent epidemic as seen in 2012, there is need for reconsidering the vaccination schedules against pertussis in order to increase protection of the vulnerable new-borns. PMID- 24075919 TI - Genetic variants within the MHC region are associated with immune responsiveness to childhood vaccinations. AB - The influence of genetic variability within the major histocompatibility complex (MHC) region on variations in immune responses to childhood vaccination was investigated. The study group consisted of 135 healthy infants who had been immunized with hepatitis B (HBV), 7-valent pneumococcal conjugate (PCV7), and diphtheria, tetanus, acellular pertussis (DTaP) vaccines according to standard childhood immunization schedules. Genotype analysis was performed on genomic DNA using Illumina Goldengate MHC panels (Mapping and Exon Centric). At the 1 year post vaccination check-up total, isotypic, and antigen-specific serum antibody levels were measured using multiplex immunoassays. A number of single nucleotide polymorphisms (SNPs) within MHC Class I and II genes were found to be associated with variations in the vaccine specific antibody responses and serum levels of immunoglobulins (IgG, IgM) and IgG isotypes (IgG1, IgG4) (all at p<0.001). Linkage disequilibrium patterns and functional annotations showed that significant SNPs were strongly correlated with other functional regulatory SNPs. These SNPs were found to regulate the expression of a group of genes involved in antigen processing and presentation including HLA-A, HLA-C, HLA-G, HLA-H, HLA DRA, HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DOB, and TAP-2. The results suggest that genetic variations within particular MHC genes can influence immune response to common childhood vaccinations, which in turn may influence vaccine efficacy. PMID- 24075920 TI - Evaluation of safety and immunogenicity of recombinant influenza hemagglutinin (H5/Indonesia/05/2005) formulated with and without a stable oil-in-water emulsion containing glucopyranosyl-lipid A (SE+GLA) adjuvant. AB - BACKGROUND: Expression of recombinant hemagglutinin (rHA) in insect cells represents a technology with proven efficacy in seasonal influenza and with the potential for a rapid response to the emergence of new, pandemic strains. We evaluated the safety and immunogenicity of rHA vaccine (H5/Indonesia/5/05) produced in SF+ insect cells using a baculovirus expression vector system (BEVS). The rHA vaccine was tested with and without the adjuvant glucopyranosyl lipid A/stable emulsion (GLA/SE). METHODS: Healthy adults 18-49 were randomized to two IM doses on Days 0 and 21 of placebo; unadjuvanted rHA 135 MUg or 45 MUg, or rHA 45 MUg, 15 MUg, 7.5 MUg or 3.8 MUg with GLA/SE. A pioneer group was monitored through Day 42 before randomizing remaining subjects. H5-specific antibody was determined by hemagglutination inhibition (HAI) and microneutralization (MN) on Days 0, 21 and 42. RESULTS: 392 subjects were randomized, of whom 380 (97%) received two doses and 386 (98%) completed 12 months of follow-up. Injection site pain and tenderness were seen in 50-70% of rHA+GLA/SE recipients and 4-9% of rHA alone and placebo recipients, but most complaints were mild to moderate in intensity. After two doses, the proportions of subjects with HAI titers >=1:40 were 32% and 15% in the unadjuvanted 135 MUg and 45 MUg groups, and 82%, 75%, 66%, and 72% in those receiving 45 MUg, 15 MUg, 7.5 MUg, or 3.8 MUg with GLA/SE. The geometric mean titers (GMTs) of HAI antibody on Day 42 were 128, 95, 69, and 72 in the 45 MUg, 15 MUg, 7.5 MUg, or 3.8 MUg with GLA/SE groups, respectively. CONCLUSIONS: rHA GLA/SE was well tolerated and immunogenic in healthy adults, and GLA/SE substantially improved the serum antibody response. rHA expressed using BEVS recombinant DNA platform technology represents a promising strategy for pandemic control. PMID- 24075921 TI - Vaccine potential of recombinant saposin-like protein 2 against Fasciolosis gigantica in mice. AB - Saposin-like protein 2 (SAP-2) is a protein that adult of Fasciola spp. use to lyse plasma membrane of red blood cells, so that their contents can be digested by proteases for the parasites' nutrients. Thus SAP-2 is a plausible target for vaccination against these parasites. Recombinant Fasciola gigantica saposin-like protein 2 (rFgSAP-2) was expressed in Escherichia coli BL21 (DE3). A vaccination was performed in ICR mice (n=10) by subcutaneous injection with 50MUg of rFgSAP-2 combined with Freund's adjuvant. At 2 weeks after the second boost, mice were infected with 30 F. gigantica metacercariae by oral route. The percentages of protection of rFgSAP-2 vaccine against F. gigantica were estimated to be 76.4 78.5% when compared with non vaccinated-infected and adjuvant-infected controls, respectively. The antibodies in immune sera of vaccinated mice were shown by immuno-blotting to react with native FgSAP-2 in the extract of 2- and 4-week-old juvenile parasites. By determining the levels of IgG1 and IgG2a in the immune sera, which are indicative of Th2 and Th1 immune responses, it was found that both Th1 and Th2 humoral immune response were significantly increased in rFgSAP-2 immunized group compared with the control groups, with higher levels of Th2 (IgG1) than Th1 (IgG2a). The levels of serum aspartate aminotransferase (AST) and alanine transaminase (ALT) in rFgSAP-2-immunized group showed no significant difference from those of the non-immunized and infected group, indicating that early juvenile parasites induced liver parenchyma damage, even though the numbers of worm recoveries were significantly different. This study indicates that rFgSAP 2 has a high potential as a vaccine candidate against F. gigantica in mice, and this potential will be tested in larger economic animals. PMID- 24075922 TI - In touch but not up-to-date: ambulatory visits and vaccination status in a cohort of young Swiss children. AB - OBJECTIVE: Incomplete and delayed vaccination is a barrier to individual and population protection from vaccine-preventable diseases. We aimed to assess visit frequency and pattern in relation to vaccination status in a Swiss cohort of 2 year-old children in order to review opportunities for completion of scheduled immunizations. METHOD: A retrospective dynamic cohort study design involving children insured with a single health insurer in Switzerland was chosen. Time-to event analysis was used to evaluate timing of defined immunizations of interest from submitted invoices. Diphtheria, tetanus, acellular pertussis (DTaP) and measles, mumps and rubella (MMR) immunizations administered to children registered with this health insurer were assessed. The specified vaccines are recommended at 2, 4, 6 and 15-24 months, and 12 and 15-24 months of age, respectively. RESULTS: 21,588 children born between January 1st, 2006 and June 30th, 2008 and registered with the health insurer from no later than 4 weeks of age were included. Only 40.9% of the cohort was up-to-date for both vaccines (DTaP and MMR) at 2 years of age. The average number of visits made during up to 2 years of age was 14.7 (95% CI: 15.9-16.3). Less than 5% of children made fewer than 5 visits, the minimum number required to complete all recommended immunizations by 2 years of age. Although number of visits varied by final vaccination status, more than 90% of the cohort made sufficient visits to complete the specified courses, even when contraindications were assumed to be present at up to half the visits. CONCLUSION: Swiss children who are not fully immunized at 2 years of age make fewer visits to ambulatory health care up to that age, but they have more than sufficient opportunities to complete immunizations as scheduled. Ambulatory healthcare providers in Switzerland have ample opportunity to promote and administer vaccinations in a timely manner. PMID- 24075924 TI - Coupling of drug containing liposomes to microbubbles improves ultrasound triggered drug delivery in mice. AB - Local extravasation and triggered drug delivery by use of ultrasound and microbubbles is a promising strategy to target drugs to their sites of action. In the past we have developed drug loaded microbubbles by coupling drug containing liposomes to the surface of microbubbles. Until now the advantages of this drug loading strategy have only been demonstrated in vitro. Therefore, in this paper, microbubbles with indocyanine green (ICG) containing liposomes at their surface or a mixture of ICG-liposomes and microbubbles was injected intravenously in mice. Immediately after injection the left hind leg was exposed to 1 MHz ultrasound and the ICG deposition was monitored 1, 4 and 7 days post-treatment by in vivo fluorescence imaging. In mice that received the ICG-liposome loaded microbubbles the local ICG deposition was, at each time point, about 2-fold higher than in mice that received ICG-liposomes mixed with microbubbles. We also showed that the perforations in the blood vessels allow the passage of ICG liposomes up to 5h after microbubble and ultrasound treatment. An increase in tissue temperature to 41 degrees C was observed in all ultrasound treated mice. However, ultrasound tissue heating was excluded to cause the local ICG deposition. We concluded that coupling of drug containing liposomes to microbubbles may increase ultrasound mediated drug delivery in vivo. PMID- 24075923 TI - Mitochondrial genetics and obesity: evolutionary adaptation and contemporary disease susceptibility. AB - Obesity is a leading risk factor for a variety of metabolic diseases including cardiovascular disease, diabetes, and cancer. Although in its simplest terms, obesity may be thought of as a consequence of excessive caloric intake and sedentary lifestyle, it is also evident that individual propensity for weight gain can vary. The etiology of individual susceptibility to obesity seems to be complex-involving a combination of environmental-genetic interactions. Herein, we suggest that the mitochondrion plays a major role in influencing individual susceptibility to this disease via mitochondrial-nuclear interaction processes and that environmentally influenced selection events for mitochondrial function that conveyed increased reproductive and survival success during the global establishment of human populations during prehistoric times can influence individual susceptibility to weight gain and obesity. PMID- 24075925 TI - Self-assembled phenylalanine-alpha,beta-dehydrophenylalanine nanotubes for sustained intravitreal delivery of a multi-targeted tyrosine kinase inhibitor. AB - Current standard of care for sustained back of the eye drug delivery is surgical placement or injection of large, slow release implants using a relatively large 22 gauge needle. We designed novel dipeptide (phenylalanine-alpha,beta dehydrophenylalanine; Phe-?Phe) based nanotubes with a diameter of ~15-30 nm and a length of ~1500 nm that could be injected with a 33 gauge needle for sustained intravitreal delivery of pazopanib, a multi-targeted tyrosine kinase inhibitor. The drug could be loaded during nanotube assembly or post-loaded after nanotube formation, with the former being more efficient at 25% w/w pazopanib loading and ~55% loading efficiency. Plain and peptide loaded nanotube were non-cytotoxic to retinal pigment epithelial cells even at a concentration of 200 MUg/ml. Following intravitreal injection of fluorescently labeled nanotubes using a 33 gauge needle in a rat model, the nanotube persistence and drug delivery were monitored using noninvasive fluorophotometry, electron microscopy and mass spectrometry analysis. Nanotubes persisted in the vitreous humor during the 15 days study and pazopanib levels in the vitreous humor, retina, and choroid-RPE at the end of the study were 4.5, 5, and 2.5-folds higher, respectively, compared to the plain drug. Thus, Phe-?Phe nanotubes allow intravitreal injections with a small gauge needle and sustain drug delivery. PMID- 24075928 TI - Cancer of the Indiana Pouch: a case report and review of the literature. PMID- 24075927 TI - Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles. AB - Nanoparticle drug delivery to the tumor is impacted by multiple factors: nanoparticles must evade clearance by renal filtration and the reticuloendothelial system, extravasate through the enlarged endothelial gaps in tumors, penetrate through dense stroma in the tumor microenvironment to reach the tumor cells, remain in the tumor tissue for a prolonged period of time, and finally release the active agent to induce pharmacological effect. The physicochemical properties of nanoparticles such as size, shape, surface charge, surface chemistry (PEGylation, ligand conjugation) and composition affect the pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. On the other hand, tumor biology (blood flow, perfusion, permeability, interstitial fluid pressure and stroma content) and patient characteristics (age, gender, tumor type, tumor location, body composition and prior treatments) also have impact on drug delivery by nanoparticles. It is now believed that both nanoparticles and the tumor microenvironment have to be optimized or adjusted for optimal delivery. This review provides a comprehensive summary of how these nanoparticle and biological factors impact nanoparticle delivery to tumors, with discussion on how the tumor microenvironment can be adjusted and how patients can be stratified by imaging methods to receive the maximal benefit of nanomedicine. Perspectives and future directions are also provided. PMID- 24075929 TI - The structural organization of the N-terminus domain of SopB, a virulence factor of Salmonella, depends on the nature of its protein partners. AB - The TTSS is used by Salmonella and many bacterial pathogens to inject virulence factors directly into the cytoplasm of target eukaryotic cells. Once translocated these so-called effector proteins hijack a vast array of crucial cellular functions to the benefit of the bacteria. In the bacterial cytoplasm, some effectors are stabilized and maintained in a secretion competent state by interaction with specific type III chaperones. In this work we studied the conformation of the Chaperone Binding Domain of the effector named Salmonella Outer protein B (SopB) alone and in complex with its cognate chaperone SigE by a combination of biochemical, biophysical and structural approaches. Our results show that the N-terminus part of SopB is mainly composed by alpha-helices and unfolded regions whose organization/stabilization depends on their interaction with the different partners. This suggests that the partially unfolded state of this N-terminal region, which confers the adaptability of the effector to bind very different partners during the infection cycle, allows the bacteria to modulate numerous host cells functions limiting the number of translocated effectors. PMID- 24075930 TI - Capsaicin induces cytotoxicity in pancreatic neuroendocrine tumor cells via mitochondrial action. AB - Capsaicin (CAP), the pungent ingredient of chili peppers, inhibits growth of various solid cancers via TRPV1 as well as TRPV1-independent mechanisms. Recently, we showed that TRPV1 regulates intracellular calcium level and chromogranin A secretion in pancreatic neuroendocrine tumor (NET) cells. In the present study, we characterize the role of the TRPV1 agonist - CAP - in controlling proliferation and apoptosis of pancreatic BON and QGP-1 NET cells. We demonstrate that CAP reduces viability and proliferation, and stimulates apoptotic death of NET cells. CAP causes mitochondrial membrane potential loss, inhibits ATP synthesis and reduces mitochondrial Bcl-2 protein production. In addition, CAP increases cytochrome c and cleaved caspase 3 levels in cytoplasm. CAP reduces reactive oxygen species (ROS) generation. The antioxidant N-acetyl-l cysteine (NAC) acts synergistically with CAP to reduce ROS generation, without affecting CAP-induced toxicity. TRPV1 protein reduction by 75% reduction fails to attenuate CAP-induced cytotoxicity. In summary, these results suggest that CAP induces cytotoxicity by disturbing mitochondrial potential, and inhibits ATP synthesis in NET cells. Stimulation of ROS generation by CAP appears to be a secondary effect, not related to CAP-induced cytotoxicity. These results justify further evaluation of CAP in modulating pancreatic NETs in vivo. PMID- 24075926 TI - Progress in microRNA delivery. AB - MicroRNAs (miRNAs) are non-coding endogenous RNAs that direct post transcriptional regulation of gene expression by several mechanisms. Activity is primarily through binding to the 3' untranslated regions (UTRs) of messenger RNAs (mRNA) resulting in degradation and translation repression. Unlike other small RNAs, miRNAs do not require perfect base pairing, and thus, can regulate a network of broad, yet specific, genes. Although we have only just begun to gain insights into the full range of biologic functions of miRNA, their involvement in the onset and progression of disease has generated significant interest for therapeutic development. Mounting evidence suggests that miRNA-based therapies, either restoring or repressing miRNAs expression and activity, hold great promise. However, despite the early promise and exciting potential, critical hurdles often involving delivery of miRNA-targeting agents remain to be overcome before transition to clinical applications. Limitations that may be overcome by delivery include, but are not limited to, poor in vivo stability, inappropriate biodistribution, disruption and saturation of endogenous RNA machinery, and untoward side effects. Both viral vectors and nonviral delivery systems can be developed to circumvent these challenges. Viral vectors are efficient delivery agents but toxicity and immunogenicity limit their clinical usage. Herein, we review the recent advances in the mechanisms and strategies of nonviral miRNA delivery systems and provide a perspective on the future of miRNA-based therapeutics. PMID- 24075931 TI - Risk factors for early postoperative morbidity and mortality in patients underwent radical surgery for gastric carcinoma: a single center experience. AB - BACKGROUND: Aim of this study is to analyze the incidence and risk factors for early postoperative morbidity and mortality that occur after gastric carcinoma surgery. MATERIALS AND METHODS: All consecutive patients with gastric adenocarcinoma resected with curative intent between 2005 and 2011 were included to a retrospective analysis. Patient, disease and operation related parameters were questioned as risk factors for postoperative morbidity and mortality. RESULTS: A total of 160 patients (103 [64.8%] male and the average age was 62.4 +/- 11.5) were abstracted. Early postoperative morbidity, operation related morbidity and mortality were observed in 46 (28.7%), 31 (19.4%) and 19 (11.9%) cases, respectively. No other factors but ASA score was found to be a risk factor for overall morbidity (p = 0.021 and 0.033 in univariate and multivariate analyses, respectively). The incidence of anastomotic leak was increasing in patients who received a D2 dissection in univariate analysis (p = 0.039), but not in multivariate calculation. There were no factors effecting surgical site infection risk. Although univariate analysis revealed that age over 70 (p = 0.008), ASA score (p = 0.018), operation time (p = 0.032), D2 dissection (p = 0.026) and type of anastomosis (p = 0.023) were effecting the risk for early mortality, multivariate analysis showed that age was the only risk factor (p = 0.005). CONCLUSION: Current study has revealed that early morbidity and mortality are not rare after gastric cancer surgery with curative intent. Since multivariate analyses have revealed that ASA score and older age may be only risk factors for postoperative morbidity and 30-day mortality, respectively; it may be logical to consider these factors during the preoperative decision making in patients with gastric cancer. PMID- 24075932 TI - Isolation, characterization and evaluation of the Pichia pastoris sorbitol dehydrogenase promoter for expression of heterologous proteins. AB - Sorbitol is used as a non-repressive carbon source to develop fermentation process for Mut(s) recombinant clones obtained using the AOX1 promoter in Pichia pastoris. Sorbitol dehydrogenase is an enzyme in the carbohydrate metabolism that catalyzes reduction of D-fructose into D-sorbitol in the presence of NADH. The small stretch of 211bps upstream region of sorbitol dehydrogenase coding gene has all the promoter elements like CAAT box, GC box, etc. It is able to promote protein production under repressive as well as non-repressive carbon sources. In this study, the strength of the sorbitol dehydrogenase promoter was evaluated by expression of two heterologous proteins: human serum albumin and erythrina trypsin inhibitor. Sorbitol dehydrogenase promoter allowed constitutive expression of recombinant proteins in all carbon sources that were tested to grow P. pastoris and showed activity similar to GAP promoter. The sorbitol dehydrogenase promoter was active in all the growth phases of the P. pastoris. PMID- 24075933 TI - Response to "A closer look at FBXO41 as a Parkinson's disease risk factor". PMID- 24075934 TI - A bioenergetic profile of non-transformed fibroblasts uncovers a link between death-resistance and enhanced spare respiratory capacity. AB - Apoptosis-resistance and metabolic imbalances are prominent features of cancer cells. We have recently reported on populations of human fibroblasts that exhibit resistance to mitochondrial-mediated apoptosis, acquired as a result of a single genotoxic exposure. The objective of the present study was to investigate the intrinsic bioenergetic profile of the death-resistant cells, as compared to the clonogenic control cells. Therefore, we analyzed the basic bioenergetic parameters including oxygen consumption and extracellular acidification rates, coupling efficiency, and spare respiratory capacity. Our data demonstrate a strong correlation between enhanced spare respiratory capacity and death resistance, which we postulate to be indicative of the earliest stages of carcinogenesis. PMID- 24075935 TI - Neurological features and long-term follow-up in 15q11.2-13.1 duplication. AB - Various rearrangements occurring in the 15q11-q13 region have been reported in association with epilepsy. Deletions are the most frequent and are associated with Angelman or Prader-Willi syndrome. Duplications feature complex phenotypes including developmental delay, autistic-like behaviour and seizures. Among these, trisomy has been described as a milder phenotype compared to tetrasomy, but reports are rare and the phenotype is not yet defined. Here we report two adult cases with a 15q11.2-13.1 duplication showing a complex and similar epileptic phenotype. PMID- 24075936 TI - Anti-arthritic and anti-inflammatory activity of combined pioglitazone and prednisolone on adjuvant-induced arthritis. AB - The aim of the present study was to evaluate the effect of combined treatment of pioglitazone (PGZ) and prednisolone (PDL) on the progression of adjuvant-induced arthritis in rats. Adjuvant arthritis was induced by single intra-dermal injection of 0.1 ml Freund's complete adjuvant (0.05% w/v Mycobacterium butyricum in mineral oil) into foot pads of left hind paws of Wistar rats of either sex. There were six experimental groups: Group I was healthy animals as control, Group II was arthritic animals without drug treatment, Group III was arthritic animals treated with a standard non-steroidal anti-inflammatory drug aspirin (100 mg/kg), Group IV was arthritic animals received PGZ (10 mg/kg) alone, Group V was arthritic animals received PDL (10 mg/kg) alone, and Group VI was arthritic animals treated with a combined suspension of PGZ and PDL (20 mg/kg). Drugs were administered daily orally at day 0 and continued upto 28th day after induction of arthritis. Induction of arthritis significantly increased hind paw volume (HPV), loss of body weight (BW), enhanced tibiotarsal joint thickness (TJT), and increased plasma tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 levels. Treatment with aspirin or combined suspension of PGZ and PDL in the arthritic animals produced significant reductions in HPV and TJT, normalized BW, and significantly decreased plasma levels of TNF-alpha and IL-6. These observations suggest that the combined administration of PGZ and PDL was effective in modulating the inflammatory response and suppress arthritis progression in experimental animal model. These findings may help to improve the treatment of rheumatoid arthritis. PMID- 24075937 TI - Lycopene protects against memory impairment and mito-oxidative damage induced by colchicine in rats: an evidence of nitric oxide signaling. AB - Oxidative-nitrosative stress and mitochondrial dysfunction plays an important role in the onset of various neurodegenerative diseases. Lycopene, a carotenoid antioxidant, has received considerable scientific interest in recent years. Present study was designed to evaluate the possible nitric oxide mechanism in protective effects of lycopene against the colchicine induced cognitive impairment and mito-oxidative damage in rats. Wistar rats were received i.c.v. colchicine (15 ug/5 ul). Lycopene (2.5 and 5mg/kg), NO modulators e.g. l-Arginine (50mg/kg) l-NAME (5mg/kg) administered for 21 days. Behavioural alterations were assessed in between study period. Animals were killed immediately following the last behavioral session, and mitochondrial enzymes, oxidative parameters, inflammatory mediators (TNF-alpha, IL-6) and caspase-3 activity were measured. I.C.V. administration of colchicine impaired memory performance in Morris water maze, oxidative defense and mitochondrial complex enzymes activities as compared to sham group. A significant increase of TNF-alpha, IL-6 and caspase-3 activity in hippocampus and cortex was also noted. Chronic treatment lycopene significantly improved memory retention and attenuated mito-oxidative damage parameters, inflammatory markers and apoptosis in colchicine treated rats. Further, l-arginine pretreatment with sub effective dose of lycopene significantly reversed the protective effect of lycopene. However, l-NAME pretreatment with sub effective dose of lycopene significantly potentiated the protective effect of lycopene which was significant as compared to their effect per se. These results suggest that lycopene exhibit a neuroprotective effect by accelerating brain anti-oxidant defense mechanisms and down regulating nitric oxide pathways. Thus, lycopene may be used as therapeutic agent in preventing complications in memory dysfunction. PMID- 24075938 TI - Drug/drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with the anti platelet activity of aspirin at the level of the platelet cyclooxygenase-1 (COX 1) enzyme. In order to examine the interference of common NSAIDs with the anti platelet activity of aspirin the human platelet rich plasma from voluntary donors was used for arachidonic acid-induced aggregation and determination of thromboxane synthesis. Further, docking studies were used to explain the molecular basis of the NSAID/aspirin interaction. The experimental results showed that celecoxib, dipyrone (active metabolite), ibuprofen, flufenamic acid, naproxen, nimesulide, oxaprozin, and piroxicam significantly interfere with the anti-platelet activity of aspirin, while diclofenac, ketorolac and acetaminophen do not. Docking studies suggested that NSAIDs forming hydrogen bonds with Ser530, Arg120, Tyr385 and other amino acids of the COX-1 hydrophobic channel interfere with antiplatelet activity of aspirin while non interfering NSAIDs do not form relevant hydrogen bond interactions within the aspirin binding site. In conclusion, docking analysis of NSAID interactions at the COX-1 active site appears useful to predict their interference with the anti-platelet activity of aspirin. The results, demonstrate that some NSAIDs do not interfere with the antiplatelet action of aspirin while many others do and provide a basis for understanding the observed differences among individual non-aspirin NSAIDs. PMID- 24075939 TI - 'Surfing the Silk Road': a study of users' experiences. AB - INTRODUCTION: The online drug marketplace called 'Silk Road' has operated anonymously on the 'Deep Web' since 2011. It is accessible through computer encrypting software (Tor) and is supported by online transactions using peer to peer anonymous and untraceable crypto-currency (Bit Coins). The study aimed to describe user motives and realities of accessing, navigating and purchasing on the 'Silk Road' marketplace. METHODS: Systematic online observations, monitoring of discussion threads on the site during four months of fieldwork and analysis of anonymous online interviews (n=20) with a convenience sample of adult 'Silk Road' users was conducted. RESULTS: The majority of participants were male, in professional employment or in tertiary education. Drug trajectories ranged from 18 months to 25 years, with favourite drugs including MDMA, 2C-B, mephedrone, nitrous oxide, ketamine, cannabis and cocaine. Few reported prior experience of online drug sourcing. Reasons for utilizing 'Silk Road' included curiosity, concerns for street drug quality and personal safety, variety of products, anonymous transactioning, and ease of product delivery. Vendor selection appeared to be based on trust, speed of transaction, stealth modes and quality of product. Forums on the site provided user advice, trip reports, product and transaction reviews. Some users reported solitary drug use for psychonautic and introspective purposes. A minority reported customs seizures, and in general a displacement away from traditional drug sourcing (street and closed markets) was described. Several reported intentions to commence vending on the site. CONCLUSION: The study provides an insight into 'Silk Road' purchasing motives and processes, the interplay between traditional and 'Silk Road' drug markets, the 'Silk Road' online community and its communication networks. PMID- 24075940 TI - Transthyretin suppresses the toxicity of oligomers formed by misfolded proteins in vitro. AB - Although human transthyretin (TTR) is associated with systemic amyloidoses, an anti-amyloidogenic effect that prevents Abeta fibril formation in vitro and in animal models has been observed. Here we studied the ability of three different types of TTR, namely human tetramers (hTTR), mouse tetramers (muTTR) and an engineered monomer of the human protein (M-TTR), to suppress the toxicity of oligomers formed by two different amyloidogenic peptides/proteins (HypF-N and Abeta42). muTTR is the most stable homotetramer, hTTR can dissociate into partially unfolded monomers, whereas M-TTR maintains a monomeric state. Preformed toxic HypF-N and Abeta42 oligomers were incubated in the presence of each TTR then added to cell culture media. hTTR, and to a greater extent M-TTR, were found to protect human neuroblastoma cells and rat primary neurons against oligomer induced toxicity, whereas muTTR had no protective effect. The thioflavin T assay and site-directed labeling experiments using pyrene ruled out disaggregation and structural reorganization within the discrete oligomers following incubation with TTRs, while confocal microscopy, SDS-PAGE, and intrinsic fluorescence measurements indicated tight binding between oligomers and hTTR, particularly M TTR. Moreover, atomic force microscopy (AFM), light scattering and turbidimetry analyses indicated that larger assemblies of oligomers are formed in the presence of M-TTR and, to a lesser extent, with hTTR. Overall, the data suggest a generic capacity of TTR to efficiently neutralize the toxicity of oligomers formed by misfolded proteins and reveal that such neutralization occurs through a mechanism of TTR-mediated assembly of protein oligomers into larger species, with an efficiency that correlates inversely with TTR tetramer stability. PMID- 24075941 TI - LRRK2 guides the actin cytoskeleton at growth cones together with ARHGEF7 and Tropomyosin 4. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common genetic cause of Parkinson's disease (PD). However, LRRK2 function and molecular mechanisms causing the parkinsonian phenotype remain widely unknown. Most of LRRK2 knockdown and overexpression models strengthen the relevance of LRRK2 in regulating neurite outgrowth. We have recently identified ARHGEF7 as the first guanine nucleotide exchange factor (GEF) of LRRK2. This GEF is influencing neurite outgrowth through regulation of actin polymerization. Here, we examined the expression profile of neuroblastoma cells with reduced LRRK2 and ARHGEF7 levels to identify additional partners of LRRK2 in this process. Tropomyosins (TPMs), and in particular TPM4, were the most interesting candidates next to other actin cytoskeleton regulating transcripts in this dataset. Subsequently, enhanced neurite branching was shown using primary hippocampal neurons of LRRK2 knockdown animals. Furthermore, we observed an enhanced number of growth cones per neuron and a mislocalization and dysregulation of ARHGEF7 and TPM4 in these neuronal compartments. Our results reveal a fascinating connection between the neurite outgrowth phenotype of LRRK2 models and the regulation of actin polymerization directing further investigations of LRRK2-related pathogenesis. PMID- 24075942 TI - Obesity and post-cardiopulmonary bypass-associated acute kidney injury: a single center retrospective analysis. AB - OBJECTIVE: The authors specifically explored the association of obesity (based on body mass index [BMI]) and the risk of developing acute kidney injury after cardiopulmonary bypass (AKICPB). DESIGN: Single-center retrospective study. SETTING: Academic medical center. PARTICIPANTS AND INTERVENTIONS: After IRB approval, 376 eligible adults who underwent cardiac surgery with cardiopulmonary bypass between 2006-2010 were included in the final retrospective analysis. Patients undergoing "off-pump" procedures, cardiac transplants, repair of congenital heart disease, and patients with preoperative circulatory assist devices were excluded. RESULTS: The overall incidence of developing AKICPB in this population based on the Acute Kidney Injury Network serum creatinine criteria was 39% (147 of 376). Among the BMI classes, the morbidly obese cohort (ie, BMI>40 kg/m(2)) had a significantly greater risk of developing AKICPB than those in lower BMI classes. BMI>40 kg/m(2) was significantly associated with development of AKICPB even after accounting for covariates (ie, diabetes mellitus, hypertension, age, severity of illness, and CPB time) (overall p = 0.018). The odds ratio of AKICPB in the BMI>40 kg/m(2) cohort relative to BMI<25 kg/m(2) was 2.39 (95% CI: 0.98, 5.82; p = 0.055), with no significant difference in risk of developing AKICPB among the 4 lower BMI classes. CONCLUSION: BMI>40 kg/m(2) is associated with a significantly higher risk of developing of AKICPB. PMID- 24075943 TI - Pathologic examination of Lambl's excrescence. PMID- 24075944 TI - Partial equilibrium approximations in apoptosis. I. The intracellular-signaling subsystem. AB - Apoptosis is one of the most basic biological processes. In apoptosis, tens of species are involved in many biochemical reactions with times scales of widely differing orders of magnitude. By the law of mass action, the process is mathematically described with a large and stiff system of ODEs (ordinary differential equations). The goal of this work is to simplify such systems of ODEs with the PEA (partial equilibrium approximation) method. In doing so, we propose a general framework of the PEA method together with some conditions, under which the PEA method can be justified rigorously. The main condition is the principle of detailed balance for fast reactions as a whole and the framework provides some meaningful physical insights of the full chemical kinetics. With the justified method as a tool, we simplify the Fas-signaling pathway model due to Hua et al. [6] under the empirical assumption that nine reactions therein can be well regarded as relatively fast. This paper reports our simplification, together with numerical results which confirm the reliability of both our simplified model and the empirical assumption. PMID- 24075945 TI - Association of the frontal QRS-T angle with adverse cardiac remodeling, impaired left and right ventricular function, and worse outcomes in heart failure with preserved ejection fraction. AB - BACKGROUND: No prior studies have investigated the association of QRS-T angle with cardiac structure and function and outcomes in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to test the hypothesis that increased frontal QRS-T angle is associated with worse cardiac function and remodeling and adverse outcomes in HFpEF. METHODS: A total of 376 patients with HFpEF (i.e., symptomatic heart failure with left ventricular ejection fraction > 50%) were prospectively studied. The frontal QRS-T angle was calculated from the 12-lead electrocardiogram. Patients were divided into tertiles by frontal QRS-T angle (0 degrees -26 degrees , 27 degrees -75 degrees , and 76 degrees -179 degrees ), and clinical, laboratory, and echocardiographic data were compared among groups. Cox proportional-hazards analyses were performed to determine the association between QRS-T angle and outcomes. RESULTS: The mean age of the cohort was 64 +/- 13 years, 65% were women, and the mean QRS-T angle was 61 +/- 51 degrees . Patients with increased QRS-T angles were older; had lower body mass indices; more frequently had coronary artery disease, diabetes, chronic kidney disease, and atrial fibrillation; and had higher B-type natriuretic peptide levels (P < .05 for all comparisons). After multivariate adjustment, patients with increased QRS-T angles had higher B-type natriuretic peptide levels in addition to higher left ventricular mass indices, worse diastolic function parameters, more right ventricular remodeling, and worse right ventricular systolic function (P < .05 for all associations). QRS-T angle was independently associated with the composite outcome of cardiovascular hospitalization or death on multivariate analysis, even after adjusting for B-type natriuretic peptide (heart rate for the highest QRS-T tertile, 2.0; 95% confidence interval, 1.2-3.4; P = .008). CONCLUSIONS: In HFpEF, increased QRS-T angle is independently associated with worse left and right ventricular function and remodeling and adverse outcomes. PMID- 24075946 TI - An adult man with acute dysphagia and systemic inflammation. PMID- 24075947 TI - Dysphagia in Lynch syndrome. PMID- 24075948 TI - A case of gastric adenocarcinoma with conspicuous binuclear cytologic features. AB - Binuclear cells have been occasionally observed in nonneoplastic and carcinoma cells. However, in clinical cases, few reports have analyzed and discussed the origins and features, including the proliferative capacity, of binuclear cells. We describe the case of a 75-year-old man with gastric cancer with microscopically prominent binuclear cells in the resected tissue and ascitic fluid. Image cytometry and chromosomal analysis were performed on cells isolated from the ascitic fluid. The DNA histogram pattern showed aneuploidy and the fluorescence in situ hybridization pattern of centromeres 7 and 11 was similar to that of most other mononuclear cancer cells. Furthermore, the binuclear cells showed low proliferative capability based on 5-bromo-2'-deoxyuridine incorporation. Our results demonstrated that the binuclear cells were derived from mononuclear aneuploid cells through incomplete cell division, and, in this case, may have impaired proliferative capacity. PMID- 24075949 TI - Tissue specific specialization of the nanoscale architecture of Arabidopsis. AB - The Arabidopsis stem is composed of five tissues - the pith, xylem, phloem, cortex and epidermis - each of which fulfills specific roles in support of the growth and survival of the organism. The lignocellulosic scaffolding of cell walls is specialized to provide optimal support for the diverse functional roles of these layers, but little is known about this specialization. X-ray scattering can be used to study this tissue-specific diversity because the cellulosic components of the cell walls give rise to recognizable scattering features interpretable in terms of the underlying molecular architecture and distinct from the largely unoriented scatter from other constituents. Here we use scanning X ray microdiffraction from thin sections to characterize the diversity of molecular architecture in the Arabidopsis stem and correlate that diversity to the functional roles the distinct tissues of the stem play in the growth and survival of the organism. PMID- 24075951 TI - Xmipp 3.0: an improved software suite for image processing in electron microscopy. AB - Xmipp is a specialized software package for image processing in electron microscopy, and that is mainly focused on 3D reconstruction of macromolecules through single-particles analysis. In this article we present Xmipp 3.0, a major release which introduces several improvements and new developments over the previous version. A central improvement is the concept of a project that stores the entire processing workflow from data import to final results. It is now possible to monitor, reproduce and restart all computing tasks as well as graphically explore the complete set of interrelated tasks associated to a given project. Other graphical tools have also been improved such as data visualization, particle picking and parameter "wizards" that allow the visual selection of some key parameters. Many standard image formats are transparently supported for input/output from all programs. Additionally, results have been standardized, facilitating the interoperation between different Xmipp programs. Finally, as a result of a large code refactoring, the underlying C++ libraries are better suited for future developments and all code has been optimized. Xmipp is an open-source package that is freely available for download from: http://xmipp.cnb.csic.es. PMID- 24075950 TI - Zernike phase contrast cryo-electron tomography of whole bacterial cells. AB - Cryo-electron tomography (cryo-ET) provides three-dimensional (3D) structural information of bacteria preserved in a native, frozen-hydrated state. The typical low contrast of tilt-series images, a result of both the need for a low electron dose and the use of conventional defocus phase-contrast imaging, is a challenge for high-quality tomograms. We show that Zernike phase-contrast imaging allows the electron dose to be reduced. This limits movement of gold fiducials during the tilt series, which leads to better alignment and a higher-resolution reconstruction. Contrast is also enhanced, improving visibility of weak features. The reduced electron dose also means that more images at more tilt angles could be recorded, further increasing resolution. PMID- 24075952 TI - Reporting quality of systematic review abstracts in leading oral implantology journals. AB - OBJECTIVES: Abstracts of systematic reviews are of critical importance, as consumers of research often do not access the full text. This study aimed to assess the reporting quality of systematic review (SR) abstracts in leading oral implantology journals. METHODS: Six specialty journals were screened for SRs between 2008 and 2012. A 16-item checklist, based on the PRISMA statement, was used to examine the completeness of abstract reporting. RESULTS: Ninety-three SR abstracts were included in this study. The majority were published in Clinical Oral Implants Research (43%). The mean overall reporting quality score was 72.5% (95% CI: 70.8-74.2). Most abstracts were structured (97.9%), adequately reporting objectives (97.9%) and conclusions (93.6%). Conversely, inadequate reporting of methods of the study, background (79.6%), appraisal (65.6%), and data synthesis (65.6%) were observed. Registration of reviews was not reported in any of the included abstracts. Multivariate analysis revealed no difference in reporting quality with respect to continent, number of authors, or meta-analysis conduct. CONCLUSIONS: The results of this study suggest that the reporting quality of systematic review abstracts in implantology journals requires further improvement. CLINICAL SIGNIFICANCE: Better reporting of SR abstracts is particularly important in ensuring the reliability of research findings, ultimately promoting the practice of evidence-based dentistry. Optimal reporting of SR abstracts should be encouraged, preferably by endorsing the PRISMA for abstracts guidelines. PMID- 24075955 TI - Chromosome instability predicts the progression of premalignant oral lesions. AB - OBJECTIVES: One of the main problems in reducing the incidence of oral squamous cell carcinoma (OSCC) is the inability to appropriately deal with leukoplakia. Accurately identifying lesions which will progress to malignancy is currently not possible. The present study aims to establish the value of chromosome instability (CI) detection by DNA image cytometry and FISH analysis for prognosis and monitoring of oral leukoplakia. MATERIALS AND METHODS: For this purpose, we included from our archives 102 oral leukoplakia cases, which had been diagnosed between 1991 and 2008. Patient follow-up data were collected and the histopathological diagnosis was revised. CI assessment was carried out on paraffin-embedded tissue sections using both DNA image cytometry (ICM) and dual target FISH for chromosomes 1 and 7. RESULTS: 16 of 102 Patients developed carcinoma in situ or OSCC. Both detection methods were found to yield prognostic information independent of the histopathological diagnosis. CI was a strong individual marker of progression, with hazard ratios (HRs) of 7.2 and 6.8 for ICM and FISH respectively. Moreover, this approach seems suitable for monitoring lesions over time (especially ICM). Combining histopathology and CI enables subdivision of patients into three risk groups, with different probabilities of malignant progression. CONCLUSION: CI detection seems a reliable method for risk assessment of oral premalignancies and its application may contribute to a better risk-counselling and appropriate treatment regimen or watchfull-waiting approach of patients. PMID- 24075956 TI - Regional changes in cardiac and stellate ganglion norepinephrine transporter in DOCA-salt hypertension. AB - Uptake of norepinephrine via the neuronal norepinephrine transporter is reduced in the heart during deoxycorticosterone (DOCA)-salt hypertension. We hypothesized that this was due to reduced norepinephrine transporter mRNA and/or protein expression in the stellate ganglia and heart. After 4 weeks of DOCA-salt treatment there was no change in norepinephrine transporter mRNA in either the right or the left stellate ganglia from hypertensive rats (n=5-7, p>0.05). Norepinephrine transporter immunoreactivity in the left stellate ganglion was significantly increased (n=4, p<0.05) while the right stellate ganglion was unchanged (n=4, p>0.05). Whole heart norepinephrine content was significantly reduced in DOCA rats consistent with reduced uptake function; however, when norepinephrine was assessed by chamber, a significant decrease was noted only in the right atrium and right ventricle (n=6, p<0.05). Cardiac norepinephrine transport binding by chamber revealed that it was only reduced in the left atrium (n=5-7, p>0.05). Therefore, 1) contrary to our hypothesis reduced reuptake in the hypertensive heart is not exclusively due to an overall reduction in norepinephrine transporter mRNA or protein in the stellate ganglion or heart, and 2) norepinephrine transporter regulation occurs regionally in the heart and stellate ganglion in the hypertensive rat heart. PMID- 24075957 TI - Static magnetic fields increase tumor microvessel leakiness and improve antitumoral efficacy in combination with paclitaxel. AB - Static magnetic fields (SMF) induce an intratumoral edema possibly by increasing microvessel permeability. The aim of this study was to evaluate the effects of SMF on tumor microvessel permeability and on treatment effects of conventional cytotoxic chemotherapy. Using intravital microscopy in skinfold chamber preparations in A-Mel-3-tumor-bearing hamsters, functional tumor microcirculation, microvessel permeability and leukocyte-endothelial cell interactions were measured under SMF-exposure (587 mT). Combining SMF-exposure with paclitaxel-chemotherapy, tumor growth was analyzed. SMF inhibited tumor angiogenesis and increased tumor microvessel permeability significantly. This was not mediated by inflammatory leukocyte-endothelial cell interactions. Further, SMF increased the effectiveness of paclitaxel-chemotherapy significantly. These findings support that SMF possibly open the blood-tumor-barrier to small molecular therapeutics. PMID- 24075958 TI - MYB down-regulation enhances sensitivity of U937 myeloid leukemia cells to the histone deacetylase inhibitor LBH589 in vitro and in vivo. AB - The effect of combining MYB suppression with the histone deacetylase inhibitor LBH589 was studied in human myeloid leukemia cell lines. MYB knockdown inhibited proliferation and induced apoptosis in U937 and K562 cells in vitro, and also sensitized both to the pro-apoptotic effect of LBH589. This was accompanied by enhanced expression of the pro-apoptotic BCL2 family members BOK and BIM. U937 cells carrying inducible MYB shRNA were also transplanted into NOD/SCID mice. The combination of MYB knockdown and LBH589 prolonged survival compared to either treatment alone, suggesting that further development of such combinations might lead to effective and safe leukemia therapies. PMID- 24075959 TI - Differential diagnosis of membranous nephropathy with autoantibodies to phospholipase A2 receptor 1. AB - Membranous nephropathy (MN) accounts for most cases of the nephrotic syndrome in adults. Recently, studies on the underlying pathomechanisms led to the identification of the podocyte M-type receptor for secretory phospholipase A2 (PLA2R1) as a target antigen of circulating autoantibodies. Autoantibodies to PLA2R1 may not only play a role in the development of primary MN, but also serve as a marker for diagnosis, disease activity and therapy monitoring. Antibody detection is crucial to discriminate between patients with primary MN and those with a secondary form of the disease, as both forms require different diagnostic approaches and treatment strategies. Standardized test systems based on recombinant PLA2R1 allow for the sensitive and specific analysis of anti-PLA2R1 autoantibodies. Further research into pathogenic mechanisms and other disease markers can pave the way for improved patient care. PMID- 24075960 TI - A novel gene mutation in PANK2 in a patient with an atypical form of pantothenate kinase-associated neurodegeneration. AB - Pantothenate kinase-associated neurodegeneration (PKAN) disease is an autosomal recessive neurodegenerative disorder with iron storage in the brain due to PANK2 gene mutations. Brain magnetic resonance imaging (MRI) shows the typical "eye-of the-tiger" sign. The aim of the present study was to describe clinical, MRI and molecular findings in a 26-year-old male with atypical PKAN disease in whom, brain MRI scans showed bilateral pallidal T2-hypointensity with a small central region of T2-hyperintensity, resembling the "eye-of-the-tiger" typical image. Genetic analysis identified two mutations in PANK2: c.1561G>A and c.1663G>A, being the latter never described before. Due to limited phenotype-genotype correlation among patients with movement disorders, if "eye-of-the-tiger" brain MRI is present, PANK2 mutations investigation are needed to confirm PKAN disease. PMID- 24075961 TI - Synthesis and evaluation of cyclosporine A-loaded polysialic acid polycaprolactone micelles for rheumatoid arthritis. AB - Polysialic acid (PSA) has been identified as a natural, hydrophilic polymer that can be used to extend circulation time and improve therapeutic efficacy when used as the basis of drug carrier systems. Here, to further investigate the potential of PSA to alter the pharmacokinetic and pharmacodynamic profiles of associated therapeutics, PSA-based micelles were formed via self-assembly of PSA grafted with polycaprolactone (PCL) at a critical micelle concentration of 84.7+/-13.2 MUg/ml. Cyclosporine A (CyA), a therapeutic used in the treatment of rheumatoid arthritis, was loaded into the PSA-PCL micelles with a loading capacity and loading efficiency of 0.09+/-0.02 mg CyA/mg PSA-PCL and 29.3+/-6.4%, respectively. CyA loading resulted in a size increase from 73.8+/-12.4 nm to 107.5+/-9.3 nm at 25 degrees C and from 138.4+/-40.7 nm to 195.3+/-52.1 nm at 37 degrees C, favorable size ranges for drug delivery to inflamed tissue characterized by leaky vasculature, as occurs during rheumatoid arthritis pathogenesis. As an indicator of the stealth nature the micelles are expected to exhibit in vivo, the fixed aqueous layer thickness of the PSA-PCL micelles was determined to be 0.63+/-0.02 nm, comparable to that obtained for traditionally utilized poly(ethylene glycol) coated liposomes. The PSA-PCL micelles had a negligible effect on the viability of the SW982 synovial fibroblast cell line. Fluorescent microscopy was utilized to demonstrate uptake by the synovial fibroblasts through a non-receptor mediated form of endocytosis and partitioning of CyA into the membrane. PMID- 24075962 TI - Effects of verapamil on the pharmacokinetics and hepatobiliary disposition of fexofenadine in pigs. AB - The pharmacokinetics (PK) of fexofenadine (FEX) in pigs were investigated with the focus on exploring the interplay between hepatic transport and metabolism when administered intravenously (iv) alone or with verapamil. The in vivo pig model enabled simultaneous sampling from plasma (pre-liver, post-liver and peripheral), bile and urine. Each animal was administered FEX 35mg iv alone or with verapamil 35mg. Plasma, bile and urine were analyzed with liquid chromatography-tandem mass spectrometry. Non-compartmental analysis (NCA) was used to estimate traditional PK parameters. In addition, a physiologically based pharmacokinetic (PBPK) model consisting of 11 compartments (6 tissues +5 sample sites) was applied for mechanistic elucidation and estimation of individual PK parameters. FEX had a terminal half-life of 1.7h and a liver extraction of 3%. The fraction of the administered dose of unchanged FEX excreted into the bile was 25% and the bile exposure was more than 100 times higher than the portal vein total plasma exposure, indicating carrier-mediated (CM) disposition processes in the liver. 23% of the administered dose of FEX was excreted unchanged in the urine. An increase in FEX plasma exposure (+50%) and a decrease in renal clearance (-61%) were detected by NCA as a direct effect of concomitant administration of verapamil. However, analysis of the PBPK model also revealed that biliary clearance was significantly inhibited (-53%) by verapamil. In addition, PBPK analysis established that metabolism and CM uptake were important factors in the disposition of FEX in the liver. In conclusion, this study demonstrated that CM transport of FEX in both liver and kidneys was inhibited by a single dose of verapamil. PMID- 24075963 TI - Luminal matrices: an inside view on organ morphogenesis. AB - Tubular epithelia come in various shapes and sizes to accommodate the specific needs for transport, excretion and absorption in multicellular organisms. The intestinal tract, glandular organs and conduits for liquids and gases are all lined by a continuous layer of epithelial cells, which form the boundary of the luminal space. Defects in epithelial architecture and lumen dimensions will impair transport and can lead to serious organ malfunctions. Not surprisingly, multiple cellular and molecular mechanisms contribute to the shape of tubular epithelial structures. One intriguing aspect of epithelial organ formation is the highly coordinate behavior of individual cells as they mold the mature lumen. Here, we focus on recent findings, primarily from Drosophila, demonstrating that informative cues can emanate from the developing organ lumen in the form of solid luminal material. The luminal material is produced by the surrounding epithelium and helps to coordinate changes in shape and arrangement of the very same cells, resulting in correct lumen dimensions. PMID- 24075964 TI - Reflux induces DNA strand breaks and expression changes of MMP1+9+14 in a human miniorgan culture model. AB - Gastroesophageal reflux disease has been implicated in the pathogenesis of adenocarcinoma of the oesophagus. The same applies to laryngopharyngeal reflux (LPR) and squamous cell cancer of the head and neck, but so far, this link has not been proven. The impact of low pH and bile acids has not been studied extensively in cells other than oesophageal cancer cell lines and tissue. The aims of this study were to investigate the pathogenic potential of reflux and its single components on the mucosa of the upper respiratory tract. We measured DNA stability in human miniorgan cultures (MOCs) and primary epithelial cell cultures (EpCs) in response to reflux by the alkaline comet assay. As matrix metalloproteinases (MMPs) are involved in extracellular matrix remodelling processes and may contribute to cancer progression, we studied the expression of MMP1, -9, and -14 in MOCs, EpC, UM-SCC-22B, and FADUDD. DNA strand breaks (DNA SBs) increased significantly at low pH and after incubation with human or artificial gastric juice. Single incubation with glycochenodeoxycholic acid also showed a significant increase in DNA-SBs. In epithelial cell cultures, human gastric juice increased the number of DNA-SBs at pH 4.5 and 5.5. Artificial gastric juice significantly up regulated the gene expression of MMP9. Western blot analysis confirmed the results of gene expression analysis, but the up regulation of MMP1, -9, and -14 was donor-specific. Reflux has the ability to promote genomic instability and may contribute to micro environmental changes suitable for the initiation of malignancy. Further functional gene analysis may elucidate the role of laryngopharyngeal reflux in the development of head neck squamous cell carcinoma (HNSCC). PMID- 24075965 TI - FoxJ1-expressing cells contribute to neurogenesis in forebrain of adult rats: evidence from in vivo electroporation combined with piggyBac transposon. AB - Ependymal cells in the lateral ventricular wall are considered to be post-mitotic but can give rise to neuroblasts and astrocytes after stroke in adult mice due to insult-induced suppression of Notch signaling. The transcription factor FoxJ1, which has been used to characterize mouse ependymal cells, is also expressed by a subset of astrocytes. Cells expressing FoxJ1, which drives the expression of motile cilia, contribute to early postnatal neurogenesis in mouse olfactory bulb. The distribution and progeny of FoxJ1-expressing cells in rat forebrain are unknown. Here we show using immunohistochemistry that the overall majority of FoxJ1-expressing cells in the lateral ventricular wall of adult rats are ependymal cells with a minor population being astrocytes. To allow for long-term fate mapping of FoxJ1-derived cells, we used the piggyBac system for in vivo gene transfer with electroporation. Using this method, we found that FoxJ1-expressing cells, presumably the astrocytes, give rise to neuroblasts and mature neurons in the olfactory bulb both in intact and stroke-damaged brain of adult rats. No significant contribution of FoxJ1-derived cells to stroke-induced striatal neurogenesis was detected. These data indicate that in the adult rat brain, FoxJ1 expressing cells contribute to the formation of new neurons in the olfactory bulb but are not involved in the cellular repair after stroke. PMID- 24075966 TI - Emergency cross-cover of surgical specialties: consensus recommendations by the Association of Surgeons in Training. AB - In recent years, working time restrictions and a restructuring of postgraduate surgical training have resulted in increased reliance on emergency cross-cover (ECC)--the provision of emergency care by a doctor trained or training in a different specialty to that which they are requested to assess or manage. There are increasing concerns surrounding the provision of ECC, particularly regarding appropriate supervision of trainees and in turn their competence, experience and confidence in dealing with surgical problems of outside their own specialty. Surgical training has failed to keep pace with workforce changes and in this document we outline the key principles of providing safe ECC. In particular this includes the medico-legal implications of providing such cover outside a surgical trainee's normal area of practice, particularly without previous experience or means for regular skills practice and up-dating. We report the findings of an ASiT snapshot survey that demonstrates concerns surrounding existing cross-cover arrangements. Variable access to senior support, together with varied willingness to provide this, and a paucity of specific training opportunities for trainees required to provide cross-cover were highlighted. These have the potential to promote variability in patient care and resource use by those providing care outside of their usual specialty. This document provides consensus recommendations to address these issues, including clarification of curricula and improved provision of training for, and supervision of, trainees who are expected to deliver cross-cover. PMID- 24075967 TI - Developing future surgical workforce structures: a review of post-training non Consultant grade specialist roles and the results of a national trainee survey from the Association of Surgeons in Training. AB - The optimal workforce model for surgery has been much debated historically; in particular, whether there should be a recognised role for those successfully completing training employed as non-Consultant grade specialists. This role has been termed the 'sub-consultant' grade. This paper discusses historical and future career structures in surgery, draws international comparisons, and presents the results of a national trainee survey examining the post-Certificate of Completion of Training (CCT) non-consultant specialist grade. Junior doctors in surgical training (i.e. pre-CCT) were invited to participate in an electronic, 38-item, self-administered national training survey. Of 1710 questionnaires submitted, 1365 were appropriately completed and included in the analysis. Regarding the question 'Do you feel that there is a role in the surgical workforce for a post-CCT non-consultant specialist ("sub-consultant") grade in surgery?', 56.0% felt there was no role, 31.1% felt there was a role and 12.8% were uncertain. Only 12.6% of respondents would consider applying for such a post, while 72.4% would not and 15.0% were uncertain. Paediatric (23.3%), general (15.7%) and neurosurgery (11.6%) were the specialties with the highest proportions of trainees prepared to consider applying for such a role. For both questions, there was a significant gender difference in responses (p < 0.0001, Chi-square test) with female trainees more likely to consider applying. Overall 50.8% of respondents felt that the introduction of a post-CCT non-consultant specialist grade would impact positively upon service provision, however, only 21.6% felt it would have a positive impact on patient care, 13.9% a positive impact on surgical training, 11.1% a positive impact on the surgical profession and just 7.9% a positive impact on their surgical career. This survey indicates that the introduction of a 'sub-consultant' grade for surgeons who have completed training would be unpopular, with the majority believing it would be to the detriment of both patient care and surgical training. Changes to surgical career structures must be made in the interests of patient safety and quality, and on this basis ASiT supports the continued provision of primarily Consultant delivered care. PMID- 24075968 TI - Siloxanes removal from biogas by high surface area adsorbents. AB - Biogas utilized for energy production needs to be free from organic silicon compounds, as their burning has damaging effects on turbines and engines; organic silicon compounds in the form of siloxanes can be found in biogas produced from urban wastes, due to their massive industrial use in synthetic product, such as cosmetics, detergents and paints. Siloxanes removal from biogas can be carried out by various methods (Mona, 2009; Ajhar et al., 2010 May; Schweigkofler and Niessner, 2001); aim of the present work is to find a single practical and economic way to drastically and simultaneously reduce both the hydrogen sulphide and the siloxanes concentration to less than 1 ppm. Some commercial activated carbons previously selected (Monteleone et al., 2011) as being effective in hydrogen sulfide up taking have been tested in an adsorption measurement apparatus, by flowing the most volatile siloxane (hexamethyldisiloxane or L2) in a nitrogen stream, typically 100-200 ppm L2 over N2, through an activated carbon powder bed; the adsorption process was analyzed by varying some experimental parameters (concentration, grain size, bed height). The best activated carbon shows an adsorption capacity of 0.1g L2 per gram of carbon. The next thermogravimetric analysis (TGA) confirms the capacity data obtained experimentally by the breakthrough curve tests. The capacity results depend on L2 concentration. A regenerative carbon process is then carried out by heating the carbon bed up to 200 degrees C and flushing out the adsorbed L2 samples in a nitrogen stream in a three step heating procedure up to 200 degrees C. The adsorption capacity is observed to degrade after cycling the samples through several adsorption-desorption cycles. PMID- 24075969 TI - Expedient synthesis of 17alpha,21-dihydroxy-9beta,11beta-epoxy-16alpha methylpregna-1,4-diene-3,20-dione 21-acetate from prednisolone utilising a novel Mattox rearrangement. AB - A six step transformation of prednisolone to 17alpha,21-dihydroxy-9beta,11beta epoxy-16alpha-amethylpregna-1,4-diene-3,20-dione 21-acetate has been achieved in 13% unoptimised yield. Novel conditions for effecting a Mattox rearrangement and double dehydration of prednisolone were identified. Enhanced knowledge on the oxidation of silyl Delta(19,20)-enol ethers and structural factors that impact the success of the oxidation are also presented. PMID- 24075970 TI - Catalytic cycloalumination in steroid chemistry II: selective functionalization of 2'-methylidene-2',3'-ethano-(5alpha)-cholestane. AB - The catalytic cycloalumination of 2'-methylidene-2',3'-ethano-(5alpha)-cholestane with Et3Al catalyzed by Cp2ZrCl2 was performed for the first time to give spiro[2',3'-ethano-(5alpha)-cholestane-2',3"-aluminacyclopentane] in a ~75% yield and with high stereoselectivity (>98%). The obtained cyclic organoaluminum compound was transformed in situ into heterocyclic spiran derivatives of 2',3' ethano-(5alpha)-cholestane. PMID- 24075971 TI - Is the full potential of the biopharmaceutics classification system reached? AB - In this paper we analyse how the biopharmaceutics classification system (BCS) has been used to date. A survey of the literature resulted in a compilation of 242 compounds for which BCS classes were reported. Of these, 183 compounds had been reported to belong to one specific BCS class whereas 59 compounds had been assigned to multiple BCS classes in different papers. Interestingly, a majority of the BCS class 2 compounds had fraction absorbed (FA) values >85%, indicating that they were completely absorbed after oral administration. Solubility was computationally predicted at pH 6.8 for BCS class 2 compounds to explore the impact of the pH of the small intestine, where most of the absorption occurs, on the solubility. In addition, the solubilization capacity of lipid aggregates naturally present in the intestine was studied computationally and experimentally for a subset of 12 compounds. It was found that all acidic compounds with FA>85% were completely dissolved in the pH of the small intestine. Further, lipids at the concentration used in fasted state simulated intestinal fluid (FaSSIF) dissolved the complete dose given of the most lipophilic (logD6.5>3) compounds studied. Overall, biorelevant dissolution media (pure buffer of intestinal pH or FaSSIF) identified that for 20 of the 29 BCS class 2 compounds with FA>85% the complete dose given orally would be dissolved. These results indicate that a more relevant pH restriction for acids and/or dissolution medium with lipids present better forecast solubility-limited absorption in vivo than the presently used BCS solubility criterion. The analysis presented herein further strengthens the discussion on the requirement of more physiologically relevant dissolution media for the in vitro solubility classification performed to reach the full potential of the BCS. PMID- 24075972 TI - N-Acetylglucosamine-conjugated block copolymer consisting of poly(ethylene oxide) and cationic polyaspartamide as a gene carrier for targeting vimentin-expressing cells. AB - Gene therapy is not successful due to lack of safe gene delivery vector, low transfection efficiency and inability to target the particular cells. Here, we synthesized a biocompatible block copolymer (abbreviated as PASPG) which consists of cationic poly[(aspartamide)(spermine)] for complexation with DNA and enhancing transfection efficiency due to buffering ability of spermine, poly(ethylene oxide)(PEO) for stability after systemic administration of the gene and N acetylglucosamine (GlcNAc) as a specific ligand to target vimentin-expressing cells. Primarily, PASPG showed efficient complexation with DNA. Cell viability assay demonstrated that PASPG had low toxicity compared to polyethylenimine 25K. Furthermore, PASPG showed higher transfection efficiency in vimentin-expressing cells than vimentin-deficient ones due to the recognition of GlcNAc in the polymeric gene carrier by vimentin in the cells for the receptor-mediated endocytosis of PASPG. Favorably, the serum had no effect on transfection efficiency of PASPG due to the presence of hydrophilic PEO in the block copolymer. This study reveals that GlcNAc-coupled biocompatible block copolymer can specifically deliver gene to vimentin-expressing cells. PMID- 24075973 TI - Differential effect of viral overexpression of nucleus accumbens shell 5-HT1B receptors on stress- and cocaine priming-induced reinstatement of cocaine seeking. AB - 5-HT1B receptors are densely expressed on terminals of medium spiny neurons projecting from the nucleus accumbens shell (NAccSh) to the ventral tegmental area, where 5-HT1B receptors modulate GABA release directly, and firing of dopaminergic neurons indirectly. While interactions between NAccSh 5-HT1B receptors and stress have been reported in early stages of psychostimulant induced neuroadaptations, specifically psychomotor sensitization, the effect of this interaction on later stages of drug seeking is currently unknown. Here, we examined the effect of herpes simplex virus (HSV)-mediated overexpression of NAccSh 5-HT1B receptors on reinstatement of cocaine seeking induced by exposure to stress or a cocaine prime. Rats were trained to self-administer cocaine (0.75 mg/kg/infusion) and the operant response was extinguished. Rats were then injected with viral vector expressing 5-HT1B and green fluorescent protein (GFP) or GFP alone into the NAccSh. The effect of 5-HT1B receptor overexpression was assessed on reinstatement induced by intermittent footshock (0.5 mA for 15 min) or a cocaine prime (10mg/kg, ip). Results indicate that NAccSh 5-HT1B receptor overexpression had no effect on footshock reinstatement while significantly decreasing cocaine priming-induced reinstatement. We also found that NAccSh overexpression of 5-HT1B receptors had no effect on saccharin intake following social defeat stress. These results suggest that the efficacy of pharmacological agents targeting 5-HT1B receptors for the treatment of cocaine relapse will depend largely on the nature of the reinstating stimulus. Taken together with previous results, it appears that NAccSh 5-HT1B receptors influence stress responses in early, but not in the later stages of psychostimulant-induced neuroadaptations. PMID- 24075974 TI - Oral administration of GZ-793A, a VMAT2 inhibitor, decreases methamphetamine self administration in rats. AB - Despite the high prevalence of use of methamphetamine (METH), there is no FDA approved pharmacological treatment available currently for METH addiction. The vesicular monoamine transporter (VMAT2) has been proposed as a novel target to treat METH abuse. GZ-793A, a lobelane analog and selective VMAT2 inhibitor, has been shown previously to decrease METH self-administration specifically when administered via the subcutaneous route in rats. Since oral administration is the preferred clinical route, the present experiments determined if oral administration of GZ-793A would decrease specifically METH self-administration. Experiments 1 and 2 assessed the dose-effect functions of oral administration of GZ-793A (30-240 mg/kg) on intravenous METH self-administration and food maintained responding, respectively. Experiments 3 and 4 assessed the time-course (20-180 min pretreatment) of oral administration of GZ-793A on METH self administration and food-maintained responding, respectively. Oral administration of GZ-793A dose-dependently decreased METH self-administration, with the highest dose (240 mg/kg) producing an 85% decrease compared to control baseline. The decrease in METH self-administration produced by GZ-793A (120 mg/kg) lasted at least 180 min. In contrast, GZ-793A failed to alter food-maintained responding at any of the doses or pretreatment intervals tested. The oral effectiveness and the specificity of GZ-793A to decrease methamphetamine self-administration support the feasibility of developing VMAT2 inhibitors as treatments for METH abuse. PMID- 24075975 TI - Biogenesis and transport of membrane domains-potential implications in brain pathologies. AB - Lipids in biological membranes show astonishing chemical diversity, but they also show some key conserved structures in different organisms. In addition, some of their biophysical properties have been related to specific functions. In this review, we aim to discuss the role of sphingolipids- and cholesterol-rich micro- and nano-membrane domains (MD) and highlight their pivotal role in lipid-protein clustering processes, vesicle biogenesis and membrane fusion. We further review potential connections between human pathologies and defects in MD biosynthesis, recycling and homeostasis. Brain, which is second only to the adipose tissues in term of lipid abundance, is particularly affected by MD defects which are linked to neurodegenerative disorders. Finally we propose a potential connection between MD and several nutrient-related processes and envision how diet and autophagy could bring insights towards understanding the impact of global lipid homeostasis on human health and disease. PMID- 24075976 TI - Hippocampal protein kinase C family members in spatial memory retrieval in the mouse. AB - Although a few individual members of the protein kinase C (PKC) family were studied in spatial memory no systematic approach was carried out to concomitantly determine all described PKC family members in spatial memory of the mouse. It was therefore the aim of the current study to link hippocampal PKCs to memory retrieval in the Morris water maze (MWM). CD1 mice were trained (n=9) or untrained (n=9) in the MWM, hippocampi were taken 6h following the test for memory retrieval and PKCs were determined in mouse hippocampi by immunoblotting. The trained animals learned the spatial memory task and kept memory at the probe trial. PKCs alpha and epsilon were comparable between groups while PKCs beta, delta, gamma (two forms, i.e. two bands on Western blotting), zeta (2 forms) were higher in trained mice and theta (2 forms) were lower in trained mice. PKC gamma (1 form) was significantly correlating with the time spent in the target quadrant (r=0.7933; P=0.0188). Changes of hippocampal levels of PKCs beta, delta, gamma, zeta and theta were paralleling memory retrieval of the MWM task but correlations revealed that spatial memory retrieval was only linked to one form of PKC gamma. Results are also in agreement with a recent publication showing that PKM zeta is not required for memory formation. These findings may be relevant for the interpretation of previous work and the design of future work on the protein kinase C family in spatial memory of the mouse. PMID- 24075977 TI - The basal ganglia is necessary for learning spectral, but not temporal, features of birdsong. AB - Executing a motor skill requires the brain to control which muscles to activate at what times. How these aspects of control-motor implementation and timing-are acquired, and whether the learning processes underlying them differ, is not well understood. To address this, we used a reinforcement learning paradigm to independently manipulate both spectral and temporal features of birdsong, a complex learned motor sequence, while recording and perturbing activity in underlying circuits. Our results uncovered a striking dissociation in how neural circuits underlie learning in the two domains. The basal ganglia was required for modifying spectral, but not temporal, structure. This functional dissociation extended to the descending motor pathway, where recordings from a premotor cortex analog nucleus reflected changes to temporal, but not spectral, structure. Our results reveal a strategy in which the nervous system employs different and largely independent circuits to learn distinct aspects of a motor skill. PMID- 24075979 TI - An example of how to handle amorphous fractions in API during early pharmaceutical development: SAR114137--a successful approach. AB - The so-called pharmaceutical solid chain, which encompasses drug substance micronisation to the final tablet production, at pilot plant scale is presented as a case study for a novel, highly potent, pharmaceutical compound: SAR114137. Various solid-state analytical methods, such as solid-state Nuclear Magnetic Resonance (ssNMR), Differential Scanning Calorimetry (DSC), Dynamic Water Vapour Sorption Gravimetry (DWVSG), hot-stage Raman spectroscopy and X-ray Powder Diffraction (XRPD) were applied and evaluated to characterise and quantify amorphous content during the course of the physical treatment of crystalline active pharmaceutical ingredient (API). DSC was successfully used to monitor the changes in amorphous content during micronisation of the API, as well as during stability studies. (19)F solid-state NMR was found to be the method of choice for the detection and quantification of low levels of amorphous API, even in the final drug product (DP), since compaction during tablet manufacture was identified as a further source for the formation of amorphous API. The application of different jet milling techniques was a critical factor with respect to amorphous content formation. In the present case, the change from spiral jet milling to loop jet milling led to a decrease in amorphous API content from 20-30 w/w% to nearly 0 w/w% respectively. The use of loop jet milling also improved the processability of the API. Stability investigations on both the milled API and the DP showed a marked tendency for recrystallisation of the amorphous API content on exposure to elevated levels of relative humidity. No significant impact of amorphous API on either the chemical stability or the dissolution rate of the API in drug formulation was observed. Therefore, the presence of amorphous content in the oral formulation was of no consequence for the clinical trial phases I and II. PMID- 24075978 TI - Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. AB - Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy. PMID- 24075980 TI - Preparation of an amorphous sodium furosemide salt improves solubility and dissolution rate and leads to a faster Tmax after oral dosing to rats. AB - Amorphous forms of furosemide sodium salt and furosemide free acid were prepared by spray drying. For the preparation of the amorphous free acid, methanol was utilised as the solvent, whereas the amorphous sodium salt was formed from a sodium hydroxide-containing aqueous solvent in equimolar amounts of NaOH and furosemide. Information about the structural differences between the two amorphous forms was obtained by Fourier Transform Infrared Spectroscopy (FTIR), and glass transition temperature (Tg) was determined using Differential Scanning Calorimetry (DSC). The stability and devitrification tendency of the two amorphous forms were investigated by X-ray Powder Diffraction (XRPD). The apparent solubility of the two amorphous forms and the crystalline free acid form of furosemide in various gastric and intestinal stimulated media was determined. Moreover, the dissolution characteristics of the two amorphous forms and of crystalline free acid were investigated. FTIR confirmed molecular differences between the amorphous free acid and salt. The amorphous salt showed a Tg of 101.2 degrees C, whereas the Tg for the amorphous free acid was found to be 61.8 degrees C. The amorphous free acid was physically stable for 4 days at 22 degrees C and 33% relative humidity (RH), while the amorphous salt exhibited physical stability for 291 days at the same storage conditions. When storing the amorphous forms at 40 degrees C and 75% RH both forms converted to crystalline forms after 2 days. The apparent solubility of the amorphous salt form was higher than that of both amorphous and crystalline free acid in all media studied. All three forms of furosemide exhibited a greater solubility in the presence of biorelevant media as compared to buffer, however, an overall trend for a further increase in solubility in relation to an increase in media surfactant concentration was not seen. The amorphous salt demonstrated an 8- and 20-fold higher intrinsic dissolution rate (IDR) when compared to amorphous and crystalline free acid, respectively. The promising properties of the amorphous salt in vitro were further evaluated in an in vivo study, where solid dosage forms of the amorphous salt, amorphous and crystalline free acid and a solution of furosemide were administered orally to rats. The amorphous salt exhibited a significantly faster Tmax compared to the solution and amorphous and crystalline free acid. Cmax for the solution was significantly higher compared to the three furosemide forms. No significant difference was found in AUC and absolute bioavailability for the solution, crystalline free acid and the two amorphous forms of furosemide. It can be concluded that the higher IDR and higher apparent solubility of the amorphous salt resulted in a faster Tmax compared to the amorphous and crystalline free acid. PMID- 24075981 TI - Quantitative proteomic investigation employing stable isotope labeling by peptide dimethylation on proteins of strawberry fruit at different ripening stages. AB - A quantitative proteomic investigation of strawberry fruit ripening employing stable isotope labeling by peptide dimethylation was conducted on 'Mira' and 'Honeoye' strawberry fruit. Postharvest physiological quality indices, including volatile production, total phenolics, total anthocyanins, antioxidant capacity, soluble solids and titratable acidity, were also characterized in white, pink and red fruit. More than 892 and 848 proteins were identified and quantified in the 'Mira' and 'Honeoye' fruit, respectively, using at least two peptides for each protein identification. Using the normalized ratio of protein abundance changes, proteins that changed two-fold or more were identified as proteins that are up- or down-regulated during fruit ripening. Among the quantified proteins, 111 proteins were common to both cultivars and represented five significant clusters based on quantitative changes. Among the up-regulated proteins were proteins involved in metabolic pathways including flavonoid/anthocyanin biosynthesis, volatile biosynthesis, antioxidant metabolism, stress responses and allergen formation. Proteins that decreased during fruit ripening were found to be responsible for methionine metabolism, antioxidant-redox, energy metabolism and protein synthesis. Our results show that strawberry ripening is a highly complex system involving multi-physiological processes made possible through changes in protein expression. This study provides new insights on the regulation of proteins during strawberry fruit ripening that lay the foundation for further targeted studies. BIOLOGICAL SIGNIFICANCE: Research on the postharvest physiology and biochemistry of strawberry fruit as a model of non-climacteric fruit ripening has been conducted for many years. However, the mechanism(s) for the initiation and metabolic regulation of non-climacteric fruit ripening remains unknown. Little information on strawberry fruit ripening is available at the proteome level. This paper is the first report of a quantitative proteomic investigation of strawberry fruit ripening employing stable isotope labeling by peptide dimethylation. Postharvest physiological quality indices, including volatile production, total phenolics, total anthocyanins, antioxidant capacity, soluble solids and titratable acidity, were also characterized in ripening fruit. Significant biological changes associated with ripening were revealed and proteins that change significantly under these conditions were identified. Therefore, our study links the biological events of strawberry fruit ripening with proteomic information and provides insights into possible mechanisms of regulation. Proteins that changed during ripening were analyzed through function analysis, which provides new insights into metabolic changes occurring during ripening. Findings from this paper not only provide proteome information on fruit ripening, but also pave the way for further quantitative studies using SMR to investigate certain proteins and pathways involved in fruit ripening. PMID- 24075982 TI - Cryptic diversity and population genetic structure in the rare, endemic, forest obligate, slender geckos of the Philippines. AB - Recent studies of forest lizards in Southeast Asia have highlighted spectacular morphological and cryptic genetic diversity in several poorly known clades. Unfortunately, many of the included species have microhabitat preferences for forested environments, and therefore they are threatened by extensive forest destruction throughout the region. This is particularly true in the Philippines, an archipelago with a strikingly high proportion (84%) of endemic geckos. Abundances inferred from historical museum collections suggests that we are in a critical period where apparent declines in population viability and species' abundance have taken place faster than the growth in our understanding of alpha diversity. This phenomenon is exemplified in the exceedingly rare Philippine slender forest geckos of the genus Pseudogekko. Most of the known species are rarely encountered by field biologists, and species boundaries are unclear; this poor state of knowledge impedes effective conservation measures. Using the first multilocus phylogeny for these taxa, and phylogenetic and population genetic approaches, we elucidate evolutionary lineages and delimit species-level conservation targets in this unique radiation of endemic Philippine geckos. The results support the presence of widespread cryptic diversity in the genus, providing a framework for the re-evaluation of conservation priorities aimed at protecting these rare, forest-obligate species. PMID- 24075983 TI - Further insights into the phylogeny of two ciliate classes Nassophorea and Prostomatea (Protista, Ciliophora). AB - The Nassophorea and Prostomatea are two of the key classes in understanding the morphological diversification and higher classification of the phylum Ciliophora. However, their phylogenetic relationships with other ciliate groups within the subphylum Intramacronucleata remain elusive. In this study, we investigated the small and large subunit (SSU and LSU) rRNA gene-based phylogeny of these groups with sequences of additional taxa including several key species. The results show that: (1) the class Nassophorea remains polyphyletic, with the microthoracids clustering with the Phyllopharyngea, whereas the nassulids represent a basal group of the CONthreeP superclade in the SSU tree; (2) the Prostomatea is not depicted as a monophyletic group in phylogenetic trees, and the monophyly of this class is marginally rejected by statistical tree topology tests; (3) the nassulid genus Parafurgasonia is more closely related to the family Colpodidiidae than to Furgasonia; (4) Paranassula, which was previously thought to be a nassulid, is phylogenetically related to the oligohymenophorean peniculids in both the SSU and LSU trees; (5) the microthoracid genus Discotricha does not group with the other microthoracids in either SSU or LSU trees; (6) the family Plagiocampidae is closely related to the prostome parasite Cryptocaryon irritans and to the family Urotrichidae in the order Prorodontida; and (7) the family Placidae, represented by Placus salinus, is sister to the family Holophryidae in the order Prorodontida. Based on the present data, we consider the genus Discotricha to be an unclassified taxon within the CONthreeP. We also propose resurrecting the order Paranassulida and classifying it within the subclass Peniculia, class Oligohymenophorea. Primary and secondary structure signatures for higher taxa within Phyllopharyngea and Nassophorea are supplied. PMID- 24075984 TI - Evolution of glucose utilization: glucokinase and glucokinase regulator protein. AB - Glucose is an essential nutrient that must be distributed throughout the body to provide energy to sustain physiological functions. Glucose is delivered to distant tissues via be blood stream, and complex systems have evolved to maintain the levels of glucose within a narrow physiological range. Phosphorylation of glucose, by glucokinase, is an essential component of glucose homeostasis, both from the regulatory and metabolic point-of-view. Here we review the evolution of glucose utilization from the perspective of glucokinase. We discuss the origin of glucokinase, its evolution within the hexokinase gene family, and the evolution of its interacting regulatory partner, glucokinase regulatory protein (GCKR). Evolution of the structure and sequence of both glucokinase and GCKR have been necessary to optimize glucokinase in its role in glucose metabolism. PMID- 24075985 TI - A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses. AB - Lysine63-linked ubiquitin (K63-Ub) chains represent a particular ubiquitin topology that mediates proteasome-independent signaling events. The deubiquitinating enzyme (DUB) BRCC36 segregates into distinct nuclear and cytoplasmic complexes that are specific for K63-Ub hydrolysis. RAP80 targets the five-member nuclear BRCC36 complex to K63-Ub chains at DNA double-strand breaks. The alternative four-member BRCC36 containing complex (BRISC) lacks a known targeting moiety. Here, we identify serine hydroxymethyltransferase (SHMT) as a previously unappreciated component that fulfills this function. SHMT directs BRISC activity at K63-Ub chains conjugated to the type 1 interferon (IFN) receptor chain 1 (IFNAR1). BRISC-SHMT2 complexes localize to and deubiquitinate actively engaged IFNAR1, thus limiting its K63-Ub-mediated internalization and lysosomal degradation. BRISC-deficient cells and mice exhibit attenuated responses to IFN and are protected from IFN-associated immunopathology. These studies reveal a mechanism of DUB regulation and suggest a therapeutic use of BRISC inhibitors for treating pathophysiological processes driven by elevated IFN responses. PMID- 24075987 TI - The peroxisomal enzyme L-PBE is required to prevent the dietary toxicity of medium-chain fatty acids. AB - Specific metabolic pathways are activated by different nutrients to adapt the organism to available resources. Although essential, these mechanisms are incompletely defined. Here, we report that medium-chain fatty acids contained in coconut oil, a major source of dietary fat, induce the liver omega-oxidation genes Cyp4a10 and Cyp4a14 to increase the production of dicarboxylic fatty acids. Furthermore, these activate all omega- and beta-oxidation pathways through peroxisome proliferator activated receptor (PPAR) alpha and PPARgamma, an activation loop normally kept under control by dicarboxylic fatty acid degradation by the peroxisomal enzyme L-PBE. Indeed, L-pbe(-/-) mice fed coconut oil overaccumulate dicarboxylic fatty acids, which activate all fatty acid oxidation pathways and lead to liver inflammation, fibrosis, and death. Thus, the correct homeostasis of dicarboxylic fatty acids is a means to regulate the efficient utilization of ingested medium-chain fatty acids, and its deregulation exemplifies the intricate relationship between impaired metabolism and inflammation. PMID- 24075986 TI - Alternative spliceosome assembly pathways revealed by single-molecule fluorescence microscopy. AB - Removal of introns from nascent transcripts (pre-mRNAs) by the spliceosome is an essential step in eukaryotic gene expression. Previous studies have suggested that the earliest steps in spliceosome assembly in yeast are highly ordered and the stable recruitment of U1 small nuclear ribonucleoprotein particle (snRNP) to the 5' splice site necessarily precedes recruitment of U2 snRNP to the branch site to form the "prespliceosome." Here, using colocalization single-molecule spectroscopy to follow initial spliceosome assembly on eight different S. cerevisiae pre-mRNAs, we demonstrate that active yeast spliceosomes can form by both U1-first and U2-first pathways. Both assembly pathways yield prespliceosomes functionally equivalent for subsequent U5.U4/U6 tri-snRNP recruitment and for intron excision. Although fractional flux through the two pathways varies on different introns, both are operational on all introns studied. Thus, multiple pathways exist for assembling functional spliceosomes. These observations provide insight into the mechanisms of cross-intron coordination of initial spliceosome assembly. PMID- 24075988 TI - Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve. AB - Schwann cells are highly plastic cells that dedifferentiate to a progenitor-like state following injury. However, deregulation of this plasticity, may be involved in the formation of neurofibromas, mixed-cell tumors of Schwann cell (SC) origin that arise upon loss of NF1. Here, we show that adult myelinating SCs (mSCs) are refractory to Nf1 loss. However, in the context of injury, Nf1-deficient cells display opposing behaviors along the wounded nerve; distal to the injury, Nf1(-/ ) mSCs redifferentiate normally, whereas at the wound site Nf1(-/-) mSCs give rise to neurofibromas in both Nf1(+/+) and Nf1(+/-) backgrounds. Tracing experiments showed that distinct cell types within the tumor derive from Nf1 deficient SCs. This model of neurofibroma formation demonstrates that neurofibromas can originate from adult SCs and that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury. These findings have implications for both the characterization and treatment of neurofibromas. PMID- 24075989 TI - Signaling network assessment of mutations and copy number variations predict breast cancer subtype-specific drug targets. AB - Individual cancer cells carry a bewildering number of distinct genomic alterations (e.g., copy number variations and mutations), making it a challenge to uncover genomic-driven mechanisms governing tumorigenesis. Here, we performed exome sequencing on several breast cancer cell lines that represent two subtypes, luminal and basal. We integrated these sequencing data and functional RNAi screening data (for the identification of genes that are essential for cell proliferation and survival) onto a human signaling network. Two subtype-specific networks that potentially represent core-signaling mechanisms underlying tumorigenesis were identified. Within both networks, we found that genes were differentially affected in different cell lines; i.e., in some cell lines a gene was identified through RNAi screening, whereas in others it was genomically altered. Interestingly, we found that highly connected network genes could be used to correctly classify breast tumors into subtypes on the basis of genomic alterations. Further, the networks effectively predicted subtype-specific drug targets, which were experimentally validated. PMID- 24075990 TI - Multiple enhancers regulate Hoxd genes and the Hotdog LncRNA during cecum budding. AB - Hox genes are required for the development of the intestinal cecum, a major organ of plant-eating species. We have analyzed the transcriptional regulation of Hoxd genes in cecal buds and show that they are controlled by a series of enhancers located in a gene desert flanking the HoxD cluster. The start site of two opposite long noncoding RNAs (lncRNAs), Hotdog and Twin of Hotdog, selectively contacts the expressed Hoxd genes in the framework of a topological domain, coinciding with robust transcription of these genes during cecum budding. Both lncRNAs are specifically transcribed in the cecum, albeit bearing no detectable function in trans. Hedgehogs have kept this regulatory potential despite the absence of the cecum, suggesting that these mechanisms are used in other developmental situations. In this context, we discuss the implementation of a common "budding toolkit" between the cecum and the limbs. PMID- 24075991 TI - An Iml3-Chl4 heterodimer links the core centromere to factors required for accurate chromosome segregation. AB - Accurate segregation of genetic material in eukaryotes relies on the kinetochore, a multiprotein complex that connects centromeric DNA with microtubules. In yeast and humans, two proteins-Mif2/CENP-C and Chl4/CNEP-N-interact with specialized centromeric nucleosomes and establish distinct but cross-connecting axes of chromatin-microtubule linkage. Proteins recruited by Chl4/CENP-N include a subset that regulates chromosome transmission fidelity. We show that Chl4 and a conserved member of this subset, Iml3, both from Saccharomyces cerevisiae, form a stable protein complex that interacts with Mif2 and Sgo1. We have determined the structures of an Iml3 homodimer and an Iml3-Chl4 heterodimer, which suggest a mechanism for regulating the assembly of this functional axis of the kinetochore. We propose that at the core centromere, the Chl4-Iml3 complex participates in recruiting factors, such as Sgo1, that influence sister chromatid cohesion and encourage sister kinetochore biorientation. PMID- 24075992 TI - Dendritic glutamate receptor mRNAs show contingent local hotspot-dependent translational dynamics. AB - Protein synthesis in neuronal dendrites underlies long-term memory formation in the brain. Local translation of reporter mRNAs has demonstrated translation in dendrites at focal points called translational hotspots. Various reports have shown that hundreds to thousands of mRNAs are localized to dendrites, yet the dynamics of translation of multiple dendritic mRNAs has remained elusive. Here, we show that the protein translational activities of two dendritically localized mRNAs are spatiotemporally complex but constrained by the translational hotspots in which they are colocalized. Cotransfection of glutamate receptor 2 (GluR2) and GluR4 mRNAs (engineered to encode different fluorescent proteins) into rat hippocampal neurons demonstrates a heterogeneous distribution of translational hotspots for the two mRNAs along dendrites. Stimulation with s-3,5-dihydroxy phenylglycine modifies the translational dynamics of both of these RNAs in a complex saturable manner. These results suggest that the translational hotspot is a primary structural regulator of the simultaneous yet differential translation of multiple mRNAs in the neuronal dendrite. PMID- 24075993 TI - The deubiquitinase USP28 stabilizes LSD1 and confers stem-cell-like traits to breast cancer cells. AB - LSD1 is a critical chromatin modulator that controls cellular pluripotency and differentiation through the demethylation of H3K4me1/2. Overexpression of LSD1 has been observed in many types of tumors and is correlated with its oncogenic effects in tumorigenesis. However, the mechanism leading to LSD1 upregulation in tumors remains unclear. Using an unbiased siRNA screening against all the human deubiquitinases, we identified USP28 as a bona fide deubiquitinase of LSD1. USP28 interacted with and stabilized LSD1 via deubiquitination. USP28 overexpression correlated with LSD1 upregulation in multiple cancer cell lines and breast tumor samples. Knockdown of USP28 resulted in LSD1 destabilization, leading to the suppression of cancer stem cell (CSC)-like characteristics in vitro and inhibition of tumorigenicity in vivo, which can be rescued by ectopic LSD1 expression. Our study reveals a critical mechanism underlying the epigenetic regulation by USP28 and provides another treatment approach against breast cancer. PMID- 24075995 TI - Targeted disruption of Hotair leads to homeotic transformation and gene derepression. AB - Long noncoding RNAs (lncRNAs) are thought to be prevalent regulators of gene expression, but the consequences of lncRNA inactivation in vivo are mostly unknown. Here, we show that targeted deletion of mouse Hotair lncRNA leads to derepression of hundreds of genes, resulting in homeotic transformation of the spine and malformation of metacarpal-carpal bones. RNA sequencing and conditional inactivation reveal an ongoing requirement of Hotair to repress HoxD genes and several imprinted loci such as Dlk1-Meg3 and Igf2-H19 without affecting imprinting choice. Hotair binds to both Polycomb repressive complex 2, which methylates histone H3 at lysine 27 (H3K27), and Lsd1 complex, which demethylates histone H3 at lysine 4 (H3K4) in vivo. Hotair inactivation causes H3K4me3 gain and, to a lesser extent, H3K27me3 loss at target genes. These results reveal the function and mechanisms of Hotair lncRNA in enforcing a silent chromatin state at Hox and additional genes. PMID- 24075994 TI - Circadian and circalunar clock interactions in a marine annelid. AB - Life is controlled by multiple rhythms. Although the interaction of the daily (circadian) clock with environmental stimuli, such as light, is well documented, its relationship to endogenous clocks with other periods is little understood. We establish that the marine worm Platynereis dumerilii possesses endogenous circadian and circalunar (monthly) clocks and characterize their interactions. The RNAs of likely core circadian oscillator genes localize to a distinct nucleus of the worm's forebrain. The worm's forebrain also harbors a circalunar clock entrained by nocturnal light. This monthly clock regulates maturation and persists even when circadian clock oscillations are disrupted by the inhibition of casein kinase 1delta/epsilon. Both circadian and circalunar clocks converge on the regulation of transcript levels. Furthermore, the circalunar clock changes the period and power of circadian behavior, although the period length of the daily transcriptional oscillations remains unaltered. We conclude that a second endogenous noncircadian clock can influence circadian clock function. PMID- 24075996 TI - Cloning, characterization and expression analysis of a caspase-8 like gene from the Hong Kong oyster, Crassostrea hongkongensis. AB - Apoptosis plays a key role in many biological processes, including homeostasis within the immune system. A family of cysteine proteases, the caspases, constitutes the core of the apoptotic machinery. We have characterized the first bivalve caspase-8 ortholog from the Hong Kong oyster Crassostrea hongkongensis (designated ChCaspase-8). The full-length cDNA is 1945 bp in length encoding a putative protein of 557 amino acids that contains two N-terminal DED domains, and a CASc domain at the C-terminus. ChCaspase-8 is ubiquitously expressed in oysters, with highest expression levels in the gonad and labial palps. Following microbial infection, the expression of ChCaspase-8 increased in hemocytes from 12 to 72 h post-challenge. When expressed in HeLa cells, ChCaspase-8 is located in the cytoplasm, while over-expression of ChCaspase-8 in HEK293T cells activates the transcriptional activities of NF-kappaB. These results indicate that ChCaspase-8 might play an important role in the immune and apoptotic responses of oysters. PMID- 24075997 TI - Laccase-like activity in the hemolymph of Venerupis philippinarum: characterization and kinetic properties. AB - The phenoloxidases (POs) include tyrosinases (EC 1.14.18.1), catecholases (EC 1.10.3.1) and laccases (EC 1.10.3.2) and are known to play a role in the immune defences of many invertebrates. For the Manila clam, Venerupis philippinarum, the exact role is not known, especially with regard to defences against Brown Ring Disease (BRD), which leads to high mortalities along European coasts. In order to understand the role and functioning of PO in V. philippinarum, the first step, and aim of this study, was to biochemically characterize the PO activity in the circulating hemolymph. Various substrates were tested and the common PO substrates L-DOPA, Catechol and dopamine exhibited good affinity with the enzyme and consequent low K(m) values (3.75, 1.97, 4.91 mM, respectively). A single tyrosinase-specific substrate, PHPPA, was oxidized, but the affinity for it was low (K(m) = 47.33 mM). Three tested laccase-specific substrates were oxidized by V. philippinarum PO (PPD, OPD and hydroquinone) and affinity was higher than for PHPPA. The results obtained with the substrate were confirmed by the use of different inhibitors: CTAB, a laccase-specific inhibitor inhibited PO activity greatly but not completely, whereas 4-Hr, specific to catecholases and tyrosinases, inhibited PO activity to a lesser extent. The results lead us to conclude that V. philippinarum PO activity in the circulating hemolymph, is mainly a laccase-like activity but there is also a smaller-scale tyrosinase-like activity. The inhibition mechanisms were also determined using dose-response substrate concentration for an inhibitor concentration equal or close to the IC50. Optimal conditions for the enzyme activity were also determined using L DOPA as substrate, showing that its optimal temperature and pH are around 40 degrees C and 8.4 respectively. The enzyme is denatured for temperatures above 50 degrees C. PMID- 24075998 TI - Clinical and computed tomography-radiologic outcome after bony glenoid augmentation in recurrent anterior shoulder instability without significant glenoid bone loss. AB - BACKGROUND: The presence of a significant bony defect in anterior shoulder instability cases warrants glenoid reconstruction surgery typically by means of an autograft. Some surgeons use the same graft techniques even in the absence of a significant bony defect, thus augmenting the glenoid surface. The goal of this study is to investigate the clinical and computed tomography-radiologic outcome after glenoid augmentation surgery. METHODS: Between 2006 and 2011, 11 patients with recurrent anterior shoulder instability and glenoid bone loss of 5% or less were treated with an iliac crest autograft. Of the patients, 9 were available for follow-up at a mean of 34.6 months (range, 12 to 80 months), including apprehension testing, Western Ontario Shoulder Instability Index, Rowe score, Simple Shoulder Value, and 3-dimensional computed tomography examination. RESULTS: The mean Rowe score achieved was 85.0 points (range, 51 to 100 points); Simple Shoulder Value, 80.5 points (range, 30 to 100 points); and Western Ontario Shoulder Instability Index, 373.5 points (range, 61 to 878 points). Two patients reported a recurrence of instability, and one featured a positive apprehension test. The mean glenoid surface area was 96.5% (95% confidence interval [CI], 95.5% to 97.4%) preoperatively, increased after graft implantation to 119.5% (95% CI, 105.6% to 133.3%), and decreased to 102.8% (95% CI, 98.6% to 107.1%) at follow-up, concordant to an intact glenoid surface area. From preoperatively to follow-up, the mean increase in glenoid surface area was 6.4% (95% CI, 2.1% to 10.6%; P = .008); in concavity diameter, 2.0 mm (95% CI, -0.9 to 4.9 mm; P = .168); in concavity depth, 0.9 mm (95% CI, 0.3 to 1.5 mm; P = .005); and in concavity retroversion, 2.4 degrees (95% CI, -1.2 degrees to 6.1 degrees ; P = .178). CONCLUSION: Because of anatomic bony remodeling processes, glenoid augmentation surgery seems to be subject to extensive graft osteolysis and, consequently, unsatisfactory clinical outcome in terms of stability in some cases. PMID- 24075999 TI - Feasibility of an osteochondral allograft for biologic glenoid resurfacing. AB - BACKGROUND: Concerns regarding insufficient press fit and glenoid vault cortical blowout make glenoid osteochondral allografting uncommon. We used 3-dimensional computed tomography modeling to test glenoid osteochondral allografting feasibility. MATERIALS AND METHODS: Sixteen cadaveric shoulders without osteoarthritis underwent computed tomography scans to create 3-dimensional models. The diameter of circular center-based reaming reaching the medial endosteal surface at depths of 4, 6, and 8 mm and the clock face position of the most shallow points were calculated. Demographic factors associated with graft diameter were analyzed by step-wise multiple regressions. RESULTS: Shallower graft depths allowed larger graft diameters (P < .001). With a graft depth of 4 mm, 56% of glenoids allowed 20-mm-diameter grafts and 94% accommodated 16-mm grafts versus 31% and 75%, respectively, for a graft depth of 6 mm and 13% and 38%, respectively, for a graft depth of 8 mm. Increasing graft depth decreased graft glenoid coverage: mean coverage was 51.9% +/- 12.2%, 36.3% +/- 12.9%, and 23.8% +/- 14.2% for 4-, 6-, and 8-mm depths, respectively. The glenoid's most shallow point was between the 1:30 clock face position and 3-o'clock position in reference to a right shoulder in 69%, 75%, and 44% of glenoids for 4-, 6-, and 8 mm depths, respectively. Although female gender, patient height, and glenoid height and width were associated with graft diameter, multiple regression analysis showed that patient height was the only independent variable associated with accommodated graft diameter at depths of 4, 6, and 8 mm (P = .001, P = .001, and P = .003, respectively). CONCLUSION: Most glenoids support center-based grafts of 16 to 20 mm in diameter at a depth of 4 mm, covering an average of 51.9% of the glenoid. Accommodated graft size decreases as reaming depth increases. PMID- 24076000 TI - Reverse total shoulder arthroplasty for acute proximal humeral fracture: comparison to open reduction-internal fixation and hemiarthroplasty. AB - BACKGROUND: Significant controversy surrounds optimal treatment of displaced 4 part proximal humeral fractures. Reverse total shoulder arthroplasty (RTSA) has recently been proposed as an alternative to hemiarthroplasty (HA) and open reduction-internal fixation (ORIF). Several authors have questioned the additional implant cost for RTSA. The purpose of this study was to compare outcomes and cost of RTSA, HA, and ORIF. MATERIALS AND METHODS: We prospectively evaluated patients who underwent RTSA for displaced 3- and 4-part proximal humeral fractures and then retrospectively developed age- and sex-matched control groups with 3- and 4-part proximal humeral fractures who underwent HA and ORIF. Range of motion including active forward elevation and external rotation and time to achieve active forward elevation >90 degrees were recorded. American Shoulder and Elbow Surgeons (ASES), Short-Form 12-item (SF-12), and Simple Shoulder Test (SST) scores were recorded. In addition, treatment cost was assessed by Medicare data and implant list prices. RESULTS: This study enrolled 27 patients; 9 underwent RTSA, 9 HA, and 9 ORIF. Minimum follow-up was 1 year. No significant differences were seen in SST, ASES, or SF-12 scores. Significantly more patients achieved >90 degrees of active forward elevation after RTSA (P = .012). RTSA provided significant cost savings to Medicare compared with HA and ORIF (P = .002.) CONCLUSION: In this case-control study, RTSA appears to provide superior range of motion earlier and more predictably than HA and ORIF, with significant cost savings to Medicare. PMID- 24076001 TI - Feasibility of latissimus and teres major transfer to reconstruct irreparable subscapularis tendon tear: an anatomic study. AB - BACKGROUND: Several tendon transfers have been described to reconstruct irreparable subscapularis (SS) tears, but their outcomes are variable and unsatisfactory in the presence of anterior glenohumeral subluxation. We evaluated the anatomic feasibility of the latissimus dorsi (LD) or teres major (TM) muscle tendon transfer to reconstruct an irreparable SS tendon tear. MATERIALS AND METHODS: The dimensions of the LD and TM tendons and the distance between their insertion and the SS tendon insertion were determined In 20 cadaveric shoulders. Feasibility of the isolated LD and TM tendon transfer to 3 locations on the SS tendon insertion, transfer of the LD to the proximal half, TM to the lower half of the SS tendon, and combined transfer of the LD/TM tendon to the central aspect of the SS tendon was assessed. RESULTS: The LD and TM were an average length of 5.9 cm and 2.3 cm and an average width of 2.2 cm and 2.4 cm, respectively. The mean distances from the center of the LD and TM tendons insertion to the central aspect of the SS tendon insertion was 4.0 cm and 4.7 cm, respectively. All of the tendon transfers were feasible, and the risk of nerve compression was low, except for the combined tendon LD/TM transfer to the proximal third of the SS tendon. CONCLUSIONS: This study shows that transfer of the LD/TM to the lesser tuberosity to reconstruct an irreparable SS tear is feasible, with a low risk of nerve compression, with the exception of the combined LD/TM and more proximal TM tendon transfers. PMID- 24076002 TI - The AO Foundation and Orthopaedic Trauma Association (AO/OTA) scapula fracture classification system: focus on body involvement. AB - BACKGROUND: A comprehensive system has been developed by the AO Classification Advisory Group to allow in-depth classification of scapular fractures for clinical research and surgical decision making. This paper evaluates a detailed classification system of scapular body fractures to better address the need for clinical relevance. METHODS: Seven experienced shoulder and orthopaedic trauma specialist surgeons participated in a follow-up series of agreement studies to specify and to evaluate the involvement of the body in scapula fractures. The last evaluation was conducted on a consecutive collection of 120 scapula fractures. RESULTS: There was agreement in 82% of the 120 cases with an overall kappa of 0.75 when the surgeons identified body (B) fractures. Surgeons were in full agreement about involvement of the lateral inferior, medial, and superior borders in 72%, 51%, and 69% of the 101 cases identified with body involvement, respectively. The proportion of correctly classified cases with lateral inferior, medial, and superior border involvements was 78% or greater. CONCLUSION: Body involvement can be reliably identified by use of 3-dimensional computed tomography images. Surgeons could reliably and accurately identify superior, medial, and lateral border involvement, which is considered clinically relevant and likely sufficient for the treatment decision process and outcome prognosis. It should be applied by surgeons with a special interest in the shoulder in the framework of clinical routine as well as in research activities. PMID- 24076003 TI - Dynamic genotype-selective "phenotypic switching" of CGRP expression contributes to differential neuropathic pain phenotype. AB - Using a genetic model we demonstrate the role played by "phenotypic switching" of calcitonin gene related peptide (CGRP) expression in axotomized large Abeta afferents in the development of neuropathic pain behavior in rats. After nerve injury both substance P and CGRP are upregulated in Abeta afferents in the corresponding DRGs. It has been proposed that intraspinal release of these neurotransmitters upon gentle stroking of skin drives ascending pain signaling pathways resulting in tactile allodynia. We reported previously that in rat lines genetically selected for high (HA) vs. low (LA) pain phenotype, SP is upregulated equally in both strains, but that CGRP is upregulated exclusively in the pain prone HA line (Nitzan-Luques et al., 2011). This implicates CGRP as the principal driver of tactile allodynia. Here we confirm this conclusion by showing: 1) that the time of emergence of CGRP-IR in DRG Abeta neurons and their central terminals in HA rats matches that of pain behavior, 2) that following spinal nerve lesion (SNL) selective activation of low threshold afferents indeed drives postsynaptic pain-signaling neurons and induces central sensitization in HA rats, as monitored using c-Fos as a marker. These changes are much less prominent in LA rats, 3) that intrathecal (i.t.) administration of CGRP induces tactile allodynia in naive rats and 4) that i.t. administration of the CGRP-receptor antagonist BIBN4096BS (Olcegepant) attenuates SNL-evoked tactile allodynia, without blocking baseline nociception. Together, these observations support the hypothesis that genotype selective phenotypic switching of CGRP expression in Abeta afferents following nerve injury is a fundamental mechanism of neuropathic tactile allodynia. PMID- 24076004 TI - Infusion of anti-Nogo-A antibodies in adult rats increases growth and synapse related proteins in the absence of behavioral alterations. AB - Restricted structural re-growth in the adult CNS is a major limitation to fully functional recovery following extensive CNS trauma. This limitation is partly due to the presence of growth inhibitory proteins, in particular, Nogo-A. Pre clinical studies have demonstrated that intrathecally infused anti-Nogo-A antibodies are readily distributed via the cerebrospinal fluid penetrating throughout the spinal cord and brain, where they promote sprouting, axonal regeneration and improved functional recovery after CNS injury. Whether anti-Nogo A treatments of intact animals might induce behavioral alterations has not been systematically tested. This is addressed here in an adult rat model of chronic intrathecal infusion of function-blocking anti-Nogo-A antibodies for 2 to 4weeks. We observed by proteomic and immunohistochemical techniques that chronic Nogo-A neutralization in the intact CNS increased expression of cytoskeletal, fiber growth-related, and synaptic proteins in the hippocampus, a brain region which might be particularly sensitive to Nogo-A depletion due to the high expression level of Nogo-A. Despite such molecular and proteomic changes, Nogo-A blockade was not associated with any pronounced cognitive-behavioral changes indicative of hippocampal functional deficiency across several critical tests. Our results suggest that the plastic changes induced by Nogo-A blockade in the adult hippocampus are counter-balanced by homeostatic mechanisms in the intact and the injured CNS. The data indicate that anti-Nogo-A therapy appears safe in the adult CNS over 4weeks of continuous administration. PMID- 24076005 TI - Juvenile traumatic brain injury evolves into a chronic brain disorder: behavioral and histological changes over 6months. AB - Traumatic brain injury (TBI) refers to physical trauma to the brain that can lead to motor and cognitive dysfunctions. TBI is particularly serious in infants and young children, often leading to long-term functional impairments. Although clinical research is useful for quantifying and observing the effects of these injuries, few studies have empirically assessed the long-term effects of juvenile TBI (jTBI) on behavior and histology. After a controlled cortical impact delivered to postnatal 17day old rats, functional abilities were measured after 3, 5, and 6months using open field (activity levels), zero maze (anxiety-like behaviors), rotarod (sensorimotor abilities, coordination, and balance), and water maze (spatial learning and memory, swim speed, turn bias). Sensorimotor function was impaired for up to 6months in jTBI animals, which showed no improvement from repeated test exposure. Although spatial learning was not impaired, spatial memory deficits were observed in jTBI animals starting at 3months after injury. Magnetic resonance imaging and histological data revealed that the effects of jTBI were evolving for up to 6months post-injury, with reduced cortical thickness, decreased corpus callosum area and CA1 neuronal cell death in jTBI animals distant to the impact site. These findings suggest that this model of jTBI produces long-term impairments comparable to those reported clinically. Although some deficits were stable over time, the variable nature of other deficits (e.g., memory) as well as changing properties of the lesion itself, suggest that the effects of a single jTBI produce a chronic brain disorder with long-term complications. PMID- 24076006 TI - Effects of fumaric acid esters on blood-brain barrier tight junction proteins. AB - The blood-brain barrier (BBB) is composed of a network of tight junctions (TJ) which interconnect cerebral endothelial cells (EC). Alterations in the TJ proteins are common in inflammatory diseases of the central nervous system (CNS) like multiple sclerosis (MS). Modulation of the BBB could thus represent a therapeutic mechanism. One pathway to modulate BBB integrity could be the induction of nuclear-factor (erythroid derived 2) related factor-2 (Nrf2) mediated oxidative stress responses which are targeted by fumaric acid esters (FAE). Here we analyze effects of FAE on the expression of TJ proteins in the human cerebral endothelial cell line hCMEC/D3 and experimental autoimmune encephalomyelitis (EAE). We show that dimethylfumarate (DMF) and its primary metabolite monomethylfumarate (MMF) induce the expression of the Nrf2/NQO1 pathway in endothelial cells. Neither MMF nor DMF had a consistent modulatory effect on the expression of TJ molecules in hCMEC/D3 cells. Tumor necrosis factor (TNFalpha)-induced downregulation of TJ proteins was at least partially reversed by treatment with FAE. However, DMF had no effect on claudin-5 expression in EAE, despite its effect on the clinical score and infiltration of immune cells. These data suggest that the modulation of the BBB is not a major mechanism of action of FAE in inflammatory demyelinating diseases of the CNS. PMID- 24076007 TI - Genetic analysis of the S100B gene in Chinese patients with Parkinson disease. AB - There is growing evidence that genetic abnormalities play an important role in the pathogenesis of Parkinson disease (PD). At least 18 genetic loci and 13 disease-related genes for parkinsonism have been identified. The S100 calcium binding beta (S100B), which is expressed and secreted by astrocytes, has been found to be associated with PD. To evaluate whether the S100B variants are related to PD in Chinese Han population, we conducted genetic examination of the S100B gene in 502 PD patients from Mainland China. We did identify two known variants c.279+4T>C (rs187503470) and c.99C>G (p.Leu33Leu, rs1051169) in our patients. Neither of these two variants is predicted to change amino acid or splice site, indicating that they are not pathogenic mutations. Our results suggest that mutations in the coding region or intron/exon boundaries of the S100B gene play little or no role in the development of PD in Chinese population. PMID- 24076009 TI - Identification of catalytically important amino acid residues for enzymatic reduction of glyoxylate in plants. AB - NADPH-dependent glyoxylate reductases from Arabidopsis thaliana (AtGLYR) convert both glyoxylate and succinic semialdehyde into their corresponding hydroxyacid equivalents. The primary sequence of cytosolic AtGLYR1 reveals several sequence elements that are consistent with the beta-HAD (beta-hydroxyacid dehydrogenase) protein family, whose members include 3-hydroxyisobutyrate dehydrogenase, tartronate semialdehyde reductase and 6-phosphogluconate dehydrogenase. Here, site-directed mutagenesis was utilized to identify catalytically important amino acid residues for glyoxylate reduction in AtGLYR1. Kinetic studies and binding assays established that Lys170 is essential for catalysis, Phe231, Asp239, Ser121 and Thr95 are more important in substrate binding than in catalysis, and Asn174 is more important in catalysis. The low activity of the mutant enzymes precluded kinetic studies with succinic semialdehyde. The crystal structure of AtGLYR1 in the absence of substrate was solved to 2.1A by molecular replacement using a previously unrecognized member of the beta-HAD family, cytokine-like nuclear factor, thereby enabling the 3-D structure of the protein to be modeled with substrate and co-factor. Structural alignment of AtGLYR1 with beta-HAD family members provided support for the essentiality of Lys170, Phe173, Asp239, Ser121, Asn174 and Thr95 in the active site and preliminary support for an acid/base catalytic mechanism involving Lys170 as the general acid and a conserved active site water molecule. This information established that AtGLYR1 is a member of the beta-HAD protein family. Sequence and activity comparisons indicated that AtGLYR1 and the plastidial AtGLYR2 possess structural features that are absent in Arabidopsis hydroxypyruvate reductases and probably account for their stronger preference for glyoxylate over hydroxypyruvate. PMID- 24076008 TI - Cancer-induced bone pain: Mechanisms and models. AB - Cancerous cells can originate in a number of different tissues such as prostate, breast and lung, but often go undetected and are non-painful. Many types of cancers have a propensity to metastasize to the bone microenvironment first. Tumor burden within the bone causes excruciating breakthrough pain with properties of ongoing pain that is inadequately managed with current analgesics. Part of this failure is due to the poor understanding of the etiology of cancer pain. Animal models of cancer-induced bone pain (CIBP) have revealed that the neurochemistry of cancer has features distinctive from other chronic pain states. For example, preclinical models of metastatic cancer often result in the positive modulation of neurotrophins, such as NGF and BDNF, that can lead to nociceptive sensitization. Preclinical cancer models also demonstrate nociceptive neuronal expression of acid-sensing receptors, such as ASIC1 and TRPV1, which respond to cancer-induced acidity within the bone. CIBP is correlated with a significant increase in pro-inflammatory mediators acting peripherally and centrally, contributing to neuronal hypersensitive states. Finally, cancer cells generate high levels of oxidative molecules that are thought to increase extracellular glutamate concentrations, thus activating primary afferent neurons. Knowledge of the unique neuro-molecular profile of cancer pain will ultimately lead to the development of novel and superior therapeutics for CIBP. PMID- 24076010 TI - A favorable built environment is associated with better physical fitness in European adolescents. AB - OBJECTIVE: To assess the association between the built environment and physical fitness and physical activity in adolescents. METHODS: The study included 3528 adolescents, aged 12.5-17.5 years, who participated in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study. The health-related physical fitness components were assessed using the physical fitness tests. Participants wore a uniaxial accelerometer (ActiGraph(r)) for 7 days to measure physical activity. A specific questionnaire addressing the built environment was used. Potential confounding factors including age, gender, body mass index, body composition, pubertal status, smoking, educational level of parents, and socioeconomic status were analyzed using backward stepwise linear regression analysis. RESULTS: Heavy traffic in the neighborhood was the strongest factor negatively associated with both physical fitness and physical activity (both P<0.05). Conversely, a secure bicycling or walking route from home to school was positively associated with various components of physical fitness and physical activity (P<0.01). Outdoor fields and gymnasiums near home were also associated with better physical fitness (P<0.01), but not with physical activity. CONCLUSIONS: A favorable built environment may contribute to health-related physical fitness and physical activity of adolescents and should be considered in future interventions and health promotion strategies. PMID- 24076011 TI - The FABS trial: a randomised control trial of the effects of a 6-month physical activity intervention on adherence and long-term physical activity and self efficacy in older adults with memory complaints. AB - OBJECTIVE: The aim of this study is to assess in older adults with memory complaints, the effects of a 6-month home-based physical activity (PA) intervention on short-term adherence, short and long-term self-efficacy and the predictors of adherence. METHODS: Participants with memory complaints with or without mild cognitive impairment (MCI) were recruited from Perth, Western Australia between May 2004 and July 2006 and randomly assigned to a control or an intervention group. The intervention group received a 6-month PA programme and recorded sessions on a diary. Pedometer readings, questionnaires, and physical and cognitive measures were completed at 0, 6, 12 and 18 months. RESULTS: One hundred and seventy participants started the study. Retention rates were similar for both groups at all time-points however retention was higher for men than women (P<0.01). Adherence to the prescribed PA was 72.8% (95% CI, 70.8 74.9%). Men had higher adherence rate than women (P<0.001). Those with and without MCI had similar adherence. Compared to controls self-efficacy was higher in the intervention group after 6 months only (P<0.01). CONCLUSIONS: Older adults with memory complaints, with or without MCI, can successfully participate in and enjoy home-based PA programmes. Long-term adherence to such interventions may require continued support and increased self-efficacy. ( TRIAL REGISTRATION: ACTRN012605000136606.). PMID- 24076013 TI - Dopamine interferes with appetitive long-term memory formation in honey bees. AB - Studies in vertebrates and invertebrates have proved the instructive role that different biogenic amines play in the neural representation of rewards and punishments during associative learning. Results from diverse arthropods and using different learning paradigms initially agreed that dopamine (DA) is needed for aversive learning and octopamine (OA) is needed for appetitive learning. However, the notion that both amines constitute separate pathways for appetitive and aversive learning is changing. Here, we asked whether DA, so far only involved in aversive memory formation in honey bees, does also modulate appetitive memory. Using the well characterized appetitive olfactory conditioning of the proboscis extension reflex (PER), we show that DA impairs appetitive memory consolidation. In addition, we found that blocking DA receptors enhances appetitive memory. These results are consistent with the view that aversive and appetitive components interact during learning and memory formation to ensure adaptive behavior. PMID- 24076012 TI - Combining fMRI and behavioral measures to examine the process of human learning. AB - Prior to the advent of fMRI, the primary means of examining the mechanisms underlying learning were restricted to studying human behavior and non-human neural systems. However, recent advances in neuroimaging technology have enabled the concurrent study of human behavior and neural activity. We propose that the integration of behavioral response with brain activity provides a powerful method of investigating the process through which internal representations are formed or changed. Nevertheless, a review of the literature reveals that many fMRI studies of learning either (1) focus on outcome rather than process or (2) are built on the untested assumption that learning unfolds uniformly over time. We discuss here various challenges faced by the field and highlight studies that have begun to address them. In doing so, we aim to encourage more research that examines the process of learning by considering the interrelation of behavioral measures and fMRI recording during learning. PMID- 24076014 TI - Nuclear gating of a Drosophila dCREB2 activator is involved in memory formation. AB - The transcription factor CREB is an important regulator of many adaptive processes in neurons, including sleep, cellular homeostasis, and memory formation. The Drosophila dCREB2 family includes multiple protein isoforms generated from a single gene. Overexpression of an activator or blocker isoform has been shown to enhance or block memory formation, but the molecular mechanisms underlying these phenomena remain unclear. In the present study, we generate isoform-specific antibodies and new transgenic flies to track and manipulate the activity of different dCREB2 isoforms during memory formation. We find that nuclear accumulation of a dCREB2 activator-related species, p35+, is dynamically regulated during memory formation. Furthermore, various dCREB2 genetic manipulations that enhance or block memory formation correspondingly increase or decrease p35+ levels in the nucleus. Finally, we show that overexpression of S6K can enhance memory formation and increase p35+ nuclear abundance. Taken together, these results suggest that regulation of dCREB2 localization may be a key molecular convergence point in the coordinated host of events that lead to memory formation. PMID- 24076015 TI - Nuclear phospholipase C-beta1 and diacylglycerol LIPASE-alpha in brain cortical neurons. AB - Phosphoinositide (PtdIns) signaling involves the generation of lipid second messengers in response to stimuli in a receptor-mediated manner at the plasma membrane. In neuronal cells of adult brain, the standard model proposes that activation of metabotropic receptors coupled to Phospholipase C-beta1 (PLC-beta1) is linked to endocannabinoid signaling through the production of diacylglycerol (DAG), which could be systematically metabolized by 1,2-diacylglycerol Lipases (DAGL) to produce an increase of 2-arachidonoyl-glycerol (2-AG), the most abundant endocannabinoid in the brain. However, the existence of a nuclear PtdIns metabolism independent from that occurring elsewhere in the cell is now widely accepted, suggesting that the nucleus constitutes both a functional and a distinct compartment for PtdIns metabolism. In this review, we shall highlight the main achievements in the field of neuronal nuclear inositol lipid metabolism with particular attention to progress made linked to the 2-AG biosynthesis. Our aim has been to identify potential sites of 2-AG synthesis other than the neuronal cytoplasmic compartment by determining the subcellular localization of PLC-beta1 and DAGL-alpha, which is much more abundant than DAGL-beta in brain. Our data show that PLC-beta1 and DAGL-alpha are detected in discrete brain regions, with a marked predominance of pyramidal morphologies of positive cortical cells, consistent with their role in the biosynthesis and release of 2 AG by pyramidal neurons to control their synaptic inputs. However, as novelty, we showed here an integrated description of the localization of PLC-beta1 and DAGL alpha in the neuronal nuclear compartment. We discuss our comparative analysis of the expression patterns of PLC-beta1 and DAGL-alpha, providing some insight into the potential autocrine role of 2-AG production in the neuronal nuclear compartment that probably subserve additional roles to the recognized activation of the CB1 cannabinoid receptor. PMID- 24076016 TI - Estradiol responsiveness of synaptopodin in hippocampal neurons is mediated by estrogen receptor beta. AB - In the hippocampus, synaptic proteins, as studied so far, have been shown to be upregulated by 17beta-estradiol, while inhibition of local estradiol synthesis consistently downregulates them. As an exception to this rule, we have previously shown that synaptopodin, an actin-associated postsynaptic protein, is downregulated in response to estradiol in dissociated cultured hippocampal neurons. In this study, we show, unexpectedly, that synaptopodin is downregulated in the hippocampus of aromatase knock-out mice and that inhibition of neuronal estradiol synthesis using the aromatase inhibitor letrozole also downregulates synaptopodin in these cultures. Moreover, the effects of estradiol and letrozole are additive, suggesting a subtle balance between available ligand and receptor. Using selective estrogen receptor agonists and antagonists, we consequently studied the effects of estrogen receptor subtypes on synaptopodin expression in our hippocampal cultures. We found that estradiol-induced downregulation of synaptopodin is mediated by estrogen receptor beta. Estrogen receptor beta in turn, is upregulated in response to intracellular estradiol ablation following inhibition of estradiol synthesis by letrozole in dissociated hippocampal cultures, as well as in the hippocampus of the aromatase knock-out mouse. Thus, it appears that both the application of estradiol, via binding to estrogen receptor beta, and letrozole, via upregulation of estrogen receptor beta, eventually result in a downregulation of synaptopodin. Our data show that the synaptic plasticity caused by estradiol is subject to a subtle balance of the levels of estrogen receptor subtypes regulated by the available ligands. In addition, both seem to be part of a homeostatic feedback mechanism. PMID- 24076018 TI - Profiling motives behind hedonic eating. Preliminary validation of the Palatable Eating Motives Scale. AB - The purpose of this study was to validate a new scale designed to measure individual motives for eating tasty foods and determine if any specific motive(s) are associated with obesity. The "Palatable Eating Motives Scale" (PEMS) is a self-report measure adapted from the Drinking Motives Questionnaire Revised (DMQ R). N=150 racially-diverse college students (mean age: 24.4, BMI: 16-51kg/m(2)) were administered the PEMS along with the Binge-Eating Scale (BES) and the Yale Food Addiction Scale (YFAS) to test for convergent and incremental validity and the Sensitivity to Punishment and Reward Questionnaire (SPSRQ) for discriminant validity. The PEMS identified four motives for eating tasty food, the same ones found with the DMQ-R for alcohol intake: Social, Conformity, Enhancement, and Coping motives. The scales had good convergent validity with BES and YFAS scores but discriminated from the broader motivational constructs of inhibition and activation measured by the SPSRQ. Of the PEMS motives, Coping (eating tasty food to deal with problems and negative feelings) accounted for unique variance in BMI, and added to variance in BMI contributed by BES scores, showing incremental validity. YFAS scores did not contribute to BMI after controlling for binge eating. Coping subscale scores were also significantly higher (p<0.001) among the severely obese (BMI>40). Motives behind palatable food intake are not homogenous and should be considered in personalized weight-loss strategies in future studies. In normal weight individuals, knowing one's dominant motive for eating tasty foods may help promote healthier food choices in times and places where they are most vulnerable to do otherwise. PMID- 24076017 TI - O-GlcNAcylation at promoters, nutrient sensors, and transcriptional regulation. AB - Post-translational modifications play important roles in transcriptional regulation. Among the less understood PTMs is O-GlcNAcylation. Nevertheless, O GlcNAcylation in the nucleus is found on hundreds of transcription factors and coactivators and is often found in a mutually exclusive ying-yang relationship with phosphorylation. O-GlcNAcylation also links cellular metabolism directly to the proteome, serving as a conduit of metabolic information to the nucleus. This review serves as a brief introduction to O-GlcNAcylation, emphasizing its important thematic roles in transcriptional regulation, and highlights several recent and important additions to the literature that illustrate the connections between O-GlcNAc and transcription. PMID- 24076019 TI - Behavioural strategies to control the amount of food selected and consumed. AB - Several factors within the food environment may stimulate overconsumption. The present study aimed to (1) identify behavioural strategies to cope with this environment to control the amount of food consumed, (2) examine the feasibility and usefulness of the strategies, and (3) evaluate the association between the strategies and body mass index (BMI). After the literature was screened for evidence of factors that contribute to the consumption of large amounts of food, 32 behavioural strategies were identified to overcome these influences (study 1). Subjectively reported feasibility and usefulness of the 32 behavioural strategies in weight management were explored using a pretest post-test study (study 2: n = 52). Additionally, two cross-sectional questionnaire studies (study 3a: n = 120 and study 3b: n = 278) were conducted to evaluate the association between the 32 behavioural strategies and BMI. The strategies were subjectively reported as feasible and useful in weight management. Frequent use of strategies discriminated non-overweight from overweight individuals, but did not discriminate overweight from obese individuals. In conclusion, the findings provided preliminary evidence for the acceptability and validity of the strategies. The effectiveness of the strategies for controlling the amount consumed should be further investigated, especially in overweight and obese participants. PMID- 24076020 TI - "It was an education in portion size". Experience of eating a healthy diet and barriers to long term dietary change. AB - The aim of the study was to explore the expectations and experience of actually eating a healthy diet and using this experience to identify barriers to healthy eating and sustainable dietary change. Fifty participants (19-63 yrs) were provided with a healthy diet (i.e. complied with dietary recommendations) for three consecutive days. Afterwards a semi-structured interview was carried out to explore expectations, experience and barriers to healthy eating. Using a thematic analysis approach eight dominant themes emerged from the interviews. Four related to expectations and experience of healthy eating; realisation of what are appropriate portion sizes, an expectation to feel hungry, surprise that healthy diets comprised normal food, the desire for sweet snacks (e.g. chocolate). This demonstrated there are some misconception about healthy eating and distorted views of portion size. Four more themes emerged relating to barriers to healthy eating; competing priorities, social, peer and time pressure, importance of value for money, a lack of desire to cook. Poor knowledge of healthy eating or a lack of cooking skills were the least common barrier, suggesting that future interventions and policy to improve dietary intakes need to focus on social, cultural and economic issues rather than on lack of knowledge or skills. PMID- 24076022 TI - Small molecule stimulation enhances bone regeneration but not titanium implant osseointegration. AB - The osteogenic and osseointegrative potential of a small molecule was examined to assess its usefulness in regenerative procedures. Purmorphamine was used to stimulate bone growth and repair in an in vitro cell-based assay and an in vivo chick embryo CAM-assay with and without the presence of an implant. Purmorphamine adhered to precipitated hydroxyapatite coating, could activate the sonic hedgehog pathway and thereby stimulated osteodifferentiation. Porous calcium phosphate beads were used to deliver this small molecule in vivo and showed that purmorphamine increased the trabecular bone to bone area significantly. The assay showed purmorphamine failed to induce any significant difference in osseointegration on titanium coated PTFE implants. This suggests that, while a small molecule can enhance osteogenesis and might be useful in regenerative procedures, it failed to enhance the osseointegration of a Ti coated implant, suggesting that this sort of stimulation might be useful for enhancing bone regeneration where bone loss due to disease exists, but not for enhancing early stability of an implant. PMID- 24076021 TI - Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals. AB - Proton pump inhibitors (PPIs) are highly effective in the treatment of upper gastrointestinal acid-related conditions and are fast becoming one of the most frequently prescribed treatments in adult or older persons. Recent data show that long-term use of PPIs in older subjects is associated with important undesirable effects, including a higher risk of osteoporotic fractures. The mechanisms of this association are unclear and the relationship between the use of PPIs and parameters of bone mass and geometry has never been fully explored. This study investigates the relationship between the chronic use of PPIs and the parameters of bone mass (cortical and trabecular bone mineral density - vBMDc and vBMDt) and bone geometry (cortical and trabecular cross sectional area - tCSA and cCSA) in older individuals. The study population consisted of 1038 subjects (452 men and 586 women) 65years or older, selected from the InCHIANTI study, with complete information on computerized tomography performed at tibial level (pQCT) and on medications. Participants were classified as PPI users and nonusers based on self report of PPI use over the last 15days, with PPI users (36 subjects, 14 men and 22 women) making up 3.4% of the study population (mean age 75.7+/-7.4years). The relationship between use of PPIs and pQCT bone parameters was tested by multivariate linear regression analysis adjusted for age, sex and several clinical factors and/or statistically confounding variables identified by partial correlation coefficient and Spearman partial rank order correlation coefficients, as appropriate (age, sex, BMI, caloric intake, IGF-1, IL-6, calcium, estradiol, bioavailable testosterone, vitamin D, parathyroid hormone, cross-sectional muscle area, and level of physical activity). PPI users showed age- and sex-adjusted lower vBMDt than nonusers (180.5+/-54.8 vs. 207.9+/-59.4, p=0.001). The inverse association between PPI use and vBMDt remained almost unchanged after adjustment for multiple confounders. There was no statistically significant difference in vBMDc, tCSA and cCSA between PPI users and nonusers. In community dwelling older persons, the use of PPIs is inversely associated with vBMDt, an early marker of the osteoporotic process. These findings suggest that PPI use might increase the risk of fractures in older subjects through its detrimental effects on trabecular bone. PMID- 24076023 TI - Novel sandwich ELISAs for rat DMP1: age-related decrease of circulatory DMP1 levels in male rats. AB - Dentin matrix protein 1 (DMP1), a noncollagenous bone matrix protein produced by osteocytes, regulates matrix mineralization and phosphate homeostasis. The lack of a precise assay for circulating DMP1 levels impairs further investigation of the protein's biological significance. Because full-length precursor DMP1 is cleaved into NH2- and COOH-terminal fragments during the secretory process, we developed two new sandwich ELISAs for the NH2- and COOH-terminal fragments of rat DMP1. One of these ELISAs, ELISA 1-2, is based on two affinity-purified polyclonal antibodies against the DMP1-1 and DMP1-2 peptides of the NH2-terminal fragment, whereas the other, ELISA 4-3, is based on two affinity-purified polyclonal antibodies against the DMP1-3 and DMP1-4 peptides of the COOH-terminal fragment. The polyclonal antibodies were characterized in immunohistochemical and liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) studies. Immunohistochemical analyses of rat bone using these polyclonal antibodies revealed DMP1 immunoreactivity in osteocytes and pericanalicular matrix, consistent with the previously reported osteocyte-specific expression of DMP1. LC-MS/MS analyses of rat plasma-derived immunoreactive products affinity extracted with these antibodies revealed the presence of DMP1 in circulating blood. The ELISAs established with these antibodies met accepted standards for reproducibility, repeatability, precision, and accuracy. Circulating DMP1 and levels of other biochemical markers (osteocalcin, Trap5b, Dkk-1, and SOST) were measured in 2-, 4-, 8-, 12-, 18-, 24-, 72-, and 96-week-old Wistar male rats. Circulating DMP1 levels determined by ELISAs 1-2 and 4-3 significantly decreased with age. During rapid skeletal growth (2-12weeks), DMP1 levels measured by ELISA 4-3 were over three times higher than those measured by ELISA 1-2; however, DMP1 levels in old animals (72 and 96weeks) were almost the same when measured by either ELISA. DMP1 levels determined by both ELISAs were most highly positively correlated with the level of Dkk-1, second most highly correlated with the level of osteocalcin, and less highly correlated with the levels of Trap5b and SOST. These novel sandwich ELISAs for rat DMP1 are highly specific and allow precise measurements of circulating DMP1, which may be a new biochemical marker for osteocyte-mediated bone turnover. PMID- 24076024 TI - Structure of the Toll/interleukin 1 receptor (TIR) domain of the immunosuppressive Brucella effector BtpA/Btp1/TcpB. AB - BtpA/Btp1/TcpB is a virulence factor produced by Brucella species that possesses a Toll interleukin-1 receptor (TIR) domain. Once delivered into the host cell, BtpA interacts with MyD88 to interfere with TLR signalling and modulates microtubule dynamics. Here the crystal structure of the BtpA TIR domain at 3.15 A is presented. The structure shows a dimeric arrangement of a canonical TIR domain, similar to the Paracoccus denitrificans Tir protein but secured by a unique long N-terminal alpha-tail that packs against the TIR:TIR dimer. Structure based mutations and multi-angle light scattering experiments characterized the BtpA dimer conformation in solution. The structure of BtpA will help with studies to understand the mechanisms involved in its interactions with MyD88 and with microtubules. PMID- 24076025 TI - Ankyrin repeat and BTB/POZ domain containing protein-2 inhibits the aggregation of alpha-synuclein: implications for Parkinson's disease. AB - Aggregation of alpha-synuclein is a pathological hallmark of sporadic or familial PD. However, the detailed molecular mechanism responsible for the aggregation of alpha-synuclein has not been properly explored. In the present study, we have identified a novel role of an anti-tumorigenic BTB/POZ domain containing protein 2 (BPOZ-2) in the regulation of alpha-synuclein accumulation in dopaminergic (DA) neurons. MPP(+), an etiological factor for PD, significantly downregulated the expression of BPOZ-2 ahead of alpha-synuclein upregulation. Moreover, siRNA knockdown of BPOZ-2 alone stimulated the aggregation of alpha-synuclein protein; the effect was further induced in presence of MPP(+) in mouse primary DA neurons. Finally, the absence of BPOZ-2 in alpha-synuclein expressing neuronal populations of MPTP-intoxicated mouse and primate nigra indicates that the suppression of BPOZ-2 could be involved in the accumulation of alpha-synuclein protein. PMID- 24076026 TI - Arabidopsis cysteine proteinase inhibitor AtCYSb interacts with a Ca(2+) dependent nuclease, AtCaN2. AB - Plant cysteine proteinase inhibitors (cystatins) play important roles in plant defense mechanisms. Some proteins that interact with cystatins may defend against abiotic stresses. Here, we showed that AtCaN2, a Ca(2+)-dependent nuclease in Arabidopsis, is transcribed in senescent leaves and stems and interacts with an Arabidopsis cystatin (AtCYSb) in a yeast two-hybrid screen. The interaction between AtCYSb and AtCaN2 was confirmed by in vitro pull-down assay and bimolecular fluorescence complementation. Agarose gel electrophoresis showed that the nuclease activity of AtCaN2 against lambdaDNA was inhibited by AtCYSb, which suggests that AtCYSb regulates nucleic acid degradation in cells. PMID- 24076027 TI - Prizes awarded by FEBS Letters and FEBS Journal from 2015. PMID- 24076028 TI - Distinct tRNA modifications in the thermo-acidophilic archaeon, Thermoplasma acidophilum. AB - Thermoplasma acidophilum is a thermo-acidophilic archaeon. We purified tRNA(Leu) (UAG) from T. acidophilum using a solid-phase DNA probe method and determined the RNA sequence after determining via nucleoside analysis and m(7)G-specific aniline cleavage because it has been reported that T. acidophilum tRNA contains m(7)G, which is generally not found in archaeal tRNAs. RNA sequencing and liquid chromatography-mass spectrometry revealed that the m(7)G modification exists at a novel position 49. Furthermore, we found several distinct modifications, which have not previously been found in archaeal tRNA, such as 4-thiouridine9, archaeosine13 and 5-carbamoylmethyuridine34. The related tRNA modification enzymes and their genes are discussed. PMID- 24076029 TI - Determination of topological structure of ARL6ip1 in cells: identification of the essential binding region of ARL6ip1 for conophylline. AB - Conophylline (CNP) has various biological activities, such as insulin production. A recent study identified ADP-ribosylation factor-like 6-interacting protein 1 (ARL6ip1) as a direct target protein of CNP. In this study, we revealed that ARL6ip1 is a three-spanning transmembrane protein and determined the CNP-binding domain of ARL6ip1 by deletion mutation analysis of ARL6ip1 with biotinyl-amino CNP. These results suggest that CNP is expected to be useful for future investigation of ARL6ip1 function in cells. Because of the anti-apoptotic function of ARL6ip1, CNP may be an effective therapeutic drug and/or a novel chemosensitizer for human cancers and other diseases. PMID- 24076030 TI - Metabolic and endocrine effects of valproic acid chronic treatment. AB - Treatment of epileptic patients with valproic acid (VPA) may be associated with substantial weight changes that may increase morbidity and impair adherence to the treatment regimen. VPA-induced weight gain seems to be associated with many metabolic disturbances; the most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance. Patients who gain weight during VPA therapy can develop dyslipidemia and metabolic syndrome that are associated with long-term vascular complications such as hypertension and atherosclerosis. Moreover, an elevation in the levels of uric acid and homocysteine, together with oxidative stress, may contribute to atherosclerotic risk in patients under long-term therapy with VPA. The aim of this review is to discuss the metabolic and endocrine effects of VPA chronic treatment in patients with epilepsy. PMID- 24076031 TI - Antimicrobial activity of a honeybee (Apis cerana) venom Kazal-type serine protease inhibitor. AB - Insect-derived Kazal-type serine protease inhibitors exhibit thrombin, elastase, plasmin, proteinase K, or subtilisin A inhibition activity, but so far, no functional roles for bee-derived Kazal-type serine protease inhibitors have been identified. In this study, a bee (Apis cerana) venom Kazal-type serine protease inhibitor (AcKTSPI) that acts as a microbial serine protease inhibitor was identified. AcKTSPI contained a single Kazal domain that displayed six conserved cysteine residues and a P1 threonine residue. AcKTSPI was expressed in the venom gland and was present as a 10-kDa peptide in bee venom. Recombinant AcKTSPI Kazal domain (AcKTSPI-Kd) expressed in baculovirus-infected insect cells demonstrated inhibitory activity against subtilisin A (Ki 67.03 nM) and proteinase K (Ki 91.53 nM), but not against alpha-chymotrypsin or trypsin, which implies a role for AcKTSPI as a microbial serine protease inhibitor. However, AcKTSPI-Kd exhibited no detectable inhibitory effects on factor Xa, thrombin, tissue plasminogen activator, or elastase. Additionally, AcKTSPI-Kd bound directly to Bacillus subtilis, Bacillus thuringiensis, Beauveria bassiana, and Fusarium graminearum but not to Escherichia coli. Consistent with these findings, AcKTSPI-Kd showed antibacterial activity against Gram-positive bacteria and antifungal activity against both plant-pathogenic and entomopathogenic fungi. These findings constitute molecular evidence that AcKTSPI acts as an inhibitor of microbial serine proteases. This paper provides a novel view of the antimicrobial functions of a bee venom Kazal-type serine protease inhibitor. PMID- 24076032 TI - Induced neural stem cells generated from rat fibroblasts. AB - The generation of induced tissue-specific stem cells has been hampered by the lack of well-established methods for the maintenance of pure tissue-specific stem cells like the ones we have for embryonic stem (ES) cell cultures. Using a cocktail of cytokines and small molecules, we demonstrate that primitive neural stem (NS) cells derived from mouse ES cells and rat embryos can be maintained. Furthermore, using the same set of cytokines and small molecules, we show that induced NS (iNS) cells can be generated from rat fibroblasts by forced expression of the transcriptional factors Oct4, Sox2 and c-Myc. The generation and long-term maintenance of iNS cells could have wide and momentous implications. PMID- 24076034 TI - Improvement on dissolution rate of inclusion complex of Rifabutin drug with beta cyclodextrin. AB - The effect of beta-cyclodextrin (beta-CD) on the improvement of solubility and antimicrobial activity of poorly water soluble drug Rifabutin (RFB) was studied. The solid inclusion complex is prepared under different methods and it is characterized by FT-IR, XRD, DSC and SEM methods. Solubility type, stability constant, stoichiometric ratio were investigated from phase solubility diagram of inclusion complex (RFB with beta-CD). The dissolution profiles of the inclusion complexes were carried out and obvious increase in dissolution rate was observed when compared with pure RFB drug. Inclusion complexation process was further confirmed by molecular docking studies using PatchDock server. The in vitro antimicrobial and antibiofilm activity of RFB sensible microorganisms was significantly increased by on inclusion complexation process. This trend of inclusion complexation of poorly water soluble drugs is highly recognized as a successful and useful approach for the application in pharmaceutical field. PMID- 24076033 TI - Vitamin D deficiency in reproductive age Mongolian women: a cross sectional study. AB - Vitamin D production is critical not only for rickets prevention but for its role in several chronic diseases of adulthood. Maternal vitamin D status also has consequences for the developing fetus. This study assessed the prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D]<20ng/ml) and insufficiency [25(OH)D=20-29ng/ml] in spring, among reproductive age Mongolian women. Blood was drawn in March and April, 2009 from 420 Mongolian women, 18-44 years of age. Serum 25(OH)D concentrations were measured, anthropometric measurements were performed and information was collected by interview on lifestyle, dietary and reproductive factors. Logarithm-transformed 25(OH)D levels were compared across risk factor categories by analysis of variance. Linear regression analysis was used to assess the independent associations of factors with vitamin D status. Cutaneous vitamin D3 synthesis was assessed between December and July using a standard 7-dehydrocholesterol ampoule model. The vast majority of women 415 (98.8%) had serum 25(OH)D<20ng/ml (50nmol/l) with an additional 4 women (<1%) in the insufficient range (20-29ng/ml); only one women (0.2%) had sufficient levels (>30ng/ml or 75nmol/l). 25(OH)D concentrations were positively and independently associated with educational status and use of vitamin D supplements, but not with other demographic, lifestyle, reproductive, or anthropometric factors. 25(OH)D levels were not associated with dietary factors in this population, as there is little access to foods containing vitamin D in Mongolia. No production of previtamin D3 was observed until March and was maximally effective in April and was sustained through July. These data suggest that the prevalence of vitamin D deficiency in spring among reproductive age women in Mongolia is high. Given the lack of naturally vitamin D-rich food in the diet and limited use of vitamin D supplements, food fortification and/or supplementation with vitamin D should be considered among these women. PMID- 24076035 TI - Interoceptive awareness moderates neural activity during decision-making. AB - The current study examined the relationship between conscious perception of somatic feedback (interoceptive awareness) and neural responses preceding decision-making. Previous research has suggested that decision-making is influenced by body signals from the periphery or the central representation of the periphery. Using event-related fMRI, participants whose interoceptive awareness was assessed using a heartbeat perception paradigm performed the Iowa Gambling Task. The results show a positive relationship between the degree of interoceptive awareness and selection related activity in the right anterior insula and the left postcentral gyrus. Neural activity within the right anterior insula was associated with decision-making performance only in individuals with accurate but not in those with non-accurate interoceptive awareness. These findings support the role of somatic feedback in decision-making processes. They indicate that the right anterior insula holds a representation of somatic markers and that these are more strongly processed with increased interoceptive awareness. PMID- 24076036 TI - Cellular vacuolation and mitochondrial-associated factors induced by Clostridium perfringens epsilon toxin detected using acoustic flow cytometry. AB - Epsilon toxin (ETX) produced by Clostridium perfringens types B and D is a potent toxin that is responsible for fatal enterotoxaemia. In vitro, ETX, which is considered as a pore-forming toxin, forms a heptamer in Madin-Darby canine kidney (MDCK) cell membranes, which is considered to be a pre-pore stage. After binding of the ETX, vacuoles inside cell cytoplasm are produced. ETX causes decreased levels of essential coenzymes required for host cell energy. Here, we optimized and applied acoustic flow cytometry analysis in order to gain further insight into ETX-pathogenesis. Using acoustic flow cytometer analysis, which considered highly sensitive, ETX-exposed MDCK cells revealed mitochondrial membrane decreases followed by 25.48% and 45.45% of the exposed cells expressing the Bax and BCL-2 proteins at a pre-pore stage, respectively. These results together with high cytotoxicity and visualization of cell vacuoles, demonstrates that acoustic flow cytometry analysis potentially represents an effective tool to study ETX pathogenesis. PMID- 24076037 TI - Primary spinal leptomeningeal gliomatosis in a 3-year-old boy revealed with MRI and FDG PET/CT mimicking tuberculosis meningitis. PMID- 24076038 TI - Mediastinal germ cell tumor presenting with bone marrow metastases: an unusual pattern of relapse demonstrated with (18)F-FDG PET-CT. PMID- 24076039 TI - Immune reconstitution syndrome-like entity in lung transplant recipients with invasive aspergillosis. AB - BACKGROUND: Incidence, characteristics, and risk-factors for invasive aspergillosis (IA)-associated immune reconstitution syndrome (IRS) in lung transplant recipients are not known. METHODS: Patients comprised 68 lung transplant recipients with proven/probable IA followed for 12 months. IRS was defined based on previously proposed criteria. RESULTS: In all, 7.3% (5/68) of the patients developed IRS based on aforementioned criteria, a median of 56 days after initiation of antifungal therapy. This entity was associated with heart lung transplantation (p=0.006), anti T-cell agent use (p=0.003), discontinuation of calcineurin inhibitor agent (p=0.002), and disseminated IA (p=0.069). In a risk assessment model, IRS developed in 0% (0/55) of the patients with none of the aforementioned factors, 28.6% (2/7) with one, 33.3% (1/3) with two, and in 1/1 patient with 3 factors (X(2) for trend p=0.0001). Three out of 5 patients with IRS died and 2 of 3 deaths in this group were due to chronic rejection. CONCLUSIONS: Overall 7% of the lung transplant recipients with IA appear to develop an IRS-like entity. Clinically assessable factors can identify patients at risk for post-transplant IA-associated IRS. Deaths due to chronic rejection were significantly higher in patients with IRS than those without IRS. PMID- 24076040 TI - Topical corticosteroids and secondary adrenal insufficiency: a relationship in the shade. PMID- 24076041 TI - Diel sugar feeding and reproductive behaviours of Aedes aegypti mosquitoes in Trinidad: with implications for mass release of sterile mosquitoes. AB - Studies on the diel sugar feeding periodicity of male and female Aedes aegypti were conducted under laboratory conditions and monitored in single cages using the polyphagometer device and examined every 2h. Males mosquitoes displayed two peaks in sugar feeding, a small morning peak at 06.00-08.00 h (16% of sugar feeding) and a significant evening peak at 16.00-18.00 h (40% of sugar feeding). A similar pattern was observed among females: a small early morning peak (18% of sugar feeding) and a significant peak in the evening 16.00-18.00 h (42% of sugar feeding). Studies on the effects of sugar feeding on the excitation of males showed 100% erect antennal fibrillae after 36 h. In contrast, only 15% of the water-fed males responded. Laboratory studies on the effects of sugar feeding on the insemination rates of A. aegypti females showed similar inseminations rates among sugar and water fed males but after 4 days all water fed males died while the sugar fed males continued to survive and inseminate females. The synchronization of the male and female diel sugar feeding periodicity is discussed in the context of sterile insect techniques or genetic control methods. PMID- 24076042 TI - Exploring new limits in complex biological structures. PMID- 24076043 TI - Cracking the code, slowly: the state of carbohydrate-active enzymes in 2013. PMID- 24076044 TI - Faster, higher, stronger: to the gold medal podium? PMID- 24076045 TI - Similarities between exercise-induced hypoalgesia and conditioned pain modulation in humans. AB - Pain inhibitory mechanisms are often assessed by paradigms of exercise-induced hypoalgesia (EIH) and conditioned pain modulation (CPM). In this study it was hypothesized that the spatial and temporal manifestations of EIH and CPM were comparable. The participants were 80 healthy subjects (40 females), between 18 and 65 years of age in this randomized, repeated-measures cross-over trial that involved data collection on 2 different days. CPM was assessed by 2 different cold pressor tests (hand and foot). EIH was assessed by 2 intensities of aerobic bicycling exercises and 2 intensities of isometric muscle contraction exercises (arm and leg). Pressure pain thresholds (PPTs) were recorded before, during, after, and 15 minutes after conditioning/exercise at sites local to and remote from the extremity used for cold pressor stimulation and exercise. PPTs increased at local as well as at remote sites during both cold pressor tests and after all of the exercise conditions except low-intensity bicycling. EIH after bicycling was higher in women than in men. CPM and the EIH responses after isometric exercises were comparable in men and women and were not affected by age. The EIH response was larger in the exercising body part compared with nonexercising body parts for all exercise conditions. High-intensity exercise produced greater EIH responses than did low-intensity exercise. The change in PPTs during cold pressor tests and the change in PPTs after exercises were not correlated. The CPM response was not dominated by local manifestations, and the effect was seen only during the stimulation, whereas exercise had larger local manifestations, and the effects were also found after exercise. PMID- 24076046 TI - Expectation requires treatment to boost pain relief: an fMRI study. AB - We investigated the effect of a possible interaction between topical analgesic treatment and treatment expectation on pain at the behavioral and neuronal level by combining topical lidocaine/prilocaine treatment with an expectancy manipulation in a 2 by 2 within-subject design (open treatment, hidden treatment, placebo, control). Thirty-two healthy subjects received heat pain stimuli on capsaicin-pretreated skin and rated their experienced pain during functional magnetic resonance imaging. This allowed us to separate drug- and expectancy related effects at the behavioral and neuronal levels and to test whether they interact during the processing of painful stimuli. Pain ratings were reduced during active treatment and were associated with reduced activity in the anterior insular cortex. Pain ratings were lower in open treatment compared with hidden treatment and were related to reduced activity in the anterior insular cortex, the anterior cingulate cortex, the secondary somatosensory cortex, and the thalamus. Testing for an interaction revealed that the expectation effect was significantly larger in the active treatment conditions compared with the no treatment conditions and was associated with signal changes in the anterior insular cortex, the anterior cingulate cortex, and the ventral striatum. In conclusion, this study shows that even in the case of a topical analgesic, expectation interacts with treatment at the level of pain ratings and neuronal responses in placebo-related brain regions. Our results are highly relevant in the clinical context as they show (i) that expectation can boost treatment and (ii) that expectation and treatment are not necessarily additive as assumed in placebo-controlled clinical trials. PMID- 24076047 TI - Sensory findings after stimulation of the thoracolumbar fascia with hypertonic saline suggest its contribution to low back pain. AB - Injection of hypertonic saline into deep tissues of the back (subcutis, muscle, or the surrounding fascia) can induce acute low back pain (LBP). So far, no study has analyzed differences in temporal, qualitative, and spatial pain characteristics originating from these tissues. The current study aimed to investigate the role of the thoracolumbar fascia as a potential source of LBP. In separate sessions, 12 healthy subjects received ultrasound-guided bolus injections of isotonic saline (0.9%) or hypertonic saline (5.8%) into the erector spinae muscle, the thoracolumbar fascia (posterior layer), and the overlying subcutis. Subjects were asked to rate pain intensity, duration, quality, and spatial extent. Pressure pain thresholds were determined pre and post injection. Injections of hypertonic saline into the fascia resulted in significantly larger area under the curve of pain intensity over time than injections into subcutis (P<0.01) or muscle (P<0.001), primarily based on longer pain durations and, to a lesser extent, on higher peak pain ratings. Pressure hyperalgesia was only induced by injection of hypertonic saline into muscle, but not fascia or subcutis. Pain radiation and pain affect evoked by fascia injection exceeded those of the muscle (P<0.01) and the subcutis significantly (P<0.05). Pain descriptors after fascia injection (burning, throbbing, and stinging) suggested innervation by both A- and C-fiber nociceptors. These findings show that the thoracolumbar fascia is the deep tissue of the back that is most sensitive to chemical stimulation, making it a prime candidate to contribute to nonspecific LBP but not to localized pressure hyperalgesia. PMID- 24076048 TI - Irritable bowel syndrome in female patients is associated with alterations in structural brain networks. AB - Alterations in gray matter (GM) density/volume and cortical thickness (CT) have been demonstrated in small and heterogeneous samples of subjects with differing chronic pain syndromes, including irritable bowel syndrome (IBS). Aggregating across 7 structural neuroimaging studies conducted at University of California, Los Angeles, Los Angeles, CA, USA, between August 2006 and April 2011, we examined group differences in regional GM volume in 201 predominantly premenopausal female subjects (82 IBS, mean age: 32+/-10 SD, 119 healthy controls [HCs], 30+/-10 SD). Applying graph theoretical methods and controlling for total brain volume, global and regional properties of large-scale structural brain networks were compared between the group with IBS and the HC group. Relative to HCs, the IBS group had lower volumes in the bilateral superior frontal gyrus, bilateral insula, bilateral amygdala, bilateral hippocampus, bilateral middle orbital frontal gyrus, left cingulate, left gyrus rectus, brainstem, and left putamen. Higher volume was found in the left postcentral gyrus. Group differences were no longer significant for most regions when controlling for the Early Trauma Inventory global score, with the exception of the right amygdala and the left postcentral gyrus. No group differences were found for measures of global and local network organization. Compared to HCs, in patients with IBS, the right cingulate gyrus and right thalamus were identified as being significantly more critical for information flow. Regions involved in endogenous pain modulation and central sensory amplification were identified as network hubs in IBS. Overall, evidence for central alterations in patients with IBS was found in the form of regional GM volume differences and altered global and regional properties of brain volumetric networks. PMID- 24076049 TI - Transforming growth factor-beta signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. AB - Tissue-resident memory T (Trm) cells represent a population of memory CD8+ T cells that can act as first responders to local infection. The mechanisms regulating the formation and maintenance of intestinal Trm cells remain elusive. Here we showed that transforming growth factor-beta (TGF-beta) controlled both stages of gut Trm cell differentiation through different mechanisms. During the formation phase of Trm cells, TGF-beta signaling inhibited the migration of effector CD8+ T cells from the spleen to the gut by dampening the expression of integrin alpha4beta7. During the maintenance phase, TGF-beta was required for the retention of intestinal Trm cells at least in part through the induction of integrins alphaEbeta7 and alpha1, as well as CD69. Thus, the cytokine acts to control cytotoxic T cell differentiation in lymphoid and peripheral organs. PMID- 24076050 TI - Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. AB - CD4+ T cell differentiation is regulated by specialized antigen-presenting cells. Dendritic cells (DCs) produce cytokines that promote naive CD4+ T cell differentiation into T helper 1 (Th1), Th17, and inducible T regulatory (iTreg) cells. However, the initiation of Th2 cell responses remains poorly understood, although it is likely that more than one mechanism might be involved. Here we have defined a specific DC subset that is involved in Th2 cell differentiation in vivo in response to a protease allergen, as well as infection with Nippostrongylus brasiliensis. We have demonstrated that this subset is controlled by the transcription factor interferon regulatory factor 4 (IRF4), which is required for their differentiation and Th2 cell-inducing function. IRF4 is known to control Th2 cell differentiation and Th2 cell-associated suppressing function in Treg cells. Our finding suggests that IRF4 also plays a role in DCs where it controls the initiation of Th2 cell responses. PMID- 24076051 TI - CD301b+ dermal dendritic cells drive T helper 2 cell-mediated immunity. AB - Unlike other types of T helper (Th) responses, whether the development of Th2 cells requires instruction from particular subset of dendritic cells (DCs) remains unclear. By using an in vivo depletion approach, we have shown that DCs expressing CD301b were required for the generation of Th2 cells after subcutaneous immunization with ovalbumin (OVA) along with papain or alum. CD301b+ DCs are distinct from epidermal or CD207+ dermal DCs (DDCs) and were responsible for transporting antigen injected subcutaneously with Th2-type adjuvants. Transient depletion of CD301b+ DCs resulted in less effective accumulation and decreased expression of CD69 by polyclonal CD4+ T cells in the lymph node. Moreover, despite intact cell division and interferon-gamma production, CD301b+ DC depletion led to blunted interleukin-4 production by OVA-specific OT-II transgenic CD4+ T cells and significantly impaired Th2 cell development upon infection with Nippostrongylus brasiliensis. These results reveal CD301b+ DDCs as the key mediators of Th2 immunity. PMID- 24076052 TI - Identifying better surgical candidates among recursive partitioning analysis class 2 patients who underwent surgery for intracranial metastases. AB - OBJECTIVE: The management of patients with brain metastases is typically dependent on their prognosis. Recursive partitioning analysis (RPA) is the most commonly used method for prognosticating survival, but has limitations for patients in the intermediate class. The aims of this study were to ascertain preoperative risk factors associated with survival, develop a preoperative prognostic grading system, and evaluate the utility of this system in predicting survival for RPA class 2 patients. METHODS: Adult patient who underwent intracranial metastatic tumor surgery at an academic tertiary care institution from 1997 to 2011 were retrospectively reviewed. Multivariate proportional hazards regression analysis was used to identify preoperative factors associated with survival. The identified associations were then used to develop a grading system. Survival as a function of time was plotted using the Kaplan-Meier method, and survival rates were compared using log-rank analyses. RESULTS: A total of 421 (59%) of 708 patients were RPA class 2. The preoperative factors found to be associated with poorer survival were: male gender (P < 0.0001), motor deficit (P = 0.0007), cognitive deficit (P = 0.0004), nonsolitary metastases (P = 0.002), and tumor size >2 cm (P = 0.003). Patients having 0-1, 2, and 3-5 of these variables were assigned a preoperative grade of A, B, and C, respectively. Patients with a preoperative grade of A, B, and C had a median survival of 17.0, 10.3, and 7.3 months, respectively. These grades had distinct survival times (P < 0.05). CONCLUSIONS: The present study devised a preoperative grading system that may provide prognostic information for RPA class 2 patients, which may also guide medical and surgical therapies before any intervention is pursued. PMID- 24076054 TI - A novel virtual reality simulation for hemostasis in a brain surgical cavity: perceived utility for visuomotor skills in current and aspiring neurosurgery residents. AB - OBJECTIVE: To understand the perceived utility of a novel simulator to improve operative skill, eye-hand coordination, and depth perception. METHODS: We used the ImmersiveTouch simulation platform (ImmersiveTouch, Inc., Chicago, Illinois, USA) in two U.S. Accreditation Council for Graduate Medical Education-accredited neurosurgical training programs: the University of Chicago and the University of Texas Medical Branch. A total of 54 trainees participated in the study, which consisted of 14 residents (group A), 20 senior medical students who were neurosurgery candidates (group B), and 20 junior medical students (group C). The participants performed a simulation task that established bipolar hemostasis in a virtual brain cavity and provided qualitative feedback regarding perceived benefits in eye-hand coordination, depth perception, and potential to assist in improving operating skills. RESULTS: The perceived ability of the simulator to positively influence skills judged by the three groups: group A, residents; group B, senior medical students; and group C, junior medical students was, respectively, 86%, 100%, and 100% for eye-hand coordination; 86%, 100%, and 95% for depth perception; and 79%, 100%, and 100% for surgical skills in the operating room. From all groups, 96.2% found the simulation somewhat or very useful to improve eye-hand coordination, and 94% considered it beneficial to improve depth perception and operating room skills. CONCLUSION: This simulation module may be suitable for resident training, as well as for the development of career interest and skill acquisition; however, validation for this type of simulation needs to be further developed. PMID- 24076053 TI - Isolated cerebral aspergillosis in immunocompetent patients. AB - BACKGROUND: Isolated cerebral aspergillosis (ICA) traditionally has been associated with immunocompromised patients with dismal outcomes. Cases of ICA in immunocompetent patients are very rare and poorly described. We describe our experience of 5 immunocompetent patients with ICA and compare our experience with the literature. METHODS: During the period 1996-2011, ICA was diagnosed in 5 otherwise healthy, immunocompetent patients at our institution. Medical records of the patients were reviewed with standardized data collection, including demographics, clinical presentation, radiologic features, histopathology results, treatment, and outcome. RESULTS: All 5 patients had radiologic evidence of cerebral disease, purely parenchymal in 4 patients and dural-based in 1 patient. Radiology showed the paranasal sinuses and lungs to be clear in all patients. All patients underwent resection with antifungal therapy. All patients were female with a mean age of 23 years (range, 13-36 years). Headache (n = 5) and seizures (n = 4) were the primary presenting manifestations. Brain magnetic resonance imaging was performed in 5 patients preoperatively, and computed tomography was performed preoperatively in 4 patients. The diagnosis was made by histopathology (n = 5) and fungal cultures (n = 3) of the excised mass. Surgical resection was performed in all patients followed by treatment with amphotericin B for 2-4 weeks then oral voriconazole for 6 months. Overall mortality was 20% (n = 1). Average follow-up period was 32 months (range, 12-51 months) with interval brain magnetic resonance imaging to document eradication. CONCLUSIONS: ICA in otherwise healthy immunocompetent hosts seems to have a more favorable prognosis than what is reported for immunocompromised hosts. PMID- 24076055 TI - Spinal parasites. PMID- 24076056 TI - Bilateral pallidal deep brain stimulation for X-linked dystonia-parkinsonism. AB - BACKGROUND: X-linked dystonia-parkinsonism (XDP) is a progressively debilitating movement disorder that begins with focal dystonia and eventually generalizes. It exclusively affects Filipino inhabitants of the island of Panay. We report a case of XDP successfully treated by deep brain stimulation (DBS) and review the literature. METHODS: A 36-year-old man with XDP failed medical management and underwent bilateral globus pallidus internus DBS. A search of the PubMed database was performed to identify all articles discussing DBS and XDP. "Stimulation," "DYT3," "Lubag," "torsion dystonia," and "dystonia-parkinsonism" were used as MeSH headings. RESULTS: The patient's postoperative course was notable for delayed emergence from anesthesia. When stimulation was started, he had immediate improvement in his symptoms, and at 6-month follow-up, he is able to ambulate with the assistance of a walker. Review of the literature revealed 5 previously reported cases of XDP treated with DBS. CONCLUSIONS: The published experience with globus pallidus internus DBS for XDP has been very positive to date. Although long-term follow-up data are needed, early results provide optimism for patients with this debilitating disorder. PMID- 24076057 TI - Jazz, guitar, and neurosurgery: the Pat Martino case report. AB - OBJECTIVE: We present the case of a professional jazz guitarist with temporal lobe epilepsy secondary to an arteriovenous cerebral malformation. CASE DESCRIPTION: The patient underwent a left temporal lobectomy in 1980. After surgery, he presented with severe retrograde amnesia and complete loss of musical interest and capabilities. The patient's musical abilities recovered over time, and he regained his previous virtuoso status. In 2007, his medical history, neuropsychologic functions, and structural magnetic resonance imaging study were examined and revealed a remarkable degree of recovery of memory and musical abilities in the context of extensive temporal lobe resection. The neuropsychologic findings and neuroanatomic features of the magnetic resonance imaging study were analyzed to try to understand the high degree of recovery of both long-term memory and musical processing abilities in this musician. CONCLUSIONS: This case reveals the possibility of an unusual degree of cerebral plasticity and reorganization. Additionally, it emphasizes the question of musical virtuosity. This report shows that the musical capabilities of professional musicians, in specific cases, can completely recover even when much of the left temporal lobe has been removed. PMID- 24076058 TI - Clip or coil-is some of the effect on outcome related to the risk of delayed cerebral ischemia? PMID- 24076059 TI - A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. AB - BACKGROUND & AIMS: A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) often is used to manage functional gastrointestinal symptoms in patients with irritable bowel syndrome (IBS), yet there is limited evidence of its efficacy, compared with a normal Western diet. We investigated the effects of a diet low in FODMAPs compared with an Australian diet, in a randomized, controlled, single-blind, cross-over trial of patients with IBS. METHODS: In a study of 30 patients with IBS and 8 healthy individuals (controls, matched for demographics and diet), we collected dietary data from subjects for 1 habitual week. Participants then randomly were assigned to groups that received 21 days of either a diet low in FODMAPs or a typical Australian diet, followed by a washout period of at least 21 days, before crossing over to the alternate diet. Daily symptoms were rated using a 0- to 100-mm visual analogue scale. Almost all food was provided during the interventional diet periods, with a goal of less than 0.5 g intake of FODMAPs per meal for the low FODMAP diet. All stools were collected from days 17-21 and assessed for frequency, weight, water content, and King's Stool Chart rating. RESULTS: Subjects with IBS had lower overall gastrointestinal symptom scores (22.8; 95% confidence interval, 16.7-28.8 mm) while on a diet low in FODMAPs, compared with the Australian diet (44.9; 95% confidence interval, 36.6-53.1 mm; P < .001) and the subjects' habitual diet. Bloating, pain, and passage of wind also were reduced while IBS patients were on the low-FODMAP diet. Symptoms were minimal and unaltered by either diet among controls. Patients of all IBS subtypes had greater satisfaction with stool consistency while on the low-FODMAP diet, but diarrhea predominant IBS was the only subtype with altered fecal frequency and King's Stool Chart scores. CONCLUSIONS: In a controlled, cross-over study of patients with IBS, a diet low in FODMAPs effectively reduced functional gastrointestinal symptoms. This high-quality evidence supports its use as a first-line therapy. CLINICAL TRIAL NUMBER: ACTRN12612001185853. PMID- 24076060 TI - Prior colorectal neoplasia is associated with increased risk of ileoanal pouch neoplasia in patients with inflammatory bowel disease. AB - BACKGROUND & AIMS: Although restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) substantially reduces the risk of colorectal cancer in patients with inflammatory bowel disease (IBD), subsequent pouch neoplasia can develop. There are few data on the incidence of and risk factors for neoplasia, so there is no consensus on the need for pouch surveillance. We aimed to determine the cumulative incidence of pouch neoplasia in patients with IBD and identify risk factors for developing pouch neoplasia. METHODS: We searched the Dutch Pathology Registry (PALGA) to identify all patients with IBD and IPAA in The Netherlands from January 1991 to May 2012. We calculated the cumulative incidence of pouch neoplasia and performed a case-control study to identify risk factors. Demographic and clinical variables were analyzed with univariable and multivariable Cox regression analyses. RESULTS: We identified 1200 patients with IBD and IPAA; 25 (1.83%) developed pouch neoplasia, including 16 adenocarcinomas. Respective cumulative incidences at 5, 10, 15, and 20 years were 1.0%, 2.0%, 3.7%, and 6.9% for pouch neoplasia and 0.6%, 1.4%, 2.1%, and 3.3% for pouch carcinoma. A history of colorectal neoplasia was the only risk factor associated with pouch neoplasia. Hazard ratios were 3.76 (95% confidence interval, 1.39 10.19) for prior dysplasia and 24.69 (95% confidence interval, 9.61-63.42) for prior carcinoma. CONCLUSIONS: The incidence of pouch neoplasia in patients with IBD without a history of colorectal neoplasia is relatively low. Prior dysplasia or colon cancer is associated with an approximate 4- and 25-fold increase in risk, respectively, of developing pouch neoplasia. PMID- 24076062 TI - Preoperative 18F-FDG PET/CT in the management of advanced epithelial ovarian cancer. AB - OBJECTIVE: The introduction of 18-FDG-PET/CT during preoperative evaluation of patients with epithelial ovarian cancer (EOC) has led to an increase of the detection of extra-abdominal metastases. However, the clinical impact of this upstage remains unclear. METHODS: Patients with suspected advanced EOC underwent 18-FDG-PET/CT within two weeks prior to debulking surgery. RESULTS: Between 2006 and 2011 95 patients met the inclusion criteria. Based on the concordance or the discrepancy of clinical and PET/CT stage, patients were divided into 3 groups (A: clinical and PET III; B: clinical III and PET IV; C: clinical and PET IV). Twenty five patients were upstaged from FIGO stage III to stage IV by PET/CT. The proportion of patients who achieved a residual tumor <1cm in group B and C was similar, whereas it was significantly lower compared to group A. Similarly, complete response to adjuvant chemotherapy was achieved more frequently in patients in group A. PFS was similar in the three groups (17, 17 and 12 months in group A, B and C), as well as OS (51, 41 and 35 months). CONCLUSIONS: PET/CT is able to detect distant metastases in EOC patients. The presence of extra abdominal disease probably indicates a more aggressive disease which also shows a lower response to standard chemotherapy. However, upstaged patients have a similar prognosis compared to stage III patients, probably because intra abdominal disease is more likely to lead patients to death. This might also explain why residual tumor is the most important prognostic factor for advanced EOC patients. PMID- 24076061 TI - Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of Crohn's disease. AB - BACKGROUND & AIMS: Genetic susceptibility loci for Crohn's disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD. METHODS: We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections. RESULTS: The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and presence of granuloma. In addition, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. CONCLUSIONS: Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features. PMID- 24076063 TI - Neoadjuvant treatment of endometrial cancer using anastrozole: a randomised pilot study. AB - OBJECTIVE: Excessive oestrogenic stimulation is a well-known risk factor for the development and progression of endometrial cancer. Aromatase is the key enzyme which catalyses the conversion of androgens to oestrogens in postmenopausal women. Inhibition of aromatase may therefore be a useful strategy in the management of endometrial cancer. A pilot study was designed to assess the feasibility of a neoadjuvant model and understand the biological effects of anastrozole, an aromatase inhibitor, in the treatment of endometrial cancer. METHODS: Patients with endometrial cancer who consented to participate in the study were randomised to receive anastrozole or placebo for a minimum of 14 days prior to definitive surgery. Endometrial samples were obtained before and after treatment. Immunohistochemistry was performed to ascertain the expression of oestrogen receptor alpha (ERalpha), progesterone receptor (PR), androgen receptor (AR), ki-67 and Bcl2 before and after treatment in glands and stroma of the endometrium. RESULTS: A total of 16 patients were randomised to the anastrozole arm and 8 to the placebo arm (2:1 randomisation). A significant decrease in the glandular expression of ERalpha and AR was observed in the anastrozole arm. There was no significant change in the expression of PR or Bcl2. Expression of ki-67, a proliferation marker, also decreased significantly following treatment with anastrozole. CONCLUSIONS: Treatment with anastrozole caused a significant decrease in proliferation as demonstrated by decreased ki-67 expression. A large randomised controlled trial is warranted to fully assess the role of anastrozole in the neoadjuvant treatment of endometrial cancer. PMID- 24076064 TI - Gray matter volume and rapid decision-making in major depressive disorder. AB - BACKGROUND: Reduced motivation and blunted decision-making are key features of major depressive disorder (MDD). Patients with MDD show abnormal decision-making when given negative feedback regarding a reward. The brain mechanisms underpinning this behavior remain unclear. In the present study, we examined the association between rapid decision-making with negative feedback and brain volume in MDD. METHODS: Thirty-six patients with MDD and 54 age-, sex- and IQ-matched healthy subjects were studied. Subjects performed a rapid decision-making monetary task in which participants could make high- or low-risk choices. We compared between the 2 groups the probability that a high-risk choice followed negative feedback. In addition, we used voxel-based morphometry (VBM) to compare between group differences in gray matter volume, and the correlation between the probability for high-risk choices and brain volume. RESULTS: Compared to the healthy group, the MDD group showed significantly lower probabilities for high risk choices following negative feedback. VBM analysis revealed that the MDD group had less gray matter volume in the right medial prefrontal cortex and orbitofrontal cortex (OFC) compared to the healthy group. The right OFC volume was negatively correlated with the probability that a high-risk choice followed negative feedback in patients with MDD. We did not observe these trends in healthy subjects. CONCLUSIONS: Patients with MDD show reduced motivation for monetary incentives when they were required to make rapid decisions following negative feedback. We observed a correlation between this reduced motivation and gray matter volume in the medial and ventral prefrontal cortex, which suggests that these brain regions are likely involved in the pathophysiology of aberrant decision-making in MDD. PMID- 24076065 TI - Adult zebrafish model for pneumococcal pathogenesis. AB - Streptococcus pneumoniae (pneumococcus) is a leading cause of community acquired pneumonia, septicemia, and meningitis. Due to incomplete understanding of the host and bacterial factors contributing to these diseases optimal treatment and prevention methods are lacking. In the present study we examined whether the adult zebrafish (Danio rerio) can be used to investigate the pathophysiology of pneumococcal diseases. Here we show that both intraperitoneal and intramuscular injections of the pneumococcal strain TIGR4 cause a fulminant, dose-dependent infection in adult zebrafish, while isogenic mutant bacteria lacking the polysaccharide capsule, autolysin, or pneumolysin are attenuated in the model. Infection through the intraperitoneal route is characterized by rapid expansion of pneumococci in the bloodstream, followed by penetration of the blood-brain barrier and progression to meningitis. Using Rag1 mutant zebrafish, which are devoid of somatic recombination and thus lack adaptive immune responses, we show that clearance of pneumococci in adult zebrafish depends mainly on innate immune responses. In conclusion, this study provides evidence that the adult zebrafish can be used as a model for a pneumococcal infection, and that it can be used to study both host and bacterial factors involved in the pathogenesis. However, our results do not support the use of the zebrafish in studies on the role of adaptive immunity in pneumococcal disease or in the development of new pneumococcal vaccines. PMID- 24076066 TI - PmTBC1D20, a Rab GTPase-activating protein from the black tiger shrimp, Penaeus monodon, is involved in white spot syndrome virus infection. AB - TBC (TRE2/BUB2/CDC16) domain proteins contain an ~ 200-amino-acid motif and function as Rab GTPase-activating proteins that are required for regulating the activity of Rab proteins, and so, in turn, endocytic membrane trafficking in cells. TBC domain family member 20 (TBC1D20) has recently been reported to mediate Hepatitis C virus replication. Herein, PmTBC1D20 identified from the black tiger shrimp, Penaeus monodon, was characterized and evaluated for its role in white spot syndrome virus (WSSV) infection. The full-length cDNA sequence of PmTBC1D20 contains 2003 bp with a predicted 1443 bp open reading frame encoding a deduced 480 amino acid protein. Its transcript levels were significantly up regulated at 24 and 48 h by ~ 2.3- and 2.1-fold, respectively, after systemic infection with WSSV. In addition, depletion of PmTBC1D20 transcript in shrimps by double stranded RNA interference led to a decrease in the level of transcripts of three WSSV genes (VP28, ie1 and wsv477). This suggests the importance of PmTBC1D20 in WSSV infection. This is the first report of TBC1D20 in a crustacean and reveals the possible mechanism used by WSSV to modulate the activity of the host protein, PmTBC1D20, for its benefit in viral trafficking and replication. PMID- 24076067 TI - Ovary ecdysteroidogenic hormone functions independently of the insulin receptor in the yellow fever mosquito, Aedes aegypti. AB - Most mosquito species must feed on the blood of a vertebrate host to produce eggs. In the yellow fever mosquito, Aedes aegypti, blood feeding triggers medial neurosecretory cells in the brain to release insulin-like peptides (ILPs) and ovary ecdysteroidogenic hormone (OEH). Theses hormones thereafter directly induce the ovaries to produce ecdysteroid hormone (ECD), which activates the synthesis of yolk proteins in the fat body for uptake by oocytes. ILP3 stimulates ECD production by binding to the mosquito insulin receptor (MIR). In contrast, little is known about the mode of action of OEH, which is a member of a neuropeptide family called neuroparsin. Here we report that OEH is the only neuroparsin family member present in the Ae. aegypti genome and that other mosquitoes also encode only one neuroparsin gene. Immunoblotting experiments suggested that the full length form of the peptide, which we call long OEH (lOEH), is processed into short OEH (sOEH). The importance of processing, however, remained unclear because a recombinant form of lOEH (rlOEH) and synthetic sOEH exhibited very similar biological activity. A series of experiments indicated that neither rlOEH nor sOEH bound to ILP3 or the MIR. Signaling studies further showed that ILP3 activated the MIR but rlOEH did not, yet both neuropeptides activated Akt, which is a marker for insulin pathway signaling. Our results also indicated that activation of TOR signaling in the ovaries required co-stimulation by amino acids and either ILP3 or rlOEH. Overall, we conclude that OEH activates the insulin signaling pathway independently of the MIR, and that insulin and TOR signaling in the ovaries is coupled. PMID- 24076069 TI - Identifying dominant conformations of N-acetyl-L-cysteine methyl ester and N acetyl-L-cysteine in water: VCD signatures of the amide I and the C=O stretching bands. AB - Infrared (IR) and vibrational circular dichroism (VCD) spectra of N-Acetyl-L Cysteine Methyl Ester (NALCME) and N-Acetyl-L-Cysteine (NALC) in D2O under different pHs were measured. We focus on the VCD signatures of the amide I and the C=O stretching spectral signatures of the neutral NALCME and NALC species and the related ones of the deprotonated NALC species in the region of 1800-1500 cm( 1). A sign inversion is observed for the amide I VCD band going from the neutral NALCME and NALC to the deprotonated NALC species. Density functional theory (DFT) calculations were carried out to search for the possible conformations of these three species and to simulate their IR and VCD spectra at the B3LYP/aug-cc-pVTZ level in the gas phase and with the polarization continuum model of water solvent. The most stable conformations found for neutral NALCME and NALC exhibit drastically difference VCD patterns, whereas those of deprotonated NALC show similar patterns. We establish an empirical structural-spectral relationship where the aforementioned VCD signatures can be used as spectral markers to identify dominant conformations of these two amino acid derivatives under different pHs. It is recognized that the dominant conformers identified using the VCD spectral markers differ from those based on the relative DFT energies for neutral NALCME and NALC. The influence of solvent on both the conformational geometries and their relative stabilities is discussed. The aforementioned discrepancy can be attributed to the explicit solute-solvent hydrogen-bonding interactions which are not accounted for in the calculations. The empirical structural-spectral relationship identified can potentially be applied to large, related amino acids and polypeptides in water. PMID- 24076068 TI - Functional characterisation of a SNP in the ABCC11 allele - effects on axillary skin metabolism, odour generation and associated behaviours. AB - BACKGROUND: A single nucleotide polymorphism (SNP), 538G->A, leading to a G180R substitution in the ABCC11 gene results in reduced concentrations of apocrine derived axillary odour precursors. OBJECTIVE: Determine the axillary odour levels in the SNP ABCC11 genotype variants and to investigate if other parameters associated with odour production are affected. METHODS: Axillary odour was assessed by subjective quantification and gas chromatography headspace analysis. Metabolite profiles, microbiome diversity and personal hygiene habits were also assessed. RESULTS: Axillary odour in the A/A homozygotes was significantly lower compared to the G/A and G/G genotypes. However, the perception-based measures still detected appreciable levels of axillary odour in the A/A subjects. Metabolomic analysis highlighted significant differences in axillary skin metabolites between A/A subjects compared to those carrying the G allele. These differences resulted in A/A subjects lacking specific volatile odourants in the axillary headspace, but all genotypes produced odoriferous short chain fatty acids. Microbiomic analysis revealed differences in the relative abundance of key bacterial genera associated with odour generation between the different genotypes. Deodorant usage indicated a high level of self awareness of axillary odour levels with A/A individuals less likely to adopt personal hygiene habits designed to eradicate/mask its presence. CONCLUSIONS: The SNP in the ABCC11 gene results in lower levels of axillary odour in the A/A homozygotes compared to those carrying the G allele, but A/A subjects still produce noticeable amounts of axillary odour. Differences in axillary skin metabolites, bacterial genera and personal hygiene behaviours also appear to be influenced by this SNP. PMID- 24076071 TI - Prevention of infection in external fixator pin sites. AB - Infection in external fixator pins is known to be a significant problem, with incidences between 3% and 80% reported in the literature. An infection occurs when planktonic bacteria adhere to external fixator pins and subsequently produce a biofilm which protects the bacteria from host defences. The most commonly implicated organisms are Staphylococcus aureus and Staphylococcus epidermidis. Once an infection occurs, treatment is difficult. Systemic antibiotics have limited benefits and considerable side-effects. The only definitive management is removal of the pin. This review will consider the current and potential future strategies for reducing pin site infection. Techniques to prevent infection must prevent bacterial adhesion, allow good osteointegration and have a low toxicity. Current areas of interest reviewed are titanium-copper alloys, nanosilver coatings, nitric oxide coatings, chitosan coatings, chlorhexidine and iodine, hydroxyapatite and antibiotic coatings. At present there is no consensus on the prevention of pin site infection, and there is a paucity of randomized controlled trials on which to draw a conclusion. Whilst a number of these strategies have potential future use, many of the above strategies need further studies in animal models to ensure no cytotoxicity and prevention of osteointegration. Following this, well-designed randomized controlled clinical trials are required to give future ways to prevent external fixator pin site infections. PMID- 24076070 TI - Swelling equilibrium of dentin adhesive polymers formed on the water-adhesive phase boundary: experiments and micromechanical model. AB - During their application to the wet, oral environment, dentin adhesives can experience phase separation and composition change, which can compromise the quality of the hybrid layer formed at the dentin-adhesive interface. The chemical composition of polymer phases formed in the hybrid layer can be represented using a ternary water-adhesive phase diagram. In this paper, these polymer phases are characterized using a suite of mechanical tests and swelling experiments. The experimental results were evaluated using a granular micromechanics-based model incorporating poro-mechanical effects and polymer-solvent thermodynamics. The variation in the model parameters and model-predicted polymer properties was studied as a function of composition along the phase boundary. The resulting structure-property correlations provide insight into interactions occurring at the molecular level in the saturated polymer system. These correlations can be used for modeling the mechanical behavior of the hybrid layer, and are expected to aid in the design and improvement of water-compatible dentin adhesive polymers. PMID- 24076072 TI - Sustained release of triamcinolone acetonide from an episcleral plaque of multilayered poly-epsilon-caprolactone matrix. AB - A subtenon injection of triamcinolone acetonide (TA) is a widely used treatment modality for various chorio-retinal diseases. Although it is less invasive than intravitreal injection, it can produce dose-associated ocular complications and has the disadvantages associated with systemic TA exposure. In this study we have developed and evaluated an episcleral film consisting of TA and poly-epsilon caprolactone (PCL). The films were prepared by spraying a mixture of PCL in dichloromethane and TA in acetone. The films were produced as 6mm wide and 12 mm long episcleral plaques. X-ray diffraction demonstrated an even distribution of TA crystals in PCL, although the TA was less crystalized than a native TA control. Fourier transform infrared spectroscopy revealed effective integration of TA within the PCL matrix. An in vitro study of the release of TA from the episcleral plaques showed that TA release rate was only 40-50% that of the equivalent native TA control. An in vivo study demonstrated that the plaques were well tolerated in rabbit eyes with significantly less systemic TA exposure. The episcleral plaques provided therapeutic vitreous TA levels for 3 months, while TA levels in the vitreous were detectable for only 1 month following an equivalent dose by subtenon TA injection. The PCL-TA 30-60 episcleral plaque may be further developed as a better alternative treatment for many chronic vitreo-retinal diseases, providing longer and controlled release and fewer drug-associated complications than those associated with a conventional subtenon injection of TA. PMID- 24076073 TI - Bone healing and the effect of implant surface topography on osteoconduction in hyperglycemia. AB - Dental implant failures that occur clinically for unknown reasons could be related to undiagnosed hyperglycemia. The exact mechanisms that underlie such failures are not known, but there is a general consensus that bone growth is compromised in hyperglycemia. Nevertheless, contradictory findings exist related to peri-implant bone healing in hyperglycemia. We hypothesized that hyperglycemia delays early bone healing by impeding osteoconduction, and that the compromised implant integration due to hyperglycemia could be abrogated by using nanotopographically complex implants. Thus we undertook two parallel experiments, an osteotomy model and a bone in-growth chamber model. The osteotomy model tracked temporal bone healing in the femora of euglycemic and hyperglycemic rats using micro computed tomography (microCT) analysis and histology. The bone in growth chamber model used implant surfaces of either micro- or nanotopographical complexity and measured bone-implant contact (BIC) using backscattered electron imaging in both metabolic groups. Quantitative microCT analyses on bone volume, trabeculae number and trabeculae connectivity density provided clear evidence that bone healing, both reparative trabecular bone formation and remodeling, was delayed in hyperglycemia, and the reparative bone volume changed with time between metabolic groups. Furthermore, fluorochrome labeling showed evidently less mineralized bone in hyperglycemic than euglycemic animals. An increased probability of osteoconduction was seen on nano-compared with microtopographically complex surfaces, independent of metabolic group. The nanotopographically complex surfaces in hyperglycemia outperformed microtopographically complex surfaces in euglycemic animals. In conclusion, the compromised implant integration in hyperglycemia is abrogated by the addition of nanotopographical features to an underlying microtopographically complex implant surface. PMID- 24076074 TI - Electrochemical behavior of (Ti 1-x Nb x)5Si3 nanocrystalline films in simulated physiological media. AB - In this paper, (Ti1-xNbx)5Si3 nanocrystalline films were synthesized and their potential as highly corrosion-resistant coatings for the biomedical alloy Ti-6Al 4V was explored. To assess the electrochemical behavior of the as-deposited films, the samples were immersed in Ringer's solution open to air at 37 degrees C. The processes that govern the electrochemical reactions at the film surface were analyzed using a combination of complementary electrochemical measurement techniques such as potentiodynamic polarization, electrochemical impedance spectroscopy and Mott-Schottky analysis. The results show that the (Ti1-xNbx)5Si3 nanocrystalline films offer Ti-6Al-4V a strong shield from corrosive attack and the addition of Nb in the films greatly enhances their resistance to corrosion, and in so doing, minimizes metal ion release. Collectively, our data suggest that (Ti1-xNbx)5Si3 nanocrystalline films as supreme coatings with anti-corrosive properties have potential to improve the performance and extend the service life of orthopedic and cochlear implants. PMID- 24076075 TI - Intervertebral discs influence vertebral body bone. PMID- 24076076 TI - Functional characterization of the hexose transporter Hxt13p: an efflux pump that mediates resistance to miltefosine in yeast. AB - Miltefosine (MI) has in vitro fungicidal activity against pathogenic fungi. However, mechanisms of resistance to MI have not been studied. By screening a genomic library of the model yeast, Saccharomyces cerevisiae, we identified HXT13 as a candidate genetic determinant of MI resistance. HXT13 belongs to the yeast hexose transporter family, which mediates hexose sugar uptake and is included in the major facilitator superfamily (MFS). We now report that overexpression of HXT13, but not of the closely-related genes, HXT15 and HXT17, and the more distantly related HXT14, resulted in a stable MI-resistant phenotype in S. cerevisiae. Resistance of the HXT13 overexpressing strain to MI correlated with higher cell viability following MI exposure as assessed by SYTOX(r) green staining compared with the control and overexpressing HXT14 strains. The mechanism of resistance in the HXT13 overexpressing strain was due to increased ATP-independent MI efflux. However, resistance to MI of the HXT13-overexpressing strain did not extend to other drugs including the echinocandins, amphotericin B, azoles, cycloheximide and sulfometuron methyl, ruling out the involvement of HXT13 in multidrug resistance. In summary, we have identified a new function of the hexose sugar transporter gene HXT13 when overexpressed in S. cerevisiae, namely, in efflux of MI and in mediating MI resistance. PMID- 24076077 TI - Impact of alg3 gene deletion on growth, development, pigment production, protein secretion, and functions of recombinant Trichoderma reesei cellobiohydrolases in Aspergillus niger. AB - Dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl alpha-1,3-mannosyltransferase (also known as "asparagine-linked glycosylation 3", or ALG3) is involved in early N linked glycan synthesis and thus is essential for formation of N-linked protein glycosylation. In this study, we examined the effects of alg3 gene deletion (alg3Delta) on growth, development, pigment production, protein secretion and recombinant Trichoderma reesei cellobiohydrolase (rCel7A) expressed in Aspergillus niger. The alg3Delta delayed spore germination in liquid cultures of complete medium (CM), potato dextrose (PD), minimal medium (MM) and CM with addition of cAMP (CM+cAMP), and resulted in significant reduction of hyphal growth on CM, potato dextrose agar (PDA), and CM+cAMP and spore production on CM. The alg3Delta also led to a significant accumulation of red pigment on both liquid and solid CM cultures. The relative abundances of 54 of the total 215 proteins identified in the secretome were significantly altered as a result of alg3Delta, 63% of which were secreted at higher levels in alg3Delta strain than the parent. The rCel7A expressed in the alg3Delta mutant was smaller in size than that expressed in both wild-type and parental strains, but still larger than T. reesei Cel7A. The circular dichroism (CD)-melt scans indicated that change in glycosylation of rCel7A does not appear to impact the secondary structure or folding. Enzyme assays of Cel7A and rCel7A on nanocrystalline cellulose and bleached kraft pulp demonstrated that the rCel7As have improved activities on hydrolyzing the nanocrystalline cellulose. Overall, the results suggest that alg3 is critical for growth, sporulation, pigment production, and protein secretion in A. niger, and demonstrate the feasibility of this alternative approach to evaluate the roles of N-linked glycosylation in glycoprotein secretion and function. PMID- 24076078 TI - New features on Pso2 protein family in DNA interstrand cross-link repair and in the maintenance of genomic integrity in Saccharomyces cerevisiae. AB - Pso2 protein, a member of the highly conserved metallo-beta-lactamase (MBL) super family of nucleases, plays a central role in interstrand crosslink repair (ICL) in yeast. Pso2 protein is the founder member of a distinct group within the MBL superfamily, called beta-CASP family. Three mammalian orthologs of this protein that act on DNA were identified: SNM1A, SNM1B/Apollo and SNM1C/Artemis. Yeast Pso2 and all three mammalian orthologs proteins have been shown to possess nuclease activity. Besides Pso2, ICL repair involves proteins of several DNA repair pathways. Over the last years, new homologs for human proteins have been identified in yeast. In this review, we will focus on studies clarifying the function of Pso2 protein during ICL repair in yeast, emphasizing the contribution of Brazilian research groups in this topic. New sub-pathways in the mechanisms of ICL repair, such as recently identified conserved Fanconi Anemia pathway in yeast as well as a contribution of non-homologous end joining are discussed. PMID- 24076079 TI - Systematic review of home-based exercise programmes for individuals with intermittent claudication. AB - We aimed to conduct a systematic review of the evidence for structured, home based exercise programmes (HEPs) in patients with intermittent claudication. The Medline, PsycINFO, EMBASE, and Cochrane databases were searched up to April 2013 for terms related to walking, self-management, and intermittent claudication. Descriptive, methodological and outcome data were extracted from eligible articles. Trial quality was assessed using the GRADE system. Seventeen studies were included with 1,457 participants. Six studies compared HEPs with supervised exercise training, five compared HEPs with usual care/observation control, and seven evaluated HEPs in a single-group design. Trial heterogeneity prevented meta analysis. Nevertheless, there was "low-level" evidence that HEPs can improve walking capacity and quality of life in patients with intermittent claudication when compared with baseline or in comparison to usual care/observation control. In addition, improvements with HEPs may be inferior to those evoked by supervised exercise training. Considerable uncertainty exists regarding the long-term clinical and cost effectiveness of HEPs in patients with intermittent claudication. Thus, more robust trials are needed to build evidence about these interventions. Nevertheless, clinicians should consider using structured interventions to promote self-managed walking in patients with intermittent claudication, as opposed to simple "go home and walk" advice, when supervised exercise training is unavailable or impractical. PMID- 24076080 TI - Prevalence of severe subclinical coronary artery disease on cardiac CT and MRI in patients with extra-cardiac arterial disease. AB - OBJECTIVE: Patients with extra-cardiac arterial disease (ECAD) are at high risk of coronary artery disease (CAD). Prevalence of silent, significant CAD in patients with stenotic or aneurysmal ECAD was examined. Early detection and treatment may reduce CAD mortality in this high-risk group. MATERIALS AND METHODS: ECAD patients without cardiac complaints underwent computed tomography (CT) for calcium scoring, coronary CT angiography (cCTA) if calcium score was 1,000 or under, and adenosine perfusion magnetic resonance imaging (APMR) if there was no left main stenosis. Significant CAD was defined as calcium score over 1,000, cCTA-detected coronary stenosis of at least 50% lumen diameter, and/or APMR-detected inducible myocardial ischemia. In cases of left main stenosis (or equivalent) or myocardial ischemia, patients were referred to a cardiologist. RESULTS: The prevalence of significant CAD was 56.8% (95% CI 47.5 to 66.0). One-hundred and eleven patients were included. Eighty-four patients (76%) had stenotic ECAD, and 27 (24%) had aneurysmal disease. In patients with stenotic ECAD, significant coronary stenosis was present in 32 (38%) and inducible ischemia in eight (12%). Corresponding results in aneurysmal ECAD were eight (30%) and two (11%), respectively (p for difference >.05). Sixteen (19%) patients with stenotic and six (22%) with aneurysmal ECAD were referred to a cardiologist, with subsequent cardiac intervention in seven (44%) and three (50%), respectively (both p >.05). CONCLUSIONS: Patients with stenotic or aneurysmal ECAD have a high prevalence of silent, significant CAD. PMID- 24076081 TI - Standardized definitions and clinical endpoints in trials investigating endovascular repair of aortic dissections. AB - OBJECTIVES: Endovascular therapy is a rapidly expanding option for the treatment of patients with aortic dissection (AD) and various studies have been published. These trials, however, are often difficult to interpret and compare because they do not utilize uniform clinical endpoint definitions. METHODS: The DEFINE Group is a collaborative effort of an ad hoc multidisciplinary team from various specialties involved in AD therapy in Europe and the United States. DEFINE's goal was to arrive at a broad based consensus for baseline and endpoint definitions in trials for endovascular therapy of various vascular pathologies. In this project, which started in December 2006, the individual team members reviewed the existing pertinent literature. Following this, a series of telephone conferences and face to-face meetings were held to agree upon definitions. Input was also obtained from regulatory (United States Food and Drug Administration) and industry (device manufacturers with an interest in peripheral endovascular revascularization) stakeholders, respectively. RESULTS: These efforts resulted in the present document containing proposed baseline and endpoint definitions for clinical and morphological outcomes. Although the consensus has inevitably included certain arbitrary consensus choices and compromises, adherence to these proposed standard definitions would provide consistency across future trials, thereby facilitating evaluation of clinical effectiveness and safety of various endovascular revascularization techniques. CONCLUSIONS: This current document is based on a broad based consensus involving relevant stakeholders from the medical community, industry and regulatory bodies. It is proposed that the consensus document may have value for study design of future clinical trials in endovascular AD therapy as well as for regulatory purposes. PMID- 24076083 TI - Development and use of a knowledge translation tool: the rehabilitation measures database. AB - Clinical translation of research evidence is a challenge for rehabilitation clinicians. Publicly accessible and free, online educational resources that summarize research evidence can support implementation of research evidence into practice. Several online resources have been developed recently to overcome common knowledge translation barriers. The Rehabilitation Measures Database (RMD) is a free, web-based searchable database of standardized instruments that was designed to support knowledge translation. It helps clinicians select valid and sensitive instruments for screening patients, monitoring progress, and assessing rehabilitation outcomes. The RMD was developed using feedback from focus groups and beta-test participants. Since its launch in 2011, RMD use has grown to an average of 1851 hits per day from 168 countries. As of September 2013, 202 instrument summaries are viewable in the RMD. Most summaries are linked to copies of the instrument or to purchase instructions. A challenge in updating and expanding the RMD is securing the resources to ensure its future. Collaborative relationships with professional associations and graduate programs in the health sciences are critical in sustaining this resource. PMID- 24076082 TI - Analysis of PTP1B sumoylation. AB - Signaling enzymes are typically regulated by a variety of post-translational modifications. One such enzyme, protein tyrosine phosphatase (PTP) 1B, which plays an important role in metabolic and growth signaling, has recently been shown to be inhibited by posttranslational modifications by ubiquitin-related proteins of the SUMO family. We have adapted several approaches to analyzing the sites and effects of sumoylation of PTP1B in cells and in vitro. The principal outline of the assays should be applicable to other enzymes as well. PMID- 24076084 TI - Estimating postural control with the balance rehabilitation unit: measurement consistency, accuracy, validity, and comparison with dynamic posturography. AB - OBJECTIVE: To examine the psychometric properties (test-retest reliability, concurrent validity, construct validity) of the Balance Rehabilitation Unit (BRU) during testing of sensory integration processes in healthy adults and individuals with vestibular disorders. DESIGN: Experimental cross-sectional design. SETTING: Clinic. PARTICIPANTS: Participants (N=90) included 30 subjects with vestibular disorders (age range, 18-85y), 30 young healthy adults (age range, 18-50y), and 30 older healthy adults (age range, 60-85y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were tested twice with the BRU and once with the SMART EquiTest Sensory Organization Test (SOT). The center of pressure (COP) in the anteroposterior direction (COPap) and the COP in the mediolateral direction (COPml) were recorded. The COPap and COPml time series were used to estimate the area and velocity of the COP. RESULTS: The intraclass correlation coefficient of the COP area and velocity measures for the BRU for all subjects was at least .76 in all sensory organization conditions (P<.001). Significant correlations were found between the BRU and the SOT, ranging from .64 to .81 for COP area and from .44 to .76 for COP velocity. The older control group had significantly greater COP area and velocity compared with younger controls for the BRU and the SOT. The COP (area, velocity) was significantly higher for the younger individuals in the vestibular group than the younger controls. CONCLUSIONS: The reliability and validity of COP measurements obtained during testing of the sensory integration processes were demonstrated using the BRU. Future work should examine the responsiveness of these measures when individuals with balance disorders participate in rehabilitation. PMID- 24076085 TI - Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway. AB - During early brain development, N-methyl-d-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3 monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61 8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog. PMID- 24076086 TI - Postnatal neuronal apoptosis in the cerebral cortex: physiological and pathophysiological mechanisms. AB - In the first week of postnatal life of all examined mammalian species, there is a wave of apoptosis in the cerebral cortex, accounting for a loss of up to 30% of neuronal content from birth to adulthood. In this review we examine recent advances in the understanding of this curious phenomenon. We survey the phenomenological literature and elaborate a putative relationship between the formation of active neuronal networks and selective apoptosis of non participatory neurons. The underlying reason for this apoptotic wave remains unclear, but molecular mechanisms are starting to be elucidated that account for its mechanism, including a role for insulin-like growth factor I (IGF-1) and the Rho GTPases RhoA and RhoB. In addition, we discuss pathophysiological situations in which a variety of common drugs used either recreationally or for medical purposes, or pharmacological blockade of N-methyl-d-aspartate receptor (NMDAR) function, can also cause massive levels of apoptosis in this same developmental window. Experimentation linking molecular causes of developmental and pathophysiological apoptosis in postnatal cerebral cortex is discussed. PMID- 24076088 TI - Antinociception and prevention of hyperalgesia by intrathecal administration of Ro 25-6981, a highly selective antagonist of the 2B subunit of N-methyl-D aspartate receptor. AB - BACKGROUND: NR2B subunits (NMDA receptor 2B subunit) play an important role in generation of pain and forming central sensitization of pain. Ro 25-6981, a highly selective NR2B antagonist, gained much attention in recent years. In this study, we used a rat model of incisional pain to investigate effects of postoperative analgesia and changes of postoperative hyperalgesia induced by remifentanil through the pretreatment of intrathecal administration with Ro 25 6981. METHODS: The behavioral changes of rats have been evaluated by the paw withdrawal mechanical threshold and paw withdrawal thermal latency after intrathecal injection of Ro 25-6981. The expression of NR2B with tyrosine phosphorylation in the spinal dorsal horn was analyzed by Western blotting. RESULTS: Intrathecal injection of Ro 25-6981 significantly enhanced the paw withdrawal mechanical threshold and paw withdrawal thermal latency after the operation. Significant change has been observed after intrathecal injection of 800.0 MUg of Ro 25-6981 and at 2h after operation in the oblique pull test degree and BBB rating score. Pretreatment of Ro 25-6981 decreased the high level expression of NR2B with tyrosine phosphorylation in spinal dorsal horn of the rat model after the operation. CONCLUSIONS: Intrathecal injection of Ro 25-6981 had significant analgesic effects on incision pain in rats and effectively attenuated postoperative hyperalgesia induced by remifentanil. PMID- 24076087 TI - Chronic binge-like alcohol consumption in adolescence causes depression-like symptoms possibly mediated by the effects of BDNF on neurogenesis. AB - Here we investigated whether changes in neurogenesis and brain-derived neurotrophic factor (BDNF) expression are possible mechanisms involved in the depression-like symptom during the withdrawal/abstinence period after chronic binge-pattern alcohol consumption given the limited number of studies addressing the link between these factors in the adolescent brain. Forty-seven male Sprague Dawley rats were used in the study and the experimental protocol started when rats were 25-days old. Rats were assigned to either: (a) ethanol or (b) control group. Animals in each group were further randomized to receive either: BDNF receptor agonist or vehicle. Rats were trained to self-administer ethanol and the binge protocol consisted of daily 30-min experimental sessions 4h into the dark period for 12days. Two days after the last drinking session, rats were tested in the sucrose preference test to evaluate anhedonia and the open field test after habituation to evaluate behavioral despair. Our data showed that: (1) self administration of alcohol in a binge-like pattern causes inebriation as defined by the National Institute on Alcohol Abuse and Alcoholism and this pattern of alcohol exposure is associated with the development of a depression-like symptom; (2) no significant difference in blood alcohol levels between the two ethanol groups; and (3) chronic binge drinking resulted in the development of a depressive phenotype, decreased survival and neuronal differentiation of neural progenitor cells in the hippocampus, and decreased BDNF effect during the withdrawal period. But the most important finding in our study is that augmenting BDNF actions through the use of tyrosine kinase B (TrkB, a BDNF receptor) agonist restored neurogenesis and abolished the alcohol-induced anhedonia and despair behaviors seen during the withdrawal/abstinence period. Our results suggest that BDNF might be a molecule that can be targeted for interventions in alcoholism depression co-incidence. PMID- 24076089 TI - Proteolytic activity regarding Sarconesiopsis magellanica (Diptera: Calliphoridae) larval excretions and secretions. AB - Sarconesiopsis magellanica (Diptera: Calliphoridae) is a medically important necrophagous fly which is used for establishing the post-mortem interval. Diptera maggots release proteolytic enzymes contained in larval excretion and secretion (ES) products playing a key role in digestion. Special interest in proteolytic enzymes has also been aroused regarding understanding their role in wound healing since they degrade necrotic tissue during larval therapy. This study was thus aimed at identifying and characterising S. magellanica proteolytic enzyme ES products for the first time. These products were obtained from first-, second- and third-instar larvae taken from a previously-established colony. ES proteins were separated by SDS-PAGE and their proteolytic activity was characterised by zymograms and inhibition assays involving BAPNA (Nalpha-benzoyl-dl-Arg-p nitroanilide) and SAPNA substrates, using synthetic inhibitors. The protein profile ranged from ~69kDa to ~23kDa; several of them coincided with the Lucilia sericata ES protein profile. Serine-protease hydrolysis activity (measured by zymogram) was confirmed when a ~25kDa band disappeared upon ES incubation with PMSF inhibitor at pH 7.8. Analysis of larval ES proteolytic activity on BAPNA and SAPNA substrates (determined by using TLCK and TPCK specific inhibitors) suggested a greater amount of trypsin-like protease. These results support the need for further experiments aimed at validating S. magellanica use in larval therapy. PMID- 24076090 TI - Longitudinal T cell-derived IFN-gamma/IL-17 balances do not correlate with the disease course in two mouse models of experimental autoimmune encephalomyelitis. AB - The concept of TH17 stemness is attracting increasing attention in the field of tumor immunology. The expression of stem cell-like properties and the promotion of long-term immunity by TH17 cells are also of outmost relevance for autoimmunity. Studying two mouse models of multiple sclerosis (MS), we show that CNS antigen-specific TH17 cells occur in high frequencies in the individual mice. However, there was no preferential shift towards a TH17 response over time. These data suggest that there is no evidence for a differential apoptosis rate in TH1 versus TH17 cells in EAE. Apparently the selective enrichment of TH17 cells that can occur under certain conditions such as cancer does not result from an intrinsic property of TH17 cells, but rather from selective pressure present in the microenvironment. PMID- 24076091 TI - Further clinical evidence for the existence of neurotoxicity in a population of the European adder (Vipera berus berus) in eastern Hungary: second authenticated case. AB - We report a recent case of common adder (Vipera berus) envenoming causing paralytic signs and symptoms. A 12-year-old girl was bitten by the nominate subspecies of the common adder (V. berus berus) in eastern Hungary on May 2, 2012, 22 km away from where the first neurotoxic V. berus berus envenoming was reported in 2008. The patient developed unambiguous cranial nerve disturbances, manifested in bilateral impairment characterized by oculomotor paralysis with partial ptosis, gaze paresis, and diplopia. Drowsiness and photophobia were her additional symptoms; both occurred only during the first day of envenoming. Until now among viper envenomings in Europe, photophobia has only been documented by victims of Vipera aspis. Supportive and symptomatic treatments were administered during 3 days of hospitalization. Although case reports of V. berus berus envenomings are often published, clinical experience with neurotoxicity by this subspecies still remains rare. Population-based and geographic variation of venom composition in V. berus berus seems to include neurotoxic envenomings in certain populations. This second authenticated case provides new clinical evidence for the existence of a possible neurotoxic V. berus berus population in a restricted geographical area in eastern Hungary. PMID- 24076092 TI - Dental extractions using improvised equipment. AB - Extracting a tooth is the final treatment for multiple dental problems. Persons who are not dentists, however, have little experience with tooth extractions. When a remote setting makes it impossible to send a patient for optimal dental treatment, the clinician may need to extract teeth, sometimes using improvised equipment. The following cases of two patients with three carious, painful molars describe such a situation. The non-dental clinicians had to improvise not only appropriate dental tools, but also personal protective equipment, a functional suction machine, medications for a dental block, a dental chair, and dental consent forms and follow-up instructions in the patients' language. In these cases, they also communicated with their patients through a translator. To prepare to do tooth extractions in remote settings, clinicians should learn and practice dental blocks and review extraction techniques before they deploy. If they must do an extraction, clinicians should use the closest approximation available to the appropriate dental tools. When done correctly, a dental extraction can take some time and should not be rushed. PMID- 24076093 TI - Functional and physiological outcomes following repair of obstetrics anal sphincter injury. A case. AB - INTRODUCTION: Obstetric anal sphincter injury has important psychosocial implications and impact on subsequent pregnancies. Sound operative repair is essential, yet between 14 and 61% patients with obstetric anal sphincter injuries report incontinence symptoms. Objective assessment of the outcome following repair can be performed using anorectal manometry and endoanal ultrasonography. The aim of this study was to assess functional and physiological outcome in patients undergoing operative repair of third or fourth degree tears. METHODS: Demographic information and obstetric details were collected retrospectively for patients who sustained a third or fourth degree anal sphincter injury between the periods of 1st January 2008-31st December 2009. All patients were followed up by the Colorectal Nurse Specialist in a dedicated clinic. A detailed history, examination, anorectal manometry (AM) and endoanal ultrasound (EAU) were performed. RESULTS: Of 210 patients identified data was available for 190 (90%). Median age was 29 years and 74% of the patients were primagravida. Twenty one (11%) patients had grade 3 tear, 81 (43%) grade 3a, 63 (33%) grade 3b, 15 (8%) grade 3c and 10 (5%) patients had grade 4 tears. All patients underwent primary repair: where data was available for operative technique 68 (36%) patients underwent end-to-end and 96 (51%) had overlap repair. 177 (93%) of the repairs were performed by Registrars. Median follow up was 3 months and data was available for 142 (75%) patients. 29 (20%) patients exhibited symptoms of incontinence. Anal resting and squeeze pressure were reduced in patients experiencing incontinence symptoms (66 mHg vs 58 mmHg and 120 mmHg vs 98 mmHg respectively). EAU revealed one EAS (external anal sphincter)/IAS (internal AS) defect, seven IAS defects and 33 thinning of IAS. One quarter of patients with IAS thinning or defect exhibited incontinence symptoms. CONCLUSION: One fifth of patients experienced some incontinence following repair of obstetric anal sphincter injury, but only 2 patients were incontinent of faeces at 3 month follow up. This represents some improvement in outcome compared to results from the last two decades. Anal pressures in patients experiencing incontinence were reduced, and thinning of the IAS was more common in patients with incontinence symptoms. Efforts to identify occult IAS injury and repair this as well as the EAS may improve patient outcome. PMID- 24076094 TI - Vaginal metastases from colorectal cancer. AB - BACKGROUND: Vaginal metastases originating from colorectal carcinoma are very rare. Due to the limited number of reported cases, there is no proposed standard treatment and little is known about its management outcome. AIM: The aim of this article is to review the available literature to establish the clinical presentation, trends in treatment and prognosis of vaginal metastases from colorectal malignancy. METHODS: A literature search using keywords used for database search were 'colorectal carcinoma', 'colorectal cancer', 'colon cancer' and 'vaginal metastasis'. RESULTS: Of the 30 articles identified, 37 reported cases, were accessible for full evaluation. Cases reported originates from various countries and majority presented with vaginal bleeding. Diagnosis was established after histological examination and treatment options consist of surgical resection, radiotherapy or chemotherapy that have been used individually or in combination. Association with disseminated metastatic disease indicates ominous prognosis as seen in 32.4% (n = 12) cases. CONCLUSION: Vaginal metastasis of colorectal cancer should be included in the differential diagnosis of a vaginal swelling. There is no proposed standard treatment for vaginal metastases but surgical resection is an appropriate approach for local control when no disseminated metastatic disease is documented. PMID- 24076095 TI - Cytokine regulation of mammary gland development and epithelial cell functions through discrete activities of Stat proteins. PMID- 24076096 TI - The immune privilege of testis and gravid uterus: same difference? AB - The fetus in the gravid uterus and the developing spermatogenic cells in the adult testis both comprise special challenges for the host immune system. Protection of the neoantigens of the fetus and male germ cells from immune attack, defined as immune privilege, is fundamental for the propagation of species. Immune privilege is not simply the absence of leukocytes, but involves immune and non-immune cells acting synergistically together at multiple levels to create a unique tolerogenic environment. A number of the pathways are shared by the testis and gravid uterus. Amongst them steroid hormones, namely testosterone in the male and progesterone in the female, seem to function as key molecules that govern the local production of immunoregulatory factors which finally control the overall immune environment. PMID- 24076097 TI - Control of mammalian germ cell entry into meiosis. AB - Germ cells are unique in undergoing meiosis to generate oocytes and sperm. In mammals, meiosis onset is before birth in females, or at puberty in males, and recent studies have uncovered several regulatory steps involved in initiating meiosis in each sex. Evidence suggests that retinoic acid (RA) induces expression of the critical pre-meiosis gene Stra8 in germ cells of the fetal ovary, pubertal testis and adult testis. In the fetal testis, CYP26B1 degrades RA, while FGF9 further antagonises RA signalling to suppress meiosis. Failsafe mechanisms involving Nanos2 may further suppress meiosis in the fetal testis. Here, we draw together the growing knowledge relating to these meiotic control mechanisms, and present evidence that they are co-ordinately regulated and that additional factors remain to be identified. Understanding this regulatory network will illuminate not only how the foundations of mammalian reproduction are laid, but also how mis-regulation of these steps can result in infertility or germline tumours. PMID- 24076098 TI - Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. AB - Cannabinoids, the active components of cannabis (Cannabis sativa) extracts, have attracted the attention of human civilizations for centuries, much earlier than the discovery and characterization of their substrate of action, the endocannabinoid system (ECS). The latter is an ensemble of endogenous lipids, their receptors [in particular type-1 (CB1) and type-2 (CB2) cannabinoid receptors] and metabolic enzymes. Cannabinoid signaling regulates cell proliferation, differentiation and survival, with different outcomes depending on the molecular targets and cellular context involved. Cannabinoid receptors are expressed and functional from the very early developmental stages, when they regulate embryonic and trophoblast stem cell survival and differentiation, and thus may affect the formation of manifold adult specialized tissues derived from the three different germ layers (ectoderm, mesoderm and endoderm). In the ectoderm-derived nervous system, both CB1 and CB2 receptors are present in neural progenitor/stem cells and control their self-renewal, proliferation and differentiation. CB1 and CB2 show opposite patterns of expression, the former increasing and the latter decreasing along neuronal differentiation. Recently, endocannabinoid (eCB) signaling has also been shown to regulate proliferation and differentiation of mesoderm-derived hematopoietic and mesenchymal stem cells, with a key role in determining the formation of several cell types in peripheral tissues, including blood cells, adipocytes, osteoblasts/osteoclasts and epithelial cells. Here, we will review these new findings, which unveil the involvement of eCB signaling in the regulation of progenitor/stem cell fate in the nervous system and in the periphery. The developmental regulation of cannabinoid receptor expression and cellular/subcellular localization, together with their role in progenitor/stem cell biology, may have important implications in human health and disease. PMID- 24076099 TI - Levodopa induces long-lasting modification in the functional activity of the nigrostriatal pathway. AB - Much controversy exists concerning the effect of levodopa on striatal dopaminergic markers in Parkinson's disease (PD) and its influence on functional neuroimaging. To deal with this issue we studied the impact of neurotoxin 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and chronic levodopa administration on striatal (18)F-DOPA uptake (Ki) in an animal model of PD. The levels of several striatal dopaminergic markers and the number of surviving dopaminergic neurons in the substantia nigra (SN) were also assessed. Eleven Macaca fascicularis were included in the study. Eight animals received weekly intravenous injections of MPTP for 7weeks and 3 intact animals served as controls. MPTP-monkeys were divided in two groups. Group I was treated with placebo while Group II received levodopa. Both treatments were maintained for 11months and then followed by a washout period of 6months. (18)F-DOPA positron emission tomography (PET) scans were performed at baseline, after MPTP intoxication, following 11months of treatment, and after a washout period of 1, 3 and 6months. Monkeys were sacrificed 6months after concluding either placebo or levodopa treatment and immediately after the last (18)F-DOPA PET study. Striatal dopamine transporter (DAT) content, tyrosine hydroxylase (TH) content and aromatic l-amino acid decarboxylase (AADC) content were assessed. In Group II (18)F-DOPA PET studies performed at 3 and 6months after interrupting levodopa showed a significantly increased Ki in the anterior putamen as compared to Group I. Levodopa and placebo treated animals exhibited a similar number of surviving dopaminergic cells in the SN. Striatal DAT content was equally reduced in both groups of animals. Animals in Group I exhibited a significant decrease in TH protein content in all the striatal regions assessed. However, in Group II, TH levels were significantly reduced only in the anterior and posterior putamen. Surprisingly, in the levodopa-treated animals the TH levels in the posterior putamen were significantly lower than those in the placebo group. AADC levels in MPTP groups were similar to those of control animals in all striatal areas analyzed. This study shows that chronic levodopa administration to monkeys with partial nigrostriatal degeneration followed by a washout period induces modifications in the functional activity of the dopaminergic nigrostriatal pathway. PMID- 24076100 TI - Increased misfolding and truncation of tau in APP/PS1/tau transgenic mice compared to mutant tau mice. AB - Neurofibrillary degeneration in transgenic models of tauopathies has been observed to be enhanced when these models are crossed with transgenic models developing an Abeta pathology. The mechanisms leading to this enhanced tau pathology are not well understood. We have performed a detailed analysis of tau misprocessing in a new transgenic mouse model combining APP, PS1 and tau mutations (5xFAD*Tg30 mice) by comparison with littermates expressing only a FTD mutant tau (Tg30 mice). These 5xFAD*Tg30 mice showed a more severe deficient motor phenotype than Tg30 mice and developed with age a dramatically accelerated NFT load in the brain compared to Tg30 mice. Insoluble tau in 5xFAD*Tg30 mice compared to insoluble tau in Tg30 mice showed increased phosphorylation, enhanced misfolding and truncation changes mimicking more closely the post-translational changes characteristic of PHF-tau in Alzheimer's disease. Endogenous wild-type mouse tau was recruited at much higher levels in insoluble tau in 5xFAD*Tg30 than in Tg30 mice. Extracellular amyloid load, Abeta40 and Abeta42, beta-CTFs and beta CTF phosphorylation levels were lower in 5xFAD*Tg30 mice than in 5xFAD mice. Despite this reduction of Abeta, a significant hippocampal neuronal loss was observed in 5xFAD*Tg30 but not in 5xFAD mice indicating its closer association with increased tau pathology. This 5xFAD*Tg30 model thus mimics more faithfully tau pathology and neuronal loss observed in AD and suggests that additional post translational changes in tau and self-recruitment of endogenous tau drive the enhanced tau pathology developing in the presence of Abeta pathology. PMID- 24076102 TI - IgM levels in plasma predict outcome in severe pandemic influenza. AB - BACKGROUND: Little is known on the participation of immunoglobulin isotypes and subclasses in the pathogenesis of the severe disease caused by the pandemic influenza virus (influenza A(H1N1)pdm09). OBJECTIVES: (1) To evaluate the association between plasma levels of IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE and outcome in patients with severe pandemic influenza. (2) To evaluate the association between immunoglobulin and cytokine levels in these patients. STUDY DESIGN: 40 critically ill patients with community acquired pneumonia and influenza A(H1N1)pdm09 infection were recruited from November 2010 to February 2011. Plasma samples were collected during the first 24h following admission to the ICU. Immunoglobulins and 17 major cytokines were profiled in plasma. RESULTS: 15 patients died (37.5%). When the association between clinical variables and prognosis was assessed, prior immunosuppression, APACHE II score, levels of IgG2 and levels of IgM were associated with outcome in a univariate Cox regression analysis. Kaplan Meier analysis showed that patients with levels of IgG2 and IgM < 59 and<58 mg/dl respectively died earlier. Multivariate Cox regression analysis showed that APACHE II score and levels of IgM were the best predictors of outcome, being levels of IgM a protective factor against mortality. IgM was the immunoglobulin showing the largest number of negative correlations with cytokine levels. CONCLUSIONS: Our results support a central role of IgM in preventing uncontrolled inflammatory response and mortality in severe pandemic influenza. Early assessment of IgM could contribute to guide clinical decisions in these patients. PMID- 24076103 TI - Influence of chlorhexidine digluconate on the clinical performance of adhesive restorations: a 3-year follow-up. AB - OBJECTIVES: The aim of this clinical study was to evaluate the long-term clinical performance of non-carious Class V restorations with and without application of chlorhexidine digluconate to acid-etched dentine. METHODS: After the approval of the Ethics and Informed Consent Committee, 70 non-carious cervical lesions were selected and randomly assigned into two groups, according to the split mouth design. The control group was restored with a two-step etch-and-rinse adhesive (Adper Single Bond 2) following manufacturer's instructions; whereas in the experimental group 2% chlorhexidine digluconate solution was applied to acid etched dentine for 30s after etching and prior to the adhesive application. All lesions were restored with a nanofilled composite resin (Filtek Supreme XT) and polymerized with a light-curing unit operating at 600mW/cm(2). Clinical performance was recorded after 1 week, 6, 12, and 36 months using modified Ryge/USPHS criteria in terms of retention, marginal discoloration, marginal integrity, post-operative sensitivity, and secondary caries incidence. Data were analyzed using Chi-Square, Fisher's exact test and McNemar tests (alpha=.05). RESULTS: After 36 months the control group showed a success rate of 88% in comparison to 76% of experimental group; however, no statistically difference between them was found (p=.463). Moreover, no statistical differences were observed between groups in the criteria post-operative sensitivity, marginal discoloration, marginal integrity, and secondary caries incidence between the two groups. CONCLUSION: The addition of 2% chlorhexidine digluconate conditioning step does not improve the clinical durability of adhesive restorations. PMID- 24076104 TI - A cellular and metabolic assessment of the thermal stress responses in the endemic gastropod Benedictia limnaeoides ongurensis from Lake Baikal. AB - Our objective was to determine if the Lake Baikal endemic gastropod Benedictia limnaeoides ongurensis, which inhabits in stable cold waters expresses a thermal stress response. We hypothesized that the evolution of this species in the stable cold waters of Lake Baikal resulted in a reduction of its thermal stress-response mechanisms at the biochemical and cellular levels. Contrary to our hypothesis, our results show that exposure to a thermal challenge activates the cellular and biochemical mechanisms of thermal resistance, such as heat shock proteins and antioxidative enzymes, and alters energetic metabolism in B. limnaeoides ongurensis. Thermal stress caused the elevation of heat shock protein 70 and the products of anaerobic glycolysis together with the depletion of glucose and phosphagens in the studied species. Thus, a temperature increase activates the complex biochemical system of stress response and alters the energetic metabolism in this endemic Baikal gastropod. It is concluded that the deepwater Lake Baikal endemic gastropod B. limnaeoides ongurensis retains the ability to activate well developed biochemical stress-response mechanisms when exposed to a thermal challenge. PMID- 24076106 TI - The role of antennae in the thermopreference and biting response of haematophagous bugs. AB - Insects sense thermal cues mainly through thermoreceptors located in the antenna. To analyse the impact of antennectomy on the thermal behaviour of the haematophagous bug Triatomainfestans, we studied the distribution of intact and antennectomised bugs in an experimental arena where a temperature gradient was established, as well as the biting response of insects with and without antennae to objects at the temperature of a potential host. Antennectomy did not abolish thermopreference, but modified the temperature at which the insects preferred to stay. In the arena, antennectomised insects chose to remain at a higher temperature (ca. 3 degrees C higher in unfed bugs), and exhibited a larger dispersion around that preferred temperature, than intact bugs. In addition, ablated insects temporarily lost their ability to bite an object at the temperature of a potential host, but that ability was gradually recovered after the fifth day post-antennectomy. Results presented here show that thermoreceptors other than those located on the antennae can also guide thermal behaviours. We conclude that the function of antennal thermoreceptors can be taken over by other receptors located in different regions of the body. Those receptors have a different sensitivity and confer the insects with a different responsiveness. PMID- 24076105 TI - Does PKM(zeta) maintain memory? AB - Work on the long-term stability of memory has identified a potentially critical role for protein kinase Mzeta (PKMzeta) in maintaining established memory. PKMzeta, an autonomously active isoform of PKC, is hypothesized to sustain those changes that occurred during memory formation in order to preserve the memory engram over time. Initial studies investigating the role of PKMzeta were largely successful in demonstrating a role for the kinase in memory maintenance; disrupting PKMzeta activity with zeta-inhibitory peptide (ZIP) was successful in disrupting a variety of established associations in a number of key brain regions. More recent work, however, has questioned both the role of PKMzeta in memory maintenance and the effectiveness of ZIP as a specific inhibitor of PKMzeta activity. Here, we outline the research both for and against the idea that PKMzeta is a memory maintenance mechanism and discuss how these two lines of research can be reconciled. We conclude by proposing a number of studies that would help to clarify the role of PKMzeta in memory and define other mechanisms the brain may use to maintain memory. PMID- 24076107 TI - Dodecyl and octyl esters of fluorescein as protonophores and uncouplers of oxidative phosphorylation in mitochondria at submicromolar concentrations. AB - In our search for fluorescent uncouplers of oxidative phosphorylation, three esters of fluorescein, n-butyl-, n-octyl-, and n-dodecyl-oxycarbonyl-fluorescein (C4-FL, C8-FL, C12-FL) were synthesized and characterized. With increasing liposomal lipid content, the long-chain alkyl derivatives of fluorescein (C8-FL, C12-FL and commercially available C18-FL), but not C4-FL and unsubstituted fluorescein, exhibited an increase in fluorescence polarization reflecting the dye binding to liposomes. C12-FL induced proton permeability in lipid membranes, while C4-FL was inactive. In contrast to C4-FL and C18-FL, C12-FL and C8-FL increased the respiration rate and decreased the membrane potential of isolated rat liver mitochondria with half-maximal effective concentrations of 700nM and 300nM, respectively. The effect of Cn-FL on the respiration correlated with that on proton permeability of the inner mitochondrial membrane, as measured by induction of mitochondria swelling in the potassium acetate medium. Binding of C8 FL to mitochondria depended on their energization, which was apparently associated with pH gradient generation across the inner mitochondrial membrane in the presence of a respiratory substrate. In wild-type yeast cells, C12-FL localized predominantly in plasma membrane, whereas in AD1-8 mutants lacking MDR pumps, it stained cytoplasmic organelles with some preference for mitochondria. Fluorescent uncouplers can be useful as a tool for determining their localization in a cell or distribution between different tissues in a living animal by fluorescent microscopy. PMID- 24076108 TI - Prevalence and risk factors of osteopenia/osteoporosis in Turkish HIV/AIDS patients. AB - BACKGROUND: Recent studies showed a high frequency of low bone mineral density (BMD) in HIV-infected patients and no reports have been issued in Turkey. Our aim was to evaluate BMD and risk factors for osteopenia/osteoporosis in HIV-infected patients that attended an outpatient clinic in Istanbul, Turkey. METHOD: In order to determine the prevalence of BMD, 126 HIV-infected patients had been studied with dual energy X-ray absorptiometry (DEXA). The association between BMD and age, gender, body mass index (BMI), habits, 25(OH)vitamin D, HIV RNA, CD4 lymphocyte nadir, using and duration of highly active antiretroviral treatment (HAART) were investigated by using multivariate analysis. RESULTS: Median age was 40.1 years (range, 20-70); 84% were male; 35.7% patients had AIDS, 63.5% were treated with HAART. Osteopenia and osteoporosis were diagnosed in 53.9% and 23.8%, respectively. Mean plasma HIV RNA was 5.2 (SD 1.0) log10 copies/mL and CD4 lymphocyte nadir was 313.8 (SD 226.2)/mm(3). Factors associated with bone loss were high viral load (p=0.034), using (p=0.033) and duration of HAART (p=0.008). No correlation had been seen between sex and osteopenia/osteoporosis (p=0.794). However, males showed higher rates of osteoporosis than females (p=0.042). CONCLUSIONS: Our results show a very high prevalence of bone mass reduction in Turkish HIV-infected patients. This study supports the importance of both HIV and antiretroviral therapy in low BMD. PMID- 24076109 TI - Mycobacterium neoaurum causing prosthetic valve endocarditis: a case report and review of the literature. AB - Mycobacterium neoaurum is a rare cause of bacteremia, and infection usually occurs in an immunocompromised host in the setting of an indwelling catheter. Prosthetic valve endocarditis due to non-tuberculous mycobacteria typically carries a dismal prognosis; we report a case of M. neoaurum prosthetic valve endocarditis with favorable response to antimicrobial therapy without surgical intervention. PMID- 24076101 TI - Development of allosteric modulators of GPCRs for treatment of CNS disorders. AB - The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction. PMID- 24076110 TI - Purpura fulminans: an unusual complication of malaria. PMID- 24076111 TI - Methicillin-resistant Staphylococcus aureus nasal carriage in neonates and children attending a pediatric outpatient clinics in Brazil. AB - BACKGROUND: In Latin America, few studies have been carried out on methicillin resistant Staphylococcus aureus carriage in the pediatric population. We conducted a survey of nasal S. aureus carriage in neonates and in children attending the pediatric outpatient clinics in a large Brazilian city with high antimicrobial consumption. METHODS: Pernasal swabs of neonates were collected upon admission and at discharge in four neonatal intensive care units and of children less than five years of age during outpatient visits. Methicillin resistant S. aureus isolates were characterized for antibiotic susceptibility, mec gene presence, pulsed-field gel electrophoresis, spa type, SCCmec-type, multilocus sequence type, and presence of Panton-Valentine leukocidin genes. RESULTS: S. aureus was carried by 9.1% and 20.1% of the 701 neonates and of 2034 children attending the outpatient clinics, respectively; methicillin-resistant S. aureus carriage was detected in 0.6% and 0.2%, of the these populations, respectively. Healthcare-associated methicillin-resistant S. aureus strains found in neonates from neonatal intensive care units and outpatients were genetically related to the Brazilian (SCCmec-III, ST239) and to the Pediatric (SCCmec-IV, ST5) clones. Community-associated methicillin-resistant S. aureus was only detected in outpatients. None of the methicillin-resistant S. aureus strains contained the Panton-Valentine leukocidin gene. Methicillin-resistant S. aureus strains related to the Brazilian clone showed multidrug resistance pattern. CONCLUSIONS: Despite the high antibiotic pressure in our area, and the cross transmission of the healthcare-associated methicillin-resistant S. aureus clones between neonatal intensive care units and outpatients, the prevalence of methicillin-resistant S. aureus carriage is still low in our setting. PMID- 24076112 TI - Clinical and laboratory characteristics of severe fever with thrombocytopenia syndrome in Chinese patients. AB - Severe fever with thrombocytopenia syndrome (SFTS) associated with severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging infectious disease. 12 patients with severe fever with thrombocytopenia syndrome in our study were presented mainly with fever and severe malaise. The clinical manifestations typically became worse on the 6th or 7th day. The average fever time is 9.11 +/- 1.54 days. Most of them had multiorgan dysfunction, and part of them had hemophagocytic lymphohistiocytosis histiocytosis (HLH). The characteristic laboratory findings in the early stage were the drop of white blood cells (WBC), platelets (PLT) and serum Ca++, while increase of aspartate amino transferase (AST), creatine kinase (CK), and lactate dehydrogenase (LDH). CD3+CD4+ were significantly decreased, while CD3-CD56+ were significantly increased, whereas CD3+CD8+ were constantly elevated throughout the disease course. Ten to 14 days after illness onset, symptoms were improved, accompanied by resolution of laboratory abnormalities. These results indicate that severe fever with thrombocytopenia syndrome has an acute onset and self-limited course. It is a systemic infection. The host immune response caused tissues and organs injury. The improvement of symptoms and laboratory tests is consistent with the elimination of the virus and recover of immune response. Further investigation should be done in order to better understand this disease and guide the clinical treatment. PMID- 24076113 TI - Polyomavirus infection in renal allograft. PMID- 24076114 TI - Rotavirus in adults, Brazil, 2004-2011: G2P[4] dominance and potential impact on vaccination. AB - OBJECTIVES: The aim of this study was to monitor rotavirus (RV) infections in adults >18 years with acute gastroenteritis during 2004-2011 national Brazilian RV surveillance. In addition, to characterize the RV group A (RVA) strains in order to gain insight into the supposed vaccine selective pressure imposed to Brazilian children population. METHODS: A total of 2102 convenient fecal specimens were investigated by ELISA, PAGE, and RT-PCR. RESULTS: RV was detected in 203 (9.6%) of 2102 specimens, and showed a marked peak of detection in September. RVA infection was detected in 9.4% (197/2102) and RV group C (RVC) in 0.3% (6/2102). The most frequent genotypes detected in 2004 and 2005 were G9P[8] (38.5%; 5/13) and G1P[8] (54.5%; 6/11), respectively. The dominant genotype identified from 2006 to 2011 was G2P[4] (64.4%; 116/180). Detection rate varied during the 8-year period of the study from 0.7% to 12.9%. CONCLUSION: The high detection rate of G2P[4] in adults provides further evidence that its dominance reflects the seasonality of RVA strains instead of the supposed selective advantage created by vaccination program. It also can be suggested that adult infections may serve as a reservoir to maintain RVA strains in childhood gastroenteritis. Considering the detection rate, the evident reduction of RVA frequency observed in children after vaccine introduction was not present in adults. PMID- 24076115 TI - What do we know about resistance to colistin in Enterobacteriaceae in avian and pig production in Europe? AB - Colistin is a cyclic decapeptide bound to a fatty acid chain. It is active against many Gram-negative bacteria by destabilising the bacterial outer membrane. Bacteria can become resistant to colistin by modification of their lipopolysaccharide, thereby reducing the affinity of polymyxins. Colistin is often administered orally in poultry and pig production to control colibacillosis. Resistant isolates are sometimes recovered from pathological cases, particularly in piglets. However, in Europe the percentage of resistance to colistin in Escherichia coli strains isolated from the digestive tract microbiota of healthy animals remains <1%. PMID- 24076116 TI - Hematopoietic defects and iPSC disease modeling: lessons learned. AB - Hematopoiesis is a paradigm for stem cell biology in that it centers on differentiation of a self-renewing pluripotent precursor into multiple committed cell types with specific functions. The use of induced pluripotent stem cells (iPSCs) as a disease modeling tool has revealed numerous insights into the underlying pathophysiology of hematological diseases - those disorders arising from defective hematopoiesis. Likewise, studying hematopoiesis and the defects that can arise offer clues to understanding general stem cell survival and differentiation. PMID- 24076117 TI - Acute myeloid leukemia and novel biological treatments: monoclonal antibodies and cell-based gene-modified immune effectors. AB - In the context of acute myeloid leukemia (AML) treatment, the interface between chemotherapy and immunotherapy is at present getting closer as never before. Scientific research is oriented in overcoming the main limits of actual chemotherapeutic regimens against AML, which still accounts for a considerable number of relapsed or resistant forms. A lot of investments have been done in the use of monoclonal antibodies (mAbs) and recently gene-modified immune cells have been considered as an alternative approach whenever chemotherapy fails to eradicate the disease. In this sense, AML is a potential suitable target for immunotherapeutic approaches, due to overexpression of several tumor antigens. Here we describe the state of the art of mAbs and cellular therapies employing engineered immune effectors, developed against specific AML antigens, in a window embracing preclinical research and translational studies to the clinical setting. PMID- 24076119 TI - Emergence of a strain of methicillin-resistant Staphylococcus aureus with decreased susceptibility to vancomycin 7 months after treatment with glycopeptide antibiotics. AB - This case report describes a methicillin-resistant Staphylococcus aureus isolated repeatedly from the blood of a patient with community-acquired endocarditis who developed a four-fold increase in the minimal inhibitory concentration of vancomycin and daptomycin 7 months after his last exposure to glycopeptide antibiotics. This is contrary to the expected situation in which antimicrobial resistance tends to decrease after a patient is no longer exposed to vancomycin. PMID- 24076118 TI - Re-evaluation of the involvement of NK cells and C-type lectin-like NK receptors in modulation of immune responses by multivalent GlcNAc-terminated oligosaccharides. AB - Recognition of glycosylation patterns is one of the basic features of innate immunity. Ability of C-type lectin-like receptors such as NKR-P1 to bind saccharide moieties has become recently a controversial issue. In the present study, binding assay with soluble fluorescently labeled recombinant rat NKR-P1A and mouse NKR-P1C proteins revealed apparently no affinity to the various neoglycoproteins. Lack of functional linkage between NKR-P1 and previously described saccharide binder was supported by the fact, that synthetic N-acetyl-D glucosamine octabranched dendrimer on polyamidoamine scaffold (GN8P) did not change gene expression of NKR-P1 isoforms in C57BL/6 and BALB/c mice divergent in the NK gene complex (both in vitro and in vivo). Surprisingly, N-acetyl-D glucosamine-coated tetrabranched polyamido-amine dendrimer specifically binds to NKT cells and macrophages but not to NK cells (consistently with changes in cytokine patterns). Despite the fact that GN8P has been tested as an immunomodulator in anti-cancer treatment animal models for many years, surprisingly no changes in cytokine profiles in serum relevant to anti-cancer responses using B16F10 and CT26 harboring mouse strains C57BL/6 and BALB/c are observed. Our results indicate possible indirect involvement of NK cells in GN8P mediated immune responses. PMID- 24076120 TI - The mammary gland in domestic ruminants: a systems biology perspective. AB - Milk and dairy products are central elements in the human diet. It is estimated that 108kg of milk per year are consumed per person worldwide. Therefore, dairy production represents a relevant fraction of the economies of many countries, being cattle, sheep, goat, water buffalo, and other ruminants the main species used worldwide. An adequate management of dairy farming cannot be achieved without the knowledge on the biological mechanisms behind lactation in ruminants. Thus, understanding the morphology, development and regulation of the mammary gland in health, disease and production is crucial. Presently, innovative and high-throughput technologies such as genomics, transcriptomics, proteomics and metabolomics allow a much broader and detailed knowledge on such issues. Additionally, the application of a systems biology approach to animal science is vastly growing, as new advances in one field of specialization or animal species lead to new lines of research in other areas or/and are expanded to other species. This article addresses how modern research approaches may help us understand long-known issues in mammary development, lactation biology and dairy production. BIOLOGICAL SIGNIFICANCE: Dairy production depends upon the knowledge of the morphology and regulation of the mammary gland and lactation. High throughput technologies allow a much broader and detailed knowledge on the biology of the mammary gland. This paper reviews the major contributions that genomics, transcriptomics, metabolomics and proteomics approaches have provided to understand the regulation of the mammary gland in health, disease and production. In the context of mammary gland "omics"-based research, the integration of results using a Systems Biology Approach is of key importance. PMID- 24076121 TI - High glucose-induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: Implications for cerebral microvascular disease in diabetes. AB - Hyperglycemia-induced oxidative stress leads to diabetes-associated damage to the microvasculature of the brain. Pericytes in close proximity to endothelial cells in the brain microvessels are vital to the integrity of the blood-brain barrier and are especially susceptible to oxidative stress. According to our recently published results, streptozotocin-diabetic mouse brain exhibits oxidative stress and loose pericytes by twelve weeks of diabetes, and cerebral pericytes cultured in high glucose media suffer intracellular oxidative stress and apoptosis. Oxidative stress in diabetes is hypothesized to be caused by reactive oxygen species (ROS) produced during hyperglycemia-induced enhanced oxidative metabolism of glucose (respiration). To test this hypothesis, we investigated the effect of high glucose on respiration rate and ROS production in mouse cerebral pericytes. Previously, we showed that pharmacological inhibition of mitochondrial carbonic anhydrases protects the brain from oxidative stress and pericyte loss. The high glucose-induced intracellular oxidative stress and apoptosis of pericytes in culture were also reversed by inhibition of mitochondrial carbonic anhydrases. Therefore, we extended our current study to determine the effect of these inhibitors on high glucose-induced increases in pericyte respiration and ROS. We now report that both the respiration and ROS are significantly increased in pericytes challenged with high glucose. Furthermore, inhibition of mitochondrial carbonic anhydrases significantly slowed down both the rate of respiration and ROS production. These data provide new evidence that pharmacological inhibitors of mitochondrial carbonic anhydrases, already in clinical use, may prove beneficial in protecting the brain from oxidative stress caused by ROS produced as a consequence of hyperglycemia-induced enhanced respiration. PMID- 24076122 TI - Fem1b promotes ubiquitylation and suppresses transcriptional activity of Gli1. AB - The mammalian Fem1b gene encodes a homolog of FEM-1, a protein in the sex determination pathway of the nematode Caenorhabditis elegans. Fem1b and FEM-1 proteins each contain a VHL-box motif that mediates their interaction with certain E3 ubiquitin ligase complexes. In C. elegans, FEM-1 negatively regulates the transcription factor TRA-1, and functions as an E3 ubiquitin ligase substrate recognition subunit to target TRA-1 for ubiquitylation. TRA-1 is homologous to the mammalian Gli1 protein, a transcription factor that mediates Hedgehog signaling as well as having Hedgehog-independent functions. Whether the interaction between nematode FEM-1 and TRA-1 proteins is conserved, between corresponding mammalian homologs, has not been reported. Herein, we show that Fem1b interacts with Gli1 within cells, and directly binds Gli1. Fem1b also promotes ubiquitylation of Gli1, suppresses transcriptional activation by Gli1, and attenuates an oncogenic Gli1 autoregulatory loop in cancer cells, all dependent on the VHL-box of Fem1b. These findings have implications for understanding the cellular functions of Fem1b, and the regulation of Gli1 oncoprotein activity. PMID- 24076123 TI - Diagnostic utility of a direct immunofluorescence test to detect feline coronavirus antigen in macrophages in effusive feline infectious peritonitis. AB - The antemortem diagnosis of feline infectious peritonitis (FIP) remains challenging in clinical practice, since current testing methods have suboptimal diagnostic accuracy. Immunohistochemical testing of biopsy specimens and postmortem examination are the standard diagnostic methods, although direct immunofluorescence (DIF) testing to detect feline coronavirus in macrophages in effusion specimens has been reported to have 100% specificity and has been recommended as an antemortem confirmatory test. The aim of this study was to compare the results of DIF testing in antemortem feline effusions with postmortem results using field samples. Effusion specimens were collected antemortem from 17 cats and tested by DIF, followed by postmortem examination. Histopathological examination of specimens collected at postmortem confirmed FIP in 10/17 cases and ruled out FIP out in 7/17 cases. Antemortem DIF testing was positive in all 10 cases confirmed as FIP at postmortem examination. In the seven cats where FIP was ruled out at postmortem examination, DIF was negative in five cases and positive in the remaining two cases. The calculated sensitivity of DIF testing was 100% and the specificity was 71.4%. Duplicate effusion specimens from eight cats that were initially DIF positive were stored refrigerated (4 degrees C) or at room temperature (22-25 degrees C) and subjected to serial DIF testing to determine the duration of positive results. DIF-positive specimens stored at both temperatures retained their positive status for at least 2 days. PMID- 24076124 TI - The effect of spaying on the racing performance of female greyhounds. AB - The effect of spaying (ovariohysterectomy) on racing greyhound performance was analysed. Using data from a longitudinal observational study design, random effects models were used to compare the racing performance before and after spaying. Greyhounds were matched by distance and date of racing, and then both spayed and entire bitches were compared for each stadium which had spayed greyhounds on the racing strength. The racing performance of entire females was selected from the anoestral period (from 90 days post-oestrus to the next oestrus). Spaying had no real effect on performance, with a mean difference of +0.066 seconds (90% CI: -0.004, +0.135 s) over 480 metres. The effect of time since spaying had no effect (90% CI: -0.0002 to +0.0001 s/day). Spaying of racing greyhound bitches produced no overall change in performance, and had no apparent long term effect on performance. These results are discussed within the context of the current information on the advantages and disadvantages of spaying at a young age. PMID- 24076125 TI - Disposition of firocoxib in equine plasma after an oral loading dose and a multiple dose regimen. AB - The objective of this study was to determine if a single loading dose (LD), 3* the label dose of firocoxib oral paste, followed by nine maintenance doses at the current label dose achieves and maintains near steady state concentrations. Six healthy, adult mares were administered 0.3mg/kg of firocoxib on Day 0, and 0.1 mg/kg 24 h later on Day 1, and at 24 h intervals from Day 2 to Day 9, for a total of 10 doses. Blood samples were collected throughout the study. The mean firocoxib maximum plasma concentration and standard deviation was 199+/-97 ng/mL, 175+/-44 ng/mL and 183+/-50 ng/mL after the LD, and first and last maintenance doses, respectively. The minimum mean concentration (C(min)) increased from 100+/ 23 ng/mL after the LD to 132+/-38 ng/mL at Day 7. Then, the C(min) remained constant until Day 9. The average concentration at steady state (C(avg)) was 150+/-45 ng/mL, which compares well to the C(avg) (130+/-36 ng/mL) reported after multiple daily doses at 0.1 mg/kg. The administration of the single LD allowed achievement of the average steady state drug concentrations faster than a multi dose regimen without a loading dose. After the LD, firocoxib at 0.1 mg/kg every 24 h was able to maintain a relatively constant average drug concentration which should produce less variability in onset of action and efficacy. PMID- 24076126 TI - Heuman indices of hydrophobicity of bile acids and their comparison with a newly developed and conventional molecular descriptors. AB - Bile salts (BSs), in addition to their physiological role in the digestion of lipids in vertebrates, are also of significant importance in biomedical investigations. For predicting biological-pharmacological activity and physico chemical properties of BSs it is important to develop such molecular descriptors that adequately describe the structural characteristics of the steroid skeleton. The present study encompassed the following bile acids (BAs): cholic, chenodeoxycholic, deoxycholic, hyodeoxycholic, ursodeoxycholic, hyocholic, and ursocholic acid, as well as oxo derivatives of certain BAs. For all of them, Heuman hydrophobicity indices (HI(BA)) (RP-HPLC parameters) were determined, and a detailed conformational analysis of the steroid skeleton showed that HI(BA) has the discrimination power for BAs based on the size of the hydrophobic surface on the beta side and the lateral L7 and L12 sides of the steroid skeleton. Also, HI(BA) discerns the regiochemical characteristics of OH and oxo groups. Based on a survey of the structural factors of the steroid skeleton that influence the HI(BA) values of the tested BAs, we constructed a new molecular descriptor, CHIBA, with the characteristics of 2D and 3D topological descriptors. In respect of the structure of the steroid skeleton, the descriptor CHIBA behaves as a reversed-phase chromatographic descriptor of BAs. PMID- 24076127 TI - Mitochondrial dysfunction and oxidative damage cooperatively fuel axonal degeneration in X-linked adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited monogenic demyelinating disease (minimal incidence 1:17,000). It is often lethal and currently lacks a satisfactory therapy. The disease is caused by loss of function of the ABCD1 gene, a peroxisomal ATP-binding cassette transporter, resulting in the accumulation of VLCFA (very long-chain fatty acids) in organs and plasma. Understanding of the aetiopathogenesis is a prerequisite for the development of novel therapeutic strategies. Functional genomics analysis of an ABCD1 null mouse, a mouse model for adrenomyeloneuropathy, has revealed presymptomatic alterations in several metabolic pathways converging on redox and bioenergetic homeostasis, with failure of mitochondrial OXPHOS disruption and mitochondrial depletion. These defects could be major contributors to the neurodegenerative cascade, as has been reported in several neurodegenerative disorders. Drugs targeting the redox imbalance/mitochondria dysfunction interplay have shown efficacy at halting axonal degeneration and associated disability in the mouse, and thus offer therapeutic hope. PMID- 24076129 TI - START ships lipids across interorganelle space. AB - The family of StAR related lipid transfer proteins (START) is so-named based on the distinctive capacity for these proteins to transport lipids between membranes. The START domain is a module of about 210 residues, which binds lipids such as glycerolipids, sphingolipids and sterols. This domain has a deep lipid binding pocket - which shields the hydrophic ligand from the external aqueous environment - covered by a lid. Based on their homology, the fifteen START proteins in mammals have been allocated to six distinct subfamilies, each subfamily being more specialized in the transport and/or sensing of a lipid ligand species. However within the same subgroup, their expression profile and their subcellular localization distinguish them and are critical for their different biological functions. Indeed, START proteins act in a variety of distinct physiological processes, such as lipid transfer between intracellular compartments, lipid metabolism and modulation of signaling events. Mutation or deregulated expression of START proteins is linked to pathological processes, including genetic disorders, autoimmune diseases and cancers. Besides the common single START domain, which is always located at the carboxy-terminal end in mammals, most START proteins harbor additional domains predicted to be critical in favoring lipid exchange. Evidence from well characterized START proteins indicates that these additional domains might be tethering machineries able to bring distinct organelles together and create membrane contact sites prone to lipid exchange via the START domain. PMID- 24076128 TI - To be or not to be a nucleoid protein: a comparison of mass-spectrometry based approaches in the identification of potential mtDNA-nucleoid associated proteins. AB - In the last decade it has become increasingly clear that mitochondrial DNA (mtDNA) is not naked but associated with proteins in poorly defined structures called nucleoids that are essential for mtDNA maintenance. The function of nucleoids is not simply to package mtDNA but also to provide a stable environment for its replication, transcription and repair. Even though their properties and dynamics have begun to be revealed in recent years, their structural and molecular organization remains largely unknown in mammals. Although, there are a number of proteins identified to be nucleoid associated by using several biochemical isolation methods combined with mass spectrometric analysis, the main difficulties in the identification of these proteins are their low abundance and the assumed dynamic composition of nucleoids. Considering various purification methods, there is a thin line between the stringency and specificity in the identification of potential nucleoid associated proteins. In this review, the main focus is to provide a comprehensive comparison of the so far published purification and analysis methods to generate a list of potentially nucleoid associated proteins, but also, to discuss the disadvantages and possible improvements in proteomic analyses. PMID- 24076130 TI - Smoking cessation interventions for ethnic minority groups--a systematic review of adapted interventions. AB - OBJECTIVE: Existing smoking cessation interventions tend to be under utilized by ethnic minority groups. We sought to identify smoking cessation interventions that have been adapted to meet the needs of African-, Chinese- and South Asian origin populations, to increase understanding of the approaches used to promote behavior change, to assess their acceptability to the target populations, and to evaluate their effectiveness. METHODS: Two reviewers independently searched for, identified, critically appraised and extracted data from studies identified from 11 databases (January 1950-April 2013). Study quality was assessed using validated instruments (EPHPP and STROBE). Adaptations were independently coded using an established typology, and findings descriptively summarized and thematically synthesized. RESULTS: 23 studies described interventions adapted for African-Americans, and five for Chinese-origin populations. No intervention adapted for South-Asian populations was identified. Six studies directly compared a culturally adapted versus a non-adapted intervention. Adapted interventions were more acceptable to ethnic minority groups, but this did not translate into improvements in smoking cessation outcomes. CONCLUSIONS: Given the evidence of greater acceptability of adapted interventions, it may be ethically preferable to use these. There is, however, no clear evidence of the effectiveness of adapted interventions in promoting smoking cessation in ethnic minority groups. PMID- 24076131 TI - Genetic variants in BMP8B gene are associated with growth traits in Chinese native cattle. AB - As a signaling molecule, bone morphogenetic protein 8B (BMP8B) plays an essential role in bone metabolism and is able to regulate thermogenesis and energy balance, which suggests that BMP8B gene may be a new candidate for growth traits. Here, to characterize the effects of BMP8B gene on growth traits, we first used three Chinese indigenous cattle breeds (n=845) to detect single nucleotide polymorphisms (SNPs). Five novel SNPs of BMP8B gene (g.-242C>T, g.2164C>T, g.2639T>C, g.2900C>G and g.10817C>T) were identified by DNA pool sequencing and forced PCR-RFLP. And then we associated the five SNPs with four growth traits (body weight, body length, heart girth, and hucklebone width). Results from association analysis showed that the SNPs 1, 2, and 3 affected growth trait(s) markedly (P<0.05). Further, 6 combined haplotypes were constructed to guarantee the reliability of analysis results. There were also significant differences in body length, heart girth and body weight between the 6 combined haplotypes (P<0.05), but not in hucklebone width (P>0.05). Collectively, our results suggest a modulatory role of BMP8B gene in cattle growth and development, and 3 SNPs could be used as molecular markers in early marker assisted selection (MAS) in beef cattle breeding program. PMID- 24076132 TI - Diagnostic and prognostic value of circulating miR-21 for cancer: a systematic review and meta-analysis. AB - BACKGROUND: MicroRNAs (miRNAs) have been reported to be aberrantly expressed in patients with cancer. Many studies have shown that circulating miRNAs could play potential roles as diagnostic and prognostic biomarkers of cancers. The aim of this meta-analysis is to summarize the role of circulating miR-21 as a biomarker in patients with a variety of carcinomas. MATERIAL AND METHODS: Eligible studies were identified and assessed for quality through multiple search strategies. For diagnostic meta-analysis, the sensitivity, specificity, and other measures of miR 21 in the diagnosis of cancer were pooled using bivariate random-effects approach models. For prognostic meta-analysis, pooled hazard ratios (HRs) of circulating miR-21 for survival were calculated. RESULTS: A total of 36 studies dealing with various carcinomas were included for the systemic review. Among them, 23 studies were finally enrolled in the global meta-analysis (17 studies for diagnosis and 6 studies for prognosis). For diagnostic meta-analysis, the overall pooled results for sensitivity, specificity, positive likelihood ratio (LRP), negative likelihood ratios (LRN) and diagnostic odds ratio (DOR) were 75.7% (95% CI: 67.1% 82.6%), 79.3% (95% CI: 74.2%-83.5%), 3.65 (95% CI: 2.83-4.70), 0.31 (95% CI: 0.22 0.43), and 11.88 (95% CI: 6.99-20.19), respectively. For prognostic meta analysis, the pooled HR of higher miR-21 expression in circulation was 2.37 (95% CI: 1.83-3.06, P<0.001), which could significantly predict poorer survival in general carcinomas. Importantly, subgroup analysis suggested that higher expression of miR-21 correlated with worse overall survival (OS) significantly in carcinomas of digestion system (HR, 5.77 [95% CI: 2.65-12.52]). CONCLUSIONS: Our findings suggest that circulating miR-21 may not suitable to be a diagnostic biomarker, but it has a prognostic value in patients with cancer. PMID- 24076133 TI - Local contextual processing in major depressive disorder. AB - OBJECTIVE: The study investigated local contextual processing in patients with major depressive disorder (MDD). This was defined as the ability to utilize predictive contextual information to facilitate detection of predictable versus random targets. METHOD: We recorded EEG in 15 MDD patients and 14 age-matched controls. Recording blocks consisted of targets preceded by randomized sequences of standards and by sequences of standards that included a predictive sequence signaling the occurrence of a subsequent target event. RESULTS: Both MDD patients and age-matched controls demonstrated a significant reaction time (RT) and P3b latency differences between predicted and random targets. However, patients demonstrated a specific prolongation of these measures during processing of predicted targets, as well as an attenuation of P3b amplitudes for the predictive sequence. In addition, patients target N1 amplitudes were attenuated compared with controls. CONCLUSION: MDD patients were able to utilize predictive context in order to facilitate processing of deterministic targets, however, this ability was limited compared to controls, as demonstrated by context-dependent P3b deficits. SIGNIFICANCE: These findings suggest that patients with major depression have altered processing of local contextual processing. PMID- 24076134 TI - Mastoid and vertex low-frequency vibration-induced oVEMP in relation to medially directed acceleration of the labyrinth. AB - OBJECTIVE: To explore the stimulus site and stimulus configuration dependency for bone-conducted low-frequency vibration-induced ocular vestibular evoked myogenic potentials (oVEMPs). METHODS: oVEMPs were tested in response to 125 Hz single cycle bone-conducted vibration in healthy subjects (n=12) and in patients with severe unilateral vestibular lesions (n=10). The stimulus sites were the mastoids and vertex. Both directions of initial stimulus motion were used. RESULTS: At mastoid stimulation, the oVEMP to initial laterally directed acceleration of the labyrinth was delayed approximately the length of time of a stimulus half-cycle, as compared with the response to initial medially directed acceleration. At vertex stimulation, the oVEMP to positive initial acceleration was similar to the oVEMP to mastoid stimulation causing lateral initial acceleration. Likewise, the oVEMP to vertex negative initial acceleration was similar to mastoid stimulation causing initial medial acceleration. Further, patients with unilateral vestibular loss had, compared to healthy subjects, similar oVEMP from the healthy labyrinth. CONCLUSIONS: A fundamental dependency on medially directed accelerations of the labyrinth, based on the latency differences revealed, may theoretically account for oVEMP in response to low-frequency stimulation. SIGNIFICANCE: Low-frequency bone vibration stimulation at vertex might serve for simultaneous oVEMP testing of both ears. PMID- 24076135 TI - Developmental expression of IL-33 in the mouse brain. AB - IL-33 has important functions in inflammatory and autoimmune diseases. In the brain, models of experimental encephalomyelitis are accompanied by up-regulation of IL-33 expression, and the cytokine is seen as an amplifier of the innate immune response. Little is known, however, about IL-33 the normal brain in adult life, or during development. We have analyzed the expression of IL-33 in the mouse brain during embryonic and postnatal development. Here we report that IL-33 expression was first detected in the CNS during late embryogenesis. From postnatal day 2 (P2) until P9 the expression increased and was strongest in the cerebellum, pons and thalamus, as well as in olfactory bulbs. Expression of IL-33 then became weaker and declined until P23, and it was not present in the adult brain. Both astrocytes and oligodendrocyte precursors expressed IL-33. The vast majority of IL-33 positive cells in the brain displayed nuclear staining, and this was found to be the case also in vitro, using mixed glial cultures. Our data suggest that IL-33 expression is under tight regulation in the normal brain. Its detection during the first three weeks of postnatal life coincides with important parts of the CNS developmental programs, such as general growth and myelination. This opens the possibility that IL-33 plays a role also in the absence of an inflammatory response. PMID- 24076137 TI - Twinkle mutation in an Italian family with external progressive ophthalmoplegia and parkinsonism: a case report and an update on the state of art. AB - The objective is to describe the clinical phenotype and genetic basis of a family with autosomal dominant progressive external ophthalmoplegia and parkinsonism with a Twinkle mutation. The proband, an 82 years old female, reported since childhood bilateral eyelid ptosis, ophthalmoplegia, sensorineural hypoacusis, mild depression since she was 45, with a positive familiar anamnesis of eyelid ptosis (father, two sisters and a son). She developed mild bilateral parkinsonism with a moderate clinical response to levodopa. The (123)I-FP-CIT SCAN evidenced a marked bilateral putaminal reduction and moderate caudate uptake reduction. Her 79 years old sister reported eyelid ptosis since she was 45 with ophthalmoplegia and developed a mild bilateral rest and postural tremor with moderate right arm plastic hypertonia when she was 76. The parkinsonism was confirmed with (123)I-FP CIT SCAN. One of the two sons presented eyelid ptosis since he was 30 years old, with peripheral neuropathy with biopsy evidence of myopathy. We identified a G1750A mutation in the c10orf2 gene in the three patients. Mitochondrial dysfunction has been implicated in the pathogenesis of sporadic, idiopathic Parkinson disease (PD). In some cases, mitochondrial DNA primary genetic abnormalities or more commonly secondary rearrangements due to polymerase gamma (POLG) gene mutation can directly cause parkinsonism. Parkinsonism has been reported as a rare symptom associated to Twinkle (c10orf2). Parkinsonism has to be investigated in patients with PEO with analysis of Twinkle mutation. PMID- 24076136 TI - Effects of saikosaponin A on cocaine self-administration in rats. AB - We have previously demonstrated that saikosaponin A (SSA) attenuated morphine self-administration behavior. In the present study, we evaluated the effects of SSA on cocaine-maintained responding using self-administration procedure. Rats self-administered cocaine (0.25mg/kg per infusion) under a fixed ratio 1 schedule of reinforcement during daily 3-h session. Once stable basal responses were obtained, rats were pretreated with each doses of SSA (1.0, 2.5, 5.0mg/kg) or its vehicle (5% Tween-80) by an intraperitoneal injection 30min before the start of self-administration testing. Additionally, different groups of rats received either the selective GABAB antagonist SCH 50911 or the GABAA antagonist bicuculline before systemic administration of SSA at dose of 2.5mg/kg. Results showed that SSA significantly reduced cocaine self-administration without affecting food consumption. SSA inhibition of cocaine reinforced-responding was blocked by SCH 50911, but not bicuculline. Results suggest that SSA may attenuate cocaine-reinforced behavior through activation of GABAB receptors. PMID- 24076138 TI - Regional cerebral blood flow alterations in obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a condition characterized by upper airway muscle atonia with continued diaphragmatic efforts, resulting in repeated airway obstructions, periods of intermittent hypoxia, large thoracic pressure changes, and substantial shifts in arterial pressure with breathing cessation and resumption. The hypoxic exposure and hemodynamic changes likely induce the structural and functional deficits found in multiple brain areas, as shown by magnetic resonance imaging (MRI) procedures. Altered cerebral blood flow (CBF) may contribute to these localized deficits; thus, we examined regional CBF, using arterial spin labeling procedures, in 11 OSA (age, 49.1+/-12.2 years; 7 male) and 16 control subjects (42.3+/-10.2 years; 6 male) with a 3.0-Tesla MRI scanner. CBF maps were calculated, normalized to a common space, and regional CBF values across the brain quantified. Lowered CBF values emerged near multiple bilateral brain sites in OSA, including the corticospinal tracts, superior cerebellar peduncles, and pontocerebellar fibers. Lateralized, decreased CBF appeared near the left inferior cerebellar peduncles, left tapetum, left dorsal fornix/stria terminalis, right medial lemniscus, right red nucleus, right midbrain, and midline pons. Regional CBF values in OSA are significantly reduced in major sensory and motor fiber systems and motor regulatory sites, especially in structures mediating motor coordination; those reductions are often lateralized. The asymmetric CBF declines in motor regulatory areas may contribute to loss of coordination between upper airway and diaphragmatic musculature, and lead to further damage in the syndrome. PMID- 24076139 TI - Prolonged protein deprivation differentially affects calretinin- and parvalbumin containing interneurons in the hippocampal dentate gyrus of adult rats. AB - Protein deprivation is a detrimental nutritional state that induces several deleterious changes in the rat hippocampal formation. In this study, we compared the effects of protein deprivation in the number of parvalbumin (PV) immunoreactive and calretinin (CR)-immunoreactive interneurons of the dentate gyrus, which are involved in the control of calcium homeostasis and fine tuning of the hippocampal circuits. Two month-old rats were randomly assigned to control and low-protein diet groups. The rats of the latter group were fed with a low protein diet (8% casein) for 6 months. All animals were perfused at 8 months of age. The number of neurons expressing CR in the molecular layer and in the hilus of dentate gyrus was reduced in protein-deprived rats. Conversely, protein deprivation increased the number of PV-containing interneurons in the dentate granule cell layer and hilus. These results support the view that protein deprivation may disturb calcium homeostasis, leading to neuronal death including GABAergic interneurons expressing CR. In the other hand, the up-regulation of PV cells may reflect a protective mechanism to counteract the calcium overload and protect the remaining neurons of the dentate gyrus. PMID- 24076140 TI - Nitric oxide synthase (NOS) in the cyprid of Amphibalanus amphitrite (Cirripedia, Crustacea). AB - The Amphibalanus amphitrite barnacle is a sessile marine crustacean and a major constituent of benthic as well as intertidal communities. A. amphitrite is also an important component of biofouling on artificial substrates. The role of nitric oxide (NO) was recently observed in the settlement of this species. In this work, we used immunohistochemical and histoenzymatic methods to investigate, for the first time, the presence and distribution of NO synthetic enzymes (NOS) in the competent-for-settlement cyprid of A. amphitrite. NOS-like immunoreactivity was observed in various regions of the cyprid: gut mucosa, mantel epithelium, thoracic muscle, and abductor muscles. Intense immunoreactivity was also present in the cement gland and oil cells, while widespread immunoreactivity was observed in the compound eye. NADPH-diaphorase method was used to provide further data and understand NOS-distribution. The results show that NOS is likely to be present in structures - such as muscles and cement gland - which are key for settlement. PMID- 24076141 TI - Enriched environment induces higher CNPase positive cells in aged rat hippocampus. AB - It had been reported that enriched environment was beneficial for the brain cognition and for the neurons and synapses in hippocampus. Previous study reported that the oligodendrocyte density in hippocampus was increased when the rats were reared in the enriched environment from weaning to adulthood. However, biological conclusions based on density were difficult to interpret because the changes in density could be due to an alteration of total quantity and/or an alteration in the reference volume. In the present study, we used unbiased stereological methods to investigate the effect of enriched environment on the total number of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) positive cells in CA1 and dentate gyrus (DG) of the hippocampus in aged rats. Our results indicated that there was significant difference in the total numbers of CNPase positive cells in both CA1 and DG between enriched environment group and standard environment group. The present study provided the first evidence for the protective effects of enriched environment on the CNPase positive cells in aged hippocampus. PMID- 24076142 TI - Determination of allelic expression of SNP rs1880676 in choline acetyltransferase gene in HeLa cells. AB - Recently, we reported that several polymorphisms and haplotypes in the choline acetyltransferase gene (ChAT) are associated with nicotine dependence (ND). Of them, SNP rs1880676 is of particular interest because: (1) it is a non-synonymous variant located in the coding region of an alternatively spliced form of ChAT and (2) it is located in several haplotypes that are significantly associated with ND. The objective of this study was to determine, using an in vitro system, whether the alleles G (coding for aspartic acid) or A (coding for asparagine) of rs1880676 have any allele-specific effect on ChAT expression. We first used site directed mutagenesis to construct two expression vectors differed in the allelic position of rs1880676 (G/A), which were transfected into HeLa cells. We then measured expression of ChAT associated with each allele. We found significant expression differences for the two alleles, with the G allele being expressed significantly greater than A allele (P<0.01 at both mRNA and protein levels). Further, we validated the ChAT expression of the G allele was significantly higher than that of the A allele by using ELISA assay (P=0.00016). We concluded that rs1880676 is functional and that the allelic variations of this polymorphism are involved in developing ND by altering ChAT expression. PMID- 24076143 TI - High voltage with little current as an unconditional stimulus for taste avoidance conditioning in Lymnaea stagnalis. AB - A new and better taste avoidance conditioning paradigm for Lymnaea has been developed that replaces the previously used tactile unconditional stimulus (US) with an brief electrical stimulus (1000V, 80MUA), while continuing to use a sucrose application to the lips as the conditional stimulus (CS). With 15 paired CS-US presentations on a single day, we were able to elicit both short-term memory (STM) and long-term memory (LTM). The LTM persisted for at least one week. While STM was elicited with 5, 8, or 10 paired presentations of the CS-US on a single day, LTM was not. The new US used here was more consistent than the previously used US, and this stimulus consistency may explain why 15 paired CS-US presentations now result in LTM formation. PMID- 24076144 TI - Enhanced temporal pain processing in multiple system atrophy. AB - Pain processing has been poorly studied in multiple system atrophy (MSA), notwithstanding these subjects complaint pain very frequently. We hypothesized that, as observed in other basal ganglia neurodegenerative disorders involving the striatonigral projections, also in MSA with predominant parkinsonian signs could be detected an abnormal pain processing. We used the temporal summation threshold (TST) of the nociceptive withdrawal reflex (NWR) and the related pain sensation to evaluate the temporal pain processing at spinal level in eleven MSA subjects and compared them with fifteen Parkinson's disease (PD) subjects, in both during "on" and "off" treatment with l-Dopa, and fifteen healthy subjects. MSA showed a significant reduction in NWR TST as well as facilitation in other pain responses when compared to healthy subjects; no differences were detected between "on" and "off" condition; no differences were detected between MSA and PD subjects in term of neurophysiological and pharmacological responses. We demonstrated a facilitated temporal processing of pain in MSA subjects paralleling findings from PD. We hypothesize that the abnormal pain processing detected in both MSA and PD, could represent a consequence of the striatonigral neurodegeneration which in turn make these subjects more prone to develop pain conditions. PMID- 24076145 TI - Engineering a synthetic pathway in cyanobacteria for isopropanol production directly from carbon dioxide and light. AB - Production of alternate fuels or chemicals directly from solar energy and carbon dioxide using engineered cyanobacteria is an attractive method to reduce petroleum dependency and minimize carbon emissions. Here, we constructed a synthetic pathway composed of acetyl-CoA acetyl transferase (encoded by thl), acetoacetyl-CoA transferase (encoded by atoAD), acetoacetate decarboxylase (encoded by adc) and secondary alcohol dehydrogenase (encoded by adh) in Synechococcus elongatus strain PCC 7942 to produce isopropanol. The enzyme-coding genes, heterogeneously originating from Clostridium acetobutylicum ATCC 824 (thl and adc), Escherichia coli K-12 MG1655 (atoAD) and Clostridium beijerinckii (adh), were integrated into the S. elongatus genome. Under the optimized production conditions, the engineered cyanobacteria produced 26.5 mg/L of isopropanol after 9 days. PMID- 24076147 TI - A comparative LCA of rice straw utilization for fuels and fertilizer in Thailand. AB - Life cycle assessment of four rice straw utilization systems including; (1) direct combustion for electricity, (2) biochemical conversion to bio-ethanol and biogas, (3) thermo-chemical conversion to bio-DME, and (4) incorporation into the soil as fertilizer have been conducted to compare their environmental performances. The results showed that per ton of dry rice straw, the bio-ethanol pathway resulted in the highest environmental sustainability with regards to reductions in global warming and resource depletion potentials. Rice straw bio DME was preferable vis-a-vis reduction in acidification potential. Rice straw electricity and fertilizer also brought about several environmental benefits. The key environmental benefit of rice straw utilization came from avoiding the deleterious effects from burning straw in situ in the field. Recommendations for enhancing environmental sustainability of rice straw utilization for fuels and fertilizer are provided. PMID- 24076148 TI - A novel mixing strategy for maximizing yields of glucose and reducing sugar in enzymatic hydrolysis of cellulose. AB - This work explores the effects of mixing on enzymatic hydrolysis of cellulose to innovate a novel mixing strategy that maximizes glucose and reducing sugar yields for production of cellulosic ethanol while reducing the power required for reactor mixing. Batch experiments of cellulose hydrolysis are performed under aseptic conditions for 72 h at various substrate loading (2-6% wt./vol.), where the reactor mixing is terminated after different intervals of time ranging from 0 to 72 h. We find that initial mixing for a certain 'optimal mixing time' followed by no mixing for the rest of the reaction time maximizes glucose and reducing sugar yields. We report a maximum of 26% and 31% increase in glucose and reducing yields, respectively, in case of optimal mixing over continuous mixing for 2% substrate loading. We obtain an algebraic expression that predicts that the optimal mixing time increases exponentially with substrate loading. PMID- 24076149 TI - Identification of immune response-related genes in the Chinese oak silkworm, Antheraea pernyi by suppression subtractive hybridization. AB - Insects possess an innate immune system that responds to invading microorganisms. In this study, a subtractive cDNA library was constructed to screen for immune response-related genes in the fat bodies of Antheraea pernyi (Lepidoptera: Saturniidae) pupa challenged with Escherichia coli. Four hundred putative EST clones were identified by suppression subtractive hybridization (SSH), including 50 immune response-related genes, three cytoskeleton genes, eight cell cycle and apoptosis genes, five respiration and energy metabolism genes, five transport genes, 40 metabolism genes, ten stress response genes, four transcription and translation regulation genes and 77 unknown genes. To verify the reliability of the SSH data, the transcription of a set of randomly selected immune response related genes were confirmed by semi-quantitative reverse transcription-PCR (RT PCR) and real-time quantitative reverse transcription-PCR (qRT-PCR). These identified immune response-related genes provide insight into understanding the innate immunity in A. pernyi. PMID- 24076150 TI - Sex differences in spatial memory using serial and search tasks. AB - The present study assessed the spatial abilities of male and female human participants using different versions of the non-navigational Corsi block-tapping test (CBT) and a search task. Males performed significantly better than females on the standard manual version of the CBT; however, the standard CBT does not allow discrimination between spatial memory span and the role of spatial organisational factors (structure, path length and presence of crossings) in the sequences to recall. These organisational factors were assessed, therefore, in an experiment in which 7-block-sequences had to be recalled in a computerised version of the CBT. No sex differences in performance were observed on the computerised CBT, indicating that males do not make better use of spatial organisational principles. Accordingly, sex differences observed in the manual CBT are likely to rely upon differences in memory span between males and females. In the search task, participants could locate a goal by reference to a Euclidian space (the geometry of a virtual enclose) or to proximal non-geometric cues. Both male and female participants showed a preference for the non-geometric cues, which overshadowed learning about the geometric cues when the two sets were available simultaneously during the training stage. These results indicate that sex differences do exist in those tests which are dependent on memory span. Sex differences were absent, however, in spatial organisational skills or in the usage of Euclidian and egocentric strategies to solve problems relying on spatial ability. PMID- 24076151 TI - Forebrain gene expression predicts deficits in sensorimotor gating after isolation rearing in male rats. AB - Compared to socially housed (SH) rats, adult isolation-reared (IR) rats exhibit phenotypes relevant to schizophrenia (SZ), including reduced prepulse inhibition (PPI) of startle. PPI is normally regulated by the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked local field potentials (LFPs) and expression of seven PPI- and SZ-related genes in the mPFC and NAC, in IR and SH rats. Buffalo (BUF) rats were raised in same-sex groups of 2-3 (SH) or in isolation (IR). PPI was measured early (d53) and later in adulthood (d74); LFPs were measured approximately on d66. Brains were processed for RT-PCR measures of mPFC and NAC expression of Comt, Erbb4, Grid2, Ncam1, Slc1a2, Nrg1 and Reln. Male IR rats exhibited PPI deficits, most pronounced at d53; male and female IR rats had significantly elevated startle magnitude on both test days. Gene expression levels were not significantly altered by IR. PPI levels (d53) were positively correlated with mPFC expression of several genes, and negatively correlated with NAC expression of several genes, in male IR but not SH rats. Late (P90) LFP amplitudes correlated significantly with expression levels of 6/7 mPFC genes in male rats, independent of rearing. After IR that disrupts early adult PPI in male BUF rats, expression levels of PPI- and SZ associated genes in the mPFC correlate positively with PPI, and levels in the NAC correlate negatively with PPI. These results support the model that specific gene behavior relationships moderate the impact of early-life experience on SZ-linked behavioral and neurophysiological markers. PMID- 24076153 TI - Sustained delivery of dbcAMP by poly(propylene carbonate) micron fibers promotes axonal regenerative sprouting and functional recovery after spinal cord hemisection. AB - This study describes the use of poly(propylene carbonate) (PPC) electrospun fibers as vehicle for the sustained delivery of dibutyryl cyclic adenosine monophosphate (dbcAMP) to the hemisected spinal cord. The dbcAMP and PPC were uniformly mixed with acetonitrile; then, electrospinning was used to generate micron fibers. The release of dbcAMP was assessed by ELISA in vitro. Our results showed that the encapsulation of dbcAMP in the fibers led to stable and prolonged release in vitro. The PPC micron fibers containing dbcAMP and the PPC micron fibers without dbcAMP were then implanted into the hemisected thoracic spinal cord, followed by testing of the functional recovery and immunohistochemistry. Compared with the control group, sustained delivery of dbcAMP promoted axonal regenerative sprouting and functional recovery and reduced glial scar formation, and the PPC micron fibers without dbcAMP did not have these effects. Our findings demonstrated the feasibility of using PPC electrospun fibers containing dbcAMP for spinal cord injury. The approach described here also will provide a platform for the potential delivery of other axon-growth-promoting or scar-inhibiting agents. PMID- 24076154 TI - Crystal structure of rat intestinal alkaline phosphatase--role of crown domain in mammalian alkaline phosphatases. AB - Intestinal alkaline phosphatases (IAPs) are involved in the cleavage of phosphate prodrugs to liberate the drug for absorption in the intestine. To facilitate in vitro characterization of phosphate prodrugs, we have cloned, expressed, purified and characterized IAPs from rat and cynomolgus monkey (rIAP and cIAP respectively) which are important pre-clinical species for drug metabolism studies. The recombinant rat and monkey enzymes expressed in Sf9 insect cells (IAP-Ic) were found to be glycosylated and active. Expression of rat IAP in Escherichia coli (rIAP-Ec) led to ~200-fold loss of activity that was partially recovered by the addition of external Zn(2+) and Mg(2+) ions. Crystal structures of rIAP-Ec and rIAP-Ic were determined and they provide rationale for the discrepancy in enzyme activities. Rat IAP-Ic retains its activity in presence of both Zn(2+) and Mg(2+) whereas activity of most other alkaline phosphatases (APs) including the cIAP was strongly inhibited by excess Zn(2+). Based on our crystal structure, we hypothesized the residue Q317 in rIAP, present within 7 A of the Mg(2+) at M3, to be important for this difference in activity. The Q317H rIAP and H317Q cIAP mutants showed reversal in effect of Zn(2+), corroborating the hypothesis. Further analysis of the two structures indicated a close linkage between glycosylation and crown domain stability. A triple mutant of rIAP, where all the three putative N-linked glycosylation sites were mutated showed thermal instability and reduced activity. PMID- 24076152 TI - The pattern of striatal dopaminergic denervation explains sensorimotor synchronization accuracy in Parkinson's disease. AB - The basal ganglia are thought to play a critical role in duration perception and production. However, experimental evidence for impaired temporal processing in Parkinson's disease (PD) patients is mixed. This study examined the association between striatal dopaminergic denervation in PD patients and sensorimotor synchronization. Twenty-eight mild-to-moderate stage PD patients synchronized finger taps to tone sequences of either 500 ms, 1000 ms or 1500 ms time intervals while ON levodopa (l-DOPA) or placebo pill (on separate test days) with the index finger of their more and less affected hands. We measured the accuracy and variability of synchronization. In a separate session, patients underwent (11)C dihydrotetrabenazine ((11)C-DTBZ) PET scanning to measure in vivo striatal dopaminergic denervation. Patients were less accurate synchronizing to the 500 ms target time interval, compared to the 1000 ms and 1500 ms time intervals, but neither medication state nor hand affected accuracy; medication state, hand nor the target time interval affected synchronization variability. Regression analyses revealed no strong relationships between synchronization accuracy or variability and striatal dopaminergic denervation. We performed a cluster analysis on the degree of dopaminergic denervation to determine whether patient subgroup differences underlie our results. Three patient subgroups showed behavioral differences in synchronization accuracy, but not variability, paralleling their pattern of denervation. These findings provide further evidence for the role of the basal ganglia and dopamine in duration production and suggest that the degree of striatal dopaminergic denervation may explain the heterogeneity of performance between PD patients on the sensorimotor synchronization task. PMID- 24076155 TI - Bone quality around bioactive silica-based coated stainless steel implants: analysis by micro-Raman, XRF and XAS techniques. AB - Surface modification of surgical stainless steel implants by sol gel coatings has been proposed as a tool to generate a surface that besides being protective could also create a "bioactive" interface to generate a natural bonding between the metal surface and the existing bone. The aim of this work is to analyze the quality and bone formation around hybrid bioactive coatings containing glass ceramic particles, made by sol-gel process on 316L stainless steel used as permanent implant in terms of mineralization, calcium content and bone maturity with micro Raman, X-ray microfluorescence and X-ray absorption techniques. Uncoated implants seem to generate a thin bone layer at the beginning of osseointegration process and then this layer being separated from the surface with time. The hybrid coatings without glass-ceramic particles generate new bone around implants, with high concentration of Ca and P at the implant/tissue interface. This fact seems to be related with the presence of silica nanoparticles in the layer. The addition of bioactive particles promotes and enhances the bone quality with a homogeneous Ca and P content and a low rate of beta carbonate substitution and crystallinity, similar to young and mechanical resistant bone. PMID- 24076156 TI - Effect of glutamate transporter EAAT2 gene variants and gray matter deficits on working memory in schizophrenia. AB - Glutamate is the major excitatory neurotransmitter in the brain, with up to 40% of all synapses being glutamatergic. An altered glutamatergic transmission could play a critical role in working memory deficts observed in schizophrenia and could underline progressive changes such as grey matter loss throughout the brain. The aim of the study was to investigate if gray matter volume and working memory could be modulated by a genetic polymorphism related to glutamatergic function. Fifty schizophrenia patients underwent magnetic resonance and working memory testing outside of the scanner and were genotyped for rs4354668 EAAT2 polymorphism. Carriers of the G allele had lower gray matter volumes than T/T homozygote and worse working memory performance. Poor working memory performance was associated with gray matter reduction. Differences between the three genotypes are more relevant among patients showing poor performance at the 2-back task. Since glutamate abnormalities are known to be involved in excitotoxic processes, the decrease in cortical thickness observed in schizophrenia patients could be linked to an excess of extracellular glutamate. The differential effect of EAAT2 observed between good and poor performers suggests that the effect of EEAT2 on gray matter might reveal in the presence of a pathological process affecting gray matter. PMID- 24076157 TI - Affective dimensions as a diagnostic tool for bipolar disorder in first psychotic episodes. AB - OBJECTIVE: To examine the predictive diagnostic value of affective symptomatology in a first-episode psychosis (FEP) sample with 5 years' follow-up. METHOD: Affective dimensions (depressive, manic, activation, dysphoric) were measured at baseline and 5 years in 112 FEP patients based on a factor structure analysis using the Young Mania Rating Scale and Hamilton Depression Rating Scale. Patients were classified as having a diagnosis of bipolar disorder at baseline (BDi), bipolar disorder at 5 years (BDf), or "other psychosis". The ability of affective dimensions to discriminate between these diagnostic groups and to predict a bipolar disorder diagnosis was analysed. RESULTS: Manic dimension score was higher in BDi vs. BDf, and both groups had higher manic and activation scores vs. "other psychosis". Activation dimension predicted a bipolar diagnosis at 5 years (odds ratio=1.383; 95% confidence interval, 1.205-1.587; P=0.000), and showed high levels of sensitivity (86.2%), specificity (71.7%), positive (57.8%) and negative predictive value (90.5%). Absence of the manic dimension and presence of the depressive dimension were both significant predictors of an early misdiagnosis. CONCLUSION: The activation dimension is a diagnostic predictor for bipolar disorder in FEP. The manic dimension contributes to a bipolar diagnosis and its absence can lead to early misdiagnosis. PMID- 24076158 TI - Identification of the C/EBPalpha C-terminal tail residues involved in the protein interaction with GABP and their potency in myeloid differentiation of K562 cells. AB - The CCAAT/enhancer-binding protein alpha (C/EBPalpha) is the member of a family of related basic leucine zipper (bZIP) transcription factors and is critical for granulopoiesis. We previously demonstrated that C/EBPalpha interacts with the ETS domain of widely expressed GABPalpha, which leads to cooperative transcriptional activation of the myeloid-specific promoter for human FCAR encoding the Fc receptor for IgA (FcalphaR, CD89) in part by facilitating recruitment of C/EBPalpha to the promoter. The C/EBPalpha molecule contains transactivation domains (TADs) at its N-terminus and a DNA-binding and dimerization bZIP structure at its C-terminus. We demonstrate here that GABPalpha interacts with the last 18 residues of the C/EBPalpha C-terminus beyond the bZIP DNA-binding and dimerizing region. Deletion of this C-terminus resulted in loss of GABPalpha interaction but not affecting its DNA binding ability, indicating that it is not required for homodimer formation. Moreover, the C-terminus confers the ability to functionally synergize with GABP on a heterologous TAD when fused to the C terminus of the VP16 TAD. We identified a three-amino acid stretch (amino acids 341-343) that is important for both functional and protein interactions with GABP. Ectopic expression in K562 cells of C/EBPalpha mutant incapable of interacting with GABPalpha does not induce expression of granulocytic differentiation markers including CD15, CD11b, GCSF-R and C/EBPepsilon, and does not inhibit proliferation, whereas wild type does. These results demonstrate the functional importance of the C/EBPalpha C-terminus beyond the bZIP DNA-binding and dimerization region, which may mediate cooperative activation by C/EBPalpha and GABP of myeloid-specific genes involved in C/EBPalpha-dependent granulopoiesis. PMID- 24076159 TI - An Eimeria vaccine candidate based on Eimeria tenella immune mapped protein 1 and the TLR-5 agonist Salmonella typhimurium FliC flagellin. AB - Immune mapped protein-1 (IMP1) is a new protective protein in apicomplexan parasites, and exits in Eimeria tenella. But its structure and immunogenicity in E. tenella are still unknown. In this study, IMPI in E. tenella was predicted to be a membrane protein. To evaluate immunogenicity of IMPI in E. tenella, a chimeric subunit vaccine consisting of E. tenella IMP1 (EtIMP1) and a molecular adjuvant (a truncated flagellin, FliC) was constructed and over-expressed in Escherichia coli and its efficacy against E. tenella infection was evaluated. Three-week-old AA broiler chickens were vaccinated with the recombinant EtIMP1 truncated FliC without adjuvant or EtIMP1 with Freund's Complete Adjuvant. Immunization of chickens with the recombinant EtIMP1-truncated FliC fusion protein resulted in stronger cellular immune responses than immunization with only recombinant EtIMP1 with adjuvant. The clinical effect of the EtIMP1 truncated FliC without adjuvant was also greater than that of the EtIMP1 with adjuvant, which was evidenced by the differences between the two groups in body weight gain, oocyst output and caecal lesions of E. tenella-challenged chickens. The results suggested that the EtIMP1-flagellin fusion protein can be used as an effective immunogen in the development of subunit vaccines against Eimeria infection. This is the first demonstration of antigen-specific protective immunity against avian coccidiosis using a recombinant flagellin as an apicomplexan parasite vaccine adjuvant in chickens. PMID- 24076161 TI - 2013 International Society for Clinical Densitometry Position Development Conference: Task Force on Normative Databases. AB - Following the standard protocol for development of Official Positions for the International Society for Clinical Densitometry, the Expert Panel heard the report and recommendations from the Task Force on Normative Databases; using the RAND methodology, agreement was reached on the following statements: 1. Manufacturers should continue to use their own databases for the lumbar spine as the reference standard for T-scores. 2. Manufacturers should continue to use National Health and Nutrition Examination Survey III data as the reference standard for femoral neck and total hip T-scores. 3. If local reference data are available, they should be used to calculate only Z-scores but not T-scores. 4. A uniform Caucasian (non-race adjusted) female reference database should be used to calculate T-scores for men of all ethnic groups. PMID- 24076163 TI - Opioids for chronic musculoskeletal pain: putting patient safety first. PMID- 24076164 TI - Percutaneous left atrial appendage occlusion with a Watchman device following recurrent stroke on warfarin and rivaroxaban in patient with paroxysmal atrial fibrillation. AB - The optimal management of recurrent cardioembolic stroke in a patient on oral anticoagulation is controversial. Therapeutic strategies for secondary stroke prevention in such circumstances may include the intensification of oral anticoagulation, the addition of antiplatelet therapy to warfarin, or the use of a non-vitamin K antagonist instead of warfarin. However, there is no evidence to support these interventions, and indeed these strategies are not endorsed by the 2011 Guidelines on the Secondary Prevention of Stroke issued by the American Heart Association/American Stroke Association. Percutaneous occlusion of the left atrial appendage (LAA) has recently emerged as an acceptable non-pharmacological strategy to reduce the risk of cardioembolism in patients who cannot tolerate oral anticoagulation, but there is little evidence to support its use in the context of recurrent stroke despite oral anticoagulation. We present the case of a 66 year-old male with paroxysmal atrial fibrillation who experienced recurrent stroke despite treatment with warfarin initially, and rivaroxaban subsequently. After excluding non-cardioembolic causes of recurrent stroke, we proceeded with percutaneous occlusion of the LAA with a Watchman device. Nine months post procedure he has not experienced recurrence of neurological symptoms. Our case provides anectodal evidence that catheter-based LAA occlusion can be beneficial in secondary stroke prevention where oral anticoagulation has been problematic. PMID- 24076162 TI - Postnatal maturation of endogenous opioid systems within the periaqueductal grey and spinal dorsal horn of the rat. AB - Significant opioid-dependent changes occur during the fourth postnatal week in supraspinal sites (rostroventral medulla [RVM], periaqueductal grey [PAG]) that are involved in the descending control of spinal excitability via the dorsal horn (DH). Here we report developmentally regulated changes in the opioidergic signalling within the PAG and DH, which further increase our understanding of pain processing during early life. Microinjection of the MU-opioid receptor (MOR) agonist DAMGO (30 ng) into the PAG of Sprague-Dawley rats increased spinal excitability and lowered mechanical threshold to noxious stimuli in postnatal day (P)21 rats, but had inhibitory effects in adults and lacked efficacy in P10 pups. A tonic opioidergic tone within the PAG was revealed in adult rats by intra-PAG microinjection of CTOP (120 ng, MOR antagonist), which lowered mechanical thresholds and increased spinal reflex excitability. Spinal administration of DAMGO inhibited spinal excitability in all ages, yet the magnitude of this was greater in younger animals than in adults. The expression of MOR and related peptides were also investigated using TaqMan real-time polymerase chain reaction and immunohistochemistry. We found that pro-opiomelanocortin peaked at P21 in the ventral PAG, and MOR increased significantly in the DH as the animals aged. Enkephalin mRNA transcripts preceded the increase in enkephalin immunoreactive fibres in the superficial dorsal horn from P21 onwards. These results illustrate that profound differences in the endogenous opioidergic signalling system occur throughout postnatal development. PMID- 24076165 TI - Cell type-dependent agonist/antagonist activities of polybrominated diphenyl ethers. AB - There have been many concerns expressed regarding the possible adverse effects of thyroid hormone-disrupting chemicals including polychlorinated biphenyls and polybrominated diphenyl ethers (PBDEs), since thyroid hormones play crucial roles in normal vertebrate development. A vast amount of PBDEs have been used as flame retardants for the last two decades and our environment has been contaminated with them. Some PBDEs, especially hydroxylated PBDEs, reportedly show an affinity to the thyroid hormone receptor (TR) and act as thyroid hormone agonists, but in other studies they were reported to inhibit the actions of thyroid hormones. Therefore, in the present study, we investigated the binding affinities of PBDEs and their metabolites to TR and their ability to induce thyroid hormone responsive transcription using luciferase reporter gene assays in two different cell lines, a pituitary cell line, MtT/E-2, and Chinese hamster ovary (CHO) cells. The binding assay showed that many of the examined PBDEs have significant affinity to TR. Interestingly, some of these PBDEs, such as 4'-OH-BDE-17 and 2' OH-BDE-28, acted as agonists in the reporter gene assay in MtT/E-2 cells, while they acted as antagonists in CHO cells. Our results demonstrated that whether PBDEs and their metabolites are TR agonists or antagonists depends on the cell type used in the assay, which may suggest that the thyroid hormone-disrupting actions of PBDEs differ among target tissues or species. PMID- 24076166 TI - Carbocysteine regulates innate immune responses and senescence processes in cigarette smoke stimulated bronchial epithelial cells. AB - Cigarette smoke represents the major risk factor for chronic obstructive pulmonary disease (COPD). Cigarette smoke extracts (CSE) alter TLR4 expression and activation in bronchial epithelial cells. Carbocysteine, an anti-oxidant and mucolytic agent, is effective in reducing the severity and the rate of exacerbations in COPD patients. The effects of carbocysteine on TLR4 expression and on the TLR4 activation downstream events are largely unknown. This study was aimed to explore whether carbocysteine, in a human bronchial epithelial cell line (16-HBE), counteracted some pro-inflammatory CSE-mediated effects. In particular, TLR4 expression, LPS binding, p21 (a senescence marker), IL-8 mRNA and release in CSE-stimulated 16-HBE as well as actin reorganization in neutrophils cultured with supernatants from bronchial epithelial cells which were stimulated with CSE and/or carbocysteine were assessed. TLR4 expression, LPS binding, and p21 expression were assessed by flow cytometry, IL-8 mRNA by Real Time PCR and IL-8 release by ELISA. Actin reorganization, a prerequisite for cell migration, was determined using Atto 488 phalloidin in neutrophils by flow cytometry and fluorescence microscopy. CSE increased: (1) TLR4, LPS binding and p21 expression; (2) IL-8 mRNA and IL-8 release due to IL-1 stimulation; (3) neutrophil migration. Carbocysteine in CSE stimulated bronchial epithelial cells, reduced: (1) TLR4, LPS binding and p21; (2) IL-8 mRNA and IL-8 release due to IL-1 stimulation; (3) neutrophil chemotactic migration. In conclusion, the present study provides compelling evidences that carbocysteine may contribute to control the inflammatory and senescence processes present in smokers. PMID- 24076167 TI - Molecular cloning of the alpha subunit of complement component C8 (CpC8alpha) of whitespotted bamboo shark (Chiloscyllium plagiosum). AB - Complement-mediated cytolysis is the important effect of immune response, which results from the assembly of terminal complement components (C5b-9). Among them, alpha subunit of C8 (C8alpha) is the first protein that traverses the lipid bilayer, and then initiates the recruitment of C9 molecules to form pore on target membranes. In this article, a full-length cDNA of C8alpha (CpC8alpha) is identified from the whitespotted bamboo shark (Chiloscyllium plagiosum) by RACE. The CpC8alpha cDNA is 2183 bp in length, encoding a protein of 591 amino acids. The deduced CpC8alpha exhibits 89%, 49% and 44% identity with nurse shark, frog and human orthologs, respectively. Sequence alignment indicates that the C8alpha is well conserved during the evolution process from sharks to mammals, with the same modular architecture as well as the identical cysteine composition in the mature protein. Phylogenetic analysis places CpC8alpha and nurse shark C8alpha in cartilaginous fish clade, in parallel with the teleost taxa, to form the C8alpha cluster with higher vertebrates. Hydrophobicity analysis also indicates a similar hydrophobicity of CpC8alpha to mammals. Finally, expression analysis revealed CpC8alpha transcripts were constitutively highly expressed in shark liver, with much less expression in other tissues. The well conserved structure and properties suggests an analogous function of CpC8alpha to mammalian C8alpha, though it remains to be confirmed by further study. PMID- 24076168 TI - Regulation of prostaglandin F2alpha against beta amyloid clearance and its inflammation induction through LXR/RXR heterodimer antagonism in microglia. AB - Alzheimer's disease (AD) is characterized by extracellular deposit of beta amyloid (Abeta) and accumulation of intracellular neurofibrillary tangles in the brain. Prostaglandin F2alpha (PGF2alpha) is one of the major metabolites of arachidonic acid (AA), and plays essential roles in a series of key physiological processes like luteolysis and parturition. Additionally, PGF2alpha is also involved in the regulation of chronic and acute inflammation processes. Recent clinical studies have revealed the high content of PGF2alpha metabolite, 15-keto dihydro-PGF2alpha in AD patients, implying the activation of in vivo PGF2alpha biosynthesis. However, the mechanism underlying the involvement of PGF2alpha in the progression of AD still remains unclear. Here we discovered that PGF2alpha selectively antagonized LXR (liver X receptors)/RXR (retinoid X receptor alpha) and RXR/RXR dimers. Cell based assays indicated that PGF2alpha effectively antagonized the activation of LXR agonist (t0901317) on Abeta clearance via inhibiting apolipoprotein E (apoE) expression, and cell apoptosis alleviation by accelerating inflammatory response to Abeta or Lipopolysaccharide (LPS) in microglia. Therefore, our current findings have addressed the potential association of PGF2alpha with AD progression, and highlighted that inhibition of PGF2alpha biosynthesis might be a useful therapeutic strategy against AD. PMID- 24076169 TI - Synthesis of azide derivative and discovery of glyoxalase pathway inhibitor against pathogenic bacteria. AB - A glyoxalase inhibitor was synthesized and tested against Staphylococcus aureus for first time and showed MIC90 of 20 MUg/ml. Henceforth, we synthesized unnatural azide derivative of the same inhibitor to improve the biological activity. In that order, an azide carboxylate was synthesized from dimethyl tartrate by tosylation and azide substitution. The synthesized, azide compound was coupled with glutathione derivative in high yield and tested against S. aureus and showed improved MIC90 of 5 MUg/ml. In general, it can be also easily converted to unnatural beta-amino acid in good yield. The shown methodology will be extended to study induced suicide in Burkholderia mallei, Francisella tularensis and Mycobacterium tuberculosis in future. PMID- 24076170 TI - 2-Phenylbenzofuran derivatives alleviate mitochondrial damage via the inhibition of beta-amyloid aggregation. AB - To obtain modulators for reducing mitochondrial damage by the inhibition of Abeta oligomer formation, 2-phenylbenzofuran derivatives were designed and prepared. Their inhibitory activity against Abeta fibril formation was screened using ThT fluorescence assay, and the effect of derivatives on mitochondrial function was evaluated using JC-1 and MTT assay. 2-Phenylbenzofuran derivatives with dimethylamino group at p-position had an excellent inhibitory activity against Abeta fibril formation. Particularly, compound 19m alleviated mitochondrial damage remarkably and possessed protective effects against Abeta-induced cytotoxicity. PMID- 24076160 TI - Controversies and evolving new mechanisms in subarachnoid hemorrhage. AB - Despite decades of study, subarachnoid hemorrhage (SAH) continues to be a serious and significant health problem in the United States and worldwide. The mechanisms contributing to brain injury after SAH remain unclear. Traditionally, most in vivo research has heavily emphasized the basic mechanisms of SAH over the pathophysiological or morphological changes of delayed cerebral vasospasm after SAH. Unfortunately, the results of clinical trials based on this premise have mostly been disappointing, implicating some other pathophysiological factors, independent of vasospasm, as contributors to poor clinical outcomes. Delayed cerebral vasospasm is no longer the only culprit. In this review, we summarize recent data from both experimental and clinical studies of SAH and discuss the vast array of physiological dysfunctions following SAH that ultimately lead to cell death. Based on the progress in neurobiological understanding of SAH, the terms "early brain injury" and "delayed brain injury" are used according to the temporal progression of SAH-induced brain injury. Additionally, a new concept of the vasculo-neuronal-glia triad model for SAH study is highlighted and presents the challenges and opportunities of this model for future SAH applications. PMID- 24076171 TI - Total syntheses and cytotoxicity of kealiiquinone, 2-deoxy-2-aminokealiiquinone and analogs. AB - Concise syntheses of two Leucetta-derived naphthimidazole alkaloids, kealiiquinone and 2-deoxy-2-aminokealiiquinone, are described based on a biosynthetic-guided hypothesis. Advanced intermediates containing the full naphthimidazole framework are constructed through Friedel-Crafts chemistry followed by oxidation of the electron rich C-ring with hydrogen peroxide. The cytotoxicity of these alkaloids in a breast cancer cell line along with several closely related marine-derived natural products kealiinines A-C and analogs are reported. PMID- 24076172 TI - Discovery of a potent, selective, and orally bioavailable histamine H3 receptor antagonist SAR110068 for the treatment of sleep-wake disorders. AB - Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), K(i)=8.6 nM, rhesus monkey (rh-H3R), K(i)=1.2 nM, and rat (r-H3R), K(i)=16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders. PMID- 24076173 TI - Reversible inhibition of human acetylcholinesterase by methoxypyridinium species. AB - The irreversible inhibition of acetylcholinesterase (AChE) by organophosphorous chemical warfare agents necessitates that antidotes be administered for effective treatment. Currently no antidote is known that resurrects the phosphyl-AChE complex once aging has occurred. This report characterizes the affinities of over 30 new AChE inhibitors which could act as resurrecting agents for the aged AChE OP adduct. PMID- 24076174 TI - Two putative protein export regulators promote Plasmodium blood stage development in vivo. AB - Protein export is considered an essential feature of malaria parasite blood stage development. Here, we examined five components of the candidate Plasmodium translocon of exported proteins (PTEX), a complex thought to mediate protein export across the parasitophorous vacuole membrane into the host cell. Using the murine malaria model parasite Plasmodium berghei, we succeeded in generating parasite lines lacking PTEX88 and thioredoxin 2 (TRX2). Repeated attempts to delete the remaining three translocon components failed, suggesting essential functions for EXP2, PTEX150, and heat shock protein 101 (HSP101) during blood stage development. To analyze blood infections of the null-mutants, we established a flow cytometry-assisted intravital competition assay using three novel high fluorescent lines (Bergreen, Beryellow, and Berred). Although blood stage development of parasites lacking TRX2 was affected, the deficit was much more striking in PTEX88 null-mutants. The multiplication rate of PTEX88-deficient parasites was strongly reduced resulting in out-competition by wild-type parasites. Endogenous tagging revealed that TRX2::tag resides in distinct punctate organelles of unknown identity. PTEX88::tag shows a diffuse intraparasitic pattern in blood stage parasites. In trophozoites, PTEX88::tag also localized to previously unrecognized extensions reaching from the parasite surface into the erythrocyte cytoplasm. Together, our results indicate auxiliary roles for TRX2 and PTEX88 and central roles for EXP2, PTEX150, and HSP101 during P. berghei blood infection. PMID- 24076175 TI - How parents make decisions about their children's vaccinations. AB - BACKGROUND: Continued parental acceptance of childhood vaccination is essential for the maintenance of herd immunity and disease prevention. As such, understanding parents' decision-making in relation to their children's vaccinations is vitally important. OBJECTIVE: This qualitative study sought to develop an understanding of the general process parents go through when making decisions about their children's vaccinations. METHODS: Interviews were conducted with U.S.-born parents living in King County, Washington who had children <=18 months of age. These interviews were recorded and transcribed verbatim. RESULTS: Through the application of grounded theory, a general decision-making process was identified. Stages in this process included: awareness, assessing and choosing, followed by either stasis or ongoing assessment. The greatest variation occurred during the assessing stage, which involved parents examining vaccination-related issues to make subsequent decisions. This research suggests that three general assessment groups exist: acceptors, who rely primarily on general social norms to make their vaccination decisions; reliers, who rely primarily on other people for information and advice; and searchers, who seek for information on their own, primarily from published sources. CONCLUSIONS: These results imply that one-size fits-all approaches to vaccination interventions are inappropriate. Instead, this research suggests that interventions must be targeted to parents based on how they assess vaccination. PMID- 24076176 TI - Influenza vaccination during pregnancy: coverage rates and influencing factors in two urban districts in Sydney. AB - BACKGROUND: Pregnant women have an increased risk of complications from influenza. Influenza vaccination during pregnancy is considered effective and safe; however estimates of vaccine coverage are low. This study aimed to determine influenza vaccination coverage and factors associated with vaccine uptake in pregnant women in two Sydney-based health districts. METHODS: A random sample of women who delivered a baby in a public hospital in Sydney and South Western Sydney Local Health Districts between June and September 2012 were surveyed using a computer assisted telephone interviewing service. RESULTS: Of the 462 participants (participation rate 92%), 116 (25%) reported receiving the influenza vaccine during their pregnancy. In univariate analysis, vaccination coverage varied significantly depending on antenatal care type, hospital of birth, and parity (p<0.05), but not for age category, highest level of education, country of birth, language spoken at home, or Aboriginal status. Women who received antenatal care through a general practitioner (GP) had 2.3 (95% CI 1.4 3.6) times the odds (unadjusted) of receiving the influenza vaccination than those who received their antenatal care through a public hospital. The main reason cited for vaccination was GP recommendation (37%), while non recommendation (33%) and lack of knowledge (26%) were cited as main reasons for not receiving the vaccination. 30% of women recalled receiving a provider recommendation for the vaccination and these women had 33.0 times the odds (unadjusted) of receiving the vaccination than women who had not received a recommendation. In a multivariate model a provider recommendation was the only variable that was significantly associated with vaccination (OR 41.9; 95% CI 20.7 84.9). CONCLUSION: Rates of influenza vaccination during pregnancy are low. There is a significant relationship between healthcare provider recommendation for the vaccination and vaccine uptake. Increasing provider recommendation rates has the potential to increase coverage rates of influenza vaccination in pregnant women. PMID- 24076177 TI - Collagenous colitis and ankylosing spondylitis. PMID- 24076178 TI - Efficacy of tocilizumab in refractory adult-onset Still's disease; report of 2 cases. PMID- 24076179 TI - The regulation of NHE1 and NHE3 activity by angiotensin II is mediated by the activation of the angiotensin II type I receptor/phospholipase C/calcium/calmodulin pathway in distal nephron cells. AB - Angiotensin II (Ang II), acting via the AT1 receptor, induces an increase in intracellular calcium [Ca(2+)]i that then interacts with calmodulin (CaM). The Ca(2+)/CaM complex directly or indirectly activates sodium hydrogen exchanger 1 (NHE1) and phosphorylates calmodulin kinase II (CaMKII), which then regulates sodium hydrogen exchanger 3 (NHE3) activity. In this study, we investigated the cellular signaling pathways responsible for Ang II-mediated regulation of NHE1 and NHE3 in Madin-Darby canine kidney (MDCK) cells. The NHE1- and NHE3-dependent pHi recovery rates were evaluated by fluorescence microscopy using the fluorescent probe BCECF/AM, messenger RNA was evaluated with the reverse transcription polymerase chain reaction (RT-PCR), and protein expression was evaluated by immunoblot. We demonstrated that treatment with Ang II (1pM or 1 nM) for 30 min induced, via the AT1 but not the AT2 receptor, an equal increase in NHE1 and NHE3 activity that was reduced by the specific inhibitors HOE 694 and S3226, respectively. Ang II (1 nM) did not change the total expression of NHE1, NHE3 or calmodulin, but it induced CaMKII, cRaf-1, Erk1/2 and p90(RSK) phosphorylation. The stimulatory effects of Ang II (1 nM) on NHE1 or NHE3 activity or protein abundance was reduced by ophiobolin-A (CaM inhibitor), KN93 (CaMKII inhibitor) or PD98059 (Mek inhibitor). These results indicate that after 30 min, Ang II treatment may activate G protein-dependent pathways, including the AT1/PLC/Ca(2+)/CaM pathway, which induces CaMKII phosphorylation to stimulate NHE3 and induces cRaf-1/Mek/Erk1/2/p90(RSK) activity to stimulate NHE1. PMID- 24076180 TI - Inhibition of Ca(2+)-regulated exocytosis by levetiracetam, a ligand for SV2A, in antral mucous cells of guinea pigs. AB - Levtiracetam (Lev), an inhibitor of SV2A (synaptic vesicle protein A2), affected the ATP-dependent priming of Ca(2+)-regulated exocytosis in antral mucous cells of guinea pig. In antral mucous cells, the Ca(2+)-regulated exocytosis, which is activated by acetylcholine (ACh), consists of an initial peak that declines rapidly (initial phase) followed by a second slower decline (late phase). Dinitrophenol (DNP), which depletes ATP, inhibits the ATP-dependent priming. DNP abolished the initial phase by reducing the number of primed granules, Lev decreased the frequency of initial phase, but not in the presence of DNP. Moreover, 8-bromoguanosine 3'5'-cyclic monophosphate (8BrcGMP) accelerates the ATP-dependent priming. 8BrcGMP enhances the frequency of initial phase by increasing the number of primed granule. Lev added prior to 8BrcGMP addition decreased the frequency of initial phase, but Lev added after 8BrcGMP addition did not. Thus, Lev affected the granules in the process of priming, but it did not affect the granules already primed. Lev did not affect [Ca(2+)]i in unstimulated or ACh-stimulated antral mucous cells. Immunohistochemistry and western blotting demonstrated that SV2A exists in antral mucous cells. The results suggest that SV2A plays an essential role in maintaining the process of ATP-dependent priming in antral mucous cells. In conclusion, Lev decreases the frequency of Ca(2+)-regulated exocytosis the number of primed granules by inhibiting SV2A functions, leading to a decrease in antral mucous cells. PMID- 24076181 TI - Effects of the neurotensin NTS1 receptor agonist PD149163 on visual signal detection in rats. AB - Antipsychotic drugs provide limited efficacy for cognitive impairment in schizophrenia. Recent studies have found that the neurotensin NTS1 receptor agonist and putative atypical antipsychotic drug PD149163 reverses deficits in sensory-gating and novel object recognition, suggesting that this compound may have the potential to improve cognitive functioning in schizophrenia. The present study sought to extend these investigations by evaluating the effects of PD149163 on sustained attention using a visual signal detection operant task in rats. PD149163, the atypical antipsychotic drug clozapine, and the dopamine D2/3 receptor antagonist raclopride all significantly decreased percent "hit" accuracy, while none of these compounds altered "correct rejections" (compared to vehicle control). Clozapine and raclopride significantly increased response latency, while high doses of PD149163 and raclopride significantly increased trial omissions. Nicotine, which was tested as a positive control, significantly improved overall performance in this task and did not affect response latency or trial omissions. The present findings suggest that neurotensin NTS1 receptor agonists, like antipsychotic drugs, may inhibit sustained attention in this task despite having different pharmacological mechanisms of action. PMID- 24076182 TI - Chronic antidepressant treatments resulted in altered expression of genes involved in inflammation in the rat hypothalamus. AB - To gain insight into the possible immune targets of antidepressant, we evaluated the expression of several inflammatory mediators in the hypothalamus of rats chronically (28 days) treated with the serotonin selective reuptake inhibitor fluoxetine (5mg/kg, i.p.) or the tricyclic compound imipramine (15 mg/kg, i.p.). We focused our attention on the hypothalamus as it plays a key role in determining many of the somatic symptoms experienced by depressed patients. This brain region, critical also for expression of motivated behaviours, participates in the control of the hypothalamic-pituitary-adrenal axis activity and in stress response as well as coordinates physiological functions such as sleep and food intake that have been found altered in a high percentage of depressed patients. Notably, hypothalamus is a key structure for brain cytokine expression and function as it integrates signals from the neuro, immune, endocrine systems. By means of quantitative Real Time PCR experiments we demonstrated that a chronic treatment with either fluoxetine or imipramine resulted in a reduction of IL-6 and IFN-gamma mRNAs and increased IL-4 mRNA expression in the rat hypothalamus. Moreover, we demonstrated that hypothalamic expression of members of IL-18 system was differentially affected by chronic antidepressant treatments. Chronically administered fluoxetine decreased IL-8 and CX3CL1 hypothalamic expression, while a chronic treatment with imipramine decreased p11 mRNA. Our data suggest that a shift in the balance of the inflammation toward an anti-inflammatory state in the hypothalamus may represent a common mechanism of action of both the chronic treatments with fluoxetine and imipramine. PMID- 24076183 TI - Synthesis, crystal structures, and anti-drug-resistant Staphylococcus aureus activities of novel 4-hydroxycoumarin derivatives. AB - Four novel 4-hydroxycoumarin derivatives (4-MBH, 3-MBH, 4-MDT and 3-MDT) were successfully synthesized and their structures were verified by single-crystal X ray crystallography. All target compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus (S. aureus ATCC 29213), methicillin-resistant S. aureus (MRSA XJ 75302), vancomycin-intermediate S. aureus (Mu50 ATCC 700699), and USA 300 (Los Angeles County clone, LAC). The minimum inhibitory concentration and time-kill curves were obtained for the test compounds and antibiotics. Among the tested compounds, 3-MBH showed the most potent antibacterial activities. PMID- 24076184 TI - Effects of a combination of ketanserin and propranolol on inflammatory hyperalgesia in rats. AB - Pain management is still challenging in clinic as current analgesics either are not very effective or produce serious adverse effects. This study aimed to examine if old drugs could display the new use and to develop a novel therapy for inflammatory pain. Injection of carrageenan in hindpaw evoked hyperalgesia detected by noxious heat stimulation. Intraplantar (i.pl.) injection of the 5 HT1A receptor antagonist WAY-100635 increased paw withdrawal latency (PWL) above normal level (hypoalgesia) during the late phase of carrageenan-evoked inflammation. The hypoalgesia was completely abolished by systemic injection of naloxone chloride and naloxone methiodide. Moreover, i.pl. injection of a combination of WAY-100635 and ketanserin, a 5-HT2A receptor antagonist, at their minimal doses attenuated hyperalgesia in the late phase of carrageenan-evoked inflammation. Subcutaneous (s.c.) injection of both ketanserin and propranolol dose-dependently inhibited carrageenan-evoked hyperalgesia. The treatment with a combination of ketanserin and propranolol by s.c. injection abolished carrageenan evoked hyperalgesia at the doses, at which the drugs failed to alter the hypersensitivity when they were given alone. Furthermore, the combination of ketanserin and propranolol was also effective in relieving arthritic hyperalgesia and muscle pain at a minimal dose. The present study suggests that the activation of 5-HT1A receptors suppressed naloxone-reversible antinociception contributing to the maintenance of inflammatory pain, and that the concomitant blockade of 5 HT1A and 5-HT2A receptors in the periphery produced synergistic effects on inflammatory hyperalgesia. It is proposed that the combination of ketanserin and propranolol injected s.c. could be a promising therapy for relieving inflammatory pain with minimal side effects. PMID- 24076185 TI - Novel function of N,N-bis(2-chloroethyl)docos-13-enamide for reversal of multidrug resistance in tongue cancer. AB - Multidrug resistance (MDR) is a key element in the failure of chemotherapies, and development of agents to overcome MDR is crucial to improving cancer treatments. The overexpression of glutathione-S-transferases (GSTs) is one of the major mechanisms of MDR. Because some agents used in traditional Chinese medicine have strong antitumor effects coupled with low toxicity; we investigated the ability of N,N-bis(2-chloroethyl)docos-13-enamide (compound J), the synthesized analog of a highly unsaturated fatty acid from Isatis tinctoria L., to reverse the MDR induced by adriamycin (ADM) in TCA8113/ADM cells. We found that compound J significantly increased the cytotoxicity of ADM in TCA8113/ADM cells, with a reversal fold of 2.461. Analysis of the mechanisms through which compound J reversed MDR indicated that compound J significantly decreased the activity of GSTs and enhanced the depletion of GSH in TCA8113/ADM cells, but did not affect the P-glycoprotein (P-gp) efflux. Taken together, our data suggested that compound J was an excellent candidate for reversing MDR in cancer therapy. PMID- 24076186 TI - Analysis of anandamide- and lysophosphatidylinositol-induced inhibition of the vasopressor responses produced by sympathetic stimulation or noradrenaline in pithed rats. AB - The endocannabinoid system exhibits multiple functions in cardiovascular regulation mainly by cannabinoid (CB1 and CB2) receptors, vanilloid TRPV1 receptors and, probably, by the orphan G protein-coupled receptor 55 (GPR55). Hence, the role of these receptors was investigated in Wistar pithed rats on anandamide- and lysophosphatidylinositol (LPI)-induced inhibition of the vasopressor responses induced by preganglionic (T7-T9) stimulation of the vasopressor sympathetic outflow or i.v. bolus injections of noradrenaline. The corresponding frequency- and dose-dependent vasopressor responses were analyzed before and during i.v. continuous infusions of anandamide (CB1, CB2, TRPV1 and GPR55), JWH-015 (CB2) and LPI (GPR55) in animals receiving (i.v.) the antagonists NIDA41020 (CB1), AM630 (CB2), capsazepine (TRPV1) and/or cannabidiol (GPR55). Anandamide (0.1-3.1 MUg/kg min) inhibited the vasopressor responses by electrical stimulation, but not those by noradrenaline; while LPI (5.6-10 MUg/kg min) inhibited both responses. In contrast, JWH-015 (5.6-10 MUg/kg min) failed to induce sympatho-inhibition. Anandamide-induced sympatho-inhibition was: (i) dose dependently blocked by 31 and 100 MUg/kg NIDA41020; (ii) slightly blocked by 310 MUg/kg AM630 or 31 MUg/kg cannabidiol; and (iii) unaffected by 310 MUg/kg capsazepine. Moreover, LPI-induced inhibition of both vasopressor responses was blocked and abolished by 10 and 31 MUg/kg cannabidiol, respectively, and weakly blocked by 100 MUg/kg NIDA41020. Thus, the sympatho-inhibition by anandamide is primarily mediated by cannabinoid CB1 and, minimally, by cannabidiol-sensitive receptors. In contrast, LPI-induced inhibition of both responses seems to be mainly mediated by postjunctional cannabidiol-sensitive (presumably endothelial GPR55) receptors. PMID- 24076187 TI - Silibinin promotes osteoblast differentiation of human bone marrow stromal cells via bone morphogenetic protein signaling. AB - Silibinin is the major active constituent of the natural compound silymarin; several studies suggest that silibinin possesses antihepatotoxic properties and anticancer effects against carcinoma cells. However, no study has yet investigated the effect of silibinin on osteogenic differentiation of human bone marrow stem cells (hBMSCs). The aim of this study was to evaluate the effect of silibinin on osteogenic differentiation of hBMSCs. In this study, the hBMSCs were cultured in an osteogenic medium with 0, 1, 10 or 20 MUmol/l silibinin respectively. hBMSCs viability was analyzed by cell number quantification assay and cells osteogenic differentiation was evaluated by alkaline phosphatas (ALP) activity assay, Von Kossa staining and real time-polymerase chain reaction (RT PCR). We found that silibinin promoted ALP activity in hBMSCs without affecting their proliferation. The mineralization of hBMSCs was enhanced by treatment with silibinin. Silibinin also increased the mRNA expressions of Collagen type I (COL I), ALP, Osteocalcin (OCN), Osterix, bone morphogenetic protein-2 (BMP-2) and Runt-related transcription factor 2 (RUNX2). The BMP antagonist noggin and its receptor kinase inhibitors dorsomorphin and LDN-193189 attenuated silibinin promoted ALP activity. Furthermore, BMP-responsive and Runx2-responsive reporters were activated by silibinin treatment. These results indicate that silibinin enhances osteoblast differentiation probably by inducing the expressions of BMPs and activating BMP and RUNX2 pathways. Thus, silibinin may play an important therapeutic role in osteoporosis patients by improving osteogenic differentiation of BMSCs. PMID- 24076188 TI - Ploidy effects on genes regulating growth mechanisms during fasting and refeeding in juvenile rainbow trout (Oncorhynchus mykiss). AB - Diploid and triploid rainbow trout weighing approximately 3g were either fed for five weeks, or feed deprived for one week, followed by refeeding. During feed deprivation gastrointestinal somatic index decreased in diploids, but not triploids, and during refeeding, carcass growth rate recovered more quickly in triploids. Although not affected by ploidy, liver ghr2 and igfbp2b expression increased and igfbp1b decreased in fasted fish. Effects of ploidy on gene expression indicate potential mechanisms associated with improved recovery growth in triploids, which include decreased hepatic igfbp expression, which could influence IGF-I bioavailability, differences in tissue sensitivity to TGFbeta ligands due to altered tgfbr and smad expression, and differences in expression of muscle regulatory genes (myf5, mstn1a, and mstn1b). These data suggest that polyploidy influences the expression of genes critical to muscle development and general growth regulation, which may explain why triploid fish recover from nutritional insult better than diploid fish. PMID- 24076189 TI - Genomes and G-quadruplexes: for better or for worse. AB - Genomic integrity is crucial for correct chromosome segregation and physiological rates of cell proliferation. Mutations, deletions and translocations, hallmarks of human tumors, drive the aberrant proliferation and metastatic behavior of cancer cells. These chromosomal rearrangements often occur at genomic sites susceptible to breakage during DNA replication, including regions with G quadruplex (G4)-forming potential. G4s are stable secondary structures that guanine-rich single-stranded DNA can readily adopt in vitro. However, their formation in eukaryotic cells has remained elusive and thus a subject of debate ever since they were first described. Recent work has more convincingly implicated G4s in a variety of biological processes including telomere maintenance, gene expression, epigenetic regulation and DNA replication. However, the downside of employing thermodynamically very stable alternative DNA structures as regulatory entities lies in their potential to also interfere with normal DNA metabolic processes, such as transcription and replication, which require readability of each base to faithfully transmit genetic information. Indeed, it has become clear that G4 structures can pose prominent barriers to replication fork progression and that they are also intrinsically recombinogenic. Here, we discuss mechanisms that cells evolved to counteract these detrimental effects, thereby ensuring the faithful inheritance of G4-containing genomes. PMID- 24076190 TI - Time to be versatile: regulation of the replication timing program in budding yeast. AB - Eukaryotic replication origins are activated at different times during the S phase of the cell cycle, following a temporal program that is stably transmitted to daughter cells. Although the mechanisms that control initiation at the level of individual origins are now well understood, much less is known on how cells coordinate replication at hundreds of origins distributed on the chromosomes. In this review, we discuss recent advances shedding new light on how this complex process is regulated in the budding yeast Saccharomyces cerevisiae. The picture that emerges from these studies is that replication timing is regulated in cis by mechanisms modulating the chromatin structure and the subnuclear organization of origins. These mechanisms do not affect the licensing of replication origins but determine their ability to compete for limiting initiation factors, which are recycled from early to late origins throughout the length of the S phase. PMID- 24076192 TI - Green synthesis of silver nanoparticles using glucan from mushroom and study of antibacterial activity. AB - This work demonstrates synthesis of silver nanoparticles (AgNPs) using glucan isolated from a mushroom Pleurotus florida blue variant. UV-vis spectroscopy showed maximum absorbance at 425 nm due to surface plasmon resonance of AgNPs. Average diameter of the synthesized AgNPs was 2.445 +/- 1.08 nm as revealed from TEM analysis. XRD analysis confirmed the face-centered cubic (fcc) crystalline structure of metallic silver. The synthesized AgNPs-glucan conjugates exhibited antibacterial activity against multiple antibiotic resistant (MAR) bacterium Klebsiella pneumoniae YSI6A and the activity was possibly due to damage of cellular macromolecules by the generation of reactive oxygen species (ROS) which was supported by observed degradation of bacterial DNA. Decrease of bactericidal effect of AgNPs-glucan conjugates in dose-dependent manner in presence of a ROS scavenger histidine further ascertained the involvement of ROS in antibacterial activity. AgNPs-glucan conjugates at LD50 dose caused least damage (0.68% hemolysis) to human RBCs. This particular dose of AgNPs-glucan conjugates in combination with each of the four antibiotics (ampicillin, azithromycin, cefepime and tetracycline) to which K. pneumoniae YSI6A was resistant, showed synergistic effect to inhibit almost 100% bacterial growth. It thus opens an avenue to use antibiotics in combination with minimum dosages of AgNPs-glucan conjugates to control MAR bacteria. PMID- 24076191 TI - Crystal structure of human poly(A) polymerase gamma reveals a conserved catalytic core for canonical poly(A) polymerases. AB - In eukaryotes, the poly(A) tail added at the 3' end of an mRNA precursor is essential for the regulation of mRNA stability and the initiation of translation. Poly(A) polymerase (PAP) is the enzyme that catalyzes the poly(A) addition reaction. Multiple isoforms of PAP have been identified in vertebrates, which originate from gene duplication, alternative splicing or post-translational modifications. The complexity of PAP isoforms suggests that they might play different roles in the cell. Phylogenetic studies indicate that vertebrate PAPs are grouped into three clades termed alpha, beta and gamma, which originated from two gene duplication events. To date, all the available PAP structures are from the PAPalpha clade. Here, we present the crystal structure of the first representative of the PAPgamma clade, human PAPgamma bound to cordycepin triphosphate (3'dATP) and Ca(2+). The structure revealed that PAPgamma closely resembles its PAPalpha ortholog. An analysis of residue conservation reveals a conserved catalytic binding pocket, whereas residues at the surface of the polymerase are more divergent. PMID- 24076193 TI - Salicylic acid and some of its derivatives as antibacterial agents for viscose fabric. AB - Salicylic acid and three of its derivatives were used to provide antibacterial properties to viscose fabrics. The four bactericides used were bonded to the viscose fabrics using epichlorohydrin or polymer binders. Optimization of the salicylic acid and its derivatives as well as the concentration of polymers was reported. The ability of the polymer binders to attract and bind the four bactericides was observed. The overall results show that the antibacterial reactivity of salicylic acid and its derivatives are in the following order 5 bromosalicylic acid>salicylic acid>5-chlorosalicylic acid>4-chlorosalicylic acid. Using epichlorohydrin as a binding agent, unfortunately, inhibits the bactericidal activity of the four bactericides. The FTIR study concludes that the reaction between salicylic acid as well as its derivatives with epichlorohydrin takes place through the phenolic group of the acids. The unexpected deterioration in the bactericidal properties of salicylic acid and its derivatives as a result of the treatment with epichlorohydrin could be due to the nature of interaction between the epichlorohydrin molecule and the acids molecules. PVP and PU show superior ability to sustain the four bactericides used even after 10 washing cycles. PMID- 24076194 TI - The graft polymers from different species of lignin and acrylic acid: synthesis and mechanism study. AB - The influence of lignin species on the grafting mechanism of lignosulfonate (from eucalyptus and pine, recorded as HLS and SLS, respectively) with acrylic acid (AA) was investigated. The graft polymers were confirmed by the absorption of carbonyl groups in the FTIR spectra. The decreasing phenolic group's content (Ph OH) is not only due to its participation as grafting site but also to the negative effect of initiator. In the initial period (0-60 min), HLS and SLS both accelerate the polymerization of AA. Additionally, Ph-OH group's content is proportional to product yield (Y%), monomer conversion (C%) and grafting efficiency (GE%), strongly indicating that it acts as active center. Nevertheless, compared with HLS, Y% and C% in SLS grafting system are lower though it has higher Ph-OH group's content, which is due to the quinonoid structure formed by the self-conjugated of phenoxy radical in Guaiacyl unit. Finally, the lignosulfonate grafting mechanism was proposed. PMID- 24076195 TI - Modification of chitosan with carboxyl-functionalized ionic liquid for anion adsorption. AB - We report a novel chitosan derivative, chitosan-ionic liquid (CS-IL) conjugation for anion adsorption. Specifically, CS-IL conjugation was synthesized through the reaction of amino groups of chitosan with carboxylic groups of 1-carboxybutyl-3 methylimidazolium chloride. Due to the amphiphilic structure, CS-IL conjugation could self-assemble into nanoparticles in distilled water. This novel chitosan derivative revealed good anion adsorption performance, and the adsorption capacity of Cr2O7(2-) and PF6(-) was 0.422 mmol/g and 0.840 mmol/g, respectively. The adsorption of Cr2O7(2-) and PF6(-) could be improved at low pH, which was ascribed to the adsorption of protonated NH2 on chitosan. Importantly, the chitosan derivative would aggregate in the water after the adsorption and could be easily separated. The properties enable CS-IL conjugation to be used as a novel anion adsorbent for wastewater treatment. PMID- 24076196 TI - Biosorption potential of Gum ghatti-g-poly(acrylic acid) and susceptibility to biodegradation by B. subtilis. AB - This article reports the biosorption potential of Gum ghatti (Gg)-grafted-acrylic acid (AA) polymer and its susceptibility to biodegradation by Bacillus subtilis (BS) in two different liquid media, i.e. phosphate buffered saline (PBS) and mineral salt medium (MSM). The progress of biodegradation was monitored after every 15 days using FT-IR and SEM techniques. The degradation of the polymer was further evidenced by a loss of weight of 23.2% and 27% in BS-MSM and BS-PBS, respectively, after 60 days. The AA-grafted polymer was then utilized for the removal of Pb(II) and Cu(II) from aqueous solution. The adsorption isotherm data were studied using Langmuir, Freundlich, Temkin, Flory-Huggins and Dubinin Kaganer-Radushkevich isothermal models. High values of correlation coefficients confirmed the applicability of Langmuir isotherm model used to determine the adsorption capacity of the AA-grafted polymer. The maximum adsorption capacity was found to be 84.74 mg/g for Cu(II) and 310.55 mg/g for Pb(II). Kinetic data were evaluated using pseudo first order, pseudo second order, Elovich, intraparticle diffusion and liquid film diffusion models. The experimental kinetic data fitted well with the pseudo second order rate model. PMID- 24076197 TI - Physical, barrier and antioxidant properties of a novel plasticized edible film from quince seed mucilage. AB - In this study, we investigated the potential of quince seed mucilage (QSM) as a new source for preparation of edible films and determined the physical, mechanical, barrier, antioxidant, microstructural and thermal properties. QSM films were prepared by incorporation of three levels of glycerol (25-50%, w/w). As glycerol concentration increased, water vapor permeability (WVP), oxygen permeability (O2P), elongation at break (EB), water solubility and moisture content of QSM films increased while, tensile strength (TS), density and surface hydrophobicity decreased significantly. The measurement of color values showed that by the increasing of the glycerol concentration in polymer matrix, the b and L values increased while DeltaE value decreased. Microscopic views indicated smooth and uniform surface morphology without obvious cracks, breaks, or openings on the surfaces after the incorporation of glycerol as a plasticizer. The results of the present study suggest that QSM as a new antioxidant edible film with interesting specifications can potentially be used for packaging of a wide range of food products. PMID- 24076198 TI - Synthesis of chitosan-gallic acid conjugate: structure characterization and in vitro anti-diabetic potential. AB - In this study, chitosan grafted copolymer with gallic acid (GA) was synthesized by a novel and efficient free radical mediated method. The optimal grafting conditions, structural characterization, alpha-glucosidase and alpha-amylase inhibitory activities of chitosan grafted copolymers were investigated. Results showed that the maximum grafting ratio (128.3 mg GA equivalents/g) was obtained at 12 h with 5 g/L chitosan, 16 g/L GA, 2 g/L ascorbic acid and 0.2 M hydrogen peroxide. UV-vis, Fourier-transform infrared and nuclear magnetic resonance spectroscopy all confirmed the successful grafting of GA onto chitosan. The conjugation of GA onto chitosan probably occurred between amine (C-2), hydroxyl groups (C-3 and C-6) of chitosan and carboxyl groups of GA, forming amide and ester linkages, respectively. Differential scanning calorimetry and X-ray diffraction spectra indicated that GA grafted chitosan (GA-g-chitosan) had decreased thermal stability and crystallinity as compared to chitosan. Notably, GA-g-chitosan showed increased alpha-glucosidase and alpha-amylase inhibitory activity with the increase of grafting ratio. These results indicated the potential of GA-g-chitosan in the development of an effective anti-diabetic agent. PMID- 24076199 TI - Interaction of nanoparticles with arginine kinase from Trypanosoma brucei: kinetic and mechanistic evaluation. AB - Arginine kinase is not only absent from mammalian hosts but is critical to the survival of trypanosomes under stressful conditions and consequently its inhibition may lead to an effective treatment for trypanosomiasis. The His-tagged enzyme was cloned from Trypanosoma brucei genomic DNA, expressed in Escherichia coli BL21 DE3 cells and purified on a Ni-affinity column and by FPLC on a Superdex 200 HR. The enzyme had a specific activity of 2.92 MUmol min(-1) mg protein(-1), molecular mass of 40 kDa, temperature and pH optima of 30 degrees C and 7.8, and Km and Vmax as 2.94 mM and 0.161 MUmol ml(-1) min(-1) (arginine substrate). The interaction of the enzyme with silver and gold nanoparticles showed a non-competitive inhibition with, respectively, 75% and 62% decrease in activity; Ki values ranged from 1.5 nM (Ag) to 3.1 nM (Au). A mechanism for this inhibition was by interaction with Cys(271) positioned 3.3 A from the reactive NH(1) of substrate arginine. This cysteine controls electrophilic and nucleophilic character of the guanidinium group that is crucial for enzymatic phosphoryl transfer between ADP and ATP. PMID- 24076200 TI - Renoprotective effect of ramulus mori polysaccharides on renal injury in STZ diabetic mice. AB - Recently, increasing evidences have suggested that inflammatory stress is markedly occurred in the impaired tissue. Thus, the streptozotocin (STZ)-induced diabetic mice were used to investigate the potential renoprotective effect of ramulus mori polysaccharides (RMP) and to discuss the underlying mechanism. The results from the present study showed that RMP significantly lowered the blood glucose and serum levels of glycosylated protein, cholesterol, urea nitrogen (Urea-N), creatinine (Cr) and 24-hour urine protein, while the albumin content was elevated. Meanwhile, the proinflammatory cytokines such as interleukin-6 (IL 6), interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in renal tissue of STZ-lesioned mice were reduced by RMP treatment. Similarly, pathological examination indicated that STZ-induced renal injury was effectively mitigated. In addition, the protein levels of interleukin-1 (IL-1) and interleukin-1 receptor (IL-1R) in renal tissue were notably decreased. Moreover, the endogenous expressions of phosphorylated-IkappaB (p-IkappaB) and nuclear factor-kappa B (NF-kappaB) were down-regulated, respectively. Together, these findings revealed that RMP treatment effectively attenuated STZ-induced cytotoxicity in renal tissue, in which RMP-exerted renoprotection was associated with intrarenally debilitating inflammation reaction through blocking the IL-1/NF kappaB pathway, thereby maintaining the renal homeostasis. PMID- 24076201 TI - Biological properties and biodegradation studies of chitosan biofilms plasticized with PEG and glycerol. AB - Chitosan biofilms, prepared by casting method at various percentage of plasticizer (PEG and glycerol), were evaluated for their biological, structural and thermal properties. The addition of PEG at 30% (w/w) and glycerol at 10% (w/w) to chitosan has increased the antioxidant activity of biofilm with the percentages of 22 and 26%, respectively. The increase of ferric reducing power was noted for the mixtures of chitosan-PEG (70-30) and chitosan-GLY (75-25). Additionally, the antibacterial properties of several biofilms were tested against E. coli and S. aureus. Biofilms with 70-30 and 90-10 blends ratio of chitosan-PEG and chitosan-GLY showed the best inhibitory effect against E. coli and S. aureus with 12 and 27%, respectively. All biofilms were degraded in compost in liquid and the addition of plasticizer PEG to chitosan increased his biodegradability with a value of BOD5 about 2.33 O2/mg CO. FT-IR spectra showed that the addition of plasticizer promoted the interactions through hydrogen bonding as reflected on the shifting of main peaks but there is no effect on biodegradation. PMID- 24076202 TI - Morphological features and physicochemical properties of waxy wheat starch. AB - Morphological features, granule composition, and physicochemical properties of waxy wheat starch were compared with those of normal wheat starch. The morphologies and granule populations were found to be similar for the two starches. However, waxy wheat starch contained a smaller proportion of B-type granules, had a larger average granule diameter, and a higher degree of crystallinity than normal wheat starch, as measured by particle size analysis and differential scanning calorimetry. These differences resulted in a higher gelatinization temperature, transition enthalpy, peak viscosity, breakdown, swelling power, lower peak viscosity temperature and final viscosity in waxy wheat starch. These points suggest that waxy wheat starch should have greater resistance to retrogradation during cooling and higher water-holding capacity under dry conditions. Highlighting the differences in physicochemical properties of waxy and normal wheat starches should help point toward effective applications of waxy wheat starch in the food industry. PMID- 24076203 TI - Preparation of cellulose/polyvinyl alcohol biocomposite films using 1-n-butyl-3 methylimidazolium chloride. AB - This study has been focused on developing cellulose/polyvinyl alcohol (PVA), a biocomposite film, pretreated with 1-n-butyl-3-methylimidazolium chloride ([bmim]Cl). The dissolved polymers were blended and their biocomposite films including cellulose and cellulose/PVA were prepared. The effect of PVA composition with cellulose was evaluated by comparing the physical, mechanical, chemical and thermal characteristics of produced films with neat cellulosic film. The results showed that the ionic liquid had a great capability in dissolving the polymers. Furthermore, in composition of the raw cellulose some chemical bonds were incorporated between the two components. Water uptake, thickness swelling and water vapor permeability of blend films were increased comparing to cellulosic film. Mechanical strength and Young's modulus of the films made of cellulose/PVA were decreased while the strain at break was increased. The optical transparency and thermal properties of the blend films were almost the same as neat cellulosic film. This work demonstrated a promising route for the preparation of biodegradable green composites. In addition, this biocomposite film is composed of sustainable biodegradable resources, which is suitable for release to the environment. The biocomposite films showed good optical transparency, thermal stabilities properties. PMID- 24076204 TI - Synthesis and properties of isomeric pyridyl-containing chitosan derivatives. AB - Here we report on the method of synthesis in gel of a new heterocyclic aminopolymer-N-2-(4-pyridyl)ethylchitosan (4-PEC) via direct addition of 4 vinylpyridine to chitosan that yields a derivative with the substitution degree (DS) up to 0.8. The comparison of reactivity, thermal, spectroscopic, and sorption properties of a new derivative and its isomer N-2-(2 pyridyl)ethylchitosan (2-PEC) is presented. 2-PEC has higher sorption capacity and forms more stable chelates with [PdCl4](2-) and [PtCl6](2-) ions than 4-PEC, but the latter shows higher selectivity to noble metals ions in the presence of Cl(-) ions. A gradual increase of the sorption capacities and the affinity coefficient for Cu(2+) and Ni(2+) in the row chitosan<4-PEC<2-PEC was related to the increase of electron donor nitrogen atoms content and chelating properties of 2-PEC. A nearly negligible increase of the 4-PEC sorption capacity for Ag(+), as compared to plain chitosan, was suggested to be dependent on the difference in complexation models for 2-PEC and 4-PEC derivatives. The density functional theory (DFT) calculations have shown that the "pendant" model of the complex with Ag(I) is energetically favorable only for 2-PEC derivative, while in cases of chitosan and 4-PEC only "bridge" complexes can be formed that results in lower sorption capacity. PMID- 24076205 TI - Preparation, investigation of metal ion removal and flocculation performances of grafted hydroxyethyl starch. AB - Ceric ion induced graft copolymerization of N,N-dimethyl acrylamide (DMA) and acryl amide (AM) were carried out onto the hydroxyethyl starch (HES). These grafted copolymers were used for the removal of metal ions from their aqueous solutions. Flocculation performances of the synthesized graft copolymers were evaluated in 1.0 wt% silica suspensions. A comparative study of the flocculation performances of the synthetic graft copolymers was also made. The different factors affecting metal ion absorption, namely pH, treatment time, temperature and polymer dose were studied. A comparative study of the metal ion removal capacity of the two synthetic graft copolymers was also made in five metal ions namely Ni(II), Zn(II), Cu(II), Pb(II) and Hg(II). The metal ion removal capacity follows the order Hg(II)>Cu(II)>Zn(II)>Ni(II)>Pb(II) in both the two synthetic polymers. Between the two graft copolymers, graft copolymer based on AM shows better performance than that based on DMA in all the metal solutions. But the flocculation performance of DMA based graft copolymer showed better performances than that AM based graft copolymer. The former also performed best when compared to the commercial flocculants in the same suspension. PMID- 24076206 TI - Social cognition and the cerebellum: a meta-analysis of over 350 fMRI studies. AB - This meta-analysis explores the role of the cerebellum in social cognition. Recent meta-analyses of neuroimaging studies since 2008 demonstrate that the cerebellum is only marginally involved in social cognition and emotionality, with a few meta-analyses pointing to an involvement of at most 54% of the individual studies. In this study, novel meta-analyses of over 350 fMRI studies, dividing up the domain of social cognition in homogeneous subdomains, confirmed this low involvement of the cerebellum in conditions that trigger the mirror network (e.g., when familiar movements of body parts are observed) and the mentalizing network (when no moving body parts or unfamiliar movements are present). There is, however, one set of mentalizing conditions that strongly involve the cerebellum in 50-100% of the individual studies. In particular, when the level of abstraction is high, such as when behaviors are described in terms of traits or permanent characteristics, in terms of groups rather than individuals, in terms of the past (episodic autobiographic memory) or the future rather than the present, or in terms of hypothetical events that may happen. An activation likelihood estimation (ALE) meta-analysis conducted in this study reveals that the cerebellum is critically implicated in social cognition and that the areas of the cerebellum which are consistently involved in social cognitive processes show extensive overlap with the areas involved in sensorimotor (during mirror and self judgments tasks) as well as in executive functioning (across all tasks). We discuss the role of the cerebellum in social cognition in general and in higher abstraction mentalizing in particular. We also point out a number of methodological limitations of some available studies on the social brain that hamper the detection of cerebellar activity. PMID- 24076208 TI - Electrophysiological evidence for emotional valence and competitive arousal effects on insight problem solving. AB - Accumulating evidence suggests that insight can be substantially influenced by task-irrelevant emotion stimuli and interpersonal competitive situation, and a close link might exist between them. Using a learning-testing paradigm and Event Related Potentials (ERPs), the present study investigated the independent and joint effects of emotional and competitive information on insight problem solving especially their neural mechanisms. Subjects situated in either competitive or non-competitive condition learned heuristic logogriphs first and then viewed task irrelevant positive or negative emotional pictures, which were followed by test logogriphs to solve. Both behavioral and ERP findings showed a more evident insight boost following negative emotional pictures in competitive context. Results demonstrated that negative emotion and competitive situation might promote insight by a defocused mode of attention (as indicated by N1 and P2), the enhanced semantic integration and breaking mental set (as indicated by N450), and the increased forming of novel associations activated by motivational arousal originating from competition (as indicated by P800-1600 and P1600-2500). These results indicate that the dynamic interactions between emotional valence and competitive arousal effects on insight. PMID- 24076207 TI - Affective and neuroendocrine effects of withdrawal from chronic, long-acting opiate administration. AB - Although the long-acting opiate methadone is commonly used to treat drug addiction, relatively little is known about the effects of withdrawal from this drug in preclinical models. The current study examined affective, neuroendocrine, and somatic signs of withdrawal from the longer-acting methadone derivative l alpha-acetylmethydol (LAAM) in rats. Anxiety-like behavior during both spontaneous and antagonist-precipitated withdrawal was measured by potentiation of the startle reflex. Withdrawal elevated corticosterone and somatic signs and blunted circadian variations in baseline startle responding. In addition, fear to an explicit, Pavlovian conditioned stimulus (fear-potentiated startle) was enhanced. These data suggest that anxiety-like behavior as measured using potentiated startle responding does not emerge spontaneously during withdrawal from chronic opiate exposure - in contrast to withdrawal from acute drug exposure - but rather is manifested as exaggerated fear in response to explicit threat cues. PMID- 24076209 TI - Evidence for a medial prefrontal cortex-hippocampal axis associated with heart rate control in conscious humans. AB - Cardiovascular arousal correlates to activity within the medial prefrontal cortex (MPFC). Additional evidence provides anatomical and functional links between the MPFC and hippocampus (HC). This study tested the hypothesis that the MPFC and HC form a sub-network associated with rapid heart rate (HR) responses to volitional effort. Primary analyses were performed on 29 individuals (18 males) ranging from 21 to 80 years of age, who produced a HR response >3bpm to an isometric handgrip (IHG) task. HR and cortical activity were recorded using functional magnetic resonance imaging with blood oxygen level-dependent contrast. The average change in HR from baseline was 6bpm +/-2. Activity in the MPFC and left HC was reduced relative to baseline in all subjects when correlated with the HR time course. Measures of connectivity demonstrated that the MPFC engaged in significantly stronger functional connectivity to the left HC during a 40% IHG task. Effective connectivity revealed a directionality of influence from the MPFC to the left HC. A second group (n=15) of individuals without a HR response (~1bpm) to IHG were studied post-hoc and these individuals showed no deactivation in either the MPFC or left HC. These results suggest the presence of a MPFC-HC axis that participates in the neurally-mediated HR response to exercise. PMID- 24076210 TI - Editorial introduction to Hearing Research special issue on communication sounds and the brain: new directions and perspectives. PMID- 24076211 TI - In memoriam Ladislau Steiner, neurosurgeon: some people from transylvania do live forever. AB - We review the extraordinary professional trajectory of Ladislau Steiner, a prolific neurosurgeon and radiosurgeon, who died earlier this year. Dr. Steiner trained and practiced as a neurosurgeon in his native Romania until he was 42, before moving to Stockholm. After 25 years at the Karolinska Institute, when most people consider retirement, he spent the following 25 years of his life as director of the Lars Leksell Center for Gamma Knife Radiosurgery at the University of Virginia, Charlottesville, Virginia. At 90, nostalgia for Europe made him accept the position of director of the Gamma Knife Center at the International Neuroscience Institute in Hannover, Germany. His life was dedicated to the 15,000 patients whose lives he saved in his lengthy career. PMID- 24076212 TI - Avoiding complications after carotid endarterectomy. PMID- 24076213 TI - Is a sylvian fissure hematoma caused by leaking vessels? PMID- 24076214 TI - Complications in anterior cervical discectomy and fusion for cervical degenerative disc disease. PMID- 24076215 TI - Surgery of the skull base by 3 pioneering 19th-century Italian surgeons--a surgical subspecialty that has been around for a long time. PMID- 24076216 TI - Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway. AB - Prostate cancer (CaP) is the second leading malignancy in men. The role of epithelial cell adhesion molecule (EpCAM), also known as CD326, in CaP progression and therapeutic resistance is still uncertain. Here, we aimed to investigate the roles of EpCAM in CaP metastasis and chemo/radioresistance. Expression of EpCAM in CaP cell lines and human CaP tissues was assessed using immunofluorescence and immunohistochemistry, respectively. EpCAM was knocked down (KD) in PC-3, DU145 and LNCaP-C4-2B cells using small interfering RNA (siRNA), and KD results were confirmed by confocal microscope, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Cell growth was evaluated by proliferation and colony formation assays. The invasive potential was assessed using a matrigel chamber assay. Tumorigenesis potential was measured by a sphere formation assay. Chemo-/radiosensitivity were measured using a colony formation assay. Over-expression of EpCAM was found in primary CaP tissues and lymph node metastases including cancer cells and surrounding stromal cells. KD of EpCAM suppressed CaP proliferation and invasive ability, reduced sphere formation, enhanced chemo-/radiosensitivity, and down-regulated E-cadherin, p Akt, p-mTOR, p-4EBP1 and p-S6K expression in CaP cells. Our findings suggest that EpCAM plays an important role in CaP proliferation, invasion, metastasis and chemo-/radioresistance associated with the activation of the PI3K/Akt/mTOR signaling pathway and is a novel therapeutic target to sensitize CaP cells to chemo-/radiotherapy. PMID- 24076217 TI - Arginine methylation-dependent reader-writer interplay governs growth control by E2F-1. AB - The mechanisms that underlie and dictate the different biological outcomes of E2F 1 activity have yet to be elucidated. We describe the residue-specific methylation of E2F-1 by the asymmetric dimethylating protein arginine methyltransferase 1 (PRMT1) and symmetric dimethylating PRMT5 and relate the marks to different functional consequences of E2F-1 activity. Methylation by PRMT1 hinders methylation by PRMT5, which augments E2F-1-dependent apoptosis, whereas PRMT5-dependent methylation favors proliferation by antagonizing methylation by PRMT1. The ability of E2F-1 to prompt apoptosis in DNA damaged cells coincides with enhanced PRMT1 methylation. In contrast, cyclin A binding to E2F-1 impedes PRMT1 methylation and augments PRMT5 methylation, thus ensuring that E2F-1 is locked into its cell-cycle progression mode. The Tudor domain protein p100-TSN reads the symmetric methylation mark, and binding of p100-TSN downregulates E2F-1 apoptotic activity. Our results define an exquisite level of precision in the reader-writer interplay that governs the biological outcome of E2F-1 activity. PMID- 24076219 TI - Cooperative control of holliday junction resolution and DNA repair by the SLX1 and MUS81-EME1 nucleases. AB - Holliday junctions (HJs) are X-shaped DNA structures that arise during homologous recombination, which must be removed to enable chromosome segregation. The SLX1 and MUS81-EME1 nucleases can both process HJs in vitro, and they bind in close proximity on the SLX4 scaffold, hinting at possible cooperation. However, the cellular roles of mammalian SLX1 are not yet known. Here, we use mouse genetics and structure function analysis to investigate SLX1 function. Disrupting the murine Slx1 and Slx4 genes revealed that they are essential for HJ resolution in mitotic cells. Moreover, SLX1 and MUS81-EME1 act together to resolve HJs in a manner that requires tethering to SLX4. We also show that SLX1, like MUS81-EME1, is required for repair of DNA interstrand crosslinks, but this role appears to be independent of HJ cleavage, at least in mouse cells. These findings shed light on HJ resolution in mammals and on maintenance of genome stability. PMID- 24076220 TI - SOD1 as a molecular switch for initiating the homeostatic ER stress response under zinc deficiency. AB - Zinc is an essential trace element, and impaired zinc homeostasis is implicated in the pathogenesis of various human diseases. However, the mechanisms cells use to respond to zinc deficiency are poorly understood. We previously reported that amyotrophic lateral sclerosis (ALS)-linked pathogenic mutants of SOD1 cause chronic endoplasmic reticulum (ER) stress through specific interactions with Derlin-1, which is a component of the ER-associated degradation machinery. Moreover, we recently demonstrated that this interaction is common to ALS-linked SOD1 mutants, and wild-type SOD1 (SOD1(WT)) comprises a masked Derlin-1 binding region (DBR). Here, we found that, under zinc-deficient conditions, SOD1(WT) adopts a mutant-like conformation that exposes the DBR and induces the homeostatic ER stress response, including the inhibition of protein synthesis and induction of a zinc transporter. We conclude that SOD1 has a function as a molecular switch that activates the ER stress response, which plays an important role in cellular homeostasis under zinc-deficient conditions. PMID- 24076218 TI - Distinct properties of cell-type-specific and shared transcription factor binding sites. AB - Most human transcription factors bind a small subset of potential genomic sites and often use different subsets in different cell types. To identify mechanisms that govern cell-type-specific transcription factor binding, we used an integrative approach to study estrogen receptor alpha (ER). We found that ER exhibits two distinct modes of binding. Shared sites, bound in multiple cell types, are characterized by high-affinity estrogen response elements (EREs), inaccessible chromatin, and a lack of DNA methylation, while cell-specific sites are characterized by a lack of EREs, co-occurrence with other transcription factors, and cell-type-specific chromatin accessibility and DNA methylation. These observations enabled accurate quantitative models of ER binding that suggest tethering of ER to one-third of cell-specific sites. The distinct properties of cell-specific binding were also observed with glucocorticoid receptor and for ER in primary mouse tissues, representing an elegant genomic encoding scheme for generating cell-type-specific gene regulation. PMID- 24076221 TI - Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells. AB - Holliday junctions (HJs) are four-way DNA intermediates that form during homologous recombination, and their efficient resolution is essential for chromosome segregation. Here, we show that three structure-selective endonucleases, namely SLX1-SLX4, MUS81-EME1, and GEN1, define two pathways of HJ resolution in human cells. One pathway is mediated by GEN1, whereas SLX1-SLX4 and MUS81-EME1 provide a second and genetically distinct pathway (SLX-MUS). Cells depleted for SLX-MUS or GEN1 pathway proteins exhibit severe defects in chromosome segregation and reduced survival. In response to CDK-mediated phosphorylation, SLX1-SLX4 and MUS81-EME1 associate at the G2/M transition to form a stable SLX-MUS holoenzyme, which can be reconstituted in vitro. Biochemical studies show that SLX-MUS is a HJ resolvase that coordinates the active sites of two distinct endonucleases during HJ resolution. This cleavage reaction is more efficient and orchestrated than that mediated by SLX1-SLX4 alone, which exhibits a potent nickase activity that acts promiscuously upon DNA secondary structures. PMID- 24076222 TI - In vitro and in vivo evaluation of (11)C-SD5024, a novel PET radioligand for human brain imaging of cannabinoid CB1 receptors. AB - We recently developed a novel cannabinoid subtype-1 (CB1) receptor radioligand (11)C-SD5024 for brain imaging. This study aimed to evaluate (11)C-SD5024 both in vitro and in vivo and compare it with the other CB1 receptor ligands previously used in humans, i.e., (11)C-MePPEP, (11)C-OMAR, (18)F-MK-9470, and (18)F-FMPEP d2. In vitro experiments were performed to measure dissociation constant (Ki) in the human brain and to measure the lipophilicity of the five CB1 receptor ligands listed above. In vivo specific binding in monkeys was measured by comparing total distribution volume (VT) at baseline and after full receptor blockade. The kinetics of (11)C-SD5024 in humans were evaluated in seven healthy subjects with compartmental modeling. SD5024 showed Ki=0.47nM, which was at an intermediate level among the five CB1 receptor ligands. Lipophilicity (LogD7.4) was 3.79, which is appropriate for brain imaging. Monkey scans showed high proportion of specific binding: ~80% of VT. In humans, (11)C-SD5024 showed peak brain uptake of 1.5-3 standardized uptake value, which was slightly higher than that of (11)C OMAR and (18)F-MK-9470. One-compartment model showed good fitting, consistent with the vast majority of brain uptake being specific binding found in the monkey. Regional VT values were consistent with known distribution of CB1 receptors. VT calculated from 80 and 120min of scan data was strongly correlated (R(2)=0.97), indicating that 80min provided adequate information for quantitation and that the influence of radiometabolites was low. Intersubject variability for VT of (11)C-SD5024 was 22%, which was low among the five radioligands and indicated precise measurement. In conclusion, (11)C-SD5024 has appropriate affinity and lipophilicity, high specific binding, moderate brain uptake, and provides good precision to measure the binding. The results suggest that (11)C SD5024 is slightly better than or equivalent to (11)C-OMAR and that both are suitable for clinical studies, especially those that involve two scans in one day. PMID- 24076223 TI - A bilateral cortical network responds to pitch perturbations in speech feedback. AB - Auditory feedback is used to monitor and correct for errors in speech production, and one of the clearest demonstrations of this is the pitch perturbation reflex. During ongoing phonation, speakers respond rapidly to shifts of the pitch of their auditory feedback, altering their pitch production to oppose the direction of the applied pitch shift. In this study, we examine the timing of activity within a network of brain regions thought to be involved in mediating this behavior. To isolate auditory feedback processing relevant for motor control of speech, we used magnetoencephalography (MEG) to compare neural responses to speech onset and to transient (400ms) pitch feedback perturbations during speaking with responses to identical acoustic stimuli during passive listening. We found overlapping, but distinct bilateral cortical networks involved in monitoring speech onset and feedback alterations in ongoing speech. Responses to speech onset during speaking were suppressed in bilateral auditory and left ventral supramarginal gyrus/posterior superior temporal sulcus (vSMG/pSTS). In contrast, during pitch perturbations, activity was enhanced in bilateral vSMG/pSTS, bilateral premotor cortex, right primary auditory cortex, and left higher order auditory cortex. We also found speaking-induced delays in responses to both unaltered and altered speech in bilateral primary and secondary auditory regions, left vSMG/pSTS and right premotor cortex. The network dynamics reveal the cortical processing involved in both detecting the speech error and updating the motor plan to create the new pitch output. These results implicate vSMG/pSTS as critical in both monitoring auditory feedback and initiating rapid compensation to feedback errors. PMID- 24076224 TI - Food can lift mood by affecting mood-regulating neurocircuits via a serotonergic mechanism. AB - It is commonly assumed that food can affect mood. One prevalent notion is that food containing tryptophan increases serotonin levels in the brain and alters neural processing in mood-regulating neurocircuits. However, tryptophan competes with other long-neutral-amino-acids (LNAA) for transport across the blood-brain barrier, a limitation that can be mitigated by increasing the tryptophan/LNAA ratio. We therefore tested in a double-blind, placebo-controlled crossover study (N=32) whether a drink with a favourable tryptophan/LNAA ratio improves mood and modulates specific brain processes as assessed by functional magnetic resonance imaging (fMRI). We show that one serving of this drink increases the tryptophan/LNAA ratio in blood plasma, lifts mood in healthy young women and alters task-specific and resting-state processing in brain regions implicated in mood regulation. Specifically, Test-drink consumption reduced neural responses of the dorsal caudate nucleus during reward anticipation, increased neural responses in the dorsal cingulate cortex during fear processing, and increased ventromedial prefrontal-lateral prefrontal connectivity under resting-state conditions. Our results suggest that increasing tryptophan/LNAA ratios can lift mood by affecting mood-regulating neurocircuits. PMID- 24076225 TI - FMEM: functional mixed effects modeling for the analysis of longitudinal white matter Tract data. AB - Many longitudinal imaging studies have collected repeated diffusion tensor magnetic resonance imaging data to understand white matter maturation and structural connectivity pattern in normal controls and diseased subjects. There is an urgent demand for the development of statistical methods for the analysis of diffusion properties along fiber tracts and clinical data obtained from longitudinal studies. Jointly analyzing repeated fiber-tract diffusion properties and covariates (e.g., age or gender) raises several major challenges including (i) infinite-dimensional functional response data, (ii) complex spatial-temporal correlation structure, and (iii) complex spatial smoothness. To address these challenges, this article is to develop a functional mixed effects modeling (FMEM) framework to delineate the dynamic changes of diffusion properties along major fiber tracts and their association with a set of covariates of interest and the structure of the variability of these white matter tract properties in various longitudinal studies. Our FMEM consists of a functional mixed effects model for addressing all three challenges, an efficient method for spatially smoothing varying coefficient functions, an estimation method for estimating the spatial temporal correlation structure, a test procedure with local and global test statistics for testing hypotheses of interest associated with functional response, and a simultaneous confidence band for quantifying the uncertainty in the estimated coefficient functions. Simulated data are used to evaluate the finite sample performance of FMEM and to demonstrate that FMEM significantly outperforms the standard pointwise mixed effects modeling approach. We apply FMEM to study the spatial-temporal dynamics of white-matter fiber tracts in a clinical study of neurodevelopment. PMID- 24076226 TI - External and semi-internal controls for PCR amplification of homologous sequences in mixed templates. AB - In a mixed template, the presence of homologous target DNA sequences creates environments that almost inevitably give rise to artifacts and biases during PCR. Heteroduplexes, chimeras, and skewed template-to-product ratios are the exclusive attributes of mixed template PCR and never occur in a single template assay. Yet, multi-template PCR has been used without appropriate attention to quality control and assay validation, in spite of the fact that such practice diminishes the reliability of results. External and internal amplification controls became obligatory elements of good laboratory practice in different PCR assays. We propose the inclusion of an analogous approach as a quality control system for multi-template PCR applications. The amplification controls must take into account the characteristics of multi-template PCR and be able to effectively monitor particular assay performance. This study demonstrated the efficiency of a model mixed template as an adequate external amplification control for a particular PCR application. The conditions of multi-template PCR do not allow implementation of a classic internal control; therefore we developed a convenient semi-internal control as an acceptable alternative. In order to evaluate the effects of inhibitors, a model multi-template mix was amplified in a mixture with DNAse-treated sample. Semi-internal control allowed establishment of intervals for robust PCR performance for different samples, thus enabling correct comparison of the samples. The complexity of the external and semi-internal amplification controls must be comparable with the assumed complexity of the samples. We also emphasize that amplification controls should be applied in multi template PCR regardless of the post-assay method used to analyze products. PMID- 24076227 TI - A simplified and cost-effective method combining real-time PCR and pyrosequencing for detection of aac(6')-Ib-cr gene. AB - We previously described a pyrosequencing-based method able to guarantee detection of aac(6')-Ib-cr by characterizing precisely the single nucleotide polymorphisms leading to Trp102Arg and Asp179Tyr. By gaining in simplicity and cost effectiveness, through the use of real-time PCR, we propose here a cutting-edge evolution of our existing pyrosequencing method. PMID- 24076229 TI - Polyvinyl acetate-based film coatings. AB - Polyvinyl acetate-based colloidal aqueous polymer dispersion Kollicoat((r)) SR 30 D results in coatings characterized by moderate swelling behaviour, lipophilicity, pH-independent permeability for actives and high flexibility to withstand mechanical stress and is therefore used for controlled release coating. The colloidal aqueous polymer dispersion of Kollicoat((r)) SR 30 D can be easily processed due to an optimal low minimum film forming temperature (MFT) of 18 degrees C without plasticizer addition and a thermal after-treatment (curing) of coated pellets. The drug release from Kollicoat((r)) SR 30 D coated pellets was almost pH independent. Drug release could be easily adjusted by coating level or addition of soluble pore forming polymers. Physically stable Kollicoat((r)) SR 30 D dispersions were obtained with the water-soluble polymers Kollidon((r)) 30 and Kollicoat((r)) IR up to 50% w/w. The addition of only 10% w/w triethyl citrate as plasticizer improved the flexibility of the films significantly and allowed compaction of the pellets. The drug release was almost independent of the compression force and the pellet content of the tablets. The inclusion of various tableting excipients slightly affected the drug release, primarily because of a different disintegration rate of the tablets. A combination of Kollicoat((r)) SR 30 D and Kollicoat((r)) IR with higher coating levels>10 mg/cm(2) is a relatively new alternative to OROS system which does not require drilling. PMID- 24076228 TI - Encapsulation of paclitaxel into lauric acid-O-carboxymethyl chitosan-transferrin micelles for hydrophobic drug delivery and site-specific targeted delivery. AB - Transferrin/PEG/O-carboxymethyl chitosan/fatty acid/paclitaxel (TPOCFP) micelles were tested for suitability as a drug carrier characterized by low cytotoxicity, sustained release, high cellular uptake, and site-specific targeted delivery of hydrophobic drugs. Characterization, drug content, encapsulation efficiency, and in vitro drug release were investigated. When the feeding amount of paclitaxel (PTX) was increased, the drug content increased, but loading efficiency decreased. TPOCFP micelles had a spherical shape, with a particle size of approximately 140-649 nm. In vitro cell cytotoxicity and hemolysis assays were conducted to confirm the safety of the micelles. Anticancer activity and confocal laser scanning microscopy (CLSM) were used to confirm the targeting efficiency of target ligand-modified TPOCFP micelles. Anticancer activity and CLSM results clearly demonstrated that transferrin-modified TPOCFP micelles were quickly taken up by the cell. The endocytic pathway of TPOCFP micelles was analyzed by flow cytometry, revealing transfection via receptor-mediated endocytosis. These results suggest that PTX-encapsulated TPOCFP micelles may be used as an effective cancer-targeting drug delivery system for chemotherapy. PMID- 24076230 TI - Montmorillonite nanodevices for the colon metronidazole delivery. AB - The adsorption profiles of the antibiotic metronidazole (MNE) into the K10 montmorillonite (MMT-K10) clay and the subsequent release have been investigated as a function of pH and MNE/MMT-K10 ratio, in order to evaluate the potential of the MNE/MMT-K10 hybrids as controlled drug delivery system. The adsorption mechanism has been first elucidated by performing complementary equilibrium and kinetic studies and through the X-ray diffractometry (XRD) characterization of the obtained composite materials. The gathered results allowed us to propose a mechanism consisting of a multi-step pathway involving the neutral and the cationic form of the drug, which interact with different sites of the clay surfaces, i.e. the interlayer region and the faces of the lamella. In a second step the drug release kinetics has been studied under physiological pH mimicking conditions simulating the oral drug administration and delivery. For the sake of comparison the commercial formulation has also been employed for the release studies. The investigation of the release profiles and the comparison with the commercial formulation of the drug reveal that the new-tailor made formulation could be fruitful exploited for successfully prolonged the action of drug in the desired site. PMID- 24076231 TI - New insights on how to adjust the release profile from coated pellets by varying the molecular weight of ethyl cellulose in the coating film. AB - The major aims of this work were to study the effect of the molecular weight (Mw) of ethyl cellulose (EC) on the drug release profile from metoprolol succinate pellets coated with films comprising EC and hydroxypropyl cellulose (HPC) with a weight ratio of 70:30, and to understand the mechanisms behind the different release profiles. A broad range of Mws was used, and the kinetics of drug release and HPC leaching followed. The higher the Mw of EC, the slower the HPC leaching and the drug release processes. Drug release occurred by diffusion through the pores created in the coating by the HPC leaching. A novel method was used to explain the differences in the release profiles: the effective diffusion coefficient (De) of the drug in the coating film was determined using a mechanistic model and compared to the amount of HPC leached. A linear dependence was found between De and the amount of HPC leached and, importantly, the value of the proportionality constant decreased with increasing Mw of EC. This suggests that the Mw of EC affects the drug release profile by affecting the phase separated microstructure of the coating and the hindrance it imparts to drug diffusion. PMID- 24076232 TI - Non-adsorbing macromolecules promote endothelial adhesion of erythrocytes with reduced sialic acids. AB - BACKGROUND: Abnormal adhesion of red blood cells (RBCs) to vascular endothelium is often associated with reduced levels of sialic acids on RBC membranes and with elevated levels of pro-adhesive plasma proteins. However, the synergistic effects of these two factors on the adhesion are not clear. In this work, we tested the hypothesis that macromolecular depletion interaction originating from non adsorbing macromolecules can promote the adhesion of RBCs with reduced sialic acid content to the endothelium. METHODS: RBCs are treated with neuraminidase to specifically remove sialic acids from their surface followed by the evaluation of their deformability, zeta potential and membrane proteins. The adhesion of these enzyme-treated RBCs to cultured human umbilical vein endothelial cells (ECs) is studied in the presence of 70 or 500kDa dextran with a flow chamber assay. RESULTS: Our results demonstrate that removal of sialic acids from RBC surface can induce erythrocyte adhesion to endothelial cells and that such adhesion is significantly enhanced in the presence of high-molecular weight dextran. The adhesion-promoting effect of dextran exhibits a strong dependence on dextran concentration and molecular mass, and it is concluded to originate from macromolecular depletion interaction. CONCLUSION: These results suggest that elevated levels of non-adsorbing macromolecules in plasma might play a significant role in promoting endothelial adhesion of erythrocytes with reduced sialic acids. GENERAL SIGNIFICANCE: Our findings should therefore be of great value in understanding abnormal RBC-EC interactions in pathophysiological conditions (e.g., sickle cell disease and diabetes) and after blood transfusions. PMID- 24076233 TI - The influence of 5-lipoxygenase on cigarette smoke-induced emphysema in mice. AB - BACKGROUND: Pulmonary emphysema is characterized by the loss of lung architecture. Our hypothesis is that the inhibition of 5-lipoxygenase (5-LO) production may be an important strategy to reduce inflammation, oxidative stress, and metalloproteinases in lung tissue resulting from cigarette smoke (CS)-induced emphysema. METHODS: 5-LO knockout (129S2-Alox5(tm1Fun)/J) and wild-type (WT) mice (129S2/SvPas) were exposed to CS for 60days. Mice exposed to ambient air were used as Controls. Oxidative, inflammatory, and proteolytic markers were analyzed. RESULTS: The alveolar diameter was decreased in CS 5-LO(-/-) mice when compared with the WT CS group. The CS exposure resulted in less pronounced pulmonary inflammation in the CS 5-LO(-/-) group. The CS 5-LO(-/-) group showed leukotriene B4 values comparable to those of the Control group. The expression of MMP-9 was decreased in the CS 5-LO(-/-) group when compared with the CS WT group. The expression of superoxide dismutase, catalase, and glutathione peroxidase were decreased in the CS 5-LO(-/-) group when compared with the Control group. The protein expression of nuclear factor (erythroid-derived 2)-like 2 was reduced in the CS 5-LO(-/-) group when compared to the CS WT group. CONCLUSION: In conclusion, we show for the first time that 5-LO deficiency protects 129S2 mice against emphysema caused by CS. We suggest that the main mechanism of pathogenesis in this model involves the imbalance between proteases and antiproteases, particularly the association between MMP-9 and TIMP-1. General significance This study demonstrates the influence of 5-LO mediated oxidative stress, inflammation, and proteolytic markers in CS exposed mice. PMID- 24076234 TI - A putative phospholipase C is involved in Pichia fermentans dimorphic transition. AB - BACKGROUND: Pichia fermentans DiSAABA 726 is a dimorphic yeast that reversibly shifts from yeast-like to pseudohyphal morphology. This yeast behaves as a promising antagonist of Monilia spp. in the yeast-like form, but becomes a destructive plant pathogen in the pseudohyphal form thus raising the problem of the biological risk associated with the use of dimorphic yeasts as microbial antagonists in the biocontrol of phytopathogenic fungi. METHODS: Pichia fermentans DiSAABA 726 was grown in urea- and methionine-containing media in order to induce and separate yeast-like and pseudohyphal morphologies. Total RNA was extracted from yeast-like cells and pseudohyphae and retro-transcribed into cDNA. A rapid subtraction hybridization approach was utilized to obtain the cDNA sequences putatively over-expressed during growth on methionine-containing medium and involved in pseudohyphal transition. RESULTS: Five genes that are over expressed during yeast-like/pseudohyphal dimorphic transition were isolated. One of these, encoding a putative phospholipase C, is involved in P. fermentans filamentation. In fact, while the inhibition of phospholipase C, by means of 1-O octadecyl-2-O-methyl-rac-glycero-3-phosphorylcholine (Et-18), is accompanied by a significant reduction of pseudohyphae formation in P. fermentans, the addition of exogenous cAMP fully restores pseudohyphal growth also in the presence of Et-18. CONCLUSION: Phospholipase C is part of a putative "methionine sensing machinery" that activates cAMP-PKA signal transduction pathway and controls P. fermentans yeast-like/pseudohyphal dimorphic transition. GENERAL SIGNIFICANCE: Phospholipase C is a promising molecular target for further investigations into the link between pseudohyphae formation and pathogenicity in P. fermentans. PMID- 24076235 TI - T cells expressing VHH-directed oligoclonal chimeric HER2 antigen receptors: towards tumor-directed oligoclonal T cell therapy. AB - BACKGROUND: Adoptive cell therapy with engineered T cells expressing chimeric antigen receptors (CARs) originated from antibodies is a promising strategy in cancer immunotherapy. Several unsuccessful trials, however, highlight the need for alternative conventional binding domains and the better combination of costimulatory endodomains for CAR construction to improve the effector functions of the engineered T cells. Camelid single-domain antibodies (VHHs), which are the smallest single domain antibodies, can endow great targeting ability to CAR engineered T cells. METHODS: We have developed a method to generate genetically engineered Jurkat T cells armed with a CAR comprising the anti-HER2 VHH as targeting moiety. From an immune camel library, five VHH clones were selected as a set of oligoclonal anti-HER2 VHHs that exhibited diverse binding abilities and joined them to CD28-CD3zeta and CD28-OX40-CD3zeta signaling endodomains. Jurkat T cells expression of VHH-CARs and cell functions were evaluated. RESULTS: The oligoclonal engineered T cells showed higher proliferation, cytokine secretion and cytotoxicity than each individual VHH-CAR-engineered Jurkat T cells. CONCLUSIONS: The combination of superior targeting ability of oligoclonal VHHs with the third generation CAR can substantially improve the function of engineered T cells. GENERAL SIGNIFICANCE: Antigen-specific directed oligoclonal T cells are alternatively promising, but safer systems, to combat tumor cells. PMID- 24076236 TI - Yeast reveals unexpected roles and regulatory features of aquaporins and aquaglyceroporins. AB - BACKGROUND: The yeast Saccharomyces cerevisiae provides unique opportunities to study roles and regulation of aqua/glyceroporins using frontline tools of genetics and genomics as well as molecular cell and systems biology. SCOPE OF REVIEW: S. cerevisiae has two similar orthodox aquaporins. Based on phenotypes mediated by gene deletion or overexpression as well as on their expression pattern, the yeast aquaporins play important roles in key aspects of yeast biology: establishment of freeze tolerance, during spore formation as well as determination of cell surface properties for substrate adhesion and colony formation. Exactly how the aquaporins perform those roles and the mechanisms that regulate their function under such conditions remain to be elucidated. S. cerevisiae also has two different aquaglyceroporins. While the role of one of them, Yfl054c, remains to be determined, Fps1 plays critical roles in osmoregulation by controlling the accumulation of the osmolyte glycerol. Fps1 communicates with two osmo-sensing MAPK signalling pathways to perform its functions but the details of Fps1 regulation remain to be determined. MAJOR CONCLUSIONS: Several phenotypes associated with aqua/glyceroporin function in yeasts have been established. However, how water and glycerol transport contribute to the observed effects is not understood in detail. Also many of the basic principles of regulation of yeast aqua/glyceroporins remain to be elucidated. GENERAL SIGNIFICANCE: Studying the yeast aquaporins and aquaglyceroporins offers rich insight into the life style, evolution and adaptive responses of yeast and rewards us with discoveries of unexpected roles and regulatory mechanisms of members of this ancient protein family. This article is part of a Special Issue entitled Aquaporins. PMID- 24076237 TI - TRAIL on trial: preclinical advances in cancer therapy. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand, or TRAIL, is a promising anticancer agent as it can induce apoptosis in a wide range of cancers whilst generally sparing non-malignant cells. However, the translation of TRAIL into the clinic has been confounded by its short half-life, inadequate delivery methods, and TRAIL-resistant cancer cell populations. In this review, we discuss how TRAIL has been functionalized to diversify its traditional tumor-killing role and novel strategies to facilitate its effective deployment in preclinical cancer models. The successes and failures of the most recent clinical trials using TRAIL agonists are highlighted and we provide a perspective for improving its clinical implementation. PMID- 24076238 TI - ArfGAP3 regulates the transport of cation-independent mannose 6-phosphate receptor in the post-Golgi compartment. AB - ArfGAPs are known to be involved in cargo sorting in COPI transport. However, the role of ArfGAPs in post-Golgi membrane traffic has not been defined. To determine the function of ArfGAPs in post-Golgi traffic, we used small interfering RNA to examine each of 25 ArfGAPs for effects on cation-independent mannose 6-phosphate receptor (CIMPR) localization. We found that downregulation of ArfGAP3 resulted in the peripheral localization of CIMPR. The effect was specific for ArfGAP3 and dependent on its GAP activity, because the phenotype was rescued by ArfGAP3 but not by ArfGAP1, ArfGAP2, or the GAP domain mutants of ArfGAP3. ArfGAP3 localized to the trans-Golgi network and early endosomes. In cells with reduced expression of ArfGAP3, Cathepsin D maturation was slowed and its secretion was accelerated. Also retrograde transport from the endosomes to the trans-Golgi network of endogenous CIMPR, but not truncated CIMPR lacking the luminal domain, was perturbed in cells with reduced expression of ArfGAP3. Furthermore the exit of epidermal growth factor receptor (EGFR) from the early endosomes and degradation of EGFR after EGF stimulation was slowed in cells with reduced expression of ArfGAP3. ArfGAP3 associates with Golgi-localized, gamma-ear-containing, ADP ribosylation factor binding proteins (GGAs), and ArfGAP3 knockdown reduces membrane association of GGAs. A possible mechanism explaining our results is that ArfGAP3 regulates transport from early endosomes to late endosomes. We suggest a model in which ArfGAP3 regulates Golgi association of GGA clathrin adaptors. PMID- 24076239 TI - Defining the site of light perception and initiation of phototropism in Arabidopsis. AB - Phototropism is an adaptive response allowing plants to optimize photosynthetic light capture. This is achieved by asymmetric growth between the shaded and lit sides of the stimulated organ. In grass seedlings, the site of phototropin mediated light perception is distinct from the site of bending; however, in dicotyledonous plants (e.g., Arabidopsis), spatial aspects of perception remain debatable. We use morphological studies and genetics to show that phototropism can occur in the absence of the root, lower hypocotyl, hypocotyl apex, and cotyledons. Tissue-specific expression of the phototropin1 (phot1) photoreceptor demonstrates that light sensing occurs in the upper hypocotyl and that expression of phot1 in the hypocotyl elongation zone is sufficient to enable a normal phototropic response. Moreover, we show that efficient phototropism occurs when phot1 is expressed from endodermal, cortical, or epidermal cells and that its local activation rapidly leads to a global response throughout the seedling. We propose that spatial aspects in the steps leading from light perception to growth reorientation during phototropism differ between grasses and dicots. These results are important to properly interpret genetic experiments and establish a model connecting light perception to the growth response, including cellular and morphological aspects. PMID- 24076240 TI - A tympanal insect ear exploits a critical oscillator for active amplification and tuning. AB - A dominant theme of acoustic communication is the partitioning of acoustic space into exclusive, species-specific niches to enable efficient information transfer. In insects, acoustic niche partitioning is achieved through auditory frequency filtering, brought about by the mechanical properties of their ears. The tuning of the antennal ears of mosquitoes and flies, however, arises from active amplification, a process similar to that at work in the mammalian cochlea. Yet, the presence of active amplification in the other type of insect ears--tympanal ears--has remained uncertain. Here we demonstrate the presence of active amplification and adaptive tuning in the tympanal ear of a phylogenetically basal insect, a tree cricket. We also show that the tree cricket exploits critical oscillator-like mechanics, enabling high auditory sensitivity and tuning to conspecific songs. These findings imply that sophisticated auditory mechanisms may have appeared even earlier in the evolution of hearing and acoustic communication than currently appreciated. Our findings also raise the possibility that frequency discrimination and directional hearing in tympanal systems may rely on physiological nonlinearities, in addition to mechanical properties, effectively lifting some of the physical constraints placed on insects by their small size [6] and prompting an extensive reexamination of invertebrate audition. PMID- 24076241 TI - Postcopulatory sexual selection generates speciation phenotypes in Drosophila. AB - BACKGROUND: Identifying traits that reproductively isolate species, and the selective forces underlying their divergence, is a central goal of evolutionary biology and speciation research. There is growing recognition that postcopulatory sexual selection, which can drive rapid diversification of interacting ejaculate and female reproductive tract traits that mediate sperm competition, may be an engine of speciation. Conspecific sperm precedence (CSP) is a taxonomically widespread form of reproductive isolation, but the selective causes and divergent traits responsible for CSP are poorly understood. RESULTS: To test the hypothesis that postcopulatory sexual selection can generate reproductive isolation, we expressed GFP or RFP in sperm heads of recently diverged sister species, Drosophila simulans and D. mauritiana, to enable detailed resolution of species specific sperm precedence mechanisms. Between-species divergence in sperm competition traits and mechanisms prompted six a priori predictions regarding mechanisms of CSP and degree of cross asymmetry in reproductive isolation. We resolved four distinct mechanisms of CSP that were highly consistent with predictions. These comprise interactions between multiple sex-specific traits, including two independent mechanisms by which females exert sophisticated control over sperm fate to favor the conspecific male. CONCLUSIONS: Our results confirm that reproductive isolation can quickly arise from diversifying (allopatric) postcopulatory sexual selection. This experimental approach to "speciation phenotypes" illustrates how knowledge of sperm precedence mechanisms can be used to predict the mechanisms and extent of reproductive isolation between populations and species. PMID- 24076242 TI - The progressive loss of syntactical structure in bird song along an island colonization chain. AB - Cultural transmission can increase the flexibility of behavior, such as bird song. Nevertheless, this flexibility often appears to be constrained, sometimes by preferences for learning certain traits over others, a phenomenon known as "biased" learning or transmission. The sequential colonization of the Atlantic Islands by the chaffinch (Fringilla coelebs) provides a unique model system in which to investigate how the variability of a cultural trait has evolved. We used novel computational methods to analyze chaffinch song from twelve island and continental populations and to infer patterns of evolution in song structure. We found that variability of the subunits within songs ("syllables") differed moderately between populations but was not predicted by whether the population was continental or not. In contrast, we found that the sequencing of syllables within songs ("syntax") was less structured in island than continental populations and in fact decreased significantly after each colonization. Syntactical structure was very clear in the mainland European populations but was almost entirely absent in the most recently colonized island, Gran Canaria. Our results suggest that colonization leads to the progressive loss of a species specific feature of song, syntactical structure. PMID- 24076243 TI - Information sharing in the brain indexes consciousness in noncommunicative patients. AB - Neuronal theories of conscious access tentatively relate conscious perception to the integration and global broadcasting of information across distant cortical and thalamic areas. Experiments contrasting visible and invisible stimuli support this view and suggest that global neuronal communication may be detectable using scalp electroencephalography (EEG). However, whether global information sharing across brain areas also provides a specific signature of conscious state in awake but noncommunicating patients remains an active topic of research. We designed a novel measure termed "weighted symbolic mutual information" (wSMI) and applied it to 181 high-density EEG recordings of awake patients recovering from coma and diagnosed in various states of consciousness. The results demonstrate that this measure of information sharing systematically increases with consciousness state, particularly across distant sites. This effect sharply distinguishes patients in vegetative state (VS), minimally conscious state (MCS), and conscious state (CS) and is observed regardless of etiology and delay since insult. The present findings support distributed theories of conscious processing and open up the possibility of an automatic detection of conscious states, which may be particularly important for the diagnosis of awake but noncommunicating patients. PMID- 24076244 TI - Dissociation of circadian and circatidal timekeeping in the marine crustacean Eurydice pulchra. AB - BACKGROUND: Tidal (12.4 hr) cycles of behavior and physiology adapt intertidal organisms to temporally complex coastal environments, yet their underlying mechanism is unknown. However, the very existence of an independent "circatidal" clock has been disputed, and it has been argued that tidal rhythms arise as a submultiple of a circadian clock, operating in dual oscillators whose outputs are held in antiphase i.e., ~12.4 hr apart. RESULTS: We demonstrate that the intertidal crustacean Eurydice pulchra (Leach) exhibits robust tidal cycles of swimming in parallel to circadian (24 hr) rhythms in behavioral, physiological and molecular phenotypes. Importantly, ~12.4 hr cycles of swimming are sustained in constant conditions, they can be entrained by suitable stimuli, and they are temperature compensated, thereby meeting the three criteria that define a biological clock. Unexpectedly, tidal rhythms (like circadian rhythms) are sensitive to pharmacological inhibition of Casein kinase 1, suggesting the possibility of shared clock substrates. However, cloning the canonical circadian genes of E. pulchra to provide molecular markers of circadian timing and also reagents to disrupt it by RNAi revealed that environmental and molecular manipulations that confound circadian timing do not affect tidal timing. Thus, competent circadian timing is neither an inevitable nor necessary element of tidal timekeeping. CONCLUSIONS: We demonstrate that tidal rhythms are driven by a dedicated circatidal pacemaker that is distinct from the circadian system of E. pulchra, thereby resolving a long-standing debate regarding the nature of the circatidal mechanism. PMID- 24076245 TI - A 3D map of the yeast kinetochore reveals the presence of core and accessory centromere-specific histone. AB - The budding yeast kinetochore is ~68 nm in length with a diameter slightly larger than a 25 nm microtubule. The kinetochores from the 16 chromosomes are organized in a stereotypic cluster encircling central spindle microtubules. Quantitative analysis of the inner kinetochore cluster (Cse4, COMA) reveals structural features not apparent in singly attached kinetochores. The cluster of Cse4 containing kinetochores is physically larger perpendicular to the spindle axis relative to the cluster of Ndc80 molecules. If there was a single Cse4 (molecule or nucleosome) at the kinetochore attached to each microtubule plus end, the cluster of Cse4 would appear geometrically identical to Ndc80. Thus, the structure of the inner kinetochore at the surface of the chromosomes remains unsolved. We have used point fluorescence microscopy and statistical probability maps to deduce the two-dimensional mean position of representative components of the yeast kinetochore relative to the mitotic spindle in metaphase. Comparison of the experimental images to three-dimensional architectures from convolution of mathematical models reveals a pool of Cse4 radially displaced from Cse4 at the kinetochore and kinetochore microtubule plus ends. The pool of displaced Cse4 can be experimentally depleted in mRNA processing pat1Delta or xrn1Delta mutants. The peripheral Cse4 molecules do not template outer kinetochore components. This study suggests an inner kinetochore plate at the centromere-microtubule interface in budding yeast and yields information on the number of Ndc80 molecules at the microtubule attachment site. PMID- 24076246 TI - Cognitive unbinding: a neuroscientific paradigm of general anesthesia and related states of unconsciousness. AB - "Cognitive unbinding" refers to the impaired synthesis of specialized cognitive activities in the brain and has been proposed as a mechanistic paradigm of unconsciousness. This article draws on recent neuroscientific data to revisit the tenets and predictions of cognitive unbinding, using general anesthesia as a representative state of unconsciousness. Current evidence from neuroimaging and neurophysiology supports the proposition that cognitive unbinding is a parsimonious explanation for the direct mechanism (or "proximate cause") of anesthetic-induced unconsciousness across multiple drug classes. The relevance of cognitive unbinding to sleep, disorders of consciousness, and psychological processes is also explored. It is concluded that cognitive unbinding is a viable neuroscientific framework for unconscious processes across the fields of anesthesiology, sleep neurobiology, neurology and psychoanalysis. PMID- 24076247 TI - Myoglobin expression in renal cell carcinoma is regulated by hypoxia. AB - Myoglobin is a member of the hemoprotein superfamily, which additionally includes hemoglobin, neuroglobin and cytoglobin. Cytoplasmic localized myoglobin functions as a radical scavenger and prevents hypoxia. Besides muscle tissue MB expression could also be observed in other tissues as well as in different types of cancer. For the correlation between the expression of myoglobin, hypoxia-inducible-factor 1alpha, and capillary density tissue of 86 different renal cell carcinomas were immunohistochemically stained with myoglobin-specific and hypoxia-inducible factor-1alpha-specific antibodies as well as with CD31 antibody. Four different renal carcinoma cell lines were cultivated under hypoxic conditions and the expression of myoglobin and hypoxia-inducible-factor-1alpha was evaluated by real time PCR and Western blot. Renal cell carcinoma including clear cell, papillary, and chromophobe subtypes expressed myoglobin with an inverse relationship to capillary density being highly significant for clear cell renal cell carcinoma. For hypoxia-inducible-factor-1alpha a significant correlation with capillary density could also be observed in clear cell RCC. In renal cell carcinoma cell lines hypoxia induced a significant increase of myoglobin expression up to 62 fold, whereas hypoxia-inducible-factor-1alpha only increased up to 5 fold. The PCR results of myoglobin expression could be confirmed by Western blot. Myoglobin seems to be a sensitive marker for hypovascularized tumor entities especially during the early phase of hypoxia. Such neoplasias may benefit from an antiangiogenic therapy. PMID- 24076248 TI - Sequence variability of the MspI satellite DNA family of the pinewood nematode Bursaphelenchus xylophilus at different geographic scales. AB - Tandemly repeated sequences known as satellite DNA (satDNA) generally exhibit complex evolutionary patterns of concerted evolution in which mutations are homogenized and fixed in a stochastic process of molecular drive. Here, the nucleotidic variability of the MspI satDNA family of the pinewood nematode Bursaphelenchus xylophilus is analyzed in order to understand the evolutionary dynamics of satDNA at the intraspecific level. A total of 425 MspI monomer units, either PCR-amplified from isolates of local (Peninsula of Setubal, Portugal) or worldwide origin, or retrieved from the B. xylophilus genome sequence, were characterized and compared. Whatever their origin, sliding window analysis of sequence variability patterns among monomers revealed low, moderate and highly variant domains, indicating that variable levels of evolutionary constraint may act upon the entire monomers. The phylogenetic inference based on the different sets of MspI satDNA family for this species shows a broad polymorphism of the individual monomers, which were distributed into four main clusters. However, such clustering appeared independent from the geographic origin of the nematodes, and could not discriminate isolates or groups of geographically close isolates. Rather, the formation of different phylogenetic groups within this satDNA family suggests an a priori embodying of a set of diverging repeats from a common ancestor satDNA library, which have been differently amplified along the evolutionary pathway of this species. The present work improves knowledge on the evolutionary dynamics of satDNA at the intraspecific level, and provides new information on satDNA sequence variability among natural populations sampled at a local geographic scale. PMID- 24076249 TI - Phylogenetic relationships of the operculate land snail genus Cyclophorus Montfort, 1810 in Thailand. AB - Operculate land snails of the genus Cyclophorus are distributed widely in sub tropical and tropical Asia. Shell morphology is traditionally used for species identification in Cyclophorus but their shells exhibit considerable variation both within and between populations; species limits have been extremely difficult to determine and are poorly understood. Many currently recognized species have discontinuous distributions over large ranges but geographical barriers and low mobility of snails are likely to have led to long periods of isolation resulting in cryptic speciation of allopatric populations. As a contribution towards solving these problems, we reconstructed the molecular phylogeny of 87 Cyclophorus specimens, representing 29 nominal species (of which one was represented by four subspecies), plus three related out-group species. Molecular phylogenetic analyses were used to investigate geographic limits and speciation scenarios. The analyses of COI, 16S rRNA and 28S rRNA gene fragments were performed using neighbour-joining (NJ), maximum likelihood (ML), and Bayesian inference (BI) methods. All the obtained phylogenetic trees were congruent with each other and in most cases confirmed the species level classification. However, at least three nominate species were polyphyletic. Both C. fulguratus and C. volvulus appear to be species complexes, suggesting that populations of these species from different geographical areas of Thailand are cryptic species. C. aurantiacus pernobilis is distinct and likely to be a different species from the other members of the C. aurantiacus species complex. PMID- 24076250 TI - BaCoCa--a heuristic software tool for the parallel assessment of sequence biases in hundreds of gene and taxon partitions. AB - BaCoCa (BAse COmposition CAlculator) is a user-friendly software that combines multiple statistical approaches (like RCFV and C value calculations) to identify biases in aligned sequence data which potentially mislead phylogenetic reconstructions. As a result of its speed and flexibility, the program provides the possibility to analyze hundreds of pre-defined gene partitions and taxon subsets in one single process run. BaCoCa is command-line driven and can be easily integrated into automatic process pipelines of phylogenomic studies. Moreover, given the tab-delimited output style the results can be easily used for further analyses in programs like Excel or statistical packages like R. A built in option of BaCoCa is the generation of heat maps with hierarchical clustering of certain results using R. As input files BaCoCa can handle FASTA and relaxed PHYLIP, which are commonly used in phylogenomic pipelines. BaCoCa is implemented in Perl and works on Windows PCs, Macs and Linux operating systems. The executable source code as well as example test files and a detailed documentation of BaCoCa are freely available at http://software.zfmk.de. PMID- 24076251 TI - Reference intervals for serum concentrations of three bone turnover markers for men and women. AB - OBJECTIVE: Bone turnover markers (BTMs) reflect the metabolic activity of bone tissue and can be used to monitor osteoporosis therapy. To adequately interpret BTMs, method-specific reference intervals are needed. We aimed to determine reference intervals for serum concentrations of intact amino-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BAP) and carboxy-terminal telopeptide of type I collagen (CTX). MATERIAL AND METHODS: We established a healthy reference population of 1107 men as well as 382 pre- and 450 postmenopausal women, who participated in the first follow-up of the Study of Health in Pomerania. Serum PINP, BAP and CTX concentrations were measured on the IDS-iSYS Automated System (Immunodiagnostic Systems, Frankfurt am Main, Germany). The reference interval was defined as the central 95% range. We determined age specific reference intervals for PINP, BAP, and CTX for men by quantile regression. Reference intervals for women were age-independent. RESULTS: Reference intervals for men for PINP and CTX decreased with age (25-29year-old men: PINP 31.1-95.9ng/mL, CTX 0.12-0.83ng/mL; 75-79year-old men: PINP 15.7 68.1ng/mL, CTX 0.05-0.58ng/mL). The reference interval for men for BAP did not significantly change with age (25-29year-old men: 7.4-27.7ng/mL; 75-79year-old men: 7.6-24.4ng/mL). The reference intervals for 30-54year-old premenopausal women were: PINP 19.3-76.3ng/mL, BAP 6.0-22.7ng/mL, and CTX 0.05-0.67ng/mL. The reference intervals for 50-79year-old postmenopausal women were: PINP 18.2 102.3ng/mL, BAP 8.1-31.6ng/mL, and CTX 0.09-1.05ng/mL. CONCLUSION: An intensively characterized, large reference population free of bone-related diseases allowed us to determine robust reference intervals for serum concentrations of PINP, BAP and CTX. Our normative data may aid to interpret bone turnover in adult men and pre- and postmenopausal women. PMID- 24076253 TI - Presepsin (sCD14-ST) in emergency department: the need for adapted threshold values? AB - Presepsin is elevated in patients developing infections and increases in a severity-dependent manner. We aimed to evaluate circulating values of this new biomarker in a population free of any acute infectious disorder. We recruited 144 consecutive patients presenting at the emergency department (ED) without acute infection or acute/unstable disorder, and 54 healthy participants. Presepsin plasmatic concentrations were measured on the PATHFAST point-of-care analyzer. The 95th percentile of presepsin values in the ED population is 750ng/L. Presepsin was significantly increased in patients aged >=70years vs. younger patients (470 [380-601] ng/L vs. 300 [201-457] ng/L, p<0.001). Prevalence of elevated presepsin values was increased in patients in comparison to controls (80% vs.13%, p<0.001), and in patients aged >=70years in comparison to younger patients (87% vs. 47%, p<0.001). Presepsin concentrations were significantly increased in patients with kidney dysfunction. Aging was an independent predictor of an elevated presepsin value. In conclusion, presepsin concentrations increase with age and kidney dysfunction. Therefore interpretation of presepsin concentrations might be altered in the elderly or in patients with impaired renal function. Adapted thresholds are needed for specific populations. PMID- 24076252 TI - The association between circulating endothelial progenitor cells and outcome in different subtypes of acute ischemic stroke. AB - OBJECTIVES: This study evaluated the relationship between serial changes in circulating endothelial progenitor cells (EPCs) and outcomes in patients with different subtypes of acute ischemic stroke (AIS). METHODS: This prospective cohort study evaluated 65 patients with AIS, including 45 with small-vessel and 20 with large-vessel diseases. The circulating level of EPCs (CD133(+)/CD34(+) and KDR(+)/CD34(+) cells) was determined at different time points (within 48h and on Days 7 and 30 post-stroke). For comparison, the EPC levels of 65 age- and sex matched controls were also evaluated. RESULTS: The levels of CD133(+)/CD34(+) and KDR(+)/CD34(+) EPCs were significantly lower in the AIS group than in the control group (p<0.05). There were fewer CD133(+)/CD34(+) EPCs in the large-vessel disease group than in the small-vessel disease group on Day 1 post-stroke (p<0.05). After adjusting for covariance using stepwise logistic regression, only stroke subtype (OR: 30.2, 95% CI: 5.3-171.4; p<0.001) and KDR(+)/CD34(+) on admission (OR: 0.188, 95% CI: 0.04-0.86; p=0.031) were independently associated with 6-month outcome. CONCLUSIONS: The number of circulating EPCs is significantly lower in patients with large-vessel disease than in those with small-vessel disease. Fewer number of EPCs on admission is an independent risk factor for poor 6-month outcome in patients with AIS. PMID- 24076254 TI - Management structure: establishing a laboratory utilization program and tools for utilization management. AB - As laboratories are challenged to do more with fewer resources, the pathologist and laboratory director will play a greater role in improving the effectiveness of the laboratory, as well as addressing the overuse, misuse and underuse of laboratory testing. We describe the necessary characteristics for pathologists and laboratory directors to successfully lead utilization efforts, as well as key leadership tools and essential steps in creating a utilization management program. When we established a laboratory test utilization program de novo, it became clear how important the laboratory director was in guiding those initiatives by working with stakeholders outside of the laboratory, particularly clinicians, nurses and administrators. PMID- 24076255 TI - From biomarkers to medical tests: the changing landscape of test evaluation. AB - Regulators and healthcare payers are increasingly demanding evidence that biomarkers deliver patient benefits to justify their use in clinical practice. Laboratory professionals need to be familiar with these evidence requirements to better engage in biomarker research and decisions about their appropriate use. This paper by a multidisciplinary group of the European Federation of Clinical Chemistry and Laboratory Medicine describes the pathway of a laboratory assay measuring a biomarker to becoming a medically useful test. We define the key terms, principles and components of the test evaluation process. Unlike previously described linearly staged models, we illustrate how the essential components of analytical and clinical performances, clinical and cost effectiveness and the broader impact of testing assemble in a dynamic cycle. We highlight the importance of defining clinical goals and how the intended application of the biomarker in the clinical pathway should drive each component of test evaluation. This approach emphasizes the interaction of the different components, and that clinical effectiveness data should be fed back to refine analytical and clinical performances to achieve improved outcomes. The framework aims to support the understanding of key stakeholders. The laboratory profession needs to strengthen collaboration with industry and experts in evidence-based medicine, regulatory bodies and policy makers for better decisions about the use of new and existing medical tests. PMID- 24076256 TI - Transplantation with retinal progenitor cells repairs visual function in rats with retinal ischemia-reperfusion injury. AB - The retinal ischemia-reperfusion injury (RIR) is a common pathological process that leads to progressive visual loss and blindness in many retinal diseases such as retinal vascular occlusion disease, diabetic retinopathy, and acute glaucoma. Currently, there has been no effective therapy. The purpose of this study was to investigate the effects of transplantation of retinal progenitor cells (RPCs) into the subretinal space (SRS) and the superior colliculus (SC) in a rat model of RIR injury. We used cultured postnatal day 1 rat RPCs transfected with adeno associated virus containing the cDNA encoding enhanced green fluorescence protein (EGFP) for transplantation. RIR injury was induced by increases in the intraocular pressure to 110 mmHg for 60 min. The effects of transplantation were evaluated by immunohistochemistry, electroretinography (ERG), and visual evoked potentials (VEP). We found that in rats with RIR injury, RPCs transplanted into the SRS and the SC survived for at least 8 weeks, migrated into surrounding tissues, and improved the ERG and VEP responses. Cells transplanted into the SC improved the VEP response more than those transplanted into the SRS. Our data suggest that transplantation of RPCs into the SRS and the SC may be a possible method for cell replacement therapy for retinal diseases. PMID- 24076257 TI - Total monitor units influence on plan quality parameters in volumetric modulated arc therapy for breast case. AB - PURPOSE: To investigate the correlation between total monitor units (MU), dosimetric findings, and pre-treatment quality assurance for volumetric modulated arc therapy (VMAT) by RapidArc (RA). METHODS AND MATERIALS: Ten patients with breast cancer were considered. Dose prescriptions were: 48 Gy and 40.5 Gy in 15 fractions to, respectively, PTV(Boost) and PTVWholeBreast. A reference plan was optimized and four more plans using the "MU Objective", a tool for total MU controlling, were prepared imposing +/- 20 and +/- 50% total MU for inducing different complexities. Plan objectives were: D95% > 95% for both PTVs, and D2% < 107% for PTV(Boost); mean dose < 9.5 Gy and V20 Gy < 10% for ipsilateral lung; V18 Gy < 5% for heart; mean dose <3 Gy for controlateral breast; furthermore V5 Gy, V10 Gy, V20 Gy, and V30 Gy to body were minimized. Plans were evaluated in terms of technical parameters, dosimetric plan objectives findings and pre treatment quality assurance (QA). RESULTS: Concerning PTVs, there were no significant differences for target coverage (D95%); mean doses for ipsilateral lung and controlateral breast, and V18 Gy for heart decreased with MUs increasing, reaching a plateau with reference plan. Body volume receiving low dose (V5-10 Gy) was minimized for reference plans. All plans had GAI (3 mm, 3%) > 95%. CONCLUSIONS: The data suggest that the best plan is the reference one, where the "MU Objective" tool was not used during optimisation. Nevertheless, it is advisable to use the "MU Objective" tool for re-planning when low GAI is found to increase its value. In this case, attention should be paid to OARs dose limits, since their values may be increased. PMID- 24076258 TI - Pharmacokinetic changes of unbound theophylline are due to plasma protein binding displacement and CYP1A2 activity inhibition by baicalin in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Baicalin is one of the major bioactive constituents of Scutellariae Radix, the root of Scutellariae baicalensis Georgi and possesses a wide variety of pharmacological properties. AIM OF THE STUDY: To elucidate the effect of baicalin on the pharmacokinetics of theophylline in rats, focusing on plasma protein binding displacement and inhibition effect on CYP1A2 in vivo and in vitro. MATERIALS AND METHODS: The study was a randomized, three period crossover design. Nine rats were given saline (control) or 450 mg/kg baicalin (dosage regimen A or B). Dosage regimen A was administered once at 0 h. Dosage regimen B was divided into three dosages (225,112.5, 112.5 mg/kg) and was given at 0, 2 and 4 h, respectively. Then theophylline (5 mg/kg, i.v.) was administered immediately. The effect of baicalin on CYP1A2 activity was determined by metabolism of phenacetin in vitro and plasma protein binding of theophylline was determined by ultrafiltration. RESULTS: C(max) decreased from (12.4 +/- 1.6) to (8.7 +/- 0.9) and (8.6 +/- 2.0) mg/L, T(1/2) increased by 116 and 96%, V(d) increased by 51 and 49% for total theophylline in rats treated with dosage regimen A and B of baicalin, respectively. Cmax was significantly increased, V(d) decreased by 43 and 29% for unbound theophylline in rats treated with dosage regimen A and B of baicalin, respectively (P < 0.01). T(1/2) of unbound theophylline increased by 104% only in rats treated with dosage regimen B. No significant effects on the CL and AUC of both total and unbound theophylline were observed in the rats treated with dosage regimen A, but the CL decreased and AUC increased for total theophylline and CL decreased for unbound theophylline in the group treated with dosage regimen B (P < 0.05). Correlation analysis showed that the mean unbound theophylline (%) and mean baicalin concentration was in good correlation (P < 0.01). Baicalin decreased metabolism of phenacetin and exhibited a mixed-type inhibition in rat liver microsomes, with a K(i) value of 88.1 MUM in vitro. Moreover baicalin was a competitive displacer of theophylline from plasma protein in vitro. CONCLUSIONS: The changes in Cmax, T(1/2), CL and AUC of theophylline due to baicalin may be attributed to two mechanisms, plasma protein binding displacement and CYP1A2 activity inhibition. PMID- 24076259 TI - Elucidation of the transport mechanism of baicalin and the influence of a Radix Angelicae Dahuricae extract on the absorption of baicalin in a Caco-2 cell monolayer model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Angelicae Dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav combined with Radix Scutellariae baicalensis Georgi has been widely used in traditional Chinese medicine (TCM) as an antipyretic analgesic and anti inflammatory drug. Modern pharmacological studies have demonstrated that the compatible application of these two drugs is an effective treatment for hepatitis. A previous study indicated that a Radix Angelicae Dahuricae extract enhanced the intestinal absorption of the baicalin found in Radix Scutellariae; however, the underlying compatibility mechanism of these two herbs remains unknown. In this study, we further examined the effect of a Radix Angelicae Dahuricae extract on the absorption and transport properties of baicalin in a Caco-2 cell model to determine the compatibility mechanism of these two herbs. AIM OF THE STUDY: The aim of this work was to study the transport properties of baicalin in Radix Scutellariae across cell membranes and the effects of a Radix Angelicae Dahuricae extract on baicalin absorption using the well-characterized, human-based intestinal Caco-2 cell model. MATERIALS AND METHODS: We assessed the absorption, bidirectional transport and toxicity of baicalin using a range of parameters, including drug concentration, pH, a P-glycoprotein (P-gp) inhibitor (Verapamil), an MRP inhibitor (MK-571) and EDTA-Na2 (tight junction modulator). Next, we studied the influence of a Radix Angelicae Dahuricae extract on the transport of baicalin under the same conditions. Drug concentration was measured by HPLC, and the apparent permeability coefficient (Papp) and apparent permeability ratio (PDR) were subsequently calculated. RESULTS: The results showed that baicalin is non-toxic within a concentration range of 800 ug/mL to 4800 ug/mL. The transport of baicalin showed time and concentration dependence. The absorption of baicalin was optimal at pH 7.4 in 37 degrees C; however, the absorption decreased at 4 degrees C. The Papp of baicalin transport through the Caco-2 cell monolayer model was altered when specific inhibitors of P-gp or MRP were added to the cells. However, there was no significant difference in the PDR value. The Papp of baicalin improved when it was combined with the Radix Angelicae Dahuricae extract. The influence of EDTA-Na2 on the transport of baicalin showed that the permeability of baicalin significantly increased. The result further indicated that the mechanism of baicalin intestinal absorption in the Caco-2 cell monolayer involves passive transcellular diffusion. CONCLUSIONS: Passive diffusion is the main mode of intestinal absorption of bacalin and it involved in the efflux of proteins. The enhanced intestinal absorption of baicalin by Radix Angelicae Dahuricae can be due to opening of the tight junctions between cells and inhibition of MRP efflux protein expression or function. PMID- 24076260 TI - Wind and gravity mechanical effects on leaf inclination angles. AB - In a tree, the distribution of leaf inclination angles plays an important role in photosynthesis and water interception. We investigate here the effect of mechanical deformations of leaves due to wind or their own weight on this distribution. First, the specific role of the geometry of the tree is identified and shown to be weak, using models of idealized tree and tools of statistical mechanics. Then the deformation of individual leaves under gravity or wind is quantified experimentally. New dimensionless parameters are proposed, and used in simple models of these deformations. By combining models of tree geometry and models of leaf deformation, we explore the role of all mechanical parameters on the Leaf Inclination Angle Distributions. These are found to have a significant influence, which is exemplified finally in computations of direct light interception by idealized trees. PMID- 24076261 TI - Dynamics of evolutionary rescue in changing environments and the emergence of antibiotic resistance. AB - Populations can go extinct when their environments deteriorate, but evolutionary rescue occurs when a shrinking population adapts to the new environmental conditions. The emergence of resistance from a drug sensitive bacterial population under treatment can be regarded as an instance of evolutionary rescue. Understanding evolutionary rescue in a particular context such as drug resistance requires knowledge of how the environment changes and how selection coefficients change as a result. In this study, we propose a model for evolutionary rescue under three different scenarios of environmental change: abrupt change, periodic fluctuation and gradual decay. The model makes use of the notion of reaction norms to describe fitness values that depend on both genotype and environmental state. We find that although drug sensitive bacterial populations may be large, allowing them to generate resistant mutants frequently, a harsh abrupt change due to the drug usually drives them extinct. Evolutionary rescue occurs far more frequently under the milder forms of environmental change we investigated. Rescue is favoured when the absolute fitnesses of individuals remain sufficiently high over the range of environment qualities experienced by the population. The minimum environment quality, which is inversely related to drug dose in the antibiotic context, is thus an important factor. Interestingly, in the periodic fluctuation model, the inter-dose period is less influential in promoting rescue through resistance unless the minimum environment quality is in a particular range. We also investigated fitness trade-offs across environments including the case of a resistant allele not subject to any trade-off (a "superbug"). This fitness trade-off affects the probability of rescue in decaying environments, but surprisingly has only a weak effect in the periodic fluctuation scenario. Finally, we use the model to show how niche construction, whereby organisms are the source of environmental change, produces more complex dynamics. PMID- 24076262 TI - Advances in the development of Rho-associated protein kinase (ROCK) inhibitors. AB - Rho-associated protein kinases (ROCK1 and ROCK2) belong to the AGC family of serine-threonine kinases, and regulate a wide range of fundamental cell functions. Inhibition of ROCK has been proven to be of potential therapeutic benefit for a variety of diseases. In this review, the structures and therapeutic importance of ROCK are discussed briefly. Then, the recent status of the development of ROCK inhibitors is also summarized. Our review offers a foundation outline from which strategies to design new leads against ROCK can be developed. PMID- 24076263 TI - Exiting the ER: what we know and what we don't. AB - The vast majority of proteins that are transported to different cellular compartments and secreted from the cell require coat protein complex II (COPII) for export from the endoplasmic reticulum (ER). Many of the molecular mechanisms underlying COPII assembly are understood in great detail, but it is becoming increasingly evident that this basic machinery is insufficient to account for diverse aspects of protein export from the ER that are observed in vivo. Here we review recent data that have furthered our mechanistic understanding of COPII assembly and, in particular, how genetic diseases associated with the early secretory pathway have added fundamental insights into the regulation of ER derived carrier formation. We also highlight some unresolved issues that future work should address to better understand the physiology of COPII-mediated transport. PMID- 24076264 TI - Observation of 2,3-butanediol biosynthesis in Lys regulator mutated Klebsiella pneumoniae at gene transcription level. AB - Microorganisms that produce 2,3-butanediol (2,3-BDO) are mostly mixed acid fermentation microorganisms, and they synthesize 2,3-BDO in order to suppress medium acidification. The 2,3-BDO operon (budBAC) is activated by the LysR regulator protein derived from the budR. In this study, the effect of the budR on 2,3-BDO-biosynthesis was observed at gene transcription level. The Klebsiella pneumoniae strains (wabG-deleted strain (SGSB100), budR over-expressed strain (SGSB101), and the budR-deleted strain (SGSB102)) were constructed. The resulting strains were cultivated in unified conditions. Samples were obtained at the lag-, log-, and stationary-phase of cell growth, and gene transcription levels of the budR, 2,3-BDO-biosynthesis-related (budB, budA, and budC), and acid-biosynthesis related (ldhA and ack) genes were observed. During the lag-phase of cell growth in SGSB101, the budR transcription level increased approximately 8-fold, and 2,3 BDO production increased approximately 2-fold, when compared to SGSB100. Also in SGSB101 the transcription level of the acid-biosynthesis-related genes (ldhA and ack) increased approximately up to 11-fold during the lag-phase of cell growth compared to SGSB100. On contrast, in SGSB102 budR transcription was not detected, and the transcription level of the acid-biosynthesis-related genes (ldhA and ack) decreased approximately 70-fold during the lag-phase of cell growth compared to SGSB100. This is by far the first observation of 2,3-BDO regulation mechanism at gene transcription level in K. pneumoniae, and therefore may be useful for understanding and improving 2,3-BDO biosynthesis metabolic network. PMID- 24076265 TI - Dietary cholesterol degrades rabbit long term memory for discrimination learning but facilitates acquisition of discrimination reversal. AB - We have shown previously that feeding dietary cholesterol before learning can improve acquisition whereas feeding cholesterol after learning can degrade long term memory. To examine these different findings within a single paradigm, we fed groups of rabbits 2% cholesterol or normal chow with or without 0.12 ppm copper added to the drinking water following two-tone discrimination learning of the nictitating membrane response in which a 8-kHz tone (conditioned stimulus, CS+) was followed by air puff and a 1-kHz tone (CS-) was not. After eight weeks on the diet, we assessed the rabbits' conditioned responding during testing and retraining. We then reversed the two-tone discrimination and assessed responding to the 1-kHz tone CS+ and the 8-kHz CS-. During testing, rabbits given cholesterol without copper had lower levels of responding to CS+ than rabbits in the other groups suggesting they did not retain the discrimination as well. However, during a brief discrimination retraining session, their response levels to the CS+ returned to the level of the other groups, demonstrating a return of the memory of the original discrimination. At the end of discrimination reversal, these same rabbits exhibited superior discrimination indexed by lower response levels to CS- but similar levels to CS+, suggesting they were better able to acquire the new relationship between the two tones by inhibiting CS- responses. These results add to our previous data by showing cholesterol diet-induced degradation of an old memory and facilitation of a new memory can both be demonstrated within a discrimination reversal paradigm. Given discrimination reversal is a hippocampally-dependent form of learning, the data support the role of cholesterol in modifying hippocampal function as we have shown previously with in vitro brain slice recordings. PMID- 24076266 TI - Targeting notch signaling pathway in cancer: clinical development advances and challenges. AB - Notch signaling plays an important role in development and cell fate determination, and it is deregulated in human hematologic malignancies and solid tumors. This review includes a brief introduction of the relevant pathophysiology of Notch signaling pathway and primarily focuses on the clinical development of promising agents that either obstruct Notch receptor cleavages such as gamma secretase inhibitors (GSIs) or interfere with the Notch ligand-receptor interaction by monoclonal antibodies (mAbs). Antitumor activity by GSIs and mAbs administered as single agent in early phases of clinical trials has been observed in advanced or metastatic thyroid cancer, non-small cell lung cancer, intracranial tumors, sarcoma or desmoid tumors, colorectal cancer with neuroendocrine features, melanoma and ovarian cancer. A number of mechanism-based adverse events particularly gastrointestinal toxicities emerged and mitigation strategies are developed after testing multiple GSIs and Notch targeting mAbs. We also discuss pharmacodynamic biomarkers in conjunction with methods of assessment of the molecular target inhibition validation. Biomarkers of efficacy or benefit may be of importance for a successful development of this class of drugs. PMID- 24076267 TI - Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: A quantitative systematic review. AB - UDP-glucuronosyltransferases (UGT) catalyze the biotransformation of many endobiotics and xenobiotics, and are coded by polymorphic genes. However, knowledge about the effects of these polymorphisms is rarely used for the individualization of drug therapy. Here, we present a quantitative systematic review of clinical studies on the impact of UGT variants on drug metabolism to clarify the potential for genotype-adjusted therapy recommendations. Data on UGT polymorphisms and dose-related pharmacokinetic parameters in man were retrieved by a systematic search in public databases. Mean estimates of pharmacokinetic parameters were extracted for each group of carriers of UGT variants to assess their effect size. Pooled estimates and relative confidence bounds were computed with a random-effects meta-analytic approach whenever multiple studies on the same variant, ethnic group, and substrate were available. Information was retrieved on 30 polymorphic metabolic pathways involving 10 UGT enzymes. For irinotecan and mycophenolic acid a wealth of data was available for assessing the impact of genetic polymorphisms on pharmacokinetics under different dosages, between ethnicities, under comedication, and under toxicity. Evidence for effects of potential clinical relevance exists for 19 drugs, but the data are not sufficient to assess effect size with the precision required to issue dose recommendations. In conclusion, compared to other drug metabolizing enzymes much less systematic research has been conducted on the polymorphisms of UGT enzymes. However, there is evidence of the existence of large monogenetic functional polymorphisms affecting pharmacokinetics and suggesting a potential use of UGT polymorphisms for the individualization of drug therapy. PMID- 24076268 TI - Bevacizumab and micrometastases: revisiting the preclinical and clinical rollercoaster. AB - The use of bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with standard therapeutic approaches, has offered clinical benefit for patients with advanced colorectal, breast, ovarian, renal, non small-cell lung cancer and glioblastoma. However, the strategy of administering bevacizumab until disease progression has been challenged by certain preclinical evidence, suggesting that prolonged exposure to anti-VEGF treatment may elicit an adaptive-evasive response, resulting in a more aggressive tumor phenotype. Moreover, the use of bevacizumab in adjuvant chemotherapeutic regimens has led to less promising results than expected. Despite our poor understanding of how bevacizumab acts in micrometastatic disease, numerous clinical trials (involving >20,000 cancer patients) are ongoing or are planned to test the therapeutic benefit in the adjuvant setting. The discrepancy of bevacizumab's efficiency in the two settings calls into question the validity of current strategies that use similar treatment regimens for early and advanced diseases. Herein, we review the mechanisms of bevacizumab activity in the macro- as compared to the micrometastatic environment and discuss possible alternative strategies in the adjuvant setting that might spur attention for future clinical trials. Rather than providing an encyclopedic survey of the literature, we highlight exemplary principles. PMID- 24076269 TI - Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. AB - Interleukin-6 (IL-6) is a pleiotropic cytokine with significant functions in the regulation of the immune system. As a potent pro-inflammatory cytokine, IL-6 plays a pivotal role in host defense against pathogens and acute stress. However, increased or deregulated expression of IL-6 significantly contributes to the pathogenesis of various human diseases. Numerous preclinical and clinical studies have revealed the pathological roles of the IL-6 pathway in inflammation, autoimmunity, and cancer. Based on the rich body of studies on biological activities of IL-6 and its pathological roles, therapeutic strategies targeting the IL-6 pathway are in development for cancers, inflammatory and autoimmune diseases. Several anti-IL-6/IL-6 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials. Tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis. It is the only IL-6 pathway targeting agent approved by the regulatory agencies for clinical use. Siltuximab, an anti-IL-6 antibody, has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs. Several other anti IL-6-based therapies are also under clinical development for various diseases. IL 6 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs. New strategies, such as combination of IL-6 blockade with inhibition of other signaling pathways, may further improve IL-6 targeted immunotherapy of human diseases. PMID- 24076270 TI - Termination of trigeminal primary afferents on glossopharyngeal-vagal motoneurons: possible neural networks underlying the swallowing phase and visceromotor responses of prey-catching behavior. AB - Prey-catching behavior (PCB) of the frog consists of a sequence of coordinated activity of muscles which is modified by various sensory signals. The aim of the present study was, for the first time, to examine the involvement of the trigeminal afferents in the swallowing phase of PCB. Experiments were performed on Rana esculenta, where the trigeminal and glossopharyngeal (IX)-vagus (X) nerves were labeled simultaneously with different fluorescent dyes. Using confocal laser scanning microscope, close appositions were detected between the trigeminal afferent fibers and somatodendritic components of the IX-X motoneurons of the ambiguus nucleus (NA). Neurolucida reconstruction revealed spatial distribution of the trigeminal afferents in the functionally different parts of the NA. Thus, the visceromotor neurons supplying the stomach, the heart and the lung received about two third of the trigeminal contacts followed by the pharyngomotor and then by the laryngomotor neurons. On the other hand, individual motoneurons responsible for innervation of the viscera received less trigeminal terminals than the neurons supplying the muscles of the pharynx. The results suggest that the direct contacts between the trigeminal afferents and IX-X motoneurons presented here may be one of the morphological substrate of a very quick response during the swallowing phase of PCB. Combination of direct and indirect trigeminal inputs may contribute to optimize the ongoing motor execution. PMID- 24076271 TI - The role of adenosine in preconditioning by brief pressure overload in rats. AB - BACKGROUND/PURPOSE: Brief pressure overload of the left ventricle reduced myocardial infarct (MI) size in rabbits has been previously reported. Its effects in other species are not known. This study investigates effects of pressure overload and the role of adenosine in rats in this study. METHODS: MI was induced by 40-minute occlusion of the left anterior descending coronary artery followed by 3-hour reperfusion. MI size was determined by triphenyl tetrazolium chloride staining. Brief pressure overload was induced by two 10-minute episodes of partial snaring of the ascending aorta. Systolic left ventricular pressure was raised 50% above the baseline value. Ischemic preconditioning was elicited by two 10-minute coronary artery occlusions. RESULTS: The MI size (mean +/- standard deviation), expressed as percentage of area at risk, was significantly reduced in the pressure overload group as well as in the ischemic preconditioning group (17.4 +/- 3.0% and 18.2 +/- 1.5% vs. 26.6 +/- 2.4% in the control group, p < 0.001). Pretreatment with 8-(p-sulfophenyl)-theophylline (SPT), an inhibitor of adenosine receptors, did not significantly limit the protection by pressure overload and ischemic preconditioning (18.3 +/- 1.5% and 18.2 +/- 2.0%, respectively, p < 0.001). SPT itself did not affect the extent of infarct (25.4 +/- 2.0%). The hemodynamics, area at risk and mortality were not significantly different among all groups of animals. CONCLUSION: Brief pressure overload of the left ventricle preconditioned rat myocardium against infarction. Because SPT did not significantly alter MI size reduction, our results did not support a role of adenosine in preconditioning by pressure overload in rats. PMID- 24076273 TI - Tracheoinnominate artery fistula after percutaneous tracheostomy. PMID- 24076272 TI - Predictors of 1-year outcomes in the Taiwan Acute Coronary Syndrome Full Spectrum Registry. AB - BACKGROUND/PURPOSE: Evidence-based guidelines have been formulated for optimal management of acute coronary syndrome (ACS). The Taiwan ACS Full Spectrum Registry aimed to evaluate the ACS management and identify the predictors of clinical outcomes of death/myocardial infarction/stroke 1 year post hospital discharge. METHODS: Three thousand and eighty confirmed ACS patients enrolled in this registry were followed up for 1 year at 3-month intervals. Patient data on medical interventions as well as clinical events were recorded and analyzed by descriptive statistics. RESULTS: One-year mortality among patients with ST segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and unstable angina was 6.1%, 10.1%, and 6.2%, respectively. Use of secondary preventive therapies was suboptimal throughout the follow-up phase, especially dual antiplatelet therapy, which fell from 74.8% patients at discharge to 24.9% patients at 1-year follow-up. The odds of an adverse incidence of death/myocardial infarction/stroke 1 year after discharge was significantly reduced in patients receiving aspirin and clopidogrel for >=9 months and was consequently higher in patients in whom dual antiplatelet therapy was discontinued or prescribed for <9 months. Chronic renal failure, in-hospital bleeding, a diagnosis of NSTEMI, and antiplatelet therapy discontinuation had a negative association with 1-year outcomes, whereas the use of drug-eluting stents and antiplatelet agents, clopidogrel and aspirin, were predictors of positive outcomes. CONCLUSION: There is a significant deviation from evidence-based guidelines in ACS management in Taiwan as reported in other countries. Policy adherence, especially with regard to dual antiplatelet therapy may hold the key to long-term favorable outcomes and improved survival rates in ACS patients in Taiwan. PMID- 24076274 TI - Hippocampal long term memory: effect of the cholinergic system on local protein synthesis. AB - The present study was aimed at establishing a link between the cholinergic system and the pathway of mTOR and its downstream effector p70S6K, likely actors in long term memory encoding. We performed in vivo behavioral experiments using the step down inhibitory avoidance test (IA) in adult Wistar rats to evaluate memory formation under different conditions, and immunohistochemistry on hippocampal slices to evaluate the level and the time-course of mTOR and p70S6K activation. We also examined the effect of RAPA, inhibitor of mTORC1 formation, and of the acetylcholine (ACh) muscarinic receptor antagonist scopolamine (SCOP) or ACh nicotinic receptor antagonist mecamylamine (MECA) on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition test was performed 30 min after i.c.v. injection of RAPA, a time sufficient for the drug to diffuse to CA1 pyramidal neurons, as demonstrated by MALDI-TOF-TOF imaging. Recall test was performed 1 h, 4 h or 24 h after acquisition. To confirm our results we performed in vitro experiments on live hippocampal slices: we evaluated whether stimulation of the cholinergic system with the cholinergic receptor agonist carbachol (CCh) activated the mTOR pathway and whether the administration of the above-mentioned antagonists together with CCh could revert this activation. We found that (1) mTOR and p70S6K activation in the hippocampus were involved in long term memory formation; (2) RAPA administration caused inhibition of mTOR activation at 1 h and 4 h and of p70S6K activation at 4 h, and long term memory impairment at 24 h after acquisition; (3) scopolamine treatment caused short but not long term memory impairment with an early increase of mTOR/p70S6K activation at 1 h followed by stabilization at longer times; (4) mecamylamine plus scopolamine treatment caused short term memory impairment at 1 h and 4 h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1 h and 4 h; (5) mecamylamine plus scopolamine treatment did not impair long term memory formation; (6) in vitro treatment with carbachol activated mTOR and p70S6K and this effect was blocked by scopolamine and mecamylamine. Taken together our data reinforce the idea that distinct molecular mechanisms are at the basis of the two different forms of memory and are in accordance with data presented by other groups that there exist molecular mechanisms that underlie short term memory, others that underlie long term memories, but some mechanisms are involved in both. PMID- 24076276 TI - The HIV care cascade through time. PMID- 24076275 TI - Altered epigenetic regulation of homeobox genes in human oral squamous cell carcinoma cells. AB - To gain insight into oral squamous cell carcinogenesis, we performed deep sequencing (RNAseq) of non-tumorigenic human OKF6-TERT1R and tumorigenic SCC-9 cells. Numerous homeobox genes are differentially expressed between OKF6-TERT1R and SCC-9 cells. Data from Oncomine, a cancer microarray database, also show that homeobox (HOX) genes are dysregulated in oral SCC patients. The activity of Polycomb repressive complexes (PRC), which causes epigenetic modifications, and retinoic acid (RA) signaling can control HOX gene transcription. HOXB7, HOXC10, HOXC13, and HOXD8 transcripts are higher in SCC-9 than in OKF6-TERT1R cells; using ChIP (chromatin immunoprecipitation) we detected PRC2 protein SUZ12 and the epigenetic H3K27me3 mark on histone H3 at these genes in OKF6-TERT1R, but not in SCC-9 cells. In contrast, IRX1, IRX4, SIX2 and TSHZ3 transcripts are lower in SCC 9 than in OKF6-TERT1R cells. We detected SUZ12 and the H3K27me3 mark at these genes in SCC-9, but not in OKF6-TERT1R cells. SUZ12 depletion increased HOXB7, HOXC10, HOXC13, and HOXD8 transcript levels and decreased the proliferation of OKF6-TERT1R cells. Transcriptional responses to RA are attenuated in SCC-9 versus OKF6-TERT1R cells. SUZ12 and H3K27me3 levels were not altered by RA at these HOX genes in SCC-9 and OKF6-TERT1R cells. We conclude that altered activity of PRC2 is associated with dysregulation of homeobox gene expression in human SCC cells, and that this dysregulation potentially plays a role in the neoplastic transformation of oral keratinocytes. PMID- 24076277 TI - The cascade of HIV care in British Columbia, Canada, 1996-2011: a population based retrospective cohort study. AB - BACKGROUND: The cascade of HIV care has become a focal point for implementation efforts to maximise the individual and public health benefits of antiretroviral therapy. We aimed to characterise longitudinal changes in engagement with the cascade of HIV care in British Columbia, Canada, from 1996 to 2011. METHODS: We used estimates of provincial HIV prevalence from the Public Health Agency of Canada and linked provincial population-level data to define, longitudinally, the numbers of individuals in each of the eight stages of the cascade of HIV care (HIV infected, diagnosed, linked to HIV care, retained in HIV care, highly active antiretroviral therapy (HAART) indicated, on HAART, adherent to HAART, and virologically suppressed) in British Columbia from 1996 to 2011. We used sensitivity analyses to determine the sensitivity of cascade-stage counts to variations in their definitions. FINDINGS: 13,140 people were classified as diagnosed with HIV/AIDS in British Columbia during the study period. We noted substantial improvements over time in the proportions of individuals at each stage of the cascade of care. Based on prevalence estimates, the proportion of unidentified HIV-positive individuals decreased from 49.0% (estimated range 36.2 57.5%) in 1996 to 29.0% (11.6-40.7%) in 2011, and the proportion of HIV-positive people with viral suppression reached 34.6% (29.0-43.1%) in 2011. INTERPRETATION: Careful mapping of the cascade of care is crucial to understanding what further efforts are needed to maximise the beneficial effects of available interventions and so inform efforts to contain the spread of HIV/AIDS. FUNDING: British Columbia Ministry of Health, US National Institute on Drug Abuse (National Institutes of Health). PMID- 24076278 TI - Calpain2 protease: A new member of the Wnt/Ca(2+) pathway modulating convergent extension movements in Xenopus. AB - Calpains are a family of calcium-dependent intracellular cysteine proteases that regulate several physiological processes by limited cleavage of different substrates. The role of Calpain2 in embryogenesis is not clear with conflicting evidence from a number of mouse knockouts. Here we report the temporal and spatial expression of Calpain2 in Xenopus laevis embryos and address its role in Xenopus development. We show that Calpain2 is expressed maternally with elevated expression in neural tissues and that Calpain2 activity is spatially and temporally regulated. Using a Calpain inhibitor, a dominant negative and a morpholino oligonoucleotide we demonstrate that impaired Calpain2 activity results in defective convergent extension both in mesodermal and neural tissues. Specifically, Calpain2 downregulation results in loss of tissue polarity and blockage of mediolateral intercalation in Keller explants without affecting adherens junction turnover. We further show that Calpain2 is activated in response to Wnt5a and that the inhibitory effect of Wnt5a expression on animal cap elongation can be rescued by blocking Calpain2 function. This suggests that Calpain2 activity needs to be tightly regulated during convergent extension. Finally we show that expression of Xdd1 blocks the membrane translocation of Calpain2 suggesting that Calpain2 activation is downstream of Dishevelled. Overall our data show that Calpain2 activation through the Wnt/Ca(2+) pathway and Dishevelled can modulate convergent extension movements. PMID- 24076279 TI - Altered cardiac innervation predisposes to ventricular arrhythmia: targeted positron emission tomography identifies risk in ischemic cardiomyopathy. PMID- 24076280 TI - Do statins reduce the risk of contrast-induced acute kidney injury in patients undergoing coronary angiography or percutaneous coronary interventions? PMID- 24076281 TI - Quality of care for heart failure patients hospitalized for any cause. AB - OBJECTIVES: The study sought to assess the quality of care for heart failure patients who are hospitalized for all causes. BACKGROUND: Performance measures for heart failure target patients with a principal diagnosis of heart failure. However, patients with heart failure are commonly hospitalized for other causes and may benefit from treatments such as angiotensin-converting enzyme (ACE) inhibitors for left ventricular (LV) systolic dysfunction. METHODS: We assessed rates of compliance with care measures for patients hospitalized with acute or chronic heart failure in the ARIC (Atherosclerosis Risk In Communities) study surveillance catchment area from 2005 to 2009. Rates of compliance were compared between patients with a principal discharge diagnosis of heart failure and those with another principal discharge diagnosis. RESULTS: Of 4,345 hospitalizations of heart failure patients, 39.6% carried a principal diagnosis of heart failure. Patients with a principal heart failure diagnosis had higher rates of LV function assessment (89.1% vs. 82.5%; adjusted prevalence ratio [aPR]: 1.07; 95% confidence interval [CI]: 1.04 to 1.10) and discharge ACE inhibitor/angiotensin receptor blocker (ARB) in LV dysfunction (64.1% vs. 56.3%; aPR: 1.11; 95% CI: 1.03 to 1.20) as compared to patients hospitalized for another cause. LV assessment and ACE inhibitor/ARB use were associated with reductions in 1-year post-discharge mortality (adjusted odds ratio: 0.66, 95% CI: 0.51 to 0.85; adjusted odds ratio: 0.72, 95% CI: 0.54 to 0.96, respectively) that did not differ for patients with versus without a principal heart failure diagnosis. CONCLUSIONS: Compared with individuals hospitalized with a principal diagnosis of heart failure, heart failure patients hospitalized for other causes were less likely to receive guideline recommended care. Quality initiatives may improve care by targeting hospitalizations with either principal or secondary heart failure diagnoses. PMID- 24076282 TI - The prognostic value of pre-operative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: a systematic review and individual patient data meta-analysis. AB - OBJECTIVES: The objective of this study was to determine whether measuring post operative B-type natriuretic peptides (NPs) (i.e., B-type natriuretic peptide [BNP] and N-terminal fragment of proBNP [NT-proBNP]) enhances risk stratification in adult patients undergoing noncardiac surgery, in whom a pre-operative NP has been measured. BACKGROUND: Pre-operative NP concentrations are powerful independent predictors of perioperative cardiovascular complications, but recent studies have reported that elevated post-operative NP concentrations are independently associated with these complications. It is not clear whether there is value in measuring post-operative NP when a pre-operative measurement has been done. METHODS: We conducted a systematic review and individual patient data meta analysis to determine whether the addition of post-operative NP levels enhanced the prediction of the composite of death and nonfatal myocardial infarction at 30 and >=180 days after surgery. RESULTS: Eighteen eligible studies provided individual patient data (n = 2,179). Adding post-operative NP to a risk prediction model containing pre-operative NP improved model fit and risk classification at both 30 days (corrected quasi-likelihood under the independence model criterion: 1,280 to 1,204; net reclassification index: 20%; p < 0.001) and >=180 days (corrected quasi-likelihood under the independence model criterion: 1,320 to 1,300; net reclassification index: 11%; p = 0.003). Elevated post operative NP was the strongest independent predictor of the primary outcome at 30 days (odds ratio: 3.7; 95% confidence interval: 2.2 to 6.2; p < 0.001) and >=180 days (odds ratio: 2.2; 95% confidence interval: 1.9 to 2.7; p < 0.001) after surgery. CONCLUSIONS: Additional post-operative NP measurement enhanced risk stratification for the composite outcomes of death or nonfatal myocardial infarction at 30 days and >=180 days after noncardiac surgery compared with a pre operative NP measurement alone. PMID- 24076283 TI - Early high-dose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: Results from the PRATO-ACS Study (Protective Effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome). AB - OBJECTIVES: This study sought to determine if in addition to standard preventive measures on-admission, high-dose rosuvastatin exerts a protective effect against contrast-induced acute kidney injury (CI-AKI). BACKGROUND: Patients with acute coronary syndrome (ACS) are at high risk for CI-AKI, and the role of statin pre treatment in preventing renal damage remains uncertain. METHODS: Consecutive statin-naive non-ST elevation ACS patients scheduled to undergo early invasive strategy were randomly assigned to receive rosuvastatin (40 mg on admission, followed by 20 mg/day; statin group n = 252) or no statin treatment (control group n = 252). CI-AKI was defined as an increase in creatinine concentration of >=0.5 mg/dl or >=25% above baseline within 72 h after contrast administration. RESULTS: The incidence of CI-AKI was significantly lower in the statin group than in controls (6.7% vs. 15.1%; adjusted odds ratio: 0.38; 95% confidence interval [CI]: 0.20 to 0.71; p = 0.003). The benefits against CI-AKI were consistent, even applying different CI-AKI definition criteria and in all the pre-specified risk categories. The 30-day incidence of adverse cardiovascular and renal events (death, dialysis, myocardial infarction, stroke, or persistent renal damage) was significantly lower in the statin group (3.6% vs. 7.9%, respectively; p = 0.036). Moreover, statin treatment given on admission was associated with a lower rate of death or nonfatal myocardial infarction at 6 month follow-up (3.6% vs. 7.2%, respectively; p = 0.07). CONCLUSIONS: High-dose rosuvastatin given on admission to statin-naive patients with ACS who are scheduled for an early invasive procedure can prevent CI-AKI and improve short-term clinical outcome. (Statin Contrast Induced Nephropathy Prevention [PRATO-ACS]; NCT01185938). PMID- 24076285 TI - Internal atrial defibrillation revisited: how low can we go? PMID- 24076284 TI - Multistage electrotherapy delivered through chronically-implanted leads terminates atrial fibrillation with lower energy than a single biphasic shock. AB - OBJECTIVES: The goal of this study was to develop a low-energy, implantable device-based multistage electrotherapy (MSE) to terminate atrial fibrillation (AF). BACKGROUND: Previous attempts to perform cardioversion of AF by using an implantable device were limited by the pain caused by use of a high-energy single biphasic shock (BPS). METHODS: Transvenous leads were implanted into the right atrium (RA), coronary sinus, and left pulmonary artery of 14 dogs. Self sustaining AF was induced by 6 +/- 2 weeks of high-rate RA pacing. Atrial defibrillation thresholds of standard versus experimental electrotherapies were measured in vivo and studied by using optical imaging in vitro. RESULTS: The mean AF cycle length (CL) in vivo was 112 +/- 21 ms (534 beats/min). The impedances of the RA-left pulmonary artery and RA-coronary sinus shock vectors were similar (121 +/- 11 Omega vs. 126 +/- 9 Omega; p = 0.27). BPS required 1.48 +/- 0.91 J (165 +/- 34 V) to terminate AF. In contrast, MSE terminated AF with significantly less energy (0.16 +/- 0.16 J; p < 0.001) and significantly lower peak voltage (31.1 +/- 19.3 V; p < 0.001). In vitro optical imaging studies found that AF was maintained by localized foci originating from pulmonary vein-left atrium interfaces. MSE Stage 1 shocks temporarily disrupted localized foci; MSE Stage 2 entrainment shocks continued to silence the localized foci driving AF; and MSE Stage 3 pacing stimuli enabled consistent RA-left atrium activation until sinus rhythm was restored. CONCLUSIONS: Low-energy MSE significantly reduced the atrial defibrillation thresholds compared with BPS in a canine model of AF. MSE may enable painless, device-based AF therapy. PMID- 24076286 TI - Surgery casualties: do not leave hearts behind enemy lines. PMID- 24076287 TI - Performance matters in heart failure. PMID- 24076288 TI - Forging a future of better cardiovascular health: addressing childhood obesity. AB - This paper describes ongoing National, Heart, Lung, and Blood Institute (NHLBI) initiated childhood obesity research. It calls on clinicians, researchers, and cardiologists to work with other healthcare providers, community agencies, schools and caregivers to foster better cardiovascular health in children by intervening on multiple levels of influence on childhood obesity. PMID- 24076289 TI - Inherited arrhythmia syndromes: exome sequencing opens a new door to diagnosis. PMID- 24076290 TI - A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular fibrillation in childhood and adolescence. AB - OBJECTIVES: This study aimed to identify the genetic defect in a family with idiopathic ventricular fibrillation (IVF) manifesting in childhood and adolescence. BACKGROUND: Although sudden cardiac death in the young is rare, it frequently presents as the first clinical manifestation of an underlying inherited arrhythmia syndrome. Gene discovery for IVF is important as it enables the identification of individuals at risk, because except for arrhythmia, IVF does not manifest with identifiable clinical abnormalities. METHODS: Exome sequencing was carried out on 2 family members who were both successfully resuscitated from a cardiac arrest. RESULTS: We characterized a family presenting with a history of ventricular fibrillation (VF) and sudden death without electrocardiographic or echocardiographic abnormalities at rest. Two siblings died suddenly at the ages of 9 and 10 years, and another 2 were resuscitated from out-of-hospital cardiac arrest with documented VF at ages 10 and 16 years, respectively. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.F90L) in the CALM1 gene encoding calmodulin. This mutation was also carried by 1 of the siblings who died suddenly, from whom DNA was available. The mutation was present in the mother and in another sibling, both asymptomatic but displaying a marginally prolonged QT interval during exercise. CONCLUSIONS: We identified a mutation in CALM1 underlying IVF manifesting in childhood and adolescence. The causality of the mutation is supported by previous studies demonstrating that F90 mediates the direct interaction of CaM with target peptides. Our approach highlights the utility of exome sequencing in uncovering the genetic defect even in families with a small number of affected individuals. PMID- 24076291 TI - Management of tricuspid regurgitation by caval valve implantation: from technical feasibility to evaluation of efficacy. PMID- 24076292 TI - Rare insight into the rapid evolution of a coronary aneurysm and fistula. PMID- 24076294 TI - Ruptured sinus of valsalva with ventricular septal defect: evaluation by 3 dimensional echocardiography: advantage of the third dimension. PMID- 24076293 TI - Reply: management of tricuspid regurgitation by caval valve implantation: from technical feasibility to evaluation of efficacy. PMID- 24076295 TI - Peptide receptor-targeted radionuclide therapy alters inflammation in atherosclerotic plaques. PMID- 24076296 TI - Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy. AB - OBJECTIVES: The PAREPET (Prediction of ARrhythmic Events with Positron Emission Tomography) study sought to test the hypothesis that quantifying inhomogeneity in myocardial sympathetic innervation could identify patients at highest risk for sudden cardiac arrest (SCA). BACKGROUND: Left ventricular ejection fraction (LVEF) is the only parameter identifying patients at risk of SCA who benefit from an implantable cardiac defibrillator (ICD). METHODS: We prospectively enrolled 204 subjects with ischemic cardiomyopathy (LVEF <=35%) eligible for primary prevention ICDs. Positron emission tomography (PET) was used to quantify myocardial sympathetic denervation ((11)C-meta-hydroxyephedrine [(11)C-HED]), perfusion ((13)N-ammonia) and viability (insulin-stimulated (18)F-2 deoxyglucose). The primary endpoint was SCA defined as arrhythmic death or ICD discharge for ventricular fibrillation or ventricular tachycardia >240 beats/min. RESULTS: After 4.1 years follow-up, cause-specific SCA was 16.2%. Infarct volume (22 +/- 7% vs. 19 +/- 9% of left ventricle [LV]) and LVEF (24 +/- 8% vs. 28 +/- 9%) were not predictors of SCA. In contrast, patients developing SCA had greater amounts of sympathetic denervation (33 +/- 10% vs. 26 +/- 11% of LV; p = 0.001) reflecting viable, denervated myocardium. The lower tertiles of sympathetic denervation had SCA rates of 1.2%/year and 2.2%/year, whereas the highest tertile had a rate of 6.7%/year. Multivariate predictors of SCA were PET sympathetic denervation, left ventricular end-diastolic volume index, creatinine, and no angiotensin inhibition. With optimized cut-points, the absence of all 4 risk factors identified low risk (44% of cohort; SCA <1%/year); whereas >=2 factors identified high risk (20% of cohort; SCA ~12%/year). CONCLUSIONS: In ischemic cardiomyopathy, sympathetic denervation assessed using (11)C-HED PET predicts cause-specific mortality from SCA independently of LVEF and infarct volume. This may provide an improved approach for the identification of patients most likely to benefit from an ICD. (Prediction of ARrhythmic Events With Positron Emission Tomography [PAREPET]; NCT01400334). PMID- 24076297 TI - Short-term rosuvastatin therapy for prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease. AB - OBJECTIVES: This study sought to evaluate the safety and efficacy of rosuvastatin in preventing contrast-induced acute kidney injury (CI-AKI) in patients with diabetes mellitus (DM) and chronic kidney disease (CKD). BACKGROUND: CI-AKI is an important complication after contrast medium injection. While small studies have shown positive results with statin therapy, the role of statin therapy in prevention of CI-AKI remains unknown. METHODS: We randomized 2,998 patients with type 2 DM and concomitant CKD who were undergoing coronary/peripheral arterial angiography with or without percutaneous intervention to receive rosuvastatin, 10 mg/day (n = 1,498), for 5 days (2 days before, and 3 days after procedure) or standard-of-care (n = 1,500). Patients' renal function was assessed at baseline, 48 h, and 72 h after exposure to contrast medium. The primary endpoint of the study was the development of CI-AKI, which was defined as an increase in serum creatinine concentration >=0.5 mg/dl (44.2 MUmol/l) or 0.25% above baseline at 72 h after exposure to contrast medium. RESULTS: Patients randomized to the rosuvastatin group had a significantly lower incidence of CI-AKI than controls (2.3% vs. 3.9%, respectively; p = 0.01). During 30 days' follow-up, the rate of worsening heart failure was significantly lower in the patients treated with rosuvastatin than that in the control group (2.6% vs. 4.3%, respectively; p = 0.02). CONCLUSIONS: Rosuvastatin significantly reduced the risk of CI-AKI in patients with DM and CKD undergoing arterial contrast medium injection. (Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes [TRACK-D]; NCT00786136). PMID- 24076298 TI - Identification of a linear B-Cell epitope on avian reovirus protein sigmaC. AB - SigmaC (sigmaC) protein, which mediates virus attachment to target cells, is the most variable proteins of avian reovirus (ARV). It is responsible for inducing protective antibody immune responses in animals. To understand the antigenic determinants of sigmaC protein, a set of partially overlapping and consecutive peptides spanning sigmaC were expressed and then screened with the monoclonal antibody (mAb) 2B5 directed against sigmaC. The mAb 2B5 recognized peptides with the sigmaC motif (45)ELLHRSISDISTTV(58). Further identification of the displayed B-cell epitope was conducted with a set of truncated peptides expressed as GST fusion proteins. The Western blot and ELISA results indicated that (45)ELLHRSISDI(54) was the minimal determinant of the linear B-cell epitope. Using sequences analysis, we found that this epitope was not a common motif shared among the other members of the ARV and DRV groups. Furthermore, cross reactivity analysis showed that the associated coding motif of other ARV and DRV groups was not recognized by 2B5. These data suggested that (45)ELLHRSISDI(54) was a type-specific linear B-cell epitope of avian reovirus. The results in this study may have potential applications in the development of diagnostic techniques and epitope-based marker vaccines against ARV, which is prevalent in China. PMID- 24076299 TI - Complete genomic sequence of a Rubus yellow net virus isolate and detection of genome-wide pararetrovirus-derived small RNAs. AB - Rubus yellow net virus (RYNV) was cloned and sequenced from a red raspberry (Rubus idaeus L.) plant exhibiting symptoms of mosaic and mottling in the leaves. Its genomic sequence indicates that it is a distinct member of the genus Badnavirus, with 7932bp and seven ORFs, the first three corresponding in size and location to the ORFs found in the type member Commelina yellow mottle virus. Bioinformatic analysis of the genomic sequence detected several features including nucleic acid binding motifs, multiple zinc finger-like sequences and domains associated with cellular signaling. Subsequent sequencing of the small RNAs (sRNAs) from RYNV-infected R. idaeus leaf tissue was used to determine any RYNV sequences targeted by RNA silencing and identified abundant virus-derived small RNAs (vsRNAs). The majority of the vsRNAs were 22-nt in length. We observed a highly uneven genome-wide distribution of vsRNAs with strong clustering to small defined regions distributed over both strands of the RYNV genome. Together, our data show that sequences of the aphid-transmitted pararetrovirus RYNV are targeted in red raspberry by the interfering RNA pathway, a predominant antiviral defense mechanism in plants. PMID- 24076300 TI - The role of alcohol use on recent trends in distracted driving. AB - Distracted driving is now an increasingly deadly threat to road safety. We provide evidence that intoxicated driving is increasingly responsible for recent increases in fatalities from distracted driving crashes. This study describes trends in deaths on U.S. public roads caused by alcohol-involved and distracted drivers using the Fatality Analysis Reporting System (FARS)-a census of fatal crashes on U.S. public roads. Fatality rates per vehicle-miles traveled are calculated using data from the Federal Highway Administration. Alcohol-involved drivers who are simultaneously distracted were responsible for 1750 deaths in 2009, an increase of more than 63% from 2005 when there were 1072 deaths. Alcohol use while driving is increasingly responsible for a growing number of fatalities from distracted driving, accounting for 32% of deaths from distracted driving in 2009 versus 24% in 2005. The fatality rate from these crashes increased from 35.9 to 59.2 deaths per 100 billion vehicle-miles traveled after 2005. Alcohol use is quickly increasing as an important factor behind distracted driving fatalities. This has implications for policies combating distracted driving that do not address the role of alcohol use in distracted driving. PMID- 24076301 TI - Psychological factors for driver distraction and inattention in the Australian and New Zealand rail industry. AB - A signal passed at danger (SPAD) event occurs when a train moves past a stop signal into a section of unauthorised track. SPAD events are frequently attributed to driver distraction and inattention, but few studies have explored the failure mode from the perspective of task demand and the ability of the driver to self-regulate in response to competing activities. This study aimed to provide a more informed understanding of distraction, inattention and SPAD-risk in the passenger rail task. The research approach combined focus groups with a generative task designed to stimulate situational insight. Twenty-eight train drivers participated from 8 different rail operators in Australia and New Zealand. Data were analysed thematically and revealed several moderating factors for driver distraction. Time-keeping pressure and certain aspects of the driver controller dynamic were considered to distort performance, and distractions from station dwelling and novel events increased SPAD-risk. The results are conceptualised in a succinct model of distraction linking multiple factors with mechanisms that induced the attentional shift. The commonalities and inter dynamics of the factors revealed insight into driving anxiety in the passenger rail mode, and suggested that SPAD-risk was intensified when three or more factors converged. The paper discusses these issues in the context of misappropriated attention, taxonomic implications, and directions for future research. PMID- 24076302 TI - Drug use and fatal motor vehicle crashes: a case-control study. AB - Drugged driving is a serious safety concern, but its role in motor vehicle crashes has not been adequately studied. Using a case-control design, the authors assessed the association between drug use and fatal crash risk. Cases (n=737) were drivers who were involved in fatal motor vehicle crashes in the continental United States during specific time periods in 2007, and controls (n=7719) were participants of the 2007 National Roadside Survey of Alcohol and Drug Use by Drivers. Overall, 31.9% of the cases and 13.7% of the controls tested positive for at least one non-alcohol drug. The estimated odds ratios of fatal crash involvement associated with specific drug categories were 1.83 [95% confidence interval (CI): 1.39, 2.39] for marijuana, 3.03 (95% CI: 2.00, 4.48) for narcotics, 3.57 (95% CI: 2.63, 4.76) for stimulants, and 4.83 (95% CI: 3.18, 7.21) for depressants. Drivers who tested positive for both alcohol and drugs were at substantially heightened risk relative to those using neither alcohol nor drugs (Odds Ratio=23.24; 95% CI: 17.79, 30.28). These results indicate that drug use is associated with a significantly increased risk of fatal crash involvement, particularly when used in combination with alcohol. PMID- 24076303 TI - Determinants of personal protective equipment (PPE) use in UK motorcyclists: exploratory research applying an extended theory of planned behaviour. AB - Despite evident protective value of motorcycle personal protective equipment (PPE), no research has assessed considerations behind its uptake in UK riders. A cross-sectional online questionnaire design was employed, with riders (n=268) recruited from online motorcycle forums. Principal component analysis found four PPE behavioural outcomes. Theoretical factors of intentions, attitudes, injunctive and descriptive subjective norms, risk perceptions, anticipated regret, benefits and habit were also identified for further analysis. High motorcycle jacket, trousers and boots wear, middling high-visibility wear and low non-Personal Protective Equipment wear were found. Greater intentions, anticipated regret and perceived benefits were significantly associated with increased motorcycle jacket, trousers and boots wear, with habit presence and scooter use significantly associated with increased high-visibility wear. Lower intentions, anticipated regret and risk perceptions, being female, not holding a car licence and urban riding were significantly associated with increased non-PPE wear. A need for freedom of choice and mixed attitudes towards PPE use were evident in additional comments. PPE determinants in this sample provide a preliminary basis for future uptake interventions. Larger scale and qualitative research is needed to further investigate relevant constructs. PMID- 24076304 TI - Testing the validity of the International Atomic Energy Agency (IAEA) safety culture model. AB - This paper takes the first steps to empirically validate the widely used model of safety culture of the International Atomic Energy Agency (IAEA), composed of five dimensions, further specified by 37 attributes. To do so, three independent and complementary studies are presented. First, 290 students serve to collect evidence about the face validity of the model. Second, 48 experts in organizational behavior judge its content validity. And third, 468 workers in a Spanish nuclear power plant help to reveal how closely the theoretical five dimensional model can be replicated. Our findings suggest that several attributes of the model may not be related to their corresponding dimensions. According to our results, a one-dimensional structure fits the data better than the five dimensions proposed by the IAEA. Moreover, the IAEA model, as it stands, seems to have rather moderate content validity and low face validity. Practical implications for researchers and practitioners are included. PMID- 24076306 TI - A prospective study of obesity, and the incidence and progression of lower urinary tract symptoms. AB - PURPOSE: We prospectively evaluated the association between adiposity and the risk of lower urinary tract symptoms incidence and progression in the Health Professionals Followup Study (HPFS). MATERIALS AND METHODS: At baseline participants reported current height and weight, and weight at age 21 years. A year later they reported waist and hip circumferences, and every 2 years thereafter they reported weight. Participants periodically completed the International Prostate Symptom Score (I-PSS) and reported surgery or medication use for lower urinary tract symptoms. We used Cox proportional hazards regression to estimate the multivariable adjusted association between adiposity and lower urinary tract symptoms incidence and progression. The incidence analytical cohort of 18,055 men had no lower urinary tract symptoms at baseline. A total of 6,461 men entered the progression analytical cohort when they first experienced lower urinary tract symptoms. RESULTS: The risk of lower urinary tract symptoms in 4,088 cases increased with increasing body mass index (35 kg/m(2) or greater vs 23 to less than 25 HR 1.61, 95% CI 1.31-1.99), waist circumference (greater than 42 inches vs 33 or less HR 1.39, 95% CI 1.19-1.63) and weight gain since age 21 years (50 pounds or greater vs stable weight HR 1.31, 95% CI 1.17-1.46, each p trend <0.0001). The risk of lower urinary tract symptom progression in 1,691 cases increased with body mass index (35 kg/m(2) or greater vs 23 to less than 25 HR 1.44, 95% CI 1.04-2.00, p trend <0.0001), weight gain since age 21 years (50 pounds or greater vs stable weight HR 1.35, 95% CI 1.14-1.60, p trend <0.0001) and waist circumference (greater than 42 inches vs 33 or less HR 1.32, 95% CI 0.95-1.85, p trend 0.005). CONCLUSIONS: Men with higher total and abdominal adiposity and those who gained weight were more likely to have lower urinary tract symptoms develop or progress. Our findings support the notion that obesity may be an important target for lower urinary tract symptom prevention and intervention. PMID- 24076305 TI - BAP1 immunohistochemistry predicts outcomes in a multi-institutional cohort with clear cell renal cell carcinoma. AB - PURPOSE: Mutations in the tumor suppressor gene BAP1 occur in approximately 15% of clear cell renal cell carcinoma cases. Sequencing efforts demonstrated worse outcomes in patients with BAP1 mutated clear cell renal cell carcinoma. We investigated the clinicopathological significance and oncologic outcomes of BAP1 loss using a previously validated immunohistochemical assay. MATERIALS AND METHODS: Immunohistochemistry for BAP1 was performed on tissue microarray sections from 559 nonmetastatic clear cell renal cell carcinoma cases treated with nephrectomy at multiple institutions. The association of BAP1 expression with clinicopathological parameters was analyzed using the Wilcoxon rank sum and Cochran-Mantel-Haenszel tests. Survival was assessed by Cox regression analysis, which also identified independent predictors of time dependent outcomes. RESULTS: At a median followup of 50 months (range 0 to 183) 86 of 483 patients (17.8%) experienced recurrence and 121 of 559 (21.6%) had died. BAP1 was negative in 82 of 559 tumors (14.7%). BAP1 loss was associated with adverse clinicopathological variables, including high Fuhrman grade (p <0.0001), advanced pT stage (p = 0.0021), sarcomatoid dedifferentiation (p = 0.0001) and necrosis (p <0.0001). Cox regression revealed that patients with BAP1 negative tumors had significantly worse disease-free survival (HR 2.9, 95% CI 1.8-4.7, p <0.0001) and overall survival (HR 2.0, 95% CI 1.3-3.1, p = 0.0010) than patients with BAP1 positive tumors. CONCLUSIONS: Immunohistochemistry for BAP1 serves as a powerful marker to predict poor oncologic outcomes and adverse clinicopathological features in patients with nonmetastatic clear cell renal cell carcinoma. BAP1 assessment using immunohistochemistry on needle biopsy may benefit preoperative risk stratification and guide treatment planning in the future. PMID- 24076308 TI - Maintenance percutaneous posterior nerve stimulation for refractory lower urinary tract symptoms in patients with multiple sclerosis: an open label, multicenter, prospective study. AB - PURPOSE: Percutaneous tibial nerve stimulation is an effective second line therapy for lower urinary tract symptoms. Data on percutaneous tibial nerve stimulation maintenance treatment are scarce. In this study we evaluate its effectiveness and propose an algorithm of percutaneous tibial nerve stimulation maintenance treatment in patients with multiple sclerosis. MATERIALS AND METHODS: In this prospective, multicenter, open label trial consecutive patients with multiple sclerosis and lower urinary tract symptoms unresponsive to medical therapy were treated with 12 weekly sessions of percutaneous tibial nerve stimulation. Responder patients (50% or greater improvement of lower urinary tract symptoms as measured by the patient perception of bladder condition questionnaire) entered a maintenance phase with individualized treatment frequency based on patient response. Lower urinary tract symptoms were assessed using a 3-day frequency volume chart, urodynamics and patient perception of bladder condition questionnaire. Treatment satisfaction was evaluated using a global response assessment scale and a treatment satisfaction visual analog scale. RESULTS: A total of 83 patients were included in the study and 74 (89%) responded to initial treatment. Persistent efficacy occurred in all initial responders after a mean treatment of 24 months. The greatest frequency of maintenance percutaneous tibial nerve stimulation was every 2 weeks. Lower urinary tract symptoms and patient treatment satisfaction improved with time compared to initial treatment (p <0.05). Bladder diary parameters and voiding parameters improved compared to baseline (p <0.05). CONCLUSIONS: Prolonged percutaneous tibial nerve stimulation treatment leads to a persistent improvement of lower urinary tract symptoms in patients with multiple sclerosis. PMID- 24076307 TI - Measuring and predicting prostate cancer related quality of life changes using EPIC for clinical practice. AB - PURPOSE: We expanded the clinical usefulness of EPIC-CP (Expanded Prostate Cancer Index Composite for Clinical Practice) by evaluating its responsiveness to health related quality of life changes, defining the minimally important differences for an individual patient change in each domain and applying it to a sexual outcome prediction model. MATERIALS AND METHODS: In 1,201 subjects from a previously described multicenter longitudinal cohort we modeled the EPIC-CP domain scores of each treatment group before treatment, and at short-term and long-term followup. We considered a posttreatment domain score change from pretreatment of 0.5 SD or greater clinically significant and p <= 0.01 statistically significant. We determined the domain minimally important differences using the pooled 0.5 SD of the 2, 6, 12 and 24-month posttreatment changes from pretreatment values. We then recalibrated an EPIC-CP based nomogram model predicting 2-year post-prostatectomy functional erection from that developed using EPIC-26. RESULTS: For each health related quality of life domain EPIC-CP was sensitive to similar posttreatment health related quality of life changes with time, as was observed using EPIC-26. The EPIC-CP minimally important differences in changes in the urinary incontinence, urinary irritation/obstruction, bowel, sexual and vitality/hormonal domains were 1.0, 1.3, 1.2, 1.6 and 1.0, respectively. The EPIC-CP based sexual prediction model performed well (AUC 0.76). It showed robust agreement with its EPIC-26 based counterpart with 10% or less predicted probability differences between models in 95% of individuals and a mean +/- SD difference of 0.0 +/- 0.05 across all individuals. CONCLUSIONS: EPIC-CP is responsive to health related quality of life changes during convalescence and it can be used to predict 2-year post-prostatectomy sexual outcomes. It can facilitate shared medical decision making and patient centered care. PMID- 24076309 TI - Associative and temporal processes: a dual process approach. AB - Approaches to the study of associative learning and interval timing have traditionally diverged on methodological and theoretical levels of analysis. However, more recent attempts have been made to explain one class of phenomena in terms of the other using various single-process approaches. In this paper we suggest that an interactive dual-process approach might more accurately reflect underlying behavioral and neural processes. We will argue that timing in Pavlovian conditioning is best understood in terms of an abstract temporal code that is not a feature of the predictive stimulus (i.e., the conditioned stimulus, CS), per se. Rather, we assume that the time between the CS and the unconditioned stimulus (US) is encoded in the form of an abstract representation of this temporal interval produced as an output of a central multiple-oscillator interval timing system. As such, associations can then develop between the CS and this abstract temporal code in much the same way that the CS develops associations with different features of the US. To support the dual-process approach, we first show that exposure to a Pavlovian zero contingency procedure results in a failure to acquire new associations, not a failure to express learning due to some temporally defined performance mask. We also consider evidence that supports the abstract temporal coding idea in a US preexposure task, and, finally, present some evidence to encourage the dissociation between basic associative and temporal learning processes by exploring reward devaluation effects in a peak timing task. PMID- 24076311 TI - Impaired endocannabinoid signalling in the rostral ventromedial medulla underpins genotype-dependent hyper-responsivity to noxious stimuli. AB - Pain is both a sensory and an emotional experience, and is subject to modulation by a number of factors including genetic background modulating stress/affect. The Wistar-Kyoto (WKY) rat exhibits a stress-hyper-responsive and depressive-like phenotype and increased sensitivity to noxious stimuli, compared with other rat strains. Here, we show that this genotype-dependent hyperalgesia is associated with impaired pain-related mobilisation of endocannabinoids and transcription of their synthesising enzymes in the rostral ventromedial medulla (RVM). Pharmacological blockade of the Cannabinoid1 (CB1) receptor potentiates the hyperalgesia in WKY rats, whereas inhibition of the endocannabinoid catabolising enzyme, fatty acid amide hydrolase, attenuates the hyperalgesia. The latter effect is mediated by CB1 receptors in the RVM. Together, these behavioural, neurochemical, and molecular data indicate that impaired endocannabinoid signalling in the RVM underpins hyper-responsivity to noxious stimuli in a genetic background prone to heightened stress/affect. PMID- 24076310 TI - Ontogenic changes in lung cholesterol metabolism, lipid content, and histology in mice with Niemann-Pick type C disease. AB - Niemann-Pick Type C (NPC) disease is caused by a deficiency of either NPC1 or NPC2. Loss of function of either protein results in the progressive accumulation of unesterified cholesterol in every tissue leading to cell death and organ damage. Most literature on NPC disease focuses on neurological and liver manifestations. Pulmonary dysfunction is less well described. The present studies investigated how Npc1 deficiency impacts the absolute weight, lipid composition and histology of the lungs of Npc1(-/-) mice (Npc1(nih)) at different stages of the disease, and also quantitated changes in the rates of cholesterol and fatty acid synthesis in the lung over this same time span (8 to 70days of age). Similar measurements were made in Npc2(-/-) mice at 70days. All mice were of the BALB/c strain and were fed a basal rodent chow diet. Well before weaning, the lung weight, cholesterol and phospholipid (PL) content, and cholesterol synthesis rate were all elevated in the Npc1(-/-) mice and remained so at 70days of age. In contrast, lung triacylglycerol content was reduced while there was no change in lung fatty acid synthesis. Despite the elevated PL content, the composition of PL in the lungs of the Npc1(-/-) mice was unchanged. H&E staining revealed an age related increase in the presence of lipid-laden macrophages in the alveoli of the lungs of the Npc1(-/-) mice starting as early as 28days. Similar metabolic and histologic changes were evident in the lungs of the Npc2(-/-) mice. Together these findings demonstrate an intrinsic lung pathology in NPC disease that is of early onset and worsens over time. PMID- 24076312 TI - Novel perspectives on dendritic cell-based immunotherapy of cancer. AB - Advances in immunobiology knowledge as well as in cell culture processes that generate large numbers of purified and functionally mature dendritic cells (DCs) have raised the possibility that DCs might represent promising clinical agents to generate effective immune responses against cancer. Here, we discuss the present pitfalls of dendritic cell vaccines for the treatment of human cancer with regard to the most recent knowledge in the biology of DCs. In particular, we highlight the relevance of improving our current understanding of DC trafficking, functions and interactions with other cells of innate immunity for the development of more effective cancer vaccines. PMID- 24076313 TI - Understanding human NK cell differentiation: clues for improving the haploidentical hematopoietic stem cell transplantation. AB - The study of in vitro and in vivo NK cell differentiation from hematopoietic precursors revealed the existence of discrete stages of development. These stages are characterized by the progressive acquisition of markers and receptors that play a crucial role in NK cell function. The knowledge acquired has revealed particularly relevant for improving the HSCT to cure high-risk leukemias in the haplo-HSCT setting, in which NK cells play a central role in the clearance of leukemic cells and in the positive clinical outcome. PMID- 24076314 TI - Advances in cellular reprogramming: moving toward a reprieve from immunogenicity. AB - Somatic cell nuclear reprogramming is opening new doors for the modeling of human disease phenotypes in vitro, the identification of novel therapeutic compounds and diagnostic factors as well as future autologous cell replacement therapies. Despite the potential that reprogramming technologies bring, there are remaining concerns preventing their broad application in the short-term. One of them is the safety concern associated with the use of stem cell derivatives, those generated by reprogramming or even when embryonic stem cells are employed. Here we summarize the current knowledge in the field of stem cells and reprogramming with a particular focus on the pitfalls preventing rapid translation of stem cell technologies into the clinic. We discuss the most recent findings on immunogenicity and tumorigenicity of reprogrammed cells. We additionally provide an overview on the potential applications that reprogramming approaches might bring to the immunological field and elaborate on the use of induced pluripotent stem cells (iPSCs) with pre-arranged immune receptors for the development of future immunotherapeutic approaches. The use of reprogramming approaches can represent and provide groundbreaking strategies previously unachievable for stem cell engineering aimed at modulating immune responses. In summary, we provide an overview on the different topics related to the use of stem cells and highlight the most provocative, yet perhaps currently underappreciated, aspect of combining immunological and reprogramming strategies for the treatment of human disease. PMID- 24076316 TI - Accelerated long-term forgetting: a newly identified memory impairment in epilepsy. AB - Recently, a pattern referred to as accelerated long-term forgetting (ALF) has been described in patients with epilepsy. In ALF, acquisition and retention over standard delayed recall intervals (up to 30 minutes) tend to be intact, but there is an abnormally rapid rate of forgetting over delays of days or weeks. ALF is associated with everyday memory complaints as well as impairments in autobiographical memory, but goes largely undetected by traditional neuropsychological measures. We consider here the characteristics of ALF and possible contributors to its underlying pathophysiology. Overall, a better understanding of this relatively newly recognised memory disorder should improve clinical treatment. PMID- 24076315 TI - CMV induces rapid NK cell maturation in HSCT recipients. AB - Natural killer (NK) cells are important effectors of innate immune responses against virally infected cells and tumors. Since NK cells are the first lymphocyte population to recover after hematopoietic stem cell transplantation, they are thought to play a crucial role in early immunity after transplantation against infections. In individuals experiencing HCMV reactivation after transplantation, NK cells rapidly achieved a fully differentiated stage of maturation, characterized by a KIR(+)NKG2A(-)NKG2C(+)CD57(+)p75/AIRM1(-) surface phenotype. Patients who never had HCMV reactivation maintained an immature NK phenotype for a long time. Thus, HCMV reactivation, by providing stimulatory signals to maturing NK cells, could be beneficial rather than detrimental. HCMV infection has been reported to induce a persistent reconfiguration of the NK-cell compartment not only in immunocompromised patients but also in healthy individuals, the hallmark of which is the expansion of an NK-cell subset displaying high surface levels of the CD94/NKG2C receptor. Moreover, as suggested by studies in mice, NK cells developing after CMV reactivation could contain "memory" or "long-lived" NK cells that could be exploited for therapeutic purposes. PMID- 24076317 TI - [Infantile visceral leishmaniasis, an etiology of easily curable hemophagocytic lymphohistiocytosis syndrome]. AB - Infantile visceral leishmaniasis associated hemophagocytic lymphohistiocytosis (HLH) is a rare clinicopathological entity, difficult to diagnose and fatal if untreated. The diagnosis should be considered in young infants with fever and splenomegaly. We report two cases of HLH caused by visceral leishmaniasis. In the first case, a 3-month-old boy was admitted with fever and pancytopenia, leading to the diagnosis of HLH based on complete clinical and biological features including hemophagocytosis on bone marrow smears. Investigations for an underlying genetic, metabolic disease and an infectious trigger were negative. Primary or genetic hemophagocytic syndrome was suspected and immunosuppressive treatment (steroids and cyclosporin) was instituted. A second bone marrow examination performed 1 month later revealed leishmania. The boy was treated with liposomal amphotericin and recovered rapidly. In the second case, a 10-year-old child was hospitalized with fever, pancytopenia, and a tumoral syndrome. He had a history of recurrent infections. The bone marrow biopsy showed leishmania and treatment with liposomal amphotericin was delivered. After 3 days of treatment, the improvement was judged inadequate and the boy presented biological signs of HLH. He was treated with steroids. An underlying primary immunodeficiency (interleukin-12/interferon-gamma axis disorder) was secondarily diagnosed. PMID- 24076318 TI - Murine models to study Clostridium difficile infection and transmission. AB - Clostridium difficile is the leading cause of antibiotic-associated diarrhea in healthcare facilities worldwide. C. difficile infections are difficult to treat because of the high rate of disease recurrence after antibiotic therapy, leaving few treatment options for patients. C. difficile is also difficult to contain within a healthcare setting due to a highly-transmissible, resistant spore form that challenges standard infection control measures. The recent development of murine infection models to study the interactions between C. difficile, the host and the microbiota are providing novel insight into the mechanisms of pathogenesis and transmission that should guide the development of therapies and intervention measures. PMID- 24076319 TI - [Personalising patient care in the hospital environment: does it influence the perceived quality?]. PMID- 24076320 TI - [Assessment of the professional practice environment by Spanish nurses who participate in Internet forums]. AB - AIM: To assess the professional work environment by Spanish nurses who participate in professional discussion groups on the Internet. METHOD: A cross sectional study (online survey) developed in 2011. The study variables were: socio-demographic and professional data; nursing practice environment, using the questionnaire Practice Environment Scale of the Nursing Work Index (PES-NWI). RESULTS: Out of a total of 295 questionnaires received, 214 were valid (72.54%). Most of the nurses were female (70.6%), with an average age of 43.55 years (SD = 9.82). The average score of the PES-NWI was 2.45 (SD = 0.63). The work environment was assessed as a mixed type, as three subscales scored over 2.5 (nursing foundations for quality of care, nurse manager leadership and support of nurses, and nurse-physician relations). The work environment assessment was influenced by several factors: professional category (P <.001); function (P <.001); and type of centre, which only affected the perception of the nurse physician relations subscale. CONCLUSIONS: The work environment received a moderate evaluation by participants. The staffing and resource adequacy subscale scored the worst, while the nursing foundations for quality of care was the highest scored. Nurses with management function and those with higher positions tended to give a better assessment of the work environment. The nurse-physician relations dimension was higher rated in primary care and nursing homes than in hospitals. PMID- 24076321 TI - Regulation of mouse lens maturation and gene expression by Kruppel-like factor 4. AB - Conditional disruption of Klf4 in the surface ectoderm-derived tissues of the eye results in defective cornea, conjunctiva and the lens. This report describes the effects of disruption of Klf4 in the lens in greater detail. Expression of Klf4, first detected in the embryonic day-12 (E12) mouse lens, peaked at E16 and was decreased in later stages. Early embryonic disruption of Klf4 resulted in a smaller lens with cortical vacuolation and nuclear opacity. Microarray comparison of Klf4CN and WT lens transcriptomes revealed fewer changes in the E16.5 (59 increases, 20 decreases of >1.5-fold) than the PN56 Klf4CN lens (239 increases, 182 decreases of >2-fold). Klf4-target genes in the lens were distinct from those previously identified in the cornea, suggesting disparate functions for Klf4 in these functionally related tissues. Transcripts encoding different crystallins were down-regulated in the Klf4CN lens. Shsp/alphaB-crystallin promoter activity was stimulated upon co-transfection with pCI-Klf4. Mitochondrial density was significantly higher in the Klf4CN lens epithelial cells, consistent with mitochondrial dysfunction being the most significantly affected pathway within the PN56 Klf4CN lens. The Klf4CN lens contained elevated levels of Alox12 and Alox15 transcripts, less reduced glutathione (GSH) and more oxidized glutathione (GSSG) than the WT, suggesting that it is oxidatively stressed. Although the expression of 2087 genes was modulated during WT lens maturation, transcripts encoding crystallins were abundant at E16.5 and remained stable at PN56. Among the 1065 genes whose expression increased during WT lens maturation, there were 104 Klf4-target genes (9.8%) with decreased expression in the PN56 Klf4CN lens. Taken together, these results demonstrate that Klf4 expression is developmentally regulated in the mouse lens, where it controls the expression of genes associated with lens maturation and redox homeostasis. PMID- 24076324 TI - Sergentomyia (Parrotomyia) jerighatiansis, a new species of sand fly (Diptera: Psychodidae: Phlebotominae) from Kandhamal district, Orissa, India. AB - Sergentomyia (Parrotomyia) jerighatiansis a new species of sand fly (Diptera: Psychodidae: Phlebotominae) from the villages of Kandhamal district, Orissa, located on the east coast of India is described. Descriptive morphology, character measurements, and illustrations of males and females are provided and its taxonomic position within the genus is also defined. Voucher specimens of the new species have been deposited at the museum, Vector Control Research Centre (Indian Council of Medical Research), Puducherry, India and Zoological Survey of India, India. PMID- 24076323 TI - Outcome and prognostic factors for patients who relapse after allogeneic hematopoietic stem cell transplantation. AB - Disease relapse remains a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT), yet little is known about the relevant prognostic factors after relapse. We studied 1080 patients transplanted between 2004 and 2008, among whom 351 relapsed. The 3-year postrelapse overall survival (prOS) rate was 19%. Risk factors for mortality after relapse included shorter time to relapse, higher disease risk index at HSCT, myeloablative conditioning, high pretransplantation comorbidity index, and graft-versus-host disease (GVHD) occurring before relapse. Important prognostic factors did not vary by disease type. Based on this, we could stratify patients into 3 groups, with 3-year prOS rates of 36%, 14%, and 3% (P < .0001). This score was validated in an historical cohort of 276 patients. Postrelapse donor lymphocyte infusion or repeat HSCT was associated with improved prOS, as was the development of GVHD after relapse. These differences remained significant in models that accounted for other prognostic factors and in landmark analyses of patients who survived at least 2 months from relapse. The results of this study may aid with prognostication and management of patients who relapse after HSCT and motivate the design of clinical trials aimed at relapse prevention or treatment in higher risk patients. PMID- 24076322 TI - Loss of the small heat shock protein alphaA-crystallin does not lead to detectable defects in early zebrafish lens development. AB - Alpha crystallins are small heat shock proteins essential to normal ocular lens function. They also help maintain homeostasis in many non-ocular vertebrate tissues and their expression levels change in multiple diseases of the nervous and cardiovascular system and during cancer. The specific roles that alpha crystallins may play in eye development are unclear. Studies with knockout mice suggested that only one of the two mammalian alpha-crystallins is required for normal early lens development. However, studies in two fish species suggested that reduction of alphaA-crystallin alone could inhibit normal fiber cell differentiation, cause cataract and contribute to lens degeneration. In this study we used synthetic antisense morpholino oligomers to suppress the expression of zebrafish alphaA-crystallin to directly test the hypothesis that, unlike mammals, the zebrafish requires alphaA-crystallin for normal early lens development. Despite the reduction of zebrafish alphaA-crystallin protein to undetectable levels by western analysis through 4 days of development we found no changes in fiber cell differentiation, lens morphology or transparency. In contrast, suppression of AQP0a expression, previously shown to cause lens cataract, produced irregularly shaped lenses, delay in fiber cell differentiation and lens opacities detectable by confocal microscopy. The normal development observed in alphaA-crystallin deficient zebrafish embryos may reflect similarly non-essential roles for this protein in the early stages of both zebrafish and mammalian lens development. This finding has ramifications for a growing number of researchers taking advantage of the zebrafish's transparent external embryos to study vertebrate eye development. Our demonstration that lens cataracts can be visualized in three-dimensions by confocal microscopy in a living zebrafish provides a new tool for studying the causes, development and prevention of lens opacities. PMID- 24076325 TI - Comparison of virus shedding after lived attenuated and pentavalent reassortant rotavirus vaccine. AB - Transmission of rotavirus vaccine or vaccine-reassortant strains to unvaccinated contacts has been reported. Therefore, it is essential to evaluate and characterize the nature of vaccine-virus shedding among rotavirus vaccine recipients. Two groups of healthy infants who received a complete course of RotaTeq (RV5) or Rotarix (RV2) were enrolled (between March 2010 and June 2011) to compare fecal shedding for one month after each vaccine dose. Shedding was assessed using both enzyme immunoassay (EIA) and real-time reverse transcription polymerase chain reaction (RT-PCR). Eighty-seven infants (34 girls and 53 boys) were enrolled in the study. After the first vaccine dose, the peak time of virus shedding occurred between day 4 and day 7, with positive detection rates of 80 90% by real-time RT-PCR and 20-30% by EIA. In both groups, vaccine shedding occurred as early as one day and as late as 25-28 days. Mixed effects logistic regression analysis of real-time RT-PCR data showed no significant differences between two groups when shedding rates were compared after the first vaccine dose (odds ratio [OR] 1.26; P=0.71) or after the second vaccine dose (odds ratio [OR] 1.26; P=0.99). However, infants receiving RV2 shed significantly higher viral loads than those receiving RV5 when compared after the first vaccine dose (P=0.001) and after the second dose (P=0.039). In terms of shedding rates detected by real-time RT-PCR, vaccine uptake of RV5 or RV2 among infants in Taiwan was comparable. Clinical significance of higher shedding viral loads in RV2 should be further observed. PMID- 24076326 TI - The inhibition of JNK MAPK and NF-kappaB signaling by tenuifoliside A isolated from Polygala tenuifolia in lipopolysaccharide-induced macrophages is associated with its anti-inflammatory effect. AB - The root of Polygala tenuifolia Willd. (Polygalaceae) is well known for its use in the treatment of neurasthenia, amnesia, and inflammation. In this study, we isolated phenyl propanoid type metabolite tenuifoliside A, one of the phenylpropanoids from P. tenuifolia, and investigated its anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 and murine peritoneal macrophages. The results showed that tenuifoliside A inhibited the production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), prostaglandin E2 (PG E2), and cyclooxygenase (COX)-2. In addition, tenuifoliside A suppressed the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF) alpha and interleukin (IL)-1beta. We also evaluated the effects of tenuifoliside A on the activation of nuclear factor-kappaB (NF-kappaB). Tenuifoliside A inhibited the translocation of the NF-kappaB subunit p65 into the nucleus by interrupting the phosphorylation and degradation of inhibitor kappa B (IkappaB) alpha in LPS-stimulated murine peritoneal macrophages. Moreover, we confirmed that the suppression of the inflammatory process by tenuifoliside A was mediated through the mitogen-activated protein kinases (MAPKs) pathway based on the fact that tenuifoliside A significantly decreased p-c-Jun N-terminal kinase (p-JNK) protein expression in LPS-stimulated murine peritoneal macrophages. Taken together, the anti-inflammatory effects of tenuifoliside A were mediated by the inhibition of the NF-kappaB and MAPK pathways. This study is the first report on the anti-inflammatory effects of tenuifoliside A, and the strong anti inflammatory effects of tenuifoliside A provide potential compound to be developed as therapeutic for inflammatory diseases. PMID- 24076327 TI - Curcumin modulates cannabinoid receptors in liver fibrosis in vivo and inhibits extracellular matrix expression in hepatic stellate cells by suppressing cannabinoid receptor type-1 in vitro. AB - Activation of hepatic stellate cells (HSCs) is a pivotal event leading to extracellular matrix (ECM) overproduction during hepatic fibrogenesis. Compelling evidence indicates that cannabinoid receptors (CBRs) play an important role in chronic liver disease. Antagonism of hepatic CBR type 1 (CBR1) could be a novel therapeutic strategy for liver fibrosis. Our previous studies have demonstrated that curcumin has potent antifibrotic activity, but the mechanisms remain to be elucidated. The current work was to examine the curcumin effect on CBRs system and its relevance to inhibition of ECM expression in HSCs. Our in vivo data demonstrated that curcumin ameliorated fibrotic injury, and downregulated CBR1 but upregulated CBR2 at both mRNA and protein levels in rat fibrotic liver caused by carbon tetrachloride. The subsequent in vitro investigations showed that curcumin reduced the mRNA and protein abundance of CBR1 in cultured HSCs and decreased the expression of three critical ECM proteins. Further analyses revealed that CBR1 agonist abrogated the curcumin inhibition of ECM expression, but CBR1 antagonist mimicked and reinforced the curcumin effects. Autodock simulations predicted that curcumin could bind to CBR1 with two hydrogen bonds. Collectively, our current studies revealed that curcumin reduction of liver fibrosis was associated with modulation of CBRs system and that antagonism of CBR1 contributed to curcumin inhibition of ECM expression in HSCs. PMID- 24076328 TI - Bioreductive activation of mitoxantrone by NADPH cytochrome P450 reductase does not change its apoptotic stimuli properties in regard to sensitive and multidrug resistant leukaemia HL60 cells. AB - The objective of this study was to examine the effect of bioreductive activation of antitumour drug, mitoxantrone (MX), by liver NADPH cytochrome P450 reductase (CPR) on inducing apoptosis of human promyelocytic sensitive leukaemia HL60 cell line and its multidrug resistance (MDR) sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX). It was found that non-activated as well as CPR-activated form of MX used at IC90 were able to influence cell cycle of sensitive HL60 as well as resistant cells and induce apoptosis. Interestingly, it was evidenced that HL60/VINC cells were more susceptible to undergo caspase-3/caspase-8-dependent apoptosis induced by both studied forms of MX compared to HL60 and HL60/DOX cells. However, the examined agent did not change the expression of Fas receptors on the surface of HL60 sensitive as well as resistant cells regardless of its form used in the study. Obtained results suggest that CPR-dependent reductive activation of MX does not change its apoptotic stimuli properties in regard to sensitive HL60 and multidrug resistant (HL60/VINC and HL60/DOX) leukaemia cells. Nevertheless, taking into account that side toxic effects observed in course of patient treatment with antitumour drugs are dose-dependent, it seems that the reported increase in antiproliferative activity and ability to induce apoptosis of MX after its reductive activation by exogenous CPR against the MDR cells overexpressing both P-glycoprotein and MRP1 at much more lower concentrations of this drug could be of clinical importance for the treatment of tumours resistant to classical chemotherapy.